PMID- 28552592 TI - Concurrent anticipation of two object dimensions during grasping in 10-month-old infants: A quantitative analysis. AB - The anticipation of more than one object dimension while grasping for objects has been rarely investigated in infancy. The few existing studies by Newell et al. and Schum et al. have revealed mixed results probably mainly due to methodological limitations. Therefore, the present experiments tested concurrent anticipatory grasping for two object dimensions, namely, object size and object orientation using a quantitative motion capture system (Vicon), in 10-month-old infants and adults. We presented objects varying in size (small vs. large) and orientation (horizontally vs. vertically) and analyzed participants' anticipatory hand configurations. As with adults, we observed that infants rotated their wrists, thumbs, and index fingers as a function of object orientation and adjusted their maximum grip apertures and their grip apertures shortly before they touched the objects as a function of object size. Analyses on an individual level showed that infants like adults anticipated both dimensions when the maximal values of aperture and angle were used but not when the measures shortly before touch were considered. Thus, the ability to anticipate more than one object dimension can already be observed at 10 months of age but seems to improve considerably over the first year of life. PMID- 28552593 TI - Tyrphostin A9 improves blastocyst development in porcine embryos through induction of dynamin-related protein 1-dependent mitochondrial fission. AB - Mitochondrial dynamics are associated with the development of porcine embryos. However, little is known about the effects of mitochondrial dynamics-related genes (Drp1 and pDrp1-Ser616) on early porcine embryo development. Here, we investigated the effect of Drp1-dependent mitochondrial fission signaling on the development of porcine embryos using the mitochondrial fission inducer, tyrphostin A9 (TA9). We determined that TA9 (1MUM) treated embryos were increased the mitochondrial functions, blastocyst development rate and quality, as well as decreased mitochondria-specific superoxide and mitochondrial apoptosis. Thus, TA9 induced appropriate mitochondrial fission improved the developmental competence via maintenance of a balance in mitochondrial dynamics in porcine embryo. PMID- 28552595 TI - Both non-covalent and covalent interactions were involved in the mechanism of detoxifying effects of persimmon tannin on Chinese cobra PLA2. AB - Persimmon tannin (PT) has been shown to inhibit snake venom activities and toxicities both in vitro and in vivo. To clarify the detoxifying mechanism of PT on snake venom, the interaction of characteristic structural elements of PT (EGCG, ECG, EGCG dimer and ECG dimer) and Chinese cobra phospholipase A2 (PLA2) was studied. The results revealed that except non-covalent bonds like hydrogen bonds, hydrophobic bonds and iron bonds were formed between PT and PLA2, covalent interaction was also occurred. PT could bind with the key active residues of PLA2, such as lysine, histidine, tryptophan and tyrosine, restraining their activity and disturbing the structure of PLA2, thus showing detoxifying effects on snake venom. PMID- 28552594 TI - Plasma concentration and cardiovascular effects of intramuscular medetomidine combined with three doses of the peripheral alpha2-antagonist MK-467 in dogs. AB - OBJECTIVE: We investigated the plasma concentrations and cardiovascular effects of intramuscularly (IM) administered medetomidine, administered alone or with three different doses of MK-467. STUDY DESIGN: Prospective, randomized, open, crossover trial. ANIMALS: Eight purpose-bred healthy Beagle dogs. METHODS: Each dog was administered four treatments: medetomidine 20 MUg kg-1 IM alone or mixed in the same syringe with MK-467 (200 MUg kg-1, 400 MUg kg-1 or 600 MUg kg-1). Instrumentation was performed under standardized anaesthesia. The dogs were allowed to recover before measurement of baseline values. Composite sedation scores, cardiovascular variables, i.e., heart rate (HR), cardiac output (CO), mean arterial and central venous blood pressures (MAP and CVP) and arterial blood gases were recorded at baseline and for 60 minutes after treatment. Drug concentrations in venous plasma were analysed. Generalized linear mixed models for repeated measures with post hoc Bonferroni correction were used with statistical significance level set at alpha=0.05. RESULTS: All treatments initially demonstrated the effects of medetomidine: HR and CO decreased and CVP increased. MAP transiently increased and then significantly decreased from baseline with the two highest MK-467 doses. The cardiovascular effects of medetomidine disappeared more rapidly with MK-467 than with medetomidine alone. With medetomidine alone, sedation scores remained high until the end of the 60 minute follow-up. Maximum concentrations of medetomidine were more rapidly achieved and were higher with MK-467. CONCLUSIONS AND CLINICAL RELEVANCE: Initial haemodynamic effects of medetomidine were not prevented by MK-467, but these effects were attenuated and their duration shortened by MK-467, independently of dose. Absorption of medetomidine was accelerated by MK-467, when administered concomitantly IM, resulting in faster sedation; addition of MK-467 shortened the sedative effect of medetomidine. PMID- 28552596 TI - Gram-scale purification of aconitine and identification of lappaconitine in Aconitum karacolicum. AB - Aconitum karacolicum from northern Kyrgyzstan (Alatau area) contains about 0.8-1% aconitine as well as other aconite derivatives that have already been identified. In this paper, we compare several methods for the further purification of an Aconitum karacolicum extract initially containing 80% of aconitine. Reverse-phase flash chromatography, reverse-phase semi-preparative HPLC, centrifugal partition chromatography (CPC) and recrystallization techniques were evaluated regarding first their efficiency to get the highest purity of aconitine (over 96%) and secondly their applicability in a semi-industrial scale purification process (in our case, 150g of plant extract). Even if the CPC technique shows the highest purification yield (63%), the recrystallization remains the method of choice to purify a large amount of aconitine as i) it can be easily carried out in safe conditions; ii) an aprotic solvent is used, avoiding aconitine degradation. Moreover, this study led us to the identification of lappaconitine in Aconitum karacolicum, a well-known alkaloid never found in this Aconitum species. PMID- 28552597 TI - Vasodilation effect of volatile oil from Allium macrostemon Bunge are mediated by PKA/NO pathway and its constituent dimethyl disulfide in isolated rat pulmonary arterials. AB - The present study aimed to investigate the vasodilation effects of Allium macrostemon Bunge (AMB) on isolated rat pulmonary arterials (PAs) and to assess the underling mechanisms. The volatile oil was extracted by steam distillation from the bulbs of AMB. Then the volatile oil from AMB was studied on isolated rat PA, removal of endothelium, or pretreatment with nitro oxide (NO) synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME), or with protein kinase A (PKA) inhibitor PKI but not cyclooxygenase inhibitor indomethacin significantly blocked the AMB induced relaxation on PE-contracted PA rings. AMB increased the phosphorylation level of NOS in a dose and time-dependent manner, which was through PKA activation. AMB dose-dependently increased the [Ca2+]i through Ca2+ influx in cultured pulmonary artery endothelial cells. A total of 18 components from the volatile oil of AMB were identified. The principle constituents of AMB, Dimethyl Disulfide (DMDS) but not Dimethyltrisulfide displayed dilation effects in PAs. Our results suggest that AMB induces relaxation in rat PAs via an endothelium-dependent mechanism involving Ca2+ entry, PKA dependent NOS phosphorylation and NO signaling. The vasodilator activities of AMB may through its constituent DMDS. The present study indicates therapeutic potentials of AMB on pulmonary hypertension. PMID- 28552598 TI - Synthesis and in vitro antiproliferative evaluation of PEGylated triterpene acids. AB - A set of PEGylated derivatives of oleanolic and maslinic acids has been semi synthesised, attaching ethylene glycol, diethylene glycol, triethylene glycol or tetraethylene glycol to the C-28 carboxyl group of these natural triterpenes and some derivatives. Another set of PEGylated derivatives has been semi-synthesised by connecting the same four ethylene glycols to the hydroxyl groups of the A ring of these triterpenic acids, through a carbonate linker, by reaction with trichloromethyl chloroformate. The aqueous solubility of some of these PEGylated derivatives has been compared with that of maslinic acid. The cytotoxic effects of 28 triterpenic PEGylated derivatives in three cancer-cell lines (B16-F10, HT29, and Hep G2) have been assayed. The best results have been achieved with the HT29 cell line, and specifically with the oleanolic acid derivatives having ethylene glycol or tetraethylene glycol attached to the C-28 carboxyl group, which are approximately 27-fold more effective than their natural precursor. Eight PEGylated derivatives have been selected to compare the cytotoxicity results in the HT29 cancer-cell line with those of a non-tumour cell line of the same tissue (IEC-18), four of which were less cytotoxic in the non-tumour cell line. These compounds showed apoptotic effects on treated cells, with percentages of total apoptosis between 20% and 53%, relative to control, at 72h and IC50 concentration, and between 29% to 62%, relative to control, for the same time and IC80 concentration. We have also found that with the treatment of these compounds in HT29 cancer cells, cell-cycle arrest occurred in the G0/G1 phase. Finally, we have also studied changes in mitochondrial membrane potential during apoptosis of HT29 cancer cells, and the results suggest an activation of the extrinsic apoptotic pathway for these compounds. PMID- 28552599 TI - Spectral and temporal properties of calls reveal deficits in ultrasonic vocalizations of adult Fmr1 knockout mice. AB - The Fmr1 knockout (KO) mouse has commonly been used to investigate communication impairments, one of the key diagnostic symptoms observed in Fragile X syndrome (FXS) and Autism spectrum disorder (ASD). Many studies have found alterations in ultrasonic vocalizations (USVs) in neonatal Fmr1 KO mice, however, there is limited research investigating whether these deficits continue into adulthood. In the present study, we examine differences in female urine-induced ultrasonic vocalizations, scent marking behavior, odor discrimination, and open field activity in adult male Fmr1 KO and wildtype (WT) mice. Overall, we found extensive alterations between genotypes in both spectral and temporal properties of ultrasonic vocalizations. There was no difference in the average number of calls emitted by both genotypes, however, Fmr1 KO mice emitted calls of a higher frequency, decreased amplitude, and shorter duration than WT mice. Spectrographic analyses revealed statistically significant differences between genotypes in the types of calls emitted. Contrastingly, we found no differences in scent marking behavior, a form of social communication, or in odor discrimination and activity levels of the mice. The results corroborate previous studies emphasizing the importance of qualitative differences observed in vocalization behavior of Fmr1 KO mice, rather than quantitative measurements such as number of calls emitted. Overall, the study confirms the presence of abnormalities in vocalization behavior in adult Fmr1 KO mice that we believe are consistent with communication deficits seen in the syndrome. PMID- 28552600 TI - Altered reward sensitivity in female offspring of cocaine-exposed fathers. AB - Recent rodent studies have demonstrated that parental cocaine exposure can influence offspring behavior, supporting the idea that environmental insults can impact subsequent generations. However, studies on the effects of paternal cocaine exposure are limited and multiple inconsistencies exist. In the current study, we behaviorally characterize the effects of paternal cocaine exposure in a C57BL/6J intergenerational mouse model. Male sires were administered cocaine hydrochloride (20mg/kg) or saline (0.01mL/g) once a day for 75days, and bred with drug naive females twenty-four hours after the final injection. Offspring, separated by sex, were tested in a battery of behaviors. We found that paternal cocaine exposure altered sensitivity to the rewarding and stimulant effects of psychostimulants and natural reward (sucrose) in female offspring; female cocaine sired offspring showed blunted cocaine preference using cocaine conditioned place preference (CPP) at a low dose (5mg/kg), but displayed similar preference at a higher dose (10mg/kg) compared to saline-sired controls. Additionally, cocaine sired female offspring exhibited higher psychomotor sensitivity to cocaine (10mg/kg) and amphetamine (2mg/kg) and consumed more sucrose. Cocaine-sired males exhibited increased psychomotor effects of cocaine and amphetamine. Male offspring also displayed an anxiety-like phenotype. No effect of paternal cocaine exposure was observed on depressive-like, learning and memory or social behavior in male or female offspring. Collectively, our findings show that paternal, chronic cocaine exposure induces intergenerational behavioral effects in male and female offspring with greatest impact on sensitivity to psychostimulants and sucrose in females. PMID- 28552601 TI - Habenula and interpeduncular nucleus differentially modulate predator odor induced innate fear behavior in rats. AB - Fear is an important behavioral system helping humans and animals to survive potentially dangerous situations. Fear can be innate or learned. Whereas the neural circuits underlying learned fear are already well investigated, the knowledge about the circuits mediating innate fear is still limited. We here used a novel, unbiased approach to image in vivo the spatial patterns of neural activity in odor-induced innate fear behavior in rats. We intravenously injected awake unrestrained rats with a 99m-technetium labeled blood flow tracer (99mTc HMPAO) during ongoing exposure to fox urine or water as control, and mapped the brain distribution of the trapped tracer using single-photon emission computed tomography (SPECT). Upon fox urine exposure blood flow increased in a number of brain regions previously associated with odor-induced innate fear such as the amygdala, ventromedial hypothalamus and dorsolateral periaqueductal grey, but, unexpectedly, decreased at higher significance levels in the interpeduncular nucleus (IPN). Significant flow changes were found in regions monosynaptically connected to the IPN. Flow decreased in the dorsal tegmentum and entorhinal cortex. Flow increased in the habenula (Hb) and correlated with odor effects on behavioral defensive strategy. Hb lesions reduced avoidance of but increased approach to the fox urine while IPN lesions only reduced avoidance behavior without approach behavior. Our study identifies a new component, the IPN, of the neural circuit mediating odor-induced innate fear behavior in mammals and suggests that the evolutionarily conserved Hb-IPN system, which has recently been implicated in cued fear, also forms an integral part of the innate fear circuitry. PMID- 28552602 TI - Classification and Functional Characterization of Vasa Vasorum-Associated Perivascular Progenitor Cells in Human Aorta. AB - In the microcirculation, pericytes are believed to function as mesenchymal stromal cells (MSCs). We hypothesized that the vasa vasorum harbor progenitor cells within the adventitia of human aorta. Pericytes, endothelial progenitor cells, and other cell subpopulations were detected among freshly isolated adventitial cells using flow cytometry. Purified cultured pericytes were enriched for the MSC markers CD105 and CD73 and depleted of the endothelial markers von Willebrand factor and CD31. Cultured pericytes were capable of smooth muscle lineage progression including inducible expression of smooth muscle myosin heavy chain, calponin, and alpha-smooth muscle actin, and adopted a spindle shape. Pericytes formed spheroids when cultured on Matrigel substrates and peripherally localized with branching endothelial cells in vitro. Our results indicate that the vasa vasorum form a progenitor cell niche distinct from other previously described progenitor populations in human adventitia. These findings could have important implications for understanding the complex pathophysiology of human aortic disease. PMID- 28552603 TI - Inhibition of KLF4 by Statins Reverses Adriamycin-Induced Metastasis and Cancer Stemness in Osteosarcoma Cells. AB - Adriamycin-based combination chemotherapy is the standard first-line treatment for osteosarcoma, but tumor recurrence and metastasis occurs in most cases. Recent evidence suggests that microenvironmental stress such as chemotherapy can lead to the enrichment of cancer stem cells (CSCs), which result in cancer metastasis, recurrence, and drug resistance. However, the exact mechanisms underlying this phenomenon and how to target CSCs are still open questions. Herein, we report that Adriamycin treatment induces a stem-like phenotype and promotes metastatic potential in osteosarcoma cells through upregulating KLF4. KLF4 knockdown blocks Adriamycin-induced stemness phenotype and metastasis capacity. We further screen that statins remarkably reverse Adriamycin-induced CSC properties and metastasis by downregulating KLF4. Most strikingly, simvastatin severely impaired Adriamycin-enhanced tumorigenesis of KHOS/NP cells in vivo. These data suggest that Adriamycin-based chemotherapeutics may simulate CSCs through activation of KLF4 signaling and that selective inhibition of KLF4 with statins should be considered in the development of osteosarcoma therapeutics. PMID- 28552604 TI - Evidence of In Vitro Preservation of Human Nephrogenesis at the Single-Cell Level. AB - During nephrogenesis, stem/progenitor cells differentiate and give rise to early nephron structures that segment to proximal and distal nephron cell types. Previously, we prospectively isolated progenitors from human fetal kidney (hFK) utilizing a combination of surface markers. However, upon culture nephron progenitors differentiated and could not be robustly maintained in vitro. Here, by culturing hFK in a modified medium used for in vitro growth of mouse nephron progenitors, and by dissection of NCAM+/CD133- progenitor cells according to EpCAM expression (NCAM+/CD133-/EpCAM-, NCAM+/CD133-/EpCAMdim, NCAM+/CD133 /EpCAMbright), we show at single-cell resolution a preservation of uninduced and induced cap mesenchyme as well as a transitioning mesenchymal-epithelial state. Concomitantly, differentiating and differentiated epithelial lineages are also maintained. In vitro expansion of discrete stages of early human nephrogenesis in nephron stem cell cultures may be used for drug screening on a full repertoire of developing kidney cells and for prospective isolation of mesenchymal or epithelial renal lineages for regenerative medicine. PMID- 28552605 TI - Defined and Scalable Differentiation of Human Oligodendrocyte Precursors from Pluripotent Stem Cells in a 3D Culture System. AB - Oligodendrocyte precursor cells (OPCs) offer considerable potential for the treatment of demyelinating diseases and injuries of the CNS. However, generating large quantities of high-quality OPCs remains a substantial challenge that impedes their therapeutic application. Here, we show that OPCs can be generated from human pluripotent stem cells (hPSCs) in a three-dimensional (3D), scalable, and fully defined thermoresponsive biomaterial system. We used CRISPR/Cas9 to create a NKX2.2-EGFP human embryonic stem cell reporter line that enabled fine tuning of early OPC specification and identification of conditions that markedly increased the number of OLIG2+ and NKX2.2+ cells generated from hPSCs. Transplantation of 50-day-old OPCs into the brains of NOD/SCID mice revealed that progenitors generated in 3D without cell selection or purification subsequently engrafted, migrated, and matured into myelinating oligodendrocytes in vivo. These results demonstrate the potential of harnessing lineage reporter lines to develop 3D platforms for rapid and large-scale production of OPCs. PMID- 28552606 TI - Differentiation and Transplantation of Embryonic Stem Cell-Derived Cone Photoreceptors into a Mouse Model of End-Stage Retinal Degeneration. AB - The loss of cone photoreceptors that mediate daylight vision represents a leading cause of blindness, for which cell replacement by transplantation offers a promising treatment strategy. Here, we characterize cone differentiation in retinas derived from mouse embryonic stem cells (mESCs). Similar to in vivo development, a temporal pattern of progenitor marker expression is followed by the differentiation of early thyroid hormone receptor beta2-positive precursors and, subsequently, photoreceptors exhibiting cone-specific phototransduction related proteins. We establish that stage-specific inhibition of the Notch pathway increases cone cell differentiation, while retinoic acid signaling regulates cone maturation, comparable with their actions in vivo. MESC-derived cones can be isolated in large numbers and transplanted into adult mouse eyes, showing capacity to survive and mature in the subretinal space of Aipl1-/- mice, a model of end-stage retinal degeneration. Together, this work identifies a robust, renewable cell source for cone replacement by purified cell suspension transplantation. PMID- 28552607 TI - cFOS-SOX9 Axis Reprograms Bone Marrow-Derived Mesenchymal Stem Cells into Chondroblastic Osteosarcoma. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) are proposed as the cells of origin of several subtypes of osteosarcoma (OS). However, signals that direct BMSCs to form different subtypes of OS are unclear. Here we show that the default tumor type from spontaneously transformed p53 knockout (p53_KO) BMSCs is osteoblastic OS. The development of this default tumor type caused by p53 loss can be overridden by various oncogenic signals: RAS reprograms p53_KO BMSCs into undifferentiated sarcoma, AKT enhances osteoblastic OS, while cFOS promotes chondroblastic OS formation. We focus on studying the mechanism of cFOS-induced chondroblastic OS formation. Integrated genome-wide studies reveal a regulatory mechanism whereby cFOS binds to the promoter of a key chondroblastic transcription factor, Sox9, and induces its transcription in BMSCs. Importantly, SOX9 mediates cFOS-induced cartilage formation in chondroblastic OS. In summary, oncogenes determine tumor types derived from BMSCs, and the cFOS-SOX9 axis is critical for chondroblastic OS formation. PMID- 28552608 TI - Reply to letter to the Editor 'Changes in biochemical markers following spinal manipulation - A systematic review and meta-analysis'. PMID- 28552609 TI - Retention systems for extraoral maxillofacial prosthetic implants: a critical review. AB - We describe the techniques available for retention of implant-supported prostheses: bar-clips, O-rings, and magnets. We present reported preferences and, although this is limited by the heterogeneity of methods used and patients studied, we hope we have identified the best retention systems for maxillofacial prosthetic implants. If practitioners know the advantages and disadvantages of each system, they can choose the most natural and comfortable prosthesis. We searched the PubMed and Scopus databases, and restricted our search to papers published 2001-13. MeSH terms used were Maxillofacial prosthesis and Craniofacial prosthesis OR Craniofacial prostheses. We found a total of 2630 papers, and after duplicates had been removed we analysed the rest and found 25 papers for review. Of these, 12 were excluded because they were case reports or non-systematic reviews. Of the remaining 13, 10 described group analyses and seemed appropriate to find practitioner's choices, as cited in the abstract (n=1611 prostheses). Three papers did not mention the type of prosthetic connection used, so were excluded. The most popular choices for different conditions were analysed, though the sites and retention systems were not specified in all 10 papers. The bar-clip system was the most used in auricular (6/10 papers) and nasal prostheses (4/10). For the orbital region, 6/10 favoured magnets. Non-osseointegrated mechanical or adhesive retention techniques are the least expensive and have no contraindications. When osseointegrated implants are possible, each facial region has a favoured system. The choice of system is influenced by two factors: standard practice and the abilities of the maxillofacial surgeon and maxillofacial prosthetist. PMID- 28552610 TI - Virtual planning of a composite model of bone and teeth to facilitate the adjustment of a hybrid distractor for the transport of alveolar bone. PMID- 28552611 TI - Care of long-term survivors of head and neck cancer after treatment with oral or facial prostheses, or both. AB - The current evidence of good practice in the delivery of long-term supportive care to patients who have been treated for head and neck cancer is sparse. We recruited 10 survivors so that we could follow their experience after their acute treatment was over. There were six men (mean (range) age 72 (54-86) years) and four women (mean (range) age 69 (67-73) years). After ethics committee approval had been given, we used structured interviews and questionnaires to investigate the impact of the resection and reconstruction, the patients' perceived needs, and their use of supportive care services. Their experiences were in line with current treatment of head and neck cancer. Whether they would survive the cancer was an initial fear (up to a year postoperatively), and some subjects reported problems more than five years after treatment, particularly with swallowing, quality of saliva, and intelligible speech. This small group of survivors of head and neck cancer maintained a good quality of life physically, socially, and emotionally. Limitations were put down to their age rather than their diagnosis of cancer or their rehabilitation. Analysis of their perceived needs showed that supportive care services were readily available and were valued by the patients, and that all their needs were met. PMID- 28552612 TI - Efficacy and safety of incretin-based drugs in patients with type 1 diabetes mellitus: A systematic review and meta-analysis. AB - AIMS: In patients with type 2 diabetes, incretin-based therapies can improve glucose control without increased weight gain or hypoglycemia. Incretin-based drugs added to insulin therapy in type 1 diabetes (T1DM) have also been tried in many studies. However, the results were controversial. We thus performed a meta analysis to assess the efficacy and safety of incretin-based therapies in patients with T1DM. METHODS: We systematically searched Medline, EMBASE, and Cochrane Central Register of Controlled Trials for relevant studies published before August 25, 2016. Data was extracted by two independent reviewers. The main outcomes included glycosylated hemoglobin (HbA1c), insulin dose, weight, hypoglycemia, ketosis and ketoacidosis. All pooled data were assessed using random-effects model. RESULTS: Twelve randomized controlled trials with a total of 2903 individuals were finally included into the meta-analysis. Incretin-based drugs could significantly reduce HbA1c (MD -0.20, 95% CI -0.30 to -0.10), weight (MD -2.83, 95% CI -4.00 to -1.65) and insulin dose (MD -4.55, 95% CI -6.15 to 2.94). Furthermore, incretin-based drugs did not increase relative risk of severe hypoglycemia (RR 0.79, 95% CI 0.58 to 1.06), ketosis (RR 1.37, 95% CI 0.95 to 1.97) and ketoacidosis (RR 2.62, 95% CI 0.31 to 21.99). CONCLUSIONS: Incretin based treatment in patients with T1DM may improve glycemic control and reduce insulin dose and weight without increasing the risk of serious adverse event, such as severe hypoglycemia, ketosis or ketoacidosis. The current evidence for the aforementioned adverse effects, however, is weak. A rigorous monitoring of these adverse events should be implemented in well-designed observational studies. PMID- 28552613 TI - Corrigendum re: "Urinary Incontinence and Erectile Dysfunction After Robotic Versus Open Radical Prostatectomy: A Prospective, Controlled, Nonrandomised Trial" [Eur Urol 2015;68:216-25]. PMID- 28552614 TI - Local Therapy for Disseminated Prostate Cancer: Improved Outcomes or Biased Confounders? PMID- 28552615 TI - SUMO-Targeted DNA Translocase Rrp2 Protects the Genome from Top2-Induced DNA Damage. AB - The action of DNA topoisomerase II (Top2) creates transient DNA breaks that are normally concealed inside Top2-DNA covalent complexes. Top2 poisons, including ubiquitously present natural compounds and clinically used anti-cancer drugs, trap Top2-DNA complexes. Here, we show that cells actively prevent Top2 degradation to avoid the exposure of concealed DNA breaks. A genome-wide screen revealed that fission yeast cells lacking Rrp2, an Snf2-family DNA translocase, are strongly sensitive to Top2 poisons. Loss of Rrp2 enhances SUMOylation dependent ubiquitination and degradation of Top2, which in turn increases DNA damage at sites where Top2-DNA complexes are trapped. Rrp2 possesses SUMO-binding ability and prevents excessive Top2 degradation by competing against the SUMO targeted ubiquitin ligase (STUbL) for SUMO chain binding and by displacing SUMOylated Top2 from DNA. The budding yeast homolog of Rrp2, Uls1, plays a similar role, indicating that this genome protection mechanism is widely employed, a finding with implications for cancer treatment. PMID- 28552617 TI - Extending the Host Range of Bacteriophage Particles for DNA Transduction. AB - A major limitation in using bacteriophage-based applications is their narrow host range. Approaches for extending the host range have focused primarily on lytic phages in hosts supporting their propagation rather than approaches for extending the ability of DNA transduction into phage-restrictive hosts. To extend the host range of T7 phage for DNA transduction, we have designed hybrid particles displaying various phage tail/tail fiber proteins. These modular particles were programmed to package and transduce DNA into hosts that restrict T7 phage propagation. We have also developed an innovative generalizable platform that considerably enhances DNA transfer into new hosts by artificially selecting tails that efficiently transduce DNA. In addition, we have demonstrated that the hybrid particles transduce desired DNA into desired hosts. This study thus critically extends and improves the ability of the particles to transduce DNA into novel phage-restrictive hosts, providing a platform for myriad applications that require this ability. PMID- 28552618 TI - Expression, purification, and characterization of a novel acidic Lipoxygenase from Myxococcus xanthus. AB - The gene encoding a novel acidic lipoxygenase from Myxococcus xanthus DK1622 (accession: WP_011551853.1) was cloned into vector pET-28a and expressed in Escherichia coli BL21(DE3). The recombinant enzyme (rMxLOX), with a molecular weight of approximately 80 kDa, was purified to homogeneity using one-step nickel affinity chromatography and showed an activity of 5.6 * 104 U/mg. The optimum pH and temperature for rMxLOX activity were found to be 3.0 and 30 degrees C, respectively. Purified rMxLOX exhibited activity towards linoleic acid and arachidonic acid as substrates, with linoleic acid being the better substrate (Km and kcat values of 0.048 mM and 13.3/s, respectively). The synthetic dye aniline blue was decolorized 69.7 +/- 3.5%, following incubation with rMxLOX for 35 min. These results reveal the potential for the use of rMxLOX in the pulp, textile, and wastewater treatment industries. PMID- 28552616 TI - Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy. AB - Overcoming metabolic stress is a critical step in tumor growth. Acetyl coenzyme A (acetyl-CoA) generated from glucose and acetate uptake is important for histone acetylation and gene expression. However, how acetyl-CoA is produced under nutritional stress is unclear. We demonstrate here that glucose deprivation results in AMP-activated protein kinase (AMPK)-mediated acetyl-CoA synthetase 2 (ACSS2) phosphorylation at S659, which exposed the nuclear localization signal of ACSS2 for importin alpha5 binding and nuclear translocation. In the nucleus, ACSS2 binds to transcription factor EB and translocates to lysosomal and autophagy gene promoter regions, where ACSS2 incorporates acetate generated from histone acetylation turnover to locally produce acetyl-CoA for histone H3 acetylation in these regions and promote lysosomal biogenesis, autophagy, cell survival, and brain tumorigenesis. In addition, ACSS2 S659 phosphorylation positively correlates with AMPK activity in glioma specimens and grades of glioma malignancy. These results underscore the significance of nuclear ACSS2-mediated histone acetylation in maintaining cell homeostasis and tumor development. PMID- 28552619 TI - Differentiation of subsequent memory effects between retrieval practice and elaborative study. AB - Retrieval practice enhances memory retention more than re-studying. The underlying mechanisms of this retrieval practice effect have remained widely unclear. According to the elaborative retrieval hypothesis, activation of elaborative information occurs to a larger extent during testing than re studying. In contrast, the episodic context account has suggested that recollecting prior episodic information (especially the temporal context) contributes to memory retention. To adjudicate the distinction between these two accounts, the present study used the classical retrieval practice effect paradigm to compare retrieval practice and elaborative study. In an initial behavioral experiment, retrieval practice produced greater retention than elaboration and re studying in a one-week delayed test. In a subsequent event-related potential (ERP) experiment, retrieval practice resulted in reliably superior accuracy in the delayed test compared to elaborative study. In the ERPs, a frontally distributed subsequent memory effect (SME), starting at 300ms, occurred in the elaborative study condition, but not in the retrieval practice condition. A parietal SME emerged in the retrieval practice condition from 500 to 700ms, but was absent in the elaborative study condition. After 700ms, a late SME was present in the retrieval practice condition, but not in the elaborative study condition. Moreover, SMEs lasted longer in retrieval practice than in elaboration. The frontal SME in the elaborative study condition might be related to semantic processing or working memory-based elaboration, whereas the parietal and widespread SME in the retrieval practice condition might be associated with episodic recollection processes. These findings contradict the elaborative retrieval theory, and suggest that contextual recollection rather than activation of semantic information contributes to the retrieval practice effect, supporting the episodic context account. PMID- 28552620 TI - In Vivo Imaging Reveals Existence of Crypt Fission and Fusion in Adult Mouse Intestine. AB - The intestinal epithelium is a repetitive sheet of crypt and villus units with stem cells at the bottom of the crypts. During postnatal development, crypts multiply via fission, generating 2 daughter crypts from 1 parental crypt. In the adult intestine, crypt fission is observed at a low frequency. Using intravital microscopy in Lgr5EGFP-Ires-CreERT2 mice, we monitored individual crypt dynamics over multiple days with single-cell resolution. We discovered the existence of crypt fusion, an almost exact reverse phenomenon of crypt fission, in which 2 crypts fuse into 1 daughter crypt. Examining 819 crypts in 4 mice, we found that 3.5% +/- 0.6% of all crypts were in the process of fission, whereas 4.1 +/- 0.9% of all crypts were undergoing crypt fusion. As counteracting processes, crypt fission and fusion could regulate crypt numbers during the lifetime of a mouse. Identifying the mechanisms that regulate rates of crypt fission and fusion could provide insights into intestinal adaptation to altered environmental conditions and disease pathogenesis. PMID- 28552621 TI - Intestinal Epithelial Sirtuin 1 Regulates Intestinal Inflammation During Aging in Mice by Altering the Intestinal Microbiota. AB - BACKGROUND & AIMS: Intestinal epithelial homeostasis is maintained by complex interactions among epithelial cells, commensal gut microorganisms, and immune cells. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD), but the mechanisms of this process are not clear. We investigated how Sirtuin 1 (SIRT1), a conserved mammalian NAD+ dependent protein deacetylase, senses environmental stress to alter intestinal integrity. METHODS: We performed studies of mice with disruption of Sirt1 specifically in the intestinal epithelium (SIRT1 iKO, villin-Cre+, Sirt1flox/flox mice) and control mice (villin-Cre-, Sirt1flox/flox) on a C57BL/6 background. Acute colitis was induced in some mice by addition of 2.5% dextran sodium sulfate to drinking water for 5-9 consecutive days. Some mice were given antibiotics via their drinking water for 4 weeks to deplete their microbiota. Some mice were fed with a cholestyramine-containing diet for 7 days to sequester their bile acids. Feces were collected and proportions of microbiota were analyzed by 16S rRNA amplicon sequencing and quantitative PCR. Intestines were collected from mice and gene expression profiles were compared by microarray and quantitative PCR analyses. We compared levels of specific mRNAs between colon tissues from age matched patients with ulcerative colitis (n=10) vs without IBD (n=8, controls). RESULTS: Mice with intestinal deletion of SIRT1 (SIRT1 iKO) had abnormal activation of Paneth cells starting at the age of 5-8 months, with increased activation of NF-kappaB, stress pathways, and spontaneous inflammation at 22-24 months of age, compared with control mice. SIRT1 iKO mice also had altered fecal microbiota starting at 4-6 months of age compared with control mice, in part because of altered bile acid metabolism. Moreover, SIRT1 iKO mice with defective gut microbiota developed more severe colitis than control mice. Intestinal tissues from patients with ulcerative colitis expressed significantly lower levels of SIRT1 mRNA than controls. Intestinal tissues from SIRT1 iKO mice given antibiotics, however, did not have signs of inflammation at 22-24 months of age, and did not develop more severe colitis than control mice at 4-6 months. CONCLUSIONS: In analyses of intestinal tissues, colitis induction, and gut microbiota in mice with intestinal epithelial disruption of SIRT1, we found this protein to prevent intestinal inflammation by regulating the gut microbiota. SIRT1 might therefore be an important mediator of host-microbiome interactions. Agents designed to activate SIRT1 might be developed as treatments for IBDs. PMID- 28552622 TI - Minilaparotomy Versus Laparoscopic Myomectomy After Cessation of Power Morcellation: Rate of Wound Complications. AB - STUDY OBJECTIVE: After the US Food and Drug Administration statement warning against electronic morcellation devices, gynecologic surgeons are performing laparoscopic and robotic myomectomies with minilaparotomy incisions for tissue morcellation and removal. No data exist that focus on the superficial wound complications as a result of these larger incisions. The objective of this study is to compare the rate of wound complications for myomectomy via minilaparotomy versus laparoscopic or robotic myomectomy. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Kaiser Permanente Northern California, a large integrated healthcare delivery system. PATIENTS: Women > 18 years of age who underwent a myomectomy from either complete laparoscopic or robotic approach (LR) were compared with minilaparotomy myomectomy (MM), comprising complete minilaparotomy (ML) and laparoscopic or robotic assisted by a minilaparotomy for morcellation purposes only (LRM) from January 2011 through December 2014. INTERVENTION: Myomectomy via LR, complete ML, and LRM. MEASUREMENTS AND MAIN RESULTS: Medical records were reviewed for outcomes of interest, including superficial wound complications and surgical and demographic data. After exclusion criteria were met, 405 cases were included in the study; 270 cases were classified as MM, which included ML (n = 224), or LRM (n = 46). One hundred thirty-five cases were classified as LR. Parametric and nonparametric analyses were used to compare the 2 groups. There was no significant difference between the groups insofar as patient morbidity, including the primary outcome of wound complications and other postoperative complications; emergency visits; or readmissions. There were 2 (1.5%) wound complications in the LR group and 7 (2.6%) in the MM group (p = .72). Similarly, there were no significant differences in the subcategories of wound complications, including cellulitis, seroma, hematoma, skin separation, wound infection, or postprocedure wound complication. The distribution of estimated blood loss was significantly different between LR and MM groups with an interquartile range of 50 to 150 mL in the LR group versus 50 to 300 mL in the MM group (p < .01). The MM group experienced a shorter procedure time with a median procedure time of 125 minutes compared with 169.5 minutes in LR surgeries (p < .01). The LR group demonstrated a significantly shorter median length of hospital stay (LR 5.0 hours vs MM 23 hours; p < .01). CONCLUSION: Compared with MM, LR is associated with a shorter length of hospital stay and longer operating time but no reduction in wound complication or other patient morbidity. PMID- 28552623 TI - Meta-Analysis of Two Studies With Random Effects? PMID- 28552624 TI - Is the prognosis of occult N2 disease similar to that of positive positron emission tomography-computed tomography (PET/CT) scan single-station N2 disease in patients with non-small cell lung cancer treated by surgical resection? AB - OBJECTIVE: A retrospective study, using a prospective database, was conducted on patients treated with surgery in order to analyze the prognosis between two groups: NSCLC (non-small cell lung cancer) patients with occult N2 disease and patients with single station N2 disease observed on pre-operative integrated PET/CT scan. METHODS: A total of 772 patients underwent surgical treatment for lung cancer from January 2007 to December 2014. All of them had an integrated PET/CT scan in the pre-operative work-up and a pulmonary resection plus mediastinal lymphadenectomy were performed in all cases. In the selected cases, no one received induction treatment. All patients from both groups had N2 disease after examination of the histopathology specimen. Clinical and pathological characteristics, disease free survival, and overall survival, were analyzed in both groups. RESULTS: A total of 34 cases presented occult N2 disease, whereas 11 cases showed single station N2 disease on pre-operative PET/CT scan. Mean disease free survival and mean overall survival for occult N2 disease compared to single station N2 disease on PET/CT scan was 36.0 months (95% CI: 24.9-47.1) and 38.9 months (95% CI: 20.6-57.1), p=.586; and 52.3 months (95% CI: 38.9-65.7) and 38.2 months (95% CI: 21.9-54.5), p=.349, respectively. CONCLUSION: The prognosis of patients with single-station N2 disease on PET/CT scan treated by surgical resection and mediastinal lymphadenectomy as first line treatment was similar to those with occult N2 disease. More studies are needed to support our findings. PMID- 28552625 TI - The current status and unmet needs in the management of psoriatic arthritis: Viewpoint from physicians in Taiwan. AB - BACKGROUND/PURPOSE: To analyze the real-world clinical practice for the treatment of psoriatic arthritis (PsA) and to assess physicians' prescription, difficulties in diagnosis, therapeutic strategy, rationales for biologic therapies and unmet needs in Taiwan. METHODS: We conducted a nationwide cross-sectional observational study by face-to-face in depth interviews with 50 rheumatologists and 30 dermatologists who took care of patients with PsA. RESULTS: The major procedures for recognizing PsA included joint, skin and nail examinations, radiographic imaging, and medical history. More dermatologists established the diagnosis when psoriatic patients with arthritis didn't present with rheumatoid factors (p < 0.05). For milder arthritis, physicians tended to prescribe etanercept in combination with conventional disease-modifying antirheumatic drugs (DMARDs). The efficacy, safety, retention rate, and non-parenteral administration are the major concerns of physicians which are also the primary unmet needs in the current management of PsA. CONCLUSION: This survey showed the status quo in Taiwan of the clinical management for PsA including diagnostic difficulties, therapeutic consideration, rationales for biologic DMARDs selection and unmet needs in treatment. It has indicated that interdisciplinary collaboration may further improve the quality for PsA care. These results may help establish new strategy to develop next generation biologics. PMID- 28552626 TI - Hereditary angioedema and Graves' disease: The first case report. PMID- 28552627 TI - Perioperative statin use is associated with decreased incidence of primary graft dysfunction after lung transplantation. AB - BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early morbidity and mortality after lung transplantation. Statins reduce the risk of chronic rejection after lung transplantation, but their effects on PGD are unknown. We hypothesized that perioperative statin therapy decreases the risk for PGD after lung transplantation. METHODS: We retrospectively reviewed records of all patients undergoing lung transplantation between January 1999 and December 2014 at the University of Virginia Health System. The primary outcome was PGD (grades 1-3). Secondary outcomes included grade 3 PGD, length of intensive care unit and hospital stay, and mortality. RESULTS: Of 266 patients who met final inclusion criteria, 138 (52%) were diagnosed with PGD. In-hospital mortality among patients with PGD was 6.5%. There were no deaths in patients without PGD (p < 0.001). PGD was diagnosed in 24 patients taking statins (34.8%) and in 114 patients (57.9%) who did not take statins (p = 0.001). After propensity score adjustments, perioperative statin use was independently associated with a reduced risk for PGD (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.20-0.84, p = 0.015) and reduced risk to develop grade 3 PGD (OR 0.42, 95% CI 0.18-0.94, p = 0.036). Other risk factors associated with PGD included intraoperative use of cardiopulmonary bypass (OR 3.74, 95% CI 1.75-8.02, p = 0.001) and positive donor smoking status (OR 2.27, 95% CI 1.18-4.35, p = 0.014). CONCLUSIONS: The results demonstrate that perioperative use of statins is independently associated with reduced risk for PGD after lung transplantation. PMID- 28552628 TI - Effects of PCB-126 on aryl hydrocarbon receptor, ubiquitin and p53 expression levels in Sparus aurata. AB - The aim of the present study is to determine if Ahr ligands as PCB-126, a dioxin like, might contribute to inhibition of the tumor suppressor p53 by promoting its degradation through proteasome-ubiquitin system (UPS). The findings show, in the presence of PCB-126, a significant increase of p53 immunoreactivity in fish compared to the control. Subsequently, there is a decrease of p53 immunoreactivity at 24h which is maintained even at 72h. At the same time there is a slight decrease of ubiquitin immunoreactivity to 12h compared to the control and a marked decrease to 24 and 72h. The induction of ubiquitin expression is resulted very marked in the control and preserved at 12h. It's very important to underline as in our study we demonstrate a marked decrease of ubiquitin and p53 immunoreactivity at 24h and 72h. AHR activation, by ligands as PCB-126, increases p53 ubiquitation inhibiting its expression, in addition it decreases the free ubiquitin promoting disruption of Ub homeostasis; this is the first report that establishes a relationship between AhR, increases p53 ubiquitation, and reduction of free ubiquitin. Our result emphasize the need to deeply the role of this receptor in UPS regulation as potential therapeutic target for cancer treatment. PMID- 28552629 TI - Clinical and pathological analysis of 19 cases of medullary thyroid carcinoma without an increase in calcitonin. AB - BACKGROUND: Medullary thyroid carcinoma (MTC), defined as a malignant tumour with C-cell differentiation, is of neuroendocrine origin and is characterized by the synthesis and secretion of calcitonin (CT). MTC without CT secretion has been reported on rare occasions. The purpose of this study was to evaluate the histological, immunohistochemical, and molecular pathologic features as well as the clinical significance of non-secretory MTC (NCR-MTC). METHODS: A retrospective analysis of patients with NCR-MTC was performed. The clinical features of NCR-MTC, including age, gender, tumour size and number, clinical signs of hypocalcaemia and diarrhoea, and the presence of lymph node metastasis, as well as the pathologic features of the disease, including tumour morphology, presence of neuroendocrine structures, capsular invasion, and immunohistochemical expression and presence of mutations in the RET gene, were evaluated. RESULTS: Nineteen patients with NCR-MTC were identified among 158 patients with MTC, resulting in a prevalence rate of 12.02%. Patients with NCR-MTC typically had masses less than 1cm in size (73.7%, 14/19). Hypocalcaemia was not present in 94.7% (18/19) of patients. While 42.1% (8/19) of patients with NCR-MTC did not have amyloid deposits, only 18% (25/139) of patients with secretory MTC did not have such deposits. While 95.7% (133/139) of the control group of patients with secretory MTC had neuroendocrine tumour structure, only 84.2% (16/19) of the patients with NCR-MTC had this type of tumour structure. Patients with NCR-MTC were also less likely to have vascular tumour thrombus, lymph node metastasis or thyroid capsular invasion. With regard to immunohistochemistry, CT expression was mostly negative, and carcinoembryonic antigen (CEA) expression was positive in 21.1% (4/19) of patients with NCR-MTC, while only 5.8% (8/139) of patients in the control group had positive CEA expression. CONCLUSIONS: The prevalence of NCR-MTC was low (12.02%). This type of tumour was smaller in size and more differentiated. Compared with the control group, relatively few patients had obvious symptoms, hypocalcaemia, lymph node metastasis, thyroid capsular or vascular invasion, or tumours with amyloid or neuroendocrine tumour structure. PMID- 28552630 TI - Protective effects of melatonin on long-term administration of fluoxetine in rats. AB - The degree and consequence of tissue injury are highly regarded during long-term exposure to selective antidepressant fluoxetine. Melatonin has been shown to palliate different lesions by scavenging free radicals, but its role in the reduction of the fluoxetine-induced injuries has been little known. Thirty-six mature male Wistar rats were randomly assigned into control and experimental groups. The experimental rats were included as following; 24mg/kg/bw fluoxetine for 4 weeks; 1mg/kg/bw melatonin for 4 weeks; fluoxetine+1-week melatonin, fluoxetine+2-week melatonin and fluoxetine+4-week melatonin. In the current experiment, we investigated weight gain, hematological and biochemical parameters, pathological injuries and oxidative status. We noted the positive effect of melatonin in weight loss of fluoxetine-treated rats (p<0.05). The significant reduction of superoxide dismutase, glutathione peroxidase, catalase activities in blood, liver, and kidneys and changes in serum total antioxidant capacity caused by fluoxetine were reversed by melatonin (p<0.05). Melatonin reduced the increased lipid peroxidation and transaminase activity in rats received fluoxetine (p<0.05). We also showed the potency of fluoxetine in inducing leukopenia, thrombocytopenia and hypochromic and macrocytic anemia which was blunted by melatonin. Both RBCs and platelets indices were also corrected. Rats received melatonin in combination with fluoxetine showed a reduction in the severity of degeneration and inflammatory changes in different tissues, brain, heart, liver, lungs, testes and kidneys as compared to the fluoxetine group. Therefore, melatonin fundamentally reversed the side effects of fluoxetine in the rat model which is comparable to human medicine. PMID- 28552631 TI - Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy. AB - Ferroptosis is a form of regulated cell death that is dependent on iron and reactive oxygen species (ROS) and is characterized by lipid peroxidation. It is morphologically and biochemically distinct and disparate from other processes of cell death. As ferroptosis is induced by inhibition of cysteine uptake or inactivation of the lipid repair enzyme glutathione peroxidase 4 (GPX4), the process is favored by chemical or mutational inhibition of the cystine/glutamate antiporter and culminates in the accumulation of reactive oxygen species (ROS) in the form of lipid hydroperoxides. Excessive lipid peroxidation leads to death by ferroptosis and the phenotype is accentuated respectively by the repletion and depletion of iron and glutathione in cells. Furthermore, oxidized phosphatidylethanolamines (PE) harbouring arachidonoyl (AA) and adrenoyl moieties (AdA) have been shown as proximate executioners of ferroptosis. Induction of ferroptosis due to cysteine depletion leads to the degradation of ferritin (i.e. ferritinophagy), which releases iron via the NCOA4-mediated autophagy pathway. Evidence of the manifestation of ferroptosis in vivo in iron overload mice mutants is emerging. Thus, a concerted synchronization of iron availability, ROS generation, glutamate excess and cysteine deficit leads to ferroptosis. A number of questions on the molecular mechanisms of some features of ferroptosis are highlighted as subjects for future investigations. PMID- 28552632 TI - Structural basis for the magnesium-dependent activation of transketolase from Chlamydomonas reinhardtii. AB - BACKGROUND: In photosynthetic organisms, transketolase (TK) is involved in the Calvin-Benson cycle and participates to the regeneration of ribulose-5-phosphate. Previous studies demonstrated that TK catalysis is strictly dependent on thiamine pyrophosphate (TPP) and divalent ions such as Mg2+. METHODS: TK from the unicellular green alga Chlamydomonas reinhardtii (CrTK) was recombinantly produced and purified to homogeneity. Biochemical properties of the CrTK enzyme were delineated by activity assays and its structural features determined by CD analysis and X-ray crystallography. RESULTS: CrTK is homodimeric and its catalysis depends on the reconstitution of the holo-enzyme in the presence of both TPP and Mg2+. Activity measurements and CD analysis revealed that the formation of fully active holo-CrTK is Mg2+-dependent and proceeds with a slow kinetics. The 3D-structure of CrTK without cofactors (CrTKapo) shows that two portions of the active site are flexible and disordered while they adopt an ordered conformation in the holo-form. Oxidative treatments revealed that Mg2+ participates in the redox control of CrTK by changing its propensity to be inactivated by oxidation. Indeed, the activity of holo-form is unaffected by oxidation whereas CrTK in the apo-form or reconstituted with the sole TPP show a strong sensitivity to oxidative inactivation. CONCLUSION: These evidences indicate that Mg2+ is fundamental to allow gradual conformational arrangements suited for optimal catalysis. Moreover, Mg2+ is involved in the control of redox sensitivity of CrTK. GENERAL SIGNIFICANCE: The importance of Mg2+ in the functionality and redox sensitivity of CrTK is correlated to light-dependent fluctuations of Mg2+ in chloroplasts. PMID- 28552633 TI - Early and late gene expression profiles of the ovine mucosa in response to Haemonchus contortus infection employing Illumina RNA-seq technology. AB - We conducted herein transcriptome sequencing of the ovine abomasal tissues using the Illumina HiSeq 4000 platform to segregate early and late H. contortus infected sheep (7 and 50days post-infected groups, respectively) from the control naive ones. A total of 548, 357 and 7 were substantially induced genes in 7days post-infection versus uninfected-control group, 50days post-infection versus 7days post-infection (7dpi), and 50days post-infection (50dpi) versus uninfected control group, respectively. However, a total of 301, 355 and 11 were significantly repressed genes between 7dpi versus uninfected-control group, 50dpi versus 7dpi, and 50dpi versus uninfected-control group, correspondingly. This indicates that H. contortus infection induced a more potent activation of abomasal gene expression in the early stage of infection as compared to the late stage. Seven pathways were annotated by Kyoto Encyclopedia of Genes, and Genomes pathway analysis accounted for the significant percentage in early H. contortus infection. This study shows for the first time that both galectin-11 and matricellular protein osteopontin are up-regulated in abomasal tissue after chronic H. contortus infection, while galectin-4 is specifically down-regulated in the early infection. Additionally, our results showed that the induction or repression of these molecules is likely to determine the infection progression. PMID- 28552634 TI - iTRAQ-based quantitative proteomic analysis reveals Bai-Hu-Tang enhances phagocytosis and cross-presentation against LPS fever in rabbit. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bai-Hu-Tang (BHT), a classical anti-febrile Chinese formula comprising of liquorice, anemarrhena rhizome, gypsum and rice, has been traditionally used to anti-febrile treatment and promote the production of body fluid to relieve thirst. In this paper, we aim to explore anti-febrile mechanism of BHT at protein level through analyzing alteration of differentially expressed proteins (DEPs) both lipopolysaccharide (LPS) fever syndrome and that was treated with BHT in rabbits. MATERIALS AND METHODS: Febrile model was induced by LPS injection (i.v.) in rabbits, and BHT (750mg dry extract/kg body weight) was gavaged to another group of LPS fever rabbits. After sacrifice of animals, total protein of liver tissue was isolated, and two-dimensional liquid chromatography (LC) - tandem mass spectrometry (MS) coupled with isobaric tags for relative and absolute quantification (iTRAQ) labeling analysis was employed to quantitatively identify differentially expressed proteins in two group animals, which were compared with control group. Then bioinformatic analysis of DEPs was conducted through hierarchical Clustering, Venn analysis, gene ontology (GO) annotation enrichment, and kyoto encyclopedia of genes and genomes (KEGG) pathways enrichment. RESULT: The results demonstrated there were 63 and 109 DEPs in LPS fever group and BHT-treated group, respectively. Enrichment analysis of GO annotations indicated that BHT mainly regulated expression of some extracellular structural proteins for response to stimulus and stress. KEGG analysis showed that ribosome and phagosome were the most significant pathways. Thereinto, several proteins in phagosome pathway were significantly up-regulated by BHT, including F-actin, coronin, Rac, and major histocompatibility complex class I (MHC I), which work in phagocytosis and cross-presentation CONCLUSION: BHT may contribute to pyrogen clearance by boosting antigenic phagocytosis, degradation, and cross presentation in the liver. PMID- 28552635 TI - The in vitro and in vivo protective effects of tannin derivatives against Salmonella enterica serovar Typhimurium infection. AB - In this study, we investigated the protective effects of tannin-derived components, gallic acid (GA) and tannic acid (TA), in vitro and in vivo against Salmonella infection in mice. Both GA and TA showed antibacterial effects against Salmonella (S.) Typhimurium as well as inhibitory effects on the adherence, invasion, and intracellular growth of the pathogens in macrophages. Following a lethal dose of Salmonella infection in mice, reduced virulence in both GA- and TA treated groups was observed based on reduced mortality rates. In the non-infected groups, the average weights of the spleens and livers of GA- or TA-treated mice were not significantly different with the control group. In addition, the average weights of these organs in all of the Salmonella-infected groups were not significantly different but the numbers of bacteria in the spleens and livers in both GA- and TA-treated mice were significantly reduced. The levels of cytokine production in non-infected mice revealed that GA-treated and TA-treated mice elicited an increased level of IFN-gamma, and both IFN-gamma and MCP-1, respectively, as compared with the PBS-treated group. These findings highlight the potential of GA and TA as alternatives for the treatment of salmonellosis and as supplements to conventional antimicrobial food additives. PMID- 28552636 TI - Expression of CXCR1 (IL-8 receptor A) in splenic, peritoneal macrophages and resident bone marrow cells after acute live or heat killed Staphylococcus aureus stimulation in mice. AB - Literature reveals that interaction with live Staphylococcus aureus (S. aureus) or heat killed S. aureus (HKSA) promotes secretion of CXCL-8 or interleukin-8 (IL 8) from leukocytes, however, the expressions of CXCR1 in murine splenic (SPM), peritoneal macrophages (PM) and resident fresh bone marrow cells (FBMC) have not been identified. Currently, very few studies are available on the functional characterization of CXCR1 in mouse macrophage subtypes and its modulation in relation to acute S. aureus infection. SPM, PM and FBMCs were infected with viable S. aureus or stimulated with HKSA in presence and absence of anti-CXCR1 antibody in this study. We reported here that CXCR1 was not constitutively expressed by macrophage subtypes and the receptor was induced only after S. aureus stimulation. The CXCR1 band was found specific as we compared with human polymorphonuclear neutrophils (PMNs) as a positive control (data not shown). Although, we did not show that secreted IL-8 from S. aureus-infected macrophages promotes migration of PMNs. Blocking of cell surface CXCR1 decreases the macrophage's ability to clear staphylococcal infection, attenuates proinflammatory cytokine production and the increased catalase and decreased superoxide dismutase (SOD) enzymes of the bacteria might indicate their role in scavenging macrophage derived hydrogen peroxide (H2O2). The decreased levels of cytokines due to CXCR1 blockade before S. aureus infection appear to regulate the killing of bacteria by destroying H2O2 and nitric oxide (NO). Moreover, functional importance of macrophage subpopulation heterogeneity might be important in designing new effective approaches to limit S. aureus infection induced inflammation and cytotoxicity. PMID- 28552637 TI - Variance in infra-patellar fat pad volume: Does the body mass index matter?-Data from osteoarthritis initiative participants without symptoms or signs of knee disease. AB - The infra-patellar fat pad (IPFP) has been proposed to represent an endocrine link between obesity and knee osteoarthritis (OA). The purpose of the current study has been to explore the extent to which IPFP volume is related to body mass index (BMI). A total of 152 participants (age 56+/-7 years) without knee OA were studied. These consisted of 19 men and 19 women of normal weight (BMI 18.5-25), 19/19 pre-obese (BMI 25-30), 19/19 obese class I (BMI 30-35) and 19/19 obese class II (BMI 35-40), who were matched 1:1 for age and height. The IPFP volume was manually segmented from sagittal fat-suppressed magnetic resonance images (MRI). An ANOVA of repeated measures was used to assess whether IPFP volume was related to BMI. The IPFP volume differed significantly between the BMI strata (ANOVA: p=0.001): It was 27.1+/-6.7cm3 (mean+/-SD) in normal weight, 29.3+/ 6.9cm3 in pre-obese, 31.0+/-6.9cm3 in obese class I, and 30.4+/-6.6cm3 in obese class II participants; the difference in IPFP volume (and body weight) relative to normal weight subjects was 10% (18%) in pre-obese, 17% (39%) in obese class I, and 15% (59%) in obese class II participants. Stratification by sex showed similar results. In conclusion, IPFP volume is shown to be related to BMI, albeit the relative increase (compared with normal weight) does not appear to be proportional to that in body weight. Nonetheless, these findings support the hypothesis that the IPFP may represent a potential endocrine link between obesity and OA, with more intra-articular adipose tissue potentially releasing greater amounts of adipokines. PMID- 28552638 TI - Interprofessional education in pediatrics-Child protection and family services as a teaching example. AB - Interprofessional collaboration between different professional groups in the health care system is essential to efficient and effective patient care. Especially in pediatrics, in the field of child protection, and family services it is mandatory to involve experts from different health-care professions to optimize support for children and their families. Interprofessional education in medical schools and specifically in pediatrics is rare in Germany, but is called for by the German National Competence Based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM). We developed an interprofessional course aimed at bringing medical students together with students of psychology, social work, clinical education, and educational science to learn from, about and with each other in the context of child protection and family services. This offers opportunities for all participants to understand profession-specific competencies, roles, attitudes, and limits of their professional roles. The course is led by an interprofessional teaching tandem (social scientist & physician); further input is provided by other health and social care professionals. After the students get a brief overview about the requirements for a successful interprofessional cooperation they solve case studies in interprofessional teams with online support by the teaching tandem. We assess the feasibility and acceptability of this interprofessional course and describe challenges encountered when conducting this kind of learning concept for health care professions. All conducted courses over five consecutive terms were evaluated with an arithmetic mean of AM=1.32 on a 6-point scale (1="excellent", 6="insufficient"), the teaching tandem was evaluated with AM=1.1. All participants (N=85 complete evaluations) voted for the course to be continued in the following terms. Especially the opportunity to discuss cases with students from different degree programs was highly valued as were interprofessional discussions and more in-depth understanding of other professions' competencies and roles. PMID- 28552639 TI - Neuroprotective effects of food restriction on autonomic innervation of the lacrimal gland in the rat. AB - Inflammatory mechanisms and oxidative stress play important roles in age-related lacrimal gland (LG) degeneration as well as neural degeneration. Research suggests that caloric restriction can prevent age-related LG dysfunction and increase the life span of neurons. In the present study, we hypothesized that caloric restriction prevents age-related LG dysfunction by ameliorating the influence of inflammatory/oxidative stress on autonomic neurons controlling lacrimal function. We evaluated the effects of food restriction (FR) on inflammatory/oxidative status and on autonomic neural/neuroglial cell populations in LGs from aging rats. A total of 45 female albino rats were divided into young adult, aged, and aged-FR groups. The FR group was subjected to a 50% reduction in food from 14 to 20 months of age. LG samples were collected for each group and subjected to biochemical, histological, and immunohistochemical studies. LGs from aged-FR rats, rather than those from aged rats, showed preservation of their cellular structures, organelles, and Schwan cell units. LG preservation was associated with a marked decrease in inflammatory markers, an increase in cellular antioxidants, and the up-regulation of choline acetyltransverase, tyrosine hydroxylase, neuron-specific enolase and S100. These findings strongly suggest that in aged rats, both oxidative and inflammatory stressors directly contribute to LG dysfunction by mediating the degeneration of autonomic neurons, and that FR can protect against these effects. PMID- 28552640 TI - Platelet-released growth factors induce psoriasin in keratinocytes: Implications for the cutaneous barrier. AB - Millions of patients around the world suffer minor or major extremity amputation due to progressive wound healing complications of chronic or infected wounds, the therapy of which remains a challenge. One emerging therapeutic option for the treatment of these complicated wounds is the local application of an autologous thrombocytes concentrate lysate (e.g. platelet-released growth factors ((PRGF)) or Vivostat PRF(r)) that contains a multitude of chemokines, cytokines and growth factors and is therefore supposed to stimulate the complex wound healing process. Although PRGF and Vivostat PRF(r) are already used successfully to support healing of chronic, hard-to-heal and infected wounds the underlying molecular mechanisms are not well understood. Psoriasin, also termed S100A7, is a multifunctional antimicrobial protein expressed in keratinocytes and is involved in various processes such as wound-healing, angiogenesis, innate immunity and immune-modulation. In this study, we investigated the influence of PRGF on psoriasin expression in human primary keratinocytes in vitro and the influence of Vivostat PRF(r) on psoriasin expression in experimentally generated skin wounds in vivo. PRGF treatment of primary keratinocytes caused a significant concentration- and time-dependent increase of psoriasin gene and protein expression in vitro that were partially mediated by the epidermal growth factor receptor (EGFR) and the interleukin-6 receptor (IL-6R). In accordance with these cell culture data, Vivostat PRF(r) induced a significant psoriasin gene and protein expression when applied to artificially generated skin wounds in vivo. The observed psoriasin induction in keratinocytes may contribute to the wound healing-promoting effects of therapeutically used thrombocyte concentrate lysates. PMID- 28552641 TI - pCramoll and rCramoll lectins induce cell death in human prostate adenocarcinoma (PC-3) cells by impairment of mitochondrial homeostasis. AB - Lectins from Cratylia mollis seed have shown potential in vivo antitumor actions, however the mechanism have not yet been addressed. Here we evaluated the antitumor effects of native (pCramoll) and recombinant (rCramoll) lectins from C. mollis against human prostate adenocarcinoma (PC-3) cells. The viability of PC-3 cells was analyzed with the MTT assay and ANNEXIN V/propidium iodide staining. The actions of pCramoll or rCramoll on mitochondrial superoxide production, free cytosolic calcium concentration and mitochondrial membrane potential were evaluated using fluorescent probes (MitoSox Red, Fura 2-AM and safranin O, respectively). pCramoll and rCramoll reduced the viability of PC-3 cells in a dose-dependent manner. Both lectins increased the generation of mitochondrial superoxide as well as the concentration of cytosolic calcium. These changes led to a decrease in oxidative phosphorylation, which impaired the formation of ATP. The resulting cell death was not blocked by MPT (mitochondrial permeability transition) inhibitors (Debio 025 or bongkrekic acid). Thus pCramoll and rCramoll promote PC-3 cell death through calcium signaling, leading to mitochondrial collapse. This work provides more insights into the action of pCramoll and rCramoll against cancer cells. These lectins represent valuable tools for biomedical research. PMID- 28552642 TI - Functionalised collagen spheres reduce H2O2 mediated apoptosis by scavenging overexpressed ROS. AB - Excess reactive oxygen species (ROS) has been implicated in numerous diseases including cancer, cardiovascular and neurodegenerative diseases. Overexpression of ROS can lead to oxidative stress and subsequently to H2O2-mediated cell apoptosis. In this study, it was demonstrated that biodegradable PLGA microspheres coated with collagen type I and decorated with MnO2 nanoparticles acted as ROS scavengers controlling the H2O2-mediated apoptosis of cells undergoing oxidative stress. The results showed that the functionalized collagen spheres can protect cells even under very harsh conditions of oxidative stress. PMID- 28552643 TI - Formation of graphene oxide-hybridized nanogels for combinative anticancer therapy. AB - The low efficacy and high toxicity of chemotherapy have been driving increasing attention on development of combined anticancer therapy technique. In the current work, graphene oxide (GO)-hybridized nanogels (AGD) were developed for delivery of an anticancer drug (doxorubicin (DOX)), which simultaneously presented photothermal therapeutic effects against cancer cells. AGD nanogels were fabricated by in situ incorporating GO nanoplatelets into a biodegradable polymer (alginate) via a double emulsion approach using a disulfide molecule as crosslinker, followed by DOX encapsulation via electrostatic interactions. The nanogels released DOX drug in an accelerated way under both acidic and reducible conditions mimicking extracellular tumor microenvironments and intracellular compartments. The stimulative release controllability of the nanogels improved the DOX internalization and long-term drug accumulation inside A549 cells (an adenocarcinoma human alveolar basal epithelial cell line), which, together with their photothermal effect, resulted in a good anticancer cytotoxicity, indicating their promising potential for combinative anticancer therapy. PMID- 28552644 TI - Recent advances in bioactive 1D and 2D carbon nanomaterials for biomedical applications. AB - One-dimensional (1D) carbon nanotubes (CNTs) and the two-dimensional (2D) graphene represent the most widely studied allotropes of carbon. Due to their unique structural, electrical, mechanical and optical properties, 1D and 2D carbon nanostructures are considered to be leading candidates for numerous applications in biomedical fields, including tissue engineering, drug delivery, bioimaging and biosensors. The biocompatibility and toxicity issues associated with these nanostructures have been a critical impediment for their use in biomedical applications. In this review, we present an overview of the various materials types, properties, functionalization strategies and characterization methods of 1D and 2D carbon nanomaterials and their derivatives in terms of their biomedical applications. In addition, we discuss various factors and mechanisms affecting their toxicity and biocompatibility. PMID- 28552645 TI - Sculpting neurotransmission during synaptic development by 2D nanostructured interfaces. AB - Carbon nanotube-based biomaterials critically contribute to the design of many prosthetic devices, with a particular impact in the development of bioelectronics components for novel neural interfaces. These nanomaterials combine excellent physical and chemical properties with peculiar nanostructured topography, thought to be crucial to their integration with neural tissue as long-term implants. The junction between carbon nanotubes and neural tissue can be particularly worthy of scientific attention and has been reported to significantly impact synapse construction in cultured neuronal networks. In this framework, the interaction of 2D carbon nanotube platforms with biological membranes is of paramount importance. Here we study carbon nanotube ability to interfere with lipid membrane structure and dynamics in cultured hippocampal neurons. While excluding that carbon nanotubes alter the homeostasis of neuronal membrane lipids, in particular cholesterol, we document in aged cultures an unprecedented functional integration between carbon nanotubes and the physiological maturation of the synaptic circuits. PMID- 28552646 TI - Ultrasound-activated piezoelectric P(VDF-TrFE)/boron nitride nanotube composite films promote differentiation of human SaOS-2 osteoblast-like cells. AB - Piezoelectric films of poly(vinylidenedifluoride-trifluoroethylene) (P(VDF-TrFE)) and of P(VDF-TrFE)/boron nitride nanotubes (BNNTs) were prepared by cast annealing and used for SaOS-2 osteoblast-like cell culture. Films were characterized in terms of surface and bulk features, and composite films demonstrated enhanced piezoresponse compared to plain polymeric films (d31 increased by ~80%). Osteogenic differentiation was evaluated in terms of calcium deposition, collagen I secretion, and transcriptional levels of marker genes (Alpl, Col1a1, Ibsp, and Sparc) in cells either exposed or not to ultrasounds (US); finally, a numerical model suggested that the induced voltage (~20-60 mV) is suitable for cell stimulation. Although preliminary, our results are extremely promising and encourage the use of piezoelectric P(VDF-TrFE)/BNNT films in bone tissue regeneration. PMID- 28552648 TI - Ultrasmall graphene oxide based T1 MRI contrast agent for in vitro and in vivo labeling of human mesenchymal stem cells. AB - Herein, we report on development of a two-dimensional nanomaterial graphene oxide (GO)-based T1 magnetic resonance imaging (MRI) contrast agent (CA) for in vitro and in vivo labeling of human mesenchymal stem cells (hMSCs). The CA was synthesized by PEGylation of ultrasmall GO, followed by conjugation with a chelating agent DOTA and then gadolinium(III) to form GO-DOTA-Gd complexes. Thus prepared GO-DOTA-Gd complexes exhibited significantly improved T1 relaxivity, and the r1 value was 14.2 mM-1s-1 at 11.7 T, approximately three times higher than Magnevist, a commercially available CA. hMSCs can be effectively labeled by GO DOTA-Gd, leading to remarkably enhanced cellular MRI effect without obvious adverse effects on proliferation and differentiation of hMSCs. More importantly, in vivo experiment revealed that intracranial detection of 5*105 hMSCs labeled with GO-DOTA-Gd is achieved. The current work demonstrates the feasibility of the GO-based T1 MRI CA for stem cell labeling, which may find potential applications in regenerative medicine. PMID- 28552647 TI - Current approaches for modulation of the nanoscale interface in the regulation of cell behavior. AB - Regulation of cell behavior in response to nanoscale features has been the focus of much research in recent years and the successful generation of nanoscale features capable of mimicking the natural nanoscale interface has been of great interest in the field of biomaterials research. In this review, we discuss relevant nanofabrication techniques and how they are combined with bioengineering applications to mimic the natural extracellular matrix (ECM) and create valuable nanoscale interfaces. PMID- 28552649 TI - Laponite(r): A key nanoplatform for biomedical applications? AB - Laponite(r) is a synthetic smectite clay that already has many important technological applications, which go beyond the conventional uses of clays in pharmaceutics and cosmetics. In biomedical applications, particularly in nanomedicine, this material holds great potential. Laponite(r) is a 2-dimensional (2D) nanomaterial composed of disk-shaped nanoscale crystals that have a high aspect ratio. These disks can strongly interact with many types of chemical entities (from small molecules or ions, to natural or synthetic polymers, to different inorganic nanoparticles) and are also easily functionalized and readily degraded in the physiological environment giving rise to non-toxic and even bioactive products. This review will highlight the potential of Laponite(r) as a nanomaterial in the fields of drug delivery, bioimaging, tissue engineering and regenerative medicine. New concepts, as well as novel innovative materials that stand out from the usual ones due to the unique properties of Laponite(r), will also be presented and discussed. PMID- 28552650 TI - Enhanced neural stem cell functions in conductive annealed carbon nanofibrous scaffolds with electrical stimulation. AB - Carbon-based nanomaterials have shown great promise in regenerative medicine because of their unique electrical, mechanical, and biological properties; however, it is still difficult to engineer 2D pure carbon nanomaterials into a 3D scaffold while maintaining its structural integrity. In the present study, we developed novel carbon nanofibrous scaffolds by annealing electrospun mats at elevated temperature. The resultant scaffold showed a cohesive structure and excellent mechanical flexibility. The graphitic structure generated by annealing renders superior electrical conductivity to the carbon nanofibrous scaffold. By integrating the conductive scaffold with biphasic electrical stimulation, neural stem cell proliferation was promoted associating with upregulated neuronal gene expression level and increased microtubule-associated protein 2 immunofluorescence, demonstrating an improved neuronal differentiation and maturation. The findings suggest that the integration of the conducting carbon nanofibrous scaffold and electrical stimulation may pave a new avenue for neural tissue regeneration. PMID- 28552651 TI - The Gut Microbiota as a Mediator of Metabolic Benefits after Bariatric Surgery. AB - Bariatric surgery is based on major anatomic rearrangements in the gastrointestinal tract that coincide with functional and taxonomic changes in gut microbial communities. These alterations in gut anatomy and in the microbiota are associated with early resolution of obesity-related impairment of glycemic control and are marked weight loss in the long term. Moreover, altered bile acid metabolism has been implicated in the control of energy homeostasis, emerging as a pivotal orchestrator in the gut microbiota-mediated effects of bariatric surgery. In this review, we summarize the growing body of evidence linking changes in the gut microbiota to the metabolic benefits of bariatric surgery and discuss the potential mechanisms involved. PMID- 28552652 TI - Blood Pressure Management in Adults With Type 2 Diabetes: Insights From the Diabetes Mellitus Status in Canada (DM-SCAN) Survey. AB - OBJECTIVES: Optimal treatment of blood pressure (BP) and other cardiovascular risk factors, including hyperglycemia, is integral to diabetes management. There are limited data from the primary care setting concerning the contemporary and comprehensive management of type 2 diabetes and other cardiovascular risk factors in relation to guideline-recommended BP target achievement. METHODS: The Diabetes Mellitus Status in Canada (DM-SCAN) survey included 5172 ambulatory patients with type 2 diabetes. Data were collected on patient demographics, medical histories, medication usage, BP levels and laboratory investigations. We stratified the study population based on their attainment of the BP target recommended by the Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada and the Canadian Hypertension Education Program (<130/80 mmHg) and compared patient clinical characteristics and treatments. RESULTS: Of the 5145 patients with available BP data, 36% achieved the BP target. Prevalence of smoking, known coronary artery disease, retinopathy, neuropathy and nephropathy were similar in the groups with BP 130/80 mmHg or higher and BP 130/80 mmHg or lower. Patients with BP 130/80 mmHg or higher were taking more antihypertensive agents and were more likely to be taking angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers, diuretics and calcium channel blockers. They also had significantly higher glycated hemoglobin and low-density lipoprotein-cholesterol levels. Overall, these patients were also less likely to achieve guideline-recommended glycemic and lipid targets. CONCLUSIONS: Only about one-third of patients with diabetes achieved the target BP of below 130/80 mmHg. Patients with BP 130/80 mmHg or higher were also less likely to achieve optimal guideline-recommended glycated hemoglobin and low-density lipoprotein-cholesterol targets. Improved comprehensive management of all risk factors in patients with diabetes is warranted. PMID- 28552653 TI - High-throughput metaproteomics data analysis with Unipept: A tutorial. AB - In recent years, shotgun metaproteomics has established itself as an important tool to study the composition of complex ecosystems and microbial communities. Two key steps in metaproteomics data analysis are the inference of proteins from the identified peptides, and the determination of the taxonomic origin and function of these proteins. This tutorial therefore introduces the Unipept command line interface (http://unipept.ugent.be/clidocs) as a platform independent tool for such metaproteomics data analyses. First, a detailed overview is given of the available Unipept commands and their functions. Next, the power of the Unipept command line interface is illustrated using two case studies that analyze a single tryptic peptide, and a set of peptides retrieved from a shotgun metaproteomics experiment, respectively. Finally, the analysis results obtained using these command line tools are compared with the interactive taxonomic analysis that is available on the Unipept website. PMID- 28552654 TI - MicroRNA hsa-miR-370-3p suppresses the expression and induction of CYP2D6 by facilitating mRNA degradation. AB - Cytochrome P450 2D6 (CYP2D6) participates in the metabolism of approximately 20 25% of prescribed drugs. Genetic polymorphisms influence the expression and/or activity of CYP2D6, and inter-individual differences in drug activation and elimination caused by CYP2D6 genetic variants were reported. However, little is known about the potential modulation of CYP2D6 expression by microRNAs (miRNAs). In the current study, by using in silico prediction of the stabilities of miRNA/mRNA complexes, we screened 38 miRNA candidates that may interact with the transcript of CYP2D6. An inverse correlation between the expression of miRNA hsa miR-370-3p and the expression of CYP2D6 was observed in human liver tissue samples. Electrophoretic mobility shift assays confirmed that hsa-miR-370-3p was able to directly bind to its cognate target within the coding region of the CYP2D6 transcript. The transfection of hsa-miR-370-3p mimics into the HepG2CYP2D6 cell line, a genetically modified cell line that overexpresses exogenous CYP2D6, was able to suppress the expression of CYP2D6 significantly at both mRNA and protein levels. The transfection of hsa-miR-370-3p mimics was also able to inhibit endogenous mRNA expression and/or protein production of CYP2D6 in HepaRG cells. Furthermore, in HepaRG, HepG2, and Huh7 cells, dexamethasone-induced expression of CYP2D6 was inhibited by hsa-miR-370-3p mimics. To investigate whether the miRNA mediated suppression is caused by inhibiting protein translation or promoting mRNA degradation, an actinomycin D assay was used to measure the stability of CYP2D6 transcripts. The results indicated that hsa-miR 370-3p mimics facilitated significantly the degradation of CYP2D6 mRNA. In addition, proteomics analyses of proteins isolated from the miRNA/mRNA/protein complex suggested that a group of multifunctional proteins facilitated the interaction between hsa-miR-370-3p and CYP2D6, thereby promoting mRNA degradation. PMID- 28552655 TI - Uterine-Sparing Laparoscopic Pelvic Plexus Ablation, Uterine Artery Occlusion, and Partial Adenomyomectomy for Adenomyosis. AB - STUDY OBJECTIVE: To evaluate safety, feasibility, and long-term clinical effects of adding laparoscopic pelvic plexus ablation to uterine-sparing procedures (uterine artery occlusion and partial adenomyomectomy) for adenomyosis. DESIGN: A prospective controlled study (Canadian Task Force classification II-1). SETTING: A teaching hospital. PATIENTS: A total of 112 patients with symptomatic adenomyosis were eligible for uterine-sparing laparoscopy. INTERVENTIONS: Laparoscopic pelvic plexus ablation, uterine artery occlusion, and partial adenomyomectomy. MEASUREMENTS AND MAIN RESULTS: After the exclusion of patients with malignant tumors or those lost to follow-up, 102 women underwent laparoscopic uterine artery occlusion and partial adenomyomectomy; 50 of these patients also had laparoscopic uterine pelvic plexus ablation (group A) with the remaining 52 patients serving as the control group (group B). Other than operative time (107.0 +/- 15.4 vs 98.9 +/- 20.2 minutes, p = .02), there were no statistical differences regarding other operative parameters between groups A and B. Relief of severe dysmenorrhea (Visual Analogue Scale score >= 7) at 36 months was higher in group A than in group B (100% vs 76.9%, p < .01). No patient suffered constipation or uroschesis in either group. CONCLUSION: Adding laparoscopic uterine pelvic plexus ablation to laparoscopic uterine artery occlusion and partial adenomyomectomy was more effective in relieving dysmenorrhea. PMID- 28552656 TI - Prevalence, natural history, and time-dependent outcomes of a multi-center North American cohort of out-of-hospital cardiac arrest extracorporeal CPR candidates. AB - AIM: Estimate prevalence of ECPR-eligible subjects in a large, North American, multi-center cohort, describe natural history with conventional resuscitation, and predict optimal timing of transition to ECPR. METHODS: Secondary analysis of clinical trial enrolling adults with non-traumatic OHCA. Primary outcome was survival to discharge with favorable outcome (mRS 0-3). Subjects were additionally classified as survival with unfavorable outcome (mRS 4-5), ROSC without survival (mRS 6), or without ROSC. We plotted subject accrual as a function of resuscitation duration (CPR onset to return of spontaneous circulation (ROSC) or termination of resuscitation), and estimated time-dependent probabilities of ROSC and mRS 0-3 at discharge. Adjusted logistic regression models tested the association between resuscitation duration and survival with mRS 0-3. RESULTS: Of 11,368 subjects, 1237 (10.9%; 95%CI 10.3-11.5%) were eligible for ECPR, Of these, 778 (63%) achieved ROSC, 466 (38%) survived to discharge, and 377 (30%) had mRS 0-3 at discharge. Half with eventual mRS 0-3 achieved ROSC within 8.8min (95%CI 8.3-9.2min) of resuscitation, and 90% within 21.0min (95%CI 19.1-23.7min). Time-dependent probabilities of ROSC and mRS 0-3 declined over elapsed resuscitation, and the likelihood of additional cases with mRS 0-3 beyond 20min was 8.4% (95%CI 5.9-11.0%). Resuscitation duration was independently associated with survival to discharge with mRS 0-3 (OR 0.95; 95%CI 0.92-0.97). CONCLUSION: Approximately 11% of subjects were eligible for ECPR. Only one-third survived to discharge with favorable outcome. Performing 9-21min of conventional resuscitation captured most ECPR-eligible subjects with eventual mRS 0-3 at hospital discharge. PMID- 28552657 TI - Out-of-hospital cardiac arrests during exercise among urban inhabitants in Japan: Insights from a population-based registry of Osaka City. AB - BACKGROUND: The patient characteristics, pre-hospital interventions, and outcomes of out-of-hospital cardiac arrests (OHCA) occurring during exercise, have not been sufficiently investigated among the general population. METHODS: OHCA data from 2009 to 2015 were obtained from the population-based OHCA registry in Osaka City, Japan. Patients who suffered OHCA, which occurred during exercise before the arrival of emergency medical service personnel, were included. The primary endpoint was one-month survival with a favourable neurological outcome after OHCA, defined using the Glasgow-Pittsburgh cerebral performance category scale 1 or 2. RESULTS: During the 7-year study period, 16,278 OHCAs were observed, and 52 (0.3%) occurred during exercise (male, n=41 [79%]; median age, 62 years). These incidents occurred mainly during running activities (n=14), followed by swimming (n=8), dance/social dance (n=6), tennis (n=4), and weight training (n=3). Within these exercise-related OHCAs, 47 (90%) were of cardiac origin, 45 (87%) were bystander-witnessed cardiac arrests, 49 (94%) received bystander-initiated cardiopulmonary resuscitation, and 30 (57%) received public-access defibrillation (PAD). Overall, 56% (29/52) had one-month survival with a favourable neurological outcome after OHCA, which was significantly higher among OHCAs of cardiac origin with PAD (77%, 23/30) than among those of cardiac origin without PAD (35%, 6/17) and among those of non-cardiac origin (0%, 0/5) (p<0.001). CONCLUSION: In Osaka, OHCAs during exercise represented a small subset of the overall OHCA burden, but occurred during a wide variety of exercise activities. Patients with OHCA of cardiac origin had a good prognosis, and PAD played an important role in improving patient outcomes. PMID- 28552658 TI - Epinephrine dosing interval and survival outcomes during pediatric in-hospital cardiac arrest. AB - BACKGROUND: Current guidelines recommend epinephrine every 3-5min during cardiopulmonary resuscitation. For adults with in-hospital cardiac arrest (IHCA), longer dosing intervals are associated with improved survival to discharge. This study investigates whether longer epinephrine dosing intervals were associated with improved survival to discharge during pediatric IHCA. METHODS: Retrospective review of AHA Get With The Guidelines-Resuscitation registry identified 1630 pediatric IHCAs that met inclusion criteria. Average epinephrine dosing interval was defined by dividing duration of resuscitation after first dose of epinephrine by total doses. Average dosing intervals were categorized as 1-5min, >5 to <8min, and 8 to <10min/dose. Primary outcome was survival to hospital discharge. Multivariable logistic regression models controlled for age, gender, illness category, location of arrest, arrest duration, time of day, and time to first epinephrine dose. Secondary analysis separated patients on vasoactive infusion at the time of arrest from those without an infusion in place. RESULTS: Odds ratios (OR) calculated using 1-5min/dose interval as reference. For the total cohort, adjusted OR for survival to hospital discharge for >5 to <8min was 1.81 (95% CI 1.26-2.59), and 8 to <10min 2.64 (95% CI 1.53-4.55). For patients not receiving vasoactive infusion, adjusted OR for survival to discharge for >5 to <8min was 1.99 (95% CI 1.29-3.06) and 8 to <10min 2.67 (95% CI 1.14-5.04). CONCLUSIONS: Longer average dosing intervals than currently recommended for epinephrine administration during pediatric IHCA were associated with improved survival to hospital discharge. PMID- 28552659 TI - Antimicrobial activity evaluation and comparison of methods of susceptibility for Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacter spp. isolates. AB - The production of KPC (Klebsiella pneumoniae carbapenemase) is the major mechanism of resistance to carbapenem agents in enterobacterias. In this context, forty KPC-producing Enterobacter spp. clinical isolates were studied. It was evaluated the activity of antimicrobial agents: polymyxin B, tigecycline, ertapenem, imipenem and meropenem, and was performed a comparison of the methodologies used to determine the susceptibility: broth microdilution, Etest(r) (bioMerieux), Vitek 2(r) automated system (bioMerieux) and disc diffusion. It was calculated the minimum inhibitory concentration (MIC) for each antimicrobial and polymyxin B showed the lowest concentrations for broth microdilution. Errors also were calculated among the techniques, tigecycline and ertapenem were the antibiotics with the largest and the lower number of discrepancies, respectively. Moreover, Vitek 2(r) automated system was the method most similar compared to the broth microdilution. Therefore, is important to evaluate the performance of new methods in comparison to the reference method, broth microdilution. PMID- 28552660 TI - Technology and safety assessment for lactic acid bacteria isolated from traditional Bulgarian fermented meat product "lukanka". AB - The present work discusses the technological and new selection criteria that should be included for selecting lactic acid bacteria for production of fermented meat. Lactic acid bacteria isolated from Bulgarian traditional fermented "lulanka" salami was studied regarding some positive technological parameters (growth at different temperature, pH, and proteolytic activity). The presence of genes related to the virulence factors, production of biogenic amines, and vancomycin resistance were presented in low frequency in the studied lactic acid bacteria. On the other hand, production of antimicrobial peptides and high spread of bacteriocin genes were broadly presented. Very strong activity against L. monocytogenes was detected in some of the studied lactic acid bacteria. In addition, the studied strains did not present any antimicrobial activity against tested closely related bacteria such as Lactobacillus spp., Lactococcus spp., Enterococcus spp. or Pediococcus spp. To our knowledge this is the first study on the safety and antimicrobial properties of lactic acid bacteria isolated from Bulgarian lukanka obtained by spontaneous fermentation. PMID- 28552661 TI - 30years of DXA technology innovations. AB - As the successor of Dual Photon Absorptiometry (DPA), Dual X-ray Absorptiometry (DXA) has seen 30years of continuous technological innovations. Implementation of measures for standardization and quality assurance made DXA a reliable and clinically useful approach. Its use in clinical multicenter drug studies in osteoporosis lead to general acceptance as the standard technique of bone densitometry. The limitations of DXA are well established. As a measure of areal bone mineral density (aBMD) it depends on bone size and is biased by overlaying soft tissue and calcified structures. To some extent these errors can be reduced by estimation of bone depth and/or lateral imaging. DXA based aBMD can be supplemented by additional information obtainable from DXA scans: geometric indices such as hip axis length or complex models like 2-D finite element analysis have been developed and tested. Given the drastic improvement in image quality current DXA scans can be used for Vertebral Fracture Analysis (VFA) or grading of Abdominal Aortic Calcifications. A textural measure, Trabecular Bone Score (TBS) provides independent information on fracture risk. DXA devices can also be used for assessments beyond bone density. Periprosthetic aBMD changes can be monitored to study the mechanical fitting of bone implants. Total body composition measurements are increasingly being used in studies on nutrition, obesity, and sarcopenia. 30years after its inception DXA is the undisputed standard imaging technique for the assessment of osteoporotic fracture risk with new applications beyond bone densitometry adding to its value. PMID- 28552662 TI - Misdiagnosis of vertebral fractures: Unresolved but resolvable problem. PMID- 28552663 TI - Sex differences in the neuroendocrine control of metabolism and the implication of astrocytes. AB - Males and females have distinct propensities to develop obesity and its related comorbidities, partially due to gonadal steroids. There are sex differences in hypothalamic neuronal circuits, as well as in astrocytes, that participate in metabolic control and the development of obesity-associated complications. Astrocytes are involved in nutrient transport and metabolism, glucose sensing, synaptic remodeling and modulation of neuronal signaling. They express receptors for metabolic hormones and mediate effects of these metabolic signals on neurons, with astrogliosis occurring in response to high fat diet and excess weight gain. However, most studies of obesity have focused on males. Recent reports indicate that male and female astrocytes respond differently to metabolic signals and this could be involved in the differential response to high fat diet and the onset of obesity-associated pathologies. Here we focus on the sex differences in response to obesogenic paradigms and the possible role of hypothalamic astrocytes in this phenomenon. PMID- 28552664 TI - Saccharomyces cerevisiae cells lacking Pex3 contain membrane vesicles that harbor a subset of peroxisomal membrane proteins. AB - Pex3 has been proposed to be important for the exit of peroxisomal membrane proteins (PMPs) from the ER, based on the observation that PMPs accumulate at the ER in Saccharomyces cerevisiae pex3 mutant cells. Using a combination of microscopy and biochemical approaches, we show that a subset of the PMPs, including the receptor docking protein Pex14, localizes to membrane vesicles in S. cerevisiae pex3 cells. These vesicles are morphologically distinct from the ER and do not co-sediment with ER markers in cell fractionation experiments. At the vesicles, Pex14 assembles with other peroxins (Pex13, Pex17, and Pex5) to form a complex with a composition similar to the PTS1 import pore in wild-type cells. Fluorescence microscopy studies revealed that also the PTS2 receptor Pex7, the importomer organizing peroxin Pex8, the ubiquitin conjugating enzyme Pex4 with its recruiting PMP Pex22, as well as Pex15 and Pex25 co-localize with Pex14. Other peroxins (including the RING finger complex and Pex27) did not accumulate at these structures, of which Pex11 localized to mitochondria. In line with these observations, proteomic analysis showed that in addition to the docking proteins and Pex5, also Pex7, Pex4/Pex22 and Pex25 were present in Pex14 complexes isolated from pex3 cells. However, formation of the entire importomer was not observed, most likely because Pex8 and the RING proteins were absent in the Pex14 protein complexes. Our data suggest that peroxisomal membrane vesicles can form in the absence of Pex3 and that several PMPs can insert in these vesicles in a Pex3 independent manner. PMID- 28552665 TI - Functional morphology of comminuting feeding structures of Trichodactylus borellianus (Brachyura, Decapoda, Trichodactylidae), an omnivorous freshwater crab. AB - Crustaceans exhibit great diversity of feeding structures with morphological traits that are useful to infer the general trophic habits of species. In this study, we analyzed the functional morphology of comminuting feeding structures (mandibles, chelipeds, gastric mill) of the freshwater crab Trichodactylus borellianus directly related with the food fragmentation. The heterochely and mechanical advantage (MA) of the chelae were also studied. In both analyses, we considered the relationship between morphology and the natural diet. We expected to find a consistent relation between feeding habits and morphological traits. In general, we found simple structures armed with uniform setal systems and feeding appendages without pronounced teeth or spines. Mandibles have primarily cutting functions, helping with the food anchoring and fragmentation with mandibular palps armed with pappose setae. Chelipeds were covered with spines and simple setae. Adult males exhibited right-handedness with high MA of the major chelae. The ingested, relatively large pieces of food are finally chewed by a gastric mill equipped with sharp cusps characteristic of decapods with low ingestion of crude fiber material. The morphology of the feeding apparatus revealed that it is well adapted to an omnivorous diet, being able to cope with dietary changes. PMID- 28552666 TI - Effects of force detecting sense organs on muscle synergies are correlated with their response properties. AB - Sense organs that monitor forces in legs can contribute to activation of muscles as synergist groups. Previous studies in cockroaches and stick insects showed that campaniform sensilla, receptors that encode forces via exoskeletal strains, enhance muscle synergies in substrate grip. However synergist activation was mediated by different groups of receptors in cockroaches (trochanteral sensilla) and stick insects (femoral sensilla). The factors underlying the differential effects are unclear as the responses of femoral campaniform sensilla have not previously been characterized. The present study characterized the structure and response properties (via extracellular recording) of the femoral sensilla in both insects. The cockroach trochantero-femoral (TrF) joint is mobile and the joint membrane acts as an elastic antagonist to the reductor muscle. Cockroach femoral campaniform sensilla show weak discharges to forces in the coxo-trochanteral (CTr) joint plane (in which forces are generated by coxal muscles) but instead encode forces directed posteriorly (TrF joint plane). In stick insects, the TrF joint is fused and femoral campaniform sensilla discharge both to forces directed posteriorly and forces in the CTr joint plane. These findings support the idea that receptors that enhance synergies encode forces in the plane of action of leg muscles used in support and propulsion. PMID- 28552667 TI - Lenalidomide acts as an adjuvant for HCV DNA vaccine. AB - Hepatitis C virus (HCV) is a blood-borne pathogen which has chronically infected people worldwide. Therefore, it is of utmost importance to design prophylactic and therapeutic vaccine in order to control HCV infection. To date, several researchers have attempted to improve the efficiency of HCV vaccine by using different adjuvants. However, a few studies have focused on the synthetic immunomodulatory drugs as adjuvants for HCV vaccine. Recently, researchers have shown that lenalidomide, which is used to treat the patients with multiple myeloma, is capable of improving the immune system factors. In this paper, two doses of lenalidomide along with pcDNA3.1+NS3 as HCV DNA vaccine were administrated in mice models and the percentage of regulatory T cells (Treg cells) and the cells with PD-1+ expression in spleen of mice model were investigated by flow cytometry method. Additionally, activities of CTL cells and NK cells were evaluated in spleen of prophylactic and therapeutic mice models via LDH method. Results of the Treg and PD-1 analysis showed that low dose of lenalidomide along with pcDNA3.1+NS3 can noticeably decrease the percentage of Treg cells and the cells with PD-1+ expression, while lenalidomide can significantly increase the CTL and NK activity in mice models. Also, results of the therapeutic mice model, in which SP2/0 cells- challenged mice were treated with 5mg/kg lenalidomide in combination with pcDNA3.1+NS3, reasonably agreed with those of the prophylactic model. Finally, it was found that lenalidomide can reduce the level of Treg cells which results in lower the cells with PD-1+ expression and subsequently higher CTL and NK cell activities. This study concluded that lenalidomide possess the characteristics of an ideal adjuvant candidate for use in combination with HCV DNA vaccine in order to promote the immune response and vaccine efficiency. PMID- 28552669 TI - Psychometric properties of the Kids' Child Feeding Questionnaire-Restriction. AB - BACKGROUND: Research exploring parental restrictive feeding is mixed and shows that it both negatively and positively affects children's dietary intake. One hypothesis for these inconsistent findings is the use of parent-report vs. youth report measures of parental restrictive feeding, but there are limited psychometrically-sound youth-report measures of this construct. Therefore, the current study aims to evaluate the psychometric properties of a measure of parent restrictive feeding practices, the Kids' Child Feeding Questionnaire-Restriction (KCFQ-R), from the youth perspective. METHODS: The 7-item, youth-report KCFQ-R is composed of the restriction subscale from the Kids' Child Feeding Questionnaire. This measure was completed by 225 youth attending a primary care appointment. RESULTS: Initial exploratory factor analysis and communalities yielded a single factor solution explaining 39.93% of the variability in the data. Internal consistency using the seven items was .73. The KCFQ-R demonstrated external validity through its significant relationship with parent concern about child overweight. CONCLUSIONS: Results provide preliminary support that the KCFQ-R is a psychometrically sound and reliable measure of youth-reported parental restrictive feeding practices. Given the mixed research on the effects of parent reported parental feeding restriction on various child outcomes, this youth report measure may help clarify these relationships. Future research should examine youth-report measures of other parent feeding domains. PMID- 28552668 TI - beta1-Integrin Accumulates in Cystic Fibrosis Luminal Airway Epithelial Membranes and Decreases Sphingosine, Promoting Bacterial Infections. AB - Chronic pulmonary colonization with bacterial pathogens, particularly Pseudomonas aeruginosa, is the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). We observed that beta1-integrins accumulate on the luminal membrane of upper-airway epithelial cells from mice and humans with CF. beta1 integrin accumulation is due to increased ceramide and the formation of ceramide platforms that trap beta1-integrins on the luminal pole of bronchial epithelial cells. beta1-integrins downregulate acid ceramidase expression, resulting in further accumulation of ceramide and consequent reduction of surface sphingosine, a lipid that kills bacteria. Interrupting this vicious cycle by triggering surface beta1-integrin internalization via anti-beta1-integrin antibodies or the RGD peptide ligand-or by genetic or pharmacological correction of ceramide levels normalizes beta1-integrin distribution and sphingosine levels in CF epithelial cells and prevents P. aeruginosa infection in CF mice. These findings suggest a therapeutic avenue to ameliorate CF-associated bacterial infections. PMID- 28552670 TI - Altered brain correlates of response inhibition and error processing in females with obesity and sweet food addiction: A functional magnetic imaging study. AB - BACKGROUND: The aim of the present study was to evaluate the impulsivity and brain correlates of response inhibition and error processing among females with obesity and sweet food addiction (O & SFA). METHODS: We evaluated the response inhibition and error processing by functional magnetic resonance imaging (fMRI) in subjects with O & SFA and controls. Twenty females with O & SFA and 20 controls were recruited. All subjects performed the event-related designed Go/No go task under fMRI and completed questionnaires related to food craving and impulsivity. RESULTS: The O & SFA group exhibited a higher score for impulsivity than did the control group. The O & SFA also exhibited lower brain activation when processing response inhibition over the right rolandic operculum and thalamus than controls. Both O & SFA and control groups exhibited activation of the insula and caudate during error processing. The activation over the left insula, precuneus, and bilateral putamen were higher in the subjects with O & SFA than for those in the control group. CONCLUSION: Our results support the fact that the fronto-striatal network is involved in response inhibition, and the caudate and insula contributes to error processing. Furthermore, women with O & SFA have impaired rolandic operculum when processing response inhibition and have greater insular and putamen activation in maintain their error processing function. PMID- 28552671 TI - Morbid obesity and psoriasis: Disease remission after laparoscopic sleeve gastrectomy. AB - Psoriasis is more frequent and severe in populations with obesity, and both have been associated with a higher cardiovascular risk. Recent studies suggest that weight loss may improve psoriasis and metabolic comorbidities in individuals with obesity. We present a case of a female patient affected by psoriasis, morbid obesity and other metabolic comorbidities, who experienced dramatic improvement in skin and joint symptoms and metabolic parameters after weight loss surgery with sleeve gastrectomy. PMID- 28552672 TI - Possible involvement of CREB/BDNF signaling pathway in neuroprotective effects of topiramate against methylphenidate induced apoptosis, oxidative stress and inflammation in isolated hippocampus of rats: Molecular, biochemical and histological evidences. AB - Chronic abuse of methylphenidate (MPH) can cause serious neurotoxicity. The neuroprotective effects of topiramate (TPM) were approved, but its putative mechanism remains unclear. In current study the role of CREB/BDNF signaling pathway in TPM protection against methylphenidate-induced neurotoxicity in rat hippocampus was evaluated. 60 adult male rats were divided randomly into six groups. Groups received MPH (10mg/kg) only and concurrently with TPM (50mg/kg and 100mg/kg) and TPM (50 and 100mg/kg) only for 14 days. Open field test (OFT) was used to investigate motor activity. Some biomarkers of apoptotic, anti-apoptotic, oxidative, antioxidant and inflammatory factors were also measured in hippocampus. Expression of total (inactive) and phosphorylated (active) CREB and BDNF were also measured in gene and protein levels in dentate gyrus (DG) and CA1 areas of hippocampus. MPH caused significant decreases in motor activity in OFT while TPM (50 and 100mg/kg) inhibited MPH-induced decreases in motor activity. On the other hand, MPH caused remarkable increases in Bax protein level, lipid peroxidation, catalase activity, IL-1beta and TNF-alpha levels in hippocampal tissue. MPH also caused significant decreases of superoxide dismutase, activity and also decreased CREB, in both forms, BDNF and Bcl-2 protein levels. TPM, by the mentioned doses, attenuated these effects and increased superoxide dismutase, glutathione peroxidase and glutathione reductase activities and also increased CREB, in both forms, BDNF and Bcl-2 protein levels and inhibited MPH induced increase in Bax protein level, lipid peroxidation, catalase activity, IL-1beta and TNF-alpha levels. TPM also inhibited MPH induced decreases in cell number and changes in cell shapes in DG and CA1 areas. TPM can probably act as a neuroprotective agent against MPH induced neurotoxicity and this might have been mediated by CREB/BDNF signaling pathway. PMID- 28552673 TI - Neuroprotective effects of sulfiredoxin-1 during cerebral ischemia/reperfusion oxidative stress injury in rats. AB - As an endogenous antioxidant protein, Sulfiredoxin1 (Srxn1) can prevent cell oxidative stress damage. However, its role in cerebral ischemia/reperfusion (I/R) injury and the underlying signaling mechanisms remain largely unknown. Here, we explored effects of Srxn1 knockdown on oxidative stress using in vitro and in vivo I/R models and investigated related neuroprotective mechanisms. For in vitro studies, primary cortical neuronal cultures were transfected with an interfering lentivirus targeting Srxn1. Oxygen-glucose deprivation (OGD) was conducted after Srxn1 knockdown. MTS and lactate dehydrogenase assays indicated that knockdown of Srxn1 increased cell death and reduced cell viability. Similarly, superoxide dismutase (SOD) and reduced glutathionekits assays showed that knockdown of Srxn1 worsened oxidative stress injury. For in vivo studies, siRNA for Srxn1 or negative control siRNA was injected intracerebroventricularly 24h before middle cerebral artery occlusion (MCAO). Data shows silencing Srxn1 resulted in a significant increase in cerebral infarction, neurological deficits, histological injury, and oxidative stress injury 24h after ischemic stroke. Moreover, immunoblot analysis assessed the relationship between Srxn1 levels and Prdx1-4 as well as Prdx-SO3 activity both in vitro and in vivo models. We found that decreased Srxn1 reduced Prdx1-4 and enhanced Prdx-SO3 protein levels. In addition, knockdown of Nrf2 was performed; immunoblot analysis was used to measure Srxn1 and NQO1 protein levels. We further found that interference of Nrf2 reduced Srxn1 and NQO1 protein levels. In summary, Srxn1 can protect neurons from I/R oxidative stress injury and the mechanism involves Prdx activity. Srxn1, which might be downstream of Nrf2, can prevent cerebral ischemia reperfusion by reversing overoxidized Prdx and restoring antioxidant activity of Prdx. PMID- 28552675 TI - The era of 3Rs implementation in developmental and reproductive toxicity (DART) testing: Current overview and future perspectives. AB - Since adoption of the first globally implemented guidelines for developmental and reproductive toxicity (DART) testing for pharmaceuticals, industrial chemicals and agrochemicals, many years passed without major updates. However in recent years, significant changes in these guidelines have been made or are being implemented. These changes have been guided by the ethical drive to reduce, refine and replace (3R) animal testing, as well as the addition of endocrine disruptor relevant endpoints. Recent applied improvements have focused on reduction and refinement. Ongoing scientific and technical innovations will provide the means for replacement of animal testing in the future and will improve predictivity in humans. The aim of this review is to provide an overview of ongoing global DART endeavors in respect to the 3Rs, with an outlook towards future advances in DART testing aspiring to reduce animal testing to a minimum and the supreme ambition towards animal-free hazard and risk assessment. PMID- 28552674 TI - Enrichment increases hippocampal neurogenesis independent of blood monocyte derived microglia presence following high-dose total body irradiation. AB - Birth of new neurons in the hippocampus persists in the brain of adult mammals and critically underpins optimal learning and memory. The process of adult neurogenesis is significantly reduced following brain irradiation and this correlates with impaired cognitive function. In this study, we aimed to compare the long-term effects of two environmental paradigms (i.e. enriched environment and exercise) on adult neurogenesis following high-dose (10Gy) total body irradiation. When housed in standard (sedentary) conditions, irradiated mice revealed a long-lasting (up to 4 months) deficit in neurogenesis in the granule cell layer of the dentate gyrus, the region that harbors the neurogenic niche. This depressive effect of total body irradiation on adult neurogenesis was partially alleviated by exposure to enriched environment but not voluntary exercise, where mice were single-housed with unlimited access to a running wheel. Exposure to voluntary exercise, but not enriched environment, did lead to significant increases in microglia density in the granule cell layer of the hippocampus; our study shows that these changes result from local microglia proliferation rather than recruitment and infiltration of circulating Cx3cr1+/gfp blood monocytes that subsequently differentiate into microglia-like cells. In summary, latent neural precursor cells remain present in the neurogenic niche of the adult hippocampus up to 8 weeks following high-dose total body irradiation. Environmental enrichment can partially restore the adult neurogenic process in this part of the brain following high-dose irradiation, and this was found to be independent of blood monocyte-derived microglia presence. PMID- 28552676 TI - Common allergies do not influence the prevalence of cutaneous hypersensitivity reactions to antiepileptic drugs. AB - OBJECTIVE: The aim of the study was to establish whether the presence of common allergies increases the risk of drug-related hypersensitivity reactions among patients with epilepsy treated with antiepileptic drugs (AEDs). METHODS: We studied 753 patients with epilepsy seen in tertiary outpatient epilepsy clinic. We obtained data related to epilepsy type, past and ongoing treatment with AEDs, occurrence of maculopapular exanthema or more serious cutaneous adverse reactions (Stevens-Johnson syndrome - SJS) and their characteristics. We noted an occurrence of allergic reactions unrelated to treatment with AED, including rash unrelated to AED, bronchial asthma, persistent or seasonal allergic rhinitis, atopic dermatitis, rash after specific food and other allergic reactions. RESULTS: There were 61 cases of AED-related cutaneous hypersensitivity reaction (including 3 cases of SJS) noted in association with 2319 exposures to AEDs (2.63%) among 55 out of 753 patients (7.3%). Cutaneous hypersensitivity reaction to AED was most commonly noted after lamotrigine (12.1%), carbamazepine (5.4%) and oxcarbazepine (4.1%). Prevalence of allergic reactions unrelated to AED was similar between patients with and without AED-related cutaneous hypersensitivity reaction (rash unrelated to AED: 16.4% vs. 10.2%; bronchial asthma: 1.8% vs. 0.1%; persistent allergic rhinitis: 7.3% vs. 10.2%; seasonal allergic rhinitis: 7.3% vs. 11.7%; atopic dermatitis: 0 vs. 0.7%; rash after specific food: 5.4% vs. 6.4%; other allergic reactions: 5.4% vs. 5.2%, respectively; P>0.1 for each difference). CONCLUSIONS: Presence of common allergies is not a significant risk factor for AED-related cutaneous hypersensitivity reaction among patients with epilepsy. PMID- 28552677 TI - A long term follow-up study of the development of hip disease in Mucopolysaccharidosis type VI. AB - Hip problems in Mucopolysaccharidosis type VI (MPS VI) lead to severe disability. Lack of data on the course of hip disease in MPS VI make decisions regarding necessity, timing and type of surgical intervention difficult. We therefore studied the development of hip pathology in MPS VI patients over time. Data were collected as part of a prospective follow-up study. Standardized supine AP pelvis and frog leg lateral radiographs of both hips were performed yearly or every 2years. Image assessment was performed quantitatively (angle measurements) and qualitatively (hip morphology). Clinical burden of hip disease was evaluated by physical examination, six minute walking test (6MWT) and a questionnaire assessing pain, wheelchair-dependency and walking distance. A total of 157 pelvic radiographs of 14 ERT treated MPS VI patients were evaluated. Age at first image ranged from 2.0 to 21.1years. Median follow up duration was 6.8years. In all patients, even in the youngest, the acetabulum and os ilium were dysplastic. Coverage of the femoral head by the acetabulum improved over time, but remained insufficient. While the femoral head appeared normal in the radiographs at young age, the ossification pattern became abnormal in all patients over time. In all patients the distance covered in the 6MWT was reduced (median Z scores -3.3). Twelve patients had a waddling gait. Four patients were partially wheelchair dependent and ten patients had limitations in their maximum walking distance. In conclusion, clinically significant hip abnormalities develop in all MPS VI patients from very early in life, starting with deformities of the os ilium and acetabulum. Femoral head abnormalities occur later, most likely due to altered mechanical forces in combination with epiphyseal abnormalities due to glycosaminoglycan storage. The final shape and angle of the femoral head differs significantly between individual MPS VI patients and is difficult to predict. PMID- 28552678 TI - Detection of 6-demethoxyubiquinone in CoQ10 deficiency disorders: Insights into enzyme interactions and identification of potential therapeutics. AB - Coenzyme Q10 (CoQ10) is an essential cofactor of the mitochondrial oxidative phosphorylation (OXPHOS) system and its deficiency has important implications for several inherited metabolic disorders of childhood. The biosynthesis of CoQ10 is a complicated process, which involves at least 12 different enzymes. One of the metabolic intermediates that are formed during CoQ10 biosynthesis is the molecule 6-demethoxyubiquinone (6-DMQ). This CoQ precursor is processed at the level of COQ7 and COQ9. We selected this metabolite as a marker substance for metabolic analysis of cell lines with inherited genetic defects (COQ2, COQ4, COQ7 and COQ9) or siRNA knockdown in CoQ biosynthesis enzymes using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). In COQ4, COQ7 and COQ9 deficient cell lines, we detected significantly elevated levels of 6 DMQ. This suggests a functional interplay of these proteins. However, additional siRNA studies demonstrated that elevated 6-DMQ levels are not an exclusive marker of the COQ7/COQ9 enzymatic step of CoQ10 biosynthesis but constitute a more general phenomenon that occurs in disorders impairing the function or stability of the CoQ-synthome. To further investigate the interdependence of CoQ10 biosynthesis enzyme expression, we performed immunoblotting in various cell lines with CoQ10 deficiency, indicating that COQ4, COQ7 and COQ9 protein expression levels are highly regulated depending on the underlying defect. Supplementation of cell lines with synthetic CoQ precursor compounds demonstrated beneficial effects of 2,4-dihydroxybenzoic acid in COQ7 and COQ9 deficiency. Moreover, vanillic acid selectively stimulated CoQ10 biosynthesis and improved cell viability in COQ9 deficiency. However, compounds tested in this study failed to rescue COQ4 deficiency. PMID- 28552679 TI - Informational needs and recall of in-hospital medication changes of recently discharged patients. AB - PURPOSE: The need for information for patients and caregivers at the point of hospital discharge is paramount and potentially extensive. OBJECTIVE: The objective of this study was to assess patients' informational needs at hospital discharge, patients' recall of medication changes implemented in the hospital and patients' medication related problems experienced one week after hospital discharge. METHODS: The study was conducted in a teaching hospital where patients received structured discharge counseling. Patients were interviewed at hospital discharge regarding their informational needs. One week post-discharge, patients were interviewed by phone to assess any changes in informational needs, their recall regarding in-hospital medication changes and the medication related problems. Descriptive analysis and logistic regression were used to address study objectives. RESULTS: The 124 patients in the study regarded the following topics as most relevant for counseling: what the medicine is for (57%), side effects (52%), drug-drug interactions (45%), action of the drug (37%) and reimbursement (31%). In 9% of patients the informational needs changed post-discharge, e.g. the topic side effects increased in importance. Forty-nine percent could recall whether and which medication was changed during hospitalization. Medication related problems and side effects were reported by respectively 27% and 15% of patients, whereas only 7% contacted their doctor or pharmacist. CONCLUSIONS: Patients' informational needs are very individual and can change post-discharge. Despite structured counseling, only half of the patients were able to recall the medication changes implemented in the hospital. Furthermore, patients reported several problems for which they did not consult a healthcare provider. This insight could help in smoothing the transition from hospital to the primary care setting. PMID- 28552680 TI - Community pharmacy modifications to non-prescription medication requests: A simulated patient study. AB - BACKGROUND: Self-care, and hence self-medication, is becoming an increasingly popular practice worldwide. Community pharmacies are an important destination for those seeking non-prescription medicines, and pharmacists and their staff are in a prime position to facilitate appropriate and safe self-medication. PURPOSE: To determine what modifications (for example, a change in brand, change in drug, or non-supply) pharmacy staff make when presented with a request for a non prescription medicine, and to determine what factors influence whether a modification is made. METHODS: Sixty-one third year Bachelor of Pharmacy students from The University of Sydney were trained as mystery shoppers to make 9 visits once a week to 36 community pharmacies in the metropolitan region of Sydney, Australia from March-October 2015. Students presented to a different, pre allocated pharmacy once a week with a direct product request for a non prescription medicine relating to a common ailment (e.g. asthma, insomnia, allergic rhinitis) for 9 weeks. Student mystery shoppers audio-recorded each visit and collected the details of the interaction and product sold. Descriptive statistics, chi-squared analyses, and binary logistic regression were performed to find factors influencing modifications made by pharmacy staff to the simulated patient initial request. RESULTS: Of 540 completed visits, 497 were eligible for analysis. Modification (change in brand, intra/interclass change, companion sale, or no product supplied) occurred in 49% (n = 245) of visits. Whether the product requested was deemed "not appropriate" given the scenario outline was the only significant predictor of whether a modification to the request occurred (42% modification, "appropriate" scenarios vs. 57% modification, "not appropriate" scenarios; chi2 = 8.90; p < 0.01). CONCLUSIONS: Modification from the original non-prescription medicine request occurred in approximately half the reported requests. A request for a product that was considered "not appropriate" was more likely to elicit a modification than a request for an "appropriate" non prescription medicine. PMID- 28552681 TI - Evaluation of quality indicator instruments for pharmaceutical care services: A systematic review and psychometric properties analysis. PMID- 28552682 TI - Quantitative proteomic analysis revealed changes in protein synthesis and mitochondrial functions after acute DNA damage in mouse neural stem cells. AB - Considering the accumulation of DNA damages are frequently associated with neurodevelopmental disease, neurodegeneration, and brain tumors, exploration of the molecular mechanisms in mouse neural stem cells (NSCs) after DNA damage would be paramount useful for understanding the pathogenesis of these diseases. In present study, we utilized hydroxyurea (HU) treatment to cultured mouse NSCs to induce acute DNA damages. After HU treatment, mouse NSCs displayed elevated reactive oxygen species (ROS) level and compromised DNA repair in HR and NHEJ pathways. Furthermore, we performed quantitative proteomic analysis to unravel the protein variations. GO analysis and IPA suggested proteins participated in protein synthesis, mitochondrial metabolism and oxidative phosphorylation were under great changes after acute DNA damage. Overall, these data provide valuable insight into the molecular and biological changes in NSCs in the circumstance of acute DNA damage, and will help to discover the connections between DNA damage and potential diseases in brain. PMID- 28552683 TI - [Paralysis of the abdominal muscles after herpes zoster. Case series]. PMID- 28552684 TI - [Primary care in Italy]. AB - Italy is not a country where Spanish doctors emigrate, as there is an over-supply of health care professionals. The Italian Servizio Sanitario Nazionale has some differences compared to the Spanish National Health System. The Servizio Sanitario Nazionale is financed by national and regional taxes and co-payments. There are taxes earmarked for health, and Primary Care receives 50% of the total funds. Italian citizens and residents in Italy have the right to free health cover. However, there are co-payments for laboratory and imaging tests, pharmaceuticals, specialist ambulatory services, and emergencies. Co-payments vary in the different regions. The provision of services is regional, and thus fragmentation and major inequities are the norm. Doctors in Primary Care are self employed and from 2000 onwards, there are incentives to work in multidisciplinary teams. Salary is regulated by a national contract and it is the sum of per-capita payments and extra resources for specific activities. Responsibilities are similar to those of Spanish professionals. However, medical care is more personal. Relationships between Primary Care and specialised care depend on the doctors' relationships. Primary Care doctors are gatekeepers for specialised care, except for gynaecology, obstetrics and paediatrics. Specialised training is compulsory in order to work as general practitioner. The Italian Health Care System is a national health system like the Spanish one. However, health care professionals are self-employed, and there are co-payments. In spite of co payments, Italians have one of the highest average life expectancy, and they support a universal and publicly funded health-care system. PMID- 28552685 TI - [Comment on the Letter to the Editor on "Non-steroidal anti-inflammatory drugs (NSAIDs) and fertility"]. PMID- 28552686 TI - [Eosinophilic panniculitis associated with low complement and a paraproteinaemia]. PMID- 28552687 TI - [Self-assessment of opinions, habits and oral health status by pregnant women in the south of Galicia, Spain]. AB - An association has been found between oral health problems and obstetric complications during pregnancy. The main aim of this study was to assess the perception by pregnant women on their oral health and related habits and beliefs. A questionnaire was designed in order to obtain information from 96 pregnant women attending the Valdeorras Local Hospital and the primary health dental practice in the Valle Inclan Health Center. It was found that many pregnant women perceived they were suffering from some kind of problem affecting their mouth. It was shown that pregnant women had adequate habits regarding oral health, but they believed that their pregnancy would implicitly cause them to have mouth problems. Pregnant women are able to understand the impact of their oral health on their general well-being and the health of their unborn child. It has been detected that a series of habits and beliefs would ideally need to be acted upon in order to reduce health problems. PMID- 28552688 TI - [Isolated haemoptysis in a non-smoker patient]. PMID- 28552689 TI - IL-10 gene polymorphism c.-592C>A increases HPV infection susceptibility and influences IL-10 levels in HPV infected women. AB - Interleukin-10 (IL-10) influences HPV infection and viral persistence, favoring cervical immunosuppression and cervical carcinogenesis. IL-10 levels may be influenced by HPV itself and by IL-10 polymorphisms, including rs1800872 (c. 592C>A). Therefore, we evaluated the influence of IL-10 c.-592C>A polymorphism in HPV infection and in IL-10 plasmatic/cervical levels in HPV infected and non infected women. The study included 174 infected and 186 non-infected patients. Cervical epithelial scrapings were obtained to determine HPV DNA presence PCR. Peripheral blood samples were obtained to determine IL-10 polymorphism by PCR RFLP, while IL-10 levels were assessed by ELISA. HPV was more prevalent among allele A carriers (p<0.001), with IL-10 c.-592C>A polymorphism being associated with HPV infection. As demonstrated by binary logistic regression analysis, heterozygotes [ORadj=2.081 95% CI (1.222-3.544), p=0.007] and homozygotes [ORadj=3.745 95% CI (1.695-8.271), p=0.001] showed approximately 2 and 4 time's greater odds, respectively, of presenting HPV when compared to CC patients. Moreover, HPV infected patients carrying polymorphic allele A showed higher IL-10 cervical levels (p=0.039). Binary logistic regression analysis demonstrated that IL-10 cervical levels were not independently associated to CA+AA genotypes (p=0.162), neither to HPV's presence (p=0.061), thus IL-10 cervical levels are possibly increased because of both HPV and allele A presence. Taken together, these findings suggest that IL-10 c.-592C>A polymorphism is independently associated with HPV infection susceptibility exerting influence on IL-10 cervical levels in HPV infected women, thus contributing to cervical carcinogenesis. PMID- 28552690 TI - Coloaded Nanoparticles of Paclitaxel and Piperlongumine for Enhancing Synergistic Antitumor Activities and Reducing Toxicity. AB - The purpose of this study was to develop a nanocarrier system for codelivery of paclitaxel (PTX) and piperlongumine (PL) and investigate the therapeutic potential of improving efficacy and reducing toxicity. PTX and PL were formulated into poly lactic-co-glycolic acid and D-alpha-tocopheryl polyethylene glycol succinate via organic solvent evaporation method. The average diameter was 117.1 +/- 1.9 nm, and the zeta potential was -43.25 +/- 2.76 mV. PL facilitated the cellular uptake of PTX, and the increased cytotoxicity was similarly displayed. The formulation with the PTX/PL concentration ratio at 1:200 showed the best antitumor activity, the IC50 of PTX were 5.10 +/- 0.08 nM in HepG2 cells, and 3.79 +/- 1.01 nM in Michigan Cancer Foundation-7 cells. Correspondingly, the combination index was 0.79 and 0.76. Furthermore, intracellular uptake of PTX toward HepG2 cells in coencapsulated nanoparticles was significantly more than free solution. In addition, the antitumor effect of PTX/PL-PTNPs in the HepG2 xenograft tumor model suggested that the nanoparticles showed a higher antitumor efficacy with reduced toxicity to other tissues compared with free PTX. In summary, the results indicated that PTX/PL-PTNPs processed well characteristics and enhanced its therapeutic efficacy; thus, this delivery system could be clinically effective for treatment of cancers. PMID- 28552691 TI - Identification of Bile Acids Responsible for Inhibiting the Bile Salt Export Pump, Leading to Bile Acid Accumulation and Cell Toxicity in Rat Hepatocytes. AB - Inhibition of bile salt export pump (BSEP) causes hepatic accumulation of toxic bile acid (BA), leading to hepatocyte death. We reported a sandwich-cultured hepatocyte (SCH)-based model that can estimate potential cholestatic compounds by assessing their ability to induce hepatotoxicity in combination with a titrated amount of human 12 BA species. However, there is little information about the specific BAs responsible for hepatotoxicity, when BSEP is inhibited. This study measured the accumulation of each BA in rat SCHs in the presence of 10 MUM cyclosporine A (CsA), which only inhibits BSEP, and 50 MUM CsA, which further inhibits basolateral BA efflux transporters. The accumulation of all BAs (not significant for deoxycholic acid [DCA]) was observed in the presence of 10 MUM CsA. In particular, 3 BAs (chenodeoxycholic acid [CDCA], DCA, and glyco-DCA [GDCA]) showed increased toxicity in the presence of 10 MUM CsA, whereas the other BAs did not. In addition to these BAs, taurolithocholic acid, glyco-CDCA, and glycocholic acid showed increased toxicity in the presence of 50 MUM CsA, but additional accumulation of these BAs could not be observed. These results indicate the inhibiting BSEP results in the accumulation of CDCA, GDCA, and partially DCA, thereby resulting in hepatotoxicity. PMID- 28552692 TI - A Combinatorial Statistical Design Approach to Optimize the Nanostructured Cubosomal Carrier System for Oral Delivery of Ubidecarenone for Management of Doxorubicin-Induced Cardiotoxicity: In Vitro-In Vivo Investigations. AB - Present work aims to optimize and characterize orally administered, ubidecarenone (UDC)-loaded glycerylmonooleate-based cubosome (GCBMs) and phytantriol based cubosomes (PCBMs) for effective management of doxorubicin-induced cardiotoxicity and to enhance bioavailability of UDC. Formulations optimized using statistical hybrid-design approach exhibited particle size of 152.0 +/- 1.78 and 248.8 +/- 1.83 nm, polydispersity index of 0.183 +/- 0.021 and 0.225 +/- 0.018 with zeta potential of -26.8 +/- 0.76 and -23.3 +/- 0.22 mV and percentage entrapment efficiency (% EE) of 92.3 +/- 4.99% and 94.7 +/- 5.67%, for GCBMs and PCBMs, respectively. High-resolution transmission electron microscopy revealed agreement with the particle size and shows the discrete cubic geometry of particles, while small-angle X-ray scattering analysis confirmed the primitive (Im3m) and diamond (Pn3m) type crystalline cubic self-assemble structure of the particles. The comparative bioavailability profiles of UDC from GCBMs and PCBMs (AUC0->infinity = 19,546.8 +/- 512.88 ng.h/L for GCBMs and 27,961.99 +/- 602.46 ng.h/L for PCBMs) were approximately 6.5- and 7.0-fold higher than that of UDC suspension (AUC0 >infinity = 3132.806 +/- 405.44 ng.h/L). Cardioprotective assessment showed a significant increase in superoxide dismutase and beta-glutathione peroxidase levels, while a decrease in the level of catalase, creatine kinase-MB isoenzyme, lactate dehydrogenase, and lipid peroxidation was observed in animals pre-treated with developed CBMs. Histopathology studies revealed no significant damage, infiltrated cells, and signs of fibrosis in the CBM-treated groups. PMID- 28552693 TI - Preface to the Special Issue on 4-Hydroxynonenal and Related Lipid Oxidation Products. PMID- 28552694 TI - Mesna (2-mercaptoethane sodium sulfonate) functions as a regulator of myeloperoxidase. AB - Myeloperoxidase (MPO), an abundant protein in neutrophils, monocytes, and macrophages, is thought to play a critical role in the pathogenesis of various disorders ranging from cardiovascular diseases to cancer. We show that mesna (2 mercaptoethanesulfonic acid sodium salt), a detoxifying agent, which inhibits side effects of oxazaphosphorine chemotherapy, functions as a potent inhibitor of MPO; modulating its catalytic activity and function. Using rapid kinetic methods, we examined the interactions of mesna with MPO compounds I and II and ferric forms in the presence and absence of chloride (Cl-), the preferred substrate of MPO. Our results suggest that low mesna concentrations dramatically influenced the build-up, duration, and decay of steady-state levels of Compound I and Compound II, which is the rate-limiting intermediate in the classic peroxidase cycle. Whereas, higher mesna concentrations facilitate the porphyrin-to-adjacent amino acid electron transfer allowing the formation of an unstable transient intermediate, Compound I*, that displays a characteristic spectrum similar to Compound I. In the absence of plasma level of chloride, mesna not only accelerated the formation and decay of Compound II but also reduced its stability in a dose depend manner. Mesna competes with Cl-, inhibiting MPO's chlorinating activity with an IC50 of 5uM, and switches the reaction from a 2e- to a 1e- pathway allowing the enzyme to function only with catalase-like activity. A kinetic model which shows the dual regulation through which mesna interacts with MPO and regulates its downstream inflammatory pathways is presented further validating the repurposing of mesna as an anti-inflammatory drug. PMID- 28552695 TI - Identification of novel human renin inhibitors through a combined approach of pharmacophore modelling, molecular DFT analysis and in silico screening. AB - Renin is an aspartyl protease of the renin-angiotensin system (RAS) and the first enzyme of the biochemical pathway for the generation of angiotensin II - a potent vasoconstrictor involved in the maintenance of cardiovascular homeostasis and the regulation of blood pressure. High enzymatic specificity of renin and its involvement in the catalysis of the rate-limiting step of the RAS hormone system qualify it as a good target for inhibition of hypertension and other associated diseases. Ligand-based pharmacophore model (Hypo1) was generated from a training set of 24 compounds with renin inhibitory activity. The best hypothesis consisted of one Hydrogen Bond Acceptor (HBA), three Hydrophobic Aliphatic (HY-Al) and one Ring Aromatic (AR) features. This well-validated pharmacophore hypothesis (correlation coefficient 0.95) was further utilized as a 3D query to screen database compounds, which included structures from two natural product repositories. These screened compounds were further analyzed for drug-likeness and ADMET studies. The compounds which satisfied the qualifying criteria were then subjected to molecular docking and Density Functional Theory (DFT) analysis in order to discern their atomic level interactions at the active site of the 3D structure of rennin. The pharmacophore-based modelling that has been used to generate the novel findings of the present study would be an avant-garde approach towards the development of potent inhibitors of renin. PMID- 28552696 TI - A Novel Tool for Deformity Surgery Planning: Determining the Magnitude of Lordotic Correction Required to Achieve a Desired Sagittal Vertical Axis. AB - OBJECTIVE: We sought to create a model capable of predicting the magnitude of pelvic incidence-lumbar lordosis (PI-LL) correction necessary to achieve a desired change in sagittal vertical axis (SVA). METHODS: A retrospective review was conducted of a prospectively maintained multicenter adult spinal deformity database collected by the International Spine Study Group between 2009 and 2014. The independent variable of interest was the degree of correction achieved in the PI-LL mismatch 6 weeks after surgery. Primary outcome was the change in global sagittal alignment 6 weeks and 1 year after surgery. We used a linear mixed effects model to determine the extent to which corrections in the PI-LL relationship affected postoperative changes in SVA. RESULTS: A total of 1053 adult patients were identified. Of these patients, 590 were managed surgically. Eighty-seven surgically managed patients were excluded because of incomplete or missing PI-LL measurements on follow-up; the remaining 503 patients were selected for inclusion. For each degree of improvement in the PI-LL mismatch at 6 weeks, the SVA decreased by 2.18 mm (95% confidence interval, -2.56, -1.79; P < 0.01) and 1.67 mm (95% confidence interval, -2.07, -1.27; P < 0.01) at 6 weeks and 12 months, respectively. A high SVA measurement (>50 mm) 1 year after surgery was negatively associated with health-related quality of life as measured by the Scoliosis Research Society 22 outcomes assessment. CONCLUSIONS: We describe a novel model that shows how surgical correction of the PI-LL relationship affects postoperative changes in SVA. This model may enable surgeons to determine preoperatively the amount of LL necessary to achieve a desired change in SVA. PMID- 28552697 TI - A New Sling Technique in Cervical Radiculopathy Caused by Vertebral Artery Loop Compression. AB - BACKGROUND: A 52-year-old woman had a 20-month history of progressive radiating pain in the left arm and numbness on C7 dermatome. CASE DESCRIPTION: On physical examination, left head rotation aggravated the radiculopathic pain. For an anatomic diagnosis of the vertebral artery and nerve root, magnetic resonance angiography was performed (computed tomography angiography was not possible because of her dye allergy history). Magnetic resonance angiography showed a left vertebral artery loop entering at the C6-7 intervertebral foramen. Surgical microvascular decompression was performed by an anterior cervical approach and the loop of the artery was fixed using a sling technique. Postoperative computed tomography angiography showed that the left vertebral artery was retracted anteriorly and the C7 nerve root was decompressed in the intervertebral foramen at the left C6-7 level. CONCLUSIONS: The patient's radiculopathic symptoms were improved and especially the aggravated pain by left head rotation subsided dramatically. PMID- 28552698 TI - A Novel Approach for Percutaneous Vertebroplasty Based on Preoperative Computed Tomography-Based Three-Dimensional Model Design. AB - OBJECTIVE: To describe a new technique for the efficient use of preoperative planning based on preoperative computed tomography-based three-dimensional (3D) model design for percutaneous vertebroplasty (PVP) in a patient with osteoporotic vertebral compression fracture. METHODS: A 76-year-old woman with acute osteoporotic vertebral compression fracture (L1 level) accepted a novel precise PVP. A 3D model of thoracolumbar vertebrae (T12-L2) based on preoperative computed tomography scanning data and a simulative PVP (via a bilateral transpedicular approach) were built in MIMICS (Materialise Interactive Medical Image Control System) software. With the help of 3 radiopaque markers located at the skin of the back and preoperative digital design by MIMICS, bilateral skin entry points, needles direction including abduction angle and head inclination angle, and needle insertion depth were established. RESULTS: During surgery, only 1 shot of fluoroscopy was required to confirm the skin entry points. The operation took only about 23 minutes and total patient exposure dose was 4.5 mSv. The intraoperative radiologic results showed that the cement distribution in the L1 vertebra was good without any puncture-related complications. The patient's visual analog scale score improved from 9 points preoperatively to 2 points postoperatively. The patient's preoperative Oswestry Disability Index score was 80 points, which improved to 57.8 points postoperatively. CONCLUSIONS: The novel precise PVP based on preoperative 3D model design allows 1) visualization of the morphology of the fractured vertebral body, 2) increased precision of puncture with decreasing incidence of puncture-related complications and reduced radiation exposure, and 3) less operation time, decreasing the learning curve of beginners with limited experience. PMID- 28552699 TI - The Impact of Kidney Disease on Acute Tubular Necrosis and Surgical Site Infection After Lumbar Fusion. AB - BACKGROUND: Kidney disease in spine surgery can be associated with serious complications. OBJECTIVE: To investigate the rate of acute tubular necrosis (ATN) and surgical site infection (SSI) after lumbar fusion in patients with kidney disease. METHODS: A review of the U.S. Nationwide Inpatient Sample from 2002 to 2011 was performed to identify patients who underwent lumbar fusion for degenerative spine disease or disk herniation. Four groups were established: no kidney disease, chronic kidney disease (CKD), end-stage renal disease (ESRD), and posttransplant. A multivariate analysis was performed to control for age, sex, and comorbidities. RESULTS: A total of 268,158 patients met the criteria; 263,757 with no kidney disease (98.4%), 3576 with CKD (1.3%), 586 with ESRD (0.2%), and 239 posttransplant (0.1%). Rates of ATN were 0.1%, 2.9%, 3.6%, and 0.0% for the 4 groups, respectively (P < 0.001). Rates of SSI were 0.3%, 0.4%, 1.0%, and 0.0%, respectively (P = 0.002). After controlling for patient age, sex, and medical comorbidities, patients with CKD (odds ratio [OR], 5.42; 95% confidence interval [CI], 4.14-7.09; P < 0.001) and ESRD (OR, 6.32; 95% CI, 3.89-10.33; P < 0.001) were significantly more likely to develop ATN compared with patients without kidney disease. However, CKD (OR, 0.80; 95% CI, 0.20-3.12; P = 0.754) or ESRD (OR, 1.96; 95% CI, 0.38-10.00; P = 0.415) did not increase the risk for SSI on multivariate analysis. DISCUSSION: The rate of ATN significantly increases based on severity of kidney disease. However, patients with transplants have ATN and SSI rates comparable with patients without kidney disease. PMID- 28552700 TI - Analysis of Factors Related to Hypopituitarism in Patients with Nonsellar Intracranial Tumor. AB - OBJECTIVE: Previous studies have suggested that postoperative hypopituitarism in patients with nonsellar intracranial tumors is caused by traumatic surgery. However, with development of minimally invasive and precise neurosurgical techniques, the degree of injury to brain tissue has been reduced significantly, especially for parenchymal tumors. Therefore, understanding preexisting hypopituitarism and related risk factors can improve perioperative management for patients with nonsellar intracranial tumors. METHODS: Chart data were collected retrospectively from 83 patients with nonsellar intracranial tumors admitted to our hospital from May 2014 to April 2015. Pituitary function of each subject was determined based on results of preoperative serum pituitary hormone analysis. Univariate and multivariate logistic regression methods were used to analyze relationships between preoperative hypopituitarism and factors including age, sex, history of hypertension and secondary epilepsy, course of disease, tumor mass effect, site of tumor, intracranial pressure (ICP), cerebrospinal fluid content, and pituitary morphology. RESULTS: A total of 30 patients (36.14%) presented with preoperative hypopituitarism in either 1 axis or multiple axes; 23 (27.71%) were affected in 1 axis, and 7 (8.43%) were affected in multiple axes. Univariate analysis showed that risk factors for preoperative hypopituitarism in patients with a nonsellar intracranial tumor include an acute or subacute course (<=3 months), intracranial hypertension (ICP >200 mm H2O), and mass effect (P < 0.05). Multivariate logistic regression analysis showed that mass effect is an independent risk factor for preoperative hypopituitarism in patients with nonsellar intracranial tumors (P < 0.05; odds ratio, 3.197). CONCLUSIONS: Prevalence of hypopituitarism is high in patients with nonsellar intracranial tumors. The occurrence of hypopituitarism is correlated with factors including an acute or subacute course (<=3 months), intracranial hypertension (ICP >200 mm H2O), and mass effect (P < 0.05). Mass effect is an independent risk factor for hypopituitarism. PMID- 28552701 TI - Formulation of a Three-Tier Cisternal Grade as a Predictor of In-Hospital Outcome from a Prospective Study of Patients with Traumatic Intracranial Hematoma. AB - OBJECTIVE: Outcome prediction is of paramount importance in traumatic brain injury. Our objective of conducting this prospective study was to identify the predictors needed to formulate a prognostic score. METHODS: Clinical and radiologic characteristics of 100 patients with traumatic intracranial hematoma were analyzed. Key measurements were taken in the midbrain and pontine regions and the status of each of the 9 basal cisterns was noted, by giving a score of 1 if they were visible and 0 if not. All the predictors were analyzed for outcome. RESULTS: Total cisternal score was found to be an independent predictor of outcome. A grade was formulated by dividing the score into 3 levels. CONCLUSIONS: The model based on cisternal status described in the study is technically simple and conveys the information regarding the outcome to the treating neurosurgeon. Because the score obtained seems to have low interobserver variation, we believe that it can be a useful tool not only in recording data in case files and interphysician communication but also in research into traumatic brain injury. PMID- 28552702 TI - Struggling to maintain individuality - Describing the experience of food in nursing homes for people with dementia. AB - PURPOSE OF THE STUDY: To describe the food and dining experience of people with cognitive impairment and their family members in nursing homes. DESIGN AND METHODS: Interviews and focus groups with people with cognitive impairment and their family members (n=19). Thematic analysis was undertaken using NVivo10 data analysis software package to determine key themes. RESULTS: The main themes identified tracked a journey for people with cognitive impairment in nursing homes, where they initially sought to have their individual needs and preferences recognised and heard, expressed frustration as they perceived growing barriers to receiving dietary care which met their preferences, and ultimately described a deterioration of the amount of control and choice available to the individual with loss of self-feeding ability and dysphagia. IMPLICATIONS: Further consideration of how to incorporate individualised dietary care is needed to fully implement person-centred care and support the quality of life of those receiving nursing home care. PMID- 28552703 TI - Phenotype of a leaf beetle larva depends on host plant quality and previous test experience. AB - Phenotypic expressions of insects are strongly dependent on various external and internal factors, like diet or density and age or sex. However, environmental effects on the behavioural phenotype and repeatability are rather unexplored for holometabolous insects in their larval stage. We examined the effects of the food environment (young versus old cabbage leaves) and previous test experience on growth and behaviour of Phaedon cochleariae larvae. A more nutritious diet, i.e., young leaves, had beneficial consequences on larval growth. Contrary to findings on adults, the behaviour of larvae was neither consistent over time nor across contexts, thus larvae did not show personality. Furthermore, larval behaviour was shaped independent of the diet, pointing to a stage-dependent receptivity towards diet conditions in this species. Besides, larval activity was significantly influenced by former test experience, with naive larvae being more active than previously tested larvae. In general, in insects memories in an olfactory or sexual behaviour context can lead to behavioural responses later in life. Mechanisms of memory-learning should be further explored in different contexts in insects. Overall, the present study reveals that growth-related traits are diet dependent and that the activity of a holometabolous larva is shaped in dependence of its previous test experience. PMID- 28552705 TI - Metabolic costs of the mechanical components of the apparent specific dynamic action in the Dungeness crab, Cancer magister. AB - The specific dynamic action (SDA) describes the postprandial increase in metabolism. It is a composite of mechanical and chemical digestion, nutrient transport and protein synthesis. How these individual events contribute to the overall SDA has not been worked out fully for any organism. The mechanical events associated with the SDA were investigated in Dungeness crabs, Cancer magister. Following consumption of a meal, oxygen consumption (MO2) remained elevated for several hours. When the crabs were presented with fish scent there was a 2 fold increase in MO2, which rapidly decreased once the stimulus was removed. Crabs were then offered fish in a perforated tube. There was a rapid increase in MO2 associated with handling which returned to pre-treatment levels within an hour of removal of the tube. Finally the crabs were fed a piece of foam that had been soaked in fish water to determine the costs of mechanical digestion. The mechanical breakdown of the meal accounted for 29.9+/-3.3% of the overall SDA. Since food handling produced a large increase in MO2, it was reinvestigated using crabs that had one or both claws removed. Although there were no statistically significant differences as a function of claw removal there was a consistent trend in the data. The maximum MO2, scope, duration and SDA increased from animals with 0 claws through 1 claw to 2 claws. The results showed that the mechanical portion of the SDA can account for a significant portion of the overall budget in decapod crustaceans. PMID- 28552704 TI - Amylin receptor activation in the ventral tegmental area reduces motivated ingestive behavior. AB - Amylin is produced in the pancreas and the brain, and acts centrally to reduce feeding and body weight. Recent data show that amylin can act in the ventral tegmental area (VTA) to reduce palatable food intake and promote negative energy balance, but the behavioral mechanisms by which these effects occur are not fully understood. The ability of VTA amylin signaling to reduce intake of specific palatable macronutrients (fat or carbohydrate) was tested in rats in several paradigms, including one-bottle acceptance tests, two-bottle choice tests, and a free-choice diet. Data show that VTA amylin receptor activation with the amylin receptor agonist salmon calcitonin (sCT) preferentially and potently reduces intake of fat, with more variable suppression of sucrose intake. Intake of a non nutritive sweetener is also decreased by intra-VTA administration of sCT. As several feeding-related signals that act in the mesolimbic system also impact motivated behaviors besides feeding, we tested the hypothesis that the suppressive effects of amylin signaling in the VTA extend to other motivationally relevant stimuli. Results show that intra-VTA sCT reduces water intake in response to central administration of the dipsogenic peptide angiotensin II, but has no effect on ad libitum water intake in the absence of food. Importantly, open field and social interaction studies show that VTA amylin signaling does not produce anxiety-like behaviors. Collectively, these findings reveal a novel ability of VTA amylin receptor activation to alter palatable macronutrient intake, and also demonstrate a broader role of VTA amylin signaling for the control of motivated ingestive behaviors beyond feeding. PMID- 28552706 TI - Mother-young recognition in goitered gazelle during hiding period. AB - The mother-young recognition process is crucial for the growth and survival of progeny. In "follower" ungulate species, vocal and visual cues have been found to play a leading role in the mother-young identification process from the first days postpartum, with olfactory cues also important in establishing the initial selective mother-young bond immediately after birth. In "hider" species, however, much less has been documented of mother-young recognition behaviors, especially in their natural habitat. In this paper, we investigated this process in goitered gazelle (Gazella subgutturosa), a typical hider species, in its native environment in Kazakhstan. Over the course of our study period, we investigated the behaviors of 257 females with twins and 158 females with singles through visual observations. We found that within the first month after birth, when females spend only a short time with their young, mothers recognized their fawns using mostly olfactory cues, while vision was used to locate their hiding offspring. Fawns vocalized very rarely, producing only distress calls that did not seem intended for individual identification. Licking of young by their mothers was observed frequently, not only during the first week after birth, when this action was very important for fawn stimulation for a number of physiological functions, but for several weeks after (until one month of age), when licking lost its physiological importance and likely became more of a recognition procedure. Fawns did not recognize their mothers at all, either through vision or vocalizations, since during their first weeks after birth, they responded to any gazelle that approached their hiding area. By a month after birth, when mothers and fawns began to stay together for longer periods of time, their recognition process became more enhanced, and in addition to olfactory cues, the mother and her young began to use more and more visual cues for longer distance identification, as well as vocalizations for shorter distances. Similar dynamics are likely typical for most hiding species, although information for wild ungulates is still very limited, especially for those with strong hider behaviors. PMID- 28552707 TI - Flexibility in the social behavior of captive female capybaras (Mammalia, Rodentia). AB - Capybara (Hydrochoerus hydrochaeris) lives in stable groups composed of adult males and females with their young. The species shows flexibility in social organization in response to short-term environmental changes, but apparently does not show flexibility in social behavior. To gain insights into mechanisms underlying changes in social relationships, we analyzed the social dominance hierarchy of five captive capybara groups, composed of four to 13 adult females kept in outdoor paddocks ranging from 400 to 4500m2. In addition, we evaluated the effects of group size and space allowance on two complementary properties of social structure: linearity and steepness. Captive female capybaras exhibit a linear social dominance hierarchy. There was also more predictability in the dominance success- hierarchical steepness - in the dominance hierarchy with a decrease in the space per individual. This variability in response to changing circumstances shows flexibility in capybara's social behavior. PMID- 28552708 TI - Recent Changes in Prostate Cancer Screening Practices and Epidemiology. AB - PURPOSE: Prostate specific antigen based screening for prostate cancer has had a significant impact on the epidemiology of the disease. Its use has been associated with a significant decrease in prostate cancer mortality but has also resulted in the over diagnosis and overtreatment of indolent prostate cancer, exposing many men to the harms of treatment without benefit. The USPSTF (U.S. Preventive Services Task Force) in 2008 issued a recommendation against screening men older than 75 years, and in 2012 against routine screening for all men, indicating that in its interpretation the harms of screening outweigh the benefits. We review changes in the use of prostate specific antigen testing, performance of prostate biopsy, incidence of prostate cancer and stage of disease at presentation since 2012. MATERIALS AND METHODS: An English language literature search was performed for terms that included "prostate specific antigen," "screening" and "United States Preventive Services Task Force" in various combinations. A total of 26 original studies had been published on the effects of the USPSTF recommendations on prostate specific antigen based screening or prostate cancer incidence in the United States as of December 1, 2016. RESULTS: Review of the literature from 2012 through the end of 2016 indicates that there has been a decrease in prostate specific antigen testing and prostate biopsy. As a result, there has been a decline in the incidence of localized prostate cancer, including low, intermediate and high risk disease. The data regarding stage at presentation have yet to mature but there are some early signs of a shift toward higher burden of disease at presentation. CONCLUSIONS: These findings raise concern about a reversal of the observed improvement in prostate cancer specific mortality during preceding decades. Alternative screening strategies would 1) incorporate patient preferences by allowing shared decision-making, 2) preserve the survival benefits associated with screening, 3) improve the specificity of screening to reduce unnecessary biopsies and detection of low risk disease, and 4) promote the use of active surveillance for low risk cancers if they are detected. PMID- 28552709 TI - Morbidity and Mortality of Locally Advanced Prostate Cancer: A Population Based Analysis Comparing Radical Prostatectomy versus External Beam Radiation. AB - PURPOSE: The management of locally advanced prostate cancer remains controversial. We compared the effect of primary external beam radiation therapy vs radical prostatectomy for locally advanced prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed the records of 2,935 elderly men 65 years old or older in the SEER (Surveillance, Epidemiology and End Results)-Medicare linked database who underwent external beam radiation therapy or radical prostatectomy for locally advanced prostate cancer. Propensity adjusted Cox proportional hazard and regression models were fit to examine urinary and gastrointestinal toxicities, the use of androgen deprivation therapy, and overall and prostate cancer specific mortality. RESULTS: A total of 1,429 men (48.69%) underwent radical prostatectomy and had a median followup of 11.47 years (IQR 6.17-17.17) years. A total of 1,506 men (51.31%) received external beam radiation therapy and had a median followup of 7.04 years (IQR 4.11-10.51, p <0.001). Patients treated with radical prostatectomy were at significantly higher risk for urinary and sexual toxicities (HR 1.93, 95% CI 1.66-2.24 and HR 5.50, 95% CI 3.59 8.42, respectively). However, they were at lower risk for gastrointestinal toxicities (HR 0.75, 95% CI 0.65-0.86) than those treated with external beam radiation therapy. Radical prostatectomy was associated with lower odds of androgen deprivation therapy 5 years after primary treatment (OR 0.53, 95% CI 0.41-0.69, p <0.001). External beam radiation therapy was associated with higher overall and prostate specific mortality (HR 1.41, 95% CI 1.09-1.82 and HR 2.35, 95% CI 1.85-2.98, respectively). CONCLUSIONS: We found significant toxicity and survival differences in elderly men who underwent primary external beam radiation therapy vs radical prostatectomy for locally advanced prostate cancer. While our findings must be interpreted within the limitations of studies that rely on administrative claims, they may yet help tailor individual therapies for elderly men who present with locally advanced prostate cancer. PMID- 28552710 TI - Clinical Outcomes and Testosterone Levels Following Continuous Androgen Deprivation in Patients with Relapsing or Locally Advanced Prostate Cancer: A Post Hoc Analysis of the ICELAND Study. AB - PURPOSE: Lower serum testosterone levels correlate with improved cause specific survival and longer time to progression in year 1 of continuous androgen deprivation in men with prostate cancer. ICELAND was a large European study demonstrating the efficacy of leuprorelin (Eligard(r)) during continuous androgen deprivation. In this post hoc analysis we investigated serum testosterone levels within year 1 of continuous androgen deprivation to determine survival and time to progression. MATERIALS AND METHODS: In ICELAND (ClinicalTrials.gov NCT00378690) patients with locally advanced or relapsing nonmetastatic prostate cancer and with prostate specific antigen 1 ng/ml or less following 6-month induction with leuprorelin 3-month depot 22.5 mg (plus bicalutamide 50 mg per day for 1 month) were randomized 1:1 to continuous androgen deprivation (361) or intermittent androgen deprivation (340) with leuprorelin for 36 months. Patients receiving continuous androgen deprivation were stratified by minimum, median and maximum testosterone levels during year 1 of therapy into 20 or less, greater than 20 to 50 and greater than 50 ng/dl subgroups. Cause specific survival and time to prostate specific antigen (castrate resistant prostate cancer) progression were analyzed. RESULTS: A total of 90.1%, 83.5% and 74.5% of patients receiving continuous androgen deprivation achieved minimum, median and maximum serum testosterone levels of 20 ng/dl or less, respectively. Cause specific survival rates and time to prostate specific antigen progression did not differ among the testosterone subgroups. CONCLUSIONS: In patients receiving continuous androgen deprivation cause specific survival and time to prostate specific antigen progression did not differ according to testosterone levels in year 1 of therapy. This finding may in part be due to the induction period and the effectiveness of leuprorelin in lowering testosterone. PMID- 28552711 TI - ALA16VAL-MnSOD gene polymorphism and stroke: Association with dyslipidemia and glucose levels. AB - Stroke risk has been associated to the progression of carotid plaques due to high glucose levels and lipid accumulation, which are greatly associated to cerebral injury, brain oxidative stress, and apoptosis. The ALA16VAL-MnSOD gene single nucleotide polymorphism (SNP) has shown to modulate risk factors of several metabolic and vascular diseases, such as blood glucose (GLU) and lipid levels. However, the association of these factors in stroke patients has not been studied to date. Thus, we evaluated the influence of the Ala16Val-MnSOD SNP on lipid profile, GLU levels, oxidative and DNA damage of 44 patients in a late phase of stroke (>6months). The statistical analysis showed a greater proportion of VV carries in stroke patients. The results also indicated that stroke patients had higher cholesterol (CHO) and GLU levels when compared to healthy counterparts. Interestingly, V allele carriers with stroke showed higher levels of CHO and GLU when compared to AA stroke and healthy counterparts. Our findings suggest that oxidative stress markers are still increased even after 6 months of cerebral injury. Furthermore, we propose that the Ala16Val-MnSOD SNPs may contribute to hypercholesterolemia and higher GLU levels, increasing the risk to neurovascular events that may lead to stroke. PMID- 28552712 TI - Identification of the conserved and novel microRNAs by deep sequencing and prediction of their targets in Topmouth culter. AB - MicroRNAs (miRNAs) are endogenous non-coding small RNAs that play important roles in regulation of almost all biological processes in organisms. Topmouth culter is an economically important fish species in the Chinese freshwater polyculture system for its delicacy and high economic value. However, to date, no miRNAs have been reported in Topmouth culter species. In this study, the liver, muscle, spleen and kidney of Topmouth culter are sampled and used for construction of a small RNA library for deep sequencing. A total of 273 conserved miRNAs/miRNAs star and 8 novel miRNAs/miRNAs-star were discovered, these miRNAs belong to 86 different miRNA families. There is a strong base bias on miRNA nucleotide compositions at certain positions. U is the dominant nucleotide, particularly at the beginning, middle, and end of conserved miRNAs. The expression of all 8 novel identified miRNAs in Topmouth culter was validated by using stem-loop qRT-PCR. Furthermore, the potential targets were predicted for these miRNAs, which were found to be involved in diverse biological processes. Our study is the first significantly enriches the Topmouth culter miRNA repertoire and provides a reference for further elucidation of complex miRNA-mediated regulatory networks for gene expression in the growth and developmental progression of Topmouth culter. PMID- 28552713 TI - Mass spectrometric detection combined with bioinformatic analysis identified possible protein markers and key pathways associated with bladder cancer. AB - We aimed to find possible protein markers and key pathways related to bladder cancer. In total, we extracted three bladder cancer tissues and three paracancerous tissues from Jiangsu Provincial People's Hospital Urology Department, and performed mass spectrometric detection with Q Exactive. Subsequently, we screened the differentially expressed proteins in the disease group and the normal group using the LIMMA package, and performed functional enrichment analyses using DAVID. Further, we constructed protein-protein interaction (PPI) networks with Cytoscape software, and analyzed modules with ClusterONE. In total, 165 differentially expressed proteins including 19 upregulated and 146 downregulated ones were obtained. ACTA2 (Actin, Alpha 2, Smooth Muscle, Aorta), ACTN1 (Actinin, Alpha 1), and VCL (Vinculin) were significant nodes with higher degrees in the PPI network. These three nodes were also hub nodes in module 2. Besides, functional enrichment analysis suggested that ECM-receptor interaction and focal adhesion were significant pathways, and these two pathways were also enriched in three network modules. In addition, ACTN1 and VCL were enriched in the focal adhesion pathway in module 2. Thus, ACTA2, ACTN1, and VCL may play important roles in bladder cancer progression and may be protein markers for this disease. The ECM-receptor interaction pathway and the focal adhesion pathway may be involved in the progression of bladder cancer. Furthermore, ACTN1 and VCL may play roles in bladder cancer development, partly via the focal adhesion pathway. PMID- 28552714 TI - Genetic and environmental-genetic interaction rules for the myopia based on a family exposed to risk from a myopic environment. AB - OBJECTIVE: To quantitatively assess the role of heredity and environmental factors in myopia based on the family with enough exposed to risk from myopic environment for establishment of environmental and genetic index (EGI). METHODS: A pedigree analysis unit was defined as one child (university student), father, and mother. Information pertaining to visual acuity, experience in participating in the college entrance examination in mainland of China (regarded as a strong environmental risk for myopia), and occupation for pedigree analysis units were obtained. The difference between effect of both genetic and environmental factors (myopia prevalence in children with two myopic parents) and environmental factors (myopia prevalence in children of whom neither parent was myopic) was defined as the EGI. Multiple regression analysis was performed for 114 pedigree using diopters of father, mother, average diopters in parents, maximum and minimum diopters in father and mother as variables. A total of 353 farmers and 162 farmer families were used as a control group. RESULTS: A distinct difference in myopia rate (96.2% versus 57.7%) was observed for children from parents with myopia and parents without myopia (EGI=0.385). The maximum diopter was included to regression equation which was statistically significant. The prevalence of myopia was 9.9% in the farmer. The prevalence in children is similar between the farmer and other families. CONCLUSION: A new genetic rule that myopia in children was directly related with maximum diopters in father and mother may be suggested. Environmental factors may play a leading role in the formation of myopia. PMID- 28552715 TI - Influence of SCARB1 gene SNPs on serum lipid levels and susceptibility to coronary heart disease and cerebral infarction in a Chinese population. AB - The SCARB1 gene encodes human scavenger receptor class B type I (SR-BI), the primary receptor for high-density lipoprotein (HDL)- cholesteryl ester uptake, and polymorphisms in this gene may influence SR-BI protein expression and serum lipid levels, modulating susceptibility to coronary heart disease (CHD) and cerebral infarction (CI). Therefore, we investigated the association between singlenucleotide polymorphisms (SNPs) in the SCARB1 gene and serum lipid levels as well as risk of CHD and CI in the Chinese Han population. Genotypes in 295 CHD patients, 302 CI patients and 312 healthy controls matched for age and gender were determined by high-resolution melting (HRM). Among the 5 SNPs investigated in this study, rs10846744 and rs2278986 were significantly associated with CHD risk. The frequency of the C allele for rs10846744 and that of the T allele for rs2278986 appeared to be significantly increased in the CHD group (OR: 1.416, 95%CI: 1.128-1.778, P=0.0058 and OR: 1.681, 95%CI: 1.327-2.130, P<0.0001, respectively). CHD patients with genotypes CC and CG for rs10846744 had a higher HDL-c level than those with genotype GG, and CHD patients with genotypes CC and CT for the rs2278986 SNP had a higher HDL-c level compared to those with the TT allele. The other 3 SNPs, rs5888, rs10744182 and rs838893, showed no significant association with serum lipid levels and CHD or CI risk in the Chinese population. The CCCTT and CCTTC haplotypes of rs5888, rs10846744, rs10744182, rs2278986 and rs838893 appear to significantly increase CHD risk, whereas the CGTTC, CCTCT and TGCTC haplotypes appear to significantly reduce risk. Overall, the CCTTC and TGTTC haplotypes acted as a significant risk for CI, with the CGCTC and CCCCT haplotypes conferring significantly reduced risk. These results suggest that SCARB1 gene polymorphisms may contribute to genetic susceptibility to CHD; in particular, the C allele of rs10846744 and the C allele of rs2278986 may serve as risk and protective factors for CHD, respectively. PMID- 28552716 TI - Nrf2 activation by tauroursodeoxycholic acid in experimental models of Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Although the cause of PD remains elusive, mitochondrial dysfunction and severe oxidative stress are strongly implicated in the cell death that characterizes the disease. Under oxidative stress, the master regulator of cellular redox status, nuclear factor erythroid 2 related factor 2 (Nrf2), is responsible for activating the transcription of several cytoprotective enzymes, namely glutathione peroxidase (GPx) and heme oxygenase-1 (HO-1). Nrf2 is a promising target to limit reactive oxygen species (ROS)-mediated damage in PD. Here, we show that tauroursodeoxycholic acid (TUDCA) prevents both 1-methyl-4 phenylpyridinium (MPP+)- and alpha-synuclein-induced oxidative stress, through Nrf2 activation, in SH-SY5Y cells. Additionally, we used C57BL/6 male mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to elucidate the effect of TUDCA in this in vivo model of PD. In vivo, TUDCA treatment increases the expression of Nrf2, Nrf2 stabilizer DJ-1, and Nrf2 downstream target antioxidant enzymes HO-1 and GPx. Moreover, we found that TUDCA enhances GPx activity in the brain. Altogether, our results suggest that TUDCA is a promising agent to limit ROS-mediated damage, in different models of PD acting, at least in part, through modulation of the Nrf2 signaling pathway. Therefore, TUDCA should be considered a promising therapeutic agent to be implemented in PD. PMID- 28552717 TI - Exploring acute-to-chronic neuropathic pain in rats after contusion spinal cord injury. AB - Spinal cord injury (SCI) causes chronic pain in 65% of individuals. Unfortunately, current pain management is inadequate for many SCI patients. Rodent models could help identify how SCI pain develops, explore new treatment strategies, and reveal whether acute post-SCI morphine worsens chronic pain. However, few studies explore or compare SCI-elicited neuropathic pain in rats. Here, we sought to determine how different clinically relevant contusion SCIs in male and female rats affect neuropathic pain, and whether acute morphine worsens later chronic SCI pain. First, female rats received sham surgery, or 150kDyn or 200kDyn midline T9 contusion SCI. These rats displayed modest mechanical allodynia and long-lasting thermal hyperalgesia. Next, a 150kDyn (1s dwell) midline contusion SCI was performed in male and female rats. Interestingly, males, but not females showed SCI-elicited mechanical allodynia; rats of both sexes had thermal hyperalgesia. In this model, acute morphine treatment had no significant effect on chronic neuropathic pain symptoms. Unilateral SCIs can also elicit neuropathic pain that could be exacerbated by morphine, so male rats received unilateral T13 contusion SCI (100kDyn). These rats exhibited significant, transient mechanical allodynia, but not thermal hyperalgesia. Acute morphine did not exacerbate chronic pain. Our data show that specific rat contusion SCI models cause neuropathic pain. Further, chronic neuropathic pain elicited by these contusion SCIs was not amplified by our course of early post trauma morphine. Using clinically relevant rat models of SCI could help identify novel pain management strategies. PMID- 28552718 TI - Perampanel in the general population and in people with intellectual disability: Differing responses. AB - PURPOSE: There is a shortfall of suitably powered studies to provide evidence for safe prescribing of AEDs to people with Intellectual Disability (ID). We report clinically useful information on differences in response to Perampanel (PER) adjunctive treatment for refractory epilepsy between ID sub-groups and general population from the UK Ep-ID Research Register. METHOD: Pooled retrospective case notes data of consented people with epilepsy (PWE) prescribed PER from 6 UK centres was classified as per WHO guidance into groups of moderate -profound ID, mild ID and General population. Demographics, concomitant AEDs, starting and maximum dosage, exposure length, adverse effects, dropout rates, seizure type and frequency were collected. Group differences were reported as odds ratios estimated from univariable logistic regression models. RESULTS: Of the 144 PWE (General population 71, Mild ID 48, Moderate to profound ID 48) examined the association between withdrawal and ID type was marginally statistically significant (p=0.07). Moderate to profound ID PWE were less likely to come off PER compared to mild ID (OR=0.19, CI=0.04-0.92, p=0.04). Differences in mental health side effects by groups was marginally statistically significant (p=0.06). Over 50% seizure improvement was seen in 11% of General population, 24% mild ID and 26% Moderate to profound ID. CONCLUSIONS: PER seems safe in PWE with ID. It is better tolerated by PWE with Moderate to profound ID than PWE with higher functioning. Caution is advised when history of mental health problems is present. The standardised approach of the Ep-ID register UK used confirms that responses to AEDs by different ID groups vary between themselves and General population. PMID- 28552719 TI - Regulation of longevity by FGF21: Interaction between energy metabolism and stress responses. AB - Fibroblast growth factor 21 (FGF21) is a hormone-like member of FGF family which controls metabolic multiorgan crosstalk enhancing energy expenditure through glucose and lipid metabolism. In addition, FGF21 acts as a stress hormone induced by endoplasmic reticulum stress and dysfunctions of mitochondria and autophagy in several tissues. FGF21 also controls stress responses and metabolism by modulating the functions of somatotropic axis and hypothalamic-pituitary-adrenal (HPA) pathway. FGF21 is a potent longevity factor coordinating interactions between energy metabolism and stress responses. Recent studies have revealed that FGF21 treatment can alleviate many age-related metabolic disorders, e.g. atherosclerosis, obesity, type 2 diabetes, and some cardiovascular diseases. In addition, transgenic mice overexpressing FGF21 have an extended lifespan. However, chronic metabolic and stress-related disorders involving inflammatory responses can provoke FGF21 resistance and thus disturb healthy aging process. First, we will describe the role of FGF21 in interorgan energy metabolism and explain how its functions as a stress hormone can improve healthspan. Next, we will examine both the induction of FGF21 expression via the integrated stress response and the molecular mechanism through which FGF21 enhances healthy aging. Finally, we postulate that FGF21 resistance, similarly to insulin resistance, jeopardizes human healthspan and accelerates the aging process. PMID- 28552720 TI - Remote tissue conditioning - An emerging approach for inducing body-wide protection against diseases of ageing. AB - We have long accepted that exercise is 'good for us'; that - put more rigorously moderate exercise is associated with not just aerobic fitness but also reduced morbidity and reduced mortality from cardiovascular disease and even malignancies. Caloric restriction (moderate hunger) and our exposure to dietary phytochemicals are also emerging as stresses which are 'good for us' in the same sense. This review focuses on an important extension of this concept: that stress localized within the body (e.g. in a limb) can induce resilience in tissues throughout the body. We describe evidence for the efficacy of two 'remote' protective interventions - remote ischemic conditioning and remote photobiomodulation - and discuss the mechanisms underlying their protective actions. While the biological phenomenon of remote tissue conditioning is only partially understood, it holds promise for protecting critical-to-life tissues while mitigating risks and practical barriers to direct conditioning of these tissues. PMID- 28552722 TI - A novel immuno-gold labeling protocol for nanobody-based detection of HER2 in breast cancer cells using immuno-electron microscopy. AB - Immuno-electron microscopy is commonly performed with the use of antibodies. In the last decade the antibody fragment indicated as nanobody (VHH or single domain antibody) has found its way to different applications previously done with conventional antibodies. Nanobodies can be selected to bind with high affinity and specificity to different antigens. They are small (molecular weight ca. 15kDa) and are usually easy to produce in microorganisms. Here we have evaluated the feasibility of a nanobody binding to HER2 for application in immuno-electron microscopy. To obtain highest labeling efficiency combined with optimal specificity, different labeling conditions were analysed, which included nanobody concentration, fixation and blocking conditions. The obtained optimal protocol was applied for post-embedment labeling of Tokuyasu cryosections and for pre embedment labeling of HER2 for fluorescence microscopy and both transmission and scanning electron microscopy. We show that formaldehyde fixation after incubation with the anti-HER2 nanobody, improves labeling intensity. Among all tested blocking agents the best results were obtained with a mixture of cold water fish gelatine and acetylated bovine serum albumin, which prevented a-specific interactions causing background labeling while preserving specific interactions at the same time. In conclusion, we have developed a nanobody-based protocol for immuno-gold labeling of HER2 for Tokuyasu cryosections in TEM as well as for pre embedment gold labeling of cells for both TEM and SEM. PMID- 28552721 TI - Improved metrics for comparing structures of macromolecular assemblies determined by 3D electron-microscopy. AB - Recent developments in 3-dimensional electron microcopy (3D-EM) techniques and a concomitant drive to look at complex molecular structures, have led to a rapid increase in the amount of volume data available for biomolecules. This creates a demand for better methods to analyse the data, including improved scores for comparison, classification and integration of data at different resolutions. To this end, we developed and evaluated a set of scoring functions that compare 3D EM volumes. To test our scores we used a benchmark set of volume alignments derived from the Electron Microscopy Data Bank. We find that the performance of different scores vary with the map-type, resolution and the extent of overlap between volumes. Importantly, adding the overlap information to the local scoring functions can significantly improve their precision and accuracy in a range of resolutions. A combined score involving the local mutual information and overlap (LMI_OV) performs best overall, irrespective of the map category, resolution or the extent of overlap, and we recommend this score for general use. The local mutual information score itself is found to be more discriminatory than cross correlation coefficient for intermediate-to-low resolution maps or when the map size and density distribution differ significantly. For comparing map surfaces, we implemented two filters to detect the surface points, including one based on the 'extent of surface exposure'. We show that scores that compare surfaces are useful at low resolutions and for maps with evident surface features. All the scores discussed are implemented in TEMPy (http://tempy.ismb.lon.ac.uk/). PMID- 28552723 TI - Enhanced effect of folated pluronic F87-PLA/TPGS mixed micelles on targeted delivery of paclitaxel. AB - Targeted drug delivery systems have great potential to overcome the side effect and improve the bioavailability of conventional anticancer drugs. In order to further improve the antitumor efficacy of paclitaxel (PTX) loaded in folated Pluronic F87/poly(lactic acid) (FA-F87-PLA) micelles, D-alpha-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS or Vitamin E TPGS) were added into FA F87-PLA to form FA-F87-PLA/TPGS mixed micelles. The LE of PTX-loaded mixed micelles (13.5%) was highest in the mass ratio 5 to 3 of FA-F87-PLA to TPGS. The in vitro cytotoxicity assays indicated that the IC50 values for free PTX injections, PTX-loaded FA-F87-PLA micelles and PTX-loaded FA-F87-PLA/TPGS mixed micelles after 72h of incubation were 1.52, 0.42 and 0.037mg/L, respectively. The quantitative cellular uptake of coumarin 6-loaded FA-F87-PLA/TPGS and FA-F87-PLA micelles showed that the cellular uptake efficiency of mixed micelles was higher for 2 and 4h incubation, respectively. In vivo pharmacokinetic studies found that the AUC of PTX-loaded FA-F87-PLA/TPGS mixed micelles is almost 1.4 times of that of PTX-loaded FA-F87-PLA micelles. The decreased particle size and inhibition of P-glycoprotein effect induced by the addition of TPGS could result in enhancing the cellular uptake and improving the antitumor efficiency of PTX-loaded FA-F87 PLA/TPGS mixed micelles. PMID- 28552724 TI - Nano-liposomal entrapment of bioactive peptidic fraction from fish gelatin hydrolysate. AB - This study guided the potential of nanoliposomal vesicles for the encapsulation of an active peptidic fraction from the fish skin gelatin by enzymatic hydrolysis using alcalase. The average particle size of peptide-loaded nanoliposomes was found to be in the range 134-621nm, with a zeta-potential of 0.06-8.65mV and a polydispersity index of 0.27-0.49, when the initial peptide content was 0 10mg/ml. The FTIR analysis showed that there was an effective hydrophobic interaction as well as hydrogen bonding between phosphatidylcholine and peptidic fraction. The encapsulation efficiency (EE) was remarkably influenced by peptide concentration and the maximum EE (84.5%) was achieved with 1mg/ml peptide concentration. A prolonged release of peptide from nanoliposomes was also observed as compared to free peptidic fraction. The results showed that the encapsulation of gelatin peptidic fraction using liposomal nanocarrier could represent a useful approach to overcome the issues associated with direct application of these antioxidant peptides in foodstuffs. PMID- 28552725 TI - The inhibitory effect of anti- tumor polysaccharide from Punica granatum on metastasis. AB - Galactomannan (PSP001) isolated from the fruit rind of Punica granatum was demonstrated as an excellent antioxidant, immunomodulatory and anticancer agent both in vitro and in vivo models. Since the most lethal and debilitating attribute of cancer cells is their ability to evolve to a state of malignancy, with key features like increased angiogenesis, invasion, migration, colony formation, and metastasis, the present study focused on evaluating the effects of the galactomannan on tumor and malignancy. PSP001 effectively reduced the neovascularization in chick embryos highlighting its potential as an angiogenic inhibitor. Furthermore, the invasion, migration and clonogenic capacity of human and murine cancer cells were dramatically inhibited by PSP001. Evaluation of the molecular mechanism of its unique potential revealed the down regulation of key players including VEGF, MMP-2, and MMP-9 with marked elevation of TIMP-1 and TIMP 2. The anti-metastatic potential of PSP001 tested in pulmonary metastasis C57BL/6 mice model deciphered the combinatorial administration with vincristine deliberated better survival rates and decreased metastatic index. The angiogenic inhibition potential of PSP001 was further proved with peritoneal angiogenesis assay in BALB/c mice ascitic tumor model. The outcomes of the current investigation highlight the mode of action of antitumor galactomannan in the reduction of tumor malignancy. PMID- 28552726 TI - A new cold-adapted serine peptidase from Antarctic Lysobacter sp. A03: Insights about enzyme activity at low temperatures. AB - Currently, there is a great interest for customized biocatalysts that can supply the ongoing demand of industrial processes, but also deal with the growing concern about the environment. In this scenario, cold-adapted enzymes have features that make them very attractive for industrial and biotechnological purposes. Here, we describe A03Pep1, a new cold-adapted serine peptidase isolated from Lysobacter sp. A03 by screening a genomic library. The enzyme is synthesized as a large inactive prepropeptidase that, after intramolecular processing, gives rise to the active form, of 35kDa. The heterologous expression of A03Pep1 was carried out in E. coli cells harboring the vector pGEX-4T-2-a0301. Its activity was optimal at pH 9.0 and 40 degrees C, in the presence of 25mM Ca2+, which may contribute to the thermal stability of the enzyme. The 3D structure modelling predicted a less deep and more open binding pocket in A03Pep1 than that observed in the crystal structure of its mesophilic homologous AprV2, presumably as a way to enhance the probability of substrate binding at low temperatures. These results provide possible approaches in developing new biotechnologically relevant peptidases active at low to moderate temperatures. PMID- 28552727 TI - Disseminated intravascular coagulation caused by moojenactivase, a procoagulant snake venom metalloprotease. AB - Snake venom toxins that activate coagulation factors are key players in the process of venom-induced coagulopathy, and account for severe clinical manifestations. The present study applies a variety of biochemical, hematological, and histopathological approaches to broadly investigate the intravascular and systemic effects of moojenactivase (MooA), the first described PIIId subclass metalloprotease isolated from Bothrops sp. venom that activates coagulation factors. MooA induced consumption coagulopathy with high toxic potency, characterized by prolongation of prothrombin and activated partial thromboplastin time, consumption of fibrinogen and the plasma coagulation factors X and II, and thrombocytopenia. MooA promoted leukocytosis and expression of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha, accompanied by tissue factor-dependent procoagulant activity in peripheral blood mononuclear cells. This metalloprotease also caused intravascular hemolysis, elevated plasma levels of creatine kinase-MB, aspartate transaminase, and urea/creatinine, and induced morphopathological alterations in erythrocytes, heart, kidney, and lungs associated with thrombosis and hemorrhage. Diagnosis of MooA-induced disseminated intravascular coagulation represents an important approach to better understand the pathophysiology of Bothrops envenomation and develop novel therapeutic strategies targeting hemostatic disturbances. PMID- 28552728 TI - Can natural polymers assist in delivering insulin orally? AB - Diabetes mellitus is one of the most grave and lethal non communicable diseases. Insulin is normally used to medicate diabetes. Due to bioavailability issues, the most regular route of administration is through injection, which may pose compliance problems to treatment. The oral administration thus appears as a suitable alternative, but with several important problems. Low stability of insulin in the gastrointestinal tract and low intestinal permeation are some of the issues. Encapsulation of insulin into polymer-based particles emerges as a plausible strategy. Different encapsulation approaches and polymers have been used in this regard. Polymers with different characteristics from natural or synthetic origin have been assessed to attain this goal, with natural polymers being preferable. Natural polymers studied so far include chitosan, alginate, carrageenan, starch, pectin, casein, tragacanth, dextran, carrageenan, gelatine and cyclodextrin. While some promising knowledge and results have been gained, a polymeric-based particle system to deliver insulin orally has not been introduced onto the market yet. In this review, effectiveness of different natural polymer materials developed so far along with fabrication techniques are evaluated. PMID- 28552729 TI - Effect of blueberry agro-industrial waste addition to corn starch-based films for the production of a pH-indicator film. AB - Intelligent packaging is an emerging area of food technology that can provide better preservation and be of further convenience for consumers. It is recommended that biodegradable materials be used to develop low-impact designs for better packaging, which could benefit the environment by simply expanding their use to new areas. In this work, corn starch, glycerol and blueberry powder (with and without prior fruit bleaching) were used to produce films by casting. Blueberry powder, a co-product from juice processing, which is rich in anthocyanins, was added in the films to evaluate its potential as a colorimetric indicator, due to the ability of anthocyanin to change color when placed in an acidic or basic environment. After the films were immersed in different buffer solutions, visual color changes were observed, where the films became reddish at acidic pH and bluish at basic pH. The DeltaE* values were greater than 3, suggesting a visually perceptible change to the human eye. The samples with fruit bleaching (CB) were visually darker (lower luminance values), while the samples without bleaching (SB) had a lighter color and higher brightness, represented by larger L* values. These results indicate the potential of blueberry powder as a pH indicator for intelligent food packaging or even for sensing food deterioration. PMID- 28552730 TI - Searching for behavior relating to grey matter volume in a-priori defined right dorsal premotor regions: Lessons learned. AB - Recently, we showed that the functional heterogeneity of the right dorsal premotor (PMd) cortex could be better understood by dividing it into five subregions that showed different behavioral associations according to task-based activations studies. The present study investigated whether the revealed behavioral profile could be corroborated and complemented by a structural brain behavior correlation approach in two healthy adults cohorts. Grey matter volume within the five volumes of interest (VOI-GM) was computed using voxel-based morphometry. Associations between the inter-individual differences in VOI-GM and performance across a range of neuropsychological tests were assessed in the two cohorts with and without correction for demographical variables. Additional analyses were performed in random smaller subsamples drawn from each of the two cohorts. In both cohorts, correlation coefficients were low; only few were significant and a considerable number of correlations were counterintuitive in their directions (i.e., higher performance related to lower grey matter volume). Furthermore, correlation patterns were inconsistent between the two cohorts. Subsampling revealed that correlation patterns could vary widely across small samples and that negative correlations were as likely as positive correlations. Thus, the structural brain-behavior approach did not corroborate the functional profiles of the PMd subregions inferred from activation studies, suggesting that local recruitment by fMRI studies does not necessarily imply covariance of local structure with behavioral performance in healthy adults. We discuss the limitations of such studies and related recommendations for future studies. PMID- 28552731 TI - Safety issues associated with the use of nanoparticles in human body. AB - Nanotechnology has transformed the world by the introduction of a distinctive class of materials and products in a wide array of fields. It has contributed to the production of innovative materials and devices. Having unique advantages and domestic along with industrial applications, however, has raised the issue of safety for consumers, producers and environment. Having a comparative smaller dimension and other exclusive properties, nanoparticles have the ability to harm human body by interacting through various mechanisms. Here, we endeavoured to review and discuss the characteristics of nanoparticles relevant to their toxicity, conceivable exposure routes of nanoparticles to human body like skin contact, inhalation, and ingestion, and the basic approaches which can aid to control human exposures to toxic nanoparticles have been discussed. PMID- 28552732 TI - Integrating genome-wide association study and expression quantitative trait loci data identifies multiple genes and gene set associated with neuroticism. AB - Neuroticism is a fundamental personality trait with significant genetic determinant. To identify novel susceptibility genes for neuroticism, we conducted an integrative analysis of genomic and transcriptomic data of genome wide association study (GWAS) and expression quantitative trait locus (eQTL) study. GWAS summary data was driven from published studies of neuroticism, totally involving 170,906 subjects. eQTL dataset containing 927,753 eQTLs were obtained from an eQTL meta-analysis of 5311 samples. Integrative analysis of GWAS and eQTL data was conducted by summary data-based Mendelian randomization (SMR) analysis software. To identify neuroticism associated gene sets, the SMR analysis results were further subjected to gene set enrichment analysis (GSEA). The gene set annotation dataset (containing 13,311 annotated gene sets) of GSEA Molecular Signatures Database was used. SMR single gene analysis identified 6 significant genes for neuroticism, including MSRA (p value=2.27*10-10), MGC57346 (p value=6.92*10-7), BLK (p value=1.01*10-6), XKR6 (p value=1.11*10-6), C17ORF69 (p value=1.12*10-6) and KIAA1267 (p value=4.00*10-6). Gene set enrichment analysis observed significant association for Chr8p23 gene set (false discovery rate=0.033). Our results provide novel clues for the genetic mechanism studies of neuroticism. PMID- 28552734 TI - Melanocortin-4 receptor regulation of pain. AB - An increasingly high occurrence of chronic pain in patients highlights the importance of fundamental research. The melanocortin-4 receptor (MC4R) regulation of pain has attracted much attention in recent years due to its high expression in the mammalian brain regions related to nociception and pain. This review is devoted to anatomic distribution of MC4R in the brain and interaction between MC4R and other pathways for pain modulation. The experimental evidence available at present had expanded our understanding of melanocortin-4 receptor regulation of pain. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao. PMID- 28552733 TI - FLT3 ligand regulates thymic precursor cells and hematopoietic stem cells through interactions with CXCR4 and the marrow niche. AB - Impaired immune reconstitution after hematopoietic stem cell transplantation (HSCT) is attributed in part to impaired thymopoiesis. Recent data suggest that precursor input may be a point of regulation for the thymus. We hypothesized that administration of FLT3 ligand (FLT3L) would enhance thymopoiesis after adoptive transfer of aged, FLT3L-treated bone marrow (BM) to aged, Lupron-treated hosts by increasing murine HSC (Lin[minus]Sca1+c-Kit+ [LSK] cells) trafficking and survival. In murine models of aged and young hosts, we show that FLT3L enhances thymopoiesis in aged, Lupron-treated hosts through increased survival and export of LSK cells via CXCR4 regulation. In addition, we elucidate an underlying mechanism of FLT3L action on BM LSK cells-FLT3L drives LSK cells into the stromal niche using Hoescht (Ho) dye perimortem. In summary, we show that FLT3L administration leads to: (1) increased LSK cells and early thymocyte progenitor precursors that can enhance thymopoiesis after transplantation and androgen withdrawal, (2) mobilization of LSK cells through downregulation of CXCR4, (3) enhanced BM stem cell survival associated with Bcl-2 upregulation, and (4) BM stem cell enrichment through increased trafficking to the BM niche. Therefore, we show a mechanism by which FLT3L activity on hematopoeitic and thymic progenitor cells may contribute to thymic recovery. These data have potential clinical relevance to enhance thymic reconstitution after cytoreductive therapy. PMID- 28552735 TI - N-cadherin regulates signaling mechanisms required for lens fiber cell elongation and lens morphogenesis. AB - Tissue development and regeneration involve high-ordered morphogenetic processes that are governed by elements of the cytoskeleton in conjunction with cell adhesion molecules. Such processes are particularly important in the lens whose structure dictates its function. Studies of our lens-specific N-cadherin conditional knockout mouse (N-cadcKO) revealed an essential role for N-cadherin in the migration of the apical tips of differentiating lens fiber cells along the apical surfaces of the epithelium, a region termed the Epithelial Fiber Interface (EFI), that is necessary for normal fiber cell elongation and the morphogenesis. Studies of the N-cadcKO lens suggest that N-cadherin function in fiber cell morphogenesis is linked to the activation of Rac1 and myosin II, both signaling pathways central to the regulation of cell motility including determining the directionality of cellular movement. The absence of N-cadherin did not disrupt lateral contacts between fiber cells during development, and the maintenance of Aquaporin-0 and increased expression of EphA2 at cell-cell interfaces suggests that these molecules may function in this role. E-cadherin was maintained in newly differentiating fiber cells without interfering with expression of lens specific differentiation proteins but was not able to replace N-cadherin function in these cells. The dependence of migration of the fiber cell apical domains along the EFI for lens morphogenesis on N-cadherin provides new insight into the process of tissue development. PMID- 28552736 TI - Analysis of Prognostic Factors, Survival Rates, and Treatment in Anaplastic Hemangiopericytoma. AB - OBJECTIVE: In this study, we aimed to identify prognostic factors in anaplastic hemangiopericytoma (AHPC) and clinical behaviors that differentiate primary and secondary AHPC. METHODS: The clinical data associated with 52 cases of AHPC that were surgically treated between 2008 and 2015 were reviewed. The patients were classified into the following 2 groups: primary AHPC (AHPC diagnosed at the first surgery) and secondary AHPC (malignant transformation from a lower-grade tumor). RESULTS: The study included 27 men and 25 women. The participants had a mean age of 43 years old. The 3- and 5-year progression-free survival (PFS) rates were 63.4% and 53.5%, respectively, and the corresponding overall survival rates were 78.7% and 70.9%, respectively. At the final follow-up, there were 22 (42.3%) recurrences, 4 (7.7%) extracranial metastases, and 11 (21.2%) deaths. On the basis of multivariate analysis, primary AHPC (hazard ratio [HR] = 0.293, 95% CI 0.122-0.705) and postoperative radiotherapy (PRT) (HR = 0.372, 95% confidence interval [CI] 0.148-0.932; P = 0.035) were significantly associated with increased PFS, and gross total resection (HR = 3.512, 95% CI 1.060-11.634; P = 0.040) and PRT (HR = 0.165, 95% CI 0.035-0.771; P = 0.022) were independent favorable factors for overall survival. CONCLUSION: Gross total resection and PRT following surgery are recommended in AHPC. Identifying clinical behaviors that differentiate primary and secondary AHPC improved our understanding of this type of tumor and guided treatment strategies. PMID- 28552737 TI - Association of Different Stenting Procedures with Symptomatic Thromboembolic Complications in Stent-Assisted Coiling of Ruptured Wide-Necked Intracranial Aneurysms. AB - OBJECTIVE: This study aimed to evaluate the association of different stenting procedures with the procedure-related complications in stent-assisted coiling (SAC) of ruptured wide-necked aneurysms. METHODS: Consecutive patients undergoing SAC of ruptured wide-necked aneurysms were retrospectively reviewed between December 2011 and June 2016. They received 1 of the 3 stenting procedures during SAC: 1) the coiling microcatheter was "jailed" outside of the stent and the coil embolization proceeded above the stent; 2) initial stent deployment followed by the coils through the stent's strut technique; or 3) the coil-then-stent technique. The effect of different stenting procedures on clinical complications and outcomes was estimated by logistic regression models. RESULTS: Of the 93 patients enrolled in this study, 11 of them (11.8%) suffered from symptomatic thromboembolic events and 10 of them (10.8%) had hemorrhagic complications. SAC with different stenting procedures (odds ratio [OR] = 4.10, 95% confidence interval [CI]: 1.20-13.97, P = 0.024) was the only independent risk factor for symptomatic thromboembolic events. The coil-then-stent technique had a higher ischemic complications rate than the other 2 stenting procedures (P = 0.023). Serum glucose (OR = 1.48, P = 0.014) and systolic blood pressure on admission (OR = 0.97, P = 0.046) were independent predictors of hemorrhagic complications during SAC. However, different stenting procedures and stent types were correlated with neither aneurysm occlusion at the end of procedure (P = 0.498 and 0.176, respectively) nor favorable outcome at discharge (P = 0.710 and 0.928, respectively). CONCLUSION: Different stenting procedures were associated with thromboembolic but not hemorrhagic complications in SAC of ruptured wide-necked aneurysms. PMID- 28552738 TI - Dumbbell-Shape Hydatid Cyst of Meckel Cave Extending to Cerebellopontine Angle and Middle Fossa; Surgical Technique and Outcome of Rare Case. AB - BACKGROUND: Cerebral hydatid cyst is among the rare presentations of echinococcosis. Almost all the reported cases of intracranial hydatid cysts are in the cortical regions (parietal lobe in the territory of the middle cerebral artery), and all have been removed surgically using the water jet dissection technique. However, in locations in which there are several neuronal structures, such as the cerebellopontine angle, this method might not be applicable. CASE DESCRIPTION: A 62-year-old lady presented to our outpatient clinic with left sided facial deviation, inability to close the eyes, and diplopia since a month before. She was diagnosed with having a dumbbell-shape lesion in the Meckel cave extending to the left cerebellopontine angle and middle fossa just lateral to the cavernous sinus. As it was adherent to the surrounding structures, we evacuated the contents using a fine needle and then dissected the cyst totally. The patient's symptoms alleviated after the surgery, and there was no residue. After the 2-year follow-up, our patient does not have recurrence. CONCLUSIONS: The Meckel cave and cerebellopontine angle are rare locations for hydatid cysts, and the surgical technique is different due to adhesion of the cyst to several neuronal structures (lower cranial nerve, brainstem, and cerebellum). Needle aspiration along with dissection of the cyst microsurgically is recommended in similar cases. PMID- 28552739 TI - A left thoracoabdominal approach for transdiaphragmatic fistulas following bariatric surgery. PMID- 28552740 TI - Hepatic encephalopathy after sleeve gastrectomy: a hypothesis of its development. PMID- 28552741 TI - Comment on: Bariatric surgery in young adults: a multicenter study into weight loss, dietary adherence and quality of life. PMID- 28552742 TI - Oxalobacter formigenes colonization normalizes oxalate excretion in a gastric bypass model of hyperoxaluria. AB - BACKGROUND: Hyperoxaluria and oxalate kidney stones frequently develop after Roux en-Y gastric bypass (RYGB). Oxalobacter formigenes can degrade ingested oxalate. OBJECTIVES: Examine the effect of O. formigenes wild rat strain (OXWR) colonization on urinary oxalate excretion and intestinal oxalate transport in a hyperoxaluric RYGB model. SETTING: Basic Science Laboratory, United States. METHODS: At 21 weeks of age, 28 obese male Sprague-Dawley rats survived Sham (n = 10) or RYGB (n = 18) surgery and were maintained on a 1.5% potassium oxalate, 40% fat diet. At 12 weeks postoperatively, half the animals in each group were gavaged with OXWR. At 16 weeks, percent dietary fat content was lowered to 10%. Urine and stool were collected weekly to determine oxalate and colonization status, respectively. At week 20, [14 C]-oxalate fluxes and electrical parameters were measured in vitro across isolated distal colon and jejunal (Roux limb) tissue mounted in Ussing Chambers. RESULTS: RYGB animals lost 22% total weight while Shams gained 5%. On a moderate oxalate diet, urinary oxalate excretion was 4-fold higher in RYGB than Sham controls. OXWR colonization, obtained in all gavaged animals, reduced urinary oxalate excretion 74% in RYGB and 39% in Sham and was further augmented by lowering the percentage of dietary fat. Finally, OXWR colonization significantly enhanced basal net colonic oxalate secretion in both groups. CONCLUSIONS: In our model, OXWR lowered urinary oxalate by luminal oxalate degradation in concert with promotion of enteric oxalate elimination. Trials of O. formigenes colonization and low-fat diet are warranted in calcium oxalate stone formers with gastric bypass and resistant hyperoxaluria. PMID- 28552743 TI - "Candy cane syndrome:" an underappreciated cause of abdominal pain and nausea after Roux-en-Y gastric bypass surgery. AB - BACKGROUND: "Candy cane" syndrome (a blind afferent Roux limb at the gastrojejunostomy) has been implicated as a cause of abdominal pain, nausea, and emesis after Roux-n-Y gastric bypass (RYGB) but remains poorly described. OBJECTIVES: To report that "candy cane" syndrome is real and can be treated effectively with revisional bariatric surgery SETTING: All patients underwent "candy cane" resection at University Hospitals of Cleveland. METHODS: All patients who underwent resection of the "candy cane" between January 2011 and July 2015 were included. All had preoperative workup to identify "candy cane" syndrome. Demographic data; pre-, peri-, and postoperative symptoms; data regarding hospitalization; and postoperative weight loss were assessed through retrospective chart review. Data were analyzed using Student's t test and chi2 analysis where appropriate. RESULTS: Nineteen patients had resection of the "candy cane" (94% female, mean age 50+/-11 yr), within 3 to 11 years after initial RYGB. Primary presenting symptoms were epigastric abdominal pain (68%) and nausea/vomiting (32%), particularly with fibrous foods and meats. On upper gastrointestinal study and endoscopy, the afferent blind limb was the most direct outlet from the gastrojejunostomy. Only patients with these preoperative findings were deemed to have "candy cane" syndrome. Eighteen (94%) cases were completed laparoscopically. Length of the "candy cane" ranged from 3 to 22 cm. Median length of stay was 1 day. After resection, 18 (94%) patients had complete resolution of their symptoms (P<.001). Mean body mass index decreased from 33.9+/ 6.1 kg/m2 preoperatively to 31.7+/-5.6 kg/m2 at 6 months (17.4% excess weight loss) and 30.5+/-6.9 kg/m2 at 1 year (25.7% excess weight loss). The average length of latest follow-up was 20.7 months. CONCLUSION: "Candy cane" syndrome is a real phenomenon that can be managed safely with excellent outcomes with resection of the blind afferent limb. A thorough diagnostic workup is paramount to proper identification of this syndrome. Surgeons should minimize the size of the blind afferent loop left at the time of initial RYGB. PMID- 28552744 TI - Reduction in serum fibroblast growth factor-21 after gastric bypass is related to changes in hepatic fat content. AB - BACKGROUND: Fibroblast growth factor 21 (FGF21) is elevated in obesity. OBJECTIVES: We investigated the circulating level of FGF21 and the expression of FGF21, beta-klotho (KLB), and FGF receptor 1 (FGFR1) in adipose tissue in relation to weight, fat distribution, and Roux-en-Y gastric bypass (RYGB)-induced weight loss. SETTING: The Department of Endocrinology at Aarhus University Hospital. METHODS: Thirty-one obese patients were enrolled. Visceral adipose tissue volume measured by magnetic resonance imaging, hepatic fat content measured by magnetic resonance spectroscopy, and body composition measured by dual-energy x-ray absorbtiometry were determined at baseline and 12 months after RYGB. Fasting blood samples and subcutaneous and visceral adipose tissue samples were obtained. Moreover, 25 lean controls were enrolled. RESULTS: FGF21 was significantly elevated in obese patients compared with lean patients (281+/-151 pg/mL versus 149+/-99 pg/mL, P<.05). RYGB-induced weight loss resulted in a smaller reduction in FGF21 (P = .08). However, a significant reduction was seen in obese patients with initially high FGF21 levels (42% reduction, P<.001). A significant association was found between FGF21 and hepatic fat content at baseline (r = 0.40, P<.05). Moreover, DeltaFGF21 was significantly associated with Deltahepatic fat content after RYGB (r = 0.39, P<.05). FGF21 mRNA was not detectable in AT from either lean or obese patients. KLB and FGFR1 were upregulated in AT in relation to obesity, and both were further increased 12 months after RYGB. CONCLUSIONS: FGF21 is reduced in relation to weight loss in patients with initial high levels of FGF21 and this reduction is significantly associated with a reduction in hepatic fat content. Thus, changes in FGF21 after RYGB-induced weight loss are closely related to changes in liver fat content. PMID- 28552745 TI - A critical role for cystathionine-beta-synthase in hydrogen sulfide-mediated hypoxic relaxation of the coronary artery. AB - Hypoxia-induced coronary artery vasodilatation protects the heart by increasing blood flow under ischemic conditions, however its mechanism is not fully elucidated. Hydrogen sulfide (H2S) is reported to be an oxygen sensor/transducer in the vasculature. The present study aimed to identify and characterise the role of H2S in the hypoxic response of the coronary artery, and to define the H2S synthetic enzymes involved. Immunoblotting and immunohistochemistry showed expression of all three H2S-producing enzymes, cystathionine-beta-synthase (CBS), cystathionine-gamma-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST), in porcine coronary artery. Artery segments were mounted for isometric tension recording; hypoxia caused a transient endothelium-dependent contraction followed by prolonged endothelium-independent relaxation. The CBS inhibitor amino oxyacetate (AOAA) reduced both phases of the hypoxic response. The CSE inhibitor dl-propargylglycine (PPG) and aspartate (limits MPST) had no effect alone, but when applied together with AOAA the hypoxic relaxation response was further reduced. Exogenous H2S (Na2S and NaHS) produced concentration-dependent contraction followed by prolonged relaxation. Responses to both hypoxia and exogenous H2S were dependent on the endothelium, NO, cGMP, K+ channels and Cl /HCO3- exchange. H2S production in coronary arteries was blocked by CBS inhibition (AOAA), but not by CSE inhibition (PPG). These data show that H2S is an endogenous mediator of the hypoxic response in coronary arteries. Of the three H2S-producing enzymes, CBS, expressed in the vascular smooth muscle, appears to be the most important for H2S generated during hypoxic relaxation of the coronary artery. A contribution from other H2S-producing enzymes only becomes apparent when CBS activity is inhibited. PMID- 28552746 TI - Chronic administration of sodium nitrite prevents hypertension and protects arterial endothelial function by reducing oxidative stress in angiotensin II infused mice. AB - AIM: Endothelial dysfunction accompanied by an increase in oxidative stress is a key event leading to hypertension. As dietary nitrite has been reported to exert antihypertensive effect, the present study investigated whether chronic oral administration of sodium nitrite improves vascular function in conduit and resistance arteries of hypertensive animals with elevated oxidative stress. METHODS: Sodium nitrite (50mg/L) was given to angiotensin II-infused hypertensive C57BL/6J (eight to ten weeks old) mice for two weeks in the drinking water. Arterial systolic blood pressure was measured using the tail-cuff method. Vascular responsiveness of isolated aortae and renal arteries was studied in wire myographs. The level of nitrite in the plasma and the cyclic guanosine monophosphate (cGMP) content in the arterial wall were determined using commercially available kits. The production of reactive oxygen species (ROS) and the presence of proteins (nitrotyrosine, NOx-2 and NOx-4) involved in ROS generation were evaluated with dihydroethidium (DHE) fluorescence and by Western blotting, respectively. RESULTS: Chronic administration of sodium nitrite for two weeks to mice with angiotensin II-induced hypertension decreased systolic arterial blood pressure, reversed endothelial dysfunction, increased plasma nitrite level as well as vascular cGMP content. In addition, sodium nitrite treatment also decreased the elevated nitrotyrosine and NOx-4 protein level in angiotensin II-infused hypertensive mice. CONCLUSIONS: The present study demonstrates that chronic treatment of hypertensive mice with sodium nitrite improves impaired endothelium function in conduit and resistance vessels in addition to its antihypertensive effect, partly through inhibition of ROS production. PMID- 28552747 TI - The oxidative TCA cycle operates during methanotrophic growth of the Type I methanotroph Methylomicrobium buryatense 5GB1. AB - Methanotrophs are a group of bacteria that use methane as sole carbon and energy source. Type I methanotrophs are gamma-proteobacterial methanotrophs using the ribulose monophosphate cycle (RuMP) cycle for methane assimilation. In order to facilitate metabolic engineering in the industrially promising Type I methanotroph Methylomicrobium buryatense 5GB1, flux analysis of cellular metabolism is needed and 13C tracer analysis is a foundational tool for such work. This biological system has a single-carbon input and a special network topology that together pose challenges to the current well-established methodology for 13C tracer analysis using a multi-carbon input such as glucose, and to date, no 13C tracer analysis of flux in a Type I methanotroph has been reported. In this study, we showed that by monitoring labeling patterns of several key intermediate metabolites in core metabolism, it is possible to quantitate the relative flux ratios for important branch points, such as the malate node. In addition, it is possible to assess the operation of the TCA cycle, which has been thought to be incomplete in Type I methanotrophs. Surprisingly, our analysis provides direct evidence of a complete, oxidative TCA cycle operating in M. buryatense 5GB1 using methane as sole carbon and energy substrate, contributing about 45% of the total flux for de novo malate production. Combined with mutant analysis, this method was able to identify fumA (METBUDRAFT_1453/MBURv2__60244) as the primary fumarase involved in the oxidative TCA cycle, among 2 predicted fumarases, supported by 13C tracer analysis on both fumA and fumC single knockouts. Interrupting the oxidative TCA cycle leads to a severe growth defect, suggesting that the oxidative TCA cycle functions to not only provide precursors for de novo biomass synthesis, but also to provide reducing power to the system. This information provides new opportunities for metabolic engineering of M. buryatense for the production of industrially relevant products. PMID- 28552748 TI - Characterization of a previously unrecognized clinical phenomenon: Delayed shock after cardiac implantable electronic device extraction. AB - BACKGROUND: Transvenous lead extraction remains a challenging procedure with inherent risk and associated complications. OBJECTIVE: We sought to characterize and evaluate predictors of delayed shock after transvenous lead extraction with no intraprocedural complications. METHODS: We retrospectively analyzed data of 217 consecutive patients who underwent extraction between 2010 and 2015. The primary end point was sudden onset of shock more than 4 hours after the completion of the procedure. Shock was defined as at least 30 minutes of persistent hypotension, necessitating vasopressors. Patients with mechanical or hemorrhagic shock were excluded. RESULTS: Seventeen patients (9%) developed delayed shock during the first 24 hours. Reasons for shock were sepsis (47%) or no apparent cause (53%). In multivariate analysis, patients with delayed shock had significantly lower glomerular filtration rate (median estimated glomerular filtration rate 53 mL/min vs 73 mL/min; P = .001), had more signs of systemic infection before extraction (fever, bacteremia, and leukocytosis; P < .05), and had more lead/tip remnants (29% vs 3%; P < .001). Patients presenting with delayed shock had significantly higher mortality rates at 1-year follow-up (10 [59%] vs 40 [23%], respectively; P < .01). Multivariate analysis adjusted for 1 year mortality risk was 114% higher (hazard ratio 2.14; 95% confidence interval 1.02-4.47; P < .05) in patients presenting with delayed shock. CONCLUSION: We describe a previously unrecognized clinical phenomenon of delayed shock developing after extraction. Patients with predictors of this condition at baseline should be identified and followed up closely. Even with prompt treatment, long-term mortality rates remain high. PMID- 28552749 TI - The Tpeak - Tend interval as an electrocardiographic risk marker of arrhythmic and mortality outcomes: A systematic review and meta-analysis. AB - BACKGROUND: The Tpeak - Tend interval (the interval from the peak to the end of the T wave), an electrocardiographic marker reflecting transmural dispersion of repolarization, has been used to predict ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death in different clinical settings. OBJECTIVE: This systematic review and meta-analysis evaluated the significance of the Tpeak - Tend interval in predicting arrhythmic and/or mortality end points. METHODS: PubMed, Embase, Cochrane Library, and CINAHL Plus databases were searched through November 30, 2016. RESULTS: Of the 854 studies identified initially, 33 observational studies involving 155,856 patients were included in our meta analysis. Tpeak - Tend interval prolongation (mean cutoff value 103.3 +/- 17.4 ms) was a significant predictor of the arrhythmic or mortality outcomes (odds ratio [OR] 1.14; 95% confidence interval [CI] 1.11-1.17; P < .001). When different end points were analyzed, the ORs were as follows: VT/VF, 1.10 (95% CI 1.06-1.13; P < .0001); sudden cardiac death, 1.27 (95% CI 1.17-1.39; P < .0001); cardiovascular death, 1.40 (95% CI 1.19-1.64; P < .0001); and all-cause mortality, 4.56 (95% CI 0.62-33.68; P < .0001). Subgroup analysis for each disease revealed that the risk of VT/VF or death was highest for Brugada syndrome (OR 5.68; 95% CI 1.57-20.53; P < .01), followed by hypertension (OR 1.52; 95% CI 1.26-1.85; P < .0001), heart failure (OR 1.07; 95% CI 1.04-1.11; P < .0001), and ischemic heart disease (OR 1.06; 95% CI 1.02-1.10; P = 0.001). CONCLUSION: The Tpeak - Tend interval is a useful risk stratification tool in different diseases and in the general population. PMID- 28552750 TI - [Does customized weight curves improve prenatal diagnosis of fetuses small for gestational age in a high-risk population?] AB - OBJECTIVES: To assess the accuracy of customized growth charts for the ultrasound antenatal diagnostic of fetus small for gestational age in a high-risk population of preterm. METHODS: All premature infants born in a French university maternity center for a year and classified as small for gestational age at birth by using customized growth charts developed by Ego et al. were included in this retrospective study. At the ultrasound performed closest to the term, customized growth charts and population growth curves were compared for the antenatal diagnosis of a premature infants group classified small for gestational age in post-natal by customized growth charts and more at risk of perinatal complications. RESULTS: Sixty-seven newborns were included in the study. Fifty one (76.1%) were secondarily classified as small for gestational age although they were eutrophic on the basis of population growth curves and 16 (23.9%) were small for gestational age on both curves. The average time between the last ultrasound and birth was 2.2 weeks. On the threshold of the tenth percentile, the sensitivities of customized growth charts and curves in population were not significantly different (29.85% versus 41.79% P=0.05) for antenatal detection of fetus small for gestational age. CONCLUSION: In our study, the use of customized growth charts does not improve the antenatal detection of most at-risk children. PMID- 28552751 TI - [Ultrasound of the fetal urinary system during the first trimester of pregnancy]. AB - The detection of abnormalities of the fetal urinary system in the first trimester of pregnancy is constantly improving, namely owing to the improved resolution of the image, the use of the endovaginal approach and thanks to sonographers' constant training. The pathological aspects, usually detected in the second trimester of pregnancy, can be suspected early in the first trimester and range from kidneys' cavity dilation to bilateral renal agenesis, polycystic kidney disease, multi-cystic dysplasia and bladder megavessia or bladder exstrophy. A poly-malformative syndrome is to be found out. The detection of an abnormality of the urinary tract requires a close ultrasound check. Very often, the pathological aspects tend to disappear spontaneously. In particular, the non-visualization of the bladder requires repeated examinations during the same session or even a little later in the pregnancy. We will carry out a review of the literature by pointing out the usual and unusual aspects of the fetal urinary system visible in the first trimester and we will as well propose an algorithm describing how to deal with abnormalities of the urinary tract that can be found out at first trimester ultrasound. PMID- 28552752 TI - [Original management of small cell carcinoma of the endometrium]. PMID- 28552753 TI - [Premature rupture of membranes>=37 weeks of gestation: Predictive factors for labour onset within 24hours]. AB - OBJECTIVES: To identify predictive criteria for a positive expectation in the context of rupture of membranes after 37 WG. METHODS: Single-center retrospective study including ROM>=37 WG. The primary outcome was labour onset within 24hours. We compared predictive factors for occurrence of spontaneous labour and described obstetrical and neonatal outcomes according to initial Bishop score<6 or >=6. RESULTS: From January 2013 to December 2014, 520 patients were included. The predictive factors in case of unfavorable cervix were clinical leakage (P<0.001) and a cervical dilatation>=2cm (P<0.001) according to multivariate analysis. When the expectancy failed, there was a higher rate of cesarean section (24.3% vs. 9.6% P<0.001) but no more proven maternal-fetal infection. In case of Bishop>=6, we identified no predictive factor for labour onset but Apgar<7 at 5minutes (18.7% vs. 3.2% P=0.01) and admission to neonatal unit (18.8% vs. 3.2% P=0.04) were more frequent without majoration of maternal-fetal infection. CONCLUSION: The favorable expectation was the outcome for 70.8% of ROM at term. Clinical leakage and dilated cervix appeared as the main predictors in case of Bishop<6. Majoration of low Apgar score and admission to neonatal unit could be increased when no labour onset occurred despite Bishop>=6. PMID- 28552754 TI - [Interstitial, angular and cornual pregnancies: Diagnosis, treatment and subsequent fertility]. AB - OBJECTIVE: Interstitial, angular and corneal pregnancies are not very frequent and often mistaken, each with its own definition and prognosis. The objective of this work is to relate 10 years experience of ectopic pregnancies at the UH in Dijon, based on the latest data from the literature in term of diagnosis, management and subsequent fertility. METHOD: This is a retrospective study carried out at the UH of Dijon from 01/01/2005 to 01/01/2015. From the medical records of each patient who presented a corneal, interstitial or angular pregnancy, we identified the risk factors for ectopic pregnancy (EG), the diagnostic and therapeutic means used, and the subsequent obstetrical events. RESULTS: In 10 years, 532 EG were managed including 10 interstitials, one angular and nine cornual. The main risk factors were previous EG (50%), salpingectomy (55%), curettage (45%) and smoking (40%). The localization of the EG was done in 75% by the endo-vaginal sonography, in 25% in peroperative. Thirty-five percent were treated with methotrexate, 20% had surgery and 40% had both. Seventy-five percent of patients had at least one ulterior pregnancy. In the case of caesarean section, no dehiscence of the corneal scar was identified. CONCLUSION: This study shows the presence of medical antecedents which are risk factors of the tubular EG. A methotrexate protocol should be proposed first. Even after corneal surgery, vaginal delivery may remain possible. PMID- 28552755 TI - [Morbidity and functional long-term follow-up of patients with surgical treatment of urinary tract endometriosis]. AB - OBJECTIVE: To assess postoperative complications, improvement of pain symptoms and residual urinary functional symptoms after surgery for deep infiltrative endometriosis affecting ureter or bladder. METHODS: Retrospective study of complications (Clavien-Dindo classification), pain (visual analog scale [VAS]) and urinary functional symptoms (Urinary Symptom Profile questionnaire [USP]) of patients surgically treated between 2007 and 2015 in University Hospitals of Lyon. RESULTS: Among 31 patients with endometriosis involving the bladder, 83.9% had a partial cystectomy and 16.1% an extra-mucosal resection. Among patients (n=20) with ureteral involvement, 85% had ureterectomy with ureterocystoneostomy and 15% had only ureterolysis. Grade III postoperative complications occurred in 6% and 0% of patients with bladder or ureteral surgery, respectively and no grade IV or V complications were reported. Mean bladder VAS dropped from 5.3+/-4.2 to 0.3+/-0.9 after a follow-up of 42 months (P<0.0001). In patients with ureteral involvement, mean flank VAS dropped from 3.6 to 0.9 after a follow-up of 33 months (P<0.0005). Mean postoperative USP score for dysuria and detrusor overactivity were 1.35/9 and 2.48/21 in case of bladder involvement, and 1.10/9 and 2.15/21 in case of ureteral involvement. CONCLUSION: Multidisciplinary surgical management of deep infiltrative endometriosis affecting urinary tract was associated to a low risk of severe postoperative complications and to a long term significant improvement of pain symptoms without significant residual functional urinary symptoms. PMID- 28552756 TI - Dopamine modified hyperbranched TiO2 arrays based ultrasensitive photoelectrochemical immunosensor for detecting neuron specific enolase. AB - In this work, three-dimensional (3D) hyperbranched TiO2 nanorod arrays were synthesized and used to fabricate dopamine sensitized photoelectrochemical (PEC) biosensor. To increase the lifetime of charge carriers and enhance the photocurrent responses signal, a delicate signal amplification strategy by introducing dopamine (DA) as sensitizer was developed. The dopamine sensitized TiO2 can shorten the carrier diffusion distance, improve light harvesting efficiency and charge collection efficiency, which results in performance improvement of the as-obtained PEC sensor. This proposed biosensor for determination of neuron specific enolase (NSE) demonstrated a good linear relationship range from 0.1 ng mL-1 to 1000 ng mL-1 with a detection limit of 0.05 ngmL-1 (S/N = 3). In addition, the as-prepared immunosensor exhibits excellent selectivity, stability and reproducibility, which could be extended to other label-free sensing fields. Therefore, this proposed method may also provide potential applications for the clinical examination. PMID- 28552757 TI - Selective fluorescence detection method for selenide and selenol using monochlorobimane. AB - The low redox potential of selenide and selenol is physiologically important, as it confers efficient catalytic abilities to selenoproteins. Quantitative determination of selenol and selenide provide important clues for understanding the metabolism and physiological function of selenium. However, selective detection of selenol and selenide is extremely difficult because of their chemical similarity to thiol and sulfide. In this study, we established a highly sensitive, selective, quantitative, and simple method for detection of selenol and selenide, using a reaction with monochlorobimane (MCB), followed by ethyl acetate extraction of the product syn-(methyl,methyl)bimane. We analyzed selenide production from selenite, catalyzed by human glutathione reductase, and also determined selenide and selenol concentrations in Hepa1-6 cells using the MCB method, to demonstrate its practical applications. This study provides a new tool for selenium detection in biology. PMID- 28552758 TI - Fluorescence polarization-based competition binding assay for c-Jun N-terminal kinases 1 and 2. AB - In order to evaluate the isoform selectivity of novel inhibitors within the c-Jun N-terminal kinase (JNK) family, a fluorescence polarization-based competition binding assay, previously developed for JNK3, was extended to the other isoforms JNK1 and JNK2. The assay is based on the displacement of a versatile fluorescent pyridinylimidazole-based probe and was validated by testing the precursor of the probe as well as standard JNK inhibitors. PMID- 28552759 TI - Generation of SMURF2 knockout human cells using the CRISPR/Cas9 system. AB - The HECT domain E3 ubiquitin ligase SMURF2 regulates stability of several key protein targets involved in tumorigenesis, cell proliferation, migration, differentiation, and senescence. While altered levels and aberrant cellular distribution of SMURF2 were reported in different types of cancer, its role in tumorigenesis is far from understood. To elucidate the role of SMURF2 in cancer, appropriate human cancer cell models are needed. Here, we describe approaches that can be used to generate human normal and cancer cell strains knocked-out for SMURF2 using the clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene-editing technology. PMID- 28552760 TI - Denervation of the wrist with two surgical incisions. Is it effective? A review of 33 patients with an average of 41months' follow-up. AB - : The goal of wrist denervation is to decrease pain at the wrist, whether caused by an intra- or extra-articular problem or even when the reason for the pain is unknown. It is an alternative to partial or total arthrodesis and proximal row carpectomy. Our hypothesis was that wrist denervation with a two-incision technique was a reliable and efficient way to treat painful degenerative wrists. Thirty-three patients, 48years old on average, were included in this study. Indications were scapholunate advanced collapse (SLAC) in 18 cases, scaphoid nonunion advanced collapse (SNAC) in 10, distal radius fracture sequelae with advanced radiocarpal osteoarthritis in 4, and post-traumatic ulnocarpal impingement in 1 case. At 41 months' follow-up (12-161), there was a 75% reduction in pain levels, decreasing from 7.1 to 1.8 on a visual analog scale (VAS). There were no modifications related to wrist range of motion or grip strength. The QuickDASH averaged 23 points (5 to 70). Radiographic evaluation showed progression of intracarpal degeneration in 6 patients. All but 2 patients returned to their previous work. Persistent dysesthesia was observed in 7 patients; it resolved in 3 cases and persisted in 4. One patient developed complex regional pain syndrome (CRPS). A midcarpal arthrodesis with scaphoidectomy was performed in one patient because of disabling pain 5months after surgery. Wrist denervation with a two-incision technique for post-traumatic osteoarthritis led to satisfactory results in 75% of cases with reduction in pain, preservation of range of motion and grip strength. However, this technique does not stop the progression of osteoarthritis. It can be discussed as a therapeutic alternative to proximal row carpectomy or intracarpal arthrodesis to treat degenerative painful wrists. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28552761 TI - Hematopoietic stem cell transplantation for RelB deficiency. PMID- 28552762 TI - ImmunoCAP assays: Pros and cons in allergology. AB - Allergen-specific IgE measurements and the clinical history are the cornerstones of allergy diagnosis. During the past decades, both characterization and standardization of allergen extracts and assay technology have improved. Here we discuss the uses, advantages, misinterpretations, and limitations of ImmunoCAP IgE assays (Thermo Fisher Scientific/Phadia, Uppsala, Sweden) in the field of allergology. They can be performed as singleplex (ImmunoCAP) and, for the last decade, as multiplex (Immuno Solid-phase Allergen Chip [ISAC]). The major benefit of ImmunoCAP is the obtained quantified allergen-specific IgE antibody level and the lack of interference from allergen-specific IgG antibodies. However, ImmunoCAP allergen extracts are limited to the composition of the extract. The introduction of allergen molecules has had a major effect on analytic specificity and allergy diagnosis. They are used in both singleplex ImmunoCAP and multiplex ImmunoCAP ISAC assays. The major advantage of ISAC is the comprehensive IgE pattern obtained with a minute amount of serum. The shortcomings are its semiquantitative measurements, lower linear range, and cost per assay. With respect to assay performance, ImmunoCAP allergen extracts are good screening tools, but allergen molecules dissect the IgE response on a molecular level and put allergy research on the map of precision medicine. PMID- 28552763 TI - Prevention of food allergy development and suppression of established food allergy by neutralization of thymic stromal lymphopoietin, IL-25, and IL-33. AB - BACKGROUND: Food allergy (FA) is an increasing problem that has no approved treatment. The pro-TH2 cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) are associated with FA, and mAbs to these cytokines are reported to suppress murine FA development. OBJECTIVE: We sought to determine whether anti pro-TH2 cytokine mAbs can block both FA maintenance and induction. METHODS: IgE mediated FA was induced in BALB/c mice by oral gavage with medium-chain triglycerides (MCTs) plus egg white (EW) and was characterized by increased numbers of lamina propria TH2 cells, mast cells, and eosinophils, shock (hypothermia), mast cell degranulation (increased serum mouse mast cell protease 1), increased serum IgG1 anti-EW and IgE levels, and increased IL-4 and IL-13 secretion after MCT/EW challenge. Mice were injected with anti-IL-25, IL-33 receptor, and/or TSLP mAbs before initial oral gavage with MCT/EW to suppress FA development; treatment with the same mAbs was initiated after FA development to suppress established FA. RESULTS: Injection of an mAb to IL-25, IL-33 receptor, or TSLP strongly inhibited FA development. No single mAb to a pro-TH2 cytokine could suppress established FA, and optimal FA suppression required treatment with a cocktail of all 3 anti-pro-TH2 mAbs. Treatment with the 3-mAb cocktail during initial MCT/EW immunization induced EW tolerance. CONCLUSION: All of the pro-TH2 cytokines are required to induce our model of FA, whereas any pro-TH2 cytokine can maintain established FA. Pro-TH2 cytokines prevent oral tolerance. Combined treatment with antagonists to all 3 pro-TH2 cytokines or with an inhibitor of pro TH2 cytokine production might be able to suppress established human FA. PMID- 28552764 TI - Metalware-associated orthopaedic infections caused by Staphylococcus lugdunensis: An emerging pathogen. PMID- 28552765 TI - Comprehensive Analysis of the Discordance of EGFR Mutation Status between Tumor Tissues and Matched Circulating Tumor DNA in Advanced Non-Small Cell Lung Cancer. AB - INTRODUCTION: This study aimed to address the underlying reasons for and clinical significance of the discordant EGFR mutation (EGFRm) status between tumor tissue (TT) and circulating tumor DNA (ctDNA). METHODS: Three groups of EGFR tyrosine kinase inhibitor (EGFR TKI)-treated patients whose EGFRm status was determined by the amplification refractory mutation system (ARMS) were included (group A, TT positive/ctDNA-positive EGFRm status; group B, TT-negative/ctDNA-positive EGFRm status; and group C, TT-positive/ctDNA-negative EGFRm status). Patients with discordant EGFRm status were reevaluated by droplet digital polymerase chain reaction (ddPCR) and next-generation sequencing. Meanwhile, surgical tumor specimens were microdissected for EGFRm detection by ddPCR. RESULTS: Of the 2463 patients with matched TT and ctDNA specimens, 1017 patients carried EGFRm in TT and/or ctDNA by the ARMS. Of these 1017 patients, 472 received EGFR TKIs, including 264, 28, and 180 in groups A, B, and C, respectively. The median progression-free survivals of those receiving EGFR TKIs across the three groups were similar (p = 0.062). Through ddPCR and next-generation sequencing of biopsy specimens (n = 22) and microdissected surgical specimens (n = 5), 27 patients in group B were identified as harboring EGFRm. After reevaluation by ddPCR, 64 patients in group C tested positive for EGFRm in their ctDNA. ctDNA as a screen for EGFRm then tissues as supplement (ctDNA->TT pattern) had similar detection efficiency and saved about 30% of TT compared with TT for initial EGFRm detection followed by ctDNA (TT->ctDNA pattern). CONCLUSIONS: Intratumor heterogeneity and the relatively low sensitivity of the ARMS contributed to discordant EGFRm status between TT specimens and ctDNA. The ctDNA->TT pattern might be a rational clinical procedure for EGFRm determination. PMID- 28552767 TI - Parenteral nanoemulsions of risperidone for enhanced brain delivery in acute psychosis: Physicochemical and in vivo performances. AB - This work aimed to deepen the lately acquired knowledge about parenteral nanoemulsions as carriers for brain delivery of risperidone, a poorly water soluble antipsychotic drug, through establishing the prospective relationship between their physicochemical, pharmacokinetic, biodistribution, and behavioral performances. For this purpose, two optimized risperidone-loaded nanoemulsions, stabilized by lecithin or lecithin/polysorbate 80 mixture, and costabilized by sodium oleate, were produced by high-pressure homogenization. The characterization revealed the favorable droplet size, narrow size distribution, high surface charge, with proven stability to autoclaving and long-term stability for at least one year at 25+/-2 degrees C. Pharmacokinetic and tissue distribution results demonstrated improved plasma, liver, and brain pharmacokinetic parameters, resulting in 1.2-1.5-fold increased relative bioavailability, 1.1-1.8-fold decreased liver distribution, and about 1.3-fold improved brain uptake of risperidone active moiety following intraperitoneal administration of nanoemulsions relative to solution in rats. In behavioral study, investigated nanoemulsions showed pronounced reduction in basal and, more pertinently, amphetamine-induced locomotor activity in rats, with an early onset of antipsychotic action, and this effect lasted at least 90min after drug injection. Together, these findings corroborate the applicability of parenteral nanoemulsions as carriers for enhanced brain delivery of risperidone, further suggesting their promise in acute psychosis treatment or other emergency situations. PMID- 28552766 TI - The Influence of Body Mass Index on Overall Survival Following Surgical Resection of Non-Small Cell Lung Cancer. AB - BACKGROUND: Population studies suggest that high body mass index (BMI) correlates with a reduced risk for death from lung cancer. The aim of our study was to evaluate definitively the influence of BMI on long-term overall survival (OS) in surgical patients with NSCLC. METHODS: The study population consisted of 1935 patients who underwent surgical resection for lung cancer at M. D. Anderson Cancer Center (2000-2014). Study variables included both patient- and treatment related characteristics. Univariate and multivariate Cox regression analyses were performed to identify variables associated with OS. RESULTS: On univariate analysis, significant predictors of improved survival were higher BMI, pathologic tumor stage (stage I versus stage II, III, or IV), type of surgical procedure (lobectomy/pneumonectomy versus wedge resection/segmentectomy), younger age, female sex, and adenocarcinoma histologic subtype (versus squamous) (all p < 0.05). Morbidly obese patients (BMI >= 35) demonstrated a trend toward better outcomes than those classified as obese (BMI >=30 and <35 kg/m2) (p = 0.05), overweight (BMI >= 25 and <30 kg/m2) (p = 0.13), or healthy weight (BMI <25 kg/m2) (p = 0.37) (hazard ratio = 0.727, 0.848, 0.926, and 1, respectively). On multivariate analysis, BMI remained an independent predictor of survival (p = 0.02). Propensity matching analysis demonstrated significantly better OS (p = 0.003) in patients with a BMI of 30 kg/m2 or higher as compared with a BMI of 25 kg/m2. CONCLUSIONS: In this large, retrospective, single-center series, after control for disease stage and other variables, higher BMI was associated with improved OS after surgical resection of NSCLC. Further studies are necessary to elucidate the precise relationship between BMI and treatment outcomes. PMID- 28552768 TI - Supramolecular polypseudorotaxane gels for controlled delivery of rAAV vectors in human mesenchymal stem cells for regenerative medicine. AB - The aim of this work was to investigate, for the first time, the possibility of using supramolecular polypseudorotaxane gels as scaffolds that can durably deliver rAAV vectors for applications in cartilage regeneration. Dispersions of Pluronic(r) F68 (PF68) or Tetronic(r) 908 (T908) containing either hyaluronic acid (HA) or chondroitin sulfate (CS) were prepared in PBS. Then, alpha cyclodextrin (alphaCD) was added to some dispersions to form polypseudorotaxane gels. Polysaccharides and alphaCD reinforced the viscoelasticity of the gels, which could withstand autoclaving without changes. In vitro release of rAAV vectors and subsequent transduction of human mesenchymal stem cells (hMSCs) by rAAV vectors from the release medium and from gels in direct contact with the cells were investigated. Compared with free vectors, the gels provided higher levels of transgene expression. CS (or HA)/PF68/alphaCD gels rapidly released rAAV vectors while CS (or HA)/T908/alphaCD gels provided sustained release probably due to different interactions with the viral vectors. Incorporation of alphaCD into CS (or HA)/PF68 gels resulted on higher rAAV concentrations and sustained levels of transgene expression over time. HA increased the bioactivity and cytocompatibility of the gels, especially those based on T908. Overall, combining rAAV gene transfer with polypseudorotaxane gels may provide new, promising tools for human tissue engineering and regenerative medicine strategies. PMID- 28552769 TI - An investigation into the ability of alendronate ion pairs to increase oral absorption. AB - The purpose of this study is to increase oral absorption of the highly charged drug alendronate using an ion pair strategy. Ion pairing is a formulation approach in drug delivery that is performed to improve the lipophilicity of ionized drugs. Cationic counter ions, such as arginine, phenazopyridine, hyoscine and pyridostigmine, were selected to enhance the lipophilicity and permeability of alendronate. Data obtained from quasi-equilibrium analysis were used to calculate the binding constant and intrinsic partition coefficient of ion pairs in an octanol/water system. The results of the partitioning study in an octanol/water system were confirmed using in vitro transport models with PAMPA and Caco-2 monolayer assays. Two counter ions, phenazopyridine and arginine, substantially increased the partition coefficient of alendronate by up to 1.15 and 0.73 units, respectively, in the octanol/water system. Binding constants of 117M-1 for alendronate-arginine and 90M-1 for alendronate-phenazopyridine ion pairs were obtained using quasi equilibrium analysis. Arginine and phenazopyridine enhanced the apparent permeability of alendronate by 14- and 26 fold in the PAMPA model and 6.5- and 4.4-fold across caco-2 cell monolayers, respectively. Based on this study, the lipophilicity and permeability of alendronate across lipophilic membranes was increased by suitable counter ions and could be used to establish a new formulation to increase the oral absorption of alendronate. PMID- 28552770 TI - Synbiotic loaded chitosan-Ca-alginate microparticles reduces inflammation in the TNBS model of rat colitis. AB - New therapeutic strategies against inflammatory bowel disease (IBD) consider the usage of probiotics, prebiotics and synbiotics as beneficial for the intestinal microbial balance. Limitations of such an approach are addressed into difference in survival, persistence, colonization and variable effects among different probiotic strains, lack in understanding of probiotic mechanisms of action, as well the complex etiology of IBD. The anti-inflammatory activity of Lactobacillus casei 01 (L. casei 01) was assessed in trinitrobenzenesulphonic (TNBS) acid model of rat colitis when the probiotic was used alone and/or in combination with oligofructose-enriched inulin (Synergy 1), and as synbiotic (L. casei 01+Synergy 1) loaded chitosan-Ca-alginate microparticles; all suspended in ayran. The results from the probiotic/synbiotic treatments (8.5-8.9log CFU g-1L. casei 01 and 1.5% Synergy 1) have shown reduction in the colonic damage and increased lactobacilli counts in feces. Lactobacilli translocation to sterile extra intestinal organs demonstrated acceptable safety of the probiotic strain used. The best effect at reducing inflammation and lesions associated with a significant decline in myeloperoxidase (MPO) activity was observed in rats that received synbiotic microparticles. This finding suggests colon targeted delivery of the probiotics/synbiotics, as an advantageous approach in prevention and treatment of IBD. PMID- 28552771 TI - Dose-dependent effect and pharmacokinetics of fexinidazole and its metabolites in a mouse model of human African trypanosomiasis. AB - Human African trypanosomiasis (HAT) is a neglected tropical disease, with a population of 70 million at risk. Current treatment options are limited. In the search for new therapeutics, the repurposing of the broad-spectrum antiprotozoal drug fexinidazole has completed Phase III trials with the anticipation that it will be the first oral treatment for HAT. This study used the recently validated bioluminescence imaging model to assess the dose and rate of kill effect of fexinidazole in infected mice, and the dose-dependent effect of fexinidazole on trypanosome infection. Pharmacokinetics of fexinidazole in plasma and central nervous system (CNS) compartments were similar in both infected and uninfected mice. Drug distribution within the CNS was further examined by microdialysis, showing similar levels in the cortex and hippocampus. However, high variability in drug distribution and exposure was found between mice. PMID- 28552772 TI - PCB 28 metabolites elimination kinetics in human plasma on a real case scenario: Study of hydroxylated polychlorinated biphenyl (OH-PCB) metabolites of PCB 28 in a highly exposed German Cohort. AB - Polychlorinated biphenyls (PCBs) are suspected of carcinogenic, neurotoxic and immunotoxic effects in animals and humans. Although background levels of PCBs have been slowly decreased after their ban, they are still among the most persistent and ubiquitous pollutants in the environment, remaining the subject of great concern. PCB 28 is a trichlorinated PCB found in high concentrations not only in human plasma but also in indoor air in Europe, yet little is known about its metabolic pathway and potential metabolites in humans. The present study aims to elucidate the kinetics of metabolite formation and elimination by analyzing four hydroxylated PCBs (OH-PCBs) in human plasma as potential metabolites of the PCB 28 congener. For this purpose, the study was conducted in plasma samples of highly PCB-exposed individuals (N=268), collected from 2010 to 2014 as a representation of a real case scenario with longitudinal data. OH-PCBs have been predicted, synthesized in the course of this study and further identified and quantitated in human plasma. This is the first time that previously unknown PCB 28 metabolites have been measured in human plasma and half-lives have been estimated for PCB metabolites, which could then provide further understanding in the toxicological consequences of exposure to PCBs in humans. PMID- 28552773 TI - Voltage gated ion channels blockade is the underlying mechanism of BIMU8 induced cardiotoxicity. AB - BIMU8 is a 5-HT4a receptor agonist and used as an experimental drug to counteract opioid induced respiratory depression. In preliminary experiments serious disturbances in ECG were observed in anesthetized rabbits which prompted us to explore the underlying cause of BIMU8 induced abnormal changes in ECG recordings. Electrophysiological experiments were performed on HEK-293 cells expressing hERG, CaV1.2 and NaV1.5 ion channels. In whole-cell recordings BIMU8 effectively blocked these three channels, with IC50 values of 0.06+/-0.05, 1.46+/-0.26 and 4.66+/-0.58MUM for hERG, NaV1.5 and CaV1.2, respectively. Additionally it also produced a hyperpolarizing shift of 3.27mV in half maximal activation and 12.87mV in fast inactivation of NaV1.5 channel. These experimental findings indicate that BIMU8 is a potent blocker of hERG, NaV1.5 and CaV1.2 cardiac ion channels thus revealing its proarrhythmic potential. PMID- 28552774 TI - Uptake of perfluorooctanoic acid by Caco-2 cells: Involvement of organic anion transporting polypeptides. AB - The mechanism underlying the intestinal absorption of perfluorooctanoic acid (PFOA) was investigated using Caco-2 cells. The uptake of PFOA from the apical membrane of Caco-2 cells was fast, and pH, temperature, and concentration dependent, but Na+ independent. Coincubation with sulfobromophthalein (BSP), glibenclamide, estron-3-sulfate, cyclosporine A or rifamycin SV, which are typical substrates or inhibitors of organic anion transporting polypeptides (OATPs), significantly decreased the uptake of PFOA. However, coincubation with probenecid or p-aminohippuric acid, typical substrates of organic anion transporters, did not decrease the uptake of PFOA. Furthermore, coincubation with l-lactic acid or benzoic acid, substrates of monocarboxylic acid transporters, did not decrease PFOA uptake. The relationship between the initial uptake of PFOA and its concentration was saturable, suggesting the involvement of a carrier mediated process. The calculated Km and uptake clearance (Vmax/Km) values for PFOA were 8.3MUM and 55.0MUL/mg protein/min, respectively. This clearance value was about 3-fold greater than that of the non-saturable uptake clearance (Kd: 18.1MUL/mg protein/min). Lineweaver-Burk plots revealed that BSP competitively inhibits the uptake of PFOA, with a Ki value of 23.1MUM. These results suggest that the uptake of PFOA from the apical membranes of Caco-2 cells could be, at least in part, mediated by OATPs along with BSP. PMID- 28552775 TI - Evaluation of in-line Raman data for end-point determination of a coating process: Comparison of Science-Based Calibration, PLS-regression and univariate data analysis. AB - A multivariate analysis method, Science-Based Calibration (SBC), was used for the first time for endpoint determination of a tablet coating process using Raman data. Two types of tablet cores, placebo and caffeine cores, received a coating suspension comprising a polyvinyl alcohol-polyethylene glycol graft-copolymer and titanium dioxide to a maximum coating thickness of 80um. Raman spectroscopy was used as in-line PAT tool. The spectra were acquired every minute and correlated to the amount of applied aqueous coating suspension. SBC was compared to another well-known multivariate analysis method, Partial Least Squares-regression (PLS) and a simpler approach, Univariate Data Analysis (UVDA). All developed calibration models had coefficient of determination values (R2) higher than 0.99. The coating endpoints could be predicted with root mean square errors (RMSEP) less than 3.1% of the applied coating suspensions. Compared to PLS and UVDA, SBC proved to be an alternative multivariate calibration method with high predictive power. PMID- 28552776 TI - Differential sensitivities of cellular XPA and PARP-1 to arsenite inhibition and zinc rescue. AB - Arsenite directly binds to the zinc finger domains of the DNA repair protein poly (ADP ribose) polymerase (PARP)-1, and inhibits PARP-1 activity in the base excision repair (BER) pathway. PARP inhibition by arsenite enhances ultraviolet radiation (UVR)-induced DNA damage in keratinocytes, and the increase in DNA damage is reduced by zinc supplementation. However, little is known about the effects of arsenite and zinc on the zinc finger nucleotide excision repair (NER) protein xeroderma pigmentosum group A (XPA). In this study, we investigated the difference in response to arsenite exposure between XPA and PARP-1, and the differential effectiveness of zinc supplementation in restoring protein DNA binding and DNA damage repair. Arsenite targeted both XPA and PARP-1 in human keratinocytes, resulting in zinc loss from each protein and a pronounced decrease in XPA and PARP-1 binding to chromatin as demonstrated by Chip-on-Western assays. Zinc effectively restored DNA binding of PARP-1 and XPA to chromatin when zinc concentrations were equal to those of arsenite. In contrast, zinc was more effective in rescuing arsenite-augmented direct UVR-induced DNA damage than oxidative DNA damage. Taken together, our findings indicate that arsenite interferes with PARP-1 and XPA binding to chromatin, and that zinc supplementation fully restores DNA binding activity to both proteins in the cellular context. Interestingly, rescue of arsenite-inhibited DNA damage repair by supplemental zinc was more sensitive for DNA damage repaired by the XPA associated NER pathway than for the PARP-1-dependent BER pathway. This study expands our understanding of arsenite's role in DNA repair inhibition and co carcinogenesis. PMID- 28552777 TI - Comparison of the toxicity of sintered and unsintered indium-tin oxide particles in murine macrophage and epidermal cells. AB - Indium-tin oxide (ITO) is used to produce flat panel displays and several other technology products. Composed of 90% indium oxide (In2O3) and 10% tin oxide (SnO2) by weight, ITO is synthesized under conditions of high heat via a process known as sintering. Indium lung disease, a recently recognized occupational illness, is characterized by pulmonary alveolar proteinosis, fibrosis, and emphysema. Murine macrophage (RAW 264.7) and epidermal (JB6) cells stably transfected with AP-1 to study tumor promoting potential, were used to differentiate between the toxicological profiles of sintered ITO (SITO) and unsintered mixture (UITO). We hypothesized that sintering would play a key role in free radical generation and cytotoxicity. Exposure of cells to both UITO and SITO caused a time and dose dependent decrease of the viability of cells. Intracellular ROS generation was inversely related to the dose of both UITO and SITO, a direct reflection of the decreased number of viable RAW 264.7 and JB6/AP 1 cells observed at higher concentrations. Electron spin resonance showed significantly increased hydroxyl radical (OH) generation in cells exposed to UITO compared to SITO. This is different from LDH release, which showed that SITO caused significantly increased damage to the cell membrane compared to UITO. Lastly, the JB6/AP-1 cell line did not show activation of the AP-1 pathway. Our results highlight both the differences in the mechanisms of cytotoxicity and the consistent adverse effects associated with UITO and SITO exposure. PMID- 28552778 TI - The impact of Zearalenone on the meiotic progression and primordial follicle assembly during early oogenesis. AB - Zearalenone (ZEA) is a mycotoxin produced by fusarium graminearum. It can cause abnormal reproductive function by acting as an environmental estrogen. Research has traditionally focused on acute and chronic injury on mammalian reproductive capacity after ZEA treatment. Little research has been done studying the effects of ZEA exposure on early oogenesis. In this study, we investigate the effects of ZEA exposure on meiotic entry, DNA double-strand breaks (DSBs), and primordial follicle assembly during murine early oogenesis. The results show that ZEA exposure significantly decreased the percentage of diplotene stage germ cells, and made more germ cells remain at zygotene or pachytene stages. Moreover, the mRNA expression level of meiosis-related genes was significantly reduced after ZEA treatment. ZEA exposure significantly increased DNA-DSBs at the diplotene stage. Meanwhile, DNA damage repair genes such as RAD51 and BRCA1 were activated. Furthermore, maternal exposure to ZEA significantly decreased the number of primordial follicles in newborn mouse ovaries. In conclusion, ZEA exposure impairs mouse female germ cell meiotic progression, DNA-DSBs, and primordial follicle assembly. PMID- 28552779 TI - Nickel-induced HIF-1alpha promotes growth arrest and senescence in normal human cells but lacks toxic effects in transformed cells. AB - Nickel is a human carcinogen that acts as a hypoxia mimic by activating the transcription factor HIF-1alpha and hypoxia-like transcriptomic responses. Hypoxia and elevated HIF-1alpha are typically associated with drug resistance in cancer cells, which is caused by increased drug efflux and other mechanisms. Here we examined the role of HIF-1alpha in uptake of soluble Ni(II) and Ni(II)-induced cell fate outcomes using si/shRNA knockdowns and gene deletion models. We found that HIF-1alpha had no effect on accumulation of Ni(II) in two transformed (H460, A549) and two normal human cell lines (IMR90, WI38). The loss of HIF-1alpha also produced no significant impact on p53-dependent and p53-independent apoptotic responses or clonogenic survival of Ni(II)-treated transformed cells. In normal human cells, HIF-1alpha enhanced the ability of Ni(II) to inhibit cell proliferation and cause a permanent growth arrest (senescence). Consistent with its growth-suppressive effects, HIF-1alpha was important for upregulation of the cell cycle inhibitors p21 (CDKN1A) and p27 (CDKN1B). Irrespective of HIF-1alpha status, Ni(II) strongly increased levels of MYC protein but did not change protein expression of the cell cycle-promoting phosphatase CDC25A or the CDK inhibitor p16. Our findings indicate that HIF-1alpha limits propagation of Ni(II) damaged normal cells, suggesting that it may act in a tumor suppressor-like manner during early stages of Ni(II) carcinogenesis. PMID- 28552781 TI - Dissociated neural basis of two behavioral hallmarks of holistic face processing: The whole-part effect and composite-face effect. AB - It has been long proposed that our extraordinary face recognition ability stems from holistic face processing. Two widely-used behavioral hallmarks of holistic face processing are the whole-part effect (WPE) and composite-face effect (CFE). However, it remains unknown whether these two effects reflect similar or different aspects of holistic face processing. Here we investigated this question by examining whether the WPE and CFE involved shared or distinct neural substrates in a large sample of participants (N=200). We found that the WPE and CFE showed hemispheric dissociation in the fusiform face area (FFA), that is, the WPE was correlated with face selectivity in the left FFA, while the CFE was correlated with face selectivity in the right FFA. Further, the correlation between the WPE and face selectivity was largely driven by the FFA response to faces, whereas the association between the CFE and face selectivity resulted from suppressed response to objects in the right FFA. Finally, we also observed dissociated correlation patterns of the WPE and CFE in other face-selective regions and across the whole brain. These results suggest that the WPE and CFE may reflect different aspects of holistic face processing, which shed new light on the behavioral dissociations of these two effects demonstrated in literature. PMID- 28552780 TI - The Genome of Medicinal Plant Macleaya cordata Provides New Insights into Benzylisoquinoline Alkaloids Metabolism. AB - The overuse of antibiotics in animal agriculture and medicine has caused a series of potential threats to public health. Macleaya cordata is a medicinal plant species from the Papaveraceae family, providing a safe resource for the manufacture of antimicrobial feed additive for livestock. The active constituents from M. cordata are known to include benzylisoquinoline alkaloids (BIAs) such as sanguinarine (SAN) and chelerythrine (CHE), but their metabolic pathways have yet to be studied in this non-model plant. The active biosynthesis of SAN and CHE in M. cordata was first examined and confirmed by feeding 13C-labeled tyrosine. To gain further insights, we de novo sequenced the whole genome of M. cordata, the first to be sequenced from the Papaveraceae family. The M. cordata genome covering 378 Mb encodes 22,328 predicted protein-coding genes with 43.5% being transposable elements. As a member of basal eudicot, M. cordata genome lacks the paleohexaploidy event that occurred in almost all eudicots. From the genomics data, a complete set of 16 metabolic genes for SAN and CHE biosynthesis was retrieved, and 14 of their biochemical activities were validated. These genomics and metabolic data show the conserved BIA metabolic pathways in M. cordata and provide the knowledge foundation for future productions of SAN and CHE by crop improvement or microbial pathway reconstruction. PMID- 28552782 TI - A fast and implicit measure of semantic categorisation using steady state visual evoked potentials. AB - There is a great need for objective measures of perception and cognition that are reliable at the level of the individual subject. Although traditional electroencephalography (EEG) techniques can act as valid bio-markers of cognition, they typically involve long recording times and the computation of group averages. To overcome these well-known limitations of EEG, vision scientists have recently introduced a steady state method known as fast periodic visual stimulation (FPVS). This method allows them to study visual discrimination at the individual level. Inspired by their work, we examined whether FPVS could be used equally effectively to capture abstract conceptual processes. Twenty subjects (20.9 (+/-2.1) yrs, 6 male) were asked to complete a FPVS-oddball paradigm that assessed their spontaneous ability to differentiate between rapidly presented images on the basis of semantic, rather than perceptual, properties. At the group level, this approach returned a reliable oddball detection response after only 50s of stimulus presentation time. Moreover, a stable oddball response was found for each participating individual within 100s. As such, the FPVS oddball paradigm returned an objective, non-verbal marker of semantic categorisation in single subjects in under two minutes. This finding establishes the FPVS-oddball paradigm as a powerful new tool in cognitive neuroscience. PMID- 28552784 TI - Misdiagnosis of vertebral fractures on plain films: Are radiologists really working so bad? PMID- 28552783 TI - Cognitive persistence: Development and validation of a novel measure from the Wisconsin Card Sorting Test. AB - The Wisconsin Card Sorting Test (WCST) has long been used as a neuropsychological assessment of executive function abilities, in particular, cognitive flexibility or "set-shifting". Recent advances in scoring the task have helped to isolate specific WCST performance metrics that index set-shifting abilities and have improved our understanding of how prefrontal and parietal cortex contribute to set-shifting. We present evidence that the ability to overcome task difficulty to achieve a goal, or "cognitive persistence", is another important prefrontal function that is characterized by the WCST and that can be differentiated from efficient set-shifting. This novel measure of cognitive persistence was developed using the WCST-64 in an adult lifespan sample of 230 participants. The measure was validated using individual variation in cingulo-opercular cortex function in a sub-sample of older adults who had completed a challenging speech recognition in noise fMRI task. Specifically, older adults with higher cognitive persistence were more likely to demonstrate word recognition benefit from cingulo-opercular activity. The WCST-derived cognitive persistence measure can be used to disentangle neural processes involved in set-shifting from those involved in persistence. PMID- 28552785 TI - Co-occurrence of aflatoxins and ochratoxin A in dried fruits in Iran: Dietary exposure risk assessment. AB - In this study, the contamination levels of aflatoxins (AFs) and ochratoxin A (OTA) in 88 collected samples from Iran's market including dried mulberry, date, fig, and apricot were evaluated. The margin of exposure (MOE) was estimated to assess the risk of dietary intake of aflatoxin B1 (AFB1) and OTA. The incidence of AFB1 in dried mulberry, date, fig and apricot samples was 45.5, 40.9, 59.1, and 81.8%, respectively. Although the mean total AFs content in contaminated samples of date (2.61 MUg/kg), fig (3.43 MUg/kg) and apricot (2.91 MUg/kg) was lower than the maximum limit set in the European Union (EU) (4 MUg/kg), dried mulberry samples showed a higher contamination level (4.12 MUg/kg). The co occurrence of OTA and AFs were noted in 4 (18.9%), 2 (9.1%), 4 (18.2%), and 10 (45.5%) in the dried mulberry, date, fig and apricot samples, respectively. Based on the calculated MOE, the dietary exposure to AFs through the consumption of dried fruit in Iran poses a potential risk to consumer health. OTA was detected in 45.45%, 22.72%, 45.45%, and 50% of mulberry, date, fig and apricot samples, respectively. However, OTA levels in all types of dried fruit were below recommended level in EU regulation (10 MUg/kg) and MOE >10000, representing no toxicological concerns for consumers. PMID- 28552786 TI - Metabolism and pharmacokinetics of zearalenone following oral and intravenous administration in juvenile female pigs. AB - Zearalenone (ZEN) is a well-studied mycotoxin whose potent estrogenic properties have been used by international regulatory bodies to set health-based guidance values for ZEN exposure in grain-based foods from changes in hormonally responsive tissues of juvenile female pigs. The role of metabolism in determining estrogenic responses in vivo is a major uncertainty in inter-species extrapolation to humans and in assessing the potential for added susceptibility in sensitive subpopulations. This study evaluated the metabolism of ZEN and pharmacokinetics in ~2 month-old female pigs using oral and intravenous dosing. The absolute bioavailability (AUCoral/AUCIV) of receptor-active ZEN aglycone was 1.8 +/- 0.80%, consistent with extensive pre-systemic Phase II conjugation. Reductive metabolism to alpha-zearalenol (alpha-ZEL) was extensive, with smaller amounts of beta-ZEL. When combined with its higher binding affinity, relative to ZEN and beta-ZEL, alpha-ZEL was the predominant contributor to total estrogen receptor ligand activity (~90%) after oral dosing with ZEN. The apparent similarities of reductive and Phase II conjugation metabolism of ZEN between pigs and humans support the use of juvenile female pigs as a sensitive model for risk assessments of estrogenic effects from dietary ZEN. PMID- 28552787 TI - Assessment of antioxidant, antitumor and pro-apoptotic effects of Salvia fruticosa Mill. subsp. thomasii (Lacaita) Brullo, Guglielmo, Pavone & Terrasi (Lamiaceae). AB - The aim of the present study was to investigate the in vitro antioxidant and antitumor effects of Salvia fruticosa Mill subsp. thomasii (Lacaita) Brullo, Guglielmo, Pavone & Terrasi (Lamiaceae). The aerial parts were extracted by maceration with methanol. This extract was partitioned with methanol and n hexane. Luteolin, luteolin 7-O-glucoside, rutin and salvigenin were isolated from the methanol-soluble fraction. n-Hexane fraction showed viridiflorol, beta pinene, 1,8-cineole, as main components. The methanol-soluble fraction exerted antitumor activity against human breast cancer (MCF-7 and MDA-MB-231) and human colorectal carcinoma (RKO and Caco-2) cells. TUNEL test revealed that S. fruticosa subsp. thomasii leads to cells death by apoptosis, with low cytotoxic effects on non-tumoral 3T3-L1 cells. Moreover, it exerted the highest protection of lipid peroxidation and reduced the oxidative stress induced by menadione treatment in 3T3-L1 murine fibroblasts. S. fruticosa subsp. thomasii bioactivity could promote its use not only as food but also in nutraceutical/pharmaceutical industries. PMID- 28552788 TI - Solasodine-3-O-beta-d-glucopyranoside kills Candida albicans by disrupting the intracellular vacuole. AB - The increasing incidence of fungal infections and emergence of drug resistance underlie the constant search for new antifungal agents and exploration of their modes of action. The present study aimed to investigate the antifungal mechanisms of solasodine-3-O-beta-d-glucopyranoside (SG) isolated from the medicinal plant Solanum nigrum L. In vitro, SG displayed potent fungicidal activity against both azole-sensitive and azole-resistant Candida albicans strains in Spider medium with its MICs of 32 MUg/ml. Analysis of structure and bioactivity revealed that both the glucosyl residue and NH group were required for SG activity. Quantum dot (QD) assays demonstrated that the glucosyl moiety was critical for SG uptake into Candida cells, as further confirmed by glucose rescue experiments. Measurement of the fluorescence intensity of 2',7'-dichlorofluorescin diacetate (DCFHDA) by flow cytometry indicated that SG even at 64 MUg/ml just caused a moderate increase of reactive oxygen species (ROS) generation by 58% in C. albicans cells. Observation of vacuole staining by confocal microscopy demonstrated that SG alkalized the intracellular vacuole of C. albicans and caused hyper-permeability of the vacuole membrane, resulting in cell death. These results support the potential application of SG in fighting fungal infections and reveal a novel fungicidal mechanism. PMID- 28552789 TI - Dynamic ventilatory responses of females and males to acute isocapnic and poikilocapnic hypoxia. AB - The human ventilatory response during acute hypoxia appears to be biphasic (growth and decay), but the effect of sex on the size and timing of this response is not known. We studied the effects of 15min of poikilocapnic and isocapnic hypoxia (FiO2~0.10) on ventilation (Vi) in 14 healthy female and 13 healthy male subjects. Parameters (amplitudes, time delays, time constants) describing individual Vi responses were estimated using a biexponential function. There were no significant effects of sex on any of these parameters. CO2 regulation significantly altered the amplitudes of growth and decay phases and the onset of the latter phase in females and males. These human data suggest that sex does not affect the biphasic response of ventilation during hypoxia. However, additional evidence in this study suggests that sex influences the breathing frequency response during hypoxia and that this effect depends on the control of CO2. PMID- 28552790 TI - Short-term expiratory muscle strength training attenuates sleep apnea and improves sleep quality in patients with obstructive sleep apnea. AB - This study investigated the effects of 5 weeks of expiratory muscle strength training (EMST) on sleep apnea, sleep quality, and respiratory muscle strength in patients with different levels of obstructive sleep apnea (OSA). Twenty-five outpatients who received a diagnosis of OSA participated in the study and were assigned to either the EMST group (n=13) or control group (CTRL, n=12). The training intensity for the EMST group was 75% of the maximum static expiratory (PEmax) score (5days/week). The PEmax, apnea-hypoapnea index (AHI), Epworth Sleepiness Scale (ESS), and Pittsburgh Sleep Quality Index (PSQI) scores were evaluated before and after the treatment. EMST improved the scores for AHI ( 40%), PEmax (+68%), and PSQI (-28%) and reduced the PSQI scores of the moderate OSA subgroup but not the mild OSA subgroup. The percent changes (Delta%) in the AHI and PEmax scores of participants with OSA were negatively correlated. We demonstrated that EMST effectively improved sleep apnea, sleep quality, and expiratory muscle strength in participants with OSA. Participants with moderate OSA exhibited greater improvement than did those with mild OSA, and the improvement in PEmax scores was correlated with a decrease in sleep apnea. PMID- 28552791 TI - Three-dimensional printing: technologies, applications, and limitations in neurosurgery. AB - Three-dimensional (3D) printers are a developing technology penetrating a variety of markets, including the medical sector. Since its introduction to the medical field in the late 1980s, 3D printers have constructed a range of devices, such as dentures, hearing aids, and prosthetics. With the ultimate goals of decreasing healthcare costs and improving patient care and outcomes, neurosurgeons are utilizing this dynamic technology, as well. Digital Imaging and Communication in Medicine (DICOM) can be translated into Stereolithography (STL) files, which are then read and methodically built by 3D Printers. Vessels, tumors, and skulls are just a few of the anatomical structures created in a variety of materials, which enable surgeons to conduct research, educate surgeons in training, and improve pre-operative planning without risk to patients. Due to the infancy of the field and a wide range of technologies with varying advantages and disadvantages, there is currently no standard 3D printing process for patient care and medical research. In an effort to enable clinicians to optimize the use of additive manufacturing (AM) technologies, we outline the most suitable 3D printing models and computer-aided design (CAD) software for 3D printing in neurosurgery, their applications, and the limitations that need to be overcome if 3D printers are to become common practice in the neurosurgical field. PMID- 28552792 TI - Plasmodium glyceraldehyde-3-phosphate dehydrogenase: A potential malaria diagnostic target. AB - Malaria rapid diagnostic tests (RDTs) are immunochromatographic tests detecting Plasmodial histidine-rich protein 2 (HRP2), lactate dehydrogenase (LDH) and aldolase. HRP2 is only expressed by Plasmodium falciparum parasites and the protein is not expressed in several geographic isolates. LDH-based tests lack sensitivity compared to HRP2 tests. This study explored the potential of the Plasmodial glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), as a new malaria diagnostic biomarker. The P. falciparum and P. yoelii proteins were recombinantly expressed in BL21(DE3) Escherischia coli host cells and affinity purified. Two epitopes (CADGFLLIGEKKVSVFA and CAEKDPSQIPWGKCQV) specific to P. falciparum GAPDH and one common to all mammalian malaria species (CKDDTPIYVMGINH) were identified. Antibodies were raised in chickens against the two recombinant proteins and the three epitopes and affinity purified. The antibodies detected the native protein in parasite lysates as a 38 kDa protein and immunofluorescence verified a parasite cytosolic localization for the native protein. The antibodies suggested a 4-6 fold higher concentration of native PfGAPDH compared to PfLDH in immunoprecipitation and ELISA formats, consistent with published proteomic data. PfGAPDH shows interesting potential as a malaria diagnostic biomarker. PMID- 28552793 TI - Artichoke leaf extract protects liver of Schistosoma mansoni infected mice through modulation of hepatic stellate cells recruitment. AB - Schistosomiasis is the second most common human parasitic disease worldwide. It is responsible for 300000 deaths per year. Liver fibrosis is the main pathology of schistosomiasis and its complications are the major cause of death in infected cases. Unfortunately, the therapeutic dose of praziquantel (PZQ) - the main drug treatment - doesn't markedly affect fibrosis. In the present study, antiparasitic and hepatoprotective properties of artichoke leaf extract (ALE) were tested on mice experimentally infected with Schistosoma mansoni (S. mansoni) and were compared to PZQ. Four mice groups were infected with S. mansoni. The first three groups received ALE, ALE + PZQ and PZQ respectively. The 4th was the positive control and the 5th was the negative control group. Worm load, egg count, granuloma numbers and diameters were measured to assess ALE anti-schistoaomal properties. Masson's trichrome staining of fibrosis, immune staining of hepatic stellate cells (HSCs) and estimation of liver enzymes were done to assess its hepato-protective action. Although it had no significant effects on worm or tissue egg load and granuloma number, ALE caused significant reduction of granuloma diameter, improvement of liver functions and liver fibrosis. ALE caused statistically significant changes in HSCs distribution. It reduced granuloma size by increasing HSCs recruitment inside granuloma and limited liver fibrosis by their inhibition in the peri- and inter-granuloma liver tissue. It was concluded that despite failure of ALE to treat S. mansoni infection, it can limit liver damage caused by this parasite by modulating HSCs recruitment. PMID- 28552794 TI - Front-line glioblastoma chemotherapeutic temozolomide is toxic to Trypanosoma brucei and potently enhances melarsoprol and eflornithine. AB - Sleeping sickness is an infectious disease that is caused by the protozoan parasite Trypanosoma brucei. The second stage of the disease is characterised by the parasites entering the brain. It is therefore important that sleeping sickness therapies are able to cross the blood-brain barrier. At present, only three medications for chemotherapy of the second stage of the disease are available. As these trypanocides have serious side effects and are difficult to administer, new and safe anti-trypanosomal brain-penetrating drugs are needed. For these reasons, the anti-glioblastoma drug temozolomide was tested in vitro for activity against bloodstream forms of T. brucei. The concentration of the drug required to reduce the growth rate of the parasites by 50% was 29.1 MUM and to kill all trypanosomes was 125 MUM. Importantly, temozolomide did not affect the growth of human HL-60 cells up to a concentration of 300 MUM. Cell cycle analysis revealed that temozolomide induced DNA damage and subsequent cell cycle arrest in trypanosomes exposed to the compound. As drug combination regimes often achieve greater therapeutic efficacy than monotherapies, the interactions of temozolomide with the trypanocides eflornithine and melarsoprol, respectively, was determined. Both combinations were found to produce an additive effect. In conclusion, these results together with well-established pharmacokinetic data provide the basis for in vivo studies and potentially for clinical trials of temozolomide in the treatment of T. brucei infections and a rationale for its use in combination therapy, particularly with eflornithine or melarsoprol. PMID- 28552795 TI - rHuKGF ameliorates protease/anti-protease imbalance in emphysematous mice. AB - We attempted to elucidate the beneficial role of rHuKGF supplementation in the amelioration of protease/antiprotease imbalance and TGF-beta1 signaling pathway leading to alveolar tissue maintenance in elastase induced emphysematous mice. Thirty two male C57BL mice were divided into four groups i.e. control, emphysema, therapy and rHuKGF only and were oropharyngeally instilled with saline/porcine pancreatic elastase/rHuKGF. Subsequently, lungs from mice were collected for histopathology and molecular biology studies. rHuKGF supplementation significantly ameliorated the mRNA expressions of CRP, TNF-alpha, MMP-2, MMP-7, MMP-8, MMP-9, MMP-12, A1AT, TIMP1, TIMP2, PCNA, Ki67, SPB, SPC and PdPn. MMP-2 and TIMP-1 enzyme activity was resolved due to rHuKGF. Likewise, due to rHuKGF supplementation the protein expressions of CRP, MMP2, MMP7, MMP8 & CTSE, SERPINE1, SERPINA1, TIMP4, GSTA1, HDAC3, PCNA, CDH1, SP-B & SP-C were ameliorated. Moreover, the mRNA expressions of overall TGFbeta-1 pathway was also significantly ameliorated due to rHuKGF supplementation. Lung histopathology represents recovery of lost alveolar septa due to rHuKGF supplementation. Moreover, positive DAB staining of PCNA, SP-B & SP-C was observed due to rHuKGF supplementation at tissue level. rHuKGF is therapeutically potent in maintaining pulmonary tissue integrity by amelioration of protease/antiprotease imbalance and TGFbeta-1 pathway in emphysema. PMID- 28552796 TI - Epigenetic modifications in poorly differentiated and anaplastic thyroid cancer. AB - Well-differentiated thyroid cancer accounts for the majority of endocrine malignancies and, in general, has an excellent prognosis. In contrast, the less common poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are two of the most aggressive human malignancies. Recently, there has been an increased focus on the epigenetic alterations underlying thyroid carcinogenesis, including those that drive PDTC and ATC. Dysregulated epigenetic candidates identified include the Aurora group, KMT2D, PTEN, RASSF1A, multiple non-coding RNAs (ncRNA), and the SWI/SNF chromatin-remodeling complex. A deeper understanding of the signaling pathways affected by epigenetic dysregulation may improve prognostic testing and support the advancement of thyroid-specific epigenetic therapies. This review outlines the current understanding of epigenetic alterations observed in PDTC and ATC and explores the potential for exploiting this understanding in developing novel therapeutic strategies. PMID- 28552797 TI - Hospital organizational factors affect the use of immediate breast reconstruction after mastectomy for breast cancer in the Netherlands. AB - OBJECTIVES: Significant hospital variation in the use of immediate breast reconstruction (IBR) after mastectomy exists in the Netherlands. Aims of this study were to identify hospital organizational factors affecting the use of IBR after mastectomy for ductal carcinoma in situ (DCIS) or invasive breast cancer (BC) and to analyze whether these factors explain the variation. MATERIALS AND METHODS: Patients with DCIS or primary invasive BC treated with mastectomy between 2011 and 2013 were selected from the national NABON Breast Cancer Audit. Hospital and organizational factors were collected with an online web-based survey. Regression analyses were performed to determine whether these factors accounted for the hospital variation. RESULTS: In total, 78% (n = 72) of all Dutch hospitals participated in the survey. In these hospitals 16,471 female patients underwent a mastectomy for DCIS (n = 1,980) or invasive BC (n = 14,491) between 2011 and 2014. IBR was performed in 41% of patients with DCIS (hospital range 0-80%) and in 17% of patients with invasive BC (hospital range 0-62%). Hospital type, number of plastic surgeons available and attendance of a plastic surgeon at the MDT meeting increased IBR rates. For invasive BC, higher percentage of mastectomies and more weekly MDT meetings also significantly increased IBR rates. Adjusted data demonstrated decreased IBR rates for DCIS (average 35%, hospital range 0-49%) and invasive BC (average 15%, hospital range 0-18%). CONCLUSION: Hospital organizational factors affect the use of IBR in the Netherlands. Although only partly explaining hospital variation, optimization of these factors could lead to less variation in IBR rates. PMID- 28552798 TI - Efficacy assessment of self-assembled PLGA-PEG-PLGA nanoparticles: Correlation of nano-bio interface interactions, biodistribution, internalization and gene expression studies. AB - The aim of our study was to develop and compare the biological performance of two types of biodegradable SN-38 loaded nanoparticles (NPs) with various surface properties, composed of low and high Mw triblock PLGA-PEG-PLGA copolymers, applying rational quality and safety by design approach. Therefore, along with the optimization of crucial physico-chemical properties and in order to evaluate the therapeutical potential and biocompatibility of prepared polymeric nanoparticles, analysis of nano-bio interactions, cell internalization, gene expression and biodistribution studies were performed. The optimized formulations, one of low Mw and one composed of high Mw PLGA-PEG-PLGA copolymer, exhibited different characteristics in terms of surface properties, particle size, zeta potential, drug loading, protein adsorption and biodistribution, which may be attributed to the variations in nano-bio interface interactions due to different NP building blocks length and Mw. On the contrary to protein adsorption and biodistribution studies, both types of NPs exhibited similar results during cell internalization and gene expression studies performed in cell culture medium containing serum proteins. This pool of useful data for internalization and efficacy as well as the notable advance in the circulation time of low Mw NPs may be further employed for shaping the potential of the designed nanocarriers. PMID- 28552799 TI - An explorative analysis of process and formulation variables affecting comilling in a vibrational mill: The case of praziquantel. AB - Praziquantel, a BCS II class anthelmintic drug used for the treatment of schistosome infections, was coground in a vibrational mill with different polymers (linear and crosslinked povidone, copovidone and sodium starch glycolate). An explorative analysis of formulation variables (drug-polymer wt ratio and polymer type) and process parameters (type of grinding media, grinding time and frequency) was carried out with the help of an experimental screening design. The influence of the above mentioned factors on three PZQ characteristics (residual crystallinity, water solubility enhancement and drug recovery) was studied. The variation of carrier amount proved to be by far the most important variable affecting all the experimental responses. A lower impact and, in some cases, rather null effect, had the variation of the process variables. All coground systems were characterized by a high amorphous degree and a solubility significantly higher than the API. A very promising product was obtained by processing at 20Hz for 4h, using 3 spheres of 15mm as grinding media, i.e. a coground having a 50% API content, showing a 4.6-fold greater solubility at 20 degrees C than pure praziquantel. This product maintained the same antischistosomal activity of pure API and was both physically and chemically stable for at least 6 months. PMID- 28552800 TI - 3D printed orodispersible films with Aripiprazole. AB - Three dimensional printing technology is gaining in importance because of its increasing availability and wide applications. One of the three dimensional printing techniques is Fused Deposition Modelling (FDM) which works on the basis of hot melt extrusion-well known in the pharmaceutical technology. Combination of fused deposition modelling with preparation of the orodispersible film with poorly water soluble substance such as aripiprazole seems to be extra advantageous in terms of dissolution rate. 3D printed as well as casted films were compared in terms of physicochemical and mechanical properties. Moreover, drug-free films were prepared to evaluate the impact of the extrusion process and aripiprazole presence on the film properties. X-ray diffractometry and thermal analyses confirmed transition of aripiprazole into amorphous state during film preparation using 3D printing technique. Amorphization of the aripiprazole and porous structure of printed film led to increased dissolution rate in comparison to casted films, which, however have slightly better mechanical properties due to their continuous structure. It can be concluded that fused deposition modelling is suitable technique and polyvinyl alcohol is applicable polymer for orodispersible films preparation. PMID- 28552801 TI - Interferon-Free Regimens in Hepatitis B Surface Antigen/Anti-Hepatitis C Virus Positive Patients: The Need to Control Hepatitis B Virus Replication to Avoid Hepatitis B Virus Reactivation. PMID- 28552802 TI - No Association Between Quick Sequential Organ Failure Assessment and Outcomes of Patients With Cirrhosis and Infections. PMID- 28552803 TI - High Resolution Manometry in Scleroderma Patients. PMID- 28552804 TI - Features and Treatment of Dapsone-Induced Hepatitis, Based on Analysis of 44 Cases and Literature Review. PMID- 28552805 TI - Novel RAG1 mutation and the occurrence of mycobacterial and Chromobacterium violaceum infections in a case of leaky SCID. AB - Severe combined immunodeficiency (SCID) is a potentially fatal primary immunodeficiency (PID) that is caused by mutations in genes such as IL2RG, JAK3, IL7RA, RAG1, RAG2, and ADA. The products of these genes are involved in the development of several immune cells such as T, B and natural killer (NK) cells. Most of the SCID forms are autosomal recessive with the exception of IL2RG defects that cause an X-linked SCID. Among the different SCID types, there is a rare SCID form called leaky SCID, which is less severe when compared to the other classical SCID phenotypes. Leaky SCID can be caused by hypomorphic mutations in RAG1 and RAG2 that result in only partial loss of enzymatic function of the proteins respectively encoded by these genes. Here we report a novel missense mutation (c. 307C > T/p.H103Y) in the RAG1 gene in a patient with leaky SCID. In addition, we characterize the clinical and immunological features of this patient that developed along with other severe and recurrent infections such as mycobacterial diseases (BCGitis and pulmonary tuberculosis), the first occurrence of Chromobacterium violaceum in a patient with SCID. Understanding the increased susceptibility to mycobacteria presented by the patient, in which a functional investigation of IL-12/IFN-gamma axis was performed, which demonstrated reduced production of IFN-gamma in the supernatans of peripheral blood mononuclear cell cultures from the patient compared with those from healthy subjects. In conclusion, our data expands the molecular and clinical spectrum associated with the leaky SCID phenotype. PMID- 28552806 TI - Effects of anti-Helicobacter pylori concomitant therapy and probiotic supplementation on the throat and gut microbiota in humans. AB - The microbiota within humans maintains homeostasis and plays important roles in human health. However, some situations such as the use of antibiotics may disrupt the microbiota balance and result in a series of adverse effects. This study aimed to investigate the effects of a commonly used anti-Helicobacter pylori concomitant therapy on the composition of the gut and throat microbiota and any antibiotic resistance that may develop. In addition to the standard regimen, two different supplementary probiotic regimens that both used Saccharomyces boulardii were included. Microbiological culture-based techniques were used to analyse the microbiota composition and antibiotic resistance. Our results showed marked quantitative and qualitative alterations in both the gut and throat microbiota after treatment with not only the standard concomitant therapy but also with either supplementary probiotic regimen. Nevertheless, most of the changes in the gut microbiota (except for yeast and Bacteroides spp. counts) reverted by Day 71, whereas the alterations in the throat microbiota appeared to persist. Patients treated with the eradication therapy in the absence of probiotic supplementation experienced the most pronounced disturbances in the throat microbiota, whereas changes in the throat microbiota appeared to stabilize in the groups that received probiotic supplementation. We also detected higher antibiotic resistance rates for Enterobacteriaceae, Enterococcus spp. and Bacteroides spp. after treatment with the eradication therapy. Co-administration of probiotics is likely to be more effective than post-antibiotic supplementation, and although some beneficial effects were observed, the probiotic combination did not exert significant effects on the unbalanced commensal gut and throat microbiota composition. PMID- 28552807 TI - Glycyrrhizin inhibits LPS-induced inflammatory mediator production in endometrial epithelial cells. AB - Endometriosis is a continuous inflammation of uterine endometrium that usually affects women of reproductive age. Glycyrrhizin, a triterpene isolated from the roots and rhizomes of licorice (Glycyrrhiza glabra), has been known to have anti inflammatory effect. The purpose of this study was to investigate the anti inflammatory effect of glycyrrhizin on LPS-stimulated mouse endometrial epithelial cells (MEEC). The levels of TNF-alpha, IL-1beta, and PGE2 were measured by ELISA. The expression of COX-2, iNOS, TLR4, and NF-KB were detected by western blot analysis. The results showed that glycyrrhizin significantly suppressed LPS-induced TNF-alpha, IL-1beta, NO, and PGE2 production. Also, LPS induced iNOS and COX-2 expression were attenuated by glycyrrhizin. Furthermore, glycyrrhizin significantly attenuated TLR4 expression and NF-kappaB activation induced by LPS in MEEC. In conclusion, the present study demonstrated that glycyrrhizin inhibited LPS-induced inflammatory response by inhibiting TLR4 signaling pathway in MEEC. Glycyrrhizin may be used as a potential agent for the treatment of endometriosis. PMID- 28552808 TI - Phytochemical composition, anti-biofilm and anti-quorum sensing potential of fruit, stem and leaves of Salvadora persica L. methanolic extracts. AB - Emergence of antibiotic resistance among pathogenic bacteria encourages us to search for new molecules as an alternative treatment. The aim of this study was to evaluate the antiquorum sensing (anti-QS) and antibiofilm potential of Salvadora persica L. methanolic extracts to prevent the infections due to Staphylococcus as an alternate to antibiotics. The methanolic extracts of S. persica L. fruit, leaves and stems was assessed for their activity in inhibiting QS-depedent phenomenon such as violacein pigment production in Chromobacterium violaceum, swarming motility of Pseudomonas aeruginosa PAO1 and biofilm formation in oral Staphylococcus strains on polymethylmetacrylate (PMMA). Methanolic fruit extract of S. persica L. showed a high degree of anti-biofilm formation on PMMA and on violacein inhibition with a percentage of reduction equal to 90% when MIC value (20 mg/ml) was used. 100 MUg/ml of S. persica L. leaves exhibited inhibition in swarming motility of PAO1 at 29.17%. Because the methanolic extracts of S. persica L. demonstrated anti-QS and antibiofilm activity at very low concentrations, it could be further exploited for novel molecules to treat oral Staphylococcus infections. PMID- 28552809 TI - 17beta-Estradiol inhibits estrogen binding protein-mediated hypha formation in Candida albicans. AB - Candida albicans is one of the most prevalent and clinically important fungal pathogens. The ability to change form depending on environmental stress is an important microbial virulence factor. A survey of compounds that inhibit this morphological change identified various steroids, including 17beta-estradiol. Interestingly, C. albicans has proteins capable of binding to steroids, including estrogen binding protein (Ebp1). Estrogens regulate cell differentiation and proliferation in humans through estrogen receptor proteins. To determine whether EBP1 regulates a virulence factor, we investigated the effect of 17beta-estradiol on the morphological transition of C. albicans using an ebp1 deletion mutant. Treatment with 10 MUg/mL of 17beta-estradiol inhibited hypha formation, whereas its effect on the ebp1 deletion mutant was decreased compared to that on the wild type and revertant strains. These data suggest a new pathway for the yeast-to hypha transition via EBP1 in C. albicans. PMID- 28552810 TI - Frideswide - An artificial intelligence deep learning algorithm for audits and quality improvement in the neurosurgical practice. PMID- 28552811 TI - Periumbilical vs transumbilical laparoscopic incision: A patients' satisfaction centered randomised trial. AB - BACKGROUND: While studies suggested that transumbilical incisions (TUI) incur better postoperative cosmetic satisfaction scores (CSS) and shorter operative time (OT) than periumbilical incisions (PUI) during general surgery laparoscopic interventions, others did not. Concerns have been raised toward the potential negative impact of TUI on the incidence of surgical site infection (SSI) but this issue is under documented. METHODS: A controlled trial was conducted between August 2014 and August 2015 in our hospital. Individuals aged 18-70 undergoing a laparoscopic rectopexy, cholecystectomy, appendectomy or proctocolectomy were considered. Patients were randomized in two groups (PUI or TUI) following a 1:1 allocation ratio. Participants with a body mass index >40, with a history of abdominal surgery, undergoing co-operations, requesting a specific incision or converted to open surgery were excluded. RESULTS: Among the 56 randomized patients, 50 (27 PUI vs 23 PUI) produced analyzable data. There were no significant difference between the characteristics of both groups. CSS evolution (pre-op vs 1 month post-op), SSI incidence and OT were also comparable. Only 28% of participants valued the appearance of their umbilicus prior to intervention. Those who did had a significantly worst CSS evolution (OR -1.7; IC95-2.6/-0.72, p = 0.001). Higher preoperative CSS was also a predictor of postoperative CSS decline (OR -0.4; IC95-0.6/-0.2, p = 0.001). CONCLUSIONS: SUI and TUI were similar for all tested outcomes. Among the participants, the minority of patients who valued the appearance of their umbilicus and those with a high preoperative CSS were particularly prone to postoperative CSS decline. PMID- 28552812 TI - Retroinfundibular laparoscopic cholecystectomy versus standard laparoscopic cholecystectomy in difficult cases. AB - BACKGROUND: Laparoscopic cholecystectomy becomes the gold standard surgical procedure for treating gallstones. Standard laparoscopic cholecystectomy (SLC) requires proper dissection of Calot's triangle to achieve the critical view of safety. This may be difficult in certain conditions, resulting in higher incidence of bile duct injury and conversion to open. We aimed to compare the outcomes of laparoscopic cholecystectomy by retroinfundibular (RI) approach to that of SLC, in difficult cases. PATIENTS AND METHODS: This study is prospective cohort study, in which 60 patients were operated by SLC and 65 patients by laparoscopic cholecystectomy by RI approach. RESULTS: From the total 125 cases, 95 (76%) patients were male and 30 (24%) were female. The mean age was 59.5 +/- 5.5 years. The mean operative time in SLC group was 128 +/- 17 min VS. 114 +/- 10 min in RI group. Conversion to open occurred in 10% in SLC group VS. 1.5% in RI group. Biliary injury occurred in 3.3% in SLC group VS. 0% in RI group. The mean hospital stay in SLC was 3.7 +/- 5.3 days VS. 2.1 +/- 0.3 days in RI group. CONCLUSION: In difficult cholecystectomy, RI approach is feasible and safe alternative to SLC. PMID- 28552813 TI - The Established Acute Surgical Unit: A reduction in nighttime appendicectomy without increased morbidity. AB - INTRODUCTION: Nighttime surgery for non-life threatening disease has been associated with poorer outcomes, but delaying surgery for acute appendicitis may also be detrimental. The aim was to assess the effect of the Acute Surgical Unit [ASU] model on nighttime surgery rates and outcomes for patients undergoing appendicectomy. METHOD: A retrospective review of medical records of patients having an appendicectomy. Primary outcomes were nighttime surgery rate, time from presentation to surgery, perforation rate, complication rate and length of stay. RESULTS: There was a large increase in workload: Pre ASU 278, Early ASU 553 and Est. ASU 923. There was a significant decrease in nighttime surgery rates: Pre ASU 46.9%, Early ASU 30.2% and Established ASU 28.3% (Pre vs. Early p < 0.001; Pre vs. Est. p < 0.001; Early vs. Est p = 0.004). When comparing the Pre ASU and Established ASU groups there was an increase in mean time from presentation to surgery (Pre 14.43 Hrs, Est. 18.65 Hrs; p = 0.001), an increase in perforation rate that was not significant (Pre 9.8%, Est. 14.2%; p = 0.05) and similar complication rates (Pre 8.66%, Est. 7.04%; p = 0.37). There was a significant decrease in length of stay between the Early and Established ASU groups (Pre 3.1 D, Est. 2.8D, p = 0.01). At our institution there was no statistically significant increase in complications for patients undergoing nighttime appendicectomy (Night 10.0%, Day 8.2%; p = 0.16). CONCLUSION: There was a significant decrease in nighttime surgery, without any difference in morbidity or length of stay for patients treated within the Established ASU (compared to Pre ASU group). LEVEL OF EVIDENCE: IIb. PMID- 28552814 TI - Guiding recombinant antivenom development by omics technologies. AB - In this review, the different approaches that have been employed with the aim of developing novel antivenoms against animal envenomings are presented and discussed. Reported efforts have focused on the use of innovative immunization strategies, small molecule inhibitors against enzymatic toxins, endogenous animal proteins with toxin-neutralizing capabilities, and recombinant monoclonal antibodies. Harnessing either of these approaches, antivenom development may benefit from an in-depth understanding of venom compositions and the medical importance of individual venom toxins. Focus is thus also directed towards the different omics technologies (particularly venomics, antivenomics, and toxicovenomics) that are being used to uncover novel animal toxins, shed light on venom complexity, and provide directions for how to determine the medical relevance of individual toxins within whole venoms. Finally, techniques for assessing antivenom specificity and cross-reactivity are reviewed, with special focus on antivenomics and high-density peptide microarray technology. PMID- 28552816 TI - Spanish strategy on bioeconomy: Towards a knowledge based sustainable innovation. AB - Spain launched its own strategy on bioeconomy in January 2016 aiming at boosting a bioeconomy based on the sustainable and efficient production and use of biological resources. It highlights global societal challenges related with agricultural and biotechnological sciences in Spain and the great dynamism of the private sectors involved, particularly the agri-food, biotech and biomass sectors. The targeted sectors are food, agriculture and forestry, conditioned by water availability. It also includes the production of those industrial bioproducts and bioenergy obtained from the use and valorisation of wastes and residues and other non-conventional sources of biomass, in a circular economy. The strategy also puts a focus on rural and coastal development through several uses and services linked to ecosystems. The capacity to generate know-how in this area and the promotion of public and private collaboration are important pillars in order to enhance existing value chains and to create new ones. The strategy is led by R&I and Agriculture, Food and Environment policy managers and largely supported at regional level too. The strategic objective is the maintenance of the bioeconomy as an essential part of Spanish economy to contribute to the economic growth by creating new jobs and fostering investments. PMID- 28552817 TI - How to capture the bioeconomy's industrial and regional potential through professional cluster management. AB - The bioeconomy transforms the fossil-based economy by forming new value chains and linking until now distinct industrial sectors. It provides an opportunity for rural as well as industrialized regions. The transformation process can be accelerated by building bioeconomy clusters comprising industries, academia and investors. Using the model of the German cluster CLIB2021 the role of cluster organisations and professional cluster management in moderating the transformation process and gaining a competetive advantage is discussed. In addition examples of how cluster management supports the formation of an industrial consortium and the analysis of regional options are presented. PMID- 28552815 TI - Leisure-time physical activity and leukocyte telomere length among older women. AB - BACKGROUND: Shortened leukocyte telomere length (LTL), a purported marker of cellular aging, is associated with morbidity and mortality. However, the association of physical activity, a modifiable lifestyle behavior, with LTL has not been adequately studied among older adults. METHODS: In this cross-sectional study, we examined associations of various intensity levels of leisure-time physical activity with LTL among 1476 older white and African American women from the Women's Health Initiative Objective Physical Activity and Cardiovascular Health study. Self-reported physical activity was assessed by questionnaire, and LTL was measured by Southern blot. The association between physical activity and LTL was evaluated using multiple linear regression models adjusted for demographic characteristics, lifestyle behaviors, and health-related variables. RESULTS: Women were on average aged 79.2 (standard deviation 6.7) years old. In the final model adjusted for age, race/ethnicity, education, marital status, smoking, alcohol, body mass index, a history of chronic diseases, and hormone therapy use, LTL was on average 110 (95% confidence interval, 20-190) base pairs longer among women in the highest (>=17.00MET-hours/week) compared with the lowest (<1.25MET-hours/week) level of total leisure-time physical activity (P for trend=0.02). Higher levels of moderate-to-vigorous physical activity (P for trend=0.04) and faster walking speed (P for trend=0.03) were also associated with longer LTL in the fully-adjusted models. CONCLUSION: Older women participating in greater amounts of total leisure-time physical activity and moderate-to-vigorous physical activity had longer LTL. PMID- 28552818 TI - Natural History of Low-stage Urethral Strictures. AB - OBJECTIVE: To determine the natural history and rate of progression of incidental wide-caliber, anterior urethral strictures (USs) in men using a validated stricture staging system. SUBJECTS AND METHODS: Men with incidental findings of anterior US on cystoscopy performed for urologic conditions other than US were retrospectively reviewed from 2001 through 2016. Diagnosis of US on cystoscopy was made according to a validated staging system: stage 0 = no stricture; stage 1 = wide-caliber stricture; stage 2 = requires gentle dilation with a flexible cystoscope; stage 3 = impassable stricture with a visible lumen; and stage 4 = no visible lumen. Using this staging system, this study assessed the change over time of US in patients found to have a stage 1 stricture. The primary outcome was the US grade at time of follow-up. Secondary outcomes include the need for further intervention. RESULTS: Thirty-two patients with 42 separate strictures were evaluated. Median length of follow-up between first cystoscopy and ultimate cystoscopy was 23 months, with a median of 4 cystoscopies per patient. Of the 42 strictures, 15 regressed to a stage 0 (36%), 22 remained as stage 1 (52%), and 5 (12%) progressed to stage 2. None of the patients required additional intervention. CONCLUSION: The majority of low-stage USs does not progress. This supports the notion that strictures are a graded phenomenon, and not all require surgical intervention. PMID- 28552819 TI - Prostate Cancer Antigen 3 Score Does Not Predict for Adverse Pathologic Features at Radical Prostatectomy or for Progression-free Survival in Clinically Localized, Intermediate- and High-risk Prostate Cancer. AB - OBJECTIVE: To evaluate whether preoperative urinary prostate cancer antigen 3 (PCA3) scores predict for adverse pathologic features (APFs) or progression-free survival (PFS) in men with intermediate- or high-risk prostate cancer (PCa) undergoing radical prostatectomy (RP). MATERIALS AND METHODS: One hundred nine men with intermediate- (n = 52) or high-risk (n = 57) PCa who underwent RP were retrospectively identified. Logistic regression analysis was performed to evaluate the association of PCA3 score with various APFs (eg, extracapsular extension, seminal vesicle invasion, etc.). Among 78 men with >=1 year of follow up, the association between PCA3 score and PFS was assessed using Cox regression analysis. RESULTS: At RP, 52% of patients had at least 1 APF, and with median follow-up of 2.3 years, overall 3-year PFS was 70%. PCA3 was not a significant predictor of any APF on multivariate analysis (MVA), whereas canonical predictors (eg, biopsy Gleason score and initial prostate-specific antigen) remained predictive of various APFs. No significant predictors for PFS were found on MVA, although certain canonical predictors (eg, National Comprehensive Cancer Network risk group) were significant predictors of PFS on univariate analysis (UVA). PCA3 score was not a significant predictor of PFS on either UVA or MVA. CONCLUSION: Unlike in lower risk cohorts, increasing PCA3 score was not associated with any APF in this higher risk cohort, despite enrichment for APFs, nor was it associated with PFS. Notably, multiple known preoperative predictors for APFs were significant on MVA, and multiple predictors were associated with PFS on UVA. Therefore, PCA3 may not be a useful adjunct predictive marker in men with intermediate- or high-risk PCa. PMID- 28552820 TI - Avidin-conjugated calcium phosphate nanoparticles as a modular targeting system for the attachment of biotinylated molecules in vitro and in vivo. AB - : Avidin was covalently conjugated to the surface of calcium phosphate nanoparticles, coated with a thin silica shell and terminated by sulfhydryl groups (diameter of the solid core about 50nm), with a bifunctional crosslinker connecting the amino groups of avidin to the sulfhydryl group on the nanoparticle surface. This led to a versatile nanoparticle system where all kinds of biotinylated (bio-)molecules can be easily attached to the surface by the non covalent avidin-biotin-complex formation. It also permits the attachment of different biomolecules on the same nanoparticle (heteroavidity), creating a modular system for specific applications in medicine and biology. The variability of the binding to the nanoparticle surface of the was demonstrated with various biotinylated molecules, i.e. fluorescent dyes and antibodies. The accessibility of the conjugated avidin was demonstrated by a fluorescence-quenching assay. About 2.6 binding sites for biotin were accessible on each avidin tetramer. Together with a number of about 240 avidin tetramer units per nanoparticle, this offers about 600 binding sites for biotin on each nanoparticle. The uptake of fluorescently labelled avidin-conjugated calcium phosphate nanoparticles by HeLa cells showed the co-localization of fluorescent avidin and fluorescent biotin, indicating the stability of the complex under cell culture conditions. CD11c antibody functionalized nanoparticles specifically targeted antigen-presenting immune cells (dendritic cells; DCs) in vitro and in vivo (mice) with high efficiency. STATEMENT OF SIGNIFICANCE: Calcium phosphate nanoparticles have turned out to be very useful transporters for biomolecules into cells, both in vitro and in vivo. However, their covalent surface functionalization with antibodies, fluorescent dyes, or proteins requires a separate chemical synthesis for each kind of surface molecule. We have therefore developed avidin-terminated calcium phosphate nanoparticles to which all kinds of biotinylated molecules can be easily attached, also as a mixture of two or more molecules. This non-covalent bond is stable both in cell culture and after injection into mice in vivo. Thus, we have created a highly versatile system for many applications, from the delivery of biomolecules over the targeting of cells and tissue to in vivo imaging. PMID- 28552821 TI - Utilization of isolated marine mussel cells as an in vitro model to assess xenobiotics induced genotoxicity. AB - Freshly isolated cells are used as an ideal experimental model in in vitro toxicology analysis, especially the detection of diverse xenobiotics induced genotoxic effects. In present study, heavy metals (Zn, Cu, Cd, Pb) and PCBs were selected as representative xenobiotics to verify the ability of in vitro model in assessing genotoxic effects in cells of marine mussels (Mytilus galloprovincialis). DNA damage and chromosome aberration were assessed in freshly isolated cells from haemolymph, gill and digestive gland by single cell gel electrophoresis and micronucleus assay respectively. Gill cells showed more sensitive to Zn exposure among three types of cells, indicating tissue-specific genotoxicity. Significantly higher DNA aberrations were induced by Cu in haemocytes compared to Cd and Pb, indicating chemical-specific genotoxicity. An additive effect was detected after combined heavy metals and PCBs exposure, suggesting the interaction of selected xenobiotics. To our knowledge, this is the first attempt to study the complex effects of organic and/or inorganic contaminants using freshly isolated cells from marine mussels. Genetic responses are proved to occur and maintained in vitro in relation to short-term xenobiotics induced stresses. The utilization of the in vitro model could provide a rapid tool to investigate the comprehensive toxic effects in marine invertebrates and monitor environmental health. PMID- 28552823 TI - High failure rate of anterior cruciate ligament reconstruction with bimeniscal repair: A case-control study. AB - BACKGROUND: Bimeniscal lesions are common in patients with anterior cruciate ligament (ACL) tears. However, bimeniscal repair is rarely performed during ACL reconstruction. OBJECTIVE: To assess outcomes after ACL reconstruction with bimeniscal repair. HYPOTHESIS: Bimeniscal lesions, even when repaired, are associated with poorer outcomes of ACL reconstruction. MATERIAL AND METHODS: A retrospective case-control design was used. The cases were 15 patients who underwent ACL reconstruction, without procedures on any other ligaments, combined with bimeniscal repair, between May 2009 and May 2013 (3.2% of all ACL reconstructions during the study period). This group (2-Mc group) was matched on age, gender, body mass index, and time to surgery to 30 patients who underwent ACL reconstruction and had no meniscal lesions (0-Mc group) and to 30 patients who underwent ACL reconstruction and repair of the medial meniscus (1-Mc group). After a mean follow-up of 3.6 years, clinical outcomes were assessed based on the KOOS, Lysholm, and IKDC scores and knee laxity based on TELOS and GNRB measurements. The primary outcome measure was the rate of ACL re-rupture. Secondary outcome measures were functional outcomes and rate of delayed meniscectomy. RESULTS: The ACL re-rupture rate was significantly higher in the 2 Mc group than in the 0-Mc and 1-Mc groups pooled (20%, vs. 1.7%; P=0.02). The functional scores showed no significant differences across groups. Post-operative differential laxity was significantly greater in the 2-Mc group (3.3mm by TELOS, P=0.02; and 2.5mm by GNRB, P=0.03) than in the 0-Mc and 1-Mc groups pooled. Delayed meniscectomy was performed in none of the 2-Mc group patients and in 2 of the 1-Mc group patients. CONCLUSION: ACL reconstruction combined with bimeniscal repair is a rarely performed procedure. It is associated with a high ACL re rupture rate and greater differential laxity. Meniscal outcomes of bimeniscal repair, in contrast, are good. LEVEL OF EVIDENCE: III, matched case-control study. PMID- 28552822 TI - Changes in DNA methylation of erythroid-specific genes in K562 cells exposed to catechol in long term. AB - Catechol is one of phenolic metabolites of benzene that is a general occupational hazard and a ubiquitous environmental air pollutant. Catechol also occurs naturally in fruits, vegetables and cigarettes. Previous studies have revealed that 72h exposure to catechol improved hemin-induced erythroid differentiation of K562 cells accompanied with elevated methylation in erythroid specific genes. In present study, K562 cells were treated with 0, 10 or 20MUM catechol for 1-4weeks, hemin-induced hemoglobin synthesis increased in a concentration- and time dependent manner and the enhanced hemoglobin synthesis was relatively stable. The mRNA expression of alpha-, beta- and gamma-globin genes, erythroid heme synthesis enzymes PBGD and ALAS2, transcription factor GATA-1 and NF-E2 showed a significant increase in K562 cells exposed to 20MUM catechol for 3w, and catechol enhanced hemin-induced mRNA expression of these genes. Quantitative MassARRAY methylation analysis also confirmed that the exposure to catechol changed DNA methylation levels at several CpG sites in several erythroid-specific genes and their far upstream of regulatory elements. These results demonstrated that long term exposure to low concentration of catechol enhanced the hemin-induced erythroid differentiation of K562 cells, in which DNA methylation played a role by up-regulating erythroid specific genes. PMID- 28552824 TI - Functional recovery following early mobilization after middle third clavicle osteosynthesis for acute fractures or nonunion: A case-control study. AB - BACKGROUND: Good outcomes have been reported after surgical treatment for acute or nonunion of displaced midshaft clavicle fractures. However, the postoperative rehabilitation and timeline for a complete functional recovery are poorly documented. The purpose of the current study was to evaluate the efficacy of an immediate motion protocol following plate fixation of a midshaft clavicle fracture and to compare functional recovery between acute and nonunion cases. METHODS: Between October 2011 and July 2015, all patients above the age of 18, having either an acute or a nonunion of the midshaft clavicle fracture, were considered as potentially eligible for inclusion in this prospective case-control study. Postoperatively, no immobilization was recommended and patients were to undergo rehabilitation protocol consisting of hourly stretching. RESULTS: Forty two patients were included (31 with acute and 11 with delayed fixation) at a mean follow-up of 33months (range, 12 to 78months). Surgical complications consisted of one transient frozen shoulder, one delayed union, and two superficial infections. All patients returned to work, retrieved full shoulder range of motion (ROM), and returned to heavy sports and activities. Function returned faster in the acute group compared to the nonunion group based on the SANE score at 2weeks (73+/-21 vs. 45+/-26 respectively, P=0.01), SANE score at 6weeks (89+/ 15 vs. 66+/-23 respectively, P=0.01), SANE score at 3months (96+/-10 vs. 85+/-14 respectively, P=0.03), and based on return of full ROM (17+/-25 vs. 44+/-31 days respectively, P=0.01). A trend was observed for nonunion cases needing more time to return to work and sports activities. CONCLUSION: Functional outcome is excellent following the treatment of both acute and non-united clavicle fractures, but recovery occurs earlier following acute treatment. An early mobilization rehab protocol can be safely recommended for both types of conditions and may result in substantial healthcare cost-savings, without increasing complication rate and decreasing patient satisfaction. LEVEL OF EVIDENCE: Level III; case-control study; treatment study. PMID- 28552826 TI - Diagnostic utility of IDH1/2 mutations to distinguish dedifferentiated chondrosarcoma from undifferentiated pleomorphic sarcoma of bone. AB - Histologically, it is nearly impossible to distinguish the dedifferentiated component of dedifferentiated chondrosarcoma from undifferentiated pleomorphic sarcoma (UPS) of bone when the low-grade cartilaginous component is absent. Previous studies have revealed that isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are present in a significant number of cartilaginous tumors including most conventional chondrosarcomas and dedifferentiated chondrosarcomas. These mutations have not been studied in UPSs of bone. We sought to investigate whether an IDH1 or IDH2 mutation signature could be used as a clinically diagnostic marker for the distinction of dedifferentiated component of chondrosarcoma from UPS of bone. Sixty-eight bone tumor cases, including 31 conventional chondrosarcomas, 23 dedifferentiated chondrosarcomas, and 14 UPSs of bone, were collected for IDH1/2 mutation analysis either using the Qiagen IDH1/2 RGQ PCR Kit or using whole-exome sequencing. IDH1/2 mutations were detected in 87% (20/23) of dedifferentiated chondrosarcomas and 30% (6/20) of conventional chondrosarcomas. No mutations were detected in the IDH1/2 codon 132 or codon 172 among 14 UPSs of bone. Identification of IDH1 or IDH2 mutations supports the diagnosis of dedifferentiated chondrosarcoma rather than UPS of bone while also providing some insight into the pathogenesis of these 2 lesions. PMID- 28552825 TI - Viral strategies for targeting cortical circuits that control cocaine-taking and cocaine-seeking in rodents. AB - Addiction to cocaine is a chronic disease characterized by persistent drug-taking and drug-seeking behaviors, and a high likelihood of relapse. The prefrontal cortex (PFC) has long been implicated in the development of cocaine addiction, and relapse. However, the PFC is a heterogeneous structure, and understanding the role of PFC subdivisions, cell types and afferent/efferent connections is critical for gaining a comprehensive picture of the contribution of the PFC in addiction-related behaviors. Here we provide an update on the role of the PFC in cocaine addiction from recent work that used viral-mediated optogenetic and chemogenetic tools to study the role of the PFC in drug-taking and drug-seeking behavior in rodents. Following overviews of rodent PFC neuroanatomy and of viral mediated optogenetic and chemogenetic techniques, we review studies of manipulations within the PFC, followed by a review of work that utilized targeted manipulations to PFC inputs and outputs. PMID- 28552827 TI - Metastatic thyroid carcinoma without identifiable primary tumor within the thyroid gland: a retrospective study of a rare phenomenon. AB - Metastatic papillary thyroid carcinoma (PTC) without an identifiable primary tumor despite extensive microscopic examination of the thyroid gland is a rare but true phenomenon.We retrieved 7 of such cases and described in detail the clinical and pathologic features of these tumors. BRAF V600E immunohistochemistry and Sequenom molecular profile were conducted in selected cases. All patients harbored metastatic disease in the central (n=3), lateral (n=3), or both neck compartments (n=1). The histotype of the metastatic disease was PTC (n=5), poorly differentiated thyroid carcinoma in association with a PTC columnar variant (n=1), and anaplastic thyroid carcinoma in association with a PTC tall cell variant (n=1). Fibrosis was present in the thyroid of 5 patients. All patients with PTC were alive without evidence of recurrence. The 76-year-old patient with poorly differentiated thyroid carcinoma did not recur and died of unknown causes. Finally, the patient with anaplastic thyroid carcinoma was alive with distant metastasis at last follow-up. The median follow-up for this cohort was 2.2years (range, 0.8-17). BRAF V600E was detected in 4 of 6 cases by immunohistochemistry. In conclusion, metastatic nodal disease without identifiable thyroid primary is a rare but real phenomenon of unknown mechanisms. Although most tumors are low grade and well differentiated, aggressive behavior due to poorly differentiated or anaplastic carcinoma can happen. Most cases are BRAFV600E-positive thyroid tumors. A papillary carcinoma phenotype is found in all reported cases. PMID- 28552828 TI - Down-regulation of polycystin in lymphatic malformations: possible role in the proliferation of lymphatic endothelial cells. AB - Lymphatic malformations (LMs) are composed of aberrant lymphatic vessels and regarded as benign growths of the lymphatic system. Recent studies have demonstrated that the mutant embryos of PKD1 and PKD2, encoding polycystin-1 (PC 1) and polycystin-2 (PC-2), respectively, result in aberrant lymphatic vessels similar to those observed in LMs. In this study, for the first time, we investigated PC-1 and PC-2 expression and assessed their roles in the development of LMs. Our results demonstrated that PC-1 and PC-2 gene and protein expressions were obviously decreased in LMs compared with normal skin tissues. In addition, the expression of phosphorylated ERK but not total ERK was up-regulated in LMs and negatively correlated with the expression of PC-1 and PC-2. Moreover, up regulation of Ki67 was detected in LMs and positively correlated with ERK phosphorylation levels. Furthermore, cluster analysis better reflected close correlation between these signals. All of the above results provided strong evidence suggesting that the hyperactivation of the ERK pathway may be caused by down-regulation of PC-1 and PC-2 in LMs, contributing to increased proliferation of lymphatic endothelial cells in LMs. Our present study sheds light on novel potential mechanisms involved in LMs and may help to explore novel treatments for LMs. PMID- 28552829 TI - Identification of male-specific AFLP and SCAR markers in the dioecious plant Humulus scandens. AB - In this study, 17 male-specific amplified fragment length polymorphism (AFLP) markers were identified between male and female Humulus scandens plants. BLAST analysis revealed that 7 of the 17 sex-linked sequences were highly similar to retrotransposons. Two stable male-specific sequence-characterized amplified regions (SCAR) markers were developed. These AFLP and SCAR markers are novel molecular probes that can be used efficiently to identify the genetic gender of H. scandens and may provide a basis for further investigations on the evolution of sex chromosomes. PMID- 28552831 TI - Extended-spectrum beta-lactamase-producing Escherichia coli isolated from healthy humans in Mexico, including subclone ST131-B2-O25:H4-H30-Rx. AB - OBJECTIVES: The resistance mechanisms, molecular type and plasmid content of cefotaxime-resistant Escherichia coli isolated from faecal samples of healthy volunteers in Puebla, Mexico, were characterised. METHODS AND RESULTS: Cefotaxime resistant E. coli were recovered from 11 (18%) of 60 healthy volunteers. The isolates (one per sample) were characterised as multidrug-resistant and phenotypically extended-spectrum beta-lactamase (ESBL)-producing strains. Genes encoding resistance to beta-lactams (blaCTX-M-15, blaCTX-M-14a, blaCTX-M-14b, blaOXA-1, blaTEM-1b), quinolones [aac(6')-Ib-cr, qnrB19], aminoglycosides [aac(3')-II] and tetracycline [tet(A), tet(B)] were detected among the 11 ESBL producing E. coli by PCR and sequencing, as well as gene cassette arrays in class 1 (dfrA17-aadA5) and class 2 (dfrA1-sat2-aadA1) integrons. Seven pulsotypes were identified by XbaI PFGE and the strains were distributed into phylogroups (number of isolates) A (2), B2 (4) and D (5). Seven sequence types were identified, four of them novel (ST5060, ST5079, ST5080 and ST5081), associated with phylogroups A D. Transfer of a 140-kb IncFIA plasmid carrying the blaCTX-M-15 gene was evidenced in the ST5060 strain. Four CTX-M-15-producing E. coli strains of phylogroup B2 belonged to the ST131 complex, and IncFIB plasmids of 130kb and 155kb were detected in two of them. Multiple plasmid addiction systems were also found. Serotyping and fimH subtyping of ST131-B2 strains identified the ST131-B2 O25:H4-H30-Rx subclone. Additionally, this subclone and CTX-M-14-producing isolates were detected among residents living in the same household, suggesting clonal dissemination. CONCLUSIONS: This study reports the detection of E. coli ST131-B2-O25:H4-H30-Rx subclone in healthy humans in Mexico, highlighting its dissemination in the community setting. PMID- 28552830 TI - Understanding Response Rates to Surveys About Family Members' Psychological Symptoms After Patients' Critical Illness. AB - CONTEXT: Achieving adequate response rates from family members of critically ill patients can be challenging, especially when assessing psychological symptoms. OBJECTIVES: To identify factors associated with completion of surveys about psychological symptoms among family members of critically ill patients. METHODS: Using data from a randomized trial of an intervention to improve communication between clinicians and families of critically ill patients, we examined patient level and family-level predictors of the return of usable surveys at baseline, three months, and six months (n = 181, 171, and 155, respectively). Family-level predictors included baseline symptoms of psychological distress, decisional independence preference, and attachment style. We hypothesized that family with fewer symptoms of psychological distress, a preference for less decisional independence, and secure attachment style would be more likely to return questionnaires. RESULTS: We identified several predictors of the return of usable questionnaires. Better self-assessed family member health status was associated with a higher likelihood and stronger agreement with a support-seeking attachment style with a lower likelihood, of obtaining usable baseline surveys. At three months, family-level predictors of return of usable surveys included having usable baseline surveys, status as the patient's legal next of kin, and stronger agreement with a secure attachment style. The only predictor of receipt of surveys at six months was the presence of usable surveys at three months. CONCLUSION: We identified several predictors of the receipt of surveys assessing psychological symptoms in family of critically ill patients, including family member health status and attachment style. Using these characteristics to inform follow-up mailings and reminders may enhance response rates. PMID- 28552832 TI - Decrease of ceftriaxone susceptibility in Klebsiella pneumoniae according to biofilm maturation. PMID- 28552833 TI - Wheat glutenin: the "tail" of the 1By protein subunits. AB - Gluten-forming storage proteins play a major role in the viscoelastic properties of wheat dough through the formation of a continuous proteinaceous network. The high-molecular-weight glutenin subunits represent a functionally important subgroup of gluten proteins by promoting the formation of large glutenin polymers through interchain disulphide bonds between glutenin subunits. Here, we present evidences that y-type glutenin subunits encoded at the Glu-B1 locus are prone to proteolytic processing at the C-terminus tail, leading to the loss of the unique cysteine residue present at the C-terminal domain. Results obtained by intact mass measurement and immunochemistry for each proteoform indicate that the proteolytic cleavage appears to occur at the carboxyl-side of two conserved asparagine residues at the C-terminal domain start. Hence, we hypothesize that the responsible enzymes are a class of cysteine endopeptidases - asparaginyl endopeptidases - described in post-translational processing of other storage proteins in wheat. Biological significance The reported study provides new insights into wheat storage protein maturation. In view of the importance of gluten proteins on dough viscoelastic properties and end-product quality, the reported C-terminal domain cleavage of high-molecular-weight glutenin subunits is of particular interest, since this domain possesses a unique conserved cysteine residue which is assumed to participate in gluten polymerization. PMID- 28552834 TI - High-impact sport after hip resurfacing: The Ironman triathlon. AB - BACKGROUND: Returning to high-impact sport is an increasingly frequent functional demand following hip replacement. The literature, however, is sparse on the subject and nonexistent regarding triathlon. We therefore conducted a retrospective study of hip resurfacing in triathlon players, to determine: (1) whether it is possible to return to this kind of sport; (2) if so, whether it is possible to return to the same level; and (3) how a resurfaced hip behaves under these conditions. HYPOTHESIS: Hip resurfacing allows return to competition level in long-distance triathlon. MATERIAL AND METHODS: A single-center single-operator retrospective study included patients undergoing hip resurfacing with the Conserve Plus implant inserted through a posterolateral approach, who had ceased long-distance triathlon practice due to osteoarthritis of the hip. Fifty-one of the 1688 patients undergoing resurfacing during the inclusion period were long distance triathlon players. RESULTS: The series comprised 48 patients: 51 implants; 43 male, 5 female; mean age, 44.8 years (range, 28.2-58.9 years). At a mean 4.7 years' follow-up (range, 2.2-7.6 years), all clinical scores showed significant improvement; Merle d'Aubigne and Harris scores rose respectively from 12.3 (5-16) and 42 (37-56) preoperatively to 17.5 (13-18) and 93.2 (73-100) (P<0.001). There were no cases of dislocation or implant revision. Forty-five patients returned to sport (94%). Rates of return to swimming, cycling and running were respectively 38/48 (79%), 41/48 (85%) and 33/48 (69%). Preoperatively, all patients had taken part in at least 1 competition: 29 with distance=70.3km and 19 with distance=140.6km. At follow-up, 28 patients had taken part in an Ironman competition: 21 with distance=70.3km and 7 with distance=140.6km. Mean competition performance did not differ between pre and postoperative periods. DISCUSSION: Return-to-sport rates were good following hip resurfacing. Non-impact sports (swimming, cycling) predominated postoperatively, whereas the rate of impact sport (running) diminished. Return to competition level sport (extreme triathlon) was possible for 28/48 patients (58%). Implant survival seemed unaffected by this high-impact sports activity at a mean 4.7 years' follow-up. LEVEL OF EVIDENCE: IV, retrospective, non-controlled. PMID- 28552835 TI - Effect of Propionibacterium acnes (PA) injection on intervertebral disc degeneration in a rat model: Does it mimic modic changes? AB - INTRODUCTION: Multiple reports of bacterial isolates in human disc tissue have suggested a role of low-grade infection on intervertebral disc degeneration and modic changes (MC) generation. Animal models have been extensively used to study IDD; however, until recently, no consideration had been given to eventual infectious processes. To reproduce the phenomena by inoculating an infecting agent would support the infectious hypothesis. Therefore, we studied the effect of Propionibacterium acnes (PA) inoculation on rat-tails and determined whether it would produce MCs on the adjacent endplates. HYPOTHESIS: Disc infection with PA would accelerate IDD compared with the standard model and would also lead to MCs on the adjacent endplates. METHODS: Twelve Sprague-Dawley rats were randomized to receive a needle puncture in a caudal tail disc with either saline (control) or an inoculum of 5*107 CFU of strain 1a PA. Twelve weeks later, the rats were euthanized and the tails were analyzed. The main assessment criteria were obtained from the post-mortem MRI: T2 values of punctured discs and adjacent endplates, as well as disc volumes. A histological grading score for IDD was also used, measuring the morphology and cellularity of the nucleus and annulus, as well as endplate disruption. RESULTS: The median T2 value and disc volume were smaller in PA-punctured discs [T2 value: 30ms (23-44) vs. 61ms (38-132), respectively, P=0.01; 0.01mm3 (0.01-0.05) vs. 0.5mm3 (0.01-5.35), respectively; P=0.049]. There was no change in the adjacent endplates. There was no significant difference in histological grading between the test and control [13 (10-14) vs. 10.5 (6-13); P=0.05]. DISCUSSION: Inoculation of caudal discs with PA generated increased degeneration; however, no MCs were observed on the adjacent endplates. A better understanding of low-grade disc infections is still needed. LEVEL OF EVIDENCE: V (animal study). PMID- 28552836 TI - An original fibular shortening osteotomy technique in tibiotalar arthrodesis. AB - Tibiotalar arthrodesis (TTA) is the gold-standard treatment for advanced ankle osteoarthritis. We describe an original fibular shortening osteotomy (FSO) performed during TTA, to allow complete talar ascension and reduce the nonunion rate. Forty-two FSOs were associated to TTA (19 fixed by cross-screwing and 23 by anatomic plates) and assessed clinically and radiographically. At 24.7 months' follow-up, fusion rates were 97.6% for TTA and 100% for FSO, with mean fusion time of 5.2 months. One infection and 1 nonunion (4.7%) required further surgery, with complete resolution. Radiological and clinical outcome in TTA, lack of specific complications of FSO and ease of implementation encourage us to publish the technique. PMID- 28552837 TI - The effect of vitamin D levels on pain in carpal tunnel syndrome. AB - BACKGROUND: Carpal tunnel syndrome (CTS) and vitamin D deficiency are two discrete common clinical pictures that can cause chronic pain. In this study, we aimed to evaluate the association of 25 (OH) D deficiency with electrophysiological findings and severity of pain in patients with mild CTS. METHOD: The consecutive patients admitted to our laboratory with the symptoms of CTS between May 2016 and August 2016 were enrolled in this study. According to their electrophysiological examination results, only the patients with normal conduction results and ones with mild grade CTS were included. Demographic data, the results of the electrophysiological studies, vitamin D levels (our laboratory normal is>20ng/mL), duration of pain and pain intensity due to CTS, which was assessed with visual analog scale, were collected. RESULTS: Totally, 76 patients (36 patients with mild CTS and 40 without CTS) were included. In the mild CTS patients, vitamin D levels were significantly lower than those electrophysiologically normal patients (P=0.003). The relationship between gender, duration of pain and vitamin D levels were evaluated in the normal and mild CTS group. There was no significant relationship between the pain and vitamin D levels in the normal group, while vitamin D level was significantly lower in the mild CTS group (P=0.730 and P=0.002; respectively). DISCUSSION: Vitamin D deficiency increases the pain intensity in patients with CTS. Treatment of vitamin D deficiency in these patients may play a role in pain relief. Further studies involving analyses of post-vitamin D replacement therapy are warranted to confirm the association between vitamin D deficiency and pain due to CTS. PMID- 28552838 TI - Medicine in Balkans during the Roman Period. AB - The aim of this study is to investigate the archaeological finds to enlighten the medical methods of treatments and operations applied in Balkans during Roman Period. Some independent local and regional find groups, taken from existing publications will be grouped together and a holistic point-of-view will be taken against medicine in Balkan Geography during Roman Period. Due to basic differences it contained, the data before Roman Period are excluded. Most of Greece and Aegean Islands are also excluded since the topic selected is "Medicine of Roman Period." Greece and Aegean Islands should be evaluated in another study in connection with West Anatolia which is closer than the Balkan Geography in terms of social relations. The spread of medical tools in Balkans during Roman Period is concentrated around military garrisons, and in settlements built around military pathways, and in settlements containing an amphitheater associated with gladiators. This spread is verified by the studies on Bulgaria in general. The data is also compatible with the assertion suggesting that the amount of application of pharmaceutical treatment increases when one moves away from the military centres. PMID- 28552839 TI - Endocrinological Evaluations of a Neurofibromatosis Type 1 Cohort: Is it Necessary to Evaluate Autoimmune Thyroiditis in Neurofibromatosis Type 1? AB - BACKGROUND: Neurofibromatosis type 1 is an autosomal dominant neurocutaneous disorder in which the coexistence of autoimmune thyroiditis and thyroid gland tumours has been reported previously. AIMS: To determine the thyroid function and autoimmune thyroid diseases in neurofibromatosis type 1 patients in order to identify the possible association between neurofibromatosis type 1 and thyroid diseases. STUDY DESIGN: Case-control study. METHODS: The study includes 78 consecutive patients diagnosed with neurofibromatosis type 1 between June 2010 and June 2014 and 50 healthy controls. Baseline demographic data were generated from patient examination record forms, including age, sex, height, and weight, as well as levels of free triiodothyronine, free thyroxine, thyroid-stimulating hormone, anti-thyroid peroxidase and anti-thyroglobulin levels. RESULTS: Mean age, sex, and body mass index were similar in both groups (p>0.05). The mean levels of free triiodothyronine, free thyroxine, and thyroid-stimulating hormone were not statistically different between the neurofibromatosis type 1 and control groups. Similarly, no statistically significant difference was observed between the neurofibromatosis type 1 and control groups for anti-thyroid peroxidase and anti-thyroglobulin positivity (2.5% vs 0%, p>0.05). CONCLUSION: Screening for autoimmune thyroid disease and thyroid function seems to be unnecessary in patients with neurofibromatosis type 1. PMID- 28552840 TI - Shrinkage of Nasal Mucosa and Cartilage During Formalin Fixation. AB - BACKGROUND: After resection, specimens are subjected to formalin fixation during histological processing. This procedure can result in tissue shrinkage, with the amount of shrinkage related to tissue composition and tissue type. AIMS: To evaluate the shrinkage of nasal mucosa and cartilage tissue and compare differences in shrinkage after resection, after formalin fixation, and during microscopic examination to understand differences in the rate of shrinkage of different tissue types. STUDY DESIGN: Animal experimentation. METHODS: Fresh nasal septa were excised from sheep (10 mm diameter in 40 sheep and 20 mm diameter in 40 sheep). The mucosa was separated from one side of the cartilage, with the contralateral mucosa remaining attached to the cartilage. Specimen diameters were measured in situ, after resection, after fixation for 6 or 24 hours (10% formalin), and during microscopic examination. RESULTS: There were no differences between the in situ and after resection diameters of any tissue components (free mucosa, mucosa attached to cartilage, and cartilage) of all nasal specimens (10- or 20-mm diameter and 6- or 24-hour fixation). However, significant shrinkage occurred between resection and after-fixation. Regarding tissue specimens that were fixed for different durations (6 or 24 hours), we observed a significantly smaller mean tissue diameter in specimens fixed for 24 hours versus those fixed for 6 hours for mucosa attached to cartilage (in the 10 mm diameter after-fixation samples), free mucosa (in the 20-mm diameter after fixation samples), mucosa attached to cartilage (in the 20-mm diameter after fixation and microscopic measurement samples), and cartilage (in the 20-mm diameter after-fixation samples). Tissue shrinkage was greatest in free mucosal tissue and least in cartilage. CONCLUSION: These results should be considered when evaluating patients undergoing surgical procedures for nasal cavity and paranasal sinus malignancies. Surgical margins should be measured before fixation or evaluated if possible before fixation and shrinkage. PMID- 28552841 TI - Comparison of the T2-star Values of Placentas Obtained from Pre-eclamptic Patients with Those of a Control Group: an Ex-vivo Magnetic Resonance Imaging Study. AB - BACKGROUND: Endotel dysfunction, vasoconstriction, and oxidative stress are described in the pathophysiology of pre-eclampsia, but its aetiology has not been revealed clearly. AIMS: To examine whether there is a difference between the placentas of pre-eclamptic pregnant women and those of a control group in terms of their T2 star values. STUDY DESIGN: Case-control study. METHODS: Twenty patients diagnosed with pre-eclampsia and 22 healthy controls were included in this study. The placentas obtained after births performed via Caesarean section were taken into the magnetic resonance imaging area in plastic bags within the first postnatal hour, and imaging was performed via modified DIXON-Quant sequence. Average values were obtained by performing T2 star measurements from four localisations on the placentas. RESULTS: T2 star values measured in the placentas of the control group were found to be significantly lower than those in the pre-eclampsia group (p<0.01). While the mean T2 star value in the pre eclamptic group was found to be 37.48 ms (standard deviation +/- 11.3), this value was 28.74 (standard deviation +/- 8.08) in the control group. The cut-off value for the T2 star value, maximising the accuracy of diagnosis, was 28.59 ms (area under curve: 0.741; 95% confidence interval: 0.592-0.890); sensitivity and specificity were 70% and 63.6%, respectively. CONCLUSION: This study, the T2 star value, which is an indicator of iron amount, was found to be significantly lower in the control group than in the pre-eclampsia group. This may be related to the reduction in blood flow to the placenta due to endothelial dysfunction and vasoconstriction, which are important in pre-eclampsia pathophysiology. PMID- 28552842 TI - Beyond Urticaria: Schnitzler Syndrome. PMID- 28552851 TI - [Stem Cell System. The intestinal stem cell system.] AB - The intestinal epithelium harbors stem cells at the bottom of crypts. Intestinal stem cells(ISCs)differentiate toward two alternative lineages of secretory or absorptive cells in a unidirectional manner. Studies have revealed factors that are indispensable for maintaining proliferation and differentiation of ISCs, which are provided from the surrounding environment. Additionally, several back up systems compensating the sudden and massive loss of the ISC pool has been reported. Recent development of the three-dimensional culture system of ISCs in vitro has greatly contributed to elucidate these functional analyses of ISCs. PMID- 28552843 TI - Cost of elective percutaneous coronary intervention in Malaysia: a multicentre cross-sectional costing study. AB - OBJECTIVES: Limitations in the quality and access of cost data from low-income and middle-income countries constrain the implementation of economic evaluations. With the increasing prevalence of coronary artery disease in Malaysia, cost information is vital for cardiac service expansion. We aim to calculate the hospitalisation cost of percutaneous coronary intervention (PCI), using a data collection method customised to local setting of limited data availability. DESIGN: This is a cross-sectional costing study from the perspective of healthcare providers, using top-down approach, from January to June 2014. Cost items under each unit of analysis involved in the provision of PCI service were identified, valuated and calculated to produce unit cost estimates. SETTING: Five public cardiac centres participated. All the centres provide full-fledged cardiology services. They are also the tertiary referral centres of their respective regions. PARTICIPANTS: The cost was calculated for elective PCI procedure in each centre. PCI conducted for urgent/emergent indication or for patients with shock and haemodynamic instability were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: The outcome measures of interest were the unit costs at the two units of analysis, namely cardiac ward admission and cardiac catheterisation utilisation, which made up the total hospitalisation cost. RESULTS: The average hospitalisation cost ranged between RM11 471 (US$3186) and RM14 465 (US$4018). PCI consumables were the dominant cost item at all centres. The centre with daycare establishment recorded the lowest admission cost and total hospitalisation cost. CONCLUSIONS: Comprehensive results from all centres enable comparison at the levels of cost items, unit of analysis and total costs. This generates important information on cost variations between centres, thus providing valuable guidance for service planning. Alternative procurement practices for PCI consumables may deliver cost reduction. For countries with limited data availability, costing method tailored based on country setting can be used for the purpose of economic evaluations. REGISTRATION: Malaysian MOH Medical Research and Ethics Committee (ID: NMRR-13-1403-18234 IIR). PMID- 28552852 TI - The Effect of n-3 PUFA on the Development of Abdominal Aortic Aneurysm. PMID- 28552859 TI - Radiobiological Implications of Fukushima Nuclear Accident for Personalized Medical Approach. AB - On March 11, 2011, a devastating earthquake and subsequent tsunami caused serious damage to areas of the Pacific coast in Fukushima prefecture and prompted fears among the residents about a possible meltdown of the Fukushima Daiichi Nuclear Power Plant reactors. As of 2017, over six years have passed since the Fukushima nuclear crisis and yet the full ramifications of the biological exposures to this accidental release of radioactive substances remain unclear. Furthermore, although several genetic studies have determined that the variation in radiation sensitivity among different individuals is wider than expected, personalized medical approaches for Fukushima victims have seemed to be insufficient. In this commentary, we discuss radiobiological issues arising from low-dose radiation exposure, from the cell-based to the population level. We also introduce the scientific utility of the Integrative Japanese Genome Variation Database (iJGVD), an online database released by the Tohoku Medical Megabank Organization, Tohoku University that covered the whole genome sequences of 2,049 healthy individuals in the northeastern part of Japan in 2016. Here we propose a personalized radiation risk assessment and medical approach, which considers the genetic variation of radiation sensitivity among individuals, for next-step developments in radiological protection. PMID- 28552860 TI - Sequence analysis of the hypervariable region in hmtp210 of Avibacterium paragallinarum. AB - The hmtp210 gene of Avibacterium paragallinarum, the causative agent of infectious coryza, encodes an outer-membrane hemagglutinin (HA) that plays an essential role in pathogenicity. A hypervariable region within this HA, which is highly antigenic, is proposed as a candidate for recombinant vaccine production. Nonetheless, little is known about its genetic variability. We performed sequencing analysis of the hmtp210 hypervariable region in 16 clinical isolates from Costa Rica and compared them with 4 vaccine strains and the hmtp210 sequences available in public databases. Except for isolate ApCR12, all isolates showed high identity with reference vaccine strains 0083 and H18. Better genetic characterization of the hypervariable region of hmtp210 is necessary to develop better immunogenic strategies and improved molecular typing methods. PMID- 28552861 TI - Effects of pentosan polysulfate and polysulfated glycosaminoglycan on chondrogenesis of canine bone marrow-derived mesenchymal stem cells in alginate and micromass culture. AB - Mesenchymal stem cells (MSC) are a potential alternative source of differentiated chondrocytes for cartilage tissue regeneration and repair of osteoarthritic (OA) joints. We investigated the effects of pentosan polysulfate (PPS) and polysulfated glycosaminoglycan (PSGAG) on chondrogenesis of canine bone marrow derived mesenchymal stem cells (cBMSC) in alginate and micromass cultures (MMC). Chondrogenic differentiation medium (CDM) was supplemented with PPS or PSGAG at concentrations of 0 (positive control; PC), 1, 3 and 5 ug/ml. 10% DMEM was used as negative control. Chondrocyte phenotype was analyzed by quantitative real-time PCR (qPCR) for alginate cultures and Alcian blue staining for proteoglycan (PG) synthesis for MMC. In alginate culture, PPS and PSGAG showed no significant effect on type II collagen, aggrecan and HIF-2alpha mRNA expression. PPS had no significant effect on type I collagen whereas PSGAG significantly upregulated (P<0.05) it at all concentrations relative to other treatments. PPS demonstrated a dose-dependent inhibitory effect on type X collagen mRNA with significant inhibition observed at 5 ug/ml compared to the NC. PSGAG showed an inverse effect on type X collagen with 1 ug/ml significantly inhibiting its expression while increase in the concentration correspondingly increased type X collagen expression. In MMC, PPS significantly enhanced chondrogenesis and PG deposition whereas PSGAG inhibited chondrogenesis and promoted a fibrocartilage-like phenotype with reduced PG deposition. While PPS enhances chondrogenesis of cBMSC in MMC, the response of MSC to chondroinductive factors is culture system dependent and varies significantly between alginate and MMC. PMID- 28552862 TI - Imbalanced Angiogenesis in Peripartum Cardiomyopathy - Diagnostic Value of Placenta Growth Factor. AB - BACKGROUND: Concentrations of the anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) are altered in peripartum cardiomyopathy (PPCM). In this study we investigated changes in the angiogenesis balance in PPCM.Methods and Results:Plasma concentrations of sFlt-1 and the pro-angiogenic placenta growth factor (PlGF) were determined in patients with PPCM during the post-partum phase (n=83), in healthy women at delivery (n=30), and in patients with acute heart failure (AHF; n=65). Women with cardiac failure prepartum or associated with any form of hypertension, including pre-eclampsia, were excluded. Compared with non-pregnant women, in women with AHF and PPCM, median PlGF concentrations were greater (19 [IQR 16-22] and 98 [IQR 78-126] ng/mL, respectively; P<0.001) and the sFlt-1/PlGF ratio was lower (9.8 [6.6-11.3] and 1.2 [0.9-2.8], respectively; P<0.001). The sFlt-1/PlGF ratio was lower in PPCM than in normal deliveries (1.2 [0.9-2.8] vs. 94.8 [68.8-194.1], respectively; P<0.0001). The area under the curve for PlGF (cut-off value: 50ng/mL) and/or the sFlt-1/PlGF ratio (cut-off value: 4) to distinguish PPCM from either normal delivery or AHF was >0.94. Median plasma concentrations of the anti-angiogenic factor relaxin-2 were lower in PPCM and AHF (0.3 [IQR 0.3-1.7] and 0.3 [IQR 0.3-1] ng/mL, respectively) compared with normal deliveries (1,807 [IQR 1,101-4,050] ng/mL; P<0.001). CONCLUSIONS: Plasma of PPCM patients shows imbalanced angiogenesis. High PlGF and/or low sFlt-1/PlGF may be used to diagnose PPCM. PMID- 28552863 TI - Atrial Natriuretic Peptide - Old But New Therapeutic in Cardiovascular Diseases. AB - With the discovery of atrial natriuretic peptide (ANP), the heart as an endocrine organ was established. Basic science revealed that ANP, through the particulate guanylyl cyclase A receptor and cGMP, plays a fundamental role in cardiorenal biology. This work has led to the development of ANP as a therapeutic, especially in heart failure (HF). Human genomics has strengthened our understanding of ANP, revealing specific ANP gene variants that may be associated with biological dysfunction, but also may mediate protective properties, including in metabolic syndrome. Advances in understanding the processing and degradation of ANP molecular forms have resulted in therapeutic breakthroughs, especially inhibition of ANP degradation by neprilysin inhibitors. Although ANP is administered intravenously for acute HF, a novel therapeutic strategy is its chronic delivery by subcutaneous injection. An innovative therapeutic development is engineering to develop ANP-based peptides for chronic use. These interconnected topics of ANP biology and therapeutics will be reviewed in detail. PMID- 28552864 TI - Development-related changes in the expression of the ovarian Kiss1 and Kiss1r genes and their sensitivity to human chorionic gonadotropin in prepubertal female rats. AB - Kisspeptin, which is encoded by the Kiss1 gene, and its receptor, the G protein coupled receptor 54 (Kiss1r), play important roles in the regulation of reproductive functions in mammals. Several studies have shown that the Kiss1 and Kiss1r genes are expressed in the rat, primate, and human ovaries, and that the ovarian kisspeptin system plays a pivotal role in ovulation at the proestrous stage in adulthood. The purpose of this study was to evaluate development-related changes in the expression of ovarian Kiss1 and Kiss1r genes and in kisspeptin levels, and to identify the regulatory factors for these genes during the prepubertal period. The serum kisspeptin level was also measured to examine whether ovarian kisspeptin affects serum kisspeptin levels. Variations in the ovarian Kiss1 and Kiss1r mRNA levels were observed during the prepubertal period in female rats, with levels peaking around postnatal days 20 and 15, respectively. Nevertheless, the ovarian kisspeptin content per total protein level was stably maintained. Serum kisspeptin levels at postnatal days 30 and 35 were higher than those at earlier postnatal days. The pattern of the ovarian Kiss1 mRNA levels was similar to that of the serum luteinizing hormone (LH) levels, and the ovarian Kiss1 mRNA level increased after injection with human chorionic gonadotropin (HCG) on postnatal day 20, but not on postnatal days 10 and 30. These data indicate that ovarian Kiss1 and Kiss1r mRNA levels are increased on postnatal days 20 and 15, respectively, and that changes in the serum LH level and the ovarian sensitivity to LH may be involved in the alteration of ovarian Kiss1 mRNA levels. PMID- 28552865 TI - New development of diagnosis and treatment for Parkinson's disease. AB - New methods for the diagnosis and new treatments for Parkinson's disease (PD) were explained. As imaging tools, neuromelanin imaging using brain MRI, meta iodobenzylguanidine (MIBG) cardiac scintigraphy, dopamine transporter scintigraphy, and transcranial sonography were introduced. Olfactory dysfunction and REM sleep behavior disorders (RBD), which are important non-motor symptoms, and the new Clinical Criteria for PD launched by Movement Disorder Society (MDS) were also described. Investigative new medications and new anti-PD medications, which recently became available in Japan, were introduced. I explained the rationale of early treatment, strategy of initial treatment, the significance of continuous dopaminergic stimulation, strategy of treatment for advanced PD, and deep brain stimulation as a surgical treatment together with promising new treatments including gene therapy and cell transplantation. PMID- 28552866 TI - Meningeal plasma cell granuloma in the early stage of relapsing polychondritis. AB - A 77-year-old man showed an asymptomatic meningeal lesion beneath the dura matter in the left fronto-parietal region on MRI during an examination for recurrent hoarsness. The lesion showed no gadolinium enhancement, and extended to neither the sulci nor skull. Neurological examinations revealed hoarseness, cochlear and vestibular dysfunction of the right ear, and mildly decreased Achilles tendon reflexes bilaterally. Laboratory findings showed marked inflammatory responses, but no abnormalities for LDH, IgG4, angiotensin-converting enzyme, or soluble IL 2 receptor. There was no serum monoclonal protein. Autoantibody panels in the serum were unremarkable except for an elevation of anti-type II collagen antibodies to a borderline value. Cerebrospinal fluid analysis disclosed an elevated protein concentration (152 mg/dl) and IgG index (1.41) with normal cell counts, negative results for bacterial/tubercular infection, and a normal cytology. 18F-fluorodeoxyglucose positron emission tomography showed increased uptake in the left frontal region (Max SUV: 7.54). Swelling of the vocal cord, arytenoid cartilage, false vocal cord, and vocal cord palsy on the right side were seen on laryngoscopy, all of which were ameliorated by dexamethasone administration. A meningeal biopsy contained the dura matter and arachnoid, in which a granulation composed of massive mature plasma cells with many Russel bodies, accompanied by occasional lymphocytes and histiocytes were observed. Three months after the biopsy, he developed bilateral auricular chondritis and conjunctivitis. Based on these findings, we diagnosed him with relapsing polychondritis (RP). Prednisolone administration (40 mg/day) improved the chondritis and meningeal lesion. Central nervous system involvement is rare in patients with RP, and meningeal complications, such as aseptic meningitis or pachymeningitis, are mostly observed after the diagnosis of RP. However, due to its rarity, it still remains to be clarified whether a similar pathogenesis of meningeal complications underlies RP. The present case is indicative in that predominant meningeal granuloma arose during chondritis of several portions that had gradually developed, which suggests that meningeal complications could be derived from RP. PMID- 28552867 TI - An unusual case of sodium channel myotonia with transient weakness upon initiating movements which is characteristic in Becker disease. AB - We reported a 32-year-old man who was a sporadic case of myotonic syndrome with muscle stiffness or transient weakness of limbs upon initiating movements after rest. On examination, he showed painless myotonia with warm-up phenomenon, Hercules-like hypertrophic musculature and myotonic discharges in EMG. The clinical findings resembled to those of Becker disease rather than Thomsen disease. But electrodiagnosis suggested sodium channel myotonia instead of chloride channelopathy. Genetic testing detected a novel missense mutation (p.V1166A) in the SCN4A gene but not in the CLCN1 gene. Transient weakness upon initiating movements is usually observed in Becker disease but rare in Thomsen disease, which is not reported in sodium channel myotonia so far. He was probably the first case of sodium channel myotonia with transient weakness upon initiating movements, which was confirmed by 10 Hz repetitive nerve stimulation test as depolarization block. PMID- 28552868 TI - Delays in clinical development of neurological drugs in Japan. AB - The delays in the approval and development of neurological drugs between Japan and other countries have been a major issue for patients with neurological diseases. The objective of this study was to analyze factors contributing to the delay in the launching of neurological drugs in Japan. We analyzed data from Japan and the US for the approval of 42 neurological drugs, all of which were approved earlier in the US than in Japan, and examined the potential factors that may cause the delay of their launch. Introductions of the 42 drugs in Japan occurred at a median of 87 months after introductions in the US. The mean review time of new drug applications for the 20 drugs introduced in Japan in January 2011 or later (15 months) was significantly shorter than that for the other 22 drugs introduced in Japan in December 2010 or earlier (24 months). The lag in the Japan's review time behind the US could not explain the approval delays. In the 31 of the 42 drugs, the application data package included overseas data. The mean review time of these 31 drugs (17 months) was significantly shorter than that of the other 11 drugs without overseas data (26 months). The mean approval lag behind the US of the 31 drugs (78 months) was also significantly shorter than that of the other 11 drugs (134 months). These results show that several important reforms in the Japanese drug development and approval system (e.g., inclusion of global clinical trial data) have reduced the delays in the clinical development of neurological drugs. PMID- 28552869 TI - Foreign accent syndrome caused by the left precentral infarction-a case report. AB - A 57-year-old right-handed man was admitted to our hospital because of right facial paresis and acute-onset dysarthria. He presented with non-fluent aphasia. His aphasia gradually improved, but he started speaking with a strange accent and intonation from the fifth hospital day. He was diagnosed with foreign accent syndrome (FAS), which lasted for 2 months. MRI revealed ischemic infarction with edema in the superior, middle, and inferior parts of the left precentral gyrus. One year later, MRI revealed old, small infarct lesions in the left precentral gyrus, middle frontal gyrus, and postcentral gyrus. We suspected that FAS developed because of disturbance of prosody in the speaking network on improving his aphasia. His meticulous character was probably influenced on developing FAS. The responsible lesions possibly were those in the reversible parts of the left precentral gyrus with edema on acute stage. PMID- 28552870 TI - Adult-onset neuronal intranuclear inclusion disease presented transient global amnesia-a case report. AB - A 65-year-old man had a transient amnesia for about 3 hours. Similar symptoms appeared three years ago. He did not manifest dementia, cerebellar ataxia and involuntary movements. Peripheral neuropathy was observed by the neurophysiological examinations. Diffusion weighted image showed high intensity signal in the area of the corticomedullary junction of the frontal to parietal lobes and immunohistochemical studies of biopsied skin revealed many intranuclear inclusion bodies. Adult-onset neuronal intranuclear inclusion disease was diagnosed. As there was no similar member in his family, he was a sporadic case. Clinical characteristics of his amnesia was fulfilled with the criteria of transient global amnesia (TGA). The transient disturbance of limbic system was suspected. PMID- 28552871 TI - A case of stiff-person syndrome due to secondary adrenal insufficiency. AB - We report a case of flexion contractures in a patient's legs secondary to postpartum hypopituitarism. A 56-year-old woman presented with a 3-year history of worsening flexion contractures of the hips and knees. On admission, her hips and knees could not be extended, and she had muscle stiffness and tenderness to palpation of the lower extremities. We first suspected stiff-person syndrome or Isaacs' syndrome because of her muscle stiffness. However, multiple hormones did not respond to stimulation tests, and an MRI of the brain showed atrophy of the pituitary gland with an empty sella. A subsequent interview revealed that she had suffered a severe hemorrhage while delivering her third child. She was diagnosed with panhypopituitarism and started on cortisol replacement therapy. After 1 week of treatment with hydrocortisone (10 mg/day), her symptoms quickly improved. We then added 75 MUg/day of thyroid hormone. During the course of her treatment, autoantibodies against VGKC complex were found to be weakly positive. However, we considered the antibodies to be unrelated to her disease, because her symptoms improved markedly with low-dose steroid treatment. There are a few reports describing flexion contractures of the legs in patients with primary and secondary adrenal insufficiency. As these symptoms are similar to those seen in stiff-person syndrome, adrenal and pituitary insufficiency should be taken into account to achieve the correct diagnosis and treatment in patients with flexion contractures and muscle stiffness. PMID- 28552872 TI - Mononeuritis multiplex in a patient with cutaneous arteritis diagnosed by skin biopsy. AB - A 55-year-old man was admitted with paralysis of the left lower leg. He had purpura in the left lower extremity for three years, left calf pain for two years, and dysesthesia in the left plantar region and first toe for one year. A physical examination revealed livedo reticularis on the left leg and mononeuritis multiplex was diagnosed in the bilateral tibial and left peroneal nerve area. Anti-neutrophil cytoplasmic antibody was negative. A nerve conduction study showed decreased amplitude of compound muscle-action potential in the bilateral tibial and the left peroneal nerve, sensory nerve action potential in the bilateral sural nerve. A skin biopsy revealed inflammatory cells on blood vessel walls and cutaneous arteritis was diagnosed. Cyclophosphamide pulse therapy with steroid and anti-coagulation improved the neurological symptoms. A skin biopsy should be considered when patients present with mononeuritis multiplex in the lower extremities and cutaneous findings such as livedo reticularis in the symptomatic area. PMID- 28552873 TI - The therapeutic efficacy of allyl isothiocyanate in cows with bovine digital dermatitis. AB - Bovine digital dermatitis (BDD) is the most prevalent infectious cause of lameness in cattle. Because Treponema infection is a major etiology of BDD, the most common treatment of BDD is an antibiotic. Nonetheless, dairy cows require a withdrawal period after antibiotic treatment before their milk can be marketed. To address the problem, in this study, we tested whether 3 nonantibiotic agents (used separately)-allyl isothiocyanate (AITC), sodium alginate, and calcium hydroxide-alleviate BDD lesions in dairy cows. The AITC treatment improved the BDD lesions, whereas the sodium alginate and calcium hydroxide treatments did not. Therapeutic efficacy of AITC was similar to that of lincomycin, a topical antibiotic prescribed for BDD. These results suggest that AITC is a promising nonantibiotic agent for BDD treatment in dairy cows. PMID- 28552874 TI - Intake of Diet Including 1% Ovomucoid for 4 Weeks Induces Oral Desensitization in Ovomucoid-Specific Allergic Mouse Model. AB - We propose a new oral immunotherapy (OIT) method that includes a small amount of a food allergen in the diet. However, it is not clear whether this method will induce oral desensitization and immune tolerance. Therefore, we investigated the therapeutic effectiveness using a 1% food allergen diet in an allergic mouse model. C3H/HeJ mice were sensitized to ovomucoid (OM) in alum four times at 12-d intervals. Sensitized mice were divided into two groups: the OIT group (19% casein diet with 1% OM) and the non-treated group (20% casein diet without OM). The non-sensitized mice served as the non-allergy group. The OIT treatment was performed for 4 wk. To assess desensitization and immune tolerance, we performed oral and intraperitoneal OM challenges, assessed vascular permeability of the dorsal skin, and measured allergic biomarkers. The OIT group exhibited significantly lower oral symptom scores and vascular permeability than the non treated group, but the two groups did not differ in intraperitoneal allergy symptom scores. Furthermore, the OIT group had significantly higher OM-specific IgA levels in their plasma than the non-treated group. However, the plasma levels of OM-specific IgE, IgG1, and IgG2a were not significantly different between the OIT and the non-treated groups. These results suggest that the proposed OIT using an OM-supplemented diet may induce desensitization, but not immune tolerance, in an OM allergic mouse model. PMID- 28552875 TI - Egg White Hydrolysate Can Be a Low-Allergenic Food Material to Suppress Ectopic Fat Accumulation in Rats Fed an Equicaloric Diet. AB - Egg white (EW) is known as a nutritional protein but can induce allergic reactions in humans. We investigated the dietary effects of EW and its hydrolysate (EWH), which contains less allergen, on body fat accumulation in Wistar rats fed an equicaloric high-fat and high-sucrose diet for 8 wk (Exp A). The pair-feeding of EW and equicaloric-feeding of EWH increased fecal fat excretion and suppressed lipid accumulation in the liver and muscles but not in the abdominal adipose tissues, carcass, or total body. Dietary EWH also suppressed the serum glucose level and alkaline phosphatase activity. Further, we showed a higher dispersibility of EW and EWH in physicochemical assay (Exp B). Next, we investigated the suppressive effects of a single administration of EW and EWH on lipid-induced hypertriglyceridemia and small intestinal meal transit in ddY mice (Exp C). However, a single administration of EW or EWH did not suppress the lipid-induced hypertriglyceridemia nor did it delay the rate of small intestinal transit. These findings indicated that dietary EW and EWH reduce hepatic and muscular (ectopic) fat accumulation mainly by suppressing fat absorption and supplying fat to the liver and muscles. Therefore, the low allergenic EWH can be effective for the prevention of high-fat-diet-induced obesity. PMID- 28552876 TI - Effects of Eggshell Calcium Supplementation on Bone Mass in Postmenopausal Vietnamese Women. AB - Bone mass decreases along with aging, especially for women after menopause because of lower estrogen secretion together with low calcium intake. This study was conducted to study the effect of eggshell calcium supplementation on bone mass in 54 postmenopausal Vietnamese women living in a farming area about 60 km from Hanoi, Vietnam. Sets of 3 subjects matched by age, bone mass, BMI and calcium intake were divided randomly into 3 groups with 18 subjects in each group. The eggshell calcium group was administered 300 mg/d calcium from eggshell, the calcium carbonate group 300 mg/d calcium from calcium carbonate and the placebo group received no calcium supplementation. Bone mass (Speed of Sound (SOS)) was measured at the beginning (the baseline), the middle (6th month) and the end of the study (12th month) by the single blind method. SOS of the eggshell group increased significantly at 12 mo (p<0.05) and was significantly higher than that of the placebo and calcium carbonate groups at 12 mo (p<0.05). The SOS of the calcium carbonate group tended to be higher than that of the placebo group but without a significant difference (p>0.05). In conclusion, eggshell calcium was more effective in increasing bone mass than calcium carbonate in postmenopausal Vietnamese women. PMID- 28552877 TI - Gluten-Free Flours from Different Raw Materials as the Source of Vitamin B1, B2, B3 and B6. AB - Gluten-free (GF) products are those with a natural absence or acceptable level (<20 mg/kg) of gluten. They should be a part of a diet for people with gluten related disorders, like celiac disease. Recently the popularity of a gluten-free diet (GFD) has risen extremely, because a lot of healthy individuals exclude gluten from their menus. According to the literature data on nutritional deficiencies in the GFD, this trend seems to be risky. This paper describes the nutritional value of 14 flours from different GF raw materials from the aspect of B-group vitamin content (B1, B2, B3, B6). Vitamins were determined using high performance liquid chromatography after enzymatic and acid hydrolysis of the samples. The vitamin contents significantly differed in the analysed flours. The content (in 100 g of the product) of vitamin B1 ranged from 0.01 mg (amaranth flour) to 0.60 mg (teff flour), vitamin B2 from 0.03 mg (GF flour with oats) to 0.22 mg (buckwheat flour), vitamin B3 from below 0.01 mg (amaranth flour) to 6.02 mg (millet flour), and vitamin B6 from 0.03 mg (acorn flour) to 0.69 mg (amaranth flour). The content of vitamins in the analysed GF flours was also compared to gluten-containing flours. Obtained results indicate that flours from teff, millet, chestnut, buckwheat, and amaranth are better sources of certain B-group vitamins than flours from corn, rice, and some flours with gluten. PMID- 28552878 TI - Medium-Chain Triglycerides in Combination with Leucine and Vitamin D Benefit Cognition in Frail Elderly Adults: A Randomized Controlled Trial. AB - The combined supplementation of medium-chain triglycerides (MCTs), L-leucine-rich amino acids, and cholecalciferol (vitamin D3) increase muscle strength and function in frail elderly individuals. However, their effects on cognition are unknown. We enrolled 38 elderly nursing home residents (mean age+/-SD, 86.6+/-4.8 y) in a 3-mo randomized, controlled, parallel group trial. The participants were randomly allocated to 3 groups: the first group received a L-leucine (1.2 g)- and cholecalciferol (20 MUg)-enriched supplement with 6 g of MCT (LD+MCT); the second group received the same supplement with 6 g of long-chain triglycerides (LD+LCT); and the third group did not receive any supplements (control). Cognition was assessed at baseline and after the 3-mo intervention. The difference in changes among the groups was assessed with ANCOVA, adjusting for age and the baseline value as covariates. After 3 mo, the Mini-Mental State Examination (MMSE) score in the LD+MCT group increased by 10.6% (from 16.6 to 18.4 points, p<0.05). After 3 mo, the Nishimura geriatric rating scale for mental status (NM scale) score in the LD+MCT group increased by 30.6% (from 24.6 to 32.2 points, p<0.001), whereas that in the LD+LCT and control groups decreased by 11.2% (from 31.2 to 27.7 points, p<0.05) and 26.1% (from 27.2 to 20.1 points, p<0.001), respectively. The combined supplementation of MCTs (6 g), L-leucine-rich amino acids, and cholecalciferol may improve cognitive function in frail elderly individuals. PMID- 28552879 TI - Energy Requirement Assessment and Water Turnover in Japanese College Wrestlers Using the Doubly Labeled Water Method. AB - Estimated energy requirements (EERs) are important for sports based on body weight classifications to aid in weight management. The basis for establishing EERs varies and includes self-reported energy intake (EI), predicted energy expenditure, and measured daily energy expenditure. Currently, however, no studies have been performed with male wrestlers using the highly accurate and precise doubly labeled water (DLW) method to estimate energy and fluid requirement. The primary aim of this study was to compare total energy expenditure (TEE), self-reported EI, and the difference in collegiate wrestlers during a normal training period using the DLW method. The secondary aims were to measure the water turnover and the physical activity level (PAL) of the athletes, and to examine the accuracy of two currently used equations to predict EER. Ten healthy males (age, 20.4+/-0.5 y) belonging to the East-Japan college league participated in this study. TEE was measured using the DLW method, and EI was assessed with self-reported dietary records for ~1 wk. There was a significant difference between TEE (17.9+/-2.5 MJ*d-1 [4,283+/-590 kcal*d-1]) and self reported EI (14.4+/-3.3 MJ*d-1 [3,446+/-799 kcal*d-1]), a difference of 19%. The water turnover was 4.61+/-0.73 L*d-1. The measured PAL (2.6+/-0.3) was higher than two predicted values during the training season and thus the two EER prediction equations produced underestimated values relative to DLW. We found that previous EERs were underestimating requirements in collegiate wrestlers and that those estimates should be revised. PMID- 28552880 TI - Genotyping Analysis of Bitter-Taste Receptor Genes TAS2R38 and TAS2R46 in Japanese Patients with Gastrointestinal Cancers. AB - Type-2 bitter-taste receptors (TAS2Rs) are important for the evaluation of food quality and the nutritional control in animals. Mutations in some TAS2Rs including TAS2R38 are known to increase susceptibility to various diseases. However, the involvement of TAS2Rs in cancers has not been well understood. We conducted a pilot study by genotyping two TAS2R genes, TAS2R38 and TAS2R46, in Japanese cancer patients diagnosed with the following types of cancer: biliary tract cancer, hepatocellular carcinoma, pancreatic cancer, colorectal cancer and gastric cancer. We selected the two TAS2Rs because they carry virtually non functional alleles in human populations. We found that cancer risk is not associated with any TAS2R46 genotypes since there were no significant differences in genotype frequencies between cancer patients and controls. On the other hand, we confirmed that phenylthiocarbamide (PTC) non-tasters homozygous (AVI/AVI) for TAS2R38 were more frequent among Japanese cancer patients than those among controls as suggested in a previous study. The AVI/AVI genotype was therefore considered to increases cancer risk. In contrast, we also found that homozygous (PAV/PAV) PTC tasters are less frequent among cancer patients, suggesting that the PAV/PAV is a cancer resistant genotype that decreases cancer risk. Genotype frequencies for heterozygous AVI/PAV genotype were not significantly different between the two groups. It is suggested that the risk and resistance of cancers is antagonistically controlled by the two TAS2R38 alleles, PAV and AVI, rather than by the AVI allele alone. PMID- 28552881 TI - Vitamin D Deficiency and Associated Factors in Patients with Mental Disorders Treated in Routine Practice. AB - This research aimed to investigate factors associated with vitamin D deficiency and to provide data about its prevalence in patients suffering from different psychiatric illnesses. The study had a cross-sectional design and it included 220 patients of both genders, aged from 19-81 y, with a wide range of mental disorders (F00-F89), and treated in routine ambulatory and hospital practice. The researchers collected data from three sources: medical records, a study questionnaire and biochemical analysis of patients' serum samples (concentration of vitamin D measured as 25(OH)D, calcium, phosphorus, magnesium, sodium and potassium). Data were analyzed using descriptive statistics, methods for hypothesis testing and binary logistic regression, at the p<=0.05 level. A total of 140 patients (64%) had a deficiency of vitamin D (<12 ng/mL), and 45 (20%) had inadequate vitamin D serum levels (12-20 ng/mL), while 35 (16%) had sufficient vitamin D serum concentrations (>20 ng/mL). Among variables related to demographics, life style habits, mental illness, comorbid disorders and drugs, two of them, female gender (odds ratio (OR)=2.5, 95% confidence interval (CI)=1.3 4.9, p=0.006) and using clozapine (OR=15.6, 95% CI 1.7-144.7, p=0.02), were significantly associated with vitamin D deficiency. Physical activity (OR= 0.4, 95% CI 0.2-0.9, p=0.02), exercising (OR=0.2, 95% CI <0.1-0.7, p=0.02) and offal in the diet (OR=0.5, 95% CI 0.3-0.9, p=0.03) significantly aggregated in the patients who had a 25(OH)D serum concentration above the deficiency cut-off level. Patients with mental disorders are at high risk for vitamin D deficiency, particularly females and clozapine users as well as those having no adequate physical activity or dietary habits. PMID- 28552882 TI - The Impact of Supplementation with Folic Acid on Homocysteine Concentration and Selected Lipoprotein Parameters in Patients with Primary Hypertension. AB - The aim of the study was the assessment of the impact of supplementation with folic acid on the concentration of homocysteine, total cholesterol (TC), HDL- and LDL-cholesterol, triglycerides (TG), apoprotein AI (apoAI) and apoprotein B (apoB) in patients suffering from primary hypertension. The examined group comprised 42 patients suffering from primary hypertension. All examined patients underwent laboratory tests as follows: concentration of homocysteine, folic acid, TC, LDL-cholesterol, HDL-cholesterol, TG, apoAI and apoB. All patients were orally administered with 15 mg of folic acid per day for 45 d. After this period, all laboratory tests were repeated. Homocysteine concentration was measured by the FPIA method, concentrations of apoAI and apoB were measured by the nephelometric method, and other parameters with routine methods. After administration of 15 mg of folic acid to patients with primary hypertension, a considerable decrease in the concentration of homocysteine was observed in parallel with a substantive growth of HDL-cholesterol, as well as apoprotein AI concentrations and a reduction of the apoprotein B concentration. Results of statistical analysis indicated a significant correlation between the decline in homocysteine concentration and the increase in HDL-cholesterol concentration, as well as between the increase of folic acid concentration and the increase in apoAI concentration in patients following the intake of folic acid. The drop in homocysteine concentration through the supplementation with folic acid can cause quantitative changes in the lipid and lipoprotein parameters which, in consequence, may lead to the mitigation of risk concerning the development of atherosclerosis. PMID- 28552883 TI - SEL1L-dependent Substrates Require Derlin2/3 and Herp1/2 for Endoplasmic Reticulum-associated Degradation. AB - Accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR). The ATF6 pathway is one of the three major pathways in vertebrates. Although ATF6, a transmembrane-type glycoprotein in the ER, functions as a UPR sensor/transducer, it is an unstable protein with a half-life of approximately 2 h and is constitutively subjected to the ER-associated degradation system with the location of the misfolded part in the ER lumen (ERAD-L). ERAD-L substrates are delivered to the cytosol through the retrotranslocon, which likely contains HRD1 (E3), gp78 (E3), SEL1L (a partner of HRD1), Derlin1/2/3 and Herp1/2. We previously showed that ATF6 represents a novel transmembrane-type ERAD-L substrate requiring both EDEM1/2/3-mediated mannose trimming and SEL1L. Here, by constructing and analyzing chicken DT40 cells deficient in various components of the retrotranslocon, we show that degradation of ATF6 requires Derlin2 or Derlin3 and that Derlin2 and Derlin3 are redundant for ERAD-L of ATF6. We further show that degradation of ATF6 requires Herp1 or Herp2 and that Herp1 and Herp2 are redundant for ERAD-L of ATF6. Furthermore, by investigating five more ERAD-L substrates, we show that SEL1L-dependent substrates require Derlin2/3 and Herp1/2 regardless of their soluble or transmembrane nature. Our results suggest that ERAD-L substrates take several routes to the cytosol. The HRD1-engaged route 1 requires SEL1L, Derlin2 or Derlin3, and Herp1 or Herp2, whereas the HRD1-engaged route 2 does not require them functionally. It remains to be determined whether the latter requires Derlin1 and whether these two routes are compositionally distinct.Key words: endoplasmic reticulum, proteasome, protein degradation, protein misfolding, ubiquitin. PMID- 28552884 TI - Ranolazine Facilitates Termination of Ventricular Tachyarrhythmia Associated With Acute Myocardial Ischemia Through Suppression of Late INa-Mediated Focal Activity. AB - BACKGROUND: Ventricular tachycardia/fibrillation (VT/VF) associated with acute myocardial ischemia is the most common cause of sudden cardiac death, but its underlying mechanisms are incompletely understood. It is hypothesized that late Na+current (INa) contributes to arrhythmogenic activity in ischemic myocardium.Methods and Results:Langendorff-perfused rabbit hearts with regional ischemia in ventricles were optically mapped. Perfusion with ranolazine (10 MUmol/L), a selective inhibitor of lateINa, significantly reduced excitation frequency and facilitated termination of VT/VF induced after occlusion of the left main coronary trunk. The activation pattern during ischemic VT/VF was characterized by breakthrough-type excitations (BEs) from multiple origins, predominantly in the ischemic border zone (BZ) and occasional short-lived rotors. Ranolazine perfusion significantly reduced the incidence of BEs in the BZ. Rotors tended to decrease with progression of ischemia and disappeared after ranolazine perfusion. During constant pacing, ranolazine attenuated ischemia-induced shortening of action potentials in the BZ without affecting conduction velocity, probably due toIKrinhibition. In intact hearts without coronary occlusion, ranolazine (10 MUmol/L) terminated aconitine-induced VT by inhibiting focal arrhythmogenic activity in the injection site. CONCLUSIONS: LateINa-mediated focal arrhythmogenic activity plays important roles in the maintenance of ischemic VT/VF in isolated rabbit hearts. Suppression of lateINaby ranolazine may be a promising therapeutic strategy to reduce arrhythmic death during the acute phase of myocardial infarction. PMID- 28552885 TI - Novel Strategies for the Management of Nocturnal Hypertension. PMID- 28552886 TI - Administration of gonadotropin-releasing hormone agonist on Day 5 increases luteal blood flow and improves pregnancy prediction accuracy on Day 14 in recipient Holstein cows. AB - This study assessed the effects of gonadotropin-releasing hormone (GnRH) treatment on Day 5 (Day 0 = estrus) on luteal blood flow and accuracy of pregnancy prediction in recipient cows. On Day 5, 120 lactating Holstein cows were randomly assigned to a control group (n = 63) or GnRH group treated with 100 MUg of GnRH agonist (n = 57). On Days 3, 5, 7, and 14, each cow underwent ultrasound examination to measure the blood flow area (BFA) and time-averaged maximum velocity (TAMV) at the spiral arteries at the base of the corpus luteum using color Doppler ultrasonography. Cows with a corpus luteum diameter >= 20 mm (n = 120) received embryo transfers on Day 7. The BFA values in the GnRH group were significantly higher than those in the control group on Days 7 and 14. TAMV did not differ between these groups. According to receiver operating characteristic analyses to predict pregnancy, a BFA cutoff of 0.52 cm2 yielded the highest sensitivity (83.3%) and specificity (90.5%) on Day 7, and BFA and TAMV values of 0.94 cm2 and 44.93 cm/s, respectively, yielded the highest sensitivity (97.1%) and specificity (100%) on Day 14 in the GnRH group. The areas under the curve for the paired BFA and TAMV in the GnRH group were 0.058 higher than those in the control group (0.996 and 0.938, respectively; P < 0.05). In conclusion, GnRH treatment on Day 5 increased the luteal BFA in recipient cows on Days 7 and 14, and improved the accuracy of pregnancy prediction on Day 14. PMID- 28552887 TI - Selection of viable in vitro-fertilized bovine embryos using time-lapse monitoring in microwell culture dishes. AB - Conventionally, in vitro-fertilized (IVF) bovine embryos for transfer are morphologically evaluated at day 7-8 of embryo culture. This method is, however, subjective and results in unreliable selection. We previously described a novel selection system for IVF bovine blastocysts for transfer that traces the development of individual embryos with time-lapse monitoring in our specially developed microwell culture dishes (LinKID micro25). The system can noninvasively identify prognostic factors that reflect viability after transfer. By assessing a combination of identified prognostic factors -timing of the first cleavage; number of blastomeres at the end of the first cleavage; and number of blastomeres at the onset of lag-phase, which results in temporary developmental arrest during the fourth or fifth cell cycle- the pregnancy rate was improved over using conventional morphological evaluation. Time-lapse monitoring with LinKID micro25 could facilitate objective and reliable selection of healthy IVF bovine embryos. Here, we review the novel bovine embryo selection system that allows for prediction of viability after transfer. PMID- 28552888 TI - Cylindrical Inversion Pulse for the Reduction of Cardiac Motion Artifacts in Contrast-enhanced Breast MRI. AB - We proposed a simple technique for reduction of cardiac-related motion artifacts on contrast-enhanced images in the breast by using cylindrical regional suppression technique (CREST) that can directly suppress the heart signals. The purpose of this study was to select the optimal scan parameters and to evaluate the feasibility in the breast. We demonstrated that the optimized CREST could dramatically reduce the cardiac-related flow artifacts without any penalty to the acquisition time, signal-to-noise ratio and contrast-enhanced lesion-to parenchyma contrast. PMID- 28552889 TI - Present Situation of Opisthorchiasis in Vientiane Capital, Lao Peoples' Democratic Republic. AB - Opisthorchiasis is the commonest liver disease caused by Opisthorchis viverrini in Thailand, Lao People's Democratic Republic (PDR) and Cambodia, which will be a major cause of future human cholangiocarcinoma in these regions. In this short review, we describe the epidemic aspects of this parasite infection and the outline of results of our recent surveys of the fluke in humans and its intermediate hosts in Vientiane Capital, where information on the opisthorchiasis epidemic is insufficient. We examined the stool from a total of 296 persons living in the Phailom village (population, 1545, 1999) from 2011 to 2012. As a result, the intestinal parasitism rate was very high from 54 to 59%. Among intestinal infections, O. viverrini infection was observed at highest rates from 51 to 53%. On the other hand, the rate of infection by nematodes was very low. We also conducted intermediate-host investigations in the river and damp areas at 3 villages in the Vientiane capital and 2 villages in Vientiane Province in 2012. As shown by these results, no Opisthorchis species was detected in 147 samples of the host genus Bythinia. However, metacercariae were detected in 3 samples of Cyclocheilichthys sp. and in a Hampala sp. in 303 cyprinid fishes collected from the Haikham village area of Vientiane Capital. PMID- 28552891 TI - Collaborative Research with Chinese, Indian, Filipino and North European Research Organizations on Infectious Disease Epidemics. AB - In this report, we present a short review of applications of time series analysis, which consists of spectral analysis based on the maximum entropy method in the frequency domain and the least squares method in the time domain, to the incidence data of infectious diseases. This report consists of three parts. First, we present our results obtained by collaborative research on infectious disease epidemics with Chinese, Indian, Filipino and North European research organizations. Second, we present the results obtained with the Japanese infectious disease surveillance data and the time series numerically generated from a mathematical model, called the susceptible/exposed/infectious/recovered (SEIR) model. Third, we present an application of the time series analysis to pathologic tissues to examine the usefulness of time series analysis for investigating the spatial pattern of pathologic tissue. It is anticipated that time series analysis will become a useful tool for investigating not only infectious disease surveillance data but also immunological and genetic tests. PMID- 28552890 TI - Collaborative Research on Puerperal Infections in Bangladesh. AB - Bangladesh is considered as a high-risk country for emerging infectious diseases because of its high population density, poverty, and unhygienic conditions. Although control efforts have primarily been focused on major infectious diseases such as diarrheal diseases, tuberculosis, malaria, and HIV infection, the prevalence and impact of many local or minor infectious diseases are still unclarified in this country. In this review, we present our recent experience and outcomes of collaborative research on puerperal infection (PI), which is a poorly defined infectious disease in Bangladesh. PI is the most common complication during the perinatal period in developing countries. We investigated the incidence of individual species of aerobic bacteria causing PIs and their drug resistance, and the genetic traits of isolates during the two-year period (2010 2012). The common species of isolates from patients with PIs were Escherichia coli, Enterococcus faecalis, Staphylococcus haemolyticus, Proteus mirabilis, Staphylococcus aureus, and Klebsiella pneumoniae. A remarkable finding was the high rates of resistance to cephalosporins among Gram-negative bacteria harboring extended-spectrum beta-lactamase genes, which were associated with carbapenem resistance in a few isolates. This study defined the importance of control of antimicrobial resistance in Bangladesh, and provided suggestions for the future direction of collaborative research on infectious diseases in Bangladesh. PMID- 28552892 TI - Analysis of Distribution of Vector-Borne Diseases Using Geographic Information Systems. AB - The distribution of vector-borne diseases is changing on a global scale owing to issues involving natural environments, socioeconomic conditions and border disputes among others. Geographic information systems (GIS) provide an important method of establishing a prompt and precise understanding of local data on disease outbreaks, from which disease eradication programs can be established. Having first defined GIS as a combination of GPS, RS and GIS, we showed the processes through which these technologies were being introduced into our research. GIS-derived geographical information attributes were interpreted in terms of point, area, line, spatial epidemiology, risk and development for generating the vector dynamic models associated with the spread of the disease. The need for interdisciplinary scientific and administrative collaboration in the use of GIS to control infectious diseases is highly warranted. PMID- 28552893 TI - Participant Characteristics in the Kumamoto University Regional Center of Japan Environment and Children's Study (JECS): Association of Pregnancy Outcomes with Pregestational Maternal Body Mass Index and Maternal Weight Gain during Pregnancy. AB - PURPOSE: The purpose of this study was to identify participant characteristics in the Kumamoto University Regional Center of the Japan Environment and Children's Study (K-JECS) and to investigate the association of pregnancy outcomes with pregestational maternal body mass index (BMI) and maternal weight gain during pregnancy (MWG). METHODS: The subjects were women with singleton birth, who had been recruited by the K-JECS, and were registered in the data systems for the first and second questionnaires and transcripts of medical records. The subjects were categorized by BMI with further classification by MWG. The chi-squared test and one-way analysis of variance were performed to determine the correlations of BMI and MWG with perinatal outcomes. Logistic regression analysis was performed to examine perinatal outcome risks. RESULTS: The subject characteristics were similar to the trends observed in the Japanese general population. The odds ratio for natural delivery was low in the overweight groups (OW) and normal weight groups (NW) with excessive weight gain. On the other hand, the risk of cesarean section was high in the OW, and risk of induced or accelerated delivery was high in the NW with excessive weight gain. The risks of preterm birth and LBW were high in the insufficient weight gain groups regardless of BMI. The risks of pregnancy-induced hypertension and gestational diabetes were high in the OW. PMID- 28552894 TI - To the memory of the late Dr. Takeo Yamamoto. PMID- 28552895 TI - Editor's Note. PMID- 28552896 TI - Detection of Salmonella in That Luang Marsh, Vientiane, Lao PDR: Improvement of the Accuracy of Salmonella Detection Using Visualization of Hydrogen Sulfate Production by Salmonella. AB - In this study, Salmonella is used as the standard bacterium for evaluation of pollution of water environments. The author continued to improve Salmonella detection by visualization of hydrogen sulfide production, which is characteristic of Salmonella. At the same time, the positivity rate of Salmonella in rural Lao was investigated. According to the survey conducted so far, it has been found that the Salmonella positivity rate in residents of Laos is markedly higher than that in Japan. It is conceivable that the level by contamination of Salmonella in sewage drained from each house in Laos will be higher than that in Japan. There is no sewage treatment facility in Laos even in the capital Vientiane. In the city, a vast wetland named That Luang Marsh functions as sewage reception. In the case of contamination that exceeds the purification capacity of the wetland, detection of Salmonella in the water of the Mekong River will indicate the deterioration of water quality. PMID- 28552898 TI - Sustained release vancomycin-coated titanium alloy using a novel electrostatic dry powder coating technique may be a potential strategy to reduce implant related infection. AB - In order to tackle the implant-related infection, a novel way was developed in this study to coat vancomycin particles mixed with controlled release coating materials onto the surface of titanium alloy by using an electrostatic dry powder coating technique. To characterize this sustained release antibacterial coating, surface morphology, in vitro and in vivo drug release were sequentially evaluated. In vitro cytotoxicity was tested by Cell Counting Kit-8 (CCK-8) assay and cytological changes were observed by inverted microscope. The antibacterial properties against MRSA, including a bacterial growth inhibition assay and a colony-counting test by spread plate method were performed. Results indicated that the vancomycin-coated sample was biocompatible for Human osteoblast cell line MG-63 and displayed effective antibacterial ability against MRSA. The coating film was revealed uniform by scanning electron microscopy. Both the in vitro and in vivo drug release kinetics showed an initially high release rate, followed by an extended period of sustained drug release over 7 days. These results suggest that with good biocompatibility and antibacterial ability, the sustained release antibacterial coating of titanium alloy using our novel electrostatic dry powder coating process may provide a promising candidate for the treatment of orthopedic implant-related infection. PMID- 28552899 TI - The impacts of computer adaptive testing from a variety of perspectives. AB - Computer adaptive testing (CAT) is a kind of tailored testing, in that it is a form of computer-based testing that is adaptive to each test-taker's ability level. In this review, the impacts of CAT are discussed from different perspectives in order to illustrate crucial points to keep in mind during the development and implementation of CAT. Test developers and psychometricians often emphasize the efficiency and accuracy of CAT in comparison to traditional linear tests. However, many test-takers report feeling discouraged after taking CATs, and this feeling can reduce learning self-efficacy and motivation. A trade-off must be made between the psychological experiences of test-takers and measurement efficiency. From the perspective of educators and subject matter experts, nonstatistical specifications, such as content coverage, content balance, and form length are major concerns. Thus, accreditation bodies may be faced with a discrepancy between the perspectives of psychometricians and those of subject matter experts. In order to improve test-takers' impressions of CAT, the author proposes increasing the target probability of answering correctly in the item selection algorithm even if doing so consequently decreases measurement efficiency. Two different methods, CAT with a shadow test approach and computerized multistage testing, have been developed in order to ensure the satisfaction of subject matter experts. In the shadow test approach, a full length test is assembled that meets the constraints and provides maximum information at the current ability estimate, while computerized multistage testing gives subject matter experts an opportunity to review all test forms prior to administration. PMID- 28552897 TI - Are Short Chain Fatty Acids in Gut Microbiota Defensive Players for Inflammation and Atherosclerosis? AB - Intestinal flora (microbiota) have recently attracted attention among lipid and carbohydrate metabolism researchers. Microbiota metabolize resistant starches and dietary fibers through fermentation and decomposition, and provide short chain fatty acids (SCFAs) to the host. The major SCFAs acetates, propionate and butyrate, have different production ratios and physiological activities. Several receptors for SCFAs have been identified as the G-protein coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3), GPR43/FFAR2, GPR109A, and olfactory receptor 78, which are present in intestinal epithelial cells, immune cells, and adipocytes, despite their expression levels differing between tissues and cell types. Many studies have indicated that SCFAs exhibit a wide range of functions from immune regulation to metabolism in a variety of tissues and organs, and therefore have both a direct and indirect influence on our bodies. This review will focus on SCFAs, especially butyrate, and their effects on various inflammatory mechanisms including atherosclerosis. In the future, SCFAs may provide new insights into understanding the pathophysiology of chronic inflammation, metabolic disorders, and atherosclerosis, and we can expect the development of novel therapeutic strategies for these diseases. PMID- 28552900 TI - Establishment of a dental license regulation authority is required in Korea: results of the Delphi technique. AB - PURPOSE: In addition to dental education, a system for the evaluation and management of dental licensing and certification is required to meet the growing societal demand for more competent dentists. In this study, the Delphi technique was used to gather opinions from a variety of professionals on the problems of and remedies for the dental license management system in Korea. METHODS: Delphi surveys were conducted from April 2016 to October 2016 in South Korea. A variety of dental professionals were included and categorized into 3 groups according to their expertise as follows: the basic dentistry group, the clinical dentistry group, and the policy group. The Delphi technique was conducted in 3 rounds of e mail surveys, each with different questions that probed with increasing depth on the dental license management system. In each successive round, the responses were categorized, scored on a Likert scale, and statistically analyzed. RESULTS: After categorizing the results of the first survey and ranking the results of the second survey using the Delphi technique, regulation by a licensing authority was found to be the most critical issue. This was followed by the license renewal system, continuing education, a tiered licensure system, improvement of foreign license approval, and utilization of retirees, in decreasing order of importance. The third Delphi survey showed a similar ranking, with regulation by a licensing authority being the major concern. Opinions regarding the dental license management system were provided as open-ended responses. The responses of the 3 groups showed statistically significant differences in the scores for the issue of regulation by a licensing authority. After re-grouping into the dentistry group and the policy group, the issue received a significantly higher score in the dentistry group. CONCLUSION: The quality of dental treatment should be managed to protect patients and dental professionals. For this purpose, the establishment of an independent license regulation authority along with legislative changes is required. PMID- 28552901 TI - The Impact of Obesity on the Clinical Course of Inflammatory Bowel Disease: A Meta-Analysis. AB - BACKGROUND Obesity has been linked with a pro-inflammatory state and the development of inflammatory diseases, including inflammatory bowel disease (IBD). However, there is some controversy regarding whether obesity is associated with an adverse clinical course in patients with IBD. The aim of this meta-analysis was to assess the association between obesity and clinical outcomes in IBD patients. MATERIAL AND METHODS Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched for studies investigating the association between obesity and clinical outcomes in patients with IBD. A meta-analysis was performed using Review Manager software. RESULTS Among the 4,798 articles identified, seven met the inclusion criteria for our meta-analysis. The pooled data revealed that obese patients were significantly less likely to undergo IBD-related surgery, receive hormone therapy, and experience hospitalization compared with non-obese patients. However, no statistically significant difference was observed in perianal disease, anti-TNF use, and immunomodulator use between the two groups. CONCLUSIONS Our meta analysis indicated that clinical outcomes were significantly different in obese versus non-obese patients with IBD. We found that obesity was associated with a less severe disease course of IBD. Future prospective studies are needed to confirm the relationship between obesity and the clinical course of IBD. PMID- 28552902 TI - IgG4-Related Disease Manifesting as Interstitial Nephritis Accompanied by Hypophysitis. AB - BACKGROUND IgG4-related disease is a systemic disease with marked infiltration of IgG4-positive plasma cells into affected organs and elevated serum IgG4. On clinical examination, swelling, nodules, and hypertrophic lesions might appear simultaneously or metachronously in different organs. CASE REPORT An 85-year-old man with sudden-onset polydipsia and polyuria insipidus was transported to our hospital because of hypothermia and general malaise. Laboratory tests revealed renal failure and central diabetes insipidus. According to his serum IgG4 level, the patient was diagnosed with possible IgG4-related kidney disease accompanied by IgG4-related hypophysitis. Abdominal contrast-enhanced computed tomography, hypophysis magnetic resonance imaging, and histological examination of the kidney were performed. Glucocorticoid therapy was administered and his renal function improved gradually. However, his central diabetes insipidus did not improve. CONCLUSIONS Glucocorticoid therapy showed different therapeutic effects on the kidney and posterior lobe of the hypophysis. It is possible that glucocorticoid therapy needs to be supported by other immunomodulatory therapies to have an effect on all affected organs. PMID- 28552903 TI - THEMIS, the new kid on the block for T-cell development. PMID- 28552904 TI - Crystal structure of HLA-B*5801 with a TW10 HIV Gag epitope reveals a novel mode of peptide presentation. PMID- 28552905 TI - Harnessing class II histone deacetylases in macrophages to combat breast cancer. PMID- 28552906 TI - Novel PDGFRB fusions in childhood B- and T-acute lymphoblastic leukemia. PMID- 28552907 TI - A versatile nanoplatform for synergistic combination therapy to treat human esophageal cancer. AB - One of the major goals of precision oncology is to promote combination therapy to improve efficacy and reduce side effects of anti-cancer drugs based on their molecular mechanisms. In this study, we aimed to develop and validate new nanoformulations of docetaxel (DTX) and bortezomib (BTZ) for targeted combination therapy to treat human esophageal cancer. By leveraging our versatile disulfide cross-linked micelles (DCMs) platform, we developed nanoformulations of DTX and BTZ (named DTX-DCMs and BTZ-DCMs). Their physical properties were characterized; their anti-cancer efficacies and mechanisms of action were investigated in a human esophageal cancer cell line in vitro. Furthermore, the in vitro anti-tumor activities of combination therapies (concurrent drug treatment, sequential drug treatment, and treatment using different ratios of the drugs) were examined in comparison with the single drug treatment and free drug strategies. These drug loaded nanoparticles were spherical in shape and relatively small in size of approximately 20-22 nm. The entrapment efficiencies of DTX and BTZ into nanoparticles were 82.4% and 84.1%, respectively. The drug release rates of DTX DCMs and BTZ-DCMs were sustained, and greatly increased in the presence of GSH. These nanodrugs were effectively internalized by KYSE30 esophageal cancer cells, and dose-dependently induced cell apoptosis. We further revealed a strong synergistic effect between DTX-DCMs and BTZ-DCMs against KYSE30 esophageal cancer cells. Sequential combination therapy with DTX-DCMs followed by BTZ-DCMs exhibited the best anti-tumor efficacy in vitro. This study demonstrates that DTX and BTZ could be successfully nanoformulated into disulfide cross-linked micelles. The nanoformulations of DTX and BTZ demonstrate an immense potential for synergistic combination therapy to treat human esophageal cancer. PMID- 28552908 TI - Xyloketal B alleviates cerebral infarction and neurologic deficits in a mouse stroke model by suppressing the ROS/TLR4/NF-kappaB inflammatory signaling pathway. AB - Xyloketal B (Xyl-B) is a novel marine compound isolated from mangrove fungus Xylaria sp. We previously demonstrated that pretreatment with Xyl-B exerted neuroprotective effects and attenuated hypoxic-ischemic brain injury in neonatal mice. In the present study we investigated the neuroprotective effects of pre- and post-treatment with Xyl-B in adult mice using a transient middle cerebral artery occlusion (tMCAO) model, and explored the underlying mechanisms. Adult male C57 mice were subjected to tMCAO surgery. For the pre-treatment, Xyl-B was given via multiple injections (12.5, 25, and 50 mg.kg-1.d-1, ip) 48 h, 24 h and 30 min before ischemia. For the post-treatment, a single dose of Xyl-B (50 mg/kg, ip) was injected at 0, 1 or 2 h after the onset of ischemia. The regional cerebral perfusion was monitored using a laser-Doppler flowmeter. TTC staining was performed to determine the brain infarction volume. We found that both pre treatment with Xyl-B (50 mg/kg) and post-treatment with Xyl-B (50 mg/kg) significantly reduced the infarct volume, but had no significant hemodynamic effects. Treatment with Xyl-B also significantly alleviated the neurological deficits in tMCAO mice. Furthermore, treatment with Xyl-B significantly attenuated ROS overproduction in brain tissues; increased the MnSOD protein levels, suppressed TLR4, NF-kappaB and iNOS protein levels; and downregulated the mRNA levels of proinflammatory cytokines, including IL-1beta, TNF-alpha, IL-6 and IFN-gamma. Moreover, Xyl-B also protected blood-brain barrier integrity in tMCAO mice. In conclusion, Xyl-B administered within 2 h after the onset of stroke effectively protects against focal cerebral ischemia; the underlying mechanism may be related to suppressing the ROS/TLR4/NF-kappaB inflammatory signaling pathway. PMID- 28552909 TI - Enhanced intracellular delivery and controlled drug release of magnetic PLGA nanoparticles modified with transferrin. AB - Owing to the presence of multidrug resistance in tumor cells, conventional chemotherapy remains clinically intractable. To enhance the therapeutic efficacy of chemotherapeutic agents, targeting strategies based on magnetic polymeric nanoparticles modified with targeting ligands have gained significant attention in cancer therapy. In this study, we synthesized transferrin (Tf)-modified poly(D,L-lactic-co-glycolic acid) nanoparticles (PLGA NPs) loaded with paclitaxel (PTX) and superparamagnetic nanoparticle (MNP) using a solid-in-oil-in-water solvent evaporation method, followed by Tf adsorption on the surface of NPs. The Tf-modified magnetic PLGA NPs were characterized in terms of particle morphology and size, magnetic properties, encapsulation efficiency and drug release. Furthermore, the cytotoxicity and cellular uptake of the drug-loaded magnetic PLGA NPs were evaluated in both MCF-7 breast cancer and U-87 glioma cells in vitro. We found that Tf-modified PTX-MNP-PLGA NPs showed the highest cytotoxicity effect and cellular uptake efficiency under Tf receptor mediation in both MCF-7 and U-87 cells compared to unmodified PLGA NPs and free PTX. The cellular uptake efficiency of Tf-modified magnetic PLGA NPs appeared to be facilitated by the applied magnetic field, but the difference did not reach statistical significance. This study illustrates that this proposed formulation can be used as one new alternative treatment for patients bearing inaccessible tumors. PMID- 28552910 TI - Conjugated polymer nanomaterials for theranostics. AB - Conjugated polymer nanomaterials (CPNs), as optically and electronically active materials, hold promise for biomedical imaging and drug delivery applications. This review highlights the recent advances in the utilization of CPNs in theranostics. Specifically, CPN-based in vivo imaging techniques, including near infrared (NIR) imaging, two-photon (TP) imaging, photoacoustic (PA) imaging, and multimodal (MM) imaging, are introduced. Then, CPN-based photodynamic therapy (PDT) and photothermal therapy (PTT) are surveyed. A variety of stimuli responsive CPN systems for drug delivery are also summarized, and the promising trends and translational challenges are discussed. PMID- 28552911 TI - Plumbagin suppresses chronic periodontitis in rats via down-regulation of TNF alpha, IL-1beta and IL-6 expression. AB - Chronic periodontitis (CP) is one of the most common oral diseases, which causes alveolar bone absorption and tooth loss in adults. In this study we aimed to investigate the potential of plumbagin (PL), a widely-investigated active compound extracted from the traditional Chinese herb Plumbago zeylanica L in treating CP. Human periodontal ligament stem cells (PDLSCs) were used for in vitro studies, whereas an animal model of CP was established in SD rats by ligation+Porphyromonas gingivalis (Pg) stimulation. The rats were injected with PL (2, 4, and 6 mg.kg-1.d-1, ip) for 4 weeks. Treatment of PDLSCs with TNF-alpha (10 ng/mL) markedly stimulated the expression of the proinflammatory cytokines TNF-alpha, IL-1beta and IL-6, as well as the chemokines CCL-2 and CCL-5, which were dose-dependently suppressed by co-treatment with PL (1.25-5 MUmol/L). Furthermore, PL (3.75 MUmol/L) markedly suppressed TNF-alpha-induced activation of the MAPK, NF-kappaB and JAK/STAT signaling pathways in PDLSCs. In consistence with the in vitro studies, PL administration significantly decreased the expression of TNF-alpha, IL-1beta and IL-6 in gingiva of the rat with CP, with the dosage 4 mg.kg-1.d-1 showing the best anti-inflammatory effect. Moreover, PL administration decelerated bone destruction in the rat with CP, evidenced by the aveolar bone loss (ABL) and H&E staining results. In conclusion, PL suppresses CP progression in rats by downregulating the expressions of TNF-alpha, IL-1beta and IL-6 and inhibiting the MAPK, NF-kappaB and JAK/STAT signaling pathways. PMID- 28552912 TI - Pterostilbene suppresses human endometrial cancer cells in vitro by down regulating miR-663b. AB - Resveratrol has long been known as an antioxidant and a chemopreventive agent. Similar to resveratrol, pterostilbene (PT) is also a phenolic compound extracted from the Vitis species. However, there are few studies on the antitumor effect of PT. Thus, we investigated the effects of PT on the endometrial cancer (EC) cells in vitro and the related molecular mechanisms. Treatment of EC cell lines HTB-111 and Ishikawa with PT (25-100 MUmol/L) dose-dependently suppressed the cell viability and induced apoptosis. Using miR microarrays, we examined the miR expression profile in Ishikawa cells with or without PT, and revealed that miR 663b was the most decreased in PT-treated Ishikawa cells. Furthermore, we predicted and verified that the pro-apoptosis factor BCL2L14 is the direct target of miR-663b. Over-expression of miR-663b and knock-down of BCL2L14 counteracted the suppressing effects of PT on HTB-111 and Ishikawa cells. In addition, we evaluated the miR-663b levels in EC tissues of 51 patients using an in situ hybridization technique. With the median of the score of miR-663b as a cut-off value, these EC patients were divided into two groups, and the patients with high miR-663b expression had significantly poor prognosis. PMID- 28552913 TI - Population pharmacokinetic analysis of tacrolimus in Chinese myasthenia gravis patients. AB - The importance of tacrolimus in the treatment of myasthenia gravis (MG) as a substitute for corticosteroid-dependent immunosuppressive therapy is increasing. Thus far, however, no population pharmacokinetic (PopPK) analysis of tacrolimus in treating MG patients has been published. This article aimed to construct a PopPK model of tacrolimus for Chinese MG patients with the goal of improving its performance in MG treatment. A total of 253 trough concentration records were obtained from 83 Chinese MG patients. The effects of demographics, lifestyle and health status, biochemical test data, disease progression and treatment-related information (including co-administered medications) as covariates on the various parameters were investigated. The covariate selection was based on biological plausibility, clinical significance, statistical significance and reduction in inter-individual variability (IIV). Bootstrap and normalized prediction distribution error (NPDE) analysis were performed to validate the final model. A one-compartment PopPK model with first-order elimination and a fixed absorption phase was constructed. The estimated apparent oral clearance (CL/F) and apparent oral volume of distribution (V/F) were 3.6 L/h and 1700 L, respectively, in the MG patients. Hematocrit and blood urea nitrogen were identified as two covariates that significantly influenced the CL/F. Immunoglobulin treatment (PRO) also had the potential to influence V/F, which was consistent with the clinical observations and the high protein-binding property of tacrolimus. Other covariates including age, weight, gender and co-administered medications had no obvious influence on CL/F or V/F. The first PopPK model of tacrolimus in MG patients was established. The identified covariates were of biological plausibility and clinical importance to help individualize the dosing schedule in MG patients. PMID- 28552914 TI - Claudin 4-targeted nanographene phototherapy using a Clostridium perfringens enterotoxin peptide-photosensitizer conjugate. AB - In this study we designed a claudin 4-directed dual photodynamic and photothermal system, in which a 30-amino acid claudin 4-binding peptide, Clostridium perfringens enterotoxin (CPE), was linked to a photodynamic agent chlorin e6 (Ce6) through a polyethylene glycol spacer (CPC) and anchored onto reduced graphene oxide (rGO) nanosheets to form CPC/rGO nanosheets. For comparison, a conjugate of polyethylene glycol and Ce6 (PC) was anchored onto the rGO nanosheets to generate PC/rGO. Both PC and CPC generated reactive oxygen species upon irradiation at 660 nm. Application of CPC/rGO to claudin 4-overexpressing U87 glioblastoma cells in vitro resulted in a significantly higher cellular uptake compared to application of PC/rGO. Upon irradiation at 660 and 808 nm, the CPC/rGO-treated U87 cells generated significantly higher reactive oxygen species and caused significantly higher temperature increase, and showed most potent anticancer effect compared to the other groups. Taken together, these results suggest that CPC/rGO is potentially useful as a tumor-specific combined phototherapy. PMID- 28552916 TI - Magneto-therapy of human joint cartilage. AB - PURPOSE: The topic of the present paper concerns the human joint cartilage therapy performed by the magnetic induction field. There is proved the thesis that the applied magnetic field for concrete cartilage illness should depend on the proper relative and concrete values of applied magnetic induction, intensity as well the time of treatment duration. Additionally, very important are frequencies and amplitudes of magnetic field as well as magnetic permeability of the synovial fluid. MATERIAL AND METHODS: The research methods used in this paper include: magnetic induction field produced by a new Polish and German magneto electronic devices for the therapy of human joint cartilage diseases, stationary and movable magnetic applicators, magnetic bandage, ferrofluid injections, author's experience gained in Germany research institutes and practical results after measurements and information from patients. RESULTS: The results of this paper concern concrete parameters of time dependent electro-magnetic field administration during the joint cartilage therapy duration and additionally concern the corollaries which are implied from reading values gained on the magnetic induction devices. CONCLUSIONS: The main conclusions obtained in this paper are as follows: Time dependent magnetic induction field increases the dynamic viscosity of movable synovial fluid and decreases symptoms of cartilage illness for concrete intensity of magnetic field and concrete field line architecture. The ferrofluid therapy and phospholipids bilayer simultaneously with the administrated external electromagnetic field, increases the dynamic viscosity of movable synovial fluid. PMID- 28552915 TI - The regioselective glucuronidation of morphine by dimerized human UGT2B7, 1A1, 1A9 and their allelic variants. AB - Uridine diphosphate-glucuronosyltransferase (UGT) 2B7 is expressed mostly in the human liver, lung and kidney and can transfer endogenous glucuronide group into its substrate and impact the pharmacological effects of several drugs such as estriol, AZT and morphine. UGT2B7 and its allelic variants can dimerize with the homologous enzymes UGT1A1 and UGT1A9, as well as their allelic variants, and then change their enzymatic activities in the process of substrate catalysis. The current study was designed to identify this mechanism using morphine as the substrate of UGT2B7. Single-recombinant allozymes, including UGT2B7*1 (wild type), UGT2B7*71S (A71S, 211G>T), UGT2B7*2 (H268Y, 802C>T), UGT2B7*5 (D398N, 1192G>A), and double-recombinant allozymes formed by the dimerization of UGT1A9*1 (wild type), UGT1A9*2 (C3Y, 8G>A), UGT1A9*3 (M33T, 98T>C), UGT1A9*5 (D256N, 766G>A), UGT1A1 (wild type) with its splice variant UGT1A1b were established and incubated with morphine in vitro. Each sample was analyzed with HPLC-MS/MS. All enzyme kinetic parameters were then measured and analyzed. From the results, the production ratio of its aberrant metabolism and subsequent metabolites, morphine 3-glucuronide (M3G) and morphine-6-glucuronide (M6G), changes regioselectively. Double-recombinant allozymes exhibit stronger enzymatic activity catalyzing morphine than the single-recombinant alloyzymes. Compared to UGT2B7*1, UGT2B7*2 singles or doubles have lower Km values for M3G and M6G, whereas UGT2B7*5 allozymes perform opposite effects. The double allozymes of UGT1A9*2 or UGT1A9*5 with UGT2B7 tend to produce M6G. Interestingly, the majority of single or double allozymes significantly reduce the ratio of M3G to M6G. The UGT1A9*2-UGT2B7*1 double enzyme has the lowest M3G:M6G ratio, reflecting that more M6G would form in morphine glucuronide metabolism. This study demonstrates that UGT2B7 common SNPs and their dimers with UGT1A1 and UGT1A9 and their allelic variants can regioselectively affect the generation of two metabolites of morphine via altering the CLint ratios of M3G to M6G. These results may predict the effectiveness of morphine antinociception in individualized opioid treatment. PMID- 28552917 TI - The evaluation of resorbable haemostatic wound dressings in contact with blood in vitro. AB - PURPOSE: For many years research has been conducted on the development of resorbable, polymer, haemostatic materials designed to provide first aid and preliminary protection of injuries. The biological properties in vitro of a dressing in powder form called Hemoguard are expected to provide the ability to instantaneously stem bleeding with safe conditions of use. The aim of the study was to evaluate the haemostatic properties of a model of dressing based on micro- and nanofibrids of the chitosan, sodium/calcium alginate and/or carboxymethylcellulose complex. Dressings were prepared by spray-drying and freeze-drying. METHODS: Human whole blood was subjected to timed contact with the haemostatic dressing model. Haemolytic action was determined by assaying the degree of haemolysis and evaluating blood cell morphology. Haemostatic action was determined on the basis of selected parameters of plasmatic clotting systems. RESULTS: Dressings prepared by freeze-drying activated the coagulation system. The haemolytic index, plasma haemoglobin concentration values and blood cell morphological shapes were normal. Dressings prepared by spray-drying significantly activated coagulation. Activation of the coagulation process was evidenced by shorter clotting time of the plasma coagulation system and a longer process of clot formation. The dressing was associated with an increased haemolytic index and higher plasma haemoglobin concentration. The morphological shape of blood cells changed. CONCLUSIONS: The model of multi-resorbable wound dressings has haemostatic properties. The materials activate the clotting process more quickly than a single-dressing model. Increased activity was found for dressings prepared by spray-drying. PMID- 28552918 TI - DMA analysis of the structure of crosslinked poly(methyl methacrylate)s. AB - PURPOSE: This paper presents the study aimed at the development of crosslinked poly(methyl methacrylate)s (X-PMMA) of varied crosslink density and the investigation of the relationships between the polymer network structure and dynamic mechanical properties. METHODS: A series of model X-PMMA networks were crosslinked by the introduction of: 1, 2, 5, 10 and 20% of triethylene glycol dimethacrylate (TEGDMA). The copolymerizations led to various glass-rubber relaxation properties of the polymer networks, as revealed by dynamic-mechanical analysis (DMA). Glass temperature (Tg) and storage modulus above the Tg (Er?ubbery ) were a sensitive function of network architecture. DMA data were used for calculating the network parameter (Mc), crosslink density (q) and its alternative measure - the degree of crosslinking (DX). RESULTS: The viscoelastic properties as well as structural parameters calculated from those showed correlation with the amount of the crosslinker. The increase in TEGDMA content resulted in the Tg, q and DX increases, whereas Mc decrease. The possible incomplete conversion of double bonds was detected in the DMA analysis, which was confirmed by the degree of conversion (DC), measured by FTIR spectroscopy. Additionally, some amount of sol fraction was found by 1H NMR experiments. CONCLUSIONS: The structure-property relationships developed for the system presented in this work could be useful in tissue engineering, where X-PMMA is applied. The direct measure of storage modulus values before and above glass transition may serve as a simple and fast indicator of the X-PMMA crosslink density. PMID- 28552919 TI - Methods for acquiring data on terrain geomorphology, course geometry and kinematics of competitors' runs in alpine skiing: a historical review. AB - PURPOSE: This paper aims at the description and comparison of methods of topographic analysis of racing courses at all disciplines of alpine skiing sports for the purposes of obtaining: terrain geomorphology (snowless and with snow), course geometry, and competitors' runs. METHODS: The review presents specific methods and instruments according to the order of their historical appearance as follows: (1) azimuth method with the use of a compass, tape and goniometer instruments; (2) optical method with geodetic theodolite, laser and photocells; (3) triangulation method with the aid of a tape and goniometer; (4) image method with the use of video cameras; (5) differential global positioning system and carrier phase global positioning system methods. RESULTS: Described methods were used at homologation procedure, at training sessions, during competitions of local level and during International Ski Federation World Championships or World Cups. Some methods were used together. CONCLUSIONS: In order to provide detailed data on course setting and skiers' running it is recommended to analyse course geometry and kinematics data of competitors' running for all important competitions. PMID- 28552920 TI - An alternative 3D numerical method to study the biomechanical behaviour of the human inner ear semicircular canal. AB - PURPOSE: The vestibular system is the part of the inner ear responsible for balance. Vertigo and dizziness are generally caused by vestibular disorders and are very common symptoms in people over 60 years old. One of the most efficient treatments at the moment is vestibular rehabilitation, permitting to improve the symptoms. However, this rehabilitation therapy is a highly empirical process, which needs to be enhanced and better understood. METHODS: This work studies the vestibular system using an alternative computational approach. Thus, part of the vestibular system is simulated with a three dimensional numerical model. Then, for the first time using a combination of two discretization techniques (the finite element method and the smoothed particle hydrodynamics method), it is possible to simulate the transient behavior of the fluid inside one of the canals of the vestibular system. RESULTS: The obtained numerical results are presented and compared with the available literature. The fluid/solid interaction in the model occurs as expected with the methods applied. The results obtained with the semicircular canal model, with the same boundary conditions, are similar to the solutions obtained by other authors. CONCLUSIONS: The numerical technique presented here represents a step forward in the biomechanical study of the vestibular system, which in the future will allow the existing rehabilitation techniques to be improved. PMID- 28552921 TI - The influence of landing mat composition on ankle injury risk during a gymnastic landing: a biomechanical quantification. AB - PURPOSE: About 70% injury of gymnasts happened during landing - an interaction between gymnast and landing mat. The most injured joint is the ankle. The current study examined the effect of mechanical properties of landing mat on ankle loading with aims to identify means of decreasing the risk of ankle injury. METHOD: Gymnastic skill - salto backward stretched with 3/2 twist was captured by two high-speed camcorders and digitized by using SIMI-Motion software. A subject specific, 14-segment rigid-body model and a mechanical landing-mat model were built using BRG.LifeMODTM. The landings were simulated with varied landing-mat mechanical properties (i.e., stiffness, dampness and friction coefficients). RESULT: Real landing performance could be accurately reproduced by the model. The simulations revealed that the ankle angle was relatively sensitive to stiffness and dampness of the landing mat, the ankle loading rate increased 26% when the stiffness was increased by 30%, and the changing of dampness had notable effect on horizontal ground reaction force and foot velocity. Further, the peak joint reaction force and joint torque were more sensitive to friction than to stiffness and dampness of landing mat. Finally, ankle muscles would dissipate about twice energy (189%) when the friction was increased by 30%. CONCLUSION: Loads to ankles during landing would increase as the stiffness and dampness of the landing mat increase. Yet, increasing friction would cause a substantial rise of the ankle internal loads. As such, the friction should be a key factor influencing the risk of injury. Unfortunately, this key factor has rarely attracted attention in practice. PMID- 28552922 TI - Influence of size and CCD-angle of a short stem hip arthroplasty on strain patterns of the proximal femur - an experimental study. AB - PURPOSE: The number of primary total hip arthroplasties (THA) is steadily increasing. Over the last decade numerous so-called short stem hip arthroplasties were introduced on the market. The aim of these implants with a predominantly metaphyseal anchorage is to reduce stress shielding and thereby the risk of aseptic loosening. One of the short stem arthroplasties with predominant metaphyseal fixation is the METHA(r) short stem (Aesculap, Tuttlingen, Germany). In order to reconstruct the biomechanics the METHA stem is available in different sizes with different centrum-collum-diaphysis-angles (CCD-angle). In this study, we want to address the research question of how the size of the implant and different CCD-angles influence the strain patterns of the proximal femur. METHODS: Three different stem sizes (size 2, 3 and 4 - CCD-angle 130 degrees ) and three stems with different CCD-angles (size 3 - 120 degrees , 130 degrees and 135 degrees CCD-angle) were successively implanted in a synthetic femur. Eight strain gauges monitored the corresponding strain patterns of the proximal femur. RESULTS: Independent of stem size and CCD-angle only small changes in the strains were recorded around the distal part of the METHA stem when compared to the intact femur. However, all stems increased the strains in the region of the calcar. This was most pronounced by smaller CCD-angles and major sizes. CONCLUSION: The stem size and CCD-angle primarily influence the region of the calcar. Greater sizes and smaller CCD-angles lead to increased strains at the calcar. The other regions are hardly influenced by the stem size and CCDangle of the femoral component. PMID- 28552923 TI - The influence of aging on the isometric torque sharing patterns among the plantar flexor muscles. AB - PURPOSE: Physiological cross-sectional area (PCSA) reduction of the triceps surae (TS) muscles during aging suggests a proportional loss of torque among its components: soleus, medial and lateral gastrocnemii. However, direct measurements of muscle forces in vivo are not feasible. The purpose of this paper was to compare, between older and young women, isometric ankle joint torque sharing patterns among TS muscles and tibialis anterior (TA). METHODS: An EMG-driven model was used for estimating individual muscle torque contributions to the total plantar flexor torque, during sustained contractions of 10% and 40% of maximum voluntary contraction (MVC). RESULTS: Relative individual muscle contributions to the total plantar flexion torque were similar between older and young women groups, for both intensities, increasing from LG, MG to SOL. Muscle strength (muscle torque/body mass) was significantly greater for all TS components in 40% MVC contractions. Increased TA activation was observed in 10% of MVC for older people. CONCLUSIONS: Despite the reduced maximum isometric torque and muscle strength, the results suggest small variations of ankle muscle synergies during the aging process. PMID- 28552924 TI - Drilling resistance: A method to investigate bone quality. AB - PURPOSE: Bone drilling is a major part of orthopaedic surgery performed during the internal fixation of fractured bones. At present, information related to drilling force, drilling torque, rate of drill-bit penetration and drill-bit rotational speed is not available to orthopaedic surgeons, clinicians and researchers as bone drilling is performed manually. METHODS: This study demonstrates that bone drilling force data if recorded in-vivo, during the repair of bone fractures, can provide information about the quality of the bone. To understand the variability and anisotropic behaviour of cortical bone tissue, specimens cut from three anatomic positions of pig and bovine were investigated at the same drilling speed and feed rate. RESULTS: The experimental results showed that the drilling force does not only vary from one animal bone to another, but also vary within the same bone due to its changing microstructure. Drilling force does not give a direct indication of bone quality; therefore it has been correlated with screw pull-out force to provide a realistic estimation of the bone quality. A significantly high value of correlation (r2 = 0.93 for pig bones and r2 = 0.88 for bovine bones) between maximum drilling force and normalised screw pull-out strength was found. CONCLUSIONS: The results show that drilling data can be used to indicate bone quality during orthopaedic surgery. PMID- 28552925 TI - Gait features analysis using artificial neural networks - testing the footwear effect. AB - PURPOSE: The aim of this paper is to provide the methods for automatic detection of the difference in gait features depending on a footwear. METHODS: Artificial neural networks were applied in the study. The gait data were recorded during the walk with different footwear for testing and validation of the proposed method. The gait properties were analyzed considering EMG (electromyography) signals and using two types of artificial neural networks: the learning vector quantization (LVQ) classifying network, and the clustering competitive network. RESULTS: Obtained classification and clustering results were discussed. For comparative studies, velocities of the leg joint trajectories, and accelerations were used. The features indicated by neural networks were compared with the conclusions formulated analyzing the above mentioned trajectories for ankle and knee joints. CONCLUSIONS: The matching between experimentally recorded joint trajectories and the results given by neural networks was studied. It was indicated what muscles are most influenced by the footwear, the relation between the footwear type and the muscles work was concluded. PMID- 28552926 TI - Modelling and structural analysis of skull/cranial implant: beyond mid-line deformities. AB - PURPOSE: This computational study explores modelling and finite element study of the implant under Intracranial pressure (ICP) conditions with normal ICP range (7 mm Hg to 15 mm Hg) or increased ICP (>I5 mm Hg). The implant fixation points allow implant behaviour with respect to intracranial pressure conditions. However, increased fixation points lead to variation in deformation and equivalent stress. Finite element analysis is providing a valuable insight to know the deformation and equivalent stress. METHODS: The patient CT data (Computed Tomography) is processed in Mimics software to get the mesh model. The implant is modelled by using modified reverse engineering technique with the help of Rhinoceros software. This modelling method is applicable for all types of defects including those beyond the middle line and multiple ones. It is designed with eight fixation points and ten fixation points to fix an implant. Consequently, the mechanical deformation and equivalent stress (von Mises) are calculated in ANSYS 15 software with distinctive material properties such as Titanium alloy (Ti6Al4V), Polymethyl methacrylate (PMMA) and polyether-ether ketone (PEEK). RESULTS: The deformation and equivalent stress results are obtained through ANSYS 15 software. It is observed that Ti6Al4V material shows low deformation and PEEK material shows less equivalent stress. Among all materials PEEK shows noticeably good result. CONCLUSIONS: Hence, a concept was established and more clinically relevant results can be expected with implementation of realistic 3D printed model in the future. This will allow physicians to gain knowledge and decrease surgery time with proper planning. PMID- 28552927 TI - Fixation of distal fibular fractures: A biomechanical study of plate fixation techniques. AB - Ankle fractures are complex injuries with variable prognoses that depend upon many factors. The aim of the treatment is to restore the ankle joint biomechanical stability with maximum range of motion. Most ankle fractures are fibular fractures, which have a typical oblique fracture line in the distal fibula located in the area of the tibiofibular syndesmosis. The aim of this study was to simulate numerically several fixation techniques of the distal fibular fractures, evaluate their stability, determine their impact on surrounding tissue load, and correlate the results to clinical treatment experience. The following three models of fibular fracture fixation were used: (a) plate fixation with three screws attached above/below and lag screws, (b) plate fixation with two screws attached above/below and lag screws, and (c) three lag screws only. All three fracture fixation models were analyzed according to their use in both healthy physiological bone and osteoporotic bone tissue. Based on the results of Finite Element Analysis for these simulations, we found that the most appropriate fixation method for Weber-B1 fibular fractures was an unlocked plate fixation using six screws and lag screws, both in patients with physiological and osteoporotic bone tissue. Conversely, the least appropriate fixation method was an unlocked plate fixation with four screws and lag screws. Although this fixation method reduces the stress on patients during surgery, it greatly increased loading on the bone and, thus, the risk of fixation failure. The final fixation model with three lag screws only was found to be appropriate only for very limited indications. PMID- 28552928 TI - Can concurrent teaching promote equal biomechanical adaptations at front crawl and backstroke swimming? AB - PURPOSE: The biomechanical adaptations in front crawl and backstroke swimming, as influenced by the implementation of a concurrent teaching programme were analysed. METHODS: Sixteen participants (19.75 +/- 1.13 years) underwent a 30 weeks intervention characterized by an increasing complexity to accomplish motor skills in the following order: (i) lower limbs propulsion; (ii) lower limbs propulsion synchronized with breathing cycle; (iii) lower limbs propulsion synchronized with one upper limb action; (iv) lower limbs propulsion synchronized with both breathing cycle and one upper limb action; (v) full swimming stroke; (vi) motor trajectory of the arms stroke. Performance and biomechanics were measured at front crawl and backstroke during three time points throughout the programme. RESULTS: There were improvements in performance over time at front crawl (21.49 s to 19.99 s, p<0.01) and backstroke (27.15 s to 24.60 s, p = 0.01). Significant improvements were found for velocity at front crawl (1.13 m/s to 1.22 m/s, p<0.01) and backstroke (0.92 m/s to 1.00 m/s, p<0.01). Stroke frequency increased at backstroke (0.64 to 0.73 Hz, p = 0.01), while the intra-cyclic variation of the velocity decreased at front crawl (0.13 to 0.12%, p = 0.02). There was also a moderate-high inter-subject variability in response to the programme. CONCLUSIONS: These findings prove that a programme of 30 weeks teaching concurrently front crawl and backstroke is effective to promote similar biomechanical adaptations in low-tier swimmers. However, each subject shows an individual response to better adapt the biomechanical actions and to reach a higher level of expertise. PMID- 28552929 TI - Correlations between somatic features, anteroposterior spinal curvatures and trunk muscle strength in schoolchildren. AB - BACKGROUND: Evaluation of body posture and strength of spinal muscles in children during their progressive ontogenesis is significant for the evaluation of their physical health condition and physical fitness. It is also a reference point in a process of control and medical care. PURPOSE: The aim if this study was to evaluate correlation between the selected features of somatic body structure, shape of anteroposterior spinal curves and force-velocity (FV) parameters of trunk muscles in school children. PARTICIPANTS AND METHODS: The sample involved 104 children aged 10-11 years, 60 females (10.74 +/-0.7) and 44 males (10.50 +/ 0.9). Body posture was assessed using the Moire photogrammetry while trunk muscles (flexors and extensors) strength was measured isokinetically. RESULTS: The results of the research revealed the existence of many average and strong correlations observed between the analysed somatic characteristics and forcevelocity (FV) parameters of trunk muscles. Correlation between the volume of the spinal curvatures in the sagittal plane and forcevelocity parameters of trunk extensors and flexors were average or weak for both groups of children. CONCLUSION: Somatic features indicated stronger correlation with trunk muscles' strength than with the size of the anteroposterior spinal curves. PMID- 28552930 TI - A comparison of impact force reduction by polymer materials used for mouthguard fabrication. AB - PURPOSE: The essential function of mouthguards is protection against the effects of injuries sustained during sports activities. This purpose will be successfully achieved if appropriate materials ensuring sufficient reduction of the injury force are used for mouthguard fabrication. OBJECTIVE: The objective of the study was to investigate the force reduction capability of selected materials as well as to identify which material reduces the impact force to the highest degree. METHODS: The material for the study were samples of polymers (6 samples in total), obtained during the process of deep pressing (2 samples), flasking (3 samples) and thermal injection (1 sample), which were tested for impact force damping using an impact device - Charpy impact hammer. The control group comprised of the ceramic material samples subjected to the hammer impact. The statistical analysis applied in this study were one-way Welch ANOVA with post-hoc Games-Howell pairwise comparisons. RESULTS: The test materials reduced the impact force of the impact hammer to varying degrees. The greatest damping capability was demonstrated for the following materials: Impak with 1:1 powder-to-liquid weight ratio polymerized with the conventional flasking technique, and Corflex Orthodontic used in the thermal injection technique of mouthguard fabrication. CONCLUSIONS: Impak with 1:1 weight ratio and Corflex Orthodontic should be recommended for the fabrication of mouthguards since they demonstrated the most advantageous damping properties. PMID- 28552931 TI - The follow-up posturography in rehabilitation after total hip arthroplasty. AB - PURPOSE: Presentation of the results of clinical study on new supplementary method applied in the physical rehabilitation of patients who underwent total hip arthroplasty. The standard rehabilitation program was supplemented with the lower limb loading symmetry training based on the follow-up posturography with an adaptively modified visual biofeedback, performed on a double plate posturographic platform. METHODS: The research involved 60 randomly selected patients included in prospective and comparative clinical study in the scheme of the parallel groups. The subjects were divided into two groups comprised of 30 patients each. In both groups a conventional 21-day rehabilitation was carried out. Additionally, in experimental group the limb loading symmetry restoration training based on the follow-up posturography with an adaptively modified biofeedback was implemented. The biofeedback coefficient reflected the distribution of loading exerted on a given patient's legs and was evaluated during the static posturography examinations carried out before each symmetry training session. RESULTS: The eyes-open static posturography examinations indicated significant improvement in the lower limb loading symmetry in 29 (97%) patients from the experimental group ( p = 0.000003). In the control group, such an improvement was observed in 20 (67%) patients ( p = 0.034796). In the eyes closed examinations correction in the limb loading symmetry was evident in 23 (77%) patients from the experimental group ( p = 0.000247) and 18 (60%) patients from the control group ( p = 0.043327). CONCLUSIONS: Significant improvement in the lower limb loading symmetry was observed in patients who underwent rehabilitation supplemented with the herein discussed training method. PMID- 28552932 TI - Biomechanical properties of alternative suture technique for flexor tendon repair. AB - PURPOSE: Flexor injuries are most common in the hand and require special attention and experience from the surgeon. Both quality and technique affect the stability of the suture. The selection of the optimum method will influence the process of rehabilitation. The aim of this study was to compare three different suture techniques based on the strength, depending on the method of breakage, i.e., axial or pulley load. METHODS: The study was divided into six sessions. The research material was dissected deep flexor porcine tendons. Three types of stitches were used: the modified Kessler suture with an additional running suture, the cruciate four-strand suture with an additional running suture and the multistrand running suture. We obtained 120 sutures, 40 for each technique. Breaking strength was assessed using a tensile machine in two ways, i.e., axial or pulley load, with 20 sutures per group. RESULTS: The strongest suture for both axial and pulley load was the cruciate four-strand suture. Between the multistrand running suture and the modified Kessler suture, there was no statistically significant difference in the strength of breaking for both axial and pulley load. Comparing the two ways of breaking, there was no statistically significant difference in the strength of the suture. CONCLUSIONS: The multistrand running locking suture is a good alternative to widely used core sutures. It not only provides the same strength as other techniques examined by us but also reduces the procedure time and trauma to the tips of the tendon. PMID- 28552933 TI - The evaluation of the effect of carbon dioxide laser radiation on dentine tissue. AB - : of this study was to analyze the effects of carbon dioxide (CO2) laser light on the structure and elemental composition of dentine. METHODS: The evaluation was conducted on samples from extracted teeth. The surface of the dentine was exposed to the radiation from a CTL 1401 CO2 laser (Centre of Laser Technology, Poland). The radiation and frequency parameters were as follows: group I with 5 W and 1 Hz, group II with 10 W and 1 Hz, group III with 5 W and 5 Hz, and group IV with 10 W and 5 Hz. The altered dentine structure was macroscopically and microscopically evaluated using a Nova NanoSEM 200 Scanning Electron Microscope (FEI Europe) with integrated microanalysis X-ray system for elemental analysis in points. RESULTS: There were significant differences between groups in the macro- and microstructure of laser defects. CONCLUSIONS: CO2 laser radiation causes irreversible, destructive changes in dentine. The structural dentine lesions developed under the influence of the CO2 laser radiation may hinder proper adhesion of bonding systems with the damaged tissue. Laser defects in the structure should be treated like defects of noncarious origin requiring preparation and filling with composite materials in accordance with the procedures. PMID- 28552934 TI - Corrosion resistance of PLGA-coated biomaterials. AB - The aim of the study was to determine the influence of PLGA bioresorbable polymer coating on corrosion resistance of metal biomaterial. Polymer coating deposited by immersion method was applied. Corrosion resistance of metal biomaterials (stainless steel, Ti6Al4V, Ti6Al7Nb) coated with PLGA polymer, after 90 days exposure to Ringer's solution was tested. The amount of metal ions released to the solution was also investigated (inductively coupled plasma-atomic emission spectrometry (ICP-AES) method). The surface of the samples was observed using atomic force microscopy (AFM) and scanning electron microscopy (SEM). Degradation of PLGA was monitored with the use of the 1H NMR spectroscopy and GPC (Gel Permeation Chromatography). The studies were carried out for non-sterilized (NS) and sterilized (S) samples. Application of the polymer coating causes a reduction of release of metal ions to the solution. Depending on metal substrate different course of destruction of polymer layer was observed. After 90 days of incubation in Ringer's solution polymer layer was highly degraded, however, the composition of copolymer (ratio of the comonomeric units in the chain) remained unchanged during the whole process, which suggests even degradation. The polymer layer reduced degradation kinetics of the metal substrate. Moreover, degradation process did not change surface morphology of metal substrate and did not disturb its integrity. The results obtained indicate that the applied polymer layer improves corrosion resistance of the alloys being investigated. Thus, the developed implants with bioresorbable coatings could be advantageous for medical applications. PMID- 28552935 TI - Optimal strategy in chemotherapy for Malthusian model of cancer growth. AB - PURPOSE: The problem of optimal strategy in cancer chemotherapy is reconsidered. Two incompatible goals should be completed: the number of cancer cells in the patient's body should be reduced and the toxic effect of the therapy should be minimized. Such problem may be formulated in optimal control. The control function is the amount of the drug administered in the time unit. METHODS: The Malthusian model of cell population growth is employed where the rate of increase of the number of cancer cells is proportional to the number of cells in population and an intrinsic rate that usually is assumed to be constant. The performance index is the amount of the drug cumulated in the patient's body and it is minimized. A non-standard method of optimal control is used - method of Miele. RESULTS: The optimal solutions are obtained for three cases: constant intrinsic rate, monotonically increasing/decreasing intrinsic rate and for periodic intrinsic rate. The optimal control is ununique for the first case - the result is irrespective of the strategy. Such result has been known earlier. The optimal control is unique for other cases and it is of bang-bang type. CONCLUSIONS: The ununique solution for constant intrinsic rate is surprising, therefore a mechanical analogy is given. The optimal strategy is in accordance with clinical experience for decreasing intrinsic rate. The optimal control is a periodic function of time for the intrinsic rate of sin/cos type - the drug should be administered, as its value is relatively high. PMID- 28552937 TI - Philanthro-metrics: Mining multi-million-dollar gifts. AB - The Million Dollar List (MDL, online at http://www.milliondollarlist.org) is a compilation of publicly announced charitable donations of $1 million or more from across the United States since 2000; as of December 2016, the database contains close to 80,000 gifts made by U.S. individuals, corporations, foundations, and other grant-making nonprofit organizations. This paper discusses the unique value of the Million Dollar List and provides unique insights to key questions such as: How does distance affect giving? How do networks impact million-dollar-plus gifts? Understanding the geospatial and temporal dimensions of philanthropy can assist researchers and policymakers to better understand the role of private funding in innovation and discovery. Moreover, the results from the paper emphasize the importance of philanthropy for fueling research and development in science, the arts, environment, and health. The paper also includes the limitations of the presented analyses and promising future work. PMID- 28552936 TI - Tau secretion is correlated to an increase of Golgi dynamics. AB - Tau protein can be released by neurons, an event linked to the propagation of Tau pathology in Alzheimer'disease (AD). Neuronal hyperexcitability was shown to significantly increase Tau release by neurons. We confirmed this in the present study. In a previous study, it was demonstrated that hyperexcitability induces Golgi apparatus dynamics resulting in its fragmentation. Our present results revealed that the increase of Tau secretion upon hyperexcitability could be significantly reduced by preventing Golgi dynamics through the inactivation of cdk5. We then verified whether a Golgi fragmentation not induced by hyperexcitability could also increase Tau secretion. The suppression of Rab1A, Rab GTPase associated with the Golgi membranes, known to induce a Golgi fragmentation increased Tau secretion by both neurons and HeLa cells. Although it remains to be demonstrated whether the Golgi is directly involved in Tau secretion, the present results demonstrate that its dynamics are correlated to a modulation of Tau secretion. PMID- 28552938 TI - Interactions between temperature and drought in global and regional crop yield variability during 1961-2014. AB - Inter-annual crop yield variation is driven in large parts by climate variability, wherein the climate components of temperature and precipitation often play the biggest role. Nonlinear effects of temperature on yield as well as interactions among the climate variables have to be considered. Links between climate and crop yield variability have been previously studied, both globally and at regional scales, but typically with additive models with no interactions, or when interactions were included, with implications not fully explained. In this study yearly country level yields of maize, rice, soybeans, and wheat of the top producing countries were combined with growing season temperature and SPEI (standardized precipitation evapotranspiration index) to determine interaction and intensification effects of climate variability on crop yield variability during 1961-2014. For maize, soybeans, and wheat, heat and dryness significantly reduced yields globally, while global effects for rice were not significant. But because of interactions, heat was more damaging in dry than in normal conditions for maize and wheat, and temperature effects were not significant in wet conditions for maize, soybeans, and wheat. Country yield responses to climate variability naturally differed between the top producing countries, but an accurate description of interaction effects at the country scale required sub national data (shown only for the USA). Climate intensification, that is consecutive dry or warm years, reduced yields additionally in some cases, however, this might be linked to spillover effects of multiple growing seasons. Consequently, the effect of temperature on yields might be underestimated in dry conditions: While there were no significant global effects of temperature for maize and soybeans yields for average SPEI, the combined effects of high temperatures and drought significantly decreased yields of maize, soybeans, and wheat by 11.6, 12.4, and 9.2%, respectively. PMID- 28552939 TI - Genome-wide survey of B-box proteins in potato (Solanum tuberosum) Identification, characterization and expression patterns during diurnal cycle, etiolation and de-etiolation. AB - Plant B-box domain proteins (BBX) mediate many light-influenced developmental processes including seedling photomorphogenesis, seed germination, shade avoidance and photoperiodic regulation of flowering. Despite the wide range of potential functions, the current knowledge regarding BBX proteins in major crop plants is scarce. In this study, we identify and characterize the StBBX gene family in potato, which is composed of 30 members, with regard to structural properties and expression profiles under diurnal cycle, etiolation and de etiolations. Based on domain organization and phylogenetic relationships, StBBX genes have been classified into five groups. Using real-time quantitative PCR, we found that expression of most of them oscillates following a 24-h rhythm; however, large differences in expression profiles were observed between the genes regarding amplitude and position of the maximal and minimal expression levels in the day/night cycle. On the basis of the time-of-day/time-of-night, we distinguished three expression groups specifically expressed during the light and two during the dark phase. In addition, we showed that the expression of several StBBX genes is under the control of the circadian clock and that some others are specifically associated with the etiolation and de-etiolation conditions. Thus, we concluded that StBBX proteins are likely key players involved in the complex diurnal and circadian networks regulating plant development as a function of light conditions and day duration. PMID- 28552940 TI - Sequence statistics of tertiary structural motifs reflect protein stability. AB - The Protein Data Bank (PDB) has been a key resource for learning general rules of sequence-structure relationships in proteins. Quantitative insights have been gained by defining geometric descriptors of structure (e.g., distances, dihedral angles, solvent exposure, etc.) and observing their distributions and sequence preferences. Here we argue that as the PDB continues to grow, it may become unnecessary to reduce structure into a set of elementary descriptors. Instead, it could be possible to deduce quantitative sequence-structure relationships in the context of precisely-defined complex structural motifs by mining the PDB for closely matching backbone geometries. To validate this idea, we turned to the the task of predicting changes in protein stability upon amino-acid substitution-a difficult problem of broad significance. We defined non-contiguous tertiary motifs (TERMs) around a protein site of interest and extracted sequence preferences from ensembles of closely-matching substructures in the PDB to predict mutational stability changes at the site, DeltaDeltaGm. We demonstrate that these ensemble statistics predict DeltaDeltaGm on par with state-of-the-art statistical and machine-learning methods on large thermodynamic datasets, and outperform these, along with a leading structure-based modeling approach, when tested in the context of unbiased diverse mutations. Further, we show that the performance of the TERM-based method is directly related to the amount of available relevant structural data, automatically improving with the growing PDB. This enables a means of estimating prediction accuracy. Our results clearly demonstrate that: 1) statistics of non-contiguous structural motifs in the PDB encode fundamental sequence-structure relationships related to protein thermodynamic stability, and 2) the PDB is now large enough that such statistics are already useful in practice, with their accuracy expected to continue increasing as the database grows. These observations suggest new ways of using structural data towards addressing problems of computational structural biology. PMID- 28552941 TI - CCL20 secreted from IgA1-stimulated human mesangial cells recruits inflammatory Th17 cells in IgA nephropathy. AB - IgA nephropathy (IgAN) is the most common primary glomerulonephritis characterized by human mesangial cells (HMC) proliferation and extracellular matrix expansion associated with immune deposits consisting of galactose deficient IgA1. However, how IgA1 contributes to IgAN has yet to be completely elucidated. In this study, the expression profile of chemokines was more altered in IgA1-treated HMC than in the control group. CCL20 was significantly higher either in the serum of IgAN patients or in IgA1-treated HMC. Further experiments demonstrated that CCR6, the only receptor of CCL20, was highly expressed in activated T cells. Intracellular staining assay and cytokine expression profile implied that CCR6+ T cells produced high IL-17 levels. Transwell experiment immunohistochemistry and immunofluorescence experiments extensively demonstrated that CCL20 could recruit inflammatory Th17 cells to the kidneys. These phenomena caused a series of immune inflammatory responses and further damaged the kidneys. Therefore, HMC stimulated by IgA1 could produce CCL20 and consequently recruit inflammatory Th17 cells to the kidneys to induce further lesion in IgA nephropathy. PMID- 28552943 TI - If you want to save, focus on the forest rather than on trees. The effects of shifts in levels of construal on saving decisions. AB - Although financial decisions are expected to be rational, there is a growing body of experimental research indicating that small psychological changes in one's mind-set in the actual decision-making moment might affect saving ratios. In this article, another type of change in one's mind-set, which can influence saving decisions, is explored, namely the level of construal. Construal level is a key descriptor of people's cognitive representations of targets, and is a way of characterising the mental mind-sets people use. Building on recent advances in the link between construal levels and intertemporal choices, the present research evaluates the effect of shifts in levels of construal in the very moment of decision making on people's propensity to save money. It is suggested that triggering a high-level construal mind-set would influence individuals' financial decisions and result in greater willingness to save than triggering a low-level construal mind-set. This assumption is supported by the findings: across three experiments, those with an abstract mind-set showed an increased willingness to save when compared to those with a concrete mind-set. The first experiment demonstrated that people in an abstract mind-set are more willing to delay financial gratification than those in a concrete mind-set. In the second and third experiments, those with an abstract mind-set showed an increased willingness to save when compared to those with a concrete mind-set. The research provides further evidence that mental states, which can be evoked by previous, unrelated tasks, such as level of cognitive abstraction, can influence everyday financial decisions. It, thus, highlights the role of situational factors that consumers may be not aware of, which still affect their savings decisions. PMID- 28552942 TI - Measuring cannabis consumption: Psychometric properties of the Daily Sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory (DFAQ-CU). AB - OBJECTIVE: We created the Daily Sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory (DFAQ-CU) because the current lack of psychometrically sound inventories for measuring these dimensions of cannabis use has impeded research on the effects of cannabis in humans. METHOD: A sample of 2,062 cannabis users completed the DFAQ-CU and was used to assess the DFAQ-CU's factor structure and reliability. To assess validity, a subsample of 645 participants completed additional measures of cannabis dependence and problems (Marijuana Smoking History Questionnaire [MSHQ], Timeline Followback [TLFB], Cannabis Abuse Screening Test [CAST], Cannabis Use Disorders Identification Test Revised [CUDIT R], Cannabis Use Problems Identification Test [CUPIT], and Alcohol Use Disorder Identification Test [AUDIT]). RESULTS: A six-factor structure was revealed, with factors measuring: daily sessions, frequency, age of onset, marijuana quantity, cannabis concentrate quantity, and edibles quantity. The factors were reliable, with Cronbach's alpha coefficients ranging from .69 (daily sessions) to .95 (frequency). Results further provided evidence for the factors' convergent (MSHQ, TLFB), predictive (CAST, CUDIT-R, CUPIT), and discriminant validity (AUDIT). CONCLUSIONS: The DFAQ-CU is the first psychometrically sound inventory for measuring frequency, age of onset, and quantity of cannabis use. It contains pictures of marijuana to facilitate the measurement of quantity of marijuana used, as well as questions to assess the use of different forms of cannabis (e.g., concentrates, edibles), methods of administering cannabis (e.g., joints, hand pipes, vaporizers), and typical THC levels. As such, the DFAQ-CU should help facilitate research on frequency, quantity, and age of onset of cannabis use. PMID- 28552944 TI - Intraoperative tranexamic acid is associated with postoperative stroke in patients undergoing cardiac surgery. AB - BACKGROUND: Stroke is a devastating and potentially preventable complication of cardiac surgery. Tranexamic acid (TXA) is a commonly antifibrinolytic agent in cardiac surgeries with cardiopulmonary bypass (CPB), however, there is concern that it might increase incidence of stroke after cardiac surgery. In this retrospective study, we investigated whether TXA usage could increase postoperative stroke in cardiac surgery. METHODS: A retrospective study was conducted from January 1, 2010, to December 31, 2015, in 2,016 patients undergoing cardiac surgery, 664 patients received intravenous TXA infusion and 1,352 patients did not receive any antifibrinolytic agent. Univariate and propensity-weighted multivariate regression analysis were applied for data analysis. RESULTS: Intraoperative TXA administration was associated with postoperative stroke (1.7% vs. 0.5%; adjusted OR, 4.11; 95% CI, 1.33 to 12.71; p = 0.014) and coma (adjusted OR, 2.77; 95% CI, 1.06 to 7.26; p = 0.038) in cardiac surgery. As subtype analysis was performed, TXA administration was still associated with postoperative stroke (1.7% vs. 0.3%; adjusted OR, 5.78; 95% CI, 1.34 to 27.89; p = 0.018) in patients undergoing valve surgery or multi-valve surgery only, but was not associated with postoperative stroke (1.7% vs. 1.3%; adjusted OR, 5.21; 95% CI, 0.27 to 101.17; p = 0.276) in patients undergoing CABG surgery only. However, TXA administration was not associated with postoperative mortality (adjusted OR, 1.31; 95% CI, 0.56 to 3.71; p = 0.451), seizure (adjusted OR, 1.13; 95% CI, 0.42 to 3.04; p = 0.816), continuous renal replacement therapy (adjusted OR, 1.36; 95% CI, 0.56 to 3.28; p = 0.495) and resternotomy for postoperative bleeding (adjusted OR, 1.55; 95% CI, 0.55 to 4.30; p = 0.405). No difference was found in postoperative ventilation time (adjusted B, -1.45; SE, 2.33; p = 0.535), length of intensive care unit stay (adjusted B, -0.12; SE, 0.25; p = 0.633) and length of hospital stay (adjusted B, 0.48; SE, 0.58; p = 0.408). CONCLUSIONS: Based on the 5-year experience of TXA administration in cardiac surgery with CPB, we found that postoperative stroke was associated with intraoperative TXA administration in patients undergoing cardiac surgery, especially in those undergoing valve surgeries only. This study may suggest that TXA should be administrated according to clear indications after evaluating the bleeding risk in patients undergoing cardiac surgery, especially in those with high stroke risk. PMID- 28552945 TI - Does nitrogen fertilization history affects short-term microbial responses and chemical properties of soils submitted to different glyphosate concentrations? AB - The use of nitrogen (N) fertilizer and glyphosate-based herbicides is increasing worldwide, with agriculture holding the largest market share. The agronomic and socioeconomic utilities of glyphosate are well established; however, our knowledge of the potential effects of glyphosate applied in the presence or absence of long-term N fertilization on microbial functional activities and the availability of soil nutrients remains limited. Using an ex situ approach with soils that did (N+) or did not (N0) receive synthetic N fertilization for 6 years, we assessed the impact of different rates (no glyphosate, CK; field rate, FR; 100 * field rate, 100FR) of glyphosate application on biological and chemical parameters. We observed that, after immediate application (1 day), the highest dose of glyphosate (100FR) negatively affected the alkaline phosphatase (AlP) activity in soils without N fertilization history and decreased the cation exchange capacity (CEC) in N0 compared to CK and FR treatments with N+. Conversely, the 100FR application increased nitrate (NO3-) and available phosphorus (PO43-) regardless of N fertilization history. Then, after 8 and 15 days, the N+?100FR and N+?FR treatments exhibited the lowest values for dehydrogenase (DH) and AlP activities, respectively, while urease (URE) activity was mainly affected by N fertilization. After 15 days and irrespective of N fertilization history, the FR glyphosate application negatively affected the degradation of carbon substrates by microbial communities (expressed as the average well color development, AWCD). By contrast, the 100FR treatment positively affected AWCD, increasing PO43- by 5 and 16% and NO3- by 126 and 119% in the N+ and N0 treatments, respectively. In addition, the 100FR treatment resulted in an increase in the average net nitrification rate. Principal component analysis revealed that the 100FR glyphosate treatment selected microbial communities that were able to metabolize amine substrates. Overall, the lack of N fertilization in the 6 past years combined with the highest glyphosate application rate (100FR) induced the highest values of AWCD, functional diversity, NO3-, PO43- and nitrification. We concluded that the intensive use of N fertilization for 6 years may change the non-target effects of glyphosate application on enzyme activities. The functional activities, nitrification and nutrient contents were increased by glyphosate only when applied at 100 times the field application rate. PMID- 28552946 TI - Partial sequencing analysis of the NS5B region confirmed the predominance of hepatitis C virus genotype 1 infection in Jeddah, Saudi Arabia. AB - Chronic hepatitis C virus (HCV) infection and its progression are major health problems that many countries including Saudi Arabia are facing. Determination of HCV genotypes and subgenotypes is critical for epidemiological and clinical analysis and aids in the determination of the ideal treatment strategy that needs to be followed and the expected therapy response. Although HCV infection has been identified as the second most predominant type of hepatitis in Saudi Arabia, little is known about the molecular epidemiology and genetic variability of HCV circulating in the Jeddah province of Saudi Arabia. The aim of this study was to determine the dominance of various HCV genotypes and subgenotypes circulating in Jeddah using partial sequencing of the NS5B region. To the best of our knowledge, this is the first study of its kind in Saudi Arabia. To characterize HCV genotypes and subgenotypes, serum samples from 56 patients with chronic HCV infection were collected and subjected to partial NS5B gene amplification and sequence analysis. Phylogenetic analysis of the NS5B partial sequences revealed that HCV/1 was the predominant genotype (73%), followed by HCV/4 (24.49%) and HCV/3 (2.04%). Moreover, pairwise analysis also confirmed these results based on the average specific nucleotide distance identity: +/-0.112, +/-0.112, and +/ 0.179 for HCV/1, HCV/4, and HCV/3, respectively, without any interference between genotypes. Notably, the phylogenetic tree of the HCV/1 subgenotypes revealed that all the isolates (100%) from the present study belonged to the HCV/1a subgenotype. Our findings also revealed similarities in the nucleotide sequences between HCV circulating in Saudi Arabia and those circulating in countries such as Morocco, Egypt, Canada, India, Pakistan, and France. These results indicated that determination of HCV genotypes and subgenotypes based on partial sequence analysis of the NS5B region is accurate and reliable for HCV subtype determination. PMID- 28552947 TI - Relationship of mechanical impact magnitude to neurologic dysfunction severity in a rat traumatic brain injury model. AB - OBJECTIVE: Traumatic brain injury (TBI) is a major brain injury type commonly caused by traffic accidents, falls, violence, or sports injuries. To obtain mechanistic insights about TBI, experimental animal models such as weight-drop induced TBI in rats have been developed to mimic closed-head injury in humans. However, the relationship between the mechanical impact level and neurological severity following weight-drop-induced TBI remains uncertain. In this study, we comprehensively investigated the relationship between physical impact and graded severity at various weight-drop heights. APPROACH: The acceleration, impact force, and displacement during the impact were accurately measured using an accelerometer, a pressure sensor, and a high-speed camera, respectively. In addition, the longitudinal changes in neurological deficits and balance function were investigated at 1, 4, and 7 days post TBI lesion. The inflammatory expression markers tested by Western blot analysis, including glial fibrillary acidic protein, beta-amyloid precursor protein, and bone marrow tyrosine kinase gene in chromosome X, in the frontal cortex, hippocampus, and corpus callosum were investigated at 1 and 7 days post-lesion. RESULTS: Gradations in impact pressure produced progressive degrees of injury severity in the neurological score and balance function. Western blot analysis demonstrated that all inflammatory expression markers were increased at 1 and 7 days post-impact injury when compared to the sham control rats. The severity of neurologic dysfunction and induction in inflammatory markers strongly correlated with the graded mechanical impact levels. CONCLUSIONS: We conclude that the weight-drop-induced TBI model can produce graded brain injury and induction of neurobehavioral deficits and may have translational relevance to developing therapeutic strategies for TBI. PMID- 28552949 TI - Retraction: Have We Substantially Underestimated the Impact of Improved Sanitation Coverage on Child Health? A Generalized Additive Model Panel Analysis of Global Data on Child Mortality and Malnutrition. PMID- 28552950 TI - Genomic profile of human meningioma cell lines. AB - Meningiomas, derived from arachnoid cap cells, are the most common intracranial tumor. High-grade meningiomas, as well as those located at the skull base or near venous sinuses, frequently recur and are challenging to manage. Next-generation sequencing is identifying novel pharmacologic targets in meningiomas to complement surgery and radiation. However, due to the lack of in vitro models, the importance and implications of these genetic variants in meningioma pathogenesis and therapy remain unclear. We performed whole exome sequencing to assess single nucleotide variants and somatic copy number variants in four human meningioma cell lines, including two benign lines (HBL-52 and Ben-Men-1) and two malignant lines (IOMM-Lee and CH157-MN). The two malignant cell lines harbored an elevated rate of mutations and copy number alterations compared to the benign lines, consistent with the genetic profiles of high-grade meningiomas. In addition, these cell lines also harbored known meningioma driver mutations in neurofibromin 2 (NF2) and TNF receptor-associated factor 7 (TRAF7). These findings demonstrate the relevance of meningioma cell lines as a model system, especially as tools to investigate the signaling pathways of, and subsequent resistance to, therapeutics currently in clinical trials. PMID- 28552948 TI - Association of gain-of-function EPHX2 polymorphism Lys55Arg with acute kidney injury following cardiac surgery. AB - Twenty to thirty percent of patients undergoing cardiac surgery develop acute kidney injury (AKI). In mice, inhibition of soluble epoxide hydrolase (sEH) attenuates renal injury following ischemia-reperfusion. We tested the hypothesis that functional variants of EPHX2, encoding sEH, are associated with AKI after cardiac surgery. We genotyped patients in two independent cardiac surgery cohorts for functional EPHX2 polymorphisms, Lys55Arg and Arg287Gln, and determined AKI using Acute Kidney Injury Network criteria. The 287Gln variant was not associated with AKI. In the discovery cohort, the gain-of-function 55Arg variant was associated with an increased incidence of AKI in univariate (p = 0.03) and multivariable (p = 0.04) analyses. In white patients without chronic kidney disease (CKD), the 55Arg variant was independently associated with AKI with an OR of 2.04 (95% CI 0.95-4.42) for 55Arg heterozygotes and 31.53 (1.57-633.19) for homozygotes (p = 0.02), after controlling for age, sex, body mass index, baseline estimated glomerular filtration rate, and use of cardiopulmonary bypass. These findings were replicated in the second cardiac surgery cohort. 12,13- and total- dihydroxyoctadecanoic acids (DiHOME): epoxyoctadecanoic acids (EpOME) ratios were increased in EPHX2 55Arg variant carriers, consistent with increased hydrolase activity. The EPHX2 Lys55Arg polymorphism is associated with AKI following cardiac surgery in patients without preexisting CKD. Pharmacological strategies to decrease sEH activity might decrease postoperative AKI. PMID- 28552951 TI - Common variants near IKZF1 are associated with primary Sjogren's syndrome in Han Chinese. AB - Primary Sjogren's syndrome (pSS) is a systematic autoimmune disease with evidence of genetic predisposition. The IKZF1 (IKAROS family zinc finger 1 (Ikaros)) gene is located at 7p12.2, encodes a transcription factor related to chromatin remodeling, regulates lymphocyte differentiation, and has been reported to be associated with some autoimmune diseases. However, there have been no reports of an association between IKZF1 and pSS. To investigate the possibility of an association between the IKZF1 locus and pSS, we selected two single nucleotide polymorphisms (SNPs) in the IKZF1 locus, rs4917129 and rs4917014, based on a detailed analysis of genome-wide association study (GWAS) data and performed genotyping in 665 Han Chinese pSS patients and 863 healthy controls. The results of an association test showed significant association signals (rs4917129: P-value = 5.5e-4, OR (odds ratio) = 0.72, 95% CI (confidence interval) = 0.60-0.87; rs4917014: P-value = 1.2e-3, OR = 0.76, 95% CI = 0.64-0.89). A meta-analysis that combined the above results with data from previous GWAS, further confirmed these associations (rs4917129: Pmeta = 4.24e-8, ORmeta = 0.70, 95% CI = 0.61-0.79; rs4917014: Pmeta = 6.0e-8, ORmeta = 0.72, 95% CI = 0.64-0.81). A bioinformatics analysis indicated that both SNPs were located in a putative enhancer area in immune-related cell lines and tissues. A protein-protein interaction analysis found that IKZF1, together with GTF2I (an SS susceptibility gene newly identified through GWAS), could interact with histone deacetylase family proteins. In summary, this is the first study to report an association between IKZF1 and SS in Han Chinese. PMID- 28552952 TI - Asymmetric regulation of quorum-sensing receptors drives autoinducer-specific gene expression programs in Vibrio cholerae. AB - Quorum sensing (QS) is a mechanism of chemical communication that bacteria use to monitor cell-population density and coordinate group behaviors. QS relies on the production, detection, and group-wide response to extracellular signal molecules called autoinducers. Vibrio cholerae employs parallel QS circuits that converge into a shared signaling pathway. At high cell density, the CqsS and LuxPQ QS receptors detect the intra-genus and inter-species autoinducers CAI-1 and AI-2, respectively, to repress virulence factor production and biofilm formation. We show that positive feedback, mediated by the QS pathway, increases CqsS but not LuxQ levels during the transition into QS-mode, which amplifies the CAI-1 input into the pathway relative to the AI-2 input. Asymmetric feedback on CqsS enables responses exclusively to the CAI-1 autoinducer. Because CqsS exhibits the dominant QS signaling role in V. cholerae, agonism of CqsS with synthetic compounds could be used to control pathogenicity and host dispersal. We identify nine compounds that share no structural similarity to CAI-1, yet potently agonize CqsS via inhibition of CqsS autokinase activity. PMID- 28552954 TI - Scaling relationships of twig biomass allocation in Pinus hwangshanensis along an altitudinal gradient. AB - Understanding the response of biomass allocation in twigs (the terminal branches of current-year shoots) to environmental change is crucial for elucidating forest ecosystem carbon storage, carbon cycling, and plant life history strategies under a changing climate. On the basis of interspecies investigations of broad-leaved plants, previous studies have demonstrated that plants respond to environmental factors by allocating biomass in an allometric manner between support tissues (i.e., stems) and the leaf biomass of twigs, where the scaling exponent (i.e., slope of a log-log linear relationship, alpha) is constant, and the scaling constant (i.e., intercept of a log-log linear relationship, log beta) varies with respect to environmental factors. However, little is known about whether the isometric scaling exponents of such biomass allocations remain invariant for single species, particularly conifers, at different altitudes and in different growing periods. In this study, we investigated how twig biomass allocation varies with elevation and period among Pinus hwangshanensis Hsia trees growing in the mountains of Southeast China. Specifically, we explored how twig stem mass, needle mass, and needle area varied throughout the growing period (early, mid-, late) and at three elevations in the Wuyi Mountains. Standardized major axis analysis was used to compare the scaling exponents and scaling constants between the biomass allocations of within-twig components. Scaling relationships between these traits differed with growing period and altitude gradient. During the different growing periods, there was an isometric scaling relationship, with a common slope of 1.0 (i.e., alpha ~ 1.0), between needle mass and twig mass (the sum of the total needle mass and the stem mass), whereas there were allometric scaling relationships between the stem mass and twig mass and between the needle mass and stem mass of P. hwangshanensis. The scaling constants (log beta) for needle mass vs. twig mass and for needle mass vs. stem mass increased progressively across the growing stages, whereas the scaling constants of stem mass vs. twig mass showed the opposite pattern. The scaling exponents (alpha) of needle area with respect to needle biomass increased significantly with growing period, changing from an allometric relationship (i.e., alpha < 1.0) during the early growing period to a nearly isometric relationship (i.e., alpha ~ 1.0) during the late growing period. This change possibly reflects the functional adaptation of twigs in different growing periods to meet their specific reproductive or survival needs. At different points along the altitudinal gradient, the relationships among needle mass, twig mass, and stem mass were all isometric (i.e., alpha ~ 1.0). Moreover, significant differences were found in scaling constants (log beta) along the altitudinal gradient, such that species had a smaller stem biomass but a relatively larger needle mass at low altitude. In addition, the scaling exponents remained numerically invariant among all three altitudes, with a common slope of 0.8, suggesting that needle area failed to keep pace with the increasing needle mass at different altitudes. Our results indicated that the twig biomass allocation pattern was significantly influenced by altitude and growing period, which reflects the functional adaptation of twigs to meet their specific survival needs under different climatic conditions. PMID- 28552953 TI - A unique profilin-actin interface is important for malaria parasite motility. AB - Profilin is an actin monomer binding protein that provides ATP-actin for incorporation into actin filaments. In contrast to higher eukaryotic cells with their large filamentous actin structures, apicomplexan parasites typically contain only short and highly dynamic microfilaments. In apicomplexans, profilin appears to be the main monomer-sequestering protein. Compared to classical profilins, apicomplexan profilins contain an additional arm-like beta-hairpin motif, which we show here to be critically involved in actin binding. Through comparative analysis using two profilin mutants, we reveal this motif to be implicated in gliding motility of Plasmodium berghei sporozoites, the rapidly migrating forms of a rodent malaria parasite transmitted by mosquitoes. Force measurements on migrating sporozoites and molecular dynamics simulations indicate that the interaction between actin and profilin fine-tunes gliding motility. Our data suggest that evolutionary pressure to achieve efficient high-speed gliding has resulted in a unique profilin-actin interface in these parasites. PMID- 28552955 TI - Stem carbohydrate dynamics and expression of genes involved in fructan accumulation and remobilization during grain growth in wheat (Triticum aestivum L.) genotypes with contrasting tolerance to water stress. AB - The genetic and physiological mechanisms underlying the relationship between water-soluble carbohydrates (WSC) and water stress tolerance are scarcely known. This study aimed to evaluate the main WSC in stems, and the expression of genes involved in fructan metabolism in wheat genotypes growing in a glasshouse with water stress (WS; 50% field capacity from heading) and full irrigation (FI; 100% field capacity). Eight wheat genotypes (five tolerant and three susceptible to water stress) were evaluated initially (experiment 1) and the two most contrasting genotypes in terms of WSC accumulation were evaluated in a subsequent experiment (experiment 2). Maximum accumulation of WSC occurred 10-20 days after anthesis. Under WS, the stress-tolerant genotype exhibited higher concentrations of WSC, glucose, fructose and fructan in the stems, compared to FI. In addition, the stress-tolerant genotype exhibited higher up-regulation of the fructan 1 fructosyltransferase B (1-FFTB) and fructan 1-exohydrolase w2 (1-FEHw2) genes, whereas the susceptible cultivar presented an up-regulation of the fructan 6 fructosyltransferase (6-SFT) and fructan 1-exohydrolase w3 (1-FEHw3) genes. Our results indicated clear differences in the pattern of WSC accumulation and the expression of genes regulating fructan metabolism between the tolerant and susceptible genotypes under WS. PMID- 28552956 TI - Sex-specific effect of CPB2 Ala147Thr but not Thr325Ile variants on the risk of venous thrombosis: A comprehensive meta-analysis. AB - BACKGROUND: Thrombin activatable fibrinolysis inhibitor (TAFI), encoded by the Carboxypeptidase B2 gene (CPB2), is an inhibitor of fibrinolysis and plays a role in the pathogenesis of venous thrombosis. Experimental findings support a functional role of genetic variants in CPB2, while epidemiological studies have been unable to confirm associations with risk of venous thrombosis. Sex-specific effects could underlie the observed inconsistent associations between CPB2 genetic variants and venous thrombosis. METHODS: A comprehensive literature search was conducted for associations between Ala147Thr and Thr325Ile variants with venous thrombosis. Authors were contacted to provide sex-specific genotype counts from their studies. Combined and sex-specific random effects meta-analyses were used to estimate a pooled effect estimate for primary and secondary genetic models. RESULTS: A total of 17 studies met the inclusion criteria. A sex-specific meta-analysis applying a dominant model supported a protective effect of Ala147Thr on venous thrombosis in females (OR = 0.81, 95%CI: 0.68,0.97; p = 0.018), but not in males (OR = 1.06, 95%CI:0.96-1.16; p = 0.263). The Thr325Ile did not show a sex-specific effect but showed variation in allele frequencies by geographic region. A subgroup analysis of studies in European countries showed decreased risk, with a recessive model (OR = 0.83, 95%CI:0.71-0.97, p = 0.021) for venous thrombosis. CONCLUSIONS: A comprehensive literature review, including unpublished data, provided greater statistical power for the analyses and decreased the likelihood of publication bias influencing the results. Sex specific analyses explained apparent discrepancies across genetic studies of Ala147Thr and venous thrombosis. While, careful selection of genetic models based on population genetics, evolutionary and biological knowledge can increase power by decreasing the need to adjust for testing multiple models. PMID- 28552957 TI - Safety and EEG data quality of concurrent high-density EEG and high-speed fMRI at 3 Tesla. AB - PURPOSE: Concurrent EEG and fMRI is increasingly used to characterize the spatial temporal dynamics of brain activity. However, most studies to date have been limited to conventional echo-planar imaging (EPI). There is considerable interest in integrating recently developed high-speed fMRI methods with high-density EEG to increase temporal resolution and sensitivity for task-based and resting state fMRI, and for detecting interictal spikes in epilepsy. In the present study using concurrent high-density EEG and recently developed high-speed fMRI methods, we investigate safety of radiofrequency (RF) related heating, the effect of EEG on cortical signal-to-noise ratio (SNR) in fMRI, and assess EEG data quality. MATERIALS AND METHODS: The study compared EPI, multi-echo EPI, multi-band EPI and multi-slab echo-volumar imaging pulse sequences, using clinical 3 Tesla MR scanners from two different vendors that were equipped with 64- and 256-channel MR-compatible EEG systems, respectively, and receive only array head coils. Data were collected in 11 healthy controls (3 males, age range 18-70 years) and 13 patients with epilepsy (8 males, age range 21-67 years). Three of the healthy controls were scanned with the 256-channel EEG system, the other subjects were scanned with the 64-channel EEG system. Scalp surface temperature, SNR in occipital cortex and head movement were measured with and without the EEG cap. The degree of artifacts and the ability to identify background activity was assessed by visual analysis by a trained expert in the 64 channel EEG data (7 healthy controls, 13 patients). RESULTS: RF induced heating at the surface of the EEG electrodes during a 30-minute scan period with stable temperature prior to scanning did not exceed 1.0 degrees C with either EEG system and any of the pulse sequences used in this study. There was no significant decrease in cortical SNR due to the presence of the EEG cap (p > 0.05). No significant differences in the visually analyzed EEG data quality were found between EEG recorded during high-speed fMRI and during conventional EPI (p = 0.78). Residual ballistocardiographic artifacts resulted in 58% of EEG data being rated as poor quality. CONCLUSION: This study demonstrates that high-density EEG can be safely implemented in conjunction with high-speed fMRI and that high-speed fMRI does not adversely affect EEG data quality. However, the deterioration of the EEG quality due to residual ballistocardiographic artifacts remains a significant constraint for routine clinical applications of concurrent EEG-fMRI. PMID- 28552959 TI - Multiparametric quantification of thermal heterogeneity within aqueous materials by water 1H NMR spectroscopy: Paradigms and algorithms. AB - Processes involving heat generation and dissipation play an important role in the performance of numerous materials. The behavior of (semi-)aqueous materials such as hydrogels during production and application, but also properties of biological tissue in disease and therapy (e.g., hyperthermia) critically depend on heat regulation. However, currently available thermometry methods do not provide quantitative parameters characterizing the overall temperature distribution within a volume of soft matter. To this end, we present here a new paradigm enabling accurate, contactless quantification of thermal heterogeneity based on the line shape of a water proton nuclear magnetic resonance (1H NMR) spectrum. First, the 1H NMR resonance from water serving as a "temperature probe" is transformed into a temperature curve. Then, the digital points of this temperature profile are used to construct a histogram by way of specifically developed algorithms. We demonstrate that from this histogram, at least eight quantitative parameters describing the underlying statistical temperature distribution can be computed: weighted median, weighted mean, standard deviation, range, mode(s), kurtosis, skewness, and entropy. All mathematical transformations and calculations are performed using specifically programmed EXCEL spreadsheets. Our new paradigm is helpful in detailed investigations of thermal heterogeneity, including dynamic characteristics of heat exchange at sub-second temporal resolution. PMID- 28552958 TI - Characterization of basal and lipopolysaccharide-induced microRNA expression in equine peripheral blood mononuclear cells using Next-Generation Sequencing. AB - The innate immune response to lipopolysaccharide contributes substantially to the morbidity and mortality of gram-negative sepsis. Horses and humans share an exquisite sensitivity to lipopolysaccharide and thus the horse may provide valuable comparative insights into this aspect of the inflammatory response. MicroRNAs, small non-coding RNA molecules acting as post-transcriptional regulators of gene expression, have key roles in toll-like receptor signaling regulation but have not been studied in this context in horses. The central hypothesis of this study was that lipopolysaccharide induces differential microRNA expression in equine peripheral blood mononuclear cells in a manner comparable to humans. Illumina Next Generation Sequencing was used to characterize the basal microRNA transcriptome in isolated peripheral blood mononuclear cells from healthy adult horses, and to evaluate LPS-induced changes in microRNA expression in cells cultured for up to four hours. Selected expression changes were validated using quantitative reverse-transcriptase PCR. Only miR-155 was significantly upregulated by LPS, changing in parallel with supernatant tumor necrosis factor-alpha concentration. Eight additional microRNAs, including miR-146a and miR-146b, showed significant expression change with time in culture without a clear LPS effect. Target predictions indicated a number of potential immunity-associated targets for miR-155 in the horse, including SOCS1, TAB2 and elements of the PI3K signaling pathway, suggesting that it is likely to influence the acute inflammatory response to LPS. Gene alignment showed extensive conservation of the miR-155 precursor gene and associated promoter regions between horses and humans. The basal and LPS-stimulated microRNA expression pattern characterized here were similar to those described in human leukocytes. As well as providing a resource for further research into the roles of microRNAs in immune responses in horses, this will facilitate inter-species comparative study of the role of microRNAs in the inflammatory cascade during endotoxemia and sepsis. PMID- 28552960 TI - Electrostatic forces govern the binding mechanism of intrinsically disordered histone chaperones. AB - A unified picture to understand the protein recognition and function must include the native binding complex structure ensembles and the underlying binding mechanisms involved in specific biological processes. However, quantifications of both binding complex structures and dynamical mechanisms are still challenging for IDP. In this study, we have investigated the underlying molecular mechanism of the chaperone Chz1 and histone H2A.Z-H2B association by equilibrium and kinetic stopped-flow fluorescence spectroscopy. The dependence of free energy and kinetic rate constant on electrolyte mean activity coefficient and urea concentration are uncovered. Our results indicate a previous unseen binding kinetic intermediate. An initial conformation selection step of Chz1 is also revealed before the formation of this intermediate state. Based on these observations, a mixed mechanism of three steps including both conformation selection and induced fit is proposed. By combination of the ion- and denaturant induced experiments, we demonstrate that electrostatic forces play a dominant role in the recognition of bipolar charged intrinsically disordered protein Chz1 to its preferred partner H2A.Z-H2B. Both the intra-chain and inter-chain electrostatic interactions have direct impacts on the native collapsed structure and binding mechanism. PMID- 28552961 TI - Optimising cluster survey design for planning schistosomiasis preventive chemotherapy. AB - BACKGROUND: The cornerstone of current schistosomiasis control programmes is delivery of praziquantel to at-risk populations. Such preventive chemotherapy requires accurate information on the geographic distribution of infection, yet the performance of alternative survey designs for estimating prevalence and converting this into treatment decisions has not been thoroughly evaluated. METHODOLOGY/PRINCIPAL FINDINGS: We used baseline schistosomiasis mapping surveys from three countries (Malawi, Cote d'Ivoire and Liberia) to generate spatially realistic gold standard datasets, against which we tested alternative two-stage cluster survey designs. We assessed how sampling different numbers of schools per district (2-20) and children per school (10-50) influences the accuracy of prevalence estimates and treatment class assignment, and we compared survey cost efficiency using data from Malawi. Due to the focal nature of schistosomiasis, up to 53% simulated surveys involving 2-5 schools per district failed to detect schistosomiasis in low endemicity areas (1-10% prevalence). Increasing the number of schools surveyed per district improved treatment class assignment far more than increasing the number of children sampled per school. For Malawi, surveys of 15 schools per district and 20-30 children per school reliably detected endemic schistosomiasis and maximised cost-efficiency. In sensitivity analyses where treatment costs and the country considered were varied, optimal survey size was remarkably consistent, with cost-efficiency maximised at 15-20 schools per district. CONCLUSIONS/SIGNIFICANCE: Among two-stage cluster surveys for schistosomiasis, our simulations indicated that surveying 15-20 schools per district and 20-30 children per school optimised cost-efficiency and minimised the risk of under-treatment, with surveys involving more schools of greater cost efficiency as treatment costs rose. PMID- 28552962 TI - Retinoic acid receptor gamma impacts cellular adhesion, Alpha5Beta1 integrin expression and proliferation in K562 cells. AB - The interplay between cellular adhesion and proliferation is complex; however, integrins, particularly the alpha5beta1 subset, play a pivotal role in orchestrating critical cellular signals that culminate in cellular adhesion and growth. Retinoids modify the expression of a variety of adhesive/proliferative signaling proteins including alpha5beta1 integrins; however, the role of specific retinoic acid receptors involved in these processes has not been elucidated. In this study, the effect of all-trans-retinoic acid receptor (RAR) agonists on K562 cellular adhesion, proliferation, and alpha5beta1 integrin cell surface expression was investigated. RARgamma agonist exposure increased K562 cellular adhesion to RGD containing extracellular matrix proteins fibronectin and FN-120 in a time- and concentration dependent manner, while RARalpha or RARbeta agonist treatment had no effect on cellular adhesion. Due to the novel RARgamma- dependent cellular adhesion response exhibited by K562 cells, we examined alpha5 and beta1 integrin subunit expression when K562 cells were exposed to retinoid agonists or vehicle for 24, 48, 72 or 96 hours. Our data demonstrates no differences in K562 cell surface expression of the alpha5 integrin subunit when cells were exposed to RARalpha, RARbeta, or RARgamma agonists for all time points tested. In contrast, RARgamma agonist exposure resulted in an increase in cell surface beta1 integrin subunit expression within 48 hours that was sustained at 72 and 96 hours. Finally, we demonstrate that while exposure to RARalpha or RARbeta agonists have no effect on K562 cellular proliferation, the RARgamma agonist significantly dampens K562 cellular proliferation levels in a time- and concentration- dependent manner. Our study is the first to report that treatment with a RARgamma specific agonist augments cellular adhesion to alpha5beta1 integrin substrates, increases cell surface levels of the beta1 integrin subunit, and dampens cellular proliferation in a time and concentration dependent manner in a human erythroleukemia cell line. PMID- 28552963 TI - Bim expression in endothelial cells and pericytes is essential for regression of the fetal ocular vasculature. AB - Apoptosis plays a central role in developmental and pathological angiogenesis and vessel regression. Bim is a pro-apoptotic Bcl-2 family member that plays a prominent role in both developmental and pathological ocular vessel regression, and neovascularization. Endothelial cells (EC) and pericytes (PC) each play unique roles during vascular development, maintenance and regression. We recently showed that germline deletion of Bim results in persistent hyaloid vasculature, increased retinal vascular density and prevents retinal vessel regression in response to hyperoxia. To determine whether retinal vascular regression is attributable to Bim expression in EC or PC we generated mice carrying a conditional Bim allele (BimFlox/Flox) and VE-cadherin-cre (BimEC mice) or Pdgfrb cre (BimPC mice). BimEC and BimPC mice demonstrated attenuated hyaloid vessel regression and postnatal retinal vascular remodeling. We also observed decreased retinal vascular apoptosis and proliferation. Unlike global Bim -/- mice, mice conditionally lacking Bim in EC or PC underwent hyperoxia-mediated vessel obliteration and subsequent retinal neovascularization during oxygen-induced ischemic retinopathy similar to control littermates. Thus, understanding the cell autonomous role Bim plays in the retinal vascular homeostasis will give us new insight into how to modulate pathological retinal neovascularization and vessel regression to preserve vision. PMID- 28552964 TI - Criticality meets learning: Criticality signatures in a self-organizing recurrent neural network. AB - Many experiments have suggested that the brain operates close to a critical state, based on signatures of criticality such as power-law distributed neuronal avalanches. In neural network models, criticality is a dynamical state that maximizes information processing capacities, e.g. sensitivity to input, dynamical range and storage capacity, which makes it a favorable candidate state for brain function. Although models that self-organize towards a critical state have been proposed, the relation between criticality signatures and learning is still unclear. Here, we investigate signatures of criticality in a self-organizing recurrent neural network (SORN). Investigating criticality in the SORN is of particular interest because it has not been developed to show criticality. Instead, the SORN has been shown to exhibit spatio-temporal pattern learning through a combination of neural plasticity mechanisms and it reproduces a number of biological findings on neural variability and the statistics and fluctuations of synaptic efficacies. We show that, after a transient, the SORN spontaneously self-organizes into a dynamical state that shows criticality signatures comparable to those found in experiments. The plasticity mechanisms are necessary to attain that dynamical state, but not to maintain it. Furthermore, onset of external input transiently changes the slope of the avalanche distributions - matching recent experimental findings. Interestingly, the membrane noise level necessary for the occurrence of the criticality signatures reduces the model's performance in simple learning tasks. Overall, our work shows that the biologically inspired plasticity and homeostasis mechanisms responsible for the SORN's spatio-temporal learning abilities can give rise to criticality signatures in its activity when driven by random input, but these break down under the structured input of short repeating sequences. PMID- 28552965 TI - Does salt stress affect the interspecific interaction between regionally dominant Suaeda salsa and Scirpus planiculumis? AB - Plant-plant interactions that change along environmental gradients can be affected by different combinations of environmental characteristics, such as the species and planting density ratios. Suaeda salsa and Scirpus planiculumis are regionally dominant species in the Shuangtai estuarine wetland. Compared with non clonal S. salsa, clonal S. planiculumis has competitive advantages because of its morphological plasticity. However, salt-tolerant S. salsa may grow faster than S. planiculumis in saline-alkali estuary soil. Whether the interactions between these two species along salinity gradients are affected by the level of salt stress and mixed planting density ratio remains unclear. Thus, to test the effects of salt stress and planting density ratios on the interactions between S. planiculumis and S. salsa in the late growing season, we conducted a greenhouse experiment consisting of 3 salinity levels (0, 8 and 15ppt) and 5 planting density ratios. Our results showed that the promotion of S. salsa growth and inhibition of S. planiculumis growth at low salinity levels (8 ppt) did not alter the interactions between the two species. Facilitation of S. salsa occurred at high salinity levels, and the magnitude of this net outcome decreased with increases in the proportion of S. salsa. These results suggest that competition and facilitation processes not only depend on the combinations of different life history characteristics of species but also on the planting density ratio. These findings may contribute to the understanding of the responses of estuarine wetland plant-plant interactions to human modifications of estuarine salinity. PMID- 28552966 TI - Even- and odd-chain saturated fatty acids in serum phospholipids are differentially associated with adipokines. AB - BACKGROUND: Saturated fatty acids are generally thought to have detrimental effects on health. However, a recent study showed that even- and odd-chain saturated fatty acids had opposite associations with type 2 diabetes. Limited studies of Western populations examined the associations of circulating saturated fatty acids with adipokines, an important role in glucose metabolism. OBJECTIVE: We examined the associations of saturated fatty acids in serum phospholipids with circulating levels of adipokines among a Japanese population. DESIGN: A cross sectional study was conducted among 484 Japanese employees (284 men and 200 women) aged 20-65 years. The serum fatty acid composition in the phospholipid fraction was measured by gas-chromatography. Serum leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), resistin, and visfatin were measured using a Luminex suspension bead-based multiplexed array. Multiple linear regression analysis was performed to assess the association between saturated fatty acids and adipokines, with adjustment for potential confounding variables. RESULTS: Even- and odd-chain saturated fatty acids were differentially associated with adipokines. Higher levels of even-chain saturated fatty acids (14:0 myristic, 16:0 palmitic, and 18:0 stearic acids) were associated with higher levels of resistin (P for trend = 0.048) and lower levels of adiponectin (P for trend = 0.003). By contrast, odd-chain saturated fatty acids (15:0 pentadecanoic and 17:0 heptadecanoic acids) showed inverse associations with leptin and PAI-1 (P for trend = 0.048 and 0.02, respectively). Visfatin was positively associated with both even- and odd-chain saturated fatty acids. CONCLUSIONS: The results suggest that even- and odd-chain saturated fatty acids are differentially associated with adipokine profile. PMID- 28552967 TI - Automated analysis of co-localized protein expression in histologic sections of prostate cancer. AB - An automated approach based on routinely-processed, whole-slide immunohistochemistry (IHC) was implemented to study co-localized protein expression in tissue samples. Expression of two markers was chosen to represent stromal (CD31) and epithelial (Ki-67) compartments in prostate cancer. IHC was performed on whole-slide sections representing low-, intermediate-, and high grade disease from 15 patients. The automated workflow was developed using a training set of regions-of-interest in sequential tissue sections. Protein expression was studied on digital representations of IHC images across entire slides representing formalin-fixed paraffin embedded blocks. Using the training set, the known association between Ki-67 and Gleason grade was confirmed. CD31 expression was more heterogeneous across samples and remained invariant with grade in this cohort. Interestingly, the Ki-67/CD31 ratio was significantly increased in high (Gleason >= 8) versus low/intermediate (Gleason <=7) samples when assessed in the training-set and the whole-tissue block images. Further, the feasibility of the automated approach to process Tissue Microarray (TMA) samples in high throughput was evaluated. This work establishes an initial framework for automated analysis of co-localized protein expression and distribution in high resolution digital microscopy images based on standard IHC techniques. Applied to a larger sample population, the approach may help to elucidate the biologic basis for the Gleason grade, which is the strongest, single factor distinguishing clinically aggressive from indolent prostate cancer. PMID- 28552968 TI - Pharmacokinetic/pharmacodynamic integration and modelling of florfenicol for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida. AB - Pharmacokinetic-pharmacodynamic (PK/PD) integration and modelling were used to predict dosage schedules for florfenicol for two pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Pharmacokinetic data were pooled for two bioequivalent products, pioneer and generic formulations, administered intramuscularly to pigs at a dose rate of 15 mg/kg. Antibacterial potency was determined in vitro as minimum inhibitory concentration (MIC) and Mutant Prevention Concentration in broth and pig serum, for six isolates of each organism. For both organisms and for both serum and broth MICs, average concentration:MIC ratios over 48 h were similar and exceeded 2.5:1 and times greater than MIC exceeded 35 h. From in vitro time-kill curves, PK/PD modelling established serum breakpoint values for the index AUC24h/MIC for three levels of inhibition of growth, bacteriostasis and 3 and 4log10 reductions in bacterial count; means were 25.7, 40.2 and 47.0 h, respectively, for P. multocida and 24.6, 43.8 and 58.6 h for A. pleuropneumoniae. Using these PK and PD data, together with literature MIC distributions, doses for each pathogen were predicted for: (1) bacteriostatic and bactericidal levels of kill; (2) for 50 and 90% target attainment rates (TAR); and (3) for single dosing and daily dosing at steady state. Monte Carlo simulations for 90% TAR predicted single doses to achieve bacteriostatic and bactericidal actions over 48 h of 14.4 and 22.2 mg/kg (P. multocida) and 44.7 and 86.6 mg/kg (A. pleuropneumoniae). For daily doses at steady state, and 90% TAR bacteriostatic and bactericidal actions, dosages of 6.2 and 9.6 mg/kg (P. multocida) and 18.2 and 35.2 mg/kg (A. pleuropneumoniae) were required. PK/PD integration and modelling approaches to dose determination indicate the possibility of tailoring dose to a range of end-points. PMID- 28552969 TI - Automatic adventitious respiratory sound analysis: A systematic review. AB - BACKGROUND: Automatic detection or classification of adventitious sounds is useful to assist physicians in diagnosing or monitoring diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD), and pneumonia. While computerised respiratory sound analysis, specifically for the detection or classification of adventitious sounds, has recently been the focus of an increasing number of studies, a standardised approach and comparison has not been well established. OBJECTIVE: To provide a review of existing algorithms for the detection or classification of adventitious respiratory sounds. This systematic review provides a complete summary of methods used in the literature to give a baseline for future works. DATA SOURCES: A systematic review of English articles published between 1938 and 2016, searched using the Scopus (1938-2016) and IEEExplore (1984 2016) databases. Additional articles were further obtained by references listed in the articles found. Search terms included adventitious sound detection, adventitious sound classification, abnormal respiratory sound detection, abnormal respiratory sound classification, wheeze detection, wheeze classification, crackle detection, crackle classification, rhonchi detection, rhonchi classification, stridor detection, stridor classification, pleural rub detection, pleural rub classification, squawk detection, and squawk classification. STUDY SELECTION: Only articles were included that focused on adventitious sound detection or classification, based on respiratory sounds, with performance reported and sufficient information provided to be approximately repeated. DATA EXTRACTION: Investigators extracted data about the adventitious sound type analysed, approach and level of analysis, instrumentation or data source, location of sensor, amount of data obtained, data management, features, methods, and performance achieved. DATA SYNTHESIS: A total of 77 reports from the literature were included in this review. 55 (71.43%) of the studies focused on wheeze, 40 (51.95%) on crackle, 9 (11.69%) on stridor, 9 (11.69%) on rhonchi, and 18 (23.38%) on other sounds such as pleural rub, squawk, as well as the pathology. Instrumentation used to collect data included microphones, stethoscopes, and accelerometers. Several references obtained data from online repositories or book audio CD companions. Detection or classification methods used varied from empirically determined thresholds to more complex machine learning techniques. Performance reported in the surveyed works were converted to accuracy measures for data synthesis. LIMITATIONS: Direct comparison of the performance of surveyed works cannot be performed as the input data used by each was different. A standard validation method has not been established, resulting in different works using different methods and performance measure definitions. CONCLUSION: A review of the literature was performed to summarise different analysis approaches, features, and methods used for the analysis. The performance of recent studies showed a high agreement with conventional non-automatic identification. This suggests that automated adventitious sound detection or classification is a promising solution to overcome the limitations of conventional auscultation and to assist in the monitoring of relevant diseases. PMID- 28552970 TI - Genetic structuring, dispersal and taxonomy of the high-alpine populations of the Geranium arabicum/kilimandscharicum complex in tropical eastern Africa. AB - The scattered eastern African high mountains harbor a renowned and highly endemic flora, but the taxonomy and phylogeographic history of many plant groups are still insufficiently known. The high-alpine populations of the Geranium arabicum/kilimandscharicum complex present intricate morphological variation and have recently been suggested to comprise two new endemic taxa. Here we aim to contribute to a clarification of the taxonomy of these populations by analyzing genetic (AFLP) variation in range-wide high-alpine samples, and we address whether hybridization has contributed to taxonomic problems. We identified only two genetic groups. One corresponded to G. kilimandscharicum, which has been reported as exclusively high-alpine and confined to the eastern Rift mountains in East Africa. The other corresponded to G. arabicum, reported from lower altitudes on the same mountains as well as from a wide altitudinal span in Ethiopia and on the western Rift mountains in East Africa. The four populations analyzed of a recently described species from the Bale Mts in Ethiopia were admixed, indicating that they result from recent long-distance dispersal of G. kilimandscharicum from East Africa followed by hybridization with local G. arabicum in naturally disturbed habitats. Some admixture between the two genetic groups was also inferred on other mountains, supporting earlier suggestions of introgression based on morphology. We did not find support for recognition of the recently suggested new subspecies of G. arabicum in Ethiopia. Interestingly, the high alpine G. kilimandscharicum lacked clear geographic structuring, suggesting a recent history of colonization of the different mountains or extensive intermountain gene flow. PMID- 28552971 TI - Qualitative analysis of how patients decide that they want risk-reducing mastectomy, and the implications for surgeons in responding to emotionally motivated patient requests. AB - OBJECTIVE: Contemporary approaches to medical decision-making advise that clinicians should respect patients' decisions. However, patients' decisions are often shaped by heuristics, such as being guided by emotion, rather than by objective risk and benefit. Risk-reducing mastectomy (RRM) decisions focus this dilemma sharply. RRM reduces breast cancer (BC) risk, but is invasive and can have iatrogenic consequences. Previous evidence suggests that emotion guides patients' decision-making about RRM. We interviewed patients to better understand how they made decisions about RRM, using findings to consider how clinicians could ethically respond to their decisions. METHODS: Qualitative face-to-face interviews with 34 patients listed for RRM surgery and two who had decided against RRM. RESULTS: Patients generally did not use objective risk estimates or, indeed, consider risks and benefits of RRM. Instead emotions guided their decisions: they chose RRM because they feared BC and wanted to do 'all they could' to prevent it. Most therefore perceived RRM to be the 'obvious' option and made the decision easily. However, many recounted extensive post-decisional deliberation, generally directed towards justifying the original decision. A few patients deliberated before the decision because fears of surgery counterbalanced those of BC. CONCLUSION: Patients seeking RRM were motivated by fear of BC, and the need to avoid potential regret for not doing all they could to prevent it. We suggest that choices such as that for RRM, which are made emotionally, can be respected as autonomous decisions, provided patients have considered risks and benefits. Drawing on psychological theory about how people do make decisions, as well as normative views of how they should, we propose that practitioners can guide consideration of risks and benefits even, where necessary, after patients have opted for surgery. This model of practice could be extended to other medical decisions that are influenced by patients' emotions. PMID- 28552972 TI - Pseudomonas aeruginosa urinary tract infections in hospitalized patients: Mortality and prognostic factors. AB - BACKGROUND: The aim of this study was to analyze the mortality and predictors of 30-day mortality among hospitalized patients with Pseudomonas aeruginosa urinary tract infection (PAUTI) and the impact of antibiotic treatment on survival. METHODS: Patients admitted to our hospital with PAUTI or those diagnosed of PAUTI during hospitalization for other disease between September 2012 and September 2014 were included. Repeated episodes from the same patient were excluded. Database with demographic, clinical and laboratory items was created. Empirical and definitive antibiotic therapy, antimicrobial resistance and all-cause mortality at 30 and 90 days were included. RESULTS: 62 patients were included, with a mean age of 75 years. 51% were male. Mortality was 17.7% at 30 days and 33.9% at 90 days. Factors associated with reduced survival at 30 days were chronic liver disease with portal hypertension (P<0,01), diabetes mellitus (P = 0,04) chronic renal failure (P = 0,02), severe sepsis or septic shock (P<0,01), Charlson index > 3 (P = 0.02) and inadequated definitive antibiotic treatment (P<0,01). Independent risk factors for mortality in multivariate analysis were advanced chronic liver disease (HR 77,4; P<0,01), diabetes mellitus (HR 3,6; P = 0,04), chronic renal failure (HR 4,1; P = 0,03) and inadequated definitive antimicrobial treatment (HR 6,8; P = 0,01). CONCLUSIONS: PAUTI are associated with high mortality in hospitalized patients, which increases significantly in those with severe comorbidity such as chronic renal failure, advanced liver disease or diabetes mellitus. Inadequated antibiotic treatment is associated with poor outcome, which remarks the importance of adjusting empirical antibiotic treatment based on the microbiological susceptibility results. PMID- 28552973 TI - Identification of foot and mouth disease risk areas using a multi-criteria analysis approach. AB - Foot and mouth disease (FMD) is a highly infectious disease that affects cloven hoofed livestock and wildlife. FMD has been a problem for decades, which has led to various measures to control, eradicate and prevent FMD by National Veterinary Services worldwide. Currently, the identification of areas that are at risk of FMD virus incursion and spread is a priority for FMD target surveillance after FMD is eradicated from a given country or region. In our study, a knowledge driven spatial model was built to identify risk areas for FMD occurrence and to evaluate FMD surveillance performance in Rio Grande do Sul state, Brazil. For this purpose, multi-criteria decision analysis was used as a tool to seek multiple and conflicting criteria to determine a preferred course of action. Thirteen South American experts analyzed 18 variables associated with FMD introduction and dissemination pathways in Rio Grande do Sul. As a result, FMD higher risk areas were identified at international borders and in the central region of the state. The final model was expressed as a raster surface. The predictive ability of the model assessed by comparing, for each cell of the raster surface, the computed model risk scores with a binary variable representing the presence or absence of an FMD outbreak in that cell during the period 1985 to 2015. Current FMD surveillance performance was assessed, and recommendations were made to improve surveillance activities in critical areas. PMID- 28552974 TI - Correction: Immorally obtained principal increases investors' risk preference. AB - [This corrects the article DOI: 10.1371/journal.pone.0175181.]. PMID- 28552975 TI - Long-term genetic monitoring of a riverine dragonfly, Orthetrum coerulescens (Odonata: Libellulidae]: Direct anthropogenic impact versus climate change effects. AB - Modern conservationists call for long term genetic monitoring datasets to evaluate and understand the impact of human activities on natural ecosystems and species on a global but also local scale. However, long-term monitoring datasets are still rare but in high demand to correctly identify, evaluate and respond to environmental changes. In the presented study, a population of the riverine dragonfly, Orthetrum coerulescens (Odonata: Libellulidae), was monitored over a time period from 1989 to 2013. Study site was an artificial irrigation ditch in one of the last European stone steppes and "nature heritage", the Crau in Southern France. This artificial riverine habitat has an unusual high diversity of odonate species, prominent indicators for evaluating freshwater habitats. A clearing of the canal and destruction of the bank vegetation in 1996 was assumed to have great negative impact on the odonate larval and adult populations. Two mitochondrial markers (CO1 & ND1) and a panel of nuclear microsatellite loci were used to assess the genetic diversity. Over time they revealed a dramatic decline in diversity parameters between the years 2004 and 2007, however not between 1996 and 1997. From 2007 onwards the population shows a stabilizing trend but has not reached the amount of genetic variation found at the beginning of this survey. This decline cannot be referred to the clearing of the canal or any other direct anthropogenic impact. Instead, it is most likely that the populations' decay was due to by extreme weather conditions during the specific years. A severe drought was recorded for the summer months of these years, leading to reduced water levels in the canal causing also other water parameters to change, and therefore impacting temperature sensitive riverine habitat specialists like the O. coerulescens in a significant way. The data provide important insights into population genetic dynamics and metrics not always congruent with traditional monitoring data (e.g. abundance); a fact that should be regarded with caution when management plans for developed landscapes are designed. PMID- 28552976 TI - Aged dissolved organic carbon exported from rivers of the Tibetan Plateau. AB - The role played by river networks in regional and global carbon cycle is receiving increasing attention. Despite the potential of radiocarbon measurements (14C) to elucidate sources and cycling of different riverine carbon pools, there remain large regions such as the climate-sensitive Tibetan Plateau for which no data are available. Here we provide new 14C data on dissolved organic carbon (DOC) from three large Asian rivers (the Yellow, Yangtze and Yarlung Tsangpo Rivers) running on the Tibetan Plateau and present the carbon transportation pattern in rivers of the plateau versus other river system in the world. Despite higher discharge rates during the high flow season, the DOC yield of Tibetan Plateau rivers (0.41 gC m-2 yr-1) was lower than most other rivers due to lower concentrations. Radiocarbon ages of the DOC were older/more depleted (511+/-294 years before present, yr BP) in the Tibetan rivers than those in Arctic and tropical rivers. A positive correlation between radiocarbon age and permafrost watershed coverage was observed, indicating that 14C-deplted/old carbon is exported from permafrost regions of the Tibetan Plateau during periods of high flow. This is in sharp contrast to permafrost regions of the Arctic which export 14C-enriched carbon during high discharge periods. PMID- 28552977 TI - Validity and responsiveness of the Global Physical Activity Questionnaire (GPAQ) in assessing physical activity during pregnancy. AB - The physiological and biomechanical changes that occur during pregnancy make accurate measurement of physical activity (PA) a challenge during this unique period. The Global Physical Activity Questionnaire (GPAQ) has been used extensively in low-to-middle income countries, but has never been validated in a pregnant population. In this longitudinal study, 95 pregnant women (mean age: 29.5+/-5.7 years; BMI: 26.9+/-5.0 kg/m2) completed the GPAQ and were asked to wear an accelerometer for 7 days at two time points during pregnancy (14-18 and 29-33 weeks gestation). There was a significant difference between accelerometry and GPAQ when measuring moderate-to-vigorous physical activity (MVPA) at 29-33 weeks gestation (16.6 vs 21.4 min/day; p = 0.02) as well as sedentary behaviour (SB) at both 14-18 weeks (457.0 vs 300 min/day; p < 0.01) and 29-33 weeks gestation (431.5 vs 300 min/day; p < 0.01). There was poor agreement between the GPAQ and accelerometry for both PA and SB at both time points (ICC: -0.05-0.08). Bland Altman plots indicated that the GPAQ overestimates PA by 14.8 min/day at 14 18 weeks and by 15.8 min/day at 29-33 weeks gestation. It underestimates SB by 127.5 min/day at 14-18 weeks and by 89.2 min/day at 29-33 weeks gestation. When compared to accelerometry, the GPAQ shows poor agreement and appears to overestimate PA and underestimate SB during pregnancy. PMID- 28552978 TI - Highly dynamic temporal changes of TSPY gene copy number in aging bulls. AB - The Y-chromosomal TSPY gene is one of the highest copy number mammalian protein coding gene and represents a unique biological model to study various aspects of genomic copy number variations. This study investigated the age-related copy number variability of the bovine TSPY gene, a new and unstudied aspect of the biology of TSPY that has been shown to vary among cattle breeds, individual bulls and somatic tissues. The subjects of this prospective 30-month long study were 25 Holstein bulls, sampled every six months. Real-time quantitative PCR was used to determine the relative TSPY copy number (rTSPY CN) and telomere length in the DNA samples extracted from blood. Twenty bulls showed an altered rTSPY CN after 30 months, although only 9 bulls showed a significant change (4 significant increase while 5 significant decrease, P<0.01). The sequential sampling provided the flow of rTSPY CN over six observations in 30 months and wide-spread variation of rTSPY CN was detected. Although a clear trend of the direction of change was not identifiable, the highly dynamic changes of individual rTSPY CN in aging bulls were observed here for the first time. In summary we have observed a highly variable rTSPY CN in bulls over a short period of time. Our results suggest the importance of further long term studies of the dynamics of rTSPY CN variablility. PMID- 28552979 TI - Correction: Bleeding Efficiency, Microbiological Quality and Oxidative Stability of Meat from Goats Subjected to Slaughter without Stunning in Comparison with Different Methods of Pre-Slaughter Electrical Stunning. AB - [This corrects the article DOI: 10.1371/journal.pone.0152661.]. PMID- 28552981 TI - Tetracycline does not directly inhibit the function of bacterial elongation factor Tu. AB - Understanding the molecular mechanism of antibiotics that are currently in use is important for the development of new antimicrobials. The tetracyclines, discovered in the 1940s, are a well-established class of antibiotics that still have a role in treating microbial infections in humans. It is generally accepted that the main target of their action is the ribosome. The estimated affinity for tetracycline binding to the ribosome is relatively low compared to the actual potency of the drug in vivo. Therefore, additional inhibitory effects of tetracycline on the translation machinery have been discussed. Structural evidence suggests that tetracycline inhibits the function of the essential bacterial GTPase Elongation Factor (EF)-Tu through interaction with the bound nucleotide. Based on this, tetracycline has been predicted to impede the nucleotide-binding properties of EF-Tu. However, detailed kinetic studies addressing the effect of tetracycline on nucleotide binding have been prevented by the fluorescence properties of the antibiotic. Here, we report a fluorescence based kinetic assay that minimizes the effect of tetracycline autofluorescence, enabling the detailed kinetic analysis of the nucleotide-binding properties of Escherichia coli EF-Tu. Furthermore, using physiologically relevant conditions, we demonstrate that tetracycline does not affect EF-Tu's intrinsic or ribosome stimulated GTPase activity, nor the stability of the EF-Tu*GTP*Phe-tRNAPhe complex. We therefore provide clear evidence that tetracycline does not directly impede the function of EF-Tu. PMID- 28552980 TI - Salt stress responsiveness of a wild cotton species (Gossypium klotzschianum) based on transcriptomic analysis. AB - Cotton is a pioneer of saline land crop, while salt stress still causes its growth inhibition and fiber production decrease. Phenotype identification showed better salt tolerance of a wild diploid cotton species Gossypium klotzschianum. To elucidate the salt-tolerant mechanisms in G. klotzschianum, we firstly detected the changes in hormones, H2O2 and glutathione (GSSH and GSH), then investigated the gene expression pattern of roots and leaves treated with 300 mM NaCl for 0, 3, 12, 48 h, and each time control by RNA-seq on the Illumina-Solexa platform. Physiological determination proved that the significant increase in hormone ABA at 48 h, while that in H2O2 was at 12 h, likewise, the GSH content decrease at 48 h and the GSSH content increase at 48 h, under salt stress. In total, 37,278 unigenes were identified from the transcriptome data, 8,312 and 6,732 differentially expressed genes (DEGs) were discovered to be involved in salt stress tolerance in roots and leaves, respectively. Gene function annotation and expression analysis elucidated hormone biosynthesis and signal transduction, reactive oxygen species (ROS), and salt overly sensitive (SOS) signal transduction related genes revealed the important roles of them in signal transmission, oxidation balance and ion homeostasis in response to salinity stress. This is a report which focuses on primary response to highly salty stress (upto 300 mM NaCl) in cotton using a wild diploid Gossypium species, broadening our understanding of the salt tolerance mechanism in cotton and laying a solid foundation of salt resistant for the genetic improvement of upland cotton with the resistance to salt stress. PMID- 28552982 TI - Decreased health-related quality of life in angiodysplasia patients: A cross sectional cohort. AB - Gastrointestinal angiodysplasias may cause anemia. Quality of life (QoL) is a valid patient reported outcome and improvement of QoL represents an important treatment goal. There is a paucity of data on the effect of angiodysplasias on QoL. Therefore, we aim to evaluate QoL and fatigue in angiodysplasia patients. We performed a cross-sectional patient-reported outcome study. We included patients with endoscopy proven angiodysplasias and measured QoL with Short Form-36 and level of fatigue using Multi Fatigue Inventory-20. We distinguished three subgroups of patients according to disease severity: 1) with treatment for angiodysplasias, 2) without treatment for angiodysplasias and 3) without recent hospital visits. The primary outcome was the physical component summary (PCS) score on the SF-36. Multivariate regression analysis were performed to correct for differences at baseline. A total of 144 patients completed the questionnaires (response rate = 62%; mean age 68 years; 65% men). Angiodysplasia patients have a significant lower PCS compared to the age-matched general population (respectively 41.0 vs. 43.3, p = 0.01). Disease severity is independently associated with a negative outcome on QoL (beta -4.6, 95% CI -7.8--1.3). Similarly patients score lower on multiple QoL subdomains, i.e. role limitations due to physical health problems (40.8 vs. 44.0, p<0.01), general health (39.7 vs. 47.3, p<0.01). Angiodysplasia patients are more fatigued compared to the general population (male 56.1 vs. 48.5, p<0.01, female 59.2 vs. 51.5, p = 0.01). In conclusion, angiodysplasias are independently associated with clinically significant impairments in multiple domains of health-related QoL, especially in measures of functional limitation. PMID- 28552983 TI - Recombinant human G6PD for quality control and quality assurance of novel point of-care diagnostics for G6PD deficiency. AB - BACKGROUND: A large gap for the support of point-of-care testing is the availability of reagents to support quality control (QC) of diagnostic assays along the supply chain from the manufacturer to the end user. While reagents and systems exist to support QC of laboratory screening tests for glucose-6-phosphate dehydrogenase (G6PD) deficiency, they are not configured appropriately to support point-of-care testing. The feasibility of using lyophilized recombinant human G6PD as a QC reagent in novel point-of-care tests for G6PD deficiency is demonstrated. METHODS: Human recombinant G6PD (r-G6PD) was expressed in Escherichia coli and purified. Aliquots were stored at -80 degrees C. Prior to lyophilization, aliquots were thawed, and three concentrations of r-G6PD (representing normal, intermediate, and deficient clinical G6PD levels) were prepared and mixed with a protective formulation, which protects the enzyme activity against degradation from denaturation during the lyophilization process. Following lyophilization, individual single-use tubes of lyophilized r-G6PD were placed in individual packs with desiccants and stored at five temperatures for one year. An enzyme assay for G6PD activity was used to ascertain the stability of r-G6PD activity while stored at different temperatures. RESULTS: Lyophilized r G6PD is stable and can be used as a control indicator. Results presented here show that G6PD activity is stable for at least 365 days when stored at -80 degrees C, 4 degrees C, 30 degrees C, and 45 degrees C. When stored at 55 degrees C, enzyme activity was found to be stable only through day 28. CONCLUSIONS: Lyophilized r-G6PD enzyme is stable and can be used as a control for point-of care tests for G6PD deficiency. PMID- 28552984 TI - Methodological approach to the ex vivo expansion and detection of T. cruzi specific T cells from chronic Chagas disease patients. AB - The discovery of T cell epitopes is essential not only for gaining knowledge about host response to infectious disease but also for the development of immune intervention strategies. In Chagas disease, given the size and complexity of the Trypanosoma cruzi proteome and its interaction with the host's immune system, the fine specificity of T cells has not been extensively studied yet, and this is particularly true for the CD4+ T cell compartment. The aim of the present work was to optimize a protocol for the generation of parasite-specific memory T cell lines, representative of their in vivo precursor populations and capable of responding to parasite antigens after long-term culture. Accordingly, peripheral blood mononuclear cells (PBMC) from both chronic asymptomatic and cardiac patients, and from non-infected individuals, underwent different in vitro culture and stimulation conditions. Subsequently, cells were tested for their capacity to respond against T. cruzi lysate by measuring [3H]-thymidine incorporation and interferon-gamma and GM-CSF secretion. Results allowed us to adjust initial T. cruzi lysate incubation time as well as the number of expansions with phytohemagglutinin (PHA) and irradiated allogeneic PBMC prior to specificity evaluation. Moreover, our data demonstrated that parasite specific T cells displayed a clear and strong activation by using T. cruzi lysate pulsed, Epstein Barr virus (EBV)-transformed human B lymphocytes (B-LCL), as autologous antigen presenting cells. Under these culture conditions, we generated a clone from an asymptomatic patient's memory CD4+ T cells which responded against epimastigote and trypomastigote protein lysate. Our results describe a culture method for isolating T. cruzi specific T cell clones from patients with Chagas disease, which enable the acquisition of information on functionality and specificity of individual T cells. PMID- 28552985 TI - Pathways from problems in adolescent family relationships to midlife mental health via early adulthood disadvantages - a 26-year longitudinal study. AB - Poor childhood family conditions have a long-term effect on adult mental health, but the mechanisms behind this association are unclear. Our aim was to study the pathways from problematic family relationships in adolescence to midlife psychological distress via disadvantages in early adulthood. Participants of a Finnish cohort study at the age of 16 years old in 1983 were followed up at ages 22, 32 and 42 years old (N = 1334). Problems in family relationships were measured with poor relationship with mother and father, lack of parental support in adolescent's individuation process and poor home atmosphere, and mental health was assessed using Kessler's Psychological Distress Scale (K10). We analyzed the indirect effects of adolescent family relations on mental health at age 42 years old via various disadvantages (somatic and psychological symptoms, relationship/marital status, low education/unemployment and heavy drinking) at ages 22 and 32 years old. Problematic adolescent family relationships were associated with midlife psychological distress in women (0.19; 95% CI 0.11, 0.26) and men (0.13; 95% CI 0.04, 0.21). However, after adjustment for adolescent psychological symptoms, the association was only significant for women (0.12; 95% CI 0.04, 0.20). Poor family relationships were associated with various disadvantages in early adulthood. The association from poor family relationships (16 years old) to psychological distress (42 years old) was in part mediated via psychological symptoms in women (0.03; 95% CI 0.01, 0.04) and men (0.02; 95% CI 0.00, 0.04) and in women also via heavy drinking in early adulthood (0.02; 95% CI 0.00, 0.03). Adolescent family relationships have a role in determining adult mental health. Targeted support addressing psychological well-being and hazardous drinking for adolescents with problematic family relationships might prevent disadvantages in early adulthood, and further prevent poor midlife mental health. PMID- 28552986 TI - Nutrient addition shifts plant community composition towards earlier flowering species in some prairie ecoregions in the U.S. Central Plains. AB - The distribution of flowering across the growing season is governed by each species' evolutionary history and climatic variability. However, global change factors, such as eutrophication and invasion, can alter plant community composition and thus change the distribution of flowering across the growing season. We examined three ecoregions (tall-, mixed, and short-grass prairie) across the U.S. Central Plains to determine how nutrient (nitrogen (N), phosphorus, and potassium (+micronutrient)) addition alters the temporal patterns of plant flowering traits. We calculated total community flowering potential (FP) by distributing peak-season plant cover values across the growing season, allocating each species' cover to only those months in which it typically flowers. We also generated separate FP profiles for exotic and native species and functional group. We compared the ability of the added nutrients to shift the distribution of these FP profiles (total and sub-groups) across the growing season. In all ecoregions, N increased the relative cover of both exotic species and C3 graminoids that flower in May through August. The cover of C4 graminoids decreased with added N, but the response varied by ecoregion and month. However, these functional changes only aggregated to shift the entire community's FP profile in the tall-grass prairie, where the relative cover of plants expected to flower in May and June increased and those that flower in September and October decreased with added N. The relatively low native cover in May and June may leave this ecoregion vulnerable to disturbance-induced invasion by exotic species that occupy this temporal niche. There was no change in the FP profile of the mixed and short-grass prairies with N addition as increased abundance of exotic species and C3 graminoids replaced other species that flower at the same time. In these communities a disturbance other than nutrient addition may be required to disrupt phenological patterns. PMID- 28552988 TI - Introducing a novel mushroom from mycophagy community with emphasis on biomedical potency. AB - Mushrooms have been prized by humankind as medicine and culinary wonder since antiquity. Though several species are ethnically valued; many prospective species are still being discovered. One such wild macrofungus has recently been discovered during subsequent field surveys in West Bengal, India which in turn exposed as a traditionally consumed popular myco-food. The collected taxon was found to be unique with regard to its morphological as well as genetical features. After detailed characterizations, the fungus was identified as a novel taxon belonging to the genus Russula (Russulaceae, Basidiomycota). Besides, the investigation was further extended in search of new functional ingredients and in this context, a water soluble crude polysaccharide rich extract (Rusalan) was isolated from dried basidiocarps. Accumulating evidences from GC-MS, HPTLC, FT-IR along with several spectrophotometric methods postulated that the fraction consisted mainly of carbohydrate in triple helical conformation, where glucose was the major monosaccharide mostly with beta-type glycosidic linkage. Conversely, Rusalan showed pronounced antioxidant activity in six in vitro assay systems with EC50 value ranging from 190-1328 MUg/ml concentration. The crude polysaccharide was also evaluated against six bacterial strains using microdilution method and the growth of Staphylococcus aureus and Bacillus subtilis were found to be inhibited effectively. In addition, immune-stimulatory assays demonstrated that Rusalan could evidently promote proliferation, induce phagocytosis, release NO, produce intracellular ROS and upregulate mRNA expression of iNOS, TNF-alpha, COX-2, as well as IL-6 genes in in mouse macrophage cells. Therefore, aim of the present study was not only to describe a new taxon to the world mycoflora but also to introduce a potent therapeutic agent that could be explored for food and pharmaceutical purposes. However, isolation of active component and in vivo studies need to be designed further. PMID- 28552987 TI - Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis. AB - BACKGROUND: Inhibition of programmed death-ligand 1 (PD-L1) with atezolizumab can induce durable clinical benefit (DCB) in patients with metastatic urothelial cancers, including complete remissions in patients with chemotherapy refractory disease. Although mutation load and PD-L1 immune cell (IC) staining have been associated with response, they lack sufficient sensitivity and specificity for clinical use. Thus, there is a need to evaluate the peripheral blood immune environment and to conduct detailed analyses of mutation load, predicted neoantigens, and immune cellular infiltration in tumors to enhance our understanding of the biologic underpinnings of response and resistance. METHODS AND FINDINGS: The goals of this study were to (1) evaluate the association of mutation load and predicted neoantigen load with therapeutic benefit and (2) determine whether intratumoral and peripheral blood T cell receptor (TCR) clonality inform clinical outcomes in urothelial carcinoma treated with atezolizumab. We hypothesized that an elevated mutation load in combination with T cell clonal dominance among intratumoral lymphocytes prior to treatment or among peripheral T cells after treatment would be associated with effective tumor control upon treatment with anti-PD-L1 therapy. We performed whole exome sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing (TCR seq) of pretreatment tumor samples as well as TCR-seq of matched, serially collected peripheral blood, collected before and after treatment with atezolizumab. These parameters were assessed for correlation with DCB (defined as progression-free survival [PFS] >6 months), PFS, and overall survival (OS), both alone and in the context of clinical and intratumoral parameters known to be predictive of survival in this disease state. Patients with DCB displayed a higher proportion of tumor-infiltrating T lymphocytes (TIL) (n = 24, Mann-Whitney p = 0.047). Pretreatment peripheral blood TCR clonality below the median was associated with improved PFS (n = 29, log-rank p = 0.048) and OS (n = 29, log rank p = 0.011). Patients with DCB also demonstrated more substantial expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after starting treatment (n = 22, Mann-Whitney p = 0.022). The combination of high pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in tumor tissue was strongly associated with poor clinical outcomes (n = 10, hazard ratio (HR) (mean) = 89.88, HR (median) = 23.41, 95% CI [2.43, 506.94], p(HR > 1) = 0.0014). Marked variations in mutation loads were seen with different somatic variant calling methodologies, which, in turn, impacted associations with clinical outcomes. Missense mutation load, predicted neoantigen load, and expressed neoantigen load did not demonstrate significant association with DCB (n = 25, Mann-Whitney p = 0.22, n = 25, Mann-Whitney p = 0.55, and n = 25, Mann-Whitney p = 0.29, respectively). Instead, we found evidence of time-varying effects of somatic mutation load on PFS in this cohort (n = 25, p = 0.044). A limitation of our study is its small sample size (n = 29), a subset of the patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory analyses performed, we intend for these results to be hypothesis-generating. CONCLUSIONS: These results demonstrate the complex nature of immune response to checkpoint blockade and the compelling need for greater interrogation and data integration of both host and tumor factors. Incorporating these variables in prospective studies will facilitate identification and treatment of resistant patients. PMID- 28552990 TI - Correction: Pre-breeding food restriction promotes the optimization of parental investment in house mice, Mus musculus. AB - [This corrects the article DOI: 10.1371/journal.pone.0173985.]. PMID- 28552989 TI - Structure of sweet potato (Ipomoea batatas) diversity in West Africa covaries with a climatic gradient. AB - Sub-Saharan agriculture has been identified as vulnerable to ongoing climate change. Adaptation of agriculture has been suggested as a way to maintain productivity. Better knowledge of intra-specific diversity of varieties is prerequisites for the successful management of such adaptation. Among crops, root and tubers play important roles in food security and economic growth for the most vulnerable populations in Africa. Here, we focus on the sweet potato. The Sweet potato (Ipomoea batatas) was domesticated in Central and South America and was later introduced into Africa and is now cultivated throughout tropical Africa. We evaluated its diversity in West Africa by sampling a region extending from the coastal area of Togo to the northern Sahelian region of Senegal that represents a range of climatic conditions. Using 12 microsatellite markers, we evaluated 132 varieties along this gradient. Phenotypic data from field trials conducted in three seasons was also obtained. Genetic diversity in West Africa was found to be 18% lower than in America. Genetic diversity in West Africa is structured into five groups, with some groups found in very specific climatic areas, e.g. under a tropical humid climate, or under a Sahelian climate. We also observed genetic groups that occur in a wider range of climates. The genetic groups were also associated with morphological differentiation, mainly the shape of the leaves and the color of the stem or root. This particular structure of diversity along a climatic gradient with association to phenotypic variability can be used for conservation strategies. If such structure is proved to be associated with specific climatic adaptation, it will also allow developing strategies to adapt agriculture to ongoing climate variation in West Africa. PMID- 28552992 TI - MicroRNA-200b is downregulated in colon cancer budding cells. AB - BACKGROUND: The microRNA-200 (miR-200) family acts as a major suppressor of epithelial-mesenchymal transition (EMT). Impaired miR-200 expression may lead to EMT initiation and eventually cancer dissemination. The presence of tumor budding cells (TBC) is associated with metastasis and poor prognosis, and molecular similarities to EMT indicate that these cells may reflect ongoing EMT. The aim of this study was to investigate the expression of miR-200b in budding cells of colon cancer and the relationship with the EMT-markers E-cadherin, beta-catenin and laminin-5gamma2. MATERIAL & METHODS: MiR-200b was investigated by in situ hybridization in 58 cases of stage II (n = 36) and III colon (n = 22) cancers with tumor budding. Expression of E-cadherin, beta-catenin and laminin-5gamma2 was examined by immunohistochemistry. A multiplex fluorescence assay combining miR-200b with cytokeratin and laminin-5gamma2 was employed on a subset of 16 samples. RESULTS: MiR-200b was downregulated in the TBC at the invasive front of 41 out of 58 (71%) cases. The decline was present in both mismatch satellite stable and instable adenocarcinomas. The majority of cases also showed loss of membranous E-cadherin and increased nuclear beta-catenin in the TBC, while laminin-5gamma2 expression was upregulated at the invasive front and in the tumor buds of approximately half the adenocarcinomas. However, the miR-200b decline was not statistically associated with the expression of any of the EMT-markers. The miR-200b decline was also documented by multiplex fluorescence. Fourteen out of fifteen cases showed a decrease in miR-200b expression in the majority of the TBC, but no obvious relationship between miR-200b and laminin-5gamma2 expression was observed. Conclusion: The findings support the assumption of a miR-200b related downregulation in colon cancer budding cells. Whether miR-200b expression may be of clinical significance awaits further studies. PMID- 28552991 TI - Exploring the molecular basis of adaptive evolution in hydrothermal vent crab Austinograea alayseae by transcriptome analysis. AB - Elucidating the genetic mechanisms of adaptation to the hydrothermal vent in organisms at genomic level is significant for understanding the adaptive evolution process in the extreme environment. We performed RNA-seq on four different tissues of a vent crab species, Austinograea alayseae, producing 725,461 unigenes and 134,489 annotated genes. Genes related to sensory, circadian rhythm, hormone, hypoxia stress, metal detoxification and immunity were identified. It was noted that in the degenerated eyestalk, transcription of phototransduction related genes which are important for retinal function was greatly reduced; three crucial neuropeptide hormones, one molt-inhibiting and two crustacean hyperglycemic hormone precursors were characterized with conserved domains; hypoxia-inducible factor 1 and two novel isoforms of metallothioneins in the vent crabs were discovered. An analysis of 6,932 orthologs among three crabs A. alayseae, Portunus trituberculutus and Eriocheir sinensis revealed 19 positive selected genes (PSGs). Most of the PSGs were involved in immune responses, such as crustins and anti-lipopolysaccharide factor, suggesting their function in the adaptation to environment. The characterization of the first vent crab transcriptome provides abundant resources for genetic and evolutionary studies of this species, and paves the way for further investigation of vent adaptation process in crabs. PMID- 28552993 TI - Rhinovirus infection results in stronger and more persistent genomic dysregulation: Evidence for altered innate immune response in asthmatics at baseline, early in infection, and during convalescence. AB - BACKGROUND: Rhinovirus (HRV) is associated with the large majority of virus induced asthma exacerbations in children and young adults, but the mechanisms remain poorly defined. METHODS: Asthmatics and non-asthmatic controls were inoculated with HRV-A16, and nasal epithelial samples were obtained 7 days before, 36 hours after, and 7 days after viral inoculation. RNA was extracted and subjected to RNA-seq analysis. RESULTS: At baseline, 57 genes were differentially expressed between asthmatics and controls, and the asthmatics had decreased expression of viral replication inhibitors and increased expression of genes involved in inflammation. At 36 hours (before the emergence of peak symptoms), 1329 genes were significantly altered from baseline in the asthmatics compared to 62 genes in the controls. At this time point, asthmatics lacked an increase in IL 10 signaling observed in the controls. At 7 days following HRV inoculation, 222 genes were significantly dysregulated in the asthmatics, whereas only 4 genes were dysregulated among controls. At this time point, the controls but not asthmatics demonstrated upregulation of SPINK5. CONCLUSIONS: As judged by the magnitude and persistence of dysregulated genes, asthmatics have a substantially different host response to HRV-A16 infection compared with non-asthmatic controls. Gene expression differences illuminate biologically plausible mechanisms that contribute to a better understanding of the pathogenesis of HRV induced asthma exacerbations. PMID- 28552994 TI - A versatile cell-penetrating peptide-adaptor system for efficient delivery of molecular cargos to subcellular destinations. AB - Cell penetrating peptides have long held great potential for delivery of biomolecular cargos for research, therapeutic and diagnostic purposes. They allow rapid, relatively nontoxic passage of a wide variety of biomolecules through the plasma membranes of living cells. However, CPP-based research tools and therapeutics have been stymied by poor efficiency in release from endosomes and a great deal of effort has been made to solve this 'endosomal escape problem.' Previously, we showed that use of a reversible, noncovalent coupling between CPP and cargo using calmodulin and a calmodulin binding motif allowed efficient delivery of cargo proteins to the cytoplasm in baby hamster kidney and other mammalian cell lines. The present report demonstrates the efficacy of our CPP adaptor scheme for efficient delivery of model cargos to the cytoplasm using a variety of CPPs and adaptors. Effective overcoming of the endosomal escape problem is further demonstrated by the delivery of cargo to the nucleus, endoplasmic reticulum and peroxisomes by addition of appropriate subcellular localization signals to the cargos. CPP-adaptors were also used to deliver cargo to myotubes, demonstrating the feasibility of the system as an alternative to transfection for the manipulation of hard-to-transfect cells. PMID- 28552995 TI - Is American Health Care Uniquely Inefficient? Evidence from Prescription Drugs. PMID- 28552996 TI - Recurrent Interstitial Pregnancy: a Review of the Literature. AB - Interstitial pregnancies account for 2-4 % of all ectopic pregnancies. Despite its rarity, various treatment options exist. However, no gold standard has yet been defined and data regarding recurrence of interstitial pregnancies in subsequent pregnancies after different treatments are sparse. This makes it very difficult to provide adequate patient counselling for treatment options with regards to the treatment-related risk of recurrence. The present literature review demonstrates that recurrent interstitial pregnancy is a rare condition and more likely when additional anatomy-related risk factors for ectopic pregnancies are present, such as hydrosalpinges, blocked tubes, endometriosis, fibroids or prior tubal ectopic pregnancies. Therefore, at first appearance and in absence of additional anatomy-related risk factors, methotrexate intravenously, intramuscularly or into the amnion may be the first choice. In case of anatomical risk factors, cornual wedge resection seems to be first choice. In case of recurrence, cornual wedge resection is particularly justified in patients with anatomical alterations of the salpinges. The role of conservative surgical treatments in recurrence as cornuotomy, salpingectomy, endoloop ligation and resection and curettage under laparoscopic guidance remains unclear due to sparse data. PMID- 28552997 TI - Implementation of the Recommendation to Vaccinate Pregnant Women against Seasonal Influenza - Vaccination Rates and Acceptance. AB - Introduction In Germany vaccination recommendations are revised annually and published by the Standing Committee on Vaccination at the Robert Koch Institute (STIKO). In 2010 the vaccination recommendations were amended to include the proposal that pregnant women in the 2nd trimester of pregnancy and pregnant women with additional underlying disease in the 1st trimester of pregnancy should be vaccinated against seasonal influenza. This paper reports on vaccination rates and the factors influencing them. Method A cross-sectional study was carried out in two level 1 perinatal centers in two different German federal states (Saarland and Rhineland-Palatinate) during the influenza seasons of 2012/2013 and 2013/2014. A total of 253 pregnant women were included in the study. Pregnant women were interviewed using a standardized, pre-tested questionnaire and asked whether they were aware of the recommendation to vaccinate against seasonal influenza and about possible factors which might influence their decision to be vaccinated. In addition, data from their vaccination certificates and pregnancy passports were evaluated. Results Overall, the records of only 19.5 % of the pregnant women showed that they had been vaccinated against influenza in pregnancy. Among the group of pregnant women who had a previous history of vaccinations against influenza the willingness to be vaccinated was high (43.3 %) and this figure was statistically significant. The vaccination rate was even higher (49.9 %) and even more statistically significant among pregnant women whose gynecologist or family physician had recommended that they should be vaccinated. In contrast, only 3.3 % of pregnant women who had not been given the recommendation to vaccinate by their physicians were vaccinated against influenza. Discussion The failure to recommend that pregnant women be vaccinated against influenza and women's lack of any previous experience of influenza vaccination were the main reasons for the inadequate influenza vaccination coverage in pregnancy. Conclusion One of the key points to increase the influenza vaccination rate is to intensify the counselling of the pregnant women through the gynecologist. PMID- 28552998 TI - Termination of Pregnancy for Medical Indications under Sec. 218a Para. 2 of the German Criminal Code - Real-life Data from the "Giebetaen Model". AB - Background Following the legal provisions on the termination of pregnancies in Art. 13 of the SFHG (Law on the Assistance for Pregnant Women and Families, passed on 27.07.1992, BGBl. I, p. 1398) the so-called embryopathic indication for termination was abandoned. Since then, sec. 218a para. 2 of the German Criminal Code (StGB) states that for late terminations, i.e., terminations after the 12th week of gestation post conception, the pregnant woman must be in exceptional distress "according to medical opinion". Method Between 01.05.2012 and 25.07.2016, a total of 160 pregnancy terminations were carried out in Giebetaen University Hospital under sec. 218a para. 2 StGB. The following data were obtained from the patients' files: age of the pregnant woman, number of pregnancies, type of fetal disease or malformation, time of diagnosis, medical and psychosocial counseling given to the pregnant woman, time of termination or delivery, type of termination, fetal gender. Results 160 pregnant women (mean age: 31.6 years) underwent termination of pregnancy between the 13th - 37th week of gestation. Chromosomal anomalies were diagnosed prenatally in 60 cases, and anomalies were diagnosed on ultrasonography in 100 cases, with the preponderance of cases presenting with developmental disorders of the central nervous system and cardiovascular system. Conclusion In addition to recording intrauterine fetal disorders, when pregnancies are terminated under sec. 218a para. 2 StGB, treating physicians are expected to give plausible reasons why "according to medical opinion" the pregnancy represents a danger to the life of the pregnant woman or of grave injury to her physical or mental health and enter these reasons in the patient's medical records. PMID- 28552999 TI - Development and Validation of a Questionnaire for the Assessment of Pelvic Floor Disorders and Their Risk Factors During Pregnancy and Post Partum. AB - Introduction The aim of this study was to develop and validate a questionnaire for the assessment of pelvic floor disorders, their symptoms and risk factors in pregnancy and after birth including symptom course, severity and impact on quality of life. Methods The validated German pelvic floor questionnaire was modified and a new risk factor domain developed. The questionnaire was initially completed by 233 nulliparous women in the third trimester of pregnancy and at six weeks (n = 148) and one year (n = 120) post partum. Full pyschometric testing was performed. The clinical course of symptoms and the influence of risk factors were analysed. Results Study participants had a median age of 31 (19-46) years. 63 % had spontaneous vaginal deliveries, 15 % operative vaginal deliveries and 22 % were delivered by caesarean section. Content validity: Missing answers never exceeded 4 %. Construct validity: The questionnaire distinguished significantly between women who reported bothersome symptoms and those who did not. Reliability: Cronbach's alpha values exceeded 0.7 for bladder, bowel and support function, and 0.65 for sexual function. The test-retest analysis showed moderate to almost complete concordance. The intraclass coefficients for domain scores (between 0.732 and 0.818) were in acceptable to optimal range. Reactivity: The questionnaire was able to track changes significantly with good effect size for each domain. Risk factors for pelvic floor symptoms included familial predisposition, maternal age over 35 years, BMI above 25, nicotine abuse, subjective inability to voluntarily contract the pelvic floor musculature and postpartum wound pain. Conclusion This pelvic floor questionnaire proved to be valid, reliable and reactive for the assessment of pelvic floor disorders, their risk factors, incidence and impact on quality of life during pregnancy and post partum. The questionnaire can be utilised to assess the course of symptoms and treatment effects using a scoring system. PMID- 28553000 TI - Psychosocial Stress, Course of Pregnancy and Pregnancy Outcomes in the Context of the Provision of Sexual Services. AB - Introduction There has been very little medical research into pregnancies which occur in the context of prostitution, even though the associated health risks for mother and child, e.g. violence or maternal drug abuse, are well known. The aim of this study was to compile and summarize what is known (inter-)nationally about this topic and identify key points of support as part of a uniform standard of healthcare in pregnancy. Material and Methods A selective search of the literature was done in Pubmed and Livivo/Medpilot and in the databases NIH, Cochrane, DARE, NHSEED and HTA on the factors influencing preterm delivery. Results There are no systematic studies on pregnancy risks in the context of sexual services. But there is data available on specific risk factors, for example the increased risk of prematurity associated with sexual/physical violence (OR = 1.28-4.7). The Prostitute Protection Act provides only limited protection for affected women, and statutory maternity protection regulations also have little impact as they require a formal contract of employment which rarely exists even in the context of legal prostitution. Conclusion Approximately 400 000 women are currently working as prostitutes in the Federal Republic of Germany. The number of unreported cases is high. Nevertheless, there is little concrete data available on the probable health risks if these women become pregnant. The existing laws that should offer protection fall short of the mark. There is a need for more research into the future implementation of the Prostitute Protection Act which should focus on health counselling, health promotion and additional protective legislation. Low-threshold healthcare services offered in the context of prenatal care could be an opportunity to improve care. PMID- 28553001 TI - Hypohidrotic Ectodermal Dysplasia: Breastfeeding Complications Due to Impaired Breast Development. AB - Background X-linked hypohidrotic ectodermal dysplasia (XLHED), the most common form of ectodermal dysplasia, is caused by mutations in the gene EDA. While only affected men develop the full-blown clinical picture, females who are heterozygous for an EDA mutation often also show symptoms such as hypodontia, hypotrichosis and hypohidrosis. These women may also suffer from malformations of the mammary gland which represent not just a cosmetic problem but can limit their breastfeeding capability. This paper summarizes the findings of the first systematic study on the impact of hypohidrotic ectodermal dysplasia on breastfeeding. Patients Thirty-eight adult female members of the German-Swiss Austrian ectodermal dysplasia patient support group participated in a structured interview; most of them also agreed to a photodocumentation of their mammary region. Thirty-one women carried mutations in EDA (Group A) and seven were affected by other forms of hypohidrotic ectodermal dysplasia (Group B). Results 39 % of the women of Group A reported that their breasts were of different size or entirely absent on one side. In Group B, 86 % of the women reported differently sized or even absent breasts; two of these women lacked both breasts entirely. Most women described their nipples as exceptionally flat. 10 % of the women of Group A had more than two nipples. The high percentage of deviations from the norm was confirmed in the photodocumentation. Both groups had few or no sebaceous glands of Montgomery in the areolar region. Around 80 % of interviewed women had children and had attempted to breastfeed their first child. 67 % of the mothers in Group A had had difficulty in breastfeeding their infants and generally attributed this difficulty to their flat nipples. All of the mothers in Group B reported difficulties in breastfeeding; 60 % had not been able to breastfeed their first child. Conclusion Mothers with hypohidrotic ectodermal dysplasia very often have difficulty in breastfeeding because of their impaired breast development. This causal relationship needs to be taken into account in lactation counseling. PMID- 28553002 TI - Full Characterization of Multiphase, Multimorphological Kinetics in Flow-Induced Crystallization of IPP at Elevated Pressure. AB - Understanding the complex crystallization behavior of isotactic polypropylene (iPP) in conditions comparable to those found in polymer processing, where the polymer melt experiences a combination of high shear rates and elevated pressures, is key for modeling and therefore predicting the final structure and properties of iPP products. Coupling a unique experimental setup, capable to apply wall shear rates similar to those experienced during processing and carefully control the pressure before and after flow is imposed, with in situ X ray scattering and diffraction techniques (SAXS and WAXD) at fast acquisition rates (up to 30 Hz), a well-defined series of short-term flow experiments are carried out using 16 different combinations of wall shear rates (ranging from 110 to 440 s-1) and pressures (100-400 bar). A complete overview on the kinetics of structure development during and after flow is presented. Information about shish formation and growth of alpha-phase parents lamellae from the shish backbones is extracted from SAXS; the overall apparent crystallinity evolution, amounts of different phases (alpha, beta, and gamma), and morphologies developing in the shear layer (parent and daughter lamellae both in alpha and gamma phase) are fully quantified from the analysis of WAXD data. Both flow rate and pressure were found to have a significant influence on the nucleation and the growth process of oriented and isotropic structures. Flow affects shish formation and the growth of alpha-parents; pressure acts on relaxation times, enhancing the effect of flow, and (mainly) on the growth rate of gamma-phase. The remarkably high amount of gamma-lamellae found in the oriented layer strongly indicates the nucleation of gamma directly from the shish backbone. All the observations were conceptually in agreement with the flow-induced crystallization model framework developed in our group and represent a unique and valuable data set that will be used to further validate and implement our numerical modeling, filling the gap for quantitatively modeling crystallization during complicated processing operations like injection molding. PMID- 28553003 TI - Skeletal and Appendage Diversity as Design Elements in the Synthesis of a Discovery Library of Nonaromatic Polycyclic 5-Iminooxazolidin-2-ones, Hydantoins, and Acylureas. AB - Amino acid-derived cross-conjugated trienes were used as a starting point for the synthesis of a discovery library of over 200 polycyclic 5-iminooxazolidin-2-ones, hydantoins, and acylureas. The main feature of this library synthesis is a triple branching strategy which provides efficient access to five skeletally diverse scaffolds. In addition, four sets of building blocks were applied in both a front end and a back end diversification strategy. Multiple fused rings were obtained by cyclization of diamides with phosgene and stereoselective Diels-Alder reactions with maleimides. The 5-iminooxazolidin-2-one scaffold was rearranged into the isomeric hydantoin scaffold through a sequence of ring opening and ring closing reactions. PMID- 28553004 TI - Relationships Among Caregiving, Income, Gender, and Health: A Cross-Sectional Examination of a Representative Sample of Older Americans. AB - Although there is substantial evidence to support the impact of burden on caregivers, few studies have compared caregivers to their non-caregiving counterparts on the basis of health and wellbeing outcomes. This study examines the relationship between caregiving and health, and whether other factors may have stronger influence on well-being measures. Using a nationally representative sample of older adults in the United States (N=3,005), this study examines relationships between caregiving status, gender, and income, and nine outcomes (self-rated physical and mental health, time since seeing a doctor, time since most recent pap smear or prostate-specific antigen [PSA] test, depression, loneliness, stress, anxiety), using logistic and linear regression models. Results support that paradoxically, caregiving was associated with increased likelihood of PSA test in male caregivers, although data also indicated higher levels of anxiety and stress, as might be expected. Income was associated with eight of nine outcomes, and gender predicted depression, anxiety, stress, and self-rated mental health. The study highlighted the importance of psychosocial stressors, such as income and gender on the health outcomes of older adults who may be caregiving. Considering complexity of unique experience is necessary to accurately assess vulnerability to poor mental health or health related outcomes. PMID- 28553005 TI - Phosphonium ionic liquids as extractants for recovery of ruthenium(III) from acidic aqueous solutions. AB - The aim of this work is to investigate extraction of ruthenium(III) from acidic aqueous solutions with phosphonium ionic liquids such as trihexyl(tetradecyl)phosphonium chloride (Cyphos IL 101), trihexyl(tetradecyl)phosphonium bis(2,4,4-trimethylpentyl)phosphinate (Cyphos IL 104) and tributyl(tetradecyl)phosphonium chloride (Cyphos IL 167) as extractants. The influence of HCl content in the feed solutions on extraction of Ru(III) was investigated. The research was performed for model solutions containing Ru(III) and a mixture of waste solutions containing Ru(III) and Rh(III). In addition, investigation of the type of extractant and its concentration in the organic phase on extraction of Ru(III) was carried out. Co-extraction of protons to the organic phase was determined. To the best of our knowledge, the extraction of Ru(III) with Cyphos IL 167 (tributyl(tetradecyl)phosphonium chloride) as an extractant has not yet been described in the scientific literature. PMID- 28553006 TI - Determination of mycotoxins, alkaloids, phytochemicals, antioxidants and cytotoxicity in Asiatic ginseng (Ashwagandha, Dong quai, Panax ginseng). AB - Mycotoxins and selected hazardous alkaloids in the medicinal plants (Panax ginseng, Angelica sinensis, and Withania somnifera) and dietary supplements were determined. Purine alkaloids were found in majority of samples; however, isoquinoline alkaloids were less abundant than indole. The predominant alkaloids appear to be caffeine (purine group), harman (indole group) and berberine (isoquinoline). Examined medicinal plants and dietary supplements were contaminated by mycotoxins (especially ochratoxin A 1.72-5.83 ug kg-1), and many species of mold (e.g. Cladosporium, Eurotium, Aspergillus, Rhizopus, Penicillium). MTT cytotoxicity tests revealed that plant and supplements extracts exhibited medium or high cytotoxicity (only Dong quai-low). Moreover, antioxidant activity, total phenolics content and selected phytochemicals were analyzed by spectrophotometric and chromatographic methods. Quercetin and rutin were predominant flavonols (1.94-9.51 and 2.20-7.28 mg 100 g-1, respectively). Analysis of phenolic acids revealed-gallic acid, as the most abundant, except Panax ginseng, where ferulic acid was prevailing. The results were analyzed by chemometric methods (cluster analysis, ANOVA). PMID- 28553007 TI - Histology and ultrastructure of the integumental chromatophores in tokay gecko (Gekko gecko) (Linnaeus, 1758) skin. AB - This paper describes the relationship between the arrangement of dermal chromatophores in tokay gecko (Gekko gecko) skin and the formation of wild-type colouration, with emphasis on the ultrastructure of chromatophores. The samples of the tokay gecko skin were collected from wild-type colouration adult specimens. Morphology and distribution of chromatophores was determined by using light microscopy and transmission electron microscopy. The present study revealed that orange/red coloured skin of G. gecko contained erythrophores, which were located under basement membrane, and usually comprised deeper situated iridophores and melanophores which were form single layer with iridophores or were occupying the deepest region of dermis. In orange/red coloured skin, erythrophores were the predominant chromatophores. However in blue areas these cells occurred in small numbers or were not noticed at all. In blue pigmented areas predominated iridophores and melanophores. Iridophores were found just under basement membrane, but this superficial location of iridophores occured only in areas without erythrophores. Distribution of erythrophores, melanophores, and iridophores determines the characteristic blue colour of the tokay gecko skin with orange/red dots on the whole body. PMID- 28553008 TI - Song duration mediates responses of territory owner in a songbird species with a small song repertoire. AB - Song is a sexually selected trait that is involved in mate attraction and territory defence in birds. Songs may convey information about different male quality components. They are flexible in terms of frequency, amplitude, and duration. Although changes in song duration are common, the function of this behaviour has been studied less strongly. It is known that song duration changes within a singing bout and may provide information about aggressive motivation. We tested whether the elongation and shortening of songs affects the responses of territorial ortolan bunting males to neighbour song playback. If changing song duration signals level of aggressiveness, then songs differing solely in duration may elicit behavioural responses of different strength. We performed two tests with different males assigned to two experimental groups and measured approaching and vocal response. In Experiment 1, we tested 18 males, which responded to the playbacks of elongated and normal (control) neighbour songs. In Experiment 2, we tested 17 males, which responded to the playbacks of shortened and normal (control) neighbour songs. Males responded significantly stronger to longer songs in both experiments as measured by the approach variable. Vocal response was not affected by treatment, but it was affected by the order of playback presentation. Our results indicate that song duration might be used for signalling current aggressive motivation during close interactions with rivals. PMID- 28553009 TI - A novel strategy to escape a poor habitat: red-necked grebes transfer flightless young to other ponds. AB - Animals confronted with the threat of the death of their offspring may exhibit unusual and risk-prone behaviours. Grebes (Podicipediformes) are water birds which cannot effectively walk, thus unfledged young are assumed to be unable to depart from their natal ponds by land. We provide evidence that red-necked grebes Podiceps grisegena, breeding on ponds with scarce food resources, transferred their flightless young (2-4 weeks old) to other, unconnected ponds by land or air. Although a large proportion of breeding grebes in the study area nested on food-poor fish ponds acting as ecological traps, where they suffered significant brood losses, brood movements to new ponds accounted for only 3.3% of such breeding attempts. The infrequency of this strategy may be explained by the lack of suitable territories in close proximity and the high risk of predation or fatal injury. The means of chick transfer remains unclear; the chicks may have followed or been carried by parents shuffling across the pond levees; alternatively, parents may have carried the young on their backs in flight. Our findings indicate that red-necked grebes assess the current level of resources available for chicks and may adopt novel and risky strategies to escape total brood failure. PMID- 28553010 TI - Parent Management of Organization, Time Management, and Planning Deficits among Adolescents with ADHD. AB - Organization, Time Management, and Planning (OTP) problems are a key mechanism of academic failure for adolescents with ADHD. Parents may be well positioned to promote remediation of these deficits; yet, almost nothing is known about OTP management behaviors among parents of middle and high school students with ADHD. In a sample of 299 well-diagnosed adolescents with ADHD, a measure of parental OTP management was psychometrically validated. Latent Class Analysis was conducted to detect distinct patterns of parental OTP management and yielded four unique classes: Parental Control (18.7 %), Parent-Teen Collaboration (20.4 %), Homework Assistance (20.4 %), and Uninvolved (40.5 %). Logistic Regression analyses indicated that maladaptive parental OTP strategies were related to higher levels of parent and adolescent psychopathology. Parental OTP management did not relate to current adolescent OTP skills or GPA, indicating that parents did not select OTP management strategies in immediate response to adolescent functioning. Implications for parent-directed intervention are discussed. PMID- 28553011 TI - Computational Fluid Dynamics-Discrete Element Method (CFD-DEM) Study of Mass Transfer Mechanisms in Riser Flow. AB - We report a computational fluid dynamics-discrete element method (CFD-DEM) simulation study on the interplay between mass transfer and a heterogeneous catalyzed chemical reaction in cocurrent gas-particle flows as encountered in risers. Slip velocity, axial gas dispersion, gas bypassing, and particle mixing phenomena have been evaluated under riser flow conditions to study the complex system behavior in detail. The most important factors are found to be directly related to particle cluster formation. Low air-to-solids flux ratios lead to more heterogeneous systems, where the cluster formation is more pronounced and mass transfer more influenced. Falling clusters can be partially circumvented by the gas phase, which therefore does not fully interact with the cluster particles, leading to poor gas-solid contact efficiencies. Cluster gas-solid contact efficiencies are quantified at several gas superficial velocities, reaction rates, and dilution factors in order to gain more insight regarding the influence of clustering phenomena on the performance of riser reactors. PMID- 28553012 TI - Does Aggregated Returns Disclosure Increase Portfolio Risk Taking? AB - Many experiments have found that participants take more investment risk if they see returns less frequently, see portfolio-level returns (rather than each individual asset's returns), or see long-horizon (rather than one-year) historical return distributions. In contrast, we find that such information aggregation treatments do not affect total equity investment when we make the investment environment more realistic than in prior experiments. Previously documented aggregation effects are not robust to changes in the risky asset's return distribution or the introduction of a multi-day delay between portfolio choice and return realizations. PMID- 28553013 TI - The Effect of Having Aggressive Friends on Aggressive Behavior in Childhood: Using Propensity Scores to Strengthen Causal Inference. AB - This study uses propensity scores to statistically approximate the causal effect of having aggressive friends on aggressive behavior in childhood. Participants were 1,355 children (53% girls; 31% minority) in 97 third and fifth grade classrooms enrolled in the Classroom Peer Ecologies Project. Propensity scores were calculated to control for the impact of 21 relevant confounder variables related to having aggressive friendships and aggressive behavior. The 21 variables included demographic, social, and behavioral characteristics measured at the beginning of the school year. Presence/absence of aggressive friends was measured in the middle of the school year, and aggressive behavior was measured at the end of the school year. Results indicate a significant effect of having one or more aggressive friends on children's aggressive behavior above and beyond the effects of the 21 demographic, social, and behavioral variables. The propensity score model is compared to two other models of peer influence. The strengths and practical challenges of using propensity score analysis to study peer influence are discussed. PMID- 28553015 TI - Interluekin-35 in Asthma and Its Potential as an Effective Therapeutic Agent. AB - Interleukin- (IL-) 35 is a member of the IL-12 cytokine family and a heterodimeric protein formed by Epstein-Barr-induced gene 3 (EBI3) and IL-12p35. Emerging evidence shows that IL-35 is a key player in the regulation of cellular communication, differentiation, and inflammation. Altered IL-35 expression has been found in disease conditions such as cancer, rheumatoid arthritis, and, more recently, asthma. In cancer, IL-35 is involved in the regulation of tumorigenesis, cancer progression, and metastasis. In rheumatoid arthritis, IL-35 acts as a negative regulator of inflammation. Similarly, IL-35 also appears to suppress allergic inflammation in asthma. In an in vivo murine model of asthma, transfer of adenovirus-mediated IL-35 markedly reduced the degree of airway hyperresponsiveness (AHR) and inflammatory cell infiltration. Many studies have shown the involvement of IL-35 in a number of aspects of allergic inflammation, such as eosinophil and neutrophil recruitment as well as inhibition of inflammatory mediators of the Th2 subtype. However, the exact molecular mechanisms underlying the role of IL-35 in human asthma have yet to be fully elucidated. This review describes the current evidence regarding the role of IL 35 in the pathophysiology of asthma and evaluates the potential of IL-35 as a biomarker for airway inflammation and a therapeutic target for the treatment of asthma. PMID- 28553014 TI - Paracoccidioides Spp.: Virulence Factors and Immune-Evasion Strategies. AB - Paracoccidioides spp. are dimorphic fungal pathogens responsible for one of the most relevant systemic mycoses in Latin America, paracoccidioidomycosis (PCM). Their exact ecological niche remains unknown; however, they have been isolated from soil samples and armadillos (Dasypus novemcinctus), which have been proposed as animal reservoir for these fungi. Human infection occurs by inhalation of conidia or mycelia fragments and is mostly associated with immunocompetent hosts inhabiting and/or working in endemic rural areas. In this review focusing on the pathogen perspective, we will discuss some of the microbial attributes and molecular mechanisms that enable Paracoccidioides spp. to tolerate, adapt, and ultimately avoid the host immune response, establishing infection. PMID- 28553016 TI - Urinary Levels of IL-1beta and GDNF in Preterm Neonates as Potential Biomarkers of Motor Development: A Prospective Study. AB - Objectives. To evaluate the association between inflammatory biomarkers, neurotrophic factors, birth conditions, and the presence of motor development abnormalities in preterm neonates. Methods. Plasma and urinary levels of cytokines (IL-1beta, IL-6, IL-10, TNF, and IL-12p70), chemokines (CXCL8/IL-8, CCL2/MCP-1, CCL5/RANTES, CXCL10/IP-10, and CXCL9/MIG), and neurotrophic factors (BDNF and GDNF) were evaluated in 40 preterm neonates born between 28 and 32 incomplete weeks of gestation, at four distinct time points: at birth (umbilical cord blood) (T0), at 48 (T1), at 72 hours (T2), and at 3 weeks after birth (T3). Biomarkers levels were compared between different time points and then associated with Test of Infant Motor Performance (TIMP) percentiles. Results. Maternal age, plasma, and urinary concentrations of inflammatory molecules and neurotrophic factors were significantly different between groups with normal versus lower than expected motor development. Higher levels of GDNF were found in the group with lower than expected motor development, while IL-1beta and CXCL8/IL-8 values were higher in the group with typical motor development. Conclusion. Measurements of cytokines and neurotrophic factors in spot urine may be useful in the follow-up of motor development in preterm neonates. PMID- 28553018 TI - 'Civilising' Deaf people in Tibet and Inner Mongolia: governing linguistic, ethnic and bodily difference in China. AB - The People's Republic of China is home to over 20 million d/Deaf and hard-of hearing people, many among them belonging to ethnic minorities. Drawing on ethnographic fieldwork in two minority regions, the Tibet Autonomous Region and the Inner Mongolian Autonomous Region, this article comparatively discusses findings on sign language use, education and state welfare policies. The situation in these domains is analysed through the framework of the 'civilising project', coined by Harrell, and its impacts on the d/Deaf and hard-of-hearing among ethnic minorities are shown. For instance, through the promotion of Chinese and Chinese Sign Language over and above the use of local sign and written languages as well as through education and the medicalisation of disabilities. PMID- 28553019 TI - Challenging Times for Public Health Towards Attaining Sustainable Development Goals. PMID- 28553017 TI - Capsular Polysaccharide is a Main Component of Mycoplasma ovipneumoniae in the Pathogen-Induced Toll-Like Receptor-Mediated Inflammatory Responses in Sheep Airway Epithelial Cells. AB - Mycoplasma ovipneumoniae (M. ovipneumoniae) is characterized as an etiological agent of primary atypical pneumonia that specifically infects sheep and goat. In an attempt to better understand the pathogen-host interaction between the invading M. ovipneumoniae and airway epithelial cells, we investigated the host inflammatory responses against capsular polysaccharide (designated as CPS) of M. ovipneumoniae using sheep bronchial epithelial cells cultured in an air-liquid interface (ALI) model. Results showed that CPS derived from M. ovipneumoniae could activate toll-like receptor- (TLR-) mediated inflammatory responses, along with an elevated expression of nuclear factor kappa B (NF-kappaB), activator protein-1 (AP-1), and interferon regulatory factor 3 (IRF3) as well as various inflammatory-associated mediators, representatively including proinflammatory cytokines, such as IL1beta, TNFalpha, and IL8, and anti-inflammatory cytokines such as IL10 and TGFbeta of TLR signaling cascade. Mechanistically, the CPS induced inflammation was TLR initiated and was mediated by activations of both MyD88-dependent and MyD88-independent signaling pathways. Of importance, a blockage of CPS with specific antibody led a significant reduction of M. ovipneumoniae-induced inflammatory responses in sheep bronchial epithelial cells. These results suggested that CPS is a key virulent component of M. ovipneumoniae, which may play a crucial role in the inflammatory response induced by M. ovipneumoniae infections. PMID- 28553020 TI - Zika Virus: Can India Win the Fight? AB - Zika virus is an emerging arbovirus of public health importance transmitted by Aedes mosquito which also transmits dengue, chikungunya and yellow fever. The disease has been spreading at an alarming rate in Africa, Pacific Islands, and the Americas. Given the expansion of environments where mosquitoes can live and breed, facilitated by urbanization and globalization, there is potential for major urban epidemics of Zika virus disease to occur globally. World Health Organization (WHO) has declared Zika virus disease to be a Public Health Emergency of International Concern (PHEIC). Our failed attempts to control dengue epidemics in the past call for concern and we need to be to prepared to fight Zika virus before it arrives at our doors. PMID- 28553021 TI - Improving Access to Institutional Delivery through Janani Shishu Suraksha Karyakram: Evidence from Rural Haryana, North India. AB - BACKGROUND: In India, Janani Shishu Suraksha Karyakaram (JSSK) was launched in the year 2011 to assure cashless institutional delivery to pregnant women, including free transport and diet. OBJECTIVE: To assess the impact of JSSK on institutional delivery. MATERIALS AND METHODS: A record review was done at the primary health care facility in Faridabad district of Haryana from August 2010 to March 2013. Focus group discussion/ informal interviews were carried out to get an insight about various factors determining use / non-use of health facilities for delivery. RESULTS: Institutional delivery increased by almost 2.7 times (197 Vs 537) after launch of JSSK (p < 0.001). For institutional deliveries, the most important facilitator as well as barrier was identified as ambulance service under JSSK and pressure by elders in the family respectively. CONCLUSIONS: JSSK scheme had a positive impact on institutional deliveries. It should be supported with targeted intervention designed to facilitate appropriate decision-making at family level in order to address barriers to institutional delivery. PMID- 28553022 TI - From Policy to Practice: Lessons from Karnataka about Implementation of Tobacco Control Laws. AB - BACKGROUND: Tobacco use accounts for eight to nine lakh adult deaths annually in India. India enacted a national legislation "Cigarettes and Other Tobacco Products Act, 2003" (COTPA) to protect health of non-smokers and reduce tobacco consumption. However, even a decade after enacting this law, its implementation remains suboptimal and variable across the Indian states. Karnataka has shown leadership on this front by enacting a state law and implementing COTPA at (sub-) district levels. We, therefore, aim to analyze COTPA implementation processes in Karnataka to understand how COTPA can be effectively implemented. METHODS: We developed a case study of COTPA implementation in Karnataka using reports from health, police, education, and transport departments as well as government orders and media reports related to COTPA. We analyzed these data to map and understand the role played by the government agencies in COTPA implementation. We used the proportion of the districts reporting COTPA violations, the number of COTPA violations cases reported, and the proportion of schools reporting compliance with COTPA as proxy measures for COTPA implementation. RESULTS: We found that five government agencies (police, education, health, transport, and urban development) played a major role in COTPA implementation. All the police districts reported COTPA violations with 59,594 cases in a year (April 2013-March 2014). Three of the district anti-tobacco cells and two of the transport divisions reported 1130 and 14,543 cases of COTPA violations, respectively, in the same year. In addition, 84.7% of schools complied with signage requirements of COTPA. COTPA reporting was made part of the reporting systems within health, police, and education departments. The health department created awareness on tobacco harms and COTPA. CONCLUSIONS: COTPA implementation in Karnataka was made possible through integrating COTPA implementation within structure/functions of five government agencies. PMID- 28553023 TI - Process Evaluation of Communitisation Programme in Public Sector Health Facilities, Mokokchung District, Nagaland, 2015. AB - BACKGROUND: Public sector health facilities were poorly managed due to a history of conflict in Nagaland, India. Government of Nagaland introduced "Nagaland Communitisation of Public Institutions and Services Act" in 2002. Main objectives of the evaluation were to review the functioning of Health Center Managing Committees (HCMCs), deliver health services in the institutions managed by HCMC, identify strengths as well as challenges perceived by HCMC members in the rural areas of Mokokchung district, Nagaland. MATERIALS AND METHODS: The evaluation was made using input, process and output indicators. A doctor, the HCMC Chairman and one member from each of the three community health centers (CHC) and four primary health centers (PHC) were surveyed using a semi-structured questionnaire and an in-depth interview guide. Proportions for quantitative data were computed and key themes from the same were identified. RESULTS: Overall; the infrastructure, equipment and outpatient/inpatient service availability was satisfactory. There was a lack of funds and shortage of doctors, drugs as well as laboratory facilities. HCMCs were in place and carried out administrative activities. HCMCs felt ownership, mobilized community contributions and managed human resources. HCMC members had inadequate funds for their transport and training. They faced challenges in service delivery due to political interference and lack of adequate human, material, financial resources. CONCLUSIONS: Communitisation program was operational in the district. HCMC members felt the ownership of health facilities. Administrative, political support and adequate funds from the government are needed for effective functioning of HCMCs and optimal service delivery in public sector facilities. PMID- 28553024 TI - Nutritional Status of Preschool Children in Andaman and Nicobar Islands and Food Insecurity, Food Groups, and Nutrient Consumption among Population. AB - BACKGROUND: Childhood undernutrition is a public health concern in India. But on such a serious issue, there are no data available from the Union Territory of Andaman and Nicobar (A and N) Islands. OBJECTIVES: Present study was designed to know the prevalence of food insecurity, to estimate food group and nutrient intake among the community, and undernutrition and clinical signs of micronutrient deficiency among the preschool children of A and N islands. MATERIALS AND METHODS: Multistage random sampling was followed to select the households containing children aged 6-59 months. In the selected households' sociodemographic particulars, Household Food Insecurity Access Scale (HFIAS), among preschoolers the weight and height were recorded along with the documentation of clinical signs of micronutrient deficiency, morbidities suffered over previous fortnight, and measurement of hemoglobin. Diet survey was carried out in every fourth household. RESULTS: A total of 1259 preschoolers residing in 1082 households were examined, HFIAS was measured in 710 households in Andaman group of islands and diet survey was conducted in 290 households. The prevalence of undernutrition was around 27%, stunting was 36%, and anemia was around 81%. Undernutrition and anemia prevalence were significantly low among Nicobarese children. After adjusting for all the determinants, tribal in domicile had favorable outcome [odds ratio (OR): 0.28 (0.18, 0.43)], while below poverty line family had adverse outcome on undernutrition [OR: 1.72 (1.20, 2.46)]. CONCLUSION: Though the prevalence of undernutrition is relatively low in the islands, but high prevalence of anemia needs to be addressed. Nicobarese children fare better in almost all indicators of nutritional well-being except for stunting. KEY MESSAGES: The prevalence of undernutrition is relatively low in Andaman and Nicobar Islands. Nicobarese children fare better in almost all indicators of nutritional well-being. However high prevalence of stunting among Nicobarese children needs further research with appropriate methodology. High prevalence of anemia in the islands needs to be addressed. A socially and culturally specific intervention strategy needs to be envisaged. PMID- 28553025 TI - Depression, Anxiety and Stress Among Higher Secondary School Students of Imphal, Manipur. AB - INTRODUCTION: Adolescence is a stressful period due to physical, psychological, sexual changes, and the presence of psychiatric disorders such as depression, anxiety, and stress at this stage of life is a matter of concern. OBJECTIVES: The objectives of the study were to determine the prevalences of depression, anxiety, and stress among higher secondary school students of Imphal and to determine the association between depression, anxiety, and stress and selected variables such as gender, standard, and religion. MATERIALS AND METHODS: From September 2014 to October 2014, a cross-sectional study was conducted among higher secondary school students of Imphal. The sample size was calculated to be 750. Seven schools were randomly selected, and all the students in that school were enrolled in the study. The study tool used was a questionnaire containing DASS (Depression Anxiety Stress Scale) and sociodemographic characteristics. RESULTS: The prevalences of depression, anxiety, and stress among 830 valid respondents were 19.5%, 24.4%, and 21.1%, respectively. In total, 81.6% of the respondents had at least one of the studied disorders and 34.7% of the respondents had all the three negative states. The prevalences of depression, anxiety, and stress were high among females and were significant for anxiety (P = 0.00) and stress (P = 0.04). The prevalences of depression and stress were significantly higher among 12th standard students with P-values of 0.00 and 0.02. CONCLUSION: The prevalences of depression, anxiety, and stress were high with anxiety and stress significantly higher among females, whereas prevalences of depression and stress were significantly higher among 12th standard students. More studies are recommended to determine the factors leading to these mental disorders. PMID- 28553026 TI - A Score-based Performance Assessment of Maternal and Child Health Services Provided by USHA of Rajkot City. AB - BACKGROUND: Urban Social Health Activists (USHAs) are the grass root health care workers of urban areas. There are 290 USHAs distributed in various Urban Health Centers (UHCs) of Rajkot city. OBJECTIVES: To compare the (i) effectiveness of the training received by the USHAs on their knowledge and counseling skills (ii) knowledge and counseling skills of USHAs on the awareness and utilization of Maternal and Child Health (MCH) care services by their beneficiaries. METHODS: This cross-sectional study involved 32 USHAs and 416 beneficiaries served by the same USHAs. 32 USHAs serving in the same field practice area for more than two years were randomly selected. The beneficiaries were those mothers who had a child between 1-2 years age, and who had availed their antenatal and postnatal services in the same area. A scoring system was used to assess the knowledge and counseling skills of the USHAs and the knowledge and utilization of services by their beneficiaries. RESULTS: The utilization of health services was significantly more in the beneficiaries who were serviced by USHAs having comparatively better knowledge (72.7% vs. 35.3%) and counseling skills (62.2% vs. 30.6%). The median score for knowledge (41 vs. 30) and counseling skills (20 vs. 16) of the USHAs was found to be more (P < 0.05) in those who had undertaken induction training. CONCLUSIONS: Induction training helped the USHAs to improve their knowledge and counseling skills. Utilization of MCH services was more in those areas served by USHAs having better knowledge and counseling skills. PMID- 28553027 TI - A Ten Year Audit of Maternal Mortality: Millennium Development Still a Distant Goal. AB - OBJECTIVE: To assess various causes of maternal mortality over a ten year period. DESIGN: Retrospective audit of hospital case records. SETTING: Tertiary care hospital. POPULATION: Pregnant women who expired in the premises of GTB Hospital. MATERIALS AND METHODS: A retrospective audit of case records of maternal deaths was conducted for a ten year period (January 2005 to December 2014). RESULTS: There were a total of 647 maternal deaths out of 1,16,641 live births. Sixty eight percent (n = 445) of women were aged 21-30 years, while 10.5% (n = 68) were <20 years of age. The most common direct causes of maternal mortality were preeclampsia/eclampsia in 24.4% (n = 158), obstetric hemorrhage in 19.1% (n = 124) and puerperal sepsis in 14.5% (n = 94). With regards to indirect causes, anemia accounted for 15.3% (n = 99) mortality. There was only 1 (0.1%) mortality because of HIV/AIDS. Other notable causes of maternal mortality were infective hepatitis in 7.1% (n = 46). Tuberculosis, that is a disease of tropical countries, accounted for 3.0% (n = 20) of the total deaths. CONCLUSION: High maternal mortality in GTB hospital can be due to it being a tertiary hospital with referrals from all neighbouring states. Accessible antenatal care can help prevent these maternal deaths. Female education can be of immense help in dealing with the problem and improving the utilization of public health facilities. KEY MESSAGE: Preeclampsia/eclampsia and obstetric hemorrhage have been the main causes of maternal mortality for ages. Regular antenatal visits and the judicious training of grassroot level workers to pick-up complications early on in the pregnancy can be an effective way to deal the morbidity and mortality associated with these problems. The Janani Suraksha Yojana (JSY) and Janani Shishu Suraksha Karyakaram (JSSK) in India are pioneer steps in this direction. PMID- 28553028 TI - Role of Community in Swachh Bharat Mission. Their Knowledge, Attitude and Practices of Sanitary Latrine Usage in Rural Areas, Tamil Nadu. AB - BACKGROUND: In most developing countries, open defecation is the 'way of life'. This practice is considered as the most serious health and environmental hazard. Prime Minister of India launched the "Swachh Bharat Mission" to accelerate the efforts for achieving universal sanitation coverage and to put focus on sanitation. OBJECTIVE: To find the knowledge, attitude and practices of sanitary latrines usage in rural area, Tamil Nadu. MATERIALS AND METHODS: This was a cross sectional study conducted among rural population in Kuthambakkam village, Tamil Nadu. There were a total of 1175 households in Kuthambakkam village. These households were serially numbered and of these a sample of 275 households were selected for the study using simple random sampling technique by lottery method. A structured questionnaire was used to collect information regarding the background characteristics, their knowledge, attitude and practices towards sanitary latrines usage. Descriptive statistics were calculated for background variables, the prevalence of sanitary latrines usage and open air defecation. Association between factors responsible for open air defecation was found by using chi square test. RESULTS: The prevalence of usage of household sanitary latrine and community latrines was 62.5% and 4.3% respectively. The prevalence of open air defecation among the study participants was 33.1%.Significant association was found between low standard of living and open air defecation practice. CONCLUSIONS: To solve the problem of underutilization of sanitary latrines, planning and conducting Information Education Communication activities is very essential. Effective political and administrative support is needed to scale up the sanitation program. PMID- 28553029 TI - Summer Temperature and Spatial Variability of all-Cause Mortality in Surat City, India. AB - BACKGROUND: Ample information is available on extreme heat associated mortality for few Indian cities, but scant literature is available on effect of temperature on spatial variability of all-cause mortality for coastal cities. OBJECTIVE: To assess the effect of daily maximum temperature, relative humidity and heat index on spatial variability of all-cause mortality for summer months (March to May) from 2014 to 2015 for the urban population of Surat (coastal) city. MATERIALS AND METHODS: Retrospective analysis of the all-cause mortality data with temperature and humidity was performed on a total of 9,237 deaths for 184 summer days (2014 2015). Climatic and all-cause mortality data were obtained through Tutiempo website and Surat Municipal Corporation respectively. Bivariate analysis performed through SPSS. OBSERVATIONS: Mean daily mortality was estimated at 50.2 +/- 8.5 for the study period with a rise of 20% all-cause mortality at temperature >= 40 degrees C and rise of 10% deaths per day during extreme danger level (HI: > 54 degrees C) days. Spatial (Zone wise) analysis revealed rise of 61% all-cause mortality for Southeast and 30% for East zones at temperature >= 40 degrees C. CONCLUSIONS: All-cause mortality increased on high summer temperature days. Presence of spatial variation in all-cause mortality provided the evidence for high risk zones. Findings may be helpful in designing the interventions at micro level. PMID- 28553030 TI - Improving Perinatal Health: Are Indian Health Policies Progressing In The Right Direction? AB - BACKGROUND: Strategic investments and policy directives of the Indian Government has demonstrated highest degree of political commitment for maternal and child health care. OBJECTIVES: To evaluate the impact of the rise in institutional deliveries in India on perinatal mortality. METHODS: Hospital delivery rate and perinatal mortality rate (PNMR), reported by Sample Registration System, Registrar General of India, on a representative sample was used. The correlation between relative change in hospital deliveries and PNMR was examined. RESULTS: In rural areas of India, hospital deliveries have increased during 2005-2013 from 24.4 to 69.7% and PNMR has declined from 40 to 28 per 1000 births. At the state level, there was significant correlation between the rise in hospital delivery rate and decline in PNMR (r 0.4, p 0.04). CONCLUSIONS: Decline in perinatal rates can be attributed to India's strategic initiatives in health policy and planning for increasing deliveries in hospitals. PMID- 28553031 TI - Leprosy: An Urgent Need to Step Up Surveillance. PMID- 28553032 TI - Stroke in Patients with Chronic Kidney Disease...: How do we Approach and Manage it? AB - Renal failure is a potent risk factor for stroke, which is a leading cause of morbidity and mortality worldwide. The risk of stroke is 5-30 times higher in patients with chronic kidney disease (CKD), especially on dialysis. Case fatality rates are also higher reaching almost 90%. It is therefore important to understand the factors that predispose to stroke in this vulnerable population to better apply preventive strategies. The heightened risk of stroke in CKD represents the interplay of the vascular co-morbidities that occur with renal impairment and factors specific to renal failure such as malnutrition inflammation-atherosclerosis complex, the effect of uremic toxins, dialysis techniques, vascular access, and the use of anticoagulants to maintain flow in the extracorporeal circuit. Old age, hypertension, diabetes, and previous cerebrovascular disease are all risk factors for stroke with the period of dialysis initiation constituting the highest risk period for developing new stroke. Patients with CKD-stage 3-5 have worse survival and diminished functional outcomes following stroke. Thrombolytic therapy for stroke in CKD has shown an increased risk of symptomatic intracranial hemorrhage or serious systemic hemorrhage, and the therapeutic effects may be attenuated. Benefit of statin therapy in dialysis patient as preventive therapy has not been shown to be beneficial. Control of hypertension and the judicious use of antiplatelet agents form the mainstay of stroke prevention. The benefit of antiplatelet therapies and oral anticoagulants has to be balanced against the real and increased risk of bleeding that is most evident in dialysis cohorts. An increased risk of vascular calcification particularly intracerebral vascular calcification has been seen in patientsreceiving warfarin as prophylaxis in atrial fibrillation. Newer anticoagulants have not been tested in patients with glomerular filtration rate <30 ml/min and hence have to be used with caution. This article is a review of stroke in patients with CKD and approach to managing it. PMID- 28553033 TI - Ambulatory Blood Pressure Monitoring - Kids Need it Too? PMID- 28553034 TI - Hemodialysis Vascular Access: The Perils and Potentials. PMID- 28553035 TI - Brachiocephalic Arteriovenous Fistula for Hemodialysis through the Median Antecubital Vein. AB - In patients unsuitable for radiocephalic fistula creation, the next option is brachiocephalic fistula. In such patients, we exploited the venous interconnections in the cubital fossa for median cubital vein-Brachiocephalic arteriovenous fistula (AVF) creation. In this article, we describe our experience in the creation of such technical variant of the brachiocephalic fistula AVF, its success and associated complications. A retrospective review of such AVF created between September 2014 and August 2015 was done. The data collected included demographics, co-morbidities, basic disease, operative details, patency, complications, and mortality. A total of 68 vascular access surgeries were done which included 26 (38.2%) brachiocephalic AVF using the median antecubital vein. The mean cephalic vein diameter and mean flow rate were 7.18 mm and 1415 ml/min, respectively 2 months after fistula creation. The primary and secondary failure rates were 3.87% and 7.69% respectively. Complications included aneurysm (7.69%), edema (19.23%), hematoma (11.53%), and wound infection (3.8%). Using reverse flow in the median antecubital vein is a safe and simple way to perform brachiocephalic AVF before brachiobasilic AVF and grafts. PMID- 28553036 TI - Postpartum Acute Kidney Injury: Experience of a Tertiary Care Center. AB - Pregnancy-related-acute kidney injury (PR-AKI) had decreased from 40% to 20% in 1960 to <10% in recent series, mostly due to meticulous antenatal management. Postpartum-AKI (PP-AKI) resulting from late obstetric complications has become more apparent after improvement in antenatal care and legalization of medical termination of pregnancy. Women with renal injury in peripartum period admitted to our hospital over a period of 2 years (April 2013 to May 2015) were studied. Of 713 patients of AKI admitted, 61 had PR-AKI with an incidence of 4.27%. Out of the 61 patients, 28 had PP-AKI with an incidence of 1.96%. The mean age of patients with PP-AKI was 26.10 +/- 4.3 years. Sepsis was the most common cause accounting for 11 (39.28%) cases followed by postpartum hemorrhage (PPH) in 7 (25%) cases. Renal biopsy was done in nine patients, out of whom four were having cortical necrosis. Patients having diffuse cortical necrosis remained dialysis dependent. High contribution of sepsis and PPH to PP-AKI in our setting makes it an ideal target for rectification. Protocolized peripartum monitoring and standard clinical practices of asepsis will go long way in decreasing the incidence of PP-AKI and maternal morbidity in our valley. PMID- 28553037 TI - A Comparison of Practice Pattern and Outcome of Twice-weekly and Thrice-weekly Hemodialysis Patients. AB - Renal replacement therapy (RRT) options and practice varies in countries worldwide and is influenced by patients' choice, nephrologists' practice patterns, health system, payer practice, public policy, and socioeconomic factors. In India, hemodialysis (HD) remains the dominant RRT modality, and the practice is largely influenced by socioeconomics of the region of practice since third party payer is limited. Resource stretch to maximize outcome benefit is essential and HD session twice weekly is an improvized and cost-effective clinical practice. However, within the country, the patient characteristics, practice patterns, and outcomes of twice-weekly HD compared against patients dialyzed thrice weekly remain unclear. We did a retrospective analysis of patients who underwent twice- and thrice-weekly HD in a single center under similar settings. The patients on thrice a week dialysis were older and with a higher proportion of diabetics and were insured by private payers. Weight gain, ultrafiltration rates, blood pressures, and hemoglobin remained more favorable in the thrice-weekly patients. There was no significant difference in the hospitalization rates or mortality rates in the two groups. Patients who undergo twice-weekly HD have poorer intermediate measures of the outcome; although, morbidity and survival were not different in a small study population with short follow-up. The small sample size and the short duration of follow-up may limit the scope of findings of our study. PMID- 28553038 TI - The Relationship between Metabolic Acidosis and Nutritional Parameters in Patients on Hemodialysis. AB - The progressive loss of kidney function is accompanied by metabolic acidosis. The relationship between metabolic acidosis, nutritional status, and oral bicarbonate supplementation has not been assessed in the Indian chronic kidney disease (CKD) population who are on maintenance hemodialysis (MHD). This is a single-center prospective study conducted in the Western part of India. Thirty-five patients, who were receiving MHD were assessed for metabolic acidosis along with various nutritional parameters at the baseline and at the follow-up after 3 months, postcorrection of acidosis with oral sodium bicarbonate supplements. The relationship between the correction of metabolic acidosis with oral bicarbonate supplements and changes in dietary and various nutritional parameters were evaluated. Metabolic acidosis at the baseline evaluation was found in 62.86% cases of the cohort with a mean serum bicarbonate value of 20.18 +/- 4.93 mmol/L. The correction of acidosis with increment in the mean dosage of oral sodium bicarbonate supplements from 0.69 +/- 0.410 mmol/kg/day at baseline to 1.04 +/- 0.612 mmol/kg/day, significantly reduced the prevalence of metabolic acidosis to 23.33% cases at the follow-up. Improvement in serum bicarbonate level showed significant dietary, anthropometric, and nutritional improvements in these patients. Hence, we conclude that correction of metabolic acidosis with optimal oral bicarbonate supplementation plays a pivotal role in the treatment of malnourished CKD patients on MHD. PMID- 28553039 TI - Baseline Anti-blood Group Antibody Titers and their Response to Desensitization and Kidney Transplantation. AB - In recent years, immunological barriers historically considered as absolute contraindications to transplantation are being reevaluated. One such barrier is the ABO blood group incompatibility. With better understanding of immunological mechanisms and effective various regimens for controlling it, ABO-incompatible (ABO-I) kidney transplantation is now being performed with increasing frequency. For good outcome, most important is to achieve and maintain low anti-blood group antibody titers (ABGATs). Twenty-two patients with ABO-I donors have been studied. The anti-A and anti-B antibody titers (IgG and IgM) were estimated by column agglutination technology using Automated Ortho BioVue System. For desensitization, pretransplant plasmapheresis and/or immunoadsorption and rituximab were used. ABGAT was determined before transplant and periodically after transplant. It was observed that one-third of the patients have low baseline ABGAT. In these cases with low ABGAT, transplant can be performed without any desensitization. In those with titers <1:256, rituximab (two doses of 200 mg weekly) and 3-6 sessions of plasmapheresis can bring down titers to <1:32. In those with titers >1:256, immunoadsorption may be used from the beginning to reduce ABGAT. After transplant, the titers drop to <1:8 in majority. Rise in titers to >1:64 require close observation and biopsy. If there is evidence of antibody-mediated rejection, treatment should be promptly started. Rise in titers 4-6 weeks after transplant is not associated with any graft dysfunction, and hence not of any clinical significance. PMID- 28553040 TI - Prosthetic Hemodialysis Access-induced Distal Hand Ischemia and its Contributors in Diabetics. AB - Avoidance of hand ischemia in the construction of prosthetic access for hemodialysis in diabetics that have no suitable vein for arteriovenous fistula is appreciated. Taper type may be an appropriately matched conduit to prevent its occurrence. This is a prospective controlled trial of 38 selected diabetics requiring hemodialysis, who were referred to our clinic during a period of 6 months. The aim of the study was to evaluate the efficacy of tapered grafts in preventing distal hand hypoperfusion and determining its most likely contributors. In 18 intervening cases, taper 4 mm * 7 mm and in twenty cases (control group), standard 6 mm polytetrafluoroethylene as straight Brachial Axillary access was used. Graft flow rates, artery and vein diameters, and mean arterial pressure were included for evaluation. Within the control group, 11 patients (55%) (7 cases Grade 1, 3 Grade 2, 1 Grade 3) and in intervening group, 2 cases (11%) (Grade 1, Grade 3) developed Steal syndrome. There was no significant difference in the mean flow rates (P = 0.82). Increased risk of distal hypoperfusion was observed in the control group when flow rates were more than 1000 ml/min. Arterial diameters (P = 0.011) and mean arterial pressure (P = 0.05) were found to be important contributing factors. Taper grafts causes reduced incidence of distal hand hypoperfusion. When artery diameter was <6 mm and mean arterial pressure lower than 100 mmHg and the index (brachial artery diameter * mean arterial pressure) was under 500, distal hand ischemia occurred in standard and tapper type. We therefore recommend selective usage of taper grafts in diabetics with diminished distal hand pulses, considering the contributing factors when fistula first is not feasible. PMID- 28553041 TI - A Single-center Experience of Kidney Transplantation from Donation after Circulatory Death: Challenges and Scope in India. AB - Donation after circulatory death (DCD) has never been attempted in India because of legal constraints and lack of guidelines for the withdrawal of life support in end-of-life situations. The present report describes the initial experience of transplantation of organs from DCD donors in a tertiary care center in India. Between 2011 and 2015, five donors had kidneys retrieved after cardiac arrest. These patients were declared dead after waiting for 5 min with no electrocardiographic signal on monitor following cardiopulmonary resuscitation (CPR), which was restarted in three patients till organ retrieval. All donors received heparin and underwent rapid cannulation of aorta, infusion of preservative cold solution, and immediate surface cooling of organs during retrieval surgery. 9/10 kidneys were utilized. Mean donor age was 29.6 +/- 16.3 years, M:F 4:1 and mean age of recipients was 38.7 +/- 10.8 years, M:F 7:2. Seven patients required dialysis in postoperative period. Mean postoperative day 0 urine output was 1.9 +/- 2.6 L. Baseline creatinine achieved was 1.38 +/- 0.35 mg/dl after a mean duration of 26.12 +/- 15.4 days. Kidneys from donors where CPR was continued after the declaration of death (n = 3) had better recovery of renal function (time to reach baseline creatinine 21.2 +/- 7.2 vs. 34.3 +/- 23.7 days, baseline creatinine 1.36 +/- 0.25 vs. 1.52 +/- 0.45 mg%). In donors without CPR, one kidney never functioned and others had patchy cortical necrosis on protocol biopsy, which was not seen in the kidneys from donors with CPR. Kidneys from DCD donors can serve as a useful adjunct in deceased donor program. Continuing CPR after the declaration of death seems to help in improving outcomes. PMID- 28553042 TI - Successful Renal Transplantation Across HLA Barrier: Report from India. AB - Organ donors are sometimes found "unsuitable" due to the presence of donor specific anti-HLA antibodies in the recipient. In recent years, improved desensitization protocols have successfully helped to overcome HLA incompatibility hurdle. We present three cases where optimum desensitization was achieved in patients with the donor-specific anti-HLA antibody (DSA) leading to successful renal transplantation. All patient-donor pair underwent HLA typing, complement dependent cytotoxicity crossmatch (CDC-XM), flow cytometry XM (FC-XM), and panel reactive antibody. If any of the three tests was positive, single antigen bead assay was performed to determine the specificity of the anti-HLA antibody (s). Patients with DSA were offered organ-swap or anti-HLA antibody desensitization followed by transplantation. Desensitization protocol consisted of single dose rituximab and cascade plasmapheresis (CP) along with standard triple immunosuppression. The target DSA mean fluorescence index (MFI) was <500, along with negative CDC-XM and FC-XM for both T- and B-cells. Three patients with anti-HLA DSA, who did not find a suitable match in organ swap program, consented to anti-HLA antibody desensitization, followed by transplantation. Mean pre desensitization antibody MFI was 1740 (1422-2280). Mean number of CP required to achieve the target MFI was 2.3 (2-3). All the three patients are on regular follow-up and have normal renal function test at a mean follow-up of 8 months. This report underlines successful application of desensitization protocol leading to successful HLA-antibody incompatible renal transplants and their continued normal renal functions. PMID- 28553043 TI - Unusual Case of Acute Lung Injury in a Renal Allograft Recipient. AB - A renal allograft recipient developed cough with hemoptysis on the 1st postoperative day. A chest X-ray was performed which was suggestive of fluid overload. His fluid was restricted and diuretics were added. On the same day, his pulmonary infiltrates worsened and a computed tomography (CT) of the chest was carried out, which was suggestive of the right lower lobe consolidation and left pleural effusion. He underwent a bronchoscopy and the lavage was sent for cultures, which did not grow any infective organism. Besides routine antibiotics, treatment for possible cytomegalovirus, fungal infections, and pneumocystis infection was instituted. Noninvasive ventilation was started on day 8. A repeat CT of the chest on the postoperative day 8 showed further worsening of the pulmonary infiltrates. As all the initial cultures and serology were negative, a possibility of interstitial pneumonitis was considered. Mycophenolate sodium was considered as a possible cause of the lung infiltrates and was withdrawn. The patient showed progressive improvement. His antibiotics were withdrawn. He was discharged on day 14. A repeat CT 4 weeks post transplant showed significant improvement in his pulmonary pathology. The acute lung injury was considered to be a drug reaction secondary to mycophenolate sodium. In a renal allograft recipient with persistent pulmonary infiltrates, interstitial involvement secondary to drugs should be considered if the patient does not improve with the standard treatment measures. PMID- 28553044 TI - Postrenal Transplant Metastatic Colonic Neoplasm: Posttransplant Lymphoproliferative Disorder or Adenocarcinoma? AB - Transplant recipients are vulnerable to a horde of infections and neoplastic conditions due to immunosuppression. Posttransplant lymphoproliferative disorder (PTLD) is a condition unique to the transplant recipient occurring due to monoclonal lymphocytic proliferation. It may affect any organ system with reportedly highest incidence in the gastrointestinal tract. The incidence of adenocarcinoma of the colon, however, has not been shown to be uniformly higher in transplant recipients. We report here an unusual case of adenocarcinoma of the ascending colon presenting with liver, lymph node and skin metastasis in a transplant recipient, which simulated PTLD both clinically and radiologically. For any gastrointestinal lesion in transplant recipient, the possibility of carcinoma must be considered. However, a high index of suspicion for PTLD facilitates early diagnosis since the treatment of the two conditions is starkly different. PMID- 28553045 TI - Clinical and Genetic Profile of Indian Children with Primary Hyperoxaluria. AB - Primary hyperoxaluria (PH) has heterogeneous renal manifestations in infants and children. This often leads to delay in diagnosis. In the past 3 years, genetic samples were sent for seven children with a clinical diagnosis of PH. Their medical records were reviewed for clinical presentation and outcomes. Of the seven children, three were males. The median age of presentation was 4.9 years with the youngest presenting at 3 months of age. Nephrolithiasis, the most common presentation was associated with renal dysfunction in two children. Two children with no significant history presented in end-stage renal disease (ESRD). The sibling of one of the children in ESRD, with a history of consanguinity in parents, was screened for asymptomatic nephrolithiasis. Bilateral multiple renal calculi were found in majority of children followed by echogenic kidneys on ultrasound examination. Genetic analysis suggested PH Type 1 in five children and type 2 in two children. The mutations detected in our cohort were different from the previously reported common mutations. There was no obvious genotype-phenotype correlation noticed. Three children in ESRD are on maintenance dialysis. Nephrolithiasis being a common presentation of PH needs prompt evaluation. Mutations are generally population specific, and whole gene sequence analysis is critical in diagnosis. PMID- 28553046 TI - Amelogenesis Imperfecta with Distal Renal Tubular Acidosis: A Novel Syndrome? AB - Amelogenesis imperfecta (AI) is a heterogeneous group of inherited dental enamel defects. It has rarely been reported in association with multiorgan syndromes and metabolic disorders. The metabolic disorders that have been reported in association with AI include hypocalciuria, impaired urinary concentrating ability, and Bartter-like syndrome. In literature, only three cases of AI and distal renal tubular acidosis (dRTA) have been described: two cases in adults and a solitary case in the pediatric age group. Here, we report a child with AI presenting with dRTA; to the best of our knowledge, our reported case is the only second such case in pediatric age group. Our case highlights the importance of recognizing the possibility of renal abnormalities in patients with AI as it will affect the long-term prognosis. PMID- 28553047 TI - De Novo Collapsing Glomerulopathy in Renal Allograft in Association with BK Virus Nephropathy in a Child and Stabilization of Renal Function by Elimination of Viremia. AB - Well-recognized association between HIV 1 infection and collapsing glomerulopathy (CG) raises the possibility that intrarenal infection by other viruses may also contribute to the development of this lesion in native or post-transplant kidneys. There is evidence in literature about association of these lesions with cytomegalovirus, Epstein-Barr virus, hepatitis C virus, and parvovirus B19 infections. Here, we present a case report of post-transplant BK virus nephropathy in a male child who was found to have CG in subsequent biopsy 2 months later. His renal function and proteinuria were stabilized on elimination of viremia. PMID- 28553048 TI - Acute Ciprofloxacin-Induced Crystal Nephropathy with Granulomatous Interstitial Nephritis. AB - Crystal-induced acute kidney injury (AKI) is caused by the intratubular precipitation of crystals, which results in obstruction and kidney injury. Ciprofloxacin, a commonly used antibiotic, causes AKI secondary to immune mediated interstitial injury. Rare mechanisms of ciprofloxacin-induced renal injury include crystalluria, rhabdomyolysis, and granulomatous interstitial nephritis. Clinical and experimental studies have suggested that crystalluria and crystal nephropathy due to ciprofloxacin occur in alkaline urine. Preexisting kidney function impairment, high dose of the medication, and advanced age predispose to this complication. We report a case of ciprofloxacin-induced crystal nephropathy and granulomatous interstitial nephritis in a young patient with no other predisposing factors. The patient responded to conservative treatment without the need for glucocorticoids. PMID- 28553049 TI - A Case of Chylothorax in a Hemodialysis Patient with Left Innominate Venous Stenosis. AB - Chylothorax is defined as accumulation of chyle-containing lymphatic fluid within the pleural space. Chylothorax is very rarely seen in hemodialysis patients. We report a case of a patient on hemodialysis who developed chylothorax secondary to left innominate vein stenosis, with other features of venous hypertension such as arm edema successfully treated with angioplasty and pigtail drainage. PMID- 28553050 TI - Successful Treatment of Multiple Angiomyolipomas with Sirolimus in a Child. AB - Tuberous sclerosis complex frequently results in the formation of renal angiomyolipomas (AMLs). Sirolimus (SIR) or everolimus can be used to treat large AMLs, although this treatment has rarely been described in children, particularly for multiple renal AMLs. A 15-year-old girl presented with bilateral severe chronic flank pain coinciding with increased renal size and hundreds of renal AMLs. We opted to treat her with SIR over the course of 3.5 years. Following her treatment, her renal size had substantially decreased and the AMLs had shrunk. The patient's pain subsided as well. Our case, which has never been described in published literature, demonstrates that a child with multiple renal AMLs can be treated with SIR, and suggests that this treatment may be a viable option for preventing the development of secondary morbidities such as chronic pain. PMID- 28553051 TI - Lumps All Over: A Case of Chronic Tophaceous Gout (Harrison Syndrome). PMID- 28553052 TI - Reusing Immunoadsorption Column - Making the ABO Incompatible Renal Transplant Affordable. PMID- 28553053 TI - Nephrotoxicity in a Patient Treated with Pemetrexed. PMID- 28553054 TI - Cardiogenic Shock: The Main Cause of Mortality in Acute Aluminum Phosphide Poisoning. PMID- 28553055 TI - A new S-type upper bound for the largest singular value of nonnegative rectangular tensors. AB - By breaking [Formula: see text] into disjoint subsets S and its complement, a new S-type upper bound for the largest singular value of nonnegative rectangular tensors is given and proved to be better than some existing ones. Numerical examples are given to verify the theoretical results. PMID- 28553056 TI - Monotonicity rule for the quotient of two functions and its application. AB - In the article, we provide a monotonicity rule for the function [Formula: see text], where [Formula: see text] is a positive differentiable and decreasing function defined on [Formula: see text] ([Formula: see text]), and [Formula: see text] and [Formula: see text] are two real power series converging on [Formula: see text] such that the sequence [Formula: see text] is increasing (decreasing) with [Formula: see text] and [Formula: see text] for all [Formula: see text]. As applications, we present new bounds for the complete elliptic integral [Formula: see text] ([Formula: see text]) of the second kind. PMID- 28553057 TI - Abstract generalized vector quasi-equilibrium problems in noncompact Hadamard manifolds. AB - This paper deals with the abstract generalized vector quasi-equilibrium problem in noncompact Hadamard manifolds. We prove the existence of solutions to the abstract generalized vector quasi-equilibrium problem under suitable conditions and provide applications to an abstract vector quasi-equilibrium problem, a generalized scalar equilibrium problem, a scalar equilibrium problem, and a perturbed saddle point problem. Finally, as an application of the existence of solutions to the generalized scalar equilibrium problem, we obtain a weakly mixed variational inequality and two mixed variational inequalities. The results presented in this paper unify and generalize many known results in the literature. PMID- 28553058 TI - New generalizations of Popoviciu-type inequalities via new Green's functions and Montgomery identity. AB - The inequality of Popoviciu, which was improved by Vasic and Stankovic (Math. Balk. 6:281-288, 1976), is generalized by using new identities involving new Green's functions. New generalizations of an improved Popoviciu inequality are obtained by using generalized Montgomery identity along with new Green's functions. As an application, we formulate the monotonicity of linear functionals constructed from the generalized identities, utilizing the recent theory of inequalities for n-convex functions at a point. New upper bounds of Gruss and Ostrowski type are also computed. PMID- 28553059 TI - A mathematical model for three-phase-lag dipolar thermoelastic bodies. AB - In this study we approach a mixed initial-boundary value problem to modeling a three-phase-lag dipolar thermoelastic body. The constitutive laws in this context are given. We establish a uniqueness result and prove a reciprocal theorem. The variational principle obtained in this context is a generalization of the known Gurtin's principle for classical elasticity. PMID- 28553060 TI - Fast convergence of generalized DeTemple sequences and the relation to the Riemann zeta function. AB - In this paper, we introduce new sequences, which generalize the celebrated DeTemple sequence, having enhanced speed of convergence. We also give a new representation for Euler's constant in terms of the Riemann zeta function evaluated at positive odd integers. PMID- 28553061 TI - Some results on random smoothness. AB - Based on the analysis of stratification structure on random normed modules, we first present the notion of random smoothness in random normed modules. Then, we establish the relations between random smoothness and random strict convexity. Finally, a type of Gateaux differentiability is defined for random norms, and its relation to random smoothness is given. The results are helpful in the further study of geometry of random normed modules. PMID- 28553062 TI - Dedicated Followers of Fashion? Bioarchaeological Perspectives on Socio-Economic Status, Inequality, and Health in Urban Children from the Industrial Revolution (18th-19th C), England. AB - The 18th and 19th centuries in England were characterised by a period of increasing industrialisation of its urban centres. It was also one of widening social and health inequalities between the rich and the poor. Childhood is well documented as being a stage in the life course during which the body is particularly sensitive to adverse socio-economic environments. This study therefore aims to examine the relationship between health and wealth through a comprehensive skeletal analysis of a sample of 403 children (0-17 years), of varying socio-economic status, from four cemetery sites in London (c.1712-1854). Measurements of long bone diaphyseal length, cortical thickness, vertebral neural canal size, and the prevalence of a range of pathological indicators of health stress were recorded from the Chelsea Old Church (high status), St Benet Sherehog (middle status), Bow Baptist (middle status), and Cross Bones (low status) skeletal collections. Children from the low status Cross Bones site demonstrated deficient growth values, as expected. However, those from the high status site of Chelsea Old Church also demonstrated poor growth values during infancy. Fashionable child-care practices (e.g. the use of artificial infant feeds and keeping children indoors) may have contributed to poor infant health amongst high status groups. However, differing health risks in the lower status group revealed the existence of substantial health inequality in London at this time. PMID- 28553063 TI - Preserving Neighborhood Opportunity: Where Federal Housing Subsidies Expire. AB - Rent burdens are increasing in U.S. metropolitan areas while subsidies on privately owned, publicly subsidized rental units are expiring. As a result, some of the few remaining affordable units in opportunity neighborhoods are at risk of being converted to market rate. Policy makers face a decision about whether to devote their efforts and scarce resources toward developing new affordable housing, recapitalizing existing subsidized housing, and/or preserving properties with expiring subsidies. There are several reasons to preserve these subsidies, one being that properties may be located in neighborhoods with greater opportunity. In this article, we use several sources of data at the census tract level to learn how subsidy expirations affect neighborhood opportunity for low income households. Our analysis presents several key findings. First, we find that units that left the project-based Section 8 program were - on average - in lower opportunity neighborhoods, but these neighborhoods were improving. In addition, properties due to expiry from the Section 8 program between 2011 and 2020 are in higher opportunity neighborhoods than any other subsidy program. On the contrary, new Low-Income Housing Tax Credit (LIHTC) units were developed in tracts similar to those where LIHTC units are currently active, which tend to be lower opportunity neighborhoods. PMID- 28553064 TI - Degeneration pattern in somatic embryos of Pinus sylvestris L. AB - Somatic embryos can be used for propagating forest trees vegetatively, which is of great importance for capturing the genetic gain in breeding programs. However, many economically important Pinus species are difficult or impossible to propagate via somatic embryogenesis. In order to get a better understanding of the difficulties to propagate Pinus species via somatic embryogenesis, we are studying the developmental pathway of somatic embryos in different cell lines. In a previous study, we showed that the morphology of early somatic embryos in Scots pine (Pinus sylvestris) differs between cell lines giving rise to normal or abnormal cotyledonary embryos. In this study, we have compared the proliferation and degeneration pattern of early and late embryos in a normal and abnormal cell line. In both cell lines, a high frequency of the embryos degenerated. Among the degenerating embryos, two main degeneration patterns could be distinguished. In the normal cell line, the embryos degenerated similar to how the subordinate embryos are degraded in the seed. In the abnormal cell line, the degeneration of the embryos resulted in a continuous loop of embryo degeneration and differentiation of new embryos. We observed a similar degeneration pattern when embryogenic tissue was initiated from megagametophytes containing zygotic embryos at the stage of cleavage polyembryony. Based on our results, we suggest that the degeneration pattern in abnormal cell lines starts during initiation of embryogenic cultures. PMID- 28553065 TI - Enhanced production of hyoscyamine and scopolamine from genetically transformed root culture of Hyoscyamus reticulatus L. elicited by iron oxide nanoparticles. AB - The medicinal plant Hyoscyamus reticulatus L. is a rich source of hyoscyamine and scopolamine, the tropane alkaloids. The use of hairy root cultures has focused significant attention on production of important metabolites such as stable tropane alkaloid production. Elicitation is an effective approach to induce secondary metabolite biosynthetic pathways. Hairy roots were derived from cotyledon explants inoculated with Agrobacterium rhizogenes and elicited by iron oxide nanoparticles (FeNPs) at different concentrations (0, 450, 900, 1800, and 3600 mg L-1) for different exposure times (24, 48, and 72 h). The highest hairy root fresh and dry weights were found in the medium supplemented with 900 mg L-1 FeNPs. Antioxidant enzyme activity was significantly increased in induced hairy roots compared to non-transgenic roots. The highest hyoscyamine and scopolamine production (about fivefold increase over the control) was achieved with 900 and 450 mg L-1 FeNPs at 24 and 48 h of exposure time, respectively. This is the first report of the effect of FeNP elicitor on hairy root cultures of a medicinal plant. We suggest that FeNPs could be an effective elicitor in hairy root cultures in order to increase tropane alkaloid production. PMID- 28553066 TI - Usefulness of the CRAFFT to Diagnose Alcohol or Cannabis Use Disorders in a Sample of Emerging Adults with Past-Month Alcohol or Cannabis Use. PMID- 28553067 TI - Diversifying the STEM pipeline. AB - PURPOSE: The current paper focuses on the description and evaluation of a two year STEM intervention targeting underserved middle schools students from minority and low SES backgrounds. DESIGN/METHODOLOGY/APPROACH: Middle school students from low-income and minority backgrounds (n = 166) were targeted to participate in a two-year, intensive, hands-on science and technology intervention to increase their interest in biomedical and health sciences. Quantitative and qualitative data were collected from TRY-IT! Students as well as a control group that did not participate in the intervention, teachers, and parents to assess changes in attitudes and knowledge with respect to a variety of STEM-related topics. FINDINGS: Quantitative analyses did not reveal significant long-lasting differences between the TRY-IT! and the control group, thus providing a mixed assessment of the effectiveness of the intervention. However, qualitative student responses collected during the second year of participation revealed positive attitudes toward the program experience and benefits of their exposure to science. In light of these findings, insights drawn from reflecting on successes and challenges experienced during the course of planning and implementing the study are provided to guide future programs and research. ORIGINALITY/VALUE: The intervention was developed in response to the continued under representation of minority and lower SES individuals in STEM careers. An effort to boost positive attitudes toward science and math, as well as confidence in the accessibility of STEM careers among this population is important given the promising outlook of this career field compared to others for future generations. PMID- 28553068 TI - Comparison of retina specialist preferences regarding spectral-domain and swept source optical coherence tomography angiography. AB - PURPOSE: The aim of this study was to compare physician preferences regarding the commercially available spectral-domain (SD) optical coherence tomography angiography (OCTA) and swept-source (SS) OCTA prototype device. DESIGN: Comparative analysis of diagnostic instruments was performed. PATIENTS AND METHODS: Subjects at the University of Washington Eye Institute and Harborview Medical Center were prospectively recruited and imaged with the Zeiss SD OCTA (HD 5000, Angioplex) and Zeiss SS OCTA (Plex Elite, Everest) devices on the same day. The study included 10 eyes from 10 subjects diagnosed with a retinal/choroidal disease. Deidentified images were compiled into a survey and sent to retina specialists in various countries. The survey presented masked SD and SS images of each eye for each retinal sublayer side by side. Respondents were asked about their image preference and impact on clinical management. A priori and post hoc preferences for SD vs SS were collected. RESULTS: Fifty-four retina specialists responded to the survey. Median years in practice was 3.00 (interquartile range [IQR] 1.50-17.00). At baseline, 23 (48%) physicians owned an OCTA machine. The majority of physician responses showed a preference for the SS over SD OCTA, independent of the retinal pathology shown (n=454 overall responses, 74%). Nevertheless, the majority indicated that both SD and SS would be equally valuable in informing clinical decisions (n=374 overall responses, 61%). CONCLUSION: These findings indicate that the majority of retina specialists surveyed prefer SS over SD OCTA based on image quality, regardless of the retinal pathology shown. Regarding the clinical utility of each modality, the majority of physicians perceive SD and SS as equally effective. PMID- 28553069 TI - The use of WaveLight(r) Contoura to create a uniform cornea: the LYRA Protocol. Part 1: the effect of higher-order corneal aberrations on refractive astigmatism. AB - PURPOSE: To demonstrate how higher-order corneal aberrations can cancel out, modify, or induce lower-order corneal astigmatism. PATIENTS AND METHODS: Six representative eyes are presented that show different scenarios in which higher order aberrations interacting with corneal astigmatism can affect the manifest refraction. WaveLight(r) Contoura ablation maps showing the higher-order aberrations are shown, as are results of correction with full measured correction using the LYRA (Layer Yolked Reduction of Astigmatism) Protocol. RESULTS: Higher order corneal aberrations such as trefoil, quadrafoil, and coma can create ovalization of the central cornea, which can interact with the ovalization caused by lower-order astigmatism to either induce, cancel out, or modify the manifest refraction. Contoura processing successfully determines the linkage of these interactions resulting in full astigmatism removal. Purely lenticular astigmatism appears to be rare, but a case is also demonstrated. The author theorizes that all aberrations require cerebral compensatory processing and can be removed, supported by the facts that full removal of aberrations and its linkage with lower-order astigmatism with the LYRA Protocol has not resulted in worse or unacceptable vision for any patients. CONCLUSION: Higher-order aberrations interacting with lower-order astigmatism is the main reason for the differences between manifest refraction and Contoura measured astigmatism, and the linkage between these interactions can be successfully treated using Contoura and the LYRA Protocol. Lenticular astigmatism is relatively rare. PMID- 28553070 TI - The use of WaveLight(r) Contoura to create a uniform cornea: the LYRA Protocol. Part 2: the consequences of treating astigmatism on an incorrect axis via excimer laser. AB - PURPOSE: To show how an incorrect manifest astigmatism axis can cause an abnormal induced astigmatism on a new axis. PATIENTS AND METHODS: Four eyes of three patients were treated primarily with WaveLight(r) EX500 wavefront optimized (WFO) treatments for astigmatism. All four eyes needed enhancements and were analyzed retrospectively via WaveLight(r) Contoura to determine the reason for the incorrect astigmatism treatment. Two of the eyes were retreated with topographic guided ablation, and two were treated with WFO correction. RESULTS: The eyes that had an incorrect manifest axis resulted in a new abnormal induced astigmatism on a wholly new axis. Treatment with topographic-guided ablation completely eliminated the newly induced astigmatism. Treatment with WFO of an abnormal induced astigmatism corrected the refraction but still left topographic evidence of the abnormal astigmatism behind. One eye was incorrectly treated for astigmatism due to coma affecting refraction when the patient was dilated. This eye had a normal induced astigmatism on a perpendicular axis and was corrected using WFO. The use of manifest refraction with WaveLight(r) Contoura topographic guided ablation will lead to incorrect astigmatism correction when the manifest astigmatism and axis differ from the WaveLight(r) Contoura measured. CONCLUSION: Correction of an incorrect manifest refraction astigmatic axis does not simply create undercorrection of the astigmatism but induces an entirely new abnormal astigmatism on a different axis. Manifest refraction is less accurate and can lead to abnormal astigmatism when laser ablation is performed. PMID- 28553071 TI - The use of WaveLight(r) Contoura to create a uniform cornea: the LYRA Protocol. Part 3: the results of 50 treated eyes. AB - PURPOSE: To demonstrate how using the Wavelight Contoura measured astigmatism and axis eliminates corneal astigmatism and creates uniformly shaped corneas. PATIENTS AND METHODS: A retrospective analysis was conducted of the first 50 eyes to have bilateral full WaveLight(r) Contoura LASIK correction of measured astigmatism and axis (vs conventional manifest refraction), using the Layer Yolked Reduction of Astigmatism Protocol in all cases. All patients had astigmatism corrected, and had at least 1 week of follow-up. Accuracy to desired refractive goal was assessed by postoperative refraction, aberration reduction via calculation of polynomials, and postoperative visions were analyzed as a secondary goal. RESULTS: The average difference of astigmatic power from manifest to measured was 0.5462D (with a range of 0-1.69D), and the average difference of axis was 14.94 degrees (with a range of 0 degrees -89 degrees ). Forty-seven of 50 eyes had a goal of plano, 3 had a monovision goal. Astigmatism was fully eliminated from all but 2 eyes, and 1 eye had regression with astigmatism. Of the eyes with plano as the goal, 80.85% were 20/15 or better, and 100% were 20/20 or better. Polynomial analysis postoperatively showed that at 6.5 mm, the average C3 was reduced by 86.5% and the average C5 by 85.14%. CONCLUSIONS: Using WaveLight(r) Contoura measured astigmatism and axis removes higher order aberrations and allows for the creation of a more uniform cornea with accurate removal of astigmatism, and reduction of aberration polynomials. WaveLight(r) Contoura successfully links the refractive correction layer and aberration repair layer using the Layer Yolked Reduction of Astigmatism Protocol to demonstrate how aberration removal can affect refractive correction. PMID- 28553072 TI - Preoperative measurement vs intraoperative aberrometry for the selection of intraocular lens sphere power in normal eyes. AB - PURPOSE: This study aimed to assess the value of intraoperative aberrometry (IA) in determining the intraocular lens (IOL) sphere power in eyes with no previous ocular surgery. PATIENTS AND METHODS: We conducted a retrospective review of patients who underwent uncomplicated cataract surgery where standard preoperative (Preop) measurements and IA were performed. Calculated IOL sphere powers and postoperative refractions, both actual and theoretical, were compared based on the measurement method and lens type; lens types included multifocal, toric and aspheric single-vision non-toric IOLs. RESULTS: A total of 160 eyes of 112 patients were analyzed. The Preop lens power calculated was the same as the IA lens power 46% of the time, though this percentage was lower for multifocal IOLs. Across all lens types, there was a statistically significant bias (chi-square test, P<0.01) toward the IA method suggesting a lower powered lens. Actual postoperative refractive errors were not statistically significantly different when categorized by measurement method. Calculated errors by measurement method showed no statistically significant differences in expected outcomes. There were 63 cases where the Preop calculation and the intraoperative aberrometer calculation differed by 0.5 D. In 56% (35/63) of these cases, the IA result was a better option, and in 44% (28/63) of cases, the Preop calculation was better; this was not statistically significantly different from random expectation (50/50, P=0.53). In the three cases where calculated powers differed by 1.5 D, there appeared to be a positive effect of adjusting the Preop power toward the IA power. CONCLUSION: The use of IA for the determination of sphere power in eyes with no previous ocular surgery does not appear to improve overall expected clinical outcomes, but it may be helpful in cases where the difference between IA and Preop calculations is high. PMID- 28553073 TI - Involvement of NF-kappaB and HSP70 signaling pathways in the apoptosis of MDA-MB 231 cells induced by a prenylated xanthone compound, alpha-mangostin, from Cratoxylum arborescens [Retraction]. AB - [This retracts the article on p. 1629 in vol. 8.]. PMID- 28553074 TI - Design, synthesis, and biological evaluation of novel EF24 and EF31 analogs as potential IkappaB kinase beta inhibitors for the treatment of pancreatic cancer. AB - Given the important role that inhibitory kappa B (IkappaB) kinase beta (IKKbeta) plays in pancreatic cancer (PC) development and progression, inhibitors targeting IKKbeta are believed to be increasingly popular as novel anti-PC therapies. Two synthetic molecules, named EF24 and EF31, exhibited favorable potential in terms of inhibition of both IKKbeta activity and PC cell proliferation. Aiming to enhance their cellular efficacy and to analyze their structure-activity relationship, four series of EF24 and EF31 analogs were designed and synthesized. Through kinase activity and vitality screening of cancer cells, D6 displayed excellent inhibition of both IKKbeta activity and PC cell proliferation. Additionally, multiple biological evaluations showed that D6 was directly bound to IKKbeta and significantly suppressed the activation of the IKKbeta/nuclear factor kappaB pathway induced by tumor necrosis factor-alpha, as well as effectively inducing cancer cell apoptosis. Moreover, molecular docking and molecular dynamics simulation analysis indicated that the dominant force between D6 and IKKbeta comprised hydrophobic interactions. In conclusion, D6 may be a promising therapeutic agent for PC treatment and it also provides a structural lead for the design of novel IKKbeta inhibitors. PMID- 28553075 TI - Fabrication, characterization and in vitro evaluation of silibinin nanoparticles: an attempt to enhance its oral bioavailability. AB - BACKGROUND: Silibinin has gained in importance in the past few decades as a hepatoprotector and is used widely as oral therapy for toxic liver damage, liver cirrhosis, and chronic inflammatory liver diseases, as well as for the treatment of different types of cancers. Unfortunately, it has low aqueous solubility and inadequate dissolution, which results in low oral bioavailability. MATERIALS AND METHODS: In this study, nanoparticles (NPs) of silibinin, which is a hydrophobic drug, were manufactured using two cost-effective methods. Antisolvent precipitation with a syringe pump (APSP) and evaporative precipitation of nanosuspension (EPN) were used. The prepared NPs were characterized using different analytical techniques such as scanning electron microscopy (SEM), fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffractometry (XRD) and were sifted for their bioavailability through in vitro dissolution and solubility studies. Moreover, the prepared NPs were evaluated for antimicrobial activity against a battery of bacteria and yeast. RESULTS: DSC and XRD studies indicated that the prepared NPs were amorphous in nature, with more solubility and dissolution compared to the crystalline form of this drug. NPs prepared through the EPN method had better results than those prepared using the APSP method. Antimicrobial activities of the NPs were improved compared to the unprocessed drugs, while having comparable activities to standard antimicrobial drugs. CONCLUSION: Results indicate that the NPs have significantly increased solubility, dissolution rate, and antimicrobial activities due to the conversion of crystalline structure into amorphous form. PMID- 28553076 TI - Higher dose of palonosetron versus lower dose of palonosetron plus droperidol to prevent postoperative nausea and vomiting after eye enucleation and orbital hydroxyapatite implant surgery: a randomized, double-blind trial. AB - OBJECTIVE: Postoperative nausea and vomiting (PONV) is commonly observed after eye enucleation and orbital hydroxyapatite implant surgery. This prospective, randomized, double-blind trial was conducted to investigate the hypothesis that compared with monotherapy using a higher dose of palonosetron, using a lower dose of palonosetron in combination with droperidol could reduce the incidence of PONV and achieve similar prophylaxis against PONV after the aforementioned surgery. PATIENTS AND METHODS: A total of 129 patients who were in the American Society of Anesthesiologists Classes I and II, aged between 18 and 70 years, and scheduled for eye enucleation and orbital hydroxyapatite implant surgery, were enrolled in this study. They were randomized into three groups: Group P2.5 (2.5 MUg/kg palonosetron), Group P7.5 (7.5 MUg/kg palonosetron), and Group P+D (2.5 MUg/kg palonosetron and 15 MUg/kg droperidol). Patients received the different antiemetic regimens intravenously 5 min before surgery. The severity of nausea and vomiting and the complete response (CR) rate during a 72-h postoperative period were assessed. RESULTS: All patients completed the trial. The nausea score of Group P2.5 was significantly higher than those of the other two groups at 0-4 h and 24-48 h (P<0.05). Vomiting scores among all groups were similar during all intervals (P>0.05). Compared with Group P2.5, the CR rate was significantly improved at all intervals in Group P+D, except at 4-72 h, and was also elevated at 24-72 h in Group P7.5 (P<0.05). Fewer patients in Group P2.5 did not experience any nausea or vomiting throughout the study (49%) compared with those in Group P7.5 (67%) and Group P+D (81%; P<0.01). CONCLUSION: Combining low-dose palonosetron with droperidol potentiated prophylaxis for PONV and achieved a similar prophylactic effect as that with a higher dose of palonosetron. PMID- 28553077 TI - Spotlight on dupilumab in the treatment of atopic dermatitis: design, development, and potential place in therapy. AB - Atopic dermatitis (AD) is among the most common inflammatory skin diseases in children and adults in industrialized countries. Up to one-third of adults (probably a smaller proportion in childhood) suffer from moderate-to-severe AD, whose recommended treatment is usually based on systemic therapies. The currently available therapeutics are limited, and AD management becomes challenging in most cases. Over the last few years, new advances in the understanding of AD pathogenic mechanisms and inflammatory pathways have led to the identification of specific therapeutic targets and new molecules have been tested. Dupilumab is a fully human monoclonal antibody directed against the IL-4 receptor alpha subunit that is able to block the signaling of both IL-4 and IL-13 and achieve rapid and significant improvements in adults with moderate-to-severe AD. Dupilumab is ready to inaugurate a long and promising biological target treatment option for Th2 cell-mediated atopic immune response that characterizes AD. PMID- 28553078 TI - Effects of metformin extended release compared to immediate release formula on glycemic control and glycemic variability in patients with type 2 diabetes. AB - PURPOSE: The purpose of this study is to evaluate, in a randomized clinical trial, the effects of metformin immediate release (IR) compared with metformin extended release (XR) on the gastrointestinal tolerability and glycemic control. MATERIALS AND METHODS: We enrolled 253 Caucasian patients with type 2 diabetes not well controlled by diet (glycated hemoglobin [HbA1c] >7.0% and <8.5%). Patients were randomized to metformin IR or metformin XR for a period of 6 months at the maximum tolerated dose. The average dose of metformin IR used was 2,000+/ 1,000 mg/day, while that of metformin XR was 1,000+/-500 mg/day. We evaluated body weight, HbA1c, fasting and postprandial glucose, fasting plasma insulin (FPI) and homeostasis model assessment insulin resistance (HOMA-IR), lipid profile, and levels of some adipocytokines, including tumor necrosis factor-alpha (TNF-alpha), high-sensitivity C-reactive protein (hs-CRP), visfatin, and vaspin. Moreover, at the baseline and after 6 months, we administered patients some validated questionnaires to assess patients' satisfaction toward treatments. RESULTS: After 6 months, both formulations gave a similar reduction in body weight and body mass index (BMI); however, metformin XR gave a greater improvement in glycemic control, FPI, and HOMA-IR, compared with both baseline and metformin IR. A reduction in total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol was observed with metformin XR compared with IR. Levels of TNF-alpha, hs-CRP, and vaspin were reduced by metformin XR but not by the IR formulation. Metformin XR also raised the levels of visfatin. CONCLUSION: Metformin XR formulation seems to be more effective than metformin IR in improving glyco-metabolic control, lipid profile, and levels of some adipocytokines in patients with type 2 diabetes mellitus. PMID- 28553079 TI - Ten years' clinical experience with biosimilar human growth hormone: a review of efficacy data. AB - In 2006, the European Medicines Agency (EMA) approved Omnitrope(r) as a biosimilar recombinant human growth hormone (rhGH), on the basis of comparable quality, safety, and efficacy to the reference medicine (Genotropin(r), Pfizer). Data continue to be collected on the long-term efficacy of biosimilar rhGH from several on-going postapproval studies. Particular topics of interest include efficacy in indications granted on the basis of extrapolation, and whether efficacy of growth hormone treatment is affected when patients are changed to biosimilar rhGH from other rhGH products. Data from clinical development studies and 10 years of postapproval experience affirm the clinical efficacy and effectiveness of biosimilar rhGH across all approved indications. In addition, the decade of experience with biosimilar rhGH since it was approved in Europe confirms the scientific validity of the biosimilar pathway and the approval process. Concerns about clinical effect in extrapolated indications, and also about the impact of changing from other rhGH preparations, have been alleviated. Biosimilar rhGH is an effective treatment option for children who require therapy with rhGH. PMID- 28553080 TI - Ten years of clinical experience with biosimilar human growth hormone: a review of safety data. AB - Safety concerns for recombinant human growth hormone (rhGH) treatments include impact on cancer risk, impact on glucose homeostasis, and the formation of antibodies to endogenous/exogenous GH. Omnitrope(r) (biosimilar rhGH) was approved by the European Medicines Agency in 2006, with approval granted on the basis of comparable quality, safety, and efficacy to the reference medicine (Genotropin(r)). Additional concerns that may exist in relation to biosimilar rhGH include safety in indications granted on the basis of extrapolation and the impact of changing to biosimilar rhGH from other rhGH treatments. A substantial data set is available to fully understand the safety profile of biosimilar rhGH, which includes data from its clinical development studies and 10 years of post approval experience. As of June 2016, 106,941,419 patient days (292,790 patient years) experience has been gathered for biosimilar rhGH. Based on the available data, there have been no unexpected or unique adverse events related to biosimilar rhGH treatment. There is no increased risk of cancer, adverse glucose homeostasis, or immunogenic response with biosimilar rhGH compared with the reference medicine and other rhGH products. The immunogenicity of biosimilar rhGH is also similar to that of the reference and other rhGH products. Physicians should be reassured that rhGH products have a good safety record when used for approved indications and at recommended doses, and that the safety profile of biosimilar rhGH is in keeping with that of other rhGH products. PMID- 28553081 TI - Ten years of biosimilar recombinant human growth hormone in Europe. AB - Recombinant human growth hormone (rhGH) has been in clinical use for more than 30 years. With the expiration of patent exclusivity for the first wave of rhGH products and other biopharmaceuticals, the opportunity emerged for the development of biosimilar medicines. A biosimilar is defined by the European Medicines Agency (EMA) as a biological medicine that is similar to another biological medicine that has already been authorized for use. The EMA led the way (well ahead of the Food and Drug Administration in the US) in developing the biosimilar concept, and the type of science-based regulatory framework required to ensure high-quality, safe, and effective biosimilar medicines; the provisions for approval of biosimilars have been in place in Europe since 2005. Under these provisions, Omnitrope(r) was approved by the EMA in 2006 as the world's first biosimilar medicine; 2016 therefore marks the 10th anniversary of its approval in Europe. A substantial data set, based on clinical development studies and 10 years of postapproval use, has now accumulated for biosimilar rhGH; this data set shows that the product is an effective treatment option for children who require rhGH treatment, and has a safety profile that is consistent with the rhGH class. The decade since the EMA approved biosimilar rhGH has seen the successful approval and clinical use of 20 biosimilar medicines, confirming the integrity of the scientific basis for the biosimilar concept, as well as the quality of regulatory decision-making. PMID- 28553082 TI - Ten years of biosimilars in Europe: development and evolution of the regulatory pathways. AB - A biosimilar is defined by the European Medicines Agency as a biological medicine that is similar to another biological medicine that has already been authorized for use. A science-based regulatory framework to ensure high-quality biosimilars has been established in Europe since 2005 and is monitored and updated on an ongoing basis. The guiding principle of a biosimilar development program is to establish similarity between the biosimilar and the reference medicine by the best possible means, ensuring that the previously proven safety and efficacy of the reference medicinal product also applies to the biosimilar. Development of a biosimilar is underpinned by state-of-the-art analytical techniques to characterize both reference medicines and biosimilars. The extent and nature of the nonclinical in vivo studies and clinical studies to be performed depend on the level of evidence obtained in the previous step(s), including the robustness of the physicochemical, biological, and nonclinical in vitro data. Extrapolation is an important element of the biosimilarity concept. When biosimilar comparability has been demonstrated in one indication, extrapolation of the data package to other indications of the reference medicine could be acceptable, but needs to be scientifically justified and considered in light of the demonstrated level of sameness by all analytical, nonclinical, and clinical data. The credibility of the scientific basis behind the biosimilar concept, and quality of regulatory decision-making, is demonstrated by the successful approval and clinical use of 20 biosimilar medicines since 2006 when Omnitrope(r) was the first biosimilar to be approved. The regulatory environment for biosimilars continues to evolve, both in recognition of advances in technology/analytical methods and the availability of new targets for biosimilar development. PMID- 28553083 TI - Cisplatin induces protective autophagy through activation of BECN1 in human bladder cancer cells. AB - PURPOSE: Cisplatin-based chemotherapy is the first line treatment for several cancers including bladder cancer (BC). Autophagy induction has been implied to contribute to cisplatin resistance in ovarian cancer; and a high basal level of autophagy has been demonstrated in human bladder tumors. Therefore, it is reasonable to speculate that autophagy may account for the failure of cisplatin single treatment in BC. This study investigated whether cisplatin induces autophagy and the mechanism involved using human BC cell lines. MATERIALS AND METHODS: Human BC cells (5637 and T24) were used in this study. Cell viability was detected using water soluble tetrazolium-8 reagents. Autophagy induction was detected by monitoring the levels of light chain 3 (LC3)-II and p62 by Western blot, LC3-positive puncta formation by immunofluorescence, and direct observation of the autophagolysosome (AL) formation by transmission electron microscopy. Inhibitors including bafilomycin A1 (Baf A1), chloroquine (CQ), and shRNA-based lentivirus against autophagy-related genes (ATG7 and ATG12) were utilized. Apoptosis level was detected by caspase 3/7 activity and DNA fragmentation. RESULTS: Cisplatin decreased cell viability and induced apoptosis of 5637 and T24 cells in a dose-and time-dependent manner. The increased LC3-II accumulation, p62 clearance, the number of LC3-positive puncta, and ALs in cisplatin-treated cells suggested that cisplatin indeed induces autophagy. Inhibition of cisplatin induced autophagy using Baf A1, CQ, or ATG7/ATG12 shRNAs significantly enhanced cytotoxicity of cisplatin toward BC cells. These results indicated that cisplatin induced protective autophagy which may contribute to the development of cisplatin resistance and resulted in treatment failure. Mechanistically, upregulation of beclin-1 (BECN1) was detected in cisplatin-treated cells, and knockdown of BECN1 using shRNA attenuated cisplatin-induced autophagy and subsequently enhanced cisplatin-induced apoptosis. CONCLUSION: Collectively, the study results indicated that cisplatin-induced autophagy is mediated by BECN1 in BC cells. Therefore, combinative treatment using cisplatin and autophagy inhibitors could potentially overcome cisplatin resistance related to autophagy induction. PMID- 28553084 TI - Engagement-focused care during transitions from inpatient and emergency psychiatric facilities. AB - OBJECTIVES: As many as 40% of those with serious mental illness (SMI) do not attend any outpatient visits in the 30 days following discharge. We examined engagement-focused care (EFC) versus treatment as usual in a university-based transitional care clinic (TCC) with a 90-day program serving individuals with SMI discharged from hospitals and emergency rooms. EFC included a unique group intake process (access group) designed to get individuals into care rapidly and a shared decision-making coach. METHODS: Assessments of quality of life, symptomatology, and shared decision-making preferences were conducted at baseline, at 3 months corresponding to the end of TCC treatment and 6 months after TCC discharge. Communication among the patients and providers was assessed at each visit as was service utilization during and after TCC. RESULTS: Subjective quality of life improved in EFC. Prescribers and patients saw communication more similarly as time went on. Ninety-one percent of patients wanted at least some say in decisions about their treatment. CONCLUSIONS: SDM coaching and improved access improve quality of life. Most people want a say in treatment decisions. PMID- 28553085 TI - Psychometric properties of the Ruminative Response Scale-short form in a clinical sample of patients with major depressive disorder. AB - BACKGROUND: The Ruminative Response Scale (RRS)-short form is one of the most widely used measures of rumination, comprising ten items and two components: reflection and brooding. The aim of this study was to investigate RRS validity and reliability in a clinical sample of French patients with major depressive disorder (MDD). SUBJECTS AND METHODS: Outpatients with a DSM-IV-TR diagnosis of MDD were recruited from a public academic hospital in France. Depressive symptoms were evaluated by the Beck Depression Inventory, anxiety by the State-Trait Anxiety Inventory - state scale, and quality of life by the 36-Item Short Form Health Survey (SF-36) questionnaire. Confirmatory factor analyses, item-dimension correlations, Cronbach's alpha-coefficients, Rasch statistics, and external validity were tested. Differential item functioning analyses were performed for sex. RESULTS: A total of 109 patients participated. The final reflection-brooding two-factor model of the RRS showed a good fit (root-mean-square error of approximation 0.041, comparative fit index 0.987, standardized root-mean-square residual 0.048) after removing one item (daily diary writing). Internal item consistency and reliability were satisfactory for the two dimensions. External validity testing confirmed that RRS scores were correlated with Beck Depression Inventory, State-Trait Anxiety Inventory, and SF-36 scores. There was no differential item functioning across sexes. CONCLUSION: These results demonstrated good scale reliability and validity for assessing rumination in patients with MDD. PMID- 28553086 TI - Adherence to systemic therapies for immune-mediated inflammatory diseases in Lebanon: a physicians' survey from three medical specialties. AB - BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are chronic conditions that may cause tissue damage and disability, reduced quality of life and increased mortality. Various treatments have been developed for IMIDs, including immune modulators and targeted biologic agents. However, adherence remains suboptimal. METHODS: An adherence survey was used to evaluate physicians' beliefs about adherence to medication in IMID and to evaluate if and how they manage adherence. The survey was distributed to 100 randomly selected physicians from three different specialties. Results were analyzed by four academic experts commissioned to develop an action plan to address practical and perceptual barriers to adherence, integrating it into treatment goals to maximize outcomes in IMID, thereby elevating local standards of care. RESULTS: Eighty-two physicians participated in this study and completed the questionnaire. Most defined adherence as compliance with prescribed treatment. Although the majority of surveyed physicians (74%) did not systematically measure adherence in their practice, 54% identified adherence as a treatment goal of equal or greater importance to therapeutic endpoints. Lack of time and specialized nursing support was reported as an important barrier to measuring adherence. The expert panel identified four key areas for action: 360 degrees education (patient-nurse physician), patient-physician communication, patient perception and concerns, and market access/cost. An action plan was developed centered on education and awareness, enhanced benefit-risk communication, development of adherence assessment tools and promotion of patient support programs. CONCLUSION: Nonadherence to medication is a commonly underestimated problem with important consequences. A customized target-based strategy to address the root causes of non-adherence is essential in the management of chronic immune-mediated diseases. PMID- 28553087 TI - Association of dry eye disease with psychiatric or neurological disorders in elderly patients. AB - Dry eye disease (DED) is a common disease that can impair quality of life significantly. Its prevalence increases with advancing age, and the economic burden of the disease on both a patient and the society is increasing with elongation of life expectancy. The diagnosis and treatment of DED are often difficult due to the discordance between symptoms and signs of the disease. Recent studies have suggested the role of neurological or psychological factors in the development of dry eye symptoms and discrepancy of the symptoms and signs, particularly in elderly patients. In this review, the authors discuss the association of DED with various psychiatric and neurological disorders. In addition to psychiatric conditions, including depression, anxiety, stress, posttraumatic stress disorder and sleep disorders, medications for the psychiatric disorders have association with DED. Neurological disorders, such as neuropathic pain, chronic pain syndrome, peripheral neuropathy and several central nervous system disorders, are related to DED. Treatment of DED, combined with psychiatric or neurological disorders, is also discussed. Attention should be paid to the DED patients with discordant symptoms and signs, and unsatisfactory response to conventional treatment for associated psychiatric or neurological disorders, as well as an integrated treatment approach, could be helpful for these patients. PMID- 28553089 TI - Effect of frailty syndrome on treatment compliance in older hypertensive patients. AB - BACKGROUND: Frailty syndrome (FS) is an important problem in older persons. It may develop concomitantly to many aging-related diseases, including arterial hypertension, and exerts detrimental effects on both their outcomes and treatment compliance. OBJECTIVE: To analyze the effect of FS on treatment compliance in older hypertensive patients. MATERIALS AND METHODS: This study of 300 hypertensive patients (167 women and 133 men) aged between 65 and 91 years (mean 71.75+/-7.79 years) was based on the analysis of medical documentation and survey with the Tilburg Frailty Indicator (TFI) and Hill-Bone High Blood Pressure Compliance Scale. RESULTS: Mean systolic and diastolic blood pressure values of the study subjects were 141.97 and 85.16 mm Hg, respectively. Mean time elapsed since the diagnosis of arterial hypertension was 13.74 years. FS was diagnosed in 65.67% of the study subjects. Mean global score of the Hill-Bone High Blood Pressure Compliance Scale was 20.75 points. TFI scores correlated significantly with the global score of the Hill-Bone High Blood Pressure Compliance Scale (R=0.509, P<0.001) and the values of its 2 subscales: Appointment Keeping (R=0.34, P<0.001) and Medication Taking (R=0.537, P<0.001). CONCLUSION: FS exerts a significant effect on treatment compliance of older hypertensive patients. Treatment compliance is modulated by patients' sex (worse compliance in men), education (better compliance in subjects with higher education), and TFI scores (worse compliance in patients with FS). PMID- 28553088 TI - Blood pressure reactivity to mental stress is attenuated following resistance exercise in older hypertensive women. AB - PURPOSE: This study aimed to investigate the effects of resistance exercise (RE) on autonomic control and blood pressure (BP) reactivity during mental stress (MS) in treated older hypertensive women. METHODS: Ten older hypertensive women (age =71.1+/-5.5 years; body mass index =24.2+/-3.9; mean BP [MBP] =85.4+/-3.5) underwent a protocol consisting of BP and heart rate variability (HRV) output assessments at baseline and during MS, and these measurements were taken before and 60 minutes after two bouts of RE (traditional and circuit). MS was induced through a computerized 3-minute Stroop color-word test before and 1 hour after each exercise session; BP was measured every minute during MS, and HRV was monitored as a measure of cardiac autonomic control. RESULTS: A significant effect of time on systolic BP (Deltapre =17.4+/-12.8 versus Deltapost =12.5+/ 9.6; P=0.01), diastolic BP (Deltapre =13.7+/-7.1 versus Deltapost =8.8+/-4.5; P=0.01), and MBP (Deltapre =14.0+/-7.7 versus Deltapost =9.3+/-5.4; P<0.01) after RE was observed, with no differences between the two sessions. In addition, a significant effect of time on log-normalized low-frequency component of HRV (ms2; 5.3+/-0.8 pre-exercise MS versus 4.8+/-1.0 baseline value; P=0.023) was also observed, showing a significant change from baseline to MS before RE, but not after RE sessions. These results may be related to a lessened RE-mediated cardiac sympathetic activity during MS. CONCLUSION: RE is an effective tool to reduce BP reactivity to MS, which could therefore be associated with an acute reduction in cardiovascular risk. This result presents relevant clinical implications, combining previous evidence that recommends this exercise modality as an important component of an exercise program designed for the older and hypertensive subjects. PMID- 28553090 TI - Anti-amyloid aggregation activity of novel carotenoids: implications for Alzheimer's drug discovery. AB - Alzheimer's disease (AD) is the leading cause of dementia, affecting approximately 33.5 million people worldwide. Aging is the main risk factor associated with AD. Drug discovery based on nutraceutical molecules for prevention and treatment of AD is a growing topic. In this sense, carotenoids are phytochemicals present mainly in fruits and vegetables with reported benefits for human health. In this research, the anti-amyloidogenic activity of three carotenoids, cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin, was assessed. Cryptocapsin showed the highest bioactivity, while cryptocapsin-5,6 epoxide and zeaxanthin exhibited similar activity on anti-aggregation assays. Molecular modeling analysis revealed that the evaluated carotenoids might follow two mechanisms for inhibiting Abeta aggregation: by preventing the formation of the fibril and through disruption of the Abeta aggregates. Our studies provided evidence that cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin have anti amyloidogenic potential and could be used for prevention and treatment of AD. PMID- 28553091 TI - Improving the diagnosis and treatment of osteoporosis using a senior-friendly peer-led community education and mentoring model: a randomized controlled trial. AB - BACKGROUND: This randomized controlled trial (RCT) evaluated a 6-month peer-led community education and mentorship program to improve the diagnosis and management of osteoporosis. METHODS: Ten seniors (74-90 years of age) were trained to become peer educators and mentors and deliver the intervention. In the subsequent RCT, 105 seniors (mean age =80.5+/-6.9; 89% female) were randomly assigned to the peer-led education and mentorship program (n=53) or control group (n=52). Knowledge was assessed at baseline and 6 months. Success was defined as discussing osteoporosis risk with their family physician, obtaining a bone mineral density assessment, and returning to review their risk profile and receive advice and/or treatment. RESULTS: Knowledge of osteoporosis did not change significantly. There was no difference in knowledge change between the two groups (mean difference =1.3, 95% confidence interval [CI] of difference -0.76 to 3.36). More participants in the intervention group achieved a successful outcome (odds ratio 0.16, 95% CI 0.06-0.42, P<0.001). CONCLUSION: Peer-led education and mentorship can promote positive health behavior in seniors. This model was effective for improving osteoporosis risk assessment, diagnosis, and treatment in a community setting. PMID- 28553092 TI - Relationship between sarcopenia and physical activity in older people: a systematic review and meta-analysis. AB - Physical activity (PA) has been identified as beneficial for many diseases and health disorders, including sarcopenia. The positive influence of PA interventions on sarcopenia has been described previously on many occasions. Current reviews on the topic include studies with varied PA interventions for sarcopenia; nevertheless, no systematic review exploring the effects of PA in general on sarcopenia has been published. The main aim of this study was to explore the relationship between PA and sarcopenia in older people on the basis of cross-sectional and cohort studies. We searched PubMed, Scopus, EBSCOhost, and ScienceDirect for articles addressing the relationship between PA and sarcopenia. Twenty-five articles were ultimately included in the qualitative and quantitative syntheses. A statistically significant association between PA and sarcopenia was documented in most of the studies, as well as the protective role of PA against sarcopenia development. Furthermore, the meta-analysis indicated that PA reduces the odds of acquiring sarcopenia in later life (odds ratio [OR] =0.45; 95% confidence interval [CI] 0.37-0.55). The results of this systematic review and meta-analysis confirm the beneficial influence of PA in general for the prevention of sarcopenia. PMID- 28553093 TI - Applications of direct-to-consumer hearing devices for adults with hearing loss: a review. AB - BACKGROUND: This systematic literature review is aimed at investigating applications of direct-to-consumer hearing devices for adults with hearing loss. This review discusses three categories of direct-to-consumer hearing devices: 1) personal sound amplification products (PSAPs), 2) direct-mail hearing aids, and 3) over-the-counter (OTC) hearing aids. METHOD: A literature review was conducted using EBSCOhost and included the databases CINAHL, MEDLINE, and PsycINFO. After applying prior agreed inclusion and exclusion criteria, 13 reports were included in the review. RESULTS: Included studies fell into three domains: 1) electroacoustic characteristics, 2) consumer surveys, and 3) outcome evaluations. Electroacoustic characteristics of these devices vary significantly with some meeting the stringent acoustic criteria used for hearing aids, while others producing dangerous output levels (ie, over 120-dB sound pressure level). Low-end (or low-cost) devices were typically poor in acoustic quality and did not meet gain levels necessary for most adult and elderly hearing loss patterns (eg, presbycusis), especially in high frequencies. Despite direct-mail hearing aids and PSAPs being associated with lower satisfaction when compared to hearing aids purchased through hearing health care professionals, consumer surveys suggest that 5%-19% of people with hearing loss purchase hearing aids through direct-mail or online. Studies on outcome evaluation suggest positive outcomes of OTC devices in the elderly population. Of note, OTC outcomes appear better when a hearing health care professional supports these users. CONCLUSION: While some direct-to consumer hearing devices have the capability to produce adverse effects due to production of dangerously high sound levels and internal noise, the existing literature suggests that there are potential benefits of these devices. Research of direct-to-consumer hearing devices is limited, and current published studies are of weak quality. Much effort is needed to understand the benefits and limitations of such devices on people with hearing loss. PMID- 28553094 TI - Effects of a simple prototype respiratory muscle trainer on respiratory muscle strength, quality of life and dyspnea, and oxidative stress in COPD patients: a preliminary study. AB - BACKGROUND: The aim of this study was to evaluate the efficiency of a simple prototype device for training respiratory muscles in lung function, respiratory muscle strength, walking capacity, quality of life (QOL), dyspnea, and oxidative stress in patients with COPD. METHODS: Thirty COPD patients with moderate severity of the disease were randomized into three groups: control (n=10, 6 males and 4 females), standard training (n=10, 4 males and 6 females), and prototype device (n=10, 5 males and 5 females). Respiratory muscle strength (maximal inspiratory pressure [PImax] and maximal expiratory pressure [PEmax]), lung function (forced vital capacity [FVC], percentage of FVC, forced expiratory volume in 1 second [FEV1], percentage of FEV1 [FEV1%], and FEV1/FVC), 6-minute walking distance (6MWD), QOL, and oxidative stress markers (total antioxidant capacity [TAC]), glutathione (GSH), malondialdehyde (MDA), and nitric oxide (NO) were evaluated before and after 6 weeks of training. Moreover, dyspnea scores were assessed before; during week 2, 4, and 6 of training; and at rest after training. RESULTS: All parameters between the groups had no statistical difference before training, and no statistical change in the control group after week 6. FVC, FEV1/FVC, PImax, PEmax, QOL, MDA, and NO showed significant changes after 6 weeks of training with either the standard or prototype device, compared to pre-training. FEV1, FEV1%, 6MWD, TAC, and GSH data did not change statistically. Furthermore, the results of significant changes in all parameters were not statistically different between training groups using the standard and prototype device. The peak dyspnea scores increased significantly in week 4 and 6 when applying the standard or prototype device, and then lowered significantly at rest after 6 weeks of training, compared to pre-training. CONCLUSION: This study proposes that a simple prototype device can be used clinically in COPD patients as a standard device to train respiratory muscles, improving lung function and QOL, as well as involving MDA and NO levels. PMID- 28553095 TI - Deterioration of quality of life is associated with the exacerbation frequency in individuals with alpha-1-antitrypsin deficiency - analysis from the German Registry. AB - BACKGROUND: Alpha-1-antitrypsin deficiency (AATD) is a rare hereditary disease that is associated with a higher risk to develop chronic obstructive pulmonary disease and liver cirrhosis. Previous cross-sectional studies on AATD individuals have shown a relationship between worse St George's Respiratory Questionnaire (SGRQ) scores and elevated exacerbation rate or high cigarette consumption. There is a lack of longitudinal data on the relationship between the exacerbation rate and worsening of SGRQ during disease. The aim of this study was to provide not only cross-sectional data but also information about the deterioration in quality of life over a follow-up period up to 7 years (median follow-up period of 3.33 years). METHODS: We investigated questionnaire-based data of the German AATD registry concerning the relationship between SGRQ and exacerbation frequency, smoking history, forced expiratory volume in 1 second (FEV1) and carbon monoxide diffusion capacity (DLCO) first in cross-sectional analysis and later in longitudinal analysis. RESULTS: Eight hundred sixty-eight individuals with protease inhibitor ZZ (PiZZ) genotype with an average age of 52.6+/-12.8 years had an SGRQ score of 45.7+/-20.6. SGRQ significantly correlated with the exacerbation frequency within the last 2 years (r=0.464; P<0.001), smoking history (r=0.233; P<0.001), FEV1 (r=-0.436; P<0.001), DLCO (r=-0.333; P<0.001), and patients' age (r=0.292; P<0.001). Individuals with occupational dust exposure had significantly worse quality of life (P<0.001). Mean annual deterioration of SGRQ in all patients with available follow-up data (n=286) was 1.21+/-4.45 points per year. Univariate and multivariate analysis showed a significant relationship between worsening of SGRQ/year and exacerbation frequency in the follow-up period (r=0.144; P=0.015). CONCLUSION: Worsening of SGRQ is associated with the exacerbation frequency in individuals with PiZZ AATD. PMID- 28553096 TI - Pulmonary artery to aorta ratio is associated with cardiac structure and functional changes in mild-to-moderate COPD. AB - BACKGROUND: The ratio of the diameter of the pulmonary artery (PA) to the diameter of the aorta (PA:A) on computed tomography (CT) imaging is associated with both COPD exacerbation and pulmonary hypertension. The mechanisms of PA enlargement in COPD are poorly understood. METHODS: In this retrospective, single center study we evaluated pulmonary function, CT scans, right heart catheterizations, and echocardiography in 88 subjects with mild-to-moderately severe COPD. A sensitivity analysis was performed in 43 subjects in whom CT scan and echocardiogram were performed within 50 days of each other. To evaluate the association between PA:A ratio and echocardiographic parameters and hemodynamics, we performed simple correlations and multivariable linear regression analysis adjusting for lung function, age, sex, race, and diastolic function. RESULTS: All subjects had preserved left ventricular (LV) systolic function (LV ejection fraction 62.7%+/-5.5%). Among them, 56.8% had evidence of diastolic dysfunction. There was no association between PA:A ratio and the presence of diastolic dysfunction. In a multivariable model, PA:A ratio was associated with right ventricular (RV) chamber size (beta=0.015; P<0.003), RV wall thickness (beta=0.56; P<0.002), and RV function (-0.49; P=0.05). In the subgroup of subjects with testing within 50 days, the association with RV chamber size persisted (beta=0.017; P=0.04), as did the lack of association with diastolic function. PA:A ratio was also associated with elevated PA systolic pressures (r=0.62; P=0.006) and pulmonary vascular resistance (r=0.46; P=0.05), but not pulmonary arterial wedge pressure (r=0.17; P=0.5) in a subset of patients undergoing right heart catheterization. CONCLUSION: In patients with mild-to moderately severe COPD and preserved LV function, increased PA:A ratio occurs independent of LV diastolic dysfunction. Furthermore, the PA:A ratio is associated with right heart structure and function changes, as well as pulmonary hemodynamics. These findings indicate that PA:A ratio is a marker of intrinsic pulmonary vascular changes rather than impaired LV filling. PMID- 28553097 TI - Two CHRN susceptibility variants for COPD are genetic determinants of emphysema and chest computed tomography manifestations in Chinese patients. AB - Quantitative computed tomography (CT) measures of emphysema have been shown to be associated with increased mortality in humans, but genetic variants affecting the quantitative parameters of chest CT that measure degree of emphysema have not yet been examined. In this study, using available chest CT data from a total of 344 emphysema patients, we assessed the correlations between five chronic obstructive pulmonary disease (COPD) susceptibility variants in the cholinergic receptor nicotinic (CHRN) genes and the degree of emphysema and chest CT manifestations. We verified that most of the parameters were significantly correlated with the degree of emphysema. Compared to rs76071148AA and TT genotype carriers, the rs76071148AT genotype carriers exhibited a decreased probability of having severe emphysema (odds ratio [OR] =0.63, 95% confidence interval [CI] =0.40-0.99), whereas the variant rs8040868C allele was negatively correlated with the emphysema index (P=0.002). Interestingly, further stratification analysis grouped by spirometry-diagnosed COPD status revealed that the variant rs8040868C (CT + CC) genotypes exerted a protective effect against severe emphysema with borderline significance (OR =0.41, 95% CI =0.16-1.05) and affected the mean lung density, emphysema index, ratio of airway wall thickness to airway dimensions (AWT/AD), and AWT grade in spirometry-diagnosed non-COPD subjects. The rs76071148 variant was also significantly associated with AWT/AD and AWT grade in those individuals. In summary, we determined that rs8040868 and rs76071148 are promising indicators of the degree of emphysema and chest CT manifestations, especially in spirometry-diagnosed non-COPD subjects. PMID- 28553098 TI - The effect of COPD severity and study duration on exacerbation outcome in randomized controlled trials. AB - BACKGROUND: When discontinuation in COPD randomized controlled trials (RCTs) is unevenly distributed between treatments (differential dropout), the capacity to demonstrate treatment effects may be reduced. We investigated the impact of the time of differential dropout on exacerbation outcomes in RCTs, in relation to study duration and COPD severity. METHODS: A post hoc analysis of 2,345 patients from three RCTs of 6- and 12-month duration was performed to compare budesonide/formoterol and formoterol in moderate, severe, and very severe COPD. Outcomes were exacerbation rate, time-to-first exacerbation, or discontinuation; patients were stratified by disease severity. Outcomes were studied by censoring data monthly from 1 to 12 months. RESULTS: In patients treated with budesonide/formoterol, annualized exacerbation rates (AERs) were comparable for each study duration (rate ratio [RR] =0.6). With formoterol, the AER decreased with study duration (RR =1.20 at 1 month to RR =0.86 at 12 months). There was a treatment-related difference in exacerbation rates of 45%-48% for shorter study durations (<=4 months) and 27% for 12-month duration. This treatment-related difference in exacerbation rates was comparable for the three disease severities in studies <=4 months (range: 39%-51%), but this difference decreased with longer study durations, especially in more severe groups (22% and 29% at 12 months). There were fewer discontinuations with budesonide/formoterol; the treatment related difference in time-to-first discontinuation decreased by study duration (35%, 30%, 26%, and 22% at 3, 6, 9, and 12 months, respectively). Numbers of differential dropouts increased with increasing disease severity, being greatest during second, third, and fourth months. CONCLUSIONS: COPD severity and study duration impact exacerbation as an outcome in double-blind RCTs. This effect is most obvious in patients with severe/very severe COPD and in studies that are longer than 4 months. Early differential dropout particularly impacts study outcome, producing a "healthy survivor effect," which reduces estimations of treatment impact on exacerbations. PMID- 28553099 TI - Development of a self-scored persistent airflow obstruction screening questionnaire in a general Japanese population: the Hisayama study. AB - BACKGROUND: The use of a simple screening questionnaire to detect persistent airflow obstruction (AO) in COPD may facilitate the early, accurate diagnosis of COPD in general practice settings. OBJECTIVE: This study developed an original persistent AO questionnaire for screening individuals with COPD in a general Japanese population. METHODS: A working group was established to generate initial draft questionnaire items about COPD. Eligible subjects aged 40 and older living in Japan were solicited to participate in a health checkup from 2014 to 2015. In study I, 2,338 subjects who fully completed the initial draft questionnaire and who had valid spirometry measurements were statistically analyzed to determine the final questionnaire items as a COPD screening questionnaire (COPD-Q). Persistent AO was defined as a post-bronchodilator FEV1/FVC <0.70. In study II, the working group analyzed the weighted scores for individual items and established a cutoff point for the COPD-Q based on the data of 2,066 subjects in the Hisayama study. Receiver operating characteristic (ROC) curves were used to examine the ability of the COPD-Q to discriminate between subjects with and without AO. RESULTS: The five-item COPD-Q was established based on 19 initial draft items in study I and the weighted scores of individual items. The overall area under the ROC curve for the COPD-Q was 0.796 (95% confidence interval, 0.707 0.788). A cutoff of 4 points resulted in a sensitivity of 71.0% and a specificity of 70.1%. The positive predictive value was 10.8%, and the negative predictive value was 97.9%. The crude odds ratio of the COPD-Q for AO was 5.8. CONCLUSION: The five-item COPD-Q is a useful questionnaire for diagnosing persistent AO in a general Japanese population and is expected to be an effective first-stage screening tool for detecting COPD. PMID- 28553100 TI - Relationships between heart rate target determined in different exercise testing in COPD patients to prescribed with individualized exercise training. AB - BACKGROUND: It has been scientifically proven that pulmonary rehabilitation improves exercise tolerance and facilitates the carrying out of daily physical activities. To optimize the physical and physiological benefits, it is necessary to individualize the training intensity for each patient. The aim of this study is to compare the heart rate (HR) responses to three exercise modalities measuring aerobic fitness in chronic obstructive pulmonary disease patients, in order to easily prescribe individual target HRs for endurance training. PATIENTS AND METHOD: Fifty COPD patients (mean age: 60.1+/-8.5 years) were included in the study. Each patient carried out a cardiopulmonary exercise test, a 6-minute walk test (6MWT) and a 6-minute stepper test (6MST). During these tests, HR was recorded continuously. After the cardiopulmonary exercise test, the HR was noted at the ventilatory threshold (VT) and at the end of the two exercise field tests (6MWTpeak and 6MSTpeak). The values of the HR during the last 3 minutes of both field tests were averaged (6MWT456 and 6MST456). Finally, the HR at 60% of the HR reserve was calculated with the values of the HR measured during 6MWT and 6MST (HRr60%walk, HRr60%step). RESULTS: The HRs measured during the 6MST were significantly higher than those measured during the 6MWT. The HRr60%step was not significantly different from 6MWT456 and 6MWTpeak HR (P=0.51; P=0.48). A significant correlation was observed between 6MWT456 and 6MWTpeak (r=0.58). The 6MWT456 and 6MWTpeak HR were correlated with HRr60%step (r=0.68 and r=0.62). The VT could be determined in 28 patients. The HRVT was not different from 6MWT456, 6MWTpeak, and HRr60%step (P=0.57, P=0.41 and P=0.88) and was correlated to 6MWT456, 6MWTpeak, and HRr60%step (r=0.45, r=0.40, r=0.48). CONCLUSION: An individualized target HR for endurance training can be prescribed from the HR measured during routine tests, such as 6MWT or 6MST. PMID- 28553101 TI - The PLATINO study: description of the distribution, stability, and mortality according to the Global Initiative for Chronic Obstructive Lung Disease classification from 2007 to 2017. AB - BACKGROUND: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report provides a framework for classifying COPD reflecting the impacts of disease on patients and for targeting treatment recommendations. The GOLD 2017 introduced a new classification with 16 subgroups based on a composite of spirometry and symptoms/exacerbations. METHODS: Data from the population-based PLATINO study, collected at baseline and at follow-up, in three sites in Latin America were analyzed to compare the following: 1) the distribution of COPD patients according to GOLD 2007, 2013, and 2017; 2) the stability of the 2007 and 2013 classifications; and 3) the mortality rate over time stratified by GOLD 2007, 2013, and 2017. RESULTS: Of the 524 COPD patients evaluated, most of them were classified as Grade I or II (GOLD 2007) and Group A or B (GOLD 2013), with ~70% of those classified as Group A in GOLD 2013 also classified as Grade I in GOLD 2007 and the highest percentage (41%) in Group D (2013) classified as Grade III (2007). According to GOLD 2017, among patients with Grade I airflow limitation, 69% of them were categorized into Group A, whereas Grade IV patients were more evenly distributed among Groups A-D. Most of the patients classified by GOLD 2007 remained in the same airflow limitation group at the follow-up; a greater temporal variability was observed with GOLD 2013 classification. Incidence-mortality rate in patients classified by GOLD 2007 was positively associated with increasing severity of airflow obstruction; for GOLD 2013 and GOLD 2017 (Groups A-D), highest mortality rates were observed in Groups C and D. No clear pattern was observed for mortality across the GOLD 2017 subgroups. CONCLUSION: The PLATINO study data suggest that GOLD 2007 classification shows more stability over time compared with GOLD 2013. No clear patterns with respect to the distribution of patients or incidence-mortality rates were observed according to GOLD 2013/2017 classification. PMID- 28553102 TI - Two-dimensional collagen-graphene as colloidal templates for biocompatible inorganic nanomaterial synthesis. AB - In this study, natural graphite was first converted to collagen-graphene composites and then used as templates for the synthesis of nanoparticles of silver, iron oxide, and hydroxyapatite. X-ray diffraction did not show any diffraction peaks of graphene in the composites after inorganic nucleation, compared to the naked composite which showed (002) and (004) peaks. Scanning electron micrographs showed lateral gluing/docking of these composites, possibly driven by an electrostatic attraction between the positive layers of one stack and negative layers of another, which became distorted after inorganic nucleation. Docking resulted in single layer-like characteristics in certain places, as seen under transmission electron microscopy, but sp2/sp3 ratios from Raman analysis inferred three-layer composite formation. Strain-induced folding of these layers into uniform clusters at the point of critical nucleation, revealed beautiful microstructures under scanning electron microscopy. Lastly, cell viability studies using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays showed the highest cell viability for the collagen-graphene hydroxyapatite composites. In this manner, this study provided - to the field of nanomedicine - a new process for the synthesis of several nanoparticles (with low toxicity) of high interest for numerous medical applications. PMID- 28553103 TI - The metal nanoparticle-induced inflammatory response is regulated by SIRT1 through NF-kappaB deacetylation in aseptic loosening. AB - Aseptic loosening is the most common cause of total hip arthroplasty (THA) failure, and osteolysis induced by wear particles plays a major role in aseptic loosening. Various pathways in multiple cell types contribute to the pathogenesis of osteolysis, but the role of Sirtuin 1 (SIRT1), which can regulate inflammatory responses through its deacetylation, has never been investigated. We hypothesized that the downregulation of SIRT1 in macrophages induced by metal nanoparticles was one of the reasons for osteolysis in THA failure. In this study, the expression of SIRT1 was examined in macrophages stimulated with metal nanoparticles from materials used in prosthetics and in specimens from patients suffering from aseptic loosening. To address whether SIRT1 downregulation triggers these inflammatory responses, the effects of the SIRT1 activator resveratrol on the expression of inflammatory cytokines in metal nanoparticle stimulated macrophages were tested. The results demonstrated that SIRT1 expression was significantly downregulated in metal nanoparticle-stimulated macrophages and clinical specimens of prosthesis loosening. Pharmacological activation of SIRT1 dramatically reduced the particle-induced expression of inflammatory cytokines in vitro and osteolysis in vivo. Furthermore, SIRT1 regulated particle-induced inflammatory responses through nuclear factor kappa B (NF-kappaB) acetylation. Thus, the results of this study suggest that SIRT1 plays a key role in metal nanoparticle-induced inflammatory responses and that targeting the SIRT1 pathway may lead to novel therapeutic approaches for the treatment of aseptic prosthesis loosening. PMID- 28553104 TI - Nanoporosity improved water absorption, in vitro degradability, mineralization, osteoblast responses and drug release of poly(butylene succinate)-based composite scaffolds containing nanoporous magnesium silicate compared with magnesium silicate. AB - Bioactive composite macroporous scaffold containing nanoporosity was prepared by incorporation of nanoporous magnesium silicate (NMS) into poly(butylene succinate) (PBSu) using solvent casting-particulate leaching method. The results showed that the water absorption and in vitro degradability of NMS/PBSu composite (NMPC) scaffold significantly improved compared with magnesium silicate (MS)/PBSu composite (MPC) scaffold. In addition, the NMPC scaffold showed improved apatite mineralization ability, indicating better bioactivity, as the NMPC containing nanoporosity could induce more apatite and homogeneous apatite layer on the surfaces than MPC scaffold. The attachment and proliferation of MC3T3-E1 cells on NMPC scaffold increased significantly compared with MPC scaffold, and the alkaline phosphatase (ALP) activity of the cells on NMPC scaffold was expressed at considerably higher levels compared with MPC scaffold. Moreover, NMPC scaffold with nanoporosity not only had large drug loading (vancomycin) but also exhibited drug sustained release. The results suggested that the incorporation of NMS into PBSu could produce bioactive composite scaffold with nanoporosity, which could enhance water absorption, degradability, apatite mineralization and drug sustained release and promote cell responses. PMID- 28553105 TI - Preparation of a dual cored hepatoma-specific star glycopolymer nanogel via arm first ATRP approach. AB - A reductase-cleavable and thermo-responsive star-shaped polymer nanogel was prepared via an "arm-first" atom transfer radical polymerization approach. The nanogel consists of a thermo- and redox-sensitive core and a zwitterionic copolymer block. The dual sensitive core is composed of poly(N isopropylacrylamide) that is formed by disulfide crosslinking of N isopropylacrylamide. The zwitterionic copolymer block contains a poly(sulfobetaine methacrylate) component, a known anti-adsorptive moiety that extends blood circulation time, and a lactose motif of poly(2-lactobionamidoethyl methacrylamide) that specifically targets the asialoglycoprotein receptors (ASGP Rs) of hepatoma. Doxorubicin (DOX) was encapsulated into the cross-linked nanogels via solvent extraction/evaporation method and dialysis; average diameter of both blank and DOX-loaded nanogels was ~120 nm. The multi-responsiveness of nanogel drug release in different temperatures and redox conditions was assessed. After 24 h, DOX release was only ~20% at 30 degrees C with 0 mM glutathione (GSH), whereas over 90% DOX release was observed at 40 degrees C and 10 mM GSH, evidence of dual responsiveness to temperature and reductase GSH. The IC50 value of DOX-loaded nanogels was much lower in human hepatoma (HepG2) cells compared to non-hepatic HeLa cells. Remarkably, DOX uptake of HepG2 cells differed substantially in the presence and absence of galactose (0.31 vs 1.42 ug/mL after 48 h of incubation). The difference was non-detectable in HeLa cells (1.21 vs 1.57 ug/mL after 48 h of incubation), indicating that the overexpression of ASGP Rs leads to the DOX-loaded lactosylated nanogels actively targeting hepatoma. Our data indicate that the lactose-decorated star-shaped nanogels are dual responsive and hepatoma targeted, and could be employed as hepatoma-specific anti-cancer drug delivery vehicle for cancer chemotherapy. PMID- 28553106 TI - A green single-step procedure to synthesize Ag-containing nanocomposite coatings with low cytotoxicity and efficient antibacterial properties. AB - Implant-associated infections still pose a serious threat leading to several complications. This study reported an environmentally benign Ag-containing nanocomposite coating with efficient antibacterial property fabricated on the metal implant via electrophoretic deposition (EPD). In such coatings, Ag2O/AgCl mixed with chitosan/gelatin (CS/G) polymers work together to exert the antibacterial property which could act as an alternative to traditional Ag nanoparticles. Scanning electron microscopy images showed the shuttle fiber-like morphology distributed lamellarly and some nanoparticles carved uniformly into the cross section. Transmission electron microscopy results revealed a core-shell like structure of the released nanoparticles in experimental groups. The Ag containing coatings exhibited strong antibacterial properties against Staphylococcus aureus strains and Escherichia coli strains. Meanwhile, the CCK-8 tests showed that after assembling with chitosan and gelatin polymers, the cytotoxicity of Ag was largely decreased. In addition, such coatings also exhibited strong bond strength with metal substrates and good degradable properties. Therefore, such Ag-containing CS/G coatings fabricated via EPD may be a promising candidate to be administrated in controlling the implant-associated infections. PMID- 28553107 TI - 10-Hydroxycamptothecin (HCPT) nanosuspensions stabilized by mPEG1000-HCPT conjugate: high stabilizing efficiency and improved antitumor efficacy. AB - In this study, polyethylene glycol (PEG)ylated 10-hydroxycamptothecin (mPEG1000 HCPT) was synthesized and used as a stabilizer to prepare 10-hydroxycamptothecin (HCPT) nanosuspensions for their in vitro and in vivo antitumor investigation. The resultant HCPT nanosuspensions (HCPT-NSps) had a very high drug payload of 94.90% (w/w) and a mean particle size of 92.90+/-0.20 nm with narrow size distribution (polydispersity index of 0.16+/-0.01). HCPT-NSps could be lyophilized without the need of the addition of any cryoprotectant and then be reconstituted into nanosuspensions of a similar size by direct resuspension in water. HCPT was in crystalline form in HCPT-NSps. Using mPEG1000-HCPT as stabilizer, insoluble camptothecin and 7-ethyl-10-hydroxycamptothecin could also be easily made into nanosuspensions with similar features such as high drug payload, small particle size, and cryoprotectant-free freeze drying. The 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay indicated that the HCPT-NSps had a significantly higher cytotoxicity than HCPT injections, with 3.77 times lower IC50 value against HepG2 cells and 14.1 times lower IC50 value against MCF-7 cells. An in vivo study in H22 tumor-bearing mice after intravenous injection of HCPT-NSps demonstrated that HCPT-NSps significantly improved the antitumor efficacy compared to the commercially available HCPT injections (86.38% vs 34.97%) at the same dose of 5 mg/kg. Even at 1/4 of the dose, HCPT-NSps could also achieve a similar antitumor efficacy to that of HCPT injections. mPEG1000 HCPT may be a highly efficient stabilizer able to provide camptothecin-based drugs, and probably other antitumor agents containing aromatic structure, with unique nanosuspensions or nanocrystals for improved in vivo therapeutic efficacy. PMID- 28553108 TI - Platinum covalent shell cross-linked micelles designed to deliver doxorubicin for synergistic combination cancer therapy. AB - The preparation of polymer therapeutics capable of controlled release of multiple chemotherapeutic drugs has remained a tough problem in synergistic combination cancer therapy. Herein, a novel dual-drug co-delivery system carrying doxorubicin (DOX) and platinum(IV) (Pt[IV]) was developed. An amphiphilic diblock copolymer, PCL-b-P(OEGMA-co-AzPMA), was synthesized and used as a nanoscale drug carrier in which DOX and Pt(IV) could be packaged together. The copolymers were shell cross linked by Pt(IV) prodrug via a click reaction. Studies on the in vitro drug release and cellular uptake of the dual-drug co-delivery system showed that the micelles were effectively taken up by the cells and simultaneously released drugs in the cells. Futhermore, the co-delivery polymer nanoparticles caused much higher cell death in HeLa and A357 tumor cells than either the free drugs or single-drug-loaded micelles at the same dosage, exhibiting a synergistic combination of DOX and Pt(IV). The results obtained with the shell cross-linked micelles based on an anticancer drug used as a cross-linking linkage suggested a promising application of the micelles for multidrug delivery in combination cancer therapy. PMID- 28553109 TI - Bitistatin-functionalized fluorescent nanodiamond particles specifically bind to purified human platelet integrin receptor alphaIIbbeta3 and activated platelets. AB - Thromboembolic events (TEE) underwrite key causes of death in developed countries. While advanced imaging technologies such as computed tomography scans serve to diagnose blood clots during acute cardiovascular events, no such technology is available in routine primary care for TEE risk assessment. Here, we describe an imaging platform technology based on bioengineered fluorescent nanodiamond particles (F-NDPs) functionalized with bitistatin (Bit), a disintegrin that specifically binds to the alphaIIbbeta3 integrin, platelet fibrinogen receptor (PFR) on activated platelets. Covalent linkage of purified Bit to F-NDP was concentration-dependent and saturable, as validated by enzyme linked immunosorbent assay using specific anti-Bit antibodies. F-NDP-Bit interacted with purified PFR, either in immobilized or soluble form. Lotrafiban, a nonpeptide, alphaIIbbeta3 receptor antagonist, specifically blocked F-NDP-Bit PFR complex formation. Moreover, F-NDP-Bit specifically binds to activated platelets incorporated into a clot generated by thrombin-activated rat platelet rich plasma (PRP). Our results suggest that engineered F-NDP-Bit particles could serve as noninvasive, "real-time" optical diagnostics for clots present in blood vessels. PMID- 28553110 TI - Cisplatin-resistant lung cancer cell-derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100-5p-dependent manner. AB - Exosomes derived from lung cancer cells confer cisplatin (DDP) resistance to other cancer cells. However, the underlying mechanism is still unknown. A549 resistance to DDP (A549/DDP) was established. Microarray was used to analyze microRNA (miRNA) expression profiles of A549 cells, A549/DDP cells, A549 exosomes, and A549/DDP exosomes. There was a strong correlation of miRNA profiles between exosomes and their maternal cells. A total of 11 miRNAs were significantly upregulated both in A549/DDP cells compared with A549 cells and in exosomes derived from A549/DDP cells in contrast to exosomes from A549 cells. A total of 31 downregulated miRNAs were also observed. miR-100-5p was the most prominent decreased miRNA in DDP-resistant exosomes compared with the corresponding sensitive ones. Downregulated miR-100-5p was proved to be involved in DDP resistance in A549 cells, and mammalian target of rapamycin (mTOR) expression was reverse regulated by miR-100-5p. Exosomes confer recipient cells' resistance to DDP in an exosomal miR-100-5p-dependent manner with mTOR as its potential target both in vitro and in vivo. Exosomes from DDP-resistant lung cancer cells A549 can alter other lung cancer cells' sensitivity to DDP in exosomal miR-100-5p-dependent manner. Our study provides new insights into the molecular mechanism of DDP resistance in lung cancer. PMID- 28553111 TI - Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma. AB - In a previous study, a formulation of methotrexate (MTX) incorporated in the lipid bilayer of 100-nm liposomes in the form of diglyceride ester (MTX-DG, lipophilic prodrug) was developed. In this study, first, the interactions of MTX DG liposomes with various human and mouse tumor cell lines were studied using fluorescence techniques. The liposomes composed of egg phosphatidylcholine (PC)/yeast phosphatidylinositol/MTX-DG, 8:1:1 by mol, were labeled with fluorescent analogs of PC and MTX-DG. Carcinoma cells accumulated 5 times more MTX-DG liposomes than the empty liposomes. Studies on inhibitors of liposome uptake and processing by cells demonstrated that the formulation used multiple mechanisms to deliver the prodrug inside the cell. According to the data from the present study, undamaged liposomes fuse with the cell membrane only 1.5-2 hours after binding to the cell surface, and then, the components of liposomal bilayer enter the cell separately. The study on the time course of plasma concentration in mice showed that the area under the curve of MTX generated upon intravenous injection of MTX-DG liposomes exceeded that of intact MTX 2.5-fold. These data suggested the advantage of using liposomal formulation to treat systemic manifestation of hematological malignancies. Indeed, the administration of MTX-DG liposomes to recipient mice bearing T-cell leukemic lymphoma using a dose-sparing regimen resulted in lower toxicity and retarded lymphoma growth rate as compared with MTX. PMID- 28553112 TI - IONP-doped nanoparticles for highly effective NIR-controlled drug release and combination tumor therapy. AB - Despite advances in controlled drug delivery, drug delivery systems (DDSs) with controlled activated drug release and high spatial and temporal resolution are still required. Theranostic nanomedicine is capable of diagnosis, therapy, and monitoring the delivery and distribution of drug molecules and has received growing interest. In this study, a near-infrared light-controlled "off-on" DDS with magnetic resonance imaging and magnetic targeting properties was developed using a hybrid nanoplatform (carbon nanotubes [CNTs]-iron oxide nanoparticle). Doxorubicin (DOX) and distearoyl-sn-glycero-3-phosphoethanolamine-PEG were adsorbed onto CNTs-iron oxide nanoparticle, and then to avoid the unexpected drug release during circulation, 1-myristyl alcohol was used to encapsulate the CNTs drug complex. Herein, multifunctional DOX-loaded nanoparticles (NPs) with "off on" state were developed. DOX-NPs showed an obvious "off-on" effect (temperature increase, drug release) controlled by near-infrared light in vitro and in vivo. In the in vivo and in vitro studies, DOX-NPs exhibited excellent magnetic resonance imaging ability, magnetic targeting property, high biosafety, and high antitumor combined therapeutic efficacy (hyperthermia combined with chemotherapy). These results highlight the great potential of DOX-NPs in the treatment of cancer. PMID- 28553113 TI - Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats. AB - PURPOSE: Acute myocardial infarction (MI) is accompanied by myocardial inflammation, fibrosis, and ventricular remodeling that, when excessive or not properly regulated, may lead to heart failure. Previously, lipid core nanoparticles (LDE) used as carriers of the anti-inflammatory drug methotrexate (MTX) produced an 80-fold increase in the cell uptake of MTX. LDE-MTX treatment reduced vessel inflammation and atheromatous lesions induced in rabbits by cholesterol feeding. The aim of the study was to investigate the effects of LDE MTX on rats with MI, compared with commercial MTX treatment. MATERIALS AND METHODS: Thirty-eight Wistar rats underwent left coronary artery ligation and were treated with LDE-MTX, or with MTX (1 mg/kg intraperitoneally, once/week, starting 24 hours after surgery) or with LDE without drug (MI-controls). A sham surgery group (n=12) was also included. Echocardiography was performed 24 hours and 6 weeks after surgery. The animals were euthanized and their hearts were analyzed for morphometry, protein expression, and confocal microscopy. RESULTS: LDE-MTX treatment achieved a 40% improvement in left ventricular (LV) systolic function and reduced cardiac dilation and LV mass, as shown by echocardiography. LDE-MTX reduced the infarction size, myocyte hypertrophy and necrosis, number of inflammatory cells, and myocardial fibrosis, as shown by morphometric analysis. LDE-MTX increased antioxidant enzymes; decreased apoptosis, macrophages, reactive oxygen species production; and tissue hypoxia in non-infarcted myocardium. LDE MTX increased adenosine bioavailability in the LV by increasing adenosine receptors and modulating adenosine catabolic enzymes. LDE-MTX increased the expression of myocardial vascular endothelium growth factor (VEGF) associated with adenosine release; this correlated not only with an increase in angiogenesis, but also with other parameters improved by LDE-MTX, suggesting that VEGF increase played an important role in the beneficial effects of LDE-MTX. Overall effects of commercial MTX were minor, and did not improve LV function or infarction size. Both treatments did not induce any toxicity. CONCLUSION: The remarkable improvement in heart function and reduction in infarction size achieved by LDE-MTX supports future clinical trials. PMID- 28553114 TI - Ravuconazole self-emulsifying delivery system: in vitro activity against Trypanosoma cruzi amastigotes and in vivo toxicity. AB - Self-emulsifying drug delivery systems (SEDDSs) are lipid-based anhydrous formulations composed of an isotropic mixture of oil, surfactant, and cosurfactants usually presented in gelatin capsules. Ravuconazole (Biopharmaceutics Classification System [BCS] Class II) is a poorly water-soluble drug, and a SEDDS type IIIA was designed to deliver it in a predissolved state, improving dissolution in gastrointestinal fluids. After emulsification, the droplets had mean hydrodynamic diameters <250 nm, zeta potential values in the range of -45 mV to -57 mV, and showed no signs of ravuconazole precipitation. Asymmetric flow field-flow fractionation with dynamic and multiangle laser light scattering was used to characterize these formulations in terms of size distribution and homogeneity. The fractograms obtained at 37 degrees C showed a polydisperse profile for all blank and ravuconazole-SEDDS formulations but no large aggregates. SEDDS increased ravuconazole in vitro dissolution extent and rate (20%) compared to free drug (3%) in 6 h. The in vivo toxicity of blank SEDDS comprising Labrasol(r) surfactant in different concentrations and preliminary safety tests in repeated-dose oral administration (20 days) showed a dose dependent Labrasol toxicity in healthy mice. Ravuconazole-SEDDS at low surfactant content (10%, v/v) in Trypanosoma cruzi-infected mice was safe during the 20-day treatment. The anti-T. cruzi activity of free ravuconazole, ravuconazole-SEDDS and each excipient were evaluated in vitro at equivalent ravuconazole concentrations needed to inhibit 50% or 90% (IC50 and IC90), respectively of the intracellular amastigote form of the parasite in a cardiomyocyte cell line. The results showed a clear improvement of the ravuconazole anti-T. cruzi activity when associated with SEDDS. Based on our results, the repurposing of ravuconazole in SEDDS dosage form is a strategy that deserves further in vivo investigation in preclinical studies for the treatment of human T. cruzi infections. PMID- 28553115 TI - PMMA denture base material enhancement: a review of fiber, filler, and nanofiller addition. AB - This paper reviews acrylic denture base resin enhancement during the past few decades. Specific attention is given to the effect of fiber, filler, and nanofiller addition on poly(methyl methacrylate) (PMMA) properties. The review is based on scientific reviews, papers, and abstracts, as well as studies concerning the effect of additives, fibers, fillers, and reinforcement materials on PMMA, published between 1974 and 2016. Many studies have reported improvement of PMMA denture base material with the addition of fillers, fibers, nanofiller, and hybrid reinforcement. However, most of the studies were limited to in vitro investigations without bioactivity and clinical implications. Considering the findings of the review, there is no ideal denture base material, but the properties of PMMA could be improved with some modifications, especially with silanized nanoparticle addition and a hybrid reinforcement system. PMID- 28553116 TI - Comparative efficacy and safety of antipsychotics in the treatment of schizophrenia: a network meta-analysis in a Japanese population. AB - BACKGROUND: The relative efficacy and tolerability of antipsychotics for schizophrenia are considerably well studied. This study aimed to examine whether previous findings could be replicated in a genetically distinct and homogenous group (ie, Japanese patients with schizophrenia) and whether previous findings could be extended to a broader range of antipsychotics with previously unclear relative efficacy and tolerability. METHODS: Bayesian network meta-analysis was performed in which randomized trials comparing any of the following interventions were included: second-generation antipsychotics, haloperidol, or placebo. The primary outcomes for efficacy and acceptability were the response rate and all cause discontinuation. The secondary outcomes included the improvement of Positive and Negative Syndrome Scale scores, discontinuation because of adverse events, and individual adverse events. RESULTS: Eighteen relevant studies were identified (total n=3,446; aripiprazole =267, blonanserin =285, clozapine =47, clocapramine =295, haloperidol =857, mosapramine =493, olanzapine =179, paliperidone =136, perospirone =146, placebo =138, quetiapine =212, and risperidone =338; mean study duration =8.33+/-1.41 weeks). In primary outcomes, olanzapine and paliperidone showed efficacy than placebo, and olanzapine and paliperidone showed superior acceptability compared with placebo. There were differences in the incidences of individual adverse events (the best antipsychotic: extrapyramidal symptoms = olanzapine, hyperprolactinemia- related symptoms = quetiapine, sedation = paliperidone, and weight change = blonanserin) among antipsychotics. CONCLUSION: Although the current analysis exclusively included Japanese patients with schizophrenia, no remarkable differences were observed in efficacy and safety compared with previous meta-analyses. Diverse hierarchies in safety outcomes also support the implication that individual risk expectations for adverse events can guide clinical decisions. However, the sample size was relatively limited. Additional efficacy and safety data are required to fully obtain a conclusive understanding. PMID- 28553117 TI - Robot-assisted gait training for stroke patients: current state of the art and perspectives of robotics. AB - In this review, we give a brief outline of robot-mediated gait training for stroke patients, as an important emerging field in rehabilitation. Technological innovations are allowing rehabilitation to move toward more integrated processes, with improved efficiency and less long-term impairments. In particular, robot mediated neurorehabilitation is a rapidly advancing field, which uses robotic systems to define new methods for treating neurological injuries, especially stroke. The use of robots in gait training can enhance rehabilitation, but it needs to be used according to well-defined neuroscientific principles. The field of robot-mediated neurorehabilitation brings challenges to both bioengineering and clinical practice. This article reviews the state of the art (including commercially available systems) and perspectives of robotics in poststroke rehabilitation for walking recovery. A critical revision, including the problems at stake regarding robotic clinical use, is also presented. PMID- 28553119 TI - Potential role of pre- and postnatal testosterone levels in attention deficit/hyperactivity disorder: is there a sex difference? AB - OBJECTIVE: Both prenatal testosterone (T) exposure and postnatal T levels have been associated with developing neural circuitry and behavioral systems. This study examined the potential correlation between pre- and postnatal T levels and behavioral and neurocognitive profiles of children with attention deficit/hyperactivity disorder (ADHD). METHODS: Two hundred ADHD patients with a mean age of 8.7+/-2.0 years (158 boys and 42 girls) were recruited. The ratio of the length of the right index finger (2D) to that of the right ring finger (4D) (2D/4D ratio) served as a surrogate of prenatal T exposure, and postnatal T was determined using salivary T concentration. Behavioral symptoms were evaluated using the Swanson, Nolan, and Pelham - Version IV Scale for ADHD (SNAP-IV). Neurocognitive function was assessed using the Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV) and Conners' Continuous Performance Test (CPT). RESULTS: Lower 2D/4D ratios were associated with comorbid disruptive behavior disorders (t=2.15, P=0.033) in all participants. Among the boys with ADHD, neither 2D/4D ratios nor salivary T levels were associated with behavioral symptoms or neurocognitive function. Among the girls with ADHD, the salivary T level was positively correlated with the Perceptual Reasoning Index of the WISC IV (r=0.48, P=0.001) and the Confidence Index (r=0.37, P=0.017) and Omission Errors of the CPT (r=0.62, P<0.001). CONCLUSION: Findings suggest that a higher prenatal T exposure is associated with a greater risk of developing disruptive behavior disorders, and T may exert differential neurocognitive effects between boys and girls with ADHD. However, the neurobiological mechanisms of T involved in the pathogenesis of ADHD warrant further investigation. PMID- 28553120 TI - Productivity and deadweight losses due to relapses of schizophrenia in Japan. AB - BACKGROUND: No study has examined the financial impact of relapses on schizophrenia from the perspective of Japanese society. This study aimed to estimate the societal costs in Japan caused by the relapses of schizophrenia. METHODS: The societal costs in Japan in 2013 due to relapses of schizophrenia were estimated by summing the productivity loss and deadweight loss caused by schizophrenia relapses in 2013. Deterministic sensitivity analysis was conducted for deadweight loss rate, relapse rate, and patient income. RESULTS: Japan incurred JPY 55,039 million societal costs because of relapses in 2013. This consists of JPY 3,990 million for productivity loss and JPY 51,049 million for deadweight loss. Rate of deadweight loss is the most significant cost driver in the sensitivity analysis. CONCLUSION: Relapses of schizophrenia could generate huge amount of societal costs by reducing labor productivity and economic efficiency. To curb these costs, relapse prevention is desired in treating schizophrenia. PMID- 28553121 TI - Iatrogenic visual aura: a case report and a brief review of the literature. AB - Iatrogenic migraine aura following transseptal catheterization has only rarely been reported in the literature. We report the case of a 60-year-old female who presented with new onset of migraine with visual aura 1 day after transseptal cryoballoon catheter ablation for atrial fibrillation. The patient had a 5-year history of typical migraine without aura and had never experienced visual aura before the cardiac intervention. The neurological examination, fundoscopy, and blood tests were normal. The magnetic resonance imaging of the brain showed small vessel ischemia without evidence of vessel ischemic changes in the occipital lobes and large blood vessel disease. A change in the characteristics of existing migraine could occur following an iatrogenic episode, which in this case was catheter ablation for atrial fibrillation. A new onset of aura is considered an indication for a brain scan as it may signify underlying new pathology. PMID- 28553118 TI - Psychosis in parkinsonism: an unorthodox approach. AB - Psychosis in Parkinson's disease (PD) is currently considered as the occurrence of hallucinations and delusions. The historical meaning of the term psychosis was, however, broader, encompassing a disorganization of both consciousness and personality, including behavior abnormalities, such as impulsive overactivity and catatonia, in complete definitions by the International Classification of Diseases-10 (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Our review is aimed at reminding that complex psychotic symptoms, including impulsive overactivity and somatoform disorders (the last being a recent controversial entity in PD), were carefully described in postencephalitic parkinsonism (PEP), many decades before dopaminergic treatment era, and are now described in other parkinsonisms than PD. Eminent neuropsychiatrists of the past century speculated that studying psychosis in PEP might highlight its mechanisms in other conditions. Yet, functional assessments were unavailable at the time. Therefore, the second part of our article reviews the studies of neural correlates of psychosis in parkinsonisms, by taking into account both theories on the narrative functions of the default mode network (DMN) and hypotheses on DMN modulation. PMID- 28553122 TI - Peripheral venous blood neutrophil-to-lymphocyte ratio predicts survival in patients with advanced gastric cancer treated with neoadjuvant chemotherapy. AB - BACKGROUND: Accurate and useful predictors of gastric carcinoma treated with neoadjuvant chemotherapy are lacking at present. We aim to explore the potential prognostic significance of the neutrophil-to-lymphocyte ratio (NLR) in advanced gastric cancer receiving S-1 plus oxaliplatin (SOX) or oxaliplatin and capecitabine (XELOX) regimen. METHODS: We enrolled 91 patients with advanced gastric cancer treated with neoadjuvant chemotherapy from August 2008 to September 2015. The peripheral venous blood samples were collected before neoadjuvant chemotherapy. The NLR was divided into two groups: low NLR <2.17 group and high NLR >=2.17 group. Univariate analysis on disease-free survival (DFS) and overall survival (OS) were generated using the Kaplan-Meier method and compared using the log-rank test. Prognostic factors were assessed by univariate analyses, and the independent prognostic factors were evaluated using multivariate analysis (Cox's proportional-hazards regression model). RESULTS: The univariate analysis showed that median DFS and median OS were worse for high NLR values than low NLR values before neoadjuvant chemotherapy (median DFS: 19.97 and 26.87 months, respectively, P=0.299; median OS: 25.83 and 29.73 months, respectively, P=0.405). Multivariate analysis showed that the NLR before neoadjuvant chemotherapy was not an independent prognostic factor for DFS and OS. However, median DFS and median OS were worse for high neutrophil values than for low neutrophil values (median DFS: 21.03 and 26.87 months, respectively, P=0.396; median OS: 24.43 and 29.37 months, respectively, P=0.534); for low lymphocyte values than for high lymphocyte values before neoadjuvant chemotherapy (median DFS: 22.33 and 26.87 months, respectively, P=0.624; median OS: 26.37 and 27.93 months, respectively, P=0.584). Nevertheless, patients with low NLR had better 1 year, 3-year, and 5-year DFS and OS rates. CONCLUSION: NLR may serve as a cheap and convenient prognostic indicator in gastric carcinoma patients receiving SOX or XELOX neoadjuvant chemotherapy. Low NLR may help the doctors to take efficient treatment measures for gastric cancer. PMID- 28553123 TI - The HIV protease inhibitor, nelfinavir, as a novel therapeutic approach for the treatment of refractory pediatric leukemia. AB - PURPOSE: Refractory pediatric leukemia remains one of the leading causes of death in children. Intensification of current chemotherapy regimens to improve the outcome in these children is often limited by the effects of drug resistance and cumulative toxicity. Hence, the search for newer agents and novel therapeutic approaches are urgently needed to formulate the next-generation early-phase clinical trials for these patients. MATERIALS AND METHODS: A comprehensive library of antimicrobials, including eight HIV protease inhibitors (nelfinavir [NFV], saquinavir, indinavir, ritonavir, amprenavir, atazanavir, lopinavir, and darunavir), was tested against a panel of pediatric leukemia cells by in vitro growth inhibition studies. Detailed target modulation studies were carried out by Western blot analyses. In addition, drug synergy experiments with conventional and novel antitumor agents were completed to identify effective treatment regimens for future clinical trials. RESULTS: Several of the HIV protease inhibitors showed cytotoxicity at physiologically relevant concentrations (half maximal inhibitory concentration values ranging from 1-24 uM). In particular, NFV was found to exhibit the most potent antileukemic properties across all cell lines tested. Mechanistic studies show that NFV leads to the induction of autophagy and apoptosis possibly through the induction of endoplasmic reticulum stress. Furthermore, interference with cell signaling pathways, including Akt and mTOR, was also noted. Finally, drug combination studies have identified agents with potential for synergy with NFV in its antileukemic activity. These include JQ1 (BET inhibitor), AT101 (Bcl-2 family inhibitor), and sunitinib (TK inhibitor). CONCLUSION: Here, we show data demonstrating the potential of a previously unexplored group of drugs to address an unmet therapeutic need in pediatric oncology. The data presented provide preclinical supportive evidence and rationale for future studies of these agents for refractory leukemia in children. PMID- 28553124 TI - Efficacy and safety of pemetrexed on recurrent primary central nervous system lymphomas in China: a prospective study. AB - BACKGROUND: Pemetrexed, a new and novel agent for primary central nervous system lymphomas (PCNSLs), has shown to be efficient as a savage therapy for recurrent PCNSLs. However, more studies are needed. A prospective study was performed on 17 recurrent PCNSL patients with pemetrexed at Shandong Tumor Hospital in China to assess the efficacy and safety of pemetrexed for recurrent PCNSL patients. MATERIALS AND METHODS: The medical records and imaging data on all the cases of recurrent PCNSL patients with pemetrexed in our study were collected during August 2012 and April 2015. Folic acid, B12, and dexamethasone were used to induce toxicities related to pemetrexed. Patients were treated with pemetrexed at a dose of 900 mg/m2 intravenously every 3 weeks, and one cycle consists of 6 weeks. RESULTS: A total of 17 cases of recurrent PCNSL patients were enrolled in our study, including 10 males and 7 females with a median age of 66.2 years (ranging from 35 to 81). After the treatment, five cases had complete remission, with partial remission in five cases, stable disease in four cases, and progressive disease in three cases. Consequently, the overall response rate was 58.8%, and the disease control rate was 82.4%. The median overall survival was 7.8 months (95% confidence interval: 5.9-9.6 months) in the study of recurrent PCNSL patients. CONCLUSION: This study has been the first clinical trial that applied pemetrexed to treat recurrent PCNSL patients in China, and results indicated that chemotherapy using large pemetrexed may become an effective treatment for PCNSL recurrence with modest toxicity. PMID- 28553125 TI - Holliday junction-recognizing protein promotes cell proliferation and correlates with unfavorable clinical outcome of hepatocellular carcinoma. AB - AIM: To investigate the expression and clinical significance of Holliday junction recognizing protein (HJURP) in hepatocellular carcinoma (HCC). METHODS: In this study, we detected the expression of HJURP protein in samples of 164 patients with HCC, and based on this, we divided the patients into two cohorts: high expression of HJURP and low expression of HJURP. We analyzed the correlation between HJURP expression and the clinicopathological factors using chi-square test. Survival significance of HJURP was defined by Kaplan-Meier method and log rank test, and the independent prognostic factors were identified by Cox regression model. Using function assays of HCC cell lines, we investigated the influence of HJURP on the proliferation of HCC cells. RESULTS: In our study, the proportion of patients with high HJURP expression was 25.6%, which was significantly associated with the tumor size and Barcelona clinic liver cancer stage. Univariate analysis confirmed that high HJURP expression was remarkably associated with poorer overall survival rates (P=0.003), as well as tumor number (P=0.016), tumor differentiation (P=0.047), TNM stage (P=0.005), and Barcelona clinic liver cancer stage (P=0.004). Multivariate analysis confirmed that high HJURP expression (P<0.001) acted as an independent prognostic risk factor of unfavorable prognosis. Real-time polymerase chain reaction analysis revealed that the expression of HJURP was significantly higher in HCC tissues than that in the corresponding normal liver tissues. Moreover, we demonstrated that HJURP overexpression could accelerate HCC cell line proliferation, whereas HJURP knockdown could attenuate the proliferation. CONCLUSION: High HJURP expression was an independent prognostic biomarker of HCC, predicting poorer prognosis. HJURP also played an important role in HCC cell proliferation. PMID- 28553126 TI - RNA-binding protein HuR promotes bladder cancer progression by competitively binding to the long noncoding HOTAIR with miR-1. AB - The elevated expressions of RNA-binding protein HuR and long noncoding HOX transcript antisense RNA (HOTAIR) are observed in numerous cancers. And HuR often exerts its promotive effects on tumorigenesis via binding to AU-rich elements in target transcripts and thus regulating the expression of target transcripts. However, the roles and related mechanisms of HuR/HOTAIR in bladder cancer progression have never been formally tested. Here, we found that the expression level of HuR was higher in clinical bladder cancer samples than in normal adjacent samples, mirroring that of HOTAIR, and their expression showed strong correlation. Knockdown of HuR/HOTAIR in bladder cancer inhibited cell proliferation, migration, invasion, and promoted cell apoptosis. Notably, HuR interacted and stabilized HOTAIR mRNA and knockdown of HuR decreased HOTAIR expression. Additionally, HOTAIR was identified as a potential target of miR-1 in bladder cancer cells. Interestingly, overexpression of HOTAIR enhanced HuR expression and increased cytoplasmic accumulation of HuR, thus enhancing HOTAIR expression in turn. But mutation of miR-1 binding site in HOTAIR canceled the effects of HOTAIR on HuR expression. Overall, we identified a regulatory loop between HOTAIR and HuR during the progression of bladder cancer, which could be exploited to curb bladder cancer progression. PMID- 28553127 TI - Real-world health care utilization in asthma patients using albuterol sulfate inhalation aerosol (ProAir (r) HFA) with and without integrated dose counters. AB - BACKGROUND: Accurate tracking of the administered dose of asthma rescue inhalers is critical for optimal disease management and is related to reductions in rates of unscheduled health care utilization in asthma patients. There are few published data on the real-world impact of rescue inhalers with integrated dose counters (IDCs) on health care resource utilization (HRU) for asthma patients. This study evaluates HRU among users of ProAir(r) hydrofluoroalkane (HFA) (albuterol sulfate inhalation aerosol), with IDC versus without IDC, in asthma patients. METHODS: This was a retrospective administrative claims study of asthma patients receiving a new prescription for albuterol inhalation aerosol without IDC during 2 years (January 2011-December 2012) or with IDC during the first full year after IDC implementation in the USA (July 2013-July 2014). Six months of continuous enrollment with medical and prescription drug benefits were required before and after the first prescription during the study period. Data on respiratory-related hospitalizations and emergency department (ED) visits were collected during the follow-up period. RESULTS: A total of 135,305 (32%) patients used albuterol inhalation aerosol with IDC, and 287,243 (68%) patients received albuterol inhalation aerosol without IDC. After adjusting for baseline confounding factors, the odds ratio (OR) for experiencing a respiratory-related hospitalization (OR=0.92; 95% confidence interval [CI] 0.88-0.96) or ED visit (OR=0.92; 95% CI 0.90-0.94) was significantly lower among patients using albuterol inhalation aerosol with IDC versus without IDC. CONCLUSION: In a real world setting, asthma patients using ProAir HFA with IDC experienced significantly fewer hospitalizations and ED visits compared with patients using ProAir HFA without IDC. Dosage information provided by IDCs may allow providers to better understand patients' disease severity and aid in titrating controller medications and also decrease the likelihood that the canister will be empty when needed, thereby enhancing disease management and reducing HRU. PMID- 28553128 TI - A retrospective analysis of delays in the diagnosis of lung cancer and associated costs. AB - PURPOSE: Diagnosis of lung cancer at advanced stages can result in missed treatment opportunities, worse outcomes, and higher health care costs. This study evaluated the wait time to diagnose non-small-cell lung cancer (NSCLC) and the cost of diagnosis and treatment based on the stage at diagnosis. PATIENTS AND METHODS: Adult patients diagnosed with NSCLC between January 2007 and September 2011 were identified from a proprietary oncology registry and linked to health insurance claims from a large US health insurance company. Continuous enrollment in the health plan was required for at least 12 months prediagnosis (baseline) and at least 3 months postdiagnosis (follow-up). Use of diagnostic tests and time to diagnosis were examined. The rates of health care utilization and per-patient per-month (PPPM) health care costs were calculated. RESULTS: A total of 1,210 patients with NSCLC were included in the analysis. Most patients (93.6%) had evidence of diagnostic tests beginning 5 to 6 months prior to diagnosis, and most were diagnosed at an advanced stage (23% Stage IIIb and 46% Stage IV). The PPPM total health care costs in USD pre- and postdiagnosis were $2,407+/-$3,364 (mean+/-standard deviation) and $16,577+/-$33,550, respectively. PPPM total health care costs and utilization after lung cancer diagnosis were significantly higher among patients diagnosed at Stage IV disease and lowest among patients diagnosed at Stage I disease ($7,239 Stage I, $9,484 Stage II, $11,193 Stage IIIa, $17,415 Stage IIIb, and $21,441 Stage IV). CONCLUSION: This study showed that most patients experienced long periods of delay between their first diagnostic test for lung cancer and a definitive diagnosis, and the majority were diagnosed at advanced stages of disease. Costs associated with the management of lung cancer increased substantially with higher stages at diagnosis. Procedures that diagnose lung cancer at earlier stages may allow for less resource use and costs among patients with lung cancer. PMID- 28553129 TI - Medical resource utilization in dermatomyositis/polymyositis patients treated with repository corticotropin injection, intravenous immunoglobulin, and/or rituximab. AB - BACKGROUND: Dermatomyositis and polymyositis (DM/PM) are rare, incurable inflammatory diseases that cause progressive muscle weakness and can be associated with increased medical resource use (MRU). When corticosteroid treatment is unsuccessful, patients may receive intravenous immunoglobulin (IVIg), rituximab, or repository corticotropin injection (RCI). This study compared real-world, non-medication MRU between patients treated with RCI and those treated with IVIg and/or rituximab for DM/PM. METHODS: Claims of DM/PM patients were analyzed from the combination of three commercial health insurance databases in the United States from July 2009 to June 2014. Patients treated with RCI were propensity score matched to those treated with IVIg, rituximab, and both (IVIg+rituximab) based on demographics, prior clinical characteristics, and prior MRU. Per-patient per-month (PPPM) MRU and costs were compared using Poisson regression and generalized linear modeling, respectively. RESULTS: One-hundred thirty-two RCI, 1,150 IVIg, and 562 rituximab patients had an average age of 52.6, 46.6, and 51.7 years, respectively, and roughly two-thirds were female. After matching, there were no significant differences in demographics or prior clinical characteristics. RCI patients had fewer PPPM hospitalizations (0.09 vs 0.17; P=0.049), shorter length of stay (LOS; 3.24 days vs 4.55 days; P=0.004), PPPM hospital outpatient department (HOPD) visits (0.60 vs 1.39; P<0.001), and PPPM physician office visits (2.01 vs 2.33; P=0.035) than IVIg. RCI had fewer PPPM HOPD visits (0.56 vs 0.92; P<0.001) than rituximab. Patients treated with RCI had shorter LOS (2.18 days vs 5.15; P<0.001) and less PPPM HOPD visits (0.53 vs 1.26; P<0.001) than IVIg+rituximab. Total non-medication PPPM costs were 23% 75% lower for RCI compared to IVIg ($2,126 vs $3,964; P<0.001), rituximab ($2,008 vs $2,607; P=0.018), and IVIg+rituximab ($1,234 vs $4,858; P<0.001). CONCLUSION: Patients treated with RCI had less PPPM non-medication MRU and costs than those treated with IVIg and/or rituximab, particularly in the hospital setting where significant costs are incurred. PMID- 28553130 TI - Patient satisfaction and reported outcomes on the management of actinic keratosis. AB - Actinic keratosis (AK) is a common dermatologic condition in which hyperplastic epidermal lesions develop in response to excessive and chronic exposure to ultraviolet (UV) radiation. If left untreated, AK can progress to squamous cell carcinomas of the skin. Incidence is rising worldwide as a result of the progressive aging of populations and an increase in lifetime cumulative exposure to UV radiation. Currently, various treatment options exist, which range from topical medications to light-based therapies and procedural modalities. In this article, we will review the treatment options for AK with a focus on assessments of patient satisfaction with treatment. PMID- 28553131 TI - Antipollution skin protection - a new paradigm and its demonstration on two active compounds. AB - BACKGROUND: Urban pollution is a major source of concern for human health and is a complex of many environmental factors. The topical exposure to pollution activates cutaneous stress. OBJECTIVE: In this study, we tested the antipollution protection of two active components: Dead Sea minerals (Dead Sea mineral-rich water [DSW]) and anionic polysaccharide (PolluStop(r) [PS]). MATERIALS AND METHODS: Two representative pollution models were studied using reconstructed epidermis: 1) mixture of pollutants (MOP) containing heavy metals and atmospheric particulate matter and 2) ozone exposure. DSW and PS were topically applied alone or in combination, and their protection against pollution was assessed by testing the levels of the inflammation markers interleukin 1alpha (IL-1alpha) and prostaglandin E2 (PGE2). RESULTS: MOP exposure induced IL-1alpha release, which was attenuated following pre-application with DSW and PS alone or in combination. Ozone exposure induced IL-1alpha and PGE2 release. Pre-application with DSW or PS alone did not inhibit IL-1alpha and PGE2 overproduction. Only when DSW and PS were mixed together, inhibition of these inflammatory markers was observed. CONCLUSION: The observations reveal the potential use of active agents in combination for a selective mode of protection from urban pollution. This is because many active materials cannot solely provide a broad protection against different types of pollutants. This strategy might be beneficial for future antipollution regimen formulated in both pharmaceutical and cosmetic products. PMID- 28553132 TI - CYP2C19*2 status in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. AB - PURPOSE: Genetic polymorphisms have been linked to an increased predisposition to developing certain diseases. For example, patients of Han-Chinese descent carrying the HLA-B*1502 allele are at an increased risk of developing Stevens Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) if given carbamazepine. Given the complexity of in vivo drug metabolism, it is plausible that the activity of enzyme systems unrelated to specific drug metabolism may be important. Although multiple biomarkers have been identified in unique ethnic groups, there has yet to be a study investigating the presence of the slow metabolizing allele of CYP2C19, denoted CYP2C19*2, in diverse groups and the risk of developing SJS/TEN. PATIENTS AND METHODS: This study looked into the carrier status of CYP2C19*2, a poor metabolizing variant of CYP2C19, in patients diagnosed with SJS/TEN. We looked at its status in our series as a whole and when patients were divided by ethnicity. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissue of patients with biopsy-proven SJS/TEN and real-time polymerase chain reaction was used to assess for the presence of CYP2C19*2. RESULTS: CYP2C19*2 status was determined in 47 patients. Twenty-nine of these 47 patients had a single medication implicated as causing their disease, and eight of these patients were heterozygous or homozygous for CYP2C19*2. There was insufficient evidence to conclude that the presence of CYP2C19*2 is an independent predictor of risk for developing SJS/TEN in our series as a whole. This analysis also confirmed that the frequency of the CYP2C19*2 polymorphism within the different ethnicities in our series did not vary statistically from reported ethnic rates. CONCLUSION: Our study was unable to show a relationship between CYP2C19*2 status and predisposition toward SJS/TEN. We had a heterogeneous population, making it difficult to control for possible confounding factors. PMID- 28553133 TI - Inter-instrumental comparison for the measurement of electrolytes in patients admitted to the intensive care unit. AB - OBJECTIVE: To investigate whether benchtop auto-analyzers (AAs) and arterial blood gas (ABG) analyzers, for measuring electrolyte levels of patients admitted to intensive care units (ICU), are equal and whether they can be used interchangeably. MATERIALS AND METHOD: This study was conducted on 98 patients admitted to the ICU of the Institute of Medicine, Kathmandu, Nepal between 15 October and 15 December 2016. The sample for AA was collected from the peripheral vein through venipuncture, and that for ABG analyzer was collected from radial artery simultaneously. Electrolyte levels were measured with ABG analyzer in the ICU itself, and with benchtop AA in the central clinical biochemistry laboratory. RESULTS: The mean value for sodium by AA was 144.6 (standard deviation [SD] 7.63) and by ABG analyzer 140.1 (SD 7.58), which was significant (p-value <0.001). The mean value for potassium by AA was 3.6 (SD 0.52) and by ABG analyzer 3.58 (SD 0.66). The Bland-Altman analysis with the 95% limit of agreement between methods were -4.45 to 13.11 mmol/L for sodium and the mean difference was 4.3 mmol/L and 1.15 to 1.24 mmol/L for potassium and the mean difference was 0.04 mmol/L. The United States Clinical Laboratory Improvement Amendments accepts a 0.5 mmol/L difference in measured potassium levels and a 4 mmol/L difference in measured sodium levels, in the gold standard measure of the standard calibration solution. The passing and Bablok regression with 95% confidence interval has an intercept of zero and slope one for both sodium and potassium, and the 95% of random difference is -6.32 to 6.32 for sodium and -0.84 to 0.84 for potassium, showing no significant deviation from linearity. CONCLUSION: It can be concluded that AA and ABG analyzers may be used interchangeably for measurement of potassium in the Institute of Medicine, while the same cannot be concluded for the measurement of sodium, because of the significant difference in sodium measurement by the two instruments. PMID- 28553134 TI - Validation of the Norwegian Pain Sensitivity Questionnaire. AB - BACKGROUND AND PURPOSE: There is a large variation in people's reactions to painful stimuli. Although some conditions are more painful, the variation between people is larger than the reaction to pain across conditions. Induced experimental pain is one way to assess some aspects of these differences in pain perception. Experimental nociceptive testing is time consuming and not always feasible in a clinical setting. In order to overcome the obstacles of assessing pain sensitivity using experimental stimulation, the Pain Sensitivity Questionnaire (PSQ) was developed. The purpose of this study is to validate the Norwegian version of the PSQ. METHODS: Construct validity was examined through an exploratory principal component factor analysis with varimax rotation. Internal consistency was measured by Cronbach's alpha reliability for subscales and the total PSQ. As confounding variables such as age and gender may contribute to the experience of pain, a regression analysis was performed with demographic variables and PSQ scores as independent variables and the experimental measures of pain as the dependent variable. RESULTS: The factor analysis yielded at two factor solution, with an eigenvalue greater than one, explain 58% of the variance. Cronbach's alpha for the PSQ was 0.92. In the regression analysis, only PSQ scores contributed to explain the experimental pain intensity and tolerance. Gender only influenced the experimental pain threshold, as men had statistically significant higher heat pain threshold than women. CONCLUSION: This study shows that PSQ is a valid and reliable questionnaire and might be a promising instrument for assessing pain sensitivity in Norwegian clinical settings. Further studies are needed to examine whether the PSQ can be used in clinical settings to predict postoperative pain and the development of chronic pain. PMID- 28553135 TI - Impact of different analgesic depths and abdominal trauma of different severities on stress and recovery of rats undergoing total intravenous anesthesia. AB - A number of animal models have been developed to examine the pathophysiological consequences of surgical procedures, but anesthetic methods, monitoring, and management measures in these models are very different from those used in humans. This study was designed to create a rat model of abdominal surgery using anesthetic methods and perioperative treatment similar to those used in the clinic and to investigate the effects of different injury severities and depths of anesthesia and analgesia on surgical stress and postoperative recovery. Abdominal skin/muscle incision was compared with exploratory laparotomy in rats under propofol intravenous anesthesia, accompanied by perioperative measures such as oxygen inhalation, fluid infusion, warmth, blood gas analysis, and infection prevention. Stress indices (mean arterial pressure, heart rate, blood glucose, and plasma corticosterone) were monitored during anesthesia and surgery, and recovery indicators (body weight, food consumption, and pain) were measured after surgery. In addition, animals undergoing laparotomy were subjected to low and high dosages of propofol and sufentanil, in order to examine the relationship between anesthetic and analgesic depth and stress on recovery. Exploratory laparotomy induced a greater stress response and caused slower postoperative recovery as measured than somatic injury. High-dose sufentanil downregulated plasma corticosterone and improved postoperative recovery more effectively than high-dose propofol (P<0.05). Taken together, a rat model of abdominal surgery using anesthetic methods and perioperative treatment similar to those used in the clinic was successfully developed. It showed a positive correlation between severity of surgical trauma and stress response and postoperative recovery and a significant role of adequate analgesia in reducing surgical stress and improving postoperative recovery. PMID- 28553136 TI - Chronic stress moderates the impact of social exclusion on pain tolerance: an experimental investigation. AB - BACKGROUND: Experiences of social pain due to social exclusion may be processed in similar neural systems that process experiences of physical pain. The present study aimed to extend the findings on social exclusion and pain by examining the impact of social exclusion on an affective (ie, heat pain tolerance) and a sensory component of pain (ie, heat pain intensity). Whether a potential effect may be moderated by chronic life stress, social status, or social sup-port was further examined. MATERIALS AND METHODS: A community-based sample of 59 women was studied. Social exclusion and inclusion were experimentally manipulated by using a virtual ball-tossing game called Cyberball in which participants were randomly assigned to either being excluded or being included by two other virtual players. Heat pain tolerance and intensity were assessed before and after the game. Potential psychosocial moderators were assessed via a questionnaire. RESULTS: The main finding of this study is that chronic stress moderates the impact of social exclusion on pain tolerance (p<0.05). When chronic stress was high, socially excluded participants showed a lower heat pain tolerance than participants who were socially included. Contrary to the authors' hypothesis, pain sensitivity was increased in socially included participants compared with socially excluded participants after the game (p<0.05). CONCLUSION: Higher levels of chronic stress may enhance the vulnerability of affective pain processing to acute social exclusion. PMID- 28553137 TI - Post-sternotomy pain syndrome following cardiac surgery: case report. AB - Over 2 million people undergo sternotomy worldwide for heart surgery each year, and many develop post-sternotomy pain syndrome (PSPS) which persists in the anterior thorax. In some patients, PSPS lasts for many years or suddenly reappears a long time after the sternotomy. The exact etiology of PSPS is unknown. This article presents a case report of a patient with a diagnosis of PSPS (after cardiac surgery 4 years prior) for whom an osteopathic approach was used, which successfully eliminated the pain. In a previous study, we demonstrated that this osteopathic procedure could reduce sternal pain associated with a recent surgical wound. Further efforts are needed to understand the reasons for PSPS. In light of new scientific data, these osteopathic techniques could contribute to a multidisciplinary approach to solve the problem. PMID- 28553138 TI - Children's and adolescents' relationship to pain during cancer treatment: a preliminary validation of the Pain Flexibility Scale for Children. AB - OBJECTIVES: Children with cancer often suffer from pain. Pain is associated with psychological distress, which may amplify the pain experience. In chronic pain, it has been shown that psychological acceptance is helpful for both adults and children. For experimentally induced pain, interventions fostering psychological acceptance have been shown to predict increases in pain tolerance and reductions in pain intensity and discomfort of pain. A single subject study aiming to nurture psychological acceptance for children with cancer experiencing pain has shown promising results. No instruments measuring psychological acceptance in acute pain are yet available. The aim of the current study was to develop and preliminarily evaluate an instrument to measure psychological acceptance in children experiencing pain during cancer treatment. METHODS: A test version of the Pain Flexibility Scale for Children was sent to all children aged 7-18 years undergoing cancer treatment in Sweden at the time of the study. Exploratory factor analysis was used. Internal consistency, test-retest reliability, and convergent validity were examined. RESULTS: Sixty-one children participated in the study. A two-factor solution with Promax rotation was found to best represent the data. Internal consistency was good to excellent (a =0.87-0.91). The total scale and the subscales demonstrated temporal stability (Intraclass correlation coefficient =0.56-0.61) and satisfactory convergent validity (r=-0.27 to -0.68). DISCUSSION: The Pain Flexibility Scale for Children measuring psychological acceptance in children with cancer experiencing pain is now available for use. This enables the evaluation of acceptance as a mediator for treatment change in the context of acute pain in children with cancer, which in turn is a step forward in the development of psychological treatments to help children cope with the pain during these difficult circumstances. The scale shows good psychometric properties but needs further validation, particularly considering the small sample size. PMID- 28553139 TI - Periarticular dextrose prolotherapy instead of intra-articular injection for pain and functional improvement in knee osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is a degenerative disease that can lead to painful and dysfunctional joints. Prolotherapy involves using injections to produce functional restoration of the soft tissues of the joint. Intra-articular injections are controversial because of the introduction of needles into the articular capsule. OBJECTIVES: To compare the effect of periarticular versus intra-articular prolotherapy on pain and disability in patients with knee OA. STUDY DESIGN: Randomized double-blind controlled clinical trial. SETTING: Single center, university hospital (Imam Hossein Hospital, Tehran, Iran). METHODS: A total of 104 patients with chronic knee OA were enrolled. In the intra-articular group, 8 mL of 10% dextrose and 2 mL of 2% lidocaine were injected. Injections were repeated at 1 and 2 weeks after the first injection. In the periarticular group, 5 mL of 20% dextrose and 5 mL of 1% lidocaine were injected subcutaneously at 4 points in the periarticular area. Pain and disability, as assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), were recorded at each follow-up visit at 1, 2, 3, 4, and 5 months post-injection. RESULTS: The visual analog scale score was significantly lower in the periarticular compared with the intra-articular group at the 2-, 3-, 4-, and 5 month visits but not at 1 month. Morning stiffness and difficulty in rising from sitting were improved in both groups and were not signifi-cantly different in the peri- and intra-articular groups. Pain, joint locking, and limitation scores were all improved in both groups. Difficulty in walking on flat surfaces or climbing stairs, and sitting and standing pain, were all improved in both groups from 1 to 5 months after treatment. LIMITATIONS: WOMAC scores are subjective and could be a limitation of the study. CONCLUSION: Periarticular prolotherapy has comparable effects on pain and disability due to knee OA to intra-articular injections, while avoiding risks of complications. PMID- 28553140 TI - Current perspectives on CHEK2 mutations in breast cancer. AB - Checkpoint kinase 2 (CHEK2) is a serine/threonine kinase which is activated upon DNA damage and is implicated in pathways that govern DNA repair, cell cycle arrest or apoptosis in response to the initial damage. Loss of kinase function has been correlated with different types of cancer, mainly breast cancer. CHEK2 functionality is affected by different missense or deleterious mutations. CHEK2*1100delC and I157T are most studied in populations all over the world. Although these variants have been identified in patients with breast cancer, their frequency raises doubts about their importance as risk factors. The present article reviews the recent advances in research on CHEK2 mutations, focusing on breast cancer, based on the latest experimental data. PMID- 28553141 TI - Invasive lobular carcinoma of the male breast - a systematic review with an illustrative case study. AB - Male breast cancer is rare, comprising only 1% of all mammary cancers; invasive ductal carcinoma is by far the commonest subtype in both men and women. Though lobular breast cancer is the second most common subtype seen in women, such cancers are extremely uncommon in men, and this is likely related to the lack of lobular development in the male breast. Thus, due to the rarity of this subtype among breast cancers, compounded by the overall rarity of breast cancer in men, current understanding of the pathogenesis of this disease and its management is largely derived from case series and extrapolation of information from the larger cohort of female patients. This paper provides a systematic review on invasive lobular carcinoma of the male breast in the context of an illustrative case study. A comprehensive analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results Data 1973-2013 leading to an exploration of the pathogenesis, epidemiology, clinical presentation, diagnosis, tumor characteristics, and management of lobular breast carcinoma in men is also discussed. Lobular subtype of breast cancer remains an enigmatic elusive disease that needs additional research to unravel its overall pathogenesis and molecular profile to provide insight for improved therapeutic management options. PMID- 28553142 TI - Considering renal risk while managing cancer. AB - Renal function is an important consideration in the management of patients with advanced cancer. There is a reciprocal relationship between cancer and the kidney: chronic kidney disease can increase the risk of developing cancer, and patients with cancer often experience renal impairment owing to age, disease related factors and nephrotoxic treatments. As therapies for cancer continue to improve, patients are living longer with their disease, potentially extending the period over which they are susceptible to long-term complications. Furthermore, secondary symptoms, such as bone metastases or infections, may arise that will require treatment. Certain treatments, including chemotherapy, antibiotics and some bone-targeted agents, are nephrotoxic and may require dose modifications or interruptions to prevent renal injury. Nephrologists should play a key role in the identification and management of renal impairment in patients with cancer. Furthermore, they may be able to provide advice on protecting the kidneys in instances where nephrotoxic agents require dose reductions or interruptions, and when novel therapies or combinations are used. Collaboration between oncologists and nephrologists is important to optimal patient management. This article reviews the relationship between cancer and kidney disease and examines the treatments that may impact kidney function. Considerations for monitoring renal function are also discussed. PMID- 28553143 TI - Simvastatin modulates gingival cytokine and MMP production in a rat model of ligature-induced periodontitis. AB - PURPOSE: The aim of this study was to evaluate the effect of simvastatin on the synthesis of cytokines TNF-alpha and IL-10 and metalloproteinase (MMPs) 2 and 9 in a rat model of ligature-induced periodontitis. MATERIALS AND METHODS: Twenty Wistar rats were used, and a cotton ligature was place in a subgingival position encircling the entire cervix of the first molar of the left (ipsilateral) side of the mandible. The right (contralateral) side of the mandible had no ligature placed and was used as control. After the ligature placement, animals were randomly assigned to two experimental groups (n=10): 1) rats with ligature + vehicle (saline; 10 mL/kg; orally) and 2) rats with ligature + simvastatin (25 mg/kg; orally). After 14 days of treatment, the animals were euthanized by anesthetic overdose and the gingival tissue was removed and homogenized in appropriate buffer. MMP-2 and -9 release as well as the IL-10 and TNF-alpha levels were detected by enzyme-linked immunosorbent assay. Statistical comparison was performed by unpaired Student's t-test, with p<0.05 representing significance. RESULTS: No differences were observed for TNF-alpha production between the groups (p>0.05). However, IL-10 was upregulated in simvastatin treated animals (1.8-fold increase) in comparison with the vehicle-treated group (p<0.05). Simvastatin reduced the gingival levels of MMP-9 (64.3%) in comparison with vehicle-treated samples (p<0.05). CONCLUSION: Oral treatment with simvastatin increased the release of IL-10 and reduced the MMP-9 in ligature induced periodontitis model in rats. PMID- 28553144 TI - Transdermal delivery of combined hormonal contraception: a review of the current literature. AB - The transdermal patch provides an effective and convenient option for hormonal contraception. The patch currently on the US market contains 150 ug norelgestromin and 35 ug ethinylestradiol (EE). The 20 cm2 patch is applied once weekly for 3 weeks, followed by a patch-free week, for a 21-7 cycle. Typical failure rates are similar to that of combined oral contraceptives (COCs). Transdermal delivery results in less peaks and troughs of estrogen, but a higher total estrogen exposure compared with COCs. Though studies show mixed results, the risk of developing venous thromboembolism (VTE) is about twice as high with the patch as with COCs; however, the absolute risk of VTE remains low. The side effect profile is similar to that of COCs, with slightly higher rates of breast tenderness plus a unique adverse effect of application site reactions. Two new patches have been developed, one containing gestodene and EE in Europe and another containing levonorgestrel and EE. Overall, the patch provides an alternative to COCs for women who want autonomy and the benefit of not needing to take a pill daily, with similar efficacy and tolerability. PMID- 28553145 TI - Anxiety and depression in patients with endometriosis: impact and management challenges. AB - Endometriosis is one of the most common gynecological diseases and affects ~10% of women in reproductive age. The most common clinical signs of endometriosis are menstrual irregularities, chronic pelvic pain (CPP), dysmenorrhea, dyspareunia and infertility. Symptoms of endometriosis often affect psychological and social functioning of patients. For this reason, endometriosis is considered as a disabling condition that may significantly compromise social relationships, sexuality and mental health. Considering this point, the aim of this narrative review is to elucidate the impact of anxiety and depression in the management of women with endometriosis. Psychological factors have an important role in determining the severity of symptoms, and women who suffer from endometriosis report high levels of anxiety, depression and other psychiatric disorders. In addition, endometriosis is one of the most important causes of CPP; women with endometriosis suffer from a wide range of pelvic pain such as dysmenorrhea, dyspareunia, nonmenstrual (chronic) pelvic pain, pain at ovulation, dyschezia and dysuria. Several studies have underlined the influence of CPP on quality of life and psychological well-being of women with endometriosis. Data suggest that the experience of pelvic pain is an important component of endometriosis and may significantly affect emotive functioning of affected women. It has been demonstrated that high levels of anxiety and depression can amplify the severity of pain. Further studies are needed to better understand the relationship between psychological factors and perception of pain. Treatment of endometriosis may be hormonal or surgical. Surgery is the primary treatment for more severe forms of endometriosis. There are few data in the literature about the influence of psychological factors and psychiatric comorbidities on the effectiveness of treatments. It is important to evaluate the presence of previous psychiatric diseases in order to select the most appropriate treatment for the patient. PMID- 28553147 TI - Inappropriate gestational weight gain among teenage pregnancies: prevalence and pregnancy outcomes. AB - OBJECTIVE: To study the prevalence and pregnancy outcomes of inappropriate gestational weight gain (GWG) among teenage pregnant women. METHODS: A retrospective descriptive study was conducted on 2,165 teenage pregnant women who attended our antenatal clinic between January 2007 and August 2015. Adverse pregnancy outcomes, including maternal and neonatal outcomes of women with inappropriate GWG, including underweight and overweight, were studied and compared with those of women with appropriate GWG. RESULTS: Complete data of 1,943 women were obtained. Among these women, the mean age was 17.4+/-1.4 years and mean body mass index at first visit was 19.1+/-3.0 kg/m2. The prevalence of inappropriate GWG was 61.7%. Underweight women were more likely to experience anemia and preterm delivery, whereas overweight women required more cesarean sections because of cephalopelvic disproportion and preeclampsia, compared to women with appropriate weight gain (all P<0.001). The rates of gestational diabetes mellitus among women who were underweight, overweight, or appropriate weight were not significantly different. CONCLUSION: More than 60% of teenage pregnancies showed inappropriate GWG. GWG had a significant impact on pregnancy outcomes. PMID- 28553148 TI - Severe preeclampsia and eclampsia: incidence, complications, and perinatal outcomes at a low-resource setting, Mpilo Central Hospital, Bulawayo, Zimbabwe. AB - BACKGROUND: Severe preeclampsia is a disorder of pregnancy characterized by high blood pressure and significant proteinuria after 20 weeks gestation. Severe preeclampsia and eclampsia have considerable adverse impacts on maternal, fetal, and neonatal health especially in low-resource countries. Hypertensive disorders of pregnancy are the third leading cause of maternal deaths in Sub-Saharan Africa. Significant avoidable maternal and neonatal morbidity and mortality may result. OBJECTIVES: This study aimed 1) to determine the incidence of severe preeclampsia/eclampsia in a low-resource setting; 2) to determine the maternal complications of severe preeclampsia/eclampsia in a low-resource setting; 3) to determine the perinatal outcomes of severe preeclampsia/eclampsia in a low resource setting. METHODS: This was a retrospective descriptive cohort study carried out at Mpilo Central Hospital, a tertiary teaching referral government hospital in a low-resource setting in Bulawayo, Zimbabwe. Data were obtained from the birth registers in labor ward, intensive care unit, and neonatal intensive care unit of patients who had a diagnosis of severe preeclampsia or eclampsia for the period January 1, 2016, to December 31, 2016. The case notes were retrieved and the demographic, clinical, and outcome data were gathered. RESULTS: There were 9,086 deliveries at the institution during the period January 1, 2016, to December 31, 2016. There were 121 cases of severe preeclampsia/eclampsia. The incidence of severe preeclampsia/eclampsia was 1.3% at Mpilo Central Hospital. The most common major complication was HELLP syndrome (9.1%). Maternal mortality was 1.7%. There were 127 babies born with six sets of twins, 49.6% of the babies were lost through stillbirths and early neonatal deaths. CONCLUSION: The incidence of severe preeclampsia/eclampsia at Mpilo Central Hospital was 1.3%. The most common maternal complication was hemolysis elevated liver enzymes low platelet syndrome. Maternal mortality was 1.7% due to acute renal failure. Nearly half (49.6%) of the babies born were lost to stillbirths and early neonatal deaths. PMID- 28553146 TI - Recurrent pregnancy loss: current perspectives. AB - Recurrent pregnancy loss is an important reproductive health issue, affecting 2% 5% of couples. Common established causes include uterine anomalies, antiphospholipid syndrome, hormonal and metabolic disorders, and cytogenetic abnormalities. Other etiologies have been proposed but are still considered controversial, such as chronic endometritis, inherited thrombophilias, luteal phase deficiency, and high sperm DNA fragmentation levels. Over the years, evidence-based treatments such as surgical correction of uterine anomalies or aspirin and heparin for antiphospholipid syndrome have improved the outcomes for couples with recurrent pregnancy loss. However, almost half of the cases remain unexplained and are empirically treated using progesterone supplementation, anticoagulation, and/or immunomodulatory treatments. Regardless of the cause, the long-term prognosis of couples with recurrent pregnancy loss is good, and most eventually achieve a healthy live birth. However, multiple pregnancy losses can have a significant psychological toll on affected couples, and many efforts are being made to improve treatments and decrease the time needed to achieve a successful pregnancy. This article reviews the established and controversial etiologies, and the recommended therapeutic strategies, with a special focus on unexplained recurrent pregnancy losses and the empiric treatments used nowadays. It also discusses the current role of preimplantation genetic testing in the management of recurrent pregnancy loss. PMID- 28553149 TI - A multicenter prospective study of patients undergoing open ventral hernia repair with intraperitoneal positioning using the monofilament polyester composite ventral patch: interim results of the PANACEA study. AB - PURPOSE: This study assessed the recurrence rate and other safety and efficacy parameters following ventral hernia repair with a polyester composite prosthesis (ParietexTM Composite Ventral Patch [PCO-VP]). PATIENTS AND METHODS: A single arm, multicenter prospective study of 126 patients undergoing open ventral hernia repair with the PCO-VP was performed. Patient outcomes were assessed at discharge and at 10 days, 1, 6, 12, and 24 months postoperative. RESULTS: All patients had hernioplasty for umbilical (n = 110, 87.3%) or epigastric hernia (n = 16, 12.7%). Mean hernia diameter was 1.8 +/- 0.8 cm. Mean operative time was 36.2 +/-15.6 minutes, with a mean mesh positioning time of 8.1 +/- 3.4 minutes. Surgeons reported satisfaction with mesh ease of use in 95% of surgeries. The cumulative hernia recurrence rate at 1 year was 2.8% (3/106). Numeric Rating Scale (NRS) pain scores showed improvement from 2.1 +/- 2.0 at preoperative baseline to 0.5 +/- 0.7 at 1 month postoperative (P < 0.001), and this low pain level was maintained at 12 months postsurgery (P < 0.001). The mean global Carolina's Comfort Scale(r) (CCS) score improved postoperatively from 3.8 +/- 6.2 at 1 month to 1.6 +/- 3.5 at 6 months (P < 0.001). One patient was unsatisfied with the procedure. CONCLUSION: This 1-year interim analysis using PCO-VP for primary umbilical and epigastric defects shows promising results in terms of mesh ease of use, postoperative pain, and patient satisfaction. Recurrence rate is low, but, as laparoscopic evaluation shows a need for patch repositioning in some cases, an accurate surgical technique remains of utmost importance. PMID- 28553150 TI - Hepatitis C infection in Egypt: prevalence, impact and management strategies. AB - Hepatitis C virus (HCV) infection is a major public health burden in Egypt, where it bears the highest prevalence rate in the world. Estimates for prevalence are based upon data reported from the 2008 and 2015 Egypt Demographic Health Surveys. In this review, we demonstrate the prevalence results of both surveys and analyze the difference in the results. The overall HCV prevalence is estimated to be declining. However, the clinical impact of chronic HCV infection is expected to grow considerably. A mathematical model shows that by increasing the rate of treatment, the expected number of patients will decline significantly in 2030. The current and expected future burden of chronic HCV infection to the Egyptian economy, including direct and indirect costs due to disability and loss of lives, has been estimated and discussed in this review. The economic burden will continue to grow, but a model shows that the introduction of highly effective therapies will result in a significant reduction in the cumulative total economic burden of HCV by 2030. In recognition of the HCV tremendous health and economic burden, the Egyptian government established the National Committee for Control of Viral Hepatitis to implement an integrated nationwide strategy to provide patient care and ensure global treatment access. This review illustrates the epidemiological and disease burden aspects of HCV in Egypt in addition to introducing the national plan and program for managing HCV, which has been successful so far in treating a large number of patients, with the aim of achieving disease control and eventual elimination in Egypt. PMID- 28553151 TI - Infant sleep and its relation with cognition and growth: a narrative review. AB - OBJECTIVE: Infant sleep development is a highly dynamic process occurring in parallel to and in interaction with cognitive and physical growth. This narrative review aims to summarize and discuss recent literature and provide an overview of the relation between infant sleep and cognitive development as well as physical growth. METHODS: We conducted online literature search using MEDLINE, Embase, and Cochrane Library databases. We considered original research on humans published in the English language from January 2005 to December 2015. Search terms included "sleep" AND "infant" AND "cognition" OR "memory" OR "executive functioning", OR "growth" OR "obesity" OR "growth hormone" OR "stunting", and combinations thereof. RESULTS: Ten studies on infant sleep and cognition were included in this review. Overall, findings indicated a positive association between sleep, memory, language, executive function, and overall cognitive development in typically developing infants and young children. An additional 20 studies support the positive role of infant sleep in physical growth, with the current literature focusing largely on weight gain and obesity rather than healthy growth. Existing evidence in both the domains is mainly based on cross-sectional designs, on association studies, and on parental reports. In contrast, there were limited studies on longitudinal sleep trajectories and intervention effects, or studies have not used more objective sleep measures such as actigraphy and polysomnography. CONCLUSION: The reviewed studies support a critical and positive role of infant sleep in cognition and physical growth. Future studies should consider key environmental and parental confounders, include a combination of more objective (actigraphy) and subjective measures (sleep diaries and questionnaires), and move towards longitudinal trajectory designs of infant sleep and development. PMID- 28553153 TI - Interprofessional education development: not for the faint of heart. AB - Interprofessional education (IPE) has the potential to improve communication, collaboration and coordination of care, leading to improved health care outcomes. Promoting IPE has become an aim for many professional schools. However, there are challenges to implementing meaningful curricula that involve multiple health care professional schools. In this study, we outline 12 lessons learned when designing and implementing an Interprofessional Longitudinal Clinical Experience (ILCE) for 247 students from a School of Nursing, Medicine and Physician Associate Program in New England. Lessons learned over 4 years include pilot, evaluate and refine projects; create a formal interprofessional organizational structure; involve faculty who are passionate ambassadors for IPE; procure and maintain financial support; recognize power struggles and bias; overcome logistical conundrums to realize common goals, secure clinical sites and prepare IPE coaches; expect there will always be another hurdle; do not go it alone; recruit experts; recognize role differentiation and similarities; be aware of fragility of students and faculty and collect data to assess, evaluate, improve and gain buy-in. We were able to successfully implement a large program for students from three different health care professional schools that takes place in the clinical setting with faculty coaches, patients and their families. We hope that the lessons learned can be instructive to those considering a similar effort. PMID- 28553152 TI - Exhaled breath analysis for the early detection of lung cancer: recent developments and future prospects. AB - In lung cancer, the prognosis and treatment options depend directly on tumor size and its spread at the time of diagnosis. There is therefore a constant search for methods that will allow early detection of cancerous lung nodules. With advancing imaging technology and implantation of screening routines in high-risk populations by low-dose computerized tomography, a significant increase in the number of diagnosed small peripheral lesions can be expected. While early detection of small cancerous lesions carries the benefit of wider treatment options and better prognosis, the process of obtaining a biopsy to confirm a cancerous tissue is not free of complications and bears inconveniences and stress to the patient. This review discusses the potential use of exhaled breath analysis as a simple, noninvasive tool for early detection of lung cancer and characterization of suspicious lung nodules. PMID- 28553154 TI - Long-term treatment-related morbidity in differentiated thyroid cancer: a systematic review of the literature. AB - BACKGROUND: Differentiated thyroid cancer (DTC) occurs in relatively young patients and is associated with a good prognosis and long survival. The management of this disease involves thyroidectomy, radioiodine therapy, and long term thyroid-stimulating hormone suppression therapy (THST). The long-term effects of the treatment and the interaction between subclinical hyperthyroidism and long-term hypoparathyroidism are poorly understood. This review sought to examine the available evidence. METHODS: A PubMed search was carried out using the search terms "Thyroid Neoplasms" AND ("Thyroxine" OR "Hypocalcemia" OR "Thyrotropin"). Original English language articles published in the last 30 years studying the morbidity from thyroid-stimulating hormone (TSH) suppression and hypoparathyroidism following a surgery for DTC were retrieved and reviewed by 2 authors. RESULTS: Of the 3,000 results, 66 papers including 4,517 patients were selected for the present study. Studies reported on a range of skeletal (included in 34 studies, 1,647 patients), cardiovascular (17 studies, 957 patients), psychological (10 studies, 663 patients), and other outcomes (10 studies, 1,348 patients). Nine of 26 studies on patients who underwent THST showed a reduction in bone density, and 13 of 23 studies showed an increase in bone turnover markers. Skeletal effects were more marked in postmenopausal women. There was no evidence of increased fracture risk, and only little data were available on hypoparathyroidism. Four of five studies showed an increased left ventricular mass index on echocardiography, and one study showed a higher prevalence of atrial fibrillation (AF). There was little difference in basic physiological parameters and limited literature regarding symptoms or significant events. Six studies showed associations between long-term TSH suppression and impaired quality of life. Impaired glucose metabolism and prothrombotic states were also found in DTC patients. CONCLUSION: There is limited literature regarding long term DTC treatment-related morbidity, particularly regarding the effects of long term hypocalcemia. Most studies have focused on surrogate markers and not on clinical outcomes. A large prospective study on defined clinical outcomes would help characterize the morbidity of treatment and stimulate research on tailoring treatment strategies. PMID- 28553155 TI - Global multi-layer network of human mobility. AB - Recent availability of geo-localized data capturing individual human activity together with the statistical data on international migration opened up unprecedented opportunities for a study on global mobility. In this paper, we consider it from the perspective of a multi-layer complex network, built using a combination of three datasets: Twitter, Flickr and official migration data. Those datasets provide different, but equally important insights on the global mobility - while the first two highlight short-term visits of people from one country to another, the last one - migration - shows the long-term mobility perspective, when people relocate for good. The main purpose of the paper is to emphasize importance of this multi-layer approach capturing both aspects of human mobility at the same time. On the one hand, we show that although the general properties of different layers of the global mobility network are similar, there are important quantitative differences among them. On the other hand, we demonstrate that consideration of mobility from a multi-layer perspective can reveal important global spatial patterns in a way more consistent with those observed in other available relevant sources of international connections, in comparison to the spatial structure inferred from each network layer taken separately. PMID- 28553157 TI - Promises and lies: can observers detect deception in written messages. AB - We design a laboratory experiment to examine predictions of trustworthiness in a novel three-person trust game. We investigate whether and why observers of the game can predict the trustworthiness of hand-written communications. Observers report their perception of the trustworthiness of messages, and make predictions about the senders' behavior. Using observers' decisions, we are able to classify messages as "promises" or "empty talk." Drawing from substantial previous research, we hypothesize that certain factors influence whether a sender is likely to honor a message and/or whether an observer perceives the message as likely to behonored: the mention of money; the use of encompassing words; and message length. We find that observers have more trust in longer messages and "promises"; promises that mention money are significantly more likely to be broken; and observers trust equally in promises that do and do not mention money. Overall, observers perform slightly better than chance at predicting whether a message will be honored. We attribute this result to observers' ability to distinguish promises from empty talk, and to trust promises more than empty talk. However, within each of these two categories, observers are unable to discern between messages that senders will honor from those that they will not. PMID- 28553156 TI - Isoflavones, their Glycosides and Glycoconjugates. Synthesis and Biological Activity. AB - Glycosylation of small biologically active molecules, either of natural or synthetic origin, has a profound impact on their solubility, stability, and bioactivity, making glycoconjugates attractive compounds as therapeutic agents or nutraceuticals. A large proportion of secondary metabolites, including flavonoids, occur in plants as glycosides, which adds to the molecular diversity that is much valued in medicinal chemistry studies. The subsequent growing market demand for glycosidic natural products has fueled the development of various chemical and biotechnological methods of glycosides preparation. The review gives an extensive overview of the processes of the synthesis of isoflavones and discusses recently developed major routes towards isoflavone-sugar formation processes. Special attention is given to the derivatives of genistein, the main isoflavone recognized as a useful lead in several therapeutic categories, with particular focus on anticancer drug design. The utility of chemical glycosylations as well as glycoconjugates preparation is discussed in some theoretical as well as practical aspects. Since novel approaches to chemical glycosylations and glycoconjugations are abundant and many of them proved suitable for derivatization of polyphenols a new body of evidence has emerged, indicating that sugar moiety can play a much more significant role, when attached to a pharmacophore, then being a mere "solubilizer". In many cases, it has been demonstrated that semisynthetic glycoconjugates are much more potent cytostatic and cytotoxic agents than reference isoflavones. Moreover, the newly designed glycosides or glycoside mimics can act through different mechanisms than the parent active molecule. PMID- 28553158 TI - The impact of stress on tournament entry. AB - Individual willingness to enter competitive environments predicts career choices and labor market outcomes. Meanwhile, many people experience competitive contexts as stressful. We use two laboratory experiments to investigate whether factors related to stress can help explain individual differences in tournament entry. Experiment 1 studies whether stress responses (measured as salivary cortisol) to taking part in a mandatory tournament predict individual willingness to participate in a voluntary tournament. We find that competing increases stress levels. This cortisol response does not predict tournament entry for men but is positively and significantly correlated with choosing to enter the tournament for women. In Experiment 2, we exogenously induce physiological stress using the cold pressor task. We find a positive causal effect of stress on tournament entry for women but no effect for men. Finally, we show that although the effect of stress on tournament entry differs between the genders, stress reactions cannot explain the well-documented gender difference in willingness to compete. PMID- 28553159 TI - Safety assessment of nanomaterials using an advanced decision-making framework, the DF4nanoGrouping. AB - As presented at the 2016 TechConnect World Innovation Conference on 22-25 May 2016 in Washington DC, USA, the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) 'Nano Task Force' proposes a Decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping) consisting of three tiers to assign nanomaterials to four main groups with possible further subgrouping to refine specific information needs. The DF4nanoGrouping covers all relevant aspects of a nanomaterial's life cycle and biological pathways: intrinsic material properties and system-dependent properties (that depend upon the nanomaterial's respective surroundings), biopersistence, uptake and biodistribution, and cellular and apical toxic effects. Use, release, and exposure route may be applied as 'qualifiers' to determine if, e.g., nanomaterials cannot be released from products, which may justify waiving of testing. The four main groups encompass (1) soluble, (2) biopersistent high aspect ratio, (3) passive, and (4) active nanomaterials. The DF4nanoGrouping foresees a stepwise evaluation of nanomaterial properties and effects with increasing biological complexity. In case studies covering carbonaceous nanomaterials, metal oxide, and metal sulfate nanomaterials, amorphous silica and organic pigments (all nanomaterials having primary particle sizes below 100 nm), the usefulness of the DF4nanoGrouping for nanomaterial hazard assessment was confirmed. The DF4nanoGrouping facilitates grouping and targeted testing of nanomaterials. It ensures that sufficient data for the risk assessment of a nanomaterial are available, and it fosters the use of non-animal methods. No studies are performed that do not provide crucial data. Thereby, the DF4nanoGrouping serves to save both animals and resources. PMID- 28553160 TI - Safety assessments of subcutaneous doses of aragonite calcium carbonate nanocrystals in rats. AB - Calcium carbonate nanoparticles have shown promising potentials in the delivery of drugs and metabolites. There is however, a paucity of information on the safety of their intentional or accidental over exposures to biological systems and general health safety. To this end, this study aims at documenting information on the safety of subcutaneous doses of biogenic nanocrystals of aragonite polymorph of calcium carbonate derived from cockle shells (ANC) in Sprague-Dawley (SD) rats. ANC was synthesized using the top-down method, characterized using the transmission electron microscopy and field emission scanning electron microscope and its acute and repeated dose 28-day trial toxicities were evaluated in SD rats. The results showed that the homogenous 30 +/- 5 nm-sized spherical pure aragonite nanocrystals were not associated with mortality in the rats. Severe clinical signs and gross and histopathological lesions, indicating organ toxicities, were recorded in the acute toxicity (29,500 mg/m2) group and the high dose (5900 mg/m2) group of the repeated dose 28-day trial. However, the medium- (590 mg/m2 body weight) and low (59 mg/m2)-dose groups showed moderate to mild lesions. The relatively mild lesions observed in the low toxicity dosage group marked the safety margin of ANC in SD rats. It was concluded from this study that the toxicity of CaCO3 was dependent on the particulate size (30 +/- 5 nm) and concentration and the route of administration used. PMID- 28553161 TI - Presentation of a method at the Exploration Stage according to IDEAL: Percutaneous nephrolithotomy (PCNL) under local infiltrative anesthesia is a feasible and effective method - retrospective analysis of 439 patients. AB - INTRODUCTION: This study addresses minimally invasive anesthesiologic and analgetic approaches for stone surgery in the upper urinary tract. Aim of this retrospective analysis is to compare feasibility, safety and complication rates of percutaneous nephrolithotomy (PCNL) under local infiltration anesthesia alone (Group I) and additive intravenous analgetics and/or sedative medications (Group II). MATERIAL AND METHODS: This is a single center study. A total of 439 patients have been included from November 2003 until March 2012. A total of 226 patients were assigned to Group I receiving local infiltration anesthesia alone, whereas 213 patients were assigned to Group II receiving additive intravenous analgetics and/or sedative medications. Demographic characteristics and stone characteristics have been evaluated to determine feasibility, complication rates for safety, and stone-free rates for effectiveness. The study and the reported technique have then been retrospectively analysed according to the IDEAL stages of surgical innovation. RESULTS: All included patients who accepted local infiltration anesthesia underwent PCNL successfully. The mean American Society of Anesthesiologists score (ASA) of the included patients was 2.15 +/-0.37 (range, 1 4). PCNL was indicated in 138 patients due to pelvic calculi, in 171 patients due to renal calculi, in 66 patients due to partial staghorn, in 48 patients due to complete staghorn and in 16 patients due to upper ureteral stones. The total stone free rate in our patients was 78.4% over all stone localizations. Compared to the possibility of using additive intravenous analgetics and/or sedative medications we could show differences in the median age (p=0.005) suggesting that older patients did better tolerate the infiltration anesthesia than patients at younger ages. We did also remark not statistically significant differences in Group I and Group II as for number of tracts, operation duration, hemoglobin drop, fever, transfusion rate, and stone free rate, but not for severe complications such as perirenal hematoma, colon perforation, pleura perforation, AV fistula, skin fistula, and mortality rate. CONCLUSION: PCNL performed under local infiltration anesthesia is a feasible method. It provides satisfactory positive clinical outcomes. Younger age seems to predispose to conversion to extended anesthesiologic procedures. When retrospectively applying the IDEAL criteria, the method can be assigned to the E level or stage 2b. PMID- 28553162 TI - Bladder Reconstruction with Human Amniotic Membrane in a Xenograft Rat Model: A Preclinical Study. AB - Background: Human amniotic membranes (HAMs) are assumed to have a number of unique characteristics including durability, hypoallergenic and anti-inflammatory properties. Materials and Methods: Multilayer HAMs from caesarian sections were applied to repair defined bladder defects in male Sprague-Dawley rats. The animals were sacrificed at 7, 21 and 42 days after implantation. Bladder volume capacity after grafting was measured. Histological analyses were performed to asses a number of parameters including HAM degradation, inflammatory reaction, graft rejection and smooth muscle ingrowth. Results: One rat died from sepsis in the treated group. No severe complications or signs of leakage were observed. Bladder capacity did not change over time. The initially increased inflammation in the HAM group diminished significantly over time (p<0.05). No signs of HAM degradation were observed and smooth muscle staining increased over time. Conclusions: HAMs appear to be durable and hypoallergenic grafts. The assumed suitability for the reconstruction of urinary tract justifies further research on detailed immunological process in larger grafts. PMID- 28553163 TI - Parkinson's disease might increase the risk of cerebral ischemic lesions. AB - BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease in the elderly. Cerebrovascular diseases such as cerebral ischemic lesion (CIL) also commonly occur in elderly adults. However, previous studies on the relationship between PD and cerebrovascular disease have not found consistent results. Therefore, we conducted this study to evaluate whether or not PD is related to an increased prevalence of ischemic cerebrovascular lesions. METHODS: This study recruited 241 patients with PD and 112 healthy controls (HCs). All subjects underwent brain magnetic resonance imaging and general neuropsychological tests. The motor severity of PD was evaluated according to the Hoehn and Yahr stage (HY stage), and the severity of CIL in all subjects was classified according to Fazekas grade. The PD patients were classified into two subgroups according to HY stage (Group 1 - HY 1, 2; Group 2 - HY 3 to 5). RESULTS: Among all PD patients, 76% had small vessel disease, while 44% of all HCs had small vessel disease (p<0.001). Regarding the difference between the two subgroups according to motor severity, group 2 showed significantly higher Fazekas scale score and more severe CIL, indicating a higher prevalence of small vessel disease compared to group 1. CONCLUSION: This study demonstrates that PD patients have a significantly higher prevalence of CIL compared to HCs. Therefore, although the present study is not a large-scale study, we cautiously suggest that PD can play an important role as a risk factor in the occurrence of ischemic cerebrovascular disease. PMID- 28553164 TI - TBX20 loss-of-function mutation responsible for familial tetralogy of Fallot or sporadic persistent truncus arteriosus. AB - Congenital heart disease (CHD), the most common form of developmental abnormality in humans, remains a leading cause of morbidity and mortality in neonates. Genetic defects have been recognized as the predominant causes of CHD. Nevertheless, CHD is of substantial genetic heterogeneity and the genetic defects underlying CHD in most cases remain unclear. In the current study, the coding regions and splicing junction sites of the TBX20 gene, which encodes a T-box transcription factor key to cardiovascular morphogenesis, were sequenced in 175 unrelated patients with CHD, and a novel heterozygous TBX20 mutation, p.K274X, was identified in an index patient with tetralogy of Fallot (TOF). Genetic analysis of the proband's available family members showed that his father, elder brother and son had also TOF. In addition, his father and elder brother had also atrial septal defect, and his niece had persistent truncus arteriosus and ventricular septal defect. Analysis of the pedigree revealed that the mutation co segregated with CHD transmitted in an autosomal dominant fashion, with complete penetrance. The nonsense mutation, which was absent in the 800 control chromosomes, was predicted to produce a truncated protein with only the amino terminus and partial T-box domain left. Functional analyses by using a dual luciferase reporter assay system showed that the mutant TBX20 lost the ability to transactivate the target gene ANF. Furthermore, the mutation reduced the synergistic activation between TBX20 and NKX2.5 as well as GATA4, two other transcriptional factors previously associated with various CHD, encompassing TOF. This study firstly links TBX20 loss-of-function mutation to familial TOF or sporadic persistent truncus arteriosus, providing novel insight into the molecular pathogenesis of CHD. PMID- 28553165 TI - GSK-3beta as a target for protection against transient cerebral ischemia. AB - Stroke remains the leading cause of death and disability worldwide. This fact highlights the need to search for potential drug targets that can reduce stroke related brain damage. We showed recently that a glycogen synthase kinase-3beta (GSK-3beta) inhibitor attenuates tissue plasminogen activator-induced hemorrhagic transformation after permanent focal cerebral ischemia. Here, we examined whether GSK-3beta inhibition mitigates early ischemia-reperfusion stroke injury and investigated its potential mechanism of action. We used the rat middle cerebral artery occlusion (MCAO) model to mimic transient cerebral ischemia. At 3.5 h after MCAO, cerebral blood flow was restored, and rats were administered DMSO (vehicle, 1% in saline) or GSK-3beta inhibitor TWS119 (30 mg/kg) by intraperitoneal injection. Animals were sacrificed 24 h after MCAO. TWS119 treatment reduced neurologic deficits, brain edema, infarct volume, and blood brain barrier permeability compared with those in the vehicle group. TWS119 treatment also increased the protein expression of beta-catenin and zonula occludens-1 but decreased beta-catenin phosphorylation while suppressing the expression of GSK-3beta. These results indicate that GSK-3beta inhibition protects the blood-brain barrier and attenuates early ischemia-reperfusion stroke injury. This protection may be related to early activation of the Wnt/beta catenin signaling pathway. PMID- 28553166 TI - Recombinant AAV8-mediated intrastriatal gene delivery of CDNF protects rats against methamphetamine neurotoxicity. AB - Methamphetamine (METH) exerts significant neurotoxicity in experimental animals and humans when taken at high doses or abused chronically. Long-term abusers have decreased dopamine levels, and they are more likely to develop Parkinson's disease (PD). To date, few medications are available to treat the METH-induced damage of neurons. Glial cell line-derived neurotrophic factor (GDNF) has been previously shown to reduce the dopamine-depleting effects of neurotoxic doses of METH. However, the effect of cerebral dopamine neurotrophic factor (CDNF), which has been reported to be more specific and efficient than GDNF in protecting dopaminergic neurons against 6-OHDA toxicity, in attenuating METH neurotoxicity has not been determined. Thus, the present study aimed to evaluate the neuroprotective effect of CDNF against METH-induced damage to the dopaminergic system in vitro and in vivo. In vitro, CDNF protein increased the survival rate and reduced the tyrosine hydroxylase (TH) loss of METH-treated PC12 cells. In vivo, METH was administered to rats following human CDNF overexpression mediated by the recombinant adeno-associated virus. Results demonstrated that CDNF overexpression in the brain could attenuate the METH-induced dopamine and TH loss in the striatum but could not lower METH-induced hyperthermia. PMID- 28553167 TI - Maternal Active Mastication during Prenatal Stress Ameliorates Prenatal Stress Induced Lower Bone Mass in Adult Mouse Offspring. AB - Chronic psychological stress is a risk factor for osteoporosis. Maternal active mastication during prenatal stress attenuates stress response. The aim of this study is to test the hypothesis that maternal active mastication influences the effect of prenatal stress on bone mass and bone microstructure in adult offspring. Pregnant ddY mice were randomly divided into control, stress, and stress/chewing groups. Mice in the stress and stress/chewing groups were placed in a ventilated restraint tube for 45 minutes, 3 times a day, and was initiated on day 12 of gestation and continued until delivery. Mice in the stress/chewing group were allowed to chew a wooden stick during the restraint stress period. The bone response of 5-month-old male offspring was evaluated using quantitative micro-CT, bone histomorphometry, and biochemical markers. Prenatal stress resulted in significant decrease of trabecular bone mass in both vertebra and distal femur of the offspring. Maternal active mastication during prenatal stress attenuated the reduced bone formation and increased bone resorption, improved the lower trabecular bone volume and bone microstructural deterioration induced by prenatal stress in the offspring. These findings indicate that maternal active mastication during prenatal stress can ameliorate prenatal stress-induced lower bone mass of the vertebra and femur in adult offspring. Active mastication during prenatal stress in dams could be an effective coping strategy to prevent lower bone mass in their offspring. PMID- 28553168 TI - The Effects and Mechanism of YK-4-279 in Combination with Docetaxel on Prostate Cancer. AB - Background: Docetaxel is the first-line treatment for castration-resistant prostate cancer (CRPC). The limited survival benefit associated with the quick emergence of resistance and systemic toxicity diminishes its efficacy in high dose monotherapy. YK-4-279 is a small molecule inhibitor of ETV1 that plays an important role in the progression of prostate cancer. The aim of this study was to evaluate the hypothesis that the combination of docetaxel and YK-4-279 will have a synergistic effect on inhibiting growth and accelerating apoptosis in human prostate cancer cells. Methods: Cell growth assessed using CCK-8 and trypan blue exclusion assays. Cell apoptosis was determined by morphological assessment in cells stained with propidium iodide. Standard scratch migration and Matrigel coated transwell invasion assays were used to assess cell migration and invasion, respectively. Western blotting was used to investigate the levels of ETV1, AR, PSA, p-STAT3, survivin, Bcl-2, and p-Akt in prostate cancer cells. Results: The combination of low-dose docetaxel and YK-4-279 synergistically inhibited growth and induced apoptosis in human prostate cancer cells. The combination also more efficiently suppressed the migration and invasion of LNCaP and PC-3 cells. The combination of low-dose docetaxel and YK-4-279 caused a stronger decrease in the levels of ETV1, AR, PSA, p-STAT3, survivin, Bcl-2, and p-Akt in LNCaP cells and of p-Akt, Bcl-2, and p-STAT3 in PC-3 cells compared with either drug alone. Conclusions: These data suggest that the combination of docetaxel and YK-4-279 may be an effective approach for inhibiting the growth and metastasis of prostate cancer. This could permit a decrease in the docetaxel dose necessary for patients with CRPC and thereby lower its systemic toxicity. PMID- 28553169 TI - In vivo application of Granulocyte-Macrophage Colony-stimulating Factor enhances postoperative qualitative monocytic function. AB - BACKGROUND: Granulocyte macrophage colony-stimulating factor (GM-CSF) can be used as a potent stimulator for immune suppressed patients as defined by a decrease of human leukocyte antigen-D related expression on monocytes (mHLA-DR) after surgery. However, the exact role of GM-CSF on monocytic and T cell function is unclear. METHODS: In this retrospective randomized controlled trial (RCT) subgroup analysis, monocytic respectively T cell function and T cell subspecies of 20 immune suppressed (i.e. mHLA-DR levels below 10,000 monoclonal antibodies (mAb) per cell at the first day after surgery) patients after esophageal or pancreatic resection were analyzed. Each 10 patients received either GM-CSF (250 MUg/m2/d) or placebo for a maximum of three consecutive days if mHLA-DR levels remained below 10,000 mAb per cell. mHLA-DR and further parameters of immune function were measured preoperatively (od) until day 5 after surgery (pod5). Statistical analyses were performed using nonparametric statistical procedures. RESULTS: In multivariate analysis, mHLA-DR significantly differed between the groups (p < 0.001). mHLA-DR was increased on pod2 (p < 0.001) and pod3 (p = 0.002) after GM-CSF application. Tumor necrosis factor-alpha (TNF-alpha) release of lipopolysaccharide (LPS) stimulated monocytes multivariately significantly differed between the groups (p < 0.008) and was increased in the GM-CSF group on pod2 (p < 0.001) and pod3 (p = 0.046). Th17/regulatory T (Treg) cell ratio was higher after GM-CSF treatment on pod2 (p = 0.041). No differences were seen in lymphocytes and T helper cell (Th)1/Th2 specific cytokine production after T cell stimulation with Concanavalin (Con) A between the groups. CONCLUSIONS: Postoperative application of GM-CSF significantly enhanced qualitative monocytic function by increased mHLA-DR and TNF-alpha release after LPS stimulation and apparently enhanced Th17/Treg ratio. Clinical trial registered with www.controlled-trials.com (ISRCTN27114642) 05 December 2008. PMID- 28553170 TI - New Optimal Needle Entry Angle for Cervical Transforaminal Epidural Steroid Injections: A Retrospective Study. AB - Objective: A cervical epidural steroid injection is one of the most commonly performed interventions to manage chronic neck pain and cervical radiculopathy. Despite its many severe complications, cervical transforaminal epidural steroid injection (CTFESI) is a clinically necessary modality for managing neck pain and cervical radiculopathy. We aimed in this study to find a safer optimal needle entry angle to decrease the chance of an accidental vertebral artery (VA) puncture even with a proper needle entry angle and to visualize the target of the needle tip. Methods: This retrospective study included 312 patients with neck pain or cervical radiculopathy who had undergone magnetic resonance imaging scans for diagnosis and treatment. The first line was drawn from the midpoint of the two articular pillars and passed through the exact midline of the spinous process. The second line was drawn parallel to the ventral lamina line (conventional transforaminal approach line, CTAL). The third line was drawn parallel to the ventral margin at the midpoint of the superior articular process's ventral border (new transforaminal approach line, NTAL). The angle of intersection between the midline and CTAL versus with NTAL were measured from both sides (right and left) at C5-6, C6-7, and C7-T1 levels. Also, the distance of CTAL and NTAL from VA were measured from both sides at each level. We examined whether the CTAL and NTAL would penetrate the ipsilateral VA, internal carotid artery (ICA), and internal jugular vein (IJV). Results: There were significant differences between CTAL and NTAL angles at all levels (P < 0.001). There were significant differences between the distance of CTAL and NTAL from VA at all levels (P < 0.001). There were also significant differences between the observed frequency of CTAL and NTAL that would penetrate the major ipsilateral vessel (VA, ICA, and IJV) on all levels and sides (P < 0.001~0.030). Conclusion: The angle of NTAL (approximately 70 degrees ) is safer than the angle of CTAL (approximately 50 degrees ) when considering vascular injuries to vessels, such as the VA, ICA, and IJV. PMID- 28553171 TI - TGF-beta Stimulates Endochondral Differentiation after Denervation. AB - Transforming growth factor beta (TGF-beta) is a multifunctional protein that induces gene expression of cartilage-specific molecules, but its exact role in the process of chondrogenesis is unclear. Because recent studies suggest that TGF beta can facilitate chondrogenic precursor cells differentiating into chondrocytes, we sought to determine whether TGF-beta prevents denervation induced reduction of endochondral bone formation in an experimental model. Mice were treated daily with recombinant human TGF-beta1 (rhTGF-beta1) for 3 weeks. We found that rhTGF-beta1 not only prevented denervation-induced reduction of gene expression of type II collagen, type X collagen, aggrecan, Indian hedgehog, and parathyroid hormone-related peptide, but also synergized endochondral differentiation. These results demonstrate that short-term systemic administration of TGF-beta substantially prevents denervation-induced reduction of endochondral bone formation via stimulating endochondral differentiation. Potential therapeutic applications will be pursued in further studies that address the molecular biological mechanism of TGF-beta on endochodral bone formation after denervation in animal models. PMID- 28553173 TI - Effective Radiological Imaging for the Good of Patients: Weighing Benefits and Risks. PMID- 28553172 TI - Current status of the treatment of blood blister-like aneurysms of the supraclinoid internal carotid artery: A review. AB - Currently, the treatment of blood blister-like aneurysms (BBAs) of the supraclinoid internal carotid artery (ICA) is challenging and utilizes many therapeutic methods, including direct clipping and suturing, clipping after wrapping, clipping after suturing, coil embolization, stent-assisted coil embolization, multiple overlapping stents, flow-diverting stents, covered stents, and trapping with or without bypass. In these therapeutic approaches, the optimal treatment method for BBAs has not yet been defined based on the current understanding of BBAs of the supraclinoid ICA. Therefore, in this study, we aimed to review the literature from PubMed to discuss and analyze the pros and cons of the above approaches while adding our own viewpoints to the discussion. Among the surgical methods, direct clipping was the easiest method if the compensation of the collateral circulation of the intracranial distal ICA was sufficient or direct clipping did not induce stenosis in the parent artery. In addition, the clipping after wrapping technique should be chosen as the optimal surgical modality to prevent rebleeding from these lesions. Among the endovascular methods, multiple overlapping stents (>=3) with coils may be a feasible alternative for the treatment of ruptured BBAs. In addition, flow-diverting stents appear to have a higher rate of complete occlusion and a lower rate of retreatment and are a promising treatment method. Finally, when all treatments failed or the compensation of the collateral circulation of the intracranial distal ICA was insufficient, the extracranial-intracranial (EC-IC) arterial bypass associated with surgical or endovascular trapping, a complex and highly dangerous method, was used as the treatment of last resort. PMID- 28553175 TI - Cadmium Telluride Semiconductor Detector for Improved Spatial and Energy Resolution Radioisotopic Imaging. AB - The detector in single-photon emission computed tomography has played a key role in the quality of the images. Over the past few decades, developments in semiconductor detector technology provided an appropriate substitution for scintillation detectors in terms of high sensitivity, better energy resolution, and also high spatial resolution. One of the considered detectors is cadmium telluride (CdTe). The purpose of this paper is to review the CdTe semiconductor detector used in preclinical studies, small organ and small animal imaging, also research in nuclear medicine and other medical imaging modalities by a complete inspect on the material characteristics, irradiation principles, applications, and epitaxial growth method. PMID- 28553176 TI - Metabolic Activity Value in the Posterior Cingulate Cortex Using F-18 Fluorodeoxyglucose Positron Emission Tomography Brain to Predict the Severity of Alzheimer's. AB - Alzheimer's disease (AD) is a type of dementia which is known as one of a major problem in elderly. Clinicians commonly use mini-mental state examination (MMSE) score to determine the severity of cognitive decline, but MMSE has some limitations such as more subjective, influenced by age, educational degree, and local culture. F-18 fluorodeoxyglucose positron emission tomography (F-18 FDG PET) can be used to assess the process of glucose metabolism in posterior cingulate cortex (PCC) area which endures a central role in supporting cognitive function directly. The purpose of this study is to observe a correlation between metabolic activity value of PCC and MMSE score in predicting the severity of AD. A cross-sectional study was done to 30 subjects suspect AD disease with aged 60 years and older. Characteristic data including gender, age, and education, MMSE scoring by psychiatrist, and imaging of F-18 FDG PET were established. The results of correlation test between the value of FDG metabolic activity and MMSE score shows that the value of metabolic activity in the PCC area tends to increase along with the increase of MMSE score (rs = 0.411, P = 0.024). While from the results of multiple regression test with predictor variable consisting of F-18 FDG metabolic activity in the PCC, gender, age, education level, and the interaction between the metabolic activity of F-18 FDG at PCC and gender, a regression model was obtained. There is a significant correlation observed between the captured of F-18 FDG radioactivity with MMSE score in PCC area which can be used as a tool to predict the severity of AD. PMID- 28553174 TI - Technetium-99m Methylene Diphosphonate Single-photon Emission Computed Tomography/Computed Tomography of the Foot and Ankle. AB - The complex anatomy and function of the foot and ankle can make it difficult to determine the cause of symptoms in patients with foot and ankle pathology. Following initial clinical and radiographic assessment, additional imaging with magnetic resonance imaging may be required, which is often seen as the modality of choice. Although sensitive to pathological changes in bone metabolism and vascularity, technetium-99m (Tc-99m) bone scintigraphy often lacks the specificity and resolution required to evaluate the structures of the foot and ankle. Tc-99m methylene diphosphonate single-photon emission computed tomography/computed tomography (SPECT/CT) combines this sensitivity with the superior anatomical detail of CT, enabling better localization of pathological uptake and evaluation of associated structural changes. As a result, SPECT/CT has been growing in popularity for the assessment of patients with foot and ankle pathology where it can provide additional information that may change the initial diagnosis and subsequent management plan. Studies have reported modification of the surgical approach and site of intra-articular local anesthetic injections following SPECT/CT with good results. Interpretation of SPECT/CT studies requires an understanding of the pathological changes that result in increased tracer accumulation in addition to the CT changes that may be seen. This review aims to highlight the advantages of SPECT/CT, potential applications and explain the imaging appearances of common pathologies that may be observed. PMID- 28553177 TI - Specific Absorbed Fractions of Internal Photon and Electron Emitters in a Human Voxel-based Phantom: A Monte Carlo Study. AB - The specific absorbed fraction (SAF) of energy is an essential element of internal dose assessment. Here reported a set of SAFs calculated for selected organs of a human voxel-based phantom. The Monte Carlo transport code GATE version 6.1 was used to simulate monoenergetic photons and electrons with energies ranging from 10 keV to 2 MeV. The particles were emitted from three source organs: kidneys, liver, and spleen. SAFs were calculated for three target regions in the body (kidneys, liver, and spleen) and compared with the results obtained using the MCNP4B and GATE/GEANT4 Monte Carlo codes. For most photon energies, the self-irradiation is higher, and the cross-irradiation is lower in the GATE results compared to the MCNP4B. The results show generally good agreement for photons and high-energy electrons with discrepancies within - 2% +/ 3%. Nevertheless, significant differences were found for cross-irradiation of photons of lower energy and electrons of higher energy due to statistical uncertainties larger than 10%. The comparisons of the SAF values for the human voxel phantom do not show significant differences, and the results also demonstrated the usefulness and applicability of GATE Monte Carlo package for voxel level dose calculations in nonuniform media. The present SAFs calculation for the Zubal voxel phantom is validated by the intercomparison of the results obtained by other Monte Carlo codes. PMID- 28553178 TI - Number of Foci of Functioning Thyroid Tissue Remaining after Thyroidectomy for Differentiated Thyroid Cancer: Institutional Experience. AB - Radioiodine imaging of the neck with a pinhole collimator (PinC) is frequently performed in differentiated thyroid cancer (DTC) patients for visualizing individual, and a total number of foci (NOF) of functioning residual thyroid tissue (FRTT) within the thyroid bed in postthyroidectomy patients. The objective of this study was to determine our experience regarding the NOF of FRTT visualized on pretherapy radioiodine PinC images. We performed a retrospective review of radioiodine PinC images of the neck of patients with very low-risk DTC and who had thyroidectomy performed by selected surgeons at MedStar Washington Hospital Center. For each patient's image, the NOF of FRTT was determined by two blind readers. Statistical analysis was performed. One hundred and twenty-six patients met the criteria. Surgeon (S1, S2, S3, and S4) performed 17, 10, 86, and 13 thyroidectomies, respectively. The analysis (mean, range, and standard deviation) of NOF of FRTT was: S1: (2.2, 0-5, 1.3); S2: (1.6, 1-3, 0.8); S3: (2.6, 0-7, 1.5); S4: (3.3, 1-5, 1.3). The percentages of < 2, <=3, <=4, and <5 foci remaining were 4.9%, 21.5%, 77.0%, and 91.3%, respectively. For the selected surgeons, the NOF of FRTT in the thyroid bed or neck in postthyroidectomy patients never exceeded 7, rarely exceeded 5 (2.4%), and infrequently exceeded 4 (8.7%). Based on these data, our thresholds of the NOF for which we perform further workup for possible locoregional disease are >=5. Each facility is encouraged to establish their own criteria for their facility and preferably for each of their surgeons. PMID- 28553179 TI - Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE for Metastatic Neuroendocrine Tumor Occurring in Association with Multiple Endocrine Neoplasia Type 1 and Cushing's Syndrome. AB - Neuroendocrine tumor (NET) occurring in association with other endocrine syndromes forms a distinct entity. The aim was to assess the therapy response profile of the routine peptide receptor radionuclide therapy (PRRT) in this relatively uncommon but clinically challenging subgroup of patients. A retrospective analysis was undertaken from the case records from those who were treated with 177Lu-DOTATATE for metastatic NET. In addition to assessing the therapeutic efficacy, emphasis was also given to study lesional sites and scan pattern. A total of 5 cases were found: In this series of five cases, four belonged to multiple endocrine neoplasia type 1 (MEN1) syndrome; in these four MEN1 syndrome patients, the primary site of NET was thymic region (n = 1), duodenum (n = 1), and pancreas (n = 2). The fifth case was of Cushing's syndrome with the primary site of NET in the thymus. A good symptomatic response was observed in all MEN1 syndrome cases (100%) and progression of symptoms in the patient with Cushing's syndrome. The biochemical response (assessed by measurement of tumor marker serum chromogranin A) demonstrated very good partial response (defined by more than 75% reduction of tumor marker) in 2 MEN1 cases and Cushing's syndrome, good partial response (25-75% reduction of tumor marker) in the remaining 2 MEN1 cases. Scan wise (assessed by technetium [99mTc] hydrazinonicotinamide [HYNIC]-tektrotyd [TOC]/68Ga-DOTA-NOC/TATE positron emission tomography-computed tomography [PET-CT] and fluorodeoxyglucose [FDG] PET CT) partial response was observed in 3 MEN1 cases, stable disease was noted in one MEN1 case and disease progression was noted in the patient with Cushing's syndrome. The change in FDG uptake was found to be an important sensitive scan parameter in the treatment evaluation of NETs compared to somatostatin receptor based imaging in the cases with low MiB1 index. In our series, good palliative response to 177Lu-DOTA-octreotate (DOTATATE) PRRT was observed in most NET patients associated with MEN1 syndrome without any major hematological or renal toxicity. PMID- 28553180 TI - Can 18F-Fluoroestradiol Positron Emission Tomography Become a New Imaging Standard in the Estrogen Receptor-positive Breast Cancer Patient: A Prospective Comparative Study with 18F-Fluorodeoxyglucose Positron Emission Tomography? AB - Correct staging is the most crucial for the treatment outcome in cancer management. Molecular imaging with 18F-fluoroestradiol (FES) positron emission tomography-computed tomography (PET-CT) targets estrogen receptor (ER) and may have a higher incremental value in diagnosis by aiding specificity. We enrolled 12 female breast cancer patients prospectively and did 18F-FES PET-CT and 18F fluorodeoxyglucose (FDG) PET-CT within 1 week interval time. Lesion detection sensitivity was compared for a total number of lesions and for nonhepatic lesions only by McNemar test. 18F-FES PET-CT was taken as reference in case of indeterminate lesions. The incremental value reported by identifying 18F-FES exclusive lesions and by characterization of 18F-FDG indeterminate lesions. Spearman rank test was used to correlate ER expression and maximum standardized uptake value (SUVmax). Two ER-negative patients with no 18F-FES uptake were excluded. Ten ER-positive patients with 154 disease lesions were finally analyzed. 18F-FDG picked-up 142 lesions (sensitivity 92.21%), whereas 18F-FES picked-up 116 lesions (sensitivity 75.32%) and this difference was statistically significant. For nonhepatic lesions (n = 136) detectability, 18F-FDG picked-up 124 (sensitivity 91.18%), whereas 18F-FES picked-up 116 (sensitivity 85.29%) lesions and this difference was not statistically significant. Beside 12 exclusive lesions, 18F-FES characterized 41 (27.5%) 18F-FDG indeterminate lesions. Overall 18F-FES impacted 20% patient management. The positive trend was also seen with 18F-FES SUVmax with ER expression and negative with 18F-FDG SUVmax. We conclude, 18F-FDG has overall better sensitivity than 18F-FES PET-CT, however for nonhepatic metastasis difference was not significant. 18F-FES PET-CT better-characterized lesions and impacted 20% patient management. Therefore, 18F FES PET-CT should be used with 18F-FDG PET-CT in strongly ER expressing patients for better specificity. PMID- 28553181 TI - Initial Clinical Experience with 68Ga-DOTA-NOC Prepared Using 68Ga from Nanoceria polyacrylonitrile Composite Sorbent-based 68Ge/68Ga Generator and Freeze-dried DOTA-NOC Kits. AB - Somatostatin receptor positron emission tomography-computed tomography (PET/CT) with 68Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) peptides have become an indispensable part of disease assessment in patients with neuroendocrine tumors and forms the basis of personalized therapy with peptide receptor-based radionuclide therapy. With growing utilization of PET/CT in developing countries, availability of the indigenous GMP-certified 68Ge/68Ga generators is expected to further promote cost-effective molecular imaging service to the cancer patients. We present our initial clinical experience in 32 patients injected with 68Ga-DOTA-NOC prepared using 68Ga eluted from Bhabha Atomic Research Centre nanoceria-polyacrylonitrile sorbent-based 68Ge/68Ga generator and freeze-dried DOTA-NOC cold kits. PMID- 28553183 TI - An Evaluation of Deviation from the International Atomic Energy Agency International Commission on Radiological Protection Proposed Equation for Calculation of Radiation Dose Rate Emanating from the Patients with Differentiated Thyroid Cancer Undergoing Radioiodine (I-131) Therapy. AB - The main purpose of this study was to investigate dose rate emanating from patients treated with 131I to evaluate which of the theoretical formulas, inverse square law (ISL) and International Atomic Energy Agency-International Commission on Radiological Protection (IAEA-ICRP) suggested equation, can provide a sufficiently close approximation of the measured dose rate. Measurements were performed based on the IAEA safety report No. 63 method at 0, 12, 24, and 48 h after administration of radioiodine at a distance of 1 m for 69 patients and for the rest of 67 patients, dose rate was measured at 2, 4, 24, and 48 h at a distance of 2 m. Results revealed that the ISL formula gained better approximation of measured dose rates than the IAEA-ICRP equation with the lesser error. The ISL formula is still more reliable than the novel method of dose calculation in the vicinity of patients. This finding reminded us the prime importance of distance as a radiation protection principle. PMID- 28553182 TI - Ultrastructure of Hyperfunctioning Parathyroid Glands: Does it Explain Various Patterns of 99mTc-sestamibi Uptake. AB - The aim of this study was to correlate the uptake of 99mTc-methoxy-isobutyl isonitrile (MIBI) with ultra-structural features of parathyroid adenomas. Twenty patients with proven primary hyperparathyroidism were evaluated prospectively. Preoperative double-phase 99mTc-MIBI scintigraphy was performed in all patients and the degree of tracer uptake by the parathyroid lesions was assessed visually and semi-quantitatively. The excised glands were examined histologically and ultrastructurally, and their features were correlated with the degree of the radiotracer uptake. At surgery, 21 parathyroid adenomas were removed (double adenoma in one patient and a solitary adenoma in each of the remaining 19 patients). 99mTc-MIBI scan detected 18 of the 21 adenomas. There was positive correlation between the degree of 99mTc-MIBI uptake and the mitochondrial contents of the parathyroid adenoma cells. Four adenomas with intense uptake had high content of mitochondria in the cells. The three false-negative scans had low to-moderate mitochondrial content. 99mTc-MIBI uptake is related to the mitochondrial content of the parathyroid adenoma cells. PMID- 28553184 TI - Initial Experience in the Use of Technetium-99 Metastable Hydroxymethylene Diphosphonate as an Alternative Ventilation Agent During Periods of Interim Shortage. AB - Sporadic supply interruptions of select radiopharmaceuticals on the global market require consideration of alternative agents to support continuity of essential nuclear medicine examinations. During an acute shortage of Xenon-133 and technetium-99 metastable (Tc-99m) diethylene-triamine-pentaacetate (DTPA), our institution used aerosolized Tc-99m hydroxymethylene diphosphonate (HDP), a radiopharmaceutical traditionally used in bone scintigraphy, in lieu of traditional ventilation agents, for two cases of suspected pulmonary embolism. Similar to Tc-99m-DTPA, Tc-99m-HDP was readily available and easily compounded in our pharmacy, and tolerated well by patients. Identical delivery equipment was used for administration of Tc-99m-HDP as that used in Tc-99m-DTPA, and thus, there was no requirement for a negative pressure room. Similar to Tc-99m-DTPA and unlike Xenon-133, Tc-99m-HDP allowed direct comparison of all 8 ventilation perfusion images. In addition, the cost per dose of Tc-99m-HDP proved to be less than Tc-99m-DTPA. Despite these favorable characteristics of Tc-99m-HDP, our experience identified an important challenge in obtaining an optimal flux override ratio of > 3 in a reasonable time frame while obtaining ventilation and perfusion images sequentially despite reversing the imaging order in an attempt to overcome this limitation. Although our experience with Tc-99m-HDP in these two cases was favorable, more clinical experience and investigation are warranted before Tc-99m-HDP can be incorporated as a standard alternative ventilation agent. PMID- 28553185 TI - Acute Hematogenous Osteomyelitis Presenting as a "Cold" Rib in a Child. AB - A "cold" defect or an area of decreased radiotracer deposition is the less common appearance of acute hematogenous osteomyelitis (AHO) on a Tc99 m-methylene disphosphonate (Tc99 m-MDP) bone scan. Group A beta-hemolytic Streptococcus (GABHS) is a significantly less common cause of AHO than Staphylococcus aureus, particularly when the infection involves the pelvis or flat bones such as the ribs. Here, we present a case report of isolated acute "cold" hematogenous osteomyelitis in a rib of a child with GABHS bacteremia that was detected on 99Tc MDP bone scan, with magnetic resonance imaging correlation, and pathologic confirmation after rib resection. PMID- 28553186 TI - Liver Metastasis of Lung Cancer Detected with Similar Uptake Pattern on Bone Scintigraphy and Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography: What's the Pathophysiologic Mechanism? AB - Bone scintigraphy with 99mTc diphosphonates may exhibit extraosseous lesions in addition to metastatic lesions. Multiple factors can affect extraosseous 99mTc methylene diphosphonate (MDP) uptake. Similar uptake pattern of 99mTc MDP and fluorine-18 fluorodeoxyglucose (18F FDG) in hepatic metastasis was not already notified. In our case, initial tumor necrosis and subsequent intracellular calcification resulted in similar 99mTc MDP and 18F FDG accumulation in the metastatic area. PMID- 28553187 TI - False Negative 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Primary B-cell Lymphoma of the Bone. AB - We present a case of a 15-year-old male with primary bone lymphoma who was initially referred for suspicion of chronic osteomyelitis of the mandible. A bone scan and gallium scan demonstrated congruent uptake in the mandible, suggestive of chronic osteomyelitis. A biopsy subsequently showed B-cell lymphoma of the bone with low Ki-67. A fluorodeoxyglucose positron emission tomography (FDG-PET) scan performed before therapy for staging revealed no increased uptake in the mandible. This case shows an atypical presentation of a rare disorder and is presented to emphasize the importance of baseline FDG-PET. PMID- 28553188 TI - Incidental Detection of Synchronous Medullary Thyroid Carcinoma with Bilateral Adrenal Pheochromocytoma on Iodine-123 Metaiodobenzylguanidine Scintigraphy, Leading to Diagnosis of Multiple Endocrine Neoplasia 2A. AB - We report a case of a 29-year-old female with the family history of medullary thyroid carcinoma (MTC) presenting with hematuria and tachycardia, who was found to have bilateral adrenal masses on abdominal computed tomography and biochemical testing compatible with pheochromocytoma. Iodine-123 (I-123) metaiodobenzylguanidine (MIBG) scintigraphy for preoperative planning prior to planned adrenalectomy revealed incidental synchronous unifocal MTC, along with expected bilateral adrenal pheochromocytomas. Pathology confirmed these findings, and subsequent genetic testing confirmed a rearranged during transfection proto oncogene mutation on exon 11, confirming the clinical diagnosis of multiple endocrine neoplasia 2A (MEN 2A). The unexpected incidental finding of synchronous MTC highlights the importance of considering MEN in the differential diagnosis when encountered with newly diagnosed pheochromocytoma and highlights the utility of I-123 MIBG scintigraphy in diagnostic workup of newly diagnosed pheochromocytoma. PMID- 28553189 TI - The Role of Bone Scintigraphy with Single-photon Emission Computed Tomography computed Tomography in the Diagnosis and Evaluation of Calciphylaxis. AB - Calciphylaxis, also known as calcific uremic arteriolopathy, is an uncommon disease, typically found in patients with the end-stage renal disease. Pathophysiological features include small vessel vasculopathy with mural calcification, fibrosis, and thrombosis. The clinical presentation varies but often consists of the necrosis of skin and subcutaneous tissues, with or without visceral organ involvement due to small vessel vasculopathy. This condition has a significant morbidity and mortality, making accurate diagnosis imperative. We present a case of calciphylaxis investigated using planar bone scintigraphy and single-photon emission computed tomography-computed tomography (SPECT-CT). This case stresses the value of SPECT-CT to accurately localize the abnormal uptake in subcutaneous soft tissue microcalcifications and confirms the exact location and extent of pathology. PMID- 28553190 TI - FINANCIAL LITERACY AROUND THE WORLD: AN OVERVIEW. AB - In an increasingly risky and globalized marketplace, people must be able to make well-informed financial decisions. Yet new international research demonstrates that financial illiteracy is widespread when financial markets are well developed as in Germany, the Netherlands, Sweden, Japan, Italy, New Zealand, and the United States, or when they are changing rapidly as in Russia. Further, across these countries, we show that the older population believes itself well informed, even though it is actually less well informed than average. Other common patterns are also evident: women are less financially literate than men and are aware of this shortfall. More educated people are more informed, yet education is far from a perfect proxy for literacy. There are also ethnic/racial and regional differences: city-dwellers in Russia are better informed than their rural counterparts, while in the U.S., African Americans and Hispanics are relatively less financially literate than others. Moreover, the more financially knowledgeable are also those most likely to plan for retirement. In fact, answering one additional financial question correctly is associated with a 3-4 percentage point higher chance of planning for retirement in countries as diverse as Germany, the U.S., Japan, and Sweden; in the Netherlands, it boosts planning by 10 percentage points. Finally, using instrumental variables, we show that these estimates probably underestimate the effects of financial literacy on retirement planning. In sum, around the world, financial literacy is critical to retirement security. PMID- 28553191 TI - Financial Literacy and Financial Sophistication in the Older Population. AB - Using a special-purpose module implemented in the Health and Retirement Study, we evaluate financial sophistication in the American population over the age of 50. We combine several financial literacy questions into an overall index to highlight which questions best capture financial sophistication and examine the sensitivity of financial literacy responses to framing effects. Results show that many older respondents are not financially sophisticated: they fail to grasp essential aspects of risk diversification, asset valuation, portfolio choice, and investment fees. Subgroups with notable deficits include women, the least educated, non-Whites, and those over age 75. In view of the fact that retirees increasingly must take on responsibility for their own retirement security, such meager levels of knowledge have potentially serious and negative implications. PMID- 28553192 TI - Patient Satisfaction With Videoconferencing-based Treatment for Alcohol Use Disorders. AB - OBJECTIVES: The objectives of this study are (1) to compare the satisfaction between patients who have received treatment as usual face-to-face (TAU group) and patients who have received optional videoconferencing-based treatment for alcohol use disorders (TAU+I group); and (2) to elaborate on the TAU+I group's satisfaction with the treatment in general and the technical equipment. METHODS: The design consisted of mixed methods: a survey and a qualitative study. Data consisted of self-reported data from questionnaires filled out by both groups and semistructured interviews with the TAU+I group. Data from the questionnaires were analyzed statistically using Stata. The semistructured interviews were analyzed using a general inductive approach. RESULTS: The survey indicated that the TAU+I group and TAU group were equally satisfied with the elements in the treatment. The interview indicated that the TAU+I group seemed to have a high satisfaction with most elements in the treatment. Patients who used videoconferencing were satisfied with establishing the videoconferencing connection and with the picture quality but less satisfied with the sound quality. CONCLUSIONS: Overall, the patients were satisfied with the treatment. We saw a nonsignificant tendency that the TAU+I group were more satisfied with the treatment in general, compared with the TAU group. It is a possibility that patients in this group felt more satisfied with the treatment as they had the opportunity to choose videoconferencing. Offering videoconferencing-based treatment may be a positive feature in the treatment and lead to improved outcomes of the treatment courses. The technical equipment and routine using it should be improved in future studies or during implementation. PMID- 28553193 TI - Peer Effects in Pro-Social Behavior: Social Norms or Social Preferences? AB - We compare social preference and social norm based explanations for peer effects in a three-person gift-exchange experiment. In the experiment a principal pays a wage to each of two agents, who then make effort choices sequentially. In our baseline treatment we observe that the second agent's effort is influenced by the effort choice of the first agent, even though there are no material spillovers between agents. This peer effect is predicted by the Fehr-Schmidt (1999) model of social preferences. As we show from a norms-elicitation experiment, it is also consistent with social norms compliance. A conditional logit investigation of the explanatory power of payoff inequality and elicited norms finds that the second agent's effort is best explained by the social preferences model. In further experiments we find that the peer effects change as predicted by the social preferences model. Again, a conditional logit analysis favors an explanation based on social preferences, rather than social norms. Our results suggest that, in our context, the social preferences model provides a parsimonious explanation for the observed peer effect. PMID- 28553194 TI - The Cyanation of Prochiral Aldehydes with Chiral Copper Complexes of R-(+)/S-(-) alpha-Ethylphenyl Amine in Methanol. AB - Interesting and unexpected results on the cyanation of prochiral aldehydes catalyzed by chiral copper complexes of R-(+)/(S)-(-) alpha-ethylphenyl amine (I/II) in anhydrous methanol are presented. The cyanation reaction with chiral copper complexes of R-(+)/S-(-) alpha-ethylphenyl amines, acetols in methanol perform to afford a series of chiral products such as amines and acetonitriles (compounds 4-6, 8, 10 and 11). The obtained products are fully characterized by NMR, IR and X-ray analysis. The proposed mechanism for the formation of a series of chiral products can be concluded that methanol firstly promotes the decomposition of the copper complexes bearing R-(+)/S-(-) alpha-ethylphenyl amines to the ligand R-(+)/ S-(-)-alpha-ethylphenyl amine, which then conjugated with the initial TMS ether of the cyanohydrin or cyanohydrin to afford the chiral compounds 4-6, 8, 10 and 11. PMID- 28553195 TI - Characterization of the Cultivable Gut Microflora in Wild-Caught ?Mediterranean Fish Species. AB - BACKGROUND: Microflora of the gastrointestinal tract plays important roles in food digestion, nutrient absorption and in host defense against ingested pathogens. Several studies have focused on the microflora of farmed fishes, but the gut flora of wild fishes remains poorly characterized. The aim of this work was to provide an overview of the bacteria colonizing the gut of wild-caught fishes and to determine whether some bacterial species can be pathogenic. RESULTS: We isolated cultivable bacteria from fifteen wild-caught Mediterranean fish species corresponding to different habitat, diet and origin. Bacterial species identity was determined by 16s rRNA gene sequencing for the 61 isolates. The potential pathogenicity of isolated bacteria was investigated using fruit fly (Drosophila melanogaster) and zebrafish (Danio rerio) as model organisms. Two bacterial strains (Serratia sp. and Aeromonas salmonicida) were lethal when microinjected to Drosophila, while zebrafish did not develop any disease when exposed to any of 34 isolated bacterial strains. However, it was interesting to note that two bacterial strains (Shewanella and Arthrobacter) isolated from marine fishes were able to colonize the guts of freshwater zebrafish. CONCLUSION: The results of this study give an overview of the bacterial species found in the guts of wild fishes living off Beirut seashore. It shows that some parameters believed to be limiting factors to host-gut colonization by bacteria can be overcome by some species. This pilot study could be extended by sampling a larger number of fish species with several specimens per fish species, and by identifying uncultivable bacteria that reside in the fish guts. Our results may have implications for the utilization of certain bacterial species in fish farming or their use as bio-indicators for water and/or food quality. PMID- 28553196 TI - Diagnostic Imaging of Hepatocellular Carcinoma - A Pictorial Essay. AB - Hepatocellular carcinoma (HCC) is the most common primary liver cancer, which develops mostly in the setting of chronic liver disease. European Association for the Study of the Liver (EASL) and European Organization for Research and Treatment of Cancer (EORTC) prepared guidelines for screening, follow-up and diagnosis of HCC to facilitate decision making and optimize both diagnostic and therapeutic protocols. The review briefly describes etiology, epidemiology and histopathology of HCC and presents EASL-EORTC guidelines for surveillance and diagnosis of HCC. Target population and screening algorithm is presented in the surveillance section. Ultrasound imaging of HCC and the role of contrast enhanced ultrasound are described as well as the value of laboratory tests in screening. Further, radiological features of HCC in multiphase CT and dynamic contrast enhanced MRI and diagnostic criteria are presented. Additionally, the advantages of advanced techniques in MRI such as diffusion weighed imaging and the use of hepatocyte-specific contrast agents are discussed. Lastly, the EASL-EORTC guidelines are compared with the guidelines of the American Association for the Study of Liver Diseases and the Japan Society of Hepatology. Also LI-RADS and the Barcelona Clinic Liver Cancer classification are mentioned. In the near future, due to the ongoing advances in imaging a revision of the guidelines may be expected. PMID- 28553197 TI - Effects of DARPP-32 Genetic Variation on Prefrontal Cortex Volume and Episodic Memory Performance. AB - Despite evidence of a fundamental role of DARPP-32 in integrating dopamine and glutamate signaling, studies examining gene coding for DARPP-32 in relation to neural and behavioral correlates in humans are scarce. Post mortem findings suggest genotype specific expressions of DARPP-32 in the dorsal frontal lobes. Therefore, we investigated the effects of genomic variation in DARPP-32 coding on frontal lobe volumes and episodic memory. Volumetric data from the dorsolateral (DLPFC), and visual cortices (VC) were obtained from 61 younger and older adults (?54%). The major homozygote G, T, or A genotypes in single nucleotide polymorphisms (SNPs: rs879606; rs907094; rs3764352, the two latter in complete linkage disequilibrium), at the DARPP-32 regulating PPP1R1B gene, influenced frontal gray matter volume and episodic memory (EM). Homozygous carriers of allelic variants with lower DARPP-32 expression had an overall larger prefrontal volume in addition to greater EM recall accuracy after accounting for the influence of age. The SNPs did not influence VC volume. The genetic effects on DLPFC were greater in young adults and selective to this group for EM. Our findings suggest that genomic variation maps onto individual differences in frontal brain volumes and cognitive functions. Larger DLPFC volumes were also related to better EM performance, suggesting that gene-related differences in frontal gray matter may contribute to individual differences in EM. These results need further replication from experimental and longitudinal reports to determine directions of causality. PMID- 28553198 TI - A Resilient, Non-neuronal Source of the Spatiotemporal Lag Structure Detected by BOLD Signal-Based Blood Flow Tracking. AB - Recent evidence has suggested that blood oxygenation level-dependent (BOLD) signals convey information about brain circulation via low frequency oscillation of systemic origin (sLFO) that travels through the vascular structure ("lag mapping"). Prompted by its promising application in both physiology and pathology, we examined this signal component using multiple approaches. A total of 30 healthy volunteers were recruited to perform two reproducibility experiments at 3 Tesla using multiband echo planar imaging. The first experiment investigated the effect of denoising and the second was designed to study the effect of subject behavior on lag mapping. The lag map's intersession test-retest reproducibility and image contrast were both diminished by removal of either the neuronal or the non-neuronal (e.g., cardiac, respiratory) components by independent component analysis-based denoising, suggesting that the neurovascular coupling also comprises a part of the BOLD lag structure. The lag maps were, at the same time, robust against local perfusion increases due to visuomotor task and global changes in perfusion induced by breath-holding at the same level as the intrasession reliability. The lag structure was preserved after time-locked averaging to the visuomotor task and breath-holding events, while any preceding signal changes were canceled out for the visuomotor task, consistent with the passive effect of neurovascular coupling in the venous side of the vasculature. These findings support the current assumption that lag mapping primarily reflects vascular structure despite the presence of sLFO perturbation of neuronal or non neuronal origin and, thus, emphasize the vascular origin of the lag map, encouraging application of BOLD-based blood flow tracking. PMID- 28553200 TI - Phase-II Clinical Validation of a Powered Exoskeleton for the Treatment of Elbow Spasticity. AB - Introduction: Spasticity is a typical motor disorder in patients affected by stroke. Typically post-stroke rehabilitation consists of repetition of mobilization exercises on impaired limbs, aimed to reduce muscle hypertonia and mitigate spastic reflexes. It is currently strongly debated if the treatment's effectiveness improves with the timeliness of its adoption; in particular, starting intensive rehabilitation as close as possible to the stroke event may counteract the growth and postpone the onset of spasticity. In this paper we present a phase-II clinical validation of a robotic exoskeleton in treating subacute post-stroke patients. Methods: Seventeen post-stroke patients participated in 10 daily rehabilitation sessions using the NEUROExos Elbow Module exoskeleton, each one lasting 45 min: the exercises consisted of isokinetic passive mobilization of the elbow, with torque threshold to detect excessive user's resistance to the movement. We investigated the safety by reporting possible adverse events, such as mechanical, electrical or software failures of the device or injuries or pain experienced by the patient. As regards the efficacy, the Modified Ashworth Scale, was identified as primary outcome measure and the NEEM metrics describing elbow joint resistance to passive extension (i.e., maximum extension torque and zero-torque angle) as secondary outcomes. Results: During the entire duration of the treatments no failures or adverse events for the patients were reported. No statistically significant differences were found in the Modified Ashworth Scale scores, between pre-treatment and post treatment and between post-treatment and follow-up sessions, indicating the absence of spasticity increase throughout (14 days) and after (3-4 months follow up) the treatment. Exoskeleton metrics confirmed the absence of significant difference in between pre- and post-treatment data, whereas intra-session data highlighted significant differences in the secondary outcomes, toward a decrease of the subject's joint resistance. Conclusions: The results show that our robotic exoskeleton can be safely used for prolonged sessions in post-stroke and suggest that intensive early rehabilitation treatment may prevent the occurrence of spasticity at a later stage. Moreover, the NEEM metrics were found to be reliable compared to the Modified Ashworth Scale and sensitive to revealing intra-session changes of elbow resistance to passive extension, in agreement with clinical evidences. PMID- 28553199 TI - Aberrant Functional Connectivity Architecture in Participants with Chronic Insomnia Disorder Accompanying Cognitive Dysfunction: A Whole-Brain, Data-Driven Analysis. AB - Objectives: Although it is widely observed that chronic insomnia disorder (CID) is associated with cognitive impairment, the neurobiological mechanisms underlying this remain unclear. Prior neuroimaging studies have confirmed that a close correlation exists between functional connectivity and cognitive impairment. Based on this observation, in this study we used resting-state functional magnetic resonance imaging (rs-fMRI) to study the relationship between whole brain functional connectivity and cognitive function in CID. Methods: We included 39 patients with CID and 28 age-, gender-, and education-matched healthy controls (HC). Abnormalities in functional connectivity were identified by comparing the correlation coefficients for each pair of 116 brain regions between CID and HC. Results: Cognitive impairment was associated with reduced subjective insomnia scores after controlling for age, gender, and educational effects. Compared with HC, patients with CID had larger negative correlations within the task-negative network [medial prefrontal cortex (mPFC), precuneus, inferior temporal gyrus, cerebellum, and superior parietal gyrus], and between two intrinsic anti-correlation networks (mPFC and middle temporal gyrus; supplementary motor area and cerebellum). Patients with CID also had decreased positive correlations within the default mode network (DMN), and between the cerebellum and DMN, which mainly comprises the mPFC and posterior cingulated cortex. There were positive correlations of decreased positive connectivity with subjective sleep scores and MMSE scores, and increased negative correlations between the task-negative-network and MMSE scores in CID. Conclusions: Using rs fMRI, our results support previous observations of cortical disconnection in CID in the prefrontal and DMN networks. Moreover, abnormal correlations within the task-negative network, and between two intrinsically anti-correlation networks, might be important neurobiological indicators of CID and associated cognitive impairment. PMID- 28553201 TI - Fe65-PTB2 Dimerization Mimics Fe65-APP Interaction. AB - Physiological function and pathology of the Alzheimer's disease causing amyloid precursor protein (APP) are correlated with its cytosolic adaptor Fe65 encompassing a WW and two phosphotyrosine-binding domains (PTBs). The C-terminal Fe65-PTB2 binds a large portion of the APP intracellular domain (AICD) including the GYENPTY internalization sequence fingerprint. AICD binding to Fe65-PTB2 opens an intra-molecular interaction causing a structural change and altering Fe65 activity. Here we show that in the absence of the AICD, Fe65-PTB2 forms a homodimer in solution and determine its crystal structure at 2.6 A resolution. Dimerization involves the unwinding of a C-terminal alpha-helix that mimics binding of the AICD internalization sequence, thus shielding the hydrophobic binding pocket. Specific dimer formation is validated by nuclear magnetic resonance (NMR) techniques and cell-based analyses reveal that Fe65-PTB2 together with the WW domain are necessary and sufficient for dimerization. Together, our data demonstrate that Fe65 dimerizes via its APP interaction site, suggesting that besides intra- also intermolecular interactions between Fe65 molecules contribute to homeostatic regulation of APP mediated signaling. PMID- 28553202 TI - A Systematic RNAi Screen Reveals a Novel Role of a Spindle Assembly Checkpoint Protein BuGZ in Synaptic Transmission in C. elegans. AB - Synaptic vesicles (SV) store various neurotransmitters that are released at the synapse. The molecular mechanisms of biogenesis, exocytosis, and endocytosis for SV, however, remain largely elusive. In this study, using Complex Object Parametric Analysis and Sorter (COPAS) to monitor the fluorescence of synapto pHluorin (SpH), we performed a whole-genome RNAi screen in C. elegans to identify novel genetic modulators in SV cycling. One hundred seventy six genes that up regulating SpH fluorescence and 96 genes that down-regulating SpH fluorescence were identified after multi-round screen. Among these genes, B0035.1 (bugz-1) encodes ortholog of mammalian C2H2 zinc-finger protein BuGZ/ZNF207, which is a spindle assembly checkpoint protein essential for mitosis in human cells. Combining electrophysiology, imaging and behavioral assays, we reveal that depletion of BuGZ-1 results in defects in locomotion. We further demonstrate that BuGZ-1 promotes SV recycling by regulating the expression levels of endocytosis related genes such as rab11.1. Therefore, we have identified a bunch of potential genetic modulators in SV cycling, and revealed an unexpected role of BuGZ-1 in regulating synaptic transmission. PMID- 28553204 TI - Leucine-Rich Repeat Kinase 2 (LRRK2) Stimulates IL-1beta-Mediated Inflammatory Signaling through Phosphorylation of RCAN1. AB - Leucine-rich repeat kinase 2 (LRRK2) is a Ser/Thr kinase having mixed lineage kinase-like and GTPase domains, controlling neurite outgrowth and neuronal cell death. Evidence suggests that LRRK2 is involved in innate immune response signaling, but the underlying mechanism is yet unknown. A novel protein inhibitor of phosphatase 3B, RCAN1, is known to positively regulate inflammatory signaling through modulation of several intracellular targets of interleukins in immune cells. In the present study, we report that LRRK2 phosphorylates RCAN1 (RCAN1-1S) and is markedly up-regulated during interleukin-1beta (IL-1beta) treatment. During IL-1beta treatment, LRRK2-mediated phosphorylation of RCAN1 promoted the formation of protein complexes, including that between Tollip and RCAN1. LRRK2 decreased binding between Tollip and IRAK1, which was accompanied by increased formation of the IRAK1-TRAF6 complex. TAK1 activity was significantly enhanced by LRRK2. Furthermore, LRRK2 enhanced transcriptional activity of NF-kappaB and cytokine IL-8 production. These findings suggest that LRRK2 might be important in positively modulating IL-1beta-mediated signaling through selective phosphorylation of RCAN1. PMID- 28553205 TI - Dopamine and Serotonin-Induced Modulation of GABAergic and Glutamatergic Transmission in the Striatum and Basal Forebrain. AB - Catecholamine receptor-mediated modulation of glutamatergic or GABAergic transmission in the striatum as well as basal forebrain (BF) has been intensively studied during these two decades. In the striatum, activation of dopamine (DA) D2 receptors in GABAergic terminals inhibits GABA release onto cholinergic interneurons by selective blockade of N-type calcium channels. In the BF, glutamatergic transmission onto cholinergic projection neurons is inhibited via DA D1-like receptors by selective blockade of P/Q-type calcium channels. On the other hand, presynaptic inhibition of the GABA release onto cholinergic neurons mediated by D1-like receptors or 5-HT1B receptors is independent of calcium influx. In addition, the DA receptor-mediated calcium influx dependent presynaptic inhibition mentioned above decreases with postnatal development, with selective coupling between DA receptors and each subtype of calcium channels being unchanged. Furthermore, the precise origin of these GABAergic or glutamatergic inputs to postsynaptic neurons can be identified by recent optogenetic approaches. Thus, modulatory mechanisms in specific synaptic connections between certain types of neurons in the striatum and BF are being identified. PMID- 28553206 TI - A Toolbox for Optophysiological Experiments in Freely Moving Rats. AB - Simultaneous recordings and manipulations of neural circuits that control the behavior of animals is one of the key techniques in modern neuroscience. Rapid advances in optogenetics have led to a variety of probes combining multichannel readout and optogenetic write in. Given the complexity of the brain, it comes as no surprise that the choice of the device is constrained by several factors such as the animal model, the structure and location of the brain area of interest, as well as the behavioral read out. Here we provide an overview of available devices for chronic simultaneous neural recordings and optogenetic manipulation in awake behaving rats. We focus on two fixed arrays and two moveable drives. For both options, we present data from one custom-made (in house) and one commercially available device. Here we provide evidence that simultaneous neural recordings and optogenetic manipulations are feasible with all four tested devices. Further we give detailed information about the recording quality, and also contrast the different features of the probes. As we provide detailed information about equipment and building procedures for combined chronic multichannel readout and optogenetic control with maximum performance at minimized costs, this overview might help especially researchers who want to enter the field of in vivo optophysiology. PMID- 28553203 TI - Autophagy as an Emerging Common Pathomechanism in Inherited Peripheral Neuropathies. AB - The inherited peripheral neuropathies (IPNs) comprise a growing list of genetically heterogeneous diseases. With mutations in more than 80 genes being reported to cause IPNs, a wide spectrum of functional consequences is expected to follow this genotypic diversity. Hence, the search for a common pathomechanism among the different phenotypes has become the holy grail of functional research into IPNs. During the last decade, studies on several affected genes have shown a direct and/or indirect correlation with autophagy. Autophagy, a cellular homeostatic process, is required for the removal of cell aggregates, long-lived proteins and dead organelles from the cell in double-membraned vesicles destined for the lysosomes. As an evolutionarily highly conserved process, autophagy is essential for the survival and proper functioning of the cell. Recently, neuronal cells have been shown to be particularly vulnerable to disruption of the autophagic pathway. Furthermore, autophagy has been shown to be affected in various common neurodegenerative diseases of both the central and the peripheral nervous system including Alzheimer's, Parkinson's, and Huntington's diseases. In this review we provide an overview of the genes involved in hereditary neuropathies which are linked to autophagy and we propose the disruption of the autophagic flux as an emerging common pathomechanism. We also shed light on the different steps of the autophagy pathway linked to these genes. Finally, we review the concept of autophagy being a therapeutic target in IPNs, and the possibilities and challenges of this pathway-specific targeting. PMID- 28553207 TI - Dm5-HT2B: Pharmacological Characterization of the Fifth Serotonin Receptor Subtype of Drosophila melanogaster. AB - Serotonin (5-hydroxytryptamine, 5-HT) is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects) and deuterostomes (e.g., mammals). In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster, a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT1A, Dm5-HT1B, and Dm5-HT7 couple to cAMP signaling cascades, the Dm5-HT2A receptor leads to Ca2+ signaling in an inositol-1,4,5-trisphosphate-dependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT2B receptor. Knowledge about this receptor's pharmacological properties is very limited. This is quite surprising because Dm5-HT2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5-HT2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT2B's pharmacology, we evaluated the receptor's response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT2B signaling in vitro and in vivo. PMID- 28553208 TI - Childhood Trauma and Functional Connectivity between Amygdala and Medial Prefrontal Cortex: A Dynamic Functional Connectivity and Large-Scale Network Perspective. AB - Altered functional connectivity (FC) between the medial prefrontal cortex (mPFC) and amygdala is widely implicated as a neural mechanism explaining risk for psychopathology among those exposed to early life trauma. Nonetheless, contemporary neuroimaging research has shifted toward large-scale network models of brain function, and it is not clear how this common bi-nodal finding fits into larger-scale network models. Here, using dynamic functional connectivity (DFC) approaches combined with large-scale network analyses, the larger role of bi nodal FC between mPFC and amygdala among a sample of adolescent girls is investigated. The sample was comprised of 30 healthy control girls and 26 girls exposed to either physical or sexual assault who underwent a resting-state scan during 3T MRI. DFC using a sliding window approach was used to create weighted, undirected, graphs from the resting-state data following parcellation with a 215 regions-of-interest (ROI) atlas. Using a priori ROI, the predicted finding of lessor FC between mPFC and amygdala as a function of early life trauma was replicated in this sample. By contrast, early life trauma was associated with greater large-scale network modularity. Using a dynamic FC approach, it is also demonstrated that within-subject variability in this bi-nodal FC closely tracks within-subject fluctuations in large-scale network patterns, including connectivity between a limbic and default mode network (in which the amygdala and mPFC nodes belong, respectively) as well as overall modular organization. These results suggest that bi-nodal FC, such as amygdala-mPFC FC, may generally reflect larger-scale network patterns. Future research is necessary to understand whether these associations between nodal FC and large-scale network organization better reflect top-down processes (larger-scale network organization drives bi-nodal FC) or bottom-up processes (bi-nodal FC drives larger-scale network organization) and the related impact of early life trauma. PMID- 28553210 TI - Evidence for a Priori Existence of Attentional Bias Subgroups in Emotional Processing of Aversive Stimuli. AB - Little is known regarding inter-individual differences in attentional biases for pain-related information; more knowledge is crucial, since these biases have been associated with differences in pain processing as well as in predicting the risk of postoperative pain. The present study investigated EEG correlates of attentional bias patterns for pain-related information, with specific focus on avoidance- and vigilance-like behavior. Forty-one participants performed a dot probe task, where neutral and pain-related words were used to create neutral, congruent, incongruent, and double (two pain-related words) trials. EEG was recorded, which was used to generate ERP's of the word-processing phase and the post-dot phase. Participants were placed in two subgroups based on the direction of their attentional bias (either positive; toward the pain-related words, or negative; away from pain-related words). Using t-profiles, four latency windows were identified on which the two subgroups differed significantly. These latency windows yield areas which correspond with the P1-N1 domain and the P3b for the word-processing phase, while the post-dot phase latency windows cover the areas of the P200 and the P3b. The two subgroups show differences on congruent, incongruent, and the double trials, but interestingly also on the neutral trials. Most notably, the area in the word-phase associated with the P3b is diminished in the subgroup showing a negative bias. The deflections associated with both early and late attentional components, including the P3B, as well as a positive deflection in the timeframe of proposed response evaluation processes differ significantly between subgroups. In this study we demonstrated that different attentional biases exist in the healthy population, by showing differences in ERP's. We also show differences in processing neutral trials, which suggests there are fundamental differences between these groups in processing words in general. PMID- 28553211 TI - Kinoscope: An Open-Source Computer Program for Behavioral Pharmacologists. AB - Behavioral analysis in preclinical neuropsychopharmacology relies on the accurate measurement of animal behavior. Several excellent solutions for computer-assisted behavioral analysis are available for specialized behavioral laboratories wishing to invest significant resources. Herein, we present an open source straightforward software solution aiming at the rapid and easy introduction to an experimental workflow, and at the improvement of training staff members in a better and more reproducible manual scoring of behavioral experiments with the use of visual aids-maps. Currently the program readily supports the Forced Swim Test, Novel Object Recognition test and the Elevated Plus maze test, but with minor modifications can be used for scoring virtually any behavioral test. Additional modules, with predefined templates and scoring parameters, are continuously added. Importantly, the prominent use of visual maps has been shown to improve, in a student-engaging manner, the training and auditing of scoring in behavioral rodent experiments. PMID- 28553212 TI - Evidence for Ancestral Programming of Resilience in a Two-Hit Stress Model. AB - In a continuously stressful environment, the effects of recurrent prenatal stress (PS) may accumulate across generations and alter stress vulnerability and resilience. Here, we report in female rats that a family history of recurrent ancestral PS facilitates certain aspects of movement performance, and that these benefits are abolished by the experience of a second hit, induced by a silent ischemia during adulthood. Female F4-generation rats with and without a family history of cumulative multigenerational PS (MPS) were tested for skilled motor function before and after the induction of a minor ischemic insult by endothelin 1 infusion into the primary motor cortex. MPS resulted in improved skilled motor abilities and blunted hypothalamic-pituitary-adrenal (HPA) axis function compared to non-stressed rats. Deep sequencing revealed downregulation of miR-708 in MPS rats along with upregulation of its predicted target genes Mapk10 and Rasd2. Through miR-708 stress may regulate mitogen-activated protein kinase (MAPK) pathway activity. Hair trace elemental analysis revealed an increased Na/K ratio, which suggests a chronic shift in adrenal gland function. The ischemic lesion activated the HPA axis in MPS rats only; the lesion, however, abolished the advantage of MPS in skilled reaching. The findings indicate that MPS generates adaptive flexibility in movement, which is challenged by a second stressor, such as a neuropathological condition. Thus, a second "hit" by a stressor may limit behavioral flexibility and neural plasticity associated with ancestral stress. PMID- 28553214 TI - From Thirst to Satiety: The Anterior Mid-Cingulate Cortex and Right Posterior Insula Indicate Dynamic Changes in Incentive Value. AB - The cingulate cortex and insula are among the neural structures whose activations have been modulated in functional imaging studies examining discrete states of thirst and drinking to satiation. Building upon these findings, the present study aimed to identify neural structures that change their pattern of activation elicited by water held in the mouth in relation to the internal body state, i.e., proportional to continuous water consumption. Accordingly, participants in a thirsty state were scanned while receiving increments of water until satiety was reached. As expected, fluid ingestion led to a clear decrease in self-reported thirst and the pleasantness ratings of the water ingested. Furthermore, linear decreases in the blood oxygenation level dependent (BOLD) response to water ingestion were observed in the anterior mid-cingulate cortex (aMCC) and right posterior insula as participants shifted towards the non-thirsty state. In addition, regions in the superior temporal gyrus (STG), supplementary motor area (SMA), superior parietal lobule (SPL), precuneus and calcarine sulcus also showed a linear decrease with increasing fluid consumption. Further analyses related single trial BOLD responses of associated regions to trial-by-trial ratings of thirst and pleasantness. Overall, the aMCC and posterior insula may be key sites of a neural network representing the motivation for drinking based on the dynamic integration of internal state and external stimuli. PMID- 28553213 TI - Fast Brain Plasticity during Word Learning in Musically-Trained Children. AB - Children learn new words every day and this ability requires auditory perception, phoneme discrimination, attention, associative learning and semantic memory. Based on previous results showing that some of these functions are enhanced by music training, we investigated learning of novel words through picture-word associations in musically-trained and control children (8-12 year-old) to determine whether music training would positively influence word learning. Results showed that musically-trained children outperformed controls in a learning paradigm that included picture-sound matching and semantic associations. Moreover, the differences between unexpected and expected learned words, as reflected by the N200 and N400 effects, were larger in children with music training compared to controls after only 3 min of learning the meaning of novel words. In line with previous results in adults, these findings clearly demonstrate a correlation between music training and better word learning. It is argued that these benefits reflect both bottom-up and top-down influences. The present learning paradigm might provide a useful dynamic diagnostic tool to determine which perceptive and cognitive functions are impaired in children with learning difficulties. PMID- 28553209 TI - Mystic Acetaldehyde: The Never-Ending Story on Alcoholism. AB - After decades of uncertainties and drawbacks, the study on the role and significance of acetaldehyde in the effects of ethanol seemed to have found its main paths. Accordingly, the effects of acetaldehyde, after its systemic or central administration and as obtained following ethanol metabolism, looked as they were extensively characterized. However, almost 5 years after this research appeared at its highest momentum, the investigations on this topic have been revitalized on at least three main directions: (1) the role and the behavioral significance of acetaldehyde in different phases of ethanol self-administration and in voluntary ethanol consumption; (2) the distinction, in the central effects of ethanol, between those arising from its non-metabolized fraction and those attributable to ethanol-derived acetaldehyde; and (3) the role of the acetaldehyde-dopamine condensation product, salsolinol. The present review article aims at presenting and discussing prospectively the most recent data accumulated following these three research pathways on this never-ending story in order to offer the most up-to-date synoptic critical view on such still unresolved and exciting topic. PMID- 28553215 TI - EEG Cortical Connectivity Analysis of Working Memory Reveals Topological Reorganization in Theta and Alpha Bands. AB - Numerous studies have revealed various working memory (WM)-related brain activities that originate from various cortical regions and oscillate at different frequencies. However, multi-frequency band analysis of the brain network in WM in the cortical space remains largely unexplored. In this study, we employed a graph theoretical framework to characterize the topological properties of the brain functional network in the theta and alpha frequency bands during WM tasks. Twenty-eight subjects performed visual n-back tasks at two difficulty levels, i.e., 0-back (control task) and 2-back (WM task). After preprocessing, Electroencephalogram (EEG) signals were projected into the source space and 80 cortical brain regions were selected for further analysis. Subsequently, the theta- and alpha-band networks were constructed by calculating the Pearson correlation coefficients between the power series (obtained by concatenating the power values of all epochs in each session) of all pairs of brain regions. Graph theoretical approaches were then employed to estimate the topological properties of the brain networks at different WM tasks. We found higher functional integration in the theta band and lower functional segregation in the alpha band in the WM task compared with the control task. Moreover, compared to the 0-back task, altered regional centrality was revealed in the 2-back task in various brain regions that mainly resided in the frontal, temporal and occipital lobes, with distinct presentations in the theta and alpha bands. In addition, significant negative correlations were found between the reaction time with the average path length of the theta-band network and the local clustering of the alpha-band network, which demonstrates the potential for using the brain network metrics as biomarkers for predicting the task performance during WM tasks. PMID- 28553216 TI - Autistic Children Show a Surprising Relationship between Global Visual Perception, Non-Verbal Intelligence and Visual Parvocellular Function, Not Seen in Typically Developing Children. AB - Despite much current research into the visual processing style of individuals with Autism Spectrum Disorder (ASD), understanding of the neural mechanisms is lagging, especially with respect to the contributions of the overlapping dichotomies of magnocellular/parvocellular (afferent neural pathways), global/local (perception) and dorsal/ventral (cortical streams). Here, we addressed this deficiency by measuring inspection times (ITs) for novel global/local stimuli as well as recording nonlinear visually evoked potentials (VEPs), in particular, magnocellular and parvocellular temporal efficiencies. The study was conducted on a group of male ASD children and a typically developing (TD) group matched for mean age and mean non-verbal intelligence, as measured by the Raven's Progressive Matrices. The IT results did not differ between groups, however a negative correlation between global IT and Raven's score was found in the ASD group, that was not evident in the TD group. Nonlinear VEP showed the ASD group had smaller amplitude parvocellular-generated second order responses compared to the TD group. This is a sign of improved temporal responsiveness in ASD vs. TD groups. Principal Component Analysis linked global IT, non-verbal intelligence scores and VEP parvocellular efficiency in a single factor for the ASD but not the TD group. The results are suggestive of a constraint on pathways available for cognitive response in the ASD group, with temporal processing for those with ASD becoming more reliant on the parvocellular pathway. PMID- 28553220 TI - The Influence of Volume Conduction on DTF Estimate and the Problem of Its Mitigation. PMID- 28553219 TI - A Bayesian Reformulation of the Extended Drift-Diffusion Model in Perceptual Decision Making. AB - Perceptual decision making can be described as a process of accumulating evidence to a bound which has been formalized within drift-diffusion models (DDMs). Recently, an equivalent Bayesian model has been proposed. In contrast to standard DDMs, this Bayesian model directly links information in the stimulus to the decision process. Here, we extend this Bayesian model further and allow inter trial variability of two parameters following the extended version of the DDM. We derive parameter distributions for the Bayesian model and show that they lead to predictions that are qualitatively equivalent to those made by the extended drift diffusion model (eDDM). Further, we demonstrate the usefulness of the extended Bayesian model (eBM) for the analysis of concrete behavioral data. Specifically, using Bayesian model selection, we find evidence that including additional inter trial parameter variability provides for a better model, when the model is constrained by trial-wise stimulus features. This result is remarkable because it was derived using just 200 trials per condition, which is typically thought to be insufficient for identifying variability parameters in DDMs. In sum, we present a Bayesian analysis, which provides for a novel and promising analysis of perceptual decision making experiments. PMID- 28553218 TI - The Effects of Mirror Feedback during Target Directed Movements on Ipsilateral Corticospinal Excitability. AB - Mirror visual feedback (MVF) training is a promising technique to promote activation in the lesioned hemisphere following stroke, and aid recovery. However, current outcomes of MVF training are mixed, in part, due to variability in the task undertaken during MVF. The present study investigated the hypothesis that movements directed toward visual targets may enhance MVF modulation of motor cortex (M1) excitability ipsilateral to the trained hand compared to movements without visual targets. Ten healthy subjects participated in a 2 * 2 factorial design in which feedback (veridical, mirror) and presence of a visual target (target present, target absent) for a right index-finger flexion task were systematically manipulated in a virtual environment. To measure M1 excitability, transcranial magnetic stimulation (TMS) was applied to the hemisphere ipsilateral to the trained hand to elicit motor evoked potentials (MEPs) in the untrained first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles at rest prior to and following each of four 2-min blocks of 30 movements (B1-B4). Targeted movement kinematics without visual feedback was measured before and after training to assess learning and transfer. FDI MEPs were decreased in B1 and B2 when movements were made with veridical feedback and visual targets were absent. FDI MEPs were decreased in B2 and B3 when movements were made with mirror feedback and visual targets were absent. FDI MEPs were increased in B3 when movements were made with mirror feedback and visual targets were present. Significant MEP changes were not present for the uninvolved ADM, suggesting a task-specific effect. Analysis of kinematics revealed learning occurred in visual target-directed conditions, but transfer was not sensitive to mirror feedback. Results are discussed with respect to current theoretical mechanisms underlying MVF-induced changes in ipsilateral excitability. PMID- 28553217 TI - Electrocorticography of Spatial Shifting and Attentional Selection in Human Superior Parietal Cortex. AB - Spatial-attentional reorienting and selection between competing stimuli are two distinct attentional processes of clinical and fundamental relevance. In the past, reorienting has been mainly associated with inferior parietal cortex. In a patient with a subdural grid covering the upper and lower bank of the left anterior and middle intraparietal sulcus (IPS) and the superior parietal lobule (SPL), we examined the involvement of superior parietal cortex using a hybrid spatial cueing paradigm identical to that previously applied in stroke and in healthy controls. In SPL, as early as 164 ms following target onset, an invalidly compared to a validly cued target elicited a positive event-related potential (ERP) and an increase in intertrial coherence (ITC) in the theta band, regardless of the direction of attention. From around 400-650 ms, functional connectivity [weighted phase lag index (wPLI) analysis] between SPL and IPS briefly inverted such that SPL activity was driving IPS activity. In contrast, the presence of a competing distracter elicited a robust change mainly in IPS from 300 to 600 ms. Within superior parietal cortex reorienting of attention is associated with a distinct and early electrophysiological response in SPL while attentional selection is indexed by a relatively late electrophysiological response in the IPS. The long latency suggests a role of IPS in working memory or cognitive control rather than early selection. PMID- 28553221 TI - Tumors Presenting as Multiple Cranial Nerve Palsies. AB - Cranial nerve palsy could be one of the presenting features of underlying benign or malignant tumors of the head and neck. The tumor can involve the cranial nerves by local compression, direct infiltration or by paraneoplastic process. Cranial nerve involvement depends on the anatomical course of the cranial nerve and the site of the tumor. Patients may present with single or multiple cranial nerve palsies. Multiple cranial nerve involvement could be sequential or discrete, unilateral or bilateral, painless or painful. The presentation could be acute, subacute or recurrent. Anatomic localization is the first step in the evaluation of these patients. The lesion could be in the brain stem, meninges, base of skull, extracranial or systemic disease itself. We present 3 cases of underlying neoplasms presenting as cranial nerve palsies: a case of glomus tumor presenting as cochlear, glossopharyngeal, vagus and hypoglossal nerve palsies, clivus tumor presenting as abducens nerve palsy, and diffuse large B-cell lymphoma presenting as oculomotor, trochlear, trigeminal and abducens nerve palsies due to paraneoplastic involvement. History and physical examination, imaging, autoantibodies and biopsy if feasible are useful for the diagnosis. Management outcomes depend on the treatment of the underlying tumor. PMID- 28553222 TI - Dynamic Arc SUMOylation and Selective Interaction with F-Actin-Binding Protein Drebrin A in LTP Consolidation In Vivo. AB - Activity-regulatedcytoskeleton-associated protein (Arc) protein is implicated as a master regulator of long-term forms of synaptic plasticity and memory formation, but the mechanisms controlling Arc protein function are little known. Post-translation modification by small ubiquitin-like modifier (SUMO) proteins has emerged as a major mechanism for regulating protein-protein interactions and function. We first show in cell lines that ectopically expressed Arc undergoes mono-SUMOylation. The covalent addition of a single SUMO1 protein was confirmed by in vitro SUMOylation of immunoprecipitated Arc. To explore regulation of endogenous Arc during synaptic plasticity, we induced long-term potentiation (LTP) in the dentate gyrus of live anesthetized rats. Using coimmunoprecipitation of native proteins, we show that Arc synthesized during the maintenance phase of LTP undergoes dynamic mono-SUMO1-ylation. Levels of unmodified Arc increase in multiple subcellular fractions (cytosol, membrane, nuclear and cytoskeletal), whereas enhanced Arc SUMOylation was specific to the synaptoneurosomal and the cytoskeletal fractions. Dentate gyrus LTP consolidation requires a period of sustained Arc synthesis driven by brain-derived neurotrophic factor (BDNF) signaling. Local infusion of the BDNF scavenger, TrkB-Fc, during LTP maintenance resulted in rapid reversion of LTP, inhibition of Arc synthesis and loss of enhanced Arc SUMO1ylation. Furthermore, coimmunoprecipitation analysis showed that SUMO1-ylated Arc forms a complex with the F-actin-binding protein drebrin A, a major regulator of cytoskeletal dynamics in dendritic spines. Although Arc also interacted with dynamin 2, calcium/calmodulindependentprotein kinase II-beta (CaMKIIbeta), and postsynaptic density protein-95 (PSD-95), these complexes lacked SUMOylated Arc. The results support a model in which newly synthesized Arc is SUMOylated and targeted for actin cytoskeletal regulation during in vivo LTP. PMID- 28553223 TI - Chronic Monoarthritis Pain Accelerates the Processes of Cognitive Impairment and Increases the NMDAR Subunits NR2B in CA3 of Hippocampus from 5-month-old Transgenic APP/PS1 Mice. AB - Many factors impact cognitive impairment; however, the effects of chronic pain and the mechanisms underlying these effects on cognitive impairment are currently unknown. Here we tested the hypothesis that chronic pain accelerates the transition from normal cognition to mild cognitive impairment (MCI) in 5-month old transgenic APP/PS1 mice, an animal model of Alzheimer's disease (AD), and that neurotoxicity induced by N-methyl-D-aspartic acid receptor (NMDAR) subunits may be involved in this process. Chronic monoarthritis pain was induced in transgenic APP/PS1 mice and 5-month-old wild-type (WT) mice by intra- and pre articular injections of Freund's complete adjuvant (FCA) into one knee joint. Pain behavior, learning and memory function, and the distribution and quantity of NMDAR subunits (NR1, NR2A and NR2B) in hippocampal CA1 and CA3 regions were assessed. Our results showed that although persistent and robust monoarthritis pain was induced by the FCA injections, only the transgenic APP/PS1 mice with chronic monoarthritis pain exhibited marked learning and memory impairments. This result suggested that chronic monoarthritis pain accelerated the cognitive impairment process. Furthermore, only transgenic APP/PS1 mice with chronic monoarthritis pain exhibited an overexpression of NR2B and an increased NR2B/NR2A ratio in the hippocampus CA3. These findings suggest that chronic pain is a risk factor for cognitive impairment and that increased neurotoxicity associated with NMDAR subunit activation may underpin the impairment. Thus, NMDARs may be a therapeutic target for the prevention of chronic pain-induced cognitive impairment. PMID- 28553224 TI - Docking Studies and Biological Evaluation of a Potential beta-Secretase Inhibitor of 3-Hydroxyhericenone F from Hericium erinaceus. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting approximately more than 5% of the population worldwide over the age 65, annually. The incidence of AD is expected to be higher in the next 10 years. AD patients experience poor prognosis and as a consequence new drugs and therapeutic strategies are required in order to improve the clinical responses and outcomes of AD. The purpose of the present study was to screen a certain number of potential compounds from herbal sources and investigate their corresponding mode of action. In the present study, the learning and memory effects of ethanol:water (8:2) extracts from Hericium erinaceus were evaluated on a dementia rat model. The model was established by intraperitoneal injection of 100 mg/kg/d D-galactose in rats. The results indicated that the extracts can significantly ameliorate the learning and memory abilities. Specific active ingredients were screened in vivo assays and the results were combined with molecular docking studies. Potential receptor-ligand interactions on the BACE1-inhibitor namely, 3-Hydroxyhericenone F (3HF) were investigated. The isolation of a limited amount of 3HF from the fruit body of H. erinaceus by chemical separation was conducted, and the mode of action of this compound was verified in NaN3-induced PC12 cells. The cell-based assays demonstrated that 3HF can significantly down-regulate the expression of BACE1 (p < 0.01), while additional AD intracellular markers namely, p-Tau and Abeta1-42 were further down-regulated (p < 0.05). The data further indicate that 3HF can ameliorate certain mitochondrial dysfunction conditions by the reversal of the decreasing level of mitochondrial respiratory chain complexes, the calcium ion levels ([Ca2+]), the inhibiton in the production of ROS, the increase in the mitochondrial membrane potential and ATP levels, and the regulation of the expression levels of the genes encoding for the p21, COX I, COX II, PARP1, and NF kappaB proteins. The observations suggest the use of H. erinaceus in traditional medicine for the treatment of various neurological diseases and render 3HF as a promising naturally occurring chemical constituent for the treatment of AD via the inhibition of the beta-secretase enzyme. PMID- 28553225 TI - Cardioprotective Action of Ginkgo biloba Extract against Sustained beta Adrenergic Stimulation Occurs via Activation of M2/NO Pathway. AB - Ginkgo biloba is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of Ginkgo biloba on cardiovascular diseases remain poorly elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of Ginkgo biloba-mediated neuroprotection, we aimed to investigate whether Ginkgo biloba extract (GBE) promotes cardioprotection via activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o.) reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic beta-adrenergic receptor stimulation (beta-AR, 4.5 mg/kg/day for 8 days, i.p.). Moreover, GBE prevented the upregulation of muscarinic receptors (M2) and downregulation of beta1-AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection in vivo, we performed in vitro studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs via activation of M2/NO pathway uncovering a new mechanism involved in the cardioprotective action of Ginkgo biloba. PMID- 28553226 TI - beta-Sitosterol Reduces the Expression of Chemotactic Cytokine Genes in Cystic Fibrosis Bronchial Epithelial Cells. AB - Extracts from Nigella arvensis L. seeds, which are widely used as anti inflammatory remedies in traditional medicine of Northern Africa, were able to inhibit the expression of the pro-inflammatory neutrophil chemokine Interleukin (IL)-8 in Cystic Fibrosis (CF) bronchial epithelial IB3-1 cells exposed to the Gram-negative bacterium Pseudomonas aeruginosa. The chemical composition of the extracts led to the identification of three major components, beta-sitosterol, stigmasterol, and campesterol, which are the most abundant phytosterols, cholesterol-like molecules, usually found in plants. beta-sitosterol (BSS) was the only compound that significantly reproduced the inhibition of the P. aeruginosa-dependent expression of IL-8 at nanomolar concentrations. BSS was tested in CF airway epithelial CuFi-1 cells infected with P. aeruginosa. BSS (100 nM), showed a significant and consistent inhibitory activity on expression of the P. aeruginosa-stimulated expression chemokines IL-8, GRO-alpha GRO-beta, which play a pivotal role in the recruitment of neutrophils in CF inflamed lungs. Preliminary mechanistic analysis showed that BSS partially inhibits the P. aeruginosa-dependent activation of Protein Kinase C isoform alpha, which is known to be involved in the transmembrane signaling activating IL-8 gene expression in bronchial epithelial cells. These data indicate BSS as a promising molecule to control excessive lung inflammation in CF patients. PMID- 28553227 TI - SRT1720 Alleviates ANIT-Induced Cholestasis in a Mouse Model. AB - Intrahepatic cholestasis is a kind of clinical syndrome along with hepatotoxicity which caused by intrahepatic and systemic accumulations of bile acid. There are several crucial generating factors of the pathogenesis of cholestasis, such as inflammation, dysregulation of bile acid transporters and oxidative stress. SIRT1 is regarded as a class III histone deacetylase (HDAC). According to a set of researches, SIRT1 is one of the most important factors which can regulate the hepatic bile acid metabolism. SRT1720 is a kind of activator of SIRT1 which is 1000 times more potent than resveratrol, and this paper is aimed to study its protective influence on hepatotoxicity and cholestasis induced by alpha naphthylisothiocyanate (ANIT) in mice. The findings revealed that SRT1720 treatment increased FXR and Nrf2 gene expressions to shield against hepatotoxicity and cholestasis induced by ANIT. The mRNA levels of hepatic bile acid transporters were also altered by SRT1720. Furthermore, SRT1720 enhanced the antioxidative system by increasing Nrf2, SOD, GCLc, GCLm, Nqo1, and HO-1 gene expressions. In conclusion, a protective influence could be provided by SRT1720 to cure ANIT-induced hepatotoxicity and cholestasis, which was partly through FXR and Nrf2 activations. These results indicated that SIRT1 could be regarded as a therapeutic target to cure the cholestasis. PMID- 28553228 TI - How General Practitioners and Their Patients Adhere to Osteoporosis Management: A Follow-Up Survey among Czech General Practitioners. AB - Introduction: General practitioners (GPs) are key participants in osteoporosis (OP) management. The aim was to evaluate their adherence to lege artis management of the disease, potential barriers, and to discuss differences observed in comparison with the baseline survey carried out in 2007; the focus was on secondary prevention. Methods: On behalf of two professional associations, 2 round postal survey among randomly selected GPs (>1/4 of all Czech GPs) was performed in 2014. The questionnaire covered areas concerning GP's role in the fight against OP, knowledge about OP, management of OP-related fractures, barriers to the management of OP, system- and patient-related in particular, and availability and use of information sources. Results: The overall questionnaire return rate was 37% (551 respondents); mean age of the respondents was 53 year (37% men). The GP's role in the treatment of OP was rated as essential in 28 and 37% of men and women, respectively (P = 0.012). The guideline for diagnosis and treatment of OP for GPs was considered accessible by 92% of respondents. As much as 60% of the respondents were adherent to the guideline, i.e., used it repeatedly. The knowledge of several risk factors was very good, however, recommended daily intake of calcium was stated correctly by only 41% of respondents, and daily intake of vitamin D by only 40%. Three quarters reported active steps after a fracture: referral to a specialist, life-style recommendations, prescription of calcium/vitamin D supplements. Half of the respondents focus on fall prevention. System-related barriers, such as lack of possibility to prescribe selected drugs (61%) and financial limits set by health insurance company (44%) were most frequently reported. Patient-related barriers were also common, patient's non-adherence (reported by 29%) and patient's reluctance to go to a specialist (18%). Conclusion: GPs adhered to OP management more than in 2007. Knowledge of risk factors and involvement in post-fracture care was relatively high. Compared to baseline survey, patient-related barriers, patient non-adherence in particular, were more common. Prescribing conditions are still an important issue. Among GPs, education should be focused on calcium and vitamin D intake, doses, sources, and supplements. PMID- 28553229 TI - Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life. AB - The purpose of this study was to investigate whether the anxiolytic effect of cannabidiol (CBD) in humans follows the same pattern of an inverted U-shaped dose effect curve observed in many animal studies. Sixty healthy subjects of both sexes aged between 18 and 35 years were randomly assigned to five groups that received placebo, clonazepam (1 mg), and CBD (100, 300, and 900 mg). The subjects were underwent a test of public speaking in a real situation (TPSRS) where each subject had to speak in front of a group formed by the remaining participants. Each subject completed the anxiety and sedation factors of the Visual Analog Mood Scale and had their blood pressure and heart rate recorded. These measures were obtained in five experimental sessions with 12 volunteers each. Each session had four steps at the following times (minutes) after administration of the drug/placebo, as time 0: -5 (baseline), 80 (pre-test), 153 (speech), and 216 (post-speech). Repeated-measures analyses of variance showed that the TPSRS increased the subjective measures of anxiety, heart rate, and blood pressure. Student-Newman-Keuls test comparisons among the groups in each phase showed significant attenuation in anxiety scores relative to the placebo group in the group treated with clonazepam during the speech phase, and in the clonazepam and CBD 300 mg groups in the post-speech phase. Clonazepam was more sedative than CBD 300 and 900 mg and induced a smaller increase in systolic and diastolic blood pressure than CBD 300 mg. The results confirmed that the acute administration of CBD induced anxiolytic effects with a dose-dependent inverted U-shaped curve in healthy subjects, since the subjective anxiety measures were reduced with CBD 300 mg, but not with CBD 100 and 900 mg, in the post-speech phase. PMID- 28553230 TI - The LRRC8A Mediated "Swell Activated" Chloride Conductance Is Dispensable for Vacuolar Homeostasis in Neutrophils. AB - The dialysis of human and mouse neutrophils in patch clamp experiments in the conventional whole-cell mode induces the emergence of a chloride (Cl-) current that appeared to be primarily regulated by cytoplasmic ionic strength. The characteristics of this current resembled that of the classical, and ubiquitous volume-sensitive outwardly rectifying Cl- current: strong outward rectification, selectivity sequence of the Eisenman1 type, insensitivity to external pH and strong inhibition by tamoxifen, DCPIB and WW781. We show that this current is essentially supported by the leucine rich repeat containing 8 A (LRRC8A); the naturally occurring LRRC8A truncation mutant in ebo/ebo mice drastically reduced Cl- conductance in neutrophils. Remarkably, the residual component presents a distinct pharmacology, but appears equally potentiated by reduced ionic strength. We have investigated the role of the LRRC8A-supported current in the ionic homeostasis of the phagosomal compartment. The vacuolar pH, measured using SNARF 1 labeled Candida albicans, normally rises because of NADPH oxidase activity, and this elevation is blocked by certain Cl- channel inhibitors. However, the pH rise remains intact in neutrophils from the ebo/ebo mice which also demonstrate preserved phagocytic and respiratory burst capacities and normal-sized vacuoles. Thus, the LRRC8A-dependent conductance of neutrophils largely accounts for their "swell activated" Cl- current, but is not required for homeostasis of the phagosomal killing compartment. PMID- 28553231 TI - Hydroxysafflor Yellow A Suppresses MRC-5 Cell Activation Induced by TGF-beta1 by Blocking TGF-beta1 Binding to TbetaRII. AB - Hydroxysafflor yellow A (HSYA) is an active ingredient of Carthamus tinctorius L.. This study aimed to evaluate the effects of HSYA on transforming growth factor-beta1 (TGF-beta1)-induced changes in proliferation, migration, differentiation, and extracellular matrix accumulation and degradation in human fetal lung fibroblasts (MRC-5), to explore the mechanisms whereby HSYA may alleviate pulmonary fibrosis. MRC-5 cells were incubated with various doses of HSYA and/or the TGF-beta receptor type I kinase inhibitor SB431542 and then stimulated with TGF-beta1. Cell proliferation was measured by 3-(4,5 dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfo-phenyl)-2H tetrazolium inner salt assay. Cell migration was detected by wound-healing assay. Protein levels of alpha-smooth muscle actin (alpha-SMA), collagen I alpha 1 (COL1A1), and fibronectin (FN) were measured by immunofluorescence. Protein levels of matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-1, tissue inhibitor of matrix metalloproteinase-2, TGF-beta type II receptor (TbetaRII), and TGF-beta type I receptor were detected by western blotting. TbetaRII knockdown with siRNA interfered with the inhibitory effect of HSYA on alpha-SMA, COL1A1, and FN expression, and TGF-beta1-induced Sma and Mad protein (Smad), and extracellular signal-regulated kinase/mitogen activated protein kinase signaling pathway activation. The antagonistic effect of HSYA on the binding of fluorescein isothiocyanate-TGF-beta1 to MRC-5 cell cytoplasmic receptors was measured by flow cytometry. HSYA significantly suppressed TGF-beta1-induced cell proliferation and migration. HSYA could antagonize the binding of FITC-TGF-beta1 to MRC-5 cell cytoplasmic receptors. Also HSYA inhibited TGF-beta1-activated cell expression of alpha-SMA, COL1A1, and FN and phosphorylation level of Smad2, Smad3, and ERK by targeting TbetaRII in MRC-5 cells. These findings suggest that TbetaRII might be the target responsible for the inhibitory effects of HSYA on TGF-beta1-induced pathological changes in pulmonary fibrosis. PMID- 28553232 TI - Integrated Analysis of DNA Methylation and mRNA Expression Profiles to Identify Key Genes in Severe Oligozoospermia. AB - Severe oligozoospermia (SO) is a complex disorder, whose etiology is the combined effect of genetic factors and epigenetic conditions. In this study, we examined DNA methylation and mRNA expression status in a set of testicular tissues of SO patients (n = 3), and compared methylated data with those derived from obstructive azoospermia (OA) patients (n = 3) with normal spermatogenesis phenotype. We identified 1,960 differentially methylated CpG sites showing significant alterations in SO vs. OA using the Illumina Infinium HumanMethylation450 bead array. By integrating above DNA methylation data and mRNA expression results, we totally identified 72 methylated CpG sites located in 65 genes with anti-correlation between DNA methylation and mRNA expression. Integrated pathways analysis indicates that these genes are involved in response to hormone stimulus, activation of protein kinase activity, and apoptotic process, among others. We also observed some genes with inversely correlated difference is novel in male infertility field, including PTPRN2, EPHX1, SERPINB9, SLIT3, etc. Our results lay a groundwork for further biological study of SO. Moreover, we generated a workflow for integrated analysis of DNA methylation and mRNA expression, which is expandable to other study types. PMID- 28553233 TI - Coherent Multimodal Sensory Information Allows Switching between Gravitoinertial Contexts. AB - Whether the central nervous system is capable to switch between contexts critically depends on experimental details. Motor control studies regularly adopt robotic devices to perturb the dynamics of a certain task. Other approaches investigate motor control by altering the gravitoinertial context itself as in parabolic flights and human centrifuges. In contrast to conventional robotic experiments, where only the hand is perturbed, these gravitoinertial or immersive settings coherently plunge participants into new environments. However, radically different they are, perfect adaptation of motor responses are commonly reported. In object manipulation tasks, this translates into a good matching of the grasping force or grip force to the destabilizing load force. One possible bias in these protocols is the predictability of the forthcoming dynamics. Here we test whether the successful switching and adaptation processes observed in immersive environments are a consequence of the fact that participants can predict the perturbation schedule. We used a short arm human centrifuge to decouple the effects of space and time on the dynamics of an object manipulation task by adding an unnatural explicit position-dependent force. We created different dynamical contexts by asking 20 participants to move the object at three different paces. These contextual sessions were interleaved such that we could simulate concurrent learning. We assessed adaptation by measuring how grip force was adjusted to this unnatural load force. We found that the motor system can switch between new unusual dynamical contexts, as reported by surprisingly well-adjusted grip forces, and that this capacity is not a mere consequence of the ability to predict the time course of the upcoming dynamics. We posit that a coherent flow of multimodal sensory information born in a homogeneous milieu allows switching between dynamical contexts. PMID- 28553234 TI - Starvation Promotes Autophagy-Associated Maturation of the Ovary in the Giant Freshwater Prawn, Macrobrachium rosenbergii. AB - Limitation of food availability (starvation) is known to influence the reproductive ability of animals. Autophagy is a lysosomal driven degradation process that protects the cell under metabolic stress conditions, such as during nutrient shortage. Whether, and how starvation-induced autophagy impacts on the maturation and function of reproductive organs in animals are still open questions. In this study, we have investigated the effects of starvation on histological and cellular changes that may be associated with autophagy in the ovary of the giant freshwater prawn, Macrobachium rosenbergii. To this end, the female prawns were daily fed (controls) or unfed (starvation condition) for up to 12 days, and the ovary tissue was analyzed at different time-points. Starvation triggered ovarian maturation, and concomitantly increased the expression of autophagy markers in vitellogenic oocytes. The immunoreactivities for autophagy markers, including Beclin1, LC3-II, and Lamp1, were enhanced in the late oocytes within the mature ovaries, especially at the vitellogenic stages. These markers co-localized with vitellin in the yolk granules within the oocytes, suggesting that autophagy induced by starvation could drive vitellin utilization, thus promoting ovarian maturation. PMID- 28553235 TI - 4-phenylbutyrate Mitigates Fluoride-Induced Cytotoxicity in ALC Cells. AB - Chronic fluoride over-exposure during pre-eruptive enamel development can cause dental fluorosis. Severe dental fluorosis is characterized by porous, soft enamel that is vulnerable to erosion and decay. The prevalence of dental fluorosis among the population in the USA, India and China is increasing. Other than avoiding excessive intake, treatments to prevent dental fluorosis remain unknown. We previously reported that high-dose fluoride induces endoplasmic reticulum (ER) stress and oxidative stress in ameloblasts. Cell stress induces gene repression, mitochondrial damage and apoptosis. An aromatic fatty acid, 4-phenylbutyrate (4PBA) is a chemical chaperone that interacts with misfolded proteins to prevent ER stress. We hypothesized that 4PBA ameliorates fluoride-induced ER stress in ameloblasts. To determine whether 4PBA protects ameloblasts from fluoride toxicity, we analyzed gene expression of Tgf-beta1, Bcl2/Bax ratio and cytochrome c release in vitro. In vivo, we measured fluorosis levels, enamel hardness and fluoride concentration. Fluoride treated Ameloblast-lineage cells (ALC) had decreased Tgf-beta1 expression and this was reversed by 4PBA treatment. The anti apoptotic Blc2/Bax ratio was significantly increased in ALC cells treated with fluoride/4PBA compared to fluoride treatment alone. Fluoride treatment induced cytochrome-c release from mitochondria into the cytosol and this was inhibited by 4PBA treatment. These results suggest that 4PBA mitigates fluoride-induced gene suppression, apoptosis and mitochondrial damage in vitro. In vivo, C57BL/6J mice were provided fluoridated water for six weeks with either fluoride free control chow or 4PBA-containing chow (7 g/kg 4PBA). With few exceptions, enamel microhardness, fluorosis levels, and fluoride concentrations of bone and urine did not differ significantly between fluoride treated animals fed with control chow or 4PBA-chow. Although 4PBA mitigated high-dose fluoride toxicity in vitro, a diet rich in 4PBA did not attenuate dental fluorosis in rodents. Perhaps, not enough intact 4PBA reaches the rodent ameloblasts necessary to reverse the effects of fluoride toxicity. Further studies will be required to optimize protocols for 4PBA administration in vivo in order to evaluate the effect of 4PBA on dental fluorosis. PMID- 28553236 TI - Standardization of a Continuous Assay for Glycosidases and Its Use for Screening Insect Gut Samples at Individual and Populational Levels. AB - Glycoside Hydrolases (GHs) are enzymes able to recognize and cleave glycosidic bonds. Insect GHs play decisive roles in digestion, in plant-herbivore, and host pathogen interactions. GH activity is normally measured by the detection of a release from the substrate of products as sugars units, colored, or fluorescent groups. In most cases, the conditions for product release and detection differ, resulting in discontinuous assays. The current protocols result in using large amounts of reaction mixtures for the obtainment of time points in each experimental replica. These procedures restrain the analysis of biological materials with limited amounts of protein and, in the case of studies regarding small insects, implies in the pooling of samples from several individuals. In this respect, most studies do not assess the variability of GH activities across the population of individuals from the same species. The aim of this work is to approach this technical problem and have a deeper understanding of the variation of GH activities in insect populations, using as models the disease vectors Rhodnius prolixus (Hemiptera: Triatominae) and Lutzomyia longipalpis (Diptera: Phlebotominae). Here we standardized continuous assays using 4-methylumbelliferyl derived substrates for the detection of alpha-Glucosidase, beta-Glucosidase, alpha-Mannosidase, N-acetyl-hexosaminidase, beta-Galactosidase, and alpha Fucosidase in the midgut of R. prolixus and L. longipalpis with results similar to the traditional discontinuous protocol. The continuous assays allowed us to measure GH activities using minimal sample amounts with a higher number of measurements, resulting in data that are more reliable and less time and reagent consumption. The continuous assay also allows the high-throughput screening of GH activities in small insect samples, which would be not applicable to the previous discontinuous protocol. We applied continuous GH measurements to 90 individual samples of R. prolixus anterior midgut homogenates using a high-throughput protocol. alpha-Glucosidase and alpha-Mannosidase activities showed the normal distribution in the population. beta-Glucosidase, beta-Galactosidase, N-acetyl hexosaminidase, and alpha-Fucosidase activities showed non-normal distributions. These results indicate that GHs fluorescent-based high-throughput assays apply to insect samples and that the frequency distribution of digestive activities should be considered in data analysis, especially if a small number of samples is used. PMID- 28553237 TI - A Longitudinal Study of Relationships between Identity Continuity and Anxiety Following Brain Injury. AB - Objective: Anxiety is of particular importance following acquired brain injury (ABI), because anxiety has been identified as a significant predictor of functional outcomes. Continuity of self has been linked to post ABI adjustment and research has linked self-discrepancy to anxiety. This longitudinal study investigates the impact of affiliative and 'self as doer' self-categorisations anxiety. Materials and Methods: Data was collected at two time points. Fifty three adult ABI survivors participating in post-acute community neuro rehabilitation participated at time one and 32 of these participated at time two. Participants completed a 28-item identity questionnaire based on Leach et al.'s (2008) multicomponent model of ingroup identification which measured the strength of affiliative and self as doer identities. Anxiety was measured using the Hospital Anxiety and Depression Scale. Results: Analysis indicates a significant mediated relationship between affiliative identification and anxiety via self as doer identification. Contrary to initial prediction, this relationship was significant for those with consistency in affiliative self-categorisation and inconsistency in 'self as doer' self-categorisation. Conclusion: These findings can be interpreted as evidencing the importance of identity continuity and multiplicity following ABI and contribute to the understanding of these through the use of a social identity approach. PMID- 28553238 TI - A Meta-Analysis of Odor Thresholds and Odor Identification in Autism Spectrum Disorders. AB - Autism Spectrum Disorders (ASD) are often accompanied by atypical visual, auditory, and tactile sensory behavior. Evidence also suggests alterations of the olfactory system, but the pattern of findings appears mixed. To quantify this pattern systematically, we conducted a meta-analysis. Studies were included if they examined olfactory function (i.e., odor threshold, or odor identification) in ASD compared with healthy age-matched control groups. We also coded for the potential moderators gender, age, and IQ. Articles were identified through computerized literature search using Web of Science, PubMed, and Scopus databases. A total of 11 articles compared odor threshold and/or odor identification between cases and controls (for threshold, n = 143 ASD and 148 controls; and for identification, n = 132 ASD and 139 controls). Effects sizes showed a substantial heterogeneity. As a result, the 95% prediction intervals were wide and ranged between a large negative and a large positive effect size for odor threshold, [-1.86, 2.05], and for odor identification, [-1.51, 2.52]. Exploratory analyses suggested that age and IQ may be potential moderators. To conclude, the large heterogeneity is consistent with the notion of both hyposensitivity and hypersensitivity in individuals with ASD. However, future research needs to predict and test the specific direction of the effect to provide convincing evidence for atypical olfactory functions in ASD. PMID- 28553239 TI - The Daily Relation between Parental Rejection and Emotional Eating in Youngsters: A Diary Study. AB - KEY POINTS Cross-sectional survey studies have demonstrated significant associations between parental rejection and peer rejection on the one hand and disturbed eating in youngsters, like emotional eating, on the other hand. In this study, we wanted to expand our knowledge on these relationships by investigating the daily fluctuations in these variables. Youngsters completed a 7-day diary to assess daily parental rejection, peer rejection and emotional eating. Using multilevel analyses, our results showed that daily variations in parental rejection were related to daily variations in emotional eating of the youngsters. This highlights the importance of addressing the parent-child relationship in interventions for emotional eating in youngsters. Background: This study investigated the daily relation between parental rejection and peer rejection on the one hand and emotional eating in youngsters on the other hand. Methods: Participants (N = 55) between the ages of 11 and 15 years completed a 7-day diary. A multilevel design was used to examine day-to-day within-person relationships between parental and peer rejection (measured by CHS) and emotional eating (measured by DEBQ-C) of youngsters. Results: The results showed that daily variations in parental rejection were related to daily variations in emotional eating of the youngsters. Daily peer rejection was only marginally significantly related to the emotional eating of the youngsters. Conclusions: These results indicate that especially parental rejection, and to a lesser extent peer rejection, are associated with the emotional eating of youngsters. The findings highlight the importance of addressing the parent-child relationship in interventions for emotional eating in youngsters. PMID- 28553240 TI - The Role of the Human Mirror Neuron System in Supporting Communication in a Digital World. AB - Humans use both verbal and non-verbal communication to interact with others and their environment and increasingly these interactions are occurring in a digital medium. Whether live or digital, learning to communicate requires overcoming the correspondence problem: There is no direct mapping, or correspondence between perceived and self-produced signals. Reconciliation of the differences between perceived and produced actions, including linguistic actions, is difficult and requires integration across multiple modalities and neuro-cognitive networks. Recent work on the neural substrates of social learning suggests that there may be a common mechanism underlying the perception-production cycle for verbal and non-verbal communication. The purpose of this paper is to review evidence supporting the link between verbal and non-verbal communications, and to extend the hMNS literature by proposing that recent advances in communication technology, which at times have had deleterious effects on behavioral and perceptual performance, may disrupt the success of the hMNS in supporting social interactions because these technologies are virtual and spatiotemporal distributed nature. PMID- 28553241 TI - Assessing Dispositions Toward Ridicule and Laughter in the Workplace: Adapting and Validating the PhoPhiKat-9 Questionnaire. AB - The current paper addresses the measurement of three dispositions toward ridicule and laughter; i.e., gelotophobia (the fear of being laughed at), gelotophilia (the joy of being laughed at), and katagelasticism (the joy of laughing at others). These traits explain inter-individual differences in responses to humor, laughter, and social situations related to humorous encounters. First, an ultra short form of the PhoPhiKat-45 (Ruch and Proyer, 2009) was adapted in two independent samples (Construction Sample N = 157; Replication Sample N = 1,774). Second, we tested the validity of the PhoPhiKat-9 in two further independent samples. Results showed that the psychometric properties of the ultra-short form were acceptable and the proposed factor structure could be replicated. In Validation Sample 1 (N = 246), we investigated the relation of the three traits to responses in a ridicule and teasing scenario questionnaire. The results replicated findings from earlier studies by showing that gelotophobes assigned the same emotions to friendly teasing and malicious ridicule (predominantly low joy, high fear, and shame). Gelotophilia was mainly predicted by relating joy to both, teasing and ridicule scenarios, while katagelasticism was predicted by assigning joy and contempt to ridicule scenarios. In Validation Sample 2 (N = 1,248), we investigated whether the fear of being laughed at is a vulnerability at the workplace: If friendly teasing and laughter of co-workers, superiors, or customers are misperceived as being malicious, individuals may feel less satisfied and more stressed. The results from a representative sample of Swiss employees showed that individuals with a fear of being laughed at are generally less satisfied with life and work and experience more work stress. Moreover, gelotophilia went along with positive evaluations of one's life and work, while katagelasticism was negatively related to work satisfaction and positively related to work stress. In order to establish good work practices and build procedures against workplace bullying, one needs to consider that individual differences impact on a person's perception of being bullied and assessing the three dispositions may give important insights into team processes. PMID- 28553242 TI - Comparison of Different LGM-Based Methods with MAR and MNAR Dropout Data. AB - The missing not at random (MNAR) mechanism may bias parameter estimates and even distort study results. This study compared the maximum likelihood (ML) selection model based on missing at random (MAR) mechanism and the Diggle-Kenward selection model based on MNAR mechanism for handling missing data through a Monte Carlo simulation study. Four factors were considered, including the missingness mechanism, the dropout rate, the distribution shape (i.e., skewness and kurtosis), and the sample size. The results indicated that: (1) Under the MAR mechanism, the Diggle-Kenward selection model yielded similar estimation results with the ML approach; Under the MNAR mechanism, the results of ML approach were underestimated, especially for the intercept mean and intercept slope (MU i and MU s ). (2) Under the MAR mechanism, the 95% CP of the Diggle-Kenward selection model was lower than that of the ML method; Under the MNAR mechanism, the 95% CP for the two methods were both under the desired level of 95%, but the Diggle Kenward selection model yielded much higher coverage probabilities than the ML method. (3) The Diggle-Kenward selection model was easier to be influenced by the non-normal degree of target variable's distribution than the ML approach. The level of dropout rate was the major factor affecting the parameter estimation precision, and the dropout rate-induced difference of two methods can be ignored only when the dropout rate falls below 10%. PMID- 28553243 TI - From Research to Clinical Settings: Validation of the Affect in Play Scale - Preschool Brief Version in a Sample of Preschool and School Aged Italian Children. AB - Affect in Play Scale-Preschool (APS-P) is one of the few standardized tools to measure pretend play. APS-P is an effective measure of symbolic play, able to detect both cognitive and affective dimensions which classically designated play in children, but often are evaluated separately and are scarcely integrated. The scale uses 5 min standardized play task with a set of toys. Recently the scale was extended from 6 to 10 years old and validated in Italy preschool and school aged children. Some of the main limitations of this measure are that it requires videotaping, verbatim transcripts, and an extensive scoring training, which could compromise its clinical utility. For these reasons, a Brief version of the measure was developed by the original authors. This paper will focus on an APS-P Brief Version and its Extended Version through ages (6-10 years), which consists "in vivo" coding. This study aimed to evaluate construct and external validity of this APS-P Brief Version and its Extended Version in a sample of 538 Italian children aged 4-to-10 years. Confirmatory factor analysis yielded a two correlated factor structure including an affective and a cognitive factor. APS-P BR and its Extended Version factor scores strongly related to APS-P Extended Version factor scores. Significant relationships were found with a divergent thinking task. Results suggest that the APS-P-BR and its Extended Version is an encouraging brief measure assessing pretend play using toys. It would easily substitute the APS-P and its Extended Version in clinical and research settings, reducing time and difficulties in scoring procedures and maintaining the same strengths. PMID- 28553244 TI - Can Leader-Member Exchange Contribute to Safety Performance in An Italian Warehouse? AB - Introduction: The research considers safety climate in a warehouse and wants to analyze the Leader-Member Exchange (LMX) role in respect to safety performance. Griffin and Neal's safety model was adopted and Leader-Member Exchange was inserted as moderator in the relationships between safety climate and proximal antecedents (motivation and knowledge) of safety performance constructs (compliance and participation). Materials and Methods: Survey data were collected from a sample of 133 full-time employees in an Italian warehouse. The statistical framework of Hayes (2013) was adopted for moderated mediation analysis. Results: Proximal antecedents partially mediated the relationship between Safety climate and safety participation, but not safety compliance. Moreover, the results from the moderation analysis showed that the Leader-Member Exchange moderated the influence of safety climate on proximal antecedents and the mediation exist only at the higher level of LMX. Conclusion: The study shows that the different aspects of leadership processes interact in explaining individual proficiency in safety practices. Practical Implications: Organizations as warehouses should improve the quality of the relationship between a leader and a subordinate based upon the dimensions of respect, trust, and obligation for high level of safety performance. PMID- 28553245 TI - Mastery in Goal Scoring, T-Pattern Detection, and Polar Coordinate Analysis of Motor Skills Used by Lionel Messi and Cristiano Ronaldo. AB - Research in soccer has traditionally given more weight to players' technical and tactical skills, but few studies have analyzed the motor skills that underpin specific motor actions. The objective of this study was to investigate the style of play of the world's top soccer players, Cristiano Ronaldo and Lionel Messi, and how they use their motor skills in attacking actions that result in a goal. We used and improved the easy-to-use observation instrument (OSMOS-soccer player) with 9 criteria, each one expanded to build 50 categories. Associations between these categories were investigated by T-pattern detection and polar coordinate analysis. T-pattern analysis detects temporal structures of complex behavioral sequences composed of simpler or directly distinguishable events within specified observation periods (time point series). Polar coordinate analysis involves the application of a complex procedure to provide a vector map of interrelated behaviors obtained from prospective and retrospective sequential analysis. The T patterns showed that for both players the combined criteria were mainly between the different aspects of motor skills, namely the use of lower limbs, contact with the ball using the outside of the foot, locomotion, body orientation with respect to the opponent goal line, and the criteria of technical actions and the right midfield. Polar coordinate analysis detected significant associations between the same criteria included in the T-patterns as well as the criteria of turning the body, numerical equality with no pressure, and relative numerical superiority. PMID- 28553246 TI - Role of Two Types of Syntactic Embedding in Belief Attribution in Adults with or without Asperger Syndrome. AB - The role of syntax in belief attribution (BA) is not completely understood in healthy adults and understudied in adults with autism spectrum disorder. Embedded syntax could be useful either for the development of Theory of Mind (ToM) (Emergence account) or more generally over the lifespan (Reasoning account). Two hypotheses have been explored, one suggesting that embedding itself (Relatives and Complement sentences and Metarepresentation account) is important for ToM and another one considering that the embedding of a false proposition into a true one (Complement sentences and Misrepresentation account) is important. The goals of this study were to evaluate (1) the role of syntax in ToM (Emergence vs. Reasoning account), (2) the type of syntax implied in ToM (Metarepresentation vs. Misrepresentation account), and (3) the verbally mediated strategies which compensate for ToM deficits in adults with Asperger Syndrome (AS). Fifty NeuroTypical (NT) adults and 22 adults with AS were involved in a forced-choice task including +/-ToM tasks (BA and a control task, physical causation, PC) under four Interference conditions (silence, syllable repetition, relative sentences repetition, and complement sentences repetition). The non-significant +/-ToM * Interference interaction effect in the NT group did not support the Reasoning account and thus suggests that syntax is useful only for ToM development (i.e., Emergence account). Results also indicated that repeating complement clauses put NT participants in a dual task whereas repeating relative clauses did not, suggesting that repeating relatives is easier for NT than repeating complements. This could be an argument in favor of the Misrepresentation account. However, this result should be interpreted with caution because our results did not support the Reasoning account. Moreover, AS participants (but not NT participants) were more disrupted by +/-ToM tasks when asked to repeat complement sentences compared to relative clause sentences. This result is in favor of the Misrepresentation account and indirectly suggests verbally mediated strategies for ToM in AS. To summarize, our results are in favor of the Emergence account in NT and of Reasoning and Misrepresentation accounts in adults with AS. Overall, this suggests that adults with AS use complement syntax to compensate for ToM deficits. PMID- 28553247 TI - Education and Decision-Making: An Experimental Study on the Framing Effect in China. AB - China's higher education expansion policy has been in effect for almost two decades. Under this policy, a growing number of youths have gained access to higher education, which aims to train students to be more rational. This study examines human rationality at a Chinese college through an experiment based on the risky-choice framing effect. The basic results show no classical framing effect with regard to individual decisions for the entire sample in a benchmark setting. However, when the participants' roles were manipulated and subsamples were investigated, a significant framing effect was found that appeared to be role-related and that varied by sex. These results help to elucidate evaluations of the effects of China's higher education policy and may assist in guiding further policy reforms. PMID- 28553248 TI - Comparing Indirect Effects in Different Groups in Single-Group and Multi-Group Structural Equation Models. AB - In this article, we evaluated the performance of statistical methods in single group and multi-group analysis approaches for testing group difference in indirect effects and for testing simple indirect effects in each group. We also investigated whether the performance of the methods in the single-group approach was affected when the assumption of equal variance was not satisfied. The assumption was critical for the performance of the two methods in the single group analysis: the method using a product term for testing the group difference in a single path coefficient, and the Wald test for testing the group difference in the indirect effect. Bootstrap confidence intervals in the single-group approach and all methods in the multi-group approach were not affected by the violation of the assumption. We compared the performance of the methods and provided recommendations. PMID- 28553249 TI - Yoga Poses Increase Subjective Energy and State Self-Esteem in Comparison to 'Power Poses'. AB - Research on beneficial consequences of yoga focuses on the effects of yogic breathing and meditation. Less is known about the psychological effects of performing yoga postures. The present study investigated the effects of yoga poses on subjective sense of energy and self-esteem. The effects of yoga postures were compared to the effects of 'power poses,' which arguably increase the sense of power and self-confidence due to their association with interpersonal dominance (Carney et al., 2010). The study tested the novel prediction that yoga poses, which are not associated with interpersonal dominance but increase bodily energy, would increase the subjective feeling of energy and therefore increase self-esteem compared to 'high power' and 'low power' poses. A two factorial, between participants design was employed. Participants performed either two standing yoga poses with open front of the body (n = 19), two standing yoga poses with covered front of the body (n = 22), two expansive, high power poses (n = 21), or two constrictive, low power poses (n = 20) for 1-min each. The results showed that yoga poses in comparison to 'power poses' increased self-esteem. This effect was mediated by an increased subjective sense of energy and was observed when baseline trait self-esteem was controlled for. These results suggest that the effects of performing open, expansive body postures may be driven by processes other than the poses' association with interpersonal power and dominance. This study demonstrates that positive effects of yoga practice can occur after performing yoga poses for only 2 min. PMID- 28553250 TI - Yes: The Symptoms of OCD and Depression Are Discrete and Not Exclusively Negative Affectivity. AB - Although Obsessive-Compulsive Disorder (OCD) and Depression are classified as separate disorders, the high incidence of co-morbidity and the strong correlations between measures of each has led to debate about the nature of their relationship. Some authors have proposed that OCD is in fact a mood disorder while others have suggested that the two disorders are grounded in negative affectivity. A third proposition is that depression is an essential part of OCD but that OCD is a separate disorder from depression. The aim in this study was to investigate these diverse propositions in a non-clinical sample and also to determine whether factors implicated in each, that is anxious and depressive cognitions, hopelessness, and self-criticism, would demonstrate commonality as predictors of the symptoms of OCD and of depression. Two hundred participants (59% female) (M age = 34 years, SD = 16) completed the Padua Inventory, Carroll Rating Scale, Cognitions Checklist, Self-Criticism Scale, Beck Hopelessness Scale, Buss-Durkee Hostility Inventory-Revised and a Negative Affectivity Schedule. Results indicated a strong correlation between OCD and depression, depression, and negative affectivity but a weaker relationship between OCD and negative affectivity. Path analyses revealed that both anxious and depressive cognitions, as well as hostility predicted both disorders but the Beta-weights were stronger on OCD. Self-criticism predicted only depression while hopelessness failed to predict either disorder but was itself predicted by depressive cognitions. Depression was a stronger indicator of negative affect than OCD and while OCD positively predicted depression, depression was a negative indicator of OCD. These results support the hypothesis that OCD and depression are discrete disorders and indicate that while depression is implicated in OCD, the reverse does not hold. While both disorders are related to negative affectivity, this relationship is much stronger for depression thus failing to confirm that both are subsumed by a common factor, in this case, negative affectivity. The proposition that depression is part of OCD but that OCD is not necessarily implicated in depression and is, in fact, a separate disorder, is supported by the current model. Further research is required to support the utility of the model in clinical samples. PMID- 28553251 TI - No Difference in Mood and Quality of Life in DHEA-S Deficient Adults with Addison's Disease vs. Type 2 Diabetes Patients with Normal DHEA-S Levels: Implications for Management of These Conditions. AB - Patients with Addison's disease have relatively high rates of depression and anxiety symptoms compared with population-based reference samples. Addison's disease results in deficiency of dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S). There is considerable debate about the specific effects of DHEA deficiency on energy level and mood. We measured emotional well-being in 16 patients with Addison's disease and a group of 16 hospital attendees with type 2 diabetes. Participants completed the General Health Questionnaire-28 (GHQ-28), the Hospital Anxiety and Depression Scale (HADS), the World Health Organization's quality of life assessment (WHOQOL-BREF) and the Holmes-Rahe life event scale. DHEA-S was low in Addison's patients (Addison's men: 0.5 +/- 0.1 MUmol/l [normal range: 2.1-10.8] compared with diabetes men: 3.2 +/- 1.2 MUmol/l; Addison's women: 0.4 +/- 0.01 MUmol/l [normal range: 1.0-11.5] compared with diabetes women: 2.2 +/- 0.71 MUmol/l). Testosterone levels were similar in both groups studied. There were no differences in emotional well-being and quality of life (QOL) between patients with Addison's disease and Type 2 Diabetes Mellitus as measured by GHQ-28 (Addison's: 22.4 +/- 2.6, Diabetes: 19.6 +/- 2.7), HADS Depression (Addison's: 5.4 +/- 0.9, Diabetes: 4.5 +/- 1.4), HADS Anxiety and WHOQOL-BREF. There were no gender differences in affective symptomatology within the Addison's group. Life event scores were above average in both groups (Addison's: 195 +/- 39.6, Diabetes: 131 +/- 43.8), but not significant for difference between groups as was GHQ-28 total score. Both groups scored highly on the GHQ-28 and the life event scale, indicative of poorer health perceptions than the general population. This could be due to the chronicity of both disorders. We have not identified any specific effects of DHEA-S deficiency on mood or QOL. PMID- 28553252 TI - Validating the Italian Version of the Disgust and Propensity Scale-Revised. AB - The aim of this work is to evaluate the factor structure and psychometric properties of the Italian version of the Disgust Propensity and Sensitivity Scale Revised (DPSS-R, 16 items) in two samples taken from the general population. In the first study, 285 participants completed the DPSS-R questionnaire through a web-based survey. Exploratory factor analysis for ordinal Likert-type data supported the existence of four underlying factors, reflecting self-focused disgust, disgust propensity, somatic anxiety and disgust sensitivity. In the second study, an independent sample of 293 participants was enrolled as a test set to validate the factor structure obtained in the exploratory phase. The factor solution was confirmed, but showed quite highly correlated latent factors. We fitted the model and tested whether or not the bifactor structure was better than the previous one (four correlated factors). Actually, we had evidence supporting the presence of a general factor, providing a measure of disgust susceptibility, along with the four specific factors previously defined. This result could be useful also from the clinical perspective since the DPSS-R questionnaire will be used in clinical context, where underlying factors may be related to different and specific psychopathological profiles. Finally, we examined and visualized the interrelationships among the four DPSS-R factors and the external scales (Anxiety Sensitivity, Disgust Scale and Padua) using a graphical model approach. PMID- 28553253 TI - Resting-State fMRI Associated with Stop-Signal Task Performance in Healthy Middle Aged and Elderly People. AB - Several brain regions and connectivity networks may be altered as aging occurs. We are interested in investigating if resting-state functional magnetic resonance imaging (RS-fMRI) can also be valid as an indicator of individual differences in association with inhibition performance among aged (including middle-aged) people. Seventy-two healthy adults (40-77 years of age) were recruited. Their RS fMRI images were acquired and analyzed via two cluster-analysis methods: local synchronization of spontaneous brain activity measured by regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFF) of blood oxygenation level-dependent signals. After the RS-fMRI acquisition, participants were instructed to perform a stop-signal task, in which the stop signal reaction time (SSRT) was calculated based on the horse-race model. Among participants, the ReHo/fALFF and SSRT were correlated with and without partialling-out the effect of age. The results of this study showed that, although aging may alter brain networks, the spontaneous activity of the age-related brain networks can still serve as an effective indicator of individual differences in association with inhibitory performance in healthy middle-aged and elderly people. This is the first study to use both ReHo and fALFF on the same dataset for conjunction analyses showing the relationship between stopping performance and RS-fMRI in the elderly population. The relationship may have practical clinical applications. Based on the overall results, the current study demonstrated that the bilateral inferior frontal gyrus and parts of the default mode network activation were negatively correlated with SSRT, suggesting that they have crucial roles in inhibitory function. However, the pre-supplementary motor area (pre-SMA) and SMA played only a small role during the resting state in association with stopping performance. PMID- 28553254 TI - A First Step toward the Understanding of Implicit Learning of Hazard Anticipation in Inexperienced Road Users Through a Moped-Riding Simulator. AB - Hazard perception is considered one of the most important abilities in road safety. Several efforts have been devoted to investigating how it improves with experience and can be trained. Recently, research has focused on the implicit aspects of hazard detection, reaction, and anticipation. In the present study, we attempted to understand how the ability to anticipate hazards develops during training with a moped-riding simulator: the Honda Riding Trainer (HRT). Several studies have already validated the HRT as a tool to enhance adolescents' hazard perception and riding abilities. In the present study, as an index of hazard anticipation, we used skin conductance response (SCR), which has been demonstrated to be linked to affective/implicit appraisal of risk. We administered to a group of inexperienced road users five road courses two times a week apart. In each course, participants had to deal with eight hazard scenes (except one course that included only seven hazard scenes). Participants had to ride along the HRT courses, facing the potentially hazardous situations, following traffic rules, and trying to avoid accidents. During the task, we measured SCR and monitored driving performance. The main results show that learning to ride the simulator leads to both a reduction in the number of accidents and anticipation of the somatic response related to hazard detection, as proven by the reduction of SCR onset recorded in the second session. The finding that the SCR signaling the impending hazard appears earlier when the already encountered hazard situations are faced anew suggests that training with the simulator acts on the somatic activation associated with the experience of risky situations, improving its effectiveness in detecting hazards in advance so as to avoid accidents. This represents the starting point for future investigations into the process of generalization of learning acquired in new virtual situations and in real-road situations. PMID- 28553255 TI - Development of the Korean Facial Emotion Stimuli: Korea University Facial Expression Collection 2nd Edition. AB - Background: Developing valid emotional facial stimuli for specific ethnicities creates ample opportunities to investigate both the nature of emotional facial information processing in general and clinical populations as well as the underlying mechanisms of facial emotion processing within and across cultures. Given that most entries in emotional facial stimuli databases were developed with western samples, and given that very few of the eastern emotional facial stimuli sets were based strictly on the Ekman's Facial Action Coding System, developing valid emotional facial stimuli of eastern samples remains a high priority. Aims: To develop and examine the psychometric properties of six basic emotional facial stimuli recruiting professional Korean actors and actresses based on the Ekman's Facial Action Coding System for the Korea University Facial Expression Collection Second Edition (KUFEC-II). Materials And Methods: Stimulus selection was done in two phases. First, researchers evaluated the clarity and intensity of each stimulus developed based on the Facial Action Coding System. Second, researchers selected a total of 399 stimuli from a total of 57 actors and actresses, which were then rated on accuracy, intensity, valence, and arousal by 75 independent raters. Conclusion: The hit rates between the targeted and rated expressions of the KUFEC-II were all above 80%, except for fear (50%) and disgust (63%). The KUFEC-II appears to be a valid emotional facial stimuli database, providing the largest set of emotional facial stimuli. The mean intensity score was 5.63 (out of 7), suggesting that the stimuli delivered the targeted emotions with great intensity. All positive expressions were rated as having a high positive valence, whereas all negative expressions were rated as having a high negative valence. The KUFEC II is expected to be widely used in various psychological studies on emotional facial expression. KUFEC-II stimuli can be obtained through contacting the corresponding authors. PMID- 28553256 TI - The Mediating Roles of Upward Social Comparison and Self-esteem and the Moderating Role of Social Comparison Orientation in the Association between Social Networking Site Usage and Subjective Well-Being. AB - The increased pervasiveness of social media use has raised questions about potential effects on users' subjective well-being, with studies reaching contrasting conclusions. To reconcile these discrepancies and shed new light on this phenomenon, the current study examined: (1) whether upward social comparison and self-esteem mediate the association between social networking site (SNS) usage and users' subjective well-being, and (2) whether the association between SNS usage and upward social comparison is moderated by users' social comparison orientation. Data from 696 participants were collected. Structural equation modeling revealed that upward social comparison and self-esteem mediated the relationship between SNS usage and users' subjective well-being. We found that social comparison orientation moderated the association between passive SNS usage and users' upward social comparison. Specifically, social comparison orientation strengthened the association between passive SNS usage and upward social comparison. The results might suggest a process through which passive SNS usage is related to subjective well-being, and identify a context under which these associations may differ. PMID- 28553257 TI - An Overview of Interrater Agreement on Likert Scales for Researchers and Practitioners. AB - Applications of interrater agreement (IRA) statistics for Likert scales are plentiful in research and practice. IRA may be implicated in job analysis, performance appraisal, panel interviews, and any other approach to gathering systematic observations. Any rating system involving subject-matter experts can also benefit from IRA as a measure of consensus. Further, IRA is fundamental to aggregation in multilevel research, which is becoming increasingly common in order to address nesting. Although, several technical descriptions of a few specific IRA statistics exist, this paper aims to provide a tractable orientation to common IRA indices to support application. The introductory overview is written with the intent of facilitating contrasts among IRA statistics by critically reviewing equations, interpretations, strengths, and weaknesses. Statistics considered include rwg, [Formula: see text], r'wg, rwg(p), average deviation (AD), awg, standard deviation (Swg), and the coefficient of variation (CVwg). Equations support quick calculation and contrasting of different agreement indices. The article also includes a "quick reference" table and three figures in order to help readers identify how IRA statistics differ and how interpretations of IRA will depend strongly on the statistic employed. A brief consideration of recommended practices involving statistical and practical cutoff standards is presented, and conclusions are offered in light of the current literature. PMID- 28553258 TI - An Overview of Monthly Rhythms and Clocks. AB - Organisms have evolved to cope with geophysical cycles of different period lengths. In this review, we focus on the adaptations of animals to the lunar cycle, specifically, on the occurrence of biological rhythms with monthly (circalunar) or semi-monthly (circasemilunar) period lengths. Systematic experimental investigation, starting in the early twentieth century, has allowed scientists to distinguish between mythological belief and scientific facts concerning the influence of the lunar cycle on animals. These studies revealed that marine animals of various taxa exhibit circalunar or circasemilunar reproductive rhythms. Some of these rely on endogenous oscillators (circalunar or circasemilunar clocks), whereas others are directly driven by external cues, such as the changes in nocturnal illuminance. We review current insight in the molecular and cellular mechanisms involved in circalunar rhythms, focusing on recent work in corals, annelid worms, midges, and fishes. In several of these model systems, the transcript levels of some core circadian clock genes are affected by both light and endogenous circalunar oscillations. How these and other molecular changes relate to the changes in physiology or behavior over the lunar cycle remains to be determined. We further review the possible relevance of circalunar rhythms for terrestrial species, with a particular focus on mammalian reproduction. Studies on circalunar rhythms of conception or birth rates extend to humans, where the lunar cycle was suggested to also affect sleep and mental health. While these reports remain controversial, factors like the increase in "light pollution" by artificial light might contribute to discrepancies between studies. We finally discuss the existence of circalunar oscillations in mammalian physiology. We speculate that these oscillations could be the remnant of ancient circalunar oscillators that were secondarily uncoupled from a natural entrainment mechanism, but still maintained relevance for structuring the timing of reproduction or physiology. The analysis and comparison of circalunar rhythms and clocks are currently challenging due to the heterogeneity of samples concerning species diversity, environmental conditions, and chronobiological conditions. We suggest that future research will benefit from the development of standardized experimental paradigms, and common principles for recording and reporting environmental conditions, especially light spectra and intensities. PMID- 28553259 TI - A Retrospective Study of Progression-Free and Overall Survival in Pediatric Medulloblastoma Based on Molecular Subgroup Classification: A Single-Institution Experience. AB - BACKGROUND: Medulloblastoma (MB) has been classified into four core subgroups according to the transcriptional profile in recent years. However, some disagreement among researchers remains regarding the prognoses and most effective treatments of the different subgroups with different age distributions. OBJECTIVE: The objective of this study was to analyze MB prognosis in children population based on the classification of four molecular subgroups. METHODS: From January 2011 to January 2013, 84 consecutive MB patients aged underwent tumor removal at Beijing Tiantan Hospital. A total of 55 patients who ranged in age from 4 to 18 years underwent detailed follow-up. Molecular subgrouping was performed using RT-PCR. RESULTS: The 2-year progression-free survival (PFS) and overall survival (OS) rates for the entire cohort were 76.2 +/- 5.8 and 81.8 +/- 5.2%, respectively. Univariate analysis revealed that the Group 4 patients had a better survival (2-year OS, 90.6 +/- 5.2%) than the SHH subgroup (P = 0.002) and Group 3 patients (P = 0.008). Only two of the 23 non-metastasized Group 4 patients relapsed, and chemotherapy did significantly affect these patients (PFS, P = 0.685). One out of five WNT patients had tumor relapse and died at last. Large cell/anaplastic (LC/A) histology and chemotherapy were independent risk factors in multivariate analysis. CONCLUSION: In our study, the non-metastasized Group 4 patients had an excellent prognosis. The SHH subgroup and Group 3 patients had worst prognoses. LC/A histology had a dismal prognosis in our cohorts, which warrants intensive treatment. PMID- 28553260 TI - Vale Colin Ward-A Leader in Receptor Structural Biology. PMID- 28553261 TI - Editorial: Perspectives for the Next Generation of Virus Research: Spearheading the Use of Innovative Technologies and Methodologies. PMID- 28553262 TI - Differing Complex Microbiota Alter Disease Severity of the IL-10-/- Mouse Model of Inflammatory Bowel Disease. AB - It is estimated that 1.4 million people in the United States suffer from Inflammatory Bowel Disease (IBD), with an overall annual health care cost of more than $1.7 billion. Although the exact etiology of this disease remains unknown, research suggests that it is a multifactorial disease associated with aberrant gastrointestinal microbial populations (dysbiosis). The C57BL/6 and C3H/HeJBir mouse strains with targeted mutations in the IL-10 gene are commonly used models to study IBD. However, anecdotally, disease phenotype can vary in severity from lab to lab. Moreover, studies using germfree and monocolonized mice have suggested that gut microbiota (GM) are critical to disease induction in these models. With recent studies suggesting variation in naturally occurring GM composition and complexity among mouse producers, we hypothesized that differences in these naturally occurring complex GM profiles may modulate disease severity in the IL-10-/- mouse model. To test this hypothesis, we use a technique referred to as complex microbiota targeted rederivation (CMTR) to transfer genetically identical C57BL/6 IL-10-/- and C3H/HeJBir IL-10-/- embryos into surrogate CD-1 or C57BL/6 dams from different commercial producers with varying microbiota complexity and composition. We found that disease severity significantly and reproducibly differed among mice in both IL-10-/- strains, dependent on differing maternally inherited GM. Furthermore, disease severity was associated with alterations in relative abundance of several physiologically relevant bacterial species. These findings suggest that the composition of the resident GM is a primary determinant of disease severity in IBD and provide proof of-concept that CMTR can be used to investigate the contribution of contemporary complex GM on disease phenotype and reproducibility. PMID- 28553263 TI - Spatial Structure of the Mormon Cricket Gut Microbiome and its Predicted Contribution to Nutrition and Immune Function. AB - The gut microbiome of insects plays an important role in their ecology and evolution, participating in nutrient acquisition, immunity, and behavior. Microbial community structure within the gut is heavily influenced by differences among gut regions in morphology and physiology, which determine the niches available for microbes to colonize. We present a high-resolution analysis of the structure of the gut microbiome in the Mormon cricket Anabrus simplex, an insect known for its periodic outbreaks in the western United States and nutrition dependent mating system. The Mormon cricket microbiome was dominated by 11 taxa from the Lactobacillaceae, Enterobacteriaceae, and Streptococcaceae. While most of these were represented in all gut regions, there were marked differences in their relative abundance, with lactic-acid bacteria (Lactobacillaceae) more common in the foregut and midgut and enteric (Enterobacteriaceae) bacteria more common in the hindgut. Differences in community structure were driven by variation in the relative prevalence of three groups: a Lactobacillus in the foregut, Pediococcus lactic-acid bacteria in the midgut, and Pantoea agglomerans, an enteric bacterium, in the hindgut. These taxa have been shown to have beneficial effects on their hosts in insects and other animals by improving nutrition, increasing resistance to pathogens, and modulating social behavior. Using PICRUSt to predict gene content from our 16S rRNA sequences, we found enzymes that participate in carbohydrate metabolism and pathogen defense in other orthopterans. These were predominately represented in the hindgut and midgut, the most important sites for nutrition and pathogen defense. Phylogenetic analysis of 16S rRNA sequences from cultured isolates indicated low levels of divergence from sequences derived from plants and other insects, suggesting that these bacteria are likely to be exchanged between Mormon crickets and the environment. Our study shows strong spatial variation in microbiome community structure, which influences predicted gene content and thus the potential of the microbiome to influence host function. PMID- 28553265 TI - Adaptive Laboratory Evolution of Antibiotic Resistance Using Different Selection Regimes Lead to Similar Phenotypes and Genotypes. AB - Antibiotic resistance is a global threat to human health, wherefore it is crucial to study the mechanisms of antibiotic resistance as well as its emergence and dissemination. One way to analyze the acquisition of de novo mutations conferring antibiotic resistance is adaptive laboratory evolution. However, various evolution methods exist that utilize different population sizes, selection strengths, and bottlenecks. While evolution in increasing drug gradients guarantees high-level antibiotic resistance promising to identify the most potent resistance conferring mutations, other selection regimes are simpler to implement and therefore allow higher throughput. The specific regimen of adaptive evolution may have a profound impact on the adapted cell state. Indeed, substantial effects of the selection regime on the resulting geno- and phenotypes have been reported in the literature. In this study we compare the geno- and phenotypes of Escherichia coli after evolution to Amikacin, Piperacillin, and Tetracycline under four different selection regimes. Interestingly, key mutations that confer antibiotic resistance as well as phenotypic changes like collateral sensitivity and cross-resistance emerge independently of the selection regime. Yet, lineages that underwent evolution under mild selection displayed a growth advantage independently of the acquired level of antibiotic resistance compared to lineages adapted under maximal selection in a drug gradient. Our data suggests that even though different selection regimens result in subtle genotypic and phenotypic differences key adaptations appear independently of the selection regime. PMID- 28553266 TI - The Grapevine and Wine Microbiome: Insights from High-Throughput Amplicon Sequencing. AB - From the time when microbial activity in wine fermentation was first demonstrated, the microbial ecology of the vineyard, grape, and wine has been extensively investigated using culture-based methods. However, the last 2 decades have been characterized by an important change in the approaches used for microbial examination, due to the introduction of DNA-based community fingerprinting methods such as DGGE, SSCP, T-RFLP, and ARISA. These approaches allowed for the exploration of microbial community structures without the need to cultivate, and have been extensively applied to decipher the microbial populations associated with the grapevine as well as the microbial dynamics throughout grape berry ripening and wine fermentation. These techniques are well established for the rapid more sensitive profiling of microbial communities; however, they often do not provide direct taxonomic information and possess limited ability to detect the presence of rare taxa and taxa with low abundance. Consequently, the past 5 years have seen an upsurge in the application of high throughput sequencing methods for the in-depth assessment of the grapevine and wine microbiome. Although a relatively new approach in wine sciences, these methods reveal a considerably greater diversity than previously reported, and identified several species that had not yet been reported. The aim of the current review is to highlight the contribution of high-throughput next generation sequencing and metagenomics approaches to vineyard microbial ecology especially unraveling the influence of vineyard management practices on microbial diversity. PMID- 28553267 TI - Effect of Feed Additives on Productivity and Campylobacter spp. Loads in Broilers Reared under Free Range Conditions. AB - The poultry reservoir, especially broiler meat, is generally recognized as one of the most-important sources for human Campylobacteriosis. The measures to control Campylobacter targeted essentially the primary production level. The aim of this work was to evaluate the effectiveness of different treatments against natural Campylobacter colonization in a French experimental farm of free-range broilers during the whole rearing period. Five commercial products and a combination of two of them were tested and all the products were added to feed or to water at the dose recommended by the suppliers. Campylobacter loads in caeca and on carcasses of broilers at the slaughter were determined by culture methods. Natural contamination of the flock occurred at the end of the indoor rearing period between day 35 and day 42. At day 42, the multispecies probiotic added to the feed reduced the contamination of 0.55 log10 CFU/g (p = 0.02) but was not significant (p > 0.05) at the end of rearing at day 78. However, another treatment, a combination of a cation exchange clay-based product in feed and an organic acid mixture (formic acid, sodium formate, lactic acid, propionic acid) in water, led to a slight but significant reduction of 0.82 +/- 0.25 log10 CFU/g (p = 0.02) compared to the control group at day 78. Testing this combination in field conditions in several flocks is needed to determine if it is biologically relevant and if it could be a valuable measure to reduce Campylobacter in broiler flocks. PMID- 28553264 TI - The Hologenome Across Environments and the Implications of a Host-Associated Microbial Repertoire. AB - Our understanding of the diverse interactions between hosts and microbes has grown profoundly over the past two decades and, as a product, has revolutionized our knowledge of the life sciences. Through primarily laboratory experiments, the current framework for holobionts and their respective hologenomes aims to decipher the underpinnings and implications of symbioses between host and microbiome. However, the laboratory setting restricts the full spectrum of host associated symbionts as compared to those found in nature; thus, limiting the potential for a holistic interpretation of the functional roles the microbiome plays in host biology. When holobionts are studied in nature, associated microbial communities vary considerably between conditions, resulting in more microbial associates as part of the "hologenome" across environments than in either environment alone. We review and synthesize empirical evidence suggesting that hosts may associate with a larger microbial network that, in part, corresponds to experiencing diverse environmental conditions. To conceptualize the interactions between host and microbiome in an ecological context, we suggest the "host-associated microbial repertoire," which is the sum of microbial species a host may associate with over the course of its life-history under all encountered environmental circumstances. Furthermore, using examples from both terrestrial and marine ecosystems, we discuss how this concept may be used as a framework to compare the ability of the holobiont to acclimate and adapt to environmental variation, and propose three "signatures" of the concept. PMID- 28553269 TI - Editorial: Petroleum Microbial Biotechnology: Challenges and Prospects. PMID- 28553271 TI - Molecular Epidemiology and Antibiotic Resistance Profiles of Methicillin Resistant Staphylococcus aureus Strains in a Tertiary Hospital in China. AB - Analysis of the genotypic characteristics and antimicrobial susceptibility patterns of methicillin-resistant Staphylococcus aureus (MRSA) is essential for the control and treatment of diseases caused by this important pathogen. In this study, MRSA isolates obtained from a tertiary caret hospital in China were subjected to spa typing, SCCmec typing, multiple locus sequence typing (MLST), and PCR targeting of the genes encoding Panton-Valentine leukocidin (PVL). The disk diffusion method was used to test the antimicrobial susceptibility of the isolates to 10 non-beta-lactam antibiotics. Among the 120 MRSA isolates studied, 18 spa types and 15 ST types were identified. The spa t311 type was the most common (a total of 60 isolates; 50%) among the study strains, and nearly all the t311 strains belonged to ST5, which is the most common ST type that was previously reported from China among the t002 isolates. ST5-II/t311 was the major prevalent clone (55, 45.8%), which was followed by ST5-II/t002 (12, 10.0%) and ST59-IV/t437 (11, 9.2%). PVL-encoding genes were found in 6.7% of the isolates. Although the ST5-II/t311 and ST5-II/t002 clones are different spa types, they shared the same resistance profile (clindamycin, erythromycin, and ciprofloxacin). Most isolates of the ST239-III/t037 clone were resistant to clindamycin, erythromycin, ciprofloxacin, gentamicin, tetracycline, and trimethoprim/sulfamethoxazole. By contrast, the MRSA isolates of the ST239 III/t030 clone were more resistant to rifampin, but they were susceptible to trimethoprim/sulfamethoxazole. Our data emphasize the need for ongoing epidemiologic surveillance. PMID- 28553270 TI - Time-Resolved Transcriptomics and Constraint-Based Modeling Identify System-Level Metabolic Features and Overexpression Targets to Increase Spiramycin Production in Streptomyces ambofaciens. AB - In this study we have applied an integrated system biology approach to characterize the metabolic landscape of Streptomyces ambofaciens and to identify a list of potential metabolic engineering targets for the overproduction of the secondary metabolites in this microorganism. We focused on an often overlooked growth period (i.e., post-first rapid growth phase) and, by integrating constraint-based metabolic modeling with time resolved RNA-seq data, we depicted the main effects of changes in gene expression on the overall metabolic reprogramming occurring in S. ambofaciens. Moreover, through metabolic modeling, we unraveled a set of candidate overexpression gene targets hypothetically leading to spiramycin overproduction. Model predictions were experimentally validated by genetic manipulation of the recently described ethylmalonyl-CoA metabolic node, providing evidence that spiramycin productivity may be increased by enhancing the carbon flow through this pathway. The goal was achieved by over expressing the ccr paralog srm4 in an ad hoc engineered plasmid. This work embeds the first metabolic reconstruction of S. ambofaciens and the successful experimental validation of model predictions and demonstrates the validity and the importance of in silico modeling tools for the overproduction of molecules with a biotechnological interest. Finally, the proposed metabolic reconstruction, which includes manually refined pathways for several secondary metabolites with antimicrobial activity, represents a solid platform for the future exploitation of S. ambofaciens biotechnological potential. PMID- 28553268 TI - Global Gene-expression Analysis of the Response of Salmonella Enteritidis to Egg White Exposure Reveals Multiple Egg White-imposed Stress Responses. AB - Chicken egg white protects the embryo from bacterial invaders by presenting an assortment of antagonistic activities that combine together to both kill and inhibit growth. The key features of the egg white anti-bacterial system are iron restriction, high pH, antibacterial peptides and proteins, and viscosity. Salmonella enterica serovar Enteritidis is the major pathogen responsible for egg borne infection in humans, which is partly explained by its exceptional capacity for survival under the harsh conditions encountered within egg white. However, at temperatures up to 42 degrees C, egg white exerts a much stronger bactericidal effect on S. Enteritidis than at lower temperatures, although the mechanism of egg white-induced killing is only partly understood. Here, for the first time, the impact of exposure of S. Enteritidis to egg white under bactericidal conditions (45 degrees C) is explored by global-expression analysis. A large scale (18.7% of genome) shift in transcription is revealed suggesting major changes in specific aspects of S. Enteritidis physiology: induction of egg white related stress-responses (envelope damage, exposure to heat and alkalinity, and translation shutdown); shift in energy metabolism from respiration to fermentation; and enhanced micronutrient provision (due to iron and biotin restriction). Little evidence of DNA damage or redox stress was obtained. Instead, data are consistent with envelope damage resulting in cell death by lysis. A surprise was the high degree of induction of hexonate/hexuronate utilization genes, despite no evidence indicating the presence of these substrates in egg white. PMID- 28553272 TI - RpoN Promotes Pseudomonas aeruginosa Survival in the Presence of Tobramycin. AB - Pseudomonas aeruginosa has developed diverse strategies to respond and adapt to antibiotic stress. Among the factors that modulate survival in the presence of antibiotics, alternative sigma factors play an important role. Here, we demonstrate that the alternative sigma factor RpoN (sigma54) promotes survival in the presence of tobramycin. The tobramycin-sensitive phenotype of logarithmic phase DeltarpoN mutant cells is suppressed by the loss of the alternative sigma factor RpoS. Transcriptional analysis indicated that RpoN positively regulates the expression of RsmA, an RNA-binding protein, in the P. aeruginosa stationary growth phase in a nutrient-rich medium. The loss of RpoS led to the upregulation of gacA expression in the nutrient-limited medium-grown stationary phase cells. Conversely, in the logarithmic growth phase, the DeltarpoS mutant demonstrated lower expression of gacA, underscoring a regulatory role of RpoS for GacA. Supplementation of tobramycin to stationary phase DeltarpoN mutant cells grown in nutrient-rich medium resulted in decreased expression of gacA, relA, and rpoS without altering the expression of rsmA relative to wild-type PAO1. The observed downregulation of gacA and relA in the DeltarpoN mutant in the presence of tobramycin could be reversed through the mutation of rpoS in the DeltarpoN mutant background. The tobramycin-tolerant phenotype of the DeltarpoNDeltarpoS mutant logarithmic phase cells may be associated with the expression of relA, which remained unresponsive upon addition of tobramycin. The logarithmic phase DeltarpoS and DeltarpoNDeltarpoS mutant cells demonstrated increased expression of gacA in response to tobramycin. Together, these results suggest that a complex regulatory interaction between RpoN, RpoS, the Gac/Rsm pathway, and RelA modulates the P. aeruginosa response to tobramycin. PMID- 28553273 TI - Direct Binding of the pH-Regulated Protein 1 (Pra1) from Candida albicans Inhibits Cytokine Secretion by Mouse CD4+ T Cells. AB - Opportunistic infections with the saprophytic yeast Candida albicans are a major cause of morbidity in immunocompromised patients. While the interaction of cells and molecules of innate immunity with C. albicans has been studied to great depth, comparatively little is known about the modulation of adaptive immunity by C. albicans. In particular, direct interaction of proteins secreted by C. albicans with CD4+ T cells has not been studied in detail. In a first screening approach, we identified the pH-regulated antigen 1 (Pra1) as a molecule capable of directly binding to mouse CD4+ T cells in vitro. Binding of Pra1 to the T cell surface was enhanced by extracellular Zn2+ ions which Pra1 is known to scavenge from the host in order to supply the fungus with Zn2+. In vitro stimulation assays using highly purified mouse CD4+ T cells showed that Pra1 increased proliferation of CD4+ T cells in the presence of plate-bound anti-CD3 monoclonal antibody. In contrast, secretion of effector cytokines such as IFNgamma and TNF by CD4+ T cells upon anti-CD3/ anti-CD28 mAb as well as cognate antigen stimulation was reduced in the presence of Pra1. By secreting Pra1 C. albicans, thus, directly modulates and partially controls CD4+ T cell responses as shown in our in vitro assays. PMID- 28553275 TI - Host Immune Selection of Rumen Bacteria through Salivary Secretory IgA. AB - The rumen microbiome is integral to efficient production in cattle and shows strong host specificity, yet little is known about what host factors shape rumen microbial composition. Secretory immunoglobulin A (SIgA) is produced in large amounts in the saliva, can coat both commensal and pathogenic microbes within the gut, and presents a plausible mechanism of host specificity. However, the role salivary SIgA plays in commensal bacteria selection in ruminants remains elusive. The main objectives of this study were to develop an immuno-affinity benchtop method to isolate SIgA-tagged microbiota and to determine if salivary SIgA preferentially binds selected bacteria. We hypothesized that SIgA-tagged bacteria would differ from total bacteria, thus supporting a potential host-derived mechanism in commensal bacterial selection. Whole rumen (n = 9) and oral secretion samples (n = 10) were incubated with magnetic beads conjugated with anti-secretory IgA antibodies to enrich SIgA-tagged microbiota. Microbial DNA from the oral secretion, whole rumen, SIgA-tagged oral secretion, and SIgA-tagged rumen was isolated for amplicon sequencing of V1-V3 region of 16S rDNA genes. Whole rumen and oral secretion had distinctive (P < 0.05) bacterial compositions indicated by the non-parametric multidimensional scaling plot using Euclidean distance metrics. The SIgA-tagged microbiota from rumen and oral secretion had similar abundance of Bacteroidetes, Actinobacteria, Fibrobacter, candidate phyla TM7, and Tenericutes and are clustered tightly. Composition of SIgA-tagged oral secretion microbiota was more similar to whole rumen microbiota than whole oral secretion due to enrichment of rumen bacteria (Lachnospiraceae) and depletion of oral taxa (Streptococcus, Rothia, Neisseriaceae, and Lactobacillales). In conclusion, SIgA-tagged oral secretion microbiota had an increased resemblance to whole rumen microbiota, suggesting salivary SIgA-coating may be one host-derived mechanism impacting commensal colonization. Further studies, to explore the variations in antibody affinity between different animals as a driver of microbial composition are warranted. PMID- 28553274 TI - Association between Yogurt Consumption and Intestinal Microbiota in Healthy Young Adults Differs by Host Gender. AB - Human intestinal microbiota are influenced by various factors viz. diet, environment, age, gender, geographical, and socioeconomic situation, etc. among which diet has the most profound impact. However, studies investigating this impact have mostly included subjects from diverse geographic/socioeconomic backgrounds and hence the precise effects of dietary factors on gut microbiota composition remain largely confounded. Herein, with an aim to evaluate the association between dietary habits, specifically yogurt consumption, and the gut microbiota in healthy young adults sharing similar age, lifestyle routine, geographical setting, etc., we conducted a cross-sectional study wherein 293 collegiate freshmen answered a questionnaire about their frequency of yogurt consumption over the last 2 months and provided stool specimens for microbiota analysis. Fecal microbiota were analyzed by highly sensitive reverse transcription-quantitative-PCR assays targeting bacterial 16S rRNA molecules. Fecal organic acids were measured by HPLC. Overall, the gut microbiota were predominated (97.1 +/- 8.6%) by Clostridium coccoides group, Clostridium leptum subgroup, Bacteroides fragilis group, Bifidobacterium and Atopobium cluster. Interestingly, after adjusting the data for yogurt consumption, females were found to have higher total bacterial (P = 0.013) and Bifidobacterium (P = 0.046) count and fecal pH (P = 0.007) and lower fecal concentration of total organic acids (P = 0.030), succinic acid (P = 0.007) and formic acid (P = 0.046) as compared to males. Altogether, yogurt consumption showed positive linear association with Lactobacillus and Lactobacillus gasseri subgroup in both male and female subjects; however, several gender-specific disparities were also detected in this yogurt-microbiota association. Yogurt consumption demonstrated a negative association with L. sakei subgroup, Enterobacteriaceae and Staphylococcus in males but shared a positive association with L. casei subgroup and succinic acid in female subjects. The study manifests the association between yogurt consumption and gut microbiota in a healthy homogeneous cohort and show how this association can differ by host gender. The findings should be helpful for prospective studies investigating the diet-microbiome interaction in human health and disease. PMID- 28553276 TI - Tobamovirus 3'-Terminal Gene Overlap May be a Mechanism for within-Host Fitness Improvement. AB - Overlapping genes (OGs) are a universal phenomenon in all kingdoms, and viruses display a high content of OGs combined with a high rate of evolution. It is believed that the mechanism of gene overlap is based on overprinting of an existing gene. OGs help virus genes compress a maximum amount of information into short sequences, conferring viral proteins with novel features and thereby increasing their within-host fitness. Analysis of tobamovirus 3'-terminal genes reveals at least two modes of OG organization and mechanisms of interaction with the host. Originally isolated from Solanaceae species, viruses (referred to as Solanaceae-infecting) such as tobacco mosaic virus do not show 3'-terminal overlap between movement protein (MP) and coat protein (CP) genes but do contain open reading frame 6 (ORF6), which overlaps with both genes. Conversely, tobamoviruses, originally isolated from Brassicaceae species (referred to as Brassicaceae-infecting) and also able to infect Solanaceae plants, have no ORF6 but are characterized by overlapping MP and CP genes. Our analysis showed that the MP/CP overlap of Brassicaceae-infecting tobamoviruses results in the following: (i) genome compression and strengthening of subgenomic promoters; (ii) CP gene early expression directly from genomic and dicistronic MP subgenomic mRNA using an internal ribosome entry site (IRES) and a stable hairpin structure in the overlapping region; (iii) loss of ORF6, which influences the symptomatology of Solanaceae-infecting tobamoviruses; and (iv) acquisition of an IRES polypurine rich region encoding an MP nuclear localization signal. We believe that MP/CP gene overlap may constitute a mechanism for host range expansion and virus adjustment to Brassicaceae plants. PMID- 28553277 TI - Structural Analysis of Porcine Reproductive and Respiratory Syndrome Virus Non structural Protein 7alpha (NSP7alpha) and Identification of Its Interaction with NSP9. AB - Non-structural protein 7 (NSP7), which can be further cleaved into NSP7alpha and NSP7beta, is one of the most conserved proteins of porcine reproductive and respiratory syndrome virus (PRRSV). NSP7 plays a role in provoking the humoral immune system in PRRSV-infected swine, but its structure and function are still not fully understood. Here, we analyzed the expression of NSP7, NSP7alpha, and NSP7beta in PRRSV-infected MARC-145 cells. The solution structure of NSP7alpha was determined by using nuclear magnetic resonance (NMR). Although the structure provided little clue to its function, based on the structure of NSP7alpha, we predicted and further identified some key amino acids on NSP7alpha for the interaction of NSP7alpha with NSP9, the RNA dependent RNA polymerase of PRRSV. This study provided some new insights into the structure and function of PRRSV NSP7. PMID- 28553278 TI - A Thiazole Orange Derivative Targeting the Bacterial Protein FtsZ Shows Potent Antibacterial Activity. AB - The prevalence of multidrug resistance among clinically significant bacteria calls for the urgent development of new antibiotics with novel mechanisms of action. In this study, a new small molecule exhibiting excellent inhibition of bacterial cell division with potent antibacterial activity was discovered through cell-based screening. The compound exhibits a broad spectrum of bactericidal activity, including the methicillin-resistant Staphylococcus aureus, vancomycin resistant Enterococcus and NDM-1 Escherichia coli. The in vitro and in vivo results suggested that this compound disrupts the dynamic assembly of FtsZ protein and Z-ring formation through stimulating FtsZ polymerization. Moreover, this compound exhibits no activity on mammalian tubulin polymerization and shows low cytotoxicity on mammalian cells. Taken together, these findings could provide a new chemotype for development of antibacterials with FtsZ as the target. PMID- 28553279 TI - Vaccination of Mice with Virulence-Associated Protein G (VapG) Antigen Confers Partial Protection against Rhodococcus equi Infection through Induced Humoral Immunity. AB - Rhodococcus equi is a facultative intracellular bacterium causing severe pyogranulomatous pneumonia, ulcerative enterocolitis, and mesenteric lymphadenopathy in foals aged less than 6 months. Less frequently, this pathogen affects various other species, such as pigs, cattle, cats, and even humans. Although rhodococcosis is treated with a combination of antimicrobial agents, resistance is developed in some cases, and thus, antimicrobial susceptibility must be monitored and managed. Considering these limitations of the current therapy and unavailability of a vaccine to prevent the disease, research is particularly focused on the development of an effective vaccine against rhodococcosis. Most vaccines undergoing development utilize the virulence associated protein (Vap) A antigen, which was identified previously as a key virulence factor of R. equi. Nevertheless, other proteins, such as VapG, present in most virulent R. equi strains, are also encoded by vap genes located on the R. equi bacterial virulence plasmid. In the present study, we evaluated the effect of VapG immunization on the survival of R. equi-challenged mice. We used attenuated Salmonella as a carrier for VapG (Salmonella-vapG+), a procedure previously adopted to develop a VapA-based vaccine. We observed that vaccination with Salmonella-vapG+ induced both an increased IFN-gamma, IL-12, and TNF-alpha production, and a decreased bacterial burden in organs of the R. equi-challenged mice. Nevertheless, Salmonella-vapG+ vaccination protected only 50% of the mice challenged with a lethal dose of R. equi. Interestingly, we observed an increased frequency of B cells in the spleen of Salmonella-vapG+-vaccinated mice and showed that Salmonella-vapG+-vaccinated R. equi-challenged B-cell-knockout mice did not reduce the bacterial burden. Given these results, we discussed the potential role of the humoral immune response induced by Salmonella-vapG+ vaccination in conferring protection against R. equi infection, as well as the employment of VapG antigen for obtaining hyperimmune plasma to prevent rhodoccocosis in young foals. PMID- 28553280 TI - Atypical Porcine Pestivirus as a Novel Type of Pestivirus in Pigs in China. AB - Pestiviruses are highly variable RNA viruses. A growing number of novel pestiviruses has been discovered in domestic and wild species in the last two decades. Recently, a novel atypical porcine pestivirus (APPV) linked with the development of congenital tremor (CT) in neonatal pigs was described in Europe and the Americas. Here, the first Asian APPV complete polyprotein coding sequence was assembled from serum samples from newborn piglets affected with CT in Southern China, and termed APPV_GD. 14 organ samples from affected piglets were analyzed by quantitative RT-PCR (qRT-PCR) to investigate the tissue tropism of APPV, and 135 serum samples from pigs from 10 farms were used for identifying APPV in adult pigs. The highest genome loads were found in submaxillary lymph nodes, and PCR-based detection showed that APPV genomes were present in seven samples from five farms. A phylogenetic tree was constructed based on the full length genomes of the pestiviruses, and APPV_GD appeared on a new branch with another newly discovered APPV. Nucleotide identity analysis demonstrated that APPV_GD shared the highest nucleotide sequence identity with a German APPV. Bayesian inference was performed using 25 partial sequences of the APPV NS5B gene (528 bp) isolated from four countries in recent years. According to this analysis, the most recent common ancestor (tMRCA) of the current APPV strains might have emerged in Germany and then diversified and spread to Asia, the Americas, and other countries in Europe. However, the result of bayesian inference could change when more APPV strains are isolated in the future. The present study is the first to report APPV in China and infers the origin and dissemination of the current strains of the virus. PMID- 28553281 TI - Evasion Mechanisms Used by Pathogens to Escape the Lectin Complement Pathway. AB - The complement system is a crucial defensive network that protects the host against invading pathogens. It is part of the innate immune system and can be initiated via three pathways: the lectin, classical and alternative activation pathway. Overall the network compiles a group of recognition molecules that bind specific patterns on microbial surfaces, a group of associated proteases that initiates the complement cascade, and a group of proteins that interact in proteolytic complexes or the terminal pore-forming complex. In addition, various regulatory proteins are important for controlling the level of activity. The result is a pro-inflammatory response meant to combat foreign microbes. Microbial elimination is, however, not a straight forward procedure; pathogens have adapted to their environment by evolving a collection of evasion mechanisms that circumvent the human complement system. Complement evasion strategies features different ways of exploiting human complement proteins and moreover features different pathogen-derived proteins that interfere with the normal processes. Accumulated, these mechanisms target all three complement activation pathways as well as the final common part of the cascade. This review will cover the currently known lectin pathway evasion mechanisms and give examples of pathogens that operate these to increase their chance of invasion, survival and dissemination. PMID- 28553282 TI - Co-Inflammatory Roles of TGFbeta1 in the Presence of TNFalpha Drive a Pro inflammatory Fate in Mesenchymal Stem Cells. AB - High plasticity is a hallmark of mesenchymal stem cells (MSCs), and as such, their differentiation and activities may be shaped by factors of their microenvironment. Bones, tumors, and cardiomyopathy are examples of niches and conditions that contain MSCs and are enriched with tumor necrosis factor alpha (TNFalpha) and transforming growth factor beta1 (TGFbeta1). These two cytokines are generally considered as having opposing roles in regulating immunity and inflammation (pro- and anti-inflammatory, respectively). Here, we performed global gene expression analysis of human bone marrow-derived MSCs and identified overlap in half of the transcriptional programs that were modified by TNFalpha and TGFbeta1. The two cytokines elevated the mRNA expression of soluble factors, including mRNAs of pro-inflammatory mediators. Accordingly, the typical pro inflammatory factor TNFalpha prominently induced the protein expression levels of the pro-inflammatory mediators CCL2, CXCL8 (IL-8), and cyclooxygenase-2 (Cox-2) in MSCs, through the NF-kappaB/p65 pathway. In parallel, TGFbeta1 did not elevate CXCL8 protein levels and induced the protein expression of CCL2 at much lower levels than TNFalpha; yet, TGFbeta1 readily induced Cox-2 and acted predominantly via the Smad3 pathway. Interestingly, combined stimulation of MSCs by TNFalpha + TGFbeta1 led to a cooperative induction of all three inflammatory mediators, indicating that TGFbeta1 functioned as a co-inflammatory cytokine in the presence of TNFalpha. The cooperative activities of TNFalpha + TGFbeta1 that have led to CCL2 and CXCL8 induction were almost exclusively dependent on p65 activation and were not regulated by Smad3 or by the upstream regulator TGFbeta-activated kinase 1 (TAK1). In contrast, the TNFalpha + TGFbeta1-induced cooperative elevation in Cox-2 was mostly dependent on Smad3 (demonstrating cooperativity with activated NF-kappaB) and was partly regulated by TAK1. Studies with MSCs activated by TNFalpha + TGFbeta1 revealed that they release factors that can affect other cells in their microenvironment and induce breast tumor cell elongation, migration, and scattering out of spheroid tumor masses. Thus, our findings demonstrate a TNFalpha + TGFbeta1-driven pro-inflammatory fate in MSCs, identify specific molecular mechanisms involved, and propose that TNFalpha + TGFbeta1 stimulated MSCs influence the tumor niche. These observations suggest key roles for the microenvironment in regulating MSC functions, which in turn may affect different health-related conditions. PMID- 28553283 TI - The Recombinant Sea Urchin Immune Effector Protein, rSpTransformer-E1, Binds to Phosphatidic Acid and Deforms Membranes. AB - The purple sea urchin, Strongylocentrotus purpuratus, possesses a sophisticated innate immune system that functions without adaptive capabilities and responds to pathogens effectively by expressing the highly diverse SpTransformer gene family (formerly the Sp185/333 gene family). The swift gene expression response and the sequence diversity of SpTransformer cDNAs suggest that the encoded proteins have immune functions. Individual sea urchins can express up to 260 distinct SpTransformer proteins, and their diversity suggests that different versions may have different functions. Although the deduced proteins are diverse, they share an overall structure of a hydrophobic leader, a glycine-rich N-terminal region, a histidine-rich region, and a C-terminal region. Circular dichroism analysis of a recombinant SpTransformer protein, rSpTransformer-E1 (rSpTrf-E1) demonstrates that it is intrinsically disordered and transforms to alpha helical in the presence of buffer additives and binding targets. Although native SpTrf proteins are associated with the membranes of perinuclear vesicles in the phagocyte class of coelomocytes and are present on the surface of small phagocytes, they have no predicted transmembrane region or conserved site for glycophosphatidylinositol linkage. To determine whether native SpTrf proteins associate with phagocyte membranes through interactions with lipids, when rSpTrf-E1 is incubated with lipid-embedded nylon strips, it binds to phosphatidic acid (PA) through both the glycine-rich region and the histidine-rich region. Synthetic liposomes composed of PA and phosphatidylcholine show binding between rSpTrf-E1 and PA by fluorescence resonance energy transfer, which is associated with leakage of luminal contents suggesting changes in lipid organization and perhaps liposome lysis. Interactions with liposomes also change membrane curvature leading to liposome budding, fusion, and invagination, which is associated with PA clustering induced by rSpTrf-E1 binding. Longer incubations result in the extraction of PA from the liposomes, which form disorganized clusters. CD shows that when rSpTrf-E1 binds to PA, it changes its secondary structure from disordered to alpha helical. These results provide evidence for how SpTransformer proteins may associate with molecules that have exposed phosphates including PA on cell membranes and how the characteristic of protein multimerization may drive changes in the organization of membrane lipids. PMID- 28553285 TI - Antitumor Activity of a Mesenchymal Stem Cell Line Stably Secreting a Tumor Targeted TNF-Related Apoptosis-Inducing Ligand Fusion Protein. AB - Mesenchymal stem cells (MSCs) are currently exploited as gene delivery systems for transient in situ expression of cancer therapeutics. As an alternative to the prevailing viral expression, we here describe a murine MSC line stably expressing a therapeutic protein for up to 42 passages, yet fully maintaining MSC features. Because of superior antitumoral activity of hexavalent TNF-related apoptosis inducing ligand (TRAIL) formats and the advantage of a tumor-targeted action, we choose expression of a dimeric EGFR-specific diabody single-chain TRAIL (Db scTRAIL) as a model. The bioactivity of Db-scTRAIL produced from an isolated clone (MSC.TRAIL) was revealed from cell death induction in Colo205 cells treated with either culture supernatants from or cocultured with MSC.TRAIL. In vivo, therapeutic activity of MSC.TRAIL was shown upon peritumoral injection in a Colo205 xenograft tumor model. Best antitumor activity in vitro and in vivo was observed upon combined treatment of MSC.TRAIL with bortezomib. Importantly, in vivo combination treatment did not cause apparent hepatotoxicity, weight loss, or behavioral changes. The development of well characterized stocks of stable drug producing human MSC lines has the potential to establish standardized protocols of cell-based therapy broadly applicable in cancer treatment. PMID- 28553286 TI - Assessment of Spanish Panel Reactive Antibody Calculator and Potential Usefulness. AB - BACKGROUND AND OBJECTIVES: The calculated panel reactive of antibodies (cPRAs) necessary for kidney donor-pair exchange and highly sensitized programs are estimated using different panel reactive antibody (PRA) calculators based on big enough samples in Eurotransplant (EUTR), United Network for Organ Sharing (UNOS), and Canadian Transplant Registry (CTR) websites. However, those calculators can vary depending on the ethnic they are applied. Here, we develop a PRA calculator used in the Spanish Program of Transplant Access for Highly Sensitized patients (PATHI) and validate it with EUTR, UNOS, and CTR calculators. METHODS: The anti human leukocyte antigen (HLA) antibody profile of 42 sensitized patients on waiting list was defined, and cPRA was calculated with different PRA calculators. RESULTS: Despite different allelic frequencies derived from population differences in donor panel from each calculator, no differences in cPRA between the four calculators were observed. The PATHI calculator includes anti-DQA1 antibody profiles in cPRA calculation; however, no improvement in total cPRA calculation of highly sensitized patients was demonstrated. INTERPRETATION AND CONCLUSION: The PATHI calculator provides cPRA results comparable with those from EUTR, UNOS, and CTR calculators and serves as a tool to develop valid calculators in geographical and ethnic areas different from Europe, USA, and Canada. PMID- 28553284 TI - Divergent Expression of CXCR5 and CCR5 on CD4+ T Cells and the Paradoxical Accumulation of T Follicular Helper Cells during HIV Infection. AB - Viral infection sets in motion a cascade of immune responses, including both CXCR5+CD4+ T follicular helper (Tfh) cells that regulate humoral immunity and CCR5+CD4+ T cells that mediate cell-mediated immunity. In peripheral blood mononuclear cells, the majority of memory CD4+ T cells appear to fall into either of these two lineages, CCR5-CXCR5+ or CCR5+CXCR5-. Very high titers of anti-HIV IgG antibodies are a hallmark of infection, strongly suggesting that there is significant HIV-specific CD4+ T cell help to HIV-specific B cells. We now know that characteristic increases in germinal centers (GC) in lymphoid tissue (LT) during SIV and HIV-1 infections are associated with an increase in CXCR5+PD-1high Tfh, which expand to a large proportion of memory CD4+ T cells in LT, and are presumably specific for SIV or HIV epitopes. Macaque Tfh normally express very little CCR5, yet are infected by CCR5-using SIV, which may occur mainly through infection of a subset of PD-1intermediateCCR5+Bcl-6+ pre-Tfh cells. In contrast, in human LT, a subset of PD-1high Tfh appears to express low levels of CCR5, as measured by flow cytometry, and this may also contribute to the high rate of infection of Tfh. Also, we have found, by assessing fine-needle biopsies of LT, that increases in Tfh and GC B cells in HIV infection are not completely normalized by antiretroviral therapy (ART), suggesting a possible long-lasting reservoir of infected Tfh. In contrast to the increase of CXCR5+ Tfh, there is no accumulation of proliferating CCR5+ CD4 T HIV Gag-specific cells in peripheral blood that make IFN-gamma. Altogether, CXCR5+CCR5- CD4 T cells that regulate humoral immunity are allowed greater freedom to operate and expand during HIV-1 infection, but at the same time can contain HIV DNA at levels at least as high as in other CD4 subsets. We argue that early ART including a CCR5 blocker may directly reduce the infected Tfh reservoir in LT and also interrupt cycles of antibody pressure driving virus mutation and additional GC responses to resulting neoantigens. PMID- 28553287 TI - Hypoxia Modulates the Response of Mast Cells to Staphylococcus aureus Infection. AB - To study the antimicrobial function of immune cells ex vivo, cells are commonly cultivated under atmospheric oxygen concentrations (20-21%; normoxia), although the physiological oxygen conditions in vivo are significantly lower in most tissues. Especially during an acute infection, oxygen concentration locally decreases to hypoxic levels around or below 1%. The goal of this study was to investigate the effect of hypoxia on the activity of mast cells (MCs). MCs were cultivated for 3 or 24 h at 1% O2 in a hypoxia glove box and co-incubated with heat-inactivated Staphylococcus aureus. When incubating the cells for 24 h under hypoxia, the transcriptional regulator hypoxia-inducible factor 1alpha (HIF 1alpha) was stabilized and resulted in increased extracellular trap formation and decreased phagocytosis. Interestingly, while phagocytosis of fluorescent S. aureus bioparticles as well as the release of extracellular traps remained unaffected at 3 h hypoxia, the secretion of the prestored mediator histamine was increased under hypoxia alone. In contrast, the release of TNF-alpha was generally reduced at 3 h hypoxia. Microarray transcriptome analysis revealed 13 genes that were significantly downregulated in MCs comparing 3 h hypoxia versus normoxia. One interesting candidate is sec24, a member of the pre-budding complex of coat protein complex II (COPII), which is responsible for the anterograde transport of proteins from the ER to the Golgi apparatus. These data lead to the suggestion that de novo synthesized proteins including crucial factors, which are involved in the response to an acute infection like TNF-alpha, may eventually be retained in the ER under hypoxia. Importantly, the expression of HIF-1alpha was not altered at 3 h. Thus, our data exhibit a HIF-1alpha-independent reaction of MCs to short-term hypoxia. We hypothesize that MCs respond to short-term low oxygen levels in a HIF-1alpha-independent manner by downregulating the release of proinflammatory cytokines like TNF-alpha, thereby avoiding uncontrolled degranulation, which could lead to excessive inflammation and severe tissue damage. PMID- 28553289 TI - Major CD4 T-Cell Depletion and Immune Senescence in a Patient with Chronic Granulomatous Disease. AB - Chronic granulomatous disease (CGD) results from primary defects in phagocytic reactive oxygen species (ROS) production. T-cell evaluation is usually neglected during patients' follow-up, although T-cell depletion has been reported in CGD through unknown mechanisms. We describe here a 36-year-old patient with X-linked CGD with severe CD4 T-cell depletion <200 CD4 T-cells/MUl, providing insights into the mechanisms that underlie T-cell loss in the context of oxidative burst defects. In addition to the typical infections, the patient featured a progressive T-cell loss associated with persistent lymphocyte activation, expansion of interleukin (IL)-17-producing CD4 T-cells, and impaired thymic activity, leading to a reduced replenishment of the T-cell pool. A relative CD4 depletion was also found at the gut mucosal level, although no bias to IL-17 production was documented. This immunological pattern of exhaustion of immune resources favors prompt, potentially curative, therapeutic interventions in CGD patients, namely, stem-cell transplantation or gene therapy. Moreover, this clinical case raises new research questions on the interplay of ROS production and T-cell homeostasis and immune senescence. PMID- 28553288 TI - Mycobacterium tuberculosis Induction of Heme Oxygenase-1 Expression Is Dependent on Oxidative Stress and Reflects Treatment Outcomes. AB - The antioxidant enzyme heme oxygenase-1 (HO-1) is implicated in the pathogenesis of tuberculosis (TB) and has been proposed as a biomarker of active disease. Nevertheless, the mechanisms by which Mycobacterium tuberculosis (Mtb) induces HO 1 as well as how its expression is affected by HIV-1 coinfection and successful antitubercular therapy (ATT) are poorly understood. We found that HO-1 expression is markedly increased in rabbits, mice, and non-human primates during experimental Mtb infection and gradually decreased during ATT. In addition, we examined circulating concentrations of HO-1 in a cohort of 130 HIV-1 coinfected and uninfected pulmonary TB patients undergoing ATT to investigate changes in expression of this biomarker in relation to HIV-1 status, radiological disease severity, and treatment outcome. We found that plasma levels of HO-1 were elevated in untreated HIV-1 coinfected TB patients and correlated positively with HIV-1 viral load and negatively with CD4+ T cell count. In both HIV-1 coinfected and Mtb monoinfected patients, HO-1 levels were substantially reduced during successful TB treatment but not in those who experienced treatment failure or subsequently relapsed. To further delineate the molecular mechanisms involved in induction of HO-1 by Mtb, we performed a series of in vitro experiments using mouse and human macrophages. We found that Mtb-induced HO-1 expression requires NADPH oxidase-dependent reactive oxygen species production induced by the early secreted antigen ESAT-6, which in turn triggers nuclear translocation of the transcription factor NRF-2. These observations provide further insight into the utility of HO-1 as a biomarker of both disease and successful therapy in TB monoinfected and HIV-TB coinfected patients and reveal a previously undocumented pathway linking expression of the enzyme with oxidative stress. PMID- 28553290 TI - Fifth Percentile Cutoff Values for Antipneumococcal Polysaccharide and Anti Salmonella typhi Vi IgG Describe a Normal Polysaccharide Response. AB - BACKGROUND: Serotype-specific antibody responses to unconjugated pneumococcal polysaccharide vaccine (PPV) evaluated by a World Health Organization (WHO) standardized enzyme-linked immunosorbent assay (ELISA) are the gold standard for diagnosis of specific polysaccharide antibody deficiency (SAD). The American Academy of Allergy, Asthma and Immunology (AAAAI) has proposed guidelines to interpret the PPV response measured by ELISA, but these are based on limited evidence. Additionally, ELISA is costly and labor-intensive. Measurement of antibody response to Salmonella typhi (S. typhi) Vi vaccine and serum allohemagglutinins (AHA) have been suggested as alternatives. However, there are no large cohort studies and cutoff values are lacking. OBJECTIVE: To establish cutoff values for antipneumococcal polysaccharide antibody response, anti-S. typhi Vi antibody, and AHA. METHODS: One hundred healthy subjects (10-55 years) were vaccinated with PPV and S. typhi Vi vaccine. Blood samples were obtained prior to and 3-4 weeks after vaccination. Polysaccharide responses to 3 serotypes were measured by WHO ELISA and to 12 serotypes by an in-house bead-based multiplex assay. Anti-S. typhi Vi IgG were measured with a commercial ELISA kit. AHA were measured by agglutination method. RESULTS: Applying AAAAI criteria, 30% of healthy subjects had a SAD. Using serotype-specific fifth percentile (p5) cutoff values for postvaccination IgG and fold increase pre- over postvaccination, only 4% of subjects had SAD. One-sided 95% prediction intervals for anti-S. typhi Vi postvaccination IgG (>=11.2 U/ml) and fold increase (>=2) were established. Eight percent had a response to S. typhi Vi vaccine below these cutoffs. AHA titer p5 cutoffs were 1/2 for anti-B and 1/4 for anti-A. CONCLUSION: We establish reference cutoff values for interpretation of PPV response measured by bead-based assay, cutoff values for S. typhi Vi vaccine responses, and normal values for AHA. For the first time, the intraindividual consistency of all three methods is studied in a large cohort. PMID- 28553291 TI - Detrimental Impact of Microbiota-Accessible Carbohydrate-Deprived Diet on Gut and Immune Homeostasis: An Overview. AB - Dietary fibers are non-digestible polysaccharides functionally known as microbiota-accessible carbohydrates (MACs), present in inadequate amounts in the Western diet. MACs are a main source of energy for gut bacteria so the abundance and variety of MACs can modulate gut microbial composition and function. This, in turn, impacts host immunity and health. In preclinical studies, MAC-deprived diet and disruption of gut homeostasis aggravate the development of inflammatory diseases, such as allergies, infections, and autoimmune diseases. The present review provides a synopsis on the impact of a low-MAC diet on gut homeostasis or, more specifically, on gut microbiota, gut epithelium, and immune cells. PMID- 28553292 TI - ASCT2 (SLC1A5)-Deficient Mice Have Normal B-Cell Development, Proliferation, and Antibody Production. AB - SLC1A5 (solute carrier family 1, member 5) is a small neutral amino acid exchanger that is upregulated in rapidly proliferating lymphocytes but also in many primary human cancers. Furthermore, cancer cell lines have been shown to require SLC1A5 for their survival in vitro. One of SLC1A5's primary substrates is the immunomodulatory amino acid glutamine, which plays an important role in multiple key processes, such as energy supply, macromolecular synthesis, nucleotide biosynthesis, redox homeostasis, and resistance against oxidative stress. These processes are also essential to immune cells, including neutrophils, macrophages, B and T lymphocytes. We show here that mice with a stop codon in Slc1a5 have reduced glutamine uptake in activated lymphocytes and primary fibroblasts. B and T cell populations and maturation in resting mice were not affected by absence of SLC1A5. Antibody production in resting and immunized mice and the germinal center response to immunization were also found to be normal. SLC1A5 has been recently described as a novel target for the treatment of a variety of cancers, and our results indicate that inhibition of SLC1A5 in cancer therapy may be tolerated well by the immune system of cancer patients. PMID- 28553294 TI - In Vivo and In Vitro Study on the Efficacy of Terpinen-4-ol in Dextran Sulfate Sodium-Induced Mice Experimental Colitis. AB - The purpose of this study was to investigate the protective effects of Terpinen-4 ol (TER) on dextran sulfate sodium (DSS)-induced experimental colitis and clarify the possible mechanisms. In vivo, an acute colitis model was used to confirm the anti-inflammatory activity and the possible mechanisms of TER in C57BL/6 and NLRP3-/- mice. In vitro, we performed further study, using RAW264.7 cells and Caco-2 cells, to confirm the molecular mechanisms of TER on inflammatory response. In C57BL/6 mice, TER alleviated DSS-induced disease activity index (DAI), colon length shortening, colonic pathological damage, and myeloperoxidase (MPO) activities. The production of pro-inflammatory mediators was significantly decreased by TER. Furthermore, TER inhibited NF-kappaB and NLRP3 inflammasome activation. Surprisingly, TER reduced the plasmatic lipopolysaccharide (LPS) concentration and re-balanced Escherichia coli (E. coli) and Lactobacillus levels. In addition, TER prevented the impairment of colon epithelium barrier by regulating the expression of zonula occludens-1 and occludin. In vitro, the results showed that TER significantly suppressed NLRP3 inflammasome activation in LPS-stimulated RAW264.7 cells, as indicated by decreased expression of NLRP3 and caspase-1, and lowered interleukin-1beta secretion. In contrast, mice deficient for NLRP3 were less sensitive to DSS-induced acute colitis, and TER treatment exerted little protective effect on DSS-induced intestinal inflammation in NLRP3 /- mice. The protective effect of TER may be largely attributed to its inhibition of NLRP3 inflammasome activation in colon. Taken together, our findings showed that TER might be a potential agent for the treatment of ulcerative colitis. PMID- 28553295 TI - Developing an Integrated, Brief Biobehavioral HIV Prevention Intervention for High-Risk Drug Users in Treatment: The Process and Outcome of Formative Research. AB - To date, HIV prevention efforts have largely relied on singular strategies (e.g., behavioral or biomedical approaches alone) with modest HIV risk-reduction outcomes for people who use drugs (PWUD), many of whom experience a wide range of neurocognitive impairments (NCI). We report on the process and outcome of our formative research aimed at developing an integrated biobehavioral approach that incorporates innovative strategies to address the HIV prevention and cognitive needs of high-risk PWUD in drug treatment. Our formative work involved first adapting an evidence-based behavioral intervention-guided by the Assessment Decision-Administration-Production-Topical experts-Integration-Training-Testing model-and then combining the behavioral intervention with an evidence-based biomedical intervention for implementation among the target population. This process involved eliciting data through structured focus groups (FGs) with key stakeholders-members of the target population (n = 20) and treatment providers (n = 10). Analysis of FG data followed a thematic analysis approach utilizing several qualitative data analysis techniques, including inductive analysis and cross-case analysis. Based on all information, we integrated the adapted community-friendly health recovery program-a brief evidence-based HIV prevention behavioral intervention-with the evidence-based biomedical component [i.e., preexposure prophylaxis (PrEP)], an approach that incorporates innovative strategies to accommodate individuals with NCI. This combination approach-now called the biobehavioral community-friendly health recovery program-is designed to address HIV-related risk behaviors and PrEP uptake and adherence as experienced by many PWUD in treatment. This study provides a complete example of the process of selecting, adapting, and integrating the evidence-based interventions-taking into account both empirical evidence and input from target population members and target organization stakeholders. The resultant brief evidence-based biobehavioral approach could significantly advance primary prevention science by cost-effectively optimizing PrEP adherence and HIV risk reduction within common drug treatment settings. PMID- 28553297 TI - Agronomic Trait Variations and Ploidy Differentiation of Kiwiberries in Northwest China: Implication for Breeding. AB - Polyploid plants often have higher biomass and superior crop qualities. Breeders therefore search for crop germplasm with higher ploidy levels; however, whether higher ploidy levels are associated with better performance remains unclear. Actinidia arguta and related species, whose commercialized fruit are referred to as kiwiberries, harbor a series of ploidy races in nature, offering an opportunity to determine the link between ploidy levels and agronomic traits. In the present study, we determined the ploidy levels of A. arguta var. arguta, A. arguta var. giraldii, and A. melanandra in 16 natural populations using flow cytometry, and examined 31 trait variations in fruits, leaves and flowers by field observations, microscopic examination and laboratory analyses. Our results showed that octaploid and decaploid A. arguta var. giraldii had larger dimension of leaves than tetraploid A. arguta var. arguta and A. melanandra, but their fruits were significantly smaller. In addition, A. arguta var. giraldii (8x and 10x) had higher contents of nutrients such as ascorbic acid and amino acids; however, some important agronomic traits, including the content of total sugar and total acid, were significantly lower in the octaploids and decaploids. Moreover, octaploids and decaploids did not result in greater ecological adaptability for the challenging environments and climates. In conclusion, the differentiation of ecological adaptability and traits among natural kiwiberries' cytotypes suggested that higher ploidy levels are not inevitably advantageous in plants. The findings of A. arguta and related taxa in geographical distribution and agronomic trait variations will facilitate their germplasm domestication. PMID- 28553293 TI - A Role for Neutrophils in Viral Respiratory Disease. AB - Neutrophils are immune cells that are well known to be present during many types of lung diseases associated with acute respiratory distress syndrome (ARDS) and may contribute to acute lung injury. Neutrophils are poorly studied with respect to viral infection, and specifically to respiratory viral disease. Influenza A virus (IAV) infection is the cause of a respiratory disease that poses a significant global public health concern. Influenza disease presents as a relatively mild and self-limiting although highly pathogenic forms exist. Neutrophils increase in the respiratory tract during infection with mild seasonal IAV, moderate and severe epidemic IAV infection, and emerging highly pathogenic avian influenza (HPAI). During severe influenza pneumonia and HPAI infection, the number of neutrophils in the lower respiratory tract is correlated with disease severity. Thus, comparative analyses of the relationship between IAV infection and neutrophils provide insights into the relative contribution of host and viral factors that contribute to disease severity. Herein, we review the contribution of neutrophils to IAV disease pathogenesis and to other respiratory virus infections. PMID- 28553299 TI - Screening of Proximal and Interacting Proteins in Rice Protoplasts by Proximity Dependent Biotinylation. AB - Proximity-dependent biotin identification (BioID), which detects physiologically relevant proteins based on the proximity-dependent biotinylation process, has been successfully used in different organisms. In this report, we established the BioID system in rice protoplasts. Biotin ligase BirAG was obtained by removing a cryptic intron site in the BirA* gene when expressed in rice protoplasts. We found that protein biotinylation in rice protoplasts increased with increased expression levels of BirAG. The biotinylation effects can also be achieved by exogenous supplementation of high concentrations of biotin and long incubation time with protoplasts. By using this system, multiple proteins were identified that associated with and/or were proximate to OsFD2 in vivo. Our results suggest that BioID is a useful and generally applicable method to screen for both interacting and neighboring proteins in their native cellular environment in plant cell. PMID- 28553298 TI - Vegetable Grafting: The Implications of a Growing Agronomic Imperative for Vegetable Fruit Quality and Nutritive Value. AB - Grafting has become an imperative for intensive vegetable production since chlorofluorocarbon-based soil fumigants were banned from use on grounds of environmental protection. Compelled by this development, research into rootstock scion interaction has broadened the potential applications of grafting in the vegetable industry beyond aspects of soil phytopathology. Grafting has been increasingly tapped for cultivation under adverse environs posing abiotic and biotic stresses to vegetable crops, thus enabling expansion of commercial production onto otherwise under-exploited land. Vigorous rootstocks have been employed not only in the open field but also under protected cultivation where increase in productivity improves distribution of infrastructural and energy costs. Applications of grafting have expanded mainly in two families: the Cucurbitaceae and the Solanaceae, both of which comprise major vegetable crops. As the main drives behind the expansion of vegetable grafting have been the resistance to soilborne pathogens, tolerance to abiotic stresses and increase in yields, rootstock selection and breeding have accordingly conformed to the prevailing demand for improving productivity, arguably at the expense of fruit quality. It is, however, compelling to assess the qualitative implications of this growing agronomic practice for human nutrition. Problems of impaired vegetable fruit quality have not infrequently been associated with the practice of grafting. Accordingly, the aim of the current review is to reassess how the practice of grafting and the prevalence of particular types of commercial rootstocks influence vegetable fruit quality and, partly, storability. Physical, sensorial and bioactive aspects of quality are examined with respect to grafting for watermelon, melon, cucumber, tomato, eggplant, and pepper. The physiological mechanisms at play which mediate rootstock effects on scion performance are discussed in interpreting the implications of grafting for the configuration of vegetable fruit physicochemical quality and nutritive value. PMID- 28553296 TI - Use of Natural Diversity and Biotechnology to Increase the Quality and Nutritional Content of Tomato and Grape. AB - Improving fruit quality has become a major goal in plant breeding. Direct approaches to tackling fruit quality traits specifically linked to consumer preferences and environmental friendliness, such as improved flavor, nutraceutical compounds, and sustainability, have slowly been added to a breeder priority list that already includes traits like productivity, efficiency, and, especially, pest and disease control. Breeders already use molecular genetic tools to improve fruit quality although most advances have been made in producer and industrial quality standards. Furthermore, progress has largely been limited to simple agronomic traits easy-to-observe, whereas the vast majority of quality attributes, specifically those relating to flavor and nutrition, are complex and have mostly been neglected. Fortunately, wild germplasm, which is used for resistance against/tolerance of environmental stresses (including pathogens), is still available and harbors significant genetic variation for taste and health promoting traits. Similarly, heirloom/traditional varieties could be used to identify which genes contribute to flavor and health quality and, at the same time, serve as a good source of the best alleles for organoleptic quality improvement. Grape (Vitis vinifera L.) and tomato (Solanum lycopersicum L.) produce fleshy, berry-type fruits, among the most consumed in the world. Both have undergone important domestication and selection processes, that have dramatically reduced their genetic variability, and strongly standardized fruit traits. Moreover, more and more consumers are asking for sustainable production, incompatible with the wide range of chemical inputs. In the present paper, we review the genetic resources available to tomato/grape breeders, and the recent technological progresses that facilitate the identification of genes/alleles of interest within the natural or generated variability gene pool. These technologies include omics, high-throughput phenotyping/phenomics, and biotech approaches. Our review also covers a range of technologies used to transfer to tomato and grape those alleles considered of interest for fruit quality. These include traditional breeding, TILLING (Targeting Induced Local Lesions in Genomes), genetic engineering, or NPBT (New Plant Breeding Technologies). Altogether, the combined exploitation of genetic variability and innovative biotechnological tools may facilitate breeders to improve fruit quality tacking more into account the consumer standards and the needs to move forward into more sustainable farming practices. PMID- 28553300 TI - RUN1 and REN1 Pyramiding in Grapevine (Vitis vinifera cv. Crimson Seedless) Displays an Improved Defense Response Leading to Enhanced Resistance to Powdery Mildew (Erysiphe necator). AB - Fungal pathogens are the cause of the most common diseases in grapevine and among them powdery mildew represents a major focus for disease management. Different strategies for introgression of resistance in grapevine are currently undertaken in breeding programs. For example, introgression of several resistance genes (R) from different sources for making it more durable and also strengthening the plant defense response. Taking this into account, we cross-pollinated P09-105/34, a grapevine plant carrying both RUN1 and REN1 pyramided loci of resistance to Erysiphe necator inherited from a pseudo-backcrossing scheme with Muscadinia rotundifolia and Vitis vinifera 'Dzhandzhal Kara,' respectively, with the susceptible commercial table grape cv. 'Crimson Seedless.' We developed RUN1REN1 resistant genotypes through conventional breeding and identified them by marker assisted selection. The characterization of defense response showed a highly effective defense mechanism against powdery mildew in these plants. Our results reveal that RUN1REN1 grapevine plants display a robust defense response against E. necator, leading to unsuccessful fungal establishment with low penetration rate and poor hypha development. This resistance mechanism includes reactive oxygen species production, callose accumulation, programmed cell death induction and mainly VvSTS36 and VvPEN1 gene activation. RUN1REN1 plants have a great potential as new table grape cultivars with durable complete resistance to E. necator, and are valuable germplasm to be included in grape breeding programs to continue pyramiding with other sources of resistance to grapevine diseases. PMID- 28553301 TI - Ralstonia solanacearum and R. pseudosolanacearum on Eucalyptus: Opportunists or Primary Pathogens? AB - Ralstonia solanacearum and R. pseudosolanacearum are well known primary pathogens of herbaceous crops. Reports of wilt caused by these pathogens in tree species are limited other than on Eucalyptus species. Despite the widespread occurrence of so-called bacterial wilt on eucalypts in tropical and sub-tropical parts of Africa, Asia, and the Americas, there remain many contradictions relating to the disease. Our field observations over many years in most regions where the disease occurs on Eucalyptus show that it is always associated with trees that have been subjected to severe stress. The disease is typically diagnosed by immersing cut stems in water and observing bacterial streaming, but the identity of the bacteria within this suspension is seldom considered. To add to the confusion, pathogenicity tests on susceptible species or clones are rarely successful. When they do work, they are on small plants in greenhouse trials. It has become all to easy to attribute Eucalyptus death exclusively to Ralstonia infection. Our data strongly suggest that Ralstonia species and probably other bacteria are latent colonists commonly occurring in healthy and particularly clonally propagated eucalypts. The onset of stress factors provide the bacteria with an opportunity to develop. We believe that the resulting stress weakens the defense systems of the trees allowing Ralstonia and bacterial endophytes to proliferate. Overall our research suggests that R. solanacearum and R. pseudosolanacearum are not primary pathogens of Eucalyptus. Short of clear evidence that they are primary pathogens of Eucalyptus it is inappropriate to attribute this disease solely to infection by Ralstonia species. PMID- 28553302 TI - Transcriptome Analysis of Floral Buds Deciphered an Irregular Course of Meiosis in Polyploid Brassica rapa. AB - Polyploidy is a fundamental process in plant evolution. Understanding the polyploidy-associated effects on plant reproduction is essential for polyploid breeding program. In the present study, our cytological analysis firstly demonstrated that an overall course of meiosis was apparently distorted in the synthetic polyploid Brassica rapa in comparison with its diploid progenitor. To elucidate genetic basis of this irregular meiosis at a molecular level, the comparative RNA-seq analysis was further used to investigate differential genetic regulation of developing floral buds identified at meiosis between autotetraploid and diploid B. rapa. In total, compared to its diploid counterparts, among all 40,927 expressed genes revealed, 4,601 differentially expressed genes (DEGs) were identified in the floral buds of autotetraploid B. rapa, among which 288 DEGs annotated were involved in meiosis. Notably, DMC1 identified as one previously known meiosis-specific gene involved in inter-homologous chromosome dependent repair of DNA double stranded breaks (DSBs), was significantly down-regulated in autotetraploid B. rapa, which presumably contributed to abnormal progression during meiosis I. Although certain DEGs associated with RNA helicase, cell cycling, and somatic DNA repair were up-regulated after genome duplication, genes associated with meiotic DSB repair were significantly down-regulated. Furthermore, the expression of randomly selected DEGs by RNA-seq analysis was confirmed by quantitative real-time PCR analysis in both B. rapa and Arabidopsis thaliana. Our results firstly account for adverse effects of polyploidy on an entire course of meiosis at both cytological and transcriptomic levels, and allow for a comprehensive understanding of the uniformity and differences in the transcriptome of floral buds at meiosis between diploid and polyploid B. rapa as well. PMID- 28553303 TI - Phenylpyruvate Contributes to the Synthesis of Fragrant Benzenoid Phenylpropanoids in Petunia * hybrida Flowers. AB - Phenylalanine (Phe) is a precursor for a large group of plant specialized metabolites, including the fragrant volatile benzenoid-phenylpropanoids (BPs). In plants, the main pathway leading to production of Phe is via arogenate, while the pathway via phenylpyruvate (PPY) is considered merely an alternative route. Unlike plants, in most microorganisms the only pathway leading to the synthesis of Phe is via PPY. Here we studied the effect of increased PPY production in petunia on the formation of BPs volatiles and other specialized metabolites originating from Phe both in flowers and leaves. Stimulation of the pathway via PPY was achieved by transforming petunia with PheA* , a gene encoding a bacterial feedback insensitive bi-functional chorismate mutase/prephenate dehydratase enzyme. PheA* overexpression caused dramatic increase in the levels of flower BP volatiles such as phenylacetaldehyde, benzaldehyde, benzyl acetate, vanillin, and eugenol. All three BP pathways characterized in petunia flowers were stimulated in PheA* flowers. In contrast, PheA* overexpression had only a minor effect on the levels of amino acids and non-volatile metabolites both in the leaves and flowers. The one exception is a dramatic increase in the level of rosmarinate, a conjugate between Phe-derived caffeate and Tyr-derived 3,4 dihydroxyphenylacetate, in PheA* leaves. PheA* petunia flowers may serve as an excellent system for revealing the role of PPY in the production of BPs, including possible routes directly converting PPY to the fragrant volatiles. This study emphasizes the potential of the PPY route in achieving fragrance enhancement in flowering plants. PMID- 28553304 TI - Reference Gene Selection for qRT-PCR Normalization Analysis in kenaf (Hibiscus cannabinus L.) under Abiotic Stress and Hormonal Stimuli. AB - Kenaf (Hibiscus cannabinus L.), an environmental friendly and economic fiber crop, has a certain tolerance to abiotic stresses. Identification of reliable reference genes for transcript normalization of stress responsive genes expression by quantitative real-time PCR (qRT-PCR) is important for exploring the molecular mechanisms of plants response to abiotic stresses. In this study, nine candidate reference genes were cloned, and their expression stabilities were assessed in 132 abiotic stress and hormonal stimuli samples of kenaf using geNorm, NormFinder, and BestKeeper algorithms. Results revealed that HcPP2A (Protein phosphatase 2A) and HcACT7 (Actin 7) were the optimum reference genes across all samples; HcUBC (Ubiquitin-conjugating enzyme like protein) was the worst reference gene for transcript normalization. The reliability of the selected reference genes was further confirmed by evaluating the expression profile of HcWRKY28 gene at different stress durations. This work will benefit future studies on discovery of stress-tolerance genes and stress-signaling pathways in this important fiber crop. PMID- 28553305 TI - A Dominant Negative OsKAT2 Mutant Delays Light-Induced Stomatal Opening and Improves Drought Tolerance without Yield Penalty in Rice. AB - Stomata are the main gateways for water and air transport between leaves and the environment. Inward-rectifying potassium channels regulate photo-induced stomatal opening. Rice contains three inward rectifying shaker-like potassium channel proteins, OsKAT1, OsKAT2, and OsKAT3. Among these, only OsKAT2 is specifically expressed in guard cells. Here, we investigated the functions of OsKAT2 in stomatal regulation using three dominant negative mutant proteins, OsKAT2(T235R), OsKAT2(T285A) and OsKAT2(T285D), which are altered in amino acids in the channel pore and at a phosphorylation site. Yeast complementation and patch clamp assays showed that all three mutant proteins lost channel activity. However, among plants overexpressing these mutant proteins, only plants overexpressing OsKAT2(T235R) showed significantly less water loss than the control. Moreover, overexpression of this mutant protein led to delayed photo-induced stomatal opening and increased drought tolerance. Our results indicate that OsKAT2 is an inward- rectifying shaker-like potassium channel that mainly functions in stomatal opening. Interestingly, overexpression of OsKAT2(T235R) did not cause serious defects in growth or yield in rice, suggesting that OsKAT2 is a potential target for engineering plants with improved drought tolerance without yield penalty. PMID- 28553306 TI - Novel Sources of Stripe Rust Resistance Identified by Genome-Wide Association Mapping in Ethiopian Durum Wheat (Triticum turgidum ssp. durum). AB - Stripe rust of wheat, caused by Puccinia striiformis f. sp. tritici (Pst), is a global concern for wheat production, and has been increasingly destructive in Ethiopia, as well as in the United States and in many other countries. As Ethiopia has a long history of stripe rust epidemics, its native wheat germplasm harbors potentially valuable resistance loci. Moreover, the Ethiopian germplasm has been historically underutilized in breeding of modern wheat worldwide and thus the resistance alleles from the Ethiopian germplasm represent potentially novel sources. The objective of this study was to identify loci conferring resistance to predominant Pst races in Ethiopia and the United States. Using a high-density 90 K wheat single nucleotide polymorphism array, a genome-wide association analysis (GWAS) was conducted on 182 durum wheat landrace accessions and contemporary varieties originating from Ethiopia. Landraces were detected to be more resistant at the seedling stage while cultivars were more resistant at the adult-plant stages. GWAS identified 68 loci associated with seedling resistance to one or more races. Six loci on chromosome arms 1AS, 1BS, 3AS, 4BL, and 5BL were associated with resistance against at least two races at the seedling stage, and five loci were previously undocumented. GWAS analysis of field resistance reactions identified 12 loci associated with resistance on chromosomes 1A, 1B, 2BS, 3BL, 4AL, 4B and 5AL, which were detected in at least two of six field screening nurseries at the adult-plant stage. Comparison with previously mapped resistance loci indicates that six of the 12 resistance loci are newly documented. This study reports effective sources of resistance to contemporary races in Ethiopia and the United States and reveals that Ethiopian durum wheat landraces are abundant in novel Pst resistance loci that may be transferred into adapted cultivars to provide resistance against Pst. PMID- 28553308 TI - Identification of Putative Genes Involved in Limonoids Biosynthesis in Citrus by Comparative Transcriptomic Analysis. AB - Limonoids produced by citrus are a group of highly bioactive secondary metabolites which provide health benefits for humans. Currently there is a lack of information derived from research on the genetic mechanisms controlling the biosynthesis of limonoids, which has limited the improvement of citrus for high production of limonoids. In this study, the transcriptome sequences of leaves, phloems and seeds of pummelo (Citrus grandis (L.) Osbeck) at different development stages with variances in limonoids contents were used for digital gene expression profiling analysis in order to identify the genes corresponding to the biosynthesis of limonoids. Pair-wise comparison of transcriptional profiles between different tissues identified 924 differentially expressed genes commonly shared between them. Expression pattern analysis suggested that 382 genes from three conjunctive groups of K-means clustering could be possibly related to the biosynthesis of limonoids. Correlation analysis with the samples from different genotypes, and different developing tissues of the citrus revealed that the expression of 15 candidate genes were highly correlated with the contents of limonoids. Among them, the cytochrome P450s (CYP450s) and transcriptional factor MYB demonstrated significantly high correlation coefficients, which indicated the importance of those genes on the biosynthesis of limonoids. CiOSC gene encoding the critical enzyme oxidosqualene cyclase (OSC) for biosynthesis of the precursor of triterpene scaffolds was found positively corresponding to the accumulation of limonoids during the development of seeds. Suppressing the expression of CiOSC with VIGS (Virus-induced gene silencing) demonstrated that the level of gene silencing was significantly correlated to the reduction of limonoids contents. The results indicated that the CiOSC gene plays a pivotal role in biosynthesis of limonoids. PMID- 28553307 TI - GmWRKY31 and GmHDL56 Enhances Resistance to Phytophthora sojae by Regulating Defense-Related Gene Expression in Soybean. AB - Phytophthora root and stem rot of soybean [Glycine max (L.) Merr.] caused by the oomycete Phytophthora sojae, is a destructive disease worldwide. The molecular mechanism of the soybean response to P. sojae is largely unclear. We report a novel WRKY transcription factor (TF) in soybean, GmWRKY31, in the host response to P. sojae. Overexpression and RNA interference analysis demonstrated that GmWRKY31 enhanced resistance to P. sojae in transgenic soybean plants. GmWRKY31 was targeted to the nucleus, where it bound to the W-box and acted as an activator of gene transcription. Moreover, we determined that GmWRKY31 physically interacted with GmHDL56, which improved resistance to P. sojae in transgenic soybean roots. GmWRKY31 and GmHDL56 shared a common target GmNPR1 which was induced by P. sojae. Overexpression and RNA interference analysis demonstrated that GmNPR1 enhanced resistance to P. sojae in transgenic soybean plants. Several pathogenesis-related (PR) genes were constitutively activated, including GmPR1a, GmPR2, GmPR3, GmPR4, GmPR5a, and GmPR10, in soybean plants overexpressing GmNPR1 transcripts. By contrast, the induction of PR genes was compromised in transgenic GmNPR1-RNAi lines. Taken together, these findings suggested that the interaction between GmWRKY31 and GmHDL56 enhances resistance to P. sojae by regulating defense-related gene expression in soybean. PMID- 28553309 TI - The TOR Pathway Is Involved in Adventitious Root Formation in Arabidopsis and Potato. AB - In the agriculture industry, adventitious root formation is a core issue of plants asexual propagation. However, the underlying molecular mechanism of adventitious root formation is far beyond understanding. In present study we found that target of rapamycin (TOR) signaling plays a key role in adventitious root formation in potato and Arabidopsis. The core components of TOR complex including TOR, RAPTOR, and LST8 are highly conserved in potato, but the seedlings of potato are insensitive to rapamycin, implying FK506 Binding Protein 12 KD (FKBP12) lost the function to bridge the interaction of rapamycin and TOR in potato. To dissect TOR signaling in potato, the rapamycin hypersensitive potato plants (BP12-OE) were engineered by introducing yeast FKBP12 (ScFKBP12) into potato. We found that rapamycin can significantly attenuate the capability of adventitious root formation in BP12-OE potatoes. KU63794 (KU, an active-site TOR inhibitor) combined with rapamycin can more significantly suppress adventitious root formation of BP12-OE potato than the single treatments, such as KU63794 or rapamycin, indicating its synergistic inhibitory effects on potato adventitious root formation. Furthermore, RNA-seq data showed that many genes associated with auxin signaling pathway were altered when BP12-OE potato seedlings were treated with rapamycin + KU, suggesting that TOR may play a major role in adventitious root formation via auxin signaling. The auxin receptor mutant tir1 was sensitive to TOR inhibitors and the double and quadruple mutants including tir1afb2, tir1afb3, and tir1afb1afb2afb3 displayed more sensitive to asTORis than single mutant tir1. Consistently, overexpression of AtTIR1 in Arabidopsis and potato can partially overcome the inhibitory effect of asTORis and promote adventitious root formation under asTORis treatments. These observations suggest that TOR signaling regulates adventitious root formation by mediating auxin signaling in Arabidopsis and potato. PMID- 28553310 TI - Effects of Melatonin on Anti-oxidative Systems and Photosystem II in Cold Stressed Rice Seedlings. AB - Melatonin (N-acetyl-5-methoxytryptamine) plays important role in multiple plant developmental processes and stress responses. We investigated the possible mediatory role of melatonin in growth, photosynthesis, and the response to cold stress in rice by using three different experiments: soaking seed; immersing roots, and spraying to leaves with 0, 20, or 100 MUM melatonin. After 6 days of cold stress, the growth of rice seedlings was significantly inhibited, but this inhibition was alleviated by exogenous melatonin. Furthermore, exogenous melatonin pretreatment alleviated the accumulation of reactive oxygen species, malondialdehyde and cell death induced by cold stress. Melatonin pretreatment also relieved the stress-induced inhibitions to photosynthesis and photosystem II activities. Further investigations showed that, antioxidant enzyme activities and non-enzymatic antioxidant levels were increased by melatonin pretreatments. The treatment methods of seed soaking and root immersion were more effective in improving cold stress resistance than the spraying method. The results also indicated the dose-dependent response of melatonin on rice physiological, biochemical, and photosynthetic parameters. PMID- 28553311 TI - Corrigendum: New Insights on Leucine-Rich Repeats Receptor-Like Kinase Orthologous Relationships in Angiosperms. AB - [This corrects the article on p. 381 in vol. 8, PMID: 28424707.]. PMID- 28553312 TI - Gender Differences in Verbal and Visuospatial Working Memory Tasks in Patients with Mild Cognitive Impairment and Alzheimer Disease. AB - BACKGROUND/AIMS: To date, there are few studies on gender differences in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). In the present study, the existence of differences between sexes in verbal and visuospatial working memory tasks in the evolution of cognitive and pathological aging was examined. METHOD: Ninety participants took part in this study: 30 AD, 30 MCI, and 30 healthy elderly participants (50% men and 50% women). RESULTS: There were no significant differences between men and women with AD in visuospatial tasks, whereas these differences were found within the MCI group, with the average of men achieving significantly higher results than women. In verbal tasks, there were no differences between sexes for any of the groups. CONCLUSION: Execution in visuospatial tasks tends to depend on gender, whereas this does not occur for verbal tasks. PMID- 28553314 TI - Effect of the Sonas Programme on Communication in People with Dementia: A Randomized Controlled Trial. AB - BACKGROUND: Strategies to improve communication in people with dementia are warranted. We examined the effect of the Sonas programme on communication ability in persons with moderate to severe dementia. METHODS: A 24-week 3-armed (Sonas, reading, and control group) randomized controlled trial including 120 nursing home residents with dementia was conducted; 105 completed the follow-up assessments. The main outcome was change in communication abilities measured by the Holden Communication Scale (HCS). RESULTS: We found no overall significant effect of the Sonas programme with regard to communication ability as measured by the HCS. However, an effect between the Sonas group and the reading group and between the Sonas group and the control group from T0 to T1 and T2 was found, as well as a significant improvement in communication in the Sonas group. Among people with severe dementia, the Sonas group scored significantly better on the HCS compared to the reading group after 12 weeks, but not after 24 weeks. CONCLUSION: This study failed to document an overall effect of the Sonas programme on communication; however, the findings indicate that the Sonas programme has a significant effect on communication among those with severe dementia. PMID- 28553313 TI - Associations between Pain and Quality of Life in Severe Dementia: A Norwegian Cross-Sectional Study. AB - BACKGROUND/AIMS: Many variables influence the quality of life in older adults with dementia. We aim to quantify how the relationship between pain and quality of life in nursing home residents with severe dementia can be explained by neuropsychiatric symptoms, depressive symptoms, and activities of daily living. METHODS: This article presents cross-sectional baseline data from a cluster randomised controlled trial. RESULTS: The total and direct effects of pain on quality of life were statistically significant. Both neuropsychiatric and depressive symptoms partially mediated the relationship between pain and quality of life. Activities of daily living acted as a mediator only when modelled together with depressive symptoms. CONCLUSION: Pain, neuropsychiatric symptoms, and depressive symptoms appear to be important factors that influence the quality of life for nursing home residents with severe dementia. Therefore, multidimensional interventions may be beneficial for maintaining or improving quality of life in this population. PMID- 28553315 TI - Improving CKD Diagnosis and Blood Pressure Control in Primary Care: A Tailored Multifaceted Quality Improvement Programme. AB - BACKGROUND: Chronic kidney disease (CKD) is a worldwide public health issue. From 2009 to 2014, the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care Greater Manchester (NIHR CLAHRC GM) in England ran 4 phased, 12-month quality improvement (QI) projects with 49 primary care practices in GM. Two measureable aims were set - halve undiagnosed CKD in participating practices using modelled estimates of prevalence; and optimise blood pressure (BP) control (<140/90 mm Hg in CKD patients without proteinuria; <130/80 mm Hg in CKD patients with proteinuria) for 75% of recorded cases of CKD. The 4 projects ran as follows: P1 = Project 1 with 19 practices (September 2009 to September 2010), P2 = Project 2 with 11 practices (March 2011 to March 2012), P3 = Project 3 with 12 practices (September 2012 to October 2013), and P4 = Project 4 with 7 practices (April 2013 to March 2014). METHODS: Multifaceted intervention approaches were tailored based on a contextual analysis of practice support needs. Data were collected from practices by facilitators at baseline and again at project close, with self-reported data regularly requested from practices throughout the projects. RESULTS: Halving undiagnosed CKD as per aim was exceeded in 3 of the 4 projects. The optimising BP aim was met in 2 projects. Total CKD cases after the programme increased by 2,347 (27%) from baseline to 10,968 in a total adult population (aged >=18 years) of 231,568. The percentage of patients who managed to appropriate BP targets increased from 34 to 74% (P1), from 60 to 83% (P2), from 68 to 71% (P3), and from 63 to 76% (P4). In nonproteinuric CKD patients, 88, 90, 89, and 91%, respectively, achieved a target BP of <140/90 mm Hg. In proteinuric CKD patients, 69, 46, 48, and 45%, respectively, achieved a tighter target of <130/80 mm Hg. Analysis of national data over similar timeframes indicated that practices participating in the programme achieved higher CKD detection rates. CONCLUSIONS: Participating practices identified large numbers of "missing" CKD patients with comparator data showing they outperformed non-QI practices locally and nationally over similar timeframes. Improved BP control also occurred through this intervention, but overall achievement of the tighter BP target in proteinuric patients was notably less. PMID- 28553316 TI - MicroRNA-155 and Anti-Mullerian Hormone: New Potential Markers of Subfertility in Men with Chronic Kidney Disease. AB - BACKGROUND/AIMS: Men with terminal renal failure are often infertile. Anti mullerian hormone (AMH), a marker of Sertoli cell function, is decreased among men with chronic kidney disease (CKD). Recently, a microRNA, miR-155, has been shown to be a potential marker for subfertility. We studied miR-155 and semen parameters in patients with CKD who were not yet on dialysis. We also aimed to study possible associations between AMH, miR-155, and semen parameters to evaluate them as markers of fertility. METHODS: Thirty male patients with CKD 1-4 as well as 18 healthy controls were enrolled. RESULTS: Serum levels of miR-155 were significantly higher among men with CKD stages 1-2 (4.51 +/- 3.81 [p = 0.01]) and stages 3-4 (2.75 +/- 1.77 [p = 0.006]) than in controls (1.09 +/- 0.44). Sperm concentration was significantly lower among men with CKD 3-4 (42 +/- 29) *106/mL compared to controls (88 +/- 42) *106/mL (p = 0.011). High levels of miR-155 were associated with a relatively low sperm concentration (p = 0.02) and with a low total sperm number (p = 0.005). Low AMH levels were associated with a decreased percentage of motile sperm cells (p = 0.02). CONCLUSIONS: We conclude that men with stage 3-4 CKD had lower sperm concentrations than healthy fertile men and that increased serum miR-155 in men with stage 1-4 CKD was associated with semen parameters that indicate subfertility. Low AMH levels were associated with a low percentage of the total number of motile sperm cells. miR-155 and AMH may be potential markers of subfertility in men with CKD. PMID- 28553317 TI - Meta Analysis of Human AlzGene Database: Benefits and Limitations of Using C. elegans for the Study of Alzheimer's Disease and Co-morbid Conditions. AB - Human genome-wide association studies (GWAS) and linkage studies have identified 695 genes associated with Alzheimer's disease (AD), the vast majority of which are associated with late-onset AD. Although orthologs of these AD genes have been studied in several model species, orthologs in the nematode, Caenorhabditis elegans, remain incompletely identified, with orthologs to only 17 AD-related genes identified in the C. elegans database, WormBase. Therefore, we performed a comprehensive search for additional C. elegans orthologs of AD genes using well established programs, including OrthoList, which utilizes four ontology prediction programs. We also validated 680 of the AD genes as a unique gene from the AlzGene database, including 431 genes (63%) that are predicted to have orthologs in C. elegans. Another 178 human AD genes (26%) were associated with one or more other neurological diseases, including amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and schizophrenia. Of these, there were 105 genes (59%) with orthologs in C. elegans. Interestingly, three AD genes (ACE, TNF, and MTHFR) were associated with all four of the other neurological diseases. The human AD genes were enriched in three major ontology pathway groups, including lipoprotein metabolism, hemostasis, and extracellular matrix organizations, as well as in pathways that are amyloid related (NOTCH signaling) and associated with neural (neurotransmitter clearance) and immune (advanced glycation end-product receptor signaling and TRAF6-NF-kappaB) systems. Thus, the results from this study provide a potentially useful system for assessing comorbidities that may be associated with late-onset AD and other neurological conditions. The technical advantages and limitations of the ortholog searches are further discussed. PMID- 28553318 TI - Non-coding RNAs in the Ovarian Follicle. AB - The mammalian ovarian follicle is the complex reproductive unit comprising germ cell, somatic cells (Cumulus and Granulosa cells), and follicular fluid (FF): paracrine communication among the different cell types through FF ensures the development of a mature oocyte ready for fertilization. This paper is focused on non-coding RNAs in ovarian follicles and their predicted role in the pathways involved in oocyte growth and maturation. We determined the expression profiles of microRNAs in human oocytes and FF by high-throughput analysis and identified 267 microRNAs in FF and 176 in oocytes. Most of these were FF microRNAs, while 9 were oocyte specific. By bioinformatic analysis, independently performed on FF and oocyte microRNAs, we identified the most significant Biological Processes and the pathways regulated by their validated targets. We found many pathways shared between the two compartments and some specific for oocyte microRNAs. Moreover, we found 41 long non-coding RNAs able to interact with oocyte microRNAs and potentially involved in the regulation of folliculogenesis. These data are important in basic reproductive research and could also be useful for clinical applications. In fact, the characterization of non-coding RNAs in ovarian follicles could improve reproductive disease diagnosis, provide biomarkers of oocyte quality in Assisted Reproductive Treatment, and allow the development of therapies for infertility disorders. PMID- 28553319 TI - Heterogeneous populations of neural stem cells contribute to myelin repair. AB - As ingenious as nature's invention of myelin sheaths within the mammalian nervous system is, as fatal can be damage to this specialized lipid structure. Long-term loss of electrical insulation and of further supportive functions myelin provides to axons, as seen in demyelinating diseases such as multiple sclerosis (MS), leads to neurodegeneration and results in progressive disabilities. Multiple lines of evidence have demonstrated the increasing inability of oligodendrocyte precursor cells (OPCs) to replace lost oligodendrocytes (OLs) in order to restore lost myelin. Much research has been dedicated to reveal potential reasons for this regeneration deficit but despite promising approaches no remyelination promoting drugs have successfully been developed yet. In addition to OPCs neural stem cells of the adult central nervous system also hold a high potential to generate myelinating OLs. There are at least two neural stem cell niches in the brain, the subventricular zone lining the lateral ventricles and the subgranular zone of the dentate gyrus, and an additional source of neural stem cells has been located in the central canal of the spinal cord. While a substantial body of literature has described their neurogenic capacity, still little is known about the oligodendrogenic potential of these cells, even if some animal studies have provided proof of their contribution to remyelination. In this review, we summarize and discuss these studies, taking into account the different niches, the heterogeneity within and between stem cell niches and present current strategies of how to promote stem cell-mediated myelin repair. PMID- 28553321 TI - RhoA as a target to promote neuronal survival and axon regeneration. AB - Paralysis following spinal cord injury (SCI) is due to failure of axonal regeneration. It is believed that the capacities of neurons to regrow their axons are due partly to their intrinsic characteristics, which in turn are greatly influenced by several types of inhibitory molecules that are present, or even increased in the extracellular environment of the injured spinal cord. Many of these inhibitory molecules have been studied extensively in recent years. It has been suggested that the small GTPase RhoA is an intracellular convergence point for signaling by these extracellular inhibitory molecules, but due to the complexity of the central nervous system (CNS) in mammals, and the limitation of pharmacological tools, the specific roles of RhoA are unclear. By exploiting the anatomical and technical advantages of the lamprey CNS, we recently demonstrated that RhoA knockdown promotes true axon regeneration through the lesion site after SCI. In addition, we found that RhoA knockdown protects the large, identified reticulospinal neurons from apoptosis after their axons were axotomized in spinal cord. Therefore, manipulation of the RhoA signaling pathway may be an important approach in the development of treatments that are both neuroprotective and axon regeneration-promoting, to enhance functional recovery after SCI. PMID- 28553320 TI - Axon degeneration: make the Schwann cell great again. AB - Axonal degeneration is a pivotal feature of many neurodegenerative conditions and substantially accounts for neurological morbidity. A widely used experimental model to study the mechanisms of axonal degeneration is Wallerian degeneration (WD), which occurs after acute axonal injury. In the peripheral nervous system (PNS), WD is characterized by swift dismantling and clearance of injured axons with their myelin sheaths. This is a prerequisite for successful axonal regeneration. In the central nervous system (CNS), WD is much slower, which significantly contributes to failed axonal regeneration. Although it is well documented that Schwann cells (SCs) have a critical role in the regenerative potential of the PNS, to date we have only scarce knowledge as to how SCs 'sense' axonal injury and immediately respond to it. In this regard, it remains unknown as to whether SCs play the role of a passive bystander or an active director during the execution of the highly orchestrated disintegration program of axons. Older reports, together with more recent studies, suggest that SCs mount dynamic injury responses minutes after axonal injury, long before axonal breakdown occurs. The swift SC response to axonal injury could play either a pro degenerative role, or alternatively a supportive role, to the integrity of distressed axons that have not yet committed to degenerate. Indeed, supporting the latter concept, recent findings in a chronic PNS neurodegeneration model indicate that deactivation of a key molecule promoting SC injury responses exacerbates axonal loss. If this holds true in a broader spectrum of conditions, it may provide the grounds for the development of new glia-centric therapeutic approaches to counteract axonal loss. PMID- 28553323 TI - Phosphatidylserine improves axonal transport by inhibition of HDAC and has potential in treatment of neurodegenerative diseases. AB - Familial dysautonomia (FD) is a rare children neurodegenerative disease caused due to a point mutation in the IKBKAP gene that results in decreased IKK complex associated protein (IKAP) protein production. The disease affects mostly the dorsal root ganglion (DRG) and the sympathetic ganglion. Recently, we found that the molecular mechanisms underlying neurodegeneration in FD patients are defects in axonal transport of nerve growth factors and microtubule stability in the DRG. Neurons are highly polarized cells with very long axons. In order to survive and maintain proper function, neurons depend on transport of proteins and other cellular components from the neuronal body along the axons. We further demonstrated that IKAP is necessary for axon maintenance and showed that phosphatidylserine acts as an HDAC6 inhibitor to rescue neuronal function in FD cells. In this review, we will highlight our latest research findings. PMID- 28553322 TI - The reasons for end-to-side coaptation: how does lateral axon sprouting work? AB - Nerve fibers are attracted by sutureless end-to-side nerve coaptation into the recipient nerve. Opening a window in the epineurium enhances axon attraction and myelination. The authors analyze the features of nerve repair by end-to-side coaptation. They highlight the known mechanisms of axon sprouting and different hypotheses of start up signals (presence or absence of an epineurial window, role of Schwann cells, signaling from the distal trunk). The clinical literature is also presented and differences between experimental and clinical applications are pointed out. The authors propose their point of view and perspectives deriving from recent experimental and clinical experiences. PMID- 28553326 TI - Endothelial progenitor cells as a therapeutic option in intracerebral hemorrhage. AB - Intracerebral hemorrhage (ICH) is the most severe cerebrovascular disease, which represents a leading cause of death and disability in developed countries. However, therapeutic options are limited, so is mandatory to investigate repairing processes after stroke in order to develop new therapeutic strategies able to promote brain repair processes. Therapeutic angiogenesis and vasculogenesis hold promise to improve outcome of ICH patients. In this regard, circulating endothelial progenitor cells (EPCs) have recently been suggested to be a marker of vascular risk and endothelial function. Moreover, EPC levels have been associated with good neurological and functional outcome as well as reduced residual hematoma volume in ICH patients. Finally, experimental and clinical studies indicate that EPC might mediate endothelial cell regeneration and neovascularization. Therefore, EPC-based therapy could be an excellent therapeutic option in ICH. In this mini-review, we discuss the present status of knowledge about the possible therapeutic role of EPCs in ICH, molecular mechanisms, and the future perspectives and strategies for their use in clinical practice. PMID- 28553324 TI - The complexities underlying age-related macular degeneration: could amyloid beta play an important role? AB - Age-related macular degeneration (AMD) causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests from midlife onwards to affect a large proportion of the elderly. Although genetic as well as non genetic/environmental risks are recognized, its complex aetiology makes it difficult to identify susceptibility, or indeed what type of AMD develops or how quickly it progresses in different individuals. Here we summarize the literature describing how the Alzheimer's-linked amyloid beta (Abeta) group of misfolding proteins accumulate in the retina. The discovery of this key driver of Alzheimer's disease in the senescent retina was unexpected and surprising, enabling an altogether different perspective of AMD. We argue that Abeta fundamentally differs from other substances which accumulate in the ageing retina, and discuss our latest findings from a mouse model in which physiological amounts of Abeta were subretinally-injected to recapitulate salient features of early AMD within a short period. Our discoveries as well as those of others suggest the pattern of Abeta accumulation and pathology in donor aged/AMD tissues are closely reproduced in mice, including late-stage AMD phenotypes, which makes them highly attractive to study dynamic aspects of Abeta-mediated retinopathy. Furthermore, we discuss our findings revealing how Abeta behaves at single-cell resolution, and consider the long-term implications for neuroretinal function. We propose Abeta as a key element in switching to a diseased retinal phenotype, which is now being used as a biomarker for late-stage AMD. PMID- 28553327 TI - A tale of motor neurons and CD4+ T cells: moving forward by looking back. AB - Amyotrophic lateral sclerosis (ALS) is a fatal progressive disorder characterized by the selective degeneration of motor neurons (MN). The impact of peripheral immune status on disease progression and MN survival is becoming increasingly recognized in the ALS research field. In this review, we briefly discuss findings from mouse models of peripheral nerve injury and immunodeficiency to understand how the immune system regulates MN survival. We extend these observations to similar studies in the widely used superoxide dismutase 1 (SOD1) mouse model of ALS. Last, we present future hypotheses to identify potential causative factors that lead to immune dysregulation in ALS. The lessons from preceding work in this area offer new exciting directions to bridge the gap in our current understanding of immune-mediated neuroprotection in ALS. PMID- 28553328 TI - Analyzing the role of extracellular matrix during nervous system development to advance new regenerative strategies. PMID- 28553325 TI - Neurotrophic factors in Alzheimer's and Parkinson's diseases: implications for pathogenesis and therapy. AB - Neurotrophic factors comprise essential secreted proteins that have several functions in neural and non-neural tissues, mediating the development, survival and maintenance of peripheral and central nervous system. Therefore, neurotrophic factor issue has been extensively investigated into the context of neurodegenerative diseases. Alzheimer's disease and Parkinson's disease show changes in the regulation of specific neurotrophic factors and their receptors, which appear to be critical for neuronal degeneration. Indeed, neurotrophic factors prevent cell death in degenerative processes and can enhance the growth and function of affected neurons in these disorders. Based on recent reports, this review discusses the main findings related to the neurotrophic factor support - mainly brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor - in the survival, proliferation and maturation of affected neurons in Alzheimer's disease and Parkinson's disease as well as their putative application as new therapeutic approach for these diseases management. PMID- 28553329 TI - Nerves and hydrogen peroxide: how old enemies become new friends. PMID- 28553330 TI - Ghosts in the shell: identification of microglia in the human central nervous system by P2Y12 receptor. PMID- 28553331 TI - RhoA/ROCK activation in major pelvic ganglion mediates caspase-3 dependent nitrergic neuronal apoptosis following cavernous nerve injury. PMID- 28553332 TI - Why and how does light therapy offer neuroprotection in Parkinson's disease? PMID- 28553333 TI - Delivery of therapeutics to posterior eye segment: cell-encapsulating systems. PMID- 28553334 TI - Role of the STRIPAK complex and the Hippo pathway in synaptic terminal formation. PMID- 28553335 TI - Regulatory role of microRNA on inflammatory responses of diabetic retinopathy. PMID- 28553336 TI - Food, polyphenols and neuroprotection. PMID- 28553337 TI - Recent advances and future directions for the pharmacogenetic basis of anti-VEGF treatment response in neovascular age-related macular degeneration. PMID- 28553338 TI - Translational research in early neuroscience careers of high school students. PMID- 28553339 TI - Tibolone modulates neuronal plasticity through regulating Tau, GSK3beta/Akt/PI3K pathway and CDK5 p35/p25 complexes in the hippocampus of aged male mice. AB - Aging is a key risk factor for cognitive decline and age-related neurodegenerative disorders. Also, an age-related decrease in sex steroid hormones may have a negative impact on the formation of neurofibrillary tangles (NFTs); these hormones can regulate Tau phosphorylation and the principal kinase GSK3beta involved in this process. Hormone replacement therapy decreases NFTs, but it increases the risk of some types of cancer. However, other synthetic hormones such as tibolone (TIB) have been used for hormone replacement therapy. The aim of this work was to evaluate the long-term effects of TIB (0.01 mg/kg and 1 mg/kg, intragastrically for 12 weeks) on the content of total and hyperphosphorylated Tau (PHF-1) proteins and the regulation of GSK3beta/Akt/PI3K pathway and CDK5/p35/p25 complexes in the hippocampus of aged male mice. We observed that the content of PHF-1 decreased with TIB administration. In contrast, no changes were observed in the active form of GSK3beta or PI3K. TIB decreased the expression of the total and phosphorylated form of Akt while increased that of p110 and p85. The content of CDK5 was differentially modified with TIB: it was increased at low doses and decreased at high doses. When we analyzed the content of CDK5 activators, an increase was found on p35; however, the content of p25 decreased with administration of low dose of TIB. Our results suggest a possible mechanism of action of TIB in the hippocampus of aged male mice. Through the regulation of Tau and GSK3beta/Akt/PI3K pathway, and CDK5/p35/p25 complexes, TIB may modulate neuronal plasticity and regulate learning and memory processes. PMID- 28553341 TI - Diffusion tensor imaging assesses white matter injury in neonates with hypoxic ischemic encephalopathy. AB - With improvements in care of at-risk neonates, more and more children survive. This makes it increasingly important to assess, soon after birth, the prognosis of children with hypoxic-ischemic encephalopathy. Computed tomography, ultrasound, and conventional magnetic resonance imaging are helpful to diagnose brain injury, but cannot quantify white matter damage. In this study, ten full term infants without brain injury and twenty-two full-term neonates with hypoxic ischemic encephalopathy (14 moderate cases and 8 severe cases) underwent diffusion tensor imaging to assess its feasibility in evaluating white matter damage in this condition. Results demonstrated that fractional anisotropy, voxel volume, and number of fiber bundles were different in some brain areas between infants with brain injury and those without brain injury. The correlation between fractional anisotropy values and neonatal behavioral neurological assessment scores was closest in the posterior limbs of the internal capsule. We conclude that diffusion tensor imaging can quantify white matter injury in neonates with hypoxic-ischemic encephalopathy. PMID- 28553340 TI - Aerobic exercise combined with huwentoxin-I mitigates chronic cerebral ischemia injury. AB - Ca2+ channel blockers have been shown to protect neurons from ischemia, and aerobic exercise has significant protective effects on a variety of chronic diseases. The present study injected huwentoxin-I (HWTX-I), a spider peptide toxin that blocks Ca2+ channels, into the caudal vein of a chronic cerebral ischemia mouse model, once every 2 days, for a total of 15 injections. During this time, a subgroup of mice was subjected to treadmill exercise for 5 weeks. Results showed amelioration of cortical injury and improved neurological function in mice with chronic cerebral ischemia in the HWTX-I + aerobic exercise group. The combined effects of HWTX-I and exercise were superior to HWTX-I or aerobic exercise alone. HWTX-I effectively activated the Notch signal transduction pathway in brain tissue. Aerobic exercise up-regulated synaptophysin mRNA expression. These results demonstrated that aerobic exercise, in combination with HWTX-I, effectively relieved neuronal injury induced by chronic cerebral ischemia via the Notch signaling pathway and promoting synaptic regeneration. PMID- 28553342 TI - Low frequency repetitive transcranial magnetic stimulation improves motor dysfunction after cerebral infarction. AB - Low frequency (<= 1 Hz) repetitive transcranial magnetic stimulation (rTMS) can affect the excitability of the cerebral cortex and synaptic plasticity. Although this is a common method for clinical treatment of cerebral infarction, whether it promotes the recovery of motor function remains controversial. Twenty patients with cerebral infarction combined with hemiparalysis were equally and randomly divided into a low frequency rTMS group and a control group. The patients in the low frequency rTMS group were given 1-Hz rTMS to the contralateral primary motor cortex with a stimulus intensity of 90% motor threshold, 30 minutes/day. The patients in the control group were given sham stimulation. After 14 days of treatment, clinical function scores (National Institute of Health Stroke Scale, Barthel Index, and Fugl-Meyer Assessment) improved significantly in the low frequency rTMS group, and the effects were better than that in the control group. We conclude that low frequency (1 Hz) rTMS for 14 days can help improve motor function after cerebral infarction. PMID- 28553343 TI - Magnetic resonance imaging-three-dimensional printing technology fabricates customized scaffolds for brain tissue engineering. AB - Conventional fabrication methods lack the ability to control both macro- and micro-structures of generated scaffolds. Three-dimensional printing is a solid free-form fabrication method that provides novel ways to create customized scaffolds with high precision and accuracy. In this study, an electrically controlled cortical impactor was used to induce randomized brain tissue defects. The overall shape of scaffolds was designed using rat-specific anatomical data obtained from magnetic resonance imaging, and the internal structure was created by computer-aided design. As the result of limitations arising from insufficient resolution of the manufacturing process, we magnified the size of the cavity model prototype five-fold to successfully fabricate customized collagen-chitosan scaffolds using three-dimensional printing. Results demonstrated that scaffolds have three-dimensional porous structures, high porosity, highly specific surface areas, pore connectivity and good internal characteristics. Neural stem cells co cultured with scaffolds showed good viability, indicating good biocompatibility and biodegradability. This technique may be a promising new strategy for regenerating complex damaged brain tissues, and helps pave the way toward personalized medicine. PMID- 28553344 TI - Ca2+ involvement in activation of extracellular-signal-regulated-kinase 1/2 and m calpain after axotomy of the sciatic nerve. AB - Detailed mechanisms behind regeneration after nerve injury, in particular signal transduction and the fate of Schwann cells (SCs), are poorly understood. Here, we investigated axotomy-induced activation of extracellular-signal-regulated kinase 1/2 (ERK1/2; important for proliferation) and m-calpain in vitro, and the relation to Ca2+ deletion and Schwann cell proliferation and death after rat sciatic nerve axotomy. Nerve segments were cultured for up to 72 hours with and without ethylene glycol-bis(beta-aminoethyl ether)-N, N, N', N'-tetraacetic acid (EGTA). In some experiments, 5-bromo-2'-deoxyuridine (BrdU) was added during the last 24 hours to detect proliferating cells and propidium iodide (PI) was added at the last hour to detect dead and/or dying cells. Immunohistochemistry of sections of the cultured nerve segments was performed to label m-calpain and the phosphorylated and activated form of ERK1/2. The experiments revealed that immunoreactivity for p-ERK1/2 increased with time in organotypically cultured SCs. p-ERK1/2 and m-calpain were also observed in axons. A significant increase in the number of dead or dying SCs was observed in nerve segments cultured for 24 hours. When deprived of Ca2+, activation of axonal m-calpain was reduced, whereas p-ERK1/2 was increased in SCs. Ca2+ deprivation also significantly reduced the number of proliferating SCs, and instead increased the number of dead or dying SCs. Ca2+ seems to play an important role in activation of ERK1/2 in SCs and in SC survival and proliferation. In addition, extracellular Ca2+ levels are also required for m-calpain activation and up-regulation in axons. Thus, regulation of Ca2+ levels is likely to be a useful method to promote SC proliferation. PMID- 28553345 TI - Recombinant human fibroblast growth factor-2 promotes nerve regeneration and functional recovery after mental nerve crush injury. AB - Several studies have shown that fibroblast growth factor-2 (FGF2) can directly affect axon regeneration after peripheral nerve damage. In this study, we performed sensory tests and histological analyses to study the effect of recombinant human FGF-2 (rhFGF2) treatment on damaged mental nerves. The mental nerves of 6-week-old male Sprague-Dawley rats were crush-injured for 1 minute and then treated with 10 or 50 MUg/mL rhFGF2 or PBS in crush injury area with a mini Osmotic pump. Sensory test using von Frey filaments at 1 week revealed the presence of sensory degeneration based on decreased gap score and increased difference score. However, at 2 weeks, the gap score and difference score were significantly rebounded in the mental nerve crush group treated with 10 MUg/mL rhFGF2. Interestingly, treatment with 10 MUg/mL rhFGF had a more obviously positive effect on the gap score than treatment with 50 MUg/mL rhFGF2. In addition, retrograde neuronal tracing with Dil revealed a significant increase in nerve regeneration in the trigeminal ganglion at 2 and 4 weeks in the rhFGF2 groups (10 MUg/mL and 50 MUg/mL) than in the PBS group. The 10 MUg/mL rhFGF2 group also showed an obviously robust regeneration in axon density in the mental nerve at 4 weeks. Our results demonstrate that 10 MUg/mL rhFGF induces mental nerve regeneration and sensory recovery after mental nerve crush injury. PMID- 28553346 TI - Exenatide promotes regeneration of injured rat sciatic nerve. AB - Damage to peripheral nerves results in partial or complete dysfunction. After peripheral nerve injuries, a full functional recovery usually cannot be achieved despite the standard surgical repairs. Neurotrophic factors and growth factors stimulate axonal growth and support the viability of nerve cells. The objective of this study is to investigate the neurotrophic effect of exenatide (glucagon like peptide-1 analog) in a rat sciatic nerve neurotmesis model. We injected 10 MUg/d exenatide for 12 weeks in the experimental group (n = 12) and 0.1 mL/d saline for 12 weeks in the control group (n = 12). We evaluated nerve regeneration by conducting electrophysiological and motor functional tests. Histological changes were evaluated at weeks 1, 3, 6, and 9. Nerve regeneration was monitored using stereomicroscopy. The electrophysiological and motor functions in rats treated with exenatide were improved at 12 weeks after surgery. Histological examination revealed a significant increase in the number of axons in injured sciatic nerve following exenatide treatment confirmed by stereomicroscopy. In an experimentally induced neurotmesis model in rats, exenatide had a positive effect on nerve regeneration evidenced by electromyography, functional motor tests, histological and stereomicroscopic findings. PMID- 28553347 TI - Mitomycin C induces apoptosis in human epidural scar fibroblasts after surgical decompression for spinal cord injury. AB - Numerous studies have shown that topical application of mitomycin C after surgical decompression effectively reduces scar adhesion. However, the underlying mechanisms remain unclear. In this study, we investigated the effect of mitomycin C on the proliferation and apoptosis of human epidural scar fibroblasts. Human epidural scar fibroblasts were treated with various concentrations of mitomycin C (1, 5, 10, 20, 40 MUg/mL) for 12, 24 and 48 hours. Mitomycin C suppressed the growth of these cells in a dose- and time-dependent manner. Mitomycin C upregulated the expression levels of Fas, DR4, DR5, cleaved caspase-8/9, Bax, Bim and cleaved caspase-3 proteins, and it downregulated Bcl-2 and Bcl-xL expression. In addition, inhibitors of caspase-8 and caspase-9 (Z-IETD-FMK and Z-LEHD-FMK, respectively) did not fully inhibit mitomycin C-induced apoptosis. Furthermore, mitomycin C induced endoplasmic reticulum stress by increasing the expression of glucose-regulated protein 78, CAAT/enhancer-binding protein homologous protein (CHOP) and caspase-4 in a dose-dependent manner. Salubrinal significantly inhibited the mitomycin C-induced cell viability loss and apoptosis, and these effects were accompanied by a reduction in CHOP expression. Our results support the hypothesis that mitomycin C induces human epidural scar fibroblast apoptosis, at least in part, via the endoplasmic reticulum stress pathway. PMID- 28553348 TI - Neuroprotective mechanism of Kai Xin San: upregulation of hippocampal insulin degrading enzyme protein expression and acceleration of amyloid-beta degradation. AB - Kai Xin San is a Chinese herbal formula composed of Radix Ginseng, Poria, Radix Polygalae and Acorus Tatarinowii Rhizome. It has been used in China for many years for treating amnesia. Kai Xin San ameliorates amyloid-beta (Abeta)-induced cognitive dysfunction and is neuroprotective in vivo, but its precise mechanism remains unclear. Expression of insulin-degrading enzyme (IDE), which degrades Abeta, is strongly correlated with cognitive function. Here, we injected rats with exogenous Abeta42 (200 MUM, 5 MUL) into the hippocampus and subsequently administered Kai Xin San (0.54 or 1.08 g/kg/d) intragastrically for 21 consecutive days. Hematoxylin-eosin and Nissl staining revealed that Kai Xin San protected neurons against Abeta-induced damage. Furthermore, enzyme-linked immunosorbent assay, western blot and polymerase chain reaction results showed that Kai Xin San decreased Abeta42 protein levels and increased expression of IDE protein, but not mRNA, in the hippocampus. Our findings reveal that Kai Xin San facilitates hippocampal Abeta degradation and increases IDE expression, which leads, at least in part, to the alleviation of hippocampal neuron injury in rats. PMID- 28553350 TI - Recovery of multiply injured ascending reticular activating systems in a stroke patient. PMID- 28553351 TI - Fast Recall for Complex-Valued Hopfield Neural Networks with Projection Rules. AB - Many models of neural networks have been extended to complex-valued neural networks. A complex-valued Hopfield neural network (CHNN) is a complex-valued version of a Hopfield neural network. Complex-valued neurons can represent multistates, and CHNNs are available for the storage of multilevel data, such as gray-scale images. The CHNNs are often trapped into the local minima, and their noise tolerance is low. Lee improved the noise tolerance of the CHNNs by detecting and exiting the local minima. In the present work, we propose a new recall algorithm that eliminates the local minima. We show that our proposed recall algorithm not only accelerated the recall but also improved the noise tolerance through computer simulations. PMID- 28553349 TI - Effects of medicinal plants on Alzheimer's disease and memory deficits. AB - Alzheimer's disease is an age-related neurodegenerative disorder characterized by memory deficits. Various studies have been carried out to find therapeutic approaches for Alzheimer's disease. However, the proper treatment option is still not available. There is no cure for Alzheimer's disease, but symptomatic treatment may improve the memory and other dementia related problems. Traditional medicine is practiced worldwide as memory enhancer since ancient times. Natural therapy including herbs and medicinal plants has been used in the treatment of memory deficits such as dementia, amnesia, as well as Alzheimer's disease since a long time. Medicinal plants have been used in different systems of medicine, particularly Unani system of medicines and exhibited their powerful roles in the management and cure of memory disorders. Most of herbs and plants have been chemically evaluated and their efficacy has also been proven in clinical trials. However, the underlying mechanisms of actions are still on the way. In this paper, we have reviewed the role of different medicinal plants that play an important role in the treatment of Alzheimer's disease and memory deficits using conventional herbal therapy. PMID- 28553352 TI - Hepatitis C Virus and Nonliver Solid Cancers: Is There an Association between HCV and Cancers of the Pancreas, Thyroid, Kidney, Oral Cavity, Breast, Lung, and Gastrointestinal Tract? AB - Hepatitis C virus (HCV) is known for its oncogenic potential and has been found to be associated with hepatocellular carcinoma (HCC) and non-Hodgkin lymphoma. It has also been postulated that HCV may play a role in the development of other extrahepatic solid tumors of other organs of the body since it has been isolated from the vessel wall, kidney, and oral mucosa. In this article, we have reviewed epidemiological studies that have been done to look into the relationship of HCV with nonliver solid cancers of the pancreas, thyroid, renal, oral cavity, breast, and lung and nonpancreatic gastrointestinal cancers. Based on this review, HCV might be associated with an increased risk of renal cell and lung cancers. PMID- 28553353 TI - New Modified UPLC/Tandem Mass Spectrometry Method for Determination of Risperidone and Its Active Metabolite 9-Hydroxyrisperidone in Plasma: Application to Dose-Dependent Pharmacokinetic Study in Sprague-Dawley Rats. AB - Sensitive and specific liquid-chromatography tandem mass spectrometry (UPLC MS/MS) assay has been developed and validated for simultaneous quantification of risperidone (RIS) and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) in rat plasma using olanzapine (OLA) as internal standard (IS). Pharmacokinetics of risperidone and its active metabolite 9-hydroxyrisperidone was compared across different doses (0.3, 1.0, and 6.0 mg/kg). Serial blood sample was collected over a time of 48 hours and analyzed for risperidone and its active metabolite 9 hydroxyrisperidone. The pharmacokinetics parameters including Cmax, tmax, and AUC were determined for risperidone and its active ingredient. The method was linear in the concentration range of 0.2-500 ng/mL for risperidone and 9-OH-risperidone, with coefficients of determination greater than 0.998 and lower limit of quantitation of 0.2 ng/mL. Blood levels of risperidone and its active metabolite were roughly dose-proportional. The method developed herein is simple and rapid and was successfully applied for dose-dependent pharmacokinetic study. PMID- 28553354 TI - Construct, Face, and Content Validation on Voxel-Man(r) Simulator for Otologic Surgical Training. AB - Objective. To assess the face, content, and construct validity of the Voxel-Man TempoSurg Virtual Reality simulator. Participants and Methods. 74 ear, nose, and throat (ENT) surgeons participated. They were assigned to one of two groups according to their level of expertise: the expert group (n = 16) and the novice group (n = 58). The participants performed four temporal bone dissection tasks on the simulator. Performances were assessed by a global score and then compared to assess the construct validity of the simulator. Finally, the expert group assessed the face and content validity by means of a five-point Likert-type scale. Results. experienced surgeons performed better (p < .01) and faster (p < .001) than the novices. However, the groups did not differ in terms of bone volume removed (p = .11) or number of injuries (p = .37). 93.7% of experienced surgeons stated they would recommend this simulator for anatomical learning. Most (87.5%) also thought that it could be integrated into surgical training. Conclusion. The Voxel-Man TempoSurg Virtual Reality simulator constitutes an interesting complementary tool to traditional teaching methods for training in otologic surgery. PMID- 28553355 TI - Innovative 3D Model of the Human Middle Ear in High Resolution with a Histological Microgrinding Method: A Feasibility Study and Comparison with MUCT. AB - Conclusion. The development of a histological 3D model of the tympanic cavity visualizes the exact microanatomy of the sound conduction organ and is therefore essential for finite elements simulations and surgical training. Objectives. So far, no accurate histological 3D model of the sound conduction system existed in literature. For 3D reconstruction of the very fine structures inside and outside the auditory ossicles, a method based on histological slices allows a more differential analysis of both hard and soft tissues and could thus be superior to MUCT. Method. A complete temporal bone was embedded in epoxy resin and microground in distances of about 34 MUm. After photodocumentation of every plane, a 3D reconstruction was performed by using the Computer Aided Design (CAD) program Rhinoceros 5(r). For comparison, a MUCT of the same specimen resulted in a 3D model of the calcified structures in the middle ear. Results. The histological 3D model gives an excellent overview to all anatomical soft and bony tissues of the human auditory ossicles. Specifically the fine blood vessel system and the exact dimension of cartilage areas inside the ossicles can be illustrated much more precisely than with MUCT data. The present technique also allows the evaluation of the fine connecting ligaments inside the tympanic cavity. PMID- 28553356 TI - Asymptomatic Brain Edema after Hemodialysis Initiation in a Patient with Severe Uremia. AB - A 66-year-old man with severe renal insufficiency presented with mild confusion associated with uremia. Cranial magnetic resonance imaging (MRI) showed no remarkable changes. The patient was placed on short-duration hemodialysis (2 hours) with smaller surface area and low blood flow (100 mL/min) to avoid dialysis disequilibrium syndrome (DDS). His consciousness gradually improved and he did not develop apparent DDS symptoms. However, T2-weighted FLAIR MRI showed increased signal intensities bilaterally in the cortical and subcortical areas of the occipital lobe on day 15. In other words, cranial MRI showed cerebral edema, indicating asymptomatic DDS. On day 29, cranial MRI showed a return to findings on admission. In this case, because the patient did not have apparent DDS symptoms despite MRI changes, we diagnosed asymptomatic cerebral edema. The patient was discharged on regular intermittent HD without any neurological deficits. No further neurological disturbances were noted during 1-year follow up. MRI findings in ESKD patients without DDS symptoms help to clarify the diagnosis of cerebral edema. In this case, the patient did not have apparent DDS symptoms and was therefore diagnosed with asymptomatic cerebral edema. PMID- 28553357 TI - Human Adipose-Derived Stem Cells Exhibit Enhanced Proliferative Capacity and Retain Multipotency Longer than Donor-Matched Bone Marrow Mesenchymal Stem Cells during Expansion In Vitro. AB - Bone marrow-derived mesenchymal stem cells (MSCs) and adipose-derived multipotent/mesenchymal stem cells (ASCs) have been proposed as the ideal cell types for a range of musculoskeletal tissue engineering and regenerative medicine therapies. However, extensive in vitro expansion is required to generate sufficient cells for clinical application and previous studies have demonstrated differences in the proliferative capacity and the impact of expansion on differentiation capacity of both MSCs and ASCs. Significantly, these studies routinely use cells from different donors, making direct comparisons difficult. Importantly, this study directly compared the proliferative capacity and multipotency of human MSCs and ASCs from the same donors to determine how each cell type was affected by in vitro expansion. The study identified that ASCs were able to proliferate faster and undergo greater population doublings than donor matched MSCs and that senescence was primarily driven via telomere shortening and upregulation of p16ink4a. Both donor-matched MSCs and ASCs were capable of trilineage differentiation early in cultures; however, while differentiation capacity diminished with time in culture, ASCs retained enhanced capacity compared to MSCs. These findings suggest that ASCs may be the most appropriate cell type for musculoskeletal tissue engineering and regenerative medicine therapies due to their enhanced in vitro expansion capacity and limited loss of differentiation potential. PMID- 28553358 TI - Inhibition of Lysyl Oxidases Impairs Migration and Angiogenic Properties of Tumor Associated Pericytes. AB - Pericytes are important cellular components of the tumor microenviroment with established roles in angiogenesis and metastasis. These two cancer hallmarks are modulated by enzymes of the LOX family, but thus far, information about LOX relevance in tumor-associated pericytes is lacking. Here, we performed a comparative characterization of normal and tumoral pericytes and report for the first time the modulatory effects of LOX enzymes on activated pericyte properties. Tumoral pericytes isolated from childhood ependymoma and neuroblastoma specimens displayed angiogenic properties in vitro and expressed typical markers, including CD146, NG2, and PDGFRbeta. Expression of all LOX family members could be detected in both normal and tumor-associated pericytes. In most pericyte samples, LOXL3 was the family member displaying the highest transcript levels. Inhibition of LOX/LOXL activity with the inhibitor beta aminopropionitrile (betaAPN) significantly reduced migration of pericytes, while proliferation rates were kept unaltered. Formation of tube-like structures in vitro by pericytes was also significantly impaired upon inhibition of LOX/LOXL activity with betaAPN, which induced more prominent effects in tumor-associated pericytes. These findings reveal a novel involvement of the LOX family of enzymes in migration and angiogenic properties of pericytes, with implications in tumor development and in therapeutic targeting tumor microenvironment constituents. PMID- 28553359 TI - Bone Regeneration Induced by Bone Porcine Block with Bone Marrow Stromal Stem Cells in a Minipig Model of Mandibular "Critical Size" Defect. AB - Introduction. Adding stem cells to biodegradable scaffolds to enhance bone regeneration is a valuable option. Different kinds of stem cells with osteoblastic activity were tested, such as bone marrow stromal stem cells (BMSSCs). Aim. To assess a correct protocol for osteogenic stem cell differentiation, so BMSSCs were seeded on a bone porcine block (BPB). Materials and Methods. Bone marrow from six minipigs was extracted from tibiae and humeri and treated to isolate BMSSCs. After seeding on BPB, critical-size defects were created on each mandible of the minipigs and implanted with BPB and BPB/BMSSCs. After three months, histomorphometric analysis was performed. Results. Histomorphometric analysis provided percentages of the three groups. Tissues present in control defects were 23 +/- 2% lamellar bone, 28 +/- 1% woven bone, and 56 +/- 4% marrow spaces; in BPB defects were 20 +/- 5% BPB, 32 +/- 2% lamellar bone, 24 +/- 1% woven bone, and 28 +/- 2% marrow spaces; in BPB/BMSSCs defects were 17 +/- 4% BPB/BMSSCs, 42 +/- 2% lamellar bone, 12 +/- 1% woven bone, and 22 +/- 3% marrow spaces. Conclusion. BPB used as a scaffold to induce bone regeneration may benefit from the addition of BDPSCs in the tissue-engineered constructs. PMID- 28553360 TI - In Vivo Immunogenic Response to Allogeneic Mesenchymal Stem Cells and the Role of Preactivated Mesenchymal Stem Cells Cotransplanted with Allogeneic Islets. AB - Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into cells from the mesenchymal lineage. The hypoimmunogenic characteristic of MSCs has encouraged studies using allogeneic MSCs for the treatment of autoimmune diseases and inflammatory conditions. Promising preclinical results and the safety of allogeneic MSC transplantation have created the possibility of "off-the shelf" clinical application of allogeneic cells. This study has aimed to evaluate the survival of untreated and IFN-gamma- and TNF-alpha-treated (preactivated) allogeneic MSCs transplanted under the kidney capsule of immunocompetent mice together with the role of preactivated MSCs after cotransplantation with allogeneic islets. The preactivation of MSCs upregulated the gene expression of anti-inflammatory molecules and also enhanced their immunomodulatory capacity in vitro. In vivo, allogeneic MSCs provoked an immunogenic response, with the infiltration of inflammatory cells at the transplant site and full graft rejection in both the untreated and preactivated groups. Allogeneic islets cotransplanted with preactivated MSCs prolonged graft survival for about 6 days, compared with islet alone. The present results corroborate the hypothesis that allogeneic MSCs are not immune-privileged and that after playing their therapeutic role they are rejected. Strategies that reduce allogeneic MSC immunogenicity can potentially prolong their in vivo persistence and improve the therapeutic effects. PMID- 28553361 TI - Charting Availability of Processed and Unprocessed Foods in School Neighbourhood Nutrition Environments in an Urban Australian Setting. AB - School Neighbourhood Nutrition Environments (SNNEs) can facilitate or impede healthy eating. This study describes the SNNEs surrounding 6 Good Start Program (GSP) schools in 5 suburbs in Logan, Queensland. Relative density of healthy and unhealthy food outlets was calculated for SNNEs surrounding GSP (6) and non-GSP (10) schools within the 5 suburbs. Relative accessibility of minimally processed and highly processed food and drink in SNNEs of the 6 GSP schools was determined using shelf measurements of snack foods. Unhealthy outlets greatly outnumber healthy outlets (mean relative density 15.6%, median 19.1%). The majority of outlets stock predominantly highly processed food and drink. Study areas are dominated by unhealthy food outlets and highly processed food. PMID- 28553363 TI - Pancake bouncing on superhydrophobic surfaces. AB - Engineering surfaces that promote rapid drop detachment1,2 is of importance to a wide range of applications including anti-icing3-5, dropwise condensation6, and self-cleaning7-9. Here we show how superhydrophobic surfaces patterned with lattices of submillimetre-scale posts decorated with nano-textures can generate a counter-intuitive bouncing regime: drops spread on impact and then leave the surface in a flattened, pancake shape without retracting. This allows for a four fold reduction in contact time compared to conventional complete rebound1,10-13. We demonstrate that the pancake bouncing results from the rectification of capillary energy stored in the penetrated liquid into upward motion adequate to lift the drop. Moreover, the timescales for lateral drop spreading over the surface and for vertical motion must be comparable. In particular, by designing surfaces with tapered micro/nanotextures which behave as harmonic springs, the timescales become independent of the impact velocity, allowing the occurrence of pancake bouncing and rapid drop detachment over a wide range of impact velocities. PMID- 28553362 TI - Modified Suanzaorentang Had the Treatment Effect for Generalized Anxiety Disorder for the First 4 Weeks of Paroxetine Medication: A Pragmatic Randomized Controlled Study. AB - Background. Paroxetine does not show satisfactory therapeutic effect for generalized anxiety disorder (GAD) patients for the first 2-4 weeks of medication. Diazepam is always concurrently used although it has some shortcomings such as physical dependence and withdrawal reactions. In this study, we aimed to identify whether modified Suanzaorentang (MSZRT), a combined Chinese formula including Suanzaorentang (SZRT) and Zhizichitang (ZZCT), could control the anxiety of GAD for the first 4 weeks of paroxetine medication. Methods. 156 GAD patients were randomized to the treatment of paroxetine, paroxetine-diazepam, or paroxetine-MSZRT for 4 weeks. Hamilton Anxiety Scale (HAMA) Test and Self Rating Anxiety Scale (SAS) Test were determined each week as the evaluation of clinical efficacy. Adverse events (AEs) were also closely observed by performing the Treatment Emergent Symptom Scale (TESS) Test. Results. Both paroxetine-MSZRT and paroxetine-diazepam decreased more HAMA and SAS total scores than paroxetine from weeks 1 to 3. Paroxetine-MSZRT as well as paroxetine-diazepam had an obviously higher onset rate than paroxetine in each week. After 4 weeks' treatment, the overall effectiveness rate in the paroxetine-MSZRT group (90.00%) was obviously higher than those of the paroxetine group (74.42%) but did not significantly differ from the paroxetine-diazepam group (93.88%). Conclusion. MSZRT had the treatment effect for GAD when paroxetine was used for the first 4 weeks. PMID- 28553364 TI - Crystal Structure of the Superconducting Phase of Sulfur Hydride. AB - A superconducting critical temperature above 200 K has recently been discovered in H2S (or D2S) under high hydrostatic pressure1, 2. These measurements were interpreted in terms of a decomposition of these materials into elemental sulfur and a hydrogen-rich hydride that is responsible for the superconductivity, although direct experimental evidence for this mechanism has so far been lacking. Here we report the crystal structure of the superconducting phase of hydrogen sulfide (and deuterium sulfide) in the normal and superconducting states obtained by means of synchrotron X-ray diffraction measurements, combined with electrical resistance measurements at both room and low temperatures. We find that the superconducting phase is mostly in good agreement with theoretically predicted body-centered cubic (bcc) structure for H3S (Ref.3). The presence of elemental sulfur is also manifest in the X-ray diffraction patterns, thus proving the decomposition mechanism of H2S to H3S + S under pressure4-6. PMID- 28553365 TI - Mini Electrodes on Ablation Catheters: Valuable Addition or Redundant Information?-Insights from a Computational Study. AB - Radiofrequency ablation has become a first-line approach for curative therapy of many cardiac arrhythmias. Various existing catheter designs provide high spatial resolution to identify the best spot for performing ablation and to assess lesion formation. However, creation of transmural and nonconducting ablation lesions requires usage of catheters with larger electrodes and improved thermal conductivity, leading to reduced spatial sensitivity. As trade-off, an ablation catheter with integrated mini electrodes was introduced. The additional diagnostic benefit of this catheter is still not clear. In order to solve this issue, we implemented a computational setup with different ablation scenarios. Our in silico results show that peak-to-peak amplitudes of unipolar electrograms from mini electrodes are more suitable to differentiate ablated and nonablated tissue compared to electrograms from the distal ablation electrode. However, in orthogonal mapping position, no significant difference was observed between distal electrode and mini electrodes electrograms in the ablation scenarios. In conclusion, catheters with mini electrodes bring about additional benefit to distinguish ablated tissue from nonablated tissue in parallel position with high spatial resolution. It is feasible to detect conduction gaps in linear lesions with this catheter by evaluating electrogram data from mini electrodes. PMID- 28553366 TI - Dysphonic Voice Pattern Analysis of Patients in Parkinson's Disease Using Minimum Interclass Probability Risk Feature Selection and Bagging Ensemble Learning Methods. AB - Analysis of quantified voice patterns is useful in the detection and assessment of dysphonia and related phonation disorders. In this paper, we first study the linear correlations between 22 voice parameters of fundamental frequency variability, amplitude variations, and nonlinear measures. The highly correlated vocal parameters are combined by using the linear discriminant analysis method. Based on the probability density functions estimated by the Parzen-window technique, we propose an interclass probability risk (ICPR) method to select the vocal parameters with small ICPR values as dominant features and compare with the modified Kullback-Leibler divergence (MKLD) feature selection approach. The experimental results show that the generalized logistic regression analysis (GLRA), support vector machine (SVM), and Bagging ensemble algorithm input with the ICPR features can provide better classification results than the same classifiers with the MKLD selected features. The SVM is much better at distinguishing normal vocal patterns with a specificity of 0.8542. Among the three classification methods, the Bagging ensemble algorithm with ICPR features can identify 90.77% vocal patterns, with the highest sensitivity of 0.9796 and largest area value of 0.9558 under the receiver operating characteristic curve. The classification results demonstrate the effectiveness of our feature selection and pattern analysis methods for dysphonic voice detection and measurement. PMID- 28553367 TI - A Novel Remote Rehabilitation System with the Fusion of Noninvasive Wearable Device and Motion Sensing for Pulmonary Patients. AB - Chronic obstructive pulmonary disease is a type of lung disease caused by chronically poor airflow that makes breathing difficult. As a chronic illness, it typically worsens over time. Therefore, pulmonary rehabilitation exercises and patient management for extensive periods of time are required. This paper presents a remote rehabilitation system for a multimodal sensors-based application for patients who have chronic breathing difficulties. The process involves the fusion of sensory data-captured motion data by stereo-camera and photoplethysmogram signal by a wearable PPG sensor-that are the input variables of a detection and evaluation framework. In addition, we incorporated a set of rehabilitation exercises specific for pulmonary patients into the system by fusing sensory data. Simultaneously, the system also features medical functions that accommodate the needs of medical professionals and those which ease the use of the application for patients, including exercises for tracking progress, patient performance, exercise assignments, and exercise guidance. Finally, the results indicate the accurate determination of pulmonary exercises from the fusion of sensory data. This remote rehabilitation system provides a comfortable and cost-effective option in the healthcare rehabilitation system. PMID- 28553368 TI - Detection of X-ray photons by solution-processed organic-inorganic perovskites. AB - The evolution of real-time medical diagnostic tools such as angiography and computer tomography from radiography based on photographic plates was enabled by the development of integrated solid-state X-ray photon detectors, based on conventional solid-state semiconductors. Recently, for optoelectronic devices operating in the visible and near infrared spectral regions, solution-processed organic and inorganic semiconductors have also attracted immense attention. Here we demonstrate a possibility to use such inexpensive semiconductors for sensitive detection of X-ray photons by direct photon-to-current conversion. In particular, methylammonium lead iodide perovskite (CH3NH3PbI3) offers a compelling combination of fast photoresponse and a high absorption cross-section for X-rays, owing to the heavy Pb and I atoms. Solution processed photodiodes as well as photoconductors are presented, exhibiting high values of X-ray sensitivity (up to 25 uC mGyair-1 cm-3) and responsivity (1.9*104 carriers/photon), which are commensurate with those obtained by the current solid-state technology. PMID- 28553369 TI - Efficacy comparison of lyophilised black raspberries and combination of celecoxib and PBIT in prevention of carcinogen-induced oesophageal cancer in rats. AB - The objective of this study was to compare the efficacy and mechanism of lyophilized black raspberries (BRB) versus the combination of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, and S,S'-1,4-phenylene-bis(1,2 ethanediyl)bis-isothiourea (PBIT), a selective inducible nitric oxide synthase (iNOS) inhibitor in inhibition of carcinogen-induced esophageal squamous cell carcinoma in rats. Our data indicated that tumor multiplicity and histologic grade of esophageal precancerous lesions were reduced in animals fed BRB compared to those fed celecoxib + PBIT. The mechanistic studies showed that BRB and its major anthocyanin suppressed cell proliferation and oncogenic signaling. Our findings demonstrated that dietary BRB is superior to the combination of two pharmaceutical drugs in esophageal cancer prevention. These observations suggest the potential value of translational studies using BRB food products for esophageal cancer prevention in humans, particularly those with high-risk premalignant lesions. PMID- 28553370 TI - Neonatal Hypoxic-ischemic Encephalopathy: A Radiological Review. AB - Neonatal hypoxic-ischemic encephalopathy (HIE) is a devastating condition that may result in death or severe neurologic deficits in children. Neuroimaging with cranial ultrasound (US), computed tomography and magnetic resonance imaging are valuable tools in the workup of patients with HIE. The pattern of brain injury depends on the severity and duration of hypoxia and degree of brain maturation. Mild to moderate HI injury results in periventricular leukomalacia and germinal matrix bleed in preterm neonates, and parasagittal watershed infarcts in full term neonates. Severe HI injury involves deep gray matter in both term and preterm infants. Treatment of HIE is largely supportive. The current article reviews the etiopathophysiology and clinical manifestations of HIE, role of imaging in the evaluation of the condition, patterns of brain injury in term and preterm neonates, the treatment and the prognosis. PMID- 28553371 TI - Effect of Nimodipine on Morphine-related Withdrawal Syndrome in Rat Model: An Observational Study. AB - OBJECTIVE: To observe the effect of L-type calcium channel blocker like nimodipine on morphine's withdrawal when it was administered continuously along with morphine versus a single bolus dose of nimodipine, which was administered at the end of the experiment before the precipitation of withdrawal reaction in morphine-dependent rats. MATERIALS AND METHODS: Four groups of adult male Wistar rats were rendered morphine dependent by subcutaneous injections of morphine at a dose of 10 mg/kg for 10 days. Nimodipine 10 mg/kg intraperitoneally (ip) administered to one group once daily before morphine administration in the entire experimental period, and another group received nimodipine only once at the end of the experiment as a single bolus dose 2 mg/kg before the administration of naloxone. Naloxone 3 mg/kg was administered ip to all the groups to precipitate withdrawal reactions. The withdrawal reactions were evaluated and scored as per the Gellert and Holtzman global withdrawal rating scale. RESULTS: Nimodipine when administered as a single bolus dose before naloxone administration in morphine dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period. CONCLUSION: We discovered that nimodipine helps in attenuating the severity of morphine withdrawal having potential role encountered during pharmacotherapy with morphine management of opioid dependence, well memory, impairement, cell signaling and phosphorylation of neuron. PMID- 28553372 TI - Clinical Spectrum, Comorbidities, and Risk Factor Profile of Cerebral Palsy Children: A Prospective Study. AB - AIM AND OBJECTIVE: Cerebral palsy (CP) is the most common motor disability in childhood. This study aimed to describe clinical spectrum, comorbidities, and risk factors associated with CP children. MATERIALS AND METHODS: This hospital based observational study was conducted in tertiary level hospital in Jaipur including 180 CP children aged 1-12 years, attending the Paediatric Neurology Outdoor and Child Development Centre. A detailed history of antenatal, natal, and postnatal events taken and thorough examination was performed to stratify children in proper topographical and physiological classification. RESULTS: Mothers of 47.7% CP children were primigravida and 17.7% mothers had anemia during pregnancy. Among natal factors, asphyxia contributed to maximum cases (52.2%). Seizure in postnatal life was the second most common risk factor for CP after asphyxia. Spastic CP (84.4%) was the most common physiological type, and quadriplegia (56.6%) was the most common topographical type observed in this study. Intellectual disability (47.7%) followed by epilepsy (41.6%) was the most common comorbidity. CONCLUSION: Even with the advancement of health-care system, asphyxia is the most common risk factor, and spastic quadriplegia is the most common type of CP. There is still a need of improving the health facilities to overcome this costly and common neuromotor disability. Widespread knowledge of common risk factors that can predispose to CP can prevent the CP development to some extent and knowledge of clinical spectrum, and comorbidities can improve their targeted treatment which can improve their growth and social participation. PMID- 28553373 TI - Resection of Pediatric Brain Tumors: Intraoperative Ultrasound Revisited. AB - BACKGROUND: Extent of resection is a very important prognostic marker in most pediatric brain tumors. Intraoperative imaging facilitates resection control. Intraoperative ultrasound (IOUS) is a cost-effective alternative to intraoperative magnetic resonance, but scant literature addresses its utility in this context. METHODS: We retrospectively reviewed all pediatric brain tumors operated at our center using navigated three-dimensional ultrasound (US). The utility of the US in resection control was recorded and extent of resection evaluated. RESULTS: IOUS was used in 20 cases (3 for frameless biopsy and 17 for tumor resection control). It was 100% accurate in localizing all tumors and yielded 100% diagnosis in the biopsy cases. Technical limitations precluded its use in 2 of the 17 cases of tumor resection. In the remaining 15, it correctly predicted the residual tumor status in 13 cases (87%). A gross total resection was achieved overall in 12 cases (80%) with postoperative morbidity in only one case. CONCLUSIONS: IOUS is a useful tool to localize intracranial tumors and guide the resection reliably. Widespread use can improve its applicability and make it an effective intraoperative imaging tool in pediatric brain tumors. PMID- 28553374 TI - Levetiracetam in Neonatal Seizures as First-line Treatment: A Prospective Study. AB - AIM OF THE STUDY: The aim of this study is to evaluate the efficacy and safety of levetiracetam (LEV) as first-line treatment of neonatal seizures. MATERIALS AND METHODS: This study was conducted in patients of Neonatal Intensive Care Unit of Santo Bambino Hospital, University of Catania, Italy, from January to August 2016. A total of 16 neonates with convulsions not associated with major syndromes, which required anticonvulsant therapy, were included and underwent IV LEV at standard doses. RESULTS: All patients responded to treatment, with a variety range of seizure resolution period (from 24 h to 15 days; mean hours: 96 +/- 110.95). No patient required a second anticonvulsant therapy. Regarding safety of LEV, no major side-effects were observed. CONCLUSIONS: To our knowledge, it is one of the few studies confirming the efficiency of LEV as first line treatment in seizures of this age group. LEV was effective in resolving seizures and was safely administered in the current study. PMID- 28553375 TI - Neurenteric Cyst: Magnetic Resonance Imaging Findings in an Adolescent. AB - Intracranial neurenteric cysts are uncommon congenital space-occupying lesions that may be misinterpreted for other more frequent nonneoplastic cysts and cystic tumors. We discuss the imaging findings of this lesion in a 16-year-old female who presented with chronic headaches. PMID- 28553376 TI - Two Cases of Craniospinal Rachischisis Totalis: Role of Magnetic Resonance Imaging in Diagnosis and Review of Neural Tube Defects in the Indian Context with Implications for Folate Fortification. AB - Craniospinal rachischisis is a rare and severe form of neural tube defects (NTDs), which is always fatal. It is characterized by anencephaly accompanied by a bony defect of the spine and exposure of neural tissue. We describe the two patients with ultrasonographic and magnetic resonance imaging appearance of craniospinal rachischisis totalis, detected antenatally at 22 and 25 weeks of gestation, and confirmed after termination of pregnancy. The multifactorial etiology of NTDs, with specific reference to folate deficiency, is discussed with possible role of folate fortification in the Indian context. PMID- 28553377 TI - Sporadic Hyperekplexia Plus Syndrome. AB - A disorder of infants and children with pathological startle response, features of other system involvement, falls, and stiffness with retained consciousness. It should be differentiated from conditions such as myoclonic epilepsy, psychogenic movement disorder, Isaac syndrome, Schwartz-Jampel syndrome, Gilles de la Tourette, and culture-specific startle syndromes such as jumping Frenchman of Maine. A 5-year-old child symptomatic with repeated falls spontaneously as well as by sound and activities since neonatal period. He was having hyperalert facies, intelligent, cooperative with mild dysmorphism. His investigations were noncontributory except giant somatosensory evoked potentials and skeletal abnormalities. He showed excellent response to clonazepam and no complications on withdrawing the antiepileptic drugs. Proper diagnosis is of great therapeutic relevance and is based on high degree of suspicion. PMID- 28553379 TI - Noncontiguous Double Spinal Lipoma with Tethered Cord and Polydactyly: Two Different Embryological Events in One Patient. AB - Lumbosacral lipoma is reported to occur in 4-8 of 100,000 patients. Sixty-six percent of lipomyelomeningocele in young patients have accompanied by hypertrophic filum terminale. It is rare to find two isolated spinal lipomas simultaneously. Embryological origin of dorsal and filar lipomas is different from each other and hence rarer to find them together. Radical resection is now being preferred for better long-term progression-free survival. We report an interesting case of spinal dysraphism in a 4-month-old female child with protruding, nontender, soft, subcutaneous 5 cm * 7 cm mass of the lumbosacral area that had been present since birth. Other anomalies included polydactyly of left hand. Magnetic resonance imaging demonstrated two isolated spinal lipomas, a transitional type and a terminal type filum lipoma with an interval of normal filum between the two. The findings were confirmed at surgery and detethering done along the white plane with neural placode reconstruction as described by Dachling Pang. The child had an uneventful postoperative recovery. PMID- 28553378 TI - Dermoid of the Posterior Fossa in Chiari II Malformation: The First Reported Case. AB - Dermoid cysts are rare lesions, particularly in children. Chiari II malformations are seen in patients with myelomeningocele. Here, we present a child with Chiari II malformation who, during a Chiari II decompression, was found to have a dermoid cyst. To the best of our knowledge, this is the first such case ever reported. PMID- 28553380 TI - Giant Occipital Meningoencephalocele in a Neonate: A Therapeutic Challenge. AB - Encephalocele is a rare lesion, being an embryological mesodermal anomaly which results in a defect in the cranium and dura, associated with herniation of meninges, cerebrospinal fluid, or brain tissues through a defect usually covered by scalp. Surgical management of children with giant occipital encephalocele requires careful attention to pediatric anesthetic and surgical principles. We present a case of a giant occipital encephalocele highlighting the problems encountered in its management. PMID- 28553381 TI - Unusual Presentation of Intrasacral Meningocele: A Case Report and Overview. AB - Intrasacral meningocele is an unusual congenital lesion. It is an intrathecal cystic formation arising as a protrusion of the arachnoid through a congenitally weak place in the dura mater. We report a case of a 12-year-old child with chronic pain with an intrasacral meningocele identified on magnetic resonance imaging. PMID- 28553382 TI - Klippel-Feil Syndrome Associated with Sacral Agenesis, Low Lying Cord, Lipomyelomeningocele and Split Cord Malformation Presenting with Tethered Cord Syndrome: Pentads Neural Tube Defects Spread along Whole Spinal Axis. AB - Neural tube defects are congenital development anomaly of the central nervous system and usually have relatively more predilection to affect at anterior and posterior neuropore embryological development sites, so usually one or two defects are commonly encountered. However, occurrence of simultaneous multiple neural tube defects is very rare, presence of constellation of five neural defects is extremely rare, and all defects add up together to produce gross neurological deficit. We present an interesting case of a 23-year-old male who presented with history of lower backache and noticed wasting and weakness of lower limbs associated with difficulty in walking for the last 2 years but had no associated sphincter disturbances. He was operated for lumbosacral lipomeningocoele repair at the age of 1 year. He was asymptomatic, following the first surgical intervention. At the current admission, he underwent re exploration of surgical wound with surgical repair although suffered mild temporary neurological worsening in the immediate postoperative period. Imaging feature and management of such rare constellation of five embryological anomalies and its significance and brief literature are discussed. PMID- 28553384 TI - An Unusual Complication following Ventriculoperitoneal Shunting. AB - We present the case of a ten-year old boy diagnosed with a rare syndrome as a complication of a commonly performed Neurosurgical procedure. To our knowledge this association has not been described in the literature and we discuss the plausible aetiology. PMID- 28553385 TI - Ossified Cephalhematoma: An Unusual Cause of Calvarial Mass in Infancy. AB - Cephalhematomas occurring in newborn usually resolve within a month. Rarely, they tend to ossify and present as hard scalp swelling. Unless one is aware of this possibility, this condition may be misinterpreted as bony tumor and cause needless apprehension to parents as well as the treating physician. A suspicion that ossified cephalhematoma (OC) could present in such a manner supported by careful history taking and relevant imaging (X-ray/computed tomography) would help in appropriate evaluation of this benign condition. The management of OC is controversial. Occasionally, they undergo spontaneous remodeling. Those with secondary craniosynostosis and/or disfigurement are treated surgically. Simple ossified lesions with no significant cosmetic issues may be conservatively tackled. We report such a case in a 3-month-old child. The other management options are briefly discussed. PMID- 28553383 TI - Hemophagocytic Lymphohistiocytosis: A Diagnostic Conundrum. AB - Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune activation causing widespread inflammation and tissue destruction leading to multi-organ dysfunction and failure. Making the diagnosis of HLH could be quite challenging due to the broad range of presenting symptoms and their lack of specificity. After ruling out considerations for differential diagnoses, recognizing the most common presenting signs and symptoms of HLH, including neurologic dysfunction, and having a high clinical suspicion for HLH in the setting of inflammatory/demyelinating diseases are important for prompt diagnosis and treatment. PMID- 28553386 TI - Solitary Plasmacytoma of Bone Involving Spine in a 12-year-old Boy: Report of a Rare Case and Review of Literature. AB - Solitary plasmacytoma of the bone (SPB) is a rare plasma cell neoplasm representing only about 5% of plasma cell neoplasia. It usually presents as a lytic lesion mainly localized within the axial skeleton. SPB is exceedingly rare in young individuals, and only few cases have been reported so far in patients younger than 20 years of age. In view of rarity of disease, definitive treatment guidelines have not been established. We hereby report a case of SPB involving of lumbar vertebra (L5) in a 12-year-old boy. He was initially treated with antilymphoma therapy and curative radiotherapy considering as primary bone lymphoma. However, he had local recurrence with paraparesis after 9 months which was diagnosed as solitary bone plasmacytoma for which he was treated with decompressive laminectomy and chemotherapy (bortezomib, lenalidomide, and dexamethasone). The purpose of this article is to report a rare case of SPB in a pediatric patient and to review the available literature and treatment options. SPB should be considered in the differential diagnosis of osteolytic bone lesions even in young patients. PMID- 28553387 TI - Case of Atlantoaxial Dislocation with Assimilated C1, Absent Posterior C2, Butterfly C3, and Fused Subaxial Cervical Spine: Management Dilemma with Multiple Segmentation and Formation Defects. AB - Segmentation defects are often seen with congenital atlantoaxial dislocation (AAD) though an associated absence of posterior arch of C2 and butterfly C3 is rare. Apart from rarity, the combination of formation and segmentation defects adds to the management dilemma. We report a case of AAD with assimilated atlas, absent C2 posterior arch, C3 butterfly vertebra with floating posterior elements, and fused C4-C6. The child was managed by C1-C2 fusion alone with immediate symptomatic improvement. The presence of formation defects such as adjacent butterfly vertebra and absent posterior elements does not alter the management of AAD. Fusing the C1-C2 joints appears to be a balanced approach. PMID- 28553388 TI - Penetrating Vertebral and Spinal Trauma Complicated by Meningitis in a 2-year-old Child: A Rare Clinical Case. AB - The selection of a treatment approach for a 2-year-old child with penetrating vertebral and spinal trauma, complicated by meningitis, is presented here. This pathology occurs rather rarely, which complicates the development of a uniform approach for the management of such patients. After surgical treatment of the wound in the lumbar region at L5-S1 level due to trauma, the leakage of a transparent discharge had been observed, the nature of which was unclear; it was considered at this treatment stage to be injury to the right ureter. The secondary surgical treatment of the wound was performed with local flap grafting, external lumbar drainage, and antibacterial therapy. The described treatment approach led to the involution of the main symptoms, and normalization of cerebrospinal fluid indicators resulting in an improvement in the child's condition. The represented supervision certifies that the penetrating wound does not always require laminotomy. PMID- 28553389 TI - Sandhoff Disease without Hepatosplenomegaly Due to Hexosaminidase B Gene Mutation. AB - Sandhoff disease is a neurodegenerative disease caused due to deficiency of hexosaminidase (HEX) A and B. A 1-year-old male child presented with regression of milestones, exaggerated startle response, decreased vision, and seizures from 6 months of age. The child had coarse facies without hepatosplenomegaly. Serum levels of beta hexosaminidase total (A + B) were low. Genetic testing for Sandhoff disease revealed a homozygous missense variant on HEXB gene. The case is presented to highlight that the absence of hepatosplenomegaly should not restrain in suspecting Sandhoff disease. PMID- 28553390 TI - A Neonate with X-linked Lissencephaly with Ambiguous Genitalia. AB - X-linked lissencephaly with ambiguous genitalia is a rare and recently described syndrome. We report a neonate presenting with the classical features of the syndrome which includes lissencephaly, agenesis of the corpus callosum, intractable epilepsy of neonatal onset, acquired microcephaly, and male genotype with ambiguous genitalia. The baby was managed aggressively with antiepileptics. Early clinical suspicion of the syndrome can prevent future such occurrences in the family through genetic counseling. PMID- 28553391 TI - Aspergillus Growth within Ventriculoperitoneal Shunt Tube. AB - Cerebrospinal fluid (CSF) shunt failure is commonly associated with infection or mechanical obstruction of the shunt system. A 4-year-old male child who had undergone multiple shunt revisions at another hospital for congenital hydrocephalus and later for shunt obstruction, presented with exposed shunt at the supraclavicular region. Shunt revision was performed. The CSF culture showed no growth; however, the histopathological examination of shunt tube showed Aspergillus growth inside the lumen of silicone tube well away from the tip of ventriculoperitoneal shunt. The skin biopsy from the exposed site revealed foreign body giant cell granulomatous reaction. The patient was discharged on postoperative day 6 without any complications. At 3 months follow-up, the patient is doing well. A growth of Aspergillus within the shunt tube prompted us to think of how the hardware can get infected and may remain a source of constant infection. PMID- 28553392 TI - Glutaric Aciduria Type I: A Rare Metabolic Disorder Mimicking as Choreoathetoid Cerebral Palsy. AB - Glutaric aciduria type I (GA I) is an autosomal recessive inborn error of metabolism caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase. This disorder is characterized by progressive dystonia, choreoathetosis, and dyskinesia. It is often misdiagnosed as athetoid cerebral palsy. Laboratory evaluation usually demonstrates increased urinary excretion of gluataric acid and 3-hydroxyglutaric acid. We report a case of a 7-year-old boy presenting with choreoathetosis and dystonia, mimicking as choreoathetoid cerebral palsy. The presence of characteristic neuroimaging and biochemical studies led to the diagnosis of GA I. PMID- 28553393 TI - Osteoblastoma Mimicking an Idiopathic Intracranial Hypertension Syndrome. AB - Osteoblastomas are rare, benign bone tumors mainly arising from the long bones and the posterior vertebral arches. Skull localizations account for approximately 15% of cases. A total amount of thirty cases involving the temporal bone are reported in the literature. Clinical presentation of temporal osteoblastomas often includes local pain and swelling, while 7th and 8th cranial nerve impairment is rare. We report the novel finding of increase intracranial pressure syndrome secondary to dominant transverse-sigmoid sinus junction compression caused by a small temporal bone osteoblastoma. Excision of the tumor with the restoration of venous flow in the sigmoid sinus was followed by a prompt clinical improvement. In the management of patients with a venous sinus compression, restoration of venous drainage should be a priority. PMID- 28553394 TI - Parainfectious Ocular Flutter and Truncal Ataxia in Association with Dengue Fever. AB - Ocular flutter is an eye movement disorder characterized by purely horizontal rapid saccadic oscillations lasting for a few minutes which stops spontaneously. Postinfectious ocular flutter and truncal ataxia are a rare entity. There are reported cases of opsoclonus myoclonus ataxia in association with dengue virus infection. However, there are no reported cases of parainfectious ocular flutter and truncal ataxia in association with dengue virus infection. Hereby, we report a child with dengue fever who had ocular flutter and truncal ataxia. PMID- 28553395 TI - Retrograde Partial Migration of Ventriculoperitoneal Shunt with Chamber: Review of Causative Factors and Its Prevention. AB - Distal migration of shunt is a very common occurrence. Proximal migration of shunt is rare and possible pathophysiological mechanisms to explain this unusual complication is rarely attempted. A 5-month-old child shunted for posttraumatic hydrocephalus presented 1.5 years later with raised intracranial pressure and seizures. Imaging showed subdural hygroma, partial intracranial migration of shunt/chamber. On endoscopy, choroid plexus was adherent to shunt tip and some pericranial tissue was found in the anchoring suture (intraventricularly displaced). Shunt was retrieved endoscopically and diversion established by endoscopic third ventriculostomy with symptoms free follow-up. Host-related and surgical factors have been postulated. Tug-of-war effect on the anchoring suture and collapsing cortex are the possible mechanisms that explain proximal migration in our case. Three-point fixation of the chamber to pericranium, small burr hole with a smaller durotomy, can prevent shunt migration. Proximal shunt migrations should be dealt with endoscopy so as to avoid complications. PMID- 28553396 TI - A Rare Case of Repeated Migration and Transurethral Extrusion of Ventriculoperitoneal Shunt. AB - Bladder migration and transurethral extrusion is an extremely rare complication of ventriculoperitoneal (VP) shunt. Only eight cases have been reported in the English literature since 1995. We report a case of a 4-year-old boy with cerebral palsy, hydrocephalus, and VP shunted on both sides who presented with a protruded distal VP shunt from his urethral orifice. The patient was reported for having previous shunt extrusion through the anus. The patient was treated on by a multidisciplinary approach, involving a neurosurgeon and urologist. Shunt removal with simple procedure was smoothly achieved without morbidities. He was discharged home in satisfactory condition. PMID- 28553397 TI - Solitary Intramedullary Cervical Cysticercosis without Neurological Deficit: A Rare Case Report. AB - Neurocysticercosis is commonly seen intracranially and its incidence in the spinal cord is very low. Among spine dorsal region is more common due to more blood flow in this region and it is usually associated with lesion at other sites. The intramedullary location is rarer than extramedullary. Hence, solitary intramedullary cervical spine cysticercosis (ICC) is extremely rare entity. Only a handful numbers of cases are reported in the literature. All reported cases are presented with the neurological deficit as spinal canal diameter is very low and any space occupying lesion is not tolerated. We are presenting a 6-year-old girl having solitary ICC with intact neurology, diagnosed by an appreciation of scolex on magnetic resonance imaging and were treated successfully with albendazole. Follow-up was performed by the estimation of Ag-ELISA which was negative after 2 months of completion of treatment and patient was asymptomatic at 2 years of follow-up. PMID- 28553398 TI - Partial Encephalocraniocutaneous Lipomatosis Syndrome. AB - Encephalocranial lipomatosis is a rare disorder that characteristically involves ectomesodermal tissues such as skin, eye, and the central nervous system. Here, we report a 3-year-old girl presented with developmental delay, seizures, limbal dermoid, and weakness of right lower limb. Imaging revealed hemiatrophy, arachnoid cyst, and polymicrogyria. The constellation of clinical finding and imaging leads to the diagnosis. PMID- 28553399 TI - The Gut-brain Axis: A New Pathogenic View of Neurologic Symptoms - Description of a Pediatric Case. AB - Recent literature data have given emphasis to the relationship between gastrointestinal (GI) disorders and neurologic diseases, underlying a new pathogenic pathway: The so-called "gut-brain axis." Herein, authors report a case of a 10-month-old male infant, admitted for drug-resistant epilepsy, associated with irritable behavior and GI discomfort, secondary to cow's milk protein allergy. Seizures were described by parents as upward eye movements that were mostly deviated to the right and were associated with slight extension of his neck. They were infrequent at first, but had increased gradually during the course of 3 days (up to 15-20 times/day). No anticonvulsant therapy was effective. Only a cow's milk protein-free diet, accidentally started during a gastroenteritis episode, was effective in stopping seizures. Our case underlines the peculiar vulnerability of the blood-brain barrier under 1 year of age, for which children of this age group experience neurologic manifestations during episodes of systemic inflammation. PMID- 28553400 TI - Proteus Syndrome with Neurological Manifestations: A Rare Presentation. AB - Proteus syndrome (PS) is an extremely rare and complex disorder. Approximately 200 cases have been reported, and it seems to affect people of all ethnic and racial groups. PS is characterized by segmental overgrowth of multiple tissues and organs including vascular malformations, lipomatous overgrowth, hyperpigmentation, and various types of nevi. We hereby present a 7-year-old boy who presented with seizures and overgrowth of one-half of the body. Although classical physical features have been described, epilepsy and other neurological manifestations are rarely reported features of PS. Early detection of association of epilepsy and hemimegalencephaly with PS can prevent/minimize the neurological complications, disability, morbidity, and mortality. PMID- 28553401 TI - Hippocampal Sclerosis in a Child with Multiple Neurocysticercosis. PMID- 28553402 TI - Proline-rich Transmembrane Protein 2 Gene Mutation in a Sporadic Paroxysmal Kinesigenic Dyskinesia. PMID- 28553403 TI - Autism Spectrum Disorders: The Troubles with the Diagnostic and Statistical Manual of Mental Disorders 5th Edition. PMID- 28553404 TI - Mucolipidosis Type II Secondary to GNPTAB Gene Deletion from India. PMID- 28553405 TI - CDKL-5 Encephalopathy in an Indian Girl: Partial Response to the Modified Atkins Diet. PMID- 28553406 TI - A Rare Cause of Pleural Effusion; Cerebrospinal Fluid Leakage. PMID- 28553407 TI - Sleep Disturbance During Smoking Cessation: Withdrawal or Side Effect of Treatment? AB - INTRODUCTION: The nicotine-metabolite ratio (NMR) predicts treatment response and is related to treatment side effect severity. Sleep disturbance may be one important side effect, but understanding sleep disturbance effects on smoking cessation is complicated by the fact that nicotine withdrawal also produces sleep disturbance. AIMS: To evaluate the effects of withdrawal and treatment side effects on sleep disturbance. METHODS: This is a secondary analysis of data from a clinical trial (Lerman et al., 2015) of 1,136 smokers randomised to placebo (n = 363), transdermal nicotine (TN; n = 381), or varenicline (n = 392) and stratified based on NMR (559 slow metabolisers; 577 normal metabolisers). Sleep disturbance was assessed at baseline and at 1-week following the target quit date (TQD). We also examined whether sleep disturbance predicted 7-day point prevalence abstinence at end-of-treatment (EOT). RESULTS: The varenicline and TN groups exhibited greater increases in sleep disturbance (vs. placebo; treatment * time interaction; p = 0.005), particularly among those who quit smoking at 1-week post-TQD. There was a main effect of NMR (p = 0.04), but no interactions with treatment. TN and varenicline attenuated withdrawal symptoms unrelated to sleep (vs. placebo). Greater baseline sleep disturbance predicted relapse at EOT (p = 0.004). CONCLUSIONS: Existing treatments may not mitigate withdrawal-related sleep disturbance and adjunctive treatments that target sleep disturbance may improve abstinence rates. PMID- 28553408 TI - Identification of Cysteine Ubiquitylation Sites on the Sec23A Protein of the COPII Complex Required for Vesicle Formation from the ER. AB - BACKGROUND: COPII is a multiprotein complex that surrounds carrier vesicles budding from the Endoplasmic Reticulum and allows the recruitment of secretory proteins. The Sec23a protein plays a crucial role in the regulation of the dynamics of COPII formation ensuring the proper function of the secretory pathway. OBJECTIVE: Since few evidences suggest that ubiquitylation could have a role in the COPII regulation, the present study was aimed to establish whether the Sec23a component of the vesicular envelope COPII could be ubiquitylated. METHOD: Sec23a ubiquitylation was revealed by co-immunoprecipitation experiments. Recombinant Sec23a was gel-purified and analyzed by mass spectrometry subjected to trypsin proteolysis. Signature peptides were identified by the presence of Gly Gly remnants from the C-terminus of the ubiquitin attached to the amino acid residues of the substrate. Recombinant Sec23a proteins bearing mutations in the ubiquitylation sites were used to evaluate the effect of ubiquitylation in the formation of COPII. RESULTS: We identified two cysteine ubiquitylation sites showed at position 432 and 449 of the Sec23a protein sequence. Interestingly, we revealed that the amino acid residues of Sec23a joined to ubiquitin were cysteine instead of the conventional lysine residues. This unconventional ubiquitylation consists of the addition of one single ubiquitin moiety that is not required for Sec23a degradation. Immunofluorescence results showed that Sec23a ubiquitylation might influence COPII formation by modulating Sec23a interaction with the ER membrane. Presumably, this regulation could occur throughout continual ubiquitylation/de-ubiquityliation cycles. CONCLUSION: Our results suggest a novel regulatory mechanism for the Sec23a function that could be crucial in several pathophysiological events known to alter COPII recycling. PMID- 28553409 TI - Synthesis of Oxadiazolyl, Pyrazolyl and Thiazolyl Derivatives of Thiophene-2 Carboxamide as Antimicrobial and Anti-HCV Agents. AB - INTRODUCTION: Three series of pyrazole, thiazole and 1,3,4-oxadiazole, derivatives were synthesized starting from 5-amino-4-(hydrazinocarbonyl)-3 methylthiophene-2-carboxamide (2). METHODS: All compounds were investigated for their preliminary antimicrobial activity. They were proved to exhibit remarkable antimicrobial activity against Pseudomonas aeruginosa with insignificant activity towards Gram positive bacterial strains and fungi. RESULTS: In-vitro testing of the new compounds on hepatitis-C virus (HCV) replication in hepatocellular carcinoma cell line HepG2 infected with the virus utilizing the reverse transcription polymerase chain reaction technique (RT-PCR) generally showed inhibition of the replication of HCV RNA (-) strands at low concentration, while, eight compounds; 3a, 6, 7a, 7b, 9a, 9b, 10a and 11b proved to inhibit the replication of HCV RNA (+) and (-) strands at very low concentration range 0.08 0.36 MUg/mL. CONCLUSION: Compounds 7b and 11b displayed the highest anti-HCV and antimicrobial activities in this study. PMID- 28553410 TI - Socioeconomic Factors and Severity of Coronary Artery Disease in Patients Undergoing Coronary Angiography: A Multicentre Study of Arabian Gulf States. AB - INTRODUCTION: Coronary artery disease (CAD) is a leading cause of death worldwide. The association of socioeconomic status with CAD is supported by numerous epidemiological studies. Whether such factors also impact the number of diseased coronary vessels and its severity is not well established. MATERIALS AND METHODS: We conducted a prospective multicentre, multi-ethnic, cross sectional observational study of consecutive patients undergoing coronary angiography (CAG) at 5 hospitals in the Kingdom of Saudi Arabia and the United Arab Emirates. Baseline demographics, socioeconomic, and clinical variables were collected for all patients. Significant CAD was defined as >=70% luminal stenosis in a major epicardial vessel. Left main disease (LMD) was defined as >=50% stenosis in the left main coronary artery. Multi-vessel disease (MVD) was defined as having >1 significant CAD. RESULTS: Of 1,068 patients (age 59 +/- 13, female 28%, diabetes 56%, hypertension 60%, history of CAD 43%), 792 (74%) were from urban and remainder (26%) from rural communities. Patients from rural centres were older (61 +/- 12 vs 58 +/- 13), and more likely to have a history of diabetes (63 vs 54%), hypertension (74 vs 55%), dyslipidaemia (78 vs 59%), CAD (50 vs 41%) and percutaneous coronary intervention (PCI) (27 vs 21%). The two groups differed significantly in terms of income level, employment status and indication for angiography. After adjusting for baseline differences, patients living in a rural area were more likely to have significant CAD (adjusted OR 2.40 [1.47, 3.97]), MVD (adjusted OR 1.76 [1.18, 2.63]) and LMD (adjusted OR 1.71 [1.04, 2.82]). Higher income was also associated with a higher risk for significant CAD (adjusted OR 6.97 [2.30, 21.09]) and MVD (adjusted OR 2.49 [1.11, 5.56]), while unemployment was associated with a higher risk of significant CAD (adjusted OR 2.21, [1.27, 3.85]). CONCLUSION: Communal and socioeconomic factors are associated with higher odds of significant CAD and MVD in the group of patients referred for CAG. The underpinnings of these associations (e.g. pathophysiologic factors, access to care, and system-wide determinants of quality) require further study. PMID- 28553411 TI - Knowledge About Chronic Orofacial Pain Among General Dentists of Kermanshah, Iran. AB - BACKGROUND AND OBJECTIVE: Diagnosis and treatment of chronic orofacial pain are one of the most challenging issues in dentistry. The purpose of this study was to assess the knowledge of general dentists regarding orofacial pain in Kermanshah, Iran. METHODS: This cross-sectional study was conducted in 2016 including general dentists of Kermanshah city. A researcher-designed questionnaire was administered to collect demographic data as well as measuring knowledge of the dentists in four sections including etiology, clinical presentations, physical examination, and treatment of chronic orofacial pain. The questionnaire had acceptable validity (content validity > 0.9) and reliability (intraclass correlation coefficient= 0.857 for test re-test; Cronbach's alpha= 0.72 for internal consistency). The data were analyzed by the SPSS software (ver. 18.0) using Spearman's correlation coefficient (P < 0.05). RESULTS: There were 121 male (72.9%) and 45 female (27.1%) dentists with mean (SD) age of 40.55 (8.03) years and mean (SD) practice history of 13.28 (8.43) years. Mean (SD) knowledge score was 10.54 (2.36) (maximum possible score= 15). 48.2% of dentists had good knowledge in overall. 48.2% about etiology, 45.2% about clinical presentations, 36.1% about physical examination, and 7.8% about treatment had good knowledge. Knowledge had direct and significant relationship with age (r = 0.179; P = 0.022) and practice history (r = 0.18; P = 0.021). CONCLUSION: The results showed that the studied dentists did not have enough knowledge about chronic orofacial pain especially in the treatment field. Therefore, it is recommended to implement educational programs to improve their knowledge. PMID- 28553412 TI - Dental and Oral Problem Patterns and Treatment Seeking Behavior of Geriatric Population. AB - BACKGROUND: The manifestations of oral changes and disorders affecting the geriatric population are different from the rest of the population. Inaccessibility to dental care is a compelling impediment to avail oral health services. OBJECTIVE: The aims were to assess the dental and oral problems and to find out the determinants of oral health seeking behaviour among elderly population of Al-Jouf province, Saudi Arabia. METHODS: The present cross sectional study included geriatric patients of 60 years and above, who visited the College of Dentistry, Al-Jouf University. A simple pre-structured questionnaire was filled by the patients, which comprised of demographic details and the different oral complaints of elderly and the type of health care utilized for those complaints. RESULTS: Out of total 892 elderly persons included, 51.79% were males and 48.21 were females. The most common oral problem was missing tooth (78.69%) followed by gum problems (74.21%). 39.5% males and 28.0% females visited general dental practitioners for oral health care. Majority of the participants (32.8%) suggested accessibility as a basic factor in determining the health care source. The difference in the distribution of male and females or association between the type of care and gender and distribution for choosing a health care source was found to be statistically significant (p < 0.05). CONCLUSION: Inaccessibility to dental care emerged as an important barrier to avail oral health services. Adequate access to medical and dental care can reduce premature morbidity and mortality, preserve function, and enhance overall quality of life. PMID- 28553413 TI - Dentofacial Deformity Caused by Bulky Osteochondroma: Report of an Unusual Case and the Importance of Cone Beam Computed Tomography. AB - INTRODUCTION: Osteochondroma of mandibular condyle is a rare benign tumor. CASE REPORT: This case report described clinical, radiographic features, differential diagnosis, histopathologic correlation and treatment of condylar osteochondroma. CONCLUSION: Conebeam computed tomography (CBCT) is an alternative modality to CT or MRI that should be performed in all cases of suspected osteochondroma of the mandibular condyle. PMID- 28553415 TI - Use of Proviral DNA to Investigate Virus Resistance Mutations in HIV-infected Zimbabweans. AB - BACKGROUND: Antiretroviral therapy (ART) to suppress HIV replication has reduced morbidity and mortality yet effectiveness of current HIV drugs is threatened by HIV drug resistance (HIVDR) mutations. OBJECTIVE: To determine HIVDR mutations using proviral DNA from specimens of patients presenting to an HIV treatment clinic. METHODS: DNA from 103 patients, 86 treatment-experienced, 17 treatment naive, were genotyped for the HIV-1C reverse transcriptase gene (RT; codons 21 304) using Sanger sequencing and sequences analyzed using Sequencher software. Resistance mutations were interpreted using Stanford HIVDR reference database. RESULTS: Median age was 39 (IQR, 33-46) years and 80% of patients were female. Six-percent (n=6) had at least one HIVDR mutation, comprising NRTI-associated mutations, (M184V, T69D, T69N and V75I); NNRTI-associated mutations (G190A, K103N, V106M, Y181C) and thymidine analogue associated mutations (D67N, K70R, K219Q, L210W, M41L, T215Y). Of the six participants, with at least one HIVDR mutation, all were treatment experienced, five were on tenofovir, lamivudine and nevirapine and one was on tenofovir, lamivudine and atazanavir. There was no difference in median CD4 count and viral loads when patients were compared by presence of HIVDR mutations. CONCLUSION: We demonstrated the use of proviral DNA in HIVDR testing in adult patients and present that all the patients with various kinds of HIVDR mutations were treatment experienced, pointing to the role of drug regimens in driving viral mutations. Thus, the use of proviral DNA has potential to help provide surveillance on risk of HIVDR in HIV-infected individuals who are on treatment, which may assist in corrective treatment. PMID- 28553414 TI - ESBL Production Among E. coli and Klebsiella spp. Causing Urinary Tract Infection: A Hospital Based Study. AB - INTRODUCTION: Increase in extended-spectrum beta-lactamases (ESBL) producing microbes in recent years has led to limitations of treatment options. This study aimed to assess the prevalence of ESBL producing E. coli and Klebsiella spp. at a tertiary hospital in Nepal. METHODS: A total of 2209 non-repetitive mid-stream urine (MSU) samples were collected during the study period (March to September 2014). Identification of the isolates was done by Gram's staining followed by biochemical tests. Antibiotic susceptibility testing was done by modified Kirby Bauer disc diffusion method and interpretation was done following Clinical and Laboratory Standard Institute (CLSI) guidelines, 2013. ESBL screening among E. coli and Klebsiella spp. isolates were done using ceftriaxone, cefotaxime, ceftazidime and cefpodoxime. The confirmation was done by phenotypic disc diffusion test (combined disc method) using ceftazidime (30ug) and ceftazidime plus clavulanic acid (30/10ug), and cefotaxime (30ug) and cefotaxime plus clavulanic acid (30/10ug) disc as per CLSI guidelines. RESULTS: A total of 451 samples showed significant bacteriuria with 365 (80.9%) E. coli, 17 (3.8%) Klebsiella pneumoniae and 3 (0.7%) Klebsiella oxytoca. Of 451 isolates, 236 (52.3%) were found MDR strains. By combined disk test, 33 (91.7%) E. coli and 3 (8.3%) Klebsiella spp. were found ESBL producers. CONCLUSION: Higher prevalence of ESBL producing E. coli and Klebsiella spp. was observed warranting prompt need of surveillance for effective management of such MDR strains. PMID- 28553416 TI - Understanding the Mechanism of Bacterial Biofilms Resistance to Antimicrobial Agents. AB - A biofilm is a group of microorganisms, that causes health problems for the patients with indwelling medical devices via attachment of cells to the surface matrix. It increases the resistance of a microorganism for antimicrobial agents and developed the human infection. Current strategies are removed or prevent the microbial colonies from the medical devices, which are attached to the surfaces. This will improve the clinical outcomes in favor of the patients suffering from serious infectious diseases. Moreover, the identification and inhibition of genes, which have the major role in biofilm formation, could be the effective approach for health care systems. In a current review article, we are highlighting the biofilm matrix and molecular mechanism of antimicrobial resistance in bacterial biofilms. PMID- 28553417 TI - Synergistic Effect of Colistin and Rifampin Against Multidrug Resistant Acinetobacter baumannii: A Systematic Review and Meta-Analysis. AB - The existence of infections caused by multidrug resistant (MDR) Acinetobacter baumannii is a growing problem because of the difficulty to treat them. We examined the published literature and focused our analysis on the investigation of the synergism of colistin and rifampin against MDR A. baumannii isolates via systematic review and meta-analysis. A systematic literature search was performed using the following 4 databases (PubMed, Scopus, EMBASE and ISI Web of Sciences). The related articles were evaluated during the period from December 2014 to January 2015. Information based on resistance and sensitivity to antibiotics, the minimum inhibitory concentration and the effects of two antibiotics on each other including synergism, antagonism, relative synergism and additive antagonism were extracted. A meta-analysis of 17 studies including 448 samples was brought into process and 2% (95% CI 0-4%) and 72% (95% CI 56-89%) resistance to colistin and rifampin were observed, respectively. 42% of all isolates showed MIC = 4 ug/ml (95% CI 14-69%) to rifampin and 30% MIC= 2 ug/ml to colistin (95% CI 3.8-78%). MIC50 and MIC90 for both rifampin and colistin were 2 ug/ml and 4 ug/ml, respectively. 63% of the strains demonstrated synergy (95% CI 37-90%), 7% were highlighted as relative synergism (95% CI 0.0- 13%), 3% showed an additive effect (95% CI -0.0-7%) and 14% were indifferent (95% CI 6-23%). The antagonistic effect was not observed in this combination. Synergy rates of time-kill assay in rifampin and colistin combinations were generally higher than those of check bored microdilution and E-test method. The results demonstrated that the combination therapy could be more useful when compared to monotherapy and that this strategy might reduce the resistance rate to rifampin in MDR A. baumannii isolates. PMID- 28553419 TI - The Use of patient Reported Outcome Measures for Rheumatoid Arthritis in Japan: A Systematic Literature Review. AB - BACKGROUND: Patient-reported outcomes (PRO) obtained through routine medical care may identify patients' day-to-day burden and help tackle the disease from the patients' perspective. However, there is a paucity of information regarding the availability of PRO data and PRO tools for rheumatoid arthritis (RA) in Japan. OBJECTIVE: We reviewed the literature on PRO data availability and to identify PRO measures implemented in Japan for RA patients. METHOD: We conducted a systematic literature review using ICHUSHI and the PubMed databases on PRO measures for RA published from January 2011 to August 2015 in Japan. RESULTS: After removing duplicates, 2423 manuscripts were found. From these, 100 manuscripts were included for review and analysis. We found 29 PRO tools that were used to assess various domains of health such as general well-being, pain, functionality, and fatigue. More than 90% of the studies utilized PRO tools for research purpose. Only one study reported PRO tool implementation in the routine medical care. CONCLUSION: The importance of PROs is recognized in Japan. PRO tools varied significantly and were mostly used for research purposes, while reports on the use of PRO measures in routine medical care were limited. Despite the awareness of PROs in the research community, unmet needs remain among RA patients in Japan. Further work is needed to investigate ways in which PROs can better reflect these unmet needs and be utilized in routine medical care. PMID- 28553418 TI - Analysis of the Literature on Chronic Cough in Children. AB - Throughout childhood, various developmental phenomena influence the cough reflex. Among these are the modifications in the anatomy and functions of the respiratory tract and the central and peripheral nervous systems. Moreover, after birth, the immunological response undergoes progressive transformations with the acquisition of immune memory processes. These conditions make infections and airway abnormalities the overwhelming cause of chronic cough in children and infants. In children, chronic cough should be treated on the basis of etiology. The aim of this article is to provide thorough research and analysis of the medical literature published up to 2014 on chronic cough in children as a disease entity, including the epidemiologic, etiologic, diagnostic, prognostic, and therapeutic aspects. Our results demonstrate differences in the definition of chronic cough, the characteristics of diagnostic procedures, study settings, and prevalence of the main causes. However, few studies regarding epidemiology and the quality of life have been reported. Many therapeutic approaches that are considered effective in adults with chronic cough seem to be less efficient in children. Regardless of the setting, whether pediatric or non-pediatric, children with chronic cough should be carefully evaluated using child-specific protocols and algorithms. Awareness of the various pathophysiological conditions associated with chronic cough is vital for making a correct diagnosis and providing appropriate treatment. The prevalence of the different causes of chronic cough depends on various issues. Among these are the population under consideration and its age range, infectious disease control and prevention, the diagnostic procedures employed, disease definition criteria, and the local health system. Clinical guidelines for the management of children with chronic cough should take these components into consideration. Further clinical and basic research studies are still needed for better diagnosis, treatment, and prevention of chronic cough in children. PMID- 28553420 TI - A New Reconstructive Technique of the Anterolateral Ligament with Iliotibial Band Strip. AB - BACKGROUND: Anterior cruciate ligament (ACL) reconstruction is a well-established surgical procedure for the correction of ACL ruptures. However, the incidence of instability following ACL reconstruction is substantial. Recent studies have led to greater insight into the anatomy and the radiographic characteristics of the native anterolateral ligament (ALL), along with its possible role in residual instability after ACL reconstruction. METHOD: The current paper describes a lateral extra-articular tenodesis to reconstruct the ALL during ACL procedures, using a short iliotibial band strip. The distal insertion of this strip is left intact on the anterolateral side of the proximal tibia, and the proximal part is fixed at the anatomic femoral insertion of the ALL. RESULTS: Our technique avoids the sacrifice of one of the hamstring tendons for the ALL reconstruction. Additionally, there is no interference with the anatomical location or function of the LCL. CONCLUSION: Our technique offers a minimally invasive and nearly complete anatomical reconstruction of the ALL with minimal additional operative time. PMID- 28553421 TI - Irreducible Anterior Shoulder Dislocation with Interposition of the Long Head of the Biceps and Greater Tuberosity Fracture: A Case Report and Review of the Literature. AB - BACKGROUND: Failure of closed manipulative reduction of an acute anterior shoulder dislocation is seldom reported in the literature and is usually due to structural blocks such as soft tissue entrapment (biceps, subscapularis, labrum), bony fragments (glenoid, greater tuberosity) and severe head impaction (Hill Sachs lesion). CASE REPORT: We present a case of an irreducible anterior shoulder dislocation in a 57-year-old male patient after a road-traffic accident. He had severe impaction of the head underneath glenoid rim and associated fracture of the greater tuberosity. Closed reduction performed in the emergency room under sedation and later at the theatre under general anaesthesia was unsuccessful. Open reduction using the dectopectoral approach revealed that the reason for obstruction was the posterolateral entrapment of the biceps tendon between the humeral head and the tuberosity fragment. Reduction was achieved after subscapularis tenotomy and opening of the joint; the tuberosity fragment was fixed with transosseous sutures and the long head of the biceps tendon was tenodesized. The patient had an uneventful postoperative recovery and at his last follow up, 12 months postoperatively, he had a stable joint, full range of motion and a Constant score of 90. CONCLUSION: A comprehensive literature review revealed 22 similar reports affecting a total of 30 patients. Interposition of the LHBT alone or in combination with greater tuberosity fracture was the most common obstacle to reduction, followed by subscapularis tendon interposition and other less common reasons. Early surgical intervention with open reduction and confrontation of associated injuries is mandatory for a successful outcome. PMID- 28553422 TI - Current Concepts in Pediatric Orthopedics. PMID- 28553424 TI - Bilateral Idiopathic Sclerochoroidal Calcifications. AB - BACKGROUND: Sclerochoroidal calcification (SCC) is a rare and benign condition found mostly in middle-aged and elderly Caucasian men, characterized by multiple yellow-white lesions seen most commonly in the temporal regions of the fundus. While they may be concerning for benign tumors, primary neoplasias or metastases, SCCs most commonly present as asymptomatic findings during routine ophthalmologic testing and have a very good prognosis as they rarely cause visual deficits. OBJECTIVE: To report and describe the findings in a case of bilateral idiopathic sclerochoroidal calcifications. METHODS: A retrospective case report. RESULTS: Repeated ophthalmological exams, including fundoscopic examination, ultrasonography, optical coherence tomography and fluorescein angiography, were all consistent bilateral idiopathic sclerochoroidal calcifications. CONCLUSION: While most cases of idiopathic sclerochoroidal calcifications represent a benign ophthalmological condition, there are known associations with other systemic conditions, such as hyperthyroidism, hyperparathyroidism, Bartter's syndrome and Gitelman's syndrome. It is for this reason that these patients warrant a full systemic work-up in addition to careful ophthalmological monitoring. PMID- 28553425 TI - Treatment of Symptomatic Vitreomacular Adhesion with Expansile Sulfur Hexafluoride (SF6) Gas. AB - BACKGROUND: To evaluate intravitreal injection of expansile sulfur hexafluoride (SF6) as a low cost and effective treatment for symptomatic vitreomacular adhesion (sVMA). METHODS: Retrospective analysis of all patients with sVMA treated with pneumatic vitreolysis using SF6 gas presenting to a clinical practice from January 2005 and June 2013. RESULTS: Six cases were included in the study. Five patients (83%) experienced complete resolution of the vitreomacular adhesion. One patient had a partial release of the vitreomacular adhesion. Four patients (67%) had a one line improvement in best corrected visual acuity. CONCLUSION: Due to its low cost, wide availability, and apparent efficacy, intravitreal injection of expansile SF6 should be investigated further as a possible treatment modality for sVMA. PMID- 28553423 TI - Corneal Refractive Procedures for the Treatment of Presbyopia. AB - PURPOSE: Refractive surgery has been in use for a long time and is evolving at a fast pace with several new corneal procedures being used for the correction of presbyopia. The purpose of this article is to give a comprehensive review of the literature to evaluate the outcome and success of different corneal refractive surgical procedures in presbyopic patients. METHODS: We performed a comprehensive search on PubMed to identify published reports of the various procedures utilized in the past and present to correct presbyopia. The outcomes of these procedures were recorded. RESULTS AND CONCLUSION: We found that varying rates of success have been reported with these procedures. The results of our exhaustive search are presented in this report for review. PMID- 28553426 TI - Characteristics of Anterior Lens Opacities in Children. AB - BACKGROUND: Anterior lens opacities (ALO) are found in 3-14% of pediatric patients with cataracts. No clear guidelines exist in the management and treatment of these cataracts. OBJECTIVE: To evaluate pediatric patients with anterior lens opacities and assess rate of amblyopia and need for surgery over time. METHODS: A retrospective chart review was performed on patients with unilateral and bilateral anterior lens opacities (ALOs) seen between January 2008 and December 2014. Size, location, and type of ALO were noted. Refractive error, necessity for treatment of amblyopia, and interventions were recorded. RESULTS: A total of 31 patients were included in the study. 17 patients had unilateral ALOs and 14 had bilateral ALOs. The majority of the cataracts (90.3%) were centrally located. The most common type of cataract was the polar type of cataract and the vast majority (48.4%) was < 1mm in size. 38.7% of patients had concurrent ocular conditions and 9.7% had systemic associations. 28.6% of patients with bilateral cataracts and 35.3% of the patients with unilateral cataracts were treated for amblyopia. Three patients required cataract surgery. CONCLUSION: About half of anterior lens opacities are less than 1mm in size and the majority are of the polar type. Risk of amblyopia in these patients is higher than in the general population. Anisometropia is the most common cause of amblyopia. Ocular associations are seen at a relatively high frequency and systemic associations can occur but are uncommon. The need for surgical intervention is infrequent; however, growth of ALOs and associated cortical changes may be risk factors for surgery. PMID- 28553428 TI - Clinical Improvement by Switching to an Integrase Strand Transfer Inhibitor in Hemophiliac Patients with HIV: The Japan Cohort Study of HIV Patients Infected through Blood Products. AB - OBJECTIVE: This study aimed to determine improvement in HIV RNA levels and the CD4 cell count by switching to an antiretroviral regimen with an integrase strand transfer inhibitor (INSTI) in patients with HIV. METHOD: This study was conducted on Japanese patients with HIV who were infected by blood products in the 1980s. Data were collected between 2007 and 2014. Data of 564 male hemophiliac patients with HIV from the Japan Cohort Study of HIV Patients Infected through Blood Products were available. Changes in antiretroviral regimen use, HIV RNA levels, and the CD4 cell count between 2007 and 2014 were examined. RESULTS: From 2007 to 2014, the proportion of use of a regimen with an INSTI increased from 0.0% to 41.0%. For patients with HIV who used a regimen, including an INSTI, the proportion of HIV RNA levels <50 copies/mL significantly increased from 58.3% in 2007 to 90.6% in 2014. Additionally, the median CD4 cell count significantly increased from 380/MUL to 438/MUL. CONCLUSION: There is a large effect of switching to an antiretroviral regimen with an INSTI for Japanese patients with HIV who are infected by blood products. This suggests that performing this switch in clinical practice will lead to favorable effects. PMID- 28553427 TI - Functional Evaluation of Awareness in Vegetative and Minimally Conscious State. AB - OBJECTIVE: The aim of this study was to assess differences in brain activation in a large sample of Vegetative State (VS) and Minimally Conscious State (MCS) patients, using functional magnetic resonance imaging (fMRI). METHODS: We studied 50 patients four to seven months after brain injury. By using international clinical criteria and validated behavioural scales such as the Glasgow Coma Scale and the Clinical Unawareness Assessment Scale, the patients were grouped into VS (n=23) and MCS (n=27). All patients underwent to fMRI examination. After 6 months, the patients were reassessed using Glasgow Outcome Scale and Revised Coma Recovery Scale. RESULTS: fMRI showed significant (p<0.01, cluster-corrected) brain activation in the primary auditory cortex bilaterally during the acoustic stimuli in patients with both VS and MCS. However, ten patients clinically classified as VS, showed a pattern of brain activation very similar to that of MCS patients. Six months later, these ten VS patients had significant clinical improvement, evolving into MCS, whereas the other VS patients and patients with MCS remained clinically stable. CONCLUSION: Brain activity could help in discerning whether the status of wakefulness in VS is also accompanied by partial awareness, as occurs in MCS. This may have very important prognostic implications. PMID- 28553429 TI - Plasma IP-10 Concentrations Correlate Positively with Viraemia and Inversely with CD4 Counts in Untreated HIV Infection. AB - BACKGROUND: Chronic immune activation is a feature of HIV infection associated with accelerated HIV disease progression. There is conflicting data on the association of biomarkers of immune activation with traditional markers of HIV disease progression; CD4 counts and viral load (VL). OBJECTIVE: The study aimed to determine the association of biomarkers of immune activation; interferon (IFN) gamma-induced protein 10 (IP-10) and soluble cluster of differentiation 14 (sCD14) in chronic HIV infection with traditional markers of HIV disease progression. METHODS: We collected demographic data, enumerated CD4 counts and quantified VL in 183 antiretroviral therapy (ART)-naive adults with chronic HIV infection. Plasma concentrations of IP-10 and sCD14 were quantified in the ART naive adults with chronic HIV infection and 75 HIV-uninfected controls. RESULTS: IP-10 concentrations were significantly higher in the HIV-infected group (median; 257.40pg/ml, IQR; 174.08-376.32) than in the HIV-uninfected (median; 86.19pg/ml, IQR; 67.70-116.39) (P<0.001). Similarly, sCD14 concentrations were significantly higher in the HIV-infected (median; 1.45ug/ml, IQR; 1.02-2.16) group than in the controls (median; 0.89u/ml, IQR; 0.74-1.18) (P<0.001). High log10 IP-10 concentrations were positively correlated with high log10 viral loads (Spearman's correlation coefficient [R]=0.21, P=0.003) and inversely correlated with low CD4 counts (R= -0.19, P=0.011). In contrast, log10 sCD14 was not significantly associated with either log10 viral loads (R=0.03, P=0.707) nor CD4 count (R= 0.04, P=0.568). CONCLUSION: We conclude that plasma sCD14 and IP-10 were elevated in the HIV-infected patients compared to HIV-uninfected individuals possibly due to on-going immune activation. In addition, plasma high concentrations of IP-10 but not sCD14 concentrations are associated with high VL and low CD4 count. PMID- 28553430 TI - Plasma Level of Soluble ST2 in Chronically Infected HIV-1 Patients with Suppressed Viremia. AB - INTRODUCTION: Interleukin-33 (IL-33) is a cell damage-induced alarmin. The plasma concentration of suppression of tumorogenicity (sST2), a surrogate marker of IL 33 production, is a prognostic marker of cardiovascular disease. OBSERVATION: Recently, we reported that sST2 plasma levels were elevated in early HIV-1 infection and linked to markers of microbial translocation and of T cell activation. RESULTS: Here we show that it is not the case in patients with suppressed viremia. Thus, IL-33 plays its alarmin role only during the early phase of the infection. PMID- 28553431 TI - Quantitative Analysis of Electron Beam Damage in Organic Thin Films. AB - In transmission electron microscopy (TEM) the interaction of an electron beam with polymers such as P3HT:PCBM photovoltaic nanocomposites results in electron beam damage, which is the most important factor limiting acquisition of structural or chemical data at high spatial resolution. Beam effects can vary depending on parameters such as electron dose rate, temperature during imaging, and the presence of water and oxygen in the sample. Furthermore, beam damage will occur at different length scales. To assess beam damage at the angstrom scale, we followed the intensity of P3HT and PCBM diffraction rings as a function of accumulated electron dose by acquiring dose series and varying the electron dose rate, sample preparation, and the temperature during acquisition. From this, we calculated a critical dose for diffraction experiments. In imaging mode, thin film deformation was assessed using the normalized cross-correlation coefficient, while mass loss was determined via changes in average intensity and standard deviation, also varying electron dose rate, sample preparation, and temperature during acquisition. The understanding of beam damage and the determination of critical electron doses provides a framework for future experiments to maximize the information content during the acquisition of images and diffraction patterns with (cryogenic) transmission electron microscopy. PMID- 28553432 TI - HIV-1 Transactivator Protein Induces ZO-1 and Neprilysin Dysfunction in Brain Endothelial Cells via the Ras Signaling Pathway. AB - Amyloid beta (Abeta) deposition is increased in human immunodeficiency virus-1- (HIV-1-) infected brain, but the mechanisms are not fully understood. The aim of the present study was to evaluate the role of Ras signaling in HIV-1 transactivator protein- (Tat-) induced Abeta accumulation in human cerebral microvascular endothelial cells (HBEC-5i). Cell viability assay showed that 1 MUg/mL Tat and 20 MUmol/L of the Ras inhibitor farnesylthiosalicylic acid (FTS) had no significant effect on HBEC-5i cell viability after 24 h exposure. Exposure to Tat decreased protein and mRNA levels of zonula occludens- (ZO-) 1 and Abeta degrading enzyme neprilysin (NEP) in HBEC-5i cells as determined by western blotting and quantitative real-time polymerase chain reaction. Exposure to Tat also increased transendothelial transfer of Abeta and intracellular reactive oxygen species (ROS) levels; however, these effects were attenuated by FTS. Collectively, these results suggest that the Ras signaling pathway is involved in HIV-1 Tat-induced changes in ZO-1 and NEP, as well as Abeta deposition in HBEC-5i cells. FTS partially protects blood-brain barrier (BBB) integrity and inhibits Abeta accumulation. PMID- 28553433 TI - Application of Numerical Analysis of the Shape of Electron Paramagnetic Resonance Spectra for Determination of the Number of Different Groups of Radicals in the Burn Wounds. AB - Background. The evidence exists that radicals are crucial agents necessary for the wound regeneration helping to enhance the repair process. Materials and methods. The lineshape of the electron paramagnetic resonance (EPR) spectra of the burn wounds measured with the low microwave power (2.2 mW) was numerically analyzed. The experimental spectra were fitted by the sum of two and three lines. Results. The number of the lines in the EPR spectrum corresponded to the number of different groups of radicals in the natural samples after thermal treatment. The component lines were described by Gaussian and Lorentzian functions. The spectra of the burn wounds were superposition of three lines different in shape and in linewidths. The best fitting was obtained for the sum of broad Gaussian, broad Lorentzian, and narrow Lorentzian lines. Dipolar interactions between the unpaired electrons widened the broad Gaussian and broad Lorentzian lines. Radicals with the narrow Lorentzian lines existed mainly in the tested samples. Conclusions. The spectral shape analysis may be proposed as a useful method for determining the number of different groups of radicals in the burn wounds. PMID- 28553434 TI - Protective Effects of Methane-Rich Saline on Rats with Lipopolysaccharide-Induced Acute Lung Injury. AB - Objective. The aim of this research is to evaluate the protective effects of methane-rich saline (MS) on lipopolysaccharide- (LPS-) induced acute lung injury (ALI) and investigate its potential antioxidative, anti-inflammatory, and antiapoptotic activities. Methods. LPS-induced (20 mg/kg) ALI rats were injected with MS (2 ml/kg and 20 ml/kg) before the initiation of LPS induction. Survival rate was determined until 96 h after LPS was induced. Lung injury was assayed by oxygenation index, lung permeability index (LPI), wet-to-dry weight (W/D), and histology. The cells in the bronchoalveolar lavage fluid (BALF) were counted. Oxidative stress was examined by the level of malondialdehyde (MDA) and superoxide dismutase (SOD). Inflammatory factors including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) in BALF were determined by ELISA. Lung tissue apoptosis was detected by TUNEL staining and western blotting of caspase-3. Results. It was found that methane significantly prolonged the rat survival, decreased the lung W/D ratio and the content of the inflammatory factors, and reduced the amount of caspase-3 and apoptotic index. In addition, MS increased the level of SOD and decreased the level of MDA significantly. Conclusions. MS protects the LPS-challenged ALI via antioxidative, anti-inflammatory, and antiapoptotic effect, which may prove to be a novel therapy for the clinical management of ALI. PMID- 28553435 TI - Therapeutic Hypothermia Reduces Oxidative Damage and Alters Antioxidant Defenses after Cardiac Arrest. AB - After cardiac arrest, organ damage consequent to ischemia-reperfusion has been attributed to oxidative stress. Mild therapeutic hypothermia has been applied to reduce this damage, and it may reduce oxidative damage as well. This study aimed to compare oxidative damage and antioxidant defenses in patients treated with controlled normothermia versus mild therapeutic hypothermia during postcardiac arrest syndrome. The sample consisted of 31 patients under controlled normothermia (36 degrees C) and 11 patients treated with 24 h mild therapeutic hypothermia (33 degrees C), victims of in- or out-of-hospital cardiac arrest. Parameters were assessed at 6, 12, 36, and 72 h after cardiac arrest in the central venous blood samples. Hypothermic and normothermic patients had similar S100B levels, a biomarker of brain injury. Xanthine oxidase activity is similar between hypothermic and normothermic patients; however, it decreases posthypothermia treatment. Xanthine oxidase activity is positively correlated with lactate and S100B and inversely correlated with pH, calcium, and sodium levels. Hypothermia reduces malondialdehyde and protein carbonyl levels, markers of oxidative damage. Concomitantly, hypothermia increases the activity of erythrocyte antioxidant enzymes superoxide dismutase, glutathione peroxidase, and glutathione S-transferase while decreasing the activity of serum paraoxonase-1. These findings suggest that mild therapeutic hypothermia reduces oxidative damage and alters antioxidant defenses in postcardiac arrest patients. PMID- 28553438 TI - Common Mistakes in Manuscripts Submitted for Publication. PMID- 28553437 TI - Healthcare Costs Associated With Chronic Opioid Use and Fibromayalgia Syndrome. AB - BACKGROUND: Fibromyalgia (FM) is an idiopathic, functional syndrome characterized by chronic, widespread pain and diffuse tenderness. This disorder affects more than 6 million patients in the United States and is associated with significant clinical and economic burdens. OBJECTIVES: The objectives of this study were to: 1) estimate the costs associated with a FM diagnosis; and 2) estimate the impact of chronic opioid use on the costs of FM patients. RESEARCH DESIGN: Case-control study. METHODS: Subjects were identified in a large nationally representative database of commercially insured patients. Propensity score-matched analyses included 445,912 FM-control pairs in the first analysis, while the second analysis included 48,333 chronic opioid users with the FM-control pairs. Primary outcomes of interest were the medical and prescription costs compared between matched pairs, based on propensity for being a case as evidenced by coefficients obtained from a first-stage logistic regression. Patient characteristics considered include: state of residence, diagnosing provider type, comorbid conditions, and concurrent medication use. RESULTS: When controlling for propensity to receive a FM diagnosis, the actual diagnosis has a small effect on medical (-$83.54 [95% CI, -152.55 to -16.53]) and prescription ($120.31 [95% CI, 109.98-130.62]) costs. However, the effect of chronic opioid use in FM patients on medical ($9094.05 [95% CI, 8924.79-9263.31]) and prescription ($3391.81 [95% CI, 3368.84-3414.79]) costs is much more substantial. CONCLUSIONS: While the differences seen in FM patients and controls are marginal, those attributed to chronic opioid use in these patients are significantly higher. Chronic opioid therapy to treat FM is a practice based not on evidence available to practitioners, but on other variables. PMID- 28553436 TI - Cytoprotective Mechanisms Mediated by Polyphenols from Chilean Native Berries against Free Radical-Induced Damage on AGS Cells. AB - The prevalence of cytoprotective mechanisms induced by polyphenols such as activation of intracellular antioxidant responses (ICM) and direct free radical scavenging was investigated in native Chilean species of strawberries, raspberries, and currants. Human gastric epithelial cells were co- and preincubated with polyphenolic-enriched extracts (PEEs) from Chilean raspberries (Rubus geoides), strawberries (Fragaria chiloensis ssp. chiloensis f. chiloensis), and currants (Ribes magellanicum) and challenged with peroxyl and hydroxyl radicals. Cellular protection was determined in terms of cell viability, glyoxalase I and glutathione s-transferases activities, and carboxymethyl lysine (CML) and malondialdehyde levels. Our results indicate that cytoprotection induced by ICM was the prevalent mechanism for Rubus geoides and F. chiloensis. This agreed with increased levels of glyoxalase I and glutathione S-transferase activities in cells preincubated with PEEs. ORAC index indicated that F. chiloensis was the most efficient peroxyl radical scavenger. Moreover, ICM mediated by F. chiloensis was effective in protecting cells from CML accumulation in contrast to the protective effects induced by free radical scavenging. Our results indicate that although both polyphenol-mediated mechanisms can exert protective effects, ICM was the most prevalent in AGS cells. These results suggest a potential use of these native berries as functional food. PMID- 28553439 TI - Check-Rein Technique for Management of Neglected Locked Posterior Shoulder Dislocations: Evaluation of Mid-term Outcome of a Novel Technique. AB - Introduction: Neglected locked posterior shoulder dislocations, although rare, are quiet perplexing to manage. Various treatment methods have been explained for their management, but a consensus is still lacking. Besides describing a novel technique for the management of these lesions, this study aims to evaluate the mid-term outcome of this technique. Method: This prospective study involved seven consecutive patients with locked posterior dislocation of the shoulder with humeral defect between 25% and 50%. All patients underwent open reduction of the locked posterior dislocation with the current technique. The final outcome was assessed at a mean follow up of 3.5 years (range 2-5 years) using the DASH score. Result: The mean age of the patients was 32 years (range 21-44) and all were men. The mean time to presentation from initial injury was 2.4 years (range 2-4 years). The patient related outcome as measured by DASH score improved from a preoperative mean of 59.1 to mean value of 8.6 at the time of final follow up. There were no cases of graft pull out, nonunion at the graft site or infection. Conclusion: This technique results in pain-free range of motion with a stable shoulder though a larger sample population with a longer follow up is required to further support our observations. PMID- 28553440 TI - Prospective Study to compare Intra-articular versus Intravenous Tranexemic Acid in reducing Post-operative Blood Loss in staged bilateral Total Knee Arthroplasty. AB - The number of total knee arthroplasties (TKA) performed is around two million annually worldwide and this number is expected to increase fivefold by 2025. The most common indication is osteoarthritis of the knee. Blood loss is significant during the post-operative period and blood transfusion when necessary has its own drawbacks. The use of intravenous tranexamic acid has significantly reduced blood loss. We analysed 35 patients who underwent staged bilateral TKA between August 2013 and February 2016 and had administered intra-articular tranexamic acid for one knee and intravenous tranexamic acid for the other knee. The results were analysed based on post-operative blood loss, change in haemoglobin (Hb) level and haematocrit (PCV) and the need for blood transfusion. The average postoperative blood loss was 129.57 ml and 277.71 ml for intra articular group and intravenous group respectively. A control group (no drug or placebo group) with age matched patients (n= 21) was chosen from medical records. The average blood loss in the control group was 493.81 ml. The fall in Hb level and PCV was 0.72 gm/dl and 2.62 % (Intra-articular Group), 1.36 gm/dl and 4.34 % (Intravenous Group) and 2.62 gm/dl and 5.52 % (Control). The number of transfusions were two (Intra-articular Group), five (Intravenous Group) and nine (Control). We conclude that when compared with intravenous route, intra-articular administration has significantly reduced blood loss, Hb level and PCV fall and the rate of blood transfusion. PMID- 28553441 TI - Prospective Case Study of Outcome of Tibial Plateau Fractures Treated with Locking Condylar Plate. AB - Introduction: Tibial plateau injury involves the articular surface of the proximal tibia with diverse group of fractures that represent a wide spectrum of severity that challenge even the most experienced surgeons, but with the invent of modern diagnostic technology and the advent of locking plates, results appear to be improving over time. Method: The study was conducted on thirty patients admitted in the department of orthopaedics with diagnoses of tibial plateau fractures treated with Locking Condylar Plate. The patients were followed up for a minimum period of six months and clinico-radiological progression of fracture union with the functional outcome was studied using 100 point rating system devised by Delamarter et al. Result: Twenty-two patients showed excellent results while eight patients had good to fair and none with poor result. The average time for radiological union was 17.5 weeks. Conclusion: The results of the study concluded that while locking condylar plate seems to show excellent results in low energy tibial plateau fractures, it can probably be used to successfully treat patients with high energy fracture patterns without the need for additional medial stabilization. PMID- 28553442 TI - Physical and Clinical Evaluation of Hip Spica Cast applied with Three-slab Technique using Fibreglass Material. AB - Introduction: Hip spica casting is an important component of treatment for developmental dysplasia of the hip (DDH) and popular treatment method for femur fractures in children. Breakage at the hip region is a relatively common problem of this cast. We have developed a three-slab technique of hip spica application using fibreglass as the cast material. The purpose of this review was to evaluate the physical durability of the spica cast and skin complications with its use. Methodology: A retrospective review of children with various conditions requiring hip spica immobilisation which was applied using our method. Study duration was from 1st of January 2014 until 31st December 2015. Our main outcomes were cast breakage and skin complications. For children with hip instability, the first cast would be changed after one month, and the second cast about two months later. Results: Twenty-one children were included, with an average age of 2.2 years. The most common indication for spica immobilisation was developmental dysplasia of the hip. One child had skin irritation after spica application. No spica breakage was noted. Conclusion: This study showed that the three-slab method of hip spica cast application using fibreglass material was durable and safe with low risk of skin complications. PMID- 28553443 TI - Pattern of Presentation and Outcome of Short-term Treatment for Idiopathic Clubfoot / CTEV with Ponseti Method. AB - Introduction: Congenital Talipes Equinovarus (CTEV) is a common congenital foot deformity that is associated with long term disability. Treatment with Ponseti method has been successful especially for children who present early. We conducted this study to investigate the age of presentation of children and report the early outcome. Materials: This is a retrospective study from a single institution. We included 31 patients with 45 idiopathic clubfeet and investigated problems and success rate at the end of serial casting. Results: Mean age at presentation was 4.9 months. The mean number of casting was 6 and mean duration of casting was 2.7 months. The initial success rate of 91.1%, with four feet (8.8%) diagnosed as resistant clubfoot and eventually required soft tissue surgery. With mean follow up of 14.1 months, four other feet (8.8%) developed relapse but were treated with repeat Ponseti method. Conclusion: Many CTEV patients present late for treatment. However, the Ponseti method remained effective with high initial success rate of 91.1%. Relapsed CTEV can still be treated successfully with repeat casting using the Ponseti method. PMID- 28553444 TI - Role of Local Infiltration of Tranexamic Acid in Reducing Blood Loss in Peritrochanteric Fracture Surgery in the Elderly Population. AB - Introduction: Peritrochanteric fractures are common injuries occurring in elderly patients. Surgeries for these fractures are associated with significant blood loss. Intravenous tranexamic acid has a proven track record in many orthopaedic surgeries including trauma, arthroplasty and spine surgeries. Objective: To study the effect of local subfascial and intramuscular infiltration of tranexamic acid in reducing blood loss and the requirement for blood transfusion in intertrochanteric fracture surgery. Study Design: Single centre prospective analytical study. Materials and Methods: One hundred and thirty seven patients above 65 years of age were included in the study, divided into two groups: the intervention group received subfascial and intramuscular infiltration of 2g tranexamic acid before wound closure and the control group of alternate patients did not receive any tranexamic acid infiltration. The postoperative drain output was recorded, as well as the haemoglobin level and the patients needing blood transfusion. Results and Conclusions: The preoperative and postoperative haemoglobin values were recorded. The mean preoperative haemoglobin was 10.9% and 10.8% (p=0.79) in the trial and control groups respectively. The mean postoperative haemoglobin was 9.5gm% and 9.2gm% (p=0.36) in the two groups. The total postoperative blood loss in the tranexamic acid group and the control group was 190.3ml and 204.3ml respectively (p=0.25). Ten patients (14.9%) in the intervention group and 12 patients (17.1%) in the control group required blood transfusion. We conclude that tranexamic acid does not play a significant role in reducing postoperative blood loss and blood transfusion when used locally in peritochanteric fracture surgery. However a larger double blinded study comparing various modalities of use of tranexamic acid is needed to conclusively establish its role. PMID- 28553446 TI - Brachial Artery Injury in a Child following Closed Elbow Dislocation: Case Report of a Rare Injury. AB - Elbow dislocation, though a common orthopaedic emergency is rare with brachial artery injury and is even more uncommon in the paediatric age group. We present the case of a child who sustained trauma resulting in closed elbow dislocation with brachial artery injury. Elbow dislocation with brachial artery injury can present with palpable distal pulses and good capillary refill because of rich collaterals at the elbow. But this patient presented with signs of frank ischemia distally, and was managed with ipsilateral reverse cephalic vein graft. He had good volume pulses at one year follow-up. Patients with such presentation should have careful clinical and radiological assessment to exclude complicated elbow dislocation. PMID- 28553445 TI - A Cross-sectional Analysis of Glove Perforation in Primary and Revision Total Hip Arthroplasty. AB - The number of total hip arthroplasties is ever increasing. Literature about glove perforation rates in arthroplasties in India is very scarce. The purpose of our study was to determine the incidence of glove perforation and increasing the awareness of possible glove perforations to decrease the risk of infection. We performed a prospective study in which we tested gloves worn by all scrubbed personnel. A total of 1408 gloves were collected from 42 primary total hip and 13 revision total hip arthroplasties. Incidence of glove perforation was found to be more in revision total hip arthroplasty. We found a greater outer glove perforation rate of about 38.33% as compared to 25 % inner glove perforation rate. Outer glove perforation was recognized 100% of time intraoperatively but inner glove perforation was noted only 17% of time. First assistant recorded highest rate of glove perforation. PMID- 28553447 TI - Benign Subcutaneous Emphysema of the Upper Limb: A Case Report. AB - Subcutaneous emphysema is the presence of gas or air in the subcutaneous tissue plane. The term is generally used to describe any soft tissue emphysema of the body wall or limbs, it can result from benign causes, most commonly secondary to trauma or from a life-threatening infection by gas gangrene or necrotising fasciitis. A case of subcutaneous emphysema involving the upper limb resulting from a trivial laceration to the elbow is reported and the importance of distinguishing between the two causes of subcutaneous emphysema is highlighted. PMID- 28553448 TI - Multicentric Disappearing Bone Disease treated with Arthroplasty. AB - Multicentric disappearing bone disease, or Gorham disease, is a rare entity. A middle age woman, presented to us with left sided antalgic gait and severe bony deformity of her left knee. Radiograph revealed massive bone defect of the medial condyle of the left tibia with subluxation of the knee joint. She was scheduled for knee replacement in six months. However, she developed another lesion over the right hip that typically mimicked the disease progression of disappearing bone disease. The right femoral head vanished progressively within three months without significant history of infection or trauma. Subsequent bone biopsy of the right femoral head and left tibia condyle confirmed the diagnosis. Total knee replacement was carried out for her left knee. She remained pain free on her left knee. A year later, after confirming by sequential radiographs that the osteolysis had stopped, total right hip replacement was performed. Five years later, she remained pain free and both the arthroplasties were stable. PMID- 28553449 TI - Post-operative Hypertension following Correction of Flexion Deformity of the Knees in a Spastic Diplegic Child: A Case Report. AB - An adolescent boy with spastic diplegic cerebral palsy presented with crouch gait. He had bilateral severe flexion deformities of knees and hips. He was treated with single event multilevel surgery for the correction of deformities. Surgical procedures included bilateral adductor release, iliopsoas lengthening, bilateral femoral shortening and patella plication. Persistent hypertension was noted in the post-operative period. All causes of secondary hypertension were ruled out. Having persistent hypertension following the femoral shortening procedure is unusual. Antihypertensive medication controlled his blood pressure 15 months after surgery. Hypertension following correction of knee flexion deformity and limb lengthening is well known. Hypertension has not been described with the shortening osteotomy of the femur. Hypertension is a rare complication following the corrective surgery for the treatment of crouch gait. Blood pressure should be monitored during the post-operative period to detect such a rare complication. PMID- 28553450 TI - Calf Compartment Syndrome associated with the Use of an Intra-osseous Line in an Adult Patient: A Case Report. AB - We present a case of a lower limb compartment syndrome associated with the use of an intra-osseous line inserted into the proximal tibia in an adult patient. An unconscious 59-year old male with multiple injuries presented to our Emergency Department after a road traffic accident. Bilateral proximal tibial intra osseous lines were inserted due to poor venous access. After resuscitation his left leg was noted to be tense and swollen with absent pulses. Acute compartment syndrome was diagnosed both clinically and with compartment pressure measurement. Two incision fasciotomy on his left lower leg was performed. Intra osseous-lines in the proximal tibia are increasingly used in adult patients in the pre-hospital setting by paramedics and emergency physicians. Their use, along with the possible complications of these devices, such as the development of compartment syndrome or osteomyelitis leading to amputation, is well reported in the paediatric literature. To the best of our knowledge, there have not been any previous reports of complications in the adult patient. We present a case of lower leg compartment syndrome developing from the use of an intra-osseous line in the proximal tibia in an adult patient. With the increasing use of intra osseous lines in adult patients, clinicians should be aware of the possibility of developing compartment syndrome which may lead to disability or amputation in severe cases. PMID- 28553451 TI - The Use of Dual Reconstruction Plates for Failed Fixation of Patellar Fracture after Total Knee Replacement: A Case Report. AB - Patellar fracture after total knee replacement (TKR) is one of the challenging problems in periprosthetic fracture. Open reduction with internal fixation (ORIF), as tension band wiring (TBW), usually required in cases with extensor mechanism disruption. However, many studies reported a high failure rate after using this technique. In this report, we presented an interesting case of periprosthetic patellar fracture after TKR with TBW failure that was successfully treated with double non-locking reconstruction plates fixation and TBW augmentation. PMID- 28553452 TI - Open Reduction of Neglected Knee Dislocation: Case Report of a Rare Injury. AB - Old neglected dislocation of knee joint is a rare injury. Any orthopaedic surgeon would have faced only a few cases of unreduced neglected dislocation in his life time practice. We report the case of a 30-year old male patient with one month old unreduced knee dislocation which was managed with open reduction and stabilization with two intra-articular crossed Steinman pins for six weeks, followed by removal of the pins and gradual weight bearing in hinged knee brace. At the end of one year, range of movement of knee joint was 0 to 50 degree with minimal knee pain on walking. PMID- 28553453 TI - Tophaceous Gout simulating infected Ankle Implants. AB - Gout is a well known metabolic disorder characterized by the formation of urate crystals in joints resulting in recurrent attacks of acute inflammatory arthritis following which tophi can occur in joints or subcutaneous tissues. We report a rare localization of gouty tophi in a 52 years old male. The tophi had formed over the stainless steel implant used for the fixation of a lateral malleolus fracture 20 years ago. PMID- 28553454 TI - A Case of undiagnosed Pseudoaneurysm caused by an open tibial fracture. PMID- 28553455 TI - Tincture of Benzoin to Prevent Cast Slippage in Clubfoot. PMID- 28553456 TI - Macrocycles: lessons from the distant past, recent developments, and future directions. AB - A noticeable increase in molecular complexity of drug targets has created an unmet need in the therapeutic agents that are larger than traditional small molecules. Macrocycles, which are cyclic compounds comprising 12 atoms or more, are now recognized as molecules that "are up to the task" to interrogate extended protein interfaces. However, because macrocycles (particularly the ones based on peptides) are equipped with large polar surface areas, achieving cellular permeability and bioavailability is anything but straightforward. While one might consider this to be the Achilles' heel of this class of compounds, the synthetic community continues to develop creative approaches toward the synthesis of macrocycles and their site-selective modification. This perspective provides an overview of both mechanistic and structural issues that bear on macrocycles as a unique class of molecules. The reader is offered a historical foray into some of the classic studies that have resulted in the current renaissance of macrocycles. In addition, an attempt is made to overview the more recent developments that give hope that macrocycles might indeed turn into a useful therapeutic modality. PMID- 28553458 TI - Charge-tagged ligands: useful tools for immobilising complexes and detecting reaction species during catalysis. AB - In recent years, charge-tagged ligands (CTLs) have become valuable tools in organometallic catalysis. Insertion of an ionic side chain into the molecular skeleton of a known ligand has become a useful protocol for anchoring ligands, and consequently catalysts, in polar and ionic liquid phases. In addition, the insertion of a cationic moiety into a ligand is a powerful tool that can be used to detect reaction intermediates in organometallic catalysis through electrospray ionisation mass spectrometry (ESI-MS) experiments. The insertion of an ionic tag ensures the charge in the intermediates independently of the ESI-MS. For this reason, these ligands have been used as ionic probes in mechanistic studies for several catalytic reactions. Here, we summarise selected examples on the use of CTLs as immobilising agents in organometallic catalysis and as probes for studying mechanisms through ESI-MS. PMID- 28553460 TI - A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N6-methyladenosine demethylase FTO. AB - The AlkB family of nucleic acid demethylases are of intense biological and medical interest because of their roles in nucleic acid repair and epigenetic modification. However their functional and molecular mechanisms are unclear, hence, there is strong interest in developing selective inhibitors for them. Here we report the identification of key residues within the nucleotide-binding sites of the AlkB subfamilies that likely determine their substrate specificity. We further provide proof of principle that a strategy exploiting these inherent structural differences can enable selective and potent inhibition of the AlkB subfamilies. This is demonstrated by the first report of a subfamily-selective and cell-active FTO inhibitor 12. The distinct selectivity of 12 for FTO against other AlkB subfamilies and 2OG oxygenases shall be of considerable interest with regards to its potential use as a functional probe. The strategy outlined here is likely applicable to other AlkB subfamilies, and, more widely, to other 2OG oxygenases. PMID- 28553457 TI - Designing logical codon reassignment - Expanding the chemistry in biology. AB - Over the last decade, the ability to genetically encode unnatural amino acids (UAAs) has evolved rapidly. The programmed incorporation of UAAs into recombinant proteins relies on the reassignment or suppression of canonical codons with an amino-acyl tRNA synthetase/tRNA (aaRS/tRNA) pair, selective for the UAA of choice. In order to achieve selective incorporation, the aaRS should be selective for the designed tRNA and UAA over the endogenous amino acids and tRNAs. Enhanced selectivity has been achieved by transferring an aaRS/tRNA pair from another kingdom to the organism of interest, and subsequent aaRS evolution to acquire enhanced selectivity for the desired UAA. Today, over 150 non-canonical amino acids have been incorporated using such methods. This enables the introduction of a large variety of structures into proteins, in organisms ranging from prokaryote, yeast and mammalian cells lines to whole animals, enabling the study of protein function at a level that could not previously be achieved. While most research to date has focused on the suppression of 'non-sense' codons, recent developments are beginning to open up the possibility of quadruplet codon decoding and the more selective reassignment of sense codons, offering a potentially powerful tool for incorporating multiple amino acids. Here, we aim to provide a focused review of methods for UAA incorporation with an emphasis in particular on the different tRNA synthetase/tRNA pairs exploited or developed, focusing upon the different UAA structures that have been incorporated and the logic behind the design and future creation of such systems. Our hope is that this will help rationalize the design of systems for incorporation of unexplored unnatural amino acids, as well as novel applications for those already known. PMID- 28553459 TI - Thin metal nanostructures: synthesis, properties and applications. AB - Two-dimensional nanomaterials, especially graphene and single- or few-layer transition metal dichalcogenide nanosheets, have attracted great research interest in recent years due to their distinctive physical, chemical and electronic properties as well as their great potentials for a broad range of applications. Recently, great efforts have also been devoted to the controlled synthesis of thin nanostructures of metals, one of the most studied traditional materials, for various applications. In this minireview, we review the recent progress in the synthesis and applications of thin metal nanostructures with a focus on metal nanoplates and nanosheets. First of all, various methods for the synthesis of metal nanoplates and nanosheets are summarized. After a brief introduction of their properties, some applications of metal nanoplates and nanosheets, such as catalysis, surface enhanced Raman scattering (SERS), sensing and near-infrared photothermal therapy are described. PMID- 28553462 TI - Selecting reactions and reactants using a switchable rotaxane organocatalyst with two different active sites. AB - The activation mode of a rotaxane-based organocatalyst with both secondary amine and squaramide catalytic units can be switched with acid or base. The macrocycle blocks whichever of the catalytic sites it is positioned over. The switchable rotaxane catalyst generates different products from a mixture of three building blocks according to the location of the macrocyclic ring in the rotaxane. PMID- 28553461 TI - A comparative study of the coordination behavior of cyclo-P5 and cyclo-As5 ligand complexes towards the trinuclear Lewis acid complex (perfluoro-ortho phenylene)mercury. AB - Reactions of the cyclo-E5 sandwich complexes [Cp*Fe(eta5-P5)] (1) and [Cp*Fe(eta5 As5)] (2) with the planar Lewis acid trimeric (perfluoro-ortho-phenylene)mercury [(o-C6F4Hg)3] (3) afford compounds that show distinctly different assemblies in the solid state. The phosphorus containing ligand 1 forms dimeric coordination units with two molecules of 3, with one P atom of each cyclo-P5 ligand positioned in close proximity to the center of a molecule of 3. In contrast to the coordination behavior of 1, the arsenic analog 2 shows simultaneous interaction of three As atoms with the Hg atoms of 3. A DFT study and subsequent AIM analyses of the products suggest that electrostatic forces are prevalent over donor acceptor interactions in these adducts, and may play a role in the differences in the observed coordination behavior. Subsequently, a series of [CpRFe(eta5-P5)] (CpR = C5H5-ntBu n , n = 1-3, 6a-c) sandwich complexes was prepared and also reacted with [(o-C6F4Hg)3]. In the solid state the obtained products 7a-c with increasing steric demand of the CpR ligands show no significant change in their assembly compared to the Cp* analog 4. All of the products were characterized by single crystal X-ray structure analysis, mass spectrometry and elemental analysis as well as NMR spectroscopy and IR spectrometry. PMID- 28553463 TI - Applications of dynamic combinatorial chemistry for the determination of effective molarity. AB - A new strategy for determining thermodynamic effective molarities (EM) for macrocylisation reactions using dynamic combinatorial chemistry under dilute conditions is presented. At low concentrations, below the critical value, Dynamic Libraries (DLs) of bifunctional building blocks contain only cyclic species, so it is not possible to quantify the equilibria between linear and cyclic species. However, addition of a monofunctional chain stopper can be used to promote the formation of linear oligomers allowing measurement of EM for all cyclic species present in the DL. The effectiveness of this approach was demonstrated for DLs generated from mixtures of 1,3-diimine calix[4]arenes, linear diaminoalkanes and monoaminoalkanes. For macrocycles deriving from one bifunctional calixarene and one diamine, there is an alternating pattern of EM values with the number of methylene units in the diamine: odd numbers give significantly higher EMs than even numbers. For odd numbers of methylene units, the alkyl chain can adopt an extended all anti conformation, whereas for even numbers of methylene units, gauche conformations are required for cyclisation, and the associated strain reduces EM. The value of EM for the five-carbon linker indicates that this macrocycle is a strainless ring. PMID- 28553465 TI - From TcVII to TcI; facile syntheses of bis-arene complexes [99(m)Tc(arene)2]+ from pertechnetate. AB - Bis-arene complexes of technetium represent a fundamental class of organometallic compounds. Due to complex synthetic routes, no detailed insights into their properties have been reported so far. Reacting [99TcO4]- with arenes in the exclusive presence of AlCl3 gives highly stable [99Tc(arene)2]+ in good yields. These complexes have extraordinarily high stabilities, where oxidation is found to occur at potentials higher than +1.3 V and reduction at potentials below -2 V vs. Fc/Fc+. The 99mTc analogues are similarly synthesised by applying a novel ionic liquid extraction pathway. Complexes of 99mTc with suitably functionalized arenes will represent new building blocks for bioorganometallic pharmaceuticals in molecular imaging. PMID- 28553464 TI - Extremely strong tubular stacking of aromatic oligoamide macrocycles. AB - As the third-generation rigid macrocycles evolved from progenitor 1, cyclic aromatic oligoamides 3, with a backbone of reduced constraint, exhibit extremely strong stacking with an astoundingly high affinity (estimated lower limit of Kdimer > 1013 M-1 in CHCl3), which leads to dispersed tubular stacks that undergo further assembly in solution. Computational study reveals a very large binding energy (-49.77 kcal mol-1) and indicates highly cooperative local dipole interactions that account for the observed strength and directionality for the stacking of 3. In the solid-state, X-ray diffraction (XRD) confirms that the aggregation of 3 results in well-aligned tubular stacks. The persistent tubular assemblies of 3, with their non-deformable sub-nm pore, are expected to possess many interesting functions. One such function, transmembrane ion transport, is observed for 3. PMID- 28553466 TI - Ultrafast delocalization of excitation in synthetic light-harvesting nanorings. AB - Rings of chlorophyll molecules harvest sunlight remarkably efficiently during photosynthesis in purple bacteria. The key to their efficiency lies in their highly delocalized excited states that allow for ultrafast energy migration. Here we show that a family of synthetic nanorings mimic the ultrafast energy transfer and delocalization observed in nature. pi-Conjugated nanorings with diameters of up to 10 nm, consisting of up to 24 porphyrin units, are found to exhibit excitation delocalization within the first 200 fs of light absorption. Transitions from the first singlet excited state of the circular nanorings are dipole-forbidden as a result of symmetry constraints, but these selection rules can be lifted through static and dynamic distortions of the rings. The increase in the radiative emission rate in the larger nanorings correlates with an increase in static disorder expected from Monte Carlo simulations. For highly symmetric rings, the radiative rate is found to increase with increasing temperature. Although this type of thermally activated superradiance has been theoretically predicted in circular chromophore arrays, it has not previously been observed in any natural or synthetic systems. As expected, the activation energy for emission increases when a nanoring is fixed in a circular conformation by coordination to a radial template. These nanorings offer extended chromophores with high excitation delocalization that is remarkably stable against thermally induced disorder. Such findings open new opportunities for exploring coherence effects in nanometer molecular rings and for implementing these biomimetic light harvesters in man-made devices. PMID- 28553467 TI - Oxygen evolution on well-characterized mass-selected Ru and RuO2 nanoparticles. AB - Oxygen evolution was investigated on model, mass-selected RuO2 nanoparticles in acid, prepared by magnetron sputtering. Our investigations include electrochemical measurements, electron microscopy, scanning tunneling microscopy and X-ray photoelectron spectroscopy. We show that the stability and activity of nanoparticulate RuO2 is highly sensitive to its surface pretreatment. At 0.25 V overpotential, the catalysts show a mass activity of up to 0.6 A mg-1 and a turnover frequency of 0.65 s-1, one order of magnitude higher than the current state-of-the-art. PMID- 28553468 TI - Biphen[n]arenes. AB - To design and exploit novel macrocyclic synthetic receptors is a permanent and challenging topic in supramolecular chemistry. Here we describe the one-pot synthesis, unique geometries and intriguing host-guest properties of a new class of supramolecular macrocycles - biphen[n]arenes (n = 3, 4), which are made up of 4,4'-biphenol or 4,4'-biphenol ether units linked by methylene bridges at the 3- and 3'- positions. The biphenarene macrocycles are conveniently accessible/modifiable and extremely guest-friendly. Particularly, biphen[4]arene is capable of forming inclusion complexes with not only organic cationic guests but also neutral pi-electron deficient molecules. Compared with calixarenes, resorcinarenes, cyclotriveratrylenes and pillararenes with substituted mono benzene units, the biphen[n]arenes reported here possess significantly different characteristics in both their topologic structures and their recognition properties, and thus can find broad applications in supramolecular chemistry and other areas. PMID- 28553469 TI - Organic/inorganic double-layered shells for multiple cytoprotection of individual living cells. AB - The cytoprotection of individual living cells under in vitro and daily-life conditions is a prerequisite for various cell-based applications including cell therapy, cell-based sensors, regenerative medicine, and even the food industry. In this work, we use a cytocompatible two-step process to encapsulate Saccharomyces cerevisiae in a highly uniform nanometric (<100 nm) shell composed of organic poly(norepinephrine) and inorganic silica layers. The resulting cell in-shell structure acquires multiple resistance against lytic enzyme, desiccation, and UV-C irradiation. In addition to the UV-C filtering effect of the double-layered shell, the biochemical responses of the encapsulated yeast are suggested to contribute to the observed UV-C tolerance. This work offers a chemical tool for cytoprotecting individual living cells under multiple stresses and also for studying biochemical behavior at the cellular level. PMID- 28553470 TI - Regulating signal enhancement with coordination-coupled deprotonation of a hydrazone switch. AB - Proton relay plays an important role in many biocatalytic pathways. In order to mimic such processes in the context of molecular switches, we developed coordination-coupled deprotonation (CCD) driven signaling and signal enhancement sequences. This was accomplished by using the zinc(ii)-initiated CCD of a hydrazone switch to instigate an acid catalyzed imine bond hydrolysis that separates a quencher from a fluorophore thus leading to emission amplification. Because CCD is a reversible process, we were able to show that the catalysis can be regulated and turned "on" and "off" using a metalation/demetalation cycle. PMID- 28553471 TI - An organometallic structure-activity relationship study reveals the essential role of a Re(CO)3 moiety in the activity against gram-positive pathogens including MRSA. AB - The worrying appearance of microbial resistance to antibiotics is a worldwide problem which needs to be tackled urgently. Microbial resistance to the common classes of antibiotics involving purely organic compounds unfortunately develops very rapidly and in most cases, resistance was detected soon after or even before release of the antibiotic to the market. Therefore, novel concepts for antibiotics must be investigated, and metal-containing compounds hold particular promise in that area. Taking a trimetallic complex (1a) which contains a ferrocenyl (Fc), a CpMn(CO)3 (cymantrene) and a [(dpa)Re(CO)3] residue as the lead structure, a systematic structure-activity relationship (SAR) study against various gram-positive pathogenic bacteria including methicillin-resistant Staphylococcus aureus (MRSA) strains was performed. The [(dpa)Re(CO)3] moiety was discovered to be the essential unit for the observed antibacterial activity of 1a. The ferrocenyl and CpMn(CO)3 units can be replaced one by one or both together by organic moieties such as a phenyl ring without loss of antibacterial activity. The most potent mono-metallic complex (9c') has an antibacterial activity comparable to the well-established organic drugs amoxicillin and norfloxacin and importantly, only moderate cytotoxicity against mammalian cells. Microbiological studies on membrane potential, membrane permeabilization, and cell wall integrity revealed that 9c' targets the bacterial membrane and disturbs cell wall integrity, but shows more efficient membrane permeabilization than the lead structure 1a. PMID- 28553472 TI - Chelate-free metal ion binding and heat-induced radiolabeling of iron oxide nanoparticles. AB - A novel reaction for chelate-free, heat-induced metal ion binding and radiolabeling of ultra-small paramagnetic iron oxide nanoparticles (USPIOs) has been established. Radiochemical and non-radioactive labeling studies demonstrated that the reaction has a wide chemical scope and is applicable to p-, d- and f block metal ions with varying ionic sizes and formal oxidation states from 2+ to 4+. Radiolabeling studies found that 89Zr-Feraheme (89Zr-FH or 89Zr-ferumoxytol) can be isolated in 93 +/- 3% radiochemical yield (RCY) and >98% radiochemical purity using size-exclusion chromatography. 89Zr-FH was found to be thermodynamically and kinetically stable in vitro using a series of ligand challenge and plasma stability tests, and in vivo using PET/CT imaging and biodistribution studies in mice. Remarkably, ICP-MS and radiochemistry experiments showed that the same reaction conditions used to produce 89Zr-FH can be employed with different radionuclides to yield 64Cu-FH (66 +/- 6% RCY) and 111In-FH (91 +/- 2% RCY). Electron magnetic resonance studies support a mechanism of binding involving metal ion association with the surface of the magnetite crystal core. Collectively, these data suggest that chelate-free labeling methods can be employed to facilitate clinical translation of a new class of multimodality PET/MRI radiotracers derived from metal-based nanoparticles. Further, this discovery is likely to have broader implications in drug delivery, metal separation science, ecotoxicology of nanoparticles and beyond. PMID- 28553473 TI - Reversible assembly of enantiomeric helical polymers: from fibers to gels. AB - A novel class of stereocomplexes is described by the interaction of helically complementary poly(phenylacetylene)s (PPAs) carrying an alpha-methoxy-alpha trifluoromethylphenylacetamide pendant group. The formation of the stereocomplex requires the presence of cis amide bonds on the external crest of the polymer to provide efficient cooperative supramolecular hydrogen bonding between matching enantiomeric helical structures. The interlocking of the chains gives rise to supramolecular fiber-like aggregates that, at higher concentrations, result in gels. The modification of the cis-trans amide conformation at the pendant groups allows the controlled formation and cleavage of the stereocomplex due to a dramatic change between the intermolecular and intramolecular hydrogen bond interactions. PMID- 28553474 TI - Impact and oxidation of single silver nanoparticles at electrode surfaces: one shot versus multiple events. AB - Single nanoparticle (NP) electrochemical impacts is a rapidly expanding field of fundamental electrochemistry, with applications from electrocatalysis to electroanalysis. These studies, which involve monitoring the electrochemical (usually current-time, I-t) response when a NP from solution impacts with a collector electrode, have the scope to provide considerable information on the properties of individual NPs. Taking the widely studied oxidative dissolution of individual silver nanoparticles (Ag NPs) as an important example, we present measurements with unprecedented noise (< 5 pA) and time resolution (time constant 100 MUs) that are highly revealing of Ag NP dissolution dynamics. Whereas Ag NPs of diameter, d = 10 nm are mostly dissolved in a single event (on the timescale of the measurements), a wide variety of complex processes operate for NPs of larger diameter (d >= 20 nm). Detailed quantitative analysis of the I-t features, consumed charge, event duration and impact frequency leads to a major conclusion: Ag NPs undergo sequential partial stripping (oxidative dissolution) events, where a fraction of a NP is electrochemically oxidized, followed by the NP drifting away and back to the tunnelling region before the next partial stripping event. As a consequence, analysis of the charge consumed by single events (so-called "impact coulometry") cannot be used as a general method to determine the size of colloidal NPs. However, a proper analysis of the I-t responses provides highly valuable information on the transient physicochemical interactions between NPs and polarized surfaces. PMID- 28553475 TI - Tracking motion trajectories of individual nanoparticles using time-resolved current traces. AB - Single nanoparticle (NP) electrochemical measurements are widely described, both theoretically and experimentally, as they enable visualization of the electrochemical signal of a single NP that is masked in ensemble measurements. However, investigating the behavior of individual NPs using electrochemical signals remains a significant challenge. Here we report experiments and simulations demonstrating that multiple distinct motion trajectories could be discerned from time-resolved current traces by dynamic Monte Carlo simulations. We show that continuous monitoring and quantification of electrochemical oxidation of individual AgNPs using a low-noise electrochemical measurement platform produce significantly distinguished current traces due to the size dependent motions of AgNPs. Our findings offer a view of the electrochemical signals of individual NPs that are largely different from that in the literature, and underscore the significance of motion behaviors in single NP electrochemistry. PMID- 28553476 TI - Neutral chiral cyclopentadienyl Ru(ii)Cl catalysts enable enantioselective [2+2] cycloadditions. AB - Cyclopentadienyl ruthenium(ii) complexes with a large number of available coordination sites are frequently used catalysts for a broad range of transformations. To be able to render these transformations enantioselective, we have designed a chiral neutral CpxRu(ii)Cl complex basing on an atropchiral cyclopentadienyl (Cpx) ligand which is accessed in a streamlined C-H functionalisation approach. The catalyst displays excellent levels of reactivity and enantioselectivity for enantioselective [2+2]-cycloadditions leading to strained chiral cyclobutenes, allowing for catalyst loadings as low as 1 mol%. A very strong counterion effect of a bound chloride anion transforms the corresponding unselective cationic complex into a highly enantioselective neutral version. Moreover, by adding norbornadiene at the end of the reaction the catalyst can be recovered and subsequently reused. PMID- 28553477 TI - The influence of acceptor nucleophilicity on the glycosylation reaction mechanism. AB - A set of model nucleophiles of gradually changing nucleophilicity is used to probe the glycosylation reaction mechanism. Glycosylations of ethanol-based acceptors, bearing varying amounts of fluorine atoms, report on the dependency of the stereochemistry in condensation reactions on the nucleophilicity of the acceptor. Three different glycosylation systems were scrutinized, that differ in the reaction mechanism, that - putatively - prevails during the coupling reaction. It is revealed that the stereoselectivity in glycosylations of benzylidene protected glucose donors are very susceptible to acceptor nucleophilicity whereas condensations of benzylidene mannose and mannuronic acid donors represent more robust glycosylation systems in terms of diastereoselectivity. The change in stereoselectivity with decreasing acceptor nucleophilicity is related to a change in reaction mechanism shifting from the SN2 side to the SN1 side of the reactivity spectrum. Carbohydrate acceptors are examined and the reactivity-selectivity profile of these nucleophiles mirrored those of the model acceptors studied. The set of model ethanol acceptors thus provides a simple and effective "toolbox" to investigate glycosylation reaction mechanisms and report on the robustness of glycosylation protocols. PMID- 28553478 TI - Nature's hydrides: rapid reduction of halocarbons by folate model compounds. AB - Halocarbons R-X are reduced to hydrocarbons R-H by folate model compounds under biomimetic conditions. The reactions correspond to a halide-hydride exchange with the methylenetetrahydrofolate (MTHF) models acting as hydride donors. The MTHF models are also functional equivalents of dehalohydrogenases but, unlike these enzymes, do not require a metal cofactor. The reactions suggest that halocarbons have the potential to act as endocrinological disruptors of biochemical pathways involving MTHF. As a case in point, we observe the rapid reaction of the MTHF models with the inhalation anaesthetic halothane. The ready synthetic accessibility of the MTHF models as well as their dehalogenation activity in the presence of air and moisture allow for the remediation of toxic, halogenated hydrocarbons. PMID- 28553479 TI - A DNA-based parity generator/checker for error detection through data transmission with visual readout and an output-correction function. AB - During any type of binary data transmission, the occurrence of bit errors is an inevitable and frequent problem suffered. These errors, which have fatal effects on the correct logic computation, especially in sophisticated logic circuits, can be checked through insertion of a parity generator (pG) at the transmitting end and a parity checker (pC) at the receiving end. Herein, taking even pG/pC as a model device, we constructed the first DNA-based molecular parity generator/checker (pG/pC) for error detection through data transmission, on a universal single-strand platform according to solely DNA hybridization. Compared with previous pG/pC systems, the distinct advantage of this one is that it can present not only fluorescence signals but also visual outputs, which can be directly recognized by the naked eye, using DNA inputs modulated split-G quadruplex and its DNAzyme as signal reporters, thus greatly extending its potential practical applications. More importantly, an "Output-Correction" function was introduced into the pC for the first time, in which all of the erroneous outputs can be adequately corrected to their normal states, guaranteeing the regular operation of subsequent logic devices. Furthermore, through negative logic conversion towards the constructed even pG/pC, the odd pG/pC with equal functions was obtained. Furthermore, this system can also execute multi-input triggered concatenated logic computations with dual output modes, which largely fulfilled the requirements of complicated computing. PMID- 28553480 TI - Selective anomeric acetylation of unprotected sugars in water. AB - High yielding selective acetylation of only the anomeric hydroxyl of unprotected sugars is possible in aqueous solution using 2-chloro-1,3-dimethylimidazolinium chloride (DMC), thioacetic acid, and a suitable base. The reaction, which may be performed on a multi-gram scale, is stereoselective for sugars that possess a hydroxyl group at position-2, exclusively yielding the 1,2-trans products. The use of an iterative reagent addition procedure allows the use of sodium carbonate as the base, avoiding the formation of triethylammonium salts, which may hamper product purification. The glycosyl acetate products may be used as donor substrates for glycosidase-catalysed synthesis. The crude aqueous acetylation reaction mixture may also be used for this purpose. PMID- 28553481 TI - White-light emission from a single heavy atom-free molecule with room temperature phosphorescence, mechanochromism and thermochromism. AB - Two heavy atom-free luminophores (SHB2t and SDB2t) with simple molecular structures have been synthesized via Suzuki coupling reactions in which both display white-light emission with prompt fluorescence and room temperature phosphorescence (RTP) in the solid state. The impressive RTP of the luminophores is produced by a synergistic effect of the strong intermolecular hydrogen bonding in addition to the spin-orbit coupling of the sulfonyl oxygen atoms and the moderate singlet-triplet energy gaps (DeltaEST). These factors facilitate the intersystem crossing (ISC) process to generate triplet excitons in which the molecular conformations become immobilized to effectively suppress radiationless decay. Under the stimuli of mechanical force and solvent vapor, the RTP of SHB2t and SDB2t can be simply turned off and on by breaking and reforming the robust hydrogen bonding, which leads to remarkable and reversible mechanochromism between white and deep-blue emission. Moreover, two different thermochromic processes have been observed for the pristine and ground samples of SDB2t, in which a tricolor switching system between white, deep-blue and blue emission has been successfully achieved through the sequential control of grinding, heating and fuming. From detailed studies we have determined that the mechanism for the thermochromism of SDB2t is correlated with the rearrangement of the white-light emitting molecules to a new packing mode without RTP emission. PMID- 28553482 TI - Sensing telomerase: From in vitro detection to in vivo imaging. AB - Telomerase is a ribonucleoprotein reverse transcriptase that is responsible for maintaining the telomere length in cells. Telomerase overexpresses in almost all malignant tumor cells, and it has become a promising biomarker and a potential therapy target for cancers. Consequently, accurate and efficient quantification of the telomerase is highly essential to medical diagnostics and therapeutics. Recently, a series of novel telomerase detection methods with excellent performance have been developed, but a overview of in vivo telomerase detection methods is lacking. In this Minireview, we summarize the emerging strategies for telomerase assays in the last five years, including both in vitro assays and in vivo imaging methods, and discuss their future directions as well. PMID- 28553483 TI - Fully conjugated ladder polymers. AB - Fully conjugated ladder polymers (cLPs), in which all the backbone units on the polymer main-chain are pi-conjugated and fused, have attracted great interest owing to their intriguing properties, remarkable chemical and thermal stability, and potential suitability as functional organic materials. The synthesis of cLPs can be, in general, achieved by two main strategies: single-step ladderization and post-polymerization ladderization. Although a variety of synthetic methods have been developed, the chemistry of cLPs must contend with structural defects and low solubility that prevents complete control over synthesis and structural characterization. Despite these challenges, cLPs have been used for a wide range of applications such as organic light emitting diodes (OLEDs) and organic field effect transistors (OFETs), paralleling developments in processing methods. In this perspective, we discuss the background of historical syntheses including the most recent synthetic approaches, challenges related to the synthesis and structural characterization of well-defined cLPs with minimum levels of structural defects, cLPs' unique properties, and wide range of applications. In addition, we propose outlooks to overcome the challenges limiting the synthesis, analysis, and processing of cLPs in order to fully unlock the potential of this intriguing class of organic materials. PMID- 28553484 TI - Metal halide perovskite nanomaterials: synthesis and applications. AB - Nanomaterials refer to those with at least one dimension being at the nanoscale (i.e. <100 nm) such as quantum dots, nanowires, and nanoplatelets. These types of materials normally exhibit optical and electrical properties distinct from their bulk counterparts due to quantum confinement or strong anisotropy. In this perspective, we will focus on a particular material family: metal halide perovskites, which have received tremendous interest recently in photovoltaics and diverse photonic and optoelectronic applications. The different synthesis approaches and growth mechanisms will be discussed along with their novel characteristics and applications. Taking perovskite quantum dots as an example, the quantum confinement effect and high external quantum efficiency are among these novel properties and their excellent performance in applications, such as single photon emitters and LEDs, will be discussed. Understanding the mechanism behind the formation of these nanomaterial forms of perovskite will help researchers to come up with effective strategies to combat the emerging challenges of this family of materials, such as stability under ambient conditions and toxicity, towards next generation applications in photovoltaics and optoelectronics. PMID- 28553485 TI - Visualization of drug delivery processes using AIEgens. AB - Drug delivery systems (DDSs) have been extensively studied as carriers to deliver small molecule chemo-drugs to tumors for cancer therapy. The therapeutic efficiency of chemo-drugs is crucially dependent on the effective drug concentrations in tumors and cancer cells. Novel DDSs that can simultaneously unveil drug distribution, drug release/activation behaviors and offer early evaluation of their therapeutic responses are highly desirable. Traditional fluorescent dye-labeled DDSs may suffer from notorious aggregation-caused quenching (ACQ) with limited sensitivity for bioimaging; in addition, the intrinsic fluorescence of these dyes requires careful selection of energy acceptor or quencher moieties for a light-up probe design, which complicates the development of self-reporting DDSs, especially the ones for reporting multiple processes. The recently emerged fluorogens with aggregation-induced emission characteristics (AIEgens) offer a straightforward solution to tackle this challenge. Thanks to the unique properties of AIEgens, new theranostic DDSs have been developed for simultaneous drug delivery and bioimaging with high signal to background ratio and multiple signal reporting capabilities. In this mini-review, we summarize the recent development of theranostic DDSs based on AIEgens for monitoring the drug distribution, drug activation and prediction of the therapeutic responses. Through illustration of their design principles and application examples, we hope to stimulate the interest in the design of more advanced theranostic DDSs for biomedical research. PMID- 28553486 TI - Artificial disulfide-rich peptide scaffolds with precisely defined disulfide patterns and a minimized number of isomers. AB - Disulfide-rich peptides are emerging as potential templates for drug design applications. However, the synthesis and reengineering of disulfide-rich peptides are challenging, owing to the complexity of the oxidative folding process involving a number of diverse isomeric structures. Novel disulfide-rich peptide scaffolds that are not besieged by their disulfide isomers are still greatly desired. In this work, we report the design and synthesis of a novel class of artificial disulfide-rich peptide scaffolds with precisely defined disulfide patterns and a minimized number of isomers. In theory, natural peptides with three disulfide bonds have 15 possible isomers. By rationally engineering the thiol-framework of a peptide containing six cysteines with penicillamines and a dithiol amino acid, we demonstrated, for the first time, that the total number of isomers formed after oxidative folding can be decreased to a minimum of two (i.e., from 15 to 2). As fewer isomeric folds are involved in the oxidative folding, the pathway of the folding becomes more concise and the yield of the artificial scaffolds is substantially increased compared to that of its six cysteine-containing analogue, which makes the artificial disulfide-rich scaffolds (with only 2 predefined isomeric folds) extremely promising for being exploited as structurally complex templates for the design of peptide therapeutics and ligands. PMID- 28553487 TI - Reduction chemistry of neptunium cyclopentadienide complexes: from structure to understanding. AB - Neptunium complexes in the formal oxidation states II, III, and IV supported by cyclopentadienyl ligands are explored, and significant differences between Np and U highlighted as a result. A series of neptunium(iii) cyclopentadienyl (Cp) complexes [Np(Cp)3], its bis-acetonitrile adduct [Np(Cp)3(NCMe)2], and its KCp adduct K[Np(Cp)4] and [Np(Cp')3] (Cp' = C5H4SiMe3) have been made and characterised providing the first single crystal X-ray analyses of NpIII Cp complexes. In all NpCp3 derivatives there are three Cp rings in eta5-coordination around the NpIII centre; additionally in [Np(Cp)3] and K[Np(Cp)4] one Cp ring establishes a MU-eta1-interaction to one C atom of a neighbouring Np(Cp)3 unit. The solid state structure of K[Np(Cp)4] is unique in containing two different types of metal-Cp coordination geometries in the same crystal. NpIII(Cp)4 units are found exhibiting four units of eta5-coordinated Cp rings like in the known complex [NpIV(Cp)4], the structure of which is now reported. A detailed comparison of the structures gives evidence for the change of ionic radii of ca. 8 pm associated with change in oxidation state between NpIII and NpIV. The rich redox chemistry associated with the syntheses is augmented by the reduction of [Np(Cp')3] by KC8 in the presence of 2.2.2-cryptand to afford a neptunium(ii) complex that is thermally unstable above -10 degrees C like the UII and ThII complexes K(2.2.2-cryptand)[Th/U(Cp')3]. Together, these spontaneous and controlled redox reactions of organo-neptunium complexes, along with information from structural characterisation, show the relevance of organometallic Np chemistry to understanding fundamental structure and bonding in the minor actinides. PMID- 28553488 TI - Radically promoted formation of a molecular lasso. AB - Two potential viologen-based molecular lasso precursors-both composed of a 4,4' bipyridinium (BIPY2+) unit as part of a rope appended to a cyclobis(paraquat-p phenylene) (CBPQT4+) loop-that have been designed to mimic the threading/unthreading motion of lasso peptides, have been synthesised and characterised. Solution and solid-state experiments reveal that, when the BIPY2+ unit in the rope and the CBPQT4+ loop are connected by a bulky linker, no lasso like conformational transformation is observed between the different redox states on account of steric effects. In sharp contrast, when the linker size is small, the molecule can be switched between (i) a free rope-like conformation in its fully oxidised state and (ii) a self-entangled lasso-like conformation under reducing conditions employing either chemical or electrochemical stimuli: the BIPY+ unit in the rope resides inside the cavity of the CBPQT2(+) loop, forming a pseudo[1]rotaxane. The switching process is reversible and stereochemically unambiguous. This research shows how tiny structural differences can induce significantly different self-complexing properties and sheds light on designing functional artificial actuators. PMID- 28553489 TI - Electrochemical promotion of catalysis over Pd nanoparticles for CO2 reduction. AB - Electrochemical promotion of catalysis (EPOC) has been shown to accelerate the rate of many heterogeneous catalytic reactions; however, it has rarely been reported in low-temperature aqueous electrochemical reactions. Herein, we report a significant EPOC effect for the CO2 reduction to generate formate over Pd nanoparticles (NPs) in a 1 M KHCO3 aqueous solution. By applying a negative potential over differently-sized Pd NPs, the rate of formate production is greatly improved as compared to that at an open-circuit voltage, with a rate enhancement ratio ranging from 10 to 143. The thermocatalytic and electrocatalytic reduction of CO2 compete with each other and are promoted by the applied negative potential and H2 in the feeds, respectively. Inspired by the EPOC effect, a composite electrode containing Pd/C and Pt/C catalysts on different sides of a carbon paper was constructed for catalyzing the CO2 reduction without adding H2 to the feeds. Water electrolysis over Pt NPs generates H2, which then effectively promotes formate production over Pd NPs. PMID- 28553490 TI - Visible light-induced water splitting in an aqueous suspension of a plasmonic Au/TiO2 photocatalyst with metal co-catalysts. AB - We found that plasmonic Au particles on titanium(iv) oxide (TiO2) act as a visible-light-driven photocatalyst for overall water splitting free from any additives. This is the first report showing that surface plasmon resonance (SPR) in a suspension system effectively induces overall water splitting. Modification with various types of metal nanoparticles as co-catalysts enhanced the evolution of H2 and O2. Among these, Ni-modified Au/TiO2 exhibited 5-times higher rates of H2 and O2 evolution than those of Ni-free Au/TiO2. We succeeded in designing a novel solar energy conversion system including three elemental technologies, charge separation with light harvest and an active site for O2 evolution (plasmonic Au particles), charge transfer from Au to the active site for H2 production (TiO2), and an active site for H2 production (Ni cocatalyst), by taking advantage of a technique for fabricating size-controlled Au and Ni nanoparticles. Water splitting occurred in aqueous suspensions of Ni-modified Au/TiO2 even under irradiation of light through an R-62 filter. PMID- 28553491 TI - The tetrahedral structure and luminescence properties of Bi-metallic Pt1Ag28(SR)18(PPh3)4 nanocluster. AB - The atomic-structure characterization of alloy nanoclusters (NCs) remains challenging but is crucial in order to understand the synergism and develop new applications based upon the distinct properties of alloy NCs. Herein, we report the synthesis and X-ray crystal structure of the Pt1Ag28(S-Adm)18(PPh3)4 nanocluster with a tetrahedral shape. Pt1Ag28 was synthesized by reacting Pt1Ag24(SPhMe2)18 simultaneously with Adm-SH (1-adamantanethiol) and PPh3 ligands. A tetrahedral structure is found in the metal framework of Pt1Ag28 NC and an overall surface shell (Ag16S18P4), as well as discrete Ag4S6P1 motifs. The Pt1Ag12 kernel adopts a face-centered cubic (FCC) arrangement, which is observed for the first time in alloy nanoclusters in contrast to the commonly observed icosahedral structure of homogold and homosilver NCs. The Pt1Ag28 nanocluster exhibits largely enhanced photoluminescence (quantum yield QY = 4.9%, emission centered at ~672 nm), whereas the starting material (Pt1Ag24 NC) is only weakly luminescent (QY = 0.1%). Insights into the nearly 50-fold enhancement of luminescence were obtained via the analysis of electronic dynamics. This study demonstrates the atomic-level tailoring of the alloy nanocluster properties by controlling the structure. PMID- 28553492 TI - Cobalt-catalysed C-H carbonylative cyclisation of aliphatic amides. AB - A cobalt-catalysed C-H carbonylation of aliphatic carboxamide derivatives is described, employing commercially available Co(ii)-salts in the presence of a silver oxidant. This operationally simple process utilises an atmospheric pressure of CO and generates a range of substituted succinimide products bearing diverse functional groups that can be successfully accessed via this methodology. PMID- 28553493 TI - Anion exchange coupled with the reduction and dimerisation of a copper(ii) nitrate complex of tripyridyl dithioether via a single-crystal-to-single-crystal transformation. AB - It is a challenge to develop methodologies involving multiple transformations for preparing new materials that cannot be obtained via direct synthesis. Herein, we report an anion exchange process accompanying cation reduction and dimerisation via a single-crystal-to-single-crystal transformation. First, a direct reaction of the flexible tripyridyl dithioether ligand L with CuI afforded a mixture of four bis(ligand) complexes (1a-1d). To avoid the formation of undesired mixed products, a copper(ii) nitrate complex-mediated approach involving anion exchange and cation reduction was employed to generate a monomeric complex, [CuII(L)NO3]NO3.toluene (2). When the dark blue crystals of 2 were immersed in an aqueous NaI solution, the crystals were transformed to a pale yellow dimeric copper(i) iodide complex, [(MU-CuI2I2)(L)2] (3). The observed anion exchange promotes the reduction of copper(ii) to copper(i) at the expense of I-/I3- oxidation as well as dimerisation via the formation of a Cu2I2 cluster. This result corresponds to the synthesis of a compound that otherwise was not able to be prepared via a direct synthetic procedure. PMID- 28553494 TI - Molecular dynamics and charge transport in organic semiconductors: a classical approach to modeling electron transfer. AB - Organic photovoltaics (OPVs) are a promising carbon-neutral energy conversion technology, with recent improvements pushing power conversion efficiencies over 10%. A major factor limiting OPV performance is inefficiency of charge transport in organic semiconducting materials (OSCs). Due to strong coupling with lattice degrees of freedom, the charges form polarons, localized quasi-particles comprised of charges dressed with phonons. These polarons can be conceptualized as pseudo-atoms with a greater effective mass than a bare charge. We propose that due to this increased mass, polarons can be modeled with Langevin molecular dynamics (LMD), a classical approach with a computational cost much lower than most quantum mechanical methods. Here we present LMD simulations of charge transfer between a pair of fullerene molecules, which commonly serve as electron acceptors in OSCs. We find transfer rates consistent with experimental measurements of charge mobility, suggesting that this method may provide quantitative predictions of efficiency when used to simulate materials on the device scale. Our approach also offers information that is not captured in the overall transfer rate or mobility: in the simulation data, we observe exactly when and why intermolecular transfer events occur. In addition, we demonstrate that these simulations can shed light on the properties of polarons in OSCs. Much remains to be learned about these quasi-particles, and there are no widely accepted methods for calculating properties such as effective mass and friction. Our model offers a promising approach to exploring mass and friction as well as providing insight into the details of polaron transport in OSCs. PMID- 28553496 TI - Highly selective one-step dehydration, decarboxylation and hydrogenation of citric acid to methylsuccinic acid. AB - The one-step dehydration, decarboxylation and hydrogenation of the bio-based and widely available citric acid is presented. This reaction sequence yields methylsuccinic acid with yields of up to 89%. Optimal balances between the reaction rates of the different steps were found by varying the hydrogenation catalyst and the reaction parameters (H2 pressure, pH, temperature, time and catalyst-to-substrate ratio). PMID- 28553495 TI - Dual gold and photoredox catalysis: visible light-mediated intermolecular atom transfer thiosulfonylation of alkenes. AB - Regioselective difunctionalization of alkenes has attracted significant attention from synthetic chemists and has the advantage of introducing diverse functional groups into vicinal carbons of common alkene moieties in a single operation. Herein, we report an unprecedented intermolecular atom transfer thiosulfonylation reaction of alkenes by combining gold catalysis and visible-light photoredox catalysis. A trifluoromethylthio group (SCF3) and other functionalized thio groups together with a sulfonyl group were regioselectively introduced into alkenes in the most atom economical manner. A detailed mechanism study indicated that a synergistic combination of gold catalysis and photoredox catalysis is crucial for this reaction. PMID- 28553497 TI - Mapping a protein recognition centre with chiral photoactive ligands. An integrated approach combining photophysics, reactivity, proteomics and molecular dynamics simulation studies. AB - A multidisciplinary strategy to obtain structural information on the intraprotein region is described here. As probe ligands, (S)- and (R)-CPFMe (the methyl esters of the chiral drug carprofen) have been selected, while bovine alpha1-acid glycoprotein (BAAG) has been chosen as a biological host. The procedure involves the separate irradiation of the BAAG/(S)-CPFMe and BAAG/(R)-CPFMe complexes, coupled with fluorescence spectroscopy, laser flash photolysis, proteomic analysis, docking and molecular dynamics simulations. Thus, irradiation of the BAAG/CPFMe complexes at lambda = 320 nm was followed by fluorescence spectroscopy. The intensity of the emission band obtained after irradiation indicated photodehalogenation, whereas its structureless shape suggested covalent binding of the resulting radical CBZMe to the biopolymer. After gel filtration chromatography, the spectra still displayed emission, in agreement with covalent attachment of CBZMe to BAAG. Stereodifferentiation was observed in this process. After trypsin digestion and ESI-MS/MS, the incorporation of CBZMe was detected at Phe68. Docking and molecular dynamics simulation studies, which were carried out using a homology model of BAAG, reveal that the closer proximity of the aromatic moiety of the (S)-enantiomer to the phenyl group of Phe68 would be responsible for the experimentally observed, more effective chemical modification of the protein. The proposed tridimensional structure of BAAG covalently modified by the two enantiomers is also provided. In principle, this approach can be extended to a variety of protein/ligand complexes. PMID- 28553498 TI - Aggregation-induced emission: mechanistic study of the clusteroluminescence of tetrathienylethene. AB - In this work we have investigated the aggregation-induced emission (AIE) behaviour of 1,1,2,2-tetra(thiophen-2-yl)ethene (tetrathienylethene, TTE). The semi-locked and fully-locked derivatives (sl-TTE and fl-TTE) have been synthesized to better understand the mechanism behind the solid state photoluminescence of TTE. TTE is a typical AIEgen and its luminescence can be explained through the mechanistic understanding of the restriction of intramolecular motions (RIM). The emissive behaviour of TTE in the THF/water aggregates and crystal state have also been studied, revealing a remarkable red shift of 35 nm. A similar red-shift emission of 37 nm from the THF/water aggregates to the crystal state is also observed for (E)-1,2-di(thiophen-2 yl)ethene (trans-dithienylethene, DTE). Crystal analysis has revealed that the emission red-shifts are ascribable to the presence of strong sulfur-sulfur (S...S) intra- and intermolecular interactions that are as close as 3.669 A for TTE and 3.679 A for DTE. These heteroatom interactions could help explain the photoluminescence of non-conventional luminophores as well as the luminescence of non-conjugated biomacromolecules. PMID- 28553499 TI - Understanding gas capacity, guest selectivity, and diffusion in porous liquids. AB - Porous liquids are a new class of material that could have applications in areas such as gas separation and homogeneous catalysis. Here we use a combination of measurement techniques, molecular simulations, and control experiments to advance the quantitative understanding of these liquids. In particular, we show that the cage cavities remain unoccupied in the absence of a suitable guest, and that the liquids can adsorb large quantities of gas, with gas occupancy in the cages as high as 72% and 74% for Xe and SF6, respectively. Gases can be reversibly loaded and released by using non-chemical triggers such as sonication, suggesting potential for gas separation schemes. Diffusion NMR experiments show that gases are in dynamic equilibrium between a bound and unbound state in the cage cavities, in agreement with recent simulations for related porous liquids. Comparison with gas adsorption in porous organic cage solids suggests that porous liquids have similar gas binding affinities, and that the physical properties of the cage molecule are translated into the liquid state. By contrast, some physical properties are different: for example, solid homochiral porous cages show enantioselectivity for chiral aromatic alcohols, whereas the equivalent homochiral porous liquids do not. This can be attributed to a loss of supramolecular organisation in the isotropic porous liquid. PMID- 28553500 TI - Zwitterionic near infrared fluorescent agents for noninvasive real-time transcutaneous assessment of kidney function. AB - We developed novel zwitterionic near infrared (NIR) fluorescent agents (ABZWCY HPbetaCD and AAZWCY-HPbetaCD), which exhibit favorable hydrophilicity, low plasma protein binding, high stability and non-toxicity. These attractive characteristics ensure that they are excreted rapidly, without any skin accumulation or metabolism in vivo. More importantly, zwitterionic HPbetaCD based agents can be efficiently filtrated by the glomerulus and completely excreted through the kidneys into urine without reabsorption or secretion in the kidney proximal tubule. Relying on these novel zwitterionic NIR agents and a transcutaneous device, we demonstrate a rapid, robust and biocompatible approach for assessing kidney function in rat models of both healthy rats and those with kidney disease, without the need for time-consuming blood/urine sample preparation. Our work provides a promising tool for in vivo real-time non invasive kidney function assessment in preclinical applications. PMID- 28553501 TI - Silica-supported isolated gallium sites as highly active, selective and stable propane dehydrogenation catalysts. AB - Single-site gallium centers on the surface of silica are prepared via grafting of [Ga(OSi(OtBu)3)3(THF)] on SiO2-700 followed by a thermolysis step. The resulting surface species corresponds to well-defined tetra-coordinate gallium single sites, [( 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 SiO)3Ga(XOSi)] (X = -H or Si) according to IR, X-ray absorption near-edge structure and extended X-ray absorption fine structure analysis. These gallium sites show high activity, selectivity and stability for propane dehydrogenation with an initial turnover frequency of 20 per h per gallium center, propylene selectivity of >=93% and remarkable stability over 20 h. The stability of the catalyst probably results from site-isolation of the active site on a non reducible support such as silica, diminishing facile reduction typical of Ga2O3 based catalysts. PMID- 28553502 TI - Spectroscopic observation of two-center three-electron bonded (hemi-bonded) structures of (H2S) n+ clusters in the gas phase. AB - A two-center three-electron 2c-3e bond (hemi-bond) is a non-classical chemical bond, and its existence has been supposed in radical cation clusters with lone pairs. Though the nature of the hemi-bond and its role in the reactivity of radical cations have attracted great interest, spectroscopic observations of hemi bonded structures have been very scarce. In the present study, the presence of a stable hemi-bonded core (H2S?SH2)+ in (H2S) n+ (n = 3-6) in the gas phase is demonstrated by infrared spectroscopy combined with quantum chemical calculations. The spectral features of the free SH stretch of the ion core show that the hemi-bond motif of the ion core is maintained up to the completion of the first H-bonded solvation shell. All of the observed spectra are well reproduced by the minimum energy hemi-bonded isomers, and no sign of the proton transferred ion core type H3S+-SH, which is estimated to have a much higher energy, is found. Spin density calculations show that the excess charge is almost equally delocalized over the two H2S molecules in the cluster for n = 3 to 6. This also indicates the hemi-bond nature of the (H2S?SH2)+ ion core and the small impact of the formation of a solvation shell on the ion core. PMID- 28553504 TI - Thermally activated delayed fluorescent phenothiazine-dibenzo[a,j]phenazine phenothiazine triads exhibiting tricolor-changing mechanochromic luminescence. AB - Novel U-shaped donor-acceptor-donor (D-A-D) pi-conjugated multi-functional molecules comprising dibenzo[a,j]phenazine (DBPHZ) as an acceptor and phenothiazines (PTZ) as donors have been developed. Most importantly, the D-A-D compounds exhibit not only distinct tricolor-changeable mechanochromic luminescence (MCL) properties but also efficient thermally activated delayed fluorescence (TADF). Quantum chemical calculations, X-ray diffraction analysis, and systematic studies on the photophysical properties indicated that the "two conformation-switchable" PTZ units play a highly important role in achieving multi-color-changing MCL. Time-resolved photophysical measurements revealed that the developed D-A-D compounds also exhibit efficient orange-TADF. Furthermore, organic light-emitting diode (OLED) devices fabricated with the new TADF emitters have achieved high external quantum efficiencies (EQEs) up to 16.8%, which significantly exceeds the theoretical maximum (~5%) of conventional fluorescent emitters. PMID- 28553503 TI - Heterogeneous catalase-like activity of gold(i)-cobalt(iii) metallosupramolecular ionic crystals. AB - Unique heterogeneous catalase-like activity was observed for metallosupramolecular ionic crystals [AuI4CoIII2(dppe)2(d-pen)4]X n ([1]X n ; dppe = 1,2-bis(diphenylphosphino)ethane; d-pen = d-penicillaminate; X n = (Cl-)2, (ClO4-)2, (NO3-)2 or SO42-) consisting of AuI4CoIII2 complex cations, [1]2+, and inorganic anions, X- or X2-. Treatment of the ionic crystals with an aqueous H2O2 solution led to considerable O2 evolution with a high turnover frequency of 1.4 * 105 h-1 for the heterogeneous cobalt complexes, which was dependent on their size and shape as well as the arrangement of cationic and anionic species. These dependencies were rationalized by the presence of cobalt(ii) centers on the crystal surface and their efficient exposure on the (111) plane rather than the (100) plane based on morphological and theoretical studies. PMID- 28553505 TI - Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo. AB - UNC-51-like kinase 1 (ULK1) is well-known to initiate autophagy, and the downregulation of ULK1 has been found in most breast cancer tissues. Thus, the activation of ULK1-modulated autophagy could be a promising strategy for breast cancer therapy. In this study, we found that ULK1 was remarkably downregulated in breast cancer tissue samples by The Cancer Genome Atlas (TCGA) analysis and tissue microarray (TMA) analysis, especially in triple negative breast cancer (TNBC). To design a ULK1 agonist, we integrated in silico screening and chemical synthesis to acquire a series of small molecule candidates. After rounds of kinase and anti-proliferative activity screening, we discovered the small molecule, LYN-1604, to be the best candidate for a ULK1 agonist. Additionally, we identified that three amino acid residues (LYS50, LEU53, and TYR89) were key to the activation site of LYN-1604 and ULK1 by site-directed mutagenesis and biochemical assays. Subsequently, we demonstrated that LYN-1604 could induce cell death, associated with autophagy by the ULK complex (ULK1-mATG13-FIP200-ATG101) in MDA-MB-231 cells. To further explore LYN-1604-induced autophagic mechanisms, we found some potential ULK1 interactors, such as ATF3, RAD21, and caspase3, by performing comparative microarray analysis. Intriguingly, we found that LYN-1604 induced cell death involved in ATF3, RAD21, and caspase3, accompanied by autophagy and apoptosis. Moreover, we demonstrated that LYN-1604 has potential for good therapeutic effects on TNBC by targeting ULK1-modulated cell death in vivo; thus making this ULK1 agonist a novel potential small-molecule drug candidate for future TNBC therapy. PMID- 28553506 TI - Selective N-terminal functionalization of native peptides and proteins. AB - We report an efficient, highly selective modification on the N-terminal amines of peptides and proteins using aldehyde derivatives via reductive alkylation. After modification of a library of unprotected peptides XYSKEASAL (X varies over 20 natural amino acids) by benzaldehyde at room temperature, pH 6.1 resulted in excellent N-terminal selectivity (alpha-amino/epsilon-amino: >99 : 1) and high reaction conversion for 19 out of the 20 peptides. Under similar conditions, highly selective N-terminal modifications were achieved with a variety of aldehydes. Furthermore, N-termini of native peptides and proteins could be selectively modified under the same conditions to introduce bioorthogonal functional groups. Using human insulin as an example, we further demonstrated that preserving the positive charge in the N-terminus using reductive alkylation instead of acylation leads to a 5-fold increase in bioactivity. In summary, our reported method provides a universal strategy for site-selective N-terminal functionalization in native peptides and proteins. PMID- 28553507 TI - Light-up probe based on AIEgens: dual signal turn-on for caspase cascade activation monitoring. AB - Direct monitoring of multiple enzyme activities in a given biological process is extremely important for disease diagnosis. Herein, we report a single fluorescent probe that targets two caspase activities in living cells. The probe consists of three parts that includes two AIE fluorogens with distinctive green and red emission colors excitable at a single wavelength, and a hydrophilic peptide as the substrate of the apoptosis initiator caspase-8 and the effector caspase-3. The probe is non-fluorescent in aqueous media. The green and red fluorescence can be sequentially turned on when the peptide substrate is cleaved by the cascade activation of caspase-8 and caspase-3 in early apoptotic HeLa cells induced by hydrogen peroxide. This sequential fluorescence turn-on allows real-time monitoring of the caspase cascade activation during the apoptotic process, which was further explored for evaluating the therapeutic efficiency of anticancer drugs. The probe design strategy developed in this study also proved to be general, which opens a new avenue for real-time, multiplexed imaging of cellular enzyme activity in a biological process. PMID- 28553508 TI - Template-directed synthesis of linear porphyrin oligomers: classical, Vernier and mutual Vernier. AB - Three different types of template-directed syntheses of linear porphyrin oligomers are presented. In the classical approach the product has the same number of binding sites as the template, whereas in Vernier reactions the product has the lowest common multiple of the numbers of binding sites in the template and the building block. Mutual Vernier templating is like Vernier templating except that both strands of the Vernier complex undergo coupling simultaneously, so that it becomes impossible to say which is the 'template' and which is the 'building block'. The template-directed synthesis of monodisperse linear oligomers is more difficult than that of cyclic oligomers, because the products of linear templating have reactive ends. All three types of templating are demonstrated here, and used to prepare a nickel(ii) porphyrin dodecamer with 4 pyridyl substituents on all twelve porphyrin units. The stabilities and cooperativities of the double-strand complexes involved in these reactions were investigated by UV-vis-NIR titration. The four-rung ladder duplex has a stability constant of about 2 * 1018 M-1 in dichloromethane at 298 K. PMID- 28553509 TI - Generalized-active-space pair-density functional theory: an efficient method to study large, strongly correlated, conjugated systems. AB - Predicting ground- and excited-state properties of open-shell organic molecules by electronic structure theory can be challenging because an accurate treatment has to correctly describe both static and dynamic electron correlation. Strongly correlated systems, i.e., systems with near-degeneracy correlation effects, are particularly troublesome. Multiconfigurational wave function methods based on an active space are adequate in principle, but it is impractical to capture most of the dynamic correlation in these methods for systems characterized by many active electrons. We recently developed a new method called multiconfiguration pair density functional theory (MC-PDFT), that combines the advantages of wave function theory and density functional theory to provide a more practical treatment of strongly correlated systems. Here we present calculations of the singlet-triplet gaps in oligoacenes ranging from naphthalene to dodecacene. Calculations were performed for unprecedently large orbitally optimized active spaces of 50 electrons in 50 orbitals, and we test a range of active spaces and active space partitions, including four kinds of frontier orbital partitions. We show that MC-PDFT can predict the singlet-triplet splittings for oligoacenes consistent with the best available and much more expensive methods, and indeed MC PDFT may constitute the benchmark against which those other models should be compared, given the absence of experimental data. PMID- 28553510 TI - Model-free extraction of spin label position distributions from pseudocontact shift data. AB - A significant problem with paramagnetic tags attached to proteins and nucleic acids is their conformational mobility. Each tag is statistically distributed within a volume between 5 and 10 Angstroms across; structural biology conclusions from NMR and EPR work are necessarily diluted by this uncertainty. The problem is solved in electron spin resonance, but remains open in the other major branch of paramagnetic resonance - pseudocontact shift (PCS) NMR spectroscopy, where structural biologists have so far been reluctantly using the point paramagnetic centre approximation. Here we describe a new method for extracting probability densities of lanthanide tags from PCS data. The method relies on Tikhonov regularised 3D reconstruction and opens a new window into biomolecular structure and dynamics because it explores a very different range of conditions from those accessible to double electron resonance work on paramagnetic tags: a room temperature solution rather than a glass at cryogenic temperatures. The method is illustrated using four different Tm3+ DOTA-M8 tagged mutants of human carbonic anhydrase II; the results are in good agreement with rotamer library and DEER data. The wealth of high-quality pseudocontact shift data accumulated by the biological magnetic resonance community over the last 30 years, and so far only processed using point models, could now become a major source of useful information on conformational distributions of paramagnetic tags in biomolecules. PMID- 28553511 TI - Piezochromism and hydrochromism through electron transfer: new stories for viologen materials. AB - While viologen derivatives have long been known for electrochromism and photochromism, here we demonstrated that a viologen-carboxylate zwitterionic molecule in the crystalline state exhibits piezochromic and hydrochromic behaviors. The yellow crystal undergoes a reversible color change to red under high pressure, to green after decompression, and finally back to yellow upon standing at ambient pressure. Ultraviolet-visible spectroscopy, X-ray photoelectron spectroscopy, electron paramagnetic resonance X-ray diffraction and DFT calculations suggested that the piezochromism is due to the formation of radicals via pressure-induced electron transfer from carboxylate to pyridinium, without a crystallographic phase transition. It was proposed that electron transfer is induced by pressure-forced reduction of intermolecular donor-acceptor contacts. The electron transfer can also be induced by dehydration, which gives a stable green anhydrous radical phase. The color change is reversible upon reabsorption of water, which triggers reverse electron transfer. The compound not only demonstrates new chromic phenomena for viologen compounds, but also represents the first example of organic mechanochromism and hydrochromism associated with radical formation via electron transfer. PMID- 28553512 TI - Sub-1.1 nm ultrathin porous CoP nanosheets with dominant reactive {200} facets: a high mass activity and efficient electrocatalyst for the hydrogen evolution reaction. AB - The exploration of a facile strategy to synthesize porous ultrathin nanosheets of non-layered materials, especially with exposed reactive facets, as highly efficient electrocatalysts for the hydrogen evolution reaction (HER), remains challenging. Herein we demonstrate a chemical transformation strategy to synthesize porous CoP ultrathin nanosheets with sub-1.1 nm thickness and exposed {200} facets via phosphidation of Co3O4 precursors. The resultant samples exhibit outstanding electrochemical HER performance: a low overpotential (only 56 and 131 mV are required for current densities of 10 and 100 mA cm-2, respectively), a small Tafel slope of 44 mV per decade, a good stability of over 20 h, and a high mass activity of 151 A g-1 at an overpotential of 100 mV. The latter is about 80 times higher than that of CoP nanoparticles. Experimental data and density functional theory calculations reveal that a high proportion of reactive {200} facets, high utilization efficiency of active sites, metallic nature, appropriate structural disorder, facile electron/mass transfer and rich active sites benefiting from the unique ultrathin and porous structure are the key factors for the greatly improved activity. Additionally, this facile chemical conversion strategy can be developed to a generalized method for preparing porous ultrathin nanosheets of CoSe2 and CoS that cannot be obtained using other methods. PMID- 28553514 TI - Long wavelength excitable near-infrared fluorescent nanoparticles with aggregation-induced emission characteristics for image-guided tumor resection. AB - Near infrared (NIR) fluorescence imaging (700-900 nm) is a promising technology in preclinical and clinical tumor diagnosis and therapy. The availability of excellent NIR fluorescent contrast agents is still the main barrier to implementing this technology. Herein, we report the design and synthesis of two series of NIR fluorescent molecules with long wavelength excitation and aggregation-induced emission (AIE) characteristics by fine-tuning their molecular structures and substituents. Further self-assembly between an amphiphilic block co-polymer and the obtained AIE molecules leads to AIE nanoparticles (AIE NPs), which have absorption maxima at 635 nm and emission maxima between 800 and 815 nm with quantum yields of up to 4.8% in aggregated states. In vitro and in vivo toxicity results demonstrate that the synthesized AIE NPs are biocompatible. Finally, the synthesized AIE NPs have been successfully used for image-guided tumor resection with a high tumor-to-normal tissue signal ratio of 7.2. PMID- 28553515 TI - Molecular catalysis at polarized interfaces created by ferroelectric BaTiO3. AB - The local environment at polarized solid-liquid interfaces provides a unique medium for chemical reactions that could be exploited to control the selectivity of non-faradaic reactions. Polarized interfaces are commonly prepared by applying a voltage to an electrode in an electrolyte solution, but it is challenging to achieve high surface charge densities while suppressing faradaic reactions. Ferroelectric materials have permanent surface charge densities that arise from the dipole moments of ferroelectric domains and can be used to create polarized solid-liquid interfaces without applying a voltage. We studied the effects of ferroelectric oxides on the selectivity of a Rh porphyrin-catalyzed carbene rearrangement. The addition of ferroelectric BaTiO3 nanoparticles to the reaction solution changed the product ratio in the same direction and by a similar magnitude as performing the reaction at an electrode-electrolyte interface polarized by a voltage. The results demonstrate that colloidal suspensions of BaTiO3 nanoparticles act as a dispersible polarized interface that can influence the selectivity of non-faradaic reactions. PMID- 28553513 TI - A new H2S-specific near-infrared fluorescence-enhanced probe that can visualize the H2S level in colorectal cancer cells in mice. AB - Near-infrared (NIR) fluorescence-based sensors capable of selective detection of H2S in vivo would be useful tools to understand the mechanisms of diseases. A new NIR fluorescence probe 1 was developed for the detection of endogenous H2S in colorectal cancer cells in mice. 1 displayed an 87-fold fluorescence enhancement at 796 nm (with excitation at 730 nm) when reacted with H2S in a buffer (pH 7.4). 1 was water-soluble, cell-membrane-permeable, had low cytotoxicity and high selectivity and sensitivity for H2S. The properties of 1 enable its use in monitoring endogenous H2S in living cells, tissues, and mice. The bioimaging results indicated that (1) d-Cys could induce endogenous H2S production in living cells and stimulate angiogenesis; (2) tail intravenous injection of 1 into mice generated strong fluorescence in the liver while intraperitoneal injection of d Cys could further enhance fluorescence in the liver in vivo; (3) importantly, endogenous H2S in colorectal cancer cells (HCT116, HT29) in vitro and in murine tumor models could be quickly and selectively detected by intratumoral injection of 1. These results indicated that our new probe could serve as an efficient tool for the detection of cellular H2S in living animals and even for cancer diagnosis. PMID- 28553517 TI - The protecting-group free selective 3'-functionalization of nucleosides. AB - The direct and chemoselective 3'-phosphoramidation, phosphorylation and acylation of nucleosides are described. Upon the discovery of a novel 3' phosphorylamidation of therapeutic nucleoside analogues with DBU, we explored the mechanism of this rare selectivity through a combination of NMR spectroscopy and computational studies. The NMR and computational findings allowed us to develop a predictive computational model that accurately assesses the potential for 3' functionalization for a broad range of nucleosides and nucleoside mimetics. The synthetic utility of this model was exemplified by demonstration on a broad scope of nucleosides and electrophiles yielding targets that were previously only accessible via a protection/deprotection sequence or an enzymatic approach. PMID- 28553516 TI - A practical strategy to design and develop an isoform-specific fluorescent probe for a target enzyme: CYP1A1 as a case study. AB - The development of isoform-specific probe(s) for a target enzyme with multiple homologs is always challenging. Herein, a practical strategy was used to design and develop an isoform-specific probe for CYP1A1, a key cytochrome P450 isoenzyme involved in xenobiotic metabolism and bioactivation. On the basis of the subtle differences in 3D structure and substrate preference between CYP1A1 and its homolog CYP1A2, we proposed that it was possible to design a CYP1A1-specific probe via local modification of the reaction site on known CYP1A substrates. To validate this hypothesis, 4-hydroxy-1,8-naphthalimide (HN) was selected as the basic fluorophore due to its excellent optical properties, while a series of O alkylated HN derivatives were prepared to evaluate their specificity towards CYP1A1. Our results revealed that the introduction of a chloroethyl to HN could get the best isoform selectivity towards CYP1A1 over other CYPs including CYP1A2. The newly developed probe NBCeN exhibited excellent specificity, high sensitivity, and a ratiometric fluorescence response following CYP1A1-catalyzed O dechloroethylation. NBCeN was successfully used to real-time monitor the activity of CYP1A1 in complex biological samples and to rapidly screen CYP1A1 modulators in living systems. NBCeN could also be used for two-photon imaging of intracellular CYP1A1 in living cells and tissues with high ratiometric imaging resolution and deep tissue penetration. All these findings demonstrated that local modification of non-specific substrates was a practical strategy to develop an isoform-specific probe for a target isoenzyme, while NBCeN could serve as a specific imaging tool to explore the biological functions of CYP1A1 in complex biological systems. PMID- 28553518 TI - Enantioselective [2 + 2] cycloaddition of N-allenamides with cyclic N sulfonylketimines: access to polysubstituted azetidines bearing quaternary stereocenters. AB - A Ni(ClO4)2-catalyzed enantioselective [2 + 2] cycloaddition of N-allenamides with cyclic N-sulfonylketimines was developed, which regioselectively occurred at the proximal CC bonds of the N-allenamides. Broad substrate scope of N allenamides and cyclic N-sulfonylketimines was observed. A range of fused polysubstituted azetidines bearing quaternary stereocenters were afforded in good yields and with excellent enantioselectivities (up to 99%). PMID- 28553519 TI - Nuclear-targeted siRNA delivery for long-term gene silencing. AB - Developing effective nonviral siRNA delivery systems for long-term gene silencing remains a great challenge. Here we present a nuclear-targeted siRNA delivery system that can induce long-term gene silencing in cancer cells. The nanocarrier consists of gold nanoparticles modified with a dense shell of synthetic siRNAs and nuclear localization signal (NLS) peptides. The NLS peptide could translocate the nanocarrier into the nucleus and the siRNA was designed to target the promoter of thymidine kinase 1 and trigger the RNA-directed DNA methylation, thereby enabling the nuclear-targeted gene silencing. Compared with traditional gene silencing in cytoplasm, long-lasting gene knockdown could be achieved for the nuclear-targeted nanocarrier, which lasts for more than 30 days. The long term gene silencing induced by nuclear-targeted siRNA delivery could effectively inhibit the proliferation of cancer cells and prevent the formation of a tumor in a mouse model. PMID- 28553520 TI - Watasemycin biosynthesis in Streptomyces venezuelae: thiazoline C-methylation by a type B radical-SAM methylase homologue. AB - 2-Hydroxyphenylthiazolines are a family of iron-chelating nonribosomal peptide natural products that function as virulence-conferring siderophores in various Gram-negative bacteria. They have also been reported as metabolites of Gram positive Streptomyces species. Transcriptional analyses of Streptomyces venezuelae ATCC 10712 revealed that its genome contains a putative 2 hydroxyphenylthiazoline biosynthetic gene cluster. Heterologous expression of the gene cluster in Streptomyces coelicolor M1152 showed that the mono- and dimethylated derivatives, thiazostatin and watasemycin, respectively, of the 2 hydroxyphenylthiazoline enantiopyochelin are two of its metabolic products. In addition, isopyochelin, a novel isomer of pyochelin containing a C-methylated thiazolidine, was identified as a third metabolic product of the cluster. Metabolites with molecular formulae corresponding to aerugine and pulicatins A/B were also detected. The structure and stereochemistry of isopyochelin were confirmed by comparison with synthetic standards. The role of two genes in the cluster encoding homologues of PchK, which is proposed to catalyse thiazoline reduction in the biosynthesis of enantiopyochelin in Pseudomonas protegens, was investigated. One was required for the production of all the metabolic products of the cluster, whereas the other appears not to be involved in the biosynthesis of any of them. Deletion of a gene in the cluster encoding a type B radical-SAM methylase homologue abolished the production of watasemycin, but not thiazostatin or isopyochelin. Feeding of thiazostatin to the mutant lacking the functional PchK homologue resulted in complete conversion to watasemycin, demonstrating that thiazoline C-methylation by the type B radical-SAM methylase homologue is the final step in watasemycin biosynthesis. PMID- 28553521 TI - A smart ZnO@polydopamine-nucleic acid nanosystem for ultrasensitive live cell mRNA imaging by the target-triggered intracellular self-assembly of active DNAzyme nanostructures. AB - Efficient strategies for the ultrasensitive imaging of gene expression in living cells are essential in chemistry and cell biology. Here, we report a novel and efficient enzyme-free dual signal amplification strategy for live cell mRNA imaging by using a smart nucleic acid hairpin-based nanosystem. This nanosystem consists of a ZnO nanoparticle core, an interlayer of polydopamine and an outer layer of four hairpin DNA (hpDNA) probes. Such a core-shell nanosystem facilitates the cellular uptake of molecular hairpin payloads, protects them from nuclease digestion, and delivers them into the cytoplasm by the acid-triggered dissolution of the ZnO core. In the presence of target mRNA, the released hpDNA probes self-assemble via HCR into wire-shaped active DNAzymes that catalyze the generation of a fluorescence signal. The target-initiated HCR events and DNAzyme cascades offer efficient dual amplification and enable the ultrasensitive detection of mRNA with a femtomolar detection limit. Live cell assays show an intense fluorescence response from a tumor-related biomarker survivin mRNA only in tumor cells untreated with a survivin expression repressor YM155, but not in normal cells. The developed nanosystem provides a potential platform for the amplified imaging of low-abundance disease-related biomarkers in live cells. PMID- 28553523 TI - Intramolecular water-splitting reaction in single collisions of water ions with surfaces. AB - We report the direct formation of H2 and O pair ions through single collisions of water ions with metal surfaces at hyperthermal energies. This unusual intramolecular reaction proceeds also for heavy and semi-heavy water, producing molecular D2 and HD ions. The selectivity of this water splitting channel is estimated at being between 9 and 13% versus complete dissociation. The collision kinematics support the hypothesis of a water molecule colliding with a single surface atom, thereby forming an excited precursor (Rydberg?) state, which dissociates subsequently to form the molecular hydrogen ion with high kinetic energy. Inelastic energy loss considerations yield an estimate for the energy of the excited precursor state of ~7 eV and ~11 eV at low and high incidence energies. These energies are close to the A state (1B1, 7.5 eV) and B state (1A1, 9.7 eV) of excited water (Rydberg states). PMID- 28553522 TI - A rational pre-catalyst design for bis-phosphine mono-oxide palladium catalyzed reactions. AB - Significant catalyst loading reduction and increased reaction robustness have been achieved for a Pd-catalyzed asymmetric intramolecular C-N coupling through comprehensive mechanistic studies. Detailed kinetic, spectroscopic, and crystallographic analyses revealed that the mono-oxidation of the bis-phosphine ligand is critical for a successful transformation. 31P NMR studies provided an understanding of the inefficient activation of the Pd(OAc)2/(R,R)-QuinoxP* pre catalyst to form the active bis-phosphine mono-oxide-Pd(0) catalyst with competitive formation of a less active (R,R)-QuinoxP*.PdBr2 complex. Based on these detailed mechanistic studies, a new series of bis-phosphine mono-oxides (BPMO)-ligated Pd(ii) pre-catalysts have been rationally developed that allow for reliable and complete catalyst activation which should have general utility in academic and industrial settings. PMID- 28553524 TI - High temperature ferromagnetism in pi-conjugated two-dimensional metal-organic frameworks. AB - We use first-principles calculations to show that the square symmetry of two dimensional (2D) metal-organic frameworks (MOFs) made from octaamino-substituted phthalocyanines and square planar Ni2+ ions, which enable strong conjugation of pi electrons, has a critical impact on the magnetic properties of the lattice. In particular, we predict the unexpected emergence of a rare high-temperature ferromagnetic half-metallic ground state in one case. Among charge neutral MOFs made from (2,3,9,10,16,17,23,24)-octaiminophthalocyanine (OIPc) metallated with divalent first-row transition metal ions (M-OIPc; M = Cr2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+) and connected through square planar Ni-bisphenylenediimine moieties, NiMn-OIPc exhibits a half-metallic and ferromagnetic ground state with a large exchange energy resulting from the unique strong hybridization between the d/pi orbitals of Mn, the Pc ring, and the Ni-bisphenylenediimine nodes. Notably, we show that for NiMn-OIPc there is a considerable difference between the ferromagnetic ordering temperature (Tc) predicted by a 2D Ising model, which exceeds 600 K, and a Tc of 170 K predicted by our more realistic Monte Carlo simulation that includes magnetic anisotropy. Critically, our simulations adopt two spin models that incorporate magnetic anisotropy in the form of exchange anisotropy and single-ion anisotropy. We further show that in the bulk, 2D layers of NiMn-OIPc adopt a slipped-parallel stacking configuration, and exhibit interlayer magnetic coupling that is sensitive to the relative in-plane displacement between adjacent layers. These results highlight the critical role of magnetic anisotropy in modeling the properties of 2D magnetic systems. More generally, it demonstrates that strong hybridization between open-shell ions and delocalized aromatic pi systems with appropriate symmetry, combined with large magnetic anisotropy, will be an effective design strategy to realize ferromagnetic 2D MOFs with high Tc. PMID- 28553526 TI - Synthesis and stabilities of peptide-based [1]rotaxanes: molecular grafting onto lasso peptide scaffolds. AB - The chemical synthesis of peptide-based [1]rotaxanes (lasso peptides) was achieved by [2]rotaxane formation followed by two chemoselective ligation reactions. Our approach enabled incorporation of various peptide sequences into a common rotaxane structure. The synthetic lasso peptides were characterized by NMR, chromatography, and partial degradation by proteases. A linear peptide epitope grafted onto the rotaxane scaffold showed significantly improved proteolytic stability. PMID- 28553525 TI - The effects of thioamide backbone substitution on protein stability: a study in alpha-helical, beta-sheet, and polyproline II helical contexts. AB - Thioamides are single atom substitutions of the peptide bond that serve as versatile probes of protein structure. Effective use of thioamides requires a robust understanding of the impact that the substitution has on a protein of interest. However, the thermodynamic effects of thioamide incorporation have only been studied in small structural motifs, and their influence on secondary structure in the context of full-length proteins is not known. Here we describe a comprehensive survey of thioamide substitutions in three benchmark protein systems (calmodulin, the B1 domain of protein G, and collagen) featuring the most prevalent secondary structure motifs: alpha-helix, beta-sheet, and polyproline type II helix. We find that in most cases, effects on thermostability can be understood in terms of the positioning and local environment of the thioamide relative to proximal structural elements and hydrogen bonding networks. These observations set the stage for the rational design of thioamide substituted proteins with predictable stabilities. PMID- 28553527 TI - Dual gold and photoredox catalysed C-H activation of arenes for aryl-aryl cross couplings. AB - A mild and fully catalytic aryl-aryl cross coupling via gold-catalysed C-H activation has been achieved by merging gold and photoredox catalysis. The procedure is free of stoichiometric oxidants and additives, which were previously required in gold-catalysed C-H activation reactions. Exploiting dual gold and photoredox catalysis confers regioselectivity via the crucial gold-catalysed C-H activation step, which is not present in the unselective photocatalysis-only counterpart. PMID- 28553528 TI - Copper(i)-catalyzed sulfonylative Suzuki-Miyaura cross-coupling. AB - Using a simple copper(i) catalyst has allowed a high yielding sulfonylative Suzuki-Miyaura cross-coupling reaction to be developed. The process provides a single step route to diaryl sulfones from the direct combination of aryl boronic acids, sulfur dioxide and aryl iodides, and represents the first sulfonylative variant of a classic cross-coupling reaction. Sulfur dioxide is delivered from the surrogate reagent, DABSO. Variation of the reaction conditions allowed interruption of the sulfonylative-Suzuki coupling, resulting in the formation of a presumed Cu-sulfinate intermediate. These sulfinates could be trapped as their sodium salts and treated with electrophiles to allow access to arylalkyl sulfones, beta-hydroxyl sulfones, sulfonamides and sulfonyl fluorides. PMID- 28553529 TI - Catalytic asymmetric synthesis of CF3-substituted tertiary propargylic alcohols via direct aldol reaction of alpha-N3 amide. AB - Organofluorine compounds are found in several important classes of chemicals, such as pharmaceuticals, agrochemicals, and functional materials. Chemists have been immensely interested in the development of methodologies for expeditious access to fluorine containing building blocks. In this study, we report a new method for the catalytic asymmetric synthesis of CF3-substituted tertiary propargylic alcohols with two contiguous stereogenic centers via the direct aldol reaction of an alpha-N3 amide to trifluoromethyl ketones. The key to the success of this method is the identification of a catalyst comprising Cu(ii)/chiral hydroxamic acid to promote the desired aldol reaction, constructing a tetrasubstituted carbon in a highly stereoselective fashion. Despite substantial prior advances in asymmetric catalysis, this class of catalysts has not been utilized for the formation of carbon-carbon bond-forming reactions. Our mechanistic study sheds light on the unique profile of this catalytic system, where the Cu(ii) complex plays a bifunctional role of serving as a Lewis acid and a Bronsted base. Furthermore, the densely functionalized aldol adducts undergo chemoselective transformations, affording a series of fluorine containing chiral building blocks with widespread application. PMID- 28553530 TI - Quantifying the efficiency of CO2 capture by Lewis pairs. AB - A microfluidic strategy has been used for the time- and labour-efficient evaluation of the relative efficiency and thermodynamic parameters of CO2 binding by three Lewis acid/base combinations, where efficiency is based on the amount of CO2 taken up per binding unit in solution. Neither tBu3P nor B(C6F5)3 were independently effective at CO2 capture, and the combination of the imidazolin-2 ylidenamino-substituted phosphine (NIiPr)3P and B(C6F5)3 was equally ineffective. Nonetheless, an archetypal frustrated Lewis pair (FLP) comprised of tBu3P and B(C6F5)3 was shown to bind CO2 more efficiently than either the FLP derived from tetramethylpiperidine (TMP) and B(C6F5)3 or the highly basic phosphine (NIiPr)3P. Moreover, the proposed microfluidic platform was used to elucidate the thermodynamic parameters for these reactions. PMID- 28553531 TI - Cellular and cell-free studies of catalytic DNA cleavage by ruthenium polypyridyl complexes containing redox-active intercalating ligands. AB - The ruthenium(ii) polypyridyl complexes (RPCs), [(phen)2Ru(tatpp)]2+ (32+ ) and [(phen)2Ru(tatpp)Ru(phen)2]4+ (44+ ) are shown to cleave DNA in cell-free studies in the presence of a mild reducing agent, i.e. glutathione (GSH), in a manner that is enhanced upon lowering the [O2]. Reactive oxygen species (ROS) are involved in the cleavage process as hydroxy radical scavengers attenuate the cleavage activity. Cleavage experiments in the presence of superoxide dismutase (SOD) and catalase reveal a central role for H2O2 as the immediate precursor for hydroxy radicals. A mechanism is proposed which explains the inverse [O2] dependence and ROS data and involves redox cycling between three DNA-bound redox isomers of 32+ or 44+ . Cultured non-small cell lung cancer cells (H358) are sensitive to 32+ and 44+ with IC50 values of 13 and 15 MUM, respectively, and xenograft H358 tumors in nude mice show substantial (~80%) regression relative to untreated tumors when the mice are treated with enantiopure versions of 32+ and 44+ (Yadav et al. Mol Cancer Res, 2013, 12, 643). Fluorescence microscopy of H358 cells treated with 15 MUM 44+ reveals enhanced intracellular ROS production in as little as 2 h post treatment. Detection of phosphorylated ATM via immunofluorescence within 2 h of treatment with 44+ reveals initiation of the DNA damage repair machinery due to the ROS insult and DNA double strand breaks (DSBs) in the nuclei of H358 cells and is confirmed using the gammaH2AX assay. The cell data for 32+ is less clear but DNA damage occurs. Notably, cells treated with [Ru(diphenylphen)3]2+ (IC50 1.7 MUM) show no extra ROS production and no DNA damage by either the pATM or gammaH2AX even after 22 h. The enhanced DNA cleavage under low [O2] (4 MUM) seen in cell-free cleavage assays of 32+ and 44+ is only partially reflected in the cytotoxicity of 32+ and 44+ in H358, HCC2998, HOP-62 and Hs766t under hypoxia (1.1% O2) relative to normoxia (18% O2). Cells treated with RPC 32+ show up to a two-fold enhancement in the IC50 under hypoxia whereas cells treated with RPC 44+ gave the same IC50 whether under hypoxia or normoxia. PMID- 28553532 TI - Optimizing side chains for crystal growth from water: a case study of aromatic amide foldamers. AB - The growth of crystals of aromatic compounds from water much depends on the nature of the water solubilizing functions that they carry. Rationalizing crystallization from water, and structure elucidation, of aromatic molecular and supramolecular systems is of general value across various fields of chemistry. Taking helical aromatic foldamers as a test case, we have validated several short polar side chains as efficient substituents to provide both solubility in, and crystal growth ability from, water. New 8-amino-2-quinolinecarboxylic acids bearing charged or neutral aminomethyl, carboxymethyl, sulfonic acid, or bis(hydroxymethyl)-methoxy side chains in position 4 or 5, were prepared on a multi gram scale. Fmoc protection of the main chain amine and suitable protections of the side chains ensured compatibility with solid phase synthesis. One tetrameric and five octameric oligoamides displaying these side chains were synthesized and shown to be soluble in water. In all cases but one, crystals were obtained using the hanging drop method, thus validating the initial design principle to combine polarity and rigidity. The only case that resisted crystallization appeared to be due to exceedingly high water solubility endowed by eight sulfonic acid functions. The neutral side chain did provide crystal growth ability from water but contributed poorly to solubility. PMID- 28553533 TI - The marriage of AIE and interface engineering: convenient synthesis and enhanced photovoltaic performance. AB - As a promising option out of all of the well-recognized candidates that have been developed to solve the coming energy crisis, polymer solar cells (PSCs) are a kind of competitive clean energy source. However, as a convenient and efficient method to improve the efficiency of PSCs, the inherent mechanism of the interfacial modification was still not so clear, and interfacial materials constructed with new units were limited to a large degree. Here we present a new kind of interfacial material consisting of AIE units for the first time, with an efficiency of 8.94% being achieved by inserting TPE-2 as a cathode interlayer. This is a relatively high PCE for PC71BM:PTB7-based conventional PSCs with a single-junction structure. Different measurements, including TEM, AFM, SEM, GIXRD, UPS, SKPM, and SCLC, were conducted to investigate the properties in detail. All of the obtained experimental results confirmed the advantages of the utilization of new interfacial materials with AIE characteristics in polymer solar cells, thus providing an additional choice to develop new organic cathode interfacial layers with high performances. PMID- 28553534 TI - Two-dimensional crystal engineering using halogen and hydrogen bonds: towards structural landscapes. AB - Two-dimensional (2D) crystallization on solid surfaces is governed by a subtle balance of supramolecular and interfacial interactions. However, these subtle interactions often make the prediction of supramolecular structure from the molecular structure impossible. As a consequence, surface-based 2D crystallization has often been studied on a case-by-case basis, which hinders the identification of structure-determining relationships between different self assembling systems. Here we begin the discussion on such structure-determining relationships by comparing the 2D crystallization of two identical building blocks based on a 1,3,5-tris(pyridine-4-ylethynyl)benzene unit at the solution solid interface. The concepts of supramolecular synthons and structural landscapes are introduced in the context of 2D crystallization on surfaces to identify common structural elements. The systems are characterized using scanning tunneling microscopy (STM). This strategy involves carrying out minor structural modifications on the parent compound to access supramolecular patterns that are otherwise not obtained. We demonstrate that this chemical perturbation strategy translates equally well for 2D co-crystallization experiments with halogen bond donors yielding porous bi-component networks. The holistic approach described here represents a stepping stone towards gaining predictive power over the 2D crystallization of molecules on solid surfaces. PMID- 28553535 TI - Dopamine-modified TiO2 monolith-assisted LDI MS imaging for simultaneous localization of small metabolites and lipids in mouse brain tissue with enhanced detection selectivity and sensitivity. AB - Localization of metabolites using multiplexed mass spectrometry imaging (MSI) provides important chemical information for biological research. In contrast to matrix-assisted laser desorption/ionization (MALDI), TiO2-assisted laser desorption/ionization (LDI) for MSI improves detection of low molecular mass metabolites (<500 Da) by reducing matrix background. However, the low UV absorption of TiO2 nanoparticles and their ester hydrolysis catalytic activity hinder the detection of phospholipids and many low-abundance molecules. To address these challenges, we evaluated and optimized the material morphology and composition of TiO2. Dopamine (DA) was found to be an efficient ligand for TiO2, resulting in increased UV light absorption, higher surface pH, and formation of monolithic TiO2-DA structures. The sub-micron scale and higher surface pH of the TiO2 particle sizes led to improved detection of phospholipid signals. Compared to unmodified TiO2 sub-micron particles, the DA-modified TiO2 monolith led to 10- to 30-fold increases in the signal-to-noise ratios of a number of compound peaks. The TiO2-DA monolith-assisted LDI MSI approach has higher selectivity and sensitivity for Lewis basic compounds, such as fatty acids, cholesterols, ceramides, diacylglycerols, and phosphatidylethanolamine, when analyzed in positive mode, than traditional MALDI MS. Using this new method, over 100 molecules, including amino acids, alkaloids, free fatty acids, peptides, and lipids, were localized in mouse brain sections. By comparing the presence and localization of those molecules in young and old mouse brains, the approach demonstrated good performance in the determination of aging-related neurochemical changes in the brain. PMID- 28553537 TI - Solvent modified spin crossover in an iron(iii) complex: phase changes and an exceptionally wide hysteresis. AB - Solvent effects in a series of Fe(iii) spin crossover (SCO) complexes [Fe(qsal I)2]OTf.sol (sol = MeOH 1, EtOH 2, n-PrOH 3, i-PrOH 4, acetone 5 and MeCN 6) are explored. SCO is abrupt in 1 (following MeOH loss) and 2, gradual for 3 (T1/2 = 199 K) and 4 (T1/2 = 251 K) and incomplete, even up to 350 K, for 5 and 6. In [Fe(qsal-I)2]OTf SCO occurs at T1/2? = 225 K and T1/2? = 234 K (DeltaT = 9 K), while aged samples of 2 exhibit an exceptionally wide hysteresis of 80 K (T1/2? = 139 K and T1/2? = 219 K). In contrast, fresh samples of 2 exhibit stepped SCO with hysteresis varying from 2 to 42 K. VT-PXRD (variable temperature powder X ray diffraction) studies indicate a new phase, 2b, is formed upon cooling below 180 K along with a minor LS phase 2c. Phase 2c and the HS phase 2a undergo a spin transition at T1/2? = 180 K and T1/2? = 215 K with phase 2b exhibiting two-step SCO. Structural studies in both spin states, except 6, show the cations are linked through extensive pi-pi interactions to form 1D chains. A combination of P4AE (parallel fourfold aryl embrace) and I...X (X = I, O, pi) interactions create tightly packed 3D supramolecular networks. This study emphasizes that while solvent may result in only small structural changes SCO characteristics can be impacted dramatically. PMID- 28553536 TI - Gel-based morphological design of zirconium metal-organic frameworks. AB - The ability of metal-organic frameworks (MOFs) to gelate under specific synthetic conditions opens up new opportunities in the preparation and shaping of hierarchically porous MOF monoliths, which could be directly implemented for catalytic and adsorptive applications. In this work, we present the first examples of xero- or aerogel monoliths consisting solely of nanoparticles of several prototypical Zr4+-based MOFs: UiO-66-X (X = H, NH2, NO2, (OH)2), UiO-67, MOF-801, MOF-808 and NU-1000. High reactant and water concentrations during synthesis were observed to induce the formation of gels, which were converted to monolithic materials by drying in air or supercritical CO2. Electron microscopy, combined with N2 physisorption experiments, was used to show that irregular nanoparticle packing leads to pure MOF monoliths with hierarchical pore systems, featuring both intraparticle micropores and interparticle mesopores. Finally, UiO 66 gels were shaped into monolithic spheres of 600 MUm diameter using an oil-drop method, creating promising candidates for packed-bed catalytic or adsorptive applications, where hierarchical pore systems can greatly mitigate mass transfer limitations. PMID- 28553538 TI - Site selective reading of epigenetic markers by a dual-mode synthetic receptor array. AB - Variably functionalized self-folding deep cavitands form an arrayed, fluorescent indicator displacement assay system for the detection of post-translationally modified (PTM) histone peptides. The hosts bind trimethyllysine (KMe3) groups, and use secondary upper rim interactions to provide more sensitive discrimination between targets with identical KMe3 binding handles. The sensor array uses multiple different recognition modes to distinguish between miniscule differences in target, such as identical lysine modifications at different sites of histone peptides. In addition, the sensor is affected by global changes in structure, so it is capable of discriminating between identical PTMs, at identical positions on amino acid fragments that vary only in peptide backbone length, and can be applied to detect non-methylation modifications such as acetylation and phosphorylations located multiple residues away from the targeted binding site. The synergistic application of multiple variables allows dual-mode deep cavitands to approach levels of recognition selectivity usually only seen with antibodies. PMID- 28553539 TI - Determination of a complex crystal structure in the absence of single crystals: analysis of powder X-ray diffraction data, guided by solid-state NMR and periodic DFT calculations, reveals a new 2'-deoxyguanosine structural motif. AB - Derivatives of guanine exhibit diverse supramolecular chemistry, with a variety of distinct hydrogen-bonding motifs reported in the solid state, including ribbons and quartets, which resemble the G-quadruplex found in nucleic acids with sequences rich in guanine. Reflecting this diversity, the solid-state structural properties of 3',5'-bis-O-decanoyl-2'-deoxyguanosine, reported in this paper, reveal a hydrogen-bonded guanine ribbon motif that has not been observed previously for 2'-deoxyguanosine derivatives. In this case, structure determination was carried out directly from powder XRD data, representing one of the most challenging organic molecular structures (a 90-atom molecule) that has been solved to date by this technique. While specific challenges were encountered in the structure determination process, a successful outcome was achieved by augmenting the powder XRD analysis with information derived from solid-state NMR data and with dispersion-corrected periodic DFT calculations for structure optimization. The synergy of experimental and computational methodologies demonstrated in the present work is likely to be an essential feature of strategies to further expand the application of powder XRD as a technique for structure determination of organic molecular materials of even greater complexity in the future. PMID- 28553542 TI - Regio- and stereospecific rhodium-catalyzed allylic alkylation with an acyl anion equivalent: an approach to acyclic alpha-ternary beta,gamma-unsaturated aryl ketones. AB - The regio- and stereospecific rhodium-catalyzed allylic alkylation of secondary allylic carbonates with cyanohydrin pronucleophiles facilitates the direct construction of acyclic alpha-ternary beta,gamma-unsaturated aryl ketones. Interestingly, this study illustrates the impact of deaggregating agents on regiocontrol and the electronic nature of the aryl component to suppress olefin isomerization. In addition, we demonstrate that the dimethylamino substituent, which modulates the pKa of the alpha-ternary beta,gamma-unsaturated aryl ketone, provides a useful synthetic handle for further functionalization via Kumada cross coupling of the aryl trimethylammonium salt. Finally, the stereospecific alkylation of a chiral nonracemic secondary allylic carbonate affords the enantioenriched alpha-ternary aryl ketone, which was employed in a formal synthesis of trichostatic acid to illustrate that the allylic alkylation proceeds with net retention of configuration. PMID- 28553541 TI - Adsorption and molecular siting of CO2, water, and other gases in the superhydrophobic, flexible pores of FMOF-1 from experiment and simulation. AB - FMOF-1 is a flexible, superhydrophobic metal-organic framework with a network of channels and side pockets decorated with -CF3 groups. CO2 adsorption isotherms measured between 278 and 313 K and up to 55 bar reveal a maximum uptake of ca. 6.16 mol kg-1 (11.0 mol L-1) and unusual isotherm shapes at the higher temperatures, suggesting framework expansion. We used neutron diffraction and molecular simulations to investigate the framework expansion behaviour and the accessibility of the small pockets to N2, O2, and CO2. Neutron diffraction in situ experiments on the crystalline powder show that CO2 molecules are favourably adsorbed at three distinct adsorption sites in the large channels of FMOF-1 and cannot access the small pockets in FMOF-1 at 290 K and oversaturated pressure at 61 bar. Stepped adsorption isotherms for N2 and O2 at 77 K can be explained by combining Monte Carlo simulations in several different crystal structures of FMOF 1 obtained from neutron and X-ray diffraction under different conditions. A similar analysis is successful for CO2 adsorption at 278 and 283 K up to ca. 30 bar; however, at 298 K and pressures above 30 bar, the results suggest even more substantial expansion of the FMOF-1 framework. The measured contact angle for water on an FMOF-1 pellet is 158 degrees , demonstrating superhydrophobicity. Simulations and adsorption measurements also show that FMOF-1 is hydrophobic and water is not adsorbed in FMOF-1 at room temperature. Simulated mixture isotherms of CO2 in the presence of 80% relative humidity predict that water does not influence the CO2 adsorption in FMOF-1, suggesting that hydrophobic MOFs could hold promise for CO2 capture from humid gas streams. PMID- 28553540 TI - Stimuli-responsive multifunctional glyconanoparticle platforms for targeted drug delivery and cancer cell imaging. AB - Targeted bioimaging or chemotherapeutic drug delivery to achieve the desired therapeutic effects while minimizing side effects has attracted considerable research attention and remains a clinical challenge. Presented herein is a multi component delivery system based on carbohydrate-functionalized gold nanoparticles conjugated with a fluorophore or prodrug. The system leverages active targeting based on carbohydrate-lectin interactions and release of the payload by biological thiols. Cell-type specific delivery of the activatable fluorophore was examined by confocal imaging on HepG2 cells, and displays distinct selectivity towards HepG2 cells over HeLa and NIH3T3 cells. The system was further developed into a drug delivery vehicle with camptothecin (CPT) as a model drug. It was demonstrated that the complex exhibits similar cytotoxicity to that of free CPT towards HepG2 cells, and is significantly less cytotoxic to normal HDF and NIH3T3 cells, indicating excellent specificity. The delivery vehicle itself exhibits excellent biocompatibility and offers an attractive strategy for cell-type specific delivery depending on the carbohydrates conjugated in the system. PMID- 28553543 TI - Evaluation of MMP substrate concentration and specificity for neovascularization of hydrogel scaffolds. AB - Controlled vascular response in scaffolds following implantation remains a significant clinical challenge. A critical biomaterial design criterion is the synchronization of the rates of scaffold degradation and vascularized tissue formation. Matrix metalloproteinases (MMPs) are key enzymes that regulate neovascularization and extracellular matrix remodelling. Synthetic protease sensitive hydrogels offer controllable environments for investigating the role of matrix degradation on neovascularization. In this study, PEG hydrogels containing MMP-sensitive peptides with increased catalytic activity for MMPs expressed during neovascularization were investigated. Scaffolds were functionalized with MMP-2-, MMP-14- or general collagenase-sensitive peptides and with varying peptide concentration using crosslinkers containing one (SSite) or multiple (TSite) repeats of each protease-sensitive sequence. Increasing peptide concentration enhanced the degradation kinetics of scaffolds functionalized with MMP-specific sequences while 80% of the collagenase-sensitive scaffolds remained upon exposure to MMP-2 and MMP-14. In vitro neovascularization was consistent with in vivo tissue invasion with significantly increased invasion occurring within SSite MMP-specific as compared to collagenase-sensitive hydrogels and with further invasion in TSite as compared to SSite hydrogels regardless of peptide specificity. All scaffolds supported in vivo neovascularization; however, this was not dependent on peptide specificity. These findings demonstrate that peptide concentration and specificity regulate in vivo scaffold degradation, neovascularization and matrix remodelling. PMID- 28553544 TI - Development of novel approach to diagnostic imaging of lung cancer with 18F Nifene PET/CT using A/J mice treated with NNK. AB - Development of novel methods of early diagnosis of lung cancer is one of the major tasks of contemporary clinical and experimental oncology. In this study, we utilized the tobacco nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer in A/J mice as an animal model for development of a new imaging technique for early diagnosis of lung cancer. Lung cancer cells in A/J mice overexpress nicotinic acetylcholine receptors. Longitudinal CT scans were carried out over a period of 8 months after NNK treatment, followed by PET/CT scans with 18F-Nifene that binds to alpha4-made nicotinic receptors with high affinity. PET/CT scans of lungs were also obtained ex vivo. CT revealed the presence of lung nodules in 8-month NNK-treated mice, while control mice had no tumors. Imaging of live animals prior to necropsy allowed correlation of results of tumor load via PET/CT and histopathological findings. Significant amount of 18F-Nifene was seen in the lungs of NNK-treated mice, whereas lungs of control mice showed only minor uptake of 18F-Nifene. Quantitative analysis of the extent and amount of 18F-Nifene binding in lung in vivo and ex vivo demonstrated a higher tumor/nontumor ratio due to selective labeling of tumor nodules expressing abundant alpha4 nicotinic receptor subunits. For comparison, we performed PET/CT studies with 18F-FDG, which is used for the imaging diagnosis of lung cancer. The tumor/nontumor ratios for 18F-FDG were lower than for 18F-Nifene. Thus, we have developed a novel diagnostic imaging approach to early diagnosis of lung cancer using 18F-Nifene PET/CT. This technique allows quantitative assessment of lung tumors in live mice, which is critical for establishing tumor size and location, and also has salient clinical implications. PMID- 28553546 TI - Effect of a Clinical and Translational Science Award institute on grant funding in a major research university. AB - INTRODUCTION: Previous studies have examined the impact of Clinical and Translational Science Awards programs on other outcomes, but not on grant seeking. The authors examined the effects on grant seeking of the Michigan Institute for Clinical & Health Research (MICHR), a Clinical and Translational Science Awards institute at the University of Michigan. METHODS: We assessed over 63,000 grant proposals submitted at the University of Michigan in the years 2002 2012 using data from the university and MICHR's Tracking Metrics and Reporting System. We used a retrospective, observational study of the dynamics of grant seeking success and award funding. Heckman selection models were run to assess MICHR's relationship with a proposal's success (selection), and subsequently the award's size (outcome). Models were run for all proposals and for clinical and translational research (CTR) proposals alone. Other covariates included proposal classification, type of grant award, academic unit, and year. RESULTS: MICHR had a positive and statistically significant relationship with success for both proposal types. For all grants, MICHR was associated with a 29.6% increase in award size. For CTR grants, MICHR had a statistically nonsignificant relationship with award size. CONCLUSIONS: MICHR's infrastructure, created to enable and enhance CTR, has also created positive spillovers for a broader spectrum of research and grant seeking. PMID- 28553545 TI - Rheumatic autoimmune diseases in women and midlife health. AB - Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (scleroderma) preferentially affect women, and are characterized by systemic inflammation leading to target organ dysfunction. The public health burden of autoimmune diseases, which collectively represent a leading cause of morbidity and mortality among women throughout adulthood, is substantial. While some features of these diseases have been observed to improve over the menopausal transition, such as disease flare rate in SLE and skin softening and thinning in scleroderma, others, such as swollen and tender joints and radiographically confirmed damage in RA may worsen. The general trends, however, are not consistent or conclusive for all disease-related manifestations. Of great importance is the recognition that comorbid diseases, including osteoporosis and accelerated cardiovascular disease, contribute excess morbidity and mortality that becomes increasingly apparent as women with autoimmune diseases undergo the menopausal transition. PMID- 28553548 TI - Potential Utility of a 4K Consumer Camera for Surgical Education in Ophthalmology. AB - Purpose. We evaluated the potential utility of a cost-effective 4K consumer video system for surgical education in ophthalmology. Setting. Tokai University Hachioji Hospital, Tokyo, Japan. Design. Experimental study. Methods. The eyes that underwent cataract surgery, glaucoma surgery, vitreoretinal surgery, or oculoplastic surgery between February 2016 and April 2016 were recorded with 17.2 million pixels using a high-definition digital video camera (LUMIX DMC-GH4, Panasonic, Japan) and with 0.41 million pixels using a conventional analog video camera (MKC-501, Ikegami, Japan). Motion pictures of two cases for each surgery type were evaluated and classified as having poor, normal, or excellent visibility. Results. The 4K video system was easily installed by reading the instructions without technical expertise. The details of the surgical picture in the 4K system were highly improved over those of the conventional pictures, and the visual effects for surgical education were significantly improved. Motion pictures were stored for approximately 11 h with 512 GB SD memory. The total price of this system was USD 8000, which is a very low price compared with a commercial system. Conclusion. This 4K consumer camera was able to record and play back with high-definition surgical field visibility on the 4K monitor and is a low-cost, high-performing alternative for surgical facilities. PMID- 28553547 TI - Changes in Anterior, Posterior, and Total Corneal Astigmatism after Descemet Membrane Endothelial Keratoplasty. AB - Purpose. To evaluate changes in anterior, posterior, and total corneal astigmatism in patients after Descemet membrane endothelial keratoplasty (DMEK). Methods. We retrospectively included 29 eyes of 23 patients (age 67.6 +/- 9.8 years, 13 female, 10 male) after DMEK surgery. The magnitude and axis orientation of anterior, posterior, and total corneal astigmatism before and after DMEK were determined using a rotating Scheimpflug system (Pentacam HR, Oculus). Results. The magnitude of anterior, posterior, and total corneal astigmatism in the central cornea did not change significantly after surgery. Before surgery, we found a significant correlation between the magnitudes of anterior and posterior corneal astigmatism (Spearman's correlation coefficient (rS) = 0.526, P = 0.003), while after surgery this correlation was no longer significant (rS = 0.038, P = 0.843). There was a significant correlation between the vector difference between preoperative and postoperative posterior astigmatism and the change in corneal pachymetry (rP = 0.47, P = 0.010). Conclusions. Posterior corneal astigmatism (especially the orientation) and therefore the relationship between anterior and total corneal astigmatism may change after DMEK. This should be considered to improve the accuracy of toric IOL power calculations following phakic DMEK or in combined procedures. PMID- 28553549 TI - Twenty-Four-Hour Variation of Intraocular Pressure in Primary Open-Angle Glaucoma Treated with Triple Eye Drops. AB - Objectives. To evaluate 24-hour intraocular pressure (IOP) variation in patients with primary open-angle glaucoma (POAG) treated with triple eye drops. Subjects and Methods. The IOP was measured in 74 eyes in 74 POAG patients (seated) on triple therapy (PG analogue, beta-blocker, carbonic anhydrase inhibitor) at about every 3 hours. Results. The peak IOP was 13.5 +/- 3.1 at 1:00, and the trough IOP was at 12.6 +/- 2.4 mmHg at 7:00. The IOP at 7:00 was significantly lower than that at 10:00, 1:00, and 3:00 (p < 0.05). Based on the time of the peak IOP, we classified the patients into two groups: diurnal (28 eyes) and nocturnal types (37 eyes). There was significant difference at the spherical equivalent between diurnal and nocturnal types (p = 0.014). To assess the influence of reflective error, we conducted subanalysis for two groups: high myopic (26 eyes, <=-6D) and low/nonmyopic (24 eyes, >=-2D) groups. In the low/nonmyopia group, the IOP was significantly higher at 1:00 and 3:00 than at 13:00, 16:00, and 7: 00 (p < 0.05). Conclusion. The mean of IOP elevated outside of clinic hour in the POAG patients on triple therapy. The low/nonmyopia patient should be carefully treated because the IOP of the patients at night elevated significantly. PMID- 28553550 TI - Intraoperative Macula Protection by Perfluorocarbon Liquid for the Metallic Intraocular Foreign Body Removal during 23-Gauge Vitrectomy. AB - Purpose. To evaluate visual and safety outcomes of 23-gauge (G) pars plana vitrectomy (PPV) with application of perfluorocarbon liquid (PFCL) for intraoperative protection of the macula during intraocular foreign body (IOFB) removal. Methods. Retrospective study of 42 patients who underwent 23 G PPV for IOFB removal from posterior segment with intraoperative PFCL application for the macula shielding. Collected data included corrected distance visual acuity (CDVA), size of IOFB, and complication rate. The mean follow-up period was 12 months. Results. The mean preoperative CDVA was 0.54 logMAR (SD 0.46), and the final mean CDVA was 0.68 logMAR (SD 0.66). All IOFBs were metallic with mean dimensions of 4.6 mm * 2.1 mm. Twenty-two IOFBs were removed through the corneal tunnel and 20 IOFBs through the sclerotomy. No intraoperative iatrogenic lesion of the macula was observed. As a tamponade, silicon oil was applied in 31 eyes, SF6 gas in 5 eyes, air in 4 eyes, and 2 eyes required no tamponade. Secondary retinal detachment was observed in 17% of cases, but at the end of the follow-up, all the retinas were attached. Conclusion. PFCL application during PPV is a safe method of protecting the macula from unexpected falling of the metallic IOFB during its removal. PMID- 28553551 TI - Glaucomatous Optic Nerve Changes and Thyroid Dysfunction in an Urban South Korean Population. AB - Purpose. This study was performed to evaluate the relationship between intraocular pressure (IOP) and glaucomatous optic nerve change and thyroid factors in Korean population. Materials and Methods. The study included subjects who underwent health screening in Kangbuk Samsung Hospital. Detailed history taking and systemic and ocular examination including fundus photography were performed for all participants. All fundus photographs were divided into two groups based on disc and RNFL appearance: nonglaucoma and glaucoma group. Subjects were also divided into quartiles of each thyroid function parameter, and the relationship with IOP and glaucoma were analysed. Results. In univariate analysis, free T4, T3, and TSH in normal subjects and T3 in thyroid disease group were associated with the IOP. After adjusting for age and sex, the IOP tended to slightly decrease according to the level of the quartile of free T4 and T3 in normal subjects. In terms of glaucoma, on multivariate analysis, it did not show a significant correlation with any thyroid function tests. Conclusions. In normal subjects, the IOP tended to be decreased according to the level of free T4 and T3 but the amounts were clinically insignificant. Thyroid factors are not an independent risk factor for the development of glaucoma. PMID- 28553552 TI - A Case of Urinary Tract Infection and Severe Sepsis Caused by Kluyvera ascorbata in a 73-Year-Old Female with a Brief Literature Review. AB - Infections that are caused by Kluyvera bacteria have been previously reported in the medical literature; however, they seem to be less common. Herein, we report a case of urinary tract infection and severe sepsis caused by Kluyvera ascorbata in a 73-year-old female. We also did a brief literature review of infections caused by this organism in adults. PMID- 28553553 TI - Use of Chlorothiazide in the Management of Central Diabetes Insipidus in Early Infancy. AB - Management of central diabetes insipidus in infancy is challenging. The various forms of desmopressin, oral, subcutaneous, and intranasal, have variability in the duration of action. Infants consume most of their calories as liquids which with desmopressin puts them at risk for hyponatremia and seizures. There are few cases reporting chlorothiazide as a temporizing measure for central diabetes insipidus in infancy. A male infant presented on day of life 30 with holoprosencephaly, cleft lip and palate, and poor weight gain to endocrine clinic. Biochemical tests and urine output were consistent with central diabetes insipidus. The patient required approximately 2.5 times the normal fluid intake to keep up with the urine output. Patient was started on low renal solute load formula and oral chlorothiazide. There were normalization of serum sodium, decrease in fluid intake close to 1.3 times the normal, and improved urine output. There were no episodes of hyponatremia/hypernatremia inpatient. The patient had 2 episodes of hypernatremia in the first year of life resolving with few hours of hydration. Oral chlorothiazide is a potential bridging agent for treatment of central DI along with low renal solute load formula in early infancy. It can help achieve adequate control of DI without wide serum sodium fluctuations. PMID- 28553554 TI - A Case of Sporadic Creutzfeldt-Jakob Disease Presenting as Conversion Disorder. AB - Background. Creutzfeldt-Jakob disease is a rare disorder of the central nervous system. Its initial diagnosis may be obscured by its variable presentation. This case report illustrates the complexity of diagnosing this disease early in the clinical course, especially when the initial symptoms may be psychiatric. It offers a brief review of the literature and reinforces a role for consultation psychiatry services. Methods. PUBMED/MEDLINE was searched using the terms "Creutzfeldt-Jakob disease", "psychiatric symptoms", "conversion disorder", "somatic symptom disorder", "functional movement disorder", and "functional neurologic disorder". Case. The patient was a 64-year-old woman with no prior psychiatric history who was initially diagnosed with conversion disorder and unspecified anxiety disorder but soon thereafter was discovered to have Creutzfeldt-Jakob disease. Discussion. This case highlights the central role of psychiatric symptoms in early presentations of Creutzfeldt-Jakob disease. Still, few other cases in the literature report functional neurological symptoms as an initial sign. The consultation psychiatrist must remain alert to changing clinical symptoms, especially with uncharacteristic disease presentations. PMID- 28553555 TI - Magnetic Resonance Imaging-Guided Focused Ultrasound Surgery for the Treatment of Symptomatic Uterine Fibroids. AB - Uterine fibroids, the most common benign tumor in women of childbearing age, may cause symptoms including pelvic pain, menorrhagia, dysmenorrhea, pressure, urinary symptoms, and infertility. Various approaches are available to treat symptomatic uterine fibroids. Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS) represents a recently introduced noninvasive safe and effective technique that can be performed without general anesthesia, in an outpatient setting. We review the principles of MRgFUS, describing patient selection criteria for the treatments performed at our center and we present a series of five selected patients with symptomatic uterine fibroids treated with this not yet widely known technique, showing its efficacy in symptom improvement and fibroid volume reduction. PMID- 28553557 TI - Factors Affecting Herd Status for Bovine Tuberculosis in Dairy Cattle in Northern Thailand. AB - The objective of this case-control study was to identify farm-level risk factors associated with bovine tuberculosis (bTB) in dairy cows in northern Thailand. Spatial analysis was performed to identify geographical clustering of case-farms located in Chiang Mai and Chiang Rai provinces in northern Thailand. To identify management factors affecting bTB status, a matched case-control study was conducted with 20 case-farms and 38 control-farms. Case-farms were dairy farms with at least single intradermal tuberculin test- (SIT-) reactor(s) in the farms during 2011 to 2015. Control-farms were dairy farms with no SIT-reactors in the same period and located within 5 km from case-farms. Questionnaires were administered for data collection with questions based on epidemiological plausibility and characteristics of the local livestock industry. Data were analyzed using multiple logistic regressions. A significant geographic cluster was identified only in Chiang Mai province (p < 0.05). The risk factor associated with presence of SIT-reactors in dairy herds located in this region was purchasing dairy cows from dealers (OR = 5.85, 95% CI = 1.66-20.58, and p = 0.006). From this study, it was concluded that geographic clustering was identified for dairy farms with SIT-reactors in these provinces, and the cattle movements through cattle dealers increased the risks for SIT-reactor farm status. PMID- 28553556 TI - The Role of Toll-Like Receptors in Autoimmune Diseases through Failure of the Self-Recognition Mechanism. AB - Toll-like receptors (TLRs), part of the innate immune system that recognises molecular signatures, are important in the recognition of pathogenic components. However, when specific cellular contexts develop in which TLRs are inappropriately activated by self-components, this may lead to sterile inflammation and result in the occurrence of autoimmunity. This review analyses the available data regarding TLR biochemistry, the specific mechanisms which are brought about by TLR activation, and the importance of these mechanisms in the light of any existing and potential therapies in the field of autoimmunity. PMID- 28553558 TI - Phosphorylation of group I metabotropic glutamate receptors in drug addiction and translational research. AB - Protein phosphorylation is an important posttranslational modification of group I metabotropic glutamate receptors (mGluR1 and mGluR5 subtypes) which are widely distributed throughout the mammalian brain. Several common protein kinases are involved in this type of modification, including protein kinase A, protein kinase C, and extracellular signal-regulated kinase. Through constitutive and activity dependent phosphorylation of mGluR1/5 at specific residues, protein kinases regulate trafficking, subcellular/subsynaptic distribution, and function of modified receptors. Increasing evidence demonstrates that mGluR1/5 phosphorylation in the mesolimbic reward circuitry is sensitive to chronic psychostimulant exposure and undergoes adaptive changes in its abundance and activity. These changes contribute to long-term excitatory synaptic plasticity related to the addictive property of drugs of abuse. The rapid progress in uncovering the neurochemical basis of addiction has fostered bench-to-bed translational research by targeting mGluR1/5 for developing effective pharmacotherapies for treating addiction in humans. This review summarizes recent data from the studies analyzing mGluR1/5 phosphorylation. Phosphorylation dependent mechanisms in stimulant-induced mGluR1/5 and behavioral plasticity are also discussed in association with increasing interest in mGluR1/5 in translational medicine. PMID- 28553559 TI - Next Generation PERG Method: Expanding the Response Dynamic Range and Capturing Response Adaptation. AB - PURPOSE: To compare a new method for steady-state pattern electroretinogram (PERGx) with a validated method (PERGLA) in normal controls and in patients with optic neuropathy. METHODS: PERGx and PERGLA were recorded in a mixed population (n = 33, 66 eyes) of younger controls (C1; n = 10, age 38 +/- 8.3 years), older controls (C2; n = 11, 57.9 +/- 8.09 years), patients with early manifest glaucoma (G; n = 7, 65.7 +/-11.6 years), and patients with nonarteritic ischemic optic neuropathy (N; n = 5, mean age 59.4 +/- 8.6 years). The PERGx stimulus was a black-white horizontal grating generated on a 14 * 14 cm LED display (1.6 cycles/deg, 15.63 reversals/s, 98% contrast, 800 cd/m2 mean luminance, 25 degrees field). PERGx signal and noise were averaged over 1024 epochs (~2 minutes) and Fourier analyzed to retrieve amplitude and phase. Partial averages (16 successive samples of 64 epochs each) were also analyzed to quantify progressive changes over recording time (adaptation). RESULTS: PERGLA and PERGx amplitudes and latencies were correlated (Amplitude R2 = 0.59, Latency R2 = 0.39, both P < 0.0001) and were similarly altered in disease. Compared to PERGLA, however, PERGx had shorter (16 ms) latency, higher (1.39*) amplitude, lower (0.37*) noise, and higher (4.2*) signal-to-noise ratio. PERGx displayed marked amplitude adaptation in C1 and C2 groups and no significant adaptation in G and N groups. CONCLUSIONS: The PERGx high signal-to-noise ratio may allow meaningful recording in advanced stages of optic nerve disorders. In addition, it quantifies response adaptation, which may be selectively altered in glaucoma and optic neuropathy. TRANSLATIONAL RELEVANCE: A new PERG method with increased dynamic range allows recording of retinal ganglion cell function in advanced stages of optic nerve disorders. It also quantifies the response decline during the test, an autoregulatory adaptation to metabolic challenge that decreases with age and presence of disease. PMID- 28553560 TI - Optical Coherence Tomography Reveals Changes to Corneal Reflectivity and Thickness in Individuals with Tear Hyperosmolarity. AB - PURPOSE: To investigate whether tear hyperosmolarity, a feature of dry eye disease (DED), affects central corneal thickness (CCT), corneal light reflectivity, and/or tear film reflectivity. METHODS: This prospective, cross sectional study involved 48 participants (38 with hyperosmolar tears and 10 controls with normo-osmolar tears). Symptoms and signs of DED (tear osmolarity, sodium fluorescein tear break-up time, ocular surface staining, Schirmer test) were assessed. CCT, and the reflectivity of the cornea and the tear-epithelial interface were quantified relative to background noise using Fourier-domain optical coherence tomography (FD-OCT). RESULTS: CCT of eyes with severe tear hyperosmolarity, defined as eyes in the upper quartile of the hyperosmolar group, was less than control eyes (539.1 +/- 7.4 vs. 583.1 +/- 15.0 MUm, P = 0.02) and eyes with less severe tear hyperosmolarity, defined as hyperosmolar eyes in the lower quartile (622.7 +/- 5.8 MUm, P < 0.0001). CCT showed a negative linear relationship with tear osmolarity for values above 316 mOsmol/L (R2 = 0.17, P = 0.01). Central corneal reflectivity was lower in hyperosmolar eyes than normo osmolar eyes (45.1 +/- 0.3 vs. 48.1 +/- 0.6 pixels, P = 0.02); the greatest relative difference was in the anterior stroma, where corneal reflectivity was 4.7 +/- 1.9% less in hyperosmolar eyes (P < 0.01). Peak reflectivity of the tear epithelial interface was 4.8% +/- 3.5% higher in the hyperosmolar group than the normo-osmolar tear group (P = 0.04). CONCLUSION: Individuals with significant tear hyperosmolarity and clinical signs of symptoms of DED show reduced CCT and altered corneal reflectivity. TRANSLATIONAL RELEVANCE: Anterior segment FD-OCT provides novel insight into corneal microstructural differences in individuals with DED. PMID- 28553561 TI - Diagnostic Ability and Repeatability of a New Supra-Threshold Glaucoma Screening Program in Standard Automated Perimetry. AB - PURPOSE: We assess the diagnostic ability and repeatability of a new suprathreshold glaucoma screening test (GST) comprising 28 test points and a 1-of 3 sampling strategy at 95% of the normal limit for standard automated perimetry (SAP) in early to advanced glaucoma. METHODS: This prospective cross-sectional study included 96 eyes of patients with early, moderate, or advanced glaucoma and 37 eyes of normal controls. Participants were evaluated by the G-Dynamic threshold test once and the GST twice, in random order, using the Octopus 600 perimeter. The diagnostic ability of GST was assessed by comparison with the G Dynamic threshold obtained by receiver operating characteristic analysis. Repeatability was assessed by kappa statistics for agreement on glaucoma diagnosis and each test point. RESULTS: Although the G-Dynamic test exhibited significantly higher areas under the curve (AUC) than the GST1st (P = 0.009) in early glaucoma, there were no significant differences in any other AUCs between the two methods. The kappa values for repeatability of glaucoma diagnosis and each test point were 0.747 to 1.0 and 0.537 to 1.0, respectively. The duration of the GST in the control and early glaucoma groups was less than a minute, while that in the moderate and advanced glaucoma groups was within 1.5 minutes. CONCLUSION: The diagnostic ability of the new suprathreshold GST for early to advanced glaucoma was high, with moderate to strong repeatability and short test duration. TRANSLATIONAL RELEVANCE: There currently are no prominent suprathreshold screening strategies using SAP. The GST would be an effective clinical method for glaucoma screening. PMID- 28553562 TI - The Association of Glaucomatous Visual Field Loss and Balance. AB - PURPOSE: To relate balance measures to visual field (VF) damage from glaucoma. METHODS: The OPAL kinematic system measured balance, as root mean square (RMS) sway, on 236 patients with suspect/diagnosed glaucoma. Balance was measured with feet shoulder width apart while standing on a firm/foam surface with eyes opened/closed (Instrumental Clinical Test of Sensory Integration and Balance [ICTSIB] conditions), and eyes open on a firm surface under feet together, semi tandem, or tandem positions (standing balance conditions). Integrated VF (IVF) sensitivities were calculated by merging right and left eye 24-2 VF data. RESULTS: Mean age was 71 years (range, 57-93) and mean IVF sensitivity was 27.1 dB (normal = 31 dB). Lower IVF sensitivity was associated with greater RMS sway during eyes-open foam-surface testing (beta = 0.23 z-score units/5 dB IVF sensitivity decrement, P = 0.001), but not during other ICTSIB conditions. Lower IVF sensitivity also was associated with greater RMS sway during feet together standing balance testing (0.10 z-score units/5 dB IVF sensitivity decrement, P = 0.049), but not during other standing balance conditions. Visual dependence of balance was lower in patients with worse IVF sensitivity (beta = -21%/5 dB IVF sensitivity decrement, P < 0.001). Neither superior nor inferior IVF sensitivity consistently predicted balance measures better than measures of overall VF sensitivity. CONCLUSIONS: Balance was worse in glaucoma patients with greater VF damage under foam surface testing (designed to inhibit proprioceptive contributions to balance) as well as feet-together firm-surface conditions when somatosensory inputs were available. TRANSLATIONAL RELEVANCE: Good balance is essential to avoid unnecessary falls and patients with VF loss from glaucoma may be at higher risk of falls because of poor balance. PMID- 28553563 TI - Targeted Delivery of FLT-Morpholino Using Cyclic RGD Peptide. AB - PURPOSE: We previously showed that intravitreal injection of the sFLT morpholino oligomer (FLT-MO) suppresses laser-induced choroidal neovascularization (CNV) in mice by decreasing the membrane bound form of Flt-1 while increasing the soluble form of Flt-1 via alternative splicing shift. In this study, we examined whether cyclic RGD peptide (cRGD) can promote morpholino-oligomer accumulation in CNV following tail vein injection, and whether systemic cRGD conjugated FLT-MO (cRGD FLT-MO) suppresses CNV growth. METHODS: cRGD conjugated fluorescent morpholino oligomer (cRGD-F-MO) was injected via tail vein into mice with previous retinal laser photocoagulation and examined for cRGD-F-MO accumulation in CNV. To examine whether cRGD-FLT-MO suppresses CNV growth, mice were tail-vein injected with cRGD FLT-MO, cRGD conjugated standard morpholino-oligomer (cRGD-STD-MO), or Dulbecco's Phosphate-Buffered Saline (DPBS) 1 and 4 days postlaser photocoagulation. Seven days postlaser photocoagulation, eyes were harvested and laser CNV was stained with isolectin GS-IB4, allowing quantification of CNV size by confocal microscopy. RESULTS: cRGD-F-MO accumulation in CNV commenced immediately after tail vein injection and could be observed even 1 day after injection. cRGD-FLT-MO tail vein injection significantly suppressed CNV size (2.7 * 105 +/- 0.3 * 105 MUm3, P < 0.05 by Student's t-test) compared with controls (DPBS: 5.1 * 105 +/- 0.6 * 105 MUm3 and cRGD-STD-MO: 5.5 * 105 +/- 0.8 * 105 MUm3). CONCLUSIONS: cRGD peptide facilitates morpholino-oligomer accumulation in CNV following systemic delivery. cRGD-FLT-MO suppressed CNV growth after tail-vein injection, demonstrating the potential utility of cRGD peptide for morpholino-oligomer delivery to CNV. TRANSLATIONAL RELEVANCE: Current therapy for neovascular age related macular degeneration involves intravitreal injection of anti-vascular endothelial growth factor drugs. Our results indicate that CNV can be treated systemically, thus eliminating risks and hazards associated with intravitreal injection. PMID- 28553565 TI - Overview of FDA's Expanded Access Program for Investigational Drugs. AB - Expanded access, also called "compassionate use," provides a pathway for patients to gain access to investigational drugs, biologics, and medical devices used to diagnose, monitor, or treat patients with serious diseases or conditions for which there are no comparable or satisfactory therapy options available outside of clinical trials. The US Food and Drug Administration (FDA) facilitates the expanded access process; however, access to investigational treatments requires not only FDA's review and authorization but also the active involvement and cooperation of other parties, including drug companies and health care providers, in order to be successful. PMID- 28553564 TI - Affect systems, changes in body mass index, disordered eating and stress: an 18 month longitudinal study in women. AB - Background: Evidence suggests that stress plays a role in changes in body weight and disordered eating. The present study examined the effect of mood, affect systems (attachment and social rank) and affect regulatory processes (self criticism, self-reassurance) on the stress process and how this impacts on changes in weight and disordered eating. Methods: A large sample of women participated in a community-based prospective, longitudinal online study in which measures of body mass index (BMI), disordered eating, perceived stress, attachment, social rank, mood and self-criticism/reassurance were measured at 6 monthly intervals over an 18-month period. Results: Latent Growth Curve Modelling showed that BMI increased over 18 months while stress and disordered eating decreased and that these changes were predicted by high baseline levels of these constructs. Independently of this, however, increases in stress predicted a reduction in BMI which was, itself, predicted by baseline levels of self-hatred and unfavourable social comparison. Conclusions: This study adds support to the evidence that stress is important in weight change. In addition, this is the first study to show in a longitudinal design, that social rank and self-criticism (as opposed to self-reassurance) at times of difficulty predict increases in stress and, thus, suggests a role for these constructs in weight regulation. PMID- 28553566 TI - Ten-Year Experience for the Center for Drug Evaluation and Research, Part 2: FDA's Role in Ensuring Patient Safety. AB - BACKGROUND: The purpose of this study was to describe the role of the US Food and Drug Administration (FDA) in ensuring the safety of patients receiving investigational drugs under expanded access. METHODS: To better define FDA's role in the review of requests for expanded access, multiple queries of FDA's Center for Drug Evaluation and Research (CDER) document tracking system were performed. The queries identified reasons for, and outcomes of, expanded access requests for investigational drugs that were either not allowed to proceed or denied over a 10 year time period. An in-depth review of a random sample of single-patient, non emergency investigational new drug (IND) applications that were allowed to proceed was also conducted. RESULTS: Overall, 99.3% of the applications for almost 9000 expanded access of an investigational drug were allowed to proceed. There were 62 requests that were either denied (38 emergency INDs) or not allowed to proceed (24 non-emergency INDs). The most common reasons for denying emergency INDs was that the patient was stable on current therapy and that it was not deemed an emergency. The most common reasons for not allowing non-emergency expanded access INDs to proceed were incomplete application, unsafe dosing, demonstrated lack of efficacy for intended use, availability of adequate alternative therapies, and inadequate information provided in the application on which to base a decision. A review of a random sample of 150 single-patient, non emergency INDs revealed that FDA recommended changes to dosing, safety monitoring, or informed consent in 11%. CONCLUSIONS: FDA plays a significant role in the protection of patients who receive investigational drugs under expanded access. An extremely small percentage of applications received are not allowed to proceed; however, FDA provides significant input based on information that may not be available to treating physicians in order to ensure patient safety under the applications that do proceed. PMID- 28553567 TI - Improvised Neutral Zone Technique in a Completely Edentulous Patient with an Atrophic Mandibular Ridge and Neuromuscular Incoordination: A Clinical Tip. AB - Resorption of mandibular ridges is a multifactorial and biomechanical disease that is chronic, progressive, irreversible, and cumulative leading to loss of sulcular depth, vertical dimension loss, and decreased lower facial height. Some common neurological, hormonal, and metabolic disorders affect the adaptability of dentures, and this can be diagnosed by a trained prosthodontist with proper history-taking and clinical examination.The denture becomes passive due to complex neuromuscular control and causes difficulties in impression-making, mastication, and swallowing, which in turn leads to loss of retention and stability in complete dentures. Hence, residual ridge resorption becomes a challenging scenario for a clinician during fabrication of complete dentures. The neutral zone concept plays a significant role in overcoming these challenges. The neutral zone is the area where the outward forces from the tongue are neutralized or nullified by the forces of the lips and cheeks acting inward during functional movements.The neutral zone technique is an alternative approach for the construction of lower complete dentures. It is most effective for dentures where there is a highly atrophic ridge and history of denture instability. The technique aims to construct a denture that is shaped by muscle function and is in harmony with the surrounding oral structures. The technique is by no means new, but it is a valuable one. It is rarely used because of the extra clinical step involved and its complexity. Complete and partial denture failures are often related to non-compliance with neutral zone factors. Thus, the evaluation of the neutral zone is an important factor. Increased retention and stability with reduced chairside time are the salient features of this new approach to any clinically challenging situation in complete dentures.This clinical report describes a modification of the conventional neutral zone technique using improvised procedures to minimize chairside visits for a patient with an atrophic mandibular ridge and neuromuscular incoordination. PMID- 28553568 TI - Colorectal Cancer Presenting with Constipation During Pregnancy. AB - Colorectal cancer is a rare occurrence during pregnancy and can present with symptoms that are common during pregnancy such as constipation.This can make the diagnosis of colorectal cancer during pregnancy difficult. Management of colorectal cancer during pregnancy is similar to the treatment of non-pregnant patients, but with fetal safety in mind. This case report describes a 33-year-old female gravida two para one (G2P1) at 29 weeks gestation who presented with a complete bowel obstruction. Colonoscopy, magnetic resonance imaging (MRI) and later resection showed an obstructing malignancy which was then resected through an exploratory laparotomy with left hemicolectomy. Postoperatively, there was a concern for sepsis, so labor was induced and the baby was delivered vaginally. The patient then continued with chemotherapy with hematology-oncology. High clinical suspicion is needed to diagnose colorectal cancer during pregnancy. Once diagnosed, surgery can be considered if resectable, taking into account gestational age. Fetal safety is a major consideration during treatment. PMID- 28553569 TI - A Case Of Awake Percutaneous Extracorporeal Membrane Oxygenation For High-risk Percutaneous Coronary Intervention. AB - With significant improvements in percutaneous coronary intervention (PCI) technology, complex high risk PCI is increasingly offered to patients with limited revascularization options. Percutaneous mechanical circulatory support devices are often utilized for hemodynamic support during these complex procedures. Veno-arterial extracorporeal membrane oxygenation (ECMO) allows full hemodynamic support and provides systemic oxygenation. We describe a case of left main bifurcation stenting performed at our center with ECMO support in an awake patient without general anesthesia. PMID- 28553570 TI - Radiation Oncology Physician Practice in the Modern Era: A Statewide Analysis of Medicare Reimbursement. AB - INTRODUCTION: In recent years, major changes in health care policy have affected oncology practice dramatically. In this context, we examined the effect of practice structure on volume and payments for radiation oncology services using the 2013 Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File (POSPUF) for New York State radiation oncologists. METHODS: The Medicare POSPUF data was queried, and individual physicians were classified into freestanding office-based and hospital-based practices. Freestanding practices were further subdivided into urology, hematology-oncology, and other ownership structures. Additional variables analyzed included gender, year of medical school graduation, and Herfindahl-Hirschman Index (HHI). Statistical analyses were performed to assess the impact of the above-mentioned variables on reimbursements. RESULTS: There were 236 New York State radiation oncologists identified in the 2013 Medicare POSPUF dataset, with a total reimbursement of $91,525,855. Among freestanding centers, the mean global Medicare reimbursement was $832,974. Global Medicare reimbursement was $1,328,743 for urology practices, compared to $754,567 for hematology-oncology practices and $691,821 for other ownership structures (p < 0.05). The mean volume of on treatment visits (OTVs) was 240.5 per year, varying by practice structure. The mean annual OTV volumes for urology practices, hematology-oncology practices, other freestanding practices, and hospital-based programs were 424.6, 311.5, 247.5, and 209.3, respectively. After correcting for gender, physician experience, and HHI, practice structure was predictive of freestanding reimbursement and on treatment visit volume. CONCLUSION: Higher Medicare payment was significantly predicted by the type of practice structure, with urology-based and hematology-oncology practices accounting for the highest total reimbursement and OTV volume. PMID- 28553571 TI - Pancreatitis in the Setting of Vaso-occlusive Sickle Cell Crisis: A Rare Encounter. AB - Acute pancreatitis is a common cause of acute abdominal pain. Gallstones and alcohol abuse account for the majority of the cases. Pancreatic ischemia is an uncommon but established cause of pancreatitis associated with connective tissue diseases, vasculitis, and shock. Our case highlights a rare case of vaso occlusive crisis (VOC) in a patient with sickle cell (SC) disease leading to pancreatitis. Treatment remains largely conservative but exchange transfusion may be the therapy of choice in severely hypoxic patients or in patients with high pre-treatment hemoglobin S levels. PMID- 28553572 TI - Think Before Chopping a Diabetic Foot: Insight to Vascular Intervention. AB - Diabetes mellitus is a most commonly occurring chronic disease around the world, resulting in damage to multiple organs. One of the consequences of poorly controlled diabetes is vascular damage resulting in peripheral artery disease, leading to inadequate perfusion of the foot and eventually gangrene and amputation. Research over the past decade or so has provided us with the statistics that vascular intervention has better clinical outcomes including patient mortality, morbidity, quality of life, and patient satisfaction. This editorial advocates the importance of pursuing a vascular plan prior to a limb salvaging procedure. We highlight some important aspects of saving a diabetic foot and encourage the importance of giving a vascular trial. PMID- 28553573 TI - Psychometric Properties and Performance of the Patient Reported Outcomes Measurement Information System(r) (PROMIS(r)) Depression Short Forms in Ethnically Diverse Groups. AB - : Short form measures from the Patient Reported Outcomes Measurement Information System(r) (PROMIS(r)) are used widely. The present study was among the first to examine differential item functioning (DIF) in the PROMIS Depression short form scales in a sample of over 5000 racially/ethnically diverse patients with cancer. DIF analyses were conducted across different racial/ethnic, educational, age, gender and language groups. METHODS: DIF hypotheses, generated by content experts, informed the evaluation of the DIF analyses. The graded item response theory (IRT) model was used to evaluate the five-level ordinal items. The primary tests of DIF were Wald tests; sensitivity analyses were conducted using the IRT ordinal logistic regression procedure. Magnitude was evaluated using expected item score functions, and the non-compensatory differential item functioning (NCDIF) and T1 indexes, both based on group differences in the item curves. Aggregate impact was evaluated with expected scale score (test) response functions; individual impact was assessed through examination of differences in DIF adjusted and unadjusted depression estimates. RESULTS: Many items evidenced DIF; however, only a few had slightly elevated magnitude. No items evidenced salient DIF with respect to NCDIF and the scale-level impact was minimal for all group comparisons. The following short form items might be targeted for further study because they were also hypothesized to evidence DIF. One item showed slightly higher magnitude of DIF for age: nothing to look forward to; conditional on depression, this item was more likely to be endorsed in the depressed direction by individuals in older groups as contrasted with the cohort aged 21 to 49. This item was also hypothesized to show age DIF. Only one item (failure) showed DIF of slightly higher magnitude (just above threshold) for Whites vs. Asians/Pacific Islanders in the direction of higher likelihood of endorsement for Asians/Pacific Islanders. This item was also hypothesized to show DIF for minority groups. The impact of DIF was negligible. Conditional on depression, the items, worthless and hopeless were more likely to be endorsed in the depressed direction by respondents with less than high school education vs. those with a graduate degree; the magnitude of DIF was slightly above the T1 threshold, but not that of NCDIF. These items were also hypothesized to show DIF in the direction of more feelings of worthlessness by groups with lower education. While the magnitude and aggregate impact of DIF was small, in a few instances, individual impact was observed. Information provided was relatively high, particularly in the middle upper (depressed) tail of the distribution. Reliability estimates were high (> 0.90) across all studied groups, regardless of estimation method. CONCLUSIONS: This was the first study to evaluate measurement equivalence of the PROMIS Depression short forms across large samples of ethnically diverse groups. There were few items with DIF, and none of high magnitude, thus supporting the use of PROMIS Depression short form measures across such groups. These results could be informative for those using the short forms in minority populations or clinicians evaluating individuals with the depression short forms. PMID- 28553575 TI - Effects of Eleutherococcus senticosus Cortex on Recovery from the Forced Swimming Test and Fatty Acid beta-Oxidation in the Liver and Skeletal Muscle of mice. AB - OBJECTIVE: The root and stem barks of Eleutherococcus senticosus have been used to treat emotional and physical fatigue in China, Russia, Korea, and Japan. The effects of E. senticosus on recovery from physical fatigue and the expenditure of energy currently remain unclear. We herein examined the effects of E. senticosus extract on recovery from physical fatigue after the forced swimming test as well as fatty acid beta-oxidation in the liver and skeletal muscle of mice. METHODS: 1) Physical fatigue; E. senticosus extract (500 and 1000 mg/kg, twice daily) was administered orally to ICR male mice for 7 consecutive days. After swimming had been performed for 15 min, each mouse was placed on the cover of a 100-mm culture plate, and the time for each mouse to move away from the cover was measured. 2) Fatty acid beta-oxidation in the liver and skeletal muscle; E. senticosus extract (500 and 1000 mg/kg) was administered orally twice daily to C57BL/6J male mice for 21 consecutive days. The initial and final body and liver weight were measured, and then fatty acid beta-oxidation activity in the liver and skeletal muscle was measured by methods using [1-14C] palmitic acid. KEY FINDINGS: Recovery times after forced swimming were shorter in E. senticosus extract (500 and 1000 mg/kg)-treated mice than in vehicle-treated mice. The body and liver weight had no effect by the oral administration of E. senticosus extract, vitamin mixture and L-carnitine. Fatty acid beta-oxidation activity in skeletal muscle was increased by E. senticosus extract (500 and 1000 mg/kg). CONCLUSION: E. senticosus may enhance recovery from physical fatigue induced by forced swimming by accelerating energy changes through fatty acid beta-oxidation in skeletal muscle. PMID- 28553574 TI - Digital Cognitive Behavioral Therapy (dCBT) for Insomnia: a State-of-the-Science Review. AB - PURPOSE OF REVIEW: Over the past decade, digital solutions have been developed to support the dissemination of Cognitive Behavioral Therapy (CBT). In this paper, we review the evidence for and implications of digital CBT (dCBT) for insomnia. RECENT FINDINGS: We propose three categories of dCBT, which differ in the amount of clinician time needed, level of automatization, costs, and scalability: dCBT as support, guided dCBT, and fully automated dCBT. Consistent evidence has been published on the effectiveness of dCBT to address insomnia disorder, in a variety of populations, with effects extending into well-being. Important gaps in the literature are identified around moderators and mediators of dCBT, cost effectiveness, and the implementation of dCBT. SUMMARY: The evidence base for dCBT is rapidly developing and already suggests that dCBT for insomnia is effective. However, further science and digital innovation is required to realize the full potential of dCBT and address important clinical questions. PMID- 28553576 TI - Characterization of an Eukaryotic PL-7 Alginate Lyase in the Marine Red Alga Pyropia yezoensis. AB - BACKGROUND: Alginate lyases belonging to polysaccharide lyase family-7 (PL-7) are the most well studied on their structures and functions among whole alginate lyases. However, all characterized PL-7 alginate lyases are from prokaryotic bacteria cells. Here we report the first identification of eukaryotic PL-7 alginate lyase from marine red alga Pyropia yezoensis. METHODS: The cDNA encoding an alginate lyase PyAly was cloned and was used for the construction of recombinant PyAly (rPyAly) expression system in Escherichia coli. Purified rPyAly was assayed to identify its enzymatic properties. Its expression pattern in P. yessoensis was also investigated. RESULTS: PyAly is likely a secreted protein consisting of an N-terminal signal peptide of 25 residues and a catalytic domain of 216 residues. The amino-acid sequence of the catalytic domain showed 19-29% identities to those of bacterial characterized alginate lyases classified into family PL-7. Recombinant PyAly protein, rPyAly, which was produced with E. coli BL21(DE3) by cold-inducible expression system, drastically decreased the viscosity of alginate solution in the early stage of reaction. The most preferable substrate for rPyAly was the poly(M) of alginate with an optimal temperature and pH at 35oC and 8.0, respectively. After reaction, unsaturated tri and tetra-saccharides were produced from poly(M) as major end products. These enzymatic properties indicated that PyAly is an endolytic alginate lyase belonging to PL-7. Moreover, we found that the PyAly gene is split into 4 exons with 3 introns. PyAly was also specifically expressed in the gametophytic haplopid stage. CONCLUSION: This study demonstrates that PyAly in marine red alga P. yezoensis is a novel PL-7 alginate lyase with an endolytic manner. PyAly is a gametophyte-specifically expressed protein and its structural gene is composed of four exons and three introns. Thus, PyAly is the first enzymatically characterized eukaryotic PL-7 alginate lyase. PMID- 28553577 TI - Recent Major Advances of Biotechnology and Sustainable Aquaculture in China. AB - BACKGROUND: Global aquaculture production has increased continuously over the last five decades, and particularly in China. Its aquaculture has become the fastest growing and most efficient agri-sector, with production accounting for more than 70% of the world's aquaculture output. In the new century, with serious challenges regarding population, resources and the environment, China has been working to develop high-quality, effective, healthy, and sustainable blue agriculture through the application of modern biotechnology. Sound knowledge related to the biology and ecology of aquatic organisms has laid a solid foundation and provided the innovation and technology for rapid development of the aquaculture industry. Marine biotechnology, which is enabling solutions for ocean productivity and sustainability, has been promoted since the last decades of the 20th Century in China. OBJECTIVE: In this article, priority areas of research, mainly genetic breeding, omics studies, novel production systems, biosecurity, bioprocesses and biorefinery, as well as the major progress of marine biotechnology R&D in China are reviewed. CONCLUSION: Current innovative achievements in China are not enough and the level and frequency of academic advancements must be improved. International cooperation and assistance remain crucial for the success of marine biotechnology. PMID- 28553578 TI - A Comprehensive Study of Retinal Vessel Classification Methods in Fundus Images. AB - Nowadays, it is obvious that there is a relationship between changes in the retinal vessel structure and diseases such as diabetic, hypertension, stroke, and the other cardiovascular diseases in adults as well as retinopathy of prematurity in infants. Retinal fundus images provide non-invasive visualization of the retinal vessel structure. Applying image processing techniques in the study of digital color fundus photographs and analyzing their vasculature is a reliable approach for early diagnosis of the aforementioned diseases. Reduction in the arteriolar-venular ratio of retina is one of the primary signs of hypertension, diabetic, and cardiovascular diseases which can be calculated by analyzing the fundus images. To achieve a precise measuring of this parameter and meaningful diagnostic results, accurate classification of arteries and veins is necessary. Classification of vessels in fundus images faces with some challenges that make it difficult. In this paper, a comprehensive study of the proposed methods for classification of arteries and veins in fundus images is presented. Considering that these methods are evaluated on different datasets and use different evaluation criteria, it is not possible to conduct a fair comparison of their performance. Therefore, we evaluate the classification methods from modeling perspective. This analysis reveals that most of the proposed approaches have focused on statistics, and geometric models in spatial domain and transform domain models have received less attention. This could suggest the possibility of using transform models, especially data adaptive ones, for modeling of the fundus images in future classification approaches. PMID- 28553580 TI - Fast and Efficient Four-class Motor Imagery Electroencephalography Signal Analysis Using Common Spatial Pattern-Ridge Regression Algorithm for the Purpose of Brain-Computer Interface. AB - Brain-computer interfaces enable users to control devices with electroencephalographic (EEG) activity from the scalp or with single-neuron activity from within the brain. One of the most challenging issues in this regard is the balance between the accuracy of brain signals from patients and the speed of interpreting them into machine language. The main objective of this paper is to analyze different approaches to achieve the balance more quickly and in a better way. To reduce the ocular artifacts, the symmetric prewhitening independent component analysis (ICA) algorithm has been evaluated, which has the lowest runtime and lowest signal-to-interference (SIR) index, without destroying the original signal. After quick elimination of all undesirable signals, two successful feature extractors - the log-band power algorithm and common spatial patterns (CSPs) - are used to extract features. The emphasis is on identifying discriminative properties of the feature sets representing EEG trials recorded during the imagination of the tongue, feet, and left-right-hand movement. Finally, three well-known classifiers are evaluated, where the ridge regression classifier and CSPs as feature extractor have the highest accuracy classification rate about 83.06% with a standard deviation of 1.22%, counterposing the recent studies. PMID- 28553579 TI - Optogenetics, Tools and Applications in Neurobiology. AB - Comprehension of the brain function can be helpful for therapy of neurodegenerative diseases. The brain consists of various types of neuron sets, which organize in three-dimensional complex networks and form neural circuits underlying different behaviors. The circuits act based on the patterns that encode the brain functions. Recognition of the neural patterns requires methods to manipulate the neurons. Electrical stimulation may be the most common method. However, it has significant drawbacks including failure to identify specific neurons in experiments. As an alternative, optical stimulation is a new method that acts in combination with genetic approaches. The novel, optogenetic technology makes it feasible to manipulate either the specific cell types or the neural circuits. This is associated with minimum tissue damages as well as side effects. In this study, a new technology has been introduced, and then its optical and genetical tools have been investigated. PMID- 28553581 TI - Speckle Noise Reduction in Optical Coherence Tomography Using Two-dimensional Curvelet-based Dictionary Learning. AB - The process of interpretation of high-speed optical coherence tomography (OCT) images is restricted due to the large speckle noise. To address this problem, this paper proposes a new method using two-dimensional (2D) curvelet-based K-SVD algorithm for speckle noise reduction and contrast enhancement of intra-retinal layers of 2D spectral-domain OCT images. For this purpose, we take curvelet transform of the noisy image. In the next step, noisy sub-bands of different scales and rotations are separately thresholded with an adaptive data-driven thresholding method, then, each thresholded sub-band is denoised based on K-SVD dictionary learning with a variable size initial dictionary dependent on the size of curvelet coefficients' matrix in each sub-band. We also modify each coefficient matrix to enhance intra-retinal layers, with noise suppression at the same time. We demonstrate the ability of the proposed algorithm in speckle noise reduction of 100 publically available OCT B-scans with and without non neovascular age-related macular degeneration (AMD), and improvement of contrast to-noise ratio from 1.27 to 5.12 and mean-to-standard deviation ratio from 3.20 to 14.41 are obtained. PMID- 28553582 TI - Segmentation of White Blood Cells From Microscopic Images Using a Novel Combination of K-Means Clustering and Modified Watershed Algorithm. AB - Recognition of white blood cells (WBCs) is the first step to diagnose some particular diseases such as acquired immune deficiency syndrome, leukemia, and other blood-related diseases that are usually done by pathologists using an optical microscope. This process is time-consuming, extremely tedious, and expensive and needs experienced experts in this field. Thus, a computer-aided diagnosis system that assists pathologists in the diagnostic process can be so effective. Segmentation of WBCs is usually a first step in developing a computer aided diagnosis system. The main purpose of this paper is to segment WBCs from microscopic images. For this purpose, we present a novel combination of thresholding, k-means clustering, and modified watershed algorithms in three stages including (1) segmentation of WBCs from a microscopic image, (2) extraction of nuclei from cell's image, and (3) separation of overlapping cells and nuclei. The evaluation results of the proposed method show that similarity measures, precision, and sensitivity respectively were 92.07, 96.07, and 94.30% for nucleus segmentation and 92.93, 97.41, and 93.78% for cell segmentation. In addition, statistical analysis presents high similarity between manual segmentation and the results obtained by the proposed method. PMID- 28553583 TI - Assessment and Comparison of Homogeneity and Conformity Indexes in Step-and-Shoot and Compensator-Based Intensity Modulated Radiation Therapy (IMRT) and Three Dimensional Conformal Radiation Therapy (3D CRT) in Prostate Cancer. AB - Intensity modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3D CRT) are two treatment modalities in prostate cancer, which provide acceptable dose distribution in tumor region with sparing the surrounding normal tissues. IMRT is based on inverse planning optimization; in which, intensity of beams is modified by using multileaf collimators and also compensators with optimum shapes in step and shoot (SAS) and compensator-based method, respectively. In the recent study, some important parameters were compared in two IMRT and 3D CRT methods. Prescribed dose was 80 Gy for both IMRT procedures and 70 Gy for 3D CRT. Treatment plans of 15 prostate cancer candidates were compared to target the minimum dose, maximum dose, V 76 Gy (for IMRT plans) V 66.5 Gy (for 3D CRT), mean dose, conformity index (CI), and homogeneity index (HI). Dose conformity in compensators-based IMRT was better than SAS and 3D CRT. The same outcome was also achieved for homogeneity index. The target coverage was achieved 95% of prescribed dose to 95% of planning target volume (PTV) in 3D CRT and 95% of prescribed dose to 98% of PTV in IMRT methods. IMRT increases maximum dose of tumor region, improves CI and HI of target volume, and also reduces dose of organs at risks. PMID- 28553584 TI - An Approach in Radiation Therapy Treatment Planning: A Fast, GPU-Based Monte Carlo Method. AB - An accurate and fast radiation dose calculation is essential for successful radiation radiotherapy. The aim of this study was to implement a new graphic processing unit (GPU) based radiation therapy treatment planning for accurate and fast dose calculation in radiotherapy centers. A program was written for parallel running based on GPU. The code validation was performed by EGSnrc/DOSXYZnrc. Moreover, a semi-automatic, rotary, asymmetric phantom was designed and produced using a bone, the lung, and the soft tissue equivalent materials. All measurements were performed using a Mapcheck dosimeter. The accuracy of the code was validated using the experimental data, which was obtained from the anthropomorphic phantom as the gold standard. The findings showed that, compared with those of DOSXYZnrc in the virtual phantom and for most of the voxels (>95%), <3% dose-difference or 3 mm distance-to-agreement (DTA) was found. Moreover, considering the anthropomorphic phantom, compared to the Mapcheck dose measurements, <5% dose-difference or 5 mm DTA was observed. Fast calculation speed and high accuracy of GPU-based Monte Carlo method in dose calculation may be useful in routine radiation therapy centers as the core and main component of a treatment planning verification system. PMID- 28553585 TI - Dosimetric and Radiobiological Evaluation of Multiparametric MRI-Guided Dose Painting in Radiotherapy of Prostate Cancer. AB - Radiotherapy is one of the treatment options for locally advanced prostate cancer; however, with standard radiation doses, it is not always very effective. One of the strategies to improve the efficiency of radiotherapy is increasing the dose. In this study, to increase tumor local control rates, a new radiotherapy method, known as dose painting (DP), was investigated. To compare 3-dimensional conformal radiotherapy (3D-CRT) and intensity modulated radiotherapy (IMRT) plans with DP for prostate cancer. Twenty-four consecutive patients with locally advanced prostate cancer who underwent an multiparametric-magnetic resonance imaging (MP-MRI) (T2w, diffusion weighted image, dynamic contrast enhancement, and MRS) scan before a diagnostic biopsy from September 2015 to April 2016 were invited to take part in this study. The tumor local control probability (TCP) values for 3D-CRT, IMRT, and DP techniques were 45, 56, and 77%, respectively. The DP technique had a 37.5 and 71% higher TCP than IMRT and 3D-CRT, and these differences were statistically significant (P = 0.001). The mean normal tissue complication probability (NTCP) values of the organ at risks for 3D-CRT, IMRT, and DP showed that there were statistically significant differences among them in three plans (P = 0.01). DP by contours using MP-MRI is technically feasible. This study evaluated biological modeling based on both MP-MRI defined subvolumes and pathologically defined subvolumes. The MP-MRI-guided DP results in better TCP/NTCP than 3D-CRT and IMRT. PMID- 28553586 TI - Responsible Patient-centered Care. PMID- 28553587 TI - Diagnosis and Treatment of Hypovitaminosis D: Recommendations from India and Brazil. PMID- 28553588 TI - Does Time of Sampling or Food Intake Alter Thyroid Function Test? AB - CONTEXT: A common question from most patients or laboratories is whether blood sample for thyroid-stimulating hormone (TSH) and free T4 (fT4) needs to be collected in a fasting state and whether time of the day when sample is collected matters. AIMS: The aim of the study was to study the impact of the time of day and food intake on levels of TSH and fT4. SETTINGS AND DESIGN: Cross-sectional prospective data collection. SUBJECTS AND METHODS: We prospectively collected data from 52 volunteers who were not known to have any thyroid disorder and were not on any thyroid-related medication. Blood samples for TSH and fT4 were collected on day 1 at 8 am and 10 am with the patient remaining in the fasting state till the collection of the second sample at 10 am. On day 2, samples were collected at 8 am (fasting state) and at 10 am (2 h postprandial state). In 22 volunteers from the group, the tests were performed in three common assay techniques including chemiluminescent assays (chemiluminescent immunoassay [CLIA] and chemiluminescent microparticle immunoassay [CMIA]) and enzyme-linked fluorescence assay. RESULTS: The mean (standard deviation) and median (interquartile range) TSH during the extended fast on day 1 were 2.26 +/- 1.23 and 2.19 (1.21-3.18), which was significantly lower than the fasting TSH performed on day 1 (P < 0.001). Similarly, the values of TSH 2 h postmeal on day 2 of the testing (mean 1.93 +/- 1.12; median 1.64 [1.06-2.86]) were significantly lower than TSH performed in the fasting state on day 2 (P < 0.001). The mean fT4 value was 1.01 +/- 0.15 with median of 0.99 (0.91-1.11) in the fasting state and there was no significant difference between the fT4 values performed during fasting, extended fasting, and postmeal state. Among the volunteers in whom the test was performed in the three different assay techniques, the TSH was not statistically different either in the fasting (P = 0.801), extended fasting (P = 0.955), and postprandial samples (P = 0.989). The fT4 values did not vary significantly when done by the same assay method. However, the fT4 levels varied significantly (P < 0.001) when done by another assay method. CONCLUSIONS: We conclude stating that the timing of the test affects TSH values and this should be factored in making decisions in diagnosis of subclinical hypothyroidism. PMID- 28553589 TI - Primary Healthcare-based Diabetes Registry in Puducherry: Design and Methods. AB - BACKGROUND: Diabetes registries monitor the population prevalence and incidence of diabetes, monitor diabetes control program, provide information of quality of care to health service providers, and provide a sampling frame for interventional studies. This study documents the process of establishing a prospective diabetes registry in a primary health-care setting in Puducherry. METHODS: This is a facility-based prospective registry conducted in six randomly selected urban health centers in Puducherry, with enrollment of all known patients with diabetes attending chronic disease clinics. Administrative approvals were obtained from Government Health Services. Manuals for training of medical officers, health-care workers, and case report forms were developed. Diabetes registry was prepared using Epi Info software. RESULTS: In the first phase, demographic characteristics, risk factors, complications, coexisting chronic conditions, lifestyle and medical management, and clinical outcomes were recorded. Around 2177 patients with diabetes have been registered in six Primary Health Centres out of a total of 2948 participants seeking care from chronic disease clinic. Registration coverage ranges from 61% to 105% in these centers. CONCLUSION: This study has documented methodological details, and learning experiences gained while developing a diabetes registry at the primary health care level and the scope for upscaling to a Management Information System for Diabetes and a State wide Registry. Improvement in patient care through needs assessment and quality assurance in service delivery is an important theme envisioned by this registry. PMID- 28553590 TI - Growth Hormone Treatment in Turner's Syndrome: A Real World Experience. AB - OBJECTIVE: Short stature is a universal clinical feature of Turner's syndrome (TS). Growth failure begins in fetal life, and adults with TS are on an average 20 cm shorter than the normal female population. Since there is a paucity of data from India regarding the effect of growth hormone (GH) on TS patients, we retrospectively analyzed the data of TS patients who are on GH treatment. METHODS: This hospital-based observational retrospective study was conducted in a tertiary care hospital of Hyderabad. The data such as height, weight, and bone age of 16 patients who are diagnosed with TS on GH therapy for at least 6 months were included in the study. All the patients were treated with human recombinant GH at the dose of 0.3 mg/kg/week administered as daily subcutaneous injections. RESULTS: The mean age at diagnosis was 12.7 years. The mean height at the start of GH therapy was 1.26 m, and mean height standard deviation score (HSDS) was 0.61 when compared to Turner's specific reference data. With a mean duration of GH therapy of 25 months, the mean height at the end of therapy was 1.37 m and the mean height as per HSDS was + 0.37 resulting in a mean height gain of + 0.99 HSDS. CONCLUSION: Our observation shows that girls with TS benefit from early diagnosis and initiation of treatment with GH. PMID- 28553591 TI - Impact of Self-monitoring of Blood Glucose Log Reliability on Long-term Glycemic Outcomes in Children with Type 1 Diabetes. AB - INTRODUCTION: Logbooks of self-monitoring of blood glucose (SMBG) are useful in the modulation of insulin regimens, which aid in achieving glycemic control in type 1 diabetes mellitus (T1DM). However, discrepancies in SMBG charting may impede its utility. This study aimed to assess the accuracy of log entries and its impact on long-term glycemic control. METHODS: SMBG in logbooks was compared with readings in glucometer memory and discrepancies between the two were evaluated in 101 children with T1DM. The relationship between these discrepancies and glycated hemoglobin (HbA1c) over 44 months was assessed. RESULTS: Errors in glucose charting were observed in 32.67% children. The most common observed error was omission (42.42%), followed by fabrication (27.27%), erroneous (18.18%), and others (12.12%). Age was not significantly different among children having accurate versus inaccurate SMBG logs. During follow-up of 44 months, children with accurate SMBG logs consistently had lower HbA1c as compared to children having inaccurate logs, which was statistically significant at 4, 16, 20, and 28 months' follow-up. The same was reflected in the proportion of children achieving HbA1c <7% and 7%-9%. Of the 14 children who had omissions, 9 had omission of high values only, 3 patients had omission of low values only, 1 had omission of both high and low values, and 1 had omission of normal values. Among logs with fabrication, parents were responsible in 2 of 9 incidents. In the remaining 7, it was the child himself/herself. Children with fabrication consistently had the highest HbA1c values among the different types of inaccurate blood glucose chartings, which was statistically significant at 32 and 36 months of follow-up. CONCLUSIONS: Reliability of SMBG logs is a significant problem among children with T1DM at our center. Children with accurate logs of SMBG readings were more likely to have better glycemic control on long-term follow-up. PMID- 28553592 TI - Study of Neutrophil-lymphocyte Ratio as Novel Marker for Diabetic Nephropathy in Type 2 Diabetes. AB - INTRODUCTION: Diabetic nephropathy (DN) is a microvascular complication of diabetes. DN is clinically manifested as an increase in urine albumin excretion. Total white blood cell count is a crude but sensitive indicator of inflammation and studied in many cardiac and noncardiac diseases as an inflammatory marker such as acute myocardial infarction, stroke, and heart failure. In this study, the association of neutrophil-lymphocyte ratio (NLR) with DN is studied. PATIENTS AND METHODS: It is an observational cross-sectional study. Totally 115 diagnosed type 2 diabetes mellitus patients were registered in this study. NLR was calculated by analyzing differential leukocyte count in complete blood picture. Albuminuria was tested by MICRAL-II TEST strips by dipstick method. RESULTS: Totally 115 diabetic patients were registered. About 56 patients had DN and 59 had normal urine albumin. Mean NLR for a normal group is 1.94 +/- 0.65 and in DN group is 2.83 +/- 0.85 which was highly significant (P < 0.001). Estimated glomerular filtration rate (P = 0.047) and serum glutamate pyruvate transaminase (P < 0.001) were also significant. CONCLUSION: The results of our study show that there was a significant relation between NLR and DN. Therefore, NLR may be considered as a novel surrogate marker of DN in early stages. PMID- 28553593 TI - Randomized Control Trial Assessing Impact of Increased Sunlight Exposure versus Vitamin D Supplementation on Lipid Profile in Indian Vitamin D Deficient Men. AB - BACKGROUND: Despite abundance of sunshine in India, Vitamin D deficiency is common and therefore there is an increasing trend toward taking Vitamin D supplements either as prescription medicine or as a nutritional supplement. Studies have suggested that duration of sun exposure may influence serum lipid profile. OBJECTIVES: To study the effect of increased sunlight exposure versus Vitamin D supplementation on Vitamin D status and lipid profile in individuals with Vitamin D deficiency (25-hydroxyvitamin-D [25OHD] <50 nmol/L). DESIGN: A prospective, randomized open-label trial was carried out in apparently healthy Indian men (40-60 years). Based on 25OHD concentrations, individuals were divided into control (>50 nmol/L, n = 50) and intervention (<50 nmol/L, n = 100) groups. Individuals from intervention group were randomly allocated to two groups; either "increased sunlight exposure group" (n = 50, received at least 20 min sunlight exposure to forearms and face between 11 a.m. and 3 p.m. over and above their current exposure) or "cholecalciferol supplement group" (n = 50, received oral cholecalciferol 1000 IU/day). RESULTS: Significant increase in 25OHD concentrations was seen in both intervention groups (P < 0.01). Significant decrease in total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), and low-density-lipoprotein cholesterol (LDL-C) was seen in individuals with increased sunlight exposure (P < 0.05). Cholecalciferol supplement group showed a significant increase in TC and HDL-C (P < 0.05) and insignificant increase in LDL C. CONCLUSIONS: Increase in Vitamin D concentrations through sunlight exposure significantly reduced TC, LDL-C, and HDL-C concentrations, and cholecalciferol supplementation increased TC and HDL-C concentrations. PMID- 28553594 TI - Comparison of 18F-Fluorocholine Positron Emission Tomography/Computed Tomography and Four-dimensional Computed Tomography in the Preoperative Localization of Parathyroid Adenomas-initial Results. AB - OBJECTIVE: We aimed to compare the diagnostic accuracy of 18F-Fluorocholine (FCH) positron emission tomography/computed tomography (PET/CT) and four-dimensional (4D)- CT in detection and localization of eutopic and ectopic parathyroid adenoma (PA) in patients with hyperparathyroidism. MATERIALS AND METHODS: Five patients with primary hyperparathyroidism underwent FCH-PET/CT after 60 min of 185 MBq of intravenous 18F-FCH administration. Images were acquired from head to mediastinum at 3 min per bed position. No intravenous contrast was used. All patients underwent 4D-CT within 2 weeks of the FCH-PET/CT, with a precontrast, post contrast arterial, and venous phase with 75 ml intravenous Iohexol 350 followed by 25 ml saline chase. Histopathology was considered as the gold standard. RESULTS: Both modalities showed 100% concordance in the detection of parathyroid lesions. Both FCH-PET/CT and 4D-CT detected 7 lesions in 5 patients, with 4 patients having a single lesion, and 1 patient having three lesions. Of the 7 reported lesions, 4 were eutopic and 3 were ectopic. No additional lesions were detected by either modality in comparison to the other. All 7 specimens were resected and histopathology showed PA/hyperplasia. CONCLUSION: FCH-PET/CT and 4D CT are equally efficacious in detection and localization of eutopic and ectopic PA. This may open up the possibility of using FCH-PET/CT in patients with negative conventional imaging who cannot undergo contrast studies. PMID- 28553595 TI - Does One Size Fit Everyone? Replacement Dose of Levothyroxine in Long-standing Primary Hypothyroidism in Adults. AB - OBJECTIVES: The recommended starting dose of levothyroxine (LT4) in primary hypothyroidism is 1.6 MUg/kg body weight and is based on presumption of minimal residual thyroid function in autoimmune hypothyroidism. This study aimed at finding the range and determining factors for LT4 dose in long-standing hypothyroidism. METHODS: A cross-sectional study of individuals with primary autoimmune hypothyroidism on LT4 replacement was done between March 2015 and January 2016. Individuals enrolled were euthyroid based on recent serum thyroid stimulating hormone. The inclusion criteria included LT4 intake in the morning empty stomach, maintenance of at least 1-h food gap, not on medications known to hamper LT4 absorption within 4 h of dosing, diagnosis of hypothyroidism at least for 1 year, and on a minimum 25 MUg LT4. P < 0.05 was considered statistically significant. RESULTS: A total of 346 individuals (290 women and 56 men; 214 premenopausal and 76 postmenopausal women) were enrolled. The mean duration of hypothyroidism and age were 5.7 years and 42.1 years, respectively. The range and mean of absolute LT4 daily dose (ADD), LT4 dose based on body weight (D/W), and LT4 dose based on ideal body weight (D/IBW) were 25-200 MUg daily and 77.1 MUg, 0.3-2.82 MUg/kg and 1.21 MUg/kg, and 0.42-3.5 MUg/kg and 1.58 MUg/kg, respectively. Duration of hypothyroidism was significant predictors of ADD, D/W, and D/IBW. Gender-based difference in ADD and D/IBW was explained by gender difference in anthropometry. CONCLUSION: Long-standing primary autoimmune hypothyroidism has variable dose requirement of LT4 for achieving euthyroidism and may be dependent on the degree of residual functional thyroid. Duration of hypothyroidism was significant positive predictor for either ADD, D/W, or D/IBW. PMID- 28553596 TI - Glycosylation Gap in Patients with Diabetes with Chronic Kidney Disease and Healthy Participants: A Comparative Study. AB - AIM: The aim of this study it to determine the level of glycosylation gap in patients with type 2 diabetes and its relation with kidney dysfunction. MATERIALS AND METHODS: In this study, 150 individuals were enrolled (aged 20-75 year) and divided into three groups. Group 1 included 50 nondiabetic individuals who served as control. Group 2 included 50 patients with type 2 diabetes without chronic kidney disease (CKD), and in Group 3, there were 50 patients with type 2 diabetes with CKD. Glycated hemoglobin (HbA1c) and fructosamine (FA) were measured in all groups to determine the glycosylation gap (GG), predicted HbA1c, and mean blood glucose (MBG). GG is defined as the difference between measured HbA1c and HbA1c predicted from FA based on the population regression of HbA1c on FA. The variables were compared by correlation analysis. RESULTS: Serum creatinine level was significantly high in patients with CKD (1.93 +/- 0.99) as compared to patients with diabetes and control (0.891 +/- 0.16; 0.912 +/- 0.1), respectively. The study demonstrated a significant elevation in serum FA, measured HbA1c and predicted HbA1c, MBG in patients with diabetes with CKD as compared with those of without CKD, and controls. GG was found in healthy control (0.51 +/- 0.78), patients with type 2 diabetes without CKD (0.62 +/- 0.45), and patients with diabetes with CKD (1.0 +/- 0.91), respectively. CONCLUSION: It is concluded that GG may be a useful clinical research tool for evaluating pathological source of variation in diabetes complications such as kidney disease. PMID- 28553597 TI - Efficacy of Teriparatide in Patients with Hypoparathyroidism: A Prospective, Open label Study. AB - CONTEXT: Conventional treatment of hypoparathyroidism with calcium, Vitamin D analogs, and thiazide diuretics is often suboptimal, and these patients have poor quality of life. Teriparatide (parathyroid hormone 1-34 [PTH (1-34)]), an amide of PTH, is widely available for the use in osteoporosis; however, its use in hypoparathyroidism is limited. AIMS: The aim of this study is to evaluate the efficacy of PTH (1-34) in the treatment of patients with hypoparathyroidism. SETTINGS AND DESIGN: This was a prospective, open-label interventional study in a tertiary care hospital of Indian Armed Forces. SUBJECTS AND METHODS: All patients with hypoparathyroidism presented to the endocrinology outpatient department were included and were exhibited injection PTH (1-34) 20 MUg twice daily that was gradually reduced to 10 MUg twice daily along with calcium, active Vitamin D (alfacalcidol), and hydrochlorothiazide. Oral calcium and alfacalcidol doses were also reduced to maintain serum calcium within normal range. The quality of life (QOL) score was calculated using RAND 36 QOL questionnaire at baseline and termination of the study. STATISTICAL ANALYSIS USED: Paired t-test was used to calculate pre- and post-treatment variables. RESULTS: Eight patients (two males) were included in this study having mean age of 35.8 years. PTH (1-34) treatment led to the improvement in serum calcium (6.81-8.84 mg/dl), phosphorous (5.8-4.2 mg/dl), and 24 h urinary calcium excretion (416-203.6 mg). Parameters of QOL showed the improvement in overall QOL, physical performance, energy, and fatigue scores. No major adverse events were noted. CONCLUSIONS: Treatment of hypoparathyroidism with PTH (1-34) leads to improvement in calcium profile, reduction in hypercalciuria, and improvement in QOL, whereas it is safe and well tolerated. PMID- 28553598 TI - Visual Evoked Potentials in Overt Hypothyroid Patients before and after Achievement of Euthyroidism. AB - BACKGROUND: Visual evoked potential (VEP) measures the time taken for visual stimulus to travel from the eye to the occipital cortex. Hypothyroidism affects the central nervous system (CNS) through its role in gene expression, myelin production, axonal transportation, and neurotransmitters. Delay in the conduction of impulses results in abnormal VEP. OBJECTIVE: Correlate the electrophysiological findings of VEP in newly diagnosed treatment-naive hypothyroid patients before and after 3 months of treatment and to find the correlation with serum thyroid-stimulating hormone (TSH) levels. MATERIALS AND METHODS: VEP was measured using Recorders and Medicare Systems Electromyograph Evoked Potential Mark II machine in 30 patients (serum TSH >=10 mIU/L) between 18 and 50 years of age who were followed up after 3 months of treatment. RESULTS: The mean age (+/-standard deviation) of the patients was 31.8 (+/-8.3) years. There was prolongation of VEP latencies which tends to decrease following hormone replacement therapy. It was found to be most significant for P100 (ms) waveform (P < 0.001). The amplitude (P100-N75 mV) which was decreased in hypothyroid patients showed improvement following achievement of euthyroidism. Significant positive correlation was found between P100, N75 latency and pretreatment serum TSH levels. CONCLUSION: Hypothyroid patients may have changes in the latencies and the amplitude of VEP which are reversible to a great extent with thyroxine replacement therapy. VEP thus acts as a dependable marker for CNS affection in thyroid diseases to detect subtle early changes and to assess the response to treatment in correlation with the clinical improvement. PMID- 28553599 TI - Serum Vitamin B12 Levels in Type 2 Diabetes Patients on Metformin Compared to those Never on Metformin: A Cross-sectional Study. AB - CONTEXT: There are limited data about the effect of metformin use on serum Vitamin B12 levels in type 2 diabetes patients from India. AIMS: We studied serum Vitamin B12 levels in patients with type 2 diabetes mellitus who were receiving metformin and compared them to those never treated with metformin. SUBJECTS AND METHODS: A total of 183 patients ("metformin" group 121, "no metformin" group 63) of type 2 diabetes from the endocrinology clinic of a tertiary care center in North India were studied. Serum Vitamin B12 levels were measured in all patients. Diabetic neuropathy symptom score (DNS) and diabetic neuropathy examination score (DNE) were used to assess peripheral neuropathy while hemoglobin and mean corpuscular volume (MCV) were used to assess anemia. RESULTS: The serum Vitamin B12 levels were 267.7 +/- 194.4 pmol/l in metformin group and 275.1 +/- 197.2 pmol/l in the no metformin group (P = 0.78). When adjusted for duration of diabetes, metformin use was associated with a 87.7 +/- 37.7 pmol/l (95% confidence interval [CI], -162.1--3.3, P = 0.02) lower serum Vitamin B12 levels. No significant increase in the prevalence of neuropathy (DNS and DNE scores), anemia, or MCV was found in the Vitamin B12 deficient patients (levels <150 pmol/l) as compared to patients with normal Vitamin B12. However, serum Vitamin B12 levels for the entire cohort were higher by 12.2 +/- 3.0 pmol/l (95% CI 6.4 18.0, P < 0.001) for every 1 year increase in the duration of diabetes. CONCLUSIONS: Metformin use was associated with a lower serum Vitamin B12 levels when adjusted for duration of diabetes. Increasing duration of diabetes was associated with higher serum Vitamin B12 levels. PMID- 28553600 TI - Knowledge, Awareness, Practices and Adherence to Treatment of Patients with Primary Hypothyroidism in Delhi. AB - BACKGROUND: There is a paucity of data on knowledge, awareness, and practices (KAP) of patients with hypothyroidism in India. AIMS AND OBJECTIVES: To study the KAP and adherence to treatment of participants with primary hypothyroidism. MATERIALS AND METHODS: An observational cross-sectional study was conducted in Endocrinology Outpatient Department of Maharaja Agrasen Hospital, Punjabi Bagh, New Delhi. Two-fifty consecutive primary hypothyroidism participants, aged >=18 years, who were on treatment for at least 3 months responded to a structured questionnaire, to assess their KAP about the disease and adherence to treatment. RESULTS: A total of 250 patients completed the questionnaire. The mean age of the participants was 43.24 +/- 10.80 years; with majority being females (85.6%). The median duration of hypothyroidism was 8 years (range: 3-10). Most were well educated, with 53.6% being graduates/postgraduates. Knowledge and awareness related to hypothyroidism was poor in majority of participants. Only 35.2% and 51.2% knew correct meaning of the terms "thyroid" and "hypothyroidism" respectively. Only 25.6% participants knew correctly that thyroxine (T4) is used to replace and normalize blood levels of thyroid hormone. Forty percent had false dietary beliefs in the context of hypothyroidism. Ten percent participants felt T4 can be stopped once laboratory reports return to normal. Only 36.4% participants knew correctly that T4 need to be continued during pregnancy. Many participants (30.4%) believed hypothyroidism can lead to weight gain in excess of 10 kg. Regarding adherence, 90.4% participants were adherent to T4, 2.4% were moderately adherent, and remaining 7.2% participants were nonadherent to T4. CONCLUSION: A large number of patients with primary hypothyroidism lack basic knowledge about disease and have dietary and treatment-related prejudices and poor treatment adherence. Public health measures are required to improve KAP in patients with primary hypothyroidism. PMID- 28553601 TI - Pubertal Onset in Apparently Healthy Indian Boys and Impact of Obesity. AB - OBJECTIVE: Primary - to determine the age of pubertal onset in Indian boys. Secondary - (a) to assess the impact of obesity on pubertal timing, (b) to assess the relationship between gonadotropins and puberty. DESIGN: Cross-sectional. SETTING: General community-seven schools across New Delhi. PARTICIPANTS: Random sample of 1306 school boys, aged 6-17 years. MATERIALS AND METHODS: Anthropometric measurement for weight and height and pubertal staging was performed for all subjects. Body mass index (BMI) was calculated to define overweight/obesity. Serum luteinizing hormone (LH), follicle stimulating hormone, and serum testosterone were measured in every sixth subject. MAIN OUTCOME MEASURE: Age at pubertal onset-testicular volume >=4 mL (gonadarche) and pubic hair Stage II. RESULTS: Median age of attaining gonadarche and pubarche was 10.41 years (95% confidence interval [CI]: 10.2-10.6 years) and 13.60 (95% CI: 13.3 14.0 years), respectively. No significant difference in the age of attainment of gonadarche was observed in boys with normal or raised BMI, though pubarche occurred 8 months earlier in the latter group. Serum gonadotropins and testosterone increased with increasing stages of puberty but were unaffected by BMI. Serum LH level of 1.02 mIU/mL and testosterone level of >0.14 ng/mL showed the best prediction for pubertal onset. CONCLUSION: The study establishes a secular trend of the age of onset of puberty in Indian boys. Pubarche occurred earlier in overweight/obese boys. The cutoff levels of serum LH and testosterone for prediction of pubertal onset have been established. PMID- 28553602 TI - Patterns and Correlates of Serum Magnesium Levels in Subsets of Type 2 Diabetes Mellitus Patients in Nigeria. AB - BACKGROUND: Magnesium (Mg) is the 4th most common mineral and the 2nd most abundant intracellular cation in the body. It plays major roles in various physiological activities and has been implicated in many disease states. AIM: The aim of this study was to study the patterns and correlates of serum Mg in cohorts of type 2 diabetic patients in Nigeria. SUBJECTS AND METHODS: One hundred and twenty-five patients comprising 63 with type 2 diabetes mellitus (T2DM) alone and 62 with diabetes and hypertension (HT) were compared with fifty controls matched for sex and age. Basic data, HbA1c, and fasting blood glucose (FBG) were obtained while serum Mg was measured by colorimeter. Relationship between serum Mg and glucose control was considered while serum Mg < 1.6 mg/dl was considered as hypomagnesemia. RESULTS: The mean serum Mg of all patients was 2.06 +/- 0.49 mg/dl, not statistically different from controls at 2.22 +/- 0.48 mg/dl. About 1/4 (23.2%) of the patients had hypomagnesemia which was significantly more than 12% of controls. Although the patients with diabetes and HT were older and more of females than those with DM alone, the mean serum Mg was comparable (2.03 +/- 0.49 vs. 2.09 + 0.50 mg/dl). Twenty-seven percent (27%) of patients who had DM alone was more than 19.3% with HT and diabetes combined. Whereas the FBG was comparable in patients with hypomagnesemia and normal serum Mg, HbA1c was significantly higher in the hypomagnesemia group (8.39 +/- 0.98 vs. 6.75 +/- 1.22%, P = 0.021). CONCLUSION: Hypomagnesemia is common in T2DM outpatients occurring approximately one in four patients. It is associated with poor long term control. PMID- 28553603 TI - An Audit of Insulin Usage and Insulin Injection Practices in a Large Indian Cohort. AB - INTRODUCTION: Insulin remains the cornerstone of therapy in a substantial number of patients with type 2 diabetes mellitus (T2DM). Inadequate knowledge regarding insulin usage is likely to influence its acceptance and adherence, and outcome of therapy, underscoring great need to investigate knowledge, attitude, and practice of insulin usage in patients with T2DM. METHODOLOGY: A cross-sectional registry based retrospective study analyzed data collected from 748 respondents (male: 466, female: 282), mostly from high or middle economic status, who were enrolled as outpatient in a referral clinic during last 10 years (2006-2016), to assess the general characteristics of patients with type 2 diabetes and their baseline knowledge, attitude, and practice of insulin usage and injection practices. RESULTS: Mean +/- standard deviation (SD) of duration of diabetes was 12.24 +/- 7.60 years and mean +/- SD duration of insulin therapy was 3.42 +/- 4.18 years, which was initiated after a mean +/- SD diabetes duration of 8.80 +/- 6.42 years. Mean insulin dose per kilogram of body weight/day was 0.51 +/- 0.27 units. Total daily dose of insulin was 33.36 +/- 18.44 units and number of injections/day (mean +/- SD) was 2.06 +/- 0.73. Among the respondents, 58.96% were on human insulin and 35.70% were on analog insulin. Pen devices were used by 66.08% of the population whereas 31.76% used insulin syringes. The prevalence of lipohypertrophy (LH) was 12.57%, which was significantly (P < 0.001) associated with wrong technique with regard to injection angle (10.45% vs. 23.02%), site of injection (7.00% vs. 30.51%), rotation of site of injection (0.88% vs. 17.66%), and reuse of needle (5.77% vs. 15.19%). LH was also significantly (P < 0.05) associated with the use of human (14.74%) compared to analog insulin (8.24%). CONCLUSION: The current study highlights the unique patterns of insulin usage and associated high prevalence of LH among insulin users in India. PMID- 28553604 TI - Diabetes Care: Inspiration from Sikhism. AB - Religion has been proposed as a means of enhancing patient and community acceptance of diabetes and cultural specific motivational strategies to improve diabetes care. Sikhism is a young and vibrant religion, spread across the world and the Holy Scripture Sri Guru Granth Sahib (SGGS) is regarded as the living Guru by all Sikhs. The three key pillars of Sikhism are Kirat Karni (honest living), Vand Chakna (sharing with others) and Naam Japna (focus on God). They can help encourage the diabetes care provider, patient and community to engage in lifestyle modification, shared responsibility, positive thinking and stress management. The verses (Sabads) from the SGGS, with their timeless relevance, span the entire spectrum of diabetes care, from primordial and primary, to secondary and tertiary prevention. They can provide us with guidance towards a holistic approach towards health and lifestyle related diseases as diabetes. The SGGS suggests that good actions are based on one's body and highlights the relevance of mind-body interactions and entraining the mind to cultivate healthy living habits. The ethics of sharing, community and inclusiveness all lay emphasis on the need for global and unified efforts to manage and reduce the burden of the diabetes pandemic. PMID- 28553605 TI - Management of Glycemia in Acute Febrile Illness. AB - With increasing the prevalence of diabetes and prediabetes across the globe, a large number of patients with acute febrile illness (AFI) are likely to have concomitant diabetes or stress hyperglycemia. Management of associated hyperglycemia in patients with AFI is of utmost importance for early recovery and to prevent complications. There is no published literature, detailing the strategies and targets for glycemic control in AFI specifically; however, guidelines do exist for the management of hyperglycemia in hospitalized or outpatients in general. This review attempts to provide pragmatic and practical suggestions to facilitate effective and safe management of hyperglycemia in patients with AFI. PMID- 28553606 TI - Endocrine Glands and Hearing: Auditory Manifestations of Various Endocrine and Metabolic Conditions. AB - The aetiology of hearing loss in humans is multifactorial. Besides genetic, environmental and infectious causes, several endocrine and metabolic abnormalities are associated with varying degrees of hearing impairment. The pattern of hearing loss may be conductive, sensori-neural or mixed. The neurophysiology of hearing as well as the anatomical structure of the auditory system may be influenced by changes in the hormonal and metabolic milieu. Optimal management of these conditions requires the integrated efforts of the otolaryngologist and the endocrinologist. The presence of hearing loss especially in the young age group should prompt the clinician to explore the possibility of an associated endocrine or metabolic disorder for timely referral and early initiation of treatment. PMID- 28553607 TI - Characteristics of Pediatric Pheochromocytoma/paraganglioma. AB - The "rule of 10" used to describe pheochromocytoma/paragangliomas (PCC/PGLs) has been challenged. However, recent studies suggested that pediatric PCC/PGLs may follow a pattern. Hence, we reviewed the available literature to verify the same. We searched PubMed, Scopus, ProQuest, and Google Scholar for studies describing the genotype and/or phenotype characteristics of pediatric PCC/PGL cohorts published after 2000 in English language and those with sample size more than 35 were included in this review. Pediatric PCC/PGLs were malignant in 10%, synchronous bilateral in 20%, extra-adrenal in 30%, among which, 30% were extra abdominal and familial in 40%. PCC/PGL diagnosed during pediatric age recurs in 50% by 30 years of follow-up and 60% cases occur in boys. Seventy percent of children with PCC/PGL are likely to have sustained hypertension. Germline mutations could be identified in 80% of children with PCC/PGL and 90% are secretory. The review concludes that pediatric PCC/PGLs follow a pattern, which we call "10%-90% rule." This new rule will help easily remember the characteristics of pediatric PCC/PGLs. PMID- 28553608 TI - Patient-centered Management of Hypothyroidism. AB - This communication from the National Indian Patient-centered Thyroid management group (InPACT) deals with a novel, yet essential, aspect of hypothyroidism management. The authors describe the role and scope of patient-centered care in this condition. They focus on the relevance of a patient-centered clinical approach, which will help decide appropriate targets, as well as techniques to achieve those targets. Means of helping persons with hypothyroidism live a healthy life, such as education about precaution in concomitant food and medications intake, as well as sick day management, are discussed. PMID- 28553610 TI - Diabetes Destiny in our Hands: Achieving Metabolic Karma. AB - Karma is the ancient Indian philosophy of cause and effect, which implies that an individual's intentions, and actions, both have consequences. None can escape the consequences of one's actions. Applying the principle of karma to medicine and healthcare, the significance of optimal and timely interventions at various stages of disease, may be realized. A holistic approach to metabolic control in diabetes translates into improved clinical outcomes, as evident from the result of STENO-2, EMPA-REG OUTCOME, or LEADER trials. The principle of karma in the management of diabetes may have implications at the transgenerational level during pregnancy and nursing, at the individual patient-level based on phenotype, and at the community level in preventive medicine. The concept of metabolic karma can be used as an effective motivational tool to encourage better health care seeking behavior and adherence to prescribed interventions. PMID- 28553609 TI - Choice of Insulin in Type 2 Diabetes: A Southeast Asian Perspective. AB - Southeast Asia faces a diabetes epidemic, which has created significant challenges for health care. The unique Asian diabetes phenotype, coupled with peculiar lifestyle, diet, and healthcare-seeking behavior, makes it imperative to develop clinical pathways and guidelines which address local needs and requirements. From an insulin-centric viewpoint, the preparations prescribed in such pathways should be effective, safe, well tolerated, nonintrusive, and suitable for the use in multiple clinical situations including initiation and intensification. This brief communication describes the utility of premixed or dual action insulin in such clinical pathways and guidelines. PMID- 28553611 TI - Gestational Pituitary Apoplexy. PMID- 28553612 TI - Prevalence of Islet Autoantibodies in Type 1 Diabetes. PMID- 28553613 TI - Indian and American Guidance on Psychosocial Care of Persons with Diabetes. PMID- 28553615 TI - A Single-Institution Analysis of 126 Patients Treated with Stereotactic Radiosurgery for Brain Metastases. AB - BACKGROUND: The objective of this study was to report our institutional experience with Gamma Knife(r) Radiosurgery (GKRS) in the treatment of patients with brain metastases. METHODS: Retrospectively collected demographic and clinical data on 126 patients with intracranial metastases were reviewed. The patients in our study underwent GKRS at Vidant Medical Center between 2009 and 2014. Kaplan-Meier curves were used to compare survival based on clinical characteristics for univariate analysis, and a Cox proportional hazards model was used for multivariate analysis. RESULTS: The median age of the patient population was 62 years. Medicare patients constituted 51% of our patient cohort and Medicaid patients 15%. The most common tumor histologies were non-small cell lung cancer (50%), breast cancer (12.7%), and melanoma (11.9%). The median overall survival time for all patients was 5.8 months. Patients with breast cancer had the longest median survival time of 9.15 months, while patients with melanoma had the shortest median survival time of 2.86 months. On univariate analysis, the following factors were predictors for improved overall survival, ECOG score 0 or 1 vs. 2 or greater (17.0 vs. 1.8 months, p < 0.001), controlled extracranial disease vs. progressive extracranial disease (17.4 vs. 4.6 months, p = 0.0001), recursive partitioning analysis Stage I vs. II-III (18.2 vs. 6.2 months, p < 0.007), multiple GKRS treatments (p = 0.002), prior brain metastasectomy (p = 0.012), and prior chemotherapy (p = 0.021). Age, ethnicity, gender, previous external beam radiation therapy, number of brain metastases, and hemorrhagic vs. non-hemorrhagic tumors were not predictors of longer median survival time. Number of metastatic brain lesions of 1-3 vs. >=4 (p = 0.051) and insurance status of Medicare/Medicaid vs. commercial insurance approached significance (13.7 vs. 6.8 months, p = 0.08). On multivariate analysis, ECOG performance status 0-1 (p < 0.001), multiple GKRS treatments (p = 0.003), and control of extracranial disease (p = 0.001) remained significant predictors of survival. CONCLUSION: ECOG score, control of extracranial disease, and multiple GKRS treatments are predictors of longer median survival following GKRS in our patient population. GKRS is an effective treatment for brain metastases, but these factors may be considered in patient selection for GKRS. PMID- 28553614 TI - Emerging Role of the Pentose Phosphate Pathway in Hepatocellular Carcinoma. AB - In recent years, there has been a revival of interest in metabolic changes of cancer cells as it has been noticed that malignant transformation and metabolic reprogramming are closely intertwined. The pentose phosphate pathway (PPP) is one of the fundamental components of cellular metabolism crucial for cancer cells. This review will discuss recent findings regarding the involvement of PPP enzymes in several types of cancer, with a focus on hepatocellular carcinoma (HCC). We will pay considerable attention to the involvement of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the PPP. Subsequently, we discuss the inhibition of the PPP as a potential therapeutic strategy against cancer, in particular, HCC. PMID- 28553616 TI - The Oncolytic Virotherapy Era in Cancer Management: Prospects of Applying H-1 Parvovirus to Treat Blood and Solid Cancers. AB - Non-Hodgkin lymphoma (NHL) and leukemia are among the most common cancers worldwide. While the treatment of NHL/leukemia of B-cell origin has much progressed with the introduction of targeted therapies, few treatment standards have been established for T-NHL/leukemia. As presentation in both B- and T NHL/leukemia patients is often aggressive and as prognosis for relapsed disease is especially dismal, this cancer entity poses major challenges and requires innovative therapeutic approaches. In clinical trials, oncolytic viruses (OVs) have been used against refractory multiple myeloma (MM). In preclinical settings, a number of OVs have demonstrated a remarkable ability to suppress various types of hematological cancers. Most studies dealing with this approach have used MM or B- or myeloid-cell-derived malignancies as models. Only a few describe susceptibility of T-cell lymphoma/leukemia to OV infection and killing. The rat H 1 parvovirus (H-1PV) is an OV with considerable promise as a novel therapeutic agent against both solid tumors (pancreatic cancer and glioblastoma) and hematological malignancies. The present perspective article builds on previous reports of H-1PV-driven regression of Burkitt's lymphoma xenografts and on unpublished observations demonstrating effective killing by H-1PV of cells from CHOP-resistant diffuse large B-cell lymphoma, cutaneous T-cell lymphoma, and T cell acute lymphoblastic leukemia. On the basis of these studies, H-1PV is proposed for use as an adjuvant to (chemo)therapeutic regimens. Furthermore, in the light of a recently completed first parvovirus clinical trial in glioblastoma patients, the advantages of H-1PV for systemic application are discussed. PMID- 28553617 TI - Bioluminescence Imaging to Track Bacteroides fragilis Inhibition of Vibrio parahaemolyticus Infection in Mice. AB - Bacteroides fragilis is an anaerobic, Gram-negative, commensal bacterium of the human gut. It plays an important role in promoting the maturation of the immune system, as well as suppressing abnormal inflammation. Many recent studies have focused on the relationship between B. fragilis and human immunity, and indicate that B. fragilis has many useful probiotic effects. As inhibition of intestinal pathogens is an important characteristic of probiotic strains, this study examined whether B. fragilis could inhibit pathogenic bacteria. Results showed that Vibrio parahaemolyticus was inhibited by B. fragilis in vitro, and that B. fragilis could protect both RAW 264.7 and LoVo cells from damage caused by V. parahaemolyticus. Using in vivo imaging, we constructed a light-emitting V. parahaemolyticus strain and showed that B. fragilis might shorten the colonization time and reduce the number of lux-expressing bacteria in a mouse model. These results provide useful information for developing B. fragilis into a probiotic product, and also indicate that this commensal bacterium might aid in the clinical treatment of gastroenteritis caused by V. parahaemolyticus. PMID- 28553618 TI - Effective Protection Induced by a Monovalent DNA Vaccine against Dengue Virus (DV) Serotype 1 and a Bivalent DNA Vaccine against DV1 and DV2 in Mice. AB - Dengue virus (DV) is the causal pathogen of dengue fever, which is one of the most rapidly spread mosquito-borne disease worldwide and has become a severe public health problem. Currently, there is no specific treatment for dengue; thus, a vaccine would be an effective countermeasure to reduce the morbidity and mortality. Although, the chimeric Yellow fever dengue tetravalent vaccine has been approved in some countries, it is still necessary to develop safer, more effective, and less costly vaccines. In this study, a DNA vaccine candidate pVAX1 D1ME expressing the prME protein of DV1 was inoculated in BALB/c mice via intramuscular injection or electroporation, and the immunogenicity and protection were evaluated. Compared with traditional intramuscular injection, administration with 50 MUg pVAX1-D1ME via electroporation with three immunizations induced persistent humoral and cellular immune responses and effectively protected mice against lethal DV1 challenge. In addition, immunization with a bivalent vaccine consisting of pVAX1-D1ME and pVAX1-D2ME via electroporation generated a balanced IgG response and neutralizing antibodies against DV1 and DV2 and could protect mice from lethal challenge with DV1 and DV2. This study sheds new light on developing a dengue tetravalent DNA vaccine. PMID- 28553619 TI - Human Neutrophils Produce CCL23 in Response to Various TLR-Agonists and TNFalpha. AB - CCL23, also known as myeloid progenitor inhibitory factor (MPIF)-1, macrophage inflammatory protein (MIP)-3, or CKbeta8, is a member of the CC chemokine subfamily exerting its effects via CCR1 binding. By doing so, CCL23 selectively recruits resting T lymphocytes and monocytes, inhibits proliferation of myeloid progenitor cells and promotes angiogenesis. Previously, we and other groups have reported that human neutrophils are able to produce chemokines upon appropriate activation, including CCR1-binding CCL2, CCL3, and CCL4. Herein, we demonstrate that human neutrophils display the capacity to also express and release CCL23 when stimulated by R848 and, to a lesser extent, by other pro-inflammatory agonists, including LPS, Pam3CSK4, and TNFalpha. Notably, we show that, on a per cell basis, R848-activated neutrophils produce higher levels of CCL23 than autologous CD14+-monocytes activated under similar experimental conditions. By contrast, we found that, unlike CD14+-monocytes, neutrophils do not produce CCL23 in response to IL-4, thus indicating that they express CCL23 in a stimulus specific fashion. Finally, we show that the production of CCL23 by R848 stimulated neutrophils is negatively modulated by IFNalpha, which instead enhances that of CCL2. Together, data extend our knowledge on the chemokines potentially produced by neutrophils. The ability of human neutrophils to produce CCL23 further supports the notion on the neutrophil capacity of orchestrating the recruitment of different cell types to the inflamed sites, in turn contributing to the control of the immune response. PMID- 28553620 TI - Comparative Genomics of Mycoplasma bovis Strains Reveals That Decreased Virulence with Increasing Passages Might Correlate with Potential Virulence-Related Factors. AB - Mycoplasma bovis is an important cause of bovine respiratory disease worldwide. To understand its virulence mechanisms, we sequenced three attenuated M. bovis strains, P115, P150, and P180, which were passaged in vitro 115, 150, and 180 times, respectively, and exhibited progressively decreasing virulence. Comparative genomics was performed among the wild-type M. bovis HB0801 (P1) strain and the P115, P150, and P180 strains, and one 14.2-kb deleted region covering 14 genes was detected in the passaged strains. Additionally, 46 non sense single-nucleotide polymorphisms and indels were detected, which confirmed that more passages result in more mutations. A subsequent collective bioinformatics analysis of paralogs, metabolic pathways, protein-protein interactions, secretory proteins, functionally conserved domains, and virulence related factors identified 11 genes that likely contributed to the increased attenuation in the passaged strains. These genes encode ascorbate-specific phosphotransferase system enzyme IIB and IIA components, enolase, L-lactate dehydrogenase, pyruvate kinase, glycerol, and multiple sugar ATP-binding cassette transporters, ATP binding proteins, NADH dehydrogenase, phosphate acetyltransferase, transketolase, and a variable surface protein. Fifteen genes were shown to be enriched in 15 metabolic pathways, and they included the aforementioned genes encoding pyruvate kinase, transketolase, enolase, and L lactate dehydrogenase. Hydrogen peroxide (H2O2) production in M. bovis strains representing seven passages from P1 to P180 decreased progressively with increasing numbers of passages and increased attenuation. However, eight mutants specific to eight individual genes within the 14.2-kb deleted region did not exhibit altered H2O2 production. These results enrich the M. bovis genomics database, and they increase our understanding of the mechanisms underlying M. bovis virulence. PMID- 28553621 TI - Ehrlichia chaffeensis Tandem Repeat Effector Targets Differentially Influence Infection. AB - Ehrlichia chaffeensis infects mononuclear phagocytes and survives intracellularly by exploiting host cell processes to evade host defenses. The mechanisms involved are not fully defined, but appear to rely largely on a subset of tandem repeat proteins (TRP) effectors. E. chaffeensis TRPs are type 1 secreted effectors that interact with a functionally diverse group of host cell targets associated with various biological processes. In this study, we investigated the influence of TRP host target proteins on ehrlichial infection by RNA interference. In total, 138 TRP-interacting host proteins identified by yeast two-hybrid were targeted by siRNA and the infection level determined by real-time qPCR. Knockdown of 124 (89%) TRP target proteins had significant influence on infection either by inhibiting (85%) or promoting (15%) ehrlichial infection. Notably, knockdown of 18 host proteins which interacted with TRP120 promoted the infection, suggesting that these targets may be degraded to promote infection. Host proteins that interact with TRPs are involved in cellular processes, including cell signaling, vesicle trafficking and intracellular transport, transcriptional regulation, metabolism, protein posttranslational modification, and apoptosis. Selected host targets were examined by immunofluorescent microscopy during infection and were found to localize with the morulae, or in the host cell cytoplasm adjacent to morulae. This study confirms that the majority of host proteins known to interact with TRP effectors influence infection and further extends the current knowledge that E. chaffeensis TRPs participate in a complex array of host protein interactions in order to reprogram the host cell and promote intracellular survival. PMID- 28553622 TI - Commentary: The Role of Neutrophils in the Induction of Specific Th1 and Th17 during Vaccination against Tuberculosis. PMID- 28553624 TI - Screening for hepatocellular carcinoma: patient selection and perspectives. AB - Hepatocellular carcinoma (HCC) develops on the background of liver cirrhosis often from multiple, simultaneous factors. The diagnosis of a single small HCC comes with good prognosis and provides a potential for cure. In contrast, the diagnosis of multifocal, large HCC has high mortality and poor prognosis. Unfortunately, the majority of HCC is diagnosed at such late stages. A surveillance program endorsed by regional liver societies involves six-monthly ultrasound surveillance of at-risk patients. This had been in action for the last two decades. It has led to marked increase in the proportion of patients presenting with small unifocal nodules found on surveillance. The development of tools to enhance our ability in optimizing available surveillance is likely to improve the prognosis of patients with HCC. In this review, we discuss the difficulties in utilizing HCC surveillance and possible means of improvement. PMID- 28553625 TI - The Comparison Effects of Two Methods of (Adaptive Support Ventilation Minute Ventilation: 110% and Adaptive Support Ventilation Minute Ventilation: 120%) on Mechanical Ventilation and Hemodynamic Changes and Length of Being in Recovery in Intensive Care Units. AB - BACKGROUND: The conventional method for ventilation is supported by accommodative or adaptive support ventilation (ASV) that the latter method is done with two methods: ASV minute ventilation (mv): 110% and ASV mv: 120%. Regarding these methods this study compared the differences in duration of mechanical ventilation and hemodynamic changes during recovery and length of stay in Intensive Care Units (ICU). MATERIALS AND METHODS: In a clinical trial study, forty patients candidate for ventilation were selected and randomly divided into two groups of A and B. All patients were ventilated by Rafael ventilator. Ventilator parameters were set on ASV mv: 110% or ASV mv: 120% and patients were monitored on pulse oximetry, electrocardiography monitoring, central vein pressure and arterial pressure. Finally, the data entered to computer and analyzed by SPSS software. RESULTS: The time average of connection to ventilator in two groups in modes of ASV mv: 110% and 120% was 12.3 +/- 3.66 and 10.8 +/- 2.07 days respectively, and according to t-test, there was no significant difference between two groups (P = 0.11). The average of length of stay in ICU in two groups of 110% and 120% was 16.35 +/- 3.51 and 15.5 +/- 2.62 days respectively, and according to t-test, there found to be no significant difference between two groups (P = 0.41). CONCLUSION: Using ASV mv: 120% can decrease extubation time compared with ASV mv: 110%. Furthermore, there is not a considerable side effect on hemodynamic of patients. PMID- 28553623 TI - Productive and Penicillin-Stressed Chlamydia pecorum Infection Induces Nuclear Factor Kappa B Activation and Interleukin-6 Secretion In Vitro. AB - Nuclear factor kappa B (NFkappaB) is an inflammatory transcription factor that plays an important role in the host immune response to infection. The potential for chlamydiae to activate NFkappaB has been an area of interest, however most work has focused on chlamydiae impacting human health. Given that inflammation characteristic of chlamydial infection may be associated with severe disease outcomes or contribute to poor overall fitness in farmed animals, we evaluated the ability of porcine chlamydiae to induce NFkappaB activation in vitro. C. pecorum infection induced both NFkappaB nuclear translocation and activation at 2 hours post infection (hpi), an effect strongly enhanced by suppression of host de novo protein synthesis. C. suis and C. trachomatis showed less capacity for NFkappaB activation compared to C. pecorum, suggesting a species-specific variation in NFkappaB activation. At 24 hpi, C. pecorum induced significant NFkappaB activation, an effect not abolished by penicillin (beta lactam)-induced chlamydial stress. C. pecorum-dependent secretion of interleukin 6 was also detected in the culture supernatant of infected cells at 24 hpi, and this effect, too, was unchanged by penicillin-induced chlamydial stress. Taken together, these results suggest that NFkappaB participates in the early inflammatory response to C. pecorum and that stressed chlamydiae can promote inflammation. PMID- 28553626 TI - Insecticide Activity of Ageratina jahnii and Ageratina pichinchensis (Asteraceae) against Lutzomyia migonei (Diptera: Psychodidae). AB - BACKGROUND: Insects are mostly pathogens transmitters, thus the necessity of finding effective bioinsecticides to combat them. In the present investigation, the insecticide activity of Ageratina jahnii and Ageratina pichinchensis (Asteraceae) essential oils, methanol, and aqueous extracts was evaluated against Lutzomyia migonei (Diptera: Psychodidae) females, Leishmania transmitters, a wide distributed parasitosis in Latin America. MATERIALS AND METHODS: All extracts were prepared by maceration at room temperature, and essential oils were obtained by hydrodistillation process. Females of L. migonei were used in the bioassays using the adulticide test in pots. RESULTS: Essential oils from both assayed plant species showed 100% of L. migonei mortality at 48 h of exposure at the concentration of 10 mg/ml. A. jahnii essential oil exhibited the following values, LD50 = 0.39 mg/ml, LD90 = 1.57 mg/ml, LD95 = 2.31 mg/ml, and LD99 = 4.80 mg/ml while for A. pichinchensis essential oil values were LD50 = 0.31 mg/ml, LD90 = 0.99 mg/ml, LD95 = 1.38 mg/ml, and LD99 = 2.55 mg/ml. CONCLUSION: Higher toxicity was observed with A. pichinchensis essential oil against L. migonei, comparing to A. jahnii oil. Two new plant species are being reported, showing bioactive properties against common tropical disease vectors such as L. migonei, hence, opening possibilities to a more environmental friendly control. PMID- 28553627 TI - Nosocomial Infections in Intensive Care Unit: Pattern of Antibiotic-resistance in Iranian Community. AB - BACKGROUND: Bacterial infections are responsible for great number of mortality in Intensive Care Unit (ICU). Knowledge about prevalence of bacterial infections and their antibiotic-resistance pattern would be a great step for their treatment and management. MATERIALS AND METHODS: Data about nosocomial infections in ICUs of Alzahra Hospital (referral hospital in Isfahan, center of Iran) were gathered during the years 2007-2010. A questionnaire was fulfilled for any specific patient with nosocomial infection containing demographic data of patient and also characteristics of the infection. RESULTS: Out of all patients, 707 individuals (65.6%) were male and 370 (34.4%) were female. Our data revealed that Pseudomonas aeruginosa (13.9%), Klebsiella (11%), and Escherichia coli (6.4%) were the most prevalent bacterial infections. The most common sites of nosocomial infections in the ICU were respiratory system (399 cases, 37%), urinary system (230 cases, 21.4%), and blood (102 cases, 9.5%). The antibiotic-resistance of each bacteria in ICU ward was assessed and data were categorized in a table. There were less documentary about bacterial cultures in the year 2007 when compared with the next years. CONCLUSION: We found some differences (such as bacterial prevalence in ICU wards which caused nosocomial infections) in our local prevalence of nosocomial infections and also in their resistance pattern compared to other centers. Knowing about our data will help physicians to administer the most suitable antibiotics for treatment of nosocomial infections in our area. PMID- 28553629 TI - EPCAM Expression in Colon Adenocarcinoma and its Relationship with TNM Staging. AB - BACKGROUND: Since epithelial cell adhesion molecule glycoprotein (EPCAM) is associated with the development and metastasis of colon adenocarcinoma, it can be helpful in predicting the tumor stage before surgery. In this study, we investigated EPCAM glycoprotein expression in colon adenocarcinoma and its relationship with tumor staging. MATERIALS AND METHODS: This study was done on formalin-fixed and paraffin-embedded tissues of 71 patients diagnosed with colon adenocarcinoma, together with normal tissues around them, which were available at the archive of pathology lab of Al-Zahra hospital, Isfahan. Hematoxylin and eosin (HandE) and immunohistochemistry (IHC) staining methods for EPCAM marker were performed on paraffin-embedded blocks. RESULTS: The percentage of staining of EPCAM glycoprotein in the tumoral and normal tissues of 71 patients with colon adenocarcinoma was studied and compared. In normal tissue, 84.5% showed strong staining, 15.5% showed moderate to strong, and none of the patients showed moderate, weak, or no staining at all. In the tumoral tissue, 25.4% had strong, 25.4% had moderate to strong, 26.8% showed moderate, 16.9% showed weak and 5.6% had no staining at all. EPCAM expression was significantly less in tumoral tissue than in normal. CONCLUSION: There was an inverse relationship between tumor staging and the percentage of staining in EPCAM glycoprotein so this marker can be used for predicting the tumor stage. PMID- 28553628 TI - The Comparison between Effects of 12 weeks Combined Training and Vitamin D Supplement on Improvement of Sensory-motor Neuropathy in type 2 Diabetic Women. AB - BACKGROUND: Peripheral neuropathy is a common complaint of diabetes. This study aimed to determine the effects of 12 weeks combined training with Vitamin D supplement on improvement of sensory-motor neuropathy in women with diabetic neuropathy. MATERIALS AND METHODS: This clinical trial study conducted on 90 patients were selected and randomly divided into two groups. Finally, 81 adult females with diabetes type II (20-55 years old) were interred in this study. The control group had no training, but received Vitamin D. The experimental group received Vitamin D and 12 weeks training program (3 days a week, 60 min/session) including aerobic exercises, strength, and flexibility. Aerobic exercise intensity was set at 60-70% maximum heart rate and resistance training intensity was determined by 10 R.M. Michigan neuropathy questionnaire, reflex hammer and tuning fork 128 Hz used to screening tense of neuropathy (Michigan Neuropathy Screening Instrument) that were used for pretest and posttest. RESULTS: Following 3 months combined training and supplementation with Vitamin D, had observed a significant reduction in numbness (P = 0.001), pain (0.002), tingling (P = 0.001), and weakness (P = 0.002) in the lower limb and also increases in sense of touch intervention (P = 0.005), detects the position of the fingers (P = 0.001) and vibration perception (P = 0.001) in tissues. Knee reflexes (P = 0.77) and ankles reflexes (P = 0.47) did not significantly change after interventions. CONCLUSION: It seems that taking part in combined training and supplementation with Vitamin D can improve the symptoms of sensory-motor neuropathy. PMID- 28553630 TI - Choice of Allograft in Patients Requiring Intestinal Transplantation: A Critical Review. AB - Intestinal transplantation (ITx) is indicated in patients with irreversible intestinal failure (IF) and life-threatening complications related to total parenteral nutrition (TPN). ITx can be classified into three main types. Isolated intestinal transplantation (IITx), that is, transplantation of the jejunoileum, is indicated in patients with preserved liver function. Combined liver-intestine transplantation (L-ITx), that is, transplantation of the liver and the jejunoileum, is indicated in patients with liver failure related to TPN. Thus, patients with cirrhosis or advanced fibrosis should receive a combined allograft, while patients with lower grades of liver fibrosis can usually safely undergo ITx. Reflecting their degree of sickness, the waitlist mortality rate and the early posttransplant outcomes of patients receiving L-ITx are worse than IITx. However, L-ITx is associated with better long-term graft and patient survival. Multivisceral transplantation (MVTx), that is, transplantation of the organs dependent on the celiac axis and superior mesenteric artery, can be classified into full MVTx if it includes the liver and modified MVTx if it does not. The most common indications for MVTx are extensive portomesenteric thrombosis and diffuse gastrointestinal pathology such as motility disorders and polyposis syndrome. Every patient with IF should undergo a multidisciplinary evaluation by an experienced ITx team. PMID- 28553632 TI - Hydroquinone; A Novel Bioactive Compound from Plant-Derived Smoke Can Cue Seed Germination of Lettuce. AB - Plant-derived smoke has been known to play an important role in distribution and growth of vegetation. Using a proficiently designed furnace, we extracted smoke from the leaves of four plant viz. Helianthus annuus,Aloe vera,Ginkgo biloba, and Cymbopogon jwarancusa. Smoke dilutions obtained from these plants were obtained in different concentrations to identify potential lettuce growth promoting smoke solution. Results revealed that smoke obtained from G. biloba significantly enhanced the lettuce seed germination. This solution was then partitioned into ethyl acetate, dichloromethane, n-hexane, chloroform and ether fractions. Ethyl acetate fraction was found to be potent to enhance seed germination. This fraction was subjected to column chromatography and spectroscopic techniques to obtain compound 1. This compound was identified as hydroquinone using 1D and 2D NMR techniques. At low concentrations (5, 10, and 20 ppm), compound 1 enhanced the lettuce seed germination; however, higher concentrations inhibited its growth as compared to control. PMID- 28553631 TI - Left Ventricular Hypertrophy in Pediatric Hypertension: A Mini Review. AB - Adults with arterial hypertension (HTN) have stroke, myocardial infarction, end stage renal disease (ESRD), or die at higher rates than those without. In children, HTN leads to target organ damage, which includes kidney, brain, eye, blood vessels, and heart, which precedes "hard outcomes" observed in adults. Left ventricular hypertrophy (LVH) or an anatomic and pathologic increase in left ventricular mass (LVM) in response to the HTN is a pediatric surrogate marker for HTN-induced morbidity and mortality in adults. This mini review discusses current definitions, clinically relevant methods of LVM measurements and normalization methods, its epidemiology, management, and issue of reversibility in children with HTN. Pediatric definition of LVH and abnormal LVM is not uniformed. With multiple definitions, prevalence of pediatric HTN-induced LVH is difficult to ascertain. In addition while in adults cardiac magnetic resonance imaging is considered "the gold standard" for LVM and LVH determination, pediatric data are limited to "special populations": ESRD, transplant, and obese children. We summarize available data on pediatric LVH treatment and reversibility and offer future directions in addressing LVH in children with HTN. PMID- 28553633 TI - Emerging applications of porphyrins in photomedicine. AB - Biomedical applications of porphyrins and related molecules have been extensively pursued in the context of photodynamic therapy. Recent advances in nanoscale engineering have opened the door for new ways that porphyrins stand to potentially benefit human health. Metalloporphyrins are inherently suitable for many types of medical imaging and therapy. Traditional nanocarriers such as liposomes, dendrimers and silica nanoparticles have been explored for photosensitizer delivery. Concurrently, entirely new classes of porphyrin nanostructures are being developed, such as smart materials that are activated by specific biochemicals encountered at disease sites. Techniques have been developed that improve treatments by combining biomaterials with photosensitizers and functional moieties such as peptides, DNA and antibodies. Compared to simpler structures, these more complex and functional designs can potentially decrease side effects and lead to safer and more efficient phototherapies. This review examines recent research on porphyrin-derived materials in multimodal imaging, drug delivery, bio-sensing, phototherapy and probe design, demonstrating their bright future for biomedical applications. PMID- 28553635 TI - Alcoholic Fractions F5 and F6 from Withania somnifera Leaves Show a Potent Antileishmanial and Immunomodulatory Activities to Control Experimental Visceral Leishmaniasis. AB - Visceral leishmaniasis (VL) causes fatal life-threatening disease, if left untreated. The current drugs have various limitations; hence, natural products from medicinal plants are being focused in search of new drugs to treat leishmaniasis. The aim of the present study was to evaluate the antileishmanial and immunomodulatory activities of F5 and F6 alcoholic fractions from Withania somnifera leaves and purified withaferin-A in Leishmania donovani-infected peritoneal macrophages and BALB/c mice. We observed that F5 (15 ug/mL), F6 (10 ug/mL), and withaferin-A (1.5 uM) reduce amastigote count in peritoneal macrophages and induce reactive oxygen species and significant decrease in IL-10 mRNA expression compared to control upon treatment. Subsequently, in vivo study mice were treated with F5 (25 and 50 mg/kg b.wt.), F6 (25 and 50 mg/kg b.wt.) orally, and withaferin-A (2 mg/kg b.wt.) intraperitoneally for 10 consecutive days and a drastic reduction in parasite burden in both spleen and liver were observed. The treatment resulted in the reduction in IL-10, IL-4, and TGF-beta mRNA expression and a significant increase in IFN-gamma/IL-10 expression ratio in the treated group compared to control. The humoral response of these alcoholic fractions and withaferin-A shows increased IgG2a levels when compared with IgG1 in treated mice. Taken together, our result concludes that withanolides in alcoholic fractions demonstrate a potent antileishmanial and immunomodulatory activities in experimental VL. PMID- 28553636 TI - Non-Conscious Effect of Food Odors on Children's Food Choices Varies by Weight Status. AB - OBJECTIVE: Food cues are omnipresent in the daily environment and may influence eating behavior even non-consciously. An increased reactivity to food cues, such as food odors, has been shown to be correlated with obesity in children. The objective of this study is to investigate whether the non-conscious influence of food odors on children's food choices varies by their weight status. METHODS: Seventy-four children, of whom 29 were obese, took part in this study. The children performed a food choice intention task presented as a computer game in which 30 pairs of food images (a fatty-sweet food picture vs. a fruit picture) successively appeared on the screen. The children had to choose the item "they most wanted to eat at the present moment" for each pair. While performing this task, the children wore a headset in which the microphone foam was odorized with a fruity odor, a fatty-sweet odor or no odor. They performed the intention task three times, one time for each olfactory condition. The odors were non attentively perceived, i.e., none of the children were aware of the odorization of the microphone foams. The modeled probability is the probability to choose a fruit. RESULTS: In children with obesity, the fruity odor increased the likelihood of a fruit to be chosen compared to the no-odor condition [OR (95% CL) = 1.42 (1.13-1.78), P = 0.0028], while the fatty-sweet odor had no effect on food choice [OR (95% CL) = 1.07 (0.85-1.36), P = 0.55]. In children without obesity, both the fruity and the fatty-sweet odors decreased the likelihood to choose a fruit compared to the no-odor condition [OR (95% CL) = 0.76 (0.64-0.90), P = 0.0015, for the fruity odor and OR (95% CL) = 0.79 (0.66-0.93), P = 0.0062, for the fatty-sweet odor]. CONCLUSION: The different patterns of results obtained in both groups of children suggest differences in the mental representations activated by non-attentively perceived olfactory cues based on weight status. PMID- 28553637 TI - Anthropometric and Laboratory Variables Related to Weight Loss-Comparison of Heart Failure Patients with Tumor Patients and Control Population. AB - BACKGROUND: Body weight loss is an important feature of heart failure (HF) and tumors. It is related to both reduced survival and adverse reactions to therapy in both of these conditions. The mechanisms of body weight loss in patients with HF and tumors are considered to be similar. Yet, studies comparing those two populations are generally lacking. The aim of this study was to compare anthropometric and laboratory data, related to weight loss, between patients with chronic HF and patients with different tumors as well as control population. METHODS: Laboratory and anthropometric data on 143 consecutive patients with chronic HF and malignant diseases as well as data for 20 controls were collected. RESULTS: Patients with HF had lower levels of C-reactive protein (CRP) and albumin compared to controls. Anthropometric measurements revealed lower body mass index (BMI), muscle strength, mid-arm circumference, and waist circumference in patients with HF compared to controls. Measurements of biceps, triceps, subscapular, and suprailiac skinfolds were also lower in HF group. Compared to solid tumor group, HF patients had lower levels of CRP and higher levels of hemoglobin. Solid tumor patients had lower values of BMI and subscapular skinfold thickness, as well as higher muscle strength compared to HF group. Finally, compared to patients with solid hematological tumors, HF group had lower levels of albumin, lower muscle strength, as well as lower mid-arm circumference. CONCLUSION: We found differences in anthropometric and laboratory features, related to weight loss, in patients with HF compared to control population that were expected. On the other hand, observed differences in HF group compared to patients with various tumors could imply different pathophysiological mechanisms of weight loss between those groups. Such data could serve as a cornerstone for studies with larger numbers of patients and deeper pathophysiological insight. PMID- 28553638 TI - Torsin ATPases: Harnessing Dynamic Instability for Function. AB - Torsins are essential, disease-relevant AAA+ (ATPases associated with various cellular activities) proteins residing in the endoplasmic reticulum and perinuclear space, where they are implicated in a variety of cellular functions. Recently, new structural and functional details about Torsins have emerged that will have a profound influence on unraveling the precise mechanistic details of their yet-unknown mode of action in the cell. While Torsins are phylogenetically related to Clp/HSP100 proteins, they exhibit comparatively weak ATPase activities, which are tightly controlled by virtue of an active site complementation through accessory cofactors. This control mechanism is offset by a TorsinA mutation implicated in the severe movement disorder DYT1 dystonia, suggesting a critical role for the functional Torsin-cofactor interplay in vivo. Notably, TorsinA lacks aromatic pore loops that are both conserved and critical for the processive unfolding activity of Clp/HSP100 proteins. Based on these distinctive yet defining features, we discuss how the apparent dynamic nature of the Torsin-cofactor system can inform emerging models and hypotheses for Torsin complex formation and function. Specifically, we propose that the dynamic assembly and disassembly of the Torsin/cofactor system is a critical property that is required for Torsins' functional roles in nuclear trafficking and nuclear pore complex assembly or homeostasis that merit further exploration. Insights obtained from these future studies will be a valuable addition to our understanding of disease etiology of DYT1 dystonia. PMID- 28553640 TI - Resource Estimations in Contingency Planning for Foot-and-Mouth Disease. AB - Preparedness planning for a veterinary crisis is important to be fast and effective in the eradication of disease. For countries with a large export of animals and animal products, each extra day in an epidemic will cost millions of Euros due to the closure of export markets. This is important for the Danish husbandry industry, especially the swine industry, which had an export of ?4.4 billion in 2012. The purposes of this project were to (1) develop an iterative tool with the aim of estimating the resources needed during an outbreak of foot and-mouth disease (FMD) in Denmark, (2) identify areas, which can delay the control of the disease. The tool developed should easily be updated, when knowledge is gained from other veterinary crises or during an outbreak of FMD. The stochastic simulation model DTU-DADS was used to simulate spread of FMD in Denmark. For each task occurring during an epidemic of FMD, the time and personnel needed per herd was estimated by a working group with expertise in contingency and crisis management. By combining this information, an iterative model was created to calculate the needed personnel on a daily basis during the epidemic. The needed personnel was predicted to peak within the first week with a requirement of approximately 123 (65-175) veterinarians, 33 (23-64) technicians, and 36 (26-49) administrative staff on day 2, while the personnel needed in the Danish Emergency Management Agency (responsible for the hygiene barrier and initial cleaning and disinfection of the farm) was predicted to be 174 (58-464), mostly recruits. The time needed for surveillance visits was predicted to be the most influential factor in the calculations. Based on results from a stochastic simulation model, it was possible to create an iterative model to estimate the requirements for personnel during an FMD outbreak in Denmark. The model can easily be adjusted, when new information on resources appears from management of other crisis or from new model runs. PMID- 28553634 TI - Neural Stem Cell Plasticity: Advantages in Therapy for the Injured Central Nervous System. AB - The physiological and pathological properties of the neural germinal stem cell niche have been well-studied in the past 30 years, mainly in animals and within given limits in humans, and knowledge is available for the cyto-architectonic structure, the cellular components, the timing of development and the energetic maintenance of the niche, as well as for the therapeutic potential and the cross talk between neural and immune cells. In recent years we have gained detailed understanding of the potentiality of neural stem cells (NSCs), although we are only beginning to understand their molecular, metabolic, and epigenetic profile in physiopathology and, further, more can be invested to measure quantitatively the activity of those cells, to model in vitro their therapeutic responses or to predict interactions in silico. Information in this direction has been put forward for other organs but is still limited in the complex and very less accessible context of the brain. A comprehensive understanding of the behavior of endogenous NSCs will help to tune or model them toward a desired response in order to treat complex neurodegenerative diseases. NSCs have the ability to modulate multiple cellular functions and exploiting their plasticity might make them into potent and versatile cellular drugs. PMID- 28553641 TI - Use of Temperature, Humidity, and Slaughter Condemnation Data to Predict Increases in Transport Losses in Three Classes of Swine and Resulting Foregone Revenue. AB - The United States Department of Agriculture (USDA) Animal and Plant Health Inspection Service (APHIS) conducts weekly surveillance of slaughter condemnation rates to provide early warning for emerging diseases and to monitor health trends in swine. Swine deaths in-transit are an animal welfare concern and represent lost revenue for the swine industry. This retrospective observational study used ambient temperature and humidity data from weather stations near United States slaughter plants collected from 2010 to 2015 to predict the incidence and risk of death among swine in-transit and just prior to slaughter. The risk of death for market swine at a heat index (HI), which combines the effects of temperature and humidity, indicating moderately hot weather conditions between 85 and 92 degrees F was 1.37 times greater than that of the baseline temperature range of 54-79 degrees F. The risk of death for cull sows at an HI between 85 and 92 degrees F was 1.93 times greater than that of average temperatures ranging from 54 to 79 degrees F. Roaster swine (weigh < 220 lbs and often used for whole carcass roasting), however, had 0.80 times the risk when the HI was 85-92 degrees F compared to a baseline temperature of 54-79 degrees F. The risk of death for roaster swine at a minimum temperature between 40 and 50 degrees F was 1.21 times greater than that of average temperatures ranging from 54 to 79 degrees F. The risk of death for market swine at a minimum temperature range of 40-50 degrees F was 0.97 times that of average temperatures ranging from 54 to 79 degrees F. And for cull sows, the risk of death at a minimum temperature range of 40-50 degrees F was 0.81 times the risk at the average temperature ranging from 54 to 79 degrees F. Across the study period, cumulative foregone revenue, or revenue not realized due to swine condemnations, for all swine was $18.6 million and $4.3 million for cold temperatures and high HI ranges above the baseline, respectively. Marginal foregone revenue per hog in hotter months is higher due to seasonal peaks in swine prices. As a result of this study, the USDA-APHIS swine condemnation surveillance can incorporate weekly estimated HI values and ambient temperature data for slaughter establishments to provide additional information for analysts investigating signals (noteworthy increases above baseline) for "dead" condemnations. This study suggests that current mitigation measures are often not sufficient to prevent swine deaths due to ambient temperature extremes. PMID- 28553639 TI - Role of Endoplasmic Reticulum Stress, Autophagy, and Inflammation in Cardiovascular Disease. AB - Cardiovascular diseases are a class of heart or blood vessels diseases, which are now considered to be the leading cause of death globally. A number of recent studies have reported key roles for inflammation in the progression of diseased vessels and systematic heart failure. In particular, endoplasmic reticulum (ER) stress, which is mechanistically implicated in inflammation and autophagy, has now been associated with pathophysiological states in the cardiovascular system. Autophagy has also been identified as an important process in the progression of multiple cardiovascular diseases such as in atherosclerosis plaque progression and ischemia and/or reperfusion. In light of the above, it has been proposed that a link between inflammation, autophagy, and ER stress may exist that contribute to diseases of the heart and its supporting vessels. This review highlights current knowledge on the cross talk between these three biological processes, and the potential of targeting this pathway as a therapeutic approach for cardiovascular disorders and its related diseases. PMID- 28553643 TI - Comparative Transcriptome Analyses of Resistant and Susceptible Near-Isogenic Wheat Lines following Inoculation with Blumeria graminis f. sp. tritici. AB - Powdery mildew is one of the most important diseases of wheat. In this study, the leaf RNA samples of wheat NILs carrying powdery mildew resistant and susceptible Pm2 alleles (L031 and Chancellor) and its F1 hybrid at two time points (16 h and 96 h postinoculation) were used for RNA-seq analysis. We carry comparison between similar materials at different times and between different materials at same times. The overlapping DEGs between the dominant phenotypes (L031 and F1 hybrid) and the recessive phenotype (Chancellor) were 1028 and 2214 DEGs, which were clearly lower than those between the dominant and recessive parents and thus could provide relatively accurate and valuable information. GO and KEGG enrichment analysis of DEGs revealed that other than the expected defense-related genes, differential up- and downregulation of genes from many other signaling networks were also involved. Comparative transcriptome analysis also revealed that early-stage postinoculation is important and suitable time points to study expression profiles and signaling pathways of resistance-related genes following fungal inoculation. qRT-PCR analyses showed highly consistent expression patterns of genes with RNA-seq data. The results will aid in the identification of genes and signaling pathways involved in powdery mildew response in wheat. PMID- 28553642 TI - An Update on Drugs Used for Lumbosacral Epidural Anesthesia and Analgesia in Dogs. AB - This review aims to report an update on drugs administered into the epidural space for anesthesia and analgesia in dogs, describing their potential advantages and disadvantages in the clinical setting. Databases searched include Pubmed, Google scholar, and CAB abstracts. Benefits of administering local anesthetics, opioids, and alpha2 agonists into the epidural space include the use of lower doses of general anesthetics (anesthetic "sparing" effect), perioperative analgesia, and reduced side effects associated with systemic administration of drugs. However, the potential for cardiorespiratory compromise, neurotoxicity, and other adverse effects should be considered when using the epidural route of administration. When these variables are considered, the epidural technique is useful as a complementary method of anesthesia for preventive and postoperative analgesia and/or as part of a balanced anesthesia technique. PMID- 28553644 TI - Biochemical and Molecular Analysis of the Hb Lepore Boston Washington in a Syrian Homozygous Child. AB - Hemoglobin (Hb) Lepore is composed of two normal alpha chains and two deltabeta fusion globins that arise from unequal crossover events between the delta- and beta-globin genes. The Hb Lepore is widespread all over the world and in many ethnic groups. It includes some of the few clinically significant Hb variants that are associated with a beta-thalassemia phenotype. Here, we describe the first occurrence of Hb Lepore Boston Washington in a Syrian individual. The patient, a 10-year-old child, shows severe anemia with a Hb level of 6.85 g/dL and typical thalassemic red cell indices. The diagnostic procedure implies hematological, biochemical, and molecular analysis, including multiplex ligation dependent probe amplification (MLPA) assay, GAP-PCR, and DNA sequencing. This latter allowed us to define the correct structure of the hybrid deltabeta-globin gene. The knowledge of the spectrum of mutations associated with different geographical areas is the prerequisite to set up large-scale screening programs and be able to offer genetic counseling to couples at risk. PMID- 28553645 TI - Minimally Invasive Percutaneous Nephrolithotomy versus Retrograde Intrarenal Surgery for Upper Urinary Stones: A Systematic Review and Meta-Analysis. AB - Minimally invasive percutaneous nephrolithotomy (mini-PCNL) and retrograde intrarenal surgery (RIRS) are both alternatives for PCNL to treat renal calculi. This study is aimed at comparing the stone-free rate (SFR) and other surgery parameters of two approaches for treating upper urinary calculi. We performed this meta-analysis in September 2016 by searching studies about mini-PCNL and RIRS for treating upper urinary calculi in various databases, and RevMan v.5.3 was applied. Three randomized controlled trials and ten nonrandomized trials were included, involving a total of 1317 patients. Meta-analysis showed that mini-PCNL group led to a higher SFR [odds ratio: 1.96; 95% confidence interval: 1.46-2.64; P < 0.00001] but brought a larger postoperative decrease in hemoglobin levels compared with RIRS. RIRS provided a shorter hospital time. There was no significant difference in operation time. Higher postoperative complications were detected in the mini-PCNL, but the difference was not significant. Grade I and III complications did not vary between two procedures, but grade II complications were of lower incidence in RIRS group. In the light of these results, compared with RIRS, mini-PCNL provided significantly higher SFR and efficiency quotient for managing calculi; however, it resulted in higher incidence of postoperative complications, larger hemoglobin drops, and longer hospital stay. PMID- 28553646 TI - Protection against Blast-Induced Traumatic Brain Injury by Increase in Brain Volume. AB - Blast-induced traumatic brain injury (bTBI) is a leading cause of injuries in recent military conflicts and it is responsible for an increased number of civilian casualties by terrorist attacks. bTBI includes a variety of neuropathological changes depending on the intensity of blast overpressure (BOP) such as brain edema, neuronal degeneration, diffuse axonal damage, and vascular dysfunction with neurological manifestations of psychological and cognitive abnormalities. Internal jugular vein (IJV) compression is known to reduce intracranial compliance by causing an increase in brain volume and was shown to reduce brain damage during closed impact-induced TBI. We investigated whether IJV compression can attenuate signs of TBI in rats after exposure to BOP. Animals were exposed to three 110 +/- 5 kPa BOPs separated by 30 min intervals. Exposure to BOP resulted in a significant decrease of neuronal nuclei (NeuN) together with upregulation of aquaporin-4 (AQP-4), 3-nitrotyrosine (3-NT), and endothelin 1 receptor A (ETRA) expression in frontal cortex and hippocampus one day following exposures. IJV compression attenuated this BOP-induced increase in 3-NT in cortex and ameliorated the upregulation of AQP-4 in hippocampus. These results suggest that elevated intracranial pressure and intracerebral volume have neuroprotective potential in blast-induced TBI. PMID- 28553648 TI - Serum Vaspin Concentration in Elderly Type 2 Diabetes Mellitus Patients with Differing Body Mass Index: A Cross-Sectional Study. AB - Aims. This study was to evaluate the association of serum vaspin concentrations with body mass index (BMI) among elderly patients (>60 years old). Methods. A total of 227 elderly individuals included 76 healthy with normal glucose tolerance, which divided into normal weight control (BMI < 25, n = 38) and overweight or obese control (BMI >= 25, n = 38) subgroups, and 150 T2DM patients, which divided into normal weight diabetes (BMI < 25, n = 55), overweight diabetes (30 > BMI >= 25, n = 52), and obese diabetes (BMI >= 30, n = 43) subgroups. Relevant parameters were matched for age and gender ratio. Serum vaspin concentrations were measured by enzyme-linked immunosorbent assay. Results. Serum vaspin concentration was significantly higher in the T2DM than the healthy (451.9 +/- 32.6 versus 284.2 +/- 21.7, P < 0.01). In the diabetic patients, the vaspin concentration was significantly higher in the obese group than the normal weight group (498.2 +/- 17.1 versus 382.1 +/- 21.3, P < 0.05). In addition, the concentration of vaspin in normal weight T2DM was higher than in healthy control group with normal weight (382.1 +/- 21.3 versus 192.5 +/- 45.2, P < 0.05). Multiple regression analysis revealed that BMI was independent factors influencing the serum vaspin concentration in all participants. Conclusion. Vaspin may play an important compensatory role in obesity and insulin resistance in elderly people. The clinical trial registration number is ChiCTR-OPC-14005698. PMID- 28553647 TI - Association of Irisin Plasma Levels with Anthropometric Parameters in Children with Underweight, Normal Weight, Overweight, and Obesity. AB - The correlations between irisin levels, physical activity, and anthropometric measurements have been extensively described in adults with considerable controversy, but little evidence about these relationships has been found in children. The objective of this study is to correlate the plasma levels of irisin in underweight, normal weight, overweight, and obese children with anthropometric parameters and physical activity levels. A cross-sample of 40 children was divided into the following groups on the basis of body mass index (BMI) percentile. The correlations of plasma irisin levels with physical activity, anthropometric, and metabolic measurements were determined. Plasma irisin levels (ng/mL) were lower for the underweight group (164.2 +/- 5.95) than for the normal weight and obese groups (182.8 +/- 5.58; p < 0.05). Irisin levels correlated positively with BMI percentile (0.387), waist circumference (0.373), and fat-free mass (0.353; p < 0.05), but not with body muscle mass (-0.027). After a multiple linear regression analysis, only BMI percentile (0.564; p < 0.008) showed a positive correlation with irisin. Our results indicated no association with metabolic parameters. A negative correlation with physical activity was observed. Interrelationships among body components might influence irisin levels in children. PMID- 28553649 TI - Myocardial Perfusion in Rheumatoid Arthritis Patients: Associations with Traditional Risk Factors and Novel Biomarkers. AB - Introduction. Cardiovascular (CV) diseases are a major cause of death in rheumatoid arthritis (RA) patients. Novel biomarkers [B-type natriuretic peptide (BNP); osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL) ratio; and dickkopf-1 (DKK-1)] have been used in CV risk assessment. We analysed, in established RA patients, the presence of silent myocardial ischemia and its association with clinical variables, BNP, and bone and atheroma biomarkers. Methods. From a single-center tertiary referral hospital, RA patients asymptomatic for CV disease were submitted to myocardial perfusion scintigraphy (MPS) under adenosine stress and biomarkers measurements. Logistic regression was used to estimate crude odds ratios (OR) and 95% confidence intervals (CI). Results. In 189 patients, perfusion defects were frequent (25%) and associated with BNP >= 100 pg/mL (OR = 5.68; 95% CI: 2.038-15.830), fourth log OPG/RANKL ratio quartile (OR = 2.88; 95% CI: 1.091-7.622), and DKK-1 >= 133 pmol/L (OR = 2.69; 95% CI: 1.058-6.840). Similar associations were confirmed in those with C reactive protein > or <= 3 mg/L. No relationship was found with the majority of traditional CV factors nor with disease variables. Conclusions. Our results corroborated the hypothesis that MPS could reveal subclinical CV dysfunction, supported the utility of BNP measurements as a screening tool, and put in perspective the potential usefulness of complementary approaches in CV risk assessment in RA patients. PMID- 28553650 TI - Recent Treatment Advances and New Trials in Adult Nephrotic Syndrome. AB - The etiology of nephrotic syndrome is complex and ranges from primary glomerulonephritis to secondary forms. Patients with nephrotic syndrome often need immunosuppressive treatment with its side effects and may progress to end stage renal disease. This review focuses on recent advances in the treatment of primary causes of nephrotic syndrome (idiopathic membranous nephropathy (iMN), minimal change disease (MCD), and focal segmental glomerulosclerosis (FSGS)) since the publication of the KDIGO guidelines in 2012. Current treatment recommendations are mostly based on randomized controlled trials (RCTs) in children, small RCTs, or case series in adults. Recently, only a few new RCTs have been published, such as the Gemritux trial evaluating rituximab treatment versus supportive antiproteinuric and antihypertensive therapy in iMN. Many RCTs are ongoing for iMN, MCD, and FSGS that will provide further information on the effectiveness of different treatment options for the causative disease. In addition to reviewing recent clinical studies, we provide insight into potential new targets for the treatment of nephrotic syndrome from recent basic science publications. PMID- 28553651 TI - A Review on Recent Computational Methods for Predicting Noncoding RNAs. AB - Noncoding RNAs (ncRNAs) play important roles in various cellular activities and diseases. In this paper, we presented a comprehensive review on computational methods for ncRNA prediction, which are generally grouped into four categories: (1) homology-based methods, that is, comparative methods involving evolutionarily conserved RNA sequences and structures, (2) de novo methods using RNA sequence and structure features, (3) transcriptional sequencing and assembling based methods, that is, methods designed for single and pair-ended reads generated from next-generation RNA sequencing, and (4) RNA family specific methods, for example, methods specific for microRNAs and long noncoding RNAs. In the end, we summarized the advantages and limitations of these methods and pointed out a few possible future directions for ncRNA prediction. In conclusion, many computational methods have been demonstrated to be effective in predicting ncRNAs for further experimental validation. They are critical in reducing the huge number of potential ncRNAs and pointing the community to high confidence candidates. In the future, high efficient mapping technology and more intrinsic sequence features (e.g., motif and k-mer frequencies) and structure features (e.g., minimum free energy, conserved stem-loop, or graph structures) are suggested to be combined with the next- and third-generation sequencing platforms to improve ncRNA prediction. PMID- 28553652 TI - Serum Sclerostin Levels in Patients with Ankylosing Spondylitis and Rheumatoid Arthritis: A Systematic Review and Meta-Analysis. AB - Objective. Current studies of serum sclerostin levels in AS and RA patients are inconsistent. This meta-analysis was performed to identify the association of serum sclerostin level with AS and RA patients. Methods. Embase, PubMed, MEDLINE, and Cochrane Library databases (up to 25 January 2017) were used to collect all relevant published articles. Studies were pooled and standard mean difference (SMD) with 95% confidence interval (CI) was calculated. All data analyses were performed using RevMan 5.3. Results. Totally eight studies of AS including 420 AS patients and 317 healthy controls (HC) and three studies of RA including 145 RA patients and 127 HC were finally included in this meta-analysis. The results revealed that the serum sclerostin levels in both AS patients (SMD = -0.14; 95% CI = [-0.39,0.11]; P = 0.28) and RA patients (SMD = -0.10; 95% CI = [-0.34,0.15]; P = 0.43) were not significantly different from those in HC. Conclusion. The difference of serum sclerostin levels in AS and RA patients was not significantly different from HC, indicating that the sclerostin may not associate with the development of AS and RA. PMID- 28553653 TI - Not Only Glycaemic But Also Other Metabolic Factors Affect T Regulatory Cell Counts and Proinflammatory Cytokine Levels in Women with Type 1 Diabetes. AB - Type 1 diabetic (T1D) patients suffer from insulinopenia and hyperglycaemia. Studies have shown that if a patient's hyperglycaemic environment is not compensated, it leads to complex immune dysfunctions. Similarly, T1D mothers with poor glycaemic control exert a negative impact on the immune responses of their newborns. However, questions concerning the impact of other metabolic disturbances on the immune system of T1D mothers (and their newborns) have been raised. To address these questions, we examined 28 T1D women in reproductive age for the relationship between various metabolic, clinical, and immune parameters. Our study revealed several unexpected correlations which are indicative of a much more complex relationship between glucose and lipid factors (namely, glycosylated haemoglobin Hb1Ac, the presence of one but not multiple chronic diabetic complications, and atherogenic indexes) and proinflammatory cytokines (IL-1alpha and TNF-alpha). Regulatory T cell counts correlated with HbA1c, diabetic neuropathy, lipid spectra parameters, and IL-6 levels. Total T-helper cell count was interconnected with BMI and glycaemia variability correlated with lipid spectra parameters, insulin dose, and vitamin D levels. These and other correlations revealed in this study provide broader insight into the association of various metabolic abnormalities with immune parameters that may impact T1D mothers or their developing child. PMID- 28553655 TI - Financial Literacy and Economic Outcomes: Evidence and Policy Implications. AB - This paper reviews what we have learned over the past decade about financial literacy and its relationship to financial decision-making around the world. Using three questions, we have surveyed people in several countries to determine whether they have the fundamental knowledge of economics and finance needed to function as effective decision-makers. We find that levels of financial literacy are low not only in the United States. but also in many other countries including those with well-developed financial markets. Moreover, financial illiteracy is particularly acute for some demographic groups, especially women and the less educated. These findings are important since financial literacy is linked to borrowing, saving, and spending patterns. We also offer new evidence on financial literacy among high school students drawing on the 2012 Programme for International Student Assessment implemented in 18 countries. Last, we discuss the implications of this research for policy. PMID- 28553656 TI - Effect of filling rate on cystometric parameters in young and middle aged mice. AB - OBJECTIVES: To investigate the effect of changing the bladder filling rate during cystometry in younger (2-3 months) and older (13-14 months) C57BL/6J male mice. METHODS: Cystometry was performed on mice under anesthesia. Voiding cycles were established in each mouse at a pump delivery rate of 17 MUl/min. After 30 min, the rate was increased sequentially to 25, 33, 41 and 49 MUl/min. Each rate was maintained for 30 min. The following cystometric parameters were quantified: peak pressure amplitude, intercontractile interval (ICI), compliance, micturition pressure threshold and voiding efficiency. RESULTS: Bladder weights were significantly greater in older mice (42 mg vs. 27 mg, P < 0.01), but functional capacities were not different. The pressure amplitudes did not change as filling rate increased, nor did they differ between the 4-month and 13-month-old males. ICIs were not significantly different between young and mature mice. However, both groups exhibited a non-linear reduction in ICI with increasing filling rate, best described by a power curve (R2 > 0.93). Compliance was higher in the older mice at low filling rates (17 and 25 MUl/min) but this difference diminished at higher rates. Compliance decreased with increasing flow rate in a non-linear manner, again with greater effects at low filling rates. Micturition pressure thresholds increased with increasing flow rate in a linear manner and older mice began voiding at higher pressures than younger. Both young and old mice exhibited voiding efficiencies of ~70%. CONCLUSIONS: The rate of volume delivery has complex effects on the timing of voiding and compliance. These findings argue for greater standardization of cystometry protocols and further investigation into afferent signaling to higher centers at different filling rates. PMID- 28553654 TI - The CNDP1 (CTG)5 Polymorphism Is Associated with Biopsy-Proven Diabetic Nephropathy, Time on Hemodialysis, and Diabetes Duration. AB - Considering that the homozygous CNDP1 (CTG)5 genotype affords protection against diabetic nephropathy (DN) in female patients with type 2 diabetes, this study assessed if this association remains gender-specific when applying clinical inclusion criteria (CIC-DN) or biopsy proof (BP-DN). Additionally, it assessed if the prevalence of the protective genotype changes with diabetes duration and time on hemodialysis and if this occurs in association with serum carnosinase (CN-1) activity. Whereas the distribution of the (CTG)5 homozygous genotype in the no-DN and CIC-DN patients was comparable, a lower frequency was found in the BP-DN patients, particularly in females. We observed a significant trend towards high frequencies of the (CTG)5 homozygous genotype with increased time on dialysis. This was also observed for diabetes duration but only reached significance when both (CTG)5 homo- and heterozygous patients were included. CN-1 activity negatively correlated with time on hemodialysis and was lower in (CTG)5 homozygous patients. The latter remained significant in female subjects after gender stratification. We confirm the association between the CNDP1 genotype and DN to be likely gender-specific. Although our data also suggest that (CTG)5 homozygous patients may have a survival advantage on dialysis and in diabetes, this hypothesis needs to be confirmed in a prospective cohort study. PMID- 28553658 TI - A Consistent Definition of Phase Resetting Using Hilbert Transform. AB - A phase resetting curve (PRC) measures the transient change in the phase of a neural oscillator subject to an external perturbation. The PRC encapsulates the dynamical response of a neural oscillator and, as a result, it is often used for predicting phase-locked modes in neural networks. While phase is a fundamental concept, it has multiple definitions that may lead to contradictory results. We used the Hilbert Transform (HT) to define the phase of the membrane potential oscillations and HT amplitude to estimate the PRC of a single neural oscillator. We found that HT's amplitude and its corresponding instantaneous frequency are very sensitive to membrane potential perturbations. We also found that the phase shift of HT amplitude between the pre- and poststimulus cycles gives an accurate estimate of the PRC. Moreover, HT phase does not suffer from the shortcomings of voltage threshold or isochrone methods and, as a result, gives accurate and reliable estimations of phase resetting. PMID- 28553659 TI - A NOVEL MUTATION CAUSING COMPLETE THYROID BINDING GLOBULIN DEFICIENCY (TBG-CD MIA) IN A MALE WITH COEXISTING GRAVES DISEASE. AB - OBJECTIVE: An asymptomatic male was found on screening to have a low serum TSH and total T4. The diagnosis of Graves' disease was made with positive thyroid stimulating immunoglobulin (TSI) and elevated free T4 in the presence of complete TBG deficiency (TBG-CD). Genetic testing of the patient and family members revealed a novel frameshift mutation in the TBG (SERPINA7) gene resulting in a complete deficiency of the protein. METHODS: The laboratory testing included total T4, free T4 by analog method and direct dialysis and TBG measurements. Sequencing of genomic DNA was performed from peripheral blood. RESULTS: A 35-year old East Indian male was referred to endocrinology because of abnormal thyroid function tests (TFTs): TSH 0.01 mIU/L (0.4-3.6), total T4 3.0 ug/dl (5.5-10.5) done as part of a "routine office visit". Upon further testing, the serum free T4 2.0 ng/dl (0.8-1.8) and TSI 355% (<140% baseline) were elevated and the diagnosis of Graves' disease was made. TBG deficiency was suspected because the total T4 concentration was inconsistent with hyperthyroidism and further testing confirmed TBG was undetectable. Sequencing of the TBG gene revealed a novel hemizygous frameshift mutation: p.Ala64ProfsTer106, TBG-CD Mia (numbering excludes 20 a.a. signal peptide) associated with the complete deficiency of TBG in a patient with Graves' disease. CONCLUSION: Patients with Graves' disease harboring a TBG mutation have conflicting TFTs. If a clinically hyperthyroid patient presents with normal or low total T4, serum TBG should be measured to identify an abnormality and prevent unnecessary testing. PMID- 28553657 TI - Cancer Is to Embryology as Mutation Is to Genetics: Hypothesis of the Cancer as Embryological Phenomenon. AB - Despite numerous advances in cell biology, genetics, and developmental biology, cancer origin has been attributed to genetic mechanisms primarily involving mutations. Embryologists have expressed timidly cancer embryological origin with little success in leveraging the discussion that cancer could involve a set of conventional cellular processes used to build the embryo during morphogenesis. Thus, this "cancer process" allows the harmonious and coherent construction of the embryo structural base, and its implementation as the embryonic process involves joint regulation of differentiation, proliferation, cell invasion, and migration, enabling the human being recreation of every generation. On the other hand, "cancer disease" is the representation of an abnormal state of the cell that might happen in the stem cells of an adult person, in which the mechanism for joint gene regulating of differentiation, proliferation, cell invasion, and migration could be reactivated in an entirely inappropriate context. PMID- 28553660 TI - MRI-Guided Stereotactic Biopsy of Murine GBM for Spatiotemporal Molecular Genomic Assessment. AB - Brain tumor biopsies that are routinely performed in clinical settings significantly aid in diagnosis and staging. The aim of this study is to develop and evaluate a methodological image-guided approach that would allow for routine sampling of glioma tissue from orthotopic mouse brain tumor models. A magnetic resonance imaging-guided biopsy method is presented to allow for spatially precise stereotaxic sampling of a murine glioma coupled with genome-scale technology to provide unbiased characterization of intra- and intertumoral clonal heterogeneity. Longitudinal and multiregional sampling of intracranial tumors allows for successful collection of tumor biopsy samples, thus allowing for a pathway-enrichment analysis and a transcriptional profiling of RNA sequencing data. Spatiotemporal gene expression pattern variations revealing genomic heterogeneity were found. PMID- 28553661 TI - Maternal Beliefs Surrounding Infant Feeding, but Not Maternal BMI or Hospital Experience, Predict Breastfeeding Exclusivity and Behavior. AB - BACKGROUND: Overweight/Obese (OW/Ob) women are at risk for breastfeeding failure. How maternal BMI affects lactation support received in-hospital, or maternal attitudes and beliefs surrounding infant feeding remains poorly understood. We investigated 1) the impact of in-hospital lactation support and maternal attitudes and behaviors regarding infant feeding on breastfeeding exclusivity, and 2) whether these potentially modifiable attitudes and behaviors differed between normal weights (NW) versus OW/Ob women. METHODS: NW (n=18) and OW/Ob (n=20) women and their infants were followed from birth to 4-months postpartum. In-hospital experiences, problems and help received regarding breastfeeding were documented. Six maternal attitudes and behaviors surrounding infant feeding were assessed at 2-weeks and 4-months. These factors were compared between NW and OW/OB women, and in relation to breastfeeding exclusivity. RESULTS: In-hospital experiences, assistance received regarding breastfeeding difficulties, and infant breastfeeding exposure did not differ between NW and OW/Ob women. At 4-months OW/Ob women were more likely to feed their infant on a schedule (p<0.03); this was the only difference in attitudes/behaviors between BMI-groups. Feeding the infant on a schedule was predictive of lower total breastfeeding exposure (p<0.05). Maternal concern about infant under-eating/becoming underweight was associated with several negative feeding behaviors, including reduced breastfeeding exposure (p<0.02), pressuring feeding style (p<0.01), and feeding to calm fussiness (p<0.01). CONCLUSION: This hospital setting provided equitable breastfeeding support to OW/Ob and NW women. Maternal concern over infant under eating/under-gaining and encouragement to feed on-demand are prime interventional targets to improve breastfeeding outcomes; the latter may be especially relevant to OW/Ob mothers. PMID- 28553662 TI - Subsistence styles shape human social learning strategies. AB - Social learning is a fundamental element of human cognition. Learning from others facilitates the transmission of information that helps individuals and groups rapidly adjust to new environments and underlies adaptive cultural evolution1-6. While basic human propensities for social learning are traditionally assumed to be species-universal1,7, recent empirical studies show that they vary between individuals and populations8-13. Yet the causes of this variation remain poorly understood9. Here we show that interdependence in everyday social and economic activities can strongly amplify social learning. With an experimental decision making task we examine individual versus social learning in three recently diverged populations of a single-ethnic group, whose subsistence styles require varying degrees of interdependence. Interdependent pastoralists and urban dwellers have markedly higher propensities for social learning than independent horticulturalists, who predominantly rely on individual payoff information. These results indicate that everyday social and economic practices can mould human social learning strategies and they highlight the flexibility of human cognition to change with local ecology. Our study further suggests that shifts in subsistence styles - which can occur when humans inhabit new habitats or cultural niches2 - can alter reliance on social learning and may therefore impact the ability of human societies to adapt to novel circumstances. PMID- 28553663 TI - Does the Implantable Cardioverter-Defibrillator Benefit Vary With the Estimated Proportional Risk of Sudden Death in Heart Failure Patients? AB - BACKGROUND: Prediction of which heart failure patients are most likely to die of sudden death vs. non-sudden death is an important factor in determining who will benefit the most from an ICD. OBJECTIVE: We developed the Seattle Proportional Risk Model (SPRM) to estimate the proportion of total mortality due to sudden death. We prospectively validated the model in HF-ACTION and tested whether the ICD benefit varied with the SPRM. METHODS: Among 2331 patients enrolled, 1947 patients were retained for analysis over a median follow-up of 2.5 years. The SPRM was calculated using age, gender, diabetes, BMI, SBP, EF, NYHA, sodium, creatinine, and digoxin use. RESULTS: ICD use (ICD or CRT-D) was present prior to death in 1204 patients (62%). SPRM was predictive of sudden death vs. non-sudden death in those without an ICD (P=0.002). The hazard ratio representing ICD versus no ICD was 0.63 for all-cause mortality (P=0.0002). The ICD benefit varied with the SPRM for all-cause mortality (P=0.001), with a greater benefit in those with a higher conditional probability of sudden death. CONCLUSIONS: In an ambulatory NYHA II-IV HF population and EF <=35%, the SPRM was predictive of the proportional risk of sudden vs. non-sudden death. ICDs were associated with a decreased risk of all-cause mortality by 37% and the ICD benefit varied with the SPRM. The SPRM may have utility in risk stratifying patients for a primary prevention ICD. PMID- 28553664 TI - Diagnosis and Control of Hypertension in the Elderly Populations of Japan and the United States. AB - The Japanese have the highest life expectancy in the world while the United States (U.S.) has relatively low life expectancy. Furthermore, the Americans have relatively poorer health compared to the Japanese. Examination of the treatment of specific conditions such as hypertension in these two countries may provide insights into how the health care system contributes to the relative health in these two countries. In this study, we focus on the treatment of hypertension, as this is the most common condition requiring therapeutic interventions in seniors. This study examines hypertension diagnoses and controls in nationally representative samples of the older populations (68 years-or-older) of Japan and the U.S. Data come from two nationally representative samples: the Nihon University Japanese Longitudinal Study of Aging (NUJLSOA) (n=2,309) and the U.S. Health and Retirement (HRS) Study (n=3,517). The overall prevalence of hypertension is higher in Japan than the U.S. Undiagnosed hypertension is about four times higher in Japan than in the U.S., while the control of blood pressure is more than four times higher in the U.S. than in Japan. Thus, the use of antihypertensive medication is much more frequent and more effective in the U.S. The medical care system seems to be more effective in controlling hypertension in the U.S. than in Japan. This may be due to the more aggressive diagnosis and treatment of hypertension in the U.S. PMID- 28553665 TI - Urinary Arsenic Speciation in Children and Pregnant Women from Spain. AB - Inorganic arsenic (i-As) is a non-threshold human carcinogen that has been associated with several adverse health outcomes. Exposure to i-As is of particular concern among pregnant women, infants and children, as they are specifically vulnerable to the adverse health effects of i-As, and in utero and early-life exposure, even low to moderate levels of i-As, may have a marked effect throughout the lifespan. Ion chromatography-mass spectrometry detection (IC-ICP-MS) was used to analyse urinary arsenic speciation, as an exposure biomarker, in samples of 4-year-old children with relatively low-level arsenic exposure living in different regions in Spain including Asturias, Gipuzkoa, Sabadell and Valencia. The profile of arsenic metabolites in urine was also determined in samples taken during pregnancy (1st trimester) and in the children from Valencia of 7 years old. The median of the main arsenic species found in the 4-year-old children was 9.71 MUg/l (arsenobetaine-AsB), 3.97 MUg/l (dimethylarsinic acid-DMA), 0.44 MUg/l (monomethylarsonic acid-MMA) and 0.35 MUg/l (i-As). Statistically significant differences were found in urinary AsB, MMA and i-As according to the study regions in the 4-year-old, and also in DMA among pregnant women and their children. Spearman's correlation coefficient among urinary arsenic metabolites was calculated, and, in general, a strong methylation capacity to methylate i-As to MMA was observed. PMID- 28553666 TI - Elevated Arsenic and Uranium Concentrations in Unregulated Water Sources on the Navajo Nation, USA. AB - Regional water pollution and use of unregulated water sources can be an important mixed metals exposure pathway for rural populations located in areas with limited water infrastructure and an extensive mining history. Using censored data analysis and mapping techniques we analyzed the joint geospatial distribution of arsenic and uranium in unregulated water sources throughout the Navajo Nation, where over 500 abandoned uranium mine sites are located in the rural southwestern United States. Results indicated that arsenic and uranium concentrations exceeded national drinking water standards in 15.1 % (arsenic) and 12.8 % (uranium) of tested water sources. Unregulated sources in close proximity (i.e., within 6 km) to abandoned uranium mines yielded significantly higher concentrations of arsenic or uranium than more distant sources. The demonstrated regional trends for potential co-exposure to these chemicals have implications for public policy and future research. Specifically, to generate solutions that reduce human exposure to water pollution from unregulated sources in rural areas, the potential for co exposure to arsenic and uranium requires expanded documentation and examination. Recommendations for prioritizing policy and research decisions related to the documentation of existing health exposures and risk reduction strategies are also provided. PMID- 28553667 TI - Translation of Cardiac Myosin Activation with 2-deoxy-ATP to Treat Heart Failure via an Experimental Ribonucleotide Reductase-Based Gene Therapy. AB - Despite recent advances, chronic heart failure remains a significant and growing unmet medical need, reaching epidemic proportions carrying substantial morbidity, mortality, and costs. A safe and convenient therapeutic agent that produces sustained inotropic effects could ameliorate symptoms, and improve functional capacity and quality of life. We discovered small amounts of 2-deoxy-ATP (dATP) activate cardiac myosin leading to enhanced contractility in normal and failing heart muscle. Cardiac myosin activation triggers faster myosin crossbridge cycling with greater force generation during each contraction. We describe the rationale and results of a translational medicine effort to increase dATP levels using a gene therapy strategy that upregulates ribonucleotide reductase, the rate limiting enzyme for dATP synthesis, selectively in cardiomyocytes. In small and large animal models of heart failure, a single dose of this gene therapy has led to sustained inotropic effects with no toxicity or safety concerns identified to date. Further animal studies are being conducted with the goal of testing this agent in patients with heart failure. PMID- 28553668 TI - The clinical spectrum of Erdheim-Chester disease: an observational cohort study. AB - Erdheim-Chester Disease (ECD) is a rare, potentially fatal, multi-organ myeloid neoplasm occurring mainly in adults. The diagnosis is established by clinical, radiologic, and histologic findings; ECD tumors contain foamy macrophages that are CD68+, CD163+, CD1a-, and frequently S100-. The purpose of this report is to describe the clinical and molecular variability of ECD. Sixty consecutive ECD patients (45 males, 15 females) were prospectively evaluated at the NIH Clinical Center between 2011 and 2015. Comprehensive imaging and laboratory studies were performed, and tissues were examined for BRAF V600E and MAPK pathway mutations. Mean age at first manifestations of ECD was 46 years; a diagnosis was established, on average, 4.2 years after initial presentation. Bone was the most common tissue affected, with osteosclerosis in 95% of patients. Other manifestations observed in one-third to two-thirds of patients include cardiac mass and periaortic involvement, diabetes insipidus, retro-orbital infiltration, retroperitoneal, lung, CNS, skin and xanthelasma, usually in combination. Methods of detection included imaging studies of various modalities. Mutation in BRAF V600E was detected in 51% of 57 biopsies. One patient had an ARAF D228V mutation, and one had an activating ALK fusion. Treatments included interferon alpha, imatinib, anakinra, cladribine, vemurafenib and dabrafenib with trametinib; eleven patients received no therapy. The diagnosis of ECD is elusive because of the rarity and varied presentations of the disorder. Identification of BRAF and other MAPK pathway mutations in biopsies improves ECD diagnosis, allows for development of targeted treatments, and demonstrates that ECD is a neoplastic disorder. PMID- 28553670 TI - VISAGE: Interactive Visual Graph Querying. AB - Extracting useful patterns from large network datasets has become a fundamental challenge in many domains. We present VISAGE, an interactive visual graph querying approach that empowers users to construct expressive queries, without writing complex code (e.g., finding money laundering rings of bankers and business owners). Our contributions are as follows: (1) we introduce graph autocomplete, an interactive approach that guides users to construct and refine queries, preventing over-specification; (2) VISAGE guides the construction of graph queries using a data-driven approach, enabling users to specify queries with varying levels of specificity, from concrete and detailed (e.g., query by example), to abstract (e.g., with "wildcard" nodes of any types), to purely structural matching; (3) a twelve-participant, within-subject user study demonstrates VISAGE's ease of use and the ability to construct graph queries significantly faster than using a conventional query language; (4) VISAGE works on real graphs with over 468K edges, achieving sub-second response times for common queries. PMID- 28553669 TI - Simultaneous dexamethasone intravitreal implant and anti-VEGF therapy for neovascular age-related macular degeneration resistant to anti-VEGF monotherapy. AB - PURPOSE: To evaluate the efficacy of a dexamethasone intravitreal implant in combination with intravitreal anti-VEGF agents for treatment resistant neovascular age-related macular degeneration (nvAMD). METHODS: This study was designed as a single-center, retrospective interventional case series. Consecutive patients with treatment-resistant nvAMD underwent simultaneous combined injection of anti-VEGF agent and dexamethasone intravitreal implant. Eighteen patients with mean age of 81.5 years were included. Patients received average of 26.3 anti-VEGF injections before dual therapy, with mean follow up of 8.2 months after dual therapy. RESULTS: Dual therapy produced a significant mean decrease in CFT (126.3 MUm), compared to a mean increase of 29.9 MUm when treated with anti-VEGF monotherapy (p=0.0017). Patients also had mean decrease in MCV of 0.85 mm3 with dual therapy compared with anti-VEGF monotherapy (p=0.0014). There was a moderate correlation between the number of prior anti-VEGF injections and the magnitude of anatomic response, suggesting that shorter disease duration may positively influence response to combined treatment. Although there was a slight trend towards improved mean visual acuity after dual therapy, these differences did not reach statistical significance. Nevertheless, with combination treatment, 33% of patients gained one or more lines of vision. Dual therapy resulted in a significantly lower number of required anti-VEGF injections (4.25 vs 5.33) and an increase of the anti-VEGF injection-free interval to 1.41 months from 1.12 months during the 6 months following dual therapy compared to the same interval before dual therapy. Dual therapy was well tolerated; two eyes developed mild IOP elevation effectively managed with topical therapy and one patient developed worsening cataract. CONCLUSIONS: Combined treatment of anti-VEGF with the dexamethasone intravitreal implant is a viable alternative for treatment resistant nvAMD, and may reduce treatment burden. Earlier treatment with dual therapy may be beneficial to maximize anatomic and visual outcomes in these patients. PMID- 28553671 TI - Psychological Wellbeing in the Face of Adversity among American Indians: Preliminary Evidence of a New Population Health Paradox? AB - Our objective was to determine self-reported psychological wellbeing of American Indians (AIs). Data are from two surveys, a) 218 adults from the 2011 - 2012 Mino Giizhigad study including Ojibwe adults in Minnesota and Wisconsin, and b) 146 AI women aged 15 - 35 years from the 2011 Sacred Journey study residing in the Pacific Northwest. Reports of AI mental wellness/positive mental health were on par with or higher than found in previous studies with non-AI samples despite simultaneously disparate rates of AI anxiety, depressive symptoms, and differential exposure to sociohistorical stressors. Results are a paradoxical mismatch between mental wellness and mental stressors consistent across two separate, diverse samples of AI adults. PMID- 28553672 TI - Neighborhood Influences on Seasonal Influenza Vaccination among Older African Americans in Atlanta, Georgia. AB - BACKGROUND: Influenza vaccination coverage in the US is lower than the recommended Healthy People 2020 threshold, especially among older African Americans. This analysis explores the complex relationship among neighborhood level factors, socio behavioral influences, and influenza vaccination outcomes among older African Americans. METHODS: We analyzed data from 221 Black/African American participants' age >=50 years living in Atlanta, Georgia. Generalized Estimating Equations for linear and logistic models assessed associations among socio demographic factors, census-tract neighborhood characteristics, and reported 2012-2013 seasonal influenza vaccination receipt, controlling for correlations among individuals within the same census tracts. Evaluated environmental factors included neighborhood deprivation indicators such as vacant housing percentage, vehicle availability, area violent crimes, and racial/ethnic composition. RESULTS: Reported greater influenza immunization uptake was significantly associated with older age >=65 years [OR=1.05, p=0.04], positive vaccination attitudes [OR=5.30, p<0.01], having health insurance [OR=14.37, p=0.03], lower perceived neighborhood security [OR=0.51, p=0.02], and lower neighborhood vehicle ownership [OR=1.07, p=0.04], a proxy for neighborhood affluence and transportation ease. Having a post-secondary education was significantly associated with both positive perceived neighborhood security [beta=0.28, p=0.02] and positive vaccination attitudes [beta=0.27, p=0.02]. CONCLUSION: The findings provide evidence for distal neighborhood-level influences on influenza vaccination uptake among older African Americans. Lower vehicle ownership and lower perceived neighborhood security influenced seasonal influenza immunizations. Those who perceived personal risk, based on reported neighborhood security, displayed intent to obtain the seasonal influenza vaccine. Further investigation of multilevel, socio geographic factors is therefore warranted to more effectively address suboptimal influenza vaccine coverage among this population. PMID- 28553674 TI - Analytic quantification of bias and variance of coil sensitivity profile estimators for improved image reconstruction in MRI. AB - Magnetic resonance (MR) imaging provides a unique in-vivo capability of visualizing tissue in the human brain non-invasively, which has tremendously improved patient care over the past decades. However, there are still prominent artifacts, such as intensity inhomogeneities due to the use of an array of receiving coils (RC) to measure the MR signal or noise amplification due to accelerated imaging strategies. It is critical to mitigate these artifacts for both visual inspection and quantitative analysis. The cornerstone to address this issue pertains to the knowledge of coil sensitivity profiles (CSP) of the RCs, which describe how the measured complex signal decays with the distance to the RC. Existing methods for CSP estimation share a number of limitations: (i) they primarily focus on CSP magnitude, while it is known that the solution to the MR image reconstruction problem involves complex CSPs and (ii) they only provide point estimates of the CSPs, which makes the task of optimizing the parameters and acquisition protocol for their estimation difficult. In this paper, we propose a novel statistical framework for estimating complex-valued CSPs. We define a CSP estimator that uses spatial smoothing and additional body coil data for phase normalization. The main contribution is to provide detailed information on the statistical distribution of the CSP estimator, which yields automatic determination of the optimal degree of smoothing for ensuring minimal bias and provides guidelines to the optimal acquisition strategy. PMID- 28553673 TI - Fractal Regulation in Temporal Activity Fluctuations: A Biomarker for Circadian Control and Beyond. AB - Motor activity in humans and other animals possesses fractal temporal fluctuations that co-exists with circadian or daily activity rhythms. The perturbations in fractal activity patterns are often accompanied by altered circadian/daily rhythms. The goal of this study is to test whether fractal regulation in motor activity provides physiological information independent from 24-h/circadian rhythmicity. To achieve the goal, we studied locomotor activity recordings of rats with the lesion of the suprachiasmatic nucleus (SCN) that are known to have diminished circadian/daily activity rhythms and perturbed fractal regulation. By restricting feeding time (i.e., food was only availability in the dark period of the 12h: 12h light-dark cycles), we found that mean activity levels in these animals displayed significant 24-h rhythms. In contrast, the restricted feeding had no influences on the perturbed fractal regulation in these SCN-lesioned animals, i.e., activity fluctuations in these animals remained random over a wide range of time scales from 2-20h. Our results indicate that 24 h rhythm of food availability can restore/improve circadian/daily rhythms in the SCN-lesioned animals but not necessarily improve the disrupted fractal activity regulation in these animals. This study provides clear and direct evidence that fractal activity patterns offer complementary information about motor activity regulation at multiple time scales that is beyond 24-h rhythm control. PMID- 28553675 TI - ActivityAware: An App for Real-Time Daily Activity Level Monitoring on the Amulet Wrist-Worn Device. AB - Physical activity helps reduce the risk of cardiovascular disease, hypertension and obesity. The ability to monitor a person's daily activity level can inform self-management of physical activity and related interventions. For older adults with obesity, the importance of regular, physical activity is critical to reduce the risk of long-term disability. In this work, we present ActivityAware, an application on the Amulet wrist-worn device that measures daily activity levels (sedentary, moderate and vigorous) of individuals, continuously and in real-time. The app implements an activity-level detection model, continuously collects acceleration data on the Amulet, classifies the current activity level, updates the day's accumulated time spent at that activity level, logs the data for later analysis, and displays the results on the screen. We developed an activity-level detection model using a Support Vector Machine (SVM). We trained our classifiers using data from a user study, where subjects performed the following physical activities: sit, stand, lay down, walk and run. With 10-fold cross validation and leave-one-subject-out (LOSO) cross validation, we obtained preliminary results that suggest accuracies up to 98%, for n=14 subjects. Testing the ActivityAware app revealed a projected battery life of up to 4 weeks before needing to recharge. The results are promising, indicating that the app may be used for activity-level monitoring, and eventually for the development of interventions that could improve the health of individuals. PMID- 28553677 TI - Low to moderate relationships between gait and postural responses in Parkinson disease. AB - OBJECTIVE: To evaluate the relationship between spatiotemporal parameters of forward and backward gait and quality of compensatory stepping responses in forward and backward directions in people with Parkinson's disease with and without freezing of gait. DESIGN: Cross-sectional analysis. SUBJECTS: A total of 111 individuals with mild to moderate Parkinson's disease. METHODS: Forward and backward gait velocity and step length were evaluated using a GAITRite walkway. Forward and backward postural responses were evaluated using items from the Mini Balance Evaluation Systems Test and the Movement Disorders Society Unified Parkinson Disease Rating Scale motor subsection. Relationships between gait and postural responses were examined for the full sample and for sub-groups with and without freezing of gait. RESULTS: There were significant (p < 0.05) low to moderate correlations between postural responses and gait overall. Correlations were similar in the freezer and non-freezer sub-groups. Freezers performed worse than non-freezers on all gait parameters and backward postural response items (p < 0.05). CONCLUSION: Low to moderate relationships between gait and postural responses indicate the complexity of postural control and the potential involvement of different neural circuitry across these tasks. Better understanding of the relationships between gait and postural deficits in Parkinson's disease may inform the future development of targeted interventions to address these impairments. PMID- 28553678 TI - Population Study Confirms Serum Proteins' Change and Reveals Diagnostic Values in Congenital Ventricular Septal Defect. AB - This study was designed to validate thrombospondin 1 (TSP-1), vascular endothelial-cadherin complex (VE-cad), insulin-like growth factor 2 (IGF-2), and amyloid precursor protein (APP) and assess their diagnostic value in ventricular septal defect (VSD). We investigated the serum levels of TSP-1, VE-cad, IGF-2, and APP by enzyme-linked immunosorbent assay in a hospital-based case-control study that included 40 VSD children and 40 healthy controls. Logistic regression analysis was applied to evaluate the relationship of the proteins and VSD, and receiver operating characteristic (ROC) curve was used to assess the diagnostic value of the significant proteins. The serum levels of TSP-1, VE-cad, and IGF-2 were significantly higher in VSD patients than those in healthy controls (p < 0.05). Multivariate logistic regression analysis demonstrated that high levels of TSP-1, VE-cad, and IGF-2 were significantly associated with an increased risk of VSD [TSP-1 (OR 26.91, 95% CI 6.60-72.66, p < 0.001), VE-cad (OR 11.91, 95% CI 3.90-36.36, p < 0.001), IGF-2 (OR 3.25, 95% CI 1.25-8.43, p = 0.015)]. Areas under the ROC curve for TSP-1, VE-cad, and IGF-2 were 0.985, 0.838, and 0.658, respectively. These data demonstrated that TSP-1, VE-cad, and IGF-2 were significantly associated with risk of VSD and manifested diagnostic values, which may provide new evidence for understanding the etiology and promote the early diagnosis and prevention of VSD. PMID- 28553679 TI - Computational modelling of wounded tissue subject to negative pressure wound therapy following trans-femoral amputation. AB - Proof-of-concept computational models were developed and applied as tools to gain insights into biomechanical interactions and variations of oxygen gradients of wounded tissue subject to negative pressure wound therapy (NPWT), following trans femoral amputation. A macro-scale finite-element model of a lower limb was first developed based on computed tomography data, and distributions of maximum and minimum principal stress values we calculated for a region of interest (ROI). Then, the obtained results were applied iteratively as new sets of boundary conditions for a specific spatial position in a capillary sub-model. Data from coupled capillary stress and mass- diffusion sub-models were transferred to the macro-scale model to map the spatial changes of tissue oxygen gradients in the ROI. The -70 mmHg NPWT resulted in a dramatic change of a wound surface area and the greatest relative contraction was observed at -150 mmHg. Tissue lateral to the depth of the wound cavity revealed homogenous patterns of decrease in oxygenation area and the extent of such decrease was dependent on the distance from the wound surface. However, tissue lateral to the width of the wound demonstrated heterogeneous patterns of change, as evidenced by both gradual increase and decrease in the oxygenation area. The multiscale models developed in the current study showed a significant influence of NPWT on both macro deformations and changes of tissue oxygenation. The patterns of changes depended on the depth of the tissue, the geometry of the wound, and also the location of tissue plane. PMID- 28553680 TI - The choice of comorbidity scoring system in Chinese peritoneal dialysis patients. AB - BACKGROUND: Several comorbidity scoring systems have been developed and validated, mostly in western hemodialysis patients with a high risk of cardiovascular disease. The performance of comorbidity scoring, however, depends on the patient population. In this study, we determine the optimal comorbidity scoring system for predicting survival of incident Chinese PD patients. METHODS: We studied 461 incident PD patients. The performance of Charlson Comorbidity Index (CCI), Hemmelgarn score, and Liu score as the survival predictor was compared. RESULTS: The mean age was 57.7 +/- 13.7 years. The median CCI, Hemmelgarn, and Liu scores were 4 [inter-quartile range (IQR) 2-5], 1 (IQR 0-2), and 4 (IQR 2-5), respectively. Patients were followed for 45.5 +/- 33.0 months. All 3 comorbidity scores were predictors of patient survival by univariate analysis. After adjusting for confounding factors, CCI was the best predictor of patient survival among the 3 indices, with each point increase in CCI conferring 31% excess in mortality risk [95% confidence interval (CI) 21-41%, p < 0.001]. In contrast, each point increase in Liu score confers 20% excess in mortality risk (95% CI 13-27%, p < 0.001). Although the Hemmelgarn score is an independent predictor of patient survival, over 70% of patients score 0 or 1 by this system, limiting its role as a prognostic marker. CONCLUSION: CCI should be the preferred method for quantifying comorbidity load in incident Chinese PD patients, and it is a good predictor of survival in this group of patients. PMID- 28553681 TI - Effect of different levels of intermittent hypoxia on autophagy of hippocampal neurons. AB - PURPOSE: The current study was carried out to assess the effects of different levels of intermittent hypoxia (IH) on autophagy in hippocampal neurons, and explore the extent, frequency and duration of IH for researching on autophagy in hippocampal neurons. METHODS: Hippocampal neurons were exposed to different levels of IH. To analyze the oxygen level of neuronal exposure environment, we detected the oxygen concentration in the chamber by O2 analyzer, and monitored the oxygen partial pressure (PO2), carbon dioxide partial pressure (PCO2), and pH in the culture media by blood gas analyzer. After 4-, 8-, and 12-h IH, the morphology and quantity of neurons, as well as the expression of light chain 3 (LC3)-II positive dots were observed by immunofluorescence. The expression of apoptosis marker protein cleaved caspase-3 and autophagy marker protein LC3 were examined by western blotting. RESULTS: The oxygen level in the chamber and the neuronal culture media both reached to the values set previously in three models. The level of cleaved caspase-3 and LC3 had no significant changes in IH-1 group. The morphology and quantity had no significant changes, while the levels of cleaved caspase-3 and LC3 were both increased in IH-2 group. The quantity of neurons was reduced significantly, and the chromatin condensed and nuclei fragmented in IH-3 group. CONCLUSIONS: The effects of varying degrees of IH on autophagy in hippocampal neurons are different. The IH model, hypoxia phase (1.5% O2, 5% CO2, and balance N2) for 5 min and reoxygenation phase (21% O2, 5% CO2, and balance N2) for 10 min, may be the best condition for researching on autophagy in hippocampal neurons. PMID- 28553682 TI - Glycated hemoglobin and sleep apnea syndrome in children: beyond the apnea hypopnea index. AB - PURPOSE: Snoring and obstructive sleep apnea syndrome (OSA) are frequent conditions in pediatrics. Glycated hemoglobin (HbA1C) is a useful homeostatic biomarker of glycemia and may reflect alterations deriving from sleep breathing disorders. The aim of this study was to relate the severity of OSA with blood HbA1C levels in children. METHODS: A descriptive observational study in snoring patients was performed. All patients underwent a sleep study and classified either as simple snorers (apnea-hypopnea index; AHI <= 1 episodies/h) or as OSA patients (AHI > 1 episodes/h). In the following morning, a blood glycemic profile (fasting glucose, insulin, HbA1C, and the HOMA index) was performed to every individual. RESULTS: A total of 48 patients were included. HbA1C levels were shown to be increased in the moderate OSA (AHI > 5 episodes/h) group (5.05 +/- 0.25 vs. 5.24 +/- 0.29%; p = 0.019). Significant correlations were found between HbA1C values and AHI (r = 0.345; p = 0.016) and also with oxygen desaturation index (r = 0.40; p = 0.005). Correlations remained significant after adjusting by age and body mass index. The AHI-associated change in HbA1C was 13.4% (p = 0.011). CONCLUSIONS: In the pediatric population, HbA1C is a biomarker associated with OSA severity, and this relationship is age- and obesity-independent. The fact that this association was observed in snoring patients could help the physician in the distinction between those patients affected with OSA and those with simple snoring. Therefore, HbA1C measurement could play a major role in the diagnosis and the management of the syndrome. PMID- 28553683 TI - Primary tumor location predicts the site of local relapse after nipple-areola complex (NAC) sparing mastectomy. AB - PURPOSE: To assess the oncological safety of nipple-areola complex (NAC) sparing mastectomy in breast cancer patients. METHODS: From 2010 to 2015, 518 breast cancer patients were submitted to NAC sparing mastectomy. Breast MRI and intraoperative assessment of the subareolar (SD) and proximal (ND) nipple ducts were performed to predict NAC involvement. Significant associations between pre- and postoperative variables with SD/ND involvement and with the risk of local recurrence were retrospectively investigated. RESULTS: SD/ND were involved in 26.1% of the cases. Final pathology of SD/ND was predicted by tumor-NAC distance at MRI and intraoperative pathology with 75 and 93% accuracy, respectively. NAC involvement was more frequent in case of positive ND than positive SD (68.3 vs. 38.3%; p = 0.003). Fourteen (2.7%) local relapses developed over a mean follow-up of 33 months. Ki-67 >=25% (p = 0.002) and high tumor grade (p = 0.027) correlated with local recurrence. Most relapses developed in the subcutaneous tissue of the quadrant where the primary tumor was located (12/14; 85.7%). No local relapses occurred in patients who received post-mastectomy radiotherapy as compared to patients who did not, although they had a higher rate of positive surgical margins (40.5 vs. 16.2%; p = 0.000). CONCLUSIONS: NAC involvement can be predicted by MRI and intraoperative pathology of ND/SD. Local recurrences after NAC sparing mastectomy almost invariably develop in the same quadrant where the primary tumor was located and in highly proliferative tumors. PMID- 28553685 TI - Erratum to: an update on addressing important peripheral nerve problems: challenges and potential solutions. PMID- 28553684 TI - Predictors of distress in female breast cancer survivors: a systematic review. AB - PURPOSE: Unmanaged distress has been shown to adversely affect survival and quality of life in breast cancer survivors. Fortunately, distress can be managed and even prevented with appropriate evidence-based interventions. Therefore, the objective of this systematic review was to synthesize the published literature around predictors of distress in female breast cancer survivors to help guide targeted intervention to prevent distress. METHODS: Relevant studies were located by searching MEDLINE, Embase, PsycINFO, and CINAHL databases. Significance and directionality of associations for commonly assessed candidate predictors (n >= 5) and predictors shown to be significant (p <= 0.05) by at least two studies were summarized descriptively. Predictors were evaluated based on the proportion of studies that showed a significant and positive association with the presence of distress. RESULTS: Forty-two studies met the target criteria and were included in the review. Breast cancer and treatment-related predictors were more advanced cancer at diagnosis, treatment with chemotherapy, longer primary treatment duration, more recent transition into survivorship, and breast cancer recurrence. Manageable treatment-related symptoms associated with distress included menopausal/vasomotor symptoms, pain, fatigue, and sleep disturbance. Sociodemographic characteristics that increased the risk of distress were younger age, non-Caucasian ethnicity, being unmarried, and lower socioeconomic status. Comorbidities, history of mental health problems, and perceived functioning limitations were also associated. Modifiable predictors of distress were lower physical activity, lower social support, and cigarette smoking. CONCLUSIONS: This review established a set of evidence-based predictors that can be used to help identify women at higher risk of experiencing distress following completion of primary breast cancer treatment. PMID- 28553686 TI - Legal hurdles for gastroenterologists in India. AB - Litigation and compensation claims have started occurring with increasing frequency against gastroenterologists in India. A study of few such cases decided by Indian Courts shows that commonest reason for allegations of negligence being upheld by Indian Courts is an improper consent being taken. Professional organisations need to focus on these issues more aggressively than has been done in the past. Judgments which do not appear to be in conformity with standard medical practices need to be challenged in higher courts, failing in which they would become precedents for future similar judgments. PMID- 28553687 TI - Malignant mediastinal lymphadenopathy detected by endoscopic ultrasound and guided fine needle aspiration in patients with resectable pancreaticobiliary cancer. AB - BACKGROUND: Resection surgery for pancreaticobiliary malignancies carries significant morbidity and mortality. Hence, preoperative assessment to exclude unresectable disease is mandatory. CT abdomen is the primary modality for staging of pancreaticobiliary cancers. However, some patients have malignant mediastinal lymphadenopathy (MML), which may be detected on endoscopic ultrasound (EUS) but not on CT scan. METHODS: We prospectively evaluated 75 consecutive patients (median age 54 years: 44 men) with a diagnosis of resectable pancreaticobiliary cancer (carcinoma gallbladder, carcinoma pancreas, cholangiocarcinoma, or periampullary carcinoma) for the presence of MML using EUS by an experienced endosonographer. If a lymph node had one or more features suggestive of malignancy, i.e. size exceeding 1 cm, hypoechoic appearance, a round shape, and regular margins, it was subjected to EUS-FNA. RESULTS: In seven (9.3%; 95% confidence intervals: 3.8% to 18.2%) of the 75 patients, EUS revealed enlarged mediastinal lymph nodes. The location of these lymph nodes was subcarinal in three, paraesophageal in two, and paratracheal in one patient; another patient had lymph nodes at two sites, i.e. the subcarinal and aortopulmonary window. In four of these seven patients, FNA documented the presence of MML. The overall rate of pathologically proven MML was 4/75 (5.3%; 95% CI [1.4% to 13%]). CONCLUSION: EUS-FNA diagnosed MML in 5.3% of patients with pancreaticobiliary cancer. It may be useful to consider EUS assessment in patients with otherwise resectable pancreaticobiliary malignancy. PMID- 28553688 TI - Clinical Features in Patients with Microdeletion at 6q14.1-q15. PMID- 28553689 TI - Management of Neurogenic Bladder. AB - This article provides a comprehensive summary of the clinical approach, investigative modalities and management of a child with neurogenic bladder disease due to myelodysplasia. It is aimed at pediatric physicians and surgeons working in developing nations. The methodologies suggested are simple and can be practised even in resource poor regions. The goal of management is avoidance of Chronic kidney disease and for this, meticulous bladder management is the key. PMID- 28553690 TI - Neonatal Rotaviral Encephalitis. PMID- 28553691 TI - Molecular and immune response characterizations of a novel Bax inhibitor-1 gene in pufferfish, Takifugu obscurus. AB - Apoptosis plays a crucial role in many biological processes, including development, cellular homeostasis, and immune responses. Bax inhibitor-1 (BI-1) is an anti-apoptotic protein that protects cells from endoplasmic reticulum stress-induced apoptosis. In this study, a BI-1 gene from the pufferfish Takifugu obscurus (Pf-BI-1) was identified and characterized. The full length of Pf-BI-1 cDNA was 1387 bp, including a 5'-UTR of 82 bp, a 3'-UTR of 591 bp containing a poly-(A) tail, and an open reading frame (ORF) of 714 bp that encodes a polypeptide of 237 amino acids. Pf-BI-1 was ubiquitously expressed in various tissues, with the highest expression levels in the blood, brain, and gill. The expression of Pf-BI-1 was up-regulated in a time-dependent manner after heat shock stress, ammonia stress, and bacterial challenge. Intracellular localization revealed that Pf-BI-1 was primarily localized in the cell cytoplasm. Furthermore, over-expression of Pf-BI-1 could active NF-kB reporter genes in HeLa cells. These results indicated that Pf-BI-1 may be involved in the apoptosis and immunity process against ambient stressors in pufferfish. PMID- 28553692 TI - Preventing traumatic childbirth experiences: 2192 women's perceptions and views. AB - The purpose of this study is to explore and quantify perceptions and experiences of women with a traumatic childbirth experience in order to identify areas for prevention and to help midwives and obstetricians improve woman-centered care. A retrospective survey was conducted online among 2192 women with a self-reported traumatic childbirth experience. Women were recruited in March 2016 through social media, including specific parent support groups. They filled out a 35-item questionnaire of which the most important items were (1) self-reported attributions of the trauma and how they believe the traumatic experience could have been prevented (2) by the caregivers or (3) by themselves. The responses most frequently given were (1) Lack and/or loss of control (54.6%), Fear for baby's health/life (49.9%), and High intensity of pain/physical discomfort (47.4%); (2) Communicate/explain (39.1%), Listen to me (more) (36.9%), and Support me (more/better) emotionally/practically (29.8%); and (3) Nothing (37.0%), Ask for (26.9%), or Refuse (16.5%) certain interventions. Primiparous participants chose High intensity of pain/physical discomfort, Long duration of delivery, and Discrepancy between expectations and reality more often and Fear for own health/life, A bad outcome, and Delivery went too fast less often than multiparous participants. Women attribute their traumatic childbirth experience primarily to lack and/or loss of control, issues of communication, and practical/emotional support. They believe that in many cases, their trauma could have been reduced or prevented by better communication and support by their caregiver or if they themselves had asked for or refused interventions. PMID- 28553693 TI - Assessment of right ventricular longitudinal strain by 2D speckle tracking imaging compared with RV function and hemodynamics in pulmonary hypertension. AB - The right ventricular longitudinal strain (RVLS) of pulmonary hypertension (PH) patients and its relationship with RV function parameters measured by echocardiography and hemodynamic parameters measured by right heart catheterization was investigated. According to the WHO functional class (FC), 66 PH patients were divided into FC I/II (group 1) and III/IV (group 2). RV function parameters were measured by echocardiographic examinations. Hemodynamic parameters were obtained by right heart catheterization. Patients in group 2 had higher systolic pulmonary artery pressure (sPAP; P < 0.05) than patients in group (1) significant between-group differences were observed in global RVLS (RVLSglobal), free wall RVLS (RVLSFW; P < 0.01), and RV conventional function parameters (all P < 0.05). Moreover, mPAP and PVR increased remarkably and CI decreased significantly in group (2) RVLSglobal had a positive correlation with 6 min walking distance (6MWD; r = 0.492, P < 0.001) and N-terminal pro-brain natriuretic peptide (NT-proBNP; r = 0.632, P < 0.001), while RVLSFW had a positive correlation with 6MWD (r = 0.483, P < 0.001) and NT-proBNP (r = 0.627, P < 0.001). Hemodynamics analysis revealed that RVLSglobal had a positive correlation with mPAP (r = 0.594, P < 0.001), PVR (r = 0.573, P < 0.001) and CI (r = 0.366, P = 0.003), while RVLSFW had a positive correlation with mPAP (r = 0.597, P < 0.001), PVR (r = 0.577, P < 0.001) and CI (r = 0.369, P = 0.002). According to receiver operating characteristic curves, the optimal cut-off values of RVLSglobal (-15.0%) and RVLSFW (-15.3%) for prognosis detection with good sensitivity and specificity. Evidence has shown that RVLS measurement can provide the much-needed and reliable information on RV function and hemodynamics. Therefore, this qualifies as a patient-friendly approach for the clinical management of PH patients. PMID- 28553694 TI - Investigation of different classifiers and channel configurations of a mobile P300-based brain-computer interface. AB - Innovative methods and new technologies have significantly improved the quality of our daily life. However, disabled people, for example those that cannot use their arms and legs anymore, often cannot benefit from these developments, since they cannot use their hands to interact with traditional interaction methods (such as mouse or keyboard) to communicate with a computer system. A brain computer interface (BCI) system allows such a disabled person to control an external device via brain waves. Past research mostly dealt with static interfaces, which limit users to a stationary location. However, since we are living in a world that is highly mobile, this paper evaluates a speller interface on a mobile phone used in a moving condition. The spelling experiments were conducted with 14 able-bodied subjects using visual flashes as the stimulus to spell 47 alphanumeric characters (38 letters and 9 numbers). This data was then used for the classification experiments. In par- ticular, two research directions are pursued. The first investigates the impact of different classification algorithms, and the second direction looks at the channel configuration, i.e., which channels are most beneficial in terms of achieving the highest classification accuracy. The evaluation results indicate that the Bayesian Linear Discriminant Analysis algorithm achieves the best accuracy. Also, the findings of the investigation on the channel configuration, which can potentially reduce the amount of data processing on a mobile device with limited computing capacity, is especially useful in mobile BCIs. PMID- 28553695 TI - Metal speciation in sediment and bioaccumulation in Meretrix lyrata in the Tien Estuary in Vietnam. AB - The concentrations of seven toxic metals (cadmium (Cd), nickel (Ni), chromium (Cr), arsenic (As), lead (Pb), copper (Cu), and zinc (Zn)) were determined in sediments and the soft tissues of a bivalve species (Meretrix lyrata) collected from the Tien Estuary in Tien Giang Province, South Vietnam. The total metal concentrations in sediments (mg/kg dry weight) increased as Cd (0.06) < Cu (5.0) < Pb (13.9) < As (16.3) < Ni (24) < Cr (50) < Zn (62). Speciation analysis revealed that these metals existed mainly in the residual fraction (43-94%), followed by the Fe-Mn oxide-bound (5-35%) and organic/sulfide-bound (0.6-9.2%) fractions. The metal concentrations in M. lyrata (mg/kg dry weight) were in the ranges of 1.3-1.9 (Cd), 1.5-2.8 (Ni), 1.8-3.4 (Cr), 11-16 (As), 0.3-0.6 (Pb), 6.9 8.7 (Cu), and 95-128 (Zn), which are safe for human consumption. The order of the mean biota-sediment accumulation factor (BSAF) of the metals in the non-residual fractions of the sediment for M. lyrata was Cd > Cu > As > Zn > Cr > Ni > Pb. The Risk Assessment Codes (RACs) suggest that the highest mobility of Cd (with RAC = 37%) poses greater environmental risk to aquatic biota. Correlation analysis results show that M. lyrata can be used as a biomonitor of Cd and Cu pollution in the exchangeable, acid-soluble, and non-residual sediment fractions. PMID- 28553696 TI - Acidovorax lacteus sp. nov., isolated from a culture of a bloom-forming cyanobacterium (Microcystis sp.). AB - A novel Gram-negative, rod-shaped and motile bacterial strain, designated strain M36T, was isolated from a culture of a bloom-forming cyanobacterium, Microcystis sp., collected from a eutrophic lake in Korea. Its taxonomic position was investigated by using a polyphasic taxonomic approach. The isolate was found to grow aerobically at 15-42 degrees C (optimum 25 degrees C), pH 7.0-11.0 (optimum pH 8.0) and in the presence of 0-1.0% (w/v) NaCl (optimum 0% NaCl) on R2A medium. The phylogenetic analysis based on 16S rRNA gene sequences revealed that the strain M36T is closely related to Acidovorax anthurii DSM 16745T (98.1%), Acidovorax konjaci DSM 7481T (97.7%) and Acidovorax avenae DSM 7227T (97.0%) and also formed a clear phylogenetic lineage with other Acidovorax species. DNA-DNA relatedness between strain M36T and the closely related species of the genus Acidovorax was <30%. The major fatty acid components identified included summed feature 3 (C16:1 omega7c and/or C16:1 omega6c), C16:0 and summed feature 8 (C18:0 omega7c and/or C18:0 omega6c). The DNA G+C content of strain M36T was determined to be 66.8 mol%. Based on above polyphasic evidence, strain M36T is concluded to represent a new species of genus Acidovorax, for which the name Acidovorax lacteus sp. nov. is proposed. The type strain is M36T (=KCTC 52220T = JCM 31890T). PMID- 28553697 TI - Fungal decomposers of leaf litter from an invaded and native mountain forest of NW Argentina. AB - The impact of plant species invasions on the abundance, composition and activity of fungal decomposers of leaf litter is poorly understood. In this study, we isolated and compared the relative abundance of ligninocellulolytic fungi of leaf litter mixtures from a native forest and a forest invaded by Ligustrum lucidum in a lower mountain forest of Tucuman, Argentina. In addition, we evaluated the relationship between the relative abundance of ligninocellulolytic fungi and properties of the soil of both forest types. Finally, we identified lignin degrading fungi and characterized their polyphenol oxidase activities. The relative abundance of ligninocellulolytic fungi was higher in leaf litter mixtures from the native forest. The abundance of cellulolytic fungi was negatively related with soil pH while the abundance of ligninolytic fungi was positively related with soil humidity. We identified fifteen genera of ligninolytic fungi; four strains were isolated from both forest types, six strains only from the invaded forest and five strains were isolated only from the native forest. The results found in this study suggest that L. Lucidum invasion could alter the abundance and composition of fungal decomposers. Long-term studies that include an analysis of the nutritional quality of litter are needed, for a more complete overview of the influence of L. Lucidum invasion on fungal decomposers and on leaf litter decomposition. PMID- 28553698 TI - Megadenus atrae n. sp., an endoparasitic eulimid gastropod (Mollusca) from the black sea cucumber Holothuria atra Jaeger (Aspidochirotida: Holothuriidae) in the Indo-West Pacific. AB - An eulimid gastropod, Megadenus atrae n. sp., endoparasitic in the cloacal chamber of the black sea cucumber Holothuria atra Jaeger is described from Okinawa, Japan, as the fifth species of the genus. Conspecific specimens have also been found from southeast India, northeast Australia and New Caledonia. The generic assignment is justified by the presence of (i) a thick, long proboscis that bears a large fold (pseudopallium) near the base and a collar-like structure at the middle, (ii) a thin, globose shell that is covered by the pseudopallium, and (iii) sexual dimorphism with the female generally larger than the male. The new species is distinguishable from the four previously described congeners by its cauldron-shaped pseudopallium, moderately-developed collar of the proboscis and rounded basal lip of the shell. The comparisons of the size and sex of solitary and paired individuals support a previous hypothesis that the species of Megadenus Rosen, 1910 are protandrous with environmental sex determination. The present species occurs mostly as monogamous pairs despite its very low population density, implying that the presence of a conspecific individual acts as a cue for larval settlement. Both mechanisms would increase individual reproductive success in such permanent parasites with low prevalence and abundance as the species of Megadenus. PMID- 28553699 TI - Generation of CMAHKO/GTKO/shTNFRI-Fc/HO-1 quadruple gene modified pigs. AB - As an alternative source of organs for transplantation into humans, attention has been directed to pigs due to their similarities in biological features and organ size. However, severe immune rejection has prevented successful xenotransplantation using pig organs and tissues. To overcome immune rejection, recently developed genetic engineering systems such as TALEN coupled with somatic cell nuclear transfer (SCNT) to make embryos could be used to produce pigs compatible with xenotransplantation. We used the TALEN system to target the non Gal antigen cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) gene in pigs that is naturally deleted in humans. Gal-deleted cells expressing both soluble human tumor necrosis factor receptor I IgG1-Fc (shTNFRI-Fc) and human hemagglutinin -tagged-human heme oxygenase-1 (hHO-1) were transfected with a TALEN target for CMAH. Cells lacking CMAH were negatively selected using N glyconeuraminic acid (Neu5Gc)/magnetic beads and the level of Neu5Gc expression of isolated cells were analyzed by FACS and DNA sequencing. Cloned embryos using 3 different genetically modified cell clones were respectively transferred into 3 recipients, with 55.6% (5/9) becoming pregnant and three cloned pigs were produced. Successful genetic disruption of the CMAH gene was confirmed by sequencing, showing lack of expression of CMAH in tail-derived fibroblasts of the cloned piglets. Besides decreased expression of Neu5Gc in piglets produced by SCNT, antibody-mediated complement-dependent cytotoxicity assays and natural antibody binding for examining immuno-reactivity of the quadruple gene modified pigs derived from endothelial cells and fibroblasts were reduced significantly compared to those of wild type animals. We conclude that by combining the TALEN system and transgenic cells, targeting of multiple genes could be useful for generating organs for xenotransplantation. We produced miniature pigs with quadruple modified genes CMAHKO/GTKO/shTNFRI-Fc/hHO-1 that will be suitable for xenotransplantation by overcoming hyperacute, acute and anti-inflammatory rejection. PMID- 28553700 TI - Minimally invasive radioguided parathyroid surgery using low-dose Tc-99m-MIBI - comparison with standard high dose. AB - INTRODUCTION: Surgery remains the most effective treatment for primary hyperparathyroidism (PHPT). Minimally invasive radioguided parathyroidectomy (MIRP) is a common technique for detecting and excising abnormal parathyroid glands. The aim of this study was to compare injections of low-dose and high-dose (99m) Tc methoxy isobutyl isonitrile (MIBI) for intraoperative localisation of parathyroid adenomas by means of a gamma probe in patients with primary hyperparathyroidism (PHPT). MATERIAL AND METHODS: Thirty patients with PHPT and a preoperative diagnosis of parathyroid adenoma were enrolled between 2010 and 2012. They were considered as Group B and underwent MIRP using 5 mCi Tc-99m MIBI, and their perioperative data were compared with twenty patients treated with conventional 20 mCi Tc-99m MIBI previously (Group A). RESULTS: Group A was made up of 20 patients (mean age, 41.55 years; 14 women and 6 men), and group B included 30 patients (mean age, 40.43 years; 19 women and 11 men). The mean serum parathyroid hormone (PTH) and calcium values were recorded pre- and postoperatively. The mean follow-up period for the patients in the two groups was 18.4 and 16.5 months, respectively. Pre-operative evaluation demonstrated that the groups were statistically similar. Intraoperative data and success rate of surgery showed no difference between the two groups. No significant complication was detected after surgeries and no recurrence happened in either of the two groups during the follow-up period. CONCLUSIONS: A new protocol of MIRP using low doses of Tc-99m-MIBI resulted in an excellent success rate. Comparing results of the study, we conclude that low-dose Tc-99m-MIBI may be preferred for identification of parathyroid adenomas intraoperatively by means of a gamma probe in PHPT patients because it appears to be as effective as high-dose Tc-99m-MIBI. PMID- 28553701 TI - Opioid antagonists with minimal sedation for opioid withdrawal. AB - BACKGROUND: Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment. OBJECTIVES: To assess the effects of opioid antagonists plus minimal sedation for opioid withdrawal. Comparators were placebo as well as more established approaches to detoxification, such as tapered doses of methadone, adrenergic agonists, buprenorphine and symptomatic medications. SEARCH METHODS: We updated our searches of the following databases to December 2016: CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science. We also searched two trials registers and checked the reference lists of included studies for further references to relevant studies. SELECTION CRITERIA: We included randomised and quasi-randomised controlled clinical trials along with prospective controlled cohort studies comparing opioid antagonists plus minimal sedation versus other approaches or different opioid antagonist regimens for withdrawal in opioid-dependent participants. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: Ten studies (6 randomised controlled trials and 4 prospective cohort studies, involving 955 participants) met the inclusion criteria for the review. We considered 7 of the 10 studies to be at high risk of bias in at least one of the domains we assessed.Nine studies compared an opioid antagonist-adrenergic agonist combination versus a treatment regimen based primarily on an alpha2-adrenergic agonist (clonidine or lofexidine). Other comparisons (placebo, tapered doses of methadone, buprenorphine) made by included studies were too diverse for any meaningful analysis. This review therefore focuses on the nine studies comparing an opioid antagonist (naltrexone or naloxone) plus clonidine or lofexidine versus treatment primarily based on clonidine or lofexidine.Five studies took place in an inpatient setting, two studies were in outpatients with day care, two used day care only for the first day of opioid antagonist administration, and one study described the setting as outpatient without indicating the level of care provided.The included studies were heterogeneous in terms of the type of opioid antagonist treatment regimen, the comparator, the outcome measures assessed, and the means of assessing outcomes. As a result, the validity of any estimates of overall effect is doubtful, therefore we did not calculate pooled results for any of the analyses.The quality of the evidence for treatment with an opioid antagonist-adrenergic agonist combination versus an alpha2-adrenergic agonist is very low. Two studies reported data on peak withdrawal severity, and four studies reported data on the average severity over the period of withdrawal. Peak withdrawal induced by opioid antagonists in combination with an adrenergic agonist appears to be more severe than withdrawal managed with clonidine or lofexidine alone, but the average severity over the withdrawal period is less. In some situations antagonist-induced withdrawal may be associated with significantly higher rates of treatment completion compared to withdrawal managed with adrenergic agonists. However, this result was not consistent across studies, and the extent of any benefit is highly uncertain.We could not extract any data on the occurrence of adverse events, but two studies reported delirium or confusion following the first dose of naltrexone. Delirium may be more likely with higher initial doses and with naltrexone rather than naloxone (which has a shorter half-life), but we could not confirm this from the available evidence.Insufficient data were available to make any conclusions on the best duration of treatment. AUTHORS' CONCLUSIONS: Using opioid antagonists plus alpha2 adrenergic agonists is a feasible approach for managing opioid withdrawal. However, it is unclear whether this approach reduces the duration of withdrawal or facilitates transfer to naltrexone treatment to a greater extent than withdrawal managed primarily with an adrenergic agonist.A high level of monitoring and support is desirable for several hours following administration of opioid antagonists because of the possibility of vomiting, diarrhoea and delirium.Using opioid antagonists to induce and accelerate opioid withdrawal is not currently an active area of research or clinical practice, and the research community should give greater priority to investigating approaches, such as those based on buprenorphine, that facilitate the transition to sustained-release preparations of naltrexone. PMID- 28553702 TI - Music therapy for people with schizophrenia and schizophrenia-like disorders. AB - BACKGROUND: Music therapy is a therapeutic approach that uses musical interaction as a means of communication and expression. Within the area of serious mental disorders, the aim of the therapy is to help people improve their emotional and relational competencies, and address issues they may not be able to using words alone. OBJECTIVES: To review the effects of music therapy, or music therapy added to standard care, compared with placebo therapy, standard care or no treatment for people with serious mental disorders such as schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Study-Based Register (December 2010 and 15 January, 2015) and supplemented this by contacting relevant study authors, handsearching of music therapy journals and manual searches of reference lists. SELECTION CRITERIA: All randomised controlled trials (RCTs) that compared music therapy with standard care, placebo therapy, or no treatment. DATA COLLECTION AND ANALYSIS: Review authors independently selected, quality assessed and data extracted studies. We excluded data where more than 30% of participants in any group were lost to follow-up. We synthesised non-skewed continuous endpoint data from valid scales using a standardised mean difference (SMD). We employed a fixed-effect model for all analyses. If statistical heterogeneity was found, we examined treatment dosage (i.e. number of therapy sessions) and treatment approach as possible sources of heterogeneity. MAIN RESULTS: Ten new studies have been added to this update; 18 studies with a total 1215 participants are now included. These examined effects of music therapy over the short, medium, and long-term, with treatment dosage varying from seven to 240 sessions. Overall, most information is from studies at low or unclear risk of biasA positive effect on global state was found for music therapy compared to standard care (medium term, 2 RCTs, n = 133, RR 0.38 95% confidence interval (CI) 0.24 to 0.59, low quality evidence, number needed to treat for an additional beneficial outcome NNTB 2, 95% CI 2 to 4). No binary data were available for other outcomes. Medium term continuous data identified good effects for music therapy on negative symptoms using the Scale for the Assessment of Negative Symptoms (3 RCTs, n = 177, SMD - 0.55 95% CI -0.87 to -0.24, low-quality evidence). General mental state endpoint scores on the Positive and Negative Symptoms Scale were better for music therapy (2 RCTs, n = 159, SMD -0.97 95% CI -1.31 to -0.63, low-quality evidence), as were average endpoint scores on the Brief Psychiatric Rating Scale (1 RCT, n = 70, SMD -1.25 95% CI -1.77 to -0.73, moderate-quality evidence). Medium-term average endpoint scores using the Global Assessment of Functioning showed no effect for music therapy on general functioning (2 RCTs, n = 118, SMD 0.19 CI -0.56 to 0.18, moderate-quality evidence). However, positive effects for music therapy were found for both social functioning (Social Disability Screening Schedule scores; 2 RCTs, n = 160, SMD -0.72 95% CI -1.04 to -0.40), and quality of life (General Well-Being Schedule scores: 1 RCT, n = 72, SMD 1.82 95% CI 1.27 to 2.38, moderate-quality evidence). There were no data available for adverse effects, service use, engagement with services, or cost. AUTHORS' CONCLUSIONS: Moderate- to low-quality evidence suggests that music therapy as an addition to standard care improves the global state, mental state (including negative and general symptoms), social functioning, and quality of life of people with schizophrenia or schizophrenia-like disorders. However, effects were inconsistent across studies and depended on the number of music therapy sessions as well as the quality of the music therapy provided. Further research should especially address the long-term effects of music therapy, dose-response relationships, as well as the relevance of outcome measures in relation to music therapy. PMID- 28553703 TI - Photothermal Conversion Triggered Precisely Targeted Healing of Epoxy Resin Based on Thermoreversible Diels-Alder Network and Amino-Functionalized Carbon Nanotubes. AB - In the present work, we demonstrated the recyclability and precisely targeted reparability of amino functionalized multiwall carbon nanotubes-epoxy resin based on dynamic covalent Diels-Alder (DA) network (NH2-MWCNTs/DA-epoxy) by exploring the photothermal conversion of CNTs to trigger the reactions of dynamic chemical bonds. The covalent cross-linked networks of NH2-MWCNTs/DA-epoxy resin change their topology to linear polymer by thermally activated reverse Diels-Alder (r DA) reactions at high temperatures, which endues the resin with almost 100% recyclability. The self-healing property of the epoxy resin was confirmed by the complete elimination of cracks after the reconstruction of DA network induced by heating or near-infrared (NIR) irradiation. For heat-triggered self-healing process, heat energy may also act on those uninjured parts of the resin and cause the dissociation of the whole DA network. Therefore, redundant r-DA and DA reactions, which have no contribution to self-healing, are also triggered during thermal treatment, resulting in not only a waste of energy but also the deformation of the sample under external force. Meanwhile, for the NIR-triggered self-healing process, the samples can maintain well their original shape without observable deformation after irradiation. The NIR-triggered healing process, which uses MWCNTs as the photothermal convertor, have very good regional controllability by simply tuning the MWCNTs content, the distance from NIR laser source to sample, and the laser power. The injured samples can be locally repaired with high precision and efficiency without an obvious influence on those uninjured parts. PMID- 28553704 TI - One-Step Solvent Evaporation-Assisted 3D Printing of Piezoelectric PVDF Nanocomposite Structures. AB - Development of a 3D printable material system possessing inherent piezoelectric properties to fabricate integrable sensors in a single-step printing process without poling is of importance to the creation of a wide variety of smart structures. Here, we study the effect of addition of barium titanate nanoparticles in nucleating piezoelectric beta-polymorph in 3D printable polyvinylidene fluoride (PVDF) and fabrication of the layer-by-layer and self supporting piezoelectric structures on a micro- to millimeter scale by solvent evaporation-assisted 3D printing at room temperature. The nanocomposite formulation obtained after a comprehensive investigation of composition and processing techniques possesses a piezoelectric coefficient, d31, of 18 pC N-1, which is comparable to that of typical poled and stretched commercial PVDF film sensors. A 3D contact sensor that generates up to 4 V upon gentle finger taps demonstrates the efficacy of the fabrication technique. Our one-step 3D printing of piezoelectric nanocomposites can form ready-to-use, complex-shaped, flexible, and lightweight piezoelectric devices. When combined with other 3D printable materials, they could serve as stand-alone or embedded sensors in aerospace, biomedicine, and robotic applications. PMID- 28553705 TI - Origin of Open-Circuit Voltage Loss in Polymer Solar Cells and Perovskite Solar Cells. AB - Herein, the open-circuit voltage (VOC) loss in both polymer solar cells and perovskite solar cells is quantitatively analyzed by measuring the temperature dependence of VOC to discuss the difference in the primary loss mechanism of VOC between them. As a result, the photon energy loss for polymer solar cells is in the range of about 0.7-1.4 eV, which is ascribed to temperature-independent and dependent loss mechanisms, while that for perovskite solar cells is as small as about 0.5 eV, which is ascribed to a temperature-dependent loss mechanism. This difference is attributed to the different charge generation and recombination mechanisms between the two devices. The potential strategies for the improvement of VOC in both solar cells are further discussed on the basis of the experimental data. PMID- 28553706 TI - Direct Imaging of Protein Stability and Folding Kinetics in Hydrogels. AB - We apply fast relaxation imaging (FReI) as a novel technique for investigating the folding stability and dynamics of proteins within polyacrylamide hydrogels, which have diverse and widespread uses in biotechnology. FReI detects protein unfolding in situ by imaging changes in fluorescence resonance energy transfer (FRET) after temperature jump perturbations. Unlike bulk measurements, diffraction-limited epifluorescence imaging combined with fast temperature perturbations reveals the impact of local environment effects on protein biomaterial compatibility. Our experiments investigated a crowding sensor protein (CrH2) and phosphoglycerate kinase (PGK), which undergoes cooperative unfolding. The crowding sensor quantifies the confinement effect of the cross-linked hydrogel: the 4% polyacrylamide hydrogel is similar to aqueous solution (no confinement), while the 10% hydrogel is strongly confining. FRAP measurements and protein concentration gradients in the 4% and 10% hydrogels further support this observation. PGK reveals that noncovalent interactions of the protein with the polymer surface are more important than confinement for determining protein properties in the gel: the mere presence of hydrogel increases protein stability, speeds up folding relaxation, and promotes irreversible binding to the polymer even at the solution-gel interface, whereas the difference between the 4% and the 10% hydrogels is negligible despite their large difference in confinement. The imaging capabilities of FReI, demonstrated to be diffraction limited, further revealed spatially homogeneous protein unfolding across the hydrogels at 500 nm length scales and revealed differences in protein properties at the gel-solution boundary. PMID- 28553708 TI - High-Performance Zinc Tin Oxide Semiconductor Grown by Atmospheric-Pressure Mist CVD and the Associated Thin-Film Transistor Properties. AB - Zinc tin oxide (Zn-Sn-O, or ZTO) semiconductor layers were synthesized based on solution processes, of which one type involves the conventional spin coating method and the other is grown by mist chemical vapor deposition (mist-CVD). Liquid precursor solutions are used in each case, with tin chloride and zinc chloride (1:1) as solutes in solvent mixtures of acetone and deionized water. Mist-CVD ZTO films are mostly polycrystalline, while those synthesized by spin coating are amorphous. Thin-film transistors based on mist-CVD ZTO active layers exhibit excellent electron transport properties with a saturation mobility of 14.6 cm2/(V s), which is superior to that of their spin-coated counterparts (6.88 cm2/(V s)). X-ray photoelectron spectroscopy (XPS) analyses suggest that the mist CVD ZTO films contain relatively small amounts of oxygen vacancies and, hence, lower free-carrier concentrations. The enhanced electron mobility of mist-CVD ZTO is therefore anticipated to be associated with the electronic band structure, which is examined by X-ray absorption near-edge structure (XANES) analyses, rather than the density of electron carriers. PMID- 28553707 TI - Wafer-Scale Synthesized MoS2/Porous Silicon Nanostructures for Efficient and Selective Ethanol Sensing at Room Temperature. AB - This paper presents the performance of a highly selective ethanol sensor based on MoS2-functionalized porous silicon (PSi). The uniqueness of the sensor includes its method of fabrication, wafer scalability, affinity for ethanol, and high sensitivity. MoS2 nanoflakes (NFs) were synthesized by sulfurization of oxidized radio-frequency (RF)-sputtered Mo thin films. The MoS2 NFs synthesis technique is superior in comparison to other methods, because it is chip-scalable and low in cost. Interdigitated electrodes (IDEs) were used to record resistive measurements from MoS2/PSi sensors in the presence of volatile organic compound (VOC) and moisture at room temperature. With the effect of MoS2 on PSi, an enhancement in sensitivity and a selective response for ethanol were observed, with a minimum detection limit of 1 ppm. The ethanol sensitivity was found to increase by a factor of 5, in comparison to the single-layer counterpart levels. This impressive response is explained on the basis of an analytical resistive model, the band gap of MoS2/PSi/Si, the interface formed between MoS2 and PSi, and the chemical interaction of the vapor molecules and the surface. This two-dimensional (2D) composite material with PSi paves the way for efficient, highly responsive, and stable sensors. PMID- 28553709 TI - Self-Assembled Graphene Film as Low Friction Solid Lubricant in Macroscale Contact. AB - Promoted by the demand for solid lubricants, graphene has been proved to be a promising material for potential applications in reducing friction and wear. Here, a novel lubricating system where graphene sliding against graphene is developed to achieve low friction in macroscale contact. And the large area graphene film used here were prepared by a unique self-assembly technique based on Marangoni effect. Low friction coefficient of about 0.05 is obtained, and it is demonstrated that the film thickness, applied normal load and annealing process all have important influences on the tribological properties of graphene. The expedient fabrication procedure of large-area graphene film with excellent transferability and high-performance friction-reducing behaviors of the developed lubricating system both have a promising perspective in engineering applications. PMID- 28553710 TI - Black Phosphorus Quantum Dot Induced Oxidative Stress and Toxicity in Living Cells and Mice. AB - Black phosphorus (BP), as an emerging successor to layered two-dimensional materials, has attracted extensive interest in cancer therapy. Toxicological studies on BP are of great importance for potential biomedical applications, yet not systemically explored. Herein, toxicity and oxidative stress of BP quantum dots (BPQDs) at cellular, tissue, and whole-body levels are evaluated by performing the systemic in vivo and in vitro experiments. In vitro investigations show that BPQDs at high concentration (200 MUg/mL) exhibit significant apoptotic effects on HeLa cells. In vivo investigations indicate that oxidative stress, including lipid peroxidation, reduction of catalase activity, DNA breaks, and bone marrow nucleated cells (BMNC) damage, can be induced by BPQDs transiently but recovered gradually to healthy levels. No apparent pathological damages are observed in all organs, especially in the spleen and kidneys, during the 30-day period. This work clearly shows that BPQDs can cause acute toxicities by oxidative stress responses, but the inflammatory reactions can be recovered gradually with time for up to 30 days. Thus, BPQDs do not give rise to long-term appreciable toxicological responses. PMID- 28553711 TI - The Hydration Effect and Selectivity of Alkali Metal Ions on Poly(ethylene glycol) Models in Cyclic and Linear Topology. AB - The effects of hydration and alkali metal ion (K+, Na+, Li+) bonding to two structural variants of poly(ethylene glycol) (PEG), viz., a cyclic (18-crown-6) configuration and a linear chain model with two different lengths, are studied by ab initio density functional theory calculations. A total of 24 structural models are constructed, with different conformations of the PEG chain and its molecular environment. Detailed comparisons of the results enable us to obtain conclusive evidence on the effects of the different components of the solution environment on the PEG structural variants in terms of the binding energy, partial charge distribution, solvation effect, interfacial hydrogen bonding, and cohesion between different structural units in the system composed of PEG, alkali metal ions, and water. On the basis of these comprehensive and precise comparisons, we conclude that the ion-PEG interaction is strongly influenced by the presence of solvent and that the charge transfer in the PEG complex depends crucially on its topology, the type of alkali metal ion, and the solvent. The interaction between alkali metal ions in the two PEG models does not always scale with the ion size but depends on their local environment. PMID- 28553712 TI - Shape Memory Polymers Based on Supramolecular Interactions. AB - Shape memory polymers (SMPs), with the capability to change from one or more temporary shapes to predetermined shapes in response to an external stimulus, have attracted much interest from both academia and industries. When introducing supramolecular interactions that have been featured as dynamic and reversible into the design of novel SMPs, intriguing and unique functionalities have been engendered and thereby broaden the potential applications of the SMPs to new territories. In this review, we summarize recent progress made in SMPs based on supramolecular interactions, provide insight into the material design and shape memory mechanism, elucidate and evaluate their properties and performance, and point out opportunities and applications of SMPs. PMID- 28553713 TI - Enzymatic Modification of Corn Starch Influences Human Fecal Fermentation Profiles. AB - Enzymatically modified starches have been widely used in food applications to develop new products, but information regarding digestion and fecal fermentation of these products is sparse. The objective of this study was to determine the fermentation properties of corn starch modified with alpha-amylase, amyloglucosidase, or cyclodextrin glycosyltransferase and the possible role of hydrolysis products. Samples differed in their digestibility and availability to be fermented by the microbiota, resulting in differences in microbial metabolites produced during in vitro fermentation. The presence or absence of hydrolysis products and gelatinization affected starch composition and subsequent metabolite production by the microbiota. Amyloglucosidase-treated starch led to the greatest production of short- and branched-chain fatty acid production by the microbiota. Results from this study could be taken into consideration to confirm the possible nutritional claims and potential health benefits of these starches as raw ingredients for food development. PMID- 28553714 TI - Detection of microRNA: A Point-of-Care Testing Method Based on a pH-Responsive and Highly Efficient Isothermal Amplification. AB - Laborious and costly detection of miRNAs has brought challenges to its practical applications, especially for home health care, rigorous military medicine, and the third world. In this work, we present a pH-responsive miRNA amplification method, which allows the detection of miRNA just using a pH test paper. The operation is easy and no other costly instrument is involved, making the method very friendly. In our strategy, a highly efficient isothermal amplification of miRNA is achieved using an improved netlike rolling circle amplification (NRCA) technique. Large amounts of H+ can be produced as a byproduct during the amplification to induce significant changes of pH, which can be monitored directly using a pH test paper or pH-sensitive indicators. The degree of color changes depends on the amount of miRNA, making it possible for quantitative analysis. As an example, the method is successfully applied to quantify a miRNA (miR-21) in cancer cells. The results agree well with that from the prevalent qRT PCR analysis. It is the first time that a paper-based point-of-care testing (POCT) is developed for the detection of miRNAs, which might promote the popularization of miRNAs working as biomarkers for diagnostic purposes. PMID- 28553715 TI - Novel Approach for Characterizing pH-Dependent Uptake of Ionizable Chemicals in Aquatic Organisms. AB - Here, we present and evaluate a combined experimental and modeling approach for characterizing the uptake of ionizable chemicals from water and sediments into aquatic organisms under different pH conditions. We illustrate and evaluate the approach for two pharmaceuticals (diclofenac and fluoxetine) and one personal care product ingredient (triclosan) for the oligochaete Lumbriculus variegatus. Initially, experimental data on the uptake of the three chemicals at two pH values were fitted using a toxicokinetic model to derive uptake and depuration constants for the neutral and ionized species of each molecule. The derived constants were then used to predict uptake from water and sediment for other pH conditions. Evaluation of predictions against corresponding experimental data showed good predictions of uptake for all test chemicals from water for different pH conditions and reasonable predictions of uptake of fluoxetine and diclofenac from a sediment. Predictions demonstrated that the level of uptake of the study chemicals, across pH ranges in European streams, could differ by up to a factor of 3035. Overall, the approach could be extremely useful for assessing internal exposure of aquatic organisms across landscapes with differing pH. This could help support better characterization of the risks of ionizable chemicals in the aquatic environment. PMID- 28553716 TI - Ratiometric Fluorescent Probe for Lysosomal pH Measurement and Imaging in Living Cells Using Single-Wavelength Excitation. AB - A novel lysosome-targeting ratiometric fluorescent probe (CQ-Lyso) based on the chromenoquinoline chromorphore has been developed for the selective and sensitive detection of intracellular pH in living cells. In acidic media, the protonation of the quinoline ring of CQ-Lyso induces an enhanced intramolecular charge transfer (ICT) process, which results in large red-shifts in both the absorption (104 nm) and emission (53 nm) spectra which forms the basis of a new ratiometric fluorescence pH sensor. This probe efficiently stains lysosomes with high Pearson's colocalization coefficients using LysoTrackerDeep Red (0.97) and LysoTrackerBlue DND-22 (0.95) as references. Importantly, we show that CQ-Lyso quantitatively measures and images lysosomal pH values in a ratiometric manner using single-wavelength excitation. PMID- 28553717 TI - Structural Instabilities Related to Highly Anharmonic Phonons in Halide Perovskites. AB - Hybrid perovskites have emerged over the past five years as absorber layers for novel high-efficiency low-cost solar cells combining the advantages of organic and inorganic semiconductors. Unfortunately, electrical transport in these materials is still poorly understood. Employing the linear response approach of density functional theory, we reveal strong anharmonic effects and a double-well phonon instability at the center of the Brillouin zone for both cubic and orthorhombic phases of inorganic CsPbI3. Previously reported soft phonon modes are stabilized at the actual lower-symmetry equilibrium structure, which occurs in a very flat energy landscape, highlighting the strong competition between the different phases of CsPbI3. Factoring these low-energy phonons into electron phonon interactions and band gap calculations could help better understand the electrical transport properties in these materials. Furthermore, the perovskite oscillations through the corresponding energy barrier could explain the underlying ferroelectricity and the dynamical Rashba effect predicted in halide perovskites for photovoltaics. PMID- 28553718 TI - Engineering Silver Nanowire Networks: From Transparent Electrodes to Resistive Switching Devices. AB - Metal nanowires (NWs) networks with high conductance have shown potential applications in modern electronic components, especially the transparent electrodes over the past decade. In metal NW networks, the electrical connectivity of nanoscale NW junction can be modulated for various applications. In this work, silver nanowire (Ag NW) networks were selected to achieve the desired functions. The Ag NWs were first synthesized by a classic polyol process, and spin-coated on glass to fabricate transparent electrodes. The as-fabricated electrode showed a sheet resistance of 7.158 Omega ?-1 with an optical transmittance of 79.19% at 550 nm, indicating a comparable figure of merit (FOM, or PhiTC) (13.55 * 10-3 Omega-1). Then, two different post-treatments were designed to tune the Ag NWs for not only transparent electrode but also for threshold resistive switching (RS) application. On the one hand, the Ag NW film was mechanically pressed to significantly improve the conductance by reducing the junction resistance. On the other hand, an Ag@AgOx core-shell structure was deliberately designed by partial oxidation of Ag NWs through simple ultraviolet (UV)-ozone treatment. The Ag core can act as metallic interconnect and the insulating AgOx shell acts as a switching medium to provide a conductive pathway for Ag filament migration. By fabricating Ag/Ag@AgOx/Ag planar structure, a volatile threshold switching characteristic was observed and an on/off ratio of ~100 was achieved. This work showed that through different post-treatments, Ag NW network can be engineered for diverse functions, transforming from transparent electrodes to RS devices. PMID- 28553719 TI - Quality indicators in digestive endoscopy: introduction to structure, process, and outcome common indicators. AB - The general goal of the project wherein this paper is framed is the proposal of useful quality and safety procedures and indicators to facilitate quality improvement in digestive endoscopy units. This initial offspring sets forth procedures and indicators common to all digestive endoscopy procedures. First, a diagram of pre- and post-digestive endoscopy steps was developed. A group of health care quality and/or endoscopy experts under the auspices of the Sociedad Espanola de Patologia Digestiva (Spanish Society of Digestive Diseases) carried out a qualitative review of the literature regarding the search for quality indicators in endoscopic procedures. Then, a paired analysis was used for the selection of literature references and their subsequent review. Twenty indicators were identified, including seven for structure, eleven for process (five pre procedure, three intra-procedure, three post-procedure), and two for outcome. Quality of evidence was analyzed for each indicator using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. PMID- 28553721 TI - Hatred-a public health issue. PMID- 28553720 TI - Cognitive impairment and clinical characteristics in patients with chronic obstructive pulmonary disease. AB - We aimed to investigate (1) the relationship between cognitive impairment (CI) and disease severity and (2) the potential differences in exercise performance, daily activities, health status, and psychological well-being between patients with and without CI. Clinically stable chronic obstructive pulmonary disease (COPD) patients, referred for pulmonary rehabilitation, underwent a neuropsychological examination. Functional exercise capacity (6-minute walk test [6MWT]), daily activities (Canadian Occupational Performance Measure [COPM]), health status (COPD Assessment Test [CAT]) and St George's Respiratory Questionnaire-COPD specific [SGRQ-C]), and psychological well-being (Hospital Anxiety and Depression Scale [HADS], Beck Depression Inventory [BDI], and Symptom Checklist 90 [SCL-90]) were compared between patients with and without CI. Of 183 COPD patients (mean age 63.6 (9.4) years, FEV1 54.8 (23.0%) predicted), 76 (41.5%) patients had CI. The prevalence was comparable across Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 1-4 (44.8%, 40.0%, 41.0%, 43.5%, respectively, p = 0.97) and GOLD groups A-D (50.0%, 44.7%, 33.3%, 40.2%, respectively, p = 0.91). Patients with and without CI were comparable for demographics, smoking status, FEV1% predicted, mMRC, 6MWT, COPM, CAT, HADS, BDI, and SCL-90 scores. Clinical characteristics of COPD patients with and without CI are comparable. Assessment of CI in COPD, thus, requires an active case-finding approach. PMID- 28553722 TI - Uncertainty propagation of phase contrast-MRI derived inlet boundary conditions in computational hemodynamics models of thoracic aorta. AB - This study investigates the impact that uncertainty in phase contrast-MRI derived inlet boundary conditions has on patient-specific computational hemodynamics models of the healthy human thoracic aorta. By means of Monte Carlo simulations, we provide advice on where, when and how, it is important to account for this source of uncertainty. The study shows that the uncertainty propagates not only to the intravascular flow, but also to the shear stress distribution at the vessel wall. More specifically, the results show an increase in the uncertainty of the predicted output variables, with respect to the input uncertainty, more marked for blood pressure and wall shear stress. The methodological approach proposed here can be easily extended to study uncertainty propagation in both healthy and pathological computational hemodynamic models. PMID- 28553723 TI - Two antidiabetic constituents from Roylea cinerea (D.Don) Baill. AB - Two antidiabetic compounds named 4-methoxybenzo[b]azet-2(1H)-one (1) and 3beta hydroxy-35-(cyclohexyl-5'-propan-7'-one)-33-ethyl-34-methyl-bacteriohop-16-ene (2) together with stigmasterol and beta-sitosterol were isolated from the aerial part of Roylea cinerea (D.Don) Baill. The structures of these compounds were elucidated by advanced spectroscopic methods, including two-dimensional NMR and MS techniques. These compounds were evaluated for their antidiabetic efficacy using in vitro and in vivo methods. Both compounds (1 and 2) showed a significant decline in blood glucose level of alloxan-induced diabetic rats at 10 mg/kg, p.o. when compared with glibenclamide at a similar dose. The in vitro studies revealed that compound 1 reduced alpha-amylase and alpha-glucosidase by 83.0 and 78.5%, respectively, whereas compound 2 reduced the same by 58.2 and 58.4%, respectively, at 100 MUM. The present study supports the role of R. cinerea in Ayurvedic medicine for diabetes. PMID- 28553724 TI - A new formula for predicting the position of severe arterial stenosis. AB - Noninvasive location of an occlusion or a severe stenosis in the arterial system is of a great interest for surgical interventions. Here, we present a new method to determine the location of arterial 99% stenosis in the arterial (sub) system. The method requires a measurement of propagation constant and the instantaneous flow rate or velocity at two sites of an arterial tree. The method was successfully tested using Womersley's oscillatory flow theory and the data obtained by a simulation of Fluid structure interaction (FSI). The effect of noise has been investigated to simulate experimental conditions. The results demonstrate that location of 99% severe stenosis could be accurately obtained. The spatial resolution was approximately a few centimeters and the differences between exact and computed values didn't exceed 13%. However, the identifications of stenotic sites decreased with the distance. Further investigation of the developed method in vivo and in vitro is required. PMID- 28553725 TI - Biotransformation of ursolic acid by Alternaria longipes AS3.2875. AB - Microbial transformation of ursolic acid (1) was carried out by Alternaria longipes AS 3.2875. Six transformed products (2-7) from 1 were isolated and their structures were identified as 3-carbonyl ursolic acid 28-O-beta-D-glucopyranosyl ester (2), ursolic acid 3-O-beta-D-glucopyranoside (3), ursolic acid 28-O-beta-D glucopyranosyl ester (4), 2alpha, 3beta-dihydroxy ursolic acid 28-O-beta-D glucopyranosyl ester (5), 3beta, 21beta dihydroxy ursolic acid 28-O-beta-D glucopyranosyl ester (6), and 3-O-(beta-D-glucopyranosyl)- ursolic acid 28-O (beta-D-glucopyranosyl) ester (7) based on the analysis of 1D NMR, 2DNMR and MS data. The product 2 was a new compound among them and showed stronger antibacterial activity against S. aureu, MRSA and MRCA than substrate. In this study, we modified structure of ursolic acid through biotransformation to enhance its activities and preliminarily discussed the transformation way of the products. PMID- 28553726 TI - Randomized Controlled Trial of a Clinic-Based Intervention to Promote Healthy Beverage Consumption Among Latino Children. AB - The objective of this study was to evaluate an educational module for Latino parents about the health effects of sweet beverages. Latino parents were randomized to receive the beverage module or a control module. Child beverage consumption was assessed at baseline, 2 weeks, 2 months, and 3 months via a beverage recall survey. At 2-week follow-up, children of intervention participants had a mean reduction in 7-day total sugar-sweetened beverage and 100% fruit juice consumption of 16 ounces while controls had a mean increase of 4 ounces ( P = .01). At 2-month and 3-month follow-up, there was a reduction in mean total sugar-sweetened beverage and 100% fruit juice consumption among both intervention and control children. An educational module on beverages for Latino parents reduced child consumption of sweet beverages at 2-week follow-up. However, study participation appears to have also reduced controls' beverage consumption suggesting that frequent intensive surveys of beverage intake may be an intervention unto itself. PMID- 28553728 TI - Phenanthrenes from Arundina graminifolia and in vitro evaluation of their antibacterial and anti-haemolytic properties. AB - Chemical investigation and activity test of Arundina graminifolia led to the isolation of six phenanthrenes: blestriarene A (1), shancidin (2), densiflorol B (3), ephemeranthoquinone (4), coelonin (5) and lusianthridin (6). The isolated compounds demonstrated antibacterial and anti-haemolytic activities. It was found that compounds 1 and 2 had medium antibacterial activity against Staphylococcus aureus, Bacillus subtilis and Escherichia coli, with MICs of 20-40 MUg/mL and MBCs of 40-320 MUg/mL. Bactericidal mechanisms were explored. Rupture of cell wall and membrane and leakage of nuclear mass were observed by transmission electron microscopy (TEM). Moreover, compounds 1-3 attenuated the erythrocyte damage. Compounds 1 and 2 showed significant anti-haemolytic activity with inhibition rate about 50% at 16 MUg/mL. PMID- 28553727 TI - Tobacco smoking: Health impact, prevalence, correlates and interventions. AB - BACKGROUND AND OBJECTIVES: Despite reductions in prevalence in recent years, tobacco smoking remains one of the main preventable causes of ill-health and premature death worldwide. This paper reviews the extent and nature of harms caused by smoking, the benefits of stopping, patterns of smoking, psychological, pharmacological and social factors that contribute to uptake and maintenance of smoking, the effectiveness of population and individual level interventions aimed at combatting tobacco smoking, and the effectiveness of methods used to reduce the harm caused by continued use of tobacco or nicotine in some form. RESULTS AND CONCLUSIONS: Smoking behaviour is maintained primarily by the positive and negative reinforcing properties of nicotine delivered rapidly in a way that is affordable and palatable, with the negative health consequences mostly being sufficiently uncertain and distant in time not to create sufficient immediate concern to deter the behaviour. Raising immediate concerns about smoking by tax increases, social marketing and brief advice from health professionals can increase the rate at which smokers try to stop. Providing behavioural and pharmacological support can improve the rate at which those quit attempts succeed. Implementing national programmes containing these components are effective in reducing tobacco smoking prevalence and reducing smoking-related death and disease. PMID- 28553729 TI - Chronic Achilles Tendon Ruptures. PMID- 28553730 TI - Bilateral hydronephrosis following uterine balloon tamponade in a case of massive post-partum haemorrhage with coagulopathy. PMID- 28553731 TI - MGF E peptide pretreatment improves collagen synthesis and cell proliferation of injured human ACL fibroblasts via MEK-ERK1/2 signaling pathway. AB - Injured anterior cruciate ligament (ACL) is hard to heal due to the poor proliferative potential of ACL fibroblasts. To verify whether mechano-growth factor (MGF) E peptide can restore the cell proliferation of injured ACL fibroblasts, ACL fibroblasts pretreated with MGF E peptide were subjected to injurious stretch and the outcomes were evaluated at 0 and 24 h. After injured, the type III collagen synthesis was increased at 0 h while inhibited at 24 h. The matrix metalloproteinase-2 (MMP-2) activity/expression was up-regulated, but the cell proliferation was inhibited. Fortunately, exogenous MGF E peptide decreased the type I/III collagen synthesis at 0 h but improved the type III collagen synthesis at 24 h. It decreased the MMP-2 activity/expression of injured ACL fibroblasts. Besides, MGF E peptide accelerated the cell proliferation via MEK ERK1/2 signaling pathway. Our results implied that MGF E peptide pretreatment could provide a new efficient approach for ACL regeneration. PMID- 28553732 TI - Hypoxia-inducible factor-1alpha: a promising therapeutic target for autoimmune diseases. AB - INTRODUCTION: Hypoxia-inducible factor-1alpha (HIF-1alpha) plays a crucial role in both innate and adaptive immunity. Emerging evidence indicates that HIF-1alpha is associated with the inflammation and pathologic activities of autoimmune diseases. Areas covered: Considering that the types of autoimmune diseases are complicated and various, this review aims to cover the typical kinds of autoimmune diseases, discuss the molecular mechanisms, biological functions and expression of HIF-1alpha in these diseases, and further explore its therapeutic potential. Expert opinion: Inflammation and hypoxia are interdependent. HIF 1alpha as a key regulator of hypoxia, exerts a crucial role in the balance between Th17 and Treg, and involves in the inflammation and pathologic activities of autoimmune diseases. Although there are many challenges remaining to be overcome, targeting HIF-1alpha could be a promising strategy for autoimmune diseases therapies. PMID- 28553733 TI - Tg.rasH2 Mice and not CByB6F1 Mice Should Be Used for 28-Day Dose Range Finding Studies Prior to 26-Week Tg.rasH2 Carcinogenicity Studies. AB - Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg.rasH2 mice were compared with 28-day DRF studies conducted with CByB6F1 mice. Both the 26-week and the earlier respective 28-day studies were conducted with the exact same vehicle, test article, and similar dose levels. The analysis of our results further emphasizes that the EMTD and subsequent lower doses, determined on the basis of the 28-day studies in CByB6F1 mice, may not be an accurate strategy for selecting appropriate dose levels for the 26-week carcinogenicity studies in Tg.rasH2 mice. Based on the analysis presented in this article, we propose that the Tg.rasH2 mice and not the CByB6F1 mice should be used in future DRF studies. The Tg.rasH2 mice demonstrate more toxicity than the CByB6F1 mice, possibly because of their smaller size compared to CByB6F1 mice. Also, the Tg.rasH2 males appear to be more sensitive than the female Tg.rasH2 mice. PMID- 28553734 TI - Characteristics of abnormal oral glucose tolerance test in GDM diagnosis and clinical correlation. AB - OBJECTIVES: To describe the characteristics of abnormal oral glucose tolerance test (OGTT) values at gestational diabetes mellitus (GDM) diagnosis and their associations with clinical characteristics, and to evaluate the effect on GDM diagnosis if any OGTT value was omitted. MATERIALS AND METHODS: A cross-sectional study was conducted in 415 women diagnosed with GDM. The OGTT results were recorded and analyzed. RESULTS: Of the 415 included women, mean gestational age at GDM diagnosis was 19.2 weeks and 57.6% were diagnosed before 20 weeks. The highest proportions of abnormal values were found at the 1st and 2nd hour (85.3% and 96.6%, respectively). If the 3rd hour OGTT value was omitted, 16.7% of GDM cases would be missed. Number of abnormal OGTT values and abnormal FPG were significantly associated with obesity. Only pre-pregnancy overweight and obesity independently associated with insulin requirement (adjusted OR: 2.28, 95%CI: 1.02 5.06; p = .044; and adjusted OR: 6.29, 95%CI: 2.67-14.85; p < .001, respectively). CONCLUSIONS: Over half of the GDM women had three or four abnormal OGTT values. Omission of the 3rd hour OGTT value would result in 16.7% of patients not being diagnosed with GDM. Number of abnormal OGTT values and abnormal FPG were associated with obesity, and insulin requirement was associated with pre-pregnancy overweight and obesity. PMID- 28553735 TI - Group observed structured encounter (GOSCE) for third-year medical students improves self-assessment of clinical communication. AB - OBJECTIVES: This study assesses the effectiveness of a GOSCE in teaching medical students clinical communication, as well as group collaboration and peer feedback. METHODS: The GOSCE was administered during the Internal Medicine clerkship. Groups consisted of 4-6 students and one faculty member. Students completed pre- and post-GOSCE surveys to assess confidence in clinical communication and a GOSCE evaluation to rate the overall experience. Pre- and post-GOSCE program survey scores were compared, and the mean score and standard deviation of the GOSCE evaluation was calculated. RESULTS: Students perceived improvement in their general (Mean 4.49-4.57, p < .0001), case-specific (3.61 3.84, p < .0001) and group clinical communication (3.75-4.09, p < .0001) skills. Students agreed or strongly agreed that the GOSCE taught them something new (91.20%), made them more comfortable in giving (64.31%) and receiving (66.57%) feedback and working with a group (64.22%). Students found the GOSCE to be as effective as an OSCE (70.97%). CONCLUSIONS: A GOSCE is a valuable resource for use in formative assessment of clinical communication, and it offers the benefit of group collaboration and peer feedback. These findings support the broader use of GOSCEs in undergraduate medical education. PMID- 28553736 TI - Amended Safety Assessment of Isethionate Salts as Used in Cosmetics. AB - The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) rereviewed the safety of 12 isethionate salts as used in cosmetics and concluded that these ingredients are safe in the present practices of use and concentration, when formulated to be nonirritating. These isethionate salts are reported to function mostly as surfactants and cleansing agents in cosmetic products. The Panel reviewed the available animal and clinical data as well as information from previous CIR reports. Although there are data gaps, the shared chemical core structure, expected similarities in physicochemical properties, and similar functions and concentrations in cosmetics enabled grouping these ingredients and reading across the available toxicological data to support the safety assessment of each ingredient. PMID- 28553737 TI - Safety Assessment of Anthemis nobilis-Derived Ingredients as Used in Cosmetics. AB - Anthemis nobilis (Roman chamomile) flower extract, anthemis nobilis flower oil, anthemis nobilis flower powder, and anthemis nobilis flower water are ingredients that function as fragrance ingredients and skin-conditioning agents in cosmetic products. These ingredients are being used at concentrations up to 10% (anthemis nobilis flower water) in cosmetic products. The available data indicate that these 4 ingredients are not irritating or sensitizing. Chemical composition data and the low use concentrations suggest that systemic toxicity would not be likely if percutaneous absorption of constituents were to occur. Formulations may contain more than 1 botanical ingredient; each may contribute to the final concentration of a single component. Manufacturers were cautioned to avoid reaching levels of plant constituents that may cause sensitization or other adverse effects. Industry should continue to use good manufacturing practices to limit impurities in the ingredient before blending into cosmetic formulations. The Expert Panel concluded that these ingredients are safe in the present practices of use and concentration in cosmetics, when formulated to be nonsensitizing. PMID- 28553738 TI - Safety Assessment of Amino Acid Alkyl Amides as Used in Cosmetics. AB - The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the product use, formulation, and safety data of 115 amino acid alkyl amides, which function as skin and hair conditioning agents and as surfactants-cleansing agents in personal care products. Safety test data on dermal irritation and sensitization for the ingredients with the highest use concentrations, lauroyl lysine and sodium lauroyl glutamate, were reviewed and determined to adequately support the safe use of the ingredients in this report. The Panel concluded that amino acid alkyl amides are safe in the present practices of use and concentration in cosmetics, when formulated to be nonirritating. PMID- 28553739 TI - Anatomical and Behavioral Investigation of C1ql3 in the Mouse Suprachiasmatic Nucleus. AB - Many biochemical, physiological, and behavioral processes such as glucose metabolism, body temperature, and sleep-wake cycles show regular daily rhythms. These circadian rhythms are adjusted to the environmental light-dark cycle by a central pacemaker located in the suprachiasmatic nucleus (SCN) in order for the processes to occur at appropriate times of day. Here, we investigated the expression and function of a synaptic organizing protein, C1QL3, in the SCN. We found that C1ql3 is robustly expressed in the SCN. C1ql3 knockout mice have a reduced density of excitatory synapses in the SCN. In addition, these mice exhibited less consolidated activity to the active portions of the day and period lengthening following a 15-minute phase-delaying light pulse. These data identify C1QL3 as a signaling molecule that is highly expressed in SCN neurons, where it contributes to the formation and/or maintenance of glutamatergic synapses and plays a role in circadian behaviors, which may include circadian aftereffects. PMID- 28553741 TI - Use of two test methods to ensure accurate surface firmness and stability measurements for accessibility. AB - PURPOSE: The firmness and stability of indoor and outdoor surfacing are critical to the accessibility and safety of all environments for people with mobility impairments and/or who use mobility devices. ASTM F1951 laboratory test procedures include pass/fail criteria for determining playground surface accessibility by comparing the work to propel up a 1:14 (7.1%) grade ramp to that of the test surface in a wheelchair. A portable instrumented surface indenter (ISI) was developed to validate that accessibility results obtained in the laboratory are maintained in the field where the surface is installed and used. METHODS: Accessibility measurements have been made on indoor and outdoor surfaces tested in the laboratory using both the ASTM F1951 and the ISI over 13 years. Correlations between these two methods were calculated. RESULTS: A strong correlation has been demonstrated for the sum of the ISI firmness and stability results compared to the sum of the ASTM F1951 straight propulsion and turning results (R2=0.9006). CONCLUSIONS: The portable ISI can be used to verify that the firmness and stability of an installed surface in the field correlates to the accessibility results of the surface tested in the laboratory concurrently according to ASTM F1951 and the ISI. Implications for Rehabilitation The Instrumented Surface Indenter (ISI) allows for surfaces in all environments to be tested for firmness and stability, which is critical for wheelchair user safety, especially during rehabilitation when learning to use a wheelchair. The ISI allows for surfaces in all environments to be tested for firmness and stability, which increases access to all indoor and outdoor surfaces, thereby improving the quality of life for people who have mobility impairments and/or use mobility devices, such as canes, crutches, walkers, and wheelchairs. Using the ISI to test the firmness and stability of installed playground surfaces increases access to playgrounds for children with mobility impairments, facilitating developmentally critical peer-play opportunities for children who use mobility devices. Using the ISI to test the firmness and stability of installed playground surfaces increases access to playgrounds for people with mobility impairments, allowing adults who use a mobility device to supervise and play with children in their lives. PMID- 28553740 TI - Extragastrointestinal stromal tumor of the abdominal subcutaneous tissue: Report of a very rare case at an unusual site. AB - Extragastrointestinal stromal tumors (EGISTs) are rare tumors that arise outside the digestive tract. We report a case of an EGIST arising in the subcutaneous tissue of the abdominal wall, which at this site can often be misdiagnosed as dermatofibrosarcoma protuberans. The tumor was surgically resected from a 72-year old male Chinese Han patient, and pathological examination revealed spindle shaped tumor cells with eosinophilic cytoplasm and an oval nucleus. Immunohistochemically, the tumor cells showed strong cytoplasmic positivity for CD34, c-KIT (CD117), and DOG1. Tests for activating mutations of GISTs showed that the tumor cells carried an in-frame deletion (NP_000213.1:p.Lys550_Gln556del) in exon 11 of c-KIT (CD117). Thus, an EGIST should be considered in patients with abdominal subcutaneous tumors with an epithelioid, spindle-shaped, or mixed morphology. Immunohistochemistry of c-KIT (CD117) and DOG1 and genetic testing for activating mutations are recommended to aid in the differential diagnosis of subcutaneous tumors. In short, although EGISTs are rare in the abdominal subcutaneous tissue, pathologists must be aware of their possibility. PMID- 28553742 TI - Antiribonuclease H2 antibodies are an immune biomarker for systemic lupus erythematosus. AB - We previously reported that autoantibodies against the proliferating cell nuclear antigen protein (PCNA)-binding protein chromatin assembly factor-1 (CAF-1) are specifically found in patients with systemic lupus erythematosus (SLE). PCNA and its complex constituents elicit autoimmune responses in patients with SLE, suggesting that autoantibody diversification likely occurs owing to epitope spreading. Therefore, we sought to clarify whether patients with SLE exhibit an autoimmune response to Ribonuclease H2 (RNase H2), another PCNA-binding protein that regulates cell division. As results, RNase H2 autoantibodies were detected in the sera of 33.9% (19/56) of SLE patients, which was significantly higher than that observed in sera from other patients with systemic autoimmune diseases (polymyositis/dermatomyositis, systemic sclerosis, Sjogren's syndrome, mixed connective tissue disease and rheumatoid arthritis) and healthy controls. Regression analysis also showed that serum anti-RNase H2 levels were strongly correlated to that of CAF-1 in SLE patients. Our data support the use of RNase H2 autoantibodies as a serum biomarker for SLE diagnosis. Moreover, the strong correlation observed between RNase H2 and CAF-1 suggests that intermolecular epitope spreading may play a critical role in autoantibody production and diversification in SLE. PMID- 28553743 TI - Two cases of endometrial cancer arising from adenomyosis during aromatase inhibitors therapy after mastectomy. PMID- 28553744 TI - Relationship between dietary quality, tinnitus and hearing level: data from the national health and nutrition examination survey, 1999-2002. AB - OBJECTIVE: To examine the relationship between the healthy eating index (HEI), a measure of dietary quality based on United States Department of Agriculture recommendations and report of tinnitus. DESIGN: This cross-sectional analysis was based on HEI data and report of tinnitus. STUDY SAMPLE: Data for adults between 20 and 69 years of age were drawn from the National Health and Nutrition Examination Survey (NHANES), 1999-2002. The NHANES is a programme of studies, to assess the health and nutritional status of adults and children in the United States. Two thousand one hundred and seventy-six participants were included in the analytic sample. RESULTS: Of the sample, 21.1% reported tinnitus within the past year and 11.7% reported persistent tinnitus, defined as tinnitus experienced at least monthly or greater. Controlling for age, sex, race/ethnicity, diabetes, noise exposure and smoking status, we found that with healthier diet (poorer vs. better HEI) there was decreased odds of reported persistent tinnitus [odds ratio (OR); 0.67; 95% confidence interval (CI) 0.45-0.98; p = 0.03]. CONCLUSIONS: The current findings support a possible relationship between healthier diet quality and reported persistent tinnitus. PMID- 28553745 TI - How do you choose and how well does it work?: the selection and effectiveness of emotion regulation strategies and their relationship with borderline personality disorder feature severity. AB - There is little research examining whether the selection of emotion regulation strategies is compromised among individuals characterised by emotion dysregulation. In a sample of 149 undergraduates, we examined the selection and effectiveness of 2 emotion regulation strategies (reappraisal or distraction) in response to emotionally evocative stimuli, and their relationship with emotion dysregulation, measured by borderline personality disorder (BPD) feature severity. Stimulus intensity and self-reported negative emotional intensity were also compared as predictors of strategy selection. Results indicated that self reported negative emotional intensity was a stronger predictor of strategy selection than stimulus intensity, and participants generally selected reappraisal over distraction. However, increases in self-reported negative emotional intensity was associated with an increased likelihood of choosing distraction, particularly among individuals higher in BPD features. In general, distraction exhibited less effectiveness than reappraisal, and higher BPD features did not differentially impact such effectiveness. Our findings indicate that individuals higher in emotion dysregulation prefer to use distraction as self-reported negative emotional intensity increases, a strategy which, overall, may not be as effective as reappraisal. Selection, rather than effectiveness of emotion regulation strategy might be a key feature of individuals characterised by emotion dysregulation. PMID- 28553746 TI - Can false memories prime alternative solutions to ambiguous problems? AB - Research has demonstrated that false memories are capable of priming and facilitating insight-based problem-solving tasks by increasing solution rates and decreasing solution times. The present research extended this finding by investigating whether false memories could be used to bias ambiguous insight based problem-solving tasks in a similar manner. Compound remote associate task (CRAT) problems with two possible correct answers, a dominant and a non-dominant solution, were created and normed (Experiment 1). In Experiment 2, participants were asked to solve these CRAT problems after they were given Deese/Roediger McDermott lists whose critical lures were also the non-dominant solution to half of the corresponding CRATs. As predicted, when false memories served as primes, solution rates were higher and solution times were faster for non-dominant than dominant CRAT solutions. This biasing effect was only found when participants falsely recalled the critical lure, and was not found when participants did not falsely recall the critical lure, or when they were not primed. Results are discussed with regard to spreading activation models of solution competition in problem-solving tasks and current theories of false memory priming effects. PMID- 28553747 TI - Metacognition in argument generation: the misperceived relationship between emotional investment and argument quality. AB - Overestimation of one's ability to argue their position on socio-political issues may partially underlie the current climate of political extremism in the U.S. Yet very little is known about what factors influence overestimation in argumentation of socio-political issues. Across three experiments, emotional investment substantially increased participants' overestimation. Potential confounding factors like topic complexity and familiarity were ruled out as alternative explanations (Experiments 1-3). Belief-based cues were established as a mechanism underlying the relationship between emotional investment and overestimation in a measurement-of-mediation (Experiment 2) and manipulation-of-mediator (Experiment 3) design. Representing a new bias blind spot, participants believed emotional investment helps them argue better than it helps others (Experiments 2 and 3); where in reality emotional investment harmed or had no effect on argument quality. These studies highlight misguided beliefs about emotional investment as a factor underlying metacognitive miscalibration in the context of socio political issues. PMID- 28553748 TI - Mini-Review: Toxic Tendinopathy. AB - Toxic tendinopathy is a rare but reproducible complication in humans, given agents of four drug classes: aromatase inhibitors, fluoroquinolone antibiotics, glucocorticoids (long-term regimens), and statins. Toxic tendinopathy in humans has been linked less consistently to treatment with anabolic steroids, antiretroviral agents (mainly protease inhibitors), metalloproteinase inhibitors (MMPI), and isotretinoin. Classic drug-induced tendinopathies appear as "tendinosis" (i.e., progressive tendon degeneration without inflammation), although cases associated with aromatase inhibitors exhibit mainly tenosynovitis. Any tendon may be affected, but fluoroquinolones, glucocorticoids, and statins most frequently affect large load-bearing tendons in the lower limb, especially the calcaneal ("Achilles") tendon-which ruptures in approximately 30 to 40% of cases. The time to symptom onset ranges from days (fluoroquinolones) to weeks, months, or even years. The pathogenesis is incompletely understood, but proposed mechanisms include apoptosis of tenoblasts and tenocytes, deficient tenocyte function (leading to abnormal extracellular matrix maintenance and repair as well as disrupted intercellular signaling), and structural disintegration (via a combination of increased expression of lytic enzymes, lessened cholesterol content in cell membranes, and neoangiogenesis within highly ordered tendon tissue). Nonclinical safety assessment of therapeutic candidates in these drug classes should incorporate tendon routinely as a protocol-specified tissue for pathology evaluation. PMID- 28553749 TI - Mandibular angle fractures treated with a single miniplate without postoperative maxillomandibular fixation: A retrospective evaluation of 50 patients. AB - OBJECTIVE: This retrospective study evaluated the use of a single miniplate for the treatment of mandibular angle fractures (MAF). METHODS: Fifty patients with 53 MAF were treated by open reduction and internal fixation with the use of a single miniplate and were analyzed in this study. RESULTS: Five patients with MAF had postoperative complications that required additional procedures. Three patients had postoperative infection, one patient complained of malocclusion in the first postoperative week, and one patient had miniplate exposure three months after surgery. Every additional procedure was performed in the office under local anesthesia without disruption of the initial fracture treatment. Postoperative maxillomandibular fixation (MMF) was performed in four patients. Treatment of MAF using a single miniplate was effective, with low morbidity and with low rates of postoperative complications. MAF can be treated without MMF, and stability is improved when long miniplates are used. CONCLUSIONS: The use of a single miniplate is therefore encouraged. However, postoperative MMF should be considered with the presence of little contact between bone segments, malocclusion, or extensive tooth loss. PMID- 28553750 TI - Development of a Theoretically Grounded, Web-Based Intervention to Reduce Adolescent Driver Inattention. AB - Motor vehicle crashes are the leading cause of adolescent death. Inattention to the roadway contributes to crash risk and often results from distractions, such as cell phone calls, texting, and peer passengers. We report on the development of a web-based intervention based on the Theory of Planned Behavior that aims to reduce adolescent driver inattention ( Let's Choose Ourselves). In Phase I, we collected qualitative and quantitative data on adolescents' attitudes, perceived behavioral control, and subjective norms about driver inattention through focus groups with newly licensed adolescent drivers. In Phase II, we developed the content in an e-learning delivery system, performed beta- and pilot testing, and made refinements. In Phase III, we conducted a randomized controlled trial to evaluate feasibility. The development of Let's Choose Ourselves provides information for school nurses regarding intervention development strategies as well as promotion of safe adolescent driving by reducing driver inattention. PMID- 28553751 TI - Patient-Centered Care in Small Primary Care Practices in New York City: Recognition Versus Reality. AB - BACKGROUND: The Primary Care Information Project (PCIP) is a program administered by the New York City Department of Health and Mental Hygiene to help primary care providers adopt a fully functional electronic health record (EHR) and focus on population health. PCIP also offers practices assistance with the National Committee for Quality Assurance (NCQA) patient-centered medical home (PCMH) recognition application. The objectives of this study were to assess the presence of key dimensions of PCMH among PCIP practices with 5 or fewer providers and to determine whether and to what extent NCQA recognition was related to the presence of these dimensions. METHODS: Analyses relied on data collected from a comprehensive practice assessment survey of PCIP practices administered in summer 2012. The survey was developed to assess discrete dimensions of the PCMH model and other practice characteristics. The study population includes practices for which survey results were available among PCIP practices with 5 or fewer providers (63% response rate; n = 83). RESULTS: At the time of survey, 57% of practices had received some level of NCQA recognition (n = 47). Practices with recognition scored significantly higher on several dimensions, including whole person orientation, team-based care, care coordination and integration, and quality and safety. CONCLUSIONS: Results indicate that very small urban practices in New York City are implementing many key features of PCMH. In general, practices with NCQA recognition scored higher on PCMH constructs and domains relative to practices without recognition; however, there is room for improvement on construct and domain scores in both groups. PMID- 28553752 TI - Quantitative Muscle Ultrasonography Using Textural Analysis in Amyotrophic Lateral Sclerosis. AB - The purpose of this study was to analyze differences in gray-level co-occurrence matrix (GLCM) parameters, as assessed by muscle ultrasound (MUS), between amyotrophic lateral sclerosis (ALS) patients and healthy controls, and to compare the diagnostic accuracy of these GLCM parameters with first-order MUS parameters (echointensity [EI], echovariation [EV], and muscle thickness [MTh]) in different muscle groups. Twenty-six patients with ALS and 26 healthy subjects underwent bilateral and transverse ultrasound of the biceps/brachialis, forearm flexor, quadriceps femoris, and tibialis anterior muscle groups. MTh was measured with electronic calipers, and EI, EV, and GLCM were obtained using Image J (v.1.48) software. Sensitivity, specificity, likelihood ratios, and area under the curve (AUC) were performed by logistic regression models and receiver operating characteristic curves. GLCM parameters showed reduced granularity in the muscles of ALS patients compared with the controls. Regarding the discrimination capacity, the best single diagnostic parameter in forearm flexors and quadriceps was GLCM and in biceps brachialis and tibialis anterior was EV. The respective combination of these two parameters with MTh resulted in the best AUC (over 90% in all muscle groups and close to the maximum combination model). The use of new textural parameters (EV and GLCM) combined with usual quantitative MUS variables is a promising biomarker in ALS. PMID- 28553753 TI - The ambiguity of altruism in nursing: A qualitative study. AB - BACKGROUND: For a long time, altruism was the basis for caring. Today, when society is more individualized, it is of interest to explore the meaning of altruism in nursing. METHODS: In all, 13 nurses from a Swedish acute care setting participated in two focus group interviews performed as Socratic dialogues. Data were analyzed using a phenomenological hermeneutical method. Ethical considerations: Ethical issues were considered throughout the process according to established ethical principles. Informed consent was obtained from all participants, confidentiality regarding the data was guaranteed and quotations anonymized. FINDINGS: Altruism created a sense of ambivalence and ambiguity, described as a rise of sovereign expressions of life caused by "the other's" need, but also unwillingness to take unconditional responsibility for "the other." CONCLUSION: Society's expectations of altruism and nurses' perception of their work as a salaried job collide in modern healthcare. Nurses are not willing to fully respond to the ethical demand of the patients. In case of a disaster, when nurses personal safety, life and health may be at risk, there might be reasons to question whether the healthcare organization would be able to fulfill its obligations of providing healthcare to an entire population. PMID- 28553754 TI - Commentary: Next-Generation Drug-Coated Balloons: A New Era for Endovascular Therapy of the Femoropopliteal Arteries? PMID- 28553756 TI - Experimental and modelling studies on a laboratory scale anaerobic bioreactor treating mechanically biologically treated municipal solid waste. AB - The performance of an anaerobic bioreactor in treating mechanically biologically treated municipal solid waste was investigated using experimental and modelling techniques. The key parameters measured during the experimental test period included the gas yield, leachate generation and settlement under applied load. Modelling of the anaerobic bioreactor was carried out using the University of Southampton landfill degradation and transport model. The model was used to simulate the actual gas production and settlement. A sensitivity analysis showed that the most influential model parameters are the monod growth rate and moisture. In this case, pH had no effect on the total gas production and waste settlement, and only a small variation in the gas production was observed when the heat transfer coefficient of waste was varied from 20 to 100 kJ/(m d K)-1. The anaerobic bioreactor contained 1.9 kg (dry) of mechanically biologically treated waste producing 10 L of landfill gas over 125 days. PMID- 28553755 TI - Cardiac rehabilitation in patients with ST-segment elevation myocardial infarction: can its failure be predicted? AB - BACKGROUND: The prognosis in patients after acute coronary syndromes (ACS) is significantly burdened by coexisting anaemia, leukocytosis and low glomerular filtration rate (GFR). Hyperglycaemia in the early stages of ACS is a strong predictor of death and heart failure in non-diabetic subjects. This study aimed to evaluate the effect of hyperglycaemia, anaemia, leukocytosis, thrombocytopaenia and decreased GFR on the risk of the failure of cardiac rehabilitation (phase II at the hospital) in post-ST-segment elevation myocardial infarction (STEMI) patients. METHODS: The study included 136 post-STEMI patients, 96 men and 40 women, aged 60.1 +/- 11.8 years, admitted for cardiac rehabilitation (phase II) to the Department of Internal Medicine and Cardiac Rehabilitation, WAM University Hospital in Lodz, Poland. On admission fasting blood cell count was performed and serum glucose and creatinine level was determined (GFR assessment). The following results were considered abnormal: glucose ? 100 mg/dl, GFR < 60 ml/min/1, 73 m2, red blood cells (RBCs) < 4 * 106/MUl, white blood cells (WBCs) > 10 * 103/MUl; platelets (PLTs) < 150 * 103/ml. In all patients an exercise test was performed twice, before and after the completion of the second stage of rehabilitation, to assess its effects. RESULTS: Based on logistic regression analysis and the results of an individual odds ratio (OR) of the tested parameters, their prognostic impact was determined on the risk of failure of cardiac rehabilitation. This risk has been defined on the basis of the patient's inability to tolerate workload increment >5 Watt in spite of the applied program of cardiac rehabilitation. As a result of building a logistic regression model, the most statistically significant risk factors were selected, on the basis of which cardiac rehabilitation failure index was determined. leukocytosis and reduced GFR determined most significantly the risk of failure of cardiac rehabilitation (respectively OR = 6.42 and OR = 3.29, p = 0.007). These parameters were subsequently utilized to construct a rehabilitation failure index. CONCLUSIONS: Peripheral blood cell count and GFR are important in assessing the prognosis of cardiac rehabilitation effects. leukocytosis and decreased GFR determine to the highest degree the risk of cardiac rehabilitation failure. Cardiac rehabilitation failure index may be useful in classifying patients into an appropriate model of rehabilitation. These findings support our earlier reports. PMID- 28553757 TI - Motor Disturbances in Elderly Medical Inpatients and Their Relationship to Delirium. AB - Motor disturbances in delirious patients are common, but their relationship to cognition and severity of illness has not been studied. We examined motor subtypes in an older age inpatient population, their relationship to clinical variables including delirium, and their association with 1-year mortality in a prospective study, using the Confusion Assessment Method, Acute Physiology and Chronic Health Evaluation II, Montreal Cognitive Assessment (MoCA), Barthel Index, and Delirium Rating Scale-Revised 98 (DRS-R98). Motor subtypes were evaluated using 2 items of DRS-R98. Mortality rates were investigated 1 year later. Two hundred participated (mean age 81.1 [6.5]; 50% female). Thirty-four (17%) were identified with delirium. Motor subtypes were none: 119 (59.5%), hypoactive: 37 (18.5%), hyperactive: 29 (14.5%), and mixed: 15 (7.5%). Hypoactive and mixed subtypes were significantly more frequent in delirious patients. Regression analysis showed that hypoactive subtype was significantly associated with lower MoCA. No relationship between motor subtypes and mortality was found. Motor disturbances are not unique to delirium, with hypoactivity particularly associated with impaired cognition. PMID- 28553758 TI - HPV vaccine acceptance among African-American mothers and their daughters: an inquiry grounded in culture. AB - BACKGROUND: Much of the research on African-Americans' HPV vaccine acceptance has largely focused on racial/ethnic differences related to cognitive, socio economical, and structural factors that contribute to differences in HPV vaccine acceptance and completion. A growing body of literature suggest that cultural factors, such as mistrust of healthcare providers (HCPs) and the healthcare system, religion, and social norms related to appropriate sexual behaviors, also plays a prominent role in their HPV vaccine acceptance. However, these studies were limited in their use of theoretical approaches necessary to conceptualize and operationalize culture. OBJECTIVE: To explore the influence of culture on African-American mothers' and daughters' HPV vaccine acceptance using the PEN-3, a culturally-centered conceptual framework. METHODS: Grounded theory techniques were used to explore cultural factors that influenced the acceptance of the HPV vaccine among African-American mothers (n = 28) and their daughters (n = 34). RESULTS: Positive attitudes towards vaccination stemmed from beliefs that the HPV vaccine has cancer prevention benefits and that vaccinations in general protected against infectious diseases. Negative attitudes stemmed from beliefs that the HPV vaccine was too new, not effective, daughters were too young, and that vaccines were not a one-size-fits-all intervention. Majority of mothers and daughters indicated that their religious doctrine did not impede their HPV vaccination decisions. For a few mothers, religious beliefs could not be separated from their HPV vaccination decisions and ultimately deterred HPV vaccine acceptance. HCP recommendations were valued however mothers were often dissatisfied with the detail of information communicated. Support networks provided both positive and negative types of social support to mothers and daughters. The media highlighted the cancer prevention benefits of the HPV vaccine and unintentionally communicated negative information of the HPV vaccine, which deterred HPV vaccine acceptance. CONCLUSION: Study findings can inform the development of culturally appropriate interventions that advances the evidence on cervical cancer prevention. PMID- 28553759 TI - Access to fertility services in Canada for HIV-positive individuals and couples: a comparison between 2007 and 2014. AB - In the modern era of HIV care, a multitude of clinical needs have emerged; one such need is the growing sub-specialty of HIV and reproductive health. In 2007, a study surveying Canadian fertility clinics found limited access to fertility services for HIV-positive patients. Given the extensive efforts made to address this lack of services, a follow-up assessment was warranted. This study aimed to compare the access to Canadian fertility clinics and services for HIV-positive individuals and couples in 2014 and 2007. Surveys were sent to medical or laboratory directors of assisted reproductive technology (ART) clinics in 2014 and results were compared to those sent in 2007. Main outcome measures included: the proportion of fertility clinics willing to provide ART to people with HIV, the specific services offered, and whether the 2012 Canadian HIV Pregnancy Planning Guidelines were implemented to inform practice. Across Canadian provinces, 20/34 (59%) clinics completed the survey. Ninety-five percent (19/20) of clinics accepted HIV-positive patients for consultation. Only 50% (10/20) of clinics in four provinces offered a full range of ART (defined as including in vitro fertilization [IVF]). Ten clinics (50%) in five provinces were aware that guidelines exist; half (n = 5) having read them and four reporting implementation of all the guidelines' recommendations in their practice. Compared to 2007, more clinics had implemented separate facilities (p = 0.028) to treat HIV-positive individuals, offered IVF (p = 0.013) for HIV-positive female partners, sperm washing (p = 0.033) for HIV-positive male partners, and risk reduction techniques to couples with HIV-positive men and women (p = 0.006). Access to fertility clinics for people with HIV has improved over time but is still regionally dependent and access to full ART remains limited. These findings suggest the need for advocacy targeted towards geographical-specific areas and optimizing access to comprehensive services. PMID- 28553760 TI - Comparison of different conservative treatments for idiopathic clubfoot: Ponseti's versus non-Ponseti's methods. AB - Objective Various methods are applied in the clinical treatment of idiopathic clubfoot. The purpose of this meta-analysis was to evaluate the efficacy of different conservative treatments. Methods Studies were pooled and odds ratio (ORs) with corresponding confidence intervals were calculated for evaluation of the results, relapses, and requirement for major surgery. Results A final analysis of 1435 patients from 9 eligible studies was performed. The combined OR indicated that significantly more fair and poor results were achieved and that major surgery was required significantly more often when using non-Ponseti's methods (OR = 3.33 and OR = 7.32, respectively), but no significant difference was detected in the occurrence of relapse (OR = 1.34). Pooled OR evaluation showed a significantly higher rate of fair and poor results, relapse, and requirement for major surgery when using Kite's method than when using Ponseti's method (OR = 3.93, OR = 2.53, and OR = 3.19, respectively), but no significant difference was detected between the French method and Ponseti's method (OR = 3.01, OR = 0.72, and OR = 1.26, respectively). Conclusions This meta-analysis indicates that Ponseti's method is safe and efficient for conservative treatment of clubfoot and decreases the number of surgical interventions required. It is recommended as the first-choice conservative treatment for idiopathic clubfoot. PMID- 28553761 TI - Innominate artery aneurysm, how to solve it? AB - We herein describe our *These authors contributed equally to this work. experience with a congenital innominate artery aneurysm (IAA) that was managed with a simple surgical procedure. A 44-year-old woman was admitted for chest distress. Computed tomography angiography showed a 3.6-cm IAA arising from the aortic arch and compressing the trachea. A median sternotomy was performed with the patient under general anesthesia, and the IAA was found to involve the origin of the innominate artery and the bifurcation of the right subclavian artery and common carotid artery; however, the aorta was intact. An 8-mm Dacron graft was anastomosed to the ascending aorta and distal end of the IAA without cardiopulmonary bypass. The postoperative course was uneventful, and repeat computed tomography angiography revealed no evidence of recurrence 6 months postoperatively. We also herein present a literature review of this rare clinical condition. PMID- 28553762 TI - Evaluation of serum neutrophil gelatinase-associated lipocalin in predicting acute kidney injury in critically ill patients. AB - Objective This investigation evaluated the real-time point-of-care testing (RT POCT) of neutrophil gelatinase-associated lipocalin (NGAL) for detecting acute kidney injury (AKI) and prognosis of critically ill patients. Methods A total of 249 critically ill patients in the emergency department (ED), who were diagnosed with acute decompensated heart failure, sepsis or diabetic ketoacidosis were enrolled in this study. All enrolled patients were followed up for 28 days or to death and the mortalities were recorded. Serum creatinine (sCr) and NGAL were measured. Results 40.6% enrolled patients deteriorated to AKI during the observation period. The NGAL level was significantly higher in the AKI versus non AKI group. The NGAL levels in the non-survivors group at 7-day and 28-day were significantly higher than in the survivors group. NGAL was detected as an independent risk factor of AKI, and 7-day and 28-day morality. The receiver operating characteristic curve of NGAL was calculated for diagnosing AKI; the area under the curve (AUC) was significantly higher than that of 1-day eGFR. Conclusions NGAL is an independent predictor of AKI, and 7-day and 28-day mortality in critically ill ED patients, and can be an early alert for AKI and useful for determining prognosis. PMID- 28553763 TI - Clinical characteristics of patients with diabetes mellitus and fatty liver diagnosed by liver/spleen Hounsfield units on CT scan. AB - Objective The leading cause of liver injuries in diabetes mellitus may be associated with fatty liver. We aimed to elucidate the relationship between fatty liver and diabetes characteristics. Methods Retrospectively, 970 patients with diabetes were analysed. Fatty liver was diagnosed when the liver/spleen Hounsfield unit ratio by computed tomography was below 0.9. Clinical diabetes characteristics were compared between patients with and without fatty liver. Results Of 970 patients (717 male and 253 female; mean age 64.4 years), 175 males (24.4%) and 60 females (23.7%) had fatty liver. None of the 28 patients with type 1 diabetes had fatty liver. In male patients with type 2 diabetes, age, visceral adipose tissue (VAT), albumin, alanine amino-transferase (ALT), and triglycerides were independently associated with fatty liver. In females, age and bilirubin were associated with fatty liver. Conclusions Fatty liver is associated with type 2 diabetes characteristics, including younger age and elevated VAT, albumin, ALT, and triglycerides in males and younger age and elevated bilirubin levels in females. PMID- 28553764 TI - Somatosensory tinnitus: Current evidence and future perspectives. AB - In some individuals, tinnitus can be modulated by specific maneuvers of the temporomandibular joint, head and neck, eyes, and limbs. Neuroplasticity seems to play a central role in this capacity for modulation, suggesting that abnormal interactions between the sensory modalities, sensorimotor systems, and neurocognitive and neuroemotional networks may contribute to the development of somatosensory tinnitus. Current evidence supports a link between somatic disorders and higher modulation of tinnitus, especially in patients with a normal hearing threshold. Patients with tinnitus who have somatic disorders seems to have a higher chance of modulating their tinnitus with somatic maneuvers; consistent improvements in tinnitus symptoms have been observed in patients with temporomandibular joint disease following targeted therapy for temporomandibular disorders. Somatosensory tinnitus is often overlooked by otolaryngologists and not fully investigated during the diagnostic process. Somatic disorders, when identified and treated, can be a valid therapeutic target for tinnitus; however, somatic screening of subjects for somatosensory tinnitus is imperative for correct selection of patients who would benefit from a multidisciplinary somatic approach. PMID- 28553765 TI - Short-interval postconditioning protects the bowel against ischaemia-reperfusion injury in rats. AB - Objective Acute mesenteric ischaemia leads to intestinal damage. Restoration of blood flow results in further damage to tissue, which is called reperfusion injury. This study aimed to investigate the protective effects of short-interval postconditioning and to determine the optimal interval for reperfusion in an experimental rat model of intestinal ischaemia. Methods Forty adult male Wistar rats were grouped as follows: sham (Sh), ischaemia + reperfusion (IR), ischaemia + postconditioning for 5 seconds (PC5), ischaemia + postconditioning for 10 seconds (PC10), and ischaemia + postconditioning for 20 seconds (PC20). For postconditioning, 10 cycles of reperfusion (5, 10, or 20 seconds) interspersed by 10 cycles of 10 seconds of ischaemia were performed. Blood glutathione reductase (GR) and glutathione peroxidase (GPx) levels were measured. Intestinal tissue damage was assessed histopathologically. Results GR levels were significantly higher in the PC5 group than in the IR group (37.7 +/- 9.0 vs. 18.5 +/- 2.0 min/g Hb). GPx levels were significantly higher in the PC10 group than in the IR group (43.2 +/- 9.2 vs. 15.9 +/- 4.6 U/g Hb). The histopathological score was significantly lower in the PC5 group (1.1 +/- 0.1) than in the IR group (2.1 +/- 0.2). Conclusion Short-interval postconditioning reduces reperfusion injury in the ischaemic bowel and the optimal interval for reperfusion is 5 seconds. The long-term effects of short-interval postconditioning and the optimal reperfusion interval in intestinal ischaemia-reperfusion in rats need to be investigated. PMID- 28553766 TI - Intravenous dexmedetomidine during spinal anaesthesia for caesarean section: A meta-analysis of randomized trials. AB - Objective To evaluate the efficacy and safety of spinal anaesthesia using dexmedetomidine for caesarean section. Methods PubMed, The Cochrane Library, and CNKI were searched for relevant literature. Results The incidence of nausea and vomiting in the dexmedetomidine group was significantly lower than that in the control group (OR = 0.21, 95% CI: 0.12-0.35, P < 0.00001). No difference was found in the incidence of pruritus between the two groups (OR = 1.21, 95% CI: 0.36-4.09, P = 0.76).The dexmedetomidine group had a higher incidence of bradycardia than did the control group (OR = 2.20, 95% CI: 1.02-4.77, P = 0.05). The incidence of shivering in the dexmedetomidine group was significantly lower than that in the control group (OR = 0.20, 95% CI: 0.13-0.32, P < 0.00001). The incidence of hypotension was not different between the two groups (OR = 0.88, 95% CI: 0.49-1.56, P = 0.65). Conclusion Dexmedetomidine can decrease the incidence of nausea, vomiting, bradycardia, and shivering with spinal anaesthesia during caesarean section. PMID- 28553768 TI - Improving Our Understanding of Atopic Dermatitis Will Require Research Beyond Immunology and Dermatology. PMID- 28553767 TI - Assessment of aflatoxin B1 myocardial toxicity in rats: mitochondrial damage and cellular apoptosis in cardiomyocytes induced by aflatoxin B1. AB - Objective The number of deaths from heart disease is increasing worldwide. Aflatoxin B1 (AFB1), a toxin produced by the fungi Aspergillus flavus and Aspergillus parasiticus, is frequently detected in improperly processed/stored human food products. While AFB1 hepatotoxicity and carcinogenic properties have been well addressed, its myocardial toxicity is poorly documented. This study aimed to investigate myocardial toxic activity of AFB1. Methods Ten rats were fed with AFB1 at a dose that did not result in acute toxic reactions for 30 days and 10 vehicle-fed rats served as controls. Transmission electron microscopy was used to assess mitochondrial damage in cardiomyocytes. The terminal deoxynucleotidyl transferase-mediated UTP nick-end labelling assay was performed to detect apoptosis of cardiomyocytes. Western blotting was performed to measure apoptotic proteins (i.e., active caspase-3, Bax, and Bcl-2) in heart tissue. Results AFB1 treatment resulted in mitochondrial membrane disruption and disorganization of cristae, which are indicators of mitochondrial damage. Myocardial cell apoptosis was significantly higher after AFB1 treatment (22.07% +/- 3.29%) compared with controls (6.27% +/- 2.78%, P < 0.05). AFB1 treatment enhanced expression of active caspase-3, Bax, and Bcl-2 in cardiac tissue. Conclusion Various adverse effects are exerted by AFB1 on the heart, indicating AFB1 myocardial toxicity. PMID- 28553769 TI - Editor's Note. PMID- 28553770 TI - Involvement of Reactive Metabolites of Diclofenac in Cytotoxicity in Sandwich Cultured Rat Hepatocytes. AB - BACKGROUND AND OBJECTIVES: Diclofenac (DIC) is metabolized to reactive metabolites such as diclofenac acyl-beta-d-glucuronide (DIC-AG). It is possible that such reactive metabolites could cause tissue damage by formation of covalent protein adducts and other modification of cellular proteins or by induction of immune responses against its covalent protein adducts. However, the detailed mechanisms of idiosyncratic drug-induced liver injury (DILI) have been unclear. The objective is to clarify the involvement of DIC-AG and 4'hydroxydiclofenac (4'OH-DIC) in acute DILI. METHODS: We examined the effects of inhibiting DIC-AG and 4'OH-DIC production on covalent protein adduct formation and lactate dehydrogenase leakage using sandwich-cultured rat hepatocytes (SCRHs). RESULTS: After pretreatment of SCRH with (-)-borneol (BOR, a uridine diphosphate (UDP) glucuronosyltransferase inhibitor) or sulfaphenazole (SUL, a cytochrome P450 2C9 inhibitor) for 30 minutes, intracellular concentrations of DIC, DIC-AG, and 4'OH DIC were determined after further treating cells with 300 MUM DIC for 3 hours. The decreased levels of reactive metabolites caused by BOR or SUL pretreatment resulted in decreased lactate dehydrogenase leakage from SCRH, although the formation of covalent protein adducts was not affected. CONCLUSION: These results suggested that both DIC-AG and 4'OH-DIC may be involved in acute cytotoxicity by DIC. PMID- 28553772 TI - Prenatal ultrasound parameters in single-suture craniosynostosis. AB - INTRODUCTION: Although single-suture craniosynostosis is diagnosed sporadically during pregnancy, timely referral is critical for its treatment. Additionally, craniosynostosis leads to increased maternofetal trauma during birth. In the Netherlands, 95% of pregnant women receive a standard ultrasound at around 20 weeks of gestation, potentially an ideal setting for detecting craniosynostosis prenatally. To enhance the prenatal detection of the metopic and the sagittal suture synostosis, we wished to identify new screening parameters. MATERIALS AND METHODS: We retrospectively analyzed data of the 20-week anomaly scan in trigonocephaly patients (n = 41), scaphocephaly patients (n = 41), and matched controls (n = 82). We measured six different cranial dimensions, including head circumference, biparietal diameter, and occipito-frontal diameter, defining the cephalic index as the ratio between biparietal and occipito-frontal diameter. RESULTS: Prenatal biometric measurements did not differ significantly between trigonocephaly patients and controls. Although significantly lower in scaphocephaly patients (0.76 versus 0.79; p = .000), the cephalic index by itself is not appropriate for screening at 20 weeks of gestation. Longitudinal analysis suggests that a deflection in BPD curve is found in scaphocephaly patients, starting at 20 weeks of gestation. CONCLUSIONS: Prenatal biometric measurements do not differ significantly between trigonocephaly patients and controls. The CI is lower in scaphocephaly patients. A deflection in BPD curve should be followed by 3 D imaging of the cranial sutures. PMID- 28553771 TI - The first trimester combined test for aneuploidies - a single center experience. AB - PURPOSE: We present the results of the systematic application of the first trimester combined test for aneuploidies, in a Romanian center. METHODS: Since October 2009, in Filantropia Hospital in Bucharest, we have systematically been using the FMF (Fetal Medicine Foundation) combined first trimester test to screen for common aneuploidies at 11 to 13 + 6 weeks of gestation. We assessed the crown to rump length (CRL), nuchal translucency, fetal heart rate as well as PAPP-A, and free beta-hCG in maternal serum. We evaluated additional first trimester ultrasound markers in most of the cases. The individual risk for aneuploidies was calculated using the FMF algorithm. RESULTS: Pregnancy outcome is known for 6030 euploid fetuses and 42 aneuploid fetuses from our screening population. The detection rate for trisomy 21 of the combined test was 87.5% for a screen positive rate of 1.96%. All of the trisomy 18 and trisomy 13 cases were detected prenatally. Some of the trisomy 18 cases proved not to be symptomatic in the first trimester. CONCLUSIONS: Our results are similar to those of the main studies on the FMF method of first trimester screening for aneuploidies. Our numbers are small because of limited availability of the very specialized resources involved. PMID- 28553773 TI - Evaluation of greenhouse gas emissions from waste management approaches in the islands. AB - Concerns about waste generation and climate change have attracted worldwide attention. Small islands, which account for more than one-sixth of the global land area, are facing problems caused by global climate change. This study evaluated the greenhouse gas emissions from five small islands surrounding Taiwan. These islands - Penghu County, Liuqui Island, Kinmen County, Matsu Island and Green Island - have their own waste management approaches that can serve as a guideline for waste management with greenhouse gas mitigation. The findings indicate that the total annual greenhouse gas emissions of the islands ranged from 292.1 to 29,096.2 [metric] tonne CO2-equivalent. The loading waste volumes and shipping distances were positively related to greenhouse gas emissions from transportation. The greenhouse gas emissions from waste-to-energy plants, mainly carbon dioxide and nitrous oxide, can be offset by energy recovery (approximately 38.6% of greenhouse gas emissions from incineration). In addition, about 34% and 11% of waste generated on the islands was successfully recycled and composted, respectively. This study provides valuable insights into the applicability of a policy framework for waste management approaches for greenhouse gas mitigation. PMID- 28553774 TI - Observation of a Pharmacist-Conducted Group A Streptococcal Pharyngitis Point-of Care Test: A Time and Motion Study. AB - BACKGROUND: Acute pharyngitis is among the most common infectious diseases encountered in the United States, resulting in 13 million patient visits annually, with group A streptococcus (GAS) being a common causative pathogen. It is estimated that annual expenditures for the treatment of adult pharyngitis will exceed US$1.2 billion annually. This substantial projection reinforces the need to evaluate diagnosis and treatment of adult pharyngitis in nontraditional settings. OBJECTIVE: The objective of this research is to quantify the amount of pharmacist time required to complete a point-of-care (POC) test for a patient presenting with pharyngitis symptoms. METHODS: A standardized patient with pharyngitis symptoms visited 11 pharmacies for POC testing services for a total of 33 patient encounters. An observer was present at each encounter and recorded the total encounter time, divided into 9 categories. Pharmacists conducted POC testing in 1 of 2 ways: sequence 1-pharmacists performed all service-related tasks; sequence 2-both pharmacists and pharmacist interns performed service related tasks. RESULTS: The average time for completion of a POC test for GAS pharyngitis was 25.3 +/- 4.8 minutes. The average pharmacist participation time per encounter was 12.7 +/- 3.0 minutes (sequence 1), which decreased to 2.6 +/- 1.1 minutes when pharmacist interns were involved in the testing (sequence 2). CONCLUSION: Although additional studies are required to further assess service feasibility, this study indicates that a GAS POC testing service could be implemented in a community pharmacy with limited disruption or change to workflow and staff. PMID- 28553775 TI - Electricity production from municipal solid waste in Brazil. AB - Brazil has an increasing production of municipal solid waste that, allied to the current waste management system, makes the search for alternatives of energy recovery essential. Thus, this work aims to study the incineration of municipal solid waste and the electricity production through steam cycles evaluating the influence of municipal solid waste composition. Several scenarios were studied, in which it was assumed that some fractions of municipal solid waste were removed previously. The municipal solid waste generated in Santo Andre city, Sao Paulo State, Brazil, was adopted for this study. Simulation results showed that the removal of organic matter and inert components impacts advantageously on the cycle performance, improving their parameters in some cases; in addition, there is the possibility of reusing the separated fractions. The separation of some recyclables, as plastic material, showed disadvantages by the reduction in the electricity generation potential owing to the high calorific value of plastics. Despite the high energy content of them, there are other possible considerations on this subject, because some plastics have a better recovery potential by recycling. PMID- 28553776 TI - Impact of New-Onset Left Ventricular Dysfunction on Outcomes in Mechanically Ventilated Patients With Severe Sepsis and Septic Shock. AB - BACKGROUND:: Left ventricular systolic dysfunction (LVSD) and LV diastolic dysfunction (LVDD) are commonly seen in severe sepsis and septic shock; however, their role in patients with concurrent invasive mechanical ventilation (IMV) is less well defined. METHODS:: This was a prospective observational study on all patients admitted to all the intensive care units (ICUs) at Mayo Clinic, Rochester from August 2007 to January 2009. All adult patients with severe sepsis and septic shock and concurrent IMV without prior heart failure underwent transthoracic echocardiography within 24 hours. Patients with active pregnancy, prior congenital or valvular heart disease, and prosthetic cardiac valves were excluded. Left ventricular systolic dysfunction was defined as LV ejection fraction (LVEF) <50% and LVDD as E/e' >15. Primary outcome was hospital mortality, and secondary outcomes included IMV duration, ICU length of stay (LOS), and total LOS. Two-tailed P value of <.05 was considered statistically significant. RESULTS:: In a total of 106 patients, 58 (54.7%) met our inclusion criteria, with 17 (29.3%), 11 (19.0%), and 5 (8.6%) having LVSD, LVDD, and both, respectively. The cohorts with and without LVSD and LVDD did not differ significantly in their baseline characteristics and laboratory and ventilatory parameters. Compared to those without LVSD, patients with LVSD had higher LV end systolic diameters but were not different in their left atrial diameters or E/e' ratio. Patients with LVDD had a higher E velocity and E/e' ratio compared to those without LVDD. Hospital mortality was not different in patients with and without LVSD (8 [47%] vs 21 [51%], P = 1.00) and LVDD (8 [73%] vs 21 [45%], P = .18). Secondary outcomes were not different between the 2 groups. CONCLUSION:: Left ventricular systolic or diastolic dysfunction did not influence in-hospital outcomes in patients with severe sepsis and septic shock and concurrent IMV. PMID- 28553777 TI - Avoiding key missteps on the road to publication: a view from 10,000 feet. PMID- 28553778 TI - Pulmonary hypertension and right heart failure due to severe hypernatremic dehydration. AB - INTRODUCTION: Neonates are at risk of developing hypernatremic dehydration and its associated complications, such as stroke, dural sinus thrombosis and renal vein thrombosis. Pulmonary hypertension has not been described as a complication of hypernatremia. CASE REPORT: We report a case of a seven-day-old neonate with severe hypernatremic dehydration who went on to develop pulmonary hypertension and right heart failure needing extracorporeal membrane oxygenation (ECMO). DISCUSSION: Normal or high anion gap metabolic acidosis commonly accompanies hypernatremic dehydration. The presence of acidosis and/or hypoxia can delay the normal drop in pulmonary vascular resistance (PVR) after birth, causing pulmonary hypertension and right ventricular failure. CONCLUSION: A high index of suspicion is paramount to diagnose pulmonary hypertension and aggressive correction of the acidosis and hypoxia is needed. In the presence of severe right ventricular failure, ECMO can be used as a bridge to recovery while underlying metabolic derangements are being corrected. PMID- 28553779 TI - Myocardial ischemia/reperfusion injury: the role of adaptor proteins Crk. AB - Recent studies have reported that the ischemia/reperfusion (I/R) myocardium may act as an immune system where an exaggerated inflammatory reaction initiates. With activation of the immune system, damage-associated molecular patterns migrate and adhere into the I/R region and, consequently, induce myocardial injury. Emerging data have indicated that the adaptor proteins Crk are thought to play essential roles in signaling during apoptosis and cell adhesion and migration. Accumulated data highlight that Crk proteins are potential immunotherapeutic targets in immune diseases. However, very few studies have determined the roles of Crk on myocardial I/R injury. This mini review will focus on the emerging roles of Crk adaptors during myocardial I/R injury. PMID- 28553780 TI - A comparison between minimized extracorporeal circuits and conventional extracorporeal circuits in patients undergoing aortic valve surgery: is 'minimally invasive extracorporeal circulation' just low prime or closed loop perfusion ? AB - INTRODUCTION: Even though results have been encouraging, an unequivocal conclusion on the beneficial effect of minimally invasive extracorporeal circulation (MiECC) in patients undergoing aortic valve surgery cannot be derived from previous publications. Long-term outcomes are rarely reported and a significant decrease in operative mortality has not been shown. Most studies have a limited number of patients and are underpowered. They merely report on short term results of a heterogeneous intraoperative group using different types of ECC system in aortic valve surgery. The aim of the present study was to determine whether MiECC systems are more beneficial than conventional extracorporeal systems (CECC) with regard to mortality, hospital stay and inflammation and with only haemodilution and blood-air interface as differences. METHODS: We retrospectively analysed data regarding mortality, hospital stay and inflammation in patients undergoing isolated aortic valve surgery. Forty patients were divided into two groups based on the type of extracorporeal system used; conventional (n=20) or MiECC (n=20). RESULTS: Perioperative blood product requirements were significantly lower in the MiECC group (MiECC: 0.2+/-0.5 units vs CECC: 0.9+/-1.2 units, p=0.004). No differences were seen postoperatively regarding mortality (5% vs 5%, p=0.99), total length of hospital stay (10.6+/-7.2 days (MiECC) vs 12.1+/ 5.9 days (CECC), p=0.39) or inflammation markers (CRP: MiECC: 7.09+/-13.62 mg/L vs CECC: 3.4+/-3.2 mg/L, p=0.89). CONCLUSION: MiECC provides circulatory support that is equally safe and feasible as conventional extracorporeal circuits. No differences in mortality, hospital stay or inflammation markers were observed. PMID- 28553781 TI - Modified drug-eluting balloon angioplasty to treat high-risk carotid in-stent restenosis. AB - Carotid artery stenting is commonly used to treat carotid artery stenosis. However, carotid in-stent restenosis remains a challenging problem. Herein, we report a difficult case of recurrent severe carotid in-stent restenosis with total contralateral internal carotid artery occlusion treated with repeat drug eluting balloon inflations. The outcome after one year of follow-up showed a good result. PMID- 28553782 TI - Coenzyme Q10 protects skeletal muscle from ischemia-reperfusion through the NF kappa B pathway. AB - OBJECTIVE: Coenzyme Q10 (CoQ10) has antioxidant and anti-inflammatory activity. The aim of this study was to investigate the effects of CoQ10 on the inhibition of nuclear factor-kappa B (NF-kappaB) activation during ischemia-reperfusion (I/R) of skeletal muscle. METHODS: For ischemia induction, the animals were anesthetized and the external iliac vessels blocked for three hours. CoQ10 or vehicle was given intraperitoneally during ischemia, just before reperfusion. Four groups received 3,7,14 and 28 days' reperfusion, respectively, after the intraperitoneal injection of CoQ10 and four corresponding groups received vehicle only. After reperfusion, the gastrocnemius muscles were removed, fixed and stained for the analysis of edema and mast cell infiltration. RESULTS: Immuno histochemistry staining was performed for the detection of tumor necrosis factor alpha (TNF-alpha) and NF-kappaB. CoQ10-treated groups showed a significant decrease of mast cell infiltration in the gastrocnemius muscle and edema as compared with the corresponding non-treated groups. Also, CoQ10-treated groups showed a significant TNF-alpha and NF-kappaB expression decrease when compared to the corresponding non-treated controls. The results of this study showed CoQ10 administration with ischemia decreased interstitial edema, degeneration of muscle fibers and infiltration of mast cells. CONCLUSIONS: It seems that CoQ10 has inhibitory effects on NF-kappaB and TNF-alpha activation. PMID- 28553783 TI - A retrospective cohort analysis of percutaneous versus side-graft perfusion techniques for veno-arterial extracorporeal membrane oxygenation in patients with refractory cardiogenic shock. AB - OBJECTIVES: This study was designed to compare vascular complications and the outcomes of ultrasound (US)-guided percutaneous cannulation with distal perfusion catheter (PC-DP) and arterial side-graft perfusion (SGP) techniques in patients who require veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support for refractory cardiogenic shock (RCS). METHODS: We conducted a retrospective, observational cohort study of consequtive patients with RCS treated with VA-ECMO at a single transplant center from March 2010 until August 2015. Overall, 148 patients underwent VA-ECMO for RCS (99 men, aged 56.6 +/- 12.0 years; BSA, 1.85 +/- 0.19). Patients were categorized based on VA-ECMO perfusion technique into PC DP via femoral artery and SGP via axillary/femoral artery groups. RESULTS: The median duration of VA-ECMO support was 5 days (range, 8 hours-80 days). Hospital mortality (PC-DP group, 54.7%; SGP group, 64.4%; p=0.23) and overall ECMO survival (PC-DP group, 36.9%; SGP group, 32.2%; p=0.47) was similar between the groups. There were no significant between-group differences in the rate of acute limb ischemia (PC-DP group, 4/75, 5.3%; SGP group, 2/73, 2.7%; p=0.68). However, the rate of surgical/cannulation site bleeding (PC-DP, 9/75 (12%) vs SGP, 18/73 (24.7%), p=0.05) and hyperperfusion syndrome (PC-DP, 2/75 (2.7%) vs SGP, 22/73 (30.1%),p=0.001) were higher in the SGP group than in the PC-DP group. CONCLUSIONS: We observed no significant difference in major vascular complications or survival between patients who underwent the PC-DP technique and those who underwent arterial SGP. PMID- 28553784 TI - The Association Between Excessive Daytime Sleepiness and Gait Parameters in Community-Dwelling Older Adults: Cross-Sectional Findings From the Obu Study of Health Promotion for the Elderly. AB - OBJECTIVE: This study examined the association between excessive daytime sleepiness (EDS) and gait characteristics (e.g., speed, variability) in community dwelling older adults. METHOD: This cross-sectional study included 3,901 individuals aged >=65 years. Participants answered questions about EDS, sleep duration, and other sleep-related symptoms. Gait speed, stride length, and the variability in stride length were assessed by using a stopwatch and a WalkWay device. RESULTS: EDS was significantly associated with slower gait speed among younger subjects (<75 years, p = .021) and with both slower gait speed ( p = .045) and greater variability in stride length among older subjects (>=75 years, p = .048) in a multivariate analysis adjusted for age, sex, body mass index, medication, number of comorbidities, and education. DISCUSSION: EDS associates with gait ability, particularly in older old adults. Further prospective studies are needed to determine the causal association between gait ability and sleep disturbances, including EDS. PMID- 28553785 TI - Social Isolation, Depression, and Psychological Distress Among Older Adults. AB - OBJECTIVE: To investigate the impact of objective and subjective social isolation from extended family members and friends on depressive symptoms and psychological distress among a national sample of older adults. METHOD: Data for older adults (55 years and above) from the National Survey of American Life ( N = 1,439) were used to assess level of objective social isolation and subjective social isolation and to test regression models examining their impact on depressive symptoms (Center for Epidemiologic Studies Depression [CES-D] Scale) and psychological distress (Kessler 6 [K6] Scale). RESULTS: The majority of respondents were not socially isolated from family or friends; 5% were objectively isolated from family and friends, and less than 1% were subjectively isolated from family and friends. Regression analyses using both social isolation measures indicated that objective social isolation was unrelated to depressive symptoms and psychological distress. However, subjective social isolation from both family and friends and from friends only was associated with more depressive symptoms, and subjective social isolation from friends only was associated with higher levels of psychological distress. DISCUSSION: Assessments of social isolation among older populations should account for both subjective and objective dimensions, as well as both family and friend social networks. Social isolation from friends is an important, but understudied, issue that has significant consequences for older adult mental health. PMID- 28553786 TI - Do Worries About Cognitive Functioning and Concerns About Developing Alzheimer's Disease Affect Psychological Well-Being? AB - OBJECTIVE: The objective of this study is to determine if cognitive worries affect psychological well-being, if these effects are long-term, and if such concerns affect well-being more so among persons with a parent having Alzheimer's disease (AD). METHOD: We used structural equation models with three waves of data collected from persons ages 40 to 60 at T1. We created summative scores on five indicators of concerns about cognitive functioning and worries about dementia. Well-being measures included depression, life satisfaction, stress, and mastery. RESULTS: We found (a) cognitive worries at Waves 1, 2, and 3 were generally associated with lower levels of psychological well-being at each of these waves; (b) there was no evidence of long-term, lagged effects, and (c) these relationships were statistically similar across groups of adult children and controls. DISCUSSION: Because concerns about cognitive functioning and developing AD are pervasive among middle-aged and older persons, practitioners should be aware of their potentially deleterious effect on psychological well-being. PMID- 28553787 TI - Quality of Life Trajectories Predict Mortality in Older Men: The Manitoba Follow Up Study. AB - OBJECTIVE: To describe quality of life trajectories of older men over a 10-year time frame in mental and physical health domains, and to determine if these trajectories predict death over a subsequent 9-year period. METHOD: A cohort study of Royal Canadian Air Force aircrew veterans. We used Short Form-36 (SF-36) measures of mental and physical functioning collected prospectively at six time points between 1996 to 2006 (734 men with a mean age of 85.5 [ SD 3.0] years in 2006) to determine trajectories. Continued contact with the cohort from 2006 to 2015 determined subsequent mortality. RESULTS: Men were more likely to maintain high levels of mental functioning than physical functioning. Thirty-seven percent of participants maintained a high level of both mental and physical functioning. Declining function in either mental or physical function was associated with lower survival. CONCLUSION: Men who maintain physical and mental functioning have a lower mortality rate. PMID- 28553788 TI - Reliability of a Novel Social Activity Questionnaire: Perceived Social Support and Verbal Interaction in the Wisconsin Registry for Alzheimer's Prevention. AB - OBJECTIVE: Social activity is associated with healthy aging and preserved cognition. Such activity includes a confluence of social support and verbal interaction, each influencing cognition through rarely parsed, mechanistically distinct pathways. We created a novel verbal interaction measure for the Wisconsin Registry for Alzheimer's Prevention (WRAP) and assessed reliability of resultant data, a first step toward mechanism-driven examination of social activity as a modifiable predictor of cognitive health. METHOD: Two WRAP subsamples completed a test-retest study to determine 8-week stability ( n = 107) and 2-year stability ( n = 136) of verbal interaction, and 2-year stability of perceived social support. Reliability was determined using quadratic-weighted kappa, percent agreement, or correlation coefficients. RESULTS: Reliability was fair to almost perfect. The association between social support and interaction quantity decreased with age. DISCUSSION: Social activity data demonstrate moderate to excellent temporal stability. Moreover, in older individuals, social support and verbal interaction represent two distinct dimensions of social activity. PMID- 28553789 TI - Aging Audiences: Association of Live Performance Attendance and Cognitive Decline in a Biracial Sample. AB - OBJECTIVES: To examine if attendance in live performances was associated with change in cognition among African Americans (AAs) and European Americans (EAs). METHOD: The study consisted of 5,567 older adults with at least follow-up interview and analyzed using a linear mixed effects regression model adjusting for demographic and health variables. RESULTS: We found that frequent performance attendance was associated with slower decline in composite cognitive function among older AAs and EAs. Attending 10 or more performances per year was associated with 23% slower cognitive decline among AAs and 31% slower cognitive decline among EAs compared with those who never attend any performance. However, this difference was not significant ( p = .56). Attending live performances was also associated with slower decline in individual tests of perceptual speed, episodic memory, and mini-mental state exam (MMSE). DISCUSSION: Our findings suggest that live performances form a valuable component of arts engagement and should be encouraged for potential cognitive benefits. PMID- 28553790 TI - Loneliness and Depression Among Older Adults in Urban Subsidized Housing. AB - OBJECTIVE: Depression is particularly prevalent in low-income and disabled older adults, and minority populations face a greater risk of poverty and earlier disability onset. Yet, little is known about the mental health of older subsidized housing residents, a population which is disproportionately composed of persons of color. The study's aim was therefore to explore the prevalence and correlates of depression in this target population, with a particular focus on the role of loneliness. METHOD: Data are from interviews with 216 older subsidized housing residents, of which 50% identified as Black and 45% self identified as Latino. RESULTS: About 26% of participants met the criterion for depression. The hierarchical regression supported our hypothesis; after controlling for demographic, health, and stress variables, loneliness explained almost half of the total 49% of variance in depression. DISCUSSION: Care models addressing social risk factors are needed to meet the aging-in-place challenges of subsidized housing residents. PMID- 28553792 TI - Adherence to Guidelines for Screening and Medication Use: Mortality and Onset of Major Macrovascular Complications in Elderly Persons With Diabetes Mellitus. AB - OBJECTIVE: The objective of this study is to investigate relationships between adherence to recommended screening and medication use and severe macrovascular complications and all-cause mortality among persons aged above 68 years with diabetes mellitus (DM). METHOD: Data came from a 5% Medicare claims sample of beneficiaries initially diagnosed with DM during 2006-2008; follow-up was up to 7 years. RESULTS: Adherence to screening guidelines led to reduced mortality-hazard ratio (HR) = 0.57, 95% confidence interval [CI] = [0.56, 0.58]; congestive heart failure [CHF], HR = 0.89, CI = [0.87, 0.91]; acute myocardial infarction [AMI], HR = 0.90, CI = [0.85, 0.95]; and stroke/transient ischemic attack [Stroke/TIA], HR = 0.92, CI = [0.87, 0.97]-during follow-up. Recommended medication use led to lower mortality: HR = 0.72, CI = [0.70, 0.73]; CHF, HR = 0.67, CI = [0.66, 0.69]; AMI, HR = 0.68, CI = [0.65, 0.71]; and Stroke/TIA, HR = 0.79, CI = [0.76, 0.83]. DISCUSSION: Elderly persons newly diagnosed with diabetes who adhered to recommended care experienced reduced risk of mortality and severe macrovascular complications. PMID- 28553791 TI - The Impact of Three Cognitive Training Interventions on Older Adults' Physical Functioning Across 5 Years. AB - OBJECTIVE: Physical functioning is closely associated with cognition. The current study assessed the impact of three cognitive training programs on objective measures of physical functioning across 5 years. METHOD: Older adults randomized to a processing speed ( n = 702), reasoning ( n = 694), or memory ( n = 703) training intervention were compared with those randomized to a no-contact control condition ( n = 698). Intention-to-treat (ITT) and treatment-received/dosage (time-varying number of training sessions) analyses were conducted. RESULTS: There were no transfer effects in the ITT analyses. Treatment-received models demonstrated that training sessions (i.e., higher dosage) across all intervention arms transferred to better maintained Digit Symbol Copy and Turn 360 performance relative to the control group. More reasoning training transferred to better grip strength. DISCUSSION: This is the first study to demonstrate differential longitudinal cognitive training transfer effects to three performance-based physical functioning measures. Future research should investigate mechanisms of far-transfer effects. PMID- 28553794 TI - The Utilization of Health Services and Self-Care by Older Women With Sleeping Problems: Results From a Nationally Representative Sample of 9,110 Women. AB - OBJECTIVE: This research aims to investigate the health service use-including complementary and alternative medicine (CAM)-and self-care by women aged 62 to 67 with sleeping problems. METHOD: In total, 9,110 participants (99.6%) responded to questions about sleeping problems, health service utilization and self-care (e.g., herbal medicines and vitamins), demographics, and chronic illnesses. RESULTS: In all, 48.2% ( n = 4,394) women indicated that they had a sleeping problem. Women with sleeping problems consulted a general practitioner (GP) more frequently (odds ratio [OR] = 1.72; 95% confidence interval [CI] = [1.36, 2.17]; p < .005) and were more likely to be using herbal medicines (OR = 1.24; 95% CI = [1.13, 1.36]; p < .005) than women without sleeping problems. DISCUSSION: Health professionals, particularly GPs, may need to actively inquire with older patients in their care with sleeping problems about the use of herbal medicines, to ensure their sleeping problems are being directly and effectively treated, particularly in light of increased risks associated with sleeping problems for this age cohort. PMID- 28553793 TI - Modeling Exposure to Multiple Childhood Social Risk Factors and Physical Capability and Common Affective Symptoms in Later Life. AB - OBJECTIVE: This study presents three approaches, that is, cumulative risk, factor analysis, and latent class analysis, to summarize exposure to multiple childhood social risk factors and to compare their utility when examining associations with physical capability and common affective symptoms in adults aged 60 to 64 years. METHODS: Data came from the U.K. Medical Research Council (MRC) National Survey of Health and Development, with prospective childhood social risk factor data collected in 1950 to 1957 and retrospectively in 1989. Physical capability and common affective symptom data were collected in 2006 to 2011. RESULTS: The cumulative risk approach and factor analysis provided evidence that children who were exposed to multiple social risk factors had lower levels of physical capability and more symptoms of common affective symptoms in later life. DISCUSSION: The cumulative social risk approach and the use of factor analysis to identify contexts of social risk, may offer viable methods for linking multiple childhood social risk exposure to aging outcomes. PMID- 28553795 TI - Disentangling Loneliness: Differential Effects of Subjective Loneliness, Network Quality, Network Size, and Living Alone on Physical, Mental, and Cognitive Health. AB - OBJECTIVE: To examine whether different measures of social disconnectedness subjective loneliness, network quality, network size, living alone-have differential effects on the health of older adults. METHODS: We used a longitudinal sample of the German Aging Survey ( N = 4,184) and analyzed seven measures of health (life satisfaction, positive affect, negative affect, depression, cognitive performance, physical functioning, and pulmonary function) via regression analyses. RESULTS: We found that subjective loneliness and network quality best predicted mental health; contrarily, network size and living alone best predicted physical and cognitive health. DISCUSSION: Different measures of social disconnectedness have differential effects on health. Therefore, using only global measures or one aspect of social disconnectedness might obfuscate potential health hazards. Researchers and practitioners should be mindful of differences between these measures and should include multiple aspects of social disconnectedness in their research and practice. Future studies should explore the causes why these measures and their effects differ. PMID- 28553796 TI - Association Between Depression and Elder Abuse and the Mediation of Social Support: A Cross-Sectional Study of Elder Females in Mexico City. AB - OBJECTIVE: We assessed the association between depression and elder abuse, and the mediation effect of social support among elder women in Mexico City. METHOD: A total of 526 noninstitutionalized elder women, residing in Mexico City and attending public community centers were selected. Logistic regressions and structural equation models (SEM) were estimated. RESULTS: One fifth of the elderly women were at risk of depression, one third suffered some type of abuse in the past 12 months, and 82% reported low social support. Logistic models confirmed that depression was statistically associated with elder abuse and vice versa (odds ratio [OR] = 1.97 and 1.96, respectively). In both models, social support significantly reduced the association between these variables leading to study these associations through SEM. This approach highlighted that social support buffers the association between depression and elder abuse. DISCUSSION: Findings underline the relevance of programs and strategies targeted at increasing social support among urban older adults. PMID- 28553797 TI - Informal Care Networks in the Context of Multimorbidity: Size, Composition, and Associations With Recipient Psychological Well-Being. AB - OBJECTIVE: We evaluate how the size and composition of care networks change with increasing morbidity count (i.e., multimorbidity) and how larger care networks relate to recipient psychological well-being. METHOD: Using the National Health and Aging Trends study (NHATS; N = 7,026), we conduct multivariate regressions to analyze size and compositional differences in care networks by morbidity count and recipient gender, and to examine differences in recipient psychological well being linked to care network size. RESULTS: Women report larger and more diverse care networks than men. These gender differences strengthen with increasing morbidity count. Larger care networks are associated with diminished psychological well-being among care recipients, especially as morbidity increases. DISCUSSION: These findings reveal how increasing morbidity translates differently to care network size and diversity for men and women. They also suggest that having multiple caregivers may undermine the psychological well being of care recipients who face complex health challenges. PMID- 28553798 TI - Race Differences in ADL Disability Decline 1984-2004: Evidence From the National Long-Term Care Survey. AB - OBJECTIVE: Disability declined in lower levels of impairment during the late 20th century. However, it is unclear whether ADL disability also declined, or whether it did so across race. In this study, we examine cohorts entering later life between 1984 and 1999, by race, to understand changing ADL disability. METHOD: We used latent class methods to model trajectories of ADL disability and subsequent mortality in the National Long-Term Care Survey among cohorts entering older adulthood (ages 65-69) between 1984 and 1999. We examined patterns by race, focusing on chronic condition profiles. RESULTS: White cohorts experienced consistent declines in ADL disability but Blacks saw little improvement with some evidence for increased disability. Stroke, diabetes, and heart attack were predominant in predicting disability among Blacks. DISCUSSION: Declining disability trends were only observed consistently among Whites, suggesting previous and future disability trends and their underlying causes should be examined by race. PMID- 28553799 TI - Promoting Functional Activity Among Nursing Home Residents: A Cross-Sectional Study on Barriers Experienced by Nursing Staff. AB - OBJECTIVE: To obtain insight into (a) the prevalence of nursing staff-experienced barriers regarding the promotion of functional activity among nursing home residents, and (b) the association between these barriers and nursing staff perceived promotion of functional activity. METHOD: Barriers experienced by 368 nurses from 41 nursing homes in the Netherlands were measured with the MAastrIcht Nurses Activity INventory (MAINtAIN)-barriers; perceived promotion of functional activities was measured with the MAINtAIN-behaviors. Descriptive statistics and hierarchical linear regression analyses were performed. RESULTS: Most often experienced barriers were staffing levels, capabilities of residents, and availability of resources. Barriers that were most strongly associated with the promotion of functional activity were communication within the team, (a lack of) referral to responsibilities, and care routines. DISCUSSION: Barriers that are most often experienced among nursing staff are not necessarily the barriers that are most strongly associated with nursing staff-perceived promotion of functional activity. PMID- 28553800 TI - Predictors of Continued Smoking and Interest in Cessation Among Older Female Smokers. AB - OBJECTIVES: Older female smokers are highly vulnerable, yet little is known about their attitudes, beliefs, and behaviors regarding smoking cessation. METHODS: Southeast region Women's Health Initiative participants identified as smokers on at least one prior assessment were surveyed in 2012 regarding current tobacco use. RESULTS: Most of these current and former smokers ( N = 409, 63% response) were non-Hispanic White (81.7%) and had some college (80%), with mean age of 75.1 years. Current smoking was confirmed by 56%, and while 61% of these reported a past-year quit attempt, less than half used quit aids. Of current smokers, 57.5% intended to quit within 6 months (26.6% within 30 days), and 68% were interested in joining a cessation study. CONCLUSIONS: Older female smokers were highly motivated to quit, yet profoundly underutilized proven quit aids. Results support high acceptability of cessation interventions for this undertreated population. PMID- 28553802 TI - Circumstances of Falls With Fractured Femur in Residents of Australian Nursing Homes: An Analysis of Falls Reports. AB - OBJECTIVE: This study aimed to explore the circumstances and characteristics of falls with fractured femur reported in nursing homes. METHOD: Mixed methods were used. There were reports on 401 eligible falls from 88 residential care facilities in the Hunter region of Australia. A falls report form was developed for the study and was completed by nursing staff. Information was collected about the circumstances of falls with fractured femur and resident data. Descriptive and qualitative analyses were used. RESULTS: Falls with fractured neck of femur were associated with being ambulant, having dementia, increasing age, and a high falls risk assessment. Themes from the falls report data were resident-related factors, organizational or environmental issues, and activities at the time of the fall. DISCUSSION: Falls in residential care settings are very complex and difficult to prevent. Attention should be given to the needs of recently admitted residents and management of the facility environment. PMID- 28553801 TI - The Association Between Lipoproteins, Disability, and Physical Function Among Older Costa Rican Adults. AB - OBJECTIVE: To examine the relationship between total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) with disability and physical performance. METHOD: Wave 1 data were from Costa Rican Longevity and Healthy Aging Study ( n = 2,827). Lipoprotein profiles were measured using blood samples. Disability and physical functioning were measured with activities of daily living/instrumental activities of daily living (ADLs/IADLs) and objective assessment of physical performance. RESULTS: Lower HDL C was associated with greater ADL disability, and lower TC with longer time to pick-a-pencil and Time-Up-Go (TUG) test. Age interacted between (a) TG and lung function, chair stands, and pick-a-pencil, and (b) HDL-C and TUG. Stratification showed lower TG and longer time picking up a pencil only for those above 84 years. Based on significant interactions with sex, lower TC was associated with slower chair stand time in women and higher HDL-C with slower chair stand time in men. DISCUSSION: Lower levels of lipoproteins may suggest worse physical function, but the association may differ by sex. PMID- 28553803 TI - Death Following Recent Admission Into Nursing Home From Community Living: A Systematic Review Into the Transition Process. AB - OBJECTIVE: This study examines the impact of the transition process on the mortality of elderly individuals following their first admission to nursing home from the community at 1, 3, and 6 months postadmission, and causes and risk factors for death. METHOD: A systematic review of relevant studies published between 2000 and 2015 was conducted using key search terms: first admission, death, and nursing homes. RESULTS: Eleven cohort studies met the inclusion criteria. Mortality within the first 6 month postadmission varied from 0% to 34% (median = 20.2). Causes of deaths were not reported. Heightened mortality was not wholly explained by intrinsic resident factors. Only two studies investigated the influence of facility factors, and found an increased risk in facilities with high antipsychotics use. DISCUSSION: Mortality in the immediate period following admission may not simply be due to an individual's health status. Transition processes and facility characteristics are potentially independent and modifiable risk factors. PMID- 28553804 TI - Resilience in the Disabling Effect of Gait Speed Among Older Turkish and Moroccan Immigrants and Native Dutch. AB - OBJECTIVE: To investigate the factors that inhibit the disabling effect of impairments among citizens who have migrated from Turkey and Morocco and native Dutch according to a resilience perspective. METHOD: Using data from the Longitudinal Aging Study Amsterdam with 928 native Dutch, 255 Turks, and 199 Moroccans aged 55 to 65, linear regression analysis assessed whether country of origin, mastery, income, and contact frequency modified the relationship between gait speed and activity limitations. RESULTS: Turks, but not Moroccans, demonstrated stronger associations between gait speed and activity limitations than the Dutch. Mastery modified the association among the Dutch and the Turks. Income modified the association only among the Dutch. Effect modification by contact frequency was not observed. DISCUSSION: Moroccans and Dutch appeared to be more resilient against impairments than Turks. As none of the resilience factors buffered in all three populations, we conclude that resilience mechanisms are not universal across populations. PMID- 28553805 TI - Prayer, Attachment to God, and Changes in Psychological Well-Being in Later Life. AB - OBJECTIVE: The aim of this study was to investigate the effects of prayer and attachment to God on psychological well-being (PWB) in later life. METHOD: Using data from two waves of the nationwide Religion, Aging, and Health Survey, we estimate the associations between frequency of prayer and attachment to God at baseline with cross-wave changes in three measures of PWB: self-esteem, optimism, and life satisfaction. RESULTS: Prayer does not have a main effect on PWB. Secure attachment to God is associated with improvements in optimism but not self-esteem or life satisfaction. The relationship between prayer and PWB is moderated by attachment to God; prayer is associated with improvements in PWB among securely attached individuals but not those who are insecurely attached to God. DISCUSSION: These findings shed light on the complex relationship between prayer and PWB by showing that the effects of prayer are contingent upon one's perceived relationship with God. PMID- 28553806 TI - Perspectives of Patients, Clinicians, and Health System Leaders on Changes Needed to Improve the Health Care and Outcomes of Older Adults With Multiple Chronic Conditions. AB - OBJECTIVE: To ascertain perspectives of multiple stakeholders on contributors to inappropriate care for older adults with multiple chronic conditions. METHOD: Perspectives of 36 purposively sampled patients, clinicians, health systems, and payers were elicited. Data analysis followed a constant comparative method. RESULTS: Structural factors triggering burden and fragmentation include disease based quality metrics and need to interact with multiple clinicians. The key cultural barrier identified is the assumption that "physicians know best." Inappropriate decision making may result from inattention to trade-offs and adherence to multiple disease guidelines. Stakeholders recommended changes in culture, structure, and decision making. Care options and quality metrics should reflect a focus on patients' priorities. Clinician-patient partnerships should reflect patients knowing their health goals and clinicians knowing how to achieve them. Access to specialty expertise should not require visits. DISCUSSION: Stakeholders' recommendations suggest health care redesigns that incorporate patients' health priorities into care decisions and realign relationships across patients and clinicians. PMID- 28553807 TI - Outcomes of a Digital Health Program With Human Coaching for Diabetes Risk Reduction in a Medicare Population. AB - OBJECTIVE: To examine the outcomes of a Medicare population who participated in a program combining digital health with human coaching for diabetes risk reduction. METHOD: People at risk for diabetes enrolled in a program combining digital health with human coaching. Participation and health outcomes were examined at 16 weeks and 6 and 12 months. RESULTS: A total of 501 participants enrolled; 92% completed at least nine of 16 core lessons. Participants averaged 19 of 31 possible opportunities for weekly program engagement. At 12 months, participants lost 7.5% ( SD = 7.8%) of initial body weight; among participants with clinical data, glucose control improved (glycosylated hemoglobin [HbA1c] change = -0.14%, p = .001) and total cholesterol decreased (-7.08 mg/dL, p = .008). Self-reported well-being, depression, and self-care improved ( p < .0001). DISCUSSION: This Medicare population demonstrated sustained program engagement and improved weight, health, and well-being. The findings support digital programs with human coaching for reducing chronic disease risk among older adults. PMID- 28553808 TI - Medicalization of Sleep Problems in an Aging Population: A Longitudinal Cross National Study of Medication Use for Sleep Problems in Older European Adults. AB - OBJECTIVE: The association between age and sleep problems is considered to be positive, and medication use is a common health care intervention among older individuals. Because daytime consequences are often stated as a reason to seek care, we study to what extent the medicalization of sleep problems is found in an aging European population, with a focus on daily activities. METHOD: Data from the Survey of Health Ageing and Retirement in Europe are used in three-level, generalized linear mixed models. Medicalization is operationalized as the use of medication for sleep problems at least once per week. RESULTS: Men are more likely than women to use medication for sleep problems, and the process of aging is associated with a decrease in medicalization. DISCUSSION: Sleep problems seem to be medicalized particularly when they prevent aging individuals from engaging in work-related responsibilities, as medication is especially used by employed individuals with sleep problems. PMID- 28553809 TI - Public Perspectives Toward the Sexual Behavior of an Individual With Dementia Residing in Long-Term Care. AB - OBJECTIVE: This study examines public perspectives toward sexual behavior within a heterosexually married couple in which one individual has dementia and resides in a long-term care facility. METHOD: Respondents included 318 adults in the Southern United States. Paired sample t tests were used to understand how the diagnosis of dementia statistically influenced participants' responses, and a logistic regression model was used to understand how a vignette character's sex and respondent characteristics influenced attitudes. RESULTS: Fifty-eight percent of respondents believed that a sexual relationship should be permitted for an adult with dementia, and t tests revealed that dementia had a statistical effect on participants' responses. Sex of the vignette character was not a predictor of attitudes. Participant's qualitative rationales are offered for additional insight. DISCUSSION: Respondents who felt that a couple should not engage in a sexual relationship commonly cited consent-related issues as their primary concern. Implications for policy development are discussed. PMID- 28553812 TI - Does Oral Health Predict Functional Status in Late Life? Findings From a National Sample. AB - OBJECTIVE: This study aims to examine the association between oral health and the decline in functional status among middle-aged and older adults in the United States. METHOD: Generalized estimation equation (GEE) Poisson regression models with robust standard errors were used to analyze the longitudinal panel data (2008-2014) from the Health and Retirement Study ( N = 1,243). Oral health was evaluated using self-rated oral health, poor mouth condition, and tooth loss. Decline in functional status was assessed by disabilities in activities of daily living (ADLs) and instrumental activities of daily living (IADLs). RESULTS: Respondents with poor oral health were more likely to experience decline in ADLs/IADLs. Adjusting for sociodemographics and comorbidities attenuated the effects of oral health. DISCUSSION: Findings suggest that oral health might be one of the important predictors of functioning decline in late life, after adjusting sociodemographics and comorbidities. PMID- 28553811 TI - White-Black Differences in Cancer Incidence, Stage at Diagnosis, and Survival Among Older Adults. AB - OBJECTIVE: To identify potential White-Black differences in cancer incidence rates, stage at diagnosis, and relative survival probabilities among older adults using Surveillance, Epidemiology, and End Results (SEER) data. METHOD: Differences in cancer incidence, stage at diagnosis, and 5-year relative survival probability were examined for cases diagnosed within the most recent 5-year period and over time for cases diagnosed from 1973 to 2013 (incidence only) for older White and Black adults. RESULTS: Among adults aged 65 to 74, 75 to 84, and 85 years and older, Black adults had higher cancer incidence rates per 100,000 than White males from 1973 to 2013, respectively. Late stage and unstaged cancers were more common among Black adults in each of the three age groups compared with Whites. Five-year relative survival probability for all invasive cancers combined was higher for Whites than Blacks in each of the three age groups. DISCUSSION: Continued efforts are needed to reduce racial disparities in cancer incidence and mortality among older adults. PMID- 28553810 TI - The Association Between Depressive Symptoms and Cognitive Functioning in Older Hispanic/Latino Adults Enrolled in an Exercise Intervention: Results From the "!Caminemos!" Study. AB - OBJECTIVE: We examined the association between depressive symptoms and cognitive functioning in older Hispanics/Latinos enrolled in an exercise intervention. METHOD: We analyzed baseline, 1-year, and 2-year in-person interview data collected from Hispanics/Latinos aged >=60 years participating in an exercise intervention across 27 senior centers ( N = 572). RESULTS: Mean age was 73.13 years; 77% female. At baseline, older adults screening positive for depression were 1.58 times more likely to experience cognitive impairment ( p = .04); controlling for demographics and comorbid chronic conditions. Compared to peers with little to no depressive symptoms, lower cognitive functioning scores were evident at each follow-up assessment point where elevated depressive symptoms were present, but baseline depression was not associated with cognitive function in longitudinal analyses. DISCUSSION: In older Hispanics/Latinos enrolled in an exercise intervention, though baseline depression did not predict cognitive function over time, elevated symptoms of depression were associated with greater cognitive impairment at every point in this study. PMID- 28553813 TI - Social Relationships and Inflammatory Markers in the MIDUS Cohort: The Role of Age and Gender Differences. AB - OBJECTIVE: To better understand age and gender differences in associations of social relationships with chronic inflammation. METHOD: Using a sample of middle aged and older adults ( N = 963) from the Midlife Development in the United States (MIDUS) biomarker project, we examined interactions of age and gender with structural and functional social network measures in predicting interleukin-6 (IL 6) and C-reactive protein (CRP). RESULTS: Significant interactions involving age and gender showed that social support was associated with lower IL-6 in older women, whereas perceived positive relationships and social integration were related to lower IL-6 in both men and women of advanced age. Functional measures were associated with higher CRP in both men and women after adjustment for health conditions and behaviors, with some further variation by age. DISCUSSION: Greater social support may be related to lower IL-6 in older women. Further research is needed to understand observed associations of social support with higher CRP. PMID- 28553814 TI - Psychosocial and Mental Health Problems of Older People in Postearthquake Nepal. AB - OBJECTIVE: To identify community perceptions on psychosocial and mental health problems of older people in postearthquake situation in Nepal. METHOD: A qualitative methodology was adopted to explore the experience and opinions of older people, social workers, school teachers, health workers, and nongovernmental organization workers on the psychosocial and mental health problems of older people in Nepal, using key informant interviews. RESULTS: Major local vocabulary for older peoples' psychosocial and mental health problems were "bichalan" (variation in mood and feeling), "ekohoro" (becoming single minded), "athmabiswasko kami" (low self-esteem), and "bina karan rune" (crying without any reason). The major causes attributed to older people's problems were physical injury, disability, family conflict, and economic problems. Forgetfulness, tiredness, loss of concentration, restlessness, and isolation were observed in older people since the 2015 earthquake. DISCUSSION: The findings suggest that earthquake had negative impact on older people's psychosocial well-being; however, little support or treatment options have been made available to these individuals. The tailor-made community-based psychosocial and mental health programs for older people are needed. PMID- 28553815 TI - Cognition and Context: Rural-Urban Differences in Cognitive Aging Among Older Mexican Adults. AB - OBJECTIVE: To describe differences in cognitive functioning across rural and urban areas among older Mexican adults. METHOD: We include respondents aged 50+ in the 2012 Mexican Health and Aging Study (MHAS). Cognitive functioning by domain is regressed as a function of community size. The role of educational attainment in explaining rural/urban differences in cognitive functioning is examined. RESULTS: Respondents residing in more rural areas performed worse across five cognitive domains. The majority, but not all, of the association between community size and cognitive functioning was explained by lower education in rural areas. DISCUSSION: Respondents residing in more rural areas were disadvantaged in terms of cognitive functioning compared with those residing in more urban areas. Poorer cognitive functioning in late life may be the result of historical educational disadvantage in rural areas or selection through migration from rural to urban regions for employment. PMID- 28553816 TI - Heterogeneous Trajectories of Depressive Symptoms in Late Middle Age: Critical Period, Accumulation, and Social Mobility Life Course Perspectives. AB - OBJECTIVE: This study investigated patterns of depressive symptoms and whether socioeconomic status (SES) across the life course affects these trajectories using the critical period, accumulation, and social mobility models. METHOD: This study uses data from 8,532 adults, age 51 to 64, collected over 12 years from the Health and Retirement Study (observations = 25,887). A latent class analysis was performed to examine distinct depressive symptom trajectories; life course models were studied with multinomial logistic regression. RESULTS: Four heterogeneous latent classes were identified for depression: Declining, Low, Increasing, and High and Increasing. The High and Increasing group was associated with a disadvantaged childhood SES, accumulated exposure to socioeconomic risks, and persistent SES disadvantage supporting the three life course models. DISCUSSION: There was evidence of distinct profiles of depressive symptoms in late middle age and of interrelated life course mechanisms underlying the influences of childhood SES on later life depression. PMID- 28553817 TI - The Complex Association Between Fear of Falling and Mobility Limitation in Relation to Late-Life Falls: A SHARE-Based Analysis. AB - OBJECTIVE: This study examines fear of falling (FOF) in relation to falls in light of mobility limitation. METHOD: Data on community-dwelling older Europeans, aged 65+, were drawn from two consecutive waves of the Survey of Health, Ageing and Retirement in Europe (SHARE). The analysis regressed fall status in 2013 on reported FOF 2 to 3 years earlier, controlling for previous falls. RESULTS: FOF predicted subsequent falls when mobility limitation was low to moderate. However, the effect of FOF on fall probability was reversed when mobility limitation was high. DISCUSSION: The analysis underscores a complex association between FOF and mobility limitation in relation to late-life falls. People who are worried about falling tend to fall more. Those having high mobility limitation but lacking FOF are also more likely to fall. In cases of considerable mobility limitation, FOF may act as a protective buffer. The less worried in this group, however, may be subject to greater falling, and thus require greater attention. PMID- 28553818 TI - Mastery and Depressive Symptoms: How Does Mastery Influence the Impact of Stressors From Midlife to Old Age? AB - OBJECTIVE: The objective of this research is to study depressive symptoms (DS) among adults aged 40 to 79 years and examine how mastery influences the impact of sociodemographic, socioeconomic, and health factors on DS. METHOD: We used a sample of the Norwegian Life Course, Generation, and Gender (LOGG) study ( N = 6,879) and analyzed how mastery influences the independent variables on DS via regression analyses. RESULTS: Mastery affected DS directly and influenced the effects of sociodemographic, socioeconomic, and health factors on DS. There was a stronger relationship between stressors and DS among respondents with low than high mastery. DS were most prevalent among people aged 70 to 79 years. When mastery was also controlled for, the oldest group (70-79 years) had significantly fewer DS than those aged 40 to 49 years. DISCUSSION: The influence of mastery and stressors on DS seems to vary along the life span. The result that mastery was a relatively stronger buffer against DS in midlife than in old age is discussed. PMID- 28553819 TI - Educational Differences in Health Among Middle-Aged and Older Adults in Brazil and Mexico. AB - OBJECTIVE: This study examines educational differences in health conditions among middle-aged and older adults in Brazil and Mexico. METHOD: Cross-sectional data from the 2013 Brazilian National Health Survey and the 2012 Mexican National Health and Nutrition Survey were used in the analyses. We used multivariate Poisson regressions to examine the relationship between educational level and prevalence of common health conditions (obesity, abdominal obesity, diabetes, hypertension, heart disease, and hearing and visual impairments). RESULTS: Socioeconomic and sex inequalities persist in both countries. In general, low levels of education were associated with higher risk for having health conditions. However, men of lower education had a smaller risk of abdominal obesity and hypertension. DISCUSSION: Brazil and Mexico have expanded public health actions aimed at improving health behaviors, diagnosis, and access to treatment of chronic conditions. However, important social disparities remain. Improving lifestyle behaviors, such as physical activity and dietary habits, could benefit both countries. PMID- 28553820 TI - Health Behaviors and Chronic Conditions Mediate the Protective Effects of Masculinity for Physical Performance in Older Adults. AB - OBJECTIVE: We estimated the 2-year incidence of poor physical performance according to gender roles and examined mediating pathways related to health behaviors and chronic conditions. METHOD: Data are from the International Mobility in Aging Study ( n = 1,676). The Bem Sex Role Inventory was used to classify participants into four gender roles as "masculine," "feminine," "androgynous," and "undifferentiated." RESULTS: We found a higher incidence of poor physical performance among participants endorsing the feminine (adjusted incidence rate ratio [IRR] = 2.36, 95% confidence interval (CI) = [1.55, 3.60]) or the undifferentiated role (adjusted IRR = 2.19, 95% CI = [1.45, 3.30]) compared with the androgynous role. Smoking, physical activity, the number of chronic conditions, high body mass index, and depression were mediators of this association but not alcohol consumption. DISCUSSION: This study provides evidence that gender roles are independently associated with physical performance. Health behaviors and chronic conditions are mediators of the relationship between gender roles and lower extremity physical function. PMID- 28553821 TI - Relationships Between Neighborhood Social Capital and The Occurrence of Outdoor Falls in Canadian Older Adults: A Multilevel Analysis. AB - OBJECTIVE: The aim of this study was to examine whether neighborhood-level social capital is a risk factor for falls outside of the home in older adults. METHODS: Health questionnaires were completed by community-dwelling Canadians aged +65 years living in Kingston (Ontario) and St-Hyacinthe (Quebec), supplemented by neighborhood-level census data. Multilevel logistic regression models with random intercepts were fit. Variations in the occurrence of falls across neighborhoods were quantified by median odds ratio and 80% interval odds ratio. RESULTS: Between-neighborhood differences explained 7% of the variance in the occurrence of falls; this variance decreased to 2% after adjustment for neighborhood-level variables. In the fully adjusted models, higher levels of social capital increased the odds of falls by almost 2 times: (odds ratio [OR] = 2.10, 95% confidence interval [CI] = [1.19, 3.71]). DISCUSSION: Living in neighborhoods with higher levels of social capital was associated with higher risk of falling in older adults, possibly through more involvement in social activities. PMID- 28553822 TI - Functional Status and Adaptation: Measuring Activities of Daily Living and Device Use in the National Health and Aging Trends Study. AB - OBJECTIVE: The objective of this study is to evaluate the functional status and adaptation of older Americans and discover the factors that contribute to device use. METHOD: Using the community participants' portion of the first round of National Health and Aging Trends Study (NHATS), we demonstrate the prevalence of device use and reduction in activities, creating a multilevel measure of activities of daily living (ADL) functionality as compared with Katz's dichotomous measure. In determining whether adaptation is universal irrespective of age, sex, race, living arrangement, and income, or dependent on these variables, we create a measure of device use, performing a path analysis of the device use measure and sociodemographic variables, with disability score as an intervening measure. RESULTS: ADL functionality becomes more nuanced between the Katz-ADL and NHATS-ADL. Age, sex, and living arrangement were predictors of device use; income was indirectly, whereas race was not. DISCUSSION: When assessors design service plans, consideration should be given to older adults' ability, capacity, and resources to adapt. PMID- 28553823 TI - The Nature and Extent of Physical Restraint-Related Deaths in Nursing Homes: A Systematic Review. AB - OBJECTIVE: The aim of this study is to conduct a systematic review of the published research to examine the extent, nature, and risk factors of mortality due to physical restraint use. METHOD: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement, this review examined all peer-reviewed studies published in English describing mortality due to physical restraint in nursing home residents. RESULTS: The combined searches yielded 2,016 records of which eight articles were eligible for inclusion. There were 174 deaths due to physical restraint in nursing home residents across the eight studies. Neck compression ( n = 8) was the most common mechanism of harm resulting in death due to mechanical asphyxia. CONCLUSIONS: Physical restraint is associated with deaths in nursing home residents. Further research is needed to investigate alternative interventions to restraint use. PMID- 28553824 TI - The Relation of Hypertension to Performance in Immediate and Delayed Cued Recall and Working Memory in Old Age: The Role of Cognitive Reserve. AB - OBJECTIVE: We investigated the relation of hypertension to cognitive performance and its interplay with key markers of cognitive reserve in a large sample of older adults. METHOD: We assessed tests of immediate and delayed cued recall and working memory in 701 older adults. We measured systolic blood pressure and interviewed individuals on their education, past occupation, and cognitive leisure activity. RESULTS: Hypertension (>=140 mmHg) was related to lower performance in all three cognitive measures. Moderation analyses suggested that these relations were reduced in individuals with greater engaging in cognitive leisure activity. Hierarchical regression analyses showed that hypertension was not related to any of the three investigated cognitive performance measures when education, cognitive level of job, and cognitive leisure activity were simultaneously taken into account. DISCUSSION: The detrimental influences of hypertension on cognitive functioning in old age may be reduced in individuals with greater cognitive reserve accumulated during the life course. PMID- 28553825 TI - Neighborhood Context, Dementia Severity, and Mexican American Caregiver Well Being. AB - OBJECTIVE: The current study extends research on Latino caregiving to describe the role of neighborhood-level factors and dementia severity for caregiver well being. METHOD: Data are drawn from the Hispanic Established Population for the Epidemiologic Study of the Elderly (HEPESE 2010/2011, N = 343). We present regression analyses that describe the relationship between dementia severity in the older care recipient and neighborhood-level structural factors for caregiver mental health. RESULTS: Mexican Americans providing care in neighborhoods characterized by a higher percent Latino report fewer depressive symptoms and greater life satisfaction. Percent Latino and percent Spanish speaking residing in the neighborhood are especially protective of caregiver depressive symptoms when care recipients display more severe dementia-related neuropsychiatric symptoms. DISCUSSION: Neighborhood characteristics play an important role in the Latino caregiver well-being processes. Targeting neighborhoods, especially in regard to culturally competent dementia care education and services, should be the focus of intervention strategies for Mexican-origin caregivers. PMID- 28553826 TI - The Association Between Depression and Traumatic Brain Injury in Older Adults: A Nested Matched Case Control Study. AB - OBJECTIVE: Determine association between depression and traumatic brain injury (TBI) in the older adult home care population of Ontario, Canada (2003-2013). METHOD: A nested matched case control study was used, and data were retrieved for service users 65 years or older who received home care between 2003 and 2013. Incident TBI cases were matched to four controls by sex, age, and assessment date. Odds ratios and multivariable conditional logistic regression were completed. RESULTS: 554,313 service users were included of which 5,215 (0.9%) had a TBI and 39,048 (7.0%) had depression. Fall history was an effect modifier. The association between depression and TBI was 1.10 (95% confidence interval [CI] = [0.93, 1.31]) for those without a history of falling, while for those with a history of falling it was 1.24 (95% CI = [1.03, 1.48]) after adjusting for education and Alzheimer's disease. DISCUSSION: Depression is associated with sustaining a TBI in those with a history of falling. PMID- 28553827 TI - Influence of Type II Diabetes and High Depressive Symptoms on the Likelihood for Developing Activities of Daily Living (ADL) Disability and Mortality in Older Puerto Ricans. AB - OBJECTIVE: To examine the development of activities of daily living (ADL) disability and mortality according to diabetes and high depressive symptoms among Puerto Rican adults aged 60 and older. METHOD: Data came from Wave I and Wave II of the Puerto Rican Elderly: Health Conditions Study ( n = 3,419). Logistic regression was used. Using insulin and receiving psychiatric treatment were proxy measures of disease severity for diabetes and depressive symptoms, respectively. RESULTS: High depressive symptoms at baseline were associated with developing ADL disability (OR = 2.21; 95% CI = [1.68, 2.91]). Diabetes at baseline was associated with mortality at follow-up (OR = 1.72; 95% CI = [1.34, 2.19]). Baseline diabetes was associated with developing ADL disability but only for those who reported using insulin (OR = 1.69; 95% CI = [1.08, 2.61]). Participants with comorbid diabetes and high depressive symptoms had the highest odds for developing ADL disability and mortality. DISCUSSION: Diabetes and high depressive symptoms are risk factors of developing ADL disability and mortality for older Puerto Ricans. PMID- 28553828 TI - Macron's vision for the French health system. PMID- 28553829 TI - Increasing racially and ethnically underrepresented women in medical school through an innovative program. PMID- 28553830 TI - Student directed learning in medical neuroscience curricula. PMID- 28553831 TI - Depression, anxiety and stress in dental students. AB - Objectives: To measure the occurrence and levels of depression, anxiety and stress in undergraduate dental students using the Depression, Anxiety and Stress Scale (DASS-21). Methods: This cross-sectional study was conducted in November and December of 2014. A total of 289 dental students were invited to participate, and 277 responded, resulting in a response rate of 96%. The final sample included 247 participants. Eligible participants were surveyed via a self-reported questionnaire that included the validated DASS-21 scale as the assessment tool and questions about demographic characteristics and methods for managing stress. Results: Abnormal levels of depression, anxiety and stress were identified in 55.9%, 66.8% and 54.7% of the study participants, respectively. A multiple linear regression analysis revealed multiple predictors: gender (for anxiety b=-3.589, p=.016 and stress b=-4.099, p=.008), satisfaction with faculty relationships (for depression b=-2.318, p=.007; anxiety b=-2.213, p=.004; and stress b=-2.854, p<.001), satisfaction with peer relationships (for depression b=-3.527, p<.001; anxiety b=-2.213, p=.004; and stress b=-2.854, p<.001), and dentistry as the first choice for field of study (for stress b=-2.648, p=.045). The standardized coefficients demonstrated the relationship and strength of the predictors for each subscale. To cope with stress, students engaged in various activities such as reading, watching television and seeking emotional support from others. Conclusions: The high occurrence of depression, anxiety and stress among dental students highlights the importance of providing support programs and implementing preventive measures to help students, particularly those who are most susceptible to higher levels of these psychological conditions. PMID- 28553832 TI - Preoperative Phenacetin Metabolism Test in the Prediction of Postoperative Liver Dysfunction of Patients with Hepatocellular Carcinoma. AB - BACKGROUND The risk of postoperative liver dysfunction (PLD) in patients with injured livers, such as in hepatocellular carcinoma (HCC), is still not negligible. Phenacetin metabolism test can reflect hepatic functional reserve in patients with chronic hepatic damage. The aim of this study was to assess the ability of phenacetin metabolism test to predict PLD in patients with HCC receiving partial hepatectomy. MATERIAL AND METHODS Forty-nine patients with HCC undergoing partial hepatectomy between 2014 and 2016 were included at Huashan Hospital, Fudan University. The phenacetin metabolism test was used to assess the hepatic functional reserve. The ratio of total plasma paracetamol to phenacetin was collected in patients at 2 h after oral administration of 1.0 g phenacetin, recorded 5 days prior to surgery and on the fifth postoperative day. Phenacetin metabolism test, Child-Pugh classification, and Model for End-Stage Liver Disease (MELD) score were correlated with PLD. RESULTS Of 49 patients with HCC, 13 patients (26.5%) had PLD. The association between the ratio of total plasma paracetamol to phenacetin and PLD was statistically significant (p=0.0061) and the correlation coefficient was -0.647 (p=0.0082). The phenacetin metabolism test showed a larger area under the receiver operating characteristic (ROC) curve value (0.735) than Child-Pugh's classification (0.472) and MELD score (0.419). Using the calculated cutoff of 0.6, the lower ratio of total plasma paracetamol to phenacetin preoperatively was chosen to specifically identify patients with PLD. The sensitivity and specificity were 0.657 and 0.892, respectively. CONCLUSIONS Phenacetin metabolism test could be preoperatively used in predicting PLD in HCC patients receiving partial hepatectomy. It potentially provides better prediction than Child-Pugh classification and MELD score. PMID- 28553833 TI - Longitudinal Changes in Brain Metabolic Activity after Withdrawal from Escalation of Cocaine Self-Administration. AB - The chronic and relapsing nature of addiction suggests that drugs produce persistent adaptations in the brain that make individuals with drug addiction particularly sensitive to drug-related cues and stress and incapable of controlling drug-seeking and drug-taking behavior. In animal models, several long lasting neuroadaptations have been described. However, few studies have used brain-imaging techniques to provide a complete picture of brain functioning in the course of withdrawal from cocaine. In this study, we allowed rats to self administer cocaine under short-access (1-h/day) or long-access (6-h/day) conditions and used 2-deoxy-2-(18F)fluoro-d-glucose (18FDG) positron emission tomography scanning to investigate the longitudinal changes in metabolic activity 1 and 4 weeks after discontinuation of cocaine self-administration. We found that compared to naive rats, both long-access and short-access rats showed significant disruptions in basal brain metabolic activity. However, compared to short-access, long-access rats showed more intense, and long-lasting neuroadaptations in a network of brain areas. In particular, abstinence from extended access to cocaine was associated with decreased metabolic activity in the anterior cingulate cortex, the insular cortex, and the dorsolateral striatum, and increased metabolic activity in the mesencephalon, amygdala, and hippocampus. This pattern is strikingly similar to that described in humans that has led to the proposal of the Impaired Response Inhibition and Salience Attribution model of addiction. These results demonstrate that extended access to cocaine leads to persistent neuroadaptations in brain regions involved in motivation, salience attribution, memory, stress, and inhibitory control that may underlie increased risks of relapse. PMID- 28553834 TI - Evidence for a Long-Lasting Compulsive Alcohol Seeking Phenotype in Rats. AB - Excessive drinking to intoxication is the major behavioral characteristic of those addicted to alcohol but it is not the only one. Indeed, individuals addicted to alcohol also crave alcoholic beverages and spend time and put much effort into compulsively seeking alcohol, before eventually drinking large amounts. Unlike this excessive drinking, for which treatments exist, compulsive alcohol seeking is therefore another key feature of the persistence of alcohol addiction since it leads to relapse and for which there are few effective treatments. Here we provide novel evidence for the existence in rats of an individual vulnerability to switch from controlled to compulsive, punishment resistant alcohol seeking. Alcohol-preferring rats given access to alcohol under an intermittent 2-bottle choice procedure to establish their alcohol-preferring phenotype were subsequently trained instrumentally to seek and take alcohol on a chained schedule of reinforcement. When stable seeking-taking performance had been established, completion of cycles of seeking responses resulted unpredictably either in punishment (0.45 mA foot-shock) or the opportunity to make a taking response for access to alcohol. Compulsive alcohol seeking, maintained in the face of the risk of punishment, emerged in only a subset of rats with a predisposition to prefer and drink alcohol, and was maintained for almost a year. We show further that a selective and potent MU-opioid receptor antagonist (GSK1521498) reduced both alcohol seeking and alcohol intake in compulsive and non-compulsive rats, indicating its therapeutic potential to promote abstinence and prevent relapse in individuals addicted to alcohol. PMID- 28553836 TI - A Randomized, Double-Blind, Placebo-Controlled, Sequential Parallel Comparison Design Trial of Adjunctive Riluzole for Treatment-Resistant Major Depressive Disorder. AB - Riluzole is a glutamate-modulating agent with neuroprotective properties approved for use in amyotrophic lateral sclerosis. The efficacy and safety of riluzole vs placebo as an adjunct to antidepressant medication in outpatients with major depressive disorder (MDD) was examined in a 3-site, 8-week, randomized, double blind, placebo-controlled, fixed-dose trial using a sequential parallel comparison design comprised of two phases of 4 weeks. Patients with MDD in a current major depressive episode (N=104) with an inadequate response to either a prospective or a historical trial of an antidepressant medication were randomized in a 2 : 3 : 3 ratio to the treatment sequences of riluzole/riluzole, placebo/placebo, and placebo/riluzole, respectively. The primary outcome was change in depression severity, as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary efficacy outcomes included the response rate, defined as at least a 50% improvement in MADRS, Clinical Global Impressions severity and improvement subscales, and patient-reported measures of depression and cognitive function. Eighty-five patients completed the randomized treatment phases. Treatment groups did not differ in mean change in MADRS scores, response rate, or in any secondary efficacy outcomes. Riluzole was generally well tolerated, with a side effect profile consistent with its clinical use. In conclusion, a fixed dose of riluzole (100 mg/day) did not show adjunctive antidepressant efficacy compared to placebo. The trial was adequately powered to detect a moderate riluzole effect, and the risk for exaggerated placebo responses was mitigated. The lack of efficacy suggests that mechanisms underlying riluzole's neuroprotective effects are insufficient for clinical response in treatment-resistant depression. PMID- 28553838 TI - More Than Just Chillin': Interactive Effects of Menthol and Nicotine in Drug Reward. PMID- 28553835 TI - Pharmacological Manipulation of Cortical Inhibition in the Dorsolateral Prefrontal Cortex. AB - Cortical inhibition (CI) occurs largely through GABA receptor-mediated inhibitory neurotransmission, which can be modulated by cholinergic, dopaminergic, and glutamatergic inputs. Transcranial magnetic stimulation (TMS) can be used to index CI through a paradigm known as long-interval CI (LICI). When TMS is combined with electroencephalography (EEG), LICI can index GABA receptor-mediated inhibitory neurotransmission in the dorsolateral prefrontal cortex (DLPFC). We conducted a hypothesis-driven pharmacological study to assess the role of cholinergic, dopaminergic, GABAergic, and glutamatergic neurotransmission on LICI from the DLPFC using TMS-EEG. In this randomized controlled, double-blind crossover within-subject study, 12 healthy participants received five sessions of LICI to the DLPFC in a random order, each preceded by the administration of placebo or one of the four active drugs. LICI was assessed after each drug administration and compared to LICI after placebo. Relative to placebo, baclofen resulted in a significant increase in LICI, while rivastigmine resulted in a significant decrease in LICI. Dextromethorphan and L-DOPA did not result in a significant change in LICI relative to placebo. Our study confirms that LICI in the DLPFC is largely mediated by GABAB receptor-mediated inhibitory neurotransmission and also suggests that cholinergic modulation decreases LICI in the DLPFC. Such findings may help guide future work examining the neurophysiological impact of these neurotransmitters in healthy and diseased states. PMID- 28553840 TI - [2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death]. PMID- 28553839 TI - A Primer on Foraging and the Explore/Exploit Trade-Off for Psychiatry Research. AB - Foraging is a fundamental behavior, and many types of animals appear to have solved foraging problems using a shared set of mechanisms. Perhaps the most common foraging problem is the choice between exploiting a familiar option for a known reward and exploring unfamiliar options for unknown rewards-the so-called explore/exploit trade-off. This trade-off has been studied extensively in behavioral ecology and computational neuroscience, but is relatively new to the field of psychiatry. Explore/exploit paradigms can offer psychiatry research a new approach to studying motivation, outcome valuation, and effort-related processes, which are disrupted in many mental and emotional disorders. In addition, the explore/exploit trade-off encompasses elements of risk-taking and impulsivity-common behaviors in psychiatric disorders-and provides a novel framework for understanding these behaviors within an ecological context. Here we explain relevant concepts and some common paradigms used to measure explore/exploit decisions in the laboratory, review clinically relevant research on the neurobiology and neuroanatomy of explore/exploit decision making, and discuss how computational psychiatry can benefit from foraging theory. PMID- 28553837 TI - Inflexible Functional Connectivity of the Dorsal Anterior Cingulate Cortex in Adolescent Major Depressive Disorder. AB - Recent evidence suggests that anterior cingulate cortex (ACC) maturation during adolescence contributes to or underlies the development of major depressive disorder (MDD) during this sensitive period. The ACC is a structure that sits at the intersection of several task-positive networks (eg, central executive network, CEN), which are still developing during adolescence. While recent work using seed-based approaches indicate that depressed adolescents show limited task evoked vs resting-state connectivity (termed 'inflexibility') between the ACC and task-negative networks, no study has used network-based approaches to investigate inflexibility of the ACC in task-positive networks to understand adolescent MDD. Here, we used graph theory to compare flexibility of network-level topology in eight subregions of the ACC (spanning three task-positive networks) in 42 unmedicated adolescents with MDD and 53 well-matched healthy controls. All participants underwent fMRI scanning during resting state and a response inhibition task that robustly engages task-positive networks. Relative to controls, depressed adolescents were characterized by inflexibility in local efficiency of a key ACC node in the CEN: right dorsal anterior cingulate cortex/medial frontal gyrus (R dACC/MFG). Furthermore, individual differences in flexibility of local efficiency of R dACC/MFG significantly predicted inhibition performance, consistent with current literature demonstrating that flexible network organization affords successful cognitive control. Finally, reduced local efficiency of dACC/MFG during the task was significantly associated with an earlier age of depression onset, consistent with prior work suggesting that MDD may alter functional network development. Our results support a neurodevelopmental hypothesis of MDD wherein dysfunctional self-regulation is potentially reflected by altered ACC maturation. PMID- 28553845 TI - Risk assessment in patients with ST elevation myocardial infarction treated with primary percutaneous coronary angioplasty. Does reduced duration of hospital stay affect the prognosis? PMID- 28553846 TI - The effects of CD4 nadirs on vessel stiffness in HIV patients undergoing antiretroviral therapy. AB - BACKGROUND: There are many factors associated with human immunodeficiency virus (HIV) patients having a greater risk of cardiovascular diseases (CVD). HIV damages vessel endothelium through chronic inflammation, which, combined with dys lipidaemia, arterial hypertension, and antiretroviral therapy leads to the progression of atherosclerotic changes. AIM: Our goal was to determine if a CD4 nadir along with immunological, inflammatory, biochemical, and metabolic mark-ers can be associated with higher vessel stiffness and therefore an increased risk of CVD in patients undergoing antiretroviral therapy for HIV. METHODS: Endothelial damage was evaluated in 20 patients (including four female) during successful antiretroviral therapy. We assessed the endothelial stiffness by recording the reactive hyperaemia of peripheral arteries using an Endo-PAT2000 (ITAMAR(r)) device. This device allowed us to measure the arterial tonometry and to determine the augmentation index for a pulse rate of 75/min (AI@75). We set the normal value for vessel stiffness at reactive hyperaemia index (RHI) > 1.67, as recommended by the manufacturer. Additionally, we recorded the length of antiretroviral therapy, number of CD4 lymphocytes, CD4 nadir, HIV viremia, and biochemical and immunologic results. Finally, we compared patients with normal and dysfunctional endothelium. RESULTS: The only parameter significantly differentiating between the group with and group without endothelium dysfunction was platelet count (p = 0.012). CONCLUSIONS: We were not able to confirm the significance of a CD4 nadir in the progression of endothelial stiffness in HIV patients. However, platelet values could be an important complementary marker for assessing the risk for CVD amongst HIV patients undergoing antiretroviral treatment. PMID- 28553847 TI - The short-term effect of atorvastatin plus ezetimibe therapy versus atorvastatin monotherapy on clinical outcome in acute coronary syndrome patients by gender. AB - BACKGROUND: Atorvastatin reduces low-density lipoprotein cholesterol (LDL-C) levels and the risk of cardiovascular events, but whether the addition of ezetimibe (EZE), a non-statin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further, and if there any sex differences, is not known. AIM: To evaluate the effects of atorvastatin and EZE combination in acute coronary syndrome (ACS) patients on the incidence of composite endpoint in short-term follow-up and to assess differences according their gender. METHODS: We conducted a 16-week, single-centre, prospective, randomised, open-label clinical trial involving 323 patients who had been hospitalised for an ACS within the preceding 14 days. They received atorvastatin 20 mg for 28 days, and after that 292 patients who had LDL-C levels >= 1.81 mmol/L were randomised to EZE 10 mg/day co-administered with atorvastatin therapy (EZE + statin) or double their current atorvastatin dose. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalisation, coronary revascularisation (>= 30 days after randomisation), or nonfatal stroke. RESULTS: The Kaplan-Meier event-free survival rate at 16 weeks was 88.1% in the EZE + statin group patients and 77.0% in the atorvastatin monotherapy group (absolute risk reduction: 11.1 percentage points; hazard ratio: 2.099; 95% confidence interval: 1.165-3.781; p = 0.014). The log rank test indicated that there was not a statistically significant difference between male and female survival rates in both treatment groups (p = 0.897). CONCLUSIONS: The results of our study demonstrated that when added to statin therapy, EZE resulted in improved cardiovascular outcomes, and the response to atorvastatin and EZE combination was similar for both men and women. PMID- 28553848 TI - Implementation of targeted temperature management after cardiac arrest in Polish intensive care units. What has changed in the last five years? AB - BACKGROUND: Studies conducted up to 2010 indicate the underuse of targeted temperature management (TTM) in Poland. AIM: This study evaluated the current degree of TTM implementation in Polish intensive care units (ICUs) and analysed the implementation process since 2010. METHODS: A telephone survey, conducted from December 2014 to July 2015, was carried out to determine the number of ICUs using TTM in patients after cardiac arrest. We collected data on the details and prevalence of TTM, and the impact of organisational and financial issues and recently published papers on its use. RESULTS: We obtained data from 271 of 396 ICUs (68.4%). In total, 79 (29.2%) ICUs indicated TTM use and 27 (34.2%) used dedicated TTM equipment. Overall, 62% of the ICUs used TTM regardless of the cardiac arrest rhythm. Target temperatures of 32-34 degrees C and 34.1-36 degrees C were reached by 44.3% and 43.0% of ICUs, respectively. The duration of TTM was 12-24 h in 58.2% of the ICUs. The most common barriers to TTM implementation were a lack of dedicated devices (36.3%) and organ-isational and logistical issues (31.2%). Any influence of recently published data on TTM practice modifications was reported by only 23.4% of the ICUs. CONCLUSIONS: Targeted temperature management is underused in Polish ICUs. There is a need for additional educational and implementation efforts supporting the translation of knowledge into clinical practice at the regional and national levels. PMID- 28553849 TI - Effect of subchronic intake of Green Tea Extract on liver of albino rat Histomorphometric, ultrastructural and biochemical study. AB - BACKGROUND: There are conflicting reports on the effect of Green tea extract (GTE) on the liver of animals. Some studies failed to show any adverse hepatic effects following administration of GTE to mice, rats, and dogs. Others reported severe hepatic necrosis, resulting in death; in female Swiss-Webster mice following its administration. The aim of the study was to study the subchronic toxicity of GTE on the liver of the adult male albino rats. MATERIAL AND METHODS: 40 male adult Wistar albino rats were used in the study. The rats were divided into four groups; group I (control), group II (Low-dose Green Tea), group III (Medium- dose Green Tea) and group IV (High- dose Green Tea). Histological, biochemical and histomorphometric analysis were done. RESULTS: Mild hepatic affections were observed in group II. The affections were severe in groups III and IV. The central veins and hepatic sinusoids were congested. The hepatocytes were degenerated. Hypertrophy of the hepatic arteries, dilation of the bile ducts and cellular infiltration were clearly observed in the last two groups. Mild degenerative changes were observed in the hepatocytes in rat's group II; the cytoplasm was rarefied and vacuolated. Some mitochondria were ruptured. The blood sinusoids were congested. The rough endoplasmic retinaculum was fragmented in group III. More degenerative changes were observed in group IV; the hepatic architectures were lost with disruption of cell membranes. Most of the cell organelles were degenerated and most of mitochondria were ballooned. As compared to that of the control groups: the total serum protein values in groups II, III and IV showed a statistically significant decrease (12%, 20 % and 21 % respectively), the mean area percent of collagen fibers in groups III and IV increased five and seven folds. CONCLUSIONS: subchronic administration of GTE resulted in structural and functional affection of the rats' liver. The dose of 250 mg/Kg/day seemed to be safe, while the doses of 500 mg and1000 mg/Kg/day had deleterious effect being more evident in the latter dose. PMID- 28553851 TI - Morphometric parameters of cardiac implantable electronic device (CIED) pocket walls observed on device replacement. AB - BACKGROUND: The final stage of a conventional de-novo cardiac implantable electronic device (CIED) implantation procedure with transvenous lead insertion involves the formation of a pocket by tissue separation superficial to the pectoralis major muscle in the right or left infraclavicular region, where the device is subsequently placed. Over time, a scar "capsule" forms around the CIED as a result of normal biological remodeling. MATERIALS AND METHODS: The purpose of this study was to analyze the structure and present the variations of CIED capsules observed during device replacement. The nature and extent of this local tissue remodeling, which had occurred from the time of device implantation to its replacement in 2016 (10 +/-3.1 years), was analyzed in 100 patients (mean age 77.1+/-14.5 years), including 45 women and 55 men. RESULTS: The largest type of "capsules" (70% of cases) were those with similar thickness of both walls or a slightly thicker posterior (<1.0mm) than anterior wall (<0.5mm). The second most common capsule type (23% of cases) was characterized by a significantly thicker posterior wall of scar tissue (?1.0mm). The third group of capsules was characterized by various degrees of wall calcification (7% of cases). CONCLUSIONS: The extent and nature of scar tissue structure in the CIED pocket walls seems to correlate with the relative position of cardiac lead loops with respect to the device itself; where the more extensive scarring likely resulting from pocket wall irritation in the capsule formation phase due to lead movements underneath the device. The group of cases with calcified capsules was characterized by "old" device pockets (? 13 years) and the oldest population (patients in their 80s and 90s). PMID- 28553850 TI - How the three arches of the foot intercorrelate. AB - BACKGROUND: The foot is composed of medial, lateral and transverse arches which, particularly the medial arch, provide it with the ability to function both as a flexible and rigid structure for proper locomotion. Arches of the foot, as well as their effect on lower extremity function, have been studied. However, quantitative data on the relationship between these arches still remain scanty. The purpose of this study was, therefore, to examine how the three arches of the foot intercorrelate. MATERIALS AND METHODS: 76 participants (58 males, 18 females) were recruited to participate in the study. Bilateral weight-bearing lateral radiographs of the right foot were taken from each participant. Navicular heights (NH), medial cuneiform height (MCH), calcaneal inclination angle (CIA) and calcaneal-first metatarsal angle (C1MA) were measured to represent the medial arch. The lateral arch was represented by cuboid height (CH) and calcaneal-fifth metatarsal angle (C5MA) whereas; MCH and CH represented the transverse arch. Mean difference of variables between males and females was compared using independent t-test while the correlation between the variables was determined using Pearson correlation. RESULTS: All the variables were not significantly related to gender. Significant moderate to excellent linear correlations were observed between the variables. CIA showed the strongest correlation with C1MA (r = -0.90) and C5MA (r = -0.84) whereas, CH had the least correlation with other variables. CONCLUSIONS: The moderate to excellent correlations between the variables indicate that deformation or elevation of the medial arch may consequently result in similar movements of the lateral and transverse arches and vice versa. PMID- 28553852 TI - An anatomical study of additional radial wrist extensors including a unique extensor carpi radialis accessorius. AB - BACKGROUND: In this study, 82 forearms from 41 cadavers were dissected to establish the incidence of variant additional radial wrist extensors. Three variants have been described in the literature: extensor carpi radialis intermedius (ECRI), extensor carpi radialis accessorius (ECRA) and extensor carpi radialis tertius (ECRT). MATERIALS AND METHODS: Of the 41 cadavers studied, 5/41 (12%) had an additional radial wrist extensor. Of these 5 individuals, 2 had bilateral additional muscles and 3 were unilateral. Of the 82 forearms, 7/82 (9%) had additional radial wrist extensors. RESULTS: We found 4 examples of ECRI and 3 examples of ECRA. We did not find any examples of ECRT. One specimen of ECRA had an atypical, previously undescribed, course. CONCLUSIONS: These accessory muscles are of clinical relevance, as they may be a contributing factor in tennis elbow and nerve entrapment, or cause diagnostic confusion, especially in ultrasound scans. However, they may also be used for tendon transfer. Of the 7 muscles found in the current study, 3 would have been suitable for such procedures. PMID- 28553853 TI - Immunolocalisation of nitric oxide synthase isoforms in the ductuli efferentes and epididym. AB - The present research used immunohistochemistry to analyse the detection and localisation of nitric oxide synthase (NOS) isoforms in the ductuli efferentes and epididymis of prepubertal and adult alpaca. In the ductuli efferentes and epididymis of prepubertal and adult animals, nNOS and eNOS were similarly expressed in epithelial lining cells, conversely differences were observed in the immunopresence of iNOS. Our data provide evidence that NOS isoforms may have roles in reproductive functions and in the developmental processes of the excurrent duct system in the alpaca. PMID- 28553854 TI - Characteristics of yak platelet derived growth factors-alpha gene and its expression in brain tissues. AB - BACKGROUND: Platelet derived growth factors (PDGFs) are key components of autocrine and paracrine signalling, both of which play important roles in mammalian developmental processes. PDGF expression levels also relate to oxygen levels. The characteristics of yak PDGFs, which are indigenous to hypoxic environments, have not been clearly described until the current study. MATERIALS AND METHODS: We amplified the open reading frame encoding yak (Bos grunniens) platelet derived growth factor-alpha (PDGFA) from a yak skin tissue cDNA library by reverse transcriptase polymerase chain reaction (PCR) using specific primers and Sanger dideoxy sequencing. Expression of PDGFA mRNA in different portions of yak brain tissue (cerebrum, cerebellum, hippocampus, and spinal cord) was detected by quantitative real-time PCR (qRT-PCR). PDGFA protein expression levels and its location in different portions of the yak brain were evaluated by western blot and immunohistochemistry. RESULTS: We obtained a yak PDGFA 755 bp cDNA gene fragment containing a 636 bp open reading frame, encoding 211 amino acids (GenBank: KU851801). Phylogenetic analysis shows yak PDGFA to be well conserved, having 98.1% DNA sequence identity to homologous Bubalus bubalus and Bos taurus PDGFA genes. However, 8 nucleotides in the yak DNA sequence and 4 amino acids in the yak protein sequence differ from the other two species. PDGFA is widely expressed in yak brain tissue, and furthermore, PDGFA expression in the cerebrum and cerebellum are higher than in the hippocampus and spinal cord (p > 0.05). PDGFA was observed by immunohistochemistry in glial cells of the cerebrum, cerebellum, and hippocampus, as well as in pyramidal cells of the cerebrum, and Purkinje cell bodies of the hippocampus, but not in glial cells of the spinal cord. CONCLUSIONS: The PDGFA gene is well conserved in the animal kingdom; however, the yak PDGFA gene has unique characteristics and brain expression patterns specific to this high elevation species. PMID- 28553855 TI - Histomorphometric study of the effect of methionine on small intestine parameters in rat: an applied histologic study. AB - Assessment of morphological changes has more often been used in the diagnosis and assessment of intestinal pathology and development. Since methionine is widely used in nutritional and sports supplements and also there is not enough information about the effect of this amino acid on the gastrointestinal histomorphometry, the aim of this study was to assess the effect of methionine on the small intestine histomorphometry. Thirty male Wistar rats were randomly divided to 3 equal groups. Two treatment groups received 100 and 200 mg/kg L methionine solution respectively via intraperitoneal injection while the control group received normal saline. On day 21, all rats were euthanized and segments from three parts of small intestine were taken to histomorphometrical study. Paraffin sections were stained with haematoxylin & eosin, Alcian blue (AB) and periodic acid Schiff (PAS) methods separately. In order to analyze histomorphometric features of each segment, villus height, width, area, crypt depth, villus height to crypt depth ratio, goblet cell number, and muscle layer thickness were measured. Obtained results revealed that methionine may change the histomorphometric parameters of small intestine. PMID- 28553856 TI - Anatomic study of the morphology of the right and left coronary arteries. AB - Arising from the aorta, the right (RCA) and left (LCA) coronary arteries provide the arterial supply to both the atria and the ventricles of the heart. An extensive literature review revealed that most studies have either evaluated the morphology of the RCA or the LCA independently. This study aimed to document the relationship between the morphology of the RCA and LCA using coronary angiograms. In addition, variations such as split or double RCA and an absent LCA was documented. A review of 500 coronary angiograms was conducted and the RCA and LCA were classified according to their branching patterns and arterial dominance. The most prevalent branching pattern of the LCA was bifurcation [in 65.8% (329/500)], while trifurcation and quadrifurcation occurred in 20.4% (102/500) and 1.6% (8/500), respectively. The LCA was absent in 11.8% (59/500) of cases with the bifurcation and trifurcation of its branches in 10.8% (54/500) and 1.4% (7/500), respectively. The splitting of the RCA occurred in 4.2% (21/500) of the angiograms. A split RCA with concomitant absent LCA was documented in 1.2% (6/500) of the angiograms. The RCA and LCA were dominant in 77.2% (386/500) and 9.8% (49/500) of cases respectively, whereas co-dominance occurred in 13% (65/500) of the sample examined. In most cases where a split RCA was present, the RCA was found to be non-dominant. With the advent of coronary arteriography, a comprehensive understanding of coronary arterial anatomy and their anomalies has become essential. PMID- 28553857 TI - The position of the mental foramen in dentate and edentulous mandibles: clinical and surgical relevance. AB - BACKGROUND: The knowledge of the exact location of the mental foramen (MF) in dentate and edentulous mandibles is clinically important when constructing complete dentures, performing anaesthetic block of the lower-anterior teeth area and intervening in the MF nearby area. In edentulous mandibles, the bone resorption after teeth loss makes the mental nerve (MN) prone to damage due to the extreme location of the MF very close to the alveolar crest (AC). Chronic compression on the MN may result in pain in the area of MN distribution (ipsilateral face and cheek area) and numbness at the lower lip. The purpose of the current study is to evaluate the exact position of the MF, calculating the distances MF- superior border of the AC and MF- inferior border of the mandible (IBM) in dentate and edentulous mandibles. MATERIALS AND METHODS: One hundred and two (36 edentulous and 66 dentate) adult dry Greek mandibles were studied. RESULTS: In 9 out of 36 edentulous mandibles (25%), the MF was found nearby the AC, while in 27 edentulous mandibles (75%), the MF was located at an average distance 6.4 mm from the AC and 12.6 mm from the IBM. In 38 out of 66 dentate mandibles (57.6%), the MF was located at an average distance 13.6mm from the ALC and 15.2 mm from the IBM. The dental status significantly affected (p=0.001) the distances MF- AC and MF-IBM. Side symmetry was observed for both dentate and edentulous mandibles (p=0.39 and p=0.45). CONCLUSIONS: The MF is an important landmark and its location needs to be considered prior to dental implants placement in order to avoid the MN injury and related complications. The position of MF is altered in edentulous mandibles compared with the dentate ones. The MF is a symmetric structure in Greeks. PMID- 28553858 TI - Adrenergic and cholinergic innervation of the atrioventricular valves in chinchilla (Chinchilla laniger). AB - The arrangement of autonomic fibres was studied in the cardiac atrioventricular valves of small chinchillas. The dissected valves were stained entirely using the modified histochemical acetylcholine esterase technique (AChE) and the SPG-De la Torre method. Double immunocytochemical staining was also used for the expression of vesicular acetylcholine transporter (VAChT) and dopamine beta hydroxylase (DBH). The study showed the presence of both cholinergic and adrenergic fibres, forming a kind of network on all cusps of both valves. The adrenergic network is always more strongly represented than the cholinergic network. The cholinergic nerve network of the "parietal" part formed mainly the parallel arrangement. As we move towards the free parts of the cusps, the arrangement becomes netted and radiant. The adrenergic fibres formed only the netted arrangement, which was the most dense in the peripheral (parietal) part of the cusps. Some of the fibres in the vicinity of tendinous cords extended as far as the papillary muscles. Double immunocytochemical tests confirmed the presence and distribution of DBH- and VAChT-positive fibres. Some fibres (especially within the tendinous cords) show VAChT and DBH colocalisation. PMID- 28553859 TI - The relationship between selected parameters of a cephalometric analysis determining the vertical morphology of facial skeleton and bite force. AB - BACKGROUND: There are few studies devoted to an assessment of the relation between bite force and detailed results of cephalometric analysis that determine craniofacial structure. The purpose of the study was to assess the correlation between the selected criteria determining the craniofacial structure and bite force in patients with normal and increased vertical relation of the bases of jaws and skull. METHODS: The study material included 120 patients, aged between 7 and 17 years, who presented for examination and possible orthodontic treatment. The patients were divided into a study group and a control group. The basis of this division were ML-NL and ML-NSL angles, according to Segner's and Hasund's analysis standards, respectively: above 27 degrees and above 30 degrees in the study group, and 20.0+/-7.0 degrees and 28.0+/-5.0 degrees in the control group. Bite force was tested using a digital dynamometer calibrated in Newtons. The measurement was performed at the level of the first permanent molars. Vertical relations were assessed using the following cephalometric measurements: ML-NSL, ML-NL, NL-NSL, N-Me, Sp-Me, SpMe:NMe, ms-NL, SGo:NMe. RESULTS: Bite force was not found to be dependent on the lower anterior face height (Sp-Me), the ratio of anterior lower to total anterior face height (SpMe:NMe), and NL-NSL angle both in patients with abnormal and normal relations of bases of jaws and skull. Although statistically non-significant, the average mean and maximum bite force values were found to be lower in patients with high-angle relation of bases of jaws and skull than in subjects with normal relation of bases of jaws and skull. CONCLUSIONS: Among the selected parameters determining the vertical craniofacial structure, the rear height of the alveolar process (ms-NL) exerts the greatest influence on bite force in both patients with increased and normal vertical relation of bases of jaws and skull, and with an increase in the value of ms-NL, bite force is reduced. PMID- 28553860 TI - Frontal aslant tract projections to the inferior frontal gyrus. AB - BACKGROUND: Frontal aslant tract (FAT) is a white matter bundle connecting the pre-supplementary motor area (pre-SMA) and the supplementary motor area (SMA) with the inferior frontal gyrus (IFG). The purpose of the present study was to evaluate the anatomical variability of FAT. MATERIALS AND METHODS: Total number of fibres and the lateralisation index (LI) were calculated. We attempted to find factors contributing to the diversity of FAT regarding IFG terminations to the pars opercularis (IFG-Op) and to the pars triangularis (IFG-Tr). Magnetic resonance imaging of adult patients with diffusion tensor imaging (DTI) with total number of 98 hemispheres composed a cohort. V-shaped operculum was the most common (60.5%). RESULTS: Total number of FAT fibres had widespread and unimodal distribution (6 to 1765; median: 160). Left lateralisation was noted in 64.3% of cases and was positively correlated with total number of FAT fibres and the bundle projecting to IFG-Op (p < 0.01). LI correlated with total number of FAT fibres (r = 0.43, p < 0.01). FAT projected predominantly to IFG-Op (88.9%; 88 of 99). Only in 3 (3.1%) cases more fibres terminated in IFG-Tr than in IFG-Op. Total number of FAT fibres and number of fibres terminating at IFG-Op did not correlate with the ratio of fibre numbers: FAT/IFG-Op, FAT/IFG-Tr and IFG-Op/IFG Tr (p > 0.05). The greater total number of fibres to IFG-Tr was, the higher were the ratios of IFG-Tr/ /FAT (r = 0.57, p < 0.01) and IFG-Tr/IFG-Op (r = 0.32, p = 0.04). CONCLUSIONS: Among the IFG, the major termination of FAT is IFG-Op. Whereas the IFG-Tr projection seems to be related to the expansion of the entire FAT bundle regardless of side, domination and handedness. Nevertheless, FAT features a significant anatomical variability which cannot be explained in terms of DTI findings. PMID- 28553861 TI - Endothelial progenitor cells populate the stromal stem niche of tympanum. AB - The tympanic membrane (TM) integrity is of utmost integrity for the sense of hearing. Therefore, the intrinsic potential of the TM to regenerate and repair deserves complete characterization. Existing studies brought evidence on the epithelial stem niche of the TM. However, the stromal compartment was not evaluated for harbouring a distinctive stem, or progenitor, niche. We aimed doing this in transmission electron microscopy. We used TMs dissected out from 3 male Oryctolagus cuniculus rabbits. Evidence of stromal quiescent stem cells with was gathered. Moreover, endothelial progenitor cells were found in the TM, being accurately identified by two specific ultrastructural markers of the endothelial lineage: the Weibel-Palade bodies and the stomatal diaphragms of the subplasmalemmal caveolae. The stromal stem niche of the TM appears so as a distinctive contributor during physiologial and pathological processes of the TM, such as is the cholesteatoma formation, at least as a biological support for processes of vasculogenesis. However, further characterization of the molecular pattern of the stromal stem niche of the TM is mandatory. PMID- 28553862 TI - The possible protective effect of L-arginine against 5-fluorouracil-induced nephrotoxicity in male albino rats. AB - 5-fluorouracil (5-FU) is a potent antineoplastic agent used for the treatment of various malignancies. The L-arginine nitric oxide (NO) pathway involved in the pathogenesis of chemotherapy induced kidney damage. This work investigated the beneficial mechanism of L-arginine supplementation in 5-FU induced nephropathy. Eighty male Wistar rats were divided into four equal groups: control group; L arginine group (378 mg/rat/day for 4 weeks); 5-FU group (189 mg/rat/week for 4 weeks) and L-arginine for 1 week before and 4 weeks concomitant with 5-FU group. At the end of experiment, the kidney functions were assessed and kidneys specimens were processed for paraffin sections and stained with haematoxylin and eosin (H&E), Masson's trichome (MT) and periodic acid-Schiff (PAS) stains. Other sections were processed for immunohistochemical demonstration of caspase-3 and inducible NO synthase (iNOS). Image analyser was used to analyse the results morphometrically and statistically. L-arginine administration to 5-FU treated animals elicited significant reduction in serum urea and creatinine levels, urine volume, urinary protein excretion and kidney/body weight ratio in comparison to fluorouracil treated group. L-arginine improved glomeruloscelerosis, degeneration of convoluted tubules and interstitial fibrosis in 5-FU treated animals. L arginine attenuated effectively some biochemical and histological changes in 5-FU nephrotoxicity. PMID- 28553870 TI - Changing the strategy of balloon pulmonary angioplasty resulted in a reduced complication rate in patients with chronic thromboembolic pulmonary hypertension. A single-centre European experience. AB - BACKGROUND AND AIM: To assess the safety and efficacy of a refined balloon pulmonary angioplasty (BPA) strategy in patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: There were 157 BPA sessions performed in 56 CTEPH patients (47 non-operable, nine after pulmonary endarterectomy; aged 58.6 +/- 17.9 years; 28 females) with severely impaired pulmonary haemodynamics (mean pulmonary artery pressure [mPAP]: 51.3 +/- 12.2 mm Hg, pulmonary vascular resistance [PVR]: 10.1 +/- 3.9 Wood Units). The first 50 sessions aimed to recanalise chronic occlusions and prevent reocclusion with aggressive anticoagulation. The next 107 sessions aimed to relieve "web" and "ring" lesions using reduced tip load guidewires and less intensive anticoagulation. RESULTS: There was significant reduction in haemoptysis (22% vs. 7%, p = 0.01), vessel injury (30% vs. 13%, p = 0.01), and reperfusion pulmonary injuries (22% vs. 4%, p = 0.01) after changing the BPA strategy. Mortality at 14 days was also reduced (6% vs. 0%; p = 0.05). The cumulative survival rate was 94.6% at 24 months after the first BPA, which was more favourable than medically treated historic controls. In the 31 patients with > 3 BPA sessions, there was significant reduction of PVR (10.3 +/- 3.7 vs. 5.9 +/- 2.8 Wood Units; p = 0.01), mPAP (50.7 +/- 10.8 vs. 35.6 +/- 9.3 mm Hg; p = 0.01) and improvement in World Health Organisation functional class (3.19 +/- 0.48 vs. 1.97 +/- 0.80; p < 0.001). CONCLUSIONS: Balloon pulmonary angioplasty improves haemodynamics and outcome but requires refined strategy to limit early complication rate. PMID- 28553871 TI - In-hospital and long-term outcomes of coronary artery bypass graft surgery in patients <= 45 years of age and older (from the KROK registry). AB - BACKGROUND: There is a paucity of data concerning the clinical characteristics, management, and outcomes of coronary artery bypass graft surgery (CABG) in patients <= 45 years old. AIM: We aimed to compare the clinical characteristics, and in-hospital and long-term outcomes of patients <= 45 years and > 45 years old, who underwent isolated CABG. METHODS: We identified consecutive patients who had isolated CABG in the Department of Cardiac Surgery and Transplantology in the Silesian Centre for Heart Diseases in Zabrze between January 2006 and December 2011 and were enrolled in the Polish National Registry of Cardiac Surgery Procedures (KROK registry). A total of 8196 patients were identified and split into two groups, age <= 45 years old (young group; n = 130) and > 45 years old (old group; n = 8066). RESULTS: Patients <= 45 years old were less often females (18.5% vs. 27.6%, p < 0.027), more often smokers (84.6% vs. 66.9%, p < 0.0001), and had a higher incidence of previous myocardial infarction (MI) (40.8% vs. 29.6%, p = 0.008). Patients <= 45 years old more often received only one graft (27.7% vs. 15.0%, p < 0.0001), were operated on with minimally invasive direct coronary artery bypass (MIDCAB) technique (12.3% vs. 3.9%, p < 0.0001), and had complete arterial revascularisation (55.4% vs. 18.1%, p < 0.0001). There were no significant differences between the groups regarding in-hospital mortality (0.8% vs. 1.4%, p = 0.808). Long-term outcomes revealed that young patients, compared with the older patients, showed no significant differences in the number of MI (4.6% vs. 5.6%), unstable angina (8.5% vs. 9.9%), coronary angioplasty (12.3% vs. 15.1%), reCABG (0.8% vs. 0.1%), and strokes (2.3% vs. 4.3%) during the follow-up period; long-term mortality occurred less often in the young patients (4.6% vs. 15.0%, p = 0.002). CONCLUSIONS: We conclude that patients <= 45 years old requiring CABG differ from their older counterparts in clinical and surgical characteristics. We noted no significant differences in the in-hospital mortality; however, patients <= 45 years old had a lower mortality rate in the long-term follow-up. PMID- 28553872 TI - Prognostic factors in heart failure - are they all equally important? PMID- 28553873 TI - Does fluid resuscitation with balanced solutions induce electrolyte and metabolic abnormalities? An in vitro assessment. AB - BACKGROUND: Popular intravenous fluids in clinical use may have an impact on electrolyte concentration and metabolic balance and should be considered as powerful pharmacological agents. There is a growing body of evidence that fluid therapy should be more individualised and preferably based on balanced solutions. AIM: We sought to investigate the impact of three commonly used balanced fluids on electrolytes and metabolic equilibrium in an in vitro setting. METHODS: Study group comprised 32 healthy male volunteers (without history of any acute/chronic disorder or known metabolic abnormality), aged 21-35 (29 +/- 4) years, weight 59 103 (81.2 +/- 9.8) kg, from whom blood samples were withdrawn. The whole blood was diluted in 4:1 ratio with the study solutions to make an end-concentration of 20 vol.% of each solution. The test solutions included balanced crystalloid (Plasmalyte(r), Baxter, Poland [PL]), succinylated gelatin (Geloplasma(r), Fresenius Kabi, Poland [GEL]) and 6% HES 130/0.4 (Volulyte(r), Fresenius Kabi, Poland [HES]). RESULTS: All fluids caused comparable degree of haemodilution. PL and GEL decreased (104 mmol/L, interquartile range [IQR] 103-105; and 106 mmol/L, IQR 105-107.5, respectively), whereas HES increased the concentration of Cl- to 109 (IQR 108-110) mmol/L. PL and HES decreased (136, IQR 136-137 mmol/L; and 138 mmol/L, IQR 137-139, respectively), whereas GEL increased the Na+ level to 140.5 (IQR 140-141) mmol/L. PL and HES decreased osmolality (277.2 mOsm/kg, IQR 275.7 278.4; and 280.9 mOsm/kg, IQR 279.3-282.0, respectively). GEL increased it to 285.7 (IQR 283.7-286.8) mOsm/kg. All test solutions caused a similar statistically significant (p < 0.05) drop in base excess and bicarbonate concentration, and these fell outside the reference values. Due to its composition, GEL caused a significant increase in lactate concentration. HES and GEL caused a statistically significant drop in strong ion difference value. Due to high lactate level, the effect of GEL was most pronounced. CONCLUSIONS: Balanced intravenous solutions should be safe in terms of their impact on human plasma electrolyte and meta-bolic equilibrium when administered to replace up to 20% of blood volume. In metabolic acidosis, balanced succinylated gelatin should be used with caution. Therefore, arterial blood gas analysis should be performed in patients in whom significant amounts of fluid are administrated, preferably with assessment of Cl-, Na+, lactate concentrations as well as pH, osmolality, and strong ion difference. PMID- 28553874 TI - Clinical significance and determinants of prompt recruitment collaterals during primary percutaneous coronary intervention. AB - BACKGROUND: Due to ischaemic time delays from the chest pain occurrence in acute ST elevation myocardial infarction (STEMI), prompt recruitment collaterals (PRCCs) to infarct-related artery (IRA) are the major protective structures during this period. AIM: We aimed to investigate the clinical significance and determinants of PRCCs in acute STEMI patients. METHODS: A total of 1375 consecutive acute STEMI patients were prospectively enrolled in the study. The patients were divided into two groups, according to PRCCs to IRA; Rentrop <= 1 were defined as inadequate collateral development (ICD) group and Rentrop >= 2 defined as adequate collateral development (ACD) group. RESULTS: Patients in the ICD group had higher incidence of baseline risk characteristics, including older age, hypertension, and diabetes mellitus; however, pre-infarct angina incidence was lower than in the ACD group (p < 0.05 for all). In addition, the ICD group had worse haemodynamic status on admission and 30-day mortality. Compared to the ACD group, the non-IRA chronic total occlusion (CTO), peak troponin-T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high sensitivity C-reactive protein (hs-CRP) levels were higher in the ICD group. On multivariate logistic regression analysis, non-IRA CTO (b = 3.114, 95% CI 1.382-7.017, p < 0.006) with pre-infarction angina together with higher values of peak troponin-T, NT-proBNP, and hs-CRP were associated with PRCCs in acute STEMI. CONCLUSIONS: Taking into account that the main message of the study is that if patients have higher cardiac biomarkers and adverse clinical findings (which, of note, may show the extent of myocardial infarction) and have non-IRA CTO, there is a higher chance that they will have inadequate collateralisation. PMID- 28553875 TI - AssesSment of the left atrial appendage morphoLogy in patients aAfter ischaeMic Stroke - the ASSAM study protocol. AB - Stroke remains the most dangerous and frightening complication of atrial fibrillation (AF). A causal relationship between ischaemic stroke and atrial arrhythmias such as AF or atrial flutter has been well established. Numerous factors predisposing to peripheral embolism in patients with AF have been well established and included in the CHA2DS2-VASc score. Although proper anticoagulation minimises the risk attributable to "known" risk factors, stroke may still occur. Thus, "unknown" risk factors may play an important role in stroke risk stratification in patients with AF. We assume that one of the important "unknown" risk factor is the left atrial appendage morphology. The ASSAM study is planned to include 100 patients after ischaemic stroke or transient ischaemic attack (TIA) and known status of anticoagulation at the time of stroke. The control group will consist of 100 patients scheduled for AF ablation without a history of stroke or TIA. PMID- 28553876 TI - Cu2+-Loaded Polydopamine Nanoparticles for Magnetic Resonance Imaging-Guided pH- and Near-Infrared-Light-Stimulated Thermochemotherapy. AB - Cancer multimodal treatment by combining the effects of different theranostics agents can efficiently improve treatment efficacy and reduce side effects. In this work, we demonstrate the theranostics nanodevices on the basis of Cu2+ loaded polydopamine nanoparticles (CuPDA NPs), which are able to offer magnetic resonance imaging (MRI)-guided thermochemotherapy (TCT). Systematical studies reveal that after Cu2+ ions loading, the molar extinction coefficient of PDA NPs is greatly enhanced by 4 times, thus improving the performance in photothermal therapy. Despite Cu2+ ions being toxic, the release of Cu2+ is mainly stimulated in acidic environment. Once the NPs deposit in the slightly acidic tumor microenvironment (pH ~ 6.5-6.8), the release rate boosts ~30%, which effectively avoids the systematic toxicity during chemotherapy. Meanwhile, due to the increment of the electron-proton dipole-dipole interaction correlation time tauC, the spin-lattice relaxation time (T1) for PDA NPs is found to be shortened by Cu2+ loading, which boosts the longitudinal relaxivity (r1). Hence, CuPDA NPs can be used as T1-weighted contrast agent in MRI. In addition, due to the naturally existing DA in the human body with stealth effect, CuPDA NPs have an outstanding tumor retention rate as high as 8.2% ID/g. Further in vitro and in vivo tests indicate that CuPDA NPs possess long blood circulation time, good photothermal and physiological stability, and biocompatibility, which are potential nanodevices for MRI-guided TCT with minimal side effects. PMID- 28553879 TI - The relationship between lower body stiffness and injury incidence in female netballers. AB - The aim of this study was to provide contemporary information on injury rates in an elite and sub-elite netball population and to explore the relationship between lower body stiffness and lower body injuries. One elite and two sub-elite teams of female netballers (n = 29) performed the vertical hop test to assess active lower body stiffness (Kvert) and myometry to assess quasi-static stiffness. Lower body injuries were monitored via self-reporting and liaison with physiotherapists. Twelve lower body non-contact injuries were sustained by 10 players, equating to 11.29 lower body injuries per 1,000 exposure hours. The most commonly injured sites were the calf (33%) and ankle (25%). No significant differences between Kvert of injured and non-injured players were reported, however, injured elite players recorded significantly higher season mean quasi static stiffness in the soleus (p = 0.037) and Achilles (p = 0.004) than non injured elite players. Elite and sub-elite netball players recorded a higher injury incidence than previous reports of injuries in recreational netballers. Within the constraints of the study, relatively high stiffness of the soleus and Achilles appears to be related to lower body non-contact injury incidence in female netballers, particularly at the elite level. These results provide a basis for development of injury prevention strategies. PMID- 28553878 TI - Building conditions and the risk of nosocomial infection from microbial contamination of hospital appliances in a health care facility. AB - Nosocomial infections (NIs) remain a global health burden with higher incidence in Africa. We assessed building conditions and risk of NIs from microbial contamination of appliances and surfaces in a Specialist hospital in Southwest Nigeria. The study sampled 120 surfaces in 12 wards during normal occupational activities. Moulds on ceilings and dusty surfaces were observed in the wards. Microbial burden (1038.0 * 105 cfu) peaked in the ICU but was lowest (446.9 * 105 cfu) in the male ward. Bacteria counts ( * 105 cfu) of 234.7, 199.7 and 67.0 were measured on ICU tap, doorknob and ECG, respectively. Theatre diatomy machine, anaesthetic machine and operating lamp had bacteria counts ( * 105 cfu) of 40.0, 85.0 and 109.0, respectively. Highest total fungal count (58.2 * 105 cfu) was recorded on ICU trolley handle, switch and suturing tube. Our study established surfaces as major environmental routes for NI transmission in this health care facility. PMID- 28553880 TI - Dementia behaviour management programme at home: impact of a palliative care approach on care managers and professional caregivers of home care services. AB - OBJECTIVES: Care managers and professional caregivers of home care services are sometimes unaware of the psychosocial approaches to the challenging behaviour of dementia. Therefore, we developed a Behaviour Analytics & Support Enhancement (BASE) programme. We investigated the effects of the programme on the attitudes towards dementia care among professionals. METHOD: Forty-six participants in Japan received training in August 2016. The ongoing monitoring and assessment system was introduced to the participants for repeated measures of challenging behaviour. A 1-day follow-up meeting for debriefing was also performed after two months. A baseline and follow-up questionnaire survey was administered to the participating caregivers using a Japanese version of the Approaches to Dementia Questionnaire (ADQ) and the Zarit Burden Interview (ZBI). RESULTS: A significant improvement was observed in the total ADQ score among the participating caregivers from baseline to follow-up assessment. There was no significant difference between the baseline and follow-up assessment in the ZBI scores. In the follow-up meeting, several participants reported challenges and suggested solutions in facilitating a discussion on an action plan among professionals from various organizations. CONCLUSION: The implementation of the programme resulted in enhanced attitudes towards dementia care among the participants without an increased burden of care. Future studies should examine the programme's effectiveness on the challenging behaviour of persons with dementia. PMID- 28553881 TI - The relationship between levels of plasma-soluble urokinase plasminogen activator receptor (suPAR) and presence of migraine attack and aura. AB - Migraine is one of the most common types of pain associated with sterile inflammatory conditions. Soluble urokinase plasminogen activator receptor (suPAR) is a potential novel inflammatory marker. We aim to determine the association between serum values of suPAR, procalcitonin, fibrinogen, and high-sensitivity C reactive protein (hs-CRP) and migraine disease characteristics. The study involved a total of 60 migraine patients (33 patients in the interictal period, 27 patients in the attack period) and 30 healthy individuals. The serum values of suPAR were found to be significantly higher in migraine patients in the attack period than in migraine patients in the interictal period, and in healthy individuals (p < .01 for both). In addition, levels of suPAR were determined to be higher in migraine with aura patients than in migraine without aura patients. When we subdivided migraine patients according to frequency of attack (attacks/month), significant differences were found between the suPAR and procalcitonin levels (measured during the attack period) of those in the frequent attack group (4-5 or more) versus those in the less frequent attack group (less than 4). Serum levels of procalcitonin were shown to be significantly higher in migraine patients during the attack period compared with migraine patients in the interictal period and in control subjects (p = .001 for both). Significant differences were found between plasma levels of fibrinogen in migraine patients versus control subjects (p < .01). No statistically significant difference was found between levels of hs-CRP in migraine patients versus the control group. These findings may show that presenting a high level of suPAR in migraine patients with attack and aura results to predisposition to occurring on the symptoms and that high levels of suPAR, procalcitonin and fibrinogen in patients with migraine result in neurogenic inflammation during migraine headaches. PMID- 28553882 TI - Functional brain connectivity of remembered fatigue or happiness in healthy adults: Use of arterial spin labeling. AB - INTRODUCTION: Chronic fatiguing illnesses like cancer, multiple sclerosis, chronic fatigue syndrome, or depression are frequently associated with comorbidities including depression, pain, and insomnia, making the study of their neural correlates challenging. To study fatigue without such comorbidities, functional connectivity (FC) analyses were used in healthy individuals to study brain activity during recall of a fatiguing event inside the MRI scanner. A positive mood induction served as control condition. METHOD: Using SPM8 and the CONN toolbox, FC was tested using seed- and independent component- based (ICA) analyses. Differences in the FC correlations between seed-to-voxel and ICA clusters between conditions were assessed with permutation testing. RESULTS: 17 participants (59% women) achieved mean (SD) in-scanner fatigue VAS ratings of 31.85 (20.61). Positive mood induction resulted in happiness ratings of 46.07 (18.99) VAS. Brain regions where alterations in FC correlated with fatigue included the globus pallidum, left lateral occipital cortex, and cuneus. FC of happiness involved the parahippocampal gyrus, both supplemental motor areas, as well as right superior frontal gyrus. Using data-driven ICA, we identified an intra-cerebellar network where several regions were significantly associated with fatigue, but not happiness ratings. Results of permutation testing provided evidence that the detected clusters correlated differentially with self-reported fatigue and happiness. CONCLUSIONS: Our study suggests that functional interactions between globus pallidum and occipital structures contribute to experimental fatigue in healthy individuals. They also highlight the important role of cortico-cerebellar interactions in producing feelings of fatigue. FC of occipital structures contributed to both experimental fatigue and happiness ratings. PMID- 28553883 TI - ? PMID- 28553885 TI - ? PMID- 28553884 TI - ? PMID- 28553887 TI - ? PMID- 28553886 TI - ? PMID- 28553888 TI - ? PMID- 28553889 TI - ? PMID- 28553890 TI - ? PMID- 28553891 TI - ? PMID- 28553892 TI - ? PMID- 28553893 TI - Descriptions of depression and depression treatment in older Hispanic immigrants in a geriatric collaborative care program. AB - OBJECTIVES: To explore experiences with depression and depression treatment among older Hispanic immigrants participating in a collaborative care program of psychotherapy and antidepressant medication. METHOD: Semi-structured, in-depth interviews were conducted with 14 older Spanish-speaking Hispanic immigrants with major depression who participated in a collaborative care program within a public sector specialty geriatric clinic in Los Angeles, CA. RESULTS: Findings revealed that participants used various idioms to describe their experiences with depression, and that depression had a strong impact on functioning. Other findings indicated that depression was caused by various psychosocial problems, antidepressants were helpful in reducing depression, and that bilingual psychotherapists provided a welcoming and safe environment to express emotions and find solutions to problems. CONCLUSION: Results revealed participants' experiences with depression and the impact of participating in a collaborative care intervention for depression. Findings from this project should be used to inform future geriatric interventions for older Hispanic immigrants in the USA. PMID- 28553894 TI - Virtual versus Light Microscopy for Teaching Histology. PMID- 28553895 TI - DEAN is a Four-Letter Word. PMID- 28553896 TI - A Plea to Discontinue Acknowledging "Face Validity" as a Legitimate Type of Validity Evidence. PMID- 28553898 TI - Influence of Psychiatric Symptoms on Decisional Capacity in Treatment Refusal. AB - How psychiatric symptoms affect patients' decision making in practice can inform how we think-theoretically and conceptually-about what it means for those patients to have decision-making capacity. Assessment of a patient's decisional capacity allows those with adequate capacity to make choices regarding treatment and protects those who lack capacity from potential harm caused by impaired decision making. In analyzing a case in which a patient with stage II breast cancer refuses further treatment, we review the conceptual model of informed consent and approaches to assessing decision-making capacity that are in accordance with the American Medical Association Code of Medical Ethics as well as tools to assess decisional capacity. PMID- 28553897 TI - Diagnostic score for the detection of cardiac amyloidosis in patients with left ventricular hypertrophy and impact on prognosis. AB - BACKGROUND: Among diagnosis associated with left ventricular hypertrophy (LVH), cardiac amyloidosis (CA) is a progressive disease with poor prognosis. Early noninvasive identification is of growing clinical importance. The objective of our study was to integrate clinical, biologic, electrocardiographic and echocardiographic parameters to build a diagnostic score in patients with LVH. METHODS AND RESULTS: One hundred and fourteen patients with LVH underwent a cardiac magnetic resonance (CMR) and a 99mTc-hydroxymethylene-diphosphonate scintigraphy (99mTc-HMDP) allowing to discriminate three groups of diagnoses: CA (n = 50 including 31, 18 and 1 ATTR, AL and AA amyloidosis), hypertrophic cardiomyopathy (n = 19) and unspecific cardiomyopathy (n = 45). Seven continuous variables associated with CA (systolic arterial pressure <130 mmHg; PR duration >200 ms; Sokolow index <12 mV; diastolic left ventricular posterior thickness >13 mm; E/Ea ratio >10; global longitudinal strain > -12% and sum of basal longitudinal strain > -47%) were selected and dichotomized according to the best cutoff value to build the diagnostic score, which was validated in an independent cohort of 34 patients with LVH from aortic stenosis. The area under the ROC curve for the diagnosis of CA using the score was 0.933 (95%CI 0.889-0.978). The best cut off value for the score was 3 leading to a sensitivity of 90% and specificity of 81%. Area under the ROC curve for the score was 0.932 in the validation cohort. A diagnostic score >3 was associated with a poorest prognosis. CONCLUSION: An integrated evaluation of 6 diagnostic factors including arterial blood pressure, ECG and echocardiographic parameters to build a diagnostic score is a simple and easily method to discriminate the 3 main CA in patients with LVH. PMID- 28553899 TI - Do Pediatric Patients Have a Right to Know? AB - In Western medicine, a central component of respecting a person's ability to make decisions governing what happens to herself is ensuring that she is provided with sufficient relevant information to make a rational choice. For patients who lack the cognitive capacity to do so because of either inborn or acquired deficits or because of youth, the extent to which they can participate in medical decisions is variable. Minors present a unique challenge, as their ability to understand and process information usually increases with age. The case presented here poses special problems because of the parents' desire to shield their child from certain information deemed important by his physicians. I consider whether minors, particularly older ones, have a right to know that supersedes their parents' wishes. PMID- 28553900 TI - How Should Clinicians Respond to Transference Reactions with Cancer Patients? AB - Patients with cancer can feel particularly vulnerable and need special attention and support, so clinicians' attention to transference reactions-theirs and their patients-is especially important. Mismanaged transference reactions can undermine the therapeutic alliance in the patient-clinician relationship and negatively influence treatment outcomes. In oncology settings, real and perceived needs of patients in serious distress can occasion modification of usual outpatient protocols, particularly when flexible scheduling or home or hospital visits are warranted. Here, we comment on a case in which transference reactions of a young woman with cancer prompt her to terminate treatment. We discuss the importance of clinicians' recognizing and managing transference and countertransference, maintaining boundaries, and responding with empathy and integrity to cancer patients' concerns. PMID- 28553901 TI - Ethical Management of Patients with Cancer and Mental Illness. AB - Patients with co-existing cancer and mental illness must be given special attention due to the vulnerability that is created by their compromised psychological ability to comprehend the meaning of their cancer diagnosis, treatment, and prognosis. They are at increased risk for mortality due to many factors arising from their mental illness. To provide them with care that is just and compassionate, clinicians must be empathic and imaginative. Using a case and brief application of theories of justice involving vulnerable populations, we explore practical and ethical issues surrounding the care of patients with mental illness and cancer, arguing that society must provide the resources needed to provide comparable cancer care to those who are more vulnerable. PMID- 28553902 TI - How Situational Diagnosis Helps Disentangle Ethical and Psychological Features of Complex Cases. AB - We review Marguerite S. Lederberg's 1999 Acta Oncologica article entitled "Disentangling Ethical and Psychological Issues: A Guide for Oncologists," in which she introduces a method of analysis that facilitates clarification of ethical and psychological aspects of complex cases. Based on her understanding of the dynamics at play in patients', family members', and physicians' experiences, Lederberg formulated what she calls "situational diagnosis," a guide on how to distinguish ethical from psychological issues at the bedside or when an ethics consultation is requested. Here, we apply situational diagnosis to a case and consider whether and how Lederberg's guidance relates to current literature on how clinicians communicate with patients about serious illnesses. PMID- 28553903 TI - Assessing Psychological Toxicity and Patient-Reported Distress as the Sixth Vital Sign in Cancer Care and Clinical Trials. AB - As the number of available cancer therapies continues to grow, there is increasing interest in their impact on cancer patients' lived experiences. Screening for distress is one way to measure psychological dimensions of cancer patients' experiences, and doing so is increasingly part of standard operations at major cancer centers across the US. To date, however, most clinical trials have not adequately captured patients' experiences as part of their outcome assessments, so clinicians lack data needed to guide their responses to psychological features of patients' illness experiences. As distress becomes the "sixth vital sign" in routine cancer care, we argue that clinical trials should assess patients' experiences in the same way that they robustly screen for adverse events and toxicities. New interventions are needed to address distress. PMID- 28553904 TI - When and Why Should Mental Health Professionals Offer Traditional Psychodynamic Therapy to Cancer Patients? AB - Given the recent studies promoting time-limited manualized therapies in the oncology setting, clinicians may be reluctant to offer traditional psychodynamic therapy to cancer patients. However, there are no studies directly comparing psychodynamic therapy and other therapy modalities in this patient population and no data suggesting harm from psychodynamic approaches. Therefore, it is inappropriate to draw the conclusion that psychodynamic therapy is inferior to manualized therapy from existing evidence. Manualized treatment, such as cognitive behavioral therapy, is generally short term and therefore may reduce the practitioner's own anxiety stemming from exposure to patients facing grave disability and death. However, manualized treatment is not fully effective in specific clinical scenarios. We present a case reflecting these limitations and advocate for a flexible treatment approach incorporating elements of psychodynamic therapy. PMID- 28553906 TI - Prioritizing Mental Health Research in Cancer Patients and Survivors. AB - The United States spends billions of dollars annually on cancer research. Historically, compared to other areas of cancer research, very little funding has been dedicated to mental health research in cancer patients and survivors. Previous studies have indicated that psychological disorders are common in patients with cancer and might have significant influence on overall morbidity and mortality. However, adequate data are lacking to better assess this influence and the potential benefits of interventions. As the number of cancer survivors is projected to grow dramatically in the coming years, we review the importance of dedicating additional funding to mental health research in cancer patients and survivors. PMID- 28553905 TI - Decreasing Smoking but Increasing Stigma? Anti-tobacco Campaigns, Public Health, and Cancer Care. AB - Public health researchers, mental health clinicians, philosophers, and medical ethicists have questioned whether the public health benefits of large-scale anti tobacco campaigns are justified in light of the potential for exacerbating stigma toward patients diagnosed with lung cancer. Although there is strong evidence for the public health benefits of anti-tobacco campaigns, there is a growing appreciation for the need to better attend to the unintended consequence of lung cancer stigma. We argue that there is an ethical burden for creators of public health campaigns to consider lung cancer stigma in the development and dissemination of hard-hitting anti-tobacco campaigns. We also contend that health care professionals have an ethical responsibility to try to mitigate stigmatizing messages of public health campaigns with empathic patient-clinician communication during clinical encounters. PMID- 28553907 TI - Should Clinicians Intervene If They Suspect That a Caregiver Whose Child Has Cancer Is at Risk of Psychological Harm? AB - Compelling arguments suggest that pediatric oncologists who have concerns about the mental health and well-being of a child's caregiver have a duty to intervene. These arguments are rooted in fundamental principles of beneficence, nonmaleficence, and justice. Not only do patients benefit when their parents and others caregivers are happy and healthy, but when the psychological distress of a caregiver is a consequence of the experience of illness and treatment, some of the responsibility for mitigating the harm falls to those who have an active role in directing treatment-the clinicians. However, systems to support clinicians in meeting this obligation are inadequate. PMID- 28553908 TI - From Silence into Language: Questioning the Power of Physician Illness Narratives. AB - Physicians' narratives of their own experiences of illness can be a kind of empathic bridge across the divide between a professional healer and a sick patient. This essay considers ways in which physicians' narratives of their own and family members' experiences of cancer shape encounters with patients and patients' experiences of illness. It analyzes ethical dimensions of physicians' narratives (such as those by Atul Gawande, Siddhartha Mukherjee, and Paul Kalanithi) and of reflective writing in medical education. It also compares illness narratives written by physicians-turned-patients to those written by patients without medical training in order to explore questions of who ultimately benefits from these narratives and whether these narratives can engender greater empathy between clinicians and patients. PMID- 28553910 TI - [Galdestensileus en komplikation efter kronisk kolecystolitiasis]. PMID- 28553909 TI - They Are People First, Then Patients. PMID- 28553911 TI - [Effect of using an interpreter in psychotherapy]. AB - An evaluation of the effect of using an interpreter in psychotherapy is quite complex. In the few existing studies on the use of interpreters in psychotherapy no significant difference was found in treatment outcome related to whether an interpreter was used or not. On the other hand, the inclusion of an interpreter affects the therapeutic alliance and the relationships between the parties. The role of the interpreter in psychotherapy is characterized by diversity, and the included studies indicate the need for training to improve the cooperation between the interpreter and the therapist. PMID- 28553912 TI - [Blunt kidney trauma in children]. AB - Lesion of the kidney is found in 10% of children with a blunt abdominal trauma. Conservative treatment regimens are generally accepted for mild traumatic renal injury. No consensus exists regarding treatment of more severe traumatic renal lesion in children. Strategy for imaging and follow-up has also been unclear. Recent studies suggest successful conservative treatment of severe renal injury without complications. We present existing knowledge on treatment and follow-up in children with renal trauma. PMID- 28553913 TI - [Blood pressure measurement as performed in outpatient clinics is inexpedient]. AB - Traditional office blood pressure (OBP) measurement as performed in busy outpatient clinics agrees poorly with awake ambulatory BP, and generally BP is severely overestimated. Especially elderly patients may be overtreated with the risk of symptomatic hypotension and fall injuries. Furthermore, truly high OBP measurements are often ignored as white coat hypertension, which leads to undertreatment of hypertension in high-risk individuals. Traditional OBP is thus of limited use and may even be harmful. Better methods are available and should be implemented. PMID- 28553914 TI - [Displacement of endobronchial tube in a neonate in spite of using recommended methods]. AB - Placement of nasogastric tubes are common procedures in neonatal departments, but there is a risk of severe complications although it is considered an innocuous procedure. This case report describes accidental endobronchial tube displacement in a mature neonate despite using clinically recommended methods of verification. It illustrates how symptoms of tube displacement can be disregarded, especially in critically ill neonates. Radiologic examination is the recommended method to ensure tube position but it cannot be used as daily practice. Commonly used methods of bedside verification are discussed. PMID- 28553915 TI - [Oesophageal vascular ectasia in a patient with anaemia]. AB - This case report describes the findings of oesophageal vascular ectasia (OVE) in a patient with known gastric antral vascular ectasia, who presented with anaemia. OVE is a very rare endoscopic finding and therefore a diagnostic challenge. An 85 year-old male was admitted due to anaemia. He went through a gastroscopic examination where severe OVE changes were seen, along with newfound oesophageal varices. There was no need for treating the OVE, but the findings coupled with the knowledge of the varices led to the diagnosis of portal thrombosis. PMID- 28553916 TI - [Pudendal neuralgia diagnosed by electrophysiological examination]. AB - A 62-year-old man with suspected pudendal neuralgia was admitted to a department of clinical neurophysiology for examination. The patient had experienced increasingly altered sensations in the groin, particularly in form of pain in a sitting position. The neurophysiological studies substantiated the suspicion. Pudendal neuralgia is a painful neuropathic condition. The most frequent cause is entrapment of the pudendal nerve in the pelvis. The diagnosis is made clinically by using Nantes criteria, and neurophysiological studies of the perineum are important supplements when pudendal nerve entrapment is suspected. PMID- 28553917 TI - ? PMID- 28553918 TI - ? PMID- 28553920 TI - ? PMID- 28553919 TI - ? PMID- 28553921 TI - [Spontan pacemakererosion]. PMID- 28553922 TI - [Schwannoma can be a rare cause of abdominal pain]. AB - This case report describes a 43-year-old female with persisting abdominal pain. She was examined on several occasions, but no obvious reason for the pains was found. Due to recurring of the symptoms, a computed tomography was performed, and a tumour in the thoracic wall by the lower left region of the lung could be seen. Biopsy revealed a schwannoma, and an operation was conducted successfully. After radical resection, the patient's pains declined. PMID- 28553923 TI - [Gluten-free diet is for some a necessity, for others a lifestyle]. AB - This review provides a brief overview of the gluten-related conditions coeliac disease (CD), wheat allergy (WA), and non-coeliac gluten sensitivity (NCGS). NCGS is a new entity which includes individuals who report symptoms when exposed to gluten and benefit from gluten-free diet, but do not have CD or WA. The concept NCGS is still controversial and a subject of considerable overdiagnosis, and consensus regarding diagnostic criteria is lacking. Furthermore, the overlap with irritable bowel syndrome is unsettled. PMID- 28553924 TI - [Surgical treatment of mid- and low rectal cancer]. AB - Total mesorectal excision (TME) is standard treatment of mid- and low rectal cancer and has evolved with minimally invasive surgery. Laparoscopic TME has proven to be technically challenging, and recent randomized controlled studies fail to prove it oncologically superior to open TME. Robotic-assisted TME may overcome the technical difficulties and shows comparable oncological results, yet it is associated with significant additional costs. Transanal TME is a promising method which seems to overcome the technical and financial issues of the other techniques, without compromising the short-term oncological results. PMID- 28553925 TI - [Adnexal torsion in a six-year-old girl]. AB - Adnexal torsion is a rare condition but should be considered in any female patient with acute-onset lower abdominal pain regardless of age. In this case report a six-year-old girl presented with four days of lower abdominal pain. On suspicion of acute appendicitis a diagnostic laparoscopy was performed and showed left-sided adnexal torsion. The ovary was detorsed, and one third of the ovary was resected. A transabdominal ultrasound three months after surgery showed no signs of pathology. PMID- 28553926 TI - Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration. AB - Altered DNA methylation status is associated with human diseases and cancer; however, the underlying molecular mechanisms remain elusive. We previously identified many human transcription factors, including Kruppel-like factor 4 (KLF4), as sequence-specific DNA methylation readers that preferentially recognize methylated CpG (mCpG), here we report the biological function of mCpG dependent gene regulation by KLF4 in glioblastoma cells. We show that KLF4 promotes cell adhesion, migration, and morphological changes, all of which are abolished by R458A mutation. Surprisingly, 116 genes are directly activated via mCpG-dependent KLF4 binding activity. In-depth mechanistic studies reveal that recruitment of KLF4 to the methylated cis-regulatory elements of these genes result in chromatin remodeling and transcription activation. Our study demonstrates a new paradigm of DNA methylation-mediated gene activation and chromatin remodeling, and provides a general framework to dissect the biological functions of DNA methylation readers and effectors. PMID- 28553928 TI - Synergistic effects of deleting multiple nonessential elements in nonreplicative HSV-1 BAC genomic vectors play a critical role in their viability. AB - Nonreplicative Herpes simplex virus type-1 (HSV-1) genomic vectors have already entered into clinical trials for neurological gene therapy thanks to their scalable growth in permissive cells. However, the small transgene capacity of this type of HSV-1 vectors currently used in the clinic represents an important limiting factor as a gene delivery system. To develop high-capacity nonreplicative genomic HSV-1 vectors, in this study we have characterized a series of multiply deleted mutants which we have constructed in bacterial artificial chromosomes (BACs), removing up to 24 kb of unstable or dispensable genomic sequences to allow insertion of transgenes up to this size. We show that synergistic effects of deletions of: the HSV-1 replication origins oriS and oriL, the HSV-1 internal repeat region, the remaining ICP4 gene copy and the genes encoding for ICP27, UL56, UL55, can severely reduce the growth of these HSV-1 vectors. Given that several of these elements have been characterized as 'non essential' for viral growth in cell culture by single-deletion experiments of wild-type HSV-1, our study highlights the need to re-evaluate their functional contribution in the context of multiply deleted nonreplicative HSV-1 genomic vectors. Our BAC mutants described here can serve as useful starting platforms to accelerate HSV-1 vector development. PMID- 28553927 TI - Erythropoietin signaling regulates heme biosynthesis. AB - Heme is required for survival of all cells, and in most eukaryotes, is produced through a series of eight enzymatic reactions. Although heme production is critical for many cellular processes, how it is coupled to cellular differentiation is unknown. Here, using zebrafish, murine, and human models, we show that erythropoietin (EPO) signaling, together with the GATA1 transcriptional target, AKAP10, regulates heme biosynthesis during erythropoiesis at the outer mitochondrial membrane. This integrated pathway culminates with the direct phosphorylation of the crucial heme biosynthetic enzyme, ferrochelatase (FECH) by protein kinase A (PKA). Biochemical, pharmacological, and genetic inhibition of this signaling pathway result in a block in hemoglobin production and concomitant intracellular accumulation of protoporphyrin intermediates. Broadly, our results implicate aberrant PKA signaling in the pathogenesis of hematologic diseases. We propose a unifying model in which the erythroid transcriptional program works in concert with post-translational mechanisms to regulate heme metabolism during normal development. PMID- 28553929 TI - Silencing of HIV-1 by AgoshRNA molecules. AB - RNA interference (RNAi) is a sequence-specific gene silencing mechanism that is triggered by the expression of a short hairpin RNA (shRNA). shRNA molecules enter the RNAi pathway at the Dicer processing step. Recent studies indicated that the cellular microRNA miR-451 is not recognized by Dicer, but that it is processed instead by the Argonaute 2 (Ago2) protein. Subsequently, Dicer-independent shRNAs were described that rely on Ago2 for processing, as well as the subsequent silencing step. We called these AgoshRNA molecules because they depend on Ago2 both for maturation and activation. Processing of an AgoshRNA yields only a single active RNA strand, thus reducing the chance of adverse off-target effects induced by the passenger strand of regular shRNAs. In this study, we converted several anti-HIV-1 shRNAs into AgoshRNAs. Seven of the 21 designed AgoshRNAs were potent anti-HIV molecules, although their RNAi activity is generally somewhat reduced compared with the matching shRNAs. The AgoshRNA candidates revealed no cellular toxicity. This may relate to the absence of passenger strand expression, which was verified for these AgoshRNA candidates. Furthermore, we demonstrate that a toxic shRNA can be converted into a non-toxic AgoshRNA. PMID- 28553930 TI - alpha2,6-Sialylation mediates hepatocellular carcinoma growth in vitro and in vivo by targeting the Wnt/beta-catenin pathway. AB - Abnormal sialylation due to overexpression of sialyltransferases has been associated with tumorigenesis and tumor progression. Although ST6Gal-I influences cancer persistence and progression by affecting various receptors, the underlying mechanisms and mediators remain largely obscure, especially in hepatocellular carcinoma (HCC). We found that ST6Gal-I expression was markedly upregulated in HCC tissues and cells, high levels being associated with aggressive phenotype and poor prognosis. Furthermore, we examined the roles and mechanisms of ST6Gal-I in HCC tumorigenesis and metastasis in vitro and in vivo. ST6Gal-I overexpression promoted proliferation, migration and invasion of Huh-7 cells, whereas its knockdown restricted these abilities in MHCC97-H cells. Additionally, in a mouse xenograft model, ST6Gal-I-knockdown MHCC97-H cells formed significantly smaller tumors, implying that ST6Gal-I overexpression can induce HCC cell malignant transformation. Importantly, enhanced HCC tumorigenesis and metastasis by ST6Gal I may be associated with Wnt/beta-catenin signaling promotion, including beta catenin nuclear transition and upregulation of downstream molecules. Together, our results suggest a role for ST6Gal-I in promoting the growth and invasion of HCC cells through the modulation of Wnt/beta-catenin signaling molecules, and that ST6Gal-I might be a promising marker for prognosis and therapy of HCC. PMID- 28553931 TI - The immunosuppressive cytokine interleukin-4 increases the clonogenic potential of prostate stem-like cells by activation of STAT6 signalling. AB - Interleukin-4 plays a critical role in the regulation of immune responses and has been detected at high levels in the tumour microenvironment of cancer patients, where concentrations correlate with the grade of malignancy. In prostate cancer, interleukin-4 has been associated with activation of the androgen receptor, increased proliferation and activation of survival pathways such as Akt and NF kappaB. However, its role in therapy resistance has not yet been determined. Here we investigate the influence of interleukin-4 on primary epithelial cells from prostate cancer patients. Our data demonstrate an increase in the clonogenic potential of these cells when cultured in the presence of interleukin-4. In addition, a Phospho-Kinase Array revealed that in contrast to previously published work, signal transducer and activator of transcription6 (STAT6) is the only signalling molecule activated after interleukin-4 treatment. Using the STAT6 specific inhibitor AS1517499 we could confirm the role of STAT6 in increasing colony-forming frequency. However, clonogenic recovery assays revealed that interleukin-4 does not rescue the effects of either irradiation or docetaxel treatment. We therefore propose that although the interleukin-4/STAT6 axis does not appear to be involved in therapy resistance, it does play a crucial role in the colony-forming abilities of the basal cell population in prostate cancer. IL 4 may therefore contribute to disease relapse by providing a niche that is favourable for the clonogenic growth of prostate cancer stem cells. PMID- 28553932 TI - Combined mutation in Vhl, Trp53 and Rb1 causes clear cell renal cell carcinoma in mice. AB - Clear cell renal cell carcinomas (ccRCCs) frequently exhibit inactivation of the von Hippel-Lindau tumor-suppressor gene, VHL, and often harbor multiple copy number alterations in genes that regulate cell cycle progression. We show here that modeling these genetic alterations by combined deletion of Vhl, Trp53 and Rb1 specifically in renal epithelial cells in mice caused ccRCC. These tumors arose from proximal tubule epithelial cells and shared molecular markers and mRNA expression profiles with human ccRCC. Exome sequencing revealed that mouse and human ccRCCs exhibit recurrent mutations in genes associated with the primary cilium, uncovering a mutational convergence on this organelle and implicating a subset of ccRCCs as genetic ciliopathies. Different mouse tumors responded differently to standard therapies for advanced human ccRCC, mimicking the range of clinical behaviors in the human disease. Inhibition of hypoxia-inducible factor (HIF)-alpha transcription factors with acriflavine as third-line therapy had therapeutic effects in some tumors, providing preclinical evidence for further investigation of HIF-alpha inhibition as a ccRCC treatment. This autochthonous mouse ccRCC model represents a tool to investigate the biology of ccRCC and to identify new treatment strategies. PMID- 28553933 TI - Novel assay reveals a large, inducible, replication-competent HIV-1 reservoir in resting CD4+ T cells. AB - Although antiretroviral therapy can suppress HIV-1 infection to undetectable levels of plasma viremia, integrated latent HIV-1 genomes that encode replication competent virus persist in resting CD4+ T cells. This latent HIV-1 reservoir represents a major barrier to a cure. Currently, there are substantial efforts to identify therapeutic approaches that will eliminate or reduce the size of this latent HIV-1 reservoir. In this regard, a sensitive assay that can accurately and rapidly quantify inducible, replication-competent latent HIV-1 from resting CD4+ T cells is essential for HIV-1 eradication studies. Here we describe a reporter cell-based assay to quantify inducible, replication-competent latent HIV-1. This assay has several advantages over existing technology in that it (i) is sensitive; (ii) requires only a small blood volume; (iii) is faster, less labor intensive, and less expensive; and (iv) can be readily adapted into a high throughput format. Using this assay, we show that the size of the inducible latent HIV-1 reservoir in aviremic participants on therapy is approximately 70 fold larger than previous estimates. PMID- 28553934 TI - Phenotypic screening identifies Axl kinase as a negative regulator of an alveolar epithelial cell phenotype. AB - Loss of epithelial barrier integrity is implicated in a number of human lung diseases. However, the molecular pathways underlying this process are poorly understood. In a phenotypic screen, we identified Axl kinase as a negative regulator of epithelial phenotype and function. Furthermore, suppression of Axl activity by a small molecule kinase inhibitor or downregulation of Axl expression by small interfering RNA led to: (1) the increase in epithelial surfactant protein expression; (2) a cell morphology transition from front-rear polarity to cuboidal shape; (3) the cytoskeletal re-organization resulting in decreased cell mobility; and (4) the acquisition of epithelial junctions. Loss of Axl activity reduced activation of the Axl canonical pathway members, Akt and extracellular signal-regulated kinase-1/2 and resulted in the loss of gene expression of a unique profile of epithelial-to-mesenchymal transition transcription factors including SNAI2, HOXA5, TBX2 or TBX3. Finally, we observed that Axl was activated in hyperplasia of epithelial cells in idiopathic pulmonary fibrosis where epithelial barrier integrity was lost. These results suggest that the Axl kinase signaling pathway is associated with the loss integrity of alveolar epithelium in pathological remodeling of human lung diseases. PMID- 28553935 TI - Multiplexed ion beam imaging analysis for quantitation of protein expression in cancer tissue sections. AB - Part of developing therapeutics is the need to identify patients who will respond to treatment. For HER2-targeted therapies, such as trastuzumab, the expression level of HER2 is used to identify patients likely to receive benefit from therapy. Currently, chromogenic immunohistochemistry on patient tumor tissue is one of the methodologies used to assess the expression level of HER2 to determine eligibility for trastuzumab. However, chromogenic staining is fraught with serious drawbacks that influence scoring, which is additionally flawed due to the subjective nature of human/pathologist bias. Thus, to advance drug development and precision medicine, there is a need to develop technologies that are more objective and quantitative through the collection and integration of larger data sets. In proof of concept experiments, we show multiplexed ion beam imaging (MIBI), a novel imaging technology, can quantitate HER2 expression on breast carcinoma tissue with known HER2 status and those values correlate with pathologist-determined IHC scores. The same type of quantitative analysis using the mean pixel value of five individual cells and total pixel count of the entire image was extended to a blinded study of breast carcinoma samples of unknown HER2 scores. Here, a strong correlation between quantitation of HER2 by MIBI analysis and pathologist-derived HER2 IHC score was identified. In addition, a comparison between MIBI analysis and immunofluorescence-based automated quantitative analysis (AQUA) technology, an industry-accepted quantitation system, showed strong correlation in the same blind study. Further comparison of the two systems determined MIBI was comparable to AQUA analysis when evaluated against pathologist-determined scores. Using HER2 as a model, these data show MIBI analysis can quantitate protein expression with greater sensitivity and objectivity compared to standard pathologist interpretation, demonstrating its potential as a technology capable of advancing cancer and patient diagnostics. PMID- 28553936 TI - Microfluidics for rapid cytokeratin immunohistochemical staining in frozen sections. AB - Frozen sections (FS) of tumor samples represent a cornerstone of pathological intraoperative consultation and have an important role in the microscopic analysis of specimens during surgery. So far, immunohistochemical (IHC) stainings on FS have been demonstrated for a few markers using manual methods. Microfluidic technologies have proven to bring substantial improvement in many fields of diagnostics, though only a few microfluidic devices have been designed to improve the performance of IHC assays. In this work, we show optimization of a complete pan-cytokeratin chromogenic immunostaining protocol on FS using a microfluidic tissue processor into a protocol taking <12 min. Our results showed specificity and low levels of background. The dimensions of the microfluidic prototype device are compatible with the space constraints of an intraoperative pathology laboratory. We therefore anticipate that the adoption of microfluidic technologies in the field of surgical pathology can significantly improve the way FSs influence surgical procedures. PMID- 28553938 TI - The MBNL3 splicing factor promotes hepatocellular carcinoma by increasing PXN expression through the alternative splicing of lncRNA-PXN-AS1. AB - Understanding the roles of splicing factors and splicing events during tumorigenesis would open new avenues for targeted therapies. Here we identify an oncofetal splicing factor, MBNL3, which promotes tumorigenesis and indicates poor prognosis of hepatocellular carcinoma patients. MBNL3 knockdown almost completely abolishes hepatocellular carcinoma tumorigenesis. Transcriptomic analysis revealed that MBNL3 induces lncRNA-PXN-AS1 exon 4 inclusion. The transcript lacking exon 4 binds to coding sequences of PXN mRNA, causes dissociation of translation elongation factors from PXN mRNA, and thereby inhibits PXN mRNA translation. In contrast, the transcript containing exon 4 preferentially binds to the 3' untranslated region of PXN mRNA, protects PXN mRNA from microRNA-24 AGO2 complex-induced degradation, and thereby increases PXN expression. Through inducing exon 4 inclusion, MBNL3 upregulates PXN, which mediates the pro tumorigenic roles of MBNL3. Collectively, these data demonstrate detailed mechanistic links between an oncofetal splicing factor, a splicing event and tumorigenesis, and establish splicing factors and splicing events as potential therapeutic targets. PMID- 28553937 TI - Stem cell plasticity enables hair regeneration following Lgr5+ cell loss. AB - Under injury conditions, dedicated stem cell populations govern tissue regeneration. However, the molecular mechanisms that induce stem cell regeneration and enable plasticity are poorly understood. Here, we investigate stem cell recovery in the context of the hair follicle to understand how two molecularly distinct stem cell populations are integrated. Utilizing diphtheria toxin-mediated cell ablation of Lgr5+ (leucine-rich repeat-containing G-protein coupled receptor 5) stem cells, we show that killing of Lgr5+ cells in mice abrogates hair regeneration but this is reversible. During recovery, CD34+ (CD34 antigen) stem cells activate inflammatory response programs and start dividing. Pharmacological attenuation of inflammation inhibits CD34+ cell proliferation. Subsequently, the Wnt pathway controls the recovery of Lgr5+ cells and inhibition of Wnt signalling prevents Lgr5+ cell and hair germ recovery. Thus, our study uncovers a compensatory relationship between two stem cell populations and the underlying molecular mechanisms that enable hair follicle regeneration. PMID- 28553939 TI - Linking E-cadherin mechanotransduction to cell metabolism through force-mediated activation of AMPK. AB - The response of cells to mechanical force is a major determinant of cell behaviour and is an energetically costly event. How cells derive energy to resist mechanical force is unknown. Here, we show that application of force to E cadherin stimulates liver kinase B1 (LKB1) to activate AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis. LKB1 recruits AMPK to the E-cadherin mechanotransduction complex, thereby stimulating actomyosin contractility, glucose uptake and ATP production. The increase in ATP provides energy to reinforce the adhesion complex and actin cytoskeleton so that the cell can resist physiological forces. Together, these findings reveal a paradigm for how mechanotransduction and metabolism are linked and provide a framework for understanding how diseases involving contractile and metabolic disturbances arise. PMID- 28553940 TI - Single-cell genome sequencing at ultra-high-throughput with microfluidic droplet barcoding. AB - The application of single-cell genome sequencing to large cell populations has been hindered by technical challenges in isolating single cells during genome preparation. Here we present single-cell genomic sequencing (SiC-seq), which uses droplet microfluidics to isolate, fragment, and barcode the genomes of single cells, followed by Illumina sequencing of pooled DNA. We demonstrate ultra-high throughput sequencing of >50,000 cells per run in a synthetic community of Gram negative and Gram-positive bacteria and fungi. The sequenced genomes can be sorted in silico based on characteristic sequences. We use this approach to analyze the distributions of antibiotic-resistance genes, virulence factors, and phage sequences in microbial communities from an environmental sample. The ability to routinely sequence large populations of single cells will enable the de-convolution of genetic heterogeneity in diverse cell populations. PMID- 28553941 TI - Engineered bacteria can function in the mammalian gut long-term as live diagnostics of inflammation. AB - Bacteria can be engineered to function as diagnostics or therapeutics in the mammalian gut but commercial translation of technologies to accomplish this has been hindered by the susceptibility of synthetic genetic circuits to mutation and unpredictable function during extended gut colonization. Here, we report stable, engineered bacterial strains that maintain their function for 6 months in the mouse gut. We engineered a commensal murine Escherichia coli strain to detect tetrathionate, which is produced during inflammation. Using our engineered diagnostic strain, which retains memory of exposure in the gut for analysis by fecal testing, we detected tetrathionate in both infection-induced and genetic mouse models of inflammation over 6 months. The synthetic genetic circuits in the engineered strain were genetically stable and functioned as intended over time. The durable performance of these strains confirms the potential of engineered bacteria as living diagnostics. PMID- 28553942 TI - Digital-to-biological converter for on-demand production of biologics. AB - Manufacturing processes for biological molecules in the research laboratory have failed to keep pace with the rapid advances in automization and parellelization. We report the development of a digital-to-biological converter for fully automated, versatile and demand-based production of functional biologics starting from DNA sequence information. Specifically, DNA templates, RNA molecules, proteins and viral particles were produced in an automated fashion from digitally transmitted DNA sequences without human intervention. PMID- 28553943 TI - Attention-related changes in correlated neuronal activity arise from normalization mechanisms. AB - Attention is believed to enhance perception by altering the activity-level correlations between pairs of neurons. How attention changes neuronal activity correlations is unknown. Using multielectrodes in monkey visual cortex, we measured spike-count correlations when single or multiple stimuli were presented and when stimuli were attended or unattended. When stimuli were unattended, adding a suppressive, nonpreferred stimulus beside a preferred stimulus increased spike-count correlations between pairs of similarly tuned neurons but decreased spike-count correlations between pairs of oppositely tuned neurons. A stochastic normalization model containing populations of oppositely tuned, mutually suppressive neurons explains these changes and also explains why attention decreased or increased correlations: as an indirect consequence of attention related changes in the inputs to normalization mechanisms. Our findings link normalization mechanisms to correlated neuronal activity and attention, showing that normalization mechanisms shape response correlations and that these correlations change when attention biases normalization mechanisms. PMID- 28553944 TI - The cellular mechanism for water detection in the mammalian taste system. AB - Initiation of drinking behavior relies on both internal state and peripheral water detection. While central neural circuits regulating thirst have been well studied, it is still unclear how mammals recognize external water. Here we show that acid-sensing taste receptor cells (TRCs) that were previously suggested as the sour taste sensors also mediate taste responses to water. Genetic silencing of these TRCs abolished water-evoked responses in taste nerves. Optogenetic self stimulation of acid-sensing TRCs in thirsty animals induced robust drinking responses toward light even without water. This behavior was only observed when animals were water-deprived but not under food- or salt-depleted conditions, indicating that the hedonic value of water-evoked responses is highly internal state dependent. Conversely, thirsty animals lacking functional acid-sensing TRCs showed compromised discrimination between water and nonaqueous fluids. Taken together, this study revealed a function of mammalian acid-sensing TRCs that provide a cue for external water. PMID- 28553945 TI - Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A. AB - S-Adenosyl-L-methionine (SAM) is an enzyme cofactor used in methyl transfer reactions and polyamine biosynthesis. The biosynthesis of SAM from ATP and L methionine is performed by the methionine adenosyltransferase enzyme family (Mat; EC 2.5.1.6). Human methionine adenosyltransferase 2A (Mat2A), the extrahepatic isoform, is often deregulated in cancer. We identified a Mat2A inhibitor, PF 9366, that binds an allosteric site on Mat2A that overlaps with the binding site for the Mat2A regulator, Mat2B. Studies exploiting PF-9366 suggested a general mode of Mat2A allosteric regulation. Allosteric binding of PF-9366 or Mat2B altered the Mat2A active site, resulting in increased substrate affinity and decreased enzyme turnover. These data support a model whereby Mat2B functions as an inhibitor of Mat2A activity when methionine or SAM levels are high, yet functions as an activator of Mat2A when methionine or SAM levels are low. The ramification of Mat2A activity modulation in cancer cells is also described. PMID- 28553946 TI - Structural and functional characterization of the hydrogenase-maturation HydF protein. AB - [FeFe] hydrogenase (HydA) catalyzes interconversion between 2H+ and H2 at an active site composed of a [4Fe-4S] cluster linked to a 2Fe subcluster that harbors CO, CN- and azapropanedithiolate (adt2-) ligands. HydE, HydG and HydF are the maturases specifically involved in the biosynthesis of the 2Fe subcluster. Using ligands synthesized by HydE and HydG, HydF assembles a di-iron precursor of the 2Fe subcluster and transfers it to HydA for maturation. Here we report the first X-ray structure of HydF with its [4Fe-4S] cluster. The cluster is chelated by three cysteines and an exchangeable glutamate, which allows the binding of synthetic mimics of the 2Fe subcluster. [Fe2(adt)(CO)4(CN)2]2- is proposed to be the true di-iron precursor because, when bound to HydF, it matures HydA and displays features in Fourier transform infrared (FTIR) spectra that are similar to those of the native HydF active intermediate. A new route toward the generation of artificial hydrogenases, as combinations of HydF and such biomimetic complexes, is proposed on the basis of the observed hydrogenase activity of chemically modified HydF. PMID- 28553947 TI - Structural basis for high-affinity fluorophore binding and activation by RNA Mango. AB - Genetically encoded fluorescent protein tags have revolutionized proteome studies, whereas the lack of intrinsically fluorescent RNAs has hindered transcriptome exploration. Among several RNA-fluorophore complexes that potentially address this problem, RNA Mango has an exceptionally high affinity for its thiazole orange (TO)-derived fluorophore, TO1-Biotin (Kd ~3 nM), and, in complex with related ligands, it is one of the most redshifted fluorescent macromolecular tags known. To elucidate how this small aptamer exhibits such properties, which make it well suited for studying low-copy cellular RNAs, we determined its 1.7-A-resolution co-crystal structure. Unexpectedly, the entire ligand, including TO, biotin and the linker connecting them, abuts one of the near-planar faces of the three-tiered G-quadruplex. The two heterocycles of TO are held in place by two loop adenines and form a 45 degrees angle with respect to each other. Minimizing this angle would increase quantum yield and further improve this tool for in vivo RNA visualization. PMID- 28553948 TI - Lipid II overproduction allows direct assay of transpeptidase inhibition by beta lactams. AB - Peptidoglycan is an essential crosslinked polymer that surrounds bacteria and protects them from osmotic lysis. beta-lactam antibiotics target the final stages of peptidoglycan biosynthesis by inhibiting the transpeptidases that crosslink glycan strands to complete cell wall assembly. Characterization of transpeptidases and their inhibition by beta-lactams have been hampered by lack of access to a suitable substrate. We describe a general approach to accumulate Lipid II in bacteria and to obtain large quantities of this cell wall precursor. We demonstrate the utility of this strategy by isolating Staphylococcus aureus Lipid II and reconstituting the synthesis of crosslinked peptidoglycan by the essential penicillin-binding protein 2 (PBP2), which catalyzes both glycan polymerization and transpeptidation. We also show that we can compare the potencies of different beta-lactams by directly monitoring transpeptidase inhibition. The methods reported here will enable a better understanding of cell wall biosynthesis and facilitate studies of next-generation transpeptidase inhibitors. PMID- 28553950 TI - Atypical chemokine receptor 1 on nucleated erythroid cells regulates hematopoiesis. AB - Healthy individuals of African ancestry have neutropenia that has been linked with the variant rs2814778(G) of the gene encoding atypical chemokine receptor 1 (ACKR1). This polymorphism selectively abolishes the expression of ACKR1 in erythroid cells, causing a Duffy-negative phenotype. Here we describe an unexpected fundamental role for ACKR1 in hematopoiesis and provide the mechanism that links its absence with neutropenia. Nucleated erythroid cells had high expression of ACKR1, which facilitated their direct contact with hematopoietic stem cells. The absence of erythroid ACKR1 altered mouse hematopoiesis including stem and progenitor cells, which ultimately gave rise to phenotypically distinct neutrophils that readily left the circulation, causing neutropenia. Individuals with a Duffy-negative phenotype developed a distinct profile of neutrophil effector molecules that closely reflected the one observed in the ACKR1-deficient mice. Thus, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of ACKR1 in the erythroid lineage, findings with major implications for the selection advantages that have resulted in the paramount fixation of the ACKR1 rs2814778(G) polymorphism in Africa. PMID- 28553949 TI - Functional selectivity of GPCR-directed drug action through location bias. AB - G-protein-coupled receptors (GPCRs) are increasingly recognized to operate from intracellular membranes as well as the plasma membrane. The beta2-adrenergic GPCR can activate Gs-linked cyclic AMP (Gs-cAMP) signaling from endosomes. We show here that the homologous human beta1-adrenergic receptor initiates an internal Gs cAMP signal from the Golgi apparatus. By developing a chemical method to acutely squelch G-protein coupling at defined membrane locations, we demonstrate that Golgi activation contributes significantly to the overall cellular cAMP response. Golgi signaling utilizes a preexisting receptor pool rather than receptors delivered from the cell surface, requiring separate access of extracellular ligands. Epinephrine, a hydrophilic endogenous ligand, accesses the Golgi localized receptor pool by facilitated transport requiring the organic cation transporter 3 (OCT3), whereas drugs can access the Golgi pool by passive diffusion according to hydrophobicity. We demonstrate marked differences, among both agonist and antagonist drugs, in Golgi-localized receptor access and show that beta-blocker drugs currently used in the clinic differ markedly in ability to antagonize the Golgi signal. We propose 'location bias' as a new principle for achieving functional selectivity of GPCR-directed drug action. PMID- 28553951 TI - Post-translational control of T cell development by the ESCRT protein CHMP5. AB - The acquisition of a protective vertebrate immune system hinges on the efficient generation of a diverse but self-tolerant repertoire of T cells by the thymus through mechanisms that remain incompletely resolved. Here we identified the endosomal-sorting-complex-required-for-transport (ESCRT) protein CHMP5, known to be required for the formation of multivesicular bodies, as a key sensor of thresholds for signaling via the T cell antigen receptor (TCR) that was essential for T cell development. CHMP5 enabled positive selection by promoting post selection thymocyte survival in part through stabilization of the pro-survival protein Bcl-2. Accordingly, loss of CHMP5 in thymocyte precursor cells abolished T cell development, a phenotype that was 'rescued' by genetic deletion of the pro apoptotic protein Bim or transgenic expression of Bcl-2. Mechanistically, positive selection resulted in the stabilization of CHMP5 by inducing its interaction with the deubiquitinase USP8. Our results thus identify CHMP5 as an essential component of the post-translational machinery required for T cell development. PMID- 28553952 TI - The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity. AB - The single-nucleotide polymorphism rs1990760 in the gene encoding the cytosolic viral sensor IFIH1 results in an amino-acid change (A946T; IFIH1T946) that is associated with multiple autoimmune diseases. The effect of this polymorphism on both viral sensing and autoimmune pathogenesis remains poorly understood. Here we found that human peripheral blood mononuclear cells (PBMCs) and cell lines expressing the risk variant IFIH1T946 exhibited heightened basal and ligand triggered production of type I interferons. Consistent with those findings, mice with a knock-in mutation encoding IFIH1T946 displayed enhanced basal expression of type I interferons, survived a lethal viral challenge and exhibited increased penetrance in autoimmune models, including a combinatorial effect with other risk variants. Furthermore, IFIH1T946 mice manifested an embryonic survival defect consistent with enhanced responsiveness to RNA self ligands. Together our data support a model wherein the production of type I interferons driven by an autoimmune risk variant and triggered by ligand functions to protect against viral challenge, which probably accounts for its selection within human populations but provides this advantage at the cost of modestly promoting the risk of autoimmunity. PMID- 28553954 TI - E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin-negative malignant mesothelioma cells. AB - Malignant mesothelioma (MM) is an aggressive tumor commonly caused by asbestos exposure after a long latency. Focal adhesion kinase (FAK) inhibitors inhibit the cell growth of Merlin-deficient MM cells; however, their clinical efficacy has not been clearly determined. The aim of this study was to evaluate the growth inhibitory effect of the FAK inhibitor VS-4718 on MM cell lines and identify biomarkers for its efficacy. Although most Merlin-deficient cell lines were sensitive to VS-4718 compared with control MeT-5A cells, a subset of these cell lines exhibited resistance to this drug. Microarray and qRT-PCR analyses using RNA isolated from Merlin-deficient MM cell lines revealed a significant correlation between E-cadherin mRNA levels and VS-4718 resistance. Merlin- and E cadherin-negative Y-MESO-22 cells underwent apoptosis upon treatment with a low concentration of VS-4718, whereas Merlin-negative, E-cadherin-positive Y-MESO-9 cells did not undergo VS-4718-induced apoptosis. Furthermore, E-cadherin knockdown in Merlin-negative MM cells significantly sensitized cells to VS-4718 and induced apoptotic cell death upon VS-4718 treatment. Together, our results suggest that E-cadherin serves as a predictive biomarker for molecular target therapy with FAK inhibitors for patients with mesothelioma and that its expression endows MM cells with resistance to FAK inhibitors. PMID- 28553953 TI - ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner. AB - Activating transcription factor 4 (ATF4) is a critical mediator of metabolic and oxidative homeostasis and cell survival. ATF4 is elevated in response to diverse microenvironmental stresses, including starvation, ER stress damages and exposure to toxic factors. Here we show that ATF4 expression fosters the malignancy of primary brain tumors (WHO grade III and IV gliomas) and increases proliferation and tumor angiogenesis. Hence, ATF4 expression promotes cell migration and anchorage-independent cell growth, whereas siRNA-mediated knockdown of ATF4 attenuates these features of malignancy in human gliomas. Further experiments revealed that ATF4-dependent tumor promoting effects are mediated by transcriptional targeting the glutamate antiporter xCT/SCL7A11 (also known as system Xc-). Thus, xCT is elevated as a consequence of ATF4 activation. We further found evidence that ATF4-induced proliferation can be attenuated by pharmacological or genetic xCT inhibition and ferroptosis inducers such as sorafenib, erastin and GPx4 inhibitor RSL3. Further, fostered xCT expression promotes cell survival and growth in ATF4 knockdown cells. Moreover, increased xCT levels ameliorate sorafenib and erastin-induced ferroptosis. Conversely, ATF4 knockdown renders cells susceptible for erastin, sorafenib and RSL3-induced ferroptosis. We further identified that ATF4 promotes tumor-mediated neuronal cell death which can be alleviated by xCT inhibition. Moreover, elevated ATF4 expression in gliomas promotes tumor angiogenesis. Noteworthy, ATF4-induced angiogenesis could be diminished by ferroptosis inducers erastin and by GPx4 inhibitor RSL3. Our data provide proof-of-principle evidence that ATF4 fosters proliferation and induces a toxic microenvironmental niche. Furthermore, ATF4 increases tumor angiogenesis and shapes the vascular architecture in a xCT dependent manner. Thus, inhibition of ATF4 is a valid target for diminishing tumor growth and vasculature via sensitizing tumor cells for ferroptosis. PMID- 28553955 TI - Deletion of ADAM-9 in HGF/CDK4 mice impairs melanoma development and metastasis. AB - ADAM-9 is a metalloproteinase expressed in peritumoral areas by invading melanoma cells and by adjacent peritumoral stromal cells; however, its function in stromal and melanoma cells is not fully understood. To address this question in vivo in a spontaneous melanoma model, we deleted ADAM-9 in mice carrying the hepatocyte growth factor (Hgf) transgene and knock-in mutation Cdk4R24C/R24C, demonstrated to spontaneously develop melanoma. Spontaneous melanoma arose less frequently in ADAM-9-deleted mice than in controls. Similarly reduced tumor numbers (although with faster growth kinetics) were detected upon induction of melanoma with 7,12 dimethylbenz[a]anthracene (DMBA). However, more lesions were induced at early time points in the absence of ADAM-9. Increased initial and decreased late tumor numbers were paralleled by altered tumor cell proliferation, but not apoptosis or inflammation. Importantly, significantly reduced lung metastases were detected upon ADAM-9 deletion. Using in vitro assays to address this effect mechanistically, we detected reduced adhesion and transmigration of ADAM-9 silenced melanoma cells to/through the endothelium. This implies that ADAM-9 functionally and cell autonomously mediates extravasation of melanoma cells. In vitro and in vivo we demonstrated that the basement membrane (BM) component laminin beta3-chain is a direct substrate of ADAM-9, thus contributing to destabilization and disruption of the BM barrier during invasion. In in vitro invasion assays using human melanoma cells and skin equivalents, depletion of ADAM-9 resulted in decreased invasion of the BM, which remained almost completely intact, as shown by continuous staining for laminin beta3-chain. Importantly, supplying soluble ADAM-9 to the system reversed this effect. Taken together, our data show that melanoma derived ADAM-9 autonomously contributes to melanoma progression by modulating cell adhesion to the endothelium and altering BM integrity by proteolytically processing the laminin-beta3 chain. This newly described process and ADAM-9 itself may represent potential targets for anti tumor therapies. PMID- 28553956 TI - Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression. AB - The canonical WNT signaling pathway is crucial for intestinal stem cell renewal and aberrant WNT signaling is an early event in colorectal cancer (CRC) development. Here, we show for the first time that WNT2 is one of the most significantly induced genes in CRC stroma as compared to normal stroma. The impact of stromal WNT2 on carcinoma formation or progression was not addressed so far. Canonical WNT/beta-catenin signaling was assessed using a 7TGP-reporter construct. Furthermore, effects of WNT2 on fibroblast migration and invasion were determined using siRNA-mediated gene silencing. Tumor cell invasion was studied using organotypic raft cultures and in vivo significance was assessed via a xenograft mouse model. We identified cancer-associated fibroblasts (CAFs) as the main source of WNT2. CAF-derived WNT2 activated canonical signaling in adenomatous polyposis coli/beta-catenin wild-type colon cancer cells in a paracrine fashion, whereas no hyperactivation was detectable in cell lines harboring mutations in the adenomatous polyposis coli/beta-catenin pathway. Furthermore, WNT2 activated autocrine canonical WNT signaling in primary fibroblasts, which was associated with a pro-migratory and pro-invasive phenotype. We identified FZD8 as the putative WNT2 receptor in CAFs. Three dimensional organotypic co-culture assays revealed that WNT2-mediated fibroblast motility and extracellular matrix remodeling enhanced cancer cell invasion of cell lines even harboring mutations in the adenomatous polyposis coli/beta catenin pathway. Thus, suggesting a tumor-promoting influence on a broad range of CRC. In line, WNT2 also promotes tumor growth, invasion and metastasis in vivo. Moreover, high WNT2 expression is associated with poor prognosis in human CRC. The identification of the pro-malignant function of stromal derived WNT2 in CRC classifies WNT2 and its receptor as promising stromal targets to confine cancer progression in combination with conventional or targeted therapies. PMID- 28553960 TI - Cast aluminium single crystals cross the threshold from bulk to size-dependent stochastic plasticity. AB - Metals are known to exhibit mechanical behaviour at the nanoscale different to bulk samples. This transition typically initiates at the micrometre scale, yet existing techniques to produce micrometre-sized samples often introduce artefacts that can influence deformation mechanisms. Here, we demonstrate the casting of micrometre-scale aluminium single-crystal wires by infiltration of a salt mould. Samples have millimetre lengths, smooth surfaces, a range of crystallographic orientations, and a diameter D as small as 6 MUm. The wires deform in bursts, at a stress that increases with decreasing D. Bursts greater than 200 nm account for roughly 50% of wire deformation and have exponentially distributed intensities. Dislocation dynamics simulations show that single-arm sources that produce large displacement bursts halted by stochastic cross-slip and lock formation explain microcast wire behaviour. This microcasting technique may be extended to several other metals or alloys and offers the possibility of exploring mechanical behaviour spanning the micrometre scale. PMID- 28553959 TI - Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation. AB - Through exome sequencing, we identified six individuals with biallelic loss-of function mutations in TRIP13. All six developed Wilms tumor. Constitutional mosaic aneuploidies, microcephaly, developmental delay and seizures, which are features of mosaic variegated aneuploidy (MVA) syndrome, were more variably present. Through functional studies, we show that TRIP13-mutant patient cells have no detectable TRIP13 and have substantial impairment of the spindle assembly checkpoint (SAC), leading to a high rate of chromosome missegregation. Accurate segregation, as well as SAC proficiency, is rescued by restoring TRIP13 function. Individuals with biallelic TRIP13 or BUB1B mutations have a high risk of embryonal tumors, and here we show that their cells display severe SAC impairment. MVA due to biallelic CEP57 mutations, or of unknown cause, is not associated with embryonal tumors and cells from these individuals show minimal SAC deficiency. These data provide insights into the complex relationships between aneuploidy and carcinogenesis. PMID- 28553958 TI - Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis. AB - Recent evidence suggests that a substantial portion of complex disease risk alleles modify gene expression in a cell-specific manner. To identify candidate causal genes and biological pathways of immune-related complex diseases, we conducted expression quantitative trait loci (eQTL) analysis on five subsets of immune cells (CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells and monocytes) and unfractionated peripheral blood from 105 healthy Japanese volunteers. We developed a three-step analytical pipeline comprising (i) prediction of individual gene expression using our eQTL database and public epigenomic data, (ii) gene-level association analysis and (iii) prediction of cell-specific pathway activity by integrating the direction of eQTL effects. By applying this pipeline to rheumatoid arthritis data sets, we identified candidate causal genes and a cytokine pathway (upregulation of tumor necrosis factor (TNF) in CD4+ T cells). Our approach is an efficient way to characterize the polygenic contributions and potential biological mechanisms of complex diseases. PMID- 28553962 TI - Size effect and scaling power-law for superelasticity in shape-memory alloys at the nanoscale. AB - Shape-memory alloys capable of a superelastic stress-induced phase transformation and a high displacement actuation have promise for applications in micro electromechanical systems for wearable healthcare and flexible electronic technologies. However, some of the fundamental aspects of their nanoscale behaviour remain unclear, including the question of whether the critical stress for the stress-induced martensitic transformation exhibits a size effect similar to that observed in confined plasticity. Here we provide evidence of a strong size effect on the critical stress that induces such a transformation with a threefold increase in the trigger stress in pillars milled on [001] L21 single crystals from a Cu-Al-Ni shape-memory alloy from 2 MUm to 260 nm in diameter. A power-law size dependence of n = -2 is observed for the nanoscale superelasticity. Our observation is supported by the atomic lattice shearing and an elastic model for homogeneous martensite nucleation. PMID- 28553963 TI - Frequency-dependent stability of CNT Joule heaters in ionizable media and desalination processes. AB - Water shortages and brine waste management are increasing challenges for coastal and inland regions, with high-salinity brines presenting a particularly challenging problem. These high-salinity waters require the use of thermally driven treatment processes, such as membrane distillation, which suffer from high complexity and cost. Here, we demonstrate how controlling the frequency of an applied alternating current at high potentials (20 Vpp) to a porous thin-film carbon nanotube (CNT)/polymer composite Joule heating element can prevent CNT degradation in ionizable environments such as high-salinity brines. By operating at sufficiently high frequencies, these porous thin-films can be directly immersed in highly ionizable environments and used as flow-through heating elements. We demonstrate that porous CNT/polymer composites can be used as self heating membranes to directly heat high-salinity brines at the water/vapour interface of the membrane distillation element, achieving high single-pass recoveries that approach 100%, far exceeding standard membrane distillation recovery limits. PMID- 28553961 TI - Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity. AB - MDM2-MDMX complexes bind the p53 tumor-suppressor protein, inhibiting p53's transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response, but their use in the treatment of cancers that retain wild-type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2-MDMX-E2(UbcH5B)-ubiquitin complex, we designed MDM2 mutants that prevent E2-ubiquitin binding without altering the RING domain structure. These mutants lack MDM2's E3 activity but retain the ability to limit p53's transcriptional activity and allow cell proliferation. Cells expressing these mutants respond more quickly to cellular stress than cells expressing wild-type MDM2, but basal p53 control is maintained. Targeting the MDM2 E3-ligase activity could therefore widen the therapeutic window of p53 activation in tumors. PMID- 28553964 TI - Thermal desalination membranes: Carbon nanotubes keep up the heat. PMID- 28553965 TI - Fast high-resolution miniature two-photon microscopy for brain imaging in freely behaving mice. AB - Developments in miniaturized microscopes have enabled visualization of brain activities and structural dynamics in animals engaging in self-determined behaviors. However, it remains a challenge to resolve activity at single dendritic spines in freely behaving animals. Here, we report the design and application of a fast high-resolution, miniaturized two-photon microscope (FHIRM TPM) that accomplishes this goal. With a headpiece weighing 2.15 g and a hollow core photonic crystal fiber delivering 920-nm femtosecond laser pulses, the FHIRM TPM is capable of imaging commonly used biosensors (GFP and GCaMP6) at high spatiotemporal resolution (0.64 MUm laterally and 3.35 MUm axially, 40 Hz at 256 * 256 pixels for raster scanning and 10,000 Hz for free-line scanning). We demonstrate the microscope's robustness with hour-long recordings of neuronal activities at the level of spines in mice experiencing vigorous body movements. PMID- 28553979 TI - Mechanistic Investigation of Visible-Light-Induced Intermolecular [2 + 2] Photocycloaddition Catalyzed with Chiral Thioxanthone. AB - The recent thioxanthone-sensitizer-catalyzed intermolecular [2 + 2] cycloaddition induced by visible-light irradiation set the stage for the future development of feasible photocycloadditions. Nonetheless, the mechanism of this reaction still remains under debate, especially on the activation mode of the thioxanthone photosensitizer (energy transfer, bielectron exchange, and hydrogen transfer are all possible mechanisms). To settle this issue, systematic density functional theory calculations have been carried out. The results indicate that the energy transfer pathway is more favorable than the bielectron-exchange and the hydrogen transfer pathways. Meanwhile, the overall transformations involve the complexation and excitation of photosensitizer, the first C-C bond formation, the dissociation of the sensitizer, the triplet-to-singlet electronic state crossing, and the second C-C bond formation. The first C-C bond formation is the rate- and selectivity-determining step, and synergistic energy and electron transfer from photosensitizer to substrate moieties takes place along this process. On this basis, the effect of olefin substrates (ethyl vinyl ketone vs vinyl acetate) on the stereoselectivity was finally analyzed. PMID- 28553966 TI - Biosynthesis and genetic encoding of phosphothreonine through parallel selection and deep sequencing. AB - The phosphorylation of threonine residues in proteins regulates diverse processes in eukaryotic cells, and thousands of threonine phosphorylations have been identified. An understanding of how threonine phosphorylation regulates biological function will be accelerated by general methods to biosynthesize defined phosphoproteins. Here we describe a rapid approach for directly discovering aminoacyl-tRNA synthetase-tRNA pairs that selectively incorporate non natural amino acids into proteins; our method uses parallel positive selections combined with deep sequencing and statistical analysis and enables the direct, scalable discovery of aminoacyl-tRNA synthetase-tRNA pairs with mutually orthogonal substrate specificity. By combining a method to biosynthesize phosphothreonine in cells with this selection approach, we discover a phosphothreonyl-tRNA synthetase-tRNACUA pair and create an entirely biosynthetic route to incorporating phosphothreonine in proteins. We biosynthesize several phosphoproteins and demonstrate phosphoprotein structure determination and synthetic protein kinase activation. PMID- 28553980 TI - Cu-Catalyzed Cascade Annulation of Alkynols with 2-Azidobenzaldehydes: Access to 6H-Isochromeno[4,3-c]quinoline. AB - A copper-catalyzed cascade reaction of alkynols and 2-azidobenzaldehydes has been achieved, giving 6H-isochromeno[4,3-c]quinoline in yields of 40-81%. This reaction provides a novel, concise strategy for rapidly constructing compounds with fused N- and O-containing heterocycles. In contrast to previously reported reactions of alkynols in which the first step is intramolecular cycloisomerization, the first step in this novel reaction of alkynols is entropically unfavorable intermolecular addition. The resulting hemiacetal intermediate then undergoes intramolecular cyclization and aromatization to afford the product. PMID- 28553981 TI - Initiation in Photoredox C-H Functionalization Reactions. Is Dimsyl Anion a Key Ingredient? AB - Previous studies have reported the arylation of unactivated arenes with ArX, base (KOtBu or NaOtBu), and an organic additive at high temperatures. Recently, we showed that this reaction proceeds in the absence of additives at rt but employs UV-vis light. However, details of mechanisms that can use a photoinduced base promoted homolytic aromatic substitution reaction (photo-BHAS) have remained elusive until now. This work examines different mechanistic routes of the essential electron-transfer step (ET) of this reaction in order to identify a possible path for the formation of 1-adamantyl radicals from 1-haloadamantanes (initiation step). On the basis of photochemical and photophysical experiments and computational studies, we propose an unprecedented initiation step that could also be applied to other ET reactions performed in DMSO. For the first time, it is reported that dimsyl anion, formed from a strong base and DMSO (solvent), is responsible for inducing the initiation by a photo-BHAS process on alkyl halides. PMID- 28553982 TI - Direct Observation of Asphaltene Nanoparticles on Model Mineral Substrates. AB - The propensity for adherence to solid surfaces of asphaltenes, a complex solubility class of heteropolycyclic aromatic compounds from the heavy fraction of crude oil, has long been the root cause of scale deposition and remains an intractable problem in the petroleum industry. Although the adhesion is essential to understanding the process of asphaltene deposition, the relationship between the conformation of asphaltene molecules on mineral substrates and its impact on adhesion and mechanical properties of the deposits is not completely understood. To rationalize the primary processes in the process of organic scale deposition, here we use atomic force microscopy (AFM) to visualize the morphology of petroleum asphaltenes deposited on model mineral substrates. High imaging contrast was achieved by the differential adhesion of the tip between asphaltenes and the mineral substrate. While asphaltenes form smooth continuous films on all substrates at higher concentrations, they deposit as individual nanoparticles at lower concentrations. The size, shape, and spatial distribution of the nanoaggregates are strongly affected by the nature of the substrate; while uniformly distributed spherical particles are formed on highly polar and hydrophilic substrates (mica), irregular islands and thicker patches are observed with substrates of lower polarity (silica and calcite). Asphaltene nanoparticles flatten when adsorbed on highly oriented pyrolytic graphite due to pi-pi interactions with the polycyclic core. Force-distance profiles provide direct evidence of the conformational changes of asphaltene molecules on hydrophilic/hydrophobic substrates that result in dramatic changes in adhesion and mechanical properties of asphaltene deposits. Such an understanding of the nature of adhesion and mechanical properties tuned by surface properties, on the level of asphaltene nanoaggregates, would contribute to the design of efficient asphaltene inhibitors for preventing asphaltene fouling on targeted surfaces. Unlike flat surfaces, the AFM phase contrast images of defected calcite surfaces show that asphaltenes form continuous deposits to fill the recesses, and this process could trigger the onset for asphaltene deposition. PMID- 28553984 TI - Modulation of Coiled-Coil Dimer Stability through Surface Residues while Preserving Pairing Specificity. AB - The coiled-coil dimer is a widespread protein structural motif and, due to its designability, represents an attractive building block for assembling modular nanostructures. The specificity of coiled-coil dimer pairing is mainly based on hydrophobic and electrostatic interactions between residues at positions a, d, e, and g of the heptad repeat. Binding affinity, on the other hand, can also be affected by surface residues that face away from the dimerization interface. Here we show how design of the local helical propensity of interacting peptides can be used to tune the stabilities of coiled-coil dimers over a wide range. By designing intramolecular charge pairs, regions of high local helical propensity can be engineered to form trigger sequences, and dimer stability is adjusted without changing the peptide length or any of the directly interacting residues. This general principle is demonstrated by a change in thermal stability by more than 30 degrees C as a result of only two mutations outside the binding interface. The same approach was successfully used to modulate the stabilities in an orthogonal set of coiled-coils without affecting their binding preferences. The stability effects of local helical propensity and peptide charge are well described by a simple linear model, which should help improve current coiled-coil stability prediction algorithms. Our findings enable tuning the stabilities of coiled-coil-based building modules match a diverse range of applications in synthetic biology and nanomaterials. PMID- 28553983 TI - Acceleration of Linear Finite-Difference Poisson-Boltzmann Methods on Graphics Processing Units. AB - Electrostatic interactions play crucial roles in biophysical processes such as protein folding and molecular recognition. Poisson-Boltzmann equation (PBE)-based models have emerged as widely used in modeling these important processes. Though great efforts have been put into developing efficient PBE numerical models, challenges still remain due to the high dimensionality of typical biomolecular systems. In this study, we implemented and analyzed commonly used linear PBE solvers for the ever-improving graphics processing units (GPU) for biomolecular simulations, including both standard and preconditioned conjugate gradient (CG) solvers with several alternative preconditioners. Our implementation utilizes the standard Nvidia CUDA libraries cuSPARSE, cuBLAS, and CUSP. Extensive tests show that good numerical accuracy can be achieved given that the single precision is often used for numerical applications on GPU platforms. The optimal GPU performance was observed with the Jacobi-preconditioned CG solver, with a significant speedup over standard CG solver on CPU in our diversified test cases. Our analysis further shows that different matrix storage formats also considerably affect the efficiency of different linear PBE solvers on GPU, with the diagonal format best suited for our standard finite-difference linear systems. Further efficiency may be possible with matrix-free operations and integrated grid stencil setup specifically tailored for the banded matrices in PBE-specific linear systems. PMID- 28553985 TI - Peridental bone changes after orthodontic tooth movement with fixed appliances: A cone-beam computed tomographic study. AB - OBJECTIVE: To quantify treatment-related changes in peridental bone height and thickness in orthodontic patients. MATERIALS AND METHODS: Cone-beam computed tomographs (CBCTs) of 43 patients (24 female, 19 male; mean age: 25 years, 5 months) who underwent orthodontic treatment with multibracket appliances for at least 1 year were chosen for retrospective evaluation. Dehiscence depth and changes in bone width and tooth inclination were determined for 954 teeth. RESULTS: There was a significant decrease in peridental bone height (dehiscence; 0.82 +/- 1.47 mm) and bone thickness (-0.56 +/- 0.7 and -0.69 +/- 0.9 mm at 5 mm and 10 mm apical to the CEJ, respectively) during treatment (P < .001). A significantly greater dehiscence depth with increased vertical bone loss occurred in patients older than 30 years. In patients <30 years old, approximately 20% of the teeth showed defect depths >2 mm before treatment. In 90% of these patients, at least one tooth was affected. The maxillary canines and all mandibular teeth showed a higher risk for vestibular bone loss. Treatment changes in tooth inclination were correlated with horizontal bone loss. CONCLUSIONS: Based on these results, it seems reasonable to recommend that peridental bone in orthodontic patients older than 30 be evaluated on a routine basis due to the risk of increased vertical bone loss. Ninety percent of patients younger than 30 showed reduced bone height (dehiscence) of the periodontium of at least one tooth. PMID- 28553957 TI - Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. AB - Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 * 10-14) through deep resequencing of XFS cases and controls from nine countries. A genome wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 * 10-8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology. PMID- 28553986 TI - Epigenetics, nutrition and mental health. Is there a relationship? AB - Many aspects of human development and disease are influenced by the interaction between genetic and environmental factors. Understanding how our genes respond to the environment is central to managing health and disease, and is one of the major contemporary challenges in human genetics. Various epigenetic processes affect chromosome structure and accessibility of deoxyribonucleic acid (DNA) to the enzymatic machinery that leads to expression of genes. One important epigenetic mechanism that appears to underlie the interaction between environmental factors, including diet, and our genome, is chemical modification of the DNA. The best understood of these modifications is methylation of cytosine residues in DNA. It is now recognized that the pattern of methylated cytosines throughout our genomes (the 'methylome') can change during development and in response to environmental cues, often with profound effects on gene expression. Many dietary constituents may indirectly influence genomic pathways that methylate DNA, and there is evidence for biochemical links between nutritional quality and mental health. Deficiency of both macro- and micronutrients has been associated with increased behavioural problems, and nutritional supplementation has proven efficacious in treatment of certain neuropsychiatric disorders. In this review we examine evidence from the fields of nutrition, developmental biology, and mental health that supports dietary impacts on epigenetic processes, particularly DNA methylation. We then consider whether such processes could underlie the demonstrated efficacy of dietary supplementation in treatment of mental disorders, and whether targeted manipulation of DNA methylation patterns using controlled dietary supplementation may be of wider clinical value. PMID- 28553987 TI - Glycated Hemoglobin is Independently Associated with Albuminuria in Young Nondiabetic People with Obesity: A Cross-Sectional Study. AB - BACKGROUND The aim of this study was to explore the association between glycated hemoglobin (HbA1c) level and albuminuria in young nondiabetic people with obesity. MATERIAL AND METHODS A total of 537 young nondiabetic people with obesity were enrolled in this cross-sectional study, which was approved by the Rui-jin Hospital Ethics Committee. Albuminuria was defined as a urinary albumin to-creatinine ratio (ACR) >=30 mg/g. Multivariate logistic regression was used to analyze the association between HbA1c level and albuminuria. RESULTS Urinary ACR progressively increased across the tertiles of HbA1c level (P for trend <0.05). HbA1c levels were positively associated with the risk of albuminuria in the logistic regression analysis after adjustment for confounding factors. The adjusted odds ratio (OR) for albuminuria was 3.72 (95% confidence interval [CI], 1.25-11.00; P=0.017) when comparing between the highest (>=5.7%) and lowest tertiles of HbA1c level (<=5.3%). Moreover, an increment of 1 SD in HbA1c level increased the risk of albuminuria in a fully adjusted model (OR, 1.73; 95% CI, 1.25-2.46). CONCLUSIONS These data suggest that HbA1c level was independently associated with albuminuria in young nondiabetic people with obesity. PMID- 28553988 TI - Exposure to acetaminophen and all its metabolites upon 10, 15, and 20 mg/kg intravenous acetaminophen in very-preterm infants. AB - BackgroundExposure to acetaminophen and its metabolites in very-preterm infants is partly unknown. We investigated the exposure to acetaminophen and its metabolites upon 10, 15, or 20 mg/kg intravenous acetaminophen in preterm infants.MethodsIn a randomized trial, 59 preterm infants (24-32 weeks' gestational age, postnatal age <1 week) received 10, 15, or 20 mg/kg acetaminophen intravenously. Plasma concentrations of acetaminophen and its metabolites (glucuronide, sulfate, cysteine, mercapturate, and glutathione) were determined in 293 blood samples. Area under the plasma concentration-time curves (AUC0-500 min) was related to dose and gestational age.ResultsBetween 10 and 20 mg/kg dose, median AUCs of acetaminophen, glucuronide, sulfate, and cysteine increased significantly resulting in unchanged ratios of AUC of metabolite to acetaminophen. The AUC ratio of glucuronide to acetaminophen increased with gestational age, that of sulfate decreased, and the ratio of cysteine and mercapturate remained unchanged.ConclusionWe found a gestational-age-dependent increase in glucuronidation but no evidence for saturation of a specific pathway as there was a proportional increase in exposure of acetaminophen and all metabolites. Compared with adults, very low exposure to glucuronide but higher exposure to sulfate, cysteine, and mercapturate metabolites was found, of which the relevance is not yet known. PMID- 28553990 TI - Investigating the effects of cerebrospinal fluid removal on cerebral blood flow and oxidative metabolism in infants with post-hemorrhagic ventricular dilatation. AB - BackgroundPost-hemorrhagic ventricular dilatation (PHVD) is predictive of mortality and morbidity among very-low-birth-weight preterm infants. Impaired cerebral blood flow (CBF) due to elevated intracranial pressure (ICP) is believed to be a contributing factor.MethodsA hyperspectral near-infrared spectroscopy (NIRS) method of measuring CBF and the cerebral metabolic rate of oxygen (CMRO2) was used to investigate perfusion and metabolism changes in patients receiving a ventricular tap (VT) based on clinical management. To improve measurement accuracy, the spectral analysis was modified to account for compression of the cortical mantle caused by PHVD and the possible presence of blood breakdown products.ResultsFrom nine patients (27 VTs), a significant CBF increase was measured (15.6%) following VT (14.6+/-4.2 to 16.9+/-6.6 ml/100 g/min), but with no corresponding change in CMRO2 (1.02+/-0.41 ml O2/100 g/min). Post-VT CBF was in good agreement with a control group of 13 patients with patent ductus arteriosus but no major cerebral pathology (16.5+/-7.7 ml/100 g/min), whereas tissue oxygen saturation (StO2) was significantly lower (58.9+/-12.1% vs. 70.5+/ 9.1% for controls).ConclusionCBF was impeded in PHVD infants requiring a clinical intervention, but the effect is not large enough to alter CMRO2. PMID- 28553991 TI - Early career investigator-August issue. PMID- 28553989 TI - Neuroimaging in former preterm children who received erythropoiesis stimulating agents. AB - BackgroundIn premature children, erythropoiesis-stimulating agents (ESAs) may improve developmental outcome. It is not clear which of the several potential mechanisms are responsible for this improvement. High-resolution MRI and diffusion tensor imaging characterize brain structure and white matter organization, offering possible insight into the long-term effect of ESAs on brain development.MethodsMRI scans were performed at 3.5-4 years of age on former preterm infants treated with ESAs or placebo, and on healthy term controls. Mean cortical thickness, surface area, and fractional anisotropy (FA) were compared across study groups, and were correlated with general IQ measures.ResultsUnivariate analysis found no significant effect of ESAs on cortical thickness (P=0.366), surface area (P=0.940), or FA (P=0.150); however, there was a greater increase in FA among ESA-treated girls. Group analysis found significant correlations between FA and Full-Scale IQ (P=0.044) and Verbal IQ (P=0.036), although there was no significant relationship between Full-Scale IQ and FA among just the preterm children.ConclusionESA treatment may have a preferential effect on white matter development in girls, although factors other than just whole-brain FA are involved in mediating cognitive outcome. PMID- 28553992 TI - Does age modify the association between psychosocial factors at work and deterioration of self-rated health? AB - Objectives Few epidemiological studies have examined whether associations of psychosocial working conditions with risk of poor health differ by age. Based on results from mostly cross-sectional studies, we test whether (i) psychosocial relational factors (social support) are more strongly associated with declining health of older than younger employees and (ii) psychosocial job factors (workpace, influence, possibilities for development) are more strongly associated with declining health of younger than older employees. Methods We extracted two cohorts from the Danish Work Environment Cohort Study (DWECS): the 2000-2005 and 2005-2010 cohorts. The participating 5281 employees with good self-rated health (SRH) at baseline were observed in 6585 5-year time windows. Using log-binomial regression analyses, we analysed whether psychosocial factors at work predicted 5 year deterioration of SRH. Effect modification by age was estimated by calculating relative excess risk due to interaction (RERI). Results High workpace among men, low influence at work as well as low social support from colleagues among women, and low possibilities for development and low social support from supervisors among both genders predicted 5-year decline in SRH. Of the 20 interaction analyses, only 1 was statistically significant and in the opposite direction of what was hypothesized (higher risk for declining SRH among middle aged men with low possibilities for development compared to the young men with high possibilities for development). Conclusions Psychosocial working conditions predicted decline in SRH in this 5-year follow-up study. The model did not support our hypotheses about modifying effects by age. PMID- 28553993 TI - Multi-Phase Solvation Model for Biological Membranes: Molecular Action Mechanism of Amphotericin B. AB - Amphotericin B (AmB) is still the most effective drug for the treatment of systemic fungal infections in humans. Despite significant theoretical and experimental efforts trying to understand its molecular mechanism of action, the answer has remained elusive. In this work, we present a computational methodology to test the current membrane related hypotheses, namely, transmembrane ion channel, adsorption, and sterol sponge. We use a thermodynamic approach in which we represent the membrane by a multiphase solvation model with atomic detail (MMPSM) and calculate the free energy of transferring the drug between phases with different dielectric properties. Furthermore, we compare AmB to a chemical analogue with increased safety, an l-histidine methyl ester of AmB. Our findings reveal that both drugs dimerize in all solvents studied here. Also, it is energetically unfavorable for the drugs to penetrate into the hydrophobic core of the membrane, unless their concentration is high. Finally, it is thermodynamically possible that the sterols migrate from the membrane into a drug droplet adsorbed at the surface of the bilayer. In light of our results, several effects could take place in the complex antibiotic process. We suggest a molecular mechanism that connects all three hypotheses through a drug concentration dependence and propose that the drug promotes the formation of membrane toroidal pores. Because MMPSM is of general interest, we made it available at http://tripplab.com/tools/mmpsm . PMID- 28553995 TI - Mapping regulatory models for medicinal cannabis: a matrix of options. AB - Objective The aim of the present study was to develop a framework for assessing regulatory options for medicinal cannabis in Australia.Methods International regulatory regimes for medicinal cannabis were reviewed with a qualitative policy analysis approach and key policy features were synthesised, leading to a conceptual framework that facilitates decision making across multiple dimensions.Results Two central organising dimensions of medicinal cannabis regulation were identified: cannabis supply and patient authorisation (including patient access). A number of the different supply options can be matched with a number of different patient authorisation options, leading to a matrix of possible regulatory regimes.Conclusions The regulatory options, as used internationally, involve different forms of cannabis (synthetic and plant-based pharmaceutical preparations or herbal cannabis) and the varying extent to which patient authorisation policies and procedures are stringently or more loosely defined. The optimal combination of supply and patient authorisation options in any jurisdiction that chooses to make medicinal cannabis accessible will depend on policy goals.What is known about the topic? Internationally, regulation of medicinal cannabis has developed idiosyncratically, depending on formulations that were made available and local context. There has been no attempt to date in the scientific literature to systematically document the variety of regulatory possibilities for medicinal cannabis.What does this paper add? This paper presents a new conceptual schema for considering options for the regulation of medicinal cannabis, across both supply and patient authorisation aspects.What are the implications for practitioners? The design of regulatory systems in Australia, whether for pharmaceutical or herbal products, is a vital issue for policy makers right now as federal and state and territory governments grapple with the complexities of medicinal cannabis regulation. The conceptual schema presented herein provides a tool for more systematic thinking about the options. PMID- 28553996 TI - Gender dysphoria and the controversy over the Safe Schools program. AB - The Safe Schools program has attracted great controversy. On one end of the spectrum, it is defended as an anti-bullying program for young people who identify themselves as gay or lesbian, or have issues concerning their gender identity. On the other end of the spectrum, it is regarded as social engineering. This article seeks to promote a discussion of the way in which gender identity issues are addressed in the Safe Schools program. It is argued that the information in this program to Principals, teachers and young people is inaccurate and misleading. The program, as presently designed, may actually cause harm to children and young people who experience gender identity issues because it promotes gender transitioning without expert medical advice. The Safe Schools materials do not acknowledge that the great majority of children resolve gender dysphoria issues around the time of puberty. It may be much more difficult for a child to accept his or her gender at puberty if he or she has already changed name and gender identity in primary school. These deficits need to be addressed if the program is to continue. PMID- 28553994 TI - The repeated bout effect of traditional resistance exercises on running performance across 3 bouts. AB - This study investigated the repeated bout effect of 3 typical lower body resistance-training sessions on maximal and submaximal effort running performance. Twelve resistance-untrained men (age, 24 +/- 4 years; height, 1.81 +/- 0.10 m; body mass, 79.3 +/- 10.9 kg; peak oxygen uptake, 48.2 +/- 6.5 mL.kg 1.min-1; 6-repetition maximum squat, 71.7 +/- 12.2 kg) undertook 3 bouts of resistance-training sessions at 6-repetitions maximum. Countermovement jump (CMJ), lower-body range of motion (ROM), muscle soreness, and creatine kinase (CK) were examined prior to and immediately, 24 h (T24), and 48 h (T48) after each resistance-training bout. Submaximal (i.e., below anaerobic threshold (AT)) and maximal (i.e., above AT) running performances were also conducted at T24 and T48. Most indirect muscle damage markers (i.e., CMJ, ROM, and muscle soreness) and submaximal running performance were significantly improved (P < 0.05; 1.9%) following the third resistance-training bout compared with the second bout. Whilst maximal running performance was also improved following the third bout (P < 0.05; 9.8%) compared with other bouts, the measures were still reduced by 12% 20% versus baseline. However, the increase in CK was attenuated following the second bout (P < 0.05) with no further protection following the third bout (P > 0.05). In conclusion, the initial bout induced the greatest change in CK; however, at least 2 bouts were required to produce protective effects on other indirect muscle damage markers and submaximal running performance measures. This suggests that submaximal running sessions should be avoided for at least 48 h after resistance training until the third bout, although a greater recovery period may be required for maximal running sessions. PMID- 28553997 TI - Partnership agreements less likely among young gay and bisexual men in Australia data from a national online survey of gay and bisexual men's relationships. AB - BACKGROUND: How gay and bisexual men (GBM) establish partnership agreements may be affected by several factors, including age. The ability to communicate with a partner about sexual agreements has important sexual health implications for GBM. OBJECTIVE: To assess differences in partnership agreements among GBM. METHODS: We surveyed GBM about their partnerships using a national, anonymous online survey in 2013-14. We compared men who had monogamous partnerships with men who had non monogamous partnerships, according to age and other factors. RESULTS: Regarding the nature of their partnership with their primary regular partner (PRP), younger men were less likely to have an agreement of any sort and were less likely to have discussed it. Younger men were more likely to report having a monogamous partnership, but they were also less likely to report condomless anal intercourse with their PRP. In multivariate analysis of partnership arrangements, having a non-monogamous partnership with their PRP was associated with being older (adjusted odds ratio=1.03; 95% confidence interval=1.02-1.04; P<0.001). Nearly two-thirds (62.9%) of men with monogamous partnerships had a clear spoken agreement with their PRP about whether they could have sex with other men, largely regardless of age. Although slightly fewer than half the men with self described open partnerships (46.0%) actually described it as a 'relationship', younger men were particularly less likely to do so. CONCLUSIONS: Due to less communication with partners about sexual agreements, when young GBM engage in sexual risk behaviour they may be at an increased risk of HIV and other sexually transmissible infections. PMID- 28553998 TI - Splicing-related single nucleotide polymorphism of RAB, member of RAS oncogene family like 2B (RABL2B) jeopardises semen quality in Chinese Holstein bulls. AB - RAB, member of RAS oncogene family like 2B (RABL2B) is a member of a poorly characterised clade of the RAS GTPase superfamily, which plays an essential role in male fertility, sperm intraflagellar transport and tail assembly. In the present study, we identified a novel RABL2B splice variant in bovine testis and spermatozoa. This splice variant, designated RABL2B-TV, is characterised by exon 2 skipping. Moreover, a single nucleotide polymorphism (SNP), namely c.125G>A, was found within the exonic splicing enhancer (ESE) motif, indicating that the SNP caused the production of the RABL2B-TV aberrant splice variant. This was demonstrated by constructing a pSPL3 exon capturing vector with different genotypes and transfecting these vectors into murine Leydig tumour cell line (MLTC-1) cells. Expression of the RABL2B-TV transcript was lower in semen from high- versus low-performance bulls. Association analysis showed that sperm deformity rate was significantly lower in Chinese Holstein bulls with the GG or GA genotype than in bulls with the AA genotype (P<0.05). In addition, initial sperm motility was significantly higher in individuals with the GG or GA genotype than in individuals with the AA genotype (P<0.05). The findings of the present study suggest that the difference in semen quality in bulls with different RABL2B genotypes is generated via an alternative splicing mechanism caused by a functional SNP within the ESE motif. PMID- 28553999 TI - Projecting demands for renal replacement therapy in the Northern Territory: a stochastic Markov model. AB - Objective The aim of the present study was to evaluate the potential effects of different health intervention strategies on demand for renal replacement therapy (RRT) services in the Northern Territory (NT).Methods A Markov chain simulation model was developed to estimate demand for haemodialysis (HD) and kidney transplantation (Tx) over the next 10 years, based on RRT registry data between 2002 and 2013. Four policy-relevant scenarios were evaluated: (1) increased Tx; (2) increased self-care dialysis; (3) reduced incidence of end-stage kidney disease (ESKD); and (4) reduced mortality.Results There were 957 new cases of ESKD during the study period, with most patients being Indigenous people (85%). The median age was 50 years at onset and 57 years at death, 12 and 13 years younger respectively than Australian medians. The prevalence of RRT increased 5.6% annually, 20% higher than the national rate (4.7%). If current trends continue (baseline scenario), the demand for facility-based HD (FHD) would approach 100000 treatments (95% confidence interval 75000-121000) in 2023, a 5% annual increase. Increasing Tx (0.3%), increasing self-care (5%) and reducing incidence (5%) each attenuate demand for FHD to ~70000 annually by 2023.Conclusions The present study demonstrates the effects of changing service patterns to increase Tx, self-care and prevention, all of which will substantially attenuate the growth in FHD requirements in the NT.What is known about the topic? The burden of ESKD is projected to increase in the NT, with demand for FHD doubling every 15 years. Little is known about the potential effect of changes in health policy and clinical practice on demand.What does this paper add? This study assessed the usefulness of a stochastic Markov model to evaluate the effects of potential policy changes on FHD demand.What are the implications for practitioners? The scenarios simulated by the stochastic Markov models suggest that changes in current ESKD management practices would have a large effect on future demand for FHD. PMID- 28554000 TI - Health professionals. AB - Objective Globally, the degree of patient harm occurring in healthcare was first publicised in the 1990s. Although many factors affect patient safety, in the US the Institute of Medicine identified hospital organisational culture as one factor contributing to a reduction in errors. This led to the development of many tools for measuring the safety culture of hospital staff. The aim of the present study was to review the literature on patient safety culture in acute hospitals to identify: (1) how patient safety is viewed by health professionals; (2) whether patient safety culture is perceived differently at the hospital versus ward level; and (3) whether clinicians and managers place the same importance on patient safety.Methods Following a search of electronic databases using OneSearch and a manual search of grey literature, an integrative review method identified 11 articles as being suitable to meet the review's aims. The search terms of patient safety culture, patient safety and safety climate were used. To ensure relevancy to current practice, the search was restricted to the period 2010 15.Results Hospital patient safety culture is not a shared vision, because health professional groups have different views. In the present study, 67% of articles examined found doctors to have a poorer perception of the patient safety culture than nurses and allied health professionals. All health professional groups reported a more positive view of their ward safety culture than that of the hospital safety culture. Furthermore, managers of the health professionals reported more positively on patient safety culture than bedside clinicians.Conclusion This review provides an international understanding of health professionals' views of patient safety. From an Australian context, the review highlights the need for further investigation, because there is a lack of recent Australian literature in the acute hospital setting relating to patient safety culture.What is known about the topic? Globally, many research papers have reported upon the correlation between a positive patient safety culture and a reduction in healthcare errors.What does this paper add? The present integrative review highlights that regardless of the country of origin, there are differences in the way that a hospital patient safety culture is perceived among different health professional groups, particularly between managers and bedside clinicians.What are the implications for practitioners? Individual health professional groups, and managers and clinicians, have different views on the patient safety culture; therefore, training needs to involve everyone to create a shared vision for patient safety. PMID- 28554001 TI - Corrigendum to "Multimodality scoring of chondral injuries in the equine fetlock joint ex vivo" [Osteoarthritis Cartilage 25 (5) (2017 May) 790-798]. PMID- 28554002 TI - Retrospective analysis of hepatitis B virus chronic infection in 247 patients: clinical stages, response to treatment and poor prognostic factors. AB - BACKGROUND: Chronic hepatitis B is a major cause of cirrhosis, and the natural history of the disease has several clinical stages that should be thoroughly understood for the implementation of proper treatment. Nonetheless, curing the disease with antiviral treatment remains a challenge. AIMS: To describe the clinical course, response to treatment, and poor prognostic factors in 247 hepatitis B virus chronic infection patients treated in a tertiary hospital in Brazil. METHODS: This was a retrospective and observational study, by analyzing the medical records of HBV infected patients between January 2000 and January 2015. RESULTS: Most patients were male (67.2%) and 74.1% were HBeAg negative. Approximately 41% had cirrhosis and 8.5% were hepatitis C virus coinfected. The viral load was negative after two years on lamivudine, entecavir and tenofovir in 86%, 90.6%, and 92.9% of the patients, respectively. The five-year resistance rates for lamivudine, adefovir, entecavir, and tenofovir were 57.5%, 51.8%, 1.9%, and 0%, respectively. The overall seroconversion rates were 31.2% for HBeAg and 9.4% for HBsAg. Hepatocellular carcinoma was diagnosed in 9.7% of patients, liver transplantation was performed in 9.7%, and overall mortality was 10.5%. Elevations of serum alanine aminotransferase (p=0.0059) and viral load (p<0.0001) were associated with progression to liver cirrhosis. High viral load was associated with progression to hepatocellular carcinoma (p<0.0001). Significant risk factors associated with death were elevated alanine aminotransferase (p=0.0039), liver cirrhosis (p<0.0001), high viral load (p=0.007), and hepatocellular carcinoma (p=0.0008). HBeAg positive status was not associated with worse outcomes, and treatment may have been largely responsible. CONCLUSIONS: Elevations of viral load and serum alanine aminotransferase may select patients with worse prognosis, especially progression to cirrhosis and hepatocellular carcinoma, which were strongly association with death. PMID- 28554004 TI - Traffic noise and hypertension - results from a large case-control study. AB - BACKGROUND: Environmental traffic noise is a potential cause of hypertension. We aimed to study the association between hypertension as recorded in health insurance claims data and the exposure to three sources of traffic noise (aircraft, road and rail). METHODS: This large case-control study was conducted among persons aged 40 and above in 2010 and living in the region around Frankfurt airport in Germany. Individual residential noise exposure for the index year 2005 was assessed using standard noise algorithms. Cases were all newly diagnosed cases of hypertension recorded in three large health insurances databases in the period 2006-2010. Controls had no hypertension diagnosis. Categorical and continuous analyses were conducted with binary logistic regression models adjusted for sex, age and residential area-based socioeconomic information. RESULTS: The main analysis included 137,577 cases and 355,591 controls. There were no associations with any of the traffic noise sources. Odds ratios (OR) per 10dB noise increase were 0.99 (95% confidence interval: 0.98;1.01) for aircraft noise, and 1.00 (0.99;1.01) both for road and railway noise. Similarly, nighttime noise levels showed no associations with hypertension. Odds ratios were increased for the subgroup of newly diagnosed hypertension cases with a subsequent diagnosis of hypertensive heart disease: per 10dB aircraft noise there was a 13.9% OR increase (6.0% for road traffic, 5.4% for rail traffic). Increases were also noted when we analyzed cases with a longer exposure-outcome time window. CONCLUSION: Our results are suggestive of an association of noise exposure with clinically more severe hypertension diagnoses, but not with uncomplicated hypertension. The absence of individual confounder data, however, adds to the risk of bias. The results contribute to evidence on traffic noise as a cardiovascular risk factor. PMID- 28554005 TI - Contaminants and energy expenditure in an Arctic seabird: Organochlorine pesticides and perfluoroalkyl substances are associated with metabolic rate in a contrasted manner. AB - Basal metabolic rate (BMR), the minimal energetic cost of living in endotherms, is known to be influenced by thyroid hormones (THs) which are known to stimulate in vitro oxygen consumption of tissues in birds and mammals. Several environmental contaminants may act on energy expenditure through their thyroid hormone-disrupting properties. However, the effect of contaminants on BMR is still poorly documented for wildlife. Here, we investigated the relationships between three groups of contaminants (organochlorines (OCs), perfluoroalkyl substances (PFASs), and mercury) with metabolic rate (MR), considered here as a proxy of BMR and also with circulating total THs (thyroxine (TT4) and triiodothyronine (TT3)) in Arctic breeding adult black-legged kittiwakes (Rissa tridactyla) from Svalbard, during the chick rearing period. Our results indicate a negative relationship between the sum of all detected chlordanes (?CHLs) and MR in both sexes whereas perfluorotridecanoate (PFTrA) and MR were positively related in females only. MR was not associated with mercury. Additionally, levels of TT3 were negatively related to ?CHLs but not to PFTrA. The findings from the present study indicate that some OCs (in both sexes) and some PFASs (only in females) could disrupt fine adjustment of BMR during reproduction in adult kittiwakes. Importantly, highly lipophilic OCs and highly proteinophilic PFASs appear, at least in females, to have the ability to disrupt the metabolic rate in an opposite way. Therefore, our study highlights the need for ecotoxicological studies to include a large variety of contaminants which can act in an antagonistic manner. PMID- 28554003 TI - Opioids and opioid receptors orchestrate wound repair. AB - We have previously shown that topical opioids including morphine and its congeners promote healing of full thickness ischemic wounds in rats. We examined the contribution of mu opioid receptor (MOPr)-mediated healing of full thickness ischemic wounds using MOPr and delta or kappa opioid receptor knockout (KO) mice. Wound closure in the early (day 5) as well as later phases was delayed in topical morphine or PBS-treated MOPr-KO mice compared with reciprocal treatments of wounds in wild-type (WT) mice. MOPr expression was significantly upregulated at 30 min in the wound margins and colocalized with wound margins and vasculature in the epidermal and dermal layers of the skin. We next examined whether neuropeptide expression was involved in the mechanism of MOPr-mediated wound closure. Substance P (SP) and calcitonin gene-related peptide immunoreactivity (ir) was significantly increased in the skin of MOPr-KO mice as compared with WT mice. Neuropeptide-ir was increased significantly in PBS-treated wounds of MOPr and WT mice, but morphine treatment reduced neuropeptide immunoreactivity in both as compared with PBS. Wounding of keratinocytes led to the release of opioid peptide beta-endorphin (beta-END) in conditioned medium, which stimulated the proliferation of endothelial cells. MOPr-selective (D-Phe-Cys-Tyr-D-Trp-Orn-Thr Pen-Thr-NH2, CTOP) and nonselective OPr antagonist naloxone-inhibited endothelial proliferation induced by wounded keratinocyte-conditioned medium. In addition, accelerated wound area closure in vitro by morphine was suppressed by methylnaltrexone, a nonselective OPr antagonist with high affinity for MOPr. Morphine and its congeners stimulated the proliferation of endothelial cells from WT mice but not those from MOPr-KO mice. Furthermore, morphine-induced mitogen activated protein kinase/extracellular signal-regulated kinase phosphorylation in endothelial cells was significantly decreased in MOPr-KO mice as compared with WT mice. Collectively, these data suggest that MOPr plays a critical role in the proliferation phase with the formation of granulation tissue during wound healing. PMID- 28554007 TI - Combined influence of biophysical and biochemical cues on maintenance and proliferation of hematopoietic stem cells. AB - Homeostasis of hematopoietic stem and progenitor cells (HSPC) is controlled by a combination of biochemical and biophysical environmental cues in the bone marrow (BM) niche, where a tight balance of quiescence and proliferation of HSPC is maintained. Specifically, alongside soluble factors and extracellular matrix (ECM) proteins, spatial confinement and ECM stiffness have been recognized to be critical for regulation of HSPC fate. Here we employ a modular, glycosaminoglycan (GAG)-based biohybrid hydrogel system to balance proliferation of human HSPC and maintenance of quiescent hematopoietic stem cells (HSC) through simultaneous regulation of exogenous biochemical and biophysical cues. Our results demonstrate that HSPC respond to increased spatial confinement with lowered proliferation and cell cycling, which results in higher frequency of quiescent LTC-IC (long-term culture initiating cells), while GAG-rich 3D environments further support maintenance of the cells. PMID- 28554006 TI - Chronic arsenic exposure and risk of carotid artery disease: The Strong Heart Study. AB - BACKGROUND: Inorganic arsenic exposure from naturally contaminated groundwater is related to vascular disease. No prospective studies have evaluated the association between arsenic and carotid atherosclerosis at low-moderate levels. We examined the association of long-term, low-moderate inorganic arsenic exposure with carotid arterial disease. METHODS: American Indians, 45-74 years old, in Arizona, Oklahoma, and North and South Dakota had arsenic concentrations (sum of inorganic and methylated species, MUg/g urine creatinine) measured from baseline urine samples (1989-1991). Carotid artery ultrasound was performed in 1998-1999. Vascular disease was assessed by the carotid intima media thickness (CIMT), the presence of atherosclerotic plaque in the carotid, and by the number of segments containing plaque (plaque score). RESULTS: 2402 participants (mean age 55.3 years, 63.1% female, mean body mass index 31.0kg/m2, diabetes 45.7%, hypertension 34.2%) had a median (interquintile range) urine arsenic concentration of 9.2 (5.00, 17.06) ug/g creatinine. The mean CIMT was 0.75mm. 64.7% had carotid artery plaque (3% with >50% stenosis). In fully adjusted models comparing participants in the 80th vs. 20th percentile in arsenic concentrations, the mean difference in CIMT was 0.01 (95% confidence interval (95%CI): 0.00, 0.02) mm, the relative risk of plaque presence was 1.04 (95%CI: 0.99, 1.09), and the geometric mean ratio of plaque score was 1.05 (95%CI: 1.01, 1.09). CONCLUSIONS: Urine arsenic was positively associated with CIMT and increased plaque score later in life although the association was small. The relationship between urinary arsenic and the presence of plaque was not statistically significant when adjusted for other risk factors. Arsenic exposure may play a role in increasing the severity of carotid vascular disease. PMID- 28554008 TI - A bioorthogonal nanosystem for imaging and in vivo tumor inhibition. AB - Bioorthogonal bond-cleavage reactions have emerged as promising tools for manipulating biological processes, still the therapeutic effect of these reactions in vivo needs to be explored. Herein a bioorthogonal-activated prodrug has been developed for bioimaging and therapy, which is composed of a Pd-mediated cleavable propargyl, a coumarin fluorophore and a potent anticancer drug. In vitro investigations show that, the presence of a Pd complex induces the cleavage of propargyl and subsequently trigger the cascade of reactions, thereby activating the coumarin fluorophore for imaging and releasing the anticancer drug for therapy. Both the prodrug and Pd complex were then separately encapsulated into phospholipid liposomes to form a two-component bioorthogonal nanosystem. The lyposomal nanosystem can be readily internalized by HeLa cells and displays strong intracellular fluorescence under one- or two-photon excitation, indicating the release of the active drug in cells as a result of the Pd-mediated bioorthogonal bond-cleavage reaction. More importantly, the nanosystem shows considerable high activity and exerts efficient inhibition towards tumor growth in a mouse model. This work demonstrates that, if properly formulated, a bioorthogonal system can perform well in vivo. This strategy may offer a new approach for designing bioorthogonal prodrugs with imaging and therapeutic capability. PMID- 28554009 TI - High purity microfluidic sorting and in situ inactivation of circulating tumor cells based on multifunctional magnetic composites. AB - Detection and isolation of circulating tumor cells (CTCs) play a pivotal role in the diagnosis and prognosis of cancer, while the high capture efficiency and purity of CTCs are difficult to achieve simultaneously among the various isolation methods. In this work, we designed an inverted microchip integrating silicon nanowires (SiNWs) and multifunctional magnetic nanocomposites (Fe3O4@C6/Ce6@silane, Coumarin 6 (C6), Chlorin e6 (Ce6)) for enhanced capture efficiency and purity of CTCs. The Fe3O4@C6/Ce6@silane conjugated with antibody can label the CTCs and pull them to the upside SiNWs capture surface by the upward magnetic field with high purity. This inverted structure was also featured with real-time detection and photodynamic therapy (PDT) of CTCs with the confocal laser scanning microscope (CLSM). The results indicate the important role of the composites labels and the magnetic field, which greatly improves the capture purity of the CTCs to 90%. Meanwhile, capture efficiency of CTCs achieve to 90.3% in culture medium and 82% in blood with 2 mL/h flow rate, respectively. Based on the structure of the device and composites, the captured CTCs could be directly inactivated by the in situ photodynamic therapy in the capture process which holds positive impact to block cancer spread. PMID- 28554010 TI - A bilaminated decellularized scaffold for islet transplantation: Structure, properties and functions in diabetic mice. AB - Ectopic transplantation of islets provides a beta cell-replacement approach that may allow the recovery of physiological regulation of the blood sugar level in patients with Type I diabetes (T1D). In development of new extrahepatic islet transplantation protocols in support of the islet engraftment, it is pivotal to develop scaffold materials with multifaceted functions to provide beneficial microenvironment, mediate host response in favor of vascularization/islet integration and maintain long-term islet function at the transplantation site. In this study, a new composite bilaminar decellularized scaffold (CDS) was fabricated with differential structural, degradation and mechanical properties by the combination of a fast-degrading porous collagen matrix and a mechanically supportive porcine pericardium. When investigated in the epididymal fat pad in syngeneic mouse models, it was shown that CDS could serve as superior scaffolds to promote islet adhesion and viability, and islet-CDS constructs also allowed rapid reversal of the hyperglycemic condition in the host. The engraftment and effects of islets were achieved at low islet numbers, accompanied by minimal adverse tissue reactions and optimal islet integration with the surrounding fat tissue. The bioactive surface, mechanical/chemical durability and biocompatibility of the CDS may all have played important roles in facilitating the engraftment of islets. Our study provided new insights into scaffold's function in the interplay of cells, materials and host tissue and the extracellular matrix-based scaffolds have potential for clinical translation in the beta cell-replacement therapy to treat T1D. PMID- 28554011 TI - Physical chitosan microhydrogels as scaffolds for spinal cord injury restoration and axon regeneration. AB - Recovery from traumatic spinal cord injury (SCI) usually fails due to a cascade of cellular and molecular events that compromise neural tissue reconstitution by giving rise to glial scarring and cavity formation. We designed a scaffold material for SCI treatment containing only chitosan and water as fragmented physical hydrogel suspension (Chitosan-FPHS), with defined degree of acetylation (DA), polymer concentration, and mean fragment size. Implantation of Chitosan FPHS alone into rat spinal cord immediately after a bilateral dorsal hemisection promoted reconstitution of spinal tissue and vasculature, and diminished fibrous glial scarring: with astrocyte processes primarily oriented towards the lesion, the border between lesion site and intact tissue became permissive for regrowth of numerous axons into, and for some even beyond the lesion site. Growing axons were myelinated or ensheathed by endogenous Schwann cells that migrated into the lesion site and whose survival was prolonged. Interestingly, Chitosan-FPHS also modulated the inflammatory response, and we suggest that this might contribute to tissue repair. Finally, this structural remodeling was associated with significant, long-lasting gain in locomotor function recovery. Because it effectively induces neural tissue repair, Chitosan-FPHS biomaterial may be a promising new approach to treat SCI, and a suitable substrate to combine with other strategies. PMID- 28554012 TI - Hydrophobicity of carbohydrates and related hydroxy compounds. AB - The hydrophobic interaction of carbohydrates and other hydroxy compounds with a C18-modified silica gel column was measured with pure water as eluent, thereby expanding the range of measurements already published. The interaction is augmented by structure strengthening salts and decreasing temperature. Although the interaction of the solute with the hydrophobic interface is expected to only imperfectly reflect its state in aqueous bulk solution, the retention can be correlated to hydration numbers calculated from molecular mechanics studies given in the literature. No correlation can be established towards published hydration numbers obtained by physical methods (isentropic compressibility, O-17 NMR relaxation, terahertz spectroscopy, and viscosity). The hydrophobicity is discussed with respect to the chemical structure. It increases with the fraction and size of hydrophobic molecular surface regions. PMID- 28554013 TI - Conformational studies of N-(alpha-d-glucofuranurono-6,3-lactone)- and N-(methyl beta-d-glucopyranuronate)-p-nitroanilines. AB - N-(alpha-d-Glucofuranurono-6,3-lactone)-p-nitroaniline and N-(methyl beta-d glucopyranuronate)-p-nitroaniline were obtained as crystalline solids. The single crystal X-ray diffraction, NMR data and DFT calculations for N-(alpha-d glucofuranurono-6,3-lactone)-p-nitroaniline indicate that this N-furanoside adopts a 3T2/3E-like conformation in the crystal lattice, solution and gas phase. Thus, the structure of recorded for N-furanoside 1H NMR spectrum is indicative of the 3T2/3E region of the pseudorotational itinerary for furanose derivatives with alpha-d-gluco, beta-L-ido and alpha-d-xylo configurations. Moreover, it is concluded that the 1T2/E2/3T2/3E region of the pseudorotational itinerary for furanose derivatives with d-gluco, L-ido and d-xylo configurations should be characterised by the lack of coupling between H2 and H3 protons, irrespective of the anomeric configuration. Such a lack of vicinal coupling is characteristic for some of the trans-oriented furanose ring protons. The single-crystal X-ray diffraction and NMR data for N-(methyl beta-d-glucopyranuronate)-p-nitroaniline indicate that this N-glucuronide adopts the 4C1 conformation, both in the crystal lattice and solution. The occurrence of anomeric effects in the presented N glycosides is discussed. The crystal structure analysis of both N-glycosides gives evidence that the amine group in p-nitroaniline is planar due to the nitrogen sp2 hybridisation. PMID- 28554014 TI - Investigation of debranching pattern of a thermostable isoamylase and its application for the production of resistant starch. AB - Debranching enzymes contribute to the enzymatic production of resistant starch (RS) by reducing substrate molecular weight and increasing amylose yield. In the present study, the action pattern of a thermostable isoamylase-type debranching enzyme on different types of starch was investigated. The molecular weight distribution, glycosidic bond composition and contents of oligosaccharides released were monitored by various liquid chromatography techniques and nuclear magnetic resonance spectroscopy (NMR). These analyses showed that the isoamylase could specifically and efficiently attack alpha-1,6-glucosidic linkages at branch points, leaving the amylose favored by other amylolytic enzymes. Its ability to attack side chains composed of 1-3 glucose residues differentiates it from other isoamylases, a property which is also ideal for the RS preparation process. The enzyme was used as an auxiliary enzyme in the hydrolytic stage. The highest RS yield (53.8%) was achieved under the optimized conditions of 70 degrees C and pH 5.0, using 7 U isoamylase per g starch and 2 NU amylase per g starch. These data also help us better understand the application of isoamylase for preparation of other products from highly branched starch materials. PMID- 28554016 TI - Papua New Guinea midwives perspectives of the effect of a targeted village birth attendant education program. PMID- 28554015 TI - The association of lipoprotein(a) with incident heart failure hospitalization: Atherosclerosis Risk in Communities study. AB - BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is a proatherogenic lipoprotein associated with coronary heart disease, ischemic stroke, and more recently aortic stenosis and heart failure (HF). We examined the association of Lp(a) levels with incident HF hospitalization in the Atherosclerosis Risk in Communities (ARIC) study. We also assessed the relationship between Lp(a) levels and arterial stiffness as a potential mechanism for development of HF. METHODS: Lp(a) was measured in 14,154 ARIC participants without prevalent HF at ARIC visit 1 (1987 1989). The association of Lp(a) quintiles with incident HF hospitalization was assessed using Cox proportional-hazards models. Arterial stiffness parameters were stratified based on Lp(a) quintiles, and p-trend was calculated across ordered groups. RESULTS: At a median follow-up of 23.4 years, there were 2605 incident HF hospitalizations. Lp(a) levels were directly associated with incident HF hospitalization in models adjusted for age, race, gender, systolic blood pressure, history of hypertension, diabetes, smoking status, body mass index, heart rate, and high-density lipoprotein cholesterol (quintile 5 vs. quintile 1: hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.09-1.41; p-trend across increasing quintiles <0.01), but not after excluding prevalent and incident myocardial infarction cases (HR 1.07, 95% CI 0.91-1.27; p-trend = 0.70). When adjusted for age, gender, and race, Lp(a) quintiles were not significantly associated with arterial stiffness parameters. CONCLUSIONS: Increased Lp(a) levels were associated with increased risk of incident HF hospitalization. After excluding prevalent and incident myocardial infarction, the association was no longer significant. Lp(a) levels were not associated with arterial stiffness parameters. PMID- 28554017 TI - Oxidative stress biomarkers in the Mediterranean pond turtle (Mauremys leprosa) reveal contrasted aquatic environments in Southern France. AB - Increasing anthropogenic activities, like agricultural practices, constitute the main causes of the loss of water quality and disruption of freshwater ecosystems. High concentrations of pesticides, as shown under experimental conditions, can indeed impact freshwater animals. In Southern France, especially in the Pyrenees Orientales department, because agricultural activities are mainly based on fruit crops and vineyards, glyphosate and AMPA were detected in some watercourses. Thereby we investigated the effects of degraded waters on the physiology of the endemic endangered freshwater species, namely the Mediterranean pond turtle Mauremys leprosa, in contrasted environments along the same rivers on the one hand and between different rivers on the other. We measured the activity and gene expression of two enzymes involved in the oxidative detoxification processes, namely the Catalase and the Superoxide dismutase. We showed significant variations in the Catalase gene expression and activity within turtles of the Fosseille River depending of their location, i.e. upstream or downstream of the wastewater treatment plants (WTP). Because agricultural environments are similar all along this river, they can no be longer considered as the unique source of turtle stress. The processed waters discharged by the WTP, which contribute to watercourses degradation, could therefore considerably impact the biodiversity of the freshwater environments. PMID- 28554018 TI - In vitro evaluation of the cytotoxic and bactericidal mechanism of the commonly used pesticide triphenyltin hydroxide. AB - Triphenyltin hydroxide (TPTH) is a widely used pesticide that is highly toxic to a variety of organisms including humans and a potential contender for the environmental pollutant. In the present study, the cytotoxic mechanism of TPTH on mammalian cells was analyzed using HeLa cells and the antibacterial activity was analyzed using B. subtilis and E. coli cells. TPTH inhibited the growth of HeLa cells with a half-maximal inhibitory concentration of 0.25 MUM and induced mitotic arrest. Immunofluorescence microscopy analysis showed that TPTH caused strong depolymerization of interphase microtubules and spindle abnormality with the appearance of colchicine type mitosis and condensed chromosome. TPTH exhibited high affinity for tubulin with a dissociation constant of 2.3 MUM and inhibited the in vitro microtubule assembly in the presence of glutamate as well as microtubule-associated proteins. Results from the molecular docking and in vitro experiments implied that TPTH may have an overlapping binding site with colchicine on tubulin with a distance of about 11 A between them. TPTH also binds to DNA at the A-T rich region of the minor groove. The data presented in the study revealed that the toxicity of TPTH in mammalian cells is mediated through its interactions with DNA and its strong depolymerizing activity on tubulin. However, its antibacterial activity was not through FtsZ, the prokaryotic homolog of tubulin but perhaps through its interactions with DNA. PMID- 28554019 TI - Assessment of tris (1, 3-dichloro-2-propyl) phosphate toxicology in PC12 cells by using digital gene expression profiling. AB - Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP), one of the most universally used organophosphate flame retardants (OPFRs), is an environmental pollutant. However, limited information is available regarding its toxicity and environmental health risk. In the present study, PC12 cells provided a useful model for the evaluation of the toxic effects of TDCIPP. Exposure to 7.5, 15, 30, or 60 MUM TDCIPP for 72 h inhibited cell viability, and enhanced cellular apoptosis and oxidative stress. To further explore the underlying mechanisms, digital gene expression (DGE) technology was used to identify early transcriptional changes following TDCIPP exposure. Expression of the transcripts of 161 genes was significantly altered upon treatment with TDCIPP. Functional and pathway analysis of the transcriptional profile demonstrated that genes showing significant TDCIPP associated changes in expression were involved in the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway, extracellular matrix receptor interactions, protein digestion and absorption, and microRNAs in cancer. Using quantitative real-time PCR, we validated the differential expression of selected genes. These results showed that the expression profiles of cells exposed to 60 MUM TDCIPP were consistent with the DGE data. Furthermore, western blotting showed that treatment with TDCIPP reduced the Bcl-2/Bax ratio and attenuated PI3K/Akt/Myc signaling. Taken together, these data suggest that TDCIPP exposure can reduce cell viability and induce apoptosis in PC12 cells by inhibiting activation of the PI3K/Akt/Myc signaling pathway. These observations provide valuable preliminary information regarding the mechanisms of TDCIPP induced toxicity in PC12 cells and indicate that further study of the toxicity of other environmental OPFRs is warranted. PMID- 28554020 TI - Mechanism of removal and retention of heavy metals from the acid mine drainage to coastal wetland in the Patagonian marsh. AB - The attenuation of the acid mine drainage is one of the most important environmental challenges facing the mining industry worldwide. Mining waste deposits from an ancient metallurgical extraction of heavy metals were found near to the San Antonio marsh in Patagonia. The aim of this work was to determinate which mechanisms regulate the mobilization and retention of metals by acid drainage. A geological and geomorphological survey was carried out and samples from the mining waste deposits and the marsh were collected to determine soil texture, Eh pH, organic matter, Cu, Pb, Zn and Fe content, and soil mineralogical composition. Metals in marsh plants were determined in above- and below-ground structures. In the mining waste deposits polymetallic sulphides were recognized where the oxidation and formation of oxy-hydroxides and sulphates of Fe, Cu, Pb and Zn occurs. Then, by the alteration of those minerals, the metals enter in solution and are mobilized with the surface drainage towards the marsh where adsorption in the soils fine fraction and organic matter and/or by plants occurs. Locally, in the mining waste deposits, the precipitation/dissolution of Cu, Pb, and Zn sulphates take place in small centripetal drainage basins. In topographically lower portions of the marsh desorption and removal of metals by tidal flow could also be happen. The results allow to concluding that the marsh adjacent to the mining waste deposits is a geochemically active environment that naturally mitigates the contamination caused by acid drainage. PMID- 28554021 TI - The effectiveness and efficiency of phytoremediation of a multicontaminated industrial site: Porto Marghera (Venice Lagoon, Italy). AB - The Venice Lagoon is worldwide considered as a typical example of the human impact on the surrounding ecosystem. The development of the industrial zone of Porto Marghera begun in 1917 as an extension of the Venice Port, in order to sustain activities related to oil and coal, as well as to exploit the railway system. Despite the recent decrease in the number of employees, Porto Marghera is still one of the most important chemical districts in Italy. This study reports early results from the ongoing in-situ phytoextraction of potentially toxic elements (Cd, Hg, Zn) within the industrial area of Porto Marghera. Two agronomic plant species with high annual biomass yield (Helianthus annuus L., Brassica juncea (L.) Czern.) were used. This paper also reports the microcosms and mesocosms tests to evaluate the efficacy of the treatments to be applied to the in-situ phytoextraction process of the polluted site. The combined use of EDTA and Ammonium Thiosulfate during phytoextraction increases the efficiency of Cd, Hg, Zn removal from contaminated soil. PMID- 28554022 TI - Lipophilic marine toxins discovered in the Bohai Sea using high performance liquid chromatography coupled with tandem mass spectrometry. AB - Some dinoflagellates can produce lipophilic marine toxins, which pose potent threats to seafood consumers. In the Bohai Sea, an important semi-closed inland sea with intensive mariculture industry in China, there is little knowledge concerning lipophilic marine toxins and their potential threats. In this study, net-concentrated phytoplankton samples were periodically collected from 5 typical mariculture zones around the Bohai Sea, including Laishan (LS), Laizhou (LZ), Hangu (HG), Qinhuangdao (QHD) and Huludao (HLD) in 2013 and 2014, and a method using high performance liquid chromatography (HPLC) coupled with a Q-Trap mass spectrometer was applied to analyze seven representative lipophilic marine toxins, including okadaic acid (OA), dinophysistoxin-1 (DTX1), pectenotoxin-2 (PTX2), yessotoxin (YTX), azaspiracid-1 (AZA1), gymnodimine (GYM), and 13 desmethyl spirolide C (desMeC). The method had high sensitivity and repeatability, and exhibited satisfactory recoveries for most of the lipophilic marine toxins (92.1-108%) except for AZA1 (65.8-68.9%). Nearly all the lipophilic marine toxins could be detected in phytoplankton samples from the Bohai Sea. OA, DTX1 and PTX2 were predominant components and present in most of the phytoplankton samples. The maximum content of lipophilic marine toxin in phytoplankton samples concentrated from seawater (OA 464 pg L-1; DTX1 783 pg L-1; YTX 86.6 pg L-1; desMeC 15.6 pg L-1; PTX2 1.11 * 103 pg L-1) appeared in June 2014. Based on toxins present in phytoplankton samples, it is implied that seafood in the Bohai Sea is more likely to be contaminated by OA group and PTX group toxins, and spring is the high-risk season for toxin contamination. PMID- 28554024 TI - Dispersion and solubility of In, Tl, Ta and Nb in the aquatic environment and intertidal sediments of the Scheldt estuary (Flanders, Belgium). AB - Certain specialty elements are indispensable in modern technologies for their particular properties. Yet, potential risks associated to the release of these elements at any stage, remains unknown. Therefore, the dispersion of indium (In), thallium (Tl), tantalum (Ta) and niobium (Nb) in the aquatic environment of the Scheldt estuary (Flanders, Belgium) was studied. Maximum concentrations in intertidal sediments of 101 +/- 15 MUg kg-1 for In, 481 +/- 37 MUg kg-1 for Tl, 88 +/- 19 MUg kg-1 for Ta and 1162 +/- 4 MUg kg-1 for Nb appeared on the sampling location closest to the river mouth, i.e. 57.5 km upstream. Their distribution in the intertidal sediments depends on the physicochemical sediment characteristics along the flow of the river Scheldt. The same was the case for most other metals and aluminum as their occurrence also correlated (p < 0.05) with the occurrence of In, Tl and Nb. While in general, studied elements correlate to the OM content and sulfur and phosphorus herein included, a relative enrichment of In, Tl and Nb was seen at Rupelmonde (92.0 km from the river mouth). Mainly the intertidal sediment silt fraction is capable of retaining the elements by exchanging with other ions in the mineral interlayer. Increasing salinity towards the river mouth can furthermore induce the formation of insoluble chloride species. Overall, the solubility of In, Tl, Ta and Nb appeared extremely low upon extraction of pore water from intertidal sediments saturated to 100% field capacity. PMID- 28554023 TI - Uptake, biotransformation and elimination of selected pharmaceuticals in a freshwater invertebrate measured using liquid chromatography tandem mass spectrometry. AB - Methods were developed to assess uptake and elimination kinetics in Gammarus pulex of nine pharmaceuticals (sulfamethazine, carbamazepine, diazepam, temazepam, trimethoprim, warfarin, metoprolol, nifedipine and propranolol) using targeted LC-MS/MS to determine bioconcentration factors (BCFs) using a 96 h toxicokinetic exposure and depuration period. The derived BCFs for these pharmaceuticals did not trigger any regulatory thresholds and ranged from 0 to 73 L kg-1 (sulfamethazine showed no bioconcentration). Metabolism of chemicals can affect accurate BCF determination through parameterisation of the kinetic models. The added selectivity of LC-MS/MS allowed us to develop confirmatory methods to monitor the biotransformation of propranolol, carbamazepine and diazepam in G. pulex. Varying concentrations of the biotransformed products; 4 hydroxypropranolol sulphate, carbamazepine-10,11-epoxide, nordiazepam, oxazepam and temazepam were measured following exposure of the precursor compounds. For diazepam, the biotransformation product nordiazepam was present at higher concentrations than the parent compound at 94 ng g-1 dw. Overall, the results indicate that pharmaceutical accumulation is low in these freshwater amphipods, which can potentially be explained by the rapid biotransformation and excretion. PMID- 28554025 TI - Assessing the toxicity of ionic liquids - Application of the critical membrane concentration approach. AB - Charged organic chemicals are a prevailing challenge for toxicity modelling. In this contribution we strive to recapitulate the lessons learned from the well known modelling of narcosis (or baseline toxicity) of neutral chemicals and apply the concept to charged chemicals. First we reevaluate the organism- and chemical independent critical membrane concentration causing 50% mortality,.cmemtox, based on a critical revision of a previously published toxicity dataset for neutral chemicals. In accordance to values reported in the literature we find a mean value for cmemtox of roughly 100 mmol/kg (membrane lipid) for a broad variety of 42 aquatic organisms (333 different chemicals), albeit with a considerable scatter. Then we apply this concept to permanently charged ionic liquids (ILs). Using COSMOmic, a quantum mechanically based mechanistic model that makes use of the COSMO-RS theory, we predict membrane-water partition coefficients (Kmem/w) of the anionic and cationic IL components. Doing so, cmemtox(total) for permanently charged ILs can be estimated assuming independent, concentration additive contributions of the cationic and its respective anionic species. The resulting values for some of the toxicity data for ionic liquids are consistent with the expected range for baseline toxicity for neutral chemicals while other values are consistently greater or smaller. Based on the calculation of toxic ratios we identify ILs that exert a specific mode of toxic action. Limitations of the modelling approach especially but not exclusively due to the use of nominal concentrations instead of freely-dissolved concentrations in the published literature are critically discussed. PMID- 28554026 TI - Ecotoxicity of two organic UV-filters to the freshwater caddisfly Sericostoma vittatum. AB - Organic ultraviolet filters (UV-filters) used for protection against radiation in personal care products and other materials (e.g. textiles, plastic products) are considered emerging contaminants of aquatic ecosystem. Benzophenone-3 (BP3) and 3 (4-methylbenzylidene)camphor (4-MBC) are the most commonly used organic UV filters and have been reported in freshwater environments due to contamination through discharges from wastewater treatment plants and swimming pools or by direct contamination from recreational activities. Our aim was to evaluate the ecotoxicological effects of these UV-filters using the freshwater caddisfly Sericostoma vittatum' biochemical biomarkers and energy processing related endpoints (feeding behaviour, energy reserves and cellular metabolism). In laboratory trials, both compounds induced feeding inhibition of S. vittatum at 3.55 mg/kg of BP3 and at concentrations >=2.57 mg/kg of 4-MBC, decreased carbohydrates content at 3.55 and 6.95 mg/kg of BP3 and 4-MBC respectively, and increased total glutathione levels at concentrations >=1.45 and 1.35 mg/kg of BP3 and 4-MBC respectively. No significant effects were observed on endpoints associated with oxidative stress, antioxidant defences, phase II biotransformation or neurotoxicity after exposure to the two UV-filters. Our results show that environmental relevant concentrations of BP3 and 4-MBC, can negatively impact freshwater insects and demonstrate the importance of monitoring the ecological effects of organic UV-filters using non-model invertebrate species. PMID- 28554027 TI - Membrane partitioning of ionic liquid cations, anions and ion pairs - Estimating the bioconcentration potential of organic ions. AB - Recent efforts have been directed towards better understanding the persistency and toxicity of ionic liquids (ILs) in the context of the "benign-by-design" approach, but the assessment of their bioaccumulation potential remains neglected. This paper reports the experimental membrane partitioning of IL cations (imidazolium, pyridinium, pyrrolidinium, phosphonium), anions ([C(CN)3]-, [B(CN)4]-, [FSO2)2N]-, [(C2F5)3PF3]-, [(CF3SO2)2N]-) and their combinations as a measure for estimating the bioconcentration factor (BCF). Both cations and anions can have a strong affinity for phosphatidylcholine bilayers, which is mainly driven by the hydrophobicity of the ions. This affinity is often reflected in the ecotoxicological impact. Our data revealed that the bioconcentration potential of IL cations and anions is much higher than expected from octanol-water partitioning based estimations that have recently been presented. For some ILs, the membrane-water partition coefficient reached levels corresponding to BCFs that might become relevant in terms of the "B" (bioaccumulation potential) classification under REACH. However, this preliminary estimation need to be confirmed by in vivo bioconcentration studies. PMID- 28554028 TI - The effects of low-level ionizing radiation and copper exposure on the incidence of antibiotic resistance in lentic biofilm bacteria. AB - Environmental reservoirs of antibiotic resistant bacteria are poorly understood. Understanding how the environment selects for resistance traits in the absence of antibiotics is critical in developing strategies to mitigate this growing menace. Indirect or co-selection of resistance by environmental pollution has been shown to increase antibiotic resistance. However no attention has been given to the effects of low-level ionizing radiation or the interactions between radiation and heavy metals on the maintenance or selection for antibiotic resistance (AR) traits. Here we explore the effect of radiation and copper on antibiotic resistance. Bacteria were collected from biofilms in two ponds - one impacted by low-level radiocesium and the other an abandoned farm pond. Through laboratory controlled experiments we examined the effects of increasing concentrations of copper on the incidence of antibiotic resistance. Differences were detected in the resistance profiles of the controls from each pond. Low levels (0.01 mM) of copper sulfate increased resistance but 0.5 mM concentrations of copper sulfate depressed the AR response in both ponds. A similar pattern was observed for levels of multiple antibiotic resistance per isolate. The first principal component response of isolate exposure to multiple antibiotics showed significant differences among the six isolate treatment combinations. These differences were clearly visualized through a discriminant function analysis, which showed distinct antibiotic resistance response patterns based on the six treatment groups. PMID- 28554029 TI - Ingestion of micro- and nanoplastics in Daphnia magna - Quantification of body burdens and assessment of feeding rates and reproduction. AB - Evidence is increasing that micro- and nanoplastic particles can have adverse effects on aquatic organisms. Exposure studies have so far mainly been qualitative since quantitative measurements of particle ingestion are analytically challenging. The aim of this study was therefore to use a quantitative approach for determining ingestion and egestion of micro- and nanoplastics in Daphnia magna and to analyze the influence of particle size, exposure duration and the presence of food. One week old animals were exposed to 2 MUm and 100 nm fluorescent polystyrene beads (1 mg/l) for 24 h, followed by a 24 h egestion period in clean medium. During both phases body burdens of particles were determined by measuring the fluorescence intensity in dissolved tissues. Ingestion and egestion were investigated in the absence and presence of food (6.7.105 cells of Raphidocelis subcapitata per ml). Furthermore, feeding rates of daphnids in response to particle exposure were measured as well as effects on reproduction during a 21 days exposure (at 1 mg/l, 0.5 mg/l and 0.1 mg/l) to investigate potential impairments of physiology. Both particle sizes were readily ingested, but the ingested mass of particles was five times higher for the 2 MUm particles than for the 100 nm particles. Complete egestion did not occur within 24 h but generally higher amounts of the 2 MUm particles were egested. Animal body burdens of particles were strongly reduced in the presence of food. Daphnid feeding rates decreased by 21% in the presence of 100 nm particles, but no effect on reproduction was found despite high body burdens of particles at the end of 21 days exposure. The lower egestion and decreased feeding rates, caused by the 100 nm particles, could indicate that particles in the nanometer size range are potentially more hazardous to D. magna compared to larger particle sizes. PMID- 28554030 TI - Ambient sulfur dioxide levels associated with reduced risk of initial outpatient visits for tuberculosis: A population based time series analysis. AB - BACKGROUND: Recent biochemical studies suggest that exogenous sulfur dioxide (SO2) at low concentrations may have been beneficial in inhibiting mycobacteria tuberculosis (TB) growth. However, there is a dearth of population-based studies. OBJECTIVES: To examine the association of ambient SO2 levels and initial TB outpatient visits. METHODS: In Ningbo, China, we collected all daily initial outpatient visits for TB and routinely air pollution monitoring data between January 2009 and December 2013. A time-series study was conducted by using generalized additive regression (GAM) with log-linear Poisson models to estimate the associations between daily initial TB outpatient visits and daily average concentration of SO2. Other traffic-related co-pollutants were adjusted. Sensitivity analyses were conducted to examine the relationship when 1% extreme SO2 concentrations excluded or if related to the early onsets of TB symptoms. RESULTS: SO2 concentrations in Ningbo were low with a daily average of 25 MUg/m3 (i.e. 0.0089 ppm). Negative associations were identified between ambient SO2 concentrations and daily initial TB outpatient visits. A 10 MUg/m3 increase in SO2 at lag3 and lag0-3 days were associated with -2.0% (95%CI, -3.2, -0.8) and 4.6% (95%CI, -6.8, -2.4) changes, respectively, in initial TB outpatient visits according to single-pollutant models. The negative association became stronger when nitrogen dioxide (NO2) or particulate matter with aerodynamic diameter less than 10 MUm (PM10) was adjusted in two-pollutant models. This association was higher in males vs. females and in middle-aged adults vs. the elderly. We found a stronger negative association between SO2 concentration and the initial symptom occurrence. CONCLUSION: Short-term exposure to ambient SO2 was associated with reduced risk of initial TB outpatient visits, suggesting acute protective effects of low-level ambient SO2 exposure on bacteria-induced pulmonary infections. PMID- 28554032 TI - Effect of soil organic matter on antimony bioavailability after the remediation process. AB - We evaluated the long-term (18 year) and short-term (4 weeks) changes of Sb in contaminated soil with SOM increase under remediation process. In the Aznalcollar mine accident (1998) contaminated area, the remediation measurement implemented the Guadiamar Green Corridor, where residual pollution is still detected. Soils of the re-vegetated area (O2) with high pH and high SOM content, moderately re vegetated area (O1) and unvegetated area (C) were sampled. Soil pH, CEC, SOM amount and soil Sb forms were evaluated. Soil Sb was measured as total, soluble, exchangeable, EDTA extractable, acid oxalate extractable, and pyro-phosphate extractable fractions. Further, the short-term effect of artificial organic matter addition was also evaluated with incubation study by adding compost to the sampled soil from C, O1 and O2 areas. After 4 weeks of incubation, soil chemical properties and Sb forms were evaluated. In re-vegetated area (O2), soil total Sb was two times lower than in unvegetated area (C); however, soluble, exchangeable, and EDTA extractable Sb were 2-8 times higher. The mobile/bioavailable Sb increase was also observed after 4 weeks of incubation with the addition of compost. Soluble, exchangeable, and EDTA extractable Sb was increased 2-4 times by compost addition. By the linear regression analysis, the significantly related factors for soluble, exchangeable, and EDTA extractable Sb values were pH, CEC, and SOM, respectively. Soluble Sb increase was mainly related to pH rise. Exchangeable Sb should be bound by SOM-metal complex and increased with CEC. EDTA extractable fraction should be increased with increase of SOM as SOM-Fe associated Sb complex. From these results, it was shown that increase of SOM under natural conditions or application of organic amendment under remediation process should increase availability of Sb to plants. PMID- 28554031 TI - Through the sands of time: Beach litter trends from nine cleaned north cornish beaches. AB - Marine litter and its accumulation on beaches is an issue of major current concern due to its significant environmental and economic impacts. Yet our understanding of spatio-temporal trends in beach litter and the drivers of these trends are currently limited by the availability of robust long term data sets. Here we present a unique data set collected systematically once a month, every month over a six year period for nine beaches along the North Coast of Cornwall, U.K. to investigate the key drivers of beach litter in the Bude, Padstow and Porthcothan areas. Overall, an average of 0.02 litter items m-2 per month were collected during the six year study, with Bude beaches (Summerleaze, Crooklets and Widemouth) the most impacted (0.03 +/- 0.004 litter items m-2 per month). The amount of litter collected each month decreased by 18% and 71% respectively for Padstow (Polzeath, Trevone and Harlyn) and Bude areas over the 6 years, possibly related to the regular cleaning, however litter increased by 120% despite this monthly cleaning effort on the Padstow area beaches. Importantly, at all nine beaches the litter was dominated by small, fragmented plastic pieces and rope fibres, which account for 32% and 17% of all litter items collected, respectively. The weathered nature of these plastics indicates they have been in the marine environment for an extended period of time. So, whilst classifying the original source of these plastics is not possible, it can be concluded they are not the result of recent public littering. This data highlights both the extent of the marine litter problem and that current efforts to reduce littering by beach users will only tackle a fraction of this litter. Such information is vital for developing effective management strategies for beach and marine litter at both regional and global levels. PMID- 28554033 TI - Beyond face-to-face individual counseling: A systematic review on alternative modes of motivational interviewing in substance abuse treatment and prevention. AB - OBJECTIVES: This systematic review aimed to synthesize the evidence on the effectiveness of motivational interviewing (MI), delivered in modes other than face-to-face individual counseling, in preventing and treating substance abuse related behaviors. METHODS: Four databases (PubMed/MEDLINE, PsycINFO, ISI Web of Science and Cochrane Library) were searched for randomised clinical trials (RCTs) that evaluated the effectiveness of alternative modes of MI (other than face-to face individual counseling) in preventing and treating substance abuse. Eligible studies were rated on methodological quality and their findings were qualitatively synthesized. RESULTS: A total of 25 articles (on 22 RCTs) were eligible for this review. Beyond face-to-face counseling, telephone was the most frequently used medium for delivering MI (11 studies), followed by Internet communication (4 studies) and short message service (SMS) (2 studies). Mail was incorporated as a supplement in one of the studies for telephone MI. In contrast to one-to-one individual counseling, group MI was adopted in 5 studies. The effectiveness of telephone MI in treating substance abuse was supported by all of the published RCTs we located. Internet-based MI was effective in preventing and treating alcoholism, but its outcome appeared to be inconsistent for smoking cessation and poor for abstinence from illicit drugs. SMS-based MI appeared to be useful for controlling tobacco and drinking. Group MI was attempted for quitting alcohol and drugs, with mixed findings on its outcomes. CONCLUSIONS: Collectively, the studies reviewed indicate that telephone MI is a promising mode of intervention in treating and preventing substance abuse. The effectiveness of other alternative modes (SMS-based MI, Internet-based MI and group MI) remains inconclusive given the controversial findings and a limited number of studies. By synthesizing the currently available evidence, this systematic review suggested that telephone MI might be considered as an alternative to face-to-face MI for treating and preventing substance abuse. Further research is needed to investigate the effectiveness of SMS-based MI, Internet MI, group MI and other alternative modes. Studies with methodological rigor and incorporating MI fidelity measures have great potential to advance the understanding in this field. PMID- 28554034 TI - Psychosocial interventions for addiction-affected families in Low and Middle Income Countries: A systematic review. AB - AIM: To review the literature on psychosocial interventions for addiction affected family members in Low and Middle Income Countries (LMIC). METHODS: A systematic review with a detailed search strategy focussing on psychosocial interventions directed towards people affected by addiction without any gender, year or language specifications was conducted. Identified titles and abstracts were screened; where needed full papers retrieved, and then independently reviewed. Data was extracted based on the aims of the study, to describe the modalities, acceptability, feasibility and effectiveness of the interventions. RESULTS: Four papers met our selection criteria. They were published between 2003 and 2014; the total sample size was 137 participants, and two studies were from Mexico and one each from Vietnam and Malaysia. The predominantly female participants comprised of parents, spouses and siblings. The common components of all the interventions included providing information regarding addiction, teaching coping skills, and providing support. Though preliminary these small studies suggests a positive effect on affected family members (AFM). There was lowering of psychological and physical distress, along with a better understanding of addictive behaviour. The interventions led to better coping; with improvements in self-esteem and assertive behaviour. The interventions, mostly delivered in group settings, were largely acceptable. CONCLUSIONS: The limited evidence does suggest positive benefits to AFMs. The scope of research needs to be extended to other addictions, and family members other than spouse and female relatives. Indigenous and locally adapted interventions are needed to address this issue keeping in mind the limited resources of LMIC. This is a field indeed in its infancy and this under recognised and under-served group needs urgent attention of researchers and policy makers. PMID- 28554035 TI - Isolation of eudesmanes from Pluchea odorata and evaluation of their effects on cancer cell growth and tumor invasiveness in vitro. AB - The traditionally used Central American medicinal plant Pluchea odorata, known as an anti-inflammatory and cancer cell growth-inhibiting remedy, was subjected to bioassay-guided isolation. Structure elucidation by 1D- and 2D-NMR and MS techniques supported by ECD and UV spectroscopic data revealed seven structurally previously undescribed and eight known eudesmane-type sesquiterpenes. Furthermore, one previously undescribed and one known phytol-like alcohol were identified. All compounds were tested for their cytotoxicity in cancer cells and for their anti-invasive effects. Among the eudesmanes, 3alpha-(2',3'-epoxy-2' methylbutyryloxy)-4alpha-hydroxy-11-hydroperoxy-eudesm-6-en-8-one exhibited the most potent cytotoxic activity with an IC50 value of 8.8 MUM (after 48 h). Also in an in vitro model measuring the tumor-triggered breaching of the adjacent lymph endothelial cell barrier (3S*,4R*,5S*,10S*,2'R*,3'R*)-3-(2',3'-epoxy-2' methylbutyryloxy)-4,7-dihydroxy-eudesm-11-en-8-one (IC75 = 47 MUM) and (3S*,4R*,5R*,10S*,2'R*,3'R*)-3-(2',3'-epoxy-2'-methylbutyryloxy)-4-acetyloxy-6 methoxy-11-hydroxy-eudesm-6-en-8-one (IC75 = 73 MUM) showed inhibitory activities. Furthermore, preliminary structure-activity relationships (SARs) of the eudesmanes were developed. PMID- 28554036 TI - Taxonomy of prickly juniper (Juniperus oxycedrus group): A phytochemical morphometric combined approach at the contact zone of two cryptospecies. AB - Based on different essential oil composition paralleling different genotypes, Juniperus deltoides was recently segregated from Juniperus oxycedrus. Despite a clear phytochemical and molecular differentiation, J. deltoides resulted not clearly morphologically discernible from J. oxycedrus, so that it was defined as a cryptospecies. Italy represents the contact zone of their distribution, but the ranges of the two species are not sufficiently known, due to unsatisfactory morphological characterisation. To further complicate the picture, a third closely related species (ecotype), J. macrocarpa, occurs all across the Mediterranean coasts. After a preliminary phytochemical analysis to ascertain the (chemo-)identities of the studied populations, we performed a morphometric investigation to test the degree of morphological distinctiveness among the taxa. According to our analysis, some character (e.g. leaf mucro length, leaf width, seed-cone size and seed size) resulted useful to discriminate these cryptic taxa. Finally, based on these characters, an extensive revision of herbarium specimens allowed us to redefine the distribution pattern of the investigated species in the Central Mediterranean area. PMID- 28554037 TI - Fluid-structure interaction simulation of a cerebral aneurysm: Effects of endovascular coiling treatment and aneurysm wall thickening. AB - In the present study, we investigate the effect of the hemodynamic factors of the blood flow on the cerebral aneurysms. To this end, a hypothetical geometry of the aneurysm in the circle of Willis, located in the bifurcation point of the anterior cerebral artery (ACA) and anterior communicating artery (ACoA) is modeled in a three-dimensional manner. Three cases are chosen in the current study: an untreated thin wall (first case), untreated thick wall (second case), and a treated aneurysm (third case). The effect of increasing the aneurysm wall thickness on the deformation and stress distribution of the walls are studied. The obtained results showed that in the second case, a reduction in the deformations of the walls was observed. It was also shown that the Von Mises stress has a 10% reduction in the untreated thick wall aneurysm compared to the untreated thin wall aneurysm. Thus, increasing the thickness of the aneurysm wall can be proposed as temporary remedial action. In the third case, an aneurysm that has been treated by endovascular coiling is investigated. The deformation and Von Mises stress in this case was decreased more than 43% and 87% compared to the first case, respectively. The wall shear stress distribution due to the fluid flow in the first and second cases showed small amounts of shear stress on the aneurysm sac. In these two cases, the oscillatory shear index was measured to have an approximate value of 0.47 in the aneurysm region, though, this value was measured to be about 0.1 for the third case. The hybrid effect of the wall shear stress and the oscillatory shear index on the relative residence time (RRT) was also studied. When this parameter reaches its maximum, the aneurysm rupture may occur. It was shown that by treating the aneurysm (the third case), RRT parameter can be decreased ~200 times relative to the first and second cases, which suggests an appropriate treatment of the aneurysm by choosing the coiling method. PMID- 28554038 TI - Polymerization kinetics of a mixture of Lipiodol and Glubran 2 cyanoacrylate glue upon contact with a proteinaceous solution. AB - The Glubran 2 cyanoacrylate glue is a liquid embolic agent used to block blood vessels endovascularly. Typically mixed with an iodized oil (Lipiodol) for visualization under X-ray, it polymerizes when in contact with blood and tissues owing to the presence of ions and proteins. The objective of the study is to determine the influence of plasma proteins in the polymerization reaction. A triggering solution containing bovine serum albumin (BSA) and the main blood ions is used as a model of plasma. The polymerization kinetics of Glubran 2-Lipiodol mixtures is measured upon aspiration in a capillary tube and contact with the proteinaceous solution. Having varied the glue and protein concentrations, we show that glue-Lipiodol mixtures with concentrations larger or equal to 25% polymerize when put in contact with an ionic solution containing at least 4% of BSA. The reaction is decomposed into two phases: a fast zwitterionic polymerization induced by the BSA molecules followed by a slower polymerization phase. The reaction speed and extent of the solidification region mostly depend on the glue concentration. The time for the glue solution to polymerize over a 1mm thickness varies from 5s for pure glue to about 1min for a 50% glue concentration, and 10min for a 25% glue mixture. It is the first time that the kinetics of the two polymerization reactions is quantified for Glubran 2, which will provide the information needed by interventional radiologists to optimize the planning of endovascular glue injection. PMID- 28554039 TI - Mechanistic insights into how CMG helicase facilitates replication past DNA roadblocks. AB - Before leaving the house, it is a good idea to check for road closures that may affect the morning commute. Otherwise, one may encounter significant delays arriving at the destination. While this is commonly true, motorists may be able to consult a live interactive traffic map and pick an alternate route or detour to avoid being late. However, this is not the case if one needs to catch the train which follows a single track to the terminus; if something blocks the track, there is a delay. Such is the case for the DNA replisome responsible for copying the genetic information that provides the recipe of life. When the replication machinery encounters a DNA roadblock, the outcome can be devastating if the obstacle is not overcome in an efficient manner. Fortunately, the cell's DNA synthesis apparatus can bypass certain DNA obstructions, but the mechanism(s) are still poorly understood. Very recently, two papers from the O'Donnell lab, one structural (Georgescu et al., 2017 [1]) and the other biochemical (Langston and O'Donnell, 2017 [2]), have challenged the conventional thinking of how the replicative CMG helicase is arranged on DNA, unwinds double-stranded DNA, and handles barricades in its path. These new findings raise important questions in the search for mechanistic insights into how DNA is copied, particularly when the replication machinery encounters a roadblock. PMID- 28554040 TI - Facile fabrication of novel PdRu nanoflowers as highly active catalysts for the electrooxidation of methanol. AB - The shape-controlled synthesis of binary Pd-based nanocrystals bounded with abundant surface active areas and tunable atomic ratio have been of great significance in the fabrication and modification of outstandingly excellent electrocatalysts. To embody the superiority of high surface area in enhancing electrocatalysis well, the superior electrocatalyst should be supposed to combine both the morphology advantages and the synergistic effect between metals. We herein report our significant advances in engineering the unique binary PdRu nanoflowers with highly exposed active sites and tunable compositions. Owing to the bifuntional effect and electronic effect between Pd and Ru, as well as the unique flower-like structure, such special PdRu nanoflower exhibit outstandingly excellent catalytic activity towards methanol electrooxidation with the mass activity of 1280mAmg-1, 7.01 and 4.92-fold enhancement than that of pure Pd and commercial Pd/C. Our efforts in this work may open a new way for enhancing the catalytic activity by constructing the catalysts with desirable shape and maximizing the active surface areas. PMID- 28554041 TI - Rapid fabrication of support-free trimetallic Pt53Ru39Ni8 nanosponges with enhanced electrocatalytic activity for hydrogen evolution and hydrazine oxidation reactions. AB - Herein, a rapid and straightforward coreduction aqueous approach was developed for preparation of support-free trimetallic Pt53Ru39Ni8 nanosponges with clean surface. Plenty of hydrogen bubbles were in situ formed via the oxidation and hydrolysis of the reductant (sodium borohydride), which served as the dynamic template in the fabrication of the porous sponge-like structures. The shape, size, crystal structure, and composition of the products were characterized by a set of characterization techniques. The obtained Pt53Ru39Ni8 nanosponges displayed dramatically highly electrocatalytic performances for hydrogen evolution reaction (HER) and hydrazine oxidation reaction (HOR) outperformed home made PtNi nanoparticles (PtNi NPs), RuNi NPs and commercial PtRu black (50wt.%). The present route provides new insights for facile synthesis of other bi-, tri- and even multi-metallic nanocatalysts for potential applications in catalysis, energy conversion and storage. PMID- 28554042 TI - Cobalt disulfide nanoparticles/graphene/carbon nanotubes aerogels with superior performance for lithium and sodium storage. AB - A robust and interconnected three-dimensional (3D) aerogel consisting of CoS2 nanoparticles, graphene nanosheets (GNs) and carbon nanotubes (CNTs) is synthesized as an anode material (CoS2/GCAs) for lithium ion batteries (LIBs) and sodium ion batteries (SIBs). With the introduction of CNTs, the isolated CoS2 nanoparticles as well as GNs are jointed closely and cross-linked to construct a 3D conductive network. Benefited from the advantages of the positive synergistic effects of the individual components, CoS2/GCAs composite exhibits excellent electrochemical performances. When used as an anode for LIBs, it possesses a high reversible capacity of 975mAhg-1 after 100 cycles at 0.25Ag-1. Apart from that, it also manifests a superior cycling stability with capacity of 258mAhg-1 after 100 cycles at 0.05Ag-1 for SIBs. As a result of the enhanced electrochemical performance, CoS2/GCAs composite with an interconnected architecture could be regarded as a promising candidate for LIBs/SIBs. PMID- 28554043 TI - Salt induced polystyrene latex flocs investigated by neutron scattering. AB - Studies with a model system consisting of polystyrene latex particles showed that the protein from seeds of Moringa trees adsorbs to the surface and causes flocculation as unusually dense aggregates. In this study, electrolytes sodium chloride (NaCl), ferric chloride (FeCl3) and aluminium sulfate (Al2(SO4)3) have been used to aggregate model polystyrene particles. The study augments previous work using neutron scattering on the flocculation of polystyrene latex with protein from seeds of Moringa trees that had indicated higher floc dimension, df, values as the concentration of particles increased. The measurements were made using ultra small-angle neutron scattering. Generally the fractal dimension, and thus the floc density, increased with particle concentration and salt concentration. Flocculation was apparent at much lower concentrations of FeCl3 and Al2(SO4)3 than of NaCl. The values of df were found not to simply scale with ionic strength for the three electrolytes studied with FeCl3 being the most effective flocculating agent. PMID- 28554044 TI - In-droplet cell concentration using dielectrophoresis. AB - Concentrating cells or adjusting the concentration of cells are one of the most fundamental steps in cell biology experiments, and are typically achieved through centrifugation. However this step is challenging to implement in droplet microfluidics. Here we present an in-droplet cell concentrator that operates by first gradually focusing cells inside a droplet to one side of the droplet using negative dielectrophoresis (nDEP), followed by asymmetric droplet splitting using a Y-shaped junction, resulting in two daughter droplets, one of which containing all or most of the cells. The developed platform was first characterized using droplets containing different number of polystyrene (PS) particles and by varying the applied voltages, flow rates, and the width ratios of the droplet splitting microchannels. Using this platform, the volume of one daughter droplet could be reduced up to 84% compared to that of the mother droplet, which resulted in the PS particle concentration to increase by 5.6-fold, with an average recovery rate of 90%. When testing with cells (Chlamydomonas reinhardtii), recovery rates as high as 98% could be achieved while increasing the cell concentration by 5-fold. This technology adds a new capability to droplet microfluidics operation, and can be used for adjusting concentrations of cells in droplets, exchanging solutions in which cells are suspended in droplets (including cell washing steps), and separating cells of different dielectric properties inside droplets, all of which are common steps in conventional cell assays but have been so far difficult to achieve in droplet format. PMID- 28554045 TI - Transparent, mediator- and membrane-free enzymatic fuel cell based on nanostructured chemically modified indium tin oxide electrodes. AB - We detail a mediator- and membrane-free enzymatic glucose/oxygen biofuel cell based on transparent and nanostructured conducting supports. Chemically modified indium tin oxide nanoparticle modified electrodes were used to substantially increase the active surface area without significantly compromising transparency. Two different procedures for surface nanostructuring were employed, viz. spray coating and drop-coating. The spray-coated biodevice showed superior characteristics as compared to the drop-coated enzymatic fuel cell, as a result of the higher nanostructured surface area as confirmed by electrochemical characterisation, as well as scanning electron and atomic force microscopy. Subsequent chemical modification with silanes, followed by the immobilisation of either cellobiose dehydrogenase from Corynascus thermophiles or bilirubin oxidase from Myrothecium verrucaria, were performed to obtain the bioanodes and biocathodes, respectively. The optimised biodevice exhibited an OCV of 0.67V and power output of up to 1.4uW/cm2 at an operating voltage of 0.35V. This is considered a significant step forward in the field of glucose/oxygen membrane- and mediator-free, transparent enzymatic fuel cells. PMID- 28554046 TI - Non-invasive, electro-orientation-based viability assay using optically transparent electrodes for individual fission yeast cells. AB - A non-invasive assay of cylindrical yeast cell viability based on electro orientation (EO) in an alternating electric field was developed, in which cell viability can be determined by each cell's EO direction without the need for reagents. A cell suspension of a few microliters was sandwiched between a pair of optically transparent indium-tin-oxide (ITO) plate electrodes. Observation under a light microscope enabled easy identification of EO based on cell shape, e.g., cells were standing upright and appeared perfectly circular when oriented parallel to the electric field direction (standing position), and they were lying flat and had an elongated shape when oriented perpendicular to the field (lain down position). The alternative EO positions of living or dead cells were dependent on the applied frequency: opposite EO positions were obtained by applying an AC voltage of 1.5V at 10MHz; at which point, only living cells rapidly attained a standing position, whereas dead cells were lain-down within 10s. All the cell's EO positions agreed well with a viability assay by florescence staining. Therefore, at the single-cell level and fluorescently label free, it was possible to simply and accurately determine whether individual cells were alive or dead based on their shape. PMID- 28554047 TI - Ultrasensitive detection of aflatoxin B1 by SERS aptasensor based on exonuclease assisted recycling amplification. AB - Aflatoxin B1 (AFB1) is one of the most abundant and carcinogenic food contaminating mycotoxins around the world. In this study, we proposed a surface enhanced Raman scattering (SERS) sensing strategy for the determination of AFB1. An aptamer for AFB1 partially hybridized with complementary-DNA, which was released after the recognition of AFB1 and immediately hybridized with hairpin DNA on the surface of sputtering Au film. Exonuclease III hydrolyzed the double stranded DNA, leaving short single-stranded DNA on the Au surface and releasing complementary-DNA for next ring opening and digestion. SERS tag was captured on Au surface by DNA hybridization. Agarose gel electrophoresis and dynamic light scattering showed that SERS tag was successfully prepared. The detection principle was validated by electrochemical impedance spectroscopy and SERS at each step. High sensitivity and good selectivity for AFB1 detection were observed. The results showed that there was a good linear relation when the AFB1 concentration was from 1*10-6 to 1ng/mL, and the limit of detection (LOD) was 0.4 fg/mL. This sensor was also applied for quantifying AFB1 levels in spiked peanuts samples, the recoveries was in the range of 89-121%. PMID- 28554048 TI - Ascorbic acid-mediated enhanced cardiomyocyte differentiation of mouse ES-cells involves interplay of DNA methylation and multiple-signals. AB - Embryonic stem cells (ES-cells) provide a good model system to study lineage specific differentiation. Though, the differentiation of ES-cells to cardiomyocytes is documented, a clear understanding of the molecular mechanism of differentiation and improved functional-differentiation efficiency are yet to be achieved. In this regard, ascorbic acid (Aa) is shown to be one of the effective cardiac inducers in ES-cells. But, its mechanism is poorly understood. We therefore, investigated the mechanism of Aa-mediated cardiomyocyte differentiation of ES-cells. Here, we describe the potential involvement of epigenetic (DNA methylation) as well as integrin- and Erk- signaling systems during cardiomyocyte differentiation. Transgenic GS-2 ES-cells and wild-type D3 ES-cells were differentiated to cardiomyocytes, in the presence or absence of Aa and with or without inhibitors of Erk-, collagen- and integrin- pathways. At specific time points, differentiated states of ES-cells were scored by gene expression analyses and the proportion of functional cTnI+ cardiomyocytes. DNA methylation changes of Isl-1, BMP-2, GATA-4 and alpha-MHC in cardiogenic cells, following stimulation with Aa, were analyzed by using methylation specific PCR (MSP). We observed that Aa, when applied in initial phase of ES-cell differentiation, consistently enhanced cardiac differentiation (99%) over that observed during spontaneous differentiation (70%). This was associated with enhanced expressions of cardiogenesis-associated genes. A two-fold increase in cTnI+ cells was observed, with appropriate myofibril arrangement. The observed effect of Aa was due to enhanced collagen and integrin signaling, coupled with a high p-ERK1/2 expression, downstream. Besides, the involvement of DNA methylation in regulating the expression of cardiac genes i.e., Isl-1 and alpha-MHC was also observed. Overall, this study, for the first time, demonstrates that Aa-mediated cardiac enhancement is brought about, mechanistically, through the interplay of epigenetic changes in DNA methylation of cardiac genes (Isl-1 and alpha-MHC) and integrin signaling system. PMID- 28554050 TI - Xanthogranulomatous pancreatitis: A review of the imaging characteristics of this rare and often misdiagnosed lesion of the pancreas. AB - Xanthogranulomatous pancreatitis (XGP) is an extremely rare cause of a cystic pancreatic mass. The pathophysiology of this process is not entirely clear but likely results from a combination of duct obstruction, infection, and repeated hemorrhage. It is difficult to differentiate this inflammatory lesion from a cystic neoplasm and, therefore, in the majority of cases XGP is misdiagnosed as a neoplasm on preoperative imaging. In this report, we describe a case of XGP, the imaging characteristics of XGP, and a differential diagnosis for a cystic pancreatic lesion. PMID- 28554049 TI - Increased susceptibility of IDH2-deficient mice to dextran sodium sulfate-induced colitis. AB - Inflammatory bowel disease (IBD) is a group of chronic, relapsing, immunological, inflammatory disorders of the gastrointestinal tract including ulcerative colitis (UC) and Crohn's disease (CD). It has been reported that UC, which is studied using a dextran sodium sulfate (DSS)-induced colitis model, is associated with the production of reactive oxygen species (ROS) and the apoptosis of intestine epithelial cells (IEC). Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) has been reported as an essential enzyme in the mitochondrial antioxidant system via generation of NADPH. Therefore, we evaluated the role of IDH2 in DSS induced colitis using IDH2-deficient (IDH2-/-) mice. We observed that DSS-induced colitis in IDH2-/- mice was more severe than that in wild-type IDH2+/+ mice. Our results also suggest that IDH2 deficiency exacerbates PUMA-mediated apoptosis, resulting from NF-kappaB activation regulated by histone deacetylase (HDAC) activity. In addition, DSS-induced colitis is ameliorated by an antioxidant N acetylcysteine (NAC) through attenuation of oxidative stress, resulting from deficiency of the IDH2 gene. In conclusion, deficiency of IDH2 leads to increased mitochondrial ROS levels, which inhibits HDAC activity, and the activation of NF kappaB via acetylation is enhanced by attenuated HDAC activity, which causes PUMA mediated apoptosis of IEC in DSS-induced colitis. The present study supported the rationale for targeting IDH2 as an important cancer chemoprevention strategy, particularly in the prevention of colorectal cancer. PMID- 28554051 TI - Selenium accumulation and metabolism in algae. AB - Selenium (Se) is an intriguing element because it is metabolically required by a variety of organisms, but it may induce toxicity at high doses. Algae primarily absorb selenium in the form of selenate or selenite using mechanisms similar to those reported in plants. However, while Se is needed by several species of microalgae, the essentiality of this element for plants has not been established yet. The study of Se uptake and accumulation strategies in micro- and macro-algae is of pivotal importance, as they represent potential vectors for Se movement in aquatic environments and Se at high levels may affect their growth causing a reduction in primary production. Some microalgae exhibit the capacity of efficiently converting Se to less harmful volatile compounds as a strategy to cope with Se toxicity. Therefore, they play a crucial role in Se-cycling through the ecosystem. On the other side, micro- or macro-algae enriched in Se may be used in Se biofortification programs aimed to improve Se content in human diet via supplementation of valuable food. Indeed, some organic forms of selenium (selenomethionine and methylselenocysteine) are known to act as anticarcinogenic compounds and exert a broad spectrum of beneficial effects in humans and other mammals. Here, we want to give an overview of the developments in the current understanding of Se uptake, accumulation and metabolism in algae, discussing potential ecotoxicological implications and nutritional aspects. PMID- 28554052 TI - Acute effects of spinal bracing on scapular kinematics in adolescent idiopathic scoliosis. AB - BACKGROUND: Bracing is the most common nonsurgical treatment for adolescent idiopathic scoliosis. Spinal braces affect glenohumeral and scapulothoracic motion because they restrict trunk movements. However, the potential spinal bracing effects on scapular kinematics are unknown. The present study aimed to investigate the acute effects of spinal bracing on scapular kinematics in adolescent idiopathic scoliosis. METHODS: Scapular kinematics, including scapular internal/external rotation, posterior/anterior tilting, and downward/upward rotation during scapular plane elevation, were evaluated in 27 in-brace and out of-brace adolescent idiopathic scoliosis patients with a three-dimensional electromagnetic tracking system. Data on the position and orientation of the scapula at 30 degrees , 60 degrees , 90 degrees , and 120 degrees humerothoracic elevation were used for statistical comparisons. The paired t-test was used to assess the differences between the mean values of in-brace and out-of-brace conditions. FINDINGS: The in-brace condition showed significantly increased (P<0.05) scapular anterior tilting and decreased internal rotation in the resting position on the convex and concave sides; increased scapular downward rotation at 120 degrees humerothoracic elevation on the convex side and at 30 degrees , 60 degrees , 90 degrees , and 120 degrees humerothoracic elevation on the concave side; increased scapular anterior tilt at 30 degrees , 60 degrees , 90 degrees , and 120 degrees humerothoracic elevation on the convex and concave sides; and decreased (P<0.05) maximal humerothoracic elevation of the arm. INTERPRETATION: Spinal bracing affects scapular kinematics. Observed changes in scapular kinematics with brace may also affect upper extremity function for adolescents with idiopathic scoliosis. Therefore, clinicians should include assessments of the glenohumeral and scapulothoracic joints when designing rehabilitation protocols for patients with adolescent idiopathic scoliosis. PMID- 28554053 TI - Radiographic evaluation of acute distal radius fracture stability: A comparative cadaveric study between a thermo-formable bracing system and traditional fiberglass casting. AB - BACKGROUND: Distal radius fractures are common musculoskeletal injuries and many can be treated non-operatively with cast immobilization. A thermo-formable brace has been developed for management of such fractures, but no data exist regarding its comparative stabilizing efficacy to fiberglass casting. METHODS: A worst-case distal radius fracture was created in 6 cadaveric forearms. A radiolucent loading fixture was created to apply cantilever bending/compression loads ranging from 4.5N to 66.7N across the simulated fracture in the: (1) non-stabilized, (2) braced; and (3) casted forearms, each forearm serving as its own control. Fracture fragment translations and rotations were measured radiographically using orthogonal radiographs and a 2D-3D, CT-based transformation methodology. FINDINGS: Under 4.5N of load in the non-stabilized condition, average sagittal plane rotation and 3D center of mass translation of the fracture fragment were 12.3 degrees and 5.3mm, respectively. At the 4.5N load step, fragment rotation with the brace (avg. 0.0 degrees ) and cast (0.1 degrees ) reduced sagittal plane rotation compared to the non-stabilized forearm (P<0.001). There were no significant differences in measured sagittal plane fracture fragment rotations or 3D fragment translations between the brace or cast at any of the four load steps (4.5N, 22.2N, 44.5N, and 66.7N, P>=0.138). INTERPRETATION: In this in vitro radiographic study utilizing 6 cadaveric forearms with simulated severe-case, unstable and comminuted distal radius fractures, the thermo-formable brace stabilized the fracture in a manner that was not radiographically or biomechanically different from traditional fiberglass casting. Study results support the use of the thermo-formable brace clinically. PMID- 28554054 TI - Military personnel with self-reported ankle injuries do not demonstrate deficits in dynamic postural stability or landing kinematics. AB - BACKGROUND: The odds of sustaining non-contact musculoskeletal injuries are higher in Special Operations Forces operators than in infantry soldiers. The ankle is one of the most commonly injured joints, and once injured can put individuals at risk for reinjury. The purpose of this study was to determine if any differences in postural stability and landing kinematics exist between operators with a self-reported ankle injury in the past one year and uninjured controls. METHODS: A total of 55 Special Operations Forces operators were included in this analysis. Comparisons were made between operators with a self reported ankle injury within one-year of their test date (n=11) and healthy matched controls (n=44). Comparisons were also made between injured and uninjured limbs within the injured group. Dynamic postural stability and landing kinematics at the ankle, knee, and hip were assessed during a single-leg jump-landing task. Comparisons were made between groups with independent t-tests and within the injured group between limbs using paired t-tests. FINDINGS: There were no significant differences in dynamic postural stability index or landing kinematics between the injured and uninjured groups. Anterior-posterior stability index was significantly higher on the uninjured limb compared to the injured limb within the injured group (P=0.02). INTERPRETATION: Single ankle injuries sustained by operators may not lead to deficits in dynamic postural stability. Dynamic postural stability index and landing kinematics within one year after injury were either not affected by the injuries reported, or injured operators were trained back to baseline measures through rehabilitation and daily activity. PMID- 28554055 TI - Graphene oxide as an efficient antimicrobial nanomaterial for eradicating multi drug resistant bacteria in vitro and in vivo. AB - Graphene is a novel two-dimensional nanomaterial with a growing number of practical applications across numerous fields. In this work, we explored potential biomedical applications of graphene oxide (GO) by systematically studying antibacterial capacity of GO in both macrophages and animal models. Three types of bacteria, including Klebsiella pneumoniae (Kp), Escherichia coli (E. coli) and P. aeruginosa (Pa) were used for in vitro study. Kp was also selected as a representative multidrug resistant (MDR) bacterium for in vivo study. In in vitro study, GO effectively eradicated Kp in agar dishes and thus protected alveolar macrophages (AM) from Kp infection in the culture. In the in vivo evaluation, GO were introduced intranasally into mouse lungs followed by testing organ tissue damage including lung, liver, spleen, and kidneys, polymorphonuclear neutrophil (PMN) penetration, bacterial dissemination, and mortality in Kp-infected mice. We found that GO can prohibit the growth and spread of Kp both in vitro and in vivo, resulting in significantly increased cell survival rate, less tissue injury, subdued inflammatory response, and prolonged mice survival. These findings indicate that GO could be a promising biomaterial for effectively controlling MDR pathogens. PMID- 28554056 TI - Structure and antibacterial activity relationships of native and amyloid fibril lysozyme loaded on layered double hydroxide. AB - Lysozyme from hen egg white is composed by a unique linear chain of 129 amino acids. It is known to inhibit Gram positive bacteria and to form amyloid fibrils at low pH, under 75 degrees C. This work investigates the effect of the fibrillation and/or adsorption onto a layered double hydroxide material on the antibacterial properties of lysozyme. The kinetics of adsorption follows a behavior of pseudo second order model. The X-ray diffraction and the Fourier transform infrared spectroscopy highlight that adsorption occurs only on the external surface of the material. Interestingly, the amyloid fibrils of lysozyme retain their antibacterial properties when they are adsorbed on the layered double hydroxide; even if their activity is lowered, the active site of the enzyme is not fully denatured and is still accessible. This is confirmed by the study of the tryptophan using time-resolved fluorescence spectroscopy. PMID- 28554057 TI - The immune regulation in cancer by the amino acid metabolizing enzymes ARG and IDO. AB - Some enzymes degrading amino acids have evolved in mammals to dampen immune responses and maintain peripheral tolerance. The enzymes metabolizing l-arginine and l-tryptophan are particularly powerful, contributing to restrain immunity towards fetal tissues and establish neonatal tolerance. Solid tumors can hijack these formidable pathways to construct a microenvironment highly unfavorable to anti-tumor T lymphocytes able to recognize them, one of mechanisms for their immune evasion. In this review, we analyze emerging concepts in the cross-talk between cells expressing these enzymes, their immune regulatory functions and pharmacological approaches that can target them to enhance cancer immunotherapy. PMID- 28554059 TI - Residues F103 and M106 within the influenza A virus NS1 CPSF4-binding region regulate interferon-stimulated gene translation initiation. AB - Influenza A virus (IAV) non-structural protein 1 (NS1) suppresses host innate immune responses by inhibiting type I interferon (IFN) production. We provide evidence that residues F103 and M106 in the CPSF4-binding domain of A/HK/1/68 [H3N2] NS1 contribute to post-transcriptional inhibition of antiviral IFN stimulated genes (ISGs), thereby suppressing an antiviral type I IFN response. Recombinant (r) IAVs encoding F103L and M106I mutations in NS1 replicate to significantly lower viral titers in human A549 lung epithelial cells and primary type II alveolar cells. In A549 cells, rIAVs encoding these mutant NS1s induce higher levels of IFN-beta production and are more sensitive to the antiviral effects of IFN-beta treatment. qPCR characterization of polysomal mRNA, in the presence or absence of IFN-beta treatment, identified a greater proportion of heavy polysome-associated ISGs including EIF2AK2, OAS1, and MxA in A549 cells infected with rIAVs encoding these CPSF4-binding mutant NS1s, in contrast to rIAV encoding wildtype NS1. PMID- 28554058 TI - Stockpiled pre-pandemic H5N1 influenza virus vaccines with AS03 adjuvant provide cross-protection from H5N2 clade 2.3.4.4 virus challenge in ferrets. AB - Avian influenza viruses, notably H5 subtype viruses, pose a continuous threat to public health due to their pandemic potential. In recent years, influenza virus H5 subtype split vaccines with novel oil-in-water emulsion based adjuvants (e.g. AS03, MF59) have been shown to be safe, immunogenic, and able to induce broad immune responses in clinical trials, providing strong scientific support for vaccine stockpiling. However, whether such vaccines can provide protection from infection with emerging, antigenically distinct clades of H5 viruses has not been adequately addressed. Here, we selected two AS03-adjuvanted H5N1 vaccines from the US national pre-pandemic influenza vaccine stockpile and assessed whether the 2004-05 vaccines could provide protection against a 2014 highly pathogenic avian influenza (HPAI) H5N2 virus (A/northern pintail/Washington/40964/2014), a clade 2.3.4.4 virus responsible for mass culling of poultry in North America. Ferrets received two doses of adjuvanted vaccine containing 7.5ug of hemagglutinin (HA) from A/Vietnam/1203/2004 (clade 1) or A/Anhui/1/2005 (clade 2.3.4) virus either in a homologous or heterologous prime-boost vaccination regime. We found that both vaccination regimens elicited robust antibody responses against the 2004-05 vaccine viruses and could reduce virus-induced morbidity and viral replication in the lower respiratory tract upon heterologous challenge despite the low level of cross-reactive antibody titers to the challenge H5N2 virus. This study supports the value of existing stockpiled 2004-05 influenza H5N1 vaccines, combined with AS03-adjuvant for early use in the event of an emerging pandemic with H5N2-like clade 2.3.4.4 viruses. PMID- 28554060 TI - Using two detectors concurrently to monitor ambient dose equivalent rates in vehicle surveys of radiocesium contaminated land. AB - In response to the accident at Tokyo Electric Power Company's Fukushima Dai-ichi Nuclear Power Plant (FDNPP), vehicle-borne monitoring was used to map radiation levels for radiological protection of the public. By convention measurements from vehicle-borne surveys are converted to the ambient dose equivalent rate at 1 m height in the absence of the vehicle. This allows for comparison with results from other types of survey, including surveys with hand-held or airborne instruments. To improve the accuracy of the converted results from vehicle-borne surveys, we investigated combining measurements from two detectors mounted on the vehicle at different heights above the ground. A dual-detector setup was added to a JAEA monitoring car and compared against hand-held survey meter measurements in Fukushima Prefecture. The results obtained by combining measurements from two detectors were within +/-20% of the hand-held reference measurements. The mean absolute percentage deviation from the reference measurements was 7.2%. The combined results from the two detectors were more accurate than those from either the roof-mounted detector, or the detector inside the vehicle, taken alone. One issue with vehicle-borne surveys is that ambient dose equivalent rates above roads are not necessarily representative of adjacent areas. This is because radiocesium is often deficient on asphalt surfaces, as it is easily scrubbed off by rain, wind and vehicle tires. To tackle this issue, we investigated mounting heights for vehicle-borne detectors using Monte Carlo gamma-ray simulations. When radiocesium is deficient on a road compared to the adjacent land, mounting detectors high on vehicles yields results closer to the values adjacent to the road. The ratio of ambient dose equivalent rates reported by detectors mounted at different heights in a dual-detector setup indicates whether radiocesium is deficient on the road compared to the adjacent land. PMID- 28554061 TI - Comparative pharmacokinetic study of baicalin and its metabolites after oral administration of baicalin and Chaiqin Qingning capsule in normal and febrile rats. AB - An accurate, precise, selective, and sensitive high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) method was developed for the simultaneous determination of baicalin and its metabolite, baicalein 6-O-glucopyranuronoside, in normal and febrile rats plasma. Two analytes, along with hesperidin as an internal standard, were determined by multiple reactions monitoring (MRM) operated in the positive electrospray ionization (ESI) mode. Chromatographic separation was performed on an Agilent ZORBAX Extend-C18 column (100mm*2.10mm, 3.5MUm) with a mobile phase of 0.1% formic acid solution and acetonitrile at a flow rate of 0.6mL/min. The calibration curves showed good linearity (r>=0.9974) with the concentration ranges of 2.000-2000ngmL-1 for baicalin and baicalein 6-O-glucopyranuronoside. The inter- and intra-day accuracies (relative error, RE%) were between -6.62% and 6.75%, and the precisions (relative standard deviation, RSD%) were less than 9.09% for quality control samples (QCs). The method also possessed good selectivity, recovery and stability, and was successfully applied to a comparative pharmacokinetic study of baicalin and baicalein 6-O glucopyranuronoside in normal and febrile rats after oral administration of baicalin and Chaiqin Qingning capsule. PMID- 28554062 TI - An isotope-dilution UPLC-MS/MS technique for the human biomonitoring of the internal exposure to glycidol via a valine adduct at the N-terminus of hemoglobin. AB - Fatty acid esters of glycidol (glycidyl esters) are processing contaminants generated as a byproduct of the industrial deodorization of vegetable oils and fats. Oral intake of glycidyl esters leads to the release of glycidol in the gastrointestinal tract. Glycidol is carcinogenic, genotoxic and teratogenic in rodents. It is rated as probably carcinogenic to humans (IARC group 2A). The determination of internal exposure of glycidol may support the assessment of the possible human health risks related to glycidyl ester intake. For this purpose, hemoglobin adducts of glycidol may be suitable biomarkers reflecting the cumulative exposure of up to four months. We applied a modified Edman degradation to assess the glycidol adduct at the N-terminal valine, N-(2,3-dihydroxypropyl) valine (2,3-diHOPr-Val), of hemoglobin. The modified valine was cleaved with fluorescein-5-isothiocyanate (FITC), resulting in the formation of N-(2,3 dihydroxypropyl)-valine fluorescein thiohydantoin (DHP-Val-FTH). An isotope dilution technique was developed for the quantification of the thiohydantoin analyte by ultra performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS) and DHP-Val-d7-FTH as reference standard. The limit of detection was 4 fmol DHP-Val-FTH per injection corresponding to 0.7pmol 2,3-diHOPr-Val/g hemoglobin. The adduct levels in blood samples of 12 non-smoking participants were in the range of 2.2-4.9pmol 2,3-diHOPr-Val/g hemoglobin. The current work presents the first isotope-dilution technique using UPLC-MS/MS for the quantification of 2,3-diHOPr-Val at the N-terminus of hemoglobin as a sensitive and convenient alternative to earlier GC-MS methods. PMID- 28554063 TI - A meta-analysis of in-vehicle and nomadic voice-recognition system interaction and driving performance. AB - Driver distraction is a growing and pervasive issue that requires multiple solutions. Voice-recognition (V-R) systems may decrease the visual-manual (V-M) demands of a wide range of in-vehicle system and smartphone interactions. However, the degree that V-R systems integrated into vehicles or available in mobile phone applications affect driver distraction is incompletely understood. A comprehensive meta-analysis of experimental studies was conducted to address this knowledge gap. To meet study inclusion criteria, drivers had to interact with a V R system while driving and doing everyday V-R tasks such as dialing, initiating a call, texting, emailing, destination entry or music selection. Coded dependent variables included detection, reaction time, lateral position, speed and headway. Comparisons of V-R systems with baseline driving and/or a V-M condition were also coded. Of 817 identified citations, 43 studies involving 2000 drivers and 183 effect sizes (r) were analyzed in the meta-analysis. Compared to baseline, driving while interacting with a V-R system is associated with increases in reaction time and lane positioning, and decreases in detection. When V-M systems were compared to V-R systems, drivers had slightly better performance with the latter system on reaction time, lane positioning and headway. Although V-R systems have some driving performance advantages over V-M systems, they have a distraction cost relative to driving without any system at all. The pattern of results indicates that V-R systems impose moderate distraction costs on driving. In addition, drivers minimally engage in compensatory performance adjustments such as reducing speed and increasing headway while using V-R systems. Implications of the results for theory, design guidelines and future research are discussed. PMID- 28554064 TI - Driving under the influence of drugs: Perceptions and attitudes of New Zealand drivers. AB - This study explored the patterns of drug driving in New Zealand by investigating 1) drivers' perceptions about impairment caused by legal and illegal drugs 2) countermeasures employed by drivers when under the influence of drugs (e.g., decisions not to drive) 3) drivers' attitudes about police enforcement of drug driving and 4) the factors that predict the likelihood of engaging in drug driving. Participants (n=434) were licensed drivers who completed an online questionnaire. Results of the questionnaire indicated that drivers rated hallucinogens and opiates as being the illegal drugs producing the highest level of driving impairment and cannabis the lowest. For legal drugs, sedatives were rated as having the highest driving impairment and anti-nausea and anti depressants the lowest. Respondents' drug use history had an effect on their ratings of impairment for anti-anxiety drugs, anti-depressants, kava, sedatives, cannabis and hallucinogens such that drug users reported higher impairment ratings than Non-user. Making a decision not to drive after taking drugs was reported by users of alcohol (73.6%), cannabis (57.0%), strong painkillers (42.5%), and anti-depressants (10.0%). Respondents who reported drink driving were 3.26 times more likely to report drug driving than those reporting no drink driving. Respondents also showed greater acceptance towards driving under the influence of legal drugs (43.5%) compared to illegal drugs (10.3%). Those who did not have favourable attitudes about drug driving were less likely to report having driven under the influence of drugs. Drivers in this sample were less aware of the potential negative effects of legal drugs on driving compared to illegal drugs. More than half the respondents from this study acknowledged drug driving as a road safety issue which needs more resources dedicated to it. PMID- 28554065 TI - High-throughput metataxonomic characterization of the raw milk microbiota identifies changes reflecting lactation stage and storage conditions. AB - Low temperature is used to control the growth of bacteria in milk, both pre- and post-pasteurization. As the duration of refrigerated storage extends, psychrotrophs dominate the milk microbiota, that can produce heat stable lipases which negatively impact the organoleptic qualities of milk. Here we examine the influence that refrigeration temperature (2 degrees C, 4 degrees C and 6 degrees C) and storage duration (96h) have on the microbiota composition (16S profiling) of raw bulk tank milk (BTM). To reflect a proposed change to current farming practices, raw milk was blended after each milking (8 milkings) and stored for five consecutive days in each temperature-specific tank. Here 16S rRNA-based microbiota compositional analysis was performed after milk was collected on day 1 and again after the final addition of milk at day 5. In addition to assessing the impact of the duration and temperature of storage, the influence of lactation stage, i.e. mid- versus late-lactation, on the microbiota of the blended BTM was also examined. Overall, both temperature and length of storage had surprisingly little influence on the raw milk microbiota, other than an increase in proportions of Gammaproteobacteria in the blended milk samples collected after pooling on day 5, and in samples stored at 6 degrees C. However, lactation stage had a considerable influence on microbiota composition, with milk from mid lactation containing higher proportions of Bacteroides, Faecalibacterium, Campylobacter and Rhodanobacter, and late-lactation milk containing higher proportions of Actinobacteria. Overall, the study demonstrates that current temperature and storage duration practises impact the microbiota of raw milk, but these impacts are modest relative to the more considerable differences between mid and late-lactation milk. PMID- 28554066 TI - The neural basis of deficient response inhibition in children with neurofibromatosis type 1: Evidence from a functional MRI study. AB - Impaired response inhibition is a predominant feature of several neuropsychiatric disorders; in general the underlying aetiology of these disorders and associated impairments is unknown. The common occurrence of impaired response inhibition in a single gene disorder such as neurofibromatosis type 1 (NF1), provides a valuable opportunity to explore its mechanistic basis through the study of gene brain-behaviour interactions. We used functional brain imaging with a Go/No-Go task to examine the neural substrates of response inhibition in children with NF1 and age and gender matched typically developing subjects. Children with NF1 were found to have abnormal activation patterns in several cortical regions, with significantly reduced activation in the inferior occipital gyrus (IOG), the fusiform gyrus/posterior cerebellum (FG/PC), the pre-supplementary motor area (pre-SMA) and the inferior frontal gyrus (IFG). Importantly, activation in the right IFG was associated with faster task reaction times and impairment in sustained attention in subjects with NF1. Our study supports the hypothesis that a network of regions typically associated with response inhibition is dysfunctional in children with NF1 and suggests this dysfunction is linked to cognitive impairment in this disorder. PMID- 28554067 TI - Merging contemporary learning theory with mental health promotion to produce an effective schools-based program. AB - Approximately three quarters of all major mental disorders begin in adolescence. Finding ways to buffer against stress, access social support and connection and flexibly draw upon a range of coping mechanisms are vital strategies that young people can use to promote mental health and wellbeing and to navigate this turbulent life transition successfully. Within Australia, like other parts of the world such as the UK and the USA, it is a sad reality that when young people do become distressed they are not self-caring or supporting others effectively, and not seeking or receiving appropriate help. In order to respond proactively to this issue, a nurse-initiated mental health promotion program was developed. It is termed, iCARE, which stands for Creating Awareness, Resilience and Enhanced Mental Health. The aim of this paper is to discuss the underpinning educational theory that assists in developing in young people a sense of belonging, empathy, self-care and resilience, and why the strategies chosen to engage young people are likely to be effective. PMID- 28554068 TI - The Supportive Hospice and Aged Residential Exchange (SHARE) programme in New Zealand. AB - Research indicates that staff in aged residential care may be unprepared for their role in palliative care provision. In collaboration with a local hospice, the project piloted an innovative problem-based experiential learning intervention Supportive Hospice and Aged Residential Exchange (SHARE) to enhance aged residential care staff palliative care skills. The aim was to explore the impact of SHARE for staff. SHARE was implemented in two aged residential care facilities in one urban centre for six months. Measurement of the impact of the intervention consisted of 1) pre-test-post-test questionnaires (n = 27) to assess changes in staff confidence in palliative care delivery 2) Eleven post intervention interviews to describe staff perceptions of SHARE. Results from the SHARE pilot indicate that the intervention overall is seen as a success, especially in relation to advanced care planning documentation. Relationships between hospice and facility staff, and consequently facility staff and residents are seen as the key to the success of the project. Staff survey results indicated increased confidence in palliative care delivery and decreased depression. Key lessons learnt from for the development of any palliative care intervention within aged residential care include the importance of reciprocal learning, as well as the necessity of a strong partnership with key stakeholders. PMID- 28554069 TI - Where does prepotency come from on developmental tests of inhibitory control? AB - Understanding the processes that make responses prepotent is central to understanding the role of inhibitory control in cognitive development. The question of what makes responses prepotent was investigated using the two most widely studied measures of preschoolers' inhibitory control. Across two experiments, 80 children were tested either on a series of stimulus-response compatibility (SRC) tasks or on a series of Go/No-go tasks. Results indicated that high levels of prepotency on SRC tasks (such as the Day/Night task) occur only under specific conditions; making a verbal response can be highly prepotent if the stimulus and response are associated with each other (e.g., saying "cup" to a cup) but is less prepotent when they are unassociated (e.g., saying "cup" to a doorstop). Action responses (e.g., lifting a cup to your mouth) show little prepotency irrespective of whether the stimulus and response are associated. In contrast, with Go/No-go tasks, a much wider variety of behaviors are highly prepotent regardless of whether the stimulus and response are associated. These data suggest that prepotency arises in very different ways, depending on the type of task used. Although both Go/No-go tasks and SRC tasks can make inhibitory demands, they do so for fundamentally different reasons. PMID- 28554070 TI - Honored papers 2016. PMID- 28554071 TI - Comparative study of an osazone based ligand and its palladium(II) complex with human serum albumin: A spectroscopic, thermodynamic and molecular docking approach. AB - An osazone based ligand, hexane-3,4-dione-bis(2'-phenylhydrazone) (LH2), was synthesized by 1:2M Schiff base condensation of 3,4-hexanedione and phenylhydrazine in dehydrated methanol. Its palladium(II) complex (1) has also been synthesized. LH2 and 1 have thoroughly been characterized by several spectroscopic and analytical means. DFT optimized structure of 1 shows that it is a monomeric Pd(II) complex having 'N2Cl2' coordination chromophore. Our BVS analysis also satisfactorily reproduces the oxidation number of the palladium center. 1 shows irreversible Pd(II)/Pd(I) reduction in its CV in methanol. 1 is three-fold more emissive than LH2. This enhanced emission has also been supported by time correlated single photon counting (TCSPC) measurements at room temperature. Human serum albumin (HSA) binding aspects of both LH2 and 1 have been investigated through various biophysical techniques. The binding constants as determined from Benesi-Hilderbrand plot using the absorbance spectral analyses were found respectively to be 1.18*105 and 4.38*104M-1 for LH2 and 1. The experimental findings confirm that both are good HSA binders. The thermodynamic parameters (?G degrees , ?H degrees and ?S degrees ) have also been evaluated by isothermal titration calorimetric (ITC) experiments. These parameters indicate that the binding processes are spontaneous both for LH2 and 1. Molecular docking analyses reveal that both LH2 and 1 reside in domain-I of HSA. PMID- 28554072 TI - Polymer-lipid-PEG hybrid nanoparticles as photosensitizer carrier for photodynamic therapy. AB - Polymer-lipid-PEG hybrid nanoparticles were investigated as carriers for the photosensitizer (PS), 5,10,15,20-Tetrakis(4-hydroxy-phenyl)-21H,23H-porphine (pTHPP) for use in photodynamic therapy (PDT). A self-assembled nanoprecipitation technique was used for preparing two types of core polymers poly(d,l-lactide-co glycolide) (PLGA) and poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) with lipid PEG as stabilizer. The resulting nanoparticles had an average particle size of 88.5+/-3.4nm for PLGA and 215.0+/-6.3nm for PHBV. Both nanoparticles exhibited a core-shell structure under TEM with high zeta potential and loading efficiency. X ray powder diffraction analysis showed that the encapsulated pTHPP molecules in polymeric nanoparticles no longer had peaks of free pTHPP in the crystalline state. The pTHPP molecules encapsulated inside the polymeric core demonstrated improved photophysical properties in terms of singlet oxygen generation and cellular uptake rate in a FTC-133 human thyroid carcinoma cell line, compared to non-encapsulated pTHPP. The pTHPP-loaded polymer-lipid-PEG nanoparticles showed better in vitro phototoxicity compared to free pTHPP, in both time- and concentration-dependent manners. Overall, this study provides detailed analysis of the photophysical properties of pTHPP molecules when entrapped within either PLGA or PHBV nanoparticle cores, and demonstrates the effectiveness of these systems for delivery of photosensitizers. The two polymeric systems may have different potential benefits, when used with cancer cells. For instance, the pTHPP-loaded PLGA system requires only a short time to show a PDT effect and may be suitable for topical PDT, while the delayed photo-induced cytotoxic effect of the pTHPP-loaded PHBV system may be more suitable for cancer solid tumors. Hence, both pTHPP-encapsulated polymer-lipid-PEG nanoparticles can be considered promising delivery systems for PDT cancer treatment. PMID- 28554073 TI - Facile synthesis of heterostructured cerium oxide/yttrium oxide nanocomposite in UV light induced photocatalytic degradation and catalytic reduction: Synergistic effect of antimicrobial studies. AB - Ceria (CeO2) is an exciting alternative noble metal catalyst, because it has ability to release and absorb oxygen in the redox system, and function as an oxygen buffer. In this study, heterostructured catalysts consisting of CeO2/Y2O3 nanocomposites were successfully synthesized by hydrothermal method in the presence of sodium hydroxide as a reducing agent from cerium nitrate and yttrium nitrate as a precursor which was then evaluated for its photocatalytic activity in the degradation of Rhodamine B (RhB) synthetic dye. Scanning electron microscopy (SEM) imparts the surface morphology and size of the prepared sample. Elemental compositions and the purity of the nanoparticles are proved by energy dispersive X-ray Spectroscopy (EDX). CeO2/Y2O3 nanoparticles were made up of CeO and YO bonds which are confirmed by Fourier transform infrared spectroscopy (FTIR). Synthesis temperature and pressure, during hydrothermal reactions, plays a critical role in controlling the shape, size, oxygen vacancy concentration, and low temperature reducibility in CeO2 based nanocomposites. The lattice constants and oxygen vacancy concentrations of ceria nanoparticles also depend upon the concentration of hydroxide ion which leads to better morphology at low temperature and pressure. Hydrogenation of p-nitrophenol to p-aminophenol with a reducing agent is conveniently carried out in aqueous medium by using this binary metal oxide catalyst. Further, the photocatalytic performance of the synthesized nanoparticles was monitored by photocatalytic degradation of Rhodamine B synthetic dye under UV light irradiation. To get maximum photocatalytic degradation (PCD) efficiency, we have used H2O2 for the generation of excess reactive oxygen species (ROS). In addition, the antibacterial activity of nanoparticles against bacteria was also examined. The observed antibacterial activity results are comparable with the results obtained using the standard antibiotic. PMID- 28554074 TI - Photochemistry and mechanism of designed pyrenyl probe towards promoted cleavage of proteins. AB - A new photochemical reagent, succinic acid-1(1-pyrene)methylamide (PMA-SUC), was developed to recognize the specific binding sites on model proteins, egg-white lysozyme and avidin. The interaction of the photochemical reagent with the proteins was studied by UV-Vis, fluorescence spectroscopic methods and docking description. PMA-SUC was found to bind to lysozyme and avidin with binding constants (Kb) of 2.4*105 and 6.7*105 (M-1), respectively. The fluorescence intensity of PMA-SUC decreased with increasing concentration of both proteins. Quenching of PMA-SUC fluorescence, in the absence and presence of the protein by an electron acceptor (Hexaamminecobalt(III) chloride, Co(NH3)6Cl3) showed no significant changes in the Ksv values (Stern-Volmer quenching constant), indicating that PMA-SUC bound to the hydrophilic sites or near the surface of the proteins. Irradiation of protein-PMA-SUC mixture, at 342nm for a period of time, in the presence of Co(NH3)6Cl3 as an electron acceptor, resulted in the cleavage of both proteins with high specificity. Binding mechanisms were studied using Molecular docking method. Molecular docking study indicated the position of PMA SUC upon binding to the proteins by hydrogen bonding interaction with donor acceptor within the distance of less than 5A in the minimum of binding free energy. The docking results have supported the results obtained from the spectroscopic methods and cleavage studies. PMID- 28554075 TI - Association of TP53 codon 72 and CDH1 genetic polymorphisms with colorectal cancer risk in Bangladeshi population. AB - Till now no pharmacogenetic study of TP53 codon 72 (Arg72Pro) and CDH1 rs16260 ( 160C=7days, need for mechanical ventilation, septic shock, transfer to intensive-care, or 30-day mortality). Secondary outcome was 30-day mortality. RESULTS: 153 patients were included, mean age: 62.5+/-1, 82 (54%) male; 84 (55%) had a high RDW value (>14.5%) during hospitalization. Patients with high and low RDW (<=14.5%) had similar age and comorbidity profiles, but those with high RDW had lower hemoglobin and higher creatinine levels. Patients with high RDW had a higher rate of complicated hospitalization (32.5% vs. 10.3%, p<0.01) and a trend for increased 30-day mortality. In a multivariate regression model, high RDW was a predictor of complicated hospitalization (OR 5.03, 95% CI 1.81-13.93, p<0.01). Each 1-point increase in RDW was associated with a 29% increase in the risk for the primary outcome. CONCLUSION: RDW>14.5% was a predictor of severe hospital complications in patients with influenza. PMID- 28554094 TI - Serum lactate dehydrogenase is predictive of persistent organ failure in acute pancreatitis. AB - PURPOSE: Elevated serum lactate dehydrogenase (LDH) has been reported in a serious of clinical diseases. However, the relationship between LDH and the incidence of persistent organ failure (POF) in acute pancreatitis (AP) has not been characterized. MATERIALS AND METHODS: A total of 105 patients with AP who presented within 72h from symptom onset between 2014 and 2015 were included in this retrospective study. Demographic parameters and laboratory data on admission were compared between patients with and without POF. Multivariable logistic regression analyses were utilized to evaluate the prognostic value of LDH for predicting POF. RESULTS: 21 patients were diagnosed with POF. Compared to non POF, patients with POF showed a significantly higher value of serum LDH on admission (741.57+/-331.72 vs. 296.08+/-135.73U/L, P<0.001). After multivariate logistic analysis, LDH remained an independent risk factor for POF (Hazard ratio 4.38, 95%CI: 1.42-13.47; P=0.010). A LDH value of 647U/L predicted POF with an area under the curve (AUC) of 0.876, a sensitivity with 76.2% and specificity with 98.8%, respectively. CONCLUSIONS: Our results indicate that serum LDH on admission is independently associated with POF in AP and may serve as a potential prognostic factor. PMID- 28554096 TI - Phthalates and thyroid function in preschool age children: Sex specific associations. AB - BACKGROUND: Research relating either prenatal or concurrent measures of phthalate exposure to thyroid function in preschool children is inconclusive. METHODS: In a study of inner-city mothers and their children, metabolites of di-n-butyl phthalate, butylbenzyl phthalate, di-isobutyl phthalate, di(2-ethylhexyl) phthalate, and diethyl phthalate were measured in a spot urine sample collected from women in late pregnancy and from their children at age 3years. We measured children's serum free thyroxine (FT4) and thyroid stimulating hormone (TSH) at age 3. Linear regression models were used to investigate the associations between phthalate metabolites, measured in maternal urine during late pregnancy and measured in child urine at age 3 and thyroid function measured at age 3. RESULTS: Mean concentrations (ranges) were 1.42ng/dL (1.02-2.24) for FT4, and 2.62uIU/mL (0.61-11.67) for TSH. In the children at age 3, among girls, FT4 decreased with increasing loge mono-n-butyl phthalate [estimated b=-0.06; 95% CI: (-0.09, 0.02)], loge mono-isobutyl phthalate [b=-0.05; 95% CI: (-0.09, -0.01)], loge monoethyl phthalate [b=-0.04; 95% CI: (-0.07, -0.01)], and loge mono(2-ethyl-5 hydroxyhexyl) phthalate [b=-0.04; 95% CI: (-0.07, -0.003)] and loge mono(2-ethyl 5-oxy-hexyl) phthalate [b=-0.04; 95% CI: (-0.07, -0.004)]. In contrast, among boys, we observed no associations between FT4 and child phthalate metabolites at age 3. On the other hand, in late gestation, FT4 increased with increasing loge mono-(2-ethylhexyl) phthalate [estimated b=0.04; 95% CI: (0.02, 0.06)] and no sex difference was observed. We found no associations between phthalate biomarkers measured in either the child or prenatal samples and TSH at age 3. CONCLUSIONS: The data show inverse and sex specific associations between specific phthalate metabolites measured in children at age 3 and thyroid function in preschool children. These results may provide evidence for the hypothesis that reductions in thyroid hormones mediate associations between early life phthalate exposure and child cognitive outcomes. PMID- 28554098 TI - The ward as emotional ecology: Adolescent experiences of managing mental health and distress in psychiatric inpatient settings. AB - Previous research on young people's satisfaction of inpatient services has often relied on the responses of carers and relevant practitioners. It is difficult to ascertain to what extent such reporting accurately represents the satisfaction levels of young people, with emerging research suggesting wide discrepancies. As part of a wider study evaluating the effectiveness of a Supported Discharge Service (SDS) operating within South London & Maudsley NHS Foundation Trust, this paper examines how young people experience inpatient services, on a social and emotional level. Twenty young people, (10 SDS and 10 TAU) participated in a semi structured visual-interview study to examine their experiences of admission, ward life and treatment. A thematic decomposition analysis was conducted on the data and specific themes relevant to satisfaction and engagement with inpatient services was examined in-depth. These include a) Behavioural surveillance as care surrogate and b) Managing the delicate emotional ecology of the ward: openness, triggering, sterility and relational engagements. Finally, we explore some of the implications of these inpatient experiences for supported discharge services. PMID- 28554097 TI - The effect of high temperature on cause-specific mortality: A multi-county analysis in China. AB - Although existing studies have linked high temperature to mortality in a small number of regions, less evidence is available on the variation in the associations between high temperature exposure and cause-specific mortality of multiple regions in China. Our study focused on the use of time series analysis to quantify the association between high temperature and different cause-specific mortalities for susceptible populations for 43 counties in China. Two-stage analyses adopting a distributed lag non-linear model (DLNM) and a meta-analysis allowed us to obtain county-specific estimates and national-scale pooled estimates of the nonlinear temperature-mortality relationship. We also considered different populations stratified by age and sex, causes of death, absolute and relative temperature patterns, and potential confounding from air pollutants. All of the observed cause-specific mortalities are significantly associated with higher temperature. The estimated effects of high temperature on mortality varied by spatial distribution and temperature patterns. Compared with the 90th percentile temperature, the overall relative risk (RR) at the 99th percentile temperature for non-accidental mortality is 1.105 (95%CI: 1.089, 1.122), for circulatory disease is 1.107 (95%CI: 1.081, 1.133), for respiratory disease is 1.095 (95%CI: 1.050, 1.142), for coronary heart disease is 1.073 (95%CI: 1.047, 1.099), for acute myocardial infarction is 1.072 (95%CI: 1.042, 1.104), and for stroke is 1.095 (95%CI: 1.052, 1.138). Based on our findings, we believe that heat-related health effect in China is a significant issue that requires more attention and allocation of existing resources. PMID- 28554099 TI - Evaluation of ADMA, carbonyl groups, CAT and NKA in depressed patients with and without posttraumatic stress disorder. AB - BACKGROUND: It has been shown that asymmetric dimethylarginine (ADMA), carbonyl groups, catalase (CAT) and neurokinin A (NKA) are actively involved in neuronal processes such as depression and posttraumatic stress disorder (PTSD). One of their roles is to protect the body from oxidative damage. This is done by affecting neuronal growth, development and plasticity. The study aimed at assessing the concentrations of ADMA, carbonyl groups, CAT and NKA in patients with varying levels of depression severity, PTSD, and depression concurrent with PTSD. METHODS: The study covered 460 people. Out of them, 120 suffered from different types of depression. The study groups comprised: 60 subjects with mild depression (MD), 60 subjects with moderate depression (MOD), 60 subjects with severe depression (SeD), 60 subjects with MD and PTSD (MD+PTSD), 60 subjects with MOD and PTSD (MOD+PTSD), 60 subjects with SeD and PTSD (SeD+PTSD), and 60 subjects with PTSD alone. Each group of 60 participants included 30 males and 30 females. The concentrations of all blood parameters were determined at 7 a.m. using the ELISA method. RESULTS: Depressive episodes became more severe as the concentration levels of studied markers increased. CONCLUSIONS: ADMA, carbonyl groups, CAT and NKA can be useful markers of chronic stress in both males and females with depression, PTSD, and depression concurrent with PTSD. They can be utilized when making an initial diagnosis and evaluating the severity of disease. Changes in their concentration levels may show a biological response to oxidative stress characteristic of depression. PMID- 28554100 TI - Fast pyrolysis kinetics of alkali lignin: Evaluation of apparent rate parameters and product time evolution. AB - In this study, the apparent kinetics of fast pyrolysis of alkali lignin was evaluated by obtaining isothermal mass loss data in the timescale of 2-30s at 400 700 degrees C in an analytical pyrolyzer. The data were analyzed using different reaction models to determine the rate constants and apparent rate parameters. First order and one dimensional diffusion models resulted in good fits with experimental data with apparent activation energy of 23kJmol-1. Kinetic compensation effect was established using a large number of kinetic parameters reported in the literature for pyrolysis of different lignins. The time evolution of the major functional groups in the pyrolysate was analyzed using in situ Fourier transform infrared spectroscopy. Maximum production of the volatiles occurred around 10-12s. A clear transformation of guaiacols to phenol, catechol and their derivatives, and aromatic hydrocarbons was observed with increasing temperature. The plausible reaction steps involved in various transformations are discussed. PMID- 28554101 TI - Mono- and co-substrate utilization kinetics using mono- and co-culture of Clostridium beijerinckii and Clostridium saccharoperbutylacetonicum. AB - The effect of co-culturing C. beijerinckii and C. saccharoperbutylacetonicum for H2 production using mono- and co-substrates of glucose, starch, and cellulose was assessed. Monod kinetic parameters (K, maximum specific substrate utilization rate; and Ks, half-saturation constant) of the C. beijerinckii, C. saccharoperbutylacetonicum, and the co-culture were determined. Co-cultures utilizing glucose competed for the substrate, but showed enhancement for utilizing starch. The maximum values for K on glucose and starch were 0.48g substrate/gVSS.h achieved by C. saccharoperbutylacetonicum mono-culture and 0.39g substrate/gVSS.h achieved by the co-culture, respectively. The average Ks for all mono- and co-culture experiments was 0.93+/-0.03g/L. Acetate, butyrate, and propionate were the main fermentation products for all experiments. Maximum H2 production yields on glucose (2.69mol/molglucose) and starch (1.07mol/molhexose) were achieved by C. beijerinckii and C. saccharoperbutylacetonicum mono-cultures, respectively; however, neither culture was able to degrade cellulose as a mono substrate. PMID- 28554102 TI - Effects of trace metal deficiency and supplementation on a submerged anaerobic membrane bioreactor. AB - This study examined the effects of a deficiency in trace metals (TMs) on the performance of a submerged anaerobic membrane bioreactor (SAMBR). When trace metals were excluded from the feed to the SAMBR, COD removal and methane yield reduced while VFAs in the effluent increased. A reduction of up to 37.48% in the total metal content in the reactor was observed, while the less bioavailable fractions increased up to 13.29%. Pulse addition of trace metals for 7 days at 5 times the daily metal loading was effective in improving the performance of the SAMBR by increasing the amount of trace metals in the bioavailable fractions from 2.12% to 11.92%, with up to 87.7% of added metals retained in the reactor within 24h. However, the second and third pulse at 5 and 10-times daily metal loading did not result in similar changes in metal speciation and might have inhibited the methanogens. PMID- 28554103 TI - Bioelectrochemical enhancement of direct interspecies electron transfer in upflow anaerobic reactor with effluent recirculation for acidic distillery wastewater. AB - Methane production in the upflow anaerobic bioelectrochemical reactor (UABE) treating acidic distillery wastewater was compared to the upflow anaerobic sludge blanket reactor (UASB), and the electron transfer pathways for methane production were also evaluated in the effluent recirculation. The methane productions from reactors were influenced by the low pH of influent wastewater. However, the methane production rate and yield of the UABE were 2.08L/L.d and 320mL/g CODr, which were higher than the UASB. The effluent recirculation containing alkalinity neutralized the acidic influent and increased the upflow velocity in both reactors, and improved the direct interspecies electron transfer more in the UABE. When the effluent recirculation ratio was 3.0 in the UABE, the methane production rate and yield were reached up to 3.88L/L.d and 501.0mL/g CODr, respectively. The UABE requires electrode installation and electrical energy for operation, but the benefits from increased methane production are much higher. PMID- 28554104 TI - Capitellar fracture with bony avulsion of the lateral collateral ligament in a child: Case report. AB - INTRODUCTION: Isolated capitellar fracture is a rare injury accounting for 1% of all elbow fractures Bryan and Morrey (1985) and Poynton et al. (1998). In children, a fall on an outstretched hand, before the fusion of the epiphysis, usually leads to lateral condyle physeal fractures. Very few cases of capitellar fractures in the paediatric population have been reported. PRESENTATION OF CASE: Our patient, a 9-year-old girl presented with a capitellar fracture and lateral collateral ligament (LCL) avulsion of her left elbow. A type IV capitellar fracture, indicated by the double arc sign on the radiogram, was confirmed with 3 dimensional computed tomography. The patient underwent open reduction through a lateral approach and fixation with 2 Herbert's screws. The lateral collateral ligament (LCL) avulsion was repaired with 2 suture anchors. Early mobilization and rehabilitation were started soon after the surgery. Follow-up radiography showed union of the fracture with no signs of osteonecrosis. DISCUSSION: Capitellum fracture in children is easily overlooked due to its rarity. And hereby, meticulous history, clinical examination and proper radiological views with high index of suspicion is crucial in order diagnose these injuries. Our patient had type IV capitellar fracture with lateral collateral ligament avulsion. Principles of management of these intra articular fractures include accurate reduction, stable fixation and early mobilization. We used an extensile lateral approach to expose, reduce and fix the fracture. LCL avulsion was fixed with 2 suture anchors. CONCLUSION: Capitellum fractures are rare injuries in children. Careful evaluation and proper stable fixation are the cornerstones of good functional results. PMID- 28554105 TI - Comment on: "A case report of a complete degloving injury of the penile skin". AB - INTRODUCTION: We recently published an article in the International Journal of Surgical Case Reports titled: "Scrotal dartos-fascio-myo-cutaneous flap for penis elongation after catastrophic iatrogenic skin shaft sub-amputation: A case of recovery using an extremely adaptable flap". PRESENTATION OF CASE: We propose a comment on a recent article titled "A case report of a complete degloving injury of the penile skin" by Helena Aineskog and Frederik Huss that we read with great interest. DISCUSSION: Genitalia are linked to self-esteem and male sexual identity, especially among young men, who sometimes require a surgical procedure to acquire more confidence. Various techniques are available for pe-nile skin covering, such as skin grafts or cutaneous flaps. The skin of the scrotum seems to be the most suitable tissue to be used to reconstruct the skin covering of the shaft as it is the most similar. CONCLUSION: Scrotal flap is a single stage procedure that is easy and safe to perform. PMID- 28554106 TI - Chest wall reconstruction following axillary breast augmentation and desmoid tumor resection using capsular flaps and a form-stable silicone implant: A case report, diagnosis and surgical technique. AB - INTRODUCTION: Chest desmoid tumors (CDT) are rare lesions characterized by fibroblastic proliferation from the connective tissue. Although CDT have been studied previously, no cases following subfascial transaxillary breast augmentation (TBA) have been described. PRESENTATION OF CASE: The authors describe a case of CDT in a 28-year-old woman one year after TBA, which presented as a painful and progressive mass in the lower-inner right breast quadrant. MRI showed a soft-tissue tumor (6*3*4cm) that affected the region of the right anterior costal margin, without signs of structural costal invasion. Patient was treated surgically, exposing the right costal-sternal region through an inframammary approach and resecting the CDT. The remaining capsular flap was mobilized into the defect and a form-stable silicone implant was utilized to cover the chest wall defect and achieve an adequate breast contour. The patient is currently in 5th year after chest reconstruction, with satisfactory results. Neither the tumor or the symptoms recurred. DISCUSSION: CDT is an uncommon evolution following TBA. Although it is a rare disease, thoracic and plastic surgeons must be alert to avoid misdiagnosis. Defect reconstruction is necessary, mobilizing the capsular flaps and replacing the implants in order to obtain a satisfactory outcome. CONCLUSION: Knowledge of this rare post-operative evolution is crucial, and early surgical intervention is warranted in order to avoid more aggressive treatment. This case report provides general knowledge of CDT, and may be used as guidance for early diagnosis and treatment. PMID- 28554107 TI - Manual laparoscopy-assisted intraoperative reduction for adult ileocolic intussusception with ileal adenoma: A case report. AB - INTRODUCTION: Adult intussusception is a rare condition with a pathological lead point. Intraoperative reduction of adult intussusception can eliminate the need for extensive or invasive resection. We safely performed a manual laparoscopy assisted intraoperative reduction that allowed functional preservation of tissue. PRESENTATION OF CASE: A 70-year-old woman with dull right lumbar pain at regular intervals and right lower quadrant abdominal tenderness was admitted to our hospital. The ileum exhibited enhanced wall thickening and invagination into the ascending colon on computed tomography. Emergency laparoscopic surgery was chosen to treat the ileocolic intussusception. First, the right colon was mobilized. Second, the ileocecal region was pulled through a 4-cm right pararectus incision. Third, the edge of the intussusceptum was gently manipulated back upstream without tearing. After reduction, a soft mass was recognized on palpation at the lead point, located 10cm proximal to the ileocecal valve. Ileocecal resection was performed, and a laterally spreading tumor was observed in the resected specimen. The histological diagnosis was high-grade tubular adenoma. The postoperative course was uneventful. DISCUSSION: Adult intussusception has a pathological lead point, and curative treatment generally includes resection of the lesion. Complete or partial intraoperative reduction can avoid or shorten bowel resection and allow functional preservation of the tissue. CONCLUSION: Manual laparoscopy assisted intraoperative reduction with a minilaparotomy was safely performed, which eliminated the need for extensive or invasive resection. PMID- 28554108 TI - Indirect comparison between pembrolizumab and nivolumab for the treatment of non small cell lung cancer: A meta-analysis of randomized clinical trials. AB - OBJECTIVE: The purpose of this study is to evaluate the efficacy and adverse effects of nivolumab and pembrolizumab for the treatment of advanced non-small cell lung cancer (NSCLC) by meta-analysis. MATERIALS AND METHODS: This meta analysis of randomized controlled trials (RCTs) was performed after searching PubMed, EMBASE, and American Society of Clinical Oncology meeting abstracts, clinicaltrial gov, and Cochrane library databases. Two reviewers independently assessed the quality of the trials. Outcomes analysis was overall response rates (ORR), overall survival (OS), progression- free survival (PFS) and major adverse effects with odds ratio (OR) or hazard ratio (HR) and 95% confidence intervals (CI). RESULTS: Results reported from three RCTs involving 1,887 patients are included in this analysis. Indirect comparison between pembrolizumab and nivolumab in advanced NSCLC shows no statistically significant difference in ORR (OR: 1.14, 95% CI, 0.60-2.01), OS (HR: 0.98, 95% CI, 0.35-2.74) and PFS (HR: 1.12, 95% CI, 0.70-1.77). The incidence of grades>=3 adverse effects is higher with pembrolizumab as compared with nivolumab (OR: 3.44, 95% CI, 1.87-6.32). There are no significant statistical differences between severe adverse effects, such as pneumonitis and hypothyroidism, of the two drugs. CONCLUSIONS: This study has demonstrated that pembrolizumab and nivolumab have similar survival outcomes in patients with advanced NSCLC, but pembrolizumab has a higher incidence of grades>=3 adverse effects than nivolumab. PMID- 28554109 TI - Glucocorticoid receptor number and affinity differ between peripheral blood mononuclear cells and granulocytes in domestic pigs. AB - The aim of the present study was to characterize the number and affinity of glucocorticoid receptors (GR) in peripheral blood mononuclear cells (PBMC) and granulocytes of domestic pigs because glucocorticoid signaling is considered important for animal health and welfare. To investigate GR binding characteristics in intact porcine immune cells, blood samples of 6 castrated male pigs were collected via indwelling vein catheters. Porcine PBMC and granulocytes were isolated using two-layer density gradients, followed by radioligand binding assays to determine the number of GR sites per cell and the dissociation constant Kd as a measure for GR binding affinity. The present study revealed a greater number of GR sites per cell (P = 0.039) in PBMC (mean +/- SEM: 1,953 +/- 207 sites/cell) compared to granulocytes (1,561 +/- 159 sites/cell) in domestic pigs. Furthermore, porcine PBMC had a higher GR binding affinity than porcine granulocytes (P = 0.003) as the dissociation constant Kd of PBMC (1.8 +/- 0.2 nM) was lower than that of granulocytes (3.5 +/- 0.4 nM). Our results point to differences in underlying mechanisms of glucocorticoid signaling in different porcine leukocyte populations. PMID- 28554110 TI - Evaluation of the detoxification efficiencies of coking wastewater treated by combined anaerobic-anoxic-oxic (A2O) and advanced oxidation process. AB - Coking wastewater contains many types of toxic and hazardous pollutants that have serious toxic effects on human beings as well as aquatic organisms. However, few studies have evaluated the detoxification efficiencies of the treatment processes that are extensively performed in operational coking wastewater treatment plants (WWTPs). This study investigates the detoxification efficiencies of a combined anaerobic-anoxic-oxic (A2O)-ozonation and A2O-Fenton oxidation process in two coking WWTPs using an acute immobilization test for Daphnia magna, acute toxicity test for adult zebrafish, embryo toxicity test for zebrafish and the comet assay. The raw coking wastewaters displayed high acute daphnia and fish toxicity, zebrafish embryo toxicity and genotoxicity. The A2O processing unit effectively removed acute and embryo toxicity, but not genotoxicity. In addition, the A2O effluent quality did not meet the integrated wastewater discharge standard in China (GB18918-2002). The ozonation and Fenton oxidation units used as post treatments in these two plants not only treated the coking wastewater to the discharge standard but also reduced the genotoxicity. However, the final effluents still showed potential genotoxicity after high dilution. The results suggest that the discharge of treated coking wastewater probably poses potential risks to human health and the environment even if it met regulatory standards. PMID- 28554111 TI - Retrieval of Au, Ag, Cu precious metals coupled with electric energy production via an unconventional coupled redox fuel cell reactor. AB - The recovery of heavy metals from aqueous solutions or e-wastes is of upmost importance. Retrieval of Au, Ag, and Cu with electricity generation through building an ethanol-metal coupled redox fuel cells (CRFCs) is demonstrated. The cell was uniquely assembled on PdNi/C anode the electro-oxidation of ethanol takes place to give electrons and then go through the external circuit reducing metal ions to metallic on the cathode, metals are recovered. Taking an example of removal of 100mgL-1 gold in 0.5M HAc-NaAc buffer solution as the catholyte, 2.0M ethanol in 1.0M alkaline solution as the anolyte, an open circuit voltage of 1.4V, more than 96% of gold removal efficiency in 20h, and equivalent energy production of 2.0kWhkg-1 of gold can be readily achieved in this system. When gold and copper ions coexist, it was confirmed that metallic Cu is formed on the cathodic electrode later than metallic Au formation by XPS analysis. Thus, this system can achieve step by step electrodeposition of gold and copper while the two metal ions coexisting. This work develops a new approach to retrieve valuable metals from aqueous solution or e-wastes. PMID- 28554112 TI - Wastewater-based epidemiology to assess pan-European pesticide exposure. AB - Human biomonitoring, i.e. the determination of chemicals and/or their metabolites in human specimens, is the most common and potent tool for assessing human exposure to pesticides, but it suffers from limitations such as high costs and biases in sampling. Wastewater-based epidemiology (WBE) is an innovative approach based on the chemical analysis of specific human metabolic excretion products (biomarkers) in wastewater, and provides objective and real-time information on xenobiotics directly or indirectly ingested by a population. This study applied the WBE approach for the first time to evaluate human exposure to pesticides in eight cities across Europe. 24 h-composite wastewater samples were collected from the main wastewater treatment plants and analyzed for urinary metabolites of three classes of pesticides, namely triazines, organophosphates and pyrethroids, by liquid chromatography-tandem mass spectrometry. The mass loads (mg/day/1000 inhabitants) were highest for organophosphates and lowest for triazines. Different patterns were observed among the cities and for the various classes of pesticides. Population weighted loads of specific biomarkers indicated higher exposure in Castellon, Milan, Copenhagen and Bristol for pyrethroids, and in Castellon, Bristol and Zurich for organophosphates. The lowest mass loads (mg/day/1000 inhabitants) were found in Utrecht and Oslo. These results were in agreement with several national statistics related to pesticides exposure such as pesticides sales. The daily intake of pyrethroids was estimated in each city and it was found to exceed the acceptable daily intake (ADI) only in one city (Castellon, Spain). This was the first large-scale application of WBE to monitor population exposure to pesticides. The results indicated that WBE can give new information about the "average exposure" of the population to pesticides, and is a useful complementary biomonitoring tool to study population-wide exposure to pesticides. PMID- 28554113 TI - No significant interactions between nitrogen stimulation and ozone inhibition of isoprene emission in Cathay poplar. AB - Isoprene emission from plants subject to a combination of ozone (O3) and nitrogen (N) has never been investigated. Cathay poplar (Populus cathayana) saplings were exposed to O3 (CF, charcoal-filtered air, NF, non-filtered ambient air and E-O3, non-filtered air +40ppb) and N treatments (N0, 0kgNha-1year-1, N50, 50kgNha-1year 1 and N100, 100kgNha-1year-1) for 96days. Increasing O3 exposure decreased isoprene emission (11.5% in NF and 57.9% in E-O3), as well as light-saturated photosynthetic rate (Asat) and chlorophyll content, while N load increased isoprene emission (19.6% in N50 and 33.4% in N100) as well as Asat and chlorophyll content. Although O3 and N interacted significantly in Asat, N did not mitigate the negative effects of O3 on isoprene emission, i.e. the combined effects were additive and did not interact. These results warrant more research on the combined effects of co-existing global change factors on future isoprene emission and atmospheric chemical processes. PMID- 28554114 TI - Quantifying the contribution of dyes to the mutagenicity of waters under the influence of textile activities. AB - The combination of chemical analyses and bioassays allows the identification of potentially mutagenic compounds in different types of samples. Dyes can be considered as emergent contaminants and were detected in waters, under the influence of textile activities. The objective of this study was to evaluate the contribution of 9 azo dyes to the mutagenicity of representative environmental samples. Samples were collected along one year in the largest conglomerate of textile industries of Brazil. We analyzed water samples from an important water body, Piracicaba River, upstream and downstream two main discharges, the effluent of a wastewater treatment plant (WWTP) and the tributary Quilombo River, which receives untreated effluent from local industries. Samples were analyzed using a LC-MS/MS and tested for mutagenicity in the Salmonella/microsome microsuspension assay with TA98 and YG1041. Six dyes were detected in the collected samples, Disperse Blue 291, Disperse Blue 373, Disperse Orange 30, Disperse Red 1, Disperse Violet 93, and Disperse Yellow 3. The most sensitive condition for the detection of the mutagenicity was the strain YG1041 with S9. The concentration of dyes and mutagenicity levels varied along time and the dry season represented the worst condition. Disperse Blue 373 and Disperse Violet 93 were the major contributors to the mutagenicity. We conclude that dyes are contributing for the mutagenicity of Piracicaba River water; and both discharges, WWTP effluent and Quilombo River, increase the mutagenicity of Piracicaba River waters in about 10 fold. The combination of chemical analysis and bioassays were key in the identification the main drivers of the water mutagenicity and allows the selection of priority compounds to be included in monitoring programs as well for the enforcing actions required to protect the water quality for multiple uses. PMID- 28554115 TI - Blubber-depth distribution and bioaccumulation of PCBs and organochlorine pesticides in Arctic-invading killer whales. AB - Sightings of killer whales (Orcinus orca) in Greenland have increased in recent years, coincident with sea ice loss. These killer whales are likely from fish feeding North Atlantic populations, but may have access to marine mammal prey in Greenlandic waters, which could lead to increased exposures to biomagnifying contaminants. Most studies on polychlorinated biphenyl (PCB) and organochlorine (OC) contaminants in killer whales have used biopsies which may not be representative of contaminant concentrations through the entire blubber depth. Here, we measured PCB and OC concentrations in 10 equal-length blubber sections of 18 killer whales harvested in southeast Greenland (2012-2014), and 3 stranded in the Faroe Islands (2008) and Denmark (2005). Overall, very high concentrations of SigmaPCB, Sigmachlordanes (SigmaCHL), and Sigmadichlorodiphenyltrichloroethane (SigmaDDT) were found in the southeast Greenland and Denmark individuals (means of ~40 to 70mgkg-1 lipid weight). These concentrations were higher than in the Faroe Island individuals (means of ~2 to 5mgkg-1 lipid weight) and above those previously reported for other fish-feeding killer whales in the North Atlantic, likely in part due to additional feeding on marine mammals. On a wet weight basis, concentrations of all contaminants were significantly lower in the outermost blubber layer (0.15-0.65cm) compared to all other layers (p<0.01), except for Sigmahexachlorocyclohexanes. However, after lipid correction, no variation was found for SigmaCHL and Sigmachlorobenzene concentrations, while the outermost layer(s) still showed significantly lower SigmaPCB, SigmaDDT, Sigmamirex, Sigmaendosulfan, and dieldrin concentrations than one or more of the inner layers. Yet, the magnitude of these differences was low (up to 2-fold) suggesting that a typical biopsy may be a reasonable representation of the PCB and OC concentrations reported in killer whales, at least on a lipid weight basis. PMID- 28554116 TI - Riparian vegetation in the alpine connectome: Terrestrial-aquatic and terrestrial terrestrial interactions. AB - Alpine regions are under increased attention worldwide for their critical role in early biogeochemical cycles, their high sensitivity to environmental change, and as repositories of natural resources of high quality. Their riparian ecosystems, at the interface between aquatic and terrestrial environments, play important geochemical functions in the watershed and are biodiversity hotspots, despite a harsh climate and topographic setting. With climate change rapidly affecting the alpine biome, we still lack a comprehensive understanding of the extent of interactions between riparian surface, lake and catchment environments. A total of 189 glacial - origin lakes were surveyed in the Central Pyrenees to test how key elements of the lake and terrestrial environments interact at different scales to shape riparian plant composition. Secondly, we evaluated how underlying ecotope features drive the formation of natural communities potentially sensitive to environmental change and assessed their habitat distribution. At the macroscale, vegetation composition responded to pan-climatic gradients altitude and latitude, which captured in a narrow geographic area the transition between large European climatic zones. Hydrodynamics was the main catchment-scale factor connecting riparian vegetation with major water fluxes, followed by topography and geomorphology. Lake sediment Mg and Pb, and water Mn and Fe contents reflected local influences from mafic bedrock and soil water saturation. Community analysis identified four keystone ecosystems: (i) damp ecotone, (ii) snow bed-silicate bedrock, (iii) wet heath, and (iv) calcareous substrate. These communities and their connections with ecotope elements could be at risk from a number of environmental change factors including warmer seasons, snow line and lowland species advancement, increased nutrient/metal input and water level fluctuations. The results imply important natural terrestrial-aquatic linkages in the riparian environment at a wide range of scales, which could help better address further biomic impacts of environmental change. PMID- 28554117 TI - A simplified method for determining potential heavy metal loads washed-off by stormwater runoff from road-deposited sediments. AB - A simplified method is proposed for determining the potential load of heavy metals (HMs) derived from the wash-off caused by surface runoff on road-deposited sediment (RDS). The method consists of three phases: (i) characterization of RDS load wash-off, (ii) assessment of HM load in dry weather, and (iii) application of a wash-off equation. Two processes were included in the wash-off equation: HM transport (solid fraction) and HM leaching (dissolved fraction). The average wash off of HMs ranges from 16.6 to 46.3%, relative to the total mass of HMs associated with dry-weather RDS (Pb, Zn, Cu, Cr, Ni, Cd, Fe, Mn, Co, and Ba). Cd, Mn, and Zn presented the highest wash-off in the areas studied. The size fraction below 250MUm contributed an average of 86.7% of potential HM load washed-off from RDS. Based on the phenomena included in the wash-off equation, it was observed the following order of precedence: transport of RDS<250MUm, leaching of RDS<250MUm, and leaching of RDS>=250MUm. Solid and dissolved fractions contributed 70.7 and 29.3% of the potential HM load washed-off by runoff from RDS, respectively. The proposed method serves as a management tool for road HM pollution during rain. PMID- 28554118 TI - Corrigendum to "Panic and comorbid depression and their associations with stress reactivity, interoceptive awareness and interoceptive accuracy of various bioparameters" [J. Affect. Disord. 185 (2015) 170-179]. PMID- 28554120 TI - Genome-wide predicting disease-related protein complexes by walking on the heterogeneous network based on data integration and laplacian normalization. AB - BACKGROUND: Associating protein complexes to human inherited diseases is critical for better understanding of biological processes and functional mechanisms of the disease. Many protein complexes have been identified and functionally annotated by computational and purification methods so far, however, the particular roles they were playing in causing disease have not yet been well determined. RESULTS: In this study, we present a novel method to identify associations between protein complexes and diseases. First, we construct a disease-protein heterogeneous network based on data integration and laplacian normalization. Second, we apply a random walk with restart on heterogeneous network (RWRH) algorithm on this network to quantify the strength of the association between proteins and the query disease. Third, we sum over the scores of member proteins to obtain a summary score for each candidate protein complex, and then rank all candidate protein complexes according to their scores. With a series of leave-one-out cross validation experiments, we found that our method not only possesses high performance but also demonstrates robustness regarding the parameters and the network structure. We test our approach with breast cancer and select top 20 highly ranked protein complexes, 17 of the selected protein complexes are evidenced to be connected with breast cancer. CONCLUSIONS: Our proposed method is effective in identifying disease-related protein complexes based on data integration and laplacian normalization. PMID- 28554119 TI - Effectiveness and safety of ledipasvir/sofosbuvir+/-ribavirin in the treatment of HCV infection: The real-world HARVEST study. AB - BACKGROUND: To evaluate the effectiveness and safety of ledipasvir/sofosbuvir (LDV/SOF)+/-ribavirin (RBV) regimen in a real-world setting. METHODS: Patients received a fixed-dose combination tablet containing LDV and SOF with or without RBV, for 8, 12 or 24 weeks. Patients were assessed at baseline, end of treatment, and 12 weeks after the end of treatment. The primary effectiveness endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). RESULTS: Of the 86 patients, aged 20-80 years, 82.6% were HCV genotype 1b infected and 50.0% were cirrhotic. More than half (52.3%) had previously followed pegylated interferon-containing (PEG-IFN) treatment regimens, and 38.5% were null responders. SVR12 was achieved by 94.2% of patients. All non-responders were cirrhotic: two demonstrated virologic breakthrough and the remaining three relapsed. All patients treated with an 8-week regimen achieved SVR12 despite having high viral load at baseline (HCV RNA of >1 million IU/mL in 8/10 patients, including one with a viral load of >6 million IU/mL). Adverse events were generally mild and transient. Most frequently, fatigue (22.1%), headache (15.1%), and arthralgia (7.0%) were observed. Laboratory abnormalities included anemia and hyperbilirubinemia. CONCLUSIONS: Treatment with LDV/SOF+/-RBV is an effective and safe option for patients with HCV, including those with advanced liver disease or a history of non-response to PEG-IFN-based therapy. PMID- 28554121 TI - Facial decoding in schizophrenia is underpinned by basic visual processing impairments. AB - Schizophrenia is associated with a strong deficit in the decoding of emotional facial expression (EFE). Nevertheless, it is still unclear whether this deficit is specific for emotions or due to a more general impairment for any type of facial processing. This study was designed to clarify this issue. Thirty patients suffering from schizophrenia and 30 matched healthy controls performed several tasks evaluating the recognition of both changeable (i.e. eyes orientation and emotions) and stable (i.e. gender, age) facial characteristics. Accuracy and reaction times were recorded. Schizophrenic patients presented a performance deficit (accuracy and reaction times) in the perception of both changeable and stable aspects of faces, without any specific deficit for emotional decoding. Our results demonstrate a generalized face recognition deficit in schizophrenic patients, probably caused by a perceptual deficit in basic visual processing. It seems that the deficit in the decoding of emotional facial expression (EFE) is not a specific deficit of emotion processing, but is at least partly related to a generalized perceptual deficit in lower-level perceptual processing, occurring before the stage of emotion processing, and underlying more complex cognitive dysfunctions. These findings should encourage future investigations to explore the neurophysiologic background of these generalized perceptual deficits, and stimulate a clinical approach focusing on more basic visual processing. PMID- 28554122 TI - Structural studies of the O-specific polysaccharide from detergent degrading bacteria Pseudomonas putida TSh-18. AB - An O-specific polysaccharide was obtained by mild acid degradation of the lipopolysaccharide of bacteria Pseudomonas putida TSh-18, capable of degrading non-ionogenic technical detergents. The polysaccharide was found to contain a rarely occurring sugar derivative 4,6-dideoxy-4-[(R)-3-hydroxybutanoylamino]-d galactose [d-Fucp4N(RHb)]. Sugar and methylation analyses, Smith degradation, solvolysis with CF3CO2H, and 1H and 13C NMR spectroscopy enabled elucidation of the following structure of the branched trisaccharide repeating units of the polysaccharide. PMID- 28554123 TI - Stereospecific synthesis of methyl 2-amino-2-deoxy-(6S)-deuterio-alpha,beta-d glucopyranoside and methyl 2,6-diamino-2,6-dideoxy-(6R)-deuterio-alpha,beta-d glucopyranoside: Side chain conformations of the 2-amino-2-deoxy and 2,6-diamino 2,6-dideoxyglucopyranosides. AB - The stereospecifically labeled 6-monodeuterio methyl 2,6-diamino-2,6-dideoxy alpha- and beta- d-glucopyranosides were synthesized with a view to determining their side chain conformations. NMR studies in D2O at pH 5 and pH 11 reveal both anomers to adopt very predominantly the gt conformation consistent with the gauche conformation of 2-aminoethanol and its acetate salt. In contrast, as also revealed with the help of stereospecifically-labelled monodeuterio isotopomers, the methyl 2-amino-2-deoxy-alpha- and beta- d-glucopyranosides are an approximately 1:1 mixture of gg and gt conformers as is found in glucopyranose itself. PMID- 28554124 TI - Synthesis of oligo-fructopyranoside with difructopyranosyl N phenyltrifluoroacetimidate donor. AB - The hexa-fructopyranoside was synthesized with N-phenyltrifluoroacetimidate glycosylation. The synthesis was achieved by regioselective glycosylation on the 1-OH of fructopyranosyl acceptor. Fructosyl oligosaccharides were elongated with beta-(2 -> 1)-difructopyranosyl unit in every two steps, without any further protection/deprotection step. This work proved N-phenyltrifluoroacetimidate glycosylation a practical method for oligo-fructopyranoside synthesis. PMID- 28554125 TI - The inclusion of biodiversity in environmental impact assessment: Policy-related progress limited by gaps and semantic confusion. AB - Natural habitat loss and fragmentation, as a result of development projects, are major causes of biodiversity erosion. Environmental impact assessment (EIA) is the most commonly used site-specific planning tool that takes into account the effects of development projects on biodiversity by integrating potential impacts into the mitigation hierarchy of avoidance, reduction, and offset measures. However, the extent to which EIA fully address the identification of impacts and conservation stakes associated with biodiversity loss has been criticized in recent work. In this paper we examine the extent to which biodiversity criteria have been integrated into 42 EIA from 2006 to 2016 for small development projects in the Montpellier Metropolitan territory in southern France. This study system allowed us to question how EIA integrates biodiversity impacts on a scale relevant to land-use planning. We examine how biodiversity inclusion has changed over time in relation to new policy for EIA and how the mitigation hierarchy is implemented in practice and in comparison with national guidelines. We demonstrate that the inclusion of biodiversity features into EIA has increased significantly in relation to policy change. Several weaknesses nevertheless persist, including the continued absence of substitution solution assessment, a correct analysis of cumulative impacts, the evaluation of impacts on common species, the inclusion of an ecological network scale, and the lack of monitoring and evaluation measures. We also show that measures for mitigation hierarchy are primarily associated with the reduction of impacts rather than their avoidance, and avoidance and offset measures are often misleadingly proposed in EIA. There is in fact marked semantic confusion between avoidance, reduction and offset measures that may impair stakeholders' understanding. All in all, reconsideration of stakeholders routine practices associated with a more strategic approach towards impact anticipation and avoidance at a land-use planning scale is now necessary for the mitigation hierarchy to become a clear and practical hierarchy for "no net loss" objectives based on conservation priorities. PMID- 28554126 TI - Clean up fly ash from coal burning plants by new isolated fungi Fusarium oxysporum and Penicillium glabrum. AB - In Turkey approximately 45 million tons of coals are burned in a year and 19.3 million tons of fly ash have emerged. The bioremediation of heavy metals or different elements from fly ash makes them bio-available. However, in previous studies, requiring of long operational time and failing to show tolerance to high pulp densities of fly ash of selected fungal species makes them impractical. In this work, bioremediation of fly ash by new isolated fungi Fusarium oxysporum and Penicillium glabrum were investigated in one step and two step bioremediation process. Ca, Si, Fe and S were found to be considerable amount in studied fly ashes by ED-XRF element analysis. The bioremediation yields of Mo (100%), S (64.36%) Ni (50%) and Cu (33.33%) by F. oxysporum were high. The remediated elements by P. glabrum in fly ash were Mo (100%), S (57.43%), Ni (25%), Si (24.66%), V (12.5%), Ti (5%) and Sr (3.2%). The isolation of high fly ash resistant fungi and reduction of the bioremediation time will allow the practical applications of the bioremediation technology when it is scaled up. PMID- 28554127 TI - Chemometrics and chromatographic fingerprints to classify plant food supplements according to the content of regulated plants. AB - Plant food supplements are gaining popularity, resulting in a broader spectrum of available products and an increased consumption. Next to the problem of adulteration of these products with synthetic drugs the presence of regulated or toxic plants is an important issue, especially when the products are purchased from irregular sources. This paper focusses on this problem by using specific chromatographic fingerprints for five targeted plants and chemometric classification techniques in order to extract the important information from the fingerprints and determine the presence of the targeted plants in plant food supplements in an objective way. Two approaches were followed: (1) a multiclass model, (2) 2-class model for each of the targeted plants separately. For both approaches good classification models were obtained, especially when using SIMCA and PLS-DA. For each model, misclassification rates for the external test set of maximum one sample could be obtained. The models were applied to five real samples resulting in the identification of the correct plants, confirmed by mass spectrometry. Therefore chromatographic fingerprinting combined with chemometric modelling can be considered interesting to make a more objective decision on whether a regulated plant is present in a plant food supplement or not, especially when no mass spectrometry equipment is available. The results suggest also that the use of a battery of 2-class models to screen for several plants is the approach to be preferred. PMID- 28554128 TI - Mechanistic insights into the effects of quercetin and/or GLP-1 analogue liraglutide on high-fat diet/streptozotocin-induced type 2 diabetes in rats. AB - BACKGROUND: The development of complementary treatment strategies that focuses on achieving a balance between adaptive and apoptotic unfolded protein response (UPR), enhancing endoplasmic reticulum (ER) homeostasis, and thus preserving beta cell mass and function is particularly warranted. AIM: This study was designed to investigate the effectiveness of the combined treatment by Quercetin (QUE) and Liraglutide (LIRA) in modulating hyperglycemia, insulin-insensitivity, UPR/ER stress markers, apoptosis, oxidative stress and inflammation using a high-fat diet/streptozotocin -induced type 2 diabetic rat model. METHODS: Sixty male albino rats were allocated into five equal groups: normal control, diabetic control, LIRA treated diabetic; QUE treated diabetic and combined treatment diabetic groups. Fasting glucose, insulin, CHOP, macrophage inflammatory protein 1 alpha (MIP-1alpha) and Bax, Bcl2 levels were estimated by ELISA; mRNA expression levels of the spliced X-box binding protein 1 (XBP1) were estimated using quantitative real-time RT-PCR, while MDA, advanced oxidation protein products, reduced glutathione levels and protein disulfide isomerase (PDI) activity were evaluated spectrophotometrically. Pancreatic tissues were also subjected to histopathological examination. RESULTS: The combined treatment with both LIRA and QUE causes significant improvements in all the studied parameters; including XBP1 splicing, CHOP, MIP-1alpha, Bax/Bcl2 ratio, PDI activity, as well as oxidative stress markers as compared to either treatment alone. It also attenuated pancreatic histopathological damage. IN CONCLUSION: Our study nominates this combination to be used in T2DM to achieve adequate glycaemic control and to preserve optimal beta cell function. PMID- 28554129 TI - Nimbolide suppresses non-small cell lung cancer cell invasion and migration via manipulation of DUSP4 expression and ERK1/2 signaling. AB - Nimbolide plays an important role in treating human diseases. In these years, the anticancer property of nimbolide has been paid more and more attention. However, the role of nimbolide in non-small cell lung cancer (NSCLC) remains unclear. In this study, we found that nimbolide treatment suppressed the invasion and migration of NSCLC cells, in a dose-dependent manner. Moreover, nimbolide treatment dose-dependently inhibited ERK1/2 activation, decreased Snail and MMP-3 expression, and increased E-cadherin expression. Further, we found that nimbolide treatment upregulated DUSP4 expression. DUSP4 knockdown attenuated nimbolide mediated inhibition of cell invasion, migration and ERK1/2 activation. We also found that DUSP4 knockdown suppressed the effect of nimbolide on MMP-3, Snail and E-cadherin expression. Taken together, our study demonstrates that nimbolide treatment can upregulate the expression of DUSP4, thus inhibiting ERK1/2 activation. Inhibition of ERK1/2 pathway by nimbolide decreases MMP-3 and Snail expression, and increases E-cadherin expression, which finally inhibits NSCLC cell invasion and migration. Therefore, nimbolide may act as a novel drug to inhibit NSCLC invasion and metastasis through manipulation of ERK1/2 signaling and DUSP4 expression. PMID- 28554130 TI - Betulinic acid derivative B10 inhibits glioma cell proliferation through suppression of SIRT1, acetylation of FOXO3a and upregulation of Bim/PUMA. AB - Glioma is the most common primary malignant tumor of the central nervous system. B10 is a new glycosylated derivative of betulinic acid with enhanced cytotoxic activity. The present study was designed to explore the molecular mechanism underlying the anticancer effect of B10 in glioma cells. 25-50MUM B10 resulted in a significant decrease of cell viability and BrdU incorporation. 25-50mg/kg B10 significantly reduced the implanted tumor weight and volume in nude mice. Activation of apoptosis was found in glioma cells when the cells were exposed to B10, as evidenced by increased number of TUNEL-stained cells, increased caspase 3 and 9 activities, and Bax and cleaved PARP expression. B10 caused a significant decrease in mitochondrial oxygen consumption rate, mitochondrial complex I, II, III, IV, and V activities, and ATP level, and increase of mitochondrial ROS production, indicating the induction of mitochondrial dysfunction. B10 reduced the expression of sirtuin (SIRT) 1 and resulted in an increase in forkhead box O (FOXO) 3a expression and acetylation. Activation of SIRT1 by SRT-1720 and downregualtion of FOXO3a using shRNA significantly inhibited B10-induced cytotoxicity. B10 markedly increased the expression of Bim and PUMA. Downregualtion of FOXO3a or activation of SIRT1 significantly inhibited B10 induced increase of Bim and PUMA expression. Downregualtion of Bim or PUMA could suppress B10-induced increase of Bax expression. Moreover, B10-induced cytotoxicity was significantly suppressed by downregulation of Bim or PUMA. In summary, we identified B10 as a potent therapeutic candidate for glioma treatment and SIRT1-FOXO3a-Bim/PUMA axis as a novel therapeutic target. PMID- 28554131 TI - Protective role of the novel hybrid 3,5-dipalmitoyl-nifedipine in a cardiomyoblast culture subjected to simulated ischemia/reperfusion. AB - This work investigated the acute effects of the calcium channel blocker nifedipine and its new fatty hybrid derived from palmitic acid, 3,5-dipalmitoyl nifedipine, compared to endocannabinoid anandamide during the process of inducing ischemia and reperfusion in cardiomyoblast H9c2 heart cells. The cardiomyoblasts were treated in 24 or 96-well plates (according to the test being performed) and maintaining the treatment until the end of hypoxia induction. The molecules were tested at concentrations of 10 and 100MUM, cells were treated 24h after assembling the experimental plates and immediately before the I/R. Cell viability, apoptosis and necrosis, and generation of reactive oxygen species were evaluated. Nifedipine and 3,5-dipalmitoyl-nifedipine were used to assess radical scavenging potential and metal chelation. All tested molecules managed to reduce the levels of reactive oxygen species compared to the starvation+vehicle group. In in vitro assays, 3,5-dipalmitoyl-nifedipine showed more antioxidant activity than nifedipine. These results indicate the ability of this molecule to act as a powerful ROS scavenger. Cell viability was highest when cells were induced to I/R by both concentrations of anandamide and the higher concentration of DPN. These treatments also reduced cell death. Therefore, it was demonstrated that the process of hybridization of nifedipine with two palmitic acid chains assigns a greater cardioprotective effect to this molecule, thereby reducing the damage caused by hypoxia and reoxygenation in cardiomyoblast cultures. PMID- 28554132 TI - The human RNA surveillance factor Up-frameshift 1 inhibits hepatic cancer progression by targeting MRP2/ABCC2. AB - Although the roles of Up-frameshift 1 (UPF1) in hepatocellular carcinoma (HCC) have been partly revealed, the detailed mechanisms remain poorly understood. Here, quantitative real-time PCR (qRT-PCR) and immunohistochemistry assays indicated that UPF1 expression was decreased in HCC tissues compared to the corresponding adjacent tissues, and was negatively correlated with MRP2/ABCC2 expression. Cell viability and apoptosis analyses showed that overexpression of UPF1 enhanced HCC cell sensitivity to sorafenib treatment, while knockdown of UPF1 decreased the sensitivity. Additionally, ectopic expression of UPF1 suppressed the epithelial-mesenchymal transition (EMT) process and the generation of cells with stem cell properties. Mechanistically, UPF1 directly bound with ABCC2, increased nonsense-mediated mRNA decay (NMD) efficiency and thus led to downregualtion of ABCC2. Collectively, UPF1 functions as a tumor suppressor by preventing cancer stem cell (CSC)-like characteristics, inhibiting EMT process and enhancing chemotherapeutic sensitivity via inhibiting ABCC2 expression in HCC cells. These findings establish UPF1 as a potential therapeutic target for HCC patients. PMID- 28554133 TI - Melatonin attenuates behavioural deficits and reduces brain oxidative stress in a rodent model of schizophrenia. AB - Melatonin is a neurohormone that is linked to the aetiopathogenesis of schizophrenia. The aim of this study was to assess the potentials of oral melatonin supplement in the management of induced schizophrenia-like behavioural and brain oxidative status changes, using an animal model. The relative degrees of modulation of ketamine-induced behaviours by haloperidol, olanzapine or melatonin were assessed in the open-field, Y-maze, elevated plus maze and the social interaction tests. 12-week old, male mice were assigned to six groups of ten each (n=10). They were pretreated with daily intraperitoneal ketamine at 15mg/kg (except vehicle) for 10days, before commencement of 14day treatment with standard drug (haloperidol or olanzapine) or melatonin. Ketamine injection also continued alongside melatonin or standard drugs administration for the duration of treatment. Melatonin, haloperidol and olanzapine were administered by gavage. Treatments were given daily, and behaviours assessed on days 11 and 24. On day 24, animals were sacrificed and whole brain homogenates used for the estimation of glutathione, nitric oxide and malondialdehyde levels. Ketamine injection increased open-field behaviours; while it decreased working-memory, social interaction and glutathione activity. Nitric oxide and malondialdehyde levels also increased after ketamine injection. Administration of melatonin was associated with variable degrees of reversal of these effects. In conclusion, melatonin may have the potential of a possible therapeutic agent and/or adjunct in the management of schizophrenia. PMID- 28554134 TI - Lactobacillus rhamnosus ATCC 7469 exopolysaccharides synergizes with low level ionizing radiation to modulate signaling molecular targets in colorectal carcinogenesis in rats. AB - Combination therapy that targets cellular signaling pathway represents an alternative therapy for the treatment of colon cancer (CRC). The present study was therefore aimed to investigate the probable interaction of Lactobacillus rhamnosus ATCC 7469 exopolysaccharides (EPS) with low level ionizing gamma radiation (gamma-R) exposure against dimethylhydrazine (DMH)- induced colorectal carcinogenesis in rats. Colon cancer was induced with 20mg DMH/kg BW. Rats received daily by gastric gavage 100mg EPS/Kg BW concomitant with 1Gy gamma-R over two months. Colonic oxidative and inflammatory stresses were assessed. The change in the expression of p-p38 MAPK, p-STAT3, beta-catenin, NF-kB, COX-2 and iNOS was evaluated by western blotting and q-PCR. It was found that DMH treatment significantly induced colon oxidative injury accompanied by inflammatory disturbance along with increased protein expression of the targeted signaling factors p-p38 MAPK, p-STAT3 and beta-catenin. The mRNA gene expression of NF-kB, COX-2 and iNOS was significantly higher in DMH-treated animals. It's worthy to note that colon tissues with DMH treatment showed significant dysplasia and anaplasia of the glandular mucosal lining epithelium with loses of goblet cells formation, pleomorphism in the cells and hyperchromachia in nuclei. Interestingly, EPS treatment with gamma-R exposure showed statistically significant amelioration of the oxidative and inflammatory biomarkers with modulated signaling molecular factors accompanied by improved histological structure against DMH-induced CRC. In conclusion, our findings showed that Lactobacillus rhamnosus ATCC 7469 EPS with low level gamma-R in synergistic interaction are efficacious control against CRC progression throughout the modulation of key signaling growth factors associated with inflammation via antioxidant mediated anti-inflammatory and anti-proliferative activities. PMID- 28554135 TI - Anatomic evaluation of the retromolar canal by histologic and radiologic analyses. AB - OBJECTIVES: The aim of this study was to identify the detailed anatomic morphology of the retromolar canal using histologic sections and cone-beam computed tomography (CBCT) images. MATERIALS AND METHODS: Twenty-two sides of the mandible obtained from cadavers and CBCT images of 72 patients (144 sides) were analyzed. All mandibles were prepared using conventional methods of tissue processing, stained with hematoxylin-eosin, and measured to elucidate the composition and dimensions of the retromolar canal with the aid of a light microscope. In addition, the prevalence, course, opening position, and distance of the retromolar canal from the second molar were measured on CBCT images. RESULTS: The retromolar neurovascular bundle in the retromolar canal originated from the inferior alveolar neurovascular bundle, and the mean areas of the neurovascular bundle and each artery and nerve contained within it were 0.59, 0.07, and 0.05mm2, respectively. The mean horizontal and vertical diameters of the neurovascular bundle were 0.82 and 0.90mm, respectively. The retromolar canal was detected more often on CBCT images (43.1%, 31 out of 72 patients). It mainly arose vertically (71.0%) from the mandibular canal and opened in the middle portion (57.9%) of the retromolar triangle at a mean distance of 13.13mm from the second molar. CONCLUSIONS: The retromolar canal is a normal anatomic structure that is relatively common and contains both a relatively large artery and a nerve. Clinicians need to pay closer attention to vascular problems as well as nerve damage when they are performing surgical procedures in the retromolar area. PMID- 28554136 TI - Differences between the chewing and non-chewing sides of the mandibular first molars and condyles in the closing phase during chewing in normal subjects. AB - OBJECTIVE: This study aimed to assess differences between the closing paths of the chewing and non-chewing sides of mandibular first molars and condyles during natural mastication, using standardized model food in healthy subjects. DESIGN: Thirty-two healthy young adults (age: 19-25 years; 22 men, 10 women) with normal occlusion and function chewed on standardized gummy jelly. Using an optoelectric jaw-tracking system with six degrees of freedom, we recorded the path of the mandibular first molars and condyles on both sides for 10 strokes during unilateral chewing. Variables were compared between the chewing side and the non chewing side of first molars and condyles on frontal, sagittal, and horizontal views during the early-, middle- and late-closing phases. RESULTS: On superior/inferior displacements, the chewing side first molar and condyle were positioned superior to those on the non-chewing side during the early- and middle closing phases. Conversely, the first molar and condyle on the non-chewing side were positioned significantly superior to those on the chewing side during the late-closing phase. On anterior/posterior displacements, the chewing side mandibular first molar and condyle were positioned significantly posterior to those on the non-chewing side throughout all closing phases. CONCLUSION: Our results showed the differences between the mandibular first molars and condyles on both sides with respect to masticatory path during natural chewing of a model food. These differences can be useful for informing initial diagnostic tests for impaired masticatory function in the clinical environment. PMID- 28554137 TI - Evaluating the non-lethal effects of organophosphorous and carbamate insecticides on the yabby (Cherax destructor) using cholinesterase (AChE, BChE), Glutathione S Transferase and ATPase as biomarkers. AB - The toxicity of two organophosphorus insecticides, chlorpyrifos (CPF), malathion (MAL), and one carbamate insecticide, methomyl (METH), to the yabby (Cherax destructor) was assessed by measuring cholinesterase (AChE, BChE), Glutathione S Transferase (GST) and Na+/K+ATPase activity after 96h of exposure. Yabbies exposed to all three insecticides at 2 and 5ugL-1 exhibited significant AChE, BChE, GST and Na+/K+ATPase inhibition. Based on these enzyme inhibition tests, the toxicity of the three insecticides to C. destructor was CPF > MAL > METH. After 14 days of recovery the yabbies enzymatic activities of AChE, BChE, GST and Na+/K+ATPase was measured. Recovery of The enzyme activity recovery was faster after the exposure to METH than for the yabbies exposed to CPF and MAL. Slow recovery of enzyme activity could affect the physical activities of organisms and produce indirect effects on populations if such crayfish are less able to elude predators or search for food. PMID- 28554138 TI - PEGylation on mixed monolayer gold nanoparticles: Effect of grafting density, chain length, and surface curvature. AB - PEGylation on nanoparticles (NPs) is widely used to prevent aggregation and to mask NPs from the fast clearance system in the body. Understanding the molecular details of the PEG layer could facilitate rational design of PEGylated NPs that maximize their solubility and stealth ability without significantly compromising the targeting efficiency and cellular uptake. Here, we use molecular dynamics (MD) simulation to understand the structural and dynamic the PEG coating of mixed monolayer gold NPs. Specifically, we modeled gold NPs with PEG grafting densities ranging from 0-2.76chain/nm2, chain length with 0-10 PEG monomers, NP core diameter from 5nm to 500nm. It is found that the area accessed by individual PEG chains gradually transits from a "mushroom" to a "brush" conformation as NP surface curvature become flatter, whereas such a transition is not evident on small NPs when grafting density increases. It is shown that moderate grafting density (~1.0chain/nm2) and short chain length are sufficient enough to prevent NPs from aggregating in an aqueous medium. The effect of grafting density on solubility is also validated by dynamic light scattering measurements of PEGylated 5nm gold NPs. With respect to the shielding ability, simulations predict that increase either grafting density, chain length, or NP diameter will reduce the accessibility of the protected content to a certain size molecule. Interestingly, reducing NP surface curvature is estimated to be most effective in promoting shielding ability. For shielding against small molecules, increasing PEG grafting density is more effective than increasing chain length. A simple model that includes these three investigated parameters is developed based on the simulations to roughly estimate the shielding ability of the PEG layer with respect to molecules of different sizes. The findings can help expand our current understanding of the PEG layer and guide rational design of PEGylated gold NPs for a particular application by tuning the PEG grafting density, chain length, and particle size. PMID- 28554139 TI - Recent 210Pb, 137Cs and 241Am accumulation in an ombrotrophic peatland from Amsterdam Island (Southern Indian Ocean). AB - Over the past 50 years, 210Pb, 137Cs and 241Am have been abundantly used in reconstructing recent sediment and peat chronologies. The study of global aerosol climate interaction is also partially depending on our understanding of 222Rn 210Pb cycling, as radionuclides are useful aerosol tracers. However, in comparison with the Northern Hemisphere, few data are available for these radionuclides in the Southern Hemisphere, especially in the South Indian Ocean. A peat core was collected in an ombrotrophic peatland from the remote Amsterdam Island (AMS) and was analyzed for 210Pb, 137Cs and 241Am radionuclides using an underground ultra-low background gamma spectrometer. The 210Pb Constant Rate of Supply (CRS) model of peat accumulations is validated by peaks of artificial radionuclides (137Cs and 241Am) that are related to nuclear weapon tests. We compared the AMS 210Pb data with an updated 210Pb deposition database. The 210Pb flux of 98 +/- 6 Bq.m-2.y-1 derived from the AMS core agrees with data from Madagascar and South Africa. The elevated flux observed at such a remote location may result from the enhanced 222Rn activity and frequent rainfall in AMS. This enhanced 222Rn activity itself may be explained by continental air masses passing over southern Africa and/or Madagascar. The 210Pb flux at AMS is higher than those derived from cores collected in coastal areas in Argentina and Chile, which are areas dominated by marine westerly winds with low 222Rn activities. We report a 137Cs inventory at AMS of 144 +/- 13 Bq.m-2 (corrected to 1969). Our data thus contribute to the under-represented data coverage in the mid-latitudes of the Southern Hemisphere. PMID- 28554140 TI - Health-related quality-of-life implications of cardiovascular events in individuals with type 2 diabetes mellitus: A subanalysis from the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-TIMI 53 trial. AB - BACKGROUND: The impact of cardiovascular complications on health-related quality of-life (HRQoL) in type 2 diabetes mellitus has not been clearly established. Using EQ5D utility data from SAVOR-TIMI 53, a large phase IV trial of saxagliptin versus placebo, we quantified the impact of cardiovascular and other major events on HRQoL. METHODS: EQ5D utilities were recorded annually and following myocardial infarction (MI) or stroke. Utilities among patients experiencing major cardiovascular events were analyzed using linear mixed-effects regression, adjusting for baseline characteristics (including EQ5D utility), and compared to those not experiencing major cardiovascular events. Mean utility decrements with standard errors (SE) were estimated as the difference in utility before and after the event. FINDINGS: The mean EQ5D utility of the sample was 0.776 at all time points, and did not differ by treatment. However, mean baseline and month 12 utilities among those with a major cardiovascular event were 0.751 and 0.714. Mean utilities were 0.691 within 3months of, 0.691 3-6months after, and 0.714 6 12months after, a major cardiovascular event. Cardiovascular event-specific utility decrements were 0.05 (0.007) for major cardiovascular events over the same time periods. Decrements of 0.051 (0.012; myocardial infarction), 0.111 (0.022; stroke), 0.065 (0.014; hospitalization for heart failure) 0.019 (0.024; hospitalization for hypoglycemia) were estimated; all coefficients were statistically significant. INTERPRETATION: Consistent with clinical outcomes reported elsewhere, saxagliptin did not improve HRQoL. Cardiovascular complications were associated with significantly decreased HRQoL, most substantial earlier after the event. FUNDING: BMS/AZ. PMID- 28554141 TI - Effect of re-coaching on self-injection of insulin in older diabetic patients - Impact of cognitive impairment. AB - AIMS: We investigated the effect of re-coaching on self-injection of insulin and impact of cognitive function in 100 older diabetic patients. METHODS: We examined patients on a variety of skills and knowledge regarding self-injection of insulin and evaluated the effect of re-coaching the patients after 3months and 4years. We also investigated the influence of cognitive impairment (CI) on coaching. RESULTS: Skills scores for self-injection of insulin and HbA1c improved significantly 3months after re-coaching. In 51 patients followed-up for 4years, skills scores were maintained during the 4years, while knowledge scores improved after 3months but then returned to the baseline level. In the group of patients with CI as determined by the Mini-Mental Status Examination, skills scores were similar to those in the group without CI, while knowledge scores were significantly lower as compared with those in the group without CI at any time point. Skills scores were maintained during the 4years regardless of CI. CONCLUSION: The present study showed that re-coaching in skills for self injection of insulin was effective in improving and maintaining insulin treatment in older diabetic patients, even if patients had CI. PMID- 28554142 TI - Diabetes mellitus and risk of ovarian cancer. A systematic review and meta analysis of 15 cohort studies. AB - AIM: Diabetes mellitus (DM) is hypothesized to be associated with an increased risk of ovarian cancer (OC), but current evidences are inconsistent. We aimed to further study this association. METHODS: PubMed, EMBASE, Web of Science, and Scopus were searched for eligible articles. After descriptive summary of the data, a random-effects model was applied in quantitative synthesis. Subgroup analysis was performed by study locales and settings, and sensitivity analysis was conducted based on restrictive selection criteria. Funnel plots and the Egger's test were used to assess publication bias. Statistical heterogeneity in meta-analysis was assessed by the P value derived from the Cochrane Q statistic and I-squared value. RESULTS: Fourteen articles involving data of 15 cohort studies were included for our research. Overall, 17 risk ratios (RRs) were synthesized and yielded a pooled RR of 1.32 (95%CI: 1.14-1.52, PCochrane<0.001, I2=79.8%). Thirteen RRs were synthesized for type 2DM, and the pooled RR was 1.24 (95%CI: 1.06-1.44, PCochrane<0.001, I2=81.8%). Four RRs were synthesized for type 1DM, and the result was significant (RR: 1.83, 95%CI: 1.21-2.78, PCochrane=0.080, I2=55.7%). Results of sensitivity analysis suggested the robustness of a positive association between DM and OC risk, and subgroup analysis demonstrated that the association between DM and OC was much more substantial among Asia population. No publication bias was identified in meta-analysis. CONCLUSION: Our study suggests there is a moderate relative increase in the risk of OC among DM patients. Future studies should investigate the effect of duration of DM and anti-diabetes intervention to OC risk. PMID- 28554143 TI - Comparison of gene expression of Toll-like receptors and cytokines between Piau and Commercial line (Landrace*Large White crossbred) pigs vaccinated against Pasteurella multocida type D. AB - We aimed to compare Toll-like receptors (TLR) and cytokines expression in local Piau breed and a Commercial line (Landrace*Large White crossbred) pigs in response to vaccination against Pasteurella multocida type D. Seronegative gilts for Pasteurella multocida type D and Mycoplasma hyopneumoniae were used, from which peripheral blood mononuclear cells (PBMC) were collected in four time points (T0, T1, T2 and T3; before and after each vaccination dose). For bronchoalveolar lavage fluid cells (BALF), we set groups of vaccinated and unvaccinated animals for both genetic groups. Gene expression was evaluated on PBMC and BALF. In PBMC, when we analyzed time points within breeds, significant differences in expression for TLRs and cytokines, except TGFbeta, were observed for Commercial animals. For the Piau pigs, only TGFbeta showed differential expression. Comparing the expression among genetic groups, the Commercial pigs showed higher expression for TLRs after first vaccination dose, while for IL2, IL6, IL12 and IL13, higher expression was also observed in T3 and IL8 and IL10, in T1 and T3. Still comparing the breeds, the crossbred animals showed higher expression for TNFalpha in T1 and T2, while for TGFbeta only in T2. For gene expression in BALF, vaccinated Commercial pigs showed higher expression of TLR6, TLR10, IL6, IL8, IL10, TNFalpha and TGFbeta genes than vaccinated Piau pigs. The Commercial line pigs showed higher sensitivity to vaccination, while in local Piau breed lower responsiveness, which may partly explain genetic variability in immune response and will let us better understand the tolerance/susceptibility for pasteurellosis. PMID- 28554144 TI - Muscle-specific deletion of SOCS3 does not reduce the anabolic response to leucine in a mouse model of acute inflammation. AB - Excessive inflammation reduces skeletal muscle protein synthesis leading to wasting and weakness. The janus kinase/signal transducers and activators of transcription-3 (JAK/STAT3) pathway is important for the regulation of inflammatory signaling. As such, suppressor of cytokine signaling-3 (SOCS3), the negative regulator of JAK/STAT signaling, is thought to be important in the control of muscle homeostasis. We hypothesized that muscle-specific deletion of SOCS3 would impair the anabolic response to leucine during an inflammatory insult. Twelve week old (n=8 per group) SOCS3 muscle-specific knockout mice (SOCS3-MKO) and littermate controls (WT) were injected with lipopolysaccharide (LPS, 1mg/kg) or saline and were studied during fasted conditions or after receiving 0.5g/kg leucine 3h after the injection of LPS. Markers of inflammation, anabolic signaling, and protein synthesis were measured 4h after LPS injection. LPS injection robustly increased mRNA expression of inflammatory molecules (Socs3, Socs1, Il-6, Ccl2, Tnfalpha and Cd68). In muscles from SOCS3-MKO mice, the Socs3 mRNA response to LPS was significantly blunted (~6-fold) while STAT3 Tyr705 phosphorylation was exacerbated (18-fold). Leucine administration increased protein synthesis in both WT (~1.6-fold) and SOCS3-MKO mice (~1.5-fold) compared to basal levels. LPS administration blunted this effect, but there were no differences between WT and SOCS3-MKO mice. Muscle-specific SOCS3 deletion did not alter the response of AKT, mTOR, S6 or 4EBP1 under any treatment conditions. Therefore, SOCS3 does not appear to mediate the early inflammatory or leucine induced changes in protein synthesis in skeletal muscle. PMID- 28554145 TI - Physiological and biochemical perspectives of non-salt tolerant plants during bacterial interaction against soil salinity. AB - Climatic changes on earth affect the soil quality of agricultural lands, especially by increasing salt deposition in soil, which results in soil salinity. Soil salinity is a major challenge to growth and reproduction among glycophytes (including all crop plants). Soil bacteria present in the rhizosphere and/or roots naturally protect plants from the adverse effects of soil salinity by reprogramming the stress-induced physiological changes in plants. Bacteria can enrich the soil with major nutrients (nitrogen, phosphorus, and potassium) in a form easily available to plants and prevent the transport of excess sodium to roots (exopolysaccharides secreted by bacteria bind with sodium ions) for maintaining ionic balance and water potential in cells. Salinity also affects plant growth regulators and suppresses seed germination and root and shoot growth. Bacterial secretion of indole-3-acetic acid and gibberellins compensates for the salt-induced hormonal decrease in plants, and bacterial 1 aminocyclopropane-1-carboxylate (ACC) deaminase synthesis decreases ethylene production to stimulate plant growth. Furthermore, bacteria modulate the redox state of salinity-affected plants by enhancing antioxidants and polyamines, which leads to increased photosynthetic efficiency. Bacteria-induced accumulation of compatible solutes in stressed plants regulates plant cellular activities and prevents salt stress damage. Plant-bacterial interaction reprograms the expression of salt stress-responsive genes and proteins in salinity-affected plants, resulting in a precise stress mitigation metabolism as a defense mechanism. Soil bacteria increase the fertility of soil and regulate the plant functions to prevent the salinity effects in glycophytes. This review explains the current understanding about the physiological changes induced in glycophytes during bacterial interaction to alleviate the adverse effects of soil salinity stress. PMID- 28554146 TI - Improved quinoa growth, physiological response, and seed nutritional quality in three soils having different stresses by the application of acidified biochar and compost. AB - Quinoa (Chenopodium quinoa Willd.) is a traditional Andean agronomical resilient seed crop having immense significance in terms of high nutritional qualities and its tolerance against various abiotic stresses. However, finite work has been executed to evaluate the growth, physiological, chemical, biochemical, antioxidant properties, and mineral nutrients bioavailability of quinoa under abiotic stresses. Depending on the consistency in the stability of pH, intended rate of S was selected from four rates (0.1, 0.2, 0.3, 0.4 and 0.5% S) for the acidification of biochar and compost in the presence of Thiobacillus thiooxidans by pH value of 4. All three soils were amended with 1% (w/w) acidified biochar (BCA) and compost (COA). Results revealed that selective plant growth, yield, physiological, chemical and biochemical improved significantly by the application of BCA in all stressed soils. Antioxidants in quinoa fresh leaves increased in the order of control > COA > BCA, while reactive oxygen species decreased in the order of control < COA < BCA. A significant reduction in anti-nutrients (phytate and polyphenols) was observed in all stressed soils with the application of BCA. Moreover, incorporation of COA and BCA reduced the pH of rhizosphere soil by 0.4 1.6 units in all stressed soils, while only BCA in bulk soil decreased pH significantly by 0.3 units. These results demonstrate that BCA was more effective than COA to enhance the bioavailability, translocation of essential nutrients from the soil to plant and their enhanced bioavailability in the seed. PMID- 28554148 TI - Social media in epilepsy: A quantitative and qualitative analysis. AB - BACKGROUND: While the social burden of epilepsy has been extensively studied, an evaluation of social media related to epilepsy may provide novel insight into disease perception, patient needs and access to treatments. The objective of this study is to assess patterns in social media and online communication usage related to epilepsy and its associated topics. METHODS: We searched two major social media platforms (Facebook and Twitter) for public accounts dedicated to epilepsy. Results were analyzed using qualitative and quantitative methodologies. The former involved thematic and word count analysis for online posts and tweets on these platforms, while the latter employed descriptive statistics and non parametric tests. RESULTS: Facebook had a higher number of pages (840 accounts) and users (3 million) compared to Twitter (137 accounts and 274,663 users). Foundation and support groups comprised most of the accounts and users on both Facebook and Twitter. The number of accounts increased by 100% from 2012 to 2016. Among the 403 posts and tweets analyzed, "providing information" on medications or correcting common misconceptions in epilepsy was the most common theme (48%). Surgical interventions for epilepsy were only mentioned in 1% of all posts and tweets. CONCLUSIONS: The current study provides a comprehensive reference on the usage of social media in epilepsy. The number of online users interested in epilepsy is likely the highest among all neurological conditions. Surgery, as a method of treating refractory epilepsy, however, could be underrepresented on social media. PMID- 28554149 TI - Domestic violence among persons with epilepsy and their caregivers. PMID- 28554147 TI - Seizure prediction in patients with focal hippocampal epilepsy. AB - OBJECTIVE: We evaluated the performance of our previously developed seizure prediction approach on thirty eight seizures from ten patients with focal hippocampal epilepsy. METHODS: The seizure prediction system was developed based on the extraction of correlation dimension, correlation entropy, noise level, Lempel-Ziv complexity, largest Lyapunov exponent, and nonlinear interdependence from segments of intracranial EEG. RESULTS: Our results showed an average sensitivity of 86.7% and 92.9%, an average false prediction rate of 0.126 and 0.096/h, and an average minimum prediction time of 14.3 and 33.3min, respectively, using seizure occurrence periods of 30 and 50min and a seizure prediction horizon of 10s. Two-third of the analyzed seizures showed significantly increased complexity in periods prior to the seizures in comparison with baseline. In four patients, strong bidirectional connectivities between epileptic contacts and the surrounding areas were observed. However, in five patients, unidirectional functional connectivities in preictal periods were observed from remote areas to epileptogenic zones. CONCLUSIONS: Overall, preictal periods in patients with focal hippocampal epilepsy were characterized with patient-specific changes in univariate and bivariate nonlinear measures. SIGNIFICANCE: The spatio-temporal characterization of preictal periods may help to better understand the mechanism underlying seizure generation in patients with focal hippocampal epilepsy. PMID- 28554150 TI - Effect of valgus knee alignment on gait biomechanics in healthy women. AB - The purpose of this study was to compare lower extremity kinematics and kinetics between women with greater or lesser degrees of valgus knee alignment during gait. Nine women with greater valgus knee alignment (11.9+/-1.6 degrees ) were compared to nine women with lesser valgus knee alignment (6.6+/-2.4 degrees ). Participants completed a biomechanical assessment of overground walking for the right limb. Dependent variables included sagittal and frontal plane joint angles and moments for the hip, knee, and ankle at peak vertical ground reaction force, along with knee abduction angular impulse. Sagittal and frontal plane excursions for the hip, knee, and ankle were calculated from heel strike to the peak angle for each variable. The greater valgus alignment group demonstrated lower knee abduction moment (p=0.007), lower knee adduction angle (p<0.001), and greater ankle inversion moment (p=0.034) at peak vertical ground reaction force, as well as lower knee abduction angular impulse (p=0.007), and knee adduction ROM (p=0.026). No other group differences were identified for any kinematic or kinetic variables (p>0.05). Less knee adduction angle and excursion coupled with lower knee abduction moment and angular impulse in women with greater knee valgus indicates these individuals may be experiencing biomechanics which promote lateral tibiofemoral joint loading. PMID- 28554151 TI - Executive functions in alcohol-dependence: A theoretically grounded and integrative exploration. AB - BACKGROUND: Alcohol-dependence is related to large-scale cognitive impairments, particularly for executive functions (EF). These deficits persist even after long term abstinence and have a major impact on patients' everyday life and relapse risk. Earlier studies, based on multi-determined tasks, mostly focused on inhibition and did not offer a theoretically-grounded and exhaustive view of the differential deficit across EF. The present paper proposes a model-based exploration of EF in alcohol-dependent individuals (ALC), to precisely compare the specific deficit related to each executive subcomponent. METHODS: Forty-seven recently detoxified ALC were compared to 47 matched healthy participants on a nine-tasks validated neuropsychological battery, simultaneously exploring and comparing the three main executive subcomponents (shifting, updating, and inhibition). Psychopathological comorbidities were also controlled for. RESULTS: Reaction time indexes revealed a global slowing down among ALC, whatever the EF explored. Accuracy indexes revealed a moderate deficit for inhibition tasks but a massive impairment for shifting and updating ones. Complementary analyses indicated that the executive deficits observed were centrally related to alcohol dependence, while comorbid depressive symptoms appeared to intensify the deficits observed. CONCLUSIONS: By offering a direct comparison between the three major EF, these results showed that alcohol-related executive deficits extend beyond the classically described inhibition impairment. This impairment encompasses each EF subcomponent, as ALC actually presented stronger deficits for updating and shifting abilities. This first observation of a multifaceted EF deficit stresses the need for an individualized evaluation and rehabilitation of EF during and/or after the detoxification process. PMID- 28554152 TI - Aviisotricha hoazini n. gen., n. sp., the Morphology and Molecular Phylogeny of an Anaerobic Ciliate from the Crop of the Hoatzin (Opisthocomus hoazin), the Cow Among the Birds. AB - The hoatzin is the only known avian species that has evolved a foregut fermentation system similar to that of ruminant animals. Due to the closeness of the bird's fermentation chamber, the crop, to the bird's beak it exudes an unpleasant odour; therefore, the hoatzin is called the "cow among the birds". In addition to Eubacteria and Archaea, responsible for digestion of the vegetation they consume, the bird's crop contains a holotrich ciliate, described here for the first time in detail. Cytological staining of this isotrichid-like ciliate with the Chatton-Lwoff and Protargol staining procedures, as well as SEM and TEM, justified the establishment of the new genus Aviisotricha n. gen. with its new type species Aviisotricha hoazini n. gen., n. sp.. Phylogenetic analyses of a portion of the small subunit rRNA gene supported the taxonomic placement of this new genus and species in the family Isotrichidae. Aviisotricha is compared with Balantidium, Dasytricha and Isotricha with special reference to their dorsal brushes, which show similarity to the paralabial organelle of the Entodiniomorphida. The possible phylogenetic origin of Aviisotricha is discussed and a taxonomic revision of the family Isotrichidae is given. PMID- 28554153 TI - How Far do Ciliate Flagships Sail? A Proposed Gondawanaland Endemic Species at Anchor in Idaho Soils. AB - In terms of protist biogeography, "flagship species" (Foissner 2005) have been defined as those so remarkable or "showy" that they are unlikely to be overlooked when present in a given habitat. On this basis, flagship species have been suggested as an ideal or ultimate test for the existence of protist endemism. One example of a flagship ciliate is the terrestrial lepidosome-bearing trachelophyllid, Luporinophrys micelae, previously thought to be a Gondwanan endemic. This report comprises a morphologic description of two populations of L. micelae from Laurentian soils (Idaho, Northwest USA). The flagship concept is briefly reviewed and ciliate biogeography is discussed in light of these findings. PMID- 28554154 TI - Admixture analysis of age of onset in generalized anxiety disorder. AB - Age of onset is a marker of clinically relevant subtypes in various medical and psychiatric disorders. Past research has also reported that age of onset in generalized anxiety disorder (GAD) is clinically significant; but, in research to date, arbitrary cut-off ages have been used. In the present study, admixture analysis was used to determine the best fitting model for age of onset distribution in GAD. Data were derived from 459 adults with a diagnosis of GAD who took part in the Netherlands Study of Depression and Anxiety (NESDA). Associations between age of onset subtypes, identified by admixture analysis, and sociodemographic, clinical, and vulnerability factors were examined using univariate tests and multivariate logistic regression analyses. Two age of onset distributions were identified: an early-onset group (24 years of age and younger) and a late-onset group (greater than 24 years of age). Multivariate analysis revealed that early-onset GAD was associated with female gender (OR 2.1 (95%CI 1.4-3.2)), higher education (OR 1.1 (95%CI 1.0-1.2)), and higher neuroticism (OR 1.4 (95%CI 1.1-1.7)), while late-onset GAD was associated with physical illnesses (OR 1.3 (95%CI 1.1-1.7)). Study limitations include the possibility of recall bias given that age of onset was assessed retrospectively, and an inability to detect a possible very-late-onset GAD subtype. Collectively, the results of the study indicate that GAD is characterized by a bimodal age of onset distribution with an objectively determined early cut-off at 24 years of age. Early-onset GAD is associated with unique factors that may contribute to its aetiology; but, it does not constitute a more severe subtype compared to late-onset GAD. Future research should use 24 years of age as the cut-off for early-onset GAD to when examining the clinical relevance of age of onset for treatment efficacy and illness course. PMID- 28554155 TI - Salivary secretion and disgust: A pilot study. AB - Although a direct link has been established between self-experienced disgust and salivary secretion, it is unclear whether this physiological index is modulated by the social experience of disgust (i.e., exposure to the facial expression of disgust). We tested this issue in a pilot study by collecting salivary samples in a group of 20 healthy humans watching pictures of faces expressing disgust. Moreover, we tried to replicate previous evidence by testing saliva secretion in response to pictures of unpalatable (i.e., rotten) food and non-gustatory disgusting stimuli (i.e., disgusting insects). Overall, our analysis shows a general reduction of saliva secretion in response to disgust stimuli, compared to their positive counterparts, although further analyses for specific stimulus categories indicated that this difference was statistically significant only for food pictures. The non-significance of the face and insect categories might be due to insufficient power of our small sample. Overall, a general reduction of saliva secretion for different disgust-related stimuli suggests a shared mechanism of encoding, in line with theories of neural reuse. PMID- 28554156 TI - Face inversion increases attractiveness. AB - Assessing facial attractiveness is a ubiquitous, inherent, and hard-wired phenomenon in everyday interactions. As such, it has highly adapted to the default way that faces are typically processed: viewing faces in upright orientation. By inverting faces, we can disrupt this default mode, and study how facial attractiveness is assessed. Faces, rotated at 90 (tilting to either side) and 180 degrees , were rated on attractiveness and distinctiveness scales. For both orientations, we found that faces were rated more attractive and less distinctive than upright faces. Importantly, these effects were more pronounced for faces rated low in upright orientation, and smaller for highly attractive faces. In other words, the less attractive a face was, the more it gained in attractiveness by inversion or rotation. Based on these findings, we argue that facial attractiveness assessments might not rely on the presence of attractive facial characteristics, but on the absence of distinctive, unattractive characteristics. These unattractive characteristics are potentially weighed against an individual, attractive prototype in assessing facial attractiveness. PMID- 28554157 TI - Does neighbourhood deprivation affect the genetic influence on body mass? AB - Most research into the role of gene-environment interactions in the etiology of obesity has taken environment to mean behaviours such as exercise and diet. While interesting, this is somewhat at odds with research into the social determinants of obesity, in which the focus has shifted away from individuals and behaviours to the types of wider obesogenic environments in which individuals live, which influence and produce these behaviours. This study combines these two strands of research by investigating how the genetic influence on body mass index (BMI), used as a proxy for obesity, changes across different neighbourhood environments measured by levels of deprivation. Genetics are incorporated using a classical twin design with data from Twins UK, a longitudinal study of UK twins running since 1992. A multilevel modelling approach is taken to decompose variation between individuals into genetic, shared environmental, and non-shared environmental components. Neighbourhood deprivation is found to be a statistically significant predictor of BMI after conditioning on individual characteristics, and a heritability of 0.75 is estimated for the entire sample. This heritability estimate is shown, however, to be higher in more deprived neighbourhoods and lower in less deprived ones, and this relationship is statistically significant. While this research cannot say anything directly about the mechanisms behind the relationship, it does highlight how the relative importance of genetic factors can vary across different social environments, and therefore the value of considering both genetic and social determinants of health simultaneously. PMID- 28554158 TI - Effect of interrupting free healthcare for children: Drawing lessons at the critical moment of national scale-up in Burkina Faso. AB - With solid evidence that free healthcare increases the utilization of health services, Burkina Faso recently exempted all children under five and pregnant women from direct payment at health facilities. However, there is little insight into the capacity to maintain the gains attributable to free healthcare under routine conditions of implementation at the national scale. In particular, the repercussions of its interruption are unknown. The objective is to assess the effects of a sequence of natural interventions including the introduction, interruption and reintroduction of free healthcare on health-seeking practices and utilization of healthcare facilities by children under five. This is an embedded mixed methods study conducted in Kaya district, Burkina Faso. The quantitative component is based on a reversal longitudinal design. Pooled interrupted time-series analysis was performed to assess changes in the monthly number of visits from January 2005 to March 2015. Qualitative data were collected through in-depth interviews with health personnel and mothers to better understand the quantitative results. The results show that visits to health centres dropped immediately and significantly when free healthcare was interrupted (-146, CI95% [-255; -37]). They increased again when free healthcare was reintroduced (+89, CI95% [-11; 187]). Both urban and rural centres were affected. Self-medication and visits to traditional healers were reported more frequently during the withdrawal of free healthcare, and tensions between the population and health personnel increased. Implementation problems other than insufficient funding limited the coverage or intensity of free healthcare. While removing user fees could potentially improve mothers and children's health in Burkina Faso, this study shows that demand for healthcare remains highly sensitive to price changes. Gains in utilization attributable to free healthcare may vanish rapidly if user fees are reintroduced. It is essential to support an effective and sustainable implementation of this ambitious initiative. PMID- 28554160 TI - Applying economic incentives to increase effectiveness of an outpatient weight loss program (TRIO) - A randomized controlled trial. AB - The prevalence of overweight and obesity has more than doubled in the past three decades, leading to rising rates of non-communicable diseases. This study tests whether adding a payment/rewards (term reward) program to an existing evidence based weight loss program can increase weight loss and weight loss maintenance. We conducted a parallel-group randomized controlled trial from October 2012 to October 2015 with 161 overweight or obese individuals randomized to either control or reward arm in a 1:2 ratio. Control and reward arm participants received a four month weight loss program at the LIFE (Lifestyle Improvement and Fitness Enhancement) Centre at Singapore General Hospital. Those in the reward arm paid a fee of S$165.00 (1US$ = 1.35S$) to access a program that provided rewards of up to S$660 for meeting weight loss and physical activity goals. Participants could choose to receive rewards as guaranteed cash payments or a lottery ticket with a 1 in 10 chance of winning but with the same expected value. The primary outcome was weight loss at months 4, 8, and 12. 161 participants were randomized to control (n = 54) or reward (n = 107) arms. Average weight loss was more than twice as great in the reward arm compared to the control arm at month 4 when the program concluded (3.4 kg vs 1.4 kg, p < 0.01), month 8 when rewards concluded (3.3 kg vs 1.8 kg, p < 0.05), and at month 12 (2.3 kg vs 0.8 kg, p < 0.05). These results reveal that a payment/rewards program can be used to improve weight loss and weight loss maintenance when combined with an evidence-based weight loss program. Future efforts should attempt to replicate this approach and identify how to cost effectively expand these programs to maximize their reach. This study is registered at www.clinicaltrials.gov (Identifier: NCT01533454). PMID- 28554159 TI - Health system responsiveness and chronic disease care - What is the role of disease management programs? An analysis based on cross-sectional survey and administrative claims data. AB - Health system responsiveness is an important aspect of health systems performance. The concept of responsiveness relates to the interpersonal and contextual aspects of health care. While disease management programs (DMPs) aim to improve the quality of health care (e.g. by improving the coordination of care), it has not been analyzed yet whether these programs improve the perceived health system responsiveness. Our study aims to close this gap by analyzing the differences in the perceived health system responsiveness between DMP participants and non-participants. We used linked survey- and administrative claims data from 7037 patients with coronary heart disease in Germany. Of those, 5082 were enrolled and 1955 were not enrolled in the DMP. Responsiveness was assessed with an adapted version of the WHO responsiveness questionnaire in a postal survey in 2013. The survey covered 9 dimensions of responsiveness and included 17 items for each, GP and specialist care. Each item had five answer categories (very good - very bad). We handled missing values in the covariates by multiple imputation and applied propensity score matching (PSM) to control for differences between the two groups (DMP/non-DMP). We used Wilcoxon-signed-rank and McNemar test to analyze differences regarding the reported responsiveness. The PSM led to a matched and well balanced sample of 1921 pairs. Overall, DMP participants rated the responsiveness of care more positive. The main difference was found for the coordination of care at the GP, with 62.0% of 1703 non participants reporting a "good" or "very good" experience, compared to 69.1% of 1703 participants (p < 0.001). The results of our study indicate an overall high responsiveness for CHD-care, as well for DMP-participants as for non participants. Yet, the results also clearly indicate that there is still a need to improve the coordination of care. PMID- 28554161 TI - Asian Americans and disproportionate exposure to carcinogenic hazardous air pollutants: A national study. AB - Studies have demonstrated disparate exposures to carcinogenic hazardous air pollutants (HAPs) in neighborhoods with high densities of Black and Hispanic residents in the US. Asians are the fastest growing racial/ethnic group in the US, yet they have been underemphasized in previous studies of environmental health and injustice. This cross-sectional study investigated possible disparities in residential exposure to carcinogenic HAPs among Asian Americans, including Asian American subgroups in the US (including all 50 states and the District of Columbia, n = 71,208 US census tracts) using National Air Toxics Assessment and US Census data. In an unadjusted analysis, Chinese and Korean Americans experience the highest mean cancer risks from HAPs, followed by Blacks. The aggregated Asian category ranks just below Blacks and above Hispanics, in terms of carcinogenic HAP risk. Multivariate models adjusting for socioeconomic status, population density, urban location, and geographic clustering show that an increase in proportion of Asian residents in census tracts is associated with significantly greater cancer risk from HAPs. Neighborhoods with higher proportions (as opposed to lower proportions) of Chinese, Korean, and South Asian residents have significantly greater cancer risk burdens relative to Whites. Tracts with higher concentrations of Asians speaking a non-English language and Asians that are US-born have significantly greater cancer risk burdens. Asian Americans experience substantial residential exposure to carcinogenic HAPs in US census tracts and in the US more generally. PMID- 28554163 TI - The influence of temperature on adult zebrafish sensitivity to pentylenetetrazole. AB - Pentylenetetrazole (PTZ) is one of the most valuable drugs used to induce seizure like state in zebrafish especially considering the pharmacological screening for anticonvulsants and the study of basic mechanisms of epilepsy. Here, the effect of gender, weight and changes in temperature on latency to adult zebrafish reach classical seizure states induced by PTZ (10mM) was evaluated. Gender and weight (200-250mg versus 400-500mg) did not affect the profile of response to PTZ. When water temperature was changed from 22 to 30 degrees C the lower temperature increased the latency time to reach seizure states and the higher temperature significantly decreased it, in comparison to the control group maintained at 26 degrees C. The blockage of kainate receptors by DNQX (10MUM) were unable to prevent the increased susceptibility of adult zebrafish exposed to hyperthermia and PTZ-induced seizures. The NMDA block by MK-801 (2.5MUM) prevented the additive effect of hyperthermia on PTZ effects in adult zebrafish. This report emphasize that PTZ model in adult zebrafish exhibits no confounder factors from gender and weight, but water temperature is able to directly affect the response to PTZ, especially through a mechanism related to NMDA receptors. PMID- 28554162 TI - Social causation and neighborhood selection underlie associations of neighborhood factors with illicit drug-using social networks and illicit drug use among adults relocated from public housing. AB - Theories of social causation and social influence, which posit that neighborhood and social network characteristics are distal causes of substance use, are frequently used to interpret associations among neighborhood characteristics, social network characteristics and substance use. These associations are also hypothesized to result from selection processes, in which substance use determines where people live and who they interact with. The potential for these competing selection mechanisms to co-occur has been underexplored among adults. This study utilizes path analysis to determine the paths that relate census tract characteristics (e.g., economic deprivation), social network characteristics (i.e., having >= 1 illicit drug-using network member) and illicit drug use, among 172 African American adults relocated from public housing in Atlanta, Georgia and followed from 2009 to 2014 (7 waves). Individual and network-level characteristics were captured using surveys. Census tract characteristics were created using administrative data. Waves 1 (pre-relocation), 2 (1st wave post relocation), and 7 were analyzed. When controlling for individual-level sociodemographic factors, residing in census tracts with prior economic disadvantage was significantly associated with illicit drug use at wave 1; illicit drug use at wave 1 was significantly associated with living in economically-disadvantaged census tracts at wave 2; and violent crime at wave 2 was associated with illicit drug-using social network members at wave 7. Findings from this study support theories that describe social causation and neighborhood selection processes as explaining relationships of neighborhood characteristics with illicit drug use and illicit drug-using social networks. Policies that improve local economic and social conditions of neighborhoods may discourage substance use. Future studies should further identify the barriers that prevent substance users from obtaining housing in less disadvantaged neighborhoods. PMID- 28554164 TI - Association between obesity phenotypes and incident hypertension among Chinese adults: a prospective cohort study. AB - OBJECTIVES: To explore the association between obesity phenotype and the risk of hypertension among Chinese adults. STUDY DESIGN: A prospective cohort study. METHODS: Two waves of data were collected in 2009 and 2011 by the China Health Nutrition Survey. According to International Diabetes Federation and Chinese obesity criteria, participants were divided into four groups: metabolically healthy non-overweight/obesity (MHNO), metabolically healthy overweight/obesity (MHO), metabolically abnormal non-overweight/obesity (MANO), and metabolically abnormal overweight/obesity (MAO). Logistic regression model was performed to estimate the risk of hypertension with obesity phenotype. RESULTS: Among a total of 4604 adults aged 18-65 years at baseline, 467 developed hypertension during the 2-year follow-up period. After adjusting for several potential confounders, significantly increased risks for hypertension were found for participants in MHO (odd ratio [OR]: 1.78, 95% confidence interval [CI]: 1.39-2.27), MANO (OR: 1.71, 95% CI: 1.02-2.86), and MAO (OR: 3.35, 95% CI: 2.54-4.42) group compared with the MHNO group. CONCLUSION: Metabolically abnormal individuals, regardless of their body weight status, showed significantly higher risks for hypertension compared with healthy non-overweight/obese group. Furthermore, MHO individuals had significantly increased risk of incident hypertension. PMID- 28554165 TI - Network modeling of resting state connectivity points towards the bottom up theories of schizophrenia. AB - The dysconnectivity theory of schizophrenia proposes that schizophrenia symptoms arise from abnormalities in neuronal synchrony. Resting-state Functional Connectivity (FC) techniques allow us to highlight synchronization of large-scale networks, the Resting-state Networks (RNs). A large body of work suggests that disruption of RN synchronization could give rise to specific schizophrenia symptoms. The present study aimed to explore within- and between-network FC strength of 34 RNs in 29 patients suffering from schizophrenia, and their relationships with schizophrenia symptoms. Resting-state data were analyzed using independent component analysis and dual-regression techniques. Our results showed that both within-RN and between-RN FC were disrupted in patients with schizophrenia, with a global trend toward weaker FC. This decrease affected more particularly visual, auditory and crossmodal binding networks. These alterations were correlated with negative symptoms, positive symptoms and hallucinations, indicating abnormalities in visual processing and crossmodal binding in schizophrenia. Moreover, we stressed an anomalous synchronization between a visual network and a network thought to be engaged in mental imaging processes, correlated with delusions and hallucinations. Altogether, our results supported the assumption that some schizophrenia symptoms may be related to low-order sensory alterations impacting higher-order cognitive processes, i.e. the "bottom up" hypothesis of schizophrenia symptoms. PMID- 28554166 TI - Oxytocin facilitation of acceptance of social advice is dependent upon the perceived trustworthiness of individual advisors. AB - The neuropeptide oxytocin may increase social cohesion by making us more willing to trust others and/or to conform to their opinions. Here we investigated whether intranasal oxytocin can influence acceptance of advice given on solving everyday social problems by either individual expert (psychologist) or non-expert advisors with or without influencing their perceived likeability or trustworthiness. In a double-blind, between-subject, placebo-control design study in 160 male and female subjects, intranasal oxytocin (24IU) only significantly enhanced acceptance of advice given by female psychologists who were rated as the most trustworthy advisors. However, oxytocin itself did not alter either trustworthiness or likeability ratings. The oxytocin effect on acceptance of the female psychologist's advice was not maintained after a week, with subjects mainly reverting to their original solutions. These findings suggest that while oxytocin can transiently increase acceptance of advice from the most trustworthy individuals this is because it makes subjects more likely to conform to their opinions rather than enhancing their perceived trustworthiness or likeability. Thus in every day contexts oxytocin may primarily promote social cohesion by facilitating conformity towards the opinions of the most trusted individuals. PMID- 28554167 TI - Elevated paternal glucocorticoid exposure modifies memory retention in female offspring. AB - Recent studies have demonstrated that behavioral traits are subject to transgenerational modification by paternal environmental factors. We previously reported on the transgenerational influences of increased paternal stress hormone levels on offspring anxiety and depression-related behaviors. Here, we investigated whether offspring sociability and cognition are also influenced by paternal stress. Adult C57BL/6J male mice were treated with corticosterone (CORT; 25mg/L) for four weeks prior to paired-matings to generate F1 offspring. Paternal CORT treatment was associated with decreased body weights of female offspring and a marked reduction of the male offspring. There were no differences in social behavior of adult F1 offspring in the three-chamber social interaction test. Despite male offspring of CORT-treated fathers displaying hyperactivity in the Y maze, there was no observable difference in short-term spatial working memory. Spatial learning and memory testing in the Morris water maze revealed that female, but not male, F1 offspring of CORT-treated fathers had impaired memory retention. We used our recently developed methodology to analyze the spatial search strategy of the mice during the learning trials and determined that the impairment could not be attributed to underlying differences in search strategy. These results provide evidence for the impact of paternal corticosterone administration on offspring cognition and complement the cumulative knowledge of transgenerational epigenetic inheritance of acquired traits in rodents and humans. PMID- 28554168 TI - Juan Jorge Heinrich, MD, PhD, 1937-2016. PMID- 28554170 TI - How Do We Improve the Quality of Life of Haemodialysis Patients? Now That's a Good Question. PMID- 28554169 TI - Neohesperidin Exerts Lipid-Regulating Effects in vitro and in vivo via Fibroblast Growth Factor 21 and AMP-Activated Protein Kinase/Sirtuin Type 1/Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1alpha Signaling Axis. AB - The purpose of this study is to prove the lipid-regulating effects of neohesperidin (NHP) and explore the potential mechanisms related to fibroblast growth factor 21 (FGF21) and AMP-activated protein kinase (AMPK). Free fatty acids (FFAs)-induced lipid-accumulated HepG2 cells, acutely egg yolk-induced dyslipidemia and chronically diet-induced obese (DIO) model mice were treated with NHP. Biochemical analyses were carried out to determine the lipid profiles. Western blotting and real-time PCR were employed to analyze FGF21, AMPK and the related proteins or mRNA expressions. Body weight and food intake were measured in DIO mice. siRNA or inhibitors of FGF21 or AMPK were utilized in further study. NHP showed potent hypolipidemic effect in HepG2 cells loaded with FFAs and reversed the pathological changes of lipid in the acute or chronic dyslipidemia mouse model. It obviously improved the lipid profiles in plasma, liver and gastrocnemius muscles in DIO mice, and led to a significant body weight loss. Simultaneously, FGF21 protein expression or secretion, and AMPK/sirtuin type 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC 1alpha) axis or related molecules, was improved by NHP in HepG2 cells and/or DIO mice. Furthermore, the siRNA or inhibitor targeting FGF21 or AMPK rejected the triglyceride-lowering effect of NHP. In conclusion, NHP regulates lipid metabolism in vivo and in vitro via FGF21 and AMPK/SIRT1/PGC-1alpha signaling axis. PMID- 28554171 TI - Clearance of Sclerostin, Osteocalcin, Fibroblast Growth Factor 23, and Osteoprotegerin by Dialysis. AB - INTRODUCTION: Fibroblast growth factor (FGF23), sclerostin, osteocalcin, and osteoprotegerin are important factors that control mineral bone metabolism. End stage renal disease is associated with the pronounced dysregulation of mineral bone metabolism; however, the impact and clearance of mineral bone metabolism factors during dialysis remain largely undescribed. METHODS: In a cross-sectional study, 10 chronic hemodialysis patients were treated with hemodialysis for 8 h using a high-flux filter and a dialysate bath of 50% calculated total body water continuously recycled at a rate of 500 mL/min. Plasma and dialysate concentrations of FGF23, sclerostin, osteoprotegerin, and osteocalcin were measured at 1, 2, 4, 6, and 8 h permitting the estimation of dialysis clearance. RESULTS: Clearance of FGF23 was 7.7 mL/min, of sclerostin was 7.6 mL/min, of osteoprotegerin was 1.2 mL/min, and of osteocalcin was 19.7 mL/min. Clearance of FGF23 was correlated to sclerostin and osteoprotegerin clearance and also to the ultrafiltration rate. Although, osteocalcin blood concentrations decreased during dialysis, they rebounded within 6 h. Overall, no significant changes in blood concentrations of the measure mineral bone metabolism factors were observed. CONCLUSIONS: The intradialytic clearance of osteocalcin, FGF23, sclerostin, and osteoprotegerin occurs; however, only clearance of FGF23 is directly correlated with the ultrafiltration rate. The effects of dialytic clearance on mineral bone metabolism are, however, uncertain and intradialytic plasma concentrations of the studied substrates remained largely unchanged. PMID- 28554172 TI - The Circulating MicroRNA-206 Level Predicts the Severity of Pulmonary Hypertension in Patients with Left Heart Diseases. AB - BACKGROUND: MicroRNA-206 (miR-206), a muscle-specific miRNA, regulates the growth of cardiac myocytes and pulmonary artery smooth muscle cells. However, it remains unknown whether miR-206 is involved in pulmonary hypertension (PH) due to left heart diseases (PH-LHD). This study was designed to investigate the correlation between miR-206 and PH in patients with LHD. METHODS: In 82 consecutively enrolled LHD patients, we examined the serum levels of miR-206 and analyzed its correlations with pulmonary artery systolic pressure (PASP) and cardiac function. Another 36 age- and sex-matched subjects served as healthy controls. RESULTS: The patients were divided into the LHD group (n=47, PASP<50 mmHg) and the PH-LHD group (n=35, PASP>=50 mmHg). The level of miR-206 was significantly decreased in the PH-LHD group compared with that of the LHD and healthy control groups. In addition, the miR-206 level was correlated with PASP (r=-0.305, p<0.001) but not with systemic blood pressure. Univariate analyses showed that miR-206, brain natriuretic peptide (BNP), left ventricular ejection fraction and left atrial longitudinal diameter (LAD) were significantly related to PASP. Multivariate regression analysis identified miR-206 as an independent predictive factor for PH. MiR-206 alone (cut-off <0.66) demonstrated a sensitivity of 68.60% and a specificity of 65.80% in predicting PH. Moreover, the combination of miR-206, BNP and LAD (cut-off 0.21) showed a sensitivity of 97.10% and a specificity of 80.30% in predicting PH in LHD patients. CONCLUSION: A decreased circulating miR-206 level was associated with increased PASP in LHD patients. Thus, the level of miR 206, especially combined with BNP and LAD, might be helpful in the detection of PH in LHD patients. PMID- 28554173 TI - Everolimus in Neuroendocrine Tumors of the Gastrointestinal Tract and Unknown Primary. AB - PURPOSE: The RADIANT-4 randomized phase 3 study demonstrated significant prolongation of median progression-free survival (PFS) with everolimus compared to placebo (11.0 [95% CI 9.2-13.3] vs. 3.9 [95% CI 3.6-7.4] months) in patients with advanced, progressive, nonfunctional gastrointestinal (GI) and lung neuroendocrine tumors (NET). This analysis specifically evaluated NET patients with GI and unknown primary origin. METHODS: Patients in the RADIANT-4 trial were randomized 2:1 to everolimus 10 mg/day or placebo. The effect of everolimus on PFS was evaluated in patients with NET of the GI tract or unknown primary site. RESULTS: Of the 302 patients enrolled, 175 had GI NET (everolimus, 118; placebo, 57) and 36 had unknown primary (everolimus, 23; placebo, 13). In the GI subset, the median PFS by central review was 13.1 months (95% CI 9.2-17.3) in the everolimus arm versus 5.4 months (95% CI 3.6-9.3) in the placebo arm; the hazard ratio (HR) was 0.56 (95% CI 0.37-0.84). In the unknown primary patients, the median PFS was 13.6 months (95% CI 4.1-not evaluable) for everolimus versus 7.5 months (95% CI 1.9-18.5) for placebo; the HR was 0.60 (95% CI 0.24-1.51). Everolimus efficacy was also demonstrated in both midgut and non-midgut populations; a 40-46% reduction in the risk of progression or death was reported for patients in the combined GI and unknown primary subgroup. Everolimus had a benefit regardless of prior somatostatin analog therapy. CONCLUSIONS: Everolimus showed a clinically meaningful PFS benefit in patients with advanced progressive nonfunctional NET of GI and unknown primary, consistent with the overall RADIANT 4 results, providing an effective new standard treatment option in this patient population and filling an unmet treatment need for these patients. PMID- 28554175 TI - Modification of Potassium-Mortality Relationship by Ethnicity and Race: Solving the Puzzle. PMID- 28554174 TI - Postoperative Recovery of Light Sensitivity in Eyes with Rhegmatogenous Retinal Detachment. AB - PURPOSE: To investigate whether postoperative light sensitivity recovers completely to the level prior to the development of rhegmatogenous retinal detachment (RRD) after successful surgery. METHODS: We retrospectively studied 44 eyes of 44 patients with RRD who were successfully operated and who underwent Humphrey central 30-2 perimetry postoperatively. The averaged total deviation in Humphrey perimetry in the reattached retina was compared with that of the horizontal or vertical counterpart in the preoperatively non-detached retina. RESULTS: The averaged total deviation in the reattached retina was significantly lower than in its counterpart (p < 0.0001). The averaged residual loss of light sensitivity did not correlate with postoperative visual acuity (p = 0.8047) or with its change (p = 0.1242). CONCLUSIONS: Light sensitivity in the detached retina in eyes with RRD does not completely recover after successful surgery. PMID- 28554176 TI - Fine-Needle Aspiration of Metastatic Central Type Primitive Neuroectodermal Tumors in Patients with a Germ Cell Tumor. AB - OBJECTIVE: Central type primitive neuroectodermal tumors (PNET) are some of the most frequent somatic type tumors derived from germ cell tumors and can metastasize. We studied the cytomorphological features of metastatic central type PNET by fine-needle aspiration (FNA). MATERIALS AND METHODS: A computerized search of our laboratory information system was performed for the 9-year period from 2005 through 2014 to identify all cytology cases in which a diagnosis of metastatic central type PNET had been rendered. A total of 5 FNA cases were collected and direct smears were reexamined. RESULTS: All patients had a history of testicular or ovarian germ cell tumors. Direct smears displayed single and clusters of atypical round to oval cells with scant to moderate cytoplasm. Abundant naked nuclei were present in Diff-Quik-stained smears with mild to marked crushed artifacts and nuclear molding. Tumor cells showed fine granular chromatin, nuclear size variation (up to 1:3), and one or more small nucleoli. Pseudorosettes (Homer Wright-like rosette) were noticed in 1 case. Tumor cells were commonly positive for synaptophysin. CONCLUSION: Metastatic PNET can be reliably diagnosed by FNA. Differential diagnoses include Ewing sarcoma/peripheral PNET, alveolar rhabdomyosarcoma, neuroblastoma, etc. It is important to be familiar with this entity to avoid diagnostic pitfalls. PMID- 28554177 TI - High Prestroke Physical Activity Is Associated with Reduced Infarct Growth in Acute Ischemic Stroke Patients Treated with Intravenous tPA and Randomized to Remote Ischemic Perconditioning. AB - BACKGROUND: A high prestroke physical activity (PA) level is associated with reduced stroke rate, stroke mortality, better functional outcome, and possible neuroprotective abilities. The aim of the present study was to examine the possible neuroprotective effect of prestroke PA on 24-h cerebral infarct growth in a cohort of acute ischemic stroke patients treated with intravenous tPA and randomized to remote ischemic perconditioning. METHODS: In this predefined subanalysis, data from a randomized clinical trial investigating the effect of remote ischemic perconditioning (RIPerC) on AIS was used. Prestroke (7 days before admission) PA was quantified using the PA Scale for the Elderly (PASE) questionnaire at baseline. Infarct growth was evaluated using MRI (acute, 24-h, and 1-month). RESULTS: PASE scores were obtained from 102 of 153 (67%) patients with a median (interquartile range) age of 66 (58-73) years. A high prestroke PA level correlated significantly with reduced acute infarct growth (24 h) in the linear regression model (4th quartile prestroke PA level compared with the 1st quartile), beta4th quartile = -0.82 (95% CI -1.54 to -0.10). However, the effect of prestroke PA was present mainly in patients randomized to RIPerC, beta4th quartile = -1.14 (95% CI -2.04 to -0.25). In patients randomized to RIPerC, prestroke PA was a predictor of final infarct size (1-month infarct volume), beta4th quartile = -1.78 (95% CI -3.15 to -0.41). CONCLUSION: In AIS patients treated with RIPerC, as add-on to intravenous thrombolysis, the level of PA the week before the stroke was associated with decreased 24-h infarct growth and final infarct size. These results are highly encouraging and stress the need for further exploration of the potentially protective effects of both PA and remote ischemic conditioning. PMID- 28554179 TI - Skin-Dominant Phenotype in a Patient with H Syndrome: Identification of a Novel Mutation in the SLC29A3 Gene. AB - H syndrome (OMIM 602782) is a very rare autosomal recessive genodermatosis with multisystem involvement. Hallmarks of this disorder are juvenile onset and progressive, hyperpigmented, hypertrichotic lesions with histiocytic infiltration. Associated systemic manifestations form a long list, and there is high variability between patients. In some patients, dysmorphic and other systemic features may be so subtle that the disorder may readily be mistaken as an acquired skin disease and treated as such. Herein, we report a novel homozygous c.1339G>A (p.Glu447Lys) mutation in the SLC29A3 gene in a patient with skin-dominant presentation of H syndrome. Additionally, due to the present case, double superior vena cava can be added to the list of possible cardiovascular manifestations of H syndrome. PMID- 28554180 TI - Higher Ultrafiltration Rate Is Associated with Longer Dialysis Recovery Time in Patients Undergoing Conventional Hemodialysis. AB - BACKGROUND: Increased mortality and morbidity are reported in association with high ultrafiltration rate (UFR) and with long dialysis recovery time (DRT). We studied the association between UFR and DRT. METHODS: This is a cross-sectional, observational study was conducted. Patients on thrice-weekly hemodialysis (HD) with self-reported DRT between August and December 2014 were included. We examined the association of 30-day average UFR with recovery time. RESULTS: The total number of patients included in this study was 2,689. DRT in categories of immediate recovery, >0-<=2, >2-<=6, >6-<=12, and >12 h, were reported in 27, 28, 17, 9, and 20% of the patients respectively. In multivariable analysis, longer DRT was associated with female gender, non-black race, higher body weight, lower serum albumin, chronic heart failure, cerebrovascular disease, missed dialysis sessions, higher pre-dialysis systolic blood pressure, and larger UF volume. Compared to UFR of <10, UFR >=13 mL/kg/h was associated with longer DRT, OR of 1.16 (95% CI 0.99-1.36), and 1.28 (95% CI 1.06-1.54) in the unadjusted and the adjusted analyses respectively. Intradialytic hypotension was also associated with longer DRT in the unadjusted (per 10% higher frequency, OR 1.04 [95% CI 1.01 1.07]) and adjusted analyses (OR 1.03 [95% CI 1.00-1.07]). CONCLUSION: Long recovery time is common after HD. Rapid fluid removal is associated with longer DRT. PMID- 28554178 TI - Vitamin D and Albuminuria in Youth with and without Type 1 Diabetes. AB - BACKGROUND/AIMS: In adults, lower vitamin D has been associated with increased albuminuria. This association has not been extensively studied in youth with or without type 1 diabetes. METHODS: We examined the cross-sectional association between vitamin D and albuminuria (urine albumin to creatinine ratio >=30 mg/g) in 8,789 participants of the National Health and Nutrition Survey 2001-2006 (NHANES), who were 6-19 years old. Further, we examined the association between vitamin D and albuminuria in 938 participants from the SEARCH Nutritional Ancillary Study (SNAS), a longitudinal cohort of youth with type 1 diabetes. RESULTS: Of the NHANES participants, 5.3, 19.5, and 53.7% had vitamin D levels <30, 50 and 80 nmol/L, respectively. Albuminuria was present in 12.8% and was more common in younger children, females, non-Hispanic whites, non-obese children, and children with hypertension. After adjustments, there was no association between vitamin D and albuminuria. Among the SNAS participants with type 1 diabetes, we also found no association between baseline vitamin D and subsequent albuminuria in unadjusted or adjusted analyses. CONCLUSION: We did not find an association between serum vitamin D and albuminuria in either non diabetic youth or those with type 1 diabetes. Further research is needed to more fully understand this relationship. PMID- 28554181 TI - Cytosolic Cl- Affects the Anticancer Activity of Paclitaxel in the Gastric Cancer Cell Line, MKN28 Cell. AB - BACKGROUND/AIMS: Our previous study revealed that cytosolic Cl- affected neurite elongation promoted via assembly of microtubule in rat pheochromocytoma PC12D cells and Cl--induced blockade of intrinsic GTPase enhanced tubulin polymerization in vitro. Paclitaxel (PTX) is a microtubule-targeted chemotherapeutic drug and stabilizes microtubules resulting in mainly blockade of mitosis at the metaphase-anaphase transition and induction of apoptosis. In the present study, we tried to clarify whether the cytosolic Cl- affected PTX ability to inhibit cell growth in the gastric cancer cell line, MKN28. METHODS: To clarify the cytosolic Cl- action on PTX-induced cell death and metaphase-anaphase transition in the gastric cancer cell line, MKN28 cell, and PTX-induced tubulin polymerization, we performed cell proliferation assay, cytosolic Cl- concentration measurement, immunofluorescence microscopy, and in vitro tubulin polymerization assay. RESULTS: The decline of cytosolic Cl- weakened the cytotoxic effect of PTX on cell proliferation of MKN28 cells, which could pass through the metaphase-anaphase transition. Moreover, in vitro PTX-induced tubulin polymerization was diminished under the low Cl- condition. CONCLUSIONS: Our results strongly suggest that the upregulation of cytosolic Cl- concentration would enhance the antitumor effect of PTX, and that the cytosolic Cl- would be one of the key targets for anti-cancer therapy. PMID- 28554182 TI - Prognostic Significance of Fragmented QRS in Patients with Hypertrophic Cardiomyopathy. AB - OBJECTIVES: The relationship between a fragmented QRS (fQRS) and clinical outcomes in patients with hypertrophic cardiomyopathy (HCM) remains unclear. This study aimed to investigate the prognostic significance of fQRS in patients with HCM. METHODS: Between 2000 and 2012, 326 unrelated patients with HCM (72% male with a mean age of 52 years) were included and were divided into 2 groups: those with fQRS and those without fQRS. RESULTS: A total of 105/326(32.2%) patients with HCM presented with fQRS at enrollment. During a follow-up of 5.3 +/- 2.4 years, 33 patients died, 30 of cardiovascular disease (CVD). Cox regression analysis revealed that fQRS predicted a higher risk of all-cause mortality (adjusted hazard ratio [HR] 2.24; 95% confidence interval [CI] 1.08-4.64; p = 0.030) and CVD mortality (adjusted HR 2.68; 95% CI 1.22-5.91; p = 0.014). Our study also showed that fQRS increased the risk of heart failure-related death (adjusted HR 3.75; 95% CI 1.24-11.30; p = 0.019). CONCLUSIONS: Our results indicate that fQRS is associated with adverse clinical outcomes in patients with HCM. PMID- 28554184 TI - Vertebral Artery Dissection in a Bouncy Castle Injury: Case Report and Literature Review. AB - There is an increased rate of injuries associated with activities on bouncy castles. The purpose of this article was to describe the case of a 6-year-old boy who sustained a brain infarct as a consequence of a left posterior inferior cerebellar artery dissection due to improper landing in a bouncy castle and who required a suboccipital craniotomy. The second goal was to outline the literature review regarding cervical trauma related to trampoline or bouncy castle accidents in pediatric populations. Based on the described case and reviewed studies, bouncy castle or any other activity resulting in hyperflexion or hyperextension of the neck should be carefully evaluated for cervical spine fractures and vascular injuries. PMID- 28554183 TI - A Pilot Trial of S-1 and Paclitaxel in Unresectable or Postoperative Recurrent Esophageal Squamous Cell Carcinoma Pretreated by Fluorouracil, Cisplatin, and Docetaxel Chemotherapy. AB - BACKGROUND/AIMS: This study documents the clinical efficacy and toxicity of S-1 and paclitaxel (S1/PTX) in patients with unresectable or postoperative recurrent esophageal squamous cell carcinoma (ESCC) who had been previously treated with fluorouracil (5FU), cisplatin, and docetaxel. METHODS: Twenty-eight ESCC patients treated using S1/PTX at our institute since 2010 were enrolled in this study. S1 was administered orally at a dose of 80 mg/m2/day from days 1 to 14, and PTX was administered intravenously on days 1 and 8 at a dose of 80-100 mg/m2. RESULTS: A total of 106 cycles (median 2.5 cycles, range 1-12 cycles) were administered. The response rate was 14.8%, including 3 complete responses. The median progression free survival time was 137 days, and the median overall survival time was 306 days. Severe neutropenia occurred in 13 patients, and 3 showed febrile neutropenia. All non-hematological toxicities were mild, and peripheral nerve paralysis was observed in 2 patients. CONCLUSION: S1/PTX was found to have tolerable clinical efficacy in terms of the response rate, survival and toxicity in patients with unresectable or postoperative recurrent ESCC who had previously been treated with 5FU, cisplatin, and docetaxel. PMID- 28554185 TI - Clinical Challenges in Upper Gastrointestinal Malignancies after Bariatric Surgery. AB - BACKGROUND/AIMS: The incidence of morbid obesity has exponentially increased over the last decades. Bariatric surgery (BS) has been proven effective in inducing weight loss and resolving comorbidities associated with morbid obesity. However, BS can also lead to major diagnostic and treatment challenges in patients who develop upper gastrointestinal malignancies. It is important to create awareness of this rising problem. METHODS: Relevant literature was searched in PubMed. RESULTS: (Formerly) obese patients are more prone to develop upper gastrointestinal malignancies, mainly adenocarcinoma of the distal esophagus, since obesity induces a chronic pro-inflammatory state due to endocrinological changes. When an upper gastrointestinal malignancy develops after BS, diagnosis is often delayed and challenging due to a different presentation of complaints and the altered anatomy following the earlier surgery. Also, a potentially curative resection is often more complex and reconstruction of the gastrointestinal continuity can be seriously hampered. CONCLUSION: Due to the growing incidence of obesity and the increasing number of bariatric surgical procedures that are performed each year, it is expected that over the years to come, more post-BS patients will be diagnosed with upper gastrointestinal malignancies, providing great diagnostic and treatment challenges. Clinicians should be aware of this rising problem. PMID- 28554186 TI - Exposure to Cadmium Impairs Sperm Functions by Reducing CatSper in Mice. AB - BACKGROUND: Cadmium (Cd), a common environmental heavy metal and endocrine disruptor, is known to exert toxic effects on the testes. However, the mechanisms accounting for its toxicity in mature spermatozoa remain unclear. METHODS: Adult male C57BL/6 mice were orally administered with CdCl2 for 5 weeks at 3 mg.kg 1.day-1. Additionally, mouse spermatozoa were incubated in vitro with different doses of CdCl2 (0, 10, 50, 250 uM). Several sperm functions including the sperm motility, viability and acrosome reaction (AR) ratio were then examined. Furthermore, the current and expression levels of both the sperm-specific Ca2+ channel (CatSper) and the sperm-specific K+ channel (KSper) were evaluated by patch-clamping and western blotting, respectively. RESULTS: Our data showed that the motility, viability and AR of sperm exposed to cadmium significantly decreased in vivo and in vitro. Interestingly, these changes were correlated with changes in CatSper but not KSper. CONCLUSION: The findings indicate sperm dysfunction during both chronic and acute cadmium exposure as well as a specific role for CatSper in the reproductive toxicity of cadmium. PMID- 28554187 TI - Embryonic Stem Cells for Tissue Biocompatibility, Angiogenesis, and Inflammation Testing. AB - AIM: To introduce embryoid bodies derived from mouse embryonic stem (ES) cells, which differentiate blood vessel-like structures and leukocytes, as a novel in vitro model system for biocompatibility, inflammation, and angiogenesis studies. METHODOLOGY/RESULTS: Punched spherical discs of bioabsorbable polymers (epsilon caprolactone and L-lactide in different compositions) with a diameter of 2 mm and a thickness of 0.2 mm were inoculated with embryoid bodies for cocultivation. As reference material for biocompatible, nonbioabsorbable, and bioincompatible materials, polymer punched discs of petriPERM (PP) membrane (polytetrafluoroethylene) as well as polyvinylchloride (PVC) were used. Tissue outgrowth on the polymer discs decreased and cell toxicity increased upon confrontation on bioabsorbable biomaterials and PVC. Bioabsorbable polymers as well as PVC decreased the branching points and total tube length of CD31-positive vascular structures in embryoid bodies. With the exception of PP, all applied materials increased the differentiation of CD68-positive macrophages and the generation of reactive oxygen species, which is indicative of proinflammatory processes upon contact of tissue with biomaterials. Consequently, cocultivation with polymers increased secretion of the cytokines interleukin-6, monocyte chemotactic protein-1, and tumor necrosis factor-alpha. CONCLUSION: Three dimensional tissues cultivated from ES cells are well-suited for testing the biocompatibility, the vascular response, and the inflammatory reaction towards bioabsorbable and nonbioabsorbable polymers. PMID- 28554188 TI - Attention deficit/hyperactivity disorder and risk of injuries: A systematic review and meta-analysis. AB - BACKGROUND: This study systematically reviewed the literature in order to determine the effect of Attention-Deficit Hyperactivity Disorder (ADHD) on injuries and assessed the magnitude of the potential association. METHODS: A systematic review of the studies examining the association of ADHD and injuries was carried out across multiple databases. Odds ratios and standardized mean differences were pooled. RESULTS: A total of 35 studies were selected for quantitative analysis. The association of ADHD and injuries was confirmed over the meta-analysis of eligible studies. The odds ratio pooled over all comparative studies was 1.96(95% CI: 1.6-2.4) using random effects model. Pooled odds ratio of 2.1 and 2.17 were calculated respectively when cohort and case-control studies or just cohort studies were included. The pooled odds ratio reduced to 1.8(CI:1.45-2.3) when studies on specific injuries were removed. For studies comparing scores of rating scales, the pooled standardized mean difference was 0.61(95% CI: 0.03-1.2). CONCLUSIONS: Those with ADHD are nearly two times more likely to be injured. PMID- 28554190 TI - 23andMe Paves the Way for Direct-to-Consumer Genetic Health Risk Tests of Limited Clinical Utility. PMID- 28554191 TI - Toward Patient-Centered Hospital Design: What Can Airports Teach Us? PMID- 28554193 TI - Improvement at Any Cost? The Art and Science of Choosing Treatment Strategies for Rheumatoid Arthritis. PMID- 28554194 TI - New Department of Veterans Affairs and Department of Defense Guidelines on Pain Management With Opioids: Comment and Concern. PMID- 28554189 TI - Structure of the human multidrug transporter ABCG2. AB - ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs and limits the delivery of therapeutics into tumour cells, thus contributing to multidrug resistance. Here we present the structure of human ABCG2 determined by cryo-electron microscopy, providing the first high-resolution insight into a human multidrug transporter. We visualize ABCG2 in complex with two antigen-binding fragments of the human-specific, inhibitory antibody 5D3 that recognizes extracellular loops of the transporter. We observe two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between the transmembrane domains. Combined with functional in vitro analyses, our results suggest a multidrug recognition and transport mechanism of ABCG2, rationalize disease-causing single nucleotide polymorphisms and the allosteric inhibition by the 5D3 antibody, and provide the structural basis of cholesterol recognition by other G-subfamily ABC transporters. PMID- 28554192 TI - Triple Therapy Versus Biologic Therapy for Active Rheumatoid Arthritis: A Cost Effectiveness Analysis. AB - Background: The RACAT (Rheumatoid Arthritis Comparison of Active Therapies) trial found triple therapy to be noninferior to etanercept-methotrexate in patients with active rheumatoid arthritis (RA). Objective: To determine the cost effectiveness of etanercept-methotrexate versus triple therapy as a first-line strategy. Design: A within-trial analysis based on the 353 participants in the RACAT trial and a lifetime analysis that extrapolated costs and outcomes by using a decision analytic cohort model. Data Sources: The RACAT trial and sources from the literature. Target Population: Patients with active RA despite at least 12 weeks of methotrexate therapy. Time Horizon: 24 weeks and lifetime. Perspective: Societal and Medicare. Intervention: Etanercept-methotrexate first versus triple therapy first. Outcome Measures: Incremental costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Results of Base-Case Analysis: The within-trial analysis found that etanercept-methotrexate as first line therapy provided marginally more QALYs but accumulated substantially higher drug costs. Differences in other costs between strategies were negligible. The ICERs for first-line etanercept-methotrexate and triple therapy were $2.7 million per QALY and $0.98 million per QALY over 24 and 48 weeks, respectively. The lifetime analysis suggested that first-line etanercept-methotrexate would result in 0.15 additional lifetime QALY, but this gain would cost an incremental $77 290, leading to an ICER of $521 520 per QALY per patient. Results of Sensitivity Analysis: Considering a long-term perspective, an initial strategy of etanercept methotrexate and biologics with similar cost and efficacy is unlikely to be cost effective compared with using triple therapy first, even under optimistic assumptions. Limitation: Data on the long-term benefit of triple therapy are uncertain. Conclusion: Initiating biologic therapy without trying triple therapy first increases costs while providing minimal incremental benefit. Primary Funding Source: The Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, Canadian Institutes for Health Research, and an interagency agreement with the National Institutes of Health-American Recovery and Reinvestment Act. PMID- 28554195 TI - Sitagliptin and Angioedema. PMID- 28554197 TI - A New Neolignan Derivative, Balanophonin Isolated from Firmiana simplex Delays the Progress of Neuronal Cell Death by Inhibiting Microglial Activation. AB - Excessive activation of microglia causes the continuous production of neurotoxic mediators, which further causes neuron degeneration. Therefore, inhibition of microglial activation is a possible target for the treatment of neurodegenerative disorders. Balanophonin, a natural neolignoid from Firmiana simplex, has been reported to have anti-inflammatory and anti-cancer effects. In this study, we aimed to evaluate the anti-neuroinflammatory effects and mechanism of balanophonin in lipopolysaccharide (LPS)-stimulated BV2 microglia cells. BV2 microglia cells were stimulated with LPS in the presence or absence of balanophonin. The results indicated that balanophonin reduced not only the LPS mediated TLR4 activation but also the production of inflammatory mediators, such as nitric oxide (NO), prostaglandin E2 (PGE2), Interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha), in BV2 cells. Balanophonin also inhibited LPS-induced inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX2) protein expression and mitogen activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 MAPK. Interestingly, it also inhibited neuronal cell death resulting from LPS-activated microglia by regulating cleaved caspase-3 and poly ADP ribose polymerase (PARP) cleavage in N2a cells. In conclusion, our data indicated that balanophonin may delay the progression of neuronal cell death by inhibiting microglial activation. PMID- 28554198 TI - Role of TAZ in Lysophosphatidic Acid-Induced Migration and Proliferation of Human Adipose-Derived Mesenchymal Stem Cells. AB - Transcriptional co-activator with a PDZ-binding motif (TAZ) is an important factor in lysophosphatidic acid (LPA)-induced promotion of migration and proliferation of human mesenchymal stem cells (MSCs). The expression of TAZ significantly increased at 6 h after LPA treatment, and TAZ knockdown inhibited the LPA-induced migration and proliferation of MSCs. In addition, embryonic fibroblasts from TAZ knockout mice exhibited the reduction in LPA-induced migration and proliferation. The LPA1 receptor inhibitor Ki16425 blocked LPA responses in MSCs. Although TAZ knockdown or knockout did not reduce LPA-induced phosphorylation of ERK and AKT, the MEK inhibitor U0126 or the ROCK inhibitor Y27632 blocked LPA-induced TAZ expression along with the reduction in the proliferation and migration of MSCs. Our data suggest that TAZ is an important mediator of LPA signaling in MSCs in the downstream of MEK and ROCK signaling. PMID- 28554196 TI - Production of Recombinant Anti-Cancer Vaccines in Plants. AB - Plant expression systems have been developed to produce anti-cancer vaccines. Plants have several advantages as bioreactors for the production of subunit vaccines: they are considered safe, and may be used to produce recombinant proteins at low production cost. However, several technical issues hinder large scale production of anti-cancer vaccines in plants. The present review covers design strategies to enhance the immunogenicity and therapeutic potency of anti cancer vaccines, methods to increase vaccine-expressing plant biomass, and challenges facing the production of anti-cancer vaccines in plants. Specifically, the issues such as low expression levels and plant-specific glycosylation are described, along with their potential solutions. PMID- 28554199 TI - Recombinant Human Thioredoxin-1 Protects Macrophages from Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation and Cell Apoptosis. AB - Oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation and apoptosis play critical roles in the pathogenesis of atherosclerosis. Thioredoxin-1 (Trx) is an antioxidant that potently protects various cells from oxidative stress-induced cell death. However, the protective effect of Trx on ox LDL-induced macrophage foam cell formation and apoptosis has not been studied. This study aims to investigate the effect of recombinant human Trx (rhTrx) on ox LDL-stimulated RAW264.7 macrophages and elucidate the possible mechanisms. RhTrx significantly inhibited ox-LDL-induced cholesterol accumulation and apoptosis in RAW264.7 macrophages. RhTrx also suppressed the ox-LDL-induced overproduction of lectin-like oxidized LDL receptor (LOX-1), Bax and activated caspase-3, but it increased the expression of Bcl-2. In addition, rhTrx markedly inhibited the ox LDL-induced production of intracellular reactive oxygen species (ROS) and phosphorylation of p38 mitogen-activated protein kinases (MAPK). Furthermore, anisomycin (a p38 MAPK activator) abolished the protective effect of rhTrx on ox LDL-stimulated RAW264.7 cells, and SB203580 (a p38 MAPK inhibitor) exerted a similar effect as rhTrx. Collectively, these findings indicate that rhTrx suppresses ox-LDL-stimulated foam cell formation and macrophage apoptosis by inhibiting ROS generation, p38 MAPK activation and LOX-1 expression. Therefore, we propose that rhTrx has therapeutic potential in the prevention and treatment of atherosclerosis. PMID- 28554200 TI - The Memory-Enhancing Effects of Liquiritigenin by Activation of NMDA Receptors and the CREB Signaling Pathway in Mice. AB - Liquiritigenin (LQ) is a flavonoid that can be isolated from Glycyrrhiza radix. It is frequently used as a tranditional oriental medicine herbal treatment for swelling and injury and for detoxification. However, the effects of LQ on cognitive function have not been fully explored. In this study, we evaluated the memory-enhancing effects of LQ and the underlying mechanisms with a focus on the N-methyl-D-aspartic acid receptor (NMDAR) in mice. Learning and memory ability were evaluated with the Y-maze and passive avoidance tests following administration of LQ. In addition, the expression of NMDAR subunits 1, 2A, and 2B; postsynaptic density-95 (PSD-95); phosphorylation of Ca2+/calmodulin dependent protein kinase II (CaMKII); phosphorylation of extracellular signal regulated kinase 1/2 (ERK 1/2); and phosphorylation of cAMP response element binding (CREB) proteins were examined by Western blot. In vivo, we found that treatment with LQ significantly improved memory performance in both behavioral tests. In vitro, LQ significantly increased NMDARs in the hippocampus. Furthermore, LQ significantly increased PSD-95 expression as well as CaMKII, ERK, and CREB phosphorylation in the hippocampus. Taken together, our results suggest that LQ has cognition enhancing activities and that these effects are mediated, in part, by activation of the NMDAR and CREB signaling pathways. PMID- 28554201 TI - A Benzylideneacetophenone Derivative Induces Apoptosis of Radiation-Resistant Human Breast Cancer Cells via Oxidative Stress. AB - Benzylideneacetophenone derivative (1E)-1-(4-hydroxy-3-methoxyphenyl) hept-1-en-3 one (JC3) elicited cytotoxic effects on MDA-MB 231 human breast cancer cells radiation resistant cells (MDA-MB 231-RR), in a dose-dependent manner, with an IC50 value of 6 uM JC3. JC3-mediated apoptosis was confirmed by increase in sub G1 cell population. JC3 disrupted the mitochondrial membrane potential, and reduced expression of anti-apoptotic B cell lymphoma-2 protein, whereas it increased expression of pro-apoptotic Bcl-2-associated X protein, leading to the cleavage of caspase-9, caspase-3 and poly (ADP-ribose) polymerase. In addition, JC3 activated mitogen-activated protein kinases, and specific inhibitors of these kinases abrogated the JC3-induced increase in apoptotic bodies. JC3 increased the level of intracellular reactive oxygen species and enhanced oxidative macromolecular damage via lipid peroxidation, protein carbonylation, and DNA strand breakage. Considering these findings, JC3 is an effective therapy against radiation-resistant human breast cancer cells. PMID- 28554202 TI - Imperatorin is Transported through Blood-Brain Barrier by Carrier-Mediated Transporters. AB - Imperatorin, a major bioactive furanocoumarin with multifunctions, can be used for treating neurodegenerative diseases. In this study, we investigated the characteristics of imperatorin transport in the brain. Experiments of the present study were designed to study imperatorin transport across the blood-brain barrier both in vivo and in vitro. In vivo study was performed in rats using single intravenous injection and in situ carotid artery perfusion technique. Conditionally immortalized rat brain capillary endothelial cells were as an in vitro model of blood-brain barrier to examine the transport mechanism of imperatorin. Brain distribution volume of imperatorin was about 6 fold greater than that of sucrose, suggesting that the transport of imperatorin was through the blood-brain barrier in physiological state. Both in vivo and in vitro imperatorin transport studies demonstrated that imperatorin could be transported in a concentration-dependent manner with high affinity. Imperatorin uptake was dependent on proton gradient in an opposite direction. It was significantly reduced by pretreatment with sodium azide. However, its uptake was not inhibited by replacing extracellular sodium with potassium or N-methylglucamine. The uptake of imperatorin was inhibited by various cationic compounds, but not inhibited by TEA, choline and organic anion substances. Transfection of plasma membrane monoamine transporter, organic cation transporter 2 and organic cation/carnitine transporter 2/1 siRNA failed to alter imperatorin transport in brain capillary endothelial cells. Especially, tramadol, clonidine and pyrilamine inhibited the uptake of [3H]imperatorin competitively. Therefore, imperatorin is actively transported from blood to brain across the blood-brain barrier by passive and carrier-mediated transporter. PMID- 28554204 TI - Enhanced Superhydrophobic Performance of BN-MoS2 Heterostructure Prepared via a Rapid, One-Pot Supercritical Fluid Processing. AB - Fabrication of highly crystalline BN-MoS2 heterostructure with >95% yield was demonstrated using one-pot supercritical fluid processing within 30 min. The existence of 20-50 layers of BN-MoS2 in the prepared heterostructure was confirmed by AFM analysis. The HR-TEM imaging and mapping analysis revealed the well-melded BN and MoS2 nanosheets in the heterostructure. The drastic reduction in XRD line intensities corresponding to the (002) plane and broadening of the peaks for the BN system over MoS2 indicated the effective exfoliation and lateral size reduction in BN nanosheets during SCF processing. Also, the exfoliated MoS2 nanosheets are preferentially exposed rather than BN nanosheets; consequently, the MoS2 nanosheets sturdily covered BN nanosheets in the heterostructure. The exfoliated BN and MoS2 nanosheets with nanoscale roughness make the surface highly hydrophobic in nature. As a result, the BN-MoS2 heterostructure showed superior superhydrophobic performance with high water contact angle of 165.9 degrees , which is much higher than the value reported in the literature. PMID- 28554205 TI - The relationship between adherence and total spending among Medicare beneficiaries with type 2 diabetes. AB - OBJECTIVES: This study examined the relationship between medication adherence, cost sharing measured as out-of-pocket spending, and total annual spending in Medicare beneficiaries with type 2 diabetes (T2D) to evaluate whether pharmacy cost-sharing programs have the potential to decrease adherence. These programs may unintentionally increase the risk of medical complications and may result in higher spending overall. STUDY DESIGN: This retrospective study used 2006 to 2009 Medicare claims data. The sample included patients 65 years or older with T2D (at least 1 claim with International Classification of Diseases, 9th Revision, Clinical Modification codes 250.x0 and 250.x2 and at least 1 antidiabetes drug claim). METHODS: Medication adherence was measured as proportion of days covered over the first 12 months of observation. Spending and adherence outcomes were defined in deciles. RESULTS: The sample included 12,305 patient-year observations. Pharmacy spending for patients in the most adherent (10th) decile was 59% higher than that for patients in the least adherent (1st) decile ($4839 vs $3046). Yet, patients in the 10th decile had 49% lower total ($12,531 vs $24,468) and 64% lower medical spending ($7692 vs $21,421) than patients in the 1st decile. Greater out-of-pocket spending was correlated with lower adherence and higher total and medical spending. CONCLUSIONS: This study describes a widespread variation in medication adherence, pharmacy cost sharing, and medical spending in a sample of Medicare beneficiaries with T2D. We found that lower adherence was correlated with higher cost sharing in the Medicare population, perhaps because of unobserved confounding factors. However, the existing literature on patients with employer-sponsored insurance suggests some of this correlation may be indicative of causal relationships. PMID- 28554203 TI - The Expanding Significance of Inositol Polyphosphate Multikinase as a Signaling Hub. AB - The inositol polyphosphates are a group of multifunctional signaling metabolites whose synthesis is catalyzed by a family of inositol kinases that are evolutionarily conserved from yeast to humans. Inositol polyphosphate multikinase (IPMK) was first identified as a subunit of the arginine-responsive transcription complex in budding yeast. In addition to its role in the production of inositol tetrakis- and pentakisphosphates (IP4 and IP5), IPMK also exhibits phosphatidylinositol 3-kinase (PI3-kinase) activity. Through its PI3-kinase activity, IPMK activates Akt/PKB and its downstream signaling pathways. IPMK also regulates several protein targets non-catalytically via protein-protein interactions. These non-catalytic targets include cytosolic signaling factors and transcription factors in the nucleus. In this review, we highlight the many known functions of mammalian IPMK in controlling cellular signaling networks and discuss future challenges related to clarifying the unknown roles IPMK plays in physiology and disease. PMID- 28554206 TI - Concentration of high-cost patients in hospitals and markets. AB - OBJECTIVES: Although we know that healthcare costs are concentrated among a small number of patients, we know much less about the concentration of these costs among providers or markets. This is important because it could help us to understand why some patients are higher-cost compared with others and enable us to develop interventions to reduce costs for these patients. STUDY DESIGN: Observational study. METHODS: We used a 20% sample of Medicare fee-for-service claims data from 2011 and 2012, and defined high-cost patients as those in the top 10% of standardized costs. We then characterized high-concentration hospitals as those with the highest proportion of high-cost patient claims, and high concentration markets as the Hospital Referral Regions (HRRs) with the highest proportion of high-cost patients. We compared the characteristics and outcomes of each. RESULTS: High-concentration hospitals had 69% of their inpatient Medicare claims from high-cost Medicare beneficiaries compared with 51% for the remaining 90% of hospitals. These hospitals were more likely to be for-profit and major teaching hospitals, located in urban settings, and have higher readmission rates. High-concentration HRRs had 13% high-cost patients compared with 9.5% for the remaining 90% of HRRs. These HRRs had a smaller supply of total physicians, a greater supply of cardiologists, higher rates of emergency department visits, and significantly higher expenditures on care in the last 6 months of life. CONCLUSIONS: High-cost beneficiaries are only modestly concentrated in specific hospitals and healthcare markets. PMID- 28554207 TI - Provider type and management of common visits in primary care. AB - OBJECTIVES: Debate continues on whether nurse practitioners (NPs) and physician assistants (PAs) are more likely to order ancillary services, or order more costly services among alternatives, than primary care physicians (PCPs). We compared prescription medication and diagnostic service orders associated with NP/PA versus PCP visits for management of neck or back (N/B) pain or acute respiratory infection (ARI). STUDY DESIGN: Retrospective, observational study of visits from January 2006 through March 2008 in the adult primary care practice of Kaiser Permanente in Atlanta, Georgia. METHODS: Data were obtained from electronic health records. NP/PA and PCP visits for N/B pain or ARI were propensity score matched on patient age, gender, and comorbidities. RESULTS: On propensity score-matched N/B pain visits (n = 6724), NP/PAs were less likely than PCPs to order a computed tomography (CT)/magnetic resonance image (MRI) scan (2.1% vs 3.3%, respectively) or narcotic analgesic (26.9% vs 28.5%) and more likely to order a nonnarcotic analgesic (13.5% vs 8.5%) or muscle relaxant (45.8% vs 42.5%) (all P <=.05). On propensity score-matched ARI visits (n = 24,190), NP/PAs were more likely than PCPs to order any antibiotic medication (73.7% vs 65.8%), but less likely to order an x-ray (6.3% vs 8.6%), broad-spectrum antibiotic (41.5% vs 42.5%), or rapid strep test (6.3% vs 9.7%) (all P <=.05). CONCLUSIONS: In the multidisciplinary primary care practice of this health maintenance organization, NP/PAs attending visits for N/B pain or ARI were less likely than PCPs to order advanced diagnostic radiology imaging services, to prescribe narcotic analgesics, and/or to prescribe broad-spectrum antibiotics. PMID- 28554209 TI - Real-world evidence and the behavioral economics of physician prescribing. AB - The projections for the rising cost of healthcare have spurred robust dialogue, and among the many targets for cost control are specialty drugs. An important question thus becomes: Are behavioral economic factors driving physician prescribing? This article presents a review of leading behavioral economic theories and their application to the results of an Oncology Medical Home pilot that reversed incentives from drug administration to patient care. A host of these theories may explain the irrational economic actors in regard to physician prescribing, including heuristics, framing, and defaults. Ultimately, the complex interplay of behavioral economics may result in reimbursement methodology alternatives to the prevailing fee-for-service payment system having less impact on prescribing behavior than has been conjectured. PMID- 28554208 TI - Physician variation in lung cancer treatment at the end of life. AB - OBJECTIVES: To determine whether a treating oncologist's characteristics are associated with variation in use of chemotherapy for patients with advanced non small cell lung cancer (aNSCLC) at the end of life. STUDY DESIGN: Retrospective cohort. METHODS: Using the 2009 Surveillance, Epidemiology, and End Results Medicare database, we studied chemotherapy receipt within 30 days of death among Medicare enrollees who were diagnosed with aNSCLC between 1999 and 2006, received chemotherapy, and died within 3 years of diagnosis. A multilevel model was constructed to assess the contribution of patient and physician characteristics and geography to receiving chemotherapy within 30 days of death. RESULTS: Among 21,894 patients meeting eligibility criteria, 43.1% received chemotherapy within 30 days of death. In unadjusted bivariate analyses, female sex, Asian or black race, older age, and a greater number of comorbid diagnoses predicted lower likelihood of receiving chemotherapy at the end of life (P <=.038 for all comparisons). Adjusting for patient and physician characteristics, physicians in small independent practices were substantially more likely than those employed in other practice models, particularly academic practices or nongovernment hospitals, to order chemotherapy for a patient in the last 30 days of life (P <.001 for all comparisons); female physicians were less likely than males to prescribe such treatment (P = .04). CONCLUSIONS: Patients receiving care for aNSCLC in small independent oncology practices are more likely to receive chemotherapy in the last 30 days of life. PMID- 28554210 TI - Can primary care physicians accurately predict the likelihood of hospitalization in their patients? PMID- 28554211 TI - The Breathmobile improves the asthma medication ratio and decreases emergency department utilization. AB - OBJECTIVES: An Asthma Medication Ratio (AMR) of >=0.50 has gained recognition as a metric related to improved asthma outcomes. The goals of this study were to evaluate asthma outcomes in relation to this threshold in Hispanic children with high-risk asthma and to compare the effectiveness of the Breathmobile (BM) program with usual care (UC), utilizing the AMR-related emergency department utilization (ED) rate. STUDY DESIGN: Healthcare utilization and prescription claims recorded January 1, 2011, to June 23, 2014, were evaluated pre- versus post year in 164 Medicaid-enrolled children, aged 2 to 18 years, with high-risk persistent asthma (BM group: n = 72; UC group: n = 92). METHODS: High risk was defined by >=2 oral corticosteroid fills, or >=2 ED visits (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 493.0-493.9) or >=1 IP stay (ICD-9-CM codes 493.0-493.9) in the pre-year. Poisson regression was utilized to compare asthma outcomes pre- versus post year in BM and UC groups and to describe the average number of ED days per 100 patients treated in relation to AMR. RESULTS: An AMR of >=0.50 versus <0.50 was related to 49% fewer ED visits (P <.05). BM proved to be more effective than UC in increasing the percent who achieved an AMR >=0.50 from a baseline of 47.2% to 80.6% versus 50.0% to 65.2% post year, respectively. This difference was reflected in the significant 52% reduction in average number of ED visits post year for the BM cohort versus 13% for the UC cohort. CONCLUSIONS: View achievement of the AMR >=0.50 as an informative metric in program evaluation and for healthcare organizations to measure the quality of care provided to high-risk patients with asthma. PMID- 28554212 TI - Patients' preferences for receiving laboratory test results. AB - OBJECTIVES: The laboratory, as a diagnostic department in the hospital, plays an important role in the treatment and prevention of diseases. Paying attention to patients' preferences for communication of test results may provide a better and more responsive system for delivering these results. This study aimed to identify patient preferences regarding receiving their laboratory test results electronically and to identify the reasons behind their choice. STUDY DESIGN: Descriptive-analytical study. METHODS: This study was carried out in 2015 with 200 patients who had access to the internet and had been referred at least once previously to the hospital laboratory department to receive their test results. Data were collected through an expert-validated questionnaire, and its reliability was confirmed by test-retest (P = .8). Data were analyzed using chi2 and marginal independence SPSS and R software. RESULTS: Ninety-eight percent of participants preferred to be notified by short message service when their test results were ready. All participants preferred to receive their test results online, and 82.5% (n = 165) preferred to receive both normal and abnormal test results this way. The main reason for receiving results online was time savings, which was reported by 77% of participants, followed by lowering the chance of missing the results (31%). About 40% of participants thought e-mail notification was more secure than accessing the results through a hospital website. CONCLUSIONS: Findings showed that although patients wanted to benefit from online services for receiving their test results, they were concerned about confidentiality and security. Before using online technologies, security measures necessary to protect patient privacy and to gain the trust of patients should be defined. PMID- 28554213 TI - Medication burden in patients with acute coronary syndromes. AB - OBJECTIVES: Cardioprotective medications improve outcomes following acute coronary syndromes (ACS) but add to medication complexity. We set out to describe the use of these medications and quantify medication changes in patients admitted and discharged for ACS. STUDY DESIGN: Retrospective cohort study. METHODS: Using archived data from the electronic health record (EHR), we evaluated patients with ACS admitted to 1 of 2 hospitals between January 2008 and December 2012. Patients aged 18 to 89 years who were discharged with a principal diagnosis of ACS were included in the study. Descriptive statistics were compiled and medication use was compared at 3 time points: admission, discharge, and within 90 days post discharge. RESULTS: This study included 4767 patients. The mean number of total medications increased from 8.6 +/- 6.5 to 11.4 +/- 5.4 from admission to discharge, dropping slightly within 90 days post discharge (11.1 +/- 5.2). Patients taking medications at least twice daily increased from 6.4 of 10 at admission to 9 of 10 at discharge. Cardioprotective medication use increased by a relative 76% for aspirin, 72% for statins, 85% for beta-blockers, and 29% for angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers from admission to discharge, whereas P2Y12 receptor inhibitor use increased 4-fold. CONCLUSIONS: Medication complexity among patients with ACS are high, with notable changes from admission to discharge. Awareness of the extent of medication burden provides clinicians and policy makers with insight to help address medication use during the ACS peri-hospitalization period. PMID- 28554214 TI - Battling the chargemaster: a simple remedy to balance billing for unavoidable out of-network care. AB - OBJECTIVES: To develop an effective legal mechanism to combat chargemaster abuses and to facilitate price transparency. STUDY DESIGN: Applying legal doctrines to out-of-network (OON) billing disputes. METHODS: We reviewed rudimentary contract law and examined the law's handling of contracts where prices have not been specified in advance. These cases are the controlling authority to guide courts, handling of surprise and OON billing problems. We then compared legal remedies that correct OON billing abuses to prevailing legislative and regulatory approaches. RESULTS: Our analysis suggests that providers have no legal authority to collect chargemaster rates from surprise and OON billing abuses. A proper application of contract law can end such abuses and would facilitate superior pricing incentives to other strategies designed to end balance billing disputes. CONCLUSIONS: Chargemaster rates on uninsured and OON patients impose significant financial burdens on the vulnerable, distort medical prices, and inflate healthcare costs. Applying rudimentary contract law to these practices offers a solution that is simpler and more effective than other administrative and legislative schemes recently adopted in several states. It will prevent providers from hiding behind a convoluted hospital pricing system, encourage the development of attractive narrow-network insurance products, and shield urgently sick individuals from the dread of medical predation. Patients and payers should know that they are under no obligation to pay surprise bills containing chargemaster rates, and state attorneys general can use the law to prevent providers from pursuing chargemaster-related collection efforts against patients. PMID- 28554215 TI - Implantable Cardioverter Defibrillator for the Primary Prevention of Sudden Cardiac Death in Patients With Nonischemic Cardiomyopathy. AB - OBJECTIVES: The benefit of implanting patients with nonischemic cardiomyopathy (NICMP) with an implantable cardioverter defibrillator (ICD) for primary prevention has not been demonstrated in any randomized controlled trial. This also holds true for the most recent study on the subject. This systematic review and meta-analysis aims to examine the effectiveness of primary prevention using an ICD in the NICMP population. METHODS: We searched the literature for randomized controlled trials examining the effectiveness of ICD in reducing all cause mortality in patients with NICMP. The primary outcome of our analysis was all-cause mortality. A fixed-effects model was used for the primary analysis. RESULTS: A total of 5 randomized controlled trials focused on primary prevention of sudden cardiac death for patients with NICMP that met our inclusion and exclusion criteria. They have individually failed to consistently show a benefit for the use of an ICD in this population. However, the cumulative effect of ICD implantation in patients with NICMP demonstrated a 21% relative risk reduction in mortality (Relative risk [RR]: 0.79; confidence interval: 0.66-0.95). CONCLUSION: There is a decrease in mortality with the use of ICD for primary prevention in patients with NICMP having left ventricular ejection fraction <35%. PMID- 28554216 TI - Nanoparticulation improves bioavailability of Erlotinib. AB - OBJECTIVES: Nanoparticulation using fat and supercritical fluid (NUFSTM) is a drug delivery platform technology enabling efficient and effective formulation of poorly soluble drugs. We performed experiments to examine whether NUFSTM could improve poor bioavailability and reduce fed-fasted bioavailability variances of erlotinib (Ert). METHODS: NUFS-Ert was prepared using NUFSTM technology; its physical properties were characterized, and drug release was measured. Furthermore, in vitro and in vivo efficacy tests and pharmacokinetic analysis were performed. RESULTS: NUFS-Ert nanoparticles had an average size of 250 nm and were stable for 2 months at 40 degrees C, 4 degrees C, and room temperature. The dissolution rate of NUFS-Ert increased in bio-relevant dissolution media. NUFS-Ert was more potent in inhibiting EGF signaling and in suppressing the proliferation of A549, a human non-small cell lung cancer cell line. Furthermore, A549 xenografts in BALB/c nude mice treated with NUFS-Ert regressed more efficiently than those in the mice treated with vehicle or Tarceva(r). In addition, experimental lung metastasis was more efficiently inhibited by NUFS-Ert than by Tarceva(r). The relative bioavailability of NUFS-Ert compared with that of Tarceva(r) was 550% and the ratio of the area under the concentration-time curve (AUC) of fed state to the AUC of fasted state was 1.8 for NUFS-Ert and 5.8 for Tarceva(r). CONCLUSIONS: NUFS-Ert could improve poor bioavailability and reduce fed-fasted bioavailability variances of Ert. NUFS-Ert was more efficacious than Tarceva(r). PMID- 28554217 TI - Oxidative Stress Markers and Metal Ions are Correlated With Cognitive Function in Alzheimer's Disease. AB - We investigated oxidative stress markers and metal ions in patients with Alzheimer's disease (AD). The serum levels of ceruloplasmin (CER), C-reactive protein (CRP), uric acid (UA), homocysteine (Hcy), copper, iron, and zinc were determined in 125 patients with AD (mild, n = 2 8; moderate, n = 42; and severe, n = 55) and 40 healthy control (HC) participants. Compared to HC, CER and UA levels were significantly lower in moderate and severe AD groups, whereas CRP and Hcy levels were significantly higher in the severe AD group. Copper level was significantly higher in moderate and severe AD groups than the other groups. Compared to HC, iron level was significantly higher in patients with AD, whereas zinc level was significantly lower in patients with AD. In patients with AD, the severity of cognitive impairment was positively correlated with CER, UA, and zinc levels, whereas it was negatively correlated with copper level. Taken together, our findings provide a novel approach to assess AD progression. PMID- 28554218 TI - Implications of sulfotransferase activity in interindividual variability in drug response: clinical perspective on current knowledge. AB - The interindividual variability in drug response is a major issue in clinical practice and in drug development. Sulfoconjugation is an important Phase II reaction catalyzed by cytosolic sulfotransferases (SULTs), playing a major role in homeostatic functions, xenobiotic detoxification, and carcinogen bioactivation. SULT display wide interindividual variability, explained only partially by genetic variation, suggesting that other non-genetic, epigenetic, and environmental influences could be major determinants of variability in SULT activity. This review focuses on the factors known to influence SULT variability in expression and activity and the available evidence regarding the impact of SULT variability on drug response. PMID- 28554219 TI - Differential diagnosis of a rare papillary tumor and mucinous adenocarcinoma. AB - Ciliated muconodular papillary tumors are characterized as rare papillary tumors of the peripheral lung, and involve ciliated, goblet, and basal cell proliferation with mucin secretion. We report the case of a 76-year-old woman who had an irregular solid nodule in the lung on chest computed tomography during a health screening. A wedge resection was performed. Although the intraoperative cytological diagnosis was mucinous adenocarcinoma, the final histological diagnosis was ciliated muconodular papillary tumor. The postoperative course was uneventful, with no recurrence at 24 months after surgery. Cytological diagnosis of ciliated muconodular papillary tumor can be difficult because of its similarity to mucinous adenocarcinoma. PMID- 28554220 TI - Experiences of hospital-based multidisciplinary team meetings in oncology: An interview study among participating general practitioners. AB - BACKGROUND: Cancer care has become complex, requiring healthcare professionals to collaborate to provide high-quality care. Multidisciplinary oncological team (MDT) meetings in the hospital have been implemented to coordinate individual cancer patients' care. General practitioners (GPs) are invited to join, but their participation is minimal. OBJECTIVES: Aim of this study is to explore participating GPs' perceptions of their current role and to understand their preferences towards effective role execution during MDT meetings. METHODS: In May to June 2014, semi-structured interviews (n = 16) were conducted involving GPs with MDT experience in Belgium. The analysis was done according to qualitative content analysis principles. RESULTS: Attendance of an MDT meeting is perceived as part of the GP's work, especially for complex patient care situations. Interprofessional collaborative relationships and the GP's perceived benefit to the MDT meeting discussions are important motivators to participate. Enhanced continuity of information flow and optimized organizational time management were practical aspects triggering the GP's intention to participate. GPs valued the communication with the patient before and after the meeting as an integral part of the MDT dynamics. CONCLUSION: GPs perceive attendance of the MDT meeting as an integral part of their job. Suggestions are made to enhance the efficiency of the meetings. PMID- 28554221 TI - A Review of Prognostic Tools in Heart Failure. AB - A minority of patients with end-stage disease are referred to palliative medicine for consultation in advanced heart failure. Educating stakeholders, including primary care, cardiology, and critical care of the benefits of hospice and palliative medicine for patients with poor prognosis, may increase appropriately timed referrals and improve quality of life for these patients. This article reviews multiple tools useful in prognostication in the setting of advanced heart failure. PMID- 28554222 TI - Physical activity: Health impact, prevalence, correlates and interventions. AB - OBJECTIVE: To provide a broad overview of the state of physical activity (PA) research in the form of (1) definitions of PA, (2) health benefits, (3) prevalence, (4) correlates and (5) interventions. DESIGN: A high-level overview of published reviews of the literature. RESULTS: Regular PA is an effective primary and secondary preventative strategy against at least 25 chronic medical conditions with risk reduction typically in the 20-30% range. While approximately 75% of adults meet recommended PA guidelines, the prevalence is slightly lower for women compared to men, and considerably lower for youth, older adults and those in higher income countries. Motivation, self-efficacy and self-regulation remain consistent correlates of PA. Interventions show PA changes in the small effect size range for adults and youth but the heterogeneity is considerable across studies. Only a few (aggregate of behavioural regulation strategies, supervision, high frequency of contact) reliable moderators of intervention success were identified across study quality, sample characteristics, theory/behaviour change techniques and delivery modes/settings. CONCLUSION: PA research should continue to examine the mechanisms causing health outcomes, the dose that can lead to clinically relevant changes in health status, the scope and validity of PA surveillance and innovative behaviour change techniques, while improving the reach and duration of PA interventions. PMID- 28554224 TI - 'Now he sings'. The My Musical Memories Reminiscence Programme: Personalised interactive reminiscence sessions for people living with dementia. AB - This paper explores the impact of the My Musical Memories Reminiscence Programme (MMMRP), an innovative intervention that adopts a music-based reminiscence approach. MMMRP builds on the format of the popular Singing for the Brain sessions with the aim of increasing opportunities for interaction and reminiscence amongst people living with dementia. Data were collected pre- and post-intervention and three months later using structured observation, interviews and focus groups. Results suggest that the programme had a positive impact on participants by promoting engagement, reminiscence and social interaction. For some individuals the impacts continued beyond their participation in the programme. A range of key facilitators for successful implementation of this approach were identified including the Session Leader role, the involvement of informal carers and the input of volunteers. PMID- 28554223 TI - Outpatient management of severe ovarian hyperstimulation syndrome: a systematic review and a review of existing guidelines. AB - Ovarian hyperstimulation syndrome (OHSS) is a potentially serious complication of assisted reproductive treatment. Management of women with severe OHSS has traditionally included hospitalisation for close monitoring and supportive treatment. The aim of this review is to assess the evidence for safety and efficacy of outpatient management of severe OHSS. A systematic review of studies describing outpatient management options was performed. Current guidance from advisory bodies was also reviewed. Outpatient management has been found in observational studies to be safe and cost-effective compared to inpatient management. Paracentesis of ascitic fluid seems to be effective treatment for severe OHSS along with supportive management including maintenance of fluid balance and preventative measures against thrombo-embolism. GnRH antagonist was shown in few studies to be effective in treatment of early severe OHSS although further research is required to assess its role in this context. Appropriate outpatient set up and protocols are essential to provide safe outpatient management for women with severe OHSS. PMID- 28554225 TI - Lutein improves cell viability and reduces Alu RNA accumulation in hydrogen peroxide challenged retinal pigment epithelial cells. AB - PURPOSE: Dysfunction of the microRNA (miRNA)-processing enzyme DICER1 and Alu RNA accumulation are linked to the pathogenesis of age-related macular degeneration (AMD). This study determined the optimal dose of lutein (LUT) and zeaxanthin (ZEA) to protect human retinal pigment epithelium (RPE) cells against hydrogen peroxide (H2O2). The effect of the optimal dose of LUT and ZEA as DICER1 and Alu RNA modulators in cultured human RPE cells challenged with H2O2 was investigated. MATERIALS AND METHODS: ARPE-19 cells were pre-treated with LUT, ZEA, or both for 24 h before 200 MUM H2O2 challenge. Cell viability was measured by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. DICER1 and Alu RNA were quantified by western blotting and real-time polymerase chain reaction, respectively. RESULTS: H2O2 increased cell Alu RNA expression and decreased cell viability of ARPE-19, but had no significant impact on the DICER1 protein level. LUT, alone and in combination with ZEA pre-treatment, prior to H2O2 challenge significantly improved cell viability of ARPE-19 and reduced the level of Alu RNA compared to the negative control. CONCLUSIONS: These results support the use of LUT alone, and in combination with ZEA, in AMD prevention and treatment. This study is also the first to report LUT modulating effects on Alu RNA. PMID- 28554226 TI - Radiofrequency ablation using a multiple-electrode switching system for hepatocellular carcinoma within the Milan criteria: long-term results. AB - PURPOSE: To assess the long-term outcome of 516 consecutive patients treated with multiple-electrode switching system (MESS) radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) that met the Milan criteria. MATERIALS AND METHODS: We performed 522 MESS RFAs on 516 patients from December 2006 to June 2011. A total of 956 tumours that met the Milan criteria with an average diameter of 2.64 cm (range, 0.9-4.6 cm) were treated with MESS RFA. Ultrasonic contrast and serum alpha-fetoprotein (AFP) were measured every 2 months during the first postoperative year and every 4 months thereafter. Enhanced computed tomography was performed every 6 months. Survival was estimated using the Kaplan-Meier method. Follow-up was censored at 60 months. Multivariate analysis was performed using the Cox proportional hazards model. RESULTS: For the 956 HCC tumours, the complete ablation rate with MESS was 98.83% (510/516). During a median of 34 months (IQR, 23-52 months) of follow-up, 171 patients died and 4 were lost to follow-up (15, 30, 38 and 42 months). The cumulative incidence of local tumour progression at 1, 3 and 5 years was 0.39%, 4.96% and 6.66%, respectively, and the 1-, 3- and 5-year overall survival was 99.42%, 83.97% and 68.42%, respectively. Tumour size >30 mm was the only parameter that was predictive of local tumour progression (p < .0001). Risk factors associated with overall survival included prothrombin time >14 s, serum AFP levels >200 ng/mL and tumour abutting vessel diameter <5 mm. The complication rate was 1.74%. CONCLUSION: MESS RFA is a safe and effective method for HCC treatment. This approach results in a high local progression-free survival for HCC tumours that meet the Milan criteria. PMID- 28554227 TI - Modulating epigenetic memory through vitamins and TET: implications for regenerative medicine and cancer treatment. AB - Vitamins A and C represent unrelated sets of small molecules that are essential to the human diet and have recently been shown to intensify erasure of epigenetic memory in naive embryonic stem cells. These effects are driven by complementary enhancement of the ten-eleven translocation (TET) demethylases - vitamin A stimulates TET expression, whereas vitamin C potentiates TET catalytic activity. Vitamin A and C cosupplementation synergistically enhances reprogramming of differentiated cells to the naive state, but overuse may exaggerate instability of imprinted genes. As such, optimizing their use in culture media will be important for regenerative medicine and mammalian transgenics. In addition, mechanistic perception of how these vitamins interact with the epigenome may be relevant for understanding cancer and improving patient treatment. PMID- 28554228 TI - Predictive value of IL-35 and IL-17 in diagnosis of childhood asthma. AB - This study aimed to evaluate the correlation between serum levels of IL-17 and IL 35 and the presence and severity of childhood asthma. The study was performed on 60 diagnosed asthmatic children, who were further classified into four groups according to the Global Initiative for Asthma Guidelines for Asthma Severity and Control (GINA) 2016, plus 30 age- and sex-matched apparently healthy children. All participants were subjected to full medical history, clinical examination, pulmonary function tests and laboratory evaluation in the form of complete blood count (CBC), serum total IgE, IL-17 and IL-35 by ELISA. Our results revealed that eosinophils count, IgE and IL-17 were significantly higher in the asthmatic group than the control group (p < .001), while IL-35 levels were significantly lower in asthmatics than control (p < .001). A strong negative correlation was found between serum IL-17 and serum IL-35; a positive correlation was found between serum IL-17 and both of serum total IgE and eosinophils counts in atopic asthmatic patients, and serum IL-35 showed significant negative correlations with both. ROC analysis of the data showed that the cut-off value of IL-35 level was <189.5 pg/mL and for IL-17 level, it was >13.1 pg/mL; this value could predict childhood asthma with sensitivity of 81.7% and 83.3%, and specificity of 76.7% and 70%, respectively. A combination of both cytokines yielded an increase in sensitivity to 95%. In conclusion, in the current study, IL-17 is upregulated while IL-35 is downregulated in childhood asthma with a significant negative correlation between both. These results suggest that both may play an important role in the pathogenesis of childhood asthma. PMID- 28554229 TI - Positive factors associated with quality of life among Chinese patients with renal carcinoma: a cross-sectional study. AB - Quality of life and positive psychological variables has become a focus of concern in patients with renal carcinoma. However, the integrative effects of positive psychological variables on the illness have seldom been reported. The aims of this study were to evaluate the quality of life and the integrative effects of hope, resilience and optimism on the quality of life among Chinese renal carcinoma patients. A cross-sectional study was conducted at the First Hospital of China Medical University. 284 participants completed questionnaires consisting of demographic and clinical characteristics, EORTC QLQ-C30, Adult Hope Scale, Resilience Scale-14 and Life Orientation Scale-Revised from July 2013 to July 2014. Pearson's correlation and hierarchical regression analyses were performed to explore the effects of related factors. Hope, resilience and optimism were significantly associated with quality of life. Hierarchical regression analyses indicated that hope, resilience and optimism as a whole accounted for 9.8, 24.4 and 21.9% of the variance in the global health status, functioning status and symptom status, respectively. The low level of quality of life for Chinese renal carcinoma patients should receive more attention from Chinese medical institutions. Psychological interventions to increase hope, resilience and optimism may be essential to enhancing the quality of life of Chinese cancer patients. PMID- 28554231 TI - Plexiform neurofibroma as a cause of carpal tunnel syndrome in a radial deficiency patient. AB - We reported a rare peripheral nerve case, a patient developed carpal tunnel syndrome with a history of floating thumb in right hand. The median nerve was found expanded and spindle-shaped and a plexiform neurofibroma was diagnosed. Our case sheds light on anatomy and possible etiological association which may help clinical management. PMID- 28554230 TI - Transcutaneous Spinal Direct Current Stimulation Alters Resting-State Functional Connectivity. AB - Transcutaneous spinal direct current stimulation (tsDCS) is a noninvasive method that can modulate spinal reflexes, sensory afferent conduction, and even pain perception. Although neurophysiological evidence suggests that tsDCS alters somatosensory and nociceptive afferent conduction to the cortex, its supraspinal effects have not yet been investigated by using functional imaging to investigate tsDCS-induced alterations in intrinsic functional connectivity (FC). Therefore, we hypothesize that tsDCS-induced changes in neurophysiological measures might also be reflected in spontaneous brain activity. We investigated tsDCS-induced changes in somatosensory cortical connectivity by using seed-to-voxel-based analyses from the bilateral primary somatosensory cortex (S1) and the thalamus in a double-blind, crossover study design. Resting state FC was measured by using blood oxygenation level-dependent, functional magnetic resonance imaging (3T Philips) before and after anodal, cathodal, and sham tsDCS (20 min, 2.5 mA, active electrode centered over T11 spinous process, reference electrode over left shoulder blade) in a double-blind, crossover study of 20 healthy men (24 +/- 0.7 years). As compared with sham, anodal tsDCS resulted in a decreased connectivity between the S1 and the ipsilateral posterior insula for both left and right hemispheres. Anodal tsDCS also resulted in decreased thalamic connectivity with the anterior cingulate cortex, and increased connectivity between S1 and the thalamus. Cathodal tsDCS showed increased FC between the right thalamus and both left and right posterior insulae, and decreased connectivity between the S1 seeds and the occipital cortex. Our results provide evidence of supraspinal effects of tsDCS and suggest that tsDCS may provide a noninvasive intervention that is able to target cortical sensory networks. PMID- 28554232 TI - Two new monoterpenoid glycosides from the fresh rhizome of Tongling White Ginger (Zingiber officinale). AB - Two new monoterpenoid glycosides, trans-1,8-cineole-3,6-dihydroxy-3-O-beta-D glucopyranoside (1), and 5,9-dihydroxy borneol 2-O-beta-D-glucopyranoside (2), together with four known monoterpenoid glycosides (3-6), were isolated from the water-soluble constituents of the fresh rhizome of Tongling White Ginger (Zingiber officinale). Their structures were decisively elucidated by spectroscopic analysis. In vitro tests for antimicrobial activity showed that compounds 1 and 3 possess significant activity against two Gram-positive organisms, Staphylococcus aureus and Staphylococcus epidermidis. PMID- 28554234 TI - Molecular characterization and therapeutic reaction to dasatinib in a CML patient harboring a novel e8a2 BCR-ABL1 transcript with a somatic mutation in TP53BP2 and cadherin-10 genes. PMID- 28554233 TI - Hyaluronic acid and Arg-Gly-Asp peptide modified Graphene oxide with dual receptor-targeting function for cancer therapy. AB - Graphene oxide (GO) modified with hyaluronic acid (HA) and Arg-gly-asp peptide (RGD) was designed as a dual-receptor targeting drug delivery system to enhance the specificity and efficiency of anticancer drug delivery. Firstly, GO-HA-RGD conjugate was characterized to reveal its structure and morphology. Whereafter, doxorubicin (Dox) as a model drug was loaded on GO-HA-RGD carrier, which displayed a high loading rate (72.9%, GO:Dox (w/w) = 1:1), pH-response and sustained drug release behavior. Cytotoxicity experiments showed that GO-HA-RGD possessed excellent biocompatibility towards SKOV-3 and HOSEpiC cells. Additionally, the GO-HA-RGD/Dox had a stronger cytotoxicity for SKOV-3 cells than either GO-HA/Dox (single receptor) or GO/Dox (no receptor). Moreover, celluar uptake studies illustrated that GO-HA-RGD conjugate could be effectively taken up by SKOV-3 cells via a synergic effect of CD44-HA and integrin-RGD mediated endocytosis. Hence, GO-HA-RGD nanocarrier is able to be a promising platform for targeted cancer therapeutic. PMID- 28554235 TI - The influence of current mood state, number of previous affective episodes and predominant polarity on insight in bipolar disorder. AB - BACKGROUND: Although many studies have explored the effect of current affective episodes on insight into bipolar disorder, the potential interaction between current mood state and previous affective episodes has not been consistently investigated. OBJECTIVE: To explore the influence of dominant polarity, number of previous affective episodes and current affective state on insight in bipolar disorder patients in euthymia or mania. METHODS: A total of 101 patients with bipolar disorder were recruited for the study, including 58 patients in euthymia (30 with no defined predominant polarity and 28 with manic predominant polarity) and 43 in mania (26 with no defined predominant polarity and 17 with manic predominant polarity). Patients underwent a clinical assessment and insight was evaluated through the Insight Scale for Affective Disorders. RESULTS: Bipolar disorder patients in mania had worse insight than those in euthymia, with no effect of dominant polarity. In addition, positive psychotic symptoms showed a significant effect on insight and its inclusion as a covariate eliminated differences related to mood state. Finally, the number of previous manic or depressive episodes did not correlate with insight level. CONCLUSIONS: Mania is a predictor of loss of insight into bipolar disorder. However, it is possible that its contribution is linked to the more frequent presence of psychotic symptoms in this state. Dominant polarity and number/type of previous affective episodes have a limited impact on insight. PMID- 28554236 TI - Anaplastic Ependymoma With Ganglionic Differentiation: Report of a Rare Case and Implications in Diagnosis. AB - Ependymomas are glial neoplasms with rare cases exhibiting neuronal differentiation. We describe a case of spinal anaplastic ependymoma with ganglionic differentiation in a 28-year-old woman. The ganglionic component was labeled by synaptophysin, whereas the rest of the tumor showed features of an anaplastic ependymoma. Stem cell marker MELK was noted to stain both the neoplastic ependymal and ganglionic components, possibly suggesting a stem cell/progenitor origin for the tumor with subsequent divergent differentiation. PMID- 28554237 TI - Rapid and frequent psychiatric readmissions: associated factors. AB - OBJECTIVE: This article aims to examine the impact of clinical and demographic factors on both rapid readmission (being readmitted within 30 d) and frequent readmission (experiencing three or more admissions) in a London mental health trust. METHODS: A four-year study period with a sample of 7648 inpatients were examined with chi-square or Mann-Whitney U tests, and binary logistic regressions to assess the associations and possible predictors of rapid (readmitted within 30 d) and frequent (admitted at least three times) readmission. RESULTS: Frequent admitters were more likely to be unemployed, have more care-coordinators, be living in accommodation with support, be Black or Black British, and to have certain diagnoses. Binary logistic regression revealed that our variables of interest explained between 36.1 and 60.9% of the variation in number of readmissions (+/-3 admissions), and between 3.7 and 4.2% of the variation in time to readmission (+/-30 d). CONCLUSIONS: Identifying factors that are associated with rehospitalisation and understanding their importance is necessary to reduce the risk of readmission. This study suggests that particular demographic, clinical and treatment factors require consideration to tackle the seemingly wide range of factors that could be affecting readmission to inpatient services. PMID- 28554239 TI - Video Communication With Cognitively Intact Nursing Home Residents: A Scoping Review. AB - Limited research exists examining video communication among cognitively intact nursing home residents to connect with family. This scoping review evaluated existing literature for video communication usage with nursing home residents, family, and nursing homes. A comprehensive search was completed using PubMed and EBSCOhost (including AgeLine, CINAHL, and PsycINFO) between 1972 and 2016 to locate English-language articles. The analysis identified five eligible studies (four involved an intervention, one assessed family views) meeting inclusion criteria. Findings included, seeing family members separated by distance, seeing other parts of their life, and visually monitoring resident's health. Participants described frustration with technology limitations, such as video or audio lag. Current literature does not show a comprehensive assessment of video communication usage for residents, family, and nursing homes. Future studies should address the complexity of the intersection of the person, nursing home, and families in terms of potential benefits and capability of video communication use with residents. PMID- 28554238 TI - Greater sensitivity to multiple sclerosis disability worsening and progression events using a roving versus a fixed reference value in a prospective cohort study. AB - BACKGROUND: Confirmed Expanded Disability Status Scale (EDSS) progression occurring after a fixed-study entry baseline is a common measure of disability increase in relapsing-remitting multiple sclerosis (RRMS) studies but may not detect all disability progression events, especially those unrelated to overt relapses. OBJECTIVE: To evaluate possible measures of disability progression unrelated to relapse using EDSS data over ~5.5 years from the Tysabri(r) Observational Program (TOP). METHODS: TOP is an ongoing, prospective, open-label study in RRMS patients receiving intravenous 300 mg natalizumab every 4 weeks. Measures of increasing disability were assessed using as a reference either study baseline score or a "roving" system that resets the reference score after ?24- or ?48-week confirmation of a new score. RESULTS: This analysis included 5562 patients. Approximately 70% more EDSS progression events unrelated to relapse and 50% more EDSS worsening events overall were detected with a roving reference score (cumulative probability: 17.6% and 29.7%, respectively) than with a fixed reference baseline score (cumulative probability: 10.1% and 20.3%, respectively). CONCLUSION: In this long-term observational RRMS dataset, a roving EDSS reference value was more efficient than a study baseline EDSS reference in detecting progression/worsening events unrelated to relapses and thus the transition to secondary progressive disease. PMID- 28554240 TI - Numerical analysis of thermal impact of intramyocardial capillary blood flow during radiofrequency cardiac ablation. AB - PURPOSE: The thermal effect of the intramyocardial blood perfusion on the size of lesions created by radiofrequency cardiac ablation (RFCA) has not been adequately studied to date. Our objective was to assess the impact of including this phenomenon in RFCA computer modelling in terms of the thermal lesion depth created. METHODS: A computer model was built and computer simulations were conducted to assess the effect of including the blood perfusion term in the bioheat equation. This term mimics the intramyocardial blood flow (i.e., blood perfusion) in the cardiac wall at the site at which the RFCA is being conducted and hence represents a heat removing mechanism. When considered, blood perfusion rates ranged from 609 to 1719 ml/min/kg. Two electrode design and modes were considered: a non-irrigated electrode with constant temperature mode and an irrigated electrode with constant power mode. RESULTS: All the depths computed without including the blood perfusion term were larger than those that did include it, regardless of perfusion rate. The differences in lesion depth between ignoring and including blood perfusion increased over time; for a 60 s RFCA they were 0.45 and 1 mm for minimum and maximum perfusion rate, respectively. The differences were more or less independent of blood flow in the cardiac chamber, electrode type and ablation mode. CONCLUSIONS: The findings suggest that the heat sink effect of blood perfusion should be taken into account in the case of ablations (>1 minute) such as those conducted in RFCA of the ventricular wall. PMID- 28554241 TI - Interdisciplinary implementation of tacrolimus intravenous standard concentration in hematopoietic stem cell transplantation recipients. AB - Purpose Reduction in waste of intravenous (IV) tacrolimus, an immunosuppressant used to prevent graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients, was evaluated after standardizing the concentration. Methods A single-center, retrospective cohort study at a large academic comprehensive cancer center was performed comparing patient-specific intravenous tacrolimus doses (tacrolimus doses in 50, 100, or 250 mL of normal saline based on manufacturer's recommended concentration) to tacrolimus intravenous standard concentration (tacrolimus 1 mg in 250 mL of normal saline) continuous intravenous infusion titrated to prescribed dose. The cohort study was performed on two hematopoietic stem cell transplantation nursing units consisting of a prepilot phase during which time patient-specific intravenous tacrolimus doses were compounded and administered, followed by the pilot phase during which patients received tacrolimus intravenous standard concentration. The primary endpoint was reduction in tacrolimus intravenous bags wasted. Secondary endpoints were drug cost savings, decreased intravenous infusion line supplies, decrease in time needed to execute dose changes, reduction in infusion pump alerts, and number of patient safety events. Results Compared to the prepilot phase, there was a 64% reduction in tacrolimus intravenous bags wasted during the pilot phase ( p = 0.029), resulting in a mean monthly total cost savings of $224.31 for pilot units. Intravenous pump line use was reduced by 18% ( p = 0.067), yielding a monthly total cost savings of $84.02 for pilot units. The median time needed to execute dose changes and intravenous pump overrides was significantly reduced ( p < 0.0001, p < 0.0001, respectively). Conclusion This interdisciplinary quality improvement initiative led to increased efficiency, reduction in waste, and decreased intravenous pump alerts utilizing tacrolimus intravenous standard concentration. PMID- 28554242 TI - A new visualization method for navigated bronchoscopy. AB - OBJECTIVE: In flexible endoscopy techniques, such as bronchoscopy, there is often a challenge visualizing the path from start to target based on preoperative data and accessing these during the procedure. An example of this is visualizing only the inside of central airways in bronchoscopy. Virtual bronchoscopy (VB) does not meet the pulmonologist's need to detect, define and sample the frequent targets outside the bronchial wall. Our aim was to develop and study a new visualization technique for navigated bronchoscopy. MATERIAL AND METHODS: We extracted the shortest possible path from the top of the trachea to the target along the airway centerline and a corresponding auxiliary route in the opposite lung. A surface structure between the centerlines was developed and displayed. The new technique was tested on non-selective CT data from eight patients using artificial lung targets. RESULTS: The new display technique anchored to centerline curved surface (ACCuSurf) made it easy to detect and interpret anatomical features, targets and neighboring anatomy outside the airways, in all eight patients. CONCLUSIONS: ACCuSurf can simplify planning and performing navigated bronchoscopy, meets the challenge of improving orientation and register the direction of the moving endoscope, thus creating an optimal visualization for navigated bronchoscopy. PMID- 28554244 TI - Effectiveness of the progestin-only pill for migraine treatment in women: A systematic review and meta-analysis. AB - Background Migraine is highly prevalent in women (18%). Peak morbidity affects their most productive years, coinciding with peak fertility. Hormonal contraception is often tailored for migraine prevention. Estrogen-containing contraceptives may be contraindicated in women experiencing migraine with aura due to the risk of vascular events. While improvements in migraine with a progestin-only pill (POP), which inhibits ovulation are documented, the strength and quality of evidence has not been formally evaluated. Objectives To determine the effectiveness of progestin-only contraceptives for migraine treatment by systematic review and meta-analysis. Data sources and selection MEDLINE, EMBASE and Cochrane Libraries were searched (1980 to September 2016) for studies on progestin-only treatments for migraine. Studies in English on >4 non-menopausal women aged 18-50 with migraine diagnosed by formal criteria were included. Data extraction and analysis Data were quality-assessed using the GRADE system. A random effects model was used for pooled analyses. Results Pooled analyses of four studies demonstrated that desogestrel 75 mcg/day, POP significantly but modestly reduced the number of migraine attacks and migraine days. Reduced intensity and duration, reduced analgesic and triptan use were observed, along with improved headache-related quality of life. GRADE analysis indicated evidence was low to very low for each outcome measure. Adverse effects resulted in treatment cessation for <10% of participants. Two studies compared desogestrel POP to a combined oral contraceptive, demonstrating similar migraine outcomes for both treatments. Conclusions The desogestrel POP shows promise in improving migraine in women. Current evidence is observational and based on small samples of women using only one oral progestin-only formulation. Further randomized trials on additional progestin-only contraceptives are required to confirm their role in migraine management. PMID- 28554243 TI - Functional interactions between transient receptor potential M8 and transient receptor potential V1 in the trigeminal system: Relevance to migraine pathophysiology. AB - Background Recent genome-wide association studies have identified transient receptor potential M8 ( TRPM8) as a migraine susceptibility gene. TRPM8 is a nonselective cation channel that mediates cool perception. However, its precise role in migraine pathophysiology is elusive. Transient receptor potential V1 (TRPV1) is a nonselective cation channel activated by noxious heat. Both TRPM8 and TRPV1 are expressed in trigeminal ganglion (TG) neurons. Methods We investigated the functional roles of TRPM8 and TRPV1 in a meningeal inflammation based migraine model by measuring the effects of facial TRPM8 activation on thermal allodynia and assessing receptor coexpression changes in TG neurons. We performed retrograde tracer labeling to identify TG neurons innervating the face and dura. Results We found that pharmacological TRPM8 activation reversed the meningeal inflammation-induced lowering of the facial heat pain threshold, an effect abolished by genetic ablation of TRPM8. No significant changes in the heat pain threshold were seen in sham-operated animals. Meningeal inflammation caused dynamic alterations in TRPM8/TRPV1 coexpression patterns in TG neurons, and colocalization was most pronounced when the ameliorating effect of TRPM8 activation on thermal allodynia was maximal. Our tracer assay disclosed the presence of dura-innervating TG neurons sending collaterals to the face. Approximately half of them were TRPV1-positive. We also demonstrated functional inhibition of TRPV1 by TRPM8 in a cell-based assay using c-Jun N-terminal kinase phosphorylation as a surrogate marker. Conclusions Our findings provide a plausible mechanism to explain how facial TRPM8 activation can relieve migraine by suppressing TRPV1 activity. Facial TRPM8 appears to be a promising therapeutic target for migraine. PMID- 28554245 TI - A device for testing the dynamic performance of in situ force plates. AB - Force plates are often incorporated into motion capture systems for the calculation of joint kinetic variables and other data. This project aimed to create a system that could be used to check the dynamic performance of force plate in situ. The proposed solution involved the design and development of an eccentrically loaded wheel mounted on a weighted frame. The frame was designed to hold a wheel mounted in two orthogonal positions. The wheel was placed on the force plate and spun. A VICONTM motion analysis system captured the positional data of the markers placed around the rim of the wheel which was used to create a simulated force profile, and the force profile was dependent on spin speed. The root mean square error between the simulated force profile and the force plate measurement was calculated. For nine trials conducted, the root mean square error between the two simultaneous measures of force was calculated. The difference between the force profiles in the x- and y-directions is approximately 2%. The difference in the z-direction was under 0.5%. The eccentrically loaded wheel produced a predictable centripetal force in the plane of the wheel which varied in direction as the wheel was spun and magnitude dependent on the spin speed. There are three important advantages to the eccentrically loaded wheel: (1) it does not rely on force measurements made from other devices, (2) the tests require only 15 min to complete per force plate and (3) the forces exerted on the plate are similar to those of paediatric gait. PMID- 28554246 TI - Fungal infections in patients treated with ibrutinib: two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis. PMID- 28554247 TI - Association of social defeat stress-induced anhedonia-like symptoms with mGluR1 dependent decrease in membrane-bound AMPA-GluR1 in the mouse ventral midbrain. AB - Anhedonia is a core symptom of social defeat stress (SDS)-induced depression associated with the reward system. We previously reported that decreased membrane bound AMPA-GluR1 in the reward system is associated with lipopolysaccharide induced anhedonia-like symptoms. Since group I metabotropic glutamate receptor (mGluR) activation reduces the surface density of GluR1, we examined whether group I mGluR-dependent decrease in membrane-bound GluR1 in the reward system is involved in SDS-induced anhedonia-like symptoms. Mice exposed to SDS for 4 consecutive days had markedly decreased membrane-bound GluR1 and GluR2 in the prefrontal cortex (PFC) and membrane-bound GluR1 in the ventral midbrain (VM) along with lower sucrose preference (SP). Intra-PFC injection of the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG; 100 MUmol) demonstrated decrease in membrane-bound GluR1 and GluR2 in the PFC 2 and 24 h and membrane bound GluR1 in the VM 24 h after injection. Moreover, intra-PFC injection of DHPG decreased SP only in the second 24-h (24-48 h) period. Conversely, intra-VM injection of DHPG decreased SP in both the first and second 24-h period and decreased membrane-bound GluR1 in the VM 2 and 24 h after injection. Pre treatment with the mGluR1 antagonist JNJ16259685 (30 mg/kg, subcutaneous) prevented SDS-decreased SP and membrane-bound GluR1 in the VM. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP; 10 mg/kg, subcutaneous) prevented SDS-induced decrease in membrane-bound GluR1 and GluR2 in the PFC, whereas MPEP did not affect SDS-induced decrease in SP and membrane-bound GluR1 in the VM. These results suggest that mGluR1-mediated decrease in membrane-bound GluR1 in VM is involved in SDS-induced anhedonia-like symptoms. PMID- 28554248 TI - Apelin-13 attenuates cisplatin-induced cardiotoxicity through inhibition of ROS mediated DNA damage and regulation of MAPKs and AKT pathways. AB - Platinum-based chemotherapy represents one of the most effective ways in combating human cancers. However, the cardiotoxicity subsequent severely limited its clinical application. Increased evidences indicate that oxidative stress plays a crucial role in the pathological process of platinum-induced cardiotoxicity. It is reported that apelin-13 a bioactive peptide has the scavenging capacity of free radical, and it has the potential to regulate the cardiovascular system. Hence, the potential of apelin-13 to antagonize cisplatin induced cardiotoxicity was evaluated in H9c2 rat myocardial cells in vitro and in C57 mice in vivo. The results showed that cisplatin indeed caused DNA damage in H9c2 cells by promoting the accumulation of intracellular reactive oxygen species (ROS) and superoxide anion, which led to cell apoptosis and resulted in overt cardiotoxicity. However, apelin-13 pre-treatment effectively attenuated the cisplatin-induced ROS and superoxide anion generation, inhibited DNA damage, and suppressed the PARP cleavage and caspases activation. Further investigation revealed that apelin-13 blocked cisplatin-induced H9c2 cells apoptosis involving the regulation of MAPKs and PI3K/Akt signaling pathway. Importantly, apelin-13 co treatment also significantly attenuated cisplatin-induced cardiotoxicity in vivo by inhibiting myocardial cells apoptosis and improving angiogenesis in mice heart. Taken together, our results suggest that the use of apelin-13 may be an effective strategy for antagonizing the cardiotoxicity-induced by platinum-based chemotherapy. PMID- 28554249 TI - Suppression of asparaginyl endopeptidase attenuates breast cancer-induced bone pain through inhibition of neurotrophin receptors. AB - Objective Cancer-induced bone pain is a common clinical problem in breast cancer patients with bone metastasis. However, the mechanisms driving cancer-induced bone pain are poorly known. Recent studies show that a novel protease, asparaginyl endopeptidase (AEP) plays crucial roles in breast cancer metastasis and progression. We aim to determine the functions and targeted suppress of AEP in a mouse model of breast cancer-induced bone pain. Methods Breast cancer cells with AEP knocked-down or overexpression were constructed and implanted into the intramedullary space of the femur to induce pain-like behavior in mice. AEP specific inhibitors or purified AEP proteins were further used in animal model. The histological characters of femur and pain ethological changes were measured. The expressions of AEP and neurotrophin receptors (p75NTR and TrkA) in dorsal root ganglion and spinal cord were examined. Results Femur radiographs and histological analysis revealed that cells with AEP knocked-down reduced bone destruction and pain behaviors. However, cells with AEP overexpression elevated bone damage and pain behaviors. Further, Western blot results found that the expressions of p75NTR and TrkA in dorsal root ganglions and spinal cords were reduced in mice inoculated with AEP knocked-down cells. Targeted suppression of AEP with specific small compounds significantly reduced the bone pain while purified recombinant AEP proteins increased bone pain. Conclusions AEP aggravate the development of breast cancer bone metastasis and bone pain by increasing the expression of neurotrophin receptors. AEP might be an effective target for treatment of breast cancerinduced bone pain. PMID- 28554250 TI - Resveratrol-decreased hyperalgesia mediated by the P2X7 receptor in gp120-treated rats. AB - Background Chronic pain is a common symptom in human immunodeficiency virus (HIV) 1 infection/acquired immunodeficiency syndrome patients. The literature shows that the HIV envelope glycoprotein 120 (gp120) can directly cause hyperalgesia by stimulating primary sensory afferent nerves. The P2X7 receptor in the dorsal root ganglia (DRG) is closely related to neuropathic and inflammatory pain. In this study, we aimed to explore the effect of resveratrol (RES) on gp120-induced neuropathic pain that is mediated by the P2X7 receptor in the rat DRG. Results Mechanical hyperalgesia in rats treated with gp120 was increased compared with that in the sham group. The P2X7 expression levels in rats treated with gp120 were higher than those in the sham group. Co-localization of the P2X7 receptor and glial fibrillary acidic protein (GFAP, a marker of satellite glial cells [SGCs]) in the DRG SGCs of the gp120 group exhibited more intense staining than that of the sham group. RES decreased the mechanical hyperalgesia and P2X7 expression levels in gp120 treatment rats. Co-localization of the P2X7 receptor and GFAP in the gp120+ RES group was significantly decreased compared to the gp120 group. RES decreased the IL-1beta and TNF-alpha receptor (R) expression levels and ERK1/2 phosphorylation levels as well as increased IL-10 expression in the DRG of gp120-treated rats. Whole cell clamping demonstrated that RES significantly inhibited adenosine triphosphate-activated currents in HEK293 cells that were transfected with the P2X7 plasmid. Conclusions RES relieved mechanical hyperalgesia in gp120-treated rats by inhibiting the P2X7 receptor. PMID- 28554252 TI - Efficient isolation and culture of endothelial cells from venous malformation using the Rho-associated protein kinase inhibitor Y27632. AB - BACKGROUND: The investigation of primary cells from a pathological lesion can elucidate the pathogenesis of diseases, but, for vascular malformations in humans, such basic research is still stagnant, because the isolation and culture of vascular endothelial cells (ECs) is very difficult. To obtain a sufficient amount of ECs from venous malformation (VM) this study took advantage of a Rho associated protein kinase inhibitor, Y27632, which had been used for the efficient procurement of primary keratinocytes. METHODS: ECs were isolated and cultured from VM lesions, combining enzymatic digestion, cell sorting, and Y27632. The proliferative effect of Y27632 on ECs was examined by proliferation assay. The characteristics of the ECs cultured with Y27632 by EC marker expression and tube formation assay were also examined. RESULTS: Y27632 enhanced the proliferation of ECs and elongated the senescence of the cells. The expression of specific markers of ECs such as von Willebrand factor, endothelin 1, and VE-cadherin, was confirmed in the cells cultured with Y27632. In a tube formation assay, the cells cultured with Y27632 showed higher tube formation ability compared to the cells cultured without Y27632, indicating that Y27632 promoted the angiogenic capability of ECs. CONCLUSIONS: The protocol using Y27632 offers a new EC culture methodology and provides a new option for the biological investigation of vascular malformations. This new method will contribute to other types of vascular biology research as well. PMID- 28554251 TI - Association between circulating microRNA-208a and severity of coronary heart disease. AB - Circulating microRNA (miR)-208a is specifically expressed in the heart muscle, which is involved in the regulation of myosin during cardiac development. Previous studies reported that cardiac-specific miR-208a level is significantly higher in plasma of coronary heart disease (CHD) patients. However, whether it correlates with severity of CHD, has never been elucidated before. The aim of this study was to explore the association between miR-208a and the presence and severity of CHD. Samples were collected from 290 CHD patients and 110 subjects with angiographic exclusion of CHD. Circulating miRNA-208a expression was detected using quantitative real-time PCR. The Gensini score was used to evaluate the severity of coronary stenotic lesions. Expression of miRNA-208a was identified on the basis of the quartiles of the Gensini score, and association between the miRNA-208a levels and CHD was analyzed. Diagnostic potential of miR 208a of CHD was performed by ROC analysis. CHD patients had higher miRNA-208a expression (1.61, 0.45-3.86 vs. 0.66, 0.11-1.42, p < .001), and the biomarker level significantly increased following an increasing the Gensini score (p < .001). Gensini score was significantly associated with miRNA-208a expression (r = 0.8525, p < .001). The optimal cut-off value of the relative level of miR-208a was with a specificity of 93.6% and a sensitivity of 75.5%. The AUC of miR-208a was 0.919 (95% CI, 0.893-0.945; p < .001). These preliminary results suggest that the expression of miR-208a may be associated with atherogenesis. The level of circulating miR-208a in predicting the severity of coronary atherosclerosis may have a relatively certain value. PMID- 28554253 TI - Efficacy and toxicity of therapy immediately after treatment with nivolumab in relapsed multiple myeloma. PMID- 28554254 TI - Implementation of the hyaluronic acid fat graft myringoplasty technique, pitfalls and lessons learned. AB - BACKGROUND: Myringoplasty is a common procedure in otorhinolaryngology. Many techniques with different complications and outcomes have been described, one of which is hyaluronic acid fat graft myringoplasty (HAFGM). This technique, as proposed by Saliba, uses fat tissue and hyaluronic acid discs. The technique is relatively fast with a high success rate and low complications. However, what outcomes can be expected when performed by other surgeons? In this paper, we report on the technique's success in our own hands. MATERIALS AND METHODS: Based on Saliba's protocol, we performed 86 HAFGMs by a transcanal approach between 2012 and August 2014. However, our 70% success rate was significantly different from Saliba's 92% (p value 2.8e - 05). We visited Saliba's clinic in order to identify critical differences between our approaches. We adapted the differences we found in our protocol and analysed another 50 HAFGMs performed afterwards, between October 2014 and December 2015. RESULTS: The success rate increased to 86 89%, this percentage is not different compared to Saliba's results (p value .25 and .54). CONCLUSION: HAFGM is a reproducible technique in the hands of other surgeons, but critical following of the surgical protocol is important. PMID- 28554255 TI - Characterization of Water-Clear Polymeric Gels for Use as Radiotherapy Bolus. AB - Our purpose was to investigate polymeric gels for use as a highly transparent radiotherapy bolus and determine the relevant physical and dosimetric properties. We first quantified tensile properties (maximum stress, strain, and Young modulus) for various polymeric gels, along with a commercial bolus product in order to illustrate the wide variety of potential materials. For a select polymeric gel with tensile properties similar to currently used radiotherapy bolus, we also evaluated mass and electron density, effective atomic number, optical transparency, and percent depth dose in clinical megavoltage photon and electron beams. For this polymeric gel, mass density was 872 +/- 12 and 896 +/- 13 g/cm3 when measured via weight/volume and computed tomography Hounsfield units, respectively. Electron density was 2.95 +/- 0.04 *1023 electrons/cm3. Adding fused silica (9% by weight) increases density to that of water. The ratio of the effective atomic number to that of water without and with added silica was 0.780 and 0.835 at 1 MeV, 0.767 and 0.826 at 6 MeV, and 0.746 and 0.809 at 20 MeV. Percent depth dose for 6 MV photons was within 2% of water within the first 2.5 cm and after scaling by the density coincided within 1% out to >7 cm. For 6 and 20 MeV electrons, after scaling for density D80% was within 1.3 and 1.5 mm of water, respectively. The high transparency and mechanical flexibility of polymeric gels indicate potential for use as a radiotherapy bolus; differences in density from water may be managed via either using "water equivalent thickness" or by incorporating fused silica into the material. PMID- 28554256 TI - Integration of methane removal in aerobic anammox-based granular sludge reactors. AB - Combined partial nitritation-anaerobic ammonium oxidation (anammox) processes have been widely applied for nitrogen removal from anaerobic digestion reject water. However, such streams also contain dissolved methane that can escape to the atmosphere, hence contributing to global warming. This study investigates the possibility of integrating methane removal in aerobic anammox-based granular sludge reactors, through modelling and simulation. Methane removal could be established through aerobic methane-oxidizing bacteria (MOB), denitrifying anaerobic methane-oxidizing bacteria (damoB, NO2- + CH4 -> N2 + CO2), and/or archaea (damoA, NO3- + CH4 -> NO2- + CO2). The simulation results demonstrated that the combined removal of nitrogen and methane was feasible at low dissolved oxygen conditions. Aerobic MOB were the main responsible microorganisms for removing methane. A sensitivity analysis of key kinetic parameters showed a shift in the methanotrophic populations depending on the most favourable parameters for each microbial group, while keeping high nitrogen and methane removal efficiencies. Possible methane stripping during aeration could be limited by increasing the depth within the reactor column at which aeration was supplied. Overall, the integration of methane removal in aerobic anammox-based granular sludge reactors seems to be a promising process option to reduce the carbon footprint from wastewater treatment. PMID- 28554257 TI - Green synthesis of magnetic Fe3O4 nanoparticles using Couroupita guianensis Aubl. fruit extract for their antibacterial and cytotoxicity activities. AB - In the present study, a sustainable green chemistry approach was established to fabricate magnetic Fe3O4 nanoparticles (Fe3O4NPs) using the aqueous fruit extract of edible C. guianensis (CGFE). Synthesized NPs were further confirmed with different high-throughput characterization techniques such as UV-visible spectroscopy, FT-IR, XPS, DLS and zeta potential analysis. Additionally, XRD, AFM, HRTEM and SQUID VSM demonstrate the generation of crystalline CGFe3O4NPs with mean diameter of 17 +/- 10 nm. Interestingly, CGFe3O4NPs exhibit a stupendous bactericidal action against different human pathogens which depicts its antimicrobial value. A significant dose-dependent cytotoxic effect of CGFe3O4NPs was noticed against treated human hepatocellular carcinoma cells (HepG2). PMID- 28554258 TI - Investigation of transient forms of sulfur during biological treatment of spent caustic. AB - In the present study, the production of various transient forms of sulfur during biological oxidation of sulfidic spent caustics under haloalkaline conditions in a stirred tank bioreactor is investigated. Also, the effects of abiotic aeration (chemical oxidation), dissolved oxygen (DO) concentration and sodium concentration on forms of sulfur during biological treatment are demonstrated. Thioalkalivibrio versutus strain was used for sulfide oxidation in spent caustic (SC). The aeration had an important effect on sulfide oxidation and its final products. At DO concentrations above 2 mg l-1, majority of sulfide was oxidized to sulfate. Maximum sulfide removal efficiency (%R) and yield of sulfate production [Formula: see text] was obtained in Na+ concentration ranging from 0.6 to 2 M. Abiotic aeration, which is the most important factor of production of thiosulfate, resulted in the formation of an undesired product-polysulfide. However, abiotic aeration can be used as a pretreatment to biological treatment. In the bioreactor the removal efficiency was obtained as 82.7% and various forms of sulfur such as polysulfide, biosulfur, thiosulfate and sulfate was observed during biological treatment of SC. PMID- 28554259 TI - Frequency and prognostic significance of additional cytogenetic abnormalities to the Philadelphia chromosome in young and older adults with acute lymphoblastic leukemia. AB - About 25-35% of adult patients with acute lymphoblastic leukemia show the Philadelphia (Ph) chromosome. Few series have evaluated the prognosis of additional cytogenetic alterations (ACA) to the Ph chromosome. We analyzed the frequency, type and prognostic significance ofACA in adults (18-60 years) treated in the ALL-Ph-08 trial. Fifty-two out of 74 patients (70%) showed ACA and 19 (26%) presented monosomies associated with t(9;22) (monosomal karyotype, MK). Similar complete response (CR) rate, CR duration, overall survival and event-free survival (EFS) were observed in patients with or without ACA, but patients with MK showed shorter CR duration and EFS than the remaining. On multivariate analysis, the only variable with prognostic impact for CR duration and EFS was the presence of MK (p = .003 and p = .036, respectively). Although ACA associated with the Ph chromosome are frequent, only monosomies were associated with poor prognosis in this group of patients. PMID- 28554261 TI - Plasma alpha-1-acid glycoprotein as a potential predictive biomarker for non haematological adverse events of docetaxel in breast cancer patients. AB - CONTEXT: Rash and oral mucositis are major non-haematological adverse events (AEs) of docetaxel, in addition to fatigue, nausea, vomiting and diarrhoea, which restrict the use of the drug in cancer therapy. Alpha-1-acid glycoprotein (AAG) is an acute phase reactant glycoprotein and is a primary carrier of docetaxel in the blood. Docetaxel has extensive binding (>98%) to plasma proteins such as AAG, lipoproteins and albumin. OBJECTIVE: To study the association between plasma AAG level and non-haematological AEs of docetaxel in Malaysian breast cancer patients of three major ethnic groups (Malays, Chinese and Indians). MATERIALS AND METHODS: One hundred and twenty Malaysian breast cancer patients receiving docetaxel as single agent chemotherapy were investigated for AAG plasma level using enzyme-linked immunosorbent assay technique. Toxicity assessment was determined using Common Terminology Criteria of Adverse Events v4.0. The association between AAG and toxicity were then established. RESULTS: There was interethnic variation of plasma AAG level; it was 182 +/- 85 mg/dl in Chinese, 237 +/- 94 mg/dl in Malays and 240 +/- 83 mg/dl in Indians. It was found that low plasma levels of AAG were significantly associated with oral mucositis and rash. CONCLUSIONS: This study proposes plasma AAG as a potential predictive biomarker of docetaxel non-haematological AEs namely oral mucositis and rash. PMID- 28554262 TI - Fatigue limits of titanium-bar joints made with the laser and the electric resistance welding techniques: microstructural characterization and hardness properties. AB - Fatigue behavior of the titanium bars is of utmost importance for the safe and reliable operation of dental implants and prosthetic constructions based on these implants. To date, however, only few data are available on the fatigue strength of dental prostheses made with electric resistance welding and laser welding techniques. This in-vitro study highlighted that although the joints made with the laser welding approach are credited of a superior tensile strength, joints made with electric resistance welding exhibited double the minimum fatigue strength with respect to the joints made with laser welding (120 vs 60 N). PMID- 28554260 TI - Efficacy of direct hemoperfusion using polymyxin B-immobilized fiber column (PMX DHP) in rapidly progressive interstitial pneumonias: results of a historical control study and a review of previous studies. AB - BACKGROUND: Direct hemoperfusion using polymyxin B-immobilized fiber column (PMX DHP) therapy has been approved for sepsis-associated acute respiratory distress syndrome, but its efficacy for other rapidly progressive interstitial pneumonias (RPIPs) is unclear. The purpose of this study was to examine the efficacy of PMX DHP therapy for acute respiratory failure in patients with RPIPs, when compared with a historical control receiving conventional treatment without PMX-DHP. METHODS: This study comprised 77 patients with RPIPs in our institute between January 2002 and December 2015. The initial 36 patients between January 2002 and March 2007 were treated without PMX-DHP (historical control group), and the following 41 patients between April 2007 and December 2015 were treated with PMX DHP (PMX-DHP group) once daily for two successive days concurrently with corticosteroids and/or immunosuppressive agents. The 90-day mortality and clinical factors were compared between the groups. Cox proportional hazards models were constructed to analyze 90-day mortality and identify predictors. RESULTS: The 90-day mortality rate was significantly lower in the PMX-DHP group than in the controls (41.5% versus 66.7%, p = 0.019). PMX-DHP therapy was significantly associated with mortality (hazard ratio 0.505; 95% confidence interval, 0.270-0.904; p = 0.032). There were significant differences in the serial changes in the PaO2/FiO2 ratio, SOFA score, and blood neutrophil counts from days 0-5 after PMX-DHP between the survivor and non-survivor groups ( p = 0.015, p < 0.001, p = 0.035, respectively). The improved PaO2/FiO2 ratio on day 3 significantly correlated with the change in blood neutrophil counts (rs = -0.431, p = 0.006). CONCLUSIONS: PMX-DHP therapy may be effective in RPIPs patients accompanied by acute respiratory failure and is expected to reduce mortality rates. PMID- 28554263 TI - Older females in the workforce - the effects of age on psychophysical estimates of maximum acceptable lifting loads. AB - The number of older workers in the workforce is increasing substantially, and advanced age is associated with factors that could influence musculoskeletal injury risk and work capacity. This study's goals were to test whether psychophysical estimates of maximum acceptable weight of lift (liftmax) differed between younger and older workers, and to examine potential explanatory factors. Twenty-four female workers (half 50 + years; half 20-32 years) self-adjusted a box's mass to their perceived liftmax during four lifting tasks. Older workers' liftmax values were significantly lower (by approximately 24%) than their younger counterparts. There were no age-related differences in resting heart rate, or peak joint angles and final heart rate during the lifting trials. However, the older group demonstrated lower grip strength (by 24%), and lower heart rate reserve during the trials (by 18%). These results question whether current maximum acceptable lifting weights based on psychophysical information are appropriately protective for female workers greater than 50 years of age. Practitioner Summary: This psychophysical study demonstrated that older female workers (aged 50-63 years) selected maximum acceptable lift masses that were (on average) 24% lower than younger workers (aged 20-32 years), which corresponded with lower grip strength and heart rate reserve. Current maximum acceptable lifting weights based on psychophysical information may not protect female workers greater than 50 years of age. PMID- 28554265 TI - Secondary attention-deficit/hyperactivity disorder following perinatal and childhood stroke: impact on cognitive and academic outcomes. AB - This cross-sectional retrospective clinical research study examines a large group of children followed within a pediatric stroke program and a developmental attention-deficit/hyperactivity disorder (ADHD) clinic at the Hospital for Sick Children, between May 2004 and June 2016. All children with a history of stroke who participated in a neuropsychological assessment between the ages of 4 and 18 years were considered for inclusion. From a sample of 275 participants with a history of stroke, 36 children (13.1%) received a diagnosis of secondary ADHD. Children with secondary ADHD were younger at the time of stroke and more likely to be identified as having a presumed perinatal stroke and persistent seizures than children without secondary ADHD diagnoses. There were no differences in pattern of lesion, size, or laterality between children who developed secondary ADHD and those who did not. Children with secondary ADHD had the lowest scores across all cognitive and academic measures compared to children with stroke-only and developmental ADHD. Findings highlight the added risk of receiving a diagnosis of secondary ADHD following pediatric stroke. Implications for future research and directed intervention are discussed. PMID- 28554264 TI - Health Variables Are Informative in Screening for Mild Cognitive Impairment Among Elderly African Americans. AB - To aid primary care providers in identifying people at increased risk for cognitive decline, we explored the relative importance of health and demographic variables in detecting potential cognitive impairment using the Mini-Mental State Examination (MMSE). Participants were 94 older African Americans coming to see their primary care physicians for reasons other than cognitive complaints. Education was strongly associated with cognitive functioning. Among those with at least 9 years of education, patients with more vascular risk factors were at greater risk for mild cognitive impairment. For patients with fewer than 9 years of education, those with fewer prescribed medications were at increased risk for dementia. These results suggest that in addition to the MMSE, primary care physicians can make use of patients' health information to improve identification of patients at increased risk for cognitive impairment. With improved identification, physicians can implement strategies to mitigate the progression and impact of cognitive difficulties. PMID- 28554266 TI - Tolerability profile of thiopurines in inflammatory bowel disease: a prospective experience. AB - OBJECTIVES: The occurrence of thiopurine-related adverse events (AEs) may complicate the management of patients with inflammatory bowel disease (IBD). We aimed to evaluate the tolerability of thiopurines in a current IBD setting. MATERIALS AND METHODS: All consecutive patients who started a treatment with azathioprine (AZA) from January 2010 to March 2016 were entered in a prospectively maintained database, and the AEs which led to the permanent discontinuation of the drug were reported. RESULTS: Two hundred and fifty three patients were included. Median total follow-up was 32 months (range: 0.2-75 months). At the end of the study, AZA was discontinued in 160 patients (63.2%). The main reason leading to drug withdrawal was the occurrence of AEs (109/160 patients [68.1%]; cumulative incidence among the entire cohort: 43.1%). Overall, the most frequent AEs leading to treatment withdrawal were nausea (31/253 patients, 12.3%) and subjective symptoms, i.e., poorly defined side effects such as fatigue, headache and muscle pain (20/253 patients, 7.9%). Among the 109 AZA intolerant patients, a switch to 6-mercaptopurine (6-MP) was performed in 44 cases (40.4%). At the end of follow-up, 6-MP was discontinued in 35/44 patients (79.5%), mostly due to AEs (29/35 patients, 82.8%). Azathioprine-induced hepatic and pancreatic toxicity was associated with male gender (p = .01 and p = .03, respectively), and occurrence of nausea with Crohn's disease (p = .04). CONCLUSIONS: Our real-life prospective cohort showed the higher cumulative incidence of thiopurine withdrawal due to AEs reported to date. Switching from AZA to 6-MP was often ineffective. PMID- 28554267 TI - Executive function and attention in patients with stress-related exhaustion: perceived fatigue and effect of distraction. AB - Cognitive impairment has frequently been shown in patients who seek medical care for stress-related mental health problems. This study aims to extend the current knowledge of cognitive impairments in these patients by focusing on perceived fatigue and effects of distraction during cognitive testing. Executive function and attention were tested in a group of patients with stress-related exhaustion (n = 25) and compared with healthy controls (n = 25). Perceived fatigue was measured before, during and after the test session, and some of the tests were administered with and without standardized auditory distraction. Executive function and complex attention performance were poorer among the patients compared to controls. Interestingly, their performance was not significantly affected by auditory distraction but, in contrast to the controls, they reported a clear-cut increase in mental tiredness, during and after the test session. Thus, patients with stress-related exhaustion manage to perform during distraction but this was achieved at a great cost. These findings are discussed in terms of a possible tendency to adopt a high-effort approach despite cognitive impairments and the likelihood that such an approach will require increased levels of effort, which can result in increased fatigue. We tentatively conclude that increased fatigue during cognitive tasks is a challenge for patients with stress-related exhaustion and plausibly of major importance when returning to work demanding high cognitive performance. PMID- 28554268 TI - Knowledge and competence in temporomandibular disorders among Swedish general dental practitioners and dental hygienists. AB - OBJECTIVE: The aim of this study was to investigate knowledge and competence in temporomandibular disorders (TMD) among dentists and dental hygienists working in the public dental service (PDS) in Sweden. MATERIALS AND METHODS: The study population comprised all general dentists (n = 110) and dental hygienists (n = 80) working in the PDS in two Swedish counties: Kronoberg (K) and Blekinge (B). The participants filled out a questionnaire comprised of 15 questions. RESULTS: The results of these questions are presented. The overall response rate for the general dentists was 87%, while the rate for the dental hygienists was 71%. Statistically significant differences between the general dentists in the two counties were found regarding the following: education in the field of TMD over the last 5 years (K: 37%, B: 73%), evaluation of occlusion when examining patients with suspected TMD ('always': K: 61%, B: 82%), and a desire for consultation of the OFP (orofacial pain)/TMD specialist by telephone (K: 71%, B: 44%). Regarding the dental hygienists, there was a statistically significant difference concerning the use of the treatment modality 'reassurance' (K: 41%, B: 7%). CONCLUSIONS: The majority of the dental care providers in both counties - irrespective of professional category - had a positive attitude towards patients with TMD. Knowledge and competence in the field are sparse and require postgraduate education. There is a great need of an OFP/TMD specialist for more complicated patients and a need to implement updated knowledge and competence in the PDS in these two counties. PMID- 28554269 TI - Erratum: "Dioscorea nipponica Attenuates Migration and Invasion by Inhibition of Urokinase-Type Plasminogen Activator through Involving PI3K/Akt and Transcriptional Inhibition of NF-[Formula: see text]B and SP-1 in Hepatocellular Carcinoma". PMID- 28554270 TI - Dephosphorylation of myo-inositol phosphates in the in vitro intestinal Caco-2 cell model. AB - Plant and microbial phytases present in raw materials can cause a dephosphorylation of phytate (myo-inositol hexakisphosphate) (InsP6)) during food processing resulting in a broad range of different myo-inositol phosphates such as pentakisphosphate (InsP5) and tetrakisphosphate (InsP4) in foods. Here, we investigated whether the human intestinal epithelium is able to dephosphorylate myo-inositol phosphates (InsP6, InsP5-, InsP4-, InsP3-isomers) using an in vitro model with differentiated human Caco-2 cells cultured on semipermeable inserts. Incubation of InsP6 and an InsP5-isomer with cells for 3 h showed no dephosphorylation of both InsPs. Treatment of cells with a mixture of different InsP4-isomers, however, caused a formation of about 3.5% of an InsP3-isomer (Ins(1,5,6)P3) and treatment with a mixture of different InsP3-isomers caused about 20% formation of InsP2-isomers, respectively. Thus, human intestinal cells can contribute to the dephosphorylation of myo-inositol phosphates of partly dephosphorylated forms such as InsP3 and InsP4. PMID- 28554271 TI - Genetic variants and clinical relevance associated with gestational diabetes mellitus in Chinese women: a case-control study. AB - PURPOSE: Gestational diabetes mellitus (GDM) may share similar mechanisms with type 2 diabetes and obesity. In the current study, we aimed to verify twenty genes reported to be associated with type 2 diabetes and obesity in the Chinese GDM population. METHODS: Pregnant women aged 20-49 years at 24-28 gestational weeks were recruited and 556 cases and 445 controls were enrolled in the study. The genotyping of single nucleotide polymorphisms (SNPs) was performed on peripheral blood samples. RESULTS: We discovered that GDM was associated with rs945508 (OR = 1.368, 95% CI = 1.080-1.732, p = .009), rs10804591 (OR = 1.446, 95% CI = 1.192-1.754, p < .001), rs10245353 (OR = 1.204, 95% CI = 1.006-1.441, p = .043) and rs1552224 (OR = 1.451, 95% CI = 1.071-1.964, p = .016). CONCLUSIONS: We found that four SNPs associated with type 2 diabetes and obesity may also increase the risk of developing GDM in the Chinese population. Among these SNPs, we report for the first time that rs945508 in ARHGEF11, rs10804591 in PLXND1 and rs10245353 in NFE2L3 were associated with GDM. PMID- 28554273 TI - Multiple morbidities assessment. AB - The National Institute for Health and Care Excellence (NICE) has released new guidelines on the care of people with multiple morbidities. PMID- 28554272 TI - Angiogenesis in JAK2 V617F positive myeloproliferative neoplasms and ruxolitinib decrease VEGF, HIF-1 enesis in JAK2 V617F positive cells. AB - Angiogenesis and JAK2 V617F mutation are common in BCR-ABL1 negative myeloproliferative neoplasms (MPNs). Ruxolitinib, a JAK inhibitor, is an effective treatment for some MPNs. However, the relationship between angiogenesis and JAK2 V617F and the effects of ruxolitinib on angiogenesis are still unknown. Here, we observed the correlation of JAK2 V617F mutation burden with VEGF, HIF-1a and microvascular density (MVD) in MPNs. We investigate the effect of ruxolitinib on the expression of VEGF and HIF-1alpha in JAK2 V617F positive cells. We found the expression levels of p-JAK2, VEGF, HIF-1a and MVD in the newly diagnosed MPNs were significantly increased and were related to the JAK2 V617F burden. Ruxolitinib can inhibit p-JAK2, VEGF, HIF-1a expression and suppress blood vessels' formation in chick embryo choriallantoic membrane. Our findings indicated that angiogenesis is related to JAK2 V617F burden and ruxolitinib could decrease VEGF and HIF-1a expression in JAK2 V617F positive cells. PMID- 28554274 TI - Reducing the use of restrictive interventions by changing staff attitudes. AB - The use of restraint in health and social care services has had a high profile in recent years. The goal for these organisations is to reduce it, and use effective preventive interventions instead. Changing staff attitudes to restraint, as part of a comprehensive training programme, is important in reducing the use of restrictive interventions. This article describes an approach to implementing training programmes, and applies aspects of this to the challenge of creating changes in the attitude of staff. PMID- 28554275 TI - Research should be at the core of nursing. AB - If we are to improve management of long-term conditions, and address the needs of our ageing population, we must make nursing research central to nursing practice. PMID- 28554276 TI - Leading by walking around in long-term care and transitional care facilities. AB - Nursing staff in long-term care/transitional care (LTC/TC) facilities in the US work in unique environments that can be stressful and demanding. There is much in the literature that describes different leadership styles in nursing, but a limited amount on leadership in LTC/TC environments. This article explores the concept of leading by walking around (LBWA), also known as leadership by walking, to cultivate therapeutic work environments in LTC/TC facilities in the US. It defines therapeutic work environments and describes the specific environment of LTC/TC facilities. It also briefly describes the nursing hierarchy and nurse education in the US. Finally, it describes the cultivation of therapeutic work environments by using LBWA and includes two examples of the concept in action. PMID- 28554277 TI - From twitter. AB - Nurses on Twitter. PMID- 28554278 TI - Inclusive leadership. AB - NHS England's second podcast, Inclusive Leadership in the NHS, has been made available. PMID- 28554279 TI - Patient-led care. AB - Former mental health service user and public engagement practitioner David Gilbert writes a blog, the Future Patient Blog, on the possibilities of patient led and user-led healthcare. PMID- 28554280 TI - May accused of showing 'contempt'. AB - Theresa May was accused of showing 'contempt' for nurses by failing to attend RCN congress. PMID- 28554281 TI - Number crunching: are there enough nurses? AB - Throughout the election campaign, the Conservatives have been keen to point out how it has increased the number of nurses in hospitals. PMID- 28554282 TI - Public perceptions. AB - The National Centre for Social Research's annual British Social Attitudes survey records the British public's views on the NHS and healthcare. PMID- 28554284 TI - Equal gender representation. AB - A report by Ruth Sealy of the University of Exeter Business School examines the steps the NHS should take to ensure equal gender representation on boards by 2020. PMID- 28554283 TI - Why nursing needs community-centred care. AB - Patient- and family-centred care improve patient satisfaction, healthcare outcomes and healthcare delivery. But how would the addition of another layer, community-centred care, affect this model? PMID- 28554285 TI - Gluten-free food. AB - Staple gluten-free (GF) foods have been available on prescription to patients diagnosed with gluten sensitivity enteropathies, such as coeliac disease, since the late 1960s. PMID- 28554287 TI - Violence against women and girls. AB - In 2016, the Scottish Government published a revised version of Equally Safe, Scotland's strategy to eradicate violence against women and girls. PMID- 28554286 TI - RCN to ballot for industrial action if pay cap remains. AB - RCN president Cecilia Anim (pictured) has urged nurses to make their voices heard following the announcement of a summer of protest over pay. PMID- 28554288 TI - Evidence-Based Practice for Nurses & Healthcare Professionals Barker Janet Evidence-Based Practice for Nurses & Healthcare Professionals 240pp L22.99 Sage Publishing 9781473925038 1473925037 [Formula: see text]. AB - Critical appreciation of the evidence base is a requirement for professional practice and this book, now in its third edition, is a well written and useful primer to the subject. PMID- 28554289 TI - Around the world. AB - 1. 23rd World Nursing and Healthcare Conference 10-12 July, Berlin, Germany tinyurl.com/worldnursing-berlin. PMID- 28554290 TI - Nurse directors need more time and support if they are to remain in post. AB - Delegates at an RCN congress fringe event discussed how better mentoring and more time for nurse directors to 'find their feet' are needed to improve retention rates. PMID- 28554292 TI - NHS should 'focus on wellness'. AB - The NHS emphasis on illness rather than wellness could be 'disabling patients', delegates told RCN congress. PMID- 28554293 TI - Staff feeling burned out due to overlong shifts. AB - Nurses have raised concerns about how night and day shifts run into each other, leading to staff feeling burned out and wanting to leave the profession. PMID- 28554294 TI - It's time to reward nursing leadership. AB - The cover of this month's Nursing Management features Susie Scales and Amy Sims, who together won the leadership category of the prestigious RCNi Nurse Awards. The two nurses set up a school-age immunisation programme from scratch and launched it within six months. They are now responsible for vaccinations throughout Derbyshire . PMID- 28554295 TI - Noticeboard. PMID- 28554296 TI - 'An amazing feat of leadership': meet the award-winning nursing pioneers. AB - A school-age immunisation programme set up from scratch and launched within six months is delivering impressive take-up results thanks to the leadership and commitment of the two nurses who run it. PMID- 28554297 TI - 'Above all, be brave'. AB - What is your job? My new role is director of nursing at Guilford County Detention Centers, North Carolina. I manage three sites across the county, with around 1,300 inmates including men, women and juveniles. PMID- 28554298 TI - Nursing in rural India. AB - Nursing in India is evolving, and the inequality of practice and standards between cities and villages affects the health of the population. This article describes the challenges of providing healthcare in rural parts of India, and how nurses have made the best use of available resources to strive to achieve healthcare goals. PMID- 28554299 TI - Obsessive-compulsive symptoms in schizophrenia: prevalence and associated factors in a Nigerian population. AB - OBJECTIVES: The objectives of this study were to determine the prevalence of obsessive-compulsive symptoms (OCS) among subjects with schizophrenia and also to determine their associated factors. METHODS: A cross-sectional study involving 232 patients with schizophrenia were recruited from a teaching hospital in Nigeria. Socio-demographic questionnaire, Obsessive-Compulsive Inventory, Positive and Negative Syndrome Scale and Suicidality module of the MINI International Neuropsychiatric Inventory were administered. RESULTS: The prevalence of OCS was 54.3% among patients with schizophrenia, and washing symptom was the most common (51.7%). Patients with schizophrenia that had OCS had more severe psychopathologies and higher levels of suicidality. OCS among patients with schizophrenia were also associated with the use of second generation antipsychotic medications. CONCLUSIONS: OCS are common in schizophrenia. Hence, there is a need for routine screening of patients with schizophrenia for OCS and then, manage them appropriately. PMID- 28554300 TI - Relationships between clubshaft motions and clubface orientation during the golf swing. AB - Since clubface orientation at impact affects ball direction and ball spin, the ability to control clubface orientation is one of the most important skills for golfers. This study presents a new method to describe clubface orientation as a function of the clubshaft motions (i.e., swing plane orientation, clubshaft angle in the swing plane, and clubshaft rolling angle) during a golf swing and investigates the relationships between the clubshaft motions and clubface orientation at impact. The club motion data of driver shots were collected from eight skilled golfers using a three-dimensional motion capture system. The degrees of influence of the clubshaft motions on the clubface orientation were investigated using sensitivity analysis. The sensitivity analysis revealed that the swing plane horizontal angle affected the clubface horizontal angle to an extent of 100%, that the clubshaft angle in the swing plane affected both the clubface vertical and horizontal angles to extents of 74 and 68%, respectively, and that the clubshaft rolling angle affected both the clubface vertical and horizontal angles to extents of -67 and 75%, respectively. Since the method presented here relates clubface orientation to clubshaft motions, it is useful for understanding the clubface control of a golfer. PMID- 28554301 TI - Exploring disorder in the human charged biased proteins. AB - A considerable interest has been put in the identification of biased regions in proteins. These regions are frequently associated with a structural role in the cell and particularly with protein disorder. Here, we have investigated the intrinsically disordered regions (IDRs) in the human charged biased proteins identified in our earlier work. We found that 65% of charged biased proteins contained significant IDRs involved particularly in DNA and RNA binding. Also, we have observed that these proteins are well conserved in metazoans and more particularly in mammalian. In addition, the IDRs are located largely in N terminal, C-terminal sequence flanking the functional domains (FD) and slightly less in (FD) itself. Our work also supports the association between protein disorder and protein-protein/DNA interaction. An example will be described. PMID- 28554302 TI - New cardiac expression of two adenosine-2A receptor isoforms in dysfunctioning minipigs. AB - PURPOSE: Eight A2AR variants are reported in humans while no A2AR isoforms in pigs. The aim of this study was to evaluate potential isoforms presence in cardiac pig tissue to better define possible involvement of A2AR in the cardiovascular pathophysiology. MATERIALS AND METHODS: In adult male minipigs (n = 4) left ventricular dysfunction (LVD) was induced by pacing at 200 bpm in the right ventricular (RV) apex. In these animals and in sham operated pigs (C-SHAM, n = 4) cardiac tissue was collected from LV-septal wall (LV-SW)-close to pacing site-and from lateral (opposite) site (LV-OSW). A2AR specific primers, derived from Sus scrofa AY772412 sequence, were used for Real-Time PCR. The DNA was sequenced using the Sanger method. Histological analysis was also performed. RESULTS: In LV-SW of LVD minipigs the A2AR melting curves were characterized by a sharp peak between 87 and 91 degrees C (short isoform, 1-94 bp) on the right of the principal peak corresponding to a long A2AR isoform (GenBank: JQ229674.1) 1 213 bp. As for C-SHAM only one peak was observed in LV-OSW region of LVD animals. The short isoform had an alternative promoter region and a specific translated protein. Histology showed in LVD-LV-SW prominent Purkinje cells compared to LV OSW and C-SHAM. No difference in A2AR expression was observed between LVD animals and C-SHAM although a slight decrease was observed in LVD-LV-OSW. CONCLUSIONS: The presence of two different isoforms in the myocardium close to the insertion of pacing is suggestive of a differential state-specific expression of A2AR in cardiac tissue. PMID- 28554304 TI - Ginsenoside Rb1 exerts antidiabetic action on C2C12 muscle cells by leptin receptor signaling pathway. AB - CONTEXT: Ginsenoside Rb1 improves insulin sensitivity and glucose uptake in muscle cells via different signaling pathways; however, it is not clear that it has any effect on leptin signaling in skeletal muscle. OBJECTIVES: The aim of this study was to investigate the effect of ginsenoside Rb1 on leptin receptors expression and main signaling pathways of leptin (STAT3, PI3 kinase and ERK kinase) in C2C12 skeletal muscle cells. MATERIALS AND METHODS: C2C12 myotubes were incubated with various concentrations of Rb1 (0.1, 1 and 10 MUM) for different incubation times (1-12 h). Leptin receptors expression and GLUT-4 translocation were analyzed using realtime PCR and western blot analyses, respectively. PI3 and ERK kinases were blocked using their specific inhibitors (wortmannin and PD98059) in the presence and absence of RB1 to determine the main signaling pathway related to leptin receptor activation in C2C12 cells. RESULTS: Rb1 could maximally stimulate both leptin receptors (OBRa and OBRb) mRNA and protein expression and phosphorylation of STAT3, PI3K and ERK2 in C2C12 myotubes at 10 MUM for 3 h. Rb1 induced GLUT4 translocation was inhibited by the silencing of OBRb mRNA, demonstrated that glucose uptake was mediated via leptin receptor activation. GLUT4 recruitment to the cell surface induced by Rb1 was inhibited by wortmannin, an inhibitor of PI3K in combination with OBRb siRNA, but not by PD98059 an ERK2 kinase-1 inhibitor, indicating that GLUT4 translocation induced by Rb1 was associated with the leptin receptor upregulation and subsequent activation of PI3K. CONCLUSIONS: Our results suggest that Rb1 promote translocation of GLUT4 by upregulation of leptin receptors and activation of PI3K. PMID- 28554303 TI - C-type natriuretic peptide suppresses mesangial proliferation and matrix expression via a MMPs/TIMPs-independent pathway in vitro. AB - C-type natriuretic peptide (CNP) acts mainly in a local, paracrine fashion to regulate vascular tone and cell proliferation. Although several in vivo studies have demonstrated that CNP exerts an inhibitory effect on mesangial matrix generation, a limited number of reports exist about the anti-extracellular matrix (ECM) accumulation effect of CNP and its underlying mechanisms in mesangial cells (MCs) in vitro. In this study, human MCs were incubated in serum-containing medium in the absence or presence of CNP (0, 10 and 100 pM) for 24, 48 and 72 h, respectively. CNP administration significantly suppresses MCs proliferation and collagen (Col)-IV expression in a time- and dose-dependent manner. In addition, the study presented herein was designed as a first demonstration of the regulative effects of CNP on the metabolisms of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in MCs in vitro, and found that: (1) CNP administration significantly decreased the secretion and expression of MMP-2 and MMP-9 in the cultured MCs; (2) the secretion and expression of TIMP 1 progressively elevated after treatment with CNP for 24 and 48 h, whereas declined at later time point; (3) CNP expression was negatively correlated with MMP-2 and MMP-9 expression; (4) the balance of MMPs/TIMPs was shifted toward the reduction in MMP-2 and MMP-9 activity and/or the increment in TIMP-1 expression, which could not account for the down-regulation of Col-IV expression in CNP treated MCs. In conclusion, CNP suppresses mesangial proliferation and ECM expression via a MMPs/TIMPs-independent pathway in vitro. PMID- 28554306 TI - Occupational Safety and Health in the Temporary Services Industry: A Model for a Community-University Partnership. AB - Workers in the temporary staffing industry face hazardous working conditions and have a high risk of occupational injury. This project brought together local workers' centers and university investigators to build a corps of Occupational Health Promoters (OHPs) and to test a survey tool and recruitment methods to identify hazards and raise awareness among workers employed by temporary staffing companies. OHPs interviewed ninety-eight workers employed by thirty-three temporary agencies and forty-nine client companies, working mainly in shipping and packing, manufacturing, and warehousing sectors. Surveys identified workplace hazards. OHPs reported two companies to OSHA, resulting in several citations. Partners reported greater understanding of occupational safety and health challenges for temporary workers and continue to engage in training, peer education, and coalition building. PMID- 28554305 TI - "Then They Trust You ...": Managing Ergonomics in Home Care. AB - The home care workforce, already at 2.7 million caregivers, will become the nation's fastest growing occupation by 2024 as the senior boom generation accelerates the demand for in home services to meet its long-term care needs. The physically challenging work of assisting clients with intimate, essential acts of daily living places home care workers (HCWs) at risk for musculoskeletal disorders (MSDs); yet, HCWs typically receive little formal job training and may lack appropriate assistive devices. In this qualitative pilot study, HCW focus groups described workplace MSD risk factors and identified problem-solving strategies to improve ergonomic conditions. The results revealed that HCWs rely on their behavioral insights, self-styled communications skills and caring demeanor to navigate MSD risks to themselves and increase clients' physical independence of movement. We suggest changes in employer and government policies to acknowledge HCWs as valued team members in long-term care and to enhance their effectiveness as caregivers. PMID- 28554307 TI - Hypertensive Disorders in Pregnancy Current Practice Review. AB - BACKGROUND: Hypertensive disorders (preeclampsia, eclampsia, gestational hypertension, and chronic hypertension with superimposed preeclampsia) complicate 3-5% of all pregnancies and are a significant cause of maternal mortality and morbidity. Preeclampsia is a multi-system disorder characterised by new onset hypertension after the 20th week of pregnancy with proteinuria. Proteinuria is defined as 300 mg or more of protein in a 24-hour urine collection or a protein: creatinine ratio of 0.3 mg/dL using a spot urine specimen. Hypertensive disorders have a complex pathophysiology that results from abnormal placen- tation and a maternal response that develops into a clinicalsyndrome for which there is no single test or "cure". In high income countries, low rates of maternal mortality from hy- pertensive disease in pregnancy illustrate the importance of pregnant women being able to readily access antenatal care. CONCLUSION: There remains the need to develop evidence-based clinical guidelines for detection, prophylaxis and management worldwide. PMID- 28554308 TI - Lipid Metabolism in Patients with End-Stage Renal Disease: A Five Year Follow-up Study. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) exhibit high morbidity as well as mortality for atherosclerotic cardiovascular diseases (CVD). Therefore, we investigated differences in individual lipoprotein classes and subclasses in ESRD patients under chronic high volume hemodiafiltration (HV-HDF) in comparison with a control group. We also assessed the prognosis of these patients and analyzed these parameters after 5 years follow-up. METHODS: 57 patients and 50 controls were enrolled. We analysed high density (HDL) and low density (LDL) lipoprotein subfractions using the Quantimetrix Lipoprint(R) system. Subfractions were correlated with selected clinical-biochemical parameters including risk factors for atherosclerotic CVD at the beginning of and after 5 years follow-up. RESULTS: Fourteen patients survived the 5-year follow up. Follow-up results revealed a shift toward smaller HDL subfractions. In lipoproteins carrying apolipoprotein B, there was a shift of cholesterol from very low density (VLDL) to intermediate density (IDL) lipoproteins and LDLs. Hypolipidaemic therapy did not influence lipoprotein profiles in HV-HDF patients. CONCLUSION: 1. HV-HDF patients exhibit specific lipid profiles with elevated triacylglycerol, low HDL and LDL and higher content of cholesterol in remnant particles (VLDL and IDL) at the expense of large LDL. HDL subfractions were linked to the number of risk factors for CVD in the control group only. 2. Baseline lipoprotein profiles did not differ between survivors and non-survivors. Non-survivors had higher CRP and lower HDL-C. 3. During the 5 year follow-up period, cholesterol in HDL particles and lipoproteins carrying apolipoprotein B redistributed in survivors towards smaller particles, thus resembling the profile of control patients. PMID- 28554309 TI - Serum Levels of Vaspin and Its Correlation with Nitric Oxide in Type 2 Diabetic Patients with Nephropathy. AB - BACKGROUND: Diabetic Nephropathy (DN), a serious and prevalent complication of diabetes, has been rapidly raising worldwide. Vaspin, as an adipokine with anti diabetic effects, is predominantly released from visceral adipose tissue. Moreover, vaspin has the stimulatory effect on nitric oxide (NO) bioavailability through the activation of NO synthase. OBJECTIVE: The aim of the present study was to investigate the serum levels of vaspin and their correlation with NO metabolite in diabetic patients with normal renal function and renal insufficiency. METHODS: Volunteers patients with non-nephropathy Type 2 Diabetic Mellitus (T2DM) as control (n=40, age= 56.95+/-6.11 years) and patients with diabetic nephropathy (DN) (n=40, age=57.85+/-5.63 years) as case group were enrolled in this study, and serum samples were collected for the measurement of vaspin levels by ELISA technique. Also, serum levels of NO metabolites were calorimetrically assessed. RESULTS: We found that vaspin levels significantly decreased in diabetic patients with nephropathic condition as compared with diabetic patients with normal renal function (p <0.04). In addition, serum levels of NO metabolites were significantly higher in diabetic patients with nephropathy in comparison with non-nephropathic diabetics (p<0.001). When patients with DN were studied, vaspin levels positively correlated with NO metabolites and Homeostasis model assessment of insulin resistance (HOMA-IR) levels. CONCLUSION: This study showed that low serum vaspin levels may be a risk factor for nephropathy in type II diabetic patients and increased levels of NO may be a defensive mechanism in the DN. PMID- 28554310 TI - Ion Channel and Neurotransmitter Modulators as Electroceutical Approaches to the Control of Cancer. AB - The activities of individual cells must be tightly coordinated in order to build and maintain complex 3- dimensional body structures during embryogenesis and regeneration. Thus, one way to view cancer is within systems biology as a network disorder affecting the ability of cells to properly interact with a morphodynamic field of instructive signals that keeps proliferation and migration orchestrated toward the anatomical needs of the host organism. One layer of this set of instructive microenvironmental cues is bioelectrical. Voltage gradients among all somatic cells (not just excitable nerve and muscle) control cell behavior, and the ionic coupling of cells into networks via electrochemical synapses allows them to implement tissue-level patterning decisions. These gradients have been increasingly implicated in the induction and suppression of tumorigenesis and metastasis, in the emerging links between developmental bioelectricity to the cancer problem. Consistent with the well-known role of neurotransmitter molecules in transducing electrical activity to downstream cascades in the brain, serotonergic signaling has likewise been implicated in cancer. Here, we review these recent data and propose new approaches for manipulating bioelectric and neurotransmitter pathways in cancer biology based on a bioelectric view of cancer. To support this methodology, we present new data on the effects of the SSRI Prozac and its analog (ZINC ID = ZINC06811610) on survival of both cancer (MCF7) and normal (MCF10A) breast cells exposed to these compounds. We found an IC50 concentration (25 uM for Prozac and 100 uM for the Prozac analog) at which these compounds inhibited tumor cell survival and proliferation. Additionally, at these concentrations, we did not observe alterations in a non-tumoral cell line. This constitutes a proof-of-concept demonstration for our hypothesis that the use of both existing and novel drugs as electroceuticals could serve as an alternative to highly toxic chemotherapy strategies replacing or augmenting them with less toxic alternatives. We believe this new approach forms an exciting roadmap for future biomedical advances. PMID- 28554313 TI - Evaluation of Multifunctional Hybrid Analogs for Stilbenes, Chalcones and Flavanones. AB - AIMS: In this study, discovery of novel anticancer agents acting by more than one mechanism was aimed. METHOD: For this purpose, eleven previously synthesized simple-stilbene, chalcone, flavanone derivatives and 31 novel stilbene-fused chalcones and stilbene-fused flavanones were tested for their aromatase inhibition, antiangiogenic and anti-proliferative properties in cancer (PC3, MCF 7) and healthy (HUVEC) cell lines. MTT cell viability assay was used to evaluate the anti-proliferative activities of the compounds. CYP19/MFC highthroughput screening kit (BD Biosciences, Oxford, UK) was used to search the aromatase inhibition properties and matrigel tube formation assay was applied to determine the anti-angiogenic activities. RESULTS: Results indicate that the simple chalcone and flavanone derivatives were more cytotoxic than the simple- stilbenes in the both cancer cell lines. In contrast, the simple-stilbene structures were much more effective at aromatase inhibition. The cytotoxicity profiles of stilbene-fused chalcones in cancer cells imply that these molecules mostly mimic the simple chalcone structures. On the other hand, flavanones lose their cytotoxic activities after becoming fused with stilbenes. Additionally, aromatase inhibition assays showed that stilbene-fused chalcones again do mimic the simple chalcones but not simple-stilbenes and anti-angiogenic profiles of the tested molecules seem to be not related with stilbene fragments. Furthermore, stilbene fused flavanones may mimic both simple-flavanones and simple-stilbenes depending upon the type and position of the substituent in their respective terminal aromatic rings. PMID- 28554314 TI - Epigenetics in Odontogenesis and its Influences. AB - BACKGROUND: Odontogenesis is fundamentally controlled by the genome. However, epigenetic factors have indispensable effects during odontogenesis. Previous studies have shown that exogenous factors, such as the environment, that cause hypomethylation and hypermethylation in DNA may lead to dental differences in monozygotic twin pairs. In addition, abnormalities in epigenetic regulation could induce disruptions in odontogenesis, thereby causing tooth malformation or agenesis. OBJECTIVE: This review overviews the epigenetic mechanisms involved in odontogenesis with the aim of establishing a fundamental vision of tooth development, which might be useful in further research in odontogenesis and therapy for dental diseases. RESULTS: We summarized articles about epigenetics in odontogenesis. Here, we present concrete epigenetic regulation mechanisms in odontogenesis that have been reported previously, following the order of microRNA, DNA methylation and histone modification. CONCLUSION: Epigenetic factors influence the proliferation, differentiation or apoptosis of cells that play indispensable roles during the process of odontogenesis which have the ability to exquisitely regulate the tooth number, size and shape. PMID- 28554312 TI - Calcium Signaling, PKC Gamma, IP3R1 and CAR8 Link Spinocerebellar Ataxias and Purkinje Cell Dendritic Development. AB - BACKGROUND: Spinocerebellar ataxias (SCAs) are a group of cerebellar diseases characterized by progressive ataxia and cerebellar atrophy. Several forms of SCAs are caused by missense mutations or deletions in genes related to calcium signaling in Purkinje cells. Among them, spinocerebellar ataxia type 14 (SCA14) is caused by missense mutations in PRKCG gene which encodes protein kinase C gamma (PKCgamma). It is remarkable that in several cases in which SCA is caused by point mutations in an individual gene, the affected genes are involved in the PKCgamma signaling pathway and calcium signaling which is not only crucial for proper Purkinje cell function but is also involved in the control of Purkinje cell dendritic development. In this review, we will focus on the PKCgamma signaling related genes and calcium signaling related genes then discuss their role for both Purkinje cell dendritic development and cerebellar ataxia. METHODS: Research related to SCAs and Purkinje cell dendritic development is reviewed. RESULTS: PKCgamma dysregulation causes abnormal Purkinje cell dendritic development and SCA14. Carbonic anhydrase related protein 8 (Car8) encoding CAR8 and Itpr1 encoding IP3R1were identified as upregulated genes in one of SCA14 mouse model. IP3R1, CAR8 and PKCgamma proteins are strongly and specifically expressed in Purkinje cells. The common function among them is that they are involved in the regulation of calcium homeostasis in Purkinje cells and their dysfunction causes ataxia in mouse and human. Furthermore, disruption of intracellular calcium homeostasis caused by mutations in some calcium channels in Purkinje cells links to abnormal Purkinje cell dendritic development and the pathogenesis of several SCAs. CONCLUSION: Once PKCgamma signaling related genes and calcium signaling related genes are disturbed, the normal dendritic development of Purkinje cells is impaired as well as the integration of signals from other neurons, resulting in abnormal development, cerebellar dysfunction and eventually Purkinje cell loss. PMID- 28554315 TI - Pharmacophore Modelling and 4D-QSAR Study of Ruthenium(II) Arene Complexes as Anticancer Agents (Inhibitors) by Electron Conformational- Genetic Algorithm Method. AB - OBJECTIVE: The EC-GA method was employed in this study as a 4D-QSAR method, for the identification of the pharmacophore (Pha) of ruthenium(II) arene complex derivatives and quantitative prediction of activity. METHODS: The arrangement of the computed geometric and electronic parameters for atoms and bonds of each compound occurring in a matrix is known as the electron-conformational matrix of congruity (ECMC). It contains the data from HF/3-21G level calculations. Compounds were represented by a group of conformers for each compound rather than a single conformation, known as fourth dimension to generate the model. ECMCs were compared within a certain range of tolerance values by using the EMRE program and the responsible pharmacophore group for ruthenium(II) arene complex derivatives was found. For selecting the sub-parameter which had the most effect on activity in the series and the calculation of theoretical activity values, the non-linear least square method and genetic algorithm which are included in the EMRE program were used. In addition, compounds were classified as the training and test set and the accuracy of the models was tested by cross-validation statistically. RESULTS: The model for training and test sets attained by the optimum 10 parameters gave highly satisfactory results with R2 training= 0.817, q 2=0.718 and SEtraining=0.066, q2 ext1 = 0.867, q2 ext2 = 0.849, q2 ext3 =0.895, ccctr = 0.895, ccctest = 0.930 and cccall = 0.905. CONCLUSION: Since there is no 4D-QSAR research on metal based organic complexes in the literature, this study is original and gives a powerful tool to the design of novel and selective ruthenium(II) arene complexes. PMID- 28554316 TI - Beta-Hydroxy-Beta-Methyl Butyrate (HMB): From Experimental Data to Clinical Evidence in Sarcopenia. AB - beta-hydroxy-beta-methylbutyrate (HMB) is a metabolite derived from leucine and its ketoacid alpha- ketoisocaproate. Leucine has a role in regulating protein synthesis in muscle cells, and HMB seems to be a key active metabolite in such regulation. HMB has been shown to modulate muscle protein degradation by inhibiting the ubiquitin-proteasome proteolytic pathway, to up-regulate protein synthesis via the mTOR pathway, and to stabilize cell membranes via the rate limiting enzyme to cholesterol synthesis HMG- coenzyme A reductase. It can also decrease cell apoptosis, therefore improving cell survival; and increase proliferation and differentiation of muscle stem cell, via the MAPK/ERK and PI3K/Akt pathways. HMB is widely used as an ergogenic supplement by athletes and bodybuilders, usually combined with exercise training, to increase muscle mass and strength. Some studies have explored the role of HMB in chronic diseases associated with muscle wasting (cancer, acquired immunodeficiency syndrome, chronic obstructive pulmonary disease). This review focuses on the role of HMB in the management of sarcopenia (age or disease-related loss of muscle mass and function) in older persons. A small number of studies have shown increases in lean (muscle) mass and some muscle function and physical performance parameters in older people with or without resistance exercise, and preservation of muscle mass during bed rest. However, heterogeneous methodological approaches preclude solid conclusions, and more studies are needed to confirm the role of HMB as a promising agent to treat sarcopenia. PMID- 28554311 TI - The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases. AB - BACKGROUND: Widespread protein aggregation occurs in the living system under stress or during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative diseases may have a common mechanism: the failure of protein homeostasis. Perturbation of ER results in unfolded protein response (UPR). Prolonged chronical UPR may activate apoptotic pathways and cause cell death. METHODS: Research articles on Sigma-1 receptor were reviewed. RESULTS: ER is associated to mitochondria by the mitochondria-associated ER membrane, MAM. The sigma-1 receptor (Sig-1R), a well-known ER-chaperone localizes in the MAM. It serves for Ca2+-signaling between the ER and mitochondria, involved in ion channel activities and especially important during neuronal differentiation. Sig-1R acts as central modulator in inter-organelle signaling. Sig-1R helps cell survival by attenuating ER-stress. According to sequence based predictions Sig-1R is a 223 amino acid protein with two transmembrane (2TM) domains. The X-ray structure of the Sig-1R [1] showed a membrane-bound trimeric assembly with one transmembrane (1TM) region. Despite the in vitro determined assembly, the results of in vivo studies are rather consistent with the 2TM structure. The receptor has unique and versatile pharmacological profile. Dimethyl tryptamine (DMT) and neuroactive steroids are endogenous ligands that activate Sig-1R. The receptor has a plethora of interacting client proteins. Sig 1R exists in oligomeric structures (dimer-trimer-octamer-multimer) and this fact may explain interaction with diverse proteins. CONCLUSION: Sig-1R agonists have been used in the treatment of different neurodegenerative diseases, e.g. Alzheimer's and Parkinson's diseases (AD and PD) and amyotrophic lateral sclerosis. Utilization of Sig-1R agents early in AD and similar other diseases has remained an overlooked therapeutic opportunity. PMID- 28554317 TI - Exposing "Bright" Metals: Promising Advances in Photoactivated Anticancer Transition Metal Complexes. AB - BACKGROUND: Photodynamic therapy (PDT) is an increasingly prominent field in anticancer research. PDT agents are typically nontoxic in the absence of light and can be stimulated with nonionising irradiation to "activate" their cytotoxic effect. Photosensitzers are not classified as chemotherapy drugs although it is advantageous to control the toxicity of a drug through localised irradiation allowing for selective treatment. Transition metals are an extremely versatile class of compounds with various unique properties such as oxidation state, coordination number, redox potential and molecular geometry that can be tailored for specific uses. This makes them excellent PDT candidates as their properties can be manipulated to absorb a specific range of light wavelengths, cross cellular membranes or target specific sites in vitro. This article reviews recent advances in transition metal PDT agents, with a focus on structural scaffolds from which several metal complexes in a series are synthesised, as well as their in vitro cytotoxicity in the presence or absence of irradiation. CONCLUSION: The success of clinical photoactive agents such as Photofrin(r) has inspired the development of thousands of potential PDT agents. Transition metal complexes in particular have demonstrated excellent versatility and diversity when it comes to PDT for treatment of invasive cancers. This review has highlighted some of the many recent advances of transition metal PDT agents with high in vitro and in vivo phototoxic activity. Photoactive transition metal complexes have proven their potential due to their inherent physicochemical variety, allowing them to fill a niche in the PDT world. PMID- 28554318 TI - Anti-Cancer Compounds Targeted to VDAC: Potential and Perspectives. AB - BACKGROUND: VDAC (Voltage-Dependent Anion selective Channel) is a small family of abundant pore-forming proteins located in the outer mitochondrial membrane. Their role range from the most intuitive, the formation of a hydrophilic conduit through the membrane thanks to its beta-barrel structure, to less understood functions that make them essential actors in the cross-talk between the bioenergetics metabolism and the cytosol components. Due to this localization, VDAC1, in particular, has been reported to be involved in apoptosis, Hexokinase and tubulin binding, and in the Warburg effect. For these reasons, an involvement of VDAC in cancer is considered consequential and a number of compounds have been proposed and used in experimental trials to demonstrate the efficacy of molecules affecting the functions of VDAC. OBJECTIVES: In this work, we thus survey the literature describing drug compounds acting on the cancerous proliferation through VDAC. Three main categories have been assigned: molecules acting on the VDAC-Hexokinase binding, molecules directly inhibiting the VDAC conductance, molecules affecting the expression levels of the VDAC gene. The application of biological peptides for this purpose is also considered. CONCLUSION: Since the knowledges about the functional properties of VDAC protein are still insufficient, VDAC as a pharmacological target in the fight against cancer is still a very open, but very promising, field. PMID- 28554319 TI - Cyclometalated Complexes of Platinum and Gold with Biological Properties: State of-the-Art and Future Perspectives. AB - BACKGROUND: The inherent problems accompanying chemotherapy necessitate the development of new anticancer approaches. The development of compounds that can disrupt cancerous cellular machinery by novel mechanisms, via interactions with proteins and non-canonical DNA structures (e.g. G-quadruplexes), as well as by alteration of the intracellular redox balance, is nowadays focus of intense research. In this context, organometallic compounds of the noble metals Pt and Au have become prominent experimental therapeutic agents. This review provides an overview of the Pt(II) and Au(III) cyclometalated compounds with a chelating ring containing a strong C-M sigma -bond to improve the stability of the compounds with respect to ligand exchange reactions and biological reduction. Furthermore, these properties can be easily tuned by modification of either the anionic cyclometalated or the ancillary ligands. Special focus has been set to C^N, C^N^C, C^N^N and C^N^S platinum(II) and gold(III) pincer complexes regarding their synthesis and biological mechanisms of action as anticancer agents. METHODS: A structured search of both chemical and medicinal databases for peerreviewed research literature has been conducted. The quality of retrieved papers was appraised using standard tools. The synthesis as well as the chemical and biological properties of the described compounds were carefully reviewed and described. The findings were outlined using a conceptual framework. RESULTS: In this review we included 155 papers, the majority originating from high-impact papers on the synthesis and biological modes of platinum(II) and gold(III) compounds. Among them, 17 papers were highlighted to give an introduction to the use of Pt and Au compounds with medicinal properties, mainly focussing on coordination compounds. The synthesis and medicinal properties of organometallic compounds of various metals (such as Fe, Ru, Ti) were outlined in 51 papers. These compounds included metallocenes, metallo- arenes, metallo-carbonyls, metallo-carbenes (e.g. N-heterocyclic carbenes), and alkynyl complexes. The C^N, C^N^C, C^N^N and C^N^S pincer complexes of platinum( II) (46 papers) and gold(III) (44 papers) were discussed concerning their synthesis, stability and advantages to develop therapeutic compounds. We strove to show the consistent development of C^N, C^N^C, C^N^N and C^N^S platinum(II) and gold(III) pincer complexes regarding their synthesis and biological modes from the early beginnings to the most recent findings. CONCLUSION: This review supplies a profound overview of the development of organometallic compounds for medicinal purposes, setting special focus to the synthesis and stability of C^N, C^N^C, C^N^N and C^N^S pincer complexes of platinum(II) and gold(III) and their use as anticancer agents. PMID- 28554320 TI - Dietary Polyphenols and Mitochondrial Function: Role in Health and Disease. AB - Mitochondria are cytoplasmic double-membraned organelles that are involved in a myriad of key cellular regulatory processes. The loss of mitochondrial function is related to the pathogenesis of several human diseases. Over the last decades, an increasing number of studies have shown that dietary polyphenols can regulate mitochondrial redox status, and in some cases prevent or delay disease progression. This paper aims to review the role of four dietary polyphenols - resveratrol, curcumin, epigallocatechin-3-gallate (EGCG) and quercetin - in molecular pathways regulated by mitochondria and their potential impact in human health. Cumulative evidence showed that the aforementioned polyphenols improve mitochondrial functions in different in vitro and in vivo experiments. The mechanisms underlying the polyphenols' beneficial effects include, among others, the attenuation of oxidative stress, the regulation of mitochondrial metabolism and biogenesis and the modulation of cell-death signaling cascades, among other mitochondrial-independent effects. The understanding of the chemical-biological interactions of dietary polyphenols, namely with mitochondria, may have a huge impact on the treatment of mitochondrial dysfunction-related disorders. PMID- 28554321 TI - Phosphodiesterase 4 Inhibitors in Immune-mediated Diseases: Mode of Action, Clinical Applications, Current and Future Perspectives. AB - Phosphodiesterase (PDE) 4 is a superfamily of enzymes that catalyze the hydrolysis of cyclic adenosine 3',5'-monophosphate (cAMP), an intracellular second messenger and regulator of a wide array of genes and proteins. Increased levels of intracellular cAMP lead to activation of genes but also to inhibition of nuclear factor-kappa B, involved in pro-inflammatory responses. By increasing cAMP levels, PDE4 inhibitors, such as apremilast, reduced production of pro inflammatory TNFalpha, IFNgamma, and IL-17 and increased production of anti inflammatory IL-10 in lipopolysaccharide-stimulated peripheral blood mononuclear cells, and in patients with psoriatic arthritis (PsA). Among PDE4 inhibitors, apremilast, roflumilast, and crisabolore have been approved for the treatment of psoriasis and PsA, chronic obstructive pulmonary disease, and atopic dermatitis, respectively. In a preliminary study on psoriasis and PsA we showed that at 6 months apremilast decreased IFNgamma+CD3+ Th1 cells and IL- 17+CD3+ Th17 cells and increased regulatory B cells and regulatory T cells. In this review, we highlight recent findings of PDE4 inhibitors in atopic dermatitis, alopecia areata, uveitis, rheumatoid arthritis, psoriasis and PsA, systemic lupus erythematosus, vasculitis, systemic sclerosis, multiple sclerosis and inflammatory bowel disease. Given the role of cAMP as second messenger in diverse intracellular pathways, selective PDE4 inhibitors are likely to be therapeutic agents for various immune mediated diseases. PMID- 28554322 TI - Recent Advances in Antibody-Drug Conjugates for Breast Cancer Treatment. AB - Breast cancer is the most common cancer in women, with roughly half a million deaths per year worldwide. Among various approaches for breast cancer treatment, chemotherapy is predominantly used for patients at stages II-IV, and monoclonal antibody (mAb) therapy is used for patients with human epidermal growth factor receptor 2 (HER2) overexpression. Integrating the tumor specificity provided by unique mAbs and cytotoxicity of small molecule drugs, antibody-drug conjugates (ADCs) are a series of smart chemotherapeutics that have recently shown great promise in treating a number of cancer types. ADCs are designed to selectively attack and kill cancer cells with minimal toxicity to normal tissues. Ado Trastuzumab emtansine (T-DM1) was the first and only ADC approved by the US Food and Drug Administration for HER2-positive breast cancer. Following the success of T-DM1, many novel ADCs have been developed, and their anticancer efficacies are currently undergoing preclinical or clinical investigation. The development of ADCs is a rapidly progressing field, and this review aims to summarize the most recent advances in ADCs targeting breast cancer over the past five years (2011 2016). The review highlights compositions and mechanisms of action of these newly developed ADCs and discusses current challenges and future directions of developing new ADCs for improved treatment of breast cancer. PMID- 28554323 TI - Microwave: An Important and Efficient Tool for the Synthesis of Biological Potent Organic Compounds. AB - BACKGROUND: Green Chemistry is an interdisciplinary science or it can also be explained as a branch of chemistry. It is generally described as the chemistry to aim to synthesize chemical compounds to trim down the utilization of harmful chemicals proposed by the Environmental Protection Agency (EPA). Recently, the plan of academicians, researchers, industrialists is to generate greener and more efficient methodologies to carry out various organic syntheses. OBJECTIVE: In the present scenario, green chemistry utilizes the raw materials economically, minimizes the waste and prevents the uses of harmful or hazardous chemicals to make the organic reactions simple and efficient. CONCLUSION: Microwave technique is a new, simple and efficient technology which opens new prospects to the chemists to carry out various organic and inorganic reactions, which are difficult via conventional methodology. It is used to decrease the duration of time to carry various organic transformation along with maximum yield, minimum by products, minimum energy utilization, less manpower etc. e.g. various famous organic reactions have been carried out by various research groups like Aldol condensation, Knoevenagel condensation, Beckmann rearrangement, Vilsmeier reaction, Perkin reaction, Benzil-Benzilic acid rearrangement, Fischer cyclization, Mannich reaction, Claisen-Schmidt condensation, etc. Further, reduction, oxidation, coupling, condensation reaction were also performed using microwave technology. PMID- 28554324 TI - Multi-Target-Directed Ligands Affecting Serotonergic Neurotransmission for Alzheimer's Disease Therapy: Advances in Chemical and Biological Research. AB - Alzheimer's Disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive impairments and chronic inflammation that affects over 30 million people all over the world. Most of the Alzheimer's patients also suffer from psychosis, aggression, agitation, depression, anxiety, and many other behavioral and psychological symptoms of dementia. Unfortunately, the currently available anti-AD drugs provide modest symptomatic relief, and they do not reverse the neurodegeneration. Therefore, the average life expectancy after diagnosis is between six and ten years. Research data suggest that multi target-directed ligands (MTDLs) give an opportunity to prevent, halt, or reverse the progression of AD, and reduce the symptoms of the disease. The aim of this review is to update the most recent reports on the development of MTDLs affecting serotonergic neurotransmission as potential drugs for both symptomatic and disease-modifying therapy of AD. Multifunctional modulators of serotonergic system exerted procognitive, antipsychotic, antidepressant, and/or anxiolytic properties in preclinical studies. Some of them revealed their potential as modulators of tau phosphorylation or amyloid beta aggregation with neuroprotective, anti-inflammatory, and/or antioxidant properties. Among them, lumateperone - an inhibitor of serotonin transporter with a high affinity for serotonergic and dopaminergic receptors is currently being tested in clinical trials in patients with dementia, bipolar depression, or schizophrenia. The high therapeutic potential of MTDLs as anti-AD drugs seems to be the result of their involvement in multiple neurotransmitter systems and intracellular signaling pathways. PMID- 28554325 TI - Mycosporine-like Amino Acids for Skin Photoprotection. AB - Excessive human exposure to solar ultraviolet radiation (UVR) continues to be a major public health concern, with skin cancer rates increasing year on year. The major protective measure is the use of synthetic UVR filters formulated into sunscreens, but there is growing concern that these chemicals cause damage to delicate marine ecosystems. One alternative is the use of biocompatible mycosporine-like amino acids (MAA), which occur naturally and are found predominantly in a wide range of marine species. Their role within nature is mainly thought to be photoprotective. This is a consequence of their optical properties but there is increasing evidence that they are also antioxidants at a chemical level, as well by activation of endogenous cell antioxidant defence mechanisms. However, their potential for human photoprotection is largely understudied. This review explores the role of MAA in nature and considers the literature available on the use of MAA within human models for photoprotection. PMID- 28554326 TI - Update on Cardiovascular Effects of Older and Newer Anti-diabetic Medications. AB - It is known that Cardiovascular (CV) disease is the leading cause of morbidity and mortality in individuals with type 2 diabetes. Over the last years, one of the most discussed topics is the CV safety of anti-diabetic medications. Regarding CV safety of older antidiabetic agents the data are less clear and conclusions about their CV safety are mostly based on randomized controlled trials designed to assess their glucose lowering efficacy. In this review, we summarize the current knowledge about the CV safety of older and newer antidiabetic medications. According to the published literature metformin is the first line agent for the treatment of type 2 diabetes and seems to have cardio protective effects. The choice of the second line agent when metformin monotherapy fails to achieve HbA1c targets is less clear. In the light of the findings of the EMPA-REG OUTCOME trial and the recently published LEADER and SUSTAIN 6 trials, empagliflozin, liraglutide and semaglutide seem reasonable options as second line agents for patients with CV disease. Sulfonylureas on the other hand, with the exception of gliclazide, should be avoided in those patients, although CV safety trials are still lacking. In individuals without CV disease any of the other classes of anti-diabetic medication can be selected on a patient-centered approach. Saxagliptin, alogliptin, sitagliptin and lixisenatide have been evaluated in CV safety trials and have neutral effects on CV outcomes, while pioglitazone may have some CV benefits. Saxagliptin and alogliptin, however, should be avoided in patients with heart failure, while pioglitazone is contraindicated in this population. PMID- 28554327 TI - VDAC-Targeted Drugs Affecting Cytoprotection and Mitochondrial Physiology in Cerebrovascular and Cardiovascular Diseases. AB - BACKGROUND: Cerebrovascular and cardiovascular diseases are caused by impairment of the brain and/or heart circulation. Insufficient blood flow results in decreased oxygen delivery (ischemia), which affects mitochondrial functioning and consequently leads to insufficient ATP production. The predominant mitochondrial outer membrane protein, the voltage dependent anion selective channel (VDAC), is considered to be crucial for mitochondrial functioning. In human mitochondria, as in other vertebrates, three isoforms of VDAC (VDAC1-VDAC3) are present, and they likely play different roles. OBJECTIVE: In this review, we summarize the available data concerning VDAC involvement in cardiovascular and cerebrovascular diseases with regard to VDAC isoforms and discuss the use of possible VDAC related intervention targets as well as known VDAC-interacting and cytoprotection conferring molecules in the treatment of cerebrovascular and cardiovascular diseases. METHOD AND RESULTS: The suitable references on disorders defined as cerebrovascular and cardiovascular diseases as well as VDAC contribution to these conditions were searched using PubMed and ClinicalTrials.gov databases. The review is based on the 138 carefully selected articles. CONCLUSION: Mitochondrial dysfunction triggered by changes in VDAC properties undoubtedly contributes to cell death and related diseases, including cerebrovascular and cardiovascular diseases. Thus, beside diagnostic application, modulation of VDAC activity, including its isoforms, is thus of great importance for the development of efficient therapeutic interventions. Moreover, identification of VDAC-interacting molecules that protect against mitochondrial dysfunction and cell death seems to be of great importance. PMID- 28554328 TI - The Role Of Diet In The Pathogenesis Of Cholesterol Gallstones. AB - Cholesterol gallstone disease is a major health problem in Westernized countries and depends on a complex interplay between genetic factors, lifestyle and diet, acting on specific pathogenic mechanisms. Overweigh, obesity, dyslipidemia, insulin resistance and altered cholesterol homeostasis have been linked to increased gallstone occurrence, and several studies point to a number of specific nutrients as risk- or protective factors with respect to gallstone formation in humans, motivating a rising interest in the identification of common and modifiable dietetic factors that put the patients at risk of gallstones or that are able to prevent gallstone formation and growth. In particular, dietary models characterized by increased energy intake with highly refined sugars and sweet foods, high fructose intake, low fiber contents, high fat, consumption of fast food and low vitamin C intake increase the risk of gallstone formation. On the other hand, high intake of monounsaturated fats and fiber, olive oil and fish (omega-3 fatty acids) consumption, vegetable protein intake, fruit, coffee, moderate alcohol consumption and vitamin C supplementation exert a protective role. The effect of some confounding factors (e.g., physical activity) cannot be ruled out, but general recommendations about the multiple beneficial effects of diet on cholesterol gallstones must be kept in mind, in particular in groups at high risk of gallstone formation. PMID- 28554329 TI - Back to the Bench? MEK and ERK Inhibitors for the Treatment of KRAS Mutant Lung Adenocarcinoma. AB - BACKGROUND: Lung cancer accounts for one in five cancer deaths worldwide and mutations in the gene encoding for the Kirsten rat sarcoma (KRAS) oncoprotein define the largest molecular subset of non-small cell lung cancer (NSCLC). These tumors are characterized by activated MAPK signaling, however, no targeted inhibitors of mutant KRAS or of downstream signaling molecules have yet been approved for routine clinical use. OBJECTIVE: The primary objective of this review is to critically summarize the current developmental state of MEK and ERK inhibitors in pre-clinical models and in human clinical trials for KRAS mutant lung cancer particularly in light of the newly emerging concept of immune checkpoint blockade. METHOD: We performed a Pubmed-based literature search and considered publications from the fields of basic and translational biomedicinal and biochemistry research, as well as from past and ongoing human clinical trials (www.clinicaltrials.gov). RESULTS AND CONCLUSIONS: MAPK pathway targeting agents are efficacious in pre-clinical models but their benefit is limited for patients with KRAS mutant NSCLC due to the lack of predictive factors, toxicity and the adaptive dynamic kinome reprogramming within the tumor. Overall, MEK inhibitors have advanced further in clinical development compared to ERK inhibitors. New treatment strategies as e.g. immune checkpoint blockade are currently revolutionizing the treatment paradigms and future clinical trials need to show if they replace MAPK targeting strategies or are used as add-on. PMID- 28554330 TI - Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis. AB - Onconeural antibodies are associated with cancer and paraneoplastic encephalitis. While their pathogenic role is still largely unknown, their high diagnostic value is undisputed. In this study we describe the discovery of a novel target of autoimmunity in an index case of paraneoplastic encephalitis associated with urogenital cancer.A 75-year-old man with a history of invasive bladder carcinoma 6 years ago with multiple recurrences and a newly discovered renal cell carcinoma presented with seizures and progressive cognitive decline followed by super refractory status epilepticus. Clinical and ancillary findings including brain biopsy suggested paraneoplastic encephalitis. Immunohistochemistry of the brain biopsy was used to characterize the inflammatory response. Indirect immunofluorescence assay (IFA) was used for autoantibody screening. The autoantigen was identified by histo-immunoprecipitation and mass spectrometry and was validated by expressing the recombinant antigen in HEK293 cells and neutralization tests. Sera from 125 control patients were screened using IFA to test for the novel autoantibodies.IFA analysis of serum revealed a novel autoantibody against brain tissue. An intracellular enzyme, Rho-associated protein kinase 2 (ROCK2), was identified as target-antigen. ROCK2 was expressed in affected brain tissue and archival bladder tumor samples of this patient. Brain histopathology revealed appositions of cytotoxic CD8+ T cells on ROCK2 positive neurons. ROCK2 antibodies were not found in the sera of 20 patients with bladder cancer and 17 with renal cancer, both without neurological symptoms, 49 healthy controls, and 39 patients with other antineuronal autoantibodies. In conclusion, novel onconeural antibodies targeting ROCK2 are associated with paraneoplastic encephalitis and should be screened for when paraneoplastic neurological syndromes, especially in patients with urogenital cancers, occur. PMID- 28554333 TI - HEADROOM BEYOND THE QUALITY- ADJUSTED LIFE-YEAR: THE CASE OF COMPLEX PEDIATRIC NEUROLOGY. AB - OBJECTIVES: The headroom method was introduced for the very early evaluation of the potential value of new technologies. It allows for establishing a ceiling price for technologies to still be cost-effective by combining the maximum effect a technology might yield, the maximum willingness-to-pay (WTP) for this effect, and potential downstream expenses and savings. Although the headroom method is QALY-based, not all innovations are expected to result in QALY gain. METHODS: This study explores the feasibility and usefulness of the headroom method in the evaluation of technologies that are unlikely to result in QALY gain. This will be illustrated with the diagnostic trajectory of complex pediatric neurology (CPN). RESULTS: Our headroom analysis showed a large room for improvement in the current diagnostic trajectory of CPN in terms of diagnostic yield. Combining this with a maximum WTP value for an additional diagnosis and the potential downstream expenses and savings, resulted in a total headroom of ?15,028. This indicates that a new technology in this particular diagnostic trajectory, might be cost effective as long as its costs do not exceed ?15,028. CONCLUSIONS: The headroom method seems a useful tool in the very early evaluation of medical technologies, also in cases when immediate QALY gain is unlikely. It allows for allocating healthcare resources to those technologies that are most promising. It should be kept in mind, however, that the headroom assumes an optimistic scenario, and for that reason cannot guarantee future cost-effectiveness. It might be most useful for ruling out those technologies that are unlikely to be cost-effective. PMID- 28554334 TI - He said, she said: effects of bilingualism on cross-talker word recognition in infancy. AB - The purpose of the current study was to examine effects of bilingual language input on infant word segmentation and on talker generalization. In the present study, monolingually and bilingually exposed infants were compared on their abilities to recognize familiarized words in speech and to maintain generalizable representations of familiarized words. Words were first presented in the context of sentences to infants and then presented to infants in isolation during a test phase. During test, words were produced by a talker of the same gender and by a talker of the opposite gender. Results demonstrated that both bilingual and monolingual infants were able to recognize familiarized words to a comparable degree. Moreover, both bilingual and monolingual infants recognized words in spite of talker variation. Results demonstrated robust word recognition and talker generalization in monolingual and bilingual infants at 8 months of age. PMID- 28554331 TI - Outcome of acute respiratory distress syndrome in university and non-university hospitals in Germany. AB - BACKGROUND: This study investigates differences in treatment and outcome of ventilated patients with acute respiratory distress syndrome (ARDS) between university and non-university hospitals in Germany. METHODS: This subanalysis of a prospective, observational cohort study was performed to identify independent risk factors for mortality by examining: baseline factors, ventilator settings (e.g., driving pressure), complications, and care settings-for example, case volume of ventilated patients, size/type of intensive care unit (ICU), and type of hospital (university/non-university hospital). To control for potentially confounding factors at ARDS onset and to verify differences in mortality, ARDS patients in university vs non-university hospitals were compared using additional multivariable analysis. RESULTS: Of the 7540 patients admitted to 95 ICUs from 18 university and 62 non-university hospitals in May 2004, 1028 received mechanical ventilation and 198 developed ARDS. Although the characteristics of ARDS patients were very similar, hospital mortality was considerably lower in university compared with non-university hospitals (39.3% vs 57.5%; p = 0.012). Treatment in non-university hospitals was independently associated with increased mortality (OR (95% CI): 2.89 (1.31-6.38); p = 0.008). This was confirmed by additional independent comparisons between the two patient groups when controlling for confounding factors at ARDS onset. Higher driving pressures (OR 1.10; 1 cmH2O increments) were also independently associated with higher mortality. Compared with non-university hospitals, higher positive end-expiratory pressure (PEEP) (mean +/- SD: 11.7 +/- 4.7 vs 9.7 +/- 3.7 cmH2O; p = 0.005) and lower driving pressures (15.1 +/- 4.4 vs 17.0 +/- 5.0 cmH2O; p = 0.02) were applied during therapeutic ventilation in university hospitals, and ventilation lasted twice as long (median (IQR): 16 (9-29) vs 8 (3-16) days; p < 0.001). CONCLUSIONS: Mortality risk of ARDS patients was considerably higher in non-university compared with university hospitals. Differences in ventilatory care between hospitals might explain this finding and may at least partially imply regionalization of care and the export of ventilatory strategies to non university hospitals. PMID- 28554332 TI - Genomic diagnosis for children with intellectual disability and/or developmental delay. AB - BACKGROUND: Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios. METHODS: Whole-exome sequences (WES) were generated for 365 individuals (127 affected) and whole-genome sequences (WGS) were generated for 612 individuals (244 affected). RESULTS: Pathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected first-degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses, we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS and 4.7% of families with a negative result eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGaP. CONCLUSIONS: Our data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease. PMID- 28554335 TI - Processed and ultra-processed foods are associated with lower-quality nutrient profiles in children from Colombia. AB - OBJECTIVE: To determine if processed and ultra-processed foods consumed by children in Colombia are associated with lower-quality nutrition profiles than less processed foods. DESIGN: We obtained information on sociodemographic and anthropometric variables and dietary information through dietary records and 24 h recalls from a convenience sample of the Bogota School Children Cohort. Foods were classified into three categories: (i) unprocessed and minimally processed foods, (ii) processed culinary ingredients and (iii) processed and ultra processed foods. We also examined the combination of unprocessed foods and processed culinary ingredients. SETTING: Representative sample of children from low- to middle-income families in Bogota, Colombia. SUBJECTS: Children aged 5-12 years in 2011 Bogota School Children Cohort. RESULTS: We found that processed and ultra-processed foods are of lower dietary quality in general. Nutrients that were lower in processed and ultra-processed foods following adjustment for total energy intake included: n-3 PUFA, vitamins A, B12, C and E, Ca and Zn. Nutrients that were higher in energy-adjusted processed and ultra-processed foods compared with unprocessed foods included: Na, sugar and trans-fatty acids, although we also found that some healthy nutrients, including folate and Fe, were higher in processed and ultra-processed foods compared with unprocessed and minimally processed foods. CONCLUSIONS: Processed and ultra-processed foods generally have unhealthy nutrition profiles. Our findings suggest the categorization of foods based on processing characteristics is promising for understanding the influence of food processing on children's dietary quality. More studies accounting for the type and degree of food processing are needed. PMID- 28554336 TI - Assessing immune competence in pigs by immunization with tetanus toxoid. AB - Immune competence can be tested by challenging organisms with a set of infectious agents. However, disease control requirements impose restrictions on the infliction of infections upon domestic pigs. Alternatively, vaccinations induce detectable immune responses that reflect immune competence. Here, we tested this approach with tetanus toxoid (TT) in young domestic pigs. To optimize the vaccination protocol, we immunized the pigs with a commercial TT vaccine at the age of 21 or 35 days. Booster immunizations were performed either 14 or 21 days later. TT-specific antibodies in plasma as well as lymphoproliferative responses were determined both 7 and 14 days after booster immunization using ELISA and lymphocyte transformation tests, respectively. In addition, general IgG and IgM plasma concentrations and mitogen-induced proliferation were measured. The highest TT-specific antibody responses were detected when blood samples were collected 1 week after a booster immunization conducted 21 days after primary immunization. The pigs' age at primary immunization did not have a significant influence on TT-specific antibody responses. Similarly, the TT-specific proliferative responses were highest when blood samples were collected 1 week after booster immunization, while age and time of primary and booster immunization were irrelevant in our setup. While general IgG and IgM plasma levels were highly age dependent, there were no significant age effects for TT specific immune responses. In addition, mitogen-induced proliferation was independent of immunization as well as blood sampling protocols. In summary, our model of TT vaccination provides an interesting approach for the assessment of immune competence in young pigs. The detected vaccination effects were not biased by age, even though our data were acquired from immune systems that were under development during our tests. PMID- 28554337 TI - ASSESSING VALUE, BUDGET IMPACT, AND AFFORDABILITY IN ASIA. AB - OBJECTIVES: The aim of this study was to explore definitions of value and the use of budget impact and affordability considerations in health technology assessment (HTA) in the Asia region, particularly in relation to high cost technologies. METHODS: Issues were debated by senior representatives from HTA and payer systems in Asian countries, delegates from industry, and invited experts at the 2016 meeting of the HTAi Asia Policy Forum (HAPF). A premeeting survey was used to gather data on how value is assessed and budget impact calculations are used within current processes, as well as current approaches to managing affordability. RESULTS: All systems consider health benefit to be the key component of value. There is little consensus around "wider" elements of value that should be included. All systems use budget impact in decision making, although meeting attendees noted the challenges in making accurate estimates. The most common strategies used to address affordability concerns to date have been: restricting coverage, for example, to patients who are likely to get the highest value; discounts; and revenue caps. It was noted that these "solutions" may have unintended consequences of creating inequitable access to therapies and failing to provide adequate rewards for innovation. CONCLUSIONS: Decision makers, HTA agencies, and industry need to continue to work together to find mutually agreeable solutions to ensure that patients continue to get equitable access to effective therapies at costs that can be afforded throughout the Asia region. PMID- 28554338 TI - The development of an intraruminal nylon bag technique using non-fistulated animals to assess the rumen degradability of dietary plant materials. AB - Although the conventional in situ ruminal degradability method is a relevant tool to describe the nutritional value of ruminant feeds, its need for rumen fistulated animals may impose a restriction on its use when considering animal welfare issues and cost. The aim of the present work was to develop a ruminal degradability technique which avoids using surgically prepared animals. The concept was to orally dose a series of porous bags containing the test feeds at different times before slaughter, when the bags would be removed from the rumen for degradation measurement. Bags, smaller than those used in the conventional nylon bag technique, were made from woven nylon fabric, following two shape designs (rectangular flat shape, tetrahedral shape) and were fitted with one of three types of device for preventing their regurgitation. These bags were used in two experiments with individually housed non-pregnant, non-lactating sheep, as host animals for the in situ ruminal incubation of forage substrates. The bags were closed at the top edge by machine stitching and wrapped in tissue paper before oral dosing. Standard times for ruminal incubation of substrates in all of the tests were 4, 8, 16, 24, 48, 72 and 96 h before slaughter. The purpose of the first experiment was to compare the effectiveness of the three anti-regurgitation device designs, constructed from nylon cable ties ('Z-shaped', ARD1; 'double Z shaped', ARD2; 'umbrella-shaped', ARD3), and to observe whether viable degradation curves could be generated using grass hay as the substrate. In the second experiment, three other substrates (perennial ryegrass, red clover and barley straw) were compared using flat and tetrahedral bags fitted with type ARD1 anti-regurgitation devices. Non-linear mixed-effect regression models were used to fit asymptotic exponential curves of the percentage dry matter loss of the four substrates against time of incubation in the reticulorumen, and the effect of type of anti-regurgitation device and the shape of nylon bag. All three devices were highly successful at preventing regurgitation with 93% to 100% of dosed bags being recovered in the reticulorumen at slaughter. Ruminal degradation data obtained for tested forages were in accordance with those expected from the conventional degradability technique using fistulated animals, with no significant differences in the asymptotic values of degradation curves between bag shape or anti-regurgitation device. The results of this research demonstrate the potential for using a small bag technique with intact sheep to characterise the in situ ruminal degradability of roughages. PMID- 28554339 TI - Intersectoral action for health: preventing psittacosis spread after one reported case. AB - Zoonotic diseases are a significant health threat for humans and animals. To better understand the epidemiology, etiology, and pathology of infectious agents affecting humans and animals combined approaches are needed. Here we describe an epidemiological investigation conducted by physicians and veterinarians after a reported case of psittacosis. Upon admission suffering from respiratory distress syndrome in a hospital and with a history of bird contact, a female patient was serologically diagnosed with psittacosis. After the case notification, veterinarians were able to investigate the source of infection by detecting Chlamydia psittaci in her pet cockatiel. The bird was hospitalized and successfully treated. In addition, the establishment where the pet bird was purchased was traced and through molecular techniques other birds intended to be sold as pets tested positive for C. psittaci. As a result, sanitary measures were applied and the establishment then was closed down. The birds intended for the pet commerce were treated and retested with negative molecular results for C. psittaci, thus avoiding disease propagation. Reliable data about zoonotic diseases can only be generated through the application of multidisciplinary approaches which take into account the epidemiological factors and interactions of humans, animals and their environments as an integrated system. PMID- 28554340 TI - Cardiac MRI T1 mapping in unrepaired anomalous left coronary artery from the pulmonary artery. AB - A 29-year-old gravida1 para1 woman presented with increasing fatigue. Multi modality imaging demonstrated the left coronary artery arising from the main pulmonary artery with large collateral vessels in the interventricular septum, in keeping with unrepaired anomalous left coronary artery from the pulmonary artery. Cardiac MRI T1 mapping demonstrated globally elevated non-contrast T1 and extracellular volume fraction values, which suggested the presence of diffuse interstitial myocardial fibrosis. Cardiac MRI T1 mapping allows for a new dimension of myocardial characterisation, providing insight into subtle, diffuse abnormalities at the tissue level. PMID- 28554341 TI - Crowd Simulations and Determining the Critical Density Point of Emergency Situations. AB - OBJECTIVE: In modern societies, crowds and mass gatherings are recurrent. A combination of inadequate facilities and inefficient population management can lead to injury and death. Simulating people's behavior in crowds and mass gatherings can assist in the planning and management of gatherings, especially in emergency situations. METHODS: We aimed to determine the crowd pattern and the critical density point in the grand bazaar of Kerman in Iran. We collected data by use of a census method with a questionnaire. To determine the critical density point, height and weight data were placed in the equation $?,s?,{?equals}?,?sqrt {{{L{?vskip -1.5pt ?,?,?asterisk?,?,}M} ?over {3600}}} $ and the outer body surface of all the individuals in the bazaar was calculated. The crowd was simulated by use of flow-based modeling. Flow rate was determined by using the equation (flow rate=density * speed). By use of SketchUp Pro software (version 8; Trimble, Sunnyvale, CA), the movement of each person and the general flow rate were simulated in the three-dimensional environment of Kerman bazaar. RESULTS: Our findings showed that the population critical density point in Kerman bazaar would be 6112 people. In an accident, the critical density point in Kerman bazaar would be created in about 1 minute 10 seconds after the event. CONCLUSION: It seems necessary to identify and provide solutions for reducing the risk of disasters caused by overcrowding in Kerman bazaar. It is suggested that researchers conduct studies to design safe and secure emergency evacuation of Kerman bazaar as well as proper planning for better and faster access of aid squads to this location. (Disaster Med Public Health Preparedness. 2017;11:674 680). PMID- 28554342 TI - ASSESSING PATIENT'S PERCEPTION OF ORAL TELECONSULTATION. AB - OBJECTIVES: The evaluation of telemedicine from the patient's point of view has focused on the patient pathway and patient satisfaction. However, research in this field does not provide us with the means to assess a patient's perception of the procedure if their reasoning ability is impaired. In this study, we use direct observation of a patient's behavior and mood to assess their perception of an oral teleconsultation procedure. METHODS: This study has been conducted in the context of a pilot project using an asynchronous teleconsultation to improve access to dental care for the dependent elderly, disabled people, and prisoners, some of whom may be cognitively impaired. We use a direct observation form consisting of five behavioral variables and eight affect variables to reflect the patient's experience of the oral teleconsultation procedure. RESULTS: A total of 135 patients were evaluated; 10 refused the procedure. Psychotic patients (n = 33) had a somewhat negative experience during the oral teleconsultation procedure. Patients who were not psychotic had a positive experience; this decreased as we moved from the autonomous to the semi-autonomous and then to the dependent sub-group. Some gender differences were also noted. CONCLUSIONS: Improving evidence on evaluating the acceptance of the cognitively impaired is required to improve the technology development process so that it can be translated into an improved patient experience and adherence. Although the study was specifically focused on teledentistry, the approach described in this study could be adapted to other forms of teleconsultation. PMID- 28554343 TI - Quantifying respiratory sinus arrhythmia: Effects of misspecifying breathing frequencies across development. AB - Low resting respiratory sinus arrhythmia (RSA), and to a lesser extent excessive RSA reactivity to emotion evocation, are observed in many psychiatric disorders characterized by emotion dysregulation, including syndromes spanning the internalizing and externalizing spectra, and other conditions such as nonsuicidal self-injury. Nevertheless, some inconsistencies exist. For example, null outcomes in studies of RSA-emotion dysregulation relations are sometimes observed among younger participants. Such findings may derive from use of age inappropriate frequency bands in calculating RSA. We combine data from five published samples (N = 559) spanning ages 4 to 17 years, and reanalyze RSA data using age appropriate respiratory frequencies. Misspecifying respiratory frequencies results in overestimates of resting RSA and underestimates of RSA reactivity, particularly among young children. Underestimates of developmental shifts in RSA and RSA reactivity from preschool to adolescence were also observed. Although correlational analyses revealed weak negative associations between resting RSA and aggression, those with clinical levels of externalizing exhibited lower resting RSA than their peers. No associations between RSA reactivity and externalizing were observed. Results confirm that age-corrected frequency bands should be used when estimating RSA, and that literature-wide overestimates of resting RSA, underestimates of RSA reactivity, and underestimates of developmental shifts in RSA and RSA reactivity may exist. PMID- 28554344 TI - Overview of Nanoparticle Coating of Dental Implants for Enhanced Osseointegration and Antimicrobial Purposes. AB - PURPOSE: Nanomaterials are suitable candidates for coating of titanium based (Ti based) dental implants due to their unique properties. The objective of this article is to summarize the application of nanoparticles as Ti-based implant coating materials in order to control and improve the implant success rate with focus on enhanced osseointegration and antimicrobial purposes. METHOD: This review was conducted using electronic databases and MeSH keywords to detect associated scientific literature published in English. RESULTS: The reviewed articles exhibited that a significant progress in research has occurred in the case of nanomaterial-based coatings for dental implants. Coating of Ti surfaces with nanoparticles can improve soft tissue integration and osteogeneration that leads to improved fixation of implants. Furthermore, osteoconductive nanoparticles induce a chemical bond with bone to attain good biological fixation for implants. Surface modification of implants using antibacterial properties can also decrease the potential for infection, and certainly, present improve clinical outcomes. CONCLUSIONS: Considering the reported success, more clinically and in vivo information on the nanoparticle-based implant coatings will add to the successful application of the device in the clinic. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28554345 TI - Quantitative Structure - Pharmacokinetic Relationships for Plasma Clearance of Basic Drugs with Consideration of the Major Elimination Pathway. AB - PURPOSE: The success of a new drug candidate is determined not only by its efficacy and safety, but also by proper pharmacokinetic behavior. The early prediction of pharmacokinetic parameters could save time and resources and accelerate drug development process. Plasma clearance (CL) is one of the key determinants of drug dosing regimen. The aim of the study is development of quantitative structure - pharmacokinetics relationships (QSPkRs) for the CL. METHODS: A dataset consisted of 263 basic drugs, which chemical structures were described by 154 descriptors. Genetic algorithm, stepwise regression and multiple linear regression were used for variable selection and model development. Predictive ability of the models was assessed by internal and external validation. Results. A number of significant QSPkR models for the CL were derived with respect to the primary elimination pathway (renal excretion, metabolism, or CYP3A4 mediated biotransformation), as well for the unbound clearance (CLu). The models were able to predict 52 - 80% of the drugs from external validation sets within the 2-fold error of the experimental values with geometric mean fold error 1.57 - 2.00. CONCLUSIONS: Plasma protein binding was the major restrictive factor for the CL of drugs, primarily cleared by metabolism. The clearance was favored by lipophilicity and several structural features like OH-groups, aromatic rings, large hydrophobic centers, aliphatic groups, connected with electro-negative atoms, and non-substituted aromatic C atoms. The presence of Cl-atoms and abundance of 6-member aromatic rings or fused rings had negative effect. The presence of ether O-atoms contributed negatively to the CL of both metabolism and renally excreted drugs, and urine excretion was favored by the presence of 3-valence N-atoms. These findings give insight on the main structural features governing plasma CL of basic drugs and could serve as a guide for lead optimization in the drug development process. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28554346 TI - Clay and Polymer-Based Composites Applied to Drug Release: A Scientific and Technological Prospection. AB - There has been a growing trend in recent years for the development of hybrid materials, called composites, based on clay and polymers, whose innovative properties render them attractive for drug release. The objective of this manuscript was to conduct a review of original articles on this topic published over the last decade and of the body of patents related to these carriers. A scientific prospection was carried out spanning the period from 2005 to 2015 on the Web of Science database. The technological prospection encompassed the United States Patent and Trademark Office, the European Patent Office, the World International Patent Office and the National Institute of Industrial Property databases, filtering patents with the code A61K. The survey revealed a rise in the number of publications over the past decade, confirming the potential of these hybrids for use in pharmaceutical technology. Through interaction between polymer and clay, the mechanical and thermal properties of composites are enhanced, promoting stable, controlled drugs release in biological media. The most cited clays analyzed in the articles was montmorillonite, owing to its high surface area and capacity for ion exchange. The polymeric part is commonly obtained by copolymerization, particularly using acrylate derivatives. The hybrid materials are obtained mainly in particulate form on a nanometric scale, attaining a modified release profile often sensitive to stimuli in the media. A low number of patents related to the topic were found. The World International Patent Office had the highest number of lodged patents, while Japan was the country which published the most patents. A need to broaden the application of this technology to include more therapeutic classes was identified. Moreover, the absence of regulation of nanomaterials might explain the disparity between scientific and technological output. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28554347 TI - Embrace Action: Protect the Future of Nursing. PMID- 28554349 TI - 2017 Conference Highlights. PMID- 28554348 TI - Succession Planning: A Perioperative Imperative. PMID- 28554350 TI - 2017 Conference Awards. PMID- 28554351 TI - 2017 Conference Poster Winners. PMID- 28554352 TI - 2017 Conference Poster Collection. PMID- 28554353 TI - Enhanced Time Out: An Improved Communication Process. AB - An enhanced time out is an improved communication process initiated to prevent such surgical errors as wrong-site, wrong-procedure, or wrong-patient surgery. The enhanced time out at my facility mandates participation from all members of the surgical team and requires designated members to respond to specified time out elements on the surgical safety checklist. The enhanced time out incorporated at my facility expands upon the safety measures from the World Health Organization's surgical safety checklist and ensures that all personnel involved in a surgical intervention perform a final check of relevant information. Initiating the enhanced time out at my facility was intended to improve communication and teamwork among surgical team members and provide a highly reliable safety process to prevent wrong-site, wrong-procedure, and wrong-patient surgery. PMID- 28554354 TI - Association Between Acute Pain and Hemodynamic Parameters in a Postoperative Surgical Intensive Care Unit. AB - I conducted a prospective repeated-measure study in the general surgery intensive care unit to investigate the associations among acute postoperative pain, analgesic therapy, and hemodynamic parameters. I selected 33 patients and recorded 84 episodes of pain. I measured intensity of pain and hemodynamic parameters after patients were transferred from the postanesthesia care unit to the general surgery intensive care unit, immediately before analgesic therapy and at 15, 30, and 45 minutes after analgesic therapy. Acute pain increased systolic (SBP), diastolic (DBP), and mean arterial blood pressure (MAP); pulse rate (PR); and arterial oxygen saturation. Fifteen minutes after analgesic therapy, SBP and PR decreased, and DBP, MAP, and oxygen saturation increased. Thirty minutes after therapy, SBP, MAP, and PR decreased, and DBP and oxygen saturation increased. Forty-five minutes after therapy, SBP, MAP, and PR decreased, and DBP and oxygen saturation increased. I saw no significant hemodynamic parameter changes during postoperative episodes of pain. PMID- 28554355 TI - Implementing Skin-to-Skin Contact for Cesarean Birth. AB - Early skin-to-skin (STS) contact in the OR facilitates the development of mothering behaviors, breastfeeding success, and newborn adaptation to extrauterine life. A team at my institution performed a quality improvement project to implement a standard of care for STS contact in the OR during and after cesarean birth. Thirty-seven of 50 mother-infant dyads experienced STS contact in the OR or in the postanesthesia care unit. Twenty-five mothers and newborns who experienced STS contact did so on the OR bed. The median time newborns spent engaged in STS contact with their mothers was 42 minutes and 30 seconds. Developing and using a standard of care to implement this evidence-based practice facilitated acceptance of this intervention. Obstacles that staff members encountered included maternal or neonatal instability, equipment problems, and nurse staffing issues. Staff members addressed these obstacles through creative problem-solving. PMID- 28554356 TI - Radioactive Seed Localization Program for Patients With Nonpalpable Breast Lesions. AB - Without early diagnosis and treatment, many lives are lost to breast cancer. Increased breast cancer awareness has facilitated research to guide health care providers toward improving patient outcomes. Research in diagnostic and treatment modalities has expanded to focus on improving the quality of life for patients with breast cancer who are living longer than expected. Providers can offer patients with nonpalpable breast lesions new screening techniques and improved treatment options, including radioactive seed localization lumpectomy. This treatment offers patients the potential for decreased tumor re-excision for positive margins near the surgical site, a lower volume of excised breast tissue, decreased operative time, convenient surgical scheduling, and less pain. Additionally, radioactive seed localization lumpectomy can improve patient and staff member satisfaction. PMID- 28554357 TI - Accuracy of Children's Perioperative Memories. AB - Children's declarative memories of medical procedures can influence their responses to subsequent events. No previous study has examined the accuracy of children's declarative memories after surgery. We tested the memory of 34 anesthesia-naive five- to nine-year-old children undergoing ambulatory surgery for accuracy of contextual details, pain, and fear two weeks postoperatively. Parents were not present during induction, and we did not use sedative premedication. Children had a mean contextual recall accuracy of 64.5%. Most children (60.6%) remembered a prompt that was given one minute after receiving nitrous oxide. Children's memories of pain and fear were similar to their reported pain and fear on the day of surgery. Of 29 children, 6 (20.7%) exaggerated their memory of fear, and 8 of 22 children (36.4%) exaggerated their memory of pain. Although a small proportion of children had exaggerated memories, there was no evidence of consistent bias in their memory of fear or pain. PMID- 28554358 TI - Understanding and Improving Surgical Hand Hygiene Compliance. PMID- 28554359 TI - Clinical Issues-June 2017. AB - Defining a small amount of surgical smoke Key words: surgical smoke, medical surgical vacuum system, suction tubing. Assessment of hazardous medications Key words: hazardous medications, safety data sheets, OSHA hazard communication. Documentation of electrosurgical devices Key words: electrosurgical device. Developing an explant policy Key words: explant, guideline, implant, policy. PMID- 28554360 TI - Evidence appraisal of Seidi J, Ebnerasooli S, Shahsawari S, Nzarian S. The influence of oral ginger before operation on nausea and vomiting after cataract surgery under general anesthesia: a double-blind placebo-controlled randomized clinical trial.: Electron Physician. 2017;9(1):3508-3514. PMID- 28554361 TI - Guideline at a Glance: Moderate Sedation/Analgesia. PMID- 28554362 TI - Amphotericin Toxicity. PMID- 28554364 TI - Associations of treatment effects between follow-up times and between outcome domains in interventions for somatoform disorders: Review of three Cochrane reviews. AB - BACKGROUND: Interventions for somatoform disorders typically address a range of outcomes. We aimed to examine treatment effects across outcome domains and specifically assess the association, at study level, between short and long term treatment effects and between treatment effects in different outcome domains. METHODS: We used data from recent systematic reviews of interventions for somatoform disorders to address three questions: We described outcome domains and measures by compiling forest plots of standardised mean difference. We examined the association of changes in outcome between short and long-term and between different outcome domains by non-parametric correlation. RESULTS: We analysed data from 47 studies across four outcome domains: physical symptoms, health related quality of life, depression and anxiety. Short-term and long-term treatment effects within each outcome domain were broadly similar and were correlated Reported reduction in physical symptoms was correlated with reductions in depression (rho=0.73, p=0.002) and anxiety (0.70, p<0.001) and increase in quality of life (0.54, p=0.03). CONCLUSION: Short term changes in outcome measures are correlated with longer term changes; outcome changes are correlated across domains independently of the type of treatment. PMID- 28554363 TI - Social support from the closest person and sleep quality in later life: Evidence from a British birth cohort study. AB - OBJECTIVES: Supportive social relationships have been found to be related to fewer sleep problems and better sleep quality. We examined associations between positive and negative support from the nominated close person across 15years of follow-up with sleep quality in older age. METHODS: MRC National Survey of Health and Development study members reported sleep quality at age 68 (n=2446). Cumulative exposure to and changes in positive and negative support were derived from data at age 53, 60-64 and 68years. Pittsburgh Sleep Quality Index scores were regressed on social support measures adjusted for i) gender only then additionally ii) education, marital status, number in household, limiting illness, body mass index, caregiving, iii) and affective symptoms. RESULTS: Greater exposure to positive support and lower exposure to negative support over 15years were independently associated with better sleep quality at age 68. Sleep quality was poorer for those who experienced declining positive support or increasing negative support. Those who nominated their spouse/partner as their closest person at age 53 but not at age 68 had poorer sleep quality than those who nominated their spouse on both occasions. These associations were not explained by the covariates, including affective symptoms. CONCLUSIONS: Based on repeat data on support from the closest person, this study finds a link between declining social relationship quality and poor sleep quality. Whilst acknowledging that the association may be bi-directional, the study suggests that interventions to improve older people's social relationships may have benefits for sleep. PMID- 28554365 TI - Preliminary evidence for increased parasympathetic activity during social inclusion and exclusion in adolescents with functional abdominal pain. AB - OBJECTIVE: Peer victimization (e.g. social exclusion) has been shown to be associated with physical health problems such as functional somatic complaints and especially symptoms of pain. To date, no study has investigated the mechanisms underlying this association in clinical pediatric samples. The aim of this study was to evaluate the parasympathetic activity during a social exclusion experience in adolescents with functional abdominal pain (FAP). METHODS: Twenty adolecents with FAP and 21 matched healthy participants were compared regarding parameters of parasympathetic activation before, during, and after participating in the Cyberball-game, a well-established paradigm to induce social exclusion. RESULTS: Adolescents with FAP showed an increase in parasympathetic activation during both consecutive phases of the Cyberball game (inclusion as well as exclusion condition) whereas the healthy control group remained stable. There were no differences in subjective experience of in- and exclusion between the groups. CONCLUSION: The parasympathetic activation pattern may indicate altered processing of social stimuli in adolescents with FAP. PMID- 28554366 TI - Is psychotherapy for functional somatic syndromes harmful? A mixed methods study on negative effects. AB - INTRODUCTION: Concern for negative effects of psychotherapy for functional somatic syndromes (FSS) has been expressed by clinicians and some patient associations, which may prevent patients from seeking treatment. Therefore, we sought to explore the occurrence and characteristics of negative effects from group-based psychotherapy as experienced by patients with severe or multiple FSS. METHODS: An adapted version of the explanatory sequential mixed methods design was applied. We used data from an on-going pilot study on Acceptance and Commitment Therapy and Mindfulness-Based Stress Reduction. Negative effects were measured by Inventory for the assessment of Negative Effects of Psychotherapy (INEP). In addition, telephone interviews were conducted with randomly chosen patients and patients who reported negative effects. The latter were asked to elaborate on their INEP response. Quantitative data were analysed descriptively while interview transcripts were explored by thematic analysis. RESULTS: Eighty patients responded to the questionnaire (89%). Negative effects to different extent (from 'slightly agree' to 'fully agree') were reported by 25 (31%). The most frequent negative effects were dependence on the therapist (12%), feeling down after therapy (6%) and insurance problems (7%). By exploring 27 participants' experiences of negative effects 3 main themes were identified: relations in therapy, outcome and transition from therapy to everyday life. CONCLUSION: Patients with FSS reported a few specific negative effects, all with low frequency. Generally, therapy was well-received. Some patients did however express negative effects both within and outside the therapeutic context. It is important to inform patients about potential negative effects prior to psychotherapy. PMID- 28554367 TI - A systematic review of paruresis: Clinical implications and future directions. AB - OBJECTIVE: Paruresis refers to the inability to initiate or sustain urination where individuals are present due to the fear of perceived scrutiny from others. The aim of this systematic review was to evaluate four key questions: (1) What is the prevalence of paruresis and its associated demographic features; (2) What is the prevalence of psychopathology in paruresis cohorts, how does it compare to other chronic-health conditions, and what percentage of paruresis patients also have social anxiety disorder? (3) How does quality of life, and levels of anxiety and depression compare between those with and without paruresis; and (4) do psychological interventions for paruresis patients reduce paruresis symptoms, or, anxiety, or depression, or improve quality of life? METHOD: A review was conducted using PRISMA protocol for search strategy, selection criteria, and data extraction. Searched databases included PubMed, CINAHL, and PsychINFO. Over the 1418 studies screened, ten were found relating to at least one review question. RESULTS: The prevalence of paruresis ranged between 2.8 and 16.4%, and around 5.1 22.2% of individuals with paruresis also had Social Anxiety Disorder. Paruresis symptoms were shown to reduce in one intervention study. Paruresis was also associated with poorer quality of life. A key limitation of the research to date has been the notable methodological problems and lack of standardisation relating to the measurement of paruresis. CONCLUSION: Little is known about the prevalence of paruresis and more rigorous studies of paruresis are required. Recommendations in terms of clinical implications, diagnostic criteria and future research relating to paruresis are discussed. PMID- 28554368 TI - Mental disorders in patients with chronic pelvic pain syndrome (CPPS). AB - OBJECTIVE: Chronic pelvic pain syndrome (CPPS) is a debilitating pain condition with prevalence rates between 2.0% and 26.6%. Studies indicate that CPPS is often associated with psychosocial factors, but little is known about the presence of full-blown mental disorders in female and male patients with CPPS. Therefore, the aim of this study was to investigate the frequencies of mental disorders in patients with CPPS. METHODS: Cross-sectional data were collected from patients visiting a specialized outpatient clinic. Frequencies of mental disorders were investigated using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and compared to the general population. Furthermore, self-rating questionnaires were used to assess somatic symptom severity (PHQ-15), depression severity (PHQ-9) and anxiety severity (GAD-7). RESULTS: Data from 178 CPPS patients (60.1% female; age M=49.1, SD=18.0) were analyzed. Of the total sample, 95.2% (95% CI 90.8-97.9) suffered from at least one mental disorder. The most prevalent mental disorders were somatoform disorders (91.7%; 95% CI 86.4-95.4), followed by mood disorders (50.6%; 95% CI 42.8-58.4) and anxiety disorders (32.1%; 95% CI 25.2-39.8). The self-reported symptom burden was also significantly higher than in the general population. Compared to men, women met the diagnoses of somatoform (p=0.012) and anxiety disorders (p=0.027) significantly more often and reported a significantly higher total somatic symptom severity (p=0.001). CONCLUSION: Our results provide evidence for a clinically relevant psychosocial symptom burden in patients with CPPS, indicating the need for the examination of psychopathologies and multi-professional treatment for this patient group. PMID- 28554369 TI - Effects and mediators of psychosocial work characteristics on somatic symptoms six years later: Prospective findings from the Mannheim Industrial Cohort Studies (MICS). AB - OBJECTIVE: Ample evidence documented the adverse health effects of work stressors, and recent research has increasingly focused on somatic symptoms which are very common and costly. Prospective evidence is however sparse and yielded mixed findings. Furthermore, there is reason to assume that depression and anxiety might mediate the effects of adverse psychosocial work conditions on somatic symptoms. This study aimed to investigate longitudinal effects of work stressors on somatic symptoms and the potential mediation by anxiety and/or depression. METHODS: Six year follow-up data from 352 individuals - free of potentially stress-related chronic disease - were utilized. Somatic symptoms were assessed by 19 items of an established list of complaints at baseline and follow up. The effort-reward-imbalance (ERI) model measured adverse psychosocial work conditions and over-commitment (OC). Linear regressions adjusted for socio demographics, social status, lifestyle, and baseline symptoms estimated the effects of the ERI ratio, effort, reward, OC, and the ERI ratio*OC interaction on somatic symptoms six years later. Furthermore, single and multiple mediation by anxiety and/or depression was investigated. RESULTS: There was a strong longitudinal effect of the ERI ratio, as well as of its subcomponents, and OC on somatic symptoms (all Bs>=|0.49|; p-values <=0.004). Moreover, the ERI ratio*OC interaction was significant (p-value=0.047). Multiple mediation analyses revealed especially anxiety to mediate the effect of work stressors on somatic symptoms (Sobel test=0.007). CONCLUSION: Adverse psychosocial work conditions seem to longitudinally affect somatic symptoms, potentially moderated by OC, and mediated by anxiety. PMID- 28554370 TI - Measurement invariance across Genders on the Childhood Illness Attitude Scales (CIAS). AB - OBJECTIVE: The Childhood Illness Attitude Scales (CIAS) were created as a developmentally appropriate measure for symptoms of health anxiety (HA) in school aged children. Despite overall sound psychometric properties reported in previous studies, more comprehensive examination of the latent structure and potential response bias in the CIAS is needed. The purpose of the present study was to cross-validate the latent structure of the CIAS across genders and to examine gender-specific variations in CIAS scores. METHODS: The sample comprised data from 602 Canadian and Danish school-aged children (Mage=10.54, SD=0.99; 52.5% girls). Confirmatory factor analyses were conducted to test 3-, modified 3-, and 4-factor models in both samples. Multigroup confirmatory factor analysis was performed to test factor structure invariance across boys and girls in a combined sample. Differential Item Functioning (DIF) was assessed using test characteristic curves. RESULTS: A modified 3-factor solution (i.e., fears=11 items, help-seeking=6 items, and symptom effects=4 items) provided the best fit to the data (chi2 (364, N=602)=681.7, p<0.001; chi2/df=1.803; RMSEA=0.037; CFI=0.926). The factor structure was stable, well-fitting, and indicated measurement invariance across groups. DIF analyses revealed no gender-based response bias at the scale level. CONCLUSION: Results support a revised 3-factor version of the CIAS that can be used with confidence to assess symptoms of HA in school-aged boys and girls. PMID- 28554371 TI - The assessment of fatigue: Psychometric qualities and norms for the Checklist individual strength. AB - OBJECTIVE: The Checklist Individual Strength (CIS) measures four dimensions of fatigue: Fatigue severity, concentration problems, reduced motivation and activity. On the fatigue severity subscale, a cut-off score of 35 is used. This study 1) investigated the psychometric qualities of the CIS; 2) validated the cut off score for severe fatigue and 3) provided norms. METHODS: Representatives of the Dutch general population (n=2288) completed the CIS. The factor structure was investigated using an exploratory factor analysis. Internal consistency and test retest reliability were determined. Concurrent validity was assessed in two additional samples by correlating the CIS with other fatigue scales (Chalder Fatigue Questionnaire, MOS Short form-36 Vitality subscale, EORTC QLQ-C30 fatigue subscale). To validate the fatigue severity cut-off score, a Receiver Operating Characteristics analysis was performed with patients referred to a chronic fatigue treatment centre (n=5243) and a healthy group (n=1906). Norm scores for CIS subscales were calculated for the general population, patients with chronic fatigue syndrome (CFS; n=1407) and eight groups with other medical conditions (n=1411). RESULTS: The original four-factor structure of the CIS was replicated. Internal consistency (alpha=0.84-0.95) and test-retest reliability (r=0.74-0.86) of the subscales were high. Correlations with other fatigue scales were moderate to high. The 35 points cut-off score for severe fatigue is appropriate, but, given the 17% false positive rate, should be adjusted to 40 for research in CFS. CONCLUSION: The CIS is a valid and reliable tool for the assessment of fatigue, with a validated cut-off score for severe fatigue that can be used in clinical practice. PMID- 28554372 TI - Differentiating progress in a clinical group of fibromyalgia patients during and following a multicomponent treatment program. AB - OBJECTIVE: Treatments including multiple nonpharmacological components have beneficial effects on the key symptoms of fibromyalgia, although effects are limited and often do not persist. In this study, we examined different patterns of clinical progress and the dynamic interplay between predictors and outcomes over time. METHODS: Fibromyalgia patients (N=153; 135 women) followed a multidisciplinary group program spanning 12weeks, aimed at "regaining control over daily functioning". Anxiety, depression, pain coping and kinesiophobia were used as predictor variables. Outcome variables were pain severity, pain-related disability, physical functioning and functional interference. All variables were assessed at 3 moments: on the first and last day of treatment, and 12weeks after the last day of treatment. Overall treatment effects were analyzed using mixed model analyses. Latent class growth analysis identifying different treatment trajectory classes was used to investigate individual differences in treatment effects. Finally, cross-lagged structural equation models were used to investigate the dynamic interplay between predictors and outcomes over time. RESULTS: Only a fourth to a third of the total group showed improvement on the outcome variables. These patients had lower baseline anxiety, depression and kinesiophobia, and improved more on anxiety, depression and kinesiophobia. Physical well-being had a stronger effect on anxiety and depression than vice versa. Physical functioning predicted relative changes in kinesiophobia, while kinesiophobia predicted relative changes in pain-related disability. CONCLUSION: The results emphasize the importance of tailoring treatments to individual needs in order to improve overall effectiveness of treatment programs. PMID- 28554373 TI - The relationship between cancer patient's fear of recurrence and chemotherapy: A systematic review and meta-analysis. AB - OBJECTIVE: The study aim was to provide an overview of the current evidence available on the link between chemotherapy (CTX) and fear of cancer recurrence (FoR). METHODS: PubMED, Medline, Embase, PsycINFO and Web of Science databases were searched to identify relevant studies. Two authors independently selected and assessed the studies regarding eligibility criteria. Meta-analysis of suitable studies was conducted, and quality rated. RESULTS: Forty eligible studies were included in the systematic review and twenty-nine of them were included in further meta-analysis. Meta-analysis of the available data confirmed a weak relationship between CTX and FoR (29 studies, 30,176 patients, overall r=0.093, 95% CI: 0.062, 0.123, P?0.001). CONCLUSIONS: The meta-analysis demonstrates a weak but significant relationship between cancer patient's FoR and the receipt of chemotherapy. However, these results should be interpreted with caution. Further investigation is warranted to explore possible mechanisms of FoR increase in patients who receive chemotherapy. Longitudinal studies assessing the trajectory of FoR during chemotherapy are also warranted. PMID- 28554374 TI - Conditioned pain modulation among young, healthy, and physically active African American and non-Hispanic White adults. AB - OBJECTIVE: Research shows that African American (AA) adults experience more severe and frequent pain compared to non-Hispanic White (NHW) adults. Additionally, experimental studies demonstrate that AA adults exhibit less efficient central pain inhibition compared to NHW adults, which may partially explain the racial/ethnic disparities in pain. Evidence suggests that regular physical activity (PA) may help improve central pain inhibition, but research shows that AA adults engage in less PA, and are less likely to meet PA guidelines for health promotion compared to NHW adults. These observations suggest that PA levels may help better understand the racial/ethnic difference in central pain inhibition. Therefore, this study compared central pain inhibition and PA levels among AA and NHW adults. METHODS: Young and healthy participants were recruited on campus, and 27 AA and 27 NHW adults completed this study. Central pain inhibitory processing was assessed using conditioned pain modulation (CPM), where changes in electrical pain ratings were quantified during and after exposure to pressure pain compared to baseline. PA levels were assessed using self-report questionnaires and accelerometer. RESULTS: The participants were generally physically active, and most participants in both groups met the public recommendation of PA for health promotion. Electrical pain ratings were significantly reduced during and after exposure to pressure pain compared to baseline. There was no racial/ethnic difference in a magnitude of changes in electrical pain ratings. CONCLUSION: Young, healthy, and physically active AA and NHW adults exhibit similar CPM responses. Regular PA may help attenuate the racial/ethnic difference in CPM responses. PMID- 28554375 TI - Home-based COPD psychoeducation: A qualitative study of the patients' experiences. AB - OBJECTIVE: To explore the patients' experiences of a minimal home-based psychoeducative intervention aimed at reducing symptoms of anxiety. BACKGROUND: In a randomised controlled trial (RCT) we have shown that a minimal home-based and nurse-led psychoeducative intervention has a significant effect in reducing symptoms of anxiety and increasing mastery of dyspnoea in patients with advanced chronic obstructive pulmonary disease (COPD). However, we do not know if the intervention is perceived as meaningful and applicable in the everyday life of patients with advanced COPD. METHODS: We conducted a nested post-trial qualitative study. The study methodology was Interpretive Description as described by Thorne. The study was based on semi-structured interviews with twenty patients from the RCT intervention group i.g. home-living people with a diagnosis of advanced COPD and symptoms of anxiety. RESULTS: The patients described that making anxiety visible makes it manageable and provides relief. The patients described a feeling of being alone with managing anxiety and dyspnea, and the only way to gain in control of their cognitions was to mobilise internal resources. The intervention was appreciated by patients because it strengthened their internal resources. Further, it was perceived as a relief that the intervention insisted on talking about anxiety and thereby invited patients to verbalise worries related to end-of-life. CONCLUSION: This study offers knowledge to better understand the patients' experiences of a psychoeducative intervention. The intervention was perceived as comprehensible and applicable in the patients' everyday life and contributed to the patients' ability to self manage their condition. PMID- 28554376 TI - Exploring smoking, mental health and smoking-related disease in a nationally representative sample of older adults in Ireland - A retrospective secondary analysis. AB - OBJECTIVE: Smoking is the leading preventable cause of death among individuals with mental health difficulties (MHD). The aim of the current study was to determine the impact of smoking on the physical health of older adults with MHD in Ireland and to explore the extent to which smoking mediated or moderated associations between MHD and smoking-related diseases. METHODS: Cross-sectional analysis of a nationally representative sample of 8175 community-dwelling adults aged 50 and over from The Irish Longitudinal Study on Ageing (TILDA) was undertaken. Multivariate adjusted logistic regression models were used to assess the association between MHD, smoking (current/past/never) and smoking-related diseases (respiratory disease, cardiovascular disease, smoking-related cancers). A number of variables were employed to identify individuals with MHD, including prescribed medication, self-reported diagnoses and self-report scales. RESULTS: MHD was associated with current (RRRs ranging from 1.84 [1.50 to 2.26] to 4.31 [2.47 to 7.53]) and former (RRRs ranging from 1.26 [1.05 to 1.52] to 1.99 [1.19 to 3.33]) smoking and also associated with the presence of smoking-related disease (ORs ranging from 1.24 [1.01 to 1.51] to 1.62 [1.00 to 2.62]). Smoking did not mediate and rarely moderated associations between MHD and smoking-related disease. CONCLUSIONS: Older adults in Ireland with MHD are more likely to smoke than those without such difficulties. They also experience higher rates of smoking-related disease, although smoking had no mediating and no consistent moderating role in these analyses. Findings underscore the need for attention to the physical health of those with MHD including support in smoking cessation. PMID- 28554377 TI - Pharmacological treatment options for low Bone Mineral Density and secondary osteoporosis in Anorexia Nervosa: A systematic review of the literature. AB - OBJECTIVE: Although there are several evidence-based treatments available to increase Bone Mineral Density (BMD) and reduce fracture risk in aging men and women, there are still uncertainties regarding which treatments are efficacious in reducing lifetime fracture risk in women with Anorexia Nervosa (AN). METHODS: Medline, PsychInfo, Embase and the Cochrane Database were searched for English Language Studies. Inclusion criteria were studies of females of any age with AN who received pharmacological treatment with the primary aim to increase BMD or reduce fracture risk. Data were extracted from each study regarding pharmacological treatment and dosage used, BMD and bone formation marker outcomes; and participant characteristics including age, Body Mass Index (BMI), duration of AN, and duration of amenorrhea. RESULTS: 675 studies were reviewed, of which 19 fit the inclusion criteria and were included in the final review, investigating a total of 1119 participants; 10 of the 19 included studies were double-blind RCTs. The remaining studies consisted of prospective observational studies, a retrospective cohort study, a case-control study and five non randomised control trials. Bisphosphonates were effective in increasing BMD in adult women with AN, while estrogen administered transdermally resulted in significant increases in BMD in mature adolescents with AN. Administration of oral contraceptives (OC) did not significantly increase BMD in randomised or controlled trials, however, lifetime OC use was associated with higher spinal BMD. CONCLUSION: Future research should clarify the safety of long-term bisphosphonate use in adult women with AN, and verify that transdermal estrogen replacement increases BMD in women with AN. PMID- 28554378 TI - High healthcare utilization near the onset of medically unexplained symptoms. AB - OBJECTIVE: Patients with medically unexplained syndromes (MUS) often do not receive appropriate healthcare. A critical time for effective healthcare is the inception of MUS. The current study examined data from a prospective longitudinal study of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) soldiers to understand the relationship of increasing physical symptom burden to healthcare utilization. METHODS: Data was examined from a prospective study of OEF/OIF soldiers assessed before and one year after deployment (n=336). Physical symptom burden was measured with the Patient Health Questionnaire (PHQ-15). Analyses were conducted with polynomial regression and response surface analysis (RSA). RESULTS: Increases in physical symptom burden predicted greater healthcare utilization one year after deployment: primary care practitioner (slope=-0.26, F=4.07, p=0.04), specialist (slope=-0.43, F=8.67, p=0.003), allied health therapy (e.g., physical therapy) (slope=-0.41, F=5.71, p=0.02) and mental health (slope= 0.32, F=4.04, p=0.05). There were no significant difference in utilization between those with consistently high levels and those with increases in physical symptom burden. CONCLUSION: This is the first prospective study to examine, and show, a relationship between onset of clinically significant physical symptoms and greater healthcare utilization. Our data suggest that patients with increasing physical symptom burden have the same level of healthcare as patients with chronic physical symptom burden. Needed next steps are to better understand the quality of care at inception and determine how to intervene so that recommended approaches to care are provided from the onset. PMID- 28554379 TI - Time dependence of enzyme synergism during the degradation of model and natural lignocellulosic substrates. AB - Cellulosic ethanol production relies on the biochemical (enzymatic) conversion of lignocellulose to fermentable sugars and ultimately to bioethanol. However, the cost of lignocellulolytic enzymes is a limiting factor in the commercialisation of this technology. This therefore necessitates the optimisation of lignocellulolytic enzyme cocktails through the elucidation of synergistic interactions between enzymes so as to improve lignocellulose hydrolysis and also lower protein loadings in these reactions. However, many factors affect the synergism that occurs between these lignocellulolytic enzymes, such as enzyme ratios, substrate characteristics, substrate loadings, enzyme loadings and time. This review examines the effect of time on the synergistic dynamics between lignocellulolytic enzymes during the hydrolysis of both complex (true) lignocellulosic substrates and model substrates. The effect of sequential and simultaneous application of the lignocellulolytic enzymes on the synergistic dynamics during the hydrolysis of these substrates is also explored in this review. Finally, approaches are further proposed for efficient and synergistic hydrolysis of both complex lignocellulosic substrates and model substrates. With respect to the synergistic enzymatic hydrolysis of lignocellulosic biomass, this review exposed knowledge gaps that should be covered in future work in order to fully understand how enzyme synergism works: e.g. elucidating protein to protein interactions that exist between these enzymes in establishing synergy; and the effect of lignocellulose degradation products of one enzyme on the behaviour of the other enzyme and ultimately their synergistic relationship. PMID- 28554380 TI - Overexpression of hlyB and mdh genes confers halotolerance in Fremyella diplosiphon, a freshwater cyanobacterium. AB - Fremyella diplosiphon is a freshwater cyanobacterium that has great potential as a biofuel agent due to its ability to grow in low light intensity and acclimation to different wavelengths. To enhance its halotolerance for growth in 35gL-1 sodium chloride (NaCl), plasmids harboring hemolysin B (hlyB) and malate dehydrogenase (mdh) genes were transformed into wild type F. diplosiphon (WT Fd33). Electroporation-mediated overexpression of the genes resulted in two transformants, HSF33-1 and HSF33-2, with 9- and 20-fold increases in hlyB and mdh transcript levels. In addition, up-regulation of proteins at the expected size ranges of 50-60kDa for HlyB and 40-50kDa for MDH was observed. Two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry revealed a protein spot corresponding to HlyB in HSF33-1 with a significant MOWSE score of 164 and 3% sequence coverage, and a spot corresponding to MDH in HSF33-2 gave a significant MOWSE score of 124 with 10% sequence coverage. Physiological evaluation in BG11/HEPES medium and seawater adjusted to 35gL-1 NaCl confirmed that the transformants could thrive in high salinity with no loss of photosynthetic pigments. Results of the study indicate that overexpression of hlyB and mdh genes confer halotolerance in F. diplosiphon, thus maximizing its potential as a large-scale biofuel agent. PMID- 28554381 TI - Effects of high hydrostatic pressure or hydrophobic modification on thermal stability of xanthine oxidase. AB - The effect of high hydrostatic pressure (HHP) on the kinetics of thermal inactivation of xanthine oxidase (XOx) from bovine milk was studied. Inactivation of XOx followed pseudo-first-order kinetics at 0.1-300MPa and 55.0-70.0 degrees C. High pressure up to at least 300MPa stabilized XOx at all the studied temperatures. The highest stabilization effect of HHP on XOx was at 200-300MPa at 55.0 and 58.6 degrees C, and at 250-300MPa at 62.3-70.0 degrees C. The stability of XOx increased 9.5 times at 300MPa and 70.0 degrees C compared to atmospheric pressure at the same temperature. The activation energy of inactivation of XOx decreased with pressure and was 1.9 times less at 300MPa (97.0+/-8.2kJmol-1) than at 0.1MPa (181.7+/-12.1kJmol-1). High pressure decreased the dependence of the rate constant of inactivation to temperature effects compared to atmospheric pressure. The stabilizing effect of HHP on XOx was highest at 70.0 degrees C where the activation volume of inactivation of XOx was 28.9+/-2.9cm3mol-1. A second approach to try to increase XOx stability involved hydrophobic modification using aniline or benzoate. However, the thermal stability of XOx remained unaffected after 8-14 modifications of carboxyl side groups per XOx monomer with aniline, or 12-17 modifications of amino side groups per XOx monomer with benzoate. PMID- 28554382 TI - A novel alpha-galactosidase from Fusarium oxysporum and its application in determining the structure of the gum arabic side chain. AB - We previously reported that Fusarium oxysporum 12S produces two bifunctional proteins, FoAP1 and FoAP2, with alpha-d-galactopyranosidase (GPase) and beta-l arabinopyranosidase (APase) activities. The aim of this paper was to purify a third GPase, FoGP1, from culture supernatant of F. oxysporum 12S, to characterize it, and to determine its mode of action towards gum arabic. A cDNA encoding FoGP1 was cloned and the protein was overexpressed in Escherichia coli. Module sequence analysis revealed the presence of a GH27 domain in FoGP1. The recombinant enzyme (rFoGP1) showed a GPase/APase activity ratio of 330, which was quite different from that of FoAP1 (1.7) and FoAP2 (0.2). Among the natural substrates tested, rFoGP1 showed the highest activity towards gum arabic. In contrast to other well characterized GPases, rFoGP1 released a small amount of galactose from alpha galactosyl oligosaccharides such as raffinose and exhibited no activity toward galactomannans, which are highly substituted with alpha-galactosyl side chains. This indicated that FoGP1 is an unusual type of GPase. rFoGP1 released 30% of the total galactose from gum arabic, suggesting the existence of a large number of alpha-galactosyl residues at the non-reducing ends of gum arabic side chains. Together, rFoGP1 and alpha-l-arabinofuranosidase released four times more arabinose than alpha-l-arabinofuranosidase acting alone. This suggested that a large number of alpha-l-arabinofuranosyl residues is capped by alpha-galactosyl residues. 1H NMR experiments revealed that rFoGP1 hydrolyzed the alpha-1,3 galactosidic linkage within the side chain structure of [alpha-d-Galp-(1->3) alpha-l-Araf-(1->] in gum arabic. In conclusion, rFoGP1 is highly active toward alpha-1,3-galactosyl linkages but negligibly or not active toward alpha-1,6 galactosyl linkages. The novel FoGP1 might be used to modify the physical properties of gum arabic, which is an industrially important polysaccharide used as an emulsion stabilizer and coating agent. PMID- 28554383 TI - High-level expression of a bacterial laccase, CueO from Escherichia coli K12 in Pichia pastoris GS115 and its application on the decolorization of synthetic dyes. AB - Laccases are oxidoreductase catalyze the oxidation of a wide range of substrates with oxygen as the electron acceptor. This report was aimed to the high-level expression of a laccase, CueO from Escherichia coli K12 in Pichia pastoris GS115 and its application on decolorization of synthetic dyes. The yacK gene coding CueO was cloned into an expression vector of Pichia pastoris, pHBM905BDM and expressed in a secretory form with Pichia pastoris GS115 as the host. The yield of the recombinant protein was 556mg/L with high-density fermentation and the enzyme activity was about 41,000U/L. The recombinant laccase was purified and characterized. Its optimum pH and temperature was 3.0 and 55 degrees C with 2, 2' azino-bis-(3-ethylbenzothazoline-6-sulfonic acid) (ABTS) as the substrate, respectively. This recombinant protein was thermostable and its half life at 70 degrees C was about 60min. In the presence of natural redox mediator acetosyringone, the purified recombinant laccase decolorized 98.1% and 98.5% of Congo red, malachite green, respectively. It also decolorized 90.03% of Remazol brilliant blue R without this mediator. In addition, this enzyme was applied on the decolorization of wastewater from a textile printing factory and showed an obvious bleaching effect. PMID- 28554384 TI - Synthesis of fibrous and non-fibrous mesoporous silica magnetic yolk-shell microspheres as recyclable supports for immobilization of Candida rugosa lipase. AB - The mesoporous yolk-shell nanoparticles (MYSNs), with a movable Fe3O4 core inside the hollow capsules, with two different morphologies (1) Fe3O4@SiO2@hollow@fibrous SiO2 (Yolk Shell-1) (2) Fe3O4@SiO2@hollow@mesoporousSiO2 (Yolk Shell-2) were fabricated as carriers for Candida rugosa lipase (CRL) immobilization, through a template-assistant selectively etching method. Firstly the hydrophilic Fe3O4 nanoparticles were synthesized according to the solvothermal method. Then, SiO2 shell was coated on the Fe3O4 nanoparticle surface by a sol-gel reaction. Subsequently, the resorcinol farmaldehyde (RF) shell was covered on the surface of as-prepared Fe3O4@SiO2 composites and sandwiched Fe3O4@SiO2@RF composites were formed, which were finally provided with mesoporous fibrous (KCC) in the Yolk Shell-1 and mesoporous Silica in the Yolk Shell-2(Non fibrous). After selectively etching CTAB and the middle RF layer, the two kinds of yolk/shells composites were obtained. By utilization of their large and open mesopores (20-50nm) with good surface area (457.78-625.54m2/g,) CRL was immobilized after amino functionalization using glutaraldehyde as a linker. The ICRL on Y.S-1, Y.S-2 showed good loading (797-501mg/g) and enzyme activity of (1503-837U/g) respectively. Thermal stability, resistance to pH, recycling and storage capacity were improved as compare to free lipase. PMID- 28554385 TI - Co-overexpression of Mgat1 and Mgat4 in CHO cells for production of highly sialylated albumin-erythropoietin. AB - Terminal sialic acids on N-glycan of recombinant human erythropoietin are very important for in vivo half-life, as this glycoprotein has three N-glycosylation sites. N-acetylglucosaminyltransferases I, II, IV, and V (i.e. Mgat1, Mgat2, Mgat4, and Mgat5) catalyze the formation of a glycan antennary structure. These enzymes display different reaction kinetics for a common substrate and generally show low expression in Chinese hamster ovary (CHO) cells. Therefore, genetic control of Mgat expression is an effective method to increase sialic acid contents by enhancing glycan antennarity. To produce highly sialylated albumin erythropoietin (Alb-EPO), we co-overexpressed the Mgat1 and Mgat4 genes in CHO cells and determined the optimal ratio of Mgat1:Mgat4 gene expression. All transfected cell lines showed increased gene expression of Mgat4, including Mgat1 overexpressing cell line. Sialic acid content of Alb-EPO was highest in co transfected cells with excess Mgat4 gene, and these cells showed a higher tri- and tetra-antennary structure than control cells. Based on these results, we suggest that co-transfection of the Mgat1 and Mgat4 genes at a ratio of 2:8 is optimal for extension of antennary structures. Also, regulation of Mgat gene expression in the glycan biosynthesis pathway can be a novel approach to increase the terminal sialic acids of N-glycans. PMID- 28554387 TI - [Editors' corner: Anales de Pediatria annual report]. PMID- 28554388 TI - Erratum to: "Ventral and Dorsal Striatum Networks in Obesity: Link to Food Craving and Weight Gain" by Contreras-Rodriguez et al. (Biol Psychiatry 2017; 81:789-796). PMID- 28554386 TI - Synthesis and characterization of novel astragalin galactosides using beta galactosidase from Bacillus circulans. AB - Astragalin (kaempferol-3-O-beta-d-glucopyranoside, Ast) is a kind of flavonoid known to have anti-oxidant, anti-HIV, anti-allergic, and anti-inflammatory effects. It has low solubility in water. In this study, novel astragalin galactosides (Ast-Gals) were synthesized using beta-galactosidase from Bacillus circulans and reaction conditions were optimized to increase the conversion yield of astragallin. Purified Ast-Gal1 (11.6% of Ast used, w/w) and Ast-Gal2 (6.7% of Ast used, w/w) were obtained by medium pressure chromatography (MPLC) with silica C18 column and open column packed with Sephadex LH-20. The structures of Ast-Gal1 and Ast-Gal2 were identified by nuclear magnetic resonance (NMR) to be kaempferol 3-O-beta-d-glucopyranosyl-(1->6)-beta-d-galactopyranoside and kaempferol-3-O-beta d-glucopyranosyl-(1->6)-beta-d-galactopyranosyl-(1->4)-beta-d-galactopyranoside, respectively. The water solubility of Ast, Ast-Gal1, and Ast-Gal2 were 28.2+/ 1.2mg/L, 38,300+/-3.5mg/L, and 38,800+/-2.8mg/L, respectively. The SC50 value (the concentration required to scavenge 50% of the ABTS+) of Ast, Ast-Gal1, and Ast-Gal2 were 5.1+/-1.6MUM, 6.5+/-0.4MUM, and 4.9+/-1.1MUM, respectively. The IC50 values (the half maximal inhibitory concentration) of Ast, Ast-Gal1, and Ast Gal2 against angiotensin converting enzyme (ACE) were 171.0+/-1.2MUM, 186.0MUM, and 139.0+/-0.2MUM, respectively. PMID- 28554389 TI - The Behavioral Economics of Anxiety. PMID- 28554390 TI - Oxytocin and Other Pharmacologic Preventive Interventions for Posttraumatic Stress Disorder: Not a One-Size-Fits-All Approach. PMID- 28554391 TI - Predicting Posttraumatic Stress Disorder: From Circuits to Communities. PMID- 28554392 TI - Toward Micro-Switching Exposure Therapy: Potential Relevance for Posttraumatic Stress Disorder. PMID- 28554393 TI - Stem cell transplantation for spinal cord injury repair. AB - Stem cells, especially neural stem cells (NSCs), are a very attractive cell source for potential reconstruction of injured spinal cord though either neuroprotection, neural regeneration, remyelination, replacement of lost neural cells, or reconnection of disrupted axons. The later have great potential since recent studies demonstrate long-distance growth and connectivity of axons derived from transplanted NSCs after spinal cord injury (SCI). In addition, transplanted NSCs constitute a permissive environment for host axonal regeneration and serve as new targets for host axonal connection. This reciprocal connection between grafted neurons and host neurons constitutes a neuronal relay formation that could restore functional connectivity after SCI. PMID- 28554394 TI - From transplanting Schwann cells in experimental rat spinal cord injury to their transplantation into human injured spinal cord in clinical trials. AB - Among the potential therapies designed to repair the injured spinal cord is cell transplantation, notably the use of autologous adult human Schwann cells (SCs). Here, we detail some of the critical research accomplished over the last four decades to establish a foundation that enables these cells to be tested in clinical trials. New culture systems allowed novel information to be gained about SCs, including discovering ways to stimulate their proliferation to acquire adequately large numbers for transplantation into the injured human spinal cord. Transplantation of rat SCs into rat models of spinal cord injury has demonstrated that SCs promote repair of injured spinal cord. Additional work required to gain approval from the Food and Drug Administration for the first SC trial in the Miami Project is disclosed. This trial and a second one now underway are described. PMID- 28554395 TI - Recruitment of endogenous CNS stem cells for regeneration in demyelinating disease. AB - Demyelinating diseases, such as multiple sclerosis (MS), are responsible for a significant portion of the neurological disability burden worldwide, especially in young adults. Demyelination can be followed by a spontaneous regenerative process called remyelination, in which new myelin sheaths are restored to denuded axons. However, in chronic demyelinating disease such as MS, this process becomes progressively less efficient. This chapter reviews the biology of remyelination and the rationale and strategies by which it can be enhanced therapeutically in acquired demyelinating disease. PMID- 28554397 TI - Pluripotent stem cells and their utility in treating photoreceptor degenerations. AB - Age-related macular degeneration and inherited retinal degenerations represent the leading causes of blindness in industrialized countries. Despite different initiating causes, they share a common final pathophysiology, the loss of the light sensitive photoreceptors. Replacement by transplantation may offer a potential treatment strategy for both patient populations. The last decade has seen remarkable progress in our ability to generate retinal cell types, including photoreceptors, from a variety of murine and human pluripotent stem cell sources. Driven in large part by the requirement for renewable cell sources, stem cells have emerged not only as a promising source of replacement photoreceptors but also to provide in vitro systems with which to study retinal development and disease processes and to test therapeutic agents. PMID- 28554398 TI - Stem cell-derived retinal pigment epithelium transplantation for treatment of retinal disease. AB - Age-related macular degeneration remains the most common cause of blindness in the western world, severely comprising patients' and carers' quality of life and presenting a great cost to the healthcare system. As the disease progresses, the retinal pigmented epithelium (RPE) layer at the back of the eye degenerates, contributing to a series of events resulting in visual impairment. The easy accessibility of the eye has allowed for in-depth study of disease progression in patients, while in vivo studies have facilitated investigations into healthy and diseased RPE. Consequently, a number of research groups are examining different approaches for the replacement of RPE cells in age-related macular degeneration (AMD) patients. This chapter examines some of these initial proof-of-principle studies and goes on to review the use of pluripotent stem cells as a source for RPE replacement in a number of current AMD clinical trials. Finally, we consider just some of the regulatory and manufacturing challenges presented in taking a promising AMD treatment from the research bench into clinical trials in patients, and how to mitigate potential risks early in process development. PMID- 28554396 TI - Progenitor cell-based treatment of glial disease. AB - Diseases of glia, including astrocytes and oligodendrocytes, are among the most prevalent and disabling, yet least appreciated, conditions in neurology. In recent years, it has become clear that besides the overtly glial disorders of oligodendrocyte loss and myelin failure, such as the leukodystrophies and inflammatory demyelinations, a number of neurodegenerative and psychiatric disorders may also be causally linked to glial dysfunction and derive from astrocytic as well as oligodendrocytic pathology. The relative contribution of glial dysfunction to many of these disorders may be so great as to allow their treatment by the delivery of allogeneic glial progenitor cells, the precursors to both astroglia and myelin-producing oligodendrocytes. Given the development of new methods for producing and isolating these cells from pluripotent stem cells, both the myelin disorders and appropriate glial-based neurodegenerative conditions may now be compelling targets for cell-based therapy. As such, glial cell-based therapies may offer potential benefit to a broader range of diseases than ever before contemplated, including disorders such as Huntington's disease and the motor neuron degeneration of amyotrophic lateral sclerosis, which have traditionally been considered neuronal in nature. PMID- 28554399 TI - Transplantation of reprogrammed neurons for improved recovery after stroke. AB - Somatic cells such as fibroblasts, reprogrammed to induced pluripotent stem cells, can be used to generate neural stem/progenitor cells or neuroblasts for transplantation. In this review, we summarize recent studies demonstrating that when grafted intracerebrally in animal models of stroke, reprogrammed neurons improve function, probably by several different mechanisms, e.g., trophic actions, modulation of inflammation, promotion of angiogenesis, cellular and synaptic plasticity, and neuroprotection. In our own work, we have shown that human skin-derived reprogrammed neurons, fated to cortical progeny, integrate in stroke-injured neuronal network and form functional afferent synapses with host neurons, responding to peripheral sensory stimulation. However, whether neuronal replacement plays a role for the improvement of sensory, motor, and cognitive deficits after transplantation of reprogrammed neurons is still unclear. We conclude that further preclinical studies are needed to understand the therapeutic potential of grafted reprogrammed neurons and to define a road map for their clinical translation in stroke. PMID- 28554400 TI - Plasticity and regeneration in the injured spinal cord after cell transplantation therapy. AB - Spinal cord injury (SCI) typically damages the long axonal tracts of the spinal cord which results in permanent disability. However, regeneration of the injured spinal cord is approaching reality according to the advances in stem cell biology. Cell transplantation therapy holds potential to lead to recovery following SCI through some positive mechanisms. Grafted cells induce plasticity and regeneration in the injured spinal cord by promoting remyelination of damaged axons, reconstruction of neural circuits by synapse formation between host neurons and graft-derived neurons, and secreting neurotrophic factors to promote axonal elongation as well as reduce retrograde axonal degeneration. In this review, we will delineate (1) the microenvironment of the injured spinal cord that influence the plasticity and regeneration capacity after SCI, (2) a number of different kinds of cell transplantation therapies for SCI that has been extensively studied by researchers, and (3) potential mechanisms of grafted cell induced regeneration and plasticity in the injured spinal cord. PMID- 28554402 TI - Rebuilding CNS inhibitory circuits to control chronic neuropathic pain and itch. AB - Cell transplantation offers an attractive alternative to pharmacotherapy for the management of a host of clinical conditions. Most importantly, the transplanted cells provide a continuous, local delivery of therapeutic compounds, which avoids many of the adverse side effects associated with systemically administered drugs. Here, we describe the broad therapeutic utility of transplanting precursors of cortical inhibitory interneurons derived from the embryonic medial ganglionic eminence (MGE), in a variety of chronic pain and itch models in the mouse. Despite the cortical environment in which the MGE cells normally develop, these cells survive transplantation and will even integrate into the circuitry of an adult host spinal cord. When transplanted into the spinal cord, the cells significantly reduce the hyperexcitability that characterizes both chronic neuropathic pain and itch conditions. This MGE cell-based strategy differs considerably from traditional pharmacological treatments as the approach is potentially disease modifying (i.e., the therapy targets the underlying etiology of the pain and itch pathophysiology). PMID- 28554403 TI - Preface. PMID- 28554404 TI - Original descriptions of the relationship between epididymal function and sperm morphology. AB - Roussel JD, Stallcup OT, Austin CR. Selective phagocytosis of spermatozoa in the epididymis of bulls, rabits, and monkeys. Fertil Steril 1967;18(4):509-16. "Examination of histologic sections of epididymes revealed the presence of many macrophages in the lumen of all regions, and it was often possible to discern parts of engulfed spermatozoa within the macrophages." PMID- 28554405 TI - Hallmarks of Clinical Aspects of Parkinson's Disease Through Centuries. AB - James Parkinson published a treatise "An Essay on The Shaking Palsy" in 1817. However, there is historical evidence that there were rudimentary descriptions of the disease long before Parkinson brought it to light. Later day physicians have added to the spectrum of the motor aspects of the disease over the last 200 years and the gamut of its clinical presentation is now known to be more ubiquitous than what was supposed earlier. In the 1960s, atypical Parkinsonism is identified as a distinct and separate entity, and after the introduction of levodopa in clinical practice, a variety of late motor complications have been described. Various stages of disability and motor scales have been devised which have helped in identifying and classifying the degree of severity of the disease. However, such impeccable was the original description that virtually little could be modified and later works have only added to the original text. PMID- 28554401 TI - Transplantation of GABAergic interneurons for cell-based therapy. AB - Many neurological disorders stem from defects in or the loss of specific neurons. Neuron transplantation has tremendous clinical potential for central nervous system therapy as it may allow for the targeted replacement of those cells that are lost in diseases. Normally, most neurons are added during restricted periods of embryonic and fetal development. The permissive milieu of the developing brain promotes neuronal migration, neuronal differentiation, and synaptogenesis. Once this active period of neurogenesis ends, the chemical and physical environment of the brain changes dramatically. The brain parenchyma becomes highly packed with neuronal and glial processes, extracellular matrix, myelin, and synapses. The migration of grafted cells to allow them to home into target regions and become functionally integrated is a key challenge to neuronal transplantation. Interestingly, transplanted young telencephalic inhibitory interneurons are able to migrate, differentiate, and integrate widely throughout the postnatal brain. These grafted interneurons can also functionally modify local circuit activity. These features have facilitated the use of interneuron transplantation to study fundamental neurodevelopmental processes including cell migration, cell specification, and programmed neuronal cell death. Additionally, these cells provide a unique opportunity to develop interneuron-based strategies for the treatment of diseases linked to interneuron dysfunction and neurological disorders associated to circuit hyperexcitability. PMID- 28554406 TI - Clinical Assessments in Parkinson's Disease: Scales and Monitoring. AB - Measurement of disease state is essential in both clinical practice and research in order to assess the severity and progression of a patient's disease status, effect of treatment, and alterations in other relevant factors. Parkinson's disease (PD) is a complex disorder expressed through many motor and nonmotor manifestations, which cause disabilities that can vary both gradually over time or come on suddenly. In addition, there is a wide interpatient variability making the appraisal of the many facets of this disease difficult. Two kinds of measure are used for the evaluation of PD. The first is subjective, inferential, based on rater-based interview and examination or patient self-assessment, and consist of rating scales and questionnaires. These evaluations provide estimations of conceptual, nonobservable factors (e.g., symptoms), usually scored on an ordinal scale. The second type of measure is objective, factual, based on technology based devices capturing physical characteristics of the pathological phenomena (e.g., sensors to measure the frequency and amplitude of tremor). These instrumental evaluations furnish appraisals with real numbers on an interval scale for which a unit exists. In both categories of measures, a broad variety of tools exist. This chapter aims to present an up-to-date summary of the most relevant characteristics of the most widely used scales, questionnaires, and technological resources currently applied to the assessment of PD. The review concludes that, in our opinion: (1) no assessment methods can substitute the clinical judgment and (2) subjective and objective measures in PD complement each other, each method having strengths and weaknesses. PMID- 28554407 TI - Biomarkers of Parkinson's Disease: An Introduction. AB - The development of biomarkers is of great importance in Parkinson's disease (PD) as it may contribute to confirmation and support of the diagnosis, tracking of progression, and prediction of the natural history of PD. Biomarkers also help in the identification of targets for treatment and measuring the efficacy of interventions. Biomarkers are, therefore, crucial to understanding the pathophysiology of PD, the second commonest neurodegenerative disorder in the world. Modern understanding of PD suggests that it is a multipeptide, multiorgan disorder presenting with a heterogeneous clinical condition, both motor and nonmotor. Biomarkers need to reflect this neuropathological and clinical heterogeneity of PD. In this review, we outline some key advances in the field of clinical, genetic, neuroimaging, and tissue-based biomarkers proposed or used for PD. The individual sections will be covered in relevant chapters and our review is largely a primer aimed to alert readers to the current state of the various biomarkers proposed for PD. In doing so, we have also underlined the important role multimodal rather than single biomarkers could play in our future understanding of PD. PMID- 28554409 TI - Imaging in Parkinson's Disease. AB - Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by the loss of nigrostriatal dopaminergic neurons and aggregation of misfolded alpha synuclein in Lewy bodies. The underlying mechanisms of neurodegeneration in PD are still unknown, and there are no disease-modifying treatments to slow the neurodegenerative processes. There is an urgent need to identify biomarkers that are able to monitor disease progression and assess the development and efficacy of novel disease-modifying drugs. Over the past years, neuroimaging techniques such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET) have provided important advances in our understanding of PD. MRI provides information about structural and functional organization of the brain, while SPECT and PET can detect molecular changes in the brain. Here, we review the current neuroimaging literature in sporadic and genetic PD, which have contributed to our understanding of the physiopathological mechanisms of the disease. PMID- 28554408 TI - Genetics of Parkinson's Disease: Genotype-Phenotype Correlations. AB - Since the first discovery of a specific genetic defect in the SNCA gene, encoding for alpha-synuclein, as a causative factor for Parkinson's disease 20 years ago, a multitude of other genes have been linked to this disease in rare cases with Mendelian inheritance. Furthermore, the genetic contribution to the much more common sporadic disease has been demonstrated through case control association studies and, more recently, genome-wide association studies. Interestingly, some of the genes with Mendelian inheritance, such as SNCA, are also relevant to the sporadic disease, suggesting common pathogenetic mechanisms. In this review, we place an emphasis on Mendelian forms, and in particular genetic defects which present predominantly with Parkinsonism. We provide details into the particular phenotypes associated with each genetic defect, with a particular emphasis on nonmotor symptoms. For genetic defects for whom a sufficient number of patients has been assessed, there are evident genotype-phenotype correlations. However, it should be noted that patients with the same causative mutation may present with distinctly divergent phenotypes. This phenotypic variability may be due to genetic, epigenetic or environmental factors. From a clinical and genetic point of view, it will be especially interesting in the future to identify genetic factors that modify disease penetrance, the age of onset or other specific phenotypic features. PMID- 28554410 TI - The Motor Syndrome of Parkinson's Disease. AB - The clinical diagnosis of Parkinson's disease (PD) is centered on a specific motor syndrome that is characterized by the presence of bradykinesia, plus rest tremor, muscle rigidity, or both. Recently, novel criteria for diagnosing PD have been released that rehearse the motor syndrome as the core feature of PD. Beyond these three main symptoms, other motor features might be present in PD including gait difficulties and postural instability. Moreover, patients with PD usually develop motor complications 5-10 years into their disease. These motor complications are the strongest predictor of PD pathology and are in fact used clinically to support the diagnosis. Ancillary investigations are usually of little utility and to perform only in selected cases, which remarks the importance of the clinical examination for making the diagnosis of PD or suspect other condition that can be masquerading it. PMID- 28554411 TI - Cerebrospinal Fluid Biomarkers of Cognitive Decline in Parkinson's Disease. AB - Among the nonmotor symptoms in Parkinson's disease (PD), cognitive impairment is one of the most common and devastating. Over recent years, mild cognitive impairment (MCI) has become a recognized feature of PD (PD-MCI). The underlying mechanisms which influence onset, rate of decline, and conversion to dementia (PDD) are largely unknown. Adding to this uncertainty is the heterogeneity of cognitive domains affected. Currently there are no disease-modifying treatments that can slow or reverse this process. Identification of biomarkers that can predict rate and risk of cognitive decline is therefore an unmet need. Cerebrospinal fluid (CSF) is an ideal biomarker candidate as its constituents reflect the metabolic processes underlying the functioning of brain parenchyma. The pathological hallmark of PD is the presence of aggregated alpha-synuclein (alpha-Syn) in intracellular Lewy inclusions. In addition, there is concomitant Alzheimer's disease (AD) pathology. In AD, decreased CSF beta-amyloid 1-42 (Abeta42) and increased CSF tau levels are predictive of future cognitive decline, setting a precedent for such studies to be carried out in PD. CSF studies in PD have focused on the classical AD biomarkers and alpha-Syn. Longitudinal studies indicate that low levels of CSF Abeta42 are predictive of cognitive decline; however, results for tau and alpha-Syn were not consistent. This chapter summarizes recent findings of CSF biomarker studies and cognitive dysfunction in PD. PMID- 28554412 TI - Hallmarks of Treatment Aspects: Parkinson's Disease Throughout Centuries Including l-Dopa. AB - Deficit of striatal dopamine was first discovered in postmortem brain of patients with Parkinson's disease in 1960. This observation was the starting point for dopamine replacement therapy, and successful introduction of high dose l-dopa therapy in the 1969 revolutionized the treatment of Parkinson's disease. Since then, constant attempts have been made to enhance the efficacy of l-dopa and reduce motor complications by providing more continuous dopamine stimulation. This chapter traces the hallmarks of medical treatments for Parkinson's disease throughout centuries including the first description of antiparkinsonian effects of anticholinergics, the birth of apomorphine in the 1900s, then discovery of l dopa in the 1960s, and development of dopamine agonists since the 1970s. PMID- 28554413 TI - The Nonmotor Features of Parkinson's Disease. AB - Nonmotor symptoms (NMS) of Parkinson's disease (PD) were recognized by the great James Parkinson himself who mentioned symptoms such as sleep dysfunction, delirium, dementia, and dysautonomia, in his seminal 1817 essay, "An Essay on the Shaking Palsy" (Parkinson, 1817). In spite of the key impact of PD NMS on quality of life, there was little holistic research and awareness till the validation and use of comprehensive tools such as the NMS questionnaire, scale, and the revised version of the unified PD rating scale. Research studies using these tools highlighted the key impact of the burden of NMS on quality of life of PD patients and the need for NMS to be routinely assessed in clinic. We now define PD as a motor and nonmotor disorder, and the natural history includes a long prodromal phase of PD dominated by a range of NMS. The prodromal phase is the subject of much research particularly in relation to neuroprotection and identifying subjects at risk. Use of NMS tools has also validated burden grading of NMS with cutoff values, which can be used as outcome measure in clinical trials. Finally, the complex multineurotransmitter dysfunction that is seen in PD has been shown to manifest clinically as nonmotor subtypes. Recognition of such subtypes is likely to lead to the emergence of personalized and precision medicine in PD. PMID- 28554414 TI - Treatment Strategies in Early Parkinson's Disease. AB - The clinicians' approach to the treatment of early Parkinson's disease (PD) should take into account numerous aspects, including how to inform a patient upon diagnosis and the critical decision of what therapy to adopt and when to start it. The treatment of the motor disorder associated with early PD needs to consider several crucial factors, such as age at onset, comorbidities, and the patient's functional requirements, and cannot be summarized in a simple formula. In younger patients (i.e., before the age of 70) and in those without high functional requirements, treatment is usually initiated with dopamine agonists and/or monoamine oxidase-B enzyme inhibitors (MAO-B I). By contrast, in older patients, or in those with high functional requirements, low doses of levodopa are generally used when treatment is started. In younger patients, levodopa should be added to dopamine agonists and/or MAO-B I, as required by disease progression, whereas in older patients, when response to levodopa alone is not satisfactory, dopamine agonists or catechol-O-methyltransferase inhibitors may subsequently be added. PMID- 28554415 TI - Treatment of Nonmotor Symptoms in Parkinson's Disease. AB - Nonmotor symptoms (NMS) are integral to Parkinson's disease (PD) and the management can often be challenging. In spite of the growing evidence that NMS have a key impact on the quality of life of patients and caregivers, most clinical trials still focus on motor symptoms as primary outcomes. As a consequence strong evidence-based treatment recommendations for NMS occurring in PD are spare. In this chapter, the current data addressing the treatment of major NMS such as sleep, cognitive and autonomic dysfunction, and depression and anxiety are described. PMID- 28554416 TI - Treatment of Older Parkinson's Disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. The prevalence of PD increases with age. The spectrum of clinical features, the rate of progression of the disease, the burden of nonmotor symptoms, and the response to medications are different in older patients with PD from the relatively younger patients. Management of symptoms of PD in older patients is challenging because of possible existence of several age related systemic illness. While dealing with older patients, it is crucial not to attribute all the physical symptoms to PD. Thorough evaluation for existence of diseases such as normal pressure hydrocephalus and vascular parkinsonism which partially mimic the symptoms of PD carries immense importance. Medical management of parkinsonian symptoms should be preferred with levodopa monotherapy. However, in patients with significant motor fluctuations, dopaminergic agents may be added with caution, as they are notorious for several adverse reactions. Nonmotor symptoms must be provided high importance as they substantially worsen the quality of life. In addition to parkinsonian symptoms, older patients with PD may need to undergo surgery for several conditions. Meticulous perioperative management is crucial as older patients with PD may face several surgery-related complications compared to the younger patients. Compliance to treatment is an important issue in old age. Hence multidisciplinary approach to management of PD in older patients should be emphasized. PMID- 28554417 TI - New Symptomatic Treatments for the Management of Motor and Nonmotor Symptoms of Parkinson's Disease. AB - Motor symptoms are core features of Parkinson's disease, while nonmotor symptoms are present from the prodromal stage. Management strategies for the motor symptoms of Parkinson's disease have been widely researched and there have been many advances. Therapy has evolved from oral therapy to once a day to nonoral strategies, both for rescue and for infusion therapy. Treatment for nonmotor symptoms, however, has remained a key unmet need, although of late evidence base for management of some nonmotor symptoms such as pain, dementia, aspects of sleep dysfunction, and constipation has emerged. However, management of many nonmotor symptoms such as anxiety, apathy, fatigue, and insomnia remains uncharted. In this review, we address these management strategies and discuss the evidence base of available therapies. PMID- 28554418 TI - Device-Aided Treatment Strategies in Advanced Parkinson's Disease. AB - With peroral levodopa treatment, a majority of patients develop motor fluctuations and dyskinesia already within a few years of therapy. Device-aided Parkinson (PD) therapies refer to deep brain stimulation (DBS), levodopa carbidopa intestinal gel infusion (LCIG), and subcutaneous infusion of the dopamine agonist apomorphine and represent effective strategies counteracting motor fluctuations and dyskinesia. These three therapy options seem to be similarly effective in reducing "time with PD symptoms (off time)" by at least 60%-65%. The use of advanced therapy also leads to a significant reduction of dyskinesia. Recent studies also indicate that these therapies can improve a number of nonmotor symptoms in advanced PD. Altogether this results in an improved health-related quality of life in most treated patients. The side effects and complications are quite different between the three; for DBS, serious adverse events include intracranial bleeding and infection, LCIG complications relate to the infusion equipment and the establishment of the percutaneous endoscopic gastrostomy, while for apomorphine infusion the most common side effect is a formation of noduli (local inflammation) at the point of infusion. The device-aided therapies are all indicated for the treatment of motor fluctuations and/or dyskinesia when peroral/transdermal PD medications cannot be further optimized. However, the choice of device-aided therapy is made on basis of indications/contraindications, but also the patients' symptom profile and his/her personal preferences. Therefore, it is important these treatments are discussed early, well before motor and nonmotor symptoms have deteriorated excessively. PMID- 28554419 TI - Palliative Care for Patients and Families With Parkinson's Disease. AB - Parkinson's disease is the second most common neurodegenerative disease worldwide. There is widespread consensus that Parkinson patients, their carers, and clinicians involved in their care would benefit from a fully integrated, need based provision of palliative care. However, the concept of palliative care in Parkinson's disease is still poorly defined and, consequently, poorly implemented into daily clinical practice. A particular challenge is the gradually progressive nature of Parkinson's disease-with insidiously increasing disability-making it challenging to clearly define the onset of palliative care needs for Parkinson patients. As people with Parkinson's disease are now living longer than in the past, future research needs to develop a more robust evidence-based approach to clarify the disease events associated with increased palliative care needs, and to examine these, prospectively, in an integrated palliative care service. The modern palliative care outlook, termed "simultaneous care,",is no longer restricted to the final stage of disease. It involves incorporating a continuity of care, effective management of the chronic-palliative interface, and a multidisciplinary network of professionals working both in the community and in specialized clinics, with active involvement of caregivers. Although promising, there is still a need to demonstrate the effectiveness of palliative care for patients with Parkinson's disease. PMID- 28554420 TI - Multidisciplinary Care in Parkinson's Disease. AB - Parkinson's disease (PD) is now known to be a multisystemic and multipeptide neurodegenerative disorder, whereby patients have an array of symptoms both motor and nonmotor. Nonmotor features of PD have been shown to arise almost 15-20 years prior to motor symptoms and, as such, are also a key determinant to the quality of life of a patient. Therefore, there is increasing evidence that a PD patient's management must encompass a multidisciplinary approach to effectively manage and treat the patient's PD and also their individual symptoms. Therefore, the notion that a PD nurse specialist and a neurologist are the only key players, is no longer the case. Rather, the involvement of speech and language therapist, physiotherapists, palliative care, and others is vital for a patient's recovery and their effective management. Here we discuss a few professions who should ideally be present for each PD patient. PMID- 28554421 TI - The New Diagnostic Criteria for Parkinson's Disease. AB - This chapter summarizes the advances in diagnosis of Parkinson's disease (PD) that were encapsulated in new International Parkinson Disease and Movement Disorders Society diagnostic criteria for PD. Numerous changes in our understanding of PD have occurred, including our understanding of the nonmotor profile of disease, the recognition of PD as a synucleinopathy, identification of genetic causes, novel hypotheses about spread of disease, etc. These have been reflected in a new definition of PD, which includes a clinicogenetic subtype of PD, removes dementia with Lewy Bodies as an exclusion criterion against PD, and recognizes multiple stages of early disease. The Clinical Diagnostic Criteria for PD reflect these changes and offer a new standardized diagnostic method for use in clinical research and even clinical practice. The criteria for prodromal PD use a method not seen in previous diagnostic criteria; they rely upon published studies of PD predictors to calculate the probability that any individual will develop PD. The field of PD is constantly advancing, and our methods of diagnosis need to advance with it; one hopes for a future filled with constant revisions and updates in our diagnostic methodology. PMID- 28554422 TI - Advances in the Clinical Differential Diagnosis of Parkinson's Disease. AB - The differential diagnosis of Parkinson's disease has widened considerably in recent years. This chapter aims to summarize the current knowledge on the clinical differential diagnoses of sporadic Parkinson's disease. As the number of monogenic familial Parkinson's disease variants and risk factors is growing, so is the number of appreciated etiologies of atypical parkinsonian and other pallidopyramidal syndromes. This work aims at summarizing the current knowledge on both motor and nonmotor neurological signs and symptoms that aid the clinical diagnosis of Parkinson's disease and its differential diagnoses. PMID- 28554423 TI - Preface. PMID- 28554424 TI - Suicide prevention: large scale and small details. PMID- 28554425 TI - Excessive gambling and gaming: addictive disorders? PMID- 28554426 TI - Alcohol misuse and self-harm: an opportunity for early intervention in the emergency department. PMID- 28554427 TI - Ethical surgical placebo-controlled trials of deep brain stimulation for treatment-resistant anorexia nervosa. PMID- 28554428 TI - Ethical surgical placebo-controlled trials of deep brain stimulation for treatment-resistant anorexia nervosa - Authors' reply. PMID- 28554430 TI - Michelle Riba-helping emotional issues in chronic diseases. PMID- 28554431 TI - The merciless mirror: Sylvia Plath's art, suicide, and influence. PMID- 28554432 TI - Correlation of Body Composition and Low Back Pain Severity in a Cross-Section of US Veterans. AB - OBJECTIVE: Back pain is more prevalent in the obese, but whether back pain severity is directly correlated to obesity in veterans is unknown. We sought to determine if there was a correlation between body composition and low back pain severity in a sample of veterans. The hypothesis was that veterans with higher body mass index values would report higher low back pain severity scores. METHODS: This study was a retrospective chart review of 1768 veterans presenting to a Veterans Affairs chiropractic clinic with a chief complaint of low back pain between January 1, 2009 and December 31, 2014. Spearman's rho was used to test for correlation between body composition as measured by body mass index and low back pain severity as measured by the Back Bournemouth Questionnaire. RESULTS: On average, the sample was predominantly male (91%), older than 50, and overweight (36.5%) or obese (48.9%). There was no correlation between body mass index and Back Bournemouth Questionnaire scores, r = .088, p < .001. CONCLUSIONS: The majority of veterans with low back pain in this sample were either overweight or obese. There was no correlation between body composition and low back pain severity in this sample of veterans. PMID- 28554433 TI - Systematic Review of Nondrug, Nonsurgical Treatment of Shoulder Conditions. AB - OBJECTIVE: The purpose of this review was to evaluate the effectiveness of conservative nondrug, nonsurgical interventions, either alone or in combination, for conditions of the shoulder. METHODS: The review was conducted from March 2016 to November 2016 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and was registered with PROSPERO. Eligibility criteria included randomized controlled trials (RCTs), systematic reviews, or meta-analyses studying adult patients with a shoulder diagnosis. Interventions qualified if they did not involve prescription medication or surgical procedures, although these could be used in the comparison group or groups. At least 2 independent reviewers assessed the quality of each study using the Scottish Intercollegiate Guidelines Network checklists. Shoulder conditions addressed were shoulder impingement syndrome (SIS), rotator cuff-associated disorders (RCs), adhesive capsulitis (AC), and nonspecific shoulder pain. RESULTS: Twenty-five systematic reviews and 44 RCTs met inclusion criteria. Low- to moderate-quality evidence supported the use of manual therapies for all 4 shoulder conditions. Exercise, particularly combined with physical therapy protocols, was beneficial for SIS and AC. For SIS, moderate evidence supported several passive modalities. For RC, physical therapy protocols were found beneficial but not superior to surgery in the long term. Moderate evidence supported extracorporeal shockwave therapy for calcific tendinitis RC. Low-level laser was the only modality for which there was moderate evidence supporting its use for all 4 conditions. CONCLUSION: The findings of this literature review may help inform practitioners who use conservative methods (eg, doctors of chiropractic, physical therapists, and other manual therapists) regarding the levels of evidence for modalities used for common shoulder conditions. PMID- 28554434 TI - The big picture. PMID- 28554435 TI - American Board of Orthodontics responds. PMID- 28554437 TI - Precision of landmark identification in cone-beam computed tomography vs image orientation. PMID- 28554436 TI - ABO certification is a valuable learning experience. PMID- 28554438 TI - Editor's note. PMID- 28554439 TI - Authors' response. PMID- 28554440 TI - Authors' response. PMID- 28554441 TI - Simple but not so simple. PMID- 28554442 TI - Piezocision and root resorption: A biased conclusion? PMID- 28554444 TI - Correction. PMID- 28554443 TI - Authors' response. PMID- 28554445 TI - Correction. PMID- 28554447 TI - Here we go again! PMID- 28554448 TI - Stability of orthodontic treatment outcome in relation to retention status: An 8 year follow-up. AB - INTRODUCTION: Our aim was to evaluate the stability of orthodontic treatment outcome and retention status 7 or more years after active treatment in relation to posttreatment or postretention time, type of retention appliance, and duration of retainer use. METHODS: The subjects were former patients who completed orthodontic treatment with fixed appliances from 2000 to 2007. The pretreatment eligibility criteria were anterior crowding of 4 mm or more in the maxilla or the mandible and Angle Class I or Class II sagittal molar relationship. Acceptable pretreatment and posttreatment dental casts were required. A total of 67 patients participated, 24 men and 43 women, with a mean age of 24.7 years (range, 20.0 50.0 years). All participants had a follow-up clinical examination, which included impressions for follow-up casts, and each completed a questionnaire. Data were obtained from pretreatment, posttreatment, and follow-up (T2) casts as well as from the patients' dental records. Treatment stability was evaluated with the peer assessment rating (PAR) index and Little's irregularity index. RESULTS: The participation rate was 64%. The average posttreatment time was 8.5 years (range, 7.0-11.0). All participants had received a retainer in the mandible, maxilla, or both after active treatment. At T2, the PAR score showed a mean relapse of 14%. The majority (78%) of participants still had a fixed retainer at T2 (retainer group), and 22% had been out of retention for at least 1 year (postretention group). The relapse according to the PAR did not differ significantly between participants with and without a retainer at T2. From posttreatment to T2, the irregularity of the mandibular incisors increased almost 3 times more in participants with no retainer in the mandible compared with those with an intact retainer at T2 (P = 0.001). In the maxilla, no corresponding difference was found. CONCLUSIONS: Our results suggest that occlusal relapse can be expected after active orthodontic treatment irrespective of long-term use of fixed retainers. Fixed canine-to-canine retainers seem effective to maintain mandibular incisor alignment, whereas in the maxilla a fixed retainer may not make any difference in the long term. PMID- 28554449 TI - Effects of bone grafting, performed with corticotomies and buccal tooth movements, on dehiscence formation in dogs. AB - INTRODUCTION: A randomized split-mouth experiment was performed in dogs to determine the effects of bone grafting, together with corticotomies and buccal tooth movements, on dehiscence formation. METHODS: Bilateral full-thickness mucoperiosteal buccal flaps were raised, and corticotomies were performed with a piezosurgery unit adjacent to the maxillary second premolars in 7 dogs. The experimental (graft+) side received a demineralized freeze-dried allograph and a resorbable collagen membrane. The second premolars were expanded with archwires for 9 weeks, followed by 3 weeks of consolidation. Soft tissue measurements included probing depths, attachment loss, and recession. Tooth movements were monitored using intraoral, radiographic, and model measurements. Bone surrounding the second premolars was evaluated with microcomputed tomography. New bone formation was analyzed histologically using calcein and alizarin fluorescent labels, and hematoxylin and eosin stains. RESULTS: Postsurgical healing progressed normally with no signs of infection. The graft+ and control (graft-) second premolars underwent similar amounts of expansion (about 2.5 mm intraorally; about 1.7 mm radiographically) and tipping, with no statistically significant side differences. The soft tissue periodontium was not affected on either side. There were bony dehiscences on both the graft+ and graft- sides, with slightly but significantly (P = 0.038) more bone loss over the mesial root on the graft- side. Bone material density was significantly (P = 0.028) greater on the graft+ side. Buccal bone apposition was evident surrounding graft particles, and mineralized particulate graft material was present at the apical aspect of the roots on the graft+ side. CONCLUSIONS: Bone grafting does not prevent dehiscence formation because only a limited amount of new bone is formed, primarily at the more apical aspects of the tooth's roots. PMID- 28554450 TI - Oral health-related quality of life changes in patients with severe Class III malocclusion treated with the 2-jaw surgery-first approach. AB - INTRODUCTION: In this nonrandomized prospective study, we compared the effects of the surgery-first approach with conventional 2-jaw orthognathic surgery on skeletal Class III patients' oral health-related quality of life (OHRQoL), quality of the orthodontic outcome, and average treatment duration. METHODS: The sample consisted of 16 patients with severe skeletal Class III malocclusion, who needed 2-jaw orthognathic surgery: 8 were treated with the surgery-first approach, and 8 were treated with the traditional orthodontic-surgical approach. OHRQoL was assessed by using the Orthognathic Quality of Life Questionnaire (OQLQ) and the Oral Health Impact Profile-short version (OHIP-14). Malocclusion severity and esthetic self-perception were assessed with the Index of Orthodontic Treatment Need. Dental health status was determined using the Decayed, Missing and Filled Teeth Index. Tests were repeated at 7 times: baseline, 1 month after appliance placement, and 3 months, 6 months, 1 year, and 2 years after the beginning of the treatment; and for both groups, there was an also evaluation stage after the orthognathic surgery. RESULTS: After 2 years, the surgery-first group showed a significant decrease in malocclusion severity (P <0.001) and had significant reductions in OQLQ (P <0.001) and OHIP-14 scores (P <0.001). These changes began after the orthognathic surgery and were progressive throughout the evaluation periods. In the traditional orthodontic-surgical approach group, after 2 years of monitoring, all patients were still in the preoperative orthodontic preparation phase, and their malocclusion severity increased significantly, thereby resulting in a not statistically significant worsening of their OHRQoL (OHIP-14, P = 0.89; OQLQ, P = 0.11). CONCLUSIONS: OHRQoL improved significantly in a linear trend of progressive improvements in all severe Class III patients who had the surgery-first approach after the surgical procedure through 2 years of follow-up, as their malocclusion and esthetic self-perception also improved. PMID- 28554451 TI - Evaluation of masseter muscles in relation to treatment with removable bite blocks in dolichofacial growing subjects: A prospective controlled study. AB - INTRODUCTION: The aim of this prospective study was to evaluate the effects of posterior bite-blocks on masseter muscles and on facial growth in prepubertal dolichofacial subjects. METHODS: The treatment group comprised 21 consecutive prepubertal dolichofacial patients treated with rapid maxillary expansion followed by mandibular removable bite-blocks. Lateral cephalograms and ultrasonographic scans of the masseter muscles were made before (T1) and after (T2) treatment with bite-blocks. The treatment group was compared with a control group of 21 subjects matched for sex, age, and skeletal vertical pattern. An independent samples t test was used to compare the T1 to T2 changes in ultrasonographic scan measurements between the treatment group and the control group, and the T1 to T2 cephalometric changes in the treatment group. Regression analysis was performed to investigate associations between masseter muscle thickness and cephalometric treatment outcomes. RESULTS: Masseter muscle thickness showed a statistically significant decrease (-0.7 mm) in the treatment group compared with an increase (+0.6 mm) in the control group. A significant anterior rotation of the mandibular plane was observed in the treatment group as well as significant increases in overbite (1.8 mm) and total posterior facial height (1.5 mm). No significant associations were found between masseter muscle thickness and treatment outcomes apart from a tendency for overbite to increase more in subjects with thicker muscles. CONCLUSIONS: Treatment with removable bite blocks produced a decrease in masseter muscle thickness and a reduction in vertical facial dimensions due to upward and forward rotation of the mandible. No significant correlation was found between the pretreatment masseter muscle thickness and the T1 to T2 cephalometric changes in the treatment group. PMID- 28554452 TI - Characterizing the orthodontic patient's purchase decision: A novel approach using netnography. AB - INTRODUCTION: A deeper and more thorough characterization of why patients do or do not seek orthodontic treatment is needed for effective shared decision making about receiving treatment. Previous orthodontic qualitative research has identified important dimensions that influence treatment decisions, but our understanding of patients' decisions and how they interpret benefits and barriers of treatment are lacking. The objectives of this study were to expand our current list of decision-making dimensions and to create a conceptual framework to describe the decision-making process. METHODS: Discussion boards, rich in orthodontic decision-making data, were identified and analyzed with qualitative methods. An iterative process of data collection, dimension identification, and dimension refinement were performed to saturation. A conceptual framework was created to describe the decision-making process. RESULTS: Fifty-four dimensions captured the ideas discussed in regard to a patient's decision to receive orthodontic treatment. Ten domains were identified: function, esthetics, psychosocial benefits, diagnosis, finances, inconveniences, risks of treatment, individual aspects, societal attitudes, and child-specific influences, each containing specific descriptive and conceptual dimensions. A person's desires, self-perceptions, and viewpoints, the public's views on esthetics and orthodontics, and parenting philosophies impacted perceptions of benefits and barriers associated with orthodontic treatment. CONCLUSIONS: We identified an expanded list of dimensions, created a conceptual framework describing the orthodontic patient's decision-making process, and identified dimensions associated with yes and no decisions, giving doctors a better understanding of patient attitudes and expectations. PMID- 28554453 TI - Impact of cone-beam computed tomography scan mode on the diagnostic yield of chemically simulated external root resorption. AB - INTRODUCTION: The aim of this in-vitro study was to evaluate the influence of cone-beam computed tomography scans on the diagnosis of chemically simulated external root resorption. METHODS: One hundred extracted anterior teeth were selected. Subsurface demineralization was induced on a limited area of the apical third of the root of 49 teeth. Each tooth was placed in an empty socket of a partially edentulous dry mandible. Cone-beam computed tomography images were obtained according to 3 protocols: (1) half scan, 0.40-mm voxel size; (2) full scan, 0.40-mm voxel size; and (3) full scan, 0.125-mm voxel size. Three observers evaluated the images. Sensitivity, specificity, accuracy, and area under the curve were compared with the Cochran Q and Mann-Whitney U tests. RESULTS: Protocol 3 had the highest sensitivity (81.63%), accuracy (80.67%), and area under the curve (0.807). There were statistically significant differences between protocol 3 and the other 2 protocols (P <0.001). The specificity of protocol 1 (84.97%) was greater than that of protocols 2 (69.93%) and 3 (79.74%); however, a statistically significant difference was found only between protocols 1 and 2 (P = 0.005). CONCLUSIONS: A more dedicated, high-resolution scan should be acquired when one intends to investigate the early stage of external root resorption during orthodontic treatment. However, this does not imply that all orthodontic patients should be subjected to high-dose cone-beam computed tomography scans. PMID- 28554454 TI - Diagnosis and treatment planning of orthodontic patients with 3-dimensional dentofacial records. AB - INTRODUCTION: Cephalometrics has been the foundation of orthodontic diagnosis for many years. However, for many orthodontic patients, a lateral cephalogram might not be necessary. The aim of this study was to compare the diagnosis and treatment planning agreement between standard records and nonradiographic 3 dimensional (3D) dentofacial photogrammetry records. METHODS: Twenty patients had standard orthodontic records taken for their treatment as well as extraoral and intraoral 3D images. Twelve evaluators examined the standard records and then completed diagnosis and treatment planning questionnaires. They repeated the process 4 to 6 weeks later by using 3D photographic images along with the panoramic radiographs. Each evaluator also evaluated 2 random orthodontic cases twice with each method to evaluate consistency within each method. At the end of study, each evaluator was asked to complete a survey to document his or her experiences with the 3D photogrammetry method. Descriptive and kappa statistics were used to determine the agreement. RESULTS: Most diagnosis parameters had fair agreement between the methods and within each method. Skeletal and dental relationships had excellent agreement between and within the methods as well as most treatment decisions such as the need for extractions and surgery. Most evaluators (91.7%) thought that cephalometric x-rays would be needed only some of the time in diagnosis and treatment planning. Most evaluators (83.33%) thought that cephalometric radiographs are not needed in patients with a Class I +/- a quarter cusp with crowding or spacing. CONCLUSIONS: Most diagnostic decisions had fair agreement within and between the 2 methods. The decision to extract and the need for orthognathic surgery had excellent agreement between the cephalometric and photogrammetric methods. The majority of examiners agreed that patients with Class I malocclusions +/- a quarter cusp with no obvious skeletal discrepancy can be diagnosed and planned without a cephalometric radiograph. PMID- 28554455 TI - Dentoalveolar and arch dimension changes in patients treated with miniplate anchored maxillary protraction. AB - INTRODUCTION: The aim of this study was to evaluate dentoalveolar and arch dimension changes in 2 miniplate-anchored maxillary protraction protocols in relation to an untreated control group using 3-dimensional digital models. METHODS: Thirty growing Class III subjects with maxillary deficiency in the late mixed or early permanent dentition phase were randomly divided into 3 groups. In group 1 (n = 10), patients were treated with skeletally anchored facemasks anchored with miniplates placed at the zygomatic buttress. In group 2 (n = 10), patients were treated with Class III elastics extending from infrazygomatic miniplates in the maxilla to symphyseal miniplates in the mandible. Group 3 (n = 10) was an untreated control group. The decision to discontinue orthopedic treatment was made when the patients had 3 to 4 mm of positive anterior overjet. Pretreatment, posttreatment, and observation 3-dimensional digital models were analyzed, superimposed, 3 dimensionally mapped, and sectioned. RESULTS: In this study, there were no significant changes in maxillary arch depth and maxillary or mandibular intermolar width before and after maxillary protraction or after the observation period in the control group. The mandibular arch depth decreased by a small but statistically significant amount only in groups 1 and 3. Superimposition of the pretreatment and posttreatment or observation maxillary 3 dimensional digital models showed minimal clinically significant dentoalveolar changes. CONCLUSIONS: Miniplate-anchored maxillary protraction protocols can accomplish maxillary advancement by eliminating movements of teeth and dentoalveolar changes. No spontaneous improvement in transverse deficiency was detected after correction of the anteroposterior deficiency at this age. Consequently, patients with transverse maxillary deficiency should have rapid maxillary expansion before or during the miniplate-anchored protraction period to improve the transverse deficiency. PMID- 28554456 TI - Gene expression profile altered by orthodontic tooth movement during healing of surgical alveolar defect. AB - INTRODUCTION: We explored the gene expression profile altered by orthodontic tooth movement (OTM) during the healing of surgical alveolar defects in beagles. METHODS: An OTM-related healing model was established where a maxillary second premolar was protracted into the critical-sized defect for 6 weeks (group DT6). As controls, natural healing models without OTM were set at 2 weeks (group D2) and at 6 weeks (group D6) after surgery. Total RNAs were extracted from dissected tissue blocks containing the regenerated defects and additionally from sound alveolar bone as a baseline (group C). mRNA profiling was performed using microarray analysis. RESULTS: Functional annotations of gene clusters based on differentially expressed genes among groups indicated that the gene expression profile of group DT6 had a stronger similarity to that of group D2 than to group D6. The genes participating in high woven-bone fraction in group DT6 could be identified as TNFSF11, MMP13, SPP1, and DMP1, which were verified by quantitative real-time polymerase chain reactions. CONCLUSIONS: We investigated at the gene level that OTM can affect the healing state of surgical defects serving as favorable matrices for OTM with defect regeneration. It would be a basis on selecting putative genes to be therapeutically applied for tissue-friendly accelerated orthodontics in the future. PMID- 28554457 TI - Comparative evaluation of treatment outcomes between temporary anchorage devices and Class III elastics in Class III malocclusions. AB - INTRODUCTION: Our objective was to elucidate the differences in treatment outcomes caused by the different mechanics of temporary anchorage devices (TADs) and Class III elastics in patients with Class III malocclusions. METHODS: Records of 23 patients with Angle Class III malocclusion were selected retrospectively. All had been treated with nonextraction comprehensive orthodontic treatment; 11 were treated with TADs and 12 with Class III elastics. Pretreatment and posttreatment lateral cephalograms were used for evaluation of the treatment outcomes. A paired t test and a Student t test were used for statistical analysis. RESULTS: In both groups, proper overjet and Class I molar relationships were achieved, and the occlusal plane was rotated counterclockwise. In the elastics group, distal tipping of the mandibular molars, extrusion of the mandibular incisors and maxillary molars, clockwise rotation of the mandibular plane angle, and increased ANB angle were observed. In the TADs group, distal tipping and intrusion of the mandibular molars, bodily movement of the mandibular incisors, and reduced mandibular plane angle were observed. CONCLUSIONS: In nonextraction treatment for Class III malocclusions, the mandibular plane angle was increased in the elastics group, whereas it was decreased in TADs group. Thus, we suggest that Class III elastics are preferred for low-angle, short-face patients, whereas TADs are preferred for high-angle, long-face patients. PMID- 28554458 TI - Comparison of the treatment effects of different rapid maxillary expansion devices on the maxilla and the mandible. Part 1: Evaluation of dentoalveolar changes. AB - INTRODUCTION: The aim of this study was to compare the dentoalveolar treatment effects of 3 rapid maxillary expansion (RME) appliances, supported by different tissues, on the maxilla and the mandible. METHODS: Patients were assessed for eligibility, and those who met the requirements and agreed to participate were enrolled in the study. Participants were randomly allocated into 3 groups, depending on the type of expansion. The tooth-borne group (n = 16; ages, 12.63 +/ 1.36 years) had RME with a tooth-borne appliance; the bone-borne group (n = 16; ages, 12.92 +/- 1.07 years) had RME with a bone-borne appliance; and the hybrid group (n = 15; ages, 13.41 +/- 0.88 years) had RME with hybrid appliances. Dentoalveolar effects were evaluated by digitally superimposed 3-dimensional scans of maxillary dental casts on a coordinate system and linear interdental width measurements of mandibular dental casts in the pretreatment, posttreatment, and postretention periods. For intragroup and intergroup comparisons, 1-way analysis of variance for repeated measures and multivariate analysis of variance were performed, respectively. RESULTS: Similar dentoalveolar treatment effects were achieved in all groups with the exception of a small amount of expansion on the right side in the bone-borne group. CONCLUSIONS: All 3 expanders led to the expansion of maxillary dentoalveolar structures with mild relapse. However, the amount of expansion of the bone-borne expander on the right side was statistically lower. Spontaneous interdental expansion was observed in the mandibular dentitions in all groups. PMID- 28554459 TI - Relationship between molar occlusion and masticatory movement in lateral deviation of the mandible. AB - INTRODUCTION: The relationship between molar occlusion and chewing patterns was examined in subjects with laterally deviated mandibles. METHODS: Twenty-three patients with mandibular deviation from the midline (4 mm or more) and skeletal Class I (0 degrees <=ANB <=4 degrees ) were divided into 2 groups: normal bite and crossbite. The chewing pattern was classified as normal, reversed, or crossover. RESULTS: The normal bite group had a normal chewing pattern on the affected side 100% of the time and a reversed chewing pattern on the affected and unaffected sides 0% and 7.2% of the time, respectively. Additionally, the normal bite group showed no evidence of a crossover chewing pattern and also had significantly less axial inclination of the mandibular teeth on the affected side compared with the crossbite group; lingual inclination was also evident. The crossbite group had a normal chewing pattern on the affected and unaffected sides 0% and 55.6% of the time, respectively, and reversed and crossover chewing patterns on the affected side 55.6% and 44.4% of the time, respectively. CONCLUSIONS: A normal chewing pattern tends to result in lingual axial inclination of the mandibular molars on the affected side, as well as a more consistent chewing pattern. PMID- 28554460 TI - Forced eruption of a palatally impacted and transposed canine with a temporary skeletal anchorage device. AB - Treatment of palatally impacted and transposed canines is challenging for both orthodontists and oral surgeons. To treat a maxillary canine impaction without risking damage to adjacent teeth, it is necessary to use cone-beam computed tomography for proper localization and treatment planning. In this case report, a palatally impacted canine was initially retracted distally with a microimplant inserted in the palatal slope and then was moved buccally into its ideal position. The patient's occlusion and smile esthetics were significantly improved after orthodontic treatment. PMID- 28554462 TI - Treatment of Class II malocclusion with mandibular skeletal anchorage. AB - INTRODUCTION: The aim of this case report was to present the dentofacial changes obtained with bone anchorage in a Class II patient with moderate to severe crowding. METHODS: A boy, aged 14.5 years, with a dolichofacial type, convex profile, and skeletal and dental Class II relationships was examined. After evaluation, functional treatment with bone anchorage and 4 first premolar extractions was decided as the treatment approach. Miniplates were placed on the buccal shelves of the mandibular third molars. The hook of the anchor was revealed from the first molar level. After surgery, the 4 first premolars were extracted to retract the protrusive mandibular incisors. The maxillary and mandibular first molars were banded, and a lip bumper was inserted to apply elastics and to help distalize the maxillary first molars. Orthodontic forces of 300 to 500 g were applied immediately after placement, originating from the miniscrews to the hooks of the appliance to advance the mandible. RESULTS: After 20 months of treatment, the patient had a dental and skeletal Class I relationship, the mandible was advanced, the maxilla was restrained, and overjet was decreased. CONCLUSIONS: The combination of a bone anchor, Class II elastics, and an inner bow is a promising alternative to functional treatment, along with extractions, in Class II patients. PMID- 28554463 TI - Accuracy of printed dental models made with 2 prototype technologies and different designs of model bases. AB - INTRODUCTION: The aim of this study was to compare the accuracy of printed models from intraoral scans with different designs of model bases, using 2 types of 3 dimensional printing techniques. METHODS: Three types of model base design were created: regular base, horseshoe-shaped base, and horseshoe-shaped base with a bar connecting the posterior region. The digital models were printed with the 3 dimensional printers using different techniques: stereolithography and triple jetting technology (polyjet). The printed models were then scanned with a computed tomography scanner and a desktop laser scanner to create the respective digital models. Evaluation of the accuracy was done by measuring the dentitions with Ortho Analyzer software (3Shape, Copenhagen, Denmark) and by model superimposition with Geomagic Qualify software (3D Systems, Rock Hill, SC). An observer measured the distances twice, with an interval of 2 weeks. The accuracy of the printed models was statistically evaluated by the mixed-effects regression model approach. RESULTS: The results showed that printed models made by the polyjet printer were accurate, regardless of the design of the model base. Printed models made with the stereolithography technique with the regular model base and the horseshoe-shaped base with a bar were accurate, but the transversal distances measured on the printed models with a horseshoe-shaped base were statistically significantly smaller. CONCLUSIONS: Printed models with a regular base or a horseshoe-shaped base with a bar were accurate regardless of the printing technique used. Printed models with a horseshoe-shaped base made with the stereolithography printer had a statistically significant reduction in the transversal dimension that was not found in the models printed with the polyjet technique. PMID- 28554461 TI - Traction of impacted canines in a skeletal Class III malocclusion: A challenging orthodontic treatment. AB - This case report describes the successful traction of 2 severely impacted canines. The patient, a 7-year-old girl, had good general health, nasal breathing, crossbite of the lateral incisors and canines, and a Class I molar relationship. The panoramic radiograph showed that the permanent canines were positioned above the roots of the lateral incisors, with the right canine in an accentuated inclination. The cephalometric analysis showed a skeletal Class III malocclusion with a predominance of horizontal growth. The Haas appliance associated with maxillary protraction was used during the first stage of treatment for 14 months. The second stage included the extraction of the deciduous molars, distal movement of the permanent molars to create space, and traction of the canines, and was associated with complete orthodontic treatment. The patient showed good esthetic and functional results at the end of treatment, verified by the stability over a period of 8 years after retention. PMID- 28554464 TI - Sticks and stones. PMID- 28554465 TI - Conditional logistic regression. PMID- 28554466 TI - Hairy root transgene expression analysis of a secretory peroxidase (PvPOX1) from common bean infected by Fusarium wilt. AB - Plant peroxidases (POXs) are one of the most important redox enzymes in the defense responses. However, the large number of different plant POX genes makes it necessary to carefully confirm the function of each paralogous POX gene in specific tissues and disease interactions. Fusarium wilt is a devastating disease of common bean caused by Fusarium oxysporum f. sp. phaseoli. In this study, we evaluated a peroxidase gene, PvPOX1, from a resistant common bean genotype, CAAS260205 and provided direct evidence for PvPOX1's role in resistance by transforming the resistant allele into a susceptible common bean genotype, BRB130, via hairy root transformation using Agrobacterium rhizogenes. Analysis of PvPOX1 gene over-expressing hairy roots showed it increased resistance to Fusarium wilt both in the roots and the rest of transgenic plants. Meanwhile, the PvPOX1 expressive level, the peroxidase activity and hydrogen peroxide (H2O2) accumulation were also enhanced in the interaction. The result showed that the PvPOX1 gene played an essential role in Fusarium wilt resistance through the occurrence of reactive oxygen species (ROS) induced hypersensitive response. Therefore, PvPOX1 expression was proven to be a valuable gene for further analysis which can strengthen host defense response against Fusarium wilt through a ROS activated resistance mechanism. PMID- 28554467 TI - Review: Mitogen-Activated Protein Kinases in nutritional signaling in Arabidopsis. AB - Mitogen-Activated Protein Kinase (MAPK) cascades are functional modules widespread among eukaryotic organisms. In plants, these modules are encoded by large multigenic families and are involved in many biological processes ranging from stress responses to cellular differentiation and organ development. Furthermore, MAPK pathways are involved in the perception of environmental and physiological modifications. Interestingly, some MAPKs play a role in several signaling networks and could have an integrative function for the response of plants to their environment. In this review, we describe the classification of MAPKs and highlight some of their biochemical actions. We performed an in silico analysis of MAPK gene expression in response to nutrients supporting their involvement in nutritional signaling. While several MAPKs have been identified as players in sugar, nitrogen, phosphate, iron and potassium-related signaling pathways, their biochemical functions are yet mainly unknown. The integration of these regulatory cascades in the current understanding of nutrient signaling is discussed and potential new avenues for approaches toward plants with higher nutrient use efficiencies are evoked. PMID- 28554468 TI - Limited-transpiration response to high vapor pressure deficit in crop species. AB - Water deficit under nearly all field conditions is the major constraint on plant yields. Other than empirical observations, very little progress has been made in developing crop plants in which specific physiological traits for drought are expressed. As a consequence, there was little known about under what conditions and to what extent drought impacts crop yield. However, there has been rapid progress in recent years in understanding and developing a limited-transpiration trait under elevated atmospheric vapor pressure deficit to increase plant growth and yield under water-deficit conditions. This review paper examines the physiological basis for the limited-transpiration trait as result of low plant hydraulic conductivity, which appears to be related to aquaporin activity. Methodology was developed based on aquaporin involvement to identify candidate genotypes for drought tolerance of several major crop species. Cultivars of maize and soybean are now being marketed specifically for arid conditions. Understanding the mechanism of the limited-transpiration trait has allowed a geospatial analyses to define the environments in which increased yield responses can be expected. This review highlights the challenges and approaches to finally develop physiological traits contributing directly to plant improvement for water limited environments. PMID- 28554469 TI - Improved responses to elevated CO2 in durum wheat at a low nitrate supply associated with the upregulation of photosynthetic genes and the activation of nitrate assimilation. AB - Elevated CO2 often leads to photosynthetic acclimation, and N availability may alter this response. We investigated whether the coordination of shoot-root N assimilation by elevated CO2 may help to optimize the whole-plant N allocation and maximize photosynthesis in hydroponically-grown durum wheat at two NO3- supplies in interaction with plant development. Transcriptional and biochemical analyses were performed on flag leaves and roots. At anthesis, the improved photosynthetic acclimation response to elevated CO2 at low N was associated with increased Rubisco, chlorophyll and amino acid contents, and upregulation of genes related to their biosynthesis, light reactions and Calvin-Benson cycle, while a decrease was recorded at high N. Despite the decrease in carbohydrates with elevated CO2 at low N and the increase at high N, a stronger upward trend in leaf NR activity was found at low rather than high N. The induction of N recycling related genes was accompanied by an amino acids decline at high N. At the grain filling stage, the photosynthetic acclimation to elevated CO2 at high N was associated with the downregulation of both N assimilation, mainly in roots, and photosynthetic genes. At low N, enhanced root N assimilation partly compensated for slower shoot N assimilation and maximized photosynthetic capacity. PMID- 28554470 TI - Discovery of novel cold-induced CISP genes encoding small RNA-binding proteins related to cold adaptation in barley. AB - To adapt to cold conditions, barley plants rely on specific mechanisms, which have not been fully understood. In this study, we characterized a novel barley cold-induced gene identified using a PCR-based high coverage gene expression profiling method. The identified gene encodes a small protein that we named CISP1 (Cold-induced Small Protein 1). Homology searches of sequence databases revealed that CISP1 homologs (CISP2 and CISP3) exist in barley genome. Further database analyses showed that the CISP1 homologs were widely distributed in cold-tolerant plants such as wheat and rye. Quantitative reverse transcription PCR analyses indicated that the expression of barley CISP genes was markedly increased in roots exposed to cold conditions. In situ hybridization analyses showed that the CISP1 transcripts were localized in the root tip and lateral root primordium. We also demonstrated that the CISP1 protein bound to RNA. Taken together, these findings indicate that CISP1 and its homologs encoding small RNA-binding proteins may serve as RNA chaperones playing a vital role in the cold adaptation of barley root. This is the first report describing the likely close relationship between root-specific genes and the cold adaptation process, as well as the potential function of the identified genes. PMID- 28554471 TI - When is the unfolded protein response not the unfolded protein response? AB - As sessile organisms, plants are subjected to variety of stresses for which they have evolved different protection mechanisms. One mechanism involves endoplasmic reticulum (ER) stress in which the process of protein folding is disturbed and misfolded proteins accumulate in the ER. ER stress elicits the unfolded protein response (UPR) whereby the stress conditions in the ER are communicated to the nucleus to regulate stress response genes. Since the UPR is one of a number of different mechanisms by which plants respond to stress, it is often difficult to distinguish the UPR from other stress responses. Many investigators have relied on the molecular signature of the UPR, the upregulation of UPR genes to implicate the UPR in response to various stresses. However, some of these genes are activated by other stresses making it problematic to know whether the UPR is truly activated in response to a given stress or is part of a complex response. Another challenge is to understand how plants actually perceive different stress conditions. Are all stress conditions that elicit the UPR response caused by an accumulation of misfolded proteins in the ER? Is this the case for salt stress, which induces the UPR? How about biotic stresses, such as bacterial or viral infections? Do they lead to the accumulation of misfolded proteins in the ER or are there other means by which they induce the UPR? PMID- 28554472 TI - A case of neofunctionalization of a Putranjiva roxburghii PNP protein to trypsin inhibitor by disruption of PNP-UDP domain through an insert containing inhibitory site. AB - The attainment of new function by a protein is achieved through convergent/divergent evolution. In present work, the sequence analysis of a 34kDa protein from Putranjiva roxburghii, earlier reported as a potent trypsin inhibitor, showed resemblance to some of the wound inducible and vegetative storage proteins. A detailed sequence analysis revealed that these proteins belong to PNP-UDP family. In case of P. roxburghii protein, an approximately 46 residue insert disrupts the PNP domain. Similar disruption of PNP domain is observed in related plant proteins. The characterization of recombinant full length and truncated (without 46 residue insert) forms of P. roxburghii PNP family protein (PRpnp) unraveled that trypsin inhibitory active site is located within the insert. The truncated form containing uninterrupted PNP domain showed strong PNP enzymatic activity where it hydrolyzed the N-glycosidic bond of inosine and guanosine. The full length protein, however, showed weak PNP enzyme activity which may be due to presence of the insert. These results indicate towards the neofunctionalization of PRpnp to a potent trypsin inhibitor through an insert containing inhibitory residue to cater to the needs of plant defense. The similar wound inducible and vegetative storage proteins may have also evolved due to evolutionary needs. PMID- 28554473 TI - Differential proteomic analysis revealing the ovule abortion in the female sterile line of Pinus tabulaeformis Carr. AB - Ovule abortion affects the yield and quality of Pinus tabulaeformis Carr. seeds. Research into ovule abortion has importance for improving the seed setting rate and establishing artificial seed production techniques. Fertile line (FL) ovules (FL-E) and sterile line (SL) ovules (SL-E) in the early stage of free nuclear mitosis of megagametophyte (FNMM), FL ovules (FL-L) and SL ovules (SL-L) in the late stage of FNMM of P. tabulaeformis were collected as materials. 4192 proteins were identified by isobaric tags for relative and absolute quantitation (iTRAQ) based analysis. Bioinformatics analysis implied that in SL ovules, substances and energy might be deficient, perhaps leading to abnormal DNA replication. Because the incomplete antioxidant system and the abnormal expression levels of enzymes involved in cell signal transduction, DNA DSBs probably occurs. Facing the abnormities of DNA replication and damage, the cell cycle was arrested and the DNA damage failed to be repaired, potentially resulting in the occurrence of PCD. Taken together, an inference can be drawn from our study - substance and energy deficiencies, reactive oxygen stress, and the failure of both cell cycle progression and DNA damage repair, which possibly hinder FNMM, leading to ovule abortion in the female-sterile line of P. tabulaeformis. PMID- 28554474 TI - The retraction of the protoplast during PCD is an active, and interruptible, calcium-flux driven process. AB - The protoplast retracts during apoptosis-like programmed cell death (AL-PCD) and, if this retraction is an active component of AL-PCD, it should be used as a defining feature for this type of programmed cell death. We used an array of pharmacological and genetic tools to test if the rates of protoplast retraction in cells undergoing AL-PCD can be modulated. Disturbing calcium flux signalling, ATP synthesis and mitochondrial permeability transition all inhibited protoplast retraction and often also the execution of the death programme. Protoplast retraction can precede loss of plasma membrane integrity and cell death can be interrupted after the protoplast retraction had already occurred. Blocking calcium influx inhibited the protoplast retraction, reduced DNA fragmentation and delayed death induced by AL-PCD associated stresses. At higher levels of stress, where cell death occurs without protoplast retraction, blocking calcium flux had no effect on the death process. The results therefore strongly suggest that retraction of the protoplast is an active biological process dependent on an early Ca2+-mediated trigger rather than cellular disintegration due to plasma membrane damage. Therefore this morphologically distinct cell type is a quantifiable feature, and consequently, reporter of AL-PCD. PMID- 28554476 TI - Corrigendum to "Challenges to develop nitrogen-fixing cereals by direct nif-gene transfer" [Plant Sci. 225 (August) (2014) 130-137]. PMID- 28554475 TI - OsCOL16, encoding a CONSTANS-like protein, represses flowering by up-regulating Ghd7 expression in rice. AB - Flowering time is an important agronomic trait that coordinates the plant life cycle with regional adaptability and thereby impacts yield potentials for cereal crops. The CONSTANS (CO)-like gene family plays vital roles in the regulation of flowering time. CO-like proteins are typically divided into four phylogenetic groups in rice. Several genes from groups I, III, and IV have been functionally characterized, though little is known about the genes of group II in rice. We report the functional characterization in rice of a constitutive floral inhibitor, OsCOL16, encoding a group-II CO-like protein that delays flowering time and increases plant height and grain yield. Overexpression of OsCOL16 resulted in late heading under both long-day and short-day conditions. OsCOL16 expression exhibits a diurnal oscillation and serves as a transcription factor with transcriptional activation activity. We determined that OsCOL16 up-regulates the expression of the floral repressor Ghd7, leading to down-regulation of the expression of Ehd1, Hd3a, and RFT1. Moreover, genetic diversity and evolutionary analyses suggest that remarkable differences in flowering times correlate with two major alleles of OsCOL16. Our combined molecular biology and phylogeographic analyses revealed that OsCOL16 plays an important role in regulating rice photoperiodic flowering, allowing for environmental adaptation of rice. PMID- 28554477 TI - The Arabidopsis GASA10 gene encodes a cell wall protein strongly expressed in developing anthers and seeds. AB - The Arabidopsis GASA10 gene encodes a GAST1-like (Gibberellic Acid-Stimulated) protein. Reporter gene analysis identified consistent expression in anthers and seeds. In anthers expression was developmentally regulated, first appearing at stage 7 of anther development and reaching a maximum at stage 11. Strongest expression was in the tapetum and developing microspores. GASA10 expression also occurred throughout the seed and in root vasculature. GASA10 was shown to be transported to the cell wall. Using GASA1 and GASA6 as positive controls, gibberellic acid was found not to induce GASA10 expression in Arabidopsis suspension cells. Overexpression of GASA10 (35S promoter-driven) resulted in a reduction in silique elongation. GASA10 shares structural similarities to the antimicrobial peptide snakin1, however, purified GASA10 failed to influence the growth of a variety of bacterial and fungal species tested. We propose cell wall associated GASA proteins are involved in regulating the hydroxyl radical levels at specific sites in the cell wall to facilitate wall growth (regulating cell wall elongation). PMID- 28554479 TI - Rice PcG gene OsEMF2b controls seed dormancy and seedling growth by regulating the expression of OsVP1. AB - The induction and release of seed dormancy are a precisely regulated process that influences seed germination. ABA promotes seed dormancy but suppresses seed germination and seedling growth. However, how chromatin and epigenetic mechanisms regulate the expression of ABA related genes during these processes remains unclear. Polycomb gene OsEMF2b was required for regulation of seed dormancy and seedling growth by dynamically activating and repressing ABA signal response genes. Downregulation of OsEMF2b led to vivipary and decreased expression level of OsVP1, which was involved in ABA signal pathway in seed dormancy. While, the seedlings with downregulation of OsEMF2b exhibited hyper-sensitive response to ABA and the expression of OsVP1 is upregulated. Yeast one-hybrid assay and ChIP analyses proved that OsEMF2b could bind to the promoter of OsVP1 directly and affected H3K27me3 enrichments of OsVP1 in seedling. Interestingly, both H3K27me3 and H3K4me3 enrichments of OsVP1 were changed with OsEMF2b mis-expression in seed and seedling. We proposed that OsEMF2b may play a pivotal role in seed dormancy and seedling growth by regulating the expression of OsVP1 indirectly or directly. PMID- 28554478 TI - 'Bartlett' pear fruit (Pyrus communis L.) ripening regulation by low temperatures involves genes associated with jasmonic acid, cold response, and transcription factors. AB - Low temperature (LT) treatments enhance ethylene production and ripening rate in the European pear (Pyrus communis L.). However, the underlying molecular mechanisms are not well understood. This study aims to identify genes responsible for ripening enhancement by LT. To this end, the transcriptome of 'Bartlett' pears treated with LT (0 degrees C or 10 degrees C for up to 14 d), which results in faster ripening, and control pears without conditioning treatment was analyzed. LT conditioned pears reached eating firmness (18N) in 6 d while control pears took about 12 d when left to ripen at 20 degrees C. We identified 8,536 differentially expressed (DE) genes between the 0 degrees C-treated and control fruit, and 7,938 DE genes between the 10 degrees C-treated and control fruit. In an attempt to differentiate temperature-induced vs. ethylene-responsive pathways, we also monitored gene expression in fruit sequentially treated with 1-MCP then exposed to low temperature. This analysis revealed that genes associated with jasmonic acid biosynthesis and signaling, as well as the transcription factors TCP9a, TCP9b, CBF1, CBF4, AGL24, MYB1R1, and HsfB2b could be involved in the LT mediated enhancement of ripening independently or upstream of ethylene. PMID- 28554480 TI - SGD1, a key enzyme in tocopherol biosynthesis, is essential for plant development and cold tolerance in rice. AB - Tocopherols, a group of Vitamin E compounds, are essential components of the human diet. In contrast to well documented roles in animals, the functions of tocopherols in plants are less understood. In this study, we characterized two allelic rice dwarf mutant lines designated sgd1-1 and sgd1-2 (small grain and dwarf1). Histological observations showed that the dwarf phenotypes were mainly due to cell elongation defects. A map-based cloning strategy and subsequent complementation test showed that SGD1 encodes homogentisate phytyltransferase (HPT), a key enzyme in tocopherol biosynthesis. Mutation of SGD1 resulted in tocopherol deficiency in both sgd1mutants. No oxidant damage was detected in the sgd1 mutants. Further analysis showed that sgd1-2 was hypersensitive to cold stress. Our results indicate that SGD1 is essential for plant development and cold tolerance in rice. PMID- 28554481 TI - Zebrafish Keep Their Cool. PMID- 28554483 TI - Editorial overview: Many shades of grey: how immune response is regulated by tumors. PMID- 28554482 TI - Process simulation and techno economic analysis of renewable diesel production via catalytic decarboxylation of rubber seed oil - A case study in Malaysia. AB - This work describes the economic feasibility of hydroprocessed diesel fuel production via catalytic decarboxylation of rubber seed oil in Malaysia. A comprehensive techno-economic assessment is developed using Aspen HYSYS V8.0 software for process modelling and economic cost estimates. The profitability profile and minimum fuels selling price of this synthetic fuels production using rubber seed oil as biomass feedstock are assessed under a set of assumptions for what can be plausibly be achieved in 10-years framework. In this study, renewable diesel processing facility is modelled to be capable of processing 65,000 L of inedible oil per day and producing a total of 20 million litre of renewable diesel product per annual with assumed annual operational days of 347. With the forecasted renewable diesel retail price of 3.64 RM per kg, the pioneering renewable diesel project investment offers an assuring return of investment of 12.1% and net return as high as 1.35 million RM. Sensitivity analysis conducted showed that renewable diesel production cost is most sensitive to rubber seed oil price and hydrogen gas price, reflecting on the relative importance of feedstock prices in the overall profitability profile. PMID- 28554484 TI - Editorial overview: Germinal centers and memory B-cells: from here to eternity. PMID- 28554485 TI - Microbial Interactions. PMID- 28554487 TI - Methodological Remarks in the Meta-Analysis on the Impact of Baseline Pulmonary Hypertension on Post-Transcatheter Aortic Valve Implantation Outcomes. PMID- 28554486 TI - Comparison of the Antiplatelet Effects of Once and Twice Daily Low-Dose Ticagrelor and Clopidogrel After Percutaneous Coronary Intervention. AB - Although Asian people are believed to be more susceptible to bleeding on currently recommended dose of ticagrelor, there is limited evidence supporting low-dose ticagrelor. We prospectively randomized patients receiving dual antiplatelet therapy with aspirin and clopidogrel into 3 groups; aspirin plus clopidogrel 75 mg versus aspirin plus ticagrelor 90 mg once daily versus aspirin plus ticagrelor 45 mg twice daily. Platelet function assessments were conducted using VerifyNow P2Y12 assay at baseline and 28 days after randomization. No differences in baseline P2Y12 reaction unit (PRU) values were observed among the 3 groups. PRU values at the end of the treatment periods were significantly lower in low-dose ticagrelor (90 mg QD group, 98.6 +/- 73.4 and 45 mg BID group, 65.5 +/- 58.8) compared with clopidogrel (221.2 +/- 50.1, both p <0.001). There was no significant difference in PRU values between 2 groups of low-dose ticagrelor (p = 0.208). The rates of high on-treatment platelet reactivity were significantly lower in low-dose ticagrelor compared with clopidogrel, whereas clopidogrel showed higher rate of optimal on-treatment platelet reactivity than ticagrelor 45 mg BID. However, similar rate of optimal on-treatment platelet reactivity was observed in clopidogrel and ticagrelor 90 mg QD. In conclusion, low-dose ticagrelor treatment, either with 90 mg QD or 45 mg BID, was associated with a more potent antiplatelet effect compared with clopidogrel treatment and once daily dose provided similar antiplatelet effect but favorable effect on optimal platelet inhibition compared with twice daily dose. PMID- 28554488 TI - Corrigendum to: Runoff of genotoxic compounds in river basin sediment under the influence of contaminated soils [Ecotoxicol. Environ. Saf. 75 (2012) 63-72]. PMID- 28554489 TI - Hepatoprotective efficacy of Spirulina platensis against lead-induced oxidative stress and genotoxicity in catfish; Clarias gariepinus. AB - Lead (Pb) is a toxic environmental pollutant that induces a broad range of biochemical and physiological hazards in living organisms. We investigated the possible hepatoprotective effects of Spirulina platensis (SP) in counteracting the Pb-induced oxidative damage. Ninety-six adult African catfish were allocated into four equal groups. The 1st group (control) fed basal diet while the 2nd group (Pb-treated) fed on basal diet and exposed to 1mg Pb(NO3)2/L. The 3rd and 4th groups fed SP-supplemented basal diets at levels of 0.25% and 0.5%, respectively and exposed to Pb. Serum samples were used to analyze hepatic function biomarkers, electrolytes, and oxidant and antioxidant status. Lipid peroxidation and DNA fragmentation were determined in the liver tissues. Pb exposure induced hepatic dysfunction, electrolytes (Na+, K+, Ca+2, and Cl-) imbalance, as well a significant decrease in GSH content, and LDH, AChE, SOD, CAT and GST enzymes activity. SP supplementation reverted these biochemical and genetic alterations close to control levels. This amelioration was higher with 0.5% SP and at the 4th week of exposure, showing concentration- and time dependency. Thus, the current study suggests that SP could protect the catfish liver against lead-induced injury by scavenging ROS, sustaining the antioxidant status and diminishing DNA oxidative damage. The dietary inclusion of SP can be used as a promising protective agent to counteract oxidative stress-mediated diseases and toxicities. PMID- 28554491 TI - Does the emergency surgery score accurately predict outcomes in emergent laparotomies? AB - BACKGROUND: The emergency surgery score is a mortality-risk calculator for emergency general operation patients. We sought to examine whether the emergency surgery score predicts 30-day morbidity and mortality in a high-risk group of patients undergoing emergent laparotomy. METHODS: Using the 2011-2012 American College of Surgeons National Surgical Quality Improvement Program database, we identified all patients who underwent emergent laparotomy using (1) the American College of Surgeons National Surgical Quality Improvement Program definition of "emergent," and (2) all Current Procedural Terminology codes denoting a laparotomy, excluding aortic aneurysm rupture. Multivariable logistic regression analyses were performed to measure the correlation (c-statistic) between the emergency surgery score and (1) 30-day mortality, and (2) 30-day morbidity after emergent laparotomy. As sensitivity analyses, the correlation between the emergency surgery score and 30-day mortality was also evaluated in prespecified subgroups based on Current Procedural Terminology codes. RESULTS: A total of 26,410 emergent laparotomy patients were included. Thirty-day mortality and morbidity were 10.2% and 43.8%, respectively. The emergency surgery score correlated well with mortality (c-statistic = 0.84); scores of 1, 11, and 22 correlated with mortalities of 0.4%, 39%, and 100%, respectively. Similarly, the emergency surgery score correlated well with morbidity (c-statistic = 0.74); scores of 0, 7, and 11 correlated with complication rates of 13%, 58%, and 79%, respectively. The morbidity rates plateaued for scores higher than 11. Sensitivity analyses demonstrated that the emergency surgery score effectively predicts mortality in patients undergoing emergent (1) splenic, (2) gastroduodenal, (3) intestinal, (4) hepatobiliary, or (5) incarcerated ventral hernia operation. CONCLUSION: The emergency surgery score accurately predicts outcomes in all types of emergent laparotomy patients and may prove valuable as a bedside decision-making tool for patient and family counseling, as well as for adequate risk-adjustment in emergent laparotomy quality benchmarking efforts. PMID- 28554492 TI - Cerebellar Disease Mimicking Cerebrotendinous Xanthomatosis: Langerhans Cell Histiocytosis. AB - BACKGROUND: This report highlights the differential diagnosis of predominant cerebellar white matter abnormalities with dentate nuclei involvement. PATIENT DESCRIPTION: We describe two individuals with Langerhans cell histiocytosis in whom the diagnosis of cerebrotendinous xanthomatosis was initially considered. The clinical picture consisted of a progressive cerebellar syndrome with typical magnetic resonance imaging abnormalities. In both individuals, the cerebellar syndrome preceded the diagnosis of Langerhans cell histiocytosis. CONCLUSIONS: The magnetic resonance imaging abnormalities and neurological features in patients with Langerhans cell histiocytosis can be strikingly similar to those with cerebrotendinous xanthomatosis. In cerebrotendinous xanthomatosis, the cerebellar symptoms and cerebellar white matter abnormalities are usually seen in adult patients. In a pediatric patient with a cerebellar syndrome, showing these cerebellar white matter abnormalities a diagnosis of Langerhans cell histiocytosis is more likely. PMID- 28554490 TI - Candidate gene analysis for Alzheimer's disease in adults with Down syndrome. AB - Individuals with Down syndrome (DS) overexpress many genes on chromosome 21 due to trisomy and have high risk of dementia due to the Alzheimer's disease (AD) neuropathology. However, there is a wide range of phenotypic differences (e.g., age at onset of AD, amyloid beta levels) among adults with DS, suggesting the importance of factors that modify risk within this particularly vulnerable population, including genotypic variability. Previous genetic studies in the general population have identified multiple genes that are associated with AD. This study examined the contribution of polymorphisms in these genes to the risk of AD in adults with DS ranging from 30 to 78 years of age at study entry (N = 320). We used multiple logistic regressions to estimate the likelihood of AD using single-nucleotide polymorphisms (SNPs) in candidate genes, adjusting for age, sex, race/ethnicity, level of intellectual disability and APOE genotype. This study identified multiple SNPs in APP and CST3 that were associated with AD at a gene-wise level empirical p-value of 0.05, with odds ratios in the range of 1.5-2. SNPs in MARK4 were marginally associated with AD. CST3 and MARK4 may contribute to our understanding of potential mechanisms where CST3 may contribute to the amyloid pathway by inhibiting plaque formation, and MARK4 may contribute to the regulation of the transition between stable and dynamic microtubules. PMID- 28554493 TI - Statistical shape modeling predicts patellar bone geometry to enable stereo radiographic kinematic tracking. AB - Complications in the patellofemoral (PF) joint of patients with total knee replacements include patellar subluxation and dislocation, and remain a cause for revision. Kinematic measurements to assess these complications and evaluate implant designs require the accuracy of dynamic stereo-radiographic systems with 3D-2D registration techniques. While tibiofemoral kinematics are typically derived by tracking metallic implants, PF kinematic measurements are difficult as the patellar implant is radiotransparent and a representation of the resected patella bone requires either pre-surgical imaging and precise implant placement or post-surgical imaging. Statistical shape models (SSMs), used to characterize anatomic variation, provide an alternative means to obtain the representation of the resected patella for use in kinematic tracking. Using a virtual platform of a stereo-radiographic system, the objectives of this study were to evaluate the ability of an SSM to predict subject-specific 3D implanted patellar geometries from simulated 2D image profiles, and to formulate an effective data collection methodology for PF kinematics by considering accuracy for a variety of patient pose scenarios. An SSM of the patella was developed for 50 subjects and a leave one-out approach compared SSM-predicted and actual geometries; average 3D errors were 0.45+/-0.07mm (mean+/-standard deviation), which is comparable to the accuracy of traditional segmentation. Further, initial imaging of the patella in five unique stereo radiographic perspectives yielded the most accurate representation. The ability to predict the remaining patellar geometry of the implanted PF joint with radiographic images and SSM, instead of CT, can reduce radiation exposure and streamline in vivo kinematic evaluations. PMID- 28554494 TI - Effects of a viscosupplementation therapy on rabbit menisci in an anterior cruciate ligament transection model of osteoarthritis. AB - The aim of this study was to evaluate the morphological, microstructural, and mechanical effects of a viscosupplementation therapy on rabbit menisci at an early stage of osteoarthritis (OA). Anterior cruciate ligament transection (ACLT) was performed in twelve male New-Zealand White rabbits on the right knee joint. Six of these twelve rabbits received a mono intra-articular injection of high molecular weight hyaluronic acid (HA) two weeks after ACLT. Six additional healthy rabbits served as controls. Medial menisci were removed from all right knees (n=18) six weeks after ACLT and were graded macroscopically. Indentation relaxation tests were performed in the anterior and posterior regions of the menisci. Collagen fiber organization and glycosaminoglycan (GAG) content were assessed by biphotonic confocal microscopy and histology, respectively. Viscosupplementation significantly (p=0.002) improved the surface integrity of the medial menisci compared to the operated non-treated group. Moreover, the injection seems to have an effect on the GAG distribution in the anterior region of the menisci. However, the viscoelastic properties of both operated groups were similar and significantly lower than those of the healthy group, which was explained by their modified collagen fiber organization. They displayed disruption of the tie fibers due to structural alterations of the superficial layers from which they emanate, leading to modifications in the deep zone. To conclude, the viscosupplementation therapy prevents macroscopic lesions of the menisci, but it fails to restore their collagen fiber organization and their viscoelastic properties. This finding supports the role of this treatment in improving the lubrication over the knee. PMID- 28554496 TI - Update on nursing staffing challenges by state attorneys general. PMID- 28554495 TI - Response to letter to the editor concerning "A fully dynamic multi-compartmental poroelastic system: Application to aqueductal stenosis". PMID- 28554497 TI - Evaluating the older adult experience of a web-based, tablet-delivered heart failure self-care program using gerontechnology principles. AB - The goals of gerontechnology are to develop technology that facilitates goal attainment and improves satisfaction with life for older adults. Few mHealth technology systems have been evaluated using these criteria. The purpose of this paper was to present the qualitative analysis of participant post-intervention interviews from the tablet-delivered Penn State Heart Assistant intervention. Semi-structured interviews (n = 12) were conducted after the completion of a 30 day study protocol. Interviews were transcribed verbatim by a professional transcriptionist, then analyzed using an iterative process of coding, categorization, and thematic development using DeDoose software and a gerontechnology interpretive lens. Two themes with six subthemes arose: Benefits information sharing with others, usability and learnability, use of help resources; Suggestions - continuing use after the study, technical problems, participant suggested improvements. Interviews suggested improved goal attainment and satisfaction with life for the older adults with use of the tablet. PMID- 28554498 TI - Addressing refugee health through evidence-based policies: a case study. AB - The cumulative total of persons forced to leave their country for fear of persecution or organized violence reached an unprecedented 24.5 million by the end of 2015. Providing equitable access to appropriate health services for these highly diverse newcomers poses challenges for receiving countries. In this case study, we illustrate the importance of translating epidemiology into policy to address the health needs of refugees by highlighting examples of what works as well as identifying important policy-relevant gaps in knowledge. First, we formed an international working group of epidemiologists and health services researchers to identify available literature on the intersection of epidemiology, policy, and refugee health. Second, we created a synopsis of findings to inform a recommendation for integration of policy and epidemiology to support refugee health in the United States and other high-income receiving countries. Third, we identified eight key areas to guide the involvement of epidemiologists in addressing refugee health concerns. The complexity and uniqueness of refugee health issues, and the need to develop sustainable management information systems, require epidemiologists to expand their repertoire of skills to identify health patterns among arriving refugees, monitor access to appropriately designed health services, address inequities, and communicate with policy makers and multidisciplinary teams. PMID- 28554499 TI - Reply to the Letter to the Editor by Vargo et al. PMID- 28554500 TI - Semantic network analysis of vaccine sentiment in online social media. AB - OBJECTIVE: To examine current vaccine sentiment on social media by constructing and analyzing semantic networks of vaccine information from highly shared websites of Twitter users in the United States; and to assist public health communication of vaccines. BACKGROUND: Vaccine hesitancy continues to contribute to suboptimal vaccination coverage in the United States, posing significant risk of disease outbreaks, yet remains poorly understood. METHODS: We constructed semantic networks of vaccine information from internet articles shared by Twitter users in the United States. We analyzed resulting network topology, compared semantic differences, and identified the most salient concepts within networks expressing positive, negative, and neutral vaccine sentiment. RESULTS: The semantic network of positive vaccine sentiment demonstrated greater cohesiveness in discourse compared to the larger, less-connected network of negative vaccine sentiment. The positive sentiment network centered around parents and focused on communicating health risks and benefits, highlighting medical concepts such as measles, autism, HPV vaccine, vaccine-autism link, meningococcal disease, and MMR vaccine. In contrast, the negative network centered around children and focused on organizational bodies such as CDC, vaccine industry, doctors, mainstream media, pharmaceutical companies, and United States. The prevalence of negative vaccine sentiment was demonstrated through diverse messaging, framed around skepticism and distrust of government organizations that communicate scientific evidence supporting positive vaccine benefits. CONCLUSION: Semantic network analysis of vaccine sentiment in online social media can enhance understanding of the scope and variability of current attitudes and beliefs toward vaccines. Our study synthesizes quantitative and qualitative evidence from an interdisciplinary approach to better understand complex drivers of vaccine hesitancy for public health communication, to improve vaccine confidence and vaccination coverage in the United States. PMID- 28554501 TI - Burden of vaccine-preventable pneumococcal disease in hospitalized adults: A Canadian Immunization Research Network (CIRN) Serious Outcomes Surveillance (SOS) network study. AB - BACKGROUND: Pneumococcal community acquired pneumonia (CAPSpn) and invasive pneumococcal disease (IPD) cause significant morbidity and mortality worldwide. Although childhood immunization programs have reduced the overall burden of pneumococcal disease, there is insufficient data in Canada to inform immunization policy in immunocompetent adults. This study aimed to describe clinical outcomes of pneumococcal disease in hospitalized Canadian adults, and determine the proportion of cases caused by vaccine-preventable serotypes. METHODS: Active surveillance for CAPSpn and IPD in hospitalized adults was performed in hospitals across five Canadian provinces from December 2010 to 2013. CAPSpn were identified using sputum culture, blood culture, a commercial pan-pneumococcal urine antigen detection (UAD), or a serotype-specific UAD. The serotype distribution was characterized using Quellung reaction, and PCR-based serotyping on cultured isolates, or using a 13-valent pneumococcal conjugate vaccine (PCV13) serotype specific UAD assay. RESULTS AND CONCLUSIONS: In total, 4769 all-cause CAP cases and 81 cases of IPD (non-CAP) were identified. Of the 4769 all-cause CAP cases, a laboratory test for S. pneumoniae was performed in 3851, identifying 14.3% as CAPSpn. Of CAP cases among whom all four diagnostic test were performed, S. pneumoniae was identified in 23.2% (144/621). CAPSpn cases increased with age and the disease burden of illness was evident in terms of requirement for mechanical ventilation, intensive care unit admission, and 30-day mortality. Of serotypeable CAPSpn or IPD results, predominance for serotypes 3, 7F, 19A, and 22F was observed. The proportion of hospitalized CAP cases caused by a PCV13-type S. pneumoniae ranged between 7.0% and 14.8% among cases with at least one test for S. pneumoniae performed or in whom all four diagnostic tests were performed, respectively. Overall, vaccine-preventable pneumococcal CAP and IPD were shown to be significant causes of morbidity and mortality in hospitalized Canadian adults in the three years following infant PCV13 immunization programs in Canada. PMID- 28554502 TI - Protection of White Leghorn chickens by U.S. emergency H5 vaccination against clade 2.3.4.4 H5N2 high pathogenicity avian influenza virus. AB - During December 2014-June 2015, the U.S. experienced a high pathogenicity avian influenza (HPAI) outbreak caused by clade 2.3.4.4 H5Nx Goose/Guangdong lineage viruses with devastating consequences for the poultry industry. Three vaccines, developed based on updating existing registered vaccines or currently licensed technologies, were evaluated for possible use: an inactivated reverse genetics H5N1 vaccine (rgH5N1) and an RNA particle vaccine (RP-H5), both containing the hemagglutinin gene of clade 2.3.4.4 strain, and a recombinant herpesvirus turkey vectored vaccine (rHVT-H5) containing the hemagglutinin gene of clade 2.2 strain. The efficacy of the three vaccines, alone or in combination, was assessed in White Leghorn chickens against clade 2.3.4.4 H5N2 HPAI virus challenge. In Study 1, single (rHVT-H5) and prime-boost (rHVT-H5+rgH5N1 or rHVT-H5+RP-H5) vaccination strategies protected chickens with high levels of protective immunity and significantly reduced virus shedding. In Study 2, single vaccination with either rgH5N1 or RP-H5 vaccines provided clinical protection in adult chickens and significantly reduced virus shedding. In Study 3, double rgH5N1 vaccination protected adult chickens from clinical signs and mortality when challenged 20weeks post-boost, with high levels of long-lasting protective immunity and significantly reduced virus shedding. These studies support the use of genetically related vaccines, possibly in combination with a broad protective priming vaccine, for emergency vaccination programs against clade 2.3.4.4 H5Nx HPAI virus in young and adult layer chickens. PMID- 28554504 TI - Predictions of space radiation fatality risk for exploration missions. AB - : In this paper we describe revisions to the NASA Space Cancer Risk (NSCR) model focusing on updates to probability distribution functions (PDF) representing the uncertainties in the radiation quality factor (QF) model parameters and the dose and dose-rate reduction effectiveness factor (DDREF). We integrate recent heavy ion data on liver, colorectal, intestinal, lung, and Harderian gland tumors with other data from fission neutron experiments into the model analysis. In an earlier work we introduced distinct QFs for leukemia and solid cancer risk predictions, and here we consider liver cancer risks separately because of the higher RBE's reported in mouse experiments compared to other tumors types, and distinct risk factors for liver cancer for astronauts compared to the U.S. POPULATION: The revised model is used to make predictions of fatal cancer and circulatory disease risks for 1-year deep space and International Space Station (ISS) missions, and a 940 day Mars mission. We analyzed the contribution of the various model parameter uncertainties to the overall uncertainty, which shows that the uncertainties in relative biological effectiveness (RBE) factors at high LET due to statistical uncertainties and differences across tissue types and mouse strains are the dominant uncertainty. NASA's exposure limits are approached or exceeded for each mission scenario considered. Two main conclusions are made: 1) Reducing the current estimate of about a 3-fold uncertainty to a 2-fold or lower uncertainty will require much more expansive animal carcinogenesis studies in order to reduce statistical uncertainties and understand tissue, sex and genetic variations. 2) Alternative model assumptions such as non-targeted effects, increased tumor lethality and decreased latency at high LET, and non cancer mortality risks from circulatory diseases could significantly increase risk estimates to several times higher than the NASA limits. PMID- 28554503 TI - Saccharomyces cerevisiae-derived virus-like particle parvovirus B19 vaccine elicits binding and neutralizing antibodies in a mouse model for sickle cell disease. AB - Parvovirus B19 infections are typically mild in healthy individuals, but can be life threatening in individuals with sickle cell disease (SCD). A Saccharomyces cerevisiae-derived B19 VLP vaccine, now in pre-clinical development, is immunogenic in wild type mice when administered with the adjuvant MF59. Because SCD alters the immune response, we evaluated the efficacy of this vaccine in a mouse model for SCD. Vaccinated mice with SCD demonstrated similar binding and neutralizing antibody responses to those of heterozygous littermate controls following a prime-boost-boost regimen. Due to the lack of a mouse parvovirus B19 challenge model, we employed a natural mouse pathogen, Sendai virus, to evaluate SCD respiratory tract responses to infection. Normal mucosal and systemic antibody responses were observed in these mice. Results demonstrate that mice with SCD can respond to a VLP vaccine and to a respiratory virus challenge, encouraging rapid development of the B19 vaccine for patients with SCD. PMID- 28554505 TI - Long term stability of Oligo (dT) 25 magnetic beads for the expression analysis of Euglena gracilis for long term space projects. AB - The unicellular freshwater flagellate Euglena gracilis has a highly developed sensory system. The cells use different stimuli such as light and gravity to orient themselves in the surrounding medium to find areas for optimal growth. Due to the ability to produce oxygen and consume carbon dioxide, Euglena is a suitable candidate for life support systems. Participation in a long-term space experiment would allow for the analysis of changes and adaptations to the new environment, and this could bring new insights into the mechanism of perception of gravity and the associated signal transduction chain. For a molecular analysis of transcription patterns, an automated system is necessary, capable of performing all steps from taking a sample, processing it and generating data. One of the developmental steps is to find long-term stable reagents and materials and test them for stability at higher-than-recommended temperature conditions during extended storage time. We investigated the usability of magnetic beads in an Euglena specific lysis buffer after addition of the RNA stabilizer Dithiothreitol over 360 days and the lysis buffer with the stabilizer alone over 455 days at the expected storage temperature of 19 degrees C. We can claim that the stability is not impaired at all after an incubation period of over one year. This might be an interesting result for researchers who have to work under non-standard lab conditions, as in biological or medicinal fieldwork. PMID- 28554506 TI - BION-M 1: First continuous blood pressure monitoring in mice during a 30-day spaceflight. AB - Animals are an essential component of space exploration and have been used to demonstrate that weightlessness does not disrupt essential physiological functions. They can also contribute to space research as models of weightlessness induced changes in humans. Animal research was an integral component of the 30 day automated Russian biosatellite Bion-M 1 space mission. The aim of the hemodynamic experiment was to estimate cardiovascular function in mice, a species roughly 3000 times smaller than humans, during prolonged spaceflight and post flight recovery, particularly, to investigate if mice display signs of cardiovascular deconditioning. For the first time, heart rate (HR) and blood pressure (BP) were continuously monitored using implantable telemetry during spaceflight and recovery. Decreased HR and unchanged BP were observed during launch, whereas both HR and BP dropped dramatically during descent. During spaceflight, BP did not change from pre-flight values. However, HR increased, particularly during periods of activity. HR remained elevated after spaceflight and was accompanied by increased levels of exercise-induced tachycardia. Loss of three of the five mice during the flight as a result of the hardware malfunction (unrelated to the telemetry system) and thus the limited sample number constitute the major limitation of the study. For the first time BP and HR were continuously monitored in mice during the 30-day spaceflight and 7-days of post-flight recovery. Cardiovascular deconditioning in these tiny quadruped mammals was reminiscent of that in humans. Therefore, the loss of hydrostatic pressure in space, which is thought to be the initiating event for human cardiovascular adaptation in microgravity, might be of less importance than other physiological mechanisms. Further experiments with larger number of mice are needed to confirm these findings. PMID- 28554507 TI - Track structure model of microscopic energy deposition by protons and heavy ions in segments of neuronal cell dendrites represented by cylinders or spheres. AB - Changes to cognition, including memory, following radiation exposure are a concern for cosmic ray exposures to astronauts and in Hadron therapy with proton and heavy ion beams. The purpose of the present work is to develop computational methods to evaluate microscopic energy deposition (ED) in volumes representative of neuron cell structures, including segments of dendrites and spines, using a stochastic track structure model. A challenge for biophysical models of neuronal damage is the large sizes (> 100um) and variability in volumes of possible dendritic segments and pre-synaptic elements (spines and filopodia). We consider cylindrical and spherical microscopic volumes of varying geometric parameters and aspect ratios from 0.5 to 5 irradiated by protons, and 3He and 12C particles at energies corresponding to a distance of 1cm to the Bragg peak, which represent particles of interest in Hadron therapy as well as space radiation exposure. We investigate the optimal axis length of dendritic segments to evaluate microscopic ED and hit probabilities along the dendritic branches at a given macroscopic dose. Because of large computation times to analyze ED in volumes of varying sizes, we developed an analytical method to find the mean primary dose in spheres that can guide numerical methods to find the primary dose distribution for cylinders. Considering cylindrical segments of varying aspect ratio at constant volume, we assess the chord length distribution, mean number of hits and ED profiles by primary particles and secondary electrons (delta-rays). For biophysical modeling applications, segments on dendritic branches are proposed to have equal diameters and axes lengths along the varying diameter of a dendritic branch. PMID- 28554508 TI - 28Si total body irradiation injures bone marrow hematopoietic stem cells via induction of cellular apoptosis. AB - Long-term space mission exposes astronauts to a radiation environment with potential health hazards. High-energy charged particles (HZE), including 28Si nuclei in space, have deleterious effects on cells due to their characteristics with high linear energy transfer and dense ionization. The influence of 28Si ions contributes more than 10% to the radiation dose equivalent in the space environment. Understanding the biological effects of 28Si irradiation is important to assess the potential health hazards of long-term space missions. The hematopoietic system is highly sensitive to radiation injury and bone marrow (BM) suppression is the primary life-threatening injuries after exposure to a moderate dose of radiation. Therefore, in the present study we investigated the acute effects of low doses of 28Si irradiation on the hematopoietic system in a mouse model. Specifically, 6-month-old C57BL/6J mice were exposed to 0.3, 0.6 and 0.9Gy 28Si (600MeV) total body irradiation (TBI). The effects of 28Si TBI on BM hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) were examined four weeks after the exposure. The results showed that exposure to 28Si TBI dramatically reduced the frequencies and numbers of HSCs in irradiated mice, compared to non-irradiated controls, in a radiation dose-dependent manner. In contrast, no significant changes were observed in BM HPCs regardless of radiation doses. Furthermore, irradiated HSCs exhibited a significant impairment in clonogenic ability. These acute effects of 28Si irradiation on HSCs may be attributable to radiation-induced apoptosis of HSCs, because HSCs, but not HPCs, from irradiated mice exhibited a significant increase in apoptosis in a radiation dose-dependent manner. However, exposure to low doses of 28Si did not result in an increased production of reactive oxygen species and DNA damage in HSCs and HPCs. These findings indicate that exposure to 28Si irradiation leads to acute HSC damage. PMID- 28554509 TI - Low and high dose rate heavy ion radiation-induced intestinal and colonic tumorigenesis in APC1638N/+ mice. AB - Ionizing radiation (IR) is a recognized risk factor for colorectal cancer (CRC) and astronauts undertaking long duration space missions are expected to receive IR doses in excess of permissible limits with implications for colorectal carcinogenesis. Exposure to IR in outer space occurs at low doses and dose rates, and energetic heavy ions due to their high linear energy transfer (high-LET) characteristics remain a major concern for CRC risk in astronauts. Previously, we have demonstrated that intestinal tumorigenesis in a mouse model (APC1638N/+) of human colorectal cancer was significantly higher after exposure to high dose rate energetic heavy ions relative to low-LET gamma radiation. The purpose of the current study was to compare intestinal tumorigenesis in APC1638N/+ mice after exposure to energetic heavy ions at high (50cGy/min) and relatively low (0.33cGy/min) dose rate. Male and female mice (6-8 weeks old) were exposed to either 10 or 50cGy of 28Si (energy: 300MeV/n; LET: 70keV/MUm) or 56Fe (energy: 1000MeV/n; LET: 148keV/MUm) ions at NASA Space Radiation Laboratory in Brookhaven National Laboratory. Mice (n=20 mice/group) were euthanized and intestinal and colon tumor frequency and size were counted 150days after radiation exposure. Intestinal tumorigenesis in male mice exposed to 56Fe was similar for high and low dose rate exposures. Although male mice showed a decreasing trend at low dose rate relative to high dose rate exposures, the differences in tumor frequency between the two types of exposures were not statistically significant after 28Si radiation. In female mice, intestinal tumor frequency was similar for both radiation type and dose rates tested. In both male and female mice intestinal tumor size was not different after high and low dose rate radiation exposures. Colon tumor frequency in male and female mice after high and low dose rate energetic heavy ions was also not significantly different. In conclusion, intestinal and colonic tumor frequency and size was similar irrespective of energetic heavy ion radiation dose rate suggesting that carcinogenic potential of energetic heavy ions is independent of dose rate. PMID- 28554510 TI - Cosmic-ray interaction data for designing biological experiments in space. AB - There is growing interest in flying biological experiments beyond low-Earth orbit (LEO) to measure biological responses potentially relevant to those expected during a human mission to Mars. Such experiments could be payloads onboard precursor missions, including unmanned private-public partnerships, as well as small low-cost spacecraft (satellites) designed specifically for biosentinel-type missions. It is the purpose of this paper to provide physical cosmic-ray interaction data and related information useful to biologists who may be planning such experiments. It is not the objective here to actually design such experiments or provide radiobiological response functions, which would be specific for each experiment and biological endpoint. Nuclide-specific flux and dose rates were calculated using OLTARIS and these results were used to determine particle traversal rates and doses in hypothetical biological targets. Comparisons are provided between GCR in interplanetary space and inside the ISS. Calculated probabilistic estimates of dose from solar particle events are also presented. Although the focus here is on biological experiments, the information provided may be useful for designing other payloads as well if the space radiation environment is a factor to be considered. PMID- 28554511 TI - Induction of cardiac dysfunction in developing and adult zebrafish by chronic isoproterenol stimulation. AB - Zebrafish is a widely used model to evaluate genetic variants and modifiers that can cause heart muscle diseases. Surprisingly, the beta-adrenergic receptor (beta AR) pathway in zebrafish is not well characterized, although abnormal beta-AR signaling is a major contributor to human heart failure (HF). Chronic beta-AR activation in the attempt to normalize heart function in the failing heart results in a reduction of the beta-ARs expression and receptor desensitization, largely mediated through G-protein coupled receptor kinase 2 (GRK2) upregulation. This in turn leads to further deterioration of heart function and progression towards HF. This study seeks to systematically characterize the function of the beta-AR signaling in developing and adult zebrafish to ultimately assess the ability to induce HF through chronic beta-AR activation by isoproterenol (ISO) as established in the mouse model. Larval hearts first responded to ISO by 3dpf, in concordance with robust expression of key components of the beta-AR signaling pathway. Although ISO-induced beta1-AR and beta2-AR isoform upregulation persisted, chronic ISO stimulation for 5d caused systolic cardiac dysfunction concurrently with maximal expression of G-protein-coupled receptor kinase-2 (GRK2). More consistent to mammalians, adult zebrafish developed significant heart failure in concert with beta1-AR downregulation, and GRK2 and brain natriuretic peptide (BNP) upregulation in response to prolonged, 14d ISO stimulation. This was accompanied by significant cell death and inflammation without detectable fibrosis. Our study unveils important characteristics of larvae and adult zebrafish hearts pertaining to beta-AR signaling. A lack of beta AR responsiveness and atypical beta-AR/GRK2 ratios in larval zebrafish should be considered. Adult zebrafish resembled the mammalian situation on the functional and molecular level more closely, but also revealed differences to dysfunctional mammalian hearts, i.e. lack of fibrosis. Our study establishes the first ISO inducible HF model in adult zebrafish and present critical characteristics of the zebrafish heart essential to be considered when utilizing the zebrafish as a human disease and future drug discovery model. PMID- 28554512 TI - Functional atrial undersensing associated with device algorithm promoting AV conduction. AB - A 58-year-old woman received a dual chamber pacemaker (Medtronic) for sick sinus syndrome. Given intact AV conduction the Managed Ventricular Pacing mode algorithm (MVP) was programmed. The day after, she suffered from palpitations. Her ECG showed a possible loss of atrial capture accompanied by atrial undersensing. Telemetry-supported pacemaker control confirmed the loss of capture. Undersensing of atrial signal was functional, related to long atrial refractory period in MVP mode algorithm. Device algorithms could induce false suspicions. Awareness about the different pacing algorithms can be useful in order to avoid erroneous interpretations and to correct potential malfunctioning. PMID- 28554513 TI - Right ventricular apical versus non-apical implantable cardioverter defibrillator lead: A systematic review and meta-analysis. AB - INTRODUCTION: We aimed to study the effect of right ventricular implantable cardioverter defibrillator (ICD) lead positioning on clinical outcomes in patients undergoing ICD placement. METHODS: A systematic literature search was performed using PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials to identify clinical trials comparing outcomes in patients with ICD leads in apical and non-apical positions. The primary outcome of our study was death at 1-year follow-up. Secondary outcomes studied were "death at 3years", "total number of shocks", "appropriate shocks", "inappropriate shocks" and "cut to-suture time". RESULTS: We analyzed a total of 3731 patients (2852 in apical and 879 in non-apical ICD groups) enrolled in 4 clinical trials. No significant difference was observed between the apical and non-apical ICD groups in all-cause mortality at 1year (OR 0.88; 95% CI 0.51-1.49, p=0.63; I2=5.32%). Similarly, no differences were seen between the two groups in death at 3years (OR=0.76; 95% CI 0.56-1.04, p=0.08; I2=0%), total number of shocks (OR 0.99; 95% CI 0.81-1.22, p=0.95; I2=0%), appropriate shocks (OR 1.00; 95% CI 0.79-1.27, p=0.99; I2=0%), inappropriate shocks (OR 0.98; 95% CI 0.70-1.37, p=0.91; I2=0%) and cut-to-suture time (Standard mean difference=-0.03; 95% CI -0.20 to 0.14, p=0.73; I2=0%). No publication bias was seen. CONCLUSION: Non-apical RV ICD lead implantation is non inferior to traditional RV apical position with no significant differences in mortality, total number of shocks, appropriate shocks, inappropriate shocks and procedural time. PMID- 28554514 TI - Remodeling of ventricular repolarization in experimental right ventricular hypertrophy. AB - BACKGROUND: To understand electrophysiological mechanisms that underlie the progression of compensated right ventricular hypertrophy (RVH) to heart failure, the purpose of the study was to evaluate remodeling of ventricular repolarization in connection with hemodynamic abnormalities and vulnerability of the heart ventricles to arrhythmias in RVH rats with pulmonary arterial hypertension (PAH) and heart failure. METHODS: PAH followed by heart failure was induced by monocrotaline in adult female Wistar rats. Unipolar epicardial electrograms and cardiac hemodynamic parameters were recorded in situ. Vulnerability to ventricular arrhythmias was measured as the threshold dose of aconitine required to produce sustained ventricular tachycardia. Histological examination of the heart ventricles was performed. Activation-recovery intervals (ARIs) and ARI dispersions were used as indices of durations and heterogeneity of repolarization respectively to assess ventricular repolarization. RESULTS AND CONCLUSIONS: The development of compensated RVH was characterized by the dramatic prolongation of repolarization against the less expressed increase in repolarization heterogeneity, whereas the dramatic increase in repolarization heterogeneity against the less expressed but inhomogeneous prolongation of repolarization occurred in the progression of compensated RVH to heart failure. These changes increased vulnerability of the failing heart but not the compensated heart to aconitine-induced ventricular arrhythmias. PMID- 28554515 TI - Catheter ablation of epicardial ventricular tachycardia from the coronary venous system: Is endocardial mapping always required? AB - Endocardial mapping is typically considered as the first step of VT ablation procedures. Nevertheless, when the electrocardiogram is highly suggestive of an epicardial VT, a minimally invasive procedure performed exclusively via the coronary sinus might be considered. This straightforward approach avoids all potential complications associated with access to the left ventricular endocardium, the aortic root, and the pericardial space. PMID- 28554516 TI - Re: Turini et al.: The State of Prescreening Discussions About Prostate-specific Antigen Testing Following Implementation of the 2012 United States Preventive Services Task Force Statement (Urology 2017;104:122-130). PMID- 28554518 TI - Reply by the Author. PMID- 28554517 TI - Factors Associated With Erectile Dysfunction and the Peyronie's Disease Questionnaire in Patients With Peyronie Disease. AB - OBJECTIVE: To elucidate patient characteristics that impact symptom-related bother and erectile function in patients with Peyronie disease (PD). METHODS: A post hoc analysis used data from patients with PD (ie, had PD symptoms >=12 months and penile curvature deformity of 30-90 degrees) who received >=1 injection of study medication in 2 phase 3 trials of collagenase clostridium histolyticum (Investigation for Maximal Peyronie's Reduction Efficacy and Safety Study I [n = 417] and Investigation for Maximal Peyronie's Reduction Efficacy and Safety Study II [n = 415]). The Covariance Analysis of Linear Structural Equations procedure was used to estimate the potential relationship of specified variables on the level of distress and erectile dysfunction associated with PD as measured by the Peyronie's Disease Questionnaire and the International Index of Erectile Function, erectile function domain. RESULTS: Pain during intercourse (P = .02) and PD bother (P <.0001) had a significant impact on International Index of Erectile Function, erectile function scores. The Peyronie's Disease Questionnaire bother domain score was significantly affected by penile curvature deformity, penile shortening, pain during intercourse, and the presence of plaques (P <=.0005 for all), with pain during intercourse having the greatest impact (maximum likelihood estimation +/- standard error = .496 +/- .030; P <.0001). Erectile function did not appear to be directly influenced by the presence of plaques, penile curvature deformity, or penile shortening but was associated with PD bother and penile pain. CONCLUSION: This post hoc analysis provides a conceptual framework through which disease characteristics may impact PD-related bother and erectile function in patients with PD. PMID- 28554519 TI - P.L.E.A.T.-Preventing Lymphocele Ensuring Absorption Transperitoneally: A Robotic Technique. AB - OBJECTIVE: To reduce the risk of symptomatic lymphocele after robotic pelvic lymph node dissection (PLND), we present a technique, preventing lymphocele ensuring absorption transperitoneally (P.L.E.A.T.), where the peritoneum is "pleated" along its midline, leaving 2 lateral openings and allowing lymphatic fluid to drain away from the pelvis and into the abdomen. MATERIALS AND METHODS: We analyzed a single-surgeon series of PLNDs during robotic radical prostatectomy, comparing 195 "standard" PLNDs (in which the peritoneum was "re approximated" or left completely open) with 176 cases in which P.L.E.A.T. was performed. RESULTS: In the group without P.L.E.A.T., 8 cases of symptomatic (grade >=3, according to the Clavien-Dindo Classification) lymphoceles (4.1%) were recorded. Only 1 patient in the P.L.E.A.T. group complained of symptoms because of a lymphocele (P = .039). No patient reported complications because of the procedure. CONCLUSION: The P.L.E.A.T. technique is a fast, easy-to-perform, and safe method of reducing the risk of symptomatic lymphocele after transperitoneal robotic PLND. PMID- 28554520 TI - Memokath Stent Failure in Recurrent Bulbar Urethral Strictures: Results From an Investigative Pilot Stage 2A Study. AB - OBJECTIVE: To evaluate the efficacy of the Memokath stent in managing recurrent bulbar urethral strictures. MATERIALS AND METHODS: This is an investigative pilot stage 2A study in patients with a recurrent bulbar urethral stricture who underwent a Memokath stent implant from January 2014 to January 2016 in a single high-volume center for urethral reconstruction. The Memokath stent (Pnn Medical A/S, Kvistgaard, Denmark) was manufactured from nitinol, a biocompatible alloy of nickel and titanium, which was endoscopically placed. It had a 24-Fr outside diameter and was preloaded on a disposable delivery device. When correctly positioned, the stent was anchored by a warm water (55 degrees C) instillation, which expanded the proximal end of the stent from 24 to 42 Fr .The stent was provided in lengths of 3-7 cm in 1-cm increments. RESULTS: Sixteen patients were included in the study. The median follow-up was 16 months. In 7 patients (43.7%), the stent was removed within 1 year. The main adverse events were pain, encrustations, stones, and recurrent strictures. Four patients (25%) were considered a success and 12 (75%) were failures. Study limitations include the small sample. CONCLUSION: The Memokath stent was deemed to be not clinically helpful and had significant side effects, and therefore should not be considered a treatment option for men with bulbar urethral strictures. PMID- 28554521 TI - Metabolic construction strategies for direct methanol utilization in Saccharomyces cerevisiae. AB - The aim of this study was to metabolically construct Saccharomyces cerevisiae for achievement of direct methanol utilization and value added product (mainly pyruvate) production. After successful integration of methanol oxidation pathway originated from Pichia pastoris into the chromosome of S. cerevisiae, the recombinant showed 1.04g/L consumption of methanol and 3.13% increase of cell growth (OD600) when using methanol as the sole carbon source. Moreover, 0.26g/L of pyruvate was detected in the fermentation broth. The supplementation of 1g/L yeast extract could further improve cell growth with increase of 11.70% and methanol consumption to 2.35g/L. This represents the first genetically modified non-methylotrophic eukaryotic microbe for direct methanol utilization and would be of great value concerning the development of biotechnological processes. PMID- 28554522 TI - Engineering aspects of microbial exopolysaccharide production. AB - Although the ability to secrete exopolysaccharides (EPS) is widespread among microorganisms, only a few bacterial (e.g. xanthan, levan, dextran) and fungal (e.g. pullulan) EPS have reached full commercialization. During the last years, other microbial EPS producers have been the subject of extensive research, including endophytes, extremophiles, microalgae and Cyanobacteria, as well as mixed microbial consortia. Those studies have demonstrated the great potential of such microbial systems to generate biopolymers with novel chemical structures and distinctive functional properties. In this work, an overview of the bioprocesses developed for EPS production by the wide diversity of reported microbial producers is presented, including their development and scale-up. Bottlenecks that currently hinder microbial EPS development are identified, along with future prospects for further advancement. PMID- 28554523 TI - Improved ethanol production at high temperature by consolidated bioprocessing using Saccharomyces cerevisiae strain engineered with artificial zinc finger protein. AB - In this work, the consolidated bioprocessing (CBP) yeast Saccharomyces cerevisiae MNII/cocdeltaBEC3 was transformed by an artificial zinc finger protein (AZFP) library to improve its thermal tolerance, and the strain MNII-AZFP with superior growth at 42 degrees C was selected. Improved degradation of acid swollen cellulose by 45.9% led to an increase in ethanol production, when compared to the control strain. Moreover, the fermentation of Jerusalem artichoke stalk (JAS) by MNII-AZFP was shortened by 12h at 42 degrees C with a concomitant improvement in ethanol production. Comparative transcriptomics analysis suggested that the AZFP in the mutant exerted beneficial effect by modulating the expression of multiple functional genes. These results provide a feasible strategy for efficient ethanol production from JAS and other cellulosic biomass through CBP based-fermentation at elevated temperatures. PMID- 28554524 TI - Depression, Self-Esteem, and Childhood Abuse Among Hispanic Men Residing in the U.S.-Mexico Border Region. AB - Hispanics experience health disparities in mental health and HIV infection when compared to non-Hispanic Whites, which may be related to childhood abuse. The purpose of our cross-sectional study was to examine the relationship between childhood abuse and depressive symptoms in a sample of Hispanic men (N = 103) living in a metropolitan U.S.-Mexico border area. Secondarily, we examined the role of self-esteem in mediating this relationship, and the moderating role of sexual orientation. Gay/bisexual men (n = 53) were more likely to report childhood abuse than heterosexual (n = 50) counterparts (47.2% vs. 32%). Self esteem mediated the relationship between childhood abuse and depression for men who have sex with men, but not heterosexual men. Nurses should increase knowledge of mental health disparities that impact Hispanic men to ensure that appropriate treatment can be provided to reduce the risk of co-occurring health risks to these men, including risk for HIV infection. PMID- 28554525 TI - Coupling between chromosome intermingling and gene regulation during cellular differentiation. AB - In this article, we summarize current findings for the emergence of biophysical properties such as nuclear stiffness, chromatin compaction, chromosome positioning, and chromosome intermingling during stem cell differentiation, which eventually correlated with the changes of gene expression profiles during cellular differentiation. An overview is first provided to link stem cell differentiation with alterations in nuclear architecture, chromatin compaction, along with nuclear and chromatin dynamics. Further, we highlight the recent biophysical and molecular approaches, imaging methods and computational developments in characterizing transcription-related chromosome organization especially chromosome intermingling and nano-scale chromosomal contacts. Finally, the article ends with an outlook towards the emergence of a functional roadmap in setting up chromosome positioning and intermingling in a cell type specific manner during cellular differentiation. PMID- 28554526 TI - Quantitative SYBR Green qPCR technique for the detection of the nematode parasite Anisakis in commercial fish-derived food. AB - The extensive presence of anisakids in fish for human consumption has become a problem of food safety and quality. The aim of this study was to develop and assess the performance of a quantitative SYBR Green qPCR assay for the detection and quantification of Anisakis DNA in fish by-products. L3 nematode larvae of A. simplex (s.l.) (n=510), A. physeteris (n=3), Hysterothylacium sp. (n=10) and Pseudoterranova sp. (n=1), isolated from blue whiting, horse mackerel and monkfish, were used for the optimization of the molecular assay. In addition, molecularly typed larvae of A. simplex (s.s.) (n=10) and A. pegreffii (n=5) of the complex A. simplex (s.l.) were used for the specificity assay. Primers targeting the mitochondrial cytochrome c oxidase subunit II gene (COII) were selected. Analytical sensitivity and reproducibility were evaluated in a food matrix consisting of commercial fish-derived food spiked with larvae of A. simplex (s.l.). The assay proved to be specific for the three analyzed Anisakis species. A high reproducibility and sensitivity was detected, with a 95% limit of detection (LOD) of 0.30ng (95%CI 0.15-1.50) of A. simplex (s.l.) DNA per gram of food matrix and an operative LOD of 1.50ng after a PROBIT analysis. The assay was applied to study the presence of Anisakis in four types of processed commercial food, namely crab sticks, "gulas", croquettes and burgers. Overall, 180 food samples from 15 commercial brands were studied, detecting Anisakis DNA in over half of them. The analyzed surimi-based products, "gulas" and crab sticks, showed the highest Anisakis burden (5.86+/-0.69 and 4.68+/-0.73ng of Anisakis DNA per gram of food, respectively). Our results indicate that the optimized SYBR Green qPCR technique is an accurate and sensitive method that may improve detection of Anisakis in fresh and processed products. PMID- 28554527 TI - Electroencephalographic alpha activity modulations induced by breath-holding in apnoea divers and non-divers. AB - Little is known regarding cortical responses to sustained breath-holding (BH) in expert apnoea divers. The present study therefore investigated electroencephalographic (EEG) alpha activity and asymmetries in apnoea divers (experts) compared to non-divers (novices). EEG of 10 apnoea and 10 non-divers were recorded in the laboratory for either four minutes or for two minutes of BH. Alpha activity and alpha asymmetry (i.e. hemispherical EEG differences) were calculated and compared between expertise level and BH duration. Alpha amplitude in experts significantly decreased at four minutes of BH compared to resting activity, while alpha amplitude significantly decreased in novices only at centro parietal regions. Alpha-asymmetry analysis revealed that the experts' decrease in alpha at the end of BH was different in the frontal electrodes with the left prefrontal cortex activity higher than that in the right prefrontal cortex. This lateralized pattern reflected differential prefrontal processing of the unique psycho-physiological state of BH. PMID- 28554528 TI - Lobeline attenuates ethanol abstinence-induced depression-like behavior in mice. AB - Evidence indicates that the brain nicotinic acetylcholine receptor (nAChRs) ligand lobeline reduces depression-like behaviors, ethanol drinking, and nicotine withdrawal-induced depression-like behaviors. The purpose of the present study was to determine the effects of lobeline on ethanol abstinence-induced depression like behavior and associated neuroadaptive changes in mice. Adult C57BL/6J male mice were allowed to drink 10% ethanol for 4 weeks using a two-bottle choice procedure. Mice were tested after 24 h and 14 days of ethanol abstinence in a forced swim test (FST), a measure for depression-like behavior. Acute lobeline treatment (1 mg/kg) significantly reduced immobility time compared to controls after 24 h and 14 days of abstinence. In addition, abstinence from chronic ethanol exposure reduced serotonin levels in the hippocampus, which was reversed by acute lobeline treatment. Repeated lobeline treatment (1 mg/kg, once daily) for 14 days during ethanol abstinence also significantly reduced FST immobility in mice exposed to ethanol. Chronic ethanol exposure significantly reduced the number of 5-bromo 2'-deoxyuridine (BrdU)-positive cells in the dentate gyrus of the hippocampus, indicating decreased hippocampal cell proliferation. Abstinence from chronic ethanol exposure also decreased brain-derived neurotrophic factor (BDNF) in the dentate gyrus and CA3 region of the hippocampus. In contrast, repeated lobeline treatment significantly increased both BrdU- and BDNF-positive cells. Taken together, our results indicate that lobeline produced antidepressant like effects, likely by targeting brain beta2-containing nAChRs, serotonergic neurotransmission, and/or hippocampal cell proliferation. Therefore, lobeline may have therapeutic utility to treat alcohol abstinence-induced depression. PMID- 28554530 TI - Electrical Muscle Stimulation Induces an Increase of VEGFR2 on Circulating Hematopoietic Stem Cells in Patients With Diabetes. AB - PURPOSE: External electric muscle stimulation (EMS) of the thigh muscles was found to reduce pain resulting from diabetic neuropathy (DN), a vascular complication of diabetes. This study investigated circulating hematopoietic stem cells (HSCs) after EMS treatment. Impaired function of HSCs and the subpopulation endothelial progenitor cells (EPCs), important for neovascularization and endothelial repair, has been associated with DN. METHODS: Twenty-four patients with painful DN were treated 3 times with EMS over a period of 1 week. Blood samples were collected before and after the first EMS treatment. Before a fourth treatment, neuropathic pain was evaluated and a third blood sample was collected. Cells were used for flow cytometry. FINDINGS: Patients with painful DN reported that the pain decreased after 3 times of 1-hour treatments with EMS (Neuropathy Symptom Score: from 8 to 6, P = 0.001; Neuropathy Disability Score: from 5.5 to 5, P = 0.027, n = 24). At the end of the study, diastolic blood pressure had decreased from 80 to 70 mm Hg (P = 0.043), and plasma adrenaline and noradrenaline metabolites metanephrine and normetanephrine were reduced (both P <= 0.01; n = 21). A single EMS treatment caused an immediate and transient decrease in the frequency of CD34+ HSCs in circulation (-20%; P < 0.001; n = 27). In 9 of the patients with DN, the proportion of HSCs expressing vascular endothelial growth factor receptor 2 (VEGFR2; defining the HSCs as EPCs) increased by 36% (P = 0.011) after EMS treatment. Proteins required for binding to endothelium (junctional adhesion molecule A and CD31), homing toward hypoxic tissue (C-X-C chemokine receptor type 4), and endothelial differentiation (CD31) were increased on HSCs immediately after EMS treatment. An increased frequency of VEGFR2 expression was also observed on HSCs of 6 healthy control volunteers (34%; P = 0.046) after EMS treatment, but not after sham treatment. IMPLICATIONS: Three EMS treatments decreased symptoms of pain caused by DN and reduced diastolic blood pressure and biomarkers of stress. A single EMS treatment increased molecules mediating attachment and differentiation on the surface of HSCs in circulation. We hypothesize that the EMS-induced increase in surface attachment molecules on the HSCs caused the HSCs to leave circulation and that EMS treatment improves the function of HSCs and EPCs in vivo. PMID- 28554531 TI - Some Reflections on Neuropathies. PMID- 28554529 TI - Maternal alcohol exposure during mid-pregnancy dilates fetal cerebral arteries via endocannabinoid receptors. AB - Prenatal alcohol exposure often results in fetal alcohol syndrome and fetal alcohol spectrum disorders. Mechanisms of fetal brain damage by alcohol remain unclear. We used baboons (Papio spp.) to study alcohol-driven changes in the fetal cerebral artery endocannabinoid system. Pregnant baboons were subjected to binge alcohol exposure via gastric infusion three times during a period equivalent to the second trimester of human pregnancy. A control group was infused with orange-flavored drink that was isocaloric to the alcohol-containing solution. Cesarean sections were performed at a time equivalent to the end of the second trimester of human pregnancy. Fetal cerebral arteries were harvested and subjected to in vitro pressurization followed by pharmacological profiling. During each alcohol-infusion episode, maternal blood alcohol concentrations (BAC) reached 80 mg/dL, that is, equivalent to the BAC considered legal intoxication in humans. Circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) remained unchanged. Ultrasound studies on pregnant mothers revealed that fetal alcohol exposure decreased peak systolic blood velocity in middle cerebral arteries when compared to pre-alcohol levels. Moreover, ethanol-induced dilation was observed in fetal cerebral arteries pressurized in vitro. This dilation was abolished by the mixture of AM251 and AM630, which block cannabinoid receptors 1 and 2, respectively. In the presence of AM251, the cannabinoid receptor agonist AEA evoked a higher, concentration-dependent dilation of cerebral arteries from alcohol-exposed fetuses. The difference in AEA-induced cerebral artery dilation vanished in the presence of AM630. CB1 and CB2 receptor mRNA and protein levels were similar in cerebral arteries from alcohol-exposed and control-exposed fetuses. In summary, alcohol exposure dilates fetal cerebral arteries via endocannabinoid receptors and results in an increased function of CB2. PMID- 28554532 TI - Efficacy of Venlafaxine in Neuropathic Pain: A Narrative Review of Optimized Treatment. AB - PURPOSE: The prevalence of neuropathic pain is high in the general population, and high priority is given to the management of this pain condition. The treatment of neuropathic pain remains challenging, despite the publication of national and international recommendations. The purpose of this narrative review of venlafaxine (VLX) is to provide a better knowledge of the pharmacology of this drug and a clearer view of its efficacy and tolerability in neuropathic pain. METHODS: Two independent reviewers searched PubMed with the following search terms: serotonin and noradrenalin reuptake inhibitors OR VLX hydrochloride AND pain. The reviewers included all clinical studies that investigated VLX in neuropathic pain conditions and excluded animal studies, studies on fibromyalgia, studies that focused on the prevention of neuropathic pain, case reports, and studies that did not clearly describe neuropathic pain in the included patients. We describe the 13 studies that we analyzed. FINDINGS: Eleven were randomized clinical trials, and the comparator was placebo in 8 studies. Nine studies reported that VLX was effective against neuropathic pain. However, among the trials, only one against placebo included a large number of patients with >200 participants and one against pregabaline and carbamazepine had >200 patients. Most of the adverse events reported in the selected studies were consistent with known adverse events of VLX, and most were mild to moderate. However, most studies were of very short duration. IMPLICATIONS: Most of the clinical studies found that VLX was effective and well tolerated. However, given the limited number of study and the limitations of all these studies, further large clinical trials are needed. Currently, considering the limited therapeutic options for treating neuropathic pain and the highly variable nature of responses to all drugs, VLX has a place as a treatment option for neuropathic pain. PMID- 28554533 TI - Therapeutic Use of Filgrastim for Established Febrile Neutropenia Is Cost Effective Among Patients With Solid Tumors and Lymphomas. AB - PURPOSE: With the emergence of biosimilar filgrastim to the market, there is a gradual decrease in the listed price of the originator product of filgrastim over the years, and this could have an impact on the cost-effectiveness of filgrastim in the treatment of febrile neutropenia (FN). A cost-effectiveness analysis would allow clinicians to make informed decision when considering the therapeutic filgrastim among low-risk FN patients. This study aims to evaluate the cost effectiveness of adding therapeutic filgrastim to antibiotics in the treatment of established FN among patients with solid tumors and lymphomas. METHODS: A decision tree model was created to compare two treatment options for established FN as follows: (1) antibiotics alone (standard care) and (2) antibiotics with therapeutic filgrastim (comparator). The target population was a hypothetical cohort of adult cancer patients with solid tumors or lymphomas hospitalized with FN in Singapore. The analysis was performed from a hospital's perspective over a 21-day time horizon. The main outcome measures included costs, quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER). One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to evaluate the robustness of the results. FINDINGS: Compared with antibiotics alone, the treatment strategy of antibiotics with therapeutic filgrastim was a dominant choice, incurring a cost saving of US$125 per patient (comparator versus standard care: US$9110 versus US$9235) and additional health benefit of 0.0007 QALY gained per patient (comparator versus standard care: 0.0450 versus 0.0443). Model results were robust against the parameter variations in the one-way sensitivity analyses, but increasing the cost of filgrastim beyond US$87 per injection would increase the ICER to >US$50,000/QALY. Furthermore, the strategy of antibiotics with therapeutic filgrastim was the preferred choice (dominant or cost-effective) in 83.7% of the model iterations at a willingness-to-pay threshold of US$50,000/QALY. IMPLICATIONS: From a hospital's perspective, the therapeutic filgrastim, in conjunction with antibiotics, in the treatment of FN is cost effective. This provides evidence to support the routine use of filgrastim for the treatment of FN among adult cancer patients with solid tumors and lymphomas. PMID- 28554534 TI - Ophthalmic Manifestations of Xeroderma Pigmentosum: A Perspective from the United Kingdom. AB - PURPOSE: To document the ocular manifestations of xeroderma pigmentosum (XP), presenting via the United Kingdom (UK) XP service, and to analyze the correlations between XP genotype and ophthalmic phenotype. DESIGN: Prospective observational case series. SUBJECTS: Eighty-nine patients seen by the UK Nationally Commissioned XP Service, from April 2010 to December 2014, with a genetically confirmed diagnosis of XP. METHODS: Patients underwent a full ophthalmic examination at each visit. Clinical features from both eyes were recorded on a standard proforma. The most recent assessments were analyzed. A 2 tailed Fisher exact test was used to assess for differences in ocular features between patients in XP subgroups with impaired transcription coupled nucleotide excision repair (TC-NER) (category 1: XP-A, B, D, F, and G) and preserved TC-NER (category 2: XP-C, E, and V). MAIN OUTCOME MEASURES: Lid and periocular abnormalities, ocular surface pathologies, neuro-ophthalmologic abnormalities, lens and retinal abnormalities, and visual acuity (VA). RESULTS: Ninety-three percent of XP patients in our cohort had ocular involvement, with 65% describing photophobia. The most common abnormalities were in the periocular skin and ocular surface, including interpalpebral conjunctival melanosis (44%) and conjunctival injection (43%). Eleven percent of patients had required treatment for periocular cancers and 2% for ocular surface cancers. The most common neuro-ophthalmologic finding was minimal pupillary reaction to light (25%). Patients in category 2 had significantly more ocular surface abnormalities than patients in category 1, including a greater proportion of conjunctival injection (P = 0.003), conjunctival corkscrew vessels (P < 0.001), corneal scarring (P = 0.01) and pingueculae under the age of 50 (P = 0.02). Meanwhile, patients in category 1 had a higher proportion of poorly reactive pupils (P < 0.001) and abnormal ocular movements (P = 0.03) compared with those in category 2. Five patients (6%) presented to ophthalmologists with ocular surface signs related to XP, before any formal diagnosis of XP was made. CONCLUSIONS: A large proportion of XP patients have ocular involvement. Regular examination by an ophthalmologist is essential, especially in screening for eyelid and ocular surface tumors. The ocular phenotype-genotype segregation within XP patients suggests that XP is a heterogeneous and complex disease. With further study, we hope to offer these patients more individualized patient care. PMID- 28554535 TI - A phosphorylation-motif for tuneable helix stabilisation in intrinsically disordered proteins - Lessons from the sodium proton exchanger 1 (NHE1). AB - Intrinsically disordered proteins (IDPs) are involved in many pivotal cellular processes including phosphorylation and signalling. The structural and functional effects of phosphorylation of IDPs remain poorly understood and difficult to predict. Thus, a need exists to identify motifs that confer phosphorylation dependent perturbation of the local preferences for forming e.g. helical structures as well as motifs that do not. The disordered distal tail of the Na+/H+ exchanger 1 (NHE1) is six-times phosphorylated (S693, S723, S726, S771, T779, S785) by the mitogen activated protein kinase 2 (MAPK1, ERK2). Using NMR spectroscopy, we found that two out of those six phosphorylation sites had a stabilizing effect on transient helices. One of these was further investigated by circular dichroism and NMR spectroscopy as well as by molecular dynamic simulations, which confirmed the stabilizing effect and resulted in the identification of a short linear motif for helix stabilisation: [S/T]-P-{3}-[R/K] where [S/T] is the phosphorylation-site. By analysing IDP and phosphorylation site databases we found that the motif is significantly enriched around known phosphorylation sites, supporting a potential wider-spread role in phosphorylation-mediated regulation of intrinsically disordered proteins. The identification of such motifs is important for understanding the molecular mechanism of cellular signalling, and is crucial for the development of predictors for the structural effect of phosphorylation; a tool of relevance for understanding disease-promoting mutations that for example interfere with signalling for instance through constitutive active and often cancer-promoting signalling. PMID- 28554536 TI - Succinate, increased in metabolic syndrome, activates GPR91 receptor signaling in urothelial cells. AB - Metabolic syndrome is associated with overactive bladder syndrome (OAB) and increased circulating levels of succinate, an intermediate of the Krebs cycle. The urothelium is an essential regulator of bladder muscle contraction. This study aimed to determine if GPR91, the succinate receptor, is expressed and functional in the bladder. Urothelial and smooth muscle cells (SMCs) were cultured and characterized. PCR revealed that urothelial cells express GPR91, twice as much as SMCs. Incubation of cells with succinate stimulated phosphorylation of ERK and JNK in urothelial cells. Succinate also potently inhibited forskolin-stimulated cyclic AMP production in urothelial cells, an effect prevented by a protein Gi inhibitor. ERK phosphorylation stimulated by succinate was abolished by inhibitors of protein Gq, phospholipase C, MAPK pathway and PKC. Incubation of urothelial cells with succinate potently increased iNOS synthesis and secretion of nitric oxide (NO), and decreased secretion of prostaglandin E2 (PGE2). Finally, succinate triggered entry of calcium in urothelial cells. GPR91 knockdown by shRNA abolished most of these signaling effects. We conclude that in the bladder, urothelial cells are a primary target of succinate through its receptor GPR91. Its activation leads to signaling via phospholipase C, MAPK, PKC pathway and protein Gq and Gi. Succinate binding to GPR91 triggers a rise in intracellular calcium, an increase in secretion of NO and a decrease in the release of PGE2. Succinate might be essential in the understanding of OAB that occurs in metabolic syndrome. PMID- 28554537 TI - Survival rate of autotransplanted teeth after 5 years - A retrospective cohort study. AB - BACKGROUND: Autotransplantation of teeth (TX) is a predictable treatment option, although this type of therapy is often overlooked compared to other types of restorations. PURPOSE: As current literature contains few long-term studies concerning the outcome of autotransplanted immature molars, the aim was to evaluate results after a follow-up period of 5 years. MATERIAL AND METHODS: This retrospective study enrolled all patients treated with immature autotransplanted molars after a follow-up period of 5 years. In order to ensure comparable results, survival rate was investigated as well as clinical and radiological parameters. Contralateral teeth (TC) were used as controls for further assessments and for ensuring comparable future results. RESULTS: 52 patients with 66 TX were examined. Mean age at the time of surgery was 19.64 years. Tooth survival rate after 5 years was 89.39%. The results for parameters such as PPD, BOP, mobility, dental caries, periapical pathologies and endodontic treatments showed no differences. In contrast, dental restorations (p < 0.001), occlusal contacts (p = 0.003) and sensitivity (p < 0.001) differed significantly between TX and TC. CONCLUSIONS: The current findings clearly confirm that TX is an effective alternative treatment option to fixed prosthodontic restorations and dental implants, and provides for results equivalent to those with the patients' natural teeth. PMID- 28554538 TI - Editorial Comment: Schizoaffective Disorder in Later Life: "Beware the Jabberwock". PMID- 28554539 TI - Challenging Assumptions About African American Participation in Alzheimer Disease Trials. AB - OBJECTIVE: The authors investigated potential effects of increased African American participation in Alzheimer disease (AD) and mild cognitive impairment (MCI) clinical trials by examining differences in comorbid conditions and treatment outcome affecting trial design. METHODS: Using a meta-database of 18 studies from the Alzheimer's Disease Cooperative Study and the Alzheimer's Disease Neuroimaging Initiative, a cohort of 5,164 subjects were included for whom there were baseline demographic data and information on comorbid disorders, grouped by organ system. Meta-analysis was used to compare prevalence of comorbidities, dropouts, and rates of change on the cognitive subscale of the Alzheimer's Disease Assessment Scale by race. Clinical trial scenarios similar to recent therapeutic trials were simulated to determine effects of increased African American participation on statistical power. RESULTS: Approximately 7% of AD, 4% of MCI, and 11% of normal participants were African American. African American subjects had higher prevalence of cardiovascular disorders (odds ratio: 2.10; 95% confidence interval [CI]: 1.71-2.57) and higher rate of dropouts (odds ratio: 1.60; 95% CI: 1.15-2.21) compared with whites but lower rates of other disorders. There were no significant differences in rate of progression (-0.862 points/year; 95% CI: -1.89 to 0.162) by race and little effect on power in simulated trials with sample sizes similar to current AD trial designs. CONCLUSION: Increasing African American participation in AD clinical trials will require adaptation of trial protocols to address comorbidities and dropouts. However, increased diversity is unlikely to negatively affect trial outcomes and should be encouraged to promote generalizability of trial results. PMID- 28554540 TI - In Vivo Multiparametric Ultrasound Imaging of Structural and Functional Tumor Modifications during Therapy. AB - Longitudinal imaging techniques are needed that can meaningfully probe the tumor microenvironment and its spatial heterogeneity. Contrast-enhanced ultrasound, shear wave elastography and quantitative ultrasound are ultrasound-based techniques that provide information on the vascular function and micro /macroscopic tissue structure. Modifications of the tumor microenvironment induced by cytotoxic and anti-angiogenic molecules in ectopic murine Lewis lung carcinoma tumors were monitored. The most heterogenous structures were found in tumors treated with anti-angiogenic drug that simultaneously accumulated the highest levels of necrosis and fibrosis. The anti-angiogenic group presented the highest number of correlations between parameters related to vascular function and those related to the micro-/macrostructure of the tumor microenvironment. Results suggest how patterns of multiparametric ultrasound modifications can be related to provide a more insightful marker of changes occurring within tumors during therapy. PMID- 28554541 TI - Sensitive albuminuria analysis using dye-binding based test strips. AB - BACKGROUND: Populations at increased risk for chronic kidney disease should be screened for albuminuria. Possibilities of advanced urine strip readers based on complementary metal oxide semiconductor (CMOS) sensor technology were investigated for obtaining quantitative albuminuria results. METHODS: Reflectance data of test strips (Sysmex UFC 3500 reader+CMOS) were compared with albuminuria (BNII) and with proteinuria (Cobas 8000). Urinary creatinine was assayed using a Jaffe-based creatinine assay (Cobas 8000). RESULTS: Calibration curve was made between 11.5 and 121.5mg/L with detection limit of 5.5mg/L. Within-run CV values of reflectance data were 0.21% (UC-Control L; 10mg/L) and 0.37% (UC-Control H; >150mg/L) for albumin, and 0.71%/3.97% for creatinine. Between-run CV values were 0.24%/0.42% for albumin and 0.93%/5.13% for creatinine. A strong correlation (r=0.92) was obtained between albuminuria (BNII) and protein strip reflectance data. Creatinine reflectance data correlated well with Jaffe-based urinary creatinine data (r=0.90). Albumin:creatinine ratio obtained by test strip and by wet chemistry showed a good correlation (r=0.59). Carbamylated, glycated and partially hydrolyzed isoforms of albumin could be detected by test strip. CONCLUSIONS: Dye-binding based albumin test strip assay in combination with a CMOS based reader would potentially allow quantitative analysis of albuminuria and determination of albumin:creatinine ratio. PMID- 28554542 TI - Electron current recordings in living cells. AB - Living cells exploit the electrical properties of matter for a multitude of fundamental physiological processes, such as accumulation of nutrients, cellular homeostasis, signal transmission. While ion channels and transporters (able to couple ions to various substrates) have been extensively studied, direct measurements of electron currents mediated by specific proteins are just at the beginning. Here, we present the various electrophysiological approaches that have allowed recordings of electron currents and highlight the future potential of such experiments. PMID- 28554543 TI - A method for the isolation and characterization of functional murine monoclonal antibodies by single B cell cloning. AB - Monoclonal antibody technologies have enabled dramatic advances in immunology, the study of infectious disease, and modern medicine over the past 40years. However, many monoclonal antibody discovery procedures are labor- and time intensive, low efficiency, and expensive. Here we describe an optimized mAb discovery platform for the rapid and efficient isolation, cloning and characterization of monoclonal antibodies in murine systems. In this platform, antigen-binding splenic B cells from immunized mice are isolated by FACS and cocultured with CD40L positive cells to induce proliferation and mAb production. After 12days of coculture, cell culture supernatants are screened for antigen, and IgG positivity and RNA is isolated for reverse-transcription. Positive-well cDNA is then amplified by PCR and the resulting amplicons can be cloned into ligation-independent expression vectors, which are then used directly to transfect HEK293 cells for recombinant antibody production. After 4days of growth, conditioned medium can be screened using biolayer interferometry for antigen binding and affinity measurements. Using this method, we were able to isolate six unique, functional monoclonal antibodies against an antigen of the human malaria parasite Plasmodium falciparum. Importantly, this method incorporates several important advances that circumvent the need for single-cell PCR, restriction cloning, and large scale protein production, and can be applied to a wide array of protein antigens. PMID- 28554545 TI - Cyclodextrin-mesoporous silica particle composites for controlled antibiotic release. A proof of concept toward colon targeting. AB - Cyclodextrins (CDs) and mesoporous silica particles (MSPs) have been combined as composite carriers for controlled antibiotic release. CDs were employed as "gatekeeper" agents and grafted onto MSPs to retain drug molecules inside the MSP carrier. A variety of CDs (unfunctionalized, positively charged and carboxymethylated) and three different coupling strategies (covalent binding, electrostatic adsorption and inclusion complexation) were systematically investigated for their ability to control the release of two antibiotic drugs, metronidazole and clofazimine. The drugs had significantly different physicochemical properties (metronidazole - small hydrophilic, clofazimine- large hydrophobic). We report for the first time on the encapsulation and characterization of metronidazole-loaded-MSP. Each CD coating strategy reduced the drug release rate in phosphate buffer compared to unmodified MSP (from 20% to 100% retained drug). Covalent binding and inclusion complex approaches were significantly more effective than electrostatically adsorbed CD. In particular, the novel inclusion complex based on host/guest interaction between benzyl modified silica surface and alpha-CD proved to be very effective (60-100% retained drug amount). Using pharmaceutical manufacturing processes, our study shows that CD-MSP composites can retain both hydrophobic and hydrophilic antibiotic compounds with potential translation to triggered release formulation targeting bacterial infections in the colon and lower intestine. PMID- 28554544 TI - Immuno-nephelometric determination of group streptococcal anti-streptolysin O titres (ASOT) from dried blood spots: Method for validating a new assay. AB - This study was designed to determine the sensitivity and reproducibility of recovering anti-streptolysin O titres (ASOT) from dried blood spot (DBS) samples, a methodologic subcomponent of the penicillin pharmacokinetic studies in children receiving secondary prophylaxis with intramuscular benzathine penicillin for acute rheumatic fever. PMID- 28554546 TI - Cyclodextrin-based metal-organic frameworks particles as efficient carriers for lansoprazole: Study of morphology and chemical composition of individual particles. AB - Cyclodextrin-based metal-organic frameworks (CD-MOFs) represent an environment friendly and biocompatible class of MOFs drawing increasing attention in drug delivery. Lansoprazole (LPZ) is a proton-pump inhibitor used to reduce the production of acid in the stomach and recently identified as an antitubercular prodrug. Herein, LPZ loaded CD-MOFs were successfully synthesized upon the assembly with gamma-CD in the presence of K+ ions using an optimized co crystallization method. They were characterized in terms of morphology, size and crystallinity, showing almost perfect cubic morphologies with monodispersed size distributions. The crystalline particles, loaded or not with LPZ, have mean diameters of around 6MUm. The payloads reached 23.2+/-2.1% (wt) which corresponds to a molar ratio of 1:1 between LPZ and gamma-CD. It was demonstrated that even after two years storage, the incorporated drug inside the CD-MOFs maintained its spectroscopic characteristics. Molecular modelling provided a deeper insight into the interaction between the LPZ and CD-MOFs. Raman spectra of individual particles were recorded, confirming the formation of inclusion complexes within the tridimensional CD-MOF structures. Of note, it was found that each individual particle had the same chemical composition. The LPZ-loaded particles had remarkable homogeneity in terms of both drug loading and size. These results pave the way towards the use of CD-MOFs for drug delivery purposes. PMID- 28554547 TI - The influence of cardiac triggering time and an optimization strategy for improved cardiac MR spectroscopy. AB - PURPOSE: To study how cardiac motion affects the spectral quality in cardiac MR spectroscopy and to establish an optimization strategy for the cardiac triggering time for improved quality and success rate of cardiac MRS. METHOD: Water spectra were acquired while the cardiac triggering time was varied over the cardiac cycle, and five different spectral quality parameters were studied (frequency, phase, linewidth, amplitude and noise). Furthermore, three different optimization strategies for the cardiac triggering time were tested, and finally, a comparison was made between water suppressed lipid spectra acquired in systole and diastole. RESULTS: The cardiac triggering time had a high impact on the spectral quality, especially on the mean signal amplitude and the standard deviation of the signal amplitude, phase and linewidth. Generally, the highest spectral quality was observed for spectra acquired in mid to end systole, at approximately 23% of the cardiac cycle. The exact optimal triggering time differed between subjects and needed to be individually optimized. To optimize the triggering time with our proposed MRS-method gave in average 13% higher signal than when the triggering time was determined through imaging. Lipid spectra acquired in systole demonstrated higher quality with improved SNR compared with acquisitions made in diastole. CONCLUSION: This study shows that the spectral quality in cardiac MRS is strongly dependent on the cardiac triggering time, and that the spectral quality as well as the repeatability between acquisitions is greatly improved when the cardiac triggering time is individually optimized in mid to end systole using MRS. PMID- 28554548 TI - Male-biased miR-92 from early chicken embryonic gonads directly targets ATRX and DDX3X. AB - MiR-17-92 cluster consists of multifunctional miRNAs related to gonadal development in mammals. Our preliminary data showed that gga-miR-92 was male biased in chicken embryonic gonads at E5.5 and E6.5. MiR-92(a-2) and two putative targets (ATRX and DDX3X) were highly conserved and located on mammalian Chromosome X but on autosomes in chicken. Here, we studied the expression and interaction of miR-92 and the targets (ATRX and DDX3X) in chicken embryonic gonads. What's more, male-biased miR-92 shows an opposite expression tendency with ATRX and DDX3X in eight embryonic stages and different tissues at E10.5 by qRT-PCR. To verify the regulation relationship between miR-92 and two targets, we performed dual-luciferase reporter assay in DF1, overexpression and inhibition of miR-92 in chicken embryonic fibroblasts (CEFs). The results show that miR-92 directly targets ATRX and DDX3X by binding the 3' un-translated region (3'-UTR), and the over-expression and inhibition of miR-92 negatively regulates ATRX and DDX3X. After the identification of the expression of their downstream genes (AMH and WNT4) in mRNA level, we found that there is no regulatory relationship between ATRX and DDX3X. The overall results indicate that miR-92 may perform roles in early chicken gonadogenesis by regulating the expressions of ATRX and DDX3X, respectively. PMID- 28554549 TI - Utility of DXA for monitoring, technical aspects of DXA BMD measurement and precision testing. AB - Monitoring a patient's bone mineral density (BMD) is one of the main reasons for dual-energy X-ray absorptiometry (DXA) referral. It is widely recommended by clinical guidelines, and the accepted standard in practice for managing patients with osteoporosis and other disorders. Clinicians and DXA providers must be familiar with the scientific rationale and procedures involved in measurement science to obtain accurate and reproducible results. Their importance is critical to maximise the value of scan acquisition and interpretation. Scanning individual patients, with different needs and disorders, requires excellence in training, experience, and is more complex than just simply 'measuring BMD'. Over the past 3 decades many studies have validated the importance of monitoring BMD for fracture risk assessment, and for patients on osteoporosis treatment. New DXA features enhance the value of DXA monitoring today. Quality BMD measurement remains an essential component of patient care in osteoporosis and other disorders, playing a critical role in informed decision making for clinicians assessing and managing their patients. In this article we describe some of the technical aspects of measurement and discuss the utility of DXA for monitoring patients in clinical practice. PMID- 28554550 TI - Reliability of MR Quantification of Rotator Cuff Muscle Fatty Degeneration Using a 2-point Dixon Technique in Comparison with the Goutallier Classification: Validation Study by Multiple Readers. AB - RATIONALE AND OBJECTIVES: Presurgical assessment of fatty degeneration is important in the management of patients with rotator cuff tears. The Goutallier classification is widely accepted as a qualitative scoring system, although it is highly observer-dependent and has poor reproducibility. The objective of this study was to quantify fatty degeneration of the supraspinatus muscle using a 2 point Dixon technique in patients with rotator cuff tears by multiple readers, and to evaluate the reproducibility compared to Goutallier classification. MATERIALS AND METHODS: Two hundred patients with rotator cuff tears who underwent magnetic resonance imaging (MRI), including 2-point Dixon sequence at 3.0-T, were selected retrospectively. Qualitative and quantitative analyses of fatty degeneration were performed by two radiologists and three orthopedic surgeons independently. The fat quantification was performed by measuring signal intensity values of in phase (S(In)) and fat image (S(Fat)), and calculating fat fraction as S(Fat)/S(In). The reproducibility of MR quantification was analyzed by the intra- and interclass correlation coefficients and Bland-Altman plots. RESULTS: The interobserver agreement of the Goutallier classification among five readers was moderate (k = 0.51), whereas the interclass correlation coefficient regarding fat fraction value quantified in 2-point Dixon sequence was excellent (0.893). The mean differences in fat fraction values from the individual segmentation results were from -0.072 to 0.081. Proposed fat fraction grading and Goutallier grading showed similar frequency and distribution in severity of rotator cuff tears. CONCLUSIONS: Fat quantification in the rotator cuff muscles using a 2 point Dixon technique at 3.0-T MRI is highly reproducible and clinically feasible in comparison to the qualitative evaluation using Goutallier classification. PMID- 28554552 TI - Orbital and Orbitocranial Trauma From Pencil Fragments: Role of Timely Diagnosis and Management. AB - PURPOSE: To emphasize the importance of early detection and radiologic evaluation of retained organic foreign bodies (FBs) in orbital or orbitocranial penetrating injuries by pencil. DESIGN: Retrospective case series. METHODS: A retrospective chart review of patients who had penetrating orbital or orbitocranial trauma at 2 tertiary hospitals was conducted. Patients whose mechanism of injury was penetrating trauma by pencil were included. The patients' demographics, time between initial trauma and detection of foreign body, radiologic images, and resulting sequelae were reviewed. RESULTS: Four patients were included in this study. All patients were male; 3 were less than 2 years of age and 1 was 34 years old. Accidents were witnessed in 2 cases, and initial detections of FBs were delayed in 3 cases, from 2 days to 7 weeks. Three cases involved the right orbit. Computed tomography (CT) imaging of the head demonstrated penetration of the orbital walls in 3 cases. Three-dimensional CT scans were used to differentiate the penetrating graphite pencil fragments from the orbital wall, and catheter angiography was used in 1 case of suspected orbital apex penetration. Vision was lost in 1 patient while other severe neurologic deficits were fully recovered after removal of FB. CONCLUSIONS: Penetrating injury by pencils to the periorbital structures and delayed detection of retained pencil fragments can result in threat to life and vision. Radiologic examinations are essential to the detection of these retained FBs. Prompt detection and removal of the FBs within 48 hours and treatment with antibiotics can save vision and life. PMID- 28554551 TI - Applying Quantitative CT Image Feature Analysis to Predict Response of Ovarian Cancer Patients to Chemotherapy. AB - RATIONALE AND OBJECTIVES: The study aimed to investigate the role of applying quantitative image features computed from computed tomography (CT) images for early prediction of tumor response to chemotherapy in the clinical trials for treating ovarian cancer patients. MATERIALS AND METHODS: A dataset involving 91 patients was retrospectively assembled. Each patient had two sets of pre- and post-therapy CT images. A computer-aided detection scheme was applied to segment metastatic tumors previously tracked by radiologists on CT images and computed image features. Two initial feature pools were built using image features computed from pre-therapy CT images only and image feature difference computed from both pre- and post-therapy images. A feature selection method was applied to select optimal features, and an equal-weighted fusion method was used to generate a new quantitative imaging marker from each pool to predict 6-month progression free survival. The prediction accuracy between quantitative imaging markers and the Response Evaluation Criteria in Solid Tumors (RECIST) criteria was also compared. RESULTS: The highest areas under the receiver operating characteristic curve are 0.684 +/- 0.056 and 0.771 +/- 0.050 when using a single image feature computed from pre-therapy CT images and feature difference computed from pre- and post-therapy CT images, respectively. Using two corresponding fusion-based image markers, the areas under the receiver operating characteristic curve significantly increased to 0.810 +/- 0.045 and 0.829 +/- 0.043 (P < 0.05), respectively. Overall prediction accuracy levels are 71.4%, 80.2%, and 74.7% when using two imaging markers and RECIST, respectively. CONCLUSIONS: This study demonstrated the feasibility of predicting patients' response to chemotherapy using quantitative imaging markers computed from pre-therapy CT images. However, using image feature difference computed between pre- and post-therapy CT images yielded higher prediction accuracy. PMID- 28554553 TI - Probing the dynamics of disorder. AB - Intrinsically disordered proteins (IDPs) play an important role in many diseases. IDPs are a large and important class of proteins; estimated to represent a significant fraction of many genomes. In contrast to protein-protein interactions between well-folded proteins, IDPs typically bind to targets using short consecutive stretches of amino acids. Structures of IDPs complexed with a target have shown great diversity in binding modes. However, how this binding diversity is achieved at the molecular level is not well understood. Unfortunately, the prediction and detailed characterization of IDPs experimentally is still a very challenging task; however molecular mechanics based molecular dynamics simulation are well suited for studying the dynamic behavior of IDPs. We look into the current state for force fields for simulating IDPs and an example of how these methods have been applied to the p53 protein. p53 is one of the most extensively studied IDPs, with multiple intrinsically disordered regulatory domains that mediate its interactions with many other proteins engaged in multiple biological pathways. We show how molecular dynamics simulations can be used to elucidate on the mechanisms involved in selection of the different binding partners. PMID- 28554555 TI - Mitochondrial disorders due to tRNA(Pro) mutations. PMID- 28554554 TI - Expanding the phenotypic spectrum associated with mutations of DYNC1H1. AB - Autosomal dominant mutations of DYNC1H1 cause a range of neurogenetic diseases, including mental retardation with cortical malformations, hereditary spastic paraplegia and spinal muscular atrophy. Using SNP array, linkage analysis and next generation sequencing, we identified two families and one isolated proband sharing a known spinal muscular atrophy, lower extremity predominant (SMALED) causing mutation DYNC1H1 c.1792C>T, p.Arg598Cys, and another family harbouring a c.2327C>T, p.Pro776Leu mutation. Here, we present a detailed clinical and pathological examination of these patients, and show that patients with DYNC1H1 mutations may present with a phenotype mimicking a congenital myopathy. We also highlight features that increase the phenotypic overlap with BICD2, which causes SMALED2. Serial muscle biopsies were available for several patients, spanning from infancy and early childhood to middle age. These provide a unique insight into the developmental and pathological origins of SMALED, suggesting in utero denervation with reinnervation by surrounding intact motor neurons and segmental anterior horn cell deficits. We characterise biopsy features that may make diagnosis of this condition easier in the future. PMID- 28554556 TI - Dramatic elevation in urinary amino terminal titin fragment excretion quantified by immunoassay in Duchenne muscular dystrophy patients and in dystrophin deficient rodents. AB - Enzyme-linked and electrochemiluminescence immunoassays were developed for quantification of amino (N-) terminal fragments of the skeletal muscle protein titin (N-ter titin) and qualified for use in detection of urinary N-ter titin excretion. Urine from normal subjects contained a small but measurable level of N ter titin (1.0 +/- 0.4 ng/ml). A 365-fold increase (365.4 +/- 65.0, P = 0.0001) in urinary N-ter titin excretion was seen in Duchene muscular dystrophy (DMD) patients. Urinary N-ter titin was also evaluated in dystrophin deficient rodent models. Mdx mice exhibited low urinary N-ter titin levels at 2 weeks of age followed by a robust and sustained elevation starting at 3 weeks of age, coincident with the development of systemic skeletal muscle damage in this model; fold elevation could not be determined because urinary N-ter titin was not detected in age-matched wild type mice. Levels of serum creatine kinase and serum skeletal muscle troponin I (TnI) were also low at 2 weeks, elevated at later time points and were significantly correlated with urinary N-ter titin excretion in mdx mice. Corticosteroid treatment of mdx mice resulted in improved exercise performance and lowering of both urinary N-ter titin and serum skeletal muscle TnI concentrations. Low urinary N-ter titin levels were detected in wild type rats (3.0 +/- 0.6 ng/ml), while Dmdmdx rats exhibited a 556-fold increase (1652.5 +/- 405.7 ng/ml, P = 0.002) (both at 5 months of age). These results suggest that urinary N-ter titin is present at low basal concentrations in normal urine and increases dramatically coincident with muscle damage produced by dystrophin deficiency. Urinary N-ter titin has potential as a facile, non-invasive and translational biomarker for DMD. PMID- 28554558 TI - Novel truncating variant in DNA2-related congenital onset myopathy and ptosis suggests genotype-phenotype correlation. AB - DNA2 encodes a protein with nuclease, ATPase, and helicase domains, and serves to maintain mitochondrial DNA integrity. Mutations in DNA2 cause autosomal dominant progressive ophthalmoplegia with mitochondrial DNA deletions. This disorder was first reported in four patients with heterozygous, missense mutations in DNA2. Clinical symptoms include limb-girdle and lower extremity weakness, myalgia, and ophthalmoplegia. All had a slowly progressive disease course and did not present for clinical evaluation until the fifth or sixth decade. We report a case of congenital-onset myopathy and ptosis in a child who was found to have a novel DNA2 variant resulting in a premature termination codon (p.Asn568Ilefs*4). Only one other case of a truncating mutation in DNA2 has been reported, and that patient also had early-onset, severe disease. We hypothesize that haploinsufficiency for the DNA2 protein due to truncating mutations results in mitochondrial genome instability and clinical symptoms of early-onset myopathy. Missense mutations that allow for residual protein function lead to a milder clinical phenotype. PMID- 28554559 TI - Endoscopic closure of septal perforations. AB - OBJECTIVE: The management of septal perforations is a challenge for the surgeon. A wide variety of surgical techniques have been described, with different approaches. There is no scientific evidence to support a particular approach. The objective of this review is to present a practical guide on the technique of choice for each case of septal perforation. DISCUSSION: Inspection of the nasal mucosa, the size of the perforation, the location and especially the osteo cartilaginous support, are the pillars of a successful surgery. For the sliding or rotating flaps of the mucosa of the septum it is essential to know in advance if the elevation of the mucopericondrio or mucoperiosteo of the septum is possible, otherwise the use of these flaps would not be indicated. The flaps of the lateral wall or nasal floor are the alternative. The pericranial flap may be indicated in total or near total perforations. CONCLUSION: The remnant of the nasal septum and status of osteo-cartilaginous support are the determining factors in the management of septal perforations. Each case should be evaluated individually and the approach chosen according to the size and location of the perforation, mucosal quality, personal history, previous surgery and the experience of the surgeon. PMID- 28554557 TI - Screening for Pompe disease in a Portuguese high risk population. AB - Pompe disease is a rare metabolic disorder with available enzymatic replacement therapy. Contrasting with the classic infantile form, the others subtypes have a heterogeneous presentation that makes an early and accurate diagnosis difficult. We conducted a prospective, multicenter, observational study to identify undiagnosed patients. During a one-year period, patients followed in Portuguese neuromuscular outpatient clinics with proximal muscle weakness affecting upper and/or lower limbs, hyperCKemia in two or more determinations or hypotonia and hyperCKemia, were screened for acid alpha-glucosidase deficiency by dried blood spots. Lysosomal acid-alpha-1,4-glucosidase activity was determined by tandem mass spectrometry and positive results were confirmed by molecular study. From the 99 patients screened, Pompe disease was confirmed in 4, with age of onset ranging from 2.5 to 48 years, all with limb girdle muscle weakness, corresponding to a frequency of 4% in our cohort and 4.9% of limb girdle muscle weakness. Screening for Pompe disease in high risk populations, using dried blood spots, was already performed in some European populations. Apart from two negative Scandinavian studies, positive cases were confirmed in 2.8-7.9% of patients presenting with limb girdle muscle weakness and in 0-2.5% with isolated hyperCKemia. PMID- 28554560 TI - The TH1 phenotype of follicular helper T cells indicates an IFN-gamma-associated immune dysregulation in patients with CD21low common variable immunodeficiency. AB - BACKGROUND: A subgroup of patients with common variable immunodeficiency (CVID) experience immune dysregulation manifesting as autoimmunity, lymphoproliferation, and organ inflammation and thereby increasing morbidity and mortality. Therefore treatment of these complications demands a deeper comprehension of their cause and pathophysiology. OBJECTIVES: On the basis of the identification of an interferon signature in patients with CVID with secondary complications and a skewed follicular helper T-cell differentiation in defined monogenic immunodeficiencies, we sought to determine the profile of CD4 memory T cells in blood and secondary lymphatic tissues of these patients. METHODS: We quantified TH1/TH2/TH17 CD4 memory T cells in blood and lymph nodes of patients with CVID using flow cytometry, analyzed their function, and correlated all findings to the burden of immune dysregulation. RESULTS: Patients with CVID with immune dysregulation had a skewed memory CD4 T-cell differentiation toward a CXCR3+CCR6- TH1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings, we observed a higher IFN-gamma production in peripheral CD4 memory T cells and lymph node-derived follicular helper T cells of patients with CVID compared with those of healthy control subjects. Increased IFN-gamma production was accompanied by a poor germinal center output, an accumulation of T-box transcription factor (T-bet)+ B cells in lymph nodes, and an accumulation of T bet+CD21low B cells in peripheral blood of affected patients. CONCLUSION: Identification of excessive IFN-gamma production by blood and lymph node-derived T cells of patients with CVID with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21low B cells might serve as a marker of this IFN-gamma-associated dysregulation. PMID- 28554561 TI - Environmental heterogeneity and the evolution of plant-virus interactions: Viruses in wild pepper populations. AB - Understanding host-pathogen interactions requires analyses to address the multiplicity of scales in heterogeneous landscapes. Anthropogenic influence on plant communities, especially cultivation, is a major cause of environmental heterogeneity. We have approached the analysis of how environmental heterogeneity determines plant-virus interactions by studying virus infection in a wild plant currently undergoing incipient domestication, the wild pepper or chiltepin, across its geographical range in Mexico. We have shown previously that anthropogenic disturbance is associated with higher infection and disease risk, and with disrupted patterns of host and virus genetic spatial structure. We now show that anthropogenic factors, species richness, host genetic diversity and density in communities supporting chiltepin differentially affect infection risk according to the virus analysed. We also show that in addition to these factors, a broad range of abiotic and biotic variables meaningful to continental scales, have an important role on the risk of infection depending on the virus. Last, we show that natural virus infection of chiltepin plants in wild communities results in decreased survival and fecundity, hence negatively affecting fitness. This important finding paves the way for future studies on plant-virus co-evolution. PMID- 28554562 TI - Identification and pathotypical analysis of a novel VIk sub-genotype Newcastle disease virus obtained from pigeon in China. AB - Newcastle disease virus (NDV) can lead to a devastating disease to various avian species including pigeons. Genotype VI NDV is a major cause of Newcastle disease (ND) in Columbiformes (i.e. pigeons and doves). Here, we analyzed the genetic diversity of genotype VI based on the complete F gene sequences of 2 pigeon origin isolates in northeastern China in 2015, along with 238 genotype VI strains available in GenBank. The phylogenetic tree and evolutionary distances revealed that the 2 new isolates were clustered into a new sub-genotype herein proposed as VIk. Although the 2 isolates contain the 113RQKRF117 cleavage site, a feature generally associated with virulent NDV strains, the values of ICPI and MDT showed lentogenic characteristics. The challenge experiment demonstrated that the isolate Pigeon/China/Jilin/NG05/2015 was pathogenic to pigeons, causing lesions in multiple tissues and organs. The emergence and spread of the sub-genotype VIk viruses illustrated that the genotype VI NDV was undergoing evolutionary changes. It is necessary to pay close attention and carry out epidemiological surveillance in pigeons. PMID- 28554563 TI - Left Ventricular Fibrosis and Systolic Hypertension Persist in a Repaired Aortic Coarctation Model. AB - BACKGROUND: Despite successful repair in early life, patients with coarctation of the aorta (CoA) are predisposed to several cardiovascular complications in later life related to systemic hypertension or left ventricular (LV) dysfunction, or both, the pathogenesis of which is unclear. METHODS: Three-week-old Sprague Dawley rats underwent transverse aortic constriction (TAC) or a sham operation, with release of the constriction 3 weeks later. Twenty-five weeks after the repair operation, animals underwent hemodynamic assessment, LV gene profiling, and histologic analysis. RESULTS: Animals with repaired aortic constriction exhibited a significantly elevated central systolic pressure (116 +/- 5 mm Hg vs 103 +/- 4 mm Hg; p < 0.05) despite the absence of any significant pressure gradient across the former constriction site compared with shams (5 +/- 4 mm Hg vs 0 +/- 2 mm Hg; p = 0.2). They also had more than a 2-fold increase in LV collagen deposition (4.86% +/- 0.24% vs 2.40% +/- 0.18%; p < 0.001). However, no significant differences were noted between the groups in maximum LV pressure (116 +/- 3 mm Hg vs 107 +/- 3 mm Hg; p = 0.1), LV mass indexed to tibial length (p = 0.07), or myocyte size. There was no significant differential expression of hypertrophy or fibrosis-related genes in the left ventricles of the repaired animals compared with shams. CONCLUSIONS: Despite successful early relief of simulated CoA in early life, relative hypertension and LV fibrosis were demonstrable late consequences in this animal model. This abnormal fibrosis persists in the absence of altered LV hemodynamics and gene expression. PMID- 28554564 TI - The third wave: Intermediate filaments in the maturing nervous system. AB - Intermediate filaments are critical for the extreme structural specialisations of neurons, providing integrity in dynamic environments and efficient communication along axons a metre or more in length. As neurons mature, an initial expression of nestin and vimentin gives way to the neurofilament triplet proteins and alpha internexin, substituted by peripherin in axons outside the CNS, which physically consolidate axons as they elongate and find their targets. Once connection is established, these proteins are transported, assembled, stabilised and modified, structurally transforming axons and dendrites as they acquire their full function. The interaction between these neurons and myelinating glial cells optimises the structure of axons for peak functional efficiency, a property retained across their lifespan. This finely calibrated structural regulation allows the nervous system to maintain timing precision and efficient control across large distances throughout somatic growth and, in maturity, as a plasticity mechanism allowing functional adaptation. PMID- 28554565 TI - Antioxidant mechanism of mitochondria-targeted plastoquinone SkQ1 is suppressed in aglycemic HepG2 cells dependent on oxidative phosphorylation. AB - Previously suggested antioxidant mechanisms for mitochondria-targeted plastoquinone SkQ1 included: i) ion-pairing of cationic SkQ1+ with free fatty acid anions resulting in uncoupling; ii) SkQ1H2 ability to interact with lipoperoxyl radical; iii) interference with electron flow at the inner ubiquinone (Q) binding site of Complex III (Qi), involving the reduction of SkQ1 to SkQ1H2 by ubiquinol. We elucidated SkQ1 antioxidant properties by confocal fluorescence semi-quantification of mitochondrial superoxide (Jm) and cytosolic H2O2 (Jc) release rates in HepG2 cells. Only in glycolytic cells, SkQ1 prevented the rotenone-induced enhancement of Jm and Jc but not basal releases without rotenone. The effect ceased in glutaminolytic aglycemic cells, in which the redox parameter NAD(P)H/FAD increased after rotenone in contrast to its decrease in glycolytic cells. Autofluorescence decay indicated decreased NADPH/NADH ratios with rotenone in both metabolic modes. SkQ1 did not increase cell respiration and diminished Jm established high by antimycin or myxothiazol but not by stigmatellin. The revealed SkQ1 antioxidant modes reflect its reduction to SkQ1H2 at Complex I IQ or Complex III Qi site. Both reductions diminish electron diversions to oxygen thus attenuating superoxide formation. Resulting SkQ1H2 oxidizes back to SkQ1at the second (flavin) Complex I site, previously indicated for MitoQ10. Regeneration proceeds only at lower NAD(P)H/FAD in glycolytic cells. In contrast, cyclic SkQ1 reduction/SkQ1H2 oxidation does not substantiate antioxidant activity in intact cells in the absence of oxidative stress (neither pro-oxidant activity, representing a great advantage). A targeted delivery to oxidative-stressed tissues is suggested for the effective antioxidant therapy based on SkQ1. PMID- 28554566 TI - Modelling the free energy profile of the mitochondrial ADP/ATP carrier. AB - The mitochondrial ADP/ATP carrier catalyses the equimolar exchange of adenosine di- and tri-phosphates. It operates by an alternating access mechanism in which a single substrate-binding site is made available either to the mitochondrial matrix or the intermembrane space through conformational changes. These changes are prevented in the absence of substrate by a large energy barrier due to the need for sequential disruption and formation of a matrix and cytoplasmic salt bridge network that are located on either side of the central cavity. In analogy to enzyme catalysis, substrate lowers the energy barrier by binding tighter in the intermediate state. Here we provide an in-silico kinetic model that captures the free energy profile of these conformational changes and treats the carrier as a nanomachine moving stochastically from the matrix to cytoplasmic conformation under the influence of thermal energy. The model reproduces the dependency of experimentally determined kcat and KM values on the cytoplasmic network strength with good quantitative accuracy, implying that it captures the transport mechanism and can provide a framework to understand the structure-function relationships of this class of transporter. The results show that maximum transport occurs when the interaction energies of the cytoplasmic network, matrix network and substrate binding are approximately equal such that the energy barrier is minimized. Consequently, the model predicts that there will be other interactions in addition to those of the cytoplasmic network that stabilise the matrix conformation of the ADP/ATP carrier. PMID- 28554568 TI - Recombinant Acetylcholinesterase purification and its interaction with silver nanoparticle. AB - Although the use of silver nanoparticles (AgNPs) has substantial benefits, their entrance into the environment, food chain, and human body and their toxicity have come under serious scrutiny. Multiple noncovalent attractive forces between AgNPs and bio-macromolecules are responsible for immediate corona formation upon exposure to biological tissue. Here, the influence of AgNPs with neuro-enzyme Acetylcholinesterase (AChE) was investigated. AgNPs to enzyme ratio had an effect on the enzyme and features of the treated samples. It was also observed that time increments had a positive effect on the size of AgNPs and caused an increase in their initial size. In other words, smaller AgNPs resulted in size increments after interaction with enzymes, while the larger ones showed size decrements. The nano-crystalline AgNPs were identified in x-ray powder diffraction analyses before and after treatment with AChE. The (220) crystalline plane is related to the internal crystallinity of cubic Ag. The results show that the interaction between AChE and AgNPs could lead not only to a decrease in AChE activity, but also to a reduction in the crystallinity and stability of AgNPs. The circular dichroism demonstrates that the secondary structure of AChE also declined after 30 min of incubation with AgNPs at 37 degrees C. PMID- 28554567 TI - Purification and characterization of a bioactive alpha-fetoprotein produced by HEK-293 cells. AB - Alpha-fetoprotein (AFP) is a biomarker that is used to diagnose hepatocellular carcinoma (HCC) and can promote malignancy in HCC. AFP is an important target in the treatment of liver cancer. To obtain enough AFP to screen for AFP inhibitors, we expressed and purified AFP in HEK-293 cells. In the present study, we produced AFP in the cells and harvested highly pure rAFP (or recombinant expression AFP in HEK-293 cells). We also analysed the bioactivity of rAFP and found that rAFP promoted growth of the human HCC cells, antagonize paclitaxel inhibition of HCC cell proliferation, suppress expression of active caspase-3, and promote expression of Ras and survivin. This study provides a method to produce significant amounts of AFP for use in biochemical assays and functional studies and to screen AFP inhibitors for use in HCC therapy. PMID- 28554569 TI - Evolutionary perspectives on ageing. AB - From an evolutionary perspective, ageing is a decrease in fitness with chronological age - expressed by an increase in mortality risk and/or decline in reproductive success and mediated by deterioration of functional performance. While this makes ageing intuitively paradoxical - detrimental to individual fitness - evolutionary theory offers answers as to why ageing has evolved. In this review, I first briefly examine the classic evolutionary theories of ageing and their empirical tests, and highlight recent findings that have advanced our understanding of the evolution of ageing (condition-dependent survival, positive pleiotropy). I then provide an overview of recent theoretical extensions and modifications that accommodate those new discoveries. I discuss the role of indeterminate (asymptotic) growth for lifetime increases in fecundity and ageing trajectories. I outline alternative views that challenge a universal existence of senescence - namely the lack of a germ-soma distinction and the ability of tissue replacement and retrogression to younger developmental stages in modular organisms. I argue that rejuvenation at the organismal level is plausible, but includes a return to a simple developmental stage. This may exempt a particular genotype from somatic defects but, correspondingly, removes any information acquired during development. A resolution of the question of whether a rejuvenated individual is the same entity is central to the recognition of whether current evolutionary theories of ageing, with their extensions and modifications, can explain the patterns of ageing across the Tree of Life. PMID- 28554570 TI - Sex-specific lifespan and its evolution in nematodes. AB - Differences between sexes of the same species in lifespan and aging rate are widespread. While the proximal and evolutionary causes of aging are well researched, the factors that contribute to sex differences in these traits have been less studied. The striking diversity of nematodes provides ample opportunity to study variation in sex-specific lifespan patterns associated with shifts in life history and mating strategy. Although the plasticity of these sex differences will make it challenging to generalize from invertebrate to vertebrate systems, studies in nematodes have enabled empirical evaluation of predictions regarding the evolution of lifespan. These studies have highlighted how natural and sexual selection can generate divergent patterns of lifespan if the sexes are subject to different rates or sources of mortality, or if trade offs between complex traits and longevity are resolved differently in each sex. Here, we integrate evidence derived mainly from nematodes that addresses the molecular and evolutionary basis of sex-specific aging and lifespan. Ultimately, we hope to generate a clearer picture of current knowledge in this area, and also highlight the limitations of our understanding. PMID- 28554571 TI - Activity modulation of the oligopeptidase B from Serratia proteamaculans by site directed mutagenesis of amino acid residues surrounding catalytic triad histidine. AB - Oligopeptidase B (OpdB; EC 3.4.21.83) is a trypsin-like peptidase belonging to the family of serine prolyl oligopeptidases; two-domain structure of the enzyme includes C-terminal peptidase catalytic domain and N-terminal seven-bladed beta propeller domain. Importance of the interface between these domains and particularly of the 5 salt bridges for enzyme activity was established for protozoan OpdBs. However, these salt bridges are not conserved in gamma proteobacterial OpdBs including the peptidase from Serratia proteamaculans (PSP). In this work, using comparative modelling and protozoan OpdBs' crystal structures we created 3D models of PSP in open and closed forms to elucidate the mechanism underlying inactivation of the truncated form of PSP1-655 obtained earlier. Analysis of the models shows that in the closed form of PSP charged amino acid residues of histidine loop, surrounding the catalytic triad His652, participate in formation of the inter-domain contact interface between catalytic and beta propeller domains, while in the open form of PSP disconnection of the catalytic triad and distortion of these contacts can be observed. Complete destruction of this interface by site-directed mutagenesis causes inactivation of PSP while elimination of the individual contacts leads to differential effects on the enzyme activity and substrate specificity. Thus, we identified structural factors regulating activity of PSP and supposedly of other gamma-proteobacterial OpdBs and discovered the possibility of directed modulation of their enzymatic features. PMID- 28554572 TI - Electrospray ionization ion mobility mass spectrometry provides novel insights into the pattern and activity of fetal hippocampus gangliosides. AB - Gangliosides (GGs), a particular class of glycosphingolipids ubiquitously found in tissues and body fluids, exhibit the highest expression in the central nervous system, especially in brain. GGs are involved in crucial processes, such as neurogenesis, synaptogenesis, synaptic transmission, cell adhesion, growth and proliferation. For these reasons, efforts are constantly invested into development and refinement of specific methods for GG analysis. We have recently shown that ion mobility separation (IMS) mass spectrometry (MS) has the capability to provide consistent compositional and structural information on GGs at high sensitivity, resolution and mass accuracy. In the present paper, we have implemented IMS MS for the first time in the study of a highly complex native GG mixture extracted and purified from human fetal hippocampus. As compared to previous studies, where no separation techniques prior to MS were applied, IMS MS technique has not just generated valuable novel information on the GG pattern characteristic for hippocampus in early developmental stage, but also provided data related to the GG molecular involvement in the synaptic functions by the discovery of 25 novel structures modified by CH3COO-. The detection and identification in fetal hippocampus of a much larger number of GG species than ever reported before was possible due to the ion mobility separation according to the charge state, the carbohydrate chain length and the degree of sialylation. By applying IMS in conjunction with collision induced dissociation (CID) tandem MS (MS/MS), novel GG species modified by CH3COO- attachment, discovered here for the first time, were sequenced and structurally investigated in details. The present findings, based on IMS MS, provide a more reliable insight into the expression and role of gangliosides in human hippocampus, with a particular emphasis on their cholinergic activity at this level. PMID- 28554573 TI - Clinical significance of CK7, HPV-L1, and koilocytosis for patients with cervical low-grade squamous intraepithelial lesions: a retrospective analysis. AB - Most cervical low-grade squamous intraepithelial lesions (LSILs) do not progress to high-grade squamous intraepithelial lesions (HSILs); however, reliable biomarkers that predict LSIL progression are lacking. We investigated the association of cytokeratin 7 (CK7), human papillomavirus-L1 capsid protein (HPV L1), and koilocytosis with clinical outcomes of patients with LSIL. CK7, HPV-L1, Ki67, and p16-INK4A expression was determined in 72 cervical LSIL and 28 HSIL biopsy samples; koilocytosis was evaluated by reviewing biopsy slides. Fifty patients with LSIL received follow-up. CK7, HPV-L1, and koilocytosis were detected in 48.6%, 44.4%, and 52.0% of LSIL tissues and in 78.6%, 10.7%, and 64.3% of HSIL tissues, respectively. Lesion grade was correlated directly with CK7 expression (P=.007) and inversely with HPV-L1 expression (P=.004). CK7 expression in LSILs was correlated inversely with HPV-L1 expression and directly with p16-INK4A and Ki67 status. Furthermore, koilocytosis was significantly associated with HPV-L1 and p16-INK4A expression. Progression to cervical intraepithelial lesions of grades >=2 occurred in 34% of cases. CK7 negativity and HPV-L1 positivity were significantly associated with lower HSIL progression rates. HPV-L1-positive and CK7-negative LSILs showed significantly lower progression rates compared with HPV-L1-negative and CK7-positive LSILs (6.3% v positive cases showed a significantly lower progression rate (17.6%) compared with nonkoilocytic and HPV-L1-negative cases (50%). CK7-negative, HPV-L1 positive, and koilocytic LSILs showed a progression rate of 7.7%. Koilocytosis and p16-INK4A were not significantly associated with clinical outcomes. Hence, evaluating HPV-L1, CK7, and koilocytosis profiles combined may be more reliable for LSIL prognostication. PMID- 28554574 TI - p16 expression in follicular dendritic cell sarcoma: a potential mimicker of human papillomavirus-related oropharyngeal squamous cell carcinoma. AB - Follicular dendritic cell sarcoma is a rare mesenchymal neoplasm that most commonly occurs in cervical lymph nodes. It has histologic and clinical overlap with the much more common p16-positive human papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx, which characteristically has nonkeratinizing morphology and often presents as an isolated neck mass. Not surprisingly, follicular dendritic cell sarcomas are commonly misdiagnosed as squamous cell carcinoma. Immunohistochemistry is helpful in separating the 2 entities. Follicular dendritic cell sarcoma expresses dendritic markers such as CD21 and CD23 and is almost always cytokeratin negative. However, in many cases of HPV-related oropharyngeal carcinoma, only p16 immunohistochemistry as a prognostic and surrogate marker for HPV is performed. p16 expression in follicular dendritic cell sarcoma has not been characterized. Here, we investigate the expression of p16 in follicular dendritic cell sarcoma and correlate it with retinoblastoma protein expression. A pilot study of dendritic marker expression in HPV-related oropharyngeal squamous cell carcinoma was also performed. We found that 4 of 8 sarcomas expressed p16 with strong and diffuse staining in 2 cases. In 2 of the 4 cases, p16 expression corresponded to loss of retinoblastoma protein expression. Dendritic marker expression (CD21 and CD23) was not found in HPV-related oropharyngeal squamous cell carcinomas. As such, positive p16 immunohistochemistry cannot be used as supportive evidence for the diagnosis of squamous cell carcinoma as strong and diffuse p16 expression may also occur in follicular dendritic cell sarcoma. Cytokeratins and dendritic markers are critical in separating the two tumor types. PMID- 28554575 TI - Dyrk1B overexpression is associated with breast cancer growth and a poor prognosis. AB - Dyrk1B, also called minibrain-related kinase (Mirk), is a member of the dual specificity tyrosine phosphorylation-regulated kinase (Dyrk)/minibrain family of dual-specificity protein kinases. It is a serine/threonine kinase involved in the regulation of tumor progression and cell proliferation. In this study, the role of Dyrk1B in breast cancer development was investigated. The expression of Dyrk1B was detected by Western blot and immunohistochemistry staining, both of which demonstrated that Dyrk1B was overexpressed in breast cancer tissues and cells. Statistical analysis showed that the extent of Dyrk1B expression was associated with multiple clinicopathologic factors, including tumor size, grade, estrogen receptor status, and Ki-67 expression, and that high expression predicted a poor prognosis. The growth of breast cancer cells was inhibited significantly after knockout of DYRK1B by small interfering RNA (siRNA). Moreover, FoxO1 could be phosphorylated by Dyrk1B, and then FoxO1 was shuttled from the cell nucleus into the cytoplasm, which might be the mechanism of Dyrk1B-mediated survival in breast cancer cells. The results suggest that Dyrk1B plays a key role in the progression of breast cancer and provides a new target for breast cancer therapy. PMID- 28554576 TI - Congenital capillary proliferation of the kidney: a distinctive renal vascular lesion of childhood. AB - Renal vascular lesions (RVL) are rare, and their morphological spectrum remains largely unknown, particularly in children. In this study, we characterize the clinicopathological features of RVL in a cohort of 12 children. Seven lesions were classified as previously recognized entities: vascular malformations (4), papillary endothelial hyperplasia (2), and pyogenic granuloma (lobular capillary hemangioma; 1). An eighth lesion showed nonspecific findings, which were interpreted as reactive during our review. The remaining 4 cases presented either prenatally, at birth, or shortly after birth and were morphologically similar. These were characterized by a peculiar pattern of capillary proliferation with entrapment of native renal structures, variable amounts of extramedullary hematopoiesis and reactive lymphocytes, foci of infarction and hemorrhage, and the presence of feeding and draining vessels at their periphery. To our knowledge, this represents a previously undescribed congenital vascular lesion involving the kidney, which we have descriptively and provisionally termed congenital capillary proliferation of the kidney (CCPK). While it is unclear whether CCPK represents a malformation or neoplastic proliferation, it shows overlapping features with congenital hemangioma of the liver (solitary congenital hepatic hemangioma) and congenital nonprogressive hemangioma (CNH) of the skin and soft tissue, suggesting a possible common pathogenesis among these 3 entities. PMID- 28554577 TI - Molecular properties associated with transporter-mediated drug disposition. AB - Membrane transporters play a key role in the absorption, distribution, clearance, elimination, and transport of drugs. Understanding the drug properties and structure activity relationships (SAR) for affinity to membrane transporters is critical to optimize clearance and pharmacokinetics during drug design. To facilitate the early identification of clearance mechanism, a framework named the extended clearance classification system (ECCS) was recently introduced. Using in vitro and physicochemical properties that are readily available in early drug discovery, ECCS has been successfully applied to identify major clearance mechanism and to implicate the role of membrane transporters in determining pharmacokinetics. While the crystal structures for most of the drug transporters are currently not available, ligand-based modeling approaches that use information obtained from the structure and molecular properties of the ligands have been applied to associate the drug-related properties and transporter mediated disposition. The approach allows prospective prediction of transporter both substrate and/or inhibitor affinity and build quantitative structure activity relationship (QSAR) to enable early optimization of pharmacokinetics, tissue distribution and drug-drug interaction risk. Drug design applications can be further improved through uncovering transporter protein crystal structure and generation of quality data to refine and develop viable predictive models. PMID- 28554578 TI - Meningioma mimics: five key imaging features to differentiate them from meningiomas. AB - There are a wide variety of intracranial mass lesions, both benign and malignant, which can closely mimic meningioma on imaging. We present five characteristic imaging features that can alert the radiologist to consider other differential diagnoses. Of the five imaging characteristics that were rarely seen in meningiomas, but common and specific for meningioma mimics, absence of dural tail is the most common (83.7%). Homogeneous T2 hyperintensity or T2 hypointensity are seen in nearly half of meningioma mimics and osseous destruction and leptomeningeal extension are present in 40.5% and 21.6% of meningioma mimics, respectively. The distinction between meningioma and its mimics is important because a large portion of the meningioma mimics requires substantially different clinical and surgical management. PMID- 28554579 TI - Wall suction-assisted image-guided thoracentesis: a safe alternative to evacuated bottles. AB - AIM: To compare the safety of evacuated bottle-assisted thoracentesis with wall suction-assisted thoracentesis. MATERIALS AND METHODS: An institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study of 161 consecutive patients who underwent 191 evacuated bottle-assisted thoracenteses from 1 January 2012 to 30 September 2012, and 188 consecutive patients who underwent 230 wall suction-assisted thoracenteses from 1 January 2013 to 30 September 2013 was conducted. All procedures used imaging guidance. Primary diagnosis, age, gender, total fluid volume removed, and adverse events (AE) up to 30 days post-procedure were recorded and graded using Common Terminology Criteria for Adverse Events 4.0 (CTCAE)2. RESULTS: Overall AE rates were 42.9% (82/191) for the evacuated bottle group and 19.6% (45/230) for the wall suction group (p<0.0001). Grade I AE occurred more commonly in the evacuated bottle group than in the wall suction group, [41.9% (80/191) and 18.3% (42/230)], respectively (p<0.0001). No significant differences were observed in grade 2 [0.5% (1/191) and 0% (0/230), p=0.45] or grade 3 AE [0.5% (1/191) and 1.3% (3/230), p=0.63] between the evacuated bottle and wall suction groups, respectively. No grade 4 or 5 AE occurred. Excluding transient chest pain and cough, there was no statistical difference in overall AE rate between the evacuated bottle and wall suction groups [11% (21/191) and 8.3% (19/230), p=0.4]. CONCLUSION: Image-guided thoracentesis performed with wall suction is safe when compared to evacuated bottles. The use of wall suction, in comparison to evacuated bottles, may decrease the incidence of transient chest pain or cough. PMID- 28554580 TI - Prognostic value of lymph node density in buccal squamous cell carcinoma. AB - PURPOSE: Lymph node density(LND) has been shown to be a better prognosticator than conventional nodal classification to predict prognosis for squamous cell carcinoma(SCC) of the oral cavity. However, studies focusing on subsites of oral cancer are meager. The role of LND for buccal SCC was evaluated in this study. METHODS: A total of 39 patients with buccal SCC primarily treated surgically with neck dissection were identified. LND was defined as the number of positive nodes over the number of nodal yield. The cut-off of LND was <=0.07 or >0.07. Patient demographic data and clincopathologic parameters were described. Survival was expressed by Kaplan-Meier method and correlation with survival is analyzed with log-rank test. IBM SPSS Statistics version 22 was used for data computation. RESULTS: The median follow-up was 79.0months and median nodes removed was 23 (range 8-93). Positive nodal involvement was found in 19(48.7%) patients. The 5 year and 10-year OS were 67.4% and 42.5% whilst for DSS were 69.2% and 65.5%, respectively. When pT-, pN-, LND-classification and AJCC stage were analyzed for the whole series, only pN- (p=0.006) and LND-classification (p=0.002) were significant factors for OS, while pT-, pN-, LND-classification and AJCC stage were all significant factors for DSS. When only cases with positive nodal spread were considered, the pN-classification (pN1 vs pN2) was not a significant risk factor for either OS (p=0.075, HR 3.10(CI 0.89-10.76)) and DSS (p=0.074, HR 3.58(CI 0.88-14.56)). By contrast, LND-classification (<=0.07 vs >0.07) remained a significant predictor for OS (p=0.03, HR 3.95(CI 1.15-13.63)), but not for the DSS (p=0.112, HR 2.92(CI 0.78-10.99)). CONCLUSION: The prognostic value of LND on buccal SCC is supported in this study. The results also suggest that LND is better than the conventional pN-classification to predict OS. Further studies on LND with big sample size for buccal SCC or other subsites of OSCC are worthwhile. PMID- 28554581 TI - Near fatal bronchospasm and bradycardia after carbetocin administration. PMID- 28554582 TI - Geranylgeraniol prevents the simvastatin-induced PCSK9 expression: Role of the small G protein Rac1. AB - Statins are known to increase the plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) through the activation of the sterol responsive element binding protein (SREBP) pathway due to the inhibition of cholesterol biosynthesis. In the present study, we explore a possible role of the prenylated proteins on the statin-mediated PCSK9 induction in Caco-2 cells. Simvastatin (40MUM) induced both PCSK9 mRNA (10.7+/-3.2 fold) and protein (2.2+/-0.3 fold), after 24h incubation. The induction of PCSK9 mRNA was partially, but significantly, prevented by the co-incubation with mevalonate (MVA), farnesol (FOH) and geranylgeraniol (GGOH), while a complete prevention was observed on secreted PCSK9, evaluated by ELISA assay. Under the same experimental conditions, MVA, GGOH, but not FOH, prevented the activation of the PCSK9 promoter by simvastatin in a SRE-dependent manner. Simvastatin reduced by -35.7+/-15.2% the Rac1-GTP levels, while no changes were observed on RhoA- and Cdc42-GTP. This effect was prevented by MVA and GGOH. A Rac inhibitor, and N17Rac1 dominant negative mutant, significantly induced PCSK9 levels, and a suppression of Rac1 expression by siRNA, counteract the effect of simvastatin on the induction of PCSK9 mRNA. Finally, simvastatin, and Rac inhibitor inhibited the nuclear translocation of STAT3 and its knock-down by siRNA increased significantly the susceptibility of Caco-2 to simvastatin on PCSK9 expression. Taken together, the present study reveal a direct role of Rac1 on simvastatin-mediated PCSK9 expression via the reduction of STAT3 nuclear translocation. PMID- 28554583 TI - Autologous and allogeneic cardiac stem cell therapy for cardiovascular diseases. AB - Stem cell therapy is one of the most promising therapeutic innovations to help restore cardiac structure and function after ischemic insults to the heart. However, phase I and II clinical trials with autologous "first-generation stem cells" have yielded inconsistent results in ischemic cardiomyopathy patients and have not produced the definitive evidence for their broad clinical application. Recently, new cell types such as cardiac stem cells (CSC) and new allogeneic sources have attracted the attention of researchers given their inherent biological, clinical and logistic advantages. Preclinical evidence and emerging clinical data show that exogenous CSC produce a range of protein-based factors that have a powerful cardioprotective effect in the ischemic myocardium, immunoregulatory properties that promote angiogenesis and reduce scar formation, and are able to activate endogenous CSC which multiply and differentiate into cardiomyocytes and microvasculature. Furthermore, allogeneic CSC can be produced in large quantities beforehand and can be administered "off-the-shelf" early during the acute phase of myocardial ischemia. The distinctive immunological behavior of allogeneic CSC and their interaction with the host immune system is supposed to produce immunomodulatory beneficial effects in the short-term, preventing long-term side-effects after their rejection. Preclinical studies have shown highly promising results with allogeneic CSC, and clinical trials are already ongoing. Finally, unraveling questions about the biology and physiology of CSC, the characterization of their secretome, the conduction of larger clinical trials with autologous CSC, the definitive evidence on the safety and efficacy of allogeneic CSC in humans and the possibility of repeated administrations or combinations with other cell types and soluble factors will pave the road for further developments with CSC, that will undoubtedly determine the future of cardiovascular regenerative medicine in human beings. PMID- 28554584 TI - Department of Error. PMID- 28554585 TI - Predictors of response to cardiac resynchronization therapy: A prospective cohort study. AB - INTRODUCTION: Cardiac resynchronization therapy (CRT) has modified the prognosis of chronic heart failure (HF) with left ventricular systolic dysfunction. However, 30% of patients do not have a favorable response. The big question is how to determine predictors of response. AIMS: To identify baseline characteristics that might influence echocardiographic response to CRT. METHODS AND RESULTS: We performed a prospective single-center hospital-based cohort study of consecutive HF patients selected to CRT (NYHA class II-IV, left ventricular ejection fraction (LVEF) <35% and QRS complex >=120 ms). Responders were defined as those with a >=5% absolute increase in LVEF at six months. Clinical, electrocardiographic, laboratory, echocardiographic, autonomic, endothelial and cardiopulmonary function parameters were assessed before CRT device implantation. Logistic regression models were used. Seventy-nine patients were included, 54 male (68.4%), age 68.1 years (standard deviation 10.2), 19 with ischemic etiology (24%). At six months, 51 patients (64.6%) were considered responders. Although by univariate analysis baseline tricuspid annular plane systolic excursion (TAPSE) and serum creatinine were significantly different in responders, on multivariate analysis only TAPSE was independently associated with response, with higher values predicting a positive response to CRT (OR=1.13; 95% CI: 1.02-1.26; p=0.020). TAPSE >=15 mm was strongly associated with response, and TAPSE <15 mm with non-response (p=0.005). Responders had no TAPSE values below 10 mm. CONCLUSION: From a range of clinical and technical baseline characteristics, multivariate analysis only identified TAPSE as an independent predictor of CRT response, with TAPSE <15 mm associated with non-response. This study highlights the importance of right ventricular dysfunction in CRT response. ClinicalTrials.gov identifier: NCT02413151. PMID- 28554586 TI - Intense pleural FDG uptake 12 years after talc pleurodesis: PET/CT findings. PMID- 28554587 TI - A novel method for ABO-incompatible heart transplantation. AB - BACKGROUND: Since 1996, ABO-incompatible heart transplantation has been undertaken by performing whole-body plasma exchange to remove isohemagglutinins using the cardiopulmonary bypass (CPB) circuit at the time of transplantation. This requires large volumes of donated blood and blood products, causes hemodynamic instability during the exchange transfusion, and limits practical use to small children. We sought to determine the efficacy of anti-A/B immunoadsorption within the CPB circuit on removal of isohemagglutinins in an ex vivo setting before its use clinically. METHODS: An anti-A/B immunoadsorption column was placed into a CPB circuit mimicking a typical ABO-incompatible transplant patient, which had been primed with type O whole human blood. Samples were taken for determination of isohemagglutinin titers following each plasma volume pass through the anti-A/B immunoadsorption column. RESULTS: There was a linear decrease of at least 1 dilution seen in both anti-A and anti-B IgG and IgM antibodies with each plasma volume pass through the column. This predictable removal allowed the formulation of selection criteria for ABO-incompatible heart transplantation given the reciprocal of titer and patient weight. This degree of predictability allowed us to use it successfully in the clinical setting, reducing antibodies to an undetectable level during ABO-incompatible heart transplantation. CONCLUSIONS: The incorporation of an anti-A/B immunoadsorption column into the extracorporeal circuit reduces allogeneic blood product requirement for ABO-incompatible heart transplantation, while providing efficacious removal of anti-A and anti-B isohemagglutinins. This can be undertaken within the time period of CPB before graft reperfusion and expands the potential recipient pool to larger patients with higher isohemagglutinin titers. PMID- 28554589 TI - The POPOP (puffing on pulse oximeter probe) sign of ethanol withdrawal. PMID- 28554588 TI - Pathologic C-spine fracture with low risk mechanism and normal physical exam. AB - Cervical spinal fracture is a rare, but potentially disabling complication of trauma to the neck. Clinicians often rely on clinical decision rules and guidelines to decide whether or not imaging is necessary when a patient presents with neck pain. Validated clinical guidelines include the Canadian C-Spine Rule and the Nexus criteria. Studies suggest that the risks of a pathologic fracture from a simple rear end collision are negligible. We present a case of an individual who presented to an emergency department (ED) after a low speed motor vehicle collision complaining of lateral neck pain and had multiple subsequent visits for the same complaint with negative exam findings. Ultimately, he was found to have a severely pathologic cervical spine fracture with notable cord compression. Our objective is to discuss the necessity to incorporate clinical decision rules with physician gestalt and the need to take into account co morbidities of a patient presenting after a minor MVC. PMID- 28554590 TI - The antimicrobial peptide derived from insulin-like growth factor-binding protein 5, AMP-IBP5, regulates keratinocyte functions through Mas-related gene X receptors. AB - BACKGROUND: In addition to their microbicidal properties, host defense peptides (HDPs) display various immunomodulatory functions, including keratinocyte production of cytokines/chemokines, proliferation, migration and wound healing. Recently, a novel HDP named AMP-IBP5 (antimicrobial peptide derived from insulin like growth factor-binding protein 5) was shown to exhibit antimicrobial activity against numerous pathogens, even at concentrations comparable to those of human beta-defensins and LL-37. However, the immunomodulatory role of AMP-IBP5 in cutaneous tissue remains unknown. OBJECTIVES: To investigate whether AMP-IBP5 triggers keratinocyte activation and to clarify its mechanism. METHODS: Production of cytokines/chemokines and growth factors was determined by appropriate ELISA kits. Cell migration was assessed by in vitro wound closure assay, whereas cell proliferation was analyzed using BrdU incorporation assay complimented with XTT assay. MAPK and NF-kappaB activation was determined by Western blotting. Intracellular cAMP levels were assessed using cAMP enzyme immunoassay kit. RESULTS: Among various cytokines/chemokines and growth factors tested, AMP-IBP5 selectively increased the production of IL-8 and VEGF. Moreover, AMP-IBP5 markedly enhanced keratinocyte migration and proliferation. AMP-IBP5 induced keratinocyte activation was mediated by Mrg X1-X4 receptors with MAPK and NF-kappaB pathways working downstream, as evidenced by the inhibitory effects of MrgX1-X4 siRNAs and ERK-, JNK-, p38- and NF-kappaB-specific inhibitors. We confirmed that AMP-IBP5 indeed induced MAPK and NF-kappaB activation. Furthermore, AMP-IBP5-induced VEGF but not IL-8 production correlated with an increase in intracellular cAMP. CONCLUSIONS: Our findings suggest that in addition to its antimicrobial function, AMP-IBP5 might contribute to wound healing process through activation of keratinocytes. PMID- 28554591 TI - Outcome of Judet's quadricepsplasty for knee contractures and the effect of local infiltration of epinephrine on reducing blood loss. AB - OBJECTIVE: To evaluate the effectiveness of Judet's quadricepsplasty for treatment of knee contractures and to identify the effect of local infiltration of epinephrine on blood loss associated with this procedure. METHODS: A retrospective cohort study was conducted in which all cases of knee contractures managed with Judet's quadricepsplasty from 1st January 2009 to 31st December 2013 were included and were divided into two groups. The epinephrine group included patients who were infiltrated with diluted epinephrine (1:400,000) along with xylocaine, around the operative field 15 min prior to the incision time, while the control group did not receive any infiltration. Judet's outcome, blood loss, drop in hemoglobin and required blood transfusion were noted for all patients and compared between both groups. RESULTS: Most common preceding pathology identified for the development of knee contractures was periarticular fracture while ilizarov application was the most common etiology. Both groups were found similar in all preoperative characteristics except preoperative flexion contracture (p = 0.02). All functional outcome measures including Judet's outcome were similar in both groups. In contrast, duration of surgery (p = 0.01), blood loss (p = 0.02), drop in hemoglobin (p = 0.01) and number of transfusions (p = 0.03) were significantly reduced in epinephrine group. CONCLUSION: Judet's quadricepsplasty is a useful procedure to increase the range of motion of rigid knees and local infiltration of epinephrine is effective in decreasing the amount of subsequent blood loss and transfusion requirements. PMID- 28554593 TI - Erratum to "Secondary latissimus dorsi transfer after failed reverse total shoulder arthroplasty" [J Shoulder Elbow Surg 2015;24:e337-e344]. PMID- 28554592 TI - Progresses in understanding trauma-induced coagulopathy and the underlying mechanism. AB - Trauma-induced coagulopathy (TIC) is a clinical syndrome caused by imbalance between clotting, anti-coagulation and fibrinolysis resulting from multiple pathological factors such as hemorrhage and tissue injury in the early stage of trauma, and is closely related to the outcome of trauma patients. It is proved in growing evidence that the endogenous coagulation disturbance in trauma itself is the activating factor of TIC, rather than dilution or other acquired coagulopathy. Therefore, a thorough understanding of the molecular mechanisms in the pathogenesis and progression is crucial for effective prevention and treatment in patients with TIC. This review focuses on transitions in the concept of TIC and mechanical progress. PMID- 28554594 TI - Improvement of 5,6alpha-epoxycholesterol, 5,6beta-epoxycholesterol, cholestane 3beta,5alpha,6beta-triol and 6-oxo-cholestan-3beta,5alpha-diol recovery for quantification by GC/MS. AB - 5,6alpha-epoxycholesterol (5,6alpha-EC) and 5,6beta-epoxycholesterol (5,6beta-EC) are oxysterols involved in the anticancer pharmacology of the widely used antitumor drug tamoxifen. They are both metabolized into cholestane 3beta,5alpha,6beta-triol (CT) by the cholesterol-5,6-epoxide hydrolase (ChEH) enzyme, and CT is metabolized by an as-yet uncharacterized enzyme into 6-oxo cholestan-3beta,5alpha-diol (OCDO). A recent feasibility study showed that the 5,6-ECs may represent surrogate markers of tamoxifen activity in breast cancer patients undergoing endocrine therapy, thus there is a growing interest in their accurate quantification. These oxysterols are usually quantified by gas-liquid chromatography coupled to mass spectrometry (GC/MS), using an isotope dilution methodology with the corresponding deuterated oxysterol. This method is considered to be relative quantitative since all of the standards used are deuterated oxysterols, however it is not known whether the preparation of each oxysterol is affected in the same way by the extraction, pre-purification by solid phase extraction (SPE) and trimethylsilylation steps, particularly when using biological samples that contain many other reactive compounds. Thus, in this study we investigated the yield of the 5,6-ECs, CT and OCDO recovery from patient serum samples at different stages of their work-up and trimethylsilylation prior to GC/MS analysis, using [14C]-labeled analogs to follow these oxysterols at each step. We measured a 40 to 60% loss of material for the 5,6-ECs and OCDO, however we also describe the conditions that improved their recovery. Our data also show that the use of deuterated 5,6alpha-EC, 5,6beta-EC, CT and OCDO is an absolute requirement for their accurate quantification. PMID- 28554595 TI - Design of electrospun nanofibrous mats for osteogenic differentiation of mesenchymal stem cells. AB - The clinical translation potential of mesenchymal stem cells (MSCs) in regenerative medicine has been greatly exploited. With the merits of high surface area to volume ratio, facile control of components, well retained topography, and the capacity to mimic the native extracellular matrix (ECM), nanofibers have received a great deal of attention as bone tissue engineering scaffolds. Electrospinning has been considered as an efficient approach for scale-up fabrication of nanofibrous materials. Electrospun nanofibers are capable of stimulating cell-matrix interaction to form a cell niche, directing cellular behavior, and promoting the MSCs adhesion and proliferation. In this review, we give a comprehensive literature survey on the mechanisms of electrospun nanofibers in supporting the MSCs differentiation. Specifically, the influences of biological and physical osteogenic inductive cues on the MSCs osteogenic differentiation are reviewed. Along with the significant advances in the field, current research challenges and future perspectives are also discussed. PMID- 28554598 TI - Baseline risk factors for drug use among African-American patients during first month induction/stabilization on methadone. AB - Drug use during methadone induction/stabilization negatively influences later methadone-maintenance-treatment [MMT] outcomes (retention, abstinence). Our study examined the association of baseline risk factors to drug use during the first month of methadone treatment as well as longer-term treatment retention. We conducted these analyses among a race/ethnic minority group at high risk for worse MMT outcomes. African-American MMT patients (N=212) were interviewed at intake to assess clinical (drug use history), psychosocial (close family member substance abuse, psychosocial problems), and demographic factors. Outcomes were first-month opioid+ and cocaine+ urine drug screen [UDS] results and retention (days in treatment). In bivariate analyses, co-occurring cocaine abuse/dependence was associated with worse outcomes for opioid+ UDS, cocaine+ UDS, and retention. Being a primary injection opioid user and residing farther from the clinic were associated with a higher proportion of cocaine+ UDS and shorter retention, respectively. Patients with a significant other substance abuse history provided a higher proportion of both opioid+ and cocaine+ UDS. Sibling and parent substance abuse histories were associated with a higher proportion of opioid+ UDS and shorter retention. Psychosocial problems (economic, housing) were associated with a higher proportion of cocaine+ UDS. In multivariate analyses, co-occurring cocaine abuse/dependence and primary injection opioid use best accounted for first-month opioid+ and cocaine+ UDS, respectively. A higher proportion of first month opioid+ and cocaine+ UDS and living farther from the clinic accounted for retention. African-American patients reporting baseline risk factors (particularly clinical) experience worse short- and long-term MMT outcomes. Recommendations for improving standards of care are discussed. PMID- 28554596 TI - Gradient nanocomposite hydrogels for interface tissue engineering. AB - Two-dimensional (2D) nanomaterials are an emerging class of materials with unique physical and chemical properties due to their high surface area and disc-like shape. Recently, these 2D nanomaterials have been investigated for a range of biomedical applications including tissue engineering, therapeutic delivery and bioimaging, due to their ability to physically reinforce polymeric networks. Here, we present a facile fabrication of a gradient scaffold with two natural polymers (gelatin methacryloyl (GelMA) and methacrylated kappa carrageenan (MkappaCA)) reinforced with 2D nanosilicates to mimic the native tissue interface. The addition of nanosilicates results in shear-thinning characteristics of prepolymer solution and increases the mechanical stiffness of crosslinked gradient structure. A gradient in mechanical properties, microstructures and cell adhesion characteristics was obtained using a microengineered flow channel. The gradient structure can be used to understand cell-matrix interactions and to design gradient scaffolds for mimicking tissue interfaces. PMID- 28554597 TI - Why aren't physicians prescribing more buprenorphine? AB - BACKGROUND & OBJECTIVE: Buprenorphine is an underutilized pharmacotherapy that can play a key role in combating the opioid epidemic. Individuals with opioid use disorder (OUD) often struggle to find physicians that prescribe buprenorphine. Many physicians do not have the waiver to prescribe buprenorphine, and a large proportion of physicians that are waivered do not prescribe to capacity. This study aimed to quantitatively understand why physicians do not utilize buprenorphine for the treatment of OUD more frequently. METHODS: Physicians (n=558) with and without the waiver to prescribe buprenorphine were surveyed about perceived drawbacks associated with prescribing buprenorphine. Furthermore, resources were identified that would encourage those without the waiver to obtain it, and those with the waiver to accept more new patients. The survey was distributed online to physicians in the spring/summer of 2016 via the American Society for Addiction Medicine and American Medical Association listservs. RESULTS AND CONCLUSIONS: A logistic regression analysis was used to identify reasons that respondents indicated no willingness to increase prescribing (chi2(4)=73.18, p<0.001); main reasons were lack of belief in agonist treatment (OR 3.98, 95% CI, 1.43 to 11.1, p=0.008), lack of time for additional patients (OR 5.54, 95% CI, 3.5 to 8.7, p<0.001), and belief that reimbursement rates are insufficient (OR 2.50, 95% CI, 1.3 to 4.8, p=0.006). Differences between non waivered and waivered physicians concerning attitudes toward buprenorphine treatment as well as resources that would increase willingness to prescribe are also discussed. Identifying barriers to buprenorphine utilization is crucial in expanding treatment options for individuals with OUD. PMID- 28554599 TI - Pharmacokinetics and pharmacodynamics of a buprenorphine subcutaneous depot formulation (CAM2038) for once-weekly dosing in patients with opioid use disorder. AB - INTRODUCTION: Sublingual buprenorphine is effective for opioid dependence treatment but associated with misuse, abuse, and diversion. The present Phase I/II study evaluated a novel buprenorphine subcutaneous depot formulation for once-weekly dosing (CAM2038 q1w) in patients receiving maintenance treatment for opioid use disorder with daily sublingual buprenorphine. METHODS: After discontinuation of buprenorphine for 48h, patients received a single CAM2038 q1w dose based on their pre-study daily sublingual maintenance dose. CAM2038 q1w doses of 7.5, 15, 22.5, and 30mg were administered in a sequential dose escalating design. The following assessments were performed: pharmacokinetics of buprenorphine and norbuprenorphine, pharmacodynamics (evaluated using the Subjective and Clinical Opiate Withdrawal Scales), and time to intake of rescue sublingual buprenorphine medication. RESULTS: Single doses of CAM2038 q1w indicated dose-proportional buprenorphine pharmacokinetics (Cmax and AUC0-7d), with time to Cmax ~20h and an apparent terminal half-life of 3-5days, supporting once-weekly dosing. On average, patients showed a rapid and extended decrease in opiate-withdrawal symptoms from baseline, with zero or very low SOWS and COWS values measured at least up to 7days after dosing of CAM2038 q1w. The median time to first use of rescue buprenorphine was 10days. No dose dependence was seen in the pharmacodynamics, attributable to the selection of CAM2038 q1w doses based on patients' pre-study maintenance doses. CAM2038 q1w was safe and generally well tolerated. CONCLUSIONS: Pharmacokinetics and pharmacodynamics of a novel buprenorphine subcutaneous depot formulation for once-weekly dosing was evaluated, suggesting utility in maintenance treatment of patients with opioid use disorder. PMID- 28554600 TI - Gratitude, abstinence, and alcohol use disorders: Report of a preliminary finding. AB - Gratitude is a central component of addiction recovery for many, yet it has received scant attention in addiction research. In a sample of 67 individuals entering abstinence-based alcohol-use-disorder treatment, this study employed gratitude and abstinence variables from sequential assessments (baseline, 6months, 12months) to model theorized causal relationships: gratitude would increase pre-post treatment and gratitude after treatment would predict greater percent days abstinent 6months later. Neither hypothesis was supported. This unexpected result led to the theory that gratitude for sobriety was the construct of interest; therefore, the association between gratitude and future abstinence would be positive among those already abstinent. Thus, post-treatment abstinence was tested as a moderator of the effect of gratitude on future abstinence: this effect was statistically significant. For those who were abstinent after treatment, the relationship between gratitude and future abstinence was positive; for those drinking most frequently after treatment, the relationship between gratitude and future abstinence was negative. In this preliminary study, dispositional tendency to affirm that there is much to be thankful for appeared to perpetuate the status quo-frequent drinkers with high gratitude were drinking frequently 6months later; abstinent individuals with high gratitude were abstinent 6months later. Gratitude exercises might be contraindicated for clients who are drinking frequently and have abstinence as their treatment goal. PMID- 28554601 TI - Hepatitis C virus core antigen: A potential alternative to HCV RNA testing among persons with substance use disorders. AB - BACKGROUND: The hepatitis C virus (HCV) core antigen (HCVcAg) may be an alternative diagnostic method to HCV RNA especially in populations such as substance users, the homeless or in resource-limited settings. AIMS: To evaluate performance of HCVcAg test in patients with opioid use disorder (OUD) on methadone in order to document its performance characteristics in the target population and to ensure that its specificity remains consistent across different populations. METHODS: HCVcAg levels from 109 methadone-maintained patients were compared to HCV RNA levels. RESULTS: Mean age was 53.8+/-7.8years, 59.6% were male, 68.8% African American, and 44% HCV-infected. HCVcAg was detectable in 47 of 48 HCV-infected, and undetectable in all HCV RNA negative patients. The HCVcAg assay had sensitivity of 97.9% and specificity of 100%. Correlation with HCV RNA levels was excellent (r=0.88, 95% CI 0.76; 0.95, p<0.01). CONCLUSION: HCVcAg has excellent performance for the diagnosis of HCV infection in patients with OUD on methadone. PMID- 28554602 TI - The relationship between diversion-related attitudes and sharing and selling buprenorphine. AB - OBJECTIVE: Buprenorphine medication-assisted treatment (B-MAT) is an efficacious and popular outpatient treatment for opioid use disorder. However, the likelihood of buprenorphine diversion is a public health concern. We examined the relationship between attitudes toward diversion as predictors of both sharing and selling buprenorphine. METHOD: Participants (n=476) were patients undergoing short-term inpatient opioid detoxification. Multinomial logistic regression was used to estimate the adjusted association of sharing and selling buprenorphine with demographics, substance use behaviors, and attitudes toward sharing and selling buprenorphine. RESULTS: Among the two hundred persons who had ever been prescribed buprenorphine (73.4% male, 89% heroin users), 50.5% reported they had shared buprenorphine and 28.0% reported they had sold buprenorphine. Controlling for other covariates, the odds of sharing buprenorphine were 3.17 (95% CI 1.21; 8.32) times higher for persons who agreed that it was "right to share buprenorphine with dope sick friends" than for those who did not agree with this attitude. Attitudes toward selling (OR 2.92; 95% CI 1.35; 6.21) and sharing (OR 4.12; 95% CI 1.64; 10.32) buprenorphine were the only significant correlates of selling, with the odds of selling exponentially greater among persons with favorable attitudes toward sharing or selling buprenorphine. CONCLUSIONS: Although considered diversion, sharing B-MAT is normative among B-MAT patients. Assessing B-MAT patients' attitudes about diversion may help identify patients requiring enhanced oversight, education, or intervention aimed at modifying attitudes to reduce their likelihood to share or sell buprenorphine. PMID- 28554603 TI - Association between executive function and outcome measure of treatment in therapeutic community among cocaine dependent individuals. AB - The aim of this study was to examine the association between baseline executive functioning and outcome measure of treatment in 226 cocaine dependent individuals who initiated treatment in therapeutic communities TCs. The study was conducted across six TCs located in the region of Andalusia (southern Spain). Neuropsychological testing included tests of working memory, reasoning, inhibition, switching, attention interference and decision making. The outcome measures were type of discharge (treatment dropout vs. therapeutic discharge) and clinical impression of the TC outcome (clinically significant vs. non-significant changes). In the present study a prospective comparative design was used. We found significant performance differences on selective executive components which account for the type of discharge: treatment quitters had poorer attention response inhibition and attention switching than non-quitters, and the individuals who failed to achieve therapeutic objectives had poorer attention interference and inhibitory control than compliers. No significant differences were found between the outcome measure and the neuropsychological performance score on the other tasks. The results provide important information about the impact of executive components on in-treatment follow-up outcomes among dependence disorders in TC. PMID- 28554604 TI - How online counselling can support partners of individuals with problem alcohol or other drug use. AB - BACKGROUND: Problematic alcohol and other drug (AOD) use impacts partners heavily, with an increased risk of experiencing domestic violence, financial stressors, health problems and relationship challenges. However, partners often do not seek help or support due to a range of barriers (e.g., shame, stigma, practical constraints). Online counselling may facilitate help-seeking by overcoming many of these barriers, however research is needed to explore what motivates partners to contact online counselling services, their experiences and needs, and how partners can be best supported online. METHOD: One hundred transcripts of partners of individuals with problem AOD use were sampled from a 24-hour national AOD synchronous online chat counselling service. Descriptive content analysis was used to investigate themes related to help-seeking. RESULTS: Three broad themes, with seven sub-themes, were identified: (i) the reason for accessing online counselling (seeking advice, wanting to talk), (ii) discussing help-seeking and coping processes (past/present help-seeking or coping strategies, barriers and facilitators to seeking help and change), and (iii) planning for future assistance (future planning, treatment preferences). CONCLUSIONS: Partners wanted to talk about their concerns with a non-judgemental professional. However, the majority of help-seekers wanted advice and assistance in problem-solving, coping and the process of seeking further help. Future studies need to examine the impact of online help-seeking by partners. PMID- 28554605 TI - Corrigendum to "Timing matters: A randomized control trial of recovery coaches in foster care" [Journal of Substance Abuse Treatment 77 (2017) 178-184]. PMID- 28554606 TI - A randomized trial of brief assessment interventions for young adults who use drugs in the club scene. AB - BACKGROUND: Efficacious interventions to reduce drug use and its consequences for club drug using populations are not apparent in the literature. We tested interviewer- (CAPI) and self-administered (ACASI) comprehensive health and social risk assessments as distinct interventions compared to waitlist control. METHODS: 750 men and women ages 18-39 with multidrug use and heterosexual behavior were randomized in equal proportions to the three conditions. Instrumentation included well-tested measures of drug use, risky sex, mental distress and substance dependence. RESULTS: The sample was 56% male; mean age=25. Reported risk behaviors and health consequences did not differ by assessment modality. Adjusted HLM analyses showed a significant main effect of assigned condition on all outcomes. CAPI participants had greater reductions in drug use, risky sex, mental distress and substance dependence symptoms, and greater increases in abstinence, compared to ACASI intervention or control participants at 12months, except that the CAPI and ACASI conditions had similar efficacy for reductions in drug use. Effect sizes for CAPI versus ACASI participants were d=0.2-0.3, and between CAPI and controls d=0.2-0.4. Effect sizes for improved outcomes between ACASI compared to controls were small to non-significant. CONCLUSIONS: The study established the therapeutic benefit of interviewer interaction in reducing risky behavior among this young drug using population. The study demonstrated the efficacy and acceptability of a low threshold intervention in reducing drug use, sexual risk and related co-morbidities among a not-in-treatment young adult population that exhibits severe and complex levels of drug use, but that is also highly resistant to intervention. PMID- 28554607 TI - Cardiorespiratory fitness and body composition of stimulant users: A baseline analysis of the STRIDE cohort. AB - INTRODUCTION: Relatively little has been reported about the physical characteristics, such as cardiorespiratory fitness (CRF) and body composition, of stimulant users. Identifying risk factors associated with the physical health of stimulant users is an important public health issue as new treatments should better address the entire range of health concerns experienced by this population. METHODS: We examined cross-sectional data gathered at baseline from the STimulant Reduction Intervention using Dosed Exercise (STRIDE) study, a multisite randomized clinical trial that examined exercise as an adjunct to treatment as usual for individuals in residential treatment programs (RTPs). Clients were approached after intake to the RTP. Prior to randomization, eligible individuals underwent a comprehensive screening process that included medical screening, where CRF was assessed through a maximal exercise test (time on treadmill), and a series of baseline examinations assessing domains of substance use and mental health. RESULTS: Data from 295 individuals with recent stimulant use disorders were analyzed. The mean body mass index (BMI) and waist circumference (WC) and for all participants was 27.8+/-5.7kg/m2 and 93.5+/ 14.2cm, respectively, while the mean time on treadmill was 13.7+/-2.9min. Few significant associations were observed between CRF, BMI, or WC and substance use and mental health measures. CONCLUSIONS: Stimulant users in this study presented with low CRF levels and would be considered overweight based on their BMI. These individuals would likely benefit from interventions that address both their stimulant use, as well as their physical health. PMID- 28554608 TI - Documented brief intervention not associated with resolution of unhealthy alcohol use one year later among VA patients living with HIV. AB - OBJECTIVE: Unhealthy alcohol use is particularly risky for patients living with HIV (PLWH). Brief interventions reduce drinking among patients with unhealthy alcohol use, but whether its receipt in routine outpatient settings is associated with reduced drinking among PLWH with unhealthy alcohol use is unknown. We assessed whether PLWH who screened positive for unhealthy alcohol use were more likely to resolve unhealthy drinking one year later if they had brief alcohol intervention (BI) documented in their electronic health record in a national sample of PLWH from the Veterans Health Administration. METHODS: Secondary VA clinical and administrative data from the electronic medical record (EMR) were used to identify all positive alcohol screens (AUDIT-C score>=5) documented among PLWH (10/01/09-5/30/13) followed by another alcohol screen documented 9-15months later. Unadjusted and adjusted Poisson regression models assessed the association between brief intervention (advice to reduce drinking or abstain documented in EMR) and resolution of unhealthy alcohol use (follow-up AUDIT-C<5 with >=2 point reduction). RESULTS: Overall 2101 PLWH with unhealthy drinking (10/01/09-5/30/13) had repeat alcohol screens 9-15months later. Of those, 77% had brief intervention documented after their first screen, and 61% resolved unhealthy alcohol use at follow-up. Documented brief intervention was not associated with resolution [Adjusted incidence rate ratio 0.96, (95% CI 0.90-1.02)]. CONCLUSIONS: Documented brief intervention was not associated with resolving unhealthy alcohol use at follow-up screening among VA PLWH with unhealthy alcohol use. Effective methods of resolving unhealthy alcohol use in this vulnerable population are needed. PMID- 28554609 TI - Biofilm-induced changes to the composite surface. AB - OBJECTIVES: Composites may undergo biodegradation in the oral cavity. The objective was to investigate the effect of single- and multi-species biofilms on the surface roughness and topography of two composites. METHODS: Disk-shaped specimens of a paste-like, Bis-GMA-free (Gradia Direct Anterior, GC), and a flowable, Bis-GMA-based composite (Tetric EvoFlow, Ivoclar-Vivadent) were prepared. After ethylene-oxide sterilization (38 degrees C), specimens (n=3) were incubated with Streptococcus mutans or mixed bacterial culture (Streptococcus mutans, Streptococcus sanguinis, Actinomyces naeslundii and Fusobacterium nucleatum). As negative controls, unexposed specimens and specimens exposed to sterile medium (BHI) were used. Specimens exposed to acidified BHI medium (pH=5) and enzymatic solution of cholesterol esterase served as positive control. Following 6-week incubation, the attached biofilms were collected for real-time PCR assessment, after which the surface roughness and topography of the specimens were analyzed with atomic force microscopy. Surface hydrophilicity/hydrophobicity was determined by contact angle measurements. Biofilm structure was analyzed with scanning electron microscopy. RESULTS: Even though multi-species biofilms were thicker, with more cells attached, they did not significantly affect the surface roughness of the composites. On the other hand, S. mutans alone significantly increased the roughness of Tetric by 40.3%, while its effect on Gradia was lower (12%). The total amount of attached bacteria, however, did not differ between the composites. CONCLUSIONS: S. mutans can increase the surface roughness of composites, depending on their composition. This ability of S. mutans is, however, mitigated in co-culture with other species. In particular, bacterial esterases seem to be responsible for the increased composite surface roughness upon biofilms exposure. CLINICAL SIGNIFICANCE: Cariogenic bacteria can degrade composites, thereby increasing the surface roughness. Increased roughness and subsequent improved bacterial accumulation may facilitate the development of secondary caries around composites, which is the most common reason for the restoration failure. PMID- 28554610 TI - Reverse allostasis in biological systems: Minimal conditions and implications. AB - Biological control systems regulate the behavior of biological systems in a constantly changing environment. Homeostasis is the most widely studied outcome of biological control systems. Homeostatic systems maintain the system in its desired state despite variations in system parameters or the externally determined input rates of their constituents, i.e. they have zero or near zero steady state error. On the other hand, allostatic systems are not resistant against environmental changes and the steady state level of their controlled variables responds positively to the changes in their input rates. Little is known, however, on the existence and frequency of reverse allostatic systems, where the steady state value of the controlled variable correlates negatively with the input rate of that variable. In the present study, we derive the minimal conditions for the existence and local stability of reverse allostatic systems, and demonstrate in examples of metabolic, pharmacological, pathophysiological and ecological systems that the reverse allostasis requirements are relatively non stringent and may be satisfied in biological systems more commonly than usually thought. The possible existence of reverse allostatic systems in nature and their counter-intuitive implications in physiological systems, drug treatment, ecosystem management, and biological control are explored and testable predictions are made. PMID- 28554611 TI - A mathematical model of embodied consciousness. AB - We introduce a mathematical model of embodied consciousness, the Projective Consciousness Model (PCM), which is based on the hypothesis that the spatial field of consciousness (FoC) is structured by a projective geometry and under the control of a process of active inference. The FoC in the PCM combines multisensory evidence with prior beliefs in memory and frames them by selecting points of view and perspectives according to preferences. The choice of projective frames governs how expectations are transformed by consciousness. Violations of expectation are encoded as free energy. Free energy minimization drives perspective taking, and controls the switch between perception, imagination and action. In the PCM, consciousness functions as an algorithm for the maximization of resilience, using projective perspective taking and imagination in order to escape local minima of free energy. The PCM can account for a variety of psychological phenomena: the characteristic spatial phenomenology of subjective experience, the distinctions and integral relationships between perception, imagination and action, the role of affective processes in intentionality, but also perceptual phenomena such as the dynamics of bistable figures and body swap illusions in virtual reality. It relates phenomenology to function, showing the computational advantages of consciousness. It suggests that changes of brain states from unconscious to conscious reflect the action of projective transformations and suggests specific neurophenomenological hypotheses about the brain, guidelines for designing artificial systems, and formal principles for psychology. PMID- 28554612 TI - Essential oil diversity of Origanum vulgare L. populations from Southern Italy. AB - Essential oils (EOs) belonging to 25 wild populations of Origanum vulgare L. samples, growing wild in different locations of Calabria Region (Southern Italy), were analyzed using gas chromatography-mass spectrometry. The quantitative and qualitative data showed EO concentrations ranging from 0.96 to 5.10% and 37 compounds detected, representing more than 80% of the total composition of the oils. By applying hierarchical cluster analysis on the basis of the EO constituents, two main groups and three subgroups were found, reflecting the variation in the chemical composition of EOs from wild oregano populations. The first group consisted of acyclic (linalool/linalyl acetate) chemotypes with a predominant presence of linalyl acetate; the second was characterized by chemotypes rich in cymyl-compounds, mainly carvacrol, thymol and gamma-terpinene. The data obtained contribute to broaden the inventory of wild oregano populations from Calabria to plan programs for the selection of chemotypes with new and specific uses. PMID- 28554613 TI - Phytic acid-stabilized super-amphiphilic Fe3O4-graphene oxide for extraction of polycyclic aromatic hydrocarbons from vegetable oils. AB - Phytic acid-stabilized Fe3O4-graphene oxide (GOPA@Fe3O4) was assembled by microwave-enhanced hydrothermal synthesis and super-amphipathicity was demonstrated by measurement of dynamic oil and water contact angles. GOPA@Fe3O4 was used as a sorbent for enrichment of eight polycyclic aromatic hydrocarbons (PAHs) from vegetable oils by magnetic solid-phase extraction (MSPE). The extraction-desorption factors were systematically investigated and, under optimum conditions, the super-amphiphilic sorbent achieved wide linear ranges (0.2-200ngg 1), satisfactory precision (3.44-6.64% for intra-day and 5.39-8.41% for inter day) and low limits of detection (LODs, 0.06-0.15ngg-1) for PAHs. Excellent recoveries (85.6-102.3%) for spiked PAHs were obtained with genuine vegetable oil samples. These results indicate that MSPE using GOPA@Fe3O4 as the sorbent, coupled with high performance liquid chromatography (HPLC), is an efficient and simple method for the detection of low concentrations of PAHs in vegetable oils. PMID- 28554614 TI - Antibiotic use in heavy pigs: Comparison between urine and muscle samples from food chain animals analysed by HPLC-MS/MS. AB - The antibiotic overuse in zoothechnics, due to prophylactic and therapeutic treatments, or to their growth-promoting activity, is a major cause for the onset of widespread antibiotic resistance. Of particular relevance to this study, is the antibiotic abuse in pig breeding. Despite the comprehensive literature on residue controls in pig muscle, data on pig urine, a non-invasive, on-farm collectable matrix, are lacking. Therefore, we validated an HPLC-MS/MS method to detect 29 antimicrobials from eight classes and applied it to 43 anonymous pig urine and muscle paired samples and fulfilled the parameters in agreement with the Commission Decision 2002/657/UE. The analytical limits were moreover much lower than the maximum residue limits (MRLs) required by the Commission Regulation 37/2010/UE. In the samples, antibiotics were usually detected at higher frequencies and concentrations in urine than muscle. Urine proved a useful tool to detect antibiotic administration and their excessive use in pig farming is depicted. PMID- 28554615 TI - Utilization of quercetin and quercetin glycosides from onion (Allium cepa L.) solid waste as an antioxidant, urease and xanthine oxidase inhibitors. AB - This study aimed to determine the flavonol glycosides from onion solid waste (OSW) using HPLC analysis, with antioxidant and enzyme inhibitory activities. We found considerable amount of quercetin-4'-O-monoglucoside (QMG: 254.85), quercetin-3,4'-O-diglucoside (QDG: 162.34), quercetin (Q: 60.44), and isorhamnetin-3-glucoside (IMG: 23.92) (mg/100g) dry weight (DW) of OSW. For OSW, the methanol and ethanol showed the strongest antioxidant activities, followed by ethyl acetate, chloroform, and n-hexane extracts. Among the flavonols, Q and QDG possessed higher antioxidant activities. OSW and flavonol glycosides displayed significant enzyme inhibitory activity, with IC50 values ranging from 12.5+/-0.11 to 32.5+/-0.28 for OSW, 8.2+/-0.07 to 16.8+/-0.02 for flavonol glycosides, and 4.2+/-0.05MUg/mL for thiourea (positive control) towards urease; while 15.2+/-0.8 to 35.8+/-0.2 (MUg/mL) for OSW, 10.5+/-0.06 to 20.8+/-0.05 (MUg/mL) for flavonol glycosides, and 6.5+/-0.05MUg/mL for allopurinol (positive control) towards xanthine oxidase, respectively. The OSW and flavonol glycosides may thus be considered as potential antioxidant and antigout agents. PMID- 28554616 TI - Essential oils as food eco-preservatives: Model system studies on the effect of temperature on limonene antibacterial activity. AB - Antimicrobial properties of essential oils predestine these substances to be used as ecological food preservatives. However, their activity is determined by variety of factors among which external conditions and food properties are highly important. Herein the influence of limonene on artificial membranes was studied to verify the effect of temperature on the incorporation of this compound into model bacterial membrane. The investigations were done on lipid monolayers and the experiments involved the surface pressure-area measurements, penetration studies and Brewster Angle Microscopy analysis. It was found that limonene incorporates into lipid monolayers causing their fluidization. However, the magnitude of alterations depends on limonene concentration, model membrane composition and, for a given composition, on system condensation. Moreover, the influence of limonene is stronger at lower temperatures and, in the light of collected data, this may be a consequence of strong volatility and evaporation of limonene increasing with temperature. PMID- 28554617 TI - Dynamic controlled atmosphere (DCA): interaction between DCA methods and 1 methylcyclopropene on 'Fuji Suprema' apple quality. AB - The objective of the present work was to evaluate the appropriate respiratory quotient (RQ) value to achieve a safe lowest oxygen limit (LOL), during storage of 'Fuji Suprema' apples, in dynamic controlled atmosphere (DCA), treated with or without 1-methylcyclopropene (1-MCP). The apples were stored in DCA-RQ, a new technology for storing fruits, and were compared with the HarvestWatchTM, a system based on chlorophyll fluorescence DCA (DCA-CF), and static controlled atmosphere. DCA-RQ1.5 is the most suited for the storage of 'Fuji Suprema' apples. In this condition fermentative products were induced, which reduced ethylene production and respiration rate; however, it did not increase physiological disorders, and the concentration of ethyl acetate was below the odour threshold. 1-MCP application maintained higher flesh firmness and reduced the anaerobic metabolism, although it decreased fruit quality due to the occurrence of cavities, therefore its application is not recommended for 'Fuji Suprema' apple stored in DCA conditions. PMID- 28554618 TI - Graphene oxide-sensitized molecularly imprinted opto-polymers for charge-transfer fluorescent sensing of cyanoguanidine. AB - The hierarchical structuring of materials offers exciting opportunities to construct functional sensors. Multiple processes were combined to create complex materials for the selective detection of cyanoguanidine (CYA) using graphene oxide-sensitized molecularly imprinted opto-polymers (MIOP). Molecular imprinting was used to construct molecular-scale analyte-selective cavities, graphene oxide was introduced to provide a platform for the polymerization, and increase the stability and binding kinetic properties, and 3-methacryloxy propyl trimethoxy silane-modified quantum dots were combined with a functional monomer to increase the fluorescence quantum yield. Polymer cross-linking and fluorescence intensity were optimized for molecular recognition and opto-sensing detection. Selective and sensitive, fluorescence sensing of CYA was possible at concentrations as low as to 1.6MUM. It could be applied to the rapid and cost-effective monitoring of CYA in infant formula. The approach is generic and applicable to many molecules and conventional opto-sensors, based on molecularly imprinted polymer formulations, individually or in multiplexed arrays. PMID- 28554619 TI - Swarm motility inhibitory and antioxidant activities of pomegranate peel processed under three drying conditions. AB - During processing of ready-to-eat fresh fruits, large amounts of peel and seeds are discarded as waste. Pomegranate (Punicagranatum) peels contain high amounts of bioactive compounds which inhibit migration of Salmonella on wet surfaces. The metabolic distribution of bioactives in pomegranate peel, inner membrane, and edible aril portion was investigated under three different drying conditions along with the anti-swarming activity against Citrobacter rodentium. Based on the multivariate analysis, 29 metabolites discriminated the pomegranate peel, inner membrane, and edible aril portion, as well as the three different drying methods. Punicalagins (~38.6-50.3mg/g) were detected in higher quantities in all fractions as compared to ellagic acid (~0.1-3.2mg/g) and punicalins (~0-2.4mg/g). The bioactivity (antioxidant, anti-swarming) and phenolics content was significantly higher in peels than the edible aril portion. Natural anti-swarming agents from food waste may have promising potential for controlling food borne pathogens. PMID- 28554620 TI - Changes in flavonoid and phenolic acid contents in some Rosa species during ripening. AB - In this study, fruits of Rosa dumalis, R. canina, and R. villosa were cultivated and harvested at six different time points based on colour changes during the ripening period. Phenolic acid and flavonoid contents in fresh hypanthium were determined by HPLC-DAD. Derivatives of organic acid (gallic, caffeic, p-coumaric, and ferulic acids) and flavonoid (catechin, eriocitrin, rutin, apigenin, quercetin, apigenin-7-O-glucoside and kaempferol) were quantified using calibration curves. Phenolic acid contents of the Rosa species increased nonlinearly depending on the harvesting time. The highest amount of catechin was found at the fifth harvest time point (H-5) ranged from 323 to 472mgkg-1. The highest level of caffeic acid content was found in the R. dumalis ranged from 24 to 77mgkg-1. The total amount of flavonoid increased up to the fifth harvest time point (H-5), whereas the amount of total phenolic acid tended to decrease until the same harvest period. PMID- 28554621 TI - Enhancing oxidative stability in heated oils using core/shell structures of collagen and alpha-tocopherol complex. AB - In this study, collagen mesh structure was prepared by carrying alpha-tocopherol in the form of core/shell complex. Antioxidant properties of alpha-tocopherol loaded carriers were tested in moisture added bulk oils at 140 degrees C. From one gram of collagen core/shell complex, 138mg alpha-tocopherol was released in medium chain triacylglycerol (MCT). alpha-Tocopherol was substantially protected against heat treatment when alpha-tocopherol was complexed in collagen core/shell. Oxidative stability in bulk oil was significantly enhanced by added collagen mesh structure or collagen core/shell complex with alpha-tocopherol compared to that in control bulk oils (p<0.05), although no significant difference was observed between oils containing collagen mesh structure and collagen core/shell with alpha-tocopherol (p>0.05). Results of DPPH loss in methanol demonstrated that collagen core/shell with alpha-tocopherol had significantly (p<0.05) higher antioxidant properties than collagen mesh structure up to a certain period. Therefore, collagen core/shell complex is a promising way to enhance the stability of alpha-tocopherol and oxidative stability in oil-rich foods prepared at high temperature. PMID- 28554622 TI - Comparison of anti-pathogenic activities of the human and bovine milk N-glycome: Fucosylation is a key factor. AB - Health differences between breast- and formula-fed infants have long been apparent despite great efforts in improving the function of baby formula by adjusting the levels of various milk nutritional components. However, the N glycome, a type of oligosaccharide decorating a diverse range of proteins, has not been extensively studied in milk regarding its biological function. In this study, the anti-pathogenic function of the enzymatically released human and bovine milk N-glycome against 5 food-borne pathogens was investigated. The human milk N-glycome showed significantly higher activity than bovine milk. After enzymatic defucosylation of human and bovine N-glycan pool, UHPLC peak shifts were observed in both suggesting heavy fucosylation of samples. Furthermore, the anti-pathogenic activity of the defulosylated N-glycome decreased significantly, and the significance of functional difference between the two almost disappeared. This result indicates the essential role of fucosylation for the anti-pathogenic function of the milk N-glycome, especially in human milk. PMID- 28554623 TI - Environmental-friendly technologies for the production of antioxidant xylooligosaccharides from wheat chaff. AB - Ultrasound irradiation and enzymatic hydrolysis were applied for the production of antioxidant xylooligosaccharides from wheat chaff. To facilitate enzyme action, 3% (w/w) suspension of raw material was pretreated by ultrasound at 25Hz, 540W for 10min. Ultrasound treatment released xylooligosaccharides with predominant xylotriose into liquid fraction which expressed 1.03+/-0.01 (MUmolAAE/g) ABTS radicals-scavenging activity. Endo-xylanase action on pretreated wheat chaff released 21.76+/-1.42 and 32.3+/-0.75mg reducing sugars equivalents/g after 24h when applied at dosages 0.15 and 0.3U/g. respectively. With increase in reaction time portion of xylotriose and xylotetraose in hydrolysates was increase relatively to xylopentose as well as quantities of xylose and glucose. Extremely significant inverse correlation between monosaccharides/oligosaccharides ratio and ABTS radical-scavenging activity was determined. Results indicated potential of environmental friendly ultrasound and enzymatic technologies for the production of xylooligosaccharides from wheat chaff for potential food application. PMID- 28554624 TI - Quality improvement of a rice-substituted fried noodle by utilizing the protein polyphenol interaction between a pea protein isolate and green tea (Camellia sinensis) extract. AB - The quality of rice-substituted fried noodles was improved by applying interaction between pea protein isolate (PPI) and green tea extract (GTE). Radical-scavenging activities of GTE were stably maintained when exposed to acidic pH, UV light, and fluorescent light, but decreased by approximately 65% when exposed to 80 degrees C for 168h. The RVA profiles of noodle dough showed that peak viscosity and breakdown increased significantly but that setback and final viscosity remained unchanged with 20% rice flour replacement. PPI significantly decreased the viscosity parameters of rice-supplemented dough, and the addition of GTE recovered these values significantly. The cooking loss and viscoelasticity (Rmax) of cooked rice-supplemented noodles were fully restored by combined treatment of PPI and GTE. GTE decreased the peroxide value of fried noodles by 14% after storage at 63 degrees C for 16days. Therefore, PPI+GTE treatment has great potential for use in fried noodles owing to the reinforced network and antioxidant activity. PMID- 28554626 TI - Hyperspectral imaging detection of decayed honey peaches based on their chlorophyll content. AB - Honey peach is a very common but highly perishable market fruit. When pathogens infect fruit, chlorophyll as one of the important components related to fruit quality, decreased significantly. Here, the feasibility of hyperspectral imaging to determine the chlorophyll content thus distinguishing diseased peaches was investigated. Three optimal wavelengths (617nm, 675nm, and 818nm) were selected according to chlorophyll content via successive projections algorithm. Partial least square regression models were established to determine chlorophyll content. Three band ratios were obtained using these optimal wavelengths, which improved spatial details, but also integrates the information of chemical composition from spectral characteristics. The band ratio values were suitable to classify the diseased peaches with 98.75% accuracy and clearly show the spatial distribution of diseased parts. This study provides a new perspective for the selection of optimal wavelengths of hyperspectral imaging via chlorophyll content, thus enabling the detection of fungal diseases in peaches. PMID- 28554625 TI - Residue behaviors and dietary risk assessment of dinotefuran and its metabolites in Oryza sativa by a new HPLC-MS/MS method. AB - In this study, we developed a new method to detect dinotefuran and its metabolites (UF and DN) in Oryza sativa (Rice) by HPLC-MS/MS in multiple reaction monitoring (MRM) modes. The recovery rates for dinotefuran, UF and DN were 82.3 85.8%, 83.7-89.0%, and 81.6-90.2%, respectively. The dissipation kinetics of dinotefuran in rice followed a combined first+first kinetic model, where the half lives of dinotefuran and its metabolites were determined to be between 0.5 and 2.3days. The dinotefuran residue in brown rice sampled at day 7, 14, and 21 after the last application was 0.4131mg/kg with a very low risk quotient (RQ) value. We recommend that the safety interval of application for rice is 7days. The method developed in this study is simple and rapid, with high accuracy and precision which meet the requirements for quantitative analysis of dinotefuran in rice. PMID- 28554627 TI - Heavy metal exposure from cooked rice grain ingestion and its potential health risks to humans from total and bioavailable forms analysis. AB - Heavy metal in rice studies has attracted a greater concern worldwide. However, there have been limited studies on marketed rice samples although it represents a vital ingestion portion for a real estimation of human health risk. This study was aimed to determine both total and bioaccessible of trace elements and heavy metals (Cd, Cr, Cu, Co, Al, Zn, As, Pb and Fe) in 22 varieties of cooked rice using an inductively coupled plasma-optical emission spectroscopy. Both total and bioaccessible of trace elements and heavy metals were digested using closed nitric acid digestion and Rijksinstituut voor Volksgezondheid en Milieu (RIVM) in vitro digestion model, respectively. Human health risks via Health Risk Assessment (HRA) were conducted to understand exposure risks involving adults and children representing Malaysian population. Zinc was the highest while As was the lowest contents for total and in their bioavailable forms. Four clusters were identified: (1) Pb, As, Co, Cd and Cr; (2) Cu and Al; (3) Fe and (4) Zn. For HRA, there was no any risks found from single element exposure. While potential carcinogenic health risks present for both adult and children from single As exposure (Life time Cancer Risk, LCR>1*10-4). Total Hazard Quotient values for adult and children were 27.0 and 18.0, respectively while total LCR values for adult and children were 0.0049 and 0.0032, respectively. PMID- 28554628 TI - Effect of the presence of protein on lipolysis and lipid oxidation occurring during in vitro digestion of highly unsaturated oils. AB - The effect of the presence of ovalbumin and soy protein isolate on lipolysis and oxidation taking place during in vitro gastrointestinal digestion of slightly oxidized sunflower and flaxseed oils was addressed. The extent of lipolysis, the molar proportions of acyl groups/fatty acids after digestion, and the oxidation products formed were studied by Proton Nuclear Magnetic Resonance. The presence of proteins provoked a higher hydrolysis in triglycerides, a lower decrease of polyunsaturated chains, and a lower generation of oxidation compounds (conjugated dienes in chains having also hydroperoxy/hydroxy groups, epoxides and aldehydes); the formation of hydroxides was clearly favoured over that of hydroperoxides. Study of headspace composition by Solid Phase Microextraction-Gas Chromatography/Mass Spectrometry confirmed that oxidation advanced to a lesser extent in the presence of protein. Thus, amino acids/peptides released during digestion may show antioxidant properties, affecting not only the extent of lipid oxidation, but also reactions pathways. PMID- 28554629 TI - Enhancement of nutritional and bioactive compounds by in vitro culture of wild Fragaria vesca L. vegetative parts. AB - In vitro culture emerges as a sustainable way to produce bioactives for further applicability in the food industry. Herein, vegetative parts of Fragaria vesca L. (wild strawberry) obtained by in vitro culture were analyzed regarding nutritional and phytochemical compounds, as well as antioxidant activity. These samples proved to have higher content of protein, polyunsaturated fatty acids, soluble sugars, organic acids (including ascorbic acid) and tocopherols (mainly alpha-tocopherol) than wild grown F. vesca, as well as containing additional phenolic compounds. The antioxidant activity of hydromethanolic extracts could be correlated with the content of different phenolic groups and other compounds (sugars and organic acids). It was demonstrated that in vitro culture could enhance nutritional and bioactive compounds of Fragaria vesca L. plants, providing a very interesting biotechnological tool for potential food applications. PMID- 28554630 TI - Towards improved quality benchmarking and shelf life evaluation of black tiger shrimp (Penaeus monodon). AB - An improved quality benchmarking and shelf life evaluation of freshly harvested black tiger shrimp (Penaeus monodon) was pursued by combining sensory and chemical methods. This involved developing a quality index method (QIM) to further assess both freshness and shelf life of the studied shrimp samples. The quality index included the use of trimethylamine (TMA-N), total volatile basis nitrogen (TVB-N), histamine, and hypoxanthine, which were performed at scheduled times during the ten days of ice storage (0 degrees C). Shelf life of the studied shrimp was most likely to be 8days, and there were positive linear correlations between quality indices (QI) and storage period. The quality of shrimp decreased over storage time. In fact, significant changes of chemical and sensory characteristics of the shrimp samples would become more obvious from day 5 onwards. Besides, quality classification of black tiger shrimp involved four main levels, namely: excellent, good, moderately acceptable, and just acceptable. PMID- 28554632 TI - The composition of bioactive compounds and antioxidant activity of Saskatoon berry (Amelanchier alnifolia Nutt.) genotypes grown in central Poland. AB - Bioactive compounds in fruits of four Saskatoon berry genotypes grown in a trial in central Poland are presented in this paper. Two Polish breeding clones (no. 5/6 and type S) and two Canadian cultivars - 'Martin' and 'Smoky' - were used in studies conducted in 2015-2016. Fourty-eight bioactive compounds were identified in Saskatoon berry genotypes, including twenty-nine polyphenolic compounds (4 anthocyanins, 9 phenolic acids, 9 flavonols, 7 flavan-3-ols), 3 triterpenoids, 7 carotenoids, 5 chlorophylls and 4 tocopherols. The results of the analysis showed that the fruits of clone no. 5/6 had significantly lower contents of pro-healthy compounds and antioxidant activity in comparison to the other three tested genotypes. These genotypes, which may offer new functional material, can be recommended for fruit growers to increase their income. Their fruits can be used for the food processing industry and for the production of health beneficial products. PMID- 28554631 TI - C-geranylated flavanones from YingDe black tea and their antioxidant and alpha glucosidase inhibition activities. AB - YingDe black tea is produced from crude tea prepared from leaves of Camellia sinensis var. assamica. In this work, we isolated and identified five novel flavanones, namely, amelliaone A-E (1-5), along with seven known compounds 6-12 from the ethanol extract of YingDe black tea. The structures of these five novel phenolic compounds were determined using extensive 1D and 2D nuclear magnetic resonance spectroscopy experiments. The compounds were further evaluated for antioxidant, alpha-glucosidase inhibitory, and cytotoxic activities. Compound 1 exhibited higher alpha-glucosidase inhibitory activity with a half-maximum inhibitory concentration value (IC50) of 10.2uM compared with acarbose (18.2uM). PMID- 28554633 TI - Glycation of clinically relevant chickpea allergen attenuates its allergic immune response in Balb/c mice. AB - Glycation of food allergens may alter their immunological behaviour. We sought to investigate the impact of glycation on the allergenicity of a food protein. Herein, a chickpea protein (~26kDa) was purified and characterized as lectin. Further, glycation of this purified protein was carried out. Thereafter, allergic behaviour of this glycated protein was compared with its native form, using various allergic parameters in Balb/c mice. The reduced allergenicity of glycated protein was observed as lesser allergic phenotypes, reduced serum immunoglobulins and allergic mediators, lower mast cells and eosinophil counts, lower protein expressions of Th2 cytokines and associated transcription factors. In addition, more Th1 and less Th2 cytokine production in exposed splenocyte, were evident in the glycated protein treated mice as compared to its native protein treatment. Thus, glycation of the chickpea allergen attenuated the sensitizing potential and allergic responses in Balb/c mice significantly and could also be clinically beneficial. PMID- 28554634 TI - Valorization of Dacryodes rostrata fruit through the characterization of its oil. AB - Dacryodes rostrata (kembayau) is an important food and oil resource for local communities in Borneo, but it is not commonly known to wider community. The objective of this work is to valorize kembayau fruit by evaluating the characteristics of the oil from the fruit. In this study, the physicochemical characteristics and the lipophilic essential nutrient; the fatty acid composition, vitamin E and beta-carotene content of oils obtained from the peel, pulp and seeds of kembayau fruits were studied. The pulp of the kembayau fruit contained highest proportion of oil, followed by peel and seed. Kembayau fruit contained vitamin E and had trace amount of beta-carotene. Besides, kembayau fruit oils were not toxic to BRL3A cells, provided hepatoprotection and reversed lipid peroxidation in paracetamol-induced toxicity. Our results suggest that kembayau can be a potential source for cooking oil as the physicochemical characteristics are comparable with commercial source such as oil palm. PMID- 28554635 TI - Anthocyanins from purple sweet potato (Ipomoea batatas (L.) Lam.) and their color modulation by the addition of phenolic acids and food-grade phenolic plant extracts. AB - Anthocyanin profiles and contents of three purple sweet potato provenances were investigated by HPLC-DAD-MSn. In contrast to widely uniform profiles, the contents of total (558-2477mg/100gDM) and individual anthocyanins varied widely. Furthermore, quantitative and qualitative effects of intermolecular co pigmentation were studied by adding chlorogenic and rosmarinic acids, and food grade phenolic apple and rosemary extracts at various dosages to a diluted purple sweet potato concentrate at pH 0.9, 2.6, 3.6, and 4.6. Addition of co-pigments generally increased pKH estimate-values of anthocyanins from 3.28 (without co pigments) to up to 4.71, thus substantially broadening the pH range wherein colored forms prevail. The most pronounced hyperchromic shift by up to +50.5% at the absorption maximum was observed at pH 4.6. Simply by blending the co-pigments with purple sweet potato anthocyanins at pH-values ranging from 2.6 to 4.6, purplish-blue, light pink, magenta, brick-red, and intense red hues were accessible as expressed by CIE-L*a*b* color values. PMID- 28554636 TI - Ultrasonic extraction of pectin from Opuntia ficus indica cladodes after mucilage removal: Optimization of experimental conditions and evaluation of chemical and functional properties. AB - Ultrasonic assisted extraction (UAE) of pectin from Opuntia ficus indica (OFI) cladodes after mucilage removal was attempted using the response surface methodology. The process variables were optimized by the isovariant central composite design in order to improve the pectin extraction yield. The optimum condition obtained was: sonication time 70min, temperature 70 degrees C, pH 1.5 and the water-material ratio 30ml/g. This condition was validated and the performance of experimental extraction was 18.14%+/-1.41%, which was closely linked to the predicted value (19.06%). Thus, UAE present a promising alternative to conventional extraction process thanks to its high efficiency which was achieved in less time and at lower temperatures. The pectin extracted by UAE from OFI cladodes (UAEPC) has a low degree of esterification, high uronic acid content, important functional properties and good anti-radical activity. These results are in favor of the use of UAEPC as potential additive in food industry. PMID- 28554637 TI - Encapsulation of lycopene in Chlorella pyrenoidosa: Loading properties and stability improvement. AB - Aiming to improve the stability of lycopene and incorporate it into a complex nutraceutical, exogenous lycopene-loaded Chlorella pyrenoidosa cells (CPCs) were developed. The complex had an encapsulation yield of 13.06+/-0.89% and an encapsulation efficiency of 96.31+/-3.10%. Fluorescence analyses indicated that lycopene was encapsulated in the CPCs. X-ray diffraction, thermogravimetric and differential scanning calorimetric analyses were conducted and compared to those of the non-loaded CPCs, lycopene and their physical mixture. These studies demonstrated that lycopene was amorphous in the complex. The degradation kinetics indicated that encapsulation increased the stability of lycopene. The antioxidant activity of lycopene loaded CPCs against DPPH free radicals was higher than that of the unencapsulated lycopene after storage at 25 degrees C for 25d. This study proved the feasibility of encapsulation of lycopene in the CPCs and combined the activities of both materials, which could be employed in the production of novel nutraceuticals to reduce oxidative stress. PMID- 28554638 TI - Effect of cold plasma on crocin esters and volatile compounds of saffron. AB - The effect of cold plasma on crocin esters and volatile oils of saffron was studied for the first time. After the treatments, (Ar, Ar/5% O2 and Ar/10% O2 at 8 and 12kV of voltage), a decrease in crocin esters and saffranal and an increase in isophorone and 4-ketoisophorone was observed. After 4min, the saffron samples treated with Ar/20% O2 had blackened and the treatment was discontinued. The results show that increasing the input voltage and increasing the amount of added oxygen to Argon gas increased the changes in the safranal and crocin esters. There was no trans-2G, cis-4GG or cis-3Gg compounds observed after the Ar/10% O2 cold plasma treatment at 12kV. PMID- 28554639 TI - Inhibition effect of food preservatives on endoproteinases. AB - The present manuscript proposes a novel approach to assess the impact of food additives on human metabolism by analysing their effect on biomarker enzyme activity. Alterations in the activity of pancreatic enzymes, such as chymotrypsin and trypsin, which are affected by the most common food preservatives, sodium benzoate (E211), potassium sorbate (E202) and sorbic acid (E200), have been evaluated. The proteinase activity was analysed with a bioluminescent method using the light intensity decay constant. Our study revealed that the preservatives reduce proteinase activity by 50% (EC50) at a much lower concentration than their acceptable daily intake (ADI). Thus, sodium benzoate and sorbic acid have an inhibition effect on chymotrypsin at concentrations 14 times lower and 70 times lower than their ADI and this increases with exposure time. Food preservative consumption impacts negatively on protein digestion, which is especially dangerous for patients with pancreatitis. PMID- 28554640 TI - Inhibition of alpha-glucosidase and alpha-amylase by Spanish extra virgin olive oils: The involvement of bioactive compounds other than oleuropein and hydroxytyrosol. AB - Despite the wide use of extra virgin olive oil (EVOO) to combat several diseases, the antidiabetic and anti-cholinesterase activity of Spanish EVOO have not been assessed. In order to evaluate which compounds are responsible for these activities of five Spanish EVOOs, in addition to flavonoids, we investigated for the first time the effect of the contents of carotenoids, fatty acids (FAs), and phytoprostanes (PhytoPs) on four enzymes: alpha-glucosidase, alpha-amylase, acetylcholinesterase, and butyrylcholinesterase. The extracts of these five Spanish EVOOs were found to contain three flavones, three carotenoids, six FAs, and seven classes of PhytoPs. The samples exhibited no in vitro anti cholinesterase activity but presented strong antidiabetic activity, in the order: 'Arbequina'~'Picual'~'Cuquillo'>'Hojiblanca'>'Cornicabra'. The samples showed a higher in vitro hypoglycemic effect than individual or mixed standards, possibly due to interaction between multiple identified compounds and/or a very complex multivariate interaction between other factors. PMID- 28554641 TI - Indirect determination of the flavor enhancer maltol in foods and beverages through flame atomic absorption spectrometry after ultrasound assisted-cloud point extraction. AB - A simple ultrasound assisted-cloud point extraction (UA-CPE) method was developed and combined with flame atomic absorption spectrometry (FAAS) for pre concentration and indirect determination of the flavor enhancer maltol in foods and beverages. The method is based on reduction of Cu(II) to Cu(I) by maltol at pH 6.5, and subsequent selective interaction of Cu(I) with bathocuproine (BCP) to form a ternary complex in presence of sodium dodecyl sulfate (SDS). Under the optimized conditions, pre-concentration of a 35mL sample solution allowed detection of 1.24ugL-1 maltol in a linear range of 4-230ugL-1. The method was validated by intra- and inter-day precision studies ranging from 2.1 to 3.4%, and recoveries ranged from 93.3% to 104.4% using standard addition method. After pretreatment with two different sample preparation steps assisted by ultrasound energy, the proposed method was applied successfully for determination of maltol in selected foods and beverages. PMID- 28554642 TI - Chemical rules on the assessment of antioxidant potential in food and food additives aimed at reducing oxidative stress and neurodegeneration. AB - Antioxidants (aOXs) enlarge the useful life of products consumed by humans. Life requires oxidation of glucose/fatty acids and, therefore, "antioxidant" becomes an oxymoron when trying to define benefits in organisms living in an oxygen-rich atmosphere. According to basic physico-chemical principles, the in vivo aOX potential of food supplements is negligible when compared with the main aOX molecules in the animal Kingdom: glucose and fatty acids. Thus, the aOX assumption to improve life-quality is misleading as oxidative stress and exacerbation occur when oxidant foods (e.g. fava beans) are consumed. Evolution produced potent detoxification mechanisms to handle these situations. When age/genetic/environmental factors negatively impact on detoxification mechanisms, nutrition helps on providing metabolites/precursors needed for boosting innate resources. Ambiguous techniques that attempt to measure in vivo aOX power, should give way to measuring the level of supplements and their metabolites in body fluids/tissues, and to measure the efficacy on antioxidant boosting REDOX pathways. PMID- 28554643 TI - Characterisation of cold plasma treated beef and dairy lipids using spectroscopic and chromatographic methods. AB - The efficacy of cold plasma for inactivation of food-borne pathogens in foods is established. However, insights on cold plasma-food interactions in terms of quality effects, particularly for oils and fats, are sparse. This study evaluated plasma-induced lipid oxidation of model matrices, namely dairy and meat fats. Product characterisation was performed using FTIR, 1H NMR and chromatographic techniques. The oxidation of lipids by cold plasma followed the Criegee mechanism and typical oxidation products identified included ozonides, aldehydes (hexanal, pentenal, nonanal and nonenal) and carboxylic acids (9-oxononanoic acid, octanoic acid, nonanoic acid), along with hydroperoxides (9- and 13-hydroperoxy octadecadienoylglycerol species). However, these oxidation products were only identified following extended treatment times of 30min and were also a function of applied voltage level. Understanding cold plasma interactions with food lipids and the critical parameters governing lipid oxidation is required prior to the industrial adoption of this technology for food products with high fat contents. PMID- 28554644 TI - Antimicrobial potential of macro and microalgae against pathogenic and spoilage microorganisms in food. AB - Algae are a valuable and never-failing source of bioactive compounds. The increasing efforts to use ingredients that are as natural as possible in the formulation of innovative products has given rise to the introduction of macro and microalgae in food industry. To date, scarce information has been published about algae ingredients as antimicrobials in food. The antimicrobial potential of algae is highly dependent on: (i) type, brown algae being the most effective against foodborne bacteria; (ii) the solvent used in the extraction of bioactive compounds, ethanolic and methanolic extracts being highly effective against Gram positive and Gram-negative bacteria; and (iii) the concentration of the extract. The present paper reviews the main antimicrobial potential of algal species and their bioactive compounds in reference and real food matrices. The validation of the algae antimicrobial potential in real food matrices is still a research niche, being meat and bakery products the most studied substrates. PMID- 28554645 TI - Molecular interactions in gelatin/chitosan composite films. AB - Gelatin and chitosan were mixed at different mass ratios in solution forms, and the rheological properties of these film-forming solutions, upon cooling, were studied. The results indicate that the significant interactions between gelatin and chitosan promote the formation of multiple complexes, reflected by an increase in the storage modulus of gelatin solution. Furthermore, these molecular interactions hinder the formation of gelatin networks, consequently decreasing the storage modulus of polymer gels. Both hydrogen bonds and electrostatic interactions are formed between gelatin and chitosan, as evidenced by the shift of the amide-II bands of polymers. X-ray patterns of composite films indicate that the contents of triple helices decrease with increasing chitosan content. Only one glass transition temperature (Tg) was observed in composite films with different composition ratios, and it decreases gradually with an increase in chitosan proportion, indicating that gelatin and chitosan have good miscibility and form a wide range of blends. PMID- 28554646 TI - Improvement of the quality of parboiled rice by using anti-browning agents during parboiling process. AB - Browning occurs in parboiled rice as a result of the Maillard reaction that negatively affects consumers' acceptability. The aim of this study was to evaluate the ability of gallic acid, glycine, reduced glutathione and l-cysteine at 0.1, 0.5, 1.0 and 2.0% levels to inhibit browning reactions during the parboiling of rice. Gallic acid and l-cysteine did not exhibit browning inhibition effect at the studied levels. On the other hand, glycine and the higher concentrations of reduced glutathione (1.0 and 2.0%) were able to promote a whiter color and a low free 5-hydroxymethyl-2-furaldehyde content (HMF). The highest level of 2.0% for glycine and reduced glutathione favored protein extractability and a weaker protein-starch matrix, roughly increasing the broken grains percentage. Cooking time changed just for reduced glutathione-treated rice, as a result of their weaker protein-starch matrix and the greater ability of the grains to soften during cooking. PMID- 28554647 TI - Polysaccharides from by-products of the Wonderful and Laffan pomegranate varieties: New insight into extraction and characterization. AB - The main crude polysaccharides (CPS), extracted from two widely cultivated pomegranate varieties, Laffan and Wonderful, were studied and characterized. We obtained the highest CPS extraction yield (approximatively 10% w/w on dried matter) by 1h of decoction (ratio 1/40w/v). The predominant polymers (75-80%) of the CPS samples showed a hydrodynamic volume close to 2000kDa by size exclusion chromatography and the exocarp and mesocarp profiles were very similar. The proton spectra (1H NMR), according to sugar composition and gelling ability, confirmed the main polysaccharide fractions were pectin with different acylation and methylation degree. The CPS from Laffan and Wonderful mesocarp showed prebiotic properties in vitro with Lactobacillus and Bifidobacterium strains. The composition of the decoction (12% ellagitannins and 10% of CPS) obtained by a green extraction process of pomegranate by-products, makes it a suitable component of functional food formulations. PMID- 28554648 TI - Exploration of reaction mechanisms of anthocyanin degradation in a roselle extract through kinetic studies on formulated model media. AB - Effect of oxygen, polyphenols and metals was studied on degradation of delphinidin and cyanidin 3-O-sambubioside of Hibiscus sabdariffa L. Experiments were conducted on aqueous extracts degassed or not, an isolated polyphenolic fraction and extract-like model media, allowing the impact of the different constituents to be decoupled. All solutions were stored for 2months at 37 degrees C. Anthocyanin and their degradation compounds were regularly HPLC-DAD-analyzed. Oxygen concentration did not impact the anthocyanin degradation rate. Degradation rate of delphinidin 3-O-sambubioside increased 6-fold when mixed with iron from 1 to 13mg.kg-1 but decreased with chlorogenic and gallic acids. Degradation rate of cyanidin 3-O-sambubioside was not affected by polyphenols but increased by 3-fold with increasing iron concentration with a concomitant yield decrease of scission product, protocatechuic acid. Two pathways of degradation of anthocyanins were identified: a major metal-catalyzed oxidation followed by condensation and a minor scission which represents about 10% of degraded anthocyanins. PMID- 28554649 TI - Quantification of benzoxazinoids and their metabolites in Nordic breads. AB - Benzoxazinoids (Bx) and their metabolites are molecules with suggested health effects in humans, found in cereal grains and consequently in cereal foods. However, to date little is known about the amount of Bx in our diet. In this study, deuterated standards 2-hydroxy-1,4-benzoxazin-3-one (HBOA-d4) and 2 hydroxy-N-(2-hydroxyphenyl) acetamide (HHPAA-d4) were synthesized, to allow quantification of nine Bx and their metabolites in 30 breads and flours from Nordic countries by UHPLC-MS/MS. Samples containing rye had larger amounts of Bx (143-3560ug/g DM) than the ones containing wheat (11-449ug/g DM). More Bx were found in whole grain wheat (57-449ug/g DM) compared to refined wheat (11-92ug/g DM) breads. Finnish sourdough rye breads were notably high in their 2-hydroxy-N (2-hydroxyphenyl) acetamide (HHPAA) concentration (40-48ug/g DM). This new information on Bx content in flours and breads available in the Nordic countries will be useful for future work on determining dietary exposure to Bx. PMID- 28554650 TI - Wild blueberry polyphenol-protein food ingredients produced by three drying methods: Comparative physico-chemical properties, phytochemical content, and stability during storage. AB - Particulate colloidal aggregate food ingredients were prepared by complexing wheat flour, chickpea flour, coconut flour and soy protein isolate with aqueous wild blueberry pomace extracts, then spray drying, freeze drying, or vacuum oven drying to prepare dry, flour-like matrices. Physico-chemical attributes, phytochemical content and stability during storage were compared. Eighteen anthocyanins peaks were identified for samples. Spray dried matrices produced with soy protein isolate had the highest concentration of polyphenols (156.2mg GAE/g) and anthocyanins (13.4mg/g) and the most potent DPPH scavenging activity (714.1MUmolesTE/g). Spray dried blueberry polyphenols complexed with protein were protected from degradation during 16weeks at 4 degrees C and 20 degrees C. Soy protein isolate more efficiently captured and stabilized wild blueberry pomace phytochemicals than other protein sources. Overall, spray drying the blueberry extracts complexed with protein proved to be an environment-friendly strategy to produce stable functional ingredients with multiple applications for the food industry. PMID- 28554652 TI - Development of new chemiluminescence biosensors for determination of biogenic amines in meat. AB - Development of chemiluminescence one-shot biosensors for determination of biogenic amines is described and compared with high-performance liquid chromatography (HPLC) method coupled with pre-column derivatisation. The biosensors are based on enzymatic oxidation to 4-aminobutyraldehyde with putrescine oxidase or diamine oxidase as catalysts. The lowest measured concentration for the biosensor with putrescine oxidase was 1mg/L. The detection limit, calculated as 3sigma value, was 0.8mg/L. The biosensor with diamine oxidase had the lowest measured concentration of 1mg/L of putrescine. Detection limit, calculated as 3sigma value, was 1.3mg/L. Biosensors were tested on five different meat samples, and the results were compared with HPLC coupled with pre column derivatization. Results showed that new biosensors could be used in determination of putrescine concentration in meat samples but improvements, such as sample pretreatment before determination or design of interference free biosensor, are required. PMID- 28554651 TI - Fatty acid, volatile and sensory characteristics of beef as affected by grass silage or pasture in the bovine diet. AB - Fatty acids, volatile compounds and sensory attributes of beef from bulls fed concentrates to slaughter (C), grass silage for 120days (GS) followed by C (GSC), or GS followed by 100days at pasture and then C (GSPC), and slaughtered at 3 target carcass weights, were determined. Total intramuscular fat (IMF) was lower for GSPC than for GSC and C. C18:3n-3 concentration and polyunsaturated fatty acid (PUFA) to saturated fatty acid (SFA) ratio were higher and C18:2n-6 and monounsaturated fatty acid concentrations and n-6:n-3 PUFA ratio lower for GSPC than C. C16:0, C18:0 and C18:1c9 increased with carcass weight when expressed quantitatively, but not when expressed proportionately. Hexanal concentration was higher and 2-methyl-1-butanol and toluene lower for C and GSC than for GSPC. Overall liking was negatively correlated with C20:5n-3 and PUFA/SFA ratio, but differences in sensory attributes (tenderness, flavour liking, overall liking) were most strongly correlated with IMF. PMID- 28554653 TI - Dendritic cells during mousepox: The role of delayed apoptosis in the pathogenesis of infection. AB - Dendritic cells (DCs) are effector cells linking the innate immune system with the adaptive immune response. Many viruses eliminate DCs to prevent host response, induce immunosuppression and to maintain chronic infection. In this study, we examined apoptotic response of dendritic cells during in vitro and in vivo infection with ectromelia virus (ECTV), the causative agent of mousepox. ECTV-infected bone marrow dendritic cells (BMDCs) from BALB/c mice underwent apoptosis through mitochondrial pathway at 48 h post infection, up-regulated FasL and decreased expression of anti-apoptotic Bcl-2 and pro-apoptotic Fas. Similar pattern of Bcl-2, Fas and FasL expression was observed for DCs early during in vivo infection of BALB/c mice. Both BMDCs and DCs from BALB/c mice showed no maturation upon ECTV infection. We conclude that ECTV-infected DCs from BALB/c mouse strain help the virus to spread and to maintain infection. PMID- 28554654 TI - Nonsteroidal anti-inflammatory drug-induced protein-losing enteropathy: a great masquerade of Crohn's disease. PMID- 28554655 TI - Hemorrhagic angiodysplasia of the digestive tract: pathogenesis, diagnosis, and management. PMID- 28554656 TI - Colon capsule endoscopy to screen for colorectal neoplasia in those with family histories of colorectal cancer. AB - BACKGROUND AND AIMS: Colon capsule endoscopy (CCE) has been recognized as an alternative for colorectal cancer (CRC) screening in average-risk people. Our aim was to prospectively assess the accuracy of CCE as a screening tool in first degree relatives (FDRs) of people with CRC by using optical colonoscopy (OC) with segmental unblinding as the reference standard. METHODS: Consecutive patients admitted with a CRC diagnosis (index cases) were prospectively evaluated and invited to contact their FDRs. Available FDRs were invited to undergo CCE and OC on the following day, with segmental unblinding of CCE results. Sensitivity, specificity, and predictive values/negative predictive values (PPV/NPV) of CCE were assessed for detecting patients with any polyp >=6 mm and >=10 mm. RESULTS: A total of 177 FDRs (median age 57.0 years, 54.8% female) identified from 211 index cases were included. Both CCE and OC were completed in all the included FDRs. Overall, CCE identified 51 of 56 FDRs with polyps >=6 mm (sensitivity 91%; 95% CI, 81-96) and correctly classified as negative 107 of 121 participants without lesions >=6 mm (specificity 88%; 95% CI, 81-93). Per-patient positive and negative predictive values for >=6 mm lesions were 78% (95% CI, 67-87) and 95% (95% CI, 90-98), respectively. CCE detected 24 of 27 patients with polyps >=10 mm and correctly classified as negative 142 of 150 patients, corresponding to 89% sensitivity and 95% specificity. Post-CCE referral rates to colonoscopy were 37% and 18%, respectively. CONCLUSIONS: CCE is an accurate method to screen FDRs of patients with CRC and could be offered as an alternative to those who decline or are unfit for colonoscopy screening. (Clinical trial registration number: NCT01184781.). PMID- 28554657 TI - Oral Ivermectin: Regaining a Drug for the Treatment of Scabies. PMID- 28554658 TI - Prolonged exposure to particulate chromate inhibits RAD51 nuclear import mediator proteins. AB - Particulate hexavalent chromium (Cr(VI)) is a human lung carcinogen and a human health concern. The induction of structural chromosome instability is considered to be a driving mechanism of Cr(VI)-induced carcinogenesis. Homologous recombination repair protects against Cr(VI)-induced chromosome damage, due to its highly accurate repair of Cr(VI)-induced DNA double strand breaks. However, recent studies demonstrate Cr(VI) inhibits homologous recombination repair through the misregulation of RAD51. RAD51 is an essential protein in HR repair that facilitates the search for a homologous sequence. Recent studies show prolonged Cr(VI) exposure prevents proper RAD51 subcellular localization, causing it to accumulate in the cytoplasm. Since nuclear import of RAD51 is crucial to its function, this study investigated the effect of Cr(VI) on the RAD51 nuclear import mediators, RAD51C and BRCA2. We show acute (24h) Cr(VI) exposure induces the proper localization of RAD51C and BRCA2. In contrast, prolonged (120h) exposure increased the cytoplasmic localization of both proteins, although RAD51C localization was more severely impaired. These results correlate temporally with the previously reported Cr(VI)-induced RAD51 cytoplasmic accumulation. In addition, we found Cr(VI) does not inhibit interaction between RAD51 and its nuclear import mediators. Altogether, our results suggest prolonged Cr(VI) exposure inhibits the nuclear import of RAD51C, and to a lesser extent, BRCA2, which results in the cytoplasmic accumulation of RAD51. Cr(VI)-induced inhibition of nuclear import may play a key role in its carcinogenic mechanism since the nuclear import of many tumor suppressor proteins and DNA repair proteins is crucial to their function. PMID- 28554659 TI - Naloxegol, an opioid antagonist with reduced CNS penetration: Mode-of-action and human relevance for rat testicular tumours. AB - Naloxegol is an opioid antagonist which has been developed for the treatment of patients with opioid induced constipation. In the nonclinical safety program naloxegol was shown to have a very benign toxicity profile. In the rat, but not the mouse, 2-year carcinogenicity study a change in tumour pattern with an increase in testicular Leydig cell tumours (LCT) was observed after dosing at high (supra-pharmacological) concentrations. To establish the basis of the increase in LCT and to assess its potential relevance to humans, studies to exclude and potentially identify mode-of-action (MoA) were performed. A genotoxic mechanism was ruled out following negative results in the Ames, mouse lymphoma, and micronucleus assays. An effect on androgen metabolism was excluded since the treatment of rats with naloxegol for 14days did not result in any induction of CYP protein levels. It was demonstrated that administration of centrally restricted opioid antagonists naloxegol or methylnaltrexone at high doses induced an increase in LH release with no clear increase in testosterone, in contrast to the centrally acting opioid antagonist naloxone, which showed marked increases in both LH and testosterone. LCT due to increased LH stimulation is common in rats but not documented in humans. Collectively, the lack of genotoxicity signal, the lack of androgen effect, the increase in LH secretion in rats, which is no considered to be relevant for LCT formation in humans, and high margins to clinical exposures, the observed increase in LCT in the rat is not expected to be clinically relevant. PMID- 28554660 TI - Nanotechnology in agriculture: Opportunities, toxicological implications, and occupational risks. AB - Nanotechnology has the potential to make a beneficial impact on several agricultural, forestry, and environmental challenges, such as urbanization, energy constraints, and sustainable use of resources. However, new environmental and human health hazards may emerge from nano-enhanced applications. This raises concerns for agricultural workers who may become primarily exposed to such xenobiotics during their job tasks. The aim of this review is to discuss promising solutions that nanotechnology may provide in agricultural activities, with a specific focus on critical aspects, challenging issues, and research needs for occupational risk assessment and management in this emerging field. Eco toxicological aspects were not the focus of the review. Nano-fertilizers, (nano sized nutrients, nano-coated fertilizers, or engineered metal-oxide or carbon based nanomaterials per se), and nano-pesticides, (nano-formulations of traditional active ingredients or inorganic nanomaterials), may provide a targeted/controlled release of agrochemicals, aimed to obtain their fullest biological efficacy without over-dosage. Nano-sensors and nano-remediation methods may detect and remove environmental contaminants. However, limited knowledge concerning nanomaterial biosafety, adverse effects, fate, and acquired biological reactivity once dispersed into the environment, requires further scientific efforts to assess possible nano-agricultural risks. In this perspective, toxicological research should be aimed to define nanomaterial hazards and levels of exposure along the life-cycle of nano-enabled products, and to assess those physico-chemical features affecting nanomaterial toxicity, possible interactions with agro-system co-formulants, and stressors. Overall, this review highlights the importance to define adequate risk management strategies for workers, occupational safety practices and policies, as well as to develop a responsible regulatory consensus on nanotechnology in agriculture. PMID- 28554662 TI - The importance of publishing trials with negative results. PMID- 28554661 TI - Using DR52c/Ni2+ mimotope tetramers to detect Ni2+ reactive CD4+ T cells in patients with joint replacement failure. AB - T cell mediated hypersensitivity to nickel (Ni2+) is one of the most common causes of allergic contact dermatitis. Ni2+ sensitization may also contribute to the failure of Ni2+ containing joint implants, and revision to non-Ni2+ containing hardware can be costly and debilitating. Previously, we identified Ni2+ mimotope peptides, which are reactive to a CD4+ T cell clone, ANi2.3 (Valpha1, Vbeta17), isolated from a Ni2+ hypersensitive patient with contact dermatitis. This T cell is restricted to the major histocompatibility complex class II (MHCII) molecule, Human Leukocyte Antigen (HLA)-DR52c (DRA, DRB3*0301). However, it is not known if Ni2+ induced T cell responses in sensitized joint replacement failure patients are similar to subjects with Ni2+ induced contact dermatitis. Here, we generated DR52c/Ni2+ mimotope tetramers, and used them to test if the same Ni2+ T cell activation mechanism could be generalized to Ni2+ sensitized patients with associated joint implant failure. We confirmed the specificity of these tetramers by staining of ANi2.3T cell transfectomas. The DR52c/Ni2+ mimotope tetramer detected Ni2+ reactive CD4+ T cells in the peripheral blood mononuclear cells (PBMC) of patients identified as Ni2+ sensitized by patch testing and a positive Ni2+ LPT. When HLA-typed by a DR52 specific antibody, three out of four patients were DR52 positive. In one patient, Ni2+ stimulation induced the expansion of Vbeta17 positive CD4+ T cells from 0.8% to 13.3%. We found that the percentage of DR52 positivity and Vbeta17 usage in Ni2+ sensitized joint failure patients are similar to Ni sensitized skin allergy patients. Ni2+ independent mimotope tetramers may be a useful tool to identify the Ni2+ reactive CD4+ T cells. PMID- 28554663 TI - Clinical trials and tribulations: 17OHPC and preventing recurrent preterm birth. PMID- 28554665 TI - Population incidence of pedestrian traffic injury in high-income countries: A systematic review. AB - BACKGROUND: Road traffic injuries are the fifth leading cause of years of life lost, with pedestrians comprising 39% of all road deaths. International recognition of this public health issue has led to a reduction in road traffic deaths in many high-income countries. However data on non-motorised road users such as pedestrians is incomplete. Additionally, non-fatal injuries are poorly documented. The aim of this study was to identify the incidence of pedestrian traffic injury reported from high-income countries. METHODS: A systematic review of the literature was conducted using MEDLINE, Scopus, PubMed and the Cochrane library. Studies were eligible for inclusion if they reported the incidence of pedestrian injury in a defined population from a high-income country defined using the World Bank atlas method for the 2016 fiscal year. A meta-analysis was performed on the population incidence of pedestrian traffic injury by world region. RESULTS: Seventeen studies were identified from eight high-income countries that satisfied the inclusion criteria. The pooled incidence of PTI in the European region was 68.8 per 100,000 population (95%CI 50-87.7, p<0.01) and 89.3 per 100,000 (95%CI 47.2-131.4, p<0.01) in the American region. The incidence of pedestrian traffic injury varied from 20 per 100,000 in Victoria, Australia to 203 per 100,000 in New York City, United States of America. Pedestrian mortality ranged from 0.9 to 14 per 100,000 population. Wide variation in population size, location and demographics was observed between studies. CONCLUSIONS: This review concluded a high burden of pedestrian trauma in HICs with individual reports reporting from rates of 20 to 203 per 100,000 population. Recommended interventions directed at reducing the burden of pedestrian trauma were not universally present in the reported high-income countries. Implementation of such safety strategies and demonstration of improvement in pedestrian trauma rates and outcomes present directions for further research. PMID- 28554664 TI - A profile of Dr Edward J. Quilligan. PMID- 28554666 TI - Human cytomegalovirus-mediated immunomodulation: Effects on glioblastoma progression. AB - The presence of human cytomegalovirus (HCMV) and glioblastoma multiforme (GBM), first established in 2002, has developed into an area of considerable interest and controversy. Numerous studies have found evidence of possible HCMV infection of GBM tumor cells as well as myriad onco- and immunomodulatory properties exhibited by HCMV antigens and transcripts, while recent reports have failed to detect HCMV particles in GBM and question the virus' role in tumor progression. This review highlights the known immunomodulatory properties of HCMV, independent of GBM infection status, that help drive the virus from peripheral blood into the vital tissues and subsequently dampen local immune response, assisting GBM tumors in evading immune surveillance and contributing to the disease's poor prognosis. Emerging antiviral approaches to treating GBM, including antiviral drugs and immunotherapies directed against HCMV, are also examined. PMID- 28554667 TI - Microglia-glioblastoma interactions: New role for Wnt signaling. AB - Glioblastoma, the most aggressive and fatal type of brain tumor, is capable of interacting with brain immune cells such as microglia, which contributes to the growth of these tumors. Various molecules, including growth factors and cytokines, have been identified as regulators of microglia-glioblastoma interaction. Recent studies suggest that the Wnt family of lipoglycoproteins plays an important role, not only in biological events during development, but also in cancer progression, and can be part of microglia recruitment to glioblastoma as well as of tumor growth and invasion. Here, we discuss recent interesting findings that support a role for Wnt signaling pathways in the microglia-glioblastoma crosstalk. PMID- 28554668 TI - Anti-tumor effects of a 'human & mouse cross-reactive' anti-ADAM17 antibody in a pancreatic cancer model in vivo. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumor amongst all human cancers due to late diagnosis and resistant to treatment with chemotherapy and radiation. Preclinical and clinical studies have revealed that ErbB family for example epidermal growth factor receptor (EGFR) is a validated molecular target for pancreatic cancer prevention and therapy. The ErbB signaling cascade is regulated by a member of the ADAM (a disintegrin and metalloprotease) family, namely ADAM17, by enzymatic cleavage of precursor ligands into soluble cytokines and growth factors. Mouse genetic studies have demonstrated that ADAM17 is required for PDAC development. In this study, we evaluated the anti-tumor effects of A9(B8) IgG - the first specific 'human and mouse cross-reactive' ADAM17 inhibitory antibody on pancreatic malignant transformation. We found that inhibition of ADAM17 with A9(B8) IgG efficiently suppressed the shedding of ADAM17 substrates both in vivo and in vitro. Furthermore, we demonstrated that administration of A9(B8) IgG significantly suppressed motility in human pancreatic cancer cells and also significantly delayed tumorigenesis in the Pdx1Cre;KrasG12D;Trp53fl/+PDAC mouse model. Inhibition of ADAM17 with A9(B8) IgG particularly affected the progression of pre-invasive pancreatic lesions to advanced PDAC in mice. Taken together, the preclinical data presented here will provide a starting point for clinical applications of ADAM17 targeted therapy. PMID- 28554671 TI - Gastric conduit revision after esophagectomy: The raising of Lazarus. PMID- 28554670 TI - Serine protease isoforms in Gloydius intermedius venom: Full sequences, molecular phylogeny and evolutionary implications. AB - : Nine distinct venom serine proteases (vSPs) of Gloydius intermedius were studied by transcriptomic, sub-proteomic and phylogenetic analyses. Their complete amino acid sequences were deduced after Expression Sequence Tag (EST) analyses followed by cDNA cloning and sequencing. These vSPs appear to be paralogs and contain the catalytic triads and 1-4 potential N-glycosylation sites. Their relative expression levels evaluated by qPCR were grossly consistent with their EST hit-numbers. The major vSPs were purified by HPLC and their N terminal sequences matched well to the deduced sequences, while fragments of the minor vSPs were detected by LC-MS/MS identification. Specific amidolytic activities of the fractions from HPLC and anion exchange separation were assayed using four chromogenic substrates, respectively. Molecular phylogenetic tree based on the sequences of these vSPs and their orthologs revealed six major clusters, one of them covered four lineages of plasminogen activator like vSPs. N glycosylation patterns and variations for the vSPs are discussed. The high sequence similarities between G. intermedius vSPs and their respective orthologs from American pitvipers suggest that most of the isoforms evolved before Asian pitvipers migrated to the New World. Our results also indicate that the neurotoxic venoms contain more kallikrein-like vSPs and hypotensive components than the hemorrhagic venoms. SIGNIFICANCE: Full sequences and expression levels of nine paralogous serine proteases (designated as GiSPs) of Gloydius intermedius venom have been studied. A kallikrein-like enzyme is most abundant and four isoforms homologous to venom plasminogen-activators are also expressed in this venom. Taken together, the present and previous data demonstrate that the neurotoxic G. intermedius venoms contain more hypotensive vSPs relative to other hemorrhagic pitviper venoms and the pitviper vSPs are highly versatile and diverse. Their structure-function relationships remain to be explored and compared. A novel, simplified phylogenetic tree based on the sequences of GiSPs and their closely related orthologs from other pitvipers reveals six major subtypes and offers a better understanding of vSP duplication and evolution in pitvipers of both the Old and New Worlds. It is well known that specific vSPs are potential therapeutic or diagnostic agents that target the plasma proteins or coagulation factors. Our results not only render deeper insights into the variation and evolution of vSPs, but may help to choose right venoms for the development of better therapeutic leads. PMID- 28554669 TI - Patterns and associations between DAPT cessation and 2-year clinical outcomes in left main/proximal LAD versus other PCI: Results from the Patterns of Non Adherence to Dual Antiplatelet Therapy in Stented Patients (PARIS) registry. AB - OBJECTIVES: Percutaneous coronary intervention (PCI) of the left main (LM) or proximal left anterior descending artery (pLAD) is considered high-risk as these segments subtend substantial left ventricular myocardial area. We assessed the patterns and associations between dual antiplatelet therapy (DAPT) cessation and 2-year outcomes in LM/pLAD vs. other PCI from the all-comer PARIS registry. METHODS: Two-year major adverse cardiovascular events (MACE) were a composite of cardiac death, myocardial infarction, definite/probable stent thrombosis or target lesion revascularization. DAPT cessation was predefined as physician guided permanent discontinuation, temporary interruption, or non-recommended disruption due to non-compliance or bleeding. RESULTS: Of the study population (n=5018), 25.0% (n=1252) underwent LM/pLAD PCI and 75.0% (n=3766) PCI to other segments. Compared to others, LM/pLAD patients presented with fewer comorbidities, less frequent acute coronary syndromes but more multivessel and bifurcation disease treated with greater stent lengths. Two-year adjusted risk of MACE (11.4% vs. 11.6%; HR 1.10, 95% CI 0.90-1.34, p=0.36) was similar between LM/pLAD vs. other patients. DAPT discontinuation was significantly higher (43.3% vs. 39.4%, p=0.01) in LM/pLAD patients with borderline significance for lower disruption (10.0% vs. 14.7%, p=0.059) compared to other patients. DAPT discontinuation was not associated with higher risk of MACE in LM/pLAD (HR 0.65, 95% CI 0.34-1.25) or other PCI groups (HR 0.67, 95% CI 0.47-0.95). CONCLUSIONS: LM/pLAD PCI was not an independent predictor of 2-year MACE. Compared to other PCI, patients undergoing LM/pLAD PCI had higher rates of physician recommended DAPT discontinuation, however, discontinuation did not result in greater adverse events. PMID- 28554672 TI - Importance of stratifying acute kidney injury in cardiogenic shock resuscitated with mechanical circulatory support therapy. AB - OBJECTIVE: Although the outcomes of patients with cardiogenic shock remain poor, short-term mechanical circulatory support has become an increasingly popular modality for hemodynamic assistance and organ preservation. Because the kidney is exquisitely sensitive to poor perfusion, acute kidney injury is a common sequela of cardiogenic shock. This study examines the incidence and clinical impact of acute kidney injury in patients with short-term mechanical circulatory support for cardiogenic shock. METHODS: Retrospective review was performed of 293 consecutive patients with cardiogenic shock who were treated with short-term mechanical circulatory support. The well-validated 2014 Kidney Disease Improving Global Outcomes criteria were used to stage acute kidney injury. Outcomes of interest were long-term mortality and renal recovery. RESULTS: Acute kidney injury developed in 177 of 293 patients (60.4%), of whom 113 (38.6%) were classified with stage 3 (severe). Kaplan-Meier survival estimates indicated a 1 year survival of 49.2% in the nonsevere (stages 0-2) acute kidney injury cohort versus 27.3% in the severe acute kidney injury cohort (P < .001). Multivariable Cox regression demonstrated that severe acute kidney injury was a predictor of long-term mortality (hazard ratio, 1.54; confidence interval, 1.10-2.14; P = .011). Among hospital survivors, renal recovery occurred more frequently (82.4% vs 63.2%, P = .069) and more quickly (5.6 vs 24.5 days, P < .0001) in the nonsevere than in the severe acute kidney injury group. CONCLUSIONS: Acute kidney injury is common and frequently severe in patients in cardiogenic shock treated with short-term mechanical circulatory support. Milder acute kidney injury resolves with survival comparable to patients without acute kidney injury. Severe acute kidney injury is an independent predictor of long-term mortality. Nonetheless, many surviving patients with acute kidney injury do experience gradual renal recovery. PMID- 28554673 TI - Secondary sclerosing cholangitis in cardiac surgical patients: A complication with a dismal prognosis. AB - OBJECTIVES: Secondary sclerosing cholangitis in critically ill patients is a rapidly progressing disease leading to biliary fibrosis and cirrhosis. We describe the course of sclerosing cholangitis in critically ill patients after cardiac surgery and compare this with matched patients. METHODS: A retrospective search for "secondary sclerosing cholangitis" and "liver and/or hepatic failure" in all adult patients (aged 18-93 years) who underwent cardiac surgery from April 2007 to March 2016 identified 192 of 8625 patients. Of those, 12 were diagnosed with sclerosing cholangitis in critically ill patients (incidence, 0.14%). A 3:1 matching was performed. Laboratory values, pharmacologic requirements, ventilation times, mechanical circulatory support, and endoscopic retrograde cholangiopancreatography studies were extracted from the hospital database. RESULTS: A total of 9 men and 3 women were affected (age 71 years; range, 59.8 75.5 years). Critically ill patients with sclerosing cholangitis required vasoconstrictors and inotropes longer than control patients (norepinephrine 356.5 hours [264.5-621] vs 68 hours [15-132.5], P = .003; enoximone 177 hours [124.3 249.5] vs 48.5 hours [12-81 hours], P < .001, respectively). Critically ill patients with sclerosing cholangitis had longer intubation time (628.5 hours [377.3-883] vs 25 hours [9.8-117.5]; P < .001) and more surgical revisions (3 [2.5-6] vs 1 [0-2], P = .003) than the matching group. Bilirubin (23.3 mg/dL [14.4-32.9] vs 1 mg/dL [0.6-2.7]; P < .001), gamma-glutamyltransferase (1082.3 U/L [259.5-2265.7] vs 53.8 U/L [35.1-146]; P < .001), and alkaline phosphatase (751.5 U/L [372-1722.3] vs 80.5 U/L [53.3-122]; P < .001) were higher in critically ill patients with sclerosing cholangitis. One critically ill patient with sclerosing cholangitis underwent successful liver transplantation. A total of 11 patients sclerosing cholangitis died (92%) versus 12 patients (33%, P < .001) in the control group. CONCLUSIONS: Sclerosing cholangitis in critically ill patients is a fatal complication in patients undergoing cardiac surgery who have a complicated postoperative course with prolonged vasoconstrictor, inotropic, and respiratory therapy, or who require frequent surgical revisions. Liver transplantation remains the only curative option but is often precluded by the age and critical state of patients undergoing cardiac surgery. PMID- 28554674 TI - A tale of two centrifugal left ventricular assist devices. PMID- 28554675 TI - Risk models for congenital and pediatric cardiac care: The importance of timing of data collection and selection of outcome variables. PMID- 28554676 TI - How old are you, and how many of these have you done? Fielding questions of age and experience in your early career. PMID- 28554677 TI - Interstitial lung disease and lung cancer: Decisions, precision, and tuna fish sandwiches. PMID- 28554678 TI - The role of imaging, deliberate practice, structure, and improvisation in approaching surgical perfection. PMID- 28554679 TI - Blood flow into ulcer-like projection of a type B aortic dissection visualized with computational fluid dynamics. PMID- 28554680 TI - The TREAT Registry: Evolution of Knowledge From 1999 to 2017: Lessons Learned. PMID- 28554681 TI - Epiploic Appendagitis: The Uncommon Intestinal Imitator. PMID- 28554683 TI - Methodology to assess quality of estimated disturbances in active disturbance rejection control structure for mechanical system. AB - A methodology to assess the quality of estimation of disturbances in mechanical systems, by state observers, in the control structure with active compensation of disturbances (ADRC) is presented. Evaluation is carried out by four performance indices that depend on the steady-state error between reference signals and output of the plant. These indices are related with the accuracy and precision of the closed loop system in the sense of norms L2 and Linfinity, for a set of reference signals representing the typical operating conditions of the mechanism. The effectiveness of the methodology is illustrated with the quality assessment of the estimated disturbance of five state observers to control of a simple pendulum and validated on a SCARA robot arm. PMID- 28554682 TI - Liver and Cardiovascular Damage in Patients With Lean Nonalcoholic Fatty Liver Disease, and Association With Visceral Obesity. AB - BACKGROUND & AIMS: Lean nonalcoholic fatty liver disease (NAFLD) is defined as NAFLD that develops in patients with a body mass index (BMI) less than 25 kg/m2. We investigated the differences between lean NAFLD and NAFLD in overweight and obese persons, factors associated with the severity of liver and cardiovascular disease, and the effects of visceral obesity. METHODS: We performed a retrospective cohort study of 669 consecutive patients with biopsy-proven NAFLD seen at 3 liver centers in Italy. We collected anthropometric, clinical, and biochemical data, as well as information on carotid atherosclerosis (artery intima-media thickness and plaque), liver histology (nonalcoholic steatohepatitis [NASH] and fibrosis), insulin resistance, and diabetes. Overweight was defined as a BMI of 25 to 29.9 kg/m2, and obese was defined as a BMI of 30 kg/m2 or greater. Patients were assigned to groups based on waist circumference, a marker of visceral obesity (low: men, <94 cm, women <80 cm; medium: men, 94-102 cm, women 80-88 cm; or high: men >102 cm, women >88 cm). DNA samples were analyzed for the rs738409 C>G (I148M in PNPLA3), the rs58542926 C>T (E167K in TM6SF2), and single nucleotide polymorphisms. Variables in men and women were analyzed using chi squared analysis and the Mann-Whitney or Kruskal-Wallis tests. Multiple linear or logistic regression analyses were adjusted for all the variables of clinical relevance or statistically significant at univariate analyses. The primary outcome was the difference in liver and cardiovascular disease between lean NAFLD and NAFLD in overweight and obese persons. Secondary outcomes were effects of visceral obesity, based on waist circumference, on hepatic, vascular, and metabolic features. RESULTS: Significantly lower proportions of patients with lean NAFLD (143 patients; 43 women; mean age, 46 +/- 13 y) had hypertension (P = .001), diabetes (P = .0001), and metabolic syndrome (P = .0001) than overweight or obese patients with NAFLD (526 patients; 149 women; mean age, 49 +/- 12 y). Significantly lower proportions of patients with lean NAFLD had NASH (17% vs 40% of obese or overweight patients with NAFLD; P = .0001), fibrosis of F2 or higher (17% vs 42%; P = .0001), or carotid plaques (27% vs 39%; P = .03). Patients with lean NAFLD had significantly thinner carotid intima-media (0.74 +/- 0.1 mm) than obese or overweight patients with NAFLD (0.84 +/- 0.3 mm; P = .0001). There was no significant difference in the proportions of patients with rs738409 C>G in PNPLA3, but a significantly greater proportion of patients with lean NAFLD carried rs58542926 C>T in TM6SF2 (4%) than obese or overweight individuals with NAFLD (0.3%; P = .001). Of the 143 patients with lean NAFLD, 27 had grade 3 steatosis, 24 had a lobular inflammation score greater than 2, 10 had a ballooning score of 2, and 25 had a fibrosis score of 2 or higher. In patients with lean NAFLD, the only variable associated independently with NASH and a fibrosis score of 2 or higher was rs738409 C>G in PNPLA3. Patients with lean NAFLD and a medium waist circumference had a significantly higher risk of diabetes (odds ratio, 11; 95% confidence interval [CI], 1.2-106; P = .03) than overweight or obese patients with a similar waist circumference (odds ratio, 1.3; 95% CI, 0.4-4.2; P = .6). Lean and overweight or obese patients with high waist circumferences had significant increases in risk compared with patients with low and medium circumference and diabetes, hypertension, and fibrosis scores of 2 or higher. CONCLUSIONS: In a retrospective study of patients with lean NAFLD vs obese or overweight persons with NAFLD, we found 20% of patients with lean NAFLD to have NASH, fibrosis scores of 2 or higher, and carotid atherosclerosis. Lean patients with rs738409 C>G in PNPLA3 should be monitored for liver disease progression; studies including large series of patients with lean NAFLD will clarify the possible role of TM6SF2 polymorphisms. PMID- 28554685 TI - Snail mucus - glandular origin and composition in Helix pomatia. AB - Apart from their well-known culinary use, gastropod species such as Helix, which have a hydrogel-like mucus, are increasingly being exploited for cosmetic, bioengineering and medical applications. However, not only are the origin and composition of these "sticky" secretions far from being fully characterized, the number and morphology of the mucus glands involved is also uncertain. This study aims to characterize in detail the cutaneous glands of the Helix pomatia foot on morphological, histochemical and immunohistochemical levels. Hereby the focus is on the gland position and appearance on the foot sole as well as on the chemical nature of the different gland secretions. At least five different gland types can be distinguished by their microanatomy; three are located on the dorsal side and two on the ventral side of the foot sole. Most glands are reactive for acidic proteins and sugars such as mannose and fucose, indicating the presence of acidic glycosaminoglycans. One dorsal gland type shows high reactivity for acidic proteins only. The isolated mucus includes a certain amount of the elements chlorine, potassium and calcium; evidence for lipids was also confirmed in the isolated mucus. The present results for Helix pomatia show a clear difference in the number of glands compared to the related species Helix aspersa (only four mucus glands); histochemically, the glands of both species similarly produce acidic proteins as well as acidic glycosaminoglycans. While calcium ions are known to play a role in mucus formation, the presence and function of other ions such as potassium still need to be clarified. PMID- 28554684 TI - Ovarian hormones in innate inflammation. AB - AIM: A more vigorous immune system activation is generally seen in women as compared to men. The reasons for these differences are still not understood. By investigating the immune-regulatory role of estrogens, we have previously shown that estradiol (E2) can regulate and ameliorate rheumatoid arthritis models. The aim of this study was to elucidate the role of ovariectomy (ovx) and estradiol (E2) in innate immune responses. METHODS: Female mice were ovx or sham operated. After three weeks, either dorsal air pouches were established by injections of sterile air with subsequent lipopolysaccharide (LPS) injection, or LPS was injected intra-peritoneally (i.p). Mice received daily injections with E2 or vehicle for three days before challenge. 6 hours after challenge in the air pouch, blood cells were counted, leukocytes from the pouch were analyzed by flow cytometry, and cytometric bead array or ELISA were used to quantify cytokines collected from the air pouch. Blood cells were counted 1h after i.p challenge. RESULTS: Compared to sham, blood leukocyte numbers increased after ovx and ovx+E2 6 h after LPS injections into the air pouch. LPS after ovx induced neutrophil infiltration into the pouch, accompanied by increased levels of MCP-1 and IL-6. Ovx+E2 further enhanced cell infiltration after LPS; however, the cell population diversified by also including more macrophages and monocytes, with reduced MCP-1 and IL-6 levels. Compared to ovx, blood leukocyte numbers increased already 1h after i.p challenge in ovx+E2 mice. CONCLUSION: Our findings suggest that ovarian hormones and estradiol can adjust the acute innate immune reaction by regulating cell recruitment to inflammatory sites, diversify the responding cell population, and at the same time down-regulate production of certain pro-inflammatory cytokines. Our results also suggest a faster responding immune system after E2. Our results bring further information into the intricate relationship between inflammation and sex steroids. PMID- 28554686 TI - Preoperative preparation of "loss of domain" hernia. Progressive pneumoperitoneum and botulinum toxin type A. AB - Preoperative progressive pneumoperitoneum and botulinum toxin type A are useful tools in the preparation of patients with loss of domain hernias. Both procedures are complementary in the surgical repair, especially with the use of prosthetic techniques without tension, that allow a integral management of these patients. The aim of this paper is to update concepts related to both procedures, emphasizing the advantages that take place in the preoperative management of loss of domain hernias. PMID- 28554688 TI - Salt and methyl jasmonate aggravate growth inhibition and senescence in Arabidopsis seedlings via the JA signaling pathway. AB - Numerous studies have demonstrated the function of salinity or jasmonic acid (JA) in plant growth and senescence. This study evaluated how the combination of salinity and methyl jasmonate (MeJA) (SaM) worked as a novel stress and then regulated plant growth in Arabidopsis. Firstly, we found that compared with MeJA or NaCl treatment alone, SaM would significantly intensified plant growth inhibition and senescence in wild-type (WT) seedlings, and these phenotypes could be partially compromised after SaM stress in JA-insensitive mutants. Meanwhile, genes involved in JA signaling and Senescence Associated Gene 13 (SAG13) were dramatically increased by SaM stress than that by MeJA or NaCl alone in WT. Moreover, a group of secondary metabolite - indolic glucosinolates (IGs) showed obvious over-accumulation after SaM treatment than that after each single one in WT, and the seedlings treated with IGs' metabolites performed similar inhibited growth and chlorotic leaves phenotypes compared with those caused by SaM stress. All these indicated the toxicity of IGs and their metabolites would prevent the growth progress of plants. Therefore, we concluded that SaM worked as a novel stress and intensified plant growth inhibition and senescence, which was dependent on JA-dependent and -independent signaling pathways. PMID- 28554689 TI - High-biomass C4 grasses-Filling the yield gap. AB - A significant increase in agricultural productivity will be required by 2050 to meet the needs of an expanding and rapidly developing world population, without allocating more land and water resources to agriculture, and despite slowing rates of grain yield improvement. This review examines the proposition that high biomass C4 grasses could help fill the yield gap. High-biomass C4 grasses exhibit high yield due to C4 photosynthesis, long growth duration, and efficient capture and utilization of light, water, and nutrients. These C4 grasses exhibit high levels of drought tolerance during their long vegetative growth phase ideal for crops grown in water-limited regions of agricultural production. The stems of some high-biomass C4 grasses can accumulate high levels of non-structural carbohydrates that could be engineered to enhance biomass yield and utility as feedstocks for animals and biofuels production. The regulatory pathway that delays flowering of high-biomass C4 grasses in long days has been elucidated enabling production and deployment of hybrids. Crop and landscape-scale modeling predict that utilization of high-biomass C4 grass crops on land and in regions where water resources limit grain crop yield could increase agricultural productivity. PMID- 28554687 TI - Endocannabinoid Signaling in the Control of Social Behavior. AB - Many mammalian species, including humans, exhibit social behavior and form complex social groups. Mechanistic studies in animal models have revealed important roles for the endocannabinoid signaling system, comprising G protein coupled cannabinoid receptors and their endogenous lipid-derived agonists, in the control of neural processes that underpin social anxiety and social reward, two key aspects of social behavior. An emergent insight from these studies is that endocannabinoid signaling in specific circuits of the brain is context dependent and selectively recruited. These insights open new vistas on the neural basis of social behavior and social impairment. PMID- 28554690 TI - Functions of two Malus hupehensis (Pamp.) Rehd. YTPs (MhYTP1 and MhYTP2) in biotic- and abiotic-stress responses. AB - RNA binding proteins play important roles in plant responses to biotic and abiotic stresses. The YT521-B homology (YTH) domain-containing RNA binding protein (YTP) was first found in Rattus norvegicus and is related to oxygen deficient stress. The Malus YTP gene family has 15 members. Results from their functional analysis will help researchers improve stress tolerance and fruit quality in apple. We cloned two homologous YTP family members in M. hupehensis - MhYTP1 and MhYTP2 - and identified their promoter regions that contain many cis elements related to biotic and abiotic stresses. Both MhYTP1 and MhYTP2 can be induced by various treatments, e.g., methyl jasmonate (MeJA), salicylic acid (SA), abscisic acid (ABA), water-logging, water deficits, and high salinity. When compared with the wild type (WT), transgenic plants of 'GL-3' ('Royal Gala') apple that over-express MhYTP1 or MhYTP2 are more sensitive to D. mali infection, heat stress, and high salinity, more resistant to water-logging, chilling, drought and nutrition deficient conditions. All of these findings indicate that MhYTP1 and MhYTP2 participate in various biotic- and abiotic-stress responses. PMID- 28554691 TI - Melatonin confers plant tolerance against cadmium stress via the decrease of cadmium accumulation and reestablishment of microRNA-mediated redox homeostasis. AB - Although melatonin-alleviated cadmium (Cd) toxicity both in animals and plants have been well studied, little is known about its regulatory mechanisms in plants. Here, we discovered that Cd stress stimulated the production of endogenous melatonin in alfalfa seedling root tissues. The pretreatment with exogenous melatonin not only increased melatonin content, but also alleviated Cd induced seedling growth inhibition. The melatonin-rich transgenic Arabidopsis plants overexpressing alfalfa SNAT (a melatonin synthetic gene) exhibited more tolerance than wild-type plants under Cd conditions. Cd content was also reduced in root tissues. In comparison with Cd stress alone, ABC transporter and PCR2 transcripts in alfalfa seedlings, PDR8 and HMA4 in Arabidopsis, were up-regulated by melatonin. By contrast, Nramp6 transcripts were down-regulated. Changes in above transporters were correlated with the less accumulation of Cd. Additionally Cd-triggered redox imbalance was improved by melatonin. These could be supported by the changes of the Cu/Zn Superoxide Dismutase gene regulated by miR398a and miR398b. Histochemical staining, laser scanning confocal microscope, and H2O2 contents analyses showed the similar tendencies. Taking together, we clearly suggested that melatonin enhanced Cd tolerance via decreasing cadmium accumulation and reestablishing the microRNAs-mediated redox homeostasis. PMID- 28554692 TI - Transcription factor ThWRKY4 binds to a novel WLS motif and a RAV1A element in addition to the W-box to regulate gene expression. AB - WRKY transcription factors play important roles in many biological processes, and mainly bind to the W-box element to regulate gene expression. Previously, we characterized a WRKY gene from Tamarix hispida, ThWRKY4, in response to abiotic stress, and showed that it bound to the W-box motif. However, whether ThWRKY4 could bind to other motifs remains unknown. In this study, we employed a Transcription Factor-Centered Yeast one Hybrid (TF-Centered Y1H) screen to study the motifs recognized by ThWRKY4. In addition to the W-box core cis-element (termed W-box), we identified that ThWRKY4 could bind to two other motifs: the RAV1A element (CAACA) and a novel motif with sequence of GTCTA (W-box like sequence, WLS). The distributions of these motifs were screened in the promoter regions of genes regulated by some WRKYs. The results showed that the W-box, RAV1A, and WLS motifs were all present in high numbers, suggesting that they play key roles in gene expression mediated by WRKYs. Furthermore, five WRKY proteins from different WRKY subfamilies in Arabidopsis thaliana were selected and confirmed to bind to the RAV1A and WLS motifs, indicating that they are recognized commonly by WRKYs. These findings will help to further reveal the functions of WRKY proteins. PMID- 28554693 TI - Overexpression of StNF-YB3.1 reduces photosynthetic capacity and tuber production, and promotes ABA-mediated stomatal closure in potato (Solanum tuberosum L.). AB - Nuclear factor Y (NF-Y) is one of the most ubiquitous transcription factors (TFs), comprising NF-YA, NF-YB and NF-YC subunits, and has been identified and reported in various aspects of development for plants and animals. In this work, StNF-YB3.1, a putative potato NF-YB subunit encoding gene, was isolated from Solanum tuberosum by rapid amplification of cDNA ends (RACE). Overexpression of StNF-YB3.1 in potato (cv. Atlantic) resulted in accelerated onset of flowering, and significant increase in leaf chlorophyll content in field trials. However, transgenic potato plants overexpressing StNF-YB3.1 (OEYB3.1) showed significant decreases in photosynthetic rate and stomatal conductance both at tuber initiation and bulking stages. OEYB3.1 lines were associated with significantly fewer tuber numbers and yield reduction. Guard cell size and stomatal density were not changed in OEYB3.1 plants, whereas ABA-mediated stomatal closure was accelerated compared to that of wild type plants because of the up-regulation of genes for ABA signaling, such as StCPK10-like, StSnRK2.6/OST1-like, StSnRK2.7 like and StSLAC1-like. We speculate that the acceleration of stomatal closure was a possible reason for the significantly decreased stomatal conductance and photosynthetic rate. PMID- 28554695 TI - Glyphosate resistance reduces kochia fitness: Comparison of segregating resistant and susceptible F2 populations. AB - Glyphosate is considered the world's most important herbicide, but widespread and continual use has resulted in the evolution of resistance. Kochia scoparia (kochia) has evolved resistance via tandem gene amplification of glyphosate's target, 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) and resistant populations have been reported from the Canadian Prairies and the Northern Great Plains. Here, we evaluated the fitness costs of EPSPS amplification in kochia by comparing susceptible and resistant full siblings from segregating F2 populations generated from within six populations. Kochia was expected to be highly diverse because of strong gene flow; however, six of the seven field-collected parents with higher EPSPS copy number were homozygous. Under competitive greenhouse conditions, the EPSPS type of the line's maternal parent showed persistent effects: delayed emergence, delayed flowering, and reductions in viable seed count and weight overall. High EPSPS copy number individuals had reduced seed count and weight, reduced competitive ability, and reduced final height in mixed stands, but better germination of the F3. However, all characteristics were highly variable and fitness costs were not constant across genetic backgrounds. In the absence of selection from glyphosate, kochia with increased EPSPS copy number will be at a competitive disadvantage in some genetic backgrounds. PMID- 28554694 TI - Influence of altitude and enhanced ultraviolet-B radiation on tuber production, seed viability, leaf pigments and morphology in the wild potato species Solanum kurtzianum Bitter & Wittm collected from an elevational gradient. AB - Climate change could lead to an upward shift in plant distribution, exposing populations to higher levels of ultraviolet (UV)-B radiation. In the framework of an in situ strategy for conserving potato wild relatives, we evaluated the effect of high UV-B levels on natural population of Solanum kurtzianum. The hypothesis is that plants from naturally higher altitudes are more adapted to increased UV-B radiation. Two populations from low and high altitudes were field supplemented using UV-B-lamps (+UV-B) or excluded from it with plastic filters. Additionally, to assess in which extent the plant responses to these artificial experimental conditions are reproducible in natural conditions, three genotypes were cultivated in two mountain experimental gardens (EG) at different elevations. +UV B treatment induced changes in leaf morphology and increases in phenolic compounds in both populations, indicating plant adaptation, since chlorophylls and reproductive structures were not negatively affected. These results indicate that this environmental factor may not limit the displacement of populations towards sites with higher UV-B levels. Meanwhile, in higher-altitude EG a tubers yield reduction, mainly through a decreased tuber number and a bigger accumulation of phenolic compounds than in +UV-B treatment were observed, suggesting that UV-B is not the only factor involved in plants adaptation to high altitude environments. PMID- 28554696 TI - [Hypertension during Takayasu's disease: An Algerian single center experience of 279 patients]. AB - INTRODUCTION: Takayasu arteritis (TA) is an uncommon large vessel arteritis. Lesions produced by the inflammatory process can be stenotic, occlusive, or aneurysmal. Vascular changes lead to the main complications, including hypertension, most often due to renal artery stenosis or, more rarely, stenosis of the suprarenal aorta. AIM OF STUDY: Our study will assess the prevalence of hypertension during TA and describe its clinical profile. MATERIAL AND METHODS: Among 279 patients with TA resulting from single center study over a period of 35 years, we collected 128 hypertensive patients. All have benefited from a vascular exploration. Renal angiography was performed in 85 patients. The classification of Lupi Herrera allowed us to distribute our patients according to the topography of their lesions. Patients are classified according to the degree of severity of their hypertension. Results are statistically analyzed with SPSS 10.0 database. RESULTS: The prevalence of hypertension is 45.8%, mainly affecting young women (87%). It is indicative of arteritis in 24.7%. Its diagnosis is difficult and delayed when arterial stenosis exist: inter-arm blood pressure difference (53.8%), inverse coarctation (30.4%) or unmeasurable blood pressure at the 4 limbs (6.8%). In 54% of cases, hypertension was due to a renal artery stenosis. The presence of arterial hypertension was associated to a poor prognosis: it was severe in 54% of patients and was linked to 70% of deaths observed. CONCLUSION: Arterial hypertension is common during TA. It remains a factor of bad prognosis specially when renovascular hypertension is present. PMID- 28554697 TI - Orthostatic hypertension in normotensive type 2 diabetics: What characteristics? AB - AIM OF THE STUDY: We aimed to determine the prevalence of orthostatic hypertension (OHT) in normotensive, newly diagnosed type 2 diabetics, to assess clinical, biological characteristics of those patients and evaluate the evolution of their blood pressure, after one year of follow-up. MATERIALS AND METHODS: It is an observational, prospective, cohort study, on 108 normotensive, newly diagnosed diabetics, 40 men and 68 women aged from 40 to 70 ans. OHT was defined as an increase of systolic blood pressure (SBP) >=20mmHg and/or diastolic blood pressure (DBP) >=10mmHg, after 1 and 2min of standing from supine position. Arterial hypertension and metabolic syndrome were respectively defined according to WHO and AHA 2009 guidelines. Clinical and biological data were collected for all patients. They had a screening for diabetic complications and a follow-up during one year. Statistical analysis was performed with Epi-Info 6.04. RESULTS: We found OHT in 22 patients (20.4%). Patients with OHT had a higher SBP at lying position (P=0.029), a higher waist circumference (P=0.022) and LDL (P=0.041). They had more frequently obesity (P=0.036) left ventricular hypertrophy (P=0.024), metabolic syndrome (P=0.042) and cerebrovascular events (P=0.050) when compared with those with normal blood pressure response to orthostasis. One year after follow-up, the prevalence of permanent hypertension was significantly higher in the OHT group (P=0.0008). CONCLUSION: Our study suggests that OHT is associated with insulin resistance syndrome and onset of sustained arterial hypertension in normotensive, newly diagnosed diabetics. PMID- 28554698 TI - Effects of carotid baroreceptor stimulation on retinal arteriole remodeling evaluated with adaptive optics camera in resistant hypertensive patients. AB - BACKGROUND AND AIM: Baroreceptor activation therapy (BAT) leads to a decrease in blood pressure (BP) in patients affected by resistant hypertension (RH) by reducing sympathetic outflow. This study aimed at evaluating the effects of BAT on RH patients' retinal arteriolar microvasculature, a territory devoid of adrenergic innervation. PATIENTS AND METHODS: Five patients defined as affected by RH after excluding secondary causes of hypertension and based on number of antihypertensive treatments, underwent the implantation of BarostimTM neoTM. Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) were assessed by office and 24-hours ambulatory BP monitoring (ABPM). Adaptive Optics Camera RTX1(r) (ImagineEye, Orsay, France) was used to measure wall thickness (WT), internal diameter (ID), wall cross-sectional area (WCSA) and wall-to-lumen ratio (WLR). A cohort of 21 not-controlled hypertensive patients matched for age, gender and follow-up time, undergoing standard-antihypertensive therapy changes, was selected as a control group. SBP and DBP were assessed by office and home BP monitoring (HBPM). Evaluations were performed at baseline and after 6 months mean follow-up. RESULTS: Office SBP decreased by 9.7+/-12.3% and 29.7+/-12.4% in standard-therapy and BAT group respectively, while office DBP decreased by 7.6+/ 17.4% and 14.8+/-15.7%. Concerning ABPM/HBPM, a mean reduction of both SBP and DBP of 7.9+/-11% was observed for the standard-therapy while a reduction of 15.8+/-10.5% and 15.8%+/-5.3% was observed for SBP and DBP respectively in BAT group. While in the standard-therapy group a significant reduction in WLR (-5.9%) due to both ID increase (+2.3%) and WT reduction (-5.7%) was observed, without changes in WCSA (-0.3%), RH patients had a significant reduction in WCSA ( 12.1%), due to a trend in both WT and ID reduction (-6.5% and -1.7% respectively), without significant changes in WLR (-2%). CONCLUSION: While a reverse eutrophic remodeling was observed in patients undergoing a standard antihypertensive treatment, hypotrophic changes were found in RH patients undergoing BAT. Despite the lack of adrenergic receptors on retinal vessels, chronic baroreflex stimulation may exert an effect on retinal microvasculature in RH patients by more systemic than local mechanisms. PMID- 28554699 TI - [Prevalence of carotid artery stenosis in nonagenarians: Survey in a primary care hospital]. AB - AIM: Carotid artery stenosis increases with age and may cause brain ischemia if arterial hypotension occurs. We performed a monocentric pilot study to investigate its prevalence in the very elderly and to assess its potential influence on blood pressure (BP) goals during antihypertensive treatment. METHODS: All patients>=90 years of a primary care medical ward were prospectively included over 15 months. Ultrasound exams of the precerebral arteries were offered to all elderly patients for routine evaluation of their cardiovascular risk. Frequencies of stenosed common, internal and external carotid arteries (CCA, ICA, ECA) were analyzed together with clinical BP and antihypertensive therapy. Patients with circulatory shock and readmissions were excluded. RESULTS: Sixty-three patients aged 92+/-3 years (78% female) hospitalized for a median of 11 days were included. On admission, 76% were on antihypertensive drugs vs. 86% at discharge. Mean admission BP was 149/77 vs. 129/72mmHg at discharge; systolic BP<140mmHg 36% vs 64% (P<0.05). Mean intima-media thickness (ACC, right/left) was 8.7/9.4mm. Prevalence of plaque or stenosis<60% was: CCA 19.0%, ICA 19.0%, ECA 31.7%, bulb 74.6%; of stenosis>=60%: CCA 0%, ICA 7.9%, ECA 19.0%, ICA bilateral 1.6% (unilateral occlusion 3.1%, no bilateral). Coincidence of systolic BP<120mmHg and ACI stenosis>=60% had a probability of 1-2%. CONCLUSION: Concerning the risk of brain ischemia due to carotid artery stenosis, a BP goal<140mmHg should be safe for most nonagenarians. If individual BP goals are lower, searching for significant stenosis by ultrasound may be useful. PMID- 28554700 TI - [Left ventricular hypertrophy in black African subjects with artery hypertension: Results of a cross-sectional survey conducted in semi-rural area in Senegal]. AB - OBJECTIVES: To assess the prevalence of left ventricular hypertrophy according to electrocardiographic and echocardiographic criteria among hypertensive patients living in semi-rural Senegalese area. PATIENTS AND METHODS: According to the World Health Organization STEPSwise approach, we conducted, in November 2012, a cross-sectional and exhaustive study in the population aged at least 35 years old and living for at least six months in the semi-rural area of Gueoul. We researched electrocardiographic and echocardiographic left ventricular hypertrophy in hypertensive subjects. Data were analyzed with SPSS 18.0 software version. The significance level was agreed for a value of P<0.05. RESULTS: We examined 1411 subjects aged on average of 48.5+/-12.7 years. In total, 654 subjects were hypertensive and screening of left ventricular hypertrophy (LVH) was effective in 515 of them. According to Sokolow-Lyon index, 86 subjects (16.7%) presented electrocardiographic LVH, more frequently in men (P=0.002). According to Cornell index and Cornell product, LVH was founded respectively in 66 (12.8%) and 52 subjects (10.1%), more frequently in female (P=0.0001; P=0.004). It was more common in grade 3 of hypertension however criteria. In echocardiography, prevalence of LVH was 2.2% (13 cases) according to the left ventricular mass, 9.3% (48 cases) according to the left ventricular mass indexed to body surface area and 8.2% (42 cases) according to the left ventricular mass indexed to height2.7. LVH was significantly correlated with the electrocardiographic LVH according to Sokolow-Lyon index (P<0.0001) and the grade 3 of hypertension (P=0.003). CONCLUSION: Although rare in hypertensive Senegalese living in semi-rural area, left ventricular hypertrophy is correlated with severity of grade of hypertension. Screening by electrocardiogram will allow better follow-up of these hypertensive subjects. PMID- 28554701 TI - [Development of a risk calculator for drug compliance in treated hypertensives: The FLAHS Compliance Calculator]. AB - OBJECTIVE: To investigate the determinants of non-compliance with antihypertensive treatments among participants in the FLAHS 2015 survey and to develop a risk calculator for drug compliance in a hypertensive population. METHODS: The FLAHS surveys are carried out by self-questionnaire sent by mail to individuals from the TNS SOFRES (representative panel of the population living in metropolitan France) sampling frame. In 2015, FLAHS was performed in subjects aged 55years and older. Using the Girerd questionnaire, the "perfect observance" was determined for a score of 0 and "nonobservance" for a score of 1 or higher. A Poisson regression was conducted in univariate and multivariate to estimate risk ratios for each determinant. A non-compliance risk calculator is constructed from multivariate analysis. A Poisson regression was performed in univariate and multivariate to estimate risk ratios. For each sex, a probability table is produced from the equation of the multivariate analysis and then the calculation of a nonobservance probability ratio (PR) using the profile with the best probability as a reference. Each subject is then classified into one of the three classes of risk of non-compliance: low (PR <1.5), high (PR>=2) and intermediate (PR>=1.5 and <2). RESULTS: The survey included 6379 subjects and analysis based on 2370 treated hypertensives. The onset of treatment was less than 2years in 7% of subjects and the median follow-up duration of treatment was 10years. Perfect compliance was observed in 64% of subjects. Independent determinants of non compliance are: male sex, young age, number of antihypertensive tablet, treatment for a metabolic disease (diabetes, dyslipidemia), presence of other chronic illness, secondary prevention of cardiovascular disease. To get the risk class of nonobservance a web page is available at http://www.comitehta.org/flahs observance-hta/. CONCLUSION: The development of the FLAHS Compliance Test is a tool whose use is possible during an office visit. Its free availability for French doctor will be one of the actions undertaken as part of the "call for action for adherence in hypertension" proposed by the French League Against Hypertension in 2017. PMID- 28554702 TI - [Cardiac hydatid cyst about 17 operated cases]. AB - : Cardiac hydatid cyst is a rare parasitic disease. The purpose of this study was to describe the clinical, pathological features and the outcome of the surgical treatment of cardiac hydatid disease in our unit over a twenty-year period. METHODS: Between May 1994 and May 2014, seventeen cases of cardiac hydatid cysts were operated at our unit. Overall, twelve patients were male (mean age 25+/ 13years). All patients were complaining of dyspnea and 71% presented with chest pain. The diagnosis, based on histological examination, was suspected on echocardiography and computed tomography of chest. RESULTS: Our study revealed five possible locations, which were in decreasing order of frequency: left ventricle, interventricular septum, right ventricle, left atrium and pulmonary artery. The surgical procedure was a controlled puncture and aspiration of the cyst content, with cystectomy (69%), or pericystectomy (31%). The resulting cavity left open in 6 cases (37.5%) or carefully closed in 10 (62.5%). Hospital mortality was 11.8% (n=2). Morbidity was marked by conduction abnormalities (n=2), bleeding and hematoma of the residual cavity that required surgical treatment (n=3). Eleven patients were followed with a mean period of 40.5+/-19.4 months. At follow-up, neither late deaths nor recurrence have occurred. CONCLUSION: Cardiac hydatid cyst is a serious disease whose treatment is surgical. Cystectomy and pericystectomy remain the two surgical techniques able to offer good chance of cure with acceptable morbidity and mortality. PMID- 28554703 TI - Differences in prevalence, treatment and control rates of hypertension between male and female in the area of Blida (Algeria). AB - PURPOSE: To compare differences in prevalence rates, treatment and control of hypertension (AHT) between males and females in general medicine consultation in the area of Blida (Algeria). METHODS: We included 3622 patients in the study (42% males and 58% females), with a mean age of 48.14+/-10.11 years, examined between January 2014 and June 2016 in general medicine consultation in the area of Blida (Algeria). Data was collected with individual questionnaires. Measurement of blood pressure was made using validated semi-automatic devices (OMRON HEM model 705CP). Individuals using antihypertensive drugs and/or blood pressure (BP) greater than or equal to 140/90mmHg were considered as hypertensives. The knowledge about the disease was identified among those who claimed to be aware of the diagnosis before the measurements. The treatment rate was calculated with those who reported using antihypertensive drugs. Controlled blood pressure was considered in individuals with values lower than 140/90mmHg. Lipid profile (total cholesterol, triglycerides, HDL and LDL cholesterol), and fasting blood sugar were measured. All calculations and statistical analyses are processed by the SPSS 20.0. RESULTS: The prevalence of hypertension was higher among men (46.2%) than women (31.6%) (P<0.001), and among aged over 55 years (P< 0.05) and those that have referred hypertensive parents (P<0.05). Among hypertensive men, 55.7% knew the diagnosis, 63.6% of them were under treatment, and 22% had controlled BP. Among the hypertensive women 69.8% knew the diagnosis, 85.1% were under treatment and 35.6% were with controlled BP (P<0.001 for the three variables). The most frequent associated risk factors were diabetes mellitus in 36.8% of the patients, obesity in 35.7% of the patients, microalbuminuria in 23.6% of the patients, hypercholesterolemia>2g/L in 11.6% of the patients, smoking in 7.7% of them. Presence of controlled AHT was not found to be associated with presence of other risk factors. The likelihood of having AHT was higher among men, diabetics, older subjects and higher BMI. CONCLUSION: Our study confirmed the high prevalence of AHT in general medicine consultation in Blida, which is a representative city in the north of Algeria. Although women are better treated, much remains to be done to reach BP goal, much in our countries which have the least financial resources to combat cardiovascular disabilities. PMID- 28554704 TI - Duration and exclusiveness of breastfeeding and school-age lung function and asthma. AB - BACKGROUND: Breastfeeding reduces the risk of asthma in early childhood, but it is not clear whether its effect on respiratory morbidity is still present in later childhood. OBJECTIVE: To examine the associations of any breastfeeding, breastfeeding duration, and breastfeeding exclusiveness with lung function and asthma in school-aged children and whether associations were influenced by respiratory tract infections and maternal or child's atopic status. METHODS: This study of 4,464 children was embedded in a population-based prospective cohort study. Information on breastfeeding was obtained by multiple questionnaires from birth until 1 year of age. At 10 years of age, lung function was measured by spirometry, and information on asthma was obtained by questionnaire. Adjusted linear and logistic regression models were used to examine the associations. RESULTS: Shorter duration of breastfeeding was associated with a lower forced expiratory volume in 1 second (FEV1) only (z score change, -0.01; 95% confidence interval [CI], -0.02 to -0.00) per month shorter breastfeeding, but not asthma. When categorized, breastfeeding for 2 to 4 months was associated with a lower forced vital capacity (FVC) (z score change, -0.11; 95% CI, -0.20 to -0.03) compared with breastfeeding for 6 months or longer. Nonexclusive breastfeeding for 4 months was associated with a lower FVC (z score change, -0.08; 95% CI, 0.16 to -0.01) compared with exclusive breastfeeding for 4 months. Results did not materially change after additional adjustment for lower respiratory tract infections and were not modified by maternal history of asthma or atopy, child's eczema, or inhalant allergic sensitization. CONCLUSION: Shorter duration and nonexclusivity of breastfeeding were associated with a lower FEV1 and FVC but not asthma at school-age. PMID- 28554705 TI - Association of IgE Can f 2 and dyspnea in pet allergic patients. PMID- 28554706 TI - Multiplex PCR assay for genotyping of Mycobacterium tuberculosis in Lima, Peru. PMID- 28554707 TI - Squamocin, an annonaceous acetogenin, enhances naphthalene degradation mediated by Bacillus atrophaeus CN4. AB - Squamocin belongs to a group of compounds called annonaceous acetogenins. They are secondary products of Annonaceae metabolism and can be isolated from Annona cherimolia seeds. This paper deals with the stimulation of biofilm formation of Bacillus atrophaeus CN4 by employing low squamocin concentrations to increase naphthalene degradation. Bacillus atrophaeus CN4, isolated from contaminated soil, has the ability to degrade naphthalene as the only source of carbon and energy. In the absence of additional carbon sources, the strain removed 69% of the initial concentration of naphthalene (approx. 0.2mmol/l) in the first 12h of incubation. The addition of squamocin in LB medium stimulated Bacillus atrophaeus CN4 biofilm formation and enhanced naphthalene removal. Squamocin (2.5MUg/ml) does not affect planktonic growth and therefore, the observed increases are solely due to the stimulation of biofilm formation. PMID- 28554708 TI - Protothecosis in a patient with T cell lymphocytic leukemia. AB - Human protothecosis is a rare infection caused by algae of the genus Prototheca. Prototheca wickerhamii has been recognized as the main species that causes infection in immunocompromised hosts with deficits in innate or cellular immunity. We report a case of persisting subcutaneous protothecosis in a patient with T-cell large granular lymphocyte leukemia, who also presented a history of disseminated histoplasmosis. PMID- 28554709 TI - Ultrasound-guided genicular nerve block for pain control after total knee replacement: Preliminary case series and technical note. AB - INTRODUCTION: Total knee arthroplasty (TKA) is an operation with moderate to severe postoperative pain. The Fast-Track models employ local infiltration techniques with anaesthetics at high volumes (100-150ml). We proposed a genicular nerve block with low volume of local anaesthetic. The aim of our study is to evaluate the periarticular distribution of these blocks in a fresh cadaver model and to describe the technique in a preliminary group of patients submitted to TKA. MATERIALS AND METHODS: In the anatomical phase, 4 genicular nerves (superior medial, superior lateral, inferior medial and inferior lateral) were blocked with 4ml of local anaesthetic with iodinated contrast and methylene blue in each (16ml in total). It was performed on a fresh cadaver and the distribution of the injected medium was evaluated by means of a CT-scan and coronal anatomical sections on both knees. The clinical phase included 12 patients scheduled for TKA. Ultrasound-guided block of the 4 genicular nerves was performed preoperatively and their clinical efficacy evaluated by assessing pain after the reversal of the spinal block and at 12h after the block. Pain was measured using the numerical scale and the need for rescue analgesia was evaluated. RESULTS: A wide periarticular distribution of contrast was observed by CT-scan, which was later evaluated in the coronal sections. The distribution followed the joint capsule without entering the joint, both in the femur and in the tibia. The pain after the reversal of the subarachnoid block was 2+/-1, requiring rescue analgesia in 42% of the patients. At 12h, the pain according to the numerical scale was 4+/-1, 33% required rescue analgesia. CONCLUSION: The administration of 4ml of local anaesthetic at the level of the 4 genicular nerves of the knee produces a wide periarticular distribution. Our preliminary data in a series of 12 patients undergoing TKA seems to be clinically effective. Nevertheless, extensive case series and comparative studies with local infiltration techniques with anaesthetics are needed to support these encouraging results. PMID- 28554710 TI - The PECS II block as a major analgesic component for clavicle operations: A description of 7 case reports. AB - Clavicle fractures correspond to 35% of traumatic fractures of the shoulder girdle. Regional anaesthesia has shown better analgesic results than systemic treatment for perioperative management. Innervation of the clavicle is complex, at present its knowledge raises controversy. The lateral pectoral nerve through the innervating musculature predominantly participates in the lateral and anterior part of the clavicle. The following report of 7 cases describes the effective postoperative analgesia of modified PEC II block in patients with middle third clavicle fracture or acromioclavicular dislocation who underwent a modified PEC II block for postoperative pain management, in the context of a multimodal analgesia. The potential advantage of this management over other analgesic procedures should be evaluated in specific clinical trials. PMID- 28554711 TI - Scimitar syndrome: Anaesthetic management for pulmonary resection of the unaffected lung. AB - Scimitar syndrome is a rare congenital anomaly characterized by anomalous drainage of the right pulmonary veins in the inferior vena cava, frequently associated with right lung and pulmonary artery hypoplasia, dextrocardia and abnormal systemic arterial supply to the lower lobe. Pulmonary resection surgery on healthy lung is exceptional, and there are no published records of it, as far as we know. A man with scimitar syndrome diagnosed with a lung nodule with malignant features in the contralateral lung. This situation implies huge anaesthetic complexity, mainly for intraoperative ventilation. Although spirometry and stress test did not contraindicate the planned lobectomy, scintigraphy showed a hypoplastic right lung with an uptake of 15%. From an anaesthetic point of view we discarded selective ventilation of the right lung, since the shunt made it functionally non-existent. In consequence we proposed four anaesthetic possibilities. After the placement of an epidural catheter and left selective intubation, thoracoscopy with intermittent apnoeas was our first choice, and we could complete the extirpation and avoid excessive complexity. PMID- 28554712 TI - The role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in complement-mediated phagocytosis and podosome formation by human phagocytes. AB - CR3 and CR4 belong to the family of beta2-integrins and play an important role in phagocytosis, cellular adherence and migration. CR3 and CR4 are generally expected to mediate similar functions due to their structural homology, overlapping ligand specificity and parallel expression on human phagocytes. Although the different signalling pathways of these receptors suggest distinct functions, possible differences are just being revealed. Previously we proved that CR3 plays a key role in the uptake of iC3b-opsonized particles by human dendritic cells. Now, besides measuring the overall phagocytic capacity of cells including the assessment of surface bound as well as internalized particles, we extended our investigations and studied the digestion of the iC3b opsonized antigen by various human phagocytes. The participation of CR3 and CR4 was compared in the process of binding, internalization and digestion of iC3b opsonized Staphylococcus aureus by monocytes, monocyte derived macrophages (MDMs), monocyte derived dendritic cells (MDDCs), and neutrophils. Comparing the activity of the two beta2-integrin type complement receptors we found that CR3 plays a dominant role in the phagocytosis of iC3b opsonized S. aureus by all of these cell types. Studying another important integrin-mediated function we demonstrated earlier that CR4 is dominant in the adhesion of monocytes, MDMs and MDDCs to fibrinogen. Here we studied the participation of CR3 and CR4 in podosome formation by human phagocytes, since these structures are known to play an essential role in cell migration. Our confocal microscopy analysis revealed that both CD11b and CD11c concentrate in the podosome adhesion ring. In summary our data highlight differences in the function of human CR3 and CR4 in the process of uptake and digestion of complement opsonized antigen, while in the process of podosome formation, connected to cellular motility, both receptors equally take part. PMID- 28554713 TI - Different capacity of in vitro generated myeloid dendritic cells of newborns of healthy and allergic mothers to respond to probiotic strain E. coli O83:K24:H31. AB - Allergic diseases belong to one of the most common diseases with steadily increasing incidence even among young children. There is an urgent need to identify a prognostic marker pointing to increased risk of allergy development enabling early preventive measures introduction. It has been shown that administration of selected probiotic strains or mixtures could prevent allergy development. In our study, we have tested the capacity of probiotic strain Escherichia coli O83:K24:H31 (E. coli O83) to promote dendritic cell (DC) maturation and polarisation of immune responses. Increased presence of activation marker CD83 was observed on DC stimulated by E. coli O83 and DC of newborns of allergic mothers have significantly more increased cell surface presence of CD83 in comparison to children of healthy mothers. Increased gene expression and secretion of IL-10 was detected in DC stimulated with E. coli O83 being higher in DC of newborns of healthy mothers in comparison to allergic ones. Generally, increased presence of intracellular cytokines (IL-4, IL-13, IFN-gamma, IL-17A, IL 22, IL-10) was detected in CD4+ T cells cocultured with DC of children of allergic mothers in comparison to healthy ones. E. coli O83 primed DC significantly increased IL-10 and IL-17A in CD4 T cells of newborns of healthy mothers in comparison to the levels detected in CD4 T cells cocultured with control non-stimulated DC. We can conclude E. coli O83 induces dendritic cell maturation and IL-10 production in DC. Newborns of allergic mothers have generally increased reactivity of both DC and CD4 T cells which together with decreased capacity of DC of newborns of allergic mothers to produce IL-10 could support inappropriate immune responses development after allergen encounter. PMID- 28554714 TI - Analysis of shoulder abduction by dynamic shoulder radiograph following suprascapular nerve repair in brachial plexus injury. AB - BACKGROUND: Suprascapular nerve repair is a widely-prioritized procedure for shoulder reconstruction following brachial plexus injury. Although this procedure only reconstructs glenohumeral joint motion, the standard clinical assessment of shoulder function also includes the scapulothoracic joint contribution. The purpose of this preliminary study was to develop an objective method to accurately analyze shoulder abduction following suprascapular nerve repair in brachial plexus injury patients. METHODS: We introduced an objective method to accurately analyze independent shoulder abduction performed by supraspinatus muscle with the help of dynamic shoulder radiography. Antero-posterior radiographs of both shoulders in adduction and maximal active abduction were obtained. Five parameters were measured. They included global abduction, abduction in glenohumeral, scapulothoracic and clavicular joints along with lateral flexion of thoracic spine. Data were analyzed to distinguish glenohumeral joint contribution from that of scapulothoracic motion. The detailed biomechanics of glenohumeral motion were also analyzed in relation to scapulothoracic motion to separately define the contribution of each in global shoulder abduction. RESULTS: The test-retest, intra-examiner and inter-examiner reliabilities of the measurements were assessed. Intra-class correlation coefficient, Bland-Altman plots and repeatability coefficients showed excellent reliability for each parameter. The range of glenohumeral abduction showed high correlation to subtraction of the range of scapulothoracic from the range of global abduction. However, not all negative ranges of glenohumeral abduction meant non-recovery after nerve repair, because scapulothoracic motion contributed in parallel but not uniformly to global shoulder motion. CONCLUSION: The conventional measurement of shoulder global abduction with goniometer is not an appropriate method to analyze the results of suprascapular nerve repair in brachial plexus palsy patients. We recommend examination of glenohumeral and scapulothoracic motions separately with dynamic shoulder radiographic analysis. With scapulothoracic contribution to the global shoulder motion, the glenohumeral motion can be wrongly assessed. PMID- 28554715 TI - Hybrid surgery for a pseudoaneurysm caused by a clavicle fracture. PMID- 28554716 TI - Acute Hemodynamic Effects of Intra-aortic Balloon Counterpulsation Pumps in Advanced Heart Failure. AB - BACKGROUND: The utility of intra-aortic balloon counterpulsation pumps (IABPs) in low cardiac output states is unknown and no studies have explored the impact of IABP therapy on ventricular workload in patients with advanced heart failure (HF). For these reasons, we explored the acute hemodynamic effects of IABP therapy in patients with advanced HF. METHODS: We prospectively studied 10 consecutive patients with stage D HF referred for IABP placement before left ventricular assist device (LVAD) surgery and compared with 5 control patients with preserved left ventricular (LV) ejection fraction (EF) who did not receive IABP therapy. Hemodynamics were recorded using LV conductance and pulmonary artery catheters. Cardiac index (CI)-responder and CI-nonresponder status was assigned a priori as being "equal to or above" or below the median of the IABP effect on CI, respectively, within 24 hours after IABP activation. RESULTS: Compared with controls, patients with advanced HF had lower LVEF, lower LV end systolic pressure, lower LV stroke work, and higher LV end-diastolic pressures and volumes before IABP activation. IABP activation reduced LV stroke work primarily by reducing end-systolic pressure. IABP therapy increased CI by a median of 20% as well as increased diastolic pressure time index and the myocardial oxygen supply:demand ratio. Compared with CI-nonresponders, CI responders had higher systemic vascular resistance, lower right heart filling pressures, and a trend toward lower left heart filling pressures with improved indices of right heart function. Compared with CI-nonresponders, the diastolic pressure time index was increased among CI-responders. CONCLUSIONS: IABP therapy may be effective at reducing LV stroke work, increasing CI, and favorably altering the myocardial oxygen supply:demand ratio in patients with advanced HF, especially among patients with low right heart filling pressures and high systemic vascular resistance. PMID- 28554718 TI - Contryphan-Bt: A pyroglutamic acid containing conopeptide isolated from the venom of Conus betulinus. AB - A new member of the contryphans family was isolated from the venom of Conus betilinus, a vermivorous species distributed in the South China Sea. Its sequence, ZSGCO(D-W)KPWC-NH2 (Z, pyroglutamic acid), was established by a combination of de novo MS/MS sequencing and venom-duct transcriptome sequencing. The occurrence of D-Trp6 was confirmed by chemical synthesis and HPLC behavior comparison. Like known contryphans, contryphan-Bt produces the "stiff-tail" syndrome in mice and contains one disulfide bond, a hydroxyproline, a D tryptophan, and an amidated C-terminus. However, contryphan-Bt differs from previously identified contryphans by a pyroglutamic acid at the N terminus. CD spectrum reveals that contryphan-Bt possess beta-turn in solution. PMID- 28554719 TI - A systematic review and meta-analysis of placebo versus no treatment for insomnia symptoms. AB - This systematic review and meta-analysis aimed to determine the size of the placebo effect for insomnia symptoms when comparing placebo treatment with no treatment. PsycINFO, MEDLINE, and CINAHL databases were systematically searched for studies allocating participants with insomnia symptoms (diagnosed or self reported) to receive a placebo that they were led to believe was an active treatment or to a no treatment control group. Thirteen independent studies (n = 566) met inclusion criteria. Meta-analysis indicated a reliable placebo effect whereby placebo treatment led to improved perceived sleep onset latency (SOL; Hedges g = 0.272), total sleep time (TST; Hedges g = 0.322), and global sleep quality (GSQ; Hedges' g = 0.581), when compared with no treatment. There was no effect on objective assessment of SOL, however only a few studies reported this outcome and there were insufficient sample sizes to meta-analyse other objective outcomes. Moderator analysis indicated that the placebo effect for perceived insomnia symptoms was quite consistent across different variables. The present findings provide strong evidence for placebo effects for perceived insomnia symptoms, but not on the only objective measurement with sufficient sample size to meta-analyse, namely objective SOL. This has important implications for the treatment of insomnia symptoms and the design and interpretation of clinical trials for insomnia symptoms. PMID- 28554717 TI - Phenylalanine derivatives with modulating effects on human alpha1-glycine receptors and anticonvulsant activity in strychnine-induced seizure model in male adult rats. AB - The critical role of alpha1-glycine receptor (alpha1-GLYRs) in pathological conditions such as epilepsy is well known. In the present study, structure activity relations for a series of phenylalanine derivatives carrying selected hydrogen bond acceptors were investigated on the functional properties of human alpha1-GLYR expressed in Xenopus oocytes. The results indicate that one particular substitution position appeared to be of special importance for control of ligand activity. Among tested ligands (1-8), the biphenyl derivative (2) provided the most promising antagonistic effect on alpha1-GLYRs, while its phenylbenzyl analogue (5) exhibited the highest potentiation effect. Moreover, ligand 5 with most promising potentiating effect showed in-vivo moderate protection when tested in strychnine (STR)-induced seizure model in male adult rats, whereas ligand 2 with highest antagonistic effect failed to provide appreciable anti(pro)convulsant effect. Furthermore, ligands 2 and 5 with the most promising effects on human alpha1-GLYRs were examined for their toxicity and potential neuroprotective effect against neurotoxin 6-hydroxydopamine (6-OHDA). The results show that ligands 2 and 5 possessed neither significant antiproliferative effects, nor necrotic and mitochondrial toxicity (up to concentration of 50MUM). Moreover, ligand 2 showed weak neuroprotective effect at the 50MUM against 100MUM toxic dose of 6-OHDA. Our results indicate that modulatory effects of ligands 2 and 5 on human alpha1-GLYRs as well as on STR induced convulsion can provide further insights for the design of therapeutic agents in treatment of epilepsy and other pathological conditions requiring enhanced activity of inhibitory glycine receptors. PMID- 28554720 TI - The changing epidemiology and demography of cystic fibrosis. AB - Once considered a pediatric disease with a poor prognosis, individuals born with cystic fibrosis (CF) today can expect to live well into adulthood. The implementation of multidisciplinary care, novel treatments and newborn screening has resulted in the rapid evolution in the demographics of the CF population. The purpose of this review is to highlight the evolving epidemiology and demographics of the CF population internationally. PMID- 28554721 TI - Current and emerging comorbidities in cystic fibrosis. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed ubiquitously throughout the body. Thus, while respiratory manifestations dominate much of cystic fibrosis (CF) care, there are prominent multi-organ manifestations and comorbidities. In the general population, the number of comorbidities increases with aging. Few illnesses have experienced such a dramatic improvement in survival as CF, which has been transformed from an illness of childhood death to one of adult survival. Hence, as longevity increases in CF, it is paralleled by an increasing number of patients with multicomplex comorbidities availing of care from adult CF multi-disciplinary teams. This review gives an overview of the traditional CF associated comorbidities and those emerging in an aging adult cohort. While historically the treatment of CF focused on the consequences of CFTR dysfunction, the recent advent of CFTR modulators with the potential to enhance CFTR function represents an opportunity to potentially reverse or delay the development of some of the comorbidities associated with CF. Where evidence is available for the impact of CFTR modulatory therapy, namely ivacaftor on comorbidities in CF, this is highlighted. PMID- 28554722 TI - Common clinical features of CF (respiratory disease and exocrine pancreatic insufficiency). AB - First described as a disease of the pancreas, cystic fibrosis is a genetically inherited progressive disease affecting multiple organ systems. Pulmonary and pancreatic involvement is common in individuals with cystic fibrosis, and the former is attributable to most of the mortality that occurs with the condition. This chapter provides an overview of a clinical approach to the pulmonary and pancreatic manifestations of cystic fibrosis. PMID- 28554723 TI - New treatments targeting the basic defects in cystic fibrosis. AB - Cystic fibrosis (CF) is a monogenic autosomal recessive disorder affecting around 75,000 individuals worldwide. It is a multi-system disease but the main morbidity and mortality is caused by chronic lung disease. Due to newborn screening, a multidisciplinary approach to care and intensive symptomatic treatment, the prognosis has dramatically improved over the last decades and there are currently more adults than children in many countries. However, CF is still a very severe disease with a current median age of life expectancy in the fourth decade of life. The disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes the CFTR protein, a protein kinase A-activated ATP-gated anion channel that regulates the transport of electrolytes such as chloride and bicarbonate. More than 2000 mutations have been reported, although not all of these have functional consequences. An enormous research effort and progress has been made in understanding the consequences of these mutations on the CFTR protein structure and function, and this has led to the approval of two new drug therapies that are able to bind to defective CFTR proteins and partially restore their function. They are mutation-specific therapies and available at present for specific mutations only. They are the first personalized medicine for CF with a possible disease-modifying effect. A pipeline of other compounds is under development with different mechanisms of action. It is foreseeable that new combinations of compounds will further improve the correction of CFTR function. Other strategies including premature stop codon read-through drugs, antisense oligonucleotides that correct the basic defect at the mRNA level or gene editing to restore the defective gene as well as gene therapy approaches are all in the pipeline. All these strategies are needed to develop disease-modifying therapies for all patients with CF. PMID- 28554724 TI - Sepsis-associated cardiac arrest, caused or being caused? PMID- 28554725 TI - Substrate inhibition of 17beta-HSD1 in living cells and regulation of 17beta-HSD7 by 17beta-HSD1 knockdown. AB - This study addresses first the role of human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) in breast cancer (BC) cells. The enzyme has a high estrone activating activity that is subject to strong substrate inhibition as shown by enzyme kinetics at the molecular level. We used BC cells to verify this phenomenon in living cells: estrone concentration increase did reduce the reaction with 0.025 to 4MUM substrate. Moreover, 5alpha-dihydrotestosterone (DHT) demonstrated some inhibition of estrogen activation at both the molecular and cellular levels. The presence of DHT did not change the tendency toward substrate inhibition for estrone conversion, but shifted the inhibition toward higher substrate concentrations. Moreover, a binding study demonstrated that both DHT and dehydroepiandrosterone (DHEA) can be bound to the enzyme, thereby supporting the multi-specificity of 17beta-HSD1. We then followed the concentrations of estradiol and performed q-RT-PCR measurements of reductive 17beta-HSDs after 17beta-HSD1 inhibition. The estradiol decrease by the 17beta-HSD1 inhibition was demonstrated lending support to this observation. Knockdown and inhibition of 17beta-HSD1 produced reduction in estradiol levels and the down-regulation of another reductive enzyme 17beta-HSD7, thus "amplifying" the reduction of estradiol by the 17beta-HSD1 modulation itself. The critical positioning of 17beta-HSD7 in sex-hormone-regulation as well as the mutual regulation of steroid enzymes via estradiol in BC, are clearly demonstrated. Our study demonstrates that fundamental enzymological mechanisms are relevant in living cells. Moreover, further enzyme study in cells is merited to advance biological and medical research. We also demonstrated the central role of 17beta-HSD7 in sex-hormone conversion and regulation, supporting it as a novel target for estrogen-dependent (ER+) BC. PMID- 28554726 TI - Microbial expression of Exendin-4 analog and its efficacy in mice model. AB - Exendin-4 is a GLP 1 agonist incretin-mimetic peptide hormone comprising 39 amino acids. Exenatide (Byetta(r)) is a chemically synthesized version of Exendin-4 with an additional C-terminal amidation. Exenatide acts as a GLP-1 receptor agonist. This paper illustrates the method adopted for cloning, fermentation and purification of recombinant Exendin-4 analog expressed in Escherichia coli. The biologically expressed analog was extensively characterized using different orthogonal methods to confirm their biological activity and physicochemical properties. It was observed that the expressed analog showed comparable functional properties as that of Byetta(r) irrespective of their modes of development. Further, in vivo efficacy of the recombinant Exendin-4 analog was studied in Oral Glucose Tolerance Test (OGTT) in mice models. Byetta(r) and Exendin-4 analog treated groups showed comparable glucose lowering activity in the OGTT model. PMID- 28554727 TI - Testosterone modulates FoxO3a and p53-related genes to protect C2C12 skeletal muscle cells against apoptosis. AB - The loss of muscle mass and strength with aging, sarcopenia, is a prevalent condition among the elderly, associated with skeletal muscle dysfunction and enhanced muscle cell apoptosis. We have previously demonstrated that testosterone protects against H2O2-induced apoptosis in C2C12 muscle cells, at different levels: morphological, biochemical and molecular. Since we have observed that testosterone reduces p-p53 and maintains the inactive state of FoxO3a transcription factor, induced by H2O2, we analyzed if the hormone was exerting its antiapoptotic effect at transcriptional level, by modulating pro and antiapoptotic genes associated to them. We detected the upregulation of the proapoptotic genes Puma, PERP and Bim, and MDM2 in response to H2O2 at different periods of the apoptotic process, and the downregulation of the antiapoptotic gene Bcl-2, whereas testosterone was able to modulate and counteract H2O2 effects. Furthermore, ERK and JNK kinases have been demonstrated to be linked to FoxO3a phosphorylation and thus its subcellular distribution. This work show some transcription level components, upstream of the classical apoptotic pathway, that are activated during oxidative stress and that are points where testosterone exerts its protective action against apoptosis, exposing some of the puzzle pieces of the intricate network that aged skeletal muscle apoptosis represents. PMID- 28554728 TI - Multi-Centre Study on Cardiovascular Risk Management on Patients Undergoing AAA Surveillance. AB - BACKGROUND: The risk of cardiovascular events and death in patients with abdominal aortic aneurysms (AAA) is high. Screening has been introduced to reduce AAA related mortality; however, after AAA diagnosis, cardiovascular modification may be as important to patient outcomes as surveillance. The aim of this study was to assess cardiovascular risk reduction in patients with small AAA. METHODS: Institutional approval was granted for The Vascular and Endovascular Research Network (VERN) to retrospectively collect data pertaining to cardiovascular risk reduction from four tertiary vascular units in England. Patients with small AAA (January 2013-December 2015) were included. Demographic details, postcode, current medications, and smoking status were recorded using a bespoke electronic database and analysed. In a secondary analysis VERN contacted all AAA screening units in England and Wales to assess their current protocols relating to CV protection. RESULTS: In total, 1053 patients were included (mean age 74 +/- 9 years, all men). Of these, 745 patients (70.8%) had been prescribed an antiplatelet agent and 787 (74.7%) a statin. Overall, only 666 patients (63.2%) were prescribed both a statin and antiplatelet. Two hundred and sixty eight patients (32.1%) were current smokers and the proportion of patients who continued to smoke decreased with age. Overall, only 401 patients (48.1%) were prescribed a statin, antiplatelet, and had stopped smoking. In the secondary analysis 38 AAA screening units (84% national coverage) replied. Thirty-one units (82%) suggest changes to the patient's prescription; however, none monitor compliance with these recommendations or assess whether the general practitioner has been made aware of the AAA diagnosis or prescription advice. CONCLUSION: Many patients with small AAA are not prescribed an antiplatelet/statin, and still smoke cigarettes, and therefore remain at high risk of cardiovascular morbidity and mortality. National guidance to ensure this high risk group of patients is adequately protected from poor cardiovascular outcomes is lacking. PMID- 28554729 TI - Post-traumatic Femoral Arteriovenous Fistula. PMID- 28554730 TI - Synthesis and preliminary biological evaluation of radiolabeled 5-BDBD analogs as new candidate PET radioligands for P2X4 receptor. AB - P2X4 receptor has become an interesting molecular target for treatment and PET imaging of neuroinflammation and associated brain diseases such as Alzheimer's disease. This study reports the first design, synthesis, radiolabeling and biological evaluation of new candidate PET P2X4 receptor radioligands using 5 BDBD, a specific P2X4 receptor antagonist, as a scaffold. 5-(3-Hydroxyphenyl)-1 [11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD analog, [11C]9) and 5-(3-Bromophenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2 e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD, [11C]8c) were prepared from their corresponding desmethylated precursors with [11C]CH3OTf through N [11C]methylation and isolated by HPLC combined with SPE in 30-50% decay corrected radiochemical yields with 370-1110GBq/umol specific activity at EOB. 5-(3 [18F]Fluorophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]F-5 BDBD, [18F]5a) and 5-(3-(2-[18F]fluoroethoxy)phenyl)-1,3-dihydro-2H-benzofuro[3,2 e][1,4]diazepin-2-one ([18F]FE-5-BDBD, [18F]11) were prepared from their corresponding nitro- and tosylated precursors by nucleophilic substitution with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC-SPE in 5-25% decay corrected radiochemical yields with 111-740GBq/umol specific activity at EOB. The preliminary biological evaluation of radiolabeled 5-BDBD analogs indicated these new radioligands have similar biological activity with their parent compound 5 BDBD. PMID- 28554732 TI - A Randomized Controlled Trial of Atorvastatin in Patients With Bronchiectasis Infected With Pseudomonas Aeruginosa: A Proof of Concept Study. AB - BACKGROUND: There are no randomized controlled trials of statin therapy in patients with severe bronchiectasis who are chronically infected with Pseudomonas aeruginosa. METHODS: Thirty-two patients chronically infected with P aeruginosa were recruited in this double-blind cross-over randomized controlled trial. Sixteen patients were recruited in each arm, were given atorvastatin 80 mg or placebo for 3 months followed by a washout period for 6 weeks, and then crossed over and administered the alternative therapy for 3 months. RESULTS: Twenty-seven patients completed the study. Atorvastatin did not significantly improve the primary end point of cough as measured by the Leicester Cough Questionnaire (mean difference, 1.92; 95% CI for difference, -0.57-4.41; P = .12). However, atorvastatin treatment resulted in an improved St. Georges Respiratory Questionnaire (-5.62 points; P = .016) and reduced serum levels of CXCL8 (P = .04), tumor necrosis factor (P = .01), and intercellular adhesion molecule 1 (P = .04). There was a trend toward improvement in serum C-reactive protein and serum neutrophil counts (P = .07 and P = .06, respectively). We demonstrated in vitro that atorvastatin 10 MUM reduced formyl-methionyl-leucyl phenylalanine-induced upregulation of CD11b expression and changes in calcium flux, reflecting an ability to decrease neutrophil activation. CONCLUSIONS: We demonstrated that atorvastatin reduced systemic inflammation and improved quality of life in patients with bronchiectasis who were infected with P aeruginosa. These effects may be due to an ability of atorvastatin to modulate neutrophil activation. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01299194; URL: www.clinicaltrials.gov. PMID- 28554733 TI - The role of insulin signalling in the endocrine stress response in Drosophila melanogaster: A mini-review. AB - The endocrine stress response in Drosophila includes catecholamines, juvenile hormone (JH), 20-hydroxyecdysone (20E) and the insulin/insulin-like growth factor signalling pathway (IIS). Several changes in the IIS and hormonal status that occur under unfavourable conditions are universal and do not depend on the nature of stress exposure. The reviewed studies on the impact of different element of the Drosophila IIS, such as insulin-like receptor, the homologue of its substrate, CHICO, the transcription factor dFOXO and insulin like peptide 6, on the hormonal status suggest that the IIS controls catecholamine metabolism indirectly via JH, and there is a feedback loop in the interaction of JH and IIS. Moreover, at least one of the ways in which the IIS is involved in the control of stress resistance is mediated through JH/dopamine signalling. PMID- 28554734 TI - Effects of chronic intracerebroventricular infusion of neurosecretory protein GL on body mass and food and water intake in chicks. AB - Recently, we discovered a novel cDNA encoding the precursor of a small secretory protein, neurosecretory protein GL (NPGL), in the chicken mediobasal hypothalamus. In this study, immunohistochemical analysis revealed that NPGL was produced in the infundibular and medial mammillary nuclei of the mediobasal hypothalamus, with immunoreactive fibers also detected in the hypothalamus and the median eminence. As it is known that these regions are involved in feeding behavior in chicks, we surveyed the effects of chronic intracerebroventricular infusion of NPGL on feeding behavior and body mass for a period of two weeks. NPGL stimulated food and water intake, with a concomitant increase in body mass. However, NPGL did not influence mRNA expression of several hypothalamic ingestion related neuropeptides. Our data suggest that NPGL may be a novel neuronal regulator involved in growth processes in chicks. PMID- 28554731 TI - RNA G-Quadruplexes in Biology: Principles and Molecular Mechanisms. AB - G-quadruplexes (G4s) are extremely stable DNA or RNA secondary structures formed by sequences rich in guanine. These structures are implicated in many essential cellular processes, and the number of biological functions attributed to them continues to grow. While DNA G4s are well understood on structural and, to some extent, functional levels, RNA G4s and their functions have received less attention. The presence of bona fide RNA G4s in cells has long been a matter of debate. The development of G4-specific antibodies and ligands hinted on their presence in vivo, but recent advances in RNA sequencing coupled with chemical footprinting suggested the opposite. In this review, we will critically discuss the biology of RNA G4s focusing on the molecular mechanisms underlying their proposed functions. PMID- 28554735 TI - Correlation between phenotypic antibiotic susceptibility and the resistome in Pseudomonas aeruginosa. AB - Genetic determinants of antibiotic resistance (AR) have been extensively investigated. High-throughput sequencing allows for the assessment of the relationship between genotype and phenotype. A panel of 672 Pseudomonas aeruginosa strains was analysed, including representatives of globally disseminated multidrug-resistant and extensively drug-resistant clones; genomes and multiple antibiograms were available. This panel was annotated for AR gene presence and polymorphism, defining a resistome in which integrons were included. Integrons were present in >70 distinct cassettes, with In5 being the most prevalent. Some cassettes closely associated with clonal complexes, whereas others spread across the phylogenetic diversity, highlighting the importance of horizontal transfer. A resistome-wide association study (RWAS) was performed for clinically relevant antibiotics by correlating the variability in minimum inhibitory concentration (MIC) values with resistome data. Resistome annotation identified 147 loci associated with AR. These loci consisted mainly of acquired genomic elements and intrinsic genes. The RWAS allowed for correct identification of resistance mechanisms for meropenem, amikacin, levofloxacin and cefepime, and added 46 novel mutations. Among these, 29 were variants of the oprD gene associated with variation in meropenem MIC. Using genomic and MIC data, phenotypic AR was successfully correlated with molecular determinants at the whole-genome sequence level. PMID- 28554736 TI - Heat transfer and loss by whole-body hyperthermia during severe lower-body heating are impaired in healthy older men. AB - Most studies demonstrate that aging is associated with a weakened thermoregulation. However, it remains unclear whether heat transfer (for heat loss) from the lower (uncompensable) to the upper (compensable) body during passively-induced severe lower-body heating is delayed or attenuated with aging. Therefore, the main purpose of this study was to investigate heat transfer from uncompensable to compensable body areas in young men and healthy older men during passively-induced whole-body hyperthermia with a demonstrated post-heating change in core body (rectal; Tre) temperature. Nine healthy older men and eleven healthy young men (69+/-6 vs. 21+/-1 years old, mean+/-SD, P<0.05) participated in passively-induced severe lower-body heating in water at approximately 43 degrees C. Despite a similar increment in Tre (approximately 2.5 degrees C) in both groups, the heating rate was significantly lower in older men than in young men (1.69+/-0.12 vs. 2.47+/-0.29 degrees C/h, respectively; P<0.05). The temperature increase in calf muscle and calf skin (uncompensable areas) was significantly higher in older men than in young men (5.10+/-0.18 vs. 3.99+/-0.14 degrees C; P<0.05 and 9.92+/-0.22 vs. 7.65+/-0.33 degrees C; P<0.05, respectively). However, the temperature increase in back skin and forearm skin (compensable areas) was significantly lower in older men than in young men (0.76+/-0.63 vs. 2.83+/-0.68 degrees C; P<0.05 and 0.39+/-0.76 vs. 2.73+/-0.5 degrees C; P<0.05, respectively). Furthermore, a post-warming increase in Tre of approximately 0.2 degrees C was observed only in older men (P<0.05). In conclusion, older men whose lower extremities were immersed showed greater accumulation and storage of heat in the skin and deep muscles than young men, and this was associated with a greater heat-transfer delay and subsequent inertia in the increased core body (Tre) temperature. PMID- 28554738 TI - Circulating donor-specific anti-HLA antibodies are a major factor in premature and accelerated allograft fibrosis. AB - Addressing the causes of kidney allograft-accelerated aging is an important challenge for improving long-term transplant outcomes. Here we investigated the role of circulating donor-specific anti-HLA antibodies (HLA-DSAs) in the development and the progression of kidney allograft fibrosis with inclusion of traditional risk factors for allograft fibrosis. We prospectively enrolled 1539 consecutive kidney recipients transplanted in two centers and assessed interstitial fibrosis and tubular atrophy (IF/TA) in biopsies performed at one year post-transplantation. The HLA-DSAs and all traditional determinants of IF/TA were recorded at transplantation and within the first year post-transplantation, including histological diagnoses in 2260 "for cause" biopsies. This identified 498 (32%) patients with severe IF/TA (Banff IF/TA grade 2 or more). HLA-DSAs were significantly associated with severe IF/TA (adjusted odds ratio, 1.53; 95% confidence interval 1.16-2.01) after including 37 determinants. HLA-DSAs remained significantly associated with severe IF/TA in patients without antibody-mediated rejection (adjusted odds ratio 1.54; 1.11-2.14). HLA-DSAs were the primary contributor, being involved in 11% of cases, while T cell-mediated rejection, calcineurin-inhibitor toxicity, acute tubular necrosis, pyelonephritis, and BK virus-associated nephropathy were involved in 9%, 8%, 6%, 5%, and 4% of cases, respectively. One hundred fifty-four patients with HLA-DSA-associated severe IF/TA showed significantly increased microvascular inflammation, transplant glomerulopathy, C4d deposition in capillaries, and decreased allograft survival compared to 344 patients with severe IF/TA without HLA-DSAs. Three hundred seventy-eight patients with post-transplant HLA-DSAs exhibited significantly accelerated progression of IF/TA compared to 1161 patients without HLA-DSAs in the biopsies performed at one year post-transplant and beyond. Thus, circulating HLA-DSAs are major determinants of premature and accelerated allograft fibrosis acting independently of traditional risk factors and antibody-mediated rejection. PMID- 28554737 TI - Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice. AB - Activation of JAK-STAT signaling has been implicated in the pathogenesis of diabetic kidney disease. An increased expression of JAK-STAT genes was found in kidney glomerular cells, including podocytes, in patients with early diabetic kidney disease. However, it is not known whether increased expression of JAK or STAT isoforms in glomerular cells can lead to worsening nephropathy in the setting of diabetes. Therefore, we overexpressed JAK2 mRNA specifically in glomerular podocytes of 129S6 mice to determine whether this change alone could worsen diabetic kidney disease. A 2-3 fold increase in glomerular JAK2 expression, an increase similar to that found in humans with early diabetic kidney disease, led to substantial and statistically significant increases in albuminuria, mesangial expansion, glomerulosclerosis, glomerular fibronectin accumulation, and glomerular basement membrane thickening, and a significant reduction in podocyte density in diabetic mice. Treatment with a specific JAK1/2 inhibitor for 2 weeks partly reversed the major phenotypic changes of diabetic kidney disease and specifically normalized expression of a number of downstream STAT3-dependent genes implicated in diabetic kidney disease progression. Thus, moderate increases in podocyte JAK2 expression at levels similar to those in patients with early diabetic kidney disease can lead directly to phenotypic and other alterations of progressive diabetic glomerulopathy. Hence, inhibition of these changes by treatment with a JAK1/2 inhibitor suggests that such treatment may help retard progression of early diabetic kidney disease in patients. PMID- 28554739 TI - That's how "you" do it: Generic you expresses norms during early childhood. AB - Prior research indicates that children construe norms as general and construe preferences as individual. The current studies tested whether this expectation is built into how children interpret and use language. We focused on the pronoun you, which is ambiguous between a canonical interpretation (referring to the addressee) and a generic interpretation (referring to people in general). In Study 1, children (N=132, ages 3-10years) were asked a series of questions containing "you," referring to either descriptive norms (e.g., "What do you do with bikes?") or preferences (e.g., "What do you like to do with bikes?"). In Study 2, parents conversed with their children (N=28, ages 2-4years) about prescriptive norms (e.g., "What should you do with books?") and preferences (e.g., "What do you like about books?"). In both studies, children's choice of pronoun in their answer revealed whether they interpreted you in the questions as generic or canonical. Results indicated that children more often interpreted you as generic in the normative contexts (i.e., responded with generic you, e.g., "You read them") and as canonical in the preference contexts (i.e., responded with I, e.g., "I read them"). This pattern emerged by early preschool, providing the first evidence that the distinction between norms and preferences directs young children's interpretation and use of everyday language. PMID- 28554740 TI - Tuberculosis detection by pouched rats: Opportunities for reinforcement under low prevalence conditions. AB - Giant African pouched rats (Cricetomys ansorgei) have been employed successfully in two operational tuberculosis-detection projects in which they sniff sputum samples from symptomatic individuals who have visited tuberculosis clinics. The prevalence of pulmonary tuberculosis in this population is high, approximately 20% in the regions where the rats have been used. If the rats are to be used to screen individuals from lower-prevalence populations, their performance under such conditions must first be evaluated. In this study, the prevalence of tuberculosis-positive samples presented to eight pouched rats was reduced to approximately 5%, and the percentage of known-positive samples included as opportunities for reinforcement was varied in sequence from 10 to 8, 6, 4, 2, 4, and 2. Liquid food reinforcers were delivered for identification responses to known-positive samples and at no other time. The rats' accuracy was clinically and statistically significantly lower at 2% than at the other values. These results indicate that the rats can perform well in low-prevalence scenarios but, if they are used under the conditions of the present study, at least 4% of the samples presented to them must be opportunities for reinforcement. PMID- 28554741 TI - A contemporary series of renal masses with emphasis on recently recognized entities and tumors of low malignant potential: A report based on 624 consecutive tumors from a single tertiary center. AB - INTRODUCTION: A number of new renal tumor entities have been recognized by the 2016 World Health Organization classification of urologic tumors. The classification includes tumors with different behavior and introduces one tumor with low malignant potential, the multilocular cystic clear cell renal cell neoplasm of low malignant potential (mcCCRCNLMP). However, some categories still labeled as "carcinoma", such as clear cell papillary renal cell carcinoma (CCPRCC), renal angioleiomyomatous tumor (RAT), and tubulocystic carcinoma (TCRCC), all with a particularly good prognosis when diagnosed as low stage, show no malignant behavior: in fact, no metastases have been reported in these categories when surgically excised. Current experience is limited to supporting these neoplasms as benign entities although, recent literature data is defining these entities as "low malignant potential tumors". MATERIAL AND METHODS: We conducted a search through our files on a consecutive series of 624 renal tumors diagnosed over a period of 2 years to address the incidence of this category of tumors. RESULTS: Applying strict histological criteria, the "low malignant potential" tumors, comprised 7% of renal masses that are less than 4cm in size and 3.8% of renal masses measuring 4-7cm in the series of 624 renal tumors. When benign tumors are taken into considerations, the benign and "low malignant potential tumors" represent about one third of renal masses <4cm and one sixth of renal masses between 4 and 7cm. All these cases have not shown recurrence or metastasis at follow-up, mean follow-up of 18 months (range 6-30 months). CONCLUSIONS: This information may assist urologists in developing guidelines for counseling and proper clinical management for patients with "low malignant potential" tumors or small renal masses. PMID- 28554742 TI - Immunohistochemical investigation of topoIIbeta, H3K27me3 and JMJD3 expressions in medulloblastoma. AB - Topoisomerase IIbeta (topoIIbeta) is a nuclear enzyme specifically expressed in neurons, and plays an important role in the development of the cerebellum. To date, the expression of topoIIbeta protein in medulloblastoma (MB) has not been investigated. In this study, 16 MB specimens including 10 classical subtypes of MB and 6 desmoplastic subtypes of MB (DMB), along with 5 normal cerebellum samples, were obtained from clinics. With immunohistochemical staining, prominently expressed topoIIbeta was seen in normal cerebellar tissues, while there was no or less pronounced staining in classical MB cells. Interestingly, on comparing topoIIbeta expression in different regions of DMB samples, relatively high levels of topoIIbeta were revealed within nodules composed of differentiated neurocytic cells, which are known to predict a favorable clinical outcome for MB. We also examined the expression of two epigenetic factors, H3K27me3 and JMJD3 in the different tissues. Very high levels of H3K27me3 were found in all MB samples, except the intranodules of DMB, where JMJD3 expression was more prominent. Furthermore, a negative correlation between topoIIbeta and H3K27me3 in MB was revealed in this study. Thus, our data primarily indicate that topoIIbeta can be used to estimate neuronal differentiation in MB, and may serve as a target for improving the survival rates for this condition. We speculate that H3K27me3 repression of topoIIbeta at the transcriptional level may occur, although this needs to be verified using larger numbers of MB samples in future experiments. PMID- 28554743 TI - Edmondson-Steiner grade: A crucial predictor of recurrence and survival in hepatocellular carcinoma without microvascular invasio. AB - BACKGROUND: Microvascular invasion (MVI), an important pathologic parameter, has been proven to be a powerful predictor of long-term prognosis in hepatocellular carcinoma (HCC). However, prognostic factors in HCC without MVI remain unknown. The present study aimed to identify the risk factors of recurrence and poor post resectional survival in this type of HCC. METHODS AND METHODS: A total of 109 patients with MVI-absent HCC underwent radical hepatectomy were enrolled. The influence of clinicopathologic variables on recurrence and patient survival was assessed using univariate and multivariate analyses. RESULTS: Chi-square test found that Edmondson-Steiner grade and satellite nodule were significantly associated with recurrence, while the former was the single marker for early recurrence. Stepwise logistic regression analysis demonstrated the independent predictive role of Edmondson-Steiner grade for recurrence. On the other hand, Edmondson-Steiner grade, serum AFP level and satellite nodule were significant for overall and disease-free survival in univariate analysis, whereas tumor size was linked to disease-free survival. Of the variables, Edmondson-Steiner grade, serum AFP level and satellite nodule were independent indicators. CONCLUSIONS: Edmondson-Steiner grade, a histological classification, carries robust prognostic implications for all the endpoints for prognosis, thus being potential to be a crucial prognosticator in HCC without MVI. PMID- 28554744 TI - Analysis of histological and immunohistochemical patterns of benign and malignant adrenocortical tumors by computerized morphometry. AB - Diagnosis of benign and purely localized malignant adrenocortical lesions is still a complex issue. Moreover, histology-based diagnosis may suffer of a moment of subjectivity due to inter- and intra-individual variations. The aim of the present study was to assess, by computerized morphometry, the morphological features in benign and malignant adrenocortical neoplasms. Eleven adrenocortical adenomas (ACA) were compared with 18 adrenocortical cancers (ACC). All specimens were stained with H&E, cellular proliferation marker Ki-67 and reticulin. We generated a morphometric model based on the analysis of volume fractions occupied by Ki-67 positive and negative cells (nuclei and cytoplasm), vascular and inflammatory compartment; we also analyzed the surface fraction occupied by reticulin. We compared the quantitative data of Ki-67 obtained by morphometry with the quantification resulting from pathologist's visual reading. The volume fraction of Ki-67 positive cells in ACCs was higher than in ACAs. The volume fraction of nuclei in unit volume and the nuclear/cytoplasmic ratio in both Ki-67 negative cells and Ki-67 positive cells were prominent in ACCs. The surface fraction of reticulin was considerably lower in ACCs. Our computerized morphometric model is simple, reproducible and can be used by the pathologist in the histological workup of adrenocortical tumors to achieve precise and reader independent quantification of several morphological characteristics of adrenocortical tumors. PMID- 28554745 TI - Genomic profiling of esophageal squamous cell carcinoma (ESCC)-Basis for precision medicine. AB - PURPOSE: Preparing for precision medicine, we surveyed genomic alterations in esophageal squamous cell carcinoma (ESCC) and identified candidate therapeutic targets by genomic profiling using next-generation sequencing (NGS). MATERIALS AND METHODS: Single-nucleotide variations, indels, and copy number variations in 80 genes were evaluated by targeted deep sequencing in 24 surgically resected ESCC specimens. Immunohistochemistry analyses and silver in situ hybridization for ERBB2 (HER2) were conducted to verify the NGS results. Associations between clinicopathological factors and detected genomic alterations were estimated. RESULTS: The mean coverage of sequencing of the tumor tissues from 24 patients was 464.8X with 85.1% over 100X. We detected a total of 115 genetic alterations and more than one genetic alteration was detected in most patients (23/24, 95.8%). Genes with genetic alterations detected in more than 20% of cases included TP53 (20/24, 83%), NOTCH1 (7/24, 29%), and MTOR (6/24, 25%). Amplification of 7 genes was detected in 8 cases. Genes showing amplification included AKT2 (1/24, 4.2%), EGFR (2/24, 8.3%), ERBB2 (HER2; 1/24, 4.2%), FGFR1 (1/24, 4.2%), KRAS (1/24, 4.2%), MDM2 (1/24, 4.2%), and PIK3CA (1/24, 4.2%). The ERBB2 alteration was confirmed by immunohistochemistry and silver in situ hybridization. Patients with NF1 and ARID1A mutations were younger than the patients without the mutations. (p=0.024 and 0.014, respectively). NOTCH1 mutation and EGFR genetic alteration were associated with a larger tumor size (p=0.019) and lesser invasion depth (p=0.005), respectively. CONCLUSION: This study revealed the genetic profiles of ESCC, which may provide a foundation for the development of novel targeted therapy and precision medicine. PMID- 28554746 TI - EGFR and KRAS molecular genotyping for pulmonary carcinomas: Feasibility of a simple and rapid technique implementable in any department of pathology. AB - OBJECTIVES: EGFR and KRAS genes are routinely tested in lung carcinomas with therapeutic implications. However the current testing methods require complex infrastructures and the delay for diagnosis remains often rather long, especially for initiating an appropriate treatment in patients with advanced stage tumor and short life expectancy. MATERIAL AND METHODS: We evaluated the IdyllaTM fully automated molecular diagnostic system in routine conditions in 79 lung adenocarcinomas and 14 other non-small cell lung carcinomas, mostly in advanced stages (III or IV: 85%). Tests were performed on formalin-fixed paraffin-embedded (n=83) or fresh (n=10) material, including cytological (n=24) and small biopsy (n=20) samples. In prospective cases (n=82), the most likely mutated gene (EGFR in non or occasional smokers and KRAS in smokers) was tested first; the second gene being only tested in case of negativity. RESULTS: The system did not require complex training. Mutational status was obtained in few hours after making the histological diagnosis and on the day of the patient's sampling by analyzing fresh material. The sequential testing strategy avoided 15 EGFR and 15 KRAS tests that would have been negative. Compared with reference methods, global specificity and sensitivity were both 100% for EGFR mutations, and 89.1% and 91.7% for KRAS mutations, respectively. CONCLUSIONS: We demonstrated that such easy-to-use systems can permit pathologists to integrate a reliable EGFR/KRAS status in their initial pathologic report, and could be useful complementary tools to the current molecular diagnostic methods, with regard to prompt therapeutic management of lung cancer patients. PMID- 28554747 TI - Architectural overlap between benign endocervix and pattern-A endocervical adenocarcinoma: Are all pattern-A tumors invasive? AB - Studies on the pattern-based classification for invasive endocervical adenocarcinoma showed that tumors with nondestructive invasion (pattern-A) have a 0% rate of nodal metastases. Our understanding of pattern-A tumors and their distinction from in-situ adenocarcinoma requires further study. Thirteen sections diagnosed independently as pattern-A adenocarcinoma by three gynecologic pathologists, and 14 sections of benign endocervix were selected. Three additional pathologists (reviewers) evaluated a digital image from each section and classified it as pattern-A or benign based on architecture only. To blind the interpretation to cytologic features, nuclei and cytoplasm were obscured using morphometric software (Zen 2011, Carl Zeiss Microscopy, Germany). 13/27 cases (48%; 8 pattern-A, 5 benign) were correctly classified by all reviewers; 19/27 (70%; 10 pattern-A, 9 benign) were correctly classified by >=2 reviewers. 3/13 pattern-A cases (23%) were interpreted as benign by >=2 reviewers. Conversely, 5/14 benign cervices (36%) were misinterpreted as pattern-A by >=2 reviewers. The number of glands per 20* field was higher in pattern-A cases with high reviewer agreement (p=0.004). An abnormal architecture is seen in many pattern-A adenocarcinomas in support of their invasive nature; some, however, have architecture that overlaps with that of benign endocervix thus may actually represent in-situ lesions. Likewise, normal cervix can be architecturally complex and mirror patterns that pathologists would classify as pattern-A if malignant cytologic features were present. Based on this overlap and the nil risk of nodal spread, an emphasis on the non-destructive, rather than the invasive, nature of pattern-A adenocarcinoma is recommended. PMID- 28554748 TI - Nephrogenic adenoma of the urinary tract: A 6-year single center experience. AB - BACKGROUND: Nephrogenic adenoma is an uncommon benign lesion that occurs at several sites in urinary tract, from the renal pelvis to urethra, with the highest frequency in urinary bladder. Nephrogenic adenoma displays a broad spectrum of architectural and cytological features. Hence, recognition of its characteristic histopathological features is needed to distinguish this lesion from its mimickers. MATERIALS AND METHODS: A retrospective series of 21 cases of nephrogenic adenoma in 18 patients, which were diagnosed in our department between 2010 and 2016, were analyzed. All histological slides were reviewed by two pathologists and the diagnosis of each case was confirmed. Immunohistochemistry was performed for PAX-8 in all cases. CK7, PAX-2, PSA, p53, p63, GATA-3 and alpha-methylacyl-CoA racemase (AMACR) were applied in problematic cases. RESULTS: The most common location of the lesion was urinary bladder (14 patients) followed by renal pelvis (2 patients), ureter (1 patient) and urethra (1 patient). A history of urothelial carcinoma and repeated TUR procedures were observed in 12 patients. There were 2 pediatric patients aged 3 years. Both of them had undergone previous urosurgery because of megaureter in one and bladder exstrophy in the other. Other clinical antecedents included bladder diverticulum (1 patient), cystitis (1 patient) and nephrolithiasis (1 patient). Recurrence of lesion was seen in two patients (once in one case and twice in the other one). The median time to disease recurrence in these patients was 11 months (range, 2 20 months). Histologically, the lesions exhibited various morphological findings, with mixed (15 cases, 71.4%), pure tubular (3 cases, 14.3%), pure papillary (2 cases, 9.5%) and pure flat (1 case, 4.8%) growth patterns. Of the 15 cases with mixed patterns, 8 cases were tubulocystic and flat, 3 cases were tubular and flat, 2 cases were tubular, papillary and flat, 1 case was tubulocystic, papillary and flat, and 1 case was tubular and papillary. Flat pattern was observed in 15 cases (71.4%). It was seen in association with other patterns in 14 cases (mixed morphology) and purely in 1 case. Our findings suggested that the flat pattern is a frequent finding in nephrogenic adenomas. Notably one case in this series showed superficial extension into bladder muscularis propria. CONCLUSIONS: Histologically nephrogenic adenoma may simulate a variety of malignancies. Awareness of characteristic morphologic features of nephrogenic adenoma is needed to diagnose this lesion correctly. PMID- 28554749 TI - Significance of M2 macrophages in glomerulonephritis with crescents. AB - OBJECTIVES: CD163 and CD206, markers of M2 macrophages, possesses anti inflammatory properties. This study aims to investigate the clinicopathologic significance of M2 macrophages in patients of glomerulonephritis with crescents. METHODS: Renal tissue samples from patients of glomerulonephritis with more than 30% cell or cell-fibrous crescents, including lupus nephritis (LN, n=14), anti neutrophil cytoplasmic antibody-associated vasculitis (AAV, n=14), IgA nephropathy(IgAN) (n=11), Henoch Schonlein purpura glomerulonephritis(HSPGN)(n=8)were included in this study. The expression of CD163, CD206 and CD68 in renal tissues was detected by immunohistochemistry or immunofluorescence. RESULTS: (1) CD163 was mainly expressed in cell or cell fibrous crescents, proliferative glomerular lesions and acute tubulointerstitial injury. There were numerous CD163-positive cells in LN and AAV in comparison with IgAN and HSPGN. (2) CD206-positive cells were mainly observed in acute tubulointerstitial injury, and proliferative glomerular lesions, especially in LN. Patients with LN had numerous CD206-positive cells in glomerular than other groups. The number of CD163-positive cells and CD206-positive cells in acute tubulointerstitial lesions of LN and AAV were more than IgAN and HSPGN. (3) Both the number of CD163-positive cells and CD206-positive cells in acute tubulointerstitial lesions negatively correlated to estimated glomerular filtration rate. (4) In LN, activity index (AI) positively correlated with the number of CD206-positive cells and CD163-positive cells. Dual staining showed that CD163-positive cells and CD206-positive cells also expressed CD68. CONCLUSIONS: CD163-positive cells and CD206-positive cells, subpopulation of macrophages, which were involved in the pathogenesis of active crescentic glomerulonephritis, especially in LN and AAV. PMID- 28554750 TI - Evaluation of the presence of Epstein-Barr virus (EBV) in Iranian patients with thyroid papillary carcinoma. AB - BACKGROUND AND PURPOSE: Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. EBV is one of the most important viruses related to different types of malignancies. This study investigated the relationship between EBV and papillary thyroid carcinoma. MATERIAL AND METHODS: In this study the presence of Epstein-Barr Nuclear Antigen 1 (EBNA1) gene in papillary thyroid carcinoma tissues were examined by nested-PCR method. Paraffin-embedded tissues (N=41) blocks of thyroid cancer were used. DNA was extracted from all samples and then samples were evaluated for the presence of EBV gene. RESULTS: In 41 samples, EBNA1 was detected in 65.8% of patients with papillary thyroid carcinoma which was significantly higher in younger ages. CONCLUSION: The significant presence of EBV genome in papillary thyroid carcinoma suggests that this virus may play a role in this cancer especially in younger ages. As a result, monitoring of patients with EBV latent infection for PTC can be very important. PMID- 28554751 TI - Correlations of Foxo3 and Foxo4 expressions with clinicopathological features and prognosis of bladder cancer. AB - OBJECTIVE: The study is performed to explore the correlations of forkhead box O3 (FoxO3) and forkhead box O4 (FoxO4) expressions with clinicopathological features and prognosis of bladder cancer. METHODS: Bladder cancer tissues and adjacent normal tissues from the recruited 222 patients were collected. Quantitative real time polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry were applied to determine the expressions of FoxO3 and FoxO4. Spearman correlation analysis was conducted to examine the correlation between the expressions of FoxO3 and FoxO4. All patients were followed up and overall survival (OS) and disease-free survival (DFS) were recorded. Kaplan-Meier survival curve was drawn to determine the associations of FoxO3 and FoxO4 expressions and postoperative survival. Cox proportional hazards model was conducted to analyze the risk factors for poor prognosis of bladder cancer. RESULTS: The mRNA and expressions of FoxO3 and FoxO4 proteins in the bladder cancer tissues were lower than that in the adjacent normal tissues (both P<0.05). The positive rates of FoxO3 and FoxO4 were lower in the patients with lymph node metastasis than that in the patients without lymph node metastasis (P<0.05), and significantly lower in the patients with non-muscle invasive bladder cancer (Tis T1) than in those with non-muscle invasive bladder cancer (T2-T3) in TNM staging, and remarkably lower in the patients with high grade than in those with low grade in the histological type (P<0.05). Furthermore, the expressions of FoxO3 and FoxO4 were positively correlated in the bladder cancer tissues (P<0.05). Negative expressions of FoxO3 and FoxO4 and lymph node metastasis were the risk factors for the poor prognosis of bladder cancer. CONCLUSIONS: The FoxO3 and FoxO4 expressions may potentially associate with the clinicopathological features and prognosis of bladder cancer. PMID- 28554752 TI - Diagnostic utility of Ki-67 immunohistochemistry in small endoscopic biopsies of the ureter and renal pelvis. AB - Diagnosis of upper urinary tract urothelial carcinoma in ureteroscopic biopsies is challenging. Therefore, an immunohistochemical marker that can differentiate between malignant and benign urothelium and predict final pathological features is necessary. In this study, we investigated Ki-67 expression in 26 ureteroscopic biopsies of the ureter and renal pelvis diagnosed with urothelial carcinoma (UC) and in 13 biopsies with non-neoplastic urothelium, using digital image analysis. The median Ki-67 labeling index was 1.5% (range: 0.2-13.9%) in non-neoplastic urothelial specimens and 15.0% (range: 0.2-61.3%) in UC specimens (p=0.0001). In 12 of 26 (46%) UC specimens, the Ki-67 labeling index was more than 20%. By contrast, the Ki-67 labeling index was less than 5% in 11 of 13 (85%) non neoplastic urothelial specimens. Ki-67 expression in ureteroscopic biopsies was significantly correlated with high tumor grade (p=0.013), concomitant carcinoma in situ (p=0.011), and stromal invasion (p=0.048) in surgical resection specimens. Our data suggested that Ki-67 may provide supplemental, objective evidence that can aid diagnosis of upper urinary tract UC in ureteroscopic biopsy specimens. Determination of Ki-67 expression in ureteroscopic biopsy specimens is potentially helpful in clinical decision making for patients with suspected upper urinary tract UC. PMID- 28554753 TI - Clinicopathologic and prognostic significance of immunohistochemical expression of HIF-1alpha, CXCR4 and CA9 in colorectal carcinoma. AB - OBJECTIVE: To investigate the immunohistochemical expressions of HIF-1alpha, CA9 and CXCR4 in resected human CRC specimens in relation to clinicopathologic and prognostic variables. METHODS: A total of 186 patients (mean(SD) age: 56.7(12.6) years, 54.0% were males) with colorectal adenocarcinoma were included in this retrospective study. Resection specimens of the primary tumor were reviewed to confirm the diagnoses and the stage of the disease. Data on age, gender, tumor characteristics (localization, size, macroscopic growth pattern, histologic type, grade, angiolymphatic invasion, TNM stage), applied treatments and clinical outcome (overall survival, local recurrence and distant metastasis) were obtained from the hospital records. Immunohistochemical analysis of tissue specimens was performed to determine HIF-1alpha, CA9 and CXCR4 expressions. RESULTS: Overall, 94.0% of cases showed HIF-1alpha immunoreactivity, 89% showed CXCR4 immunoreactivity, and 15.6% showed CA9 immunoreactivity, while weak expression of immunohistochemical markers was noted in 51.1%, 93.0% and 50.5% of cases, respectively. HIF-1alpha expression was higher among males than in females (median (min-max) final score of 6 (0-9) vs. 3 (0-9), p=0.013). CA9 expressed at higher levels in ulcerovegetative and depressed tumors than in polypoid ones [0(0 9) vs. 0(0-6), p=0.039]. CXCR4 expression was significantly higher in tumors <5cm than >=5cm [6(0-9) vs. 3(0-9), p=0.028] and in grade 1-2 than grade 3 tumors [4(0 9) vs. 3(0-9), p=0.030]. No significant difference was noted in survival with respect to strength of HIF-1alpha, CA9 and CXCR4 immunoreactivity. CONCLUSION: In conclusion, our findings revealed weak-to-moderate HIF-1alpha and CXCR4 immunoreactivity in majority of resection samples, and weak CA9 immunoreactivity in majority of CA9 positive cases. Other than gender (HIF-1alpha), macroscopic growth pattern (CA9) and tumor size and histologic grade (for CXCR4), none of the clinicopathologic and prognostic factors investigated were associated with expression of immunohistochemical markers and level of immunoreactivity had no impact on survival. PMID- 28554754 TI - Prognostic significance of lymph node metastasis in esophageal squamous cell carcinoma. AB - Prediction of lymph node metastasis in esophageal squamous cell carcinoma (ESCC) is very important to have prognostic significance. The objective of this study which involved a relatively large number of ESCC patients was to investigate the correlated factors for lymph node metastasis and prognosis in ESCC. We analyzed a retrospective review of 446 patients with ESCC treated by esophagectomy between January 2010 and July 2016. The relationship between lymph node metastasis and clinicopathological parameters were analyzed. The association between overall survival and clinicopathological factors were evaluated using univariate and multivariable Cox regression models. In the present study, 36.8% esophageal squamous cell carcinoma patients were histologically shown to have lymph node metastasis. Lymph node metastasis was closely correlated with tumor differentiation (p=0.016), perineural invasion (p=0.022), advanced stage tumor (p<0.001) and venous invasion (p<0.001). Kaplan-Meier survival analysis revealed that patients with tumor size, higher T stage, perineuronal invasion, lymph node metastasis, N stage and LNR higher than 0.2 had unfavorable prognosis (p<0.05). The univariate analysis revealed for overall survival that tumor size, pathological stage, perineuronal invasion, lymph metastasis, N stage, involved LNR were relevant prognostic indicators. Furthermore, tumor size, lymph metastasis, N stage and LNR could as independent prognostic factors. PMID- 28554755 TI - Characterization of common and rare mutations in EGFR and associated clinicopathological features in a large population of Chinese patients with lung cancer. AB - Lung cancer with EGFR mutation is often associated pathological characteristics and good responses to EGFR tyrosine kinase inhibitors (TKIs). However, certain types of rare EGFR mutations have be linked to cases with poor response to EGFR TKIs. Therefore, extensive molecular screening and pathological characterization are essential for accurate diagnosis and selection of effective treatment plans. Although a large body of studies have established the rate of EGFR mutations as a whole entity, the rates of each individual types of mutations, especially those rare ones, have not been precisely determined in large patient populations with uniform genetic background. To address this issue, we assembled a large cohort of 456 Chinese patients with lung cancers to determine the rate of both common and rare forms of EGFR mutations and associated clinicopathological features in this retrospective study. We have found single or double EGFR mutations in 200 (43.9%) patients, including exon 19 deletions (E19del) (20%), exon 21 L858R (17.1%) and L861Q (1.5%) point mutations, exon 20 T790M (1.3%) and other mutations (1,3%), exon 18 mutations (1.3%), and double mutations (1.3%). EGFR mutation as well as its subtypes E19del, L858R, or double mutations were associated with female patients or never-smokers. In contrast, rare mutations, especially EGFR TKI resistant exon 20 mutations, were not statistically associated with any clinicopathological features, implicating that tumorigenesis driven by different EGFR mutations were mechanistically different. In summary, we have determined occurring rate of EGFR subtype mutations and demonstrated that different mutations showed different clinicopathological manifestations in lung cancer. PMID- 28554756 TI - Metanephric stromal tumor with a rare incidence of squamous epithelium: A case report and a brief review of the literature. AB - Metanephric stromal tumor (MST) of the kidney, a rare benign pediatric neoplasm recognized for less than 20 years, is not widely known. The authors describe a case of MST with rare squamous epithelium in a 14-month-old female. A renal mass was discovered during her fetal period. After her birth, computerized tomography revealed that the mass was localized in the inferior pole of her left kidney. She then underwent nephrectomy. The tumor was an unencapsulated but well-defined mass with a white, solid and firm cut surface and had dimensions of 4cm*3.5cm*3cm. The tumor was initially diagnosed as Wilms tumor because its frozen section exhibited spindle cells with cartilaginous and rare squamous epithelial elements. However, the paraffin-embedded section of the tumor exhibited bland stromal cells surrounding the entrapped tubules; this arrangement produced an "onion-skin" appearance. The rare squamous epithelial element appeared to originate from normal renal tubules. Immunohistochemistry results were positive for CD34 and INI1, as well as a low Ki-67 expression level, but were negative for S-100, Desmin, Actin, CD117 and Catenin-beta. Fluorescence in situ hybridization analysis did not detect an ETV6 rearrangement. Morphological characteristics, immunophenotyping and molecular genetic analysis indicated MST. No recurrence or metastases occurred during the follow-up period of 36 months. Epithelial elements should be examined carefully in pediatric patients with renal masses. MST should be included in their differential diagnoses. PMID- 28554757 TI - Clinicopathological significance and prognostic role of EZH2 expression in non small cell lung cancer. AB - OBJECTIVE: The aim of this study was to investigate the clinicopathological characteristics and prognostic role of enhancer of zeste homologue 2 (EZH2) expression in non-small cell lung cancer (NSCLC). METHODS: The correlation between EZH2 expression and the clinicopathological characteristics, including sex, smoking history, tumor differentiation, histologic type, tumor stage, and lymph node metastasis, was evaluated through a meta-analysis. In addition, the prognostic value of EZH2 expression was elucidated. This study included 1,932 patients with NSCLC from 11 eligible studies. RESULTS: The overall rate of EZH2 expression was 0.548 [95% confidence interval (CI) 0.491-0.604]. There were significant correlations between EZH2 expression and male sex and smoking history. The expression rate of EZH2 was significantly lower in adenocarcinoma than in other histologic types. Furthermore, EZH2 expression rates were higher in NSCLC with moderately and poorly differentiation and nodal disease than in well differentiated NSCLC without nodal disease. There was a significant correlation between EZH2 expression and worse overall and disease-free survival [hazard ratio (HR) 1.938, 95% CI 1.617-2.323 and HR 1.713, 95% CI 1.366-2.149, respectively]. Subgroup analysis revealed no significant difference for the prognostic effect of EZH2 expression between histologic types or detection methods. CONCLUSION: Our data collectively suggest that EZH2 expression is significantly correlated with aggressive tumor behavior and poor prognosis in NSCLC. PMID- 28554758 TI - Primary dura-based synovial sarcoma of the parafalcine region of brain. AB - Dura-based intracranial neoplasms include a wide range of primary and metastatic tumors, varying in their clinical, radiologic, morphologic, and immunophenotypic characteristics. At this anatomic location, sarcomas are rare, however, they exhibit close morphologic resemblances to meningioma. Herein we describe the third case of primary synovial sarcoma of the parafalcine region in a50-years-old female, who presented with left-sided hemiplegia. The radiologic survey revealed a 5.5cm*5.8cm contrast enhancing dura-based mass at the right parafalcine region with meningeal enhancement and edema in the surrounding areas. Morphologic evaluation exhibited a high-grade spindle cell neoplasm, with focal hemangiopericytomatous pattern. The tumor cells were diffusely immunoreactive for CD99, Bcl2, TLE-1, and vimentin. The Ki-67 proliferation index was 40%. Pancytokeratin was focally positive. Epithelial membrane antigen, progesterone receptor, CD34, S-100, and glial fibrillary acidic protein were negative. Fluorescence in situ hybridization confirmed tumor specific translocation t(X;18)(p11.2;q11.2). Hence, final diagnosis of synovial sarcoma was rendered. Primary meningeal synovial sarcoma should be considered in the differential of aggressive and high-grade dura-based tumors in view of their relative chemosensitivity and future prospect of a molecular target-based therapy. The index case highlights the importance of an extensive pathologic analysis of high grade mesenchymal lesions of the meninges to arrive at a definitive diagnosis and differentiate such tumors from other usual dura-based tumors, which has important therapeutic and prognostic implications. PMID- 28554759 TI - Clinicopathological analysis of concomitant hepatic embryonal rhabdomyosarcoma and hepatocellular carcinoma. AB - Hepatic embryonal rhabdomyosarcoma (ERMS) is extremely rare. Here we report the simultaneous occurrence of hepatocellular carcinoma (HCC) and ERMS of the liver in a 40-year-old man without any symptoms. Macroscopically, the mass was composed of two different tumors. The large tumor was 4.5*4*4cm and was poorly circumscribed and soft in the central region of left lateral lobe of the liver with apparently focal necrosis. The small tumor, with diameter of 1cm, was adjacent to the large tumor without clear boundary. Histologically, the large tumor was composed of numerous spindle-shaped or round cells with brightly eosinophilic cytoplasm as well as pathologic mitosis. Immunohistochemical staining was positive for MyoD1 and myogenin in nuclear testing. However, in the small tumor, cells demonstrated hepatocyte differentiation and were focally positive for HepPar1. A diagnosis of concomitant ERMS and HCC of the liver was made. The patient received no adjuvant treatment after hepatic left lateral lobectomy. The regular follow-up observation conducted by imaging examinations displayed that there was no sign of recurrence or metastasis of the mass over 32 months. To our knowledge, this is the first case report of ERMS of the liver associated with HCC. The diagnosis can only be made by pathological examination. The primary therapy method for this tumor is operative resection. PMID- 28554760 TI - Reversal of P-glycoprotein-mediated multidrug resistance is induced by saikosaponin D in breast cancer MCF-7/adriamycin cells. AB - Multidrug resistance (MDR) cells over expressing P-glycoprotein (P-gp) encoded by the MDR1 gene is major obstacles for successful cancer chemotherapy. P-gp could extrude anti-cancer drugs out of cancer cells and decrease effective intracellular drug concentrations. MDR reversal agents for P-gp can restore the sensitivity of MDR cells to such drugs. Saikosaponin D (SSd), one of the major triterpenoid saponins derived from Bupleurum chinense DC (BCDC), has been shown to possess anti-inflammatory, anti-infectious and anti-tumor properties. The aim of the present study was to investigate the reversal effect of SSd on MDR in MCF 7/adriamycin (ADR) human breast cancer cells and investigate the underlying mechanisms of SSd. The results demonstrated that SSd inhibited the proliferation of MCF-7/ADR and MCF-7 cells in a dose-dependent manner. Moreover, SSd increased the cytotoxicity of ADR on MCF-7/ADR cells and the resistance fold of SSd treatment was demonstrated to be significantly higher when compared with that of the group without SSd treatment. Additionally, the effects of the drug combination showed that SSd and ADR combination were synergistic. Accumulation and efflux studies with the P-gp substrate, rhodamine 123 (Rh123), demonstrated that SSd restored Rh123 accumulation and inhibited P-gp-mediated drug efflux. Importantly, we found that SSd could enhance the sensitivity of MCF-7/ADR cells towards ADR by down-regulating MDR1 and P-gp expression. In conclusion, the results of the present study indicated that SSd may represent a potent reversal agent for P-gp-mediated MDR in breast cancer therapy. PMID- 28554761 TI - Roles of microRNAs in cancer associated fibroblasts of gastric cancer. AB - Cancer associated fibroblasts (CAFs) are a key component of the tumor microenvironment (TME). They play critical roles in the occurrence and development of gastric cancer (GC) through controlling various cytokines secretion and direct cell-to-cell interaction. However, the underlying mechanism of CAFs in tumor progression has not been entirely elucidated. MicroRNAs (miRNAs) as important factors have a central role in the interplay between tumor cell and TME. Recent studies also highlight that the aberrant expression of miRNAs in CAFs is involved in multiple functions in tumorigenesis and malignant process of GC. In this article, we shortly introduce the miRNAs biogenesis and provide an overview of the mechanisms and emerging roles of CAFs-related miRNAs. Focusing on these miRNAs as potential therapeutic targets may bring better treatment effect on GC and other diseases. PMID- 28554762 TI - Effect of plasma-activated medium on the decrease of tumorigenic population in lymphoma. AB - Nonequilibrium atmospheric pressure plasma (NEAPP) is a novel approach for blood coagulation, wound healing, and tumor elimination. NEAPP not only directly but also indirectly affects living cells via the medium exposed to NEAPP-yielding devises, called plasma-activated medium (PAM). The conservable and portable PAM serves as an alternative and advantageous approach over direct NEAPP. Here we examined the effect of PAM on lymphoplasmacytic lymphoma (LPL) cell lines. We found that PAM induced plasma cell differentiation and reduced tumorigenic population. PAM increased the expression level of PRDM1alpha, which is a transcription factor promoting plasma cell differentiation, suggesting that plasma cell differentiation of LPL might be mediated by PRDM1alpha. We previously reported that plasma cell component of LPL is vulnerable to apoptosis and less tumorigenic. These findings suggested that PAM treatment might become a novel therapy against LPL by inducing the transition from tumorigenic to non tumorigenic population. PMID- 28554763 TI - Characterization of rhodamine 123 low staining cells and their dynamic changes during the injured-repaired progress induced by 5-FU. AB - OBJECTIVE: To investigate the characterization of intestinal epithelial stem cells stained by Rhodamine 123 (Rho) and analyze the dynamic changes of intestinal epithelial stem cells during the injured-repaired progress induced by 5-FU. METHODS: Mucosal cells were obtained from adult C57BL/6J mice. The Rho stained cells were sorted using FACS. The mouse model of intestinal mucosal injured-repaired was established by injecting 5-FU and sacrificed at different time post-injection, and the middle intestines were used for detecting the percentage of Rho low staining cell fraction by FACS and detecting the expression of the intestinal epithelial stem cells marker-musashi-1 (msi-1) by RT-PCR and immunohistochemistry. RESULTS: The Rho stained intestinal mucosal cells were divided into three fractions: Rho low staining fraction (12.35%), Rho middle staining fraction (35.5%) and Rho strong staining fraction (50.5%). The cells in Rho low staining fraction expressed rich msi-1 and most of which were in the G0/G1 phase of cell cycle. After treatment of 5-FU, the intestinal mucous were damaged, although the number of msi-1 positive cells has a little decrease, there was no statistical difference among the mice at different time after injection (P>0.05). However, the percentage of msi-1 positive cells increased significantly after injection (P<0.01), and the percentage of msi-1 positive cells decreased gradually during the repaired procedure of the intestinal mucous. There was significant positive correction between the percentage of msi-1 positive cells and the percentage of Rho low staining cell fraction (r=0.867, p<0.01) after 5-FU injection. CONCLUSIONS: The Rho low staining cell fraction from intestinal mucous contained rich intestinal epithelial stem cells, and the intestinal epithelial stem cell which expressed msi-1 played a key role in repairing the damage of intestinal mucous induced by 5-FU. PMID- 28554764 TI - Pigmented trichoblastoma developed in a sebaceous nevus: HRAS mutation as a common molecular driver. AB - A 40-year-old woman presented with a pigmented nodule on a previously existing yellowish, verrucous plaque on the scalp. The histological diagnosis was consistent with a pigmented trichoblastoma developed within a sebaceous nevus (SN). A multigene hotspot mutational profiling of the BRAF, NRAS, HRAS and KRAS genes was carried out, and a shared G13R HRAS mutation in both the trichoblastoma and the sebaceous nevus components was found. These data support a common molecular landscape of the two lesions. PMID- 28554765 TI - Evaluation of the immunohistochemical expression of Gal-1, Gal-3 and Gal-9 in the colon of chronic chagasic patients. AB - OBJECTIVE AND DESIGN: The aim of the present study was to evaluate the immunohistochemical expression of Gal-1, Gal-3 and Gal-9 in the colon of chronic chagasic patients compared to biopsied non-chagasic patients. MATERIAL OR SUBJECTS: Thirty-two colon fragments were selected from chagasic patients with megacolon (n=25) and nonchagasic patients without megacolon (n=7). METHODS: Immunohistochemistry for Gal-1, Gal-3 and Gal-9 was performed using a common light microscope and the results were scored 0-3 according to labeling intensity. Data were analyzed statistically by the chi-square test. RESULTS: Higher Gal-1, Gal-3 and Gal-9 expression was observed in the myenteric plexus ganglia of chagasic patients compared to non-chagasic patients, p=0.0487, p=0.0019 and p=0.0325, respectively, whereas no significant differences were observed between groups regarding the expression of Gal-1, Gal-3 and Gal-9 in the muscle layer. CONCLUSION: Since Gal-1, Gal-3 and Gal-9 galectin expression was higher in the myenteric plexus ganglia of chagasic patients, we believe that these lectins may be associated with ganglionitis in the chagasic megacolon. However, since the present study was the first to report the participation of Gal-9 in Chagas disease, further investigations are needed to elucidate the role of galectin 9 in this disease. PMID- 28554766 TI - The level and clinical significance of 5-hydroxymethylcytosine in oral squamous cell carcinoma: An immunohistochemical study in 95 patients. AB - Accumulating evidence has revealed that aberrant abundance of 5 hydroxymethylcytosine (5hmC) is critically involved in tumorigenesis. The aim of the present study was to investigate the level of 5hmC in primary oral squamous cell carcinoma (OSCC) and determine its clinical significance as well as prognostic value in predicting patients' outcomes. The expression levels of 5hmC in 95 human OSCC samples and 24 normal oral mucosa were evaluated by immunohistochemical staining. Moreover, the associations between the expression status of 5hmC and several clinicopathological parameters as well as patients' survival were further statistically assessed. Our immunohistochemical results revealed that 5hmC was significantly downregulated in a significant fraction of OSCC as compared their normal counterparts. However, elevated 5hmC level was found to be significantly associated with pathological grade and cervical node metastasis with P-values of 0.0239 and 0.0041, respectively. Results from Kaplan Meier cumulative survival analyses indicated that high expression of 5hmC in OSCC was significantly associated with decreased overall survival, disease-free and disease-specific survival as compared to those with low 5hmC (Log-rank, P=0.0210, 0.0313, 0.0415, respectively). Furthermore, the univariate and multivariate survival analyses further identified the expression status of 5hmC as an independent prognostic factor affecting patients' survival. Taken together, our results reveal a significant decrease of 5hmC level in a large subset of OSCC. However, high level of 5hmC associates with tumor aggressive features and unfavorable prognosis in a fraction of OSCC patients. PMID- 28554767 TI - Plasma HPV DNA is detectable in oral leukoplakia patients. AB - BACKGROUND: Oral leukoplakia is considered a potentially malignant lesion for the development of squamous cell carcinoma, and various risk factors may be related to its development and malignant transformation, including the human papillomavirus (HPV). The aim of this case-control study was to detect the presence of HPV in fresh tissue, plasma and saliva samples obtained from patients with and without oral leukoplakia, and verify the correlation of the presence of DNA of HPV between different sources of materials. METHODS: In this study, 32 patients with oral leukoplakia and 24 patients selected in a case-control manner were included. DNA extraction from the samples was performed, and afterwards it was amplified by nested polymerase chain reaction (nPCR) for the detection of HPV (nPCR: MY09-MY11/GP05+-GP06+). RESULTS: The DNA of HPV was found in 68.75% of the fresh tissue samples; in 50% of plasma, and in 62.5% of saliva samples in the group of patients with leukoplakia; in comparison with 45.8%, 54%, and 45.8%, in the fresh tissue, plasma and saliva samples, respectively, in the control group. CONCLUSION: Based on the present study, there was no difference in the rate of HPV detection in patients with or without oral leukoplakia. However all sources tested in this study were considered suitable for HPV detection, especially plasma samples, which showed be an important non-invasive source of HPV detection in leukoplakia patients. PMID- 28554768 TI - Caveolin-1 expression in oral lichen planus, dysplastic lesions and squamous cell carcinoma. AB - Caveolin-1(Cav-1), the main part of caveolae structure, is supposed to play a role in pathogenesis of many human tumors. Since oral lichen planus (OLP) is considered as a potential premalignant disease, this study evaluated Cav-1 expression in OLP in comparison with benign hyperkeratosis, dysplastic epithelium and oral squamous cell carcinoma (OSCC), to investigate its possible role in pathogenesis and malignant transformation of OLP. In this cross-sectional retrospective study, immunohistochemical expression of Cav-1 in the epithelial component and stroma was evaluated in 81 samples, including 12 cases of hyperkeratosis, 24 OLP, 22 epithelial dysplasia, and 23 OSCC samples. Correlations between Cav-1 expression and clinicopathological variables were evaluated statistically. Positive Cav-1 staining was found in 58% of OLP, 91% of hyperkeratosis, 100% of epithelial dysplasia, and 95% of OSCC samples. OSCC showed the highest Cav-1 expression and OLP had the lowest (P=0.001). The intensity of staining was significantly increased in stepwise manner from OLP to OSCC (P=0.001). Expression of Cav-1 was related to the grade of samples in OSCC and dysplastic samples (P=0.04). Based on the findings, it was concluded that Cav 1 may play a role in the pathogenesis of OLP and carcinogenesis of SCC, but its role in malignant transformation of OLP is not confirmed. Further studies are needed to evaluate its potential therapeutic function in OLP and SCC. PMID- 28554769 TI - Immunohistochemical expression of p16, Ki-67 and p53 in cervical lesions - A systematic review. AB - This study evaluated the immunohistochemical (IHC) expression of p16, p53 and Ki 67 in precancerous lesions and in cervical cancer (CC). Identification and review of publications assessing IHC expression in cervical intraepithelial neoplasia (CIN) and CC until February 15, 2017. Systematic review of studies in women with and without cervical lesions in order to evaluate whether there is overexpression of these biomarkers. A total of 28 publications met the criteria which included 6005 patients. The analysis showed that there is higher IHC expression of these biomarkers associated with the more severe lesions. Nineteen out of 22 evaluated studies have shown that there is a higher p16 expression in more severe lesions (CC), while in p53 expression only 4 out of the 9 studies showed a higher expression among more severe cases. Regarding the Ki-67 expression, it was observed that 9 out of 14 studies showed higher expression in more severe lesions. A complete absence of or just minimal IHC expression was observed in the normal cervical epithelium, whilst a significant increase in the expression of these biomarkers was detected according to the severity of lesions. Results suggest that these biomarkers can be considered useful tools for discriminating between the stages of the progressive cervical disease. PMID- 28554770 TI - The actin binding cytoskeletal protein Moesin is involved in nuclear mRNA export. AB - Current models imply that the evolutionarily conserved, actin-binding Ezrin Radixin-Moesin (ERM) proteins perform their activities at the plasma membrane by anchoring membrane proteins to the cortical actin network. Here we show that beside its cytoplasmic functions, the single ERM protein of Drosophila, Moesin, has a novel role in the nucleus. The activation of transcription by heat shock or hormonal treatment increases the amount of nuclear Moesin, indicating biological function for the protein in the nucleus. The distribution of Moesin in the nucleus suggests a function in transcription and the depletion of mRNA export factors Nup98 or its interacting partner, Rae1, leads to the nuclear accumulation of Moesin, suggesting that the nuclear function of the protein is linked to mRNA export. Moesin localizes to mRNP particles through the interaction with the mRNA export factor PCID2 and knock down of Moesin leads to the accumulation of mRNA in the nucleus. Based on our results we propose that, beyond its well-known, manifold functions in the cytoplasm, the ERM protein of Drosophila is a new, functional component of the nucleus where it participates in mRNA export. PMID- 28554771 TI - Membrane contact sites, ancient and central hubs of cellular lipid logistics. AB - Membrane contact sites (MCSs) are regions where two organelles are closely apposed to facilitate molecular communication and promote a functional integration of compartmentalized cellular processes. There is growing evidence that MCSs play key roles in controlling intracellular lipid flows and distributions. Strikingly, even organelles connected by vesicular trafficking exchange lipids en bulk via lipid transfer proteins that operate at MCSs. Herein, we describe how MCSs developed into central hubs of lipid logistics during the evolution of eukaryotic cells. We then focus on how modern eukaryotes exploit MCSs to help solve a major logistical problem, namely to preserve the unique lipid mixtures of their early and late secretory organelles in the face of extensive vesicular trafficking. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann. PMID- 28554773 TI - Modulation of neuronal activity in the Drosophila mushroom body by DopEcR, a unique dual receptor for ecdysone and dopamine. AB - G-protein-coupled receptors (GPCRs) for steroid hormones mediate unconventional steroid signaling and play a significant role in the rapid actions of steroids in a variety of biological processes, including those in the nervous system. However, the effects of these GPCRs on overall neuronal activity remain largely elusive. Drosophila DopEcR is a GPCR that responds to both ecdysone (the major steroid hormone in insects) and dopamine, regulating multiple second messenger systems. Recent studies have revealed that DopEcR is preferentially expressed in the nervous system and involved in behavioral regulation. Here we utilized the bioluminescent Ca2+-indicator GFP-aequorin to monitor the nicotine-induced Ca2+ response within the mushroom bodies (MB), a higher-order brain center in flies, and examined how DopEcR modulates these Ca2+-dynamics. Our results show that in DopEcR knockdown flies, the nicotine-induced Ca2+-response in the MB was significantly enhanced selectively in the medial lobes. We then reveal that application of DopEcR's ligands, ecdysone and dopamine, had different effects on nicotine-induced Ca2+-responses in the MB: ecdysone enhanced activity in the calyx and cell body region in a DopEcR-dependent manner, whereas dopamine reduced activity in the medial lobes independently of DopEcR. Finally, we show that flies with reduced DopEcR function in the MB display decreased locomotor activity. This behavioral phenotype of DopEcR-deficient flies may be partly due to their enhanced MB activity, since the MB have been implicated in the suppression of locomotor activity. Overall, these data suggest that DopEcR is involved in region specific modulation of Ca2+ dynamics within the MB, which may play a role in behavioral modulation. PMID- 28554775 TI - Zonula occludens-2 regulates Rho proteins activity and the development of epithelial cytoarchitecture and barrier function. AB - Silencing Zonula occludens 2 (ZO-2), a tight junctions (TJ) scaffold protein, in epithelial cells (MDCK ZO-2 KD) triggers: 1) Decreased cell to substratum attachment, accompanied by reduced expression of claudin-7 and integrin beta1, and increased vinculin recruitment to focal adhesions and stress fibers formation; 2) Lowered cell-cell aggregation and appearance of wider intercellular spaces; 3) Increased RhoA/ROCK activity, mediated by GEF-HI recruitment to cell borders by cingulin; 4) Increased Cdc42 activity, mitotic spindle disorientation and the appearance of cysts with multiple lumens; 5) Increased Rac and cofilin activity, multiple lamellipodia formation and random cell migration but increased wound closure; 6) Diminished cingulin phosphorylation and disappearance of planar network of microtubules at the TJ region; and 7) Increased transepithelial electrical resistance at steady state, coupled to an increased expression of ZO-1 and claudin-4 and a decreased expression of claudin-2 and paracingulin. Hence, ZO 2 is a crucial regulator of Rho proteins activity and the development of epithelial cytoarchitecture and barrier function. PMID- 28554776 TI - [Prostate cancer histoseminar: Update of the 2016 WHO classification - case No. 7: STUMP (stromal tumor of uncertain malignancy potential) and low grade stromal sarcoma]. PMID- 28554772 TI - ER-plasma membrane junctions: Why and how do we study them? AB - Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are membrane microdomains important for communication between the ER and the PM. ER-PM junctions were first reported in muscle cells in 1957, but mostly ignored in non excitable cells due to their scarcity and lack of functional significance. In 2005, the discovery of stromal interaction molecule 1 (STIM1) mediating a universal Ca2+ feedback mechanism at ER-PM junctions in mammalian cells led to a resurgence of research interests toward ER-PM junctions. In the past decade, several major advancements have been made in this emerging topic in cell biology, including the generation of tools for labeling ER-PM junctions and the unraveling of mechanisms underlying regulation and functions of ER-PM junctions. This review summarizes early studies, recently developed tools, and current advances in the characterization and understanding of ER-PM junctions. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann. PMID- 28554777 TI - [Prostate cancer histoseminar: Update of the 2016 WHO classification - case no1: bilateral prostatic adenocarcinoma, Gleason score 8 (4+4)]. PMID- 28554778 TI - [Prostate cancer histoseminar: Update of the 2016 WHO classification - case no5: prostatic adenocarcinoma with postradiation modifications]. PMID- 28554774 TI - Tubular lipid binding proteins (TULIPs) growing everywhere. AB - Tubular lipid binding proteins (TULIPs) have become a focus of interest in the cell biology of lipid signalling, lipid traffic and membrane contact sites. Each tubular domain has an internal pocket with a hydrophobic lining that can bind a hydrophobic molecule such as a lipid. This allows TULIP proteins to carry lipids through the aqueous phase. TULIP domains were first found in a large family of extracellular proteins related to the bacterial permeability-inducing protein (BPI) and cholesterol ester transfer protein (CETP). Since then, the same fold and lipid transfer capacity have been found in SMP domains (so-called for their occurrence in synaptotagmin, mitochondrial and lipid binding proteins), which localise to intracellular membrane contact sites. Here the methods for identifying known TULIPs are described, and used to find previously unreported TULIPs, one in the silk polymer and another in prokaryotes illustrated by the E. coli protein YceB. The bacterial TULIP alters views on the likely evolution of the domain, suggesting its presence in the last universal common ancestor. The major function of TULIPs is to handle lipids, but we still do not know how they work in detail, or how many more remain to be discovered. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann. PMID- 28554779 TI - [Prostate cancer histoseminar: Update of the 2016 WHO classification - case no 2: Prostatic adenocarcinoma, pleomorphic giant cell variant]. PMID- 28554780 TI - Interventions in type 2 diabetes mellitus and cardiovascular mortality-An overview of clinical trials. AB - Diabetes mellitus type 2 (T2DM) has been associated with an increased cardiovascular risk. Improving glycaemia or other traditional cardiovascular risk factors may reduce cardiovascular risk in patients with T2DM. However, single risk intervention in T2DM has not provided convincing evidence in the reduction of cardiovascular risk. The aim of this paper is to provide an overview of clinical trials involving reduction of cardiovascular outcomes in patients with T2DM. Trials with glucose lowering therapies have shown conflicting results. Intensive therapy to reduce glycaemia has shown some benefit on composite cardiovascular endpoints but these benefits take a longer period to emerge. Recent studies with empagliflozin and glucagon-like peptide-1 (GLP-1) agonists show promising results, but the mechanisms are most likely not mediated by improved glycaemia, given the relatively rapid effects. Both LDL-cholesterol and blood pressure reduction have been proven by large meta-analysis to reduce both cardiovascular events and mortality in all patients with T2DM. Treatment of microalbuminuria and anti-platelet therapy have only been proven in diabetic patients with increased cardiovascular risk. Classical lifestyle interventions have been disappointing with respect to cardiovascular outcome, possibly due to limited weight reduction. So far, the strongest evidence lies on bariatric surgery and a multifactorial intervention to reduce mortality and cardiovascular events in the long term. PMID- 28554781 TI - Nation-based case-control study investigating the relationship between oral corticosteroids use and pulmonary tuberculosis. AB - BACKGROUND AND OBJECTIVE: No published formal study focuses on the relationship between oral corticosteroids use and pulmonary tuberculosis in Taiwan. The aim of the study was to investigate whether oral corticosteroids use was associated with increased odds of pulmonary tuberculosis. METHODS: The retrospective, nation based, case-control study was conducted to analyze the database of the Taiwan National Health Insurance Program between 2000 and 2013. Subjects aged 20 to 84years with newly diagnosed pulmonary tuberculosis were defined as the cases (n=6021). Randomly selected subjects without pulmonary tuberculosis aged 20 to 84years were defined as the controls (n=6021). Subjects who never had a prescription for oral corticosteroids were defined as never use. Subjects who ever had a prescription for oral corticosteroids were defined as ever use. RESULTS: After adjustment for confounders, the adjusted odds ratio of pulmonary tuberculosis was 1.91 for subjects with even use of oral corticosteroids (95% confidence interval 1.73, 2.11), comparing with never use. The adjusted odds ratio of pulmonary tuberculosis was 1.03 for subjects with increasing cumulative dose of oral corticosteroids for per milligram (95% confidence interval 1.02, 1.03), comparing with never use. In addition, the adjusted odds ratios of pulmonary tuberculosis were 1.83 (95% CI 1.65, 2.02) for subjects with cumulative duration of oral corticosteroids<3months, and 2.12 (95% CI 1.87, 2.40) for subjects with cumulative duration>=3months, comparing with never use. CONCLUSION: Though the finding is not unexpected, use of oral corticosteroids is significantly associated with 1.9-fold increased odds of pulmonary tuberculosis, independent of other risk comorbidities. There are dose-dependent and duration dependent effects of oral corticosteroids use on the risk of pulmonary tuberculosis. PMID- 28554782 TI - External Validation of the HERNIAscore: An Observational Study. AB - BACKGROUND: The HERNIAscore is a ventral incisional hernia (VIH) risk assessment tool that uses only preoperative variables and predictable intraoperative variables. The aim of this study was to validate and modify, if needed, the HERNIAscore in an external dataset. STUDY DESIGN: This was a retrospective observational study of all patients undergoing resection for gastrointestinal malignancy from 2011 through 2015 at a safety-net hospital. The primary end point was clinical postoperative VIH. Patients were stratified into low-risk, medium risk, and high-risk groups based on HERNIAscore. A revised HERNIAscore was calculated with the addition of earlier abdominal operation as a categorical variable. Cox regression of incisional hernia with stratification by risk class was performed. Incidence rates of clinical VIH formation within each risk class were also calculated. RESULTS: Two hundred and forty-seven patents were enrolled. On Cox regression, in addition to the 3 variables of the HERNIAscore (BMI, COPD, and incision length), earlier abdominal operation was also predictive of VIH. The revised HERNIAscore demonstrated improved predictive accuracy for clinical VIH. Although the original HERNIAscore effectively stratified the risk of an incisional radiographic VIH developing, the revised HERNIAscore provided a statistically significant stratification for both clinical and radiographic VIHs in this patient cohort. CONCLUSIONS: We have externally validated and improved the HERNIAscore. The revised HERNIAscore uses BMI, incision length, COPD, and earlier abdominal operation to predict risk of postoperative incisional hernia. Future research should assess methods to prevent incisional hernias in moderate to-high risk patients. PMID- 28554783 TI - Carbon Concentration in Algae: Reducing CO2 From Exhaust Gas. AB - Algal carbon-concentrating mechanisms can be used to sequester CO2 from the atmosphere, and the resulting biomass can produce various value-added products. Mechanisms for carbon concentration in algae are complex and sometimes inefficient. We need to understand how algae successfully overcome these challenges while capturing CO2 from their nearby environment. PMID- 28554784 TI - DNA recovery from latent fingermarks treated with an infrared fluorescent fingerprint powder. AB - The effect of the infrared fluorescent fingermark visualisation powder, fpNatural 1TM, on the recovery of both the quantity and quality of touch DNA from fingerprints deposited on glass slides, was investigated using qPCR and STR typing. Four donors each deposited replicate marks, which were either left untreated (n=5) or treated by dusting with fpNatural 1TM (n=5). Each sample was swabbed using the double swab technique, before being extracted using the EZNA Forensic DNA kit and then DNA quantitated before being subjected to DNA profile analysis. Results showed that there was no significant effect of fpNatural 1TM on either the quantity or quality of recovered DNA. This suggests that fpNatural 1TM may prove a good choice of powder for regular use at crime scenes or in the laboratory. The fpNatural 1TM properties of low density, water immiscibility and low DNA affinity may account for these positive outcomes. PMID- 28554785 TI - Mind-Mindedness of Male and Female Caregivers in Childcare and the Relation to Sensitivity and Attachment: An Exploratory Study. AB - Mind-mindedness refers to the caregiver's ability to be attuned to the child's mental states. Within the parent-child relationship, mind-mindedness relates to parents' sensitive caregiving, and to children's secure attachment. However, the same relations are still unexplored in out-of-home care settings. We investigated the associations between childcare professionals' mind-mindedness, sensitive responsiveness and respect for autonomy, and child-caregiver attachment security. Moreover, we examined whether these relations are influenced by caregivers' and children's gender. Participants were 17 caregiver couples (17 males, 17 females) and 34 three-year-old children (17 boys, 17 girls), recruited in childcare centers. Mind-mindedness toward the boy or the girl (dyadic) or both children (non-dyadic), sensitive responsiveness and respect for autonomy were assessed during a semi-structured play. Attachment security was assessed through observations. Male and female caregivers had equivalent scores of mind mindedness, sensitive responsiveness, and respect for autonomy. Similarly, children were securely attached to male and female caregivers. Girls' and boys' secure attachment was predicted by caregivers' use of non-dyadic mind-related comments. For girls, but not for boys, the relation was partially mediated by caregivers' respect for autonomy. The results are discussed in terms of their relevance for the quality of child-caregiver relationships, and children's socio emotional development. PMID- 28554786 TI - Is sensory processing an issue for infants with colic? AB - OBJECTIVES: To determine the association between sensory functioning, sleep, cry/fuss, and feeding behaviors of infants with colic younger than 4 months of age. METHODS: Dunn's Infant/Toddler Sensory ProfileTM and a modified Barr Baby Day Diary(c) were used to assess 44 breastfed infants with colic under four months of age. Colic was defined according to Wessel's criteria. RESULTS: Thirty four of the 44 infants with colic (77%) scored as atypical for sensory processing. Of these, 56% scored atypical for sensory processing on quadrant one (Q1) (Low Registration), with 24%, 65%, and 18% scoring as atypical for sensory processing on Q2 (Sensory seeking), Q3 (Sensory sensitivity), and Q4 (Sensation avoiding), respectively. All infants demonstrating sensation avoiding also scored as Low Threshold. A moderate statistically significant correlation was found between sensation seeking and time spent sleeping (r=0.31; p=0.04). No other statistically significant associations between infant behaviors and their sensory functioning were demonstrated. Overall, infants demonstrating atypical sensory responses (in any quadrant) slept significantly more than infants demonstrating typical sensory responses (mean difference=-67.8min/day; 95% CI=-133.6 to -2.1; p=0.04). CONCLUSION: Very limited associations between infant behaviors and sensory functioning were demonstrated, suggesting that sensory functioning may not be a significant factor in the multifactorial nature of infant colic. Further well-designed studies using validated tools for infants with colic are required to determine whether associations between infant behaviors and sensory functioning exist. PMID- 28554787 TI - Spending an Evening in the Dark: The Radiology Medical Student Call Experience. AB - The level of independent decision-making required of a radiology resident, as well as the acuity of studies populating the worklist, differ between the normal workday and a call shift. However, unlike clerkships where call is standard, medical students in radiology typically only have half of the true resident experience. To expose our rotating medical students to what a future career in radiology might actually look like, we implemented a required call shift as part of our medical student curriculum. All rotating third- and fourth-year medical students were assigned a single 3-hour short call shift alongside a radiology resident during the final week of their rotation. Following this shift, students answered questions via anonymous online survey regarding their perceptions of radiology (primary end point) as well as workload and role of radiology in the clinical care of patients (secondary end points). Following medical student call, 63% of students reported a more positive view of radiology as a career. Additionally, 57% felt that radiology residents work as much or more than other specialties while one call, and several students identified communication issues regarding indications or appropriateness of studies. While we hope that this overwhelmingly positive experience will draw more students into radiology as a career, we also believe that many participating medical students will benefit from a greater understanding of what a radiologist's job entails, as well as how this may be affected by communication issues or increased utilization of imaging. PMID- 28554788 TI - Abdominal Lymphangiomatosis With Intestinal Lymphangiectasia Diagnosed by Magnetic Resonance Lymphangiography: A Case Report. PMID- 28554789 TI - Diagnostic Performance of SRU and ATA Thyroid Nodule Classification Algorithms as Tested With a 1 Million Virtual Thyroid Nodule Model. AB - PURPOSE: The Society of Radiologists in Ultrasound (SRU 2005) and American Thyroid Association (ATA 2009 and ATA 2015) have published algorithms regarding thyroid nodule management. Kwak et al. and other groups have described models that estimate thyroid nodules' malignancy risk. The aim of our study is to use Kwak's model to evaluate the tradeoffs of both sensitivity and specificity of SRU 2005, ATA 2009 and ATA 2015 management algorithms. MATERIALS AND METHODS: 1,000,000 thyroid nodules were modeled in MATLAB. Ultrasound characteristics were modeled after published data. Malignancy risk was estimated per Kwak's model and assigned as a binary variable. All nodules were then assessed using the published management algorithms. With the malignancy variable as condition positivity and algorithms' recommendation for FNA as test positivity, diagnostic performance was calculated. RESULTS: Modeled nodule characteristics mimic those of Kwak et al. 12.8% nodules were assigned as malignant (malignancy risk range of 2.0-98%). FNA was recommended for 41% of nodules by SRU 2005, 66% by ATA 2009, and 82% by ATA 2015. Sensitivity and specificity is significantly different (< 0.0001): 49% and 60% for SRU; 81% and 36% for ATA 2009; and 95% and 20% for ATA 2015. CONCLUSION: SRU 2005, ATA 2009 and ATA 2015 algorithms are used routinely in clinical practice to determine whether thyroid nodule biopsy is indicated. We demonstrate significant differences in these algorithms' diagnostic performance, which result in a compromise between sensitivity and specificity. PMID- 28554790 TI - A comparative study of the suitability of different cereal straws for lignocellulose nanofibers isolation. AB - The aim of this work is to study the suitability of different soda cereal straw pulps (wheat, barley, corn and oats) to produce lignocellulose nanofibers (LCNF). For the study of the influence of the composition and physical characteristics, the pulps were characterized, observing that the physical characteristics do not influence the nanofibrillation process. However, the composition of the fibers plays a key role, mainly the hemicellulose content. The LCNF produced were characterized: chemical structure (FTIR), crystallinity (XRD), thermal stability (TGA), size (DLS) and colloidal stability (ZP). The TO-LCNF are those which presents higher nanofibrillation yields and lower nanofibers size, however presents low crystallinity, thermal stability and a further depolymerization compared to the others LCNF. The lignin contents allow a greater thermal stability (<330 degrees C) than the same size CNF (<250 degrees C). TO-LCNF present more stable suspensions (ZP<-25mV) due to their higher surface charge (COO- groups). AF4 technique was used to effectively determine the size of polydispersed samples of LCNF by avoiding the errors committed by conventional techniques. In addition, it is observed that wheat and barley straws present the most homogeneity in the LCNF samples, being the wheat which presents the best values in the production of LCNF under the three pretreatments. PMID- 28554791 TI - Preferential role of iron in heme degradation of hemoglobin upon gamma irradiation. AB - It is usually believed that gamma-ray interaction with biomolecules is intermediately performed by reactive oxygen species (ROS) produced from radiolysis of water. Hemoglobin (Hb) as one of the most abundant biomolecule in blood and well-studied endogenously affected by ROS, was a good candidate for study. Adult human Hb was extracted and irradiated using four distinct 20, 60, 90 and 170Gy doses from Co-60 gamma-ray source. UV-vis, fluorescence and FT-IR spectroscopies were used to study the whole conformational changes and partial degradation of heme. Hb species calculated using Benesch equations indicated that the concentration of oxy-Hb was decreased from 9.97MUM to 6.56MUM, while the total metastable met and deoxy-Hb concentration were just increased 2.39MUM and about 8.4% of total heme was diminished. Heme degradation was studied using fluorescence spectra at two 321 and 460nm excitation wavelengths as fully and partially degradation of heme respectively. Inverse behavior of these two fluorescence spectra suggested a new mechanism of heme degradation in which gamma ray preferably absorbed by heme without any intermediary effects of water. It was confirmed by FT-IR spectra at 900-1000cm-1 where the FeN and NH of porphyrin indicate their own stretching vibrational bands. Thermal stability justified that the gamma radiation induced the conformational changes of Hb which is appeared during thermal unfolding. First derivative of thermal spectra indicated that the Tm of 170Gy dose irradiated sample is 2 degrees C lowered and total concentration of Hb was decreased 14%. PMID- 28554792 TI - Specificity studies on proteases for dehairing in leather processing using decorin as model conjugated protein. AB - Enzyme based dehairing of animal skins in leather processing is considered a greener alternative to conventional chemical based dehairing process. The specificity based screening of proteases would be an important criterion as it would help in removing hairs by acting particularly on the proteoglycans holding the hair to the bulb without damaging the other proteins. The present paper describes a comparative study of the specificity of a dehairing protease with non dehairing one isolated from Bacillus sps. Dehairing protease was found to be trypsin-like, non-collagenolytic and non-keratinolytic enzyme whereas non dehairing one was a metalloprotease with non-collagenolytic activity but specificity for soluble keratin. Substrate specificity was studied using decorin as model proteoglycan. The dehairing enzyme was effective in digesting the core protein of the decorin as confirmed by high performance liquid chromatography analysis and SDS-polyacrylamide gel electrophoresis. The histochemical studies on dehaired skins also confirmed preservation of skin matrix with no visible damage to collagen. This study emphasizes the importance of screening proteases based on their specificity characteristics for effective and safer enzyme-only dehairing process. The acquired knowledge can be employed in formulating bacterial growth media to produce dehairing proteases that would help in commercial exploitation of this greener option. PMID- 28554793 TI - Quantifying Na(I)-insulin and K(I)-insulin non-covalent complexes by ESI-MS method and calculation of their equilibrium constants. AB - In this study, the dissociation and formation equilibrium constants of Na(I) insulin and K(I)-insulin complexes have been calculated after the quantifying them on ESI mass spectrometer. The ESI-MS spectra of the complexes were measured by using the solvents as 50% MeOH in water and 100% water. The effect of pH on the Na(I)-insulin and K(I)-insulin complex formation were examined. Serial binding of Na(I) and K(I) ions to the insulin molecule were observed in the ESI MS measurements. The first formation equilibrium constants were calculated as Kf1: 5.48*103 1/M for Na(I)-insulin complex and Kf1: 4.87*103 1/M for K(I) insulin in water. The binding capability of Na(I) ions to insulin molecule is higher than the capability of K(I) ions. In case of a comparison together with Ca(II)-insulin and Mg(II)-insulin, the formation equilibrium constants (Kf1) are in order of Ca(II)-insulin>Mg(II)-insulin>Na(I)-insulin>K(I)-insulin in water. The results showed that Na(I) and K(I) ions are involved in the formation of the non-covalent complexes with insulin molecule, since high extracellular and intracellular concentrations of them in the body. PMID- 28554794 TI - Comparative studies of chitosan and its nanoparticles for the adsorption efficiency of various dyes. AB - Chitosan has been considered as a chelating agent with the potential for the adsorption of dyes, metal ions and proteins. This study was aimed to prepare and characterize different fungal chitosan nanoparticles (FCI-1 to FCI-6 NPs) by ionic gelation method and to evaluate its efficacy on the sorption of various commercial dyes. Morphological observations showed that the FCI-1 is nearly spherical in shape with particle size ranging from 2 to 30nm, as determined by electron microscopic studies. Electron micrograph revealed that FCI-1 NPs were stable even after eighteen months of storage at 4 degrees C. Adsorption efficiencies of FCI-1 NPs and FCI-1 were estimated against various dyes such as RBB, MO, DR, NBB and CSB using spectrophotometry. Out of the dyes tested, FCI-1 NPs showed better adsorption efficiency for CSB whereas only RBB followed Langmuir isotherm. The adsorption of remaining dyes may probably be through random adsorption. The results indicated that FCI-1 NPs could be used as efficient sorbents in treating industrial dye effluents. PMID- 28554795 TI - A review on cellulose and lignin based binders and electrodes: Small steps towards a sustainable lithium ion battery. AB - Lithium ion batteries (LIB) are the most promising energy storage systems for portable electronics and future electric or hybrid-electric vehicles. However making them safer, cost effective and environment friendly is the key challenge. In this regard, replacing petro-derived materials by introducing renewable biomass derived cellulose derivatives and lignin based materials into the battery system is a promising approach for the development of green materials for LIB. These biomaterials introduce sustainability as well as improved safety in the final disposal of LIB batteries. In this review we introduce LIB materials technology in brief and recent developments in electrodes and binders based on cellulose and their derivatives and lignin for lithium ion batteries. PMID- 28554796 TI - Detection of bone defects around zirconium component after total knee arthroplasty. AB - BACKGROUND: It is difficult to detect bone defects caused by loosening or osteolysis around the femoral component after total knee arthroplasty (TKA) because the thick metal hinders visualization of bone defects. Previous reports have shown that tomosynthesis, a novel tomographic technique, is advantageous over fluoroscopically guided plain radiography, computed tomography (CT) and magnetic resonance imaging (MRI) for the early detection of bone defects around a conventional cobalt-chromium alloy component. However, there have been no reports on a zirconium component. The purpose of this study was to examine the sensitivity and specificity of the detection of bone defects around a zirconium component using fluoroscopically guided plain radiography, tomosynthesis, CT and MRI. METHODS: Six zirconium femoral components were implanted in pig knees. Two were cemented without any bone defects. Two were cemented with cystic defects. Two were cemented with four-millimeter-thick defects between the bone cement and the bone. Defects were filled with agarose gel. Eight orthopedic surgeons examined the fluoroscopically guided plain radiography, tomosynthesis, CT and MRI images. Sensitivity and specificity of each method were analyzed. RESULTS: No bone defects were detected with plain radiography. The sensitivity and specificity of tomosynthesis were 21.9% and 36.8%, respectively. The sensitivity and specificity of CT were 15.1% and 33.0%, respectively. The sensitivity and specificity of MRI were 84.4% and 86.6%, respectively. CONCLUSIONS: For the detection of bone defects around a zirconium component after TKA, MRI is advantageous over fluoroscopically guided plain radiography, tomography and CT, in terms of sensitivity and specificity. PMID- 28554797 TI - Juxtaposing the real-time unfolding of subjective experience and ERP neuromarker dynamics. AB - Electroencephalographic (EEG) potentials have remained a valuable source of data and theories concerning neural correlates of consciousness (NCC). The EEG based methods are far from being exhausted and are continually valuable in the quest for the markers of NCC. To set the background for the research presented in this issue, we review the published work on EEG-based markers of NCC. The article is organized according to the principle of the time-course aspect of brain potentials with regard to the stimuli for which subject's awareness is experimentally measured and/or manipulated. We treat brain potentials as the principal dependent measure as well as independent variable. More specifically, we also draw attention to the fact that in the overwhelming share of studies relative negativization of the ERPs tends to mark NCC. PMID- 28554798 TI - The psychophysiology of motivation: Body and brain in action. PMID- 28554799 TI - Editorial Comment. PMID- 28554800 TI - Author Reply. PMID- 28554801 TI - Editorial Comment. PMID- 28554802 TI - Influence of chemical composition on biochemical methane potential of fruit and vegetable waste. AB - This study investigates the influence of chemical composition on the biochemical methane potential (BMP) of twelve different batches of fruit and vegetable waste (FVW) with different compositions collected over one year. BMP ranged from 288 to 516LNCH4kgVS-1, with significant statistical differences between means, which was explained by variations in the chemical composition over time. BMP was most strongly correlated to lipid content and high calorific values. Multiple linear regression was performed to develop statistical models to more rapidly predict methane potential. Models were analysed that considered chemical compounds and that considered only high calorific value as a single parameter. The best BMP prediction was obtained using the statistical model that included lipid, protein, cellulose, lignin, and high calorific value (HCV), with R2 of 92.5%; lignin was negatively correlated to methane production. Because HCV and lipids are strongly correlated, and because HCV can be determined more rapidly than overall chemical composition, HCV may be useful for predicting BMP. PMID- 28554803 TI - Integrated omics approaches to characterize a nuclear receptor corepressor associated histone deacetylase in mouse skeletal muscle. AB - Nuclear receptors regulate gene expression by differentially binding to coactivators or corepressors in a ligand-dependent manner, which further recruits a set of epigenome-modifying enzymes that remodel chromatin conformation. Histone acetylation is a major epigenomic change controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC3 is the only HDAC that confers the enzymatic activity to the complexes nucleated by nuclear receptor corepressors NCoR and SMRT. To address the metabolic function of HDAC3, we have deleted it specifically in mouse skeletal muscles. We have performed the following omics profiling in skeletal muscles of these mice: (1) RNA-seq profiling of total RNA; (2) Global nuclear run-on (GRO-seq) analysis of nascent RNAs; (3) Chromatin immuno-precipitation (ChIP-seq) of HDAC3 at both early evening and early morning; (4) proteomics profiling with mass spectrometry; (5) snap-shot metabolomics profiling of water-soluble metabolites at the basal condition; (6) snap-shot metabolomics profiling of lipid species at the basal condition; (7) kinetic fluxomics analysis of glucose utilization using 13C6-glucose In vivo during treadmill running exercise. These approaches have provided several novel insights into how nuclear receptors regulate circadian rhythm of skeletal muscle fuel metabolism, which has been published elsewhere. Here we present the original datasets and technical details during the execution, analysis, and interpretation of these omics studies. PMID- 28554804 TI - A comparison of the sexually dimorphic dexamethasone transcriptome in mouse cerebral cortical and hypothalamic embryonic neural stem cells. AB - Fetal exposure to synthetic glucocorticoids reprograms distinct neural circuits in the developing brain, often in a sex-specific manner, via mechanisms that remain poorly understood. To reveal whether such reprogramming is associated with select molecular signatures, we characterized the transcriptome of primary, embryonic mouse cerebral cortical and hypothalamic neural progenitor/stem cells derived from individual male and female embryos exposed to the synthetic glucocorticoid, dexamethasone. Gene expression profiling by RNA-Seq identified differential expression of common and unique genes based upon brain region, sex, and/or dexamethasone exposure. These gene expression datasets provide a unique resource that will inform future studies examining the molecular mechanisms responsible for region- and sex-specific reprogramming of the fetal brain brought about by in utero exposure to excess glucocorticoids. PMID- 28554805 TI - Genomics of sex hormone receptor signaling in hepatic sexual dimorphism. AB - The liver plays a crucial role in a variety of physiological processes. Sexual dimorphism is markedly defined in liver disorders, such as fatty liver diseases and liver cancer, but barely addressed in the normal liver. Distinct sex hormone signaling between male and female livers is the major driving factor for hepatic sexual dimorphism. Over 6000 genes are differently expressed between male and female livers in mice. Here we address how sex hormone receptors, estrogen receptor alpha (ERalpha) and androgen receptor (AR), mediate sexually dimorphic gene expression in mouse livers. We identified 5192 ERalpha target genes and 4154 AR target genes using ChIP-Seq. Using liver-specific ERalpha or AR knockout mice, we further identified direct and functional target genes of ERalpha (123 genes) and AR (151 genes) that contribute to hepatic sexual dimorphism. We also found that the most significant sexually dimorphic gene expression was initiated at birth by comparing hepatic gene expression data from the embryonic stage E10.5 to the postnatal stage P60 during liver development. Overall, our study indicates that sex hormone receptor signaling drives sexual dimorphism of hepatic gene expression throughout liver development. PMID- 28554807 TI - How right is left? Handedness modulates neural responses during morphosyntactic processing. AB - Most neurocognitive models of language processing generally assume population wide homogeneity in the neural mechanisms used during language comprehension, yet individual differences are known to influence these neural mechanisms. In this study, we focus on handedness as an individual difference hypothesized to affect language comprehension. Left-handers and right-handers with a left-handed blood relative, or familial sinistrals, are hypothesized to process language differently than right-handers with no left-handed relatives (Hancock and Bever, 2013; Ullman, 2004). Yet, left-handers are often excluded from neurocognitive language research, and familial sinistrality in right-handers is often not taken into account. In the current study we used event-related potentials to test morphosyntactic processing in three groups that differed in their handedness profiles: left-handers (LH), right-handers with a left-handed blood relative (RH FS+), and right-handers with no reported left-handed blood relative (RH FS-; both right-handed groups were previously tested by Tanner and Van Hell, 2014). Results indicated that the RH FS- group showed only P600 responses during morphosyntactic processing whereas the LH and RH FS+ groups showed biphasic N400-P600 patterns. N400s in LH and RH FS+ groups are consistent with theories that associate left handedness (self or familial) with increased reliance on lexical/semantic mechanisms during language processing. Inspection of individual-level results illustrated that variability in RH FS- individuals' morphosyntactic processing was remarkably low: most individuals were P600-dominant. In contrast, LH and RH FS+ individuals showed marked variability in brain responses, which was similar for both groups: half of individuals were N400-dominant and half were P600 dominant. Our findings have implications for neurocognitive models of language that have been largely formulated around data from only right-handers without accounting for familial sinistrality or including left-handers, and moreover highlight that there is systematic - and often ignored - variability in language processing outcomes in neurologically healthy populations. PMID- 28554806 TI - Blockade of ATP P2X7 receptor enhances ischiatic nerve regeneration in mice following a crush injury. AB - Preventing damage caused by nerve degeneration is a great challenge. There is a growing body of evidence implicating extracellular nucleotides and their P2 receptors in many pathophysiological mechanisms. In this work we aimed to investigate the effects of the administration of Brilliant Blue G (BBG) and Pyridoxalphosphate-6-azophenyl-2', 4'- disulphonic acid (PPADS), P2X7 and P2 non selective receptor antagonists, respectively, on sciatic nerve regeneration. Four groups of mice that underwent nerve crush lesion were used: two control groups treated with vehicle (saline), a group treated with BBG and a group treated with PPADS during 28days. Gastrocnemius muscle weight was evaluated. For functional evaluation we used the Sciatic Functional Index (SFI) and the horizontal ladder walking test. Nerves, dorsal root ganglia and spinal cords were processed for light and electron microscopy. Antinoceptive effects of BBG and PPADS were evaluated through von Frey E, and the levels of IL-1beta and TNF-alpha were analyzed by ELISA. BBG promoted an increase in the number of myelinated fibers and on axon, fiber and myelin areas. BBG and PPADS led to an increase of TNF alpha and IL-1beta in the nerve on day 1 and PPADS caused a decrease of IL-1beta on day 7. Mechanical allodynia was reversed on day 7 in the groups treated with BBG and PPADS. We concluded that BBG promoted a better morphological regeneration after ischiatic crush injury, but this was not followed by anticipation of functional improvement. In addition, both PPADS and BBG presented anti inflammatory as well as antinociceptive effects. PMID- 28554809 TI - Five-year outcomes of the First Distal Uninstrumented Vertebra after posterior fusion for Adolescent Idiopathic Scoliosis Lenke 1 or 2. AB - BACKGROUND: Tilt of the First Distal Uninstrumented Vertebra (FDUV) reflects changes in the main curve and compensatory lumbar curve after posterior fusion to treat thoracic Adolescent Idiopathic Scoliosis (AIS). HYPOTHESIS: FDUV tilt 5 years or more post-fusion depends chiefly on reduction of the main curve and on other factors such as selection of the last instrumented vertebra. MATERIAL AND METHOD: A multicenter retrospective cohort of 182 patients with Lenke 1 or 2 AIS treated with posterior instrumentation and followed up for a mean of 8 years and a minimum of 5 years was studied. The patients were divided into two groups based on whether tilt of the upper endplate of the FDUV was <=5 degrees or >5 degrees at last follow-up. Variables associated with tilt were identified by multiple logistic regression. RESULTS: Six variables were significantly associated with FDUVtilt: percentage of correction at last follow-up, correction loss, lumbar modifier B, number of instrumented vertebrae, inclusion within the instrumentation of the distal neutral vertebra, and inclusion within the instrumentation of the lowest vertebra intersected by the central sacral vertical line. DISCUSSION AND CONCLUSION: The main variables associated with FDUVtilt <=5 degrees were a final correction percentage >=60% and absence of correction loss between the postoperative period and last follow-up. Given the stable reduction provided by contemporary instrumentations, we recommend selective thoracic fusion of Lenke 1 or 2 AIS with lumbar modifiers A, B, and C. The lowest instrumented vertebra should be either the neutral vertebra or the vertebra intersected by the central sacral vertical line if it is distal to the neutral vertebra. LEVEL OF EVIDENCE IV: Retrospective multicenter study. PMID- 28554808 TI - Acute finger-tip infection: Management and treatment. A 103-case series. AB - INTRODUCTION: Acute fingertip infections (AFTI) are common. Surgical treatment is the norm in case of effusion. There is, however, no consensus on treatment modalities, or on adjuvant antibiotic therapy (AT). We present the results of a consecutive cohort of 103 AFTIs treated in emergency consultation. MATERIALS AND METHOD: One hundred and one patients were treated by excision and extensive lavage under digital anesthesia, with systematic bacteriological sampling. Patient history, treatment history, location, type of bacteria, complications or recurrences and AT prescription were recorded and analyzed. All patients were reviewed at first dressing (5-7 days) and recontacted at 1 month, to record any pain, stiffness or recurrence. Three groups were distinguished: A: without preoperative AT (n=71); B: under AT before surgery (n=14); C: with postoperative AT (for severe comorbidity) (n=16). RESULTS: Mean age was 39.7 years (range: 14 84 years). The three main types of bacteria were: Staphylococcus aureus (58.3%), polymicrobial flora (16.5%), and Streptococcus (12.6%). Mean time to first dressing was 5.7 days. There were no recurrences, whatever the bacterial type or patient group. In 5 patients in group A (8.2%), AT was later prescribed at day 5 (3 for hypercicatrization and 2 for maceration). In groups B and C, progression was unproblematic. At 1 month, all patients considered themselves cured; finger tip sensitivity was conserved in 10, and 16 were awaiting complete nail regrowth. DISCUSSION: Hospital admission, operative treatment under general anesthesia, and AT are factors exacerbating cost and increase the management burden of AFTI. Treatment in emergency consultation seems perfectly feasible. AT does not seem useful in the absence of severe comorbidities if resection is complete. Analysis of bacterial susceptibility and renewal of the initial dressing at 1 week enable progression to be monitored and treatment changed as necessary. PMID- 28554810 TI - Limiting interpedicular screw displacement increases shear forces in screws: A finite element study. AB - BACKGROUND CONTEXT: Screw loosening has been reported for non-fusion devices. Forces on pedicle screws could be related to kinematic parameters as the interpedicular displacement (ID), which consists of the displacement between superior and inferior screw heads from full extension to full flexion. PURPOSE: To investigate the relationship between ID and screw loosening for different designs of posterior implants using a finite element model. METHODS: An L3-sacrum previously validated spine FE model was used. Three-rod designs were considered in L4-L5 segment: a rigid screw-rod implant, a flexible one and a specific design with a sliding rod providing limited restrain in ID. In order to simulate intermediate configurations, the friction coefficient between the sliding rods and connectors were varied. The sacrum was rigidly fixed. Rotations (flexion extension, lateral bending and axial rotation) were applied to L3, for each modeled configuration: intact, injured, injured with different implants. Model consistency was checked with existing experimental in vitro data on intact and instrumented segments. Screw loads were computed as well as ID. RESULTS: In flexion-extension, the ID was less than 2mm for rigid (R) and flexible (F) constructs and 5.5mm for intact spine and the sliding implant (S3). Screw's shear forces were 272N, 153N, 43N respectively for R, F and S3 constructs. CONCLUSIONS: Implants that allow ID presented lower screws loads. A compromise between the ability of the implant to withstand compressive forces, which requires longitudinal stiffness, and its ability to allow ID could be important for future implant designs in order to prevent screw loosening. PMID- 28554811 TI - The Impact of Prostate Cancer Zonal Origin on Pathological Parameters at Radical Prostatectomy and Subsequent Biochemical Failure. AB - PURPOSE: We assessed the impact of prostatic zone tumor origin on pathological prognostic features and subsequent biochemical outcomes after radical prostatectomy. MATERIALS AND METHODS: A total of 7,051 patients who underwent radical prostatectomy between September 1998 and December 2016 in Western Australia were divided into a high grade group, defined as Gleason sum 4 + 3, 8 and 9 or greater and ISUP (International Society of Urological Pathology) groups 3, 4 and 5, and a low grade group, defined as Gleason sum 6 or less and 3 + 4, and ISUP groups 1 and 2. The t-test and the Pearson chi-square test were used to evaluate differences between transition zone and peripheral/central zone cancer. The Kaplan-Meier method with the log rank test was used to determine differences in biochemical recurrence-free survival at 5 years in patients with high grade disease. Univariate and multivariable Cox proportional hazard regression analyses were performed. Model calibration was determined by the internal validation method. RESULTS: High grade transition zone cancer was associated with significantly increased prostate specific antigen, tumor volume and incidence of positive surgical margins but a lower incidence of intraductal carcinoma, extraprostatic spread, seminal vesicle invasion, lymph node involvement and biochemical failure after radical prostatectomy. Patients with low grade prostate cancer had excellent biochemical recurrence-free survival regardless of tumor origin. The high grade multivariable model had a c-index of 0.78 and improved predictive accuracy, particularly for high grade transition zone disease. CONCLUSIONS: Transition zone tumor origin independently and positively impacts biochemical outcomes of high grade prostate cancer. A high grade postoperative prognostic model including transition zone tumor origin as an independent predictor was developed and predictive accuracy was significantly improved in patients with high grade, transition zone disease. PMID- 28554812 TI - Outcomes of a Cohort of Prenatally Diagnosed and Early Enrolled Patients with Congenital Solitary Functioning Kidney. AB - PURPOSE: We evaluated the clinical course of patients prenatally diagnosed and enrolled early with congenital solitary functioning kidney, and identified the risk factors for renal injury. MATERIALS AND METHODS: We retrospectively evaluated 322 patients with congenital solitary functioning kidney according to the inclusion criteria of 1) prenatal diagnosis of solitary kidney; 2) first evaluation at 1 to 3 months of life with confirmation of congenital solitary functioning kidney, and evaluation of possible associated congenital anomalies of the kidney and urinary tract by abdominal ultrasound, renal scintigraphy and cystography; and 3) absence of any condition potentially affecting renal function in the neonatal period as well as absence of renal injury at enrollment (1 to 3 months of life) confirmed by a normal estimated glomerular filtration rate, lack of proteinuria and hypertension. Followup of 306 patients was evaluated. RESULTS: Median followup was 7.2 years (range 1 to 23) and 1 or more signs of renal injury were found in 12 of 306 patients (3.9%). Considering the entire population the cumulative proportion of patients free from renal injury at 17 years old was 93.7%, vs 81.3% and 95.9% for subjects with and those without congenital anomalies of the kidney and urinary tract of congenital solitary functioning kidney (p <0.001), respectively. Of congenital anomalies of the kidney and urinary tract, congenital solitary functioning kidney resulted in significant risk factors for renal injury (HR 8.75, 95% CI 2.77-27.65). CONCLUSIONS: In an evaluation of a large cohort of patients enrolled early with congenital solitary functioning kidney with a prenatal diagnosis, excluding those with neonatal onset of renal damage, the prevalence of renal damage was 3.9%. Among congenital anomalies of the kidney and urinary tract, congenital solitary functioning kidney represented the major risk factor. PMID- 28554813 TI - Impact of Exopolysaccharides (EPSs) of Lactobacillus gasseri strains isolated from human vagina on cervical tumor cells (HeLa). AB - Lactobacilli, commonly used as probiotics, have been shown to maintain vaginal health and contribute to host microbiota interaction. Exopolysaccharides (EPSs) produced by lactobacillus have been found to have an important role in probiotic activity; however, there is limited knowledge concerning their impact on cervical cancer and urogenital health. The objective of this study is to investigate and compare EPSs of L. gasseri strains (G10 and H15), isolated from a healthy human vagina, for their capability to inhibit cervical cancer cell (HeLa) growth and modulate immune response. HeLa cells were treated with live culture at ~108 CFU/ml or increasing concentration of lyophilized EPS (L-EPS) (100, 200, or 400 MUg/ml) of L. gasseri strains and their ability to adhere to host cells, inhibit proliferation, and modulate immune response were evaluated. Additionally, monosaccharide composition of the L-EPSs produced by L. gasseri strains was determined by HPLC. The sugar component was the same; however, relative proportions of the individual monosaccharides except mannose were different. Although they both produce similar amount of EPS, the most adhesive strain was G10. Both live and L-EPS of L. gasseri strains were capable of inhibiting the cell proliferation of HeLa cells with the impact of L-EPS being strain specific. L-EPSs of L. gasseri strains induced apoptosis in HeLa cells in a strain dependent manner. The ability to induce apoptosis by G10 associated with an upregulation of Bax and Caspase 3. L. gasseri strains showed an anti-inflammatory impact on HeLa cells by decreasing the production of TNF-alpha and increasing the IL-10 production. In conclusion, diversity in sugar composition of EPS might contribute to adhesion and proliferation properties. Although our results suggest a relationship between the ability of a strain to induce apoptosis and its sugar composition of EPS, further research is required to determine the probiotic mechanisms of action by which L. gasseri strains result in strain specific anti proliferative activity. PMID- 28554814 TI - Bioaugmentation of the thermophilic anaerobic biodegradation of cellulose and corn stover. AB - Two stable, thermophilic mixed cellulolytic consortia were enriched from an industrial scale biogas fermenter. The two consortia, marked as AD1 and AD2, were used for bioaugmentation in laboratory scale batch reactors. They enhanced the methane yield by 22-24%. Next generation sequencing method revealed the main orders being Thermoanaerobacterales and Clostridiales and the predominant strains were Thermoanaerobacterium thermosaccharolyticum, Caldanaerobacter subterraneus, Thermoanaerobacter pseudethanolicus and Clostridium cellulolyticum. The effect of these strains, cultivated in pure cultures, was investigated with the aim of reconstructing the defined cellulolytic consortium. The addition of the four bacterial strains and their mixture to the biogas fermenters enhanced the methane yield by 10-11% but it was not as efficient as the original communities indicating the significant contribution by members of the enriched communities present in low abundance. PMID- 28554815 TI - Alcohol consumption and risk of heart failure: Meta-analysis of 13 prospective studies. AB - BACKGROUND & AIMS: Controversy exists on the association between alcohol consumption and risk of heart failure (HF). We carried out a meta-analysis to summarize available prospective data on alcohol consumption and HF. METHODS: We searched PubMed for relevant studies published until January 1, 2017. Relative risk (RR) estimates from individual studies were pooled in a random-effects meta analysis. RESULTS: A total of 13 prospective studies, with 13,738 HF cases and 355,804 participants, were included in the meta-analysis. Light alcohol drinking (0.1-7 drinks/week) was inversely associated with risk of HF (RR, 0.86; 95% confidence interval, 0.81-0.90). There was no statistically significant association between moderate (7.1-14 drinks/week), high (14.1-28 drinks/week), or heavy (>28 drinks/week) alcohol consumption and HF risk. Former drinking was associated with an increased risk of HF compared with never or occasional drinking (RR, 1.22; 95% confidence interval, 1.11-1.33). CONCLUSIONS: This meta analysis found that light alcohol drinking was associated with a lower risk of HF. Former drinking was associated with a higher risk of HF. PMID- 28554817 TI - Outcome of primary repair in extremely and very low-birth-weight infants with esophageal atresia/distal tracheoesophageal fistula. AB - PURPOSE: The optimal surgical management of extremely (ELBW) and very low-birth weight (VLBW) neonates with esophageal atresia and distal tracheoesophageal fistula (EA/TEF) (Gross type C) is still debated. The aim of this study was to evaluate the surgical outcome of primary repair in these patients and compare it to >=1500g neonates. METHODS: Medical records of neonates with repaired EA from 2002 to 2016 were reviewed. RESULTS: 4 ELBW, 7 VLBW, and 24 >=1500g infants had type C EA/TEF and underwent primary repair. Anastomotic leakage occurred in 0% ELBW, 0% VLBW and 8.3% >=1500g patients and anastomotic stricture in 25% ELBW, 28.5% VLBW and 37.5% >=1500g patients. 50% ELBW, 14.2% VLBW and 20.8% >=1500g patients underwent secondary fundoplication. One patient of the VLBW group and one patient of the >=1500g group died postoperatively of causes not related to EA/TEF. CONCLUSIONS: In extremely and very low-birth-weight neonates with type C EA/TEF surgical outcome after primary repair is comparable to the outcome in >=1500g neonates. Primary repair can be performed in most of these patients and staged repair can be restricted to unstable patients. LEVEL OF EVIDENCE: Treatment study level III. PMID- 28554816 TI - A pre-operative clinical scoring system to distinguish perforation risk with pediatric appendicitis. AB - IMPORTANCE: Appendicitis is a common, potentially serious pediatric disease. An important factor in determining management strategy [whether/when to perform appendectomy, duration of antibiotic therapy/hospitalization, etc.] and predicting outcome is distinguishing whether perforation is present. OBJECTIVE: The objective was to determine efficacy of commonly assessed pre-operative variables in stratifying perforation risk in children with appendicitis. DESIGN: A retrospective analysis of consecutive cases was performed. SETTING: The setting was a large urban hospital pediatric emergency department. PARTICIPANTS: Four hundred forty-eight consecutive cases of CT [computerized tomography]-confirmed pediatric appendicitis during a 6-year period in an urban pediatric ED [emergency department]: 162 with perforation and 286 non-perforated. MAIN OUTCOME(S) AND MEASURE(S): To determine efficacy of clinical and laboratory variables with distinguishing perforation outcome in children with appendicitis. RESULTS: Regression analysis identified 3 independently significant variables associated with perforation outcome - and determined their ideal threshold values: duration of symptoms>1day; ED-measured fever [body temperature >38.0 degrees C]; CBC WBC absolute neutrophil count >13,000/mm3. The resulting multivariate ROC [receiver operating characteristic] curve after applying these threshold values gave an AUC [area under curve] of 89% for perforation outcome [p<0.001]. Risk for perforation was additive with each additional predictive variable exceeding its threshold value, linearly increasing from 7% with no variable present to 85% when all 3 variables are present. CONCLUSIONS: A pre-operative scoring system comprised of 3 commonly assessed clinical/laboratory variables is useful in stratifying perforation risk in children with appendicitis. Physicians can utilize these factors to gauge pre-operative risk for perforation in children with appendicitis, which can potentially aid in planning subsequent management strategy. LEVEL OF EVIDENCE: III. PMID- 28554818 TI - Effect of portable non-invasive ventilation & environmental conditions on everyday activities. AB - The current study examined the effect of non-invasive ventilation (NIV) within environments of differing temperature and humidity on several physiological and perceptual responses while performing six activities of daily living (i.e. putting on shirt/shoes/trousers, vacuuming, hanging towels, and walking on a treadmill). Sixteen healthy participants completed the activities of varying difficulty within four experimental conditions: with and without NIV; and in temperate (22 degrees C, 40% relative humidity) and hot-humid environments (32 degrees C, 70% relative humidity). Comparisons of physiological responses between conditions were examined via repeated measures ANOVAs. Overall, NIV resulted in similar physiological and perceptual responses within all environmental conditions for healthy participants. Further, NIV use increased heart rate during the most strenuous task (29.5+/-12.7 vs. 22.8+/-12.0bpm, p=0.008) indicating NIV use may stress cardiovascular functioning during moderate-high intensity activities. Tropical conditions did not alter physiological or perceptual responses during everyday tasks with NIV use by healthy adults. Future investigations examining the independent and combined impacts of task intensity, extreme environments and NIV use will clarify the benefits of NIV for healthy and clinical populations. PMID- 28554819 TI - Interstitial lung fluid balance in healthy lowlanders exposed to high-altitude. AB - We aimed to assess lung fluid balance before and after gradual ascent to 5150m. Lung diffusion capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO) and ultrasound lung comets (ULCs) were assessed in 12 healthy lowlanders at sea-level, and on Day 1, Day 5 and Day 9 after arrival at Mount Everest Base Camp (EBC). EBC was reached following an 8-day hike at progressively increasing altitudes starting at 2860m. DLCO was unchanged from sea-level to Day 1 at EBC, but increased on Day 5 (11+/-10%) and Day 9 (10+/-9%) vs. sea-level (P<=0.047). DmCO increased from sea-level to Day 1 (9+/-6%), Day 5 (12+/-8%), and Day 9 (17+/-11%) (all P<=0.001) at EBC. There was no change in ULCs from sea level to Day 1, Day 5 and Day 9 at EBC. These data provide evidence that interstitial lung fluid remains stable or may even decrease relative to at sea level following 8days of gradual exposure to high-altitude in healthy humans. PMID- 28554820 TI - Argininic acid alters markers of cellular oxidative damage in vitro: Protective role of antioxidants. AB - We, herein, investigated the in vitro effects of argininic acid on thiobarbituric acid-reactive substances (TBA-RS), total sulfhydryl content and on the activities of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the blood, kidney and liver of 60-day-old rats. We also verified the influence of the antioxidants (each at 1.0mM) trolox and ascorbic acid, as well as of NG-nitro-l-arginine methyl ester (L-NAME) at 1.0mM, a nitric oxide synthase inhibitor, on the effects elicited by argininic acid on the parameters tested. The liver, renal cortex and renal medulla were homogenized in 10vol (1:10w/v) of 20mM sodium phosphate buffer, pH 7.4, containing 140mM KCl; and erythrocytes and plasma were prepared from whole blood samples obtained from rats. For in vitro experiments, the samples were pre incubated for 1h at 37 degrees C in the presence of argininic acid at final concentrations of 0.1, 1.0 and 5.0MUM. Control experiments were performed without the addition of argininic acid. Results showed that argininic acid (5.0MUM) enhanced CAT and SOD activities and decreased GSH-Px activity in the erythrocytes, increased CAT and decreased GSH-Px activities in the renal cortex and decreased CAT and SOD activities in the renal medulla of 60-day-old rats, as compared to the control group. Antioxidants and/or L-NAME prevented most of the alterations caused by argininic acid on the oxidative stress parameters evaluated. Data suggest that argininic acid alters antioxidant defenses in the blood and kidney of rats; however, in the presence of antioxidants and L-NAME, most of these alterations in oxidative stress were prevented. These findings suggest that oxidative stress may be make an important contribution to the damage caused by argininic acid in hyperargininemic patients and that treatment with antioxidants may be beneficial in this pathology. PMID- 28554821 TI - Stem Cell Therapy: The Phoenix in Clinical Medicine? PMID- 28554822 TI - Impact of cell adhesion and migration on nanoparticle uptake and cellular toxicity. AB - In vitro cell-nanoparticle (NP) studies involve exposure of NPs onto the monolayer cells growing at the bottom of a culture plate, and assumed that the NPs evenly distributed for a dose-responsive effect. However, only a few proportion of the administered dose reaches the cells depending on their size, shape, surface, and density. Often the amount incubated (administered dose) is misled as a responsive dose. Herein, we proposed a cell adhesion-migration (CAM) strategy, where cells incubated with the NP coated cell culture substrate to maximize the cell-NP interaction and investigated the physiological properties of the cells. In the present study, cell adhesion and migration pattern of human breast cancer cell (MCF-7) and mouse melanoma cell (B16-F10) on cell culture substrate decorated with toxic (cetyltrimethylammonium bromide, CTAB) and biocompatible (poly (sodium 4-styrenesulphonate), PSS) gold nanoparticles (AuNPs) of different sizes (5 and 40nm) were investigated and evaluated for cellular uptake efficiency, proliferation, and toxicity. Results showed enhanced cell adhesion, migration, and nanoparticle uptake only on biocompatible PSS coated AuNP, irrespective of its size. Whereas, cytotoxic NP shows retard proliferation with reduced cellular uptake efficiency. Considering the importance of cell adhesion and migration on cellular uptake and cytotoxicity assessment of nanoparticle, CAM strategy would hold great promises in cell-NP interaction studies. PMID- 28554823 TI - Mercury contamination in facial skin lightening creams and its health risks to user. AB - This study aims to determine concentrations of mercury in facial skin lightening cream according to different price categories (category I: =RM100.00) and their potential health risks to users. Prices of skin lightening creams were determined during a preliminary market survey. Thereafter, twenty samples were purchased from various locations such as cosmetic stalls, beauty shops, pharmacies and street vendors based on their stratified price categories. Samples were extracted using microwave digester and analyzed using cold vapor atomic absorption spectrometry (CV-AAS). Non-carcinogenic chronic health risks for application of facial skin lightening cream were calculated using Dermal Absorption Dose (DAD) and Hazard Quotient (HQ). Concentrations of mercury in samples were less than the United States Food and Drug Administration (USFDA) permitted trace levels (<1 ppm) except for one sample from category III which was manufactured in China. Concentrations of mercury in facial skin lightening creams ranged from not detected to 1.13 mg kg-1. There was no significant association between concentrations of mercury with price categories (p = 0.12). There was no significant non-carcinogenic health risk due to daily application of the facial skin lightening creams based on assumption of 30 years exposure period (HQ < 1). PMID- 28554824 TI - The Perception of Formant Tuning in Soprano Voices. AB - INTRODUCTION: At the upper end of the soprano range, singers adjust their vocal tract to bring one or more of its resonances (Rn) toward a source harmonic, increasing the amplitude of the sound; this process is known as resonance tuning. This study investigated the perception of (R1) and (R2) tuning, key strategies observed in classically trained soprano voices, which were expected to be preferred by listeners. Furthermore, different vowels were compared, whereas previous investigations have usually focused on a single vowel. METHODS: Listeners compared three synthetic vowel sounds, at four fundamental frequencies (f0), to which four tuning strategies were applied: (A) no tuning, (B) R1 tuned to f0, (C) R2 tuned to 2f0, and (D) both R1 and R2 tuned. Participants compared preference and naturalness for these strategies and were asked to identify each vowel. RESULTS: The preference and naturalness results were similar for /alpha/, with no clear pattern observed for vowel identification. The results for /u/ showed no clear difference for preference, and only slight separation for naturalness, with poor vowel identification. The results for /i/ were striking, with strategies including R2 tuning both preferred and considered more natural than those without. However, strategies without R2 tuning were correctly identified more often. CONCLUSIONS: The results indicate that perception of different tuning strategies depends on the vowel and perceptual quality investigated, and the relationship between the formants and (f0). In some cases, formant tuning was beneficial at lower f0s than expected, based on previous resonance tuning studies. PMID- 28554825 TI - Contact Quotient of Female Singers Singing Four Pitches for Five Vowels in Normal and Pressed Phonations. AB - OBJECTIVES: The present study aimed to investigate the contact quotient (CQ) values of breathy, normal, and pressed phonation types in four different sections of the female singing range. METHODS: Electroglottography (EGG) and acoustic signals were recorded from 10 female singing teachers. Five vowels were sung for 1-3 seconds each, in three phonation types-normal, breathy, and pressed, in four pitches representing registration change points in the singing range. CQ values were automatically generated from the EGG signal using VoceVista at 35% threshold level. Sound pressure levels were checked in Praat. Unianova and correlations were performed using an SPSS program. RESULTS: CQ values of female participants in the study yielded ranges of 0.25-0.62 in normal and 0.34-0.73 in pressed. Normal and pressed CQ differed significantly from each other at P < 0.00. Breathy samples were not viable for analysis. A concentration of CQ values from 0.5 to 0.6 of both pressed low and pressed break samples was noted, but CQ values across the pitch range showed no significant trend. CONCLUSIONS: Normal and pressed phonation CQ values beyond the speaking pitch varied among the subjects. Pressed phonation CQ values were mostly higher, but the values were only relative to the corresponding normal phonation on the same pitch. Other measurements may be more suitable for measuring vocal fold impact stress in higher frequencies, thus, distinguishing normal from pressed singing. PMID- 28554827 TI - Field-scale forward and back diffusion through low-permeability zones. AB - Understanding the effects of back diffusion of groundwater contaminants from low permeability zones to aquifers is critical to making site management decisions related to remedial actions. Here, we combine aquifer and aquitard data to develop recommended site characterization strategies using a three-stage classification of plume life cycle based on the solute origins: aquifer source zone dissolution, source zone dissolution combined with back diffusion from an aquitard, and only back diffusion. We use measured aquitard concentration profile data from three field sites to identify signature shapes that are characteristic of these three stages. We find good fits to the measured data with analytical solutions that include the effects of advection and forward and back diffusion through low-permeability zones, and linearly and exponentially decreasing flux resulting from source dissolution in the aquifer. Aquifer contaminant time series data at monitoring wells from a mature site were well described using analytical solutions representing the combined case of source zone and back diffusion, while data from a site where the source had been isolated were well described solely by back diffusion. The modeling approach presented in this study is designed to enable site managers to implement appropriate remediation technologies at a proper timing for high- and low-permeability zones, considering estimated plume life cycle. PMID- 28554826 TI - Oxidative pathways in the sickle cell and beyond. AB - Polymerization of deoxy sickle cell hemoglobin (HbS) is well recognized as the primary event that triggers the classic cycles of sickling/unsickling of patients red blood cells (RBCs). RBCs are also subjected to continuous endogenous and exogenous oxidative onslaughts resulting in hemolytic rate increases which contribute to the evolution of vasculopathies associated with this disease. Compared to steady-state conditions, the occurrences of vaso-occlusive crises increase the levels of both RBC-derived microparticles as well as extracellular Hb in circulation. Common byproduct resulting from free Hb oxidation and from Hb laden microparticles is heme (now recognized as damage associated molecular pattern (DAMP) molecule) which has been shown to initiate inflammatory responses. This review provides new insights into the interplay between microparticles, free Hb and heme focusing on Hb's pseudoperoxidative activity that drives RBC's cytosolic, membrane changes as well as oxidative toxicity towards the vascular system. Emerging antioxidative strategies that include the use of protein and heme scavengers in controlling Hb oxidative pathways are discussed. PMID- 28554828 TI - Phytochelatins and monothiols in salt marsh plants and their relation with metal tolerance. AB - Phytochelatins (PCs) and monothiols and their relation with trace element concentrations were studied in three plant species from two Portuguese salt marshes. Belowground tissues showed always higher element concentrations, while enhanced values of monothiols were found in aboveground biomass. Glutathione was usually the most abundant monothiol. The concentration of total PCs was higher in leaves or stems than in roots of Halimione portulacoides and Sarcocornia perennis, while in Spartina maritima the highest concentrations were reported in large roots. PC2 was synthesized by all tissues and species and was higher in large roots of S. maritima. PC4 and PC5 were in high levels in small roots of S. maritima. PC2 was positively correlated with As, Zn and Pb. Although being the first evidence of PCs and monothiols in these species under natural conditions, our results do not point to a simple relationship with elements concentrations, suggesting a complex mechanism involved. PMID- 28554829 TI - Bioinformatics can boost metabolomics research. AB - Metabolomics is the modern term for the field of small molecule research in biology and biochemistry. Currently, metabolomics is undergoing a transition where the classic analytical chemistry is combined with modern cheminformatics and bioinformatics methods, paving the way for large-scale data analysis. We give some background on past developments, highlight current state-of-the-art approaches, and give a perspective on future requirements. PMID- 28554830 TI - RNA-bioinformatics: Tools, services and databases for the analysis of RNA-based regulation. AB - The importance of RNA-based regulation is becoming more and more evident. Genome wide sequencing efforts have shown that the majority of the DNA in eukaryotic genomes is transcribed. Advanced high-throughput techniques like CLIP for the genome-wide detection of RNA-protein interactions have shown that post transcriptional regulation by RNA-binding proteins matches the complexity of transcriptional regulation. The need for a specialized and integrated analysis of RNA-based data has led to the foundation of the RNA Bioinformatics Center (RBC) within the German Network of Bioinformatics Infrastructure (de.NBI). This paper describes the tools, services and databases provided by the RBC, and shows example applications. Furthermore, we have setup an RNA workbench within the Galaxy framework. For an easy dissemination, we offer a virtualized version of Galaxy (via Galaxy Docker) enabling other groups to use our RNA workbench in a very simple way. PMID- 28554831 TI - A logician's approach to meta-analysis with unexplained heterogeneity. AB - Meta-analysis is a powerful tool for combining related studies but such an aggregation would be flawed if studies investigated different populations or applied different methods in this investigation. While studies with differences that are statistically detected but not explained can be analysed by techniques of random-effects meta-analysis, it is difficult to analyse a study if it provides us with complex knowledge. This paper introduces a new method for meta analysis that deals with both complex knowledge and unexplained heterogeneity, and which shares some properties with Bayesian methods. The newly developed method is applicable in a wide range of medical and also non-medical problems. A demonstration will be provided on a real medical example concerning the one-year incidence of diagnosis of cancer in patients with unprovoked venous thromboembolism. Our main findings based on several recent statistically heterogeneous studies indicate significant improvement in the cancer detection rate if routine evaluation for those patients is performed jointly with extensive screening techniques. PMID- 28554832 TI - Evolution of the histologic classification of thyroid neoplasms and its impact on clinical management. AB - The vast majority of low grade follicular cell derived thyroid carcinomas follows an indolent clinical course and is associated with very low mortality. Risk stratification using multiple clinical and pathologic characteristics has become the standard of care to guide appropriate management and avoid overtreatment. Over the past few decades, the field of thyroid pathology has witnessed several major changes that significantly impacted upon patients' care. These are: 1) The reclassification of non-invasive encapsulated follicular variant of papillary thyroid carcinoma as noninvasive follicular thyroid neoplasm with papillary-like nuclear features; 2) the diagnosis of Hurthle cell carcinoma based on the presence of capsular and vascular invasion; 3) a detailed definition of poorly differentiated thyroid carcinoma, taking into consideration mitosis and necrosis; and 4) the emphasis on a detailed pathologic analysis such as the extent of vascular invasion and extrathyroidal extension. This review describes these histological concepts and details the history, rationale, and clinical impacts of such changes. These shifts in the classification and characterization of thyroid carcinoma provided a platform supporting therapy de-escalation. In addition several lessons were learned from these changes especially from the misclassification of the non-invasive encapsulated follicular variant of papillary thyroid carcinoma. We hope that the lessons learned will help better classify tumors in the future whether arising in the thyroid or other organs. PMID- 28554834 TI - Consecutive yearly outbreaks of respiratory syncytial virus in a haemato-oncology ward and efficacy of infection control measures. AB - BACKGROUND: Respiratory syncytial virus (RSV) causes significant respiratory tract infection in immunosuppressed patients. AIM: To describe two consecutive yearly outbreaks of RSV in our haemato-oncology ward. METHODS: Haematology patients presenting with respiratory symptoms were screened by polymerase chain reaction for viral respiratory pathogens using a saline gargle. FINDINGS: None of our patients had undergone bone marrow transplant but all had underlying haematological malignancies. Eight patients were affected in the first outbreak (mortality rate: 37.5%) and 12 patients were affected in the second (mortality rate: 8.3%). Extensive infection control measures were implemented in both outbreaks and were successful in preventing further cross-transmission. CONCLUSION: There was significant learning from both outbreaks and actions implemented with the aim of reducing the likelihood and impact of future outbreaks. PMID- 28554833 TI - Optimization of mitochondrial isolation techniques for intraspinal transplantation procedures. AB - BACKGROUND: Proper mitochondrial function is essential to maintain normal cellular bioenergetics and ionic homeostasis. In instances of severe tissue damage, such as traumatic brain and spinal cord injury, mitochondria become damaged and unregulated leading to cell death. The relatively unexplored field of mitochondrial transplantation following neurotrauma is based on the theory that replacing damaged mitochondria with exogenous respiratory-competent mitochondria can restore overall tissue bioenergetics. NEW METHOD: We optimized techniques in vitro to prepare suspensions of isolated mitochondria for transplantation in vivo. Mitochondria isolated from cell culture were genetically labeled with turbo green fluorescent protein (tGFP) for imaging and tracking purposes in vitro and in vivo. RESULTS: We used time-lapse confocal imaging to reveal the incorporation of exogenous fluorescently-tagged mitochondria into PC-12 cells after brief co incubation. Further, we show that mitochondria can be injected into the spinal cord with immunohistochemical evidence of host cellular uptake within 24h. COMPARISON TO EXISTING METHODS: Our methods utilize transgenic fluorescent labeling of mitochondria for a nontoxic and photostable alternative to other labeling methods. Substrate addition to isolated mitochondria helped to restore state III respiration at room temperature prior to transplantation. These experiments delineate refined methods to use transgenic cell lines for the purpose of isolating well coupled mitochondria that have a permanent fluorescent label that allows real time tracking of transplanted mitochondria in vitro, as well as imaging in situ. CONCLUSIONS: These techniques lay the foundation for testing the potential therapeutic effects of mitochondrial transplantation following spinal cord injury and other animal models of neurotrauma. PMID- 28554835 TI - Transcriptome profiling of the Macrobrachium rosenbergii lymphoid organ under the white spot syndrome virus challenge. AB - Macrobrachium rosenbergii is a crustacean with economic importance, and adult prawns are generally thought to be tolerant to white spot syndrome virus (WSSV) infection. Although certain genes are known to respond to WSSV infection and lymphoid tissue is an important immune organ, the response of lymphoid organ to WSSV infection is unclear. Next-generation sequencing was employed in this study to determine the transcriptome differences between WSSV infection and mock lymphoid organs. A total of 44,606,694 and 40,384,856 clean reads were generated and assembled into 73,658 and 72,374 unigenes from the control sample and the WSSV infection sample, respectively. Based on homology searches, KEGG, GO, and COG analysis, 21,323 unigenes were annotated. Among them, 4951 differential expression genes were identified and categorized into 244 metabolic pathways. Coagulation cascades, and pattern recognition receptor signaling pathways were used as examples to discuss the response of host to WSSV infection. We also identified 12,308 simple sequence repeats, which can be further used as functional markers. Results contribute to a better understanding of the immune response of prawn lymphoid organ to WSSV and provide information for identifying novel genes in the absence of the prawn genome. PMID- 28554836 TI - Comparative study of three phenoloxidases in the sea cucumber Apostichopus japonicus. AB - In order to preliminarily illustrate the functional differences of phenoloxidases (POs) in Apostichopus japonicus, the full-length cDNAs of two POs (named as AjPOII and AjPOIII, respectively) were cloned from the coelomocytes of A. japonicus using 3'- and 5'-rapid amplification of cDNA ends method, and combined with the previously acquired full-length cDNA of a laccase-type PO from A. japonicus (Accession No. KF040052, named as AjPOI), the sequence structure and phylogenic status of POs from A. japonicus (AjPOs) were comparatively analyzed, and the transcriptional expression of AjPOs in different tissues, at different developmental stages and after different bacterial challenges was determined with quantitative real-time PCR method. Sequence analysis indicated AjPOII and AjPOIII were both laccase-type POs, coincident to the results of phylogenic analysis. Sequence analysis also showed that AjPOI had a transmembrane domain (J. Jiang et al., 2014), AjPOII contained a signal peptide, and AjPOIII possessed a signal peptide and a transmembrane domain, implying that three AjPOs might play different roles in immune and physiological processes. Transcriptional expression analysis showed that AjPOII and AjPOIII were most abundant in tube feet, while AjPOIhad the highest expression level in coelomocytes (J. Jiang et al., 2014), suggesting that AjPOI may be mainly involved in immune response, while AjPOII and AjPOIII are probably responsible for other physiological processes in addition to immune response. Besides, three AjPOs were determined to have different expression patterns during organism development and different spectrums of response against bacteria, which further indicated that there might be immune and physiological functional differentiation among three AjPOs. PMID- 28554837 TI - Identification, polymorphism and expression of MHC class Ialpha in golden pompano, Trachinotus ovatus. AB - The classical major histocompatibility complex class I (MHC I) plays a vital role in the immune system. In this study, we cloned and identified golden pompano (Trachinotus ovatus) MHC Ialpha (Trov-MHC Ialpha), which encodes 351 amino acid residues including a leader peptide, alpha1, alpha2, alpha3 domain, a transmembrane region and a cytoplasmic domain. Twenty six different sequences, which encoded various numbers of amino acid residues ranging from 348 to 354, were obtained from 12 individuals. Highly genetic polymorphism was found in the Trov-MHC Ialpha, especially in the alpha1 and alpha2 domains. Meanwhile, in the alpha1 and alpha2 domains, 21 positive selected positions were revealed by site models, indicating the diversity of Trov-MHC Ialpha may be mainly generated by positive selection. Moreover, quantitative real-time reverse transcription PCR and western blotting analyses demonstrated that Trov-MHC Ialpha was ubiquitously expressed in the nine tested tissues and more highly expressed in intestine, head kidney, gill, and spleen. In the head kidney and spleen, Trov-MHC Ialpha was significantly upregulated under LPS or poly I:C stimulation. The results of this study provide valuable insight into molecular polymorphism, evolutionary mechanism, expression and function of MHC Ialpha in the immune system of golden pompano. PMID- 28554838 TI - The identification of microRNAs involved in the response of Chinese shrimp Fenneropenaeus chinensis to white spot syndrome virus infection. AB - MicroRNA (miRNA) is a class of small noncoding RNA, which is involved in the post transcriptional regulation in all metazoan eukaryotes. MiRNAs might play an important role in the host response to virus infection. However, miRNAs in the aquatic crustacean species were not extensively investigated. To obtain a better understanding of the response of Chinese shrimp Fenneropenaeus chinensis to white spot syndrome virus (WSSV) infection, the sequence and expression profile of miRNAs in the hepatopancreas of WSSV-infected F. chinensis were obtained by the high-throughput Illumina HiSeq 2500 deep sequencing technique. A total number of 129 known miRNAs and 44 putative novel miRNAs were identified from the deep sequencing data. The peak size of miRNAs was 22 nt (37.0%). 25 miRNAs were significantly (P < 0.05) differentially expressed post WSSV infection. Six of the differentially expressed miRNAs were randomly selected for further verification by the real-time RT-PCR technique. The results showed that there was a consistency between the deep sequencing and real-time RT-PCR assay. The target genes of differentially expressed miRNAs were predicted. Each miRNA had 4 target genes on average. The results suggested that some specific miRNAs might be involved in the response of F. chinensis to WSSV infection, and further provided basic information for the investigation of specific miRNAs in F. chinensis. PMID- 28554839 TI - Biophysical and structural characterization of mono/di-arylated lactosamine derivatives interaction with human galectin-3. AB - Combination of biophysical and structural techniques allowed characterizing and uncovering the mechanisms underlying increased binding affinity of lactosamine derivatives for galectin 3. In particular, complementing information gathered from X-ray crystallography, native mass spectrometry and isothermal microcalorimetry showed favorable enthalpic contribution of cation-pi interaction between lactosamine aryl substitutions and arginine residues from the carbohydrate recognition domain, which resulted in two log increase in compound binding affinity. This incrementing strategy allowed individual contribution of galectin inhibitor moieties to be dissected. Altogether, our results suggest that core and substituents of these saccharide-based inhibitors can be optimized separately, providing valuable tools to study the role of galectins in diseases. PMID- 28554840 TI - Atorvastatin augments temozolomide's efficacy in glioblastoma via prenylation dependent inhibition of Ras signaling. AB - Ras signaling is often dysregulated and plays essential roles for the maintenance of glioblastoma. The proper function of Ras depends largely on the appropriate post-translational modification termed prenylation. Targeting protein prenylation therefore represents an alternative therapeutic strategy in glioblastoma. In this study, we demonstrate that prenylation inhibition by atorvastatin is active against glioblastoma. Atorvastatin alone dose-dependently inhibits growth and survival of multiple glioblastoma cell lines. Its combination with temozolomide significantly enhances temozolomide's efficacy in in vitro cultured cell system as well as in vivo xenograft glioblastoma tumor model. We further show that this is achieved by the inhibition of Ras prenylation, leading to decreased activation of Ras and its downstream signaling pathways, including Erk, rS6 and eIF4E. Our findings suggest that inhibition of Ras activity by atorvastatin effectively targets the MEK and other signaling pathways. Our study provides a fundamental evidence to repurpose atorvastatin for a potential treatment of glioblastoma. PMID- 28554842 TI - Jasmonate-induced biosynthesis of steroidal glycoalkaloids depends on COI1 proteins in tomato. AB - In tomato, perception of jasmonates by a receptor complex, which includes the F box protein CORONATINE INSENSITIVE 1 (COI1), elicits biosynthesis of defensive steroidal glycoalkaloids (SGAs) via a jasmonate-responsive ERF transcription factor, JRE4/GAME9. Although JRE4 is upregulated by jasmonate and induces the expression of many metabolic genes involved in SGA biosynthesis, it is not known whether JRE4 alone is sufficient for increased SGA biosynthesis upon activation of jasmonate signaling. Here, we show that application of methyl jasmonate induces the expression of JRE4 and SGA biosynthesis genes in leaves and hairy roots of wild-type tomato, but not in jasmonic acid insensitive 1 (jai1), a loss of-function mutant allele of the tomato COI1 gene. Induced overexpression of JRE4 increased the expression of SGA biosynthesis genes in transgenic hairy roots of both wild-type tomato and the jai1 mutant, suggesting that JRE4 is the primary transcription factor that functions downstream of the jasmonate signaling pathway. PMID- 28554841 TI - ERK1/2 signaling mediated naringin-induced osteogenic differentiation of immortalized human periodontal ligament stem cells. AB - Periodontal ligament stem cells (PDLSCs) are promising tools for the investigations of cell differentiation and bone regeneration. However, the limited life span significantly restricts their usefulness. In this study, we established an immortalized PDLSC cell line by the introduction of Bmi1 (PDLSC Bmi1). Several genes related to cell cycle, cell replication and stemness were found to be changed with the overexpression of Bmi1. Compared with primary PDLSCs, the immortalized cells had a slower aging rate, maintained in a proliferative state without crisis for more than 30 passages, and retained the molecular markers and biological functions of primary ones. Using the PDLSC-Bmi1, we confirmed the promotive effect of naringin on osteogenesis. Naringin promoted the osteogenic differentiation of PDLSC-Bmi1 manifested as the increased activity of alkaline phosphatase (ALP), expression of the runt-related transcription factor 2 (Runx2) and osteocalcin (OCN), and formation of mineralized nodules. In addition, the extracellular regulated protein kinases (ERK) 1/2 was found to be activated by naringin, and the ERK1/2 specific inhibitor significantly inhibited naringin-induced osteogenic differentiation in PDLSC-Bmi1. Our results indicated that the overexpression of Bmi1 extended the life span of PDLSCs without perturbing their biological functions, and that naringin promoted the osteogenesis of PDLSC-Bmi1 at least partially through the ERK1/2 signaling pathway. PMID- 28554843 TI - NF-kappaB signaling and cell-fate decision induced by a fast-dissociating tumor necrosis factor mutant. AB - Tumor necrosis factor (TNF) is a pluripotent inflammatory cytokine that can induce both the pro-survival nuclear factor kappa B (NF-kappaB) pathway and the pro-apoptotic caspase pathway. Selectively activating only one of the two pathways remains challenging. We used TNF mutants with different receptor binding kinetics to study their effects on NF-kappaB signaling dynamics and cell apoptosis. A TNF mutant, R1antTNF, which binds to TNFR1 with increased association and dissociation rates, induced NF-kappaB signaling with shorter response time and first peak duration. The short nuclear stay of NF-kappaB led to biased activation of downstream genes, favoring the fast response ones. At the same time, R1antTNF retains pro-apoptotic activity. At 10 ng/ml, R1antTNF selectively activated the pro-apoptotic pathway rather than the pro-survival NF kappaB pathway. Our study provides a new example for the emerging evidence that ligand-receptor binding kinetics play a key role in the selective activation of downstream pathways, which deserves more attention in future drug discovery and disease studies. PMID- 28554844 TI - Control of cancer stem cell like population by intracellular target identification followed by the treatment with peptide-siRNA complex. AB - Cancer stem cells (CSCs) are a subpopulation of cancer cells and have been known to create cancer reoccurrence during cancer therapy due to their stem cell-like characteristics. However, exact target to control the CSC has not been fully established. Here, we enriched CD44High population of MDA-MB-231 cells by CD44 antibody as a CSC marker. By Phospho Antibody Array, CD44High population of MDA MB-231 cells reveals Feline sarcoma-related tyrosine kinase (FER) protein was highly activated. When FER siRNA and low molecular weight protamine (LMWP) as cell penetrating peptides are applied to this population, cancer migration and colony forming ability are inhibited. Moreover, silencing FER using FER siRNA and LMWP conjugates enhances anti-metastasis related factors including E-cadherin, p75 and p63. Taken together, FER is a new marker for targeting breast CSCs and peptide-mediated siRNA method could be an effective and safe way of delivery and be a new therapeutic strategy for targeting breast cancer. PMID- 28554845 TI - A novel anatomical patellar plate for transverse patellar fracture - A biomechanical in-vitro study. AB - OBJECTIVE: The aim of this study was to assess the safety and stability of our novel anatomical patella plate and to compare its stability with tension band wire technique. METHODS: A total of 12 cadaveric preserved knees (six right and six left patellae) with close patellar size were chosen to form two groups of six samples. Each group received either plate or tension band-wiring fixation for an experimentally created patella fracture. Cyclic load of an average of 350 N was applied for all specimens and after accomplishing 50 cycles the displacements of all fracture edges were recorded. RESULTS: After completing 50 cycles in each group, the average fracture edges displacement measured in the plate group was 1.98 +/- 0.299 mm, whereas the average fracture edges displacement measured in the tension band-wire group was 2.85 +/- 0.768 mm (p = 0.016). CONCLUSION: In the operative treatment of displaced transverse patellar fractures, the strength of fixation obtained by titanium curved plates is highly stronger when compared to the fixation with a tension band-wire technique. Fixation with titanium curved plates provides satisfactory stability at the fracture site which allow withstanding the cyclic loads during the postoperative rehabilitation. PMID- 28554846 TI - Development of an Undergraduate Radiology Curriculum: Ten-Year Experience From the University of British Columbia. PMID- 28554847 TI - Panicolytic-like action of bradykinin in the dorsal periaqueductal gray through MU-opioid and B2-kinin receptors. AB - A wealth of evidence has shown that opioid and kinin systems may control proximal defense in the dorsal periaqueductal gray matter (dPAG), a critical panic associated area. Studies with drugs that interfere with serotonin-mediated neurotransmission suggest that the MU-opioid receptor (MOR) synergistically interacts with the 5-HT1A receptor in the dPAG to inhibit escape, a panic-related behavior. A similar inhibitory effect has also been reported after local administration of bradykinin (BK), which is blocked by the non-selective opioid receptor antagonist naloxone. The latter evidence, points to an interaction between BK and opioids in the dPAG. We further explored the existence of this interaction through the dPAG electrical stimulation model of panic. We also investigated whether intra-dPAG injection of captopril, an inhibitor of the angiotensin-converting enzyme (ACE) that also degrades BK, causes a panicolytic like effect. Our results showed that intra-dPAG injection of BK inhibited escape performance in a dose-dependent way, and this panicolytic-like effect was blocked by the BK type 2 receptor (B2R) antagonist HOE-140, and by the selective MOR antagonist CTOP. Conversely, the panicolytic-like effect caused by local administration of the selective MOR agonist DAMGO was antagonized by pre treatment with either CTOP or HOE-140, indicating cross-antagonism between MOR and B2R. Finally, intra-dPAG injection of captopril also impaired escape in a dose-dependent way, and this panicolytic-like effect was blocked by pretreatment with HOE-140, suggesting mediation by endogenous BK. The panicolytic-like effect of captopril indicates that the use of ACE inhibitors in the clinical management of panic disorder may be worth exploring. PMID- 28554848 TI - Sex- and hormone-dependent alterations in alcohol withdrawal-induced anxiety and corticolimbic endocannabinoid signaling. AB - Alcohol dependence is associated with anxiety during withdrawal. The endocannabinoid (ECB) system participates in the neuroendocrine and behavioral response to stress and changes in corticolimbic ECB signaling may contribute to alcohol withdrawal-induced anxiety. Moreover, symptoms of alcohol withdrawal differ between sexes and sexual dimorphism in withdrawal-induced ECB recruitment may be a contributing factor. Herein, we exposed intact male and female rats and ovariectomized (OVX) female rats with or without estradiol (E2) replacement to 6 weeks of chronic intermittent alcohol vapor and measured anxiety-like behavior, ECB content, and ECB-related mRNA in the basolateral amygdala (BLA) and ventromedial prefrontal cortex (vmPFC). Acute alcohol withdrawal increased anxiety-like behavior, produced widespread disturbances in ECB-related mRNA, and reduced anandamide (AEA) content in the BLA and 2-arachidonoylglycerol (2-AG) content in the vmPFC of male, but not female rats. Similar to males, alcohol exposed OVX females showed reductions in Napepld mRNA in the BLA, decreased AEA content in the BLA and vmPFC, and reductions in all ECB-related genes measured in the vmPFC. Importantly, E2 replacement prevented withdrawal-induced alterations in ECB content (but not mRNA) in OVX females, and although alcohol-exposed OVX females failed to exhibit more anxiety compared to their respective control, chronic alcohol exposure abolished the anxiolytic properties of E2 in OVX rats. These data indicate that ovarian sex hormones (but not E2 alone) protect against withdrawal-induced alterations in corticolimbic ECB signaling but do not impart resilience to withdrawal-induced anxiety. Thus, the mechanisms implicated in the manifestation of alcohol withdrawal-induced anxiety are most likely sex-specific. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". PMID- 28554849 TI - Deciding where to attend: Large-scale network mechanisms underlying attention and intention revealed by graph-theoretic analysis. AB - The neural mechanisms by which intentions are transformed into actions remain poorly understood. We investigated the network mechanisms underlying spontaneous voluntary decisions about where to focus visual-spatial attention (willed attention). Graph-theoretic analysis of two independent datasets revealed that regions activated during willed attention form a set of functionally-distinct networks corresponding to the frontoparietal network, the cingulo-opercular network, and the dorsal attention network. Contrasting willed attention with instructed attention (where attention is directed by external cues), we observed that the dorsal anterior cingulate cortex was allied with the dorsal attention network in instructed attention, but shifted connectivity during willed attention to interact with the cingulo-opercular network, which then mediated communications between the frontoparietal network and the dorsal attention network. Behaviorally, greater connectivity in network hubs, including the dorsolateral prefrontal cortex, the dorsal anterior cingulate cortex, and the inferior parietal lobule, was associated with faster reaction times. These results, shown to be consistent across the two independent datasets, uncover the dynamic organization of functionally-distinct networks engaged to support intentional acts. PMID- 28554850 TI - The role of working memory sub-components in food choice and dieting success. AB - Evidence suggests a role for self-reported working memory (WM) in self-reported food intake, but it is not known which WM sub-components are involved. It is also important to consider how individual differences in dietary restraint and disinhibition influence WM and the impact of this on food choice. The current study assessed the relationship between WM sub-components and food choice, using computerised measures of WM sub-components and a direct assessment of food intake. The role of dieting success (measured by restraint and disinhibition) as a distal predictor of food choice that influences food choices via WM, and the role of WM more generally in dieting success were investigated. Female undergraduate students (N = 117, mean age: 18.9 years, mean BMI: 21.6 kg/m2) completed computer tasks assessing three components of WM (updating, phonological loop and visuospatial sketchpad) and a snack food taste-test. Greater visuospatial WM span was associated with a higher (lower) percentage of food intake that was low (high) energy dense. It was also found that unsuccessful dieters (high restraint, high disinhibition) had poorer visuospatial WM span and consumed a lower (higher) percentage of low (high) energy dense food. Visuospatial WM span significantly mediated the relationship between dieting success and percentage of low energy dense food intake. Further, dietary restraint was associated with poorer updating ability, irrespective of disinhibition. These findings suggest that better visuospatial WM is associated with a greater (reduced) preference for low (high) energy dense foods, and that deficits in visuospatial WM may undermine dieting attempts. Future work should assess whether the ability to deal with food cravings mediates the relationship between visuospatial WM and dieting success and investigate how WM may influence the mechanisms underlying behavioural control. PMID- 28554851 TI - Executive function in childhood obesity: Promising intervention strategies to optimize treatment outcomes. AB - Executive functions (EFs) are hypothesized to play a role in the development and maintenance of obesity due to their role in self-regulatory processes that manage energy-balance behaviors. Children with obesity have well-documented deficits in EF, which may impede effectiveness of current, evidence-based treatments. This review examines top-down EF processes (e.g., inhibitory control, working memory, cognitive flexibility), as well as bottom-up automatic processes that interact with EFs (e.g., attentional bias, delay discounting) and their relation to weight loss treatment success in children. It then evaluates EF-related interventions that may improve treatment response. Empirical studies that included an intervention purported to affect EF processes as well as pre-post measurements of EF and/or relative weight in populations ages 19 or younger with overweight/obesity were reviewed. Findings indicate that poorer EF may hinder treatment response. Moreover, there is preliminary evidence that behavioral weight loss intervention and physical activity may positively affect EF and that improvements in EF are related to enhanced weight loss. Finally, novel intervention strategies, such as computer training of core EFs, attention modification programs, and episodic future thinking, show promise in influencing both EFs and EF-related skills and weight. Further research is needed to provide more conclusive evidence of the efficacy of these interventions and additional applications and settings should be considered. PMID- 28554852 TI - Gbeta1 is required for neutrophil migration in zebrafish. AB - Signaling mediated by G protein-coupled receptors (GPCRs) is essential for the migration of cells toward chemoattractants. The recruitment of neutrophils to injured tissues in zebrafish larvae is a useful model for studying neutrophil migration and trafficking in vivo. Indeed, the study of this process led to the discovery that PI3Kgamma is required for the polarity and motility of neutrophils, features that are necessary for the directed migration of these cells to wounds. However, the mechanism by which PI3Kgamma is activated remains to be determined. Here we show that signaling by specifically the heterotrimeric G protein subunit Gbeta1 is critical for neutrophil migration in response to wounding. In embryos treated with small-molecule inhibitors of Gbetagamma signaling, neutrophils failed to migrate to wound sites. Although both the Gbeta1 and Gbeta4 isoforms are expressed in migrating neutrophils, only deficiency for the former (morpholino-based knockdown) interfered with the directed migration of neutrophils towards wounds. The Gbeta1 deficiency also impaired the ability of cells to change cell shape and reduced their general motility, defects that are similar to those in neutrophils deficient for PI3Kgamma. Transplantation assays showed that the requirement for Gbeta1 in neutrophil migration is cell autonomous. Finally, live imaging revealed that Gbeta1 is required for polarized activation of PI3K, and for the actin dynamics that enable neutrophil migration. Collectively, our data indicate that Gbeta1 signaling controls proper neutrophil migration by activating PI3K and modulating actin dynamics. Moreover, they illustrate a role for a specific Gbeta isoform in chemotaxis in vivo. PMID- 28554853 TI - Severe Plasmodium falciparum malaria in the intensive care unit: A 6-year experience in Milano, Italy. AB - BACKGROUND: Severe imported Plasmodium falciparum malaria is a potentially life threatening disease with a reported mortality rate of 5-10% when patients are admitted to the Intensive Care Unit. METHODS: To retrospectively review the clinical aspects, the value of severity predictive scores and the management of patients with severe P. falciparum malaria admitted to an ICU in Milano, Italy between January 2010 and December 2015. RESULTS: Twelve patients were included: seven were male and five female with a median age of 43 years. All were initially treated with intravenous quinine. Median parasitaemia upon admission was 14,5% (range 1-20%). At the time of ICU admission, 3 patients (25%) had 5 or more World Health Organization criteria for severe malaria while another 6 of them developed one or more of the latter during their stay in ICU. Five required mechanical ventilation because of respiratory failure due to ARDS. Four patients required renal replacement therapy. Three patients underwent blood exchange transfusion. All patients survived. CONCLUSIONS: Our retrospective evaluation of adults patients admitted to the ICU with severe imported P. falciparum malaria demonstrated a favourable outcome. Severity predictive scores currently in use probably overestimate the risk of malaria mortality in patients treated in health care systems of high income countries. PMID- 28554854 TI - HGF induces EMT in non-small-cell lung cancer through the hBVR pathway. AB - The epithelial-to-mesenchymal transition (EMT) is a crucial event during non small-cell lung cancer (NSCLC) invasion and metastasis. However, the mechanisms involved in NSCLC EMT have not been fully clarified. Hepatocyte growth factor (HGF) and human biliverdin reductase (hBVR) are reported to contribute to EMT in several diseases. Here, we show that compared with transforming growth factor beta (TGF-beta), fibroblast growth factor (FGF), and epidermal growth factor (EGF), HGF is an important cell factor for EMT in NSCLC cell lines A549 and H460. Met protein, HGF receptors, and hBVR were found to be highly expressed and positively correlated with EMT in NSCLC tissue sections. In addition, HGF and hBVR induced a decrease in epithelial protein marker expression and an increase in mesenchymal protein marker expression as well as increased cellular migration and invasion, indicating that both HGF and hBVR mediate EMT in A549 and H460 cell lines. Furthermore, HGF-induced EMT and migration and invasion in both cell lines was inhibited by si-hBVR. Taken together, our data show that HGF induces EMT in NSCLC through the hBVR pathway. PMID- 28554855 TI - Sleep and the heart: Interoceptive differences linked to poor experiential sleep quality in anxiety and depression. AB - Interoception is the sense through which internal bodily changes are signalled and perceived. Individual differences in interoception are linked to emotional style and vulnerability to affective disorders. Here we test how experiential sleep quality relates to dimensions of interoceptive ability. 180 adults (42 'non clinical' individuals, 138 patients accessing mental health services) rated their quality of sleep before performing tests of cardiac interoception. Poor sleep quality was associated with lower measures of interoceptive performance accuracy, and higher self-report measures of interoceptive sensibility in individuals with diagnoses of depression and/or anxiety. Additionally, poor sleep quality was associated with impaired metacognitive interoceptive awareness in patients with diagnoses of depression (alone or with anxiety). Thus, poor sleep quality, a common early expression of psychological disorder, impacts cardiac interoceptive ability and experience across diagnoses. Sleep disruption can contribute to the expression of affective psychopathology through effects on perceptual and interpretative dimensions of bodily awareness. PMID- 28554856 TI - Beneficial Role of Low-Dose Antithymocyte Globulin in Unrelated Stem Cell Transplantation for Adult Patients with Acquired Severe Aplastic Anemia: Reduction of Graft-versus-Host Disease and Improvement of Graft-versus-Host Disease-Free, Failure-Free Survival Rate. AB - Stem cell transplantation (SCT) from an unrelated donor (URD) is often considered in patients with severe aplastic anemia (SAA) whom immunosuppressive therapy failed and matched sibling donor is not available. To reduce the incidence of graft-versus-host disease (GVHD) in URD SCT, introducting antithymocyte globulin (ATG) into the conditioning regimen has been proposed. Although ATG was shown to play a role in reducing GVHD in a cohort with diverse hematologic diseases, its role in SAA remains uncertain. The aim of this study was to determine the efficacy and toxicity of ATG in URD SCT for adult patients with SAA. We investigated 83 adult patients with SAA who underwent URD SCT between 2003 and 2014. The transplantation strategy consisted of total body irradiation (total 800 cGy) and cyclophosphamide (total 100 mg/kg to 120 mg/kg), followed by tacrolimus and a short-term methotrexate. We divided patients into 2 groups: group 1 (n = 25), which received HLA-matched (8/8) bone marrow (BM) without ATG, and group 2 (n = 58), which received SCT from either an HLA-mismatched donor or peripheral blood (PB). Thereafter, group 2 was subdivided according to ATG use into group 2A (without ATG, n = 26), which served as a historical cohort, and group 2B (with ATG, n = 32). Rabbit ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France) was used in group 2B at a dose of 2.5 mg/kg. The median age of all patients was 30 years (range, 17 to 59 years). The incidence of GVHD was significantly lower in group 2B than group 2A, as demonstrated by the rate of grade II to IV acute GVHD at day 100 (31.2% versus 61.5%, P = .003) and the rate of chronic GVHD at 3 years (21.9% versus 65.4%, P = .002). The overall survival rates of the 3 groups were similar. However, GVHD-free, failure-free survival (GFFS) was significantly higher in group 2B than group 2A (P = .034). A multivariable model identified use of ATG as an independent factor affecting grades II to IV acute GVHD (hazard ratio [HR], 2.902; 95% confidence interval [CI], 1.417 to 5.942; P = .004), chronic GVHD (HR , 3.005; 95% CI, 1.279 to 7.059; P = .012), and GFFS (HR, 2.363; 95% CI, 1.162 to 4.805; P = .014). Toxicities, including infectious complications, were not different among the 3 groups. In conclusion, low-dose ATG (2.5 mg/kg) can reduce the incidence of acute and chronic GVHD and improve the quality of life in patients with SAA who receive stem cells from either an HLA-mismatched donor or PB; importantly, these benefits are achieved without increased toxicity. Furthermore, ATG can be considered in URD SCT from HLA-matched BM cells. PMID- 28554857 TI - Effects of mammarenavirus infection (Wenzhou virus) on the morphology of Rattus exulans. AB - The circulation of mammarenaviruses in rodent populations of the Mekong region has recently been established, with a genetic variant of Wenzhou virus, Cardamones virus, detected in two Rattus species. This study tests the potential teratogenic effects of Wenzhou infection on the development of a Murid rodent, Rattus exulans. Using direct virus detection, morphological records and comparative analyses, a link was demonstrated between host infection status and host morphologies (the spleen irrespective of weight, the skull shape and the cranial cavity volume) at the level of the individual (females only). This study demonstrates that mammarenavirus infections can impact natural host physiology and/or affect developmental processes. The presence of an infecting micro parasite during the development of the rat may lead to a physiological trade-off between immunity and brain size. Alternatively, replication of virus in specialized organs can result in selective morphologic abnormalities and lesions. PMID- 28554858 TI - Influence of low frequency PSEN1 variants on familial Alzheimer's disease risk in Brazil. AB - About 30-70% of familial Alzheimer's disease (AD) cases are related to mutations in presenilin-1 gene (PSEN1). Although the role of mutations and common variants in AD had been extensively investigated, the contribution of rare or low frequency PSEN1 variants on AD risk remains unclear. In the current study, we performed a mutational screening of PSEN1 coding exons and flanking intronic sequences among 53 index cases with familial history of AD from Rio de Janeiro (Brazil). Two missense variants (rs63750592; rs17125721), one rare and a low frequency variant, and two intronic variants (rs3025786; rs165932) were identified. In silico tools were used to predict the functional impact of the variants, revealing no changes in protein functionality by exonic variants. Otherwise, all variants were predicted to alter splicing signals. Prediction results, together with previous reports, suggest a correlation between rs17125721 and AD. So, a subsequent case-control study to evaluate the role of rs1712572 on AD risk was performed in an additional sample of 120 AD sporadic cases and in 149 elderly healthy controls by TaqMan Genotyping Assay. Our data indicates a risk association for rs17125721 in familial AD cases (OR=6.0; IC95%=1.06-33.79; p=0.042). In addition, we tested the multiplicative interaction between allele epsilon4 of the apolipoprotein E (APOE) and rs17125721 and no statistical association was found. Taken together, our findings provide new insight about the genetic relevance of low frequency PSEN1 variants for familial AD development. PMID- 28554859 TI - Microtubule-associated tau contributes to intra-dendritic trafficking of AMPA receptors in multiple ways. AB - Microtubule-associated protein tau has crucial roles not only in the formation of some neurodegenerative disorders but also in normal synaptic functions, although its contributions to these are still unclear. Here, to reveal the influence of tau deletion on trafficking of synaptic receptors, we investigated the distribution of GluA2-containing AMPA-type glutamate receptors (AMPARs) within neuronal dendrites in wild-type and tau-deficient neurons using biochemical and laser-confocal imaging techniques. Under basal conditions, expression of GluA2 at tau-deficient synapses was almost normal; however, its level within dendrites in tau-deficient neurons was greater than that in wild-type neurons. After NMDA treatment, a decrease in GluA2-containing AMPARs at synapses was observed in wild type neurons, but not in tau-deficient neurons. Single-cell imaging of GluA2 within dendrites demonstrated that wild-type neurons, but not tau-deficient neurons, showed enlargement of GluA2 puncta. Interestingly, we also found that NMDA rapidly reduced the number of GluA2 puncta without changing their size in tau-deficient neurons but not wild-type neurons. These results demonstrate the multiple contributions of tau to the maintenance of dynamic AMPAR trafficking within dendrites during both stimulated and unstimulated conditions. PMID- 28554860 TI - Chronic sleep fragmentation exacerbates amyloid beta deposition in Alzheimer's disease model mice. AB - Sleep fragmentation due to intermittent nocturnal arousal resulting in a reduction of total sleep time and sleep efficiency is a common symptom among people with Alzheimer's disease (AD) and elderly people with normal cognitive function. Although epidemiological studies have indicated an association between sleep fragmentation and elevated risk of AD, a relevant disease model to elucidate the underlying mechanisms was lacking owing to technical limitations. Here we successfully induced chronic sleep fragmentation in AD model mice using a recently developed running-wheel-based device and demonstrate that chronic sleep fragmentation increases amyloid beta deposition. Notably, the severity of amyloid beta deposition exhibited a significant positive correlation with the extent of sleep fragmentation. These findings provide a useful contribution to the development of novel treatments that decelerate the disease course of AD in the patients, or decrease the risk of developing AD in healthy elderly people through the improvement of sleep quality. PMID- 28554861 TI - Galantamine alleviates senescence of U87 cells induced by beta-amyloid through decreasing ROS production. AB - Galantamine, which is currently used in the treatment of Alzheimer's disease (AD), has been shown to exert a neuroprotective effect against beta-amyloid (Abeta) peptide-induced toxicity, a critical component involved in the pathogenesis of AD. The aim of this study was to examine the effects of galantamine on proliferation, senescence and ROS production in a U87 cell line treated with Abeta. With the use of a Cell Counting Kit-8 and beta galactosidase staining assay, we observed that galantamine (0.3MUM) pretreatment significantly prevented Abeta1-40-induced cell degradation and senescence. Abeta1-40-induced ROS production and p53 expression were increased as determined by DCF-derived fluorescence using flow cytometry and Western blotting and reduced in response to galantamine pretreatment. Overall, we found that all alterations resulting from Abeta1-40 were reversed by galantamine pretreatment. In addition, we demonstrate that this neuroprotection from galantamine can be blocked by an alpha7 nAChR antagonist. Taken together, the findings of this study provide a better understanding of the mechanisms underlying the protective effects of galantamine, effects which include antioxidative properties. PMID- 28554863 TI - Lysergic acid amide as chemical marker for the total ergot alkaloids in rye flour - Determination by high-performance thin-layer chromatography-fluorescence detection. AB - Ergot alkaloids are generally determined by high-performance liquid chromatography (HPLC) coupled to fluorescence detection (FLD) or mass selective detection, analyzing the individual compounds. However, fast and easy screening methods for the determination of the total ergot alkaloid content are more suitable, since for monitoring only the sum of the alkaloids is relevant. The herein presented screening uses lysergic acid amide (LSA) as chemical marker, formed from ergopeptine alkaloids, and ergometrine for the determination of the total ergot alkaloids in rye with high-performance thin-layer chromatography fluorescence detection (HPTLC-FLD). An ammonium acetate buffered extraction step was followed by liquid-liquid partition for clean-up before the ergopeptine alkaloids were selectively transformed to LSA and analyzed by HPTLC-FLD on silica gel with isopropyl acetate/methanol/water/25% ammonium hydroxide solution (80:10:3.8:1.1, v/v/v/v) as the mobile phase. The enhanced native fluorescence of LSA and unaffected ergometrine was used for quantitation without any interfering matrix. Limits of detection and quantitation were 8 and 26MUg LSA/kg rye, which enables the determination of the total ergot alkaloids far below the applied quality criterion limit for rye. Close to 100% recoveries for different rye flours at relevant spiking levels were obtained. Thus, reliable results were guaranteed, and the fast and efficient screening for the total ergot alkaloids in rye offers a rapid alternative to the HPLC analysis of the individual compounds. PMID- 28554862 TI - A repetitive modular oscillation underlies human brain electric activity. AB - The modular function j, central in the assessment of abstract mathematical problems, describes elliptic, intertwined trajectories that move in the planes of both real and complex numbers. Recent clues suggest that the j-function might display a physical counterpart, equipped with a quantifiable real component and a hidden imaginary one, currently undetectable by our senses and instruments. Here we evaluate whether the real part of the modular function can be spotted in the electric activity of the human brain. We assessed EEGs from five healthy males, eyes-closed and resting state, and superimposed the electric traces with the bidimensional curves predicted by the j-function. We found that the two trajectories matched in more than 85% of cases, independent from the subtending electric rhythm and the electrode location. Therefore, the real part of the j function's peculiar wave is ubiquitously endowed all over normal EEGs paths. We discuss the implications of such correlation in neuroscience and neurology, highlighting how the j-function might stand for the one of the basic oscillations of the brain, and how the still unexplored imaginary part might underlie several physiological and pathological nervous features. PMID- 28554864 TI - Theoretical study of separation and concentration of solutes by closed-loop recycling liquid-liquid chromatography with multiple sample injection. AB - The method of closed-loop recycling counter-current chromatography (CLR CCC) with multiple sample injection is proposed for the separation and concentration of a target component of a mixture. Analytical expressions are developed to describe the CLR CCC separations with multiple sample injection. Several possible implementations of multiple feed injection are analyzed: the feed is injected in each cycle, after every two cycles and in an arbitrary cycle. The application of different modes of multiple feed injection to the separation and concentration of the target component from binary mixtures by CLR CCC has been studied. The results of this study indicate that it is possible to achieve simultaneously both the separation and concentration of the target component. PMID- 28554865 TI - Development of primary standards for mass spectrometry to increase accuracy in quantifying environmental contaminants. AB - Internal standards are essential in electrospray ionization liquid chromatography mass spectrometry (ESI-LC-MS) to correct for systematic error associated with ionization suppression and/or enhancement. A wide array of instrument setups and interfaces has created difficulty in comparing the quantitation of absolute analyte response across laboratories. This communication demonstrates the use of primary standards as operational qualification standards for LC-MS instruments and their comparison with commonly accepted internal standards. In monitoring the performance of internal standards for perfluorinated compounds, potassium hydrogen phthalate (KHP) presented lower inter-day variability in instrument response than a commonly accepted deuterated perfluorinated internal standard (d3 PFOS), with percent relative standard deviations less than or equal to 6%. The inter-day precision of KHP was greater than d3-PFOS over a 28-day monitoring of perfluorooctanesulfonic acid (PFOS), across concentrations ranging from 0 to 100MUg/L. The primary standard trometamol (Trizma) performed as well as known internal standards simeton and tris (2-chloroisopropyl) phosphate (TCPP), with intra-day precision of Trizma response as low as 7% RSD on day 28. The inter-day precision of Trizma response was found to be greater than simeton and TCPP, across concentrations of neonicotinoids ranging from 1 to 100MUg/L. This study explores the potential of primary standards to be incorporated into LC-MS/MS methodology to improve the quantitative accuracy in environmental contaminant analysis. PMID- 28554866 TI - Two-structured solid particle model for predicting and analyzing supercritical extraction performance. AB - Solid extraction process, using the supercritical fluid, is a modern science and technology, which has come in vogue regarding its considerable advantages. In the present article, a new and comprehensive model is presented for predicting the performance and separation yield of the supercritical extraction process. The base of process modeling is partial differential mass balances. In the proposed model, the solid particles are considered twofold: (a) particles with intact structure, (b) particles with destructed structure. A distinct mass transfer coefficient has been used for extraction of each part of solid particles to express different extraction regimes and to evaluate the process accurately (internal mass transfer coefficient was used for the intact-structure particles and external mass transfer coefficient was employed for the destructed-structure particles). In order to evaluate and validate the proposed model, the obtained results from simulations were compared with two series of available experimental data for extraction of chamomile extract with supercritical carbon dioxide, which had an excellent agreement. This is indicative of high potentiality of the model in predicting the extraction process, precisely. In the following, the effect of major parameters on supercritical extraction process, like pressure, temperature, supercritical fluid flow rate, and the size of solid particles was evaluated. The model can be used as a superb starting point for scientific and experimental applications. PMID- 28554867 TI - Ionic strength-dependent changes in tentacular ion exchangers with variable ligand density. II. Functional properties. AB - The effect of ligand density was studied on protein adsorption and transport behavior in tentacular cation-exchange sorbents at different ionic strengths. Results were obtained for lysozyme, lactoferrin and a monoclonal antibody (mAb) in order to examine the effects of protein size and charge. The combination of ligand density and ionic strength results in extensive variability of the static and dynamic binding capacities, transport rate and binding affinity of the proteins. Uptake and elution experiments were performed to quantify the transport behavior of selected proteins, specifically to estimate intraparticle protein diffusivities. The observed trend of decreasing uptake diffusivities with an increase in ligand density was correlated to structural properties of the ligand density variants, particularly the accessible porosity. Increasing the ionic strength of the equilibration buffer led to enhanced mass transfer during uptake, independent of the transport model used, and specifically for larger proteins like lactoferrin and mAb, the most significant effects were evident in the sorbent of the highest ligand density. For lysozyme, higher ligand density leads to higher static and dynamic binding capacities whereas for lactoferrin and the mAb, the binding capacity is a complex function of accessible porosity due to ionic strength-dependent changes. Ligand density has a less pronounced effect on the elution rate, presumably due to ionic strength-dependent changes in the pore architecture of the sorbents. PMID- 28554868 TI - A novel deletion of SNURF/SNRPN exon 1 in a patient with Prader-Willi-like phenotype. AB - Here we report the smallest deletion involving SNURF/SNRPN that causes major symptoms of Prader-Willi syndrome (PWS), including hypotonia, dysmorphic features, intellectual disability, and obesity. A female patient with the aforementioned and additional features was referred to the Mayo Clinic Cytogenetics laboratory for genetic testing. Chromosomal microarray analysis and subsequent Sanger sequencing identified a de novo 6.4 kb deletion at 15q11.2, containing exon 1 of the SNURF gene and exon 1 of the shortest isoform of the SNRPN gene. SNURF/SNRPN exon 1, which is methylated on the silent maternal allele, is associated with acetylated histones on the expressed paternal allele. This region also overlaps with the PWS-imprinting center (IC). Subsequent molecular methylation analysis was performed using methylation-specific MLPA (MS MLPA), which characterized that the deletion of SNURF/SNRPN exon 1 was paternal in origin, consistent with the PWS-like phenotype. Since SNURF/SNRPN gene and the PWS-IC are known to regulate snoRNAs, it is likely that the PWS-like phenotype observed in patients with paternal SNURF/SNRPN deletion is due to the disrupted expression of SNORD116 snoRNAs. PMID- 28554869 TI - Pathogenicity of three genetically diverse strains of PRRSV Type 1 in specific pathogen free pigs. AB - Studies from Eastern European countries proved that porcine reproductive and respiratory syndrome virus Type 1 (PRRSV-1) harbours high genetic diversity and that genetically divergent subtypes 2-4 circulate in this area. In the present study, we compared the pathogenicity of two different PRRSV-1 subtype 2 strains and a strain representing PRRSV-1 subtype 1. Four groups of 8-week-old specific pathogen free pigs were either infected with subtype 2 strain ILI6, subtype 2 strain or BOR59, subtype 1 strain 18794, or mock inoculated. The most pronounced clinical signs were observed in pigs infected with BOR59. Pigs from both subtype 2 strain infected groups exhibited significantly elevated mean body temperatures on DPI 2 compared to the other two groups, the difference remaining significant up to DPI 13 for the BOR59 group, only. The pigs in the latter group also displayed significantly highest levels of early viremia together with the most rapid APP response. Overall, the results indicated that BOR59 strain can be considered a highly pathogenic strain, similarly to subtype 3 strains Lena and SU1-bel, while the virulence of the other subtype 2 strain ILI6 was intermediate between BOR59 and subtype 1 strain. PMID- 28554870 TI - Anti-inflammatory effects and corresponding mechanisms of cirsimaritin extracted from Cirsium japonicum var. maackii Maxim. AB - In this study, we investigated the anti-inflammatory effects and mechanisms of cirsimaritin isolated from an ethanol extract of the aerial parts of Cirsium japonicum var. maackii Maxim. using RAW264.7 cells. The extract and its flavonoid cirsimaritin inhibited nitric oxide (NO) production and inducible nitric oxide synthase expression in RAW264.7 cells. Cirsimaritin inhibited interleukin-6, tumor necrosis factor-alpha, and NO production in a concentration-dependent manner in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. From a western blot study, pretreatment with cirsimaritin inhibited phosphorylation/degradation of IkappaBalpha and phosphorylation of Akt in LPS-stimulated RAW264.7 cells. Moreover, cirsimaritin suppressed activation of LPS-induced transcription factors, such as c-fos and signal transducer and activator of transcription 3 (STAT3), in RAW264.7 cells. Collectively, these results show that cirsimaritin possesses anti-inflammatory activity, which is regulated by inhibition of c-fos and STAT3 phosphorylation in RAW264.7 cells. PMID- 28554872 TI - Safety Window for the Volar Needle Approach for Examination of the Pronator Quadratus Using Ultrasonography. AB - OBJECTIVES: To investigate pronator quadratus (PQ) anatomy and determine the proper volar needle insertion point based on landmarks, the tip of the ulnar styloid (an imaginary vertical line passing the tip of the ulnar styloid process [U line]), and the ulnar margin of the palmaris longus tendon (uPL) using ultrasonography. DESIGN: Descriptive study. SETTING: Department of physical medicine and rehabilitation. PARTICIPANTS: Participants between 20 and 60 years without any diseases. (N=25; 13 men, 12 women; 50 forearms). INTERVENTIONS: Ultrasonography. MAIN OUTCOME MEASURES: The proximal and distal volar surface points of origin, the proximal and distal insertion sites, and the midpoint of the PQ (PQ_M) were determined. The distance of each of the PQ surface indices from the U line was measured, and the probe was positioned at the level of PQ_M parallel to the U line. The relative distances from the vertical surface points of the median nerve and ulnar artery to the uPL were measured. RESULTS: The mean age and body mass index were 32.7+/-10.4 years and 21.98+/-2.83kg/m2. The PQ_M was located at a mean distance of 2.63+/-0.35cm proximal from the U line (men 2.79+/-0.37cm and women 2.45+/-0.21cm; P<.05). The mean safety window for the volar approach was 0.72+/-1.8cm toward the radial side and 1.51+/-0.30cm toward the ulnar side from the uPL. The PQ was at a mean depth of 1.30+/-0.19cm from the skin and had a mean thickness of 1.19+/-0.24cm at the level of PQ_M. The distance between the U line and the proximal edge of the PQ, as well as the PQ thickness, was greater in men than in women. CONCLUSIONS: The volar approach for needle electromyographic examination of the PQ can be performed precisely and safely. PMID- 28554871 TI - Design, synthesis of novel furan appended benzothiazepine derivatives and in vitro biological evaluation as potent VRV-PL-8a and H+/K+ ATPase inhibitors. AB - A series of new of furan derivatised [1,4] benzothiazepine analogues were synthesized starting from 1-(furan-2-yl)ethanone. 1-(Furan-2-yl)ethanone was converted into chalcones by its reaction with various aromatic aldehydes, then were reacted with 2-aminobenzenethiol in acidic conditions to obtain the title compounds in good yields. The synthesized new compounds were characterized by 1H NMR, 13C NMR, Mass spectral studies and elemental analyses. All the new compounds were evaluated for their in vitro VRV-PL-8a and H+/K+ ATPase inhibitor properties. Preliminary studies revealed that, some molecules amongst the designed series showed promising VRV-PL-8a and H+/K+ ATPase inhibitor properties. Further, rigid body docking studies were performed to understand possible docking sites of the molecules on the target proteins and the mode of binding. This finding presents a promising series of lead molecules that can serve as prototypes for the treatment of inflammatory related disorder that can mitigate the ulcer inducing side effect shown by other NSAIDs. PMID- 28554873 TI - Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review. AB - OBJECTIVE: To evaluate the effect of exercise and cognitive training on falls reduction and on factors known to be associated with falls among community dwelling older adults with mild cognitive impairment (MCI). DATA SOURCES: Seven databases (PubMed, CINAHL, Cochrane Library, Web of Science, ProQuest, ProQuest Dissertations and Theses, Digital Dissertation Consortium) and reference lists of pertinent articles were searched. STUDY SELECTION: Randomized controlled trials (RCTs) on the effect of exercise, cognitive training, or a combination of both on falls and factors associated with falls such as balance, lower limb muscle strength, gait, and cognitive function among community-dwelling older adults with MCI were included. DATA EXTRACTION: Data were extracted using the modified Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) tool. Study quality was assessed using the JBI-MAStARI appraisal instrument. DATA SYNTHESIS: Seventeen RCTs (1679 participants; mean age +/- SD, 74.4+/-2.4y) were included. Exercise improved gait speed and global cognitive function in MCI; both are known factors associated with falls. Cognitive training alone had no significant effect on cognitive function, while combined exercise and cognitive training improved balance in MCI. Neither fall rate nor the number of fallers was reported in any of the studies included. CONCLUSIONS: This review suggests that exercise, and combined exercise and cognitive training improve specific factors associated with falls such as gait speed, cognitive function, and balance in MCI. Further research on the direct effect of exercise and cognitive training on the fall rate and incidence in older adults with MCI with larger sample sizes is highly recommended. PMID- 28554874 TI - Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling. AB - BACKGROUND & AIMS: Although obesity is a risk factor for acute liver failure, the pathogenic mechanisms are not yet fully understood. High cholesterol (HC) intake, which often underlies obesity, is suggested to play a role in the mechanism. We aimed to elucidate the effect of a HC diet on acetaminophen-induced acute liver injury, the most frequent cause of acute liver failure in the USA. METHODS: C57BL/6 Toll-like receptor 9 (TLR9) knockout (Tlr9-/-) mice and their Tlr9+/+ littermates were fed an HC diet for fourweeks and then treated with acetaminophen. Liver sinusoidal endothelial cells (LSECs) were isolated from the mice for in vivo and in vitro analyses. RESULTS: The HC diet exacerbated acetaminophen-induced acute liver injury in a TLR9/inflammasome pathway-dependent manner. LSECs played a major role in the cholesterol loading-induced exacerbation. The accumulation of free cholesterol in the endolysosomes in LSECs enhanced TLR9-mediated signaling, thereby exacerbating the pathology of acetaminophen-induced liver injury through the activation of the TLR9/inflammasome pathway. The accumulation of free cholesterol in LSEC endolysosomes induced a dysfunction of the Rab7 membrane trafficking recycling mechanism, thus disrupting the transport of TLR9 from late endosomes to the lysosomes. Consequently, the level of active TLR9 in the late endosomes increased, thereby enhancing TLR9 signaling in LSECs. CONCLUSIONS: HC intake exaggerated acetaminophen-induced acute liver injury via free cholesterol accumulation in LSECs, demonstrating a novel role of free cholesterol as a metabolic factor in TLR9 signal regulation and pathologies of acetaminophen induced liver injury. Therapeutic approaches may target this pathway. Lay summary: High cholesterol intake exacerbated acetaminophen-induced acute liver injury via the accumulation of free cholesterol in the endolysosomes of liver sinusoidal endothelial cells. This accumulation enhanced Toll-like receptor 9 signaling via impairment of its membrane trafficking mechanism. Thus, free cholesterol accumulation, as an underlying metabolic factor, exacerbated the pathology of acetaminophen-induced liver injury through activation of the TLR9/inflammasome pathway. PMID- 28554876 TI - Heart failure and endothelial nitric oxide synthase G894T gene polymorphism frequency variations within ancestries. AB - The G894T polymorphism in endothelial nitric oxide synthase enzyme gene plays an important role in heart failure (HF) and its frequency varies among populations. We investigated this association in highly admixed samples in terms of ancestry. The cohort included 210 HF patients and 106 healthy individuals. Self-reported race and NYHA class were analyzed for HF patients. G894T polymorphism was analyzed by polymerase chain reaction (PCR) and by restriction fragment length polymorphism technique. Ancestry was estimated using a PCR reaction containing 46 autosomal ancestry informative markers and an analysis by capillary electrophoresis. The GG homozygous genotype had a higher frequency in HF patients (63.8%) than in healthy individuals (48.1%), showing an increased chance (odds ratio 1.90, 95% confidence interval 1.18-3.05). The ancestry profiles in patients and controls were similar, with a major European contribution (57.1% and 63.2%), followed by African (30.2% and 24.0%) and Native American (12.7% and 12.8%), without a significant difference between both samples (p = 0.28). The GG genotype is associated to HF prognosis, and this association remains present in highly admixed sample groups. PMID- 28554875 TI - CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury. AB - BACKGROUND & AIMS: The severity of sepsis can be linked to excessive inflammatory responses resulting in hepatic injury. P2X7 receptor activation by extracellular ATP (eATP) exacerbates inflammation by augmenting cytokine production; while CD39 (ENTPD1) scavenges eATP to generate adenosine, thereby limiting P2X7 activation and resulting in A2A receptor stimulation. We aim to determine how the functional interaction of P2X7 receptor and CD39 control the macrophage response, and consequently impact on sepsis and liver injury. METHODS: Sepsis was induced by cecal ligation and puncture in C57BL/6 wild-type (WT) and CD39-/- mice. Several in vitro assays were performed using peritoneal or bone marrow derived macrophages to determine CD39 ectonucleotidase activity and its role in sepsis induced liver injury. RESULTS: CD39 expression in macrophages limits ATP-P2X7 receptor pro-inflammatory signaling. P2X7 receptor paradoxically boosts CD39 activity. Inhibition and/or deletion of P2X7 receptor in LPS-primed macrophages attenuates cytokine production and inflammatory signaling as well as preventing ATP-induced increases in CD39 activity. Septic CD39-/- mice exhibit higher levels of inflammatory cytokines and show more pronounced liver injury than WT mice. Pharmacological P2X7 blockade largely prevents tissue damage, cell apoptosis, cytokine production, and the activation of inflammatory signaling pathways in the liver from septic WT, while only attenuating these outcomes in CD39-/- mice. Furthermore, the combination of P2X7 blockade with adenosine A2A receptor stimulation completely inhibits cytokine production, the activation of inflammatory signaling pathways, and protects septic CD39-/- mice against liver injury. CONCLUSIONS: CD39 attenuates sepsis-associated liver injury by scavenging eATP and ultimately generating adenosine. We propose boosting of CD39 would suppress P2X7 responses and trigger adenosinergic signaling to limit systemic inflammation and restore liver homeostasis during the acute phase of sepsis. Lay summary: CD39 expression in macrophages limits P2X7-mediated pro-inflammatory responses, scavenging extracellular ATP and ultimately generating adenosine. CD39 genetic deletion exacerbates sepsis-induced experimental liver injury. Combinations of a P2X7 antagonist and adenosine A2A receptor agonist are hepatoprotective during the acute phase of abdominal sepsis. PMID- 28554877 TI - Comparison of Ecological Momentary Assessment Versus Direct Measurement of E Cigarette Use With a Bluetooth-Enabled E-Cigarette: A Pilot Study. AB - BACKGROUND: Assessing the frequency and intensity of e-cigarette use presents special challenges beyond those posed by cigarette use. Accurate measurement of e cigarette consumption, puff duration, and the stability of these measures over time will be informative for estimating the behavioral and health effects of e cigarette use. OBJECTIVE: The purpose of this pilot study was to compare the accuracy of self-reported e-cigarette puff counts collected via ecological momentary assessment (EMA) to objective puff count data collected by a Bluetooth enabled e-cigarette device and to examine the feasibility and acceptability of using a second-generation e-cigarette among adult smokers. METHODS: A total of 5 adult smokers were enrolled in a longitudinal parent study assessing how e cigarette use affects cigarette use among e-cigarette-naive smokers. Using a text message-based EMA system, participants reported e-cigarette puffs for 2 weeks. Participants were also given a Bluetooth-enabled e-cigarette (Smokio) that passively collected puff counts and puff duration. Comparisons between mean reports of Smokio (device-report) and EMA (self-report) use were evaluated using paired t tests. Correlation and agreement between device- and self-reports were evaluated using Pearson correlation and the concordance correlation coefficient (CCC), respectively. A linear mixed effect model was used to determine the fixed effect of timing and Smokio-reported daily puffs on report accuracy. We examined the relationship between time of day and reporting accuracy using Tukey's test for multiple pairwise comparisons. RESULTS: A total of 5 African American participants, 4 men and 1 woman, who ranged in age from 24 to 59 years completed the study, resulting in 5180 observations (device-report) of e-cigarette use. At baseline, participants reported smoking for 5 to 25 years and consumed a mean of 7 to 13 cigarettes per day (CPD); 4 smoked within 30 minutes of waking. At the 30 day follow-up, CPD range decreased to 1 to 3 cigarettes; 4 participants reported past 7-day e-cigarette use, and 1 participant reported no cigarette smoking in the past 7 days. Over 2 weeks of e-cigarette use, participants took an average of 1074 e-cigarette (SD 779.0) puffs per person as captured by the device reports. Each participant took a mean of 75.0 (SD 58.8) puffs per day, with each puff lasting an average of 3.6 (SD 2.4) seconds. Device reports captured an average of 33.3 (SD 47.8) more puffs per person per day than the self-reported e-cigarette puffs. In 87% of days, participants underestimated the number of puffs they had taken on the Smokio. There was significant moderate correlation (r=.47, P<.001) but poor agreement (pc=0.31, 95% CI 0.15-0.46) between the device- and self reported data. Reporting accuracy was affected by amount and timing of e cigarette use. CONCLUSIONS: Compared to self-reported e-cigarette use, the Bluetooth-enabled device captured significantly more e-cigarette use and allowed for examination of puff duration in addition to puff counts. A Bluetooth-enabled e-cigarette is a powerful and feasible tool for objective collection of e cigarette use behavior in the real world. PMID- 28554879 TI - A Smartphone-Based Approach for Triage of Human Papillomavirus-Positive Sub Saharan African Women: A Prospective Study. AB - BACKGROUND: Sub-Saharan African countries are marked by a high incidence of cervical cancer. Madagascar ranks 11th among the countries with the highest cervical cancer incidence worldwide. OBJECTIVE: The aim of the study was to evaluate the performances of digital smartphone-based visual inspection with acetic acid (D-VIA) and Lugol's iodine (D-VILI) for diagnosing cervical precancer and cancer. METHODS: Human papillomavirus (HPV)-positive women recruited through a cervical screening campaign had D-VIA and D-VILI examinations with endocervical curettage (ECC) and cervical biopsy. Three images were captured for each woman (native, D-VIA, D-VILI) using a smartphone camera. The images were randomly coded and distributed on 2 online databases (Google Forms). The D-VIA form included native and D-VIA images, and the D-VILI form included native and D-VILI images. Pathological cases were defined as cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Physicians rated the images as non-pathological or pathological. Using the ECC and cervical biopsy results as references, the sensitivity and specificity of D-VIA and D-VILI examinations for each and all physicians were calculated. RESULTS: Altogether, 15 clinicians assessed 240 images. Sensitivity was higher for the D-VIA interpretations (94.1%; 95% CI 81.6-98.3) than for the D VILI interpretations (78.8%; 95% CI 54.1-92.1; P=.009). In contrast, the specificity was higher for the D-VILI interpretations (56.4%; 95% CI 38.3-72.9) than for the D-VIA interpretations (50.4%; 95% CI 35.9-64.8; P=.005). CONCLUSION: Smartphone-based image for triage of HPV-positive women is more accurate for detecting CIN2+ lesions with D-VIA than D-VILI, although with a small loss of specificity. PMID- 28554880 TI - Diversity in eMental Health Practice: An Exploratory Qualitative Study of Aboriginal and Torres Strait Islander Service Providers. AB - BACKGROUND: In Australia, mental health services are undergoing major systemic reform with eMental Health (eMH) embedded in proposed service models for all but those with severe mental illness. Aboriginal and Torres Strait Islander service providers have been targeted as a national priority for training and implementation of eMH into service delivery. Implementation studies on technology uptake in health workforces identify complex and interconnected variables that influence how individual practitioners integrate new technologies into their practice. To date there are only two implementation studies that focus on eMH and Aboriginal and Torres Strait Islander service providers. They suggest that the implementation of eMH in the context of Aboriginal and Torres Strait Islander populations may be different from the implementation of eMH with allied health professionals and mainstream health services. OBJECTIVE: The objective of this study is to investigate how Aboriginal and Torres Strait Islander service providers in one regional area of Australia used eMH resources in their practice following an eMH training program and to determine what types of eMH resources they used. METHODS: Individual semistructured qualitative interviews were conducted with a purposive sample of 16 Aboriginal and Torres Strait Islander service providers. Interviews were co-conducted by one indigenous and one non indigenous interviewer. A sample of transcripts were coded and thematically analyzed by each interviewer and then peer reviewed. Consensus codes were then applied to all transcripts and themes identified. RESULTS: It was found that 9 of the 16 service providers were implementing eMH resources into their routine practice. The findings demonstrate that participants used eMH resources for supporting social inclusion, informing and educating, assessment, case planning and management, referral, responding to crises, and self and family care. They chose a variety of types of eMH resources to use with their clients, both culturally specific and mainstream. While they referred clients to online treatment programs, they used only eMH resources designed for mobile devices in their face-to-face contact with clients. CONCLUSIONS: This paper provides Aboriginal and Torres Strait islander service providers and the eMH field with findings that may inform and guide the implementation of eMH resources. It may help policy developers locate this workforce within broader service provision planning for eMH. The findings could, with adaptation, have wider application to other workforces who work with Aboriginal and Torres Strait Islander clients. The findings highlight the importance of identifying and addressing the particular needs of minority groups for eMH services and resources. PMID- 28554878 TI - Adherence to AHA Guidelines When Adapted for Augmented Reality Glasses for Assisted Pediatric Cardiopulmonary Resuscitation: A Randomized Controlled Trial. AB - BACKGROUND: The American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) are nowadays recognized as the world's most authoritative resuscitation guidelines. Adherence to these guidelines optimizes the management of critically ill patients and increases their chances of survival after cardiac arrest. Despite their availability, suboptimal quality of CPR is still common. Currently, the median hospital survival rate after pediatric in-hospital cardiac arrest is 36%, whereas it falls below 10% for out-of-hospital cardiac arrest. Among emerging information technologies and devices able to support caregivers during resuscitation and increase adherence to AHA guidelines, augmented reality (AR) glasses have not yet been assessed. In order to assess their potential, we adapted AHA Pediatric Advanced Life Support (PALS) guidelines for AR glasses. OBJECTIVE: The study aimed to determine whether adapting AHA guidelines for AR glasses increased adherence by reducing deviation and time to initiation of critical life-saving maneuvers during pediatric CPR when compared with the use of PALS pocket reference cards. METHODS: We conducted a randomized controlled trial with two parallel groups of voluntary pediatric residents, comparing AR glasses to PALS pocket reference cards during a simulation-based pediatric cardiac arrest scenario-pulseless ventricular tachycardia (pVT). The primary outcome was the elapsed time in seconds in each allocation group, from onset of pVT to the first defibrillation attempt. Secondary outcomes were time elapsed to (1) initiation of chest compression, (2) subsequent defibrillation attempts, and (3) administration of drugs, as well as the time intervals between defibrillation attempts and drug doses, shock doses, and number of shocks. All these outcomes were assessed for deviation from AHA guidelines. RESULTS: Twenty residents were randomized into 2 groups. Time to first defibrillation attempt (mean: 146 s) and adherence to AHA guidelines in terms of time to other critical resuscitation endpoints and drug dose delivery were not improved using AR glasses. However, errors and deviations were significantly reduced in terms of defibrillation doses when compared with the use of the PALS pocket reference cards. In a total of 40 defibrillation attempts, residents not wearing AR glasses used wrong doses in 65% (26/40) of cases, including 21 shock overdoses >100 J, for a cumulative defibrillation dose of 18.7 Joules per kg. These errors were reduced by 53% (21/40, P<.001) and cumulative defibrillation dose by 37% (5.14/14, P=.001) with AR glasses. CONCLUSIONS: AR glasses did not decrease time to first defibrillation attempt and other critical resuscitation endpoints when compared with PALS pocket cards. However, they improved adherence and performance among residents in terms of administering the defibrillation doses set by AHA. PMID- 28554881 TI - Incorporation of a Stress Reducing Mobile App in the Care of Patients With Type 2 Diabetes: A Prospective Study. AB - BACKGROUND: Severe and sustained emotional stress creates a physiological burden through increased sympathetic activity and higher energy demand. This may lead to increased oxidative stress and development of the metabolic syndrome. Emotional stress has been shown to contribute to the onset, progression, and control of type 2 diabetes (T2D). Stress management and biofeedback assisted relaxation have been shown to improve glycemic control. Use of a mobile app for stress management may enhance the scalability of such an approach. OBJECTIVE: The aim of this study was to assess the effect of using a mobile app of biofeedback-assisted relaxation on weight, blood pressure (BP), and glycemic measures of patients with T2D. METHODS: Adult patients with T2D and inadequate glycemic control (hemoglobin A1c [HbA1c]>7.5%) were recruited from the outpatient diabetes clinic. Baseline weight, BP, HbA1c, fasting plasma glucose (FPG), triglycerides (TG), and 7-point self-monitoring of blood glucose were measured. Patients were provided with a stress reducing biofeedback mobile app and instructed to use it 3 times a day. The mobile app-Serenita-is an interactive relaxation app based on acquiring a photoplethysmography signal from the mobile phone's camera lens, where the user places his finger. The app collects information regarding the user's blood flow, heart rate, and heart rate variability and provides real-time feedback and individualized breathing instructions in order to modulate the stress level. All clinical and biochemical measures were repeated at 8 and 16 weeks of the study. The primary outcome was changes in measures at 8 weeks. RESULTS: Seven patients completed 8 weeks of the study and 4 completed 16 weeks. At week 8, weight dropped by an average of 4.0 Kg (SD 4.3), systolic BP by 8.6 mmHg (SD 18.6), HbA1c by 1.3% (SD 1.6), FPG by 4.3 mmol/l (4.2), and serum TG were unchanged. CONCLUSIONS: Stress reduction using a mobile app based on biofeedback may improve glycemic control, weight, and BP. PMID- 28554883 TI - Streptococcus bovis prosthetic valve endocarditis associated with silent colonic carcinoma. AB - A 75-year-old woman was admitted to our hospital with a 3-month history of fever. Of note, she had a bioprosthetic mitral valve replacement 1 year prior to admission. Streptococcus bovis was isolated from three sets of blood cultures. An echocardiogram showed a flickering mass attached to the bioprosthesis. Her blood culture became sterile by the fourth day of ceftriaxone therapy. In spite of the absence of gastrointestinal symptoms, screening colonoscopy revealed an invasive colonic adenocarcinoma. The association linking S. bovis endocarditis and colonic tumours is well recognised. However, despite early reports of this association by Klein et al in 1979, a large number of practising physicians remain unaware of this phenomenon. This lack of awareness results in lost opportunities for early diagnosis and, consequently, improved outcome in such patients. Our report emphasises this association in an area with a low incidence of S. bovis endocarditis. PMID- 28554884 TI - Ichthyosis linearis circumflexa with bamboo hair: challenges in the diagnosis and management. AB - A 15-year-old boy had persistent and refractory erythroderma since early childhood. His parents noticed polycyclic skin lesions and hair fragility around the age of 5 years. He was treated by a local untrained practitioner for more than 3 years without any significant improvement, and he developed weight gain, thinning of skin, muscle weakness and growth retardation. He was evaluated in 2015 and found to have iatrogenic Cushing's disease with severe skeletal complications and pituitary-adrenal-gonadal suppression, which persisted despite gradual withdrawal of steroids. PMID- 28554886 TI - A rare case of bilateral lens dislocations. PMID- 28554882 TI - Diagnosis, Prevalence, Awareness, Treatment, Prevention, and Control of Hypertension in Cameroon: Protocol for a Systematic Review and Meta-Analysis of Clinic-Based and Community-Based Studies. AB - BACKGROUND: Hypertension holds a unique place in population health and health care because it is the leading cause of cardiovascular disease and the most common noncommunicable condition seen in primary care worldwide. Without effective prevention and control, raised blood pressure significantly increases the risk of stroke, myocardial infarction, chronic kidney disease, heart failure, dementia, renal failure, and blindness. There is an urgent need for stakeholders including individuals and families-across the health system, researchers, and decision makers to work collaboratively for improving prevention, screening and detection, diagnosis and evaluation, awareness, treatment and medication adherence, management, and control for people with or at high risk for hypertension. Meeting this need will help reduce the burden of hypertension related disease, prevent complications, and reduce the need for hospitalization, costly interventions, and premature deaths. OBJECTIVE: This review aims to synthesize evidence on the epidemiological landscape and control of hypertension in Cameroon, and to identify elements that could potentially inform interventions to combat hypertension in this setting and elsewhere in sub-Saharan Africa. METHODS: The full search process will involve several steps, including selecting relevant databases, keywords, and Medical Subject Headings (MeSH); searching for relevant studies from the selected databases; searching OpenGrey and the Grey Literature Report for gray literature; hand searching in Google Scholar; and soliciting missed publications (if any) from relevant authors. We will select qualitative, quantitative, or mixed-methods studies with data on the epidemiology and control of hypertension in Cameroon. We will include published literature in French or English from electronic databases up to December 31, 2016, and involving adults aged 18 years or older. Both facility and population-based studies on hypertension will be included. Two reviewers of the team will independently search, screen, extract data, and assess the quality of selected studies using suitable tools. Selected studies will be analyzed by narrative synthesis, meta-analysis, or both, depending on the nature of the data retrieved in line with the review objectives. RESULTS: This review is part of an ongoing research program on disease prevention and control in the context of the dual burden of communicable and noncommunicable diseases in Africa. The first results are expected in 2017. CONCLUSIONS: This review will provide a comprehensive assessment of the burden of hypertension and control measures that have been designed and implemented in Cameroon. Findings will form the knowledge base relevant to stakeholders across the health system and researchers who are involved in hypertension prevention and control in the community and clinic settings in Cameroon, as a yardstick for similar African countries. TRIAL REGISTRATION: PROSPERO registration number: CRD42017054950; http://www.crd.york.ac.uk/PROSPERO/ display_record.asp?ID=CRD42017054950 (Archived by WebCite at http://www.webcitation.org/6qYSjt9Jc). PMID- 28554885 TI - Osteolytic lesions: osteitis fibrosa cystica in the setting of severe primary hyperparathyroidism. AB - A 58-year-old female patient presented with several weeks history of significant bilateral knee pain. Initial knee radiographs demonstrated lucencies of the bony cortex while extensive osteolytic lesions on a routine chest radiograph were suggestive of multiple myeloma or bony metastases. Biochemical investigation revealed primary hyperparathyroidism with renal insufficiency. A parathyroid adenoma was demonstrated on a neck ultrasound and sestamibi scan and subsequently confirmed by histology. We illustrate a case of primary hyperparathyroidism with osteitis fibrosa cystica and brown tumours which were initially mistaken for malignant disease. PMID- 28554887 TI - Portomesenteric venous thrombosis complicated by a haemorrhagic shock: a rare complication of laparoscopic gastrectomy. AB - Portomesenteric venous thrombosis is a rare complication reported in only a few cases involving laparoscopic bariatric surgery. We report a case of a 44-year-old woman who presented 14 days after recent laparoscopic sleeve gastrectomy with the chief complaint of abdominal pain and associated nausea. Abdominal CT demonstrated thrombi in her superior mesenteric, portal and splenic veins. She was initiated on therapeutic heparin but developed haemorrhagic shock shortly afterwards. Subsequent CT angiogram failed to localise the source of her haemorrhage. Her haemodynamic instability improved following a 6-day intensive care unit stay requiring vasopressive agents and blood transfusions. Further hypercoagulable workup revealed that she was a heterozygous carrier of the prothrombin gene mutation, and thus started on lifelong oral anticoagulation. PMID- 28554889 TI - Development of Glutamatergic Proteins in Human Visual Cortex across the Lifespan. AB - Traditionally, human primary visual cortex (V1) has been thought to mature within the first few years of life, based on anatomical studies of synapse formation, and establishment of intracortical and intercortical connections. Human vision, however, develops well beyond the first few years. Previously, we found prolonged development of some GABAergic proteins in human V1 (Pinto et al., 2010). Yet as >80% of synapses in V1 are excitatory, it remains unanswered whether the majority of synapses regulating experience-dependent plasticity and receptive field properties develop late, like their inhibitory counterparts. To address this question, we used Western blotting of postmortem tissue from human V1 (12 female, 18 male) covering a range of ages. Then we quantified a set of postsynaptic glutamatergic proteins (PSD-95, GluA2, GluN1, GluN2A, GluN2B), calculated indices for functional pairs that are developmentally regulated (GluA2:GluN1; GluN2A:GluN2B), and determined interindividual variability. We found early loss of GluN1, prolonged development of PSD-95 and GluA2 into late childhood, protracted development of GluN2A until ~40 years, and dramatic loss of GluN2A in aging. The GluA2:GluN1 index switched at ~1 year, but the GluN2A:GluN2B index continued to shift until ~40 year before changing back to GluN2B in aging. We also identified young childhood as a stage of heightened interindividual variability. The changes show that human V1 develops gradually through a series of five orchestrated stages, making it likely that V1 participates in visual development and plasticity across the lifespan.SIGNIFICANCE STATEMENT Anatomical structure of human V1 appears to mature early, but vision changes across the lifespan. This discrepancy has fostered two hypotheses: either other aspects of V1 continue changing, or later changes in visual perception depend on extrastriate areas. Previously, we showed that some GABAergic synaptic proteins change across the lifespan, but most synapses in V1 are excitatory leaving unanswered how they change. So we studied expression of glutamatergic proteins in human V1 to determine their development. Here we report prolonged maturation of glutamatergic proteins, with five stages that map onto life-long changes in human visual perception. Thus, the apparent discrepancy between development of structure and function may be explained by life-long synaptic changes in human V1. PMID- 28554890 TI - Atypical aspirates of the breast: a dilemma in current cytology practice. AB - AIMS: The probabilistic approach is widely adopted for breast fine needle aspiration cytology. However, a definite cytological diagnosis is not always possible for C3 (atypia) cases, which poses a management dilemma as this represents a mixed category of benign and malignant cases. It would be beneficial to be able to predict malignancy based on specific cytological features in C3 aspirates. METHODS: A comprehensive panel of cytological features (including quantitative, cytomorphological and background features) in a large cohort of C3 breast aspirates with subsequent histological excisions was evaluated to identify relevant morphological criteria predicting the risk of subsequent malignancy. RESULTS: A total of 229 C3 specimens with histological follow-up were included. Malignant outcome was found in 30.1% of specimens and the majority were invasive cancers. Features that showed a significant association with malignant outcome included older age (p=0.001), lower percentage of epithelial cell clusters and high percentage of single cells (p=0.002), cribriform architecture in cell clusters (p=0.034), presence of intracellular mucin (p=0.027), increased cell clusters without myoepithelial cells (p=0.048), diminished fibromyxoid stromal fragments (p=0.001), reduced bipolar nuclei (p=0.021) and the presence of necrosis (p=0.023). Except for the percentages of single cells and cell clusters without myoepithelial cells, all other features were shown to be independent risk predictors in multivariate analysis. CONCLUSIONS: C3 aspirates were associated with a significant probability of histological malignancy. Certain quantitative, cytomorphological and background features were potentially helpful in predicting the risk of a malignant outcome. The prediction could be clinically useful in the management of C3 cases. PMID- 28554888 TI - What are the current challenges of managing cancer pain and could digital technologies help? AB - OBJECTIVES: Pain remains a problem for people with cancer despite effective treatments being available. We aimed to explore current pain management strategies used by patients, caregivers and professionals and to investigate opportunities for digital technologies to enhance cancer pain management. METHODS: A qualitative study comprising semistructured interviews and focus groups. Patients with cancer pain, their caregivers and health professionals from Northeast Scotland were recruited from a purposive sample of general practices. Professionals were recruited from regional networks. RESULTS: Fifty one participants took part in 33 interviews (eight patients alone, six patient/caregiver dyads and 19 professionals) and two focus groups (12 professionals). Living with cancer was hard work for patients and caregivers and comparable to a 'full-time job'. Patients had personal goals which involved controlling pain intensity and balancing this with analgesic use, side effects, overall symptom burden and social/physical activities.Digital technologies were embraced by most patients, and made living life with advanced cancer easier and richer (eg, video calls with family). Technology was underutilised for pain and symptom management. There were suggestions that technology could support self monitoring and communicating problems to professionals, but patients and professionals were concerned about technological monitoring adding to the work of managing illness. CONCLUSIONS: Cancer pain management takes place in the context of multiple, sometimes competing personal goals. It is possible that technology could be used to help patients share individual symptom experiences and goals, thus enhancing tailored care. The challenge is for digital solutions to add value without adding undue burden. PMID- 28554891 TI - DNA repair gene expressions are related to bone marrow cellularity in myelodysplastic syndrome. AB - OBJECTIVE: To evaluate the expression of genes related to nuclear excision (ERCC8, XPA and XPC), homologous recombination and non-homologous end-joining (ATM, BRCA1, BRCA2 and LIG4) repair mechanisms, using quantitative PCR methodologies, and it relation with bone marrow cellularity in myelodysplastic syndrome (MDS). METHODS AND RESULTS: A total of 51 adult de novo patients with MDS (3 refractory anaemia (RA), 11 refractory anaemia with ringed sideroblasts (RARS), 28 refractory cytopenia with multilineage dysplasia (RCMD), 3 refractory anaemia with excess blasts type I (RAEB-I), 5 refractory anaemia with excess blasts type II (RAEB-II), and 1 chronic myelomonocytic leukaemia (CMML) were evaluated. For karyotype, 16.2% patients were defined as very low prognosis, 59.5% low risk, 8.1% intermediate risk, 5.4% high risk and 10.8% very high risk. For bone marrow cellularity, 17.6%, 17.6% and 64.7% presented as hypocellular, normocellular and hypercellular, respectively. Patients with hypocellular MDS had significantly decreased expression of ATM (p=0.000), BRCA1 (p=0.014), BRCA2 (p=0.003), LIG4 (p=0.004) and ERCC8 (p=0.000) than those with normocellular/hypercellular bone marrow, whereas XPA (p=0.049) and XPC (p=0.000) genes were increased. In patients with hypoplastic MDS, a low expression of ATM (p=0.0268), LIG4 (p=0.0199) and ERCC8 (p=0.0493) was significantly associated with the presence of chromosomal abnormalities. We detected positive correlations between BRCA1 and BRCA2 (r=0.416; p=0.007), ATM and LIG4 (r=0.472; p=0.001), LIG4 and BRCA1 (r=0.333; p=0.026), LIG4 and BRCA2 (r=0.334; p=0.025), ATM and XPA (r=0.377; p=0.008), ATM and XPC (r=0.287; p=0.046), LIG4 and XPC (r=0.371; p=0.007) and XPA and XPC genes (r=0.895; p=0.0000). We also found among all patients evaluated that correlation with LIG4 occurred most often. CONCLUSIONS: These correlations demonstrate the important intrinsic relations between single and double DNA strand breaks genes in MDS, emphasising that these genes are related to MDS pathogenesis. PMID- 28554892 TI - Extrapolation in the development of paediatric medicines: examples from approvals for biological treatments for paediatric chronic immune-mediated inflammatory diseases. AB - The European Union (EU) Paediatric Regulation requires that all new medicinal products applying for a marketing authorisation (MA) in the EU provide a paediatric investigation plan (PIP) covering a clinical and non-clinical trial programme relating to the use in the paediatric population, unless a waiver applies. Conducting trials in children is challenging on many levels, including ethical and practical issues, which may affect the availability of the clinical evidence. In scientifically justified cases, extrapolation of data from other populations can be an option to gather evidence supporting the benefit-risk assessment of the medicinal product for paediatric use. The European Medicines Agency (EMA) is working on providing a framework for extrapolation that is scientifically valid, reliable and adequate to support MA of medicines for children. It is expected that the extrapolation framework together with therapeutic area guidelines and individual case studies will support future PIPs. Extrapolation has already been employed in several paediatric development programmes including biological treatment for immune-mediated diseases. This article reviews extrapolation strategies from MA applications for products for the treatment of juvenile idiopathic arthritis, paediatric psoriasis and paediatric inflammatory bowel disease. It also provides a summary of extrapolation advice expressed in relevant EMA guidelines and initiatives supporting the use of alternative approaches in paediatric medicine development. PMID- 28554893 TI - Concordance between self-reported STI history and biomedical results among men who have sex with men in Los Angeles, California. AB - OBJECTIVES: HIV studies and risk assessments among men who have sex with men (MSM) frequently use self-reported STI history as a proxy for true STI history. The objective of our study was to assess the validity of self-reported STI history through comparison with laboratory-confirmed biomedical results. METHODS: Data were analysed for MSM attending the Los Angeles LGBT Center (the Center) from August 2011 to July 2015. We identified 10 529 unique MSM who received testing for chlamydia, gonorrhoea and/or syphilis and had a later visit in which they self-reported their STI history to a clinic counsellor during a risk assessment. RESULTS: MSM who had an STI in the past year self-reported their STI history with 51%-56% accuracy, and MSM who had an STI more than a year ago self reported their STI history with 65%-72% accuracy. Among MSM with any positive STIs at the Center, black/African-American and Hispanic MSM were more likely to inaccurately self-report their positive results for gonorrhoea (adjusted OR (aOR): 1.48, 95% CI 1.09 to 2.01; aOR: 1.39, 95% CI 1.14 to 1.70). Additionally, HIV-positive MSM were more likely to inaccurately self-report their positive results for gonorrhoea (aOR: 1.63, 95% CI 1.22 to 2.18) and/or syphilis (aOR: 2.19, 95% CI 1.08 to 4.47). CONCLUSIONS: This is the first study that attempts to evaluate the validity of self-reported STI history among MSM. We found that self reported STI history may not be an appropriate proxy for true STI history in certain settings and minority populations. Clinical guidelines and research studies that rely on self-reported STI history will need to modify their recommendations in light of the limited validity of these data. PMID- 28554896 TI - Spotlight on the May 30 issue. PMID- 28554897 TI - Personal reflections about Lewis P. (Bud) Rowland (1925-2017). PMID- 28554898 TI - Alveolar echinococcosis presenting with simultaneous cerebral and spinal involvement. PMID- 28554899 TI - Editors' Note. PMID- 28554894 TI - Fam60a defines a variant Sin3a-Hdac complex in embryonic stem cells required for self-renewal. AB - Sin3a is the central scaffold protein of the prototypical Hdac1/2 chromatin repressor complex, crucially required during early embryonic development for the growth of pluripotent cells of the inner cell mass. Here, we compare the composition of the Sin3a-Hdac complex between pluripotent embryonic stem (ES) and differentiated cells by establishing a method that couples two independent endogenous immunoprecipitations with quantitative mass spectrometry. We define the precise composition of the Sin3a complex in multiple cell types and identify the Fam60a subunit as a key defining feature of a variant Sin3a complex present in ES cells, which also contains Ogt and Tet1. Fam60a binds on H3K4me3-positive promoters in ES cells, together with Ogt, Tet1 and Sin3a, and is essential to maintain the complex on chromatin. Finally, we show that depletion of Fam60a phenocopies the loss of Sin3a, leading to reduced proliferation, an extended G1 phase and the deregulation of lineage genes. Taken together, Fam60a is an essential core subunit of a variant Sin3a complex in ES cells that is required to promote rapid proliferation and prevent unscheduled differentiation. PMID- 28554895 TI - PAR-1 promotes microtubule breakdown during dendrite pruning in Drosophila. AB - Pruning of unspecific neurites is an important mechanism during neuronal morphogenesis. Drosophila sensory neurons prune their dendrites during metamorphosis. Pruning dendrites are severed in their proximal regions. Prior to severing, dendritic microtubules undergo local disassembly, and dendrites thin extensively through local endocytosis. Microtubule disassembly requires a katanin homologue, but the signals initiating microtubule breakdown are not known. Here, we show that the kinase PAR-1 is required for pruning and dendritic microtubule breakdown. Our data show that neurons lacking PAR-1 fail to break down dendritic microtubules, and PAR-1 is required for an increase in neuronal microtubule dynamics at the onset of metamorphosis. Mammalian PAR-1 is a known Tau kinase, and genetic interactions suggest that PAR-1 promotes microtubule breakdown largely via inhibition of Tau also in Drosophila Finally, PAR-1 is also required for dendritic thinning, suggesting that microtubule breakdown might precede ensuing plasma membrane alterations. Our results shed light on the signaling cascades and epistatic relationships involved in neurite destabilization during dendrite pruning. PMID- 28554901 TI - Author response: Formal faculty observation and assessment of bedside skills for 3rd-year neurology clerks. PMID- 28554900 TI - Letter re: Formal faculty observation and assessment of bedside skills for 3rd year neurology clerks. PMID- 28554902 TI - Letter re: Safety of domperidone in treating nausea associated with dihydroergotamine infusion and headache. PMID- 28554903 TI - Author response: Safety of domperidone in treating nausea associated with dihydroergotamine infusion and headache. PMID- 28554904 TI - Mystery Case: Don't fall for pseudo-INO! PMID- 28554905 TI - Clinical Reasoning: A 27-year-old man with acute-onset ataxia. PMID- 28554907 TI - MS and bone marrow transplant: Not for most patients. PMID- 28554906 TI - Clinical Reasoning: A 45-year-old woman with immobility and incontinence. PMID- 28554909 TI - Prevalence and types of rectal douches used for anal intercourse among men who have sex with men in Brazil. AB - INTRODUCTION: Rectal douching (RD) is practised among men who have sex with men (MSM), and various products and materials are used. There have been no studies in Brazil on this practice and its risks in the transmission of sexually transmitted infections and HIV. METHOD: Between June and August 2015, 401 MSM over the age of 18 were interviewed about their sexual practices associated with RD over the last 3 months. RD was associated with the reported sexual behaviour, and descriptive statistical analyses were conducted on the same. RESULTS: Among the respondents, 85.6% identified themselves as men and 14.4% as transgender; 255 declared themselves to be white (63.6%) and 104 to be mixed (25.9%). From among those who had performed anal sex within the last 3 months (n=369), 197 reported having used RD (53.4%). The most commonly used material was a shower hose (84.5%) and the main product used was water (93%). Of those interviewed, 94.5% never received guidelines from health professionals on this practice and its potential risks. Receptive anal intercourse and RD were found to be associated (p<0.001). CONCLUSIONS: RD is a common practice among the MSM population. Health professionals must deepen their knowledge of this. We propose studies in Brazil on the practice of RD that-from that knowledge strategies for prevention and harm reduction-can be incorporated to the vulnerable populations. PMID- 28554908 TI - Role of B-Type Natriuretic Peptide and N-Terminal Prohormone BNP as Predictors of Cardiovascular Morbidity and Mortality in Patients With a Recent Coronary Event and Type 2 Diabetes Mellitus. AB - BACKGROUND: Natriuretic peptides are recognized as important predictors of cardiovascular events in patients with heart failure, but less is known about their prognostic importance in patients with acute coronary syndrome. We sought to determine whether B-type natriuretic peptide (BNP) and N-terminal prohormone B type natriuretic peptide (NT-proBNP) could enhance risk prediction of a broad range of cardiovascular outcomes in patients with acute coronary syndrome and type 2 diabetes mellitus. METHODS AND RESULTS: Patients with a recent acute coronary syndrome and type 2 diabetes mellitus were prospectively enrolled in the ELIXA trial (n=5525, follow-up time 26 months). Best risk models were constructed from relevant baseline variables with and without BNP/NT-proBNP. C statistics, Net Reclassification Index, and Integrated Discrimination Index were analyzed to estimate the value of adding BNP or NT-proBNP to best risk models. Overall, BNP and NT-proBNP were the most important predictors of all outcomes examined, irrespective of history of heart failure or any prior cardiovascular disease. BNP significantly improved C statistics when added to risk models for each outcome examined, the strongest increments being in death (0.77-0.82, P<0.001), cardiovascular death (0.77-0.83, P<0.001), and heart failure (0.84-0.87, P<0.001). BNP or NT-proBNP alone predicted death as well as all other variables combined (0.77 versus 0.77). CONCLUSIONS: In patients with a recent acute coronary syndrome and type 2 diabetes mellitus, BNP and NT-proBNP were powerful predictors of cardiovascular outcomes beyond heart failure and death, ie, were also predictive of MI and stroke. Natriuretic peptides added as much predictive information about death as all other conventional variables combined. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01147250. PMID- 28554910 TI - Supportive text messages for patients with alcohol use disorder and a comorbid depression: a protocol for a single-blind randomised controlled aftercare trial. AB - INTRODUCTION: Alcohol use disorders (AUDs) and mood disorders commonly co-occur, and are associated with a range of negative outcomes for patients. Mobile phone technology has the potential to provide personalised support for such patients and potentially improve outcomes in this difficult-to-treat cohort. The aim of this study is to examine whether receiving supporting SMS text messages, following discharge from an inpatient dual diagnosis treatment programme, has a positive impact on mood and alcohol abstinence in patients with an AUD and a comorbid mood disorder. METHODS AND ANALYSIS: The present study is a single-blind randomised controlled trial. Patients aged 18-70 years who meet the criteria for both alcohol dependency syndrome/alcohol abuse and either major depressive disorder or bipolar disorder according to the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders IV Axis I will be randomised to receive twice-daily supportive SMS text messages for 6 months plus treatment as usual, or treatment as usual alone, and will be followed-up at 3, 6, 9 and 12 months postdischarge. Primary outcome measures will include changes from baseline in cumulative abstinence duration, which will be expressed as the proportion of days abstinent from alcohol in the preceding 90 days, and changes from baseline in Beck Depression Inventory scores. ETHICS AND DISSEMINATION: The trial has received full ethical approval from the St. Patrick's Hospital Research Ethics Committee (protocol 13/14). Results of the trial will be disseminated through peer-reviewed journal articles and at academic conferences. TRIAL REGISTRATION NUMBER: NCT02404662; Pre-results. PMID- 28554911 TI - Navigating high-risk surgery: protocol for a multisite, stepped wedge, cluster randomised trial of a question prompt list intervention to empower older adults to ask questions that inform treatment decisions. AB - INTRODUCTION: Older patients frequently undergo operations that carry high risk for postoperative complications and death. Poor preoperative communication between patients and surgeons can lead to uninformed decisions and result in unexpected outcomes, conflict between surgeons and patients, and treatment inconsistent with patient preferences. This article describes the protocol for a multisite, cluster-randomised trial that uses a stepped wedge design to test a patient-driven question prompt list (QPL) intervention aimed to improve preoperative decision making and inform postoperative expectations. METHODS AND ANALYSIS: This Patient-Centered Outcomes Research Institute-funded trial will be conducted at five academic medical centres in the USA. Study participants include surgeons who routinely perform vascular or oncological surgery, their patients and families. We aim to enrol 40 surgeons and 480 patients over 24 months. Patients age 65 or older who see a study-enrolled surgeon to discuss a vascular or oncological problem that could be treated with high-risk surgery will be enrolled at their clinic visit. Together with stakeholders, we developed a QPL intervention addressing preoperative communication needs of patients considering major surgery. Guided by the theories of self-determination and relational autonomy, this intervention is designed to increase patient activation. Patients will receive the QPL brochure and a letter from their surgeon encouraging its use. Using audio recordings of the outpatient surgical consultation, patient and family member questionnaires administered at three time points and retrospective chart review, we will compare the effectiveness of the QPL intervention to usual care with respect to the following primary outcomes: patient engagement in decision making, psychological well-being and post-treatment regret for patients and families, and interpersonal and intrapersonal conflict relating to treatment decisions and treatments received. ETHICS AND DISSEMINATION: Approvals have been granted by the Institutional Review Board at the University of Wisconsin and at each participating site, and a Certificate of Confidentiality has been obtained. Results will be reported in peer-reviewed publications and presented at national meetings. TRIAL REGISTRATION NUMBER: NCT02623335. PMID- 28554912 TI - A cross-sectional survey using electronic distribution of a questionnaire to subscribers of educational material written by clinicians, for clinicians, to evaluate whether practice change resulted from reading the Clinical Communique. AB - OBJECTIVE: To explore whether subscribers reported clinical practice changes as a result of reading the Clinical Communique (CC). Secondarily, to compare the characteristics of subscribers who self-reported changes to clinical practice with those who did not, and to explore subscribers' perceptions of the educational value of the CC. DESIGN, SETTING AND PARTICIPANTS: Online cross sectional survey between 21 July 2015 and 18 August 2015 by subscribers of the CC (response rate=29.9%, 1008/3373), conducted by a team from Monash University, Australia. MAIN OUTCOME MEASURES: Change in clinical practice as a result of reading the CC. RESULTS: 53.0% of respondents reported that their practice had changed after reading the CC. Respondents also found that the CC raised awareness (96.5%) and provided ideas about improving patient safety and care (94.1%) leading them to discuss cases with their colleagues (79.6%) and review their practice (75.7%). Multivariate analysis indicated that working in a residential aged care facility (p<0.05) and having taken part in an inquest (p<0.05) were significantly associated with practice change. CONCLUSION: The design and content of the CC has generated a positive impact on the healthcare community. It is presented in a format that appears to be accessible and acceptable to readers and achieves its goals of promoting safer clinical care through greater awareness of the medico-legal context of practice. PMID- 28554913 TI - Protocol for a single-centre, parallel-arm, randomised controlled superiority trial evaluating the effects of transcatheter arterial embolisation of abnormal knee neovasculature on pain, function and quality of life in people with knee osteoarthritis. AB - INTRODUCTION: Symptomatic knee osteoarthritis (OA) is common. Advanced knee OA is successfully treated with joint replacement surgery, but effectively managing mild to moderate knee OA can be difficult. Angiogenesis increases with OA and might contribute to pain and structural damage. Modifying angiogenesis is a potential treatment pathway for OA. The aim of the current study is to determine whether transcatheter arterial embolisation of abnormal neovasculature arising from the genicular arterial branches improves knee pain, physical function and quality of life in people with mild to moderate symptomatic knee OA. METHODS AND ANALYSIS: The study is a single centre, parallel-arm, double-blinded (participant and assessor), randomised controlled superiority trial with 1:1 random block allocation. Eligible participants have mild to moderate symptomatic knee OA and will be randomly assigned to receive either embolisation of aberrant knee neovasculature of genicular arterial branches or a placebo intervention. Outcome measures will be collected prior to the intervention and again 1, 6 and 12 months postintervention. The primary outcome is change in knee pain between baseline and 12 month assessment as measured by the Knee Injury and Osteoarthritis Outcome Score (KOOS). Secondary outcomes include change in self-reported physical function (KOOS), self-reported quality of life (KOOS, EuroQol: EQ-5D-5L), self reported knee joint stiffness (KOOS), self-reported global change, 6 min walk test performance, and 30 s chair-stand test performance. Intention-to-treat analysis will be performed including all participants as randomised. To detect a mean between group difference in change pain of 20% at the one year reassessment with a two-sided significance level of alpha=0.05 and power of 80% using a two sample t-test, we require 29 participants per arm which allows for 20% of participants to drop out. ETHICS AND DISSEMINATION: Barwon Health Human Research Ethics Committee, 30 May 2016, (ref:15/101). Study results will be disseminated via peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: Universal trial number U1111-1183-8503, Australian New Zealand Clinical Trials Registry, ACTRN12616001184460, approved 29 August 2016. PMID- 28554914 TI - A bespoke mobile application for the longitudinal assessment of depression and mood during pregnancy: protocol of a feasibility study. AB - INTRODUCTION: Depression is a common mental health disorder during pregnancy, with important consequences for mothers and their children. Despite this, it goes undiagnosed and untreated in many women attending antenatal care. Smartphones could help support the prompt identification of antenatal depression in this setting. In addition, these devices enable the implementation of ecological momentary assessment techniques, which could be used to assess how mood is experienced during pregnancy. With this study, we will assess the feasibility of using a bespoke mobile application (app) running on participants' own handsets for the longitudinal (6 months) monitoring of antenatal mood and screening of depression. METHODS AND ANALYSIS: We will use a randomised controlled study design to compare two types of assessment strategies: retrospective + momentary (consisting of the Edinburgh Postnatal Depression Scale plus five momentary and two contextual questions), and retrospective (consisting of the Edinburgh Postnatal Depression Scale only). We will assess the impact that these strategies have on participant adherence to a prespecified sampling protocol, dropout rates and timeliness of data completion. We will evaluate differences in acceptance of the technology through a short quantitative survey and open-ended questions. We will also assess the potential effect that momentary assessments could have on retrospective data. We will attempt to identify any patterns in app usage through the analysis of log data. ETHICS AND DISSEMINATION: This study has been reviewed and approved by the National Research Ethics Service Committee South East Coast Surrey on 15 April 2016 as a notice of substantial amendment to the original submission (9 July 2015) under the Research Ethics Committee (REC) reference 15/LO/0977. This study is being sponsored by Imperial College London under the reference number 15IC2687 and has been included in the UK Clinical Research Network Study Portfolio under the Central Portfolio Management System number 19280. The findings of this study will be disseminated through academic peer reviewed publications, poster presentations and abstracts at academic and professional conferences, discussion with peers, and social media. The findings of this study will also inform the PhD theses of JSMB and KD. PMID- 28554915 TI - Support received after bereavement by suicide and other sudden deaths: a cross sectional UK study of 3432 young bereaved adults. AB - OBJECTIVE: To test the hypothesis that people bereaved by suicide are less likely to receive formal or informal support than people bereaved by other causes of sudden death. DESIGN: National cross-sectional study. SETTING: Adults working or studying at any UK higher education institution (HEI) in 2010. PARTICIPANTS: A total of 3432 eligible respondents aged 18-40 years bereaved by the sudden death of a close friend or relative, sampled from approximately 659 572 bereaved and non-bereaved staff and students at 37 of 164 UK HEIs invited to participate. EXPOSURES: Bereavement by suicide (n=614; 18%), by sudden unnatural causes (n=712; 21%) and by sudden natural causes (n=2106; 61%). MAIN OUTCOME MEASURES: Receipt of formal and informal support postbereavement; timing of valued support. RESULTS: 21% (725/3432) of our sample of bereaved adults reported receiving no formal or informal bereavement support, with no evidence for group differences. People bereaved by suicide were less likely to have received informal support than those bereaved by sudden natural causes (adjusted OR (AOR)=0.79; 95% CI 0.64 to 0.98) or unnatural causes (AOR=0.74; 95% CI 0.58 to 0.96) but did not differ from either comparison group on receipt of formal support. People bereaved by suicide were less likely to have received immediate support (AOR=0.73; 95% CI 0.59 to 0.90) and more likely to report delayed receipt of support (AOR=1.33; 95% CI 1.08 to 1.64) than people bereaved by sudden natural causes. Associations were not modified by gender, or age bereaved, but became non-significant when adjusting for stigma. CONCLUSIONS: People bereaved by suicide are less likely to receive informal support than people bereaved by other causes of sudden death and are more likely to perceive delays in accessing any support. This is concerning given their higher risk of suicide attempt and the recommendations within suicide prevention strategies regarding their need for support. STUDY REGISTRATION: http://www.ucl.ac.uk/psychiatry/bereavementstudy/. PMID- 28554916 TI - Bone mineral density reference standards for Chinese children aged 3-18: cross sectional results of the 2013-2015 China Child and Adolescent Cardiovascular Health (CCACH) Study. AB - OBJECTIVES: No nationwide paediatric reference standards for bone mineral density (BMD) are available in China. We aimed to provide sex-specific BMD reference values for Chinese children and adolescents (3-18 years). METHODS: Data (10 818 participants aged 3-18 years) were obtained from cross-sectional surveys of the China Child and Adolescent Cardiovascular Health in 2015, which included four municipality cities and three provinces. BMD was measured using Hologic Discovery Dual Energy X-ray Absorptiometry (DXA) scanner. The DXA measures were modelled against age, with height as an independent variable. The LMS statistical method using a curve fitting procedure was used to construct reference smooth cross sectional centile curves for dependent versus independent variables. RESULTS: Children residing in Northeast China had the highest total body less head (TBLH) BMD while children residing in Shandong Province had the lowest values. Among children, TBLH BMD was higher for boys as compared with girls; but, it increased with age and height in both sexes. Furthermore, TBLH BMD was higher among US children as compared with Chinese children. There was a large difference in BMD for height among children from these two countries. US children had a much higher BMD at each percentile (P) than Chinese children; the largest observed difference was at P50 and P3 and the smallest difference was at P97. CONCLUSIONS: This is the first study to present a sex-specific reference dataset for Chinese children aged 3-18 years. The data can help clinicians improve interpretation, assessment and monitoring of densitometry results. PMID- 28554917 TI - Optimisation and validation of a remote monitoring system (Onco-TreC) for home based management of oral anticancer therapies: an Italian multicentre feasibility study. AB - INTRODUCTION: Despite the growing number of oral agents available for cancer treatment, their efficacy may be reduced due to the lack of adherence, inappropriate adverse event self-management and arbitrary dose adjustment. The management of anticancer therapies could exponentially benefit from the introduction of mobile health technologies in a highly integrated electronic oncology system. METHODS AND ANALYSIS: We plan to customise and fine-tune an existing monitoring TreC platform used in different chronic diseases in the oncology setting. This project follows a multistep approach with two major purposes: 1. participatory design techniques driven by Health Literacy and Patient Reported Outcomes principles in order to adapt the system to the oncology setting involving patients and healthcare providers; 2. a prospective training validation, interventional, non-pharmacological, multicentre study on a series of consecutive patients with cancer (20 and 60 patients in the training and validation steps, respectively) in order to assess system capability, usability and acceptability. The novel Onco-TreC 2.0 is expected to contribute to improving the adherence and safety of cancer care, promoting patient empowerment and patient-doctor communication. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Independent Ethics Committees of the participating institutions (CEIIAV protocol Number 2549/2015; reference Number 1315-PU). Informed consent will be obtained from all study participants. Findings will be disseminated through peer-reviewed journals, conferences and event presentations. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT02921724); (Pre-results). Other study ID Number: IRST100.18. PMID- 28554919 TI - Validation of asthma recording in electronic health records: protocol for a systematic review. AB - BACKGROUND: Asthma is a common, heterogeneous disease with significant morbidity and mortality worldwide. It can be difficult to define in epidemiological studies using electronic health records as the diagnosis is based on non-specific respiratory symptoms and spirometry, neither of which are routinely registered. Electronic health records can nonetheless be valuable to study the epidemiology, management, healthcare use and control of asthma. For health databases to be useful sources of information, asthma diagnoses should ideally be validated. The primary objectives are to provide an overview of the methods used to validate asthma diagnoses in electronic health records and summarise the results of the validation studies. METHODS: EMBASE and MEDLINE will be systematically searched for appropriate search terms. The searches will cover all studies in these databases up to October 2016 with no start date and will yield studies that have validated algorithms or codes for the diagnosis of asthma in electronic health records. At least one test validation measure (sensitivity, specificity, positive predictive value, negative predictive value or other) is necessary for inclusion. In addition, we require the validated algorithms to be compared with an external golden standard, such as a manual review, a questionnaire or an independent second database. We will summarise key data including author, year of publication, country, time period, date, data source, population, case characteristics, clinical events, algorithms, gold standard and validation statistics in a uniform table. ETHICS AND DISSEMINATION: This study is a synthesis of previously published studies and, therefore, no ethical approval is required. The results will be submitted to a peer-reviewed journal for publication. Results from this systematic review can be used to study outcome research on asthma and can be used to identify case definitions for asthma. PROSPERO REGISTRATION NUMBER: CRD42016041798. PMID- 28554918 TI - Speech and communication in Parkinson's disease: a cross-sectional exploratory study in the UK. AB - OBJECTIVE: To assess associations between cognitive status, intelligibility, acoustics and functional communication in PD. DESIGN: Cross-sectional exploratory study of functional communication, including a within-participants experimental design for listener assessment. SETTING: A major academic medical centre in the East of England, UK. PARTICIPANTS: Questionnaire data were assessed for 45 people with Parkinson's disease (PD), who had self-reported speech or communication difficulties and did not have clinical dementia. Acoustic and listener analyses were conducted on read and conversational speech for 20 people with PD and 20 familiar conversation partner controls without speech, language or cognitive difficulties. MAIN OUTCOME MEASURES: Functional communication assessed by the Communicative Participation Item Bank (CPIB) and Communicative Effectiveness Survey (CES). RESULTS: People with PD had lower intelligibility than controls for both the read (mean difference 13.7%, p=0.009) and conversational (mean difference 16.2%, p=0.04) sentences. Intensity and pause were statistically significant predictors of intelligibility in read sentences. Listeners were less accurate identifying the intended emotion in the speech of people with PD (14.8% point difference across conditions, p=0.02) and this was associated with worse speaker cognitive status (16.7% point difference, p=0.04). Cognitive status was a significant predictor of functional communication using CPIB (F=8.99, p=0.005, eta2 = 0.15) but not CES. Intelligibility in conversation sentences was a statistically significant predictor of CPIB (F=4.96, p=0.04, eta2 = 0.19) and CES (F=13.65, p=0.002, eta2 = 0.43). Read sentence intelligibility was not a significant predictor of either outcome. CONCLUSIONS: Cognitive status was an important predictor of functional communication-the role of intelligibility was modest and limited to conversational and not read speech. Our results highlight the importance of focusing on functional communication as well as physical speech impairment in speech and language therapy (SLT) for PD. Our results could inform future trials of SLT techniques for PD. PMID- 28554920 TI - Physical activity, immune function and inflammation in kidney patients (the PINK study): a feasibility trial protocol. AB - INTRODUCTION: Patients with chronic kidney disease (CKD) display increased infection-related mortality and elevated cardiovascular risk only partly attributed to traditional risk factors. Patients with CKD also exhibit a pro inflammatory environment and impaired immune function. Aerobic exercise has the potential to positively impact these detriments, but is under-researched in this patient population. This feasibility study will investigate the effects of acute aerobic exercise on inflammation and immune function in patients with CKD to inform the design of larger studies intended to ultimately influence current exercise recommendations. METHODS AND ANALYSIS: Patients with CKD, including renal transplant recipients, will visit the laboratory on two occasions, both preceded by appropriate exercise, alcohol and caffeine restrictions. On visit 1, baseline assessments will be completed, comprising anthropometrics, body composition, cardiovascular function and fatigue and leisure time exercise questionnaires. Participants will then undertake an incremental shuttle walk test to estimate predicted peak O2 consumption (VO2peak). On visit 2, participants will complete a 20 min shuttle walk at a constant speed to achieve 85% estimated VO2peak. Blood and saliva samples will be taken before, immediately after and 1 hour after this exercise bout. Muscle O2 saturation will be monitored throughout exercise and recovery. Age and sex-matched non-CKD 'healthy control' participants will complete an identical protocol. Blood and saliva samples will be analysed for markers of inflammation and immune function, using cytometric bead array and flow cytometry techniques. Appropriate statistical tests will be used to analyse the data. ETHICS AND DISSEMINATION: A favourable opinion was granted by the East Midlands-Derby Research Ethics Committee on 18 September 2015 (ref 15/EM/0391), and the study was approved and sponsored by University Hospitals of Leicester Research and Innovation (ref 11444). The study was registered with ISRCTN (ref 38935454). The results will be presented at relevant conferences, and it is anticipated that the reports will be published in appropriate journals in 2018. PMID- 28554921 TI - Selection by a panel of clinicians and family representatives of important early morbidities associated with paediatric cardiac surgery suitable for routine monitoring using the nominal group technique and a robust voting process. AB - OBJECTIVE: With survival following paediatric cardiac surgery improving, the attention of quality assurance and improvement initiatives is shifting to long term outcomes and early surgical morbidities. We wanted to involve family representatives and a range of clinicians in selecting the morbidities to be measured in a major UK study. SETTING: Paediatric cardiac surgery services in the UK. PARTICIPANTS: We convened a panel comprising family representatives, paediatricians from referring centres, and surgeons and other clinicians from surgical centres. PRIMARY AND SECONDARY OUTCOME MEASURES: Using the nominal group technique augmented by a robust voting process to identify group preferences, suggestions for candidate morbidities were elicited, discussed, ranked and then shortlisted. The shortlist was passed to a clinical group that provided a view on the feasibility of monitoring each shortlisted morbidity in routine practice. The panel then met again to select a prioritised list of morbidities for further study, with the list finalised by the clinical group and chief investigators. RESULTS: At the first panel meeting, 66 initial suggestions were made, with this reduced to a shortlist of 24 after two rounds of discussion, consolidation and voting. At the second meeting, this shortlist was reduced to 10 candidate morbidities. Two were dropped on grounds of feasibility and replaced by another the panel considered important. The final list of nine morbidities included indicators of organ damage, acute events and feeding problems. Family representatives and clinicians from outside tertiary centres brought some issues to greater prominence than if the panel had consisted solely of tertiary clinicians or study investigators. CONCLUSION: The inclusion of patient and family perspectives in identifying metrics for use in monitoring a specialised clinical service is challenging but feasible and can broaden notions of quality and how to measure it. PMID- 28554922 TI - Relationship between dietary factors and the number of altered metabolic syndrome components in Chinese adults: a cross-sectional study using data from the China Health and Nutrition Survey. AB - OBJECTIVES: To study the correlation between dietary factors and the number of altered metabolic syndrome components (MetS) in Chinese adults systematically. SETTING: A cross-sectional study using demographic and dietary data of adults aged 18-75 years from the China Health and Nutrition Survey (2009) was conducted in nine provinces in China. PARTICIPANTS: There were 6034 eligible subjects (2800 men and 3234 women) in this study. OUTCOMES: The primary outcome of this study were diet assessments and the number of altered MetS components. Dietary intake was measured using a combination of a 3-day period with 24-hour and household food inventory; average daily intakes of nutrients were estimated according to the Chinese Food Composition Table. Blood samples were analysed in a national central laboratory and the number of clustering MetS components was calculated by adding the presence of each MetS component. RESULTS: After adjusting for covariates, and taking zero MetS as comparison, the high risk factors correlating with increased numbers of altered MetS components in men were higher intake of protein (70.4-73.4 g; Ptrend=0.0004), cholesterol (238.7-266.6 mg; Ptrend=0.004), meat (90.6-105.7 g; Ptrend=0.016), fish/seafood (30.4-42.3 g; Ptrend=0.001), and lower intake of coarse cereals (16.5-12.7 g; Ptrend=0.051), tubers (37.3-32.7 g; Ptrend=0.030), and dietary fibre (11.7-11.5 g; ANCOVA p=0.058). Meanwhile, the high risk factors correlating with the increased number of altered MetS components in women were higher intake of wheat (101.9-112.6 g; Ptrend=0.066) and sodium (3862.3-4005.7 mg, Ptrend=0.032), and lower intake of beta-carotene (1578.6-1382.7 ug; Ptrend=0.007), milk, and dairy products (17.8-11.5 g; Ptrend=0.002). CONCLUSIONS: Some foods and nutritional factors correlate with an increased number of altered MetS components in Chinese adults. More prospective, multicentre and clinical research work to further examine these associations is underway. PMID- 28554923 TI - Trends in alcohol-related injury admissions in adolescents in Western Australia and England: population-based cohort study. AB - BACKGROUND: Alcohol-related harm in young people is now a global health priority. We examined trends in hospital admissions for alcohol-related injuries for adolescents in Western Australia (WA) and in England, identified groups most at risk and determined causes of injuries. METHODS: Annual incidence rates for alcohol-related injury rates were calculated using population-level hospital admissions data for WA and England. We compared trends in different types of alcohol-related injury by age and gender. RESULTS: Despite a decrease in the overall rate of injury admissions for people aged 13-17 years in WA, alcohol related injuries have increased significantly from 1990 to 2009 (from 8 to 12 per 10 000). Conversely, alcohol-related injury rates have declined in England since 2007. In England, self-harm is the most frequently recorded cause of alcohol related injury. In WA, unintentional injury is most common; however, violence related harm is increasing for boys and girls. CONCLUSION: Alcohol-related harm of sufficient severity to require hospital admission is increasing among adolescents in WA. Declining trends in England suggest that this trend is not inevitable or irreversible. More needs to be done to address alcohol-related harm, and on-going monitoring is required to assess the effectiveness of strategies. PMID- 28554924 TI - Optimal plateau pressure for patients with acute respiratory distress syndrome: a protocol for a systematic review and meta-analysis with meta-regression. AB - INTRODUCTION: Lower tidal volume ventilation in patients with acute respiratory distress syndrome (ARDS) is a strategy to reduce the plateau pressure and driving pressure to limit ventilator-induced lung injury (VILI). Several randomised controlled trials (RCTs) and meta-analyses showed that limiting both the plateau pressure and the tidal volume decreased mortality, but the optimal plateau pressure to demonstrate a benefit is uncertain. The aim of this systematic review is to investigate the optimal upper limit of plateau pressure in patients with ARDS to prevent VILI and improve clinical outcomes using meta-analysis with and without meta-regression. METHODS AND ANALYSIS: RCTs comparing two mechanical ventilation strategies will be included, with lower plateau pressure and with higher plateau pressure, among patients with ARDS and acute lung injury. Data sources include MEDLINE via the NCBI Entrez system, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE and Ichushi, a database of papers in Japanese. Two of three physicians will independently screen trials obtained by search for eligibility, and extract data from included studies onto standardised data recording forms. For each included trial, the risk of bias and the quality of evidence will be evaluated using the Grading of Recommendation Assessment Development and Evaluation system. ETHICS AND DISSEMINATION: This study does not require ethical approval. The results of this systematic review and meta-analysis with and without meta-regression will be disseminated through conference presentation and publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: CRD42016041924. PMID- 28554925 TI - A cross-sectional study on prevalence of chronic obstructive pulmonary disease (COPD) in India: rationale and methods. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable chronic respiratory disease, which affects 210 million people globally. Global and national guidelines exist for the management of COPD. Although evidence-based, they are inadequate to address the phenotypic and genotypic heterogeneity in India. Co-existence of other chronic respiratory diseases can adversely influence the prognosis of COPD.India has a huge burden of COPD with various risk factors and comorbid conditions. However, valid prevalence estimates employing spirometry as the diagnostic tool and data on important comorbid conditions are not available. This study protocol is designed to address this knowledge gap and eventually to build a database to undertake long-term cohort studies to describe the phenotypic and genotypic heterogeneity among COPD patients in India. OBJECTIVES: The primary objective is to estimate the prevalence of COPD among adults aged >=25 years for each gender in India. The secondary objective is to identify the risk factors for COPD and important comorbid conditions such as asthma and post-tuberculosis sequelae. It is also proposed to validate the currently available definitions for COPD diagnosis in India. METHODS AND ANALYSIS: A cross-sectional study will be undertaken among the populations of sub-urban areas of Chennai and Shillong cities, which represent the Southern and Northeastern regions of India. We will collect data on sociodemographic variables, economic characteristics, risk factors of COPD and comorbidities. The Global Initiative for Obstructive Lung Disease (GOLD) and Global Initiative for Asthma (GINA) definitions will be used for the diagnosis of COPD and asthma. Data will be analysed for estimation of the prevalence of COPD, asthma and associated factors. ETHICS AND DISSEMINATION: This study proposal was approved by the respective institutional ethics committees of participating institutions. The results will be disseminated through publications in the peer reviewed journals and a report will be submitted to the concerned public health authorities in India for developing appropriate research and management policies. PMID- 28554926 TI - Long-term antibiotics for prevention of recurrent urinary tract infection in older adults: systematic review and meta-analysis of randomised trials. AB - OBJECTIVE: To address clinical uncertainties about the effectiveness and safety of long-term antibiotic therapy for preventing recurrent urinary tract infections (UTIs) in older adults. DESIGN: Systematic review andmeta-analysis of randomised trials. METHOD: We searched Medline, Embase, The Cumulative Index to Nursing and Allied Health Literature(CINAHL), and the Cochrane Register of Controlled Trials from inception to August 2016. Eligible studies compared long-term antibiotic therapy with non-antibiotic therapy or placebo in men or women aged over 65, or in postmenopausal women, with recurrent UTIs. RESULTS: We did not identify any studies that included older men. Three randomised controlled trials compared long term antibiotics with vaginal oestrogens (n=150), oral lactobacilli (n=238) and D mannose powder (n=94) in postmenopausal women. Long-term antibiotics reduced the risk of UTI recurrence by 24% (three trials, n=482; pooled risk ratio (RR) 0.76; 95% CI 0.61 to 0.95, number needed to treat=8.5). There was no statistically significant increase in risk of adverse events (mild adverse events: pooled RR 1.52; 95% CI 0.76 to 3.03; serious adverse events: pooled RR 0.90, 95% CI 0.31 to 2.66). One trial showed 90% of urinary and faecal Escherichia coli isolates were resistant to trimethoprim-sulfamethoxazole after 1 month of prophylaxis. CONCLUSIONS: Findings from three small trials with relatively short follow-up periods suggest long-term antibiotic therapy reduces the risk of recurrence in postmenopausal women with recurrent UTI. We did not identify any evidence to inform several clinically important scenarios including, benefits and harms in older men or frail care home residents, optimal duration of prophylaxis, recurrence rates once prophylaxis stops and effects on urinary antibiotic resistance. PMID- 28554927 TI - Systemic glucocorticoid use in Denmark: a population-based prevalence study. AB - OBJECTIVES: Glucocorticoid (GC) use is widespread and associated with many adverse effects. Thus, it is important to ascertain GC utilisation patterns. In this study, we examined the annual prevalence of prescription users and amount of use of systemic GCs. DESIGN: Population-wide prevalence study. SETTING: The primary healthcare and hospital sectors in Denmark from 1999 to 2015. RESULTS: Approximately 3% of the Danish population redeemed at least one prescription for a systemic GC annually between 1999 and 2015, with annual prevalence remaining constant over the period. However, after adjusting for age and sex, we observed a decrease in annual prevalence from 1999 to 2015, with a prevalence ratio of 0.92 (95% CI 0.91 to 0.92). Annual prevalence was highest among the elderly (7.0%-8.2% among persons 65-79 years of age and 8.4%-10% among persons 80+ years of age). Prednisolone was the most frequently redeemed systemic GC, with annual prevalence increasing from 1.4% to 2.1% during the 1999-2015 period. The amount of systemic GCs provided to the hospital sector increased from 2.3 defined daily doses (DDD)/1000 inhabitants/day in 1999 to 3.5 DDD/1000 inhabitants/day in 2015, while the amount provided to the primary healthcare sector remained constant in the range of 10-11 DDD/1000 inhabitants/day. CONCLUSION: We found a high prevalence of systemic GC use of 3% with a remarkably high prevalence in elderly of up to 10%, wherefore continued awareness of its effects is mandated. PMID- 28554929 TI - Nutritional rickets in Norway: a nationwide register-based cohort study. AB - OBJECTIVES: Poor vitamin D status has been reported to be highly prevalent in many non-western immigrant groups living in Norway and other western countries. However, data on rickets are scarce, and the aim of the current study was to identify new cases of nutritional rickets in Norway in the period 2008-2012 among children under the age of 5 years. DESIGN: Register-based cohort study. SETTING: The Norwegian population from 2008 to 2012. PARTICIPANTS: Children with nutritional rickets under the age of 5 years. MAIN OUTCOME MEASURE: Nutritional rickets. Patients with ICD10 (International Statistical Classification of Diseases and Related Health Problems, 10th revision) diagnosis code E55.0 (active rickets) treated at all Norwegian hospitals were identified in the Norwegian Patient Registry. We were able to review 85% of the medical records for diagnosis confirmation. In addition, we identified patients with the diagnoses E55.9, E64.3 and E83.3 to identify individuals with rickets who had been given other diagnoses. RESULTS: Nutritional rickets was confirmed in 39 children aged 0-4 years with the diagnosis of E55.0. In addition, three patients with the diagnosis of unspecified vitamin D deficiency (E55.9) were classified as having nutritional rickets, giving a total of 42 patients. Mean age at diagnosis was 1.40 years (range 0.1-3.5 years), and 93% had a non-western immigrant background. The incidence rate of rickets was estimated to be 0.3 per 10 000 person-years in the total Norwegian child population under the age of 5 years and 3.1 per 10 000 person-years in those with an immigrant background from Asia or Africa. CONCLUSION: The number of children with nutritional rickets in Norway remained low in the period 2008-2012. Nearly all children had a non-western immigrant background. PMID- 28554930 TI - Exploring the acceptability of a 'limited patient consent procedure' for a proposed blood-borne virus screening programme: a Delphi consensus building technique. AB - OBJECTIVE: To identify components of a proposed blood-borne virus (BBV) population screening programme and its associated consent procedure that both the public and health practitioners (HPs) would find acceptable. The proposed BBV screening system would aim to reduce late diagnosis of BBVs and be used in patients undergoing routine blood tests, aided by risk stratification software to target individuals at higher risk of infection. DESIGN: A Delphi technique was used to build consensus among two separate groups, public participants and HPs in England. METHODS: A survey incorporating vignettes was developed, with input from an external panel of experts. Over three rounds, 46 public participants and 37 HPs completed the survey, rating statements on a four-point Likert scale. The survey covered issues around stigma and sensitivity, the use of risk stratification algorithms and 'limited' patient consent (ie, preinformed of the option to 'opt-out'). Consensus was defined as >70% of participants agreeing or disagreeing with each statement. RESULTS: Consensus was achieved among both groups in terms of acceptability of the screening programme. There was also consensus on using patient data to risk-stratify screening algorithms and the need to obtain some form of consent around the time of drawing blood. CONCLUSIONS: This study found that the special protected status of HIV in England is no longer deemed necessary today and hinders appropriate care. We propose that a novel 'limited consent procedure' could be implemented in future screening programmes. PMID- 28554928 TI - Epidural analgesia in critically ill patients with acute pancreatitis: the multicentre randomised controlled EPIPAN study protocol. AB - BACKGROUND: Acute pancreatitis (AP) is associated with high morbidity and mortality in its most severe forms. Most patients with severe AP require intubation and invasive mechanical ventilation, frequently for more than 7 days, which is associated with the worst outcome. Recent increasing evidence from preclinical and clinical studies support the beneficial effects of epidural analgesia (EA) in AP, such as increased gut barrier function and splanchnic, pancreatic and renal perfusion, decreased liver damage and inflammatory response, and reduced mortality. Because recent studies suggest that EA might be a safe procedure in the critically ill, we sought to determine whether EA reduced AP associated respiratory failure and other major clinical outcomes in patients with AP. METHODS AND ANALYSIS: The Epidural Analgesia for Pancreatitis (EPIPAN) trial is an investigator-initiated, prospective, multicentre, randomised controlled two arm trial with assessor-blinded outcome assessment. The EPIPAN trial will randomise 148 patients with AP requiring admission to an intensive care unit (ICU) to receive EA (with patient-controlled epidural administration of ropivacaine and sufentanil) combined with standard care based on current recommendations on the treatment of AP (interventional group), or standard care alone (reference group). The primary outcome is the number of ventilator-free days at day 30. Secondary outcomes include main complications of AP (eg, organ failure and mortality, among others), levels of biological markers of systemic inflammation, epithelial lung injury, renal failure, and healthcare-associated costs. ETHICS AND DISSEMINATION: The study was approved by the appropriate ethics committee (CPP Sud-Est VI). Informed consent is required. If the combined application of EA and standard care proves superior to standard care alone in patients with AP in the ICU, the use of EA may become standard practice in experienced centres, thereby decreasing potential complications related to AP and its burden in critically ill patients. The results will be disseminated in a peer reviewed journal. TRIAL REGISTRATION NUMBER: NCT02126332. PMID- 28554931 TI - Developing a core outcome set for infant colic for primary, secondary and tertiary care settings: a prospective study. AB - OBJECTIVE: Infant colic (IC) is defined as recurrent and prolonged crying without an obvious cause or evidence of failure to thrive or illness. It is a common problem with a prevalence of 5%-25%. The unknown aetiology results in a wide variety in interventions and use of heterogeneous outcome measures across therapeutic trials. Our aim was to develop a core outcome set (COS) for IC to facilitate and improve evidence synthesis. DESIGN AND SETTING: Prospective study design; primary, secondary and tertiary care. METHODS: The COS was developed using a modified Delphi technique. First, healthcare professionals (HCPs) and parents of infants with IC were asked to list up to five outcomes they considered relevant in the treatment of IC. Outcomes mentioned by >10% of participants were forwarded to a shortlist. In the second round, outcomes on this shortlist were rated and prioritised. The final COS was defined in a face-to-face expert meeting of paediatricians. RESULTS: F of invited stakeholders (133 HCPs and 55 parents of infants with IC) completed both Delphi rounds. Duration of crying, family stress, sleeping time of infant, quality of life (of family), discomfort of infant and hospital admission/duration were rated as most important outcomes in IC, framing the final COS. CONCLUSIONS: The use of this COS should serve as a minimum of outcomes to be measured and reported. This will benefit evidence synthesis, by enhancing homogeneity of outcomes, and enable evaluation of success in therapeutic trials on IC. Researchers are strongly encouraged to use this COS when setting up a clinical trial in primary, secondary and/or tertiary care or performing a systematic review on IC. PMID- 28554932 TI - The role of academic health centres in building equitable health systems: a systematic review protocol. AB - INTRODUCTION: Academic health centres (AHCs) are complex organisations often defined by their 'tripartite' mission: to achieve high standards of clinical care, undertake clinical and laboratory research and educate health professionals. In the last decade, AHCs have moved away from what was a dominant focus on high impact (clinical) interventions for individuals, towards a more population-oriented paradigm requiring networked institutions and responsiveness to a range of issues including distribution of health outcomes and health determinants. Reflective of this paradigm shift is a growing interest in the role of AHCs in addressing health disparities and improving health system equity. This protocol outlines a systematic review that seeks to synthesise and critically appraise the current state of evidence on the role of AHCs in contributing to equitable health systems locally and globally. METHODS AND ANALYSIS: Electronic searches will be conducted on a pilot list of bibliographic databases, including Google Scholar, Scopus, MEDLINE, PsycInfo, CINAHL, ERIC, ProQuest Dissertations & Theses, Cochrane Library, Evidence Based Medicine Reviews, Campbell Library and A+ Education, from 1 January 2000 to 31 December 2016. Apart from studies reporting clinical interventions or trials, all types of published peer-reviewed and grey literature will be included in the review. The single screening method will be employed in selecting studies, with two additional reviewers consulted where allocation is unclear. Quality and relevance appraisal utilising Joanna Briggs Institute critical appraisal tools will follow data extraction to a preprepared template. Thematic synthesis will be undertaken to develop descriptive themes and inform analysis. ETHICS AND DISSEMINATION: As the review is focused on the analysis of secondary data, it does not require ethics approval. The results of the study will be disseminated through articles in peer reviewed journals and trade publications as well as presentations at relevant national and international conferences. Results will be further disseminated through networks and associations of AHCs. PROTOCOL REGISTRATION: International Prospective Register for Systematic Reviews (PROSPERO) number CRD42016051802. PMID- 28554933 TI - An investigation on the use of snus and its association with respiratory and sleep-related symptoms: a cross-sectional population study. AB - INTRODUCTION: Studies of the health effects of moist oral tobacco, snus, have produced inconsistent results. The main objective of this study is to examine the health effects of snus use on asthma, respiratory symptoms and sleep-related problems, a field that has not been investigated before. METHODS AND MATERIAL: This cross-sectional study was based on a postal questionnaire completed by 26 697 (59.3%) participants aged 16 to 75 years and living in Sweden. The questionnaire included questions on tobacco use, asthma, respiratory symptoms and sleeping problems. The association of snus use with asthma, respiratory symptoms and sleep-related symptoms was mainly tested in never-smokers (n=16 082). RESULTS: The current use of snus in never-smokers was associated with an increased risk of asthma (OR 1.51 (95% CI 1.28 to 1.77)), asthmatic symptoms, chronic bronchitis and chronic rhinosinusitis. This association was not present among ex-snus users. Snoring was independently related to both the former and current use of snus ((OR 1.37 (95% CI 1.12 to 1.68)) and (OR 1.59 (95% CI 1.34 to 1.89), respectively)). A higher risk of difficulty inducing sleep was seen among snus users. CONCLUSION: Snus use was associated with a higher prevalence of asthma, respiratory symptoms and snoring. Healthcare professionals should be aware of these possible adverse effects of snus use. PMID- 28554934 TI - Validity of the Italian algorithm for the attribution of neuropsychiatric events in systemic lupus erythematosus: a retrospective multicentre international diagnostic cohort study. AB - OBJECTIVE: To validate the Italian algorithm of attribution of neuropsychiatric (NP) events to systemic lupus erythematosus (SLE) in an external international cohort of patients with SLE. METHODS: A retrospective cohort diagnostic accuracy design was followed. SLE patients attending three tertiary care lupus clinics, with one or more NP events, were included. The attribution algorithm, applied to the NP manifestations, considers four weighted items for each NP event: (1) time of onset of the event; (2) type of NP event (major vs minor), (3) concurrent non SLE factors; (4) favouring factors. To maintain blinding, two independent teams of assessors from each centre evaluated all NP events: the first provided an attribution diagnosis on the basis of their own clinical judgement, assumed as the 'gold standard'; the second applied the algorithm, which provides a probability score ranging from 0 to 10. The performance of the algorithm was evaluated by calculating the area under curve (AUC) of thereceiver operating characteristic curve. RESULTS: The study included 243 patients with SLE with at least one NP manifestation, for a total of 336 events. 285 (84.8%) NP events involved the central nervous system and 51 (15.2%) the peripheral nervous system. The attribution score for the first NP event showed good accuracy with an AUC of 0.893 (95% CI 0.849 to 0.937) using dichotomous outcomes for NPSLE (related vs uncertain/unrelated). The best single cut-off point to optimise classification of a first NPSLE-related event was>=7 (sensitivity 87.9%, specificity 82.6%). Satisfactory accuracy was observed also for subsequent NP events. CONCLUSIONS: Validation exercise on an independent international cohort showed that the Italian attribution algorithm is a valid and reliable tool for the identification of NP events attributed to SLE. PMID- 28554937 TI - Untargeted antifungal therapy in adult patients with complicated intra-abdominal infection: protocol for a systematic review with meta-analysis. AB - INTRODUCTION: Intra-abdominal infections are the second most frequent cause of sepsis. In a recent cohort, fungal specimens were found in 51.9% of all patients with sepsis and peritonitis. Current systematic reviews comparing untargeted antifungal treatment with placebo or no treatment in patients who are critically ill have provided conflicting results, and clinical equipoise exists. Accordingly, we aim to assess patient-important benefits and harms of untargeted antifungal therapy versus placebo or no treatment in adult patients with complicated intra-abdominal infection. METHODS AND ANALYSIS: We will conduct a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials assessing any untargeted antifungal therapy compared with placebo or no treatment in adult patients with complicated intra-abdominal infections. The primary outcome is all-cause mortality, and secondary outcomes include adverse events, duration of mechanical ventilation and inotropic support, need for renal replacement therapy, emergence of antibiotic resistance and intensive care unit and hospital length-of-stay. Conventional meta-analysis, including sensitivity and subgroup analyses, and assessment of the risk of systematic (bias) and random errors will be conducted. The review will be prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, the Cochrane methodology and the Grading of Recommendations, Assessment, Development and Evaluation. ETHICS AND DISSEMINATION: Ethical approval is not required as this systematic review only includes previously published data. We aim to publish the review in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: International Prospective Register of Systematic Reviews registration number: CRD42016053508. PMID- 28554936 TI - Selecting children with suspected inflammatory bowel disease for endoscopy with the calgranulin C or calprotectin stool test: protocol of the CACATU study. AB - INTRODUCTION: The introduction of the faecal calprotectin (FC) test to screen children with chronic gastrointestinal complaints has helped the clinician to decide whether or not to subject the patient to endoscopy. In spite of this, a considerable number of patients without inflammatory bowel disease (IBD) is still scoped. Faecal calgranulin C (S100A12) is a marker of intestinal inflammation that is potentially more specific for IBD than FC, as it is exclusively released by activated granulocytes. OBJECTIVE: To determine whether the specificity of S100A12 is superior to the specificity of FC without sacrificing sensitivity in patients with suspected IBD. METHODS: An international prospective cohort of children with suspected IBD will be screened with the existing FC stool test and the new S100A12 stool test. The reference standard (endoscopy with biopsies) will be applied to patients at high risk of IBD, while a secondary reference (clinical follow-up) will be applied to those at low risk of IBD. The differences in specificity and sensitivity between the two markers will be calculated. ETHICS AND DISSEMINATION: This study is submitted to and approved by the Medical Ethics Review Committee of the University Medical Center Groningen (the Netherlands) and the Antwerp University Hospital (Belgium). The results will be disseminated through a peer-reviewed publication, conference presentation and incorporation in the upcoming National Guideline on Diagnosis and Therapy of IBD in Children. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02197780 . PMID- 28554938 TI - Term admissions to neonatal units in England: a role for transitional care? A retrospective cohort study. AB - OBJECTIVE: To identify the primary reasons for term admissions to neonatal units in England, to determine risk factors for admissions for jaundice and to estimate the proportion who can be cared for in a transitional setting without separation of mother and baby. DESIGN: Retrospective observational study using neonatal unit admission data from the National Neonatal Research Database and data of live births in England from the Office for National Statistics. SETTING: All 163 neonatal units in England 2011-2013. PARTICIPANTS: 133 691 term babies born >=37 weeks gestational age and admitted to neonatal units in England. PRIMARY AND SECONDARY OUTCOMES: Primary reasons for admission, term babies admitted for the primary reason of jaundice, patient characteristics, postnatal age at admission, total length of stay, phototherapy, intravenous fluids, exchange transfusion and kernicterus. RESULTS: Respiratory disease was the most common reason for admission overall, although jaundice was the most common reason for admission from home (22% home vs 5% hospital). Risk factors for admission for jaundice include male, born at 37 weeks gestation, Asian ethnicity and multiple birth. The majority of babies received only a brief period of phototherapy, and only a third received intravenous fluids, suggesting that some may be appropriately managed without separation of mother and baby. Admission from home was significantly later (3.9 days) compared with those admitted from elsewhere in the hospital (1.7 days) (p<0.001). CONCLUSION: Around two-thirds of term admissions for jaundice may be appropriately managed in a transitional care setting, avoiding separation of mother and baby. Babies with risk factors may benefit from a community midwife postnatal visit around the third day of life to enable early referral if necessary. We recommend further work at the national level to examine provision and barriers to transitional care, referral pathways between primary and secondary care, and community postnatal care. PMID- 28554935 TI - The accuracy of postoperative, non-invasive Air-Test to diagnose atelectasis in healthy patients after surgery: a prospective, diagnostic pilot study. AB - OBJECTIVE: To assess the diagnostic accuracy of peripheral capillary oxygen saturation (SpO2) while breathing room air for 5 min (the 'Air-Test') in detecting postoperative atelectasis. DESIGN: Prospective cohort study. Diagnostic accuracy was assessed by measuring the agreement between the index test and the reference standard CT scan images. SETTING: Postanaesthetic care unit in a tertiary hospital in Spain. PARTICIPANTS: Three hundred and fifty patients from 12 January to 7 February 2015; 170 patients scheduled for surgery under general anaesthesia who were admitted into the postsurgical unit were included. INTERVENTION: The Air-Test was performed in conscious extubated patients after a 30 min stabilisation period during which they received supplemental oxygen therapy via a venturi mask. The Air-Test was defined as positive when SpO2 was <=96% and negative when SpO2 was >=97%. Arterial blood gases were measured in all patients at the end of the Air-Test. In the subsequent 25 min, the presence of atelectasis was evaluated by performing a CT scan in 59 randomly selected patients. MAIN OUTCOME MEASURES: The primary study outcome was assessment of the accuracy of the Air-Test for detecting postoperative atelectasis compared with the reference standard. The secondary outcome was the incidence of positive Air Test results. RESULTS: The Air-Test diagnosed postoperative atelectasis with an area under the receiver operating characteristic curve of 0.90 (95% CI 0.82 to 0.98) with a sensitivity of 82.6% and a specificity of 87.8%. The presence of atelectasis was confirmed by CT scans in all patients (30/30) with positive and in 5 patients (17%) with negative Air-Test results. Based on the Air-Test, postoperative atelectasis was present in 36% of the patients (62 out of 170). CONCLUSION: The Air-Test may represent an accurate, simple, inexpensive and non invasive method for diagnosing postoperative atelectasis. TRIAL REGISTRATION: NCT02650037. PMID- 28554939 TI - Simplified clinical algorithm for identifying patients eligible for immediate initiation of antiretroviral therapy for HIV (SLATE): protocol for a randomised evaluation. AB - INTRODUCTION: African countries are rapidly adopting guidelines to offer antiretroviral therapy (ART) to all HIV-infected individuals, regardless of CD4 count. For this policy of 'treat all' to succeed, millions of new patients must be initiated on ART as efficiently as possible. Studies have documented high losses of treatment-eligible patients from care before they receive their first dose of antiretrovirals (ARVs), due in part to a cumbersome, resource-intensive process for treatment initiation, requiring multiple clinic visits over a several week period. METHODS AND ANALYSIS: The Simplified Algorithm for Treatment Eligibility (SLATE) study is an individually randomised evaluation of a simplified clinical algorithm for clinicians to reliably determine a patient's eligibility for immediate ART initiation without waiting for laboratory results or additional clinic visits. SLATE will enrol and randomise (1:1) 960 adult, HIV positive patients who present for HIV testing or care and are not yet on ART in South Africa and Kenya. Patients randomised to the standard arm will receive routine, standard of care ART initiation from clinic staff. Patients randomised to the intervention arm will be administered a symptom report, medical history, brief physical exam and readiness assessment. Patients who have positive (satisfactory) results for all four components of SLATE will be dispensed ARVs immediately, at the same clinic visit. Patients who have any negative results will be referred for further clinical investigation, counselling, tests or other services prior to being dispensed ARVs. After the initial visit, follow-up will be by passive medical record review. The primary outcomes will be ART initiation <=28 days and retention in care 8 months after study enrolment. ETHICS AND DISSEMINATION: Ethics approval has been provided by the Boston University Institutional Review Board, the University of the Witwatersrand Human Research Ethics Committee (Medical) and the KEMRI Scientific and Ethics Review Unit. Results will be published in peer-reviewed journals and made widely available through presentations and briefing documents. TRIAL REGISTRATION: NCT02891135. PMID- 28554941 TI - Terra firma-forme dermatosis: a benign cutaneous entity with no systemic manifestations. PMID- 28554940 TI - The association between human herpesvirus infections and stroke: a systematic review protocol. AB - INTRODUCTION: After primary infection, human herpesviruses establish latency and persist lifelong. Periodic virus reactivation can lead to serious inflammatory complications. Recent research suggests that herpesvirus reactivation may also be linked to acute stroke. An improved understanding of this relationship is vital to inform public health prevention strategies. We will review the evidence regarding the role of human herpesviruses in triggering stroke. METHODS AND ANALYSIS: A systematic literature review of published and grey literature studies with a human herpesvirus (infection or reactivation) as an exposure and stroke as an outcome will be carried out. Randomised controlled trials, cohort, case control, case crossover and self-controlled case series designs will be eligible; no restrictions will be placed on publication status, language and geographical or healthcare setting. The Cochrane Central Register of Controlled Trials, Embase, Global Health, Medline, Scopus and Web of Science will be searched from dates of inception to January 2017. A prespecified search strategy of medical subject headings and free text terms (in the title and abstract) for human herpesviruses AND stroke will be used. Two reviewers will independently screen titles and abstracts for eligible studies, followed by full-text screening. The reviewers will then extract data from the eligible studies using standardised, pilot-tested tables and assess risk of bias in individual studies, in line with the Cochrane Collaboration approach. The data will be synthesised in a narrative format, and meta-analyses considered where there are sufficient data. Quality of evidence will be assessed in line with theGrading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. ETHICS AND DISSEMINATION: As this is a systematic review, ethical approval is not required. The results will be submitted for peer-review publication and presented at national conferences. A lay and short summary will be disseminated on appropriate webpages. PROSPERO REGISTRATION NUMBER: CRD42017054502. PMID- 28554942 TI - MSTO1 is a cytoplasmic pro-mitochondrial fusion protein, whose mutation induces myopathy and ataxia in humans. AB - The protein MSTO1 has been localized to mitochondria and linked to mitochondrial morphology, but its specific role has remained unclear. We identified a c.22G > A (p.Val8Met) mutation of MSTO1 in patients with minor physical abnormalities, myopathy, ataxia, and neurodevelopmental impairments. Lactate stress test and myopathological results suggest mitochondrial dysfunction. In patient fibroblasts, MSTO1 mRNA and protein abundance are decreased, mitochondria display fragmentation, aggregation, and decreased network continuity and fusion activity. These characteristics can be reversed by genetic rescue. Short-term silencing of MSTO1 in HeLa cells reproduced the impairment of mitochondrial morphology and dynamics observed in the fibroblasts without damaging bioenergetics. At variance with a previous report, we find MSTO1 to be localized in the cytoplasmic area with limited colocalization with mitochondria. MSTO1 interacts with the fusion machinery as a soluble factor at the cytoplasm-mitochondrial outer membrane interface. After plasma membrane permeabilization, MSTO1 is released from the cells. Thus, an MSTO1 loss-of-function mutation is associated with a human disorder showing mitochondrial involvement. MSTO1 likely has a physiologically relevant role in mitochondrial morphogenesis by supporting mitochondrial fusion. PMID- 28554944 TI - How good is the evidence to support primary care practice? AB - Our goal was to determine the extent to which recommendations for primary care practice are informed by high-quality research-based evidence, and the extent to which they are based on evidence of improved health outcomes (patient-oriented evidence). As a substrate for study, we used Essential Evidence, an online, evidence-based, medical reference for generalists. Each of the 721 chapters makes overall recommendations for practice that are graded A, B or C using the Strength of Recommendations Taxonomy (SORT). SORT A represents consistent and good quality patient-oriented evidence; SORT B is inconsistent or limited quality patient oriented evidence and SORT C is expert opinion, usual practice or recommendations relying on surrogate or intermediate outcomes. Pairs of researchers abstracted the evidence ratings for each chapter in tandem, with discrepancies resolved by the lead author. Of 3251 overall recommendations, 18% were graded 'A', 34% were 'B' and 49% were 'C'. Clinical categories with the most 'A' recommendations were pregnancy and childbirth, cardiovascular, and psychiatric; those with the least were haematological, musculoskeletal and rheumatological, and poisoning and toxicity. 'A' level recommendations were most common for therapy and least common for diagnosis. Only 51% of recommendations are based on studies reporting patient oriented outcomes, such as morbidity, mortality, quality of life or symptom reduction. In conclusion, approximately half of the recommendations for primary care practice are based on patient-oriented evidence, but only 18% are based on patient-oriented evidence from consistent, high-quality studies. PMID- 28554943 TI - SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes. AB - Azoospermia, characterized by the absence of spermatozoa in the ejaculate, is a common cause of male infertility with a poorly characterized etiology. Exome sequencing analysis of two azoospermic brothers allowed the identification of a homozygous splice mutation in SPINK2, encoding a serine protease inhibitor believed to target acrosin, the main sperm acrosomal protease. In accord with these findings, we observed that homozygous Spink2 KO male mice had azoospermia. Moreover, despite normal fertility, heterozygous male mice had a high rate of morphologically abnormal spermatozoa and a reduced sperm motility. Further analysis demonstrated that in the absence of Spink2, protease-induced stress initiates Golgi fragmentation and prevents acrosome biogenesis leading to spermatid differentiation arrest. We also observed a deleterious effect of acrosin overexpression in HEK cells, effect that was alleviated by SPINK2 coexpression confirming its role as acrosin inhibitor. These results demonstrate that SPINK2 is necessary to neutralize proteases during their cellular transit toward the acrosome and that its deficiency induces a pathological continuum ranging from oligoasthenoteratozoospermia in heterozygotes to azoospermia in homozygotes. PMID- 28554946 TI - Cannabis legislation fails to protect Canada's youth. PMID- 28554945 TI - Genetic background and evolution of relapses in aggressive B-cell lymphomas. AB - Relapses of aggressive B-cell lymphomas pose a higher risk to affected patients because of potential treatment resistance and usually rapid tumor growth. Recent advances, such as targeting Bruton tyrosine kinase, have provided promising results in small numbers of cases, but treatment for the majority of patients remains challenging and outcomes are generally poor. A number of recent studies have utilized state-of-the-art genomic technologies in an attempt to better understand tumor genome evolution during relapse and to identify relapse-specific genetic alterations. It has been found that in some settings (e.g. diffuse large B-cell lymphomas in immunocompromised patients, secondary diffuse large B-cell lymphomas as Richter transformations) a significant part of the recurrences are clonally-unrelated de novo neoplasms, which might have distinct genomic and drug sensitivity profiles as well as different prognoses. Similar to earlier findings in indolent lymphomas, genetic tumor evolution of clonally-related relapsing aggressive B-cell lymphomas is predominantly characterized by two patterns: early divergence from a common progenitor and late divergence/linear evolution from a primary tumor. The clinical implications of these distinct patterns are not yet clear and will require additional investigation; however, it is plausible that these two patterns of recurrence are linked to different treatment-resistance mechanisms. Attempts to identify drivers of relapses result in a very heterogeneous list of affected genes and pathways as well as epigenetic mechanisms and suggest many ways of how recurrent tumors can adapt to treatment and expand their malignant properties. PMID- 28554947 TI - Disparities in infant hospitalizations in Indigenous and non-Indigenous populations in Quebec, Canada. AB - BACKGROUND: Infant mortality is higher in Indigenous than non-Indigenous populations, but comparable data on infant morbidity are lacking in Canada. We evaluated disparities in infant morbidities experienced by Indigenous populations in Canada. METHODS: We used linked population-based birth and health administrative data from Quebec, Canada, to compare hospitalization rates, an indicator of severe morbidity, in First Nations, Inuit and non-Indigenous singleton infants (< 1 year) born between 1996 and 2010. RESULTS: Our cohort included 19 770 First Nations, 3930 Inuit and 225 380 non-Indigenous infants. Compared with non-Indigenous infants, all-cause hospitalization rates were higher in First Nations infants (unadjusted risk ratio [RR] 2.05, 95% confidence interval [CI] 1.99-2.11; fully adjusted RR 1.43, 95% CI 1.37-1.50) and in Inuit infants (unadjusted RR 1.96, 95% CI 1.87-2.05; fully adjusted RR 1.37, 95% CI 1.24-1.52). Higher risks of hospitalization (accounting for multiple comparisons) were observed for First Nations infants in 12 of 16 disease categories and for Inuit infants in 7 of 16 disease categories. Maternal characteristics (age, education, marital status, parity, rural residence and Northern residence) partly explained the risk elevations, but maternal chronic illnesses and gestational complications had negligible influence overall. Acute bronchiolitis (risk difference v. non-Indigenous infants, First Nations 37.0 per 1000, Inuit 39.6 per 1000) and pneumonia (risk difference v. non-Indigenous infants, First Nations 41.2 per 1000, Inuit 61.3 per 1000) were the 2 leading causes of excess hospitalizations in Indigenous infants. INTERPRETATION: First Nations and Inuit infants had substantially elevated burdens of hospitalizations as a result of diseases of multiple systems. The findings identify substantial unmet needs in disease prevention and medical care for Indigenous infants. PMID- 28554948 TI - Antidepressant discontinuation syndrome. PMID- 28554949 TI - Atypical presentation of syphilis as an aphthous ulcer. PMID- 28554950 TI - Ectopic tooth: an unusual cause of headache. PMID- 28554951 TI - Two documents. PMID- 28554952 TI - Questions on analysis of firearm injuries study. PMID- 28554953 TI - The authors respond to: "Questions on analysis of firearm injuries study". PMID- 28554955 TI - Increased rate of early smoking in children and adolescents with attention deficit/hyperactivity disorder. PMID- 28554954 TI - More on firearm injuries among children and youth. PMID- 28554956 TI - Is Ontario's youth pharmacare proposal just a symbolic gesture? PMID- 28554957 TI - Record number of unmatched medical graduates. PMID- 28554958 TI - Is police-public health collaboration an oxymoron? PMID- 28554960 TI - Semantic dementia, progressive non-fluent aphasia and their association with amyotrophic lateral sclerosis. PMID- 28554959 TI - Longitudinal assessment of excessive daytime sleepiness in early Parkinson's disease. AB - BACKGROUND: Excessive daytime sleepiness (EDS) is common and disabling in Parkinson's disease (PD). Predictors of EDS are unclear, and data on biological correlates of EDS in PD are limited. We investigated clinical, imaging and biological variables associated with longitudinal changes in sleepiness in early PD. METHODS: The Parkinson's Progression Markers Initiative is a prospective cohort study evaluating progression markers in participants with PD who are unmedicated at baseline (n=423) and healthy controls (HC; n=196). EDS was measured with the Epworth Sleepiness Scale (ESS). Clinical, biological and imaging variables were assessed for associations with EDS for up to 3 years. A machine learning approach (random survival forests) was used to investigate baseline predictors of incident EDS. RESULTS: ESS increased in PD from baseline to year 3 (mean+/-SD 5.8+/-3.5 to 7.55+/-4.6, p<0.0001), with no change in HC. Longitudinally, EDS in PD was associated with non-tremor dominant phenotype, autonomic dysfunction, depression, anxiety and probable behaviour disorder, but not cognitive dysfunction or motor severity. Dopaminergic therapy was associated with EDS at years 2 and 3, as dose increased. EDS was also associated with presynaptic dopaminergic dysfunction, whereas biofluid markers at year 1 showed no significant associations with EDS. A predictive index for EDS was generated, which included seven baseline characteristics, including non-motor symptoms and cerebrospinal fluid phosphorylated-tau/total-tau ratio. CONCLUSIONS: In early PD, EDS increases significantly over time and is associated with several clinical variables. The influence of dopaminergic therapy on EDS is dose dependent. Further longitudinal analyses will better characterise associations with imaging and biomarkers. PMID- 28554961 TI - Atrial fibrillation is associated with anterior predominant white matter lesions in patients presenting with embolic stroke. AB - OBJECTIVE: High white matter hyperintensity (WMH) burden is commonly found on brain MRI among patients with atrial fibrillation (AF). However, whether the link between AF and WMH extends beyond a common vascular risk factor profile is uncertain. We sought to determine whether AF relates to a distinct WMH lesion pattern which may suggest specific underlying pathophysiological relationships. METHODS: We retrospectively analysed a cohort of consecutive patients presenting with embolic stroke at an academic hospital and tertiary referral centre between March 2010 and March 2014. In total, 234 patients (53% female, 74% anterior circulation infarction) fulfilled the inclusion criteria and were included in the analyses. WMH lesion distribution was classified according to previously defined categories. Multivariable logistic regression analysis was performed to determine variables associated with AF within 90 days of index hospital discharge. RESULTS: Among included patients, 114 had AF (49%). After adjustment for the CHA2DS2-VASc score (congestive heart failure, hypertension, age >=75 years (doubled), diabetes mellitus, prior stroke/TIA (doubled), vascular disease, age 65-74 years, sex category (female)) score, WMH lesion burden as assessed on the Fazekas scale, embolic stroke pattern, infarct distribution and pertinent interaction terms, AF was significantly associated with presence of anterior subcortical WMH patches (OR 3.647, 95% CI 1.681 to 7.911, p=0.001). CONCLUSIONS: AF is associated with specific WMH lesion pattern among patients with embolic stroke aetiology. This suggests that the link between AF and brain injury extends beyond thromboembolic complications to include a cardiovasculopathy that affects the brain and can be detected and characterised by WMH. PMID- 28554963 TI - Reduced reactive hyperemia may explain impaired flow-mediated dilation after on pump cardiac surgery. AB - In previous studies, Flow Mediated Dilation (FMD) was used to study the effect of cardiac surgery on endothelial function. This study investigated the effect of on pump cardiac surgery on FMD and reactive hyperemia. The FMD-response and reactive hyperemia were measured in 25 patients the morning before- and the first morning after cardiac surgery. Brachial artery diameter and blood flow were measured with ultrasound at baseline before 5 min occlusion of the blood flow to the forearm, and continuously for 3 min after release of the occlusion. An exponential wash out model was fitted to the blood flow over time. Nineteen patients remained for final data analysis. Data are mean +/- SEM The FMD response was reduced after surgery from 3.3 +/- 0.5% to 1.4 +/- 0.6% (P = 0.02). Max blood flow after cuff release was reduced from 342 +/- 30 mL preoperatively to 305 +/- 30 mL postoperatively (P < 0.00) and fell toward baseline significantly quicker; preoperative half-life was 36 +/- 2.4 sec. versus 29 +/- 1.9 sec postoperatively (P < 0.00). Resting blood flow was reduced from 84 +/- 9 mL/min to 66 +/- 9 mL/min, (P < 0.00). Brachial artery baseline diameter was unaffected by coronary artery bypass surgery (P = 0.3). The observed reduction in brachial artery FMD after surgery, by previous authors taken to represent endothelial dysfunction, may at least partly be due to reduced hyperemic flow postoperatively. In studies where FMD is measured on multiple occasions, flow data should also be included. Reduced postoperative blood flow to the arm may indicate regional differences in vascular resistance after cardiac surgery. PMID- 28554962 TI - Local transmural action potential gradients are absent in the isolated, intact dog heart but present in the corresponding coronary-perfused wedge. AB - The left ventricular (LV) coronary-perfused canine wedge preparation is a model commonly used for studying cardiac repolarization. In wedge studies, transmembrane potentials typically are recorded; whereas, extracellular electrical recordings are commonly used in intact hearts. We compared electrically measured activation recovery interval (ARI) patterns in the intact heart with those recorded at the same location in the LV wedge preparation. We also compared electrically recorded and optically obtained ARIs in the LV wedge preparation. Five Langendorff-perfused canine hearts were paced from the right atrium. Local activation and repolarization times were measured with eight transmural needle electrodes. Subsequently, left ventricular coronary-perfused wedge preparations were prepared from these hearts while the electrodes remained in place. Three electrodes remained at identical positions as in the intact heart. Both electrograms and optical action potentials were recorded (pacing cycle length 400-4000 msec) and activation and repolarization patterns were analyzed. ARIs found in the subepicardium were shorter than in the subendocardium in the LV wedge preparation but not in the intact heart. The transmural ARI gradient recorded at the cut surface of the wedge was not different from that recorded internally. ARIs recorded internally and at the cut surface in the LV wedge preparation, both correlated with optically recorded action potentials. ARI and RT gradients in the LV wedge preparation differed from those in the intact canine heart, implying that those observations in human LV wedge preparations also should be extrapolated to the intact human heart with caution. PMID- 28554964 TI - Decreasing cerebral oxygen consumption during upright tilt in vasovagal syncope. AB - We measured changes in transcranial Doppler ultrasound (TCD) and near infrared spectroscopy (NIRS) during 70 degrees upright tilt in patients with recurrent vasovagal syncope (VVS, N = 20), postural tachycardia syndrome (POTS, N = 20), and healthy controls (N = 12) aged 15-27 years old. VVS was included if they fainted during testing within 5-15 min of upright tilt. We combined TCD and NIRS to obtain estimates of percent change in the cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow velocity (CBFv), and oxygen extraction fraction (OEF). Over the course of 10 min of upright tilt, CBFv decreased from a baseline of 70 +/- 5 to 63 +/- 5 cm/sec in controls and 74 +/- 3 to 64 +/- 3 cm/sec in POTS while decreasing from 74 +/- 4 to 44 +/- 3 cm/sec in VVS CMRO2 was unchanged in POTS and controls during tilt while OEF increased by 19 +/- 3% and 15 +/- 3%, respectively. CMRO2 decreased by 31 +/- 3% in VVS during tilt while OEF only increased by 7 +/- 3%. Oxyhemoglobin decreased by 1.1 +/- 1.3 MUmol/kg brain tissue in controls, by 1.1 +/- 1.3 MUmol/kg in POTS, and 11.1 +/- 1.3 MUmol/kg in VVS CBFv and CMRO2 fell steadily in VVS during upright tilt. The deficit in CMRO2 in VVS results from inadequate OEF in the face of greatly reduced CBF. PMID- 28554965 TI - Fetuin-A aggravates lipotoxicity in podocytes via interleukin-1 signaling. AB - Sterile inflammation is considered critical in the pathogenesis of diabetic nephropathy (DN). Here we show that Fetuin-A (FetA) or lipopolysaccharide (LPS) exacerbate palmitic acid-induced podocyte death, which is associated with a strong induction of monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC). Moreover, blockage of TLR4 prevents MCP-1 and KC secretion and attenuates podocyte death induced by palmitic acid alone or combined with FetA. In addition, inhibition of interleukin-1 (IL-1) signaling by anakinra, a recombinant human IL-1Ra, or a murinized anti-IL-1beta antibody attenuates the inflammatory and ultimate cell death response elicited by FetA alone or combined with palmitic acid. In vivo short-term therapy of diabetic DBA/2J mice with an anti-IL1-beta antibody for 4 weeks prevented an increase in serum FetA and considerably decreased urinary tumor necrosis alpha (TNF-alpha), a known risk factor for DN progression. In summary, our results suggest that FetA similarly to LPS leads to an inflammatory response in podocytes, which exacerbates palmitic acid-induced podocyte death and our data imply a critical role for IL-1beta signaling in this process. The study offers the rational for prolonged in vivo studies aimed at testing anti-IL-1beta therapy for prevention and treatment of DN. PMID- 28554966 TI - The Yin and Yang of bile acid action on tight junctions in a model colonic epithelium. AB - Gastrointestinal epithelial barrier loss due to tight junction (TJ) dysfunction and bile acid-induced diarrhea are common in patients with inflammatory diseases. Although excess colonic bile acids are known to alter mucosal permeability, few studies have compared the effects of specific bile acids on TJ function. We report that the primary bile acid, chenodeoxycholic acid (CDCA), and its 7alpha dehydroxylated derivative, lithocholic acid (LCA) have opposite effects on epithelial integrity in human colonic T84 cells. CDCA decreased transepithelial barrier resistance (pore) and increased paracellular 10 kDa dextran permeability (leak), effects that were enhanced by proinflammatory cytokines (PiC [ng/mL]: TNFalpha[10] + IL-1beta[10] + IFNgamma[30]). CDCA reversed the cation selectivity of the monolayer and decreased intercellular adhesion. In contrast, LCA alone did not alter any of these parameters, but attenuated the effects of CDCA +/- PiC on paracellular permeability. CDCA, but not PiC, decreased occludin and not claudin 2 protein expression; CDCA also decreased occludin localization. LCA +/- CDCA had no effects on occludin or claudin expression/localization. While PiC and CDCA increased IL-8 production, LCA reduced both basal and PiC +/- CDCA-induced IL-8 production. TNFalpha + IL1beta increased IFNgamma, which was enhanced by CDCA and attenuated by LCA CDCA+/-PiC increased production of reactive oxygen species (ROS) that was attenuated by LCA Finally, scavenging ROS attenuated CDCA's leak, but not pore actions, and LCA enhanced this effect. Thus, in T84 cells, CDCA plays a role in the inflammatory response causing barrier dysfunction, while LCA restores barrier integrity. Understanding the interplay of LCA, CDCA, and PiC could lead to innovative therapeutic strategies for inflammatory and diarrheal diseases. PMID- 28554967 TI - Basal late sodium current is a significant contributor to the duration of action potential of guinea pig ventricular myocytes. AB - In cardiac myocytes, an enhancement of late sodium current (INaL) under pathological conditions is known to cause prolongation of action potential duration (APD). This study investigated the contribution of INaL under basal, physiological conditions to the APD Whole-cell INaL and the APD of ventricular myocytes isolated from healthy adult guinea pigs were measured at 36 degrees C. The INaL inhibitor GS967 or TTX was applied to block INaL The amplitude of basal INaL and the APD at 50% repolarization in myocytes stimulated at a frequency of 0.17 Hz were -0.24 +/- 0.02 pA/pF and 229 +/- 6 msec, respectively. GS967 (0.01-1 MUmol/L) concentration dependently reduced the basal INaL by 18 +/- 3-82 +/- 4%. At the same concentrations, GS967 shortened the APD by 9 +/- 2 to 25 +/- 1%. Similarly, TTX at 0.1-10 MUmol/L decreased the basal INaL by 13 +/- 1-94 +/- 1% and APD by 8 +/- 1-31 +/- 2%. There was a close correlation (R2 = 0.958) between the percentage inhibition of INaL and the percentage shortening of APD caused by either GS967 or TTX MTSEA (methanethiosulfonate ethylammonium, 2 mmol/L), a NaV1.5 channel blocker, reduced the INaL by 90 +/- 5%, suggesting that the NaV1.5 channel isoform is the major contributor to the basal INaL KN-93 (10 MUmol/L) and AIP (2 MUmol/L), blockers of CaMKII, moderately reduced the basal INaL Thus, this study provides strong evidence that basal endogenous INaL is a significant contributor to the APD of cardiac myocytes. In addition, the basal INaL of guinea pig ventricular myocytes is mainly generated from NaV1.5 channel isoform and is regulated by CaMKII. PMID- 28554969 TI - Setting the scene: what did we know before Rosetta? AB - This paper provides an overview of our state of knowledge about comets prior to the Rosetta mission encounter. Starting with the historical perspective, this paper discusses the development of comet science up to the modern era of space exploration. The extent to which comets are tracers of solar system formation processes or preserve pristine interstellar material has been investigated for over four decades. There is increasing evidence that in contrast with the distinct dynamical comet reservoirs we see today, comet formation regions strongly overlapped in the protoplanetary disc and there was significant migration of material in the disc during the epoch of comet formation. Comet nuclei are now known to be very low-density highly porous bodies, with very low thermal inertia, and have a range of sizes which exhibit a deficiency of very small bodies. The low thermal inertia suggests that comets may preserve pristine materials close to the surface, and that this might be accessible to sample return missions.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554968 TI - Neonatal high protein intake enhances neonatal growth without significant adverse renal effects in spontaneous IUGR piglets. AB - In humans, early high protein (HP) intake has been recommended to prevent postnatal growth restriction and complications of intrauterine growth restriction (IUGR). However, the impact of such a strategy on the kidneys remains unknown, while significant renal hypertrophy, proteinuria, and glomerular sclerosis have been demonstrated in few experimental studies. The objective of this study was to evaluate the effects of a neonatal HP formula on renal structure in IUGR piglets. Spontaneous IUGR piglets were randomly allocated to normal protein (NP, n = 10) formula or to HP formula (+50% protein content, n = 10) up to day 28 after birth. Body weight, body composition, renal functions, and structure were assessed at the end of the neonatal period. While birth weights were similar, 28-day-old HP piglets were 18% heavier than NP piglets (P < 0.01). Carcass protein content was 22% higher in HP than in NP offspring (P < 0.01). Despite a HP intake, kidney weight and glomerular fibrosis were unaltered in HP piglets. Only a 20% increase in glomerular volume was noted in HP piglets (P < 0.05) and restricted to the inner cortical area nephrons (P = 0.03). Plasma urea/creatinine ratio and proteinuria were unchanged in HP piglets. In conclusion, neonatal HP feeding in IUGR piglets significantly enhanced neonatal growth and tissue protein deposition but mildly affected glomerular volume. It can be speculated that a sustained tissue protein anabolism in response to HP intake have limited single nephron glomerular hyperfiltration. PMID- 28554970 TI - The Philae lander mission and science overview. AB - The Philae lander accomplished the first soft landing and the first scientific experiments of a human-made spacecraft on the surface of a comet. Planned, expected and unexpected activities and events happened during the descent, the touch-downs, the hopping across and the stay and operations on the surface. The key results were obtained during 12-14 November 2014, at 3 AU from the Sun, during the 63 h long period of the descent and of the first science sequence on the surface. Thereafter, Philae went into hibernation, waking up again in late April 2015 with subsequent communication periods with Earth (via the orbiter), too short to enable new scientific activities. The science return of the mission comes from eight of the 10 instruments on-board and focuses on morphological, thermal, mechanical and electrical properties of the surface as well as on the surface composition. It allows a first characterization of the local environment of the touch-down and landing sites. Unique conclusions on the organics in the cometary material, the nucleus interior, the comet formation and evolution became available through measurements of the Philae lander in the context of the Rosetta mission.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554972 TI - The composition of cometary ices. AB - The chemical composition of cometary ices provides clues for the conditions of formation and evolution of the early Solar System. A large number of molecules have been identified in cometary atmospheres, from both ground-based observations and space, including in situ investigations. This includes large organic molecules, which are also observed in star-forming regions. This paper presents a review of molecular abundances measured in cometary atmospheres from remote sensing observations with ground-based and space-based telescopes. The diversity of composition observed in comet populations is presented and discussed.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554973 TI - D2O and HDS in the coma of 67P/Churyumov-Gerasimenko. AB - The European Rosetta mission has been following comet 67P/Churyumov-Gerasimenko for 2 years, studying the nucleus and coma in great detail. For most of these 2 years the Rosetta Orbiter Sensor for Ion and Neutral Analysis (ROSINA) has analysed the volatile part of the coma. With its high mass resolution and sensitivity it was able to not only detect deuterated water HDO, but also doubly deuterated water, D2O and deuterated hydrogen sulfide HDS. The ratios for [HDO]/[H2O], [D2O]/[HDO] and [HDS]/[H2S] derived from our measurements are (1.05 +/- 0.14) * 10-3, (1.80 +/- 0.9) * 10-2 and (1.2 +/- 0.3) * 10-3, respectively. These results yield a very high ratio of 17 for [D2O]/[HDO] relative to [HDO]/[H2O]. Statistically one would expect just 1/4. Such a high value can be explained by cometary water coming unprocessed from the presolar cloud, where water is formed on grains, leading to high deuterium fractionation. The high [HDS]/[H2S] ratio is compatible with upper limits determined in low-mass star forming regions and also points to a direct correlation of cometary H2S with presolar grain surface chemistry.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554974 TI - Comets as a possible source of nanodust in the Solar System cloud and in planetary debris discs. AB - Comets, comet-like objects and their fragments are the most plausible source for the dust in both the inner heliosphere and planetary debris discs around other stars. The smallest size of dust particles in debris discs is not known and recent observational results suggest that the size distribution of the dust extends down to sizes of a few nanometres or a few tens of nanometres. In the Solar System, electric field measurements from spacecraft observe events that are explained with high-velocity impacts of nanometre-sized dust. In some planetary debris discs an observed mid- to near-infrared emission supposedly results from hot dust located in the vicinity of the star. And the observed emission is characteristic of dust of sizes a few tens of nanometres. Rosetta observations, on the other hand, provide little information on the presence of nanodust near comet 67P/Churyumov-Gerasimenko. This article describes why this is not in contradiction to the observations of nanodust in the heliosphere and in planetary debris discs. The direct ejection of nanodust from the nucleus of the comet would not contribute significantly to the observed nanodust fluxes. We discuss a scenario that nanodust forms in the interplanetary dust cloud through the high velocity collision process in the interplanetary medium for which the production rates are highest near the Sun. Likewise, fragmentation by collisions occurs near the star in planetary debris discs. The collisional fragmentation process in the inner Solar System occurs at similar velocities to those of the collisional evolution in the interstellar medium. A question for future studies is whether there is a common magic size of the smallest collision fragments and what determines this size.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554976 TI - Interaction of the solar wind with comets: a Rosetta perspective. AB - The Rosetta mission provides an unprecedented possibility to study the interaction of comets with the solar wind. As the spacecraft accompanies comet 67P/Churyumov-Gerasimenko from its very low-activity stage through its perihelion phase, the physics of mass loading is witnessed for various activity levels of the nucleus. While observations at other comets provided snapshots of the interaction region and its various plasma boundaries, Rosetta observations allow a detailed study of the temporal evolution of the innermost cometary magnetosphere. Owing to the short passage time of the solar wind through the interaction region, plasma instabilities such as ring--beam and non-gyrotropic instabilities are of less importance during the early life of the magnetosphere. Large-amplitude ultra-low-frequency (ULF) waves, the 'singing' of the comet, is probably due to a modified ion Weibel instability. This instability drives a cross-field current of implanted cometary ions unstable. The initial pick-up of these ions causes a major deflection of the solar wind protons. Proton deflection, cross-field current and the instability induce a threefold structure of the innermost interaction region with the characteristic Mach cone and Whistler wings as stationary interaction signatures as well as the ULF waves representing the dynamic aspect of the interaction.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554975 TI - Mechanical and electrostatic experiments with dust particles collected in the inner coma of comet 67P by COSIMA onboard Rosetta. AB - The in situ cometary dust particle instrument COSIMA (COmetary Secondary Ion Mass Analyser) onboard ESA's Rosetta mission has collected about 31 000 dust particles in the inner coma of comet 67P/Churyumov-Gerasimenko since August 2014. The particles are identified by optical microscope imaging and analysed by time-of flight secondary ion mass spectrometry. After dust particle collection by low speed impact on metal targets, the collected particle morphology points towards four families of cometary dust particles. COSIMA is an in situ laboratory that operates remotely controlled next to the comet nucleus. The particles can be further manipulated within the instrument by mechanical and electrostatic means after their collection by impact. The particles are stored above 0 degrees C in the instrument and the experiments are carried out on the refractory, ice-free matter of the captured cometary dust particles. An interesting particle morphology class, the compact particles, is not fragmented on impact. One of these particles was mechanically pressed and thereby crushed into large fragments. The particles are good electrical insulators and transform into rubble pile agglomerates by the application of an energetic indium ion beam during the secondary ion mass spectrometry analysis.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554977 TI - SOHO comets: 20 years and 3000 objects later. AB - We present a summary of the more than 3000 sungrazing and near-Sun comets discovered in coronagraph images returned by the Solar and Heliospheric Observatory (SOHO), since its launch in December 1995. We address each of the four main populations of objects observed by SOHO: Kreutz (sungrazing) group, Meyer group, Marsden and Kracht (96P-family) group and non-group comets. Discussions for each group include basic properties, discovery statistics and morphological appearance. In addition to updating the community on the status of the discoveries by SOHO, we also show that the rate of discovery of Kreutz sungrazers has probably remained static since approximately 2003 and we report on the first likely fragmentation pair observed within the Meyer group.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554971 TI - The 67P/Churyumov-Gerasimenko observation campaign in support of the Rosetta mission. AB - We present a summary of the campaign of remote observations that supported the European Space Agency's Rosetta mission. Telescopes across the globe (and in space) followed comet 67P/Churyumov-Gerasimenko from before Rosetta's arrival until nearly the end of the mission in September 2016. These provided essential data for mission planning, large-scale context information for the coma and tails beyond the spacecraft and a way to directly compare 67P with other comets. The observations revealed 67P to be a relatively 'well-behaved' comet, typical of Jupiter family comets and with activity patterns that repeat from orbit to orbit. Comparison between this large collection of telescopic observations and the in situ results from Rosetta will allow us to better understand comet coma chemistry and structure. This work is just beginning as the mission ends-in this paper, we present a summary of the ground-based observations and early results, and point to many questions that will be addressed in future studies.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554978 TI - Asteroid-comet continuum objects in the solar system. AB - In this review presented at the Royal Society meeting, 'Cometary science after Rosetta', I present an overview of studies of small solar system objects that exhibit properties of both asteroids and comets (with a focus on so-called active asteroids). Sometimes referred to as 'transition objects', these bodies are perhaps more appropriately described as 'continuum objects', to reflect the notion that rather than necessarily representing actual transitional evolutionary states between asteroids and comets, they simply belong to the general population of small solar system bodies that happen to exhibit a continuous range of observational, physical and dynamical properties. Continuum objects are intriguing because they possess many of the properties that make classical comets interesting to study (e.g. relatively primitive compositions, ejection of surface and subsurface material into space where it can be more easily studied, and orbital properties that allow us to sample material from distant parts of the solar system that would otherwise be inaccessible), while allowing us to study regions of the solar system that are not sampled by classical comets.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554979 TI - Cometary dust: the diversity of primitive refractory grains. AB - Comet dust is primitive and shows significant diversity. Our knowledge of the properties of primitive cometary particles has expanded significantly through microscale investigations of cosmic dust samples (anhydrous interplanetary dust particles (IDPs), chondritic porous (CP) IDPs and UltraCarbonaceous Antarctic micrometeorites, Stardust and Rosetta), as well as through remote sensing (Spitzer IR spectroscopy). Comet dust are aggregate particles of materials unequilibrated at submicrometre scales. We discuss the properties and processes experienced by primitive matter in comets. Primitive particles exhibit a diverse range of: structure and typology; distribution of constituents; concentration and form of carbonaceous and refractory organic matter; Mg- and Fe-contents of the silicate minerals; sulfides; existence/abundance of type II chondrule fragments; high-temperature calcium-aluminium inclusions and ameboid-olivine aggregates; and rarely occurring Mg-carbonates and magnetite, whose explanation requires aqueous alteration on parent bodies. The properties of refractory materials imply there were disc processes that resulted in different comets having particular selections of primitive materials. The diversity of primitive particles has implications for the diversity of materials in the protoplanetary disc present at the time and in the region where the comets formed.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554980 TI - Comets: looking ahead. AB - We outline the key questions about comets that must be answered in order to understand cometary formation in the context of the protoplanetary disc and the role of comets in the formation and evolution of the solar system. We then discuss the new understanding of comets from Rosetta and from other recent advances, including work presented by others at the discussion meeting. Finally, we suggest some key directions for future projects to better address the above questions.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554981 TI - The Rosetta mission orbiter science overview: the comet phase. AB - The international Rosetta mission was launched in 2004 and consists of the orbiter spacecraft Rosetta and the lander Philae. The aim of the mission is to map the comet 67P/Churyumov-Gerasimenko by remote sensing, and to examine its environment in situ and its evolution in the inner Solar System. Rosetta was the first spacecraft to rendezvous with and orbit a comet, accompanying it as it passes through the inner Solar System, and to deploy a lander, Philae, and perform in situ science on the comet's surface. The primary goals of the mission were to: characterize the comet's nucleus; examine the chemical, mineralogical and isotopic composition of volatiles and refractories; examine the physical properties and interrelation of volatiles and refractories in a cometary nucleus; study the development of cometary activity and the processes in the surface layer of the nucleus and in the coma; detail the origin of comets, the relationship between cometary and interstellar material and the implications for the origin of the Solar System; and characterize asteroids 2867 Steins and 21 Lutetia. This paper presents a summary of mission operations and science, focusing on the Rosetta orbiter component of the mission during its comet phase, from early 2014 up to September 2016.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554982 TI - Cometary science after Rosetta. AB - The European Space Agency's Rosetta mission ended operations on 30 September 2016 having spent over 2 years in close proximity to its target comet, 67P/Churyumov Gerasimenko. Shortly before this, in summer 2016, a discussion meeting was held to examine how the results of the mission could be framed in terms of cometary and solar system science in general. This paper provides a brief history of the Rosetta mission, and gives an overview of the meeting and the contents of this associated special issue.This article is part of the themed issue 'Cometary science after Rosetta'. PMID- 28554984 TI - The Effect of Deoxycholic Acid on Secretion and Motility in the Rat and Guinea Pig Large Intestine. AB - Background/Aims: Bile acid is an important luminal factor that affects gastrointestinal motility and secretion. We investigated the effect of bile acid on secretion in the proximal and distal rat colon and coordination of bowel movements in the guinea pig colon. Methods: The short-circuit current from the mucosal strip of the proximal and distal rat colon was compared under control conditions after induction of secretion with deoxycholic acid (DCA) as well as after inhibition of secretion with indomethacin, 1,2-bis (o-aminophenoxy) ethane N,N,N',N'-tetra-acetic acid (an intracellular calcium chelator; BAPTA), and tetrodotoxin (TTX) using an Ussing chamber. Colonic pressure patterns were also evaluated in the extracted guinea pig colon during resting, DCA stimulation, and inhibition by TTX using a newly developed pressure-sensing artificial stool. Results: The secretory response in the distal colon was proportionate to the concentration of DCA. Also, indomethacin, BAPTA, and TTX inhibited chloride secretion in response to DCA significantly (P < 0.05). However, these changes were not detected in the proximal colon. When we evaluated motility, we found that DCA induced an increase in luminal pressure at the proximal, middle, and distal sensors of an artificial stool simultaneously during the non-peristaltic period (P < 0.05). In contrast, during peristalsis, DCA induced an increase in luminal pressure at the proximal sensor and a decrease in pressure at the middle and distal sensors of the artificial stool (P < 0.05). Conclusions: DCA induced a clear segmental difference in electrogenic secretion. Also, DCA induced a more powerful peristaltic contraction only during the peristaltic period. PMID- 28554985 TI - Evaluation of the ambulatory arterial stiffness index in lead-exposed workers. AB - OBJECTIVE: Lead exposure has been associated with various cardiovascular disorders. It may also cause increased inflammation and fibrosis in the arterial system resulting in an increase in arterial stiffness. In this study, the ambulatory arterial stiffness index (AASI), which is a technique that measures arterial stiffness, was evaluated in occupationally lead-exposed workers. METHODS: In this cross-sectional study, 68 lead-exposed workers without known cardiovascular risk factors and 68 healthy subjects were evaluated according to the 24-hour ambulatory blood pressure monitorization (ABPM) profiles and blood and 24-hour urine lead levels. A regression slope of diastolic over systolic blood pressure (BP) was computed in each participant. AASI was defined as 1 minus the regression slope. RESULTS: There were no significant differences in terms of baseline demographic, clinical, echocardiographic characteristics, and ABPM profiles between the groups. In lead-exposed workers, the mean age was 34.7+/-8.1 years, and the median blood and urine lead levels were 40.5 ug/dL and 34.9 ug/L, respectively. AASI was 0.42+/-0.10 in lead-exposed workers and 0.37+/-0.10 in control subjects (p=0.007). In correlation analysis, AASI was correlated with both blood (r=0.417, p<0.001) and urine lead (r=0.242, p=0.047) levels. In regression analysis, blood lead level was found to be associated with AASI (beta=0.086, p<0.001). CONCLUSION: AASI, which is an indicator of arterial stiffness, was found to be higher in lead-exposed workers than in healthy individuals. Increased AASI may be considered an early sign of arterial involvement in case of lead exposure. PMID- 28554983 TI - CYP2J2 metabolites, epoxyeicosatrienoic acids, attenuate Ang II-induced cardiac fibrotic response by targeting Galpha12/13. AB - The arachidonic acid-cytochrome P450 2J2-epoxyeicosatrienoic acid (AA-CYP2J2-EET) metabolic pathway has been identified to be protective in the cardiovascular system. This study explored the effects of the AA-CYP2J2-EET metabolic pathway on cardiac fibrosis from the perspective of cardiac fibroblasts and underlying mechanisms. In in vivo studies, 8-week-old male CYP2J2 transgenic mice (aMHC CYP2J2-Tr) and littermates were infused with angiotensin II (Ang II) or saline for 2 weeks. Results showed that CYP2J2 overexpression increased EET production. Meanwhile, impairment of cardiac function and fibrotic response were attenuated by CYP2J2 overexpression. The effects of CYP2J2 were associated with reduced activation of the alpha subunits of G12 family G proteins (Galpha12/13)/RhoA/Rho kinase (ROCK) cascade and elevation of the NO/cyclic guanosine monophosphate (cGMP) level in cardiac tissue. In in vitro studies, cardiac fibroblast activation, proliferation, migration, and collagen production induced by Ang II were associated with activation of the Galpha12/13/RhoA/ROCK pathway, which was inhibited by exogenous 11,12-EET. Moreover, silencing of Galpha12/13 or RhoA exerted similar effects as 11,12-EET. Furthermore, inhibitory effects of 11,12 EET on Galpha12/13 were blocked by NO/cGMP pathway inhibitors. Our findings indicate that enhancement of the AA-CYP2J2-EET metabolic pathway by CYP2J2 overexpression attenuates Ang II-induced cardiac dysfunction and fibrosis by reducing the fibrotic response of cardiac fibroblasts by targeting the Galpha12/13/RhoA/ROCK pathway via NO/cGMP signaling. PMID- 28554986 TI - Connexin 43 is involved in the sympathetic atrial fibrillation in canine and canine atrial myocytes. AB - OBJECTIVE: Atrial fibrillation (AF) is the most common rapid cardiac arrhythmia associated with high morbidity and mortality. Stimulation of the sympathetic nerve is involved in AF occurrence. The gap junction protein connexin 43 (Cx43) plays a key role in electrical conduction velocity in cardiac tissues, and under expression of Cx43 was linked with AF. The aim of this study was to investigate whether Cx43 was involved in sympathetic AF. METHODS: Fifteen dogs were randomly divided into 3 groups (5 in each group). Sympathetic AF was induced in dogs and isolated canine atrial myocytes by isoproterenol (ISO) perfusion and rapid atrium pacing (RAP). The expression levels of nerve growth factor (NGF) and tyrosine hydroxylase (TH) in the atrial tissues were detected using immunohistochemical staining. The transcription and protein expression of Cx43 in the AF cell model was measured. Subsequently, Cx43 was blocked by short interfering (si) RNA in atrial myocytes and the gap junctional intercellular communication was detected using the scrape-loading and dye transfer assay. RESULTS: Sympathetic AF was successfully induced by a combination of ISO perfusion and RAP. The expression levels of NGF and TH were increased in the RAP group, and further increased in the RAP + ISO group. Tissue samples from the AF dogs had a lower Cx43 level than those of the control group (p<0.05). The expressions of mRNA and protein of Cx43 in sympathetic AF cell model decreased by 26% and 28%, respectively, when compared with the control group, with p<0.05. Silencing Cx43 in cells by siRNA could also efficiently reduce Cx43 expression. The relative levels of Cx45 mRNA were decreased by 73% compared with unaffected cells. The scrape-loading and dye transfer assay showed that gap junctional intercellular communication was hampered in the sympathetic AF cell model and silencing Cx43 could impede channel conduction. CONCLUSION: The results suggested that low expression of Cx43 was involved in sympathetic AF by influencing intercellular channel conduction. Intervention of Cx43 expression might be an appealing therapy to sympathetic AF. PMID- 28554987 TI - The impact of cardiac rhythm on the mitral valve area and gradient in patients with mitral stenosis. AB - OBJECTIVE: The aim of this study was to evaluate the effect of cardiac rhythm on the echocardiographic mitral valve area (MVA) and transmitral gradient calculation in relation to net atrioventricular compliance (Cn). METHODS: Patients (n=22) with mild or moderate pure rheumatic mitral stenosis (MS) (MVA <2 cm2 and MVA >1 cm2) and atrial fibrillation (AF) were evaluated. All patients underwent transthoracic electrical DC cardioversion under amiodarone treatment. Nineteen of the 22 patients were successfully converted to sinus rhythm (SR). The patients were evaluated with transthoracic echocardiography before and two to three days after DC cardioversion. In order to deal with variable R-R intervals, the measurements were averaged on five to eight consecutive beats in AF. Cn was calculated with a previously validated equation [Cn (mL/mm Hg)=1.270 x MVA/E-wave downslope]. The Cn difference between AF and SR was calculated as follows: [(AF Cn-SR Cn)/AF Cn] x 100. The percentage gradient (mean or maximal) difference between AF and SR was calculated as follows: [AF gradient (mean or maximal) - SR gradient (mean or maximal)]/[AF gradient (mean or maximal)] x 100. RESULTS: The MVA was lower (MVA planimetric; 1.62+/-0.29 vs. 1.54+/-0.27; p=.003, MVA PHT; 1.66+/-0.30 vs. 1.59+/-0.26; p=0.01) but transmitral gradient (mean gradient; 6.49+/-2.51 vs. 8.89+/-3.52; p=0.001, maximal gradient: 16.94+/-5.11 vs. 18.57+/ 4.54; p=0.01) and Cn values (5.37+/-0.77 vs. 6.26+/-0.64; p<0.001) were higher in the AF than SR. There was a significant correlation between Cn difference and transmitral gradient difference (mean and maximal) (Cn difference-mean gradient difference; r=0.46; p=0.05; Cn difference-maximal gradient difference; r=0.72; p=0.001). CONCLUSION: Cardiac rhythm has a significant impact on echocardiographic evaluation of MVA, transmitral gradient, and Cn in patients with MS. PMID- 28554988 TI - Effects of garlic on brachial endothelial function and capacity of plasma to mediate cholesterol efflux in patients with coronary artery disease. AB - OBJECTIVE: This study investigated the effects of garlic on brachial endothelial function and THP-1 macrophage cholesterol efflux (CE) and examined whether garlic modulates ATP-binding cassette (ABC) A1 and ABCG1 mRNA expressions in peripheral blood mononuclear cells (PBMCs) isolated from patients with coronary artery disease (CAD). METHODS: In this randomized, placebo-controlled trial, patients with CAD were randomly divided into two groups: those receiving garlic powder or placebo tablets twice daily for 3 months. Brachial flow-mediated dilation (FMD) was assessed using ultrasound. Fasting blood samples were collected before and after period and PBMC and plasma were isolated. Human THP-1 monocytes were differentiated into macrophages, labeled with 3H-cholesterol, and incubated with plasma samples, and CE was assessed. ABCA1 and ABCG1 mRNA expressions were determined in PBMCs. RESULTS: After 3 months, brachial FMD values significantly improved (50.7%) in the garlic group compared with those in the placebo group (p=0.016). High-sensitive C-reactive protein (hs-CRP) levels significantly decreased in the garlic group, but the difference between the two groups was not statistically significant. No significant difference was observed with regard to CE and ABCA1 and ABCG1 mRNA expressions in PBMCs. CE was negatively correlated with hs-CRP levels. CONCLUSION: Short-term treatment with garlic may improve the endothelial function and may affect hs-CRP levels; however, it could neither significantly improve THP-1 macrophage CE nor affect ABCA1 or ABCG1 expressions in PBMCs. PMID- 28554989 TI - Previous cerebrovascular disease is an important predictor of clinical outcomes in elderly patients with percutaneous coronary interventions: The Nobori-Biolimus eluting stent prospective multicenter 1-year observational registry in South Korea. AB - OBJECTIVE: The appropriate selection of elderly patients for revascularization has become increasingly important because these subsets of patients are more likely to experience a major cardiac or cerebrovascular event-percutaneous coronary intervention (PCI). The objective of this study was to determine important independent risk factor for predicting clinical outcomes in the elderly patients after successful PCI, particularly in a series of South Korean population. METHODS: This study is prospective, multicenter, observational cross sectional study. A total of 1,884 consecutive patients who underwent successful PCI with Nobori(r) Biolimus A9-eluting stents were enrolled between April 2010 and December 2012. They were divided into two groups according to the age: patients <75 years old (younger patient group) and >=75 years old (elderly patient group). The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE) at 1-year after index PCI. RESULTS: The 1-year cumulative incidence of MACCE (12.9% vs. 4.3%, p<0.001) and total death (7.1% vs. 1.5%, p<0.001) was significantly higher in the elderly group than in younger group. Previous cerebrovascular disease was significantly correlated with MACCE in elderly patients 1-year after PCI (hazard ratio, 2.804; 95% confidence interval, 1.290-6.093 p=0.009). CONCLUSION: Previous cerebrovascular disease is important independent predictor of the MACCE in elderly patients at 1-year after PCI with Nobori(r) Biolimus A9-eluting stents especially in a series of South Korean population. Therefore, careful PCI with intensive monitoring and management can improve major clinical outcomes after successful PCI in elderly patients with previous cerebrovascular disease compared with younger patients. PMID- 28554990 TI - The role of SCUBE1 in the pathogenesis of no-reflow phenomenon presenting with ST segment elevation myocardial infarction. AB - OBJECTIVE: SCUBE1 [signal peptide-CUB (complement C1r/C1 s)-EGF (epidermal growth factor)-like domain-containing protein 1] might function as a novel platelet endothelial adhesion molecule and play pathological roles in cardiovascular biology. Acute myocardial infarction is one of the most common causes of death in modern society. The concept of "no reflow" (NR) refers to a state of myocardial tissue hypoperfusion in the presence of a patent epicardial coronary artery. The main mechanisms of this phenomenon are thought to be high platelet activity and much thrombus burden. So, we researched the role of SCUBE1 in the pathogenesis of NR. METHODS: A total of 142 patients with ST elevation myocardial infarction (STEMI) (n=42 with NR and n=100 without NR) and 50 healthy individuals were prospectively case-control recruited between March 2015 and October 2016 from our outpatient clinics of cardiology department. Patients with STEMI were diagnosed according to American Heart Association (AHA) guideline for the management of STEMI. RESULTS: The mean SCUBE1 levels of the control subjects were 34+/-8.4 ng/mL, the mean SCUBE1 levels of patients with STEMI who were treated successfully with primary percutaneous coronary intervention (PCI) were 51+/-6.2, and the mean SCUBE1 levels of patients with STEMI who had NR phenomenon after primary PCI procedure were 97.2+/-8.9 ng/mL. CONCLUSION: In our opinion, SCUBE1 might contribute to NR phenomenon via thrombus activation and aggregation. The pathophysiology of NR phenomenon is unclear. The present study is the first clinical study that demonstrated that serum SCUBE1 level was significantly higher in patients with NR and that serum SCUBE1 was an independent predictor for the presence of NR in our study population. PMID- 28554991 TI - Changes of Microrna Levels in Plasma of Patients with Rectal Cancer during Chemoradiotherapy. AB - Since the response to chemoradiotherapy in patients with locally advanced rectal cancer is heterogeneous, valid biomarkers are needed to monitor tumor response. Circulating microRNAs are promising candidates, however analyses of circulating microRNAs in rectal cancer are still rare. 111 patients with rectal cancer and 46 age-matched normal controls were enrolled. The expression levels of 30 microRNAs were analyzed in 17 pre-treatment patients' plasma samples. Differentially regulated microRNAs were validated in 94 independent patients. For 52 of the 94 patients a paired comparison between pre-treatment and post-treatment samples was performed. miR-17, miR-18b, miR-20a, miR-31, and miR-193a_3p, were significantly downregulated in pre-treatment plasma samples of patients with rectal cancer (p < 0.05). miR-29c, miR-30c, and miR-195 showed a trend of differential regulation. After validation, miR-31 and miR-30c were significantly deregulated by a decrease of expression. In 52 patients expression analyses of the 8 microRNAs in matched pre-treatment and post-treatment samples showed a significant decrease for all microRNAs (p < 0.05) after treatment. Expression levels of miR-31 and miR-30c could serve as valid biomarkers if validated in a prospective study. Plasma microRNA expression levels do not necessarily represent miRNA expression levels in tumor tissue. Also, expression levels of microRNAs change during multimodal therapy. PMID- 28554992 TI - Dialysis Procedures Alter Metabolic Conditions. AB - A progressive chronic kidney disease results in retention of various substances that more or less contribute to dysfunction of various metabolic systems. The accumulated substances are denominated uremic toxins. Although many toxins remain undetected, numerous newly defined toxins participate in the disturbance of food breakdown. In addition, toxic effects may downregulate other pathways, resulting in a reduced ability of free fatty acid breakdown by lipoprotein lipase (LPL) and hepatic lipase (HL). Dialysis may even worsen metabolic functions. For LPL and HL, the use of heparin and low molecular weight heparin as anticoagulation during hemodialysis (HD) initiate a loss of these enzymes from their binding sites and degradation, causing a temporary dysregulation in triglyceride breakdown. This lack of function will cause retention of the triglyceride containing lipids for at least 8 h. In parallel, the breakdown into free fatty acids is limited, as is the energy supply by them. This is repeated thrice a week for a normal HD patient. In addition, dialysis will cause a loss of amino acids and disturb glucose metabolism depending on the dialysates used. The addition of glucose in the dialysate may support oxidation of carbohydrate and the retention of Amadori products and subsequent tissue alterations. To avoid these effects, it seems necessary to further study the effects of anticoagulation in HD, the extent of use of glucose in the dialysate, and the supplementation of amino acids. PMID- 28554993 TI - A Review of the Structure, Preparation, and Application of NLCs, PNPs, and PLNs. AB - Nanostructured lipid carriers (NLCs) are modified solid lipid nanoparticles (SLNs) that retain the characteristics of the SLN, improve drug stability and loading capacity, and prevent drug leakage. Polymer nanoparticles (PNPs) are an important component of drug delivery. These nanoparticles can effectively direct drug delivery to specific targets and improve drug stability and controlled drug release. Lipid-polymer nanoparticles (PLNs), a new type of carrier that combines liposomes and polymers, have been employed in recent years. These nanoparticles possess the complementary advantages of PNPs and liposomes. A PLN is composed of a core-shell structure; the polymer core provides a stable structure, and the phospholipid shell offers good biocompatibility. As such, the two components increase the drug encapsulation efficiency rate, facilitate surface modification, and prevent leakage of water-soluble drugs. Hence, we have reviewed the current state of development for the NLCs', PNPs', and PLNs' structures, preparation, and applications over the past five years, to provide the basis for further study on a controlled release drug delivery system. PMID- 28554994 TI - Total Synthesis and Pharmacological Investigation of Cordyheptapeptide A. AB - The present investigation reports the synthesis of a phenylalanine-rich N methylated cyclopeptide, cordyheptapeptide A (8), previously isolated from the insect pathogenic fungus Cordyceps sp. BCC 1788, accomplished through the coupling of N-methylated tetrapeptide and tripeptide fragments followed by cyclization of the linear heptapeptide unit. Structure elucidation of the newly synthesized cyclopolypeptide was performed by means of FT-IR, 1H-NMR, 13C-NMR, and fast atom bombardment mass spectrometry (FABMS), and screened for its antibacterial, antidermatophytic, and cytotoxic potential. According to the antimicrobial activity results, the newly synthesized N-Methylated cyclopeptide exhibited potent antibacterial activity against Gram-negative bacteria Pseudomonas aeruginosa and Klebsiella pneumoniae and antifungal activity against dermatophytes Trichophyton mentagrophytes and Microsporum audouinii at a concentration of 6 MUg/mL, in comparison to the reference drugs, gatifloxacin and griseofulvin. In addition, cyclopolypeptide 8 displayed suitable levels of cytotoxicity against Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines. PMID- 28554996 TI - DOA Finding with Support Vector Regression Based Forward-Backward Linear Prediction. AB - Direction-of-arrival (DOA) estimation has drawn considerable attention in array signal processing, particularly with coherent signals and a limited number of snapshots. Forward-backward linear prediction (FBLP) is able to directly deal with coherent signals. Support vector regression (SVR) is robust with small samples. This paper proposes the combination of the advantages of FBLP and SVR in the estimation of DOAs of coherent incoming signals with low snapshots. The performance of the proposed method is validated with numerical simulations in coherent scenarios, in terms of different angle separations, numbers of snapshots, and signal-to-noise ratios (SNRs). Simulation results show the effectiveness of the proposed method. PMID- 28554995 TI - Curcuma mangga-Mediated Synthesis of Gold Nanoparticles: Characterization, Stability, Cytotoxicity, and Blood Compatibility. AB - The utilization of toxic chemicals as reducing and stabilizing agents in the preparation of gold nanoparticles (AuNPs) has increased in vivo toxicity and thus limited its application in clinical settings. Herein, we propose an alternative method of preparing highly stable AuNPs, where non-toxic Curcuma mangga (CM) extract was used as a single reducing and stabilizing agent to overcome the aforementioned constraints. The morphological images enunciated that the homogeneously dispersed AuNPs exhibited spherical morphology with an average particle diameter of 15.6 nm. Fourier Transform infrared (FTIR) and cyclic voltammetry analysis demonstrated that carbonyl groups of terpenoids in CM extract played an important role in the formation and stabilization of AuNPs. Green-synthesized AuNPs were found to have good stability in physiological media after 24 h of dispersion. The AuNPs were also cytocompatible with human colon fibroblast cell (CCD-18Co) and human lung fibroblast cell (MRC-5). Hemocompatibility tests revealed that the AuNPs were blood-compatible, with less than 10% of hemolysis without any aggregation of erythrocytes. The current study suggests potential in employing a CM-extract-based method in the preparation of AuNPs for anticancer diagnosis and therapy. PMID- 28554997 TI - Direct vs. Expressed Breast Milk Feeding: Relation to Duration of Breastfeeding. AB - BACKGROUND: Studies examining direct vs. expressed breast milk feeding are scarce. We explored the predictors of mode of breastfeeding and its association with breastfeeding duration in a multi-ethnic Asian population. METHODS: We included 541 breastfeeding mother-infant pairs from the Growing Up in Singapore Toward healthy Outcomes cohort. Mode of breastfeeding (feeding directly at the breast, expressed breast milk (EBM) feeding only, or mixed feeding (a combination of the former 2 modes)) was ascertained at three months postpartum. Ordinal logistic regression analyses identified predictors of breast milk expression. Cox regression models examined the association between mode of breastfeeding and duration of any and of full breastfeeding. RESULTS: Maternal factors independently associated with a greater likelihood of breast milk expression instead of direct breastfeeding were Chinese (vs. Indian) ethnicity, (adjusted odds ratio, 95% CI; 3.41, 1.97-5.91), tertiary education (vs. secondary education or lower) (2.22, 1.22-4.04), primiparity (1.54, 1.04-2.26) and employment during pregnancy (2.53, 1.60-4.02). Relative to those who fed their infants directly at the breast, mothers who fed their infants EBM only had a higher likelihood of early weaning among all mothers who were breastfeeding (adjusted hazard ratio, 95% CI; 2.20, 1.61-3.02), and among those who were fully breastfeeding (2.39, 1.05-5.41). Mothers who practiced mixed feeding, however, were not at higher risk of earlier termination of any or of full breastfeeding. CONCLUSIONS: Mothers who fed their infants EBM exclusively, but not those who practiced mixed feeding, were at a higher risk of terminating breastfeeding earlier than those who fed their infants directly at the breast. More education and support are required for women who feed their infants EBM only. PMID- 28554998 TI - Nutritional Vitamin D in Renal Transplant Patients: Speculations and Reality. AB - Reduced levels of nutritional vitamin D are commonly observed in most chronic kidney disease (CKD) patients and particularly in patients who have received a kidney transplant (KTx). In the complex clinical scenario characterizing the recipients of a renal graft, nutritional vitamin D deficiency has been put in relation not only to the changes of mineral and bone metabolism (MBM) after KTx, but also to most of the medical complications which burden KTx patients. In fact, referring to its alleged pleiotropic (non-MBM related) activities, vitamin D has been claimed to play some role in the occurrence of cardiovascular, metabolic, immunologic, neoplastic and infectious complications commonly observed in KTx recipients. Furthermore, low nutritional vitamin D levels have also been connected with graft dysfunction occurrence and progression. In this review, we will discuss the purported and the demonstrated effects of native vitamin D deficiency/insufficiency in most of the above mentioned fields, dealing separately with the MBM-related and the pleiotropic effects. PMID- 28554999 TI - The Impact of Prenatal Organophosphate Pesticide Exposures on Thai Infant Neurodevelopment. AB - A birth cohort was begun to investigate the levels and sources of pesticide exposure in pregnant women living in Thailand, and to examine the effects of pesticide exposure on infant neurodevelopment at five months of age. Subjects were interviewed using questionnaires regarding their demographic characteristics, educational background, and work and home activities related to pesticide exposures. Spot urine samples were collected at 28 weeks gestation and analyzed by gas chromatography-mass spectrometry to determine maternal metabolite levels of organophosphate pesticides including dimethyl phosphate (DMP); total DEP (diethyl phosphate (DEP), diethyl thiophosphate (DETP), and diethyl dithiophosphate (DEDTP), and total DAP (the sum of all metabolite levels). At five months of age, infant development was evaluated using the Bayley Scales of Infant and Toddler Development-III (Bayley-III). Higher total DEP and total DAP metabolite levels from the mother at 28 weeks' gestation were significantly associated with reduced motor composite scores on the Bayley-III at five months of age. The total DEP levels were also significantly associated with reduced cognitive composite scores. Prenatal concentrations of maternal urinary metabolites were associated with infant cognitive and motor development. The results of several studies now suggest the need for public health intervention to reduce prenatal pesticide exposures from both agricultural and domestic use. PMID- 28555000 TI - Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors. AB - The enzyme geranylgeranyl diphosphate synthase (GGDPS) catalyzes the synthesis of the 20-carbon isoprenoid geranylgeranyl diphosphate (GGPP). GGPP is the isoprenoid donor for protein geranylgeranylation reactions catalyzed by the enzymes geranylgeranyl transferase (GGTase) I and II. Inhibitors of GGDPS result in diminution of protein geranylgeranylation through depletion of cellular GGPP levels, and there has been interest in GGDPS inhibitors as potential anti-cancer agents. Here we discuss recent advances in the development of GGDPS inhibitors, including insights gained by structure-function relationships, and review the preclinical data that support the continued development of this novel class of drugs. PMID- 28555001 TI - Enhancement of Biomass and Lipid Productivities of Water Surface-Floating Microalgae by Chemical Mutagenesis. AB - Water surface-floating microalgae have great potential for biofuel applications due to the ease of the harvesting process, which is one of the most problematic steps in conventional microalgal biofuel production. We have collected promising water surface-floating microalgae and characterized their capacity for biomass and lipid production. In this study, we performed chemical mutagenesis of two water surface-floating microalgae to elevate productivity. Floating microalgal strains AVFF007 and FFG039 (tentatively identified as Botryosphaerella sp. and Chlorococcum sp., respectively) were exposed to ethyl methane sulfonate (EMS) or 1-methyl-3-nitro-1-nitrosoguanidine (MNNG), and pale green mutants (PMs) were obtained. The most promising FFG039 PM formed robust biofilms on the surface of the culture medium, similar to those formed by wild type strains, and it exhibited 1.7-fold and 1.9-fold higher biomass and lipid productivities than those of the wild type. This study indicates that the chemical mutation strategy improves the lipid productivity of water surface-floating microalgae without inhibiting biofilm formation and floating ability. PMID- 28555003 TI - FLOWERING LOCUS T Triggers Early and Fertile Flowering in Glasshouse Cassava (Manihot esculenta Crantz). AB - Accelerated breeding of plant species has the potential to help challenge environmental and biochemical cues to support global crop security. We demonstrate the over-expression of ArabidopsisFLOWERING LOCUS T in Agrobacterium mediated transformed cassava (Manihot esculenta Crantz; cultivar 60444) to trigger early flowering in glasshouse-grown plants. An event seldom seen in a glasshouse environment, precocious flowering and mature inflorescence were obtained within 4-5 months from planting of stem cuttings. Manual pollination using pistillate and staminate flowers from clonal propagants gave rise to viable seeds that germinated into morphologically typical progeny. This strategy comes at a time when accelerated crop breeding is of increasing importance to complement progressive genome editing techniques. PMID- 28555002 TI - Cellular and Molecular Targets of Resveratrol on Lymphoma and Leukemia Cells. AB - Resveratrol (RSV) is a well known chemopreventive molecule featuring anti-cancer properties. Our paper describes the main molecular targets of RSV linked to its antiproliferative activity on lymphoma and leukemia experimental models. It discusses further the most recent and most promising among these molecular targets for a translational application. PMID- 28555006 TI - Underwater Depth and Temperature Sensing Based on Fiber Optic Technology for Marine and Fresh Water Applications. AB - Oceanic conditions play an important role in determining the effects of climate change and these effects can be monitored through the changes in the physical properties of sea water. In fact, Oceanographers use various probes for measuring the properties within the water column. CTDs (Conductivity, Temperature and Depth) provide profiles of physical and chemical parameters of the water column. A CTD device consists of Conductivity (C), Temperature (T) and Depth (D) probes to monitor the water column changes with respect to relative depth. An optical fibre-based point sensor used as a combined pressure (depth) and temperature sensor and the sensor system are described. Measurements accruing from underwater trials of a miniature sensor for pressure (depth) and temperature in the ocean and in fresh water are reported. The sensor exhibits excellent stability and its performance is shown to be comparable with the Sea-Bird Scientific commercial sensor: SBE9Plus. PMID- 28555004 TI - Epigenetic Signature: A New Player as Predictor of Clinically Significant Prostate Cancer (PCa) in Patients on Active Surveillance (AS). AB - Widespread prostate-specific antigen (PSA) testing notably increased the number of prostate cancer (PCa) diagnoses. However, about 30% of these patients have low risk tumors that are not lethal and remain asymptomatic during their lifetime. Overtreatment of such patients may reduce quality of life and increase healthcare costs. Active surveillance (AS) has become an accepted alternative to immediate treatment in selected men with low-risk PCa. Despite much progress in recent years toward identifying the best candidates for AS in recent years, the greatest risk remains the possibility of misclassification of the cancer or missing a high risk cancer. This is particularly worrisome in men with a life expectancy of greater than 10-15 years. The Prostate Cancer Research International Active Surveillance (PRIAS) study showed that, in addition to age and PSA at diagnosis, both PSA density (PSA-D) and the number of positive cores at diagnosis (two compared with one) are the strongest predictors for reclassification biopsy or switching to deferred treatment. However, there is still no consensus upon guidelines for placing patients on AS. Each institution has its own protocol for AS that is based on PRIAS criteria. Many different variables have been proposed as tools to enrol patients in AS: PSA-D, the percentage of freePSA, and the extent of cancer on biopsy (number of positive cores or percentage of core involvement). More recently, the Prostate Health Index (PHI), the 4 Kallikrein (4K) score, and other patient factors, such as age, race, and family history, have been investigated as tools able to predict clinically significant PCa. Recently, some reports suggested that epigenetic mapping differs significantly between cancer patients and healthy subjects. These findings indicated as future prospect the use of epigenetic markers to identify PCa patients with low-grade disease, who are likely candidates for AS. This review explores literature data about the potential of epigenetic markers as predictors of clinically significant disease. PMID- 28555005 TI - Electron Paramagnetic Resonance (EPR) Spectroscopy in Studies of the Protective Effects of 24-Epibrasinoide and Selenium against Zearalenone-Stimulation of the Oxidative Stress in Germinating Grains of Wheat. AB - These studies concentrate on the possibility of using selenium ions and/or 24 epibrassinolide at non-toxic levels as protectors of wheat plants against zearalenone, which is a common and widespread mycotoxin. Analysis using the UHPLC MS technique allowed for identification of grains having the stress-tolerant and stress-sensitive wheat genotype. When germinating in the presence of 30 uM of zearalenone, this mycotoxin can accumulate in both grains and hypocotyls germinating from these grains. Selenium ions (10 uM) and 24-epibrassinolide (0.1 uM) introduced together with zearalenone decreased the uptake of zearalenone from about 295 to 200 ng/g and from about 350 to 300 ng/g in the grains of tolerant and sensitive genotypes, respectively. As a consequence, this also resulted in a reduction in the uptake of zearalenone from about 100 to 80 ng/g and from about 155 to 128 ng/g in the hypocotyls from the germinated grains of tolerant and sensitive wheat, respectively. In the mechanism of protection against the zearalenone-induced oxidative stress, the antioxidative enzymes-mainly superoxide dismutase (SOD) and catalase (CAT)-were engaged, especially in the sensitive genotype. Electron paramagnetic resonance (EPR) studies allowed for a description of the chemical character of the long-lived organic radicals formed in biomolecular structures which are able to stabilize electrons released from reactive oxygen species as well as the changes in the status of transition paramagnetic metal ions. The presence of zearalenone drastically decreased the amount of paramagnetic metal ions-mainly Mn(II) and Fe(III)-bonded in the organic matrix. This effect was particularly found in the sensitive genotype, in which these species were found at a smaller level. The protective effect of selenium ions and 24-epibrassinolide originated from their ability to inhibit the destruction of biomolecules by reactive oxygen species. An increased ability to defend biomolecules against zearalenone action was observed for 24 epibrassinolide. PMID- 28555007 TI - B-Myb Is Up-Regulated and Promotes Cell Growth and Motility in Non-Small Cell Lung Cancer. AB - B-Myb is a transcription factor that is overexpressed and plays an oncogenic role in several types of human cancers. However, its potential implication in lung cancer remains elusive. In the present study, we have for the first time investigated the expression profile of B-Myb and its functional impact in lung cancer. Expression analysis by quantificational real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry demonstrated that B-Myb expression is aberrantly overexpressed in non-small cell lung cancer (NSCLC), and positively correlated with pathologic grade and clinical stage of NSCLC. A gain-of-function study revealed that overexpression of B-Myb significantly increases lung cancer cell growth, colony formation, migration, and invasion. Conversely, a loss-of function study showed that knockdown of B-Myb decreases cell growth, migration, and invasion. B-Myb overexpression also promoted tumor growth in vivo in a NSCLC xenograft nude mouse model. A molecular mechanistic study by RNA-sequencing (RNA seq) analysis showed that B-Myb overexpression causes up-regulation of various downstream genes (e.g., COL11A1, COL6A1, FN1, MMP2, NID1, FLT4, INSR, and CCNA1) and activation of multiple critical pathways (e.g., extracellular signal regulated kinases (ERK) and phosphorylated-protein kinase B (Akt) signaling pathways) involved in cell proliferation, tumorigenesis, and metastasis. Collectively, our results indicate a tumor-promoting role for B-Myb in NSCLC and thus imply its potential as a target for the diagnosis and/or treatment of NSCLC. PMID- 28555009 TI - Acute Regression in Young People with Down Syndrome. AB - Abstract: Adolescents and young adults with Down syndrome (DS) can present a rapid regression with loss of independence and daily skills. Causes of regression are unknown and treatment is most of the time symptomatic. We did a retrospective cohort study of regression cases: patients were born between 1959 and 2000, and were followed from 1984 to now. We found 30 DS patients aged 11 to 30 years old with history of regression. Regression occurred regardless of the cognitive level (severe, moderate, or mild intellectual disability (ID)). Patients presented psychiatric symptoms (catatonia, depression, delusions, stereotypies, etc.), partial or total loss of independence in activities of daily living (dressing, toilet, meals, and continence), language impairment (silence, whispered voice, etc.), and loss of academic skills. All patients experienced severe emotional stress prior to regression, which may be considered the trigger. Partial or total recovery was observed for about 50% of them. In our cohort, girls were more frequently affected than boys (64%). Neurobiological hypotheses are discussed as well as preventative and therapeutic approaches. PMID- 28555010 TI - Adaptive Data Aggregation and Compression to Improve Energy Utilization in Solar Powered Wireless Sensor Networks. AB - A node in a solar-powered wireless sensor network (WSN) collects energy when the sun shines and stores it in a battery or capacitor for use when no solar power is available, in particular at night. In our scheme, each tiny node in a WSN periodically determines its energy budget, which takes into account its residual energy, and its likely acquisition and consumption. If it expects to acquire more energy than it can store, the data which has it has sensed is aggregated with data from other nodes, compressed, and transmitted. Otherwise, the node continues to sense data, but turns off its wireless communication to reduce energy consumption. We compared several schemes by simulation. Our scheme reduced the number of nodes forced to black out due to lack of energy so that more data arrives at the sink node. PMID- 28555011 TI - The IL-6 Gene Promoter SNP and Plasma IL-6 in Response to Diet Intervention. AB - We recently reported that interleukin-6 (IL-6), an inflammatory marker associated with breast pathology and the development of breast cancer, decreases with diet intervention and weight loss in both insulin-sensitive and insulin-resistant obese women. Here, we tested whether an individual's genotype at an IL6 SNP, rs1800795, which has previously been associated with circulating IL-6 levels, contributes to changes in IL-6 levels or modifies the effect of diet composition on IL-6 in these women. We genotyped rs1800795 in overweight/obese women (N = 242) who were randomly assigned to a lower fat (20% energy), higher carbohydrate (65% energy) diet; a lower carbohydrate (45% energy), higher fat (35% energy) diet; or a walnut-rich (18% energy), higher fat (35% energy), lower carbohydrate (45% energy) diet in a 1-year weight loss intervention study of obesity-related biomarkers for breast cancer incidence and mortality. Plasma IL-6 levels were measured at baseline, 6 and 12 months. At baseline, individuals with a CC genotype had significantly lower IL-6 levels than individuals with either a GC or GG genotype (p < 0.03; 2.72 pg/mL vs. 2.04 pg/mL), but this result was not significant when body mass index (BMI) was accounted for; the CC genotype group had lower BMI (p = 0.03; 32.5 kg/m2 vs. 33.6 kg/m2). We did not observe a 2-way interaction of time*rs1800795 genotype or diet*rs1800795 genotype. Our findings provide evidence that rs1800795 is associated with IL-6 levels, but do not support a differential interaction effect of rs1800795 and diet composition or time on changes in circulating IL-6 levels. Diet intervention and weight loss are an important strategy for reducing plasma IL-6, a risk factor of breast cancer in women, regardless of their rs1800795 genotype. PMID- 28555008 TI - Different Intestinal Microbial Profile in Over-Weight and Obese Subjects Consuming a Diet with Low Content of Fiber and Antioxidants. AB - Obesity has been related to an increased risk of multiple diseases in which oxidative stress and inflammation play a role. Gut microbiota has emerged as a mediator in this interaction, providing new mechanistic insights at the interface between fat metabolism dysregulation and obesity development. Our aim was to analyze the interrelationship among obesity, diet, oxidative stress, inflammation and the intestinal microbiota in 68 healthy adults (29.4% normal-weight). Diet was assessed through a food frequency questionnaire and converted into nutrients and dietary compounds using food composition tables. The intestinal microbiota was assessed by quantitative PCR, fecal short chain fatty acids by gas chromatography and serum biomarkers by standard protocols. Higher levels of malondialdehyde (MDA), C reactive protein (CRP), serum leptin, glucose, fat percentage and the intestinal Lactobacillus group were found in the obese people. Cluster analysis of body mass index, fat mass, glucose, LDL/HDL ratio, leptin, MDA and CRP classified the subjects into two groups. The levels of the intestinal Bacteroides-Prevotella-Porphyromonas group were lower in the cluster and linked to a higher pro-oxidant and pro-inflammatory status, whose individuals also had lower intake of fruits, dried fruits, and fish. These results could be useful for designing strategies targeted to obesity prevention. PMID- 28555013 TI - Silver Nanoparticles in Orthopedic Applications: New Insights on Their Effects on Osteogenic Cells. AB - Infections of orthopedic implants are associated with high morbidity. The emergence of antibiotic resistant strains and the tendency of microbes to form biofilms on orthopedic devices prompt the individuation of novel antimicrobial agents. Silver nanoparticles represent an interesting alternative, but their effects on bone cells need to be clarified. We focused on osteoblast-like cells and on bone marrow-mesenchymal stem cells and found that these cells are rather resistant to the cytotoxic effects of silver nanoparticles, with a half maximal inhibitory concentration around 25 ug/mL as detected by MTT assay. Within a month of treatment, osteoblast-like cells adapt to the presence of the nanoparticles by upregulating hsp70 as shown by western blot. Hsp70 overexpression correlates with the restoration of normal cell proliferation. No alterations in the extent and time requirements were detected in mesenchymal stem cell induced to differentiate in osteoblasts in the presence of silver nanoparticles. Because the concentrations of silver nanoparticles which show antimicrobial activity are lower than those exerting toxic effects on bone-forming cells in vitro, we suggest that silver nanoparticles might represent a challenging tool to fight infections in orthopedic implants. PMID- 28555015 TI - Simple Technique of Exfoliation and Dispersion of Multilayer Graphene from Natural Graphite by Ozone-Assisted Sonication. AB - Owing to its unique properties, graphene has attracted tremendous attention in many research fields. There is a great space to develop graphene synthesis techniques by an efficient and environmentally friendly approach. In this paper, we report a facile method to synthesize well-dispersed multilayer graphene (MLG) without using any chemical reagents or organic solvents. This was achieved by the ozone-assisted sonication of the natural graphite in a water medium. The frequency or number of ozone treatments plays an important role for the dispersion in the process. The possible mechanism of graphene exfoliation and the introduction of functional groups have been postulated. The experimental setup is unique for ozone treatment and enables the elimination of ozone off-gas. The heat generated by the dissipation of ultrasonic waves was used as it is, and no additional heat was supplied. The graphene dispersion was stable, and no evidence of aggregation was observed---even after several months. The characterization results show that well-dispersed MLG was successfully synthesized without any significant damage to the overall structure. The graphene obtained by this method has potential applications in composite materials, conductive coatings, energy storage, and electronic devices. PMID- 28555012 TI - Biological and Physicochemical Functions of Ubiquitylation Revealed by Synthetic Chemistry Approaches. AB - Most intracellular proteins are subjected to post-translational modification by ubiquitin. Accordingly, it is of fundamental importance to investigate the biological and physicochemical effects of ubiquitylation on substrate proteins. However, preparation of ubiquitylated proteins by an enzymatic synthesis bears limitations in terms of yield and site-specificity. Recently established chemical ubiquitylation methodologies can overcome these problems and provide a new understanding of ubiquitylation. Herein we describe the recent chemical ubiquitylation procedures with a focus on the effects of ubiquitylation on target proteins revealed by the synthetic approach. PMID- 28555014 TI - In Vitro Antioxidant Activity of Idebenone Derivative-Loaded Solid Lipid Nanoparticles. AB - Idebenone (IDE) has been proposed for the treatment of neurodegenerative diseases involving mitochondria dysfunctions. Unfortunately, to date, IDE therapeutic treatments have not been as successful as expected. To improve IDE efficacy, in this work we describe a two-step approach: (1) synthesis of IDE ester derivatives by covalent linking IDE to other two antioxidants, trolox (IDETRL) and lipoic acid (IDELIP), to obtain a synergic effect; (2) loading of IDE, IDETRL, or IDELIP into solid lipid nanoparticles (SLN) to improve IDE and its esters' water solubility while increasing and prolonging their antioxidant activity. IDE and its derivatives loaded SLN showed good physico-chemical and technological properties (spherical shape, mean particle sizes 23-25 nm, single peak in the size distribution, zeta potential values -1.76/-2.89 mV, and good stability at room temperature). In vitro antioxidant activity of these SLN was evaluated in comparison with free drugs by means of oxygen radical absorbance capacity (ORAC) test. IDETRL and IDELIP showed a greater antioxidant activity than IDE and encapsulation of IDE and its derivatives into SLN was able to prolong their antioxidant activity. These results suggest that loading IDETRL and IDELIP into SLN could be a useful strategy to improve IDE efficacy. PMID- 28555016 TI - Evaluation of Feature Extraction and Recognition for Activity Monitoring and Fall Detection Based on Wearable sEMG Sensors. AB - As an essential subfield of context awareness, activity awareness, especially daily activity monitoring and fall detection, plays a significant role for elderly or frail people who need assistance in their daily activities. This study investigates the feature extraction and pattern recognition of surface electromyography (sEMG), with the purpose of determining the best features and classifiers of sEMG for daily living activities monitoring and fall detection. This is done by a serial of experiments. In the experiments, four channels of sEMG signal from wireless, wearable sensors located on lower limbs are recorded from three subjects while they perform seven activities of daily living (ADL). A simulated trip fall scenario is also considered with a custom-made device attached to the ankle. With this experimental setting, 15 feature extraction methods of sEMG, including time, frequency, time/frequency domain and entropy, are analyzed based on class separability and calculation complexity, and five classification methods, each with 15 features, are estimated with respect to the accuracy rate of recognition and calculation complexity for activity monitoring and fall detection. It is shown that a high accuracy rate of recognition and a minimal calculation time for daily activity monitoring and fall detection can be achieved in the current experimental setting. Specifically, the Wilson Amplitude (WAMP) feature performs the best, and the classifier Gaussian Kernel Support Vector Machine (GK-SVM) with Permutation Entropy (PE) or WAMP results in the highest accuracy for activity monitoring with recognition rates of 97.35% and 96.43%. For fall detection, the classifier Fuzzy Min-Max Neural Network (FMMNN) has the best sensitivity and specificity at the cost of the longest calculation time, while the classifier Gaussian Kernel Fisher Linear Discriminant Analysis (GK-FDA) with the feature WAMP guarantees a high sensitivity (98.70%) and specificity (98.59%) with a short calculation time (65.586 ms), making it a possible choice for pre-impact fall detection. The thorough quantitative comparison of the features and classifiers in this study supports the feasibility of a wireless, wearable sEMG sensor system for automatic activity monitoring and fall detection. PMID- 28555018 TI - Adventure Behavior Seeking Scale. AB - This article presents a new tool-the Adventure Behavior Seeking Scale (ABSS). The Adventure Behavior Seeking Scale was developed to assess individuals' highly stimulating behaviors in natural environments. An exploratory factor analysis was conducted with 466 participants and resulted in one factor. The internal consistency was 0.80. A confirmatory factor analysis was performed using another sample of 406 participants, and results verified the one-factor structure. The findings indicate that people with a lot of experience in outdoor adventure have a higher score on the ABSS scale than control groups without such experience. The results also suggest that the 8-item ABSS scores were highly related to sensation seeking. The author discusses findings in regard to the ABSS as an instrument to measure outdoor adventure. However, further studies need to be carried out in other sample groups to further validate the scale. PMID- 28555017 TI - Electrolytic Manganese Dioxide Coatings on High Aspect Ratio Micro-Pillar Arrays for 3D Thin Film Lithium Ion Batteries. AB - In this work, we present the electrochemical deposition of manganese dioxide (MnO2) thin films on carbon-coated TiN/Si micro-pillars. The carbon buffer layer, grown by plasma enhanced chemical vapor deposition (PECVD), is used as a protective coating for the underlying TiN current collector from oxidation, during the film deposition, while improving the electrical conductivity of the stack. A conformal electrolytic MnO2 (EMD) coating is successfully achieved on high aspect ratio C/TiN/Si pillar arrays by tailoring the deposition process. Lithiation/Delithiation cycling tests have been performed. Reversible insertion and extraction of Li+ through EMD structure are observed. The fabricated stack is thus considered as a good candidate not only for 3D micorbatteries but also for other energy storage applications. PMID- 28555019 TI - Mutual Regulation of NOD2 and RIG-I in Zebrafish Provides Insights into the Coordination between Innate Antibacterial and Antiviral Signaling Pathways. AB - Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and retinoic acid-inducible gene I (RIG-I) are two important cytosolic pattern recognition receptors (PRRs) in the recognition of pathogen-associated molecular patterns (PAMPs), initiating innate antibacterial and antiviral signaling pathways. However, the relationship between these PRRs, especially in teleost fish models, is rarely reported. In this article, we describe the mutual regulation of zebrafish NOD2 (DrNOD2) and RIG-I (DrRIG-I) in innate immune responses. Luciferase assays were conducted to determine the activation of NF kappaB and interferon signaling. Morpholino-mediated knockdown and mRNA-mediated rescue were performed to further confirm the regulatory roles between DrNOD2 and DrRIG-I. Results showed that DrNOD2 and DrRIG-I shared conserved structural hallmarks with their mammalian counterparts, and activated DrRIG-I signaling can induce DrNOD2 production. Surprisingly, DrNOD2-initiated signaling can also induce DrRIG-I expression, indicating that a mutual regulatory mechanism may exist between them. Studies conducted using HEK293T cells and zebrafish embryos showed that DrRIG-I could negatively regulate DrNOD2-activated NF-kappaB signaling, and DrNOD2 could inhibit DrRIG-I-induced IFN signaling. Moreover, knocking down DrRIG-I expression by morpholino could enhance DrNOD2-initiated NF kappaB activation, and vice versa, which could be rescued by their corresponding mRNAs. Results revealed a mutual feedback regulatory mechanism underlying NOD2 and RIG-I signaling pathways in teleosts. This mechanism reflects the coordination between cytosolic antibacterial and antiviral PRRs in the complex network of innate immunity. PMID- 28555020 TI - N-Caffeoyltryptamine, a Potent Anti-Inflammatory Phenolic Amide, Suppressed MCP-1 Expression in LPS-stimulated THP-1 Cells and Rats Fed a High-Fat Diet. AB - Monocyte chemoattractant protein-1 (MCP-1) is a well-known chemokine critically involved in the pathophysiological progression of several inflammatory diseases including arthrosclerosis. N-caffeoyltryptamine is a phenolic amide with strong anti-inflammatory effects. Therefore, in this paper, the potential effect of N caffeoyltryptamine on MCP-1 expression was investigated as a potential p38 mitogen-activated protein (MAP) kinase inhibitor in vitro and in vivo. At the concentration of 20 MUM, N-caffeoyltryptamine significantly inhibited p38 MAP kinase alpha, beta, gamma and delta by 15-50% (p < 0.05), particularly p38 MAP kinase alpha (IC50 = 16.7 MUM) and beta (IC50 = 18.3 MUM). Also, the pretreatment of the lipopolysaccharide (LPS)-stimulated THP-1 cells with N-caffeoyltryptamine (10, 20 and 40 MUM) led to significant suppression of MCP-1 production by 10-45% (p < 0.05) in the cells. Additionally, N-caffeoyltryptamine was also able to significantly downregulate MCP-1 mRNA expression in the THP-1 cells (p < 0.05). On the basis of this strong inhibition in vitro, an animal study was conducted to confirm this inhibitory effect in vivo. Rats were divided into three groups (n = 8): a normal control diet (C), a high-fat diet (HF), or a high-fat diet supplemented with N-caffeoyltryptamine (2 mg per day) (HFS). After 16 weeks, blood samples were collected from the rats in each group, and MCP-1 levels were determined in plasma with other atherogenic markers (C-reactive protein and soluble E-selectin (sE-selectin)). As expected, the average MCP-1 levels of the HF group were found to be higher than those of the C group (p < 0.05). However, the MCP-1 levels of the HFS group were significantly lower than those of the HF group (p < 0.05), suggesting that N-caffeoyltryptamine could decrease MCP-1 expression in vivo. Related to other atherogenic markers such as C-reactive protein and sE-selectin, there was no significant difference in their levels between the HF and HFS groups. These data suggest that N-caffeoyltryptamine may specifically suppress MCP-1 expression in vitro and in vivo, possibly by inhibiting p38 MAP kinase. PMID- 28555023 TI - A Protocol Layer Trust-Based Intrusion Detection Scheme for Wireless Sensor Networks. AB - This article proposes a protocol layer trust-based intrusion detection scheme for wireless sensor networks. Unlike existing work, the trust value of a sensor node is evaluated according to the deviations of key parameters at each protocol layer considering the attacks initiated at different protocol layers will inevitably have impacts on the parameters of the corresponding protocol layers. For simplicity, the paper mainly considers three aspects of trustworthiness, namely physical layer trust, media access control layer trust and network layer trust. The per-layer trust metrics are then combined to determine the overall trust metric of a sensor node. The performance of the proposed intrusion detection mechanism is then analyzed using the t-distribution to derive analytical results of false positive and false negative probabilities. Numerical analytical results, validated by simulation results, are presented in different attack scenarios. It is shown that the proposed protocol layer trust-based intrusion detection scheme outperforms a state-of-the-art scheme in terms of detection probability and false probability, demonstrating its usefulness for detecting cross-layer attacks. PMID- 28555022 TI - Location-Enhanced Activity Recognition in Indoor Environments Using Off the Shelf Smart Watch Technology and BLE Beacons. AB - Activity recognition in indoor spaces benefits context awareness and improves the efficiency of applications related to personalised health monitoring, building energy management, security and safety. The majority of activity recognition frameworks, however, employ a network of specialised building sensors or a network of body-worn sensors. As this approach suffers with respect to practicality, we propose the use of commercial off-the-shelf devices. In this work, we design and evaluate an activity recognition system composed of a smart watch, which is enhanced with location information coming from Bluetooth Low Energy (BLE) beacons. We evaluate the performance of this approach for a variety of activities performed in an indoor laboratory environment, using four supervised machine learning algorithms. Our experimental results indicate that our location-enhanced activity recognition system is able to reach a classification accuracy ranging from 92% to 100%, while without location information classification accuracy it can drop to as low as 50% in some cases, depending on the window size chosen for data segmentation. PMID- 28555021 TI - Identification of Novel Vacuolin-1 Analogues as Autophagy Inhibitors by Virtual Drug Screening and Chemical Synthesis. AB - Autophagy is a fundamental cellular degradation process which is essential for cell homeostasis, and dysfunctional autophagy has been associated with a variety of human diseases, such as cancer. Several autophagy chemical modulators have been applied in a number of preclinical or clinical trials against these autophagy related diseases, especially cancer. Small molecule vacuolin-1 potently and reversibly inhibits both endosomal-lysosomal trafficking and autophagosome lysosome fusion, yet the molecular mechanisms underlying vacuolin-1 mediated autophagy inhibition remain unknown. Here, we first performed the virtual drug screening and identified 14 vacuolin-1 analogues as autophagy inhibitors. Based on these virtual screening results, we further designed and synthesized 17 vacuolin-1 analogues, and found that 13 of them are autophagy inhibitors and a couple of them are as potent as vacuolin-1. In summary, these studies expanded the pool of useful autophagy inhibitors and reveal the structural-activity relationship of vacuolin-1 analogues, which is useful for future development of vacuolin-1 analogues with high potency and for identification of the molecular targets of vacuolin-1. PMID- 28555024 TI - New Diagnostic and Treatment Modalities for Neurogenic Thoracic Outlet Syndrome. AB - Neurogenic thoracic outlet syndrome is a widely recognized, yet controversial, syndrome. The lack of specific objective diagnostic modalities makes diagnosis difficult. This is compounded by a lack of agreed upon definitive criteria to confirm diagnosis. Recent efforts have been made to more clearly define a set of diagnostic criteria that will bring consistency to the diagnosis of neurogenic thoracic syndrome. Additionally, advancements have been made in the quality and techniques of various imaging modalities that may aid in providing more accurate diagnoses. Surgical decompression remains the mainstay of operative treatment; and minimally invasive techniques are currently in development to further minimize the risks of this procedure. Medical management continues to be refined to provide non-operative treatment modalities for certain patients, as well. The aim of the present work is to review these updates in the diagnosis and treatment of neurogenic thoracic outlet syndrome. PMID- 28555025 TI - Investigation of Carboxymethyl Cellulose (CMC) on Mechanical Properties of Cold Water Fish Gelatin Biodegradable Edible Films. AB - The tendency to use biocompatible packages, such as biodegradable films, is growing since they contain natural materials, are recyclable and do not cause environmental pollution. In this research, cold water fish gelatin and carboxymethyl cellulose were combined for use in edible films. Due to its unique properties, gelatin is widely used in creating gel, and in restructuring, stabilizing, emulsifying, and forming foam and film in food industries. This research for the first time modified and improved the mechanical properties of cold water fish gelatin films in combination with carboxymethyl cellulose. Cold water fish gelatin films along with carboxymethyl cellulose with concentrations of 0%, 5%, 10%, 20% and 50% were prepared using the casting method. The mechanical properties were tested by the American National Standard Method. Studying the absorption isotherm of the resulting composite films specified that the humidity of single-layer water decreased (p < 0.05) and caused a reduction in the equilibrium moisture of these films. In the mechanical testing of the composite films, the tensile strength and Young's modulus significantly increased and the elongation percent significantly decreased with the increase in the concentration of carboxymethyl cellulose. Considering the biodegradability of the films and the improvement of their mechanical properties by carboxymethyl cellulose, this kind of packaging can be used in different industries, especially the food industry, as an edible coating for packaging food and agricultural crops. PMID- 28555026 TI - Structural Characterization of Lignin in Fruits and Stalks of Chinese Quince. AB - Chinese quince (Chaenomeles sinensis) is used in food and pharmaceutical products, but it is seldom eaten as a raw fruit due to its astringent, woody flesh. The structural characterization of lignin fractions from Chinese quince was very important to investigate the structure-activity relationships of lignin. In this investigation, to characterize the structure of lignin in Chinese quince fruits, the milled wood lignin sample was isolated from the fruits (FMWL) and the chemical structure of FMWL was investigated by sugar analysis, FT-IR, GPC, pyrolysis-GC/MS analysis, UV spectra analysis, thermogravimetric analysis (TGA), and advanced NMR spectroscopic techniques. In addition, the lignin fraction from the stalk of Chinese quince (SMWL) was also prepared for comparison to obtained more information of lignin structure in the fruits. The results showed that the two lignin fractions isolated from fruit and stalk of Chinese quince exhibited different structural features. The two MWL samples were mainly composed of beta-O 4 ether bonds, beta-5 and beta-beta' carbon-carbon linkages in the lignin structural units. Compared to the SMWL, the FMWL fraction had the higher S/G ratio and more carbohydrates linkages. The predominant carbohydrates associated with FMWL and SMWL fractions were glucans-type hemicelluloses and xylan-type hemicelluloses, respectively. Understanding the structure of lignin could give insight into the properties of the lignin and enable the food processing industry to separate lignin more efficiently. PMID- 28555027 TI - Performance of BDS-3: Measurement Quality Analysis, Precise Orbit and Clock Determination. AB - Since 2015, China has successfully launched five experimental BeiDou global navigation system (BDS-3) satellites for expanding the regional system to global coverage. An initial performance assessment and characterization analysis of the BDS-3 is presented. Twenty days of tracking data have been collected from eleven monitoring stations. The tracking characteristics and measurement quality are analyzed and compared with the regional BDS (BDS-2) in terms of observed carrier to-noise density ratio, pseudo-range multipath, and noise. The preliminary results suggest that the measurement quality of BDS-3 outperforms the BDS-2 for the same type of satellites. In addition, the analysis of multipath combinations reveals that the problem of satellite-induced code biases found in BDS-2 seems to have been solved for BDS-3. Precise orbit and clock determination are carried out and evaluated. The orbit overlap comparison show a precision of 2-6 dm in 3D root mean square (RMS) and 6-14 cm in the radial component for experimental BDS-3 satellites. External validations with satellite laser ranging (SLR) show residual RMS on the level of 1-3 dm. Finally, the performance of the new-generation onboard atomic clocks is evaluated and results confirm an increased stability compared to BDS-2 satellite clocks. PMID- 28555028 TI - Study of ZnS Nanostructures Based Electrochemical and Photoelectrochemical Biosensors for Uric Acid Detection. AB - Uric acid (UA) is a kind of purine metabolism product and important in clinical diagnosis. In this work, we present a study of ZnS nanostructures-based electrochemical and photoelectrochemical biosensors for UA detection. Through a simple hydrothermal method and varying the ratio of reaction solvents, we obtained ZnS nanomaterials of one-dimensional to three-dimensional morphologies and they were characterized using field emission scanning electron microscopy (FESEM) and X-ray diffraction (XRD). To fabricate the UA biosensor and study the effect of material morphology on its performance, ZnS nanomaterials were deposited on indium tin oxide (ITO) conducting glass and then coated with uricase by physical absorption. Three kinds of working electrodes were characterized by cyclic voltammetry method. The effect of material morphology on performance of UA detection was investigated via amperometric response based electrochemical method based on enzymatic reaction. The ZnS urchin-like nanostructures electrode shows better sensitivity compared with those made of nanoparticles and nanoflakes because of its high surface-area-to-volume ratio. The photoelectrochemical method for detection of UA was also studied. The sensitivity was increased 5 times after irradiation of 300 nm UV light. These results indicate that ZnS nanostructures are good candidate materials for developing enzyme-based UA biosensors. PMID- 28555029 TI - Venom On-a-Chip: A Fast and Efficient Method for Comparative Venomics. AB - Venom research has attracted an increasing interest in disparate fields, from drug development and pharmacology, to evolutionary biology and ecology, and rational antivenom production. Advances in "-omics" technologies have allowed the characterization of an increasing number of animal venoms, but the methodology currently available is suboptimal for large-scale comparisons of venom profiles. Here, we describe a fast, reproducible and semi-automated protocol for investigating snake venom variability, especially at the intraspecific level, using the Agilent Bioanalyzer on-chip technology. Our protocol generated a phenotype matrix which can be used for robust statistical analysis and correlations of venom variation with ecological correlates, or other extrinsic factors. We also demonstrate the ease and utility of combining on-chip technology with previously fractionated venoms for detection of specific individual toxin proteins. Our study describes a novel strategy for rapid venom discrimination and analysis of compositional variation at multiple taxonomic levels, allowing researchers to tackle evolutionary questions and unveiling the drivers of the incredible biodiversity of venoms. PMID- 28555030 TI - A Compact Magnetic Field-Based Obstacle Detection and Avoidance System for Miniature Spherical Robots. AB - Due to their efficient locomotion and natural tolerance to hazardous environments, spherical robots have wide applications in security surveillance, exploration of unknown territory and emergency response. Numerous studies have been conducted on the driving mechanism, motion planning and trajectory tracking methods of spherical robots, yet very limited studies have been conducted regarding the obstacle avoidance capability of spherical robots. Most of the existing spherical robots rely on the "hit and run" technique, which has been argued to be a reasonable strategy because spherical robots have an inherent ability to recover from collisions. Without protruding components, they will not become stuck and can simply roll back after running into bstacles. However, for small scale spherical robots that contain sensitive surveillance sensors and cannot afford to utilize heavy protective shells, the absence of obstacle avoidance solutions would leave the robot at the mercy of potentially dangerous obstacles. In this paper, a compact magnetic field-based obstacle detection and avoidance system has been developed for miniature spherical robots. It utilizes a passive magnetic field so that the system is both compact and power efficient. The proposed system can detect not only the presence, but also the approaching direction of a ferromagnetic obstacle, therefore, an intelligent avoidance behavior can be generated by adapting the trajectory tracking method with the detection information. Design optimization is conducted to enhance the obstacle detection performance and detailed avoidance strategies are devised. Experimental results are also presented for validation purposes. PMID- 28555031 TI - History-Based Response Threshold Model for Division of Labor in Multi-Agent Systems. AB - Dynamic task allocation is a necessity in a group of robots. Each member should decide its own task such that it is most commensurate with its current state in the overall system. In this work, the response threshold model is applied to a dynamic foraging task. Each robot employs a task switching function based on the local task demand obtained from the surrounding environment, and no communication occurs between the robots. Each individual member has a constant-sized task demand history that reflects the global demand. In addition, it has response threshold values for all of the tasks and manages the task switching process depending on the stimuli of the task demands. The robot then determines the task to be executed to regulate the overall division of labor. This task selection induces a specialized tendency for performing a specific task and regulates the division of labor. In particular, maintaining a history of the task demands is very effective for the dynamic foraging task. Various experiments are performed using a simulation with multiple robots, and the results show that the proposed algorithm is more effective as compared to the conventional model. PMID- 28555032 TI - Strawberry (cv. Romina) Methanolic Extract and Anthocyanin-Enriched Fraction Improve Lipid Profile and Antioxidant Status in HepG2 Cells. AB - Dyslipidemia and oxidation of low density lipoproteins (LDL) are recognized as critical factors in the development of atherosclerosis. Healthy dietary patterns, with abundant fruit and vegetable consumption, may prevent the onset of these risk factors due to the presence of phytochemical compounds. Strawberries are known for their high content of polyphenols; among them, flavonoids are the major constituents, and it is presumed that they are responsible for the biological activity of the fruit. Nevertheless, there are only a few studies that actually evaluate the effects of different fractions isolated from strawberries. In order to assess the effects of two different strawberry extracts (whole methanolic extract/anthocyanin-enriched fraction) on the lipid profile and antioxidant status in human hepatocellular carcinoma (HepG2) cells, the triglycerides and LDL cholesterol content, lipid peroxidation, intracellular reactive oxygen species (ROS) content and antioxidant enzymes' activity on cell lysates were determined. Results demonstrated that both strawberry extracts not only improved the lipid metabolism by decreasing triglycerides and LDL-cholesterol contents, but also improved the redox state of HepG2 cells by modulating thiobarbituric acid reactive substances production, antioxidant enzyme activity and ROS generation. The observed effects were more pronounced for the anthocyanin-enriched fraction. PMID- 28555033 TI - Annual Wormwood Leaf Inhibits the Adipogenesis of 3T3-L1 and Obesity in High-Fat Diet-Induced Obese Rats. AB - Annual wormwood (AW) (Artemisia annua L.) has anti-malarial, anti-bacterial, anti oxidant, anti-tumour, and anti-inflammatory activities. In the present study, we evaluated the effects of annual wormwood leaves (AWL) on adipocyte differentiation in 3T3-L1 cells and high-fat diet (HFD)-induced obese rats. 3T3 L1 adipocytes and HFD-induced obese rats were treated with AWL, and its effect on gene expression was analyzed using RT-PCR and Western blotting experiments. Treatment with AWL effectively prevented triglyceride accumulation during adipogenesis in a dose-dependent manner. Consistently, AWL suppressed the differentiation of 3T3-L1 preadipocytes into adipocytes through the downregulation of dexamethasone, 3-isobutyl-1- methylxanthine, and insulin (DMI) induced serine/threonine kinase protein kinase B (PKB/Akt) activation and the expression of adipogenic genes, including the CCAAT/enhancer binding protein alpha (C/EBPalpha) and peroximal proliferator-activated receptor-gamma (PPARgamma). Moreover, the expression of adipocyte fatty acid-binding protein 4 (aP2), which is a known PPARgamma-target gene, was downregulated by AWL treatment. Oral administration of AWL extracts significantly decreased the body weight gain, adipose tissue mass, adipocyte cell size, serum triglyceride (TG), and total cholesterol (TC) levels in HFD-induced obese rats. These results provide novel insight into the molecular mechanisms underlying the anti-obesity effects of AWL that are mediated by the downregulation of the expression of major adipogenic transcription factors, C/EBPalpha and PPARgamma and Akt signalling. PMID- 28555034 TI - Analytical Tools to Improve Optimization Procedures for Lateral Flow Assays. AB - Immunochromatographic or lateral flow assays (LFAs) are inexpensive, easy to use, point-of-care medical diagnostic tests that are found in arenas ranging from a doctor's office in Manhattan to a rural medical clinic in low resource settings. The simplicity in the LFA itself belies the complex task of optimization required to make the test sensitive, rapid and easy to use. Currently, the manufacturers develop LFAs by empirical optimization of material components (e.g., analytical membranes, conjugate pads and sample pads), biological reagents (e.g., antibodies, blocking reagents and buffers) and the design of delivery geometry. In this paper, we will review conventional optimization and then focus on the latter and outline analytical tools, such as dynamic light scattering and optical biosensors, as well as methods, such as microfluidic flow design and mechanistic models. We are applying these tools to find non-obvious optima of lateral flow assays for improved sensitivity, specificity and manufacturing robustness. PMID- 28555035 TI - Identification of a Blue Zone in a Typical Chinese Longevity Region. AB - Influenced by a special local environment, the proportion of centenarians is particularly high in some places, known as "blue zones". Blue zones are mysterious regions that continue to attract research. This paper explores the spatial distribution of the longevity population in a typical Chinese longevity region. Longevity evaluation indexes are used to analyze the longevity phenomenon in 88 towns between 2011 and 2015. Our research findings show that longevity is more important than birth rate and migration in shaping the degree of deep aging in the research region. Fluctuations in the proportion of centenarians are much higher than for nonagenarians, both in relation to towns and to years. This is because there are so few centenarians that data collected over a short time period cannot accurately represent the overall degree of longevity in a small region; data and statistics must be collected over a longer time period to achieve this. GIS analysis revealed a stable longevity zone located in the center of the research region. This area seems to help people live more easily to 90-99 years old; however, its ability to help nonagenarians live to 100 is a weaker effect. PMID- 28555036 TI - High Resolution Full-Aperture ISAR Processing through Modified Doppler History Based Motion Compensation. AB - A high resolution inverse synthetic aperture radar (ISAR) technique is presented using modified Doppler history based motion compensation. To this purpose, a novel wideband ISAR system is developed that accommodates parametric processing over extended aperture length. The proposed method is derived from an ISAR-to-SAR approach that makes use of high resolution spotlight SAR and sub-aperture recombination. It is dedicated to wide aperture ISAR imaging and exhibits robust performance against unstable targets having non-linear motions. We demonstrate that the Doppler histories of the full aperture ISAR echoes from disturbed targets are efficiently retrieved with good fitting models. Experiments have been conducted on real aircraft targets and the feasibility of the full aperture ISAR processing is verified through the acquisition of high resolution ISAR imagery. PMID- 28555037 TI - Evidence of the Anti-Inflammatory Effects of Probiotics and Synbiotics in Intestinal Chronic Diseases. AB - Probiotics and synbiotics are used to treat chronic diseases, principally due to their role in immune system modulation and the anti-inflammatory response. The present study reviewed the effects of probiotics and synbiotics on intestinal chronic diseases in in vitro, animal, and human studies, particularly in randomized clinical trials. The selected probiotics exhibit in vitro anti inflammatory properties. Probiotic strains and cell-free supernatants reduced the expression of pro-inflammatory cytokines via action that is principally mediated by toll-like receptors. Probiotic administration improved the clinical symptoms, histological alterations, and mucus production in most of the evaluated animal studies, but some results suggest that caution should be taken when administering these agents in the relapse stages of IBD. In addition, no effects on chronic enteropathies were reported. Probiotic supplementation appears to be potentially well tolerated, effective, and safe in patients with IBD, in both CD and UC. Indeed, probiotics such as Bifidobacterium longum 536 improved the clinical symptoms in patients with mild to moderate active UC. Although it has been proposed that probiotics can provide benefits in certain conditions, the risks and benefits should be carefully assessed before initiating any therapy in patients with IBD. For this reason, further studies are required to understand the precise mechanism by which probiotics and synbiotics affect these diseases. PMID- 28555038 TI - Table Olive Fermentation Using Starter Cultures with Multifunctional Potential. AB - Table olives are one of the most popular plant-derived fermented products. Their enhanced nutritional value due to the presence of phenolic compounds and monounsaturated fatty acids makes olives an important food commodity of the Mediterranean diet. However, despite its economic significance, table olive fermentation is mainly craft-based and empirically driven by the autochthonous microbiota of the olives depending on various intrinsic and extrinsic factors, leading to a spontaneous process and a final product of variable quality. The use of microorganisms previously isolated from olive fermentations and studied for their probiotic potential and technological characteristics as starter cultures may contribute to the reduction of spoilage risk resulting in a controlled fermentation process. This review focuses on the importance of the development and implementation of multifunctional starter cultures related to olives with desirable probiotic and technological characteristics for possible application on table olive fermentation with the main purpose being the production of a health promoting and sensory improved functional food. PMID- 28555039 TI - FADS Gene Polymorphisms, Fatty Acid Desaturase Activities, and HDL-C in Type 2 Diabetes. AB - Polyunsaturated fatty acids (PUFA) correlate with risk of dyslipidemia and cardiovascular diseases. Fatty acid desaturase (FADS) single nucleotide polymorphisms (SNPs) modulate circulating PUFA concentrations. This study examined influence of FADS1 and FADS2 genetic variants on desaturase activities and blood lipid concentrations in type 2 diabetes patients, and further assessed their interrelationships. Selected SNPs (FADS1: rs174547, rs174548, rs174550; FADS2: rs174575, rs174576, rs174583, rs498793 and rs2727270) were genotyped in 820 type 2 diabetes patients and compared with those reported in the HapMap. Patient subgroups (n = 176) without taking lipid-lowering medicine were studied to assess influence of tag SNPs including rs174547, rs174575, rs498793 and rs2727270 on delta-5 desaturase (D5D: 20:4 (n-6)/20:3 (n-6)) and delta-6 desaturase (D6D:18:3 (n-6)/18:2 (n-6)) activities, and blood lipids. FADS1 rs174547 TT/TC/CC and FADS2 rs2727270 CC/CT/TT were significantly (p for trend < 0.05) associated with reduced HDL-C, D5D and D6D activities. Upon adjustment for confounders, D5D (p = 0.006) correlated significantly and D6D marginally (p = 0.07) correlated with increased HDL-C levels, whereas rs174547 and rs2727270 polymorphisms were not associated. D6D andD5D activities may play a role in modulating HDL-C levels in type 2 diabetes. Future studies with larger sample sizes are needed to investigate how FADS genetic variations interact with desaturase activities or PUFAs in the metabolism of lipoproteins in diabetic patients. PMID- 28555040 TI - Body Composition Analysis Allows the Prediction of Urinary Creatinine Excretion and of Renal Function in Chronic Kidney Disease Patients. AB - The aim of this study was to predict urinary creatinine excretion (UCr), creatinine clearance (CCr) and the glomerular filtration rate (GFR) from body composition analysis. Body cell mass (BCM) is the compartment which contains muscle mass, which is where creatinine is generated. BCM was measured with body impedance analysis in 165 chronic kidney disease (CKD) adult patients (72 women) with serum creatinine (SCr) 0.6-14.4 mg/dL. The GFR was measured (99mTc-DTPA) and was predicted using the Modification of Diet in Renal Disease (MDRD) formula. The other examined parameters were SCr, 24-h UCr and measured 24-h CCr (mCCr). A strict linear correlation was found between 24-h UCr and BCM (r = 0.772). Multiple linear regression (MR) indicated that UCr was positively correlated with BCM, body weight and male gender, and negatively correlated with age and SCr. UCr predicted using the MR equation (MR-UCr) was quite similar to 24-h UCr. CCr predicted from MR-UCr and SCr (MR-BCM-CCr) was very similar to mCCr with a high correlation (r = 0.950), concordance and a low prediction error (8.9 mL/min/1.73 m2). From the relationship between the GFR and the BCM/SCr ratio, we predicted the GFR (BCM GFR). The BCM GFR was very similar to the GFR with a high correlation (r = 0.906), concordance and a low prediction error (12.4 mL/min/1.73 m2). In CKD patients, UCr, CCr and the GFR can be predicted from body composition analysis. PMID- 28555041 TI - The Effect of Dry Eye Disease on Scar Formation in Rabbit Glaucoma Filtration Surgery. AB - The success rate of glaucoma filtration surgery is closely related to conjunctival inflammation, and the main mechanism of dry eye disease (DED) is inflammation. The aim of this study was to evaluate the effect of DED on bleb scar formation after rabbit glaucoma filtration surgery. Sixteen New Zealand white rabbits were randomly divided into control and DED groups. A DED model was induced by twice-daily topical administration of 0.1% benzalkonium chloride (BAC) drops for three weeks. Ocular examinations were performed to verify the DED model. Surgical effects were assessed, and histologic assessments were performed on the 28th postoperative day. Higher fluorescein staining scores, lower basal tear secretion levels and goblet cell counts, and increased interleukin 1beta (IL 1beta) levels were observed in the DED group. The DED eyes displayed significantly higher intraocular pressure (IOP)% on the 14th postoperative day; a smaller bleb area on days 14, 21 and 28; and a shorter bleb survival time. Moreover, proliferating cell nuclear antigen (PCNA) and alpha-smooth muscle actin (alpha-SMA) levels were significantly increased in the DED group. These results demonstrate that DED promotes filtering bleb scar formation and shortens bleb survival time; these effects may be mediated via IL-1beta. PMID- 28555042 TI - The Cytotoxicity of the Ajoene Analogue BisPMB in WHCO1 Oesophageal Cancer Cells Is Mediated by CHOP/GADD153. AB - Garlic is a food and medicinal plant that has been used in folk medicine since ancient times for its beneficial health effects, which include protection against cancer. Crushed garlic cloves contain an array of small sulfur-rich compounds such as ajoene. Ajoene is able to interfere with biological processes and is cytotoxic to cancer cells in the low micromolar range. BisPMB is a synthetic ajoene analogue that has been shown in our laboratory to have superior cytotoxicity to ajoene. In the current study we have performed a DNA microarray analysis of bisPMB-treated WHCO1 oesophageal cancer cells to identify pathways and processes that are affected by bisPMB. The most significantly enriched biological pathways as assessed by gene ontology, KEGG and ingenuity pathway analysis were those involving protein processing in the endoplasmic reticulum (ER) and the unfolded protein response. In support of these pathways, bisPMB was found to inhibit global protein synthesis and lead to increased levels of ubiquitinated proteins. BisPMB also induced alternate splicing of the transcription factor XBP-1; increased the expression of the ER stress sensor GRP78 and induced expression of the ER stress marker CHOP/GADD153. CHOP expression was found to be central to the cytotoxicity of bisPMB as its silencing with siRNA rendered the cells resistant to bisPMB. The MAPK proteins, JNK and ERK1/2 were activated following bisPMB treatment. However JNK activation was not critical in the cytotoxicity of bisPMB, and ERK1/2 activation was found to play a pro-survival role. Overall the ajoene analogue bisPMB appears to induce cytotoxicity in WHCO1 cells by activating the unfolded protein response through CHOP/GADD153. PMID- 28555044 TI - Denoising Algorithm for CFA Image Sensors Considering Inter-Channel Correlation. AB - In this paper, a spatio-spectral-temporal filter considering an inter-channel correlation is proposed for the denoising of a color filter array (CFA) sequence acquired by CCD/CMOS image sensors. Owing to the alternating under-sampled grid of the CFA pattern, the inter-channel correlation must be considered in the direct denoising process. The proposed filter is applied in the spatial, spectral, and temporal domain, considering the spatio-tempo-spectral correlation. First, nonlocal means (NLM) spatial filtering with patch-based difference (PBD) refinement is performed by considering both the intra-channel correlation and inter-channel correlation to overcome the spatial resolution degradation occurring with the alternating under-sampled pattern. Second, a motion compensated temporal filter that employs inter-channel correlated motion estimation and compensation is proposed to remove the noise in the temporal domain. Then, a motion adaptive detection value controls the ratio of the spatial filter and the temporal filter. The denoised CFA sequence can thus be obtained without motion artifacts. Experimental results for both simulated and real CFA sequences are presented with visual and numerical comparisons to several state-of the-art denoising methods combined with a demosaicing method. Experimental results confirmed that the proposed frameworks outperformed the other techniques in terms of the objective criteria and subjective visual perception in CFA sequences. PMID- 28555043 TI - Chronic Fructose Ingestion as a Major Health Concern: Is a Sedentary Lifestyle Making It Worse? A Review. AB - Obesity contributes to metabolic abnormalities such as insulin resistance, dyslipidemia, hypertension, and glucose intolerance, all of which are risk factors associated with metabolic syndrome. The growing prevelance of metabolic syndrome seems to be an end result of our current lifestyle which promotes high caloric, high-fat foods and minimal physical activity, resulting in a state of positive energy balance. Increased adiposity and physical inactivity may represent the beginning of the appearance of these risk factors. Understanding the metabolic and cardiovascular disturbances associated with diet and exercise habits is a crucial step towards reducing the risk factors for metabolic syndrome. Although considerable research has been conducted linking chronic fructose ingestion to the increased prevalence of obesity and metabolic syndrome risk factors, these studies have mainly been performed on animals, and/or in a post-absorptive state. Further, the magnitude of the effect of fructose may depend on other aspects of the diet, including the total amount of carbohydrates and fats in the diet and the overall consumption of meals. Therefore, the overall aim of this review paper is to examine the effects of a diet high in fructose on postprandial lipidemia, inflammatory markers and glucose tolerance, all risk factors for diabetes and cardiovascular disease. Moreover, an objective is to investigate whether increased physical activity can alter such effects. PMID- 28555045 TI - Socioeconomic, Geospatial, and Geopolitical Disparities in Access to Health Care in the US 2011-2015. AB - Individuals forgoing needed medical care due to barriers associated with cost are at risk of missing needed care that may be necessary for the prevention or maintenance of a chronic condition among other things. Thus, continued monitoring of factors associated with forgone medical care, especially among vulnerable populations, is critical. National survey data (2011-2015) for non institutionalized adults residing in the USA were utilized to assess forgone medical care, defined as not seeking medical care when the individual thought it was necessary because of cost in the past 12 months. Logistic regression was used to predict forgone medical care vs. sought medical care. Racial/ethnic minority working-age adults, those with lower incomes, those with lower educations, those residing in the South, and those residing in states that failed to participate in Medicaid Expansion in 2014 were more likely (p < 0.01) to forgo medical care due to cost in the past year. Policy makers seeking to reduce barriers to forgone medical care can use this information to tailor their efforts (e.g., mechanisms targeted to bridge gaps in access to care) to those most at-risk and to consider state-level policy decisions that may impact access to care. PMID- 28555046 TI - Collagen from the Marine Sponges Axinella cannabina and Suberites carnosus: Isolation and Morphological, Biochemical, and Biophysical Characterization. AB - In search of alternative and safer sources of collagen for biomedical applications, the marine demosponges Axinella cannabina and Suberites carnosus, collected from the Aegean and the Ionian Seas, respectively, were comparatively studied for their insoluble collagen, intercellular collagen, and spongin-like collagen content. The isolated collagenous materials were morphologically, physicochemically, and biophysically characterized. Using scanning electron microscopy and transmission electron microscopy the fibrous morphology of the isolated collagens was confirmed, whereas the amino acid analysis, in conjunction with infrared spectroscopy studies, verified the characteristic for the collagen amino acid profile and its secondary structure. Furthermore, the isoelectric point and thermal behavior were determined by titration and differential scanning calorimetry, in combination with circular dichroism spectroscopic studies, respectively. PMID- 28555047 TI - Synthesis and Free Radical Scavenging Activity of New Hydroxybenzylidene Hydrazines. AB - Hydroxybenzylidene hydrazines exhibit a wide spectrum of biological activities. Here, we report synthesis and free radical scavenging activity of nine new N (hydroxybenzylidene)-N'-[2,6-dinitro-4-(trifluoromethyl)]phenylhydrazines. The chemical structures of these compounds were confirmed by 1H-NMR, 13C-NMR, 19F NMR, IR spectroscopy, LC-MS, and elemental analysis. The prepared compounds were tested for their activity to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH), galvinoxyl radical (GOR), and 2,2'-azino-bis(3-ethylbenzothiazoline)-6-sulphonic acid (ABTS) radicals. The free radical scavenging activity expressed as SC50 values of these compounds varied in a wide range, from a strong to no radical scavenging effect. The most effective radical scavengers were hydroxybenzylidene hydrazines containing three hydroxyl groups in the benzylidene part of their molecules. The prepared compounds were also tested for their activity to inhibit photosynthetic electron transport in spinach chloroplasts. IC50 values of these compounds varied in wide range, from an intermediate to no inhibitory effect. PMID- 28555048 TI - Sensitivity of HOXB13 as a Diagnostic Immunohistochemical Marker of Prostatic Origin in Prostate Cancer Metastases: Comparison to PSA, Prostein, Androgen Receptor, ERG, NKX3.1, PSAP, and PSMA. AB - AIMS: Determining the origin of metastases is an important task of pathologists to allow for the initiation of a tumor-specific therapy. Recently, homeobox protein Hox-B13 (HOXB13) has been suggested as a new marker for the detection of prostatic origin. The aim of this study was to evaluate the diagnostic sensitivity of HOXB13 in comparison to commonly used immunohistochemical markers for prostate cancer. MATERIALS AND METHODS: Histologically confirmed prostate cancer lymph node metastases from 64 cases were used to test the diagnostic value of immunohistochemical markers: prostate specific antigen (PSA), Prostatic acid phosphatase (PSAP), prostate specific membrane antigen (PSMA), homeobox gene NKX3.1, prostein, androgen receptor (AR), HOXB13, and ETS-related gene (ERG). All markers were evaluated semi-quantitatively using Remmele's immune reactive score. RESULTS: The detection rate of prostate origin of metastasis for single markers was 100% for NKX3.1, 98.1% for AR, 84.3% for PSMA, 80.8% for PSA, 66% for PSAP, 60.4% for HOXB13, 59.6% for prostein, and 50.0% for ERG. CONCLUSIONS: Our data suggest that HOXB13 on its own lacks sensitivity for the detection of prostatic origin. Therefore, this marker should be only used in conjunction with other markers, preferably the highly specific PSA. The combination of PSA with NKX3.1 shows a higher sensitivity and thus appears preferable in this setting. PMID- 28555049 TI - Recent Advances in Asymmetric Organocatalyzed Conjugate Additions to Nitroalkenes. AB - The asymmetric conjugate addition of carbon and heteroatom nucleophiles to nitroalkenes is a very interesting tool for the construction of highly functionalized synthetic building blocks. Thanks to the rapid development of asymmetric organocatalysis, significant progress has been made during the last years in achieving efficiently this process, concerning chiral organocatalysts, substrates and reaction conditions. This review surveys the advances in asymmetric organocatalytic conjugate addition reactions to alpha,beta-unsaturated nitroalkenes developed between 2013 and early 2017. PMID- 28555050 TI - A Three-Year Follow-Up Study of Antibiotic and Metal Residues, Antibiotic Resistance and Resistance Genes, Focusing on Kshipra-A River Associated with Holy Religious Mass-Bathing in India: Protocol Paper. AB - BACKGROUND: Antibiotic resistance (ABR) is one of the major health emergencies for global society. Little is known about the ABR of environmental bacteria and therefore it is important to understand ABR reservoirs in the environment and their potential impact on health. METHOD/DESIGN: Quantitative and qualitative data will be collected during a 3-year follow-up study of a river associated with religious mass-bathing in Central India. Surface-water and sediment samples will be collected from seven locations at regular intervals for 3 years during religious mass-bathing and in absence of it to monitor water-quality, antibiotic residues, resistant bacteria, antibiotic resistance genes and metals. Approval has been obtained from the Ethics Committee of R.D. Gardi Medical College, Ujjain, India (No. 2013/07/17-311). RESULTS: The results will address the issue of antibiotic residues and antibiotic resistance with a focus on a river environment in India within a typical socio-behavioural context of religious mass bathing. It will enhance our understanding about the relationship between antibiotic residue levels, water-quality, heavy metals and antibiotic resistance patterns in Escherichia coli isolated from river-water and sediment, and seasonal differences that are associated with religious mass-bathing. We will also document, identify and clarify the genetic differences/similarities relating to phenotypic antibiotic resistance in bacteria in rivers during religious mass bathing or during periods when there is no mass-bathing. PMID- 28555052 TI - Blackcurrant Alters Physiological Responses and Femoral Artery Diameter during Sustained Isometric Contraction. AB - Blackcurrant is rich in anthocyanins that may affect exercise-induced physiological responses. We examined tissue oxygen saturation, muscle activity, cardiovascular responses and femoral artery diameter during a submaximal sustained isometric contraction. In a randomised, double-blind, crossover design, healthy men (n = 13, age: 25 +/- 4 years, BMI: 25 +/- 3 kg.m-2, mean +/- SD) ingested New Zealand blackcurrant (NZBC) extract (600 mg?day-1 CurraNZTM) or placebo (PL) for 7-days separated by 14-days washout. Participants produced isometric maximal voluntary contractions (iMVC) and a 120-s 30%iMVC of the quadriceps with electromyography (EMG), near-infrared spectroscopy, hemodynamic and ultrasound recordings. There was no effect of NZBC extract on iMVC (NZBC: 654 +/- 73, PL: 650 +/- 78 N). During the 30%iMVC with NZBC extract, total peripheral resistance, systolic, diastolic, and mean arterial pressure were lower with increased cardiac output and stroke volume. With NZBC extract, EMG root mean square of the vastusmedialis and muscle oxygen saturation were lower with higher total haemoglobin. During the 30%iMVC, femoral artery diameter was increased with NZBC extract at 30 (6.9%), 60 (8.2%), 90 (7.7%) and 120 s (6.0%). Intake of NZBC extract for 7-days altered cardiovascular responses, muscle oxygen saturation, muscle activity and femoral artery diameter during a 120-s 30%iMVC of the quadriceps. The present study provides insight into the potential mechanisms for enhanced exercise performance with intake of blackcurrant. PMID- 28555053 TI - Genealogy of Conjugated Acyclic Polyenes. AB - Based on the total pi-electron energies Epis of Huckel Molecular Orbital (HMO) method for all the possible isomers of conjugated acyclic polyenes (C2nH2n+2) up to n = 7, the structure-stability relation of the possible isomers was analyzed. It was shown that the mean length of conjugation L can roughly predict the ordering of stability among isomers, while the Z-index, or Hosoya-index, can almost perfectly reproduce their stability. Further, the genealogy of the conjugated acyclic polyene family was obtained by drawing systematic diagrams connecting these isomers of different n, and governed by several simple rules. Namely, the stability change of a given isomer in the genealogy connecting n and n + 1 polyenes can be classified into three different modes of vinyl addition (elongation, inner and outer branching) and horn growing, i.e., substitution of HC=CH- moiety with -HC(=CH2)-C(=CH2)H-. By using the Z-index, we can extend this type of discussion to polyene radicals and even to "cross-conjugated" cyclic polyenes containing only one odd-membered cycle, such as radialene and fulvene. PMID- 28555051 TI - Chalcomycins from Marine-Derived Streptomyces sp. and Their Antimicrobial Activities. AB - Dihydrochalcomycin (1) and chalcomycin, (2), two known chalcomycins, and chalcomycin E (3), a new compound, were isolated from marine-derived Streptomyces sp. HK-2006-1. Their structures were elucidated by detailed spectroscopic and X ray crystallographic analysis. The antimicrobial activities against Staphylococcus aureus, Escherichia coli, Candida albicans, and Aspergillus niger of 1-3 were evaluated. Compounds 1-2 exhibited activities against S. aureus with minimal inhibitory concentrations (MICs) of 32 ug/mL and 4 ug/mL, respectively. The fact that 1-2 showed stronger activity against S. aureus 209P than 3 indicated that the epoxy unit was important for antimicrobial activity. This structure-activity tendency of chalcomycins against S. aureus is different from that of aldgamycins reported in our previous research, which provide a valuable example for the phenomenon that 16-membered macrolides with different sugars do not have parallel structure-activity relationships. PMID- 28555054 TI - Knockdown of XBP1 by RNAi in Mouse Granulosa Cells Promotes Apoptosis, Inhibits Cell Cycle, and Decreases Estradiol Synthesis. AB - Granulosa cells are crucial for follicular growth, development, and follicular atresia. X-box binding protein 1 (XBP1), a basic region-leucine zipper protein, is widely involved in cell differentiation, proliferation, apoptosis, cellular stress response, and other signaling pathways. In this study, RNA interference, flow cytometry, western blot, real-time PCR, Cell Counting Kit (CCK8), and ELISA were used to investigate the effect of XBP1 on steroidogenesis, apoptosis, cell cycle, and proliferation of mouse granulosa cells. ELISA analysis showed that XBP1 depletion significantly decreased the concentrations of estradiol (E2). Additionally, the expression of estrogen synthesis enzyme Cyp19a1 was sharply downregulated. Moreover, flow cytometry showed that knockdown of XBP1 increased the apoptosis rate and arrests the cell cycle in S-phase in granulosa cells (GCs). Further study confirmed these results. The expression of CCAAT-enhancer binding protein homologous protein (CHOP), cysteinyl aspartate specific proteases 3 (caspase-3), cleaved caspase-3, and Cyclin E was upregulated, while that of Bcl 2, Cyclin A1, and Cyclin B1 was downregulated. Simultaneously, CCK8 analysis indicated that XBP1 disruption inhibited cell proliferation. In addition, XBP1 knockdown also alters the expression of Has2 and Ptgs2, two essential genes for folliculogenesis. Collectively, these data reveal a novel critical role of XBP1 in folliculogenesis by regulating the cell cycle, apoptosis, and steroid synthesis of mouse granulosa cells. PMID- 28555056 TI - Functional Coping Dynamics and Experiential Avoidance in a Community Sample with No Self-Injury vs. Non-Suicidal Self-Injury Only vs. Those with Both Non-Suicidal Self-Injury and Suicidal Behaviour. AB - Although emotional avoidance may be a critical factor in the pathway from psychological distress to self-injury and/or suicidality, little is known about the relative importance of differing functional coping dynamics and experiential avoidance between people with self-injury histories of differing intent (e.g., Non-Suicidal Self-Injury only vs. Non-Suicidal Self-Injury plus Suicidal Behaviour; NSSI vs. NSSI + SB). A community-based survey (N = 313; female, 81%; ages 16-49 years, M = 19.78, SD = 3.48) explored self-reported experiential avoidance and functional coping dynamics in individuals with (i) no self-injury history (controls); (ii) a history of NSSI only; and (iii) a history of NSSI + SB. Jonckheere-Terpstra trend tests indicated that avoidance coping was higher in the NSSI and NSSI + SB groups than in controls. Emotion regulation was higher in controls than those with a history of self-injury (NSSI and NSSI + SB). Approach and reappraisal coping demonstrated significant ordered effects such that control participants were higher in these coping dynamics than those with a history of NSSI only, who, in turn, were higher than those with a history of NSSI + SB (Control > NSSI > NSSI + SB). Endorsement of the reappraisal/denial facet of experiential avoidance was most pronounced in those with a history of NSSI + SB (Control < NSSI < NSSI + SB). No significant ordered effects were observed for other dimensions of experiential avoidance. Understanding how the endorsement of functional coping dynamics and which components of experiential avoidance vary between groups with differing self-injury intent histories has important implications for treatment planning. PMID- 28555057 TI - Generalized Chirp Scaling Combined with Baseband Azimuth Scaling Algorithm for Large Bandwidth Sliding Spotlight SAR Imaging. AB - This paper presents an efficient and precise imaging algorithm for the large bandwidth sliding spotlight synthetic aperture radar (SAR). The existing sub aperture processing method based on the baseband azimuth scaling (BAS) algorithm cannot cope with the high order phase coupling along the range and azimuth dimensions. This coupling problem causes defocusing along the range and azimuth dimensions. This paper proposes a generalized chirp scaling (GCS)-BAS processing algorithm, which is based on the GCS algorithm. It successfully mitigates the deep focus along the range dimension of a sub-aperture of the large bandwidth sliding spotlight SAR, as well as high order phase coupling along the range and azimuth dimensions. Additionally, the azimuth focusing can be achieved by this azimuth scaling method. Simulation results demonstrate the ability of the GCS-BAS algorithm to process the large bandwidth sliding spotlight SAR data. It is proven that great improvements of the focus depth and imaging accuracy are obtained via the GCS-BAS algorithm. PMID- 28555055 TI - The Methods of Choice for Extracellular Vesicles (EVs) Characterization. AB - In recent years, extracellular vesicles (EVs) have become a subject of intense study. These membrane-enclosed spherical structures are secreted by almost every cell type and are engaged in the transport of cellular content (cargo) from parental to target cells. The impact of EVs transfer has been observed in many vital cellular processes including cell-to-cell communication and immune response modulation; thus, a fast and precise characterization of EVs may be relevant for both scientific and diagnostic purposes. In this review, the most popular analytical techniques used in EVs studies are presented with the emphasis on exosomes and microvesicles characterization. PMID- 28555058 TI - Modeling Hybridization Kinetics of Gene Probes in a DNA Biochip Using FEMLAB. AB - Microfluidic DNA biochips capable of detecting specific DNA sequences are useful in medical diagnostics, drug discovery, food safety monitoring and agriculture. They are used as miniaturized platforms for analysis of nucleic acids-based biomarkers. Binding kinetics between immobilized single stranded DNA on the surface and its complementary strand present in the sample are of interest. To achieve optimal sensitivity with minimum sample size and rapid hybridization, ability to predict the kinetics of hybridization based on the thermodynamic characteristics of the probe is crucial. In this study, a computer aided numerical model for the design and optimization of a flow-through biochip was developed using a finite element technique packaged software tool (FEMLAB; package included in COMSOL Multiphysics) to simulate the transport of DNA through a microfluidic chamber to the reaction surface. The model accounts for fluid flow, convection and diffusion in the channel and on the reaction surface. Concentration, association rate constant, dissociation rate constant, recirculation flow rate, and temperature were key parameters affecting the rate of hybridization. The model predicted the kinetic profile and signal intensities of eighteen 20-mer probes targeting vancomycin resistance genes (VRGs). Predicted signal intensities and hybridization kinetics strongly correlated with experimental data in the biochip (R2 = 0.8131). PMID- 28555059 TI - Applications of Fluorogens with Rotor Structures in Solar Cells. AB - Solar cells are devices that convert light energy into electricity. To drive greater adoption of solar cell technologies, higher cell efficiencies and reductions in manufacturing cost are necessary. Fluorogens containing rotor structures may be helpful in addressing some of these challenges due to their unique twisted structures and photophysics. In this review, we discuss the applications of rotor-containing molecules as dyes for luminescent down-shifting layers and luminescent solar concentrators, where their aggregation-induced emission properties and large Stokes shifts are highly desirable. We also discuss the applications of molecules containing rotors in third-generation solar cell technologies, namely dye-sensitized solar cells and organic photovoltaics, where the twisted 3-dimensional rotor structures are used primarily for aggregation control. Finally, we discuss perspectives on the future role of molecules containing rotor structures in solar cell technologies. PMID- 28555061 TI - Synthesis of Gallic Acid Analogs as Histamine and Pro-Inflammatory Cytokine Inhibitors for Treatment of Mast Cell-Mediated Allergic Inflammation. AB - Gallic acid (3,4,5-trihydroxybenzoic acid), is a natural product found in various foods and herbs that are well known as powerful antioxidants. Our previous report demonstrated that it inhibits mast cell-derived inflammatory allergic reactions by blocking histamine release and pro-inflammatory cytokine expression. In this report, various amide analogs of gallic acid have been synthesized by introducing different amines through carbodiimide-mediated amide coupling and Pd/C-catalyzed hydrogenation. These compounds showed a modest to high inhibitory effect on histamine release and pro-inflammatory cytokine expression. Among them, the amide bearing (S)-phenylglycine methyl ester 3d was found to be more active than natural gallic acid. Further optimization yielded several (S)- and (R) phenylglycine analogs that inhibited histamine release in vitro. Our findings suggest that some gallamides could be used as a treatment for allergic inflammatory diseases. PMID- 28555060 TI - Role of Homologous Fc Fragment in the Potency and Efficacy of Anti-Botulinum Antibody Preparations. AB - The only approved treatment for botulism relies on passive immunity which is mostly based on antibody preparations collected from hyper-immune horses. The IgG Fc fragment is commonly removed from these heterologous preparations to reduce the incidence of hyper-sensitivity reactions. New-generation therapies entering the pipeline are based on a combination of humanized monoclonal antibodies (MAbs), which exhibit improved safety and pharmacokinetics. In the current study, a systematic and quantitative approach was applied to measure the direct contribution of homologous Fc to the potency of monoclonal and polyclonal antitoxin preparations in mice. Homologous Fc increased the potency of three individual anti-botulinum toxin MAbs by up to one order of magnitude. Moreover, Fc fragment removal almost completely abolished the synergistic potency obtained from a combined preparation of these three MAbs. The MAb mixture neutralized a 400-mouse median lethal dose (MsLD50) of botulinum toxin, whereas the F(ab')2 combination failed to neutralize 10 MsLD50 of botulinum toxin. Notably, increased avidity did not compensate for this phenomenon, as a polyclonal, hyper-immune, homologous preparation lost 90% of its potency as well upon Fc removal. Finally, the addition of homologous Fc arms to a heterologous pharmaceutical anti botulinum toxin polyclonal horse F(ab')2 preparation improved its efficacy when administered to intoxicated symptomatic mice. Our study extends the aspects by which switching from animal-based to human-based antitoxins will improve not only the safety but also the potency and efficacy of passive immunity against toxins. PMID- 28555062 TI - Non-Coding RNAs in Hodgkin Lymphoma. AB - MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression by binding to the 3'-UTR of their target genes, can act as oncogenes or tumor suppressors. Recently, other types of non-coding RNAs-piwiRNAs and long non coding RNAs-have also been identified. Hodgkin lymphoma (HL) is a B cell origin disease characterized by the presence of only 1% of tumor cells, known as Hodgkin and Reed-Stenberg (HRS) cells, which interact with the microenvironment to evade apoptosis. Several studies have reported specific miRNA signatures that can differentiate HL lymph nodes from reactive lymph nodes, identify histologic groups within classical HL, and distinguish HRS cells from germinal center B cells. Moreover, some signatures are associated with survival or response to chemotherapy. Most of the miRNAs in the signatures regulate genes related to apoptosis, cell cycle arrest, or signaling pathways. Here we review findings on miRNAs in HL, as well as on other non-coding RNAs. PMID- 28555063 TI - The Occurrence of the Colistin Resistance Gene mcr-1 in the Haihe River (China). AB - Antibiotic failure is occurring worldwide. In a routine surveillance study on antibioticresistance genes (ARGs) in natural water bodies, we noted the detection of colistin-resistance gene mcr-1, previously identified in Escherichia coli and Klebsiella pneumoniae isolates from human beings and animals in several countries. The mcr-1 gene might be present in water environments, because aquatic ecosystems are recognized as reservoirs for antibiotic resistant bacteria (ARB) and ARGs. In this study, a qPCR assay was developed to monitor and quantify the mcr-1 gene in the Haihe River, China. The results showed that all 18 samples collected from different locations over 6 months along the Haihe River were positive for the mcr-1 gene, and the highest level of mcr-1 reached 3.81 * 105 gene copies (GC) per liter of water. This is the first study to quantify mcr-1 in a natural water system by qPCR. Our findings highlight the potential for this antibiotic resistance determinant to spread extensively, suggesting a significant health and ecological impact. PMID- 28555064 TI - Induction of p53-Independent Apoptosis and G1 Cell Cycle Arrest by Fucoidan in HCT116 Human Colorectal Carcinoma Cells. AB - It is well known that fucoidan, a natural sulfated polysaccharide present in various brown algae, mediates anticancer effects through the induction of cell cycle arrest and apoptosis. Nevertheless, the role of tumor suppressor p53 in the mechanism action of fucoidan remains unclear. Here, we investigated the anticancer effect of fucoidan on two p53 isogenic HCT116 (p53+/+ and p53-/-) cell lines. Our results showed that inhibition of cell viability, induction of apoptosis and DNA damage by treatment with fucoidan were similar in two cell lines. Flow cytometric analysis revealed that fucoidan resulted in G1 arrest in the cell cycle progression, which correlated with the inhibition of phosphorylation of retinoblastoma protein (pRB) and concomitant association of pRB with the transcription factor E2Fs. Furthermore, treatment with fucoidan obviously upregulated the expression of cyclin-dependent kinase (CDK) inhibitors, such as p21WAF1/CIP1 and p27KIP1, which was paralleled by an enhanced binding with CDK2 and CDK4. These events also commonly occurred in both cell lines, suggesting that fucoidan triggered G1 arrest and apoptosis in HCT116 cells by a p53-independent mechanism. Thus, given that most tumors exhibit functional p53 inactivation, fucoidan could be a possible therapeutic option for cancer treatment regardless of the p53 status. PMID- 28555065 TI - A Novel Micro Cold Atmospheric Plasma Device for Glioblastoma Both In Vitro and In Vivo. AB - Cold atmospheric plasma (CAP) treatment is a rapidly expanding and emerging technology for cancer treatment. Direct CAP jet irradiation is limited to the skin and it can also be invoked as a supplement therapy during surgery as it only causes cell death in the upper three to five cell layers. However, the current cannulas from which the plasma emanates are too large for intracranial applications. To enhance efficiency and expand the applicability of the CAP method for brain tumors and reduce the gas flow rate and size of the plasma jet, a novel micro-sized CAP device (uCAP) was developed and employed to target glioblastoma tumors in the murine brain. Various plasma diagnostic techniques were applied to evaluate the physics of helium uCAP such as electron density, discharge voltage, and optical emission spectroscopy (OES). The direct and indirect effects of uCAP on glioblastoma (U87MG-RedFluc) cancer cells were investigated in vitro. The results indicate that uCAP generates short- and long lived species and radicals (i.e., hydroxyl radical (OH), hydrogen peroxide (H2O2), and nitrite (NO2-), etc.) with increasing tumor cell death in a dose dependent manner. Translation of these findings to an in vivo setting demonstrates that intracranial uCAP is effective at preventing glioblastoma tumor growth in the mouse brain. The uCAP device can be safely used in mice, resulting in suppression of tumor growth. These initial observations establish the uCAP device as a potentially useful ablative therapy tool in the treatment of glioblastoma. PMID- 28555066 TI - Expression of Genes Related to Phenylpropanoid Biosynthesis in Different Organs of Ixeris dentata var. albiflora. AB - Members of the genus Ixeris have long been used in traditional medicines as stomachics, sedatives, and diuretics. Phenylalanine ammonia-lyase (PAL), cinnamate-4-hydroxylase (C4H), 4-coumarate: coenzyme-A (CoA) ligase (4CL), chalcone synthase (CHS), and dihydroflavonol 4-reductase (DFR) are important enzymes in the phenylpropanoid pathway. In this study, we analyzed seven genes from Ixeris dentata var. albiflora that are involved in phenylpropanoid biosynthesis, using an Illumina/Solexa HiSeq 2000 platform. The amino acid sequence alignments for IdPALs, IdC4H, Id4CLs, IdCHS, and IdDFR showed high identity to sequences from other plants. We also investigated transcript levels using quantitative real-time PCR, and analyzed the accumulation of phenylpropanoids in different organs of I. dentata var. albiflora using high performance liquid chromatography. The transcript levels of IdC4H, Id4CL1, IdCHS, and IdDFR were highest in the leaf. The catechin, chlorogenic acid, ferulic acid, and quercetin contents were also highest in the leaf. We suggest that expression of IdC4H, Id4CL1, IdCHS, and IdDFR is associated with the accumulation of phenylpropanoids. Our results may provide baseline information for elucidating the mechanism of phenylpropanoid biosynthesis in different organs of I. dentata var. albiflora. PMID- 28555067 TI - Outcome of a Modified Laparoscopic Suture Rectopexy for Rectal Prolapse with the Use of a Single or Double Suture: A Case Series of 15 Patients. AB - BACKGROUND Surgery is considered to be a mainstay of therapy for full-thickness rectal prolapse (FTRP). Surgical procedures for FTRP have been described, but optimal treatment is still controversial. The aim of this report is to evaluate the safety and feasibility of a simplified laparoscopic suture rectopexy (LSR) in a case series of 15 patients who presented with FTRP and who had postoperative follow-up for six months. CASE REPORT Fifteen patients who underwent a modified LSR at our surgical unit from September 2010 were retrospectively evaluated. The mean age of the patients was 72.5+/-10.9 years. All 15 patients underwent general anesthesia, with rectal mobilization performed according to the plane of the total mesorectal excision. By lifting the mobilized and dissected rectum cranially to the promontorium, the optimal point for subsequent suture fixation of the rectum was marked. The seromuscular layer of the anterior right wall was then sutured to the presacral fascia using only one or two interrupted nonabsorbable polypropylene sutures. The mean operative time was 176.2+/-35.2 minutes, with minimal blood loss. No moderate or severe postoperative complications were observed, and there was no postoperative mortality. One patient (6.7%) developed recurrence of rectal prolapse one month following surgery. CONCLUSIONS The advantages of this LSR procedure for the management of patients with FTRP are its simplicity, safety, efficacy, and practicality and the potential for its use in patients who can tolerate general anesthesia. PMID- 28555068 TI - Acute Phase Proteins for Monitoring Hematopoietic Recovery After Early Engrafting of CD34+ Peripheral-Blood-Stem-Cells for Autografting or Allografting in Patients with Malignant Diseases. AB - BACKGROUND Neutropenic fever (NF) is associated with delayed engraftment after peripheral blood stem cell transplantation (PBSCT). MATERIAL AND METHODS We followed the levels of acute-phase proteins (APPs) serially in 60 patients after peripheral blood stem-cell autograft (n=39) or peripheral blood stem-cell allograft (n=21) for hematologic malignancies and germinal tumors; we then examined the correlation of those levels with the presence of fever and with markers of engraftment. RESULTS Fever (present in 60% of patients) was associated with a highly statistically significant delay in reaching conventional engraftment targets (ANC >500/MUL [0.5*10^9/L]; platelets >20,000/MUL [20*10^9/L]; reticulocytes >20,000/MUL [20*10^9/L]) (for all associations, p<0.001). Every 4th day for 24 days, we measured the APPs levels and the number of neutrophils (ANC), platelets (PL), and reticulocytes (RET) to reach the reference values of >0.5 G/L or >1.0 G/L for ANC, >20 G/L or >50 G/L for PL, and >20 G/L for RET, respectively. The presence of NF resulted in longer time to engraft hematopoietic stem cells with ANC, PL, and PET counts statistically significant (range 0.001-0.004). The median day range for NF patients was 21.22 26.89 versus 13.88-19.13 for no NF patients. CONCLUSIONS Our results provide additional information for monitoring hematopoietic engraftment in patients following PBSCT; the presence of NF can be tracked by serial measurements in serum of three investigated APPs throughout an early phase of hematopoietic recovery. PMID- 28555069 TI - Association Between Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Polymorphisms and Risk of Ankylosing Spondylitis: A Meta-analysis. AB - BACKGROUND Ankylosing spondylitis (AS) is a chronic autoimmune disease that involves the imbalance of peripheral tolerance possibly caused by the negative signal of activated T cells. The polymorphisms in the human protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene have been pointed out to be related to the pathogenesis of AS, but conclusions over this issue remain contradictory. We attempted to give a more precise conclusion about the effects of PTPN22 polymorphisms on AS risk by means of a meta-analysis. MATERIAL AND METHODS PubMed, Embase, Wanfang, and Chinese National Knowledge Infrastructure (CNKI) were searched for relevant studies published in the English or Chinese language. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated with a fixed- or random-effects model to evaluate the correlation between PTPN22 rs2488457, rs1217414, and rs2476601 polymorphisms and AS susceptibility. Sensitivity analysis was also carried out to detect the stability of the results. RESULTS The present meta-analysis showed a positive correlation of both PTPN22 rs2488457 and rs1217414 polymorphisms with AS risk under CC vs. GG, CC + GC vs. GG, CC vs. GC + GG, allele C vs. allele G (OR=1.39, 95% CI=1.04 1.85, P=0.646; OR=1.29, 95% CI=1.03-1.62, P=0.426; OR=1.26, 95% CI=1.02-1.56, P=0.971; OR=1.20, 95% CI=1.05-1.38, P=0.571), and TT vs. CC and TT vs. CT + CC models (OR=3.83, 95% CI=1.11-13.24, P=0.196; OR=3.83, 95% CI=1.09-13.42, P=0.244), respectively. CONCLUSIONS PTPN22 rs2488457 and rs1217414 polymorphisms may be risk factors for AS occurrence. PMID- 28555070 TI - Absence Seizure Control by a Brain Computer Interface. AB - The ultimate goal of epileptology is the complete abolishment of epileptic seizures. This might be achieved by a system that predicts seizure onset combined with a system that interferes with the process that leads to the onset of a seizure. Seizure prediction remains, as of yet, unresolved in absence-epilepsy, due to the sudden onset of seizures. We have developed a real-time absence seizure prediction algorithm, evaluated it and implemented it in an on-line, closed-loop brain stimulation system designed to prevent the spike-wave discharges (SWDs), typical for absence epilepsy, in a genetic rat model. The algorithm corretly predicted 88% of the SWDs while the remaining were quickly detected. A high number of false-positive detections occurred mainly during light slow-wave-sleep. Inclusion of criteria to prevent false-positives greatly reduced the false alarm rate but decreased the sensitivity of the algoritm. Implementation of the latter version into a closed-loop brain-stimulation-system resulted in a 72% decrease in seizure activity. In contrast to long standing beliefs that SWDs are unpredictable, these results demonstrate that they can be predicted and that the development of closed-loop seizure prediction and prevention systems is a feasable step towards interventions to attain control and freedom from epileptic seizures. PMID- 28555072 TI - Bacterial pathogenesis: Campylobacter follows the clues. PMID- 28555071 TI - Seasonally lagged effects of climatic factors on malaria incidence in South Africa. AB - Globally, malaria cases have drastically dropped in recent years. However, a high incidence of malaria remains in some sub-Saharan African countries. South Africa is mostly malaria-free, but northeastern provinces continue to experience seasonal outbreaks. Here we investigate the association between malaria incidence and spatio-temporal climate variations in Limpopo. First, dominant spatial patterns in malaria incidence anomalies were identified using self-organizing maps. Composite analysis found significant associations among incidence anomalies and climate patterns. A high incidence of malaria during the pre-peak season (Sep Nov) was associated with the climate phenomenon La Nina and cool air temperatures over southern Africa. There was also high precipitation over neighbouring countries two to six months prior to malaria incidence. During the peak season (Dec-Feb), high incidence was associated with positive phase of Indian Ocean Subtropical Dipole. Warm temperatures and high precipitation in neighbouring countries were also observed two months prior to increased malaria incidence. This lagged association between regional climate and malaria incidence suggests that in areas at high risk for malaria, such as Limpopo, management plans should consider not only local climate patterns but those of neighbouring countries as well. These findings highlight the need to strengthen cross-border control of malaria to minimize its spread. PMID- 28555074 TI - Viral evolution: Zika is on point to increase spread. PMID- 28555075 TI - Acute ketamine administration corrects abnormal inflammatory bone markers in major depressive disorder. AB - Patients with major depressive disorder (MDD) have clinically relevant, significant decreases in bone mineral density (BMD). We sought to determine if predictive markers of bone inflammation-the osteoprotegerin (OPG)-RANK-RANKL system or osteopontin (OPN)-play a role in the bone abnormalities associated with MDD and, if so, whether ketamine treatment corrected the abnormalities. The OPG RANK-RANKL system plays the principal role in determining the balance between bone resorption and bone formation. RANKL is the osteoclast differentiating factor and diminishes BMD. OPG is a decoy receptor for RANKL, thereby increasing BMD. OPN is the bone glue that acts as a scaffold between bone tissues matrix composition to bind them together and is an important component of bone strength and fracture resistance. Twenty-eight medication-free inpatients with treatment resistant MDD and 16 healthy controls (HCs) participated in the study. Peripheral bone marker levels and their responses to IV ketamine infusion in MDD patients and HCs were measured at four time points: at baseline, and post-infusion at 230 min, Day 1, and Day 3. Patients with MDD had significant decreases in baseline OPG/RANKL ratio and in plasma OPN levels. Ketamine significantly increased both the OPG/RANKL ratio and plasma OPN levels, and significantly decreased RANKL levels. Bone marker levels in HCs remained unaltered. We conclude that the OPG RANK-RANKL system and the OPN system play important roles in the serious bone abnormalities associated with MDD. These data suggest that, in addition to its antidepressant effects, ketamine also has a salutary effect on a major medical complication of depressive illness. PMID- 28555076 TI - Comparative genomic evidence for the involvement of schizophrenia risk genes in antipsychotic effects. AB - Genome-wide association studies (GWAS) for schizophrenia have identified over 100 loci encoding >500 genes. It is unclear whether any of these genes, other than dopamine receptor D2, are immediately relevant to antipsychotic effects or represent novel antipsychotic targets. We applied an in vivo molecular approach to this question by performing RNA sequencing of brain tissue from mice chronically treated with the antipsychotic haloperidol or vehicle. We observed significant enrichments of haloperidol-regulated genes in schizophrenia GWAS loci and in schizophrenia-associated biological pathways. Our findings provide empirical support for overlap between genetic variation underlying the pathophysiology of schizophrenia and the molecular effects of a prototypical antipsychotic. PMID- 28555073 TI - Pathways to zoonotic spillover. AB - Zoonotic spillover, which is the transmission of a pathogen from a vertebrate animal to a human, presents a global public health burden but is a poorly understood phenomenon. Zoonotic spillover requires several factors to align, including the ecological, epidemiological and behavioural determinants of pathogen exposure, and the within-human factors that affect susceptibility to infection. In this Opinion article, we propose a synthetic framework for animal to-human transmission that integrates the relevant mechanisms. This framework reveals that all zoonotic pathogens must overcome a hierarchical series of barriers to cause spillover infections in humans. Understanding how these barriers are functionally and quantitatively linked, and how they interact in space and time, will substantially improve our ability to predict or prevent spillover events. This work provides a foundation for transdisciplinary investigation of spillover and synthetic theory on zoonotic transmission. PMID- 28555077 TI - The dendritic spine morphogenic effects of repeated cocaine use occur through the regulation of serum response factor signaling. AB - The nucleus accumbens (NAc) is a primary brain reward region composed predominantly of medium spiny neurons (MSNs). In response to early withdrawal from repeated cocaine administration, de novo dendritic spine formation occurs in NAc MSNs. Much evidence indicates that this new spine formation facilitates the rewarding properties of cocaine. Early withdrawal from repeated cocaine also produces dramatic alterations in the transcriptome of NAc MSNs, but how such alterations influence cocaine's effects on dendritic spine formation remain unclear. Studies in non-neuronal cells indicate that actin cytoskeletal regulatory pathways in nuclei have a direct role in the regulation of gene transcription in part by controlling the access of co-activators to their transcription factor partners. In particular, actin state dictates the interaction between the serum response factor (SRF) transcription factor and one of its principal co-activators, MAL. Here we show that cocaine induces alterations in nuclear F-actin signaling pathways in the NAc with associated changes in the nuclear subcellular localization of SRF and MAL. Using in vivo optogenetics, the brain region-specific inputs to the NAc that mediate these nuclear changes are investigated. Finally, we demonstrate that regulated SRF expression, in turn, is critical for the effects of cocaine on dendritic spine formation and for cocaine-mediated behavioral sensitization. Collectively, these findings reveal a mechanism by which nuclear-based changes influence the structure of NAc MSNs in response to cocaine. PMID- 28555078 TI - Tau-dependent suppression of adult neurogenesis in the stressed hippocampus. AB - Stress, a well-known sculptor of brain plasticity, is shown to suppress hippocampal neurogenesis in the adult brain; yet, the underlying cellular mechanisms are poorly investigated. Previous studies have shown that chronic stress triggers hyperphosphorylation and accumulation of the cytoskeletal protein Tau, a process that may impair the cytoskeleton-regulating role(s) of this protein with impact on neuronal function. Here, we analyzed the role of Tau on stress-driven suppression of neurogenesis in the adult dentate gyrus (DG) using animals lacking Tau (Tau-knockout; Tau-KO) and wild-type (WT) littermates. Unlike WTs, Tau-KO animals exposed to chronic stress did not exhibit reduction in DG proliferating cells, neuroblasts and newborn neurons; however, newborn astrocytes were similarly decreased in both Tau-KO and WT mice. In addition, chronic stress reduced phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/glycogen synthase kinase-3beta (GSK3beta)/beta-catenin signaling, known to regulate cell survival and proliferation, in the DG of WT, but not Tau-KO, animals. These data establish Tau as a critical regulator of the cellular cascades underlying stress deficits on hippocampal neurogenesis in the adult brain. PMID- 28555081 TI - Genomic determinants of chronic myelomonocytic leukemia. AB - The biology, clinical phenotype and progression rate of chronic myelomonocytic leukemia (CMML) are highly variable due to diverse initiating and secondary clonal genetic events. To determine the effects of molecular features including clonal hierarchy in CMML, we studied whole-exome and targeted next-generation sequencing data from 150 patients with robust clinical and molecular annotation assessed cross-sectionally and at serial time points of disease evolution. To identify molecular lesions unique to CMML, we compared it to the related myeloid neoplasms (N=586), including juvenile myelomonocytic leukemia, myelodysplastic syndromes (MDS) and primary monocytic acute myeloid leukemia and discerned distinct molecular profiles despite similar pathomorphological features. Within CMML, mutations in certain pathways correlated with clinical classification, for example, proliferative vs dysplastic features. While most CMML patients (59%) had ancestral (dominant/co-dominant) mutations involving TET2, SRSF2 or ASXL1 genes, secondary subclonal hierarchy correlated with clinical phenotypes or outcomes. For example, progression was associated with acquisition of new expanding clones carrying biallelic TET2 mutations or RAS family, or spliceosomal gene mutations. In contrast, dysplastic features correlated with mutations usually encountered in MDS (for example, SF3B1 and U2AF1). Classification of CMML based on hierarchies of ancestral and subclonal mutational events may correlate strongly with clinical features and prognosis. PMID- 28555080 TI - Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis. AB - The chimeric fusion oncogene early B-cell factor 1-platelet-derived growth factor receptor-beta (EBF1-PDGFRB) is a recurrent lesion observed in Philadelphia-like B acute lymphoblastic leukemia (B-ALL) and is associated with particularly poor prognosis. While it is understood that this fusion activates tyrosine kinase signaling, the mechanisms of transformation and importance of perturbation of EBF1 activity remain unknown. EBF1 is a nuclear transcription factor required for normal B-lineage specification, commitment and development. Conversely, PDGFRB is a receptor tyrosine kinase that is normally repressed in lymphocytes, yet PDGFRB remains a common fusion partner in leukemias. Here, we demonstrate that the EBF1 PDGFRB fusion results in loss of EBF1 function, multimerization and autophosphorylation of the fusion protein, activation of signal transducer and activator of transcription 5 (STAT5) signaling and gain of interleukin-7 (IL-7) independent cell proliferation. Deregulation and loss of EBF1 function is critically dependent on the nuclear export activity of the transmembrane (TM) domain of PDGFRB. Deletion of the TM domain partially rescues EBF1 function and restores IL-7 dependence, without requiring kinase inhibition. Moreover, we demonstrate that EBF1-PDGFRB synergizes with loss of IKAROS function in a fully penetrant B-ALL in vivo. Thus, we establish that EBF1-PDGFRB is sufficient to drive leukemogenesis through TM-dependent loss of transcription factor function, increased proliferation and synergy with additional genetic insults including loss of IKAROS function. PMID- 28555082 TI - Identification of a novel PML-RARG fusion in acute promyelocytic leukemia. PMID- 28555079 TI - MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs. AB - The PD-L1/PD-1 pathway is a critical component of the immunosuppressive tumor microenvironment in acute myeloid leukemia (AML), but little is known about its regulation. We investigated the role of the MUC1 oncoprotein in modulating PD-L1 expression in AML. Silencing of MUC1 in AML cell lines suppressed PD-L1 expression without a decrease in PD-L1 mRNA levels, suggesting a post transcriptional mechanism of regulation. We identified the microRNAs miR-200c and miR-34a as key regulators of PD-L1 expression in AML. Silencing of MUC1 in AML cells led to a marked increase in miR-200c and miR-34a levels, without changes in precursor microRNA, suggesting that MUC1 might regulate microRNA-processing. MUC1 signaling decreased the expression of the microRNA-processing protein DICER, via the suppression of c-Jun activity. NanoString (Seattle, WA, USA) array of MUC1 silenced AML cells demonstrated an increase in the majority of probed microRNAs. In an immunocompetent murine AML model, targeting of MUC1 led to a significant increase in leukemia-specific T cells. In concert, targeting MUC1 signaling in human AML cells resulted in enhanced sensitivity to T-cell-mediated lysis. These findings suggest MUC1 is a critical regulator of PD-L1 expression via its effects on microRNA levels and represents a potential therapeutic target to enhance anti tumor immunity. PMID- 28555083 TI - PPAR-delta modulates membrane cholesterol and cytokine signaling in malignant B cells. AB - A deeper understanding of the mechanisms that underlie aberrant signal transduction in B-cell cancers such as chronic lymphocytic leukemia (CLL) may reveal new treatment strategies. The lipid-activated nuclear receptor peroxisome proliferator-activated receptor delta (PPARdelta) accounts for a number of properties of aggressive cancers and was found to enhance Janus kinase (JAK) mediated phosphorylation of signal transducer and activator of transcription (STAT) proteins in B lymphoma cell lines and primary CLL cells. Autocrine production of cytokines such as IL10 and interferon-beta was not increased by PPARdelta but signaling responses to these cytokines were amplified and associated with increased cholesterol biosynthesis and plasma membrane levels. Plasmalemmal cholesterol and STAT phosphorylation from type 1 interferons (IFNs) were increased by PPARdelta agonists, transgenes and exogenous cholesterol, and decreased by cyclodextrin, PPARD deletion and chemical PPARdelta inhibitors. Functional consequences of PPARdelta-mediated perturbation of IFN signaling included impaired upregulation of co-stimulatory molecules. These observations suggest PPARdelta modulates signaling processes in malignant B cells in part by altering cholesterol metabolism and changes the outcomes of signaling from cytokines such as IFNs. PPARdelta antagonists may have therapeutic activity as anti-leukemic signal transduction modulators. PMID- 28555085 TI - SONGS IN THE COUNTERTRANSFERENCE OR "GILDING THE PHILOSOPHIC PILL". AB - Songs that interrupt the psychoanalytic psychotherapist's countertransference reverie are invariably relevant and potentially useful. Like any other countertransference "presence," songs accompanying the narrative may contribute to understanding both patient and analytic process. Taking their intrusive, fecund, pesky presence one step further, song lyrics may be used as metaphor saturated interventions, helping reach the well-defended patient. Five brief vignettes illustrate the process. Because we must learn to tolerate ordinary unhappiness, Blues music, a carrier of preconscious mythic themes (love and work), may prove especially useful, helping the patient indirectly embrace everyday wisdom, endure hard times, universalize misery, and see ourselves in the roomy mirror of metaphor. PMID- 28555084 TI - Mitoxantrone, etoposide and cytarabine following epigenetic priming with decitabine in adults with relapsed/refractory acute myeloid leukemia or other high-grade myeloid neoplasms: a phase 1/2 study. AB - DNA methyltransferase inhibitors sensitize leukemia cells to chemotherapeutics. We therefore conducted a phase 1/2 study of mitoxantrone, etoposide and cytarabine following 'priming' with 5-10 days of decitabine (dec/MEC) in 52 adults (median age 55 (range: 19-72) years) with relapsed/refractory acute myeloid leukemia (AML) or other high-grade myeloid neoplasms. During dose escalation in cohorts of 6-12 patients, all dose levels were well tolerated. As response rates appeared similar with 7 and 10 days of decitabine, a 7-day course was defined as the recommended phase 2 dose (RP2D). Among 46 patients treated at/above the RP2D, 10 (22%) achieved a complete remission (CR), 8 without measurable residual disease; five additional patients achieved CR with incomplete platelet recovery, for an overall response rate of 33%. Seven patients (15%) died within 28 days of treatment initiation. Infection/neutropenic fever, nausea and mucositis were the most common adverse events. While the CR rate compared favorably to a matched historic control population (observed/expected CR ratio=1.77), CR rate and survival were similar to two contemporary salvage regimens used at our institution (G-CLAC (granulocyte colony-stimulating factor (G-CSF); clofarabine; cytarabine) and G-CLAM (G-CSF; cladribine; cytarabine; mitoxantrone)). Thus, while meeting the prespecified efficacy goal, we found no evidence that dec/MEC is substantially better than other cytarabine-based regimens currently used for relapsed/refractory AML. PMID- 28555088 TI - Optimal Financial Knowledge and Wealth Inequality. AB - We show that financial knowledge is a key determinant of wealth inequality in a stochastic lifecycle model with endogenous financial knowledge accumulation, where financial knowledge enables individuals to better allocate lifetime resources in a world of uncertainty and imperfect insurance. Moreover, because of how the U.S. social insurance system works, better-educated individuals have most to gain from investing in financial knowledge. Our parsimonious specification generates substantial wealth inequality relative to a one-asset saving model and one where returns on wealth depend on portfolio composition alone. We estimate that 30-40 percent of retirement wealth inequality is accounted for by financial knowledge. PMID- 28555086 TI - Hepatic CD36 downregulation parallels steatosis improvement in morbidly obese undergoing bariatric surgery. AB - BACKGROUND: The notion that hepatic expression of genes involved in lipid metabolism is altered in obese patients is relatively new and its relationship with hepatic steatosis and cardiometabolic alterations remains unclear. OBJECTIVE: We assessed the impact of Roux-en-Y gastric bypass surgery (RYGB) on the expression profile of genes related to metabolic syndrome in liver biopsies from morbidly obese individuals using a custom-made, focused cDNA microarray, and assessed the relationship between the expression profile and hepatic steatosis regression. MATERIALS AND METHODS: Plasma and liver samples were obtained from patients at baseline and 12 months after surgery. Samples were assayed for chemical and gene expression analyses, as appropriate. Gene expression profiles were assessed using custom-made, focused TaqMan low-density array cards. RESULTS: RYGB-induced weight loss produced a favorable reduction in fat deposits, insulin resistance (estimated by homeostasis model assessment of insulin resistance (HOMA IR)), and plasma and hepatic lipid levels. Compared with the baseline values, the gene expression levels of key targets of lipid metabolism were significantly altered: CD36 was significantly downregulated (-40%; P=0.001), whereas APOB (+27%; P=0.032) and SCARB1 (+37%; P=0.040) were upregulated in response to surgery-induced weight reduction. We also observed a favorable reduction in the expression of the PAI1 gene (-80%; P=0.007) and a significant increase in the expression of the PPARA (+60%; P=0.014) and PPARGC1 genes (+36%; P=0.015). Notably, the relative fold decrease in the expression of the CD36 gene was directly associated with a concomitant reduction in the cholesterol (Spearman's r=0.92; P=0.001) and phospholipid (Spearman's r=0.76; P=0.04) contents in this tissue. CONCLUSIONS: For the first time, RYGB-induced weight loss was shown to promote a favorable downregulation of CD36 expression, which was proportional to a favorable reduction in the hepatic cholesterol and phospholipid contents in our morbidly obese subjects following surgery. PMID- 28555087 TI - Strategic incorporation of fluorine in the drug discovery of new-generation antitubercular agents targeting bacterial cell division protein FtsZ. AB - This article presents an account of our research on the discovery and development of new-generation fluorine-containing antibacterial agents against drug-resistant tuberculosis, targeting FtsZ. FtsZ is an essential protein for bacterial cell division and a highly promising therapeutic target for antibacterial drug discovery. Through design, synthesis and semi-HTP screening of libraries of novel benzimidazoles, followed by SAR studies, we identified highly potent lead compounds. However, these lead compounds were found to lack sufficient metabolic and plasma stabilities. Accordingly, we have performed extensive study on the strategic incorporation of fluorine into lead compounds to improve pharmacological properties. This study has led to the development of highly efficacious fluorine-containing benzimidazoles as potential drug candidates. We have also performed computational docking analysis of these novel FtsZ inhibitors to identify their putative binding site. Based on the structural data and docking analysis, a plausible mode-of-action for this novel class of FtsZ inhibitors is proposed. PMID- 28555089 TI - Stigmasterol Modulates Allergic Airway Inflammation in Guinea Pig Model of Ovalbumin-Induced Asthma. AB - We explored the potential benefits of stigmasterol in the treatment of asthma, an airway disorder characterized by immune pathophysiology and with an ever increasing worldwide prevalence. We assessed the modulatory effect of the intraperitoneal administration of stigmasterol on experimentally induced airway inflammation in guinea pigs. The effect of stigmasterol on inflammatory cell proliferation, oxidative stress, lung histopathology, and remodeling was investigated. The results showed significant suppressive effects on ovalbumin induced airway inflammatory damage. Stigmasterol at 10-100 mg/kg reduced proliferation of eosinophils, lymphocytes, and monocytes while reducing peribronchiolar, perivascular, and alveolar infiltration of inflammatory cells. Histopathology revealed stigmasterol maintained lung architecture and reversed collagen deposition, an index of lung remodeling. Overexpression of serum vascular cell adhesion molecule-1 (VCAM-1) and ovalbumin-specific immunoglobulin E (OVA sIgE) elicited by ovalbumin sensitization and challenge was significantly controlled with stigmasterol. Taken together, stigmasterol possessed significant antiasthmatic properties and had suppressive effects on key features of allergen induced asthma. PMID- 28555091 TI - Gravity Compensation and Feedback of Ground Reaction Forces for Biped Balance Control. AB - This paper considers the balance control of a biped robot under a constant external force or on a sloped ground. We have proposed a control method with feedback of the ground reaction forces and have realized adaptive posture changes that ensure the stability of the robot. However, fast responses have not been obtained because effective control is achieved by an integral feedback that accompanies a time delay necessary for error accumulation. To improve this response, here, we introduce gravity compensation in a feedforward manner. The stationary state and its stability are analyzed based on dynamic equations, and the robustness as well as the response is evaluated using computer simulations. Finally, the adaptive behaviors of the robot are confirmed by standing experiments on the slope. PMID- 28555090 TI - The Distribution of Activation Markers and Selectins on Peripheral T Lymphocytes in Preeclampsia. AB - INTRODUCTION: Impaired maternal immune tolerance resulting in systemic inflammation plays a pivotal role in the pathogenesis of preeclampsia. Phenotypical changes of monocytes and neutrophil granulocytes have already been studied in preeclampsia, and some studies also included T lymphocyte activation markers; however, the results are controversial and a comprehensive analysis of activation markers is lacking. The characteristics of cellular adhesion molecules in preeclampsia are yet to be described. MATERIAL AND METHODS: Peripheral blood samples of 18 preeclamptic patients and 20 healthy pregnant women in the third trimester were evaluated using flow cytometry to characterize the cell surface expression of T lymphocyte activation markers and selectins. RESULTS: We found an elevated ratio of HLA-DR and CD122-, CD62E-, and CD62L-expressing cells among the CD4+ T lymphocytes in PE in comparison to healthy pregnancy. No alterations were found in the prevalence of CD69-, CD25-, and CD62P-expressing lymphocytes and CD11c-expressing monocytes. CONCLUSIONS: Our findings support the role of activated T lymphocytes and specific cell adhesion molecules in the pathogenesis of preeclampsia. PMID- 28555092 TI - Tetrodotoxin for Moderate to Severe Cancer-Related Pain: A Multicentre, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design Trial. AB - OBJECTIVE: This study evaluated subcutaneous injections of tetrodotoxin (TTX) for the treatment of moderate to severe, inadequately controlled cancer-related pain. METHODS: Eligible patients were randomized to receive TTX (30 MUg) or placebo subcutaneously twice daily for four consecutive days. Efficacy was assessed using pain and composite endpoints (including pain and quality of life measures), and safety was evaluated using standard measures. RESULTS: 165 patients were enrolled at 19 sites in Canada, Australia, and New Zealand, with 149 patients in the primary analysis "intent-to-treat" population. The primary analysis supports a clinical benefit of TTX over placebo based on the pain endpoint alone with a clinically significant estimated effect size of 16.2% (p = 0.0460). The p value was nominally statistically significant after prespecified (Bonferroni Holm) adjustment for the two primary endpoints but not at the prespecified two-sided 5% level. The mean duration of analgesic response was 56.7 days (TTX) and 9.9 days (placebo). Most common adverse events were nausea, dizziness, and oral numbness or tingling and were generally mild to moderate and transient. CONCLUSIONS: Although underpowered, this study demonstrates a clinically important analgesic signal. TTX may provide clinically meaningful analgesia for patients who have persistent moderate to severe cancer pain despite best analgesic care. This clinical study is registered with ClinicalTrials.gov (NCT00725114). PMID- 28555093 TI - Enhanced Adsorption of Selenium Ions from Aqueous Solution Using Iron Oxide Impregnated Carbon Nanotubes. AB - The aim of this research was to investigate the potential of raw and iron oxide impregnated carbon nanotubes (CNTs) as adsorbents for the removal of selenium (Se) ions from wastewater. The original and modified CNTs with different loadings of Fe2O3 nanoparticles were characterized using high resolution transmission electron microscopy (HRTEM), scanning electron microscopy (SEM), X-ray diffractometer (XRD), Brunauer, Emmett, and Teller (BET) surface area analyzer, thermogravimetric analysis (TGA), zeta potential, and energy dispersive X-ray spectroscopy (EDS). The adsorption parameters of the selenium ions from water using raw CNTs and iron oxide impregnated carbon nanotubes (CNT-Fe2O3) were optimized. Total removal of 1 ppm Se ions from water was achieved when 25 mg of CNTs impregnated with 20 wt.% of iron oxide nanoparticles is used. Freundlich and Langmuir isotherm models were used to study the nature of the adsorption process. Pseudo-first and pseudo-second-order models were employed to study the kinetics of selenium ions adsorption onto the surface of iron oxide impregnated CNTs. Maximum adsorption capacity of the Fe2O3 impregnated CNTs, predicted by Langmuir isotherm model, was found to be 111 mg/g. This new finding might revolutionize the adsorption treatment process and application by introducing a new type of nanoadsorbent that has super adsorption capacity towards Se ions. PMID- 28555094 TI - Effects of Fat and Sugar, Either Consumed or Infused toward the Brain, on Hypothalamic ER Stress Markers. AB - Protein-folding stress at the Endoplasmic Reticulum (ER) occurs in the hypothalamus during diet-induced obesity (DIO) and is linked to metabolic disease development. ER stress is buffered by the activation of the unfolded protein response (UPR), a controlled network of pathways inducing a set of genes that recovers ER function. However, it is unclear whether hypothalamic ER stress during DIO results from obesity related changes or from direct nutrient effects in the brain. We here investigated mRNA expression of UPR markers in the hypothalamus of rats that were exposed to a free choice high-fat high-sugar (fcHFHS) diet for 1 week and then overnight fed ad libitum, or fasted, or fat/sugar deprived (i.e., switched from obesogenic diet to chow). In addition, we determined the direct effects of fat/sugar on mRNA expression of hypothalamus UPR markers by intracarotic infusions of intralipids and/or glucose in chow-fed rats that were fasted overnight. Short term (1 week) exposure to fcHFHS diet increased adiposity compared to chow-feeding. Short term exposure to a fcHFHS diet, followed by mild food restriction overnight, induced hypothalamic ER stress in rats as characterized by an increase in spliced to unspliced X-box binding protein 1 mRNA ratio in hypothalamus of fcHFHS fed rats compared to chow fed rats. Moreover, infused lipids toward the brain of overnight fasted rats, were able to induce a similar response. Non-restricted ad libitum fcHFHS-diet fed or totally fasted rats did not show altered ratios. We also observed a clear increase in hypothalamic activating transcription factor 4 mRNA in rats on the fcHFHS diet while being ad libitum fed or when infused with intralipid via the carotic artery compared to vehicle infusions. However, we did not observe induction of downstream targets implying that this effect is a more general stress response and not related to ER stress. Overall, we conclude that the hypothalamic stress response might be a sensitive sensor of fat and energy status. PMID- 28555095 TI - Nutritional Ketosis Affects Metabolism and Behavior in Sprague-Dawley Rats in Both Control and Chronic Stress Environments. AB - Nutritional ketosis may enhance cerebral energy metabolism and has received increased interest as a way to improve or preserve performance and resilience. Most studies to date have focused on metabolic or neurological disorders while anecdotal evidence suggests that ketosis may enhance performance in the absence of underlying dysfunction. Moreover, decreased availability of glucose in the brain following stressful events is associated with impaired cognition, suggesting the need for more efficient energy sources. We tested the hypotheses that ketosis induced by endogenous or exogenous ketones could: (a) augment cognitive outcomes in healthy subjects; and (b) prevent stress-induced detriments in cognitive parameters. Adult, male, Sprague Dawley rats were used to investigate metabolic and behavioral outcomes in 3 dietary conditions: ketogenic (KD), ketone supplemented (KS), or NIH-31 control diet in both control or chronic stress conditions. Acute administration of exogenous ketones resulted in reduction in blood glucose and sustained ketosis. Chronic experiments showed that in control conditions, only KD resulted in pronounced metabolic alterations and improved performance in the novel object recognition test. The hypothalamic pituitary-adrenal (HPA) axis response revealed that KD-fed rats maintained peripheral ketosis despite increases in glucose whereas no diet effects were observed in ACTH or CORT levels. Both KD and KS-fed rats decreased escape latencies on the third day of water maze, whereas only KD prevented stress induced deficits on the last testing day and improved probe test performance. Stress-induced decrease in hippocampal levels of beta-hydroxybutyrate was attenuated in KD group while both KD and KS prevented stress effects on BDNF levels. Mitochondrial enzymes associated with ketogenesis were increased in both KD and KS hippocampal samples and both endothelial and neuronal glucose transporters were affected by stress but only in the control diet group. Our results highlight the complex relationship between peripheral metabolism, behavioral performance and biochemical changes in the hippocampus. Endogenous ketosis improved behavioral and metabolic parameters associated with energy metabolism and cognition while ketone supplementation replicated the biochemical effects within the hippocampus but only showed modest effects on behavioral improvements. PMID- 28555096 TI - Role of Anterior Cingulate Cortex in Instrumental Learning: Blockade of Dopamine D1 Receptors Suppresses Overt but Not Covert Learning. AB - HIGHLIGHTS Blockade of dopamine D1 receptors in ACC suppressed instrumental learning when overt responding was required.Covert learning through observation was not impaired.After treatment with a dopamine antagonist, instrumental learning recovered but not the rat's pretreatment level of effort tolerance.ACC dopamine is not necessary for acquisition of task-relevant cues during learning, but regulates energy expenditure and effort based decision. Dopamine activity in anterior cingulate cortex (ACC) is essential for various aspects of instrumental behavior, including learning and effort based decision making. To dissociate learning from physical effort, we studied both observational (covert) learning, and trial-and-error (overt) learning. If ACC dopamine activity is required for task acquisition, its blockade should impair both overt and covert learning. If dopamine is not required for task acquisition, but solely for regulating the willingness to expend effort for reward, i.e., effort tolerance, blockade should impair overt learning but spare covert learning. Rats learned to push a lever for food rewards either with or without prior observation of an expert conspecific performing the same task. Before daily testing sessions, the rats received bilateral ACC microinfusions of SCH23390, a dopamine D1 receptor antagonist, or saline-control infusions. We found that dopamine blockade suppressed overt responding selectively, leaving covert task acquisition through observational learning intact. In subsequent testing sessions without dopamine blockade, rats recovered their overt-learning capacity but not their pre-treatment level of effort tolerance. These results suggest that ACC dopamine is not required for the acquisition of conditioned behaviors and that apparent learning impairments could instead reflect a reduced level of willingness to expend effort due to cortical dopamine blockade. PMID- 28555097 TI - Training on Movement Figure-Ground Discrimination Remediates Low-Level Visual Timing Deficits in the Dorsal Stream, Improving High-Level Cognitive Functioning, Including Attention, Reading Fluency, and Working Memory. AB - The purpose of this study was to determine whether neurotraining to discriminate a moving test pattern relative to a stationary background, figure-ground discrimination, improves vision and cognitive functioning in dyslexics, as well as typically-developing normal students. We predict that improving the speed and sensitivity of figure-ground movement discrimination (PATH to Reading neurotraining) acts to remediate visual timing deficits in the dorsal stream, thereby improving processing speed, reading fluency, and the executive control functions of attention and working memory in both dyslexic and normal students who had PATH neurotraining more than in those students who had no neurotraining. This prediction was evaluated by measuring whether dyslexic and normal students improved on standardized tests of cognitive skills following neurotraining exercises, more than following computer-based guided reading (Raz-Kids (RK)). The neurotraining used in this study was visually-based training designed to improve magnocellular function at both low and high levels in the dorsal stream: the input to the executive control networks coding working memory and attention. This approach represents a paradigm shift from the phonologically-based treatment for dyslexia, which concentrates on high-level speech and reading areas. This randomized controlled-validation study was conducted by training the entire second and third grade classrooms (42 students) for 30 min twice a week before guided reading. Standardized tests were administered at the beginning and end of 12-weeks of intervention training to evaluate improvements in academic skills. Only movement-discrimination training remediated both low-level visual timing deficits and high-level cognitive functioning, including selective and sustained attention, reading fluency and working memory for both dyslexic and normal students. Remediating visual timing deficits in the dorsal stream revealed the causal role of visual movement discrimination training in improving high-level cognitive functions such as attention, reading acquisition and working memory. This study supports the hypothesis that faulty timing in synchronizing the activity of magnocellular with parvocellular visual pathways in the dorsal stream is a fundamental cause of dyslexia and being at-risk for reading problems in normal students, and argues against the assumption that reading deficiencies in dyslexia are caused by phonological or language deficits, requiring a paradigm shift from phonologically-based treatment of dyslexia to a visually-based treatment. This study shows that visual movement-discrimination can be used not only to diagnose dyslexia early, but also for its successful treatment, so that reading problems do not prevent children from readily learning. PMID- 28555098 TI - Hemodynamic Response Alterations in Sensorimotor Areas as a Function of Barbell Load Levels during Squatting: An fNIRS Study. AB - Functional near-infrared spectroscopy (fNIRS) serves as a promising tool to examine hemodynamic response alterations in a sports-scientific context. The present study aimed to investigate how brain activity within the human motor system changes its processing in dependency of different barbell load conditions while executing a barbell squat (BS). Additionally, we used different fNIRS probe configurations to identify and subsequently eliminate potential exercise induced systemic confounders such as increases in extracerebral blood flow. Ten healthy, male participants were enrolled in a crossover design. Participants performed a BS task with random barbell load levels (0% 1RM (1 repetition maximum), 20% 1RM and 40% 1RM for a BS) during fNIRS recordings. Initially, we observed global hemodynamic response alterations within and outside the human motor system. However, short distance channel regression of fNIRS data revealed a focalized hemodynamic response alteration within bilateral superior parietal lobe (SPL) for oxygenated hemoglobin (HbO2) and not for deoxygenated hemoglobin (HHb) when comparing different load levels. These findings indicate that the previously observed load/force-brain relationship for simple and isolated movements is also present in complex multi-joint movements such as the BS. Altogether, our results show the feasibility of fNIRS to investigate brain processing in a sports-related context. We suggest for future studies to incorporate short distance channel regression of fNIRS data to reduce the likelihood of false-positive hemodynamic response alterations during complex whole movements. PMID- 28555099 TI - Load-Dependent Increases in Delay-Period Alpha-Band Power Track the Gating of Task-Irrelevant Inputs to Working Memory. AB - Studies exploring the role of neural oscillations in cognition have revealed sustained increases in alpha-band power (ABP) during the delay period of verbal and visual working memory (VWM) tasks. There have been various proposals regarding the functional significance of such increases, including the inhibition of task-irrelevant cortical areas as well as the active retention of information in VWM. The present study examines the role of delay-period ABP in mediating the effects of interference arising from on-going visual processing during a concurrent VWM task. Specifically, we reasoned that, if set-size dependent increases in ABP represent the gating out of on-going task-irrelevant visual inputs, they should be predictive with respect to some modulation in visual evoked potentials resulting from a task-irrelevant delay period probe stimulus. In order to investigate this possibility, we recorded the electroencephalogram while subjects performed a change detection task requiring the retention of two or four novel shapes. On a portion of trials, a novel, task-irrelevant bilateral checkerboard probe was presented mid-way through the delay. Analyses focused on examining correlations between set-size dependent increases in ABP and changes in the magnitude of the P1, N1 and P3a components of the probe-evoked response and how such increases might be related to behavior. Results revealed that increased delay-period ABP was associated with changes in the amplitude of the N1 and P3a event-related potential (ERP) components, and with load-dependent changes in capacity when the probe was presented during the delay. We conclude that load dependent increases in ABP likely play a role in supporting short-term retention by gating task-irrelevant sensory inputs and suppressing potential sources of disruptive interference. PMID- 28555100 TI - The Impact of Monaural Beat Stimulation on Anxiety and Cognition. AB - Application of auditory beat stimulation has been speculated to provide a promising new tool with which to alleviate symptoms of anxiety and to enhance cognition. In spite of reportedly similar EEG effects of binaural and monaural beats, data on behavioral effects of monaural beats are still lacking. Therefore, we examined the impact of monaural beat stimulation on anxiety, mood and memory performance. We aimed to target states related to anxiety levels and general well being, in addition to long-term and working memory processes, using monaural beats within the range of main cortical rhythms. Theta (6 Hz), alpha (10 Hz) and gamma (40 Hz) beat frequencies, as well as a control stimulus were applied to healthy participants for 5 min. After each stimulation period, participants were asked to evaluate their current mood state and to perform cognitive tasks examining long-term and working memory processes, in addition to a vigilance task. Monaural beat stimulation was found to reduce state anxiety. When evaluating responses for the individual beat frequencies, positive effects on state anxiety were observed for all monaural beat conditions compared to control stimulation. Our results indicate a role for monaural beat stimulation in modulating state anxiety and are in line with previous studies reporting anxiety reducing effects of auditory beat stimulation. PMID- 28555101 TI - Learning-Related Brain-Electrical Activity Dynamics Associated with the Subsequent Impact of Learnt Action-Outcome Associations. AB - Goal-directed behavior relies on the integration of anticipated outcomes into action planning based on acquired knowledge about the current contingencies between behavioral responses (R) and desired outcomes (O) under specific stimulus conditions (S). According to ideomotor theory, bidirectional R-O associations are an integral part of this knowledge structure. Previous EEG studies have identified neural activity markers linked to the involvement of such associations, but the initial acquisition process has not yet been characterized. The present study thus examined brain-electrical activity dynamics during the rapid acquisition of novel bidirectional R-O associations during instructed S-R learning. Within a trial, we inspected response-locked and stimulus-locked activity dynamics in order to identify markers linked to the forward and backward activation of bidirectional R-O associations as they were being increasingly strengthened under forced choice conditions. We found that a post-response anterior negativity following auditory outcomes was increasingly attenuated as a function of the acquired association strength. This suggests that previously reported action-induced sensory attenuation effects under extensively trained free choice conditions can be established within few repetitions of specific R-O pairings under forced choice conditions. Furthermore, we observed the even more rapid development of a post-response but pre-outcome fronto-central positivity which was reduced for high R-O learners which might indicate the rapid deployment of preparatory attention towards predictable outcomes. Finally, we identified a learning-related stimulus-locked activity modulation within the visual P1-N1 latency range which might reflect the multi-sensory integration of the perceived antecedent visual stimulus the anticipated auditory outcome. PMID- 28555102 TI - A Model of Fast Hebbian Spike Latency Normalization. AB - Hebbian changes of excitatory synapses are driven by and enhance correlations between pre- and postsynaptic neuronal activations, forming a positive feedback loop that can lead to instability in simulated neural networks. Because Hebbian learning may occur on time scales of seconds to minutes, it is conjectured that some form of fast stabilization of neural firing is necessary to avoid runaway of excitation, but both the theoretical underpinning and the biological implementation for such homeostatic mechanism are to be fully investigated. Supported by analytical and computational arguments, we show that a Hebbian spike timing-dependent metaplasticity rule, accounts for inherently-stable, quick tuning of the total input weight of a single neuron in the general scenario of asynchronous neural firing characterized by UP and DOWN states of activity. PMID- 28555103 TI - Blood Pressure Control in Aging Predicts Cerebral Atrophy Related to Small-Vessel White Matter Lesions. AB - Cerebral small-vessel damage manifests as white matter hyperintensities and cerebral atrophy on brain MRI and is associated with aging, cognitive decline and dementia. We sought to examine the interrelationship of these imaging biomarkers and the influence of hypertension in older individuals. We used a multivariate spatial covariance neuroimaging technique to localize the effects of white matter lesion load on regional gray matter volume and assessed the role of blood pressure control, age and education on this relationship. Using a case-control design matching for age, gender, and educational attainment we selected 64 participants with normal blood pressure, controlled hypertension or uncontrolled hypertension from the Northern Manhattan Study cohort. We applied gray matter voxel-based morphometry with the scaled subprofile model to (1) identify regional covariance patterns of gray matter volume differences associated with white matter lesion load, (2) compare this relationship across blood pressure groups, and (3) relate it to cognitive performance. In this group of participants aged 60 86 years, we identified a pattern of reduced gray matter volume associated with white matter lesion load in bilateral temporal-parietal regions with relative preservation of volume in the basal forebrain, thalami and cingulate cortex. This pattern was expressed most in the uncontrolled hypertension group and least in the normotensives, but was also more evident in older and more educated individuals. Expression of this pattern was associated with worse performance in executive function and memory. In summary, white matter lesions from small-vessel disease are associated with a regional pattern of gray matter atrophy that is mitigated by blood pressure control, exacerbated by aging, and associated with cognitive performance. PMID- 28555104 TI - tDCS Over the Motor Cortex Shows Differential Effects on Action and Object Words in Associative Word Learning in Healthy Aging. AB - Healthy aging is accompanied by a continuous decline in cognitive functions. For example, the ability to learn languages decreases with age, while the neurobiological underpinnings for the decline in learning abilities are not known exactly. Transcranial direct current stimulation (tDCS), in combination with appropriate experimental paradigms, is a well-established technique to investigate the mechanisms of learning. Based on previous results in young adults, we tested the suitability of an associative learning paradigm for the acquisition of action- and object-related words in a cohort of older participants. We applied tDCS to the motor cortex (MC) and hypothesized an involvement of the MC in learning action-related words. To test this, a cohort of 18 healthy, older participants (mean age 71) engaged in a computer-assisted associative word-learning paradigm, while tDCS stimulation (anodal, cathodal, sham) was applied to the left MC. Participants' task performance was quantified in a randomized, cross-over experimental design. Participants successfully learned novel words, correctly translating 39.22% of the words after 1 h of training under sham stimulation. Task performance correlated with scores for declarative verbal learning and logical reasoning. Overall, tDCS did not influence associative word learning, but a specific influence was observed of cathodal tDCS on learning of action-related words during the NMDA-dependent stimulation period. Successful learning of a novel lexicon with associative learning in older participants can only be achieved when the learning procedure is changed in several aspects, relative to young subjects. Learning success showed large inter-individual variance which was dependent on non-linguistic as well as linguistic cognitive functions. Intriguingly, cathodal tDCS influenced the acquisition of action-related words in the NMDA-dependent stimulation period. However, the effect was not specific for the associative learning principle, suggesting more neurobiological fragility of learning in healthy aging compared with young persons. PMID- 28555106 TI - High Fat Diet-Induced Hepatic 18-Carbon Fatty Acids Accumulation Up-Regulates CYP2A5/CYP2A6 via NF-E2-Related Factor 2. AB - To investigate the role of hepatic 18-carbon fatty acids (FA) accumulation in regulating CYP2A5/2A6 and the significance of Nrf2 in the process during hepatocytes steatosis, Nrf2-null, and wild type mice fed with high-fat diet (HFD), and Nrf2 silenced or over expressed HepG2 cells administered with 18 carbon FA were used. HE and Oil Red O staining were used for mice hepatic pathological examination. The mRNA and protein expressions were measured with real-time PCR and Western blot. The results showed that hepatic CYP2A5 and Nrf2 expression levels were increased in HFD fed mice accompanied with hepatic 18 carbon FA accumulation. The Nrf2 expression was increased dose-dependently in cells administered with increasing concentrations of stearic acid, oleic acid, and alpha-linolenic acid. The Nrf2 expression was dose-dependently decreased in cells treated with increasing concentrations of linoleic acid, but the Nrf2 expression level was still found higher than the control cells. The CYP2A6 expression was increased dose-dependently in increasing 18-carbon FA treated cells. The HFD-induced up-regulation of hepatic CYP2A5 in vivo and the 18-carbon FA treatment induced up-regulation of CYP2A6 in HepG2 cells were, respectively, inhibited by Nrf2 deficiency and Nrf2 silencing. While the basal expression of mouse hepatic CYP2A5 was not impeded by Nrf2 deletion. Nrf2 over expression improved the up-regulation of CYP2A6 induced by 18-carbon FA. As the classical target gene of Nrf2, GSTA1 mRNA relative expression was increased in Nrf2 over expressed cells and was decreased in Nrf2 silenced cells. In presence or absence of 18-carbon FA treatment, the change of CYP2A6 expression level was similar to GSTA1 in Nrf2 silenced or over expressed HepG2 cells. It was concluded that HFD induced hepatic 18-carbon FA accumulation contributes to the up-regulation of CYP2A5/2A6 via activating Nrf2. However, the CYP2A5/2A6 expression does not only depend on Nrf2. PMID- 28555105 TI - Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases. AB - Microglia are the resident innate immune cells of the central nervous system that mediate brain homeostasis maintenance. Microglia-mediated neuroinflammation is a hallmark shared by various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Numerous studies have shown microglial activation phenotypes to be heterogeneous; however, these microglial phenotypes can largely be categorized as being either M1 or M2 type. Although the specific classification of M1 and M2 functionally polarized microglia remains a topic for debate, the use of functional modulators of microglial phenotypes as potential therapeutic approaches for the treatment of neurodegenerative diseases has garnered considerable attention. This review discusses M1 and M2 microglial phenotypes and their relevance in neurodegenerative disease models, as described in recent literature. The modulation of microglial polarization toward the M2 phenotype may lead to development of future therapeutic and preventive strategies for neuroinflammatory and neurodegenerative diseases. Thus, we focus on recent studies of microglial polarization modulators, with a particular emphasis on the small-molecule compounds and their intracellular target proteins. PMID- 28555107 TI - Characterization and Anti-Inflammatory Potential of an Exopolysaccharide from Submerged Mycelial Culture of Schizophyllum commune. AB - Background and Purpose: Mushroom polysaccharides have attracted attention in food and pharmacology fields because of their many biological activities. The structure characterization and anti-inflammatory activity of exopolysaccharide from Schizophyllum commune were evaluated in present study. Methods: An exopolysaccharide from a submerged mycelial fermentation of S. commune was obtained using DEAE-52 cellulose and Sephadex G-150 chromatography. The molecular weight (MW), monosaccharide compositions, chemical compositions, methylation analysis, circular dichroism studies, Fourier transform infrared spectroscopy, nuclear magnetic resonance (NMR) spectra, scanning electron microscopy (SEM), and atomic force microscopy were investigated. Results: It was a homogeneous protein bound heteropolysaccharide with MW of 2,900 kDa. The exopolysaccharide contained a beta-(1->3) glycosidic backbone, (1->4)- and (1->6)- glycosidic side chain, and high amount of glucose. The anti-inflammatory activity of exopolysaccharide was assessed by inhibiting the production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), and 5- lipoxygenase (5-LOX) from macrophages. This exopolysaccharide significantly (p < 0.05) inhibited lipopolysaccharides-induced iNOS expression levels in the cells in a dose-dependent manner. Conclusion: It indicated significant anti-inflammatory effects, which showed that exopolysaccharide might be exploited as an effective anti-inflammatory agent for application in NO-related disorders such as inflammation and cancer. PMID- 28555109 TI - Rethinking the Appraisal and Approval of Drugs for Fracture Prevention. AB - Background: In January 2014, the EMA's Pharmacovigilance Risk Assessment Committee recommended that strontium ranelate no longer be used for osteoporosis. However, EMA's Committee for Medicinal Products for Human Use decided to restrict its use rather than ban it. Starting from this fact, evidence of drugs for fracture prevention over the last 30 years was reviewed and lessons to be learnt from this story are highlighted. Findings: The general belief that drug therapy may become a "solution" for fragility fractures is challenged. The key points of the article are as follows: Lessons 1-5: Bone density and morphometric vertebral compression are not reliable surrogate endpoints. In fact, clinically relevant endpoints are essential to assess harms and benefits in clinical trials. There is a need for assessing overall harm-benefit with well-designed trials, taking into account that drug therapy may not be more effective in high-risk patients. Lessons 6-10: While bisphosphonates and strontium ranelate show a questionable harm-benefit ratio on hip fracture prevention, denosumab results are inconclusive and no benefit has been proved coming from calcitonines or teriparatide. After decades of widespread use, effectiveness of drugs for osteoporosis remains uncertain, yet adverse effects are more apparent. Conclusions: Well-designed and large trials over prolonged follow-up periods, measuring clinically relevant outcomes as hip and other disabling fractures, are urgently needed in order to properly understand the harm-benefit ratio of commonly prescribed drugs. Regulatory agencies should be more transparent and make individual-patient data from all clinical trials publicly available, allowing for independent assessment and pooled analysis. PMID- 28555108 TI - Is the Comparison between Exercise and Pharmacologic Treatment of Depression in the Clinical Practice Guideline of the American College of Physicians Evidence Based? AB - Major depression disorder is most commonly treated with antidepressants. However, due to their side effects clinicians seek non-pharmacologic options, and one of these is exercise. The literature on the benefits of exercise for depression is extensive. Nevertheless, two recent reviews focusing on antidepressants vs. other therapies as a basis for clinical practice guidelines recommended mainly antidepressants, excluding exercise as a viable choice for treatment of depression. The aim of this perspective is to analyze the literature exploring the reasons for this discrepancy. Two categories of publications were examined: randomized controlled trials (RCTs) and meta-analyses or systematic reviews. Based on this reassessment, RCTs comparing exercise to antidepressants reported that exercise and antidepressants were equally effective. RCTs comparing exercise combined with antidepressants to antidepressants only reported a significant improvement in depression following exercise as an adjunctive treatment. Almost all the reviews examining exercise vs. other treatments of depression, including antidepressants, support the use of exercise in the treatment of depression, at least as an adjunctive therapy. The two reviews examining pharmacologic vs. non pharmacologic therapies as a basis for clinical practice guidelines examined limited evidence on exercise vs. antidepressants. In addition, it is possible that academics and health care practitioners are skeptical of viewing exercise as medicine. Maybe, there is a reluctance to accept that changes in lifestyle as opposed to pharmacological treatment can alter biological mechanisms. Longitudinal studies are needed for assessing the effectiveness of exercise in real clinical settings, as well as studies exploring dose-response relationship between exercise and depression. PMID- 28555110 TI - Reduced Membrane Insertion of CLC-K by V33L Barttin Results in Loss of Hearing, but Leaves Kidney Function Intact. AB - In the mammalian ear, transduction of sound stimuli is initiated by K+ entry through mechano-sensitive channels into inner hair cells. K+ entry is driven by a positive endocochlear potential that is maintained by the marginal cell layer of the stria vascularis. This process requires basolateral K+ import by NKCC1 Na+ 2Cl--K+ co-transporters as well as Cl- efflux through ClC-Ka/barttin or ClC Kb/barttin channels. Multiple mutations in the gene encoding the obligatory CLC-K subunit barttin, BSND, have been identified in patients with Bartter syndrome type IV. These mutations reduce the endocochlear potential and cause deafness. As CLC-K/barttin channels are also expressed in the kidney, patients with Bartter syndrome IV typically also suffer from salt-wasting hyperuria and electrolyte imbalances. However, there was a single report on a BSND mutation that resulted only in deafness, but not kidney disease. We herein studied the functional consequences of another recently discovered BSND mutation that predicts exchange of valine at position 33 by leucine. We combined whole-cell patch clamp, confocal microscopy and protein biochemistry to analyze how V33L affects distinct functions of barttin. We found that V33L reduced membrane insertion of CLC K/barttin complexes without altering unitary CLC-K channel function. Our findings support the hypothesis of a common pathophysiology for the selective loss of hearing due to an attenuation of the total chloride conductance in the stria vascularis while providing enough residual function to maintain normal kidney function. PMID- 28555111 TI - Novel GLP-1 Analog Supaglutide Reduces HFD-Induced Obesity Associated with Increased Ucp-1 in White Adipose Tissue in Mice. AB - GLP-1, an important incretin hormone plays an important role in the regulation of glucose homeostasis. However, the therapeutic use of native GLP-1 is limited due to its short half-life. We recently developed a novel GLP-1 mimetics (supaglutide) by genetically engineering recombinant fusion protein production techniques. We demonstrated that this formulation possessed long-lasting GLP-1 actions and was effective in glycemic control in both type 1 and type 2 diabetes rodent models. Here, we investigated the effects of supaglutide in regulating energy homeostasis in obese mice. Mice were fed with high-fat diet (HFD) for 6 months to induce obesity and then subjected to supaglutide treatment (300 MUg/kg, bi-weekly for 4 weeks), and placebo as control. Metabolic conditions were monitored and energy expenditure was assessed by indirect calorimetry (CLAMS). Cold tolerance test was performed to evaluate brown-adipose tissue (BAT) activities in response to cold challenge. Glucose tolerance and insulin resistance were evaluated by intraperitoneal glucose tolerance test and insulin tolerance tests. Liver and adipose tissues were collected for histology analysis. Expression of uncoupling protein 1(Ucp1) in adipose tissues was evaluated by Western blotting. We found that supaglutide treatment reduced body weight, which was associated with reduced food intake. Compared to the placebo control, supaglutide treatment improved lipid profile, i.e., significantly decreased circulating total cholesterol levels, declined serum triglyceride, and free fatty acid levels. Importantly, the intervention significantly reduced fatty liver, decreased liver triglyceride content, and concomitantly ameliorated liver injury exemplified by declined hepatic alanine aminotransferase (ALT) and aspartic transaminase (AST) content. Remarkably, supaglutide reduced hepatic lipid accumulation and altered morphometry in favor of small adipocytes in fat. This is consistent with the observation that supaglutide increased tolerance of the mice to cold environment associated with up-regulation of Ucp1 in the inguinal fat. Furthermore, supaglutide improved glucose tolerance, and insulin sensitivity in the obese mice suggesting improved glucose and energy homeostasis. Our findings suggest that supaglutide exerts beneficial effect on established obesity through reducing energy intake and is associated with brown remodeling of white adipose tissue. PMID- 28555112 TI - Caveolin-1: Functional Insights into Its Role in Muscarine- and Serotonin-Induced Smooth Muscle Constriction in Murine Airways. AB - An increased bronchoconstrictor response is a hallmark in the progression of obstructive airway diseases. Acetylcholine and 5-hydroxytryptamine (5-HT, serotonin) are the major bronchoconstrictors. There is evidence that both cholinergic and serotonergic signaling in airway smooth muscle (ASM) involve caveolae. We hypothesized that caveolin-1 (cav-1), a structural protein of caveolae, plays an important regulatory role in ASM contraction. We analyzed airway contraction in different tracheal segments and extra- and intrapulmonary bronchi in cav-1 deficient (cav-1-/-) and wild-type mice using organ bath recordings and videomorphometry of methyl-beta-cyclodextrin (MCD) treated and non treated precision-cut lung slices (PCLS). The presence of caveolae was investigated by electron microscopy. Receptor subtypes driving 5-HT-responses were studied by RT-PCR and videomorphometry after pharmacological inhibition with ketanserin. Cav-1 was present in tracheal epithelium and ASM. Muscarine induced a dose dependent contraction in all airway segments. A significantly higher Emax was observed in the caudal trachea. Although, caveolae abundancy was largely reduced in cav-1-/- mice, muscarine-induced airway contraction was maintained, albeit at diminished potency in the middle trachea, in the caudal trachea and in the bronchus without changes in the maximum efficacy. MCD-treatment of PLCS from cav-1-/- mice reduced cholinergic constriction by about 50%, indicating that cholesterol-rich plasma domains account for a substantial portion of the muscarine-induced bronchoconstriction. Notably, cav-1-deficiency fully abrogated 5-HT-induced contraction of extrapulmonary airways. In contrast, 5-HT-induced bronchoconstriction was fully maintained in cav-1-deficient intrapulmonary bronchi, but desensitization upon repetitive stimulation was enhanced. RT-PCR analysis revealed 5-HT1B, 5-HT2A, 5-HT6, and 5-HT7 receptors as the most prevalent subtypes in the airways. The 5-HT-induced-constriction in PCLS could be antagonized by ketanserin, a 5-HT2A receptor inhibitor. In conclusion, the role of cav-1, caveolae, and cholesterol-rich plasma domains in regulation of airway tone are highly agonist-specific and dependent on airway level. Cav-1 is indispensable for serotonergic contraction of extrapulmonary airways and modulates cholinergic constriction of the trachea and main bronchus. Thus, cav 1/caveolae shall be considered in settings such as bronchial hyperreactivity in common airway diseases and might provide an opportunity for modulation of the constrictor response. PMID- 28555113 TI - Identifying Electrophysiological Prodromes of Post-traumatic Stress Disorder: Results from a Pilot Study. AB - The objective of this research project is the identification of a physiological prodrome of post-traumatic stress disorder (PTSD) that has a reliability that could justify preemptive treatment in the sub-syndromal state. Because abnormalities in event-related potentials (ERPs) have been observed in fully expressed PTSD, the possible utility of abnormal ERPs in predicting delayed-onset PTSD was investigated. ERPs were recorded from military service members recently returned from Iraq or Afghanistan who did not meet PTSD diagnostic criteria at the time of ERP acquisition. Participants (n = 65) were followed for up to 1 year, and 7.7% of the cohorts (n = 5) were PTSD-positive at follow-up. The initial analysis of the receiver operating characteristic (ROC) curve constructed using ERP metrics was encouraging. The average amplitude to target stimuli gave an area under the ROC curve of greater than 0.8. Classification based on the Youden index, which is determined from the ROC, gave positive results. Using average target amplitude at electrode Cz yielded Sensitivity = 0.80 and Specificity = 0.87. A more systematic statistical analysis of the ERP data indicated that the ROC results may simply represent a fortuitous consequence of small sample size. Predicted error rates based on the distribution of target ERP amplitudes approached those of random classification. A leave-one-out cross validation using a Gaussian likelihood classifier with Bayesian priors gave lower values of sensitivity and specificity. In contrast with the ROC results, the leave-one-out classification at Cz gave Sensitivity = 0.65 and Specificity = 0.60. A bootstrap calculation, again using the Gaussian likelihood classifier at Cz, gave Sensitivity = 0.59 and Specificity = 0.68. Two provisional conclusions can be offered. First, the results can only be considered preliminary due to the small sample size, and a much larger study will be required to assess definitively the utility of ERP prodromes of PTSD. Second, it may be necessary to combine ERPs with other biomarkers in a multivariate metric to produce a prodrome that can justify preemptive treatment. PMID- 28555114 TI - Attitudes about Future Genetic Testing for Posttraumatic Stress Disorder and Addiction among Community-Based Veterans. AB - This study explored attitudes toward hypothetical genetic testing for posttraumatic stress disorder (PTSD) and addiction among veterans. We surveyed a random sample of community-based veterans (n = 700) by telephone. One year later, we asked the veterans to provide a DNA sample for analysis and 41.9% of them returned the DNA samples. Overall, most veterans were not interested in genetic testing neither for PTSD (61.7%) nor for addiction (68.7%). However, bivariate analyses suggested there was an association between having the condition of interest and the likelihood of genetic testing on a 5-point scale (p < 0.001 for PTSD; p = 0.001 for alcohol dependence). While ordinal regressions confirmed these associations, the models with the best statistical fit were bivariate models of whether the veteran would likely test or not. Using logistic regressions, significant predictors for PTSD testing were receiving recent mental health treatment, history of a concussion, younger age, having PTSD, having alcohol dependence, currently taking opioids for pain, and returning the DNA sample during the follow-up. For addiction testing, significant predictors were history of concussion, younger age, psychotropic medication use, having alcohol dependence, and currently taking opioids for pain. Altogether, 25.9% of veterans reported that they would have liked to have known their genetic results before deployment, 15.6% reported after deployment, and 58.6% reported they did not want to know neither before nor after deployment. As advancements in genetic testing continue to evolve, our study suggests that consumer attitudes toward genetic testing for mental disorders are complex and better understanding of these attitudes and beliefs will be crucial to successfully promote utilization. PMID- 28555116 TI - Interaction between Gender and Skill on Competitive State Anxiety Using the Time to-Event Paradigm: What Roles Do Intensity, Direction, and Frequency Dimensions Play? AB - Background and purpose: The functional understanding and examination of competitive anxiety responses as temporal events that unfold as time-to competition moves closer has emerged as a topical research area within the domains of sport psychology. However, little is known from an inclusive and interaction oriented perspective. Using the multidimensional anxiety theory as a framework, the present study examined the temporal patterning of competitive anxiety, focusing on the dimensions of intensity, direction, and frequency of intrusions in athletes across gender and skill level. Methods: Elite and semi elite table tennis athletes from the Ghanaian league (N = 90) completed a modified version of Competitive State Anxiety Inventory-2 (CSAI-2) with the inclusion of the directional and frequency of intrusion scales at three temporal phases (7 days, 2 days, and 1 h) prior to a competitive fixture. Results: Multivariate Analyses of Variance repeated measures with follow-up analyses revealed significant interactions for between-subjects factors on all anxiety dimensions (intensity, direction, and frequency). Notably, elite (international) female athletes were less cognitively anxious, showed more facilitative interpretation toward somatic anxiety symptoms and experienced less frequency of somatic anxiety symptoms than their male counterparts. However, both elite groups displayed appreciable level of self-confidence. For time-to-event effects, both cognitive and somatic anxiety intensity fluctuated whereas self-confidence showed a steady rise as competition neared. Somatic anxiety debilitative interpretation slightly improved 1 h before competition whereas cognitive anxiety frequencies also increased progressively during the entire preparatory phase. Conclusion: Findings suggest a more dynamic image of elite athletes' pre-competitive anxiety responses than suggested by former studies, potentially influenced by cultural differences. The use of psychological skills interventions that require effective structure, content, and timing in a composite manner is suggested. PMID- 28555115 TI - Long-term Results from the Empowering a Multimodal Pathway Toward Healthy Youth Program, a Multimodal School-Based Approach, Show Marked Reductions in Suicidality, Depression, and Anxiety in 6,227 Students in Grades 6-12 (Aged 11 18). AB - Here, we report on findings from a 15-month follow-up of a school-based program called Empowering a Multimodal Pathway Toward Healthy Youth (EMPATHY). This was primarily intended to reduce suicidal thinking in pre-teens, adolescents, and youth students aged 11-18 in middle schools (Grades 6-8) and high SCHOOLS (Grades 9-12). It also aimed to reduce depression and anxiety. The EMPATHY multimodal program consisted of repeated data collection, identification of a high-risk group, a rapid intervention for this high-risk group including offering supervised online cognitive behavioral therapy (CBT) program, a universal CBT intervention for those in Grades 6-8, a variety of interactions with trained staff ("Resiliency Coaches"), and referral to external medical and psychiatric services where appropriate. There were four time-points at which assessments were made: baseline, 3, 7, and 15 months. Here, we report cross-sectional findings over 15 months in a total of 6,227 students who were assessed at least once during the study period. Additionally, we report longitudinal findings from the 1,884 students who completed all 4 assessments. Our results found highly statistically significant decreases in suicidality rates, with the percentage of the total school population who were actively suicidal decreasing from 4.4% at baseline (n = 143 of 3,244) to 2.8% at 15 months (n = 125 of 4,496) (p < 0.001). There were also highly statistically significant reductions in depression and anxiety scores at each time-point. Thus, Mean Depression scores at baseline for the entire student population were 3.73 +/- 3.87 (n = 3,244) at baseline and decreased to 3.22 +/- 3.52 (n = 4,496) (p < 0.001). Since most students were not depressed, whole population changes such as this may indicate impact in many areas. In the longitudinal analysis of students who completed all four assessments, there were also highly statistically significant improvements in depression and anxiety scores at all time-points. For example, depression scores decreased from a mean of 3.43 +/- 3.67 (n = 1,884) at baseline to 2.95 +/- 3.53 (n = 1,884) at 15-months (p < 0.001), while the number who were actively suicidal decreased from 69 to 37. These results suggest that school-based multimodal programs, utilizing a combination of interventions, can have meaningful benefits across entire school populations. PMID- 28555117 TI - Social Saliency of the Cue Slows Attention Shifts. AB - Eye gaze is a powerful cue that indicates where another person's attention is directed in the environment. Seeing another person's eye gaze shift spontaneously and reflexively elicits a shift of one's own attention to the same region in space. Here, we investigated whether reallocation of attention in the direction of eye gaze is modulated by personal familiarity with faces. On the one hand, the eye gaze of a close friend should be more effective in redirecting our attention as compared to the eye gaze of a stranger. On the other hand, the social relevance of a familiar face might itself hold attention and, thereby, slow lateral shifts of attention. To distinguish between these possibilities, we measured the efficacy of the eye gaze of personally familiar and unfamiliar faces as directional attention cues using adapted versions of the Posner paradigm with saccadic and manual responses. We found that attention shifts were slower when elicited by a perceived change in the eye gaze of a familiar individual as compared to attention shifts elicited by unfamiliar faces at short latencies (100 ms). We also measured simple detection of change in direction of gaze in personally familiar and unfamiliar faces to test whether slower attention shifts were due to slower detection. Participants detected changes in eye gaze faster for familiar faces than for unfamiliar faces. Our results suggest that personally familiar faces briefly hold attention due to their social relevance, thereby slowing shifts of attention, even though the direction of eye movements are detected faster in familiar faces. PMID- 28555118 TI - Laryngeal Features Are Phonetically Abstract: Mismatch Negativity Evidence from Arabic, English, and Russian. AB - Many theories of phonology assume that the sound structure of language is made up of distinctive features, but there is considerable debate about how much articulatory detail distinctive features encode in long-term memory. Laryngeal features such as voicing provide a unique window into this question: while many languages have two-way contrasts that can be given a simple binary feature account [+/-VOICE], the precise articulatory details underlying these contrasts can vary significantly across languages. Here, we investigate a series of two-way voicing contrasts in English, Arabic, and Russian, three languages that implement their voicing contrasts very differently at the articulatory-phonetic level. In three event-related potential experiments contrasting English, Arabic, and Russian fricatives along with Russian stops, we observe a consistent pattern of asymmetric mismatch negativity (MMN) effects that is compatible with an articulatorily abstract and cross-linguistically uniform way of marking two-way voicing contrasts, as opposed to an articulatorily precise and cross linguistically diverse way of encoding them. Regardless of whether a language is theorized to encode [VOICE] over [SPREAD GLOTTIS], the data is consistent with a universal marking of the [SPREAD GLOTTIS] feature. PMID- 28555119 TI - Patterns of Alcohol Consumption in Spanish University Alumni: Nine Years of Follow-Up. AB - The aim of this study was to empirically identify different profiles of Spanish university alumni, based on their alcohol use over 9 years, and to further characterize them. A cohort study was carried out between 2005 and 2015 among university students (Compostela Cohort-Spain; n2015 = 415). Alcohol consumption was measured using the Alcohol Use Disorder Identification Test (AUDIT). A two stage cluster analysis, based on their AUDIT total scores was carried out separately for males and females. The further characterization of every profile was based on demographic data, age at onset of alcohol use, positive alcohol related expectancies, tobacco and cannabis use, as well as their answers to some European Addiction Severity Index items. Five different clusters were identified: Low users (29.2%), Moderated users (37.2%), At-risk users (14.2%), Decreasing users (13.2%) and Large users (6.2%) for females, and Low users (34.4%), At-risk users (25.6%), High-risk users (15.6%), Decreasing users (14.4%) and Large users (10.0%) for males. Being a cannabis user or a smoker was positively associated to those more hazardous clusters in both genders. Regarding females, significant differences in the age of onset and high positive expectancies were found. However, there were few significant differences among the groups in relation to their employment status and social relations. The results reveal the existence of different typologies of alcohol users among university alumni, with differences among males and females. Modifying positive expectancies, limiting access to alcohol at a young age, and reducing uses of other substances uses are key to promote healthier alcohol use profiles and to prevent hazardous uses. PMID- 28555120 TI - Psychotic-Like Experiences at the Healthy End of the Psychosis Continuum. AB - There is increasing evidence pointing toward a continuous distribution of psychotic symptoms and accompanying factors between subclinical and clinical populations. However, for the construction of continuum models, a more detailed knowledge of different types of psychotic-like experiences (PLE) and their associations with distress, functional impairment, and demographic variables is needed. We investigated PLE in a sample of healthy adults (N = 206) incorporating the recently developed revised Exceptional Experiences Questionnaire (PAGE-R). For the first time, the PAGE-R was cross validated with PLE, disorganized-, and negative-like symptoms [Schizotypal Personality Questionnaire (SPQ), Physical Anhedonia Scale (PAS)]. We subjected the PAGE-R to exploratory factor analyses and examined the resulting subtypes of EE for specific associations with contextual factors, valence ratings, socio-demographic variables, and general psychological burden (Revised Symptom-Checklist-90). Correlational cross validation suggested that the PAGE-R measures facets of PLE. Importantly, we (1) identified three types of exceptional experiences (EE): Odd beliefs, dissociative anomalous perceptions, and hallucinatory anomalous perceptions. Further, the results suggested that even in healthy individuals (2) PLE and EE are indicative of reduced functioning, as reflected by increased psychological burden and lower educational achievement. Moreover, (3) similar sex-differences might exist as in psychotic patients with women reporting more positive-like symptoms and EE but less disorganized-like symptoms than men. Importantly, (4) EE might be differentially implicated in psychological functioning. We suggest that the PAGE R holds the potential to complement the current assessment of sub-clinical psychosis. However, whereas our results might point toward a continuity of psychotic symptoms with EE and normal experiences, they require replication in larger samples as well as equivalence testing across the psychosis continuum. Future analyses incorporating the PAGE-R might shed more light onto mechanisms that are implicated in the progress or resilience toward clinical illness. PMID- 28555121 TI - Risk Factors for Gambling Problems on Online Electronic Gaming Machines, Race Betting and Sports Betting. AB - Growth of Internet gambling has fuelled concerns about its contribution to gambling problems. However, most online gamblers also gamble on land-based forms, which may be the source of problems for some. Studies therefore need to identify the problematic mode of gambling (online or offline) to identify those with an online gambling problem. Identifying most problematic form of online gambling (e.g., EGMs, race betting, sports betting) would also enable a more accurate examination of gambling problems attributable to a specific online gambling form. This study pursued this approach, aiming to: (1) determine demographic, behavioral and psychological risk factors for gambling problems on online EGMs, online sports betting and online race betting; (2) compare the characteristics of problematic online gamblers on each of these online forms. An online survey of 4,594 Australian gamblers measured gambling behavior, most problematic mode and form of gambling, gambling attitudes, psychological distress, substance use, help seeking, demographics and problem gambling status. Problem/moderate risk gamblers nominating an online mode of gambling as their most problematic, and identifying EGMs (n = 98), race betting (n = 291) or sports betting (n = 181) as their most problematic gambling form, were compared to non-problem/low risk gamblers who had gambled online on these forms in the previous 12 months (n = 64, 1145 and 1213 respectively), using bivariate analyses and then logistic regressions. Problem/moderate risk gamblers on each of these online forms were then compared. Risk factors for online EGM gambling were: more frequent play on online EGMs, substance use when gambling, and higher psychological distress. Risk factors for online sports betting were being male, younger, lower income, born outside of Australia, speaking a language other than English, more frequent sports betting, higher psychological distress, and more negative attitudes toward gambling. Risk factors for online race betting comprised being male, younger, speaking a language other than English, more frequent race betting, engaging in more gambling forms, self-reporting as semi-professional/professional gambler, illicit drug use whilst gambling, and more negative attitude toward gambling. These findings can inform improved interventions tailored to the specific characteristics of high risk gamblers on each of these online activities. PMID- 28555123 TI - Cognitive-Processing Bias in Chinese Student Teachers with Strong and Weak Professional Identity. AB - Professional identity plays an important role in career development. Although many studies have examined professional identity, differences in cognitive processing biases between Chinese student teachers with strong and weak professional identity are poorly understood. The current study adopted Tversky's social-cognitive experimental paradigm to explore cognitive-processing biases in Chinese student teachers with strong and weak professional identity. Experiment 1 showed that participants with strong professional identity exhibited stronger positive-coding bias toward positive profession-related life events, relative to that observed in those with weak professional identity. Experiment 2 showed that participants with strong professional identity exhibited greater recognition bias for previously read items, relative to that observed in those with weak professional identity. Overall, the results suggested that participants with strong professional identity exhibited greater positive cognitive-processing bias relative to that observed in those with weak professional identity. PMID- 28555122 TI - Binge Drinking Trajectory and Decision-Making during Late Adolescence: Gender and Developmental Differences. AB - Objective: Impaired affective decision-making has been consistently related to alcohol dependence. However, less is known about decision-making and binge drinking (BD) in adolescents. The main goal of this longitudinal study was to determine the association between BD and decision-making from late adolescence to early adulthood. A second aim is to assess developmental changes and performance differences in males and females. Method: An initial sample of 155 1st-year university students, (76 non-BDs, 40 females; and 79 BDs, 39 females), was followed prospectively over a 4-year period. The students were classified as stable non-BDs, stable BDs and ex-BDs according to their scores in item 3 of the AUDIT and the speed of alcohol consumption. Decision-making was assessed by the Iowa Gambling Task (IGT) three times during the study. Dependent variables were net gain and net loss. Results were analyzed using generalized linear mixed models. Results: A stable BD pattern was not associated with either disadvantageous decision-making or sensitivity to loss frequency. Performance improved significantly in both genders over the study period, especially in the last blocks of the task. Females showed a higher sensitivity to loss frequency than males. No gender-related differences were observed in gains. Conclusion: Performance in affective decision-making continues to improve in late adolescence, suggesting neuromaturational development in both genders. Females are more sensitive to loss frequency. Stable BD during late adolescence and emerging adulthood is not associated with deficits in decision-making. Poor performance of the IGT may be related to more severe forms of excessive alcohol consumption. PMID- 28555124 TI - Observational Study of 180 degrees Turning Strategies Using Inertial Measurement Units and Fall Risk in Poststroke Hemiparetic Patients. AB - OBJECTIVE: We analyzed spontaneous 180 degrees turning strategies in poststroke hemiparetic patients by using inertial measurement units (IMUs) and the association of turning strategies with risk of falls. METHODS: We included right paretic (RP) and left paretic (LP) post-stroke patients, and healthy controls (HCs) from a physical and rehabilitation department in France between July 2015 and October 2015. All subjects were right-handed and right-footed for mobilization tasks. Participants were instructed to turn 180 degrees in a self selected direction after a 10-m walk while wearing three IMUs on their trunk and both feet. We defined three turning patterns based on the number of external steps (pattern I = 1; II = 2-4 steps; and III >= 5) and four turning strategies based on the side chosen to turn (healthy or paretic) and the stance limb used during the first step of the turn (healthy or paretic). Falls in the 6 months after measurement were investigated. RESULTS: We included 17 RP [mean (SD) age 57.5 (9.5) years (range 43-73)], 20 LP patients [mean age 60.7 (8.8) years (range 43-63)], and 15 HCs [mean age 56.7 (16.1) years (range 36-83)]. The LP and RP groups behaved similarly in turning patterns, but 90% of LP patients turned spontaneously to the paretic side versus 59% of RP patients. This difference increased with turning strategies: 85% of LP versus 29% of RP patients used strategy 4 (paretic turn side with paretic limb). Patients using strategy 4 had the highest rate of falls. CONCLUSION: We propose to consider spontaneous turning strategies as new indicators to evaluate the risk of fall after stroke. IMU could be routinely used to identify this risk and guide balance rehabilitation programs. PMID- 28555125 TI - Determinants of Motion Sickness in Tilting Trains: Coriolis/Cross-Coupling Stimuli and Tilt Delay. AB - Faster trains require tilting of the cars to counterbalance the centrifugal forces during curves. Motion sensitive passengers, however, complain of discomfort and overt motion sickness. A recent study comparing different control systems in a tilting train, suggested that the delay of car tilts relative to the curve of the track contributes to motion sickness. Other aspects of the motion stimuli, like the lateral accelerations and the car jitters, differed between the tested conditions and prevented a final conclusion on the role of tilt delay. Nineteen subjects were tested on a motorized 3D turntable that simulated the roll tilts during yaw rotations experienced on a tilting train, isolating them from other motion components. Each session was composed of two consecutive series of 12 ideal curves that were defined on the bases of recordings during an actual train ride. The simulated car tilts started either at the beginning of the curve acceleration phase (no-delay condition) or with 3 s of delay (delay condition). Motion sickness was self-assessed by each subject at the end of each series using an analog motion sickness scale. All subjects were tested in both conditions. Significant increases of motion sickness occurred after the first sequence of 12 curves in the delay condition, but not in the no-delay condition. This increase correlated with the sensitivity of motion sickness, which was self-assessed by each subject before the experiment. The second sequence of curve did not lead to a significant further increase of motion sickness in any condition. Our results demonstrate that, even if the speed and amplitude are as low as those experienced on tilting trains, a series of roll tilts with a delay relative to the horizontal rotations, isolated from other motion stimuli occurring during a travel, generate Coriolis/cross-coupling stimulations sufficient to rapidly induce motion sickness in sensitive individuals. The strength and the rapid onset of the motion sickness reported confirm that, even if the angular velocity involved are low, the Coriolis/cross-coupling resulting from the delay is a major factor in causing sickness that can be resolved by improving the tilt timing relative to the horizontal rotation originating from the curve. PMID- 28555126 TI - Altered Motor Unit Discharge Coherence in Paretic Muscles of Stroke Survivors. AB - After a cerebral stroke, a series of changes at the supraspinal and spinal nervous system can alter the control of muscle activation, leading to persistent motor impairment. However, the relative contribution of these different levels of the nervous system to impaired muscle activation is not well understood. The coherence of motor unit (MU) spike trains is considered to partly reflect activities of higher level control, with different frequency band representing different levels of control. Accordingly, the objective of this study was to quantify the different sources of contribution to altered muscle activation. We examined the coherence of MU spike trains decomposed from surface electromyogram (sEMG) of the first dorsal interosseous muscle on both paretic and contralateral sides of 14 hemispheric stroke survivors. sEMG was obtained over a range of force contraction levels at 40, 50, and 60% of maximum voluntary contraction. Our results showed that MU coherence increased significantly in delta (1-4 Hz), alpha (8-12 Hz), and beta (15-30 Hz) bands on the affected side compared with the contralateral side, but was maintained at the same level in the gamma (30-60 Hz) band. In addition, no significant alteration was observed across medium-high force levels (40-60%). These results indicated that the common synaptic input to motor neurons increased on the paretic side, and the increased common input can originate from changes at multiple levels, including spinal and supraspinal levels following a stroke. All these changes can contribute to impaired activation of affected muscles in stroke survivors. Our findings also provide evidence regarding the different origins of impaired muscle activation poststroke. PMID- 28555127 TI - Cerebral Microbleeds, Hypertension, and Intracerebral Hemorrhage in Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. AB - BACKGROUND: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic cause of stroke. In addition to ischemic stroke, CADASIL predisposes to development of cerebral microbleeds (CMB). CMB and hypertension are known to be associated with intracerebral hemorrhage (ICH). The purpose of this study was to analyze the relationships among CMB, hypertension, and ICH in CADASIL. MATERIALS AND METHODS: We enrolled 94 genetically confirmed CADASIL patients from 76 unrelated families at Jeju National University Hospital (Korea) between March 2012 and February 2015. We analyzed CMB presence, number, and distribution on susceptibility weighted imaging MRI using the microbleed anatomical rating scale. Multiple logistic regression was used to determine factors associated with the presence of CMB and ICH. RESULTS: CMB were observed in 62 patients (66%), median number of CMB per patient was 4 (range 0-121). Twenty-two ICHs were found in 16 patients (17%). There was incongruence between the most common site of CMB (thalamus) and that of ICH (basal ganglia). Hypertension was independently associated with the presence of CMB (multiple regression OR, 2.71; 95% CI 1.02-7.18, p < 0.05), and CMB >= 9 (highest third) was significantly associated with the presence of ICH (multiple regression OR = 9.50, 95% CI 1.08-83.71, p < 0.05). CONCLUSION: In this CADASIL sample, presence of hypertension was independently associated with CMB presence, and CMB burden was independently associated with ICH. Incongruence of sites for CMB and ICH is currently unexplained and requires further study. PMID- 28555128 TI - A Case of Apparent Upper-Body Freezing in Parkinsonism while Using a Wheelchair. AB - Freezing of gait (FOG) is a common, disabling gait disturbance in Parkinson's disease (PD) and other Parkinsonian syndromes. Freezing also occurs during non gait movements involving the upper limbs. The mechanisms underlying freezing are complex, likely involving motor, cognitive, and sensory systems that contribute to the episodes. Here, we reported a 60-year-old female with a 24-year history of parkinsonism who experienced significant FOG when ambulatory. Disease progression resulted in her permanent use of a powered wheelchair. While using the power chair, the patient experiences apparent paroxysmal freezing in the hand and arm used to steer and propel the chair. These episodes, some lasting up to several minutes, occur only in circumstances (e.g., entering and leaving an elevator) that are similar to environments known to elicit and exacerbate FOG. Episodes are transient and can be volitionally interrupted by the patient but sometimes require external assistance. Therapeutic intervention for this type of potential freezing has yet to be determined. This case may provide insight into the complex nature of freezing behavior and suggests a need for new approaches to treating non-traditional freezing behavior. PMID- 28555129 TI - Identification of Atypical El TorV. cholerae O1 Ogawa Hosting SXT Element in Senegal, Africa. AB - Vibrio cholerae O1 is the causative agent of cholera with classical and El Tor, two well-established biotypes. In last 20 years, hybrid strains of classical and El Tor and variant El Tor which carry classical ctxB have emerged worldwide. In 2004-2005, Senegal experienced major cholera epidemic with a number of cases totalling more than 31719 with approximately 458 fatal outcomes (CFR, 1.44%). In this retrospective study, fifty isolates out of a total of 403 V. cholerae biotype El Tor serovar Ogawa isolates from all areas in Senegal during the 2004 2005 cholera outbreak were randomly selected. Isolates were characterized using phenotypic and genotypic methods. The analysis of antibiotic resistance patterns revealed the predominance of the S-Su-TCY-Tsu phenotype (90% of isolates). The molecular characterization of antibiotic resistance revealed the presence of the SXT element, a self-transmissible chromosomally integrating element in all isolates. Most of V. cholerae isolates had an intact virulence cassette (86%) (ctx, zot, ace genes). All isolates tested gave amplification with primers for classical CT, and 10/50 (20%) of isolates carried classical and El Tor ctxB. The study reveals the presence of atypical V. cholerae O1 El Tor during cholera outbreak in Senegal in 2004-2005. PMID- 28555131 TI - A Phloem-Feeding Insect Transfers Bacterial Endophytic Communities between Grapevine Plants. AB - Bacterial endophytes colonize the inner tissues of host plants through the roots or through discontinuities on the plant surface, including wounds and stomata. Little is known regarding a possible role of insects in acquiring and transmitting non-phytopathogenic microorganisms from plant to plant, especially those endophytes that are beneficial symbionts providing plant protection properties and homeostatic stability to the host. To understand the ecological role of insects in the transmission of endophytic bacteria, we used freshly hatched nymphs of the American sap-feeding leafhopper Scaphoideus titanus (vector) to transfer microorganisms across grapevine plants. After contact with the vector, sink plants were colonized by a complex endophytic community dominated by Proteobacteria, highly similar to that present in source plants. A similar bacterial community, but with a higher ratio of Firmicutes, was found on S. titanus. Insects feeding only on sink plants transferred an entirely different bacterial community dominated by Actinobacteria, where Mycobacterium sp., played a major role. Despite the fact that insects dwelled mostly on plant stems, the bacterial communities in plant roots resembled more closely those inside and on insects, when compared to those of above-ground plant organs. We prove here the potential of insect vectors to transfer entire endophytic bacterial communities between plants. We also describe the role of plants and bacterial endophytes in establishing microbial communities in plant-feeding insects. PMID- 28555130 TI - Viruses and miRNAs: More Friends than Foes. AB - There is evidence that eukaryotic miRNAs (hereafter called host miRNAs) play a role in the replication and propagation of viruses. Expression or targeting of host miRNAs can be involved in cellular antiviral responses. Most times host miRNAs play a role in viral life-cycles and promote infection through complex regulatory pathways. miRNAs can also be encoded by a viral genome and be expressed in the host cell. Viral miRNAs can share common sequences with host miRNAs or have totally different sequences. They can regulate a variety of biological processes involved in viral infection, including apoptosis, evasion of the immune response, or modulation of viral life-cycle phases. Overall, virus/miRNA pathway interaction is defined by a plethora of complex mechanisms, though not yet fully understood. This article review summarizes recent advances and novel biological concepts related to the understanding of miRNA expression, control and function during viral infections. The article also discusses potential therapeutic applications of this particular host-pathogen interaction. PMID- 28555132 TI - Stimulation of Fengycin-Type Antifungal Lipopeptides in Bacillus amyloliquefaciens in the Presence of the Maize Fungal Pathogen Rhizomucor variabilis. AB - Most isolates belonging to the Bacillus amyloliquefaciens subsp. plantarum clade retain the potential to produce a vast array of structurally diverse antimicrobial compounds that largely contribute to their efficacy as biocontrol agents against numerous plant fungal pathogens. In that context, the role of cyclic lipopeptides (CLPs) has been well-documented but still little is known about the impact of interactions with other soil-inhabiting microbes on the expression of these molecules. In this work, we wanted to investigate the antagonistic activity developed by this bacterium against Rhizomucor variabilis, a pathogen isolated from diseased maize cobs in Democratic Republic of Congo. Our data show that fengycins are the major compounds involved in the inhibitory activity but also that production of this type of CLP is significantly upregulated when co-cultured with the fungus compared to pure cultures. B. amyloliquefaciens is thus able to perceive fungal molecules that are emitted and, as a response, up-regulates the biosynthesis of some specific components of its antimicrobial arsenal. PMID- 28555133 TI - An Influenza HA and M2e Based Vaccine Delivered by a Novel Attenuated Salmonella Mutant Protects Mice against Homologous H1N1 Infection. AB - Attenuated Salmonella strains constitute a promising technology for the development of a more efficient multivalent protein based vaccines. In this study, we constructed a novel attenuated strain of Salmonella for the delivery and expression of the H1N1 hemagglutinin (HA) and the conserved extracellular domain of the matrix protein 2 (M2e). We demonstrated that the constructed Salmonella strain exhibited efficient HA and M2e protein expressions and little cytotoxicity and pathogenicity in mice. Using BALB/c mice as the model, we showed that the mice vaccinated with a Salmonella strain expressing HA and M2e protein antigens, respectively, induced significant production of HA and M2e-specific serum IgG1 and IgG2a responses, and of anti-HA interferon-gamma producing T cells. Furthermore, immunization with Salmonella-HA-M2e-based vaccine via different routes provided protection in 66.66% orally, 100% intramuscularly, and 100% intraperitoneally immunized mice against the homologous H1N1 virus while none of the animals survived treated with either the PBS or the Salmonella carrying empty expression vector. Ex vivo stimulated dendritic cells (DCs) with heat killed Salmonella expressing HA demonstrated that DCs play an important role in the elicitation of HA-specific humoral immune responses in mice. In summary, Salmonella-HA-M2e-based vaccine elicits efficient antigen-specific humoral and cellular immune responses, and provides significant immune protection against a highly pathogenic H1N1 influenza virus. PMID- 28555134 TI - The Transcription Factor ZNF683/HOBIT Regulates Human NK-Cell Development. AB - We identified ZNF683/HOBIT as the most highly upregulated transcription factor gene during ex vivo differentiation of human CD34+ cord blood progenitor cells to CD56+ natural killer (NK) cells. ZNF683/HOBIT mRNA was preferentially expressed in NK cells compared to other human peripheral blood lymphocytes and monocytes. During ex vivo differentiation, ZNF683/HOBIT mRNA started to increase shortly after addition of IL-15 and further accumulated in parallel to the generation of CD56+ NK cells. shRNA-mediated knockdown of ZNF683/HOBIT resulted in a substantial reduction of CD56-CD14- NK-cell progenitors and the following generation of CD56+ NK cells was largely abrogated. The few CD56+ NK cells, which escaped the developmental inhibition in the ZNF683/HOBIT knockdown cultures, displayed normal levels of NKG2A and KIR receptors. Functional analyses of these cells showed no differences in degranulation capacity from control cultures. However, the proportion of IFN-gamma-producing cells appeared to be increased upon ZNF683/HOBIT knockdown. These results indicate a key role of ZNF683/HOBIT for the differentiation of the human NK-cell lineage and further suggest a potential negative control on IFN-gamma production in more mature human NK cells. PMID- 28555135 TI - Why the Immune System Should Be Concerned by Nanomaterials? AB - Particles possess huge specific surface area and therefore nanomaterials exhibit unique characteristics, such as special physical properties and chemical hyper reactivity, which make them particularly attractive but also raise numerous questions concerning their safety. Interactions of nanomaterials with the immune system can potentially lead to immunosuppression, hypersensitivity (allergy), immunogenicity and autoimmunity, involving both innate and adaptive immune responses. Inherent physical and chemical NP characteristics may influence their immunotoxicity, i.e., the adverse effects that can result from exposure. This review will focus on the possible interaction of nanomaterials including protein aggregates with the innate immune system with specific emphasis on antigen presenting cells, i.e., dendritic cells, macrophages and monocytes. PMID- 28555137 TI - What We Have Learned and What We Have Missed in Tuberculosis Pathophysiology for a New Vaccine Design: Searching for the "Pink Swan". AB - This is a call to encourage the search for a new vaccine to stop the progression of Mycobacterium tuberculosis infection to tuberculosis (TB) disease. TB is a highly discreet and stigmatized disease, with a massive impact on human health. It has killed 1.2 billion people in the last 200 years and still kills 1.5 million people per year. Over the last 20 years, the TB vaccine field has experienced spectacular developments, and we have learned about (1) the importance of the Th1 response in controlling infection, mainly against RD1 and Ag85 antigens; (2) the stability of the antigenic repertoire; (3) the dynamics of M. tuberculosis granulomas; or (4) the link between typical and atypical pulmonary TB and the immune status of the host. However, we still do not (1) know how to avoid M. tuberculosis infection and reinfection; (2) understand the major role of the increase in lesion size in progression from infection to disease; (3) the role of interlobular septa in encapsulating pulmonary lesions; or (4) the role of neutrophilic infiltration and an exaggerated inflammatory response in the development of TB disease. These are strong reasons to pursue new, imaginative proposals involving both the antibody response and a balanced, tolerant immune response that averts progression toward TB. So far, the scientific mindset has been quite monolithic and has mainly focused on the stimulation of conventional T cells. But this approach has failed. For that reason, we are seeking unconventional perspectives to find a "pink swan," a more efficacious and safer vaccine candidate. PMID- 28555136 TI - Oncolytic Immunotherapy: Conceptual Evolution, Current Strategies, and Future Perspectives. AB - The concept of oncolytic virus (OV)-mediated cancer therapy has been shifted from an operational virotherapy paradigm to an immunotherapy. OVs often induce immunogenic cell death (ICD) of cancer cells, and they may interact directly with immune cells as well to prime antitumor immunity. We and others have developed a number of strategies to further stimulate antitumor immunity and to productively modulate the tumor microenvironment (TME) for potent and sustained antitumor immune cell activity. First, OVs have been engineered or combined with other ICD inducers to promote more effective T cell cross-priming, and in many cases, the breaking of functional immune tolerance. Second, OVs may be armed to express Th1 stimulatory cytokines/chemokines or costimulators to recruit and sustain the potent antitumor immunity into the TME to focus their therapeutic activity within the sites of disease. Third, combinations of OV with immunomodulatory drugs or antibodies that recondition the TME have proven to be highly promising in early studies. Fourth, combinations of OVs with other immunotherapeutic regimens (such as prime-boost cancer vaccines, CAR T cells; armed with bispecific T-cell engagers) have also yielded promising preliminary findings. Finally, OVs have been combined with immune checkpoint blockade, with robust antitumor efficacy being observed in pilot evaluations. Despite some expected hurdles for the rapid translation of OV-based state-of-the-art protocols, we believe that a cohort of these novel approaches will join the repertoire of standard cancer treatment options in the near future. PMID- 28555138 TI - Under Pressure: Interactions between Commensal Microbiota and the Teleost Immune System. AB - Commensal microorganisms inhabit every mucosal surface of teleost fish. At these surfaces, microorganisms directly and indirectly shape the teleost immune system. This review provides a comprehensive overview of how the microbiota and microbiota-derived products influence both the mucosal and systemic immune system of fish. The cross talk between the microbiota and the teleost immune system shifts significantly under stress or disease scenarios rendering commensals into opportunists or pathogens. Lessons learnt from germ-free fish models as well as from oral administration of live probiotics to fish highlight the vast impact that microbiota have on immune development, antibody production, mucosal homeostasis, and resistance to stress. Future studies should dissect the specific mechanisms by which different members of the fish microbiota and the metabolites they produce interact with pathogens, with other commensals, and with the teleost immune system. PMID- 28555140 TI - Tripartite Motif-Containing Protein 22 Interacts with Class II Transactivator and Orchestrates Its Recruitment in Nuclear Bodies Containing TRIM19/PML and Cyclin T1. AB - Among interferon (IFN) inducible antiviral factors both tripartite motif containing protein 22 (TRIM22) and class II transactivator (CIITA) share the capacity of repressing human immunodeficiency virus type 1 (HIV-1) proviral transcription. TRIM22 is constitutively expressed in a subset of U937 cell clones poorly permissive to HIV-1 replication, whereas CIITA has been shown to inhibit virus multiplication in both T lymphocytic and myeloid cells, including poorly HIV-1 permissive U937 cells, by suppressing Tat-mediated transactivation of HIV-1 transcription. Therefore, we tested whether TRIM22 and CIITA could form a nuclear complex potentially endowed with HIV-1 repressive functions. Indeed, we observed that TRIM22, independent of its E3 ubiquitin ligase domain, interacts with CIITA and promotes its recruitment into nuclear bodies. Importantly, TRIM19/promyelocytic leukemia (PML) protein, another repressor of HIV-1 transcription also acting before proviral integration, colocalize in these nuclear bodies upon TRIM22 expression induced by IFN-gamma. Finally, tTRIM22 nuclear bodies also contained CyclinT1, a crucial elongation factor of HIV-1 primary transcripts. These findings show that TRIM22 nuclear bodies are a site of recruitment of factors crucial for the regulation of HIV-1 transcription and highlight the potential existence of a concerted action between TRIM22, CIITA, and TRIM19/PML to maintain a state of proviral latency, at least in myeloid cells. PMID- 28555139 TI - Escherichia coli Heat-Labile Enterotoxin B Limits T Cells Activation by Promoting Immature Dendritic Cells and Enhancing Regulatory T Cell Function. AB - Treatments to limit T cell activation are essential for managing autoimmune and inflammatory disorders. The B subunit of Escherichia coli heat-labile enterotoxin (EtxB) is known to ameliorate inflammatory disease in vivo but the mechanism by which this is mediated is not well understood. Here, we show that following intranasal administration, EtxB acts on two key cellular regulators of T cell activation: regulatory T cells and dendritic cells (DCs). EtxB enhances the proliferation of lung regulatory T cells and doubles their suppressive function, likely through an increase in expression of the Treg effector molecule CTLA-4. EtxB supports the generation of interleukin-10-producing DCs that are unable to activate T cells. These data show, for the first time, that mucosal EtxB treatment limits T cells activation by acting jointly on two distinct types of immune cells. PMID- 28555141 TI - Characterization of Insect Resistance Loci in the USDA Soybean Germplasm Collection Using Genome-Wide Association Studies. AB - Management of insects that cause economic damage to yields of soybean mainly rely on insecticide applications. Sources of resistance in soybean plant introductions (PIs) to different insect pests have been reported, and some of these sources, like for the soybean aphid (SBA), have been used to develop resistant soybean cultivars. With the availability of SoySNP50K and the statistical power of genome wide association studies, we integrated phenotypic data for beet armyworm, Mexican bean beetle (MBB), potato leafhopper (PLH), SBA, soybean looper (SBL), velvetbean caterpillar (VBC), and chewing damage caused by unspecified insects for a comprehensive understanding of insect resistance in the United States Department of Agriculture Soybean Germplasm Collection. We identified significant single nucleotide (SNP) polymorphic markers for MBB, PLH, SBL, and VBC, and we highlighted several leucine-rich repeat-containing genes and myeloblastosis transcription factors within the high linkage disequilibrium region surrounding significant SNP markers. Specifically for soybean resistance to PLH, we found the PLH locus is close but distinct to a locus for soybean pubescence density on chromosome 12. The results provide genetic support that pubescence density may not directly link to PLH resistance. This study offers a novel insight of soybean resistance to four insect pests and reviews resistance mapping studies for major soybean insects. PMID- 28555142 TI - Oligodeoxynucleotides Can Transiently Up- and Downregulate CHS Gene Expression in Flax by Changing DNA Methylation in a Sequence-Specific Manner. AB - Chalcone synthase (CHS) has been recognized as an essential enzyme in the phenylpropanoid biosynthesis pathway. Apart from the leading role in the production of phenolic compounds with many valuable biological activities beneficial to biomedicine, CHS is well appreciated in science. Genetic engineering greatly facilitates expanding knowledge on the function and genetics of CHS in plants. The CHS gene is one of the most intensively studied genes in flax. In our study, we investigated engineering of the CHS gene through genetic and epigenetic approaches. Considering the numerous restrictions concerning the application of genetically modified (GM) crops, the main purpose of this research was optimization of the plant's modulation via epigenetics. In our study, plants modified through two methods were compared: a widely popular agrotransformation and a relatively recent oligodeoxynucleotide (ODN) strategy. It was recently highlighted that the ODN technique can be a rapid and time-serving antecedent in quick analysis of gene function before taking vector-mediated transformation. In order to understand the molecular background of epigenetic variation in more detail and evaluate the use of ODNs as a tool for predictable and stable gene engineering, we concentrated on the integration of gene expression and gene-body methylation. The treatment of flax with a series of short oligonucleotides homologous to a different part of CHS gene isoforms revealed that those directed to regulatory gene regions (5'- and 3'-UTR) activated gene expression, directed to non-coding region (introns) caused gen activity reduction, while those homologous to a coding region may have a variable influence on its activity. Gene expression changes were accompanied by changes in its methylation status. However, only certain (CCGG) motifs along the gene sequence were affected. The analyzed DNA motifs of the CHS flax gene are more accessible for methylation when located within a CpG island. The methylation motifs also led to rearrangement of the nucleosome location. The obtained results suggest high specificity of ODN action and establish a potential valuable alternative for improvement of crops. PMID- 28555143 TI - Global Transcriptome Analysis of Combined Abiotic Stress Signaling Genes Unravels Key Players in Oryza sativa L.: An In silico Approach. AB - Combined abiotic stress (CAbS) affects the field grown plants simultaneously. The multigenic and quantitative nature of uncontrollable abiotic stresses complicates the process of understanding the stress response by plants. Considering this, we analyzed the CAbS response of C3 model plant, Oryza sativa by meta-analysis. The datasets of commonly expressed genes by drought, salinity, submergence, metal, natural expression, biotic, and abiotic stresses were data mined through publically accessible transcriptomic abiotic stress (AbS) responsive datasets. Of which 1,175, 12,821, and 42,877 genes were commonly expressed in meta differential, individual differential, and unchanged expressions respectively. Highly regulated 100 differentially expressed AbS genes were derived through integrative meta-analysis of expression data (INMEX). Of this 30 genes were identified from AbS gene families through expression atlas that were computationally analyzed for their physicochemical properties. All AbS genes were physically mapped against O. sativa genome. Comparative mapping of these genes demonstrated the orthologous relationship with related C4 panicoid genome. In silico expression analysis of these genes showed differential expression patterns in different developmental tissues. Protein-protein interaction of these genes, represented the complexity of AbS. Computational expression profiling of candidate genes in response to multiple stresses suggested the putative involvement of OS05G0350900, OS02G0612700, OS05G0104200, OS03G0596200, OS12G0225900, OS07G0152000, OS08G0119500, OS06G0594700, and Os01g0393100 in CAbS. These potential candidate genes need to be studied further to decipher their functional roles in AbS dynamics. PMID- 28555144 TI - Uptake of Silicon by Sugarcane from Applied Sources May Not Reflect Plant Available Soil Silicon and Total Silicon Content of Sources. AB - Soils of the tropics and sub-tropics are typically acid and depleted of soluble sources of silicon (Si) due to weathering and leaching associated with high rainfall and temperatures. Together with intensive cropping, this leads to marginal or deficient plant Si levels in Si-accumulating crops such as rice and sugarcane. Although such deficiencies can be corrected with exogenous application of Si sources, there is controversy over the effectiveness of sources in relation to their total Si content, and their capacity to raise soil and plant Si concentrations. This study tested the hypothesis that the total Si content and provision of plant-available Si from six sources directly affects subsequent plant Si uptake as reflected in leaf Si concentration. Two trials with potted cane plants were established with the following Si sources as treatments: calcium silicate slag, fused magnesium (thermo) phosphate, volcanic rock dust, magnesium silicate, and granular potassium silicate. Silicon sources were applied at rates intended to achieve equivalent elemental soil Si concentrations; controls were untreated or lime-treated. Analyses were conducted to determine soil and leaf elemental concentrations. Among the sources, calcium silicate produced the highest leaf Si concentrations, yet lower plant-available soil Si concentrations than the thermophosphate. The latter, with slightly higher total Si than the slag, produced substantially greater increases in soil Si than all other products, yet did not significantly raise leaf Si above the controls. All other sources did not significantly increase soil or leaf Si concentrations, despite their high Si content. Hence, the total Si content of sources does not necessarily concur with a product's provision of soluble soil Si and subsequent plant uptake. Furthermore, even where soil pH was raised, plant uptake from thermophosphate was well below expectation, possibly due to its limited liming capacity. The ability of the calcium silicate to provide Si while simultaneously and significantly increasing soil pH, and thereby reducing reaction of Si with exchangeable Al3+, is proposed as a potential explanation for the greater Si uptake into the shoot from this source. PMID- 28555145 TI - RNA-Seq Analysis of Diverse Rice Genotypes to Identify the Genes Controlling Coleoptile Growth during Submerged Germination. AB - The rate of coleoptile elongation varies between different rice varieties that are grown under water during the germination stage. Compared to sensitive varieties, submergence-tolerant rice exhibits substantial coleoptile elongation in order to uptake oxygen (O2) from the surface and thus have a better chance to survive water stress. We conducted RNA-seq analysis in order to investigate 7-day old shoot transcriptome dynamics in six rice genotypes that exhibit different coleoptile elongation rates under water. This enabled us to identify the genes involved in photosynthesis, lipid metabolism, glycolysis, anaerobic fermentation, hormone synthesis, cell wall growth and elongation, and to demonstrate that these genes are differentially regulated within, and between, genotypes. Further, in addition to determining how allelic variation affects anaerobic germination, we compared the expression patterns and genomic sequences of six genotypes; this enabled us to discover that some genes carry small-to-large deletions in the coding region of sensitive varieties. These structural variations may explain the absence of transcripts in the dataset, as well as the failure of sensitive variety to respond to submergence. On the basis of these results, we hypothesize that transcriptional regulation enhances coleoptile elongation. Although this is an area for future research, the outcome of this study is expected to facilitate rice breeding for direct-seeding. PMID- 28555146 TI - Lack of Impacts during Early Establishment Highlights a Short-Term Management Window for Minimizing Invasions from Perennial Biomass Crops. AB - Managing intentional species introductions requires evaluating potential ecological risks. However, it is difficult to weigh costs and benefits when data about interactions between novel species and the communities they are introduced to are scarce. In anticipation of expanded cultivation of perennial biomass crops, we experimentally introduced Miscanthus sinensis and Miscanthus * giganteus (two non-native candidate biomass crops) into two different non-crop habitats (old field and flood-plain forest) to evaluate their establishment success and impact on ambient local communities. We followed these controlled introductions and the composition dynamics of the receiving communities over a 5 year period. Habitats differed widely in adult Miscanthus survival and reproduction potential between species, although seed persistence and seedling emergence were similar in the two biomass crops in both habitats. Few introductions survived in the floodplain forest habitat, and this mortality precluded analyses of their potential impacts there. In old field habitats, proportional survival ranged from 0.3 to 0.4, and plant survival and growth increased with age. However, there was no evidence of biomass crop species effects on community richness or evenness or strong impacts on the resident old field constituents across 5 years. These results suggest that Miscanthus species could establish outside of cultivated fields, but there will likely be a lag in any impacts on the receiving communities. Local North American invasions by M. sinensis and M. sacchariflorus display the potential for Miscanthus species to develop aggressively expanding populations. However, the weak short-term community-level impacts demonstrated in the current study indicate a clear management window in which eradicating species footholds is easily achieved, if they can be detected early enough. Diligent long-term monitoring, detection, and eradication plans are needed to successfully minimize harmful invasions from these biomass crops. PMID- 28555147 TI - Contemporary Remotely Sensed Data Products Refine Invasive Plants Risk Mapping in Data Poor Regions. AB - Invasive weeds are a serious problem worldwide, threatening biodiversity and damaging economies. Modeling potential distributions of invasive weeds can prioritize locations for monitoring and control efforts, increasing management efficiency. Forecasts of invasion risk at regional to continental scales are enabled by readily available downscaled climate surfaces together with an increasing number of digitized and georeferenced species occurrence records and species distribution modeling techniques. However, predictions at a finer scale and in landscapes with less topographic variation may require predictors that capture biotic processes and local abiotic conditions. Contemporary remote sensing (RS) data can enhance predictions by providing a range of spatial environmental data products at fine scale beyond climatic variables only. In this study, we used the Global Biodiversity Information Facility (GBIF) and empirical maximum entropy (MaxEnt) models to model the potential distributions of 14 invasive plant species across Southeast Asia (SEA), selected from regional and Vietnam's lists of priority weeds. Spatial environmental variables used to map invasion risk included bioclimatic layers and recent representations of global land cover, vegetation productivity (GPP), and soil properties developed from Earth observation data. Results showed that combining climate and RS data reduced predicted areas of suitable habitat compared with models using climate or RS data only, with no loss in model accuracy. However, contributions of RS variables were relatively limited, in part due to uncertainties in the land cover data. We strongly encourage greater adoption of quantitative remotely sensed estimates of ecosystem structure and function for habitat suitability modeling. Through comprehensive maps of overall predicted area and diversity of invasive species, we found that among lifeforms (herb, shrub, and vine), shrub species have higher potential invasion risk in SEA. Native invasive species, which are often overlooked in weed risk assessment, may be as serious a problem as non-native invasive species. Awareness of invasive weeds and their environmental impacts is still nascent in SEA and information is scarce. Freely available global spatial datasets, not least those provided by Earth observation programs, and the results of studies such as this one provide critical information that enables strategic management of environmental threats such as invasive species. PMID- 28555148 TI - Genome Wide Identification of Orthologous ZIP Genes Associated with Zinc and Iron Translocation in Setaria italica. AB - Genes in the ZIP family encode transcripts to store and transport bivalent metal micronutrient, particularly iron (Fe) and or zinc (Zn). These transcripts are important for a variety of functions involved in the developmental and physiological processes in many plant species, including most, if not all, Poaceae plant species and the model species Arabidopsis. Here, we present the report of a genome wide investigation of orthologous ZIP genes in Setaria italica and the identification of 7 single copy genes. RT-PCR shows 4 of them could be used to increase the bio-availability of zinc and iron content in grains. Of 36 ZIP members, 25 genes have traces of signal peptide based sub-cellular localization, as compared to those of plant species studied previously, yet translocation of ions remains unclear. In silico analysis of gene structure and protein nature suggests that these two were preeminent in shaping the functional diversity of the ZIP gene family in S. italica. NAC, bZIP and bHLH are the predominant Fe and Zn responsive transcription factors present in SiZIP genes. Together, our results provide new insights into the signal peptide based/independent iron and zinc translocation in the plant system and allowed identification of ZIP genes that may be involved in the zinc and iron absorption from the soil, and thus transporting it to the cereal grain underlying high micronutrient accumulation. PMID- 28555149 TI - Comparative Transcriptomics Reveals Differential Gene Expression Related to Colletotrichum gloeosporioides Resistance in the Octoploid Strawberry. AB - The strawberry is an important fruit worldwide; however, the development of the strawberry industry is limited by fungal disease. Anthracnose is caused by the pathogen Colletotrichum gloeosporioides and leads to large-scale losses in strawberry quality and production. However, the transcriptional response of strawberry to infection with C. gloeosporioides is poorly understood. In the present study, the strawberry leaf transcriptome of the 'Yanli' and 'Benihoppe' cultivars were deep sequenced via an RNA-seq analysis to study C. gloeosporioides resistance in strawberry. Among the sequences, differentially expressed genes were annotated with Gene Ontology terms and subjected to pathway enrichment analysis. Significant categories included defense, plant-pathogen interactions and flavonoid biosynthesis were identified. The comprehensive transcriptome data set provides molecular insight into C. gloeosporioides resistance genes in resistant and susceptible strawberry cultivars. Our findings can enhance breeding efforts in strawberry. PMID- 28555150 TI - Crops In Silico: Generating Virtual Crops Using an Integrative and Multi-scale Modeling Platform. AB - Multi-scale models can facilitate whole plant simulations by linking gene networks, protein synthesis, metabolic pathways, physiology, and growth. Whole plant models can be further integrated with ecosystem, weather, and climate models to predict how various interactions respond to environmental perturbations. These models have the potential to fill in missing mechanistic details and generate new hypotheses to prioritize directed engineering efforts. Outcomes will potentially accelerate improvement of crop yield, sustainability, and increase future food security. It is time for a paradigm shift in plant modeling, from largely isolated efforts to a connected community that takes advantage of advances in high performance computing and mechanistic understanding of plant processes. Tools for guiding future crop breeding and engineering, understanding the implications of discoveries at the molecular level for whole plant behavior, and improved prediction of plant and ecosystem responses to the environment are urgently needed. The purpose of this perspective is to introduce Crops in silico (cropsinsilico.org), an integrative and multi-scale modeling platform, as one solution that combines isolated modeling efforts toward the generation of virtual crops, which is open and accessible to the entire plant biology community. The major challenges involved both in the development and deployment of a shared, multi-scale modeling platform, which are summarized in this prospectus, were recently identified during the first Crops in silico Symposium and Workshop. PMID- 28555151 TI - Molecular Cytogenetic Characterization of two Triticum-Secale-Thinopyrum Trigeneric Hybrids Exhibiting Superior Resistance to Fusarium Head Blight, Leaf Rust, and Stem Rust Race Ug99. AB - Fusarium head blight (FHB), leaf rust, and stem rust are the most destructive fungal diseases in current world wheat production. The diploid wheatgrass, Thinopyrum elongatum (Host) Dewey (2n = 2x = 14, EE) is an excellent source of disease resistance genes. Two new Triticum-Secale-Thinopyrum trigeneric hybrids were derived from a cross between a hexaploid triticale (X Triticosecale Wittmack, 2n = 6x = 42, AABBRR) and a hexaploid Triticum trititrigia (2n = 6x = 42, AABBEE), were produced and analyzed using genomic in situ hybridization and molecular markers. The results indicated that line RE21 contained 14 A chromosomes, 14 B-chromosomes, three pairs of R-chromosomes (4R, 6R, and 7R), and four pairs of E-chromosomes (1E, 2E, 3E, and 5E) for a total chromosome number of 2n = 42. Line RE62 contained 14 A-chromosomes, 14 B-chromosomes, six pairs of R chromosomes, and one pair of translocation chromosomes between chromosome 5R and 5E, for a total chromosome number of 2n = 42. At the seedling and adult growth stages under greenhouse conditions, line RE21 showed high levels of resistance to FHB, leaf rust, and stem rust race Ug99, and line RE62 was highly resistant to leaf rust and stem rust race Ug99. These two lines (RE21 and RE62) display superior disease resistance characteristics and have the potential to be utilized as valuable germplasm sources for future wheat improvement. PMID- 28555152 TI - Molecular Cytogenetic Characterization of Novel Wheat-rye T1RS.1BL Translocation Lines with High Resistance to Diseases and Great Agronomic Traits. AB - Rye has been used worldwide as a source for the genetic improvement of wheat. In this study, two stable wheat-rye primary T1RS.1BL translocation lines were selected from the progeny of the crossing of the wheat cultivar Mianyang11-1 and a Chinese local rye variety, Weining. These two novel translocation lines were identified by molecular cytogenetic analysis. PCR results, multi-color fluorescence in situ hybridization (MC-FISH), and acid polyacrylamide gel electrophoresis (A-PAGE) indicated that both new translocation lines harbor a pair of T1RS.1BL translocation chromosomes, and have been named RT828-10 and RT828-11, respectively. The cytogenetic results also indicated that the pSc119.2 signals of 5AL were absent in both lines along with the pSc119.2 signals of 4AL of RT828-11. When inoculated with different stripe rust and powdery mildew isolates, both lines expressed high resistance to Puccinia striiformis f. sp. tritici and Blumeria graminis f. sp. tritici pathotypes, which are prevalent in China and are virulent on Yr9 and Pm8. The line RT828-11 also exhibited excellent agronomic traits in the field. The present study indicates that this rye variety may carry untapped variations that could potentially be used for wheat improvement. PMID- 28555153 TI - Dominant Trees in a Subtropical Forest Respond to Drought Mainly via Adjusting Tissue Soluble Sugar and Proline Content. AB - It is well-known that drought has considerable effects on plant traits from leaf to ecosystem scales; however, little is known about the relative contributions of various traits within or between tree species in determining the plant's sensitivity or the tolerance to drought under field conditions. We conducted a field throughfall exclusion experiment to simulate short-term drought (~67% throughfall exclusion during the dry season from October to March) and prolonged drought (~67% throughfall exclusion prolonging the dry season from October to May) and to understand the effects of drought on two dominant tree species (Michelia macclurei and Schima superba) in subtropical forests of southern China. The morphological, physiological, and nutritional responses of the two species to the two types of drought were determined. There were significantly different morphological (leaf max length, max width, leaf mass per area), physiological (leaf proline) and nutritional (P, S, N, K, Ca, Mg) responses by M. macclurei and S. superba to prolonged drought. Comparison between the drought treatments for each species indicated that the trees responded species-specifically to the short term and prolonged drought, with S. superba exhibiting larger plasticity and higher adaption than M. macclurei. M. macclurei responded more sensitively to prolonged drought in terms of morphology, proline content, and nutritional traits and to short-term drought with regard to soluble sugars content. The differential species-specific responses to drought will allow us to estimate the changes in dominant trees in subtropical forests of China that have experienced a decade's worth of annual seasonal drought. PMID- 28555154 TI - Amyloid beta Modification: A Key to the Sporadic Alzheimer's Disease? PMID- 28555155 TI - Review of Factors Related to the Thyroid Cancer Epidemic. AB - Thyroid cancer is the most common endocrine cancer, of which the incidence has dramatically increased worldwide in the past few decades. The reasons for the observed rapid increase still are not fully understood, but evidence suggests that overdiagnosis, with the advancement in detection methods and screening policies, is not the sole driver of the substantial increase of the incidence. However, the effect of environmental/lifestyle factors remains speculative other than that of radiation exposure at a young age. This review tries to give a balanced view of debated factors leading to the thyroid cancer epidemic, to offer some alternatives in understanding the controversies, and to suggest potential directions in the search of modifiable risk factors to help reduce thyroid cancer. PMID- 28555157 TI - Accuracy Evaluation of a Stereolithographic Surgical Template for Dental Implant Insertion Using 3D Superimposition Protocol. AB - THE AIM: of this study was to evaluate the accuracy of a stereolithographic template, with sleeve structure incorporated into the design, for computer-guided dental implant insertion in partially edentulous patients. MATERIALS AND METHODS: Sixty-five implants were placed in twenty-five consecutive patients with a stereolithographic surgical template. After surgery, digital impression was taken and 3D inaccuracy of implants position at entry point, apex, and angle deviation was measured using an inspection tool software. Mann-Whitney U test was used to compare accuracy between maxillary and mandibular surgical guides. A p value < .05 was considered significant. RESULTS: Mean (and standard deviation) of 3D error at the entry point was 0.798 mm (+/-0.52), at the implant apex it was 1.17 mm (+/-0.63), and mean angular deviation was 2.34 (+/-0.85). A statistically significant reduced 3D error was observed at entry point p = .037, at implant apex p = .008, and also in angular deviation p = .030 in mandible when comparing to maxilla. CONCLUSIONS: The surgical template used has proved high accuracy for implant insertion. Within the limitations of the present study, the protocol for comparing a digital file (treatment plan) with postinsertion digital impression may be considered a useful procedure for assessing surgical template accuracy, avoiding radiation exposure, during postoperative CBCT scanning. PMID- 28555158 TI - The Nonradiographic Axial Spondyloarthritis, the Radiographic Axial Spondyloarthritis, and Ankylosing Spondylitis: The Tangled Skein of Rheumatology. AB - Since 1984 the diagnosis of ankylosing spondylitis (AS) has been based upon the modified New York (mNY) criteria with mandatory presence of radiographic sacroiliitis, without which the diagnosis is not tenable. However, it may take years or decades for radiographic sacroiliitis to develop delaying the diagnosis for long periods. It did not matter in the past because no effective treatment was available. However, with the availability of a highly effective treatment, namely, tumour necrosis factor-alpha inhibitors (TNFi), the issue of early diagnosis of AS acquired an urgency. The Assessment of SpondyloArthritis International Society (ASAS) classification criteria published in 2009 was a significant step towards this goal. These criteria described an early stage of the disease where sacroiliitis was demonstrable only on MRI but not on standard radiograph. Therefore, this stage of the disease was labelled "nonradiographic axial SpA" (nr-axSpA). But questions have been raised if, in search of early diagnosis, specificity was compromised. The Federal Drug Administration (FDA, USA) withheld approval for the use of TNFi in patients with nr-axSpA because of issues related to the specificity of these criteria. This review attempts to clarify some of these aspects of the nr-axSpA-AS relationship and also tries to answer the question whether ASAS classifiable radiographic axial spondyloarthritis (r-axSpA) term can be interchangeably used with the term AS. PMID- 28555159 TI - Physiological Uterine Involution in Primiparous and Multiparous Women: Ultrasound Study. AB - PURPOSE: To examine the uterine involution period after uncomplicated delivery in primiparous and multiparous women. METHODS: Longitudinal prospective study. Repeated parameters were measured and endometrial contents and diastolic notch were observed. Measurements of primiparous and multiparous women were carried out after labour on the 1st, 3rd, 10th, 30th, 42nd, and 60th postpartum days. The analysis was performed using SPSS version 21. RESULTS: The median uterus parameters are bigger in multiparous group in physiological puerperium, but the decreasing trend is the same. The endometrial cavity on the 10th day was significantly wider in multiparous women and mainly echo-negative view of the uterine cavity was observed. The evaluation of the uterine angle deviation changes from an extremely retroverted position to a more anteverted position. RI of the uterine artery in both groups was low immediately after labour and significantly increased one month postpartum. Notching of the uterine artery undergoes changes, but diastolic notch does not appear in all postpartum women even after two months following labour. CONCLUSIONS: The puerperium period after normal vaginal delivery depends on parity. The trend of involution in primiparous and multiparous women follows a similar pattern, yet, it lasts longer in the multiparous women. Ultrasound of uterine is certainly a useful tool after labour and may be important in facilitating an early detection of postpartum uterine complications. PMID- 28555160 TI - Boi-ogi-to (TJ-20), a Kampo Formula, Suppresses the Inflammatory Bone Destruction and the Expression of Cytokines in the Synovia of Ankle Joints of Adjuvant Arthritic Rats. AB - TJ-20 is a formula consisting of 6 herbs that has been used in the clinical treatment of rheumatoid arthritis (RA) in China and Japan for centuries. However, scientific evidence of the effects of TJ-20 has not been established. In the present study, we focused on the therapeutic effects and investigated the main function of TJ-20 on adjuvant arthritis (AA), an animal model of RA, which was induced with complete Freund's adjuvant (CFA). TJ-20 was administered orally at 600 mg/kg once a day from 0, 7, and 10 days to 8 weeks after the CFA treatment. TJ-20 significantly ameliorated inflammatory progression and bone destruction in AA in a time-dependent manner. Furthermore, TJ-20 significantly reduced the increased changes in a number of macrophages and helper T cells. Moreover, TJ-20 suppressed the expression of TNF-alpha whereas it augmented the expression of IL 10 and attenuated Th1 cells responses in the synovia of the ankle joint. Therefore, TJ-20 regulated the expression of proinflammatory and anti inflammatory cytokines in macrophages and Th1/Th2 balance in the synovia of ankle joints in AA rats. These results suggest the positive anti-inflammatory effect of TJ-20 and provide a scientific basis for the clinical use of TJ-20 for RA. PMID- 28555161 TI - A Systems Dynamic Model for Drug Abuse and Drug-Related Crime in the Western Cape Province of South Africa. AB - The complex problem of drug abuse and drug-related crimes in communities in the Western Cape province cannot be studied in isolation but through the system they are embedded in. In this paper, a theoretical model to evaluate the syndemic of substance abuse and drug-related crimes within the Western Cape province of South Africa is constructed and explored. The dynamics of drug abuse and drug-related crimes within the Western Cape are simulated using STELLA software. The simulation results are consistent with the data from SACENDU and CrimeStats SA, highlighting the usefulness of such a model in designing and planning interventions to combat substance abuse and its related problems. PMID- 28555156 TI - Improving In Vivo Efficacy of Bioactive Molecules: An Overview of Potentially Antitumor Phytochemicals and Currently Available Lipid-Based Delivery Systems. AB - Cancer is among the leading causes of morbidity and mortality worldwide. Many of the chemotherapeutic agents used in cancer treatment exhibit cell toxicity and display teratogenic effect on nontumor cells. Therefore, the search for alternative compounds which are effective against tumor cells but reduce toxicity against nontumor ones is of great importance in the progress or development of cancer treatments. In this sense, scientific knowledge about relevant aspects of nutrition intimately involved in the development and progression of cancer progresses rapidly. Phytochemicals, considered as bioactive ingredients present in plant products, have shown promising effects as potential therapeutic/preventive agents on cancer in several in vitro and in vivo assays. However, despite their bioactive properties, phytochemicals are still not commonly used in clinical practice due to several reasons, mainly attributed to their poor bioavailability. In this sense, new formulation strategies are proposed as carriers to improve their bioefficacy, highlighting the use of lipid based delivery systems. Here, we review the potential antitumoral activity of the bioactive compounds derived from plants and the current studies carried out in animal and human models. Furthermore, their association with lipids as a formulation strategy to enhance their efficacy in vivo is also reported. The development of high effective bioactive supplements for cancer treatment based on the improvement of their bioavailability goes through this association. PMID- 28555162 TI - Red Yeast Rice Protects Circulating Bone Marrow-Derived Proangiogenic Cells against High-Glucose-Induced Senescence and Oxidative Stress: The Role of Heme Oxygenase-1. AB - The inflammation and oxidative stress of bone marrow-derived proangiogenic cells (PACs), also named endothelial progenitor cells, triggered by hyperglycemia contributes significantly to vascular dysfunction. There is supporting evidence that the consumption of red yeast rice (RYR; Monascus purpureus-fermented rice) reduces the vascular complications of diabetes; however, the underlying mechanism remains unclear. This study aimed to elucidate the effects of RYR extract in PACs, focusing particularly on the role of a potent antioxidative enzyme, heme oxygenase-1 (HO-1). We found that treatment with RYR extract induced nuclear factor erythroid-2-related factor nuclear translocation and HO-1 mRNA and protein levels in PACs. RYR extract inhibited high-glucose-induced (30 mM) PAC senescence and the development of reactive oxygen species (ROS) in a dose-dependent manner. The HO-1 inducer cobalt protoporphyrin IX also decreased high-glucose-induced cell senescence and oxidative stress, whereas the HO-1 enzyme inhibitor zinc protoporphyrin IX and HO-1 small interfering RNA significantly reversed RYR extract-caused inhibition of senescence and reduction of oxidative stress in high glucose-treated PACs. These results suggest that RYR extract serves as alternative and complementary medicine in the treatment of these diseases, by inducing HO-1, thereby decreasing the vascular complications of diabetes. PMID- 28555163 TI - Spontaneous Production of Glutathione-Conjugated Forms of 1,2-Dichloropropane: Comparative Study on Metabolic Activation Processes of Dihaloalkanes Associated with Occupational Cholangiocarcinoma. AB - Recently, epidemiological studies revealed a positive relationship between an outbreak of occupational cholangiocarcinoma and exposure to organic solvents containing 1,2-dichloropropane (1,2-DCP). In 1,2-DCP-administered animal models, we previously found biliary excretion of potentially oncogenic metabolites consisting of glutathione- (GSH-) conjugated forms of 1,2-DCP (GS-DCPs); however, the GS-DCP production pathway remains unknown. To enhance the understanding of 1,2-DCP-related risks to human health, we examined the reactivity of GSH with 1,2 DCP in vitro and compared it to that with dichloromethane (DCM), the other putative substance responsible for occupational cholangiocarcinoma. Our results showed that 1,2-DCP was spontaneously conjugated with GSH, whereas this spontaneous reaction was hardly detected between DCM and GSH. Further analysis revealed that glutathione S-transferase theta 1 (GSTT1) exhibited less effect on the 1,2-DCP reaction as compared with that observed for DCM. Although GSTT1 mediated bioactivation of dihaloalkanes could be a plausible explanation for the production of reactive metabolites related to carcinogenesis based on previous studies, this catalytic pathway might not mainly contribute to 1,2-DCP-related occupational cholangiocarcinoma. Considering the higher catalytic activity of GSTT1 on DCM as compared with that on 1,2-DCP, our findings suggested differences in the activation processes associated with 1,2-DCP and DCM metabolism. PMID- 28555164 TI - Brain Multimodality Monitoring: A New Tool in Neurocritical Care of Comatose Patients. AB - Neurocritical care patients are at risk of developing secondary brain injury from inflammation, ischemia, and edema that follows the primary insult. Recognizing clinical deterioration due to secondary injury is frequently challenging in comatose patients. Multimodality monitoring (MMM) encompasses various tools to monitor cerebral metabolism, perfusion, and oxygenation aimed at detecting these changes to help modify therapies before irreversible injury sets in. These tools include intracranial pressure (ICP) monitors, transcranial Doppler (TCD), HemedexTM (thermal diffusion probe used to measure regional cerebral blood flow), microdialysis catheter (used to measure cerebral metabolism), LicoxTM (probe used to measure regional brain tissue oxygen tension), and continuous electroencephalography. Although further research is needed to demonstrate their impact on improving clinical outcomes, their contribution to illuminate the black box of the brain in comatose patients is indisputable. In this review, we further elaborate on commonly used MMM parameters, tools used to measure them, and the indications for monitoring per current consensus guidelines. PMID- 28555165 TI - Tissue Hypoperfusion, Hypercoagulopathy, and Kidney and Liver Dysfunction after Ingestion of a Naphazoline-Containing Antiseptic. AB - Naphazoline is a peripheral alpha2-adrenergic receptor agonist commonly used as a topical decongestant. In Japan, over-the-counter antiseptics often contain naphazoline to effect local hemostasis. We present the first case involving the development of hypercoagulopathy, with kidney and liver dysfunction, following a naphazoline overdose. A 22-year-old Japanese woman with a history of depression ingested 160 mL of a commercially available antiseptic containing 0.1% naphazoline. Three days later, she was brought to the emergency department because of general fatigue, nausea, and vomiting. Physical examination revealed cool, pale extremities. Laboratory data showed evidence of severe kidney and liver dysfunction (creatinine, 9.2 mg/dL; alanine aminotransferase, 2948 IU/L), hypercoagulation (D-dimers, 58.3 MUg/mL), and thrombocytopenia (platelet count, 90,000/MUL). After infusion of normal saline, intravenous administration of alprostadil, and hemodiafiltration, her organ function completely recovered. Because both the kidney and liver express alpha2-adrenergic receptors, their failure was likely associated with naphazoline overdose-induced hypoperfusion. The most plausible causes of hypercoagulation are peripheral low perfusion and subsequent microthrombus formation. This case illustrates that severe organ dysfunction can occur following over-the-counter antiseptic ingestion and serves as a caution for both drug manufacturers and healthcare professionals. PMID- 28555166 TI - Is It Necessary to Specifically Define the Cause of Surgically Treated Biliary Tract Infections? A Rare Case of Raoultella planticola Cholecystitis and Literature Review. AB - Raoultella planticola is an aquatic and soil organism that does not notoriously cause invasive infections in humans. Infections in the literature are limited only in case reports. We present a very rare case of R. planticola cholecystitis. A 71-year-old female patient with abdominal pain was diagnosed with acute cholecystitis. Patient received intravenous antibiotic treatment, but the treatment failed and the patient underwent an open cholecystectomy. The final pathological result was gangrenous cholecystitis complicated with R. planticola. Eventually, the patient recovered with appropriate antimicrobial therapy. Patients with acute cholecystitis are usually treated without any microbiological sampling and antibiotic treatment is started empirically. To date, there have only been 5 reported biliary system related R. planticola infections in humans. We believe that Raoultella species might be a more frequent agent than usually thought, especially in resistant cholecystitis cases. Resistant strains should be considered as a possible causative organism when the patient's condition worsened despite proper antimicrobial therapy. It should be considered safe to send microbiological samples for culture and specifically define the causative microorganisms even in the setting of a cholecystectomized patient. PMID- 28555167 TI - Impaired Emotion Recognition after Left Hemispheric Stroke: A Case Report and Brief Review of the Literature. AB - Impaired recognition of emotion after stroke can have important implications for social competency, social participation, and consequently quality of life. We describe a case of left hemispheric ischemic stroke with impaired recognition of specifically faces expressing fear. Three months later, the patient's spouse reports that the patient was irritable and slow in communication, which may be caused by the impaired emotion recognition. The case is discussed in relation to the literature concerning emotion recognition and its neural correlates. Our case supports the notion that emotion recognition, including fear recognition, is regulated by a network of interconnected brain regions located in both hemispheres. We conclude that impaired emotion recognition is not uncommon after stroke and can be caused by dysfunction of this emotion-network. PMID- 28555168 TI - A Case of Sevoflurane Use during Pregnancy in the Management of Persistent Status Asthmaticus. AB - BACKGROUND: Sevoflurane is rarely used for the treatment of status asthmaticus. We report a case of sevoflurane hepatotoxicity in pregnancy with presentation similar to HELLP syndrome. CASE: A G2P1001 at 23 weeks in status asthmaticus presented with pCO2 > 130 and pH < 7. She was nonresponsive to traditional therapy. Sevoflurane was added for a 24 hr period. Respiratory status improved. Extubation occurred on day 12. Workup for preeclampsia spectrum disorders occurred due to maternal hypertension. Given the atypical presentation and hepatotoxicity, a liver biopsy was performed. Histologic features suggested drug induced hepatic injury. Liver function subsequently normalized. She delivered a term neonate without short-term complications. CONCLUSION: The use of sevoflurane is a treatment option of status asthmaticus during pregnancy. Providers should be aware of the potential for hepatotoxicity. PMID- 28555170 TI - Chronic Dialysis Dependent Renal Failure Resulting from a Massive Bladder Containing Inguinal Hernia. AB - Bladder involvement in inguinal hernia is relatively rare, 1-4%, although the incidence is increased to 10% with advancing age or obesity. There are several previously reported cases presenting with obstructive uropathy and renal failure, but all reversed with urinary diversion and hernia repair. We believe this to be the first reported case of bladder hernia leading to dialysis dependent chronic renal failure. PMID- 28555169 TI - Strongyloides Colitis as a Harmful Mimicker of Inflammatory Bowel Disease. AB - Autoinfection caused by Strongyloides stercoralis frequently becomes a life-long disease unless it is effectively treated. There is overlapping histomorphology between Strongyloides colitis and inflammatory bowel disease; a low index of suspicion can lead to misdiagnosis and fatal consequences. We present a case of Strongyloides colitis mimicking the clinical and pathologic features of inflammatory bowel disease. A 64-year-old female presented to the emergency department with a four-day history of abdominal pain, diarrhea, and hematochezia. Colonoscopy revealed diffuse inflammation suggestive of inflammatory bowel disease, which led to initiation of 5-aminosalicylic acid and intravenous methylprednisolone. Biopsies of the colon revealed increased lymphoplasmacytic infiltrate of the lamina propria with eosinophilic microabscesses and presence of larvae, consistent with Strongyloides stercoralis. Immunosuppressive medication was halted. The patient ultimately died a few days later. This case emphasizes the importance of identifying the overlapping clinical and pathologic features of Strongyloides colitis and inflammatory bowel disease. A high index of suspicion and recognition of particular histological findings, including eosinophilic microabscesses, aid in the correct diagnosis. Definitive diagnosis is crucial as each disease carries distinct therapeutic implications and outcome. PMID- 28555171 TI - Perforated Duodenal Diverticulum Treated Conservatively: Another Two Successful Cases. AB - Diverticula of the duodenum proceed those of the colon in respect to frequency of location. Incidence at times of autopsy ranges from 15 to 23%. Despite the fact that more than 90% of duodenal diverticulum cases are asymptomatic, complications if they do occur can be calamitous. Perforation is one of these rare complications. Surgical intervention has always been the mainstay for symptomatic/complicated duodenal diverticula, but with the advancement of imaging, medical treatment, and proper intensive observation, conservative treatment came forth. We hereby present two cases of duodenal diverticula, complicated by perforation and fistulization into the retroperitoneal cavity, both treated conservatively by Taylor's approach of upper gastrointestinal tract perforation. Review of other cases of duodenal diverticulum perforation has also been presented. PMID- 28555172 TI - Multimodal laser-based angioscopy for structural, chemical and biological imaging of atherosclerosis. AB - The complex nature of atherosclerosis demands high-resolution approaches to identify subtle thrombogenic lesions and define the risk of plaque rupture. Here, we report the proof-of-concept use of a multimodal scanning fiber endoscope (SFE) consisting of a single optical fiber scanned by a piezoelectric drive that illuminates tissue with red, blue, and green laser beams, and digitally reconstructs images at 30 Hz with high resolution and large fields-of-view. By combining laser-induced reflectance and fluorescence emission of intrinsic fluorescent constituents in arterial tissues, the SFE allowed us to co-generate endoscopic videos with a label-free biochemical map to derive a morphological and spectral classifier capable of discriminating early, intermediate, advanced, and complicated atherosclerotic plaques. We demonstrate the capability of scanning fiber angioscopy for the molecular imaging of vulnerable atherosclerosis by targeting proteolytic activity with a fluorescent probe activated by matrix metalloproteinases. We also show that the SFE generates high-quality spectral images in vivo in an animal model with medium-sized arteries. Multimodal laser based angioscopy could become a platform for the diagnosis, prognosis, and image guided therapy of atherosclerosis. PMID- 28555173 TI - Efficacy and Molecular Mechanisms of Differentiated Response to the Aurora and Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Models of p53-Mutated Triple Negative Breast Cancer. AB - PURPOSE: Triple-negative breast cancer (TNBC) is a subtype associated with poor prognosis and for which there are limited therapeutic options. The purpose of this study was to evaluate the efficacy of ENMD-2076 in p53-mutated TNBC patient derived xenograft (PDX) models and describe patterns of terminal cell fate in models demonstrating sensitivity, intrinsic resistance, and acquired resistance to ENMD-2076. EXPERIMENTAL DESIGN: p53-mutated, TNBC PDX models were treated with ENMD-2076 and evaluated for mechanisms of sensitivity or resistance to treatment. Correlative tissue testing was performed on tumor tissue to assess for markers of proliferation, apoptosis, senescence, and pathways of resistance after treatment and at the time of acquired resistance. RESULTS: Sensitivity to ENMD-2076 200 mg/kg daily was associated with induction of apoptosis while models exhibiting intrinsic or acquired resistance to treatment presented with a senescent phenotype. Response to ENMD-2076 was accompanied by an increase in p53 and p73 levels, even within the background of mutant p53. Treatment with ENMD-2076 resulted in a decrease in pAurA and an increase in pHH3. We observed a TNBC subtype switch from the luminal androgen receptor to the basal-like subtype at acquired resistance. CONCLUSION: ENMD-2076 has antitumor activity in preclinical models of p53-mutated TNBC. Increased levels of p53 and p73 correlated with sensitivity whereas senescence was associated with resistance to ENMD-2076. The novel finding of a TNBC subtype switch at time of acquired resistance may provide mechanistic insights into the biologic effects of selective pressure of anticancer treatments on TNBC. ENMD-2076 is currently being evaluated in a Phase 2 clinical trial in patients with metastatic, previously treated TNBC where these biologic correlates can be further explored. PMID- 28555176 TI - Editorial: ARDS: Reaching for the Horizon. PMID- 28555175 TI - MALDI-TOF MS Profiling-Advances in Species Identification of Pests, Parasites, and Vectors. AB - Invertebrate pests and parasites of humans, animals, and plants continue to cause serious diseases and remain as a high treat to agricultural productivity and storage. The rapid and accurate species identification of the pests and parasites are needed for understanding epidemiology, monitoring outbreaks, and designing control measures. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) profiling has emerged as a rapid, cost effective, and high throughput technique of microbial species identification in modern diagnostic laboratories. The development of soft ionization techniques and the release of commercial pattern matching software platforms has resulted in the exponential growth of applications in higher organisms including parasitology. The present review discusses the proof-of-principle experiments and various methods of MALDI MS profiling in rapid species identification of both laboratory and field isolates of pests, parasites and vectors. PMID- 28555174 TI - The ATP-Dependent Protease ClpP Inhibits Biofilm Formation by Regulating Agr and Cell Wall Hydrolase Sle1 in Staphylococcus aureus. AB - Biofilm causes hospital-associated infections on indwelling medical devices. In Staphylococcus aureus, Biofilm formation is controlled by intricately coordinated network of regulating systems, of which the ATP-dependent protease ClpP shows an inhibitory effect. Here, we demonstrate that the inhibitory effect of ClpP on biofilm formation is through Agr and the cell wall hydrolase Sle1. Biofilm formed by clpP mutant consists of proteins and extracellular DNA (eDNA). The increase of the protein was, at least in part, due to the reduced protease activity of the mutant, which was caused by the decreased activity of agr. On the other hand, the increase of eDNA was due to increased cell lysis caused by the higher level of Sle1. Indeed, as compared with wild type, the clpP mutant excreted an increased level of eDNA, and showed higher sensitivity to Triton-induced autolysis. The deletion of sle1 in the clpP mutant decreased the biofilm formation, the level of eDNA, and the Triton-induced autolysis to wild-type levels. Despite the increased biofilm formation capability, however, the clpP mutant showed significantly reduced virulence in a murine model of subcutaneous foreign body infection, indicating that the increased biofilm formation capability cannot compensate for the intrinsic functions of ClpP during infection. PMID- 28555177 TI - Changes in Frequency and Activation Status of Major CD4+ T-Cell Subsets after Initiation of Immunosuppressive Therapy in a Patient with New Diagnosis Childhood Onset Systemic Lupus Erythematosus. AB - BACKGROUND: Several studies suggest that defects of regulatory T-cells (Tregs) and impaired cellular immunity are secondary to an imbalance between auto aggressive T-cells and Tregs in lupus patients. Discrepancies in Tregs and effector T-cells (Teff) in active lupus patients are shown to be restored in patients upon receiving immunosuppressive therapy. Therefore, our main aim was to observe frequencies of these CD4+ T-cell subsets and Tregs/Teff ratio in a new diagnosis of childhood-onset systemic lupus erythematous (cSLE) before and after initiation of therapy. In addition, we monitored T-cell exhaustion status by examining responses to super-antigen staphylococcal enterotoxin B (SEB) and PD-1 expression in this patient. METHODS: Phenotyping of CD4+ T-cell subsets was carried out under basal conditions and after SEB stimulation using flow cytometry in one inactive (I-cSLE) and one active cSLE (A-cSLE) patient, as well as a healthy control (HC). The A-cSLE patient was a new diagnosis. Variables were measured at three consecutive time points in the active patient, reflecting various stages of disease activity. Activation status of CD4+ T-cells in the A cSLE patient was compared to that of the I-cSLE patient and HC. Disease activity was measured by calculating the systemic lupus erythematous disease activity index. RESULTS: We found that the A-cSLE patient was not Tregs deficient. The patient had increased frequency of Tregs, and the Tregs/Teff ratio increased when the disease activity became less severe. CD4+ T-cells in the I-cSLE patient and in the A-cSLE patient with milder disease activity had heightened responsiveness to SEB, whereas T-cells were relatively hypo-responsive to SEB in the A-cSLE patient when disease activity was higher. The active patient exhibited higher frequencies of PD-1+ expressing Tregs, Teff, and Tnaive/mem cells under basal conditions compared to the HC and I-cSLE patient. CONCLUSION: In the A-cSLE patient, changes in Tregs/Teff ratio correlated better with clinical improvement compared to Tregs frequencies alone and might reflect the restoration of immune homeostasis with therapy. SEB hypo-responsiveness in the A-cSLE patient when disease activity was higher paralleled with findings of greater frequencies of PD 1+ expressing Tregs, Teff, and Tnaive/mem cells, suggests a possible global exhaustion status of CD4+ T-cells in this patient. PMID- 28555179 TI - The Management of Cyanotic Spells in Children with Oesophageal Atresia. AB - Cyanotic spells, also known as blue spells, dying spells, or apparent life threatening events, refer to a bluish tone visible in the mucosal membranes and skin caused by an oxygen decrease in the peripheral circulation. Although this decrease may be transient and benign, it may also be indicative of a severe underlying problem that requires immediate intervention. Children with oesophageal atresia (OA) are at risk for a number of coexisting conditions that may trigger cyanotic spells. This current article will focus on the management of cyanotic spells both in children with innominate artery compression and those with tracheomalacia. PMID- 28555180 TI - Risk Factors for Neurocognitive Functioning in Children with Autosomal Recessive Polycystic Kidney Disease. AB - This mini review provides an overview of the issues and challenges inherent in autosomal recessive polycystic kidney disease (ARPKD), with a particular focus on the neurological factors and neurocognitive functioning of this population. ARPKD typically is discovered at the end of pregnancy or during the neonatal developmental period and occurs in approximately 1 in 20,000 live births. During the neonatal period, there is a relatively high risk of death, with many infants dying from respiratory failure. As the child ages, they experience progressive kidney disease and become increasingly vulnerable to liver disease, with many individuals eventually requiring dual organ transplants. This mini review provides a brief description of ARPKD and describes the various factors that place children with ARPKD at risk for neurological and neuropsychological impairment (e.g., a genetic condition leading to chronic kidney disease and eventual transplant; difficult-to-treat hypertension; eventual liver disease; possible dual transplantation of the kidneys and liver; chronic lung disease), including that these factors are present during a critical period of brain development. Further, the mini review discusses the available studies that have addressed the neurocognitive functioning in children with ARPKD. This paper concludes by providing the key clinical and research challenges that face the field of pediatric nephrology with respect to the clinical and scientific study of the neurocognitive functioning of children with ARPKD. Selected directions are offered in both the clinical and research arenas for this multiorgan chronic condition. PMID- 28555178 TI - Central Nervous System Complications in Children Receiving Chemotherapy or Hematopoietic Stem Cell Transplantation. AB - Therapy-related neurotoxicity greatly affects possibility of survival and quality of life of pediatric patients treated for cancer. Central nervous system (CNS) involvement is heterogeneous, varying from very mild and transient symptoms to extremely severe and debilitating, or even lethal syndromes. In this review, we will discuss the broad scenario of CNS complications and toxicities occurring during the treatment of pediatric patients receiving both chemotherapies and hematopoietic stem cell transplantation. Different types of complications are reviewed ranging from therapy related to cerebrovascular with a specific focus on neuroradiologic and clinical features. PMID- 28555181 TI - Fundoplication in Patients with Esophageal Atresia: Patient Selection, Indications, and Outcomes. AB - Patients with esophageal atresia (EA) suffer from abnormal and permanent esophageal intrinsic and extrinsic innervation that affects severely esophageal motility. The repair of EA also results in esophageal shortening that affects distal esophageal sphincter mechanism. Consequently, gastroesophageal reflux (GER) is common in these patients, overall approximately half of them suffer from symptomatic reflux. GER in EA patients often resists medical therapy and anti reflux surgery in the form of fundoplication is required. In patients with pure and long gap EA, the barrier mechanisms against reflux are even more damaged, therefore, most of these patients undergo fundoplication during first year of life. Other indications for anti-reflux surgery include recalcitrant anastomotic stenoses and apparent life-threatening episodes. In short term, fundoplication alleviates symptoms in most patients but recurrences are common occurring in at least one third of the patients. Patients with fundoplication wrap failure often require redo surgery, which may be complicated and associated with significant morbidity. A safe option in a subset of patients with failed anti-reflux surgery appears to be long-term medical treatment with proton pump inhibitors. PMID- 28555182 TI - Improving Neonatal Care with Technology. PMID- 28555183 TI - The Road to Dog Rabies Control and Elimination-What Keeps Us from Moving Faster? AB - Rabies, a vaccine preventable neglected tropical disease, still claims an estimated 35,000-60,000 human lives annually. The international community, with more than 100 endemic countries, has set a global target of 0 human deaths from dog-transmitted rabies by 2030. While it has been proven in several countries and regions that elimination of rabies as a public health problem is feasible and tools are available, rabies deaths globally have not yet been prevented effectively. While there has been extensive rabies research, specific areas of implementation for control and elimination have not been sufficiently addressed. This article highlights some of the commonest perceived barriers for countries to implementing rabies control and elimination programs and discusses possible solutions for sociopolitical, organizational, technical, and resource-linked requirements, following the pillars of the global framework for the elimination of dog-mediated human rabies adopted at the global rabies meeting in December 2015. PMID- 28555184 TI - Exploring Community Stakeholders' Perceptions of the Enhancing Family Well-being Project in Hong Kong: A Qualitative Study. AB - BACKGROUND: Community engagement is a powerful tool in bringing about positive social and community change. Community stakeholders possess critical experience and knowledge that are needed to inform the development of community-based projects. However, limited literature is available on the practical experience involved with planning and implementing community-based family programs. Even less has been published documenting efforts in Chinese communities. This paper explores community stakeholders' experiences with the enhancing family well-being project-part of a citywide project entitled the "FAMILY Project," aimed at promoting family health, happiness, and harmony in Hong Kong. METHODS: This qualitative evaluation examined the perspectives of community stakeholders. Four focus groups with social workers (n = 24) and six in-depth interviews with steering committee members were conducted from December 2012 to May 2013 in Hong Kong. Focus groups and in-depths interview were audiotaped, transcribed, and analyzed using thematic analysis techniques. RESULTS: Rich accounts were given by our respondents on various aspects of the project. Main themes and subthemes were identified and grouped into four categories (project conception, project implementation, project consolidation, and the overall impact of the project). Respondents described the practical challenges associated with the project (e.g., recruitment, balancing scientific research, and lack of resources) and identified the elements that are important to the success of the project. These included the commitment to a shared goal, multi-agency collaboration, and a platform for knowledge exchange. Finally, respondents perceived benefits of the project at both the individual and community level. CONCLUSION: Our project sheds light on many of the practical considerations and challenges associated with a designing and implementing a community-based family intervention project. Community stakeholders input provided important information on their perceived benefits and barriers and can inform and improve future development of community-based family intervention programs. PMID- 28555185 TI - Molecular Determinants of Cephalopod Muscles and Their Implication in Muscle Regeneration. AB - The ability to regenerate whole-body structures has been studied for many decades and is of particular interest for stem cell research due to its therapeutic potential. Several vertebrate and invertebrate species have been used as model systems to study pathways involved in regeneration in the past. Among invertebrates, cephalopods are considered as highly evolved organisms, which exhibit elaborate behavioral characteristics when compared to other mollusks including active predation, extraordinary manipulation, and learning abilities. These are enabled by a complex nervous system and a number of adaptations of their body plan, which were acquired over evolutionary time. Some of these novel features show similarities to structures present in vertebrates and seem to have evolved through a convergent evolutionary process. Octopus vulgaris (the common octopus) is a representative of modern cephalopods and is characterized by a sophisticated motor and sensory system as well as highly developed cognitive capabilities. Due to its phylogenetic position and its high regenerative power the octopus has become of increasing interest for studies on regenerative processes. In this paper we provide an overview over the current knowledge of cephalopod muscle types and structures and present a possible link between these characteristics and their high regenerative potential. This may help identify conserved molecular pathways underlying regeneration in invertebrate and vertebrate animal species as well as discover new leads for targeted tissue treatments in humans. PMID- 28555186 TI - Structural Equation Modeling of the Effects of Family, Preschool, and Stunting on the Cognitive Development of School Children. AB - A recent study based on a sample of 1,580 children from five adjacent geographical locations in KwaZulu-Natal, South Africa, was carried out to examine the association of nutrition, family influence, preschool education, and disadvantages in geographical location with the cognitive development of school children. Data were collected on the children from 2009 to 2011 for this developmental study and included cognitive scores and information on the health and nutrition of the children. The current study analyzed the association of demographic variables (geographical location (site)), child variables (sex, preschool education and socioeconomic status), parental level of education (maternal and paternal), child's health (HIV status and hemoglobin level) and anthropometric measures of nutritional status (height-for-age) with children's cognitive outcomes. The hypothesis is that the nutritional status of children is a pathway through which the indirect effects of the variables of interest exert influence on their cognitive outcomes. Factor analysis based on principal components was used to create a variable based on the cognitive measures, correlations were used to examine the bivariate association between the variables of interest in the preliminary analysis and a path analysis was constructed, which was used for the disaggregation of the direct and indirect effects of the predictors for each cognitive test in a structural equation model. The results revealed that nutritional status directly predicts cognitive test scores and is a path through which other variables indirectly influence children's cognitive outcome and development. PMID- 28555187 TI - Why Do Parotid Pleomorphic Adenomas Recur? A Systematic Review of Pathological and Surgical Variables. AB - BACKGROUND: The recurrence of pleomorphic adenoma (PA) has been extensively debated, mostly in relation to the extent of parotidectomy. METHODS: A systematic review was undertaken to clarify the surgical and pathological variables related to PA recurrence. Inclusion criteria were as follows: English literature, and prospective or retrospective studies. Exclusion criteria were as follows: single case reports, reviews, and lack of PA recurrence data. RESULTS: Pathology-related variables associated with recurrence include the histological subtype, the thickness and incompleteness of the tumor capsule, pseudopodia, and satellite nodules. Surgery-related variables associated with recurrence are the presence of intact margins and tumor puncture or spillage. Other factors are the size of the tumor and the age of patient. Myxoid subtypes of PA tend to have incomplete and thinner capsules and to recur more frequently. Surgical variables related to recurrence include positive margins and tumor spillage. CONCLUSION: Myxoid and/or large PA, especially in young patients, should be approached more cautiously to avoid recurrences. PMID- 28555188 TI - Educational Health Disparities in Cardiovascular Disease Risk Factors: Findings from Jamaica Health and Lifestyle Survey 2007-2008. AB - OBJECTIVES: Socioeconomic disparities in health have emerged as an important area in public health, but studies from Afro-Caribbean populations are uncommon. In this study, we report on educational health disparities in cardiovascular disease (CVD) risk factors (hypertension, diabetes mellitus, hypercholesterolemia, and obesity), among Jamaican adults. METHODS: We analyzed data from the Jamaica Health and Lifestyle Survey 2007-2008. Trained research staff administered questionnaires and obtained measurements of blood pressure, anthropometrics, glucose and cholesterol. CVD risk factors were defined by internationally accepted cut-points. Educational level was classified as primary or lower, junior secondary, full secondary, and post-secondary. Educational disparities were assessed using age-adjusted or age-specific prevalence ratios and prevalence differences obtained from Poisson regression models. Post-secondary education was used as the reference category for all comparisons. Analyses were weighted for complex survey design to yield nationally representative estimates. RESULTS: The sample included 678 men and 1,553 women with mean age of 39.4 years. The effect of education on CVD risk factors differed between men and women and by age group among women. Age-adjusted prevalence of diabetes mellitus was higher among men with less education, with prevalence differences ranging from 6.9 to 7.4 percentage points (p < 0.05 for each group). Prevalence ratios for diabetes among men ranged from 3.3 to 3.5 but were not statistically significant. Age-specific prevalence of hypertension was generally higher among the less educated women, with statistically significant prevalence differences ranging from 6.0 to 45.6 percentage points and prevalence ratios ranging from 2.5 to 4.3. Similarly, estimates for obesity and hypercholesterolemia suggested that prevalence was higher among the less educated younger women (25-39 years) and among more educated older women (40-59 and 60-74 years). There were no statistically significant associations for diabetes among women, or for hypertension, high cholesterol, or obesity among men. CONCLUSION: Educational health disparities were demonstrated for diabetes mellitus among men, and for obesity, hypertension, and hypercholesterolemia among women in Jamaica. Prevalence of diabetes was higher among less educated men, while among younger women the prevalence of hypertension, hypercholesterolemia, and obesity was higher among those with less education. PMID- 28555189 TI - Trigeminal Nerve Root Demyelination Not Seen in Six Horses Diagnosed with Trigeminal-Mediated Headshaking. AB - Trigeminal-mediated headshaking is an idiopathic neuropathic facial pain syndrome in horses. There are clinical similarities to trigeminal neuralgia, a neuropathic facial pain syndrome in man, which is usually caused by demyelination of trigeminal sensory fibers within either the nerve root or, less commonly, the brainstem. Our hypothesis was that the neuropathological substrate of headshaking in horses is similar to that of trigeminal neuralgia in man. Trigeminal nerves, nerve roots, ganglia, infraorbital, and caudal nasal nerves from horse abattoir specimens and from horses euthanized due to trigeminal-mediated headshaking were removed, fixed, and processed for histological assessment by a veterinary pathologist and a neuropathologist with particular experience of trigeminal neuralgia histology. No histological differences were detected between samples from horses with headshaking and those from normal horses. These results suggest that trigeminal-mediated headshaking may have a different pathological substrate from trigeminal neuralgia in man. PMID- 28555190 TI - Evolution of the Apicomplexan Sugar Transporter Gene Family Repertoire. AB - Apicomplexan protist parasites utilize host sugars transported into the parasite by sugar transporter proteins for use as an energy source. We performed a phylum wide phylogenetic analysis of the apicomplexan sugar transporter repertoire. Phylogenetic analyses revealed six major subfamilies of apicomplexan sugar transporters. Transporters in one subfamily have undergone expansions in Piroplasma species and Gregarina niphandrodes, while other subfamilies are highly divergent and contain genes found in only one or two species. Analyses of the divergent apicomplexan subfamilies revealed their presence in ciliates, indicating their alveolate ancestry and subsequent loss in chromerids and many apicomplexans. PMID- 28555191 TI - Percutaneous Mechanical Thrombectomy Using Rotarex(r) S Device in Acute Limb Ischemia in Infrainguinal Occlusions. AB - PURPOSE: To evaluate the effectiveness of percutaneous mechanical thrombectomy using Rotarex S in the treatment of acute limb ischemia (ALI) in infrainguinal occlusions in a retrospective study of patients treated in our institution. METHODS: In this study, we identified a total of 147 ALI patients that underwent mechanical thrombectomy using Rotarex S at our institution. In 82% of the cases, percutaneous thrombectomy was used as first-line treatment, and for the remainder of the cases, it was used as bailout after ineffective aspiration or thrombolysis. Additional fibrinolysis and adjunctive aspirational thrombectomy were utilized for outflow occlusion when required. Procedural outcomes, amputation rate, and mortality at 30 days were evaluated. RESULTS: Of the 147 patients treated with mechanical thrombectomy, Rotarex S was used as first-line treatment in 120 cases and as second-line treatment in 27 cases. Overall, we achieved 90.5% procedural revascularization success rate when combining mechanical thrombectomy with limited thrombolysis for severe outflow obstruction, and 1 death and 3 amputations were observed. We achieved primary success in 68.7% of the patients with the mechanical thrombectomy only, and in 21.8% of the patients, we successfully used additional limited thrombolysis in the outflow. The overall mortality was 0.7% and amputation rate was 2% at 30 days. CONCLUSION: Percutaneous mechanical thrombectomy as first-line mini-invasive treatment in infrainguinal ALI is safe, quick, and effective, and the performance outcomes can be superior to that of traditional surgical embolectomy. PMID- 28555192 TI - The Use of Xanthan Gum as Vaccine Adjuvant: An Evaluation of Immunostimulatory Potential in BALB/c Mice and Cytotoxicity In Vitro. AB - The successful production of new, safe, and effective vaccines that generate immunological memory is directly related to adjuvant feature, which is responsible for increasing and/or modulating the immune response. Several compounds display adjuvant activity, including carbohydrates. These compounds play important roles in the immune response, as well as having biocompatible properties in vaccine formulations. One such carbohydrate is xanthan gum, a polysaccharide that is produced by the plant-pathogenic bacterium Xanthomonas spp., which has adjuvant attributes. This study evaluated the immune response induced by xanthan gum associated with ovalbumin in BALB/c mice, which were subcutaneously immunized, in terms of antibody production (IgG1, IgG2a, IgG2b, and IgG3), and assessed the levels of IFN-gamma in the splenocyte culture using indirect ELISA. Furthermore, we investigated in vitro cytotoxicity of xanthan in the embryo fibroblasts cell line of the NIH/3T3 mouse by MTT assay and propidium iodide uptake assay. The mice immunized with ovalbumin plus xanthan gum exhibited higher antibody IgG1 responses than control groups. Furthermore, the xanthan polysaccharide was capable of increasing the immunogenicity of antigens by producing IFN-gamma and did not exhibit cytotoxicity effects in NIH/3T3 mouse fibroblast cells, considered a promising candidate for vaccine adjuvant. PMID- 28555193 TI - Helicobacter pylori from Peptic Ulcer Patients in Uganda Is Highly Resistant to Clarithromycin and Fluoroquinolones: Results of the GenoType HelicoDR Test Directly Applied on Stool. AB - BACKGROUND: Around 70-90% of peptic ulcer disease (PUD) is due to Helicobacter pylori and requires treatment with antimicrobials to which these bacteria are susceptible. Common H. pylori diagnostic tests do not provide drug susceptibility data. Using the GenoType HelicoDR PCR test designed for gastric biopsies for simultaneous detection of H. pylori and its resistance to clarithromycin (CLA)/fluoroquinolones (FLQ), we present evidence for stool as an optional test specimen and also provide data on prevalence of H. pylori resistance to CLA and FLQ in Uganda. METHODS: Stool from 142 symptomatic PUD patients at three hospitals in Kampala was screened for H. pylori using a rapid antigen test. The GenoType HelicoDR test was run on all H. pylori antigen positives to determine PCR positivity and resistance to CLA/FLQ. RESULTS: Thirty-one samples (22%) were H. pylori antigen positive, and 21 (68%) of these were H. pylori PCR positive. Six of the 21 (29%) were resistant to CLA and eight to FLQ (42%), while two gave invalid FLQ resistance results. CONCLUSION: Stool is a possible specimen for the GenoType HelicoDR test for rapid detection of H. pylori and drug resistance. In Uganda, Helicobacter pylori is highly resistant to CLA and FLQ. PMID- 28555194 TI - The Effects of Formaldehyde on Cytochrome P450 Isoform Activity in Rats. AB - Formaldehyde (FA) is an occupational and indoor pollutant. Long-term exposure to FA can irritate the respiratory mucosa, with potential carcinogenic effects on the airways. The effects of acute FA poisoning on the activities of CYP450 isoforms CYP1A2, CYP2C11, CYP2E1, and CYP3A2 were assessed by determining changes in the pharmacokinetic parameters of the probe drugs phenacetin, tolbutamide, chlorzoxazone, and testosterone, respectively. Rats were randomly divided into three groups: control, low FA dose (exposure to 110 ppm for 2 h for 3 days), and high FA dose (exposure to 220 ppm for 2 h for 3 days). A mixture of the four probe drugs was injected into rats and blood samples were taken at a series of time points. Plasma concentrations of the probe drugs were measured by HPLC. The pharmacokinetic parameters t1/2, AUC(0-t), and Cmax of tolbutamide, chlorzoxazone, and testosterone increased significantly in the high dose versus control group (P < 0.05), whereas the CL of chlorzoxazone and testosterone decreased significantly (P < 0.05). However, t1/2, AUC(0-t), and Cmax of phenacetin decreased significantly (P < 0.05), whereas the CL of phenacetin increased significantly (P < 0.05) compared to controls. Thus, acute FA poisoning suppressed the activities of CYP2C11, CYP2E1, and CYP3A2 and induced the activity of CYP1A2 in rats. And the change of CYP450 activity caused by acute FA poisoning may be associated with FA potential carcinogenic effects on the airways. PMID- 28555195 TI - Resolving the Taxonomic Status of Chamelea gallina and C. striatula (Veneridae, Bivalvia): A Combined Molecular Cytogenetic and Phylogenetic Approach. AB - The striped venus clams Chamelea gallina and C. striatula are commercially important bivalves inhabiting European and North African coastal waters. The taxonomic status of these taxa has been the subject of debate for decades. In order to elucidate this issue, we generated 5S and 28S ribosomal RNA and H3 histone gene probes and mapped them by fluorescent in situ hybridization to the chromosomes of morphologically identified striped venus clams, collected from four geographically distant Atlantic and Mediterranean populations. The nucleotide variation at the three DNA markers, that is, the nuclear internal transcribed spacer 2 (ITS2), the mitochondrial cytochrome c oxidase subunit I (COI), and the large ribosomal subunit rRNA (16S) fragments, was also studied and the resultant phylogenetic trees were evaluated. Striking differences in both the chromosome distribution of these genes and the clustering of the samples on the phylogenetic trees observed provide clear evidence that C. gallina and C. striatula are separated species. PMID- 28555196 TI - Exogenous Expressions of FTO Wild-Type and R316Q Mutant Proteins Caused an Increase in HNRPK Levels in 3T3-L1 Cells as Demonstrated by DIGE Analysis. AB - Fat mass and obesity-associated protein is an enzyme that oxidatively demethylates DNA. Although there are numerous studies regarding the catalytic function of FTO, the overall existence or absence of FTO on cellular proteome has not been investigated. This study investigated the changes in the soluble proteome of 3T3-L1 cells upon expression of the WT and the mutant (R316Q) FTO proteins. Protein extracts prepared from 3T3-L1 cells expressing either the WT or the mutant FTO proteins were used in DIGE experiments. Analysis of the data revealed the number of spots matched to every member and there were 350 +/- 20 spots with 30.5% overall mean coefficient of variation. Eleven regulated protein spots were excised from the gels and identified by MALDI-TOF/TOF. One of the identified proteins was heterogeneous nuclear ribonucleoprotein K, which displayed more than 2.6- and 3.7-fold increases in its abundance in the WT and the mutant FTO expressing cells, respectively. Western blot analysis validated these observations. This is the first study revealing the presence of a parallel increase in expressions of FTO and HNRNPK proteins. This increase may codictate the metabolic changes occurring in the cell and may attribute a significance to HNRNPK in FTO-associated transformations. PMID- 28555197 TI - Effect of Body Mass Index on Posttonsillectomy Hemorrhage. AB - OBJECTIVE: Obesity affects adverse outcomes in patients undergoing various surgeries. Tonsillectomy is one of the most common surgical procedures and posttonsillectomy hemorrhage (PTH) is the major complication in patients with tonsillectomy. However, the effect of body mass index (BMI) on posttonsillectomy bleeding episodes is not well known. This study aimed to assess the clinical association between obesity and PTH. METHODS: A total of 98 tonsillectomies were retrospectively reviewed. Patient charts were analyzed regarding demographic data and the indication for surgery. Patients with PTH were compared with uneventful cases. Patients were divided into three groups based on BMI: normal weight (BMI < 25 kg/m2), overweight (BMI >= 25 and <30 kg/m2), and obese (>=30 kg/m2). RESULTS: PTH occurred in 13% of patients with normal weight, in 23.5% of patients with overweight, and in 50% patients with obesity. The occurrence of PTH was significantly higher in patients with obesity than in those with normal weight and overweight (p = 0.008). Multivariate analysis showed that obesity was a significant factor affecting the incidence of PTH after adjusting for confounding factors. CONCLUSIONS: Our findings suggest that the obese condition is independently associated with the incidence of PTH. PMID- 28555198 TI - Reductions in Resting Blood Pressure in Young Adults When Isometric Exercise Is Performed Whilst Walking. AB - Aerobic and isometric training have been shown to reduce resting blood pressure, but simultaneous aerobic and isometric training have not been studied. The purpose of this study was to compare the changes in resting systolic (SBP), diastolic (DBP), and mean arterial blood pressure (MAP) after 6 weeks of either (i) simultaneous walking and isometric handgrip exercise (WHG), (ii) walking (WLK), (iii) isometric handgrip exercise (IHG), or control (CON). Forty-eight healthy sedentary participants (age 20.7 +/- 1.7 yrs, mass 67.2 +/- 10.2 kg, height 176.7 +/- 1.2 cm, male n = 26, and female n = 22) were randomly allocated, to one of four groups (n = 12 in each). Training was performed 4 * week-1 and involved either treadmill walking for 30 minutes (WLK), handgrip exercise 3 * 10 s at 20% MVC (IHG), or both performed simultaneously (WHG). Resting SBP, DBP, and MAP were recorded at rest, before and after the 6-week study period. Reductions in resting blood pressure were significantly greater in the simultaneous walking and handgrip group than any other group. These results show that simultaneous walking and handgrip training may have summative effects on reductions in resting blood pressure. PMID- 28555199 TI - Multidisciplinary approach for replacement ?root resorption following severe intrusive luxation: ?A case report of decoronation. AB - Intrusive luxation is a severe trauma-related event with a high frequency of pulp necrosis and root resorption. A common complication following intrusion is tooth ankylosis, which can extend to progressive replacement root resorption. An increasing infraposition in growing individuals can also occur. Decoronation is a new conservative treatment for cases of tooth ankylosis in young patients who have not finished growing. In this surgical technique, the tooth crown is removed and the root with replacement resorption process remains inside the alveolus. This treatment allows the alveolar bone to continue to develop, thus preserving bone dimensions. The purpose of this article is to report a multidisciplinary case of a young patient with anterior open bite, dental ankylosis, and tooth infraposition affected by intrusive luxation. Decoronation was the treatment of choice for this patient. The patient was then referred to orthodontic treatment to maintain the space of the maxillary right central incisor and open bite correction. After 5 years of follow-up, good clinical and radiologic results were obtained. PMID- 28555200 TI - Chlorhexidine mouthwash as an anticaries agent: ?A systematic review. AB - OBJECTIVE: To evaluate the effectiveness of chlorhexidine mouthwashes on the reduction of cariogenic bacteria on patients with moderate to high risk for dental caries. DATA SOURCES: A systematic review of the literature was performed using Cochrane Library, Embase, PubMed, Scopus and Web of Science. The search was limited to articles in English, Spanish, and Portuguese, published until January 2017. The research question was formulated following the PICO strategy. The risk of bias was evaluated using the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. CONCLUSION: All the authors found statistically significant differences in Streptococcus mutans levels during and after the use of a chlorhexidine mouthwash. Although the results are suggestive, there is a clear need for the development of new studies with higher quality and with longer follow-ups, in order to assess whether the results translate into less development of dental caries and, consequently, whether or not these products should be incorporated into prevention protocols. PMID- 28555201 TI - Reconstruction of horizontovertical alveolar defects. Presentation of a novel split-thickness flap design ?for guided bone regeneration: ?A case report with 5 year follow-up. AB - OBJECTIVE: To introduce a novel split-thickness flap design without periosteal and vertical releasing incisions for horizontovertical ridge augmentation. METHOD AND MATERIALS: Three patients with generalized chronic periodontitis presented posterior partial edentulism with class C alveolar defects according to the horizontal, vertical, and combination (HVC) classification. In all three cases, implant placement and simultaneous horizontovertical ridge augmentation utilizing a novel split-thickness flap design was performed. Hard tissue reconstruction was followed by additional soft tissue grafting at membrane removal if optimal peri implant soft tissue stability could not be ensured. Following abutment connection, fixed implant-retained partial dentures were fabricated. RESULTS: The healing procedure after surgeries was uneventful in all cases, without any serious local or systemic adverse events. After 9 months of healing, complete pocket resolution without gingival recession was observed at neighboring teeth with periodontal attachment loss. A comparison of the mean bone to implant/screw contact at first surgery and at membrane removal demonstrated a mean crestal bone regeneration of 3.08 +/- 1.25 mm. At 12 months after prosthetic loading, signs of positive bone remodeling and crestal bone maintenance were shown on intraoral radiographs in all cases. Radiographic results showed maintained alveolar crest contours during 60 months of follow-up in all three cases. CONCLUSION: The clinical and radiographic observations of the three presented cases demonstrate that the guided bone regeneration technique utilizing titanium membranes in combination with autologous and xenogeneic grafting materials applied with the presented split-thickness flap resulted in predictable three-dimensional reconstruction of hard tissues. PMID- 28555202 TI - Editorial: The scientific plague affecting medical and dental research: from fake news to fake studies. PMID- 28555203 TI - The effectiveness of systemic antibiotic prophylaxis in preventing local complications after tooth extraction. A systematic review. AB - PURPOSE: To assess the beneficial or harmful effects of systemic prophylactic antibiotics at extraction of teeth, apart from third molars, vs no antibiotic or placebo administration. Furthermore, if antibiotics are beneficial, to determine which type, dosage, duration and timing of administration is the most effective. MATERIALS AND METHODS: The Cochrane Oral Health Group's Trials Register (to 30 January 2016) and MEDLINE (1 January 1950 to 30 January 2016) were searched. There were no language or date restrictions placed on the searches of the electronic databases. Randomised controlled trials (RCTs) of parallel group design, with a follow-up of at least 2 weeks, comparing the administration of various prophylactic antibiotic regimens vs no antibiotics to people undergoing extraction of teeth, not including third molars, were included. Outcome measures were postoperative complications/adverse events, post-operative pain and swelling. Screening of eligible studies, assessment of the risk of bias of the trials and data extraction were conducted in triplicate by three independent review authors. Results were to be expressed as risk ratios (RRs) using a random effects model for dichotomous outcomes, with 95% confidence intervals (CIs). Heterogeneity, including both clinical and methodological factors, was to be investigated. RESULTS: No relevant RCT was identified. CONCLUSIONS: There is no RCT to determine if the antibiotic therapy is needed at extraction of teeth, excluding third molars. Properly designed and conducted RCTs are needed to understand the role of the antibiotic therapy for tooth extraction. Conflict-of interest statement: This systematic review was self-funded and the authors have no conflict of interests to declare. PMID- 28555204 TI - Immediate loading of two (fixed-on-2) vs four (fixed-on-4) implants placed with a flapless technique supporting mandibular cross-arch fixed prostheses: 3-year results from a pilot randomised controlled trial. AB - PURPOSE: To evaluate the outcome of two vs four implants placed flapless in fully edentulous mandibles and immediately restored with metal-resin screw-retained cross-arch prostheses. MATERIALS AND METHODS: A total of 60 patients from two different centres were randomised: 30 to the fixed-on-2 group and 30 to the fixed on-4 group according to a parallel group design. To be immediately loaded implants had to be inserted with a minimum torque of 40 Newton/cm (Ncm). Outcome measures were prosthesis and implant failures, complications, and marginal bone level changes. RESULTS: Flaps were raised in 18 patients. Two implants in two patients did not reach the planned insertion torque and were replaced immediately by larger diameter ones. Three years after loading, two patients dropped out from the fixed-on-2 group and one from the fixed-on-4 group. No implant failure or prosthetic failure occurred. A total of 12 fixed-on-2 patients were affected by one complication each vs 13 fixed-on-4 patients. There were no statistically significant differences for complications between groups (difference in proportion = -0.03; 95% CI -29 to 0.22; P [Fisher's exact test] =1.000). There were no statistically significant differences for marginal peri-implant bone loss between the two groups (mean difference = 0.14; CI 95% -0.17 to 0.45; P [ANCOVA] = 0.356), with both groups losing marginal bone in a statistically significant way (1.70 mm for fixed-on-2 implants and 1.56 mm for fixed-on-4 implants). There were statistically significant differences between the two centres, with more bone being lost for the Bologna centre (2.18 vs 1.13 mm; P (ANCOVA) < 0.001). CONCLUSIONS: Up to 3 years after loading, these preliminary results suggest that immediately loaded mandibular cross-arch fixed prostheses can be supported by only two dental implants. Longer follow-ups (about 10 years) are needed to properly evaluate this therapeutic option. Conflict of interest statement: This study was completely self-financed and no funding from the implant manufacturers has been sought or obtained, not even in the form of free materials. PMID- 28555205 TI - Conventional drills vs piezoelectric surgery preparation for placement of four immediately loaded zygomatic oncology implants in edentulous maxillae: results from 1-year split-mouth randomised controlled trial. AB - PURPOSE: To compare the outcome of site preparation for zygomatic oncology implants using conventional preparation with rotary drills or piezoelectric surgery with dedicated inserts for placing two zygomatic implants per zygoma according to a split-mouth design. MATERIALS AND METHODS: Twenty edentulous patients with severely atrophic maxillas not having sufficient bone volume for placing dental implants and less than 4 mm of bone height subantrally had their hemi-maxillas randomised according to a split-mouth design into implant site preparation with conventional rotational drills or piezoelectric surgery. Two zygomatic oncology implants (unthreaded coronal portion) were placed in each hemi maxilla. Implants that achieved an insertion torque superior to 40 Ncm were immediately loaded with screw-retained metal reinforced acrylic provisional prostheses. Outcome measures were: prosthesis and implant failures, any complications, time to place the implants, presence of post-operative haematoma, and patient's preference by independent assessors. All patients were followed up to 1 year after loading. RESULTS: In two patients drills had also to be used at the piezoelectric surgery side to enable implant sites to be prepared. One implant for the conventional drill group did not achieve an insertion torque superior to 40 Ncm since it fractured the zygoma. No patients dropped out and two distal oncology implants failed in the same patient (one per group), who was not prosthetically rehabilitated. Six complications occurred at drilled sites and three at piezoelectric surgery sites (two patients had bilateral complications), the difference being not statistically significant (P (McNemar's test) = 0.375; odds ratio = 4.00; 95% CI of odds ratio: 0.45 to 35.79). Implant placement with convention drills took on average 14.35 +/- 1.76 min and with piezoelectric surgery 23.50 +/- 2.26 min, implant placement time being significantly shorter with conventional drilling (difference = 9.15 +/- 1.69 min; 95%CI: 8.36 to 9.94 min; P < 0.001). Post-operative haematomas were more frequent at drilled sites (P = 0.001), and 16 patients found both techniques equally acceptable, while four preferred piezoelectric surgery (P = 0.125). CONCLUSIONS: Both drilling techniques achieved similar clinical results, but conventional drilling required 9 min less and could be used in all instances, although it was more aggressive. These results may be system-dependent, therefore they cannot be generalised to other zygomatic systems with confidence. Conflict-of-interest statement: This study was partially supported by Southern Implants (Irene, South Africa), the manufacturer of the zygomatic implants and the conventional drills evaluated in this study. However, data property belonged to the authors and by no means did the manufacturer interfere with the conduct of the trial or the publication of its results. Drs Felice and Pistilli developed the piezoelectric surgery zygomatic insert used in the present study. PMID- 28555206 TI - A comparison of two implants with conical vs internal hex connections: 1-year post-loading results from a multicentre, randomised controlled trial. AB - PURPOSE: To compare the clinical and radiological outcomes of identical implants with conical or internal hex connections. METHODS: A total of 90 patients with partial edentulism requiring one implant-supported prosthesis were randomly allocated in two equal groups (n = 45) to receive either implants with a conical connection or implants of the same type, but with an internal hex connection at three centres. Patients were followed for 1 year after loading. Outcome measures were implant failures, any complication and marginal bone level changes. RESULTS: One patient (2.2%) belonging to the internal hex group dropped out. One implant (2.2%) failed in the conical group. There were no statistically significant differences in implant failures between the two groups (2.2% vs. 0%, difference 2.2; 95% CI: -1.3; 5.7; P = 0.315). Two complications occurred in the conical group and two in the internal hex group (P = 1.000, difference 0.00, 95% CI: 3.1; 3.1). The 12-month peri-implant bone resorption was similar in both groups: 0.56 +/- 0.53 mm (95% CI 0.03; 1.09) in the conical group and 0.60 +/- 0.62 mm (95% CI 0.02; 1.22) in the internal hex group (difference = 0.04 +/- 0.55, 95% CI: -0.51; 0.59, P = 0.745). CONCLUSIONS: Within the limitation of this study, preliminary short-term data (1 year post-loading) did not show any statistical differences between the two internal connection types, therefore clinicians could choose whichever connection they prefer. Conflict of interest statement: Tommaso Grandi serves as consultant for J Dental Care, Modena, Italy. This study was completely self-financed and no funding was sought or obtained, not even in the form of free materials. PMID- 28555207 TI - Molar replacement with 7 mm-wide diameter implants: to place the implant immediately or to wait 4 months after socket preservation? ?1 year after loading results from a randomised controlled trial. AB - PURPOSE: To test the hypothesis that there is no difference in clinical, radiographic and aesthetic outcomes positioning single post-extractive 7 mm diameter implants or waiting 4 months after molar extraction and socket preservation procedure. MATERIAL AND METHODS: Patients requiring one implant supported single restoration to replace a failing tooth in the molar region of both maxilla and mandible were selected. Patients were randomised according to a parallel group design into two arms: implant installation in fresh extraction sockets grafted with cortico-cancellous heterologous bone and porcine derma (group A) or delayed implant installation 4 months after tooth extraction and socket preservation using the same materials (group B). Implants were submerged for 4 months. The primary outcome measures were the success rates of the implants and prostheses and the occurrence of any surgical and prosthetic complications during the entire follow-up. Secondary outcome measures were: peri-implant marginal bone level (MBL) changes, resonance frequency analysis (ISQ) and pink esthetic score (PES) values at implant placement (baseline) up to 1 year after loading. RESULTS: Twelve patients were randomised to group A and 12 to group B. No patient dropped out within 1 year after loading. No implant and prosthesis failed and no complications occurred during the entire follow-up. One year after loading, statistically significant higher mean MBL loss was experienced in group A (0.63 mm +/- 0.31 mm) compared to group B (0.23 mm +/- 0.06 mm); difference 0.41 mm (95% CI 0.17-0.53; P = 0.001). Six months after implant placement, mean ISQ value was 78.8 +/- 2.8 for group A and 79.9 +/- 3.6 for group B, showing no statistically significant difference between groups (difference 1.1; 95% CI: 0.04 to 2.96; P = 0.422). One year after loading, mean PES was 10.6 +/- 1.8 [range: 8 to13] in group A and 12.2 +/- 1.2 [range: 11 to 14] in group B. The difference was statistically significant (1.6 +/- 2.7; 95% CI -0.55-2.55; P = 0.019) with better results for group B. CONCLUSIONS: Within the limitations of this study, both procedures achieved successful results over the 1-year follow-up period, but waiting 4 months after tooth extraction and socket preservation procedure was associated with less marginal bone loss and a better aesthetic outcome. Conflict of-interest statement: Dr Marco Tallarico is Research Project Manager of Osstem AIC Italy. However no company supported this study and all authors declare no conflicts of interest. PMID- 28555208 TI - Comparison of immediately loaded flapless-placed one-piece implants and flapped placed conventionally loaded two-piece implants, both fitted with all-ceramic single crowns, ?in the posterior mandible: 3-year results from ?a randomised controlled pilot trial. AB - PURPOSE: To compare outcomes for immediately loaded one-piece implants (OPI), placed flapless, and conventionally loaded two-piece implants (TPI), placed after two-stage flapped surgery. MATERIALS AND METHODS: Thirty-eight participants were randomised to receive either one OPI (19 participants, OPI group) or one TPI (19 participants, TPI group) inserted in the posterior mandible with a torque of at least 35 Ncm according to a parallel group design. OPI were immediately loaded with non-occluding temporary crowns. After 3 months, TPI were exposed and implants in both groups were occlusally loaded with zirconia crowns. Outcome measures were implant failure, prosthesis failure, any complication and changes of probing pocket depth (PPD), plaque index (PI), gingiva index (GI), and peri implant marginal bone level, recorded by unblinded assessors. RESULTS: Three years after occlusal loading, three participants dropped out from the TPI group. There were no statistically significant differences between the groups with regard to participants with implant failure (OPI group 1/19; TPI group 0/16; difference in proportions (DIP), -5.3%; 95% confidence interval (CI) -15.3 to 4.8; P = 1.000), prosthesis failure (OPI group 3/19, TPI group 5/16; DIP, 15.5%; 95% CI -12.6 to 43.5; P = 0.424), any complication (OPI group 6/19, TPI group 5/16; DIP, -0.3%; 95% CI -31.2 to 30.5; P = 1.000), or changes of PPD (P =0.174), PI (P = 0.222), or GI (P = 0.415). Veneer chipping accounted for most prosthesis failures and complications. On average OPI and TPI lost 1.34 mm and 0.67 mm of marginal bone, respectively, the difference between groups being statistically significant (mean difference, 0.66 mm; 95% CI -0.02 to 1.34; P = 0.024) in favour of TPI implants. CONCLUSIONS: Both implant procedures might be viable in the short term, but statistically significantly more bone loss might be indicative of future problems with OPI. Because of the high incidence of chipping, veneered zirconia crowns cannot be recommended on posterior implants. Conflict-of-interest statement: The authors are grateful to Nobel Biocare for providing the study materials free of charge. Money received from the manufacturer was used to reimburse participants for regular attendance at follow-up appointments and to finance data management. The authors declare no conflict of interest. PMID- 28555210 TI - Report of a jaw osteonecrosis possibly caused?by denosumab. AB - PURPOSE: To report a case of osteonecrosis of the jaw (ONJ) occurring in an implant area possibly related to denosumab, a relatively new antiosteoporotic agent. MATERIALS AND METHODS: Two months following the extraction of both maxillary first molars, a bilateral maxillary sinus floor elevation was performed on a 64-year-old female patient under a biannual ?60 mg denosumab antiosteoporotic treatment. Seven months later, two implants were inserted in a single-stage procedure in each of the grafted sinuses. After 3 months, the implants underwent prosthetic rehabilitation at one side, and a series of failures that led to an ONJ instalment at the other side. RESULTS: The ONJ persisted over 7 months and was only resolved by a surgical approach consisting of a piezoelectric osteotomy and platelet-rich fibrin with a tension-free wound closure. CONCLUSIONS: A cumulative effect of denosumab is likely to be associated with a jaw osteonecrosis, which in this case was manageable using a surgical approach with no need to interrupt the appropriate drug treatment course. Conflict of interest statement: The authors certify that they are not affiliated with, or involved in any organisation or entity with any financial or non financial interest in the subject matter or materials discussed in this manuscript. PMID- 28555211 TI - Research in focus. AB - This section presents a brief review of articles on dental implants considered of special interest to readers, in order to encourage the development of research, the interest in data analysis and the attention to scientific publications. Your comments are welcome. Please contact Dr Michele Nieri at michelenieri@gmail.com. PMID- 28555209 TI - Characterisation of apical bone lesions: Comparison of MRI and CBCT with histological findings - a case series. AB - PURPOSE: The aim of this case series was to compare magnetic resonance imaging (MRI) with cone beam computed tomography (CBCT) in the representation of periapical osteolyses. Based on the histological findings, the potential of MRI for further lesion characterisation was investigated. MATERIALS AND METHODS: Thirteen patients (average age: 41 +/- 27 years) with a total of 15 periapical lesions (five molars, five premolars, and five front teeth) were examined. Lesion characterisation was based on the homogeneity/heterogeneity of the lesions, the signal intensity within the lesion compared to the surrounding tissue and differences in the signal intensities between different MRI contrast weightings. Results were compared with CBCT and histological findings. RESULTS: Although all patients presented with dental restorations, such as fixed partial dentures and filling materials, all periapical lesions could be diagnosed with either imaging modality. Histologically, 13 cysts and two apical granuloma were confirmed. In CBCT, the similar appearance of all lesions did not allow any further characterisation. In MRI, radicular cysts and granuloma could be characterised by their appearance in the MRI images with different contrast weightings. The MRI derived characterisations were consistent with the histological findings. CONCLUSIONS: The presented study shows that the application of multi-contrast MRI may lead to better characterisation of apical lesions, thus enabling an improved patient-specific selection of the optimal treatment option. Conflict-of-interest statement: MAG, ESS, and LKS do not report any potential conflict-of-interest; EH and JU are employees of Sirona Dental Systems; VR is receiving a research grant by Sirona Dental Systems. PMID- 28555212 TI - Enhanced photoelectrochemical response of plasmonic Au embedded BiVO4/Fe2O3 heterojunction. AB - The effect of embedding Au nanoparticles (NPs) in a BiVO4/Fe2O3 heterojunction for photoelectrochemical water splitting is studied here for the first time. The present nanostructured heterojunction offers three major advantages over pristine BiVO4 and Fe2O3: (i) the formation of a heterojunction between BiVO4 and Fe2O3 enhances the charge carrier separation and transfer, (ii) the layer of Fe2O3 provides protection to BiVO4 from photocorrosion and, (iii) the Au NPs possessing surface plasmon resonance (SPR) enhance the photoelectrochemical response by transferring energy to metal oxides by hot electron transfer (HET) and plasmon resonant energy transfer (PRET). The present study reveals that the heterojunction ITO/BiVO4/Fe2O3 (with 32% v/v Au solution in both layers) gives the best performance and mitigates the limitations of both pristine Fe2O3 and BiVO4. A thirteen-fold increment in applied bias photon-to-current conversion efficiency (ABPE) was observed at 1.24 V vs. RHE under the condition of 1 Sun illumination. Monochromatic incident photon-to-current conversion efficiency (IPCE) measurements indicated that an Au embedded heterojunction is more effective in harvesting visible light in comparison to a heterojunction without Au NPs. PMID- 28555213 TI - An encoded viral micropatch for multiplex cell-based assays through localized gene delivery. AB - The increasing number of potential drug targets and compounds has led to the development of high-throughput cell-based assays. Simultaneous processing of multiple targets in the same experiment based on localized target gene expression is a very efficient strategy for this purpose. To address this need, we present an adenoviral vector-immobilized microparticle with two-dimensional (2D) shape encoding properties that allows localized patch-like gene delivery to monolayer cultured cells. This format conveniently achieves multiplexed gene delivery compatible with both high-throughput cellular assays and fluorescence high content imaging instruments. A multiplex G protein-coupled receptor (GPCR) internalization assay was developed to demonstrate the compatibility of this system with high-throughput image-based cellular assays. PMID- 28555214 TI - The maximum penalty criterion for ridge regression: application to the calibration of the force constant in elastic network models. AB - Tikhonov regularization, or ridge regression, is a popular technique to deal with collinearity in multivariate regression. We unveil a formal analogy between ridge regression and statistical mechanics, where the objective function is comparable to a free energy, and the ridge parameter plays the role of temperature. This analogy suggests two novel criteria for selecting a suitable ridge parameter: specific-heat (Cv) and maximum penalty (MP). We apply these fits to evaluate the relative contributions of rigid-body and internal fluctuations, which are typically highly collinear, to crystallographic B-factors. This issue is particularly important for computational models of protein dynamics, such as the elastic network model (ENM), since the amplitude of the predicted internal motion is commonly calibrated using B-factor data. After validation on simulated datasets, our results indicate that rigid-body motions account on average for more than 80% of the amplitude of B-factors. Furthermore, we evaluate the ability of different fits to reproduce the amplitudes of internal fluctuations in X-ray ensembles from the B-factors in the corresponding single X-ray structures. The new ridge criteria are shown to be markedly superior to the commonly used two parameter fit that neglects rigid-body rotations and to the full fits regularized under generalized cross-validation. In conclusion, the proposed fits ensure a more robust calibration of the ENM force constant and should prove valuable in other applications. PMID- 28555216 TI - Gas/vapour separation using ultra-microporous metal-organic frameworks: insights into the structure/separation relationship. AB - The separation of related molecules with similar physical/chemical properties is of prime industrial importance and practically entails a substantial energy penalty, typically necessitating the operation of energy-demanding low temperature fractional distillation techniques. Certainly research efforts, in academia and industry alike, are ongoing with the main aim to develop advanced functional porous materials to be adopted as adsorbents for the effective and energy-efficient separation of various important commodities. Of special interest is the subclass of metal-organic frameworks (MOFs) with pore aperture sizes below 5-7 A, namely ultra-microporous MOFs, which in contrast to conventional zeolites and activated carbons show great prospects for addressing key challenges in separations pertaining to energy and environmental sustainability, specifically materials for carbon capture and separation of olefin/paraffin, acetylene/ethylene, linear/branched alkanes, xenon/krypton, etc. In this tutorial review we discuss the latest developments in ultra-microporous MOF adsorbents and their use as separating agents via thermodynamics and/or kinetics and molecular sieving. Appreciably, we provide insights into the distinct microscopic mechanisms governing the resultant separation performances, and suggest a plausible correlation between the inherent structural features/topology of MOFs and the associated gas/vapour separation performance. PMID- 28555217 TI - Lifshitz phase: the microscopic structure of aqueous and ethanol mixtures of 1,n diols. AB - We study binary mixtures of ethylene glycol and 1,3-propandiol with water or ethanol using computer simulations. Despite strong hydrogen bonding tendencies between all these molecules, we find that these mixtures are surprisingly homogeneous, in contrast to the strong micro-heterogeneity found in aqueous ethanol mixtures. The aqueous diol mixtures are found to be close to ideal mixtures, with near-ideal Kirkwood-Buff integrals. Ethanol-diol mixtures show weak non-ideality. The origin of this unexpected randomness is due to the fact that the two hydrogen bonding hydroxyl groups of the 1,n-diol are bound by the neutral alkyl bond, which prevents the micro-segregation of the different types of hydroxyl groups. These findings suggest that random disorder can arise in the presence of strong interactions - in contrast to the usual picture of random disorder due to weak interactions between the components. They point to the important role of molecular topology in tuning concentration fluctuations in complex liquids. We propose and justify herein the name of Lifshitz phases to designate such types of disordered systems. PMID- 28555218 TI - Colloidal diffusion in confined geometries. AB - Colloidal dispersions in confined geometries exhibit rich diffusive dynamics governed by an interplay between particle-particle and particle-wall interactions. This perspective reviews recent selected computational and experimental studies on diffusion of dense liquid-like dispersions in spatial confinement, with an emphasis on general physical concepts rather than system specific details. The common thread is to analyse colloidal diffusion in confined geometries in terms of the local density experienced by the colloidal particles, viz. at the level of anisotropic pair densities, which have recently become experimentally accessible. PMID- 28555220 TI - A hand-twisted helical crystal based solely on hydrogen bonding. AB - A hand twistable hydrogen bonded two-dimensional plastic crystal, 4-pyridinyl 4 nitrobenzoate hydrate, is obtained from a brittle precursor using a retrosynthetic design strategy based on molecular/supramolecular equivalence. PMID- 28555221 TI - Tunable electronic structure and magnetic moment in C2N nanoribbons with different edge functionalization atoms. AB - First principles calculations based on density functional theory were carried out to study the electronic and magnetic properties of C2N nanoribbons (C2NNRs). The electronic structure could be modified by different methods using saturated or co saturated H, O, and F on the edges, which can provide a new pathway at the nanoscale for fabricating 2D spintronic materials. It was found that the pristine armchair C2NNR (A-C2NNR) is a nonmagnetic semiconductor with a direct band gap, while the pristine zigzag C2NNRs (Z-C2NNRs) can show either magnetic semiconductor with an indirect band gap or magnetic metallic behavior depending on its ribbon widths. A-C2NNRs with one type of atom (H, O or F) saturated on the edges are nonmagnetic, while H and O (F and O) co-saturated A-C2NNRs show magnetic ground states. H and O (F and O) co-saturated Z-C2NNRs share a larger magnetic moment compared to the case with H, O and F saturated on the edges. Furthermore, O-saturated Z-C2NNR is a spin "gapless" semiconductor. Additionally, there is no need to spin flip in the process of electronic transition near the Fermi level. Therefore, C2NNRs might have potential applications in photoelectronic and spinelectronic devices. PMID- 28555222 TI - Reversible formation and cleavage of Pt->Ag dative bonds in a pre-organized cavity of a luminescent heteropolynuclear platinum(ii) complex. AB - A U-shaped Pt2Ag2 complex [Pt2Ag2(ppy)2(Ph2pz)4] with a pre-organized cavity (ppy = 2-phenylpridinate and Ph2pz = 3,5-diphenylpyrazolate) and related complexes have been prepared. The Pt2Ag2 complexes react with Ag(i) ions to give the corresponding Pt2Ag3 complexes containing Pt->Ag dative bonds. It became obvious that the existence of the C(ipso) atom in the chelate ligand is important as the driving force for forming Pt->Ag dative bonds. However, once the Pt2Ag3 complex is formed, the trapped Ag(i) ion is mainly stabilized by the Pt->Ag dative bonds, which are stronger than the Ag-C(ipso) bond. The trapped Ag(i) ion can be abstracted from the cavity selectively by adding an equivalent amount of chloride ion into the solution of Pt2Ag3 complexes to reproduce the original Pt2Ag2 complexes. PMID- 28555223 TI - N-Sulfonyl alpha-imino ester-derived chiral oxaziridines: catalytic asymmetric synthesis and application as a modular chiral organic oxidant. AB - A novel class of chiral N-sulfonyl oxaziridines is introduced for use as structurally modifiable chiral oxidants. These oxaziridines are readily prepared from N-sulfonyl alpha-imino esters in a highly enantioenriched form by oxidation with hydrogen peroxide using l-isoleucine-derived triaminoiminophosphorane as a catalyst. The distinct advantage of their structural modularity is demonstrated through the identification of an optimal oxaziridine that exhibits high reactivity and enantiospecificity in the asymmetric oxidation of a silyl enol ether and N-sulfonyl allylic and homoallylic amines. PMID- 28555224 TI - First-principles study of adsorption-desorption kinetics of aqueous V2+/V3+ redox species on graphite in a vanadium redox flow battery. AB - Vanadium redox flow batteries (VRFBs) represent a promising solution to grid scale energy storage, and understanding the reactivity of electrode materials is crucial for improving the power density of VRFBs. However, atomistic details about the interactions between vanadium ions and electrode surfaces in aqueous electrolytes are still lacking. Here, we examine the reactivity of the basal (0001) and edge (112[combining macron]0) graphite facets with water and aqueous V2+/V3+ redox species at 300 K employing Car-Parrinello molecular dynamics (CPMD) coupled with metadynamics simulations. The results suggest that the edge surface is characterized by the formation of ketonic C[double bond, length as m-dash]O functional groups due to complete water dissociation into the H/O/H configuration with surface O atoms serving as active sites for adsorption of V2+/V3+ species. The formation of V-O bonds at the surface should significantly improve the kinetics of electron transfer at the edge sites, which is not the case for the basal surface, in agreement with the experimentally hypothesized mechanism. PMID- 28555225 TI - BAR-based optimum adaptive sampling regime for variance minimization in alchemical transformation. AB - The efficiency of alchemical free energy simulations with the staging strategy is improved by adaptively manipulating the significance of each ensemble followed by importance sampling. The OBAR (optimum BAR) method introduced in this work with explicit consideration of the statistical inefficiency in each ensemble outperforms the traditional equal time rule which is used in standard applications of alchemical transformation with the window sampling regime in the sense of minimizing the total variance of the free energy estimate. The Time Derivative of total Variance (TDV) is proposed for the OBAR criterion which is linearly dependent on the variance and is more sensitive to the importance rank than the overlap matrix. The performance of OBAR workflow is demonstrated for solvation of several small molecules and a protein ligand binding system. PMID- 28555226 TI - Two-step modulation of ion recognition using a bis(saloph)-macrocyclic host having a 24-crown-8-like cavity. AB - Precise modulation of cation binding affinity was accomplished by the efficient two-step conversion of a newly synthesized macrocyclic ligand H4L2 having a 24 crown-8-like cavity and two saloph moieties. The conversion of H4L2 into L2Ni2 resulted in a 120-fold enhancement in the binding affinity towards Cs+. The electrochemical reduction of L2Ni2 further enhanced the recognition ability by 3 orders of magnitude. PMID- 28555227 TI - B-Hpi: a nonclassical hydrogen bond or dispersion contact? AB - Close B-Hpi contacts have recently been observed in crystallographic structures of Ir-dithiolene-phosphine complexes containing boron hydride cluster. This finding was interpreted using quantum chemical calculations as a new type of electrostatically driven nonclassical hydrogen bonding. However, such an explanation contradicts the wealth of evidence for unique noncovalent interactions of boron hydrides. Moreover, care must be exercised when computational methods are used to interpret new phenomena. Therefore, here, we cautiously examine the B-Hpi interaction by means of advanced quantum chemistry and disprove the claimed attractive electrostatic nature and rather define it as a nonspecific dispersion-driven contact. In summary, we present evidence that the crystallographically observed B-Hpi contacts do not constitute a novel type of hydrogen bonding of boron hydride clusters. PMID- 28555228 TI - Dehydrogenative homocoupling of tetrafluorobenzene on Pd(111) via para-selective C-H activation. AB - Aryl homocoupling reactions via meta- and ortho-selective C-H activation have been achieved on surfaces, but the highly important para-selective C-H activation has not been reported yet. Combined with scanning tunneling microscopy, time-of flight secondary ion mass spectrometry and density functional theory, here we describe dehydrogenative homocoupling of tetrafluorobenzene on Pd(111) via para selective C-H activation to form perfluorinated oligo(p-phenylene)s. PMID- 28555232 TI - Palladium-catalyzed sequential monoarylation/amidation of C(sp3)-H bonds: stereoselective synthesis of alpha-amino-beta-lactams and anti-alpha,beta-diamino acid. AB - Pd-Catalyzed sequential monoarylation/amidation of C(sp3)-H bonds of alanine enabled by a removable 5-methoxyquinolin-8-amine (MQ) auxiliary is described. This process is highly efficient and compatible with a variety of functional groups, providing a general and practical access to various alpha-amino-beta lactams. The synthetic potential of this protocol is further demonstrated by the stereoselective synthesis of orthogonally protected anti-alpha,beta-diamino acids. PMID- 28555231 TI - Micropatterned macroporous structures in microfluidic devices for viral separation from whole blood. AB - Separation and enrichment of bio-nanoparticles from cell suspensions and blood are critical steps in many chemical and biomedical practices. We demonstrate here the design and fabrication of a microfluidic immunochromatographic device incorporating regular and multiscale monolithic structures to capture viruses from blood. The device contains micropatterned arrays of macroporous materials to perform size-exclusion and affinity chromatography in a simple flow-through process. The microscale gaps in the array allow the passage of cells while the macroporous matrices promote viral capture. Computational analyses reveal that fluid permeation into the porous matrices is controllable by the micropattern shape, separation distance and dimensions. Experimental analyses using blood samples containing human immunodeficiency viruses (HIV) as a model system further prove significantly improved viral capture efficiency using devices incorporating multiscale structures than those containing solid micropatterns. Such microfluidic devices with regular and multiscale structures have a potential for the separation and concentration of a wide range of bio-nanoparticles as well as macromolecules from complex mixtures containing both nano- and micro-sized species. PMID- 28555233 TI - Identification of the protonation site of gaseous triglycine: the cis-peptide bond conformation as the global minimum. AB - Extensive ab initio investigations have been performed to characterize stable conformers of protonated triglycine (GGGH) in the gas phase. Calculations using the composite CBS-QB3 method confirmed that the most favorable site of protonation on triglycine at 298 K is still the traditional amino nitrogen, rather than the more-recently reported amide oxygen. Furthermore, a non-proline cis-peptide bond conformer is identified for the first time as the global minimum of GGGH. Further transition state calculations considering the temperature effects explained why the previous experimental infrared multiple photon dissociation (IRMPD) spectrum contains a combination of two local minima, rather than a global one. First-principles simulations have been performed for near-edge X-ray absorption fine-structure (NEXAFS) spectra and X-ray photoelectron spectra (XPS) at the C, N and O K-edges to identify the notable spectral differences that enable the unambiguous identification of different protonated forms. The calculated proton affinity (PA) and gas basicity (GB) of triglycine are in excellent agreement with the experimental values. Our study thus provides valuable insights into the protonation of short peptides and illustrates the competition between cis and trans peptide bonds. PMID- 28555234 TI - The first molecular dumbbell consisting of an endohedral Sc3N@C80 and an empty C60-fullerene building block. AB - An unprecedented hybrid dumbbell consisting of a metallofullerene and an empty fullerene was afforded via simple click reaction of suitable precursor derivatives of Sc3N@C80 and a C60 hexakisadduct. PMID- 28555235 TI - [Ge5Ni2(CO)3]2-: the first functionalized cluster of closo-[Ge5]2. AB - A new functionalized cluster, [Ge5Ni2(CO)3]2-, derived from the closo-[E5]2- (E = Si-Pb) anions which have been known for decades but whose reactivity has rarely been studied, was successfully isolated from the reaction of [Ni(PPh3)2(CO)2] and [Ge5]2- in ethylenediamine (en) solution, and its formation pathway was also investigated. PMID- 28555236 TI - Separating lanthanides and actinides from nitric acid solutions by using N,N-di(2 ethylhexyl)-diglycolamic acid (HDEHDGA). AB - The extraction of Eu(iii), U(vi), and Pu(iv) from 0.1-3 M HNO3 solutions by using N,N-di(2-ethyl-hexyl)-diglycolamic acid (HDEHDGA) is presented. In contrast to common organic acid extractants, such as long-chain carboxylic acids, organophosphorus acids, and derivatives of beta-diketones, losing extractability, HDEHDGA exhibits a strong ability to extract lanthanide and actinide ions from high HNO3 solutions. PMID- 28555237 TI - Conversion of methanol to hydrocarbons over zeolite ZSM-23 (MTT): exceptional effects of particle size on catalyst lifetime. AB - A variety of synthetic procedures have been used to obtain zeolite ZSM-23 (MTT) catalysts with crystallite sizes ranging from the micrometer to nanometer scale. When the acidic zeolite is used as a catalyst for the methanol to hydrocarbon (MTH) reaction, the catalytic lifetime is dramatically influenced by the crystallite shape and size. PMID- 28555238 TI - Formation of supramolecular hetero-triads by controlling the hydrogen bonding of conjugate bases with a diprotonated porphyrin based on electrostatic interaction. AB - The thermodynamic stability of diprotonated saddle-distorted dodecaphenylporphyrin (H4DPP2+(X-)2) was controlled by the hydrogen-bonding strength of conjugate bases (X-) of strong acids (HX) or acids (R+-COOH) having positively charged moieties. The thermodynamic control of H4DPP2+(X-)2 made it possible to achieve selective formation of supramolecular hetero-triads, H4DPP2+(X-)(Cl-). PMID- 28555239 TI - Efficient light harvesting within a C153@Zr-based MOF embedded in a polymeric film: spectral and dynamical characterization. AB - Light harvesting is a natural phenomenon that scientists try to mimic in artificial systems. Having this in mind, attention has been focused on using new smart-materials for photonics. Herein, we report on the photobehaviour of a Zr NDC MOF (NDC = dimethyl 2,6-naphthalenedicarboxylate) and its composite material, Coumarin153@Zr-NDC, embedded within a polymeric membrane of poly[bisphenol A carbonate-co-4,4'-(3,3,5-trimethylcyclohexylidene)diphenol carbonate] (PC). For the mixed matrix membrane (MMM) Zr-NDC/PC, we observed interparticle excimer-like formation, taking place in times shorter than 15 ps and giving rise to a red shifted broad emission band. The interparticle interactions are supported by the SEM images, as they reflect the contact between the MOF crystals. The C153@Zr NDC/PC material presents an energy transfer (ET) process from the excited MOF to the trapped C153 molecules in 820 ps, with a 35 nm red-shifted emission band corresponding to C153 in PC. The fluorescence quantum yield, as a result of this ET from the MOF, is high enough (25%) to explore the possibility of using this new composite material in a LED device. To elucidate the observed photobehavior, we compared it with those of C153/PC and (2,6-NDC + C153)/PC films. These results shed light on the spectroscopic and dynamical properties of these new composite materials formed by a highly fluorescent molecule, and easily synthesized MOFs and polymeric matrices, opening the way for more research based on these mixed inorganic and organic compounds for possible applications in the fields of luminescence sensing and emitting devices. PMID- 28555241 TI - Prehistoric massacre revealed. Perimortem cranial trauma from Potocani, Croatia. AB - ABSTRACT: During archaeological rescue excavations carried out in 2007 at Potocani in continental Croatia, a pit containing numerous human skeletal remains (MNI = 41) was discovered. The remains were mostly articulated but also commingled and showed no clear pattern of organization. There were no associated artifacts, just a few pottery fragments probably belonging to the Copper Age Lasinja Culture (c. 4300 to 3950 BCE). Anthropological analyses suggest the presence of individuals of all ages and both sexes with many crania exhibiting various perimortem injuries. Three human bone samples from different layers were dated to around 4100 cal BCE by radiocarbon analysis. These radiocarbon dates combined with other aspects of archaeological context, indicate that the deposition was a single episode rather than a long-term accumulation. All this suggests a single violent encounter (massacre). Here we present results of the bioarchaeological analysis of four adult crania with clear signs of perimortem trauma. These include blunt force trauma as well as cuts and penetrating injuries indicating the use of different weapons/tools. PMID- 28555242 TI - Y chromosomal deletion pattern in Koreans inhabiting Jeju Island. AB - ABSTRACT: Mutations occur in Y chromosome genes similar to autosomal genes. However, unlike autosomal genes, Y chromosome genes do not undergo recombination, which produce distinctive characteristics and distribution patterns in different geographic regions. Therefore, detailed analysis of mutations of Y chromosome genes might provide information for personal identification or analysis of phylogenetic history. In Y-STR (short tandem repeat) analysis tests on 668 habitants of Jeju Island, the largest island in the Korean peninsula located apart from the mainland, a deletion at DYS448 was found in 10 samples. The length of deletion was estimated by confirming specific Sequence Tagged Site (STS) markers ranging from G66018 to sY1201. Patterns found were similar to those of the Kalmyks, a tribe that has had strong social and genetic influences in Jeju Island in the past. Historically from 1273 on, Jeju Island was governed by Mongolian for about one hundred years. The results of this study suggest such historical aspects affected the genetic composition of people living in Jeju Island. Furthermore, previous reports showed that Y chromosomal deletions and region specific Y chromosomal mutations depended on regional differences. This study may be useful for a better understanding of the genetic structure of Jeju habitants as well as Korean population for the purpose of forensic practice and population genetics. PMID- 28555243 TI - No association between nutrition and body height in German kindergarten children a pilot study. AB - ABSTRACT: Anthropologists all over the world are discussing influences on individual height including quantity and quality of nutrition. To examine whether a relationship between nutritional components and height can be found this pilot study has been developed. The research samples consisted of 44 children (age 3-6 years) attending two different kindergartens in Germany. Height measurements were taken for each child. Furthermore the parents had to fill out a 24-hour questionnaire to document their children's eating habits during the weekend. In order to standardize the measured height values z-scores were calculated with reference to the average height of the overall cohort. The results of correlation analysis indicate that height is not significantly related to any of the main nutritional components as protein (r = -0.148), carbohydrates (r = 0.126), fat (r = 0.107), fibre (r = -0.289), vitamin (r = 0.050), calcium (r = 0.110), potassium (r = 0.189) and overall calorie intake (r = 0.302). In conclusion, it can be stated that the quality of nutrition may not have a strong influence on individual height. However, due to the small sample size further research should be provided with a larger cohort of children to verify the present results. PMID- 28555244 TI - Estimation of ancestry for an undocumented mandibular sample using dental morphology. AB - ABSTRACT: Dental morphology is a useful resource in archaeology, anthropology and paleontology, due to its genetic determination. Teeth are a material of high durability and stability. This work aims to study the dental morphology and test the Portuguese and European biological affinities of an undocumented mandibular sample, through comparison with global and Iberian samples. The dental traits in 163 mandibles (kept at the Museum of Natural History of the University of Oporto, Portugal) were scored using a standardized methodology (ASUDAS: Arizona State University Dental Anthropology System) and compared to other world-wide and Iberian samples through Principal Components (PCA) and Mean Measure of Divergence analyses. The undertaken quantitative and statistical tests demonstrated the unknown sample to be closer to the Coimbra Portuguese sample in all three comparisons. This suggests this undocumented mandibular sample is possibly of Portuguese 19th/20th century origin. PMID- 28555245 TI - 2D:4D finger length ratio and skeletal biomarker of biological aging. AB - ABSTRACT: The aim of this population-based study was to evaluate the association between the index to ring (2D:4D) finger length ratio and the osseographic score (OSS), the skeletal biomarker of biological aging. A sample included 802 males and 738 females who had participated in a Chuvashian skeletal aging study. Age, sex, basic demographics, anthropometric data and X-rays of both hands were collected. Each hand was visually classified on X-ray as either Type 1 - index finger was longer than ring finger; Type 2 - equal; or Type 3 - shorter than the ring finger. OSS is a skeletal biomarker that comprises osteoporotic and osteoarthritic changes observable on a hands X-ray. The mean age of males in the studies sample was 46.98 +/- 17.10 and mean age females was 48.65 +/- 16.62. OSS showed significant association with age (r = 0.886, p < 0.001), body mass index (BMI) (r-0.253, p < 0.001) and sex (F = 13.771, p < 0.001). Results of one-way ANCOVA for finger length ratio types of right hand showed a significant difference in OSS (d.f. = 2, F = 7.569, p = 0.001), after adjustment for age, sex, and BMI. The posthoc comparison showed that individuals with Type 3 (2D < 4D) ratio showed significantly higher OSS scores that ones with Type 1 (p = 0.012) and Type 2 (p = 0.003). In an analysis of finger length ratio types of left hand also a significant difference in OSS was found (d.f. = 2, F = 3.290, p = 0.038). The posthoc comparison showed that individuals with Type 3 (2D < 4D) ratio showed significantly higher OSS scores that ones with Type 2 (p = 0.33) ratio. Finger length ratio is associated with an OSS, a skeletal biomarker of biological aging. Individuals with Type 3 finger length pattern showed significantly higher OSS that ones with Type 1 and Type 2. PMID- 28555246 TI - Generating equations to estimate body mass of Korean skeletal remains. AB - ABSTRACT: This study aims to generate Korean specific standards for body mass estimation and compare their performance to previous techniques derived from non Korean samples. Due to a lack of known reference samples in Korea, estimation equations were generated using the hybrid method on 106 Korean unknown skeletons. In the first phase of the hybrid method (morphometric method), a downward adjustment of 4.5 kg was necessary to compensate for a systematic overestimation associated with the morphometric method being applied to Asian samples. Estimates using the adjusted morphometric method were regarded as actual body mass. New body mass equations revealed a better performance in accuracy and precision than previous techniques. However, caution is required in their forensic application because they yield an estimate for body mass around onset of adulthood, rather than the body mass at the time of death. PMID- 28555247 TI - Rib anomalies in a Neolithic period skeleton from Croatia. AB - ABSTRACT: Congenital anomalies develop during intrauterine development. They can occur in soft tissues as well as skeletal elements and vary from minor to life threatening. In this paper we present a case of an individual from the Neolithic site of Vinka, Croatia. This adult male exhibited multiple congenital anomalies on cranial and postcranial skeleton. These include several rib anomalies on the right side: hyperplasia of the third rib, bifid fourth rib and flaring of the eighth rib. Additionally, lambdoid ossicles, parastyle of the second maxillary molar and supracondylar processes of the humeri are present. In this study we put emphasis on rib anomalies, very rarely reported in archaeological settings, and compare them to clinical cases. PMID- 28555249 TI - Anatomy of the cutaneous lymphatic system of the trunk: a clinico-anatomical study of 90 cutaneous melanomas. AB - PURPOSE: The cutaneous lymphatic system of the trunk is a complex network, the anatomical knowledge of which remains unclear. The lymphatic system plays a major role in the dissemination of lymphophilic cancers like melanomas. The aim of this study was to improve our knowledge, optimize the care of patients with cutaneous tumors of the trunk, and to use our clinical experience of the topography of pathologic lymph nodes related to cutaneous melanomas and depicted by lymphoscintigraphy. MATERIALS AND METHODS: This prospective study included 90 consecutive patients who had primary resection of cutaneous melanoma of the trunk between June 2011 and January 2015. All patients had lymphatic mapping by lymphoscintigraphy, followed by sentinel lymph node procedure. We compared data of lymphatic imaging (lymphoscintigraphy and SPECT-CT) and surgery. We divided the trunk into 36 regions based on cutaneous anatomical landmarks to determine the topography of the lymphatic system for each tumor. RESULTS: Our study showed cutaneous lymphatic drainage of melanomas of the trunk in 16 different areas. This drainage could be single or multiple. We observed that drainage could be controlateral in medial regions of the trunk, and lymphatic pathway could be retrograde. This drainage could be bilateral for medial regions and mainly into axillary areas for regions above L1 level. Posterior regions of the trunk had more diversity of drainage areas than anterior regions. CONCLUSIONS: Cutaneous lymphatic drainage of the trunk was not limited to axillary and inguinal areas, showed interindividual variability, and was single or multiple, unilateral or bilateral, and unpredictable. PMID- 28555248 TI - Fat emboli syndrome and the orthopaedic trauma surgeon: lessons learned and clinical recommendations. AB - PURPOSE: Fat emboli syndrome is a rare but well-described complication of long bone fractures classically characterised by a triad of respiratory failure, mental status changes and petechial rash. In this paper, we present the case of a patient who sustained bilateral femoral fractures and subsequently developed FES. Our aim was to review and summarise the current literature regarding the pathophysiology and management of fat emboli syndrome (FES) and propose an algorithm for treating patients with bilateral femoral fractures to reduce the risk of FES. METHODS: A literature analysis was performed to determine implications in the clinical setting. RESULTS: Currently, there exists little high-quality evidence to guide the orthopaedic surgeon in identifying patients at highest risk of FES or in preventing FES in patients with multiple long-bone fractures. However, the literature does suggest that the risk is directly related to the volume of marrow displaced and inversely related to both the time to fracture stabilisation and the respiratory reserve of the patient. Based on these correlations, we propose an algorithm for treating patients with bilateral femoral fractures, taking into consideration haemodynamic and pulmonary stability. CONCLUSIONS: Our algorithm for managing bilateral femoral fractures prioritises early stabilisation with external fixation, staged intramedullary nailing and conversion to plate fixation if FES develops. This protocol is meant to be the basis of future investigations of optimal treatment strategies. PMID- 28555250 TI - Ultrasound biomechanical anatomy of the soft structures in relation to the ulnar nerve in the cubital tunnel of the elbow. AB - BACKGROUND: Chronic ulnar nerve entrapment worsened by elbow flexion is the most common injury, but rare painful conditions may also be related to ulnar nerve instability. The posterior bundle of the medial collateral ligament (pMCL) and the retinaculum, respectively form a soft floor and a ceiling for the cubital tunnel. The aim of our study was to dynamically assess these soft structures of the cubital tunnel focusing on those involved in the biomechanics of the ulnar nerve. METHODS: Forty healthy volunteers had a bilateral ultrasonography of the cubital tunnel. Elbows were scanned in full extension, 45 degrees and 90 degrees , and maximal passive flexion. Morphological changes of the nerve and related structures were dynamically assessed on transverse views. RESULTS: Both the pMCL and the retinaculum tightened with flexion. During elbow flexion, the tightening of the pMCL superficially moved the ulnar nerve remote from the osseous floor of the retroepicondylar groove. A retinaculum was visible in all 69 tunnels with stable nerves (86.3%), tightened in flexion, but absent in 11 tunnels with unstable nerves (13.7%). The retinaculum was fibrous in 60 elbows and muscular in nine, the nine muscular variants did not significantly influence the biomechanics of stable nerves. Stable nerves flattened in late flexion between the tightened pMCL and retinaculum, whereas unstable nerves transiently flattened when translating against the anterior osseous edge of the groove. CONCLUSION: The retinaculum and the pMCL are key structures in the biomechanics of the ulnar nerve in the cubital tunnel of the elbow. PMID- 28555251 TI - Post-resistance exercise ingestion of milk protein attenuates plasma TNFalpha and TNFr1 expression on monocyte subpopulations. AB - Attenuating TNFalpha/TNFr1 signaling in monocytes has been proposed as a means of mitigating inflammation. The purpose of this study was to examine the effects of a milk protein supplement on TNFalpha and monocyte TNFr1 expression. Ten resistance-trained men (24.7 +/- 3.4 years; 90.1 +/- 11.3 kg; 176.0 +/- 4.9 cm) ingested supplement (SUPP) or placebo (PL) immediately post-exercise in a randomized, cross-over design. Blood samples were obtained at baseline (BL), immediately (IP), 30-min (30P), 1-h (1H), 2-h (2H), and 5-h (5H) post-exercise to assess plasma concentrations of myoglobin; tumor necrosis factor-alpha (TNFalpha); and expression of tumor necrosis factor receptor 1 (TNFr1) on classical, intermediate, and non-classical monocytes. Magnitude-based inferences were used to provide inferences on the true effects of SUPP compared to PL. Plasma TNFalpha concentrations were "likely attenuated" (91.6% likelihood effect) from BL to 30P in the SUPP group compared with PL (d = 0.87; mean effect: 2.3 +/- 2.4 pg mL-1). TNFr1 expressions on classical (75.9% likelihood effect) and intermediate (93.0% likelihood effect) monocytes were "likely attenuated" from BL to 2H in the SUPP group compared with PL (d = 0.67; mean effect: 510 +/- 670 RFU, and d = 1.05; mean effect: 2500 +/- 2300 RFU, respectively). TNFr1 expression on non-classical monocytes was "likely attenuated" (77.6% likelihood effect) from BL to 1H in the SUPP group compared with PL (d = 0.69; mean effect: 330 +/- 430 RFU). Ingestion of a milk protein supplement immediately post-exercise appears to attenuate both plasma TNFalpha concentrations and TNFr1 expression on monocyte subpopulations in resistance-trained men. PMID- 28555253 TI - A Turkish case of galactosialidosis with a new homozygous mutation in CTSA gene. AB - Galactosialidosis is an autosamal reressive lysosomal storage disease caused by a combined deficiency of lysosomal beta-galactosidase and neuraminidase, due to a primary defect in protective protein/cathepsin A. Three subtypes are recognized: the early infantile type, the late infantile type, and the juvenile/adult type. We report here a female patient with early infantile galactosialidosis who was born at 35 weeks of gestation. After birth she remained at the neonatal intensive care unit. Physical examination revealed, coarse facial features, hepatomegaly, cardiac murmur and diffuse hypotonia. The patient's mother had a past history of fetal hydrops history. The diagnosis of galactosialidosis was confirmed by decreased activity of beta-galactosidase and undetectable neuraminidase activity in fibroblasts. Genetic examination revealed a new homozygous mutation (c.1284delG) in the CTSA gene. PMID- 28555252 TI - The perinatal effects of maternal caffeine intake on fetal and neonatal brain levels of testosterone, estradiol, and dihydrotestosterone in rats. AB - Testosterone, estradiol, and dihydrotestosterone are the main sex steroid hormones responsible for the organization and sexual differentiation of brain structures during early development. The hypothalamo-pituitary-adrenocortical axis, adrenal cells, and gonads play a key role in the production of sex steroids and express adenosine receptors. Caffeine is a non-selective adenosine antagonist; therefore, it can modulate metabolic pathways in these tissues. Besides, the proportion of pregnant women that consume caffeine is ~60%. That is why the relationship between maternal caffeine consumption and fetal development is important. Therefore, we aimed to investigate this modulatory effect of maternal caffeine consumption on sex steroids in the fetal and neonatal brain tissues. Pregnant rats were treated with a low (0.3 g/L) or high (0.8 g/L) dose of caffeine in their drinking water during pregnancy and lactation. The testosterone, estradiol, and dihydrotestosterone levels in the frontal cortex and hypothalamus were measured using radioimmunoassay at embryonic day 19 (E19), birth (PN0), and postnatal day 4 (PN4). The administration of low-dose caffeine increased the body weight in PN4 male and female rats and anogenital index in PN4 males. The administration of high-dose caffeine decreased the adrenal weight in E19 male rats and increased testosterone levels in the frontal cortex of E19 female rats and the hypothalamus of PN0 male rats. Maternal caffeine intake during pregnancy affects sex steroid levels in the frontal cortex and hypothalamus of the offspring. This concentration changes of the sex steroids in the brain may influence behavioral and neuroendocrine functions at some point in adult life. PMID- 28555254 TI - Successful Antifungal Combination Therapy and Surgical Approach for Aspergillus fumigatus Suppurative Thyroiditis Associated with Thyrotoxicosis and Review of Published Reports. AB - In immunocompromised patients, Aspergillus infections are important causes of morbidity and mortality. We describe a patient with cryoglobulinemic vasculitis who developed disseminated invasive aspergillosis with thyrotoxicosis caused by Aspergillus fumigatus. The diagnosis was based upon radiological, microbiological and pathological findings. The patient was treated successfully with voriconazole and caspofungin treatment followed by total thyroidectomy. We provide an overview of published reports on Aspergillus thyroiditis with an emphasis on therapeutic approaches. PMID- 28555255 TI - A Simple Method for the Purification of Nisin. AB - Nisin, an antimicrobial peptide showing activity against a broad range of Gram positive bacteria, is widely used as a food preservative and has potential as a therapeutic for a range of infectious diseases. Here, we present a simple purification method, based on a salting-out approach, which can produce a powder containing ~33% nisin, from a nisin-producing culture in a whey permeate-based medium. This process removes over 99% of the lactic acid, NaCl, lactose and non nisin proteins from the cell-free culture supernatant. The approach can also enrich a commonly used commercial nisin preparation over 30-fold to a purity of ~58%. These are higher purities than comparable published methods. The simplicity of this approach facilitates its use in research and also its scale-up. PMID- 28555256 TI - Minimally invasive combined glaucoma and cataract surgery: clinical results of the smallest ab interno gel stent. AB - PURPOSE: To verify the efficacy in intraocular pressure (IOP) reduction and safety of the smallest gel stent (XEN 45 Gel Stent) microincisional glaucoma surgery combined with microincisional cataract surgery (MICS). METHODS: Nonrandomized prospective clinical study. Forty-one eyes of 33 patients with open angle glaucoma underwent a XEN 45 Gel Stent implantation combined with MICS. Treatment outcomes analyzed included: IOP, medication use, intra- and postoperative complications. At the end of the follow-up, we evaluated the complete success, defined as a postoperative IOP >= 6 and <=17 mmHg without glaucoma medications and the qualified success defined as a postoperative IOP >= 6 and <=17 mmHg, with glaucoma medications. RESULTS: The mean preoperative IOP was 22.5 +/- 3.7 mmHg on 2.5 +/- 0.9 medication classes. After 12 months, the mean postoperative IOP was 13.1 +/- 2.4 mmHg (mean IOP reduction of 41.82%) with a mean of 0.4 +/- 0.8 medication classes (P < 0.05 for IOP and medications). The complete success rate was achieved in 80.4% and a qualified success in 97.5%. There were no major intra- and postoperative complications during the first year of follow-up. CONCLUSIONS: This study demonstrated that the smaller diameter XEN 45 gel implant is statistically effective in reducing IOP and medications in glaucoma patients with a low rate of complications. PMID- 28555257 TI - Professor Enrico Mihich, 1928-2016. PMID- 28555258 TI - Peripheral blood T cell alterations in newly diagnosed diffuse large B cell lymphoma patients and their long-term dynamics upon rituximab-based chemoimmunotherapy. AB - The importance of T cell-dependent immune responses in achieving long-term cure of chemoimmunotherapy-treated cancer patients is underscored by the recently described "vaccinal effect" exerted by therapeutic mAbs. In accordance, pre- and post-therapy peripheral blood lymphopenia represents a well-established negative prognostic factor in DLBCL. We analyzed the phenotypic and functional (IFNgamma production, and Granzyme B (GrzB) cytotoxic granule marker expression) profile of peripheral blood T lymphocyte subsets ("conventional" CD4+ and CD8+, FOXP3+CD25bright Treg, and "innate-like" CD56+) in DLBCL patients at diagnosis, and assessed the long-term impact of R-CHOP chemoimmunotherapy, in a prospective study. At diagnosis, DLBCL patients showed lower lymphocyte counts, due to selective decrement of CD4+ T (including Treg) and B lymphocytes. While all T cell subsets transiently decreased during therapy, CD4+ T cell and Treg remained significantly lower than controls, up to 1 year after R-CHOP. Phenotypically skewed profile of CD4+ and CD8+ T cell subsets associated with higher frequencies of IFNgamma+ and GrzB+ cells at diagnosis, that transiently decreased during therapy, and re-attained persistently elevated levels, till up to 1 year after therapy. Differently, the pre-therapy elevated levels of circulating monocytes, and of plasma IL-6 and IL-10 rapidly normalized upon R-CHOP. In sum, we describe a quantitatively and functionally altered status of the peripheral blood T cell compartment in DLBCL patients at diagnosis, that persists long-term after tumor eradication, and it is only transiently perturbed by R-CHOP chemoimmunotherapy. Moreover, data suggest the association of selected T cell functional features with DLBCL phenotype, and with therapy outcome. PMID- 28555259 TI - In vitro differentiated plasmacytoid dendritic cells as a tool to induce anti leukemia activity of natural killer cells. AB - Acute lymphoblastic leukemia (ALL) is believed to be resistant to NK cell mediated killing. To overcome this resistance, we developed an innovative approach based on NK cell stimulation with Toll-like receptor (TLR)-activated plasmacytoid dendritic cells (pDC). The translation of this approach into the clinic requires the production of high numbers of human pDC. Herein, we show that in vitro differentiation of cord blood CD34+ progenitors in the presence of aryl hydrocarbon receptor antagonists gives rise to clinically relevant numbers of pDC, as about 108 pDC can be produced from a typical cord blood unit. Blocking the aryl hydrocarbon receptor (AHR) pathway significantly increased the yield of pDC. When compared to pDC isolated from peripheral blood, in vitro differentiated pDC (ivD-pDC) exhibited an increased capacity to induce NK cell-mediated killing of ALL. Although ivD-pDC produced lower amounts of IFN-alpha than peripheral blood pDC upon TLR activation, they produced more IFN-lambda2, known to play a critical role in the induction of anti-tumoral NK cell functions. Both TLR-9 and TLR-7 ligands triggered pDC-induced NK cell activation, offering the possibility to use any clinical-grade TLR-7 or TLR-9 ligands in future clinical trials. Finally, adoptive transfer of ivD-pDC cultured in the presence of an AHR antagonist cured humanized mice with minimal ALL disease. Collectively, our results pave the way to clinical-grade production of sufficient numbers of human pDC for innate immunotherapy against ALL and other refractory malignancies. PMID- 28555260 TI - Serum Copeptin Predicts Severity and Recurrent Stroke in Ischemic Stroke Patients. AB - Several studies investigated the prognostic role of copeptin in stroke. The aim of this study is to assess copeptin levels in serum, and investigate their associations with risk of recurrent stroke in a 1-year follow-up study in patients with ischemic stroke. In this post hoc analysis, serum levels of copeptin and NIH stroke scale (NIHSS) were measured at the time of admission in a cohort of 316 patients with ischemic stroke. The end point was stroke recurrence after 1-year follow-up. We used logistic regression model to assess the relationship between copeptin levels and risk recurrent stroke. Logistic regression analysis considering traditional risk factors showed a relationship between serum copeptin levels and moderate-to-high clinical severity when serum copeptin was used as a continuous variable (OR, 1.05; 95% CI, 1.03-1.09). In the follow-up, 54 patients (17.1%) had a stroke recurrence. The stroke recurrence events distribution across the copeptin quartiles ranged between 5.1% (first quartile) to 23.1% (fourth quartile). In multivariate models comparing the third (OR = 2.78; 95% CI 1.85-3.53) and fourth quartiles (OR = 4.00; 95% CI 2.86-6.50) against the first quartile of the copeptin, levels of copeptin were associated with stroke recurrence events. A higher serum copeptin level is a predictor of both severity at admission and stroke recurrence at 1-year in stroke patients. PMID- 28555263 TI - Diamond ring sign. PMID- 28555262 TI - qRfg3, a novel quantitative resistance locus against Gibberella stalk rot in maize. AB - KEY MESSAGE: A quantitative trait locus qRfg3 imparts recessive resistance to maize Gibberella stalk rot. qRfg3 has been mapped into a 350-kb interval and could reduce the disease severity index by ~26.6%. Gibberella stalk rot, caused by the fungal pathogen Fusarium graminearum, severely affects maize yield and grain quality worldwide. To identify more resistance quantitative trait loci (QTLs) against this disease, we analyzed a recombinant inbred line (RIL) population derived from a cross between resistant H127R and susceptible C7-2 inbred lines. Within this population, maize resistance to Gibberella stalk rot had high broad-sense heritability. A major QTL, qRfg3, on chromosome 3 was consistently detected across three field trials, accounting for 10.7-19.4% of the total phenotypic variation. Using a progeny-based sequential fine-mapping strategy, we narrowed qRfg3 down to an interval of ~350 kb. We further demonstrated that qRfg3 is a recessive resistance locus to Gibberella stalk rot that reduced the disease severity index by ~26.6%. Both the gene location and recessive genetic mode distinguish qRfg3 from other stalk rot resistance loci. Hence, qRfg3 is valuable as a complement to existing resistance QTLs to improve maize resistance to Gibberella stalk rot. PMID- 28555264 TI - Right posterior hepatic notch sign. PMID- 28555261 TI - Paradigm shift of therapeutic management of brain metastases in EGFR-mutant non small cell lung cancer in the era of targeted therapy. AB - Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations commonly present brain metastases (BM) at the time of NSCLC diagnosis or during the clinical course. Conventionally, the prognosis of BM has been extremely poor, but the advent of EGFR-tyrosine kinase inhibitors (TKIs) has drastically improved the prognosis in these patients. Despite the presence of the blood-brain barrier, EGFR-TKIs have dramatic therapeutic effects on both BM and extracranial disease. In addition, recent systemic chemotherapies reportedly play a role in controlling BM. These treatment modalities can potentially replace whole brain radiotherapy (WBRT) to prevent or delay neurocognitive decline. Therefore, how to utilize these treatments is one issue. The other issue is what kind of treatment is best for recurrence after TKI therapy. Recent reports have shown a positive effect of a combination therapy of EGFR-TKI and radiotherapy on BM. Although neurocognitive decline is underscored when WBRT is considered, a survival benefit from WBRT has been proven especially in the potential long survivors with good prognostic index, especially disease-specific graded prognostic index (DS-GPA). In this review, treatment strategy including chemotherapeutic agents and radiotherapy is discussed in terms of risk-benefit balance in conjunction with DS-GPA. PMID- 28555265 TI - Whole-volume vs. segmental CT texture analysis of the liver to assess metachronous colorectal liver metastases. AB - PURPOSE: It is unclear whether changes in liver texture in patients with colorectal cancer are caused by diffuse (e.g., perfusional) changes throughout the liver or rather based on focal changes (e.g., presence of occult metastases). The aim of this study is to compare a whole-liver approach to a segmental (Couinaud) approach for measuring the CT texture at the time of primary staging in patients who later develop metachronous metastases and evaluate whether assessing CT texture on a segmental level is of added benefit. METHODS: 46 Patients were included: 27 patients without metastases (follow-up >2 years) and 19 patients who developed metachronous metastases within 24 months after diagnosis. Volumes of interest covering the whole liver were drawn on primary staging portal-phase CT. In addition, each liver segment was delineated separately. Mean gray-level intensity, entropy (E), and uniformity (U) were derived with different filters (sigma0.5-2.5). Patients/segments without metastases and patients/segments that later developed metachronous metastases were compared using independent samples t tests. RESULTS: Absolute differences in entropy and uniformity between the group without metastases and the group with metachronous metastases group were consistently smaller for the segmental approach compared to the whole-liver approach. No statistically significant differences were found in the texture measurements between both groups. CONCLUSIONS: In this small patient cohort, we could not demonstrate a clear predictive value to identify patients at risk of developing metachronous metastases within 2 years. Segmental CT texture analysis of the liver probably has no additional benefit over whole-liver texture analysis. PMID- 28555268 TI - [Medical assessment of environmental influences : New challenges for practice ante portas]. PMID- 28555266 TI - Laparoscopic surgery for congenital biliary dilatation: a single-institution experience. AB - PURPOSE: Laparoscopic surgery as a treatment for congenital biliary dilatation is uncommon. We herein present a series of laparoscopic surgeries for congenital biliary dilatation performed in our institution and review our experience with this approach over a long period of time. METHODS: Medical records of 36 consecutive patients who underwent laparoscopic surgery for congenital biliary dilatation from 1996 to 2015 were retrospectively reviewed. Data on patient demographics, operative time, blood loss, hospital stay, and complications were evaluated. A comparison between the former period (Group A, 1996-2005) and the latter period (Group B, 2006-2015) was performed. RESULTS: The patients comprised 23 females and 13 males with a median age of 34 years. The median operative time, blood loss, and hospital stay was 493 min, 154 g, and 11 days, respectively. Total early and late complications occurred in 7 (19%) and 2 (5%) patients, respectively. A comparison between Groups A and B revealed no significant difference in operative time or complications, but operative blood loss, open conversion, and hospital stay were significantly lower in Group B than in Group A (P < 0.05). CONCLUSION: Laparoscopic surgery for congenital biliary dilatation is feasible and provides acceptable results. Further prospective studies of larger numbers of patients are needed. PMID- 28555267 TI - Long-term outcome of adipose-derived regenerative cell-enriched autologous fat transplantation for reconstruction after breast-conserving surgery for Japanese women with breast cancer. AB - PURPOSE: More effective methods are needed for breast reconstruction after breast conserving surgery for breast cancer. The aim of this clinical study was to assess the perioperative and long-term outcomes of adipose-derived regenerative cell (ADRC)-enriched autologous fat grafting. METHODS: Ten female patients who had undergone breast-conserving surgery and adjuvant radiotherapy for breast cancer were enrolled. An ADRC-enriched fat graft prepared from the patient's adipose tissue was implanted at the time of adipose tissue harvest. The perioperative and long-term outcomes of the grafts, which included safety, efficacy, and questionnaire-based patient satisfaction, were investigated. RESULTS: The mean operation time was 188 +/- 30 min, and the mean duration of postoperative hospitalization was 1.2 +/- 0.4 days. No serious postoperative complications were associated with the procedure. Neither recurrence nor metastatic disease was observed during the follow-up period (7.8 +/- 1.5 years) after transplantation. Of 9 available patients, "more than or equal to average" satisfaction with breast appearance and overall satisfaction were reported by 6 (66.7%) and 5 (55.6%) patients, respectively. CONCLUSIONS: ADRC-enriched autologous fat transplantation is thus considered to be safe perioperatively, with no long-term recurrence, for patients with breast cancer treated by breast conserving surgery, and it may be an option for breast reconstruction, even after adjuvant radiotherapy. PMID- 28555269 TI - Placement accuracy of external ventricular drain when comparing freehand insertion to neuronavigation guidance in severe traumatic brain injury. AB - BACKGROUND: External ventricular drain (EVD) placement is a frequently performed neurosurgical procedure. Inaccuracies in drain positioning and the need for multiple passes using the classic freehand insertion technique is well reported in the literature, especially in the traumatic brain injury (TBI) population. The purpose of this study was to evaluate if electromagnetic neuronavigation guidance for EVD insertion improves placement accuracy and minimizes the number of passes in severe TBI patients. METHODS: Navigation was applied prospectively for all new severe TBI patients who required ventricular catheter placement over a period of 1 year, and compared with a retrospective cohort of severe TBI patients who had EVD inserted freehand in the preceding year. The placement accuracy was evaluated using the Kakarla grading system; the number of passes was also compared. RESULTS: Fifty-four cases were recruited: 35 (64.8%) had their EVD placed using the freehand technique and 19 (35.2%) using navigation guidance. In the navigation group, the placement accuracy was: 94.7% (18/19) grade 1, 5.3% (1/19) grade 2, and none at grade 3. In comparison, freehand placement was associated with misplacement (grades 2 and 3) in 42.9% of the cases (p value = 0.009). The number of passes was significantly lower in the navigation group (mean of 1.16 +/ 0.38), compared with the freehand group (mean of 1.63 +/- 0.88) (p value = 0.018). CONCLUSIONS: Using the navigation to guide EVD placement was associated with a significantly better accuracy and a lower number of passes in severe TBI patients. PMID- 28555270 TI - Critical review of brain AVM surgery, surgical results and natural history in 2017. AB - BACKGROUND: An understanding of the present standing of surgery, surgical results and the role in altering the future morbidity and mortality of untreated brain arteriovenous malformations (bAVMs) is appropriate considering the myriad alternative management pathways (including radiosurgery, embolization or some combination of treatments), varying risks and selection biases that have contributed to confusion regarding management. The purpose of this review is to clarify the link between the incidence of adverse outcomes that are reported from a management pathway of either surgery or no intervention with the projected risks of surgery or no intervention. METHODS: A critical review of the literature was performed on the outcomes of surgery and non-intervention for bAVM. An analysis of the biases and how these may have influenced the outcomes was included to attempt to identify reasonable estimates of risks. RESULTS: In the absence of treatment, the cumulative risk of future hemorrhage is approximately 16% and 29% at 10 and 20 years after diagnosis of bAVM without hemorrhage and 35% and 45% at 10 and 20 years when presenting with hemorrhage (annualized, this risk would be approximately 1.8% for unruptured bAVMs and 4.7% for 8 years for bAVMs presenting with hemorrhage followed by the unruptured bAVM rate). The cumulative outcome of these hemorrhages depends upon whether the patient remains untreated and is allowed to have a further hemorrhage or is treated at this time. Overall, approximately 42% will develop a new permanent neurological deficit or death from a hemorrhagic event. The presence of an associated proximal intracranial aneurysm (APIA) and restriction of venous outflow may increase the risk for subsequent hemorrhage. Other risks for increased risk of hemorrhage (age, pregnancy, female) were examined, and their purported association with hemorrhage is difficult to support. Both the Spetzler-Martin grading system (and its compaction into the Spetzler-Ponce tiers) and Lawton-Young supplementary grading system are excellent in predicting the risk of surgery. The 8-year risk of unfavorable outcome from surgery (complication leading to a permanent new neurological deficit with a modified Rankin Scale score of greater than one, residual bAVM or recurrence) is dependent on bAVM size, the presence of deep venous drainage (DVD) and location in critical brain (eloquent location). For patients with bAVMs who have neither a DVD nor eloquent location, the 8-year risk for an unfavorable outcome increases with size (increasing from 1 cm to 6 cm) from 1% to 9%. For patients with bAVM who have either a DVD or eloquent location (but not both), the 8-year risk for an unfavorable outcome increases with the size (increasing from 1 cm to 6 cm) from 4% to 35%. For patients with bAVM who have both a DVD and eloquent location, the 8-year risk for unfavorable outcome increases with size (increasing from 1 cm to 3 cm) from 12% to 38%. CONCLUSION: Patients with a Spetzler-Ponce A bAVM expecting a good quality of life for the next 8 years are likely to do better with surgery in expert centers than remaining untreated. Ongoing research is urgently required on the outcome of management pathways for bAVM. PMID- 28555271 TI - Delayed-onset post-craniotomy headache responsive to botulinum toxin A: a case series. AB - We report here the case of four patients presenting with delayed-onset temporal pain after pterional craniotomy. They reported similar symptoms: attacks of pain over the temporal region, ipsilateral to the operative site, irradiating around the eye and lasting from 10 min to 1 h. All patients had hypertrophy of at least one part of the temporalis muscle. All responded dramatically to botulinum toxin A injection (25 to 50 Botox(r) units) into the temporalis muscle. We suggest that the headaches were caused by aberrant nerve regeneration following surgical injury to the frontal branch of the facial nerve. PMID- 28555272 TI - Anatomical variants and bilateral lacrimal pathways surgery: avoiding unnecessary surgery. AB - Success rates (SR) of transcanalicular diode laser-assisted dacryocystorhinostomy (TCL DCR) may be affected by the presence of nasal anatomical variations and additionally by whether or not the pathology is bilateral. The aim is to determine whether it is necessary to perform preliminary nasal anatomical variations surgery and to determine whether bilateral cases may be operated simultaneously. We extracted the patients undergoing simultaneous bilateral TCL DCR and we compared SR across the different groups using ANOVA, Chi-square testing and logistical regression. 159 Lacrimal pathways were operated: 89 unilateral and 35 bilateral. Non-nasal anatomical variations (non-NAV) unilateral surgery returned a success of 72.72%. The mean SR for nasal anatomical variations (NAV) unilateral surgery was 70.1%. The SR for non-NAV bilateral surgery was 60.86%. The mean SR for nasal anatomical variations bilateral surgery was 58.33%. As we identified no significant differences in the SR for NAV and non-NAV patients, we can avoid simultaneous corrective surgery. PMID- 28555273 TI - Effects of transcutaneous electrical stimulation on vocal folds adduction. AB - According to most previous studies, inducing movements in internal laryngeal muscles by transcutaneous electrical stimulation (TES) was impossible. However, the movements have been reported after using needle electrodes inserted into the internal superior laryngeal nerve (ISLN). Herein, we aimed to apply an innovative TES protocol to cause movements in vocal folds. A short duration and high frequency electrical current was applied by two surface electrodes just above the entrance of ISLN to larynx. The subjects were 32 normal participants (mean age = 23.87; SD = 3.43). During TES application, the vocal folds' movements were examined by flexible videonasolaryngoscopy. Statistical paired t test was used to analyze the differences of vocal folds opening angle, in degrees, during rest and TES periods. Furthermore, the movements were judged by seven experienced speech pathologists via a 9-point rate scale from -1 (any abduction) to 8 (complete adduction). The mean vocal folds adduction increased by 35.68 degrees (t = 9.35, p > 0.001) due to TES application. The mean qualitative scores assigned by raters to each subject were between 6 and 7 points, which indicate an acceptable adduction in vocal folds through TES. Unlike previous studies, the applied TES protocol in this research induced significant vocal fold movements. This might be attributed to our different stimulation parameters, which were designed to penetrate deeply and stimulate ISLN specifically. It is worth noting that we introduced a novel TES protocol, which should be confirmed and then examined as a complementary therapy for neurologic voice disorders in future studies. PMID- 28555274 TI - Survival analysis of 287 oropharyngeal squamous cell carcinoma patients in a single institution: a retrospective comparison of two consecutive time intervals with surgical and conservative treatment approaches. AB - This study is a retrospective analysis of clinico-pathological data to investigate survival rates of patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with different modalities in a single academic head and neck cancer center in different time intervals. Altogether, 287 patients with OPSCC were included in this comparison. Patients were analysed during two different treatment periods: Group 1 included patients treated mainly with primary surgery +/- adjuvant radio(chemo)therapy between 2002 and 2007, while Group 2 included patients treated with organ/function-preservation protocols if indicated. Main outcome measures were overall survival (OS) and recurrence-free survival (RFS). Between 2002 and 2007, early-stage OPSCC showed a 5-year OS of 75% compared to that of 86% between 2008 and 2013. Locally advanced OPSCC showed a 5-year OS of 66% between 2002 and 2007 compared to that of 74% between 2008 and 2013. RFS in early-stage OPSCC was 48% between 2002 and 2007 in contrast to that of 77% between 2008 and 2013. With locally advanced OPSCC, RFS was 55% between 2002 and 2007 compared to that of 56% between 2008 and 2013. These differences were statistically not significant. The OS and RFS remained generally unchanged over the analysed time period. There was no significant difference in the outcomes with regards to HPV status and to their treatment modality. PMID- 28555275 TI - Control of force during rapid visuomotor force-matching tasks can be described by discrete time PID control algorithms. AB - Force trajectories during isometric force-matching tasks involving isometric contractions vary substantially across individuals. In this study, we investigated if this variability can be explained by discrete time proportional, integral, derivative (PID) control algorithms with varying model parameters. To this end, we analyzed the pinch force trajectories of 24 subjects performing two rapid force-matching tasks with visual feedback. Both tasks involved isometric contractions to a target force of 10% maximal voluntary contraction. One task involved a single action (pinch) and the other required a double action (concurrent pinch and wrist extension). 50,000 force trajectories were simulated with a computational neuromuscular model whose input was determined by a PID controller with different PID gains and frequencies at which the controller adjusted muscle commands. The goal was to find the best match between each experimental force trajectory and all simulated trajectories. It was possible to identify one realization of the PID controller that matched the experimental force produced during each task for most subjects (average index of similarity: 0.87 +/- 0.12; 1 = perfect similarity). The similarities for both tasks were significantly greater than that would be expected by chance (single action: p = 0.01; double action: p = 0.04). Furthermore, the identified control frequencies in the simulated PID controller with the greatest similarities decreased as task difficulty increased (single action: 4.0 +/- 1.8 Hz; double action: 3.1 +/- 1.3 Hz). Overall, the results indicate that discrete time PID controllers are realistic models for the neural control of force in rapid force-matching tasks involving isometric contractions. PMID- 28555276 TI - Suppression of phosphorylated MAPK and caspase 3 by carbon dioxide. AB - Although CO2 is produced during the oxidation of different substrates in all types of cells, the role of this gas in the regulation of cellular function is not clearly understood. Since changes in several signal transduction as well as apoptotic, anti-apoptotic, and other proteins are known to modify cellular function, we investigated if some of these proteins are altered upon incubating the rat hind leg skeletal muscle in a medium enriched with CO2 (1000-1200 ppm) for 30 min. CO2 was observed to depress phosphorylated levels of ERK1 (P44) and ERK2 (P42) without affecting the unphosphorylated content of these MAPK proteins. On the other hand, no change in p38 MAPK protein was found but the content of its degradation product 30 kDa proteins (both phosphorylated and unphosphorylated) was decreased. No alterations in the content of other signaling proteins (PKA and Akt), inflammatory molecule (TNF-alpha), and vascular endothelial growth factor (VEGF) were seen upon exposure of the muscle to CO2. The content for apoptotic and anti-apoptotic proteins (Bad and Bcl2), except for a decrease in caspase 3, were also not affected by CO2. These results indicate that CO2 may serve as a gasotransmitter to regulate cellular function by depressing MAPK and caspase 3 activities. PMID- 28555277 TI - Association between anti-Porphyromonas gingivalis antibody, anti-citrullinated protein antibodies, and rheumatoid arthritis : A meta-analysis. AB - OBJECTIVE: The aim of this study was to determine the relationship between anti Porphyromonas gingivalis (anti-P. gingivalis) antibody levels and rheumatoid arthritis (RA) and its correlation with anti-citrullinated protein antibodies (ACPA). METHODS: We performed a meta-analysis of studies comparing (a) anti-P. gingivalis antibody levels in RA patients and healthy controls and (b) the correlation coefficients between the anti-P. gingivalis antibody levels and ACPA in RA patients. RESULTS: The study included 14 articles with 3829 RA patients and 1239 controls. Our meta-analysis showed that anti-P. gingivalis antibody levels were significantly higher in the RA group than in the control group (standardized mean difference [SMD] = 0.630, 95% CI = 0.272-0.989, p = 0.001). Subgroup analysis revealed that RA patients had significantly elevated anti-P. gingivalis antibody levels compared with healthy controls, but not compared with the non-RA control group and also not between different sample sizes. Anti-P. gingivalis antibody levels were significantly higher in the RA group than in the control group in the age-/sex-matched population, but not in the unmatched population. Anti-P. gingivalis antibody levels were significantly higher in the ACPA-positive group than in the ACPA-negative group (SMD = 0.322, 95% CI = 0.164-0.480, p = 6.4 * 10-5). Meta-analysis of the correlation coefficients showed a significant positive correlation between anti-P. gingivalis antibody levels and ACPA (correlation coefficient = 0.147, 95% CI = 0.033-0.258, p = 0.012). CONCLUSION: Our meta-analysis demonstrated that anti-P. gingivalis antibody levels were significantly higher in patients with RA and they were positively correlated with ACPA. PMID- 28555278 TI - The response of archaeal species to seasonal variables in a subtropical aerated soil: insight into the low abundant methanogens. AB - Archaea are cosmopolitan in aerated soils around the world. While the dominance of Thaumarchaeota has been reported in most soils, the methanogens are recently found to be ubiquitous but with low abundances in the aerated soil globally. However, the seasonal changes of Archaea community in the aerated soils are still in the mist. In this study, we investigated the change of Archaea in the context of environmental variables over a period of 12 months in a subtropical soil on the Chongming Island, China. The results showed that Nitrososphaera spp. were the dominant archaeal population while the methanogens were in low proportions but highly diverse (including five genera: Methanobacterium, Methanocella, Methanosaeta, Methanosarcina, and Methanomassiliicoccus) in the aerated soil samples determined by high throughput sequencing. A total of 126 LSA correlations were found in the dataset including all the 72 archaeal OTUs and 8 environmental factors. A significance index defined as the pagerank score of each OTU divided by its relative abundance was used to evaluate the significance of each OTU. The results showed that five out of 17 methanogen OTUs were significantly positively correlated with temperature, suggesting those methanogens might increase with temperature rather than being dormant in the aerated soils. Given the metabolic response of methanogens to temperature under aerated soil conditions, their contribution to the global methane cycle warrants evaluation. PMID- 28555280 TI - Fabrication of Low-Generation Dendrimers into Nanostructures for Efficient and Nontoxic Gene Delivery. AB - Dendrimers with well-defined molecular structure and high monodispersity have gained tremendous interest in gene delivery. However, current gene carriers based on dendrimers are either not effective or are too toxic on the transfected cells. The efficacy and cytotoxicity of dendrimers are strongly correlated with their molecular weight or generation. High-generation dendrimers are reported with relatively high transfection efficacy but serious cytotoxicity due to the excess positive charges on the polymers, while low-generation dendrimers with minimal toxicity have poor polyplex stability and thus weak transfection efficacy. To break up the correlation between efficacy and toxicity, low-generation dendrimers were fabricated into various nanostructures by several strategies to improve their gene-binding capacity, polyplex stability, and transfection efficacy without inducing additional toxicity. In this review article, we will highlight recent advances in the development of assembled dendrimer nanostructures for efficient and non-toxic gene delivery. Specifically, the principles and strategies in the fabrication of dendrimer nanostructures are intensively reviewed. PMID- 28555279 TI - Mercury uptake by halophytes in response to a long-term contamination in coastal wetland salt marshes (northern Adriatic Sea). AB - Mercury (Hg) distribution in saltmarsh sediments and in three selected halophytes (Limonium narbonense, Sarcocornia fruticosa and Atriplex portulacoides) of a wetland system (Marano and Grado Lagoon, Italy) following a contamination gradient in sediments was investigated. The Hg uptake was evaluated at the root system level by calculating the enrichment factor (EF) and in the aboveground tissues by means of the translocation factor (TF). The related methylmercury (MeHg) concentrations in the halophytes were also investigated with regard to the location of the sites and their degree of contamination. Hg concentration in halophytes seemed poorly correlated both with the total Hg in rhizo-sediments and with the specific plant considered, supporting the evidence that the chemico physical parameters of sediments could significantly affect metal availability for plants. Hg concentrations in roots increased with depth and were 20-fold higher than content measured in related rhizo-sediments (high EF). A low content of Hg is translocated in aboveground tissues (very low TF values), thus highlighting a kind of avoidance strategy of these halophytes against Hg toxicity. MeHg values were comparable between the two sites and among species, but the translocation from below- to aboveground plant tissues was more active. PMID- 28555281 TI - Disease activity and mucosal healing in inflammatory bowel disease: a new role for histopathology? AB - Histologic evaluation of disease activity in the setting of inflammatory bowel disease is gaining interest within the gastroenterology community. Recent data suggests that histologic measurements of inflammation in ulcerative colitis are more sensitive at detecting disease activity and perform better than endoscopic measurements in predicting clinical outcomes. Histologic measurements are also increasingly used in ulcerative colitis clinical trials to assess response to new therapies. Histologic measurements of disease activity are less well studied in Crohn's disease, but are gaining attention. Current published treatment algorithms in inflammatory bowel disease do not take into consideration histologic activity; however, this may change in the near future. In order for histologic measurements to be included in clinical decision-making, validated, reliable, and responsive histologic scoring systems are needed. In this review, the recent literature on the significance of histologic activity in both ulcerative colitis and Crohn's disease is summarized. Histologic scoring systems are also briefly discussed. PMID- 28555283 TI - Statin use does not protect from fractures: the healthy adherer effect is a plausible explanation in observational studies. PMID- 28555282 TI - SMARCA4-deficient pulmonary adenocarcinoma: clinicopathological, immunohistochemical, and molecular characteristics of a novel aggressive neoplasm with a consistent TTF1neg/CK7pos/HepPar-1pos immunophenotype. AB - Alterations in SMARCA4, a member of the chromatin remodeling Switch Sucrose Non Fermentable (SWI/SNF) complex, characterize a subset of non-small cell lung cancer (NSCLC), but detailed morphological and immunophenotypic description of this tumor type is lacking. We describe 20 NSCLC cases found on routine screening not to express SMARCA4 by immunohistochemistry (IHC). These tumors were stained for CK7, TTF1, SMARCA2, SMARCA4, SMARCB1, and HepPar-1 and analyzed for molecular alterations, using a 160 cancer-related gene panel including the full coding sequence of SMARCA4. Patients were eight females and 12 males aged 41 to 76 (median, 60). Of 18 tumors with detailed data, 14 presented with synchronous distant metastases (M1). Histological examination showed predominantly solid adenocarcinoma (n = 15), frankly rhabdoid (n = 3) and mucinous (n = 2) patterns. Except for the rhabdoid cases, all tumors showed at least focal unequivocal glands and lacked squamous differentiation, justifying a diagnosis of adenocarcinoma. IHC showed a distinctive uniform immunophenotype (CK7+/HepPar 1+/TTF1-) in 18/20 cases. Only 2/16 cases showed limited weak expression of neuroendocrine markers. EGFR mutations and EML4-ALK and ROS1 gene rearrangements were not found in any of the examined cases. Next-generation sequencing, using a 160 cancer-related gene panel, revealed concurrent SMARCA4 and TP53 mutations in nine of the 12 (75%) successfully tested cases. Our study highlights (1) the morphological diversity of SMARCA4-deficient lung adenocarcinoma, (2) the consistent absence of expression of TTF1 in the presence of expression of HepPar 1, (3) absence of EGFR driver mutations, and (4) frequent inactivating SMARCA4 mutations as underlying mechanism of the observed SMARCA4 protein loss. SMARCA4 deficient pulmonary adenocarcinoma is emerging as a distinctive, albeit phenotypically heterogeneous molecular subgroup of TTF1-negative NSCLC. Uniform HepPar-1 expression in this subset of NSCLC may represent a diagnostic pitfall and merits further studies to explore the mechanisms involved. PMID- 28555284 TI - Statin treatment and healthy adherer effects. PMID- 28555286 TI - [Management of arterial hypertension]. AB - Arterial hypertension has a high prevalence and is a major risk factor for the development of cardiovascular diseases. It is a major contributor to worldwide morbidity and mortality and hence poses a huge socioeconomic burden. Despite great progress in perception, diagnosis and treatment of hypertension, blood pressure control is inadequate in less than half of the hypertensive patients (<140/90 mm Hg). The diagnosis of arterial hypertension starts in most patients with the conventional office blood pressure measurement. Out-of-office blood pressure measurement is an important adjunct, especially to unmask white-coat hypertension. To reach the right target blood pressure many effective antihypertensive drugs are available. By how much the blood pressure should be lowered is currently a matter of controversy. The 2013 European and the identical German national guidelines recommend a target blood pressure of <140/90 mm Hg for most patients. The recent SPRINT study revealed that some patients may benefit from an even lower blood pressure. This CME-article summarizes recent developments in the management of arterial hypertension and provides tips for daily practice based on these aims. PMID- 28555285 TI - Association of adiposity indices with bone density and bone turnover in the Chinese population. AB - : Associations of adiposity indices with bone mineral density (BMD) and bone turnover markers were evaluated in Chinese participants. Body mass index, fat mass, and lean mass are positively related to BMD in both genders. Subcutaneous fat area was proved to be negatively associated with BMD and positively correlated with osteocalcin in postmenopausal females. INTRODUCTION: Obesity is highly associated with osteoporosis, but the effect of adipose tissue on bone is contradictory. Our study aimed to assess the associations of adiposity indices with bone mineral density (BMD) and bone turnover markers (BTMs) in the Chinese population. METHODS: Our study recruited 5215 participants from the Shanghai area, evaluated related anthropometric and biochemical traits in all participants, tested serum BTMs, calculated fat distribution using magnetic resonance imaging (MRI) images and image analysis software, and tested BMD with dual-energy X-ray absorptiometry. RESULTS: When controlled for age, all adiposity indices were positively correlated with BMD of all sites for both genders. As for the stepwise regression analysis, body mass index (BMI), fat mass, and lean mass were protective for BMD in both genders. However, subcutaneous fat area (SFA) was detrimental for BMD of the L1-4 and femoral neck (beta +/- SE -0.0742 +/- 0.0174; p = 2.11E-05; beta +/- SE -0.0612 +/- 0.0147; p = 3.07E-05). Adiposity indices showed a negative correlation with BTMs adjusting for age, especially with osteocalcin. In the stepwise regression analysis, fat mass was negatively correlated with osteocalcin (beta +/- SE -8.8712 +/- 1.4902; p = 4.17E-09) and lean mass showed a negative correlation with N-terminal procollagen of type I collagen (PINP) for males (beta +/- SE -0.3169 +/- 0.0917; p = 0.0006). In females, BMI and visceral fat area (VFA) were all negatively associated with osteocalcin (beta +/- SE -0.4423 +/- 0.0663; p = 2.85E-11; beta +/- SE -7.1982 +/ 1.1094; p = 9.95E-11), while SFA showed a positive correlation with osteocalcin (beta +/- SE: 5.5993 +/- 1.1753; p = 1.98E-06). CONCLUSION: BMI, fat mass, and lean mass are proved to be beneficial for BMD in both males and postmenopausal females. SFA is negatively associated with BMD and positively correlated with osteocalcin in postmenopausal females. PMID- 28555287 TI - Genetic diagnostics of inherited aortic diseases : Medical strategy analysis. AB - Genetic aortic syndromes (GAS) include Marfan, Loeys-Dietz, vascular Ehlers Danlos, and Turner syndrome as well as congenital bicuspid aortic valve. The clinical management of these diseases has certain similarities and differences. We employed medical strategy analysis to test the utility of genetic diagnostics in the management of GAS. We chose the standpoint of the cardiologist for our analysis. In the first step, the medical goals in the management of GAS are specified. In the second step, the accuracy of genetic diagnostics for GAS is examined. Finally, conclusions can be drawn about the utility of genetic diagnostics in managing GAS. We found that genetic diagnostics is necessary to exclude GAS, to diagnose GAS, and to specify disease types. Second, combining phenotype with genotype information maximizes the predictability of the course of disease. Third, with genetic diagnostics it is possible to predict the birth of children with causative mutations for GAS and to initiate drug therapy to prevent the onset of aortic dilatation or to slow down its progression to aortic aneurysm. Finally, genetic diagnostics improves prognostic predictions and thereby contributes to a better timing of elective surgery and to a better choice of procedures. The findings of our medical strategy analysis indicate the high utility of genetic diagnostics for managing GAS. PMID- 28555289 TI - Association of high carotid bifurcation and thyrolinguofacial trunk: a rare variation. AB - Variations in the origins and the branching pattern of the carotid system of arteries are not uncommon. Here we report a rare case of higher bifurcation of the common carotid artery (CCA) (at the level of the greater cornu of the hyoid bone), thyrolinguofacial trunk (TLFT) originating from the CCA, superior laryngeal artery (SLA) arising from the external carotid artery (ECA) on the left side, and linguofacial trunk arising from the ECA on the right side. In the present case, the CCA and carotid bifurcation may have arisen from the second aortic arch. The ECA bud could have developed from parts of the first aortic arch and ventral aorta. Thus, the altered blood flow through these vessels due to high carotid bifurcation could have caused disproportionate growth and shift in the origins of the branches of the ECA. An understanding of the bifurcation of the CCA and the branching pattern of the ECA should prove useful to surgeons performing selective intra-arterial chemotherapy for head and neck cancer. PMID- 28555288 TI - [Congenital disorders of lipoprotein metabolism]. AB - Congenital disorders of lipid metabolism are caused by a wide range of variants of the genes for receptors, apolipoproteins, enzymes, transfer factors, and cellular cholesterol transporters. Clinically most relevant are autosomal dominant familial hypercholesterolemia (FH) and familial combined hyperlipoproteinemia (FCHL). FH has a prevalence of 1:250. It is due to mutations of the low density lipoprotein (LDL) receptor, less often to mutations of the apolipoprotein B (APOB), the proprotein convertase subtilisin/kexin type 9 (PCSK9), or the signal transducing adapter family member 1 (STAP1). FH often leads to early atherosclerosis. Its diagnosis can definitely be made only by molecular genetic testing. The detection of mutations of the LDLR, APOB, or PCSK9 is an indicator for extremely high cardiovascular risk, independently of the concentration of LDL cholesterol. FCHL is also common (1:100) and is seen in about 10% of patients with early myocardial infarction. It is produced by combinations of frequent genetic variants affecting triglycerides and LDL cholesterol. Other monogenic hyperlipoproteinemias (HLP) affect the catabolism of chylomicrons (familial chylomicronemia) or of remnants of triglyceride-rich lipoproteins (type III hyperlipoproteinemia). Multiple hereditary disorders in HDL metabolism - with a broad spectrum of clinical significance - are known. Currently, second generation sequencing methods are used to simultaneously analyze multiple disease-causing genes. This approach cost-neutrally provides additional information such as the genetic risk of atherosclerosis and predisposition to statin intolerance. PMID- 28555291 TI - Early Adolescents' Peer Experiences with Ethnic Diversity in Middle School: Implications for Academic Outcomes. AB - As the U.S. becomes increasingly ethnically diverse, opportunities for cross ethnic interaction at school may be increasing, and these interactions may have implications for academic outcomes for both ethnic minority and White youth. The current study examines how cross-ethnic peer relationships, measured using peer nominations for acceptance and daily lunchtime interactions, relate to academic outcomes for an ethnically diverse sample of 823 (45% boys and 55% girls; M age = 11.69) public middle school sixth graders across one Midwestern and two Western states. For White, Black, Asian, Latino/a, and Multiethnic students, self reported daily cross-ethnic peer interactions were associated with higher end-of year GPAs in core academic courses and teachers' expectations for educational attainment, but not self-reported school aversion. Making cross-ethnic acceptance nominations was not associated with any academic outcomes. Thus, daily opportunities for cross-ethnic interactions may be important school experiences for early adolescents. PMID- 28555292 TI - Associations Between Trauma Type, Timing, and Accumulation on Current Coping Behaviors in Adolescents: Results from a Large, Population-based Sample. AB - The development of adolescents' coping in response to stress is critical for adaptive functioning; these coping strategies may be shaped by numerous environmental factors during childhood, including experiences such as exposure to trauma. Childhood trauma has been shown to undermine contemporaneous coping, but how does a history of exposure to trauma and the characteristics of that trauma (type, timing, and accumulation) relate to current coping among adolescents? We addressed this question using a nationally-representative sample of 9427 adolescents (ages 13-18; 48.9% female; 66% White). Adolescents reported on their lifetime exposure to 18 different traumas, including witnessing or experiencing interpersonal violence, accidents, disasters, and violent or accidental loss of loved ones, as well as their current use of coping behaviors when under stress (problem-focused, positive emotion-focused, and negative emotion-focused coping strategies). The study's results highlight that exposure to nearly all forms of trauma was unrelated to problem-focused and positive emotion-focused coping behaviors, but strongly associated with increased negative emotion-focused coping. Use of each coping style did not vary with age at first exposure to trauma, but increased with the number of lifetime traumatic events experienced. The findings suggest that the extent of prior exposure to trauma, including variations across type and timing, may be related to a particular form of coping that has been linked to increased risk for mental health problems. Study results highlight coping strategies as a potential target for prevention and treatment efforts, and indicate a need to better understand the malleability and trajectory of coping responses to stress for promoting healthy youth development. PMID- 28555293 TI - Unpacking the Relationships between Impulsivity, Neighborhood Disadvantage, and Adolescent Violence: An Application of a Neighborhood-Based Group Decomposition. AB - Scholars have become increasingly interested in how social environments condition the relationships between individual risk-factors and adolescent behavior. An appreciable portion of this literature is concerned with the relationship between impulsivity and delinquency across neighborhood settings. The present article builds upon this growing body of research by considering the more nuanced pathways through which neighborhood disadvantage shapes the development of impulsivity and provides a situational context for impulsive tendencies to manifest in violent and aggressive behaviors. Using a sample of 12,935 adolescent from the National Longitudinal Study of Adolescent to Adult Health (Add Health) (mean age = 15.3, 51% female; 20% Black, 17% Hispanic), we demonstrate the extent to which variation in the association between impulsivity and delinquency across neighborhoods can be attributed to (1) differences in mean-levels of impulsivity and violence and (2) differences in coefficients across neighborhoods. The results of a series of multivariate regression models indicate that impulsivity is positively associated with self-reported violence, and that this relationship is strongest among youth living in disadvantaged neighborhoods. The moderating effect of neighborhood disadvantage can be attributed primarily to the stronger effect of impulsivity on violence in these areas, while differences in average levels of violence and impulsivity account for a smaller, yet nontrivial portion of the observed relationship. These results indicate that the differential effect of impulsivity on violence can be attributed to both developmental processes that lead to the greater concentration of violent and impulsive adolescents in economically deprived neighborhoods as well as the greater likelihood of impulsive adolescents engaging in violence when they reside in economically disadvantaged communities. PMID- 28555295 TI - Expression and Characterization of Hyperthermostable Exopolygalacturonase RmGH28 from Rhodothermus marinus. AB - The gene RmGH28 from the organism Rhodothermus marinus, a putative glycosyl hydrolase family 28 polygalacturonase, was expressed in Escherichia coli and biochemically characterized. The gene was found to encode an exopolygalacturonase termed RmGH28, with galacturonic acid monomer and the polymer substrate (n-1) as the products released when acting on de-esterified polygalacturonic acid from citrus pectin. The enzyme at 25 degrees C had k cat ~6 s-1 when acting on polygalacturonic acid, with K m ~0.7 MUM and a substrate inhibition constant K si ~70 MUM. The enzyme was hyperthermophilic, with one half initial enzyme activity remaining after 1-h incubation at 93.9 degrees C. Since the enzyme can function at high temperatures where reaction rates are increased and the risk of bacterial contamination is decreased, this indicates that RmGH28 can be useful in industry for generating galacturonic acid from pectin. The amino acid sequence of RmGH28 is highly homologous to the known hyperthermophilic exopolygalacturonases TtGH28 and Tm0437, which together can serve as starting points for structure-function studies and molecular breeding enzyme engineering approaches. PMID- 28555294 TI - The longitudinal relationship of work stress with peak expiratory flow: a cohort study. AB - PURPOSE: Research has suggested that psychological stress is associated with reduced lung function and with the development of respiratory disease. Among the major potential sources of stress in adulthood are working conditions. We aimed to examine the relationship of work stress with lung function. METHODS: We drew on 4-year prospective data from the Survey of Health, Ageing and Retirement in Europe. The analyzed sample comprised 2627 workers aged 50 years or older who were anamnestically free of respiratory disease. Work stress at baseline was operationalized by abbreviated instruments measuring the well-established effort reward imbalance model (seven items) and the control component of the job-demand control (two items). Peak expiratory flow (PEF) was determined at baseline and at follow-up. Continuous and categorized (i.e., by the tertile) work stress variables were employed in multivariable linear regression models to predict PEF change. RESULTS: Work stress did not show statistically significant associations with PEF change. For instance, the unstandardized regression coefficient for PEF decline according to high versus low effort-reward imbalance was -1.41 (95% confidence interval = -3.75, 0.94). CONCLUSIONS: Our study is the first to examine prospective relationships between work stress and PEF. Overall, we did not observe meaningful associations. Future studies should consider a broader spectrum of spirometric parameters and should expand research to younger and possibly less-selected working populations (i.e., aged <50 years). PMID- 28555297 TI - Abdominal pain in a 5-year-old girl with bilateral nephromegaly: Questions. PMID- 28555296 TI - Acute kidney injury in premature newborns-definition, etiology, and outcome. AB - BACKGROUND: Neonatal acute kidney injury (AKI) is common and is associated with poor outcomes. New criteria for the diagnosis of AKI were introduced based on the increase in serum creatinine (SCr) levels and/or reduction of urine output (UOP). Yet, there is no generally accepted opinion so far, which criteria (whether SCr, UOP, or their combination) are the most appropriate to diagnose neonatal AKI. METHODS: The retrospective study included 195 prematurely born neonates who fulfilled all inclusion criteria (with at least two SCr measurements). In all the neonates included in the study, AKI was diagnosed using three different definitions: (1) SCr criteria (an increase in SCr values of >=0.3 mg/dl), (2) UOP criteria (UOP < 1.5 ml/kg/h), and (3) SCr + UOP criteria. RESULTS: Out of all of the patients the study included, 85 (44%) were diagnosed with AKI. The neonates who had AKI had a significantly lower gestational age, birth weight, and Apgar score, longer duration of mechanical ventilation, and a higher mortality rate. SCr + UOP criteria showed higher sensitivity for prediction of death compared to SCr or UOP alone (p = 0.0008, 95% CI 0.040-0.154, and p = 0.0038, 95% CI 0.024 0.125, respectively). If only SCr or only UOP criterion are used, they fail to identify AKI in 61 and 67%, respectively. AKI was an independent risk factor for death (OR 7.4875; CI 3.1887-17.5816). CONCLUSIONS: Similar to other studies, our data showed that neonates with AKI have worse outcome. Neonatal AKI defined based on SCr + UOP criteria is a better predictor of death than neonatal AKI defined based only on the SCr or UOP criteria. Also, by using SCr + UOP criteria for diagnosing neonatal AKI, more patients with AKI are recruited than when only one of those criteria is used. PMID- 28555298 TI - Abdominal pain in a 5-year-old girl with bilateral nephromegaly: Answers. AB - Renal involvement in non-Hodgkin lymphoma is a recognized development, but it mostly follows a diagnosis of lymphoma. We describe a rare case of a T-cell-type non-Hodgkin lymphoma that first presents as nephromegaly in a 5-year-old girl admitted to the emergency department with abdominal pain. Further investigation revealed bilateral nephromegaly, but the results of blood tests, imaging studies, and bone marrow aspiration were inconclusive. During the second week of hospitalization, significant physical examination revealed an enlarged lymph node in the anterior cervical chains, confirming a diagnosis of Non-Hodgkin's lymphoma. This case illustrates that it is important to have a high degree of suspicion in any patient presenting with unexplained enlarged kidneys without any identifiable cause because it could be the first presentation of a hematologic malignancy. PMID- 28555299 TI - Life with one kidney. AB - Life with a solitary functioning kidney (SFK) may be different from that when born with two kidneys. Based on the hyperfiltration hypothesis, a SFK may lead to glomerular damage with hypertension, albuminuria and progression towards end stage renal disease. As the prognosis of kidney donors was considered to be very good, having a SFK has been considered to be a benign condition. In contrast, our research group has demonstrated that being born with or acquiring a SFK in childhood results in renal injury before adulthood in over 50% of those affected. Most congenital cases will be detected during antenatal ultrasound screening, but up to 38% of cases of unilateral renal agenesis are missed. In about 25-50% of cases of antenatally detected SFK there will be signs of hypertrophy, which could indicate additional nephron formation and is associated with a somewhat reduced risk of renal injury. Additional renal and extrarenal anomalies are frequently detected and may denote a genetic cause for the SFK, even though for the majority of cases no explanation can (yet) be found. The ongoing glomerular hyperfiltration results in renal injury, for which early markers are lacking. Individuals with SFK should avoid obesity and excessive salt intake to limit additional hyperfiltration. As conditions like hypertension, albuminuria and a mildly reduced glomerular filtration rate generally do not result in specific complaints but may pose a threat to long-term health, screening for renal injury in any individual with a SFK would appear to be imperative, starting from infancy. With early treatment, secondary consequences may be diminished, thereby providing the optimal life for anyone born with a SFK. PMID- 28555300 TI - Safety of Delayed Umbilical Cord Clamping in Preterm Neonates Less than 34 weeks Gestation: Correspondence. PMID- 28555302 TI - Respecting the Dignity of Children with Disabilities in Clinical Practice. AB - Prevailing philosophies about parental and other caregiver responsibilities toward children tend to be protectionist, grounded in informed benevolence in a way that countenances rather than circumvents intrusive paternalism. And among the kinds of children an adult might be called upon to parent or otherwise care for, children with disabilities figure among those for whom the strongest and snuggest shielding is supposed be deployed. In this article, we examine whether this equation of securing well-being with sheltering by protective parents and other care-givers should unreflectively be adopted for disabled children. We also consider why healthcare providers might reasonably be reluctant to yield to this principle, even if parents instinctively suppose that protectionism is the parenting policy that best serves their disabled child's interest. We contend that caregivers owe children with disabilities at least as much, and possibly more, respect for self-governance than other children need. In spite of disabled children's vulnerability and even in view of it, we argue that they should be accorded not only welfare rights to well-being but at least a modified version of liberty rights as well. Healthcare providers are especially favorably positioned to facilitate the latter response. The main components of respectful caregiving can come into conflict with one another, but we present some priorities that advise against adopting a protectionist account of parenting rights, or at least against accepting protectionist views that focus parenting narrowly on shaping ideas about the child's welfare. In sum, caring for a disabled child, we argue, involves more than creating conditions that will afford her contentment and comfort over the course of life. PMID- 28555301 TI - Nuances of electrophoresis study of titin/connectin. AB - Almost 40 years has passed since the discovery of giant elastic protein titin (also known as connectin) of striated and smooth muscles using gel electrophoresis. Sodium dodecyl sulfate polyacrylamide gel electrophoresis is a major technique for studying the isoform composition and content of titin. This review provides historical insights into the technical aspects of the electrophoresis methods used to identify titin and its isoforms. We particularly focus on the nuances of the technique that improve the preservation of its primary structure so that its high molecular weight isoforms can be visualized. PMID- 28555304 TI - Perspective. PMID- 28555303 TI - The Evolution of Spina Bifida Treatment Through a Biomedical Ethics Lens. AB - Spina bifida is a neurodevelopmental disorder that results in a broad range of disability. Over the last few decades, there have been significant advances in diagnosis and treatment of this condition, which have raised concerns regarding how clinicians prognosticate the extent of disability, determine quality of life, and use that information to make treatment recommendations. From the selective treatment of neonates in the 1970s, to the advent of maternal-fetal surgery today, the issues that have been raised surrounding spina bifida intervention invoke principles of medical bioethics such as beneficence and nonmaleficence, while also highlighting how quality of life judgments may drive care decisions. Such changes in treatment norms are also illustrative of how disability is viewed both within the medical community and by society at large. An examination of the changes in spina bifida treatment provides a model through which to understand how ethically complex decisions regarding care for children with disabilities has evolved, and the challenges faced when medical information is combined with value based judgments to guide medical decision making. PMID- 28555307 TI - The influence of ancient Greek thought on fifteenth century anatomy: Galenic influence and Leonardo da Vinci. AB - Leonardo da Vinci (1452-1519) can be called one of the earliest contributors to the history of anatomy and, by extension, the study of medicine. He may have even overshadowed Andreas Vesalius (1514-1564), the so-called founder of human anatomy, if his works had been published within his lifetime. While some of the best illustrations of their time, with our modern knowledge of anatomy, it is clear that many of da Vinci's depictions of human anatomy are inaccurate. However, he also made significant discoveries in anatomy and remarkable predictions of facts he could not yet discover with the technology available to him. Additionally, da Vinci was largely influenced by Greek anatomists, as indicated from his ideas about anatomical structure. In this historical review, we describe da Vinci's history, influences, and discoveries in anatomical research and his depictions and errors with regards to the musculoskeletal system, cardiovascular system, nervous system, and other organs. PMID- 28555305 TI - Differential regulation of glyceroneogenesis by glucocorticoids in epididymal and retroperitoneal white adipose tissue from rats. AB - PURPOSE: Investigate the glycerol-3-phosphate generation pathways in epididymal (EPI) and retroperitoneal (RETRO) adipose tissues from dexamethasone-treated rats. METHODS: Rats were treated with dexamethasone for 7 days. Glycerol-3 phosphate generation pathways via glycolysis, glyceroneogenesis and direct phosphorylation of glycerol were evaluated, respectively, by 2-deoxyglucose uptake, phosphoenolpyruvate carboxykinase (PEPCK-C) activity and pyruvate incorporation into triacylglycerol (TAG)-glycerol, and glycerokinase activity and glycerol incorporation into TAG-glycerol. RESULTS: Dexamethasone treatment markedly decreased the body weight, but increased the weight and lipid content of EPI and RETRO and plasma insulin, glucose, non-esterified fatty acid and TAG levels. EPI and RETRO from dexamethasone-treated rats showed increased rates of de novo fatty acid synthesis (80 and 100%) and basal lipolysis (20%). In EPI, dexamethasone decreased the 2-deoxyglucose uptake (50%), as well as glyceroneogenesis, evidenced by a decrease of PEPCK-C activity (39%) and TAG glycerol synthesis from pyruvate (66%), but increased the glycerokinase activity (50%) and TAG-glycerol synthesis from glycerol (72%) in this tissue. In spite of a similar reduction in 2-deoxyglucose uptake in RETRO, dexamethasone treatment increased glyceroneogenesis, evidenced by PEPCK activity (96%), and TAG-glycerol synthesis from pyruvate (110%), accompanied by a decrease in glycerokinase activity (50%) and TAG-glycerol synthesis from glycerol (50%). Dexamethasone effects on RETRO were accompanied by a decrease in p-Akt content and by lower insulin effects on the rates of glycerol release in the presence of isoproterenol and on the rates of glucose uptake in isolated adipocytes. CONCLUSION: Our data demonstrated differential regulation of glyceroneogenesis and direct phosphorylation of glycerol by glucocorticoids in EPI and RETRO from rats. PMID- 28555306 TI - Prognostic Value of Perineural Invasion in Resected Gastric Cancer Patients According to Lauren Histotype. AB - The purpose of this study is to investigate perineural invasion (PNI) as a prognostic factor in gastric cancer patients. 455 patients submitted to extended (D2 or more) lymphadenectomy (median number of 39 retrieved lymph nodes, range: 15-140) between 1995 and 2012 were retrospectively studied. Patients were categorized in two groups according to the PNI status, and PNI positivity was assessed in presence of cancer cells in the perinerium or the neural fascicles using hematoxylin and eosin staining. Median follow-up for surviving patients was 80.3 months. Survival analysis was performed by univariate and multivariate analysis, using a Cox proportional hazards model. 162 patients (33.9%) had positive PNI; this was strongly associated with advanced stages of disease, residual tumor, lymphovascular invasion, Lauren diffuse-mixed histotype and tumor size. Five-year cancer-related survival was 65,7% and 20,6% in PNI negative vs. positive groups, respectively (p < 0.001). The prognostic impact of PNI at univariate analysis was particularly evident in patients submitted to R0 surgery, early as well as advanced stage, advanced nodal stage and T status. At multivariate analysis, PNI did not result statistically significant in the overall series, but emerged as an independent prognostic factor in the group of patients with Lauren intestinal histotype (p = 0.005, hazard ratio: 1.99, 95% confidence interval 1.24-3.19). PNI is related to advanced stage and poor long term survival in gastric cancer, and may serve as an adjunctive prognostic factor in the intestinal histotype. PMID- 28555308 TI - Radiologically occult medulloblastoma with hydrocephalus: case report. AB - INTRODUCTION: There have been no reports of occult medulloblastoma nor noncommunicating hydrocephalus due to radiologically occult brain tumors. Herein, we report radiologically occult medulloblastoma with noncommunicating hydrocephalus. CASE REPORT: A 3-year-old boy presented with macrocephaly, visual field constriction, and papilledema. Neuroimagings showed enlargement of the ventricles without any mass lesions. The CT cisternography did not show influx of the contrast into the ventricles, which suggested local cerebrospinal fluid (CSF) circulatory disturbance at the outlet of the fourth ventricle. Due to possible obstructive nature of hydrocephalus, endoscopic third ventriculostomy (ETV) was performed. Three months after the ETV, he presented with repeated vomiting. Neuroimagings showed a 3-cm fourth ventricular mass with progressive hydrocephalus. Surgical resection was performed, which revealed the pathology was medulloblastoma. CONCLUSION: We report the case of radiologically occult medulloblastoma which was demonstrated radiologically in the follow-up period of ETV for noncommunicating hydrocephalus of uncertain etiology. This is the first description of a radiologically occult medulloblastoma and also the first description of an occult brain tumor with noncommunicating hydrocephalus. The occult brain tumor may be included in the etiology of hydrocephalus. PMID- 28555309 TI - Comprehensive analysis of Iranian reports of pediatric central nervous system tumors. AB - PURPOSE: Iran lacks a national registry reporting the data of central nervous system (CNS) tumors in children. Consequently, treatment success and failure rates are unknown, and a centralized system for disease-management recommendations does not exist. METHODS: To critically evaluate the current state of pediatric CNS tumor studies and reporting in Iran, we performed an extensive retrospective analysis of all known reports identified with multiple search engines. RESULTS: Of 409 initially retrieved articles, we evaluated 123 matching our inclusion criteria. We further narrowed these reports to 74 by excluding studies pertaining to adult patients only, non-CNS tumors, or brain metastases. We also excluded studies that were performed outside of Iran or that did not contain relevant data from our analysis. We divided the remaining studies into those describing exclusively pediatric patients (3484 patients) and those describing mixed populations of adults and children (18,641 patients). In total, our analysis included 22,125 patients. CONCLUSIONS: We identified many limitations in the reporting of studies describing the treatment or prevalence of CNS tumors in children in Iran. Our results may guide future efforts in Iran to improve the care for children with CNS tumors and may provide a valuable template for other comprehensive country- and disease-specific retrospective analyses. PMID- 28555310 TI - Antenatal management of fetal neurosurgical diseases. AB - The advance in the imaging tools during the pregnancy (ultrasound and magnetic resonance) allowed the early diagnose of many fetal diseases, including the neurological conditions. This progress brought the neurosurgeons the possibility to propose treatments even before birth. Myelomeningocele is the most recognized disease that can be treated during pregnancy with a high rate of success. Additionally, this field can be extended to other conditions such as hydrocephalus and encephaloceles. However, each one of these diseases has nuances in the diagnostic evaluation that should fit the requirements to perform the fetal procedure and overbalance the benefits to the patients. In this article, the authors aim to review the neurosurgical aspects of the antenatal management of neurosurgical conditions based on the experience of a pediatric neurosurgery center. PMID- 28555311 TI - Occipitocervical inclination: new radiographic parameter of neutral occipitocervical position. AB - PURPOSE: To describe occipitocervical inclination (OCI), a new parameter that could compensate for defects in existing radiographic parameters, and to define occipitocervical neutral position. METHODS: Neutral, flexion, and extension lateral cervical spine radiographs of 200 patients (100 male and 100 female patients) judged to be normal were analyzed. The mean age was 45.19 years (range 11-74; 42.84 for male and 47.53 for female patients). For OCI, the angle formed by the line connecting the posterior border of the C4 vertebral body and McGregor's line was measured. Occipitocervical angle (OCA) and occipitocervical distance (OCD) were measured and compared with OCI. RESULTS: OCI on standard, neutral lateral cervical radiographs was 102.51 degrees +/- 8.87 degrees . There was no significant gender difference in neutral OCI 102.81 degrees +/- 7.93 degrees for male and 102.21 degrees +/- 9.74 degrees for female patients (P = 0.631). The mean neutral OCA was 38.69 degrees +/- 9.23 degrees , and the mean neutral OCD was 22.98 +/- 5.10 mm. Pearson's correlation coefficient for the value of the cervical lordosis angle and that of neutral OCI was r = 0.274 (P < 0.001). Intraclass correlation coefficient values for inter- and intraobserver reliability for OCI were significantly higher than those for OCA (P < 0.001) and tended to be higher than those for OCD (P = 0.087). CONCLUSIONS: OCI is a very useful parameter for the determination of neutral position during occipitocervical fusion for patients with altered C0-C2 anatomy. PMID- 28555312 TI - Long fusions to S1 with or without pelvic fixation can induce relevant acute variations in pelvic incidence: a retrospective cohort study of adult spine deformity surgery. AB - PURPOSE: The purpose of this study is to verify if any changes occur in pelvic incidence (PI) in adult patients undergoing long fusion to sacrum for spine deformity and to describe the effect of fixation to pelvis on these variations. METHODS: We conducted a cross sectional study. Sixty-six adults patients, 87% females (mean +/- SD age: 65.1 +/- 7.6 years), undergoing fusion from the thoracic spine to the sacrum for adult spine deformity were included. Patients were divided in two different groups: Group A: sacral fixation alone and Group B: sacral fixation plus pelvis fixation. Pre and postoperative standardized full standing X-rays were analyzed with measurement of: PI, pelvic tilt (PT), lumbar lordosis (LL) and sagittal vertical axis (SVA). RESULTS: A significant effect of time interaction (preoperative to early postoperative; F = 59.93, F = 44.78 and F = 39.87, all p < 0.001) existed for PT, SS and TK in both groups (all, p < 0.001). After adjustment for patients' age (>65 vs. <65 years), a statistically significant increase of PI was observed in patients >65 years (p = 0.006) in Group A between preoperative and postoperative measurements. All patients in Group B exhibited a decrease in PI from preoperative to postoperative. CONCLUSIONS: Older patients undergoing long fusion to the sacrum without pelvic fixation had an increase in PI after surgery. Conversely, pelvic fixation with hips intraoperatively extended has decreased the value of PI from pre- to early postoperative. These changes could be related to degeneration of the sacroiliac joints causing increased rotational mobility and the magnitude of the differences is in the range of clinical relevance. PMID- 28555313 TI - Uneven intervertebral motion sharing is related to disc degeneration and is greater in patients with chronic, non-specific low back pain: an in vivo, cross sectional cohort comparison of intervertebral dynamics using quantitative fluoroscopy. AB - PURPOSE: Evidence of intervertebral mechanical markers in chronic, non-specific low back pain (CNSLBP) is lacking. This research used dynamic fluoroscopic studies to compare intervertebral angular motion sharing inequality and variability (MSI and MSV) during continuous lumbar motion in CNSLBP patients and controls. Passive recumbent and active standing protocols were used and the relationships of these variables to age and disc degeneration were assessed. METHODS: Twenty patients with CNSLBP and 20 matched controls received quantitative fluoroscopic lumbar spine examinations using a standardised protocol for data collection and image analysis. Composite disc degeneration (CDD) scores comprising the sum of Kellgren and Lawrence grades from L2-S1 were obtained. Indices of intervertebral motion sharing inequality (MSI) and variability (MSV) were derived and expressed in units of proportion of lumbar range of motion from outward and return motion sequences during lying (passive) and standing (active) lumbar bending and compared between patients and controls. Relationships between MSI, MSV, age and CDD were assessed by linear correlation. RESULTS: MSI was significantly greater in the patients throughout the intervertebral motion sequences of recumbent flexion (0.29 vs. 0.22, p = 0.02) and when flexion, extension, left and right motion were combined to give a composite measure (1.40 vs. 0.92, p = 0.04). MSI correlated substantially with age (R = 0.85, p = 0.004) and CDD (R = 0.70, p = 0.03) in lying passive investigations in patients and not in controls. There were also substantial correlations between MSV and age (R = 0.77, p = 0.01) and CDD (R = 0.85, p = 0.004) in standing flexion in patients and not in controls. CONCLUSION: Greater inequality and variability of motion sharing was found in patients with CNSLBP than in controls, confirming previous studies and suggesting a biomechanical marker for the disorder at intervertebral level. The relationship between disc degeneration and MSI was augmented in patients, but not in controls during passive motion and similarly for MSV during active motion, suggesting links between in vivo disc mechanics and pain generation. PMID- 28555315 TI - Differential efficacies of the nicotinic alpha4beta2 desensitizing agents in reducing nicotine self-administration in female rats. AB - RATIONALE AND OBJECTIVES: Desensitization of neuronal nicotinic acetylcholine receptors holds promise as an effective treatment of tobacco addiction. Previously, we found that sazetidine-A (Saz-A), which selectively desensitizes alpha4beta2 nicotinic receptors, significantly decreased intravenous (IV) nicotine self-administration (SA) in rats with an effective dose of 3 mg/kg in acute and repeated injection studies. We also found that chronic infusions of Saz A at doses of 2 and 6 mg/kg/day significantly reduced nicotine SA in rats. In continuing studies, we have characterized other Saz-A analogs, YL-2-203 and VMY-2 95, to determine their efficacies in reducing nicotine SA in rats. METHODS: Young adult female Sprague-Dawley rats were fitted with IV catheters and were trained for nicotine SA (0.03 mg/kg/infusion) on a fixed ratio 1 schedule for ten sessions. The same rats were also implanted subcutaneously with osmotic minipumps to continually deliver 2 or 6 mg/kg body weight YL-2-203, VMY-2-95, or saline for four consecutive weeks. RESULTS: Chronic administration of VMY-2-95 at doses of 2 and 6 mg/kg/day caused significant (p < 0.01) decreases in nicotine SA over the 2 weeks of continued nicotine SA and for the 1-week period of resumed access after a week of enforced abstinence, whereas chronic administration of YL-2-203 at the same doses was not found to be effective. CONCLUSIONS: These studies, together with our previous studies of Saz-A, revealed a spectrum of efficacies for these alpha4beta2 nicotinic receptor desensitizing agents and provide a path forward for the most effective compounds to be further developed as possible aids to smoking cessation. PMID- 28555316 TI - The Relationship Between Spirituality/Religiousness and Unhealthy Alcohol Use Among HIV-Infected Adults in Southwestern Uganda. AB - HIV and alcohol use are two serious and co-existing problems in sub-Saharan Africa. We examined the relationship between spirituality and/or religiousness (SR) and unhealthy alcohol use among treatment-naive HIV-infected adults attending the HIV clinic in Mbarara, Uganda. Unhealthy alcohol was defined as having either an alcohol use disorders identification test-consumption score of >=4 for men or >=3 for women, or having a phosphatidylethanol level of >=50 ng/ml based on analysis of dried bloodspot specimens. Of the 447 participants, 67.8% were female; the median age was 32 years (interquartile range [IQR] 27-40). About half reported being Protestant (49.2%), 35.1% Catholic, and 9.2% Muslim. The median SR score was high (103 [IQR 89-107]); 43.3% drank at unhealthy levels. Higher SR scores were associated with lower odds of unhealthy drinking (adjusted odds ratio [aOR]: 0.83 per standard deviation [SD] increase; 95% confidence interval [CI] 0.66-1.03). The "religious behavior" SR subscale was significantly associated with unhealthy alcohol use (aOR: 0.72 per SD increase; 95% CI 0.58 0.88). Religious institutions, which facilitate expression of religious behavior, may be helpful in promoting and maintaining lower levels of alcohol use. PMID- 28555317 TI - Trends in Sexual Behavior Among Men Who have Sex with Men (MSM) in High-Income Countries, 1990-2013: A Systematic Review. AB - HIV diagnoses among men who have sex with men (MSM) have been increasing in several high-income countries. A better understanding of the sexual behavior trends among MSM can be useful for informing HIV prevention. We conducted a systematic review of studies that examined behavioral trends (1990-2013) in any condomless anal sex, condomless anal sex with an HIV-discordant partner, and number of partners. Studies included come from the United States, Europe, and Australia. We found increasing trends in condomless anal sex and condomless anal sex with an HIV-discordant partner, and a decreasing trend in number of partners. The increase in condomless anal sex may help to explain the increase in HIV infections. More explanatory research is needed to provide insight into factors that contribute to these behavior trends. Continuous monitoring of HIV, risk behaviors, and use of prevention and treatment is needed to evaluate prevention efforts and monitor HIV transmission risk. PMID- 28555318 TI - Conformational Characteristics of Rice Hexokinase OsHXK7 as a Moonlighting Protein involved in Sugar Signalling and Metabolism. AB - Hexokinase (HXK) as a moonlighting protein involves in glucose metabolism and signalling to regulate growth and development in plants. Therefore, the clarification for the structural properties of OsHXK7 (Oryza sativa Hexokinase 7) is essential to understand its role mechanism associated with the Glc signalling and metabolism. In this study, the structural characteristics of OsHXK7 (Oryza sativa Hexokinase 7) were identified. In the fluorescence spectrum, the Trp peak representing OsHXK7 binding to D-glucose (D-Glc) and 2-deoxyglucose (2-dG) showed an obvious blue shift. The distinct change in the secondary structure of OsHXK7 after binding to Glc was also detected in circular dichroism spectra. Using superimposed modelling, OsHXK7 showed a Glc-induced structural change, in which the 76th glycine, 148th serine and 256th tryptophan were contained within the pocket region. It was further shown by site-directed mutagenesis that the 76th glycine and the 256th tryptophan, but not the 148th serine, are the pivotal sites of OsHXK7 that maintain its catalytic activity and intrinsic blue shift fluorescence. These results suggest that OsHXK7 binding to Glc leads to a conformational change, that is likely essential for the function of OsHXK7 in Glc signalling and metabolism during plant growth and development. PMID- 28555319 TI - Proteomic Analysis of Rice Seedlings Under Cold Stress. AB - Low temperature can greatly restrict the growth and development of rice. The rice seedlings show growth retardation, lamina wrap, and part of blade even died under the condition of low temperature. In order to get more information about cold stress responses in rice, two dimensional electrophoresis and bioinformatics analysis of mass spectrometry were used to preliminary survey the cold tolerance of cold sensitive line 9311 and cold resistance variety Fujisaka 5 under cold stress. Two dimensional electrophoresis maps of 9311 and Fujisaka 5 were established under cold treatment. With analysis of bioinformation, the proteins were found involve in many aspects of rice development. The largest category of proteins is functioning on metabolism. By comparing the proteins from the two varieties, it can be found that most proteins from 9311 were down-regulated and were up-regulated in Fujisaka 5. The results showed that the membrane composition and structure were damaged, metabolism changed dramatically and rice defense system was activated under the cold stimulation. Fifty-nine proteins related to the resistance of cold stress were identified in our study, and we have investigated and classified all of their biological functions. The importance of our study are providing some conduct for the research of rice resistant to cold stress, supporting auxiliary technique for rice varieties and widening the search field of cold tolerance in plants. PMID- 28555321 TI - [Rare metabolic disorders and urolithiasis]. AB - Numerous metabolic anomalies, which often have no direct pathological relevance when considered individually, are found in all people. In most patients with urinary tract stones, it can be assumed that a specific combination or interaction of these anomalies occurs, thus, resulting in stone formation, but only after individual exogenous risk factors are triggered. Lithogenesis is the result of a cascade of different "events" that are temporally close to one another, but sometimes these events interact strong enough that significant stone growth occurs. Chronic metabolic disorders usually lead to permanently altered urine compositions. The occurrence of physiological urine constituents in nonnormal concentration ratios and/or the nonphysiological excretion of metabolic products can significantly increase the lithogenicity of urine, so that urolithiasis can manifest itself as a clinical symptom. In cases of urolithiasis of unknown origin, a potentially hidden rare metabolic anomaly should always be considered. In addition, if a patient has a known metabolic disease, then this should always be taken into account as a risk factor for stone formation and attempts should be taken to clarify its influence on urine composition. This also applies to the efficacy of a therapy. A distinct link between a metabolic disease and stone formation is generally rare and will likely remain so despite significant advances regarding differential diagnosis and etiopathology. This article focuses on very rare metabolic causes and/or genetic syndromes which may be associated with urolithiasis. Patients receiving symptomatic stone treatment should receive life-long follow-up care from a urologist because reducing the recurrence rate helps to improve the quality of life of the patients. PMID- 28555320 TI - Population Pharmacokinetic Analyses of Lithium: A Systematic Review. AB - BACKGROUND AND OBJECTIVES: Even though lithium has been used for the treatment of bipolar disorder for several decades, its toxicities are still being reported. The major limitation in the use of lithium is its narrow therapeutic window. Several methods have been proposed to predict lithium doses essential to attain therapeutic levels. One of the methods used to guide lithium therapy is population pharmacokinetic approach which accounts for inter- and intra individual variability in predicting lithium doses. Several population pharmacokinetic studies of lithium have been conducted. The objective of this review is to provide information on population pharmacokinetics of lithium focusing on nonlinear mixed effect modeling approach and to summarize significant factors affecting lithium pharmacokinetics. METHODS: A literature search was conducted from PubMed database from inception to December, 2016. Studies conducted in humans, using lithium as a study drug, providing population pharmacokinetic analyses of lithium by means of nonlinear mixed effect modeling, were included in this review. RESULTS: Twenty-four articles were identified from the database. Seventeen articles were excluded based on the inclusion and exclusion criteria. A total of seven articles were included in this review. Of these, only one study reported a combined population pharmacokinetic pharmacodynamic model of lithium. Lithium pharmacokinetics were explained using both one- and two-compartment models. The significant predictors of lithium clearance identified in most studies were renal function and body size. One study reported a significant effect of age on lithium clearance. The typical values of lithium clearance ranged from 0.41 to 9.39 L/h. The magnitude of inter-individual variability on lithium clearance ranged from 12.7 to 25.1%. Only two studies evaluated the models using external data sets. CONCLUSIONS: Model methodologies in each study are summarized and discussed in this review. For future perspective, a population pharmacokinetic-pharmacodynamic study of lithium is recommended. Moreover, external validation of previously published models should be performed. PMID- 28555322 TI - Assessment of airway compression on chest radiographs in children with pulmonary tuberculosis. AB - BACKGROUND: Because small, pliable paediatric airways are easily compressed by enlarged lymph nodes, detection of radiographic airway compression might be an objective criterion for diagnosing pulmonary tuberculosis. OBJECTIVE: To investigate the frequency and inter-observer agreement of airway compression on chest radiographs in children with pulmonary tuberculosis compared to those with a different lower respiratory tract infection. MATERIALS AND METHODS: Chest radiographs of children with suspected pulmonary tuberculosis were read by two readers according to a standardised format and a third reader when there was disagreement. Radiographs of children with proven pulmonary tuberculosis were compared to those with a different lower respiratory tract infection. We evaluated frequency and location of radiographic airway compression. Findings were correlated with human immunodeficiency virus (HIV) status and age. We assessed inter-observer agreement using kappa statistics. RESULTS: We reviewed radiographs of 505 children (median age 25.9 months, interquartile range [IQR] 14.3-62.2). Radiographic airway compression occurred in 54/188 (28.7%) children with proven pulmonary tuberculosis and in 24/317 (7.6%) children with other types of lower respiratory tract infection (odds ratio [OR] 4.9; 95% confidence interval [CI] 2.9-8.3). A higher frequency of radiographic airway compression occurred in infants (22/101, or 21.8%) compared to older children (56/404, or 13.9%; OR 1.7; 95% CI 1.0-3.0). We found no association between airway compression and HIV infection. Inter-observer agreement ranged from none to fair (kappa of 0.0-0.4). CONCLUSION: There is a strong association between airway compression on chest radiographs and confirmed pulmonary tuberculosis. However this finding's clinical use as an objective criterion for diagnosis of pulmonary tuberculosis in children is limited by poor inter-observer agreement. PMID- 28555323 TI - Liquid-based endometrial cytology associated with curettage in the investigation of endometrial carcinoma in a population of 1987 women. AB - PURPOSE: The aim of this study was to investigate the diagnostic accuracy of liquid-based endometrial cytology, in comparison with histology. METHODS: 1987 patients scheduled for hysteroscopy were enrolled in this study. All patients proceeded sequentially through endometrial cytology, hysteroscopy and then dilatation and curettage (D&C). Cytology sampling was performed by brushing the uterus cavity using SAP-1 and the sample was prepared to liquid-based smear using SurePath technology. The slides were stained by Papanicolaou method. All cytological diagnosis was correlated with the D&C histological diagnosis. RESULTS: Cyto-histological correlations were possible in 1672 (89.3%) patients: in 254 (12.8%) patients the D&C was inadequate, in 75 (3.8%) patients the cytology was inadequate, and in 14 (0.7%) patients both were inadequate. In postmenopausal women, 758 of 790 cytologies (96.0%) were adequate, while 586 of 790 histologies (74.2%) were adequate. SAP-1 provided more sufficient materials for cytology than D&C for histology (P < 0.001). Taking atypical hyperplasia or worse as a positive result, the diagnostic accuracy of liquid-based endometrial cytology was 86.1%, sensitivity was estimated at 70.3%, specificity at 88.5%, positive predictive value at 48.0% and negative predictive value at 95.2%. Taking endometrial carcinoma as a positive result, the diagnostic accuracy of liquid based endometrial cytology was 94.4%; sensitivity was estimated at 53.2%, specificity at 98.6%, positive predictive value at 79.8% and negative predictive value at 95.3%. CONCLUSIONS: Liquid-based endometrial cytology can be considered a useful method for detecting of endometrial pathology as a first-line approach. PMID- 28555324 TI - Low maternal circulating levels of vitamin D as potential determinant in the development of gestational diabetes mellitus. AB - Gestational diabetes mellitus (GDM), defined as any glucose intolerance with the onset or first recognition during pregnancy, is characterized by rising incidence, fostered by the worldwide increase of pathological nutritional status from young age. Clinical research has intended to identify potential risk factors, suggested improvements in screening strategies, and recommended the combination between promotion of an appropriate lifestyle before and during pregnancy and selected therapeutic approaches. Preventing pathological hyperglycemia could have several benefits, ranging from clinical side (reduction in the risk of adverse perinatal and long-term sequelae) to financial side (cost reduction to healthcare systems). Among risk factors recognized, deficiency in 25 hydroxyvitamin D [25(OH)D], already acknowledged as involved in calcium homeostasis, pathogenesis of cardiovascular, oncological, infective and immunity diseases, could predispose to the development of both type 1 and 2 diabetes, modifying the activity of pancreatic beta-cells vitamin D (VD) receptor. In pregnant women, lower 25(OH)D concentrations have been suggested to present an inverse association with maternal glycaemia, insulin resistance, and increased risk of GDM. In spite of growing body of evidence, there is not full agreement on the therapeutic association between GDM based on VD deficiency and 25(OH)D supplementation. In the attempt to bring up-to-date the role of low VD levels on subsequent development of GDM, this narrative review, based on medium-high quality randomized clinical trials, systematic reviews, and meta-analysis published in last decade, has a twofold purpose: firstly, to elucidate the relationship between maternal VD status and GDM; and secondly, to illuminate the impact of VD supplementation on GDM onset. PMID- 28555325 TI - Erratum to: Serum HMGB1 concentrations at 4 weeks is a useful predictor of extreme poor prognosis for advanced hepatocellular carcinoma treated with sorafenib and hepatic arterial infusion chemotherapy. PMID- 28555326 TI - Pursuing a Gastroenterology Fellowship as a Foreign Medical Graduate. PMID- 28555328 TI - Evolving Concepts in Atopic Dermatitis. AB - PURPOSE OF REVIEW: Tremendous advances have been made in the field of atopic dermatitis in the past 5 years. We will explore developments in burden of disease, co-morbidities, pathogenesis, prevention, and management. RECENT FINDINGS: The tremendous burden moderate to severe atopic dermatitis (AD) places on families from a medical, psychosocial, and financial perspective has been characterized. Epidemiologic studies have identified intriguing new associations beyond the well-characterized "atopic march" of food allergies, asthma, and hay fever. Studies of primary prevention have gained traction including the remarkable impacts of early emollient therapy. Basic advances have simultaneously elucidated the nature of atopic inflammation, setting the stage for an explosion of new potential therapeutic targets. After a fallow period of nearly 15 years without a substantial therapeutic advance, this year has already seen two new FDA approved treatments for AD. AD has a tremendous impact on quality of life with an underappreciated burden of disease; there are important newly described co morbidities including ADHD and anemia; new insights into etio-pathogenesis have paved the way for novel topical therapies like crisaborole, and new systemic interventions like dupilumab. PMID- 28555327 TI - Navigation-guided clipping of a de novo aneurysm associated with superficial temporal artery-middle cerebral artery bypass combined with indirect pial synangiosis in a patient with moyamoya disease. AB - De novo aneurysms associated with superficial temporal artery (STA)-middle cerebral artery (MCA) bypass are an extremely rare complication of direct revascularization surgery for moyamoya disease (MMD). The basic pathology of MMD includes fragility of the intracranial arterial wall characterized by medial layer thinness and waving of the internal elastic lamina. However, the incidence of newly formed aneurysms at the site of anastomosis currently remains unknown. Among 317 consecutive direct/indirect combined revascularization surgeries performed for MMD, we encountered a 52-year-old woman manifesting a de novo aneurysm adjacent to the site of anastomosis 11 years after successful STA-MCA bypass with encephalo-duro-myo-synangiosis (EDMS). Although the patient remained asymptomatic, the aneurysm gradually increased in diameter to more than 6 mm with the formation of a daughter sac, and a computational fluid dynamic study revealed low wall shear stress at the aneurysm dome. The patient underwent microsurgical clipping of the aneurysm using a neuro-navigation system that permitted the minimally invasive dissection of the temporal muscle flap used for EDMS at the site of the aneurysm without affecting pial synangiosis. The aneurysm was successfully occluded using a titanium clip without complications. The postoperative course was uneventful, and the patient was discharged without neurological deficits. De novo aneurysms associated with STA-MCA bypass for MMD may be safely treated with microsurgical clipping, even in cases initially managed by a combined revascularization procedure that includes complex pial synangiosis. We recommend the application of the neuro-navigation system for the maximum preservation of pial synangiosis during this procedure. PMID- 28555329 TI - T Cells in Allergic Asthma: Key Players Beyond the Th2 Pathway. AB - Asthma is a common chronic lung disease that affects 300 million people worldwide. It causes the airways of the lungs to swell and narrow due to inflammation (swelling and excess mucus build-up in the airways) and airway constriction (tightening of the muscles surrounding the airways). Atopic asthma is the most common form of asthma, and is triggered by inhaled allergens that ultimately promote the activation of the Th2-like T cells and the development of Th2-mediated chronic inflammation. Different subsets of T cells, including T follicular helper cells, tissue-resident T, cells and Th2 effector cells, play different functions during allergic immune response. Dendritic cells (DCs) are known to play a central role in initiating allergic Th2-type immune responses and in the development of the T cell phenotype. However, this function depends on the complex interaction with other cells of the immune system and determines whether the response to environmental allergens will be one of tolerance or allergic inflammation. This review discusses cell interactions leading to the initiation and maintenance of allergic Th2-type immune responses, particularly those associated with allergic asthma. PMID- 28555331 TI - Chronic Non-Cancer Pain Management Capacity in Karachi. AB - Chronic non-cancer pain (CNCP) affects people everywhere in the world, but people in developing countries have far less access to therapies that provide relief. There are often missed opportunities to implement these therapies. Karachi shares many characteristics with megacities of the global south and represents Pakistan in the global city league. This review informs readers about the availability of health management and pain services for CNCP in Karachi, and their comparability to those found in other global cities. The literature about CNCP and its management in Karachi and Pakistan is scarce. Nevertheless, some conclusions can be made. In order to inform readers based in other global cities, a brief review of the current health system and pain services in Karachi and Pakistan are discussed together with barriers that impede pain service outputs. The present review employs vignettes to illustrate typical experiences of CNCP patients seeking pain management services in three sectors: public, charitable, and private institutions. PMID- 28555330 TI - The P2Y1 receptor-mediated leukocyte adhesion to endothelial cells is inhibited by melatonin. AB - Extracellular ATP (released by endothelial and immune cells) and its metabolite ADP are important pro-inflammatory mediators via the activation of purinergic P2 receptors (P2Y and P2X), which represent potential new targets for anti inflammatory therapy. Endothelial P2Y1 receptor (P2Y1R) induces endothelial cell activation triggering leukocyte adhesion. A number of data have implicated melatonin as a modulator of immunity, inflammation, and endothelial cell function, but to date no studies have investigated whether melatonin modulates endothelial P2YR signaling. Here, we evaluated the putative effect of melatonin on P2Y1R-mediated leukocyte adhesion to endothelial cells and TNF-alpha production, using mesenteric endothelial cells and fresh peripheral blood mononuclear cells isolated from rats. Endothelial cells were treated with the P2Y1R agonist 2MeSATP, alone or in combination with melatonin, and then exposed to mononuclear cells. 2MeSATP increased leukocyte adhesion to endothelial cells and TNF-alpha production in vitro, and melatonin inhibited both effects without altering P2Y1R protein expression. In addition, assays with the Ca2+ chelator BAPTA-AM indicate that the effect of melatonin on 2MeSATP-stimulated leukocyte adhesion depends on intracellular Ca2+ modulation. P2Y1R is considered a potential target to control chronic inflammation. Therefore, our data unveiled a new endothelial cell modulator of purinergic P2Y1 receptor signaling. PMID- 28555332 TI - Protective role of downregulated MLK3 in myocardial adaptation to chronic hypoxia. AB - A series of protective responses could be evoked to achieve compensatory adaptation once cardiomyocytes are subjected to chronic hypoxia. MLK3/JNK/c-jun signaling pathway was previously demonstrated to be involved in this process. In the present study, we aim to further examine the performance of MLK3 in hypoxic H9C2 cells and potential mechanism. Myocardial samples of patients with congenital heart disease (CHD) were collected. H9C2 cells were cultured in hypoxic conditions for various durations. MLK3 was silenced by transfection of shRNA to evaluate its role in cell viability. We found expression of MLK3 protein was lower in patients with cyanotic CHD. In hypoxic H9C2 cells, its expression was gradually decreased in a time-dependent manner. However, there was no significant difference about expression of MLK3 mRNA. According to the results of MTT, LDH, and TUNEL, faster cell growth curve, lower death rate, and less apoptotic cells could be observed in MLK-shRNA group compared with scramble-shRNA group. Silencing of MLK3 significantly reduced expression of cleaved caspase-3, cleaved PARP, Bad, and Bax, together with increased expression of Bcl-2 and ration of Bcl-2/Bax. Both ratio of phospho-JNK/total JNK and ratio of phospho-c jun/total c-jun were significantly decreased once MLK3 was silenced. At various reoxygenation time, MLK3 shRNA could significantly promote cell survival and decrease cell death according to MTT and LDH. Our results suggested that chronic hypoxia could reduce MLK3 expression in a posttranscriptional regulatory manner. Downregulation of MLK3 protects H9C2 cells from hypoxia-induced apoptosis and H/R injury via blocking the activation of JNK and c-jun. PMID- 28555333 TI - The value of [11C]-acetate PET and [18F]-FDG PET in hepatocellular carcinoma before and after treatment with transarterial chemoembolization and bevacizumab. AB - PURPOSE: This prospective study was to investigate the value of [11C]-acetate PET and [18F]-FDG PET in the evaluation of hepatocellular carcinoma (HCC) before and after treatment with transarterial chemoembolization (TACE) and vascular endothelial growth factor (VEGF) antibody (bevacizumab). METHODS: Twenty-two patients (three women, 19 men; 62 +/- 8 years) with HCC verified by histopathology were treated with TACE and bevacizumab (n = 11) or placebo (n = 11). [11C]-acetate PET and [18F]-FDG PET were performed before and after TACE with bevacizumab or placebo. Comparisons between groups were performed with t tests and Chi-squared tests, where appropriate. Overall survival (OS) was defined as the time from start of bevacizumab or placebo until the date of death/last follow-up, respectively. RESULTS: The patient-related sensitivity of [11C] acetate PET, [18F]-FDG PET, and combined [11C]-acetate and [18F]-FDG PET was 68%, 45%, and 73%, respectively. There was a significantly higher rate of conversion from [11C]-acetate positive lesions to negative lesions in patients treated with TACE and bevacizumab as compared with that in patients with TACE and placebo (p < 0.05). In patients with negative acetate PET, the mean OS in patients treated with TACE and bevacizumab was 259 +/- 118 days and was markedly shorter as compared with that (668 +/- 217 days) in patients treated with TACE and placebo (p < 0.05). In patients treated with TACE and placebo, there was significant difference in mean OS in patients with positive FDG PET as compared with that in patients with negative FDG PET (p < 0.05). The HCC lesions had different tracer avidities showing the heterogeneity of HCC. CONCLUSIONS: Our study suggests that combining [18F]-FDG with [11C]-acetate PET could be useful for the management of HCC patients and might also provide relevant prognostic and molecular heterogeneity information. PMID- 28555334 TI - Prenatal nicotine exposure induces HPA axis-hypersensitivity in offspring rats via the intrauterine programming of up-regulation of hippocampal GAD67. AB - The intrauterine programming of hypothalamic-pituitary-adrenal (HPA) axis hypersensitivity is associated with chronic adult diseases. Our previous studies demonstrated the HPA-axis hypersensitivity in offspring rats induced by prenatal nicotine exposure. The goal of the present study is to further investigate the intrauterine programming mechanism. Pregnant Wistar rats were subcutaneously administered with 2.0 mg/kg day of nicotine from gestational day (GD) 9-20. A group of the pregnant rats was euthanized at GD20, and the fetal rats were extracted. The remaining rats were left to come to term, and the adult offspring were exposed to chronic stress. For adult offspring rats, prenatal nicotine exposure induced HPA-axis hypersensitivity after chronic stress, accompanied by imbalanced glutamatergic/GABAergic afferent inputs. Moreover, prenatal nicotine exposure enhanced the expression of hippocampal glutamic acid decarboxylase 67 (GAD67), accompanied by a decreased methylation ratio within nt -1019 to -689 of the GAD67 promoter, decreased expression of Dnmt1, and an increased GABA content and density of GABAergic neurons. The fetal rats exhibited changes consistent with the adult rats. Similar effects were also observed by treating the fetal hippocampal cell line H19-7 with 1-100 MUM nicotine, while dihydro-beta erythroidine hydrobromide (DHbetaE), the specific inhibitor of alpha4beta2nAChR, can reverse the effects caused by nicotine. These results indicate that prenatal nicotine exposure can enhance the potential excitability of the hypothalamus via the intrauterine programming of up-regulation of hippocampal GAD67. All of these results contribute to the HPA-axis hypersensitivity in adult offspring. PMID- 28555335 TI - Parenting Stress through the Lens of Different Clinical Groups: a Systematic Review & Meta-Analysis. AB - Research has demonstrated an association between parenting stress and child behavior problems, and suggested levels of parenting stress are higher among parents of children at risk for behavior problems, such as those with autism and developmental delay (ASD/DD). The goal of the present study was to conduct a systematic review of parenting stress and child behavior problems among different clinical groups (i.e., ASD/DD, chronic illness, with or at-risk for behavioral and/or mood disorders). We also examined demographic and methodological variables as moderators and differences in overall levels of parenting stress between the clinical groups. This systematic review documents a link between parenting stress and child behavior problems with an emphasis on externalizing behavior. One hundred thirty-three studies were included for quantitative analysis. Parenting stress was more strongly related to child externalizing (weighted ES r = 0.57, d = 1.39) than internalizing (weighted ES r = 0.37, d = 0.79) problems. Moderation analyses indicated that the association between parenting stress and behavior problems was stronger among studies which had mostly male and clinic-recruited samples. Overall, parenting stress levels were higher for parents of children with ASD/DD compared to parents of children from other clinical groups. Findings document the association between parenting stress and child behavior problems and highlight the importance of assessing parenting stress as part of routine care and throughout behavioral intervention programs, especially for groups of children at high risk for behavior problems, such as children with ASD/DD, in order to identify support for both the parent(s) and child. PMID- 28555336 TI - A Novel Liquid-Liquid Extraction for the Determination of Sertraline in Tap Water and Waste Water at Trace Levels by GC-MS. AB - A simple, green and fast analytical method was developed for the determination of sertraline in tap and waste water samples at trace levels by using supportive liquid-liquid extraction with gas chromatography-mass spectrometry. Different parameters affecting extraction efficiency such as types and volumes of extraction and supporter solvents, extraction period, salt type and amount were optimized to get lower detection limits. Ethyl acetate was selected as optimum extraction solvent. In order to improve the precision, anthracene-D10 was used as an internal standard. The calibration plot of sertraline was linear from 1.0 to 1000 ng/mL with a correlation coefficient of 0.999. The limit of detection value under the optimum conditions was found to be 0.43 ng/mL. In real sample measurements, spiking experiments were performed to check the reliability of the method for these matrices. The spiking experiments yielded satisfactory recoveries of 91.19 +/- 2.48%, 90.48 +/- 5.19% and 95.46 +/- 6.56% for 100, 250 and 500 ng/mL sertraline for tap water, and 85.80 +/- 2.15% and 92.43 +/- 4.02% for 250 and 500 ng/mL sertraline for waste water. PMID- 28555337 TI - Occurrence, Distribution and Ecological Risks of Fluoroquinolone Antibiotics in the Dongjiang River and the Beijiang River, Pearl River Delta, South China. AB - The occurrence and distribution of five selected fluoroquinolones (FQs) were studied in the Dongjiang River and the Beijiang River, South China. Ciprofloxacin, norfloxacin and enoxacin, used as human and veterinary medicines, were detected with detection frequencies of 75%-100% and average concentrations of 9.5-18.8 ng L-1 in the two rivers. Meanwhile, enrofloxacin, which is only used as veterinary medicine, was detected at lower levels (2.9-4.0 ng L-1) than those of ciprofloxacin, norfloxacin and enoxacin. The spatial distribution of the five FQs exhibited a close relationship with the intensity of local human activity. Certain antibiotics were detected in industrial wastewater and domestic sewage at considerably higher concentrations than those measured in the river water, indicating important sources of antibiotic contamination. Finally, an ecological risk assessment based on the calculated risk quotient showed that ciprofloxacin could pose high risk to Microcystis aeruginosa (M. aeruginosa). The two rivers are important sources of drinking water and should arouse the attention of relevant departments. Effective measures must be taken to strengthen the protection of the two rivers. PMID- 28555338 TI - The affective and somatic side of depression: subtypes of depressive symptoms show diametrically opposed associations with glycemic control in people with type 1 diabetes. AB - AIMS: While depression has been linked to serious adverse outcomes in diabetes, associations with glycemic control are not conclusive. Inconsistencies could be due to the complex symptomatology of depression. Aim of this study was to analyze the associations of depressive subtypes with glycemic control in people with type 1 and type 2 diabetes. METHODS: Patients completed the Center for Epidemiological Studies-Depression scale which comprises affective, somatic, and anhedonic symptoms. These subtypes were analyzed in a joint linear regression analysis with glycemic control as a dependent variable. Subtype scores were calculated as mean item scores. Separate analyses for people with type 1 and type 2 diabetes were conducted. All analyses were controlled for demographic and medical confounders. RESULTS: The sample comprised 604 patients with type 1 and 382 patients with type 2 diabetes. In people with type 1 diabetes, the somatic and affective subtype showed diametrically opposed associations with glycemic control (somatic: beta =+0.23, p < .05; affective: beta = -0.23, p < .05). Anhedonia was not significantly associated with glycemic control. In people with type 2 diabetes, none of the depressive subtypes was significantly associated with glycemic control. CONCLUSIONS: For people with type 1 diabetes, the distinction of subtypes offered a detailed picture of the associations of depressive symptoms with glycemic control. However, due to the cross-sectional design, inferences about the direction of these associations cannot be made. In clinical practice, instead of focusing on overall depression, healthcare providers should examine the nature of depressive symptoms and how they might be related to having diabetes. PMID- 28555339 TI - Role of Mobile Technology to Improve Diabetes Care in Adults with Type 1 Diabetes: The Remote-T1D Study iBGStar(r) in Type 1 Diabetes Management. AB - INTRODUCTION: The role of mobile technology in patient-reported outcomes (PRO) and glycemic control in adults with type 1 diabetes (T1D) needs further evaluation. METHODS: The single-center, prospective, 6-month, open-label, investigator-initiated study randomized 100 subjects with T1D in a 1:1 fashion to a control group using self-monitoring of blood glucose (SMBG) with Accu-Chek Nano(r) and an intervention group using SMBG with iPhone plus glucose meter (iBGStar(r)). The primary endpoint was the change in PRO (hypoglycemia fear score, behavior and worry subscores). Secondary outcomes were the improvement in glycemic variability indices and the reduction in A1c values. RESULTS: Baseline demographics and glycosylated hemoglobin (A1c) values were similar in the two groups. There was a significant decrease in A1c value at 6 months in iBGStar(r) group compared to the control group (-0.16 vs. -0.51, p = 0.04). The total insulin dose increased significantly in the iBGStar(r) group at 3 months but did not change at 6 months. The hypoglycemia fear scale (PRO) improved in both groups at 6 months (-1.4 +/- 10.0 vs. -3.9 +/- 12.5, p = 0.32). CONCLUSION: The use of iBGStar(r) resulted in better glycemic control and improvement in some PRO (hypoglycemia fear and behavior scores) compared to the control group at 6 months with no increased risk of hypoglycemia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01825382. FUNDING: Sanofi. PMID- 28555340 TI - Erratum to: Comparison of potential higher order reference methods for total haemoglobin quantification-an interlaboratory study. PMID- 28555343 TI - Preparation of polymer brushes grafted graphene oxide by atom transfer radical polymerization as a new support for trypsin immobilization and efficient proteome digestion. AB - Highly efficient protein digestion is one of the key issues in the "bottom-up" strategy-based proteomic studies. Compared with the time-consuming solution-based free protease digestion, immobilized protease digestion offers a promising alternative with obviously improved sample processing throughput. In this study, we proposed a new immobilized protease digestion strategy using two kinds of polymer-grafted graphene oxide (GO) conjugated trypsin. The polymer brush grafted GO was prepared using in situ polymer growth on initiator-functionalized GO using surface-initiated atom transfer radical polymerization (SI-ATRP) and characterized by AFM, TEM, TGA, and XPS. The polymer brush grafted GO supports three-dimensional trypsin immobilization, which not only increases the loading amount but also improves accessibility towards protein substrates. Both of the two types of immobilized trypsin provide 700 times shorter digestion time, while maintaining comparable protein/peptide identification scale compared with that of free trypsin digestion. More interestingly, combined application of the two types of immobilized trypsin with different surface-grafted polymers leads to at least 18.3/31.3% enhancement in protein/peptide identification compared with that obtained by digestion using a single type, indicating the potential of this digestion strategy for deeper proteome coverage using limited mass spectrometer machine hour. We expect these advantages may find valuable application in high throughput clinical proteomic studies, which often involve processing of a large number of samples. Graphical abstract Preparation of polymer brushes grafted and trypsin immobilized graphene oxide and its application in proteome digestion and mass spectrometry identification. PMID- 28555341 TI - Offline pentafluorophenyl (PFP)-RP prefractionation as an alternative to high-pH RP for comprehensive LC-MS/MS proteomics and phosphoproteomics. AB - Technological advances in liquid chromatography and tandem mass spectrometry (LC MS/MS) have enabled comprehensive analyses of proteins and their post translational modifications from cell culture and tissue samples. However, sample complexity necessitates offline prefractionation via a chromatographic method that is orthogonal to online reversed-phase high-performance liquid chromatography (RP-HPLC). This additional fractionation step improves target identification rates by reducing the complexity of the sample as it is introduced to the instrument. A commonly employed offline prefractionation method is high pH reversed-phase (Hi-pH RP) chromatography. Though highly orthogonal to online RP HPLC, Hi-pH RP relies on buffers that interfere with electrospray ionization. Thus, samples that are prefractionated using Hi-pH RP are typically desalted prior to LC-MS/MS. In the present work, we evaluate an alternative offline prefractionation method, pentafluorophenyl (PFP)-based reversed-phase chromatography. Importantly, PFP prefractionation results in samples that are dried prior to analysis by LC-MS/MS. This reduction in sample handling relative to Hi-pH RP results in time savings and could facilitate higher target identification rates. Here, we have compared the performances of PFP and Hi-pH RP in offline prefractionation of peptides and phosphopeptides that have been isolated from human cervical carcinoma (HeLa) cells. Given the prevalence of isobaric mass tags for peptide quantification, we evaluated PFP chromatography of peptides labeled with tandem mass tags. Our results suggest that PFP is a viable alternative to Hi-pH RP for both peptide and phosphopeptide offline prefractionation. PMID- 28555344 TI - Analysis of the evolution of the detection limits of electrochemical nucleic acid biosensors II. AB - This critical review of electrochemical biosensors allowing direct detection of nucleic acid targets reports on different transduction pathways and their latest breakthroughs. A classification of the various strategies based on the nature of the electrochemical transduction is established to emphasize the efficiency of each of them. It provides an overall picture of the detection limit of the various approaches developed during the last two decades. Graphical Abstract Detection limits evolutions of electrochemical DNA biosensors. PMID- 28555342 TI - Microchip electrophoresis with laser-induced fluorescence detection for the determination of the ratio of nitric oxide to superoxide production in macrophages during inflammation. AB - It is well known that excessive production of reactive oxygen and nitrogen species is linked to the development of oxidative stress-driven disorders. In particular, nitric oxide (NO) and superoxide (O2*-) play critical roles in many physiological and pathological processes. This article reports the use of 4-amino 5-methylamino-2',7'-difluorofluorescein diacetate and MitoSOX Red in conjunction with microchip electrophoresis and laser-induced fluorescence detection for the simultaneous detection of NO and O2*- in RAW 264.7 macrophage cell lysates following different stimulation procedures. Cell stimulations were performed in the presence and absence of cytosolic (diethyldithiocarbamate) and mitochondrial (2-methoxyestradiol) superoxide dismutase (SOD) inhibitors. The NO/O2*- ratios in macrophage cell lysates under physiological and proinflammatory conditions were determined. The NO/O2*- ratios were 0.60 +/- 0.07 for unstimulated cells pretreated with SOD inhibitors, 1.08 +/- 0.06 for unstimulated cells in the absence of SOD inhibitors, and 3.14 +/- 0.13 for stimulated cells. The effect of carnosine (antioxidant) or Ca2+ (intracellular messenger) on the NO/O2*- ratio was also investigated. Graphical Abstract Simultaneous detection of nitric oxide and superoxide in macrophage cell lysates. PMID- 28555348 TI - [Magnetic resonance imaging : Recent studies on biological effects of static magnetic and high-frequency electromagnetic fields]. AB - PROBLEM: During the last few years, new studies on biological effects of strong static magnetic fields and on thermal effects of high-frequency electromagnetic fields used in magnetic resonance imaging (MRI) were published. Many of these studies have not yet been included in the current safety recommendations. METHOD: Scientific publications since 2010 on biological effects of static and electromagnetic fields in MRI were researched and evaluated. RESULTS: New studies confirm older publications that have already described effects of static magnetic fields on sensory organs and the central nervous system, accompanied by sensory perceptions. A new result is the direct effect of Lorentz forces on ionic currents in the semicircular canals of the vestibular system. Recent studies of thermal effects of high-frequency electromagnetic fields were focused on the development of anatomically realistic body models and a more precise simulation of exposure scenarios. RECOMMENDATION FOR PRACTICE: Strong static magnetic fields can cause unpleasant sensations, in particular, vertigo. In addition, they can influence the performance of the medical staff and thus potentially endanger the patient's safety. As a precaution, medical personnel should move slowly within the field gradient. High-frequency electromagnetic fields lead to an increase in the temperature of patients' tissues and organs. This should be considered especially in patients with restricted thermoregulation and in pregnant women and neonates; in these cases exposure should be kept as low as possible. PMID- 28555347 TI - Repetition Priming Effects in Proficient Mandarin-Cantonese and Cantonese Mandarin Bidialectals: An Event-Related Potential Study. AB - The present study adopted a repetition priming paradigm to investigate the bidialectal (bilingual) representation of speakers with different native dialects by event-related potential (ERP) technique. Proficient Mandarin-Cantonese and Cantonese-Mandarin bidialectals participated in the study. They were required to judge whether a word was a biological word or not, when the words (target word) were represented under four types of repetition priming conditions: Mandarin (prime)-Mandarin (target), Mandarin (prime)-Cantonese (target), Cantonese (prime) Cantonese (target) and Cantonese (prime)-Mandarin (target). Results of reaction time and accuracy primarily indicated larger repetition priming effects in Mandarin-Mandarin and Cantonese-Cantonese (within-language) conditions than that in Mandarin-Cantonese and Cantonese-Mandarin (between-language) conditions. But more importantly, P200 and N400 mean amplitudes revealed distinct repetition priming effects between two types of participants. Specifically, both P200 and N400 indicated that the repetition priming effect in Mandarin-Mandarin condition was larger than that in Cantonese-Cantonese condition for Mandarin-Cantonese participants, whereas it was opposite for Cantonese-Mandarin participants. In addition, P200 also suggested opposite patterns of repetition priming effects in between-language priming conditions for two groups of participants. The repetition priming effect in Mandarin-Cantonese condition was larger than that in Cantonese-Mandarin condition for Mandarin-Cantonese participants, while for Cantonese-Mandarin participants, it was opposite (Mandarin-Cantonese < Cantonese Mandarin). The results implied a clear asymmetric representation of two dialects for proficient bidialectals. They were further discussed in light of native dialect and language use frequency. PMID- 28555346 TI - Endobronchial Metastasis from Extrapulmonary Neoplasms: Analysis of Clinicopathologic Features and Cytological Evaluation by Bronchial Brushing. AB - PURPOSE: Bronchial brushings (BB) commonly aid in the diagnosis of primary lung cancer. However, the utility of this method in diagnosing endobronchial metastases (EBM) from extrapulmonic malignancies has not been thoroughly evaluated. The purpose of this study is to evaluate the sensitivity of BB in diagnosing EBM. METHODS: An institutional database was queried for all patients with cytologically or histologically confirmed extrapulmonary EBM identified by endobronchial biopsy between 1978 and 2013. Data were collected on patient demographics, histologic and cytologic diagnoses, time from primary malignancy to identification of EBM, and location of EBM. The sensitivity of BB for the diagnosis of EBM and the clinicopathologic features of extrapulmonary EBM were assessed. RESULTS: Fifty-six patients (33 females, 23 males; mean age 53 years) were identified with EBM. Diagnoses included lymphoma (21), breast adenocarcinoma (11), colonic adenocarcinoma (7), melanoma (6), renal cell carcinoma (RCC, 5), embryonal carcinoma (2), and 1 case each of tonsillar squamous cell carcinoma, thymic carcinoma, leiomyosarcoma, and sarcoma, not otherwise specified. The sensitivity of BB for identifying EBM was 85% overall and 94% for non-hematologic malignancies. The mean interval between primary diagnosis and EBM was 59 months (range 0-264 months). Excluding ten patients who had EBM at their initial presentation, lymphoma had the shortest (10 months) and RCC had the longest (264 months) mean interval between primary diagnosis and EBM. The mean time between EBM identification and death was 22.4 months (n = 24). CONCLUSION: Bronchial brushing is a sensitive technique for diagnosing non-hematologic extrapulmonic endobronchial metastases. PMID- 28555351 TI - The Promise of Enterprise Architecture for Global Health Informatics. PMID- 28555349 TI - Hospital admission for treatment of complications after extracorporeal shock wave lithotripsy for renal stones: a study of risk factors. AB - The objective of this study was to determine risk factors of hospital admission for treatment of complications after extracorporeal shock wave lithotripsy (SWL). The electronic files and images of all patients who underwent SWL for treatment of renal stones between January 2011 and December 2015 were retrospectively reviewed. All patients underwent SWL with the same electromagnetic lithotripter (Dornier Lithotripot S). The data of those who needed hospital admission for treatment of complications within 30 days after SWL were compared with patients who did not require hospital admission. Compared data included patients' demographics (age, gender, BMI, ASA score, and pre-SWL stenting), renal characters (side, hydronephrosis, and solitary kidney), and stone characters (site, length, density, and previous treatment). Univariate and multivariate statistical analyses were used to identify risk factors. The study included 1179 patients. Complications that required hospital admission were observed in 108 patients (9.2%). They included obstructing steinstrasse in 91 (7.7%), peri-renal hematoma in 3 (0.25%), and fever (>38.0 degrees C) in 14 (1.2%). Independent risk factors on multivariate analysis were solitary kidney (OR 2.855, P = 0.017), pre-SWL stenting (RR 2.03, P = 0.044), ASA II (OR 1.965, P = 0.007), hydronephrosis (RR 1.639, P = 0.024), and stone length (RR 1.083, P < 0.001). Patients with medical co-morbidities, pre-SWL ureteral stents, large stones and those with obstructed and/or solitary renal unit are more liable to post-SWL complications that need hospital admission. The probability of hospital admission has to be explained to patients with these risk factors. PMID- 28555345 TI - New Insights on Temporal Lobe Epilepsy Based on Plasticity-Related Network Changes and High-Order Statistics. AB - Epilepsy is a disorder of the brain characterized by the predisposition to generate recurrent unprovoked seizures, which involves reshaping of neuronal circuitries based on intense neuronal activity. In this review, we first detailed the regulation of plasticity-associated genes, such as ARC, GAP-43, PSD-95, synapsin, and synaptophysin. Indeed, reshaping of neuronal connectivity after the primary, acute epileptogenesis event increases the excitability of the temporal lobe. Herein, we also discussed the heterogeneity of neuronal populations regarding the number of synaptic connections, which in the theoretical field is commonly referred as degree. Employing integrate-and-fire neuronal model, we determined that in addition to increased synaptic strength, degree correlations might play essential and unsuspected roles in the control of network activity. Indeed, assortativity, which can be described as a condition where high-degree correlations are observed, increases the excitability of neural networks. In this review, we summarized recent topics in the field, and data were discussed according to newly developed or unusual tools, as provided by mathematical graph analysis and high-order statistics. With this, we were able to present new foundations for the pathological activity observed in temporal lobe epilepsy. PMID- 28555350 TI - Membranous nephropathy-one morphologic pattern with different diseases. AB - Since the discovery of the phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain-containing 7A (THSD7A) as endogenous antigens involved in the development of membranous nephropathy (MN) in over 80% of adult patients, substantial progress in the diagnosis, prognosis, and therapy of MN has been made. In most cases of patients with MN, it is now possible to specifically define the responsible pathogenic mechanisms of disease and make a diagnosis even without a renal biopsy. Moreover, the presence of antibodies in the blood and the detection of the antigens in renal biopsies allow the definite diagnosis without the morphologic uncertainties, which now still apply for only about 20% of all renal biopsies showing MN. The discovery that the expression of THSD7A in malignant tumors might serve as the site of primary antigen recognition for the immune system to start MN might lead to a better understanding of not only tumor associated MN, which accounts for up to 10% of all patients with MN, but also of the pathomechanisms relevant for MN development in general. PMID- 28555352 TI - A New mHealth App for Monitoring and Awareness of Healthy Eating: Development and User Evaluation by Spanish Users. AB - Modern-day society has moved towards a more sedentary lifestyle. Advances in technology and changes in habits in our daily lives have led a large part of the population towards a spiralling sedentary lifestyle and obesity. The main objective of this work is to develop and subsequently assess a mobile app, named DietApp, that provides advice about obtaining a healthy diet according to age, clinical history and physical condition. DietApp has been developed for iOS and Android systems, and a survey comprising 7 simple questions enabled the app to be evaluated on a user level by taking into account aspects such as its usefulness and ease of use. DietApp was assessed by 150 Spanish individuals between 18 and 69 years of age, and 84% of them thought it was easy to use. 80% of users also considered the dietary suggestions provided by the app to be very useful while 62% were of the opinion that it is very useful in general. All of them would recommend the app to other users. During the six months when the app was used, any dietary excess or shortcomings were corrected in 72% of those interviewed. A mobile app has been created that is easy to use and attractive, providing personalised suggestions according to illness that are useful for the individual. PMID- 28555353 TI - Information and Communications Technologies Health Projects in Panama: A Systematic Review and their Relation with Public Policies. AB - This paper presents a review about Information and Communications Technologies (ICTs) health projects in Panama. The main contribution is to provide a vision of the situation in Panama, allowing an understanding of the dynamics of health policies and how they have affected the implementation of ICT's Projects to improve the health of Panamanians. We analyze the projects found with ICT's in health of Panama, which allow us to see a perspective of projects information is obtained from 2000 to 2016, however it is important to highlight that there may be other projects that we do not know because we did not find enough information or evidence of the same. That is why this review has interviews with key personnel, who have guided us with the search for information. 56% of technology projects are concentrated in the capital city and only 16% in the province of Chiriqui. 64% of these projects are focused on the development of information systems, mainly focused on electronic patient registration. And 60% refers to projects related to primary health care. The MINSA and CSS both with a 20% participation in ICT project, in addition we can notice the dispersion of projects for hospitals, where each one is developing programs per their needs or priorities. The national information about ICT projects of Health, it has been notorious the state of dispersion and segmented of public health information. We consider that it is a natural consequence of Policy in Panamanian Health System. This situation limits the information retrieval and knowledge of ICT in Health of Panama. To stakeholders, this information is directed so that health policies are designed towards a more effective and integral management, administering the ICT's as tools for the well-being of most the Panamanian population, including indigenous group. PMID- 28555354 TI - Contiguous gene deletion of chromosome 2p16.3-p21 as a cause of Lynch syndrome. AB - Lynch syndrome is an autosomal dominant condition caused by pathogenic mutations in the DNA mismatch repair (MMR) genes. Although commonly associated with clinical features such as intellectual disability and congenital anomalies, contiguous gene deletions may also result in cancer predisposition syndromes. We report on a 52-year-old male with Lynch syndrome caused by deletion of chromosome 2p16.3-p21. The patient had intellectual disability and presented with a prostatic adenocarcinoma with an incidentally identified synchronous sigmoid adenocarcinoma that exhibited deficient MMR with an absence of MSH2 and MSH6 protein expression. Family history was unrevealing. Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles. The patient underwent total colectomy with ileorectal anastomosis for a pT3N1 sigmoid adenocarcinoma. Germline genetic testing of the MSH2, MSH6, and EPCAM genes revealed full gene deletions. SNP array based DNA copy number analysis identified a deletion of 4.8 Mb at 2p16.3 p21. In addition to the three Lynch syndrome associated genes, the deleted chromosomal section encompassed genes including NRXN1, CRIPT, CALM2, FBXO11, LHCGR, MCFD2, TTC7A, EPAS1, PRKCE, and 15 others. Contiguous gene deletions have been described in other inherited cancer predisposition syndromes, such as Familial Adenomatous Polyposis. Our report and review of the literature suggests that contiguous gene deletion within the 2p16-p21 chromosomal region is a rare cause of Lynch syndrome, but presents with distinct phenotypic features, highlighting the need for recognition and awareness of this syndromic entity. PMID- 28555355 TI - Laparoscopic cholecystectomy for cholelithiasis in children with sickle cell disease. AB - Patients with sickle cell disease (SCD) suffer from an increased incidence of gallstone formation due to hemolysis of sickled red blood cells; this leads to an increased level of bilirubin in secreted bile that becomes a nidus for pigment stone formation. Laparoscopic cholecystectomy (LC) is considered a standard operative procedure for gallstone disease mainly due to lower postoperative wound complaints, faster recovery, better postoperative cosmetic results, shorter hospital stay, and earlier return to work. Although numerous studies have been published addressing both the advantages and complications of LC in acute calcular cholecystitis, there is still limited evidence concerning the safety and efficacy of LC for the management of cholelithiasis in pediatric patients with SCD, and controversies remain unresolved. In this review, we aim to comprehensively study the available literature and propose evidence-based practice recommendations for the optimal management of gallstones in pediatric SCD patients. The current practice differs greatly depending on the prevalence of SCD in a particular geographic area. We acknowledge the limited number of patients reported, the lack of randomized control trials addressing the practice of specific recommendations, and the need for further evidence-based studies. PMID- 28555356 TI - The long-term prognostic value of survivin expressing circulating tumor cells in patients with high-risk non-muscle invasive bladder cancer (NMIBC). AB - OBJECTIVES: Long-term follow-up study to evaluate the impact on disease-free survival and cancer-specific survival of survivin expression in tissue and CTCs from T1G3 bladder cancer patients. PATIENTS AND METHODS: The study was conducted using tumor tissue and blood samples from 54 patients with a primary diagnosis of T1G3 NMIBC. Survivin was evaluated by reverse transcription-polymerase chain reaction in tumor tissues. CTCs were isolated from blood by CELLectionTM Dynabeads (Invitrogen, Carlsbad, CA, USA). Cells were lysed and cDNA was synthesized and analysed for the expression of CD45, CK8 and survivin. The endpoints of this long-termanalysis were disease-free survival, DFS and cancer specific survival, CSS. RESULTS: Here, we report that, at 9 years of median follow-up, disease-free survival and cancer-specific survival are both significantly influenced by the expression of survivin in tumor tissue (p = 0.006), by the presence of CTCs (p < 0.0001) and by the expression of survivin in CTCs (p < 0.0001). CONCLUSION: The statistically significant impact of survivin expressing CTCs on cancer-specific survival that we observed might be interpreted as the result of the persistence of a subpopulation of highlander cells in the blood of T1G3 bladder patients over time. PMID- 28555357 TI - Attenuation of beta-Amyloid Toxicity In Vitro and In Vivo by Accelerated Aggregation. AB - Accumulation and aggregation of beta-amyloid (Abeta) peptides result in neuronal death, leading to cognitive dysfunction in Alzheimer's disease. The self assembled Abeta molecules form various intermediate aggregates including oligomers that are more toxic to neurons than the mature aggregates, including fibrils. Thus, one strategy to alleviate Abeta toxicity is to facilitate the conversion of Abeta intermediates to larger aggregates such as fibrils. In this study, we designed a peptide named A3 that significantly enhanced the formation of amorphous aggregates of Abeta by accelerating the aggregation kinetics. Thioflavin T fluorescence experiments revealed an accelerated aggregation of Abeta monomers, accompanying reduced Abeta cytotoxicity. Transgenic Caenorhabditis elegans over-expressing amyloid precursor protein exhibited paralysis due to the accumulation of Abeta oligomers, and this phenotype was attenuated by feeding the animals with A3 peptide. These findings suggest that the Abeta aggregation-promotion effect can potentially be useful for developing strategies to reduce Abeta toxicity. PMID- 28555358 TI - Complex chromosomal rearrangement-a lesson learned from PGS. AB - PURPOSE: The aim of the study is to report a case of non-diagnosed complex chromosomal rearrangement (CCR) identified by preimplantation genetic screening (PGS) followed by preimplantation genetic diagnosis (PGD) which resulted in a pregnancy and delivery of healthy offspring. METHODS: A 29-year-old woman and her spouse, both diagnosed previously with normal karyotypes, approached our IVF-PGD center following eight early spontaneous miscarriages. PGS using chromosomal microarray analysis (CMA) was performed on biopsied trophectoderm. Fluorescence in situ hybridization (FISH), as well as re-karyotype, were performed on metaphase derived from peripheral blood of the couple. Subsequently, in the following PGD cycle, a total of seven blastocysts underwent CMA. RESULTS: A gain or loss at three chromosomes (3, 7, 9) was identified in six out of seven embryos in the first PGS-CMA cycle. FISH analysis of parental peripheral blood samples demonstrated that the male is a carrier of a CCR involving those chromosomes; this was in spite of a former diagnosis of normal karyotypes for both parents. Re karyotype verified the complex translocation of 46,XY,t (3;7;9)(q23;q22;q22). Subsequently, in the following cycle, a total of seven blastocysts underwent PGD CMA for the identified complex translocation. Two embryos were diagnosed with balanced chromosomal constitution. A single balanced embryo was transferred and pregnancy was achieved, resulting in the birth of a healthy female baby. CONCLUSIONS: PGS employing CMA is an efficient method to detect unrevealed chromosomal abnormalities, including complicated cases of CCR. The combined application of array CGH and FISH technologies enables the identification of an increased number of CCR carriers for which PGD is particularly beneficial. PMID- 28555359 TI - Broadband W-band Rapid Frequency Sweep Considerations for Fourier Transform EPR. AB - A multi-arm W-band (94 GHz) electron paramagnetic resonance spectrometer that incorporates a loop-gap resonator with high bandwidth is described. A goal of the instrumental development is detection of free induction decay following rapid sweep of the microwave frequency across the spectrum of a nitroxide radical at physiological temperature, which is expected to lead to a capability for Fourier transform electron paramagnetic resonance. Progress toward this goal is a theme of the paper. Because of the low Q-value of the loop-gap resonator, it was found necessary to develop a new type of automatic frequency control, which is described in an appendix. Path-length equalization, which is accomplished at the intermediate frequency of 59 GHz, is analyzed. A directional coupler is favored for separation of incident and reflected power between the bridge and the loop gap resonator. Microwave leakage of this coupler is analyzed. An oversize waveguide with hyperbolic-cosine tapers couples the bridge to the loop-gap resonator, which results in reduced microwave power and signal loss. Benchmark sensitivity data are provided. The most extensive application of the instrument to date has been the measurement of T1 values using pulse saturation recovery. An overview of that work is provided. PMID- 28555361 TI - Improving efficacy and efficiency through the implementation of a new organisational model in a Radiation Oncology Department. AB - BACKGROUND: To evaluate a new organisational model, "process management" (PM), implemented in the Hospital Universitario Virgen de la Victoria (HUVV) compared with traditional models used in other Radiation Oncology Departments (RODs), in terms of efficacy and efficiency. METHODS: The study period ranged from September 2011 to August 2012. Efficacy was assessed, comparing the number of patients attended in first consultation and treated per month, average waiting time from referral to first visit and average waiting time from first visit to treatment. Data were collected from two public hospitals in Andalusia: the HUVV and another Public Hospital in Andalusia (PHA1). Efficiency was assessed comparing the costs per patient attended in first visit and treated at HUVV in 2012 compared with those of a second Public Hospital in Andalusia (PHA2) for 2008. The number of sessions saved using hypofractionation versus classical schemes during the year 2012 in HUVV was estimated, and the money saved was calculated. RESULTS: In the efficacy analysis, we found significant differences in the average waiting time for first visit, start of treatment, and the number of patients seen and treated annually. After calculating the total cost generated in the ROD, the efficiency analysis showed a lower cost per patient attended in first visit (EUR 599.17) and per patient treated (EUR 783.50), with a saving of 6035 sessions using hypofractionated schemes. CONCLUSIONS: Process management in an ROD reduces time, both to first medical visit and to treatment initiation, allowing an optimisation of linear accelerator (LINAC) capacity. PMID- 28555360 TI - A correlation between long-term in vitro dynamic calcification and abnormal flow patterns past bioprosthetic heart valves. AB - In this paper, a long-term in vitro dynamic calcification of three porcine aortic heart valves was investigated using a combined approach that involved accelerated wear testing of the valves in the rapid calcification solution, hydrodynamic assessment of the progressive change of effective orifice area (EOA) along with the transaortic pressure gradient, and quantitative visualization of the flow. The motivation for this study was developing a standardized, economical, and feasible in vitro testing methodology for bioprosthetic heart valve calcification, which would address both the hydrodynamic performance of the valves as well as the subsequent changes in the flow field. The results revealed the failure of the test valves at 40 million cycles mark, associated with the critical decrease in the EOA, followed by the increase in the maximum value of viscous shear stress of up to 52%, compared to the values measured at the beginning of the study. The decrease in the EOA was subsequently followed by the rapid increase in the maximum streamwise velocity of the central orifice jet up to the value of about 2.8 m/s, compared to the initial value of 2 m/s, and to the value of 2.2 m/s in the case of a control valve along with progressive narrowing of the velocity profile for two test valves. The significance of the current work is in demonstrating a correlation between calcification of the aortic valve and spatial as well as the temporal development of abnormal flow features. PMID- 28555362 TI - The Incidence of Drug- and Herbal and Dietary Supplement-Induced Liver Injury: Preliminary Findings from Gastroenterologist-Based Surveillance in the Population of the State of Delaware. AB - BACKGROUND AND AIM: The population-based incidence rate of drug-induced liver injury (DILI) in the USA is not known. The Drug-Induced Liver Injury Network (DILIN) accrues cases of hepatotoxicity due to medications and herbal and dietary supplements (HDS) from limited geographical areas. The current analysis was an ancillary study of DILIN aimed at determining the annual incidence of DILI in the USA on a population basis, through surveillance in the state of Delaware. METHODS: At the outset of the study, there were 41 gastroenterologists in the state of Delaware and all agreed to participate in surveillance for DILI, which comprised active reporting of suspected cases to the DILIN. The gastroenterologists underwent training in the diagnosis of DILI and were provided with DILIN inclusion criteria. Only cases that met the DILIN laboratory inclusion criteria in 2014 were included in the incidence calculation, and these patients were invited to participate in the DILIN Prospective Study. The number of suspected cases that met inclusion criteria served as the numerator and the 2014 Delaware adult population as the denominator. RESULTS: During 2014, 23 patients were identified by the surveillance network, 20 of whom met DILIN laboratory inclusion criteria, leading to an incidence of 2.7 cases of DILI per 100,000 adult residents [95% confidence interval (CI) 1.5-3.9 per 100,000]. Fourteen subjects agreed to participate in the DILIN; six declined. Among enrolled cases, the mean age was 51 years, 57% were women, and 71% were white. Eight cases were attributed to antibiotics (36%) and other drugs (21%) and six to HDS (43%). The pattern of injury was hepatocellular in all HDS cases, but only 50% of conventional drug cases (p = 0.05), which more commonly presented with eosinophilia (p = 0.47) and higher alkaline phosphatase levels (p = 0.05). Half of patients were jaundiced, none developed liver failure, and all recovered without the need for transplantation. CONCLUSION: Prospective, gastroenterologist based surveillance for suspected DILI in Delaware yielded an incidence of 2.7 cases per 100,000 adults in 2014; this is the first prospective estimate of DILI for the USA. Because surveillance was limited to subspecialists, the actual incidence of DILI is likely to be higher. These findings provide a benchmark statistic for the epidemiology of DILI in the United States, to be refined with expansion of the surveillance period. PMID- 28555363 TI - Malnutrition is an independent risk factor for mortality in Mexican patients with systemic sclerosis: a cohort study. AB - Factors for mortality in systemic sclerosis (SSc) vary in different cohorts around the world. Case-control study nested in a cohort. We included patients >=16 years of age with SSc (ACR/EULAR 2013), from 2005 to 2015. Demographic and clinical variables and causes of mortality were recorded. We calculated Crude Mortality Rate (CMR), Standardized Mortality Ratio (SMR), and Kaplan-Meier survival analysis was performed. A Cox proportional hazard (HR) regression analysis of the potential risk factors associated with mortality was also performed. A total of 220 patients with SSc were included. During follow-up, 28 deaths occurred. The sum of total time contributed by all subjects was 1074 years person, the CMR was 12.72%, the overall SMR was 4.5, in women 3.7, and in men 4.7. The survival rate at 5 and 10 years was 83 and 70%, respectively. The causes of death were definitively attributed to SSc in 21.4% of the cases, probably in 28.7%, unrelated in 35.6%, and unknown in 14.3%. The direct cause of death of the patients was infection in 25% of cases, cardiovascular disease in 14%, lung involvement in 14%, pulmonary embolism in 11%, and neoplasia in 11%. The Cox regression analysis showed that the factors associated with mortality were: male gender (HR 5.84, CI 95% 1.31-26, p = 0.013), severe Medsger's score for general symptoms (HR 5.12, CI 95% 1.74-14.97, p = 0.021) and severe malnutrition (HR 3.77, CI 95% 1.23-11.06, p = 0.008). Infections, cardiovascular disease, and lung involvement were the leading cause of death. Male gender and severe general affection and malnutrition were associated with a poorer prognosis of SSc. PMID- 28555365 TI - Long-term results of rotational acetabular osteotomy for osteonecrosis with collapse of the femoral head in young patients. AB - PURPOSE: The surgical treatment of osteonecrosis with collapse of the femoral head is still controversial. The purpose of this study was to investigate the clinical outcome of rotational acetabular osteotomy by Ninomiya and Tagawa for osteonecrosis of the femoral head in young patients. PATIENTS AND METHODS: Rotational acetabular osteotomy was performed in 202 consecutive patients between 1995 and 2003. Among them, rotational acetabular osteotomy with osteonecrosis of the femoral head was performed in 31 patients (42 hips). The mean age at the time of surgery was 31.2 years (range 16-45). The mean duration of follow-up was 16.1 years (range 13.1-21 years). RESULTS: The mean preoperative Japanese Orthopedic Association hip score of 56.8 points improved to a mean of 72.4 points at the final follow-up. The 10-year survival rate with conversion to total hip arthroplasty as an end-point was 91.9%, and the 15-year survival rate was 75.5%, the 20-year survival rate was 67.9%. The conversion to total hip arthroplasty was performed in nine hips. The average time to the conversion to total hip arthroplasty was 12.1 years. CONCLUSIONS: Even though the necrotized range is wide, if normal cartilage remains on the lateral side of the femoral head, it can be utilized for the weight-bearing region by laterally rotating the acetabulum. Since the outcome was favorable, we believe that this is a valuable treatment option for this disease. PMID- 28555364 TI - Osteoclast-Associated Receptor (OSCAR) Distribution in the Synovial Tissues of Patients with Active RA and TNF-alpha and RANKL Regulation of Expression by Osteoclasts In Vitro. AB - Osteoclast-associated receptor (OSCAR) is a co-stimulatory receptor in osteoclastogenesis. Synovial tissues from active rheumatoid arthritis (RA) patients express higher levels of OSCAR compared with osteoarthritic and normal patients; however, the comparison of OSCAR levels in different regions of active RA synovium has not been reported. The regulation of OSCAR by TNF-alpha and receptor activator of NF kappa beta ligand (RANKL) in pre-osteoclasts/osteoclasts in vitro is unclear. OSCAR and tartrate-resistant acid phosphatase (TRAP) expression levels did not differ between the cartilage pannus junction (CPJ) and non-CPJ regions in active RA. We demonstrate a similar pattern of OSCAR expression in the CPJ and non-CPJ synovial tissue from patients with active RA. OSCAR was associated with mononuclear cells in both the lining and sub-lining and endothelial cells (von Willebrand factor positive). Pre-osteoclasts (TRAP positive cells) were present in the lining and sub-lining of both regions. OSCAR messenger RNA (mRNA) expression and release by pre-oscteoclasts/osteoclasts was modulated by RANKL with/without TNF-alpha in vitro. Osteoclast resorption on dentine slices was significantly greater with TNF-alpha pre-treatment and RANKL (10 ng/ml) than RANKL 10 or 50 ng/ml alone or RANKL 10 ng/ml with TNF-alpha given from day 3 post-RANKL. The lower levels of OSCAR mRNA expression corresponded with high osteoclast activity levels. PMID- 28555366 TI - Pulley lesions in rotator cuff tears: prevalence, etiology, and concomitant pathologies. AB - PURPOSE: This study aimed to demonstrate the prevalence of lesions in the biceps pulley complex in a representative, consecutive series of rotator cuff tears and rotator cuff interval treatments. We also analyzed associated tear pattern of rotator cuff injuries and superior labrum anterior-posterior (SLAP) lesions. We evaluated the relationships of these lesions to traumatic genesis and the prevalence of pulley lesions in revision cases. METHODS: This retrospective study analyzed all pre- and intra-operative documentation on arthroscopic rotator cuff reconstructions and isolated pulley lesion treatments performed by a single surgeon over 2 consecutive years. According to Habermeyer et al., we classified cases into four groups, based on the presence of additional or related complete or partial rotator cuff tears, SLAP lesions, trauma, and primary or revision surgery. RESULTS: Among 382 patients with rotator cuff tears, 345 (90.3%) had an injured pulley system; 151 (43.8%) had partial tears of the rotator cuff; out of these, 106 (30.6%) were articular-sided. All of these articular-sided partial tears showed extension into the pulley complex. In 154 cases (44.6%), history of shoulder trauma was associated with the beginning of symptoms. In addition, concomitant SLAP lesions occurred in 25-62% of pulley lesions, correlating with the severity of pulley lesions. Among the 345 cases, there have been 32 (9.3%) revision cases where a pulley lesion was intra-operatively identified and addressed. CONCLUSIONS: Pulley complex lesions are present in 90.3% of surgically treated rotator cuff lesions, particularly in articular-sided injuries. In addition, we found a significant relationship between the incidence of SLAP lesions and the severity of pulley lesions. It seems reasonable to assume an important role of pulley system injuries in the pathogenesis of rotator cuff lesions. PMID- 28555367 TI - Subtrochanteric fractures in elderly people treated with intramedullary fixation: quality of life and complications following open reduction and cerclage wiring versus closed reduction. AB - INTRODUCTION: Subtrochanteric fractures are more difficult to treat than other proximal femoral fractures. The aim of this study was to report the outcomes for patients with subtrochanteric fractures treated using a cephalomedullary nail following open reduction and cerclage wiring versus closed reduction alone, regarding health-related quality of life (HRQoL) and social function. MATERIALS AND METHODS: We performed a prospective cohort study including patients aged 60 years or older suffering fragility subtrochanteric fractures of the femur treated with cephalomedullary nails, with a minimum 2-year follow-up. We defined two treatment groups: one treated with closed reduction manoeuvres (60 patients), and another treated with open reduction and cerclage wiring (30 patients). The outcomes were mortality, orthopaedic complications (reoperation and no-union), social function (Jensen Index), and HRQoL (EQ-5D index score). RESULTS: There were no differences regarding sex, age, side affected, type of implant, anaesthetic risk, 1-year mortality, and orthopaedic complications. Surgical time was longer in the cerclage wire group, but length of stay was 2 days shorter for the cerclage group and reduction was better. Patients treated with cerclage wiring had significantly better EQ-ED at 12 months (0.66 +/- 0.22 points vs. 0.78 +/- 0.15 points); and social status at 12 and 18 months (2.77 +/- 1.00 points vs. 2.10 +/- 1.22 points). CONCLUSIONS: Better reduction is achieved when using cerclage wires for fragility subtrochanteric fractures. These fractures had a negative effect on quality of life and social function, but better outcomes were observed in the cerclage group. PMID- 28555369 TI - Role of molecular turnover in dynamic deformation of a three-dimensional cellular membrane. AB - In cells, the molecular constituents of membranes are dynamically turned over by transportation from one membrane to another. This molecular turnover causes the membrane to shrink or expand by sensing the stress state within the cell, changing its morphology. At present, little is known as to how this turnover regulates the dynamic deformation of cellular membranes. In this study, we propose a new physical model by which molecular turnover is coupled with three dimensional membrane deformation to explore mechanosensing roles of turnover in cellular membrane deformations. In particular, as an example of microscopic machinery, based on a coarse-graining description, we suppose that molecular turnover depends on the local membrane strain. Using the proposed model, we demonstrate computational simulations of a single vesicle. The results show that molecular turnover adaptively facilitates vesicle deformation, owing to its stress dependence; while the vesicle drastically expands in the case with low bending rigidity, it shrinks in that with high bending rigidity. Moreover, localized active tension on the membrane causes cellular migration by driving the directional transport of molecules within the cell. These results illustrate the use of the proposed model as well as the role of turnover in the dynamic deformations of cellular membranes. PMID- 28555370 TI - Promoting Nurturing Environments in Afterschool Settings. AB - Given the rise in dual-career and single-parent families, and the need for monitoring and supervision during out-of-school time, afterschool settings are becoming important contexts for the prevention of problem behaviors and the promotion of the positive development of youth. Research indicates that high quality afterschool programs can have positive effects on children's academic, socio-emotional, and behavioral outcomes. But less is known about how these influences occur and potential mechanisms involved in this nurturing and promotion process. This paper draws upon the current theoretical and empirical literature in school settings and beyond to examine ways in which afterschool settings can be leveraged as a potential nurturing environment. We apply the conceptualization of nurturing environments put forth by Biglan et al. (Am Psychol 67(4):257-271, 2012. doi: 10.1037/a0026796 ), which attends to the minimization of toxic social and biological conditions, reinforcement of diverse prosocial behaviors, limiting opportunities and influences for problem behavior, and promoting psychological flexibility in the pursuit of one's values and goals. This paper concludes by identifying potential future research directions and practice implications regarding afterschool settings as nurturing environments for all youth. PMID- 28555368 TI - A mutated dph3 gene causes sensitivity of Schizosaccharomyces pombe cells to cytotoxic agents. AB - Dph3 is involved in diphthamide modification of the eukaryotic translation elongation factor eEF2 and in Elongator-mediated modifications of tRNAs, where a 5-methoxycarbonyl-methyl moiety is added to wobble uridines. Lack of such modifications affects protein synthesis due to inaccurate translation of mRNAs at ribosomes. We have discovered that integration of markers at the msh3 locus of Schizosaccharomyces pombe impaired the function of the nearby located dph3 gene. Such integrations rendered cells sensitive to the cytotoxic drugs hydroxyurea and methyl methanesulfonate. We constructed dph3 and msh3 strains with mutated ATG start codons (ATGmut), which allowed investigating drug sensitivity without potential interference by marker insertions. The dph3-ATGmut and a dph3::loxP ura4-loxM gene disruption strain, but not msh3-ATGmut, turned out to be sensitive to hydroxyurea and methyl methanesulfonate, likewise the strains with cassettes integrated at the msh3 locus. The fungicide sordarin, which inhibits diphthamide modified eEF2 of Saccharomyces cerevisiae, barely affected survival of wild type and msh3Delta S. pombe cells, while the dph3Delta mutant was sensitive. The msh3 ATG mutation, but not dph3Delta or the dph3-ATG mutation caused a defect in mating-type switching, indicating that the ura4 marker at the dph3 locus did not interfere with Msh3 function. We conclude that Dph3 is required for cellular resistance to the fungicide sordarin and to the cytotoxic drugs hydroxyurea and methyl methanesulfonate. This is likely mediated by efficient translation of proteins in response to DNA damage and replication stress. PMID- 28555371 TI - Hierarchical High-Order Functional Connectivity Networks and Selective Feature Fusion for MCI Classification. AB - Conventional Functional connectivity (FC) analysis focuses on characterizing the correlation between two brain regions, whereas the high-order FC can model the correlation between two brain region pairs. To reduce the number of brain region pairs, clustering is applied to group all the brain region pairs into a small number of clusters. Then, a high-order FC network can be constructed based on the clustering result. By varying the number of clusters, multiple high-order FC networks can be generated and the one with the best overall performance can be finally selected. However, the important information contained in other networks may be simply discarded. To address this issue, in this paper, we propose to make full use of the information contained in all high-order FC networks. First, an agglomerative hierarchical clustering technique is applied such that the clustering result in one layer always depends on the previous layer, thus making the high-order FC networks in the two consecutive layers highly correlated. As a result, the features extracted from high-order FC network in each layer can be decomposed into two parts (blocks), i.e., one is redundant while the other might be informative or complementary, with respect to its previous layer. Then, a selective feature fusion method, which combines sequential forward selection and sparse regression, is developed to select a feature set from those informative feature blocks for classification. Experimental results confirm that our novel method outperforms the best single high-order FC network in diagnosis of mild cognitive impairment (MCI) subjects. PMID- 28555372 TI - Determinants of catastrophic health expenditure in Nigeria. AB - BACKGROUND: Catastrophic health expenditure is a measure of financial risk protection and it is often incurred by households who have to pay out of pocket for health care services that are not affordable. The study assessed the determinants of catastrophic health expenditure among households in Nigeria. METHODS: Secondary data from the Harmonized Nigeria Living Standard Survey (HNLSS) of 2009/10 was utilized to assess factors associated with catastrophic health expenditure in Nigeria. Household and individual characteristics associated with catastrophic health expenditure were determined using bivariate analysis and multivariate logistic regression. RESULTS: Results showed that irrespective of the threshold for the two concepts of total household expenditure and non-food expenditure, having household members aged between 6 and 14 years, having household members aged between 15 and 24 years, having household members aged between 25 and 54 years, having no education, having primary education, having secondary education, lack of health insurance coverage, visiting a private health facility, households living in north central zone, households living in north east zone and having household members with non-chronic illnesses were factors that increase the risk of incurring catastrophic health expenditure among households. CONCLUSIONS: Policy-makers and political actors need to design equitable health financing policies that will increase financial risk protection for people in both the formal and informal sectors of the economy. PMID- 28555373 TI - Blood Brain Barrier Injury in Diabetes: Unrecognized Effects on Brain and Cognition. AB - Diabetes mellitus (DM) is a disorder due to the inability properly to metabolize glucose associated with dysregulation of metabolic pathways of lipids and proteins resulting in structural and functional changes of various organ systems. DM has detrimental effects on the vasculature, resulting in the development of various cardiovascular diseases and stemming from microvascular injury. The blood brain barrier (BBB) is a highly specialized structure protecting the unique microenvironment of the brain. Endothelial cells, connected by junctional complexes and expressing numerous transporters, constitute the main cell type in the BBB. Other components, including pericytes, basement membrane, astrocytes and perivascular macrophages, join endothelial cells to form the neurovascular unit (NVU) and contribute to the proper function and integrity of the BBB. The role of the BBB in the pathogenesis of diabetic encephalopathy and other diabetes-related complications in the central nervous system is apparent. However, the mechanisms, timing and consequences of BBB injury in diabetes are not well understood. The importance of further studies related to barrier dysfunction in diabetes is dictated by its potential involvement in the cognitive demise associated with DM. This review summarizes the impact of DM on BBB/NVU integrity and function leading to neurological and cognitive complications. PMID- 28555375 TI - Overview of the 8th Edition TNM Classification for Head and Neck Cancer. AB - OPINION STATEMENT: The main purpose of the TNM system is to provide an anatomic based classification to adequately depict cancer prognosis. Accurate cancer staging is important for treatment selection and outcome prediction, research design, and cancer control activities. To maintain clinical relevance, periodical updates to TNM are necessary. The recently published 8th edition TNM classification institutes the following changes to the staging of head and neck (excluding thyroid cancer): new stage classifications [HPV-related oropharyngeal cancer (HPV+ OPC) and soft tissue sarcoma of the head and neck (HN-STS)] and modification of T and N categories [T and N categories for nasopharyngeal cancer (NPC), T categories for oral cavity squamous cell carcinomas (OSCC), N categories for non-viral related head and neck cancer and unknown primary (CUP), and T categories for head and neck cutaneous carcinoma]. These changes reflect better understanding tumor biology and clinical behavior (e.g., HPV+ OPC and HN-STS), improved outcomes associated with technical advances in diagnosis and treatment (e.g., NPC), evolving knowledge about additional prognostic factors and risk stratification from research and observation (e.g., inclusion of depth of invasion variable for OSCC, inclusion of extranodal extension variable for all non-viral head and neck cancer, and reintroduction of size criteria for non Merkel cell cutaneous carcinoma of the head and neck). This review summarizes the changes and potential advantages and limitations/caveats associated with them. Further evidence is needed to evaluate whether these changes would result in improvement in TNM stage performance to better serve the needs for clinical care, research, and cancer control. PMID- 28555374 TI - The Cisplatin Total Dose and Concomitant Radiation in Locoregionally Advanced Head and Neck Cancer: Any Recent Evidence for Dose Efficacy? AB - OPINION STATEMENT: Concurrent chemoradiotherapy (CRT) with high-dose (100 mg/m2), single-agent cisplatin is considered the standard of care for locoregionally advanced head and neck cancer (LAHNC). Poor compliance often due to significant treatment-related toxicities observed during CRT regimen has stimulated research efforts to examine for evidence of the optimal cumulative cisplatin dose and schedule. The findings from this systematic literature review demonstrate that there are insufficient prospective, randomized controlled data to determine the optimal total dose (and schedule) of cisplatin to administer concomitantly with radiotherapy in the treatment of LAHNC. Given the clinical challenges associated with administering concurrent CRT with single-agent high-dose cisplatin, as well as the long-term toxicities accompanying this treatment, an examination of the available literature for evidence of dose efficacy is of continued clinical interest. Moving forward, it is critical that researchers include complete descriptions of key disease and treatment variables (i.e. treatment compliance and HPV status) to inform and strengthen clinical decisions. The substantial heterogeneity of LAHNC has led to the focus of recent research efforts to risk stratify using a combination of clinical and molecular markers (e.g. HPV status). Thus, the optimal total dose (and schedule) of cisplatin may need to be modified to reflect the specific characteristics of the individual patient subpopulations being treated. At present, CRT remains the standard of care for LAHNC, but this field is rapidly evolving. National and international clinical trials are ongoing to evaluate treatment de-intensification in favourable risk patient subsets and treatment intensification in poor-risk patient subsets, these will provide evidence-based guidance to individualize therapy with the ultimate goal of improving patient outcomes. PMID- 28555377 TI - AlphaLISA detection of alpha-synuclein in the cerebrospinal fluid and its potential application in Parkinson's disease diagnosis. PMID- 28555376 TI - Proteomic Analysis Revealed the Fruiting-Body Protein Profile of Auricularia polytricha. AB - Auricularia polytricha is one of the most widely cultivated edible mushrooms in China. Many advances have been made to A. polytricha, but there is still no proteomic information of this species. Our current understanding was based upon the translated information of its transcriptome or other relative species. This study presented the proteomic information of fruiting-body proteins by shotgun liquid chromatography and tandem mass spectrometry (LC-MS/MS), which identified 15,508 peptides corresponding to 1850 high-confidence proteins. Of these, 1383 were annotated across the GO subcategories with 829 (44.81%) involved in biological process, 908 (49.08%) in molecular function, and 406 (21.95%) in cellular components. Among these high-confidence proteins, 132 proteins were annotated as carbohydrate-active enzymes, of which 51 were secreted enzymes. Moreover, a number of commercially important enzymes were detected, functioning as auxiliary activity (AA) family 5 glyoxal oxidase, AA5 galactose oxidase, glycoside hydrolase (GH) family 20 hexosaminidase, and GH47 alpha-mannosidase. To the best of our knowledge, this is the first study to characterize A. polytricha proteome, and also fills the gap of our knowledge on the under-developed mushroom species. PMID- 28555378 TI - [A 59-year-old woman with upper abdominal pain and fever]. AB - A 59-year-old woman suffered from fever and upper abdominal pain. The computed tomography (CT) scan revealed a liver lesion. Conventional imaging techniques (CT, magnetic resonance imaging, contrast-enhanced ultrasonography) did not allow for a consistent diagnosis. Fine needle biopsy of the liver lesion was performed. Histologically, fibrotic inflammation was found and an inflammatory pseudotumor (IPT) diagnosed. Despite treatment with steroids and antibiotics, the size of the IPT increased; thus, surgical resection was necessary. In case of fever of unknown origin, IPT should be considered as a potential diagnosis. PMID- 28555379 TI - [Recent development of hypertension and acute renal failure in a 59-year-old woman]. AB - We report on a 59-year-old woman who presented with nausea, fatigue, arterial hypertension, and acute renal failure. Clinical examination, laboratory findings of blood and urine and abdominal sonography were inconclusive. Renal biopsy revealed infiltration by a diffuse large B-cell lymphoma. In fluorodeoxyglucose positron emission tomography/computed tomography tracer enrichment was demonstrated in both kidneys, skeletal system and retroperitoneal lymph nodes. Renal function improved already after the first cycle of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). After chemotherapy, a complete remission, normalization of blood pressure and renal function were achieved. PMID- 28555380 TI - Anti-gliadin antibodies in breast milk from celiac mothers on a gluten-free diet. AB - PURPOSE: To analyze the presence of total IgA and anti-gliadin antibodies (AGA) in BM from CD mothers who follow a gluten-free diet (GFD) and from mothers on a normal gluten-containing diet (ND). METHODS: 218 samples of mature milk were obtained at different months of lactation (1-6) from 83 mothers (2 or more samples per mother) from Italy (Naples), The Netherlands (Leiden) and Spain (Madrid, Valencia and Reus): 42 CD mothers on GFD for more than 2 years and 41 non-CD mothers on a ND. Whey samples were analyzed for AGA-IgA by an indirect homemade ELISA and for total IgA (g/L) by a commercial ELISA kit. RESULTS: AGA IgA was detected in BM, both in mothers on a GFD and mothers on a ND. AGA-IgA levels in both groups of mothers, CD and non-CD, show the same trend towards decreasing slightly along the months of lactation (p = 0.91). A different trend is observed for total IgA levels, decreasing markedly in CD mothers from the first month of lactation onwards but remaining stable in non-CD mothers (p = 0.048). A statistically significant association was found between the means of total IgA and AGA-IgA (p < 0.001). CONCLUSION: AGA-IgA is present in BM from mothers on a ND as well as in BM from mothers who had been on a GFD for years. This reflects the existence of a long-lasting immunological memory independent of the mother's diet. If the presence of these antibodies has any role in promoting the acquisition of gluten tolerance in the infant, our study shows that children of CD mothers would be on equal conditions as children of non-CD mothers. PMID- 28555382 TI - Prevalence and characteristics of self-reported physical and mental disorders among adults with hearing loss in Denmark: a national survey. AB - PURPOSE: Existing research shows that people with hearing loss have a high risk of additional physical and mental disorders. However, only a few population-based studies have been conducted. This study assesses the prevalence and characteristics of additional disorders among adults with hearing loss in Denmark and thereby contributes a population-based study to this area of research. METHOD: Data on self-reported physical and mental disorders from a national survey of 772 adults with hearing loss were compared to corresponding data from a national survey of 18,017 adults from the general population. RESULTS: People with hearing loss reported more physical and mental disorders than the general population. Specifically, they reported higher incidences of visual impairment, cerebral palsy, intellectual impairment, and "other mental disorders". CONCLUSION: Adults with hearing loss have a greater risk of additional physical and mental disorders. It is important for clinicians to have some understanding of the communication needs and characteristics of deaf and hard-of-hearing patients, so that they can recognize and treat symptoms and provide appropriate support. PMID- 28555381 TI - Do racial patterns in psychological distress shed light on the Black-White depression paradox? A systematic review. AB - PURPOSE: Major epidemiologic studies in the US reveal a consistent "paradox" by which psychiatric outcomes such as major depressive disorder (MDD) are less prevalent among Blacks relative to Whites, despite greater exposure to social and economic stressors and worse physical health outcomes. A second paradox, which has received less attention and has never been systematically documented, is the discrepancy between these patterns and Black-White comparisons in psychological distress, which reveal consistently higher levels among Blacks. By systematically documenting the latter paradox, this paper seeks to inform efforts to explain the first paradox. METHODS: We conduct a systematic review of the literature estimating the prevalence of MDD and levels of psychological distress in Blacks and Whites in the US. RESULTS: The literature review yielded 34 articles reporting 54 relevant outcomes overall. Blacks have a lower prevalence of MDD in 8 of the 9 comparisons observed. In contrast, Blacks have higher levels of psychological distress (in terms of "high distress" and mean scores) than Whites in 42 of the 45 comparisons observed. Tests of statistical significance, where available, confirm this discrepant pattern. CONCLUSIONS: A systematic review of the epidemiologic evidence supports the existence of a "double paradox" by which Blacks' lower prevalence of MDD relative to Whites' is inconsistent with both the expectations of social stress theory and with the empirical evidence regarding psychological distress. Efforts to resolve the Black-White depression paradox should account for the discordant distress results, which seem to favor artifactual explanations. PMID- 28555383 TI - New fronts emerge in the influenza cytokine storm. AB - Influenza virus is a significant pathogen in humans and animals with the ability to cause extensive morbidity and mortality. Exuberant immune responses induced following infection have been described as a "cytokine storm," associated with excessive levels of proinflammatory cytokines and widespread tissue damage. Recent studies have painted a more complex picture of cytokine networks and their contributions to clinical outcomes. While many cytokines clearly inflict immunopathology, others have non-pathological delimited roles in sending alarm signals, facilitating viral clearance, and promoting tissue repair, such as the IL-33-amphiregulin axis, which plays a key role in resolving some types of lung damage. Recent literature suggests that type 2 cytokines, traditionally thought of as not involved in anti-influenza immunity, may play an important regulatory role. Here, we discuss the diverse roles played by cytokines after influenza infection and highlight new, serene features of the cytokine storm, while highlighting the specific functions of relevant cytokines that perform unique immune functions and may have applications for influenza therapy. PMID- 28555384 TI - Genetics of rheumatoid arthritis susceptibility, severity, and treatment response. AB - A decade after the first genome-wide association study in rheumatoid arthritis (RA), a plethora of genetic association studies have been published on RA and its clinical or serological subtypes. We review the major milestones in the study of the genetic architecture of RA susceptibility, severity, and response to treatment. We set the scientific context necessary for non-geneticists to understand the potential clinical applications of human genetics and its significance for a stratified approach to the management of RA in the future. PMID- 28555388 TI - Right coronary artery ectasia with coronary arteriovenous fistula mimicking Takotsubo-like left ventricular dysfunction in the electrocardiogram. AB - A coronary arteriovenous fistula is an abnormal connection between a coronary artery and any of four chambers in the heart. We repot a unique case with a fistulae originating from right coronary artery and draining into the right atrium via coronary sinus although Takotsubo-like left ventricular dysfunction or acute myocardial infarction was initially thought to have occurred according to the electrocardiogram finding. PMID- 28555386 TI - Molecular pathogenesis of viral hemorrhagic fever. AB - The clinical syndrome referred to as viral hemorrhagic fever (VHF) can be caused by several different families of RNA viruses, including select members of the arenaviruses, bunyaviruses, filoviruses, and flaviviruses. VHF is characterized by malaise, fever, vascular permeability, decreased plasma volume, coagulation abnormalities, and varying degrees of hemorrhage. Study of the filovirus Ebola virus has demonstrated a critical role for suppression of innate antiviral defenses in viral pathogenesis. Additionally, antigen-presenting cells are targets of productive infection and immune dysregulation. Among these cell populations, monocytes and macrophages are proposed to produce damaging inflammatory cytokines, while infected dendritic cells fail to undergo proper maturation, potentially impairing adaptive immunity. Uncontrolled virus replication and accompanying inflammatory responses are thought to promote vascular leakage and coagulopathy. However, the specific molecular pathways that underlie these features of VHF remain poorly understood. The arenavirus Lassa virus and the flavivirus yellow fever virus exhibit similar molecular pathogenesis suggesting common underlying mechanisms. Because non-human primate models that closely mimic VHF are available for Ebola, Lassa, and yellow fever viruses, we propose that comparative molecular studies using these models will yield new insights into the molecular underpinnings of VHF and suggest new therapeutic approaches. PMID- 28555387 TI - Ameliorating the severity of sleep-disordered breathing concomitant with heart failure status after percutaneous transluminal septal myocardial ablation for drug-refractory hypertrophic obstructive cardiomyopathy. AB - The coexistence of sleep-disordered breathing (SDB) and hypertrophic obstructive cardiomyopathy (HOCM) has widely been recognized; however, the impact of percutaneous transluminal septal myocardial ablation (PTSMA) for HOCM on SDB remains unknown. Herein, we examine cardiorespiratory polygraph parameters in patients with drug-refractory HOCM before and after PTSMA. Forty consecutive drug refractory HOCM patients, admitted to Keio University Hospital, and who underwent cardiorespiratory polygraphy were retrospectively analyzed. Cardiorespiratory polygraphy was performed before and after PTSMA if patients underwent PTSMA. Patients with an apnea-hypopnea index (AHI) >=5/h were considered to have SDB. The total number of central sleep apneas, obstructive sleep apneas, and hypopnea events was evaluated. Thirty-two out of 40 patients (80%) with drug-refractory HOCM had SDB. All patients experienced relief of heart failure-associated symptoms after PTSMA. The severity of SDB was found to be correlated with left atrial diameter. The AHI decreased after PTSMA [before 15.4 (range 10.9-23.5)/h vs. after 13.1 (8.3-17.8)/h, P = 0.02]. Especially, the hypopnea index decreased after PTSMA. The average and lowest arterial oxygen saturation also increased after PTSMA (94.2 +/- 1.9-95.7 +/- 1.6%, P = 0.009; 81.3 +/- 5.7-85.8 +/- 4.8%, P = 0.012, respectively). In patients with drug-refractory HOCM, PTSMA decreased the AHI and improved arterial oxygen saturation measures. Thus, invasive treatment of the left ventricular obstruction ameliorates the severity of SDB, in addition to improving heart failure status. PMID- 28555390 TI - Pure motor monoparesis due to infarction of the "hand knob" area: radiological and morphological features. PMID- 28555389 TI - Plaque characteristics and inflammatory markers for the prediction of major cardiovascular events in patients with ST-segment elevation myocardial infarction. AB - To investigate the clinical utility of culprit plaque characteristics and inflammatory markers for the prediction of future cardiovascular events in patients with ST-segment elevation myocardial infarction (STEMI) with successful drug-eluting stent (DES) implantation. We evaluated 172 STEMI patients with successful primary percutaneous coronary intervention (PCI) with DES using pre PCI high-sensitivity C-reactive protein (hs-CRP), neutrophil-to-lymphocyte ratio (NLR) and pre-PCI intravascular ultrasound virtual histology (IVUS-VH) of culprit lesions. The incidence of major adverse cardiovascular events (MACE) including all-cause mortality, non-fatal MI, stroke and late revascularization were recorded during hospitalization and follow-up. During follow-up (median 41 months), the incidence of MACE did not significantly differ among patients with or without all 3 high-risk plaque features on IVUS-VH (15.1 vs. 16.2%; p = 0.39). In contrast, patients with elevated hs-CRP and NLR levels were at significant risk for MACE [32.7 vs. 5.8%; hazard ratio (HR) 7.85; p < 0.001 and 43.9 vs. 6.9%; HR 8.44; p < 0.001, respectively]. High-risk plaque features had no incremental usefulness to predict future MACE. However, the incorporation of hs CRP and NLR into a model with conventional clinical and procedural risk factors significantly improved the C-statistic for the prediction of MACE (0.76-0.89; p = 0.04). High-risk plaque features identified by IVUS-VH in culprit lesions were not associated with future MACE in patients with STEMI receiving DES. However, elevated hs-CRP and NLR levels were significantly associated with poorer outcomes and had incremental predictive values over conventional risk factors. PMID- 28555385 TI - Cytokine storm and sepsis disease pathogenesis. AB - Infectious diseases are a leading cause of death worldwide. Sepsis is a severe clinical syndrome related to the host response to infection. The severity of infections is due to an activation cascade that will lead to an autoamplifying cytokine production: the cytokine storm. Cytokines are a broad category of relatively small proteins (<40 kDa) that are produced and released with the aim of cell signaling. Our understanding of the processes that trigger this tremendous amount of cytokine production has made dramatic progress over the last decades, but unfortunately, these findings could not translate yet into effective treatments; so far, all clinical trials targeting cytokine production or effects failed. This review aims to summarize the pathophysiology of the cytokine storm; to describe the type, effects, and kinetics of cytokine production; and to discuss the therapeutic challenges of targeting cytokines. New promising therapeutic strategies focusing on the endothelium, as a source and a target of cytokines, are described. PMID- 28555391 TI - Improved recovery and biological activities of an engineered polyene NPP analogue in Pseudonocardia autotrophica. AB - NPP A1 produced by Pseudonocardia autotrophica is a unique disaccharide containing polyene macrolide. NPP A1 was reported to have higher water solubility and lower hemolytic toxicity than nystatin A1 while retaining its antifungal activity. An engineered NPP A1 analogue, NPP A2, was generated by inactivation of the nppL gene, encoding a P450 monooxygenase in P. autotrophica. The resulting compound exhibited the corresponding chemical structure of NPP A1 but lacked a C10 hydroxyl group. In this study, newly developed crystallization recovery methods for NPP A2 purification, followed by an evaluation of in vitro antifungal activity and hemolytic activity, were performed. The crystallization methods were designed to eliminate the undesired viscous impurities encountered during the NPP A2 purification process, resulting in improved purity from 5.3 to 83.5% w/w. NPP A2 isolated from the improved purification process also exhibited two times higher antifungal activity and 1.8 times higher hemolytic toxicity than those of NPP A1. These results suggest that the minor structural modification of disaccharide-containing polyene macrolides, such as removing a C10 hydroxyl group, might require an alternative recovery process, such as crystallization, to confirm its improved biological activity. PMID- 28555393 TI - Income-environment relationship in Sub-Saharan African countries: Further evidence with trade openness. AB - This paper examines the dynamic relationship between energy consumption, income growth, carbon emissions and trade openness in fourteen Sub-Saharan African (SSA) countries. The autoregressive distributed lag (ARDL) approach to cointegration and the Toda-Yamamoto causality test were used to investigate the long-run and short-run properties, respectively. The long-run estimations give evidence against the environmental Kuznets curve (EKC) hypothesis in SSA countries. In contrast, the results highlight the significant and monotonically contribution of income growth and energy consumption in explaining carbon emissions in the long run and short-run in several countries. Furthermore, the results show that trade openness enhances economic growth and is not linked to causing carbon emissions in these countries. Hence, a trade incentive policy may be implemented without harmful effect on the quality of the environment. PMID- 28555392 TI - Present status of recycling waste mobile phones in China: a review. AB - A large number of waste mobile phones have already been generated and are being generated. Various countries around the world have all been positively exploring the way of recycling and reuse when facing such a large amount of waste mobile phones. In some countries, processing waste mobile phones has been forming a complete industrial chain, which can not only recycle waste mobile phones to reduce their negative influence on the environment but also turn waste into treasure to acquire economic benefits dramatically. However, the situation of recycling waste mobile phones in China is not going well. Waste mobile phones are not formally covered by existing regulations and policies for the waste electric and electronic equipment in China. In order to explore an appropriate system to recover waste mobile phones, the mobile phone production and the amount of waste mobile phones are introduced in this paper, and status of waste mobile phones recycling is described; then, the disposal technology of electronic waste that would be most likely to be used for processing of electronic waste in industrial applications in the near future is reviewed. Finally, rationalization proposals are put forward based on the current recovery status of waste mobile phones for the purpose of promoting the development of recycling waste mobile phones in developing countries with a special emphasis on China. PMID- 28555395 TI - Sorption of thiabendazole in sub-tropical Brazilian soils. AB - Thiabendazole (TBZ) is an ionizable anthelmintic agent that belongs to the class of benzimidazoles. It is widely used in veterinary medicine and as a fungicide in agriculture. Sorption and desorption are important processes influencing transport, transformation, and bioavailability of xenobiotic compounds in soils; data related to sorption capacity are therefore needed for environmental risk assessments. The aim of this work was to assess the sorption potential of TBZ in four Brazilians soils (sandy, sandy-clay, and clay soils), using batch equilibrium experiments at three pH ranges (2.3-3.0, 3.8-4.2, and 5.5-5.7). The Freundlich sorption coefficient (K F) ranged from 9.0 to 58 MUg1-1/n (mL) 1/n g 1, with higher values generally observed at the lower pH ranges (2.3-3.0 and 3.8 4.2) and for clay soils. The highest organic carbon-normalized sorption coefficients (KOC) obtained at pH 3.8-5.7 (around the natural pH range of 4.1 5.0) for both clay soils and sandy-clay soil were 3255 and 2015 mL g-1, respectively. The highest correlations K F vs SOM (r = 0.70) and K F vs clay content (r = 0.91) were observed at pH 3.8-4.2. Our results suggest that TBZ sorption/desorption is strongly pH dependent and that its mobility could be higher in the studied soils than previously reported in soils from temperate regions. PMID- 28555394 TI - The use of wastewater in livestock production and its socioeconomic and welfare implications. AB - Although epidemiological studies have found a significant amount of toxins in surface water, a complex link between animals' access to wastewater and associated animal and human welfare losses needs to be explored. The scarcity of safe water has put stress on the utilization of wastewater for crops and livestock production. The access of animals to wastewater is related to the emergence of dangerous animal's diseases, hampering productivity, increasing economic losses, and risking human health along the food chain. This review explores use of wastewater for agriculture, epidemiological evidence of microbial contamination in wastewater, and animal and human welfare disruption due to the use of wastewater for crop and livestock production. More specifically, the review delves into animals exposure to wastewater for bathing, drinking, or grazing on a pasture irrigated with contaminated water and related animal and human welfare losses. We included some scientific articles and reviews published from 1970 to 2017 to support our rational discussions. The selected articles dealt exclusively with animals direct access to wastewater via bathing and indirect access via grazing on pasture irrigated with contaminated wastewater and their implication for animal and human welfare losses. The study also identified that some policy options such as wastewater treatments, constructing wastewater stabilization ponds, controlling animal access to wastewater, and dissemination of necessary information to ultimate consumers related to the source of agricultural produce and wastewater use in animal and crop production are required to protect the human and animal health and welfare. PMID- 28555396 TI - Human health impact assessment of exposure to particulate matter: an AirQ software modeling. AB - The aim of this study was to assess the health impacts related to particulate matter less than 10 MUm (PM10) exposure in the city of Yazd, Iran. For this aim, AirQ 2.2.3 software was used to model relationship between short-term exposure to PM10 and disease cases proposed by the World Health Organization (WHO). The annual mean concentration of PM10 was 97 MUg/m3. The maximum concentration value of PM10 was measured during the summer (731 MUg/m3). 4.988% (95%CI: 3.381-6.542%) of the total mortality, 7.3% (95%CI; 4.19-10.21%) of cardiovascular mortality, and 10.21% (95%CI; 4.19-14.89%) of respiratory mortality were related to the PM10 concentrations. Consequently, the AirQ software can provide valuable information about the importance of air pollution and the substantial impacts of PM10 on the society for policymakers. PMID- 28555397 TI - Novel highly porous magnetic hydrogel beads composed of chitosan and sodium citrate: an effective adsorbent for the removal of heavy metals from aqueous solutions. AB - This research focuses on the removal of heavy metal ions from aqueous solutions using magnetic chitosan hydrogel beads as a potential sorbent. Highly porous magnetic chitosan hydrogel (PMCH) beads were prepared by a combination of in situ co-precipitation and sodium citrate cross-linking. Fourier transform infrared spectroscopy indicated that the high sorption efficiency of metal cations is attributable to the hydroxyl, amino, and carboxyl groups in PMCH beads. Thermogravimetric analysis demonstrated that introducing Fe3O4 nanoparticles increases the thermal stability of the adsorbent. Laser confocal microscopy revealed highly uniform porous structure of the resultant PMCH beads, which contained a high moisture content (93%). Transmission electron microscopy micrographs showed that the Fe3O4 nanoparticles, with a mean diameter of 5 +/- 2 nm, were well dispersed inside the chitosan beads. Batch adsorption experiments and adsorption kinetic analysis revealed that the adsorption process obeys a pseudo-second-order model. Isotherm data were satisfactorily described by the Langmuir equation, and the maximum adsorption capacity of the adsorbent was 84.02 mg/g. Energy-dispersive X-ray spectroscopy and X-ray photoelectron spectra analyses were performed to confirm the adsorption of Pb2+ and to identify the adsorption mechanism. PMID- 28555399 TI - Assessing demineralization treatments for PVC effluent reuse in the resin polymerization step. AB - To reduce fresh water consumption in a polyvinyl chloride (PVC) plant, the effluent from a biological treatment must be demineralized to be re-used in the resin polymerization process. Demineralization is a critical process, since the quality and the stability of the PVC resins are highly influenced by the water quality used in the process. The main target values for water parameters are the following: conductivity <10 MUScm-1, TOC < 10 mg L-1, and Al < 0.1 mg L-1. To achieve this quality, several reverse osmosis membranes from different materials and suppliers were tested and compared in the demineralization treatment. Polyamide membranes showed higher salt rejection compared to cellulose acetate membranes yielding both types similar flux and permeability. Two-pass reverse osmosis treatment was necessary to reach conductivities lower than 10 MUS cm-1. On the other hand, a good quality effluent for reuse was obtained by combining RO and ionic exchange resins. Results showed that good quality PVC resins in terms of color, granulometry, porosity, and bulk density were obtained when demineralized water from two-pass reverse osmosis was used as fresh water, proving the feasibility of the effluent reuse in the PVC industry. PMID- 28555398 TI - Heavy metals in soils from a typical industrial area in Sichuan, China: spatial distribution, source identification, and ecological risk assessment. AB - Anthropogenic activities could result in increasing concentrations of heavy metals in soil and deteriorating in soil environmental quality. Topsoil samples from a typical industrial area, Shiting River Valley, Sichuan, Southwest China, were collected and determined for the concentrations of Cu, Zn, Cr, Cd, As, and Hg. The mean concentrations of these metals were lower than the national threshold values, but were slightly higher than their corresponding background values, indicating enrichment of these metals in soils in the valley, especially for Cu, Zn, and Hg. The topsoils in this area demonstrated moderate pollution and low potential ecological risk. Principal component analysis coupled with cluster analysis was applied to analyze the data and identified possible sources of these heavy metals; the results showed that soil Cd, Hg, As, Cu, and Zn were predominantly controlled by human activities, whereas Cr was mainly from the parent material. The spatial distribution of the heavy metals varied distinctly and was closely correlated to local anthropogenic activities. Furthermore, the concentrations of heavy metals in the industrial land demonstrated relatively higher levels than those of other land use patterns. Soil metal concentrations decreased with the distance increase from the traffic highway (0-1.0 km) and water system (0-2.0 km). Additionally, soil properties, especially pH and soil organic matter, were found to be important factors in the distribution and composition of metals. PMID- 28555400 TI - Groundwater quality assessment and pollution source apportionment in an intensely exploited region of northern China. AB - Deterioration in groundwater quality has attracted wide social interest in China. In this study, groundwater quality was monitored during December 2014 at 115 sites in the Hutuo River alluvial-pluvial fan region of northern China. Results showed that 21.7% of NO3- and 51.3% of total hardness samples exceeded grade III of the national quality standards for Chinese groundwater. In addition, results of gray relationship analysis (GRA) show that 64.3, 10.4, 21.7, and 3.6% of samples were within the I, II, IV, and V grades of groundwater in the Hutuo River region, respectively. The poor water quality in the study region is due to intense anthropogenic activities as well as aquifer vulnerability to contamination. Results of principal component analysis (PCA) revealed three major factors: (1) domestic wastewater and agricultural runoff pollution (anthropogenic activities), (2) water-rock interactions (natural processes), and (3) industrial wastewater pollution (anthropogenic activities). Using PCA and absolute principal component scores-multivariate linear regression (APCS-MLR), results show that domestic wastewater and agricultural runoff are the main sources of groundwater pollution in the Hutuo River alluvial-pluvial fan area. Thus, the most appropriate methods to prevent groundwater quality degradation are to improve capacities for wastewater treatment and to optimize fertilization strategies. PMID- 28555401 TI - Emerging multidrug-resistant Bengal Bay clone ST772-MRSA-V in Norway: molecular epidemiology 2004-2014. AB - A multidrug-resistant, methicillin-resistant Staphylococcus aureus (MRSA) clone, PVL-positive ST772-MRSA-V, named the Bengal Bay clone, is emerging worldwide. In Norway, where MRSA prevalence is low, a sudden increase in ST772-MRSA-V initiated a nationwide molecular epidemiological study. Clinical data were obtained from the Norwegian Surveillance System for Communicable Diseases (MSIS). S. aureus isolates were characterised by antibiotic susceptibility profiles and comprehensive genotyping (spa typing, MLVA, DNA microarray). ST772-MRSA was detected in 145 individuals during 2004-2014, with 60% of cases occurring in 2013 2014. Median age was 31 years and male/female ratio 1.16. The majority had a family background from the Indian subcontinent (70%). MRSA acquisition was mainly reported as unknown (39%) or abroad (42%), the latter associated with a home country visit (59%), tourism (16%), and immigration (13%). Clinical infection was present in 75%, predominantly by SSTI (83%), 18% were admitted to hospital and 42% were linked to small-scale outbreaks (n = 25). All isolates were multidrug resistant. Most isolates were resistant to erythromycin, gentamicin and norfloxacin. Genotyping revealed a conserved clone predominated by spa type t657 (83%), MLVA-type 432 (67%) and the genes lukF/S, sea, sec/sel, egc, scn, cna, ccrAA/ccrC, agrII and cap5. A few untypical ccr gene combinations were detected. Bengal Bay isolates have likely been imported on several occasions and revision of infection control guidelines may prevent further spread. PMID- 28555402 TI - Clostridium difficile infections in Finland, 2008-2015: trends, diagnostics and ribotypes. AB - We evaluated Clostridium difficile (CD) diagnostics in Finnish clinical microbiology laboratories during 2006-2011, with an update in 2015, in relation to CD surveillance data of the National Infectious Disease Register (NIDR) and ribotyping data from the national reference laboratory during the years 2008 2015. In 2011, diagnostic activity varied regionally more than three-fold and the positivity rate ranged between 7 and 21%. Nucleic acid amplification testing (NAAT) was implemented in the regions with high activity and NAAT users tested 30% more patients and found 15% more cases per population than those not using it. Culture was performed in 79% of laboratories, primary toxin testing by enzyme immunoassay (EIA) in 83% and by NAAT in 17%. In 2014, 12/19 laboratories used NAAT as the primary detection method and four as the secondary method, and ten cultured. Increasing usage of NAAT was not systematically related to various trends detected regionally in annual CD rates. Polymerase chain reaction (PCR) ribotyping of 1771 CD isolates (4.1% of CD cases) identified 146 distinct profiles, of which 37% were binary toxin positive. The most common ribotype was 027, but its proportion decreased, while 078 slightly increased. Transition from culture to NAAT in CD infection (CDI) diagnostics did not cause a significant increase in the observed CDI incidence. Major differences between diagnostic activity, methods and strategies in different regions have persisted over the years, which should be considered when comparing the regional epidemiology of CDI. PMID- 28555403 TI - Dissemination of bla OXA-370 gene among several Enterobacteriaceae species in Brazil. AB - OXA-370 is a recently described OXA-48 variant that has only been described in a few Enterobacter spp. and Klebsiella pneumoniae isolates. The purpose of this study is to assess the prevalence of OXA-370-producing isolates in carbapenem nonsusceptible Enterobacteriaceae recovered from 28 hospitals from Brazil. Real time PCR was used to determine the presence of bla NDM-1, bla KPC-2, bla VIM type, bla GES-type, bla OXA-48-like, and bla IMP-type genes. A total of 4,451 Enterobacteriaceae were screened. The gene bla OXA-48-like was detected in 74 (2.5%) isolates, mostly of Enterobacter spp. (44.6% E. cloacae and 2.7% E. aerogenes) and Klebsiella spp. (31.1% K. pneumoniae and 6.7% K. oxytoca), followed by Escherichia coli, (6.7%), Morganella morganii, (2.7%), Citrobacter freundii (1.3%), Proteus mirabilis (1.3%), Providencia stuartii (1.3%), and Serratia spp. (1.3%). These isolates were from five hospitals, 67 (90.5%) from the hospital where the bla OXA-370 was first described. Sequencing of bla OXA-48 like was performed in 52 isolates, including E. cloacae, E. aerogenes, K. pneumoniae, K. oxytoca, E. coli, and C. freundii; all presenting 100% identity with bla OXA-370. PFGE revealed the presence of distinct clones among K. pneumoniae, E. cloacae, K. oxytoca, and E. coli. Susceptibility rates to meropenem, imipenem, and ertapenem among OXA-370-producing isolates were 92.3%, 78.8%, 7.7% respectively; the MIC50 /MIC90 were 0.38/2 mg/L and 1/3 mg/L for meropenem and imipenem respectively. Overall, antimicrobial susceptibility analysis suggests that OXA-370 lacks carbapenemase activity. Our study demonstrated that the bla OXA-370 gene is disseminated among several Enterobacteriaceae species and clones, indicating a high potential for dissemination. PMID- 28555404 TI - Abnormal Myocardial Contractility After Pediatric Heart Transplantation by Cardiac MRI. AB - Acute cellular rejection (ACR) compromises graft function after heart transplantation (HTX). The purpose of this study was to describe systolic myocardial deformation in pediatric HTX and to determine whether it is impaired during ACR. Eighteen combined cardiac magnetic resonance imaging (CMR)/endomyocardial biopsy (EMBx) examinations were performed in 14 HTX patients (11 male, age 13.9 +/- 4.7 years; 1.2 +/- 1.3 years after HTX). Biventricular function and left ventricular (LV) circumferential strain, rotation, and torsion by myocardial tagging CMR were compared to 11 controls as well as between patients with and without clinically significant ACR. HTX patients showed mildly reduced biventricular systolic function when compared to controls [LV ejection fraction (EF): 55 +/- 8% vs. 61 +/- 3, p = 0.02; right ventricular (RV) EF: 48 +/ 7% vs. 53 +/- 6, p = 0.04]. Indexed LV mass was mildly increased in HTX patients (67 +/- 14 g/m2 vs. 55 +/- 13, p = 0.03). LV myocardial deformation indices were all significantly reduced, expressed by global circumferential strain (-13.5 +/- 2.3% vs. -19.1 +/- 1.1%, p < 0.01), basal strain (-13.7 +/- 3.0% vs. -17.5 +/- 2.4%, p < 0.01), mid-ventricular strain (-13.4 +/- 2.7% vs. -19.3 +/- 2.2%, p < 0.01), apical strain (-13.5 +/- 2.8% vs. -19.9 +/- 2.0%, p < 0.01), basal rotation (-2.0 +/- 2.1 degrees vs. -5.0 +/- 2.0 degrees , p < 0.01), and torsion (6.1 +/- 1.7 degrees vs. 7.8 +/- 1.1 degrees , p < 0.01). EMBx demonstrated ACR grade 0 R in 3 HTX cases, ACR grade 1 R in 11 HTX cases and ACR grade 2 R in 4 HTX cases. When comparing clinically non-significant ACR (grades 0-1 R vs. ACR 2 R), basal rotation, and apical rotation were worse in ACR 2 R patients (-1.4 +/- 1.8 degrees vs. -4.2 +/- 1.4 degrees , p = 0.01 and 10.2 +/- 2.9 degrees vs. 2.8 +/- 1.9 degrees , p < 0.01, respectively). Pediatric HTX recipients demonstrate reduced biventricular systolic function and decreased myocardial contractility. Myocardial deformation indices by CMR may serve as non-invasive markers of graft function and, perhaps, rejection in pediatric HTX patients. PMID- 28555405 TI - Molecular characterization and expression profile of nanos in Schistosoma japonicum and its influence on the expression several mammalian stem cell factors. AB - Pluripotent stem cells, called neoblasts, are well known for the regenerative capability and developmental plasticity in flatworms. Impressive advancement has been made in free-living flatworms, while in case of its parasitic counterpart, neoblast-like stem cells have attracted recent attention for its self-renewal and differentiation capacity. Nanos is a key conserved post-transcriptional regulator critical for the formation, development, and/or maintenance of the pluripotent germ line stem cell systems in many metazoans including schistosomes. In the present study, we report the molecular cloning and expression of nanos orthologous genes nanos in Schistosoma japonicum (Sjnanos). The cDNA of Sjnanos is 826 bp long, containing an open reading frame (ORF) for 223 amino acid long protein. qRT-PCR analysis shown that Sjnanos was differently expressed in several stages of schistosomes with relatively high level in schistosomula. Additionally, Sjnanos was expressed highly in adult females compared to adult males. Transfection of recombinant plasmid for expressing Sjnanos resulted in significant proliferation and increased expression of several stem cell factors in mammalian cells. Overall, our preliminary study provides the molecular basis to further functionally characterize Sjnanos in S. japonicum. PMID- 28555407 TI - Effect of a Synthesized Amyl-Glycine1, 10-Phenanthroline Platinum Nitrate on Structure and Stability of Human Blood Carrier Protein, Albumin: Spectroscopic and Modeling Approaches. AB - In the present study, biological evaluation of a new synthesized anti-cancer compound, amyl-glycine1, 10-phenanthroline Platinum nitrate (Pt(II) complex), was investigated at different temperatures by spectroscopic methods (far-UV circular dichroism (CD) and fluorescence) and modeling methods (docking and FRET). Human serum albumin (HSA), one of the vital proteins in drug delivery system in the body, was used as a target protein. The Pt(II) complex is able to quench the intrinsic fluorescence of HSA considerably. Binding and thermodynamic parameters of the interaction between the protein and the ligand were analyzed by fluorescence quenching method. The far-UV CD spectra revealed that the secondary structure of HSA did not show any noticeable change upon interaction with Pt(II) complex at both 25 and 37 degrees C. The calculation of fluorescence resonance energy transfer (FRET) confirmed that quenching mechanism is static, and the observed distance between the donor and acceptor is 1.18 nm. Molecular docking results are in agreement with experimental data suggesting that there is one site on HSA at which Pt(II) complex binds spontaneously. Moreover, docking results together with FRET evaluation illustrated that Pt(II) complex is located near Trp214 at a distance of 1.96 nm. Our experimental and theoretical results indicated that the driving forces for Pt(II) complex interaction with HSA are hydrogen bonding and van der Waals interactions. The combination of molecular docking and spectroscopy methods suggested that use of this new Pt(II) complex as an anti-cancer agent, is an effective innovative approach in cancer chemotherapy providing a better understanding of effects of new designed drugs. PMID- 28555409 TI - Gastric Bypass and Synchronous Cholecystectomy: a Matter of Numbers? PMID- 28555410 TI - Outcomes of Bariatric Surgery in Patients with Inflammatory Bowel Disease. PMID- 28555406 TI - Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach. AB - Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes. PMID- 28555411 TI - The top ten unknowns in paediatric mechanical ventilation. PMID- 28555408 TI - Bariatric Surgery-Induced Resolution of Hypertension and Obstructive Sleep Apnea: Impact of Modulation of Body Fat, Ectopic Fat, Autonomic Nervous Activity, Inflammatory and Adipokine Profiles. AB - BACKGROUND: Obesity-associated systemic hypertension (HTN) and obstructive sleep apnea (OSA) have multiple pathophysiological pathways including ectopic fat deposition, inflammation, altered adipokine profile, and increased sympathetic nervous activity. We characterized these potential mechanisms in severely obese patients with or without HTN and OSA. We also compared changes of these mechanisms at 12 months following biliopancreatic diversion with duodenal switch (BPD-DS) surgery according to HTN and OSA resolution. METHODS: Sixty-two severely obese patients were evaluated at baseline and 12 months; 40 patients underwent BPD-DS. Blood samples, bioelectrical impedance analysis, computed tomography scan, and 24-h heart rate monitoring were performed. OSA have been determined with polysomnography and HTN with blood pressure measurement and medical file. RESULTS: Patients with HTN (n = 35) and OSA (n = 32) were older men with higher ectopic fat deposition and lower parasympathetic nervous activity without difference in adipokines and inflammatory markers. Lower reduction in weight was observed in patients with unresolved HTN (-40.9 +/- 3.3 kg vs. -55.6 +/- 3.8 kg; p = 0.001) and OSA (-41.4 +/- 10.7 kg vs. -51.0 +/- 15.2 kg; p = 0.006). Visceral adipose tissue reduction was lower in patients with unresolved HTN (-171.0 +/- 25.7 cm2 vs. -274.5 +/- 29.0 cm2; p = 0.001) in contrast to a trend for lower abdominal subcutaneous adipose tissue reduction in patients with unresolved OSA ( 247.7 +/- 91.5 cm2 vs. -390.5 +/- 109.1 cm2; p = 0.08). At 12 months, parasympathetic activity was lowest in unresolved HTN and OSA patients, without difference in adipokines and inflammatory biomarkers. CONCLUSION: Lower ectopic fat mobilization, lower level of parasympathetic nervous activity, and lower subcutaneous adiposity mobilization may play a role in the pathophysiology of unresolved HTN and OSA following BPD-DS surgery. PMID- 28555412 TI - Guest editorial: Hematopoietic stem cells. PMID- 28555413 TI - Epigenetic dysregulation of hematopoietic stem cells and preleukemic state. AB - Recent genetic analyses have revealed that premalignant somatic mutations in hematopoietic cells are common in older people without an evidence of hematologic malignancies, leading to clonal hematopoietic expansion. This phenomenon has been termed clonal hematopoiesis of indeterminate potential (CHIP). Frequency of such clonal somatic mutations increases with age: in 5-10% of people older than 70 years and around 20% of people older than 90 years. The most commonly mutated genes found in individuals with CHIP were epigenetic regulators, including DNA methyltransferase 3A (DNMT3A), Ten-eleven-translocation 2 (TET2), and Additional sex combs-like 1 (ASXL1), which are also recurrently mutated in myeloid malignancies. Recent functional studies have uncovered pleiotropic effect of mutations in DNMT3A, TET2, and ASXL1 in hematopoietic stem cell regulation and leukemic transformation. Of note, CHIP is associated with an increased risk of hematologic malignancy and all-cause mortality, albeit the annual risk of leukemic transformation was relatively low (0.5-1%). These findings suggest that clonal hematopoiesis per se may not be sufficient to engender preleukemic state. Further studies are required to decipher the exact mechanism by which preleukemic stem cells originate and transform into a full-blown leukemic state. PMID- 28555415 TI - Plasma cell myeloma with histiocyte-like morphology. PMID- 28555414 TI - Germline ETV6 mutations and predisposition to hematological malignancies. AB - Patients with thrombocytopenia 5 have an autosomal dominant disorder of decreased platelet number with tendency to bleed, usually presenting in childhood, and have been found to have germline mutations in ETV6, which encodes a master hematopoietic transcription factor. Some patients who present similarly have inherited mutations in RUNX1 or ANKRD26. All three germline syndromes are also associated with a predisposition to myelodysplastic syndrome (MDS) and acute leukemia (AL). Since the first description of germline ETV6 mutations, 18 families have been reported. The common phenotype is mild to moderate thrombocytopenia with a variable predisposition to acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and MDS. This review will focus upon the role of ETV6 in hematopoiesis, especially in myeloid differentiation and maturation, and will describe the functional effects of mutant ETV6. The review will also provide an overview of common clinical features as well as recommendations for patient screening and follow-up and will debate whether additional clinical features should be included with the germline ETV6 syndrome. PMID- 28555418 TI - Differences in quality-of-life dimensions of Adult Strabismus Quality of Life and Amblyopia & Strabismus Questionnaires. AB - PURPOSE: The Adult Strabismus Quality of Life Questionnaire (AS-20) and the Amblyopia & Strabismus Questionnaire (A&SQ) both measure health-related quality of life in strabismus patients. We evaluated to what extent these instruments cover similar domains by identifying the underlying quality-of-life factors of the combined questionnaires. METHODS: Participants were adults from a historic cohort with available orthoptic childhood data documenting strabismus and/or amblyopia. They had previously completed the A&SQ and were now asked to complete the AS-20. Factor analysis was performed on the correlation-matrix of the combined AS-20 and A&SQ data to identify common underlying factors. The identified factors were correlated with the clinical variables of angle of strabismus, degree of binocular vision, and visual acuity of the worse eye. RESULTS: One hundred ten patients completed both questionnaires (mean age, 44 years; range, 38-51 years). Six factors were found that together explained 78% of the total variance. The factor structure was dominated by the first four factors. One factor contained psychosocial and social-contact items, and another factor depth-perception items from both questionnaires. A third factor contained seven items-only from the AS-20-on eye strain, stress, and difficulties with reading and with concentrating. A fourth factor contained seven items-only from the A&SQ on fear of losing the better eye and visual disorientation, specific for amblyopia. Current visual acuity of the worse eye correlated with depth perception items and vision-related items, whereas current binocular vision correlated with psychosocial and social-contact items, in 93 patients. CONCLUSIONS: Factor analysis suggests that the AS-20 and A&SQ measure a similar psychosocial quality-of-life domain. However, functional problems like avoidance of reading, difficulty in concentrating, eye stress, reading problems, inability to enjoy hobbies, and need for frequent breaks when reading are represented only in the AS-20. During the development of the A&SQ, asthenopia items were considered insufficiently specific for strabismus and were excluded a priori. The patients who generated the items for the AS-20 had, in majority, adulthood-onset strabismus and diplopia and were, hence, more likely to develop such complaints than our adult patients with childhood-onset strabismus and/or amblyopia. PMID- 28555416 TI - Clinical characteristics and outcomes of septic bursitis. AB - PURPOSE: Limited data guide practice in evaluation and treatment of septic bursitis. We aimed to characterize clinical characteristics, microbiology, and outcomes of patients with septic bursitis stratified by bursal involvement, presence of trauma, and management type. METHODS: We conducted a retrospective cohort study of adult patients admitted to a single center from 1998 to 2015 with culture-proven olecranon and patellar septic bursitis. Baseline characteristics, clinical features, microbial profiles, operative interventions, hospitalization lengths, and 60-day readmission rates were determined. Patients were stratified by bursitis site, presence or absence of trauma, and operative or non-operative management. RESULTS: Of 44 cases of septic bursitis, patients with olecranon and patellar bursitis were similar with respect to age, male predominance, and frequency of bursal trauma; patients managed operatively were younger (p = 0.05). Clinical features at presentation and comorbidities were similar despite bursitis site, history of trauma, or management. The most common organism isolated from bursal fluid was Staphylococcus aureus. Patients managed operatively were discharged to rehabilitation less frequently (p = 0.04). CONCLUSIONS: This study of septic bursitis is among the largest reported. We were unable to identify presenting clinical features that differentiated patients treated surgically from those treated conservatively. There was no clear relationship between preceding trauma or bursitis site and clinical course, management, or outcomes. Patients with bursitis treated surgically were younger. Additional study is needed to identify patients who would benefit from early surgical intervention for septic bursitis. PMID- 28555419 TI - Assessing guideline-concordant prescribing for community-acquired pneumonia. AB - Background Current reports of outpatient antimicrobial prescribing practices may overestimate guideline concordance since they address only drug selection. Appropriate stewardship should consider all prescribing criteria (i.e., dose, frequency, duration, and route of administration) to fully assess guideline concordance. Objective Using a community-acquired pneumonia (CAP) example, the aims of this pilot study were to estimate guideline concordance in adult patients 18 years or older when all prescribing criteria are considered, and provide recommendations to optimize treatment. Specific objectives were to determine which medications were most commonly prescribed for high-and low-risk patients, respectively, and determine if prescription parameters typically meet guideline recommendations. Methods This historical (retrospective) chart review at a large, non-emergent, outpatient academic practice included adult cases of CAP identified by ICD-9 codes, 481.x-486.x, 480.x and 487.x, diagnosed between July 1, 2014 and June 30, 2015. Patients were stratified into low- or high-risk categories based on presence of comorbidities and recent antibiotic use. Descriptive statistics were used to profile the sample and estimate aggregate guideline appropriateness, based on Infectious Disease Society of America/American Thoracic Society guidelines. Cases that were not prescribed an antibiotic at the index visit were excluded from assessment of concordance. Results Of the 101 total episodes identified, 49% were treated with an antibiotic. Of the 45 cases that met low risk criteria, seven of the 24 treated cases (29%) received an appropriate antibiotic. When considering all prescription elements, all seven cases were congruent, for a composite concordance rate of 29%. Of the 56 cases that met high risk criteria, 13 of the 25 treated cases (52%) received an appropriate antibiotic, although two cases were prescribed a suboptimal dose, and one case was prescribed a suboptimal duration, dropping composite concordance to 40%. Overall, prescribing was concordant in 17 of the 49 treated cases (35%). Conclusion Concordance with current guidelines in this local sample is suboptimal. In the low-risk group, when the correct medication was chosen, dose, duration, and frequency were appropriate. Consideration of dose and duration of treatment decreased the rate of concordant prescribing in the high-risk group. PMID- 28555420 TI - Limited sampling strategy for predicting busulfan exposure in hematopoietic stem cell transplantation recipients. AB - Background Optimization of the area under the concentration-time curve (AUC) of busulfan, an essential component of conditioning regimens, improves the outcomes in patients undergoing hematopoietic stem cell transplantation (HSCT). Traditional sampling methods for calculating AUC require multiple sampling. Objective To establish a limited sampling strategy for predicting the AUC0-12 of intravenous busulfan for Chinese adult patients prior to HSCT. Methods The pharmacokinetics of twice-daily intravenous busulfan was studied in forty-five Chinese adult patients. Limited sampling models were established by the multiple linear regression analysis. The prediction error (PE) and the absolute prediction error (APE) were calculated to evaluate predictive accuracy. The agreement between the predicted and actual AUC0-12 was investigated by the Bland-Altman analysis. The accuracy and robustness of the models was validated by the bootstrap analysis. Results The AUC0-12 values of the 1st and 7th doses of busulfan were 1491 +/- 403.7 and 1908 +/- 518.5 MUmol L-1 min, respectively. The 2-sample model suggested that the predicted AUC0-12 of twice-daily intravenous busulfan could be calculated using the following equation: AUC0-12 = 40.017 + 0.955 * C3 + 1.088 * C6 with r2 = 0.919. The mean PE and APE of the model were 0.52 +/- 7.67 and 6.32 +/- 4.27%, respectively. Conclusion The 2-sample model is an effective and reliable approach to predict the AUC0-12 of twice-daily intravenous busulfan in Chinese adult patients. PMID- 28555421 TI - Improving medication adherence among community-dwelling seniors with cognitive impairment: a systematic review of interventions. AB - Background Medication non-adherence may lead to poor therapeutic outcomes. Cognitive functions deteriorate with age, contributing to decreased adherence. Interventions have been tested to improve adherence in seniors with cognitive impairment or Alzheimer disease (AD), but high-quality systematic reviews are lacking. It remains unclear which interventions are promising. Objectives We conducted a systematic review to identify, describe, and evaluate interventions aimed at improving medication adherence among seniors with any type of cognitive impairment. Methods Following NICE guidance, databases and websites were searched using combinations of controlled and free vocabulary. All adherence-enhancing interventions and study designs were considered. Studies had to include community dwelling seniors, aged 65 years or older, with cognitive impairment, receiving at least one medication for a chronic condition, and an adherence measure. Study characteristics and methodological quality were assessed. Results We identified 13 interventions, including six RCTs. Two studies were of poor, nine of low/medium and two of high quality. Seven studies had sample sizes below 50 and six interventions focused on adherence to AD medication. Six interventions tested a behavioral, four a medication oriented, two an educational and one a multi faceted approach. Studies rarely assessed therapeutic outcomes. All but one intervention showed improved adherence. Conclusion Three medium quality studies showed better adherence with patches than with pills for AD treatment. Promising interventions used educational or reminding strategies, including one high quality RCT. Nine studies were of low/moderate quality. High quality RCTs using a theoretical framework for intervention selection are needed to identify strategies for improved adherence in these seniors. PMID- 28555422 TI - Ischemic stroke and intracranial hemorrhage in patients with recurrent glioblastoma multiforme, treated with bevacizumab. AB - Bevacizumab (BVZ), a monoclonal antibody directed against vascular endothelial growth factor (VEGF), has been suspected to increase the incidence of ischemic stroke (IS) and intracranial hemorrhage (ICH) in GBM patients. Intracranial vascular events, such as IS and ICH, were retrospectively analyzed in 364 MRI scans of 82 patients with recurrent GBM (1st/2nd/3rd relapse). Out of these 82 patients, 40 were treated with BVZ (178 scans) in addition to basic treatment, whereas 42 patients matching for age and gender received basic treatment (186 scans). Distribution of typical vascular risk factors between both groups was analyzed retrospectively. In seven out of 82 patients (8%) vascular events were detected in MRI. Four vascular events were recorded in the BVZ-group (3 IS and 1 ICH), and 3 vascular events were found in the Control-group (1 IS and 2 ICH; p > 0.05 between both groups). Likewise, vascular risk factors (arterial hypertension, diabetes mellitus, obesity, former vascular event, hyperlipidemia, tobacco consumption and/or hypercholesterolemia) did not differ significantly between both groups. BVZ treatment does not seem to be associated with an increased risk for vascular events in patients with GBM in recurrence. PMID- 28555423 TI - Improving the utility of 1H-MRS for the differentiation of glioma recurrence from radiation necrosis. AB - Proton magnetic resonance spectroscopy (1H-MRS) has shown promise in distinguishing recurrent high-grade glioma from posttreatment radiation effect (PTRE). The purpose of this study was to establish objective 1H-MRS criteria based on metabolite peak height ratios to distinguish recurrent tumor (RT) from PTRE. A retrospective analysis of magnetic resonance imaging and 1H-MRS data was performed. Spectral metabolites analyzed included N-acetylaspartate, choline (Cho), creatine (Cr), lactate (Lac), and lipids (Lip). Quantitative 1H-MRS criteria to differentiate RT from PTRE were identified using 81 biopsy-matched spectral voxels. A receiver operating characteristic curve analysis was conducted for all metabolite ratio combinations with the pathology diagnosis as the classification variable. Forward discriminant analysis was used to identify ratio variables that maximized the correct classification of RT versus PTRE. Our results were applied to 205 records without biopsy-matched voxels to examine the percent agreement between our criteria and the radiologic diagnoses. Five ratios achieved an acceptable balance [area under the curve (AUC) >= 0.700] between sensitivity and specificity for distinguishing RT from PTRE, and each ratio defined a criterion for diagnosing RT. The ratios are as follows: Cho/Cr > 1.54 (sensitivity 66%, specificity 79%), Cr/Cho <= 0.63 (sensitivity 65%, specificity 79%), Lac/Cho <= 2.67 (sensitivity 85%, specificity 58%), Lac/Lip <= 1.64 (sensitivity 54%, specificity 95%), and Lip/Lac > 0.58 (sensitivity 56%, specificity 95%). Application of our ratio criteria in prospective studies may offer an alternative to biopsy or visual spectral pattern recognition to distinguish RT from PTRE in patients with gliomas. PMID- 28555424 TI - Functional analysis of the DEPDC1 oncoantigen in malignant glioma and brain tumor initiating cells. AB - DEP domain containing 1 (DEPDC1) is a novel oncoantigen expressed in cancer cells, which presents oncogenic activity and high immunogenicity. Although DEPDC1 has been predicted to be a useful antigen for the development of a cancer vaccine, its pathophysiological roles in glioma have not been investigated. Here, we analyzed the expression and function of DEPDC1 in malignant glioma. DEPDC1 expression in glioma cell lines, glioma tissues, and brain tumor initiating cells (BTICs) was assessed by western blot and quantitative polymerase chain reaction (PCR). The effect of DEPDC1 downregulation on cell growth and nuclear factor kappa B (NFkappaB) signaling in glioma cells was investigated. Overall survival was assessed in mouse glioma models using human glioma cells and induced mouse brain tumor stem cells (imBTSCs) to determine the effect of DEPDC1 suppression in vivo. DEPDC1 expression was increased in glioma cell lines, tissues, and BTICs. Suppression of endogenous DEPDC1 expression by small interfering RNA (siRNA) inhibited glioma cell viability and induced apoptosis through NFkappaB signaling. In mouse glioma models using human glioma cells and imBTSCs, downregulation of DEPDC1 expression prolonged overall survival. These results suggest that DEPDC1 represents a target molecule for the treatment of glioma. PMID- 28555425 TI - Ethical considerations of neuro-oncology trial design in the era of precision medicine. AB - The field of oncology is currently undergoing a paradigm shift. Advances in the understanding of tumor biology and in tumor sequencing technology have contributed to the shift towards precision medicine, the therapeutic framework of targeting the individual oncogenic changes each tumor harbors. The success of precision medicine therapies, such as targeted kinase inhibitors and immunotherapies, in other cancers have motivated studies in brain cancers. The high specificity and cost of these therapies also encourage a shift in clinical trial design away from randomized control trials towards smaller, more exclusive early phase clinical trials. While these new trials advance the clinical application of increasingly precise and individualized therapies, their design brings ethical challenges . We review the pertinent ethical considerations for clinical trials of precision medicine in neuro-oncology and discuss methods to protect patients in this new era of trial design. PMID- 28555426 TI - A novel approach to the extraction of fetal electrocardiogram based on empirical mode decomposition and correlation analysis. AB - Fetal heart rate monitoring is the process of checking the condition of the fetus during pregnancy and it would allow doctors and nurses to detect early signs of trouble during labor and delivery. The fetal ECG (FECG) signal is so weak and also is corrupted by other signals and noises, mainly by maternal ECG signal. It is so hard to acquire a noise-free, precise and reliable FECG using the conventional methods. In this study, a combination of empirical mode decomposition (EMD) algorithms, correlation and match filtering is used for extracting FECG from maternal abdominal ECG signals. The proposed method benefits from match filtering ability to detect fetal signal and QRS complex to detect weak QRS peaks. The combined method, has been applied successfully on different signal qualities, even for signals that their analysis was hard and complicated for other methods. This method is able to detect R-R intervals with high accuracy. It was proved that the complete ensemble empirical mode decomposition method provides a better frequency resolution of modes and also requires less iterations that leads to a considerably less computational cost than EMD and ensemble empirical mode decomposition and can reconstruct the FECG completely from the calculated modes. We believe that this method opens a new field in non invasive maternal abdominal signal processing so the FECG signal could be extracted with high speed and accuracy. PMID- 28555427 TI - Optimization of high-yielding protocol for DNA extraction from the forest rhizosphere microbes. AB - Soil is major reservoir for microbes and harbors a vast microbial diversity. Soil microbiota plays a pivotal role in biogeochemical cycles, bioremediation, and in health and disease states of humans, animals, and plants. It is imperative to understand the microbial signatures which are specific in such an ecosystem to unravel their potential role and impact on environment. During the recent years, exploration of soil microbial communities has been geared up with the advent of advanced sequencing technologies. Introduction of custom-made protocols and optimized procedures have enhanced the accuracy levels along with cost effectiveness of DNA extraction. Standardization of DNA extraction method from soil microbiota has its own limitations due to different nature of soils and the complexity of ecosystems. Though a few standardized protocols are in usage, huge variations and complexities among the microbial communities frequently suggest the optimization, based on various known and unknown factors. Therefore, a set of four standardized DNA isolation protocols was comparatively analyzed with respect to our custom-made protocol owing to the scientific fact that the same protocol does not hold good for all soil samples. Furthermore, the developed protocol has been successfully applied for the identification of efficient plant-specific Rhizobial stains for five legume plants from the soils of various locations under same geographical region. Out of 40 Badrachalam forest soils, five samples, KPFS36, CHFS17, TPFS33, GVFS06, and GPFS40, one for each of Arachis hypogaea, Vigna radiata, Vigna mungo, Glycine max, and Cicer arietinum plants, were selected, respectively, for the soil DNA extraction. A considerable improvement in the DNA yield was identified using the modified protocol with a yield of 21.08 MUg/g providing abundant DNA fragments for further investigation on Rhizobial species. PMID- 28555428 TI - Bactericidal potential of silver nanoparticles synthesized using cell-free extract of Comamonas acidovorans: in vitro and in silico approaches. AB - The need to overcome human threats from pathogenic microbes, development of nanomaterials have been provoked for a new generation of antimicrobials. In the present study, biosynthesis of silver nanoparticles (AgNPs) was acquired using Comamonas acidovorans extract within 72 h under static condition. Electron microscopy studies revealed that the size of AgNPs was ranging from 6-53 nm and had spherical, oval and irregular shapes with smooth surfaces. Prepared AgNPs interacted with proteins, carbohydrates and other aromatic molecules. Biosynthesized AgNPs were bactericidal, which significantly inhibited pathogenic microbes, i.e., Streptococcus pyogenes, Staphylococcus aureus and Escherichia coli. Higher concentrations of AgNPs (20 MUg ml-1) inhibited 92-98% growth of all tested bacteria within 24 h. AgNPs-protein network studies carried out to recognize the protein interactions with AgNPs and to understand probable bactericidal mechanisms. AgNPs may penetrate into cell through membrane proteins and damage them by modifying amino acids. Due to AgNPs-protein interactions, dysfunctions in enzymes obstruct certain metabolic processes, which cause the bacteria to die eventually. In certain pathogenic microbes, cue and cus systems detoxify Ag+ ions, transport through transporter proteins and expel them to the extracellular space, which are mainly responsible for Ag resistance. PMID- 28555429 TI - Sex-oriented research on dioecious crops of Indian subcontinent: an updated review. AB - A number of dioecious species are grown across India and some of those plants play a crucial role in the agro-based economy of the country. The diagnosis of sex is very difficult in the dioecious plant prior flowering wherein sex identification at the seedling stage is of great importance to breeders as well as farmers for crop improvement or production purpose. A comprehensive approach of sex determination comprising morphological, biochemical, cytological and molecular attributes is a must required for gender differentiation in dioecious plant species. In the present review, we highlighted the economical, medicinal as well as industrial importance of most of the dioecious species extensively grown in Indian subcontinent. In addition to that, the cytogenetic, genetic as well as molecular information in connection to their sex determination were critically discussed in this review. PMID- 28555430 TI - Effect of gene order in DNA constructs on gene expression upon integration into plant genome. AB - Several plant biotechnology applications are based on the expression of multiple genes located on a single transformation vector. The principles of stable expression of foreign genes in plant cells include integration of full-length gene fragments consisting of promoter and transcription terminator sequences, and avoiding converging orientation of the gene transcriptional direction. Therefore, investigators usually generate constructs in which genes are assembled in the same orientation. However, no specific information is available on the effect of the order in which genes should be assembled in the construct to support optimum expression of each gene upon integration in the genome. While many factors, including genomic position and the integration structure, could affect gene expression, the investigators judiciously design DNA constructs to avoid glitches. However, the gene order in a multigene assembly remains an open question. This study addressed the effect of gene order in the DNA construct on gene expression in rice using a simple design of two genes placed in two possible orders with respect to the genomic context. Transgenic rice lines containing green fluorescent protein (GFP) and beta-glucuronidase (GUS) genes in two distinct orders were developed by Cre-lox-mediated site-specific integration. Gene expression analysis of transgenic lines showed that both genes were expressed at similar levels in either orientation, and different transgenic lines expressed each gene within 1-2* range. Thus, no significant effect of the gene order on gene expression was found in the transformed rice lines containing precise site-specific integrations and stable gene expression in plant cells could be obtained with altered gene orders. Therefore, gene orientation and integration structures are more important factors governing gene expression than gene orders in the genomic context. PMID- 28555431 TI - Isolation and characterization of phosphate solubilizing bacteria from Western Indian Himalayan soils. AB - Previous studies confirmed the existence of diversified microbial flora in the rhizosphere of Himalayan Red Kidney Bean (RKB) (Phaseolus vulgaris L.). Therefore, fifteen different temperate and subtropical regions of Western Indian Himalaya (WIH) were explored for the isolation of RKB rhizosphere-associated Phosphorus (P) solubilizing bacteria. On the basis of qPCR analysis, three soils, i.e., Munsyari, Kandakhal and Nainital soils were selected for the isolation of P solubilizers. Among 133 isolates, three bacteria viz. Lysinibaccilus macroides ST 30, Pseudomonas palleroniana N-26 and Pseudomonas jessenii MP-1 were selected based on their P solubilization potential. Moreover, in vitro seed germination assay was performed to investigate their effectiveness against four native crops viz. (Cicer arietrinum L.), (Vigna radiata L.), (Pisum sativum L.) and (Zea mays L.). Treated seeds showed significant increase in germination efficiency over their respective controls. The results suggest that Lysinibaccilus macroides ST 30, strain is a potential plant growth-promoting bacterium for chickpea (Cicer arietrinum L.) and, therefore, could be implemented as a low-cost bio-inoculant in hill agriculture system. PMID- 28555432 TI - Procoagulant serine glycoprotease from Cucumis sativus L.: action on human fibrinogen and fibrin clot. AB - Upon examination of the fruit extract of Cucumis sativus L. for its pharmacological benefits, it was previously observed that it has potential proteolytic, fibrinogenolytic and procoagulant activities. These properties can be attributed to the presence of the protease. In this regard, the present study comprised of purification and characterization of protease. Purification of the enzyme involved ammonium sulfate precipitation followed by gel filtration and ion exchange chromatography. The purified cucumis protease (CPro) exhibits homogeneity as attested by SDS-PAGE and RP-HPLC with a retention time of 14.246 min with molecular mass ~75.3 kDa. CPro was identified as a glycoprotein and serine protease. Azocasein is the preferred substrate for CPro as it showed low Km value of 0.3809 mg/ml. Purified CPro exhibits optimum activity at 37 degrees C and pH 8. CPro shows its involvement in hemostasis-the very first step in wound healing. CPro degrades the subunits of human fibrinogen in the order Aalpha > Bbeta > gamma. It also hydrolyzes the subunits of the partially cross-linked fibrin clot in the order alpha-polymer > gamma-gamma dimer > beta-chain. CPro reduced the clotting time of citrated plasma, prothrombin time and activated partial thromboplastin time of plasma. CPro is neither hemorrhagic nor edema inducing, thus considered to be a non-toxic protease. This work provides evidence for the use of cucumber extract in wound healing and authenticates its use in cosmetics. PMID- 28555433 TI - Structural and activity variability of fractions with different charge density and chain length from pharmaceutical heparins. AB - Heparin is a structurally complex polysaccharide used as a clinical anticoagulant. It is comprised of a heterogeneous mixture of polysaccharide chains having a variety of sequences and lengths. The production methods and regulatory controls of pharmaceutical heparins have changed over the years. This study assesses the structural and activity uniformity of the polysaccharide chains comprising two contemporary heparin products. The heparin fractions with different sizes and charges were separated with size exclusion and ion exchange chromatography. The fractions were analyzed for their molecular weight properties, di- and tetrasaccharide compositions, and anti-factor IIa and anti factor-Xa activities. The distribution of these properties through chains of different lengths and ones with different charge density were compared. The results demonstrate that with the increase in heparin purity, activity and molecular weight required by the current pharmacopeia, the uniformity of pharmaceutical heparin products have increased. PMID- 28555434 TI - With expanded carrier screening, founder populations run the risk of being overlooked. AB - Genetically isolated populations exist worldwide. Specific genetic disorders, including rare autosomal recessive disorders may have high prevalences in these populations. We searched for Dutch genetically isolated populations and their autosomal recessive founder mutations. We investigated whether these founder mutations are covered in the (preconception) expanded carrier screening tests of five carrier screening providers. Our results show that the great majority of founder mutations are not covered in these screening panels, and these panels may thus not be appropriate for use in founder populations. It is therefore important to be aware of founder mutations in a population when offering carrier tests. PMID- 28555435 TI - Brazilian legal and bioethical approach about donation for research and patents of human body parts. AB - The aim of this paper is to explain why the Brazilian legal system does not accept commercialization or commodification of human body parts, including genes or cells. As a consequence, in Brazil, the donation of human body parts for research-including basic or translational-must be made altruistically. For the same reason, the Brazilian patent system cannot be applied to human parts, cells or genes. Here, we present a qualitative analysis of juridical, bioethical, and social reasoning related to the legal status of human body parts especially in biobanks, as well as a description of the Brazilian legal system for clarification. Our aim is to discuss the responsibility of researchers for making available the scientific information resulting from scientific research and biobank storage of human body parts and to ensure the free utilization of knowledge in human health research. PMID- 28555436 TI - Relationship of hepatitis B virus infection to the recurrence of hepatocellular carcinoma after direct acting antivirals. AB - Recently, two conflicting articles about recurrence of hepatocellular carcinoma (HCC) after direct acting antivirals (DAA) against hepatitis C virus (HCV) were published. We investigated the relationship between DAA and HCC recurrence. Eligible patients were (1) history of HCC and treated curatively with interventions, and (2) interferon-free DAA therapy was initiated after eradication of HCC. We analyzed contributing factor for HCC recurrence. Ten out of 23 participants (43%) encountered recurrence of HCC. Age, sex, diabetes mellitus, fibrosis score, chemistry, and alpha-fetoprotein did not differ between patients with recurrence and patients without recurrence. The patients with recurrence had significantly higher values of antibody to hepatitis B core antigen (anti-HBc) than the patients without recurrence, 6.06+/-3.75 vs. 0.91+/ 2.43 (p=0.0019). The relative risk of HCC recurrence comparing anti-HBc positive to negative was 5.2 (95% confidence interval 1.40 to 19.32). Odds ratio was 22.0 (95% confidence interval 2.5 to 191.1). We conclude that anti-HBc positivity was a strong contributing factor for HCC recurrence after DAA therapy. PMID- 28555438 TI - Transition index maps for urban growth simulation: application of artificial neural networks, weight of evidence and fuzzy multi-criteria evaluation. AB - Transition index maps (TIMs) are key products in urban growth simulation models. However, their operationalization is still conflicting. Our aim was to compare the prediction accuracy of three TIM-based spatially explicit land cover change (LCC) models in the mega city of Mumbai, India. These LCC models include two data driven approaches, namely artificial neural networks (ANNs) and weight of evidence (WOE), and one knowledge-based approach which integrates an analytical hierarchical process with fuzzy membership functions (FAHP). Using the relative operating characteristics (ROC), the performance of these three LCC models were evaluated. The results showed 85%, 75%, and 73% accuracy for the ANN, FAHP, and WOE. The ANN was clearly superior compared to the other LCC models when simulating urban growth for the year 2010; hence, ANN was used to predict urban growth for 2020 and 2030. Projected urban growth maps were assessed using statistical measures, including figure of merit, average spatial distance deviation, producer accuracy, and overall accuracy. Based on our findings, we recomend ANNs as an and accurate method for simulating future patterns of urban growth. PMID- 28555439 TI - Cytotoxicity and genotoxicity of Guaribas river water (Piaui, Brazil), influenced by anthropogenic action. AB - In general, tropical rivers have a great impact on human activities. Bioaccumulation of toxins is a worldwide problem nowadays and has been, historically, overlooked by the supervisory authorities. This study evaluated cytogenotoxic effects of Guaribas river (a Brazilian river) water during dry and rainy seasons of 2014 by using the Allium cepa test system. The toxicogenetic variables, including root growth, mitotic index, and chromosomal aberrations, were analyzed in meristematic cells of A. cepa exposed to water samples taken from the up-, within, and downstream of the city Picos (state: Piaui). The physical-chemical parameters were also analyzed to explain water quality and possible anthropogenic action. Additionally, the presence of heavy metals was also analyzed to explain water quality and possible damaging effects on eukaryotic cells. The results suggest that the river water exerted cytotoxic, mutagenic, and genotoxic effects, regardless of the seasons. In addition, Guaribas river presented physico-chemical values outside the Brazilian laws, which can be a characteristic of human pollution (domestic sewage, industrial, and local agriculture). The genetic damage was positively correlated with higher levels of heavy metals. The pollution of the Guaribas river water may link to the chemical contamination, including the action of heavy metals and their impacts on genetic instability in the aquatic ecosystem. In conclusion, necessary steps should be taken into account for further toxicogenetic studies of the Guaribas river water, as it has an influence in human health of the same region of Brazil. PMID- 28555440 TI - Effect of High Dietary Manganese on the Immune Responses of Broilers Following Oral Salmonella typhimurium Inoculation. AB - Manganese (Mn) is an essential nutrient for both host and pathogen. Recent studies have demonstrated the nutritional immunity of Mn against Salmonella infection in mammals. To investigate the effect of high dietary Mn on immune responses of broilers following Salmonella challenge, 144 1-day-old male broilers were fed a basal diet (containing 20.04 mg Mn/kg) plus an additional 40 (the control group) or 400 mg Mn/kg (the H-Mn group) for 7 days. The 72 broilers in each group were then orally inoculated with 5 * 107 CFUs of Salmonella typhimurium (ATCC#14028) or phosphate-buffered saline. Peripheral blood, spleens, cecal tonsils, and bursa of Fabricius were collected from Salmonella-inoculated and Salmonella-noninoculated broilers (n = 6) at 2 days post inoculation (2 DPI) and 7 days post inoculation (7 DPI). Peripheral blood lymphocyte subpopulations were determined by flow cytometry. The messenger RNA (mRNA) abundance of genes was determined by quantitative real-time polymerase chain reaction. Salmonella counts were higher (P < 0.05) in the H-Mn group than that in the control group at 2 DPI in the cecal contents of Salmonella-inoculated broilers. High dietary Mn increased CD3+CD4+ and CD3+CD8+ percentages in the peripheral blood of Salmonella inoculated broilers at 2 DPI. Salmonella inoculation increased interleukin (IL)-6 mRNA expression in spleens and bursa of Fabricius at 2 DPI and increased IL-1beta and IL-6 mRNA expression in cecal tonsils at 7 DPI in the H-Mn group. These changes were not observed in the control group. High dietary Mn increased interferon-gamma (IFN-gamma) in spleens and decreased IFN-gamma and IL-12 mRNA expression in cecal tonsils of Salmonella-inoculated broilers at 2 DPI. High dietary Mn decreased IL-17 mRNA expression in the bursa of Fabricius at 7 DPI, but increased this expression in cecal tonsils at 2 and 7 DPI in Salmonella inoculated broilers. These results suggested that dietary Mn level affected T helper (Th) 1-cytokine reaction in spleens and cecal tonsils, and Th17-mediated immunity in cecal tonsils and the bursa of Fabricius of broilers when challenged with Salmonella. PMID- 28555441 TI - Alopecia Areata of the Beard: A Review of the Literature. AB - Alopecia areata (AA) is a T-cell mediated autoimmune disorder in which inflammatory cells attack the hair follicle, resulting in round, well circumscribed patches of noncicatricial hair loss in normal appearing skin. AA affecting the beard area is well known and is referred to as AA of the beard (BAA) or AA barbae when involvement is limited exclusively to the beard. BAA has been documented in a select number of studies. We review the literature and discuss the clinical features, epidemiology, diagnosis, and treatment of BAA. Clinical presentation of BAA can vary and manifest as single small areas of hair loss, multiple small or large simultaneous focuses, or total hair loss. Most patients are middle-aged males with focal patches of round or oval hair loss, mostly localized along the jawline. Patches are characteristically well circumscribed and smooth with white hair present at the periphery. Dermoscopic features of BAA include yellow dots, broken hair, and short vellus hairs. BAA may be associated with other autoimmune disorders, including atopic dermatitis, vitiligo, and psoriasis. Many treatment modalities are available for BAA, and selection of a therapy depends on several factors, including disease activity, extent of area affected, duration of disease, and age of the patient. Topical corticosteroids are most commonly used as initial treatment, followed by intralesional steroids. Other therapeutic modalities are discussed. PMID- 28555437 TI - Autoimmunity in 2016. AB - The number of peer-reviewed articles published during the 2016 solar year and retrieved using the "autoimmunity" key word remained stable while gaining a minimal edge among the immunology articles. Nonetheless, the quality of the publications has been rising significantly and, importantly, acquisitions have become available through scientific journals dedicated to immunology or autoimmunity. Major discoveries have been made in the fields of systemic lupus erythematosus, rheumatoid arthritis, autoimmunity of the central nervous system, vasculitis, and seronegative spondyloarthrithritides. Selected examples include the role of IL17-related genes and long noncoding RNAs in systemic lupus erythematosus or the effects of anti-pentraxin 3 (PTX3) in the treatment of this paradigmatic autoimmune condition. In the case of rheumatoid arthritis, there have been reports of the role of induced regulatory T cells (iTregs) or fibrocytes and T cell interactions with exciting implications. The large number of studies dealing with neuroimmunology pointed to Th17 cells, CD56(bright) NK cells, and low-level TLR2 ligands as involved in multiple sclerosis, along with a high salt intake or the micriobiome-derived Lipid 654. Lastly, we focused on the rare vasculitides to which numerous studies were devoted and suggested that unsuspected cell populations, including monocytes, mucosal-associated invariant T cells, and innate lymphoid cells, may be crucial to ANCA-associated manifestations. This brief and arbitrary discussion of the findings published in 2016 is representative of a promising background for developments that will enormously impact the work of laboratory scientists and physicians at an exponential rate. PMID- 28555442 TI - [The treatment of acute secondary peritonitis : A retrospective analysis of the use of continuous negative pressure therapy]. AB - BACKGROUND: Patients with acute secondary peritonitis often need relaparotomies and open abdominal lavages. Continuous negative pressure therapy seems to be beneficial. OBJECTIVES: Does the efficacy of the therapy depend on the continuous negative pressure system used? MATERIALS AND METHODS: A retrospective analysis was performed in the Chirurgische Klinik der Universitatsmedizin Berlin, Charite Campus Mitte, including all patients who underwent abdominal vacuum therapy between December 2013 and February 2015. Two different systems (ABThera(r), KCI Medizinprodukte GmbH and Suprasorb(r) CNP Drainagefolie, Lohmann & Rauscher GmbH) were available for treatment. RESULTS: During the 14 month study period, 33 patients with acute secondary peritonitis were treated with abdominal negative pressure therapy. Vacuum therapy treatment was applied for a median of 4 days (range 0-22 days). Eight patients (24%) died during hospitalisation. After completion of intraabdominal vacuum therapy, direct fascial closure was feasible in 26 patients (79%). There were no differences concerning patient characteristics, duration of abdominal vacuum therapy, the possibility of direct fascial closure or morbidity and mortality with the two different systems used. CONCLUSIONS: Acute secondary peritonitis is associated with high morbidity. We achieved a lower mortality rate compared to prospective clinical trials using intraabdominal continuous negative pressure therapy. The effectiveness and cost efficiency of different therapy systems should be the topic of further research. PMID- 28555444 TI - Diverticulitis recurrence after percutaneous abscess drainage. AB - PURPOSE: Recurrent diverticulitis has been reported in 30-50% of patients who recover from an episode of diverticular-associated abscess. Our aim was to review the outcomes of patients who underwent non-operative management after percutaneous drainage (PD) of colonic diverticular abscess. METHODS: All patients with a diverticular-associated abscess were identified between 2001 and 2012. Individual charts were queried for peri-procedural data and follow-up. The most recent follow-up data were acquired via the electronic medical record or telephone call. RESULTS: A total of 165 patients underwent PD of diverticular associated abscesses. Abscess locations were pelvic (n = 122), abdominal (n = 36), and both (n = 7), while median abscess size was 6.1 +/- 2.2 cm. One hundred eighteen patients clinically improved following non-operative management, and 81 of these patients did not undergo subsequent colonic resection within 4 months of PD. Of these, 8 died within 12 months. Among the remaining 73 patients, there were no significant differences in demographics or abscess variables compared to those who underwent elective surgery within 4 months. Only 7 of 73 patients had documented episodes of recurrences, while 22 patients later had elective surgery (1.1 +/- 1.2 years from the index case). Five-year colectomy-free survival was 55% (95%CI 42-66%), while the recurrence-free survival at 5 years was 77% (95%CI 65-86%). All recurrences were managed non-operatively initially and one patient went on to have elective resection. CONCLUSION: A sizable number of patients successfully recover from complicated diverticulitis following PD. Subsequent non operative management carries an acceptable risk for recurrent episodes and may be considered as a reasonable management option. PMID- 28555443 TI - [Extracorporeal lung support]. AB - Systems for extracorporeal lung support have recently undergone significant technological improvements leading to more effective and safe treatment. Despite limited scientific evidence these systems are increasingly used in the intensive care unit for treatment of different types of acute respiratory failure. In general two types of systems can be differentiated: devices for extracorporeal carbon dioxide removal (ECCO2R) for ventilatory insufficiency and devices for extracorporeal membrane oxygenation (ECMO) for severe hypoxemic failure. Despite of all technological developments extracorporeal lung support remains an invasive and a potentially dangerous form of treatment with bleeding and vascular injury being the two main complications. For this reason indications and contraindications should always be critically considered and extracorporeal lung support should only be carried out in centers with appropriate experience and expertise. PMID- 28555445 TI - Paenibacillus aquistagni sp. nov., isolated from an artificial lake accumulating industrial wastewater. AB - Strain 11T was isolated from water of an artificial lake accumulating industrial wastewater on the outskirts of Celje, Slovenia. Phenotypic characterisation showed strain 11T to be a Gram-stain positive, spore forming bacterium. The 16S rRNA gene sequence identified strain 11T as a member of the genus Paenibacillus, closely related to Paenibacillus alvei (96.2%). Genomic similarity with P. alvei 29T was 73.1% (gANI), 70.2% (ANIb), 86.7% (ANIm) and 21.7 +/- 2.3% (GGDC). The DNA G+C content of strain 11T was determined to be 47.5%. The predominant menaquinone of strain 11T was identified as MK-7 and the major fatty acid as anteiso-C15:0. The peptidoglycan was found to contain meso-diaminopimelic acid. In contrast to its close relatives P. alvei DSM 29T, Paenibacillus apiarius DSM 5581T and Paenibacillus profundus NRIC 0885T, strain 11T was found to be able to ferment D-fructose, D-mannose and D-xylose. A draft genome of strain 11T contains a cluster of genes associated with type IV pilin synthesis usually found in clostridia, and only sporadically in other Gram-positive bacteria. Genotypic, chemotaxonomic, physiological and biochemical characteristics of strain 11T presented in this study support the creation of a novel species within the genus Paenibacillus, for which the name Paenibacillus aquistagni sp. nov. is proposed, with strain 11T (=ZIM B1027T =LMG 29561T =CCM 8679T ) as the type strain. PMID- 28555446 TI - Development of angle information system to facilitate the adjustment of needle holding posture. AB - PURPOSE: Our purpose is to develop a system based on image processing methods that can inform users of the angular relationship between the needle and the forceps. The user thereby adjusts their needle grasping posture according to the angle information, which leads to an improvement in suturing accuracy. METHODS: The system prototype consists of a camera and an image processing computer. The image captured by the camera is input to the computer, and then, the angular relationship between the forceps and needle is calculated via image processing. Then, the system informs the user of the calculated angular relationship between the needle and forceps in real time. To evaluate whether the system improves suturing accuracy, we invited 12 participants to enroll in an experiment based on a suturing task. RESULTS: The experimental results illustrate that the system allows participants to easily adjust the positional relationship between the needle and the forceps and that this adjusted angular relationship leads to higher suturing accuracy. CONCLUSIONS: Adjustment to holding the needle at a right angle before insertion has a critical effect on suturing quality. Therefore, we developed a system that informs the user of the angular relationship between the needle and the forceps. The results of the evaluation show that the system significantly improves the suturing accuracy of participants via informing them of the angle. PMID- 28555447 TI - Assessment of the myocardial FDG-PET image quality with the use of maximal Standardized Uptake Value myocardial to background index. Application of the results in regard to semiquantitative assessment of myocardial viability with cardiac dedicated softwar. AB - BACKGROUND: The objective of this study was to semiquantitatively assess the degree of myocardial fluorodeoxyglucose (FDG) uptake in glucose-loaded myocardial viability positron emission tomography/computed tomography (PET/CT) scans, to calculate the myocardial to background index, and correlate the index with image quality assessed on the basis of visual qualitative assessment. MATERIAL AND METHODS: The myocardial FDG-PET/CT study was carried out in 69 non-diabetic patients, who had known coronary artery disease, by intravenous injection of 250 +/- 70 MBq (range: 180-320 MBq) FDG. Images were interpreted visually and patients were divided into three groups according to the grade of myocardial uptake: optimal, suboptimal, and uninterpretable. Semiquantitative analysis was performed by calculating the standardized uptake value (SUVmax) for myocardium and background (blood pool) activity, and expressed as the myocardial to background (M/B) activity ratio. RESULTS: On the basis of visual (qualitative) analysis, 60/69 (86.96%) patients showed optimal quality of FDG cardiac uptake, 3/69 (4.35%) were suboptimal, and uninterpretable FDG PET scan results were found in 6/69 (8.70%) patients. The M/B index was found to be significantly higher in images of optimal vs. suboptimal quality (6.87 +/- 3.99 vs. 1.65 +/- 0.78 respectively; p < 0.0001). CONCLUSIONS: The index ratio of 2.2, which is consistent with the upper borderline value for visually uninterpretable images, was considered the cut-off value for scans of optimal and non-optimal quality. PMID- 28555449 TI - A retrospective analysis of the accuracy of radioactively labeled autologous leukocytes in patients with infected prosthetic joints. AB - BACKGROUND: Labeled leukocyte scintigraphy (LS) is considered a valuable tool in preoperative diagnosis of prosthetic joint infections (PJI). The aim of this study was to determine the accuracy of LS combined with bone marrow scintigraphy (BMS), as well as inflammation markers CRP and WBC, in detecting infection in patients with prosthetic joints. MATERIAL AND METHODS: This study included patients suspected of having PJI between January and September 2013 at the Vienna General Hospital who underwent imaging with 99mTc-HMPAO labeled autologous leukocytes and subsequent BMS. Diagnostic accuracy was assessed in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: A total of 48 patients were included. The most common joint investigated was knee (25), followed by hip (9), shoulder (2), and elbow (1). Other parts of the body investigated included the femur (6), tibia (2), leg (2), and foot (1). The pathogens most frequently isolated included Staphylococcus epidermidis and Candida albicans. The sensitivity of LS was 60%, specificity 97%, PPV 86% and NPV 90%. Overall accuracy was calculated to be 90%. CONCLUSIONS: This study was able to demonstrate that 99mTc-HMPAO labeled autologous leukocytes in patients presenting with symptoms of PJI is accurate. In contrast, however, inflammation markers CRP and WBC are not accurate pre-diagnostic markers for PJI. PMID- 28555448 TI - New synthesis route of active substance d,l-HMPAO for preparation Technetium Tc99m Exametazime. AB - BACKGROUND: Technetium Tc99m Exametazime (99mTc-HMPAO) is currently used as a radiopharmaceutical for determining regional cerebral blood flow and for the labelling of autologous leucocytes for infection and inflammation imaging. The HMPAO ligand exists in two diastereomeric forms: d,l and meso. Usually, the substance is obtained in low chemical yield in a time consuming procedure. Furthermore, the final product still contains some amounts of the meso-form. The aim of this study was to develop the efficient, reliable and fast method for isolation of the d,l-HMPAO, which would provide the ligand with high purity and free from the meso-diastereomer. MATERIAL AND METHODS: The mixture of the meso- and d,l-HMPAO was synthesized in two-steps by condensation of propanediamine with keto-oxime and the reduction of the obtained bisimine. The d- and l-enantiomers were separated individually directly from this mixture by repeated crystallizations from ethanol as their tartrate salts and pooled together in equal proportions. That substance was characterized for its identity and isomeric purity using IR, HPLC and GC methods. The meso-free d,l-HMPAO was used for the preparation of the radiopharmaceutical freeze-dried kit for technetium-99m radiolabelling. Quality assessment of obtained 99mTc-d,l-HMPAO complex was performed according to the current Ph.Eur. monograph 1925 and USP monograph - Technetium Tc99m Exametazime Injection. To verify its biological activity, the kit-prepared 99mTc-d,l-HMPAO has been used for the white blood cell (WBC) labelling. RESULTS: According to the proposed synthesis route the d,l-HMPAO was obtained with around 18-20% yield in the total time of 10 days. The ligand identity was confirmed and the HPLC analysis revealed more than 99% chemical purity. The undesired meso-form was not detected. Freeze dried kit formulation for 99mTc-labelling of d,l-HMPAO has been established and four batches of kits were manufactured. The radiochemical purity of 99mTc-d,l-HMPAO complex was high (> 95% of lipophilic technetium-99m exametazime). Brain uptake in rats reached 2.1 +/- 0.3%. The in vitro labelling of WBC resulted in 68.3 +/- 6.6% yield. CONCLUSION: A new synthesis method of d,l-HMPAO, drug substance for technetium 99m exametazime preparation has been developed. PMID- 28555451 TI - Editorial. PMID- 28555452 TI - SELECTED ABSTRACTS OF THE 20TH CONGRESS OF THE "HEVESY GYORGY" HUNGARIAN SOCIETY OF NUCLEAR MEDICINE. Budapest, May 25-27, 2017. PMID- 28555450 TI - Usefulness of parametric renal clearance images in the assessment of basic risk factors for renalnal clearance images in the assessment of basic risk factors for renal scarring in children with recurrent urinary tract infections. AB - BACKGROUND: Clinically confirmed incidents of acute pyelonephritis (APN) following recurrent infections of urinary tract (UTI) form basic risk factors for renal scarring in children. Vesico-uretheral reflux (VUR) of higher grade is additional risk factor for this scarring. Opinions on diagnostic value of summed sequential images of renal uptake phase (SUM) of dynamic renal scintigraphy in detection of renal scars are diverse. However, several publications point to higher diagnostic efficacy of clearance parametric images (PAR) generated from this study. THE AIM OF THE STUDY: To establish a clinical value of parametric renal clearance images in detection of renal scarring. MATERIAL AND METHODS: A prospective study was performed in a group of 91 children at the age of 4 to 18 years with recurrent UTI. Clinically documented incidents of APN were noted in 32 children: in 8 cases - one and in the remaining 24 - 2 to 5 (mean 3) incidents. In the remaining 59 patients only infections of the lower part of urinary tract were diagnosed. Static renal 99mTc-DMSA SPECT study and after 2-4 days dynamic renal studies (99mTc-EC) were performed in every patient not earlier than 6 months after the last documented incident of UTI. PAR images generated from a dynamic study by in-house developed software and SUM images were compared with a gold standard SPECT study. RESULTS: Percentages of children with detected renal scar(s) with SPECT and PAR methods amounted to 55% and 54%, respectively and were statistically significantly higher (p < 0.0001) than with SUM method - 31%. Scars in children with history of APN detected with SPECT and PAR methods were significantly more frequent than with infections of only lower part of urinary tract (72% vs. 46%; p = 0.017 and 69% vs. 46%; p = 0.036, respectively). A SUM method did not reveal statistically significant differences between frequencies of detection of scars in groups specified above - 38% vs. 27% (p = 0.31). Both SPECT and PAR methods showed also that frequencies of occurrence of renal scars in children with higher grades of VUR were higher than without or with lower grades of VUR: 79% vs. 50% (p = 0.048) and 79% vs. 49% (p = 0.04). A SUM method did not reveal higher frequency of renal scars in children with high VUR grades: 36% vs. 30% (p = 0.44). CONCLUSION: Results obtained with PAR and SPECT methods were similar. An advantage of PAR over SUM images obtained from a dynamic renal scintigraphy in detection of renal scars in children with UTI was confirmed. PMID- 28555453 TI - [A phenotypic description of 26 patients with Ritscher-Schinzel syndrome (cranio cerebello-cardiac dysplasia or 3C syndrome)]. AB - INTRODUCTION: Ritscher-Schinzel syndrome (also known as cranio-cerebello-cardiac dysplasia or 3C syndrome) is a rare genetic syndrome that is mainly characterised by the association of cardiac and craniofacial anomalies together with others affecting the posterior fossa. PATIENTS AND METHODS: We report on 26 patients with Ritscher-Schinzel syndrome at a hospital in Medellin, in the Department of Antioquia, Colombia. RESULTS: Males account for 69% of this cohort. The mean age of the cohort was 30 months, and 42% were under the age of one year at the time of diagnosis. All of them presented ocular disorders, and megalocornea was the most frequent ocular manifestation (69%), whereas low-set ears (80.7%) and septal heart defects (68.7%) were the most common facial and cardiac malformations, respectively. The most frequent malformations of the posterior fossa were megacisterna magna (31.8%) and Dandy-Walker malformation (27%). 84% of the cases had delayed neurodevelopment or intellectual disability. Skeletal manifestations were frequent: the group consisting of camptodactyly, single palmar crease, overlapping fingers, vertical talus and nail hypoplasia were found in hands and feet in 96% of the cases. CONCLUSIONS: Ritscher-Schinzel syndrome is a heterogeneous syndrome from the genetic and clinical point of view. These results suggest that the skeletal and ocular abnormalities that were observed can facilitate the phenotypic diagnosis. However, it is necessary to conduct further studies that allow us to gain a deeper knowledge of its prevalence and help identify other genes involved in this syndrome. PMID- 28555454 TI - [Cognitive training combined with aerobic exercises in multiple sclerosis patients: a pilot study]. AB - INTRODUCTION: The scientific evidences associated to the effectiveness of different techniques of cognitive rehabilitation are still contradictory. AIM: To compare a program of combined training (physical and cognitive) in front of a program of physical training and to observe their effectiveness about the optimization of the cognitive functions in patients with multiple sclerosis (MS). PATIENTS AND METHODS: It was carried out an experimental study in 32 patients with MS. The patients were distributed in two groups: 16 to the experimental group (combined cognitive training with aerobic exercises) and 16 patients to the control group (aerobic exercises). The intervention was planned for six weeks combining cognitive tasks by means of a game of dynamic board of cubes and signs (TaDiCS (r)) and a program of aerobic exercises. The Brief Repeatable Battery of Neuropsychological Test and the Stroop Test were applied to evaluate the cognitive yield. Also, the Beck Depression Inventory was administered. RESULTS: There were found significant differences in the intergrupal analysis after the intervention in the variable learning and visuoespacial long term memory (p = 0.000), attention (p = 0.026) and inhibitory control (p = 0.007). Also, in the intragroup analysis there were found significant differences in these variables and information processing speed in the group that received the combined training. These patients also showed a significant improvement in the emotional state (p = 0.043). CONCLUSION: The cognitive training combined with the aerobic exercises is effective to improve the cognitive performance. PMID- 28555455 TI - [Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term follow-up]. AB - AIM: To describe a series of patients with drug resistant epilepsy treated with vagus nerve stimulation in a national pediatric hospital, evaluating efficacy, safety and tolerability. PATIENTS AND METHODS: A retrospective analysis of 158 pediatric patients with epilepsy resistant to pharmacological and non pharmacological treatment including surgery that were treated with vagus nerve stimulation between 2001-2015. Patients with progressive encephalopathies, and congenital heart disease were excluded. RESULTS: 158 patients (80 male) were included, with a mean age at implantation of 11.4 years and a mean age at evolution of epilepsy of 9.5 years. Time of follow-up: 1-15 years (median: 6.9 years). Patient's age at this time: 2-31 years (median: 14.1 years). Effectiveness: 66.5% of patients showed more or equal at 50% of seizure control at 24 months of implant. Just three patients showed severe side effects (1.8%). Minor side effects were seen in 26 patients (16.4%). Without side effects: 129 (81.8%). CONCLUSION: Vagus nerve stimulation is an effective, tolerable and safe therapy in our pediatric series with refractory epilepsy. PMID- 28555456 TI - [Acute polyneuropathies in a hospital in the south of Spain: ten years' experience]. AB - INTRODUCTION: Guillain-Barre syndrome is the most frequent cause of acute flaccid paralysis in children. AIM: To describe the characteristics of patients diagnosed with acute polyneuropathies and their long-term progress. PATIENTS AND METHODS: We conducted a retrospective descriptive analysis of children under 14 years of age admitted to our hospital between January 2004 and December 2014. Clinical, demographic and neurophysiological variables were collected together with other imaging tests. RESULTS: Twenty-six patients, with a mean age of 3.83 years, were diagnosed with acute polyneuropathies, four of them of Moroccan origin. Twenty of them (76%) had a history of previous infection. The mean time elapsed since the onset of the symptoms until admission to hospital was 9.2 days, and from admission until beginning with gamma globulins it was 1.6 days. The clinical signs and symptoms prior to diagnosis were of a very heterogeneous nature. They all presented muscular weakness; 90% displayed areflexia; and 30% showed involvement of the cranial nerves. All of them (100%) received intravenous gamma globulins, and 38.4% were given systemic corticosteroids. Two patients presented chronification of the pathology. There was no mortality in the series. CONCLUSIONS: The patients included in our study presented very unspecific symptoms in the early phases, which initially led to alternative diagnoses. To avoid this delay in the diagnosis, it is essential to perform an exhaustive physical examination that includes the myotatic reflexes and to maintain a high level of suspicion of the disease even with normal results in the complementary tests if they are performed at an early stage. We detected a greater number of cases of axonal polyneuropathy, which can possibly be explained by the high number of patients of Moroccan origin who were treated. PMID- 28555457 TI - [Situs inversus of the optic nerve. A case report]. AB - INTRODUCTION: Situs inversus of the optic nerve is a congenital anomaly characterised by the emergence of the vessels in the retina towards the nose rather than in a temporal direction. It is caused by an anomalous insertion of the optic stalks into the optic vesicle that gives rise to dysversion of the head of the optic nerve. It is not an isolated condition and usually appears jointly with tilted disc syndrome and in patients with myopia. It is characterised by the presence of inferior conus atrophy, deficiencies in the temporal visual field, refraction defects and ambliopy. CASE REPORT: A 22 years-old female who attended an ophthalmological examination due to severe frontal headaches accompanied by halos and loss of sharpness in her sight. From the results of the ophthalmetric and ophthalmological examination she was diagnosed as suffering from a condition consistent with this congenital anatomical anomaly. CONCLUSIONS: Situs inversus of the optic nerve is a rare condition that may appear in isolation or accompanied by other pathologies. Application of the visual field test and new diagnostic techniques, such as optical coherence tomography, facilitates the differential diagnosis of this situation. Its prevalence remains unknown, as it is not included in the register of rare diseases. Moreover, the scant number of patients studied and the scarce literature on this anomaly do not allow us to know whether the defects it causes develop over time. It would therefore be important to perform an ophthalmological follow-up of patients with situs inversus of the optic nerve. PMID- 28555459 TI - [Reversible posterior leukoencephalopathy syndrome with isolated involvement of the brainstem and spinal cord]. PMID- 28555458 TI - [Process-based approach neuropsychological assessment: review of the evidence and proposal for improvement of dementia screening tools]. AB - A detailed neuropsychological assessment plays an important role in the diagnostic process of mild cognitive impairment. However, available brief cognitive screening tests for this clinical population are administered and interpreted based mainly, or exclusively, on total achievement scores. This score based approach can lead to erroneous clinical interpretations unless we also pay attention to the test taking behaviour or to the type of errors committed during the test performance. The goals of the current review are to present the grounds for the process-based approach to neuropsychological assessment, to offer a brief review of the evidence obtained so far regarding its usefulness, and to show the results of a systematic review of existing screening and neuropsychological assessment tools, some of which were already created and/or modified using this approach, and others that may benefit in their screening properties if they underwent modifications according to a process-based approach. It is expected that, in a relatively short period of time, process-based approach versions of screening tools will be available. These modified versions will not alter substantially the standard administration procedure, but will provide a way for scoring and interpretation that goes beyond total scores. This will allow clarifying with higher accuracy the underlying cognitive components involved in the successful or unsuccessful performance in cognitive tasks, and thus will facilitate an early diagnosis of mild cognitive impairment. PMID- 28555460 TI - [Compassionate use of cannabidiol in spray form for the treatment of spastic paraparesis in a patient with adrenomyeloneuropathy]. PMID- 28555461 TI - High-flow nasal cannulae for respiratory support in adult intensive care patients. AB - BACKGROUND: High-flow nasal cannulae (HFNC) deliver high flows of blended humidified air and oxygen via wide-bore nasal cannulae and may be useful in providing respiratory support for adult patients experiencing acute respiratory failure in the intensive care unit (ICU). OBJECTIVES: We evaluated studies that included participants 16 years of age and older who were admitted to the ICU and required treatment with HFNC. We assessed the safety and efficacy of HFNC compared with comparator interventions in terms of treatment failure, mortality, adverse events, duration of respiratory support, hospital and ICU length of stay, respiratory effects, patient-reported outcomes, and costs of treatment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3), MEDLINE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Web of Science, proceedings from four conferences, and clinical trials registries; and we handsearched reference lists of relevant studies. We conducted searches from January 2000 to March 2016 and reran the searches in December 2016. We added four new studies of potential interest to a list of 'Studies awaiting classification' and will incorporate them into formal review findings during the review update. SELECTION CRITERIA: We included randomized controlled studies with a parallel or cross-over design comparing HFNC use in adult ICU patients versus other forms of non-invasive respiratory support (low-flow oxygen via nasal cannulae or mask, continuous positive airway pressure (CPAP), and bilevel positive airway pressure (BiPAP)). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. MAIN RESULTS: We included 11 studies with 1972 participants. Participants in six studies had respiratory failure, and in five studies required oxygen therapy after extubation. Ten studies compared HFNC versus low-flow oxygen devices; one of these also compared HFNC versus CPAP, and another compared HFNC versus BiPAP alone. Most studies reported randomization and allocation concealment inadequately and provided inconsistent details of outcome assessor blinding. We did not combine data for CPAP and BiPAP comparisons with data for low-flow oxygen devices; study data were insufficient for separate analysis of CPAP and BiPAP for most outcomes. For the primary outcomes of treatment failure (1066 participants; six studies) and mortality (755 participants; three studies), investigators found no differences between HFNC and low-flow oxygen therapies (risk ratio (RR), Mantel-Haenszel (MH), random-effects 0.79, 95% confidence interval (CI) 0.49 to 1.27; and RR, MH, random-effects 0.63, 95% CI 0.38 to 1.06, respectively). We used the GRADE approach to downgrade the certainty of this evidence to low because of study risks of bias and different participant indications. Reported adverse events included nosocomial pneumonia, oxygen desaturation, visits to general practitioner for respiratory complications, pneumothorax, acute pseudo-obstruction, cardiac dysrhythmia, septic shock, and cardiorespiratory arrest. However, single studies reported adverse events, and we could not combine these findings; one study reported fewer episodes of oxygen desaturation with HFNC but no differences in all other reported adverse events. We downgraded the certainty of evidence for adverse events to low because of limited data. Researchers noted no differences in ICU length of stay (mean difference (MD), inverse variance (IV), random-effects 0.15, 95% CI -0.03 to 0.34; four studies; 770 participants), and we downgraded quality to low because of study risks of bias and different participant indications. We found no differences in oxygenation variables: partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) (MD, IV, random-effects 7.31, 95% CI -23.69 to 41.31; four studies; 510 participants); PaO2 (MD, IV, random effects 2.79, 95% CI -5.47 to 11.05; three studies; 355 participants); and oxygen saturation (SpO2) up to 24 hours (MD, IV, random-effects 0.72, 95% CI -0.73 to 2.17; four studies; 512 participants). Data from two studies showed that oxygen saturation measured after 24 hours was improved among those treated with HFNC (MD, IV, random-effects 1.28, 95% CI 0.02 to 2.55; 445 participants), but this difference was small and was not clinically significant. Along with concern about risks of bias and differences in participant indications, review authors noted a high level of unexplained statistical heterogeneity in oxygenation effect estimates, and we downgraded the quality of evidence to very low. Meta-analysis of three comparable studies showed no differences in carbon dioxide clearance among those treated with HFNC (MD, IV, random-effects -0.75, 95% CI -2.04 to 0.55; three studies; 590 participants). Two studies reported no differences in atelectasis; we did not combine these findings. Data from six studies (867 participants) comparing HFNC versus low-flow oxygen showed no differences in respiratory rates up to 24 hours according to type of oxygen delivery device (MD, IV, random-effects -1.51, 95% CI -3.36 to 0.35), and no difference after 24 hours (MD, IV, random-effects -2.71, 95% CI -7.12 to 1.70; two studies; 445 participants). Improvement in respiratory rates when HFNC was compared with CPAP or BiPAP was not clinically important (MD, IV, random-effects -0.89, 95% CI -1.74 to -0.05; two studies; 834 participants). Results showed no differences in patient-reported measures of comfort according to oxygen delivery devices in the short term (MD, IV, random-effects 0.14, 95% CI -0.65 to 0.93; three studies; 462 participants) and in the long term (MD, IV, random-effects -0.36, 95% CI -3.70 to 2.98; two studies; 445 participants); we downgraded the certainty of this evidence to low. Six studies measured dyspnoea on incomparable scales, yielding inconsistent study data. No study in this review provided data on positive end expiratory pressure measured at the pharyngeal level, work of breathing, or cost comparisons of treatment. AUTHORS' CONCLUSIONS: We were unable to demonstrate whether HFNC was a more effective or safe oxygen delivery device compared with other oxygenation devices in adult ICU patients. Meta-analysis could be performed for few studies for each outcome, and data for comparisons with CPAP or BiPAP were very limited. In addition, we identified some risks of bias among included studies, differences in patient groups, and high levels of statistical heterogeneity for some outcomes, leading to uncertainty regarding the results of our analysis. Consequently, evidence is insufficient to show whether HFNC provides safe and efficacious respiratory support for adult ICU patients. PMID- 28555462 TI - Intermuscular Adipose Tissue Content and Intramyocellular Lipid Fatty Acid Saturation Are Associated with Glucose Homeostasis in Middle-Aged and Older Adults. AB - BACKGROUND: Insulin resistance is associated with the higher content of intermuscular adipose tissue (IMAT) and the saturation of intramyocellular lipid (IMCL), but a paucity of data exist in humans. This study examined associations among IMAT content, IMCL saturation, and fasting glucose concentration in middle aged and older adults with overweight or obesity. METHODS: Seventy-five subjects (26 males, 49 females) were recruited and thigh muscle and IMAT were assessed using magnetic resonance imaging. Vastus lateralis tissue was acquired from a subset of nine subjects and IMCL content and saturation were assessed using nonlinear dual complex microscopy. RESULTS: The characteristics of the 75 subjects were as follows: age 59+/-11 years, body mass index 30+/-5 kg/m2, fasting glucose concentration 5.2+/-0.5 mmol/L, fasting insulin concentration 12.2+/-7.3 MUU/mL, fasting homeostatic model assessment of insulin resistance (HOMA-IR) 2.9+/-2.0 (mean+/-SD). IMAT to muscle tissue (MT) volume ratio was positively associated with the saturated fatty acid to unsaturated fatty acid ratio in IMCL. IMAT:MT was positively associated with fasting glucose concentration and HOMA-IR. IMCL saturation was positively associated with fasting glucose concentration while muscle cell area, IMCL area, and % IMCL in muscle cell were not associated with fasting glucose concentration. CONCLUSION: These results indicate that higher intermuscular fat content and IMCL saturation may impact fasting glucose concentration in middle-aged and older adults with overweight or obesity. The centralization of adipose tissue in the appendicular region of the body may promote insulin resistance. PMID- 28555463 TI - Association of Plasma Ghrelin Levels with Insulin Resistance in Type 2 Diabetes Mellitus among Saudi Subjects. AB - BACKGROUND: Although the exact mechanism of insulin resistance (IR) has not yet been established, IR is the hallmark characteristic of type 2 diabetes mellitus (T2DM). The aim of this study was to examine the relationship between plasma ghrelin levels and IR in Saudi subjects with T2DM. METHODS: Patients with T2DM (n=107, cases) and non-diabetic apparently healthy subjects (n=101, controls) from Saudi Arabia were included in this study. The biochemical profiles and plasma insulin levels of all subjects were analyzed, and IR was estimated using the homeostatic model assessment of insulin resistance (HOMA-IR) index. Active ghrelin levels in plasma were measured using the radioimmunoassay technique. RESULTS: Only 46.7% (50 of 107) of the T2DM subjects had IR, including 26% (28 of 107) with severe IR (HOMA-IR >=5), while 5.9% (six of 101) of the controls had moderate IR (3 <=HOMA-IR <5). HOMA-IR values were not associated with age, disease duration, or gender. Importantly, T2DM itself and the co-occurrence of IR with T2DM were significantly associated with low plasma ghrelin levels. However, ghrelin levels were inversely correlated with the HOMA-IR index, body weight, and fasting plasma insulin levels, mainly in the control subjects, which was indicative of the breakdown of metabolic homeostasis in T2DM. CONCLUSION: The prevalence of IR was relatively low, and IR may be inversely associated with plasma ghrelin levels among Saudi patients with T2DM. PMID- 28555464 TI - Glucocorticoid-Induced Diabetes Mellitus: An Important but Overlooked Problem. AB - Glucocorticoids are widely used as potent anti-inflammatory and immunosuppressive drugs to treat a wide range of diseases. However, they are also associated with a number of side effects, including new-onset hyperglycemia in patients without a history of diabetes mellitus (DM) or severely uncontrolled hyperglycemia in patients with known DM. Glucocorticoid-induced diabetes mellitus (GIDM) is a common and potentially harmful problem in clinical practice, affecting almost all medical specialties, but is often difficult to detect in clinical settings. However, scientific evidence is lacking regarding the effects of GIDM, as well as strategies for prevention and treatment. Similarly to nonsteroid-related DM, the principles of early detection and risk factor modification apply. Screening for GIDM should be considered in all patients treated with medium to high doses of glucocorticoids. Challenges in the management of GIDM stem from wide fluctuations in postprandial hyperglycemia and the lack of clearly defined treatment protocols. Together with lifestyle measures, hypoglycemic drugs with insulin sensitizing effects are indicated. However, insulin therapy is often unavoidable, to the point that insulin can be considered the drug of choice. The treatment of GIDM should take into account the degree and pattern of hyperglycemia, as well as the type, dose, and schedule of glucocorticoid used. Moreover, it is essential to instruct the patient and/or the patient's family about how to perform the necessary adjustments. Prospective studies are needed to answer the remaining questions regarding GIDM. PMID- 28555465 TI - Identification of Maturity-Onset Diabetes of the Young Caused by Glucokinase Mutations Detected Using Whole-Exome Sequencing. AB - Glucokinase maturity-onset diabetes of the young (GCK-MODY) represents a distinct subgroup of MODY that does not require hyperglycemia-lowering treatment and has very few diabetes-related complications. Three patients from two families who presented with clinical signs of GCK-MODY were evaluated. Whole-exome sequencing was performed and the effects of the identified mutations were assessed using bioinformatics tools, such as PolyPhen-2, SIFT, and in silico modeling. We identified two mutations: p.Leu30Pro and p.Ser383Leu. In silico analyses predicted that these mutations result in structural conformational changes, protein destabilization, and thermal instability. Our findings may inform future GCK-MODY diagnosis; furthermore, the two mutations detected in two Korean families with GCK-MODY improve our understanding of the genetic basis of the disease. PMID- 28555466 TI - Climate and the distribution of vector-borne diseases: what's in store? AB - Not available. PMID- 28555467 TI - Estimating small area health-related characteristics of populations: a methodological review. AB - Estimation of health-related characteristics at a fine local geographic level is vital for effective health promotion programmes, provision of better health services and population-specific health planning and management. Lack of a micro dataset readily available for attributes of individuals at small areas negatively impacts the ability of local and national agencies to manage serious health issues and related risks in the community. A solution to this challenge would be to develop a method that simulates reliable small-area statistics. This paper provides a significant appraisal of the methodologies for estimating health related characteristics of populations at geographical limited areas. Findings reveal that a range of methodologies are in use, which can be classified as three distinct set of approaches: i) indirect standardisation and individual level modelling; ii) multilevel statistical modelling; and iii) micro-simulation modelling. Although each approach has its own strengths and weaknesses, it appears that microsimulation- based spatial models have significant robustness over the other methods and also represent a more precise means of estimating health-related population characteristics over small areas. PMID- 28555468 TI - Spatial epidemiology of cancer: a review of data sources, methods and risk factors. AB - Cancer is a major concern among chronic diseases today. Spatial epidemiology plays a relevant role in this matter and we present here a review of this subject, including a discussion of the literature in terms of the level of geographic data aggregation, risk factors and methods used to analyse the spatial distribution of patterns and spatial clusters. For this purpose, we performed a websearch in the Pubmed and Web of Science databases including studies published between 1979 and 2015. We found 180 papers from 63 journals and noted that spatial epidemiology of cancer has been addressed with more emphasis during the last decade with research based on data mostly extracted from cancer registries and official mortality statistics. In general, the research questions present in the reviewed papers can be classified into three different sets: i) analysis of spatial distribution of cancer and/or its temporal evolution; ii) risk factors; iii) development of data analysis methods and/or evaluation of results obtained from application of existing methods. This review is expected to help promote research in this area through the identification of relevant knowledge gaps. Cancer's spatial epidemiology represents an important concern, mainly for public health policies design aimed to minimise the impact of chronic disease in specific populations. PMID- 28555469 TI - Impact of climate variability on the occurrence of cutaneous leishmaniasis in Khuzestan Province, southwestern Iran. AB - Leishmaniasis, one of the most important parasitic diseases worldwide, is frequently cited with respect to health risks related to climate change. The current variability of the climate may have different impacts on the transmission of cutaneous leishmaniasis (CL) depending on the various Leishmania species. The number and distribution of CL cases in Khuzestan Province, Southwestern Iran was analysed over the 2010-2014 period with regard to temperature, humidity, rainfall, sunshine hours, evaporation and wind-related climate issues. During the study period, there were 4672 recorded clinical cases of CL, the incidence of which was found to fall into three types of areas, such as high, intermediate and low-level endemic areas. Compared to the intermediate and low-endemic areas, the hyper-endemic areas showed significantly variable meteorological data with regard to rainy days, maximum/minimum temperature and humidity. Decreased temperatures in the eastern part of this province were found to promote the disease towards its centre. We conclude that the meteorological variables and incidence data of CL indicate that the number of rainy days, maximum and minimum temperatures and relative humidity are significant variables that can predict CL incidence. Indeed, the substantial climatic variability occurring during the recent 5-year period (2010-2014) in Khuzestan Province could be the main reason for the change in epidemiology and transmission of CL. PMID- 28555470 TI - Spatio-temporal dynamics of schistosomiasis in Rwanda between 2001 and 2012: impact of the national Neglected Tropical Disease control programme. AB - Schistosomiasis is recognised as a major public health problem in Rwanda. We aimed to identify the spatio-temporal dynamics of its distribution at a fine scale spatial resolution and to explore the impact of control programme interventions. Incidence data of Schistosoma mansoni infection at 367 health facilities were obtained for the period 2001-2012. Disease cluster analyses were conducted using spatial scan statistics and geographic information systems. The impact of control interventions was assessed for three distinct sub-periods. Findings demonstrated persisting, emerging and re-emerging clusters of schistosomiasis infection across space and time. The control programme initially caused an abrupt increase in incidence rates during its implementation phase. However, this was followed by declining and disappearing clusters when the programme was fully in place. The findings presented should contribute to a better understanding of the dynamics of schistosomiasis distribution to be used when implementing future control activities, including prevention and elimination efforts. PMID- 28555471 TI - Comparison of the spatial patterns of schistosomiasis in Zimbabwe at two points in time, spaced twenty-nine years apart: is climate variability of importance? AB - Temperature, precipitation and humidity are known to be important factors for the development of schistosome parasites as well as their intermediate snail hosts. Climate therefore plays an important role in determining the geographical distribution of schistosomiasis and it is expected that climate change will alter distribution and transmission patterns. Reliable predictions of distribution changes and likely transmission scenarios are key to efficient schistosomiasis intervention-planning. However, it is often difficult to assess the direction and magnitude of the impact on schistosomiasis induced by climate change, as well as the temporal transferability and predictive accuracy of the models, as prevalence data is often only available from one point in time. We evaluated potential climate-induced changes on the geographical distribution of schistosomiasis in Zimbabwe using prevalence data from two points in time, 29 years apart; to our knowledge, this is the first study investigating this over such a long time period. We applied historical weather data and matched prevalence data of two schistosome species (Schistosoma haematobium and S. mansoni). For each time period studied, a Bayesian geostatistical model was fitted to a range of climatic, environmental and other potential risk factors to identify significant predictors that could help us to obtain spatially explicit schistosomiasis risk estimates for Zimbabwe. The observed general downward trend in schistosomiasis prevalence for Zimbabwe from 1981 and the period preceding a survey and control campaign in 2010 parallels a shift towards a drier and warmer climate. However, a statistically significant relationship between climate change and the change in prevalence could not be established. PMID- 28555472 TI - Child mortality inequalities across Rwanda districts: a geoadditive continuous time survival analysis. AB - Child survival programmes are efficient when they target the most significant and area-specific factors. This study aimed to assess the key determinants and spatial variation of child mortality at the district level in Rwanda. Data from the 2010 Rwanda Demographic and Health Survey were analysed for 8817 live births that occurred during five years preceding the survey. Out of the children born, 433 had died before survey interviews were carried out. A full Bayesian geo additive continuous-time hazard model enabled us to maximise data utilisation and hence improve the accuracy of our estimates. The results showed substantial district- level spatial variation in childhood mortality in Rwanda. District specific spatial characteristics were particularly associated with higher death hazards in two districts: Musanze and Nyabihu. The model estimates showed that there were lower death rates among children from households of medium and high economic status compared to those from low-economic status households. Factors, such as four antenatal care visits, delivery at a health facility, prolonged breastfeeding and mothers younger than 31 years were associated with lower child death rates. Long preceding birth intervals were also associated with fewer hazards. For these reasons, programmes aimed at reducing child mortality gaps between districts in Rwanda should target maternal factors and take into consideration district-specific spatial characteristics. Further, child survival gains require strengthening or scaling-up of existing programmes pertaining to access to, and utilisation of maternal and child health care services as well as reduction of the household gap in the economic status. PMID- 28555473 TI - Epidemiological aspects and spatial distribution of human and canine visceral leishmaniasis in an endemic area in northeastern Brazil. AB - Visceral leishmaniasis (VL) is a systemic disease endemic in tropical countries and transmitted through sand flies. In particular, Canis familiaris (or domesticated dogs) are believed to be a major urban reservoir for the parasite causing the disease Leishmania. The average number of human VL cases was 58 per year in the state of Sergipe. The city of Aracaju, capital of Sergipe in Northeastern Brazil, had 159 cases of VL in humans. Correlatively, the percentage of serologically positive dogs for leishmaniasis increased from 4.73% in 2008 to 12.69% in 2014. Thus, these studies aimed to delineate the spatial distribution and epidemiological aspects of human and canine VL as mutually supportive for increased incidence. The number of human cases of VL and the frequency of canine positive serology for VL both increased between 2008 and 2014. Spatial distribution analyses mapped areas of the city with the highest concentration of human and canine VL cases. The neighbourhoods that showed the highest disease frequency were located on the outskirts of the city and in urbanised areas or subjected to development. Exponential increase in VL-positive dogs further suggests that the disease is expanding in urban areas, where it can serve as a reservoir for transmission of dogs to humans via the sand fly vector. PMID- 28555475 TI - Geographic clustering of elderly people with above-norm anthropometric measurements and blood chemistry. AB - The global percentage of people over 60 is strongly increasing and estimated to exceed 20% by 20,150, which means that there will be an increase in many pathological conditions related to aging. Mapping of the location of aging people and identification of their needs can be extremely valuable from a social economic point of view. Participants in this study were 148 randomly selected adults from Talca City, Chile aged 60-74 at baseline. Geographic information systems (GIS) analyses were performed using ArcGIS software through its module Spatial Autocorrelation. In this study, we demonstrated that elderly people show geographic clustering according to above-norm results of anthropometric measurements and blood chemistry. The spatial identifications found would facilitate exploring the impact of treatment programmes in communities where many aging people live, thereby improving their quality of life as well as reducing overall costs. PMID- 28555474 TI - Fine scale mapping of malaria infection clusters by using routinely collected health facility data in urban Dar es Salaam, Tanzania. AB - This study investigated whether passively collected routine health facility data can be used for mapping spatial heterogeneities in malaria transmission at the level of local government housing cluster administrative units in Dar es Salaam, Tanzania. From June 2012 to January 2013, residential locations of patients tested for malaria at a public health facility were traced based on their local leaders' names and geo-referencing the point locations of these leaders' houses. Geographic information systems (GIS) were used to visualise the spatial distribution of malaria infection rates. Spatial scan statistics was deployed to detect spatial clustering of high infection rates. Among 2407 patients tested for malaria, 46.6% (1121) could be traced to their 411 different residential housing clusters. One small spatially aggregated cluster of neighbourhoods with high prevalence was identified. While the home residence housing cluster leader was unambiguously identified for 73.8% (240/325) of malaria-positive patients, only 42.3% (881/2082) of those with negative test results were successfully traced. It was concluded that recording simple points of reference during routine health facility visits can be used for mapping malaria infection burden on very fine geographic scales, potentially offering a feasible approach to rational geographic targeting of malaria control interventions. However, in order to tap the full potential of this approach, it would be necessary to optimise patient tracing success and eliminate biases by blinding personnel to test results. PMID- 28555476 TI - Use of geographical information systems for delimiting health service areas in China. AB - With the objective of choosing a practical and valid method to delimit health service areas of regional health service centres to build a regional basic health service network, we first drew lessons from traditional geographic methods of delimiting trade areas and then applied two methods to delimit health service areas, i.e. the proximal method and the gravity method. We verified the effectiveness of these methods by an index of similarity with the aid of real in patient data. Calculation of the similarity indices shows that health service areas delimited by the proximal method has an 87.3% similarity to the real health service area, while the gravity method gives 88.6%. Our conclusion is that both methods are suitable for delimiting health service areas at regional health service centres, but find that the proximal method is more practicable in operational terms for delimiting health service areas in region health planning. PMID- 28555477 TI - An analysis of the process and results of manual geocode correction. AB - Geocoding is the science and process of assigning geographical coordinates (i.e. latitude, longitude) to a postal address. The quality of the geocode can vary dramatically depending on several variables, including incorrect input address data, missing address components, and spelling mistakes. A dataset with a considerable number of geocoding inaccuracies can potentially result in an imprecise analysis and invalid conclusions. There has been little quantitative analysis of the amount of effort (i.e. time) to perform geocoding correction, and how such correction could improve geocode quality type. This study used a low cost and easy to implement method to improve geocode quality type of an input database (i.e. addresses to be matched) through the processes of manual geocode intervention, and it assessed the amount of effort to manually correct inaccurate geocodes, reported the resulting match rate improvement between the original and the corrected geocodes, and documented the corresponding spatial shift by geocode quality type resulting from the corrections. Findings demonstrated that manual intervention of geocoding resulted in a 90% improvement of geocode quality type, took 42 hours to process, and the spatial shift ranged from 0.02 to 151,368 m. This study provides evidence to inform research teams considering the application of manual geocoding intervention that it is a low-cost and relatively easy process to execute. PMID- 28555478 TI - Comparing the accuracy of food outlet datasets in an urban environment. AB - Studies that investigate the relationship between the retail food environment and health outcomes often use geospatial datasets. Prior studies have identified challenges of using the most common data sources. Retail food environment datasets created through academic-government partnership present an alternative, but their validity (retail existence, type, location) has not been assessed yet. In our study, we used ground-truth data to compare the validity of two datasets, a 2015 commercial dataset (InfoUSA) and data collected from 2012 to 2014 through the Maryland Food Systems Mapping Project (MFSMP), an academic-government partnership, on the retail food environment in two low-income, inner city neighbourhoods in Baltimore City. We compared sensitivity and positive predictive value (PPV) of the commercial and academic-government partnership data to ground truth data for two broad categories of unhealthy food retailers: small food retailers and quick-service restaurants. Ground-truth data was collected in 2015 and analysed in 2016. Compared to the ground-truth data, MFSMP and InfoUSA generally had similar sensitivity that was greater than 85%. MFSMP had higher PPV compared to InfoUSA for both small food retailers (MFSMP: 56.3% vs InfoUSA: 40.7%) and quick-service restaurants (MFSMP: 58.6% vs InfoUSA: 36.4%). We conclude that data from academic-government partnerships like MFSMP might be an attractive alternative option and improvement to relying only on commercial data. Other research institutes or cities might consider efforts to create and maintain such an environmental dataset. Even if these datasets cannot be updated on an annual basis, they are likely more accurate than commercial data. PMID- 28555479 TI - Spatial accessibility to basic public health services in South Sudan. AB - At independence in 2011, South Sudan's health sector was almost non-existent. The first national health strategic plan aimed to achieve an integrated health facility network that would mean that 70% of the population were within 5 km of a health service provider. Publically available data on functioning and closed health facilities, population distribution, road networks, land use and elevation were used to compute the fraction of the population within 1 hour walking distance of the nearest public health facility offering curative services. This metric was summarised for each of the 78 counties in South Sudan and compared with simpler metrics of the proportion of the population within 5 km of a health facility. In 2016, it is estimated that there were 1747 public health facilities, out of which 294 were non-functional in part due to the on-going civil conflict. Access to a service provider was poor with only 25.7% of the population living within one-hour walking time to a facility and 28.6% of the population within 5 km. These metrics, when applied sub-nationally, identified the same high priority, most vulnerable counties. Simple metrics based upon population distribution and location of facilities might be as valuable as more complex models of health access, where attribute data on travel routes are imperfect or incomplete and sparse. Disparities exist in South Sudan among counties and those with the poorest health access should be targeted for priority expansion of clinical services. PMID- 28555480 TI - Assessing effects of structural zeros on models of canine cancer incidence: a case study of the Swiss Canine Cancer Registry. AB - Epidemiological research of canine cancers could inform comparative studies of environmental determinants for a number of human cancers. However, such an approach is currently limited because canine cancer data sources are still few in number and often incomplete. Incompleteness is typically due to under ascertainment of canine cancers. A main reason for this is because dog owners commonly do not seek veterinary care for this diagnosis. Deeper knowledge on under-ascertainment is critical for modelling canine cancer incidence, as an indication of zero incidence might originate from the sole absence of diagnostic examinations within a given sample unit. In the present case study, we investigated effects of such structural zeros on models of canine cancer incidence. In doing so, we contrasted two scenarios for modelling incidence data retrieved from the Swiss Canine Cancer Registry. The first scenario was based on the complete enumeration of incidence data for all Swiss municipal units. The second scenario was based on a filtered sample that systematically discarded structural zeros in those municipal units where no diagnostic examination had been performed. By means of cross-validation, we assessed and contrasted statistical performance and predictive power of the two modelling scenarios. This analytical step allowed us to demonstrate that structural zeros impact on the generalisability of the model of canine cancer incidence, thus challenging future comparative studies of canine and human cancers. The results of this case study show that increased awareness about the effects of structural zeros is critical to epidemiological research. PMID- 28555481 TI - Haemodialysis services in the northeastern region of Iran. AB - Chronic kidney disease is growing and the current estimated global prevalence exceeds 13%. As the use of haemodialysis machines for patients with end stage renal disease increases survival considerably, it is critical to plan correctly for the allocation of these machines. This study aimed to develop a geographical information systems (GIS)-based approach to predict the need for this service in the northeastern region of Iran taking into account where patients live and where haemodialysis is the most needed and identifying areas with poor access to haemodialysis centres. Patients were interviewed to obtain self-reported actual travel time and the inverse distance-weighting algorithm was used to determine access in each area. The prediction is based on the domestic growth rate for haemodialysis services and the estimated active hours of machine use for the next five years. We estimate that six new haemodialysis machines are required in northeastern Iran at the present time with 50 machines required over the next five years. Ashkhane City was identified to have the least access to haemodialysis centres in the study area. Our GIS-based model can be used to investigate not only the need for new haemodialysis machines but also to examine geographic disparities in the allocation of haemodialysis centres and to identify areas most in need of this service. It is important that policymakers consider both spatial and non-spatial dimensions of access to enable better allocation of haemodialysis services ensuring they are targeted to reach those in need. PMID- 28555482 TI - Neonatal mortality in East Africa and West Africa: a geographic analysis of district-level demographic and health survey data. AB - Under-five child mortality declined 47% since 2000 following the implementation of the United Nation's (UN) Millennium Development Goals. To further reduce under five child mortality, the UN's Sustainable Development Goals (SDGs) will focus on interventions to address neonatal mortality, a major contributor of under-five mortality. The African region has the highest neonatal mortality rate (28.0 per 1000 live births), followed by that of the Eastern Mediterranean (26.6) and South East Asia (24.3). This study used the Demographic and Health Survey Birth Recode data (http://dhsprogram.com/data/File-Types-and-Names.cfm) to identify high-risk districts and countries for neonatal mortality in two sub-regions of Africa - East Africa and West Africa. Geographically weighted Poisson regression models were estimated to capture the spatially varying relationships between neonatal mortality and dimensions of potential need i) care around the time of delivery, ii) maternal education, and iii) women's empowerment. In East Africa, neonatal mortality was significantly associated with home births, mothers without an education and mothers whose husbands decided on contraceptive practices, controlling for rural residency. In West Africa, neonatal mortality was also significantly associated with home births, mothers with a primary education and mothers who did not want or plan their last child. Importantly, neonatal mortality associated with home deliveries were explained by maternal exposure to unprotected water sources in East Africa and older maternal age and female sex of infants in West Africa. Future SDG-interventions may target these dimensions of need in priority high-risk districts and countries, to further reduce the burden of neonatal mortality in Africa. PMID- 28555483 TI - Point process methods in epidemiology: application to the analysis of human immunodeficiency virus/acquired immunodeficiency syndrome mortality in urban areas. AB - The analysis of spatio-temporal patterns of disease or death in urban areas has been developed mainly from the ecological studies approach. These designs may have some limitations like the ecological fallacy and instability with few cases. The objective of this study was to apply the point process methodology, as a complement to that of aggregated data, to study HIV/AIDS mortality in men in the city of Alicante (Spain). A case-control study in residents in the city during the period 2004-2011 was designed. Cases were men who died from HIV/AIDS and controls represented the general population, matched by age to cases. The risk surfaces of death over the city were estimated using the log-risk function of intensities, and we contrasted their temporal variations over the two periods. High risk significant areas of death by HIV/AIDS, which coincide with the most deprived areas in the city, were detected. Significant spatial change of the areas at risk between the periods studied was not detected. The point process methodology is a useful tool to analyse the patterns of death by HIV/AIDS in urban areas. PMID- 28555484 TI - Spatial analysis of the regional variation of reproductive tract infections and spousal migration correlates in Nepal. AB - Nepal has a diverse geographic landscape that could potentially create clustered subpopulations with regional socio-cultures that could result in differential health outcomes. With an alarming rise in married male populations migrating for work, it is possible that these migrants are engaged in risky sexual behaviour, putting their wives at risk for infectious disease outcomes, including reproductive tract infections (RTI), when they return home. The prevalence of male migration varies by geographic region in Nepal and this variation could potentially contribute to different RTI rates. Using a cross-sectional dataset (the 2011 Nepal Demographic and Health Survey) including 9607 married women, we investigated geospatial and socio-cultural factors associated with the symptoms of RTIs with a focus on the husbands' migration status. Choropleth maps were created to illustrate areas with high percentages of RTIs that correlated with migration patterns. Overall, 31.9% of the husbands were migrating for work. After adjusting for wealth, contraception use, age at first marriage, urban/rural status and husband's education, women whose husbands had been absent for a year or more in Nepal's Mid-West region (OR 1.93 95%, CI 1.02-3.67) or Far-West region (OR 2.89 95%, CI 1.24-6.73) were more likely to report RTI-like symptoms than others. Our results suggest a potential association between husbands' migration status and Nepali women reporting RTI symptoms by geographic regions. However, further research is needed to put this outcome on a stronger footing with respect to this under-studied population, specifically in the context of geographical variation. PMID- 28555485 TI - Cystic echinococcosis in cattle dairy farms: spatial distribution and epidemiological dynamics. AB - A study monitoring cystic echinococcosis (CE) in adult dairy cattle from intensive livestock farms located in the municipality of Arborea (Sardinia, Italy) was carried out between 2012 and 2015. A retrospective study of veterinary reporting forms of post-mortem inspections in 10 different Italian slaughterhouses was also performed. In addition, data on viability and molecular characterisation of hydatid cysts removed from parasitised organs in cattle was carried out. A geographical information system (GIS) with data layers of the study area and the geo-referenced points of 160 cattle farms was constructed. CE was found in 21.9% (35/160) of the surveyed farms. The retrospective study revealed that 0.05% (13/23,656) of adult slaughtered animals (over one year of age) from Arborea had tested positive to CE. The results stratified per year showed the following CE prevalences: 0.09% (5/5673) in 2012; 0.02% (1/5682) in 2013; 0.08% (5/6261) in 2014; and 0.03% (2/6040) in 2015 (chi2 with 3 degrees of freedom=3.81; P=0.282). The E. granulosus sensu stricto (formerly called G1 or sheep strain) was detected in all cysts subjected to molecular analysis. The GIS analysis showed that CE is fairly resilient in the Arborea territory where most of cattle farms are located, while a small cluster of cases was found located in the southeastern part of Arborea, close to districts where sheep farms are situated. The present survey reports the presence of CE in Sardinian dairy cattle intensive farms and suggests that the parasitic pressure of CE in the island continues to be very strong. PMID- 28555486 TI - Topically-administered acetyl-L-carnitine increases sciatic nerve regeneration and improves functional recovery after tubulization of transected short nerve gaps. AB - BACKGROUND: Peripheral nerve injuries repair is still among the most challenging and concern-raising tasks in neurosurgery. The effect of an acetyl-L-carnitin loaded silicone tube as an in-situ delivery system in defects bridging was studied using a rat sciatic nerve regeneration model. METHODS: A 10-mm sciatic nerve defect was bridged using a silicone tube (SIL/ALC) filled with 10 uL acetyl L-carnitine (100 ng/mL). In the control group (SIL), the tube was filled with the same volume of the phosphate-buffered solution. The regenerated fibers were studied 4, 8, 12 and 16 weeks after surgery. RESULTS: The functional study confirmed faster recovery of the regenerated axons in acetyl-L-carnitine treated than control group (P<0.05). The mean ratios of gastrocnemius muscles weight were measured. There was a statistically significant difference between the muscle weight ratios of SIL/ALC and SIL groups (P<0.05). Morphometric indices of regenerated fibers showed that the number and diameter of the myelinated fibers in SIL/ALC were significantly higher than in the control group. In immuohistochemistry, the location of reactions to S-100 in the SIL/ALC group was clearly more positive than in the SIL group. CONCLUSIONS: Acetyl-L-carnitine, when loaded in a silicone tube, can bring to an improvement in functional recovery and quantitative morphometric indices of sciatic nerve. PMID- 28555487 TI - Is stereotactic radiosurgery a treatment option for intracranial solitary fibrous tumors? PMID- 28555488 TI - The unusual subarachnoid hemorrhage presentation by a "sentinel" isolated trochlear nerve palsy of a posterior communicating artery aneurysm. PMID- 28555489 TI - Pin-point selection of recipient MCA at M4 for STA-MCA bypass using micro-Doppler ultrasonography. PMID- 28555490 TI - Spinal cord anaplastic ependymoma induced by radiation treatment of breast cancer. PMID- 28555491 TI - Insular intracranial hemangiopericytoma in a child. PMID- 28555492 TI - Equilibrium Isotherm, Kinetic Modeling, Optimization, and Characterization Studies of Cadmium Adsorption by Surface-Engineered Escherichia coli AB - Background: Amongst the methods that remove heavy metals from environment, biosorption approaches have received increased attention because of their environmentally friendly and cost-effective feature, as well as their superior performances. Methods: In the present study, we investigated the ability of a surface-engineered Escherichia coli, carrying the cyanobacterial metallothionein on the cell surface, in the removal of Ca (II) from solution under different experimental conditions. The biosorption process was optimized using central composite design. In parallel, the kinetics of metal biosorption was studied, and the rate constants of different kinetic models were calculated. Results: Cadmium biosorption is followed by the second-order kinetics. Freundlich and Langmuir equations were used to analyze sorption data; characteristic parameters were determined for each adsorption isotherm. The biosorption process was optimized using the central composite design. The optimal cadmium sorption capacity (284.69 nmol/mg biomass) was obtained at 40 degrees C (pH 8) and a biomass dosage of 10 mg. The influence of two elutants, EDTA and CaCl2, was also assessed on metal recovery. Approximately, 68.58% and 56.54% of the adsorbed cadmium were removed by EDTA and CaCl2 during desorption, respectively. The Fourier transform infrared spectrophotometer (FTIR) analysis indicated that carboxyl, amino, phosphoryl, thiol, and hydroxyl are the main chemical groups involved in the cadmium bioadsorption process. Conclusion: Results from this study implied that chemical adsorption on the heterogeneous surface of E. coli E and optimization of adsorption parameters provides a highly efficient bioadsorbent. PMID- 28555493 TI - Feedstocks to Pharmacophores: Cu-Catalyzed Oxidative Arylation of Inexpensive Alkylarenes Enabling Direct Access to Diarylalkanes. AB - A Cu-catalyzed method has been identified for selective oxidative arylation of benzylic C-H bonds with arylboronic esters. The resulting 1,1-diarylalkanes are accessed directly from inexpensive alkylarenes containing primary and secondary benzylic C-H bonds, such as toluene or ethylbenzene. All catalyst components are commercially available at low cost, and the arylboronic esters are either commercially available or easily accessible from the commercially available boronic acids. The potential utility of these methods in medicinal chemistry applications is highlighted. PMID- 28555494 TI - Self-Template Synthesis of Ag-Pt Hollow Nanospheres as Electrocatalyst for Methanol Oxidation Reaction. AB - Ag-Pt bimetallic hollow nanospheres have been prepared through a one-pot, wet chemical route. The formation of the hollow nanostructure can be explained by a self-template mechanism in which initially formed silver nanoparticles serve as the template. The Ag-Pt hollow nanospheres with an Ag/Pt ratio of 0.89:1 show the best electrochemical catalytic performances in the methanol oxidation reaction. Furthermore, the catalytic activity of the Ag-Pt hollow nanospheres is also much better than that of commercial Pt/C catalyst. The superior electrochemical performance of the Ag-Pt hollow nanospheres can be ascribed to the hollow nanostructure and the synergistic effect of Ag and Pt. PMID- 28555495 TI - Capping of Mn-Doped ZnS Quantum Dots with DHLA for Their Stabilization in Aqueous Media: Determination of the Nanoparticle Number Concentration and Surface Ligand Density. AB - Colloidal Mn2+-doped ZnS quantum dots (QDs) were synthesized, surface modified, and thoroughly characterized using a pool of complementary techniques. Cap exchange of the native l-cysteine coating of the QDs with dihydrolipoic acid (DHLA) ligands is proposed as a strategy to produce nanocrystals with a strong phosphorescent-type emission and improved aqueous stability. Moreover, such a stable DHLA coating can facilitate further bioconjugation of these QDs to biomolecules using established reagents such as cross-linker molecules. First, a structural and morphological characterization of the l-cysteine QD core was performed by resorting to complementary techniques, including X-ray powder diffraction (XRD) and microscopy tools. XRD patterns provided information about the local structure of ions within the nanocrystal structure and the number of metal atoms constituting the core of a QD. The judicious combination of the data obtained from these complementary characterization tools with the analysis of the QDs using inductively coupled plasma-mass spectrometry (ICP-MS) allowed us to assess the number concentration of nanoparticles in an aqueous sample, a key parameter when such materials are going to be used in bioanalytical or toxicological studies. Asymmetric flow field-flow fractionation (AF4) coupled online to ICP-MS detection proved to be an invaluable tool to compute the number of DHLA molecules attached to the surface of a single QD, a key feature that is difficult to estimate in nanoparticles and that critically affects the behavior of nanoparticles when entering the biological media (e.g., cellular uptake, biodistribution, or protein corona formation). This hybrid technique also allowed us to demonstrate that the elemental composition of the nanoparticle core remains unaffected after the ligand exchange process. Finally, the photostability and robustness of the DHLA-capped QDs, critical parameters for bioanalytical applications, were assessed by molecular luminescence spectroscopy. PMID- 28555496 TI - Synthesis of Core-Shell Structured Porous Nitrogen-Doped Carbon@Silica Material via a Sol-Gel Method. AB - Core-shell structured nitrogen-doped porous carbon@silica material with uniform structure and morphology was synthesized via a sol-gel method. During this process, a commercial triblock copolymer and the in situ formed pyrrole formaldehyde polymer acted as cotemplates, while tetraethyl orthosilicate acted as silica precursor. The synergetic effect of the triblock copolymer and the pyrrole-formaldehyde polymer enables the formation of the core-shell structure. Herein, the pyrrole-formaldehyde polymer acted as not only the template, but also the nitrogen-doped carbon precursor of the core. The obtained core-shell structured porous material possesses moderate Brunauer-Emmett-Teller specific surface area (410 m2 g-1) and pore volume (0.53 cm3 g-1). Moreover, corresponding hollow silica spheres or nitrogen-doped porous carbon spheres can be synthesized by calcining the core-shell structured material in air or etching it with HF. The X-ray photoelectron spectroscopy results reveal that the nitrogen states of the obtained material are mainly pyridinic-N and pyridonic-N/pyrrolic-N, which are beneficial for carbon dioxide adsorption. The carbon dioxide uptake capacity of the nitrogen-doped carbon spheres can reach 12.3 wt % at 273 K and 1.0 bar, meanwhile, the material shows good gas adsorption selectivities for CO2/CH4 and CO2/N2. PMID- 28555498 TI - Integrated Surface-Enhanced Raman Spectroscopy (SERS) Chip Based on a Total Reflection Liquid Core Waveguide. AB - This study proposes a surface-enhanced Raman scattering (SERS) chip integrated with a liquid core waveguide. Due to the total reflection, the chip suppresses the leaky waveguide mode and enables a long propagation distance for SERS signal collection. A 10 nM rhodamine 6G Raman signal was obtained using a QE65000 portable microspectrometer at a low excitation power intensity of 14.5 W/cm2. The proposed SERS chip was also used to detect the SERS spectrum of a silkworm DNA solution, the structural information of which was clearly shown. In addition, due to the lower excitation power density, damage to the structure of the biomolecule was avoided. PMID- 28555499 TI - Dangerous sadness: nervoza among first and second generation Macedonian immigrants to Australia. AB - OBJECTIVE: Nervoza is a commonly-used illness category among Macedonian Australians. Although nervoza belongs broadly to the category of 'nerve illnesses' little is known of its meaning among Macedonian immigrants, and whether there is intergenerational attrition in its meaning and use. We aimed to explore how nervoza and its treatment are perceived by members of the Macedonian community in Australia. DESIGN: In-depth interviews in Macedonian with 18 participants from the Macedonian community in Melbourne, Australia. RESULTS: Nervoza is a layered concept relating shame, emotional experience and nerves, used as an idiom of distress and sadness in the presence of acute and chronic stressors. Nervoza develops in both the social world (through poverty, grief or the loss of war), and in the psyche of distressed and isolated people. It is viewed as dangerous on many levels: to physical health, as a 'gateway condition' to long-term psychological illnesses such as depression and schizophrenia, and to the person's social well-being. The normalised treatment for nervoza in Macedonia - benzodiazepines - is the subject of significant medical control in Australia. CONCLUSION: For sufferers of nervoza, the social self is both medicalized and stigmatised. Health services in Australia are often considered marginal in the management of nervoza. Second generation Macedonians viewed the concept as unhelpful, and possibly increasing the stigmatisation of mental illnesses. The lack of knowledge about, and underutilisation of, mental health services and support groups in the Macedonian Australian community should be the focus of community-based inter-generational health literacy initiatives. PMID- 28555497 TI - LdtMav2, a nonclassical transpeptidase and susceptibility of Mycobacterium avium to carbapenems. AB - AIM: Mycobacterium avium infections, especially in immune-compromised individuals, present a significant challenge as therapeutic options are limited. In this study, we investigated if M. avium genome encodes nonclassical transpeptidases and if newer carbapenems are effective against this mycobacteria. MATERIALS & METHODS: Biochemical and microbiological approaches were used to identify and characterize a nonclassical transpeptidase, namely L,D transpeptidase, in M. avium. RESULTS & CONCLUSION: We describe the biochemical and physiological attributes of a L,D-transpeptidase in M. avium, LdtMav2. Suggestive of a constitutive requirement, levels of LdtMav2, a L,D-transpeptidase in M. avium, remain constant during exponential and stationary phases of growth. Among beta-lactam antibacterials, only a subset of carbapenems inhibit LdtMav2 and tebipenem, a new oral carbapenem, inhibits growth of M. avium. PMID- 28555500 TI - Updates on the diagnosis and treatment of prostate cancer. AB - Prostate cancer is the second most prevalent cancer in males worldwide and the commonest cancer in males in the UK. The recent updates on the diagnosis and treatment of prostate cancer were discussed at a multidisciplinary day event organized by the British Institute of Radiology and held in London in November 2016. This day covered the use of the prostate-specific antigen biomarker and of advanced imaging techniques such as multiparametric and whole-body MRI, choline positron emission tomography/CT and gallium-labelled prostate-specific membrane antigen for the detection of prostate cancer. In addition, the results of several trials assessing the management of the disease were discussed, in particular the Prostate Cancer Intervention Versus Observation Trial and Prostate Testing for Cancer and Treatment trials which evaluated the gain of intervention vs observation, and four randomized controlled trials comparing hypofractionated and standard radiotherapy regimen. Further to this event, this commentary highlights the topical issues relating to recently published guidelines and to trials for the management of prostate cancer where these were discussed. PMID- 28555501 TI - Genomic diversity and immunomodulatory activity of Lactobacillus plantarum isolated from dairy products. AB - In this study, we aimed to investigate some functional characteristics and the immunomodulatory properties of three strains of Lactobacillus plantarum of dairy origin which, in a previous screening, showed to be candidate probiotics. Genome sequencing and comparative genomics, which confirmed the presence of genes involved in folate and riboflavin production and in the immune response of dendritic cells (DCs), prompted us to investigate the ability of the three strains to accumulate the two vitamins and their immunomodulation properties. The ability of the three strains to release antioxidant components in milk was also investigated. Small amounts of folate and riboflavin were produced by the three strains, while they showed a good antioxidant capacity in milk with FRAP method. The immune response experiments well correlated with the presence of candidate genes influencing in DCs cytokine response to L. plantarum. Specifically, the amounts of secreted cytokins by DCs after stimulation with cells of Lp790, Lp813 and Lp998 resulted pro-inflammatory whereas stimulation with culture supernatants (postbiotics) inhibited the release of interleukin (IL)-12p70 and increased the release of the anti-inflammatory IL-10 cytokine. This study adds further evidence on the importance of L. plantarum in human health. Understanding how probiotics (or postbiotics) work in preclinical models can allow a rational choice of the different strains for clinical and/or commercial use. PMID- 28555502 TI - Safety and tolerance of three probiotic strains in healthy infants: a multi centre randomized, double-blind, placebo-controlled trial. AB - Some strains of species belonging to the genera Bifidobacterium and Lactobacillus are used in order to maintain health. Although these organisms have a long record of safe use, it is important to assess their safety and tolerance in potentially vulnerable populations, such as infants. The objective of this study was to evaluate the safety and tolerance of three probiotic strains (Bifidobacterium longum subsp. infantis R0033, Bifidobacterium bifidum R0071 and Lactobacillus helveticus R0052) in healthy infants aged 3 to 12 months. A multi-centre randomized, double-blind, placebo-controlled intervention study with 221 healthy full-term infants was conducted. Infants received either a placebo or one of the 3 probiotic strains (3*109 cfu) daily during an 8 week intervention period. Growth (weight, height and head circumference), adverse events (AEs)/serious adverse events (SAEs), concentrations of D-lactic acid in urine samples, characteristics of the stools and use of medication were collected for safety evaluation. All 4 groups were homogeneous with respect to age, gender, feeding type, ethnicity, height, weight and head circumference at the start of the study. The results showed that changes in growth (weight, height and head circumference) were equivalent in all 4 groups. No SAEs were reported. Total number of AEs recorded was equivalent in all groups. Thus, the use of B. infantis R0033, L. helveticus R0052 and B. bifidum R0071 in infancy is safe, and well tolerated. PMID- 28555503 TI - Spontaneous isolated dissection and atherosclerotic plaques of superior mesenteric artery: the vastly different occurrence site suggests the opposite haemodynamic aetiology. AB - OBJECTIVE: The development of atherosclerotic plaques and spontaneous isolated dissection (SID) of the superior mesenteric artery (SMA) was considered to be related to opposite haemodynamics. The purpose of this study was to compare their occurrence sites and the morphology of the SMA to confirm the haemodynamic aetiologies. METHODS: 57 patients with SID and 64 patients with atherosclerotic plaques were compared about patient characteristics, location of SID and plaque, the distance from lesion to the aortic ostia, SMA branching angle and inlet diameter of the SMA. RESULTS: The location of SID and plaque was very different (p < 0.001). The anterior wall was the most common entry site of SIDSMA (84.0%) but the least frequent origin site of atherosclerotic plaques (7.8%). The posterior, left and right walls were the frequent origin sites of atherosclerotic plaques (total 92.2%) but not for SIDSMA. Most plaques started from the aortic ostia, and their average distance to the aortic ostia was significantly less than the distance from the entry site to the aortic ostia of SIDSMA (p < 0.001). No significant difference was found between SIDSMA and the plaque groups in the branching angle and inlet diameter of the SMA. CONCLUSION: The vastly different sites of SIDSMA and atherosclerotic plaque indicate their opposite haemodynamic aetiology. Advances in knowledge: By comparing the location of the two diseases, we demonstrate their different haemodynamic causes. PMID- 28555504 TI - Prevalence and incidence of noncystic fibrosis bronchiectasis among US adults in 2013. AB - Bronchiectasis is an incurable pulmonary disorder that is characterized pathologically by permanent bronchial dilatation and severe bronchial inflammation and clinically by chronic productive cough and recurrent infectious exacerbations; bronchiectasis often occurs in the presence of chronic obstructive pulmonary disease. It is widely believed that increasing use of high-resolution computed tomography has led to a marked rise in the number of persons with diagnosed bronchiectasis in current US clinical practice; up-to-date evidence, however, is lacking. Using a retrospective cohort design and health-care claims data (2009-2013), we estimated the prevalence of bronchiectasis (noncystic fibrosis)-based on narrow case-finding criteria-to be 139 cases per 100,000 persons, to be higher among women versus men (180 vs. 95 per 100 K), and to increase substantially with age (from 7 per 100 K to 812 per 100 K aged 18-34 years and >=75 years, respectively); annual incidence was estimated to be 29 cases per 100,000 persons. Disease prevalence based on broad case-finding criteria was estimated to be 213 cases per 100,000 persons. The findings of this study suggest that between 340,000 and 522,000 adults were receiving treatment for bronchiectasis and that 70,000 adults were newly diagnosed with bronchiectasis, in 2013 US clinical practice. The findings of this study also suggest that bronchiectasis is much more common than previously reported (annual growth rate since 2001, 8%), presumably due-at least in part-to recent advances in, and increased use of, radiologic techniques. Additional research is needed to validate the findings of this study, to identify the reasons for increased prevalence, and to promote education about bronchiectasis nationally. PMID- 28555505 TI - Comparison of dose distribution for head and neck cancer patients with and without dose painting escalation during radiotherapy realized with tomotherapy unit. AB - OBJECTIVE: To determine and quantify the percentage dose increase to organs at risk (OARs) with multiple-level dose painting (DP) for patients with head and neck cancer in comparison with standard regimen. METHODS: 12 patients who had undergone fluorine-18 fludeoxyglucose (18F-FDG) positron emission tomography (PET)/CT scan were retrospectively enrolled. Two treatment plans-one using DP escalation and one without-were optimized for each patient base on PET/CT data. The following variables were assessed: dose to OARs and target volumes; execution time; equivalent uniform dose; and normal tissue complication probability. RESULTS: No statistically significant differences in beam-on time were observed between plans with and without DP. However, significantly higher doses were observed for all DP-escalated plans in the OARs, with only two exceptions: the brain stem and V60Gy for the mandible. Multiple-level DP resulted in dose increases ranging from 3.0% to 12.9%, depending on the OAR. The largest increase was seen for the parotid glands and the smallest for the mandible. Significant differences in the equivalent uniform dose were observed only for the parotid glands and spinal column, where the dose without DP was lower. The normal tissue complication probability for most OARs was very small. CONCLUSION: Importantly, even though DP escalation resulted in higher doses to OARs vs conventional treatment planning, these usually did not exceed the dose tolerance levels. However, clinical trials are necessary to confirm the benefits of DP and to guarantee no additional toxicity. Advances in knowledge: Multiple-level DP by numbers resulted in 3.0-12.9% dose increase, depending on the OAR. Our findings may suggest that DP escalation to very high doses is feasible for about 83% of patients without higher toxicity; however, it still should be confirmed on a larger group of patients. PMID- 28555507 TI - Performance Measurement and Target-Setting in California's Safety Net Health Systems. AB - Health policies encourage implementing quality measurement with performance targets. The 2010-2015 California Medicaid waiver mandated quality measurement and reporting. In 2013, California safety net hospitals participating in the waiver set a voluntary performance target (the 90th percentile for Medicare preferred provider organization plans) for mammography screening and cholesterol control in diabetes. They did not reach the target, and the difference-in differences analysis suggested that there was no difference for mammography ( P = .39) and low-density lipoprotein control ( P = .11) performance compared to measures for which no statewide quality improvement initiative existed. California's Medicaid waiver was associated with improved performance on a number of metrics, but this performance was not attributable to target setting on specific health conditions. Performance may have improved because of secular trends or systems improvements related to waiver funding. Relying on condition specific targets to measure performance may underestimate improvements and disadvantage certain health systems. Achieving ambitious targets likely requires sustained fiscal, management, and workforce investments. PMID- 28555506 TI - Capability of CBCT to identify patients with low bone mineral density: a systematic review. AB - The aim of this study was to systematically review the literature about the capability of CBCT images to identify individuals with low bone mineral density (BMD). As the literature is scarce regarding this topic, the purpose of this systematic review is also to guide future research in this area. A detailed search was performed in five databases without restrictions of time or languages. Additionally, a grey literature search was conducted. The Quality Assessment Tool for Diagnostic Accuracy Studies-2 was applied to evaluate the methodological design of selected studies. With the inclusion of only six studies, the evidence is limited to endorse the use of CBCT assertively as a diagnostic tool for low BMD. All of the three studies that analyzed radiomorphometric indices found that the linear measurements of the mandibular inferior cortex were lower in osteoporotic individuals. CBCT-derived radiographic density vertebral and mandibular measurements were also capable for differentiating individuals with osteoporosis from individuals with normal BMD. The analysis of the cervical vertebrae showed high accuracy measurements. This systematic review indicates a scarcity of studies regarding the potential of CBCT for screening individuals with low BMD. However, the studies indicate that radiomorphometric indices and CBCT-derived radiographic density should be promising tools for differentiating individuals with osteoporosis from individuals with normal BMD. PMID- 28555510 TI - Perioperative blood glucose concentrations in kittens following overnight fasting and gonadectomy. AB - Objectives The objective of this study was to determine if hypoglycemia is an effect of overnight fasting and gonadectomy in kittens, as well as to determine predictors of baseline and postoperative blood glucose. Methods This was a prospective observational study. Seventy-five kittens between the age of 8 and 16 weeks undergoing routine castration or ovariohysterectomy at an animal shelter were included. Two blood glucose measurements were analyzed per kitten after an overnight fast: a baseline reading prior to preoperative examination, and a reading immediately postoperatively. Predictors of the baseline and postoperative blood glucose levels were determined using multi-level mixed-effects linear regression. Results Kittens, when fasted overnight, were not hypoglycemic (<60 mg/dl). No kittens exhibited clinical signs consistent with hypoglycemia. No kittens had a blood glucose <70 mg/dl postoperatively. Postoperative hyperglycemia (>150 mg/dl) was observed in 44% of kittens. The only predictor of fasted blood glucose levels was body condition score. The only predictor of postoperative blood glucose levels was the fasting blood glucose value. Conclusions and relevance Overnight fasting prior to elective sterilization in 8- to 16-week-old kittens did not result in hypoglycemia. Concern regarding hypoglycemia after a prolonged fast in kittens may be unwarranted for short procedures in healthy animals. PMID- 28555508 TI - Iterative reconstruction in single-source dual-energy CT angiography: feasibility of low and ultra-low volume contrast medium protocols. AB - OBJECTIVE: To evaluate the feasibility of using contrast medium (CM) of low and ultra-low volumes and injection rates in aortic CT angiography (CTA) through the joint application of single-source dual-energy CT (ssDECT) and adaptive statistical iterative reconstruction (ASIR). METHODS: 120 patients with known or suspected aortic dissection underwent aortic CTA and were equally divided into 3 groups. Conventional 120-kVp scan with a CM volume of 70 ml and an injection rate of 5 ml s-1 was performed on Group A. Groups B and C underwent ssDECT scan with CM volumes of 0.6 and 0.4 ml kg-1, respectively. 40% and 50% ASIR algorithms were applied for Groups B and C, respectively. A five-point grading scheme was utilized to subjectively evaluate the image quality, and the CT value and contrast-to-noise ratio were recorded as objective measures. The radiation dose was also evaluated. RESULTS: Groups B and C had equivalent subjective scores and CT values as Group A, whereas they had higher or equivalent contrast-to-noise ratios. Group B had 40.1% and 30% reductions on CM volume and injection rate, respectively, than Group A. Group C further resulted in 19.2% and 22% lesser CM volume and injection rate than Group B. The average effective radiation doses for the study groups were 22.5-24.5% lower than the control group. CONCLUSION: With the aid of ASIR and ssDECT for aortic CTA, it is feasible to adopt low and ultra low CM volumes and injection rates while obtaining good quality images. Advances in knowledge: Low and ultra-low CM volumes and injection rates are feasible in CTA through the joint application of ssDECT and ASIR. PMID- 28555509 TI - Inhibitory effects of propofol on Th17 cell differentiation. AB - Propofol (2,6-diisopropylphenol) is probably the most widely used intravenous anesthetic agent in daily practice. It has been reported to show immunomodulatory activity. However, the effect of propofol on the differention of T cells remains unclear. In this study, we demonstrated for the first time that propofol inhibited both interleukin (IL)-6 plus transforming growth factor-beta (TGF-beta) induced Th17 cell differentiation in vitro and in LPS-challenged mice. Propofol also suppressed the IL-6-induced phosphorylation of Janus kinase-2 (JAK2)/signal transducer and activator of transcription (STAT3) pathway, a cytokine-activated essential transcription factor in Th17 cell development, which occurred concomitantly with the enhancement of suppressor of cytokine signaling-3 (SOCS3) expression involved in the downregulation of STAT3 phosphorylation. These data extend our knowledge of the immunosuppressive effects of propofol and their underlying mechanism. PMID- 28555511 TI - Mitigation of inflammation using the intravenous anesthetic dexmedetomidine in the mouse air pouch model. AB - Dexmedetomidine, an alpha2-adrenergic/imidazoline receptor agonist, is a widely used intravenous anesthetic. Its primary current usage is for sedation of patients in the intensive care unit. The mouse air pouch model is versatile in studying the anti-inflammatory effect of a drug on a local inflammation, which is induced by a variety of substances. In the present study, using the carrageenan induced air pouch inflammation model, we tested whether dexmedetomidine mitigates inflammation occurring locally in the mouse air pouch. We found that dexmedetomidine dose-dependently inhibited the production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in the pouch and decreased the number of white blood cells (WBC) recruited into the pouch. Dexmedetomidine also dose dependently inhibited the production of neutrophil chemokines, cxcl1 and cxcl2. Furthermore, the dexmedetomidine-induced decreased recruitment of WBC into the pouch was successfully reversed with intra-pouch administration of cxcl1/cxcl2, but not TNF-alpha or IL-6. Lastly, the inhibition of the production of the cytokines and chemokines with dexmedetomidine was reversed by the treatment of yohimbine, suggesting that dexmedetomidine's anti-inflammatory effect is primarily via the stimulation of the alpha2-adrenergic receptor. We conclude that dexmedetomidine has an anti-inflammatory property in the carrageenan-induced mouse air pouch inflammation model, and that the dexmedetomidine-induced inhibition of production of the neutrophil chemokines, cxcl1 and cxcl2, may be related, at least in part, to the inhibition of WBC intra-pouch recruitment. PMID- 28555512 TI - The use of neuropsychological tests to assess intelligence. AB - OBJECTIVE: We sought to derive a 'neuropsychological intelligence quotient' (NIQ) to replace IQ testing in some routine assessments. METHOD: We administered neuropsychological testing and a seven-subtest short form of the Wechsler Adult Intelligence Scale to a community sample of 394 adults aged 18-96 years. We regressed Wechsler Full Scale IQs (W-FSIQ) on 23 neuropsychological scores and derived an NIQ from 9 measures that explained significant variance in W-FSIQ. We then compared subgroups of 284 healthy and 108 unhealthy participants in NIQ and W-FSIQ to assess criterion validity, correlated NIQ and W-FSIQ scores with education level and independence for activities of daily living to assess convergent validity, and compared validity coefficients for the NIQ with those of 'hold' and 'no-hold' indices. RESULTS: By design, NIQ and W-FSIQ scores correlated highly (r = .84), and both were higher in healthy participants. The difference was larger for NIQ, which accounted for more variability in activities of daily living. The NIQ and 'no-hold' index were better predicted by health status and less predicted by educational status than the 'hold' index. CONCLUSIONS: We constructed an NIQ that correlates highly with Wechsler FSIQ. Tests required to obtain NIQ are commonly used and can be administered in about 45 min. Validity properties of NIQ and W-FSIQ are similar. The NIQ bore greater resemblance to a 'no-hold' than 'hold' index. One can obtain a reasonably accurate estimate of current Full Scale IQ without formal intelligence testing from a brief neuropsychological battery. PMID- 28555514 TI - Transition Phase Nutrition Recommendations: A Missing Link in the Nutrition Management of Preterm Infants AB - BACKGROUND: Despite the availability of international nutrition recommendations, preterm infants remain vulnerable to suboptimal nutrition. The standard approach of assessing nutrient intakes chronologically may make it difficult to identify the origin of nutrient deficits and/or excesses. OBJECTIVE: To develop a "nutrition phase" approach to evaluating nutrition support, enabling analysis of nutrient intakes during the period of weaning from parenteral nutrition (PN) to enteral nutrition (EN), called the transition (TN) phase, and compare the data with those analyzed using the standard "chronological age" approach to assess whether the identification of nutrient deficits and/or excesses can be improved. METHODS: Analysis of a comprehensive nutrition database developed using actual nutrient intake data collected on an hourly basis in 59 preterm infants (birth weight <=1500 g, gestation <34 weeks) over the period of PN delivery (range, 2-21 days). RESULTS: The nutrition phase analysis approach revealed substantial macronutrient and energy deficits during the TN phase. In particular, deficits were identified as maximal during the EN-dominant TN phase (enteral feeds >=80 mL/kg/d) of the infant's nutrition course. In contrast, the chronological age analysis approach did not reveal a corresponding pattern of deficit occurrence but rather intakes that approximated or exceeded recommendations. CONCLUSION: Actual intakes of nutrients, analyzed using a nutrition phase approach to evaluating nutrition support, enabled a more infant-driven rather than age-driven application of nutrition recommendations. This approach unmasked nutrient deficits occurring during the transition phase. Overcoming nutrient deficits in this nutrition phase should be prioritized to improve the nutrition management of preterm infants. PMID- 28555515 TI - Chronic Illnesses and Depressive Symptoms Among Older People: Functional Limitations as a Mediator and Self-Perceptions of Aging as a Moderator. AB - OBJECTIVE: This research examined the mediation of functional limitations in the relationship between chronic illnesses and depressive symptoms among older Americans along with tests for the moderation of self-perceptions of aging. METHOD: Data from the Health and Retirement Study (2008, 2010, and 2012) were used. Longitudinal mediation models were tested using a sample of 3,382 Americans who responded to psychosocial questions and were over 65 years old in 2008. RESULTS: Functional limitations mediated the linkage between chronic illnesses and depressive symptoms. Negative self-perceptions of aging exacerbated the effects of chronic illnesses on depressive symptoms. DISCUSSION: Health care professionals should be aware of depressive symptoms in older adults reporting chronic illnesses and particularly in those reporting functional limitations. To decrease the risk of depressive symptoms caused by chronic illnesses, negative self-perceptions of aging may need to be challenged. PMID- 28555513 TI - High-mobility group box protein 1 expression in inflammatory diseases of the middle ear. AB - High-mobility group box 1 (HMGB1) is a nuclear non-histone protein, playing a critical role as a mediator between innate and acquired immunity; when released extracellularly, it coordinates the cellular stress response (under necrosis, bacterial lipopolysaccharide stimulation) and acts as an inflammatory marker and cytokine. The aim of the study was to demonstrate whether HMGB1 is over-expressed in chronic middle-ear pathologies and whether the entity of expression and the localization are correlated with the degree of the inflammatory reaction, thus suggesting that HMGB1 may play a crucial role in chronic inflammatory disorders of the middle ear, as already demonstrated in other airway diseases. We analyzed 30 samples of middle-ear mucosa in patients affected by chronic suppurative otitis media with ear drum perforation with/without cholesteatoma and otosclerosis as control. The distribution of HMGB1 was evaluated as nuclear, cytoplasmic, and/or extracellular staining. The inflammatory cells observed in the biopsies were mostly lymphocytes and plasmacells. A statistically significant difference in inflammation score between otosclerosis and chronic otitis samples ( P < 0.01; Anova test) and between otosclerosis and cholesteatoma samples ( P < 0.05; Anova test) was observed; the HMGB1 positivity was in accordance with the density of the inflammatory infiltrate. HMGB1 is over-expressed in chronic middle ear pathologies and may play a role in the progression of the inflammatory process from recurrent acute otitis media to chronic suppurative otitis media. PMID- 28555516 TI - Clinical utility of the Rey 15-Item Test, recognition trial, and error scores for detecting noncredible neuropsychological performance in a mixed clinical sample of veterans. AB - OBJECTIVE: This cross-sectional study examined the Rey 15-Item Test (RFIT), Recognition Trial, and Error Scores for identifying noncredible performance in a mixed clinical veteran sample compared to another widely used validity measure, the Test of Memory Malingering (TOMM). METHOD: Sixty-two veterans who completed the RFIT (Recall/Recognition Trials), TOMM, and Word Memory Test (WMT) during clinical evaluation were included. Using the WMT as the criterion, 71% (N = 44) were classified as valid and 29% (N = 18) as invalid. RESULTS: Among valid participants, 25% failed the RFIT Recall, whereas 78% of invalid participants passed (sensitivity: 22%; specificity: 75%; diagnostic odds ratio [DOR]: .86). The Recognition Trial increased sensitivity to 39% for identifying invalid performance, but 25% of valid participants still scored below cut-off (specificity: 75%; DOR: 1.91). RFIT Recall and Recognition Trial logistic regression and receiver operating characteristic (ROC) analyses were nonsignificant, with respective classification accuracies of 71 and 72.6% and areas under the curve (AUCs) of .52 and .55. RFIT Error Scores also failed to differentiate validity groups. In contrast, TOMM had stronger psychometric properties (sensitivity: 50%; specificity: 97.7%; DOR: 43; classification accuracy: 82.3%; AUC: .91). Moreover, RFIT Recall and Recognition failure rates were 14 and 22% greater, respectively, among those with cognitive impairment, whereas 95% of those with impairment and 100% without passed the TOMM. CONCLUSION: Despite frequent use among VA neuropsychologists, the RFIT displayed limited ability to detect noncredible performance and misclassified a large percentage of valid participants in this mixed clinical veteran sample, suggesting limited utility with this population. PMID- 28555517 TI - In-Patient Mortality among PLHIV: A 7-Year Hospital-Based Retrospective Study in Coastal South India. AB - BACKGROUND: With the wide usage of highly active antiretroviral therapy, the morbidity and mortality due to HIV have declined gradually. The aim of our study was to determine the cause of mortality among HIV-infected patients and the factors causing early death. METHODS: Using medical records of 73 inpatients who are dead, data were collected and analyzed using SPSS version 19 (IBM SPSS Statistics). Chi-square test was performed to determine the factors contributing to early death. A P value <.05 was considered significant. RESULTS: Among 73 deaths, 50 (68.5%) were AIDS related and 23 (31.5%) were non-AIDS related. The most common opportunistic infection causing death was Pneumocystis carinii pneumonia. Early deaths were strongly attributed to low CD4 counts at admission (<100 cells), antiretroviral therapy-naive status, late presentation, and fewer admissions ( P value <.05). CONCLUSION: Although AIDS-defining illness remains the main cause of death in HIV, there is significant number of deaths due to non HIV-related causes. PMID- 28555518 TI - Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans and dioxin-like coplanar polychlorinated biphenyls in mackerel obtained from the Japanese market, 1999-2003. AB - This study analysed the concentrations and toxic-equivalent (TEQ) levels of dioxin congeners in mackerel commercially available in Japan in early 2000s. The content of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like coplanar polychlorinated biphenyls (DL PCBs) was determined in 17 mackerel samples from different areas. TEQ levels in mackerel muscle were 0.78 pg TEQ g-1 wet weight (wt) on average (range = 0.21 2.26 pg TEQ g-1 wet wt) for PCDD/Fs (PCDDs plus PCDFs), 2.81 pg TEQ g-1 wet wt on average (range = 1.02-8.5 pg TEQ g-1 wet wt) for DL-PCBs, and 3.59 pg TEQ g-1 wet wt on average (range = 1.24-10.8 pg g-1 wet wt) for dioxins (PCDD/Fs plus DL PCBs). The results revealed somewhat higher TEQ levels for dioxins compared with the other data for fish and shellfish in the Japanese market. TEQ levels were well correlated with mackerel body weight; the main contributors were tetra- and penta-CDD/Fs, some hexa-CDD/Fs, and all 12 DL-PCBs, which are known to have high bioaccumulation potential. In particular, PCB 126 was mostly responsible for the observed correlation of DL-PCB and dioxins-TEQ levels with mackerel body weight. The average daily intake of dioxins in terms of TEQ through mackerel consumption was estimated to be 4.81 pg TEQ/person/day, accounting for 7% of the total intake of dioxins-TEQ through fish and shellfish in Japan. PMID- 28555519 TI - Simplification to single-tablet regimen of elvitegravir, cobicistat, emtricitabine, tenofovir DF from multi-tablet ritonavir-boosted protease inhibitor plus coformulated emtricitabine and tenofovir DF regimens: week 96 results of STRATEGY-PI. AB - BACKGROUND: Antiretroviral therapy (ART) simplification to a single-tablet regimen can benefit HIV-1-infected, virologically suppressed, individuals on ART composed of multiple pills. OBJECTIVE: We assessed long-term efficacy and safety of switching to co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF) from multi-tablet ritonavir-boosted protease inhibitor (PI + RTV) plus F/TDF (TVD) regimens. METHODS: STRATEGY-PI was a 96-week, phase 3b, randomized (2:1), open-label, non-inferiority study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF from PI + RTV + TVD regimens in virologically suppressed individuals (HIV-1 RNA <50 copies/mL). Participants were randomized to switch to E/C/F/TDF (switch group) or to continue their PI + RTV + TVD regimens (no-switch group). Eligibility criteria included no resistance to F/TDF or history of virologic failure, and estimated creatinine clearance >=70 mL/min. RESULTS: At week 96, 87% (252/290) of switch and 70% (97/139) of no-switch participants maintained HIV-1 RNA <50 copies/mL (difference: 17%, 95% CI 8.7-26.0%, p < 0.001). Superiority of the switch to E/C/F/TDF vs. no-switch was due to a smaller proportion of both virologic failures (switch, 1% [3/290]; no-switch, 6% [8/139]) and discontinuations for non virologic reasons (switch, 11% [31/290]; no-switch, 24% [33/139]). No treatment emergent resistance was observed in switch subjects with virologic failure. Discontinuation rates from adverse events were 3% in both groups (9/293, switch; 4/140, no-switch). Switching from PI + RTV + TVD to E/C/F/TDF was associated with significant improvements in patient-reported outcomes related to gastrointestinal symptoms (nausea and bloating). CONCLUSION: E/C/F/TDF is a safe, effective long term alternative to multi-tablet PI + RTV + TVD-based regimens in virologically suppressed, HIV-1-infected adults, and improves patient-reported gastrointestinal symptoms. PMID- 28555520 TI - Modification of biochar by Fe2O3 for the removal of pyridine and quinoline. AB - The biochar produced by pyrolysis at 600 degrees C from powdered mango bark impregnated with iron, namely Fe2O3/biochar, was recognized as a multifunctional material for environmental applications. This work aims at using the above material for the removal of pyridine and quinoline from aqueous solutions. The physico-chemical properties of synthesized biochars were studied systematically with several commonly used material characterization methods including scanning electron microscope (SEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD) and Fourier transform infrared spectrometer (FTIR). Structural and morphological analyses of the biochars showed that Fe2O3 particles were nanosized and distributed evenly on the surface of biochar, and thus exhibited great adsorption capacity for the removal of pyridine and quinoline. In addition, the results suggested that the main magnetic phase is maghemite (Fe2O3). The modified biochar showed high removal capacity (99%) for quinoline, but the removal capacity of pyridine was only 73%. The pH experiment in this passage indicated that both pyridine and quinoline reached a maximum adsorption amount at pH near 9.0. Adsorption kinetics suggested that the pseudo-second-order was well fitting the experiment data. The equilibrium study showed that the Langmuir model can adequately describe the adsorption process for pyridine and quinoline. The main mechanism of pyridine and quinoline removal was possibly electrostatic interactions and pi-pi interactions between the modified biochar and the adsorbate. PMID- 28555521 TI - Prevalence of bruxism and temporomandibular disorders among orphans in southeast Uganda: A gender and age comparison. AB - OBJECTIVES: The aims of the current study were: (1) to assess the prevalence of oral habits, bruxism, and temporomandibular disorders (TMDs) among children living in Uganda; (2) to establish whether parafunctional activities are associated with TMDs; and (3) to examine the possible impact of gender and age on the prevalence of bruxism, oral habits, and TMDs. METHODS: This study included 153 children aged 6-17 years. The study consisted of a questionnaire and a clinical examination. RESULTS: TMDs were moderately prevalent (35%). Parafunctional habits were performed by 93% of the participants. When performed extensively, they were significantly related to myalgia. No gender or age significant differences were found. CONCLUSIONS: 1. Only extensive masticatory parafunctional oral activity is significantly related to myalgia. 2. Gender and age had no impact on the prevalence of bruxism, oral habits, or TMDs. 3. Sleep and awake bruxism were not related to anamnestic symptoms or clinical findings in TMD. PMID- 28555522 TI - Compositional data analysis for physical activity, sedentary time and sleep research. AB - The health effects of daily activity behaviours (physical activity, sedentary time and sleep) are widely studied. While previous research has largely examined activity behaviours in isolation, recent studies have adjusted for multiple behaviours. However, the inclusion of all activity behaviours in traditional multivariate analyses has not been possible due to the perfect multicollinearity of 24-h time budget data. The ensuing lack of adjustment for known effects on the outcome undermines the validity of study findings. We describe a statistical approach that enables the inclusion of all daily activity behaviours, based on the principles of compositional data analysis. Using data from the International Study of Childhood Obesity, Lifestyle and the Environment, we demonstrate the application of compositional multiple linear regression to estimate adiposity from children's daily activity behaviours expressed as isometric log-ratio coordinates. We present a novel method for predicting change in a continuous outcome based on relative changes within a composition, and for calculating associated confidence intervals to allow for statistical inference. The compositional data analysis presented overcomes the lack of adjustment that has plagued traditional statistical methods in the field, and provides robust and reliable insights into the health effects of daily activity behaviours. PMID- 28555523 TI - Clinical outcomes of patients with acute coronary syndrome and moderate or severe chronic anaemia undergoing coronary angiography or intervention. AB - BACKGROUND: There are limited data on the impact of chronic moderate or severe anaemia on the clinical outcomes of patients with acute coronary syndrome undergoing coronary angiography or percutaneous coronary intervention. METHODS: We retrospectively compared two groups of consecutive patients with acute coronary syndrome according to their haemoglobin level on admission. The research group ( n=89) had a haemoglobin level of 10.9 g/dl or less and a control group ( n=79) of age-matched patients had a haemoglobin level greater than 10.9 g/dl. We studied drug therapy before, during and after intervention, and performed 1-year follow-up of bleeding complications according to the Bleeding Academic Research Consortium criteria, all-cause mortality and re-infarction, as well as haemoglobin level on discharge, 6 and 12 months after admission. RESULTS: Compared to controls, a haemoglobin level less than 10.9 g?dl on admission is associated with a higher rate of major bleeding: 26 patients (32%) versus none in the control group ( P<0.001); and the use of packed red blood cell (RBC) transfusion: nine patients (11.7%) versus none in the control group ( P=0.003) within the first 6 months post-catheterisation. However, the re-infarction rate and mortality were similar in the study and control groups: 9.2% versus 9.7% ( P=0.915) and 12.6% versus 8.9% ( P=0.434), accordingly. CONCLUSIONS: Chronic moderate or severe anaemia in patients with acute coronary syndrome undergoing coronary angiography or percutaneous coronary intervention is associated with a substantially increased risk of bleeding in the first 6 months. However, rates of mortality and re-infarction were similar. PMID- 28555524 TI - Ellipticine inhibits the proliferation and induces apoptosis in rheumatoid arthritis fibroblast-like synoviocytes via the STAT3 pathway. AB - OBJECTIVE: Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) is an alkaloid isolated from Apocyanaceae plants. This study was designed to investigate the effects of ellipticine on the proliferation and apoptosis of fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA). METHODS: RA FLSs were exposed to different concentrations of ellipticine (i.e., 0.5, 1, 2, 4 and 8 MUM) for 24-72h and measured for viability, proliferation and apoptosis. The involvement of signal transducer and activators of transcription 3 (STAT3) signaling in the action of ellipticine was determined by Western blot analysis, luciferase reporter assay and rescue experiments. RESULTS: Ellipticine treatment significantly inhibited the viability and proliferation of RA-FLSs in a concentration-dependent manner. In contrast, ellipticine exposure did not alter the viability of normal human FLSs. Moreover, ellipticine triggered significant apoptosis and increased caspase-3 activity in RA-FLSs. Mechanistically, ellipticine reduced the phosphorylation of STAT3 and downregulated the expression of Mcl-1, cyclin D1 and Bcl-2. Luciferase reporter assay demonstrated that ellipticine treatment led to a significant inhibition of STAT3-mediated transcriptional activity in RA-FLSs. Overexpression of constitutively active STAT3 reversed the suppressive effects of ellipticine on RA-FLSs, which was accompanied by restoration of Mcl-1, cyclin D1 and Bcl-2. DISCUSSION AND CONCLUSIONS: Ellipticine shows anti-proliferative and pro-apoptotic effects on RA FLSs through inhibition of the STAT3 pathway and may have therapeutic potential in RA. PMID- 28555525 TI - Hepatoprotective effect of parthenolide in rat model of nonalcoholic fatty liver disease. AB - CONTEXT: The active ingredients of traditional medical herbs have been the focus of scientific interests. OBJECTIVE: This study was designed to explore the mechanisms of actions of parthenolide on nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: Thirty-five male Wistar rats were fed high-fat diet (HFD) for eight weeks with or without an intraperitoneal injection of parthenolide to develop NAFLD. Liver triacylglycerol (TG), total antioxidant capacity (TAC), total oxidative status (TOS), thiobarbituric acid reactant substances (TBARs), total thiol groups and tumor necrosis factor alpha (TNF alpha) and cytochrome P4502E1 (CYP2E1) levels as well as liver ALT, AST and catalase activities were determined. In addition, quantitative real-time PCR was performed to obtain hepatic gene expression levels of TNF-alpha, CYP2E1 and nuclear factor-kappaB (NF-kappaB). RESULTS: HFD caused a significant weight gain and increased liver TG content as well as alteration in ALT and AST activities, which were attenuated after administration of parthenoide (p < .05). Weakened liver antioxidant system (TAC, total thiol groups and catalase activity) and increased oxidative stress markers (TBARs and TOS) were mainly ameliorated by parthenolide treatment (p < .05). Increased hepatic TNF-alpha, NF-kappaB and CYP2E1 at the both gene expression and protein levels were found associated with necroinflammatory changes in histopathological observations and were abrogated almost completely after parthenolide treatment. Oxidative and inflammatory changes observed in HFD fed rats were indicative of NAFLD, which were suppressed with parthenolide treatment. CONCLUSIONS: Based on these results, parthenolide might be a candidate agent for preventing NAFLD due to its anti-inflammatory and anti-oxidative potency. PMID- 28555526 TI - Statin intolerance in heterozygous familial hypercolesterolemia with cardiovascular disease: After PCSK-9 antibodies what else? AB - Background Familial hypercholesterolemia is the elective clinical condition that deserves the maximal personalisation in lipid-lowering therapy, especially in the presence of statin intolerance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a promising approach to lower low-density lipoprotein (LDL) cholesterol. Methods We enrolled 18 patients (mean age 62 +/- 8 years, 72% men) affected by heterozygous familial hypercholesterolemia and cardiovascular disease, with a history of statin intolerance assigned to PCSK9 inhibitors. Six patients were also on LDL apheresis. Associated Lp(a) hyperlipoproteinemia (defined as >60 mg/dl) was observed in two out of 18 subjects. PCSK9 inhibitor injectable monoclonal antibodies were administered, every 2 weeks, on top of patient therapy for 12 +/- 4 weeks (evolocumab in 15 subjects, alirocumab in three subjects). Results After 3 months (12 +/- 4 weeks) of therapy, a decrease in total cholesterol (-35%), LDL cholesterol (-51%) and Lp(a) levels (-20%) was observed. Five out of 18 patients reached LDL cholesterol levels of <70 mg/dl, seven showed LDL cholesterol values between 71 and 100 mg/dl, and six out of 18 still had LDL cholesterol levels above 100 mg/dl. Among the six patients with LDL cholesterol levels >100 mg/dl, three were already on LDL apheresis before the PCSK9 inhibitor treatment, while three were referred to LDL apheresis treatment. Adverse events were reported in two out of 18 patients on evolocumab: one presented with flu-like syndrome and the other reported episodes of mild difficulty in maintaining concentration. Conclusions PCSK9 inhibitors represent a novel therapeutic tool for patients with familial hypercholesterolemia who are intolerant to statins. However, more data are needed before cleaning up the old therapeutic armamentarium, such as LDL apheresis, which is likely to preserve its valuable role also in the new lipid-lowering era. PMID- 28555527 TI - Mapping the collaterome for precision cerebrovascular health: Theranostics in the continuum of stroke and dementia. AB - Precision cerebrovascular health or individualized long-term preservation of the brain and associated blood vessels, is predicated on understanding, diagnosing, and tailoring therapies for people at risk of ischemic injury associated with stroke and vascular dementia. The associated imaging patterns are sculpted by the protective effect of the collaterome, the innate compensatory ability of the brain and vasculature to offset hypoperfusion when antegrade or normal arterial inflow pathways are compromised. Theranostics or rational and synchronous use of diagnostic studies in tandem with specific therapies to optimally guide patient outcomes in ischemic brain disorders may capitalize on the pivotal role of the collaterome. Understanding the functional impact of the collaterome across populations of individuals would advance translational science on the brain, while questions with immediate clinical implications may be prioritized. Big data and systematic analyses are necessary to develop normative standards, multimodal imaging atlases, and delineation of specific patterns to guide clinical management. Large-scale, systematic imaging analyses of the collaterome provide a platform for translational work on cerebral collateral circulation and hemodynamics and a theranostic framework with direct clinical implications. This article frames incipient research objectives to guide precision stroke medicine in coming years, building upon the collaterome concept in brain health. PMID- 28555529 TI - What and how we write becomes our footprint in transplant science. PMID- 28555528 TI - Education Before Kidney Transplantation. AB - CONTEXT: Poor knowledge about immunosuppressive (IS) medications remains a major problem for patients in the posttransplant setting. Therefore, more effective educational strategies in the pretransplant setting are being considered as a possible method to improve knowledge and readiness for the challenges of posttransplant care. However, the most effective/relevant content of a pretransplant educational program is yet to be determined. OBJECTIVE: To identify pretransplant education topics from the posttransplant patient perspective. DESIGN: A focus group meeting was conducted among 7 high-functioning, stable adult kidney transplant recipients recruited from the Saskatchewan Transplant Program. Demographic information including age, gender, occupation, background/ethnicity, and time since transplant were recorded. A moderator, assistant moderator, and research assistant facilitated the 90-minute focus group meeting using a predetermined semistructured interview guide. The session was audio recorded and transcribed verbatim. Nvivo software was used to code the data and identify emerging themes exploring views of participants relating to the educational information required for pretransplant patients. RESULTS: Patients were satisfied with the education they had received. Ideas were classified into the following major themes-patient satisfaction, transplant waitlist, surgery, medications, posttransplant complications, lifestyle and monitoring, knowledge acquisition, illusion of control, and life changes posttransplant. Knowledge gaps were identified in all areas of the transplantation process and were not exclusive to IS medications. CONCLUSION: Misconceptions regarding transplantation were identified by a group of high-functioning, stable adult recipients who were satisfied with their clinical care. Future educational strategies should aim to address the entire transplantation process and not be limited to medications. PMID- 28555530 TI - Albumin-based drug delivery using cysteine 34 chemical conjugates - important considerations and requirements. AB - The long blood circulation time of albumin has been clinically utilized as a half life extension technology for improved drug performance. The availability of one free thiol for site-selective chemical conjugation offers an alternative approach to current genetic fusion and association-based products. This special report highlights important factors for successful conjugation that allows the reader to design and evaluate next-generation albumin conjugates. Albumin type, available conjugation chemistries, linker length, animal models and influence of conjugation on albumin pharmacokinetics and drug activity are discussed. PMID- 28555531 TI - Masking the Identities of Celebrities and Personally Familiar Individuals: Effects on Visual and Auditory Recognition Performance. AB - The current study compared the effectiveness of masking on recognition performance for faces and voices of celebrities and personally familiar individuals. On the basis of the theory suggesting stronger memory representations for personally familiar individuals, we expected masking to be more effective for celebrities than for personally familiar stimulus persons. Furthermore, we sought to replicate the face recognition advantage with masked stimuli. Face pixelation and electronic changes of the voice pitch were applied as masking techniques, using four masking levels for each stimulus. Thirty-one undergraduate students were presented with the masked faces and voices of 10 celebrities and 10 personally familiar fellow students. As expected, more correct recognitions occurred for faces than for voices, suggesting that masking does not counteract the mechanisms causing the face recognition advantage. Unexpectedly, masking effectiveness did not differ between celebrities and personally familiar individuals. This may be due to the type of personally familiar individuals used. Within personally familiar stimuli, increased familiarity did not predict the effectiveness of masking. Whereas the highest masking level eliminated speaker recognition, masking did not fully eliminate face recognition. From a practical perspective, the findings especially question the suitability of pixelation as a means for identity concealment. PMID- 28555532 TI - Insights into the epidemiology, aetiology and associations of infraspinatus atrophy in overhead athletes: a systematic review. AB - Infraspinatus atrophy (IA) is much more prevalent in overhead sports compared with the general population. Its exact aetiology in this group of athletes remains unclear and definitive associations with pathology and performance have not yet been reached. The aim of this systematic review is to present the evidence on IA in overhead athletes focussing on the proposed mechanisms of suprascapular neuropathy and its associations with shoulder pathology and performance. A thorough literature search via Medline, EMBASE and Scopus was performed. From the nine articles identified, the majority of authors propose suprascapular nerve (SN) injury at the spinoglenoid notch; however, the suprascapular notch has also been suggested as a potential site of injury. With regard to the exact mechanism of suprascapular neuropathy, the majority of authors propose repeated traction of the nerve during extreme shoulder abduction and horizontal adduction and/or eccentric contractions of the infraspinatus. In the limited relevant literature, convincing links between IA and performance or shoulder pathology have not been identified. IA in overhead sports is most likely of multi-factorial aetiology. Important questions about IA and its significance in overhead sports remain unanswered and more biomechanical and prospective studies are warranted to provide further insights into this athletic injury. PMID- 28555533 TI - Reliability of peripheral arterial tonometry in patients with heart failure, diabetic nephropathy and arterial hypertension. AB - Endothelial dysfunction plays a major role in cardiovascular diseases and pulse amplitude tonometry (PAT) offers a non-invasive way to assess endothelial dysfunction. However, data about the reliability of PAT in cardiovascular patient populations are scarce. Thus, we evaluated the test-retest reliability of PAT using the natural logarithmic transformed reactive hyperaemia index (LnRHI). Our cohort consisted of 91 patients (mean age: 65+/-9.7 years, 32% female), who were divided into four groups: those with heart failure with preserved ejection fraction (HFpEF) ( n=25), heart failure with reduced ejection fraction (HFrEF) ( n=22), diabetic nephropathy ( n=21), and arterial hypertension ( n=23). All subjects underwent two separate PAT measurements at a median interval of 7 days (range 4-14 days). LnRHI derived by PAT showed good reliability in subjects with diabetic nephropathy (intra-class correlation (ICC) = 0.863) and satisfactory reliability in patients with both HFpEF (ICC = 0.557) and HFrEF (ICC = 0.576). However, in subjects with arterial hypertension, reliability was poor (ICC = 0.125). We demonstrated that PAT is a reliable technique to assess endothelial dysfunction in adults with diabetic nephropathy, HFpEF or HFrEF. However, in subjects with arterial hypertension, we did not find sufficient reliability, which can possibly be attributed to variations in heart rate and the respective time of the assessments. Clinical Trial Registration Identifier: NCT02299960. PMID- 28555534 TI - Personality risk for antisocial behavior: Testing the intersections between callous-unemotional traits, sensation seeking, and impulse control in adolescence. AB - The current project seeks to integrate literatures on personality risk for antisocial behavior (ASB) by examining how callous-unemotional traits relate to (a) the development of disinhibited traits and (b) the association between disinhibited traits and ASB. In Study 1, using a nationally representative sample of youth (N > 7,000), we examined whether conduct problems and lack of guilt assessed during ages 4-10 years predicted levels of and changes in disinhibited traits over the course of adolescence, and moderated associations between these traits and ASB. High levels of childhood conduct problems were associated with higher levels of impulsivity, sensation seeking, and ASB in early adolescence, whereas lack of guilt was associated with lower levels of sensation seeking. Neither conduct problems nor lack of guilt significantly predicted changes in impulsivity or sensation seeking, and associations among changes in sensation seeking, impulsivity, and ASB were also consistent across levels of conduct problems and lack of guilt. In Study 2, using a cross-sectional sample of adolescents (N = 970), we tested whether callous-unemotional traits moderated associations between disinhibited traits and ASB. Consistent with the results of Study 1, associations between disinhibited personality and ASB were consistent across a continuous range of callous-unemotional traits. PMID- 28555535 TI - Family environments and leukocyte transcriptome indicators of a proinflammatory phenotype in children and parents. AB - High conflict and low warmth in families may contribute to immune cells developing a tendency to respond to threats with exaggerated inflammation that is insensitive to inhibitory signaling. We tested associations between family environments and expression of genes bearing response elements for transcription factors that regulate inflammation: nuclear factor kappa B (NF-kappaB) and glucocorticoid receptor. The overall sample (47 families) completed interviews, questionnaires, and 8-week daily diary assessments of conflict and warmth, which were used to create composite family conflict and warmth scores. The diaries assessed upper respiratory infection (URI) symptoms, and URI episodes were clinically verified. Leukocyte RNA was extracted from whole blood samples provided by a subsample of 42 children (8-13 years of age) and 73 parents. In children, higher conflict and lower warmth were related to greater expression of genes bearing response elements for the proinflammatory transcription factor NF kappaB, and more severe URI symptoms. In parents, higher conflict and lower warmth were also related to greater NF-kappaB-associated gene expression. Monocytes and dendritic cells were implicated as primary cellular sources of differential gene expression in the sample. Consistent with existing conceptual frameworks, stressful family environments were related to a proinflammatory phenotype at the level of the circulating leukocyte transcriptome. PMID- 28555537 TI - Centralised databases as a primer for research. PMID- 28555536 TI - Laryngeal amyloidosis: diagnosis, pathophysiology and management. AB - BACKGROUND: Laryngeal amyloidosis represents approximately 1 per cent of all benign laryngeal lesions, and can cause variable symptoms depending on anatomical location and size. Treatment ranges from observation through to endoscopic microsurgery, laser excision and laryngectomy. OBJECTIVES: To highlight the diversity of presentations, increase awareness of paediatric amyloidosis and update the reader on current management. CASE SERIES: Five cases are illustrated. Four adult patients were female, and the one child, the second youngest in the literature, was male. Amyloid deposits were identified in all laryngeal areas, including the supraglottis, glottis and subglottis. Treatment consisted of balloon dilatation, endoscopic excision, laser cruciate incision, and resection with carbon dioxide laser, a microdebrider and coblation wands. CONCLUSION: Laryngeal amyloidosis remains a rare and clinically challenging condition. Diagnosis should be considered for unusual appearing submucosal laryngeal lesions. Treatment of this disease needs to be evaluated on a case-by-case basis and managed within an appropriate multidisciplinary team. PMID- 28555539 TI - The independence of the infundibular building blocks in the setting of double outlet right ventricle. AB - It has long been contentious as to whether the presence of bilateral infundibulums, or conuses, is a prerequisite for the diagnosis of double-outlet right ventricle. As the use of such a criterion would abrogate the so-called "morphological method", which correctly states that one variable entity should not be defined on the basis of another entity that is itself variable, it is now accepted that double outlet can exist in the setting of fibrous continuity between the leaflets of the atrioventricular and arterial valves. Although this debate has now been resolved, there are other contentious areas still requiring clarification in the setting of hearts unified because of the presence of this particular ventriculo-arterial connection - for example, it is questionable whether the channel between the ventricles should be described as a "ventricular septal defect", whereas it is equally arguable that the mere presence of fibrous continuity between the leaflets of the arterial valves does not necessarily place the channel in a doubly committed location. In this review, we describe a series of autopsied hearts in which the anatomical features serve to illuminate these various topics. We then discuss recent findings regarding cardiac development that point to the individuality of the building blocks of the ventricular outflow tracts, specifically the outlet septum, the inner heart curvature, or ventriculo infundibular fold, and the septomarginal trabeculation, or septal band. PMID- 28555538 TI - Comparison of self-expandable and balloon-expanding stents for hybrid ductal stenting in hypoplastic left heart complex. AB - OBJECTIVES: We aimed to compare the procedural and mid-term performance of a specifically designed self-expanding stent with balloon-expandable stents in patients undergoing hybrid palliation for hypoplastic left heart syndrome and its variants. BACKGROUND: The lack of specifically designed stents has led to off label use of coronary, biliary, or peripheral stents in the neonatal ductus arteriosus. Recently, a self-expanding stent, specifically designed for use in hypoplastic left heart syndrome, has become available. METHODS: We carried out a retrospective cohort comparison of 69 neonates who underwent hybrid ductal stenting with balloon-expandable and self-expanding stents from December, 2005 to July, 2014. RESULTS: In total, 43 balloon-expandable stents were implanted in 41 neonates and more recently 47 self-expanding stents in 28 neonates. In the balloon-expandable stents group, stent-related complications occurred in nine patients (22%), compared with one patient in the self-expanding stent group (4%). During follow-up, percutaneous re-intervention related to the ductal stent was performed in five patients (17%) in the balloon-expandable stent group and seven patients (28%) in self-expanding stents group. CONCLUSIONS: Hybrid ductal stenting with self-expanding stents produced favourable results when compared with the results obtained with balloon-expandable stents. Immediate additional interventions and follow-up re-interventions were similar in both groups with complications more common in those with balloon-expandable stents. PMID- 28555540 TI - A novel flavivirus detected in two Aedes spp. collected near the demilitarized zone of the Republic of Korea. AB - Flaviviruses comprise a large and diverse group of positive-stranded RNA viruses, including tick-, mosquito- and unknown-vector-borne flaviviruses. A novel flavivirus was detected in pools of Aedes vexans nipponii (n=1) and Aedes esoensis (n=3) collected in 2012 and 2013 near the demilitarized zone (DMZ), Republic of Korea (ROK). Phylogenetic analyses of the NS5, E gene and complete polyprotein coding sequence (CDS) showed that the novel virus fell within the Aedes-borne flaviviruses (ABFVs), with nucleotide identity ranging from 57.8-75.1 %, 46.1-74.2 % and 51.1-76.2 %, respectively. While the novel ABFV was distant from other flaviviruses within the group, it formed a clade with Ilomantsi virus (ILOV). Sequence alignments of the partial NS5 gene, full-length E gene and polyprotein CDS between the novel virus and ILOV showed approximately 76.2 % nucleotide identity and 90 % amino acid identity, respectively. The ABFV identified in Aedes mosquitoes from the ROK is a novel ABFV based on the sequence analyses and is designated as Panmunjeom flavivirus (PANFV). PMID- 28555541 TI - Avian influenza virus A H7N9 infects multiple mononuclear cell types in peripheral blood and induces dysregulated cytokine responses and apoptosis in infected monocytes. AB - Most patients with avian influenza A H7N9 virus (H7N9) infection suffer from severe illness, accompanied by dysregulated cytokine/chemokine response, delayed viral clearance and impaired neutralizing antibody response. Here, we evaluated the role of peripheral blood mononuclear cells (PBMCs) in the pathogenesis of H7N9 infection using an ex vivo infection model. H7N9 infected a significantly higher percentage of PBMCs (23.9 %) than those of avian influenza A H5N1 virus (H5N1) (12.3 %) and pandemic H1N1 virus (pH1N1) (5.5 %) (P<0.01). H7N9 infected significantly more B and T lymphocytes than H5N1. When compared with pH1N1, H7N9 infected PBMCs had significantly higher mRNA levels of proinflammatory cytokines and type I interferons (IFNs) at 6 h post-infection (p.i.), but significantly lower levels of IFN-gamma and IP-10 at 12 h p.i. Among the PBMCs, CD14+ monocytes were most permissive to H7N9 infection. The percentage of infected CD14+ monocytes was significantly higher for H7N9 than that of pH1N1, but not significantly different from that of H5N1. H7N9-infected monocytes showed higher expression of MIP-1alpha, MIP-1beta and RANTES than that of pH1N1 at 6 h p.i. H7N9- but not pH1N1-infected monocytes died rapidly via apoptosis. Furthermore, pH1N1- but not H7N9-infected monocytes showed increased expression of the monocyte activation and differentiation markers. Unlike pH1N1, H7N9 showed similar PBMC/monocyte cytokine/chemokine expression profile, monocyte cell death and expression of activation/differentiation markers to H5N1. Besides proinflammatory cytokine activation leading to a cytokine storm, impaired IFN gamma production, rapid monocytic death and lack of monocyte differentiation may affect the ability of H7N9-infected innate immune cells to recruit protective adaptive immunity. PMID- 28555542 TI - Rift Valley fever virus: strategies for maintenance, survival and vertical transmission in mosquitoes. AB - Rift Valley fever virus (RVFV) is a mosquito-borne arbovirus causing severe disease in humans and ruminants. Spread of RVFV out of Africa has raised concerns that it could emerge in Europe or the USA. Virus persistence is dependent on successful infection of, replication in, and transmission to susceptible vertebrate and invertebrate hosts, modulated by virus-host and vector-virus interactions. The principal accepted theory for the long-term maintenance of RVFV involves vertical transmission (VT) of virus to mosquito progeny, with the virus surviving long inter-epizootic periods within the egg. This VT hypothesis, however, is yet to be comprehensively proven. Here, evidence for and against the VT of RVFV is reviewed along with the identification of factors limiting its detection in natural and experimental data. The observations of VT for other arboviruses in the genera Alphavirus, Flavivirus and Orthobunyavirus are discussed within the context of RVFV. The review concludes that VT of RVFV is likely but that current data are insufficient to irrefutably prove this hypothesis. PMID- 28555543 TI - Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response. AB - Our previous screening of 50 240 structurally diverse compounds led to the identification of 39 influenza A virus infection inhibitors (Kao R.Y., Yang D., Lau L.S., Tsui W.H., Hu L. et al. Nat Biotechnol 2010;28:600-605). Further screening of these compounds against common respiratory viruses led to the discovery of compound FA-613. This inhibitor exhibited low micromolar antiviral activity against various influenza A and B virus strains, including the highly pathogenic influenza A strains H5N1 and H7N9, enterovirus A71, respiratory syncytial virus, human rhinovirus A, SARS- and MERS-coronavirus. No significant cellular toxicity was observed at the effective concentrations. Animal studies showed an improved survival rate in BALB/c mice that received intranasal FA-613 treatments against a lethal dose infection of A/HK/415742Md/2009 (H1N1). Further cell-based assays indicated that FA-613 interfer with the de novo pyrimidine biosynthesis pathway by targeting the dihydroorotate dehydrogenase. Surprisingly, FA-613 lost its antiviral potency in the interferon-deficient Vero cell line, while maintaining its inhibitory activity in an interferon-competent cell line which showed elevated expression of host antiviral genes when infected in the presence of FA-613. Further investigation of the specific connection between pyrimidine synthesis inhibition and the induction of host innate immunity might aid clinical development of this type of drug in antiviral therapies. Therefore, in acute cases of respiratory tract infections, when rapid diagnostics of the causative agent are not readily available, an antiviral drug with properties like FA-613 could prove to be very valuable. PMID- 28555544 TI - Development and characterization of Sindbis virus with encoded fluorescent RNA aptamer Spinach2 for imaging of replication and immune-mediated changes in intracellular viral RNA. AB - Viral RNA studies often rely on in situ hybridization and reverse transcriptase PCR to provide snapshots of RNA dynamics in infected cells. To facilitate analysis of cellular RNAs, aptamers Spinach and Spinach2 that bind and activate the conditional fluorophore 3, 5-difluoro-4-hydroxybenzylidene imidazolinon have been developed. To determine the feasibility of applying this technology to viral RNA, we have used cDNA clones of the TE strain of Sindbis virus (SINV) to construct multiple viruses containing one or two copies of tRNA-scaffolded Spinach2 after a second subgenomic promoter, TEds-1Sp and TEds-2Sp within the 3'UTR, TE-1UTRSp, or after a second subgenomic promoter and in the 3'UTR, TEds 1Sp+1 UTRSp. TEds-1Sp+1 UTRSp gave the brightest signal and replicated well in cell culture, while TEds-2Sp was the dimmest and replicated poorly. Selection of baby hamster kidney cells infected with TEds-1Sp+1 UTRSp for improved signal intensity identified a virus with a stronger signal and point mutations in the tRNA scaffold. Imaging of SINV in BHK cells showed RNA to be concentrated in filopodia that contacted and transferred RNA to adjacent cells. The effect of treatment with anti-E2 antibody, which effects non-cytolytic clearance of SINV from neurons, on viral RNA was cell-type-dependent. In antibody-treated BHK cells, intracellular viral RNA increased and spread of infection continued. In undifferentiated and differentiated AP7 neuronal cells antibody treatment induced viral RNA clearance. Both viruses with two inserted aptamers were prone to deletion. These studies form the basis for further development of aptamer labelled viral RNAs that will facilitate functional studies on the dynamics of infection and clearance. PMID- 28555545 TI - Identification of cross-reacting T-cell epitopes in structural and non-structural proteins of swine and pandemic H1N1 influenza A virus strains in pigs. AB - Heterologous protection against swine influenza viruses (SwIVs) of different lineages is an important concern for the pig industry. Cross-protection between 'avian-like' H1N1 and 2009 pandemic H1N1 lineages has been observed previously, indicating the involvement of cross-reacting T-cells. Here, reverse vaccinology was applied to identify cross-reacting MHC class I T-cell epitopes from two different SwIV H1 lineages in pigs. In silico prediction followed by in vitro and in vivo testing was used to identify SLA-1*0702 T-cell epitopes in heterologous SwIV-infected pigs. Following viral infection, tetramer specific T-cell populations were identified. The majority of the identified T-cell epitopes were conserved between the examined lineages, suggesting that targeting cross-reactive T-cell epitopes could be used to improve vaccines against SwIV in SLA-1*0702 positive pigs. PMID- 28555546 TI - ICTV Virus Taxonomy Profile: Iridoviridae. AB - The Iridoviridae is a family of large, icosahedral viruses with double-stranded DNA genomes ranging in size from 103 to 220 kbp. Members of the subfamily Alphairidovirinae infect ectothermic vertebrates (bony fish, amphibians and reptiles), whereas members of the subfamily Betairidovirinae mainly infect insects and crustaceans. Infections can be either covert or patent, and in vertebrates they can lead to high levels of mortality among commercially and ecologically important fish and amphibians. This is a summary of the current International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Iridoviridae, which is available at www.ictv.global/report/iridoviridae. PMID- 28555547 TI - Close genetic relatedness of picornaviruses from European and Asian bats. AB - Our investigation of 1004 faecal specimens from European bats for picornaviruses by broadly reactive nested reverse transcription-PCR found picornaviral RNA in 28 samples (2.8 %). Phylogenetic analysis of the partial 3D genomic region suggested that one bat virus belonged to the species Enterovirus G (EV-G, formerly Porcine enterovirus B). Bat infection was supported by relatively high EV-G concentrations of 1.1*106 RNA copies per gram of faeces. All other bat viruses belonged either to the bat-associated genus Mischivirus, or to an unclassified Picornaviridae group distantly related to the genus Sapelovirus. Members of this unclassified sapelovirus-related group had RNA secondary structures in their 3' nontranslated regions that were typical of enteroviruses and that resembled structures that occur in bat-associated coronaviruses, suggesting ancient recombination events. Based on sequence distances, several picornaviruses from European and Chinese bats were likely conspecific, suggesting connectivity of virus populations. Due to their high mutation rates and their diversity, picornaviruses may be useful tools for studies of bat and virus ecology. PMID- 28555549 TI - [Coimbra Telemedicine Service Improves Access to Pediatric Cardiology in Cape Verde]. PMID- 28555548 TI - Recombination events and variability among full-length genomes of co-circulating molluscum contagiosum virus subtypes 1 and 2. AB - Molluscum contagiosum virus (MCV) is the sole member of the Molluscipoxvirus genus and causes a highly prevalent human disease of the skin characterized by the formation of a variable number of lesions that can persist for prolonged periods of time. Two major genotypes, subtype 1 and subtype 2, are recognized, although currently only a single complete genomic sequence corresponding to MCV subtype 1 is available. Using next-generation sequencing techniques, we report the complete genomic sequence of four new MCV isolates, including the first one derived from a subtype 2. Comparisons suggest a relatively distant evolutionary split between both MCV subtypes. Further, our data illustrate concurrent circulation of distinct viruses within a population and reveal the existence of recombination events among them. These results help identify a set of MCV genes with potentially relevant roles in molluscum contagiosum epidemiology and pathogenesis. PMID- 28555550 TI - [Implementation of Telemedicine in Cape Verde: Influencing Factors]. AB - INTRODUCTION: Telemedicine is the provision of health services, where distance is a critical factor, using information and communication technologies. Cape Verde has bet on using this tool to increase access of the population of its islands to specialized care. MATERIAL AND METHODS: Qualitative study, covering the period between 2013 and 2014. It uses document analysis, semi-structured interviews and focus groups to collect data and analysis of content for their analysis. The participant population includes doctors, nurses and professionals from some institutions related to telemedicine. RESULTS: The priorities of the National Telemedicine Program are set, the cores and reference centers are operational, with trained personnel and equipment installed. Several other policy instruments and conditioning factors and facilitators of the program have been identified. DISCUSSION: Telemedicine is contributing to the reduction of inequalities in access to health, in Cape Verde. However, the full adoption of a service based on a new technology depends on conditioning factors and facilitators, and several success factors of telemedicine, identified in the literature, are not observed and in conjunction with other existing weaknesses affect the overall development of the National Telemedicine Program. However the strengths and capabilities are highlighted opportunities to act. CONCLUSION: Despite the progress, some telemedicine success factors highlighted on the literature are not seen in the country. PMID- 28555551 TI - [Economic Crisis and Portuguese National Health Service Physicians: Findings from a Descriptive Study of Their Perceptions and Reactions from Health Care Units in the Greater Lisbon Area]. AB - INTRODUCTION: In Europe, scant scientific evidence exists on the impact of economic crisis on physicians. This study aims at understanding the adjustments made by public sector physicians to the changing conditions, and their perceptions on the market for medical services in the Lisbon metropolitan area. MATERIAL AND METHODS: A random sample of 484 physicians from Sao Jose Hospital and health center groups in Cascais and Amadora, to explore their perceptions of the economic crisis, and the changes brought to their workload. This paper provides a descriptive statistical analysis of physicians' responses. RESULTS: In connection to the crisis, our surveyed physicians perceived an increase in demand but a decrease of supply of public health services, as well as an increase in the supply of health services by the private sector. Damaging government policies for the public sector, and the rise of private services and insurance providers were identified as game changers for the sector. Physicians reported a decrease in public remuneration (- 30.5%) and a small increase of public sector hours. A general reduction in living standard was identified as the main adaptation strategy to the crisis. Passion for the profession, its independence and flexibility, were the most frequently mentioned compensating factors. A percentage of 15% of physicians declared considering migration as a possibility for the near future. DISCUSSION: The crisis has brought non-negligible changes to physicians' working conditions and to the wider market for medical services in Portugal. CONCLUSION: The physicians' intrinsic motivation for the professions helped counterbalance salary cuts and deteriorating working conditions. PMID- 28555552 TI - Anxiety, Family Functioning and Neuroendocrine Biomarkers in Obese Children. AB - INTRODUCTION: This observational study explores potential links between obese children's cortisol, and parental mental state, family functioning, and the children's symptoms of anxiety and depression. MATERIAL AND METHODS: A non-random sample of 104 obese children (55 boys), mean age 10.9 years (standard deviation 1.76), was recruited from a childhood obesity clinic. Obesity was defined as body mass index above the 95th age- and gender-specific percentiles. Neuroendocrine biomarkers were measured. Symptoms of anxiety and depression were assessed with self and parent-reported questionnaires (Anxiety, Depression and Stress Scales; Child Behaviour Checklist). Family functioning was assessed with parent-reported questionnaires (Family Adaptation and Cohesion Scales-III). RESULTS: A significant, negative correlation (rs = -0.779; p = 0.003) between girls' cortisol and their parents' anxiety symptoms was found, limited to high functioning families. Boys scored significantly higher than girls on parent reported internalizing symptoms but not on self-report. No association was found between cortisol in children and parental depressive symptoms. DISCUSSION: Whether the association between cortisol levels in obese children and parental mental health is effectively restricted to girls from high functioning families or is due to study limitations, requires further research. The lack of associations between cortisol in children and parental depressive symptoms, suggests a specific association between cortisol and parental anxiety symptoms. CONCLUSION: These results highlight the importance of taking into account family functioning, parental mental state and gender, when investigating neuroendocrine biomarkers in obese children associated with symptoms of anxiety and depression. PMID- 28555553 TI - Efficacy and Safety of Foley Catheter Balloon for Cervix Priming in Term Pregnancy. AB - INTRODUCTION: Foley catheter promotes cervix priming by a direct mechanical effect of distension. MATERIAL AND METHODS: A prospective observational study was conducted at a tertiary hospital, including all cases of induction of labor with Foley catheter between September 1, 2013 and November 30, 2015. Women were eligible if they had a singleton pregnancy with a Bishop score < 6 and a gestational age >= 41 weeks or a medical indication for induction of labor. The primary outcome was the Bishop score variation (difference between Bishop score before and after insertion of Foley catheter). Mode of delivery, induction-to delivery time, uterine tachysystole with fetal decelerations, peripartum fever >= 38o C, maternal pain and mortality were also analyzed. RESULTS: Within 201 inductions with Foley catheter, average increase in Bishop score after catheter placement was three (1 - 7), with only 5% (11/201) of unmodified cervix after catheter removal/extrusion. Vaginal delivery rate was 71% (142/201) and in women with a previous cesarean section (n = 40) was 37% (15/40). Average induction-to delivery time was 38 hours (4 - 120). Uterine infection rate was 3% (6/201). There was only one case of significant vaginal bleeding which required immediate catheter removal. There has been no significative maternal or neonatal morbidity. DISCUSSION/CONCLUSION: Foley catheter is a safe and effective method of cervical priming for women with an unfavorable cervix, even in the case of a previous cesarean delivery. PMID- 28555554 TI - [Graduate Students in Medicine Course: Motivation, Socialization and Academic Recognition]. AB - INTRODUCTION: Students with a previous degree have personal and professional experiences that can contribute to a different academic path during the medical course. This study aims to: 1) analyze both satisfaction and impact of academic recognition; 2) investigate whether motivations and expectations at entrance are maintained along the course; 3) to evaluate socialization after regress to higher education. MATERIAL AND METHODS: To accomplish the first objective a questionnaire was administered to 82 students who entered the medical school from 2011/2012 to 2013/2014. For the second and third goals a focus group was run (three groups with five students each, representing the three academic years). RESULTS AND DISCUSSION: Students felt satisfied with the recognition, and 50% of them believe that accreditations replace knowledge acquired with the curricular units, and 47% preferred to obtain accreditation. Academic achievement was negatively associated with the satisfaction of recognition and positively with age, background and registration cycle. Socialization of these students is distinct from the younger ones, their motivations at entrance are intrinsic and, contrary to expectations, are maintained along the course. CONCLUSION: Students prefer recognition instead of attending the curricular units. The most satisfied with the recognition accomplish less credits and the younger ones, from health area and enrolled in the clinical cycle, accomplish more. Along the course, motivations become more solid, expectations change and socialization is carried out with greater responsibility. PMID- 28555555 TI - [Relevant Factors on Cognitive Evaluation of the Portuguese Population]. AB - INTRODUCTION: Aging is an inevitable process that has a social impact in the forecoming decades, and it will present a great challenge regarding public health. An efficient health system requires a reflection on the preventive measures to be implemented. MATERIAL AND METHODS: The study population comprised a total number of 2672 individuals of both genders, aged 55 years and over, residents in continental Portugal, to whom a questionnaire was applied that included the following sections: Social network; Locomotion; Physical autonomy; Instrumental autonomy; Cognitive assessment; Physical activity. RESULTS: The study of aging in the Portuguese population found that physical autonomy for tasks related to daily life are associated with better cognitive evaluation. A statistically significant association was found between performance in cognitive assessment and gender, age, schooling, the fact of living alone, the number of hours being alone, autonomy to walk in the street, washing, dressing, eating, preparing meals, doing shopping, managing money and taking medications and washer / treat clothing. DISCUSSION: Cognitive evaluation is negatively influenced by the number of hours that an individual is alone. CONCLUSION: Activities of daily life must be valued, since they require the ability to plan and carry out tasks and their preservation is a key component in successful aging. PMID- 28555556 TI - Playing-Related Musculoskeletal Disorders of Professional Orchestra Musicians from the North of Portugal: Comparing String and Wind Musicians. AB - INTRODUCTION: It is well known that musicians are a group prone to suffer from playing-related musculoskeletal disorders. Professional orchestra musicians play for several hours a week and have to fight against pain caused by their profession. The aim of this study was to explore and describe self-reported complaints among professional orchestra musicians and to compare its intensity and the prevalence between string and wind instruments. MATERIAL AND METHODS: Hundred and twelve professional orchestra musicians from the three main professional orchestras from the North of Portugal were individually interviewed about the prevalence and the intensity (measured by verbal numerical scale for pain) of their playing-related musculoskeletal disorders. RESULTS: About two third (62.5%) of the interviewed musicians presented playing-related musculoskeletal disorders during the time of the interview. Despite there are no significant statistic values between groups, results suggested that playing related musculoskeletal disorders are more common in string players and more intense in wind players. DISCUSSION: Referring to the prevalence of playing related musculoskeletal disorders, our data is in line with other studies from different countries. More than half of professional orchestra musicians in the North of Portugal are playing with a mild to moderate pain. CONCLUSION: Future studies focusing on working-related problems among professional orchestra musicians in Portugal would be useful to better describe the problem of occupational diseases among performing artist. PMID- 28555557 TI - [Psychological Treatments for Borderline Personality Disorder: A Review of Cognitive-Behavioral Oriented Therapies]. AB - INTRODUCTION: Borderline personality disorder is the most common personality disorder, with a global prevalence rate between 1.6% and 6%. It is characterized by affective disturbance and impulsivity, which lead to a high number of self harm behaviors and great amount of health services use. International guidelines recommend psychotherapy as the primary treatment for borderline personality disorder. This paper reviews evidence about the effects and efficacy of cognitive behavioral oriented psychological treatments for borderline personality disorder. MATERIAL AND METHODS: A literature review was conducted in Medline and PubMed databases, using the following keywords: borderline personality disorder, cognitive-behavioral psychotherapy and efficacy. RESULTS: Sixteen randomized clinical trials were evaluate in this review, which analyzed the effects of several cognitive-behavioral oriented psychotherapeutic interventions, namely dialectical behavioral therapy, cognitive behavioral therapy, schema-focused therapy and manual-assisted cognitive therapy. All above stated treatments showed clinical beneficial effects, by reducing borderline personality disorder core pathology and associated general psychopathology, as well as by reducing the severity and frequency of self-harm behaviors, and by improving the overall social, interpersonal and global adjustment. Dialectical behavioral therapy and schema-focused therapy also caused a soaring remission rate of diagnostic borderline personality disorder criteria of 57% and 94%, respectively. DISCUSSION: Although there were differences between the psychotherapeutic interventions analysed in this review, all showed clinical benefits in the treatment of borderline personality disorder. Dialectical behavioral therapy and schema-focused therapy presented the strongest scientific data documenting their efficacy, but both interventions are integrative cognitive-behavioral therapies which deviate from the traditional cognitive-behavioral model. CONCLUSION: In summary, the available studies support cognitive-behavioral psychological treatments as an efficacious intervention in borderline personality disorder. However, the existing scientific literature on this topic is still scarce and there is need for more studies, with higher methodological rigor, that should validate these results. PMID- 28555558 TI - Surgical Treatment of Rotator Cuff Tears After 65 Years of Age: A Systematic Review. AB - INTRODUCTION: The objective of this study was to analyze current evidence regarding surgical management of rotator cuff tears in patients of 65 years of age and above. Our hypothesis was that surgical repair of rotator cuff tears, in patients older than 65 years, conveys good outcome scores. We have not found a similar systematic review in current literature. MATERIAL AND METHODS: Medline(r), PubMed, Scopus, and the Cochrane Register of Controlled Trials were searched from January 1999 unto December 2015 for studies, regardless of language, including the words 'rotator cuff' and '65 years' or '70 years'. Inclusion criteria were studies (level I to IV) that reported clinical outcomes in patients older than 65 years, having undertaken surgical repair of a symptomatic rotator cuff tears. Arthroscopic, mini open and open techniques were included. Exclusion criteria were: studies with patients younger than 65 years, studies that did not use validated outcome evaluation scores as primary assessment tools and those with follow up under one year. This work followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses - PRISMA guidelines. Data abstracted included patient demographics, tear pattern, surgical procedures, clinical and repair results. Outcome scores were converted to percentages, allowing comparison of data between studies. RESULTS: After deep analysis, 14 studies met the inclusion criteria: 11 level IV studies, 1 level III study and 2 level II studies. Seven studies found statistically significant outcome improvements between pre and postoperative evaluations. All studies reported good or excellent surgical outcomes. DISCUSSION: Better results would probably be achieved if all studies had rigorous and homogeneous patient selection criteria, but the fact is, that even though this was not the case, the clinical scores remained favorable, and with statistically significant outcome improvement in all studies with prospectively collected data. CONCLUSION: Based on current literature, rotator cuff repair in patients older than 65 years imparts favorable improvement in clinical outcome scores and overall patient satisfaction. PMID- 28555559 TI - [Bisalbuminemia: A Rare Variant of Albumin]. AB - INTRODUCTION: Bisalbuminemia is a qualitative disorder of albumin and it is defined by the coexistence in the same individual of two types of serum albumin with different electrophoretic mobility. There are two forms: hereditary and permanent, or acquired and transient. CASE REPORT: Girl, 17-years-old, referenced to the hospital consult after incidental finding of bisalbuminemia detected in plasma protein electrophoresis performed within the investigation of diminished muscular tone in the lower limbs. Physical examination was normal. Secondary causes of bisalbuminemia were excluded. Later, it was confirmed the same disorder in plasma protein electrophoresis performed to her 14-years-old brother and mother. DISCUSSION: We describe a rare case of hereditary bisalbuminemia in a portuguese family. In general, this condition shows no pathological significance, however it is of interest to the clinicians the knowledge of this analytic change for better orientation of their patients. PMID- 28555560 TI - Bilateral Deep Vein Thrombosis Associated with Inferior Vena Cava Agenesis in a Young Patient Manifesting as Low Back Pain. AB - Congenital absence of the inferior vena cava is a rare vascular anomaly, and most cases are asymptomatic. Nevertheless, patients with inferior vena cava malformations may have increased risk of deep venous thrombosis. Particularly, cases of bilateral deep venous thrombosis may arise owing to an insufficient collateral venous drainage from the lower limbs. We hereby describe a case of a previously healthy young male patient presenting with bilateral lower limb deep venous thrombosis as the initial clinical manifestation of congenital inferior vena cava agenesis. We conclude that in young patients presenting with deep venous thrombosis, especially when thrombosis occurs spontaneously, bilaterally, or recurrently, inferior vena cava anomalies should be thoroughly investigated and ruled out as appropriate. PMID- 28555561 TI - Intragastric Penetration of the Connecting Tube After Laparoscopic Adjustable Gastric Banding. PMID- 28555562 TI - Diplopia as Rare Initial Manifestation of Gastric Cancer. PMID- 28555563 TI - [Genetic Study of Primary Dystonias: Recommendations from the Centro Hospitalar Sao Joao Neurogenetics Group]. AB - The primary dystonias are a particular group of dystonias of presumed genetic origin, with a wide age of onset and variable progression. The diagnosis is, therefore, a challenge and the issue of the genetic investigation presents frequently in clinical practice. In the past few years several gene mutations have been identified as causative of primary dystonias. The choice of molecular testing is complex, given the clinical specificities and low frequency of these entities and the cost of genetic testing. It must follow observation by specialized clinicians highly differentiated in this area and be supported by a rational plan of investigation. The Centro Hospitalar Sao Joao Neurogenetics Group, a multidisciplinary team of Neurologists and Geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic etiology of the primary dystonias, based on international consensus documents and recent published scientific evidence. This manuscript adopts the new classification system for genetic movement disorders, allowing for its systematic and standardized use in clinical practice. PMID- 28555564 TI - [Letter to the Editor. Urticaria in the Emergency Room: Recommendations for Diagnostic and Therapeutic Approach]. PMID- 28555566 TI - Activation of the same mGluR5 receptors in the amygdala causes divergent effects on specific versus indiscriminate fear. AB - Although mGluR5-antagonists prevent fear and anxiety, little is known about how the same receptor in the amygdala gives rise to both. Combining in vitro and in vivo activation of mGluR5 in rats, we identify specific changes in intrinsic excitability and synaptic plasticity in basolateral amygdala neurons that give rise to temporally distinct and mutually exclusive effects on fear-related behaviors. The immediate impact of mGluR5 activation is to produce anxiety manifested as indiscriminate fear of both tone and context. Surprisingly, this state does not interfere with the proper encoding of tone-shock associations that eventually lead to enhanced cue-specific fear. These results provide a new framework for dissecting the functional impact of amygdalar mGluR-plasticity on fear versus anxiety in health and disease. PMID- 28555568 TI - Famine in South Sudan. PMID- 28555565 TI - Threat of shock increases excitability and connectivity of the intraparietal sulcus. AB - Anxiety disorders affect approximately 1 in 5 (18%) Americans within a given 1 year period, placing a substantial burden on the national health care system. Therefore, there is a critical need to understand the neural mechanisms mediating anxiety symptoms. We used unbiased, multimodal, data-driven, whole-brain measures of neural activity (magnetoencephalography) and connectivity (fMRI) to identify the regions of the brain that contribute most prominently to sustained anxiety. We report that a single brain region, the intraparietal sulcus (IPS), shows both elevated neural activity and global brain connectivity during threat. The IPS plays a key role in attention orienting and may contribute to the hypervigilance that is a common symptom of pathological anxiety. Hyperactivation of this region during elevated state anxiety may account for the paradoxical facilitation of performance on tasks that require an external focus of attention, and impairment of performance on tasks that require an internal focus of attention. PMID- 28555569 TI - Breaking up is hard to do: Brexit and European science. PMID- 28555567 TI - Control of PNG kinase, a key regulator of mRNA translation, is coupled to meiosis completion at egg activation. AB - The oocyte-to-embryo transition involves extensive changes in mRNA translation, regulated in Drosophila by the PNG kinase complex whose activity we show here to be under precise developmental control. Despite presence of the catalytic PNG subunit and the PLU and GNU activating subunits in the mature oocyte, GNU is phosphorylated at Cyclin B/CDK1sites and unable to bind PNG and PLU. In vitro phosphorylation of GNU by CyclinB/CDK1 blocks activation of PNG. Meiotic completion promotes GNU dephosphorylation and PNG kinase activation to regulate translation. The critical regulatory effect of phosphorylation is shown by replacement in the oocyte with a phosphorylation-resistant form of GNU, which promotes PNG-GNU complex formation, elevation of Cyclin B, and meiotic defects consistent with premature PNG activation. After PNG activation GNU is destabilized, thus inactivating PNG. This short-lived burst in kinase activity links development with maternal mRNA translation and ensures irreversibility of the oocyte-to-embryo transition. PMID- 28555570 TI - Antimicrobial resistance and food safety in Africa. PMID- 28555571 TI - Corrections. PMID- 28555572 TI - Corrections. PMID- 28555573 TI - Corrections. PMID- 28555574 TI - MCR-1-producing Klebsiella pneumoniae outbreak in China. PMID- 28555575 TI - Defining sepsis: inspiring proposals meet practical realities. PMID- 28555576 TI - Pharmaceutical waste and antimicrobial resistance. PMID- 28555577 TI - e-learning for global antimicrobial stewardship. PMID- 28555578 TI - Staphylococcus aureus in critical care. PMID- 28555579 TI - Staphylococcus aureus in critical care - Authors' reply. PMID- 28555580 TI - Laminar flow ventilation during surgery. PMID- 28555581 TI - Helminths in organ transplantation. PMID- 28555582 TI - Helminths in organ transplantation. PMID- 28555583 TI - Helminths in organ transplantation - Authors' reply. PMID- 28555584 TI - Ending neglected tropical diseases. PMID- 28555585 TI - Highlights from the 27th ECCMID. PMID- 28555586 TI - Seasonal malaria chemoprevention in the Sahel. PMID- 28555587 TI - HIV in the Philippines. PMID- 28555590 TI - Pneumomediastinum and subcutaneous emphysema associated with influenza A H1N1 virus. PMID- 28555591 TI - Noma in a patient with HIV. PMID- 28555592 TI - Repositionable percutaneous aortic valve implantation with the LOTUS valve: 30 day and 1-year outcomes in 250 high-risk surgical patients. AB - AIMS: The REPRISE IIE trial aimed to evaluate outcomes following transcatheter aortic valve implantation of the fully repositionable and retrievable LOTUS valve with a unique seal designed to minimise paravalvular leak (PVL). METHODS AND RESULTS: This prospective, multicentre study enrolled 250 patients with severe aortic stenosis considered high-risk for surgery by a multidisciplinary Heart Team. An independent clinical events committee adjudicated events per Valve Academic Research Consortium criteria. Mean age was 84 years; 77% were in NYHA Class III/IV. LOTUS valve implantation produced significant haemodynamic improvements at one year without valve embolisation, ectopic valve deployment, or additional valve implantation. Primary endpoints were met as the 30-day mortality rate in the extended cohort (4.4%, N=250), and mean valve gradient in the main cohort (11.5+/-5.2 mmHg, N=120) were below (p<0.001) their predefined performance objectives. At 30 days, disabling stroke was 2.8% and new pacemaker implantation was 28.9% in all patients and 32.0% in pacemaker-naive patients. By one year, all cause mortality was 11.6%, disabling stroke was 3.6%, 95% of patients alive were in NYHA Class I/II, and there was no core laboratory-adjudicated moderate/severe PVL. CONCLUSIONS: LOTUS valve implantation produced good valve haemodynamics, minimal PVL, sustained significant improvement in functional status, and good clinical outcomes one year post implant. PMID- 28555593 TI - 3D printed models in patients with coronary artery fistulae: anatomical assessment and interventional planning. AB - AIMS: Coronary artery fistulae represent one of the most challenging anatomical defects to define accurately. We aimed to investigate the additional benefit conferred by volume rendering of tomographic images and 3D printing for diagnosis and interventional planning. METHODS AND RESULTS: Four cases of coronary fistulae were considered for transcatheter closure. Multidetector computed tomography (three cases) or cardiac magnetic resonance (one case) images were acquired and segmented using Mimics software. Each case was reviewed after incremental consideration of diagnostic resources: two cardiologists reported source and volume-rendered images; device closure was discussed by the interventional cardiology team. All diagnoses and planned management were reviewed after inspection of a 3D model. Using source images alone, both cardiologists correctly described the course and drainage in two out of four cases. Aided by volume rendering, this improved to three out of four cases. Inspection of the 3D printed model prompted the planned interventional approach and device sizing to be altered in two out of four cases. In one out of four cases, the intervention was abandoned after inspection of the 3D printed model. CONCLUSIONS: Diagnosis and management of patients with coronary artery fistulae rely on detailed image analyses. 3D models add value when determining the feasibility of, and the approach to intervention in these cases. PMID- 28555594 TI - Carag bioresorbable septal occluder (CBSO): histopathology of experimental implants. AB - AIMS: The aim of this study was to evaluate local biological responses to the partially bioresorbable nonmetal frame Carag bioresorbable septal occluder system in an experimental setting. METHODS AND RESULTS: A Good Laboratory Practices (GLP) study was performed with implantation of the device into the interatrial septum of 24 German Landrace pigs with follow-up periods of 3, 5, 8 and 15 months (six animals in each group). One non-implant-related death occurred one month after implantation. Histology was obtained by sawing and grinding of the hard resin embedded specimen after formalin fixation. All occlusion devices were found correctly positioned without any residual shunt at the end of the experiments. Complete endothelialisation could be confirmed histologically in all specimens independent of implantation period. There were only a few lymphocytic infiltrations locally related to the implant materials. Sporadic macrophages and foreign body giant cells were found adjacent to the textile fabric. Resorption of the biodegradable frame material was seen to proceed with implantation time. CONCLUSIONS: This is the first report on histopathology of a septal defect occluder with a bioresorbable filament structure in vivo which is already in clinical use. Good biocompatibility was demonstrated with documentation of timely degradation and substitution of the polymer material by fibromuscular cells and extracellular matrix components. PMID- 28555595 TI - Endoscopic vs Microscopic Approach in Stapes Surgery: Advantages in the Middle Ear Structures Visualization and Trainee's Point of View. AB - OBJECTIVE: Comparing the endoscopic and microscopic approaches in stapes surgery, and establishing the surgical approach that allows better results in terms of visualization of the middle ear structures and aids assistant's training. MATERIALS AND METHODS: Twenty-one residents from the first to the fifth year of training in Otolaryngology were enrolled in this prospective study. A questionnaire specifically designed to investigate the understanding of middle ear anatomy, the surgical steps, and a personal opinion about endoscopic stapes surgery was submitted to each resident. RESULTS: Statistical differences between the endoscopic and microscopic approaches were evident about identification of stapes and long process of the incus (p=0.03) and stapes footplate and the oval window (p=0.03). No substantial difference between the two surgical approaches emerged regarding the visualization of the tympanic membrane and the other middle ear structures (p>0.5). A substantial difference in favor of the endoscopic approach emerged regarding the identification of the hole creation in the footplate of the stapes. CONCLUSION: Endoscopic stapes surgery could favor an easier understanding of the surgical technique for assistants in training with little knowledge of the anatomy and surgical steps. PMID- 28555597 TI - Hyperbaric Oxygen Therapy as Salvage Therapy for Sudden Sensorineural Hearing Loss. AB - OBJECTIVE: To measure the effect of hyperbaric oxygen (HBO) therapy as salvage therapy after the failure of steroid therapy for sudden sensorineural hearing loss (SSNHL). MATERIALS AND METHODS: Ninety-three patients with SSNHL were unsuccessfully treated with systemic steroid therapy. Following steroid therapy, 43 patients received additional HBO therapy while 50 did not. Hearing levels at 0.25, 0.5, 1, 2, 4, and 8 kHz before and after therapy were measured. RESULTS: A significant difference in hearing thresholds after HBO therapy was found at all frequencies in patients with a hearing loss of >61 dB. The group of patients with a hearing threshold of <=60 dB had a significant improvement only at 250 and 500 Hz, while group of patients without additional therapy control group showed no hearing improvement. CONCLUSION: Hyperbaric oxygen therapy therapy as salvage therapy for SSNHL showed some benefits in hearing improvement. Better results could be expected in patients with severe hearing loss, while in patients with mild-or-moderate hearing loss, recovery should be expected only at low frequencies. PMID- 28555596 TI - Comparative Analysis of Laser and Non-Laser Stapes Surgeries. AB - OBJECTIVE: This study aimed to observe differences in the efficacy of laser and surgical treatments of middle-ear conductive hearing loss (MECHL). MATERIALS AND METHODS: A total of 276 ears of 267 patients with MECHL were divided into laser (n=172) and surgical (n=104) treatment groups according to the treatment method. Changes in the air-bone gap (ABG) after treatment and at the time of final follow up were compared. An ABG value <20 dB was defined as effective and an ABG value <10 dB, significantly effective. The long-term treatment effects were also compared at the time of final follow-up. Additionally, postoperative adverse reactions were recorded for both the groups. RESULTS: The mean follow-up period was 76.77+/-43.62 months (range: 12-168 months). No significant difference in ABG was found between the two groups (21.31+/-11.64 dB vs. 19.14+/-9.79 dB, p>0.05). However, the laser treatment group showed slightly better results than the surgical treatment group at the final follow-up, although the difference between the groups was not found to be significant (11.69+/-9.98 dB vs. 12.62+/-10.94 dB, p>0.05). There was no difference in the long-term treatment effects between the two groups (effective: 87.21% vs. 88.46%, p>0.05; significantly effective: 55.81% vs. 56.73%, p>0.05). The incidence rates of postoperative adverse reactions were not significantly different. CONCLUSION: The treatment efficacy of laser and surgical treatments for MECHL are similar. PMID- 28555598 TI - Test-Retest Reliability of the Components of Multi-Frequency Tympanometry. AB - OBJECTIVE: Multi-frequency tympanometry and its components are extensively used to identify middle ear disorders. However, there are a limited number of studies that have attempted to determine its test-retest reliability. Thus, the present study attempted to determine the test-retest reliability of the different components of multi-frequency tympanometry. MATERIALS AND METHODS: The resonant frequency (RF), F45, and DeltaG were determined three times in 40adults with normal hearing. The results obtained across the three trials were compared to determine the test-retest reliability. RESULTS: F45 and DeltaG had excellent intra- and inter-session reliabilities. The reliability of the RF was also good, but it was relatively less compared to that of the other two measures. The study also showed that there was no effect of gender on the reliability measures. CONCLUSION: Thus, F45 and DeltaG can be clinically used considering theirhigh reliability, and the RF should be interpreted with caution. However, further studies on a larger group of patientsincluding a clinical group are essential for determining the further applicability of these results. PMID- 28555599 TI - Speech Perception in Quiet and in Noise Condition in Individuals with Auditory Neuropathy Spectrum Disorder. AB - OBJECTIVE: The study investigated the effect of noise on syllable perception in individuals with Auditory Neuropathy Spectrum Disorder (ANSD) and compared that with the normal hearing individuals. MATERIALS AND METHODS: A total of 54 participants were considered, out of which 26 individuals were diagnosed with ANSD and 28 with normal hearing sensitivity. Syllable identification and discrimination were assessed in both the groups in quiet as well as +10 dB SNR. RESULTS: All the individuals with ANSD performed poorer on syllable identification and syllable discrimination tasks compared to individuals with normal hearing. Information transfer and d-prime analyses revealed that noise affects the perception of voicing information in individuals with ANSD compared to place and manner information. Among the consonants tested, /pa/ was more resistant to noise. CONCLUSION: Noise had deleterious effects on speech perception in individuals with ANSD. Low-frequency information appears to be more susceptible to the effects of noise in individuals with ANSD. PMID- 28555600 TI - Audiological Findings in Charcot-Marie-Tooth Disease Type 4C. AB - OBJECTIVE: Charcot-Marie-Tooth disease type 4C (CMT4C) is a hereditary demyelinating early onset neuropathy with prominent unsteadiness and occasional cranial nerve involvement. Vestibulopathy caused by the dysfunction of cranial nerve VIII has been demonstrated in a high percentage of these patients, but the presence and degree of auditory neuropathy are unknown. The aim of the study was to characterize the hearing abnormalities of a series of patients with CMT4C and to determine the presence and severity of auditory neuropathy (AN) in these patients. MATERIALS AND METHODS: Ten patients with genetically confirmed CMT4C underwent comprehensive clinical and audiological testing. The results were compared among patients in different age groups and also to the results of vestibular testing that had already been performed. RESULTS: Only 3 patients had hearing problems, but 9 had hearing abnormalities on ancillary testing that were compatible with different degrees of auditory nerve dysfunction. In the mildest cases, only the abnormality of the stapedial reflex and distortion of wave I in auditory brainstem responses could be detected. In the more severe cases, tonal audiometry revealed asymmetric hearing loss. These findings were more severe in older patients, even after correcting for age-related hypoacusia. In these patients, vestibular dysfunction could also be detected and seemed to be more profound and symmetric than hearing loss. CONCLUSION: This report confirms and defines the presence of different degrees of auditory neuropathy in all patients with CMT4C, being detectable, usually unilaterally, during infancy, and worsening with disease progression. PMID- 28555601 TI - Influence of Smoking on Ultra-High-Frequency Auditory Sensitivity. AB - OBJECTIVE: In this study, an attempt was made to determine the effect of smoking on ultra-high-frequency auditory sensitivity. The study also attempted to determine the relationship between the nature of smoking and ultra-high-frequency otoacoustic emissions (OAEs) and thresholds. MATERIALS AND METHODS: The study sample included 25 smokers and 25 non-smokers. A detailed history regarding their smoking habits was collected. High-frequency audiometric thresholds and amplitudes of high-frequency distortion-product OAEs were analyzed for both ears from all participants. RESULTS: The results showed that the ultra-high-frequency thresholds were elevated and that there was reduction in the amplitudes of ultra high-frequency OAEs in smokers. There was an increased risk of auditory damage with chronic smoking. CONCLUSION: The study results highlight the application of ultra-high-frequency OAEs and ultra-high-frequency audiometry for the early detection of auditory impairment. However, similar studies should be conducted on a larger population for better generalization of the results. PMID- 28555602 TI - Efficacy of Directional Microphones in Hearing Aids Equipped with Wireless Synchronization Technology. AB - OBJECTIVE: This study aimed to evaluate the use of directionality in hearing aids with wireless synchronization on localization and speech intelligibility in noise. MATERIALS AND METHODS: This study included 25 individuals with bilateral mild to moderate flat sensorineural hearing loss. For the localization experiment, eight loudspeakers (Genelec 8020B) arranged in a circle covering a 0 360 degrees angle and the Cubase 6 software were used for presenting the stimulus. A car horn of 260 ms was presented from these loudspeakers, one at a time, randomly. The listener was instructed to point to the direction of the source. The degree of the localization error was obtained with and without directionality and wireless synchronization options. For speech perception in a noise experiment, signal to noise ratio-50 (SNR-50) was obtained using sentences played through a speaker at a fixed angle of 0 degrees . A calibrated eight talker speech babble was used as noise and the babble was routed either through 0 degrees , 90 degrees , 270 degrees (through one speaker at a time) or through both 90 degrees and 270 degrees speakers. RESULTS: The results revealed that the conditions where both the wireless synchronization and directionality were activated resulted in a significantly better performance in both localization and speech perception in noise tasks. CONCLUSION: It can be concluded that the directionality in the wireless synchronization hearing aids coordinates with each other binaurally for better preservation of binaural cues, thus reducing the localization errors and improving speech perception in noise. The results of this study could be used to counsel and justify the selection of the directional wireless synchronization hearing aids. PMID- 28555603 TI - Virtual Auditory Space Training-Induced Changes of Auditory Spatial Processing in Listeners with Normal Hearing. AB - OBJECTIVE: Localization involves processing of subtle yet highly enriched monaural and binaural spatial cues. Remediation programs aimed at resolving spatial deficits are surprisingly scanty in literature. The present study is designed to explore the changes that occur in the spatial performance of normal hearing listeners before and after subjecting them to virtual acoustic space (VAS) training paradigm using behavioral and electrophysiological measures. MATERIALS AND METHODS: Ten normal-hearing listeners participated in the study, which was conducted in three phases, including a pre-training, training, and post training phase. At the pre- and post-training phases both behavioral measures of spatial acuity and electrophysiological P300 were administered. The spatial acuity of the participants in the free field and closed field were measured apart from quantifying their binaural processing abilities. The training phase consisted of 5-8 sessions (20 min each) carried out using a hierarchy of graded VAS stimuli. RESULTS: The results obtained from descriptive statistics were indicative of an improvement in all the spatial acuity measures in the post training phase. Statistically, significant changes were noted in interaural time difference (ITD) and virtual acoustic space identification scores measured in the post-training phase. Effect sizes (r) for all of these measures were substantially large, indicating the clinical relevance of these measures in documenting the impact of training. However, the same was not reflected in P300. CONCLUSION: The training protocol used in the present study on a preliminary basis proves to be effective in normal-hearing listeners, and its implications can be extended to other clinical population as well. PMID- 28555604 TI - Designing a Method with Physician Participation to Assess and Improve Quality of Healthcare in Otolaryngology. AB - OBJECTIVE: Patient choice of healthcare centers to be treated for specific diseases is compromised by the low accessibility of understandable information. Physicians are rarely involved in healthcare quality assessment, despite their potentially valuable input. The purpose of this study was to develop a methodology for evaluating the quality of care that specifically incorporates advice from medical specialists and provides accessible information for patients in search of high-quality healthcare. MATERIALS AND METHODS: A pilot Delphi study was conducted among 28 Spanish otolaryngology experts, seeking their opinion on the quality-of-care indicators and on their ability to recommend the most suitable department for the treatment of specific otolaryngologic diseases. RESULTS: The average acceptance rate was 91.9% for quality-of-care indicator and 96.5% for the resources needed for improving the quality of care. Furthermore, 93% experts reported that patients frequently ask for physician advice on which center provides better care for a specific disease, 92.6% experts believe they could recommend the best centers for specific otolaryngologic diseases, and 80% experts agreed that expert opinion on the quality of care offered by different centers would be a valuable addition to quality-of-care assessment. CONCLUSION: The incorporation of physician advice into healthcare quality assessment may improve the usefulness of healthcare quality indicators for patients. Assessment tools incorporating physician advice should be developed and validated. PMID- 28555605 TI - Surgical Treatment for Epstein-Barr Virus Otomastoiditis Complicated by Facial Nerve Paralysis: A Case Report of Two Young Brothers and Review of Literature. AB - We report the case of two young brothers with Epstein-Barr virus (EBV) otomastoiditis complicated by a facial nerve paralysis. The boys, aged 7 months (patient A) and 2 years and 8 months (patient B), were diagnosed with a facial nerve paralysis House-Brackmann (HB) grade IV (A) and V (B). After unsuccessful pharmacological treatment, patient A underwent mastoidectomy and atticoantrotomy and patient B underwent a transmastoidal surgical decompression of the facial nerve. They recovered to HB grades I and II facial nerve palsy (FNP), respectively. Although rare and relatively unknown, EBV should be considered in the differential diagnosis of children with FNP of unknown cause. Surgical intervention may be a viable therapy with good recovery. PMID- 28555606 TI - A Comprehensive Insight into the Rehabilitative Treatment of Persistent Benign Paroxysmal Positional Vertigo. PMID- 28555607 TI - Should Bone Cement be Used Only in Limited Ossicular Chain Defects? PMID- 28555608 TI - Does Hypericum Perforatum Have Inflammatory or Anti-Inflammatory Effects? PMID- 28555609 TI - Erratum. AB - The editorial by Arun K. Gadre entitled "The Problem of Gift and Honorary Authorship - Who is an Author?" (J Int Adv Otol 2016; 12), Obtituaries by David A. Moffat entitled "In Memoriam: Per Moller"(J Int Adv Otol 2016; 12: 222) and by Angel Ramos Macias entitled "In Memoriam: John Niparko" (J Int Adv Otol 2016; 12: 223) were published without a DOI due to a technical error. These papers were since provided with the DOIs listed below; * Arun K. Gadre. The Problem of Gift and Honorary Authorship - Who is an Author? DOI: 10.5152/iao.2017.31013 * David A. Moffat. In Memoriam: Per Moller. DOI: 10.5152/iao.2017.31011 * Angel Ramos Macias. In Memoriam: John Niparko. DOI: 10.5152/iao.2017.31012. PMID- 28555610 TI - Effect of polymer residues on the electrical properties of large-area graphene hexagonal boron nitride planar heterostructures. AB - Polymer residue plays an important role in the performance of 2D heterostructured materials. Herein, we study the effect of polymer residual impurities on the electrical properties of graphene-boron nitride planar heterostructures. Large area graphene (Gr) and hexagonal boron nitride (h-BN) monolayers were synthesized using chemical vapor deposition techniques. Atomic van-der-Waals heterostructure layers based on varied configurations of Gr and h-BN layers were assembled. The average interlayer resistance of the heterojunctions over a 1 cm2 area for several planar heterostructure configurations was assessed by impedance spectroscopy and modeled by equivalent electrical circuits. Conductive AFM measurements showed that the presence of polymer residues on the surface of the Gr and h-BN monolayers resulted in significant resistance deviations over nanoscale regions. PMID- 28555611 TI - Real-time inference of word relevance from electroencephalogram and eye gaze. AB - OBJECTIVE: Brain-computer interfaces can potentially map the subjective relevance of the visual surroundings, based on neural activity and eye movements, in order to infer the interest of a person in real-time. APPROACH: Readers looked for words belonging to one out of five semantic categories, while a stream of words passed at different locations on the screen. It was estimated in real-time which words and thus which semantic category interested each reader based on the electroencephalogram (EEG) and the eye gaze. MAIN RESULTS: Words that were subjectively relevant could be decoded online from the signals. The estimation resulted in an average rank of 1.62 for the category of interest among the five categories after a hundred words had been read. SIGNIFICANCE: It was demonstrated that the interest of a reader can be inferred online from EEG and eye tracking signals, which can potentially be used in novel types of adaptive software, which enrich the interaction by adding implicit information about the interest of the user to the explicit interaction. The study is characterised by the following novelties. Interpretation with respect to the word meaning was necessary in contrast to the usual practice in brain-computer interfacing where stimulus recognition is sufficient. The typical counting task was avoided because it would not be sensible for implicit relevance detection. Several words were displayed at the same time, in contrast to the typical sequences of single stimuli. Neural activity was related with eye tracking to the words, which were scanned without restrictions on the eye movements. PMID- 28555612 TI - Development of an advanced radioactive airborne particle monitoring system for use in early warning networks. AB - Automatic real-time warning networks are essential for the almost immediate detection of anomalous levels of radioactivity in the environment. In the case of Extremadura region (SW Spain), a radiological network (RARE) has been operational in the vicinity of the Almaraz nuclear power plant and in other areas farther away since 1992. There are ten air monitoring stations equipped with Geiger Muller counters in order to evaluate the external ambient gamma dose rate. Four of these stations have a commercial system that provides estimates of the total artificial alpha and beta activity concentrations in aerosols, and of the 131I activity (gaseous fraction). Despite experience having demonstrated the benefits and robustness of these commercial systems, important improvements have been made to one of these air monitoring systems. In this paper, the analytical and maintenance shortcomings of the original commercial air monitoring system are described first; the new custom-designed advanced air monitoring system is then presented. This system is based mainly on the incorporation of gamma spectrometry using two scintillation detectors, one of NaI:Tl and the other of LaBr3:Ce, and compact multichannel analysers. Next, a comparison made of the results provided by the two systems operating simultaneously at the same location for three months shows the advantages of the new advanced air monitoring system. As a result, the gamma spectrometry analysis allows passing from global alpha and beta activity determinations due to artificial radionuclides in aerosols, and the inaccurate measurement of the gaseous 131I activity concentration, to the possibility of identifying a large number of radionuclides and quantifying each of their activity concentrations. Moreover, the new station's dual capacity is designed to work in early warning monitoring mode and surveillance monitoring mode. This is based on custom developed software that includes an intelligent system to issue the necessary warnings when radiological anomalies or technical problems are identified. Implicitly, for the construction of the advanced station, substantial mechanical and electronic developments have been required. They have essentially consisted of integrating a new replacement device, whose operation has reduced the maintenance tasks. PMID- 28555613 TI - Superconducting gap structure in the electron doped BiS2-based superconductor. AB - The influence of electron doping on semimetallic SrFBiS2 has been investigated by means of resistivity, zero and transverse - field (ZF/TF) muon spin relaxation/rotation (MUSR) experiments. SrFBiS2 is semimetallic in its normal state and small amounts of La doping results in bulk superconductivity at 2.8 K, at ambient pressure. The temperature dependence of the superfluid density as determined by TF-MUSR can be best modelled by an isotropic s - wave type superconducting gap. We have estimated the magnetic penetration depth [Formula: see text] nm, superconducting carrier density [Formula: see text] carriers m-3 and effective-mass enhancement m * = 1.558 m e. Additionally, there is no clear sign of the occurrence of spontaneous internal magnetic fields below [Formula: see text], which implies that the superconducting state in this material can not be categorized by the broken time-reversal symmetry which is in agreement with the previous theoretical prediction. PMID- 28555614 TI - Global Regulation of Differential Gene Expression by c-Abl/Arg Oncogenic Kinases. AB - BACKGROUND Studies have found that c-Abl oncogenic kinases may regulate gene transcription by RNA polymerase II phosphorylation or by direct regulation of specific transcription factors or coactivators. However, the global regulation of differential gene expression by c-Abl/Arg is largely unknown. In this study, differentially expressed genes (DEGs) regulated by c-Abl/Arg were identified, and related cellular functions and associated pathways were investigated. MATERIAL AND METHODS RNA obtained from wild-type and c-Abl/Arg gene-silenced MCF-7 cells was analyzed by RNA-Seq. DEGs were identified using edgeR software and partially validated by qRT-PCR. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to explore the potential functions of these DEGs. RESULTS A total of 1,034 DEGs were significantly regulated by c Abl/Arg (399 were up-regulated and 635 were down-regulated after c-Abl/Arg double knockdown). GO and KEGG analyses showed that the DEGs were primarily involved in cellular metabolic processes, neurodegenerative disease, the metabolic process and signaling pathway of cAMP, angiogenesis, and cell proliferation. CONCLUSIONS Our data collectively support the hypothesis that c-Abl/Arg regulate differential gene expression, providing new insights into the biological functions of c-Abl and Arg. PMID- 28555615 TI - Hydrodynamic cavitation in Stokes flow of anisotropic fluids. AB - Cavitation, the nucleation of vapour in liquids, is ubiquitous in fluid dynamics, and is often implicated in a myriad of industrial and biomedical applications. Although extensively studied in isotropic liquids, corresponding investigations in anisotropic liquids are largely lacking. Here, by combining liquid crystal microfluidic experiments, nonequilibrium molecular dynamics simulations and theoretical arguments, we report flow-induced cavitation in an anisotropic fluid. The cavitation domain nucleates due to sudden pressure drop upon flow past a cylindrical obstacle within a microchannel. For an anisotropic fluid, the inception and growth of the cavitation domain ensued in the Stokes regime, while no cavitation was observed in isotropic liquids flowing under similar hydrodynamic parameters. Using simulations we identify a critical value of the Reynolds number for cavitation inception that scales inversely with the order parameter of the fluid. Strikingly, the critical Reynolds number for anisotropic fluids can be 50% lower than that of isotropic fluids. PMID- 28555616 TI - Central and peripheral clocks are coupled by a neuropeptide pathway in Drosophila. AB - Animal circadian clocks consist of central and peripheral pacemakers, which are coordinated to produce daily rhythms in physiology and behaviour. Despite its importance for optimal performance and health, the mechanism of clock coordination is poorly understood. Here we dissect the pathway through which the circadian clock of Drosophila imposes daily rhythmicity to the pattern of adult emergence. Rhythmicity depends on the coupling between the brain clock and a peripheral clock in the prothoracic gland (PG), which produces the steroid hormone, ecdysone. Time information from the central clock is transmitted via the neuropeptide, sNPF, to non-clock neurons that produce the neuropeptide, PTTH. These secretory neurons then forward time information to the PG clock. We also show that the central clock exerts a dominant role on the peripheral clock. This use of two coupled clocks could serve as a paradigm to understand how daily steroid hormone rhythms are generated in animals. PMID- 28555618 TI - Coherent control of the silicon-vacancy spin in diamond. AB - Spin impurities in diamond have emerged as a promising building block in a wide range of solid-state-based quantum technologies. The negatively charged silicon vacancy centre combines the advantages of its high-quality photonic properties with a ground-state electronic spin, which can be read out optically. However, for this spin to be operational as a quantum bit, full quantum control is essential. Here we report the measurement of optically detected magnetic resonance and the demonstration of coherent control of a single silicon-vacancy centre spin with a microwave field. Using Ramsey interferometry, we directly measure a spin coherence time, T2*, of 115+/-9 ns at 3.6 K. The temperature dependence of coherence times indicates that dephasing and decay of the spin arise from single-phonon-mediated excitation between orbital branches of the ground state. Our results enable the silicon-vacancy centre spin to become a controllable resource to establish spin-photon quantum interfaces. PMID- 28555617 TI - A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells. AB - Approximately 70% of breast cancer cells express oestrogen receptor alpha (ERalpha). Previous studies have shown that the Brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex has a crucial role in these cells. However, it remains unclear how BIG3 regulates the suppressive activity of PHB2. Here we demonstrate that BIG3 functions as an A-kinase anchoring protein that binds protein kinase A (PKA) and the alpha isoform of the catalytic subunit of protein phosphatase 1 (PP1Calpha), thereby dephosphorylating and inactivating PHB2. E2-induced PKA-mediated phosphorylation of BIG3-S305 and S1208 serves to enhance PP1Calpha activity, resulting in E2/ERalpha signalling activation via PHB2 inactivation due to PHB2-S39 dephosphorylation. Furthermore, an analysis of independent cohorts of ERalpha-positive breast cancers patients reveal that both BIG3 overexpression and PHB2-S39 dephosphorylation are strongly associated with poor prognosis. This is the first demonstration of the mechanism of E2/ERalpha signalling activation via the BIG3-PKA-PP1Calpha tri-complex in breast cancer cells. PMID- 28555619 TI - Probing the early stages of shock-induced chondritic meteorite formation at the mesoscale. AB - Chondritic meteorites are fragments of asteroids, the building blocks of planets, that retain a record of primordial processes. Important in their early evolution was impact-driven lithification, where a porous mixture of millimetre-scale chondrule inclusions and sub-micrometre dust was compacted into rock. In this Article, the shock compression of analogue precursor chondrite material was probed using state of the art dynamic X-ray radiography. Spatially-resolved shock and particle velocities, and shock front thicknesses were extracted directly from the radiographs, representing a greatly enhanced scope of data than could be measured in surface-based studies. A statistical interpretation of the measured velocities showed that mean values were in good agreement with those predicted using continuum-level modelling and mixture theory. However, the distribution and evolution of wave velocities and wavefront thicknesses were observed to be intimately linked to the mesoscopic structure of the sample. This Article provides the first detailed experimental insight into the distribution of extreme states within a shocked powder mixture, and represents the first mesoscopic validation of leading theories concerning the variation in extreme pressure temperature states during the formation of primordial planetary bodies. PMID- 28555620 TI - Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbalpha. AB - Inflammation and thrombosis occur together in many diseases. The leukocyte integrin Mac-1 (also known as integrin alphaMbeta2, or CD11b/CD18) is crucial for leukocyte recruitment to the endothelium, and Mac-1 engagement of platelet GPIbalpha is required for injury responses in diverse disease models. However, the role of Mac-1 in thrombosis is undefined. Here we report that mice with Mac-1 deficiency (Mac-1-/-) or mutation of the Mac-1-binding site for GPIbalpha have delayed thrombosis after carotid artery and cremaster microvascular injury without affecting parameters of haemostasis. Adoptive wild-type leukocyte transfer rescues the thrombosis defect in Mac-1-/- mice, and Mac-1-dependent regulation of the transcription factor Foxp1 contributes to thrombosis as evidenced by delayed thrombosis in mice with monocyte-/macrophage-specific overexpression of Foxp1. Antibody and small-molecule targeting of Mac-1:GPIbalpha inhibits thrombosis. Our data identify a new pathway of thrombosis involving leukocyte Mac-1 and platelet GPIbalpha, and suggest that targeting this interaction has anti-thrombotic therapeutic potential with reduced bleeding risk. PMID- 28555621 TI - Deposition and drying dynamics of liquid crystal droplets. AB - Drop drying and deposition phenomena reveal a rich interplay of fundamental science and engineering, give rise to fascinating everyday effects (coffee rings), and influence technologies ranging from printing to genotyping. Here we investigate evaporation dynamics, morphology, and deposition patterns of drying lyotropic chromonic liquid crystal droplets. These drops differ from typical evaporating colloidal drops primarily due to their concentration-dependent isotropic, nematic, and columnar phases. Phase separation occurs during evaporation, and in the process creates surface tension gradients and significant density and viscosity variation within the droplet. As a result, the drying multiphase drops exhibit different convective currents, drop morphologies, and deposition patterns (coffee-rings). PMID- 28555622 TI - Zooming in on the phycosphere: the ecological interface for phytoplankton bacteria relationships. AB - By controlling nutrient cycling and biomass production at the base of the food web, interactions between phytoplankton and bacteria represent a fundamental ecological relationship in aquatic environments. Although typically studied over large spatiotemporal scales, emerging evidence indicates that this relationship is often governed by microscale interactions played out within the region immediately surrounding individual phytoplankton cells. This microenvironment, known as the phycosphere, is the planktonic analogue of the rhizosphere in plants. The exchange of metabolites and infochemicals at this interface governs phytoplankton-bacteria relationships, which span mutualism, commensalism, antagonism, parasitism and competition. The importance of the phycosphere has been postulated for four decades, yet only recently have new technological and conceptual frameworks made it possible to start teasing apart the complex nature of this unique microbial habitat. It has subsequently become apparent that the chemical exchanges and ecological interactions between phytoplankton and bacteria are far more sophisticated than previously thought and often require close proximity of the two partners, which is facilitated by bacterial colonization of the phycosphere. It is also becoming increasingly clear that while interactions taking place within the phycosphere occur at the scale of individual microorganisms, they exert an ecosystem-scale influence on fundamental processes including nutrient provision and regeneration, primary production, toxin biosynthesis and biogeochemical cycling. Here we review the fundamental physical, chemical and ecological features of the phycosphere, with the goal of delivering a fresh perspective on the nature and importance of phytoplankton-bacteria interactions in aquatic ecosystems. PMID- 28555623 TI - Redesigning metabolism based on orthogonality principles. AB - Modifications made during metabolic engineering for overproduction of chemicals have network-wide effects on cellular function due to ubiquitous metabolic interactions. These interactions, that make metabolic network structures robust and optimized for cell growth, act to constrain the capability of the cell factory. To overcome these challenges, we explore the idea of an orthogonal network structure that is designed to operate with minimal interaction between chemical production pathways and the components of the network that produce biomass. We show that this orthogonal pathway design approach has significant advantages over contemporary growth-coupled approaches using a case study on succinate production. We find that natural pathways, fundamentally linked to biomass synthesis, are less orthogonal in comparison to synthetic pathways. We suggest that the use of such orthogonal pathways can be highly amenable for dynamic control of metabolism and have other implications for metabolic engineering. PMID- 28555624 TI - Conjugation of squalene to gemcitabine as unique approach exploiting endogenous lipoproteins for drug delivery. AB - Once introduced in the organism, the interaction of nanoparticles with various biomolecules strongly impacts their fate. Here we show that nanoparticles made of the squalene derivative of gemcitabine (SQGem) interact with lipoproteins (LPs), indirectly enabling the targeting of cancer cells with high LP receptors expression. In vitro and in vivo experiments reveal preeminent affinity of the squalene-gemcitabine bioconjugates towards LP particles with the highest cholesterol content and in silico simulations further display their incorporation into the hydrophobic core of LPs. To the best of our knowledge, the use of squalene to induce drug insertion into LPs for indirect cancer cell targeting is a novel concept in drug delivery. Interestingly, not only SQGem but also other squalene derivatives interact similarly with lipoproteins while such interaction is not observed with liposomes. The conjugation to squalene represents a versatile platform that would enable efficient drug delivery by simply exploiting endogenous lipoproteins. PMID- 28555625 TI - Co-infecting microorganisms dramatically alter pathogen gene essentiality during polymicrobial infection. AB - Identifying genes required by pathogens during infection is critical for antimicrobial development. Here, we use a Monte Carlo simulation-based method to analyse high-throughput transposon sequencing data to determine the role of infection site and co-infecting microorganisms on the in vivo 'essential' genome of Staphylococcus aureus. We discovered that co-infection of murine surgical wounds with Pseudomonas aeruginosa results in conversion of ~25% of the in vivo S. aureus mono-culture essential genes to non-essential. Furthermore, 182 S. aureus genes are uniquely essential during co-infection. These 'community dependent essential' (CoDE) genes illustrate the importance of studying pathogen gene essentiality in polymicrobial communities. PMID- 28555627 TI - Amazonian forest-savanna bistability and human impact. AB - A bimodal distribution of tropical tree cover at intermediate precipitation levels has been presented as evidence of fire-induced bistability. Here we subdivide satellite vegetation data into those from human-unaffected areas and those from regions close to human-cultivated zones. Bimodality is found to be almost absent in the unaffected regions, whereas it is significantly enhanced close to cultivated zones. Assuming higher logging rates closer to cultivated zones and spatial diffusion of fire, our spatiotemporal mathematical model reproduces these patterns. Given a gradient of climatic and edaphic factors, rather than bistability there is a predictable spatial boundary, a Maxwell point, that separates regions where forest and savanna states are naturally selected. While bimodality can hence be explained by anthropogenic edge effects and natural spatial heterogeneity, a narrow range of bimodality remaining in the human unaffected data indicates that there is still bistability, although on smaller scales than claimed previously. PMID- 28555626 TI - Discovery of extremely halophilic, methyl-reducing euryarchaea provides insights into the evolutionary origin of methanogenesis. AB - Methanogenic archaea are major players in the global carbon cycle and in the biotechnology of anaerobic digestion. The phylum Euryarchaeota includes diverse groups of methanogens that are interspersed with non-methanogenic lineages. So far, methanogens inhabiting hypersaline environments have been identified only within the order Methanosarcinales. We report the discovery of a deep phylogenetic lineage of extremophilic methanogens in hypersaline lakes and present analysis of two nearly complete genomes from this group. Within the phylum Euryarchaeota, these isolates form a separate, class-level lineage 'Methanonatronarchaeia' that is most closely related to the class Halobacteria. Similar to the Halobacteria, 'Methanonatronarchaeia' are extremely halophilic and do not accumulate organic osmoprotectants. The high intracellular concentration of potassium implies that 'Methanonatronarchaeia' employ the 'salt-in' osmoprotection strategy. These methanogens are heterotrophic methyl-reducers that use C1-methylated compounds as electron acceptors and formate or hydrogen as electron donors. The genomes contain an incomplete and apparently inactivated set of genes encoding the upper branch of methyl group oxidation to CO2 as well as membrane-bound heterodisulfide reductase and cytochromes. These features differentiate 'Methanonatronarchaeia' from all known methyl-reducing methanogens. The discovery of extremely halophilic, methyl-reducing methanogens related to haloarchaea provides insights into the origin of methanogenesis and shows that the strategies employed by methanogens to thrive in salt-saturating conditions are not limited to the classical methylotrophic pathway. PMID- 28555628 TI - Morphogenesis of liquid crystal topological defects during the nematic-smectic A phase transition. AB - The liquid crystalline phases of matter each possess distinct types of defects that have drawn great interest in areas such as topology, self-assembly and material micropatterning. However, relatively little is known about how defects in one liquid crystalline phase arise from defects or deformations in another phase upon crossing a phase transition. Here, we directly examine defects in the in situ thermal phase transition from nematic to smectic A in hybrid-aligned liquid crystal droplets on water substrates, using experimental, theoretical and numerical analyses. The hybrid-aligned nematic droplet spontaneously generates boojum defects. During cooling, toric focal conic domains arise through a sequence of morphological transformations involving nematic stripes and locally aligned focal conic domains. This simple experiment reveals a surprisingly complex pathway by which very different types of defects may be related across the nematic-smectic A phase transition, and presents new possibilities for controlled deformation and patterning of liquid crystals. PMID- 28555629 TI - Electric field imaging of single atoms. AB - In scanning transmission electron microscopy (STEM), single atoms can be imaged by detecting electrons scattered through high angles using post-specimen, annular type detectors. Recently, it has been shown that the atomic-scale electric field of both the positive atomic nuclei and the surrounding negative electrons within crystalline materials can be probed by atomic-resolution differential phase contrast STEM. Here we demonstrate the real-space imaging of the (projected) atomic electric field distribution inside single Au atoms, using sub-A spatial resolution STEM combined with a high-speed segmented detector. We directly visualize that the electric field distribution (blurred by the sub-A size electron probe) drastically changes within the single Au atom in a shape that relates to the spatial variation of total charge density within the atom. Atomic resolution electric field mapping with single-atom sensitivity enables us to examine their detailed internal and boundary structures. PMID- 28555632 TI - Corrigendum: Eluxadoline Efficacy in IBS-D Patients Who Report Prior Loperamide Use. AB - This corrects the article DOI: 10.1038/ajg.2017.72. PMID- 28555631 TI - The Conversion of Planned Colonoscopy to Sigmoidoscopy and the Effect of this Practice on the Measurement of Quality Indicators. AB - OBJECTIVES: A cecal intubation rate (CIR) of >90% is a well-accepted quality indicator of colonoscopy and is consequently monitored within endoscopy units. Endoscopists' desire to meet this target may mean that incomplete colonoscopies are recorded as flexible sigmoidoscopies. The aim of this study was to examine whether the conversion of requested colonoscopies is a clinically significant phenomenon and whether this impacts upon the measurement of quality indicators. METHODS: A retrospective review of all flexible sigmoidoscopies performed between 1 January 2015 and 31 December 2015 at Nottingham University Hospitals, Sheffield Teaching Hospitals, and Cambridge University Hospitals was performed. Where a colonoscopy was requested but a flexible sigmoidoscopy performed, the patient's records and endoscopy reports were reviewed to determine whether this conversion was decided before the start of the procedure and documented. RESULTS: During the 12-month period, 6,839 flexible sigmoidoscopies were performed by 125 endoscopists. The original requests of 149 sigmoidoscopies could not be retrieved and were therefore excluded from this analysis. Of the 6,690 sigmoidoscopy requests reviewed, 2.8% (n=190) procedures were originally requested as a colonoscopy. On review of patient records, 85 conversions were appropriate according to pre-defined criteria. However, 105 conversions were deemed inappropriate, occurring in patients who had a valid documented indication for colonoscopy and had undergone full bowel preparation. The most common reasons cited included poor bowel preparation (n=37), technically challenging procedure (n=24), at the endoscopist's discretion based on clinical factors (n=21), and obstructing patology (n=8). A clear reason for conversion was not apparent in 11 cases. During the study period, 21,271 colonoscopies were performed and so conversions represent 0.45% of the total requests. When inappropriate conversions were included in individuals' performance data, 15 endoscopists fell to <=90% target cecal intubation target. CONCLUSIONS: A small, but significant number of colonoscopies are converted to flexible sigmoidoscopies at the time of the procedure. This study demonstrates the conversion of colonoscopy to sigmoidoscopy as being a potential limitation of relying on CIR alone. Endoscopy units should consider monitoring the rate of inappropriate conversions to ensure quality. PMID- 28555634 TI - Erratum: Positive PET in a Patient With Esophageal Leiomyoma. AB - This corrects the article DOI: 10.1038/ajg.2016.205. PMID- 28555630 TI - Colorectal Cancer Screening: Recommendations for Physicians and Patients from the U.S. Multi-Society Task Force on Colorectal Cancer. AB - This document updates the colorectal cancer (CRC) screening recommendations of the U.S. Multi-Society Task Force of Colorectal Cancer (MSTF), which represents the American College of Gastroenterology, the American Gastroenterological Association, and The American Society for Gastrointestinal Endoscopy. CRC screening tests are ranked in 3 tiers based on performance features, costs, and practical considerations. The first-tier tests are colonoscopy every 10 years and annual fecal immunochemical test (FIT). Colonoscopy and FIT are recommended as the cornerstones of screening regardless of how screening is offered. Thus, in a sequential approach based on colonoscopy offered first, FIT should be offered to patients who decline colonoscopy. Colonoscopy and FIT are recommended as tests of choice when multiple options are presented as alternatives. A risk-stratified approach is also appropriate, with FIT screening in populations with an estimated low prevalence of advanced neoplasia and colonoscopy screening in high prevalence populations. The second-tier tests include CT colonography every 5 years, the FIT fecal DNA test every 3 years, and flexible sigmoidoscopy every 5 to 10 years. These tests are appropriate screening tests, but each has disadvantages relative to the tier 1 tests. Because of limited evidence and current obstacles to use, capsule colonoscopy every 5 years is a third-tier test. We suggest that the Septin9 serum assay (Epigenomics, Seattle, Wash) not be used for screening. Screening should begin at age 50 years in average-risk persons, except in African Americans in whom limited evidence supports screening at 45 years. CRC incidence is rising in persons under age 50, and thorough diagnostic evaluation of young persons with suspected colorectal bleeding is recommended. Discontinuation of screening should be considered when persons up to date with screening, who have prior negative screening (particularly colonoscopy), reach age 75 or have <10 years of life expectancy. Persons without prior screening should be considered for screening up to age 85, depending on age and comorbidities. Persons with a family history of CRC or a documented advanced adenoma in a first-degree relative age <60 years or 2 first-degree relatives with these findings at any age are recommended to undergo screening by colonoscopy every 5 years, beginning 10 years before the age at diagnosis of the youngest affected relative or age 40, whichever is earlier. Persons with a single first-degree relative diagnosed at >=60 years with CRC or an advanced adenoma can be offered average-risk screening options beginning at age 40 years. PMID- 28555633 TI - Low Birthweight Increases the Likelihood of Severe Steatosis in Pediatric Non Alcoholic Fatty Liver Disease. AB - OBJECTIVES: Small for gestational age (SGA) is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD). Our aim was to investigate the correlation of birthweight with the severity of liver damage in a large cohort of children with NAFLD. METHODS: Two hundred and eighty-eight consecutive Caucasian Italian overweight/obese children with biopsy-proven NAFLD were included in the study. We examined the relative association of each histological feature of NAFLD with metabolic alterations, insulin-resistance, I148M polymorphism in the patatin like phospholipase domain-containing protein 3 (PNPLA3) gene, and birthweight relative to gestational age. RESULTS: In the whole NAFLD cohort, 12.2% of patients were SGA, 62.8% appropriate for gestational age (AGA), and 25% large for gestational age (LGA). SGA children had a higher prevalence of severe steatosis (69%) and severe portal inflammation (14%) compared with the AGA and LGA groups. Notably, severe steatosis (>66%) was decreasing from SGA to AGA and LGA, whereas the prevalence of moderate steatosis (33-66%) was similar in three groups. The prevalence of type 1 NAFLD is higher in the LGA group with respect to the other two groups (25% vs.5.2% vs.9.4%), whereas the SGA group shows a higher prevalence of overlap type (85.8%) with respect to the LGA group (51.4%) but not compared with the AGA group (75%). At multivariable regression analysis, SGA at birth increased fourfold the likelihood of severe steatosis (odds ratio (OR) 4.0, 95% confidence interval (CI) 1.43-10.9, P=0.008) and threefold the likelihood of NAFLD Activity Score (NAS)>=5 (OR 2.98, 95% CI 1.06-8.33, P=0.037) independently of homeostasis model assessment of insulin resistance and PNPLA3 genotype. The PNPLA3-CC wild-type genotype was the strongest independent predictor of the absence of significant fibrosis (OR 0.26, 95% CI 0.13-0.52, P=<0.001). CONCLUSIONS: In children with NAFLD, the risk of severe steatosis is increased by SGA at birth, independent of and in addition to other powerful risk factors (insulin-resistance and I148M variant of the PNPLA3 gene). PMID- 28555635 TI - The Association between Distal Findings and Proximal Colorectal Neoplasia: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Whether screening participants with distal hyperplastic polyps (HPs) detected by flexible sigmoidoscopy (FS) should be followed by subsequent colonoscopy is controversial. We evaluated the association between distal HPs and proximal neoplasia (PN)/advanced proximal neoplasia (APN) in asymptomatic, average-risk patients. METHODS: We searched Ovid Medline, EMBASE, and the Cochrane Library from inception to 30 June 2016 and included all screening studies that examined the relationship between different distal findings and PN/APN. Data were independently extracted by two reviewers with disagreements resolved by a third reviewer. We pooled absolute risks and odds ratios (ORs) with a random effects meta-analysis. Seven subgroup analyses were performed according to study characteristics. Heterogeneity was characterized with the I2 statistics. RESULTS: We analyzed 28 studies (104,961 subjects). When compared with normal distal findings, distal HP was not associated with PN (OR=1.16, 95% confidence interval (CI)=0.89-1.51, P=0.14, I2=40%) or APN (OR=1.09, 95% CI=0.87-1.36, P=0.39, I2=5%), while subjects with distal non-advanced or advanced adenoma had higher odds of PN/APN. Higher odds of PN/APN were observed for more severe distal lesions. Weaker association between distal and proximal findings was noticed in studies with higher quality, larger sample size, population-based design, and more stringent endoscopy quality-control measures. The Egger's regression tests showed all P>0.05. CONCLUSIONS: Distal HP is not associated with PN/APN in asymptomatic screening population when compared with normal distal findings. Hence, the presence of distal HP alone detected by FS does not automatically indicate colonoscopy referral for all screening participants, as other risk factors of PN/APN should be considered. PMID- 28555637 TI - Sea-level records from the U.S. mid-Atlantic constrain Laurentide Ice Sheet extent during Marine Isotope Stage 3. AB - The U.S. mid-Atlantic sea-level record is sensitive to the history of the Laurentide Ice Sheet as the coastline lies along the ice sheet's peripheral bulge. However, paleo sea-level markers on the present-day shoreline of Virginia and North Carolina dated to Marine Isotope Stage (MIS) 3, from 50 to 35 ka, are surprisingly high for this glacial interval, and remain unexplained by previous models of ice age adjustment or other local (for example, tectonic) effects. Here, we reconcile this sea-level record using a revised model of glacial isostatic adjustment characterized by a peak global mean sea level during MIS 3 of approximately -40 m, and far less ice volume within the eastern sector of the Laurentide Ice Sheet than traditional reconstructions for this interval. We conclude that the Laurentide Ice Sheet experienced a phase of very rapid growth in the 15 kyr leading into the Last Glacial Maximum, thus highlighting the potential of mid-field sea-level records to constrain areal extent of ice cover during glacial intervals with sparse geological observables. PMID- 28555636 TI - Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington's disease model. AB - The structure and function of spines and excitatory synapses are under the dynamic control of multiple signalling networks. Although tyrosine phosphorylation is involved, its regulation and importance are not well understood. Here we study the role of Pyk2, a non-receptor calcium-dependent protein-tyrosine kinase highly expressed in the hippocampus. Hippocampal-related learning and CA1 long-term potentiation are severely impaired in Pyk2-deficient mice and are associated with alterations in NMDA receptors, PSD-95 and dendritic spines. In cultured hippocampal neurons, Pyk2 has autophosphorylation-dependent and -independent roles in determining PSD-95 enrichment and spines density. Pyk2 levels are decreased in the hippocampus of individuals with Huntington and in the R6/1 mouse model of the disease. Normalizing Pyk2 levels in the hippocampus of R6/1 mice rescues memory deficits, spines pathology and PSD-95 localization. Our results reveal a role for Pyk2 in spine structure and synaptic function, and suggest that its deficit contributes to Huntington's disease cognitive impairments. PMID- 28555638 TI - Recent enhancement of central Pacific El Nino variability relative to last eight centuries. AB - The far-reaching impacts of central Pacific El Nino events on global climate differ appreciably from those associated with eastern Pacific El Nino events. Central Pacific El Nino events may become more frequent in coming decades as atmospheric greenhouse gas concentrations rise, but the instrumental record of central Pacific sea-surface temperatures is too short to detect potential trends. Here we present an annually resolved reconstruction of NINO4 sea-surface temperature, located in the central equatorial Pacific, based on oxygen isotopic time series from Taiwan tree cellulose that span from 1190 AD to 2007 AD. Our reconstruction indicates that relatively warm Nino4 sea-surface temperature values over the late twentieth century are accompanied by higher levels of interannual variability than observed in other intervals of the 818-year-long reconstruction. Our results imply that anthropogenic greenhouse forcing may be driving an increase in central Pacific El Nino-Southern Oscillation variability and/or its hydrological impacts, consistent with recent modelling studies. PMID- 28555640 TI - Attosecond interferometry with self-amplified spontaneous emission of a free electron laser. AB - Light-phase-sensitive techniques, such as coherent multidimensional spectroscopy, are well-established in a broad spectral range, already spanning from radio frequencies in nuclear magnetic resonance spectroscopy to visible and ultraviolet wavelengths in nonlinear optics with table-top lasers. In these cases, the ability to tailor the phases of electromagnetic waves with high precision is essential. Here we achieve phase control of extreme-ultraviolet pulses from a free-electron laser (FEL) on the attosecond timescale in a Michelson-type all reflective interferometric autocorrelator. By varying the relative phase of the generated pulse replicas with sub-cycle precision we observe the field interference, that is, the light-wave oscillation with a period of 129 as. The successful transfer of a powerful optical method towards short-wavelength FEL science and technology paves the way towards utilization of advanced nonlinear methodologies even at partially coherent soft X-ray FEL sources that rely on self amplified spontaneous emission. PMID- 28555639 TI - Clonally stable Vkappa allelic choice instructs Igkappa repertoire. AB - Although much has been done to understand how rearrangement of the Igkappa locus is regulated during B-cell development, little is known about the way the variable (V) segments themselves are selected. Here we show, using B6/Cast hybrid pre-B-cell clones, that a limited number of V segments on each allele is stochastically activated as characterized by the appearance of non-coding RNA and histone modifications. The activation states are clonally distinct, stable across cell division and developmentally important in directing the Ig repertoire upon differentiation. Using a new approach of allelic ATAC-seq, we demonstrate that the Igkappa V alleles have differential chromatin accessibility, which may serve as the underlying basis of clonal maintenance at this locus, as well as other instances of monoallelic expression throughout the genome. These findings highlight a new level of immune system regulation that optimizes gene diversity. PMID- 28555641 TI - A parts list for fungal cellulosomes revealed by comparative genomics. AB - Cellulosomes are large, multiprotein complexes that tether plant biomass degrading enzymes together for improved hydrolysis1. These complexes were first described in anaerobic bacteria, where species-specific dockerin domains mediate the assembly of enzymes onto cohesin motifs interspersed within protein scaffolds1. The versatile protein assembly mechanism conferred by the bacterial cohesin-dockerin interaction is now a standard design principle for synthetic biology2,3. For decades, analogous structures have been reported in anaerobic fungi, which are known to assemble by sequence-divergent non-catalytic dockerin domains (NCDDs)4. However, the components, modular assembly mechanism and functional role of fungal cellulosomes remain unknown5,6. Here, we describe a comprehensive set of proteins critical to fungal cellulosome assembly, including conserved scaffolding proteins unique to the Neocallimastigomycota. High-quality genomes of the anaerobic fungi Anaeromyces robustus, Neocallimastix californiae and Piromyces finnis were assembled with long-read, single-molecule technology. Genomic analysis coupled with proteomic validation revealed an average of 312 NCDD-containing proteins per fungal strain, which were overwhelmingly carbohydrate active enzymes (CAZymes), with 95 large fungal scaffoldins identified across four genera that bind to NCDDs. Fungal dockerin and scaffoldin domains have no similarity to their bacterial counterparts, yet several catalytic domains originated via horizontal gene transfer with gut bacteria. However, the biocatalytic activity of anaerobic fungal cellulosomes is expanded by the inclusion of GH3, GH6 and GH45 enzymes. These findings suggest that the fungal cellulosome is an evolutionarily chimaeric structure-an independently evolved fungal complex that co-opted useful activities from bacterial neighbours within the gut microbiome. PMID- 28555643 TI - Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease. Various attempts are underway to convert severe DMD to a milder phenotype by modulating the splicing of the dystrophin gene and restoring its expression. In our previous study, we reported TG003, an inhibitor of CDC2-like kinase 1 (CLK1), as a splice-modifying compound for exon-skipping therapy; however, its metabolically unstable feature hinders clinical application. Here, we show an orally available inhibitor of CLK1, named TG693, which promoted the skipping of the endogenous mutated exon 31 in DMD patient-derived cells and increased the production of the functional exon 31-skipped dystrophin protein. Oral administration of TG693 to mice inhibited the phosphorylation of serine/arginine rich proteins, which are the substrates of CLK1, and modulated pre-mRNA splicing in the skeletal muscle. Thus, TG693 is a splicing modulator for the mutated exon 31 of the dystrophin gene in vivo, possibly possessing therapeutic potential for DMD patients. PMID- 28555642 TI - TGF-beta activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-beta signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-beta blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-beta is regulated at the level of activation, but how TGF-beta is activated in this disease is unknown. Here we show TGF-beta activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in Schistosoma-exposed mice. Following Schistosoma exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-beta activation and protects against PH development. TSP-1 blockade also prevents the PH in a second model, chronic hypoxia. Lastly, the plasma concentration of TSP-1 is significantly increased in subjects with scleroderma following PAH development. Targeting TSP-1-dependent activation of TGF-beta could thus be a therapeutic approach in TGF-beta-dependent vascular diseases. PMID- 28555644 TI - Coral calcification in a changing World and the interactive dynamics of pH and DIC upregulation. AB - Coral calcification is dependent on the mutualistic partnership between endosymbiotic zooxanthellae and the coral host. Here, using newly developed geochemical proxies (delta11B and B/Ca), we show that Porites corals from natural reef environments exhibit a close (r2 ~0.9) antithetic relationship between dissolved inorganic carbon (DIC) and pH of the corals' calcifying fluid (cf). The highest DICcf (~ * 3.2 seawater) is found during summer, consistent with thermal/light enhancement of metabolically (zooxanthellae) derived carbon, while the highest pHcf (~8.5) occurs in winter during periods of low DICcf (~ * 2 seawater). These opposing changes in DICcf and pHcf are shown to maintain oversaturated but stable levels of carbonate saturation (Omegacf ~ * 5 seawater), the key parameter controlling coral calcification. These findings are in marked contrast to artificial experiments and show that pHcf upregulation occurs largely independent of changes in seawater carbonate chemistry, and hence ocean acidification, but is highly vulnerable to thermally induced stress from global warming. PMID- 28555646 TI - Geomagnetic spikes on the core-mantle boundary. AB - Extreme variations of Earth's magnetic field occurred in the Levant region around 1000 BC, when the field intensity rapidly rose and fell by a factor of 2. No coherent link currently exists between this intensity spike and the global field produced by the core geodynamo. Here we show that the Levantine spike must span >60 degrees longitude at Earth's surface if it originates from the core-mantle boundary (CMB). Several low intensity data are incompatible with this geometric bound, though age uncertainties suggest these data could have sampled the field before the spike emerged. Models that best satisfy energetic and geometric constraints produce CMB spikes 8-22 degrees wide, peaking at O(100) mT. We suggest that the Levantine spike reflects an intense CMB flux patch that grew in place before migrating northwest, contributing to growth of the dipole field. Estimates of Ohmic heating suggest that diffusive processes likely govern the ultimate decay of geomagnetic spikes. PMID- 28555645 TI - A promoter-proximal transcript targeted by genetic polymorphism controls E cadherin silencing in human cancers. AB - Long noncoding RNAs are emerging players in the epigenetic machinery with key roles in development and diseases. Here we uncover a complex network comprising a promoter-associated noncoding RNA (paRNA), microRNA and epigenetic regulators that controls transcription of the tumour suppressor E-cadherin in epithelial cancers. E-cadherin silencing relies on the formation of a complex between the paRNA and microRNA-guided Argonaute 1 that, together, recruit SUV39H1 and induce repressive chromatin modifications in the gene promoter. A single nucleotide polymorphism (rs16260) linked to increased cancer risk alters the secondary structure of the paRNA, with the risk allele facilitating the assembly of the microRNA-guided Argonaute 1 complex and gene silencing. Collectively, these data demonstrate the role of a paRNA in E-cadherin regulation and the impact of a noncoding genetic variant on its function. Deregulation of paRNA-based epigenetic networks may contribute to cancer and other diseases making them promising targets for drug discovery. PMID- 28555648 TI - Public health: Public investment in childhood health: worth the cost. PMID- 28555649 TI - Basic research: PHD inhibitors miss their mark. PMID- 28555650 TI - Development: Non-muscle myosin II in kidney morphogenesis. PMID- 28555647 TI - JunB is essential for IL-23-dependent pathogenicity of Th17 cells. AB - CD4+ T-helper cells producing interleukin-17 (IL-17), known as T-helper 17 (TH17) cells, comprise heterogeneous subsets that exhibit distinct pathogenicity. Although pathogenic and non-pathogenic TH17 subsets share a common RORgammat dependent TH17 transcriptional programme, transcriptional regulatory mechanisms specific to each of these subsets are mostly unknown. Here we show that the AP-1 transcription factor JunB is critical for TH17 pathogenicity. JunB, which is induced by IL-6, is essential for expression of RORgammat and IL-23 receptor by facilitating DNA binding of BATF at the Rorc locus in IL-23-dependent pathogenic TH17 cells, but not in TGF-beta1-dependent non-pathogenic TH17 cells. Junb deficient T cells fail to induce TH17-mediated autoimmune encephalomyelitis and colitis. However, JunB deficiency does not affect the abundance of gut-resident non-pathogenic TH17 cells. The selective requirement of JunB for IL-23-dependent TH17 pathogenicity suggests that the JunB-dependent pathway may be a therapeutic target for autoimmune diseases. PMID- 28555651 TI - Heart failure: Macrophages take centre stage in the heart-brain-kidney axis. PMID- 28555653 TI - Epidemiology: Surveying kidney care worldwide. PMID- 28555654 TI - Vascular disease: Trialling stem cell treatment for vascular disease. PMID- 28555655 TI - Designing lead-free antiferroelectrics for energy storage. AB - Dielectric capacitors, although presenting faster charging/discharging rates and better stability compared with supercapacitors or batteries, are limited in applications due to their low energy density. Antiferroelectric (AFE) compounds, however, show great promise due to their atypical polarization-versus-electric field curves. Here we report our first-principles-based theoretical predictions that Bi1-xRxFeO3 systems (R being a lanthanide, Nd in this work) can potentially allow high energy densities (100-150 J cm-3) and efficiencies (80-88%) for electric fields that may be within the range of feasibility upon experimental advances (2-3 MV cm-1). In addition, a simple model is derived to describe the energy density and efficiency of a general AFE material, providing a framework to assess the effect on the storage properties of variations in doping, electric field magnitude and direction, epitaxial strain, temperature and so on, which can facilitate future search of AFE materials for energy storage. PMID- 28555656 TI - Overcoming the crystallization and designability issues in the ultrastable zirconium phosphonate framework system. AB - Metal-organic frameworks (MOFs) based on zirconium phosphonates exhibit superior chemical stability suitable for applications under harsh conditions. These compounds mostly exist as poorly crystallized precipitates, and precise structural information has therefore remained elusive. Furthermore, a zero dimensional zirconium phosphonate cluster acting as secondary building unit has been lacking, leading to poor designability in this system. Herein, we overcome these challenges and obtain single crystals of three zirconium phosphonates that are suitable for structural analysis. These compounds are built by previously unknown isolated zirconium phosphonate clusters and exhibit combined high porosity and ultrastability even in fuming acids. SZ-2 possesses the largest void volume recorded in zirconium phosphonates and SZ-3 represents the most porous crystalline zirconium phosphonate and the only porous MOF material reported to survive in aqua regia. SZ-2 and SZ-3 can effectively remove uranyl ions from aqueous solutions over a wide pH range, and we have elucidated the removal mechanism. PMID- 28555652 TI - Reducing the costs of chronic kidney disease while delivering quality health care: a call to action. AB - The treatment of chronic kidney disease (CKD) and of end-stage renal disease (ESRD) imposes substantial societal costs. Expenditure is highest for renal replacement therapy (RRT), especially in-hospital haemodialysis. Redirection towards less expensive forms of RRT (peritoneal dialysis, home haemodialysis) or kidney transplantation should decrease financial pressure. However, costs for CKD are not limited to RRT, but also include nonrenal health-care costs, costs not related to health care, and costs for patients with CKD who are not yet receiving RRT. Even if patients with CKD or ESRD could be given the least expensive therapies, costs would decrease only marginally. We therefore propose a consistent and sustainable approach focusing on prevention. Before a preventive strategy is favoured, however, authorities should carefully analyse the cost to benefit ratio of each strategy. Primary prevention of CKD is more important than secondary prevention, as many other related chronic diseases, such as diabetes mellitus, hypertension, cardiovascular disease, liver disease, cancer, and pulmonary disorders could also be prevented. Primary prevention largely consists of lifestyle changes that will reduce global societal costs and, more importantly, result in a healthy, active, and long-lived population. Nephrologists need to collaborate closely with other sectors and governments, to reach these aims. PMID- 28555657 TI - Associating cellular epigenetic models with human phenotypes. AB - Epigenetic association studies have been carried out to test the hypothesis that environmental perturbations trigger cellular reprogramming, with downstream effects on cellular function and phenotypes. There have now been numerous studies of the potential molecular mediators of epigenetic changes by epigenome-wide association studies (EWAS). However, a challenge for the field is the interpretation of the results obtained. We describe a second-generation EWAS approach, which focuses on the possible cellular models of epigenetic perturbations, studied by rigorous analysis and interpretation of genomic data. Thus refocused, epigenetics research aligns with the field of functional genomics to provide insights into environmental and genetic influences on phenotypic variation in humans. PMID- 28555660 TI - MiCASA is a new method for quantifying cellular organization. AB - While many tools exist for identifying and quantifying individual cell types, few methods are available to assess the relationships between cell types in organs and tissues and how these relationships change during aging or disease states. We present a quantitative method for evaluating cellular organization, using the mouse thymus as a test organ. The thymus is the primary lymphoid organ responsible for generating T cells in vertebrates, and its proper structure and organization is essential for optimal function. Our method, Multitaper Circularly Averaged Spectral Analysis (MiCASA), identifies differences in the tissue-level organization with high sensitivity, including defining a novel type of phenotype by measuring variability as a specific parameter. MiCASA provides a novel and easily implemented quantitative tool for assessing cellular organization. PMID- 28555661 TI - Risk factors for severe dysphagia in acute cervical spinal cord injury. AB - STUDY DESIGN: A retrospective, consecutive case series. OBJECTIVES: The relationship between dysphagia and acute cervical spinal cord injury (CSCI) has been recently reported; however, the cause and mechanism of dysphagia are still not well understood. No definitive factors have yet been established according to multivariate analysis. The objective is to elucidate the incidence and risk factors of dysphagia in patients with acute CSCI. SETTING: Spinal Injuries Center, Fukuoka, Japan. METHODS: A total of 298 patients with acute CSCI, who were evaluated for neurological impairment within 3 days after injury, were reviewed. CSCI patients with tube dependence due to obvious aspiration after injury were defined as having dysphagia. The factors postulated to increase the risk for dysphagia, including the patient's age, sex, American Spinal Injury Association (ASIA) impairment scale at 3 days after injury, level of injury, tracheostomy and operative treatment, were analyzed using a multiple logistic regression model. RESULTS: Of 298 patients, 21 were suffering from severe dysphagia after acute CSCI (7.0%). Of these 21 patients, 12 (57%) had CSCI at the C3-C4 level. Multivariable logistic regression analysis revealed that old age (>72 years), severe ASIA impairment scale (A or B) and presence of tracheostomy were significant risk factors of dysphagia. Level of injury ?C3-C4 was not a significant risk factor after adjustment for several potential confounders. CONCLUSION: The incidence of severe dysphagia associated with aspiration was 7%. Old age, severe paralysis and presence of tracheostomy may be the risk factors for dysphagia. The risk for dysphagia should be evaluated to prevent aspiration pneumonia. PMID- 28555659 TI - Human Y-chromosome variation in the genome-sequencing era. AB - The properties of the human Y chromosome - namely, male specificity, haploidy and escape from crossing over - make it an unusual component of the genome, and have led to its genetic variation becoming a key part of studies of human evolution, population history, genealogy, forensics and male medical genetics. Next generation sequencing (NGS) technologies have driven recent progress in these areas. In particular, NGS has yielded direct estimates of mutation rates, and an unbiased and calibrated molecular phylogeny that has unprecedented detail. Moreover, the availability of direct-to-consumer NGS services is fuelling a rise of 'citizen scientists', whose interest in resequencing their own Y chromosomes is generating a wealth of new data. PMID- 28555662 TI - Event centrality as a unique predictor of posttraumatic stress symptoms and perceived disability following spinal cord injury. AB - STUDY DESIGN: We conducted a cross-sectional study involving completion of self report measures. OBJECTIVES: Individuals who acquire a spinal cord injury (SCI) face numerous physical and psychological challenges, with the former receiving considerable less attention during the rehabilitation process. In this article, we examined event centrality as a unique predictor of psychological outcomes in a sample of individuals receiving rehabilitation for SCI. Event centrality refers to the extent to which individuals construe a stressful experience as a core part of their identity. In samples of individuals exposed to psychological traumas (for example, sexual assault or military combat), event centrality has emerged as a consistent and powerful predictor of posttraumatic stress symptoms (PTSSs). This is the first study to examine event centrality in an SCI sample. SETTING: Inpatient rehabilitation program in a large urban city in the Southwestern United States. METHODS: A sample of 55 participants in rehabilitation for a recent SCI completed measures of event centrality, PTSS, depressed mood and perceived disability. RESULTS: Event centrality was significantly related to perceived disability (r=0.48) and PTSS (r=0.31) and accounted for unique variance in these two outcomes after controlling for demographics and depressed mood. CONCLUSION: Event centrality is common among individuals with SCI and may be a unique contributor to worse psychological and functional outcomes. We hope our findings will alert health-care professionals to the importance of event centrality. SPONSORSHIP: This study was supported by a grant from the Danish National Research Foundation (DNRF89). PMID- 28555658 TI - TET-mediated active DNA demethylation: mechanism, function and beyond. AB - In mammals, DNA methylation in the form of 5-methylcytosine (5mC) can be actively reversed to unmodified cytosine (C) through TET dioxygenase-mediated oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5 carboxylcytosine (5caC), followed by replication-dependent dilution or thymine DNA glycosylase (TDG)-dependent base excision repair. In the past few years, biochemical and structural studies have revealed mechanistic insights into how TET and TDG mediate active DNA demethylation. Additionally, many regulatory mechanisms of this process have been identified. Technological advances in mapping and tracing the oxidized forms of 5mC allow further dissection of their functions. Furthermore, the biological functions of active DNA demethylation in various biological contexts have also been revealed. In this Review, we summarize the recent advances and highlight key unanswered questions. PMID- 28555663 TI - Comparison of three methods of penile vibratory stimulation for semen retrieval in men with spinal cord injury. AB - STUDY DESIGN: Prospective, three-way crossover design. OBJECTIVE: Penile vibratory stimulation (PVS) is recommended as the first line of treatment for semen retrieval in anejaculatory men with spinal cord injury (SCI). This study compared ejaculatory success rates and patient preference for three methods of PVS within the same group of men with SCI. SETTING: Major medical university. METHODS: Fifteen men with SCI each received three methods of PVS. Method 1 (M1): applying one FertiCare Personal device to the dorsum or frenulum of the glans penis; Method 2 (M2): 'sandwiching' the glans penis between two FertiCare devices; Method 3 (M3): sandwiching the glans penis between the two vibrating surfaces of the Viberect-X3 device. The order of M1, M2 and M3 was varied to control for sequencing effects. Following each PVS trial, subjects rated their experience on a questionnaire with scaled responses. RESULTS: Ejaculation success rates were high for each method; however, ejaculation latency was significantly longer with M3 compared with M1 or M2. In survey questions about patient preference, there were no significant differences between M1 and M2. In contrast, M3 was rated lower than M1 and M2 in patient preference. Semen collection may be more difficult with the Viberect device. CONCLUSIONS: On the basis of these findings, we recommend attempting PVS with one FertiCare device. If that fails, use two FertiCare devices. Although the Viberect-X3 was preferred less by patients, it had similar efficacy as the Ferticare vibrator(s) and may be suitable for home use by some patients. PMID- 28555664 TI - The association between injustice perception and psychological outcomes in an inpatient spinal cord injury sample: the mediating effects of anger. AB - STUDY DESIGN: Cross-sectional study design involving completion of self-report measures. OBJECTIVE: To investigate the relationship between perceived injustice, post-traumatic stress symptoms and depression in a sample of individuals receiving inpatient rehabilitation care following hospitalization for acute spinal cord injury (SCI), as well as the mediating role of anger variables. SETTING: Inpatient rehabilitation program in a large urban city in the Southwestern United States. METHODS: A sample of 53 participants with an average of 204.51 days (s.d.=410.67, median=56) post injury occurrence completed measures of perceived injustice, depression and post-traumatic stress symptoms as well as measures of trait anger, state anger, anger inhibition and anger expression. RESULTS: Perceived injustice was significantly correlated with depression and post-traumatic stress symptoms, and accounted for unique variance in depression and post-traumatic stress symptoms when controlling for demographic and injury related variables. Anger inhibition was found to mediate the relationship between perceived injustice and depression. Trait anger and anger expression were found to mediate the relationship between perceived injustice and post-traumatic stress symptoms. CONCLUSIONS: Consistent with previous research, perceived injustice was associated with greater depression and post-traumatic stress symptoms. The results support previous findings that anger inhibition mediates between perceived injustice and depression, and provides novel findings regarding mediation of post-traumatic stress symptoms. Results provide preliminary evidence for the role of perceived injustice in SCI and potential mechanisms by which it may exert its effects. PMID- 28555665 TI - International Spinal Cord Injury Core Data Set (version 2.0)-including standardization of reporting. AB - STUDY DESIGN: The study design includes expert opinion, feedback, revisions and final consensus. OBJECTIVES: The objective of the study was to present the new knowledge obtained since the International Spinal Cord Injury (SCI) Core Data Set (Version 1.0) published in 2006, and describe the adjustments made in Version 2.0, including standardization of data reporting. SETTING: International. METHODS: Comments received from the SCI community were discussed in a working group (WG); suggestions from the WG were reviewed and revisions were made. All suggested revisions were considered, and a final version was circulated for final approval. RESULTS: The International SCI Core Data Set (Version 2.0) consists of 25 variables. Changes made to this version include the deletion of one variable 'Total Days Hospitalized' and addition of two variables 'Date of Rehabilitation Admission' and 'Date of Death.' The variable 'Injury Etiology' was extended with six non-traumatic categories, and corresponding 'Date of Injury' for non traumatic cases, was defined as the date of first physician visit for symptoms related to spinal cord dysfunction. A category reflecting transgender was added. A response category was added to the variable on utilization of ventilatory assistance to document the use of continuous positive airway pressure for sleep apnea. Other clarifications were made to the text. The reporting of the pediatric SCI population was updated as age groups 0-5, 6-12, 13-14, 15-17 and 18-21. CONCLUSION: Collection of the core data set should be a basic requirement of all studies of SCI to facilitate accurate descriptions of patient populations and comparison of results across published studies from around the world. PMID- 28555666 TI - The use of the neurologic exam to predict awareness and control of lower urinary tract function post SCI. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVES: To assess whether T11-L2 sensation is significantly associated with perception of bladder filling and whether S3-S5 sensation is significantly associated with potential for voluntary voiding after spinal cord injury (SCI). SETTING: Alabama, United States. METHODS: A total of 79 men and women with SCI, and 40 able-bodied (AB) subjects, ages 19 60, seen in an outpatient academic medical center clinic, underwent International Standards for Neurological Classification of SCI (ISNCSCI) assessment along with urodynamic testing to assess lower urinary tract (LUT) function. X2 test was performed to compare: (1) bladder sensation across T11-L2 groups classified by total sensory scores and (2) ability to voluntarily void across S3-S5 scores. RESULTS: Persons with greater ability to perceive pinprick and light touch sensation in the T11-L2 dermatomes were more likely to perceive bladder filling both via self-report and by urodynamics. However, persons with greater sensation at T6-T9 and S3-5 also had a greater likelihood of perceiving bladder filling. Subjects with greater preservation of sensation in S3-5 reported greater ability to initiate and control voiding. CONCLUSION: Findings suggest ISNCSCI results along with self-report can be used to predict potential for bladder control. SPONSORSHIP: National Institute of Disability and Rehabilitation Research. PMID- 28555667 TI - The reliability of measuring wound undermining in people with spinal cord injury. PMID- 28555668 TI - Glucose represses dendritic cell-induced T cell responses. AB - Glucose and glycolysis are important for the proinflammatory functions of many immune cells, and depletion of glucose in pathological microenvironments is associated with defective immune responses. Here we show a contrasting function for glucose in dendritic cells (DCs), as glucose represses the proinflammatory output of LPS-stimulated DCs and inhibits DC-induced T-cell responses. A glucose sensitive signal transduction circuit involving the mTOR complex 1 (mTORC1), HIF1alpha and inducible nitric oxide synthase (iNOS) coordinates DC metabolism and function to limit DC-stimulated T-cell responses. When multiple T cells interact with a DC, they compete for nutrients, which can limit glucose availability to the DCs. In such DCs, glucose-dependent signalling is inhibited, altering DC outputs and enhancing T-cell responses. These data reveal a mechanism by which T cells regulate the DC microenvironment to control DC-induced T-cell responses and indicate that glucose is an important signal for shaping immune responses. PMID- 28555669 TI - Rapid mass production of two-dimensional metal oxides and hydroxides via the molten salts method. AB - Because of their exotic electronic properties and abundant active sites, two dimensional (2D) materials have potential in various fields. Pursuing a general synthesis methodology of 2D materials and advancing it from the laboratory to industry is of great importance. This type of method should be low cost, rapid and highly efficient. Here, we report the high-yield synthesis of 2D metal oxides and hydroxides via a molten salts method. We obtained a high-yield of 2D ion intercalated metal oxides and hydroxides, such as cation-intercalated manganese oxides (Na0.55Mn2O4.1.5H2O and K0.27MnO2.0.54H2O), cation-intercalated tungsten oxides (Li2WO4 and Na2W4O13), and anion-intercalated metal hydroxides (Zn5(OH)8(NO3)2.2H2O and Cu2(OH)3NO3), with a large lateral size and nanometre thickness in a short time. Using 2D Na2W4O13 as an electrode, a high performance electrochemical supercapacitor is achieved. We anticipate that our method will enable new path to the high-yield synthesis of 2D materials for applications in energy-related fields and beyond. PMID- 28555671 TI - Neuroendrocrine effects on autoimmunity. PMID- 28555672 TI - T cell-B cell collaboration. PMID- 28555674 TI - NK cell allorecognition. PMID- 28555675 TI - Reply to comment of Prof. Artur Czekierdowski. PMID- 28555673 TI - The dichotomous nature of T helper 17 cells. AB - T helper 17 (TH17) cells have been extensively studied since their discovery 10 years ago, primarily because of their known pathogenic role in many inflammatory diseases. Substantial progress has been made in understanding their development, regulation and functional activities, and genome-wide transcriptomic analysis has identified regulatory networks, nodes and interactions that provide vital clues for further studies. In this Review, we describe recent studies that have revealed the dichotomous nature of TH17 cells, which on the one hand allows these cells to be pathogenic drivers of inflammatory disorders and on the other hand allows them to support the integrity of the intestinal barrier in a non inflammatory manner. PMID- 28555677 TI - A portable visual detection method based on a target-responsive DNA hydrogel and color change of gold nanorods. AB - A new method based on a functional DNA crosslinked hydrogel as a target responsive unit and gold nanorods (AuNRs) as a multicolor signal readout circuit was developed for the sensitive and visual detection of different targets. The color variation of the AuNR solution was correlated with the concentration of the target. This system can be extended to detect various targets by designing the corresponding target-responsive DNA hydrogels. PMID- 28555680 TI - Achieving high aspect ratio wrinkles by modifying material network stress. AB - Wrinkle aspect ratio, or the amplitude divided by the wavelength, is hindered by strain localization transitions when an increasing global compressive stress is applied to synthetic material systems. However, many examples from living organisms show extremely high aspect ratios, such as gut villi and flower petals. We use three experimental approaches to demonstrate that these high aspect ratio structures can be achieved by modifying the network stress in the wrinkle substrate. We modify the wrinkle stress and effectively delay the strain localization transition, such as folding, to larger aspect ratios by using a zero stress initial wavy substrate, creating a secondary network with post-curing, or using chemical stress relaxation materials. A wrinkle aspect ratio as high as 0.85, almost three times higher than common values of synthetic wrinkles, is achieved, and a quantitative framework is presented to provide understanding the different strategies and predictions for future investigations. PMID- 28555670 TI - Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. AB - The tumour microenvironment is the primary location in which tumour cells and the host immune system interact. Different immune cell subsets are recruited into the tumour microenvironment via interactions between chemokines and chemokine receptors, and these populations have distinct effects on tumour progression and therapeutic outcomes. In this Review, we focus on the main chemokines that are found in the human tumour microenvironment; we elaborate on their patterns of expression, their regulation and their roles in immune cell recruitment and in cancer and stromal cell biology, and we consider how they affect cancer immunity and tumorigenesis. We also discuss the potential of targeting chemokine networks, in combination with other immunotherapies, for the treatment of cancer. PMID- 28555681 TI - Monitoring of bacterial film formation and its breakdown with an angular-based surface plasmon resonance biosensor. AB - Bacterial biofilms are a leading cause of infection in health-care settings. Surface plasmon resonance (SPR) biosensors stand as valuable tools not only for the detection of biological entities and the characterisation of biomaterials but also as a suitable means to monitor bacterial film formation. This article reports on a proof-of-concept study for the use of an angular-based SPR biosensor for the monitoring of bacterial cell growth and biofilm formation and removal under the effect of different cleaning agents. The benefit of this custom-made SPR instrument is that it records simultaneously both the critical and resonant angles. This provides unique information on the growth of bacterial cells which is otherwise not obtainable with commonly used intensity-based SPR systems. The results clearly showed that a multilayer biofilm can be formed in 48 hours and the steps involved can be monitored in real-time with the SPR instrument through the measurement of the refractive index change and following the evolution in the shape of the SPR curve. The number, the depth and the sharpness of the reflection ripples varied as the film became thicker. Simulation results confirmed that the number of layers of bacteria affected the number of ripples at the critical angle. Real-time monitoring of the film breakdown with three cleaning agents indicated that bleach solution at 4.5% was the most effective in disrupting the biofilm from the gold sensor. Our overall findings suggest that the SPR biosensor with angular modulation presented in this article can perform real-time monitoring of biofilm formation and has the potential to be used as a platform to test the efficiency of disinfectants. PMID- 28555682 TI - Crosslinked shells for nano-assembled capsules: a new encapsulation method for smaller Gd3+-loaded capsules with exceedingly high relaxivities. AB - Nano-assembled capsules can incorporate large payloads of high relaxivity Gd3+, permitting the development of highly detectable molecular imaging agents for MRI. A new encapsulating shell, based upon cross-linked peptides, is found to afford smaller capsules (127 nm average diameter) with exceptionally high per-Gd3+ relaxivities (70.7 s-1 mmolal-1). PMID- 28555683 TI - Foamed emulsion drainage: flow and trapping of drops. AB - Foamed emulsions are ubiquitous in our daily life but the ageing of such systems is still poorly understood. In this study we investigate foam drainage and measure the evolution of the gas, liquid and oil volume fractions inside the foam. We evidence three regimes of ageing. During an initial period of fast drainage, both bubbles and drops are very mobile. As the foam stabilises drainage proceeds leading to a gradual decrease of the liquid fraction and slowing down of drainage. Clusters of oil drops are less sheared, their dynamic viscosity increases and drainage slows down even further, until the drops become blocked. At this point the oil fraction starts to increase in the continuous phase. The foam ageing leads to an increase of the capillary pressure until the oil acts as an antifoaming agent and the foam collapses. PMID- 28555684 TI - Compression of polymer brushes in the weak interpenetration regime: scaling theory and molecular dynamics simulations. AB - We employ scaling theory and Molecular Dynamics (MD) simulations to probe the compression of the semi-dilute polymer brush bilayers (BBLs) in the weak interpenetration (IP) regime. Such a regime is characterized by two layers of interacting polymer brushes grafted on opposing planar surfaces having a separation dg, such that d0 < dg < 2d0, with d0 being the unperturbed brush height. Currently, scaling theories are known for polymer BBLs with a much larger degree of IP (i.e., dg < d0) - in such regimes, the brush height can be quantified by the corresponding IP length delta. On the other hand, we show that in the weak IP regime, the brush height is not solely dictated by delta. We develop new scaling theories to show that delta in this weak IP regime is different from that in the strong IP regime. Secondly, we establish that the compressed brush height in this weakly IP regime can be described as d ~ Nchi with chi < 1 and varying monotonically with dg/d0. MD simulations are carried out to quantify delta and chi and the results match excellently with our new scaling theory predictions. Finally, we establish that our scaling theory can reasonably predict the experimentally witnessed variation of the interaction energy dictating the compressive force between the interpenetrating brushes in this weakly IP regime. PMID- 28555685 TI - Towards higher electron mobility in modulation doped GaAs/AlGaAs core shell nanowires. AB - Precise control over the electrical conductivity of semiconductor nanowires is a crucial prerequisite for implementation of these nanostructures into novel electronic and optoelectronic devices. Advances in our understanding of doping mechanisms in nanowires and their influence on electron mobility and radiative efficiency are urgently required. Here, we investigate the electronic properties of n-type modulation doped GaAs/AlGaAs nanowires via optical pump terahertz (THz) probe spectroscopy and photoluminescence spectroscopy over the temperature range 5 K-300 K. We directly determine an ionization energy of 6.7 +/- 0.5 meV (T = 52 K) for the Si donors within the AlGaAs shell that create the modulation doping structure. We further elucidate the temperature dependence of the electron mobility, photoconductivity lifetime and radiative efficiency, and determine the charge-carrier scattering mechanisms that limit electron mobility. We show that below the donor ionization temperature, charge scattering is limited by interactions with interfaces, leading to an excellent electron mobility of 4360 +/- 380 cm2 V-1 s-1 at 5 K. Above the ionization temperature, polar scattering via longitudinal optical (LO) phonons dominates, leading to a room temperature mobility of 2220 +/- 130 cm2 V-1 s-1. In addition, we show that the Si donors effectively passivate interfacial trap states in the nanowires, leading to prolonged photoconductivity lifetimes with increasing temperature, accompanied by an enhanced radiative efficiency that exceeds 10% at room temperature. PMID- 28555688 TI - A high throughput immunoassay for the therapeutic drug monitoring of tegafur. AB - Cancer is a group of diseases in which abnormal cells grow and divide without control, with the potential to invade other parts of the body. Chemotherapy is a type of treatment that uses chemical agents to treat cancer. These drugs are toxic and produce undesirable adverse drug reactions due to their narrow therapeutic window and highly variable pharmacokinetics, thus, they need to be monitored to establish personalized treatment to achieve maximal efficiency and reduce drug toxicity. Nowadays, therapeutic drug monitoring (TDM) is not routinely used for chemotherapy agents, however, TDM has the potential to improve the clinical benefit of chemotherapy drugs. Tegafur, a prodrug of 5-fluorouracil (5FU), is one of the main anti-cancer drugs used worldwide. Herein, a reproducible and sensitive indirect competitive ELISA has been developed and validated in plasma samples. The assay reports an IC50 of 35.6 nM, reaching a limit of detection of 2.7 nM. It is highly reproducible and does not show cross reactivity with any related compound. In summary, this assay provides a sensitive, accurate and high throughput analytical method for tegafur quantification in plasma, which fits TDM requirements. PMID- 28555689 TI - Epitaxial magnetite nanorods with enhanced room temperature magnetic anisotropy. AB - Nanostructured magnetic materials with well-defined magnetic anisotropy are very promising as building blocks in spintronic devices that operate at room temperature. Here we demonstrate the epitaxial growth of highly oriented Fe3O4 nanorods on a SrTiO3 substrate by hydrothermal synthesis without the use of a seed layer. The epitaxial nanorods showed biaxial magnetic anisotropy with an order of magnitude difference between the anisotropy field values of the easy and hard axes. Using a combination of conventional magnetometry, transverse susceptibility, magnetic force microscopy (MFM) and magneto-optic Kerr effect (MOKE) measurements, we investigate magnetic behavior such as temperature dependent magnetization and anisotropy, along with room temperature magnetic domain formation and its switching. The interplay of epitaxy and enhanced magnetic anisotropy at room temperature, with respect to randomly oriented powder Fe3O4 nanorods, is discussed. The results obtained identify epitaxial nanorods as useful materials for magnetic data storage and spintronic devices that necessitate tunable anisotropic properties with sharp magnetic switching phenomena. PMID- 28555693 TI - Near-equilibrium measurement of quantum size effects using Kelvin probe force microscopy. AB - In nano-structures such as thin films electron confinement results in the quantization of energy levels in the direction perpendicular to the film. The discretization of the energy levels leads to the oscillatory dependence of many properties on the film thickness due to quantum size effects. Pb on Si(111) is a specially interesting system because a particular relationship between the Pb atomic layer thickness and its Fermi wavelength leads to a periodicity of the oscillation of two atomic layers. Here, we demonstrate how the combination of scanning force microscopy (SFM) and Kelvin probe force microscopy (KPFM) provides a reliable method to monitor the quantum oscillations in the work function of Pb ultra-thin film nano-structures on Si(111). Unlike other techniques, with SFM/KPFM we directly address single Pb islands, determine their height while suppressing the influence of electrostatic forces, and, in addition, simultaneously evaluate their local work function by measurements close to equilibrium, without current-dependent and non-equilibrium effects. Our results evidence even-odd oscillations in the work function as a function of the film thickness that decay linearly with the film thickness, proving that this method provides direct and precise information on the quantum states. PMID- 28555694 TI - Improved molecular level identification of organic compounds using comprehensive two-dimensional chromatography, dual ionization energies and high resolution mass spectrometry. AB - A new analytical methodology combining comprehensive two-dimensional gas chromatography (GC*GC), dual ionization energies and high resolution time of flight mass spectrometry has been developed that improves molecular level identification of organic compounds in complex environmental samples. GC*GC maximizes compound separation providing cleaner mass spectra by minimizing erroneous fragments from interferences and co-eluting peaks. Traditional electron ionization (EI, 70 eV) provides MS fragmentation patterns that can be matched to published EI MS libraries while vacuum ultraviolet photoionization (VUV, 10.5 eV) yields MS with reduced fragmentation enhancing the abundance of the molecular ion providing molecular formulas when combined with high resolution mass spectrometry. We demonstrate this new approach by applying it to a sample of organic aerosol. In this sample, 238 peaks were matched to EI MS library data with FM >= 800 but a fifth (42 compounds) were determined to be incorrectly identified because the molecular formula was not confirmed by the VUV MS data. This highlights the importance of using a complementary technique to confirm compound identifications even for peaks with very good matching statistics. In total, 171 compounds were identified by EI MS matching to library spectra with confirmation of the molecular formula from the high resolution VUV MS data and were not dependent on the matching statistics being above a threshold value. A large number of unidentified peaks were still observed with FM < 800, which in routine analysis would typically be neglected. Where possible, these peaks were assigned molecular formulas from the VUV MS data (211 in total). In total, the combination of EI and VUV MS data provides more than twice as much molecular level peak information than traditional approaches and improves confidence in the identification of individual organic compounds. The molecular formula data from the VUV MS data was used, in conjunction with GC*GC retention times and the observed EI MS, to generate a new, searchable EI MS library compatible with the standard NIST MS search program. This library is deliberately dynamic and editable so that other end users can add new entries and update existing entries as new information becomes available. PMID- 28555695 TI - Thermally responsive reduced graphene oxide with designable secondary functionality. AB - Both dual responsive and thermal responsive reduced graphene oxide (rGO) with a strategically inbuilt function have been successfully synthesized by utilizing non-covalent modified poly(NIPAm-co-ViEtImBr) combined with anion exchange. PMID- 28555696 TI - Towards seamlessly-integrated textile electronics: methods to coat fabrics and fibers with conducting polymers for electronic applications. AB - Traditional textile materials can be transformed into functional electronic components upon being dyed or coated with films of intrinsically conducting polymers, such as poly(aniline), poly(pyrrole) and poly(3,4 ethylenedioxythiophene). A variety of textile electronic devices are built from the conductive fibers and fabrics thus obtained, including: physiochemical sensors, thermoelectric fibers/fabrics, heated garments, artificial muscles and textile supercapacitors. In all these cases, electrical performance and device ruggedness is determined by the morphology of the conducting polymer active layer on the fiber or fabric substrate. Tremendous variation in active layer morphology can be observed with different coating or dyeing conditions. Here, we summarize various methods used to create fiber- and fabric-based devices and highlight the influence of the coating method on active layer morphology and device stability. PMID- 28555697 TI - Double network hydrogels with highly enhanced toughness based on a modified first network. AB - A novel double network (DN) hydrogel with highly enhanced toughness has been prepared using reversible addition-fragmentation transfer (RAFT)-modified poly(2 acrylamide-2-methylpropane sulfonic acid) (PAMPS) as the first network, and polyacrylamide (PAM) as the second network. The mechanical properties of the first-network-modified PAMPS/PAM DN hydrogels have been studied and the new DN hydrogel shows remarkably high fracture energy (3.3 MJ m-3) in tensile deformation, which is nearly 9 times larger than that of the unmodified PAMPS/PAM DN hydrogel. Synchrotron radiation small-angle X-ray scattering (SAXS) was used to study the microstructures of the first-network single network (SN) and DN hydrogels. It was demonstrated by the SAXS results that the introduction of the RAFT agent into the first network enlarges the size of the ordered cross-linked domains in the SN hydrogel. The large ordered domains are beneficial for entanglement and interpenetration between the first and the second networks to dissipate concentrated stress more efficiently, resulting in the enhanced toughness of the first-network-modified DN hydrogels. PMID- 28555698 TI - A smart drug: a pH-responsive photothermal ablation agent for Golgi apparatus activated cancer therapy. AB - We report a pH-responsive photothermal ablation agent (pH-PTT) based on cyanine dyes for photothermal therapy (PTT). The nanoparticles formed by BSA and pH-PTT preferentially accumulated in the Golgi apparatus of cancer cells compared to normal cells, and thus can be specifically activated by the acidic Golgi apparatus in cancer cells for effective PTT both ex vivo and in vivo. PMID- 28555699 TI - Morphological control of self-assembled multivalent (SAMul) heparin binding in highly competitive media. AB - Tuning molecular structures of self-assembling multivalent (SAMul) dendritic cationic lipopeptides controls the self-assembled morphology. In buffer, spherical micelles formed by higher generation systems bind polyanionic heparin better than worm-like micelles formed by lower generation systems. In human serum, the binding of spherical micelles to heparin is adversely affected, while worm-like micelles maintain their relative binding ability. PMID- 28555700 TI - A gigantically increased ratio of electrical to thermal conductivity and synergistically enhanced thermoelectric properties in interface-controlled TiO2 RGO nanocomposites. AB - We report synergistically enhanced thermoelectric properties through the independently controlled charge and thermal transport properties in a TiO2 reduced graphene oxide (RGO) nanocomposite. By the consolidation of TiO2-RGO hybrid powder using spark plasma sintering, we prepared an interface-controlled TiO2-RGO nanocomposite where its grain boundaries are covered with the RGO network. Both the enhancement in electrical conductivity and the reduction in thermal conductivity were simultaneously achieved thanks to the beneficial effects of the RGO network, and detailed mechanisms are discussed. This led to the gigantic increase in the ratio of electrical to thermal conductivity by six orders of magnitude and also the synergistic enhancement in the thermoelectric figure of merit by two orders. Our results present a strategy for the realization of 'phonon-glass electron-crystals' through interface control using graphene in graphene hybrid thermoelectric materials. PMID- 28555701 TI - Bifunctional plasmonic-magnetic particles for an enhanced microfluidic SERS immunoassay. AB - Surface-Enhanced Raman Scattering (SERS) is emerging as a promising strategy for the quantification of immunoglobulin G (IgG) due to its inherent high sensitivity and specificity; however, it remains challenging to integrate SERS detection with a microfluidic system in a simple, efficient and low-cost manner. Here, we report on a novel bifunctional plasmonic-magnetic particle-based immunoassay, in which plasmonic nanoparticles act as soluble SERS immunosubstrates, whereas magnetic particles are for promoting micromixing in a microfluidic chip. With this novel SERS immunosubstrate in conjunction with the unique microfluidic system, we could substantially reduce the assay time from 4 hours to 80 minutes as well as enhance the detection specificity by about 70% in comparison to a non-microfluidic immunoassay. Compared to previous microfluidic SERS systems, our strategy offers a simple microfluidic chip design with only one well for mixing, washing and detection. PMID- 28555702 TI - Morphological explanation of high tear resistance of EPDM/NR rubber blends. AB - The fatigue properties of cross-linked blends of ethylene propylene diene rubber (EPDM) with low natural rubber (NR) content and reinforced with carbon black (CB) are studied. It is found that such EPDM/NR compounds have superior crack growth resistance and fatigue lifetime. For low NR contents, transmission electron microscopy reveals that the NR phase forms small droplets of 20-50 nm. Remarkably, these droplets are even smaller than the primary CB particles. Atomic force microscopy shows that the the NR phase droplets have a higher loss factor and a smaller elastic modulus than the surrounding EPDM matrix. Rheometer measurements are used to study the effect of the phase morphology on the rubber mechanical properties. These rheological data are compared with the prediction of the Eshelby model describing the effect of elastic inclusions on solids. A complex interplay between the rubber phase morphology and the solubility of both the sulfur cross-linking system and CB is observed, which cannot be predicted theoretically. It is proposed that the soft NR droplets effectively inhibit the crack propagation in the EPDM matrix. PMID- 28555703 TI - In situ assembly of active surface-enhanced Raman scattering substrates via electric field-guided growth of dendritic nanoparticle structures. AB - Surface-enhanced Raman scattering (SERS) can provide ultrasensitive detection of chemical and biological analytes down to the level of a single molecule. The need for costly, nanostructured, noble-metal substrates, however, poses a major obstacle in the widespread application of the method. Here we present for the first time a novel type of metallic nanostructured substrates that, not only exhibit a remarkable SERS activity, but are also produced in a facile, cost effective and nanofabrication-free manner. The substrates are formed through an electric field-guided assembly process of silver nanocolloids, which results in extended and interconnected dendritic nanoparticle structures with a high density of "hot spots". A unique and significant performance attribute of these nanostructures is their ability to also function as concentration amplification devices, thereby further enhancing their analyte detection efficiency. This major advantage against conventional SERS substrates is illustrated experimentally here with the concentration and detection of proteins from solution. Low limits of detection for illicit drugs, food contaminants and pesticides in relevant matrices are also demonstrated. The SERS-active dendrites are reusable and can be removed and replaced in a few minutes. The SERS substrates presented herein constitute a significant advance towards more effective and less expensive diagnostic tools. PMID- 28555704 TI - Transdisciplinary Research In Frailty: Knowledge Translation To Inform New Models of Care. AB - Transforming care for frail older adults requires more than rigorous research. While preventing, identifying and managing frailty are critical to reducing the personal and health systems impact of frailty worldwide, collaborative approaches to research and research application that reflect stakeholder perspectives and priorities are necessary to create meaningful solutions to frailty-related challenges. In South Australia, a new Centre for Research Excellence in Frailty was recently launched with funding from the National Health and Medical Research Council of Australia. Comprised of a national team with international partnerships and expertise spanning geriatric medicine, nursing, general practice, health economics, pharmacy and rehabilitation medicine, the team is working across traditional disciplinary silos to achieve system level improvements. Drawing from this exemplar, we discuss how a co-design approach to knowledge translation underpins this transdisciplinary research, and how successfully restructuring health services to meet the physical, emotional and social needs of older adults hinges upon such collaboration. PMID- 28555705 TI - Role of Anti-Inflammatory Cytokines on Muscle Mass and Performance Changes in Elderly Men and Women. AB - OBJECTIVES: Investigate the presence of a correlation between systemic inflammatory profile of community-dwelling individuals and the loss of muscular mass and performance in old age over a 4.5y follow-up, focusing on the role of anti-inflammatory cytokines in muscular changes in elderly. DESIGN: Longitudinal clinical study. SETTING: Subjects were randomly selected from lists of 11 general practitioners in the city of Verona, Italy. PARTICIPANTS: The study included 120 subjects, 92 women and 28 men aged 72.27+/-2.06 years and with BMI of 26.52+/ 4.07 kg/m2 at baseline. MEASUREMENTS: Six minutes walking test (6MWT), appendicular and leg fat free mass (FFM) as measured with Dual Energy X-ray absorptiometry, were obtained at baseline and after 4.5 years (4.5y) of mean follow-up. Height, weight, body mass index (BMI), and circulating levels of TNFalpha, IL-4, IL-10, and IL-13 were evaluated at baseline. RESULTS: A significant reduction of appendicular FFM, leg FFM and 6MWT performance (all p<0.001) was observed after 4.5 y follow-up. In a stepwise regression model, considering appendicular FFM decline as dependent variable, lnIL-4, BMI, baseline appendicular FFM, lnTNFalpha and lnIL-13 were significant predictors of appendicular FFM decline explaining 30.8% of the variance. While building a stepwise multiple regression considering leg FFM as a dependent variable, lnIL-4, BMI and leg FFM were significant predictors of leg FFM decline and explained 27.4% of variance. When considering 6MWT decline as a dependent variable, baseline 6MWT, lnIL-13 and lnTNFalpha were significant predictors of 6MWT decline to explain 22.9% of variance. CONCLUSIONS: Our study suggest that higher serum levels of anti-inflammatory markers, and in particular IL-4 and IL-13, may play a protective role on FFM and performance maintenance in elderly subjects. PMID- 28555706 TI - Can We Predict Morbidity and Mortality of Patients Aged 75 Years and Older Undergoing Cystectomy? AB - Radical cystectomy is associated with a high postoperative mortality and morbidity in older patients. We aimed to define the predictive value of comorbidity scores and determine the prognostic factors of postoperative complications. Preoperative associated morbidities were collected and graded according to the American Society of Anesthesiologists (ASA) score system, the Adult Comorbidity Evaluation (ACE) scale and the Charlson comorbidity index. Surgical complications were graded according to Clavien classification. Early and late complications were recorded. Data are from 49 consecutive patients aged >= 75 years who had an open surgery for bladder cancer. The most commonly associated conditions were smoking, renal insufficiency, and arterial hypertension. Incidence of early and late complications was 49% and 16%, respectively. Four and 25 death events occurred during the early and late follow-up, respectively. The incidence of morbidity and mortality were not related to ASA, ACE or Charlson scores. Preoperative malnutrition, renal insufficiency, higher need of perioperative blood transfusions, and prolonged ileus were identified as risk factors of postoperative morbidity. Late complications seemed related to low weight. PMID- 28555707 TI - Components and Indicators of Frailty Measures: A Literature Review. AB - BACKGROUND: Frailty is a debilitating condition in older adults that is associated with increased risks for adverse outcomes. However, the issue of quantifying frailty remains elusive. There is a lack of consistency in the frailty components and the corresponding indicators used to quantify these components. OBJECTIVE: 1) to describe the components of frailty and examine the existing measures of frailty; and 2) to identify current gaps in knowledge of frailty measures. METHODS: The PubMed, CINAHL, and Web of Science databases were searched. Each study was reviewed to determine its fit with inclusion/exclusion criteria. RESULTS: A total of 49 studies were identified and comprised the sample. Each study described one unique measure of frailty. The frailty components and corresponding indicators within three domains (physical, psychological, and social) were described. The most frequently reported components of frailty were mobility and balance, nutrition, and cognitive function. Fifteen of 49 frailty measures included components across all three domains. Current frailty measures were critiqued and important areas for future study are identified. CONCLUSIONS: The frailty components and corresponding indicators vary considerably across different frailty measures. Future studies are needed to address inconsistences in frailty measures and models. PMID- 28555708 TI - Test-Retest Reliability of Measurements of Hand-Grip Strength Obtained by Dynamometry from Older Adults: A Systematic Review of Research in the PubMed Database. AB - A systematic review was performed to summarize literature describing the test retest reliability of grip strength measures obtained from older adults. Relevant literature was identified via a PubMed search. Seventeen articles were deemed appropriate based on inclusion and exclusion criteria. The relative test-retest reliability of grip strength measures obtained by dynamometry was good to excellent (intra-class correlation coefficients > 0.80) in all but 3 studies, which involved older adults with severe dementia. Absolute reliability, as indicated by summary statistics such as the minimum detectable change (95%), was more variable. As a percentage, that change ranged from 14.5% to 98.5%. Consequently, clinicians can be confident in the relative reliability of grip strength measures obtained from at risk older adults. However, relatively large percentage changes in grip strength may be necessary to conclude with confidence that a real change has occurred over time in some populations. PMID- 28555709 TI - The Association between Daily Walking Behavior and Self-Reported Physical Function in Community-Dwelling Older Adults. AB - Many older people do not participate in organized exercise, and daily walking may be the most substantial contributor to physical activity. To investigate the association between daily walking behavior and self-reported health-related physical function, older community-dwelling volunteers wore activity-registering sensors for three days. Self-reported health-related physical functioning was measured using the SF36 10-item Physical Function subscale. Forty-six participants wore a sensor (mean age 77.6, SD 3.6, 61 % women). In a multiple regression model, steps per day (B=.005, p<=.001) and walks per day (B=-.174, p=.010) were associated with the SF36-PF subscale. The association between physical functioning and walks per day was negative: Those who took many walks per day may have been walking more indoors. Health professionals are likely justified in advising older people to incorporate walking into daily life for health purposes. The cross-sectional design does not allow for inferences about causality. PMID- 28555710 TI - The Effect of Physical Exercise on Frail Older Persons: A Systematic Review. AB - Physical exercise is one of the most effective non-pharmacological interventions aimed to improve mobility and independence in older persons. The effect of physical exercise and the most effective type of exercise in frail older persons remain undefined. This systematic review examines the effectiveness of physical exercise on frail older persons. Seven databases were search for randomized control trials which assessed the effect of exercise on participants who were identified as being frail using specific and validated criteria. Nine articles were reviewed from eight studies, from which seven used a validated definition of frailty. Based on the articles analyzed in our systematic review, the evidence suggests that exercise has a positive effect on various measures used to determine frailty including cognition, physical functioning, and psychological wellbeing. Some studies revealed that exercise may prevent or delay the onset of frailty which can enhance quality of life in older adults. Despite the evidence for exercise interventions in frail older adults, it appears that there is no clear guidance regarding the most effective program variables. The reviewed studies were generally long in duration (>=6 months) with sessions lasting around 60 minutes performed three or more times per week, including multicomponent exercises. In conclusion, although exercise interventions appear to be effective in managing the various components of frailty and preventing/delaying the onset of frailty, the most effective exercise program in this population remains unidentified. PMID- 28555711 TI - Determination of the Mechanisms that Cause Sarcopenia through cDNA Microarray. AB - BACKGROUND: Sarcopenia, the aging-related deterioration of skeletal muscle, is a disease that is directly associated with quality of life. Given the trend of an increasing aging population worldwide, the prevention of aging-related diseases such as sarcopenia has become ever more important and urgent. OBJECTIVE: To identify potential therapeutic targets for this disease. METHODS: we used a bioinformatics approach of combining cDNA microarray analysis and protein-protein interaction prediction. RESULTS: We found 673 significant differentially expressed genes (128 upregulated and 545 downregulated) in sarcopenia patients of over 60 years of age. Most of the upregulated genes were involved in metabolic processes such as the PPAR signaling pathway. In particular, FABP4, PLIN1, and ADIPOQ were related to fatty acid and lipid metabolism. Some of the downregulated genes were located in the mitochondrial matrix. Additionally, through the protein interaction network analysis, we found two key molecules (MAP1LC3B and HSP90AB1) that were associated with autophagy. CONCLUSIONS: These results suggest that mitochondrial dysfunction and lipid metabolism are associated with sarcopenia. PMID- 28555712 TI - Frailty in End-Stage Renal Disease Patients under Dialysis and Its Association with Clinical and Biochemical Markers. AB - Frailty is a common complication in elderly patients with end-stage renal disease (ESRD) under dialysis, which is a strong risk factor for low quality of life, morbidity, and mortality. In this work, we aimed to evaluate the prevalence of frailty in a group of Portuguese ESRD patients, and its association with socio demographic, clinical and biochemical markers. We performed a cross-sectional study with 83 ESRD patients (44 males and 39 females, 64.3 [+/-14.6] years old) on regular dialysis. The classification of the ESRD patients as robust, pre-frail and frail was performed using the FRAIL questionnaire. Social support, data about sociodemographic and comorbidities, and haematological, iron status, dialysis adequacy, nutritional and inflammatory markers were also evaluated. Our results confirmed that frailty is a highly prevalent condition in ESRD patients, particularly in female patients. An association between FRAIL score and increased depressive symptoms, presence of hypertension and decrease nutritional status was also found. PMID- 28555713 TI - How Older Persons Perceive the Loss of Independence: The Need of a Holistic Approach to Frailty. AB - BACKGROUND: Since 2004, the definition of the frailty syndrome has shifted from purely physical criteria to a more comprehensive consideration of the individual, including their psychosocial criteria. In this study, qualitative research methods were used as a complementary approach in order to enrich the existing quantitative results in this area. OBJECTIVE: To understand the views of older persons on the risk of loss of independence. METHODS: The study population comprised people over 75 years of age who were living at home in the south-west of France and were considered to be at risk of losing their independence. Data were collected using individual semi-structured in-depth interviews, accompanied by observations. Inductive analysis was carried out according to grounded theory methods. RESULTS: Fifteen individual interviews were conducted to achieve theoretical data saturation. Analysis of the content of the interviews revealed seven risk factors for the loss of independence: poor mental health, poor physical health, social isolation, no longer leaving the home, an unsuitable environment, unsuitable living conditions, and few resources. CONCLUSIONS: These results complement the purely physical approach to screening for the frailty syndrome and lead us to reconsider our screening approach to include a more holistic view of the older person and their circumstances. PMID- 28555714 TI - Letter to the Editor: Promotion of a Proposal to Incorporate Advance Care Planning Conversations into Frailty Prevention Programs for Frail Older People. PMID- 28555715 TI - The dexamethasone induced osteogenic differentiation of dental follicle cells. AB - Mesenchymal stem cells are excellent for in vitro studies about biological processes during the differentiation of osteogenic progenitor cells into mineralizing cells such as osteoblasts. Human dental follicle cells (DFCs) are dental mesenchymal stem cells and they can be isolated from third molar teeth. Because DFCs are the genuine progenitor cells of periodontal tissue cells, they have been used for the evaluation of molecular mechanisms during the differentiation of undifferentiated stem cells into alveolar osteoblasts and cementoblasts. To reveal molecular mechanisms of osteogenic differentiation, initial studies investigated the proteome and the transcriptome of DFCs after the induction of the osteogenic differentiation with the glucocorticoid dexamethasone. These studies showed for example that dexamethasone induces the transcription factor ZBTB16 (zinc finger and BTB domain containing protein 16) and that ZBTB16 is crucial for osteogenic differentiation of DFCs. This article is a survey of the molecular mechanisms in DFCs during osteogenic differentiation with dexamethasone. PMID- 28555716 TI - Trajectories of attention-deficit/hyperactivity disorder dimensions in adults. AB - OBJECTIVE: There is a lack of available information on the trajectories of attention-deficit/hyperactivity disorder (ADHD) dimensions during adulthood. This study investigates the course and the predictors of change for each ADHD domain in a clinical sample of adults with ADHD. METHOD: Adults with ADHD (n = 344) were followed up for 7 years, with a final retention rate of 66.0%. Trajectories of inattention, hyperactivity, and impulsivity and their potential predictors were examined. RESULTS: On average, symptoms declined in all ADHD domains during follow-up. Despite this, rises in inattentive, hyperactive, and impulsive symptoms were observed in approximately 13%, 25%, and 17% of patients respectively. Different predictors influenced the trajectory of each ADHD dimension. Oppositional defiant disorder and social phobia were associated with the maintenance of symptoms, while alcohol use disorder was associated with both maintenance and rise of symptoms. CONCLUSION: Unexpectedly, a rise in the symptoms after 7 years was not uncommon in adults with ADHD. Prevalent comorbidities have the potential to influence the neurodevelopment and the trajectory of ADHD. Therefore, such predictors should be investigated in population cohorts to better characterize the course of ADHD. Additionally, these findings may be relevant in prevention studies and in strategies for ADHD treatment. PMID- 28555717 TI - Beyond the Individual: The Interdependence of Advance Directive Completion by Older Married Adults. AB - OBJECTIVES: To determine how individual and spousal demographic and health factors are associated with advance directive (AD) completion by married older adults. DESIGN: Dyadic structural equation modeling using the Actor-Partner Interdependence Model. SETTING: The 2004 to 2012 waves of the Health and Retirement Study. PARTICIPANTS: Community-dwelling heterosexual married couples aged 65 and older (N = 2,243). MEASUREMENTS: Structural equation modeling with a probit link function was used to estimate associations between men's and women's age, education, health status, prior hospitalization or outpatient surgery in the past 10 years, regular health care provider, and household net assets and their own and their spouses' probabilities of having an AD. RESULTS: Individual and spousal ages were each positively associated with AD completion for men and women. Those with higher education were more likely to possess ADs. Women's probabilities of having ADs were also positively associated with husbands' education. Men whose wives' were in poor health were less likely to have ADs. Men who were hospitalized or underwent outpatient surgery were more likely to have ADs, as were their wives. Women who had regular sources of health care were more likely to have completed ADs. CONCLUSION: AD completion by older married adults is associated with both individual and spousal factors. How spouses influence one another's advance care planning differs by gender. Future research should account for the dyadic nature of advance care planning, as should public education efforts and interventions promoting AD completion. PMID- 28555719 TI - A Sudden Loss Of Vision. PMID- 28555720 TI - The combination of overweight and smoking increases the severity of androgenetic alopecia. AB - INTRODUCTION: Even though androgenetic alopecia (AGA) is the most common type of alopecia, factors associated with AGA severity have been poorly investigated. OBJECTIVES: The objective of our study was to investigate risk factors for AGA severity among a Caucasian population. METHODS: A cross-sectional study was conducted among AGA subjects in the outpatient clinic of a reference hospital for skin diseases in Rome, Italy. A total of 351 Caucasian subjects with AGA, mean age 35.6 years, were enrolled in the study. Information on educational level, family history of AGA, diet, alcohol consumption, the presence of chronic diseases, the use of pills including dietary supplements, BMI, and smoking was collected by a face-to-face interview using standardized questionnaires. Norwood and Ludwig classifications were used to assess the degree of AGA. RESULTS: Subjects with a BMI of 25 or more and current smokers had circa six times an increased risk of having moderate or severe AGA (OR: 6.72; 95% CI: 2.57-17.6). In the multivariate model, after controlling for gender, age, education, dyslipidemia, dietary supplements, and wine consumption, the effect of high BMI and smoking (OR: 5.96; 95% CI: 1.65-21.5) on AGA severity remained. Only age and gender, besides the effect of BMI and smoking, remained statistically significant in the multivariate model while education, the presence of dyslipidemia, dietary supplements, and wine consumption did not remain statistically significant. CONCLUSIONS: Our study shows that the combination of overweight and smoking is associated with an increased severity of androgenetic alopecia. PMID- 28555721 TI - Seeking Value in Healthcare: The Importance of Generalists as Primary Care Physicians. PMID- 28555718 TI - Bone Turnover with Venlafaxine Treatment in Older Adults with Depression. AB - OBJECTIVES: Epidemiologic data suggest older adults receiving serotonergic antidepressants may have accelerated bone loss. We examined bone turnover marker changes and patient-level variables associated with these changes in older adults receiving protocolized antidepressant treatment. DESIGN: Open-label, protocolized treatment study. SETTING: Medical centers in Pittsburgh, St Louis, and Toronto. PARTICIPANTS: Older adults with major depression (N = 168). MEASUREMENTS: Serum levels of the bone resorption marker C-terminal cross-linking telopeptide of type 1 collagen (CTX) and the bone formation marker procollagen type 1 N propeptide (P1NP) were assayed before and after 12 weeks of treatment with venlafaxine. Whether CTX and P1NP changes were associated with depression remission and duration of depression and genetic polymorphisms in the serotonin transporter (5HTTLPR) and 1B receptor (HTR1B) were also examined. RESULTS: CTX increased and P1NP decreased during venlafaxine treatment, a profile consistent with accelerated bone loss. Two individual-level clinical variables were correlated with bone turnover; participants whose depression did not go into remission had higher CTX levels, and those with chronic depression had lower P1NP levels. HTR1B genotype predicted P1NP change, whereas 5HTTLPR genotype was unrelated to either biomarker. CONCLUSION: Bone turnover markers change with antidepressant treatment in a pattern that suggests accelerated bone loss, although the clinical significance of these changes is unclear. These data are preliminary and argue for a larger, controlled study to confirm whether antidepressants are harmful to bone metabolism and whether certain individuals might be at increased risk. PMID- 28555722 TI - The global state of psoriasis disease epidemiology: a workshop report. AB - The International Psoriasis Council, a global nonprofit organization dedicated to innovation across the full spectrum of psoriasis, led a symposium to discuss the current state of psoriasis epidemiology and to introduce the vision and development of a Global Psoriasis Atlas. The symposium was held on 9 September 2015 at the 45th annual meeting of the European Society for Dermatological Research, Rotterdam, the Netherlands. Collectively, these presentations highlighted challenges associated with assessing psoriasis epidemiology and emphasized the urgent need for an authoritative resource to clarify psoriasis disease burden on a global scale. PMID- 28555723 TI - Warfarin-induced skin necrosis accompanied by aggravation of vasculitis in a patient with cutaneous arteritis. PMID- 28555724 TI - Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia. AB - The pharmacokinetics (PK) of amoxicillin in asphyxiated newborns undergoing moderate hypothermia were quantified using prospective data (N = 125). The population PK was described by a 2-compartment model with a priori birthweight (BW) based allometric scaling. Significant correlations were observed between clearance (Cl) and postnatal age (PNA), gestational age (GA), body temperature (TEMP), and urine output (UO). For a typical patient with GA 40 weeks, BW 3,000 g, 2 days PNA (i.e., TEMP 33.5 degrees C), and normal UO, Cl was 0.26 L/h (interindividual variability (IIV) 41.9%) and volume of distribution of the central compartment was 0.34 L/kg (IIV of 114.6%). For this patient, Cl increased to 0.41 L/h at PNA 5 days and TEMP 37.0 degrees C. The respective contributions of both covariates were 23% and 27%. Based on Monte Carlo simulations we recommend 50 and 75 mg/kg/24h amoxicillin in three doses for patients with GA 36 37 and 38-42 weeks, respectively. PMID- 28555725 TI - The association between psoriasis and coeliac disease. PMID- 28555726 TI - Vector population growth and condition-dependent movement drive the spread of plant pathogens. AB - Plant viruses, often spread by arthropod vectors, impact natural and agricultural ecosystems worldwide. Intuitively, the movement behavior and life history of vectors influence pathogen spread, but the relative contribution of each factor has not been examined. Recent research has highlighted the influence of host infection status on vector behavior and life history. Here, we developed a model to explore how vector traits influence the spread of vector-borne plant viruses. We allowed vector life history (growth rate, carrying capacity) and movement behavior (departure and settlement rates) parameters to be conditional on whether the plant host is infected or healthy and whether the vector is viruliferous (carrying the virus) or not. We ran simulations under a wide range of parameter combinations and quantified the fraction of hosts infected over time. We also ran case studies of the model for Barley yellow dwarf virus, a persistently transmitted virus, and for Potato virus Y, a non-persistently transmitted virus. We quantified the relative importance of each parameter on pathogen spread using Latin hypercube sampling with the statistical partial rank correlation coefficient technique. We found two general types of mechanisms in our model that increased the rate of pathogen spread. First, increasing factors such as vector intrinsic growth rate, carrying capacity, and departure rate from hosts (independent of whether these factors were condition-dependent) led to more vectors moving between hosts, which increased pathogen spread. Second, changing condition-dependent factors such as a vector's preference for settling on a host with a different infection status than itself, and vector tendency to leave a host of the same infection status, led to increased contact between hosts and vectors with different infection statuses, which also increased pathogen spread. Overall, our findings suggest that vector population growth rates had the greatest influence on rates of virus spread, but rates of vector dispersal from infected hosts and from hosts of the same infection status were also very important. Our model highlights the importance of simultaneously considering vector life history and behavior to better understand pathogen spread. Although developed for plant viruses, our model could readily be utilized with other vector-borne pathogen systems. PMID- 28555727 TI - Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors. AB - For most inflammatory skin diseases topical glucocorticosteroids and traditional oral immunosuppressive drugs remain the principle treatment choices, but this has started to change. A deeper understanding in individual disease pathogenesis, basic immune mechanisms and molecular signalling pathways, together with advances in pharmaceutical drug development, allow us to interfere more precisely with disease-related factors. Some examples of inflammation-controlling interventions include antibodies neutralizing disease-associated cytokines, and small molecules targeting intracellular pathways relevant to cytokine production or cytokine signalling. So far, this is best established for psoriasis, an inflammatory skin disease dominated by Th17 cytokines. In this review, we focus on chronic inflammatory skin diseases where cytokines using type I/II cytokine receptors play a dominant role in disease pathogenesis and where novel treatments with inhibitors of the JAK/STAT pathway are already under clinical investigation. To better understand the rationale of using JAK/STAT inhibitors in the discussed skin diseases, we give an overview of important genetic and immunological associations with the JAK/STAT pathway and summarize the stage of clinical development of small molecular inhibitors. JAK/STAT inhibitors will presumably find wide application in dermatology, since they can be applied not only systematically but also topically for the treatment of inflammatory skin diseases. PMID- 28555728 TI - Platelet distribution width as the prognostic marker in coronary bifurcation treatment. AB - BACKGROUND: Mean platelet volume (MPV) was proved to be a reliable prognostic factor in cardiac patients. However, platelet distribution width (PDW) was disclosed to be more specific marker of platelet reactivity. The aim of study was to evaluate whether baseline PDW value can predict the outcome in patients undergoing percutaneous coronary interventions (PCI) with drug-eluting stent implantation within coronary bifurcation lesions. MATERIALS AND METHODS: It was a two-centre observational study, which included patients who underwent PCI within bifurcation lesions between January 2014 and December 2014. Thrombocytopenia below 100 000/MUL and STEMI were the exclusion criteria. Analysed data came entirely from in-hospital records and information obtained from the 12-month telephone follow-up. RESULTS: We included 269 patients. Mean PDW value was 13.4 +/- 2.5 fL, whereas median was 13 (Q1 < 11.6 fL, Q2 11.6-13 fL, Q3 13-14.8 fL and Q4 > 14.8 fL). We found strong correlation between PDW and MPV (r = 0.96, P < 0.001), but no correlation was revealed between red blood cell distribution width (RDW) and PDW (r = 0.003, P = 0.95) as well as RDW and MPV (r = 0.0018, P = 0.98). Receiver operating characteristics (ROC) curve showed that PDW for cutoff 15.8% can predict MACE rate with sensitivity of 79% and specificity of 47% (area under curve - AUC 0.654; P = 0.01). A ROC curve for PDW categorized by 1-year TLR rate was described by optimal cutoff 16.3%, with sensitivity 69% and specificity 54% (AUC 0.697; P = 0.0015). CONCLUSIONS: PDW is an affordable and reliable predictor of 1-year MACE and TLR rate after PCI within coronary bifurcation lesions. PMID- 28555730 TI - PHLOX AND COLIAS: THE EFFICIENCY OF A POLLINATION SYSTEM. PMID- 28555729 TI - Oral Health and Dental Care in Older Asian Americans in Central Texas. AB - OBJECTIVES: To examine factors associated with dental health insurance, self rated oral health, and use of preventive dental care services in older Asian Americans. DESIGN: Cross-sectional survey. SETTING: The Asian American Quality of Life Survey was conducted with 2,614 Asian Americans living in central Texas using questionnaires available in English and six Asian languages. PARTICIPANTS: Asian American Quality of Life Survey participants aged 60 and older (N = 533; mean age = 69.4 +/- 6.9). MEASUREMENTS: Participants were asked whether they had insurance that covered the cost of any dental visit, how they would rate their overall oral health status, and whether they had visited a dental clinic for a routine examination in the past 12 months. Information was also collected on sociodemographic and immigration-related variables. RESULTS: More than 61% of the sample had no dental health insurance, 45% reported that their oral health was fair or poor, and 44% had not used preventive dental care services. A series of logistic regression analyses identified factors posing a significant risk to oral health and dental care. For example, those with limited English proficiency were 3.5 times as likely to lack dental health insurance and 3.2 times as likely to rate their oral health as fair or poor. The odds of not using preventive dental care services were 6.4 times as great in those without dental health insurance. CONCLUSION: The overall findings call attention to efforts to promote oral health and dental care in older Asian Americans. PMID- 28555731 TI - RAPID EVOLUTION OF COMPETITIVE ABILITY IN LARVAL MIXTURES OF THE HOUSEFLY. PMID- 28555732 TI - DISCRIMINATION BEHAVIOR AND HYBRIDIZATION OF THE BLUE-WINGED AND GOLDEN-WINGED WARBLERS. PMID- 28555733 TI - KARYOTYPIC EVOLUTION OF BEES AND CORRESPONDING TAXONOMIC IMPLICATIONS. PMID- 28555734 TI - PREHISTORIC AGRICULTURE. PMID- 28555735 TI - CHARA VULGARIS AND C. CONTRARIA: PATTERNS OF REPRODUCTIVE ISOLATION FOR TWO COSMOPOLITAN SPECIES COMPLEXES. PMID- 28555736 TI - EVOLUTIONARY STRATEGIES IN LIFE TABLE CHARACTERISTICS AMONG FERAL AND URBAN STRAINS OF AEDES AEGYPTI (L.). PMID- 28555737 TI - POLLINATION STUDY IN A NATURAL POPULATION OF MIMULUS GUTTATUS. PMID- 28555738 TI - A POCKET OF VARIABILITY IN PINUS RIGIDA. PMID- 28555739 TI - GENETIC DISTANCE AND EVOLUTIONARY RELATIONSHIPS IN THE DROSOPHILA OBSCURA GROUP. PMID- 28555740 TI - A PATERNAL ROLE FOR BULLS OF THE GALAPAGOS ISLANDS SEA LION. PMID- 28555741 TI - GENETIC AND PHENOTYPIC DIFFERENTIATION AND GEOGRAPHIC DISTANCE IN FOUR SPECIES OF LEPIDOPTERA. PMID- 28555742 TI - POLLEN EXCHANGE AS A FUNCTION OF SPECIES PROXIMITY IN PHLOX. PMID- 28555743 TI - RECOGNITION BY DROSOPHILA MELANOGASTER OF INDIVIDUALS FROM OTHER STRAINS OR CULTURES: SUPPORT FOR THE ROLE OF OLFACTORY CUES IN SELECTIVE MATING? PMID- 28555744 TI - EGG-PRODUCTION, POLYPLOIDIZATION AND EVOLUTION IN A DIPLOID ALL-FEMALE FISH OF THE GENUS POECILIOPSIS. PMID- 28555745 TI - EVOLUTION IN THE STAPHYLINID GENUS PRIOCHIRUS (COLEOPTERA). PMID- 28555746 TI - Tropical insect diversity: evidence of greater host specialization in seed feeding weevils. AB - Host specialization has long been hypothesized to explain the extraordinary diversity of phytophagous insects in the tropics. However, addressing this hypothesis has proved challenging because of the risk of over-looking rare interactions, and hence biasing specialization estimations, and the difficulties to separate the diversity component attributable to insect specialization from that related to host diversity. As a result, the host specialization hypothesis lacks empirical support for important phytophagous insect clades. Here, we test the hypothesis in a radiation of seed-feeding insects, acorn weevils (Curculio spp.), sampled in temperate and tropical regions (California and Nicaragua, respectively) with an equivalent pool of oak host species. Using DNA sequences from three low-copy genes, we delimited to species level 778 weevil larvae extracted from host seeds and assessed their phylogenetic relationships by Maximum Likelihood and Bayesian inference. We then reconstructed the oak-weevil food webs and examined differences in alpha, beta and gamma diversity using Hill numbers of effective species. We found a higher alpha, beta and gamma diversity of weevils in Nicaragua compared to California despite similar richness of host species at both local and regional level. By means of Bayesian mixed models, we also found that tropical weevil species were highly specialized both in terms of host range and interaction strength, whereas their temperate congeners had a broader taxonomic and phylogenetic host spectrum. Finally, in Nicaraguan species, larval body size was highly correlated with the size of the acorns infested, as would be expected by a greater host specialization, whereas in California this relationship was absent. Altogether, these lines of evidence support the host specialization hypothesis and suggest contrasting eco-evolutionary dynamics in tropical and temperate regions even in absence of differences in host diversity. PMID- 28555748 TI - Patient controlled analgesia: effective and cost-effective management of acute pain within the Emergency Department? PMID- 28555749 TI - Have We Learned How to Use Bisphosphonates Yet? PMID- 28555747 TI - Liver X receptors link lipid metabolism and inflammation. AB - The response of immune cells to pathogens is often associated with changes in the flux through basic metabolic pathways. Indeed, in many cases changes in metabolism appear to be necessary for a robust immune response. The Liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that regulate gene networks controlling cholesterol and lipid metabolism. In immune cells, particularly in macrophages, LXRs also inhibit proinflammatory gene expression. This Review will highlight recent studies that connect LXR-dependent control of lipid metabolism to regulation of the immune response. PMID- 28555751 TI - Metabolic regulation of macrophages during tissue repair: insights from skeletal muscle regeneration. AB - Macrophages are highly versatile cells that are involved both in the mounting and the resolution of inflammatory responses. Besides their properties in innate immunity to fight against pathogens, macrophages are essential for tissue repair, during which they adopt sequential inflammatory status. While the acquisition of some canonical polarized inflammatory statuses in vitro (M1/M2) is beginning to be understood at the molecular level, the regulation of macrophage skewing in vivo has been less investigated. Immunometabolism, in particular, is an emerging field, and most of the studies so far have investigated the control of macrophage polarization using in vitro set-ups. In this context, skeletal muscle regeneration is an excellent paradigm to study tissue repair, since the sequential steps of inflammatory response and tissue repair are well characterized. In this Review, after introducing macrophage populations and functions during skeletal muscle regeneration, we present the current knowledge on the metabolic regulation of macrophage inflammatory status, with particular emphasis on the comparison between in vitro and in vivo models of macrophage activation. We also discuss the metabolic regulation of macrophages in vivo during skeletal muscle regeneration. PMID- 28555752 TI - Self-esteem development in the school context: The roles of intrapersonal and interpersonal social predictors. AB - OBJECTIVE: When considering that social inclusion is a basic human need, it makes sense that self-esteem is fueled by social feedback and the sense of being liked by others. This is particularly true with respect to early adolescence, when peers become increasingly important. In the current article, we tested which components of social inclusion are particularly beneficial for the development of self-esteem by differentiating between intrapersonal components (i.e., self perceptions of social inclusion) and interpersonal components (i.e., perceiver and target effects of liking). METHOD: Using longitudinal data from 2,281 fifth graders and 1,766 eighth graders (TRAIN; Jonkmann et al., 2013), we tested mean level self-esteem development and the role of intrapersonal components in this development. Using classroom round-robin data on liking from subsamples of 846 (689) fifth-(eighth-)grade students nested in 46 (39) classes, we tested effects of interpersonal relationship components on self-esteem development in the classroom context. RESULTS: The three major findings demonstrated, first, no consistent trends in mean levels of self-esteem in early to middle adolescence; second, constant positive effects of intrapersonal components between students and within students across time; and third, no stable effects of interpersonal components. CONCLUSIONS: The discussion highlights the role of intrapersonal components and the methodological challenges of our study. PMID- 28555750 TI - Research Priorities to Advance the Health and Health Care of Older Adults with Multiple Chronic Conditions. AB - OBJECTIVES: To prioritize research topics relevant to the care of the growing population of older adults with multiple chronic conditions (MCCs). DESIGN: Survey of experts in MCC practice, research, and policy. Topics were derived from white papers, funding announcements, or funded research projects relating to older adults with MCCs. SETTING: Survey conducted through the Health Care Systems Research Network (HCSRN) and Claude D. Pepper Older Americans Independence Centers (OAICs) Advancing Geriatrics Infrastructure and Network Growth Initiative, a joint endeavor of the HCSRN and OAICs. PARTICIPANTS: Individuals affiliated with the HCSRN or OAICs and national MCC experts, including individuals affiliated with funding agencies having MCC-related grant portfolios. MEASUREMENTS: A "top box" methodology was used, counting the number of respondents selecting the top response on a 5-point Likert scale and dividing by the total number of responses to calculate a top box percentage for each of 37 topics. RESULTS: The highest-ranked research topics relevant to the health and healthcare of older adults with MCCs were health-related quality of life in older adults with MCCs; development of assessment tools (to assess, e.g., symptom burden, quality of life, function); interactions between medications, disease processes, and health outcomes; disability; implementation of novel (and scalable) models of care; association between clusters of chronic conditions and clinical, financial, and social outcomes; role of caregivers; symptom burden; shared decision-making to enhance care planning; and tools to improve clinical decision-making. CONCLUSION: Study findings serve to inform the development of a comprehensive research agenda to address the challenges relating to the care of this "high-need, high-cost" population and the healthcare delivery systems responsible for serving it. PMID- 28555753 TI - Bullying and cyberbullying studies in the school-aged population on the island of Ireland: A meta-analysis. AB - BACKGROUND: Bullying research has gained a substantial amount of interest in recent years because of the implications for child and adolescent development. AIM AND SAMPLE: We conducted a meta-analysis of traditional and cyberbullying studies in the Republic and North of Ireland to gain an understanding of prevalence rates and associated issues (particularly psychological correlates and intervention strategies) among young people (primary and secondary school students). METHOD: Four electronic databases were searched (PsychArticles, ERIC, PsychInfo and Education Research Complete) for studies of traditional bullying and cyberbullying behaviours (perpetrators, victims or both) published between January 1997 and April 2016. RESULTS: A final sample of 39 articles fit our selection criteria. CMA software was used to estimate a pooled prevalence rate for traditional/cyberbullying victimization and perpetration. A systematic review on the psychological impacts for all types of bullying and previously used interventions in an Irish setting is also provided. CONCLUSIONS: The results demonstrate the influence moderating factors (e.g., assessment tools, answer scale, time frame) have on reported prevalence rates. These results are discussed in light of current studies, and points for future research are considered. PMID- 28555754 TI - Expression patterns of Sema3A in developing amniote limbs: With reference to the diversification of peripheral nerve innervation. AB - Paired limbs were acquired in the ancestor of tetrapods and their morphology has been highly diversified in amniotes in relation to the adaptive radiation to the terrestrial environment. These morphological changes may have been induced by modification of the developmental program of the skeletal or muscular system. To complete limb modification, it is also important to change the neuronal framework, because the functions of the limbs rely on neural circuits that involve coordinated movement. Previous studies have shown that class 3 semaphorins (Sema3 semaphorins), which act as repulsive axonal guidance cues, play a crucial role in the formation of the peripheral nerves in mice. Here, we studied the expression pattern of Sema3A orthologues in embryos of developing amniotes, including mouse, chick, soft-shelled turtle, and ocelot gecko. Sema3A transcripts were expressed in restricted mesenchymal parts of the developing limb primordium in all animals studied, and developing spinal nerves appeared to extend through Sema3A-negative regions. These results suggest that a Sema3A dependent guidance system plays a key role in neuronal circuit formation in amniote limbs. We also found that Sema3A partially overlapped with the distribution of cartilage precursor cells. Based on these results, we propose a model in which axon guidance and skeletogenesis are linked by Sema3A; such mechanisms may underlie functional neuron rearrangement during limb diversification. PMID- 28555755 TI - Reliability of the Assisting Hand Assessment in adolescents. AB - AIM: To investigate the interrater and test-retest reliability of the Assisting Hand Assessment in adolescents (Ad-AHA) with cerebral palsy (CP) and to evaluate the alternate-form reliability of different test activities. METHOD: Participants were 112 adolescents with unilateral CP (60 males, 52 females; mean age 14y 5mo [standard deviation {SD} 2y 8mo], Manual Ability Classification System levels I III). Reliability was evaluated using intraclass correlation coefficients (ICC), smallest detectable change (SDC), and Bland-Altman plots. RESULTS: ICCs for interrater (n=38) and test-retest reliability (n=31) were excellent: 0.97 (95% CI 0.94-0.98) and 0.99 (95% CI 0.98-0.99) respectively. The alternate-form reliability of different test activities was excellent for children (age 10-12y, n=30) performing the School-Kids AHA and Ad-AHA Board Game 0.99 (95% CI 0.98 0.99) and for adolescents (age 13-18y) performing the Ad-AHA Board Game compared to the Ad-AHA Present (n=28) 0.99 (95% CI 0.95-0.98), or the Ad-AHA Sandwich (n=29) 0.99 (95% CI 0.98-0.99) tasks. SDC for test-retest was 4.5 AHA-units. INTERPRETATION: Ad-AHA scores are consistent across different raters and occasions. The good alternate-form reliability indicates that the different test activities can be used interchangeably in adolescents with unilateral CP. Differences greater than or equal to 5 AHA-units can be considered a change beyond measurement error. The use of logit based AHA-units makes change comparable for persons at different ability levels. PMID- 28555756 TI - Design and chemical syntheses of potent matriptase-2 inhibitors based on trypsin inhibitor SFTI-1 isolated from sunflower seeds. AB - Matriptase-2 plays a pivotal role in keeping iron concentrations within a narrow physiological range in humans. The opportunity to reduce matriptase-2 proteolytic activity may open a novel possibility to treat iron overload diseases, such as hereditary hemochromatosis and thalassemia. Here, we present 23 new analogues of trypsin inhibitor SFTI-1 designed to inhibit human matriptase-2. Influence of the modifications Gly1Lys, Ile10Arg, and Phe12His, as well as the introduction of Narg in P1 or P1 and P4 positions were examined. Selected peptides were further analyzed, together with previously reported peptides, for their inhibitory activity against related human proteases, that are, matriptase-1, plasmin, thrombin and trypsin. A highly potent inhibitor of matriptase-2, the bicycylic [Arg5 , Arg10 , His12 ]SFTI-1, with a Ki value of 15 nm was obtained. PMID- 28555757 TI - Using urinary parameters to estimate seasonal variation in the physical condition of female white-faced capuchin monkeys (Cebus capucinus imitator). AB - OBJECTIVES: The physical condition of females depends on access to resources, which vary over space and time. Assessing variation in physical condition can help identify factors affecting reproductive success, but noninvasive measurement is difficult in wild animals. Creatinine concentration relative to the specific gravity (i.e., density) of urine has promise for noninvasively quantifying the relative muscle mass (RMM) of wild primates. We verified the relationship between these urinary parameters for wild white-faced capuchin monkeys, and assessed temporal changes in the RMM of females across groups and between periods of high and low resource abundance. MATERIALS AND METHODS: We collected urine from 25 adult females in three groups across varying seasons at Sector Santa Rosa, Costa Rica. We measured the specific gravity and creatinine concentration of 692 samples and the effect of specific gravity on creatinine concentration. We used the residuals of this relationship to measure effects of group and season using mixed-effects models. RESULTS: Specific gravity significantly predicted creatinine concentration. Season, group membership and the interaction between these variables were significant predictors of residual creatinine variation. Specifically, RMM was higher during months with high fruit energy density, lower in one social group, and less variable among females in the smallest group. DISCUSSION: Our findings suggest that specific gravity and creatinine may be used as urinary parameters to make inferences about the RMM of capuchins. Using this technique, we infer that females experienced changes in muscle mass according to variation in resource energy availability and social group variation. PMID- 28555758 TI - Novel dermoscopic findings in mudi-chood disease - a case report. PMID- 28555760 TI - HERMON BUMPUS AND NATURAL SELECTION IN THE HOUSE SPARROW PASSER DOMESTICUS. PMID- 28555759 TI - Postictal generalized EEG suppression and respiratory dysfunction following generalized tonic-clonic seizures in sleep and wakefulness. AB - OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is a common cause of death in epilepsy and frequently occurs following generalized tonic-clonic seizures (GTCS) in sleep. Postictal generalized electroencephalography (EEG) suppression (PGES), postictal immobility, and periictal respiratory dysfunction are potential risk factors for SUDEP. We sought to determine whether there was a difference in respiratory dysfunction, PGES, and postictal immobility for GTCS occurring during wakefulness or sleep. METHODS: We retrospectively analyzed video-EEG telemetry data in the epilepsy-monitoring unit. Patients' state at seizure onset and seizure characteristics were identified. Respiratory parameters and heart rate were recorded. Presence and duration of PGES and time to first postictal nonrespiratory movement were recorded. RESULTS: There were 165 seizures in 67 patients. There was no significant difference in the duration of postictal immobility in GTCS occurring out of wakefulness or sleep (p = 0.280). Oxygen desaturation nadir (p = 0.572) and duration of oxygen desaturation were not significantly different for GTCS starting during sleep or wakefulness (p = 0.992). PGES occurred more frequently when seizure onset was in sleep than in wakefulness (p = 0.004; odds ratio [OR] 2.760). There was no difference in the duration of PGES between the two groups. SIGNIFICANCE: PGES occurs more commonly after GTCS in sleep than in wakefulness but, in the epilepsy-monitoring unit (EMU), a patient's state at seizure onset does not affect the degree of respiratory dysfunction or duration of postictal immobility. In sleep, outside the hospital setting, GTCS are likely to go unnoticed. Postictal immobility in prone patients prevents head repositioning and unimpeded air exchange. A positive feedback cycle ensues with increasing respiratory distress, potentiating postictal immobility and PGES and eventually leading to asystole. Our findings suggest that the high incidence of nocturnal SUDEP may be related to the unsupervised environment during sleep rather than the severity of sleep-related respiratory dysfunction or PGES duration in the immediate postictal period. PMID- 28555761 TI - BREEDING SYSTEM AND GENETIC VARIATION IN LEAVENWORTHIA. PMID- 28555762 TI - THE ORIGIN OF THE ALLOTETRAPLOID CLARKIA GRACILIS. PMID- 28555763 TI - FURTHER EVIDENCE OF GENETIC AND INCREASED DEVELOPMENTAL HOMEOSTASIS IN A DROSOPHILA MELANOGASTER NATURAL POPULATION DURING A MINOR CLIMATIC SHIFT. PMID- 28555765 TI - ISOZYMIC EVIDENCE BEARING ON THE ORIGIN OF NICOTIANA TABACUM L. PMID- 28555764 TI - EVOLUTIONARY GENETICS OF CAVE-DWELLING FISHES OF THE GENUS ASTYANAX. PMID- 28555766 TI - EVIDENCE AGAINST GENETIC SELF-INCOMPATIBILITY IN THE HOMOSPOROUS FERN PTERIDIUM AQUILINUM. PMID- 28555767 TI - COURTSHIP BEHAVIOR IN THE SEMISPECIES OF THE SUPERSPECIES DROSOPHILA PAULISTORUM. PMID- 28555768 TI - DISTRIBUTION PATTERNS OF PRIOCHIRUS SPECIES (COLEOPTERA: STAPHYLINIDAE) IN THE SOLOMON ISLANDS. PMID- 28555769 TI - THE BREAKDOWN OF TRIMORPHIC INCOMPATIBILITY IN OXALIS SECTION CORNICULATAE. PMID- 28555770 TI - MATE SELECTION AND BALANCED POLYMORPHISM IN THE TROPICAL NYMPHALID BUTTERFLY, ANARTIA FATIMA. PMID- 28555771 TI - GEOGRAPHIC VARIATION AND ENVIRONMENTAL SELECTION IN GASTEROSTEUS ACULEATUS L. IN THE PACIFIC NORTHWEST, AMERICA. PMID- 28555772 TI - SELECTIVE ATTRACTION OF MALE EUGLOSSINE BEES TO ORCHID FLORAL FRAGRANCES AND ITS IMPORTANCE IN LONG DISTANCE POLLEN FLOW. PMID- 28555773 TI - Sex differences in empathy for pain: What is the role of autonomic regulation? AB - Empathy involves both affective and cognitive components whereby we understand, and express concerns for, the experiences of others. Women typically have superior trait empathy compared with men, which seems to have a neurological basis with sex differences in the structure and function of neural networks involved in empathy. This study investigated sex differences in empathy for pain using the Empathy for Pain Scale, and examined whether these trait differences were associated with disruptions in autonomic regulation, specifically via the parasympathetic nervous system (measured through the square root of the mean squared differences of successive R-R intervals; RMSSD) both at rest and during a socioevaluative stress task (i.e., the serial sevens task). Compared with men, women reported higher empathic concern (Cohen's r = .25) and affective distress (Cohen's d = 0.65) toward another in pain. In both men and women, there was a decrease in lnRMSSD in the stress task compared to rest. Sex moderated the relationship between resting lnRMSSD and self-reported empathic concern. Specifically, there was no clear association between empathic concern and lnRMSSD in men whereas in women there was a negative relationship, with lower resting lnRMSSD associated with higher empathic concern, and higher lnRMSSD associated with lower levels of empathic concern that were similar to men. These findings suggest that empathic feelings may result from poorer psychophysiological regulation, and concur with previous research displaying sex-specific relationships between resting heart rate variability and emotion regulation abilities. PMID- 28555774 TI - Post-Fordist reconfigurations of gender, work and life: theory and practice. AB - Based on an in-depth study with 56 informants (25 women and 31 men), across the ICT (information and communication technology), creative and academic sectors in one city/regional hub in Ireland, this article investigates the so-called revolution in work/life practices associated with the post-Fordist labour processes of the Knowledge Economy from the perspectives of workers themselves. Recent theorizations of post-Fordist work patterns emphasize a rearranging of work and life place boundaries; a reconfiguring of work and life time boundaries; and a dissolving of the gendered boundaries of work and life (production and social reproduction) (Adkins and Dever ; Morini and Fumagalli ; Gill and Pratt ; Weeks ; Hardt and Negri ). Our findings suggest that, instead of dissolving boundaries, workers constantly struggle to draw boundaries between what counts as work and as life, and that this varies primarily in relation to gender and stage in a gendered life trajectory. Work extensification is compensated for via a perceived freedom to shape one's own life, which is articulated in terms of individualized boundary-drawing. While younger men embraced 'always on' work, they also articulated anxieties about how these work habits might interfere with family aspirations. This was also true for younger women who also struggled to make time for life in the present. For mothers, boundary drawing was articulated as a necessity but was framed more in terms of personal choice by fathers. Although all participants distinguished between paid work and life as distinct sites of value, boundaries were individually drawn and resist any easy mapping of masculinity and femininity onto the domains of work and life. Instead, we argue that it is the process of boundary drawing that reveals gendered patterns. The personalized struggles of these relatively privileged middle-class workers centre on improving the quality of their lives, but raise important questions about the political possibilities within and beyond the world of post-Fordist labour. PMID- 28555775 TI - What weighs more-low compliance with self-deferral or minor medical procedures? Explaining the high rate of hepatitis C virus window-period donations in Poland. AB - BACKGROUND: Since the introduction of nucleic acid testing (NAT) for routine blood donor screening, hepatitis C virus (HCV) RNA-only detection rates reported from Poland have been higher than in most other European countries. STUDY DESIGN AND METHODS: To examine factors that likely contribute to these window-period donations, we conducted a case-control study among 47 recently HCV-infected blood donors (cases), who gave blood between July 2002 and June 2014, and 141 controls matched by age, sex, and donation dates. Firth-corrected, conditional logistic regression models were fitted to estimate adjusted odds ratios and 95% confidence intervals. Adjusted population-attributable fractions were calculated based on the distribution of exposure among the cases. RESULTS: On multivariate analysis, recent exposures in health care environments not routinely ascertained through predonation questionnaires were strongly associated with recently acquired HCV infection. These exposures included minor medical and dental procedures in the preceding 6 months (adjusted odds ratio, 5.77; 95 % confidence interval, 2.01 18.53). However, based on the population-attributable fraction, more important were behavioral deferrable risks that went unreported at the time of donation, such as high-risk sexual behaviors in the preceding 6 months (population attributable fraction, 34%) or lifetime histories of drug use (population attributable fraction, 28%). CONCLUSIONS: This study raises questions about the effectiveness of deferral policy in excluding high-risk individuals. In addition, it provides further evidence supporting short, temporal deferrals for small medical procedures and dental treatments in Poland. PMID- 28555776 TI - Concurrent mood and anxiety disorders are associated with pharmacoresistant seizures in patients with MTLE. AB - OBJECTIVE: To investigate whether mood disorders (MD) and anxiety disorders (AD) are associated with seizure control in patients with mesial temporal lobe epilepsy (MTLE). We compared patients without any current psychiatric disorder, patients with current MD and/or AD, patients with subsyndromic depression episodes (SSDE) and anxiety episodes (SSAE), and patients with family psychiatric history. METHODS: In a cross-sectional study, we included 144 consecutive patients with MTLE (82 pharmacoresistant and 62 treatment-responsive patients). Every patient underwent a psychiatric evaluation including the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) Axis I (SCID-I), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), and Interictal Dysphoric Disorder Inventory (IDDI). Patients were divided into four groups: PsychNeg (G1, n = 61), current SSDE and SSAE (G2, n = 26), Current MD or AD (G3, n = 25), and current mixed MD/AD (G4, n = 32). RESULTS: Among patients with pharmacoresistant MTLE, 68.3% (56/82) experienced symptoms of depression and/or anxiety (G2, G3, and G4) (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.41-5.53, p < 0.01). Patients with mixed MD/AD (G4, n = 24/32) were more likely to have pharmacoresistant MTLE (OR 4.04, 95% CI 1.57 10.42, p < 0.01) than psychiatric asymptomatic patients (G1, n = 26/61), and their seizure frequency was significantly higher (p < 0.01). Positive family psychiatric history was more frequent in pharmacoresistant patients (n = 27/82, OR 2.28, 95% CI 1.02-5.05, p = 0.04). Finally, 31.6% of patients with MD and or AD were not receiving psychiatric treatment. SIGNIFICANCE: Identification of comorbid MD/AD and of family psychiatric history is of the essence in patients with MTLE, as they appear to be associated with worse seizure control. PMID- 28555777 TI - Early ictal and interictal patterns in FIRES: The sparks before the blaze. AB - OBJECTIVE: Febrile infection-related epilepsy syndrome (FIRES) is a catastrophic epileptic encephalopathy described as explosive onset of super refractory status epilepticus (SRSE) in previously healthy children. We describe electroencephalography (EEG) abnormalities in the hyperacute phase of FIRES, with the aim of contributing to the diagnostic characterization of a syndrome otherwise lacking specific biomarkers. METHODS: This is a retrospective single center, case series of seven children with FIRES. Cases were identified from a Neurocritical Care database. Patient characteristics and clinical course were obtained from electronic medical records. Electroencephalography recordings were reviewed in two segments: the initial 12 h of recording and the 12 h prior to initiation of a medically induced burst suppression (BS). RESULTS: Fourteen 12-h segments of video-electroencephalography (EEG) recordings were analyzed for commonalities. A beta-delta complex resembling extreme delta brush (EDB) occurred in at least one 12-h segment for all patients. In six patients, seizures were brief and relatively infrequent during the first recording, with a gradual evolution to status epilepticus by the second. We observed a characteristic electrographic seizure pattern in six of seven patients with prolonged focal fast activity at onset. Shifting seizures were seen in four of seven patients. SIGNIFICANCE: The diagnosis of FIRES is typically assigned late in a patient's clinical course, which has broad implications for clinical care and research. We retrospectively analyzed acute EEG features in seven patients with FIRES and discovered three common features: gradual increase in seizure burden, presence of a recurrent EDB, and a typical seizure pattern. Recognition of this pattern may facilitate early diagnosis and treatment. PMID- 28555779 TI - Pharmacology of oxidative stress: translational opportunities. AB - LINKED ARTICLES: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. PMID- 28555778 TI - The feasibility of salivary sample collection in an international pediatric cohort: The the TEDDY study. AB - Saliva offers a relatively noninvasive method for measuring analytes such as cortisol, holding particular promise for use in pediatric populations on a large scale if a rigorous collection protocol is feasible in diverse settings. The Environmental Determinants of Diabetes in the Young study protocol, conducted in centers in the United States, Sweden, Finland, and Germany, used salivary collection to assess cortisol level as a physiologic marker of stress. Saliva was collected using Sorbettes from subjects at 3.5, 4.5, and 5.5 years of age. Parents collected a morning sample, and staff collected pre- and post-blood draw samples. Feasibility was assessed based on protocol completion, adherence with instructions, factors affecting adherence, and sufficiency of saliva sample for cortisol determination. Collection of saliva samples in a diverse pediatric population is feasible. Establishing non-invasive and acceptable methods for collecting physiological parameters of stress will allow better exploration of determinants of health in this important population. PMID- 28555780 TI - Development and psychometric properties of the Hand-Use-at-Home questionnaire to assess amount of affected hand-use in children with unilateral paresis. AB - AIM: To describe the development of the parent-rated Hand-Use-at-Home questionnaire (HUH) assessing the amount of spontaneous use of the affected hand in children with unilateral paresis, and to test its internal structure, unidimensionality, and validity. METHOD: Parents of children with unilateral cerebral palsy (CP) and professionals participated in the development of the HUH. To examine internal validity, data of 322 children (158 males, 164 females; mean age 6y 7mo, standard deviation [SD] 2y 1mo) with unilateral CP (n=131) or neonatal brachial plexus palsy (NBPP) (n=191) were collected. Rasch analysis was used to examine discriminative capacity of the 5-category rating scale as well as unidimensionality and hierarchy of the item set. Additionally, data of 55 children with typical development (24 males, 31 females; 6y 9mo, SD 2y 5mo) were used to examine construct validity. RESULTS: The 5-category rating scale was disordered in all items and was collapsed to obtain the best discriminating sum score. Ten misfitting or redundant items were removed. Eighteen hierarchically ordered bimanual items fitted the unidimensional model within acceptable range. The HUH significantly discriminated between the three groups (children with typical development, NBPP, unilateral CP; H(2) =118.985, p<0.001), supporting its construct validity. INTERPRETATION: The HUH is a valid instrument to assess the amount of spontaneous use of the affected hand in children with unilateral upper limb paresis. PMID- 28555782 TI - Stepwise partitioning of Xp21: a profiling method for XK deletions causative of the McLeod syndrome. AB - BACKGROUND: McLeod syndrome (MLS) is hematologically defined by the absence of the red blood cell (RBC) antigen Kx on the transmembrane RBC protein, XK, representing a highly specific diagnostic marker. Direct molecular assessment of XK therefore represents a desirable diagnostic tool. Whereas pathogenic point mutations may be simply identified, partial and complete deletions of XK on Xp21.1, eventually covering adjacent genes and causing multifaceted "continuous gene syndromes," are difficult to localize. STUDY DESIGN AND METHODS: Three different McLeod patient samples were tested using 16 initial positional polymerase chain reaction (PCR) procedures distributed over an approximately 2.8 Mbp Xp-chromosomal region, ranging telomeric from MAGEB16 to OTC, centromeric of XK. The molecular breakpoint of one sample with an apparent large Xp deletion was iteratively narrowed down by stepwise positioning further PCR procedures and sequenced. Two mutant XK genes, one previously published and serving as a positive control, were also sequenced. RESULTS: We confirmed the positive control as previously published and listed as XK*N.20 by the International Society of Blood Transfusion (ISBT). The other XK showed a novel four-nucleotide deletion in Exon 1, 195-198delCCGC (newly listed as XK*N.39 by the ISBT). The third sample had an approximately 151-kbp X-chromosomal deletion, reaching from Exon 2 of LANCL3, across XK to Exon 3 of CYBB (newly listed as XK*N.01.016 by the ISBT). Carrier status of the patients' sister was diagnosed using a diagnostic "gap PCR." CONCLUSIONS: The stepwise partitioning of Xp21.1 is pragmatic and cost efficient in comparison to other diagnostic techniques such as "massive parallel sequencing" given the rarity of MLS. All males with suspected MLS should be considered for molecular XK profiling. PMID- 28555784 TI - MOLECULAR EVOLUTION OVER THE MUTATIONAL LANDSCAPE. PMID- 28555781 TI - High C-Reactive Protein Predicts Delirium Incidence, Duration, and Feature Severity After Major Noncardiac Surgery. AB - OBJECTIVES: To examine associations between the inflammatory marker C-reactive protein (CRP) measured preoperatively and on postoperative day 2 (POD2) and delirium incidence, duration, and feature severity. DESIGN: Prospective cohort study. SETTING: Two academic medical centers. PARTICIPANTS: Adults aged 70 and older undergoing major noncardiac surgery (N = 560). MEASUREMENTS: Plasma CRP was measured using enzyme-linked immunosorbent assay. Delirium was assessed from Confusion Assessment Method (CAM) interviews and chart review. Delirium duration was measured according to number of hospital days with delirium. Delirium feature severity was defined as the sum of CAM-Severity (CAM-S) scores on all postoperative hospital days. Generalized linear models were used to examine independent associations between CRP (preoperatively and POD2 separately) and delirium incidence, duration, and feature severity; prolonged hospital length of stay (LOS, >5 days); and discharge disposition. RESULTS: Postoperative delirium occurred in 24% of participants, 12% had 2 or more delirium days, and the mean +/ standard deviation sum CAM-S was 9.3 +/- 11.4. After adjusting for age, sex, surgery type, anesthesia route, medical comorbidities, and postoperative infectious complications, participants with preoperative CRP of 3 mg/L or greater had a risk of delirium that was 1.5 times as great (95% confidence interval (CI) = 1.1-2.1) as that of those with CRP less than 3 mg/L, 0.4 more delirium days (P < .001), more-severe delirium (3.6 CAM-S points higher, P < .001), and a risk of prolonged LOS that was 1.4 times as great (95% CI = 1.1-1.8). Using POD2 CRP, participants in the highest quartile (>=235.73 mg/L) were 1.5 times as likely to develop delirium (95% CI = 1.0-2.4) as those in the lowest quartile (<=127.53 mg/L), had 0.2 more delirium days (P < .05), and had more severe delirium (4.5 CAM-S points higher, P < .001). CONCLUSION: High preoperative and POD2 CRP were independently associated with delirium incidence, duration, and feature severity. CRP may be useful to identify individuals who are at risk of developing delirium. PMID- 28555783 TI - Implementation of a critical care outreach service: a qualitative study. AB - AIM: The aim of this study was to explore hospital staff perceptions of the perceived challenges and outcomes of implementing a critical care outreach service. BACKGROUND: A nurse-led critical care outreach service was designed and implemented to identify and treat acutely ill patients in a large tertiary care hospital in Iran. METHODS: A qualitative analysis of data from two focus groups and seven interviews was carried out using conventional content analyses techniques. A total of 24 hospital staff members participated, including critical care outreach team members, physicians, ward head nurses and ward staff. FINDINGS: Two main categories described the perceived challenges to the implementation of the critical care outreach service: 1) the hospital context, with four subcategories related to staff shortages, the instability of physician positions, the lack of specialized essential services and the absence of a system to establish do-not-resuscitate orders, and 2) staff resistance to different nursing priorities, routines and extra work. In two additional main categories, participants also described positive and negative perceived outcomes. The positive perceived outcomes included three subcategories of alleviating equipment shortages, improving nursing knowledge and patient care and improving patient and healthcare professional satisfaction. DISCUSSION: While critical care outreach has the potential to improve patient perceived outcomes and both patient and provider satisfaction with care, the contextual and clinical realities in hospitals are significant and must be examined during the planning and implementation of future outreach. CONCLUSION AND IMPLICATIONS FOR NURSING AND HEALTH POLICY: A critical care outreach service in the context of an Iranian hospital has the potential to improve ward nurse familiarity with the care of acutely ill patients and the quality of palliative care. However, attention ought to be paid to the hospital's structural and contextual factors. Alleviating nursing shortages, reducing staff resistance and preparing goals of care guidelines that address restrictions on resuscitation could facilitate implementation of critical care outreach services. PMID- 28555785 TI - THE MANIFESTATION OF PHENOTYPIC SELECTION AT CONSTITUENT LOCI. I. STABILIZING SELECTION. PMID- 28555786 TI - POPULATION DENSITY, OUTCROSSING RATE, AND HETEROZYGOTE SUPERIORITY IN PONDEROSA PINE. PMID- 28555787 TI - INTERACTIONS BETWEEN THE AMYLASE AND ADIPOSE CHROMOSOMAL REGIONS OF DROSOPHILA MELANOGASTER. PMID- 28555788 TI - DYNAMICS OF MORPHOLOGICAL DIFFERENTIATION: TEMPORAL IMPACT OF GENE FLOW IN POCKET GOPHER POPULATIONS. PMID- 28555789 TI - EVOLUTION OF SEX DETERMINING MECHANISMS: A REVIEW OF FACT AND THEORY. PMID- 28555790 TI - DIFFERENCES IN SURVIVORSHIP, DEVELOPMENT RATE AND FERTILITY BETWEEN THE LONGWINGED AND WINGLESS MORPHS OF THE WATERSTRIDER, LIMNOPORUS CANALICULATUS. PMID- 28555791 TI - POLLEN-OVULE RATIOS AND HERMAPHRODITE SEXUAL ALLOCATION STRATEGIES. PMID- 28555792 TI - POPULATION STRUCTURE IN BLACK FLIES: ALLOZYMIC AND MORPHOLOGICAL ESTIMATES FOR PROSIMULIUM MIXTUM AND P. FUSCUM (DIPTERA: SIMULIIDAE). PMID- 28555793 TI - NATURAL SELECTION IN EXPERIMENTAL POPULATIONS OF REEF-BUILDING CORALS (SCLERACTINIA). PMID- 28555794 TI - DEVELOPMENT AND EVOLUTION: A REPORT. PMID- 28555795 TI - SELECTION FOR DELAYED SENESCENCE IN DROSOPHILA MELANOGASTER. PMID- 28555796 TI - SEXUAL SELECTION AND SEXUAL DIFFERENCES IN MORMON CRICKETS (ORTHOPTERA: TETTIGONIIDAE, ANABRUS SIMPLEX). PMID- 28555797 TI - POSSIBLE PREZYGOTIC REPRODUCTIVE ISOLATION IN SEA URCHINS SEPARATED BY THE ISTHMUS OF PANAMA. PMID- 28555798 TI - CHARACTERIZATION OF MITOCHONDRIAL DNA VARIABILITY IN A HYBRID SWARM BETWEEN SUBSPECIES OF BLUEGILL SUNFISH (LEPOMIS MACROCHIRUS). PMID- 28555799 TI - GROUP SELECTION: THE INTERACTION OF LOCAL DEME SIZE AND MIGRATION IN THE DIFFERENTIATION OF SMALL POPULATIONS. PMID- 28555800 TI - MORPHOLOGICAL DISTANCE: AN ENCOUNTER BETWEEN TWO PERSPECTIVES IN EVOLUTIONARY BIOLOGY. PMID- 28555801 TI - 1984 THEODOSIUS DOBZHANSKY PRIZE AWARDED. PMID- 28555802 TI - ON THE EVOLUTIONARY REVERSAL OF COMPETITIVE DOMINANCE. PMID- 28555803 TI - LABORATORY EVOLUTION OF POSTPONED SENESCENCE IN DROSOPHILA MELANOGASTER. PMID- 28555804 TI - OUTCROSSING AND POLLINATOR LIMITATION OF FRUIT SET: BREEDING SYSTEMS OF NEOTROPICAL INGA TREES (FABACEAE: MIMOSOIDEAE). PMID- 28555805 TI - MORPHOLOGICAL AND PHYLOGENETIC RELATIONS AMONG THE DARWIN'S FINCHES. PMID- 28555806 TI - CHANGES IN GROUP-SELECTED TRAITS THAT OCCUR WHEN GROUP SELECTION IS RELAXED. PMID- 28555807 TI - BIRD VERSUS MAMMAL MORPHOLOGICAL DIVERSITY. PMID- 28555808 TI - SPERM PREDOMINANCE AMONG DROSOPHILA PSEUDOOBSCURA KARYOTYPES. PMID- 28555809 TI - BRAIN SIZE, ADAPTATION AND HETEROCHRONY IN GEOMYOID RODENTS. PMID- 28555810 TI - Reduced right ventricular diameter during cardiac arrest caused by tension pneumothorax - a porcine ultrasound study. AB - INTRODUCTION: Advanced life support (ALS) guidelines recommend ultrasound to identify reversible causes of cardiac arrest. Right ventricular (RV) dilatation during cardiac arrest is commonly interpreted as a sign of pulmonary embolism. The RV is thus a focus of clinical ultrasound examination. Importantly, in animal studies ventricular fibrillation and hypoxia results in RV dilatation. Tension pneumothorax (tPTX) is another reversible cause of cardiac arrest, however, the impact on RV diameter remains unknown. AIM: To investigate RV diameter evaluated by ultrasound in cardiac arrest caused by tPTX or hypoxia. METHODS: Pigs were randomized to cardiac arrest by either tPTX (n = 9) or hypoxia (n = 9) and subsequently resuscitated. Tension pneumothorax was induced by injection of air into the pleural cavity. Hypoxia was induced by reducing tidal volume. Ultrasound images of the RV were obtained throughout the study. Tension pneumothorax was decompressed after the seventh rhythm analysis. The primary endpoint was RV diameter after the third rhythm analysis. RESULTS: At cardiac arrest the RV diameter was 17 mm (95% CI: 13; 21) in the tPTX group and 36 mm (95% CI: 33; 40) in the hypoxia group (P < 0.01, n = 9 for both). At third rhythm analysis RV diameter was smaller in the tPTX group: 12 mm (95% CI: 7; 16) vs. hypoxia group: 28 mm (25; 32) (P < 0.01). After decompression no difference existed between groups: tPTX 29 mm (95% CI: 23; 34) vs. hypoxia 29 mm (95% CI: 20; 38). CONCLUSION: The RV diameter is smaller during cardiopulmonary resuscitation in cardiac arrest caused by tPTX when compared with hypoxia. The difference disappears after tPTX decompression. PMID- 28555814 TI - Erratum. PMID- 28555811 TI - Long-Term Oral Bisphosphonate Therapy and Fractures in Older Women: The Women's Health Initiative. AB - OBJECTIVES: To examine the association between long-term bisphosphonate use and fracture in older women at high risk of fracture. DESIGN: Retrospective cohort. SETTING: Women's Health Initiative. PARTICIPANTS: Older women who reported at least 2 years of bisphosphonate use in 2008-09 (N = 5,120). MEASUREMENTS: Exposure data were from a current medications inventory. Outcomes (hip, clinical vertebral, wrist or forearm, any clinical fracture) were ascertained annually. Using multivariate Cox proportional hazards models, the association between duration of bisphosphonate use (3-5, 6-9, 10-13 years) and fracture was estimated, using 2 years as the referent group. RESULTS: On average participants were 80 years old and were followed for 3.7 +/- 1.2 years. There were 127 hip, 159 wrist or forearm, 235 clinical vertebral, and 1,313 clinical fractures. In multivariate-adjusted analysis, 10 to 13 years of bisphosphonate use was associated with higher risk of any clinical fracture than 2 years of use (hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.07-1.57). This association persisted in analyses limited to women with a prior fracture (HR = 1.30, 95% CI = 1.01-1.67) and women with no history of cancer (HR = 1.36, 95% CI = 1.10-1.68). The association of 10 to 13 years of use, compared with 2 years of use, was not statistically significant for hip (HR = 1.66, 95% CI = 0.81-3.40), clinical vertebral (HR = 1.65, 95% CI = 0.99-2.76), or wrist fracture (HR = 1.16, 95% CI = 0.67-2.00). CONCLUSION: In older women at high risk of fracture, 10 to 13 years of bisphosphonate use was associated with higher risk of any clinical fracture than 2 years of use. These results add to concerns about the benefit of very long term bisphosphonate use. PMID- 28555813 TI - Heterogeneity of trichoscopy findings in dissecting cellulitis of the scalp: correlation with disease activity and duration. PMID- 28555815 TI - EULOGY: THOMAS JAMES MORTON SCHOPF (1939-1984). PMID- 28555812 TI - Lung-resident gammadelta T cells and their roles in lung diseases. AB - gammadelta T cells are greatly enriched in mucosal and epithelial sites, such as the skin, respiratory, digestive and reproductive tracts, and they are defined as tissue-resident immune cells. In these tissues, the characteristics and biological roles of gammadelta T cells are distinguished from each other. The lungs represent the most challenging immunological dilemma for the host, and they have their own effective immune system. The abundance of gammadelta T cells, an estimated 8-20% of resident pulmonary lymphocytes in the lung, maintains lung tissue homeostasis. In this review, we summarize the recent research progress regarding lung-resident gammadelta T cells, including their development, residency and immune characteristics, and discuss the involvement of gammadelta T cells in infectious diseases of the lung, including bacterial, viral and fungal infections; lung allergic disease; lung inflammation and fibrosis; and lung cancer. PMID- 28555816 TI - ON THE MEASUREMENT OF NATURAL AND SEXUAL SELECTION: THEORY. PMID- 28555817 TI - THE EFFECTS OF INDIVIDUAL VARIATION IN PHYSIOLOGICAL AND MORPHOLOGICAL TRAITS ON THE REPRODUCTIVE CAPACITY OF THE COMMON COCKLEBUR, XANTHIUM STRUMARIUM L. PMID- 28555818 TI - EVOLUTIONARY CHANGE OF THE CHROMOSOMAL POLYMORPHISM IN DROSOPHILA MELANOGASTER POPULATIONS. PMID- 28555819 TI - THE QUANTITATIVE GENETICS OF POLYPHAGY IN AN INSECT HERBIVORE. I. GENOTYPE ENVIRONMENT INTERACTION IN LARVAL PERFORMANCE ON DIFFERENT HOST PLANT SPECIES. PMID- 28555820 TI - INBREEDING AND THE EVOLUTION OF ALTRUISM UNDER KIN SELECTION: EFFECTS ON RELATEDNESS AND GROUP STRUCTURE. PMID- 28555821 TI - GENETIC CHANGES COINCIDING WITH THE COLONIZATION OF CALIFORNIA BY THE WALNUT HUSK FLY, RHAGOLETIS COMPLETA. PMID- 28555822 TI - POPULATION STRUCTURE AND LOCAL SELECTION IN IMPATIENS PALLIDA (BALSAMINACEAE), A SELFING ANNUAL. PMID- 28555823 TI - THE EXPECTED FIXATION RATE OF CHROMOSOMAL INVERSIONS. PMID- 28555825 TI - THE QUANTITATIVE GENETICS OF POLYPHAGY IN AN INSECT HERBIVORE. II. GENETIC CORRELATIONS IN LARVAL PERFORMANCE WITHIN AND AMONG HOST PLANTS. PMID- 28555824 TI - COEVOLUTION IN ECOSYSTEMS: RED QUEEN EVOLUTION OR STASIS? PMID- 28555826 TI - THE EVOLUTION OF SELF-POLLINATION IN GRANITE OUTCROP SPECIES OF ARENARIA (CARYOPHYLLACEAE). I. MORPHOLOGICAL CORRELATES. PMID- 28555827 TI - SEX CHROMOSOMES AND THE EVOLUTION OF SEXUAL DIMORPHISM. PMID- 28555828 TI - ECOLOGICAL CORRELATES OF MORPHOLOGICAL EVOLUTION IN A DARWIN'S FINCH, GEOSPIZA DIFFICILIS. PMID- 28555829 TI - INFLUENCE OF FLOWER COLOR POLYMORPHISM ON GENETIC TRANSMISSION IN A NATURAL POPULATION OF THE COMMON MORNING GLORY, IPOMOEA PURPUREA. PMID- 28555830 TI - ON THE MEASUREMENT OF NATURAL AND SEXUAL SELECTION: APPLICATIONS. PMID- 28555831 TI - THE COMPARISON OF PHENOTYPIC PLASTICITY AND GENETIC VARIATION IN POPULATIONS OF THE GRASS DANTHONIA SPICATA. PMID- 28555832 TI - EVOLUTION BY KIN SELECTION: A QUANTITATIVE GENETIC MODEL ILLUSTRATED BY MATERNAL PERFORMANCE IN MICE. PMID- 28555833 TI - Predictive models in the diagnosis and treatment of autoimmune epilepsy. AB - OBJECTIVE: To validate predictive models for neural antibody positivity and immunotherapy response in epilepsy. METHODS: We conducted a retrospective study of epilepsy cases at Mayo Clinic (Rochester-MN; Scottsdale-AZ, and Jacksonville FL) in whom autoimmune encephalopathy/epilepsy/dementia autoantibody testing profiles were requested (06/30/2014-06/30/2016). An Antibody Prevalence in Epilepsy (APE) score, based on clinical characteristics, was assigned to each patient. Among patients who received immunotherapy, a Response to Immunotherapy in Epilepsy (RITE) score was assigned. Favorable seizure outcome was defined as >50% reduction of seizure frequency at the first follow-up. RESULTS: Serum and cerebrospinal fluid (CSF) from 1,736 patients were sent to the Mayo Clinic Neuroimmunology Laboratory for neural autoantibody evaluation. Three hundred eighty-seven of these patients met the diagnostic criteria for epilepsy. Central nervous system (CNS)-specific antibodies were detected in 44 patients. Certain clinical features such as new-onset epilepsy, autonomic dysfunction, viral prodrome, faciobrachial dystonic seizures/oral dyskinesia, inflammatory CSF profile, and mesial temporal magnetic resonance imaging (MRI) abnormalities had a significant association with positive antibody results. A significantly higher proportion of antibody-positive patients had an APE score >=4 (97.7% vs. 21.6%, p < 0.01). Sensitivity and specificity of an APE score >=4 to predict presence of specific neural auto-antibody were 97.7% and 77.9%, respectively. In the subset of patients who received immunotherapy (77), autonomic dysfunction, faciobrachial dystonic seizures/oral dyskinesia, early initiation of immunotherapy, and presence of antibodies targeting plasma membrane proteins (cell-surface antigens) were associated with favorable seizure outcome. Sensitivity and specificity of a RITE score >=7 to predict favorable seizure outcome were 87.5% and 83.8%, respectively. SIGNIFICANCE: APE and RITE scores can aid diagnosis, treatment, and prognostication of autoimmune epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. PMID- 28555834 TI - Effects of breeder turnover and harvest on group composition and recruitment in a social carnivore. AB - Breeder turnover can influence population growth in social carnivores through changes to group size, composition and recruitment. Studies that possess detailed group composition data that can provide insights about the effects of breeder turnover on groups have generally been conducted on species that are not subject to recurrent annual human harvest. We wanted to know how breeder turnover affects group composition and how harvest, in turn, affects breeder turnover in cooperatively breeding grey wolves (Canis lupus Linnaeus 1758). We used noninvasive genetic sampling at wolf rendezvous sites to construct pedigrees and estimate recruitment in groups of wolves before and after harvest in Idaho, USA. Turnover of breeding females increased polygamy and potential recruits per group by providing breeding opportunities for subordinates although resultant group size was unaffected 1 year after the turnover. Breeder turnover had no effect on the number of nonbreeding helpers per group. After breeding male turnover, fewer female pups were recruited in the new males' litters. Harvest had no effect on the frequency of breeder turnover. We found that breeder turnover led to shifts in the reproductive hierarchies within groups and the resulting changes to group composition were quite variable and depended on the sex of the breeder lost. We hypothesize that nonbreeding females direct help away from non-kin female pups to preserve future breeding opportunities for themselves. Breeder turnover had marked effects on the breeding opportunities of subordinates and the number and sex ratios of subsequent litters of pups. Seemingly subtle changes to groups, such as the loss of one individual, can greatly affect group composition, genetic content, and short-term population growth when the individual lost is a breeder. PMID- 28555835 TI - Antiproliferative and antimicrobial efficacy of the compounds isolated from the roots of Oenothera biennis L. AB - BACKGROUND: Oenothera biennis L., commonly known as evening primrose, harbours the flavonoids, steroids, tannins, fatty acids and terpenoids responsible for a diverse range of biological activity, such as antitumour, anti-arthritic and anti inflammatory effects. In addition to the previous reports from aerial parts of this plant, studies related to antiproliferative or antimicrobial activity from the roots are warranted. OBJECTIVE: To investigate antiproliferative and antimicrobial activity of compounds/mixture (1-8) isolated and characterized from the roots of O. biennis L. A possible mechanism of antiproliferative activity was also studied by targeting ornithine decarboxylase (ODC) and cathepsin D (CATD). STUDY DESIGN: Antiproliferative efficacy of the compounds/mixture was examined in selected cancer cell lines along with their probable mechanism of action. The antimicrobial activity was also studied against selected microbes (bacteria and fungi). METHODS: Antiproliferative potential was evaluated by MTT assay against selected cell lines. The mechanism of action was studied spectrophotometrically by targeting ODC and CATD using both an in-vitro and an in-silico approach. The antimicrobial efficiency was analysed using the disc diffusion and broth dilution methods. KEY FINDINGS: Oenotheralanosterol B (3) and the mixture of oenotheralanosterol A and oenotheralanosterol B (4) exhibited antiproliferative activity against breast, hepatic, prostate and leukaemia cancer cell lines as well as in mouse macrophages (IC50 8.35-49.69 MUg/ml). Oenotheralanosterol B (3) and the mixture of oenotheralanosterol A and oenotheralanosterol B (4) displayed a strong molecular interaction with succinate dehydrogenase (binding energy -6.23 and -6.84 kcal/mol and Ki 27.03 and 9.6 MUm, respectively). Oenotheralanosterol A (1), oenotheralanosterol B (3) and mixture of oenotheralanosterol A and oenotheralanosterol B (4) potently inhibited the ODC activity with IC50 ranging from 4.65 +/- 0.35 to 19.06 +/- 4.16 MUg/ml and also showed a strong interaction with ODC (BE -4.17 to -4.46 kcal/mol). Oenotheralanosterol A (1), cetoleilyl diglucoside (2), oenotheralanosterol B (3), dihydroxyprenylxanthone acetylated (6) and dihydroxyprenylxanthone (7) inhibited CATD activity (IC50 3.95 +/- 0.49 to 24.35 +/- 2.89 MUg/ml). The in-silico molecular interaction analysis of compounds with CATD revealed the non-specific interaction. A moderate antimicrobial activity was observed against selected microbes with a growth inhibition ranging from 6 to 14 mm and minimum inhibitory concentration between 125 and 500 MUg/ml. Oenotheralanosterol B (3) and dihydroxyprenylxanthone acetylated (6) exhibited better antimicrobial activity with an MIC range from 62.50 to 500 MUg/ml. CONCLUSION: Oenotheralanosterol B (3) exhibited stronger antiproliferative and antimicrobial potential with respect to the other compounds tested, whereas oenotheralanosterol A (1) was a potent inhibitor of ODC and CATD. Hence, it is suggested that these in-vitro findings could be studied further in vivo for biological activity, safety evaluation and derivatization to enhance potency and efficacy. PMID- 28555836 TI - Dietary composition and prey selectivity of juvenile porcupine rays Urogymnus asperrimus. AB - Fifty-five juvenile porcupine ray Urogymnus asperrimus were collected in the isolated St Joseph Atoll, Seychelles. Stomach contents were sampled using non lethal gastric lavage to determine the dietary composition, degree of prey selectivity and whether sex or size affected their diet. Sediment samples were collected to quantify prey availability so that prey selectivity could be estimated. Two phyla (Sipuncula and Nemertea) and 11 polychaete and crustacean families were recorded in stomach contents. Juvenile U. asperrimus appeared to specialize on one polychaete family, Capitellidae, which was the most important prey item (index of importance = 35%). This polychaete family was also most abundant in the sediment samples and U. asperrimus are thus considered opportunistic predators. There was evidence of a size-related shift in the crustacean families consumed by juvenile U. asperrimus. Data collected at this remote location provides important baseline ecological information that may prove useful in developing conservation strategies for this ecologically important species. PMID- 28555837 TI - Amelanotic melanoma in oculocutaneous albinism: a genetic, dermoscopic and reflectance confocal microscopy study. PMID- 28555838 TI - Spontaneous CD4+ and CD8+ T-cell responses directed against cancer testis antigens are present in the peripheral blood of testicular cancer patients. AB - Cancer/testis antigen (CTAg) expression is restricted to spermatogenic cells in an immune-privileged site within the testis. However, these proteins are expressed aberrantly by malignant cells and T-cell responses against CTAgs develop in many cancer patients. We investigated the prevalence, magnitude and phenotype of CTAg-specific T cells in the blood of patients with testicular germ cell tumors (TGCTs). CD8+ and CD4+ T-cell responses against MAGE-A family antigens were present in 44% (20/45) of patients' samples assayed by ex vivo IFN gamma ELISPOT. The presence of MAGE-specific CD8+ T cells was further determined following short-term in vitro expansion through the use of pMHC-I multimers containing known immunogenic peptides. Longitudinal analysis revealed that the frequency of MAGE-specific T cells decreased by 89% following orchidectomy suggesting that persistence of tumor antigen is required to sustain CTAg-specific T-cell immunity. Notably, this decrease correlated with a decline in the global effector/memory T-cell pool following treatment. Spontaneous T-cell immunity against CTAg proteins therefore develops in many patients with testicular cancer and may play an important role in the excellent clinical outcome of patients with this tumor subtype. PMID- 28555840 TI - The effect of interpregnancy interval on obesity/overweight among women in the first trimester of pregnancy. AB - OBJECTIVE: To determine the effect of interpregnancy interval (IPI) on obesity/overweight among pregnant Sudanese women in early pregnancy. METHODS: A cross-sectional study was conducted at Saad Abu-Alela Hospital, Khartoum, Sudan, from January to December 2015. Women with a singleton pregnancy and at least one previous pregnancy were enrolled in the first trimester. A questionnaire was used to collect clinical and sociodemographic data from the participants, and current body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. RESULTS: Among 1045 participants, 344 (32.9%), 424 (40.6%), and 277 (26.5%) women had short (<18 months), normal (18-30 months), and long IPIs (>30 months), respectively. BMI indicated 18 (1.7%), 408 (39.0%), 381 (36.5%), and 238 (22.8%) women were underweight (<18.5), normal weight (18.5 24.9), overweight (25.0-29.9), and obese (>=30.0), respectively. Age and proportion using contraceptives were increased among women with long IPI (both P<0.001). When compared with women of normal weight, overweight women and obese women were more likely to have a long IPI (odds ratio 1.72, 95% confidence interval 1.08-2.93; and 1.71, 1.05-2.94, respectively). CONCLUSION: Long IPI was associated with obesity and overweight, which were prevalent among pregnant Sudanese women. PMID- 28555839 TI - Promotion of endocytosis efficiency through an ATP-independent mechanism at rat calyx of Held terminals. AB - KEY POINTS: At rat calyx of Held terminals, ATP was required not only for slow endocytosis, but also for rapid phase of compensatory endocytosis. An ATP independent form of endocytosis was recruited to accelerate membrane retrieval at increased activity and temperature. ATP-independent endocytosis primarily involved retrieval of pre-existing membrane, which depended on Ca2+ and the activity of neutral sphingomyelinase but not clathrin-coated pit maturation. ATP independent endocytosis represents a non-canonical mechanism that can efficiently retrieve membrane at physiological conditions without competing for the limited ATP at elevated neuronal activity. ABSTRACT: Neurotransmission relies on membrane endocytosis to maintain vesicle supply and membrane stability. Endocytosis has been generally recognized as a major ATP-dependent function, which efficiently retrieves more membrane at elevated neuronal activity when ATP consumption within nerve terminals increases drastically. This paradox raises the interesting question of whether increased activity recruits ATP-independent mechanism(s) to accelerate endocytosis at the same time as preserving ATP availability for other tasks. To address this issue, we studied ATP requirement in three typical forms of endocytosis at rat calyx of Held terminals by whole-cell membrane capacitance measurements. At room temperature, blocking ATP hydrolysis effectively abolished slow endocytosis and rapid endocytosis but only partially inhibited excess endocytosis following intense stimulation. The ATP-independent endocytosis occurred at calyces from postnatal days 8-15, suggesting its existence before and after hearing onset. This endocytosis was not affected by a reduction of exocytosis using the light chain of botulinum toxin C, nor by block of clathrin coat maturation. It was abolished by EGTA, which preferentially blocked endocytosis of retrievable membrane pre-existing at the surface, and was impaired by oxidation of cholesterol and inhibition of neutral sphingomyelinase. ATP independent endocytosis became more significant at 34-35 degrees C, and recovered membrane by an amount that, on average, was close to exocytosis. The results of the present study suggest that activity and temperature recruit ATP-independent endocytosis of pre-existing membrane (in addition to ATP-dependent endocytosis) to efficiently retrieve membrane at nerve terminals. This less understood endocytosis represents a non-canonical mechanism regulated by lipids such as cholesterol and sphingomyelinase. PMID- 28555841 TI - Regulatory Consequences of "Brexit" for the Development of Medicinal Products. AB - The United Kingdom voted in a referendum in June 2016 to leave the European Union (EU) after 45 years of membership. Among the many political, social, and scientific consequences are those for the regulation of health care products. No longer will the efficacy, safety, and quality of medicines in the United Kingdom be subject to an EU regulatory framework. The European Medicines Agency (EMA), which is currently located in London, will move elsewhere in Europe. The pharmaceutical industry will reassess its commitment to the UK health scene. PMID- 28555842 TI - Continuing Professional Development Quiz. PMID- 28555843 TI - Dentistry - Why be Down in the Mouth? PMID- 28555845 TI - DEEP-SEA ASTEROIDS: HIGH GENETIC VARIABILITY IN A STABLE ENVIRONMENT. PMID- 28555846 TI - BEE FLOWERS: A HYPOTHESIS ON FLOWER VARIETY AND BLOOMING TIMES. PMID- 28555847 TI - GIBBON AND SIAMANG. PMID- 28555849 TI - SEX RATIO SELECTION IN AN AGE-STRUCTURED POPULATION. PMID- 28555848 TI - EVOLUTION IN HAWAIIAN DROSOPHILIDAE : CHROMOSOMAL PHYLOGENY OF THE DROSOPHILA CRASSIFEMUR COMPLEX. PMID- 28555850 TI - POPULATION DENSITY AND MATING RATES IN DROSOPHILA PSEUDOOBSCURA. PMID- 28555852 TI - ASPECT DIVERSITY IN MOTHS: A TEMPERATE-TROPICAL COMPARISON. PMID- 28555851 TI - Comparison of Reaction Time Distributions in Homozygous and Heterozygous Populations. PMID- 28555853 TI - GENETIC STRUCTURE OF POPULATIONS. PMID- 28555855 TI - GENETIC SIMILARITY AND DISTANCE: COMMENTS AND COMPARISONS. PMID- 28555854 TI - UNSTABLE INTERMEDIATES BETWEEN ORINOCAN AND INTERIOR SEMISPECIES OF DROSOPHILA PAULISTORUM. PMID- 28555856 TI - MARGINAL POPULATIONS OF CEPAEA NEMORALIS (L.) ON THE BRENDON HILLS, ENGLAND. II. VARIATION IN CHIASMA FREQUENCY. PMID- 28555857 TI - COMPLEMENTARY ROLES OF HALICTIDS AND SYRPHIDS IN THE POLLINATION OF JEPSONIA HETERANDRA (SAXIFRAGACEAE). PMID- 28555859 TI - DARWINIAN OR "ORIENTED" EVOLUTION? PMID- 28555858 TI - ECOLOGY AND EVOLUTION OF THE PITCHER-PLANT MOSQUITO: 1. POPULATION DYNAMICS AND LABORATORY RESPONSES TO FOOD AND POPULATION DENSITY. PMID- 28555860 TI - SONG DIALECTS AND GENETIC DIFFERENCES IN WHITE-CROWNED SPARROWS (ZONOTRICHIA LEUCOPHRYS). PMID- 28555861 TI - THE BEHAVIORAL SIGNIFICANCE OF FRILL AND HORN MORPHOLOGY IN CERATOPSIAN DINOSAURS. PMID- 28555862 TI - MARGINAL POPULATIONS OF CEPAEA NEMORALIS (L.) ON THE BRENDON HILLS, ENGLAND. I. ECOLOGY AND ECOGENETICS. PMID- 28555863 TI - REPLY TO LOFTUS-HILLS. PMID- 28555864 TI - GENE CONTROL MECHANISMS AND THEIR POSSIBLE BEARING ON THE NEUTRALIST-SELECTIONIST CONTROVERSY. PMID- 28555865 TI - PATTERN DIVERSITY OF INCOMPATIBILITY GROUPS IN JEPSONIA HETERANDRA (SAXIFRAGACEAE). PMID- 28555866 TI - ALLELIC DIVERSITY IN THE OUTCROSSING ANNUAL PLANT STEPHANOMERIA EXIGUA SSP. CAROTIFERA (COMPOSITAE). PMID- 28555867 TI - HOST CASTRATION AS A PARASITIC STRATEGY. PMID- 28555868 TI - RACE. PMID- 28555869 TI - DISTRIBUTION AND EVOLUTIONARY SIGNIFICANCE OF CHROMOSOME VARIATION IN TRILLIUM OVATUM. PMID- 28555870 TI - THE EVIDENCE FOR REPRODUCTIVE CHARACTER DISPLACEMENT BETWEEN THE TOADS BUFO AMERICANUS AND B. WOODHOUSII FOWLERI. PMID- 28555871 TI - Microanatomical diversification of the zona pellucida in aplochelioid killifishes. AB - This study investigates zona pellucida (ZP) ultrastructure in fertilized eggs of annual killifishes (suborder Aplocheiloidei), a group of highly specialized fishes that are able to survive desiccation for several weeks to months before they hatch. Little is known about ZP or chorionic ultrastructure sustaining these life-history modes, so scanning electron microscopy (SEM) was used to describe this trait in a large number of aplocheiloids with a focus on the family Rivulidae and the genus Hypsolebias. New images of ZP ultrastructure for 52 aplocheiloid species are provided, more than doubling the number characterized thus far. The evolution of chorionic structure within this group is studied using these new data. Characters were coded into a morphological matrix and optimized onto a consensus phylogeny to assess phylogenetic signal and reconstruct ancestral character states. Although ZP characters seem highly homoplastic and exhibit a large amount of structural convergence among lineages, aplocheiloid killifishes have evolved a number of unique structures associated with the chorion. Some annual species seem to have lost long filaments because eggs are deposited in the soil instead of being adhered to aquatic plants. PMID- 28555872 TI - Local density regulates migratory songbird reproductive success through effects on double-brooding and nest predation. AB - Knowledge of the density-dependent processes that regulate animal populations is key to understanding, predicting, and conserving populations. In migratory birds, density-dependence is most often studied during the breeding season, yet we still lack a robust understanding of the reproductive traits through which density influences individual reproductive success. We used 27-yr of detailed, individual level productivity data from an island-breeding population of Savannah sparrows Passerculus sandwichensis to evaluate effects of local and total annual population density on female reproductive success. Local density (number of neighbors within 50 m of a female's nest) had stronger effects on the number of young fledged than did total annual population density. Females nesting in areas of high local density were more likely to suffer nest predation and less likely to initiate and fledge a second clutch, which led to fewer young fledged in a season. Fledging fewer young subsequently decreased the likelihood of a female recruiting offspring into the breeding population in a subsequent year. Collectively, these results provide insight into the scale and reproductive mechanisms mediating density-dependent reproductive success and fitness in songbirds. PMID- 28555873 TI - Does size matter? An examination of problem gamblers' skin conductance responses to large and small magnitude rewards. AB - Previous research has shown that individuals with substance use disorder equally value small and large magnitude rewards. This has led some researchers to conceptualize the problematic behaviors associated with this disorder as being, at least in part, caused by a deficiency in processing reward stimuli. Considering the documented similarities between substance use disorder and disordered gambling, the current study sought to investigate whether problem gamblers also display such an aberrant pattern of incentive processing. Skin conductance responses (SCRs) to small and large magnitude wins were recorded from 16 problem gamblers (PGs) and 16 healthy controls (HCs) while they completed a computer-simulated electronic gaming machine task. The results show that, while large wins elicited greater SCRs compared to small wins for the HC group, no difference in SCR amplitude was found following large and small wins in the PG group. These findings suggest that problem gamblers may be less effective at evaluating the value of incentives, and are discussed in terms of relevant theoretical frameworks. PMID- 28555874 TI - Bayesian Quantile Impairment Threshold Benchmark Dose Estimation for Continuous Endpoints. AB - Quantitative risk assessment often begins with an estimate of the exposure or dose associated with a particular risk level from which exposure levels posing low risk to populations can be extrapolated. For continuous exposures, this value, the benchmark dose, is often defined by a specified increase (or decrease) from the median or mean response at no exposure. This method of calculating the benchmark dose does not take into account the response distribution and, consequently, cannot be interpreted based upon probability statements of the target population. We investigate quantile regression as an alternative to the use of the median or mean regression. By defining the dose-response quantile relationship and an impairment threshold, we specify a benchmark dose as the dose associated with a specified probability that the population will have a response equal to or more extreme than the specified impairment threshold. In addition, in an effort to minimize model uncertainty, we use Bayesian monotonic semiparametric regression to define the exposure-response quantile relationship, which gives the model flexibility to estimate the quantal dose-response function. We describe this methodology and apply it to both epidemiology and toxicology data. PMID- 28555875 TI - Enhancement of synchronized activity between hippocampal CA1 neurons during initial storage of associative fear memory. AB - KEY POINTS: Learning and memory storage requires neuronal plasticity induced in the hippocampus and other related brain areas, and this process is thought to rely on synchronized activity in neural networks. We used paired whole-cell recording in vivo to examine the synchronized activity that was induced in hippocampal CA1 neurons by associative fear learning. We found that both membrane potential synchronization and spike synchronization of CA1 neurons could be transiently enhanced after task learning, as observed on day 1 but not day 5. On day 1 after learning, CA1 neurons showed a decrease in firing threshold and rise times of suprathreshold membrane potential changes as well as an increase in spontaneous firing rates, possibly contributing to the enhancement of spike synchronization. The transient enhancement of CA1 neuronal synchronization may play important roles in the induction of neuronal plasticity for initial storage and consolidation of associative memory. ABSTRACT: The hippocampus is critical for memory acquisition and consolidation. This function requires activity- and experience-induced neuronal plasticity. It is known that neuronal plasticity is largely dependent on synchronized activity. As has been well characterized, repetitive correlated activity of presynaptic and postsynaptic neurons can lead to long-term modifications at their synapses. Studies on network activity have also suggested that memory processing in the hippocampus may involve learning induced changes of neuronal synchronization, as observed in vivo between hippocampal CA3 and CA1 networks as well as between the rhinal cortex and the hippocampus. However, further investigation of learning-induced synchronized activity in the hippocampus is needed for a full understanding of hippocampal memory processing. In this study, by performing paired whole-cell recording in vivo on CA1 pyramidal cells (PCs) in anaesthetized adult rats, we examined CA1 neuronal synchronization before and after associative fear learning. We first found in naive animals that there was a low level of membrane potential (MP) synchronization and spike synchronization of CA1 PCs. In conditioned animals, we found a significant enhancement of both MP synchronization and spike synchronization, as observed on day 1 after learning, and this enhancement was transient and not observed on day 5. Accompanying learning-induced synchronized activity was a decreased firing threshold and rise time of suprathreshold MP changes as well as an increased spontaneous firing rate, possibly contributing to the enhanced spike synchronization. The transiently enhanced CA1 neuronal synchronization may have important roles in generating neuronal plasticity for hippocampal storage and consolidation of associative memory traces. PMID- 28555876 TI - Cooperative effects of tropomyosin on the dynamics of the actin filament. AB - Tropomyosin (Tpm) plays an important role in regulating the organisation and functions of the actin cytoskeleton. Here, we describe a new approach to analyse the effects of Tpm on actin dynamics. Using F-actin proteolytically modified within the DNase-binding loop (ECP-actin), we show that Tpm binding almost completely suppresses the increased subunit exchange intrinsic for this F-actin. The effect is both concentration-dependent and cooperative, with half-maximal inhibition observed at about a 1 : 50 Tpm : actin ratio. Tpm decreases not only the number concentration of ECP-actin filaments, but also the rate of the filament subunit exchange. Our data suggest that Tpm regulates the dynamics of actin filaments by an allosteric strengthening of intermonomer contacts in the actin filament, and that this mechanism may be involved in the modulation of cytoskeletal dynamics. PMID- 28555877 TI - Synergistic protection against acute flurothyl-induced seizures by adjuvant treatment of the ketogenic diet with the type 2 diabetes drug pioglitazone. AB - OBJECTIVE: We have previously found that the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) contributes to the mechanism of action of the ketogenic diet (KD), an established treatment for pediatric refractory epilepsy. We have found that the KD increases brain PPARgamma and that inhibition or genetic loss of PPARgamma prevents the antiseizure effects of the KD on (1) acutely induced seizures in nonepileptic mice and (2) spontaneous recurrent seizures in epileptic mice. Here, we tested the hypothesis that adjuvant treatment of KD-treated mice with a PPARgamma agonist, pioglitazone, would result in an additive effect. METHODS: Acute seizures were induced in three groups of C57Bl/6 mice by inhalation exposure to flurothyl gas. In Group 1, mice were weaned onto either a standard diet or KD comprised of a fat:carbohydrate/protein ratio of either 6:1, 3:1, or 1:1 for 2 weeks. In Group 2, vehicle or pioglitazone (0.1, 1, 10, 80 mg/kg) was administered 4 h prior to flurothyl exposure. In Group 3, vehicle or increasing doses of pioglitazone were administered to KD-treated mice 4 h prior to flurothyl exposure. Latency times to clonic seizures and generalized tonic-clonic (GTC) seizures were recorded, and isobolographic analysis was used to determine combinatorial interactions. RESULTS: Neither KD treatment nor pioglitazone alone or in combination affected clonic seizures. However, the latency to GTC seizures was dose-dependently and significantly increased by both KD (~57%, p < 0.05) and pioglitazone (~28%, p < 0.05). Coadministration of an ineffective 1:1 KD and pioglitazone resulted in ~47 55% (p < 0.05) increase in latency to GTC. Isobolographic analysis indicated a synergistic interaction of the KD and pioglitazone. SIGNIFICANCE: These results suggest coadministration may enable reduction of the KD ratio without loss of seizure protection. Such adjuvant treatment could improve quality of life and limit adverse effects of a classic KD or high-dose pioglitazone. PMID- 28555878 TI - Correlation between a 2D channelized Hotelling observer and human observers in a low-contrast detection task with multislice reading in CT. AB - PURPOSE: Model observers have been successfully developed and used to assess the quality of static 2D CT images. However, radiologists typically read images by paging through multiple 2D slices (i.e., multislice reading). The purpose of this study was to correlate human and model observer performance in a low-contrast detection task performed using both 2D and multislice reading, and to determine if the 2D model observer still correlate well with human observer performance in multislice reading. METHODS: A phantom containing 18 low-contrast spheres (6 sizes * 3 contrast levels) was scanned on a 192-slice CT scanner at five dose levels (CTDIvol = 27, 13.5, 6.8, 3.4, and 1.7 mGy), each repeated 100 times. Images were reconstructed using both filtered-backprojection (FBP) and an iterative reconstruction (IR) method (ADMIRE, Siemens). A 3D volume of interest (VOI) around each sphere was extracted and placed side-by-side with a signal absent VOI to create a 2-alternative forced choice (2AFC) trial. Sixteen 2AFC studies were generated, each with 100 trials, to evaluate the impact of radiation dose, lesion size and contrast, and reconstruction methods on object detection. In total, 1600 trials were presented to both model and human observers. Three medical physicists acted as human observers and were allowed to page through the 3D volumes to make a decision for each 2AFC trial. The human observer performance was compared with the performance of a multislice channelized Hotelling observer (CHO_MS), which integrates multislice image data, and with the performance of previously validated CHO, which operates on static 2D images (CHO_2D). For comparison, the same 16 2AFC studies were also performed in a 2D viewing mode by the human observers and compared with the multislice viewing performance and the two CHO models. RESULTS: Human observer performance was well correlated with the CHO_2D performance in the 2D viewing mode [Pearson product-moment correlation coefficient R = 0.972, 95% confidence interval (CI): 0.919 to 0.990] and with the CHO_MS performance in the multislice viewing mode (R = 0.952, 95% CI: 0.865 to 0.984). The CHO_2D performance, calculated from the 2D viewing mode, also had a strong correlation with human observer performance in the multislice viewing mode (R = 0.957, 95% CI: 879 to 0.985). Human observer performance varied between the multislice and 2D modes. One reader performed better in the multislice mode (P = 0.013); whereas the other two readers showed no significant difference between the two viewing modes (P = 0.057 and P = 0.38). CONCLUSIONS: A 2D CHO model is highly correlated with human observer performance in detecting spherical low contrast objects in multislice viewing of CT images. This finding provides some evidence for the use of a simpler, 2D CHO to assess image quality in clinically relevant CT tasks where multislice viewing is used. PMID- 28555879 TI - Impact of liver disease on outcomes of patients hospitalized for epistaxis. AB - OBJECTIVES: Liver disease (LD) often results in coagulation abnormalities that may predispose to more severe epistaxis. The purpose of this analysis was to examine characteristics of patients hospitalized for epistaxis with LD and explore the impact of LD on patient outcomes. METHODS: The 2002 to 2013 National Inpatient Sample was queried for cases with a primary diagnosis of epistaxis. Cases with additional codes meeting the Agency for Healthcare Research and Quality's definition of LD were identified and compared to the non-LD cohort. RESULTS: Out of 39,879 cases meeting inclusion criteria, 3.6% had LD. LD was associated with younger age (55.7 years vs. 67.5 years; P < 0.001), longer hospital stay (3.9 days vs. 3.2 days; P < 0.001), and greater hospital charges ($26,141 vs. $18,200; P < 0.001) compared to the non-LD cohort. LD patients had higher rates of alcohol abuse, coagulopathy, chronic blood loss anemia, and renal failure. LD patients also had higher rates of sepsis, urinary/renal complications, respiratory failure, and infectious pneumonia. LD was associated with decreased rates of aggressive management (defined as ligation or embolization) (6.6%-9.0%; P < 0.002) and anterior or posterior nasal packing. In our multivariate logistic regression model correcting for age, gender, race, and significant comorbidities, LD was associated with 1.520 (1.336-1.729; P < 0.001) greater odds of transfusion and 2.264 (1.372-3.736; P = 0.001) greater odds of in hospital mortality. CONCLUSION: Among patients hospitalized for epistaxis, LD resulted in greater morbidity and mortality. Clinicians should be aware of the particular risk that LD bears on the hospitalized epistaxis patient. LEVEL OF EVIDENCE: 2C. Laryngoscope, 127:2691-2697, 2017. PMID- 28555881 TI - Parasite-microbiota interactions potentially affect intestinal communities in wild mammals. AB - Detecting interaction between species is notoriously difficult, and disentangling species associations in host-related gut communities is especially challenging. Nevertheless, due to contemporary methods, including metabarcoding and 16S sequencing, collecting observational data on community composition has become easier and much more common. We studied the previously collected datasets of intestinal bacterial microbiota and parasite compositions within longitudinally followed mouse lemurs by analysing the potential interactions with diversity metrics and novel joint species distribution modelling. Both methods showed statistical association between certain parasite species and bacterial microbiota composition. Unicellular Eimeria sp. had an effect on diversity of gut microbiota. The cestode Hymenolepis diminuta had negative associations with several bacterial orders, whereas closely related species Hymenolepis nana had positive associations with several bacterial orders. Our results reveal potential interactions between some, but not all, intestinal parasites and gut bacterial microbiota. Host variables contributed over half of the total variation explained with the model, and sex was the most important single host variable; especially with microbiota, there were sex-related differences in the community composition. This study shows how joint species distribution modelling can incorporate both within-host dynamics of several taxa and host characteristics to model potential interactions in intestinal community. These results provide new hypothesis for interactions between and among parasites and bacterial microbiota to be tested further with experimental studies. PMID- 28555880 TI - Fabrication of elastomeric silk fibers. AB - Methods to generate fibers from hydrogels, with control over mechanical properties, fiber diameter, and crystallinity, while retaining cytocompatibility and degradability, would expand options for biomaterials. Here, we exploited features of silk fibroin protein for the formation of tunable silk hydrogel fibers. The biological, chemical, and morphological features inherent to silk were combined with elastomeric properties gained through enzymatic crosslinking of the protein. Postprocessing via methanol and autoclaving provided tunable control of fiber features. Mechanical, optical, and chemical analyses demonstrated control of fiber properties by exploiting the physical cross-links, and generating double network hydrogels consisting of chemical and physical cross links. Structure and chemical analyses revealed crystallinity from 30 to 50%, modulus from 0.5 to 4 MPa, and ultimate strength 1-5 MPa depending on the processing method. Fabrication and postprocessing combined provided fibers with extensibility from 100 to 400% ultimate strain. Fibers strained to 100% exhibited fourth order birefringence, revealing macroscopic orientation driven by chain mobility. The physical cross-links were influenced in part by the drying rate of fabricated materials, where bound water, packing density, and microstructural homogeneity influenced cross-linking efficiency. The ability to generate robust and versatile hydrogel microfibers is desirable for bottom-up assembly of biological tissues and for broader biomaterial applications. PMID- 28555882 TI - Pilomatricoma: An unusual cause of lump in a male breast. AB - We present the case of a 48-year-old man who presented with a painless, progressively increasing lump in the left breast. The mammographic and sonographic appearance of the lesion was suspicious for malignancy. Fine needle aspiration cytology and histopathologic examination confirmed the diagnosis of pilomatricoma. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:209-211, 2018. PMID- 28555883 TI - Depression symptom dimensions and asymmetrical frontal cortical activity while anticipating reward. AB - Unipolar depression has been characterized as involving diminished approach motivation and reward sensitivity. A psychophysiological indicator of approach motivation involves an asymmetry in frontal EEG activity, such that greater left relative to right frontal cortical activity indicates increased approach motivation. Consistent with the perspective of reduced approach motivation tendencies, depression has been associated with decreased relative left frontal cortical activity. To date, supporting research has primarily relied on categorical diagnoses or composite symptom counts. However, given the heterogeneity in depression, it is unclear what specific symptom dimensions relate to decreased relative left frontal cortical activity. The present study examined the association between multiple depression symptom dimensions and asymmetrical frontal cortical activity while anticipating reward in separate undergraduate (n = 75) and clinical samples (current major depressive disorder [n = 68] and never depressed controls [n = 67]). All participants completed the Inventory of Depression and Anxiety Symptoms, a self-report measure of factor analytically derived symptom dimensions. Frontal cortical activity was assessed during a computerized slot machine task while participants anticipated potential monetary reward or no incentive. In undergraduates with low depression symptoms and never depressed controls, reward trials relative to no-incentive trials elicited greater relative left frontal cortical activity. Furthermore, in both samples across all participants, increased dysphoria and lassitude symptoms were associated with decreased relative left frontal cortical activity while anticipating reward. The present study suggests that depression symptoms consistent with motivational disengagement are associated with decreased relative left frontal cortical activity. PMID- 28555884 TI - Intraspecific variation in growth rate is a poor predictor of fitness for reef corals. AB - Genetic variation underlying differences in organism performance is subject to natural selection, and organisms with high values of genetically determined phenotypic measures of fitness should perform better than those that do not. Using small scleractinian corals (i.e., <=40-mm diameter), this principle was tested with 20 yr of census data from St. John, US Virgin Islands. Using growth rate (change in diameter) as a measure of fitness, growth in one year was tested for association with growth and survivorship in the following two years, and this process was repeated over 20 yr using a 3-yr sliding window. Virtually all variation in growth was independent of colony size, and growth among pairs of years was highly variable, with corals that grew fast in one year rarely growing fast in the next 2 yr. While growth in some pairs of years was positively correlated, <=4% of the growth variance was explained by growth in the preceding 2 yr. Survivorship was related positively to growth in the preceding year, but the association was weak, it did not extend over 3 yr, and was inconsistent over the study. These results demonstrate the importance of the environment in translating phenotypic measures of fitness into future performance, and for small Caribbean corals, they suggest that environmental conditions may preempt genotype in determining short-term success. PMID- 28555885 TI - Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma. AB - : Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with poor prognosis. Several conditions, such as primary sclerosing cholangitis (PSC), are risk factors. Noninvasive differential diagnosis between intrahepatic CCA and hepatocellular carcinoma (HCC) is sometimes difficult. Accurate noninvasive biomarkers for PSC, CCA, and HCC are not available. In the search for novel biomarkers, serum extracellular vesicles (EV) were isolated from CCA (n = 43), PSC (n = 30), or HCC (n = 29) patients and healthy individuals (control, n = 32); and their protein content was characterized. By using nanoparticle tracking analysis, serum EV concentration was found to be higher in HCC than in all the other groups. Round morphology (by transmission electron microscopy), size (~180 nm diameter by nanoparticle tracking analysis), and markers (clusters of differentiation 9, 63, and 81 by immunoblot) indicated that most serum EV were exosomes. Proteome profiles (by mass spectrometry) revealed multiple differentially expressed proteins among groups. Several of these proteins showed high diagnostic values with maximum area under the receiver operating characteristic curve of 0.878 for CCA versus control, 0.905 for CCA stage I-II versus control, 0.789 for PSC versus control, 0.806 for noncirhottic PSC versus control, 0.796 for CCA versus PSC, 0.956 for CCA stage I-II versus PSC, 0.904 for HCC versus control, and 0.894 for intrahepatic CCA versus HCC. Proteomic analysis of EV derived from CCA human cells in vitro revealed higher abundance of oncogenic proteins compared to EV released by normal human cholangiocytes. Orthotopic implant of CCA human cells in the liver of immunodeficient mice resulted in the release to serum of EV containing some similar human oncogenic proteins. CONCLUSION: Proteomic signatures found in serum EV of CCA, PSC, and HCC patients show potential usefulness as diagnostic tools. (Hepatology 2017;66:1125 1143). PMID- 28555886 TI - Lymphatic invasion predicts sentinel lymph node metastasis and adverse outcome in primary cutaneous melanoma. AB - BACKGROUND: Sentinel lymph node (SLN) metastasis is a powerful predictor of survival in primary cutaneous melanoma. Lymphatic invasion (LI) may correlate with increased risk of SLN metastasis. Intralymphatic metastases, often difficult to detect on hematoxylin and eosin (H&E) stained sections, are readily identified with dual immunohistochemistry for melanocytic and lymphatic markers. METHODS: We used dual S100/D240 immunohistochemistry to detect LI in 125 melanomas from patients who underwent SLN biopsy and correlated LI with melanoma staging parameters and disease status. RESULTS: Dual immunohistochemistry allowed for the identification of LI in 33 cases (26%), compared to only 2% on H&E stained sections. Melanomas with LI showed greater thickness, higher mitotic rate and more frequent ulceration. Eleven of 33 cases with LI (33%) and 10 of 92 cases without LI (11%) were associated with a positive SLN (P = .006). More patients without LI were disease-free at last follow-up (80%) than patients with LI (50%; P = .002); LI was significantly associated with decreased progression-free survival. CONCLUSION: The detection of LI is improved by dual immunohistochemistry and predicts SLN metastasis. The presence of LI may impact therapeutic planning in melanoma, such as the decision to perform a SLN biopsy. PMID- 28555888 TI - Computerized detection of leukocytes in microscopic leukorrhea images. AB - PURPOSE: Detection of leukocytes is critical for the routine leukorrhea exam, which is widely used in gynecological examinations. An elevated vaginal leukocyte count in women with bacterial vaginosis is a strong predictor of vaginal or cervical infections. In the routine leukorrhea exam, the counting of leukocytes is primarily performed by manual techniques. However, the viewing and counting of leukocytes from multiple high-power viewing fields on a glass slide under a microscope leads to subjectivity, low efficiency, and low accuracy. To date, many biological cells in stool, blood, and breast cancer have been studied to realize computerized detection; however, the detection of leukocytes in microscopic leukorrhea images has not been studied. Thus, there is an increasing need for computerized detection of leukocytes. METHODS: There are two key processes in the computerized detection of leukocytes in digital image processing. One is segmentation; the other is intelligent classification. In this paper, we propose a combined ensemble to detect leukocytes in the microscopic leukorrhea image. After image segmentation and selecting likely leukocyte subimages, we obtain the leukocyte candidates. Then, for intelligent classification, we adopt two methods: feature extraction and classification by a support vector machine (SVM); applying a modified convolutional neural network (CNN) to the larger subimages. If different methods classify a candidate in the same category, the process is finished. If not, the outputs of the methods are provided to a classifier to further classify the candidate. RESULTS: After acquiring leukocyte candidates, we attempted three methods to perform classification. The first approach using features and SVM achieved 88% sensitivity, 97% specificity, and 92.5% accuracy. The second method using CNN achieved 95% sensitivity, 84% specificity, and 89.5% accuracy. Then, in the combination approach, we achieved 92% sensitivity, 95% specificity, and 93.5% accuracy. Finally, the images with marked and counted leukocytes were obtained. CONCLUSION: A novel computerized detection system was developed for automated detection of leukocytes in microscopic images. Different methods resulted in comparable overall qualities by enabling computerized detection of leukocytes. The proposed approach further improved the performance. This preliminary study proves the feasibility of computerized detection of leukocytes in clinical use. PMID- 28555887 TI - In vitro detection of chemical allergens: an optimized assay using mouse bone marrow-derived dendritic cells. AB - BACKGROUND: Identification of the allergenic potency of chemicals is a key step in the safety assessment process. Predictive assays that require no or few animals are needed. OBJECTIVES: To develop an alternative in vitro mouse bone marrow-derived dendritic cell (BMDC) assay to determine the allergenic potential of chemicals. METHODS: BMDCs were exposed to well-known allergens and to non allergenic chemicals. Surface marker expression and cytokine release of BMDCs were analysed after treatment. RESULTS: Eleven tested chemicals showed a significant stimulation index (SI) of >1.5 (accuracy, 75%; sensitivity, 69%). The four non-allergens all showed a SI of <1.5. Eight contact allergens tested showed a significant SI of >1.5 (accuracy, 92%; sensitivity, 89%), whereas only two respiratory allergens showed a significant SI of >1.5 (accuracy, 60%; sensitivity, 33%). CONCLUSIONS: The results indicate that the BMDC assay could become a reliable test for assessment of the allergenic potential of chemicals. The next step should include the testing of further chemicals, with the aim of integrating this assay into the toolbox of in vitro methods for the evaluation of the allergenic potential of chemicals. PMID- 28555891 TI - A quantitative analysis of light-driven charge transfer processes using voronoi partitioning of time dependent DFT-derived electron densities. AB - An analytical method is presented that provides quantitative insight into light driven electron density rearrangement using the output of standard time-dependent density functional theory (TD-DFT) computations on molecular compounds. Using final and initial electron densities for photochemical processes, the subtraction of summed electron density in each atom-centered Voronoi polyhedron yields the electronic charge difference, QVECD . This subtractive method can also be used with Bader, Mulliken and Hirshfeld charges. A validation study shows QVECD to have the most consistent performance across basis sets and good conservation of charge between electronic states. Besides vertical transitions, relaxation processes can be investigated as well. Significant electron transfer is computed for isomerization on the excited state energy surface of azobenzene. A number of linear anilinepyridinium donor-bridge-acceptor chromophores was examined using QVECD to unravel the influence of its pi-conjugated bridge on charge separation. Finally, the usefulness of the presented method as a tool in optimizing charge transfer is shown for a homologous series of organometallic pigments. The presented work allows facile calculation of a novel, relevant quantity describing charge transfer processes at the atomic level. (c) 2017 Wiley Periodicals, Inc. PMID- 28555892 TI - Pain in cerebral palsy: a neglected comorbidity. PMID- 28555893 TI - INTERACTION AND COEVOLUTION. PMID- 28555889 TI - Reduced muscle strength in ether lipid-deficient mice is accompanied by altered development and function of the neuromuscular junction. AB - Inherited deficiency in ether lipids, a subgroup of phospholipids whose biosynthesis needs peroxisomes, causes the fatal human disorder rhizomelic chondrodysplasia punctata. The exact roles of ether lipids in the mammalian organism and, therefore, the molecular mechanisms underlying the disease are still largely enigmatic. Here, we used glyceronephosphate O-acyltransferase knockout (Gnpat KO) mice to study the consequences of complete inactivation of ether lipid biosynthesis and documented substantial deficits in motor performance and muscle strength of these mice. We hypothesized that, probably in addition to previously described cerebellar abnormalities and myelination defects in the peripheral nervous system, an impairment of neuromuscular transmission contributes to the compromised motor abilities. Structurally, a morphologic examination of the neuromuscular junction (NMJ) in diaphragm muscle at different developmental stages revealed aberrant axonal branching and a strongly increased area of nerve innervation in Gnpat KO mice. Post-synaptically, acetylcholine receptor (AChR) clusters colocalized with nerve terminals within a widened endplate zone. In addition, we detected atypical AChR clustering, as indicated by decreased size and number of clusters following stimulation with agrin, in vitro. The turnover of AChRs was unaffected in ether lipid-deficient mice. Electrophysiological evaluation of the adult diaphragm indicated that although evoked potentials were unaltered in Gnpat KO mice, ether lipid deficiency leads to fewer spontaneous synaptic vesicle fusion events but, conversely, an increased post-synaptic response to spontaneous vesicle exocytosis. We conclude from our findings that ether lipids are essential for proper development and function of the NMJ and may, therefore, contribute to motor performance. Read the Editorial Highlight for this article on page 463. PMID- 28555890 TI - The dual role of LESION SIMULATING DISEASE 1 as a condition-dependent scaffold protein and transcription regulator. AB - Since its discovery over two decades ago as an important cell death regulator in Arabidopsis thaliana, the role of LESION SIMULATING DISEASE 1 (LSD1) has been studied intensively within both biotic and abiotic stress responses as well as with respect to plant fitness regulation. However, its molecular mode of action remains enigmatic. Here, we demonstrate that nucleo-cytoplasmic LSD1 interacts with a broad range of other proteins that are engaged in various molecular pathways such as ubiquitination, methylation, cell cycle control, gametogenesis, embryo development and cell wall formation. The interaction of LSD1 with these partners is dependent on redox status, as oxidative stress significantly changes the quantity and types of LSD1-formed complexes. Furthermore, we show that LSD1 regulates the number and size of leaf mesophyll cells and affects plant vegetative growth. Importantly, we also reveal that in addition to its function as a scaffold protein, LSD1 acts as a transcriptional regulator. Taken together, our results demonstrate that LSD1 plays a dual role within the cell by acting as a condition-dependent scaffold protein and as a transcription regulator. PMID- 28555894 TI - ALLOZYMES AND SONG DIALECTS: A REASSESSMENT. PMID- 28555897 TI - FEMALE-BIASED SEX RATIOS IN SOCIAL INSECTS LACKING MORPHOLOGICAL CASTES. PMID- 28555896 TI - SYMPOSIUM. PMID- 28555895 TI - SEXUAL SELECTION ON BODY SIZE, TERRITORY AND PLUMAGE VARIABLES IN A POPULATION OF DARWIN'S FINCHES. PMID- 28555898 TI - HERITABILITY ESTIMATES FOR AGE AND LENGTH AT MATURITY IN TWO POPULATIONS OF MOSQUITOFISH THAT SHARED ANCESTORS IN 1905. PMID- 28555899 TI - LIFE HISTORY ADAPTATION TO DEMOGRAPHIC REGIME IN LABORATORY-CULTURED TISBE FURCATA (COPEPODA, HARPACTICOIDA). PMID- 28555900 TI - EVOLUTIONARILY STABLE REPRODUCTIVE ALLOCATIONS IN HETEROSTYLOUS PLANTS. PMID- 28555901 TI - IS A JACK-OF-ALL-TEMPERATURES A MASTER OF NONE? PMID- 28555902 TI - MEASURING THE COST OF REPRODUCTION. II. THE CORRELATION STRUCTURE OF THE LIFE TABLES OF FIVE FRESHWATER INVERTEBRATES. PMID- 28555904 TI - ICSEB - III: Third International Congress of Systematic and Evolutionary Biology, 1985. PMID- 28555903 TI - A COMPARISON OF ELECTROPHORETIC AND MORPHOMETRIC VARIABILITY IN THE FACE FLY, MUSCA AUTUMNALIS. PMID- 28555905 TI - EVOLUTIONARY LANDSCAPES FOR COMPLEX SELECTION. PMID- 28555906 TI - LIFE HISTORY VARIATION IN A FRESHWATER COPEPOD: EVIDENCE FROM POPULATION CROSSES. PMID- 28555907 TI - DIRECT EVIDENCE THAT THE ILYODON MORPHS ARE A SINGLE BIOLOGICAL SPECIES. PMID- 28555908 TI - DIFFERENCES IN FITNESS BETWEEN SEEDLINGS DERIVED FROM CLEISTOGAMOUS AND CHASMOGAMOUS FLOWERS IN IMPATIENS CAPENSIS. PMID- 28555909 TI - INCREASED DENSITY DOES NOT INCREASE REMATING FREQUENCY IN LABORATORY POPULATIONS OF DROSOPHILA MELANOGASTER. PMID- 28555910 TI - CODING MORPHOMETRIC CHARACTERS FOR CONSTRUCTING DISTANCE WAGNER NETWORKS. PMID- 28555911 TI - EVOLUTION IN A SEASONAL ENVIRONMENT: SIMPLICITY LOST? PMID- 28555912 TI - PROMETHEAN FIRE: REFLECTIONS ON THE ORIGIN OF MIND. PMID- 28555913 TI - GENETICS, SPECIATION AND THE FOUNDER PRINCIPLE. PMID- 28555914 TI - GENIC DIVERSITY AND POPULATION GENETIC STRUCTURE OF TRITURUS VULGARIS (URODELA, SALAMANDRIDAE). PMID- 28555915 TI - MUTATIONAL LOAD IN CLONAL PLANTS: A STUDY OF TWO FERN SPECIES. PMID- 28555916 TI - Society for the Study of Evolution and American Society of Naturalists 1984 Meetings. PMID- 28555917 TI - REPLY TO "ALLOZYMES AND SONG DIALECTS: A REASSESSMENT". PMID- 28555918 TI - PRIMARY AND SECONDARY TRANSITION ZONES IN SPECIATION AND POPULATION DIFFERENTIATION: A PHYLOGENETIC ANALYSIS OF RANGE EXPANSION. PMID- 28555919 TI - ANNUAL VARIATION OF SURVIVAL ADVANTAGE OF LARGE JUVENILE SIDE-BLOTCHED LIZARDS, UTA STANSBURIANA: ITS CAUSES AND EVOLUTIONARY SIGNIFICANCE. PMID- 28555920 TI - MOLECULAR EVOLUTION: THE COMING OF AGE. PMID- 28555921 TI - ADAPTIVE SIGNIFICANCE OF DELAYED PLUMAGE MATURATION IN MALE NORTHERN ORIOLES. PMID- 28555922 TI - MORPHOLOGICAL VARIATION IN FROG PECTORAL GIRDLES: TESTING ALTERNATIVES TO A TRADITIONAL ADAPTIVE EXPLANATION. PMID- 28555923 TI - MEASURING THE COST OF REPRODUCTION. I. THE CORRELATION STRUCTURE OF THE LIFE TABLE OF A PLANKTON ROTIFER. PMID- 28555924 TI - Physical-Mechanical characterization of cosmetic formulations and correlation between instrumental measurements and sensorial properties. AB - OBJECTIVE: The correct choice of raw materials in the development of cosmetic formulations is essential for obtaining stable and pleasant skin care products. Therefore, rheological, texture and sensory analyses are important to understand the behaviour and stability of the formulations. In this context, the aim of this study was to develop cosmetic formulations containing or not (vehicle) UV filters and chicory root extract, to evaluate their stability as well as to characterize their physical and texture properties and correlate them with the sensory attributes. METHODS: Four formulations containing organic UV filters and chicory extract, each alone or in combination, were developed and evaluated for 180 days with a cone and plate rheometer, a texture analyzer and consumer's sensorial analysis. Thus, the data obtained were correlated to observe the different influences. RESULTS: The developed formulations remained stable after 180 days regarding macroscopic aspects, organoleptic characteristics and pH values. The addition of the UV filters alone and in combination with the active substance resulted in significant increases in rheology properties, viscosity and consistency. The formulation with the active ingredient showed significant decreases in the texture parameters after 180 days, mainly due to its polysaccharide inulin. All formulations obtained high scores in sensorial parameters. A strong correlation was mainly found between spreadability and work of shear, and between the texture parameters. CONCLUSION: The raw materials strongly influenced the physical, texture and sensorial parameters. Finally, the UV filters showed a greater influence on the results of the formulations than the chicory root extract. In conclusion, the association of the mentioned methods allows the correct choice of ingredients and their combinations. PMID- 28555925 TI - Functional severity of CLCNKB mutations correlates with phenotypes in patients with classic Bartter's syndrome. AB - KEY POINTS: The highly variable phenotypes observed in patients with classic Bartter's syndrome (BS) remain unsatisfactorily explained. The wide spectrum of functional severity of CLCNKB mutations may contribute to the phenotypic variability, and the genotype-phenotype association has not been established. Low level expression of the human ClC-Kb channel in mammalian cells impedes the functional study of CLCNKB mutations, and the underlying cause is still unclear. The human ClC-Kb channel is highly degraded by proteasome in human embryonic kidney cells. The C-terminal in-frame green fluorescent protein fusion may slow down the proteasome-mediated proteolysis. Barttin co-expression necessarily improves the stability, membrane trafficking and gating of ClC-Kb. CLCNKB mutations in barttin-binding sites, dimer interface or selectivity filter often have severe functional consequences. The remaining chloride conductance of the ClC-Kb mutant channel significantly correlates with the phenotypes, such as age at diagnosis, plasma chloride concentration, and the degree of calciuria in patients with classic BS. ABSTRACT: Mutations in the CLCNKB gene encoding the human voltage-gated chloride ClC-Kb (hClC-Kb) channel cause classic Bartter's syndrome (BS). In contrast to antenatal BS, classic BS manifests with highly variable phenotypes. The functional severity of the mutant channel has been proposed to explain this phenomenon. Due to difficulties in the expression of hClC-Kb in heterologous expression systems, the functional consequences of mutant channels have not been thoroughly examined, and the genotype-phenotype association has not been established. In this study, we found that hClC-Kb, when expressed in human embryonic kidney (HEK) cells, was unstable due to degradation by proteasome. In-frame fusion of green fluorescent protein (GFP) to the C terminus of the channel may ameliorate proteasome degradation. Co-expression of barttin increased protein abundance and membrane trafficking of hClC-Kb and markedly increased functional chloride current. We then functionally characterized 18 missense mutations identified in our classic BS cohort and others using HEK cells expressing hClC-Kb-GFP. Most CLCNKB mutations resulted in marked reduction in protein abundance and chloride current, especially those residing at barttin binding sites, dimer interface and selectivity filter. We enrolled classic BS patients carrying homozygous missense mutations with well described functional consequences and clinical presentations for genotype phenotype analysis. We found significant correlations of mutant chloride current with the age at diagnosis, plasma chloride concentration and urine calcium excretion rate. In conclusion, hClC-Kb expression in HEK cells is susceptible to proteasome degradation, and fusion of GFP to the C-terminus of hClC-Kb improves protein expression. The functional severity of the CLCNKB mutation is an important determinant of the phenotype in classic BS. PMID- 28555926 TI - Association between vascular rings and learning performance: A cross-sectional study. AB - BACKGROUND: Chronic tracheal obstruction has been associated with learning deficits; hence, early surgical intervention has been suggested. AIM: To evaluate the relationship between learning performance and vascular ring caused by an isolated aberrant right subclavian artery. METHODS: Participants included 1,685 undergraduate students (ie, students of medical informatics and medical/public health students) in Central Taiwan. The diagnostic period was from 2005 to 2010. Vascular ring was diagnosed by two-dimensional echocardiographic screening and was validated by esophagogram. The reference group (medical students) was associated with higher learning performance, whereas the comparison group (students of medical informatics and public health) was associated with lower learning performance. Multiple logistic regression was used for analysis. RESULTS: The prevalence of vascular ring among the reference and comparison groups was 0.48 and 2.03%, respectively. The odds ratio for the vascular ring was 4.90 (95% confidence interval: 1.30-18.40) after adjusting for potential confounders. CONCLUSIONS: This study suggests that vascular ring can impact learning efficiency and advocates for larger dedicated studies. (c) 2017 The Authors Journal of Clinical Ultrasound Published by Wiley Periodicals, Inc. J Clin Ultrasound 45:556-560, 2017. PMID- 28555927 TI - Sensitization and cross-reactivity patterns of contact allergy to diisocyanates and corresponding amines: investigation of diphenylmethane-4,4'-diisocyanate, diphenylmethane-4,4'-diamine, dicyclohexylmethane-4,4'-diisocyanate, and dicylohexylmethane-4,4'-diamine. AB - BACKGROUND: Isocyanates are used in polyurethane production. Dermal exposure to isocyanates can induce contact allergy. The most common isocyanate is diphenylmethane diisocyanate used for industrial purposes. The isomer diphenylmethane-4,4'-diisocyanate (4,4'-MDI) is used in patch testing. Diphenylmethane-4,4'-diamine (4,4'-MDA) is its corresponding amine. Concurrent reactions to 4,4'-MDI and 4,4'-MDA have been reported, as have concurrent reactions to 4,4'-MDI and dicyclohexylmethane-4,4'-diisocyanate (4,4'-DMDI). OBJECTIVES: To investigate the sensitization capacities and the cross-reactivity of 4,4'-MDI, 4,4'-MDA, 4,4'-DMDI, and dicyclohexylmethane-4,4'-diamine (4,4' DMDA). METHODS: The guinea-pig maximization test (GPMT) was used. RESULTS: The GPMT showed sensitizing capacities for all investigated substances: 4,4'-MDI, 4,4'-MDA, 4,4'-DMDI, and 4,4'-DMDA (all p < 0.001). 4,4'-MDI-sensitized animals showed cross-reactivity to 4,4'-MDA (p < 0.001) and 4,4'-DMDI (all p < 0.05). 4,4'-MDA-sensitized animals showed cross-reactivity to 4,4'-DMDA (p = 0.008). CONCLUSION: All of the investigated substances were shown to be strong sensitizers. Animals sensitized to 4,4'-MDI showed cross-reactivity to 4,4'-MDA and 4,4'-DMDI, supporting previous findings in the literature. The aromatic amine 4,4'-MDA showed cross-reactivity to the aliphatic amine 4,4'-DMDA. PMID- 28555928 TI - Impact of excessive gingival display on oral health-related quality of life in a Southern Brazilian young population. AB - AIM: To compare oral health-related quality of life (OHRQoL) between individuals with and without excessive gingival display (EGD). MATERIALS AND METHODS: A cross sectional study was conducted in 53 individuals with EGD and 53 controls matched for sex and age. The outcome was OHRQoL, determined using the Oral Health Impact Profile (OHIP-14) and self-perceptions of satisfaction with smile aesthetics. A clinical examination was conducted to evaluate the smile line, colour of the teeth, tooth wear and malocclusion. Poisson regression was used to model the association between excessive gingival display and OHRQoL. RESULTS: Participants with EGD had higher total OHIP-14 score (4.81 +/- 4.76) in comparison with the controls (1.85 +/- 3.77; p < .001). The percentage of satisfied with smile individuals without and with EGD was 78.9% and 21.1%, respectively (p = .005). In the multivariate analysis, total OHIP-14 scores were 2.10-fold higher individuals with EGD, independently of the other variables analysed. Impacts were evident on the functional limitation, psychological discomfort, psychological disability and social handicap. CONCLUSIONS: The occurrence of EGD exerted a negative impact on OHRQoL independently of confounding variables in this specific population. The present findings justify the planning of treatment for individuals with EGD that impacts quality of life. PMID- 28555929 TI - PM2.5-induced lung inflammation in mice: Differences of inflammatory response in macrophages and type II alveolar cells. AB - Particulate matter 2.5 (=50% at 10 ug mL-1 . Mastoparan L showed an equal activity against C. trachomatis, C. pneumoniae, C. suis, and C. muridarum, but did not exert any inhibitory effect against C. psittaci, C. pecorum, C. abortus, and C. avium even at 80 ug mL-1 . These data suggest that CMO could be a promising compound in the prevention and treatment of chlamydial infections. PMID- 28555935 TI - A novel multilayer MV imager computational model for component optimization. AB - PURPOSE: A novel Megavoltage (MV) multilayer imager (MLI) design featuring higher detective quantum efficiency and lower noise than current conventional MV imagers in clinical use has been recently reported. Optimization of the MLI design for multiple applications including tumor tracking, MV-CBCT and portal dosimetry requires a computational model that will provide insight into the physics processes that affect the overall and individual components' performance. The purpose of the current work was to develop and validate a comprehensive computational model that can be used for MLI optimization. METHODS: The MLI model was built using the Geant4 Application for Tomographic Emission (GATE) application. The model includes x-ray and charged-particle interactions as well as the optical transfer within the phosphor. A first prototype MLI device featuring a stack of four detection layers was used for model validation. Each layer of the prototype contains a copper buildup plate, a phosphor screen and photodiode array. The model was validated against measured data of Modulation Transfer Function (MTF), Noise-Power Spectrum (NPS), and Detective Quantum Efficiency (DQE). MTF was computed using a slanted slit with 2.3 degrees angle and 0.1 mm width. NPS was obtained using the autocorrelation function technique. DQE was calculated from MTF and NPS data. The comparison metrics between simulated and measured data were the Pearson's correlation coefficient (r) and the normalized root-mean-square error (NRMSE). RESULTS: Good agreement between measured and simulated MTF and NPS values was observed. Pearson's correlation coefficient for the combined signal from all layers of the MLI was equal to 0.9991 for MTF and 0.9992 for NPS; NRMSE was 0.0121 for MTF and 0.0194 for NPS. Similarly, the DQE correlation coefficient for the combined signal was 0.9888 and the NRMSE was 0.0686. CONCLUSIONS: A comprehensive model of the novel MLI design was developed using the GATE toolkit and validated against measured MTF, NPS, and DQE data acquired with a prototype device featuring four layers. This model will be used for further optimization of the imager components and configuration for clinical radiotherapy applications. PMID- 28555936 TI - Haemodialysis significantly reduces serum levetiracetam levels inducing epileptic seizures: Case report. AB - WHAT IS KNOWN AND OBJECTIVE: Levetiracetam is used in the treatment of some forms of epilepsy. In renal impairment and patients on chronic haemodialysis, dose adjustment is required. We report a case. CASE DESCRIPTION: This case report describes a woman on levetiracetam treatment who presented with generalized tonic clonic seizures during a haemodialysis session. We report on treatment adjustment and on the impact of dialysis on levetiracetam levels. WHAT IS NEW AND CONCLUSION: Haemodialysis reduces serum levetiracetam concentration and can lead to subtherapeutic levels. Close monitoring is necessary when dialysis is used on patients receiving anticonvulsant drugs that are extensively eliminated by the procedure. PMID- 28555937 TI - Market-driven production of biospecimens and the role of NHS hospital-led biobanks. AB - Biobanks are vital for biospecimen production in research, despite the regulatory, recruitment and commercial difficulties they face. We conducted interviews with clinicians, researchers, volunteers who recruit biobank participants, regulators and NHS managers about the integration of a biobank into an NHS hospital. We show that medical waste collected for biomedical research acquires its socio-ethical and economic value from the level of integration (both technologically and organisationally) of the biobank into the NHS hospital. There is extensive investment in a range of intellectual and commercial relationships and labour among stakeholders involved in the production of biospecimens. It is not only the boundaries of research, clinical care and commercialisation of biospecimens that blur but also those of volunteerism and citizenship. Hospital led biobanks provide an opportunity to study the intertwining of biomedical innovation and healthcare. PMID- 28555938 TI - Assessment of the lethal and sublethal effects of 20 environmental chemicals in zebrafish embryos and larvae by using OECD TG 212. AB - Fish embryo toxicity tests are used to assess the lethal and sublethal effects of environmental chemicals in aquatic organisms. Previously, we used a short-term toxicity test published by the Organization for Economic Co-operation and Development (test no. 212: Fish, Short-term Toxicity Test on Embryo and Sac-Fry Stages [OECD TG 212]) to assess the lethal and sublethal effects of aniline and several chlorinated anilines in zebrafish embryos and larvae. To expand upon this previous study, we used OECD TG 212 in zebrafish embryos and larvae to assess the lethal and sublethal effects of 20 additional environmental chemicals that included active pharmaceutical ingredients, pesticides, metals, aromatic compounds or chlorinated anilines. Zebrafish embryos (Danio rerio) were exposed to the test chemicals until 8 days post-fertilization. A delayed lethal effect was induced by 16 of the 20 test chemicals, and a positive correlation was found between heart rate turbulence and mortality. We also found that exposure to the test chemicals at concentrations lower than the lethal concentration induced the sublethal effects of edema, body curvature and absence of swim-bladder inflation. In conclusion, the environmental chemicals assessed in the present study induced both lethal and sublethal effects in zebrafish embryos and larvae, as assessed by using OECD TG 212. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28555939 TI - Comparison of aloe vera and omeprazole in the treatment of equine gastric ulcer syndrome. AB - BACKGROUND: Anecdotally, aloe vera is used to treat gastric ulceration, although no studies have yet investigated its efficacy in horses. OBJECTIVES: To test the hypothesis that aloe vera would be noninferior to omeprazole in the treatment of equine gastric ulcer syndrome. STUDY DESIGN: Randomised, blinded clinical trial. METHODS: Forty horses with grade >=2 lesions of the squamous and/or glandular mucosa were randomly assigned to one of two groups. Horses received either aloe vera inner leaf gel (17.6 mg/kg bwt) b.i.d. or omeprazole (4 mg/kg bwt) s.i.d. for approximately 28 days, after which a repeat gastroscopic examination was performed to determine disease resolution. Horses with persistent lesions were offered a further 28 days of treatment with omeprazole (4 mg/kg bwt s.i.d.) and were re-examined on completion of treatment. RESULTS: Efficacy analyses were based on 39 horses that completed the trial. Equine squamous gastric disease (ESGD) was observed in 38 horses; improvement and healing rates in these horses were 56% and 17%, respectively, in the aloe vera group, and 85% and 75%, respectively, in the omeprazole group. Healing was less likely to occur in horses with prolonged gastric emptying. Equine glandular gastric disease (EGGD) was less common than ESGD (n = 14) and numbers were too small to perform meaningful statistical analyses. The hypothesis that aloe vera would be noninferior to omeprazole was not supported. MAIN LIMITATIONS: No placebo control group was included. Limited numbers preclude any comment on the efficacy of aloe vera in the treatment of EGGD. CONCLUSIONS: Treatment with aloe vera was inferior to treatment with omeprazole. PMID- 28555941 TI - Bias-Corrected Estimation in Continuous Sampling Plans. AB - Continuous sampling plans (CSPs) are algorithms used for monitoring and maintaining the quality of a production line. Although considerable work has been done on the development of CSPs, to our knowledge, there has been no corresponding effort in developing estimators with good statistical properties for data arising from a CSP inspection process. For example, information about the failure rate of the process will affect the management of the process, both in terms of selecting appropriate CSP parameters to keep the failure rate after inspection at a suitable level, and in terms of policy, for example, whether the process should be completely inspected, or shut down. The motivation for this exercise was developing sampling protocols for Australia's Department of Agriculture and Water Resources for monitoring the biosecurity compliance of incoming goods at international borders. In this study, we show that maximum likelihood estimation of the failure rate under a sampling scheme can be biased depending on when estimation is performed, and we provide explicit expressions for the main contribution of the bias under various CSPs. We then construct bias corrected estimators and confidence intervals, and evaluate their performance in a numerical study. PMID- 28555940 TI - Altered molecular profile in thyroid cancers from patients affected by the Three Mile Island nuclear accident. AB - OBJECTIVES/HYPOTHESIS: In 1979, Three Mile Island (TMI) nuclear power plant experienced a partial meltdown with release of radioactive material. The effects of the accident on thyroid cancer (TC) in the surrounding population remain unclear. Radiation-induced TCs have a lower incidence of single nucleotide oncogenic driver mutations and higher incidence of gene fusions. We used next generation sequencing (NGS) to identify molecular signatures of radiation-induced TC in a cohort of TC patients residing near TMI during the time of the accident. STUDY DESIGN: Case series. METHODS: We identified 44 patients who developed papillary thyroid carcinoma between 1974 and 2014. Patients who developed TC between 1984 and 1996 were at risk for radiation-induced TC, patients who developed TC before 1984 or after 1996 were the control group. We used targeted NGS of paired tumor and normal tissue from each patient to identify single nucleotide oncogenic driver mutations. Oncogenic gene fusions were identified using quantitative reverse transcription polymerase chain reaction. RESULTS: We identified 15 patients in the at-risk group and 29 patients in the control group. BRAFV600E mutations were identified in 53% patients in the at-risk group and 83% patients in the control group. The proportion of patients with BRAF mutations in the at-risk group was significantly lower than predicted by the The Cancer Genome Atlas cohort. Gene fusion or somatic copy number alteration drivers were identified in 33% tumors in the at-risk group and 14% of tumors in the control group. CONCLUSIONS: Findings were consistent with observations from other radiation-exposed populations. These data raise the possibility that radiation released from TMI may have altered the molecular profile of TC in the population surrounding TMI. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:S1-S9, 2017. PMID- 28555942 TI - A review of chromatographic methods for ketamine and its metabolites norketamine and dehydronorketamine. AB - Ketamine has a synthetic, sedative, nonbarbiturate and fast-acting anaesthetic properties and it is commonly used in both humans and veterinary surgery. There are many analytical methods available for the qualitative and quantitative determination of ketamine and its metabolites. We have focused on sample pre treatment and chromatographic techniques used since the year 2000 for the determination of ketamine and its metabolites in biological samples. Liquid and gas chromatography coupled with various detection techniques (mass spectrometry, ultraviolet or fluorescence detection) have been used in these publications. This review gives information on the implementation of methods for studying ketamine and its metabolites in various research applications. It could be useful in forensic sciences including doping control and also in the therapeutic drug monitoring of ketamine and norketamine in human and animal clinical surgery. PMID- 28555944 TI - Association of salivary peroxidase activity and concentration with periodontal health: A validity study. AB - AIM: Whereas the relationship between myeloperoxidase and periodontitis has been widely examined that between salivary peroxidase and periodontitis has received little attention. We examined how periodontitis depends on both salivary peroxidase activity and concentration. MATERIALS AND METHODS: A full mouth, clinical assessment of probing depth was performed in a sample of 46 participants aged 25-54 years. To minimise bias, these data were corrected by data from the general population (Study of Health in Pomerania). Using five repeated measurements of activity and concentration over 1 day, we assessed daily biological variability and increased the reliability of salivary peroxidase measurements. RESULTS: Salivary peroxidase activity was associated with probing depth (interquartile range effect = -0.48; robust estimates of 95% confidence interval: -0.90 to -0.31; p = .0052), and its effect was not confounded by salivary peroxidase concentration. In turn, the effect of salivary peroxidase concentration was confounded by salivary peroxidase activity, and it was smaller than that of activity. CONCLUSIONS: We found an inverse association between salivary peroxidase activity and probing depth. Thus, our results imply that salivary peroxidase activity could be a protective factor against periodontitis. However, large, well-designed studies are needed to explore the causal mechanisms of this association. PMID- 28555943 TI - Pro-angiogenic TIE-2-expressing monocytes/TEMs as a biomarker of the effect of sorafenib in patients with advanced hepatocellular carcinoma. AB - Sorafenib, a multi-kinase inhibitor, inhibits tumor angiogenesis and is the first line systemic therapy for patients with advanced hepatocellular carcinoma (HCC). However, due to its limited effects and frequent occurrence of side effects, biomarkers are needed to predict the effects of sorafenib. We considered the possibility of using TIE-2-expressing monocytes (TEMs) to predict the response in sorafenib-treated patients with advanced HCC. TEMs serve as a diagnostic marker of HCC and are related to angiogenesis. We analyzed 25 advanced HCC patients and prospectively evaluated TEMs before (Pre TEMs) and at 1 month after initial therapy (T1m TEMs). The radiologic response was evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Median survival time (MST) was significantly longer in the partial response/stable disease (PR/SD) group (21.8 months) than in the PD group (8.7 months). DeltaTEMs (changes of T1m TEMs compared to Pre TEMs) were significantly lower in the PR/SD group than in the PD group. MST of the DeltaTEMs low group (14.2 months) was significantly longer than that of the high group (8.7 months). Univariate and multivariate Cox regression analyses showed that DeltaTEMs [hazard ratio (HR) = 8.53, 95% confidence interval (CI) = 1.51-48.16, p = 0.015] and Child-Pugh class (HR = 5.59, 95% CI = 1.06 29.63, p = 0.043) were independently associated with overall survival. Our results suggest that DeltaTEMs could serve as a biomarker for predicting radiologic response and overall survival in sorafenib-treated patients with advanced HCC. PMID- 28555945 TI - Recommendations on the use of magnetic resonance imaging in PSC-A position statement from the International PSC Study Group. AB - : Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disorder characterized by inflammation and fibrosis of the intra- and/or extrahepatic bile ducts. Magnetic resonance imaging (MRI) is a noninvasive imaging modality that can be used to diagnose PSC and detect disease related complications. Quantitative MRI technologies also have the potential to provide valuable prognostic information. Despite the potential of this imaging technology, the clinical application of MRI in the care of PSC patients and imaging standards vary across institutions. Moreover, a unified position statement about the role of MRI in the care of PSC patients, quality imaging standards, and its potential as a research tool is lacking. CONCLUSION: Members of the International PSC Study Group and radiologists from North America and Europe have compiled the following position statement to provide guidance regarding the application of MRI in the care of PSC patients, minimum imaging standards, and future areas of research. (Hepatology 2017;66:1675-1688). PMID- 28555946 TI - Comparative Effectiveness of Oral Antiplatelet Agents in Patients with Acute Coronary Syndrome. AB - OBJECTIVE: In randomized controlled trials, prasugrel and ticagrelor reduced cardiovascular complications in patients with acute coronary syndrome (ACS) compared with clopidogrel. However, limited head-to-head comparisons have been conducted across the three antiplatelet agents using real-world data. The aim of this study was to compare clinical outcomes of three strategies during a 1-year period after percutaneous coronary intervention (PCI). METHODS: Rates of all cause and acute myocardial infarction (AMI) hospitalizations were compared retrospectively using an insurance claims database. Patients who filled a prescription for an oral antiplatelet agent between September 2011 and December 2013 for post ACS-PCI care were identified. Time to all-cause and AMI hospitalization for a 365-day postdischarge period was compared using Cox proportional hazard models controlling for potential confounders within a propensity score matched cohort. RESULTS: A matched cohort of 9504 clopidogrel, 7128 prasugrel, and 2376 ticagrelor patients was analyzed. The 1-year hazard ratio (HR) for the two newer agents versus clopidogrel was 0.84 (0.78-0.91). The HR for the newer agents versus clopidogrel of admission with AMI as the primary diagnosis was 0.78 (0.61-1.03), and for AMI as any diagnosis during a hospitalization was 0.88 (0.77-1.00). The HR of all-cause admission for ticagrelor versus prasugrel was 0.97 (0.84-1.13), and the HRs of AMI-related admission were not statistically significant between the two agents. Robustness checks across statistical methods to control for potential confounders did not influence the conclusion. CONCLUSION: This real-world study demonstrated that use of the newer agents following PCI was associated with a decrease in all-cause and AMI-related hospitalizations. However, no significant difference was found in the rate of admission between ticagrelor versus prasugrel. Due to concerns regarding statistical power, future studies should examine larger cohorts to obtain more precise estimates for AMI hospitalization for ticagrelor and prasugrel. PMID- 28555947 TI - Roaming of dogs in remote Indigenous communities in northern Australia and potential interaction between community and wild dogs. AB - OBJECTIVE: To investigate the roaming of Indigenous community dogs and potential interaction with wild dogs and dingoes. DESIGN: Cross-sectional survey and longitudinal follow-up study. METHODS: Six remote Indigenous communities in Cape York Peninsula and Arnhem Land in northern Australia were selected. Hair samples were collected from community dogs and microsatellite DNA analyses were used to determine hybrid (>10% dingo DNA) status. Dogs were fitted with GPS collars and home range (ha) was estimated during monitoring periods of up to 3 days. RESULTS: In Cape York Peninsula, 6% of the 35 dogs sampled were dingo hybrids, whereas in Arnhem Land 41% of the 29 dogs sampled were hybrids. The median extended home range was estimated to be 4.54 ha (interquartile range, 3.40 - 7.71). Seven community dogs were identified with an estimated home range > 20 ha and home ranges included the bushland surrounding communities. No significant difference in home ranges was detected between hybrid and non-hybrid dogs. CONCLUSIONS: Study results provide some evidence (dingo hybridisation, bushland forays) of the potential interaction between domestic and wild dogs in northern Australia. The nature of this interaction needs further investigation to determine its role in disease transmission; for example, in the case of a rabies incursion in this region. PMID- 28555948 TI - A suspected case of intermediate syndrome in a dog with carbamate toxicosis. AB - CASE REPORT: A 7-year-old female spayed Labrador Retriever was managed for suspected carbamate toxicosis after confirmed ingestion of a large amount of methiocarb. Therapy included decontamination, supportive care and management for aspiration pneumonia. On the third day of hospitalisation, after an initial clinical improvement, the dog developed respiratory muscle weakness, inspiratory dyspnoea and pronounced cervical muscle weakness. These delayed clinical signs were consistent with the 'intermediate syndrome' described in some cases of organophosphate and carbamate toxicoses in humans and also described in one case of organophosphate toxicosis in the dog. Intermediate syndrome has not been reported in carbamate toxicosis in the dog. CONCLUSION: This case report highlights the necessity for veterinarians to monitor for additional complications not commonly considered in acute carbamate toxicoses. PMID- 28555949 TI - End-to-side anastomosis of the left ventral colon to the small colon in a neonatal foal with segmental agenesis of the large colon. AB - CASE REPORT: A newborn foal was referred for evaluation because it had not passed meconium, despite the administration of four enemas. Abdominal radiographs and ultrasound scans showed generalised gaseous distension of the intestine and there was no observable meconium in the colon. Positive contrast colography showed contrast medium extending to the transverse colon. An exploratory laparotomy confirmed the absence of the left and right dorsal colon and the pelvic and diaphragmatic flexures. An end-to-side anastomosis of the left ventral colon to the midpoint of the small colon was performed. The foal recovered from anaesthesia and surgery uneventfully and immediately began suckling from the mare, with no signs of abdominal pain in the postoperative period. The foal began to pass soft faeces 3 days after surgery and at 6 months after surgery the foal was clinically normal and growing at a similar rate to its cohort. CONCLUSION: Intestinal atresia is a rare condition in foals, but should be considered as a differential diagnosis in foals that fail to pass meconium. Early recognition and surgical intervention can offer an improved chance of short-term survival in cases where there is adequate intestine to anastomose. An end-to-side anastomosis technique can be used where an end-to-end technique is not practical because of the difference in diameter of the proximal and distal intestinal segments. PMID- 28555950 TI - Lowland copperhead (Austrelaps superbus) envenomation causing severe neuromuscular paralysis in a dog. AB - CASE REPORT: A case of lowland copperhead snake (Austrelaps superbus) envenomation in a dog is described. The dog developed severe and prolonged neuromuscular paralysis, including ventilatory failure. The dog was treated successfully with antivenom, intravenous fluids and mechanical ventilation. CLINICAL SIGNIFICANCE: The toxic components of lowland copperhead snake venom are reviewed. PMID- 28555952 TI - Students' opinions on welfare and ethics issues for companion animals in Australian and New Zealand veterinary schools. AB - OBJECTIVE: To determine what veterinary students in Australia and New Zealand consider important competences in companion animal welfare and ethics (AWE) required on their first day of practice, and to explore how their priorities relate to gender and stage of study. METHODS: Undergraduate students at all veterinary schools in Australia and New Zealand were sent an online survey. A subset of questions required participants to rank the importance of preselected AWE topics pertaining to companion animals. Data were analysed to determine differences in the way students of different gender or academic stage prioritised each of these AWE topics. RESULTS: Of 3220 currently enrolled students, 851 participated in the survey: 79% were female, 17% male, 4% unspecified. Ranking of the AWE topics, from highest to lowest importance, was: neutering, companion animal husbandry, euthanasia, behaviour and training, animal breeding, over servicing in relation to animal needs and cosmetic surgery. Female students consistently ranked competency in AWE issues surrounding neutering more highly than male students (P = 0.006). Students in senior years of study ranked the importance of competency in animal abuse/hoarding (P = 0.048), shelter medicine (P = 0.012) and animal breeding (P = 0.002) less highly than those in junior years. CONCLUSIONS: Australasian veterinary students placed more importance on competency in AWE issues associated with clinical practice (such as neutering and euthanasia) than on professional behaviours (such as over-servicing and animal breeding). However, we consider that emphasis should still be placed on developing graduate competency in the latter categories to reflect growing societal concerns about companion animal over-supply and inappropriate professional conduct. PMID- 28555953 TI - Relationship between sources of pet acquisition and euthanasia of cats and dogs in an animal shelter: a pilot study. AB - OBJECTIVE: Approximately 140,000 unwanted dogs and cats are culled in Australia annually. There is a paucity of information linking sources of pet acquisition with subsequent euthanasia, which may inform evidence-based strategies to reduce euthanasia rates. This pilot study aimed to determine whether there is a higher risk of euthanasia related to the source of acquisition for pets surrendered to an animal shelter. METHODS: Data for 5391 dogs and 5581 cats surrendered to one Queensland shelter between January 2006 and December 2009 were analysed. RESULTS: The main sources of acquisition for owner-surrendered dogs were 'shelter' and 'pet shop' and for owner-surrendered cats were 'own litter' and 'shelter'. Euthanasia rates for different sources varied. For adult dogs, acquisition through newspaper advertisements was associated with the highest euthanasia rate. Adult cats obtained as gifts (from friend or family member) had the highest euthanasia rate. For junior cats, the overwhelming source was the owner's own litter (68% of intake) and only kittens acquired as strays were at significantly higher risk of euthanasia. For both dogs and cats, animals acquired from shelters had lower rates of euthanasia than most other sources, which suggests that shelter-sourced animals may be considered a preferred source for pet acquisition to assist in reducing the number of adoptable pets euthanased. CONCLUSION: There was evidence from the study animal shelter that the risk of euthanasia was related to acquisition source. These findings should be confirmed by prospective studies, which should also investigate the interaction between acquisition source and other factors, using larger data sets from a variety of shelters. PMID- 28555954 TI - Prevalence and effect of Theileria orientalis infection in homebred calves in the Gloucester region of New South Wales, Australia. AB - OBJECTIVES: To examine the prevalence of Theileria orientalis in the Gloucester area of New South Wales and its effect on individual animals. METHODS: Blood samples (EDTA and clotted blood) were collected from a total of 55 calves and their dams from 6 properties over a 16-week period. A total of 202 and 190 blood samples were collected from the calves and dams, respectively, and were examined via blood film for the presence of intraerythrocytic T. orientalis piroplasms. Packed cell volume (PCV) was measured to determine infection resulting in anaemia. The presence of antibodies against the T. orientalis major piroplasm surface protein (MPSP) was tested using ELISA. RESULTS: The overall prevalence of T. orientalis infection in both dams and calves from all herds examined was 95%. Mean peak parasitaemia was observed in calves between 6 and 9 weeks of age (P = 0.051), coinciding with a decline in mean PCV. Only 3 (6%) of the blood samples collected from the dams were positive for Theileria-associated antibodies and no significant relationship (P > 0.05) was found between the presence of antibodies in the dams and PCV levels in the calves. There was no evidence that passive transfer of antibodies from dams to calves protected the calves against a decline in PCV. CONCLUSION: This study confirmed a high prevalence of low-level Theileria infection, but low MPSP seroconversion rates, in dams and calves in an area where the disease has been endemic for a number of years. PMID- 28555955 TI - Mind the gap: financial London and the regional class pay gap. AB - The hidden barriers, or 'gender pay gap', preventing women from earning equivalent incomes to men is well documented. Yet recent research has uncovered that, in Britain, there is also a comparable class-origin pay gap in higher professional and managerial occupations. So far this analysis has only been conducted at the national level and it is not known whether there are regional differences within the UK. This paper uses pooled data from the 2014 and 2015 Labour Force Survey (N = 7,534) to stage a more spatially sensitive analysis that examines regional variation in the class pay gap. We find that this 'class ceiling' is not evenly spatially distributed. Instead it is particularly marked in Central London, where those in high-status occupations who are from working class backgrounds earn, on average, L10,660 less per year than those whose parents were in higher professional and managerial employment. Finally, we inspect the Capital further to reveal that the class pay gap is largest within Central London's banking and finance sector. Challenging policy conceptions of London as the 'engine room' of social mobility, these findings suggest that class disadvantage within high-status occupations is particularly acute in the Capital. The findings also underline the value of investigating regional differences in social mobility, and demonstrate how such analysis can unravel important and previously unrecognized spatial dimensions of class inequality. PMID- 28555956 TI - Physiological functioning moderates infants' sensory sensitivity in higher conflict families. AB - Children exposed to parent conflict may be at risk for emotional and behavioral disorders by becoming sensitized to conflict cues in their environments. This study explored possible precursors to negative child outcomes associated with parent conflict by examining the relation between parent conflict and infants' (N = 36; 23-42 weeks; 44% female) behavioral sensitivity to general sensory stimuli (e.g., loud noises, physical touch). To determine whether infants' characteristic autonomic arousal and regulation moderated this association, infant baseline skin conductance (SC) and respiratory sinus arrhythmia (RSA) were measured. Parents reported levels of parent conflict, and mothers reported infants' behavioral sensory sensitivity. The association between parent conflict and lower threshold for sensory sensitivity was strongest for infants with higher physiological arousal (higher SC) and lesser capacity for physiological regulation (lower RSA). Children may become more sensitive to environmental stimuli as a function of parent conflict during infancy, though this appears to depend on characteristic physiological arousal and regulation. PMID- 28555957 TI - Diethylhexyl phthalate magnifies deposition of 14 C-bisphenol A in reproductive tissues of mice. AB - Endocrine disrupting chemicals are found in diverse common products, including cosmetics, food packaging, thermal receipt paper and plastic containers. This exposes most people in developed countries through ingestion, skin absorption and inhalation. Two ubiquitous endocrine disrupting chemicals, bisphenol A (BPA) and diethylhexyl phthalate (DEHP) can interact in disrupting blastocyst implantation in inseminated females. We hypothesized that DEHP might increase the bioavailability of BPA in tissues by competing for metabolic enzymes. We injected 0, 3, 9 or 18 mg DEHP into female and male mice and allowed 30 min for the chemical to circulate before giving them a food supplement containing 50 MUg kg-1 14 C-BPA. Animals were dissected 1 h following 14 C-BPA administration and various tissue samples were acquired. Samples were solubilized and radioactivity was measured via liquid scintillation counting. In cycling females, DEHP increased BPA deposition in the muscle, uterus, ovaries and blood serum relative to controls. In peri-implantation females, DEHP increased deposition of BPA in the uterus, ovaries and serum relative to controls. In males, DEHP doses increased BPA deposition in serum and epididymis relative to controls. These results are consistent with the hypothesis that DEHP competes with BPA for conjugating enzymes such as UDP-glucuronosyltransferase, thereby magnifying the presence of BPA in estrogen-binding reproductive tissues. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28555958 TI - Industrial Safety and Utopia: Insights from the Fukushima Daiichi Accident. AB - Feedback from industrial accidents is provided by various state or even international, institutions, and lessons learned can be controversial. However, there has been little research into organizational learning at the international level. This article helps to fill the gap through an in-depth review of official reports of the Fukushima Daiichi accident published shortly after the event. We present a new method to analyze the arguments contained in these voluminous documents. Taking an intertextual perspective, the method focuses on the accident narratives, their rationale, and links between "facts," "causes," and "recommendations." The aim is to evaluate how the findings of the various reports are consistent with (or contradict) "institutionalized knowledge," and identify the social representations that underpin them. We find that although the scientific controversy surrounding the results of the various inquiries reflects different ethical perspectives, they are integrated into the same utopian ideal. The involvement of multiple actors in this controversy raises questions about the public construction of epistemic authority, and we highlight the special status given to the International Atomic Energy Agency in this regard. PMID- 28555960 TI - QUANTITATIVE GENETIC ANALYSIS OF TEMPERATURE REGULATION IN MUS MUSCULUS. III. DIALLEL ANALYSIS OF CORRELATIONS BETWEEN TRAITS. PMID- 28555961 TI - MEASUREMENT OF THE RELATIVE IMPORTANCE OF INDIVIDUAL SELECTION AND KIN SELECTION AMONG FEMALES OF THE GENUS MACACA. PMID- 28555959 TI - Design of the Magnetic Resonance Imaging Evaluation of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) Trial. AB - Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating MR antagonism in patients with type 2 diabetes mellitus (T2DM) with chronic kidney disease, at high risk for cardiovascular complications, who are otherwise not candidates for MR antagonism by virtue of heart failure. Further, there is limited information on candidate therapies that may demonstrate differential benefit from this therapy. We hypothesized that MR antagonism may provide additional protection from atherosclerosis progression in higher-risk patients who otherwise may not be candidates for such a therapeutic approach. In this double-blind, randomized, placebo-controlled trial, subjects with T2DM with chronic kidney disease (>= stage 3) will be randomized in a 1:1 manner to placebo or spironolactone (12.5 mg with eventual escalation to 25 mg daily over a 4-week period). The co-primary efficacy endpoint will be percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone vs placebo. Secondary outcomes include 24 hour mean systolic blood pressure, central aortic blood pressure, and insulin resistance (HOMA-IR) at 6 weeks. A novel measure in the study will be changes in candidate miRNAs that regulate expression of NR3C2 (MR gene) as well as measuring monocyte/macrophage polarization in response to therapy with spironolactone. We envision that our strategy of simultaneously probing the effects of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design event-based trials. PMID- 28555962 TI - ESTIMATION OF THE RATE OF GLYCEROL 3-PHOSPHATE DEHYDROGENASE EVOLUTION IN HIGHER VERTEBRATES. PMID- 28555963 TI - THE EVOLUTION OF INSECT MATING SYSTEMS. PMID- 28555964 TI - LIFE HISTORY TRAITS AND NATURAL SELECTION FOR SMALL BODY SIZE IN A POPULATION OF DARWIN'S FINCHES. PMID- 28555965 TI - THE EVOLUTION OF HABITAT PREFERENCE IN SUBDIVIDED POPULATIONS. PMID- 28555966 TI - THE NATURE OF GENETIC VARIATION FOR SPECIES FORMATION. PMID- 28555967 TI - QUANTITATIVE GENETIC ANALYSIS OF TEMPERATURE REGULATION IN MUS MUSCULUS. II. DIALLEL ANALYSIS OF INDIVIDUAL TRAITS. PMID- 28555969 TI - Erratum. PMID- 28555968 TI - QUEEN-WORKER CONFLICT AND EUSOCIAL EVOLUTION IN A POLYGYNOUS ANT SPECIES. PMID- 28555970 TI - ORIGIN AND EXPRESSION OF AN ALCOHOL DEHYDROGENASE GENE DUPLICATION IN THE GENUS DROSOPHILA. PMID- 28555971 TI - REVENGE OF THE UGLY DUCKLING. PMID- 28555973 TI - TRADEOFFS IN PERFORMANCE ON DIFFERENT HOSTS: EVIDENCE FROM WITHIN- AND BETWEEN SITE VARIATION IN THE BEETLE DELOYALA GUTTATA. PMID- 28555974 TI - GENETIC STRUCTURE AND CHANGE IN NATURAL POPULATIONS OF DROSOPHILA ROBUSTA: SYSTEMATIC INVERSION AND INVERSION ASSOCIATION FREQUENCY SHIFTS IN THE GREAT SMOKY MOUNTAINS. PMID- 28555976 TI - SPECIAL ANNOUNCEMENT. PMID- 28555975 TI - ARTIFICIAL SELECTION ON A FITNESS-COMPONENT IN DROSOPHILA MELANOGASTER. PMID- 28555977 TI - A COMMENT ON FITNESS ESTIMATION. PMID- 28555978 TI - 1984 MEETING OF THE AMERICAN SOCIETY OF ZOOLOGISTS and AMERICAN MICROSCOPICAL SOCIETY, ANIMAL BEHAVIOR SOCIETY, BIOLOGICAL SOCIETY OF WASHINGTON, CRUSTACEAN SOCIETY, INTERNATIONAL ASSOCIATION OF ASTACOLOGY, SOCIETY OF SYSTEMATIC ZOOLOGY, AND WESTERN SOCIETY OF NATURALISTS. PMID- 28555979 TI - DROSOPHILA OF THE DESERT. PMID- 28555980 TI - THE LIMITS TO LIFE HISTORY EVOLUTION IN DAPHNIA. PMID- 28555981 TI - THE EFFECT OF MUTAGENESIS ON COMPETITIVE ABILITY IN DROSOPHILA. PMID- 28555982 TI - Society for the Study of Evolution and American Society of Naturalists 1984 Meetings. PMID- 28555983 TI - STILL ANOTHER ATTEMPT TO ACHIEVE ASSORTATIVE MATING BY DISRUPTIVE SELECTION IN DROSOPHILA. PMID- 28555984 TI - ECOLOGICAL CAUSES OF SEXUAL DIMORPHISM. PMID- 28555985 TI - FREQUENCY-DEPENDENT SELECTION ARISING FROM INAPPROPRIATE FITNESS ESTIMATION. PMID- 28555986 TI - ON THE MEASUREMENT OF TOTAL AND SEXUAL SELECTION: A REPLY TO CHRISTIANSEN. PMID- 28555987 TI - COHORT SELECTION. PMID- 28555988 TI - LATERAL PLATE MORPH VARIATION IN CALIFORNIA POPULATIONS OF THE THREESPINE STICKLEBACK, GASTEROSTEUS ACULEATUS. PMID- 28555989 TI - CAN UNIFORM SELECTION RETARD RANDOM GENETIC DIVERGENCE BETWEEN ISOLATED CONSPECIFIC POPULATIONS? PMID- 28555990 TI - THE EVOLUTION OF COOPERATIVE BREEDING BY DELAYED RECIPROCITY AND QUEUING FOR FAVORABLE SOCIAL POSITIONS. PMID- 28555991 TI - FREQUENCY-DEPENDENT MATING? YES. AN ANSWER TO D. J. MERRELL. PMID- 28555992 TI - QUANTITATIVE ANALYSIS OF KARYOTYPE ALTERATION AND SPECIES DIFFERENTIATION IN MAMMALS. PMID- 28555995 TI - Second International Symposium, on the Structure and Functioning of Plant Populations. PMID- 28555993 TI - DENSITY-DEPENDENT POLLINATOR FORAGING, FLOWERING PHENOLOGY, AND TEMPORAL POLLEN DISPERSAL PATTERNS IN LINANTHUS BICOLOR. PMID- 28555996 TI - BEHAVIORAL REPRODUCTIVE ISOLATION AMONG POPULATIONS OF THE ROTIFER BRACHIONUS PLICATILIS. PMID- 28555997 TI - MOLECULAR VARIATION IN INSULAR ENDEMIC DROSOPHILA SPECIES OF THE MACARONESIAN ARCHIPELAGOS. PMID- 28555998 TI - 1983 The Theodosius Dobzhansky Prize Recipient. PMID- 28555999 TI - THE DEVELOPMENTAL GENETIC BASIS OF ORGANISMAL EVOLUTION. PMID- 28556001 TI - CURRENT PROBLEMS IN SOCIOBIOLOGY: AN ADAPTATIONIST REVIEW. PMID- 28556000 TI - GENE FLOW DISTANCES IN NATURAL POPULATIONS OF TETRAOPES TETRAOPHTHALMUS. PMID- 28556002 TI - TEMPERATURE EFFECTS ON LIFE HISTORY VARIATION IN DROSOPHILA SIMULANS. PMID- 28556003 TI - MATING BEHAVIOR AND THE EVOLUTION OF DROSOPHILA MAURITIANA. PMID- 28556004 TI - GENETIC DIFFERENTIATION DURING SPECIATION IN THE HELIANTHUS DEBILIS COMPLEX. PMID- 28556005 TI - THE RELATION OF GROWTH TO HETEROZYGOSITY IN PITCH PINE. PMID- 28556006 TI - SEXUAL REPRODUCTION: AN ADAPTATION REDUCING PARENT-OFFSPRING CONTAGION. PMID- 28556008 TI - George Gaylord Simpson Prize. PMID- 28556007 TI - A UNIQUE APPROACH TO THE EVOLUTION OF SEX. PMID- 28556009 TI - FLORAL VARIATION AND SEXUAL DIFFERENTIATION IN MUNTINGIA CALABURA (ELAEOCARPACEAE), A SPECIES WITH HERMAPHRODITE FLOWERS. PMID- 28556010 TI - GENETIC BASIS OF DIFFERENCES IN GENITAL MORPHOLOGY AMONG THREE SIBLING SPECIES OF DROSOPHILA. PMID- 28556012 TI - Society for the Study of Evolution and American Society of Naturalists 1984 Meetings. PMID- 28556011 TI - THE MEASUREMENT OF SELECTION ON CORRELATED CHARACTERS. PMID- 28556013 TI - International Organization of Plant Biosystematists. PMID- 28556015 TI - POLLEN DISPERSAL BY HUMMINGBIRDS AND BUTTERFLIES: A COMPARATIVE STUDY OF TWO LOWLAND TROPICAL PLANTS. PMID- 28556014 TI - A SIMPLE MENDELIAN MODEL FOR 13- AND 17- YEAR LIFE CYCLES OF PERIODICAL CICADAS, WITH HISTORICAL EVIDENCE OF HYBRIDIZATION BETWEEN THEM. PMID- 28556017 TI - THE INHERITANCE OF QUANTITATIVE FITNESS TRAITS IN GUPPIES, POECILIA RETICULATA (PISCES: POECILIIDAE). PMID- 28556018 TI - RARE MALE MATING DISADVANTAGE IN DROSOPHILA MELANOGASTER. PMID- 28556020 TI - The Theodosius Dobzhansky Prize. PMID- 28556019 TI - A MOLECULAR PHYLOGENETIC PERSPECTIVE ON THE ORIGINS OF A LOWLAND TROPICAL SALAMANDER FAUNA. II. PATTERNS OF MORPHOLOGICAL EVOLUTION. PMID- 28556021 TI - Hereditary progressive mucinous histiocytosis: 3 different phenotypes in 3 family members. AB - We describe 3 cases of multiple histiocytic cutaneous tumors that began in childhood and affected 3 members from 2 generations of the same family: a mother, a daughter and a nephew. The lesions were mostly skin-colored papules distributed symmetrically on the dorsum of the forearms and hands and on the face and thighs. There were no signs of spontaneous regression. The clinical and histopathological features were consistent with a diagnosis of hereditary progressive mucinous histiocytosis (HPMH), but phenotypic expression varied somewhat between the 3 patients. HPMH has only been described in 8 families to date, and just one of the reports included 3 well-documented cases. Our cases confirm that HPMH can affect males and expands the clinical spectrum of skin lesions in this disease. PMID- 28556022 TI - Predictors of premature termination from psychotherapy for anorexia nervosa: Low treatment credibility, early therapy alliance, and self-transcendence. AB - OBJECTIVE: Failure to complete treatment for anorexia nervosa (AN) is- common, clinically concerning but difficult to predict. This study examines whether therapy-related factors (patient-rated pretreatment credibility and early therapeutic alliance) predict subsequent premature termination of treatment (PTT) alongside self-transcendence (a previously identified clinical predictor) in women with AN. METHODS: 56 women aged 17-40 years participating in a randomized outpatient psychotherapy trial for AN. Treatment completion was defined as attending 15/20 planned sessions. Measures were the Treatment Credibility, Temperament and Character Inventory, Vanderbilt Therapeutic Alliance Scale and the Vanderbilt Psychotherapy Process Scale. Statistics were univariate tests, correlations, and logistic regression. RESULTS: Treatment credibility and certain early patient and therapist alliance/process subscales predicted PTT. Lower self transcendence and lower early process accounted for 33% of the variance in predicting PTT. DISCUSSION: Routine assessment of treatment credibility and early process (comprehensively assessed from multiple perspectives) may help clinicians reduce PTT thereby enhancing treatment outcomes. PMID- 28556023 TI - Index report of cutaneous angiosarcomas with strong positivity for tyrosinase mimicking melanoma with further evaluation of melanocytic markers in a large angiosarcoma series. AB - Cutaneous angiosarcoma can be challenging to diagnose particularly when poorly vasoformative and studied on biopsies. We report a case of a cutaneous angiosarcoma with strong positivity for tyrosinase, the first to our knowledge, initially misdiagnosed as melanoma. We subsequently evaluated the reactivity of panmelanocytic cocktail (tyrosinase, HMB-45 and Melan-A), SOX10, tyrosinase and MITF in a large tissue microarray (TMA) of angiosarcoma. The TMA included 142 cases of angiosarcomas (29 cutaneous, 22 primary breast, 41 post-radiation breast, 15 visceral, 26 deep soft tissue and bone, 5 chronic lymphedema associated and 4 angiosarcomas arising in other sarcomas). Immunohistochemical studies were performed with anti-panmelanocytic cocktail, anti-SOX10, anti-MITF and anti-tyrosinase antibodies. TMA staining results were scored on intensity and percentage of tumoral labeling. Aside from the index case, no cases (0 of 133) showed positivity for tyrosinase including 28 cutaneous angiosarcomas. One breast angiosarcoma (1 of 131) was positive for MITF. All cases were negative for SOX10 and panmelanocytic cocktail (0 of 132). Angiosarcomas can rarely be positive for tyrosinase and MITF. Pathologists should be cognizant of these rare exceptions to prevent confusion with melanoma. Additional immunohistochemical markers for vascular and melanocytic differentiation, thorough histological examination for vasoformative and in situ areas as well as clinical impression are helpful in these exceptionally problematic cases. PMID- 28556024 TI - Cancer of the esophagus and esophagogastric junction-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. AB - Answer questions and earn CME/CNE New to the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual for epithelial cancers of the esophagus and esophagogastric junction are separate, temporally related cancer classifications: 1) before treatment decision (clinical); 2) after esophagectomy alone (pathologic); and 3) after preresection therapy followed by esophagectomy (postneoadjuvant pathologic). The addition of clinical and postneoadjuvant pathologic stage groupings was driven by a lack of correspondence of survival, and thus prognosis, between both clinical and postneoadjuvant pathologic cancer categories (facts about the cancer) and pathologic categories. This was revealed by a machine-learning analysis of 6-continent data from the Worldwide Esophageal Cancer Collaboration, with consensus of the AJCC Upper GI Expert Panel. Survival is markedly affected by histopathologic cell type (squamous cell carcinoma and adenocarcinoma) in clinically and pathologically staged patients, requiring separate stage grouping for each cell type. However, postneoadjuvant pathologic stage groups are identical. For the future, more refined and granular data are needed. This requires: 1) more accurate clinical staging; 2) innovative solutions to pathologic staging challenges in endoscopically resected cancers; 3) integration of genomics into staging; and 4) precision cancer care with targeted therapy. It is the responsibility of the oncology team to accurately determine and record registry data, which requires eliminating both common errors and those related to incompleteness and inconsistency. Despite the new complexity of eighth edition staging of cancers of the esophagus and esophagogastric junction, these key concepts and new directions will facilitate precision cancer care. CA Cancer J Clin 2017;67:304-317. (c) 2017 American Cancer Society. PMID- 28556025 TI - Determination of Controlled Self-Assembly of a Paracrystalline Material by Homology Modelling with Hybrid NMR and TEM. AB - Controlling complexity, flexibility, and functionality of synthetic and biomimetic materials requires insight into how molecular functionalities can be exploited for steering their packing. A fused NDI-salphen (NDI=naphthalene diimide) prototypic artificial photosynthesis material, DATZnS, is shown to be comprised of a phenazine motif, in which the alignment of electric dipole moments in a P2/c supramolecular scaffold can be modulated with bulky substituents. They can also be switched between parallel stacks of dipoles running antiparallel in the DATZnS-H compared with parallel stacks of dipoles in polar layers running in opposite directions in the DATZnS(3'-NMe) parent compound. Spatial correlations obtained from HETCOR spectra, collected with a long cross polarization contact time of 2 ms, reveal an antiparallel stacking for the DATZnS-H homologue. These constraints and limited data from TEM are used to construct a structural model within the P2/c space group determined by the molecular C2 symmetry. By using homology modelling, a pseudo octahedral coordination of the Zn is shown to follow the packing-induced chirality with enantiomeric pairs of the Lambda and Delta forms alternating along antiparallel stacks. The model helps to understand how the steric hindrance modulates the self-assembly in this novel class of fused materials by steric hindrance at the molecular level. PMID- 28556027 TI - DISPERSAL AND PLANT MATING SYSTEMS: THE EVOLUTION OF SELF-FERTILIZATION IN SUBDIVIDED POPULATIONS. AB - Intermediate rates of self-fertilization can be evolutionarily stable when the progeny of self-fertilization events are less successful migrants than those of outcrossing events, unless self-fertilization reduces an individual's contribution to the pollen pool by an amount equal to the rate at which it self fertilizes. This result holds regardless of whether pollen or diaspores are more widely dispersed. The differential migration of selfed and outcrossed progeny may be a result of differential establishment with comparable rates of dispersal, or it may be a result of differential dispersal rates. In the first case, detailed predictions concerning the evolutionarily stable selfing rate can be made. In the second case, only qualitative predictions are possible in the absence of specific assumptions about how the migration rate is affected by the average selfing rate in each subpopulation. PMID- 28556026 TI - Preclinical pilot study monitoring topical drug penetration and dermal bioavailability of a peptidase inhibitor from different galenic formulations into pig dermis, using cutaneous microdialysis. AB - BACKGROUND: Cutaneous microdialysis (CM) is an ex vivo technique that allows study of tissue chemistry, including bioavailability of actual tissue concentration of unbound drug in the interstitial fluid of the body. AIM: To test the penetration and dermal bioavailability of galenic formulations of the small molecule IP10.C8, a dual-protease inhibitor of the dipeptidyl peptidase and aminopeptidase families. METHODS: Using CM, we tested the penetration and dermal bioavailability of IP10.C8 into the dermis and subcutis of pigs, and determined the tissue concentration of IP10.C8 enzymatically, using an enzyme activity assay (substrate Gly-Pro-pNA) and high performance liquid chromatography. RESULTS: Dermal bioavailability was enhanced by using microemulsion or the addition of the penetration enhancer oleic acid to a hydroxyethylcellulose (HEC) gel formulation. Dermal bioavailability was also enhanced when galenic formulations were prepared with higher pH (7.5 vs. 6.5) or higher drug concentration (5% vs. 1%) in HEC gel. CONCLUSION: It seems possible, using CM for topical skin penetration testing in anaesthetized domestic pigs, to test the bioavailability of newly designed drugs. However, the experimental time is limited due to the anaesthesia, and is dependent on drug recovery. Validation of this technique for routine use is challenging, and more experiments are needed to validate this preclinical set-up. PMID- 28556028 TI - THE NEOLITHIC TRANSITION AND THE GENETICS OF POPULATIONS IN EUROPE: A REVIEW. PMID- 28556029 TI - LOW GENIC DIFFERENTIATION AMONG ISOLATED POPULATIONS OF THE CALIFORNIA FAN PALM (WASHINGTONIA FILIFERA). AB - The purpose of this study was to assess the relative roles of population size and geographic isolation in determining population-genetic structure. Using electrophoretic techniques to quantify allozymic variation at 16 genetic loci, we measured genic variation within and among 16 natural populations of the California fan palm (Washingtonia filifera). Genotypes were determined for every individual in each population so that parametric values rather than sample estimates for measures of genic variability were obtained. Palm populations displayed low levels of within-population variability. The proportion of polymorphic loci and observed heterozygosity were 0.098 and 0.009 per population, respectively. Population size displayed a significant positive correlation with proportion of polymorphic loci, but not with observed heterozygosity. Low levels of genetic differentiation among populations were demonstrated by an F-statistic analysis and the computation of genetic similarity values. A hierarchical analysis of gene diversity revealed that only about 2% of the total gene diversity in W. filifera resides as among-population diversity. Climatic and geological changes since the Pliocene have eliminated widespread palm populations, and the species is presently restricted to isolated locations around the Colorado Desert. Existing populations in southern California are either relicts or recent recolonizations resulting from the dispersal of seeds from a refugium population in Baja California, Mexico. The observed patterns of low within- and low among-population genic diversity seem most consistent with a recent colonization by fan palms. It is hypothesized that stochastic processes reduced levels of genic variability in this refugium population during its formation. Dispersal of seeds from this refugium into suitable habitats in the Colorado Desert would produce populations with low variability and high genetic similarity because of their common ancestry. However, low intrapopulation variability and genetic homogeneity across populations could be the product of uniform selection pressures favoring a narrow array of specialized genotypes in either relict or colonizing populations. PMID- 28556030 TI - PARTIAL NICHE SEPARATION IN SPINACIA OLERACEA L.: AN EXAMINATION OF REPRODUCTIVE ALLOCATION. PMID- 28556031 TI - SYMPOSIUM TO HONOR G. LEDYARD STEBBINS. PMID- 28556032 TI - PREDATOR-INDUCED SHELL DIMORPHISM IN THE ACORN BARNACLE CHTHAMALUS ANISOPOMA. AB - Field experiments were conducted in order to determine the nature of shell dimorphism in the acorn barnacle Chthamalus anisopoma and the adaptive significance of the atypical form. The typical morph has the conical shape which is characteristic of acorn barnacles, while the atypical morph appears bent over, with the rim of its aperture oriented perpendicular to its base. The experiments showed that: 1) the bent-over morphology is an environmentally-induced developmental response to the presence of a carnivorous gastropod (Acanthina angelica) and 2) that "bents" are more resistant than "conics" to specialized predation by this snail. The results also showed that predation by A. angelica is patchy and heaviest in the near vicinity of cracks and crevices, which it uses as refuges during periods of tidal inundation. Because predation is patchy and bents are less fecund and grow slower than conics, the conditional developmental strategy is likely to be favored over strict genetical control of shell morphology. PMID- 28556033 TI - VARIATION IN CONTRIBUTIONS OF ASEXUAL REPRODUCTION TO THE GENETIC STRUCTURE OF POPULATIONS OF THE SEA ANEMONE METRIDIUM SENILE. AB - Northeastern North American populations of the sea anemone Metridium senile show marked differences in levels of genotypic diversity. Comparisons with expectations generated by computer simulation show that some populations are genotypically as diverse as expected for sexually reproducing populations with free recombination, whereas others are significantly less diverse than expected, despite efforts to avoid collecting clonemates. These reductions in diversity are not attributable to the Wahlund effect; they probably result from extensive clonal reproduction. Reduced genotypic diversity may be produced by low rates of recruitment of planktonic larvae, followed by asexual proliferation. The resulting founder effect may account for previously documented random allele frequency variation between adjacent populations. It is presently uncertain whether the few genotypes found in some populations are particularly well-adapted to local conditions. PMID- 28556035 TI - MORPHOLOGICAL EVOLUTION. PMID- 28556034 TI - GENETIC VARIATION OF ASCARIDOID WORMS WITH DIFFERENT LIFE CYCLES. PMID- 28556036 TI - COMPARISON OF POPULATION STRUCTURE IN CHROMOSOMALLY POLYTYPIC AND MONOTYPIC SPECIES OF SCELOPORUS (SAURIA: IGUANIDAE) IN RELATION TO CHROMOSOMALLY-MEDIATED SPECIATION. AB - Sceloporus grammicus has been used as an example of stasipatric speciation, and some models of chromosomal speciation have assumed that the fission rearrangements which distinguish the chromosome races within this complex are negatively heterotic in the heterozygous state. Consequently, such rearrangements are assumed to be fixed by drift in small, inbred populations. Allelic variation at 19 presumptive gene loci was examined in 13 samples of a chromosomally conservative congener, Sceloporus graciosus, and was compared to an equivalent data set for the chromosomally polytypic S. grammicus. Several estimates of population variability and structure were calculated, and results were inconsistent with models of extreme population subdivision and/or frequent bottlenecks and extinction-colonization events in S. grammicus. For example, mean level of heterozygosity and mean number of alleles per locus were significantly higher in S. grammicus than in S. graciosus, while the average genetic distance (D) was significantly higher in S. graciosus. These results are considered in light of expected "Wrightian" population genetic parameters, and we conclude that S. grammicus does not seem to have the population structure necessary for the fixation of strongly negatively heterotic rearrangements. PMID- 28556037 TI - PHYLETIC PHENOCOPIES: A USEFUL TECHNIQUE FOR PROBING THE GENETIC AND DEVELOPMENTAL BASIS OF EVOLUTIONARY CHANGE. PMID- 28556038 TI - GOOD NEWS! PMID- 28556039 TI - NATURAL SELECTION ON BEAK AND BODY SIZE IN THE SONG SPARROW. AB - We documented temporal patterns of natural selection on beak and body traits in a song sparrow population. We looked for evidence of selection in association with reproduction and overwinter survival in order to identify the conditions under which size in beak and body traits is adaptive. We also attempted to identify the specific traits most closely associated with fitness under these conditions. Selection was observed in association with both survival and reproduction. Patterns of selection differed between the sexes. Selection on males was weak and stabilizing in association with overwinter survival. Selection on females was strong, was both stabilizing and directional, and was associated with both survival and reproduction. In females, traits that enhanced juvenile survival also reduced reproductive success; i.e., there was a trade-off between survival and reproduction. Patterns of selection in the song sparrow parallel those reported for the Galapagos finch, Geospiza fortis. However, in song sparrows, selection occurred mainly on tarsus length and beak length, and not on beak depth or width as in G. fortis. This difference may occur because most North American sparrows partition food resources by habitat, while most Galapagos ground finches partition food by seed size. PMID- 28556040 TI - SEX-RATIO CONTROL IN A PARASITIC WASP, NASONIA VITRIPENNIS. II. EXPERIMENTAL ANALYSIS OF AN OPTIMAL SEX-RATIO MODEL. AB - An optimal theory of facultative sex-ratio adjustment (Werren, 1980) was tested using the data from a series of sequential oviposition experiments (Orzack and Parker, 1986). Sex ratios produced by several genotypes in previously parasitized hosts differ significantly from the theoretical prediction. In addition, there is more variance of these "second" sex ratios than would be generated purely by sampling. I outline an alternative model of sex-ratio determination, based upon an imperfect ability of second females to detect previous parasitization, which accounts for the trends observed in the data. These results imply that selection on second sex ratios is weak or that females cannot control sex ratios finely enough to manifest the proper response. This analysis along with other results (Orzack and Parker, 1986; Parker and Orzack, 1985; Grant et al., 1974; Werren et al., 1981; Skinner, 1982) suggests that we need a more comprehensive theory of sex-ratio evolution, one which accounts for the diversity of first and second sex ratio phenotypes in this species. PMID- 28556041 TI - MODE OF POLLINATION AND SELECTION ON MATING SYSTEM: A COMMENT ON AIDE'S PAPER. PMID- 28556042 TI - DISRUPTIVE SELECTION ON BODY WEIGHT IN DROSOPHILA MELANOGASTER. AB - Disruptive selection can have two consequences in a population: the rise of polymorphism or the divergence of the population. Divergence creates subpopulations which can be sexually isolated. Previous studies have shown that these consequences depend on the pattern of mate choices by the individuals. We have studied the effects of different patterns of mating (free mating, enforced random mating and enforced assortative mating) in a population of Drosophila melanogaster subjected to disruptive selection on body weight. Disruptive selection increased the weight dispersion in all mating patterns but brought about divergence within the population only when it occurred in association with enforced assortative mating (without complete sexual isolation between the subpopulations). When mating was free, the dispersion, measured by change in the coefficient of variation, was only somewhat larger than with enforced random mating: thus the principal consequence of disruptive selection was the rise of polymorphism in the population. PMID- 28556043 TI - ALLOZYME AND MORPHOLOGICAL DIFFERENTIATION OF MOUNTAIN PINE BEETLES DENDROCTONUS PONDEROSAE HOPKINS (COLEOPTERA: SCOLYTIDAE) ASSOCIATED WITH HOST TREE. AB - The purpose of this study was to determine whether mountain pine beetles utilizing different host species were differentiated for either morphological or protein variation. Genetic differentiation among host species has been reported for the southern pine beetle, the Douglas-fir beetle, the jeffrey pine beetle, and the mountain pine beetle. However, in these studies, the host trees were sampled at separate sites, and hence geographic variation and variation due to host tree were confounded. The mountain pine beetle occasionally utilizes three host trees (ponderosa pine, lodgepole pine, and limber pine) at single sites in Colorado. Five polymorphic enzyme loci and six morphological characters were used to describe beetles resident in different hosts. Differentiation within a site among host trees was detected at two of five polymorphic proteins, and for both size and morphological shape. The magnitude of genetic differentiation among hosts within a site was approximately equivalent to the magnitude of differentiation among sites. These data suggest that the species of host tree may be an important biotic factor associated with the genetic structure of bark beetle communities. The results are discussed in terms of their potential role in the process of speciation by host race formation. PMID- 28556045 TI - SSE MEETINGS: CALL FOR PROPOSALS. PMID- 28556044 TI - DISJUNCTIVE CLINE OF CRITICAL PHOTOPERIOD IN THE REPRODUCTIVE DIAPAUSE OF DROSOPHILA LACERTOSA. PMID- 28556046 TI - SEX-RATIO CONTROL IN A PARASITIC WASP, NASONIA VITRIPENNIS. I. GENETIC VARIATION IN FACULTATIVE SEX-RATIO ADJUSTMENT. AB - The precision of sex-ratio control in a parasitic wasp, Nasonia vitripennis (Pteromalidae) was investigated using a series of "sequential oviposition" experiments in which a female oviposits on hosts previously visited by another female. There are clear genotypic differences in the averages of these "second" sex ratios. Indeed, one genotype does not alter sex ratio detectably. Two genotypes with identical average sex ratios on previously unparasitized hosts have distinct second sex ratios. Artificial selection on one strain to produce less female-biased "first" sex ratios in previously unparasitized hosts has not affected the ability of that strain to adjust sex ratio, suggesting that the proximal mechanisms controlling first and second sex ratios can change independently. Adjustment of sex ratios is accomplished by the production of fewer females and more males. Sex ratios produced in control hosts indicate that sex ratios are adjusted in hosts independently of one another. Second sex-ratio response also appears to be independent of host clumping. These results represent both a challenge to our present understanding of sex-ratio evolution (see Orzack, 1986) and a foundation for experimental description of this important adaptation. PMID- 28556047 TI - THE INFLUENCE OF WIND AND ANIMAL POLLINATION ON VARIATION IN OUTCROSSING RATES. PMID- 28556049 TI - THE REPRODUCTIVE RELATIONSHIPS OF DROSOPHILA SECHELLIA WITH D. MAURITIANA, D. SIMULANS, AND D. MELANOGASTER FROM THE AFROTROPICAL REGION. AB - Hybridization tests among the four sibling species of the Drosophila melanogaster complex were made to determine the reproductive status of the recently discovered D. sechellia (which is endemic to a few islands and islets of the Seychelles archipelago) with regard to its three close relatives, D. mauritiana (endemic to Mauritius) and Afrotropical strains of the two cosmopolitan species D. melanogaster and D. simulans. Interstrain variation in the ability to hybridize with other species was also analyzed for D. melanogaster and D. simulans. D. mauritiana and D. simulans appear to be more weakly isolated from each other than either species is from D. sechellia. A striking unilateral mating success is observed in the cross of D. sechellia with D. simulans. The most extreme isolation is between D. melanogaster and its three siblings. Variation in the ability of strains to hybridize is observed in heterospecific crosses between D. simulans and either D. melanogaster or D. mauritiana. PMID- 28556050 TI - INBREEDING AND THE COST OF MEIOSIS: THE EVOLUTION OF SELFING IN POPULATIONS PRACTICING BIPARENTAL INBREEDING. AB - The effect of biparental inbreeding on the conditions governing the evolution of selfing is examined using recursions in mating-type frequencies. Sibmating in combination with random outcrossing influences two key determinants of the adaptive value of selfing: 1) the meiotic cost of biparental reproduction and 2) the level of inbreeding depression due to deleterious mutations. Biparental inbreeding serves to maintain biparental reproduction by increasing relatedness between parents and their biparentally derived offspring and introduces the possibility of an optimal mating system that incorporates both modes of reproduction. Biparental inbreeding serves to promote uniparental reproduction by reducing the relative inbreeding depression suffered by uniparental offspring. The net effect of these two antagonistic trends depends upon the extent to which mutational load accounts for differences in the numbers of the two types of offspring. A brief summary of the empirical literature suggests that: 1) biparental inbreeding may occur in populations exhibiting mixed mating systems; 2) while inbreeding depression represents an important factor, it does not account entirely for differences in offspring number between the two modes of reproduction. PMID- 28556051 TI - FACTORS INFLUENCING FREQUENCY OF THE MID-STYLED MORPH IN TRISTYLOUS POPULATIONS OF OXALIS ALPINA. AB - Genetic models and computer simulations suggest that modifications of incompatibility in tristylous populations of Oxalis alpina from southeastern Arizona should result in evolution of distyly, due to the inability of the mid floral morph to compete effectively with the short and long floral morphs. To evaluate this hypothesis, progeny testing of naturally pollinated individuals was carried out over a three-year period for populations with differing mid frequencies. In contrast to expectations, mids appeared in greater than expected proportions in many cases. Detailed analysis of results from two trimorphic populations where the mid form is relatively uncommon revealed that mid morphs produced far more mid progeny among their offspring than expected. Assuming that all compatible pollen has the same probability of deposition on appropriate stigmas, mid excesses were found among progeny of shorts and longs in these populations as well. In a third population where the mid form is abundant, mid excesses were not found among the progeny of mids, nor were mid excesses typical among the progeny of shorts and longs. Mid excesses among progeny of populations where the mid form is uncommon may explain retention of this form, despite incompatibility modifications that should favor evolution of distyly. Over representation of mids may result from gametophytic selection favoring mid alleles. If this is the case, tristylous populations may be in equilibrium, with the frequencies of the three morphs determined by the balance of the opposing selective forces resulting from incompatibility modifications and gametophytic selection. PMID- 28556052 TI - SEED SIZE VARIABILITY: A CONSEQUENCE OF VARIABLE GENETIC QUALITY AMONG OFFSPRING? PMID- 28556053 TI - EARLY HISTORY OF SEXUAL SELECTION THEORY. PMID- 28556054 TI - DEVELOPMENTAL STABILITY OF RAINBOW TROUT HYBRIDS: GENOMIC COADAPTATION OR HETEROZYGOSITY? AB - I compare the developmental stability of first generation hybrids between hatchery strains of rainbow trout (Salmo gairdneri) to that of the three pure parental strains raised in a common environment. Two of three reciprocal hybrid pairs show significantly less fluctuating asymmetry of four meristic characters than is found in parental strains. In contrast, the third hybrid pair shows reduced but not significantly lower developmental stability compared to pure strains. These hybrids had previously been found to develop slower than their maternal parental strains, indicating divergence of parental regulatory mechanisms controlling early ontogeny. A significant positive association between the degree of relative delay in hybrid developmental rate and their degree of developmental instability supports this view. For example, the only hybrid pair with decreased developmental stability also had the largest relative delay in development time of all hybrids. Neither absolute developmental rate nor enzyme heterozygosity at 42 loci alone can explain the degree of fluctuating asymmetry in these hybrids. The developmental stability of hybrids is apparently a result of the interaction between the developmental divergence between parental strains and their genomic heterozygosity due to hybridization. PMID- 28556055 TI - SELF-INCOMPATIBILITY IN THE HAWAIIAN MADIINAE (COMPOSITAE): AN EXCEPTION TO BAKER'S RULE. PMID- 28556056 TI - ANNUAL MEETING SOCIETY FOR THE STUDY OF EVOLUTION. PMID- 28556057 TI - CRANIAL MORPHOLOGY OF DOMESTIC AND WILD CANIDS: THE INFLUENCE OF DEVELOPMENT ON MORPHOLOGICAL CHANGE. AB - The domestic dog varies remarkably in cranial morphology. In fact, the differences in size and proportion between some dog breeds are as great as those between many genera of wild canids. In this study, I compare patterns of intracranial allometry and morphologic diversity between the domestic dog and wild canid species. The results demonstrate that the domestic dog is morphologically distinct from all other canids except its close relatives, the wolf-like canids. Following this, I compare patterns of static and ontogenetic scaling. Data on growth of domestic dogs are presented and used to investigate the developmental mechanisms underlying breed evolution. Apparently, most small breeds are paedomorphic with respect to certain morphologic characters. In dogs and other domestic animals, morphologic diversity among adults seems to depend on that expressed during development. PMID- 28556058 TI - ON THE COEXISTENCE AND COEVOLUTION OF ASEXUAL AND SEXUAL COMPETITORS. AB - The coexistence and coevolution of sexual and asexual species under resource competition are explored with three models: a nongenetic ecological model, a model including single locus genetics, and a quantitative-genetic model. The basic assumption underlying all three models is that genetic differences are translated into ecological differences. Hence if sexual species are genetically more variable, they will be ecologically more variable. Under classical competition theory, this increased ecological variability can, in many cases, be an advantage to individual sexual genotypes and to the sexual species as a whole. The purpose of this paper is to determine the conditions when this advantage will outway three disadvantages of sexuality: the costs of males, of segregation, and of the additive component of recombination. All three models reach similar conclusions. Although asexuality confers an advantage, it is much less than a two fold advantage because minor increases in the overall species niche width of the sexual species will offset the reproductive advantage of the asexual species. This occurs for two reasons. First, an increase in species niche width increases the resource base of the sexual species. Second, to the extent that the increase in niche width is due to increased differences between individuals, a reduction in intraspecific competition will result. This is not to imply that the sexual species will always win. The prime conditions that enable sexual species to stably coexist with or even supplant an asexual sister species are: relatively high between-genotype (but within-species) niche differentiation; significant niche differences between the species; low environmental variance; severe resource exploitation; larger within-phenotype niche width in the sexual species than in the asexual species. Spatial or temporal heterogeneities are not required in this model. This is an important difference between this model and other models for sexual advantage. Instead, depletion of resources used by common genotypes creates a rare-genotype advantage. The sexual species, with its great diversity of genotypes, is better equipped to capture this advantage. Although the mechanisms of our model are framed in terms of competition for shared resources, the important factor is that it generates frequency-dependent fitnesses. Other frequency-dependent ecological mechanisms, such as shared predators with functional responses, or shared genotypically-specific parasites, would work as well. PMID- 28556059 TI - MEASURING THE MULTIPLE INSEMINATION FREQUENCY OF DROSOPHILA IN NATURE: USE OF A Y LINKED MOLECULAR MARKER. PMID- 28556060 TI - The value of a comprehensive natural history in late infantile CLN5 disease. PMID- 28556062 TI - Clinical and microbiological effects of the adjunctive use of probiotics in the treatment of gingivitis: A randomized controlled clinical trial. AB - AIM: To evaluate the efficacy of a probiotic combination in the treatment of gingivitis and to assess its impact on the subgingival microbiota. MATERIALS AND METHODS: A placebo-controlled clinical trial was conducted in gingivitis subjects during 6 weeks. Test treatment consisted of the administration of two oral tablets per day containing the probiotic strains Lactobacillus plantarum, Lactobacillus brevis and Pediococcus acidilactici; the control group received the same tablets but without live bacteria. The main outcome variable was the changes in gingival index (GI). Subgingival samples were collected and analysed by quantitative polymerase chain reaction (qPCR) for five putative periodontal pathogens. Outcome variables were compared between and within groups, and multiple regression analysis was performed. RESULTS: A total of 59 patients (29 tests, 30 placebos) were included in the analysis. Both treatment groups experienced a statistically significant improvement in mean GI (p < .0001), but no differences between treatment groups were found for any clinical index. A significantly higher reduction in the number of sites with higher GI scores (GI = 3 at baseline) was observed in the test group. In subgingival samples, a significant reduction in T. forsythia was significant only in the test group (p < .008). CONCLUSIONS: The use of probiotic tablets containing L. plantarum, L. brevis and P. acidilactici did not lead to significant changes in mean GI; although a significant reduction occurred in the number of sites with severe inflammation. Furthermore, the adjunctive use of this probiotic promoted a significant microbiological impact. PMID- 28556064 TI - DISTANCE METHODS FOR INFERRING PHYLOGENIES: A JUSTIFICATION. PMID- 28556063 TI - GENETIC EVIDENCE FOR ALLOPATRIC AND SYMPATRIC DIFFERENTIATION AMONG COLOR MORPHS OF A LAKE MALAWI CICHLID FISH. PMID- 28556065 TI - CHANGES IN COROLLA COLOR AND OTHER FLORAL CHARACTERISTICS IN CRYPTANTHA HUMILIS (BORAGINACEAE): CUES TO DISCOURAGE POLLINATORS? PMID- 28556061 TI - Acetylsalicylic acid in critically ill patients: a cross-sectional and a randomized trial. AB - BACKGROUND: Despite decades of clinical use, the pharmacokinetics and the effects of acetylsalicylic acid (ASA) in critically ill patients remain ill-defined. We aimed to investigate the pharmacokinetics and the effects of different ASA formulations during critical illness. DESIGN: A cross-sectional study and a randomized, parallel-group trial were performed. Critically ill patients under chronic oral ASA treatment (100 mg enteric-coated) were screened for high 'on treatment' platelet reactivity (HTPR) according to arachidonic acid-induced whole blood aggregometry. Thirty patients with HTPR were randomized to receive 100 mg ASA intravenously, 100 mg enteric-coated ASA bid (bis in die) or 81 mg chewable ASA (n = 10 per group). Serum thromboxane B2 (TXB2) levels, ASA and salicylic acid levels were quantified. RESULTS: Of 66 patients, 85% (95% confidence intervals 74-93%) had HTPR. Compared to baseline infusion of 100 mg, ASA significantly reduced platelet aggregation after 24 h to median 80% (Quartiles: 66-84%). Intake of 81 mg chewable ASA significantly reduced platelet aggregation to 75% (54-86%) after four hours, but increased it to 117% after 24 h (81-163%). Treatment with 100 mg enteric-coated ASA bid decreased platelet aggregation after 24 h to median 56% (52-113%). Baseline TXB2 levels were median 0.35 ng/mL (0.07 0.94). Infusion of ASA or intake of 100 mg ASA bid reduced TXB2 levels to 0.07 0.18 ng/mL after 24 h, respectively. Chewable ASA reduced TXB2 levels only transiently. Pharmacokinetic analysis revealed highly variable absorption patterns of oral ASA formulations. CONCLUSION: There is a very high prevalence of HTPR in critically ill patients on peroral ASA therapy, caused by an incomplete suppression of TXB2 and/or by impaired absorption of ASA. PMID- 28556066 TI - BIOGEOGRAPHIC ROOTS. PMID- 28556067 TI - STATIC AND EVOLUTIONARY ALLOMETRY OF OSTEOMETRIC TRAITS IN SELECTED LINES OF RATS. PMID- 28556068 TI - EVIDENCE FOR SELECTIVE FRUIT PRODUCTION IN ASCLEPIAS. PMID- 28556069 TI - FIGHTING AND ASSESSMENT IN HARPOBITTACUS SCORPIONFLIES. PMID- 28556070 TI - ONTOGENY AND PHYLOGENY IN HORSE SKULL EVOLUTION. PMID- 28556071 TI - INBREEDING DEPRESSION AND PROXIMITY-DEPENDENT CROSSING SUCCESS IN PHLOX DRUMMONDII. PMID- 28556072 TI - BIOLOGICAL INTERACTIONS. PMID- 28556073 TI - CONDITIONAL NEUTRALITY OF POLYGENE EFFECTS. PMID- 28556074 TI - DISTRIBUTIONAL AND ECOLOGICAL DIFFERENTIATION BETWEEN ASEXUAL GYNOGENETIC PLANTHOPPERS AND RELATED SEXUAL SPECIES OF THE GENUS MUELLERIANELLA (HOMOPTERA, DELPHACIDAE). PMID- 28556075 TI - GENETIC DIVERGENCE UNDER UNIFORM SELECTION. I. SIMILARITY AMONG POPULATIONS OF DROSOPHILA MELANOGASTER IN THEIR RESPONSES TO ARTIFICIAL SELECTION FOR MODIFIERS OF ciD. PMID- 28556076 TI - THE GENETIC STRUCTURE OF A CYCLICAL PARTHENOGEN. PMID- 28556077 TI - GENETICS, SPECIATION AND THE FOUNDER PRINCIPLE. PMID- 28556078 TI - GENETIC VARIATION AND DIVERGENCE IN A DISJUNCT PHLOX. PMID- 28556079 TI - A COMPARISON BETWEEN QUANTITATIVE AND BIOCHEMICAL VARIATION IN THE WILD BARLEY HORDEUM MURINUM. PMID- 28556080 TI - DEFERRED REPRODUCTION AS A RESPONSE TO SEXUAL SELECTION IN A CORAL REEF FISH: A TEST OF THE LIFE HISTORICAL CONSEQUENCES. PMID- 28556081 TI - SOCIETY FOR THE STUDY OF EVOLUTION AND AMERICAN SOCIETY OF NATURALISTS 1984 MEETINGS. PMID- 28556082 TI - HISTOCOMPATIBILITY IN HAWAIIAN AND POLYNESIAN POPULATIONS OF THE PARTHENOGENETIC GECKO LEPIDODACTYLUS LUGUBRIS. PMID- 28556084 TI - LONG-TERM MAINTENANCE OF SIZE VARIATION IN POPULATIONS OF CENTRIS PALLIDA (HYMENOPTERA: ANTHOPHORIDAE). PMID- 28556083 TI - EXPERIMENTAL STUDIES OF THE EVOLUTIONARY SIGNIFICANCE OF SEXUAL REPRODUCTION. I. A TEST OF THE FREQUENCY-DEPENDENT SELECTION HYPOTHESIS. PMID- 28556085 TI - AN APPARENT DISJUNCTION BETWEEN THE EVOLUTION OF FORM AND SUBSTANCE IN THE GENUS TETRAHYMENA. PMID- 28556086 TI - KIN-RECOGNITION AND THE SPATIAL DISTRIBUTION OF LARVAE OF THE BRYOZOAN BUGULA NERITINA (L.). PMID- 28556087 TI - THE REBIRTH OF BIOGEOGRAPHY. PMID- 28556089 TI - ON THE EVOLUTION OF PARTHENOGENESIS: A GENETIC REPRESENTATION OF THE "COST OF MEIOSIS". PMID- 28556088 TI - EVOLUTION SOCIETY NEWS. PMID- 28556090 TI - Value of Sonography in the Diagnosis of Sialolithiasis: Comparison With the Reference Standard of Direct Stone Identification. AB - OBJECTIVES: The aim of this study was to assess the effectiveness of sonography for diagnosing sialolithiasis in comparison with the existing reference standard of direct identification of a stone. METHODS: A total of 659 glands with signs of obstructive sialadenopathy were evaluated retrospectively. Sonographic examinations of the large head salivary glands had been performed initially in all cases. Direct depiction of a stone during sialoendoscopy or transoral ductal surgery or observation of stone fragmentation with discharge of concrements after extracorporeal shock wave lithotripsy, was regarded as definitive evidence and as the reference standard for the presence of sialolithiasis. The sonographic results were compared with those for direct identification of stones. RESULTS: The sensitivity of sonography was 94.7%, with specificity of 97.4%, a positive predictive value of 99.4%, and a negative predictive value of 79.6%. Stones that were not diagnosed correctly on sonography were most often located in the distal area of the duct. CONCLUSIONS: These results show that sialolithiasis can be diagnosed by sonography with a high degree of certainty. Sonography thus appears to be highly appropriate as the examination method of choice. PMID- 28556091 TI - Incremental Sampling Methodology: Applications for Background Screening Assessments. AB - This article presents the findings from a numerical simulation study that was conducted to evaluate the performance of alternative statistical analysis methods for background screening assessments when data sets are generated with incremental sampling methods (ISMs). A wide range of background and site conditions are represented in order to test different ISM sampling designs. Both hypothesis tests and upper tolerance limit (UTL) screening methods were implemented following U.S. Environmental Protection Agency (USEPA) guidance for specifying error rates. The simulations show that hypothesis testing using two sample t-tests can meet standard performance criteria under a wide range of conditions, even with relatively small sample sizes. Key factors that affect the performance include unequal population variances and small absolute differences in population means. UTL methods are generally not recommended due to conceptual limitations in the technique when applied to ISM data sets from single decision units and due to insufficient power given standard statistical sample sizes from ISM. PMID- 28556092 TI - Reduced glial activity after surgery: A sign of immunoparalysis of the brain? PMID- 28556093 TI - Recovery of rat muscle size but not function more than 1 year after a single botulinum toxin injection. AB - INTRODUCTION: Neurotoxin injection is used to treat a wide variety of neuromuscular disorders. The purpose of this study was to measure the functional and structural properties of botulinum toxin-injected adult rat skeletal muscle over nearly the entire lifespan. METHODS: Ten groups of animals were subjected to either neurotoxin injection [Botox, Type A (BT-A); Allergan, Irvine, California] or saline solution injection. Neurotoxin-injected animals (n = 90) were analyzed at different time-points: 1 week; 1 month; 3 months; 6 months; 12 months; or 18 months. RESULTS: In spite of the recovery of structural features, such as muscle mass and fiber area, dorsiflexion torque production remained significantly depressed by 25%, even at 12 months after neurotoxin injection. DISCUSSION: The data demonstrate that, after a single BT-A injection, although gross muscle morphology recovered over a 12-month time period, loss of contractile function did not recover. Muscle Nerve 57: 435-441, 2018. PMID- 28556094 TI - Reduced growth in wild juvenile sockeye salmon Oncorhynchus nerka infected with sea lice. AB - Daily growth rings were examined in the otoliths of wild juvenile sockeye salmon Oncorhynchus nerka to determine whether infection by ectoparasitic sea lice Caligus clemensi and Lepeophtheirus salmonis was associated with reduced host body growth, an important determinant of survival. Over 98% of the sea lice proved to be C. clemensi and the fish that were highly infected grew more slowly than uninfected individuals. Larger fish also grew faster than smaller fish. Finally, there was evidence of an interaction between body size and infection status, indicating the potential for parasite-mediated growth divergence. PMID- 28556095 TI - The microbiota of diapause: How host-microbe associations are formed after dormancy in an aquatic crustacean. AB - A critical question in symbiosis research is where and how organisms obtain beneficial microbial symbionts in different ecological contexts. Microbiota of juveniles are often derived directly from their mother or from the immediate environment. The origin of beneficial symbionts, however, is less obvious in organisms with diapause and dispersal stages, such as plants with dormant seeds and animals in ephemeral or strongly seasonal habitats. In these cases, parents and offspring are separated in time and space, which may affect opportunities for both vertical and horizontal transmission of symbionts. The planktonic crustacean Daphnia produces long-lasting resting eggs to endure winter freezing and summer droughts and requires microbiota for growth and reproduction. It is unknown how hatchlings from resting stages form associations with microbial consorts after diapause. Using natural samples of D. magna resting eggs after several years of storage, we show that the total bacterial community derived from both the exterior and interior of the eggs' ephippial cases is sufficiently beneficial to ensure normal Daphnia functioning in otherwise bacteria-free conditions. We do not find direct evidence that the required bacteria are of maternal origin, though sequencing reveals that the resting stage is accompanied by bacterial taxa previously found in association with adult animals. These findings suggest that although Daphnia are strongly dependent on environmental bacteria for normal functioning, host-bacteria associations are somewhat general and availability of specific bacteria is not a strong constraint on host ecology. Nevertheless, animals and microbes may be ecologically linked through co-dispersal. PMID- 28556096 TI - Standardized toxicity testing may underestimate ecotoxicity: Environmentally relevant food rations increase the toxicity of silver nanoparticles to Daphnia. AB - Daphnia in the natural environment experience fluctuations in algal food supply, with periods when algal populations bloom and seasons when Daphnia have very little algal food. Standardized chronic toxicity tests, used for ecological risk assessment, dictate that Daphnia must be fed up to 400 times more food than they would experience in the natural environment (outside of algal blooms) for a toxicity test to be valid. This disconnect can lead to underestimating the toxicity of a contaminant. We followed the growth, reproduction, and survival of Daphnia exposed to 75 and 200 ug/L silver nanoparticles (AgNPs) at 4 food rations for up to 99 d and found that AgNP exposure at low, environmentally relevant food rations increased the toxicity of AgNPs. Exposure to AgNP at low food rations decreased the survival and/or reproduction of individuals, with potential consequences for Daphnia populations (based on calculated specific population growth rates). We also found tentative evidence that a sublethal concentration of AgNPs (75 ug/L) caused Daphnia to alter energy allocation away from reproduction and toward survival and growth. The present findings emphasize the need to consider resource availability, and not just exposure, in the environment when estimating the effect of a toxicant. Environ Toxicol Chem 2017;36:3008-3018. (c) 2017 SETAC. PMID- 28556098 TI - THE POPULATION BIOLOGY OF THE BUTTERFLY, EUPHYDRYAS EDITHA. V. CHARACTER CLUSTERS AND ASYMMETRY. PMID- 28556097 TI - Diabetic macular oedema: clinical risk factors and emerging genetic influences. AB - Diabetic macular oedema is the major cause of visual impairment in type 1 and type 2 diabetes. As type 2 diabetes becomes more prevalent worldwide, the prevalence of diabetic macular oedema is also expected to rise. Current management of diabetic macular oedema is challenging, expensive and not optimal in a subset of patients. Therefore, it is important to increase our understanding of the risk factors involved and develop preventative strategies. While clinical risk factors for diabetic macular oedema have been identified, few studies have addressed potential genetic risk factors. Epidemiology and family studies suggest genetic influences are of importance. In this review, we summarise known clinical risk factors, as well as discuss the small number of genetic studies that have been performed for diabetic macular oedema. PMID- 28556099 TI - HERBIVORY IN LIZARDS. PMID- 28556100 TI - AN ESTIMATE OF THE POTENTIAL EVOLUTIONARY INCREASE IN SPECIES DENSITY IN THE POLYNESIAN ANT FAUNA. PMID- 28556102 TI - Minutes of the Twenty-first Annual Business Meeting. PMID- 28556101 TI - A COMPARATIVE STUDY OF THE SERUM PROTEINS OF THE SPECIES OF TARICHA AND THEIR HYBRIDS. PMID- 28556103 TI - BARRIERS TO HYBRIDIZATION BETWEEN AEDES AEGYPTI AND AEDES ALBOPICTUS (DIPTERA: CULICIDAE). PMID- 28556104 TI - A STUDY OF THE GENUS CHROTOGONUS (ORTHOPTERA). VIII. PATTERNS OF VARIATION IN EXTERNAL MORPHOLOGY. PMID- 28556105 TI - A PROPOSITION ON THE POPULATION DYNAMICS OF THE STERILE t ALLELES IN THE HOUSE MOUSE. PMID- 28556106 TI - THE EFFECT OF TEMPERATURE ON REPRODUCTON IN SOME MORPHS OF THE LANDSNAIL CEPAEA NEMORALIS (L.). PMID- 28556107 TI - INCREASE IN THE VARIANCE OF FITNESS DUE TO SELECTION. PMID- 28556108 TI - STUDIES ON NATURAL POPULATIONS OF DROSOPHILA VI. COMPETITION BETWEEN DROSOPHILA MELANOGASTER AND DROSOPHILA SIMULANS. PMID- 28556109 TI - EVOLUTIONARY MORPHOGENESIS. PMID- 28556110 TI - HOST EXPLOITATION OF TWO CLOSELY RELATED WATER MITES. PMID- 28556111 TI - CERTAINTY AND CIRCULARITY IN EVOLUTIONARY TAXONOMY. PMID- 28556112 TI - DROSOPHILA IMAII, A NEW SIBLING SPECIES RELATED TO DROSOPHILA BIFASCIATA. PMID- 28556113 TI - EVOLUTIONARY AND ECOLOGICAL RELATIONSHIPS BETWEEN THREE SPECIES OF BLACKBIRDS (ICTERIDAE) IN CENTRAL MEXICO. PMID- 28556114 TI - THE HOMOLOGIES OF THE LABYRINTHODONT CENTRUM. PMID- 28556115 TI - TWO PARAPATRIC SPECIES OF POCKET GOPHERS. PMID- 28556116 TI - MATROCLINOUS INHERITANCE AND CLONAL STRUCTURE OF A MEXICAN POPULATION OF THE GYNOGENETIC FISH, POECILIA FORMOSA. PMID- 28556117 TI - VARIATION IN PHLOX DIVARICATA. PMID- 28556118 TI - SURVIVAL AND GESTATION IN PIGS. PMID- 28556119 TI - PREDATOR RESPONSES TO ARTIFICIAL BATESIAN MIMICS RELEASED IN A NEOTROPICAL ENVIRONMENT. PMID- 28556121 TI - International Conjerence on Systematic Biology. PMID- 28556120 TI - THE FORMATION OF SUBGROUPS BY THE DEVELOPMENT OF INBREEDING SYSTEMS IN A TRILLIUM POPULATION. PMID- 28556122 TI - Role of Procalcitonin in Differentiating between Infectious and Noninfectious Fevers among Patients with Lymphoma. AB - OBJECTIVE: The primary objective of this study is to prospectively evaluate the role of procalcitonin (PCT) in distinguishing infectious fever from noninfectious fever (NIF) among febrile lymphoma patients. The secondary objective is to evaluate the usefulness of PCT in distinguishing among bloodstream infections (BSI), local infections and unidentified infections (LIUI), and NIF. METHODS: Patients with lymphoma and fever were prospectively recruited between August 2014 and November 2015. PCT was measured within 24 hours of fever onset (PCT1) and 24 72 hours thereafter (PCT2). The higher PCT value between PCT1 and PCT2 was also documented (PCTmax ). PCT levels (PCT1, PCT2, and PCTmax ) were compared for BSI, LIUI, and NIF. In addition, the difference between PCT1 and PCT2 was evaluated in patients with complete data on both PCT1 and PCT2. RESULTS: Of 108 eligible patients, 12 were diagnosed with BSI, 83 with LIUI, and 13 with NIF. PCTmax was statistically different between the infectious fever (BSI and LIUI combined) and NIF groups (median PCTmax : 0.44 ng/ml vs 0.19 ng/ml; p=0.026). PCT1 was not statistically different for patients with BSI, LIUI, and NIF (p=0.217). However, PCT2 and PCTmax were significantly higher in patients with BSI compared to those with NIF (p=0.026 and 0.002, respectively). Meanwhile, patients with BSI have significantly higher PCTmax values than those with LIUI (p=0.034). Among 90 cases with complete data on both PCT1 and PCT2, PCT2 was significantly higher than PCT1 in patients with BSI (median PCT: 0.98 ng/ml vs 0.47 ng/ml; p=0.045) and patients with LIUI (median PCT: 0.43 ng/ml vs 0.24 ng/ml; p=0.004), while not significant in patients with NIF (p=0.374). CONCLUSION: Two separate PCT measurements can differentiate between infectious fever and NIF and predict for BSI in lymphoma patients with fever. PMID- 28556123 TI - When endometriosis is the barrier for fertility. PMID- 28556124 TI - Uterine adenomyosis and infertility, review of reproductive outcome after in vitro fertilization and surgery. AB - This review includes an analysis of the clinical studies evaluating reproductive outcome and adenomyosis, and a review of studies on reproductive outcome and surgical treatment options for adenomyosis. Strict diagnostic criteria and classification of disease are needed for an image diagnosis of adenomyosis. Studies of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) populations and women with surgically treated deep endometriosis have suggested that adenomyosis has a negative impact on reproductive outcome, although there are substantial variations between studies. Few data are available on the relation between the extent of disease and impact on reproductive outcome, but a correlation appears to exist. Case series seem to confirm a positive effect of gonadotropin-releasing hormone analog treatment and surgery on reproductive outcome, but there are no controlled trials. Evidence is impaired by the poor quality of many studies, a lack of strict image diagnosis, and the absence of a classification of the extent of disease. Selection of the optimal evidence-based treatment options for adenomyosis in the fertility clinic is difficult because of a lack of evidence regarding the relation between fertility and the degree and composition of adenomyosis. Adenomyosis may reduce implantation so severely that surgical or other treatment options should be recommended, but the benefit of these treatment options needs to be verified. Referral of women with adenomyosis and recurrent miscarriage and repeated failure of assisted reproductive technology to centers with a special interest in adenomyosis research and treatment may be critical. PMID- 28556125 TI - THE ORIGIN AND EVOLUTIONARY DEVELOPMENT OF HETEROSTYLY IN THE ANGIOSPERMS. PMID- 28556127 TI - STUDIES OF NATURAL POPULATIONS OF MUS. I. BIOCHEMICAL POLYMORPHISMS AND THEIR BEARING ON BREEDING STRUCTURE. PMID- 28556126 TI - THE IDENTIFICATION OF HYBRID PLANTS IN SEGREGATING POPULATIONS. PMID- 28556128 TI - THE DEVELOPMENT OF A PHYLOGENY OF FROGS. PMID- 28556129 TI - THE ESTIMATION OF RELATIVE FITNESS OF DROSOPHILA POPULATIONS. V. GENERATION INTERVAL AND HETEROGENEITY IN COMPETITION. PMID- 28556130 TI - EVOLUTION, ECOLOGY AND BEHAVIOR OF SAND WASPS. PMID- 28556131 TI - GENETIC DIFFERENTIATION AND STABILITY OF SOME CHARACTERS THAT DISTINGUISH LYCOPERSICON ESCULENTUM MILL. FROM SOLANUM PENNELLII COR. PMID- 28556133 TI - EVOLUTIONARY RELATIONSHIPS IN THE AVIAN GENUS COLUMBA AS INDICATED BY OVALBUMIN TRYPTIC PEPTIDES. PMID- 28556132 TI - VARIATIONS IN THE BREEDING SYSTEMS OF A WILD RICE, ORYZA PERENNIS. PMID- 28556134 TI - DEVELOPMENTAL RATE AND COMPETITIVE ABILITY IN TRIBOLIUM. II. CHANGES IN COMPETITIVE ABILITY FOLLOWING FURTHER SELECTION FOR DEVELOPMENTAL RATE. PMID- 28556135 TI - COMMENTS ON "THE ADAPTIVE SIGNIFICANCE OF GASTROPOD TORSION". PMID- 28556136 TI - OUTCROSSING IN NATURAL POPULATIONS. III. THE DEER CREEK POPULATION OF CLARKIA EXILIS. PMID- 28556137 TI - SERUM PROTEINS OF SALAMANDERS OF THE AMBYSTOMA JEFFERSONIANUM COMPLEX, AND THE ORIGIN OF THE TRIPLOID SPECIES OF THIS GROUP. PMID- 28556138 TI - THE ADAPTIVE VALUE OF SEXUAL DIMORPHISM: I, ANISOGAMY. PMID- 28556139 TI - SELECTION IN NATURAL POPULATIONS. 6. VARIATION GENETICS, AND MORE GRAPHS FOR ESTIMATION. PMID- 28556140 TI - DROUGHT, DIASTROPHISM, AND QUANTUM EVOLUTION. PMID- 28556141 TI - POPULATION STUDIES IN PREDOMINANTLY SELF-POLLINATED SPECIES. VIII. GENETIC VARIABILITY IN THE FESTUCA MICROSTACHYS COMPLEX. PMID- 28556142 TI - FURTHER EVIDENCE BEARING UPON THE ORIGIN OF EXTRA DIMINUTIVE CHROMOSOMES IN OENOTHERA HOOKERI. PMID- 28556143 TI - MATING BEHAVIOR AND FITNESS AS A FUNCTION OF SINGLE ALLELE DIFFERENCES IN EPHESTIA KUHNIELLA Z. PMID- 28556144 TI - EVOLUTIONARY PATTERNS IN PELYCOSAURIAN REPTILES: A FACTOR-ANALYTIC STUDY. PMID- 28556145 TI - INDEPENDENT EVOLUTION OF A POLYGENIC SYSTEM IN ISOLATED POPULATIONS OF THE FUNGUS SCHIZOPHYLLUM COMMUNE. PMID- 28556146 TI - FEMALE DIMORPHISM IN A MALE-MONOMORPHIC SPECIES. PMID- 28556148 TI - SEX CHANGE WITH INBREEDING: EXPERIMENTS ON SEPARATE VERSUS COMBINED SEXES. AB - Ipomopsis rubra plants grown in the laboratory initially produced hermaphrodite flowers, but some self- or sib-mated individuals switched to produce large numbers of pistillate (male sterile) flowers. The sex change did not occur with outcrossing. Plants with extreme male sterility were also observed in natural populations, usually in smaller individuals. Male sterility may be compensated by more seeds (resource reallocation), better seeds (avoidance of selfing), or both. Pistillate flowers were smaller, so savings could be used for additional seeds. Selfed seeds had reduced survival and fecundity, so avoidance of selfing could produce better quality offspring. We explored costs and benefits of sex change with two fitness models. The first assumes randomoutcross matings. Estimates of resource reallocation and inbreeding (selfing) depression are sufficient for pistillate inflorescences to have equal or greater fitness than hermaphrodite inflorescences if the selfing rate is high. Frequencies of sex change with intensive self-pollination were consistent with this model. The second model assumes all nonself matings are between sibs in "local mating" groups. Parents may benefit by male sterility in offspring, but gains would be higher if sex change occurred earlier and at higher than observed frequencies. PMID- 28556147 TI - EVOLUTION AND MITOCHONDRIAL DNA IN NEUROSPORA CRASSA. AB - We studied mitochondrial DNA variability in 19 natural Neurospora crassa isolates and one wild-type isolate to examine evolution of these fungi and their mitochondrial DNA (mtDNA). We combined restriction endonuclease analysis of natural isolate mtDNA with DNA-DNA hybridization to cloned EcoR I fragments of a wild-type genome to discriminate between length mutations and site changes due to nucleotide substitution. Most variability was due to length mutations (insertions and deletions); genome size could vary 25% between pairs of isolates. Length mutation distribution was not random, nor simply explained by the presence of coding versus noncoding regions. Restriction-site changes were few; the estimated amount of nucleotide substitution per nucleotide between the most divergent pair of isolates was 0.78%. Evolutionary relationships among isolates based on both types of mutations were compatible, and suggest that geographically distinct populations of mitochondrial DNA exist in the biological species, N. crassa. In contrast, no such correlation was shown by the previously determined distribution of nuclear heterokaryon incompatibility genes in the same isolates (Mylyk, 1975, 1976). PMID- 28556149 TI - WAITING FOR POST-NEO-DARWIN. PMID- 28556150 TI - GENETIC COVARIANCE BETWEEN OVIPOSITION PREFERENCE AND LARVAL PERFORMANCE IN AN INSECT HERBIVORE. AB - An experimental study determined that females of the herbivorous fly species Liriomyza sativae (Diptera: Agromyzidae) preferentially oviposit on the plant species on which their female progeny attain the greatest pupal weight. A modified parent/offspring regression was used to quantify this relationship as an additive genetic covariance between host-plant preference and relative performance of female larvae on different plant species. The implications of a genetic covariance between preference and performance on the course of evolution in herbivores are discussed. Several females from one population refused to oviposit on one of the plant species; this population also suffered the only significant larval mortality on this plant. These results corroborate the avoidance of unsuitable host plants seen in the genetic analyses of individuals, but relative to the genetic data, such population-level data are of limited usefulness in the study of evolutionary mechanisms by which insect populations become adapted to their host plants. PMID- 28556151 TI - INTRASPECIFIC SYMPATRY IN A "RING SPECIES," THE PLETHODONTID SALAMANDER ENSATINA ESCHSCHOLTZII, IN SOUTHERN CALIFORNIA. PMID- 28556153 TI - AN EXPERIMENTAL CONFIRMATION OF MORPHOLOGICAL ADAPTATION: TOE FRINGES IN THE SAND DWELLING LIZARD UMA SCOPARIA. PMID- 28556154 TI - GEOGRAPHIC VARIATION IN ALLOZYMES IN A "RING SPECIES," THE PLETHODONTID SALAMANDER ENSATINA ESCHSCHOLTZII OF WESTERN NORTH AMERICA. AB - The ring species Ensatina eschscholtzii (a plethodontid salamander) of western North America has a circle of subspecies surrounding the Central Valley of California which come into contact and are sympatric in southern California. We examined 26 proteins in 19 populations (maximum of 10 specimens per population) collected throughout the range in order to gain an understanding of the degree of differentiation in the group. Allozymic differentiation is profound, with genetic distances in excess of 0.5 (Rogers or Nei) between populations. Naturally hybridizing populations differ by genetic distances greater than 0.4. Two general classes of color morphs, blotched and unblotched, are segregated geographically, but they do not form discrete genetic units. Both are deeply differentiated, and genetic distances among populations of either class exceed those measured between the classes where they are sympatric in southern California. This study disclosed little evidence of gene exchange around the ring of populations and sampling of many additional populations in regions between populations sampled thus far will be required to determine whether smooth intergradation occurs. Although genetic distances measured exceed those between some co-occurring species of plethodontid salamanders, we find no evidence of borders between cryptic species. PMID- 28556155 TI - PATTERNS OF MULTIPLE PATERNITY IN POPULATIONS OF RAPHANUS SATIVUS. AB - Although multiple paternity has been documented for a large number of species, detailed studies of variation in multiple paternity among broods, individuals, and populations are lacking. We measured the extent of multiple paternity in the multi-seeded fruits of wild radish, Raphanus sativus, from three natural populations in southern California. Every parent sampled produced one or more multiply sired fruits, and, in most plants, over half the fruits analyzed proved to be multiply sired. In all, 75% of the 388 multi-seeded fruits analyzed showed multiple paternity. Among these fruits, the minimum number of paternal donors ranged from one to four, with a mode of two paternal parents. The fraction of multiply sired fruits varied from 68-85% among populations and from 40-100% among plants. Plants were heterogeneous for multiple paternity in the 1984 population. A significant positive correlation between multiple paternity and number of fruits per plant suggests that plants preferentially abort single sired fruits. The total number of mates that could be detected for entire plants ranged from 3 14 with a mode of seven. Multiple paternity is likely to be important in other species producing multi-seeded fruits. PMID- 28556156 TI - RULES OF INVARIANCE IN EVOLUTIONARY MORPHOLOGY: THE ORGANIZATION OF THE VERTEBRATE SKULL. PMID- 28556157 TI - DIRECT AND CORRELATED RESPONSES TO SELECTION AMONG LIFE-HISTORY TRAITS IN MILKWEED BUGS (ONCOPELTUS FASCIATUS). AB - Offspring-parent regressions provided initial estimates of heritabilities and genetic correlations among wing length, body length, pronotum width, head-capsule width, development time, age at first reproduction, and fecundity in an Iowa population of the large milkweed bug, Oncopeltus fasciatus. Replicated, bidirectional selection for wing length was imposed for nine generations. The direct response to selection revealed the existence of substantial additive genetic variance for wing length in this population. Traits were assayed for correlated responses to selection after seven generations. Body length, pronotum width, head capsule width, and fecundity showed consistent, positive correlated responses. Development time showed a negative correlated response. Age at first reproduction showed no consistent correlated response to selection on wing length. These pleiotropic effects among wing length and fecundity, development time, and body size characters provide the potential for these traits to evolve together in O. fasciatus, independently of age at first reproduction. PMID- 28556158 TI - GENETIC DETERMINATION OF PLANT SUSCEPTIBILITY TO AN HERBIVOROUS INSECT DEPENDS ON ENVIRONMENTAL CONTEXT. PMID- 28556159 TI - SYMPOSIUM TO HONOR G. LEDYARD STEBBINS. PMID- 28556160 TI - UNIDIRECTIONAL INCOMPATIBILITY BETWEEN POPULATIONS OF DROSOPHILA SIMULANS. AB - Drosophila simulans females from a strain collected at Watsonville, CA produce very few offspring when mated with males from a strain collected at Riverside 510 km away. This incompatibility does not exist in the reciprocal cross. In the incompatible cross, mating and oviposition are normal, but eggs fail to hatch. A survey of other California populations indicates that unidirectional incompatibility is widespread. The incompatibility is maternally inherited over one generation. Using older Riverside males or rearing the strains at 28 degrees C suppresses incompatibility. Culturing the strains on medium with tetracycline restores compatibility, suggesting the involvement of a microorganism. PMID- 28556161 TI - EXPERIMENTAL STUDIES OF THE EVOLUTIONARY SIGNIFICANCE OF SEXUAL REPRODUCTION. IV. EFFECT OF NEIGHBOR RELATEDNESS AND APHID INFESTATION ON SEEDLING PERFORMANCE. AB - To investigate the effect of neighbor relatedness in seedling populations, propagules of six Anthoxanthum odoratum parents, produced from a reciprocal diallel cross, were planted into the parental source population, a mown field. The propagules were either surrounded by four unrelated neighbors in a 1 cm square, four sibling neighbors, or no neighbors. About 45% of the emerging seedlings were attacked by aphids (Schizaphis graminum). Aphid infestation significantly reduced seedling survivorship and did not differ with parental genotype or neighbor relatedness; plants without neighbors had a slightly higher infestation risk. Plants without neighbors had lower survivorship than those surrounded by unrelated neighbors although this difference was only significant for plants infested by aphids. When infested by aphids, plants surrounded by siblings had lower survivorship than plants surrounded by non-relatives, suggesting the operation of minority advantage. These results are consistent with the frequency-dependent selection hypothesis for the evolution and maintenance of sexual reproduction. PMID- 28556162 TI - ENTROPY: THE GREAT ILLUSION. PMID- 28556163 TI - THE GENETIC STRUCTURE OF LARGE-LAKE DAPHNIA POPULATIONS. AB - Cyclical parthenogenesis allows study of the genetic and evolutionary characteristics of groups exhibiting both asexual and sexual reproduction. The cladoceran genus Daphnia contains species which vary with respect to the relative incidence of sexual reproduction; pond species tend to undergo sexual reproduction more regularly than species found in large lakes. Previous genetic studies have focused on pond populations, generating expectations about large lake populations that have not been fully met by recent studies. The present study of the Palearctic species Daphnia galeata further examines the genetic structure of large-lake populations. Nine local populations, from lakes in northern Germany, are examined for genetic variation at seven enzyme loci. Populations exhibit similar allelic arrays and often similar allele frequencies at the five polymorphic loci; values of Nei's genetic distance (D) ranged from 0.002 to 0.239, with a mean of 0.084. FST values range from 0.012 to 0.257, and spatial autocorrelation coefficients range from -0.533 to 0.551, for the eight alleles analyzed. With few exceptions, within-population genotypic frequencies were in Hardy-Weinberg equilibrium. There was, however, significant heterogeneity in genotypic frequencies among populations. The number of coexisting clonal groups, as determined by three locus genotypes, is high within populations. Clonal groups are widely distributed among localities. The amount of genetic divergence observed among these large-lake populations is smaller than that previously observed among pond populations and suggests that different processes may be important in determining the genetic structure and subsequent phenotypic divergence of lake versus pond populations. PMID- 28556165 TI - STAFF CHANGES. PMID- 28556164 TI - LOCAL MATE COMPETITION IN FINITE GROUPS. PMID- 28556166 TI - LIFETIME REPRODUCTIVE SUCCESS AND THE OPPORTUNITY FOR SELECTION IN A NONTERRITORIAL DAMSELFLY (ODONATA: COENAGRIONIDAE). AB - Major components of male and female lifetime reproductive success (LRS) were quantified for a damselfly that exhibits "scramble competition" for mates. The opportunity for selection on male reproduction was potentially 2.9 times that for females. Differential fertility/clutch and survivorship each accounted for about half of the total variation in female reproductive success. Variation in fertilization efficiency accounted for 7% of the total opportunity for selection on males. Although differences in survivorship and mating efficiency each contributed to about a third of the total opportunity for selection on male reproduction, both components appeared to be influenced by random factors. Survivorship was age-independent, and the mating distributions among males with equal mating opportunities were indistinguishable from those expected if matings were random with respect to male phenotype. Because the proportion of the standarized variance (I) in LRS that was attributed to sexual selection depended on the way the selective episodes were defined, the sample of individuals included in the partitioning analysis, and the degree of sexual selection on mated males that could be detected, my results caution against drawing conclusions about the dynamics of sexual selection on populations based on a superficial comparison of I values. PMID- 28556167 TI - EVOLUTIONARY GENETICS OF TWO SIBLING SPECIES, DROSOPHILA SIMULANS AND D. SECHELLIA. AB - Drosophila simulans and D. sechellia are sibling species, the former cosmopolitan and the latter restricted to the Seychelles Islands. We used classical genetic analysis to measure the numbers and effects of genes responsible for reproductive isolation and morphological differences in male genitalia between these species. At least five loci are responsible for male sterility in hybrids, with the strongest effects produced by at least two genes on the X chromosome. At least three (and probably four) loci are responsible for the interspecific difference in the size of the posterior process of the male genital arch. These genetic results, as well as the pattern of morphological divergence between the species, show several parallels with the divergence between D. simulans and its other island relative, D. mauritiana. We also present the DNA sequence of a 4.5 kilobase region containing the alcohol dehydrogenase (Adh) locus of D. sechellia, and combine this with previous data to reconstruct the phylogenies of the three species and their more distant relative D. melanogaster. Both D. mauritiana and D. sechellia are very closely related to D. simulans. Although most phylogenies show the two island species to be independent offshoots of the D. simulans lineage (with D. sechellia the more recent), the branch points are too close to make this conclusion unambiguous. The genetic and evolutionary parallels between the simulans/mauritiana and the simulans/sechellia divergences may therefore represent either a striking evolutionary convergence or a close common ancestry of the island species. A comparison of Adh alleles within species shows that the divergence among them may be almost as large as among alleles from different species. We conclude that many of the nucleotide differences among these species actually represent polymorphisms within common ancestors. It may be difficult to build accurate phylogenies using only a single DNA sequence from each species. PMID- 28556168 TI - EXPERIMENTAL STUDIES OF THE EVOLUTIONARY SIGNIFICANCE OF SEXUAL REPRODUCTION. III. MATERNAL AND PATERNAL EFFECTS DURING SEEDLING ESTABLISHMENT. AB - To determine whether genetic differences in fitness components exist among seeds and seedlings in a natural population, weighed propagules of six parents of Anthoxanthum odoratum from a reciprocal diallel cross were planted into the parental source population, a mown field. Seed families of maternal genotypes differed in germination success, while paternal families showed no detectable differences. Differential germination success could not be attributed to propagule weight. Seed families ranked differently in germination percentage in different blocks. No survivorship differences among parental seed families could be detected. There were significant cross * block * germination and cross * block * survivorship interactions; different crosses performed better or worse in different blocks. In some cases, crosses sired by different fathers within a maternal seed family differed in germination or survivorship, suggesting that natural selection may be capable of discriminating among juvenile genotypes within a maternal family despite the presence of large overall maternal effects. These results indicate that seedling establishment may differ according to genotype and that microsite heterogeneity may maintain genetic variation in juvenile traits in natural plant populations. PMID- 28556169 TI - PHILOSPHY FOR A NEW BIOLOGY. PMID- 28556170 TI - THE EVOLUTIONARY HISTORY OF DROSOPHILA BUZZATII. VIII. EVIDENCE FOR ENDOCYCLIC SELECTION ACTING ON THE INVERSION POLYMORPHISM IN A NATURAL POPULATION. AB - The pattern of selection acting in nature on the chromosomal polymorphism of the cactophilic species Drosophila buzzatii was investigated by comparing inversion and karyotypic frequencies through four different life-cycle stages: adult males, eggs, third-instar larvae, and immature adults. All population samples were obtained in June 1981 at an old Opuntia ficus-indica plantation near Carboneras, Spain. The analysis rests on several assumptions which are explicitly set forth and discussed. The results, if these assumptions prove true, indicate strong directional selection for larval viability acting on the second-chromosome karyotypes and also suggest selective differences in fecundity and longevity. Heterotic selection, however, cannot be ruled out for other fitness components such as male mating success. This kind of selection could be operating on the fourth-chromosome polymorphism as well. Some gene arrangements showed significant and opposite changes in frequency at different parts of the life cycle, thus demonstrating endocyclic selection. PMID- 28556171 TI - PARTIAL INBREEDING: EQUILIBRIUM HETEROZYGOSITY AND THE HETEROZYGOSITY PARADOX. AB - The effect of partial inbreeding on equilibrium populations has been extended to any degree of mating. As expected, for distantly related mates, the equilibrium levels of inbreeding and heterozygosity are not affected as much as by partial selfing. Formulas are also given for equilibrium levels of inbreeding and heterozygosity when two or more degrees of mating are present in a population. Inbreeding, other than selfing, may partially explain the deficiency of heterozygotes in outcrossers, part of the "heterozygosity paradox." PMID- 28556172 TI - MORE GOOD NEWS! PMID- 28556173 TI - SOME PROBLEMS IN ESTIMATING THE INTENSITY OF SELECTION THROUGH FERTILITY DIFFERENCES IN NATURAL AND EXPERIMENTAL POPULATIONS. AB - We used empirical data from a laboratory population of Heterandria formosa (Pisces, Poeciliidae) and simulations based on those data to examine methods of estimating the intensity of phenotypic selection through fertility differences when generations overlap. The correct intensity was known because we knew the history of every female, as well as the rate at which the population was growing. The net reproductive rate, which is an appropriate measure of fitness when generations do not overlap, underestimated the true intensity of selection. This measure of fitness did not provide a rank order of individuals that agreed significantly with the correct rank order. Simulated schemes of vertical sampling of females, using number of offspring produced during the sampling window as a measure of fitness, provided no consistently useful information about the direction or intensity of selection. Weighting the number of offspring by female age, to give more value to offspring of younger females, produced only a slight improvement in accuracy. Other data indicated that fertility differentials are closely tied to particular environmental conditions. When generations overlap, estimates of fertility differentials will have to be based on horizontal studies of lifetime performance of a cohort coupled with demographic information on the entire population. PMID- 28556174 TI - NULL ALLELES AS A POSSIBLE CAUSE OF HETEROZYGOTE DEFICIENCIES IN THE OYSTER CRASSOSTREA VIRGINICA AND OTHER BIVALVES. PMID- 28556175 TI - EVOLUTION OF CONDITION-DEPENDENT SEX ORNAMENTS AND MATING PREFERENCES: SEXUAL SELECTION BASED ON VIABILITY DIFFERENCES. AB - The possibility that the evolution of mating preferences and secondary sex traits can be based on heritable differences in viability is examined with a three-locus model. Earlier genetic models suggested that viability-based processes alone cannot explain the evolution of mate choice and sex ornaments that reduce survival; a Fisherian mating advantage seemed necessary. The present model is based on a monogamous mating system that precludes such a mating advantage. A key assumption is that ornament development depends on the phenotypic condition and overall genotype of the possessor; there is evidence that secondary sex traits often mirror nutritional status and health, sometimes through hormonal mediation. Ornament and preference can then hitchhike slowly to high frequency with alleles that confer a slight survival advantage, provided that such alleles become available often enough. The evolution of mating preferences and secondary sex traits that reflect overall genotypic constitution therefore can be based solely on viability differences, no Fisherian mating advantage being required. In practice, these and several other mechanisms of sexual selection may occur together. PMID- 28556176 TI - Lixisenatide, a Once-Daily Prandial Glucagon-Like Peptide-1 Receptor Agonist for the Treatment of Adults with Type 2 Diabetes. AB - Lixisenatide, a short-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA), has been available in Europe since 2013 and was recently approved in the United States for the treatment of type 2 diabetes (T2D) as an adjunct to diet and exercise. The objective of this systematic review is to describe the pharmacology, pharmacokinetics, safety, and efficacy of lixisenatide in patients with T2D. We conducted a search of the EMBASE database, limited to human studies with abstracts available in English. Published conference abstracts, limited to the American Diabetes Association (ADA) and the European Association for the Study of Diabetes meetings in 2015, as well as abstracts presented at the ADA meeting in 2016, were also screened. The abstracts retrieved were assessed for relevance; review articles and meta-analyses focusing on GLP-1 RAs as a class were excluded. Lixisenatide induced mean reductions of 0.46-0.99% in glycated hemoglobin A1c (HbA1c ), 55.86-143.43 mg/dl in 2-hour postprandial glucose (PPG) levels, and 56.58-127.75 mg/dl in mealtime glucose level variations. Changes in fasting plasma glucose (FPG) levels and weight ranged from -21.98 to +5.41 mg/dl and from -2.96 to +0.3 kg, respectively, in patients with T2D enrolled in the GetGoal clinical program (a program of clinical trials that established the efficacy and safety profile of lixisenatide 20 MUg once/day across patients with T2D with differing background therapies). Lixisenatide was well tolerated, demonstrating rates of symptomatic hypoglycemia of 0.8-42.9% and a very low rate of severe hypoglycemia (< 1.5%) as well as no increased risk of cardiovascular events. The most common adverse events were gastrointestinal in nature, mainly transient nausea and vomiting of mild-to-moderate severity. Lixisenatide effectively lowers HbA1c levels in patients with T2D through a mechanism of action complementary to that of agents that mainly target FPG, with the additional benefit of weight loss. Its once-daily administration schedule and effect on PPG levels make it an attractive option as add-on treatment to basal insulin therapy or oral antidiabetic agents. PMID- 28556177 TI - Outcome predictors in dilated cardiomyopathy or myocarditis. AB - BACKGROUND: The objective of this study was to identify parameters of prognostic relevance in patients presenting with chronic left ventricular dysfunction who underwent endomyocardial biopsy. MATERIALS AND METHODS: A total of 351 consecutive patients (age 47.7 +/- 12.6 years, 281 male) with a chronic left ventricular dysfunction were enrolled. Endomyocardial biopsies were analysed by histopathology according to Dallas criteria and immunohistological WHO criteria. Virus genome was detected by polymerase chain reaction. The combined end point was time to death or heart transplantation. RESULTS: About 19% of patients (n = 67) showed positive Dallas criteria and 39% (n = 118) immunohistochemical signs of inflammation. Viral genome was present in 58% (n = 155). During follow-up, 25% (n = 89; 76 death, 13 HTx) reached the end point. Dallas-positive histopathology (hazard ratio: 0.42; 95% CI: 0.29-0.84, P = 0.031), ejection fraction (hazard ratio: 0.97; 95% CI: 0.94-0.99, P = 0.019) and beta-blocker therapy (hazard ratio: 0.41; 95% CI: 0.23-0.69, P = 0.003) were independent outcome predictors. For patients under beta-blocker therapy, Dallas-positive histopathology (hazard ratio: 0.37; 95% CI: 0.25-0.76, P = 0.009) and NYHA class III and class IV (hazard ratio: 2.11; 95% CI: 1.04-3.12, P = 0.006) were independent predictors. CONCLUSIONS: For patients with a chronic left ventricular dysfunction, Dallas positive histopathology, beta-blocker therapy and left ventricular ejection fraction are the most striking parameters for outcome prediction. PMID- 28556178 TI - Change of appetite in patients with functional digestive disorder. Association with psychological disorders: A cross-sectional study. AB - BACKGROUND AND AIMS: Changes in appetite are a frequent complaint in patients with functional gastrointestinal disorders (FGIDs). The aims of this study are to evaluate whether the changes in appetite are associated with specific FGIDs and to explore associations of these changes with symptoms of anxiety or depression. METHODS: This study included 1009 consecutive FGID patients (71% female), aged 48.9 years who all filled out a Rome III questionnaire for the evaluation of FGIDs, submitted to a psychological evaluation of symptoms of anxiety, and completed the Beck Depression Inventory questionnaire. The patients were classified according to their appetite change using a 7-point grading scale and split into three groups: those with appetite loss, those with no change in appetite, and those with increased appetite. RESULTS: Among the 1009, 496 patients (49%) reported a change in appetite, of which 332 (33%) patients reported a decrease in appetite and 164 (16%) patients reported an increase in appetite. Appetite was not affected in 51% of patients. Changes in appetite depended on gender, body mass index and psychometric evaluation scores. Increased appetite did not have specific FGIDs associations, while decreased appetite was associated with esophageal, gastroduodenal, bowel, and anorectal symptoms. The presence of depressive symptoms was also a predictor for the majority of FGIDs in decreased appetite, while anxiety trait was significant for globus and dysphagia. CONCLUSIONS: Decreased appetite was associated with FGIDs, especially in the presence of depressive symptoms. A reduced appetite would help to predict psychological disorders associated with FGIDs. FINANCIAL DISCLOSURE: None declared. LEGAL REGISTRATION: This study was a registered study in the French National Drug Agency (ANSM, Agence Nationale de Securite du Medicamentet des produits de sante, Study Number 2016-A01120-51). COMPETING INTERESTS: Michel Bouchoucha, Marinos Fysekidis, Florence Mary, Gheorghe Airinei, Cyriaque Bon, and Robert Benamouzig have no competitive interests. PMID- 28556179 TI - Innovations in Publishing. PMID- 28556180 TI - Multiple-coil k-space interpolation enhances resolution in single-shot spatiotemporal MRI. AB - PURPOSE: Spatio-temporal encoding (SPEN) experiments can deliver single-scan MR images without folding complications and with robustness to chemical shift and susceptibility artifacts. Further resolution improvements are shown to arise by relying on multiple receivers, to interpolate the sampled data along the low bandwidth dimension. The ensuing multiple-sensor interpolation is akin to recently introduced SPEN interleaving procedures, albeit without requiring multiple shots. METHODS: By casting SPEN's spatial rasterization in k-space, it becomes evident that local k-data interpolations enabled by multiple receivers are akin to real-space interleaving of SPEN images. The practical implementation of such a resolution-enhancing procedure becomes similar to those normally used in simultaneous acquisition of spatial harmonics or sensitivity encoding, yet relaxing these methods' fold-over constraints. RESULTS: Experiments validating the theoretical expectations were carried out on phantoms and human volunteers on a 3T scanner. The experiments showed the expected resolution enhancement, at no cost to the sequence's complexity. With the addition of multibanding and stimulated echo procedures, 48-slice full-brain coverage could be recorded free from distortions at submillimeter resolution, in 3 s. CONCLUSIONS: Super-resolved SPEN with SENSE (SUSPENSE) achieves the goals of multishot SPEN interleaving delivering single-shot submillimeter in-plane resolutions in scanners equipped with suitable multiple sensors. Magn Reson Med 79:796-805, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28556181 TI - Ultrasonography in neuralgic amyotrophy: Sensitivity, spectrum of findings, and clinical correlations. AB - INTRODUCTION: The aim of this study was to assess the value of ultrasonography in neuralgic amyotrophy. METHODS: Fifty-three patients with 70 affected nerves were examined with high-resolution ultrasound. RESULTS: The most commonly affected nerve was the anterior interosseous (23%). Ultrasonographic abnormalities in the affected nerves, rather than in the brachial plexus, were observed, with an overall sensitivity of 74%. Findings included the swelling of the nerve/fascicle with or without incomplete/complete constriction and rotational phenomena (nerve torsion and fascicular entwinement). A significant difference was found among the categories of ultrasonographic findings with respect to clinical outcome (P = 0.01). In nerves with complete constriction and rotational phenomena, reinnervation was absent or negligible, indicating surgery was warranted. DISCUSSION: Ultrasonography may be used as a diagnostic aid in neuralgic amyotrophy, which was hitherto a clinical and electrophysiological diagnosis, and may also help in identifying potential surgical candidates. Muscle Nerve 56: 1054 1062, 2017. PMID- 28556182 TI - Two Novel Bioactive Peptides from Antarctic Krill with Dual Angiotensin Converting Enzyme and Dipeptidyl Peptidase IV Inhibitory Activities. AB - Inhibition of dipeptidyl peptidase IV (DPP-IV) and angiotensin converting enzyme (ACE) are considered useful in managing 2 often associated conditions: diabetes and hypertension. In this study, corolase PP was used to hydrolyze Antarctic krill protein. The hydrolysate (AKH) was isolated by ultrafiltration and purified by size-exclusion chromatography, ion exchange chromatography and reversed-phase high-performance liquid chromatography (RP-HPLC) sequentially. The in vitro inhibitory activities of all AKHs and several fractions obtained against ACE and DPP-IV were assessed. Two peptides, purified with dual-strength inhibitory activity against ACE and DPP-IV, were identified by TOF-MS/MS. Results indicated that not all fractions exhibited dual inhibitory activities of ACE and DPP-IV. The purified peptide Lys-Val-Glu-Pro-Leu-Pro had half-maximal inhibitory concentrations (IC50 ) of 0.93+/-0.05 and 0.73+/-0.04 mg/mL against ACE and DPP IV, respectively. The other peptide Pro-Ala-Leu had IC50 values of 0.64+/-0.05 and 0.88+/-0.03 mg/mL against ACE and DPP-IV, respectively. This study firstly reported the sequences of dual bioactive peptides from Antarctic krill proteins, further provided new insights into the bioactive peptides responsible for the ACE and DPP-IV inhibitory activities from the Antarctic krill protein hydrolysate to manage hypertension and diabetes. PMID- 28556183 TI - A simple blood test expedites the diagnosis of glucose transporter type 1 deficiency syndrome. AB - Glucose transporter type 1 (GLUT1) deficiency syndrome (GLUT1-DS) leads to a wide range of neurological symptoms. Ketogenic diets are very efficient to control epilepsy and movement disorders. We tested a novel simple and rapid blood test in 30 patients with GLUT1-DS with predominant movement disorders, 18 patients with movement disorders attributed to other genetic defects, and 346 healthy controls. We detected significantly reduced GLUT1 expression only on red blood cells from patients with GLUT1-DS (23 patients; 78%), including patients with inconclusive genetic analysis. This test opens perspectives for the screening of GLUT1-DS in children and adults with cognitive impairment, movement disorder, or epilepsy. Ann Neurol 2017;82:133-138. PMID- 28556184 TI - The utility of on-site ultrasound screening in population at high risk for deep venous thrombosis in temporary housing after the great East Japan Earthquake. AB - BACKGROUND: To evaluate the diagnostic performance of ultrasonography for screening of a population at risk for deep vein thrombosis (DVT) in a post disaster setting. METHODS: Ultrasonography was applied as a screening technique to the residents of a temporary housing facility who were displaced following the Great East Japan Earthquake. Thirty DVT screening sessions were held from April 2013 to June 2015. Individuals were invited to participate if they were identified as "high risk" for DVT, defined as those with low activity levels, a history of lower limb trauma, baseline lower limb pain or swelling, a cancer bearing status, or a history of venous thromboembolic event. Ultrasonographic examinations were performed from the calf to the popliteal veins using portable devices. RESULTS: Of the 3,316 subjects screened (682 men and 2,634 women) with a mean age of 71 +/- 9.7 years, DVT was diagnosed in 382 (11.5%). DVT was more likely in older, symptomatic, or female patients with a history of venous thromboembolism and attempting to perform daily exercise. The rate of DVT diagnosis increased from 9.9% in 2013 to 13.5% in 2015. CONCLUSIONS: Ultrasonography is efficient for screening at-risk populations in challenging settings. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 45:566-574, 2017. PMID- 28556185 TI - Systematic review of the diagnosis of scabies in therapeutic trials. AB - Human scabies (infestation with the mite Sarcoptes scabiei var hominis) causes a significant disease burden worldwide, yet there are no agreed diagnostic guidelines. We aimed to determine whether a consistent approach to diagnosing scabies has been used for published scabies therapeutic trials. The data sources used were the MEDLINE, Embase and Cochrane databases, from 1946 to 29 August 2013. Eligible studies were trials of therapeutic interventions against scabies in human subjects, published in English, enrolling patients with scabies, and using various therapeutic interventions. Language was a limitation of this study as some relevant trials published in languages other than English may have been excluded. Each study was reviewed by two independent authors, who assessed the clinical examination and testing approaches used for scabies diagnosis in the included studies. We found that of 71 included trials, 40 (56%) specified which clinical findings were used for diagnosis, which were predominantly rash, rash distribution, pruritus and mite burrows. Parasitological testing was used in 63% of trials (n = 45) and was used more frequently in clinic-based than in field studies. Nearly one-quarter of trials (24%, n = 17) did not define the diagnostic method used. Overall, the diagnostic approaches were poorly described, prohibiting accurate comparison of existing studies. This review further supports the need for consensus diagnostic guidelines for scabies. PMID- 28556186 TI - Factors associated with oophorectomy in children with benign ovarian masses. PMID- 28556187 TI - Lipopolysaccharide, a possible molecular mediator between periodontitis and coronary artery disease. AB - AIM: We aimed to study how lipopolysaccharide (LPS) in saliva and serum associates with each other, periodontal microbial burden, periodontitis and coronary artery disease (CAD). MATERIALS AND METHODS: The used Parogene cohort comprised N = 505 Finnish adults. Coronary diagnosis was acquired by coronary angiography, and the main outcomes were as follows: no significant CAD (n = 123), stable CAD (n = 184) and acute coronary syndrome (n = 169). Periodontitis was defined according to clinical and radiographic examinations. Levels for 75 strains of subgingival bacteria were determined by checkerboard DNA-DNA hybridization. Saliva and serum LPS activity was analysed by Limulus amebocyte lysate assay. RESULTS: The level of 11 bacterial strains, which were mainly oral and respiratory Gram-negative species, associated with salivary LPS levels in an age- and gender-adjusted linear regression. A total of 4.9% of the serum LPS, that is endotoxemia, variation was explainable by saliva LPS among patients with periodontitis (n = 247, R2 = .049, Pearson's r = .222, p < .001). Endotoxemia associated with stable CAD in a confounder adjusted multinomial logistic regression model (OR 1.99, 95% CI 1.04-3.81, p = .039, 3rd tertile). CONCLUSIONS: In particular in periodontitis patients, subgingival microbial burden contributes to endotoxemia. LPS is a possible molecular mediator between periodontitis and CAD. PMID- 28556188 TI - Effect of transcranial direct current stimulation on neuroplasticity in corticomotor pathways of the tongue muscles. AB - The aim of this study is to investigate effects of transcranial direct current stimulation (tDCS) on neuroplasticity in corticomotor pathways related to tongue muscles evoked by a training task using the tongue drive system (TDS). Using a crossover design, 13 healthy participants completed two sessions of tDCS while performing 30 min of TDS training. Sessions were spaced at least 2 weeks apart and participants randomly received anodal and sham tDCS stimulation in the first session and the other condition in the second session. Single and paired pulse transcranial magnetic stimulation was used to elicit motor evoked potentials (MEPs) of the tongue at three time-points: before, immediately after and 30 min after training. Participant-based reports of fun, pain, fatigue and motivation, level of difficulty and effort were evaluated on numerical rating scales. There was no consistent significant effect of anodal and sham stimulation on single or paired pulse stimulation MEP amplitude immediately or 30 min after TDS training. Irrespective of tDCS type, training with TDS induced cortical plasticity in terms of increased MEP amplitudes for higher stimulus intensities after 30 min compared with before and immediately after training. Participant-based reports revealed no significant difference between tDCS conditions for level of fun, fatigue, motivation, difficulty and level of effort but a significant increase in pain in the anodal condition, although pain level was low for both conditions. In conclusion, tongue MEP amplitudes appear to be sensitive to training with the tongue using TDS; however, anodal tDCS does not have an impact on training-evoked neuroplasticity of tongue corticomotor pathways. PMID- 28556189 TI - Reorganization of interaction networks modulates the persistence of species in late successional stages. AB - Ecological interaction networks constantly reorganize as interspecific interactions change across successional stages and environmental gradients. This reorganization can also be associated with the extent to which species change their preference for types of niches available in their local sites. Despite the pervasiveness of these interaction changes, previous studies have revealed that network reorganizations have a minimal or insignificant effect on global descriptors of network architecture, such as connectance, modularity and nestedness. However, little is known about whether these reorganizations may have an effect on community dynamics and composition. To answer the question above, we study the multi-year dynamics and reorganization of plant-herbivore interaction networks across secondary successional stages of a tropical dry forest. We develop new quantitative tools based on a structural stability approach to estimate the potential impact of network reorganization on species persistence. Then, we investigate whether this impact can explain the likelihood of persistence of herbivore species in the observed communities. We find that resident (early-arriving) herbivore species increase their likelihood of persistence across time and successional stages. Importantly, we demonstrate that, in late successional stages, the reorganization of interactions among resident species has a strong inhibitory effect on the likelihood of persistence of colonizing (late-arriving) herbivores. These findings support earlier predictions suggesting that, in mature communities, changes of species interactions can act as community-control mechanisms (also known as priority effects). Furthermore, our results illustrate that the dynamics and composition of ecological communities cannot be fully understood without attention to their reorganization processes, despite the invariability of global network properties. PMID- 28556191 TI - Sonography of Scrotal Wall Lesions and Correlation With Other Modalities. AB - The scrotal wall may be involved in a variety of pathologic processes. Such lesions may rise primarily from the layers of the scrotum or may be due to a process arising from scrotal content. Imaging is not needed in most cases, but it may be useful for making such differentiations and for evaluation of possible involvement of the testes and epididymides in cases of primary wall abnormalities. This pictorial essay will show the imaging findings observed in a variety of pathologic conditions affecting the scrotal wall, both common and unusual ones, with an emphasis on clinically relevant findings and features that lead to a specific diagnosis. PMID- 28556192 TI - Microsurgical anatomy of the maxillary artery for extracranial-intracranial bypass in the pterygopalatine segment of the maxillary artery. AB - The extracranial-intracranial (EC-IC) bypass using the maxillary artery (MA) has been successfully completed using a radial artery (RA) graft but the complicated anatomy and narrow exposure make it difficult. The purpose of this article is to define the microsurgical exposure of the MA through the middle fossa and describe the branches, diameter, and length of the MA available for the EC-IC bypass in the sphenopalatine fossa and anterior part of the infratemporal fossa. 5 cadaveric specimens were dissected bilaterally (10 MA dissections) to define the microsurgical anatomy of the MA through an intracranial approach. The exposable branches of the MA at the level of the infratemporal and sphenopalatine fossae were the anterior deep temporal, posterior superior alveolar, and infraorbital arteries. The origin of each branch could be exposed. The available section of the MA for use as a donor vessel is between the origin of the anterior deep temporal artery and the infraorbital artery. The mean exposable length of the MA was 19.4 mm. The mean outer diameter of the donor MA was 3.2 mm. Tension-free EC IC bypass was possible using a RA graft between the MA and the middle cerebral artery, the MA and the supraclinoid internal carotid artery (ICA), or the MA and the petrous ICA. Exposure of the MA at the infratemporal and sphenopalatine fossae is complicated but provides length and diameter suitable as a donor artery for the EC-IC bypass. Clin. Anat. 31:724-733, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28556193 TI - Addressing obesity in the dental setting: What can be learned from oral health care professionals' efforts to screen for medical conditions. AB - PURPOSE: This scoping review focused on what can be learned from oral health professionals' (OHCPs) efforts to provide screenings for medical conditions in the dental setting that could guide strategies for addressing childhood obesity. METHODS: PubMed, Embase, Cochrane, Grey Literature, and CINAHL were searched (limitation English language). Search terms covered OHCPs and various oral systemic conditions of interest (details provided in the paper. Nineteen unduplicated, relevant articles were categorized based on relationship to question. RESULTS: Screening for diabetes and heart disease risk in the dental setting has been shown to be effective and patients and providers are willing to participate, although not yet routinely implemented. Screening/counseling for tobacco-cessation has been shown to be effective, but few (<10 percent) OHCPs provided this activity or received tobacco cessation training. For obesity screening/counseling, the majority of dentists (82 percent) reported they would be more willing to offer this service if obesity were directly related to oral disease. The one healthy weight intervention pilot study was well received by caregivers/patients and resulted in improved food choices. Successful implementation included a dedicated staff member, the dental hygienist. Lack of adequate training was a commonly reported barrier for all of these conditions; in addition, for obesity screening/counseling fear of appearing judgmental, and fear of patient rejection were also commonly reported. CONCLUSIONS: Systematic studies are needed building on existing literature and exploring best implementation practices. Enhanced training is needed on relationship of oral health and systemic health and OHCPs' role. PMID- 28556194 TI - Assessment of serum beta-hCG and lipid profile in early second trimester as predictors of hypertensive disorders of pregnancy. AB - OBJECTIVE: To assess and compare the ability of serum beta-human chorionic gonadotropin (beta-hCG) and serum lipid profile in early second trimester as predictors of hypertensive disorders of pregnancy. METHODS: The present hospital based prospective study was conducted between November 24, 2012, and April 30, 2014, at a tertiary hospital in Mangalore, India. Women of any parity with a pregnancy of 14-20 weeks were included. Venous blood (3 mL) was collected, and serum beta-hCG and lipid profile were estimated by enzyme-linked immunosorbent assay and an enzymatic colorimetric test with lipid clearing factor, respectively. A cutoff value of beta-hCG for predicting hypertensive disorders was obtained by receiver operating curve analysis. RESULTS: Serum beta-hCG was significantly higher among women who subsequently developed hypertension (71 142 IU/L [n=27]) than among those who did not (20 541 IU/L [n=137]; P<0.001). The sensitivity and specificity of serum beta-hCG to predict hypertension were 92.6% and 94.9% respectively. The positive and negative predictive values were 78.1% and 98.5%, respectively. CONCLUSION: Serum beta-hCG might be used as a predictor of hypertensive disorders that complicate pregnancy. Dyslipidemia was not found to be a useful marker. PMID- 28556195 TI - Use of nystatin and chlorhexidine in oral medicine: Properties, indications and pitfalls with focus on geriatric patients. AB - OBJECTIVES: The aim of this work was to review the scientific literature on the properties, indications and pitfalls related to nystatin and chlorhexidine in oral medicine and also to compare these to other topical antifungal agents, considering the elderly population. BACKGROUND: Nystatin is a polyene antifungal widely used as a topical formulation to treat candidiasis, whereas chlorhexidine is a wide-spectrum antimicrobial, especially used against bacteria, but also effective in treating some fungal infections including those caused by Candida spp. These compounds have been prescribed for immunocompromised patients, hospitalized or not, some of them undergoing head and neck radiation therapy and/or chemotherapy, including elderly patients. MATERIALS AND METHODS: Dental and medical literature concerning the use of nystatin and chlorhexidine in oral medicine were selected and reviewed. RESULTS: Nystatin and chlorhexidine are gold standard antimicrobial mouthrinses respectively for Candida spp. and bacteria. Although recognized as effective in cotrolling oral infections, both nystatin and chlorhexidine are just complementary to systemic therapy in cases of systemic infections already established. The prescriber should also take into account that some commercial nystatin and chlorhexidine formulations contain compounds such as sugar and ethanol, which can be associated with side effects. Meanwhile, alternative formulations in which these compounds are absent are available and should be considered. CONCLUSIONS: Further studies investigating new drugs and interactions of drug combinations are necessary to improve the therapeutic management of oral infections. PMID- 28556196 TI - Serving optometry for 100 years: the story of Clinical and Experimental Optometry. PMID- 28556197 TI - Plantar warts on Tollund Man's feet (Denmark, fourth century BC). Limits of retrospective dermatological diagnosis. PMID- 28556198 TI - Can bottom-up processes of attention be a source of 'interference' in situations where top-down control of attention is crucial? AB - In this study, we investigate whether emotionally engaged bottom-up processes of attention can be a source of 'interference' in situations where top-down control of attention is necessary. Participants were asked to monitor and report on a video of a war scenario showing a developing battle in two conditions: emotionally positive and emotionally negative. Half of the participants (n = 15) were exposed to task-irrelevant pictures of positive emotional valence embedded within the scenario; the other half were exposed to task-irrelevant pictures of negative emotional valence. Sensitivity and Bias scores were calculated using signal detection theory. Overall, task accuracy scores were dependent upon the valence; negative pictures had an adverse effect on performance, whereas positive pictures improved performance. We concluded that negative emotional pictures interfered with top-down control of attention by attracting competing bottom-up processes of attention. We found the opposite effect for positive emotional stimuli. PMID- 28556199 TI - Isolation of Egg Yolk Granules as Low-Cholesterol Emulsifying Agent in Mayonnaise. AB - Egg yolk is an essential ingredient for many food products due to its excellent functional properties such as emulsification. However, the consumers' concern of its cholesterol level has led food industry to seek solutions for its replacement. Utilization of low-fat egg yolk granules as emulsifier can be an alternative strategy. In this study, granules with low cholesterol content were separated from egg yolk by a simple method under easily scalable centrifugal conditions. The egg yolk granules isolated within 0.17 M NaCl solution achieved a 22.5% yield that was similar to that using higher centrifugation speeds and longer time. The yield of egg yolk granules increased from 25% to 32% when the yolk:water ratio was changed from 1:1 to 1:2. Mayonnaise was prepared to evaluate the emulsifying capacity of the egg yolk granules. It was found that egg yolk granules exhibited similar emulsifying activity as that of whole egg yolk, but a better emulsion stabilizing property that is evidenced by the higher viscosity of mayonnaise prepared with the granules. In addition, the viscosities of mayonnaise prepared by spray dried yolk and granules were slightly higher than the liquid counterpart, showing a further improvement by spray drying on the emulsion stabilizing properties. The mechanical spectra of mayonnaise samples by frequency sweep also suggested that granules favored the formation of stronger 3 dimensional arrangements of oil droplets and therefore a more stable emulsion. Results suggest that granules isolated within 0.17 M NaCl solution present best emulsifying properties and can be applied as whole yolk replacer in food emulsions. PMID- 28556200 TI - Difficulties and practices regarding information provision among Korean and Italian nurses. AB - AIM: To investigate nurses' opinions and practices of providing information in a global context through cultural comparison. BACKGROUND AND INTRODUCTION: Providing sufficient information to patients about nursing interventions and plans is essential for patient-centred care. While many countries have specific legislation making information delivery to patients a legal duty of nurses, no such legislation exists in both the Republic of Korea and Italy; nurses' only guidance is the deontological code. METHODS: This was a cross-sectional survey study involving a convenience sample of 174 Korean nurses and 121 Italian nurses working in internal medicine and surgery at university hospitals. Data were collected using a self-administered questionnaire between February and November 2014. The questionnaire assessed demographic and professional characteristics, and difficulties and practices regarding information provision. RESULTS: Korean and Italian nurses significantly differed in all demographic and professional characteristics. More Korean than Italian participants reported that their role in providing information was well explained within their teams, but both groups reported the same level and type of difficulties in delivering information. Nurses in both countries regularly informed patients about medications and nursing procedures, but provided information about nursing care plans less frequently. Few nurses frequently provided information to relatives instead of patients. CONCLUSIONS: Despite cultural, demographic and professional differences between Korean and Italian nurses, their difficulties and practices in information delivery to patient were similar. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Hospital managers and policymakers should be aware that nurse-patient communication can be impaired by organizational factors, patient characteristics or the interaction among providers. Educational interventions and strategies are needed to increase information provision to patients about nursing care plans. PMID- 28556201 TI - A recent-onset ulcerated nodular plaque on the scalp. PMID- 28556202 TI - Confocal microscopy as an early relapse marker for acanthamoeba keratitis. AB - Acanthameoba keratitis is a serious ophthalmological condition with a potentially vision-threatening prognosis. Early diagnosis and recognition of relapse, and the detection of persistent Acanthamoeba cysts, are essential for informing the prognosis and managing the condition. We suggest the use of in vivo confocal microscopy not only to identify the early signs of relapse after keratoplasty in patients with Acanthamoeba keratitis, but also as an additional follow-up tool after antimicrobial crosslinking. This study shows that in vivo confocal microscopy is, in experienced hands, a quick and reliable diagnostic tool. Clin. Anat. 31:60-63, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28556203 TI - Linking statins and lipids in Parkinson's disease. PMID- 28556204 TI - Optimal combination of anti-scatter grids and software correction for CBCT imaging. AB - PURPOSE: Cone beam computed tomography (CBCT) has been widely adopted in clinical practice for image-guided radiotherapy. Soft tissue contrast and Hounsfield units are impaired to the presence of scattered radiation. In our previous work, we proposed a high selectivity anti-scatter grid (ASG) as a possible solution to the problem. An alternative approach is the application of iterative scatter correction using deconvolution with scatter point spread function (PSF). The purpose of this work was to compare the performance of ASGs with different selectivity with and without the iterative and uniform scatter corrections in terms of CBCT image quality. A secondary objective of this study was to develop a novel measurement approach to measure the scatter point spread functions. METHODS: The scatter PSF was modeled as a sum of two bivariate Gaussian functions. The PSF parameters were estimated from a series of transmission measurements through polystyrene slabs of varying thickness with lead partial beam-blocker for three different ASG designs ranging from low (5.6), medium (9), and high (11) selectivity. The scatter correction scheme is based on iterative convolution of the current estimate of the primary with the scatter PSF until the root mean square deviation (RMSD) of the measured projection and the sum of the estimate of primary and scatter falls below a predefined threshold. The image quality was evaluated with the CIRS CBCT Image Quality and Electron Density phantom in a head and neck and pelvis configuration and the CIRS Virtual Male Human Patient. The image quality was quantified by the contrast-to-noise ratio (CNR) relative to the uncorrected scans and the root mean square deviation of the average gray values for different regions with respect to the nominal Hounsfield units and the mean difference of the reconstructed HU between the planning CT and CBCTs of the virtual human phantom. RESULTS: For the head and neck phantom, the CNR increased with more advanced scatter correction algorithm and the ASG selectivity, reaching 3.9, 3.7, 3.5, and 3.1 for the high, medium, light, and with no grid configuration, respectively, combined with the iterative software correction. The same is true for the pelvis phantom with CNR improvement reaching 1.5 for the heavy and medium grid, 1.3 for the light grid, and 1.1 on its own. The HU RMSD for the head and neck phantom was 22 HU, 13 HU, 12 HU, and 6 HU for iterative correction without the grid, with the light grid, medium grid and the heavy grid, respectively. For same correction strategies, the values for the pelvis phantom where 170, 120, 34, and 27 HU. The average difference with the PCT of the virtual human phantom was 59 +/- 48 HU and 63 +/- 59 HU with scans reconstructed with the iterative correction and two higher selectivity grids. Visual inspection revealed similar trends for a head-and-neck and prostate cancer patient. CONCLUSIONS: The best scatter mitigation strategy was found to be a combination of a grid with selectivity larger than 9, combined with iterative scatter estimation. None of the investigated grids required increasing the imaging dose. The PSF determined using proposed method leads to image quality improvements results for all but one of the investigated scenarios. PMID- 28556205 TI - Assessment of factors associated with smoking cessation at diagnosis or during follow-up of Crohn's disease. AB - BACKGROUND AND AIM: Smoking cessation is known to improve the course of Crohn's disease (CD). However, the factors associated with smoking cessation after CD diagnosis have not been well established. METHODS: Clinical characteristics and change in smoking status were evaluated in 445 current smokers at the time of CD diagnosis. Patients were classified into three subgroups based on their final smoking status and time of smoking cessation: non-quitters, quitters at diagnosis, and quitters during follow-up. RESULTS: The overall smoking cessation rate was 55.7% (248 of 445 patients). The diagnosis of CD was the main reason for quitting (41.5%, 103 of 248 patients). Smoking cessation at the time of CD diagnosis was associated with intestinal resection within 3 months from CD diagnosis (odds ratio [OR] 2.355, 95% confidence interval [CI] 1.348-4.116, P = 0.003), light smoking (OR 2.041, 95% CI 1.157-3.602, P = 0.014), and initiation of smoking before 18 years of age (OR 0.570, 95% CI 0.327-0.994, P = 0.047). Light smoking (OR 1.762, 95% CI 1.019-3.144, P = 0.043) and initiation of smoking before 18 years (OR 0.588, 95% CI 0.381-0.908, P = 0.017) were also associated with overall smoking cessation. CONCLUSION: Quitters after CD diagnosis, including quitters at diagnosis and quitters during follow-up, had features distinct from those of non-quitters. Given the motivation at CD diagnosis, a detailed history of smoking habits should be taken and all current smokers should be encouraged to quit smoking at the time of CD diagnosis. PMID- 28556208 TI - MAGNIFICENT VOYAGERS. PMID- 28556206 TI - The differences in the incidence of diabetes mellitus and prediabetes according to the type of HMG-CoA reductase inhibitors prescribed in Korean patients. AB - BACKGROUND: Very few studies conducted in Korea have investigated the relationship between statins and the incidence of diabetes. Therefore, we analyzed the progression from normal blood glucose to prediabetes and then to diabetes mellitus (DM) according to the type, intensity, and dose of statin prescribed. METHODS: Data of patients who were first prescribed statins between 2009 and 2011 were extracted from electronic medical records. Patients with normal blood glucose or prediabetes were observed for 4 years after initiation of statin therapy. RESULTS: A total of 2890 patients were included in our study and analyzed on the basis of the first statin they were prescribed. The incidence rate of DM in patients with prediabetes was 1.72 times that of patients with normal glucose levels (odds ratio = 1.72, 95% confidence interval = 1.41-2.10, P < .001). Regarding progression from normal blood glucose to prediabetes, the incidence rate of prediabetes was significantly lower in patients prescribed pitavastatin (odds ratio = 0.62, 95% confidence interval = 0.40-0.96, P = .031) compared to that in patients prescribed atorvastatin. Regarding the progression from normal blood glucose or prediabetes to DM, there were no significant differences among all statins. CONCLUSIONS: Lower DM incidence in patients prescribed pitavastatin appears to be primarily because of the lower rate of progression from normal blood glucose to prediabetes. These findings indicate that avoiding statins because of DM risk is unjustified and that clinicians should prescribe statins from the appropriate potency group. PMID- 28556207 TI - Characterization of Self-Defining Memories in Individuals with Severe Alcohol Use Disorders After Mid-Term Abstinence: The Impact of the Emotional Valence of Memories. AB - BACKGROUND: Self-defining memories (SDM) are distinguished from other autobiographical memory (AM) processes to delineate those associated with the sense of personal identity and continuity in one's individual history. With chronic alcohol consumption, the construction of such memories may be modified in terms of specificity, valence, meaning-making, and evoked topics. This study sought to characterize SDM in a population of 27 patients with alcohol use disorder (AUD) who had been abstinent for at least 2 months compared with 28 control participants. METHODS: Besides cognitive and clinical assessment, participants were told to describe verbally and date 5 SDM and their narratives were recorded. For each memory, 5 dimensions were evaluated: level of specificity, emotional valence, integration of meaning, topics, and distance of memory in time. RESULTS: Overall, SDM of participants with AUD were specifically characterized by (i) low specificity, (ii) low integration, (iii) a predominance of memories with negative emotional valence and a low frequency of positive memories, and (iv) a low frequency of topics related to success. When different dimensions of the SDM were crossed, their characteristics depended mainly on the valence of the memory. Negative memories were more frequent, more specific and more integrated, while positive SDM were less frequent, less specific and less integrated. CONCLUSIONS: The results underline the construction of a form of SDM with drinking problems that is mainly characterized by the disruption of positive memory and the presence of highly specific and integrated negative experiences. A disruption of the integration process modulated by the valence of memories could have repercussions on maintaining a sense of personal identity, the pursuit of personal goals and on social adaptability, and could constitute one of the main risks associated with persistent drinking problems. These results highlight the relevance of developing AM training programs for patients with AUD. PMID- 28556209 TI - THE EFFECT OF NICHE PREFERENCE ON POLYMORPHISM PROTECTION IN A HETEROGENEOUS ENVIRONMENT. AB - A model is proposed in which niche choice precedes natural selection in an individual's life span; the panmictic population occupies an environment divided into niches, each contributing a constant proportion of parents to the next generation. Niche choice and fitness within the niche are controlled either by the same locus or by two linked loci. The conditions for a protected polymorphism are derived. It is shown that niche preferences can increase the protective effect of natural selection over a polymorphism. This effect depends on the existence of a positive correlation between preference for a niche and relative fitness within that niche, and also on the relative size of the niches. In the absence of within-niche fitness differences, alleles that cause preference for different niches can still be protected. Alleles that determine preference for niches contributing little to the total population can be eliminated by the ability to choose between niches. PMID- 28556210 TI - SPATIAL AND TEMPORAL FACTORS AFFECTING COEXISTENCE AMONG SEXUAL AND CLONAL FORMS OF POECILIOPSIS. AB - We examined spatial and seasonal factors affecting coexistence of closely related sexual and asexual fishes of the genus Poeciliopsis living in two ecologically distinct stream habitats. Stream order and productivity influenced frequencies of these fish, and local habitat patchiness contributed strongly to spatial segregation. The magnitude and direction of local segregation was unaffected by striking seasonal variation in one stream. For the second stream, the relative contributions of local, geographical, and seasonal components of spatial variation were assessed through estimation of variance components. Spatial segregation at the smallest scale accounted for the largest proportion of variance in the distribution of species and clones. PMID- 28556211 TI - ORIGIN AND EVOLUTION OF CONTINENTAL BIOTAS: SPECIATION AND HISTORICAL CONGRUENCE WITHIN THE AUSTRALIAN AVIFAUNA. AB - Factors governing the origin and evolution of continental biotas were investigated using an analysis of speciation patterns within the Australian avifauna. Phylogenetic relationships within seven lineages of birds were analyzed by numerical cladistic techniques applied to data sets of morphological characters. These relationships revealed extensive congruence among the spatial and temporal histories of lineages whose species are endemic to common areas of endemism. A general hypothesis is constructed to explain this congruence in which widespread biotas are postulated to have been partitioned into areas of endemism by the origin of geomorphological and/or ecological-climatic barriers. Congruence in these phylogenetic patterns of differentiation suggests the following historical pattern of interrelationships for areas of endemism along the northern and eastern coasts of Australia: (Kimberley Plateau + Arnhem Land) + ([New Guinea + Cape York Peninsula] + [Atherton Plateau + Eastern Coastal Rainforest]). Likewise, this study indicates that the arid interior avifauna was segregated into two closely related biotas (Eastern and Western Desert biotas) by the Eyrean Barrier. These biotas are, in turn, related to a more mesic avifauna that was itself subdivided into areas of endemism located in the Southwest and Southeast corners of the continent. PMID- 28556212 TI - ON BEING THE RIGHT SIZE: NATURAL SELECTION AND BODY SIZE IN THE HERRING GULL. PMID- 28556213 TI - PHENOTYPIC EVOLUTION BY NEUTRAL MUTATION. AB - A general model is developed for predicting the genetic variance within populations and the rate of divergence of population mean phenotypes for quantitative traits under the joint operation of random sampling drift and mutation in the absence of selection. In addition to incorporating the dominance effects of mutant alleles, the model yields some insight into the effects of linkage and the mating system on the mutational production of quantitative genetic variation. Despite these additional and potentially serious complications, it is found that, for small populations, the simple predictions obtained by previous investigators using additive-genetic models hold reasonably well. Even after accounting for dominance and linkage, the equilibrium level of genetic variance is unlikely to be much less than 2NVm or to be more than 4NVm , where N is the effective population size and Vm is the new variance from mutation appearing each generation. The rate of increase of the between-line variance per generation ultimately equals 2Vm regardless of population size, although the time to attain the asymptotic rate is proportional to N. Expressions are presented for the rate of approach to the equilibrium level of genetic variance and for the expected variance of the within-population and between-population genetic variances. The relevance of the derived model, which amounts to a generalization of the neutral theory to the phenotypic level, is discussed in the context of the detection of natural selection, the maintenance of pure lines for biomedical and agricultural purposes, the development of genetic conservation programs, and the design of indices of morphological distance between species. PMID- 28556215 TI - EVOLUTIONARY MONOGRAPHS. PMID- 28556214 TI - EVALUATING KINSHIP OF NEWLY SETTLED JUVENILES WITHIN SOCIAL GROUPS OF THE CORAL REEF FISH ANTHIAS SQUAMIPINNIS. AB - It is conventionally assumed that eggs and/or larvae of most coral reef fishes are thoroughly mixed during a pelagic phase, so that juvenile recruits at any particular reef site represent a random sample of the reproductive products entering the local gene pool. However, a recent review of biological factors that might limit mixing raised the testable hypothesis that groups of genetically related individuals may sometimes persist through the pelagic phase and settle as sibling cohorts (Shapiro, 1983). Here we provide a critical genetic test of this hypothesis by examining allozyme variation in juvenile aggregations of the serranid reef fish, Anthias squamipinnis. Results demonstrate that juvenile cohorts within large social groups in Anthias are not composed exclusively or predominantly of siblings, but rather represent a random sample of progeny from many matings. Also included are considerations of allelic and genotypic criteria by which hypotheses about sibling assemblages might generally be evaluated. PMID- 28556216 TI - ADAPTIVE RADIATION IN THE HAWAIIAN SILVERSWORD ALLIANCE (COMPOSITAE-MADIINAE). II. CYTOGENETICS OF ARTIFICIAL AND NATURAL HYBRIDS. AB - The Hawaiian silversword alliance of Argyroxiphium, Dubautia, and Wilkesia, in spite of exhibiting spectacular morphological, ecological, physiological, and chromosomal diversity, is remarkably cohesive, genetically. This is attested to by the ease of production of artificial hybrids and by the high frequency of spontaneous hybridization among such life forms as mat-forming subshrub, monocarpic rosette shrub, polycarpic shrub, cushion plant, tree, and vine. Even the least fertile of these hybrids is capable of producing backcross progeny. Moreover, first generation interspecific and intergeneric hybrids have been successfully used to produce trispecific hybrids in a number of instances. In general, the widest hybrid combinations have been as readily produced as crosses within a species. At present eight genomes or chromosome races distinguished by reciprocal translocations are recognized on the basis of meiotic analysis of artificial and spontaneous hybrids. Seven of these races are found among those species with 14 pairs of chromosomes. The eighth genome very likely characterizes all nine species of this alliance that have 13 pairs of chromosomes. The cytogenetic data indicate that redundancy of translocations involving the same chromosomes has been a recurrent theme in the chromosomal differentiation of these taxa. There appears to be little, if any, correlation between chromosomal evolution and adaptive radiation as assessed by gross habital differentiation in this group. However, within Dubautia, a novel ecophysiological trait associated with colonization of xeric habitats is restricted to species with n = 13. In contrast to the bulk of the Hawaiian flora, which is characterized by self compatibility and chromosomal stability, it is suggested that the occurrence of self-incompatibility in the Hawaiian Madiinae may have favored selection of supergenes via chromosomal repatterning, and this may account for the diversity of chromosome structure seen in this group. PMID- 28556217 TI - PLEISTOCENE GLACIATIONS, FLUCTUATING RANGES, AND LOW GENETIC VARIABILITY IN A LARGE MAMMAL (OVIS DALLI). PMID- 28556218 TI - EVOLUTION OF ADULT MORPHOLOGY AND LIFE-HISTORY CHARACTERS IN CAVERNICOLOUS PTOMAPHAGUS BEETLES. AB - Morphological and life-history characters were determined for a series of six increasingly cavernicolous species of eastern United States Ptomaphagus beetles. Contrary to expectations, dimensions of only some adult structural characters uniformly covary as an overall measure of evolutionary adaptation for cave life. Adult reproductive characters that show adaptation for cave life are loss of reproductive seasonality and production of fewer and larger eggs. Significant change in pre-imaginal life-cycle stages was not found. This is in contrast to cavernicolous bathysciine beetles of Europe which show remarkable adaptive trends in pre-imaginal stages, but larval adaptations are not strongly coevolved with adult cave-adaptive characters. This suggests that evolution of cave adaptation in adult endopterygote insects occurs before and independently from that in larvae. PMID- 28556219 TI - THE EVOLUTION OF PHENOTYPIC PLASTICITY IN LIFE-HISTORY TRAITS: PREDICTIONS OF REACTION NORMS FOR AGE AND SIZE AT MATURITY. AB - We used life-history theory to predict reaction norms for age and size at maturation. We assumed that fecundity increases with size and that juvenile mortality rates of offspring decrease as ages-at-maturity of parents increase, then calculated the reaction norm by varying growth rate and calculating an optimal age at maturity for each growth rate. The reaction norm for maturation should take one of at least four shapes that depend on specific relations between changes in growth rates and changes in adult mortality rates, juvenile mortality rates, or both. Most organisms should mature neither at a fixed size nor at a fixed age, but along an age-size trajectory. The model makes possible a clear distinction between the genetic and phenotypic components of variation. The evolved response to selection is reflected in the shape and position of the reaction norm. The phenotypic response of a single organism to rapid or slow growth is defined by the location of its maturation event as a point on the reaction norm. A quantitative test with data from 19 populations and species of fish showed that predictions were in good agreement with observations (r = 0.93, P < 0.0001). The predictions of the model also agreed qualitatively with observed phenotypic variation in age and size at maturity in humans, platyfish, fruit flies, and red deer. This preliminary success suggests that experiments designed to test the predictions directly will be worthwhile. PMID- 28556222 TI - SPECIAL ANNOUNCEMENT. PMID- 28556220 TI - MORPHOLOGICAL ADAPTATION TO HOST PLANTS IN UROLEUCON (HOMOPTERA: APHIDIDAE). AB - The morphology of host-specific Old World Uroleucon (Homoptera: Aphididae) species is related to features of their host plant species (Asteraceae and Campanulaceae) by canonical correlation analysis. Aphid species on pubescent host species have longer rostra and shorter hind tarsi, adaptations for feeding and walking on hirsute surfaces. Also, aphid species on taller hosts are larger. The positive relationship between rostrum length and host trichome density is further supported by simple regression analyses on two species complexes. Regression parameters differ between groups, suggesting different responses to different trichome types. This morphological adaptation involves characters used extensively by taxonomists and could result in convergence obscuring phylogenetic relationships of herbivore taxa and, particularly, the relation of herbivore phylogeny to host phylogeny. PMID- 28556223 TI - INHIBITION OF FEMALE DROSOPHILA MELANOGASTER REMATING BY A SEMINAL FLUID PROTEIN (ESTERASE 6). AB - Recent experiments have indicated that EST 6 transferred to D. melanogaster females during copulation mediates a large decrease in their attractiveness within the first six hours after mating. This decrease in attractiveness could increase the male's fitness if it were associated with less frequent remating by their mates, because a large proportion of the first male's sperm is lost if a female remates within one day. Here, I confirm a strong EST 6 influence on the receptivity of mated females; females with EST 6+ first mates remate significantly less frequently between 6 and 18 hours after mating than females that have not received EST 6 in the ejaculate. However, the previously observed effect of EST 6 on the attractiveness of mated females could not be substantiated. Transfer of EST 6 did not lead to a significant difference in attractiveness between EST 6 degrees -and EST 6+ -mated females at any time within the first 10 hours after mating for females from either of two strains. PMID- 28556224 TI - THE EVOLUTION OF WING DIMORPHISM IN INSECTS. AB - Wing-dimorphic insects are excellent subjects for a study of the evolution of dispersal since the nondispersing brachypterous morph is easily recognized. The purpose of this paper is to develop a framework within which the evolution of wing dimorphism can be understood. A review of the literature indicates that the presence or absence of wings may be controlled by a single locus, two-allele genetic system or a polygenic system. Both types of inheritance can be subsumed within a general threshold model. An increase in the frequency of a brachypterous morph in a population may result from an increased relative fitness of this morph or the emigration of the macropterous type. The abundance of wing-polymorphic species argues for an increased fitness of the brachypterous form. An analysis of the life-history characteristics of 22 species of insects indicates that the brachypterous morph is both more fecund and reproduces earlier that the macropterous morph. Unfortunately, data on males are generally lacking. It is suggested that suppression of wing production results when some hormone, perhaps juvenile hormone, exceeds a threshold value during a critical stage of development. Further, it is known that in the monomorphically winged species Oncopeltus fasciatus both flight and oviposition are regulated by the titer of juvenile hormone. These observations are used to construct a possible pathway for the evolution of wing dimorphism. This suggests that evolution to a dimorphic species requires both an increase in the rate of production of the wing suppressing hormone and a change in the threshold level at which wing and wing muscle production are suppressed. The stage in this evolutionary sequence that an organism will reach depends on the stability of the habitat. PMID- 28556225 TI - DINOSAURS FOR GROWN-UPS. PMID- 28556226 TI - GENETIC VARIATION IN PLANT-INSECT ASSOCIATIONS: SURVIVAL OF LEPTINOTARSA DECEMLINEATA POPULATIONS ON SOLANUM CAROLINENSE. AB - Populations of the Colorado potato beetle, Leptinotarsa decemlineata (Coleoptera: Chrysomelidae), from the east coast of the United States differ in their ability to survive on a wild host, Solanum carolinense (Solanaceae), but not on their most important cultivated host, Solanum tuberosum. On the wild host, the North Carolina population survived best, while populations from Virginia, New Jersey, and Connecticut exhibited uniformly low survival. Formal genetic studies of populations from Connecticut and North Carolina demonstrated heritable variation in the ability to survive on S. carolinense both between and within populations; the North Carolina population had the higher heritability for this trait. Overall, there was no genetic variation between populations or within the North Carolina population for survival on S. tuberosum, but such variation existed within the Connecticut population. Hybrids and backcrosses between these two lines all survived at intermediate levels, although survivorship did not appear to be inherited additively. Differences in survival were greater than differences in adult weight at emergence and development time of the survivors. Leptinotarsa decemlineata was first reported from North Carolina less than 100 years ago. The rapid expansion of L. decemlineata's host range in North Carolina is attributed to the poor synchrony between the insect and S. tuberosum compared to more northerly locations. In contrast to the prediction of a strong negative correlation in fitness on different host species, the ability of L. decemlineata to survive on S. carolinense was not correlated with that on S. tuberosum. Adult weight and female development time were significantly positively correlated across hosts. Our results are in accord with most previous studies in which strong negative correlations in fitness of specialized phytophagous insects feeding on different hosts were expected, sought, but not found. PMID- 28556227 TI - ECOLOGICAL ENTOMOLOGY. PMID- 28556228 TI - THE FITNESS CONSEQUENCES OF MULTIPLE-LOCUS HETEROZYGOSITY UNDER THE MULTIPLICATIVE OVERDOMINANCE AND INBREEDING DEPRESSION MODELS. AB - There is a growing body of literature suggesting that the fitness of an individual increases with the observed number of heterozygous loci. Broad theoretical considerations indicate that under various sorts of balancing selection, this is what one should generally expect in a population of multiple locus genotypes. To date, however, it has not been possible to distinguish between two potential explanations of the phenomenon. The first explanation is that the loci examined are themselves responsible for the fitness differences observed (or, equivalents, are very closely linked to those that do). The genetic variation in question is thought to be maintained in polymorphic equilibrium by some form of balancing selection. The second explanation assumes that the observed loci are themselves selectively irrelevant but that their heterozygosity reflects that of the total genome. Genomic heterozygosity is thought to be predictive of fitness, being an obverse measure of generalized inbreeding depression. We provide a formal derivation of an explicit relationship between fitness and multiple-locus genotype for a simple form of the first explanation, the multiplicative overdominance model. The inbreeding depression model is a degenerate special case of this more general formulation. A formal estimation and testing framework is constructed that should facilitate evaluation of the two models with empiric data on heterozygosity and fitness. PMID- 28556229 TI - SYMMETRY VERSUS ASYMMETRY IN SEXUAL ISOLATION EXPERIMENTS. AB - Two hypotheses predicting the ancestral or derived status of populations and based on asymmetrical mate discrimination (Kaneshiro, 1976; Watanabe and Kawanishi, 1979) were tested using nine laboratory populations of D. simulans, a highly outcrossed ancestral population, and eight populations derived from it via founder-flush-crash cycles. The data from individual mating tests using pairwise combinations of these populations fit the Kaneshiro hypothesis reasonably well, rejecting the Watanabe-Kawanishi hypothesis. However, more powerful tests rejected the Kaneshiro hypothesis for the data we analyzed. The values for derived females predicted by the Kaneshiro hypothesis were biased: they were consistently high for derived males and consistently low for ancestral males. We propose a hypothesis, based on variation in mating propensities and symmetrical mate discrimination. We assessed the power of Kaneshiro's and our hypotheses to predict the number of matings between derived females and derived males by plotting predicted vs. observed values and fitting these points to the expected line of unit slope passing through the origin. Predictions of our hypothesis explained more of the variance (r2 = 0.87) than predictions of the Kaneshiro model (r2 = 0.63). While asymmetrical sexual isolation undoubtedly occurs between some species, its existence cannot be determined simply by measuring mating frequencies in a single experiment. PMID- 28556230 TI - BODY SIZE OF INSULAR LIZARDS: A PATTERN OF HOLOCENE DWARFISM. AB - Until recently there have been scant historical data available to test and supplement studies on the evolution of body size within insular lizards. However, there is now an accumulating fossil record from islands which shows that numerous species have declined in average maximum body size since the beginning of the Holocene, regardless of phylogenetic afffinities, habits, or even size of the species itself. Coincident with decline in body size, human colonization of islands has permanently altered insular environments, with the consequence that native flora and fauna have been depleted. Indeed, the fossil record documents high extinction rates among insular vertebrates during the past few thousand years. It follows that resource deterioration may have led to the reduction of lizard body size, as expressed genotypically in selection for corresponding smaller dimensions, and phenotypically through arrested growth and development leading to compression of the age-class structure. The effect of human settlement on small islands has been underestimated, and although the consequences do not render completely in vain the attempts to understand ecological processes on them, they are of sufficient magnitude to stress caution in any assessment of a modern insular biota. PMID- 28556231 TI - GENETIC CLONAL RECOGNITION ABILITIES IN MARINE INVERTEBRATES MUST BE MAINTAINED BY SELECTION FOR SOMETHING ELSE. PMID- 28556232 TI - Decreased plasma beta-amyloid in the Alzheimer's disease APP A673T variant carriers. AB - We investigated the association of Alzheimer's disease (AD)-related rare variants APP A673T and ABCA7 rs200538373-C with the levels of beta-amyloid (Abeta) and parameters of metabolic and cardiovascular health in a population-based cohort of healthy middle-aged and elderly men. Carriers of protective APP A673T variant had, on average, 28% lower levels of Abeta40 and Abeta42 in plasma as compared to the controls and the carriers of ABCA7 rs200538373-C. This is the first report to show decreased Abeta levels in plasma in APP A673T carriers and thus provides evidence that lower Abeta levels throughout life may be protective against AD. Ann Neurol 2017;82:128-132. PMID- 28556234 TI - Diagnostic imaging of oronasal fistulas in a dachshund. AB - Oronasal fistula development is described anecdotally as a common disease process in the dachshund but little is known about its imaging appearance. This case report describes the clinical presentation, computed tomography (CT) characterisation, dental radiograph confirmation and treatment of bilateral oronasal fistulas in a 14-year-old dachshund. PMID- 28556233 TI - Poor peripheral blood stem cell mobilization affects long-term outcomes in multiple myeloma patients undergoing autologous stem cell transplantation. AB - BACKGROUND: Peripheral blood stem cell (PBSC) mobilization is routinely undertaken prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). A number of studies have identified risk factors for poor PBSC mobilization, however, little data exists to correlate mobilization with disease-specific outcomes in this patient population. Prospective work in MM has demonstrated similar outcomes in a homogenous patient population. METHODS: In this single institution analysis, we retrospectively studied the impact of poor PBSC mobilization on progression free survival (PFS) and OS in MM patients undergoing PBSC mobilization. Poor mobilizers are defined as patients that collected < 4 * 106 CD34+ cells/kg over maximum of 5 apheresis days, or those that required >=2 mobilization cycles to achieve this target. RESULTS: We confirm that poor PBSC mobilization is significantly associated with a shortened PFS (P = .0012) and OS (P = .0005) compared with good mobilizers. Our univariate analysis also shows that independent risk factors for poor mobilization include male gender, higher ideal body weight, and a greater median number of lines of chemotherapy prior to PBSC mobilization. However, by multivariate analysis, only number of prior lines of chemotherapy remains significantly predictive of poor mobilization (Odds ratio 1.857, P = .0095). The use of high-dose G-CSF (> 10 mcg/kg/day) and/or plerixafor can significantly improve mobilization and ASCT chances in this population. DISCUSSION: These data indicate that poor mobilization can be predictable and is associated with more aggressive disease biology and worse outcomes, warranting intensive post-ASCT management. PMID- 28556235 TI - Genotoxicity testing approaches for the safety assessment of substances used in food contact materials prior to their authorization in the European Union. AB - Food contact materials are all materials and articles intended to come directly or indirectly into contact with food. Before being included in the positive European "Union list" of authorized substances (monomers, other starting substances and additives) for plastic food contact materials, the European Food Safety Authority (EFSA) must assess their safety "in use". If relevant for risk, the safety of the main impurities, reaction and degradation products originating from the manufacturing process is also evaluated. Information on genotoxicity is always required irrespective of the extent of migration and the resulting human exposure, in view of the theoretical lack of threshold for genotoxic events. The 2008 EFSA approach, requiring the testing of food contact materials in three in vitro mutagenicity tests, though still acceptable, is now superseded by the 2011 EFSA Scientific Committee's recommendation for only two complementary tests including a bacterial gene mutation test and an in vitro micronucleus test, to detect two main genetic endpoints (i.e., gene mutations and chromosome aberrations). Follow-up of in vitro positive results depends on the type of genetic effect and on the substance's systemic availability. In this study, we provide an analysis of the data on genotoxicity testing gathered by EFSA on food contact materials for the period 1992-2015. We also illustrate practical examples of the approaches that EFSA took when evaluating "non standard" food contact chemicals (e.g., polymeric additives, oligomer or other reaction mixtures, and nanosubstances). Additionally, EFSA's experience gained from using non testing methods and/or future possibilities in this area are discussed. Environ. Mol. Mutagen. 58:361-374, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28556236 TI - Osteoporosis in Crisis: It's Time to Focus on Fracture. AB - A crisis in osteoporosis treatment exists; the majority of those who sustain fracture do not receive treatment to reduce future fracture risk. This crisis presents an opportunity to focus the field from osteoporosis to fracture, the outcome of consequence. Proposed here is a change in focus suggesting that 1) attempts to define the level of trauma leading to fracture are counterproductive and that all fractures in older adults merit consideration of evaluation and 2) bone loss is not the entire problem but rather part of a broader syndrome including osteoporosis, sarcopenia, and other factors leading to fracture. With this approach, all fractures in older adults should be evaluated for potential lifestyle, non-pharmacological, and pharmacological interventions that could be implemented to reduce the risk of fracture recurrence. (c) 2017 American Society for Bone and Mineral Research. PMID- 28556238 TI - X-inactive specific transcript RNA in-situ hybridization as a tool for resolving specimen contamination events. PMID- 28556237 TI - Characteristics and outcomes of patients with profound hyponatraemia due to primary polydipsia. AB - OBJECTIVE: Hyponatraemia due to excessive fluid intake (ie primary polydipsia [PP]) is common. It may culminate in profound hyponatraemia-carrying considerable risk of morbidity. However, data on patients with PP leading to hyponatraemia are lacking. Herein, we describe the characteristics of polydiptic patients hospitalized with profound hyponatraemia and assess 1-year outcomes. DESIGN: Substudy of the prospective observational Co-MED Study. PATIENTS: Patients with an episode of profound hyponatraemia (<=125 mmol/L) due to PP in the medical emergency were eligible and classified into psychogenic polydipsia (PsyP), dipsogenic polydipsia (DiP) and beer potomania (BP). MEASUREMENTS: Symptoms, laboratory findings and factors contributing to hyponatraemia (comorbidities, medication and liquid intake) were assessed. A 1-year follow-up was performed to evaluate recurrence of hyponatraemia, readmission rate and mortality. RESULTS: Twenty-three patients were included (median age 56 years [IQR 50-65], 74% female), seven had PsyP, eight had DiP and eight had BP. Median serum sodium of all patients was 121 mmol/L (IQR 114-123), median urine osmolality 167 mmol/L (IQR 105-184) and median copeptin 3.6 mmol/L (IQR 1.9-5.5). Psychiatric diagnoses, particularly dependency disorder (43%) and depression (35%), were highly prevalent. Factors provoking hyponatraemia were found in all patients (eg acute water load, medication, stress). During the follow-up period, 67% of patients were readmitted, 52% of these with rehyponatraemia, and three patients (38%) with BP died. CONCLUSION: Patients with PP are more likely to be female and to have addictive and affective disorders. Given the high recurrence, rehospitalization and mortality rate, careful monitoring and long-term follow-up including controls of serum sodium, education and behavioural therapy are needed. PMID- 28556239 TI - Simplified derivation of stopping power ratio in the human body from dual-energy CT data. AB - PURPOSE: The main objective of this study is to propose an alternative parameterization for the empirical relation between mean excitation energies (I value) and effective atomic numbers (Zeff ) of human tissues, and to present a simplified formulation (which we called DEEDZ-SPR) for deriving the stopping power ratio (SPR) from dual-energy (DE) CT data via electron density (rhoe ) and Zeff calibration. METHODS: We performed a numerical analysis of this DEEDZ-SPR method for the human-body-equivalent tissues of ICRU Report 46, as objects of interest with unknown SPR and rhoe . The attenuation coefficients of these materials were calculated using the XCOM photon cross-sections database. We also applied the DEEDZ-SPR conversion to experimental DECT data available in the literature, which was measured for the tissue-characterization phantom using a dual-source CT scanner at 80 kV and 140 kV/Sn. RESULTS: It was found that the DEEDZ-SPR conversion enables the calculation of SPR simply by means of the weighted subtraction of an electron-density image and a low- or high-kV CT image. The simulated SPRs were in excellent agreement with the reference values over the SPR range from 0.258 (lung) to 3.638 (bone mineral-hydroxyapatite). The relative deviations from the reference SPR were within +/-0.6% for all ICRU-46 human tissues, except for the thyroid that presented a -1.1% deviation. The overall root-mean-square error was 0.21%. Application to experimental DECT data confirmed this agreement within the experimental accuracy, which demonstrates the practical feasibility of the method. CONCLUSIONS: The DEEDZ-SPR conversion method could facilitate the construction of SPR images as accurately as a recent DECT-based calibration procedure of SPR parameterization based directly on the CT numbers in a DECT data set. PMID- 28556240 TI - Oocyte viability and cortical activation under different salt solutions in Prochilodus lineatus (Teleostei: Prochilodontidae). AB - This study aimed to evaluate the effect of five salt solutions in the maintenance of morphological features of cortical alveolus, hydration and fertilization capacity of Prochilodus lineatus oocytes. For this purpose, five saline solutions were tested: Ringer's solution, Ringer's lactate solution, Hank's balanced salt solution (HBSS), Hank's balanced salt solution without calcium (HBSS without calcium) and solution for salmonid eggs. Oocytes were maintained for 2 hr in saline solution with controlled temperature subsequently evaluated for hydration, cortical activation and fertilization ability. In the evaluation of the fertilization ability, two controls were used: C1-fertilized oocytes after extrusion-and C2-oocytes kept in ovarian fluid and fertilized after 2 hr. There was a significant reduction in the viability of oocytes C2 (28.8% +/- 12.9%) compared to C1 (65.3% +/- 26.7%), and no significant differences were found between treatments HBSS and HBSS without calcium and C2. Only HBSS and HBSS without calcium maintained the non-activated state of the gametes, with a fertilization rate of 16.4% +/- 6.7% and 5.6% +/- 2.3%, respectively; however, they did not extend the viability of oocytes, such that they continued to undergo degradation during the storage period, similar to oocytes retained only in ovarian fluid. PMID- 28556241 TI - Carbon and oxygen minibeam radiation therapy: An experimental dosimetric evaluation. AB - PURPOSE: To perform dosimetric characterization of a minibeam collimator in both carbon and oxygen ion beams to guide optimal setup geometry and irradiation for future radiobiological studies. METHODS: Carbon and oxygen minibeams were generated using a prototype tungsten multislit collimator presenting line apertures 700 MUm wide, which are spaced 3500 MUm centre-to-centre distance apart. Several radiation beam spots generated the desired field size of 15 * 15 mm2 and production of a 50 mm long spread out Bragg peak (SOBP) centered at 80 mm depth in water. Dose evaluations were performed with two different detectors: a PTW microDiamond(r) single crystal diamond detector and radiochromic films (EBT3). Peak-to-valley dose ratio (PVDR) values, output factors (OF), penumbras, and full width at half maximum (FWHM) were measured. RESULTS: Measured lateral dose profiles exhibited spatial fractionation of dose at depth in a water phantom in the expected form of peaks and valleys for both carbon and oxygen radiation fields. The diamond detector and radiochromic film provided measurements of PVDR in good agreement. PVDR values at shallow depth were about 60 and decreased to about 10 at 80 mm depth in water. OF in the center of the SOBP was about 0.4; this value is larger than the corresponding one in proton minibeam radiation therapy measured using a comparable collimator due to a reduced lateral scattering for carbon and oxygen minibeams. CONCLUSIONS: Carbon and oxygen minibeams may be produced by a mechanical collimator. PVDR values and output factors measured in this first study of these minibeam radiation types indicate there is potential for their therapeutic use. Optimization of minibeam collimator design and the number and size of focal spots for irradiation are advocated to improve PDVR values and dose distributions for each specific applied use. PMID- 28556243 TI - Anatomical study of the internal nasal branch of the infraorbital nerve: Application to Minimizing Nerve Damage With Surgery In and Around the Nose. AB - The internal nasal branch of the infraorbital nerve (ION) runs down the nose and around the ala to be distributed to the nasal septum and vestibule. The aim of this study was to measure the internal nasal branch around the ala of the nose and discuss its possible relevance in clinical/surgical practice. Twelve sides from seven specimens derived from fresh frozen and embalmed Caucasian cadaveric heads were dissected. The specimens included three males and four females. The ages of the cadavers at death ranged from 65 to 84 years. The diameter of the internal nasal branch, horizontal distance from the lateral contour of the ala (Point A) to the branch (distance H) and vertical distance from the bottom part of the ala (Point B) to the branch (distance V) were recorded. Distance H ranged from -1.6 to 1.5 mm on right sides and -1.0 to 1.5 mm on left sides. The diameter of the nerves at Point A ranged from 1.3 to 1.8 mm on right sides and 1.3 to 1.6 mm on left sides. Distance V ranged from -1.5 to 1.0 mm on right sides and -2.3 to 1.1 mm on left sides. The diameter of the nerves at Point B ranged from 0.7 to 1.3 mm on right sides and 0.8 to 1.2 mm on left sides. The results of this study are the first to detail the topography of the internal nasal branch of the ION. Clin. Anat. 30:817-820, 2017. (c) 2017Wiley Periodicals, Inc. PMID- 28556242 TI - Cerebral compensation during motor function in Friedreich ataxia: The IMAGE-FRDA study. AB - BACKGROUND: Friedreich ataxia is characterized by progressive motor incoordination that is linked to peripheral, spinal, and cerebellar neuropathology. Cerebral abnormalities are also reported in Friedreich ataxia, but their role in disease expression remains unclear. METHODS: In this cross sectional functional magnetic resonance imaging study, 25 individuals with Friedreich ataxia and 33 healthy controls performed simple (self-paced single finger) and complex (visually cued multifinger) tapping tasks to respectively gauge basic and attentionally demanding motor behavior. For each task, whole brain functional activations were compared between groups and correlated with disease severity and offline measures of motor dexterity. RESULTS: During simple finger tapping, cerebral hyperactivation in individuals with Friedreich ataxia at the lower end of clinical severity and cerebral hypoactivation in those more severely affected was observed in premotor/ventral attention brain regions, including the supplementary motor area and anterior insula. Greater activation in this network correlated with greater offline finger tapping precision. Complex, attentionally demanding finger tapping was also associated with cerebral hyperactivation, but in this case within dorsolateral prefrontal regions of the executive control network and superior parietal regions of the dorsal attention system. Greater offline motor precision was associated with less activation in the dorsal attention network. DISCUSSION: Compensatory activity is evident in the cerebral cortex in individuals with Friedreich ataxia. Early compensation followed by later decline in premotor/ventral attention systems demonstrates capacity-limited neural reserve, while the additional engagement of higher order brain networks is indicative of compensatory task strategies. Network-level changes in cerebral brain function thus potentially serve to mitigate the impact of motor impairments in Friedreich ataxia. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28556244 TI - Coherence enhancement in quantitative susceptibility mapping by means of anisotropic weighting in morphology enabled dipole inversion. AB - PURPOSE: To investigate an anisotropic structural prior in morphology enabled dipole inversion (MEDI) for improving accuracy in quantitative susceptibility mapping (QSM). THEORY AND METHODS: Anisotropic weighting (AW) was devised and implemented to incorporate orientation information into the edge agreement in the MEDI method. AW performance was compared with isotropic weighting by testing and validating on in vivo brain multiple orientation MRI data using COSMOS and the (33) component of the susceptibility tensor as reference. RESULTS: Suppressing streaking artifacts, AW improved not only QSM image quality but also accuracy in terms of RMSE (root mean square error), HFEN (high frequency error norm), SSIM (structural similarity index), and GDA (gradient direction agreement). In addition, it outperformed isotropic weighting in region of interest-based analysis. From a computational perspective, AW was as fast as isotropic weighting, taking approximately the same central processing unit times. CONCLUSION: Using AW in MEDI improves QSM accuracy compared with isotropic weighting. Magn Reson Med 79:1172-1180, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28556245 TI - Physico-chemical properties, rheology and degree of esterification of passion fruit (Passiflora edulis f. flavicarpa) peel flour. AB - BACKGROUND: The peel of yellow passion fruit is as an agro-industrial waste of great environmental impact, representing more than 50% of the total weight of the fruit. For this reason, and also considering its importance as a source of functional components such as pectin, this organic waste is increasingly attracting the attention of researchers. The aim of this study was to investigate the physico-chemical composition and physical properties of this material, which may be of interest to the food industry. RESULTS: We obtained two samples of passion fruit peel flour applying different processes: flour without treatment (FWOT) and flour with treatment by maceration (FWT). It was found that the flour samples contain, respectively, 372.4 g kg-1 and 246.7 kg-1 of soluble fiber and, according to the FTIR analysis, this material corresponds to high and low methoxyl pectins, respectively. CONCLUSION: The flour obtained by maceration (FWT) offers greater benefits for industrial use, with 60% fewer tannins and greater thermal stability. In addition, this sample does not reabsorb moisture as easily, although FWOT also shows potential for use in dietary products. Considering the pseudoplastic properties of the flours, the application of both samples could be expanded to many industrial sectors. (c) 2017 Society of Chemical Industry. PMID- 28556247 TI - Enhanced quantitative susceptibility mapping (QSM) using real-time field control. AB - PURPOSE: To assess the potential of a real-time field-control (FC) system for mitigating effects of spatiotemporal field fluctuations in quantitative susceptibility mapping (QSM) at 7 T. METHODS: Magnitude, phase, and QSM images of phantoms and healthy volunteers were acquired under standard conditions and under induced field perturbation (FP) (phantoms: periodic water-bottle displacement; volunteers: deep breathing and forearm movement) with and without FC, which continuously detects and minimizes magnetic-field variations. RESULTS: Field control successfully eliminated FP-induced impairment of phantom image quality and deviations from a linear susceptibility increase for increasing gadolinium concentration in a Gd dilution series (y = 320x - 0.60, R2 = 0.93 for the scan with FP and FC versus y = 259x - 0.54, R2 = 0.78 for the scan with FP and no FC (slope literature value: 326 ppm L/mol)). Similarly, in volunteers, FC allowed a recovery of a FP-induced loss of identifiable brain structures and reduced the relative change of mean susceptibilities and standard deviations (93 +/- 53% to 34 +/- 46%) in all regions of interests with respect to the reference scan. CONCLUSIONS: Real-time FC improved the delineation of brain structures and the match of susceptibility values with reference values obtained without FP. Magn Reson Med 79:770-778, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28556246 TI - Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome. AB - Dravet syndrome, an early onset epileptic encephalopathy, is most often caused by de novo mutation of the neuronal voltage-gated sodium channel gene SCN1A. Mouse models with deletion of Scn1a recapitulate Dravet syndrome phenotypes, including spontaneous generalized tonic-clonic seizures, susceptibility to seizures induced by elevated body temperature, and elevated risk of sudden unexpected death in epilepsy. Importantly, the epilepsy phenotype of Dravet mouse models is highly strain-dependent, suggesting a strong influence of genetic modifiers. We previously identified Cacna1g, encoding the Cav3.1 subunit of the T-type calcium channel family, as an epilepsy modifier in the Scn2aQ54 transgenic epilepsy mouse model. In this study, we asked whether transgenic alteration of Cacna1g expression modifies severity of the Scn1a+/- Dravet phenotype. Scn1a+/- mice with decreased Cacna1g expression showed partial amelioration of disease phenotypes with improved survival and reduced spontaneous seizure frequency. However, reduced Cacna1g expression did not alter susceptibility to hyperthermia-induced seizures. Transgenic elevation of Cacna1g expression had no effect on the Scn1a+/ epilepsy phenotype. These results provide support for Cacna1g as a genetic modifier in a mouse model of Dravet syndrome and suggest that Cav3.1 may be a potential molecular target for therapeutic intervention in patients. PMID- 28556248 TI - Use of protocatechuic acid as the sole antioxidant in the base medium for in vitro culture of ovine isolated secondary follicles. AB - This study evaluated the effect of the protocatechuic acid (PCA) as the sole antioxidant in the base medium for in vitro culture of ovine secondary follicles. Secondary follicles (200-230 MUm) were isolated and cultured in alpha-minimal essential medium supplemented with BSA, insulin, glutamine and hypoxanthine (alpha-MEM: antioxidant-free medium) or alpha-MEM also added by transferrin, selenium and ascorbic acid (alpha-MEM+: with antioxidant) or alpha-MEM added by PCA (56.25; 112.5; 225; 450; or 900 MUg/ml). Moreover, after culture, oocytes were matured and the chromatin configuration and DNA fragmentation were evaluated. After 12 days, the treatment containing 56.25 MUg/ml PCA showed higher percentage of normal follicles than control medium or the other treatments (p < .05), except for 900 MUg/ml PCA (p > .05). The antrum formation was significantly higher in treatments containing 56.25, 112.5 or 900 MUg/ml PCA, compared to the alpha-MEM and similar (p > .05) to the other treatments. The rates of fully grown oocytes (>=110 MUm) were similar (p > .05) among all treatments containing PCA and alpha-MEM+, and those were superior (p < .05) than alpha-MEM, except for 450 MUg/ml PCA (p > .05). GSH levels and mitochondrial activity were higher (p < .05) in alpha-MEM+ than in alpha-MEM and similar (p > .05) to all PCA treatments. The rates of meiotic resumption and DNA fragmentation were similar (p > .05) among alpha-MEM+ and 56.25 MUg/ml PCA. In conclusion, PCA at 56.25 MUg/ml as the sole antioxidant added to the medium for ovine isolated secondary follicle culture maintains follicular survival, GSH and active mitochondria levels, meiotic developmental competence and DNA integrity of cultured oocytes. PMID- 28556249 TI - Characterization of Sodium Mobility and Binding by 23 Na NMR Spectroscopy in a Model Lipoproteic Emulsion Gel for Sodium Reduction. AB - The effects of formulation and processing parameters on sodium availability in a model lipid/protein-based emulsion gel were studied for purposes of sodium reduction. Heat-set model gels were prepared with varying levels of protein, lipid, and NaCl contents and high pressure homogenization treatments. Single quantum and double quantum-filtered 23 Na NMR spectroscopy experiments were used to characterize sodium mobility, structural order around "bound" (restricted mobility) sodium, and sodium binding, which have been correlated to saltiness perception in food systems previously. Total sodium mobility was lower in gels with higher protein or fat content, and was not affected by changes in homogenization pressure. The gels with increased protein, fat, or homogenization pressure had increased structure surrounding "bound" sodium and more relative "bound" sodium due to increased interfacial protein interactions. The data obtained in this study provide information on factors affecting sodium availability, which can be applied towards sodium reduction in lipid/protein based foods. PMID- 28556251 TI - Involving the public in mental health and learning disability research: Can we, should we, do we? AB - : WHAT IS KNOWN ON THE SUBJECT?: UK health policy is clear that researchers should involve the public throughout the research process. The public, including patients, carers and/or local citizens can bring a different and valuable perspective to the research process and improve the quality of research undertaken. Conducting health research is demanding with tight deadlines and scarce resources. This can make involving the public in research very challenging. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This is the first time the attitudes of researchers working in mental health and learning disability services towards PPI have been investigated. The principles of service user involvement in mental health and learning disability services may support PPI in research as a tool of collaboration and empowerment. This article extends our understanding of the cultural and attitudinal barriers to implementing PPI guidelines in mental health and learning disability services. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Researchers in mental health and learning disability services need to champion, share and publish effective involvement work. Structural barriers to PPI work should be addressed locally and successful strategies shared nationally and internationally. Where PPI guidelines are being developed, attention needs to be paid to cultural factors in the research community to win "hearts and minds" and support the effective integration of PPI across the whole research process. ABSTRACT: Introduction Patient and public involvement (PPI) is integral to UK health research guidance; however, implementation is inconsistent. There is little research into the attitudes of NHS health researchers towards PPI. Aim This study explored the attitude of researchers working in mental health and learning disability services in the UK towards PPI in health research. Method Using a qualitative methodology, semi structured interviews were conducted with a purposive sample of eight researchers. A framework approach was used in the analysis to generate themes and core concepts. Results Participants valued the perspective PPI could bring to research, but frustration with tokenistic approaches to involvement work was also evident. Some cultural and attitudinal barriers to integrating PPI across the whole research process were identified. Discussion Despite clear guidelines and established service user involvement, challenges still exist in the integration of PPI in mental health and learning disability research in the UK. Implications for practice Guidelines on PPI may not be enough to prompt changes in research practice. Leaders and researchers need to support attitudinal and cultural changes where required, to ensure the full potential of PPI in mental health and learning disability services research is realized. Relevance statement Findings suggest that despite clear guidelines and a history of service user involvement, there are still challenges to the integration of PPI in mental health and learning disability research in the UK. For countries where PPI guidelines are being developed, attention needs to be paid to cultural factors in the research community to win "hearts and minds" and support the effective integration of PPI across the whole research process. PMID- 28556250 TI - Nitric oxide induces monosaccharide accumulation through enzyme S-nitrosylation. AB - Nitric oxide (NO) is extensively involved in various growth processes and stress responses in plants; however, the regulatory mechanism of NO-modulated cellular sugar metabolism is still largely unknown. Here, we report that NO significantly inhibited monosaccharide catabolism by modulating sugar metabolic enzymes through S-nitrosylation (mainly by oxidizing dihydrolipoamide, a cofactor of pyruvate dehydrogenase). These S-nitrosylation modifications led to a decrease in cellular glycolysis enzymes and ATP synthase activities as well as declines in the content of acetyl coenzyme A, ATP, ADP-glucose and UDP-glucose, which eventually caused polysaccharide-biosynthesis inhibition and monosaccharide accumulation. Plant developmental defects that were caused by high levels of NO included delayed flowering time, retarded root growth and reduced starch granule formation. These phenotypic defects could be mediated by sucrose supplementation, suggesting an essential role of NO-sugar cross-talks in plant growth and development. Our findings suggest that molecular manipulations could be used to improve fruit and vegetable sweetness. PMID- 28556252 TI - Traumatic globe rupture after deep anterior lamellar keratoplasty-A novel management technique. AB - A traumatic wound dehiscence can occur many years after surgery in 2-6% of all keratoplasties. Intraocular tissue prolapse can lead to severe visual loss. Deep anterior lamellar keratoplasty (DALK) leads to higher wound stability because of the intact Descemet membrane. We report a case of a novel management of wound dehiscence following DALK. A 59-year-old patient underwent uncomplicated DALK for advanced keratoconus. Eighteen months later he experienced a traumatic wound dehiscence (globe rupture) after a fall. Visual acuity decreased to light perception on the affected eye, the iris and prolapsed vitreous were incarcerated, and no retinal details were recognizable. The corneal graft was dehiscent over eight clock hours, the Descemet membrane was ruptured, and the stroma dissolved over 30% of its surface in a bell shape. Primary wound closure was performed with nylon 10-0 single interrupted corneal sutures. One day after emergency treatment, a 23-gauge pars-plana-vitrectomy for vitreous hemorrhage was conducted and a retinal tear was treated with laser photocoagulation. The Descemet membrane was repositioned using a 23 g vitrectomy probe under air and the globe was filled with SF6 gas. Postoperatively, visual acuity increased to 6/15 and the cornea cleared up. Corneal graft and Descemet membrane repositioning after trauma can avoid a further keratoplasty and the risk of immunological rejection of donor endothelial cells. Clin. Anat. 31:56-59, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28556253 TI - Physical characterization of the quality of medical images does not adequately reflect their clinical quality. PMID- 28556254 TI - The Influence of pH and Sodium Hydroxide Exposure Time on Glucosamine and Acrylamide Levels in California-Style Black Ripe Olives. AB - Acrylic acid, N-acetyl-glucosamine and glucosamine were investigated for their role in the formation of acrylamide in California-style black ripe olives [CBROs]. Levels of acrylic acid and glucosamine are reported for the first time in fresh (333.50 +/- 21.88 and 243.59 +/- 10.06 nmol/g, respectively) and in brine-stored olives (184.50 +/- 6.02 and 165.88 +/- 11.51 nmol/g, respectively). Acrylamide levels significantly increased when acrylic acid (35.2%), N-acetyl glucosamine (29.9%), and glucosamine (124.0%) were added to olives prior to sterilization. However, isotope studies indicate these compounds do not contribute carbon and/or nitrogen atoms to acrylamide. The base-catalyzed degradation of glucosamine is demonstrated in olive pulp and a strong correlation (r2 = 0.9513) between glucosamine in olives before sterilization and acrylamide formed in processed CBROs is observed. Treatment with sodium hydroxide (pH > 12) significantly reduces acrylamide levels over 1 to 5 d without impacting olive fruit texture. PMID- 28556255 TI - National cohort study showed that infants with Down's syndrome faced a high risk of hospitalisation for the respiratory syncytial virus. AB - AIM: The respiratory syncytial virus (RSV) is a leading cause of hospitalisation in infants. We investigated this risk in children with Down's syndrome under two years of age, adjusted for other known risk factors. METHODS: This national, retrospective 1:2 matched cohort study comprised all Swedish children born with Down's from 2006 to 2011, who were each randomly matched to two controls without Down's. Data on RSV hospitalisation and risk factors for RSV were obtained from national registers. The risk of RSV hospitalisation was assessed using multivariable Cox regression with pairwise stratification. RESULTS: The study comprised 814 children with Down's and 1628 controls. We found that 82 children with Down's (10.1%) and 22 controls (1.4%) were hospitalised for RSV. The hazard ratio for children with Down's was 4.00 (95% confidence interval 1.58-10.13) for up to one year of age and 6.60 (95% CI: 2.83-15.38) for up to two years of age, adjusted for other risk factors. During the second year of life, RSV hospitalisation continued for children with Down's, while it was minimal for the controls. CONCLUSION: Children with Down's faced a high risk of RSV hospitalisation, which continued beyond the first year of age. PMID- 28556256 TI - Two-step inversion with a logarithmic transformation for microwave breast imaging. AB - PURPOSE: The authors have developed a new two-step microwave tomographic image reconstruction process specifically designed to incorporate logarithmic transformed microwave imaging algorithms as a means of significantly improving spatial resolution and target property recovery. Log transform eliminates the need for a priori information, but spatial filtering often integrated as part of the regularization required to stabilize image recovery, generally smooths image features and reduces object definition. The new implementation begins with this smoothed image as the first step, but then utilizes it as the starting estimate for a second step which continues the iterative process with a standard weighted Euclidean distance regularization. The penalty term of the latter restricts the new image to a multi-dimensional location close to the original but allows the algorithm to optimize the image without excessive smoothing. METHODS: The overall approach is based on a Gauss-Newton iterative scheme which incorporates a log transformation as a way of making the reconstruction more linear. It has been shown to be robust and not require a priori information as a condition for convergence, but does produce somewhat smoothed images as a result of associated regularization. The new two-step process utilizes the previous technique to generate a smoothed initial estimate and then uses the same reconstruction process with a weighted Euclidean distance penalty term. A simple and repeatable method has been implemented to determine the weighting factor without significant computational burden. The reconstructions are assessed according to conventional parameter estimation metrics. RESULTS: We apply the approach to phantom experiments using large, high contrast canonical shapes followed by a set of images recovered from an actual patient exam. The image improvements are substantial in regards to improved property recovery and feature delineation without inducing unwanted artifacts. Analysis of the residual vector after the reconstruction process further emphasizes that the minimization criterion is efficient with minimal biases. CONCLUSIONS: The outcome is a novel synergism of an established stable reconstruction algorithm with a conventional regularization technique. It maintains the ability to recover high quality microwave tomographic images without the bias of a priori information while substantially improving image quality. The results are confirmed on both phantom experiments and patient exams. PMID- 28556257 TI - Hierarchically Enhanced Impact Resistance of Bioinspired Composites. AB - An order of magnitude tougher than nacre, conch shells are known for being one of the toughest body armors in nature. However, the complexity of the conch shell architecture creates a barrier to emulating its cross-lamellar structure in synthetic materials. Here, a 3D biomimetic conch shell prototype is presented, which can replicate the crack arresting mechanisms embedded in the natural architecture. Through an integrated approach combining simulation, additive manufacturing, and drop tower testing, the function of hierarchy in conch shell's multiscale microarchitectures is explicated. The results show that adding the second level of cross-lamellar hierarchy can boost impact performance by 70% and 85% compared to a single-level hierarchy and the stiff constituent, respectively. The overarching mechanism responsible for the impact resistance of conch shell is the generation of pathways for crack deviation, which can be generalized to the design of future protective apparatus such as helmets and body armor. PMID- 28556258 TI - Extramedullary disease at diagnosis of AML does not influence outcome of patients undergoing allogeneic hematopoietic cell transplant in CR1. AB - OBJECTIVE: Extramedullary disease (EMD) at diagnosis of acute myeloid leukemia (AML) has been associated with increased risk of relapse and worse outcomes post chemotherapy. This study sought to investigate the association of EMD with outcomes following allogeneic hematopoietic cell transplantation (allo-HCT). METHODS: This single-center retrospective study investigated the impact of EMD at diagnosis on the outcome of patients transplanted for AML in first complete remission (CR1). The study included 303 consecutive patients with AML transplanted in CR1, median age 51 years (range 18-71). RESULTS: EMD at diagnosis was documented in 39 patients (13%), either histologically (26 patients) or clinically/radiologically (13 patients). Among the 39 EMD patients, 16 had CNS disease, seven had gingival infiltration, and five had leukemia cutis. On univariate analysis, EMD had no significant impact on survival, with a 3-year OS of 55% (95% CI 38-69) compared to 48% for the non-EMD group (95% CI 42%-55%) (P=.84). Likewise, 3-year CIR was 18% vs 19% (P=.86) and 3-year NRM was 26% vs 33% (P=.83) for EMD vs non-EMD groups, respectively. Multivariate analysis confirmed these results. CONCLUSIONS: We conclude that EMD at diagnosis of AML does not seem to influence outcomes following allo-HCT performed in CR1. PMID- 28556260 TI - Metal-Ligand Complex-Induced Ultrafast Charge-Carrier Relaxation and Charge Transfer Dynamics in CdX (X=S, Se, Te) Quantum Dots Sensitized with Nitrocatechol. AB - The present work describes the effect of interfacial complex formation on charge carrier dynamics in CdX (X=S, Se, Te) quantum dots (QDs) sensitized nitro catechol (NCAT). To compare experiments were also carried out with catechol (CAT) where no such complexation was observed. Time-resolved emission studies suggest faster charge separation in CdS(Se)/NCAT system as compared to CdS(Se)/CAT although change in Gibbs free energy for hole transfer is less in former as compared to later. This suggests that complex formation favours charge separation. Similar studies were also carried out in CdTe/NCAT system where hole transfer process was not viable thermodynamically but due to complex formation charge separation was observed. Femtosecond transient absorption studies have been carried out to monitor charge carrier dynamics in early time scale. Transient studies show faster electron cooling in QDs/NCAT system as compared to pure QDs and has been assigned to the complex formation on QDs surface. Interestingly charge recombination dynamics is much faster in QDs/NCAT system as compared to pure QDs which can be attributed to the stronger coupling between QDs and NCAT. Our results suggest a strong metal-ligand complex formation on QDs surface that controls charge carrier dynamics in QDs/molecular adsorbate system and to the best of our knowledge it has never been reported. PMID- 28556259 TI - Phenobarbital and midazolam increase neonatal seizure-associated neuronal injury. AB - Status epilepticus is common in neonates and infants, and is associated with neuronal injury and adverse developmental outcomes. gamma-Aminobutyric acidergic (GABAergic) drugs, the standard treatment for neonatal seizures, can have excitatory effects in the neonatal brain, which may worsen the seizures and their effects. Using a recently developed model of status epilepticus in postnatal day 7 rat pups that results in widespread neuronal injury, we found that the GABAA agonists phenobarbital and midazolam significantly increased status epilepticus associated neuronal injury in various brain regions. Our results suggest that more research is needed into the possible deleterious effects of GABAergic drugs on neonatal seizures and on excitotoxic neuronal injury in the immature brain. Ann Neurol 2017;82:115-120. PMID- 28556262 TI - The test of time: a history of clock drawing. AB - OBJECTIVE: The clock drawing test (CDT) has become one of the most widely used cognitive screening instruments in clinical and research settings. Its effectiveness, acceptability, and quick and easy administration have made it a staple for cognitive screening in dementia and a wide range of brain disorders. Despite a spike in popularity since the 1990s, its origins are relatively unknown. The goal of this review is to chronicle its saga and chart its usage over time. METHODS: PsycInfo, Medline, and PubMed literature searches were performed from earliest record to June 2016, in addition to manual cross referencing of bibliographies, with a focus before 1990. Summary of relevant articles and books up until 1989 is included, as well as clinical applications and surveys that track CDT usage over time. RESULTS: While MacDonald Critchley's well-known textbook from 1953, The Parietal Lobes, is often cited as the first mention of the CDT, its recorded use actually stretches back more than a century to 1915. A review of the literature shows that the CDT began as a test for aphasia-related disorders and constructional apraxia until its entry into contemporary cognitive screening in the 1980s when it primarily became a cognitive screen. Its usage took off in 1989 with over 2000 publications since. CONCLUSIONS: Despite a fairly obscure existence for decades, the CDT has emerged as an effective and ideal cognitive screening instrument for a wide range of conditions. Its use continues to increase, and it has been incorporated into several widely used cognitive screening batteries. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28556261 TI - Technical Note: Angular dependence of a 2D monolithic silicon diode array for small field dosimetry. AB - PURPOSE: This study aims to investigate the 2D monolithic silicon diode array size of 52 * 52 mm2 (MP512) angular response. An angular correction method has been developed that improves the accuracy of dose measurement in a small field. METHODS: The MP512 was placed at the center of a cylindrical phantom, irradiated using 6 MV and 10 MV photons and incrementing the incidence of the beam angle in 15 degrees steps from 0 degrees to 180 degrees , and then in 1 degrees steps between 85 degrees and 95 degrees . The MP512 response was characterized for square field sizes varying between 1 * 1 cm2 and 10 * 10 cm2 . The angular correction factor was obtained as the ratio of MP512 response to EBT3 film measured doses as a function of the incidence angle (O) and was normalized at 0 degrees incidence angle. Beam profiles of the corrected MP512 responses were compared with the EBT3 responses to verify the effectiveness of the method adopted. RESULTS: The intrinsic angular dependence of the MP512 shows maximum relative deviation from the response normalized to 0 degrees of 18.5 +/- 0.5% and 15.5 +/- 0.5% for 6 MV and 10 MV, respectively, demonstrating that the angular response is sensitive to the energy. In contrast, the variation of angular response is less affected by field size. Comparison of cross-plane profiles measured by the corrected MP512 and EBT3 shows an agreement within +/-2% for all field sizes when the beams irradiated the array at 0 degrees , 45 degrees , 135 degrees , and 180 degrees angles of incidence from the normal to the detector plane. At 90 degrees incidence, corresponding to a depth dose measurement, up to a 6% discrepancy was observed for a 1 * 1 cm2 field of 6 MV. CONCLUSION: An angular correction factor can be adopted for small field sizes. Measurements discrepancies could be encountered when irradiating with very small fields parallel to the detector plane. Using this approach, the MP512 is shown to be a suitable detector for 2D dose mapping of small field size photon beams. PMID- 28556264 TI - Design of a Tri-PET collimator for high-resolution whole-body mouse imaging. AB - PURPOSE: Tri-PET refers to high-resolution 511-keV emission tomography using a multipinhole collimator in conjunction with lower resolution PET detectors operating in coincidence mode. Tri-PET is unique in that three spatial locations are associated with each event (two detector coordinates and one pinhole location). Spatial resolution and sensitivity are similar to that of 511-keV SPECT and are governed mainly by the collimator design. However because of a third spatial location in Tri-PET, the line-of-response is overdetermined. This feature permits new opportunities in data processing which impact collimator design. In particular, multiplexing can be avoided since the coincidence data identify the pinhole through which the photon passed. In this paper, the principles of Tri-PET collimator design are reviewed and then applied to the case of high-resolution imaging of a small animal in a clinical PET scanner. METHODS: The design of a 148-pinhole collimator for whole-body imaging of a mouse is presented. Two pinhole designs were investigated: knife-edge pinholes with 1.1 mm aperture and novel hyperboloidal pinholes with 1.2 mm aperture, both having 18 degrees cone angle. The pinhole configuration is unfocused, covering a whole body mouse field of view with nearly uniform sensitivity. Computer simulations were performed of a micro hot rods phantom imaged with this collimator in a clinical PET scanner. Sensitivity was estimated by simulating a point source centered on-axis at locations spanning a 70-mm axial range, similar to the NEMA NU-4 standard for whole-body mouse imaging. RESULTS: Reconstructed images of the hot rods phantom demonstrated the ability to resolve 1.1 mm structures with the knife-edge pinholes and 1.0 mm structures with the hyperboloidal pinholes. Sensitivity was found to be 0.093% and 0.054% for the knife-edge and hyperboloidal pinholes, respectively. CONCLUSIONS: With a properly designed multipinhole collimator, high-resolution and acceptable sensitivity are achievable with Tri-PET using ordinary clinical PET detectors. PMID- 28556263 TI - Tree water dynamics in a drying and warming world. AB - Disentangling the relative impacts of precipitation reduction and vapour pressure deficit (VPD) on plant water dynamics and determining whether acclimation may influence these patterns in the future is an important challenge. Here, we report sap flux density (FD ), stomatal conductance (Gs ), hydraulic conductivity (KL ) and xylem anatomy in pinon pine (Pinus edulis) and juniper (Juniperus monosperma) trees subjected to five years of precipitation reduction, atmospheric warming (elevated VPD) and their combined effects. No acclimation occurred under precipitation reduction: lower Gs and FD were found for both species compared to ambient conditions. Warming reduced the sensibility of stomata to VPD for both species but resulted in the maintenance of Gs and FD to ambient levels only for pinon. For juniper, reduced soil moisture under warming negated benefits of stomatal adjustments and resulted in reduced FD , Gs and KL . Although reduced stomatal sensitivity to VPD also occurred under combined stresses, reductions in Gs , FD and KL took place to similar levels as under single stresses for both species. Our results show that stomatal conductance adjustments to high VPD could minimize but not entirely prevent additive effects of warming and drying on water use and carbon acquisition of trees in semi-arid regions. PMID- 28556265 TI - Postinfectious olfactory loss: A retrospective study on 791 patients. AB - OBJECTIVES/HYPOTHESIS: Postinfectious olfactory loss is among the most common causes of olfactory impairment and has substantial negative impact on patients' quality of life. Recovery rates have been shown to spontaneously improve in most of patients, usually within 2 to 3 years. However, existing studies are limited by small sample sizes and short follow-up. We aimed to assess the prognostic factors for recovery in a large sample of 791 patients with postinfectious olfactory disorders. STUDY DESIGN: Retrospective cohort. METHODS: We performed a retrospective analysis of 791 patients with postinfectious olfactory loss. Olfactory functions were assessed using the Sniffin' Sticks test at the first and final visits (mean follow-up = 1.94 years). RESULTS: Smell test scores improved over time. In particular, patient's age and the odor threshold (T), odor discrimination (D), and odor identification (I) (TDI) score at first visit were significant predictors of the extent of change. The percentage of anosmic and hyposmic patients exhibiting clinically significant improvement was 46% and 35%, respectively. CONCLUSIONS: This study provides new evidence within the postinfectious olfactory loss literature, shedding light on the prognostic factors and showing that recovery of olfactory function is very frequent, even many years after the infection. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:10-15, 2018. PMID- 28556266 TI - Identification of stress degradation products of iloperidone using liquid chromatography coupled with an Orbitrap mass spectrometer. AB - RATIONALE: Iloperidone (ILOP) is an atypical antipsychotic drug used for the treatment of schizophrenia and related psychotic disorders. Comprehensive stress testing of the ILOP drug was carried out as per ICH guidelines to understand its degradation profile. The presence of degradation products in a drug affects not only the quality, but also the safety and efficacy of drug formulation. Thus, it is essential to develop an efficient analytical method which can be useful for the separation, identification and characterization of all possible degradation products of ILOP. METHODS: ILOP was subjected to various stress conditions such as acidic, basic, neutral hydrolysis, oxidation, photolysis and thermal conditions; and the resulting degradation products were investigated using LC-PDA HRMS and MS/MS. An efficient and simple ultra-high-performance liquid chromatography (UHPLC) method has been developed on Acquity UPLC(r) BEH C18 column (2.1 * 100mm, 1.7 MUm) using a gradient elution of heptafluorobutyric acid (0.1% HFBA) and acetonitrile as mobile phase. RESULTS: ILOP was found to degrade under acidic and basic hydrolysis and oxidative stress conditions, whereas it was stable under neutral hydrolysis, thermal and photolytic conditions. A total of seven degradation products (DP1 to DP7) were identified and characterized by LC/MS/MS in positive ion mode with accurate mass measurements. The hydrolytic degradation under acidic and basic conditions produced two DPs (DP1 and DP2) and four DPs (DP4 to DP7), respectively, whereas DP3 was formed under oxidative conditions. In silico toxicity predictions showed higher probability values for DP4, DP6 and DP7, which indicates these DPs have the potential to mutate DNA. CONCLUSIONS: ILOP was found to be labile under hydrolytic and oxidative conditions. The structures of the degradation products were rationalized by appropriate mechanisms. The proposed method can be effectively used for the determination and detection of ILOP and its degradation products. PMID- 28556267 TI - Isomerization, Ring Expansion, and Ring Contraction of 1,3-Diphosphete Complexes. AB - Reactions between the 1,3-diphosphete complex [Cp'''Co(eta4 -P2 C2 tBu2 )] (1) and Ag[Al{OC(CF3 )3 }4 ] (Ag[pftb]) were carried out under different conditions. In CH2 Cl2 , the unprecedented 1,2-diphosphete isomerization product [Ag2 {Cp'''Co(MU,eta4 :eta1 :eta1 -1,2-P2 C2 tBu2 )}2 {Cp'''Co(MU,eta4 :eta1 -1,2-P2 C2 tBu2 )}2 ]?2[pftb] (2) could be isolated. In diffusion experiments of 1 in n hexane with Ag[pftb] in CH2 Cl2 , the triphosphacobaltocenium complex [Cp'''Co(eta5 -P3 C2 tBu2 )][pftb] (4) and the phosphirenylium complex [Cp'''Co(eta3 -PC2 tBu2 )][pftb] (5) were obtained, showing a ring expansion and a ring contraction, respectively, under mild conditions. Moreover, addition of pyridine to the Ag complex 2 led to the new 1,2-diphosphete complex [Cp'''Co(eta4 -1,2-P2 C2 tBu2 )] (3). Compound 3 is also formed by thermolysis of 1, making it a promising method for this type of isomerization. 1,2-Diphosphete complexes like 3 are thermodynamically more stable but also synthetically more elusive than their 1,3-isomer counterparts. PMID- 28556268 TI - Incidence of nonamyloidogenic mutations in the transthyretin gene in patients with autonomic and small fiber neuropathy. AB - INTRODUCTION: Mutations of the transthyretin (TTR) gene have been associated with polyneuropathy; the protein product has a tendency to form amyloid deposits in the peripheral nervous system. METHODS: Patients with small fiber neuropathy (SFN) with or without autonomic symptoms were given skin biopsies to assess nerve fiber density. Any patient with autonomic symptoms was assessed for autonomic neuropathy (AN). If testing revealed no clear cause of neuropathy, the TTR gene was sequenced. RESULTS: Thirty-six percent of patients were found to harbor at least 1 mutation in the TTR gene sequence (variants of unknown significance [VUS]). Of 24 patients diagnosed with SFN, 8% of patients had a point mutation (c76G>A). Of those patients who were diagnosed with both SFN and AN, 68% of patients had a VUS within the TTR gene (c76G>A, c337-18G>C). CONCLUSIONS: The results suggest an association between presumed nonamyloidogenic mutations in the TTR gene and the development of AN and SFN. Muscle Nerve 57: 140-142, 2017. PMID- 28556269 TI - Cervical varices: An unusual source of first-trimester hemorrhage. AB - Endocervical varices are a rare cause of obstetrical hemorrhage. Usually presenting in the second and third trimesters, bleeding varices often require pregnancy termination or indicated preterm birth via cesarean delivery. Our patient experienced variceal hemorrhage at 12 weeks' gestation in a dichorionic twin pregnancy conceived through in vitro fertilization. A low-lying placenta resolved at 19 weeks followed by variceal regression at 22 weeks' gestation. Endocervical varices causing first-trimester hemorrhage may regress with resolution of a coexisting low placental implantation, permitting planned vaginal delivery, despite progressive hemodynamic changes of pregnancy. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:218-221, 2018. PMID- 28556270 TI - Premature ejaculation is not a disease. PMID- 28556271 TI - Translocation of cell-penetrating peptides into Candida fungal pathogens. AB - Cell-penetrating peptides (CPPs) are small peptides capable of crossing cellular membranes while carrying molecular cargo. Although they have been widely studied for their ability to translocate nucleic acids, small molecules, and proteins into mammalian cells, studies of their interaction with fungal cells are limited. In this work, we evaluated the translocation of eleven fluorescently labeled peptides into the important human fungal pathogens Candida albicans and C. glabrata and explored the mechanisms of translocation. Seven of these peptides (cecropin B, penetratin, pVEC, MAP, SynB, (KFF)3 K, and MPG) exhibited substantial translocation (>80% of cells) into both species in a concentration dependent manner, and an additional peptide (TP-10) exhibiting strong translocation into only C. glabrata. Vacuoles were involved in translocation and intracellular trafficking of the peptides in the fungal cells and, for some peptides, escape from the vacuoles and localization in the cytosol were correlated to toxicity toward the fungal cells. Endocytosis was involved in the translocation of cecropin B, MAP, SynB, MPG, (KFF)3 K, and TP-10, and cecropin B, penetratin, pVEC, and MAP caused membrane permeabilization during translocation. These results indicate the involvement of multiple translocation mechanisms for some CPPs. Although high levels of translocation were typically associated with toxicity of the peptides toward the fungal cells, SynB was translocated efficiently into Candida cells at concentrations that led to minimal toxicity. Our work highlights the potential of CPPs in delivering antifungal molecules and other bioactive cargo to Candida pathogens. PMID- 28556272 TI - Up to 89% of neonates received antibiotics in cross-sectional Indian study including those with no infections and unclear diagnoses. AB - AIM: There is a global lack of data on antibiotic prescribing for neonates. This study compared antibiotic prescribing practices in the neonatal intensive care units (NICUs) of two private-sector, tertiary-level hospitals. METHODS: A three year, cross-sectional study was conducted from 2008 to 2011 in the NICUs of a teaching and nonteaching hospital in the Ujjain district of India. The data were analysed using methods recommended by the World Health Organization. RESULTS: Of the 1789 inpatients, 89% (1399/1572) in the nonteaching hospital and 71% (154/217) in the teaching hospital were prescribed antibiotics and 123 patients died. All the antibiotics were prescribed empirically and cephalosporins and aminoglycosides were the most commonly prescribed subclasses. Fixed-dose combinations of cephalosporins were commonly prescribed in the nonteaching hospital. Neonatal sepsis was the most common diagnosis, in more than 30% of patients, and more than 93% neonates with sepsis were prescribed antibiotics. In addition, 40% of neonates in the nonteaching hospital were admitted for observation and were frequently prescribed antibiotics. CONCLUSION: These two Indian NICUs prescribed antibiotics for noninfectious or unclear diagnoses in addition to prescribing combinations of broad-spectrum antibiotics. Such practices increase the global risk of treatment failure, neonatal mortality rates and antibiotic resistance. PMID- 28556273 TI - Tracking and Analyzing Individual Distress Following Terrorist Attacks Using Social Media Streams. AB - Risk research has theorized a number of mechanisms that might trigger, prolong, or potentially alleviate individuals' distress following terrorist attacks. These mechanisms are difficult to examine in a single study, however, because the social conditions of terrorist attacks are difficult to simulate in laboratory experiments and appropriate preattack baselines are difficult to establish with surveys. To address this challenge, we propose the use of computational focus groups and a novel analysis framework to analyze a social media stream that archives user history and location. The approach uses time-stamped behavior to quantify an individual's preattack behavior after an attack has occurred, enabling the assessment of time-specific changes in the intensity and duration of an individual's distress, as well as the assessment of individual and social level covariates. To exemplify the methodology, we collected over 18 million tweets from 15,509 users located in Paris on November 13, 2015, and measured the degree to which they expressed anxiety, anger, and sadness after the attacks. The analysis resulted in findings that would be difficult to observe through other methods, such as that news media exposure had competing, time-dependent effects on anxiety, and that gender dynamics are complicated by baseline behavior. Opportunities for integrating computational focus group analysis with traditional methods are discussed. PMID- 28556275 TI - Physical Injury and Somatic Complaints: The Mediating Role of Posttraumatic Stress Symptoms in Young Survivors of a Terror Attack. AB - Physically injured trauma survivors have particularly high risk for later somatic complaints and posttraumatic stress symptoms (PTSS). However, the potential mediating role of PTSS linking injury to later somatic complaints has been poorly investigated. In this study, survivors (N = 255) were interviewed longitudinally at 2 timepoints after the terror attack on Utoya Island, Norway, in 2011. Assessments included injury sustained during the attack, PTSS (after 4-5 months), somatic complaints (after 14-15 months), and background factors. Causal mediation analysis was conducted to evaluate the potential mediating role of PTSS in linking injury to somatic complaints comparing 2 groups of injured survivors with noninjured survivors. For the nonhospitalized injured versus the noninjured survivors, the mediated pathway was significant (average causal mediation effect; ACME = 0.09, p = .028, proportion = 55.8%). For the hospitalized versus the noninjured survivors, the mediated pathway was not significant (ACME = 0.04, p = .453, proportion = 11.6%). PTSS may play a significant mediating role in the development of somatic complaints among nonhospitalized injured trauma survivors. Intervening health professionals should be aware of this possible pathway to somatic complaints. PMID- 28556274 TI - A new methodological approach to adjust alcohol exposure distributions to improve the estimation of alcohol-attributable fractions. AB - BACKGROUND AND AIMS: To assess the burden of excessive alcohol use, researchers estimate alcohol-attributable fractions (AAFs) routinely. However, under reporting in survey data can bias these estimates. We present an approach that adjusts for under-reporting in the estimation of AAFs, particularly within subgroups. This framework is a refinement of a previous method conducted by Rehm et al. METHODS: We use a measurement error model to derive the 'true' alcohol distribution from a 'reported' alcohol distribution. The 'true' distribution leverages per-capita sales data to identify the distribution average and then identifies the shape of the distribution with self-reported survey data. Data are from the National Alcohol Survey (NAS), the National Household Survey on Drug Abuse (NHSDA) and the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). We compared our approach with previous approaches by estimating the AAF of female breast cancer cases. RESULTS: Compared with Rehm et al.'s approach, our refinement performs similarly under a gamma assumption. For example, among females aged 18-25 years, the two approaches produce estimates from NHSDA that are within a percentage point. However, relaxing the gamma assumption generally produces more conservative evidence. For example, among females aged 18-25 years, estimates from NHSDA based on the best-fitting distribution are only 19.33% of breast cancer cases, which is a much smaller proportion than the gamma-based estimates of approximately 28%. CONCLUSIONS: A refinement of Rehm et al.'s approach to adjusting for underreporting in the estimation of alcohol-attributable fractions provides more flexibility. This flexibility can avoid biases associated with failing to account for the underlying differences in alcohol consumption patterns across different study populations. Comparisons of our refinement with Rehm et al.'s approach show that results are similar when a gamma distribution is assumed. However, results are appreciably lower when the best-fitting distribution is chosen versus gamma-based results. PMID- 28556278 TI - Acceptability of beehive products as ingredients in quinoa bars. AB - BACKGROUND: The aim of this work was to develop a puffed quinoa bar with beehive products of high content of phenolic compounds, based on acceptability and perception of consumers. A rotational central composite design of three variables (honey, pollen and propolis) was used for food product formulation. The responses to optimize were sensorial acceptability and polyphenol content. Next to acceptability a check-all-that-apply (CATA) test was performed with 115 consumers. Preference maps were used to relate acceptability and sensorial attributes of bars that cause rejection or acceptance. RESULTS: The experimental design determined that pollen and propolis significantly increased phenolic content but decreased acceptability of formulations. Preference maps established that attributes like astringency, bitter flavor, pungency and intense yellow color were associated with the low acceptability while attributes of sweetness and weak astringency were related to high acceptance of products. Range of polyphenol content determined in the widely accepted formulations was 2.15-2.91 g kg-1 , significantly higher than commercial products. CONCLUSION: The incorporation of beehive products, in quinoa bars, increased the total polyphenol content and the functional properties, but at the same time reduced the consumer acceptability. (c) 2017 Society of Chemical Industry. PMID- 28556277 TI - Distribution of blood flow velocity in the normal aorta: Effect of age and gender. AB - PURPOSE: To apply flow distribution analysis in the entire aorta across a wide age range from pediatric to adult subjects. MATERIAL AND METHODS: In all, 98 healthy subjects (age 9-78 years, 41 women) underwent 4D flow MRI at 1.5T and 3T for the assessment of 3D blood flow in the thoracic aorta. Subjects were categorized into age groups: group 1 (n = 9, 5 women): 9-15 years; group 2 (n = 13, 8 women): 16-20 years; group 3 (n = 27, 14 women): 21-39 years; group 4 (n = 40, 11 women): 40-59 years; group 5 (n = 9, 3 women): >60 years. Data analysis included the 3D segmentation of the aorta, aortic valve peak velocity, mid ascending aortic diameter, and calculation of flow velocity distribution descriptors (mean, median, standard deviation, incidence of velocities >1 m/s, skewness, and kurtosis of aortic velocity magnitude). Ascending aortic diameter was normalized by body surface area. RESULTS: Age was significantly associated with normalized aortic diameter (R = 0.73, P < 0.001), skewness (R = 0.76, P < 0.001), and kurtosis (R = 0.74, P < 0.001), all adjusted by heart rate. Aortic peak velocity and velocity distribution descriptors, adjusted by heart rate, were significantly different between age groups (P < 0.001, analysis of covariance). Skewness and kurtosis significantly increased (P < 0.001) during adulthood (>40 years) as compared with childhood (<21 years). Men and women revealed significant differences (P <= 0.05) for peak velocity, incidence, mean, median, standard deviation, and skewness, all adjusted by heart rate. CONCLUSION: Aortic hemodynamics significantly change with age and gender, indicating the importance of age- and gender-matched control cohorts for the assessment of the impact of cardiovascular disease on aortic blood flow. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:487-498. PMID- 28556276 TI - Activation of Aedes aegypti prophenoloxidase-3 and its role in the immune response against entomopathogenic fungi. AB - Serine protease cascade-mediated melanization is an important innate immune response in insects and crustaceans, which involves the proteolytic activation of prophenoloxidase (PPO). In this study, we investigated the role of Aedes aegypti PPO3 in antifungal immune defence. We expressed and purified recombinant PPO3 (rPPO3) in Escherichia coli and demonstrated that rPPO3 was activated by ethanol and, to a lesser extent, by cetylpyridinium chloride. In the presence of Cu2+ , rPPO3 exhibited enzyme activity. Immunoblot results revealed that the rPPO3 was cleaved by the haemolymph from immune-challenged mosquitoes or purified Ostrinia furnacalis serine protease 105 in vitro. The cleaved rPPO3 converted dopamine to toxic intermediates that killed fungal conidia of Beauveria bassiana in vitro. In mosquitoes challenged with Be. bassiana, cleavage of rPPO3 produced a 50 kDa phenoloxidase (PO) fragment. Further analysis revealed that the survival rate of mosquitoes with fungal infection increased significantly following injection of rPPO3 into the haemocoel. Taken together, our results suggest that proteolytic cleavage of the mosquito PPO3 plays an important role in the antifungal immune response. This has led to a better understanding of the mechanism of PPO activation in the mosquito and the role of melanization in the antifungal immune response. PMID- 28556279 TI - Porous Aromatic Framework as an Efficient Metal-Free Electro-catalyst for Non enzymatic H2 O2 Sensing. AB - A porous aromatic framework (referred as PAF-39) based on tetrakis(4-(9H-carbazol 9-yl)phenyl)methane has been designed and synthesized by oxidative coupling polymerization. PAF-39 exhibits high surface area and high heat of adsorption (Qst ) of CO2 . Especially, the PAF material was applied for non-enzymatic H2 O2 sensing. PMID- 28556280 TI - Endoscopic submucosal dissection of T1 cancer with colonic diverticulum by pocket creation method. PMID- 28556281 TI - MRI and surgical lumbosacral trunk positioning palsy. PMID- 28556283 TI - Computer-aided diagnosis program for classifying the risk of hepatocellular carcinoma on MR images following liver imaging reporting and data system (LI RADS). AB - PURPOSE: To develop and evaluate a computer-aided diagnosis (CAD) program for liver lesions on magnetic resonance (MR) images for classification of the risk of hepatocellular carcinoma (HCC) following the liver imaging reporting and data system (LI-RADS). MATERIALS AND METHODS: Liver MR images from 41 patients with hyperenhancing liver lesions categorized as LR 3, 4, and 5 were evaluated by two radiologists. The major LI-RADS features of each index liver lesion were recorded, including size (maximum transverse diameter), presence of hyperenhancement, washout appearance, and capsule appearance. A CAD program was implemented to register MR images at different contrast-enhancement phases, segment liver lesions, extract lesion features, and classify lesions according to LI-RADS. The LI-RADS features quantified by CAD were compared with those assessed by radiologists using the intraclass correlation coefficient (ICC) and receiver operator curve (ROC) analyses. The LI-RADS categorization between CAD and radiologists was evaluated using the weighted Cohen's kappa coefficient. RESULTS: The mean and standard deviation of the lesion diameters were 21 +/- 11 mm (range, 7-70 mm) by radiologists and 22 +/- 11 mm (range, 8-72 mm) by CAD (ICC, 0.96 0.97). The area under the curve (AUC) for the washout assessment by CAD was 0.79 0.93 with sensitivity 0.69-0.82 and specificity 0.79-1. The AUC for the capsule assessment by CAD was 0.79-0.9 with sensitivity 0.75-0.9 and specificity 0.82 0.96. The classifications by the radiologists and CAD coincided in 76-83% lesions (k = 0.57-0.71), while the agreements between radiologists were in 78% lesions (k = 0.59). CONCLUSION: We developed a CAD program for liver lesions on MR images and showed a substantial agreement in the LI-RADS-based classification of the risk of HCCs between the CAD and radiologists. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:710-722. PMID- 28556282 TI - Interspecific competition counteracts negative effects of dispersal on adaptation of an arthropod herbivore to a new host. AB - Dispersal and competition have both been suggested to drive variation in adaptability to a new environment, either positively or negatively. A simultaneous experimental test of both mechanisms is however lacking. Here, we experimentally investigate how population dynamics and local adaptation to a new host plant in a model species, the two-spotted spider mite (Tetranychus urticae), are affected by dispersal from a stock population (no-adapted) and competition with an already adapted spider mite species (Tetranychus evansi). For the population dynamics, we find that competition generally reduces population size and increases the risk of population extinction. However, these negative effects are counteracted by dispersal. For local adaptation, the roles of competition and dispersal are reversed. Without competition, dispersal exerts a negative effect on adaptation (measured as fecundity) to a novel host and females receiving the highest number of immigrants performed similarly to the stock population females. By contrast, with competition, adding more immigrants did not result in a lower fecundity. Females from populations with competition receiving the highest number of immigrants had a significantly higher fecundity than females from populations without competition (same dispersal treatment) and than the stock population females. We suggest that by exerting a stronger selection on the adapting populations, competition can counteract the migration load effect of dispersal. Interestingly, adaptation to the new host does not significantly reduce performance on the ancestral host, regardless of dispersal rate or competition. Our results highlight that assessments of how species can adapt to changing conditions need to jointly consider connectivity and the community context. PMID- 28556284 TI - Safety and efficacy of the combination of once-daily tadalafil and alpha-1 blocker in Japanese men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A randomized, placebo-controlled, cross-over study. AB - OBJECTIVES: To evaluate the safety and efficacy of tadalafil plus alpha1 -blocker combination therapy in Japanese patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. METHODS: The present multicenter, randomized, double-blind, placebo-controlled, two-period cross-over study compared the effects of tadalafil and a placebo added to ongoing alpha1 -blocker therapy. A total of 171 Japanese patients were randomized. RESULTS: Tadalafil combined with an alpha1 -blocker did not decrease blood pressure in the orthostatic test. The only statistically significant differences in vital signs between the combination and monotherapy groups were diastolic blood pressure and pulse (P = 0.0194 and 0.0313, respectively). However, these changes were not considered clinically meaningful. Treatment-related adverse events occurred in 28.1% (47/167) and 24.2% (39/161) of patients in the combination therapy and alpha1 -blocker monotherapy groups, respectively. Additionally, 56.7% (89/157) of patients preferred combination therapy to monotherapy, though this was not statistically significant (P = 0.0937). There was a statistically significant reduction in the International Prostate Symptom Score voiding subscore in the combination therapy group (P = 0.0442). CONCLUSIONS: Concurrent treatment with tadalafil and an alpha1 -blocker seems to be safe and well tolerated in Japanese patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Adding tadalafil to baseline alpha1 -blocker therapy does not translate in adverse effects on the blood pressure. Patients tend to prefer combination therapy over monotherapy, and there seems to be a clinical benefit when using combination therapy. PMID- 28556285 TI - Diagnostic Performance of Sonographic Features in Patients With Biliary Atresia: A Systematic Review and Meta-analysis. AB - OBJECTIVES: To evaluate the diagnostic performance of sonographic features of biliary atresia in patients with infantile cholestasis. METHODS: The Ovid-MEDLINE and EMBASE databases were searched for studies of the diagnostic performance of sonographic features of biliary atresia in patients with infantile cholestasis. A meta-analysis was performed to evaluate the diagnostic performance of the triangular cord sign and other sonographic features in patients with biliary atresia. RESULTS: Seventeen eligible studies with 1444 patients were included. The triangular cord sign had high accuracy for diagnosing biliary atresia: the meta-analytic summary sensitivity and specificity were 85% (95% confidence interval, 77%-90%) and 97% (95% confidence interval, 94%-99%), respectively. The area under the hierarchical summary receiver operating characteristic curve was 0.97. Meta-regression analysis revealed that the cutoff thickness of the triangular cord sign (3 or 4 mm) was a significant factor affecting study heterogeneity (P < .01). The proportions of nonidentification of the gallbladder (GB) ranged from 0% to 53%. Abnormal GB morphologic characteristics, nonvisualization of the common bile duct, and the presence of hepatic subcapsular flow showed relatively high sensitivities and specificities. CONCLUSIONS: The triangular cord sign and other sonographic features, including abnormal GB morphologic characteristics, nonvisualization of the common bile duct, and the presence of hepatic subcapsular flow, had high diagnostic performance for the diagnosis of biliary atresia. PMID- 28556286 TI - A Coordination Network with Ligand-Centered Redox Activity Based on facial-[CrIII (2-mercaptophenolato)3 ]3- Metalloligands. AB - The design of redox-active metal-organic frameworks and coordination networks (CNs), which exhibit metal- and/or ligand-centered redox activity, has recently received increased attention. In this study, the redox-active metalloligand (RML) [Me4 N]3 fac-[CrIII (mp)3 ] (1) (mp=2-mercaptophenolato) was synthesized and characterized by single-crystal X-ray diffraction analysis, and its reversible ligand-centered one-electron oxidation was examined by cyclic voltammetry and spectroelectrochemical measurements. Since complex 1 contains O/S coordination sites in three directions, complexation with K+ ions led to the formation of the two-dimensional honeycomb sheet-structured [K3 fac-{CrIII (mp)3 }(H2 O)6 ]n (2?6 H2 O), which is the first example of a redox-active CN constructed from a RML with o-disubstituted benzene ligands. Herein, we unambiguously demonstrate the ligand-centered redox activity of the RML within the CN 2?6 H2 O in the solid state. PMID- 28556287 TI - Differential neuronal susceptibility and apoptosis in congenital Zika virus infection. AB - To characterize the mechanism of Zika virus (ZIKV)-associated microcephaly, we performed immunolabeling on brain tissue from a 20-week fetus with intrauterine ZIKV infection. Although ZIKV demonstrated a wide range of neuronal and non neuronal tropism, the infection rate was highest in intermediate progenitor cells and immature neurons. Apoptosis was observed in both infected and uninfected bystander cortical neurons, suggesting a role for paracrine factors in induction of neuronal apoptosis. Our results highlight differential neuronal susceptibility and neuronal apoptosis as potential mechanisms in the development of ZIKV associated microcephaly, and may provide insights into the design and best timing of future therapy. Ann Neurol 2017;82:121-127. PMID- 28556288 TI - Application of Surface Click Reactions to Localized Surface Plasmon Resonance (LSPR) Biosensing. AB - Localized surface plasmon resonance (LSPR) spectroscopy is an effective tool for sensitive, affordable, and label-free biosensing. LSPR transducers based on nanoparticulate Au films have been applied to biosensing of receptor-analyte interactions, employing primarily thiolated receptors for constructing biorecognition interfaces on nanostructured Au surfaces. This popular method suffers from a major drawback, that is, the need to prepare a thiolated receptor for each system used, which is typically synthetically complex and time consuming. Herein, we present an alternative approach based on the click reaction between azide and terminal alkyne, which avoids the need to synthesize thiol derivatized receptors and is applicable to the heterogeneous morphology of LSPR transducers. The receptors are tethered with an alkyne group, which is considerably simpler than thiolation, while producing a stable product. The transducer surface is modified with a layer of a commercial long-chain thiol azide molecule, then clicked with an alkyne-dertivatized receptor to produce the biorecognition interface. This method is employed for immobilization of four different alkyne-bearing receptor molecules on Au nano-island film based LSPR transducers, followed by testing of their performance in biorecognition of specific analytes using LSPR and FTIR spectroscopies. The results establish the usefulness of click chemistry for the preparation of biorecognition interfaces on nanostructured LSPR transducers. PMID- 28556289 TI - Influence of regular reporting on local Pseudomonas aeruginosa and Acinetobacter spp. sensitivity to antibiotics on consumption of antibiotics and resistance patterns. AB - WHAT IS KNOWN AND OBJECTIVE: Regular surveillance of antimicrobial resistance is an important component of multifaceted interventions directed at the problem with resistance of bacteria causing healthcare-associated infections (HAIs) in intensive care units (ICUs). Our aim was to analyse antimicrobial consumption and resistance among isolates of Pseudomonas aeruginosa and Acinetobacter spp. causing HAIs, before and after the introduction of mandatory reporting of resistance patterns to prescribers. METHODS: A retrospective observational study was conducted between January 2011 and December 2015, at an interdisciplinary ICU of the Clinical Centre Kragujevac, Serbia. The intervention consisted of continuous resistance monitoring of all bacterial isolates from ICU patients and biannual reporting of results per isolate to prescribers across the hospital. Both utilization of antibiotics and density of resistant isolates of P. aeruginosa and Acinetobacter spp. were followed within the ICU. RESULTS AND DISCUSSION: Resistance densities of P. aeruginosa to all tested antimicrobials were lower in 2015, in comparison with 2011. Although isolates of Acinetobacter spp. had lower resistance density in 2015 than in 2011 to the majority of investigated antibiotics, a statistically significant decrease was noted only for piperacillin/tazobactam. Statistically significant decreasing trends of consumption were recorded for third-generation cephalosporins, aminoglycosides and fluoroquinolones, whereas for the piperacillin/tazobactam, ampicillin/sulbactam and carbapenems, utilization trends were decreasing, but without statistical significance. In the same period, increasing trends of consumption were observed for tigecycline and colistin. WHAT IS NEW AND CONCLUSION: Regular monitoring of resistance of bacterial isolates in ICUs and reporting of summary results to prescribers may lead to a significant decrease in utilization of some antibiotics and slow restoration of P. aeruginosa and Acinetobacter spp. susceptibility. PMID- 28556290 TI - Moderate-to-high normal levels of thyrotropin is a risk factor for urinary incontinence and an unsuitable quality of life in women over 65 years. AB - The present study aimed to investigate the relationship between normal serum concentrations of thyrotropin (TSH) and urinary incontinence (IU), urinary infections, and quality of life in old women. Euthyroid post-menopausal women without sarcopenia, estrogen replacement, emotional illness, and/or cancer were enrolled as participants. Anthropometric indicators, serum glucose and estradiol, and thyroid profile were measured. Sociodemographic, clinical, physical activity, and quality of life (SF-36) surveys were applied. One-hour pad test and International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) were used to determine UI. Urinalysis was also done. In agreement with results from the pad test (cut-off point >=1.4 g), the ICIQ-SF reveled approximately 50% of incontinent women. A high percentage of women had moderate-high bacteriuria and urinary infections. Logistic regression analysis showed that age is a risk factor for both UI and urinary infection. Diabetes, number of pregnancies or childbirths, urinary infections, and bacteriuria did not influence the presence of UI. To allocate women into four groups according to their age (<65 or >=65 years old) and TSH concentrations (0.3-1.9 or 2-10 MUUI/mL), we found that moderate-to-high normal levels of TSH is a risk factor for UI and a worse quality of life in the oldest women. Our results highlight the profit of measuring TSH concentrations in post-menopausal women. PMID- 28556291 TI - Prenatal phthalate exposure and altered patterns of DNA methylation in cord blood. AB - Epigenetic changes such as DNA methylation may be a molecular mechanism through which environmental exposures affect health. Phthalates are known endocrine disruptors with ubiquitous exposures in the general population including pregnant women, and they have been linked with a number of adverse health outcomes. We examined the association between in utero phthalate exposure and altered patterns of cord blood DNA methylation in 336 Mexican-American newborns. Concentrations of 11 phthalate metabolites were analyzed in maternal urine samples collected at 13 and 26 weeks gestation as a measure of fetal exposure. DNA methylation was assessed using the Infinium HumanMethylation 450K BeadChip adjusting for cord blood cell composition. To identify differentially methylated regions (DMRs) that may be more informative than individual CpG sites, we used two different approaches, DMRcate and comb-p. Regional assessment by both methods identified 27 distinct DMRs, the majority of which were in relation to multiple phthalate metabolites. Most of the significant DMRs (67%) were observed for later pregnancy (26 weeks gestation). Further, 51% of the significant DMRs were associated with the di-(2-ethylhexyl) phthalate metabolites. Five individual CpG sites were associated with phthalate metabolite concentrations after multiple comparisons adjustment (FDR), all showing hypermethylation. Genes with DMRs were involved in inflammatory response (IRAK4 and ESM1), cancer (BRCA1 and LASP1), endocrine function (CNPY1), and male fertility (IFT140, TESC, and PRDM8). These results on differential DNA methylation in newborns with prenatal phthalate exposure provide new insights and targets to explore mechanism of adverse effects of phthalates on human health. Environ. Mol. Mutagen. 58:398-410, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28556292 TI - A review of the role of sebum in the mechanism of acne pathogenesis. AB - Acne is one of the most common skin disorders, and its occurrence is closely related to many factors, including sebum secretion, hormone levels, bacterial infection, and inflammatory reactions. Among these, changes in sebum secretion are believed to be one important factor of acne. Increased sebum secretion can induce acne occurrence, and increasing evidence indicates sebum component changes are also strongly related to acne occurrence. Recently, developments in lipidomics have provided effective lipid analysis methods. These can help elucidate the effects of different types of sebum on acne occurrence and provide a theoretical basis for research on the mechanisms of acne pathogenesis and treatment. PMID- 28556293 TI - Bone scan index: A new biomarker of bone metastasis in patients with prostate cancer. AB - Bone scintigraphy is one of the first-line imaging modalities for the screening and follow up of bone metastasis in patients with prostate cancer. The amount (%) of bone metastasis can be calculated using a bone scan index thanks to recent advances in quantitative bone scintigraphy. Since an artificial neural network was applied for hot-spot characterization and quantitation, the bone scan index has become a simple, reproducible and practical means of quantifying bone metastasis. The bone scan index is presently considered as an imaging biomarker of bone metastasis. The present article summarizes the principles and application of bone scan index using dedicated software (EXINI bone in Europe and North America; BONENAVI in Japan), and the advantages and cautions of using the bone scan index. The bone scan index could serve as a practical marker with which to monitor disease progression and treatment effects in multicenter studies, and to manage prostate and other types of cancer in the clinical setting. PMID- 28556294 TI - Combined Angiography and Late Gadolinium Enhancement Acquisition to Improve Assessment of Pulmonary Vein Isolation for Atrial Fibrillation. AB - PURPOSE: To develop a Shared K-space (SharK) magnetic resonance imaging (MRI) sequence that combines angiographic and late gadolinium enhancement (LGE) acquisitions to improve atrial wall segmentation and scar identification, and to develop a novel visualization method that quantifies scar encirclement of pulmonary veins postablation treatment for atrial fibrillation. MATERIALS AND METHODS: A SharK sequence was developed and used at 3T to image the left atrium in 11 patients postcryoballoon ablation. The effects of sharing k-space between the angiographic and LGE acquisitions on the accuracy of scar were assessed. The left atrial wall was segmented and points about each pulmonary vein (PV) ostia were projected onto a bullseye to quantitatively compare PV encirclement. The parameters used to quantify encirclement were varied to perform a sensitivity analysis. RESULTS: Compared to using a complete set of k-space, total atrial scar differences were significant only when sharing >75% k-space (P = 0.014), and 90% sensitivity and specificity for identifying scar was achieved when sharing 50% k space. In patients, the right PVs showed more intersubject variance in encirclement compared to the left PVs. A 100 degrees anteroinferior portion of the left PVs was always encircled, while the superior segments of both right PVs was ablated in only 6/11 patients. CONCLUSION: A SharK sequence was developed to combine angiographic and LGE imaging for atrial wall segmentation and scar identification. The PV bullseye quantifies and localizes encirclement about the PVs. The left PVs showed a higher amount of scar encirclement and less variability compared to the right PVs. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:477-486. PMID- 28556295 TI - Robust rankings of socioeconomic health inequality using a categorical variable. AB - When assessing socioeconomic health inequalities, researchers often draw upon measures of income inequality that were developed for ratio scale variables. As a result, the use of categorical data (such as self-reported health status) produces rankings that may be arbitrary and contingent to the numerical scale adopted. In this paper, we develop a method that overcomes this issue by providing conditions for which these rankings are invariant to the numerical scale chosen by the researcher. In doing so, we draw on the insight provided by Allison and Foster (2004) and extend their method to the dimension of socioeconomic inequality by exploiting the properties of rank-dependent indices such as Wagstaff (2002) achievement and extended concentration indices. We also provide an empirical illustration using the National Institute of Health Survey 2012. PMID- 28556296 TI - Histological Grade and Immunohistochemical Biomarkers of Breast Cancer: Correlation to Ultrasound Features. AB - OBJECTIVES: The purpose of this study is to correlate various features of breast cancers on ultrasound to their histological grade and immunohistochemical biomarkers. METHODS: Seventy-three patients with 77 invasive breast cancers, diagnosed between August 2011 and December 2014, were included in this prospective analysis. Margin, posterior features, shape, and vascularity were determined from ultrasound and classified according to the Breast Imaging Reporting and Data System lexicon. Histological grade, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status (positive [+] or negative [-]) were determined from surgical pathology reports. The cancers were categorized into low grade (grades 1 or 2) and high grade (grade 3). Correlation of ultrasound features of the cancers to their histological grade and receptor status was performed. RESULTS: There were 47 low grade and 29 high-grade cancers. There was a significant difference in margin and posterior features between the low and high grade, ER + and ER-, and PR + and PR- (all P < .05), but not between HER2 + and HER2- cancers (both P > .05). There was no significant difference in shape and vascularity among the different subtypes (all P > .05). Spiculated margin was significantly associated with low-grade, ER+, PR + status; angular margin with high grade; microlobulated margin with ER- status; shadowing with PR + status; and enhancement with high grade, ER- status (all P < .05, all odds ratios >= 3.94). CONCLUSIONS: There was significant association of margin and posterior features of breast cancers with their histological grade and receptor status. PMID- 28556297 TI - Precise Two-Photon Photodynamic Therapy using an Efficient Photosensitizer with Aggregation-Induced Emission Characteristics. AB - Two-photon photodynamic therapy (PDT) is able to offer precise 3D manipulation of treatment volumes, providing a target level that is unattainable with current therapeutic techniques. The advancement of this technique is greatly hampered by the availability of photosensitizers with large two-photon absorption (TPA) cross section, high reactive-oxygen-species (ROS) generation efficiency, and bright two photon fluorescence. Here, an effective photosensitizer with aggregation-induced emission (AIE) characteristics is synthesized, characterized, and encapsulated into an amphiphilic block copolymer to form organic dots for two-photon PDT applications. The AIE dots possess large TPA cross section, high ROS generation efficiency, and excellent photostability and biocompatibility, which overcomes the limitations of many conventional two-photon photosensitizers. Outstanding therapeutic performance of the AIE dots in two-photon PDT is demonstrated using in vitro cancer cell ablation and in vivo brain-blood-vessel closure as examples. This shows therapy precision up to 5 um under two-photon excitation. PMID- 28556298 TI - Predictive inference for best linear combination of biomarkers subject to limits of detection. AB - Measuring the accuracy of diagnostic tests is crucial in many application areas including medicine, machine learning and credit scoring. The receiver operating characteristic (ROC) curve is a useful tool to assess the ability of a diagnostic test to discriminate between two classes or groups. In practice, multiple diagnostic tests or biomarkers are combined to improve diagnostic accuracy. Often, biomarker measurements are undetectable either below or above the so called limits of detection (LoD). In this paper, nonparametric predictive inference (NPI) for best linear combination of two or more biomarkers subject to limits of detection is presented. NPI is a frequentist statistical method that is explicitly aimed at using few modelling assumptions, enabled through the use of lower and upper probabilities to quantify uncertainty. The NPI lower and upper bounds for the ROC curve subject to limits of detection are derived, where the objective function to maximize is the area under the ROC curve. In addition, the paper discusses the effect of restriction on the linear combination's coefficients on the analysis. Examples are provided to illustrate the proposed method. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28556299 TI - Use of oxygen isotopes to differentiate between nitrous oxide produced by fungi or bacteria during denitrification. AB - RATIONALE: Fungal denitrifiers can contribute substantially to N2 O emissions from arable soil and show a distinct site preference for N2 O (SP(N2 O)). This study sought to identify another process-specific isotopic tool to improve precise identification of N2 O of fungal origin by mass spectrometric analysis of the N2 O produced. METHODS: Three pure bacterial and three fungal species were incubated under denitrifying conditions in treatments with natural abundance and stable isotope labelling to analyse the N2 O produced. Combining different applications of isotope ratio mass spectrometry enabled us to estimate the oxygen (O) exchange accelerated by denitrifying enzymes and the ongoing microbial pathway in parallel. This experimental set-up allowed the determination of delta18 O(N2 O) values and isotopic fractionation of O, as well as SP(N2 O) values, as a perspective to differentiate between microbial denitrifiers. RESULTS: Oxygen exchange during N2 O production was lower for bacteria than for fungi, differed between species, and depended also on incubation time. Apparent O isotopic fractionation during denitrification was in a similar range for bacteria and fungi, but application of the fractionation model indicated that different enzymes in bacteria and fungi were responsible for O exchange. This difference was associated with different isotopic fractionation for bacteria and fungi. CONCLUSIONS: delta18 O(N2 O) values depend on isotopic fractionation and isotopic fractionation may differ between processes and organism groups. By comparing SP(N2 O) values, O exchange and the isotopic signature of precursors, we propose here a novel tool for differentiating between different sources of N2 O. PMID- 28556301 TI - Supraventricular tachycardia after withdrawal of prolonged dexmedetomidine infusion in a paediatric patient without heart disease. AB - WHAT IS KNOWN AND OBJECTIVE: Dexmedetomidine (DEX) has been reported to be safe in paediatric patients. CASE DESCRIPTION: We present the case of a girl without heart disease admitted at our PICU due to an influenza A acute respiratory distress syndrome, who suffered a paroxysmal supraventricular tachycardia (PSVT) twelve hours after DEX progressive withdrawal was completed. WHAT IS NEW AND CONCLUSION: This is the first report of PSVT as an adverse reaction to DEX in a paediatric patient without heart disease. PMID- 28556300 TI - Development of protein degradation inducers of oncogenic BCR-ABL protein by conjugation of ABL kinase inhibitors and IAP ligands. AB - Chromosomal translocation occurs in some cancer cells, which results in the expression of aberrant oncogenic fusion proteins that include BCR-ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase, such as imatinib and dasatinib, exhibit remarkable therapeutic effects, although emergence of drug resistance hampers the therapy during long-term treatment. An alternative approach to treat CML is to downregulate the BCR-ABL protein. We have devised a protein knockdown system by hybrid molecules named Specific and Non-genetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers (SNIPER), which is designed to induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins, and a couple of SNIPER(ABL) against BCR-ABL protein have been developed recently. In this study, we tested various combinations of ABL inhibitors and IAP ligands, and the linker was optimized for protein knockdown activity of SNIPER(ABL). The resulting SNIPER(ABL)-39, in which dasatinib is conjugated to an IAP ligand LCL161 derivative by polyethylene glycol (PEG) * 3 linker, shows a potent activity to degrade the BCR-ABL protein. Mechanistic analysis suggested that both cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP) play a role in the degradation of BCR-ABL protein. Consistent with the degradation of BCR-ABL protein, the SNIPER(ABL)-39 inhibited the phosphorylation of signal transducer and activator of transcription 5 (STAT5) and Crk like proto-oncogene (CrkL), and suppressed the growth of BCR-ABL-positive CML cells. These results suggest that SNIPER(ABL)-39 could be a candidate for a degradation-based novel anti-cancer drug against BCR ABL-positive CML. PMID- 28556302 TI - The contribution of alcohol use and other behavioural, material and social factors to socio-economic differences in alcohol-related disorders in a Swedish cohort. AB - AIMS: We estimated the degree to which the relationship between socio-economic position (SEP) and alcohol-related disorders is attenuated after adjustment for levels and patterns of drinking, behavioural, material and social factors. DESIGN: A longitudinal cohort study with baseline in 2002, with linkage to register data on patient care and deaths in 2002-11 to yield the outcome measures. SETTING: Stockholm County, Sweden. PARTICIPANTS: Respondents to baseline survey aged 25-64 (n = 17 440) with information on all studied covariates. MEASUREMENTS: Occupational class was the studied SEP indicator and a combined measure of volume of weekly alcohol consumption and frequency of heavy episodic drinking, smoking, employment status, income, social support, marital status and education, all at baseline, were the studied covariates. Alcohol related disorders (n = 388) were indicated by first register entries on alcohol related medical care or death during the follow-up. FINDINGS: Unskilled workers had an approximately four times greater risk of alcohol-related disorders than higher non-manual employees, hazard ratio (HR) = 4.08 (2.78, 5.98). After adjustment for alcohol use, the SEP difference in risk for alcohol-related harm fell by a fourth for the same group, HR = 2.91 (1.96, 4.33). The difference was reduced further when behavioural factors and material factors were taken into account, HR = 2.09 (1.34, 3.26), whereas adjusting for social factors and attained education resulted in smaller reductions. CONCLUSIONS: Socio-economic differences in alcohol use explain one fourth of the socio-economic position differences in alcohol-related disorders in Stockholm, Sweden. Hazardous alcohol use and other behavioural, material and social factors together explain nearly 60% of the socio-economic position differences in alcohol-related disorders. PMID- 28556303 TI - Screening approach for identifying candidate drugs and drug-drug interactions related to hip fracture risk in persons with Alzheimer disease. AB - PURPOSE: To assess whether a "drugome-wide" screen with case-crossover design is a feasible approach for identifying candidate drugs and drug-drug interactions. METHODS: All community-dwelling residents of Finland who received a clinically verified Alzheimer disease diagnosis in 2005 to 2011 and experienced incident hip fracture (HF) afterwards (N = 4851). Three scenarios were used to test the sensitivity of this approach (1) hazard period 0 to 30 and control period 31 to 61 days before HF, (2) hazard period 0 to 30 and control period 336 to 366 days before HF, and (3) hazard period 0 to 14 and control period 16 to 30 days before HF. RESULTS: Nine, 44, and 5 drugs were associated with increased HF risk and 8, 23, and 4 with decreased risk in scenarios 1, 2, and 3, respectively. Six drugs were identified with scenario 1 only and 54 and 1 with scenarios 2 and 3, respectively. Only six drugs (metoprolol, simvastatin, trimethoprim, codeine combinations, fentanyl, and paracetamol) were associated with HF in all scenarios, four with 1 and 2 (cefalexin, buprenorphine, olanzapine, and memantine), and one with 1 and 3 (enalapril) or 2 and 3 (ciprofloxacin). The direction of associations was the same in all/both scenarios. The interaction results were equally versatile, with hydroxocobalamin*oxazepam being the only interaction observed in all scenarios. CONCLUSIONS: Case-crossover analysis is a potential approach for identifying candidate drugs and drug-drug interactions associated with adverse events as it implicitly controls for fixed confounders. The results are highly dependent on applied hazard and control periods, but the choice of periods can help in targeting the analyses to different phases of drug use. PMID- 28556304 TI - SUV2, which encodes an ATR-related cell cycle checkpoint and putative plant ATRIP, is required for aluminium-dependent root growth inhibition in Arabidopsis. AB - A suppressor mutagenesis screen was conducted in order to identify second site mutations that could reverse the extreme hypersensitivity to aluminium (Al) seen for the Arabidopsis mutant, als3-1. From this screen, it was found that a loss-of function mutation in the previously described SUV2 (SENSITIVE TO UV 2), which encodes a putative plant ATRIP homologue that is a component of the ATR-dependent cell checkpoint response, reversed the als3-1 phenotype. This included prevention of hallmarks associated with als3-1 including Al-dependent terminal differentiation of the root tip and transition to endoreduplication. From this analysis, SUV2 was determined to be required for halting cell cycle progression and triggering loss of the quiescent centre (QC) following exposure to Al. In conjunction with this, SUV2 was found to have a similar role as ATR, ALT2 and SOG1 in Al-dependent stoppage of root growth, all of which are required for promotion of expression of a suite of genes that likely are part of an Al dependent DNA damage transcriptional response. This work argues that these Al response factors work together to detect Al-dependent damage and subsequently activate a DNA damage response pathway that halts the cell cycle and subsequently promotes QC differentiation and entrance into endocycling. PMID- 28556305 TI - Hypothalamic dopamine is required for salsolinol-induced prolactin secretion in goats. AB - The aim of the present study was to clarify the relationship between hypothalamic dopamine (DA) and salsolinol (SAL) for the secretion of prolactin (PRL) in goats. SAL or thyrotropin-releasing hormone (TRH) was intravenously injected into female goats treated with or without the D2 DA receptor antagonist haloperidol (Hal), which crosses the blood-brain barrier, and the PRL-releasing response to SAL was compared with that to TRH. PRL-releasing responses to SAL, Hal, and Hal plus SAL were also examined after a pretreatment to augment central DA using carbidopa (Carbi) and L-dopa. The PRL-releasing response to Hal alone was greater than that to SAL or TRH alone. The PRL-releasing response to Hal plus SAL was similar to that of Hal alone. In contrast, the PRL-releasing response to Hal plus TRH was greater than that to TRH or Hal alone. The treatment with Carbi plus L-dopa inhibited SAL- and Hal-induced PRL secretion. The inhibition of the PRL-releasing response to SAL disappeared when SAL was injected with Hal. These results indicate that the mechanisms underlying the SAL-induced PRL response differ from those of TRH, and suggest that hypothalamic DA and its synthesis is associated in part with SAL-induced PRL secretion in goats. PMID- 28556306 TI - Differential responses of the dorsomedial prefrontal cortex and right posterior superior temporal sulcus to spontaneous mentalizing. AB - Previous research suggests a role of the dorsomedial prefrontal cortex (dmPFC) in metacognitive representation of social information, while the right posterior superior temporal sulcus (pSTS) has been linked to social perception. This study targeted these functional roles in the context of spontaneous mentalizing. An animated shapes task was presented to 46 subjects during functional magnetic resonance imaging. Stimuli consisted of video clips depicting animated shapes whose movement patterns prompt spontaneous mentalizing or simple intention attribution. Based on their differential response during spontaneous mentalizing, both regions were characterized with respect to their task-dependent connectivity profiles and their associations with autistic traits. Functional network analyses revealed highly localized coupling of the right pSTS with visual areas in the lateral occipital cortex, while the dmPFC showed extensive coupling with instances of large-scale control networks and temporal areas including the right pSTS. Autistic traits were related to mentalizing-specific activation of the dmPFC and to the strength of connectivity between the dmPFC and posterior temporal regions. These results are in good agreement with the hypothesized roles of the dmPFC and right pSTS for metacognitive representation and perception-based processing of social information, respectively, and further inform their implication in social behavior linked to autism. Hum Brain Mapp 38:3791-3803, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28556307 TI - Evaluation of peroxidative stress of cancer cells in vitro by real-time quantification of volatile aldehydes in culture headspace. AB - RATIONALE: Peroxidation of lipids in cellular membranes results in the release of volatile organic compounds (VOCs), including saturated aldehydes. The real-time quantification of trace VOCs produced by cancer cells during peroxidative stress presents a new challenge to non-invasive clinical diagnostics, which as described here, we have met with some success. METHODS: A combination of selected ion flow tube mass spectrometry (SIFT-MS), a technique that allows rapid, reliable quantification of VOCs in humid air and liquid headspace, and electrochemistry to generate reactive oxygen species (ROS) in vitro has been used. Thus, VOCs present in the headspace of CALU-1 cancer cell line cultures exposed to ROS have been monitored and quantified in real time using SIFT-MS. RESULTS: The CALU-1 lung cancer cells were cultured in 3D collagen to mimic in vivo tissue. Real-time SIFT MS analyses focused on the volatile aldehydes: propanal, butanal, pentanal, hexanal, heptanal and malondialdehyde (propanedial), that are expected to be products of cellular membrane peroxidation. All six aldehydes were identified in the culture headspace, each reaching peak concentrations during the time of exposure to ROS and eventually reducing as the reactants were depleted in the culture. Pentanal and hexanal were the most abundant, reaching concentrations of a few hundred parts-per-billion by volume, ppbv, in the culture headspace. CONCLUSIONS: The results of these experiments demonstrate that peroxidation of cancer cells in vitro can be monitored and evaluated by direct real-time analysis of the volatile aldehydes produced. The combination of adopted methodology potentially has value for the study of other types of VOCs that may be produced by cellular damage. PMID- 28556308 TI - Topical capsaicin 8% for the treatment of neuropathic itch conditions. PMID- 28556309 TI - Local sampling paints a global picture: Local concentration measurements sense direction in complex chemical gradients. AB - Detecting and interpreting extracellular spatial signals is essential for cellular orientation within complex environments, such as during directed cell migration or growth in multicellular development. Although the molecular understanding of how cells read spatial signals like chemical gradients is still lacking, recent work has revealed that stochastic processes at different temporal and spatial scales are at the core of this gradient sensing process in a wide range of eukaryotes. Fast biochemical reactions like those underlying GTPase activity dynamics form a functional module together with slower cell morphological changes driven by membrane remodelling. This biochemical morphological module explores the environment by stochastic local concentration sampling to determine the source of the gradient signal, enabling efficient signal detection and interpretation before polarised growth or migration towards the gradient source is initiated. Here we review recent data describing local sampling and propose a model of local fast and slow feedback counteracted by gradient-dependent substrate limitation to be at the core of gradient sensing by local sampling. PMID- 28556310 TI - Variation in cannabis potency and prices in a newly legal market: evidence from 30 million cannabis sales in Washington state. AB - AIMS: To (1) assess trends and variation in the market share of product types and potency sold in a legal cannabis retail market and (2) estimate how potency and purchase quantity influence price variation for cannabis flower. DESIGN: Secondary analysis of publicly available data from Washington State's cannabis traceability system spanning 7 July 2014 to 30 September 2016. Descriptive statistics and linear regressions assessed variation and trends in cannabis product variety and potency. Hedonic regressions estimated how purchase quantity and potency influence cannabis flower price variation. SETTING: Washington State, USA. PARTICIPANTS: (1) A total of 44 482 176 million cannabis purchases, including (2) 31 052 123 cannabis flower purchases after trimming price and quantity outliers. MEASUREMENTS: Primary outcome measures were (1) monthly expenditures on cannabis, total delta-9-tetrahydrocannabinol (THC) concentration and cannabidiol (CBD) concentration by product type and (2) excise tax-inclusive price per gram of cannabis flower. Key covariates for the hedonic price regressions included quantity purchased, THC and CBD. FINDINGS: Traditional cannabis flowers still account for the majority of spending (66.6%), but the market share of extracts for inhalation increased by 145.8% between October 2014 and September 2016, now comprising 21.2% of sales. The average THC-level for cannabis extracts is more than triple that for cannabis flowers (68.7% compared to 20.6%). For flower products, there is a statistically significant relationship between price per gram and both THC [coefficient = 0.012; 95% confidence interval (CI) = 0.011-0.013] and CBD (coefficient = 0.017; CI = 0.015-0.019). The estimated discount elasticity is -0.06 (CI = -0.07 to -0.05). CONCLUSIONS: In the state of Washington, USA, the legal cannabis market is currently dominated by high-THC cannabis flower, and features growing expenditures on extracts. For cannabis flower, both THC and CBD are associated with higher per-gram prices, and there are small but significant quantity discounts. PMID- 28556312 TI - Three-Dimensional Power Doppler Vascularization in Women With Ovarian Endometriomas and Relationship With Associated Painful Symptoms. AB - OBJECTIVES: The objective of the study was to evaluate the correlation between endometrioma-associated pain and lesion vascularization as measured with 3 dimensional power Doppler transvaginal sonography. METHODS: Endometriomas were examined, and 4 indices were obtained: mean grayness, flow index, vascularization index, and vascularization-flow index. Dysmenorrhea, chronic pelvic pain, and dyspareunia were analyzed in terms of severity, presence/absence, and duration. RESULTS: Twenty-nine women were selected. The univariable association of painful symptoms in terms of presence/absence and duration was low with the exception of mean grayness with the presence of chronic pelvic pain (beta = -0.106; P = .047; 95% confidence interval, 0.810 to 0.998). The R2 value increased to 0.226 for dysmenorrhea (beta = -0.475; P = .029) when analyzing the association between the vascularization index and the severity of painful symptoms. The visual analog scale scores for chronic pelvic pain and dyspareunia were higher (R2 = 0.300; beta = -0.547 and -0.548, respectively; P = .028 and .053). CONCLUSIONS: We observed an inverse association between the severity of pain and endometrioma vascularization. Further larger studies are required to confirm our findings. PMID- 28556311 TI - Defining pain in newborns: need for a uniform taxonomy? AB - : A framework for defining pain terms such as acute, persistent, prolonged or chronic pain to newborns was derived from the scientific literature on neonatal pain assessments, previous attempts to define chronic pain and the clinical and neurophysiological features of neonatal pain. This novel framework incorporates the temporal features, localising characteristics, and secondary effects of the pain experienced, as well as the behavioural and physiological response patterns of newborns. CONCLUSION: Although not evidence-based, this framework provides an initial starting point for defining commonly used neonatal pain terms. It will require future revision/refinement based on the accumulating evidence for non acute pain. PMID- 28556314 TI - EVOLUTIONARY PATTERNS OF THE THERMAL SENSITIVITY OF SPRINT SPEED IN ANOLIS LIZARDS. AB - I present evidence that the thermal sensitivity of sprint speed of Anolis lizards has evolved to match the activity body temperatures (Tb ) experienced by local populations in nature. Anolis lizards from a range of altitudes in Costa Rica have limited thermoregulatory abilities and consequently have field Tb that differ substantially in median and interquartile distance (a measure of variability). Experimentally determined maximal sprint temperatures (Tb at which lizards run fastest) were positively correlated with median field Tb , and performance breadths (ranges of Tb over which lizards run well) were correlated with the variability (interquartile distance) of field Tb in the species I examined. Such correlations would be expected if the thermal sensitivity of sprint speed and field Tb had evolved together to improve the sprint performance of lizards in nature. Integration of laboratory and field studies indicates that several species of Anolis regularly experience impaired sprint speeds in the field, despite apparent evolutionary modification of their thermal physiologies. However, this impairment would have been more severe if the thermal sensitivities of sprint speed had not evolved. Data from other groups of lizards indicate that the thermal sensitivity of sprint speed has not evolved to match Tb of local populations (Hertz et al., 1983; Crowley, 1985). These lizards experience less variable Tb and less impairment of sprint speeds in the field than do the anoles. Thus, selection for modification of the thermal sensitivity of sprint speed might have been stronger for anoles than for other groups of lizards. PMID- 28556313 TI - An analysis of purchase price of legal and illicit cigarettes in urban retail environments in 14 low- and middle-income countries. AB - BACKGROUND/AIMS: To estimate and compare price differences between legal and illicit cigarettes in 14 low- and middle-income countries (LMIC). DESIGN: A cross sectional census of all packs available on the market was purchased. SETTING: Cigarette packs were purchased in formal retail settings in three major cities in each of 14 LMIC: Bangladesh, Brazil, China, Egypt, India, Indonesia, Mexico, Pakistan, the Philippines, Russia, Thailand, Turkey, Ukraine and Vietnam. PARTICIPANTS: A total of 3240 packs were purchased (range = 58 packs in Egypt to 505 in Russia). Packs were categorized as 'legal' or 'illicit' based on the presence of a health warning label from the country of purchase and existence of a tax stamp; 2468 legal and 772 illicit packs were in the analysis. MEASUREMENTS: Descriptive statistics stratified by country, city and neighborhood socio economic status were used to explore the association between price and legal status of cigarettes. FINDINGS: The number of illicit cigarettes in the sample setting was small (n < 5) in five countries (Brazil, Egypt, Indonesia, Mexico, Russia) and excluded from analysis. In the remaining nine countries, the median purchase price of legal cigarettes ranged from US$0.32 in Pakistan (n = 72) to US$3.24 in Turkey (n = 242); median purchase price of illicit cigarettes ranged from US$0.80 in Ukraine (n = 14) to US$3.08 in India (n = 41). The difference in median price between legal and illicit packs as a percentage of the price of legal packs ranged from 32% in Philippines to 455% in Bangladesh. Median purchase price of illicit cigarette packs was higher than that of legal cigarette packs in six countries (Bangladesh, India, Pakistan, Philippines, Thailand, Vietnam). Median purchase price of illicit packs was lower than that of legal packs in Turkey, Ukraine and China. CONCLUSIONS: The median purchase price of illicit cigarettes is higher than that of legal cigarette packs in Bangladesh, India, Pakistan, Philippines, Thailand, and Vietnam, Brazil, Egypt, Indonesia, Mexico, Russia appear to have few or no illicit cigarettes for purchase from formal, urban retailers. PMID- 28556315 TI - PLANT POPULATION BIOLOGY BEYOND THE CROSSROADS. PMID- 28556316 TI - DIFFERENTIATION AMONG NINE POPULATIONS OF PHLOX. I. ELECTROPHORETIC AND QUANTITATIVE VARIATION. AB - The organization of genetic variation in Phlox drummondii was investigated using both allozyme electrophoresis and quantitative genetics. Variation at five polymorphic enzyme loci was characterized in nine populations, and variation in 16 morphological and life-history characters was examined using an analysis of full- and half-sibs in seven populations. Significant levels of genetic variation were found at enzyme loci and for metric characters. Significant heritabilities were observed for 15 of the 16 characters examined. Genetic differences among populations were revealed both by Nei's genetic distance and by phenotypic differences, summarized by discriminant analysis. Partitioning variance in allozyme frequencies among hierarchical levels of genetic organization indicated that 94% of this variance lay within populations, 4% between populations within varieties, and 2% between varieties. Partitioning phenotypic variance for metric characters indicated that 73% lay within populations, 24% lay between populations within varieties, and 3% lay between varieties. Thus, both electrophoretic and metric characters indicated that despite extensive genetic differentiation among populations, most of the evolutionary potential of the species lies within populations. PMID- 28556317 TI - ON THE INSTABILITY OF POLYGENIC SEX DETERMINATION: THE EFFECT OF SEX-SPECIFIC SELECTION. AB - A combination of analytical and simulation models is used to explore the initial evolution of genic sex determination from polygenic sex determination. Prior studies have indicated that polygenic sex determination is rare or absent in extant species but that it has likely played an important intermediate role in the evolution of other genetic sex-determination systems. This study explores why polygenic sex determination does not persist. Two possibilities are considered. First it is assumed that a major sex-determining gene also pleiotropically increases fitness. Second it is assumed that the sex-determining gene is neutral but linked to another locus segregating for a rare selectively favored allele. The major conclusion from the models is that sex-specific natural selection will cause polygenic sex determination to be a transient state in most populations. Polygenic sex determination may be an important intermediate step in the evolution of genetically controlled sexual differentiation, but it is unlikely to persist unless there is some selective advantage compared to genic sex determination. This may in part explain the relatively small number of extant species that have polygenic sex determination. PMID- 28556318 TI - TOO VALUABLE TO REVIEW. PMID- 28556319 TI - QUANTITATIVE GENETICS OF MORPHOLOGICAL DIFFERENTIATION IN PEROMYSCUS. I. TESTS OF THE HOMOGENEITY OF GENETIC COVARIANCE STRUCTURE AMONG SPECIES AND SUBSPECIES. AB - Phenotypic and additive genetic covariance matrices were estimated for 15 morphometric characters in three species and subspecies of Peromyscus. Univariate and multivariate ANOVAs indicate these groups are highly diverged in all characters, P. leucopus having the largest body size, P. maniculatus bairdii the smallest, and P. maniculatus nebrascensis being intermediate. Comparing the structure of P and G within each taxon revealed significant similarities in all three cases. This proportionality was strong enough to justify using P in the place of G to analyze evolutionary processes using quantitative genetic models when G can not be estimated, as in fossil material. However, the similarity between genetic and phenotypic covariance structures is sufficiently low that estimates of the genetic parameters should be used when possible. The additive genetic covariance matrices were compared to examine the assumption that they remain constant during evolution, an assumption which underlies many applications of quantitative-genetic models. While matrix permutation tests indicated statistically significant proportionality between the genetic covariance structures of the two P. maniculatus subspecies, there is no evidence of significant genetic structural similarity between species. This result suggests that the assumption of constant genetic covariance structure may be valid only within species. (It does not, however, necessarily imply a causal relationship between speciation and heterogeneity of genetic covariance structures.) The low matrix correlation for the two P. maniculatus subspecies' genetic covariance matrices indicates G may not be functionally constant, even within species. The lack of similarity observed here may be due partly to sampling variation. PMID- 28556321 TI - LEE R. G. SNYDER MEMORIAL FUND. PMID- 28556320 TI - EFFECTS OF PARENTAL PHOTOPERIOD REGIME ON PROGENY DEVELOPMENT TIME IN DROSOPHILA SIMULANS. PMID- 28556322 TI - ADVANTAGES AND DISADVANTAGES OF EGRET AND HERON BROOD REDUCTION. AB - Data from great egrets and great blue herons were used to test a fundamental assumption of Lack's brood-reduction hypothesis, that mortality is brood-size dependent. This was confirmed for the largest brood sizes (4 and 3), which, in egrets, also have the highest sib-fighting rates. Broods of one, however, experienced paradoxically high mortality, especially early in the season. The hypothesis is advanced that parents desert unprofitably small broods when sufficient time remains for production of a larger brood. A simple game-theory model shows that this parental desertion may hinge primarily on the overall costs of renesting. Egret brood reduction caused by sibling aggression (siblicide) occurred later than less aggressive forms of brood reduction. The inclusive fitness of senior broodmates is maximized by the successful fledging of all sibs, and the physical superiority of seniors (in food-handling for herons; food handling and aggression for egrets) usually suffices to guarantee their own welfare in brood competitions. Finally, it is shown that the last chick in asynchronously hatching broods represents two kinds of reproductive value (RV) to the parents-"extra RV" (obtained despite the survival of elder sibs) and "insurance RV" (obtained only when at least one elder sib dies first)-which can be distinguished from field data. This approach can be used in comparisons with other asynchronous species for partitioning the fitness contributions of marginal offspring. PMID- 28556323 TI - EVOLUTION OF PROKARYOTES. PMID- 28556324 TI - RESPONSE TO DENSITY IN A WILD POPULATION OF THE PERENNIAL HERB SALVIA LYRATA: VARIATION AMONG FAMILIES. AB - In order to determine the potential for natural selection to promote genetic specialization to different environments, this study quantified genetic variation for response to conspecific density and to other aspects of the environment that vary spatially. The progeny of a random collection of Salvia lyrata, a perennial herb, were planted into the source field in a range of densities and into several closely neighboring locations. The highest density and particular locations induced significantly greater mortality relative to the remaining densities and locations, indicating major effects of density and spatial location on fitness. Over the duration of the entire study, there was also significant variation among families in mortality. The survival data gave no indication of variation among families in their responses to the range of environments. Conversely, results based on growth and size indicated that different families were favored in different densities and locations, in support of the hypothesis that environment dependent selection promotes specialization to different environments in this species. The correlation among families between leaf number in high and low density was small and positive, indicating near-independence of performance in different densities. PMID- 28556325 TI - ON FACTORS AFFECTING THE FIXATION OF CHROMOSOMAL REARRANGEMENTS AND NEUTRAL GENES: COMPUTER SIMULATIONS. AB - Computer simulation models were developed to determine which conditions are favorable for the stochastic fixation of chromosomal mutations within small isolated demes. The models incorporated biological parameters of litter size, age dependent mortality, overlapping generations, potentially varying sex ratios, and fertility reduction due to meiotic problems when the mutation was present in a heterozygous condition. Results of the models indicated that random processes alone may adequately explain the frequency of fixation of chromosomal mutations under the conditions of a) the number of initial founders is small (5 or 10); b) there is relatively little fecundity reduction due to meiotic problems; c) the number of offspring per mating is high. Furthermore, results of our models imply that fixation of a mutation is unlikely when the number of karyotypic rearrangements is low and when there is high survivorship of individuals from one breeding period to the next. However, if bottlenecks involve larger numbers of individuals (20 or more), few offspring per mating, or substantial reductions in fecundity, then it is unlikely that fixation by random processes will be adequate to explain the situations observed in nature. A significant conclusion of these simulations is that when population size is reduced to five or ten individuals, the extinction rate may exceed 40% or 30%, respectively. PMID- 28556326 TI - SONORAN DESERT SPRING. PMID- 28556327 TI - FLIGHTLESSNESS IN STEAMER-DUCKS (ANATIDAE: TACHYERES): ITS MORPHOLOGICAL BASES AND PROBABLE EVOLUTION. AB - Flightlessness in Tachyeres is caused by wing-loadings in excess of 2.5 g.cm-2 , which result from the large body size and small wing areas of the flightless species. Reduced wing areas of flightless species are related to absolutely shorter remiges, and to relatively or absolutely shortened wing bones, although these reductions differ among species. Reduced lengths of the ulna, radius, and carpometacarpus are associated most strongly with flightlessness. Pectoral muscles and the associated sternal keel are well developed in all species of Tachyeres, largely because of the use of wings in "steaming," an important locomotor behavior. Relative size of these muscles was greatest in largely flighted T. patachonicus; however, sexual dimorphism in wing-loadings results in flightlessness in some males of this species. Proportions in the wing skeleton, intraspecific allometry, and limited data on growth indicate that the relatively short wing bones and remiges of flightless Tachyeres are produced developmentally by a delay in the growth of wing components, and that this heterochrony may underlie, in part, skeletal sexual dimorphism. Increased body size in flightless steamer-ducks is advantageous in territorial defense of food resources and young, and perhaps diving in cold, turbulent water; reductions in wing area probably reflect refinements for wing-assisted locomotion and combat. Flightlessness in steamer-ducks is not related to relaxed predation pressure, but instead was permitted selectively by the year-round habitability of the southern South American coasts. These conditions not only permitted the success of the three flightless species of Tachyeres, but at present may be moving marine populations of T. patachonicus toward flightlessness. PMID- 28556328 TI - EVOLUTIONARY IMPLICATIONS OF CHROMOSOMAL POLYMORPHISMS IN PEROMYSCUS BOYLII FROM SOUTHWESTERN MEXICO. PMID- 28556330 TI - LOTUS CORNICULATUS REGULATES OFFSPRING QUALITY THROUGH SELECTIVE FRUIT ABORTION. AB - Each inflorescence on Lotus corniculatus commonly aborts about half of its immature fruits. Compared to random patterns of fruit abortion, natural patterns of fruit abortion produce mature fruits that contain significantly more seeds. Moreover, these progeny are more likely to germinate, are more vigorous as seedlings, and have greater reproductive output as adults. These results indicate that L. corniculatus selectively aborts those fruits with the fewest seeds and, by doing so, increases the average quality of its offspring. PMID- 28556331 TI - VARIABLE SELECTION ON THE TIMING OF GERMINATION IN COLLINSIA VERNA (SCROPHULARIACEAE). AB - Natural selection on the timing of seed germination was investigated in a natural population of the winter annual Collinsia verna (Scrophulariaceae) for two years. The goal was to quantify 1) the importance of the timing of seed germination to life history evolution in this population and 2) variation in selection in time and space. During fall germination, seedlings were assigned to cohorts on the basis of their dates of germination. Growth, survivorship, and reproduction were censused throughout both years. Selection on the timing of germination was quantified using linear and quadratic regressions during three ecologically important periods in the life cycle, using the techniques of Lande and Arnold (1983) and Arnold and Wade (1984a, 1984b). Comparisons were made between years and on two spatial scales within years. Overall, selection favored early germinating plants in the first year. The primary determinant of the relationship of the timing of germination to fitness was fecundity selection, rather than viability selection on seedlings. Fecundity selection was respondible for from 54% to 80% of the change in the mean time of germination. Significant disruptive selection characterized the second field season, again mediated mainly through fecundity selection. There was also temporal and spatial heterogeneity in selection on this character. Transects and quadrats differed significantly in the direction and magnitude of natural selection. In addition, the direction of selection changed between episodes for the transects. The results illustrate the importance of the timing of germination to life-history evolution in this annual plant and the complex action of natural selection on this character. PMID- 28556332 TI - INBREEDING AS A STRATEGY IN SUBDIVIDED POPULATIONS. AB - A generalized expression for coefficients of consanguinity and relationship with previous inbreeding is presented to examine various breeding strategies in subdivided populations. Conditions that would favor inbreeding are developed for: 1) nonfamilial inbreeding within a deme versus outbreeding; 2) altruistic inbreeding by females versus outbreeding; 3) sib-mating versus outbreeding; and 4) sib-mating versus nonfamilial breeding within a deme. Inbreeding behavior is advantageous under certain conditions but depends on the types of mating, the previous breeding history of the deme, the rate of accumulation of inbreeding depression, and the cost of migration. In polygynous mating systems it is genetically more advantageous for males to migrate, because female emigration may 1) leave a related male with no mate or one fewer mate, or 2) force both male and female to risk the cost of migration. Nonfamilial breeding is always a better strategy than sib-mating given previous inbreeding within the deme. Even when the cost of migration is zero, inbreeding is favored if the coefficient of relationship among relatives is greater than the ratio of the probabilities of offspring inviability to offspring viability. Although high inbreeding coefficients are probably not adaptive unless the costs of migration are great or inbreeding depression constants are small, low levels of inbreeding are advantageous in many situations. Therefore, increased genetic representation by way of inbreeding and inclusive fitness is a major component of the evolutionary process. PMID- 28556333 TI - INSECTS AND FLOWERS. PMID- 28556334 TI - RACE FORMATION, SPECIATION, AND INTROGRESSION WITHIN DROSOPHILA SIMULANS, D. MAURITIANA, AND D. SECHELLIA INFERRED FROM MITOCHONDRIAL DNA ANALYSIS. AB - Mitochondrial DNA cleavage maps from three chromosomally homosequential species Drosophila simulans, D. mauritiana, and D. sechellia, were established for 12 restriction enzymes. One isofemale strain was studied in D. sechellia (se), 13 in D. simulans, and 17 in D. mauritiana: in the last two species, respectively, three (siI, II, and III) and two (maI and II) cleavage morphs were found. The evolutionary relationships based on mtDNA cleavage map comparisons show that the maI and se mtDNAs are internal branches of the phylogenetic tree of the D. simulans mtDNA. D. mauritiana and D. sechellia species appear to be derived from a population of D. simulans which carried an ancestral form of the current siI mtDNA type. In addition, two cleavage morphs (siIII [only present in D. simulans from Madagascar] and maI) appeared to be identical, although found in different species. We present a speculative interpretation of data on biogeography and hybridization which is consistent with the hypothesis of a recent introgression of mitochondrial DNA of D. simulans from Madagascar into D. mauritiana. PMID- 28556335 TI - DEFINITION AND ESTIMATION OF FIXATION INDICES. PMID- 28556336 TI - ANNUAL MEETING SOCIETY FOR THE STUDY OF EVOLUTION. PMID- 28556337 TI - SPERM COMPETITION AND THE EVOLUTION OF NUPTIAL FEEDING BEHAVIOR IN THE CRICKET, GRYLLODES SUPPLICANS (WALKER). AB - The pattern of sperm predominance in doubly mated female crickets, Gryllodes supplicans, was investigated using a radiation-sterility technique. Female G. supplicans made significant use of sperm from both males in fertilizing eggs; overall, first males to mate enjoyed a small advantage, fertilizing about 60% of the offspring produced subsequent to the second mating. The combined use of the sperm of both males in fertilizing eggs occurred soon after the second mating; evidently, mixing of ejaculates within a female's spermatheca does occur. Male G. supplicans provide females with a nuptial gift, the spermatophylax, which influences the time at which a female removes the externally attached sperm ampulla; this in turn determines the quantity of sperm that is transferred. Moreover, the degree of sperm precedence achieved by a male may be positively related to the time at which the female removes his sperm ampulla. Thus males, by feeding females, ensure not only that a sufficient number of sperm are transferred to fertilize all of a female's eggs, but also may increase the certainty of their paternity. In mating systems in which females control sperm transfer and paternity is influenced by numbers of sperm (i.e., numerical sperm competition), an increase in prezygotic investment in females may be an adaptive male response. PMID- 28556338 TI - VARIABLE ITEROPARITY AS A LIFE-HISTORY TACTIC IN THE PITCHER-PLANT MOSQUITO WYEOMYIA SMITHII. AB - Larval density, but not geographic origin (Florida to Ontario), affected female fecundity among 12 populations of W. smithii, regardless of whether or not they had opportunity to take blood meals. Neither the degree of iteroparity nor male longevity varied with density or geographic region of origin, but longevity was greater among southern, potentially blood-feeding females, than among northern, nonbiting females. Among the southern females, iteroparity, but not fecundity, increased with opportunity to take blood meals. Specifically, there was no increase in fecundity among females whose larvae were nutritionally deprived relative to females whose larvae were well fed. I interpret the retention of hematophagy and facultatively augmented iteroparity in W. smithii as a means for females developing under predictably impoverished but irregularly opportunistic conditions to reallocate and temporally diversify their reproductive effort. PMID- 28556339 TI - DELAYED PLUMAGE MATURATION IN PASSERINE BIRDS: RELIABLE SIGNALING BY SUBORDINATE MALES? AB - Three hypotheses (Cryptic, Female Mimicry, and Winter Adaptation) have been proposed to explain the occurrence of delayed plumage maturation (DPM) in passerine birds. We show that each of these hypotheses is really a composite of two different questions about: 1) the proximate function of dull plumage in second year (SY) males and 2) the selective mechanism that has favored that proximate function. We review the three hypotheses in the context of this distinction, and we find little evidence clearly supporting any of them. We propose a new Status Signaling Hypothesis (SSH) suggesting that dull SY male plumage is a reliable signal of subordinate. We suggest that female choice based on male plumage color (as an index of male quality) is the selective mechanism that has favored subordinate status signaling by SY males. If females prefer bright males, then dull plumage may be a reliable signal of subordinance and SY males may experience reduced levels of aggression from adult males. Male characters (like plumage color) are most likely to be the object of female choice when males defend simple nesting territories with little or no variation in territory quality. In such a system, SY males with low resource-holding potential would benefit (via matings or experience) by signaling subordinance and being allowed to settle among more brightly colored adults. Thus, DPM is expected to be more prevalent when males defend simple nesting territories. This prediction of the SSH is supported by data from the literature-a significantly higher proportion of species with DPM defend simple nesting territories (versus all purpose territories) than do species without DPM. PMID- 28556340 TI - NATURAL HISTORY AND EVOLUTION. PMID- 28556341 TI - INTERPOPULATION DIFFERENCES IN HOST PREFERENCE AND THE EVOLUTION OF LEARNING IN THE BUTTERFLY, BATTUS PHILENOR. AB - The host-discrimination behavior of the adult female pipevine swallowtail butterfly (Battus philenor) was investigated for two populations, an east Texas population that uses two host species with different leaf shapes and a Virginia montane population that uses one host species with a single leaf shape. While Texas and Virginia females exhibited similar chemotactile responses after landing on various host species, butterflies from each population landed more frequently on certain host species used by that particular population. Despite this difference in searching behavior, Texas and Virginia populations were equally capable of learning to search for the leaf shape of a particular host species in artificial enclosure arrays. In addition, learning of leaf-shape preference was confounded equally when each population was introduced into arrays containing all the host species found in both populations. The lack of differentiation in learning of leaf-shape preference between populations that differ in host breadth and host preference argues against the specific hypothesis that learning of leaf shape preference represents a local adaptation that permits foraging butterflies in the east Texas population to respond to seasonal changes in the relative quality or abundance of host species that differ in leaf shape. Three hypotheses are proposed to explain the apparent absence of interpopulation genetic variation in learning traits. One hypothesis supposes that learning of leaf-shape discrimination is mediated by the same physiological mechanisms that permit females to learn to discriminate among suitable and unsuitable conspecific plants. Selection for restriction of learning of leaf-shape preference in the Virginia montane population may therefore be constrained by selection for learning of other types of discrimination behavior. PMID- 28556342 TI - RANDOM DRIFT, UNIFORM SELECTION, AND THE DEGREE OF POPULATION DIFFERENTIATION. PMID- 28556344 TI - HERITABILITY AND SELECTION ON TARSUS LENGTH IN THE PIED FLYCATCHER (FICEDULA HYPOLEUCA). AB - The heritability estimate (+/-SE) for tarsus length in the pied flycatcher is 0.53 +/- 0.10, based on mother-offspring regressions. The heritability is almost the same (0.50 +/- 0.22) for offspring transferred to other nests and reared by foster parents, whereas there is no resemblance (0.04 +/- 0.23) between the offspring and their foster mothers. Hence, the nest environment does not affect parent-offspring resemblance. However, a full-sib correlation yields an estimate of the heritability twice as high as the parent-offspring regression did, indicating that shared environment effects, which are not correlated with the tarsus length of parents, must be important. An environmental deviation due to food factors affecting tarsus length is demonstrated. The most important food factors are probably associated with 1) polygyny, which leads to reduced paternal feeding at secondary nests, 2) high breeding density, and 3) progress of the breeding season. All three are associated with reductions in offspring mean tarsus length. We estimate selection on tarsus length for the major components of lifetime reproductive success. Offspring with the shortest tarsi have reduced survival from fledging until breeding, and males with tarsus length close to the mean are most successful in attracting mates. Clutch size increases with female tarsus length, except for individuals with very long tarsi. In general, directional selection is weak, but stabilizing selection is rather strong for survival and male mating success. PMID- 28556345 TI - EXTINCTION: THE LONG AND SHORT OF IT. PMID- 28556346 TI - Factors affecting masticatory function of community-dwelling older people: Investigation of the differences in the relevant factors for subjective and objective assessment. AB - OBJECTIVE: This study aimed to examine relevant factors for subjective and objective assessment of masticatory functions and elucidate any differences between the two methods. BACKGROUND: Previous studies have reported that the results of subjective and objective assessment of masticatory function in older people do not necessarily agree. MATERIALS AND METHODS: This study included 487 community-dwelling Japanese older people (205 male and 282 female; mean age 74.1+/-6.3 years) who participated in a comprehensive geriatric health examination. Basic information (gender and age), higher level of competence in daily living, depression, subjective masticatory function (SMF) and objective masticatory function (OMF) assessments, cognitive function, skeletal muscle mass, handgrip strength, gait speed and oral status (number of remaining and functional teeth, mouth dryness and occlusal force) were recorded. RESULTS: Multiple logistic regression analysis showed that depression (odds ratio [OR]: 1.181, 95% confidence interval [CI]: 1.094-1.275), mouth dryness (OR: 2.037, CI: 1.212 3.423) and occlusal force (OR: 0.997, CI: 0.996-0.999) were significantly associated with SMF, whereas higher level of competence in daily living (OR: 0.730 CI: 0.586-0.910), skeletal muscle mass (OR: 0.521 CI: 0.283-0.960), number of functional teeth (OR: 0.862 CI: 0.775-0.959), number of remaining teeth (OR: 0.868 CI: 0.810-0.930) and occlusal force (OR: 0.994, CI: 0.991-0.998) were associated with OMF. CONCLUSION: Subjective masticatory functionSMF and OMF were associated with different factors, suggesting that both mental and physical factors should be taken into consideration when treating decreased masticatory function. PMID- 28556347 TI - A case of ulcerative colitis with squamous cell carcinomas and multiple foci of squamous dysplasia. AB - Squamous cell carcinoma (SqCC) in ulcerative colitis (UC) is rare. A 38 year-old Japanese woman, who suffered from left-sided UC for 18 years, underwent total colectomy due to SqCCs in the rectum and the sigmoid colon. They were well differentiated SqCC, and metastasis was found in the paracolic lymph nodes. Multiple small foci of squamous dysplasia (SD) were noted in the rectal mucosa. Glandular dysplasia was not found. TP53 was not detected in SD. Approximately 40% of cells were immunostained with TP53 in SqCC, however no mutation was found in TP53 gene. Human papilloma virus and Epstein Barr virus were negative in SD and SqCCs. The patient is free of the disease at one and half years after surgery and chemotherapy. SD may be a precursor of SqCC. It appeared that TP53 does not play a vital role in the development of SqCCs in the current case. Careful attention should be paid to SD in UC patients. Viral infection may need to be examined. The pathogenesis of SqCC in patients of UC needs to be elucidated. PMID- 28556348 TI - Printable and Rewritable Full Block Copolymer Structural Color. AB - Structural colors (SCs) of photonic crystals (PCs) arise from selective constructive interference of incident light. Here, an ink-jet printable and rewritable block copolymer (BCP) SC display is demonstrated, which can be quickly written and erased over 50 times with resolution nearly equivalent to that obtained with a commercial office ink-jet printer. Moreover, the writing process employs an easily modified printer for position- and concentration-controlled deposition of a single, colorless, water-based ink containing a reversible crosslinking agent, ammonium persulfate. Deposition of the ink onto a self assembled BCP PC film comprising a 1D stack of alternating layers enables differential swelling of the written BCP film and produces a full-colored SC display of characters and images. Furthermore, the information can be readily erased and the system can be reset by application of hydrogen bromide. Subsequently, new information can be rewritten, resulting in a chemically rewritable BCP SC display. PMID- 28556349 TI - Actinic keratosis. Or maybe not? PMID- 28556350 TI - Effects of hemodialysis on intraneural blood flow in end-stage kidney disease. AB - INTRODUCTION: We quantified intraneural blood flow (INBF) in 18 patients with end stage kidney disease (ESKD) and examined its relationship with nerve size, neuropathy severity, and nerve excitability parameters. METHODS: Sonographic measurements of the median nerve were performed at the same site before and after hemodialysis. INBF was quantified by analyzing power Doppler sonograms to obtain the vessel score (VSc) and maximum perfusion intensity (MPI). Corresponding median motor nerve excitability studies were performed. Neuropathy severity was assessed using Total Neuropathy Score. RESULTS: A total of 39% of ESKD patients had detectable INBF compared with none in the control group (P < 0.0001). Patients with detectable INBF had larger nerves and more severe neuropathy (P < 0.01). INBF parameters were significantly reduced after a session of dialysis (VSc: P < 0.01; MPI: P < 0.01). A significant relationship was found between interdialytic change in INBF and changes in nerve excitability. CONCLUSIONS: Increased INBF is a potential marker for neuropathy severity in ESKD patients. Muscle Nerve 57: 287-293, 2018. PMID- 28556351 TI - THRIVE score predicts clinical and radiological outcome after endovascular therapy or thrombolysis in patients with anterior circulation stroke in everyday clinical practice. AB - BACKGROUND AND PURPOSE: Based on the data of several trials the Totaled Health Risks in Vascular Events (THRIVE) score has been shown to predict outcome after either intravenous thrombolysis (IVT) or endovascular therapy (ET) in acute stroke patients. It is unknown whether the THRIVE score can also predict outcome in everyday clinical practice. Using our prospectively obtained stroke database the utility of the THRIVE score to predict clinical and radiological outcome in everyday clinical practice was analysed. METHODS: The relationships between THRIVE and good outcome (modified Rankin Scale <= 2 at discharge), poor outcome (modified Rankin Scale 5-6), in-hospital death, symptomatic intracranial haemorrhage (SICH) as well as infarct size were examined in patients with distal intracranial carotid artery, M1 and M2 occlusions after either IVT or ET. RESULTS: From January 2008 to October 2016 a total of 546 patients were treated with IVT and 492 patients received ET with stent retrievers (with or without IVT). In both treatment groups the THRIVE score predicted clinical outcome (Mantel-Haenszel chi-squared tests for trend P < 0.001 for good outcome, P < 0.001 for poor outcome and P < 0.001 for in-hospital death). In the ET group the THRIVE score remained an independent predictor of outcome after controlling for recanalization. The THRIVE score was associated with the infarct size after IVT or ET, whereas it did not predict SICH rates in either treatment group. CONCLUSIONS: In everyday clinical practice the THRIVE score strongly predicts clinical outcome and the extent of ischaemia after ET or IVT in patients with anterior circulation large vessel occlusions. PMID- 28556352 TI - Connecting insomnia, sleep apnoea and depression. PMID- 28556354 TI - Modeling Precheck Parallel Screening Process in the Face of Strategic Applicants with Incomplete Information and Screening Errors. AB - In security check systems, tighter screening processes increase the security level, but also cause more congestion, which could cause longer wait times. Having to deal with more congestion in lines could also cause issues for the screeners. The Transportation Security Administration (TSA) Precheck Program was introduced to create fast lanes in airports with the goal of expediting passengers who the TSA does not deem to be threats. In this lane, the TSA allows passengers to enjoy fewer restrictions in order to speed up the screening time. Motivated by the TSA Precheck Program, we study parallel queueing imperfect screening systems, where the potential normal and adversary participants/applicants decide whether to apply to the Precheck Program or not. The approved participants would be assigned to a faster screening channel based on a screening policy determined by an approver, who balances the concerns of safety of the passengers and congestion of the lines. There exist three types of optimal normal applicant's application strategy, which depend on whether the marginal payoff is negative or positive, or whether the marginal benefit equals the marginal cost. An adversary applicant would not apply when the screening policy is sufficiently large or the number of utilized benefits is sufficiently small. The basic model is extended by considering (1) applicants' parameters to follow different distributions and (2) applicants to have risk levels, where the approver determines the threshold value needed to qualify for Precheck. This article integrates game theory and queueing theory to study the optimal screening policy and provides some insights to imperfect parallel queueing screening systems. PMID- 28556353 TI - Decreased Absorption of Dolutegravir and Tenofovir Disoproxil Fumarate, But Not Emtricitabine, in an HIV-Infected Patient Following Oral and Jejunostomy-Tube Administration. AB - The use of enteral feeding tubes to administer antiretroviral medications is necessary in certain patients with human immunodeficiency virus (HIV) infection. However, adequacy of drug exposures after these administration routes are largely unknown, making dosing recommendations and the attainment of viral suppression challenging in this patient population. This report describes a patient with advanced HIV infection and a complicated medical history including long-term intractable nausea/vomiting necessitating antiretroviral medication administration via a Roux-en-Y jejunostomy (J)-tube. Pharmacokinetic assessments were performed to compare differences in antiretroviral drug absorption and plasma exposure following oral and J-tube administration of dolutegravir, tenofovir disoproxil fumarate, and emtricitabine. Results were also compared with published pharmacokinetic data in HIV-infected individuals. Exposure to dolutegravir and tenofovir were similar between J-tube and oral administration routes, whereas emtricitabine exposure was 38% lower when administered via J tube. However, in comparison with reference data in HIV-infected individuals taking these medications orally, exposure to dolutegravir and tenofovir was 75 76% and 55-61% lower, respectively, following both routes of administration. Emtricitabine exposure was similar to and 71% higher than reference data following J-tube and oral administration, respectively. This report highlights the importance of performing pharmacokinetic assessments in patients with the potential for impaired drug absorption to ensure antiretroviral treatment success. PMID- 28556357 TI - Dyspareunia From Large Retained Fetal Bone Diagnosed by Pelvic Ultrasound. PMID- 28556355 TI - Bias and inference from misspecified mixed-effect models in stepped wedge trial analysis. AB - Many stepped wedge trials (SWTs) are analysed by using a mixed-effect model with a random intercept and fixed effects for the intervention and time periods (referred to here as the standard model). However, it is not known whether this model is robust to misspecification. We simulated SWTs with three groups of clusters and two time periods; one group received the intervention during the first period and two groups in the second period. We simulated period and intervention effects that were either common-to-all or varied-between clusters. Data were analysed with the standard model or with additional random effects for period effect or intervention effect. In a second simulation study, we explored the weight given to within-cluster comparisons by simulating a larger intervention effect in the group of the trial that experienced both the control and intervention conditions and applying the three analysis models described previously. Across 500 simulations, we computed bias and confidence interval coverage of the estimated intervention effect. We found up to 50% bias in intervention effect estimates when period or intervention effects varied between clusters and were treated as fixed effects in the analysis. All misspecified models showed undercoverage of 95% confidence intervals, particularly the standard model. A large weight was given to within-cluster comparisons in the standard model. In the SWTs simulated here, mixed-effect models were highly sensitive to departures from the model assumptions, which can be explained by the high dependence on within-cluster comparisons. Trialists should consider including a random effect for time period in their SWT analysis model. (c) 2017 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd. PMID- 28556356 TI - Identification of a functional enhancer variant within the chronic pancreatitis associated SPINK1 c.101A>G (p.Asn34Ser)-containing haplotype. AB - The haplotype harboring the SPINK1 c.101A>G (p.Asn34Ser) variant (also known as rs17107315:T>C) represents the most important heritable risk factor for idiopathic chronic pancreatitis identified to date. The causal variant contained within this risk haplotype has however remained stubbornly elusive. Herein, we set out to resolve this enigma by employing a hypothesis-driven approach. First, we searched for variants in strong linkage disequilibrium (LD) with rs17107315:T>C using HaploReg v4.1. Second, we identified two candidate SNPs by visual inspection of sequences spanning all 25 SNPs found to be in LD with rs17107315:T>C, guided by prior knowledge of pancreas-specific transcription factors and their cognate binding sites. Third, employing a novel cis-regulatory module (CRM)-guided approach to further filter the two candidate SNPs yielded a solitary candidate causal variant. Finally, combining data from phylogenetic conservation and chromatin accessibility, cotransfection transactivation experiments, and population genetic studies, we suggest that rs142703147:C>A, which disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A PTF1L CRM located ~4 kb upstream of the SPINK1 promoter, contributes to the aforementioned chronic pancreatitis risk haplotype. Further studies are required not only to improve the characterization of this functional SNP but also to identify other functional components that might contribute to this high-risk haplotype. PMID- 28556358 TI - Buffering the Uneven Impact of the Affordable Care Act: Immigrant-serving Safety net Providers in New Mexico. AB - We conducted a study in early 2014 to document how the initial implementation of the Affordable Care Act (ACA) affected health care provision to different categories of immigrants from the perspective of health care providers in New Mexico. Though ACA navigators led enrollment, a range of providers nevertheless became involved by necessity, expressing concern about how immigrants were faring in the newly configured health care environment and taking on advocacy roles. Providers described interpreting shifting eligibility and coverage, attending to vulnerable under/uninsured patients, and negotiating new bureaucratic barriers for insured patients. Findings suggest that, like past efforts, this recent reform to the fragmented health care system has perpetuated a condition in which safety-net clinics and providers are left to buffer a widening gap for immigrant patients. With possible changes to the ACA ahead, safety-net providers' critical buffering roles will likely become more crucial, underscoring the necessity of examining their experiences with past reforms. PMID- 28556359 TI - Synthesis, Solid-State Structure, and Bonding Analysis of a Homoleptic Beryllium Azide. AB - [Ph4 P]2 [Be(N3 )4 ] (1) and [PNP]2 [Be(N3 )4 ] (2; PNP=Ph3 PNPPh3 ) were synthesized by reacting Be(N3 )2 with [Ph4 P]N3 and [PNP]N3 . Compound 1 represents the first structurally characterized homoleptic beryllium azide. The electronic structure and bonding situation in the tetraazidoberyllate dianion [Be(N3 )4 ]2- were investigated by quantum-chemical calculations (NPA, ELF, LOL). PMID- 28556360 TI - Association of cytochrome P450 1B1 haplotypes with head and neck cancer risk. AB - Genetic polymorphisms have been reported in several cytochrome P450 (CYP) genes, including CYP1B1 which metabolically activates procarcinogens present in tobacco to carcinogenic intermediates. This study used a case-control approach in North Indian population to determine associations between genetic variants in CYP1B1 and risk of Head and Neck Squamous Cell Carcinoma (HNSCC). We examined the genotype and haplotype frequencies at various single-nucleotide polymorphisms (SNPs), including SNPs previously reported in the promoter region and intron 1 of CYP1B1 in Caucasians. Using cycle sequencing, 9 SNPs were identified in the promoter region, intron 1, and exons 2 and 3. Haplotype analysis revealed that 5 SNPs (those in the promoter region, intron, and Arg48Gly and Ala119Ser in exon 2) were in strong linkage disequilibrium (LD). Cases with the T-A-T-G-T haplotype were significantly associated with increased risk of HNSCC. Interestingly, qRT PCR studies revealed a significant increase in mRNA expression of CYP1B1 in peripheral blood isolated from cases with the T-A-T-G-T haplotype compared with cases with the C-G-C-C-G haplotype, and in cases compared to controls for both main haplotypes. The data thus provide evidence that CYP1B1 haplotypes could be more effective in predicting HNSCC risk. Environ. Mol. Mutagen. 58:443-450, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28556361 TI - Skin involvement as the first symptom of rapidly progressive ALK-positive systemic anaplastic large cell lymphoma. AB - Systemic anaplastic large cell lymphomas (sALCLs) comprise a heterogeneous group of relatively rare T-cell non-Hodgkin lymphomas that are characterized by CD30 expression. Anaplastic lymphoma kinase (ALK)-positive ALCL is a type of sALCL that commonly involves lymph nodes and extranodal sites. Skin involvement usually presents as tumours, nodules and ulcers. We describe an unusual case of ALK positive ALCL in an 11-year-old Chinese boy, who initially presented with skin eruption with rapid progression and poor prognosis. This case emphasizes the value of clinical factors to predict the prognosis of ALK-positive sALCL, and we recommend close collaboration between dermatologists, pathologists and haematologists/oncologists to assure the correct diagnosis and treatment. PMID- 28556362 TI - A case of primary secretory carcinoma of the thyroid with high-grade features. PMID- 28556363 TI - Photocontrolled Living Polymerization Systems with Reversible Deactivations through Electron and Energy Transfer. AB - Recently, visible-light-regulated polymerization has been gaining popularity, as it opens a range of new opportunities for the synthesis of functional polymers and materials. Here, the most recent developments in this field are summarized, which is the use of photocatalysts and catalyst-free approaches to mediate polymerization upon photoexcitation. These catalysts can transfer an electron or energy to activate an initiator. The recent achievements in light-regulated atom transfer radical polymerization, reversible addition-fragmentation chain-transfer polymerization, ring-opening metathesis polymerization, cobalt-mediated radical polymerization, iodine-mediated radical polymerization, and living cationic polymerization are reviewed. Recent development in these fields have solved important challenges in polymer chemistry, such as the development of oxygen tolerant polymerization, polymerization mediated by near-infrared, metal-free polymerization, and spatial-, temporal-, and sequence-controlled polymerization. Some applications of these techniques will be discussed, such as adapting the current photocatalytic systems to synthesize heterogeneous photocatalysts that act as recyclable photocatalysts and novel light-mediated approaches for surface functionalization of hybrid materials and living cells. Finally, the existing challenges in polymer chemistry that could be overcome by further development of light-mediated polymerization techniques are highlighted along with the future directions of this field. PMID- 28556365 TI - Identification and expression profiling of novel plant cell wall degrading enzymes from a destructive pest of palm trees, Rhynchophorus ferrugineus. AB - Plant cell wall degrading enzymes (PCWDEs) from insects were recently identified as a multigene family of proteins that consist primarily of glycoside hydrolases (GHs) and carbohydrate esterases (CEs) and play essential roles in the degradation of the cellulose/hemicellulose/pectin network in the invaded host plant. Here we applied transcriptomic and degenerate PCR approaches to identify the PCWDEs from a destructive pest of palm trees, Rhynchophorus ferrugineus, followed by a gut-specific and stage-specific differential expression analysis. We identified a total of 27 transcripts encoding GH family members and three transcripts of the CE family with cellulase, hemicellulase and pectinase activities. We also identified two GH9 candidates, which have not previously been reported from Curculionidae. The gut-specific quantitative expression analysis identified key cellulases, hemicellulases and pectinases from R. ferrugineus. The expression analysis revealed a pectin methylesterase, RferCE8u02, and a cellulase, GH45c34485, which showed the highest gut enriched expression. Comparison of PCWDE expression patterns revealed that cellulases and pectinases are significantly upregulated in the adult stages, and we observed specific high expression of the hemicellulase RferGH16c4170. Overall, our study revealed the potential of PCWDEs from R. ferrugineus, which may be useful in biotechnological applications and may represent new tools in R. ferrugineus pest management strategies. PMID- 28556364 TI - Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies. AB - The hedgehog signaling pathway regulates multiple morphogenetic processes during embryogenesis. Aberrant activation of the hedgehog pathway signal transduction in adult tissues is associated with the pathogenesis of hematologic malignancies and solid tumors. We report findings from an open-label, multicenter phase I trial of the selective, small-molecule hedgehog signaling inhibitor glasdegib (PF 04449913) in Japanese patients with select advanced hematologic malignancies. Glasdegib was administered as once-daily oral doses (25, 50 and 100 mg) in 28-day cycles after a lead-in dose on Day -5. The primary objectives were to determine first-cycle dose-limiting toxicities, safety, vital signs and laboratory test abnormalities. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics and preliminary evidence of clinical activity of glasdegib. No dose-limiting toxicities were noted in the 13 patients in the present study. All patients experienced at least one treatment-emergent, all-causality adverse event. The most frequent treatment-related adverse events (observed in >=3 patients) were dysgeusia (n = 9), muscle spasms (n = 5), alopecia, decreased appetite (n = 4 each), and increased blood creatinine phosphokinase, constipation and diarrhea (n = 3 each). Two deaths occurred during the study and were deemed not to be treatment-related due to disease progression. Glasdegib demonstrated dose-proportional pharmacokinetics, marked downregulation of the glioma associated transcriptional regulator GLI1 expression in normal skin, and evidence of preliminary clinical activity, although data are limited. Glasdegib was safe and well tolerated across the dose levels tested. It is confirmed that the 100-mg dose is safe and tolerable in Japanese patients, and this dose level will be examined in the future clinical trial. PMID- 28556367 TI - Refugee children and their health, development and well-being over the first year of settlement: A longitudinal study. AB - AIM: This study aimed to describe refugee children, their families and settlement characteristics, and how their development and social-emotional well-being change over time. METHODS: We conducted a longitudinal study of 61 refugee children (6 months to 15 years) in an Australian setting, over 2009-2013 and measured child, family and settlement factors as well as physical health, development and social emotional well-being (Strengths and Difficulties Questionnaire, SDQ). RESULTS: Questionnaires were completed with parents of 54 (89%) children at year 2 and 52 (100%) at year 3. Forty percent of parents had low levels of education, 30% of fathers were absent on arrival, 13% of children were born in refugee camps and 11% of parents self-disclosed previous trauma. Over time, there was increased parental employment (P = 0.001), improved English proficiency for partners (P = 0.02) and reduced stressful life events in the last 12 months (P = 0.003). At years 2 and 3, parents were studying English (96%; 76%), accessing government financial support (96%; 100%) and primary health care (98%; 87%), and feeling supported by their own (78%; 73%) or the general (69%; 63%) community. Fifteen percent of children had a chronic disease, and 13% were obese and overweight. In pre-school children, 27% had mild developmental problems in year 2; all were normal by year 3. Abnormal SDQ total difficulties scores reduced over time from 13 to 6% of children but this did not reach significance. CONCLUSION: Most refugee children have developmental and well-being outcomes within the normal range by year 3. However, a minority of children have persistently poor social emotional outcomes. PMID- 28556368 TI - A PDGFB mutation causes paroxysmal nonkinesigenic dyskinesia with brain calcification. PMID- 28556369 TI - Retinal pigment epithelium expansion around the neural retina occurs in two separate phases with distinct mechanisms. AB - BACKGROUND: The retinal pigment epithelium (RPE) is a specialized monolayer of epithelial cells that forms a tight barrier surrounding the neural retina. RPE cells are indispensable for mature photoreceptor renewal and survival, yet how the initial RPE cell population expands around the neural retina during eye development is poorly understood. RESULTS: Here we characterize the differentiation, proliferation, and movements of RPE progenitors in the Zebrafish embryo over the period of optic cup morphogenesis. RPE progenitors are present in the dorsomedial eye vesicle shortly after eye vesicle evagination. We define two separate phases that allow for full RPE expansion. The first phase involves a previously uncharacterized antero-wards expansion of the RPE progenitor domain in the inner eye vesicle leaflet, driven largely by an increase in cell number. During this phase, RPE progenitors start to express differentiation markers. In the second phase, the progenitor domain stretches in the dorsoventral and posterior axes, involving cell movements and shape changes, and coinciding with optic cup morphogenesis. Significantly, cell division is not required for RPE expansion. CONCLUSIONS: RPE development to produce the monolayer epithelium that covers the back of the neural retina occurs in two distinct phases driven by distinct mechanisms. Developmental Dynamics 246:598-609, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28556366 TI - A role for primary cilia in aortic valve development and disease. AB - BACKGROUND: Bicuspid aortic valve (BAV) disease is the most common congenital heart defect, affecting 0.5-1.2% of the population and causing significant morbidity and mortality. Only a few genes have been identified in pedigrees, and no single gene model explains BAV inheritance, thus supporting a complex genetic network of interacting genes. However, patients with rare syndromic diseases that stem from alterations in the structure and function of primary cilia ("ciliopathies") exhibit BAV as a frequent cardiovascular finding, suggesting primary cilia may factor broadly in disease etiology. RESULTS: Our data are the first to demonstrate that primary cilia are expressed on aortic valve mesenchymal cells during embryonic development and are lost as these cells differentiate into collagen-secreting fibroblastic-like cells. The function of primary cilia was tested by genetically ablating the critical ciliogenic gene Ift88. Loss of Ift88 resulted in abrogation of primary cilia and increased fibrogenic extracellular matrix (ECM) production. Consequentially, stratification of ECM boundaries normally present in the aortic valve were lost and a highly penetrant BAV phenotype was evident at birth. CONCLUSIONS: Our data support cilia as a novel cellular mechanism for restraining ECM production during aortic valve development and broadly implicate these structures in the etiology of BAV disease in humans. Developmental Dynamics 246:625-634, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28556370 TI - Inhibitor-Assisted High-Pressure Inactivation of Bacteria in Skim Milk. AB - The combined inactivation effects of high hydrostatic pressure (HHP) and antimicrobial compounds (potassium sorbate and epsilon-polylysine [epsilon-PL]) on 4 different bacterial strains present in skim milk and the effect of these treatments on milk quality were investigated in this study. HHP treatment at 500 MPa for 5 min reduced the populations of Escherichia coli, Salmonella enterica Typhimurium, Listeria monocytogenes, and Staphylococcus aureus from 6.5 log colony-forming units (CFUs) or higher to less than 1 log CFU/mL. Compared to HHP alone, HHP with potassium or epsilon-PL resulted in significantly higher reductions in the bacterial counts. After 5 min of treatment with HHP (500 MPa) and epsilon-PL (2 mg/mL), no growth of E. coli, S. enterica Typhimurium, or L. monocytogenes in skim milk was observed during 15 d of refrigerated storage (4 +/ 1 degrees C). Scanning electron microscopy analysis revealed that the synergistic treatments caused more serious damage to the bacterial cell walls. Quality assessments of the treated samples indicated that the combined treatments did not influence the color, the turbidity, the concentrations of -SH group of the proteins, or the in vitro digestion patterns of the milk. This study demonstrates that HHP with potassium or epsilon-PL may be useful in the processing of milk or milk-containing foods. PMID- 28556371 TI - Effects of aligned alpha-helix peptide dipoles on experimental electrostatic potentials. AB - Aligned protein alpha-helix dipoles have been implicated in protein function and structure. The recent breakthroughs in high-resolution electron microscopy (EM) of macromolecules makes it possible to explore fundamental aspects of structural biology at the detailed molecular level. The electrostatic potential (ESP) generated by aligned protein alpha-helix dipole should be observable in high resolution EM maps despite the fact that the effect may be partially screened by induced electric fields. Here, we show that aligned backbone dipoles in protein alpha-helices account for long-range features in the protein ESP functions. Our results are consistent with experimental EM maps and density functional theory calculations, including direct Fourier summation for proper calculation of the ESP due to the nonlocal nature of the ESP function from aligned dipoles and other partial atomic charges. PMID- 28556372 TI - Plant-plant interactions influence developmental phase transitions, grain productivity and root system architecture in Arabidopsis via auxin and PFT1/MED25 signalling. AB - Transcriptional regulation of gene expression influences plant growth, environmental interactions and plant-plant communication. Here, we report that population density is a key factor for plant productivity and a major root architectural determinant in Arabidopsis thaliana. When grown in soil at varied densities from 1 to 32 plants, high number of individuals decreased stem growth and accelerated senescence, which negatively correlated with total plant biomass and seed production at the completion of the life cycle. Root morphogenesis was also a major trait modulated by plant density, because an increasing number of individuals grown in vitro showed repression of primary root growth, lateral root formation and root hair development while affecting auxin-regulated gene expression and the levels of auxin transporters PIN1 and PIN2. We also found that mutation of the Mediator complex subunit PFT1/MED25 renders plants insensitive to high density-modulated root traits. Our results suggest that plant density is critical for phase transitions, productivity and root system architecture and reveal a role of Mediator in self-plant recognition. PMID- 28556373 TI - High-resolution dynamic 31 P-MRSI using a low-rank tensor model. AB - PURPOSE: To develop a rapid 31 P-MRSI method with high spatiospectral resolution using low-rank tensor-based data acquisition and image reconstruction. METHODS: The multidimensional image function of 31 P-MRSI is represented by a low-rank tensor to capture the spatial-spectral-temporal correlations of data. A hybrid data acquisition scheme is used for sparse sampling, which consists of a set of "training" data with limited k-space coverage to capture the subspace structure of the image function, and a set of sparsely sampled "imaging" data for high resolution image reconstruction. An explicit subspace pursuit approach is used for image reconstruction, which estimates the bases of the subspace from the "training" data and then reconstructs a high-resolution image function from the "imaging" data. RESULTS: We have validated the feasibility of the proposed method using phantom and in vivo studies on a 3T whole-body scanner and a 9.4T preclinical scanner. The proposed method produced high-resolution static 31 P MRSI images (i.e., 6.9 * 6.9 * 10 mm3 nominal resolution in a 15-min acquisition at 3T) and high-resolution, high-frame-rate dynamic 31 P-MRSI images (i.e., 1.5 * 1.5 * 1.6 mm3 nominal resolution, 30 s/frame at 9.4T). CONCLUSIONS: Dynamic spatiospectral variations of 31 P-MRSI signals can be efficiently represented by a low-rank tensor. Exploiting this mathematical structure for data acquisition and image reconstruction can lead to fast 31 P-MRSI with high resolution, frame rate, and SNR. Magn Reson Med 78:419-428, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28556374 TI - Oncogenic role of neurotensin and neurotensin receptors in various cancers. AB - Neurotensin (NTS) has long been recognized as a neurotransmitter or neuromodulator in the central nervous system and as an endocrine agent in the periphery via actions mediated through neurotensin receptors (NTSRs). Many studies support a role for NTS in the endocrine, autocrine and paracrine growth stimulation of cancer, with oncogenic actions described for NTS in different types of cancers and cancer cell lines at each step of cancer progression, ranging from tumour growth and survival to metastatic spread. The mechanisms underlying the effects of the NTS/NTSR system in cell proliferation, migration and invasion, as well as the anti-apoptotic effects of this system, have been elucidated in different types of cancers, and include mitogen-activated protein kinases, phosphatidylinositol 3-kinase and RhoGTPases. The present mini review summarizes recent findings relating to the oncogenic function of the NTS/NTSR system. PMID- 28556375 TI - Ichthyosis with confetti presenting as collodion baby: a novel mutation in KRT10. PMID- 28556376 TI - The Formation of Surface Lithium-Iron Ternary Hydride and its Function on Catalytic Ammonia Synthesis at Low Temperatures. AB - Lithium hydride (LiH) has a strong effect on iron leading to an approximately 3 orders of magnitude increase in catalytic ammonia synthesis. The existence of lithium-iron ternary hydride species at the surface/interface of the catalyst were identified and characterized for the first time by gas-phase optical spectroscopy coupled with mass spectrometry and quantum chemical calculations. The ternary hydride species may serve as centers that readily activate and hydrogenate dinitrogen, forming Fe-(NH2 )-Li and LiNH2 moieties-possibly through a redox reaction of dinitrogen and hydridic hydrogen (LiH) that is mediated by iron-showing distinct differences from ammonia formation mediated by conventional iron or ruthenium-based catalysts. Hydrogen-associated activation and conversion of dinitrogen are discussed. PMID- 28556377 TI - Deficiency of filaggrin regulates endogenous cysteine protease activity, leading to impaired skin barrier function. AB - BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disorder, characterized by skin barrier defects and enhanced allergen priming. Null mutations in the filaggrin gene (FLG) are strongly associated with moderate to severe AD, but the pathways linking barrier dysfunction and cutaneous inflammation are still largely unknown. AIM: To assess alteration of endogenous cysteine protease activity in FLG-deficient keratinocytes, and to determine whether the alteration in cysteine protease activity affects epidermal barrier function and associated gene and protein expression. METHODS: We established a stable FLG knockdown cell line, and reconstructed epidermal equivalents in vitro. Barrier function of the reconstructed epidermis, the barrier-associated genes and proteins, and the activity of endogenous cysteine proteases were tested. Inhibitors of cysteine proteases were used to further evaluate the role of endogenous cysteine proteases in epidermal barrier function. RESULTS: FLG knockdown induced impaired epidermal barrier function. Microarray, western blotting and fluorescence staining showed reduced expression of K10, ZO-1, E cadherin, claudin-1 and occludin in FLG knockdown keratinocytes. Compared with cysteine protease activity in control cells, protease activity was dramatically enhanced in FLG knockdown keratinocytes. Furthermore, administration of cysteine protease inhibitors significantly recovered expression of K10 and tight junction proteins, and the barrier defect induced by FLG deficiency. CONCLUSIONS: This is the first observation of elevated endogenous cysteine protease activity in FLG deficient keratinocytes, which may play an important role in impaired barrier function in AD skin. Modulation of cysteine protease activity might be a novel therapeutic approach for AD treatment. PMID- 28556378 TI - Security and the Traumatized Street Child: How Gender Shapes International Psychiatric Aid in Cairo. PMID- 28556379 TI - Role of serum steroid hormones in women with stress urinary incontinence: a case control study. AB - OBJECTIVES: To investigate the potential relationship between endogenous sex steroids and presence of stress urinary incontinence (SUI). PATIENTS AND METHODS: A total of 47 peri- and postmenopausal women with SUI were matched 1:1 with 47 continent women based on age, menopausal status, body mass index (BMI) and parity. Blood samples were drawn from all the women for assessment of oestradiol (E2), follicle-stimulating hormone, luteinizing hormone, testosterone, androstendion (AEON), dehydroepiandrosterone sulphate and sex hormone-binding globulin with an electrochemiluminescence immunoassay. RESULTS: Women with SUI had significantly lower serum levels of E2 (8.49 +/- 7.47 vs 13.09 +/- 13.80; P = 0.048) and AEON (0.59 +/- 0.41 vs 1.20 +/- 0.87; P = 0.033) compared with controls. This difference in E2 levels remained significant after controlling for age, menopausal age, years from menopause, BMI, parity, testosterone and AEON. In addition, hypertension and history of hysterectomy were observed significantly more frequently in the SUI group (P < 0.001). There was no significant association between hormone levels and degree of SUI (P > 0.05). CONCLUSION: The results of the present study indicate that a low E2 level might have a negative impact on the lower urinary tract and continence mechanism and a low E2 level is a possible risk factor for SUI in women. PMID- 28556380 TI - Waitlist Outcomes for Patients Relisted Following Failed Donation After Cardiac Death Liver Transplant: Implications for Awarding Model for End-Stage Liver Disease Exception Scores. AB - Understanding of outcomes for patients relisted for ischemic cholangiopathy following a donation after cardiac death (DCD) liver transplant (LT) will help standardization of a Model for End-Stage Liver Disease exception scheme for retransplantation. Early relisting (E-RL) for DCD graft failure caused by primary nonfunction (PNF) or hepatic artery thrombosis (HAT) was defined as relisting <=14 days after DCD LT, and late relisting (L-RL) due to biliary complications was defined as relisting 14 days to 3 years after DCD LT. Of 3908 DCD LTs performed nationally between 2002 and 2016, 540 (13.8%) patients were relisted within 3 years of transplant (168 [4.3%] in the E-RL group, 372 [9.5%] in the L RL group). The E-RL and L-RL groups had waitlist mortality rates of 15.4% and 10.5%, respectively, at 3 mo and 16.1% and 14.3%, respectively, at 1 year. Waitlist mortality in the L-RL group was higher than mortality and delisted rates for patients with exception points for both hepatocellular carcinoma (HCC) and hepatopulmonary syndrome (HPS) at 3- to 12-mo time points (p < 0.001). Waitlist outcomes differed in patients with early DCD graft failure caused by PNF or HAT compared with those with late DCD graft failure attributed to biliary complications. In L-RL, higher rates of waitlist mortality were noted compared with patients listed with exception points for HCC or HPS. PMID- 28556381 TI - The spoilage yeast Zygosaccharomyces bailii: Foe or friend? AB - Zygosaccharomyces bailii is a non-Saccharomyces budding yeast known as one of the most aggressive food spoilage microorganisms, often isolated as a contaminant during wine fermentation, as well as from many acidic, high-sugar and canned foods. The spoilage ability relies on the yeast's unique feature of tolerating the most common preservatives such as sulphite, dimethyl dicarbonate, acetic acid and sorbic acid. Therefore, many studies have focused on the description of this peculiar tolerance with the aim of developing preventative measures against Z. bailii food spoilage. These studies demonstrated the involvement of diverse molecular and physiological mechanisms in the yeast resistance, comprising detoxification of preservatives, adaptation of the cytoplasmic pH and modulation of the cell wall/membrane composition. At the same time, the described traits unveiled Z. bailii as a novel potential workhorse for industrial bioprocesses. Here we present the yeast Z. bailii starting from important aspects of its robustness and concluding with the exploitation of its potential in biotechnology. Overall, the article describes Z. bailii from different perspectives, converging in presenting it as one of the most interesting species of the Saccharomycotina subphylum. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28556382 TI - Reentrant Phase Transition Drives Dynamic Substructure Formation in Ribonucleoprotein Droplets. AB - Intracellular ribonucleoprotein (RNP) granules are membrane-less droplet organelles that are thought to regulate posttranscriptional gene expression. While liquid-liquid phase separation may drive RNP granule assembly, the mechanisms underlying their supramolecular dynamics and internal organization remain poorly understood. Herein, we demonstrate that RNA, a primary component of RNP granules, can modulate the phase behavior of RNPs by controlling both droplet assembly and dissolution in vitro. Monotonically increasing the RNA concentration initially leads to droplet assembly by complex coacervation and subsequently triggers an RNP charge inversion, which promotes disassembly. This RNA-mediated reentrant phase transition can drive the formation of dynamic droplet substructures (vacuoles) with tunable lifetimes. We propose that active cellular processes that can create an influx of RNA into RNP granules, such as transcription, can spatiotemporally control the organization and dynamics of such liquid-like organelles. PMID- 28556383 TI - 2D Porous Carbons prepared from Layered Organic-Inorganic Hybrids and their Use as Oxygen-Reduction Electrocatalysts. AB - 2D porous carbon nanomaterials have attracted tremendous attention in different disciplines especially for electrochemical catalysis. The significant advantage of such 2D materials is that nearly all their surfaces are exposed to the electrolyte and can take part in the electrochemical reaction. Here, a versatile active-salt-templating strategy to efficiently synthesize 2D porous carbon nanosheets from layered organic-inorganic hybrids is presented. The resulting heteroatom-doped carbon nanosheets (NFe/CNs) exhibit exceptional performance for the oxygen-reduction reaction and in Zn-air battery electrodes. The activity of the best catalyst within a series of NFe/CNs exceeds the performance of conventional carbon-supported Pt catalysts in terms of onset potential (0.930 vs 0.915 V of Pt/C), half-wave potential (0.859 vs 0.816 V of Pt/C), long-time stability, and methanol tolerance. Also, when applied as a cathode catalyst in a zinc-air battery the NFe/CNs presented here outperform commercial Pt/C catalysts. PMID- 28556384 TI - Migraine associated with altitude: results from a population-based study in Nepal. AB - BACKGROUND AND PURPOSE: A 1988 pilot study in Peru suggested an association between migraine and chronic exposure to high altitude. This study provides epidemiological evidence corroborating this. METHODS: In a cross-sectional nationwide population-based study, a representative sample of Nepali-speaking adults were recruited through stratified multistage cluster sampling. They were visited at home by trained interviewers using a culturally adapted questionnaire. The altitude of dwelling of each participant was recorded. RESULTS: Of 2100 participants, over half [1100 (52.4%)] were resident above 1000 m and almost one quarter [470 (22.4%)] at >=2000 m. Age- and gender-standardized migraine prevalence increased from 27.9% to 45.5% with altitude between 0 and 2499 m and thereafter decreased to 37.9% at >=2500 m. The likelihood of having migraine was greater (odds ratio, 1.5-2.2; P <= 0.007) at all higher altitudes compared with <500 m. In addition, all symptom indices increased with altitude across the range <500 m to 2000-2499 m, i.e. median attack frequency from 1.3 to 3.0 days/month (P < 0.001), median duration from 9 to 24 h (P < 0.001) and pain intensity [the proportion reporting 'bad pain' (highest intensity)] from 35.5% to 56.9% (P = 0.011). Each of these showed a downward trend above 2500 m. CONCLUSIONS: Dwelling at high altitudes increases not only migraine prevalence but also the severity of its symptoms. PMID- 28556385 TI - Atenolol Versus Propranolol for Treatment of Infantile Hemangiomas During the Proliferative Phase: A Retrospective Noninferiority Study. AB - BACKGROUND/OBJECTIVES: The nonselective beta-blocker propranolol is the current criterion standard for treatment of infantile hemangiomas (IHs) and the first therapy that the U.S. Food and Drug Administration has approved for the condition, but concern about adverse effects, such as bronchospasm, hypoglycemia, and sleep disturbances, has sparked interest in the use of alternative agents such as the selective beta1 antagonist atenolol. Our aim was to compare the efficacy and adverse effect profiles of atenolol with those of propranolol in the treatment of IHs in a retrospective noninferiority trial. METHODS: Twenty-seven children with IHs treated with atenolol according to the Cleveland Clinic foundation's standardized clinical assessment and management plan (SCAMP) met inclusion criteria and were compared with a matched group of 53 children with IHs treated with propranolol. Three reviewers assessed response to therapy using a modified version of the previously validated Hemangioma Activity Score (HAS). RESULTS: The mean change in HAS was -2.94 +/- 1.20 for patients treated with atenolol and -2.96 +/- 1.42 for those treated with propranolol. There was no statistically significant difference in pre- and posttreatment modified HAS scores between the two groups (p = 0.60). There was no significant difference in the overall rate of adverse effects (p = 0.10), although 11% of patients treated with propranolol experienced reactive airway symptoms, whereas this was not seen in any of the patients treated with atenolol. CONCLUSION: Our study supports previous findings that atenolol is at least as effective as propranolol for treatment of IHs and poses less risk of bronchospasm. Our SCAMP proposes guidelines for dosing and monitoring parameters. PMID- 28556386 TI - Simple modification of arm position improves B1+ and signal homogeneity in the thoracolumbar spine at 3T. AB - PURPOSE: To evaluate the homogeneity of the radiofrequency magnetic field (B1+ ) and signal intensity using different arm positions during 3T thoracolumbar spinal imaging. MATERIALS AND METHODS: Twenty volunteers were scanned with a four channel radiofrequency (RF) transmit coil at 3T, with arms on the bed (conventional), arms elevated by 100 mm (arm lift), or with the arms-up position (elevated arm). Axial B1+ maps and sagittal T1 -weighted image (T1 WI)-performed RF shimming were obtained for each arm position. The mean and standard deviation (SD) of the flip angle (FA) at the center of the vertebra on each B1+ map, and contrast noise ratios (CNRs) between the spinal cord and cerebrospinal fluid of sagittal T1 WI, were calculated and compared among the different arm positions. RESULTS: Mean FA values (degrees) for the arm lift and elevated arm positions were significantly larger than for the conventional position (P < 0.001 for both) at the twelfth thoracic vertebra (Th12). FA SD values for the arm lift and elevated arm position were significantly smaller than for the conventional position (P < 0.001 for both) at Th12. CNR for the arm lift and elevated arm position were significantly higher than for the conventional position (P = 0.007 and 0.002, respectively). The mean and SD of the FA and the CNR did not differ significantly for the arm lift and elevated arm positions (P = 0.591, 0.958, and 0.927, respectively). CONCLUSION: Inhomogeneities of B1+ and signal intensities were improved by simply changing the arm position in 3T thoracolumbar spinal imaging. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:123-130. PMID- 28556387 TI - Motor milestone assessment of infants with spinal muscular atrophy using the hammersmith infant neurological Exam-Part 2: Experience from a nusinersen clinical study. AB - INTRODUCTION: In this study we examined the feasibility of assessing motor milestone performance of infants with spinal muscular atrophy (SMA) using the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) in a phase 2 study of nusinersen. METHODS: Nineteen SMA infants were assessed using the HINE-2 at baseline (<=7 months of age), and periodically up to 39 months of age. We evaluated whether the HINE-2 was feasible, reliable, and sensitive to change. RESULTS: Motor milestone assessments in SMA infants were feasible using the HINE 2. Baseline test-retest reliability was excellent (R = 0.987; P < 0.0001). SMA infants were extremely low functioning at baseline and the HINE-2 was able to detect changes over time in 16 of 19 infants within all 8 domains. HINE-2 improvements were correlated with changes in other neuromuscular outcome measures. CONCLUSION: Results support the use of the HINE-2 motor milestone assessment in clinical trials of SMA infants. Muscle Nerve 57: 143-146, 2017. PMID- 28556388 TI - Dose-dependence of transient respiratory motion artifacts on gadoxetic acid enhanced arterial phase MR images. AB - PURPOSE: To compare the occurrence of transient respiratory motion (TM) artifacts between 0.05 mmol/kg and 0.025 mmol/kg gadoxetic-acid on arterial phase MRI intra individually for evaluating dose-dependence of gadoxetic acid. MATERIALS AND METHODS: This retrospective study involved 91 patients who underwent dynamic MRI at 1.5T at different times, one time with 0.05 mmol/kg and the other 0.025 mmol/kg gadoxetic-acid. Examinations with 0.05 mmol/kg totaled 91 scans, and examinations with 0.025 mmol/kg totaled 375 scans (due to multiple exams for several patients). The scan with 0.025 mmol/kg closest in time to the 0.05 mmol/kg scan was selected to minimize temporal effects. Two radiologists graded TM artifacts in the arterial phase images using a four-point scale: no, mild, moderate, and severe artifacts. Results were compared between the two protocols (0.05 mmol/kg versus all 0.025 mmol/kg and 0.05 mmol/kg versus selected 0.025 mmol/kg), and the odds ratio for moderate-to-severe artifacts was calculated. RESULTS: Significantly more TM artifacts were observed in the double dose (16/91 [17%]) scans compared with either all (17/375 [4%]; P < 0.01) or selected (3/91 [3%]; P = 0.01) standard dose scans. The odds ratio of the moderate-to-severe artifacts with the higher dose was 4.99-5.33. CONCLUSION: There appears to be dose-dependence of gadoxetic-acid and the occurrence of TM artifacts. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:433-438. PMID- 28556390 TI - PROSPECT multicenter trial-a real milestone in prolapse surgery? PMID- 28556389 TI - Current practice and challenges in night-time care for people with dementia living in care homes: a qualitative study. AB - OBJECTIVE: To explore the current practices and challenges in night-time care for people with dementia living in care homes in the UK. METHODS: Focus group discussions (FGD) were held with care staff and family carers from five care homes in South London. To supplement the FGD data, an online survey was circulated to family carers (n = 16), and informal interviews were conducted with night-time care staff and nurses (n = 19). The questions for the online survey were designed to specifically explore the themes that emerged from the FGD. RESULTS: Thematic analysis revealed eight key themes in the management of sleep disturbance in people with dementia living in care homes: current night-time care practices, dissonance in perceived causes of sleep disturbances, inconsistencies in treatment options, insufficient staffing levels, working relationships between shifts, nurse burden and responsibility, communication as a critical challenge, connecting with residents and one overarching theme of balance. CONCLUSIONS: The findings of this study highlight the need for an evidence-based sleep disturbance management programme designed for use in care homes and informed by stakeholders. The key themes identified represent the major barriers to good quality care and areas which future programmes will need to address to improve the quality of night-time care in care homes. There are clearly opportunities for future examination of non-pharmacological night-time care management programmes for use in the population. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28556391 TI - Cardiac Myxoma: A Rare Case Series of 3 Patients and a Literature Review. AB - Myxoma is the most common tumor in the heart. A typical myxoma is relatively straightforward to diagnose. However, certain cardiac myxomas have rare features. We report three extremely rare cases of cardiac myxoma. One case involved a myxoma that originated from the annulus of the tricuspid after valvuloplasty, one case involved myxomas associated with left atrial thrombus and severe mitral stenosis, and the third case involved myxoma combined with severe calcification. All three cases were diagnosed by echocardiography and pathology. We also review clinical presentations and diagnostic characteristics of cardiac myxomas. PMID- 28556392 TI - The effects of pharmacist interventions on adult outpatients with cancer: A systematic review. AB - WHAT IS KNOWN AND OBJECTIVES: Most antineoplastic drugs are highly toxic and have low therapeutic indexes, which can result in drug-related problems. In this context, pharmacist interventions may play an important role in the success of the treatment. The objective of this study was to examine the effects of pharmacist interventions on adult outpatients with cancer using antineoplastic drugs. METHODS: A literature search was performed using PubMed, ISI Web of Science and LILACS databases from January 1990 to April 2016, using MeSH terms or text words related to pharmacist interventions, cancer and outpatient care. Studies published in English, Portuguese or Spanish on the effects of pharmacist interventions in outcome measures in adult outpatients with cancer were included. Two independent authors performed study selection and data extraction with a consensus process. The articles were analysed according to previously established criteria, such as country, study design, setting, population, type of cancer, description of the intervention and control groups, outcomes, main conclusions and study limitations. RESULTS AND DISCUSSION: A total of 874 records were identified, of which 11 satisfied the inclusion criteria. The studies were conducted mainly in the United States and included patients aged >50 years. Most studies had a before-after design. Pharmacist interventions primarily included educating and counselling patients on the management of adverse events. Rates of nausea and vomiting control, medication adherence and patient satisfaction were the most common outcome measures; a significant benefit in these parameters as a result of pharmacist interventions was noted in most studies. WHAT IS NEW AND CONCLUSION: The findings from this systematic review indicate that pharmacist interventions can improve outcome measures in outpatients with cancer. However, the collective quality of the studies was poor and gaps identified indicate that further research is needed to provide more robust results. PMID- 28556393 TI - Evaluation of the safety and efficacy of a monopolar nonablative radiofrequency device for the improvement of vulvo-vaginal laxity and urinary incontinence. AB - BACKGROUND AND OBJECTIVE: Vaginal childbirth, natural process of aging, congenital factors, and surgical interventions are considered the main causes of vulvo-vaginal laxity driven by changes in collagen and elastin fibers. This causes a loss of strength and flexibility within the vaginal wall. As a result, women may experience lack of sensation and stress urinary incontinence (SUI)-the condition of involuntary loss of urine associated with activities that cause an increase in intra-abdominal pressure (eg, sneezing, coughing, and lifting). Both vaginal laxity and urinary incontinence significantly affect patients' quality of life (QoL). The aim of this study was to evaluate efficacy and safety of a noninvasive radiofrequency device when used to treat SUI and vulvo-vaginal laxity through its heating effect which stimulates collagen and elastin fibers. METHODS: Twenty-seven women (average age 44.78+/-10.04 years) with indications of mild/moderate SUI as well as vulvo-vaginal laxity were treated with a monopolar radiofrequency device. The treatment course consisted of three once-a-week sessions. Each session included intravaginal treatment followed by treatment of labia majora and the perineum. Improvement in the SUI condition was evaluated by applying the International Consultation on Incontinence Questionnaire - Urinary Incontinence Short Form (ICIQ-UI SF). Data were collected at the baseline, after the last treatment and at 1-month follow-up visit. Vaginal laxity was assessed by subjective vulvo-vaginal laxity questionnaire (VVLQ). Data were collected before the 1st treatment and during the 1-month follow-up visit. Patient's satisfaction was recorded using a satisfaction questionnaire. Data were collected after the last treatment and at the 1-month follow-up visit. Any adverse events related to the treatments were monitored. RESULTS: On a scale of 0 to 5, the average frequency of urine leak improved from "2-3 times a week" (2.15+/-1.03 points prior to treatment) to "once a week" (1.00+/-0.78 points post-treatment), and on to "never" (0.44+/-0.51 points at the 1-month follow-up visit). Sixteen subjects (59.3%) reported decrease in the amount of leakage, with 15 women (55.6%) becoming completely leak-free at the 1-month follow-up. At the 1-month follow-up visit, 24 subjects (88.9%) expressed their condition's interference with everyday life decreased and 17 patients (62.9%) said the condition did not interfere with their everyday life at all as a result of the treatment. All results are statistically significant (P<.05). No adverse events were recorded. All subjects reported improvement in vaginal laxity, from average perception of "very loose" (2.19+/-1.08 points prior to treatment) to "moderately tight" (5.74+/-0.76 points at the 1-month follow-up visit). During the follow-up visit, 89% of the patients "agreed" or "strongly agreed" that their SUI condition improved, and 93% of the patients "agreed" or "strongly agreed" that their gratification during intercourse improved. None of the subjects reported dissatisfaction. CONCLUSION: The study confirmed the monopolar radiofrequency method as an effective and safe treatment of SUI and vulvo-vaginal laxity. The treatments were well tolerated by all subjects with no adverse effects. PMID- 28556394 TI - A robust diffusion tensor model for clinical applications of MRI to cartilage. AB - PURPOSE: Diffusion tensor imaging (DTI) of articular cartilage is a promising technique for the early diagnosis of osteoarthritis (OA). However, in vivo diffusion tensor (DT) measurements suffer from low signal-to-noise ratio (SNR) that can result in bias when estimating the six parameters of the full DT, thus reducing sensitivity. This study seeks to validate a simplified four-parameter DT model (zeppelin) for obtaining more robust and sensitive in vivo DTI biomarkers of cartilage. METHODS: We use simulations in a substrate to mimic changes during OA; and analytic simulations of the DT drawn from a range of fractional anisotropies (FA) measured with high-quality DT data from ex vivo human cartilage. We also use in vivo data from the knees of a healthy subject and two OA patients with Kellgren-Lawrence (KL) grades 1 and 2. RESULTS: For simulated in vivo cartilage SNR (~25) and anisotropy levels, the estimated mean values of MD from the DT and zeppelin models were identical to the ground truth values. However, zeppelin's FA is more accurate in measuring water restriction. More specifically, the FA estimations of the DT model were additionally biased by between +2% and +48% with respect to zeppelin values. Additionally, both mean diffusivity (MD) and FA of the zeppelin had lower parameter variance compared to the full DT (F-test, P < 0.05). We observe the same trends from in vivo values of patient data. CONCLUSION: The zeppelin is more robust than the full DT for cartilage diffusion anisotropy and SNR at levels typically encountered in clinical applications of articular cartilage. Magn Reson Med 79:1157-1164, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28556397 TI - Body Image Models among Low-income African American Mothers and Daughters in the Southeast United States. AB - Obesity among low-income African American women has been studied using the concepts of both satisfaction and acceptance. The satisfaction frame suggests greater satisfaction with their bodies than their white counterparts, irrespective of size. The acceptance frame suggests that alternative aesthetics serve as resistance against intersectional marginalization. Yet, while these women accept their body size in defiance of thinness ideals, they may not be satisfied. We describe cultural models of body image among mothers and daughters in Alabama. We found that respectability, material consumption, and parental support were important factors determining positive body image, exceeding descriptions of physical features. We further found that those expressing greater body dissatisfaction emphasized respectability, whereas those with less dissatisfaction assigned importance to consumerism and physical form. These findings suggest divergences between biomedical messaging and lived experience. They also challenge uncritical or universalist applications of these frames when interpreting African American women's perceptions of their own bodies. PMID- 28556398 TI - Heterodimerization of Group I Ribozymes Enabling Exon Recombination through Pairs of Cooperative trans-Splicing Reactions. AB - Group I (GI) self-splicing ribozymes are attractive tools for biotechnology and synthetic biology. Several trans-splicing and related reactions based on GI ribozymes have been developed for the purpose of recombining their target mRNA sequences. By combining trans-splicing systems with rational modular engineering of GI ribozymes it was possible to achieve more complex editing of target RNA sequences. In this study we have developed a cooperative trans-splicing system through rational modular engineering with use of dimeric GI ribozymes derived from the Tetrahymena group I intron ribozyme. The resulting pairs of ribozymes exhibited catalytic activity depending on their selective dimerization. Rational modular redesign as performed in this study would facilitate the development of sophisticated regulation of double or multiple trans-splicing reactions in a cooperative manner. PMID- 28556395 TI - Effects of exercise training on breast cancer metastasis in a rat model. AB - Exercise training is thought to play a protective role against cancer development and metastasis, either by reducing hormonal stimulation of hormone-dependent cancers or by reducing the permeability of vascular walls towards invading metastatic cells. The purpose of this work was to evaluate the role of long-term exercise training in the development and metastasis of breast cancer, in an immune-competent 1-methyl-1-nitrosourea (MNU) induced rat model. A single MNU dose was administered to Sprague-Dawley rats at 50 days of age and the rats were subjected to exercise training on a treadmill at 20 m/min, 60 min/day, 5 days/week for 35 weeks. Exercised animals developed slightly less (2.30 +/- 1.42) tumours per animal than sedentary animals (2.55 +/- 1.44) and did not develop any metastasis, while two pulmonary metastases were observed in the sedentary group. All primary neoplasms and their metastases were positive for oestrogen (ER) alpha and progesterone (PR) receptors, indicating high hormonal sensitivity. Interestingly, exercise training increased circulating oestrogen levels, thus suggesting that the mechanism might involve either or both of a protective hormone-independent effect and modulation of tumoural vascularization. PMID- 28556399 TI - Studies on the luminescence properties of cerium co-doping on Ca2 MgSi2 O7 :Eu2+ phosphor by solid-state reaction method. AB - Ca2 MgSi2 O7 :Ce3+ , Ca2 MgSi2 O7 :Eu2+ and Ca2 MgSi2 O7 :Eu2+ ,Ce3+ phosphors were prepared using the solid-state reaction method. The crystal structures of the sintered phosphors were of melilite type, which has a tetragonal crystallography. The chemical compositions of the sintered phosphors was confirmed by energy dispersive X-ray spectroscopy. The different thermoluminescence kinetic parameters [activation energy (E), frequency factor (s) and order of the kinetics (b)] of these phosphors were evaluated and compared using the peak shape method. Under ultraviolet excitation, the emission spectra of both Ca2 MgSi2 O7 :Eu2+ and Ca2 MgSi2 O7 :Eu2+ ,Ce3+ phosphors were composed of a broad emission band peaking at 530 nm. When the Ca2 MgSi2 O7 :Eu2+ phosphor is co-doped with Ce3+ ions, photoluminescence, afterglow and mechanoluminescence intensity was strongly enhanced. Ca2 MgSi2 O7 :Eu2+ showed some afterglow with a short persist time. On incorporation of Ce3+ , efficient energy transfer from Ce3+ to Eu2+ was found and the emission intensity of Eu2+ was enhanced. The mechanoluminescence intensities of Ca2 MgSi2 O7 :Ce3+ , Ca2 MgSi2 O7 :Eu2+ and Ca2 MgSi2 O7 :Eu2+ ,Ce3+ phosphors increased proportionally increased with the increase in impact velocity, which suggests that these phosphors can be used as sensors to detect stress in an object. PMID- 28556400 TI - Real-time three-dimensional image angle rectification to improve hand-eye coordination in single-port laparoendoscopic surgery. PMID- 28556401 TI - Quantitative proteome-based systematic identification of SIRT7 substrates. AB - SIRT7 is a class III histone deacetylase that is involved in numerous cellular processes. Only six substrates of SIRT7 have been reported thus far, so we aimed to systematically identify SIRT7 substrates using stable-isotope labeling with amino acids in cell culture (SILAC) coupled with quantitative mass spectrometry (MS). Using SIRT7+/+ and SIRT7-/- mouse embryonic fibroblasts as our model system, we identified and quantified 1493 acetylation sites in 789 proteins, of which 261 acetylation sites in 176 proteins showed >=2-fold change in acetylation state between SIRT7-/- and SIRT7+/+ cells. These proteins were considered putative SIRT7 substrates and were carried forward for further analysis. We then validated the predictive efficiency of the SILAC-MS experiment by assessing substrate acetylation status in vitro in six predicted proteins. We also performed a bioinformatic analysis of the MS data, which indicated that many of the putative protein substrates were involved in metabolic processes. Finally, we expanded our list of candidate substrates by performing a bioinformatics-based prediction analysis of putative SIRT7 substrates, using our list of putative substrates as a positive training set, and again validated a subset of the proteins in vitro. In summary, we have generated a comprehensive list of SIRT7 candidate substrates. PMID- 28556402 TI - Cold Snapshot of a Molecular Rotary Motor Captured by High-Resolution Rotational Spectroscopy. AB - We present the first high-resolution rotational spectrum of an artificial molecular rotary motor. By combining chirped-pulse Fourier transform microwave spectroscopy and supersonic expansions, we captured the vibronic ground-state conformation of a second-generation motor based on chiral, overcrowded alkenes. The rotational constants were accurately determined by fitting more than 200 rotational transitions in the 2-4 GHz frequency range. Evidence for dissociation products allowed for the unambiguous identification and characterization of the isolated motor components. Experiment and complementary quantum-chemical calculations provide accurate geometrical parameters for the C27 H20 molecular motor, the largest molecule investigated by high-resolution microwave spectroscopy to date. PMID- 28556403 TI - Silver fir and Douglas fir are more tolerant to extreme droughts than Norway spruce in south-western Germany. AB - Improving our understanding of the potential of forest adaptation is an urgent task in the light of predicted climate change. Long-term alternatives for susceptible yet economically important tree species such as Norway spruce (Picea abies) are required, if the frequency and intensity of summer droughts will continue to increase. Although Silver fir (Abies alba) and Douglas fir (Pseudotsuga menziesii) have both been described as drought-tolerant species, our understanding of their growth responses to drought extremes is still limited. Here, we use a dendroecological approach to assess the resistance, resilience, and recovery of these important central Europe to conifer species the exceptional droughts in 1976 and 2003. A total of 270 trees per species were sampled in 18 managed mixed-species stands along an altitudinal gradient (400-1200 m a.s.l.) at the western slopes of the southern and central Black Forest in southwest Germany. While radial growth in all species responded similarly to the 1976 drought, Norway spruce was least resistant and resilient to the 2003 summer drought. Silver fir showed the overall highest resistance to drought, similarly to Douglas fir, which exhibited the widest growth rings. Silver fir trees from lower elevations were more drought prone than trees at higher elevations. Douglas fir and Norway spruce, however, revealed lower drought resilience at higher altitudes. Although the 1976 and 2003 drought extremes were quite different, Douglas fir maintained consistently the highest radial growth. Although our study did not examine population-level responses, it clearly indicates that Silver fir and Douglas fir are generally more resistant and resilient to previous drought extremes and are therefore suitable alternatives to Norway spruce; Silver fir more so at higher altitudes. Cultivating these species instead of Norway spruce will contribute to maintaining a high level of productivity across many Central European mountain forests under future climate change. PMID- 28556404 TI - Viral-mediated oligodendroglial alpha-synuclein expression models multiple system atrophy. AB - BACKGROUND: MSA is a fatal neurodegenerative disorder characterized by a combination of autonomic dysfunction, cerebellar ataxia, and l-dopa unresponsive parkinsonism. The hallmark of MSA is the accumulation of alpha-synuclein, forming cytoplasmic inclusions in oligodendrocytes. Adeno-associated viruses allow efficient targeting of disease-associated genes in selected cellular ensembles and have proven efficient for the neuronal overexpression of alpha-synuclein in the substantia nigra in the context of PD. OBJECTIVES: We aimed to develop viral based models of MSA. METHODS: Chimeric viral vectors expressing either human wild type alpha-synuclein or green fluorescent protein under the control of mouse myelin basic protein were injected in the striatum of rats and monkeys. Rats underwent a longitudinal motor assessment before histopathological analysis at 3 and 6 months. RESULTS: Injection of vectors expressing alpha-synuclein in the striatum resulted in >80% oligodendroglial selectivity in rats and >60% in monkeys. Rats developed progressive motor deficits that were l-dopa unresponsive when assessed at 6 months. Significant loss of dopaminergic neurons occurred at 3 months, further progressing at 6 months, together with a loss of striatal neurons. Prominent alpha-synuclein accumulation, including phosphorylated and proteinase-K-resistant alpha-synuclein, was detected in the striatum and substantia nigra. CONCLUSIONS: Viral-mediated oligodendroglial expression of alpha-synuclein allows replicating some of the key features of MSA. This flexible strategy can be used to investigate, in several species, how alpha-synuclein accumulation in selected oligodendroglial populations contributes to the pathophysiology of MSA and offers a new framework for preclinical validation of therapeutic strategies. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28556405 TI - Tuberculosis in China: A longitudinal predictive model of the general population and recommendations for achieving WHO goals. AB - BACKGROUND AND OBJECTIVE: Tuberculosis (TB) remains a major public health challenge. China accounts for more than 10% of the global TB burden, and effective modelling of TB trends remains limited. METHODS: We used data drawn primarily from two Chinese nation-wide cross-sectional epidemiological surveys combined with data from China's National Disease Reporting Network to construct an eight-state Markov model that simulates TB prevalence. By adjusting the relevant parameters, we evaluated which characteristics have the greatest bearing upon prevalence and efficacy of the response measures. RESULTS: If current trends continue, the prevalence of TB in China will enter an 8-year period of decline from approximately 390 to 200 cases per 100 000 population and stabilize at 163 cases per 100 000 population, which is a figure well above the World Health Organization (WHO) goal of eliminating TB by 2050. We find that the proportion of notified cases in the population, the rate of progression from latent to active and the overall treatment success rate are the chief factors affecting disease progression. CONCLUSION: We suggest a 90-90-90 strategy, wherein the proportion of notified cases in the population reaches 90%, the risk of progression from latent to active is decreased by 90% compared with the current level and the overall treatment success rate is increased to 90%. This strategy could reduce TB prevalence to less than 10 cases per 100 000 population within 5 years and to 1.77 cases per 100 000 population within 50 years. PMID- 28556406 TI - Disease stage and plasma levels of cytokines in Huntington's disease: A 2-year follow-up study. PMID- 28556407 TI - Creating positive practice environments in a primary health care setting. AB - AIM: The aim of this study was to explore and describe the perceptions of nurse managers, nurses, and a physician in the community health centre with the most positive practice environment in a province of South Africa. METHODS: Ten (N = 10) semistructured individual interviews were conducted with personnel of the community health centre with the most positive practice environment. RESULTS: Personnel cited the following as the most important characteristics of a positive practice environment in a primary health care setting: support, leadership and governance, collegial nurse-physician relationships, and quality of care. CONCLUSION: In a primary health care setting, it is important to train, appoint, and support managers who in turn will be able to train and support their personnel. Furthermore, reciprocal community involvement must be encouraged between personnel of the community health centre and stakeholders in the community to improve the health status of the community. Finally, group cohesions between all health care workers and managers at different organisational levels should be encouraged, as this enhances teamwork and a culture of teaching learning and improves the competence of all staff. PMID- 28556408 TI - Reprogrammable Chemical 3D Shaping for Origami, Kirigami, and Reconfigurable Molding. AB - Origami- and kirigami-based design principles have recently received strong interest from the scientific and engineering communities because they offer fresh approaches to engineering of structural hierarchy and adaptive functions in materials, which could lead to many promising applications. Herein, we present a reprogrammable 3D chemical shaping strategy for creating a wide variety of stable complex origami and kirigami structures autonomously. This strategy relies on a reverse patterning method that encodes prescribed 3D geometric information as a spatial pattern of the unlocked phase (dispersed phase) in the locked phase (matrix phase) in a pre-stretched Nafion sheet. Building upon the unique chemical reprogramming capability of the Nafion shape memory polymer, we have developed a reconfigurable molding technology that can significantly reduce time, costs, and waste by shaping various 3D materials with high fidelity. PMID- 28556409 TI - Prevention of infectious complications after prostate biopsy procedure. AB - Although febrile complications are rarely encountered after a prostate biopsy procedure, in recent years the number of cases of fatal infection after that have increased along with increases in resistant bacteria. The available biopsy approaches are transrectal and transperineal, with the transrectal approach primarily used. As the invasion path of the puncture needle differs between these approaches, pretreatment and the method of administration of preventive antimicrobial drugs should be separately considered for infection prevention. Recently, the Japanese guidelines for perioperative infection prevention in the field of urology were revised after receiving approval from the Japanese Urological Association. With use of the transrectal approach, attempts have been made to selectively administer prophylactic antibiotics by confirming the presence or absence of resistant bacteria in rectal swab culture results before carrying out a prostate biopsy procedure because of potential problems associated with resistant bacteria in rectal flora. For preventive antibiotics, a single dose of oral quinolone is recommended for patients with low risk, whereas daily administrations of piperacillin/tazobactam are recommended for those considered to be high risk. In contrast, for the transperineal procedure, a single dose of oral quinolone is recommended as a preventive antibiotic. With both approaches, it is important to empirically administer broad-spectrum antimicrobials when occurrence of a febrile infection after a prostate biopsy procedure is confirmed. PMID- 28556410 TI - Seasonal variability of the parameters of the Ball-Berry model of stomatal conductance in maize (Zea mays L.) and sunflower (Helianthus annuus L.) under well-watered and water-stressed conditions. AB - The Ball-Berry (BB) model of stomatal conductance (gs ) is frequently coupled with a model of assimilation to estimate water and carbon exchanges in plant canopies. The empirical slope (m) and 'residual' gs (g0 ) parameters of the BB model influence transpiration estimates, but the time-intensive nature of measurement limits species-specific data on seasonal and stress responses. We measured m and g0 seasonally and under different water availability for maize and sunflower. The statistical method used to estimate parameters impacted values nominally when inter-plant variability was low, but had substantial impact with larger inter-plant variability. Values for maize (m = 4.53 +/- 0.65; g0 = 0.017 +/- 0.016 mol m-2 s-1 ) were 40% higher than other published values. In maize, we found no seasonal changes in m or g0 , supporting the use of constant seasonal values, but water stress reduced both parameters. In sunflower, inter-plant variability of m and g0 was large (m = 8.84 +/- 3.77; g0 = 0.354 +/- 0.226 mol m 2 s-1 ), presenting a challenge to clear interpretation of seasonal and water stress responses - m values were stable seasonally, even as g0 values trended downward, and m values trended downward with water stress while g0 values declined substantially. PMID- 28556411 TI - The genetic landscape of familial congenital hydrocephalus. AB - OBJECTIVE: Congenital hydrocephalus is an important birth defect, the genetics of which remains incompletely understood. To date, only 4 genes are known to cause Mendelian diseases in which congenital hydrocephalus is the main or sole clinical feature, 2 X-linked (L1CAM and AP1S2) and 2 autosomal recessive (CCDC88C and MPDZ). In this study, we aimed to determine the genetic etiology of familial congenital hydrocephalus with the assumption that these cases represent Mendelian forms of the disease. METHODS: Exome sequencing combined, where applicable, with positional mapping. RESULTS: We identified a likely causal mutation in the majority of these families (21 of 27, 78%), spanning 16 genes, none of which is X linked. Ciliopathies and dystroglycanopathies were the most common etiologies of congenital hydrocephalus in our cohort (19% and 26%, respectively). In 1 family with 4 affected members, we identified a homozygous truncating variant in EML1, which we propose as a novel cause of congenital hydrocephalus in addition to its suggested role in cortical malformation. Similarly, we show that recessive mutations in WDR81, previously linked to cerebellar ataxia, mental retardation, and disequilibrium syndrome 2, cause severe congenital hydrocephalus. Furthermore, we confirm the previously reported candidacy of MPDZ by presenting a phenotypic spectrum of congenital hydrocephalus associated with 5 recessive alleles. INTERPRETATION: Our study highlights the importance of recessive mutations in familial congenital hydrocephalus and expands the locus heterogeneity of this condition. Ann Neurol 2017;81:890-897. PMID- 28556412 TI - Patient-reported outcomes in Huntington's disease: Quality of life in neurological disorders (Neuro-QoL) and Huntington's disease health-related quality of life (HDQLIFE) physical function measures. AB - BACKGROUND: There is a need for patient-reported outcome measures that capture the impact that motor impairments have on health-related quality of life in individuals with Huntington's disease. OBJECTIVES: The objectives of this study were to establish the reliability and validity of new physical functioning patient-reported outcome measures in Huntington's disease. METHODS: A total of 510 individuals with Huntington's disease completed 2 Quality of Life in Neurological Disorders (Lower Extremity Function and Upper Extremity Function) and 3 Huntington's Disease Health-Related Quality of Life (Chorea, Speech Difficulties, and Swallowing Difficulties) measures. Clinician-rated and generic self-report measures were also administered. RESULTS: Reliabilities for the new patient reported physical functioning measures were excellent (all Cronbach's alpha > .92). Convergent, discriminant validity and known group validity was supported. CONCLUSIONS: The results provide psychometric support for new patient reported physical functioning measures and the fact that these measures can be used as clinically meaningful endpoints in Huntington's disease research and clinical practice. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28556413 TI - Concomitant screening for liver fibrosis and steatosis in French type 2 diabetic patients using Fibroscan. AB - BACKGROUND: Type 2 diabetes is a risk factor for steatohepatitis and fibrosis. Non-invasive liver stiffness (LS) and controlled attenuation parameter (CAP) measurements by Fibroscan allow assessing liver fat and fibrosis. AIM: To determine the prevalence of steatosis and significant fibrosis in a community based diabetic population. METHODS: LS and CAP were measured in 705 patients using the standard "M probe." A second "XL probe" was used, without CAP measurement, in case of failure with the "M probe." RESULTS: LS and CAP measurements were obtained in 437 patients (the M group), LS measurements (LSM) with the XL probe being available in additional 232 patients. After the combined use of both probes, LSM failure and unreliable result were 1.6% and 5.6% respectively. Overall, 12.7% (n=85), 7.3% and 2.1% exhibited significant or advanced fibrosis or cirrhosis (LSM>=8 kPa, >=9.6 kPa, >=13 kPa respectively), half of the patients with LSM>=8 kPa displayed normal liver tests. Significant and severe steatosis were measured in 75% and 24% of the M group patients. By multivariate analysis, factors associated with severe fibrosis were age, overweight, high GGT. Forty-seven patients with LSM>=8 kPa underwent liver biopsy; 93% had steatosis and 51% severe fibrosis. A significant correlation was found between LSM values and fibrosis score with an accuracy rate of 83%, 68% and 83% for LSM>=8 kPa, >=9.6 kPa and >=13 kPa respectively. CONCLUSIONS: The prevalence of significant steatosis is very high and significant fibrosis affect 12.7% of the patients. Fibroscan is an effective procedure to screen for fibrosis and steatosis in diabetic patients. PMID- 28556416 TI - New developments in chyluria after global programs to eliminate lymphatic filariasis. AB - Chyluria, commonly seen in south Asian countries, is mainly a manifestation of lymphatic filariasis as a result of infestation with Wuchereria bancrofti, although many other causes can contribute. Many patients can be effectively treated with dietary modifications and drug therapy. The most widely used drug is diethyl carbamazine. The recurrences are common after such treatment. Such patients would benefit from sclerotherapy to obliterate the lympatico-renal fistulae located mainly in the renal pelvicalyceal system. The commonly used sclerosing agent is a combination of 5% povidone-iodine and 50% dextrose instilled through a ureteric catheter. A small percentage of patients who recur after sclerotherapy and those with systemic complications, such as hypoproteinemia and edema, might require surgery in the form of renal hilar lymphatic disconnection. Although it is a major operation, the success rates are >90%. Laparoscopic and robotic techniques have minimized the morbidity related to such surgery. With the advent of the global program for eradication of filariasis initiated by the World Health Organization, the incidence of the disease is decreasing. Mass chemotherapy with diethyl carbamazine is the mainstay of this global program. Many years after eliminating filariasis, chyluria continue to occur in such populations, though in dwindling numbers. Future research should aim at finding more efficacious sclerosing agents with minimal recurrences. PMID- 28556415 TI - Symptoms associated with Lewy body disease in mild cognitive impairment. AB - OBJECTIVE: Dementia with Lewy bodies (DLB) is associated with a range of cognitive and non-cognitive symptoms. We aimed to identify if some of these symptoms might aid early diagnosis of Lewy body disease in cases of mild cognitive impairment (MCI). METHODS: Lewy body MCI (MCI-LB; n = 36), Alzheimer's disease MCI (MCI-AD; n = 21), DLB (n = 36), AD (n = 21) and control (n = 20) participants were recruited. An interview-based questionnaire about the presence of symptoms thought to be associated with Lewy body disease was completed by participants with, where possible, their carer/relative. The prevalence of each symptom was compared between MCI-LB and MCI-AD and between established DLB and AD, and a symptom scale based on these findings was devised. RESULTS: Fluctuating concentration/attention; episodes of confusion; muscle rigidity; changes in hand writing, gait and posture; falls; drooling; weak voice; symptoms of REM sleep behaviour disorder (RBD) and misjudging objects were more common in MCI-LB compared with MCI-AD, and also in DLB compared with AD. Hyposmia, tremor, slowness and autonomic symptoms were not specific to Lewy body disease. REM sleep behaviour disorder and hyposmia were reported to develop several years prior to the onset of cognitive symptoms in Lewy body disease. A 10-point symptom scale differentiated between MCI-LB and MCI-AD with a sensitivity of 83% and a specificity of 100%. CONCLUSIONS: Drooling, misjudging objects and symptoms related to parkinsonism, fluctuating cognition and RBD may be the most characteristic symptoms of MCI-LB. Slowness, tremor, autonomic symptoms and hyposmia are all common in MCI-LB but are not specific to the disease. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28556414 TI - Dynamic compression of human and ovine meniscal tissue compared with a potential thermoplastic elastomer hydrogel replacement. AB - Understanding how human meniscal tissue responds to loading regimes mimetic of daily life as well as how it compares to larger animal models is critical in the development of a functionally accurate synthetic surrogate. Seven human and eight ovine cadaveric meniscal specimens were regionally sectioned into cylinders 5 mm in diameter and 3 mm thick along with 10 polystyrene-b-polyethylene oxide block copolymer-based thermoplastic elastomer (TPE) hydrogels. Samples were compressed to 12% strain at 1 Hz for 5000 cycles, unloaded for 24 h, and then retested. No differences were found within each group between test one and test two. Human and ovine tissue exhibited no regional dependency (p < 0.05). Human samples relaxed quicker than ovine tissue or the TPE hydrogel with modulus values at cycle 50 not significantly different from cycle 5000. Ovine menisci were found to be similar to human menisci in relaxation profile but had significantly higher modulus values (3.44 MPa instantaneous and 0.61 MPa after 5000 cycles compared with 1.97 and 0.11 MPa found for human tissue) and significantly different power law fit coefficients. The TPE hydrogel had an initial modulus of 0.58 MPa and experienced less than a 20% total relaxation over the 5000. Significant differences in the magnitude of compressive modulus between human and ovine menisci were observed, however the relaxation profiles were similar. Although statistically different than the native tissues, modulus values of the TPE hydrogel material were similar to those of the human and ovine menisci, making it a material worth further investigation for use as a synthetic replacement. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2722-2728, 2017. PMID- 28556417 TI - Dengue data and surveillance in Tanzania: a systematic literature review. AB - OBJECTIVE: Although there is evidence that dengue virus is circulating in Tanzania, the country lacks a dengue surveillance system. Consequently, the true estimate of dengue seroprevalence, as well as the incidence in the population, the frequency and magnitude of outbreaks is unknown. This study therefore sought to systematically review available dengue data from Tanzania. METHODS: The systematic review was conducted and reported using the PRISMA tool. Five databases (PubMed, Embase, Web of Science, WHOLIS and Google Scholar) were searched for articles using various keywords on the illness, data and geographical location. Identified articles were assessed for inclusion based on predefined eligibility criteria. Data were extracted from included articles, analysed and reported. RESULTS: Based on the 10 seroprevalence studies in defined populations with estimates of acute confirmed infections that were included in the review, the estimated seroprevalence of past dengue infection in Tanzania ranged from 50.6% in a health facility-based study to 11% in a population-based study. Acute confirmed infections of dengue were estimated to be as high as 38.2% of suspected cases. Only one study reported on an outbreak. CONCLUSIONS: It is evident that dengue needs to become part of regular disease surveillance in Tanzania. Control measures need to be instituted with a focus on building human resource capacity and integrating dengue control measures in ongoing health programmes, for both preventive and curative interventions. Systematic reviews are valuable in assessing health issues when surveillance data are not available. PMID- 28556418 TI - Phase I randomized study of KHK4083, an anti-OX40 monoclonal antibody, in patients with mild to moderate plaque psoriasis. AB - BACKGROUND: OX40 (CD134) is expressed in lesional but not healthy skin of patients with psoriasis. KHK4083 is a fully human monoclonal antibody against OX40. OBJECTIVE: The primary aim of this first-in-human phase 1 study was to determine the safety and tolerability of ascending single doses of KHK4083 in patients with mild to moderate plaque psoriasis. Secondary aims were to determine the pharmacokinetics and immunogenicity of KHK4083, and an exploratory objective was to assess clinical activity. METHODS: In phase 1a, single doses of KHK4083 0.003 and 0.001 mg/kg IV were administered open label in two cohorts (each n = 6). Phase 1b had a multicentre, randomized, double-blind, placebo-controlled, ascending single-dose design in seven cohorts. Randomization was performed 3 : 1 to KHK4083 (n = 6) or placebo (n = 2) within each cohort. Ascending doses of KHK4083 were 0.03, 0.1, 0.3, 1.0, 3.0 and 10 mg/kg IV, and 1.0 mg/kg SC. RESULTS: There were no severe or serious adverse events (AEs), or discontinuations because of AEs. The most frequent treatment-related AEs in the 55 patients who received KHK4083 were mild or moderate chills (9.1%), and infusion/injection site reactions (7.3%). No clinically meaningful or dose-related changes from baseline in laboratory values, vital signs, ECG recordings or physical examinations were observed. Some KHK4083 recipients (10/54) developed anti-KHK4083 antibodies following treatment. Mean elimination half-life (t1/2 ) increased with dose, maximum serum concentration increased in a dose-proportional manner, and area under the serum concentration-time curve increased in a more than dose proportional manner with increasing IV dose. Absolute bioavailability following SC administration was 73%. There was some indication of improvement in Psoriasis Area Severity Index (PASI) and sPGA scores at the highest IV doses (1.0 and 10 mg/kg) and the SC dose (1.0 mg/kg). The largest PASI 50 response and improvement in sPGA score >=2 occurred with KHK4083 1.0 mg/kg SC. CONCLUSION: KHK4083 administration as a single dose up to 10 mg/kg IV or 1.0 mg/kg SC was generally safe and well tolerated in patients with mild to moderate plaque psoriasis with no dose-limiting AEs. PMID- 28556420 TI - Impact of postoperative positioning on the outcome of pars plana vitrectomy with gas tamponade for primary rhegmatogenous retinal detachment: comparison between supine and prone positioning. AB - PURPOSE: To compare the postoperative anatomic success rates and the frequency of complications between prone or supine postoperative positioning after transconjunctival sutureless vitrectomy (TSV) for rhegmatogenous retinal detachment (RRD). METHODS: All patients underwent primary 27-gauge TSV for the treatment of primary RRD. Patients were divided into two groups as follows: group A was patients instructed to keep strict postoperative prone positioning for a minimum of 8 days. Group B was patients instructed to keep the prone positioning on the day of the surgery followed by supine positioning for minimum of 7 days from the day after surgery. RESULT: Sixty-two eyes were enrolled (group A: 32, group B: 30). There was no significant difference in baseline data between two groups. The initial and final anatomical success rates were 93.8% and 100% in group A and 93.3% and 100% in group B, respectively (p = 1, p = 1, respectively). Posterior synechia of the iris occurred in one eye in group A and in two eyes in group B (p = 0.61). Macular pucker and retinal fold did not occur in either group. Preoperative intraocular pressure (IOP; mmHg) was 14.5 +/- 2.9 in group A and 14.5 +/- 2.6 in group B (p = 0.92). Intraocular pressure (IOP) was not statistically different between the groups during the follow-up period (p = 0.36, p = 0.07, respectively). CONCLUSION: Supine positioning may be an option as a postoperative positioning after TSV and gas tamponade for the treatment of RRD. PMID- 28556419 TI - Association of diabetes mellitus and biochemical knee cartilage composition assessed by T2 relaxation time measurements: Data from the osteoarthritis initiative. AB - PURPOSE: To investigate the association of the presence and severity of diabetes mellitus (DM) with articular cartilage composition, using magnetic resonance imaging (MRI)-based T2 relaxation time measurements, and structural knee abnormalities. MATERIALS AND METHODS: In the Osteoarthritis Initiative 208, participants with DM (age 63.0 +/- 8.9 years; 111 females) and risk factors for osteoarthritis (OA) or mild radiographic tibiofemoral OA (Kellgren-Lawrence [KL] grade <=2) were identified and group-matched with 208 controls without DM (age 63.3 +/- 9.1 years; 111 females). Subjects with diabetes-related renal or ophthalmological complications or insulin treatment at baseline (n = 50) were defined as severe DM. 3T MR images of the right knee were assessed for articular cartilage T2 , including texture and laminar analyses derived from the patella, medial, and lateral femur and tibia and for structural abnormalities using the modified whole-organ magnetic resonance imaging score (WORMS). Clustered linear regression analyses were used to assess associations of DM with MRI findings. RESULTS: DM subjects had significantly higher cartilage T2 in the patella (mean difference 0.92 msec [95% confidence interval (CI) 0.79, 1.06]; P = 0.001) and medial femur (mean difference 0.36 msec [95% CI 0.27, 0.81]; P = 0.006) compared to controls. Averaged over all compartments, DM subjects showed significantly higher texture parameters (variance, P = 0.001; contrast, P = 0.002; entropy, P < 0.001). Subjects with severe DM additionally showed higher T2 in the medial tibial deep and superficial layers (P = 0.011 and P = 0.041) compared to controls. No significant differences in cartilage, meniscus, and overall WORMS were found between the groups (P > 0.05). CONCLUSION: In comparison to nondiabetic controls, cartilage in DM subjects showed higher and more heterogeneous cartilage T2 values, indicating increased articular cartilage degeneration. This affected even more compartments in subjects with severe DM. LEVEL OF EVIDENCE: 2 Technical Efficacy: 5 J. Magn. Reson. Imaging 2018;47:380 390. PMID- 28556421 TI - Gastrointestinal disorders after immunosuppression: an experimental model to evaluate the influence of monotherapy on motility parameters. AB - NEW FINDINGS: What is the central question of this study? The aim was to propose an animal model for investigating the effects of immunosuppressive monotherapy on gastrointestinal motility using a non-invasive biomagnetic technique. What is main finding and its importance? In our experimental study, immunosuppressive drugs currently in use accelerated gastric emptying whilst increasing the frequency and amplitude of gastric contractions after treatment, except for Mycophenolate and azathioprine. Alternating current biosusceptometry is a useful tool to evaluate side-effects of drugs on the gastrointestinal tract, which will help in understanding the symptoms and improving clinical management of patients. The aim was to propose an animal model for investigating the effects of immunosuppressive monotherapy on gastrointestinal motility using a non-invasive biomagnetic technique. Male Wistar rats were randomly distributed into the following treatment groups: ciclosporin, tacrolimus, prednisone, sirolimus, mycophenolate mofetil, everolimus, azathioprine and control. Each animal was treated for 14 days by gavage with dosages ranging from 1 to 20 mg kg-1 day-1 considering the area-to-volume ratio and hepatic metabolism. Gastrointestinal transit and gastric contractility measurements were evaluated by alternating current biosusceptometry before and after treatment. Gastric emptying was faster in animals treated with tacrolimus, prednisone, sirolimus and everolimus compared with control animals (126.7 +/- 12.7 min). There was a significant increase in the frequency of contractions after ciclosporin, tacrolimus, azathioprine and sirolimus treatment compared with control animals (4.6 +/- 0.3 cycles min-1 ). Increases in the amplitude of contraction were observed after treatment with tacrolimus, sirolimus and everolimus compared with control rats (34.9 +/- 6.0 dB). The results showed that our animal model was suitable for demonstrating that most immunosuppressive drugs currently in use impaired at least one gastrointestinal motility parameter. As a non-invasive technique, alternating current biosusceptometry is a potentially useful tool for evaluation of side effects of drugs in gastrointestinal tract, helping us to understand the symptoms to improve clinical management of patients. PMID- 28556422 TI - The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation. AB - The availability of direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) infection has resulted in a profound shift in the approach to the management of this infection. These changes have affected the practice of solid organ transplantation by altering the framework by which patients with end-stage organ disease are managed and receive organ transplants. The high level of safety and efficacy of these medications in patients with chronic HCV infection provides the opportunity to explore their use in the setting of transplanting organs from HCV-viremic patients into non-HCV-viremic recipients. Because these organs are frequently discarded and typically come from younger donors, this approach has the potential to save lives on the solid organ transplant waitlist. Therefore, an urgent need exists for prospective research protocols that study the risk versus benefit of using organs for hepatitis C-infected donors. In response to this rapidly changing practice and the need for scientific study and consensus, the American Society of Transplantation convened a meeting of experts to review current data and develop the framework for the study of using HCV viremic organs in solid organ transplantation. PMID- 28556423 TI - A rare complication of topical atropine for treatment of eccrine hidrocystoma: Pharmacological fixed dilated pupils. AB - Multiple eccrine hidrocystoma (EH) has been treated with topical atropine with variable results. However, in rare cases, anticholinergic side effects have been seen after the use of the topical form of this drug. We presented a 50-year-old woman who developed recent onset of visual disturbance and photophobia from 2 weeks prior. The diagnosis of topical atropine-induced bilateral mydriasis was made. We reported a recognized but often overlooked case of bilateral mydriasis caused by application of topical 1% atropine for treatment of multiple EH. PMID- 28556424 TI - Growth of organic films on indoor surfaces. AB - We present a model for the growth of organic films on impermeable indoor surfaces. The model couples transport through a gas-side boundary layer adjacent to the surface with equilibrium partitioning of semivolatile organic compounds (SVOCs) between the gas phase and the surface film. Model predictions indicate that film growth would primarily be influenced by the gas-phase concentration of SVOCs with octanol-air partitioning (Koa ) values in the approximate range 10<=log Koa <=13. Within the relevant range, SVOCs with lower values will equilibrate with the surface film more rapidly. Over time, the film becomes relatively enriched in species with higher log Koa values, while the proportion of gas-phase SVOCs not in equilibrium with the film decreases. Given stable airborne SVOC concentrations, films grow at faster rates initially and then subsequently diminish to an almost steady growth rate. Once an SVOC is equilibrated with the film, its mass per unit film volume remains constant, while its mass per unit area increases in proportion to overall film thickness. The predictions of the conceptual model and its mathematical embodiment are generally consistent with results reported in the peer-reviewed literature. PMID- 28556425 TI - Fibromyalgia: A "Chronic Pain Condition" or a True "Chronic Pain Disease"? PMID- 28556426 TI - Retrospective study on the incidence and outcome of proven and probable invasive fungal infections in high-risk pediatric onco-hematological patients. AB - BACKGROUND: Invasive fungal infection (IFI) is a cause of morbidity, mortality and increased health costs in children undergoing chemotherapy or hematopoietic stem cell transplant (HSCT). METHODS: Multicenter, retrospective study to assess the incidence, outcome of proven and probable IFI (PP-IFI) in children treated for acute leukemia, non-Hodgkin lymphoma or who underwent HSCT from 2006 to 2012. RESULTS: Over the 7-year period, 127 PP-IFI were diagnosed in 123 patients, median age of 9.7 years. The 1-year cumulative incidence was 2.5% (CI 1.8-3.7) after frontline chemotherapy, 9.4% (CI 5.8-15.0) after relapse, and 5.3% (CI 3.9 7.1) after HSCT. Severe neutropenia was present in 98 (77%) patients. Culture proven agents were Candida spp., mostly non-albicans, 28, mold 23, whereas three proven IFI were identified by histopathology. Favorable response to treatment within 3 months from diagnosis was observed in 77 (89%). The overall ninety-day probability of survival was 68% (CI 59-76). CONCLUSIONS: About two-thirds of pediatric patients with PP-IFI survived, regardless of whether the infection occurred after frontline chemotherapy, reinduction chemotherapy for disease relapse, or after HSCT. Further prospective studies are needed to define the impact of antifungal prophylaxis and early combination therapy on short-term overall survival. PMID- 28556427 TI - Everolimus-Based Immunosuppression in Liver Transplant Recipients. PMID- 28556429 TI - Acute nutritional axonal neuropathy. AB - INTRODUCTION: This study describes clinical, laboratory, and electrodiagnostic features of a severe acute axonal polyneuropathy common to patients with acute nutritional deficiency in the setting of alcoholism, bariatric surgery (BS), or anorexia. METHODS: Retrospective analysis of clinical, electrodiagnostic, and laboratory data of patients with acute axonal neuropathy. RESULTS: Thirteen patients were identified with a severe, painful, sensory or sensorimotor axonal polyneuropathy that developed over 2-12 weeks with sensory ataxia, areflexia, variable muscle weakness, poor nutritional status, and weight loss, often with prolonged vomiting and normal cerebrospinal fluid protein. Vitamin B6 was low in half and thiamine was low in all patients when obtained before supplementation. Patients improved with weight gain and vitamin supplementation, with motor greater than sensory recovery. DISCUSSION: We suggest that acute or subacute axonal neuropathy in patients with weight loss or vomiting associated with alcohol abuse, BS, or dietary deficiency is one syndrome, caused by micronutrient deficiencies. Muscle Nerve 57: 33-39, 2018. PMID- 28556430 TI - Sol-Gel-Derived Biohybrid Materials Incorporating Long-Chain DNA Aptamers. AB - Sol-gel-derived bio/inorganic hybrid materials have been examined for diverse applications, including biosensing, affinity chromatography and drug discovery. However, such materials have mostly been restricted to the interaction between entrapped biorecognition elements and small molecules, owing to the requirement for nanometer-scale mesopores in the matrix to retain entrapped biorecognition elements. Herein, we report on a new class of macroporous bio/inorganic hybrids, engineered through a high-throughput materials screening approach, that entrap micron-sized concatemeric DNA aptamers. We demonstrate that the entrapment of these long-chain DNA aptamers allows their retention within the macropores of the silica material, so that aptamers can interact with high molecular weight targets such as proteins. Our approach overcomes the major limitation of previous sol-gel derived biohybrid materials by enabling molecular recognition for targets beyond small molecules. PMID- 28556428 TI - Identification of tissue-specific transcriptional markers of caloric restriction in the mouse and their use to evaluate caloric restriction mimetics. AB - Caloric restriction (CR) without malnutrition has been shown to retard several aspects of the aging process and to extend lifespan in different species. There is strong interest in the identification of CR mimetics (CRMs), compounds that mimic the beneficial effects of CR on lifespan and healthspan without restriction of energy intake. Identification of CRMs in mammals is currently inefficient due to the lack of screening tools. We have performed whole-genome transcriptional profiling of CR in seven mouse strains (C3H/HeJ, CBA/J, DBA/2J, B6C3F1/J, 129S1/SvImJ, C57BL/6J, and BALB/cJ) in white adipose tissue (WAT), gastrocnemius muscle, heart, and brain neocortex. This analysis has identified tissue-specific panels of genes that change in expression in multiple mouse strains with CR. We validated a subset of genes with qPCR and used these to evaluate the potential CRMs bezafibrate, pioglitazone, metformin, resveratrol, quercetin, 2,4 dinitrophenol, and L-carnitine when fed to C57BL/6J 2-month-old mice for 3 months. Compounds were also evaluated for their ability to modulate previously characterized biomarkers of CR, including mitochondrial enzymes citrate synthase and SIRT3, plasma inflammatory cytokines TNF-alpha and IFN-gamma, glycated hemoglobin (HbA1c) levels and adipocyte size. Pioglitazone, a PPAR-gamma agonist, and L-carnitine, an amino acid involved in lipid metabolism, displayed the strongest effects on both the novel transcriptional markers of CR and the additional CR biomarkers tested. Our findings provide panels of tissue-specific transcriptional markers of CR that can be used to identify novel CRMs, and also represent the first comparative molecular analysis of several potential CRMs in multiple tissues in mammals. PMID- 28556431 TI - White matter microstructure in athletes with a history of concussion: Comparing diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). AB - Sport concussion is associated with disturbances in brain function in the absence of gross anatomical lesions, and may have long-term health consequences. Diffusion-weighted magnetic resonance imaging (MRI) methods provide a powerful tool for investigating alterations in white matter microstructure reflecting the long-term effects of concussion. In a previous study, diffusion tensor imaging (DTI) showed that athletes with a history of concussion had elevated fractional anisotropy (FA) and reduced mean diffusivity (MD) parameters. To better understand these effects, this study compared DTI results to neurite orientation dispersion and density imaging (NODDI), which was used to estimate the intracellular volume fraction (VIC ) and orientation dispersion index (ODI). Sixty-eight (68) varsity athletes were recruited, including 37 without a history of concussion and 31 with concussion >6 months prior to imaging. Univariate analyses showed elevated FA and decreased MD for concussed athletes, along with increased VIC and reduced ODI, indicating greater neurite density and coherence of neurite orientation within white matter. Multivariate analyses also showed that for athletes with a history of concussion, white matter regions with increased FA had increased VIC and decreased ODI, with greater effects among athletes who were imaged a longer time since their last concussion. These findings enhance our understanding of the relationship between the biophysics of water diffusion and concussion neurobiology for young, healthy adults. Hum Brain Mapp 38:4201-4211, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28556432 TI - Randomized controlled clinical trial comparing one-piece and two-piece dental implants supporting fixed and removable dental prostheses: 4- to 6-year observations. AB - OBJECTIVES: To test whether or not a one- (S1) and a two-piece (S2) dental implant systems render the same biological, technical, and esthetic outcomes regarding implants and implant-supported reconstructions over an observation period of 4 to 6 years. MATERIALS AND METHODS: Sixty patients were randomly assigned to receive S1 or S2 implants. The implants were restored with either fixed or removable prostheses. The insertion of the final reconstruction was chosen as baseline. One-year and 4- to 6-year (FU-5) measurements included biological (e.g. marginal bone level, probing pocket depth, peri-implant mucositis, and peri-implantitis), technical (e.g. fracture or loosening of prosthetic screws, fracture or loosening of abutments, fracture of framework, and/or veneering ceramic (minor, major), loss of retention for cemented restorations), and esthetic parameters (visibility of the crown margin, shimmering of the implant through the mucosa, the level of the facial margo mucosae compared to the contralateral tooth or implant site and the modified papilla index) for implants and reconstructions. Survival and success rates of implants and reconstructions were calculated. Because of the asymmetric data distributions, nonparametric statistical methods were applied. RESULTS: The implant-based analysis revealed a cumulative implant survival rate of 97.9% (S1: 96.6%; S2: 98.9%) at FU-5. The median marginal bone level for group S1 changed from 0.51 mm at baseline to 0.49 mm at FU-5 and for group S2 from 1.02 mm to 1.35 mm (P < 0.001). Patient-level analyses demonstrated a frequency of peri-implant mucositis of 7.7% (S1) and 10.0% (S2) and for peri-implantitis of 7.7% (S1) and 13.3% (S2) at FU-5. The patient-based cumulative implant survival rate was 94.6% (S1: 92.3%; S2: 96.7%). The overall patient-based biological complication rate amounted to 15.4% (S1) and to 23.3% (S2) (P = 0.517), whereas the overall technical complication rates were 30.8% (S1) and 13.3% (S2) (P = 0.349). The prosthetic survival rates were 93.1% for S1 and 100% for S2 (P > 0.05). CONCLUSIONS: Both implant systems reveal high survival rates on the implant and prosthetic level. Apart from marginal bone-level changes, biological and technical outcomes did not reveal significant differences between the two implant systems. PMID- 28556433 TI - It Is Bad Policy and Contrary to Federal Law to Prioritize Local Allocation of Livers to Address Geographically Based Social Inequities. PMID- 28556434 TI - Integration of reflectance confocal microscopy into clinical practice for the management of lentigo maligna. PMID- 28556435 TI - Self-Assembly of Di-N-Heterocyclic Carbene-Gold-Adorned Corannulenes on C60. AB - The deprotonation of a corannulene-based bisazolium salt allowed the preparation of a corannulene-based NHC di-AuI complex. The prepared di-AuI -complex was tested in the recognition of fullerene-C60 , demonstrating good binding affinity in toluene solution, and producing a host-guest complex with 3:1 stoichiometry, as evidenced by a combination of NMR spectroscopy and ITC titrations. The experimental results are fully supported by DFT calculations. The binding of C60 with the di-AuI complex in toluene solution is enthalpically and entropically favoured. Remarkably, the entropic term is the dominant parameter in the binding process. The good complementarity that exists between the concave shape of the corannulene-di-gold complex and the convex surface of the fullerene, together with the presence of tBu groups and the AuCl fragment are key factors for the measured high affinity between host and guest. The obtained results indicate that fullerene may be acting as a template for the formation of a self-assembled aggregate involving up to three molecules of the di-AuI complex. PMID- 28556438 TI - Anterior compartment descent: A new measure in the assessment of urethral hypermobility in women with urinary incontinence. AB - OBJECTIVES: To introduce a new, simple, non-invasive test to quantify urethral hypermobility. METHODS: We reviewed data of women with urinary incontinence who were examined at the Department for General Gynaecology and Urogynaecology, Clinic for Gynaecology and Perinatology, Maribor, Slovenia, between October 2010 and March 2014. Patients' age, diagnosis, results of the Q-tip test and Pelvic Organ Prolapse Quantification measurements were collected. In addition, a new parameter was defined as anterior compartment descent, a midline distance between the external urethral meatus and maximum descent of the anterior vaginal wall when performed the Valsalva maneuver. Statistical analysis was performed with spss software using the Mann-Whitney test, correlation, regression and receiver operating characteristic curve analysis. The analysis was also carried out separately for patients with anterior compartment prolapse stage 0 or I. RESULTS: A total of 472 women were included, 323 of them with anterior compartment prolapse stage 0 or I. Women with urethral hypermobility had significantly higher anterior compartment descent values than patients without urethral hypermobility (3.7 cm vs 2.6 cm, P < 0.001). A moderate correlation was found between anterior compartment descent and the Q-tip test (Spearman's rho = 0.55, P < 0.001). Age and anterior compartment descent were identified as independent variables for the presence of urethral hypermobility. When the cut-off value is set at 3.5 cm, anterior compartment descent represents a test for urethral hypermobility assessment with sensitivity of 65.2%, specificity of 88.6%, positive predictive value of 97.0% and negative predictive value of 30.7%. Anterior compartment descent values were also significantly higher in patients with anterior compartment prolapse stage 0 or I (3.4 +/- 0.7 cm vs 2.6 +/- 0.7 cm, P < 0.001). CONCLUSIONS: The anterior compartment descent could be a valuable tool for the assessment of urethral hypermobility. Further effort should be directed into the standardization of the technique, determination of the normal range of anterior compartment descent, and its intra- and interobserver reliability. PMID- 28556437 TI - A New Anti-Inflammatory Alkaloid from Roots of Heracleum dissectum. AB - Using various chromatographic methods, a new piperidinone alkaloid, (3S)-3-{4 [(1E)-3-hydroxyprop-1-en-1-yl]-2-methoxyphenoxy}piperidin-2-one (1), together with 10 known compounds, bergapten (2), xanthotoxol (3), isopimpinellin (4), isobergapten (5), heratomol-6-O-beta-d-glucopyranoside (6), scopoletin (7), apterin (8), 3-methoxy-4-beta-d-glucopyranosyloxypropiophenone, (praeroside; 9), tachioside (10) and coniferin (11), were isolated from roots of Heracleum dissectum Ledeb. Their structures were elucidated on the basis of physicochemical properties and the detailed interpretation of various spectroscopic data. All the isolated compounds were screened for anti-inflammatory activity in vitro. As the results, compound 1 and 8 showed significantly inhibitory activity on nitric oxide production in RAW264.7 cells. PMID- 28556436 TI - Effect of recombinant human bone morphogenic protein 9 (rhBMP9) loaded onto bone grafts versus barrier membranes on new bone formation in a rabbit calvarial defect model. AB - Recent research has demonstrated that recombinant human bone morphogenetic protein 9 (rhBMP9) has been considered the most osteoinductive growth factor of the BMP-family. In the present study, rhBMP9 was investigated for its influence in combination with two biomaterials for bone regenerative medicine. Either porcine-derived collagen membrane (CM) or deproteinized bovine bone mineral (DBM) combined with 20 ug of rhBMP9 were implanted in 6 mm rabbit calvarial defects. Bone augmentation was evaluated by microCT and histomorphometry at 8 weeks post surgery. Both CM + rhBMP9 and DBM + rhBMP9 groups significantly promoted mineralized tissue volume (microCT) and area, new bone height and area (histomorphometric measurements) when compared to CM and DBM alone groups or control (empty). All specimens in the CM + rhBMP9 group but not all in the DBM + rhBMP9 group induced a complete horizontal bone defect closure. Multinucleated giant cells (MNGCs) were observed directly in contact with DBM surfaces irrespective of rhBMP9, whereas CM was generally not associated to the presence of MNGCs. When combined with rhBMP9, DBM augmented a larger volume of mineralized tissue (including the mineralized bone graft), whereas CM induced greater volume of native host bone. While DBM in combination with rhBMP9 induced higher mineralized tissue mostly associated with the bone grafting material, CM may have presented preferable results based on a higher horizontal defect closure with a faster regeneration of host new bone. The effect of including collagen within the carrier system of rhBMP9 on bone regeneration justifies further evaluation of this combination procedure in larger animal models. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2655-2661, 2017. PMID- 28556439 TI - Latent developmental trajectories of episodic heavy drinking from adolescence to early adulthood: Predictors of trajectory groups and alcohol problems in early adulthood as outcome. AB - INTRODUCTION AND AIMS: To identify latent developmental episodic heavy drinking (EHD) trajectory groups for Norwegian adolescents, investigate risk factors associated with group membership and to assess differences in alcohol problems between different groups in early adulthood. DESIGN AND METHODS: Data were from 1266 individuals measured at four time points from age 13/14 years to age 26/27 years. Latent class growth analysis was used to identify groups with different EHD development. Multinomial logistic regression was used to investigated if gender, impulsivity, school commitment, parents' socio-economic status, frequency of seeing parents drunk and parental knowledge could predict group membership. Differences in alcohol problem scores at age 26/27 were also assessed. RESULTS: Four trajectory groups were identified: 'stable high', 'early increasers', 'late increasers' and 'stable low'. Membership of the high-risk trajectory groups 'stable high' and 'early increasers' was predicted by high impulsivity, low school commitment, high frequency of seeing parents drunk and low parental knowledge. The risk of alcohol problems at age 26/27 was greater for the 'stable high' group, the 'early increasers' and the 'late increasers' compared with the 'stable low' group. The 'stable high' and 'early increasers' had similar risk of alcohol problems. DISCUSSION AND CONCLUSIONS: Stable high and early increasing EHD in adolescence was associated with more alcohol problems in early adulthood. Such trajectories were predicted by high impulsivity, low school commitment, high frequency of seeing parents drunk and low parental knowledge. [Brunborg GS, Norstrom T, Storvoll EE. Latent developmental trajectories of episodic heavy drinking from adolescence to early adulthood: Predictors of trajectory groups and alcohol problems in early adulthood as outcome. PMID- 28556440 TI - Relationship between maternal depression and bonding failure: A prospective cohort study of pregnant women. AB - AIM: Although the association between maternal depression and bonding failure during pregnancy and after delivery has been investigated, the causal relationships remain unclear. METHODS: A total of 751 women (mean [SD] age, 32.1 [4.4] years) completed the Mother-Infant Bonding Questionnaire and the Edinburgh Postnatal Depression Scale during early pregnancy before week 25 (T1), during late pregnancy around week 36 (T2), and at 5 days after delivery (T3). We created a structural regression model to clarify the relationships between depressive mood and bonding failure during pregnancy and at 5 days after delivery. The model was tested with structural equation modeling. RESULTS: Our non-recursive model fit the data well, and we found that: (i) during T2, bonding failure predicted depressive mood (P < 0.01, r = 0.23); (ii) at T3, bonding failure predicted depressive mood (P < 0.05, r = 0.31); (iii) during T1, depressive mood was correlated with bonding failure (P < 0.01, r = 0.45); (iv) depressive mood during T1 predicted depressive mood during T2 (P < 0.01, r = 0.58); (v) depressive mood during T2 predicted depressive mood at T3 (P < 0.01, r = 0.45); (vi) bonding failure during T1 predicted bonding failure during T2 (P < 0.01, r = 0.84); and (vii) bonding failure during T2 predicted bonding failure at T3 (P < 0.01, r = 0.44). The determinant coefficients of depressive mood and bonding failure at T3 were 0.41 and 0.28, respectively. CONCLUSION: Our large-scale cohort study indicates that bonding failure predicts depressive mood during pregnancy and 5 days after delivery. These findings suggest that protection and support for pregnant women with depressive mood and bonding failure may prevent both issues during pregnancy and the early stage after delivery. PMID- 28556442 TI - How many have you done, doctor? When is enough enough? PMID- 28556441 TI - Sickle cell disease and implementation science: A partnership to accelerate advances. AB - Sickle cell disease (SCD) results in end organ damage and a shortened lifespan. Both the pathophysiology of the disease and the social determinants of health affect patient outcomes. Randomized controlled trials have been completed among this population and resulted in medical advances; however, the gestation of these advances and the lack of penetrance into clinical practice have limited advancements in clinical improvements for many people with SCD. We discuss the role of implementation science in SCD and highlight the need for this science to shorten the length of time to implement evidence-based care for more people with SCD. PMID- 28556443 TI - SWATH-based quantitative proteomics reveals the mechanism of enhanced Bombyx mori nucleopolyhedrovirus-resistance in silkworm reared on UV-B treated mulberry leaves. AB - Bombyx mori nucleopolyhedrovirus (BmNPV) is one of the most acute infectious diseases in silkworm, which has led to great economic loss in sericulture. Previous study showed that the content of secondary metabolites in mulberry leaves, particularly for moracin N, was increased after UV-B irradiation. In this study, the BmNPV resistance of silkworms reared on UV-B treated and moracin N spread mulberry leaves was improved. To uncover the mechanism of enhanced BmNPV resistance, silkworm midguts from UV-B treated mulberry leaves (BUM) and moracin N (BNM) groups were analyzed by SWATH-based proteomic technique. Of note, the abundance of ribosomal proteins in BUM and BNM groups was significantly changed to maintain the synthesis of total protein levels and cell survival. While, cytochrome c oxidase subunit II, calcium ATPase and programmed cell death 4 involved in apoptotic process were up-regulated in BNM group. Expressions of lipase-1, serine protease precursor, Rab1 protein, and histone genes were increased significantly in BNM group. These results suggest that moracin N might be the main active component in UV-B treated mulberry leaves which could improve the BmNPV-resistance of silkworm through promoting apoptotic cell death, enhancing the organism immunity, and regulating the intercellular environment of cells in silkworm. It also presents an innovative process to reduce the mortality rate of silkworms infected with BmNPV. PMID- 28556444 TI - Parent-adolescent concordance on the Revised Diagnostic Interview for Borderlines (DIB-R) and the Childhood Interview for Borderline Personality Disorder (CI-BPD). AB - While the degree of concordance between parent and adolescent self-report of internalizing and externalizing pathology is well studied, virtually nothing is known about concordance in borderline pathology and the implication of parent adolescent discrepancies for outcomes. The present study aimed to (1) examine discrepancies between parents and adolescents on two interview-based measures of borderline personality disorder (BPD)-the Revised Diagnostic Interview for Borderlines (DIB-R22 ) and the Childhood Interview for Borderline Personality Disorder (CI-BPD23 ); and (2) investigate the implications of discrepancies for clinical outcomes. Diagnostic concordance on the DIB-R and CI-BPD showed rates of 82% and 94% respectively, with lower concordance demonstrated for dimensionally scored variables. Standardized difference scores between adolescent and parent reports on both borderline measures were significantly correlated with few interview-based axis I diagnoses as reported by parents, but not adolescents themselves. Implications regarding the use of each measure for the assessment and diagnosis of borderline personality disorder are discussed. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28556445 TI - Induction of Necroptosis in Cancer Stem Cells using a Nickel(II)-Dithiocarbamate Phenanthroline Complex. AB - The cytotoxic properties of a series of nickel(II)-dithiocarbamate phenanthroline complexes is reported. The complexes 1-6 kill bulk cancer cells and cancer stem cells (CSCs) with micromolar potency. Two of the complexes, 2 and 6, kill twice as many breast cancer stem cell (CSC)-enriched HMLER-shEcad cells as compared to breast CSC-depleted HMLER cells. Complex 2 inhibits mammosphere formation to a similar extent as salinomycin (a CSC-specific toxin). Detailed mechanistic studies suggest that 2 induces CSC death by necroptosis, a programmed form of necrosis. Specifically, 2 triggers MLKL phosphorylation, oligomerization, and translocation to the cell membrane. Additionally, 2 induces necrosome-mediated propidium iodide (PI) uptake and mitochondrial membrane depolarisation, as well as morphological changes consistent with necroptotosis. Strikingly, 2 does not evoke necroptosis by intracellular reactive oxygen species (ROS) production or poly(ADP) ribose polymerase (PARP-1) activation. PMID- 28556446 TI - Multiresidue analysis of glucocorticoids in milk by LC-MS/MS with low-temperature purification and dispersive solid-phase extraction. AB - A multiresidue method for the determination of 12 glucocorticoids (clobetasol propionate, budesonide, triamcinolone, triamcinolone acetonide, fludrocortisone acetate, flumethasone, beclomethasone, prednisone acetate, 6-alpha methylprednisolone, hydrocortisone, cortisone, and prednisone) in bovine milk was developed using liquid chromatography with tandem mass spectrometry. Isoflupredone was used as an internal standard. Milk samples were treated with ethyl acetate to extract glucocorticoids and were frozen at -20 degrees C for 6 h to precipitate fat. The extract was dried under nitrogen, and residues were dissolved in an acetonitrile/water solution. A further clean-up step was used by dispersive solid-phase extraction, with octadecyl silica and primary secondary amine as the absorbents. The recoveries of glucocorticoids spiked at 0.5, 1.0, 10.0 MUg/kg ranged from 75.7 to 117.3%, except for clobetasol propionate and budesonide (16.1-49.5%). The limits of quantification were 0.01-0.5 MUg/kg in milk. This method has been successfully applied in real samples. The results demonstrated that this method is simple, robust, and suitable for identification of glucocorticoid residues in milk. PMID- 28556447 TI - Tobacco smoking and the risk of diverticular disease - a systematic review and meta-analysis of prospective studies. AB - AIM: This systematic review and meta-analysis aimed to clarify whether tobacco smoking is associated with an increased risk of diverticular disease. METHOD: The PubMed and Embase databases were searched for studies of smoking and diverticular disease up to 19 February 2016. Prospective studies that reported adjusted relative risk (RR) estimates and 95% confidence intervals (CIs) of diverticular disease associated with current or previous smoking were included. Summary RRs were estimated using a random effects model. RESULTS: We identified five prospective studies which comprised 6076 cases of incident diverticular disease (diverticulosis and diverticulitis) among 385 291 participants and three studies with 1118 cases of complications related to diverticular disease (abscess or perforation) among 292 965. The summary RR for incident diverticular disease was 1.36 (95% CI 1.15-1.61, I2 = 84%, n = 4) for current smokers, 1.17 (95% CI 1.05 1.31, I2 = 49%, n = 4) for former smokers and 1.29 (95% CI 1.16-1.44, I2 = 62%, n = 5) for ever smokers. The summary RR was 1.11 (95% CI 0.99-1.25, I2 = 82%, n = 4) per 10 cigarettes per day. Although there was some indication of nonlinearity there was a dose-dependent positive association with increasing number of cigarettes smoked per day. There was some evidence that smoking also increases the risk of complications of diverticular disease, but the number of studies was small. CONCLUSION: The current meta-analysis provides evidence that tobacco smoking is associated with an increased incidence of diverticular disease and related complications. PMID- 28556448 TI - Non-typhoidal Salmonella infections in children: Review of literature and recommendations for management. AB - Non-typhoidal Salmonellae are a major cause of infectious diarrhoea worldwide and can cause invasive diseases, including bacteraemia, meningitis and osteomyelitis. Young or immunocompromised children and those with underlying conditions such as sickle cell disease are particularly vulnerable to invasive disease. There has been an increase in the rate of resistant non-typhoidal Salmonella, which is associated with invasive disease and hospitalisation. The intracellular nature of non-typhoidal Salmonella protects against extracellular antibiotics and can facilitate disease relapse, particularly meningitis. Effective antimicrobial agents with good intracellular penetration include azithromycin, fluoroquinolones and third-generation cephalosporins. Antibiotic treatment of non-typhoidal Salmonella gastroenteritis is only indicated if there are risk factors for invasive disease as it can prolong excretion and does not shorten the duration of gastrointestinal symptoms. Optimal choice and length of therapy for gastroenteritis and invasive disease in children is not clear. Here, we provide a review of the literature and treatment recommendations. PMID- 28556450 TI - Uniform Yolk-Shell MoS2 @Carbon Microsphere Anodes for High-Performance Lithium Ion Batteries. AB - As an electrode material for lithium-ion batteries (LIBs), MoS2 has attracted much attention because of its high capacity and low cost. However, the rational design of a novel electrode structure with a high capacity, fast charge/discharge rate, and long cycling lifetime remains a great challenge. Herein, a environmentally friendly etching strategy is reported for the construction of monodisperse, inner void-controlled yolk-shell MoS2 @carbon microspheres. The resulting anode reveals an initial discharge capacity up to 1813 mAh g-1 , a high reversible capacity (1016 mAh g-1 ), excellent cycling stability (200 cycles), and superior rate performance. Such microspheres consist of nanosized MoS2 yolks (~280 nm), porous carbon shells (~25 nm) and well-controlled internal voids in between, opening a new pathway for the optimization of the electrochemical properties of MoS2 -based anodes without sacrificing their capacity. In addition, this etching strategy offers a new method for the development of functional, hollow MoS2 -based composites. PMID- 28556449 TI - Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial. AB - AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib ( 9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity. PMID- 28556451 TI - Skin Cancers in Organ Transplant Recipients. AB - Long-term utilization of immunosuppression in organ transplant recipients (OTRs) leads to decreased immune-mediated tumor surveillance and development of malignant tumors. A delicate balance needs to be maintained in the intensity of immunosuppression to keep the risk of malignancy low without jeopardizing life saving graft function. OTRs are prone to developing skin cancers that exhibit unique epidemiologic, pathophysiologic, and prognostic characteristics. In this review, we discuss the most commonly reported skin cancers in OTRs: squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Kaposi sarcoma, Merkel cell carcinoma, and malignant melanoma (MM). Tumors in this high-risk population are aggressive and may respond poorly to standard therapies; however, new targeted therapies are promising. Checkpoint inhibitor antibodies have been used for treatment of cutaneous SCC, Merkel cell carcinoma, and MM; epidermal growth factor receptor inhibitors have been used for cutaneous SCC; hedgehog pathway inhibitors have been used for BCC; and BRAF and MEK inhibitors are being used increasingly in the management of MM. Guidelines for dermatologic screening are variable and primarily based on expert opinion. Prospective evidence-based trials by multidisciplinary groups are needed to better define surveillance schedules for pre- and posttransplant cutaneous malignancies. PMID- 28556452 TI - Dimensional alterations following vertical ridge augmentation using collagen membrane and three types of bone grafting materials: A retrospective observational study. AB - BACKGROUND: Various biomaterials have been introduced for vertical ridge augmentation to replace autogenous block bone grafting. PURPOSE: This retrospective study radiographically evaluated dimensional alterations of the vertically augmented alveolar ridge using collagen membrane and 3 types of materials: autogenous bone block, allogenous bone block, and particulated bone substitute. MATERIALS AND METHODS: The electronic medical records of 32 patients who received vertical ridge augmentation using 3 types of materials were searched: 9 for autogenous bone block, 12 for allogenous bone block, and 11 for particulated bone substitutes. The vertical bone gain, progression of bone resorption, and peri-implant marginal bone loss after prosthetic loading were measured on follow-up radiographs. RESULTS: The alveolar ridge was vertically augmented by 5.13 +/- 1.61, 4.54 +/- 2.48, and 3.90 +/- 0.85 mm (mean +/- standard deviation) after grafting with autogenous bone block, allogenous bone block, and particulated bone substitute, respectively. The radiographic vertical height of the augmented ridge that received autogenous bone block reduced continuously during the first year but was stable thereafter. Sites that received allogenous bone block or particulated bone substitute exhibited dimensional shrinkage for up to 1.5 years postsurgery. However, the peri-implant marginal bone loss did not exceed 1 mm throughout the observational periods in all groups. CONCLUSIONS: The clinical findings of this study suggest that the alveolar ridge can be vertically augmented using either allogenous bone block or particulated bone substitute. However, they require a longer healing period to ensure dimensional stability compared to the autogenous bone block. PMID- 28556453 TI - HIV screening in pregnant women: A systematic review of cost-effectiveness studies. AB - INTRODUCTION: Vertical transmission represents the major route of HIV infection for children. However, the preventive interventions available are extremely effective. This review summarizes evidence regarding the cost-effectiveness of mother-to-child-transmission preventive screenings, to help policy makers in choosing the optimal antenatal screening strategy. METHODS: A systematic review following PRISMA guidelines was conducted, using 3 databases: PubMed, Scopus, and Cost-Effectiveness Analysis Registry. All articles regarding HIV screening to avoid vertical transmission were included. RESULTS: The review included 21 papers. Seven studies assessed the cost-effectiveness of universal antenatal screening during early gestation. Two papers considered the integration of HIV screening with other medical interventions. Eight works estimated the cost effectiveness of HIV screening in late pregnancy. Finally, 4 papers considered the combination of multiple strategies. The selected papers focused on both developed and developing countries, with a different HIV prevalence. The characteristics and methodology of the studies were heterogeneous. However, all studies agreed about the main findings, outlining the cost-effectiveness of both universal antenatal screening and HIV rescreening in late pregnancy. Cost effectiveness improved when HIV burden increased. The major findings were proved to be robust across various scenarios when tested in sensitivity analysis. CONCLUSIONS: The review confirmed the cost-effectiveness not only of HIV universal antenatal screening but also of rescreening in late gestation in both developed and developing countries. Universal screening is cost-effective even in case of extremely low HIV prevalence. Therefore, to maximize screening, coverage appears as a worldwide priority. In certain settings, a targeted screening towards high-risk groups could be a valuable option. PMID- 28556456 TI - Gender violence, poverty and HIV infection risk among persons engaged in the sex industry: cross-national analysis of the political economy of sex markets in 30 European and Central Asian countries. AB - OBJECTIVES: Persons engaged in the sex industry are at greater risk of HIV and other sexually transmitted infections than the general population. One major factor is exposure to higher levels of risky sexual activity. Expanding condom use is a critical prevention strategy, but this requires negotiation with those buying sex, which takes place in the context of cultural and economic constraints. Impoverished individuals who fear violence are more likely to forego condoms. METHODS: Here we tested the hypotheses that poverty and fear of violence are two structural drivers of HIV infection risk in the sex industry. Using data from the European Centre for Disease Prevention and Control and the World Bank for 30 countries, we evaluated poverty, measured using the average income per day per person in the bottom 40% of the income distribution, and gender violence, measured using homicide rates in women and the proportion of women exposed to violence in the last 12 months and/or since age 16 years. RESULTS: We found that HIV prevalence among those in the sex industry was higher in countries where there were greater female homicide rates (beta = 0.86; P = 0.018) and there was some evidence that self-reported exposure to violence was also associated with higher HIV prevalence (beta = 1.37; P = 0.043). Conversely, HIV prevalence was lower in countries where average incomes among the poorest were greater (beta = 1.05; P = 0.046). CONCLUSIONS: Our results are consistent with the theory that reducing poverty and exposure to violence may help reduce HIV infection risk among persons engaged in the sex industry. PMID- 28556454 TI - Genetics of Hereditary Ataxia in Scottish Terriers. AB - BACKGROUND: Scottish Terriers have a high incidence of juvenile onset hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex and causing slowly progressive cerebellar dysfunction. OBJECTIVE: To identify chromosomal regions associated with hereditary ataxia in Scottish Terriers. ANIMALS: One hundred and fifty-three Scottish Terriers were recruited through the Scottish Terrier Club of America. MATERIALS AND METHODS: Prospective study. Dogs were classified as affected if they had slowly progressive cerebellar signs. When possible, magnetic resonance imaging and histopathological evaluation of the brain were completed as diagnostic aids. To identify genomic regions connected with the disease, genome-wide mapping was performed using both linkage- and association-based approaches. Pedigree evaluation and homozygosity mapping were also performed to examine mode of inheritance and to investigate the region of interest, respectively. RESULTS: Linkage and genome-wide association studies in a cohort of Scottish Terriers both identified a region on CFA X strongly associated with the disease trait. Homozygosity mapping revealed a 4 Mb region of interest. Pedigree evaluation failed to identify the possible mode of inheritance due to the lack of complete litter information. CONCLUSION AND CLINICAL IMPORTANCE: This finding suggests that further genetic investigation of the potential region of interest on CFA X should be considered in order to identify the causal mutation as well as develop a genetic test to eliminate the disease from this breed. PMID- 28556457 TI - New insight into foregut functions of xenobiotic detoxification in the cockroach Periplaneta americana. AB - The physiological functions of insect foregut, especially in xenobiotic detoxification, are scarcely reported because of unimportance in appearance and insufficient molecular information. The cockroach Periplaneta americana, an entomological model organism, provides perfect material to study physiological functions of foregut tissue due to its architectural feature. Through Illumina sequencing of foregut tissue from P. americana individuals (control) or insects treated with cycloxaprid, as a novel neonicotinoid insecticide, 54 193 166 clean reads were obtained and further assembled into 53 853 unigenes with an average length of 366 bp. Furthermore, the number of unigenes involved in xenobiotic detoxification was analyzed, mainly including 70 cytochrome P450s, 12 glutathione S-transferases (GSTs), seven carboxylesterases (CarEs) and seven adenosine triphosphate-binding cassette (ABC) transporters. Compared to control, the expression of 22 xenobiotic detoxification unigenes was up-regulated after cycloxaprid application, mainly containing 18 P450s, one GST, two CarEs and one ABC adenosine triphosphate transporter, indicating that the oxidation-reduction was the major reactive process to cycloxaprid application. Through quantitative real-time polymerase chain reaction analysis, the expression of selected unigenes (six P450s, one GST and one CarE) was up-regulated at least two-fold following cycloxaprid treatment, and was generally in agreement with transcriptome data. Compared to the previous midgut transcriptome of P. americana, it looks like the expressive abundance of the xenobiotic detoxification unigenes might be important factors to the detoxifying functional differences between foregut and midgut. In conclusion, insect foregut would also play important roles in the physiological processes related to xenobiotic detoxification. PMID- 28556455 TI - The serine/threonine phosphatases of apicomplexan parasites. AB - The balance between phosphorylation and de-phosphorylation, which is delicately regulated by protein kinases and phosphatases, is critical for nearly all biological processes. The Apicomplexa are a large phylum which contains various parasitic protists, including human pathogens, such as Plasmodium, Toxoplasma, Cryptosporidium and Babesia species. The diverse life cycles of these parasites are highly complex and, not surprisingly, many of their key steps are exquisitely regulated by phosphorylation. Interestingly, many of the kinases and phosphatases, as well as the substrates involved in these events are unique to the parasites and therefore phosphorylation constitutes a viable target for antiparasitic intervention. Most progress on this realm has come from studies in Toxoplasma and Plasmodium of their respective kinomes and phosphoproteomes. Nonetheless, given their likely importance, phosphatases have recently become the focus of research within the apicomplexan parasites. In this review, we concentrate on serine/threonine phosphatases in apicomplexan parasites, with the focus on comprehensively identifying and naming protein phosphatases in available apicomplexan genomes, and summarizing the progress of their functional analyses in recent years. PMID- 28556458 TI - Behaviour change intervention to improve shared toilet maintenance and cleanliness in urban slums of Dhaka: a cluster-randomised controlled trial. AB - OBJECTIVES: Shared toilets in urban slums are often unclean and poorly maintained, discouraging consistent use and thereby limiting impacts on health and quality of life. We developed behaviour change interventions to support shared toilet maintenance and improve user satisfaction. We report the intervention effectiveness on improving shared toilet cleanliness. METHODS: We conducted a cluster-randomised controlled trial among users of 1226 shared toilets in 23 Dhaka slums. We assessed baseline toilet cleanliness in January 2015. The six-month intervention included provision of hardware (bin for solid waste, 4 l flushing bucket, 70 l water reservoir), and behaviour change communication (compound meetings, interpersonal household sessions, signs depicting rules for toilet use). We estimated the adjusted difference in difference (DID) to assess outcomes and accounted for clustering effects using generalised estimating equations. RESULTS: Compared to controls, intervention toilets were more likely to have water available inside toilet cubicles (DID: +4.7%, 95% CI: 0.2, 9.2), access to brush/broom for cleaning (DID: +8.4%, 95% CI: 2, 15) and waste bins (DID: +63%, 95% CI: 59, 66), while less likely to have visible faeces inside the pan (DID: -13%, 95% CI: -19, -5), the smell of faeces (DID: -7.6%, 95% CI: -14, -1.3) and household waste inside the cubicle (DID: -4%, 95% CI: -7, -1). CONCLUSIONS: In one of few efforts to promote shared toilet cleanliness, intervention compounds were significantly more likely to have cleaner toilets after six months. Future research might explore how residents can self-finance toilet maintenance, or employ mass media to reduce per-capita costs of behaviour change. PMID- 28556459 TI - Does coffee consumption impact on heaviness of smoking? AB - BACKGROUND AND AIMS: Coffee consumption and cigarette smoking are strongly associated, but whether this association is causal remains unclear. We sought to: (1) determine whether coffee consumption influences cigarette smoking causally, (2) estimate the magnitude of any association and (3) explore potential mechanisms. DESIGN: We used Mendelian randomization (MR) analyses of observational data, using publicly available summarized data from the Tobacco and Genetics (TAG) consortium, individual-level data from the UK Biobank and in-vitro experiments of candidate compounds. SETTING: The TAG consortium includes data from studies in several countries. The UK Biobank includes data from men and women recruited across England, Wales and Scotland. PARTICIPANTS: The TAG consortium provided data on n <= 38 181 participants. The UK Biobank provided data on 8072 participants. MEASUREMENTS: In MR analyses, the exposure was coffee consumption (cups/day) and the outcome was heaviness of smoking (cigarettes/day). In our in-vitro experiments we assessed the effect of caffeic acid, quercetin and p-coumaric acid on the rate of nicotine metabolism in human liver microsomes and cDNA-expressed human CYP2A6. FINDINGS: Two-sample MR analyses of TAG consortium data indicated that heavier coffee consumption might lead to reduced heaviness of smoking [beta = -1.49, 95% confidence interval (CI) = -2.88 to -0.09]. However, in-vitro experiments found that the compounds investigated are unlikely to inhibit significantly the rate of nicotine metabolism following coffee consumption. Further MR analyses in UK Biobank found no evidence of a causal relationship between coffee consumption and heaviness of smoking (beta = 0.20, 95% CI = -1.72 to 2.12). CONCLUSIONS: Amount of coffee consumption is unlikely to have a major causal impact upon amount of cigarette smoking. If it does influence smoking, this is not likely to operate via effects of caffeic acid, quercetin or p-coumaric acid on nicotine metabolism. The observational association between coffee consumption and cigarette smoking may be due to smoking impacting on coffee consumption or confounding. PMID- 28556460 TI - HLA genotyping using the Illumina HLA TruSight next-generation sequencing kits: A comparison. AB - Illumina first introduced their TruSight human leucocyte antigen (HLA) next generation sequencing (NGS) typing kit in 2015 and subsequently followed up with a new version in 2016. Here we report on our experience comparing the two versions of the Illumina HLA NGS kits. PMID- 28556461 TI - Double flap phalloplasty in transgender men: Surgical technique and outcome of pedicled anterolateral thigh flap phalloplasty combined with radial forearm free flap urethral reconstruction. AB - INTRODUCTION: Radial forearm free flap (RFFF) tube-in-tube phalloplasty is the most performed phalloplasty technique worldwide. The conspicuous donor-site scar is a drawback for some transgender men. In search for techniques with less conspicuous donor-sites, we performed a series of one-stage pedicled anterolateral thigh flap (ALT) phalloplasties combined with RFFF urethral reconstruction. In this study, we aim to describe this technique and assess its surgical outcome in a series of transgender men. PATIENTS AND METHODS: Between January 2008 and December 2015, nineteen transgender men (median age 37, range 21 57) underwent pedicled ALT phalloplasty combined with RFFF urethral reconstruction in one stage. The surgical procedure was described. Patient demographics, surgical characteristics, intra- and postoperative complications, hospitalization length, and reoperations were recorded. RESULTS: The size of the ALT flaps ranged from 12 * 12 to 15 * 13 cm, the size of the RFFFs from 14 * 3 to 17 * 3 cm. Median clinical follow-up was 35 months (range 3-95). Total RFFF failure occurred in two patients, total ALT flap failure in one patient, and partial necrosis of the ALT flap in one patient. Long-term urinary complications occurred in 10 (53%) patients, of which 9 concerned urethral strictures. CONCLUSIONS: In experienced hands, one-stage pedicled ALT phalloplasty combined with RFFF urethral reconstruction is a feasible alternative surgical option in eligible transgender men, who desire a less conspicuous forearm scar. Possible drawbacks comprise flap-related complications, difficult inner flap monitoring and urethral complications. PMID- 28556462 TI - GSK3 activity regulates rhythms in hippocampal clock gene expression and synaptic plasticity. AB - Hippocampal rhythms in clock gene expression, enzymatic activity, and long-term potentiation (LTP) are thought to underlie day-night differences in memory acquisition and recall. Glycogen synthase kinase 3-beta (GSK3beta) is a known regulator of hippocampal function, and inhibitory phosphorylation of GSK3beta exhibits region-specific differences over the light-dark cycle. Here, we sought to determine whether phosphorylation of both GSK3alpha and GSK3beta isoforms has an endogenous circadian rhythm in specific areas of the hippocampus and whether chronic inhibition or activation alters the molecular clock and hippocampal plasticity (LTP). Results indicated a significant endogenous circadian rhythm in phosphorylation of GSK3beta, but not GSK3alpha, in hippocampal CA1 extracts from mice housed in constant darkness for at least 2 weeks. To examine the importance of this rhythm, genetic and pharmacological strategies were used to disrupt the GSK3 activity rhythm by chronically activating or inhibiting GSK3. Chronic activation of both GSK3 isoforms in transgenic mice (GSK3-KI mice) diminished rhythmic BMAL1 expression. On the other hand, chronic treatment with a GSK3 inhibitor significantly shortened the molecular clock period of organotypic hippocampal PER2::LUC cultures. While WT mice exhibited higher LTP magnitude at night compared to day, the day-night difference in LTP magnitude remained with greater magnitude at both times of day in mice with chronic GSK3 activity. On the other hand, pharmacological GSK3 inhibition impaired day-night differences in LTP by blocking LTP selectively at night. Taken together, these results support the model that circadian rhythmicity of hippocampal GSK3beta activation state regulates day/night differences in molecular clock periodicity and a major form of synaptic plasticity (LTP). PMID- 28556464 TI - Tobacco Harms, Nicotine Pharmacology, and Pharmacologic Tobacco Cessation Interventions for Women. AB - Firsthand and secondhand tobacco use is linked to a multitude of harmful illnesses, adverse perinatal outcomes, and death. Cessation attempts among women may be hampered by their unique biologic response to nicotine. Current research has revealed epigenetic changes from intrauterine nicotine exposure that have intergenerational consequences. Multiple studies have demonstrated the efficacy of various pharmacologic tobacco cessation interventions in conjunction with behavioral counseling. Based on this evidence, the US Preventative Services Task Force (USPSTF) 2015 guideline recommends pharmacologic therapy for all nonpregnant persons who smoke in addition to behavioral counseling. The effectiveness of pharmacologic treatments among pregnant women is less clear, with far fewer studies evaluating potential benefits and harms. While exposure to pharmacologic therapies raises concerns for fetal safety, these potential risks must be weighed against those of continued tobacco use, which guarantees fetal exposure to nicotine. First-line tobacco cessation medications include nicotine replacement therapy (NRT), bupropion, and varenicline. Second-line medications include nortriptyline and clonidine. Pharmacokinetics, effectiveness, regimens, and safety profiles for nonpregnant, pregnant, and lactating women are reviewed. Alternative tobacco cessation options and potential new pharmacologic tobacco cessation agents are discussed. Initiating brief interventions, using the 5A's and 5R's model is described. PMID- 28556465 TI - Biphasic axillary synovial sarcoma diagnosed by preoperative fine-needle aspiration cytology. AB - Synovial sarcoma (SS) is a soft-tissue sarcoma which usually occurs in lower extremities. Less than 20 cases of SS located in shoulder or axillary region have been reported, and these studies describe histopathological features. We report a case of axillary SS diagnosed by fine-needle aspiration cytology, immunocytochemistry, and molecular techniques performed on cytology smears. A 48 year-old woman presented with a palpable and well-defined axillary mass which measured 4 cm. On-site smears showed high cellularity with spindle cells, and a mesenchymal tumor was suspected. Definitive cytological analysis showed cells with ovoid- or comma-shaped nuclei arranged in loose sheets and fascicles, associated with naked nuclei and isolated cells. Mitotic count was 2 mitoses/HPF. Immunocytochemical studies showed vimentin and focal CK AE1-AE3 positivity. A PCR was performed and the specific translocation t(X;18) was detected. The lesion was excised and the diagnosis of biphasic SS was confirmed. The identification of SS on cytology specimens is difficult and differential diagnosis is broad. Complementary studies are necessary and they can be performed on FNA smears or cell blocks. PMID- 28556466 TI - Microproteomics with microfluidic-based cell sorting: Application to 1000 and 100 immune cells. AB - Ultimately, cell biology seeks to define molecular mechanisms underlying cellular functions. However, heterogeneity within cell populations must be considered for optimal assay design and data interpretation. Although single-cell analyses are desirable for addressing this issue, practical considerations, including assay sensitivity, limit their broad application. Therefore, omics studies on small numbers of cells in defined subpopulations represent a viable alternative for elucidating cell functions at the molecular level. MS-based proteomics allows in depth proteome exploration, although analyses of small numbers of cells have not been pursued due to loss during the multistep procedure involved. Thus, optimization of the proteomics workflow to facilitate the analysis of rare cells would be useful. Here, we report a microproteomics workflow for limited numbers of immune cells using non-damaging, microfluidic chip-based cell sorting and MS based proteomics. Samples of 1000 or 100 THP-1 cells were sorted, and after enzymatic digestion, peptide mixtures were subjected to nano-LC-MS analysis. We achieved reasonable proteome coverage from as few as 100-sorted cells, and the data obtained from 1000-sorted cells were as comprehensive as those obtained using 1 MUg of whole cell lysate. With further refinement, our approach could be useful for studying cell subpopulations or limited samples, such as clinical specimens. PMID- 28556463 TI - A single bout of exercise increases hippocampal Bdnf: influence of chronic exercise and noradrenaline. AB - Research in human subjects suggests that acute exercise can improve memory performance, but the qualities of the exercise necessary to promote improved memory, and the signaling pathways that mediate these effects are unknown. Brain derived neurotrophic factor (Bdnf), noradrenergic signaling, and post translational modifications to AMPA receptors have all been implicated in the enhancement of memory following emotional or physical arousal; however, it is not known if a single bout of exercise is sufficient to engage these pathways. Here we use a rodent model to investigate the effects of acute and chronic exercise on hippocampal transcript-specific Bdnf expression and phosphorylation of the GluR1 subunit of the AMPA-type glutamate receptor. A single bout of treadmill exercise was insufficient to mimic the increased expression of GluR1 protein and phosphorylation at Ser845 observed following 1 month of voluntary wheel running. However, acute exercise was sufficient to increase Bdnf transcript IV messenger RNA (mRNA) expression in sedentary subjects, but not subjects housed for 1 month with a running wheel. High-intensity acute exercise increased total Bdnf mRNA in sedentary mice, but not above levels observed following chronic access to the running wheel. Although depletion of central noradrenergic signaling with DSP-4 reduced Bdnf IV mRNA, the effect of acute exercise on Bdnf mRNA persisted. Our characterization of the effects of acute exercise on Bdnf expression and persistence in the absence of noradrenergic modulation may inform strategies to employ physical activity to combat cognitive aging and mental health disorders. PMID- 28556467 TI - Association between smoking and alcohol-related behaviours: a time-series analysis of population trends in England. AB - AIMS: This paper estimates how far monthly changes in prevalence of cigarette smoking, motivation to quit and attempts to stop smoking have been associated with changes in prevalence of high-risk drinking, and motivation and attempts to reduce alcohol consumption in England. DESIGN: Data were used from the Alcohol and Smoking Toolkit Studies between April 2014 and June 2016. These involve monthly household face-to-face surveys of representative samples of ~1700 adults in England. MEASUREMENTS: Autoregressive Integrated Moving Average with Exogeneous Input (ARIMAX) modelling was used to assess the association over time between monthly prevalence of (a) smoking and high-risk drinking; (b) high motivation to quit smoking and high motivation to reduce alcohol consumption; and (c) attempts to quit smoking and attempts to reduce alcohol consumption. FINDINGS: Mean smoking prevalence over the study period was 18.6% and high-risk drinking prevalence was 13.0%. A decrease of 1% of the series mean smoking prevalence was associated with a reduction of 0.185% of the mean prevalence of high-risk drinking 2 months later [95% confidence interval (CI) = 0.033 to 0.337, P = 0.017]. A statistically significant association was not found between prevalence of high motivation to quit smoking and high motivation to reduce alcohol consumption (beta = 0.324, 95% CI = -0.371 to 1.019, P = 0.360) or prevalence of attempts to quit smoking and attempts to reduce alcohol consumption (beta = -0.026, 95% CI = -1.348 to 1.296, P = 0.969). CONCLUSION: Between 2014 and 2016, monthly changes in prevalence of smoking in England were associated positively with prevalence of high-risk drinking. There was no significant association between motivation to stop and motivation to reduce alcohol consumption, or attempts to quit smoking and attempts to reduce alcohol consumption. PMID- 28556468 TI - Association of the expression level of the neurodegeneration-related proteins with the risk of development and progression of primary open-angle glaucoma. PMID- 28556469 TI - Neuregulin 3 and its roles in schizophrenia risk and presentation. AB - Neuregulins, a four-member family of epidermal growth factor-like signaling molecules, have been studied for over two decades. They were first implicated in schizophrenia in 2002 with the detection of linkage and association at the NRG1 locus followed after a few years by NRG3. However, the associations with disease have not been very consistently observed. In contrast, association of NGR3 variants with disease presentation, specifically the presence of delusions, has been more consistent. This appears to be mediated by quantitative changes in the alternative splicing of the gene, which has also been consistently observed. Additional diseases and phenotypes, psychiatric or not, have also been connected with NRG3. These results demonstrate two important aspects of behavioral genetics research. The first is that if we only consider simple risk and fail to examine the details of each patient's individual phenotype, we will miss important insights on the disease biology. This is an important aspect of the goals of precision medicine. The second is that the functional consequences of variants are often more complex than simple alterations in levels of transcription of a particular gene, including, among others, regulation of alternative splicing. To accurately model and understand the biological consequences of phenotype associated genetic variants, we need to study the biological consequences of each specific variant. Simply studying the consequences of a null allele of the orthologous gene in a model system, runs the risk of missing the many nuances of hypomorphic and/or gain of function variants in the genome of interest. PMID- 28556470 TI - Contrast-Enhanced Ultrasound Differentiation Between Low- and High- Grade Bladder Urothelial Carcinoma and Correlation With Tumor Microvessel Density. AB - OBJECTIVES: Time-intensity curves (TICs) of contrast-enhanced ultrasound (CEUS) were analyzed retrospectively to differentiate between low-grade and high-grade bladder urothelial carcinoma, and to investigate correlation with tumor microvessel density (MVD). METHODS: The data of 105 patients with pathologically confirmed bladder urothelial carcinoma (55 low-grade and 50 high-grade) were reviewed. Lesions were examined before surgery using conventional ultrasound and CEUS with TIC analysis. The TIC parameters time from peak to one-half the signal intensity (TPH) and the corresponding descending slope (DS) of the low-grade and high-grade groups were compared, and receiver operating characteristic curves constructed. The MVDs of the resectioned tissue specimens were quantified via immunohistochemistry for CD34. RESULTS: Based on conventional ultrasound, the low grade and high-grade groups were similar in tumor shape, number, topography, internal echo, height, width, and vascularity. The TPH of the high-grade group was significantly longer than that of the low-grade group, and the DS was lower. The cutoff points of TPH and DS for differentiating low-grade and high-grade bladder urothelial carcinoma were 48.06 seconds and 0.15 dB/seconds, respectively (area under the receiver operating characteristic curve = 0.79 for both). The mean MVDs per high-power field of the low-grade and high-grade groups were 41.39 16.65 and 51.03 20.16, respectively (P = .009). The TPH correlated linearly with MVD (P < .01), as did the DS (P < .01). CONCLUSIONS: Contrast-enhanced ultrasound can be used to differentiate low from high-grade bladder urothelial carcinoma. The TIC parameters of CEUS reflect the MVD of bladder urothelial tumors and may be helpful for evaluating tumor angiogenesis, with implications for clinical diagnosis, treatment, and prognosis. PMID- 28556472 TI - Novel Donor Transfer Algorithm for Multiorgan and Facial Allograft Procurement. PMID- 28556471 TI - Putative Cerebral Microbleeds in Dogs Undergoing Magnetic Resonance Imaging of the Head: A Retrospective Study of Demographics, Clinical Associations, and Relationship to Case Outcome. AB - BACKGROUND: Cerebral microbleeds (CMBs) are focal intraparenchymal signal voids on gradient-echo magnetic resonance imaging (MRI), corresponding to regions of chronic hemorrhage. In humans, they are associated with systemic disease and shorter survival times. Although similar findings have been identified in dogs, their epidemiology and clinical correlations have not been investigated. OBJECTIVE: To determine epidemiological features, clinical associations, and associations with outcome for putative CMB-like foci (putative microbleeds [pMBs]) identified by T2*-weighted MRI in dogs. ANIMALS: Five hundred and eighty two dogs undergoing 3T brain MRI between 2011 and 2016. METHODS: Retrospective case-control study. Demographic, diagnostic, and clinicopathological data were obtained from medical records and phone follow-up. Demographic variables were compared between dogs with and without evidence of pMBs. For dogs with such evidence, and a subset of matched controls, associations with clinical presentation, concurrent disease, and survival times were evaluated. RESULTS: Dogs with pMBs were older (P < .001) and smaller (P = .004) than unaffected dogs. Compared to matched controls, they presented more frequently for vestibular signs (P = .030). Cortical atrophy occurred concurrently with pMBs in 26% (14/54) of dogs. Diagnosed renal disease was not significantly associated with pMBs, but proteinuria was more common in dogs with pMBs than in matched controls (odds ratio = 3.01, P = .005). Dogs with pMBs had a shorter median survival time than did matched controls (P = .011). CONCLUSIONS AND CLINICAL IMPORTANCE: Putative microbleeds occurred in 54 of 582 (9.3%) of dogs undergoing brain MRI, but may not be a normal consequence of aging. They were associated with shorter survival time and proteinuria in the study population. PMID- 28556473 TI - Flyweight, Superelastic, Electrically Conductive, and Flame-Retardant 3D Multi Nanolayer Graphene/Ceramic Metamaterial. AB - A ceramic/graphene metamaterial (GCM) with microstructure-derived superelasticity and structural robustness is achieved by designing hierarchical honeycomb microstructures, which are composited with two brittle constituents (graphene and ceramic) assembled in multi-nanolayer cellular walls. Attributed to the designed microstructure, well-interconnected scaffolds, chemically bonded interface, and coupled strengthening effect between the graphene framework and the nanolayers of the Al2 O3 ceramic (NAC), the GCM demonstrates a sequence of multifunctional properties simultaneously that have not been reported for ceramics and ceramics matrix-composite structures, such as flyweight density, 80% reversible compressibility, high fatigue resistance, high electrical conductivity, and excellent thermal-insulation/flame-retardant performance simultaneously. The 3D well-ordered graphene aerogel templates are strongly coupled with the NAC by the chemically bonded interface, exhibiting mutual strengthening, compatible deformability, and a linearly dependent relationship between the density and Young's modulus. Considerable size effects of the ceramic nanolayers on the mechanical properties are revealed in these ceramic-based metamaterials. The designed hierarchical honeycomb graphene with a fourth dimensional control of the ceramic nanolayers on new ways to scalable fabrication of advanced multifunctional ceramic composites with controllable design suggest a great potential in applications of flexible conductors, shock/vibration absorbers, thermal shock barriers, thermal insulation/flame-retardant skins, and porous microwave-absorbing coatings. PMID- 28556474 TI - Describing mate preference functions and other function-valued traits. AB - Mate preferences are important causes of sexual selection. They shape the evolution of sexual ornaments and displays, sometimes maintaining genetic diversity and sometimes promoting speciation. Mate preferences can be challenging to study because they are expressed in animal brains and because they are a function of the features of potential mates that are encountered. Describing them requires taking this into account. We present a method for describing and analysing mate preference functions, and introduce a freely available computer program that implements the method. We give an overview of how the program works, and we discuss how it can be used to visualize and quantitatively analyse preference functions. In addition, we provide an informal review of different methods of testing mate preferences, with recommendations for how best to set up experiments on mate preferences. Although the program was written with mate preferences in mind, it can be used to study any function-valued trait, and we hope researchers will take advantage of it across a broad range of traits. PMID- 28556475 TI - Evaluation of clinical validity of the Rabin cone contrast test in normal phakic or pseudophakic eyes and severely dichromatic eyes. AB - PURPOSE: To evaluate the clinical validity of the Rabin cone contrast test (RCCT; Innova Systems, Inc.) in patients with normal phakic/pseudophakic eyes and severe dichromatic colour vision deficiency (CVD). METHODS: We evaluated age-related changes in the RCCT scores in 166 phakic eyes and 34 pseudophakic eyes and the RCCT sensitivity and specificity in 28 men with severe dichromatic CVD (10 with protanopia, 18 with deutanopia) and nine age-matched controls. All participants had 20/20 or better Snellen best-corrected visual acuity (BCVA). The RCCT was used to measure the L, M and S-CCT scores (range, 0-100). RESULTS: In normal phakic eyes, the mean L, M and S-CCT scores decreased gradually with ageing, with normal levels in patients in the second to seventh decades of life and some below normal in the eighth and ninth decades of life. In normal pseudophakic eyes, the mean L, M and S-CCT scores were normal in patients in the seventh to ninth decades of life. In eyes with severe CVD, the mean L, M and S-CCT scores were, respectively, 31.5 +/- 18.3, 86.0 +/- 12.6 and 98.0 +/- 6.3 in patients with protanopia; 92.8 +/- 10.5, 50.8 +/- 19.6 and 97.8 +/- 5.2 in patients with deutanopia; and 99.4 +/- 1.7, 98.3 +/- 5.0 and 99.4 +/- 1.7 in controls. The RCCT sensitivity and specificity were 100% for diagnosing the CVD type. CONCLUSION: The RCCT can be used in non-visually impaired patients up to the seventh decade of life and after cataract surgery in elderly patients. The RCCT is available for CVD screening and typing and the score has a wide distribution range even in patients with severe CVD. PMID- 28556476 TI - Neurophysiological changes associated with implant-associated augmentation procedures in the lower jaw. AB - BACKGROUND: Neurophysiological changes after oral and maxillofacial surgery remain one of the topics of current research. PURPOSE: This study evaluated if implant placement associated with augmentation procedures increases the possibility of sensory disturbances or result in impaired quality of life during the healing period. MATERIAL AND METHODS: Patients who had obtained an implant placement in the lower jaw in combination with augmentation procedures were examined by implementing a comprehensive Quantitative Sensory Testing (QST) protocol for extra- and intraoral use. As augmentation procedures, we used Guided Bone Regeneration (Group A) and Customized Bone Regeneration (Group B) techniques. Patients were tested bilaterally at the chin and mucosal lower lip. Results were compared to a group without augmentation procedures (Group C). Patients' quality of life and psychological comorbidity after the surgical procedures was assessed with the Oral Health Impact Profile and the Hospital Anxiety and Depression Scale. RESULTS: For groups A (n = 20) and B (n = 8), mechanical QST parameters showed no significant differences in all qualities of the inferior alveolar nerve compared to the contralateral side and compared to the nonaugmentation control group (n = 32) as well. Evaluation of quality of life and psychological factors showed no statistical differences. CONCLUSIONS: Augmentation procedures did not increase sensory disturbances, indicating no changes in the neurophysiological pathways. Extended augmentation procedures did not lead to sensory changes either or result in an impaired quality of life or modified anxiety and depression scores. PMID- 28556477 TI - Assessing meta-regression methods for examining moderator relationships with dependent effect sizes: A Monte Carlo simulation. AB - Dependent effect sizes are ubiquitous in meta-analysis. Using Monte Carlo simulation, we compared the performance of 2 methods for meta-regression with dependent effect sizes-robust variance estimation (RVE) and 3-level modeling-with the standard meta-analytic method for independent effect sizes. We further compared bias-reduced linearization and jackknife estimators as small-sample adjustments for RVE and Wald-type and likelihood ratio tests for 3-level models. The bias in the slope estimates, width of the confidence intervals around those estimates, and empirical type I error and statistical power rates of the hypothesis tests from these different methods were compared for mixed-effects meta-regression analysis with one moderator either at the study or at the effect size level. All methods yielded nearly unbiased slope estimates under most scenarios, but as expected, the standard method ignoring dependency provided inflated type I error rates when testing the significance of the moderators. Robust variance estimation methods yielded not only the best results in terms of type I error rate but also the widest confidence intervals and the lowest power rates, especially when using the jackknife adjustments. Three-level models showed a promising performance with a moderate to large number of studies, especially with the likelihood ratio test, and yielded narrower confidence intervals around the slope and higher power rates than those obtained with the RVE approach. All methods performed better when the moderator was at the effect size level, the number of studies was moderate to large, and the between-studies variance was small. Our results can help meta-analysts deal with dependency in their data. PMID- 28556478 TI - Pattern of relapse in low-risk breast cancer patients followed within a community care network. AB - International guidelines have set the frame and methods of patients' surveillance after early breast cancer (BC) treatment. Since 1998, delegation of low-risk BC patients follow-up to nonhospital practitioners has been developed within a care network in the Paris region. We used the Gynecomed care network digital database to describe the characteristics of oncological events which occurred in the cohort, and to assess the quality of BC follow-up in relapsing patients. Events were defined as any local, contralateral, or metastatic recurrence, as well as second cancer or death due to any cause. We developed a ranked evaluation method of our surveillance program. Among the 3019 patients followed in the network, 116 (4.3%) patients had 116 events. Median follow-up was 7.1 years (0-51). First events were local-regional relapses, contralateral BCs, metastatic events, second primaries in respectively 52, 26, 14, 24 cases. During the first 5 years, 68.4% of surveillance visits were performed on time, 13.5% were behind schedule and 18.1% were not performed, while 79.1% of mammographies were performed on time, 7.7% behind schedule, and 13.2% were not performed. On schedule examinations allowed diagnosis of 77% of the local-regional, ipsilateral relapses or contralateral BCs, including 38 (69%) discovered by mammographies and 17 (31%) by clinical examination. A nonhospital practitioner care network is able to comply with good surveillance practices and deliver high quality surveillance, in accordance with international guidelines. Delegation of low-risk BC surveillance to nonhospital practitioners is reliable. PMID- 28556479 TI - Tonic and phasic changes in anteromedial globus pallidus activity in Tourette syndrome. AB - BACKGROUND: Tourette syndrome is a hyperkinetic neurodevelopmental disorder characterized by tics. OBJECTIVE: Assess the neuronal changes in the associative/limbic GP associated with Tourette syndrome. METHODS: Neurophysiological recordings were performed from the anterior (associative/limbic) GPe and GPi of 8 awake patients during DBS electrode implantation surgeries. RESULTS: The baseline firing rate of the neurons was low in a state-dependent manner in both segments of the GP. Tic-dependent transient rate changes were found in the activity of individual neurons of both segments around the time of the tic. Neither oscillatory activity of individual neurons nor correlations in their interactions were observed. CONCLUSIONS: The results demonstrate the involvement of the associative/limbic pathway in the underlying pathophysiology of Tourette syndrome and point to tonic and phasic modulations of basal ganglia output as a key mechanisms underlying the abnormal state of the disorder and the expression of individual tics, respectively. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28556481 TI - If you needed an organ transplant would you have one? The effect of reciprocity priming and mode of delivery on organ donor registration intentions and behaviour. AB - OBJECTIVE: There are approximately 6,500 people on the UK national transplant waiting list, around 400 of whom die every year. Only 35% of the UK population are currently on the organ donation register. We report two studies examining whether a reciprocity prime, in which participants were asked whether they would accept a donated organ, increased organ donation intentions and behaviour. DESIGN: Between-participants, randomized controlled design. METHODS: In two studies, participants who were not currently registered organ donors took part either face-to-face or online and were randomly allocated to a reciprocity prime or control condition. Following the manipulation, they were asked to indicate, on either a paper or online questionnaire, their intention to join the organ donor register. Study 2 was similar to Study 1 but with the addition that after reporting intention, participants were then offered an organ donation information leaflet or the opportunity to click a link for further information (proxy behavioural measure). RESULTS: In both studies, reciprocity primed participants reported greater intentions to register than controls. However, in Study 2, no effect on donation behaviour was found. CONCLUSIONS: Reciprocal altruism may be a useful tool in increasing intentions to join the organ donor register. Further evaluation is required to determine whether this increase in intention can be translated into organ donation behaviour. Statement of contribution What was already known? Demand for organs in the United Kingdom far outstrips supply, so finding strategies to increase registration on the organ donor register could save hundreds of lives per year. Despite the majority of people in the United Kingdom agreeing that organ donation is a good thing, most people do not register as donors. A limited amount of evidence of the impact of perceived reciprocity suggests that encouraging people to consider themselves as recipients and priming ideas of shared responsibility may increase the likelihood of their subsequent willingness to register. What does this study add? Novel evidence that employing a simple reciprocity prime increases organ donor registration intentions. Replication of findings across two separate studies. Novel examination of the impact of mode of delivery of messages to encourage organ donation. A basis for further research into the translation of intentions into organ donor registration behaviour. PMID- 28556480 TI - Survival after resection of appendiceal carcinoma by hemicolectomy and less radical than hemicolectomy: a population-based propensity score matched analysis. AB - AIM: The operative treatment for non-metastatic appendiceal carcinoma is controversial despite the recommendation of right hemicolectomy (RH) by many researchers. The aim of this population-based study was to compare outcomes after RH and less radical resection than right hemicolectomy (LRH). METHOD: A total of 1144 patients who underwent resection with additional lymphadenectomy of Stages I III appendiceal carcinoma from 2004 to 2012 were identified in the Surveillance, Epidemiology and End Results database. Overall survival (OS) and cancer-specific survival (CSS) after RH and LRH were assessed by unadjusted and risk-adjusted Cox regression analysis and by propensity score matched analysis. RESULTS: A total of 855 (74.7%) patients underwent RH and 289 (25.3%) underwent LRH. In an unadjusted analysis, survival after LRH and RH did not differ in OS [hazard ratio (HR) 0.95, 95% CI 0.71-1.26, P = 0.707] and CSS (HR 0.95, 95% CI 0.69-1.32, P = 0.762). The 5-year OS and CSS in patients who underwent RH were 71.6% (95% CI 67.8-75.6%) and 76.4% (95% CI 72.8-80.3) compared with 73.8% (95% CI 67.9-80.2) and 78.7% (95% CI 73.2-84.7) in patients with LRH, respectively. No relevant difference in survival between LRH and RH could be observed in a multivariable analysis (OS, HR 0.90, 95% CI 0.65-1.25, P = 0.493; CSS, HR 0.87, 95% CI 0.60-1.26, P = 0.420) and after propensity score adjusted analysis (OS, HR 0.87, 95% CI 0.62-1.22, P = 0.442; CSS, HR 0.97, 95% CI 0.67-1.40, P = 0.883). CONCLUSIONS: In this retrospective analysis, survival after RH for non-metastatic appendiceal carcinoma was not statistically significantly superior to LRH. Hence, LRH with lymphadenectomy might be sufficient for treatment of non-metastatic appendiceal carcinoma. PMID- 28556482 TI - Gingerenone A, a polyphenol present in ginger, suppresses obesity and adipose tissue inflammation in high-fat diet-fed mice. AB - SCOPE: Ginger exerts protective effects on obesity and its complications. Our objectives here are to identify bioactive compounds that inhibit adipogenesis and lipid accumulation in vitro, elucidate the anti-obesity effect of gingerenone A (GA) in diet-induced obesity (DIO), and investigate whether GA affects adipose tissue inflammation (ATI). METHODS AND RESULTS: Oil red O staining showed that GA had the most potent inhibitory effect on adipogenesis and lipid accumulation in 3T3-L1 cells among ginger components tested at a single concentration (40 MUM). Consistent with in vitro data, GA attenuates DIO by reducing fat mass in mice. This was accompanied by a modulation of fatty acid metabolism via activation of AMP-activated protein kinase (AMPK) in vitro and in vivo. Additionally, GA suppressed ATI by inhibiting macrophage recruitment and downregulating pro inflammatory cytokines. CONCLUSION: These results suggest that GA may be used as a potential therapeutic candidate for the treatment of obesity and its complications by suppressing adipose expansion and inflammation. PMID- 28556484 TI - Response to "Cortisol in human milk: The good, the bad, or the Ugly?" PMID- 28556483 TI - Drug sensitivity and resistance testing identifies PLK1 inhibitors and gemcitabine as potent drugs for malignant peripheral nerve sheath tumors. AB - Patients with malignant peripheral nerve sheath tumor (MPNST), a rare soft tissue cancer associated with loss of the tumor suppressor neurofibromin (NF1), have poor prognosis and typically respond poorly to adjuvant therapy. We evaluated the effect of 299 clinical and investigational compounds on seven MPNST cell lines, two primary cultures of human Schwann cells, and five normal bone marrow aspirates, to identify potent drugs for MPNST treatment with few side effects. Top hits included Polo-like kinase 1 (PLK1) inhibitors (volasertib and BI2536) and the fluoronucleoside gemcitabine, which were validated in orthogonal assays measuring viability, cytotoxicity, and apoptosis. DNA copy number, gene expression, and protein expression were determined for the cell lines to assess pharmacogenomic relationships. MPNST cells were more sensitive to BI2536 and gemcitabine compared to a reference set of 94 cancer cell lines. PLK1, RRM1, and RRM2 mRNA levels were increased in MPNST compared to benign neurofibroma tissue, and the protein level of PLK1 was increased in the MPNST cell lines compared to normal Schwann cells, indicating an increased dependence on these drug targets in malignant cells. Furthermore, we observed an association between increased mRNA expression of PLK1, RRM1, and RRM2 in patient samples and worse disease outcome, suggesting a selective benefit from inhibition of these genes in the most aggressive tumors. PMID- 28556485 TI - Two-year functional and anatomical results after converting treatment resistant eyes with exudative age-related macular degeneration to aflibercept in accordance with a treat and extend protocol. AB - PURPOSE: To study the effects of converting to aflibercept in accordance with a treat and extend (T&E) strategy in eyes with treatment resistant exudative age related macular degeneration (AMD). METHODS: Two-year prospective study of eyes with exudative AMD and persistent macular fluid despite monthly treatment with ranibizumab or bevacizumab. Eyes were converted to 2.0 mg aflibercept in accordance with a T&E protocol. RESULTS: Fifty eyes from 47 patients were included. At baseline, the mean central retinal thickness (CRT) was 273 MUm and mean best-corrected visual acuity (BCVA) 0.25 logarithm of the minimal angle of resolution (logMAR). The mean number of aflibercept injections the first year was 9.2. After 1 year, there was a reduction in mean CRT to 228 MUm (p < 0.001); 22 eyes (44%) had a dry macula; and the mean BCVA was 0.24 logMAR (p = 0.531). The mean number of aflibercept injections the second year was 8.0 (p = 0.013 compared to first year). After 2 years, 24 eyes (48%) received treatment more frequently than every eighth week. The mean CRT was 225 MUm (p < 0.001 compared to baseline); 31 eyes (62%) had a dry macula; and mean BCVA was 0.32 logMAR (p = 0.005 compared to baseline). Five eyes did not complete 2 years of aflibercept treatment after failing to improve. CONCLUSION: A majority of eyes showed improved anatomic outcomes. There was a small decrease in mean BCVA after the second year of treatment. About half of the eyes required treatment more frequently than the recommended aflibercept label of an 8-week interval. PMID- 28556487 TI - Response to: Prophylactic Ureteric Stents in Renal Transplant Recipients: A Multicenter Randomized Controlled Trial of Early Versus Late Removal. PMID- 28556486 TI - Endoscopic video-assisted transoral resection of lateral oropharyngeal tumors. AB - Endoscopic, video-assisted transoral resection of oropharyngeal tumors is a novel technique carried out using common instruments present in most otolaryngology departments. The technique facilitates oropharyngeal resection akin to transoral robotic surgery (TORS) without the need for a robot. A dual surgeon approach, analogous to that of endoscopic skull base surgery is used. Each surgeon can actively participate in the resection with several key advantages over current techniques. The technique is applicable to departments internationally especially where the use of a robot is prohibited by cost or availability. This is especially important given the resection of oropharyngeal tumours offers the opportunity of single modality treatment or reduced intensity adjuvant treatment compared to traditional non-surgical therapy. PMID- 28556488 TI - Induction therapy with rabbit antithymocyte globulin versus basiliximab after kidney transplantation: a health economic analysis from a German perspective. AB - A health economic analysis was undertaken based on the 1-year database from a randomized study of rabbit anti-human thymocyte immunoglobulin (rATG) versus basiliximab, in kidney transplantation using resource utilization data and cost estimates from three German hospitals. A three-state Markov model was applied to estimate cost-effectiveness to 10 years post-transplant. Total mean treatment cost per patient to year 1 post-transplant was ?62 075 vs. ?59 767 for rATG versus basiliximab (P < 0.01). rATG therapy was associated with similar treatment costs to basiliximab by year 2, and a predicted cumulative treatment cost saving of ?4 259 under rATG versus basiliximab by year 10 post-transplant. The mean number of quality-adjusted life years (QALYs) per patient by year 1 was 0.809 vs. 0.802 in the rATG and basiliximab cohorts, respectively (P = 0.38), with cumulative QALYs of 6.161 and 6.065 per patient by year 10. By year 2, the cumulative cost per QALY was slightly lower under rATG (?35 378) than basiliximab (?35 885), progressing to a saving of ?1 041 under rATG for the cumulative cost per QALY by year 10. In conclusion, this model indicates that rATG induction provides a modest increase in QALYs with lower long-term costs than basiliximab in deceased-donor high-risk kidney transplant patients. PMID- 28556489 TI - Factors associated with risk of central nervous system relapse in patients with non-core binding factor acute myeloid leukemia. AB - Central nervous system (CNS) relapse is uncommon in patients with acute myeloid leukemia (AML) with the use of high-dose cytarabine containing chemotherapy regimens. The clinical and molecular features associated with a higher risk of CNS relapse are not well defined. We assessed the incidence and outcome of CNS relapses among 1245 patients with relapsed/refractory AML referred to our institution between 2000 and 2014. CNS leukemia relapse was observed in 51 patients (4.1%). Using a multivariate regression model and after adjusting for age, FLT3-ITD mutation (OR = 2.33; P = .02) and elevated LDH (>1000 IU/L, OR = 1.99; P = .04) were independent predictive factors for CNS relapse. Patients under 64 years of age with 0, 1, or 2 baseline adverse features had a probability of 3.8%, 7.0%-8.0%, and 13.9% for developing CNS disease, respectively. Our study identifies patients with AML at higher risk for CNS relapse in whom prophylactic CNS therapy may be warranted. PMID- 28556490 TI - Aptamer-functionalized Fe3 O4 magnetic nanoparticles as a solid-phase extraction adsorbent for the selective extraction of berberine from Cortex phellodendri. AB - The extraction adsorbent was fabricated by immobilizing the highly specific recognition and binding of aptamer onto the surface of Fe3 O4 magnetic nanoparticles, which not only acted as recognition elements to recognize and capture the target molecule berberine from the extract of Cortex phellodendri, but also could favor the rapid separation and purification of the bound berberine by using an external magnet. The developed solid-phase extraction method in this work was useful for the selective extraction and determination of berberine in Cortex phellodendri extracts. Various conditions such as the amount of aptamer functionalized Fe3 O4 magnetic nanoparticles, extraction time, temperature, pH value, Mg2+ concentration, elution time and solvent were optimized for the solid phase extraction of berberine. Under optimal conditions, the purity of berberine extracted from Cortex phellodendri was as high as 98.7% compared with that of 4.85% in the extract, indicating that aptamer-functionalized Fe3 O4 magnetic nanoparticles-based solid-phase extraction method was very effective for berberine enrichment and separation from a complex herb extract. The applicability and reliability of the developed solid-phase extraction method were demonstrated by separating berberine from nine different concentrations of one Cortex phellodendri extract. The relative recoveries of the spiked solutions of all the samples were between 95.4 and 111.3%, with relative standard deviations ranging between 0.57 and 1.85%. PMID- 28556491 TI - Frequency of submicroscopic chromosomal aberrations in pregnancies without increased risk for structural chromosomal aberrations: systematic review and meta analysis. AB - OBJECTIVE: To establish, based on a systematic literature review, the frequency of pathogenic submicroscopic chromosomal aberrations in fetuses that are not at increased risk for unbalanced structural chromosomal aberrations, with the aim of determining whether high-resolution testing for submicroscopic aberrations is beneficial in a general pregnant population. METHODS: EMBASE, PubMed, Web of Science and CENTRAL databases were searched systematically on 3 June 2016 for all relevant articles on the prevalence of pathogenic submicroscopic copy number variants (CNVs) in fetuses referred for prenatal invasive testing because of advanced maternal age (AMA) or parental anxiety (ANX). Relevant full-text articles were analyzed and the prevalence of submicroscopic CNVs was calculated based on the extracted data. Meta-analysis was conducted in a pooled cohort of 10 614 fetuses based on the 10 largest studies (n > 300) of a total of 19 that were relevant. RESULTS: Pooled estimate analysis indicated that 0.84% (95% CI, 0.55 1.30%) of fetuses that had invasive testing because of AMA/ANX carried a pathogenic clinically significant submicroscopic aberration. The onset/penetrance of submicroscopic findings was studied in 10 314 fetuses reported in eight papers that presented aberrant cases with all necessary details to allow assessment of the findings. The pooled estimates resulting from meta-analysis of the data indicated that an early-onset syndromic disorder was detected in 0.37% (95% CI, 0.27-0.52%) of cases, a susceptibility CNV was found in 0.30% (95% CI, 0.14 0.67%) and late-onset diseases were reported in 0.11% (95% CI, 0.05%-0.21%). The prevalence of early-onset syndromic disorders caused by a submicroscopic aberration was calculated to be 1:270. When the risk for submicroscopic aberrations is added to the individual risk for microscopic chromosomal aberrations, all pregnant women have a risk of higher than 1 in 180 for a relevant chromosomal aberration, and pregnant women under 36 years of age have a higher risk for submicroscopic pathogenic aberrations than for Down syndrome. CONCLUSION: This systematic review shows that a significant proportion of fetuses in a general pregnant population carry a submicroscopic pathogenic CNV. Based on these figures, all women should be informed on their individual risk for all pathogenic chromosomal aberrations and not only for common trisomies. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28556492 TI - New Insights Into the Alleged Kidney Donor Profile Index Labeling Effect on Kidney Utilization. AB - The Kidney Donor Profile Index (KDPI) became a driving factor in deceased donor kidney allocation on December 4, 2014, with the implementation of the kidney allocation system (KAS). On April 20, 2016, the annual recalibration of the Kidney Donor Risk Index into KDPI was incorrectly programmed in DonorNet, resulting in erroneously high KDPI values, by between 1 and 21 percentage points (e.g. actual KDPI of 70% was displayed as 86%). The error was corrected on May 19, 2016, <24 h after being recognized. During this 30-day period, the distribution of recipients largely resembled pre-KAS patterns. The observed discard rate of 22.9% was higher than the post-KAS average of 19.6% (odds ratio [OR]: 1.22) but far lower than the projected rate of 31.4% (OR: 1.96) based on the usual discard rate by KDPI relationship, suggesting clinicians and patients did not rely heavily on this single number (KDPI) in kidney-utilization decisions. Still, risk-adjusted analyses suggest the elevated discard rate was most likely attributable to the erroneously high KDPIs, not a shift in donor characteristics or random chance. The rise in discard rate was sharply higher for kidneys with inflated KDPI that crossed the 85% policy threshold (OR: 1.46; p = 0.049) versus those that did not (OR: 1.06; p = 0.631). PMID- 28556493 TI - Multi-scale responses to warming in an experimental insect metacommunity. AB - In metacommunities, diversity is the product of species interactions at the local scale and dispersal between habitat patches at the regional scale. Although warming can alter both species interactions and dispersal, the combined effects of warming on these two processes remains uncertain. To determine the independent and interactive effects of warming-induced changes to local species interactions and dispersal, we constructed experimental metacommunities consisting of enclosed milkweed patches seeded with five herbivorous milkweed specialist insect species. We treated metacommunities with two levels of warming (unwarmed and warmed) and three levels of connectivity (isolated, low connectivity, high connectivity). Based on metabolic theory, we predicted that if plant resources were limited, warming would accelerate resource drawdown, causing local insect declines and increasing both insect dispersal and the importance of connectivity to neighboring patches for insect persistence. Conversely, given abundant resources, warming could have positive local effects on insects, and the risk of traversing a corridor to reach a neighboring patch could outweigh the benefits of additional resources. We found support for the latter scenario. Neither resource drawdown nor the weak insect-insect associations in our system were affected by warming, and most insect species did better locally in warmed conditions and had dispersal responses that were unchanged or indirectly affected by warming. Dispersal across the matrix posed a species-specific risk that led to declines in two species in connected metacommunities. Combined, this scaled up to cause an interactive effect of warming and connectivity on diversity, with unwarmed metacommunities with low connectivity incurring the most rapid declines in diversity. Overall, this study demonstrates the importance of integrating the complex outcomes of species interactions and spatial structure in understanding community response to climate change. PMID- 28556495 TI - Assessment of fracture risk in proximal tibia with tumorous bone defects by a finite element method. AB - There has not been a satisfying method to predict the fracture risk in tumorous bone lesions. To tackle this challenge, we used a finite element method to assess the fracture risk in the proximal tibia (pT) when the size and location of the tumorous defects are varied in bone. Towards this end, the circular cortical defects, mimicking the tumorous lesions by forming cortical window defects, with a diameter (F) of 20, 30, 40, or 50 mm, are structured on the anteromedial, lateral, posterior wall of pT, which is located 5, 15, and 25 mm below articular margin, respectively. We found that under walking conditions, the Von Mises Stress of each defective tibia model was larger than that of the intact tibia model and also showed a positive linear correlation with the sizes of the defects. A notable fracture risk was not observed until the defect was F30 mm or larger. When the defect emerged, the anteromedial wall resisted fracture risk more than the rest of wall. Our results show that the size and location of the bone tumors are important factors affecting the fracture risk of pT. Our findings will be beneficial to clinicians when deciding what treatment to use for pT lesions. PMID- 28556494 TI - Familial association of abstinent remission from alcohol use disorder in first degree relatives of alcohol-dependent treatment-seeking probands. AB - BACKGROUND AND AIMS: Studies that have included family history of alcohol use disorder (AUD) as a predictor of remission from AUD have yielded few significant results. The goals of this study were to estimate the association of persistent AUD, non-abstinent remission and abstinent remission ('AUD/remission status') in a proband with AUD/remission status in a relative and to test whether this association differed in related and unrelated proband-relative pairs. DESIGN: High-risk family study of alcohol dependence. Probands were recruited from treatment settings and relatives were invited to participate. Baseline assessments occurred between 1991 and 1998 with follow-up between 1996 and 2005. Half of probands were matched with a biological 1st-degree relative with life time AUD (related group) and half of probands were paired with an unrelated individual with life-time AUD (unrelated group). SETTING: Brooklyn, New York; Indianapolis, Indiana; Iowa City, Iowa; San Diego, California; Farmington, Connecticut; and St Louis, Missouri, USA. PARTICIPANTS: A total of 606 probands (25.7% female, mean age 37.7) with baseline and follow-up data and 606 of their 1st-degree relatives who had life-ime AUDs (45.8% female, mean age 36.2 years). MEASUREMENTS: Persistent AUD, non-abstinent remission and abstinent remission were based on self-report interview data on most recent AUD symptoms and alcohol consumption. Dependent variable was relatives' AUD/remission status. Independent variable was probands' AUD/remission status. FINDINGS: A total of 34.6% of probands and 20.6% of relatives were abstinent and 11.1% of probands and 22.8% of relatives were in non-abstinent remission. AUD/remission status was correlated significantly in related (r = 0.23, P = 0.0037) but not in unrelated pairs. A significant interaction of probands' abstinent remission with a variable representing related (versus unrelated, P = 0.003) pairs suggested a familial association for abstinent remission. In related pairs, individuals with an abstinent proband were more likely to be abstinent themselves than were individuals whose proband had persistent AUD [relative risk ratio = 3.27, 95% confidence interval (CI) = 1.56-6.85, P = 0.002]; this association was not significant in unrelated pairs. CONCLUSIONS: The likelihood of abstinent remission among people with alcohol use disorder appears to be more than three times greater for individuals who are related to an abstinent proband versus those related to a proband with persistent alcohol use disorder. PMID- 28556496 TI - Prevalence rates of borderline symptoms reported by adolescent inpatients with BPD, psychiatrically healthy adolescents and adult inpatients with BPD. AB - OBJECTIVE: The validity of borderline personality disorder (BPD) in children and adolescents has not been studied in a rigorous manner reflecting the criteria of Robins and Guze first detailed in 1970. This paper and the others in this series address some aspects of this multifaceted validation paradigm, which requires that a disorder has a known clinical presentation, can be delimited from other disorders, 'runs' in families, and something of its aetiology, treatment response and course is known. METHODS: Three groups of subjects were studied: 104 adolescent inpatients meeting the Revised Diagnostic Interview for Borderlines and DSM-IV criteria for BPD, 60 psychiatrically healthy adolescents and 290 adult inpatients meeting the Revised Diagnostic Interview for Borderlines and DSM-III-R criteria for BPD. RESULTS: Adolescents with BPD had significantly higher prevalence rates of 22 of the 24 symptoms studied than psychiatrically healthy adolescents. Only rates of serious treatment regressions and countertransference problems failed to reach the Bonferroni-corrected level of 0.002. Adolescents and adults with BPD had only four symptomatic differences that reached this level of significance, with adolescents with BPD reporting significantly lower levels of quasi-psychotic thought, dependency/masochism, devaluation/manipulation/sadism and countertransference problems than adults with BPD. CONCLUSIONS: Taken together, the results of this study suggest that adolescents report BPD as severe as that reported by adults. They also suggest that BPD in adolescents is not a tumultuous phase of normal adolescence. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28556497 TI - A genome-wide quantitative trait locus (QTL) linkage scan of NEO personality factors in Latino families segregating bipolar disorder. AB - Personality traits have been suggested as potential endophenotypes for Bipolar Disorder (BP), as they can be quantitatively measured and show correlations with BP. The present study utilized data from 2,745 individuals from 686 extended pedigrees originally ascertained for having multiplex cases of BP (963 cases of BPI or schizoaffective BP). Subjects were assessed with the NEO Personality Inventory, Revised (NEO PI-R) and genotyped using the Illumina HumanLinkage-24 Bead Chip, with an average genetic coverage of 0.67 cM. Two point linkage scores were calculated for each trait as a quantitative variable using SOLAR (Sequential Oligogenic Linkage Analysis Routines). Suggestive evidence for linkage was found for neuroticism at 1q32.1 (LOD = 2.52), 6q23.3 (2.32), 16p12 (2.79), extraversion at 4p15.3 (2.33), agreeableness at 4q31.1 (2.37), 5q34 (2.80), 7q31.1 (2.56), 16q22 (2.52), and conscientiousness at 4q31.1 (2.50). Each of the above traits have been shown to be correlated with the broad BP phenotype in this same sample. In addition, for the trait of openness, we found significant evidence of linkage to chromosome 3p24.3 (rs336610, LOD = 4.75) and suggestive evidence at 1q43 (2.74), 5q35.1 (3.03), 11q14.3 (2.61), 11q21 (2.30), and 19q13.1 (2.52). These findings support previous linkage findings of the openness trait to chromosome 19q13 and the agreeableness trait to 4q31 and identify a number of new loci for personality endophenotypes related to bipolar disorder. PMID- 28556499 TI - The 2015 US Food and Drug Administration Pregnancy and Lactation Labeling Rule. AB - As of 2015, the US Food and Drug Administration (FDA) discontinued the pregnancy risk categories (ABCDX) that had been used to denote the putative safety of drugs for use among pregnant women. The ABCDX system has been replaced by the FDA Pregnancy and Lactation Labeling Rule (PLLR) that requires narrative text to describe risk information, clinical considerations, and background data for the drug. The new rule includes 3 overarching categories: 1) pregnancy, which includes labor and birth; 2) lactation; and 3) females and males of reproductive potential. This article reviews the key components of the PLLR and clinical implications, and provides resources for clinicians who prescribe drugs for women of reproductive age. PMID- 28556500 TI - Evaluation of sleep quality in patients with ankylosing spondylitis and efficacy of anti-TNF-alpha therapy on sleep problems: A polisomnographic study. AB - INTRODUCTION: This study was conducted to investigate the relationship between sleep quality (SQ) and disease activity (DA) in patients with ankylosing spondylitis (AS) and to evaluate the response to anti-tumor necrosis factor alpha (anti-TNF-alpha) therapy on sleep disorders. MATERIALS AND METHODS: A total of 34 patients who met the modified New York classification criteria for AS were included in this prospective study. Patients were divided into two groups as follows: Group I (n = 15) with high DA and receiving anti-TNF-alpha therapy, and Group II (n = 19) in remission. DA was assessed by the Bath AS Disease Activity Index. Pittsburgh Sleep Quality Index (PSQI) and polysomnography (PSG) were used to determine disorders and patterns of sleep, respectively, in both groups at baseline as well as at the third month of anti-TNF-alpha therapy in Group I. RESULTS: Baseline evaluation revealed impaired SQ in 57.9% of all patients. PSG demonstrated obstructive sleep apnea syndrome, snoring and periodic leg movements in 73.7%, 74.4% and 26.3% of patients, respectively. Prior to anti-TNF-alpha therapy, PSQI and snoring score were significantly higher in Group I (P = 0.0001, P = 0.012, respectively). Although there was a significant reduction in PSQI scores in Group I (P = 0.005) at the third month of anti-TNF-alpha therapy, no change was observed in PSG parameters (P > 0.05). CONCLUSION: Sleep disorders increase in AS, particularly in patients with high DA. Anti-TNF-alpha therapy has improved SQ without any improvement in PSG. Therefore, it may be concluded that PSG parameters might be more associated with disease pathogenesis rather than DA in patients with AS. PMID- 28556498 TI - Sodium intake and multiple sclerosis activity and progression in BENEFIT. AB - OBJECTIVE: To assess whether a high-salt diet, as measured by urinary sodium concentration, is associated with faster conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and MS activity and disability. METHODS: BENEFIT was a randomized clinical trial comparing early versus delayed interferon beta-1b treatment in 465 patients with a CIS. Each patient provided a median of 14 (interquartile range = 13-16) spot urine samples throughout the 5 year follow-up. We estimated 24-hour urine sodium excretion level at each time point using the Tanaka equations, and assessed whether sodium levels estimated from the cumulative average of the repeated measures were associated with clinical (conversion to MS, Expanded Disability Status Scale [EDSS]) and magnetic resonance imaging (MRI) outcomes. RESULTS: Average 24-hour urine sodium levels were not associated with conversion to clinically definite MS over the 5-year follow-up (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.67-1.24 per 1g increase in estimated daily sodium intake), nor were they associated with clinical or MRI outcomes (new active lesions after 6 months: HR = 1.05, 95% CI = 0.97-1.13; relative change in T2 lesion volume: -0.11, 95% CI = -0.25 to 0.04; change in EDSS: -0.01, 95% CI = -0.09 to 0.08; relapse rate: HR = 0.78, 95% CI = 0.56-1.07). Results were similar in categorical analyses using quintiles. INTERPRETATION: Our results, based on multiple assessments of urine sodium excretion over 5 years and standardized clinical and MRI follow-up, suggest that salt intake does not influence MS disease course or activity. Ann Neurol 2017;82:20-29. PMID- 28556502 TI - Household coverage of Swaziland's national community health worker programme: a cross-sectional population-based study. AB - OBJECTIVES: To ascertain household coverage achieved by Swaziland's national community health worker (CHW) programme and differences in household coverage across clients' sociodemographic characteristics. METHODS: Household survey from June to September 2015 in two of Swaziland's four administrative regions using two-stage cluster random sampling. Interviewers administered a questionnaire to all household members in 1542 households across 85 census enumeration areas. RESULTS: While the CHW programme aims to cover all households in the country, only 44.5% (95% confidence interval: 38.0% to 51.1%) reported that they had ever been visited by a CHW. In both uni- and multivariable regressions, coverage was negatively associated with household wealth (OR for most vs. least wealthy quartile: 0.30 [0.16 to 0.58], P < 0.001) and education (OR for >secondary schooling vs. no schooling: 0.65 [0.47 to 0.90], P = 0.009), and positively associated with residing in a rural area (OR: 2.95 [1.77 to 4.91], P < 0.001). Coverage varied widely between census enumeration areas. CONCLUSIONS: Swaziland's national CHW programme is falling far short of its coverage goal. To improve coverage, the programme would likely need to recruit additional CHWs and/or assign more households to each CHW. Alternatively, changing the programme's ambitious coverage goal to visiting only certain types of households would likely reduce existing arbitrary differences in coverage between households and communities. This study highlights the need to evaluate and reform large long standing CHW programmes in sub-Saharan Africa. PMID- 28556503 TI - Occurrence and human exposure assessment of organophosphate flame retardants in indoor dust from various microenvironments of the Rhine/Main region, Germany. AB - We analyzed organophosphate flame retardants (OPFRs) in 74 indoor dust samples collected from seven microenvironments (building material markets, private cars, daycare centers, private homes, floor/carpet stores, offices, and schools) in the Rhine/Main region of Germany. Ten of 11 target OPFRs were ubiquitously detected, some with more than 97% detection frequency, including tris(1,3 dichloroisopropyl)phosphate (TCIPP), tris(2-butoxyethyl)phosphate (TBOEP), triphenyl phosphate (TPHP), and tris(isobutyl) phosphate (TIBP). Total concentrations (?OPFRs) ranged from 5.9 to 4800 MUg/g, with TBOEP and TCIPP being the most abundant congeners. The ?OPFRs in schools, private cars, offices, and daycare centers were significantly (P<.05) higher than in private homes. The ?OPFRs for building material markets (19 MUg/g) and floor/carpet stores (20 MUg/g) showed no significant difference to the other microenvironments, likely because of forced ventilation. The profiles of OPFRs in dust samples from offices and private homes were highly similar, while profiles from the other five microenvironments were substantially different. Comparison of our results with previous studies indicates a significant global variation in OPFR concentrations and their profiles, reflecting distinct fire safety regulations in different countries and/or different sampling strategies. Dust ingestion constitutes the major exposure pathway to OPFRs for toddlers, while air inhalation is the major pathway for adults. PMID- 28556501 TI - A three-gene signature from protein-protein interaction network of LOXL2- and actin-related proteins for esophageal squamous cell carcinoma prognosis. AB - Current staging is inadequate for predicting clinical outcome of esophageal squamous cell carcinoma (ESCC). Aberrant expression of LOXL2 and actin-related proteins plays important roles in ESCC. Here, we aimed to develop a novel molecular signature that exceeds the power of the current staging system in predicting ESCC prognosis. We found that LOXL2 colocalized with filamentous actin in ESCC cells, and gene set enrichment analysis (GSEA) showed that LOXL2 is related to the actin cytoskeleton. An ESCC-specific protein-protein interaction (PPI) network involving LOXL2 and actin-related proteins was generated based on genome-wide RNA-seq in 15 paired ESCC samples, and the prognostic significance of 14 core genes was analyzed. Using risk score calculation, a three-gene signature comprising LOXL2, CDH1, and FN1 was derived from transcriptome data of patients with ESCC. The high-risk three-gene signature strongly correlated with poor prognosis in a training cohort of 60 patients (P = 0.003). In mRNA and protein levels, the prognostic values of this signature were further validated in 243 patients from a testing cohort (P = 0.001) and two validation cohorts (P = 0.021, P = 0.007). Furthermore, Cox regression analysis revealed that the signature was an independent prognostic factor. Compared with using the signature or TNM stage alone, the combined model significantly enhanced the accuracy in evaluating ESCC prognosis. In conclusion, our data reveal that the tumor-promoting role of LOXL2 in ESCC is mediated by perturbing the architecture of actin cytoskeleton through its PPIs. We generated a novel three-gene signature (PPI interfaces) that robustly predicts poor clinical outcome in ESCC patients. PMID- 28556504 TI - Effects of conjugated linoleic acid supplementation on serum C-reactive protein: A systematic review and meta-analysis of randomized controlled trials. AB - AIM: To undertake a systematic review and meta-analysis of prospective studies to determine the effect of conjugated linoleic acids (CLAs) supplementation on serum C-reactive protein (CRP). METHOD: PubMed-Medline, Web of Science, Cochrane Database, and Google Scholar databases were searched (up until May 2016) to identify prospective studies evaluating the impact of CLAs supplementation on serum CRP. Random-effects models meta-analysis was used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. Heterogeneity was quantitatively assessed using the I2 index. Systematic review registration: CRD42016038945. RESULTS: From a total of 85 entries identified via searches, 14 studies were included in the final selection. The meta-analysis indicated a significant increase in serum CRP concentrations following supplementation with CLAs (weighted mean difference [WMD] 0.63 mg/dL, 95% confidence interval [95% CI] 0.13-1.13, N=21 arms, heterogeneity P=.026; I2 =52.3%). These findings were robust in sensitivity analyses. Random-effects meta regression revealed that changes in serum CRP levels were independent of the dosage of CLAs supplementation (slope: -0.02; 95% CI: -0.10, 0.12; P=.889) or duration of follow-up (slope: 0.271; 95% CI: -0.05, 0.59; P=.098). CONCLUSIONS: This meta-analysis suggests that CLA supplementation is associated with an increase in plasma CRP concentrations and a reduction in serum adiponectin concentrations, which indicates that CLA supplements have a proinflammatory effect. Randomized control trials with larger sample size and a longer follow-up period may be required for future investigations to provide an unequivocal answer. PMID- 28556505 TI - Restoring Maximum Vertical Browsing Reach in Sauropod Dinosaurs. AB - The ongoing controversy centered on neck posture and function in sauropod dinosaurs is misplaced for a number of reasons. Because of an absence of pertinent data it is not possible to accurately restore the posture and range of motion in long necked fossil animals, only gross approximations are possible. The existence of a single "neutral posture" in animals with long, slender necks may not exist, and its relationship to feeding habits is weak. Restorations of neutral osteological neck posture based on seemingly detailed diagrams of cervical articulations are not reliable because the pictures are not sufficiently accurate due to a combination of illustration errors, and distortion of the fossil cervicals. This is all the more true because fossil cervical series lack the critical inter-centra cartilage. Maximum vertical reach is more readily restorable and biologically informative for long necked herbivores. Modest extension of 10 degrees between each caudal cervical allowed high shouldered sauropods to raise the cranial portion of their necks to vertical postures that allowed them to reach floral resources far higher than seen in the tallest mammals. This hypothesis is supported by the dorsally extended articulation of the only known co-fused sauropod cervicals. Many sauropods appear to have been well adapted for rearing in order to boost vertical reach, some possessed retroverted pelves that may have allowed them to walk slowly while bipedal. A combination of improved high browsing abilities and sexual selection probably explains the unusually long necks of tall ungulates and super tall sauropods. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 300:1802-1825, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28556507 TI - Modified headspace solid-phase microextraction for the determination of quantitative relationships between components of mixtures consisting of alcohols, esters, and ethers - impact of the vapor pressure difference of the compounds. AB - The quantitative relationship between analytes established by the headspace solid phase microextraction procedure for multicomponent mixtures depends not only on the character and strength of interactions of individual components with solid phase microextraction fiber but also on their vapor pressure in the applied headspace solid-phase microextraction system. This study proves that vapor pressure is of minor importance when the sample is dissolved/suspended in a low volatility liquid of the same physicochemical character as that of the used solid phase microextraction fiber coating. It is demonstrated for mixtures of alcohols, esters, ethers and their selected representatives by applying a headspace solid phase microextraction system composed of Carbowax fiber and sample solutions in polyethyleneglycol. The observed differences in quantitative relations between components of the examined mixtures established by their direct analysis and by modified headspace solid-phase microextraction are insignificant (Fexp < Fcrit ). It is explained by a significant diminution in vapor pressure difference between individual components of the examined mixture in the applied headspace solid phase microextraction system due to low components concentration in polyethyleneglycol suspensions (Raoult's law) and due to strong specific interactions of analyte molecules with polyethyleneglycol molecules. PMID- 28556506 TI - Dissociated Agonist of Glucocorticoid Receptor or Prednisone for Active Rheumatoid Arthritis: Effects on P1NP and Osteocalcin Pharmacodynamics. AB - Fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, has potent anti-inflammatory activity in patients with rheumatoid arthritis with reduced adverse effects on bone health. To identify fosdagrocorat doses with bone formation marker changes similar to prednisone 5 mg, we characterized treatment-related changes in amino-terminal propeptide of type I collagen (P1NP) and osteocalcin (OC) with fosdagrocorat (1, 5, 10, or 15 mg) and prednisone (5 or 10 mg) in a phase II randomized trial (N = 323). The time course of markers utilized a mixed-effects longitudinal kinetic-pharmacodynamic model. Median predicted changes from baseline at week 8 with fosdagrocorat 5, 10, and 15 mg were -18, -22, and -22% (P1NP), and -7, -13, and -17% (OC), respectively. Changes with prednisone 5 and 10 mg were -15% and -18% (P1NP) and -10% and -17% (OC). The probability of fosdagrocorat doses up to 15 mg being noninferior to prednisone 5 mg for P1NP and OC changes was >90%. PMID- 28556508 TI - Hassall's corpuscles in the fine-needle aspiration cytology of pediatric ectopic thymic tissue. PMID- 28556509 TI - Regulating the for-profit private healthcare providers towards universal health coverage: A qualitative study of legal and organizational framework in Mongolia. AB - BACKGROUND: Regulating the behavior of private providers in the context of mixed health systems has become increasingly important and challenging in many developing countries moving towards universal health coverage including Mongolia. This study examines the current regulatory architecture for private healthcare in Mongolia exploring its role for improving accessibility, affordability, and quality of private care and identifies gaps in policy design and implementation. METHODS: Qualitative research methods were used including documentary review, analysis, and in-depth interviews with 45 representatives of key actors involved in and affected by regulations in Mongolia's mixed health system, along with long term participant observation. RESULTS: There has been extensive legal documentation developed regulating private healthcare, with specific organizations assigned to conduct health regulations and inspections. However, the regulatory architecture for healthcare in Mongolia is not optimally designed to improve affordability and quality of private care. This is not limited only to private care: important regulatory functions targeted to quality of care do not exist at the national level. The imprecise content and details of regulations in laws inviting increased political interference, governance issues, unclear roles, and responsibilities of different government regulatory bodies have contributed to failures in implementation of existing regulations. PMID- 28556510 TI - Vasa previa: easy to miss. PMID- 28556511 TI - Host-specific effects of soil microbial filtrates prevail over those of arbuscular mycorrhizae in a fragmented landscape. AB - Plant-soil interactions have been shown to determine plant community composition in a wide range of environments. However, how plants distinctly interact with beneficial and detrimental organisms across mosaic landscapes containing fragmented habitats is still poorly understood. We experimentally tested feedback responses between plants and soil microbial communities from adjacent habitats across a disturbance gradient within a human-modified tropical montane landscape. In a greenhouse experiment, two components of soil microbial communities were amplified; arbuscular mycorrhizal fungi (AMF) and a filtrate excluding AMF spores from the soils of pastures (high disturbance), coffee plantations (intermediate disturbance), and forest fragments (low disturbance), using potted seedlings of 11 plant species common in these habitats (pasture grass, coffee, and nine native species). We then examined their effects on growth of these same 11 host species with reciprocal habitat inoculation. Most plant species received a similar benefit from AMF, but differed in their response to the filtrates from the three habitats. Soil filtrate from pastures had a net negative effect on plant growth, while filtrates from coffee plantations and forests had a net positive effect on plant growth. Pasture grass, coffee, and five pioneer tree species performed better with the filtrate from "away" (where these species rarely occur) compared to "home" (where these species typically occur) habitat soils, while four shade tolerant tree species grew similarly with filtrates from different habitats. These results suggest that pastures accumulate species-specific soil enemies, while coffee plantations and forests accumulate beneficial soil microbes that benefit pioneer native plants and coffee, respectively. Thus, compared to AMF, soil filtrates exerted stronger habitat and host-specific effects on plants, being more important mediators of plant-soil feedbacks across contrasting habitats. PMID- 28556512 TI - Comparison of circumferential peripheral angle closure using iridotrabecular contact index after laser iridotomy versus combined laser iridotomy and iridoplasty. AB - PURPOSE: To compare the quantitative changes of peripheral angle after laser iridotomy (LI) alone (group A) or combined LI and Iridoplasty (group B) using iridotrabecular contact (ITC) index by swept-source anterior segment optical coherence tomography (AS-OCT). METHODS: In this prospective comparative observational study, OCT images were obtained before and after the procedure. In each image frame, scleral spur (SS) and the ITC end point (EP) were marked and ITC index was calculated as a percentage of the angle closure from 360 degrees . Age, gender, diagnosis and initial ITC index in Group B were matched with group A. Changes in ITC index, anterior chamber angle parameters, and intraocular pressure (IOP) were inspected. RESULTS: Thirty-three eyes (20 patients) with shallow anterior chamber were included in each group. Initial ITC index and initial IOP were not significantly different between the two groups (both p > 0.05). However, ITC index and IOP after the procedure were significantly lower in group B than those in group A (ITC index: 31.3 +/- 23.2 in group A, 19.0 +/- 21.3 in group B, p = 0.011, IOP: p = 0.004). All anterior chamber angle parameters in group B and all parameters in group A except nasal trabecular-iris angles (TIA) were significantly increased after the laser procedure (all p < 0.05). CONCLUSION: In patients with shallow anterior chamber, combined LI and Iridoplasty may open the peripheral angle better than LI alone. Iridoplasty may be able to additionally relieve the peripheral angle closure caused by other mechanisms than pupillary block. PMID- 28556513 TI - Ionic-liquid-functionalized zinc oxide nanoparticles for the solid-phase extraction of triazine herbicides in corn prior to high-performance liquid chromatography analysis. AB - Zinc oxide nanoparticles have recently been used as effective adsorbent materials for sample pretreatment in analytical chemistry because of their excellent properties, such as high specific surface area, high effective porosity, non toxicity, and ease of fabrication. In this study, the zinc oxide nanoparticles functionalized by an ionic liquid, 1-carboxyethyl-3-methylimidazolium chloride, were fabricated and used as the adsorbent for the solid phase extraction of five triazine herbicides in corn for the first time. High-performance liquid chromatography was employed for the determination of these triazine herbicides. Several experimental parameters affecting the extraction efficiency were investigated, including the volume of extraction solvent, the extraction time, the type of extraction solvent and elution solvent, the amount of absorbent, and the volume of elution solvent. By using the proposed method, low limits of detection and quantification for all the five triazine herbicides were obtained between 0.71-1.08 and 2.67-3.64 ng/g, respectively. Recoveries of the proposed method range from 89.05 to 100.33% with intra- and inter-day relative standard deviations lower than 8.45%. The calibration curves are linear in the concentration range of 0.005-1.00 MUg/g with the correlation coefficient higher than 0.9954. PMID- 28556514 TI - Psi Multiple eccrine spiradenomas with a zosteriform pattern-Report of a rare case diagnosed on fine needle aspiration cytology. PMID- 28556515 TI - Musculoskeletal structure and function in response to the combined effect of an obesogenic diet and age in male C57BL/6J mice. AB - SCOPE: The effects of a long-term high fat and sucrose diet (HFS) superimposed with aging on bone and muscle structure and/or function. METHODS AND RESULTS: Male C57BL/6J mice (20 weeks of age) were randomized to 1 of 3 groups: baseline (BSL, n = 12), or assigned to a control (AGE, n = 12) or HFS (HFS-AGE, n = 11) diet for 13 weeks. Trabecular bone structure, volumetric bone mineral density (vBMD), and body composition, were measured longitudinally at 20, 24, and 32 weeks of age. In vitro contractile measures were performed on isolated soleus and extensor digitorum longus (EDL) muscles for each group. Both AGE and HFS-AGE had similar declines in trabecular bone structure, while HFS-AGE resulted in increased soleus cross-sectional area (CSA) compared to AGE, but this did not translate to greater twitch or tetanic peak force. The ratio of outcomes of bone to muscle declined in both AGE and HFS-AGE compared to BSL as a result of greater declines in trabecular bone structure than muscle function. CONCLUSION: Consumption of a 13-week HFS diet at 20 weeks of age did not exacerbate age related declines in bone or muscle, but these tissues do not decline in a coordinate manner with greater declines in bone than muscle. PMID- 28556517 TI - Improving the production, activity, and stability of CLEAs with diepoxides. AB - Among enzyme immobilization techniques, the preparation of cross-linked enzyme aggregates has shown promising results in biocatalysis, because they are easy to prepare, versatile, and cheap. The method involves the precipitation of enzymes with ammonium sulfate or an organic solvent and subsequent cross-linking with glutaraldehyde. However, the Schiff base produced with glutaraldehyde is reversible and can be broken with acids or bases, releasing proteins to the reaction medium. To solve this problem, we propose replacing glutaraldehyde with diepoxide compounds to obtain an irreversible secondary amine bond. Such a substitution avoids protein leakage during the biocatalytic process, contamination of the final products, and loss of enzyme. It also improves the synthesis of the biocatalyst, because, while the Schiff base is favored at mildly acidic pH, the epoxide reaction can be made at the optimal enzyme pH, assuring its structural stability and catalytic performance. The proposed method has been successfully used in the production and optimization of aldolase epoxy-cross linked aggregates, which retain 98% activity. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1425-1429, 2017. PMID- 28556518 TI - Low glycated hemoglobin level is associated with severity of frailty in Japanese elderly diabetes patients. AB - AIMS/INTRODUCTION: Previously, a study using a narrowly defined (physical base) frailty scale reported that both good and bad (U-shaped curve) glycated hemoglobin (HbA1c) levels were frailty risk factors in patients with type 2 diabetes mellitus. However, no such studies in Japan have shown this. We aimed to evaluate the frailty risk factors including HbA1c in elderly Japanese patients with type 2 diabetes mellitus using a broadly defined (both physical and psychosocial base) frailty scale, the Clinical Frailty Scale (CFS). MATERIALS AND METHODS: We randomly enrolled 132 elderly patients with type 2 diabetes mellitus (aged >=65 years) and categorized the patients into nine stages of frailty using CFS. Because no patient had CFS 9, patients with a CFS score of 1-4 and 5-8 were defined as non-frail and frail, respectively. We attempted to identify the risk factors of frailty by investigating the association between CFS stage and various patient factors. RESULTS: Multiple regression analysis showed that an increase in age, low levels of albumin, high-density lipoprotein cholesterol, systolic blood pressure, HbA1c, total cholesterol, and bodyweight were statistically significant and strong independent risk factors for frailty, suggesting that reverse metabolism owing to malnutrition in elderly type 2 diabetes mellitus patients might be involved. CONCLUSIONS: HbA1c level was not a U-shaped risk for frailty, suggesting that relatively good glycemic control might be more important for frailty than poor control in elderly type 2 diabetes mellitus patients. PMID- 28556520 TI - Mechanism-Driven Approach To Develop a Mild and Versatile C-H Amidation through IrIII Catalysis. AB - Described herein is a mechanism-based approach to develop a versatile C-H amidation protocol under IrIII catalysis. Reaction kinetics of a key C-N coupling step with acyl azide and 1,4,2-dioxazol-5-one led us to conclude that dioxazolones are much more efficient in mediating the formation of a carbon nitrogen bond from an iridacyclic intermediate. Computational analysis revealed that the origin of higher reactivity is asynchronous decarboxylation motion, which may facilitate the formation of Ir-imido species. Importantly, stoichiometric reactivity was successfully translated into catalytic activity with a broad range of substrates (18 different types), many of which are regarded as challenging to functionalize. Application of the new method enables late-stage functionalization of drug molecules. PMID- 28556516 TI - EMT- and MET-related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities. AB - The epithelial-to mesenchymal (EMT) process is increasingly recognized for playing a key role in the progression, dissemination, and therapy resistance of epithelial tumors. Accumulating evidence suggests that EMT inducers also lead to a gain in mesenchymal properties and promote malignancy of nonepithelial tumors. In this review, we present and discuss current findings, illustrating the importance of EMT inducers in tumors originating from nonepithelial/mesenchymal tissues, including brain tumors, hematopoietic malignancies, and sarcomas. Among these tumors, the involvement of mesenchymal transition has been most extensively investigated in glioblastoma, providing proof for cell autonomous and microenvironment-derived stimuli that provoke EMT-like processes that regulate stem cell, invasive, and immunogenic properties as well as therapy resistance. The involvement of prominent EMT transcription factor families, such as TWIST, SNAI, and ZEB, in promoting therapy resistance and tumor aggressiveness has also been reported in lymphomas, leukemias, and sarcomas. A reverse process, resembling mesenchymal-to-epithelial transition (MET), seems particularly relevant for sarcomas, where (partial) epithelial differentiation is linked to less aggressive tumors and a better patient prognosis. Overall, a hybrid model in which more stable epithelial and mesenchymal intermediates exist likely extends to the biology of tumors originating from sources other than the epithelium. Deeper investigation and understanding of the EMT/MET machinery in nonepithelial tumors will shed light on the pathogenesis of these tumors, potentially paving the way toward the identification of clinically relevant biomarkers for prognosis and future therapeutic targets. PMID- 28556519 TI - Lessons Learned: Early Termination of a Randomized Trial of Calcineurin Inhibitor and Corticosteroid Avoidance Using Belatacept. AB - The intent of this National Institutes of Health-sponsored study was to compare a belatacept-based immunosuppressive regimen with a maintenance regimen of tacrolimus and mycophenolate. Nineteen primary, Epstein-Barr virus-immune renal transplant recipients with a negative cross-match were randomized to one of three groups. All patient groups received perioperative steroids and maintenance mycophenolate mofetil. Patients in groups 1 and 2 were induced with alemtuzumab and maintained on tacrolimus or belatacept, respectively. Patients in group 3 were induced with basiliximab, received 3 mo of tacrolimus, and maintained on belatacept. There was one death with a functioning allograft due to endocarditis (group 1). There were three graft losses due to vascular thrombosis (all group 2) and one graft loss due to glomerular disease (group 1). Biopsy-proven acute cellular rejection was more frequent in the belatacept-treated groups, with 10 treated episodes in seven participants compared with one episode in group 1; however, estimated GFR was similar between groups at week 52. There were no episodes of posttransplant lymphoproliferative disorder or opportunistic infections in any group. Protocol enrollment was halted prematurely because of a high rate of serious adverse events. Such negative outcomes pose challenges to clinical investigators, who ultimately must weigh the risks and benefits in randomized trials. PMID- 28556521 TI - The need to implement the landscape of fear within rodent pest management strategies. AB - Current reactive pest management methods have serious drawbacks such as the heavy reliance on chemicals, emerging genetic rodenticide resistance and high secondary exposure risks. Rodent control needs to be based on pest species ecology and ethology to facilitate the development of ecologically based rodent management (EBRM). An important aspect of EBRM is a strong understanding of rodent pest species ecology, behaviour and spatiotemporal factors. Gaining insight into the behaviour of pest species is a key aspect of EBRM. The landscape of fear (LOF) is a mapping of the spatial variation in the foraging cost arising from the risk of predation, and reflects the levels of fear a prey species perceives at different locations within its home range. In practice, the LOF maps habitat use as a result of perceived fear, which shows where bait or traps are most likely to be encountered and used by rodents. Several studies have linked perceived predation risk of foraging animals with quitting-harvest rates or giving-up densities (GUDs). GUDs have been used to reflect foraging behaviour strategies of predator avoidance, but to our knowledge very few papers have directly used GUDs in relation to pest management strategies. An opportunity for rodent control strategies lies in the integration of the LOF of rodents in EBRM methodologies. Rodent management could be more efficient and effective by concentrating on those areas where rodents perceive the least levels of predation risk. (c) 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 28556523 TI - Cytomegalovirus-Induced Polyarteritis Nodosa in a Liver Transplant Recipient. AB - Polyarteritis nodosa (PAN) is a necrotizing vasculitis that has been associated with viral infections, especially hepatitis B virus. We hereby report a case of tissue-invasive cytomegalovirus (CMV)-induced PAN in a liver transplant recipient presenting with acute kidney injury and active urinary sediment. Treatment directed against both PAN and CMV resulted in improvement in kidney function, normalization of urinary indices and resolution of the CMV infection. There was no recurrence of either PAN or CMV after a 3-year follow-up period. PMID- 28556522 TI - Prevalence rates of childhood protective factors in adolescents with BPD, psychiatrically healthy adolescents and adults with BPD. AB - OBJECTIVE: Existing literature on the aetiology of borderline personality disorder (BPD) has primarily focused on pathological childhood experiences, while little to no research has been conducted on protective factors that may serve to ameliorate these symptoms. The current study attempts to fill this gap in the literature by comparing the rates of childhood protective factors among adolescents with BPD, psychiatrically healthy adolescents and adults with BPD. METHODS: One hundred and four subjects were adolescent inpatients between the ages of 13 and 17 who met Revised Diagnostic Interview for Borderlines and Diagnostic and Statistical Manual of Mental Disorders Fourth Edition criteria for BPD. Sixty were age-matched psychiatrically healthy comparison subjects. Two hundred and ninety subjects were adult inpatients between the ages of 18 and 35 who met Revised Diagnostic Interview for Borderlines and Revised Diagnostic and Statistical Manual of Mental Disorders Third Edition criteria for BPD. All three groups were interviewed by using the Revised Childhood Experiences Questionnaire, a semi-structured interview that assesses pathological and protective childhood experiences. RESULTS: Psychiatrically healthy adolescents reported significantly higher rates of 4 out of 18 protective factors than adolescents with BPD. Adolescents with BPD reported significantly higher rates of 5 of these 18 protective factors than adults with BPD. Adults with BPD were significantly more likely to endorse having a steady after school or weekend work record than adolescents with BPD. CONCLUSIONS: Taken together, the results of this study suggest that adolescents meeting criteria for BPD report lower rates of some protective factors than psychiatrically healthy adolescents. They also suggest that they have higher rates of some protective factors than adults with BPD. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28556524 TI - Effects of comorbidity and medication use on the haemodynamic status during office-based laryngeal procedures: A prospective cohort study. AB - OBJECTIVE: Office-based laryngeal procedures (OBLPs) are emerging as effective alternative modalities for vocal disorders. This study systematically investigates the haemodynamic status of patients, specifically focusing on the potential effects of underlying comorbidity and medication use. DESIGN: Prospective cohort study. SETTING: Tertiary referral centre. PARTICIPANTS: We prospectively recruited 214 consecutive patients who received OBLPs during January-December 2015. All procedures were performed under local anaesthesia without sedation, in an upright (sitting) position. MAIN OUTCOME MEASURES: We measured heart rate (HR), systolic and diastolic blood pressure, and oxygen saturations at baseline (before procedure), immediately after local anaesthesia to the pharynx and larynx, immediately after completing of procedure, and 20 minutes after the procedure. RESULTS: Systolic, diastolic blood pressures and HR all significantly increased after local anaesthesia, and gradually decreased after the procedure (P<.01). Oxygen concentration remained unchanged. Patients with comorbidity and those receiving vasoactive medications showed significantly higher perioperative blood pressures than the other patients (P<.05), but the trend remained similar. Prominent hypertension (systolic >=160 mm Hg or diastolic >=100 mm Hg) was noted in 17 patients, more commonly in patients with older age, higher baseline blood pressures and receiving vasoactive medications. Only 2% of patients with normal baseline measurements developed prominent hypertension perioperatively. Tachycardia (HR>=100 bpm) developed in 22 patients, more frequently in patients with higher baseline HRs, and perceiving greater discomforts. CONCLUSION: This study revealed that routine haemodynamic monitoring may not be necessary for all the OBLPs, but should be considered for older patients, those with higher baseline blood pressure or HR, sensitive patients who might be more susceptible to perioperative discomfort, and those receiving vasoactive medications. PMID- 28556525 TI - Upper urinary tract washings outperform voided urine specimens to detect upper tract high-grade urothelial carcinoma. AB - BACKGROUND: Cytological examination of voided urine (VU) can reliably diagnose high-grade urothelial carcinoma (HGUC) of the lower urinary tract, but its value in the diagnosis of upper tract HGUC (UTHGUC) is less well-established. To clarify the utility of VU in the setting of UTHGUC, we examined urinary specimens from patients with UTHGUC on follow-up surgical pathology. METHODS: 52 VU specimens (47 patients) with subsequent biopsy-proven UTHGUC were identified over a 12-year period; 32 had a corresponding upper tract urinary washing (UW) specimen. Patients with concurrent bladder HGUC were excluded. The diagnoses of VU specimens were tabulated and compared to those of UW specimens. RESULTS: Three UW specimens had a less severe diagnosis, 8 had the same diagnosis, and 21 had a more severe diagnosis than the corresponding VU specimen from the same patient. Significantly more UW specimens demonstrated high-risk features as compared with VU specimens (P = .003). In specimens with atypia, a definitive diagnosis of HGUC was made significantly more often on UW vs. VU specimens (P = .003). CONCLUSIONS: Among patients with confirmed UTHGUC, 50% of preceding VU specimens demonstrated high-grade features compared to almost 90% of UW specimens. Though VU cytology shows atypia in the majority of cases, it performs inferiorly to UW for the detection of UTHGUC. Diagn. Cytopathol. 2017;45:700-704. (c) 2017 Wiley Periodicals, Inc. PMID- 28556527 TI - A T-Shaped Nickel(I) Metalloradical Species. AB - A T-shaped NiI complex was synthesized using a rigid acridane-based pincer ligand to prepare a metalloradical center. Structural data displays a nickel ion is embedded in the plane of a PNP ligand. Having a sterically exposed half-filled dx2-y2 orbital, this three-coordinate NiI species reveals unique open-shell reactivity including the homolytic cleavage of various sigma-bonds, such as H-H, N-N, and C-C. PMID- 28556526 TI - Examining the role of the physician as a source of variation: Are physician related variations necessarily unwarranted? AB - RATIONALE, AIMS, AND OBJECTIVES: The physician is often implicated as an important cause of observed variations in health care service use. However, it is not clear if physician-related variation is problematic for patient care. This paper illustrates that observed physician-related variation is not necessarily unwarranted. METHODS: This is a narrative review. RESULTS: Many studies have attributed observed variations to the physician, but little attention is given towards discriminating between those variations that exist for good reasons and those that are unwarranted. Two arguments can be made for why physician-related variation is unwarranted. The first posits that physician-related factors should not play a role in management of care decisions because such decisions should be driven by science (which is imagined to be definitive). The second considers the possibility of supplier-induced demand as a factor driving observed variations. We show that neither argument is sufficient to rule out that physician-related variations may be warranted. Furthermore, the claim that such variations are necessarily problematic for patients has yet to be substantiated empirically. CONCLUSIONS: It is not enough to simply show that physician-related variation can exist-one must also show where it is unwarranted and what is the magnitude of unwarranted variations. Failure to show this can have significant implications on how we interpret and respond to observed variations. Improved measurement of the sources of variation, especially with respect to patient preferences and context, may help us start to disentangle physician-related variation that is desirable from that which is unwarranted. PMID- 28556528 TI - Managing conflict between large carnivores and livestock. AB - Large carnivores are persecuted globally because they threaten human industries and livelihoods. How this conflict is managed has consequences for the conservation of large carnivores and biodiversity more broadly. Mitigating human predator conflict should be evidence-based and accommodate people's values while protecting carnivores. Despite much research into human and large-carnivore coexistence strategies, there have been few attempts to document the success of conflict-mitigation strategies on a global scale. We conducted a meta-analysis of global research on conflict mitigation related to large carnivores and humans. We focused on conflicts that arise from the threat large carnivores pose to livestock. We first used structured and unstructured searching to identify replicated studies that used before-after or control-impact design to measure change in livestock loss as a result of implementing a management intervention. We then extracted relevant data from these studies to calculate an overall effect size for each intervention type. Research effort and focus varied among continents and aligned with the histories and cultures that shaped livestock production and attitudes toward carnivores. Livestock guardian animals most effectively reduced livestock losses. Lethal control was the second most effective control, although its success varied the most, and guardian animals and lethal control did not differ significantly. Financial incentives have promoted tolerance of large carnivores in some settings and reduced retaliatory killings. We suggest coexistence strategies be location-specific, incorporate cultural values and environmental conditions, and be designed such that return on financial investment can be evaluated. Improved monitoring of mitigation measures is urgently required to promote effective evidence-based policy. PMID- 28556530 TI - Characterizing differences between MSCs and TM cells: Toward autologous stem cell therapies for the glaucomatous trabecular meshwork. AB - Glaucoma, a leading cause of blindness, is characterized by an increase in intraocular pressure, which is largely determined by resistance to aqueous humour outflow through the trabecular meshwork (TM). In glaucoma, the cellularity of the TM is decreased, and, as a result, stem cell therapies for the TM represent a potential therapeutic option for restoring TM function and treating glaucoma patients. We here focus on adipose derived mesenchymal stem cells (MSCs) as a potential autologous cell source for TM regenerative medicine applications and describe characterization techniques at the messenger (reverse transcription quantitative polymerase chain reaction), protein (western blotting, flow cytometry), and functional (contractility, phagocytosis) levels to distinguish MSCs from TM cells. We present a panel of 12 transcripts to allow: (a) suitable normalization of reverse transcription-quantitative polymerase chain reaction results across cell types and after exposure to potential differentiation stimuli; (b) distinguishing MSCs from TM cells; (c) distinguishing subtypes of TM cells; and (d) distinguishing TM cells from those in neighbouring tissue. At the protein level, dexamethasone induction of myocilin was a robust discriminating factor between MSCs and TM cells and was complemented by other protein markers. Finally, we show that contractility and phagocytosis differ between MSCs and TM cells. These methods are recommended for use in future differentiation studies to fully define if a functional TM-like phenotype is being achieved. PMID- 28556529 TI - Multicentre cross-sectional study for bone-articular lesions associated with dialysis related amyloidosis in Japan. AB - AIM: Dialysis-related amyloidosis (DRA) exhibits multiple bone-articular lesions, such as carpal tunnel syndrome (CTS), trigger finger (TF), spinal canal stenosis (SCS), destructive spondyloarthropathy (DSA), bone cysts, and joint pains. DRA leads to a decrease in activities of daily living (ADL). We investigated the initiation of CTS and TF, and evaluated the relationship between walking disturbances and bone-articular lesions or joint pains. METHODS: A multicentre cross-sectional study was performed. Eighty-two patients with clinical DRA from 20 hospitals in Japan were evaluated. RESULTS: Of the 82 patients, the first symptom of DRA was CTS in 39 patients (47.6%) and TF in 21 (25.6%). The mean new onset vintages of 21 earlier cases in the CTS and TF groups were 86.1 +/- 36.3 and 133.2 +/- 56.4 (mean +/- SD) months, respectively (P = 0.0091). The development of SCS and DSA appeared to be later than CTS and TF. Multiple regression analysis revealed that knee joint pain was a significant contributor to walking disturbances. CONCLUSION: Carpal tunnel syndrome appeared significantly earlier than TF since the initiation of dialysis. In the advanced phase, knee joint pain was a major cause of decreased ADL in patients with clinical DRA. PMID- 28556531 TI - Effects of uncontrolled periodontitis on marginal bone alterations around implants: A case-control study. AB - BACKGROUND: The hypothesis of bacterial infection initiating marginal bone loss around dental implant in analogy with natural tooth is still in debate. PURPOSE: The aim of this retrospective study was to investigate the effects of uncontrolled periodontitis on marginal bone alterations around implants compared with the periodontal health group at a mean follow-up of at least 6 years. MATERIALS AND METHODS: Thirty consecutive uncontrolled periodontally compromised patients (PCP) and 30 periodontally healthy patients (PHP), with a total of 96 Straumann implants (PCP = 55, PHP = 41) were matched for age, gender, smoking, and implant characteristics. The inclusion criteria for PCPs were continuing tooth loss due to uncontrolled periodontal disease and no supportive periodontal maintenance after implant therapy. Peri-implant conditions were examined and the number of teeth lost during the follow-up periods was recorded in both groups. Radiographic marginal bone loss of implants and adjacent teeth was calculated having the restoration time point as baseline. RESULTS: No implant loss occurred in both groups. The mean number of teeth lost during the follow-up periods was 0.67 +/- 0.80 in the PHP group, 3.93 +/- 2.36 in the PCP group with statistical significance. The average overall bone loss was significantly greater at teeth than that around implants in the PCP group (0.54 +/- 0.27 versus 0.22 +/- 0.25 mm, P < .001), while no statistically significant differences were observed in the PHP group (0.18 +/- 0.08 versus 0.22 +/- 0.18 mm, P = .317). No statistically significant differences were observed between PC and PH patients when comparing the peri-implant marginal bone loss. No significant correlations were found between teeth loss and crestal bone loss at implants sites in both groups. CONCLUSION: This study indicated that the marginal bone level around implants seemed more stable in comparison to that around the natural teeth when exposed to uncontrolled periodontal disease. PMID- 28556533 TI - In vitro evaluation of gel-encapsulated adipose derived stem cells: Biochemical cues for in vivo peripheral nerve repair. AB - Adipose-derived stem cells (ASC) are becoming one of the most exploited cells in peripheral nerve repair. They are fast-growing and able to protect neurons from apoptosis; they can reduce post-injury latency and the risk of muscle atrophy. This study evaluates laminin-loaded fibrin gel as an ASC-carrying scaffold for nerve repair. In vitro, ASC retained their proliferative activity but showed significant increase in proliferation rate when encapsulated in gels with low laminin concentrations (i.e., 1 MUg/mL). We observed a linear decrease of ASC proliferation rate with increasing laminin concentration from 1 to 100 MUg/mL. We next examined the effect of the ASC-carrying fibrin gels on in vitro dorsal root ganglia (DRG) neurite extension, then in vivo sciatic nerve regeneration in adult rats. The ASC-carrying gel was embedded in 15-mm-long, 1.5-mm-diameter polydimethylsiloxane regenerative conduits for in vivo evaluation. At 8-week post implantation, robust regeneration was observed across the long gap. Taken together, these results suggest ASC-carrying gels are a potential path to improve the efficacy of nerve regeneration through artificial guidance conduits and electrode nerve interfaces. PMID- 28556532 TI - Feline large granular lymphocyte lymphoma: An Italian Society of Veterinary Oncology (SIONCOV) retrospective study. AB - Feline large granular lymphocyte (LGL) lymphoma is an uncommon subtype of lymphoma characterized by a grave prognosis and scarce response to chemotherapy. There are limited reports on clinico-pathological and prognostic factors. One hundred and 9 cats with newly diagnosed LGL lymphoma that underwent initial staging (including hematology, serum biochemistry, thoracic radiographs and abdominal ultrasound), and followed-up were retrospectively evaluated. LGL lymphoma was localized within the gastrointestinal tract with or without extra intestinal involvement in 91.7% of the cases, and at extra-gastrointestinal sites in 8.3%. Symptoms were frequent. Anemia (31.2%) and neutrophilia (26.6%) were commonly observed, and 14 (12.8%) cats had neoplastic circulating cells. Frequent biochemistry abnormalities included elevated ALT (39.4%) and hypoalbuminemia (28.4%). Twenty (54.1%) of 37 cats had elevated serum LDH. Treatment varied among cats, and included surgery (11%), chemotherapy (23%), corticosteroids (38.5%) and no treatment (27.5%). Median time to progression (MTTP) was 5 days, and median survival time (MST) 21 days. MST was significantly shorter in the case of substage b, circulating neoplastic cells, lack of chemotherapy administration, and lack of treatment response. A small subset of cats (7.3%) survived more than 6 months, suggesting that a more favorable clinical course can be found among LGL lymphoma patients. PMID- 28556534 TI - Current Resources for Evidence-Based Practice, May/June 2017. PMID- 28556535 TI - Mineral Composition of Uroliths Obtained from Sheep and Goats with Obstructive Urolithiasis. AB - BACKGROUND: Knowledge of the mineral composition of the causative urolith is important to develop preventative strategies. Advances in analytic techniques have led to detection of urolith components not previously recognized. HYPOTHESIS/OBJECTIVES: The objectives of this study were to characterize uroliths in sheep and goats structurally and clinically. We hypothesized that amorphous magnesium calcium phosphate (AMCP) would be a naturally occurring urolith type in sheep and goats. ANIMALS: Forty-nine sheep and goats presenting for obstructive urolithiasis from June 15, 2014 through June 14, 2016 were reviewed along with the demographic data of all small ruminants admitted during that same period. METHODS: Medical records were reviewed for demographic and historical data, and 36 uroliths obtained from these cases during diagnostic or therapeutic procedures were analyzed by infrared spectroscopy to determine chemical composition. RESULTS: AMCP is a naturally occurring urolith type in obstructed male sheep and goats and was the most common urolith type in this study, where it occurred as a majority component with struvite (39% of uroliths) or as a pure component (11%). Pure struvite was found in 1 urolith (2%). Calcium carbonate was the second most frequent urolith with 31% of uroliths being pure calcium carbonate. CONCLUSIONS AND CLINICAL IMPORTANCE: This study demonstrates that uroliths, which appear consistent with struvite, could actually be calcium-containing AMCP. Urolith analysis is critical in determining mineral content of uroliths to guide dietary recommendations for prevention. PMID- 28556536 TI - Rapid and cost-effective method for the simultaneous quantification of seven alkaloids in Corydalis decumbens by microwave-assisted extraction and capillary electrophoresis. AB - A rapid and cost-effective method based on microwave-assisted extraction followed by capillary electrophoresis was developed for simultaneous quantification of seven alkaloids in Corydalis decumbens for the first time. The main parameters affecting microwave-assisted extraction and capillary electrophoresis separation were investigated and optimized. The optimal microwave-assisted extraction was performed at 40 degrees C for 5 min using methanol/water (90:10, v/v) as the extracting solvent. Electrophoretic separation was achieved within 15 min using an uncoated fused-silica capillary (50 MUm internal diameter and 27.7 cm effective length) and a 500 mM Tris buffer containing 45% v/v methanol (titrated to pH* 2.86 with H3 PO4 ). The developed method was successfully applied to the quantification of seven alkaloids in Corydalis decumbens obtained from different regions of China. The combination of microwave-assisted extraction with capillary electrophoresis was an effective method for the rapid analysis of the alkaloids in Corydalis decumbens. PMID- 28556537 TI - Insecticidal activities of their components derived from the essential oils of Cinnamomum sp. barks and against Ricania sp. (Homoptera: Ricaniidae), a newly recorded pest. AB - BACKGROUND: Insecticidal activities of Cinnamomum cassia and Cinnamomum zeylanicum oils and their components are not known against Ricania sp. Insecticidal activities of major components derived from C. cassia and C. zeylanicum oils were examined in spray and leaf-dipping bioassays against Ricania sp. nymphs and adults. RESULTS: The LC50 value of C. cassia and C. zeylanicum oils was 37.66 and 72.62 mg L-1 , respectively, in leaf-dipping bioassays against Ricania sp. nymphs, and 77.38 and 134.86 mg L-1 in spray bioassays against Ricania sp. adults. The insecticidal activity of C. cassia oil was 1.74-1.93 times greater than that of C. zeylanicum oil. When examined by gas chromatography mass spectrometry, the cinnamaldehyde content of C. cassia and C. zeylanicum oils was 80.20% and 46.32%, respectively. Based on the LC50 values of cinnamaldehyde, hydrocinnamaldehyde and 4-hydroxy-3-methoxycinnamaldehyde against Ricania sp. nymphs and adults, cinnamaldehyde (LC50 , 31.25 and 62.43 mg L-1 ) demonstrated the most potent insecticidal activity, followed by 4-hydroxy-3 methoxycinnamaldehyde (172.19 and 212.77 mg L-1 ) and hydrocinnamaldehyde (275.05 and 318.63 mg L-1 ). CONCLUSION: The findings revealed that C. cassia oil, C. zeylanicum oil and cinnamaldehyde have potential value in the management of Ricania sp. and could be valuable as effective insecticides. (c) 2017 Society of Chemical Industry. PMID- 28556538 TI - A retrospective database analysis to evaluate the potential of ex vivo lung perfusion to recruit declined lung donors. AB - Ex vivo lung perfusion (EVLP) is currently used for both standard and extended criteria donor (ECD) lungs. To enlarge the donor pool, we might have to extend the threshold for ECD donation. The purpose of this study was to estimate how many additional ECD lungs could be recruited by EVLP. We reviewed all multi-organ donors (MODs) from our collaborative donor hospitals (January 2010-June 2015). All unused lung donors were categorized using registered donor data and evaluated by two independent investigators to identify which lungs could be transplanted after EVLP. 584 MODs were registered at our transplant center. 268 (45.9%) were declined as lung donor at the moment of registration, and 316 (54.1%) were considered as a donor for lung transplantation. In the latter, lungs from 220 (37.7%) donors were transplanted and 96 donors (16.4%) were not. We identified 78 of 364 declined donors (21.4%) whose lungs could potentially become transplantable after EVLP. With this retrospective database analysis of unused lung donors, we identified a large potential for EVLP to further increase the donor pool in transplant centers where the majority of donor lungs are already extended. PMID- 28556539 TI - Simple, rapid, and environmentally friendly method for the separation of isoflavones using ultra-high performance supercritical fluid chromatography. AB - Isoflavones are natural substances that exhibit hormone-like pharmacological activities. The separation of isoflavones remains an analytical challenge because of their similar structures. We show that ultra-high performance supercritical fluid chromatography can be an appropriate tool to achieve the fast separation of 12 common dietary isoflavones. Among the five tested columns the Torus DEA column was found to be the most effective column for the separation of these isoflavones. The impact of individual parameters on the retention time and separation factor was evaluated. These parameters were optimized to develop a simple, rapid, and green method for the separation of the 12 target analytes. It only took 12.91 min using gradient elution with methanol as an organic modifier and formic acid as an additive. These isoflavones were determined with limit of quantitation ranging from 0.10 to 0.50 MUg/mL, which was sufficient for reliable determination of various matrixes. PMID- 28556541 TI - Development of a 3-step straight-through purification strategy combining membrane adsorbers and resins. AB - The pressures to efficiently produce complex biopharmaceuticals at reduced costs are driving the development of novel techniques, such as in downstream processing with straight-through processing (STP). This method involves directly and sequentially purifying a particular target with minimal holding steps. This work developed and compared six different 3-step STP strategies, combining membrane adsorbers, monoliths, and resins, to purify a large, complex, and labile glycoprotein from Chinese hamster ovary cell culture supernatant. The best performing pathway was cation exchange chromatography to hydrophobic interaction chromatography to affinity chromatography with an overall product recovery of up to 88% across the process and significant clearance of DNA and protein impurities. This work establishes a platform and considerations for the development of STP of biopharmaceutical products and highlights its suitability for integration with single-use technologies and continuous production methods. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:931-940, 2017. PMID- 28556540 TI - Sustained NFkappaB inhibition improves insulin sensitivity but is detrimental to muscle health. AB - Older adults universally suffer from sarcopenia and approximately 60-70% are diabetic or prediabetic. Nonetheless, the mechanisms underlying these aging related metabolic disorders are unknown. NFkappaB has been implicated in the pathogenesis of several aging-related pathologies including sarcopenia and type 2 diabetes and has been proposed as a target against them. NFkappaB also is thought to mediate muscle wasting seen with disuse, denervation, and some systemic diseases (e.g., cancer, sepsis). We tested the hypothesis that lifelong inhibition of the classical NFkappaB pathway would protect against aging-related sarcopenia and insulin resistance. Aged mice with muscle-specific overexpression of a super-repressor IkappaBalpha mutant (MISR) were protected from insulin resistance. However, MISR mice were not protected from sarcopenia; to the contrary, these mice had decreases in muscle mass and strength compared to wild type mice. In MISR mice, NFkappaB suppression also led to an increase in proteasome activity and alterations in several genes and pathways involved in muscle growth and atrophy (e.g., myostatin). We conclude that the mechanism behind aging-induced sarcopenia is NFkappaB independent and differs from muscle wasting due to pathologic conditions. Our findings also indicate that, while suppressing NFkappaB improves insulin sensitivity in aged mice, this transcription factor is important for normal muscle mass maintenance and its sustained inhibition is detrimental to muscle function. PMID- 28556542 TI - Long-term outcomes of de novo autoimmune hepatitis in pediatric liver transplant recipients. AB - The long-term course and outcome of DAIH is unknown. A retrospective multicenter study assessing associations and long-term consequences of DAIH developing in a transplanted allograft is presented. Children with DAIH were followed from diagnosis until death, re-LT, or transfer of care and for a minimum of 1 year. A total of 31 patients of 1833 (1.7%) LT were identified; 29 followed for a median of 7.1 years (range, 1.6-15); 52% had no rejection preceding diagnosis of DAIH. Transaminases fell following treatment with steroids and antimetabolites (ALT 108 vs 39 U/L (P=.002); AST 112 vs 52 U/L (P=.003); GGT 72 vs 36 U/L (P=.03), but this was not universally sustained. Transaminases >2X ULN observed in 38% of patients at last follow-up; commonly GGT, attributed to bile duct injury and ductopenia. Portal hypertension (PHT) was seen in four patients and associated with severe fibrosis and cirrhosis. Re-LT occurred in two patients for chronic rejection (CR) and uncontrolled PHT with gastrointestinal bleeding, respectively. No deaths from DAIH were reported. DAIH is an uncommon complication following pediatric LT requiring prolonged and augmented immunosuppression. It is associated with continued allograft dysfunction and may lead to bile duct injury, CR, and PHT necessitating re-LT. PMID- 28556543 TI - Westley score and clinical factors in predicting the outcome of croup in the pediatric emergency department. AB - BACKGROUND: Westley croup score has been generally used to assess the severity of croup. This study aimed to identify the individual factors associated with Westley score (WS) and other clinical factors in predicting the outcomes in the pediatric emergency department (PED). POPULATION AND METHOD: We prospectively recruited patients with croup from the PED. The individual factors of WS, fever, age, and the length of hospital stay were analyzed to predict clinical outcomes. We calculated all the areas under the receiver operating characteristic (ROC) curve to determine the cutoff values of initial WS discriminating the need for admission to the wards. RESULT: A total of 192 patients with croup were enrolled. Cyanosis and altered consciousness were not clinically significant even in patients with severe croup, whereas retraction and air entry were the major factors in WS for predicting clinical outcomes. The initial WS had a strong correlation with the length of hospital stay (r = 0.617, P < 0.001). ROC analysis showed that patients with an initial WS <2 (sensitivity, 5%; specificity, 100%; LR+ , 1.05; LR- , 0; AUC, 0.87) were discharged home while the patients with an initial WS >=5 (sensitivity, 99%; specificity, 57%; LR+ , 41.0; LR- , 0.43) were more likely to require to stay in the PED. Patients with an WS >=6 were more likely to be admitted to the wards (sensitivity, 97%; specificity, 47%; LR+ , 416.35; LR- , 0.54; AUC, 0.90) CONCLUSION: Patients with an initial WS of 1-2 could be safely treated at home and those with initial WS >5 required hospitalization for further treatment. PMID- 28556544 TI - Pituicytoma-An outlook on possible targeted therapies. AB - INTRODUCTION: Pituicytoma is a rare neoplasm of the sella region. Tumor resection is the primary treatment option, but remains subtotal due to excessive bleeding in many cases. The search for alternative or additional treatment regimens is necessary. AIMS: We aimed to determine the receptor expression of pituicytoma to find alternatives or supplements to surgical therapy in the use of targeted therapies. METHODS: Pituicytoma samples were collected from three institutions between 2006 and 2015 and were stained for vascular endothelial growth factors (VEGF), thyroid transcription factor (TTF1), and somatostatin receptors (SSTR 2/3/5). The stains were classified from 0=no staining to +++=strong staining. A complementary retrospective analysis of the patient charts regarding sex, age, and primary symptoms, pituitary function, and perioperative complications was performed. RESULTS: Ten samples were analyzed; mean patient age was 57.8 years SD 16.3 years. Seven samples were acquired from male patients (one relapse) and three from female. All tumors stained strongly positive (+++) for VEGF-R. Six samples stained positive for TTF1. As for somatostatin receptors, three samples were slightly positive for SSTR 2; seven were negative. SSTR 3 was + in one, three were ++, three were +++, and three were 0. SSTR 5 stained +++ in 1, ++ in 5, + in 1, and 0 in three patients. CONCLUSIONS: Pituicytomas were generally positive for VEGFR and showed regular expression of SSTR 3 and 5 indicating a possible treatment option through targeted therapies in cases where resection remains insufficient. Further research is necessary as to whether tumor growth can be inhibited using these pathways. PMID- 28556545 TI - Effect of timing of renal replacement therapy on outcomes of critically ill patients in the intensive care unit. AB - AIM: Currently, indications for renal replacement therapy (RRT) remain controversial. Whether early RRT can improve the prognosis of critically ill patients in the ICU is unclear. This study aimed to assess the relationship between timing of RRT initiation and short-term prognosis of patients in the ICU. METHODS: This was a retrospective study of data obtained from 28 hospitals in Beijing. The subjects received RRT treatment in the ICU from March 2012 to August 2012. RESULTS: A total of 9049 cases were reviewed, and 281 patients who underwent RRT were enrolled and divided into the non-survival (n = 144) and survival (n = 137) groups, according to their outcome at 28 days from ICU admission. Median RRT initiation times were 1 (0-25) and 1 (0-21) days in the non survival and survival groups, respectively (P = 0.001) and oliguria/anuria frequency at RRT initiation were 76.6% and 65.3% (P = 0.036), respectively. The mortality of patients administered RRT within 24 h of ICU admission was lower than that of those treated after 24 h (P = 0.014). In patients with oliguria/anuria at RRT initiation, the 28-day mortality rate was 52.8%, which was higher than 39.0% obtained for those with no oliguria/anuria at RRT initiation (P = 0.036). Multivariate logistic analysis showed that late initiation of RRT was an independent risk factor for 28-day mortality (HR = 1.139, 95%CI 1.046-1.242, P = 0.003). CONCLUSION: Timing of RRT is associated with 28-day mortality of ICU treated patients. Early RRT might improve patient survival. PMID- 28556547 TI - A systematic review on cell-seeded tissue engineering of penile corpora. AB - Tissue engineering of corporal tissue is a new development in otherwise untreatable erectile dysfunction and in urethral reconstructions to treat hypospadias or severe urethral stricture disease. Multiple complications can arise with the current treatments, whereas engineered tissue, if well vascularized and existing of autologous cells, may lead to better results. The aim of this review was to provide an overview of literature on cell-seeded-based tissue engineering of corporal penile tissue. A literature search was performed following the PRISMA guidelines. Papers describing cell-seeded tissue engineering of corporal tissue were included. Studies using different techniques, such as intracavernous injection were excluded. Fifteen articles were included in the review. Twelve of these studies described engineering of the corpus cavernosum in animal models. Two articles were found on engineering of animal corpus spongiosum and one article on engineering of the human glans. Both synthetic scaffolds and biological scaffolds were used. The advantage of a biological, acellular scaffold was that the native, complex architecture of corporal tissue was maintained. Most studies used endothelial and smooth muscle cells from corporal origin, but stem cells were also investigated. Furthermore, dynamic culturing achieved an improved cell content and functionality. This review has summarized the developments in tissue engineering of corpus cavernosum and spongiosum tissue. Functional tissue has been developed in animal studies with the use of seeded cells on scaffolds. This knowledge will form a basis for the development of tissue engineering of corporal tissue for clinical applications. PMID- 28556546 TI - A state-wide initiative to promote genetic testing in an underserved population. AB - Genetic testing for cancer susceptibility has been widely studied and utilized clinically. Access to genetic services in research and practice is largely limited to well-insured, Caucasian individuals. In 2009, the Cancer Resource Foundation (CRF) implemented the Genetic Information for Treatment Surveillance and Support (GIFTSS) program to cover the out-of-pocket expenses associated with cancer genetic testing, targeting high-risk individuals with limited financial means and limited health insurance coverage. Here, we (i) describe the characteristics of participants in the Massachusetts (MA) GIFTSS program and (ii) evaluate mutations found in this diverse sample. A secondary retrospective data analysis was performed using de-identified demographic data obtained from laboratory requisition forms and cancer genetic testing result information from the laboratory source. Eligible participants were those who utilized the MA GIFFTS program from 2009 through December of 2014. Data were summarized using descriptive measures of central tendency. Participants were residents of Massachusetts who had health insurance and had a reported income within 250-400% of the federal poverty level. Genetic testing results were categorized following clinical guidelines. Overall, 123 (13%) of participants tested positive for a mutation in a cancer susceptibility gene. For those with a cancer diagnosis, 65 (12%) were found to have a positive result and 20 (7%) had a variant of uncertain significance (VUS). For those unaffected patients, 58 (15%) had a positive result and 10 (3%) were found to have a VUS. The results from this study are useful in describing genetic testing outcomes in this high-risk underserved community. Repeatedly, the literature reports that individuals from diverse or limited resource settings are less likely to access genetic testing. Continued research efforts should be devoted to promoting the access of genetic testing in the high risk, underserved community. PMID- 28556548 TI - Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis. AB - OBJECTIVE: To determine the function and serum levels of soluble forms of programmed death 1 (sPD-1) and one of its ligands, soluble PD ligand 2 (sPD-L2), in patients with systemic sclerosis (SSc) and in a mouse model of topoisomerase I (topo I)-induced SSc. METHODS: Serum levels of sPD-1 and sPD-L2 in 91 patients with SSc were examined by enzyme-linked immunosorbent assay (ELISA). Expression of PD-1 and PD-L2 on T cells, B cells, and macrophages was quantified by flow cytometry. The effects of blockade of PD-1 and PD-L2 were analyzed by microfluidic ELISA (micro-ELISA), a technique that can measure very low amounts of cytokines. In addition, the effects of sPD-1 and sPD-L2 on disease progression were assessed in mice with topo I-induced SSc. RESULTS: Serum levels of sPD-1 and sPD-L2 were elevated in patients with SSc and correlated with the extent of fibrosis and immunologic abnormalities. Expression levels of PD-1 and PD-L2 were significantly elevated on SSc T cells, B cells, and macrophages. Micro-ELISA analysis of serum samples from patients with SSc showed that PD-L2high B cells had higher levels of interleukin-10 (IL-10) production compared with PD-L2low B cells, indicating that PD-L2 acts as a regulator of T cell cytokine production via cognate interactions with T cells and B cells. In mice with topo I-induced SSc, production of IL-10 by topo I-specific B cells in cultures with T cells and topo I protein was significantly higher than that by conventional B cells, and intraperitoneal injection of recombinant chimeric PD-1-Fc and PD-L2-Fc canceled these enhanced effects. CONCLUSION: These results suggest that sPD-1 and sPD-L2 contribute to disease development in SSc via the regulation of cognate interactions with T cells and B cells. PMID- 28556550 TI - Highlights - June 2017. PMID- 28556551 TI - Recent advancements in electrospinning design for tissue engineering applications: A review. AB - Electrospinning, a technique used to fabricate fibrous scaffolds, has gained popularity in recent years as a method to produce tissue engineered grafts with architectural similarities to the extracellular matrix. Beyond its versatility in material selection, electrospinning also provides many tools to tune the fiber morphology and scaffold geometry. Recent efforts have focused on extending the capabilities of electrospinning to produce scaffolds that better recapitulate tissue properties and enhance regeneration. This review highlights these advancements by providing an overview of the processing variables and setups used to modulate scaffold architecture, discussing strategies to improve cellular infiltration and guide cell behavior, and providing a summary of electrospinning applications in tissue engineering. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2892-2905, 2017. PMID- 28556549 TI - Methods for studying the metabolic basis of Drosophila development. AB - The field of metabolic research has experienced an unexpected renaissance. While this renewed interest in metabolism largely originated in response to the global increase in diabetes and obesity, studies of metabolic regulation now represent the frontier of many biomedical fields. This trend is especially apparent in developmental biology, where metabolism influences processes ranging from stem cell differentiation and tissue growth to sexual maturation and reproduction. In this regard, the fruit fly Drosophila melanogaster has emerged as a powerful tool for dissecting conserved mechanisms that underlie developmental metabolism, often with a level of detail that is simply not possible in other animals. Here we describe why the fly is an ideal system for exploring the relationship between metabolism and development, and outline a basic experimental strategy for conducting these studies. WIREs Dev Biol 2017, 6:e280. doi: 10.1002/wdev.280 For further resources related to this article, please visit the WIREs website. PMID- 28556552 TI - Does the presence of unilateral maxillary incisor edge asymmetries influence the perception of smile esthetics? AB - OBJECTIVE: Determine orthodontists and laypersons' perception of maxillary central and lateral incisor edge asymmetries in full-face and close-up smiles. MATERIAL AND METHODS: Four smile photos were selected for this study: two full face and two close-up smile photos of two male subjects, a white man and an Afro descendant man. Both were considered pleasant smiles, following some principles of an ideal smile. Images were digitally altered to create tooth wear asymmetries on the maxillary left central and lateral incisor in 0.5 mm increments. Final images were arranged randomly into a photo album and were shown to 86 judges (43 orthodontists and 43 laypersons). Judges were asked to evaluate the attractiveness of the images according to a visual analog scale. Data were statistically analyzed using one-way analysis of variance (ANOVA) with the Tukey's post hoc test and the Student t test. RESULTS: There was no statistically significant difference in the mean esthetic scores of the full-face and close-up smile photos. The most attractive smiles were those without asymmetries and those with 0.5 mm wear in the lateral incisor, whereas the least attractive ones were those with 1.0-1.5 mm wear in the central incisors. Statistically significant difference was found in the mean scores given by the judges in most cases. The orthodontists were more critical and assigned lower scores than the laypersons. CONCLUSIONS: The presence of maxillary incisor asymmetries is a critical factor influencing the perception of smile esthetics. The most attractive smiles of the men investigated were those without asymmetry and those with 0.5 mm incisor edge asymmetry in the lateral incisor. CLINICAL SIGNIFICANCE: The presence of incisal asymmetries (especially in maxillary central incisors) negatively influences smile esthetics, corroborating the clinical hypothesis that the closer to the facial midline, the greater the need for symmetry. PMID- 28556553 TI - Tailoring Biomaterials for Cancer Immunotherapy: Emerging Trends and Future Outlook. AB - Cancer immunotherapy, as a paradigm shift in cancer treatment, has recently received tremendous attention. The active cancer vaccination, immune checkpoint blockage (ICB) and chimeric antigen receptor (CAR) for T-cell-based adoptive cell transfer are among these developments that have achieved a significant increase in patient survival in clinical trials. Despite these advancements, emerging research at the interdisciplinary interface of cancer biology, immunology, bioengineering, and materials science is important to further enhance the therapeutic benefits and reduce side effects. Here, an overview of the latest studies on engineering biomaterials for the enhancement of anticancer immunity is given, including the perspectives of delivery of immunomodulatory therapeutics, engineering immune cells, and constructing immune-modulating scaffolds. The opportunities and challenges in this field are also discussed. PMID- 28556554 TI - Carpal Tunnel Biopsy Identifying Transthyretin Amyloidosis. PMID- 28556555 TI - Examination of Hydroxychloroquine Use and Hemolytic Anemia in G6PDH-Deficient Patients. AB - OBJECTIVE: Some sources urge caution when prescribing hydroxychloroquine (HCQ) to patients with G6PDH deficiency, presumably due to a risk of hemolytic anemia. There are limited published data, however, to support this risk. Additionally, not all patients with G6PDH deficiency are at similar risk for hemolysis, and people with the African variant are at particularly low risk. Through a retrospective chart review, we aimed to quantify the frequency of G6PDH-deficient patients with hemolysis attributed to HCQ. METHODS: We identified Duke University Medical Center rheumatology patients with HCQ use and a measured G6PDH level. A retrospective chart review was performed, recording demographics, G6PDH levels, episodes of anemia, laboratory values consistent with hemolysis, and HCQ use. RESULTS: Of the 275 patients reviewed, 84% were female; 46% were African American and 48% were white. The leading diagnoses were systemic lupus erythematosus (32%), rheumatoid arthritis (29%), and inflammatory arthritis (14%). Only 4% of patients were G6PDH deficient (all African American). Two G6PDH-deficient patients had hemolysis during severe lupus flares that occurred while not taking HCQ. There were no reported episodes of hemolysis in more than 700 months of HCQ exposure among the 11 G6PDH-deficient patients. CONCLUSION: This is the largest study to date evaluating G6PDH deficiency with concurrent use of HCQ. Of 11 patients with G6PDH deficiency, 2 had episodes of hemolysis, but these did not occur during HCQ therapy. These data do not support routine measurement of G6PDH levels or withholding HCQ therapy among African American patients with G6PDH deficiency. PMID- 28556556 TI - Competing-risks model in screening for pre-eclampsia in twin pregnancy according to maternal factors and biomarkers at 11-13 weeks' gestation. AB - OBJECTIVE: To develop a model for screening for pre-eclampsia (PE) in twin pregnancies based on maternal demographic characteristics and medical history and biomarkers at 11-13 weeks' gestation. METHODS: This was a screening study in twin pregnancies at 11-13 weeks' gestation. Bayes theorem was used to combine the a priori risk from maternal factors with various combinations of uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP), serum pregnancy associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) multiples of the median (MoM) values. The performance of screening for PE requiring delivery at < 32, < 37 and < 42 weeks' gestation was estimated in 1100 twin pregnancies and 35 948 singleton pregnancies with complete data on UtA-PI, MAP, PlGF and PAPP-A. RESULTS: In twin pregnancies that developed PE, the values of MAP and UtA-PI were increased and the values of PlGF and PAPP-A were decreased. The distributions of log10 MoM values of biomarkers with gestational age at delivery were similar to those that were previously reported in singleton pregnancies and it was therefore assumed that the same model could be used for both singleton and twin pregnancies. The performance of screening for PE by maternal factors was improved by the addition of MAP, UtA-PI and PlGF; there was no further improvement with the addition of PAPP-A. In a mixed population of singleton and twin pregnancies, combined screening by maternal factors, MAP, UtA PI and PlGF and risk cut-off of 1 in 75 for PE at < 37 weeks, the detection rate of PE at < 32, < 37 and < 42 weeks in singleton pregnancies was 91%, 77% and 57%, respectively, at a screen-positive rate (SPR) of 13%; the respective rates for twin pregnancies were 100%, 99% and 97%, at a SPR of 75%. CONCLUSION: First trimester combined screening for PE in singleton pregnancies can be adapted for screening in twins, leading to detection of nearly all affected cases but at a high SPR. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28556557 TI - Conjunctiva derived mesenchymal stem cell (CJMSCs) as a potential platform for differentiation into corneal epithelial cells on bioengineered electrospun scaffolds. AB - With the aid of tissue engineering, the capability of nanofibrous scaffolds was examined for corneal epithelial differentiation of Conjunctiva mesenchymal stem cells (CJMSCs) as a new source. This study tried to provide a synthetic corneal sheet which could be applied in corneal regeneration. The hybrid arrangement of fine Silk fibers with the diameter of 93.65 nm and the polyurethane (PU) fibers with an average diameter of 575.5 makes a mat with sufficient mechanical properties and interconnected pores that could accelerate nutrient diffusion. After methanol and plasma treatment, the highest biocompatibility of Silk-PU hybrid nanofibrous scaffolds based on cell attachment and proliferation were proven using MTT assay. The differentiation morphology of cells was observed by SEM micrographs of cells seeded on the scaffold after 12 days treatment through the differentiation medium. Despite up-regulation of Cytokeratin (CK)3, CK8, CK12, Desmocollin (DSC)1, and Desmoglein (DSG)1 in the treated PU and silk hybrid nanofibrous scaffolds, the relative expression of CK3, CK8, and CK12 genes were highest among TCP, treated PU and silk nanofibrous scaffolds. Immunocytochemistry (ICC) analysis was used to characterize the protein expression of CK3 in CJ-MSCs seeded on different groups. Although, For both TCP and hybrid group, CJ-MSCs were positive for corneal epithelial-specific marker CK3, ICC data demonstrated that CJ-MSCs seeded on the hybrid group likewise PU or Silk pure nanofibrous scaffolds, could differentiate into corneal epithelial-like cells. Finally, it was inferred that the hybrid PU and silk nanofibrous scaffold has the potential for the treatment of corneal epithelium. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2703-2711, 2017. PMID- 28556558 TI - Particulate air pollution impacts directly on bacterial pathogen behaviour and infection. PMID- 28556559 TI - Synbiotic Fermentation for the Co-Production of Lactic and Lactobionic Acids from Residual Dairy Whey. AB - Besides its properties as an antioxidant, stabilizer, or acidifier, lactobionic acid has emerged as a potential prebiotic compound, raising the possibility of being included together with the probiotic microorganism Lactobacillus casei in novel functional fermented foods with synbiotic characteristics. Their manufacturing strategy could benefit from the recently implemented microbial synthesis of lactobionic acid by the strong producer Pseudomonas taetrolens, employing residual dairy whey as raw material. The phenomenon of amensalism established between Pseudomonas and Lactobacillus makes simultaneous fermentation unfeasible. A novel sequential process has been developed in which L. casei is inoculated in a second step. Its ability to utilize lactobionic acid as a carbon and energy source was previously tested. Experimental results showed the capacity of L. casei to work efficiently on the residual substrate fermented by P. taetrolens, producing lactic acid by degrading the remaining lactose, with a lactic acid yield on substrate and productivity of 0.95 g g-1 and 0.20 g L-1 h-1 , respectively. Lactobionic acid was barely consumed in this complex growth medium, thus ensuring its presence in the resulting fermented product. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1250-1256, 2017. PMID- 28556560 TI - Association of MicroRNA-618 Expression With Altered Frequency and Activation of Plasmacytoid Dendritic Cells in Patients With Systemic Sclerosis. AB - OBJECTIVE: Plasmacytoid dendritic cells (PDCs) are a critical source of type I interferons (IFNs) that can contribute to the onset and maintenance of autoimmunity. Molecular mechanisms leading to PDC dysregulation and a persistent type I IFN signature are largely unexplored, especially in patients with systemic sclerosis (SSc), a disease in which PDCs infiltrate fibrotic skin lesions and produce higher levels of IFNalpha than those in healthy controls. This study was undertaken to investigate potential microRNA (miRNA)-mediated epigenetic mechanisms underlying PDC dysregulation and type I IFN production in SSc. METHODS: We performed miRNA expression profiling and validation in highly purified PDCs obtained from the peripheral blood of 3 independent cohorts of healthy controls and SSc patients. Possible functions of miRNA-618 (miR-618) on PDC biology were identified by overexpression in healthy PDCs. RESULTS: Expression of miR-618 was up-regulated in PDCs from SSc patients, including those with early disease who did not present with skin fibrosis. IFN regulatory factor 8, a crucial transcription factor for PDC development and activation, was identified as a target of miR-618. Overexpression of miR-618 reduced the development of PDCs from CD34+ cells in vitro and enhanced their ability to secrete IFNalpha, mimicking the PDC phenotype observed in SSc patients. CONCLUSION: Up-regulation of miR-618 suppresses the development of PDCs and increases their ability to secrete IFNalpha, potentially contributing to the type I IFN signature observed in SSc patients. Considering the importance of PDCs in the pathogenesis of SSc and other diseases characterized by a type I IFN signature, miR-618 potentially represents an important epigenetic target to regulate immune system homeostasis in these conditions. PMID- 28556561 TI - Cellular conditions that modulate the fungicidal activity of occidiofungin. AB - AIMS: To identify cellular conditions that significantly alter susceptibility of Saccharomyces cerevisiae, Candida albicans and Candida glabrata to the antimicrobial peptide, occidiofungin. METHODS AND RESULTS: Genetic and pharmacological approaches were used to determine a role for calcium signalling in occidiofungin sensitivity profiles for S. cerevisiae, C. albicans and C. glabrata strains of yeast. Minimum inhibitory concentration (MIC) and drop assays found that extracellular calcium resulted in a fourfold resistance, and this was independent of an intact calmodulin-calcineurin signalling pathway. A similar resistance was found in the presence of magnesium but not other cations. Occidiofungin was found to be ineffective against cells in a quiescent state when measured by MIC, drop assay and short-term time-kill assays. A similar resistance pattern was detected for S. cerevisiae cultures pre-exposed to cycloheximide or placed in depleted media conditions. CONCLUSIONS: Extracellular calcium results in fungal tolerance to occidiofungin bioactivity outside of the calmodulin calcineurin pathway. In addition, the resistance of quiescent cells suggests that active cellular growth is a requirement for occidiofungin's mechanism of action. SIGNIFICANCE AND IMPACT OF THE STUDY: The identification of cellular conditions that have a role in the activity of occidiofungin provided insight into potential cellular targets of this novel antifungal. PMID- 28556562 TI - Drug Release as a function of bioactivity, incubation regime, liquid, and initial load: Release of bortezomib from calcium phosphate-containing silica/collagen xerogels. AB - The ability of silica-/collagen-based composite xerogels to act as drug delivery systems was evaluated by taking into account the initial drug concentration, bioactivity of the xerogels, liquid, and incubation regime. The proteasome inhibitor bortezomib was chosen as a model drug, used for the systemic treatment of multiple myeloma. Incubation during 14 days in phosphate-buffered saline (PBS) or simulated body fluid (SBF) showed a weak initial burst and was identified to be of first order with subsequent release being independent from the initial load of 0.1 or 0.2 mg bortezomib per 60 mg monolithic sample. Faster drug release occurred during incubation in SBF compared to PBS, and during static incubation without changing the liquid, compared to dynamic incubation with daily liquid changes. Drug-loaded xerogels with hydroxyapatite as a third component exhibited enhanced bioactivity retarding drug release, explained by formation of a surface calcium phosphate layer. The fastest release of 50% of the total drug load was observed for biphasic xerogels after 7 days during dynamic incubation in SBF. As a result, the presented concept is suitable for the intended combination of the advantageous bone substitution properties of xerogels and local application of drugs exemplified by bortezomib. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1165-1173, 2018. PMID- 28556563 TI - Functionalization promotes pathogen-mimicking characteristics of polyanhydride nanoparticle adjuvants. AB - Rational design of adjuvants and delivery systems will promote development of next-generation vaccines to control emerging and re-emerging diseases. To accomplish this, understanding the immune-enhancing properties of new adjuvants relative to those induced by natural infections can help with the development of pathogen-mimicking materials that will effectively initiate innate immune signaling cascades. In this work, the surfaces of polyanhydride nanoparticles composed of sebacic acid (SA) and 1,6-bis(p-carboxyphenoxy) hexane were decorated with an ethylene diamine spacer partially modified with either a glycolic acid linker or an alpha-1,2-linked di-mannopyranoside (di-mannose) to confer "pathogen like" properties and enhance adjuvanticity. Co-incubation of linker-modified nanoparticles with dendritic cells (DCs) elicited significant increases in surface expression of MHC I, MHC II, CD86, and CD40, and enhanced secretion of IL 6, IL-12p40, and TNF-alpha. An 800% increase in uptake of ethylene-diamine spaced, linker and di-mannose functionalized polyanhydride nanoparticles was also observed. Together, our data showed that linker-functionalized polyanhydride nanoparticles demonstrate similar patterns of uptake, intracellular trafficking, particle persistence, and innate activation as did DCs exposed to Yersinia pestis or Escherichia coli. These results set the stage for rational selection of adjuvant chemistries to induce pathogen-mimicking immune responses. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2762-2771, 2017. PMID- 28556564 TI - Associations between ABO blood groups and pancreatic ductal adenocarcinoma: influence on resection status and survival. AB - Both serology-based and genetic studies have reported an association between pancreatic cancer risk and ABO blood groups. We have investigated this relationship in a cohort of pancreatic cancer patients from Western Norway (n = 237) and two control materials (healthy blood donors, n = 379; unselected hospitalized patients, n = 6149). When comparing patient and blood donor ABO allele frequencies, we found only the A1 allele to be associated with significantly higher risk for pancreatic ductal adenocarcinoma (PDAC) (23.8% vs. 17.9%; OR = 1.43, P = 0.018). Analyzing phenotypes, blood group A was more frequent among PDAC cases than blood donors (50.8% vs. 40.6%; OR = 1.51, P = 0.021), an enrichment fully explained by the A1 subgroup. Blood group O frequency was lower in cases than in blood donors (33.8% vs. 42.7%; OR = 0.69, P = 0.039). This lower frequency was confirmed when cases were compared to hospitalized patients (33.8% vs. 42.9%; OR = 0.68, P = 0.012). Results for blood group B varied according to which control cohort was used for comparison. When patients were classified according to surgical treatment, the enrichment of blood group A was most prominent among unresected cases (54.0%), who also had the lowest prevalence of O (28.7%). There was a statistically significant better survival (P = 0.04) for blood group O cases than non-O cases among unresected but not among resected patients. Secretor status did not show an association with PDAC or survival. Our study demonstrates that pancreatic cancer risk is influenced by ABO status, in particular blood groups O and A1 , and that this association may reflect also in tumor resectability and survival. PMID- 28556567 TI - Revisiting the concept of inflammatory cell-induced corrosion. AB - A peculiar type of surface pitting damage to revised joint replacement implant metal surfaces has been attributed to cellular activity and termed "inflammatory cell-induced-corrosion." We visually examined 1859 explanted metal implants to document the presence and extent of these features. The data was used to examine correlations between these features and the implant material, and modularity as well as clinical variables. The features were observed in approximately 77% of modular and 30% of monobloc hip implants in a variety of metals, as well as to some degree in various other implants. To test the possibility that these features were an artefact of electrocautery damage during revision surgery, a cleaned, flat, polished, CoCr disk was exposed to a variety of electrocautery interactions. This led to the production of pits and markings comparable to the published damage and to the damage found on the explants we examined. It is concluded that electrocautery damage rather than cellular activity is the cause of these features. Although rarely reported, this damage may be associated with femoral neck fracture. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1148-1155, 2018. PMID- 28556565 TI - Demonstration of the utility of biomarkers for dietary intake assessment; proline betaine as an example. AB - SCOPE: There is a dearth of studies demonstrating the use of dietary biomarkers for determination of food intake. The objective of this study was to develop calibration curves for use in quantifying citrus intakes in an independent cohort. METHODS AND RESULTS: Participants (n = 50) from the NutriTech food-intake study consumed standardized breakfasts for three consecutive days over three consecutive weeks. Orange juice intake decreased over the weeks. Urine samples were analyzed by NMR-spectroscopy and proline betaine was quantified and normalized to osmolality. Calibration curves were developed and used to predict citrus intake in an independent cohort; the Irish National Adult Nutrition Survey (NANS) (n = 565). Proline betaine displayed a dose-response relationship to orange juice intake in 24 h and fasting samples (p < 0.001). In a test set, predicted orange juice intakes displayed excellent agreement with true intake. There were significant associations between predicted intake measured in 24 h and fasting samples and true intake (r = 0.710-0.919). Citrus intakes predicted for the NANS cohort demonstrated good agreement with self-reported intake and this agreement improved following normalization to osmolality. CONCLUSION: The developed calibration curves successfully predicted citrus intakes in an independent cohort. Expansion of this approach to other foods will be important for the development of objective intake measurements. PMID- 28556568 TI - Cortisol in human milk: The good, the bad, or the ugly? PMID- 28556566 TI - Select human cancer mutants of NRMT1 alter its catalytic activity and decrease N terminal trimethylation. AB - A subset of B-cell lymphoma patients have dominant mutations in the histone H3 lysine 27 (H3K27) methyltransferase EZH2, which change it from a monomethylase to a trimethylase. These mutations occur in aromatic resides surrounding the active site and increase growth and alter transcription. We study the N-terminal trimethylase NRMT1 and the N-terminal monomethylase NRMT2. They are 50% identical, but differ in key aromatic residues in their active site. Given how these residues affect EZH2 activity, we tested whether they are responsible for the distinct catalytic activities of NRMT1/2. Additionally, NRMT1 acts as a tumor suppressor in breast cancer cells. Its loss promotes oncogenic phenotypes but sensitizes cells to DNA damage. Mutations of NRMT1 naturally occur in human cancers, and we tested a select group for altered activity. While directed mutation of the aromatic residues had minimal catalytic effect, NRMT1 mutants N209I (endometrial cancer) and P211S (lung cancer) displayed decreased trimethylase and increased monomethylase/dimethylase activity. Both mutations are located in the peptide-binding channel and indicate a second structural region impacting enzyme specificity. The NRMT1 mutants demonstrated a slower rate of trimethylation and a requirement for higher substrate concentration. Expression of the mutants in wild type NRMT backgrounds showed no change in N-terminal methylation levels or growth rates, demonstrating they are not acting as dominant negatives. Expression of the mutants in cells lacking endogenous NRMT1 resulted in minimal accumulation of N-terminal trimethylation, indicating homozygosity could help drive oncogenesis or serve as a marker for sensitivity to DNA damaging chemotherapeutics or gamma-irradiation. PMID- 28556569 TI - Matrilin-3 codelivery with adipose-derived mesenchymal stem cells promotes articular cartilage regeneration in a rat osteochondral defect model. AB - Matrilin-3 is an essential extracellular matrix component present only in cartilaginous tissues. Matrilin-3 exerts chondroprotective effects by regulating an anti-inflammatory function and extracellular matrix components. We hypothesized that the codelivery of matrilin-3 with infrapatellar adipose-tissue derived mesenchymal stem cells (Ad-MSCs) may enhance articular cartilage regeneration. Matrilin-3 treatment of Ad-MSCs in serum-free media induced collagen II and aggrecan expression, and matrilin-3 in chondrogenic media also enhanced in vitro chondrogenic differentiation. Next, the in vivo effect of matrilin-3 codelivery with Ad-MSCs on cartilage regeneration was assessed in an osteochondral defect model in Sprague Dawley rats: Ad-MSCs and hyaluronic acid were implanted at the defect site with or without matrilin-3 (140, 280, and 700 ng). Safranin O staining revealed that matrilin-3 (140 and 280 ng) treatment significantly improved cartilage regeneration and glycosaminoglycan accumulation. In the animals treated with 140-ng matrilin-3, in particular, the defect site exhibited complete integration with surrounding tissue and a smooth glistening surface. The International Cartilage Repair Society macroscopic and O'Driscoll microscopic scores for regenerated cartilage were furthermore shown to be considerably higher for this group (matrilin-3; 140 ng) compared with the other groups. Furthermore, the defects treated with 140-ng matrilin-3 revealed significant hyaline-like cartilage regeneration in the osteochondral defect model; in contrast, the defects treated with 700-ng matrilin-3 exhibited drastically reduced cartilage regeneration with mixed hyaline-fibrocartilage morphology. Codelivery of matrilin-3 with Ad-MSCs significantly influenced articular cartilage regeneration, supporting the potential use of this tissue specific protein for a cartilage-targeted stem cell therapy. PMID- 28556571 TI - Controlling the Resting Membrane Potential of Cells with Conducting Polymer Microwires. AB - All cells have a resting membrane potential resulting from an ion gradient across the plasma membrane. The resting membrane potential of cells is tightly coupled to regeneration and differentiation. The ability to control this parameter provides the opportunity for both biomedical advances and the probing of fundamental bioelectric pathways. The use of poly(3,4-ethylenedioxythiophene): polystyrene sulfonate (PEDOT:PSS) conducting polymer microwires to depolarize cells is tested using E. coli cells loaded with a fluorescent dye that is pumped out of the cells in response to depolarization; a more positive membrane potential. Fluorescence imaging of the cells in response to a conducting-polymer microwire applied voltage confirms depolarization and shows that the rate of depolarization is a function of the applied voltage and frequency. Microwire activity does not damage the cells, demonstrated with a propidium iodide assay of membrane integrity. The conducting polymer microwires do not penetrate the cell, or even come into contact with the cell; they only need to generate a minimum electric field, controlled by the placement of the wires. It is expected that these microwires will provide a new, noninvasive, cellular-scale tool for the control of resting membrane potential with high spatial precision. PMID- 28556570 TI - What families have in the emergency tracheostomy kits: Identifying gaps to improve patient safety. AB - OBJECTIVE: To evaluate the contents of parent-created emergency tracheostomy kits and identify deficiencies. METHODS: This was an observational study. Data on emergency tracheostomy kits were abstracted for 30 consecutive children who had a tracheostomy tube in situ during an outpatient clinic visit with the Division of Respiratory Medicine and/or the Department of Otolaryngology-Head and Neck Surgery at the Hospital for Sick Children between February 1 and October 30, 2016. A checklist of 12 essential items based on expert consensus was used to evaluate each tracheostomy kit. RESULTS: Emergency tracheostomy kits from all children were missing at least one item from the 12-item checklist. Nineteen (63%) kits had three or more critical items missing. All kits had the same size tracheotomy tube. Twenty-two (73%) kits did not have a half size smaller tracheostomy tube. Fifteen (50%) were missing a manual resuscitation bag and four (13.3%) were missing a suction machine. Children who had tracheostomy tube in situ for >=4 years were more likely to have >=3 missing items in their kit (43.4%) compared to those who had tracheostomy tube for <4 years (20%), (chi2 (1) = 9.85, P = 0.0017). CONCLUSION: Maintenance of a fully stocked emergency tracheostomy kit can save a child's life. It is incumbent upon healthcare providers to ensure ongoing reassessment of knowledge and skills required to care for a child with a tracheostomy tube and to regularly review the components of a child's emergency tracheostomy kit. PMID- 28556572 TI - The Effect of Temperature on Selectivity in the Oscillatory Mode of the Phenylacetylene Oxidative Carbonylation Reaction. AB - Reaction temperature plays a major role in product selectivity in the oscillatory mode of the palladium-catalyzed phenylacetylene oxidative carbonylation reaction. At 40 degrees C, dimethyl (2Z)-2-phenyl-2-butenedioate is the major product whereas at 0 degrees C the major product is 5,5-dimethoxy-3-phenyl-2(5H) furanone. The occurrence of oscillations in pH coincides with an increase in the rate of phenylacetylene consumption and associated product formation. Experiments were performed isothermally in a reaction calorimeter to correlate reactant consumption and product formation with the occurrence of pH oscillations and the heat released by the reaction. An increase in the size of the pH drop in a single oscillation correlates with an increase in energy, indicating that this section of a single oscillation relates to reactant consumption. Based on these observations, a reaction pathway responsible for product formation is provided. PMID- 28556573 TI - Initiating Intrapartum Nitrous Oxide in an Academic Hospital: Considerations and Challenges. AB - A 50%-50% mixture of nitrous oxide and oxygen has long been used for managing pain during labor in many countries, but only recently has this intrapartum analgesic technique become popular in the United States. Nitrous oxide is considered minimal sedation and a safe pain management alternative. Many facilities are now interested in providing laboring women this analgesic option. The process of establishing use of nitrous oxide in a large institution can be complicated and may seem daunting. This brief report describes the challenges that occurred during the process of initiating nitrous oxide for pain management during childbirth at an academic medical center and discusses various committee roles. Nurses at the University of New Mexico Hospital now directly oversee the administration of nitrous oxide to women in labor in accordance to an established guideline. Despite limited available research, the guideline also allows offering nitrous oxide as a pain management technique for women with opioid dependence. Key components of the guideline and specifics related to education, cost, and safety are reviewed. PMID- 28556574 TI - Influence of Environmental Factors on Essential Oil Variability in Origanum compactum Benth. Growing Wild in Morocco. AB - The present study aimed to evaluate the influence of environmental factors on essential oils (EOs) composition of Origanum compactum populations sampled all over the distribution area of the species in Morocco, and to determine the extent of the chemical profiles throughout the geographical distribution of the species. The chemical compositions were submitted to canonical correlation analysis and canonical discriminant analysis that indicated a significant relationship between oil components and some environmental factors. According to their chemical composition and edapho-climatic characteristics, two major groups of populations were differentiated. The first group was composed of samples growing in regions with humid climate, clayey, sandy, and alkaline soils. These samples showed high thymol, alpha-terpineol, linalool, and carvacryl methyl oxide content. The second group consisted of plants belonging to semi-arid climate, and growing at high altitudes and silty soils. These samples were characterized by high carvacrol, alpha-thujene, alpha-terpinene, and myrcene content. However, populations exposed to sub-humid climate, appeared less homogeneous and belong mainly either to the first or second group. A significant correlation between some edaphic factors (pH, K2 O content, soil texture) and the EOs yield of O. compactum plants was evidenced. In spite of the correlation obtained for the oil composition with edapho-climatic factors and the variance explained by the environmental data set, the observed EO diversity might be also genetically determined. PMID- 28556575 TI - Characterizing the impact of pressure on virus filtration processes and establishing design spaces to ensure effective parvovirus removal. AB - Virus filtration provides robust removal of potential viral contaminants and is a critical step during the manufacture of biotherapeutic products. However, recent studies have shown that small virus removal can be impacted by low operating pressure and depressurization. To better understand the impact of these conditions and to define robust virus filtration design spaces, we conducted multivariate analyses to evaluate parvovirus removal over wide ranges of operating pressure, solution pH, and conductivity for three mAb products on PlanovaTM BioEX and 20N filters. Pressure ranges from 0.69 to 3.43 bar (10.0-49.7 psi) for Planova BioEX filters and from 0.50 to 1.10 bar (7.3 to 16.0 psi) for Planova 20N filters were identified as ranges over which effective removal of parvovirus is achieved for different products over wide ranges of pH and conductivity. Viral clearance at operating pressure below the robust pressure range suggests that effective parvovirus removal can be achieved at low pressure but that Minute virus of mice (MVM) logarithmic reduction value (LRV) results may be impacted by product and solution conditions. These results establish robust design spaces for Planova BioEX and 20N filters where high parvovirus clearance can be expected for most antibody products and provide further understanding of viral clearance mechanisms. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1294-1302, 2017. PMID- 28556576 TI - Ultrafast dynamic contrast-enhanced mri of the breast using compressed sensing: breast cancer diagnosis based on separate visualization of breast arteries and veins. AB - PURPOSE: To evaluate the feasibility of ultrafast dynamic contrast-enhanced (UF DCE) magnetic resonance imaging (MRI) with compressed sensing (CS) for the separate identification of breast arteries/veins and perform temporal evaluations of breast arteries and veins with a focus on the association with ipsilateral cancers. MATERIALS AND METHODS: Our Institutional Review Board approved this study with retrospective design. Twenty-five female patients who underwent UF-DCE MRI at 3T were included. UF-DCE MRI consisting of 20 continuous frames was acquired using a prototype 3D gradient-echo volumetric interpolated breath-hold sequence including a CS reconstruction: temporal resolution, 3.65 sec/frame; spatial resolution, 0.9 * 1.3 * 2.5 mm. Two readers analyzed 19 maximum intensity projection images reconstructed from subtracted images, separately identified breast arteries/veins and the earliest frame in which they were respectively visualized, and calculated the time interval between arterial and venous visualization (A-V interval) for each breast. RESULTS: In total, 49 breasts including 31 lesions (breast cancer, 16; benign lesion, 15) were identified. In 39 of the 49 breasts (breasts with cancers, 16; breasts with benign lesions, 10; breasts with no lesions, 13), both breast arteries and veins were separately identified. The A-V intervals for breasts with cancers were significantly shorter than those for breasts with benign lesions (P = 0.043) and no lesions (P = 0.007). CONCLUSION: UF-DCE MRI using CS enables the separate identification of breast arteries/veins. Temporal evaluations calculating the time interval between arterial and venous visualization might be helpful in the differentiation of ipsilateral breast cancers from benign lesions. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:97-104. PMID- 28556577 TI - Clinical and neurobiological effects of aerobic exercise in dental phobia: A randomized controlled trial. AB - BACKGROUND: Physical activity has shown to be effective in anxiety disorders. For specific phobia, no studies are available that systematically examined the effects of an aerobic exercise intervention on phobic fear within a randomized controlled design. Therefore, we investigated the acute effect of a standardized aerobic training on clinical symptoms of dental phobia as well as on stress related neurobiological markers. METHODS: Within a crossover design, 30 patients with dental phobia (mean age: 34.1 years; mean score of the Dental Anxiety Scale: 18.8) underwent two minor dental interventions separated by 7 days. Dental treatment was performed after 30 min of physical activity at either 20% VO2 max (control) or 70% VO2 max (intervention), respectively. To control for habituation, patients were randomly assigned to one of the two conditions prior to the first intervention. Moreover, saliva samples were collected at five times in order to determine changes in salivary cortisol (sC) and alpha-amylase (sAA) due to treatment. RESULTS: In comparison to baseline, aerobic exercise within 70% VO2 max significantly reduced clinical anxiety and sC concentrations before, during, and after the dental treatment. In contrast, the control condition led to decreased sAA levels at different time points of measurement. Habituation occurred at the second study day, independent of the order. CONCLUSIONS: Our study provides evidence for an effect of moderate-intense exercise on clinical symptoms and sC in patients with dental phobia. Therefore, acute aerobic exercise might be a simple and low-cost intervention to reduce disorder-specific phobic fear. PMID- 28556578 TI - Fasting serum hippuric acid is elevated after bilberry (Vaccinium myrtillus) consumption and associates with improvement of fasting glucose levels and insulin secretion in persons at high risk of developing type 2 diabetes. AB - SCOPE: Urinary hippuric acid has been proposed as a biomarker for fruit, vegetable, and polyphenol consumption. We assessed how serum hippuric acid changes after a bilberry-enriched diet (BB; high anthocyanin intake) and another berry diet including strawberries, raspberries, and cloudberries (SRC; lower anthocyanin intake) and how these changes associate with insulin and glucose metabolism. METHODS AND RESULTS: Hippuric acid was measured with LC-QTOF-MS metabolite profiling analysis from fasting serum samples at baseline and after an 8-week intervention in 47 individuals with features of the metabolic syndrome who were randomized to either a BB diet (n = 15), an SRC diet (n = 20) or a control diet (n = 12). Fasting serum hippuric acid increased significantly (3.5-fold, p = 0.001) only in the BB group and correlated with changes in fasting plasma glucose concentration (r = -0.54, p < 0.05) and insulin secretion (r = 0.59, p < 0.05). These associations were confirmed in the Finnish Diabetes Prevention Study (n = 198). CONCLUSION: Fasting serum hippuric acid is increased after consumption of anthocyanin-rich bilberries, and may contribute to the beneficial effect of bilberry consumption through its associations with better glycemic control and beta-cell function. PMID- 28556579 TI - Abortion. PMID- 28556580 TI - Sending family history questionnaires to patients before a colonoscopy improves genetic counseling for hereditary colorectal cancer. AB - OBJECTIVES: To investigate whether sending a family history questionnaire to patients prior to undergoing colonoscopy results in an increased availability of family history and better genetic counseling. METHODS: A questionnaire was mailed to patients before they underwent outpatient colonoscopy at a university hospital in 2013. These patients' additional characteristics and referral for genetic evaluation were retrieved from the electronic medical records. Patients undergoing inpatient coloboscopy, with confirmed hereditary colorectal cancer (CRC) or inflammatory bowel disease were excluded. All study patients from 2010 to 2013 were matched with the database of the genetics department to determine who consulted a geneticist. RESULTS: A total of 6163 patients underwent colonoscopy from 2010 to 2013. Of 1421 who underwent colonoscopy in 2013, 53 (3.7%) consulted a geneticist, while 75 (1.6%) of 4742 patients undergoing colonoscopy between 2010 and 2012 did so (P < 0.01). A total of 974 patients undergoing colonoscopy in 2013 were included to evaluate the completed questionnaire. Of these, 282 (29.0%) completed the questionnaire. Family history was not recorded in the electronic medical records of 393 (40.3%). In 129 (32.8%), family history was obtained from the completed questionnaire. In 2013, 49 (60.5%) out of 81 patients referred for genetic counseling were referred based on their family history. Eight (9.9%) patients were referred based on the completed questionnaire. CONCLUSION: Screening for hereditary CRC in a population undergoing outpatient colonoscopy with a questionnaire sent by mail resulted in an increased availability of family histories and genetic counseling. PMID- 28556582 TI - Precision and accuracy of imageless navigation versus freehand implantation of total hip arthroplasty: A systematic review and meta-analysis. AB - BACKGROUND: Total hip arthroplasty (THA) is named the most successful surgical procedure of the twentieth century. To remain a success in the twenty-first century THA should meet the higher demands of patients and society with regard to technical and functional outcome, costs and implant survival. To meet these demands optimal acetabular cup positioning is necessary. An imageless navigation system (NAV) might prevent malpositioning of the acetabular cup in THA. The aim of this study has been to compare the precision and accuracy of the anteversion and inclination of the acetabular cup position after NAV implantation and after freehand implantation of THA. METHODS: A systematic review and meta-analysis was conducted to assess the precision (variance) and accuracy (deviation from the target) from all available high-quality randomised control trials to date. RESULTS: Six out of seven studies concluded a statistically significant difference in precision in anteversion between the NAV group and the freehand group. Five out of seven studies concluded a statistically significant difference in precision in inclination. There is a significantly better accuracy for the NAV group than for the freehand group for anteversion (p = 0.002) and for inclination (p = 0.01). CONCLUSION: This study showed that NAV placement is more precise and has an improved accuracy for anteversion and inclination than freehand placement of the acetabular cup. However, there is a lack of evidence to support an improved functional outcome and a reduction of complications and revisions. PMID- 28556583 TI - Learning From Lessons on Applying Information Technology in Organ Transplant: A Stepping Stone to Achieve Electronic Health Record Meaningful Use. PMID- 28556581 TI - Population Modeling of Selexipag Pharmacokinetics and Clinical Response Parameters in Patients With Pulmonary Arterial Hypertension. AB - Selexipag (Uptravi) is an oral selective IP prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension (PAH). The pivotal GRIPHON study was the largest clinical study ever conducted in PAH patients, providing long-term data from 1,156 patients. PAH comedication did not affect exposure to selexipag, while exposure to its active metabolite ACT-333679 was reduced by 30% when taken in combination, clinically not relevant in the context of individual dose up-titration. Using log-linear regression models linking model predicted steady-state exposure to pharmacodynamics (PD), exposure to selexipag and ACT-333679 showed some statistically significant, albeit not clinically relevant, effects on exercise capacity, laboratory values, and the occurrence of prostacyclin-related adverse events, but not on vital signs or adverse events denoting hemorrhage. Using suitable modeling techniques, the GRIPHON study yielded clinically relevant data with limited burden of pharmacokinetics (PK) blood sampling, demonstrating that PK/PD modeling enables firm conclusions even with sparse PK and PD sampling. PMID- 28556584 TI - Efficacy between high and medium doses of glucocorticoid therapy in remission induction of IgG4-related diseases: a preliminary randomized controlled trial. AB - AIM: In order to evaluate the efficacy and safety of high versus medium doses of glucocorticoid therapy in remission induction of immunoglobulin G4-related disease (IgG4-RD), we set up a randomized controlled study. METHOD: Newly diagnosed IgG4-RD patients were randomly assigned to two groups: high doses of prednisone (0.8-1.0 mg/kg/day) and medium doses (0.5-0.6 mg/kg/day). Patients were assessed at weeks 0, 4, 12 and 24. The primary outcome was the remission rate at week 24. The secondary endpoints included IgG4-RD responder index (IgG4 RD RI), IgG and IgG4 levels. RESULTS: Twenty cases in each group finished the study. At week 24, the total response rates were 95% and 80% in high and medium dose groups, respectively. There was no significant difference between the two groups. IgG4-RD RI reduced from 14.9 to 3.0 in the high dose group, while in the medium dose group it was from 13.1 to 3.2. At week 24, the average level of IgG4 reduced from 1576 to 324 mg/dL and from 1445 to 684 mg/dL in the two groups, respectively. Relapsed patients had higher baseline IgG4-RD RI. There was no severe adverse effect shown in both groups. CONCLUSION: The effect of remission induction was similar in high and medium glucocorticoid groups. However, patients with more organs involved and higher IgG4-RD RI score at baseline might get more benefit with high dose glucocorticoid for remission induction. PMID- 28556585 TI - Diagnosing endocrine hypertension: a practical approach. AB - Hypertension is a leading cardiovascular risk factor that remains difficult to manage in a large segment of the population. Secondary causes of hypertension, which are amenable to targeted treatment or even cure, may contribute to poor blood pressure control. The most common endocrine cause, primary aldosteronism, requires biochemical screening as there are often no symptoms or signs other than hypertension. Screening tests should be performed after adequate preparation to optimize the results and minimize the confounding effects of diet and medications. Further testing beyond the initial screen generally requires input from specialist units to coordinate confirmatory tests and radiological procedures. Other less common or even rare endocrine causes of hypertension generally present with symptoms and signs of pituitary, adrenal, thyroid or parathyroid dysfunction rather than hypertension per se. Here, we review the endocrine causes of hypertension and provide a practical approach to their diagnosis. PMID- 28556586 TI - Dihydroartemisinin-piperaquine versus artesunate-amodiaquine for treatment of malaria infection in pregnancy in Ghana: an open-label, randomised, non inferiority trial. AB - OBJECTIVE: To determine whether dihydroartemisinin-piperaquine (DHA-PPQ) is non inferior to artesunate-amodiaquine (ASAQ) for treating uncomplicated malaria infection in pregnancy. METHODS: A total of 417 second/ third trimester pregnant women with confirmed asymptomatic Plasmodium falciparum parasitaemia were randomised to receive DHA-PPQ or ASAQ over 3 days. Women were followed up on days 1, 2, 3, 7, 14, 28 and 42 after treatment start and at delivery for parasitological, haematological, birth outcomes and at 6-week post-partum to ascertain the health status of the babies. Parasitological efficacy (PE) by days 28 and 42 were co-primary outcomes. Analysis was per-protocol (PP) and modified intention-to-treat (ITT). Non-inferiority was declared if the two-sided 95% confidence interval for PE at the endpoints excluded 5% lower efficacy for DHA PPQ. Secondary outcomes were assessed for superiority. RESULTS: In PP analysis, PE was 91.6% for DHA-PPQ and 89.3% for ASAQ by day 28 and 89.0% and 86.5%, respectively, by day 42. DHA-PPQ was non-inferior to ASAQ with respect to uncorrected PE [adjusted difference by day 28 (DHA-PPQ-ASAQ); 3.5% (95%CI: -1.5, 8.5); and day 42: 3.9% (95%CI: -2.7, 10.4)]. ITT analysis gave similar results. PCR to distinguish recrudescence and reinfection was unsuccessful. DHA-PPQ recipients had fewer adverse events of vomiting, dizziness, and general weakness compared to ASAQ. Both drugs were well-tolerated, and there was no excess of adverse birth outcomes. CONCLUSION: DHA-PPQ was non-inferior to ASAQ for treatment of malaria infection during pregnancy. No safety concerns were identified. Our findings contribute to growing evidence that DHA-PPQ is useful for control of malaria in pregnancy. PMID- 28556587 TI - A graphic approach to the analysis of a large X-ray microanalysis dataset obtained via SEM-EDS. AB - A graphical method for phase analysis of advanced materials by EDS-SEM was developed and demonstrated on deformed superconducting Bi(Pb)2223 ceramics. Through visual representation, this method allows for the rapid and efficient analysis of large X-ray microanalysis datasets and to identify phase composition of fine particles of secondary phases against a background of other phases. The graphical method can be applied using existing software and therefore does not require the development of new programs or complex computations. PMID- 28556589 TI - Dual-Emission Channels for Simultaneous Sensing of Cysteine and Homocysteine in Living Cells. AB - The development of a fluorescent probe to distinguish between cysteine (Cys) and homocysteine (Hcy) is always a challenge owing to their structural similarity, and the simultaneous detection of Cys and Hcy by utilizing different emission channels is especially difficult. In this work, we designed and synthesized a new fluorescent probe to differentiate between Cys and Hcy on the basis of a coumarin derivative with a chlorine atom and an alpha,beta-unsaturated aldehyde. Cys and Hcy induced different cascade reactions with the probe, which led to different products with distinct photophysical properties. The nonfluorescent probe responded to Cys and emitted strong blue fluorescence, whereas it reacted with Hcy and generated yellow fluorescence without interference from glutathione. In addition, the probe was successfully applied to distinguish between Cys and Hcy in living cells. PMID- 28556590 TI - Biocompatibility of four common orthopedic biomaterials following neuroelectromyostimulation: An in-vivo study. AB - Despite the worldwide high prevalence of total joint arthroplasty (TJA), life expectancy of prosthesis remains limited by mechanical and chemical constraint which promote wear debris production, surrounding tissues damage and finally prosthesis loosening. Such results could be amplified by neuro myoelectrostimulation (NMES; widely used to reduce neuromuscular deficits observed following TJA surgery). It was previously described in an in vivo experiment that interactions between NMES and Ti6Al4V implant are deleterious for both implant and surrounding muscles. The purpose of the present study was to compare the biocompatibility of four common orthopedic biomaterials, two metallic (Ti6Al4V, CrCo) and two nonmetallic (PEEK, Al2 O3 ) alloys, fixed on rat tibial crest in which the surrounding muscles were electrostimulated. Muscle cell death rate was not found significantly increased, with or without electrical stimulation for nonmetallic implants. Contrary to Ti6Al4V alloy, the CrCo implant did not induce destruction of the surrounding muscle. However, cell viability decreased for both metallic alloys when NMES was applied but within a greater significant extent for Ti6Al4V implant. Otherwise, when NMES was applied, implant to-bone adhesion significantly decreased for Ti6Al4V while no significant difference was found for PEEK, Al2 O3 , and CrCo. Statistical analyses reveal also a lesser adhesion strength for Ti6Al4V compared with CrCo when NMES was applied. Selecting the most suitable material in term of biocompatibility remains a major concern and non-metallic materials seems to be more appropriated in regard to electrical currents used for post TJA care. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1156-1164, 2018. PMID- 28556591 TI - Preparation of magnetic molecularly imprinted polymers for the rapid and selective separation and enrichment of perfluorooctane sulfonate. AB - As a persistent organic pollutant, perfluorooctane sulfonate has drawn a great worldwide attention. In this contribution, a novel material of magnetic molecularly imprinted polymers, based on perfluorooctane sulfonate, as a template, molecule was prepared. The magnetic molecularly imprinted polymers were characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, and vibrating sample magnetometry. The adsorption isotherm was measured, and adsorption kinetic tests were conducted. The adsorbents possess high recognition ability (2.460 mg/g) and short adsorption equilibration time (60 min). Besides, they show good specificity and good reusability with the adsorption capacities of adsorbent toward perfluorooctane sulfonate decreasing less than 3% after five adsorption-desorption cycles. The magnetic molecularly imprinted polymers were used successfully in the separation and enrichment of perfluorooctane sulfonate in real water sample and exhibited good prospects in environmental treatment and monitoring. PMID- 28556588 TI - Effects of DNA Methylation on Progression to Interstitial Fibrosis and Tubular Atrophy in Renal Allograft Biopsies: A Multi-Omics Approach. AB - Progressive fibrosis of the interstitium is the dominant final pathway in renal destruction in native and transplanted kidneys. Over time, the continuum of molecular events following immunological and nonimmunological insults lead to interstitial fibrosis and tubular atrophy and culminate in kidney failure. We hypothesize that these insults trigger changes in DNA methylation (DNAm) patterns, which in turn could exacerbate injury and slow down the regeneration processes, leading to fibrosis development and graft dysfunction. Herein, we analyzed biopsy samples from kidney allografts collected 24 months posttransplantation and used an integrative multi-omics approach to understand the underlying molecular mechanisms. The role of DNAm and microRNAs on the graft gene expression was evaluated. Enrichment analyses of differentially methylated CpG sites were performed using GenomeRunner. CpGs were strongly enriched in regions that were variably methylated among tissues, implying high tissue specificity in their regulatory impact. Corresponding to this methylation pattern, gene expression data were related to immune response (activated state) and nephrogenesis (inhibited state). Preimplantation biopsies showed similar DNAm patterns to normal allograft biopsies at 2 years posttransplantation. Our findings demonstrate for the first time a relationship among epigenetic modifications and development of interstitial fibrosis, graft function, and inter individual variation on long-term outcomes. PMID- 28556592 TI - The effect of riboflavin/UVA cross-linking on anti-degeneration and promoting angiogenic capability of decellularized liver matrix. AB - Weak mechanical property and unstable degradation rate limited the application of decellularized liver matrix in tissue engineering. The aim of this study was to explore a new method for improving the mechanical properties, anti-degeneration and angiogenic capability of decellularized liver matrix. This was achieved by a novel approach using riboflavin/ultraviolet A treatment to induce collagen cross linking of decellularized matrix. Histological staining and scanning electron microscope showed that the diameter of cross-linked fibers significantly increased compared with the control group. The average peak load and Young's modulus of decellularized matrix were obviously improved after cross-linking. Then we implanted the modified matrix into the rat hepatic injury model to test the anti-degeneration and angiogenic capability of riboflavin/UVA cross-linked decellularized liver scaffolds in vivo. The results indicated that cross-linked scaffolds degrade more slowly than those in the control group. In the experiment group, average microvessel density in the implanted matrix was higher than that in the control group since the first week after implantation. In conclusion, we initiated the method to improve the biomechanical properties of decellularized liver scaffolds by riboflavin/UVA cross-linking, and more importantly, its improvement on anti-degeneration and angiogenesis was identified. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2662-2669, 2017. PMID- 28556594 TI - Fibroadenoma in adolescent females after living donor liver transplantation. AB - Breast FA is the most common breast tumor diagnosed in young women. Female renal transplant recipients on CsA have an increased risk of developing FA. However, reports of FA after LDLT have not been described. Our objectives were to determine the incidence of FA, analyze risk factors for FA, and evaluate treatment strategies in adolescent females after LDLT. A total of 18 female patients aged 10-19 years who underwent LDLT and survived at least one year after transplantation were enrolled in our study. The incidence of FA was 11.1%. To determine pre- or post-transplant conditions that are associated with FA after transplantation, the patients were divided into two groups according to the presence or absence of FA: FA group (n=2) and non-FA group (n=16). There were no differences in mean age at LDLT, mean age at breast evaluation, and mean duration between transplantation and breast evaluation between the two groups. However, there was a difference in the immunosuppressive regimen between the two groups. The FA group was maintained on CsA, whereas the non-FA group was maintained on tacrolimus. CsA might be implicated in FA development in adolescent females after LDLT. PMID- 28556595 TI - Strategies for Efficient Solar Water Splitting Using Carbon Nitride. AB - Graphitic carbon nitride (g-C3 N4 )-based photocatalysts are promising for photocatalytic water splitting to produce clean solar fuels due to their low cost, suitable band structure and excellent photocatalytic performance. This review focuses on the state-of-the-art progress of the strategies for modifying g C3 N4 -based photocatalysts toward efficient photocatalytic water splitting. In particular, we highlight the importance of interfacial engineering and nanostructural control to facilitating charge separation and migration. Other strategies including doping and defect engineering are also concisely discussed. Finally, the perspectives on the challenges and future development of g-C3 N4 based photocatalysts are presented. PMID- 28556593 TI - Comparative molecular profiling of HPV-induced squamous cell carcinomas. AB - Approximately 5% of all cancer incidences result from human papillomavirus (HPV) infection. HPV infection most commonly leads to cancers of the anogenital region or oropharynx. It is unknown whether different HPV-mediated cancers collectively share a molecular signature and it is important to determine if there are targetable alterations common to different types of HPV-positive tumors. We analyzed 743 p53 wild-type samples of anal, cervical, oropharyngeal, and vulvar squamous cell carcinomas which underwent multiplatform testing at a commercial molecular profiling service. Expression of 24 proteins was measured by immunohistochemistry (IHC), mutation of 48 genes was determined by next generation and Sanger sequencing, and copy number alteration for six genes was determined by in situ hybridization. The four cohorts had remarkably similar molecular profiles. No gene had a statistically significant difference in mutation frequency or copy number change between the four different types of squamous cell carcinomas. The only significant differences between cohorts were frequency of ERCC1 and SPARC loss as determined by IHC. In all four cancer types, oncogene mutation and PD-L1 expression was relatively infrequent. The most commonly mutated gene was PIK3CA, with mutations most often affecting the helical domain of the protein and accompanied by concurrent lack of PTEN expression. Loss of MGMT and RRM1 was common among the four cohorts and may be predictive of response to cytotoxic therapies not currently being used to treat these cancer types. The similar molecular profiles of the four cohorts indicate that treatment strategies may be similarly efficacious across HPV-positive cancers. PMID- 28556596 TI - Surface Energy and Surface Stability of Ag Nanocrystals at Elevated Temperatures and Their Dominance in Sublimation-Induced Shape Evolution. AB - The surface energy and surface stability of Ag nanocrystals (NCs) are under debate because the measurable values of the surface energy are very inconsistent, and the indices of the observed thermally stable surfaces are apparently in conflict. To clarify this issue, a transmission electron microscope is used to investigate these problems in situ with elaborately designed carbon-shell capsulated Ag NCs. It is demonstrated that the {111} surfaces are still thermally stable at elevated temperatures, and the victory of the formation of {110} surfaces over {111} surfaces on the Ag NCs during sublimation is due to the special crystal geometry. It is found that the Ag NCs behave as quasiliquids during sublimation, and the cubic NCs represent a featured shape evolution, which is codetermined by both the wetting equilibrium at the Ag-C interface and the relaxation of the system surface energy. Small Ag NCs (~10 nm) no longer maintain the wetting equilibrium observed in larger Ag NCs, and the crystal orientations of ultrafine Ag NCs (~6 nm) can rotate to achieve further shape relaxation. Using sublimation kinetics, the mean surface energy of Ag NCs at 1073 K is calculated to be 1.1-1.3 J m-2 . PMID- 28556597 TI - G-CSF Indirectly Induces Apoptosis of Osteoblasts During Hematopoietic Stem Cell Mobilization. AB - The objective of this study was to explore the mechanism underlying osteoblast suppression in the process of hematopoietic stem cells mobilization induced by granulocyte colony-stimulating factor (G-CSF). The apoptosis of human and mouse osteoblasts was examined by detecting caspase 3. The levels of serum DKK1 and osteocalcin in the supernatant of co-culture of mouse osteoblasts and mouse bone marrow nucleated cells were measured. The number of mouse osteoblasts co-cultured with mouse bone marrow nucleated cells was measured and the osteocalcin mRNA level was also measured. The G-CSF-induced decrease in osteoblast function was partly due to the apoptosis of osteoblasts. There was no significant difference in the level of serum DKK1 in healthy donors before and 5 days after mobilization. The osteocalcin gene and protein expression was significantly different in co-cultured osteoblasts with bone marrow nucleated cells treated with and without G-CSF. Osteoblasts undergo apoptosis during mobilization and G CSF affects osteoblasts through bone marrow nucleated cells. PMID- 28556599 TI - Updates From the Literature, May/June 2017. PMID- 28556598 TI - Single- and Multiple-Day Dosing Studies to Investigate High-Dose Pharmacokinetics of Epelsiban and Its Metabolite, GSK2395448, in Healthy Female Volunteers. AB - Open-label single- and double-blind repeat-dose studies in healthy female volunteers were conducted to investigate the pharmacokinetics (PK) and safety/tolerability of epelsiban total daily doses ranging from 600 to 900 mg. In 1 study (n = 12), epelsiban was dosed at 300 or 450 mg twice daily (every 12 hours) for a single day. In the repeat-dose double-blind study, epelsiban and placebo were administered to 31 subjects as 200 mg 3 times daily, 300 mg 3 times daily (TID), or 450 mg twice daily (BID) for 14 days. After both single and 14 daily repeat doses, the PK profiles for epelsiban and its metabolite, GSK2395448, remained linear at all administered doses. The exposures at a given total daily dose were also similar between BID and TID dosing regimens. Exposure (AUC0-tau ), based on dosing intervals, for both epelsiban and GSK2395448 was similar. However, compared with morning dosing, Cmax was lower after evening dosing, possibly because of a food effect. The highest accumulation of epelsiban and GSK2395448 exposures (AUC0-tau ) was approximately 34% for each after repeat dosing, consistent with the short half-life. At total daily doses of 600 and 900 mg, epelsiban was generally well tolerated, and there were no significant safety concerns identified. PMID- 28556600 TI - Enhanced expression of cysteine-rich antimicrobial peptide snakin-1 in Escherichia coli using an aggregation-prone protein coexpression system. AB - Snakin-1 (SN-1) is a cysteine-rich plant antimicrobial peptide and the first purified member of the snakin family. SN-1 shows potent activity against a wide range of microorganisms, and thus has great biotechnological potential as an antimicrobial agent. Here, we produced recombinant SN-1 in Escherichia coli by a previously developed coexpression method using an aggregation-prone partner protein. Our goal was to increase the productivity of SN-1 via the enhanced formation of insoluble inclusion bodies in E. coli cells. The yield of SN-1 by the coexpression method was better than that by direct expression in E. coli cells. After refolding and purification, we obtained several milligrams of functionally active SN-1, the identity of which was verified by MALDI-TOF MS and NMR studies. The purified recombinant SN-1 showed effective antimicrobial activity against test organisms. Our studies indicate that the coexpression method using an aggregation-prone partner protein can serve as a suitable expression system for the efficient production of functionally active SN-1. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1520-1528, 2017. PMID- 28556601 TI - Polymorphism at residue 156 of the new HLA-A*02:683 allele suggests immunological relevance. AB - HLA-A*02:683 is most similar to 4 different HLA-A*02 subtypes with a single nucleotide difference. PMID- 28556603 TI - Taking Care of Your Health. PMID- 28556602 TI - A Free-Radical Pathway to Hydrogenated Phenanthrene in Molecular Clouds-Low Temperature Growth of Polycyclic Aromatic Hydrocarbons. AB - The hydrogen-abstraction/acetylene-addition mechanism has been fundamental to unravelling the synthesis of polycyclic aromatic hydrocarbons (PAHs) detected in combustion flames and carbonaceous meteorites like Orgueil and Murchison. However, the fundamental reaction pathways accounting for the synthesis of complex PAHs, such as the tricyclic anthracene and phenanthrene along with their dihydrogenated counterparts, remain elusive to date. By investigating the hitherto unknown chemistry of the 1-naphthyl radical with 1,3-butadiene, we reveal a facile barrierless synthesis of dihydrophenanthrene adaptable to low temperatures. These aryl-type radical additions to conjugated hydrocarbons via resonantly stabilized free-radical intermediates defy conventional wisdom that PAH growth is predominantly a high-temperature phenomenon and thus may represent an overlooked path to PAHs as complex as coronene and corannulene in cold regions of the interstellar medium like in the Taurus Molecular Cloud. PMID- 28556604 TI - Loosening of the fixing screw in single implant crowns: predisposing factors, prevention and treatment options. AB - : The problem of technical complications in implants and implant-supported restorations has existed for decades. The most frequent complication is the loosening of the fixing screw, which although is not catastrophic, if it occurs repeatedly, it may affect the success of the implant therapy and the patient satisfaction. Factors that affect the frequency of prosthetic complications include: the implant-abutment connection, para-functional habits, cantilevers, and the type of restoration. Regarding the implant-abutment connection, the first systems were those with an external hexagon. Because of their small height and the disadvantages that this entails, other connection types were developed, such as those of hexagonal and conical connection, which decreased the complication rates, including the loosening of the fixing screw. On the dilemma "cement- or screw-retained restoration", the choice depends on biological, technical, and aesthetic factors. Cement-retained restorations are simpler in construction with lower cost and clinicians are more familiar with the clinical procedure. On the other side, if the fixing screw of the abutment is loosened in a cement-retained restoration, it may be a difficult and demanding clinical task to fix this prosthetic complication. Screw-retained restorations are more prone to loosening of the fixing screw, but allow easy retrievability and repair. Their use however, is often restricted because of diverting or unfavorable inclination of the alveolar ridge and the implant. The aim of this article was to present clinical solutions for the complication of screw-loosening through clinical examples and discuss the factors that may predispose to its occurrence. CLINICAL SIGNIFICANCE: The problem of technical complications in implants and implant-supported restorations has existed for decades. The most frequent complication is the loosening of the fixing screw which, although is not catastrophic, if it occurs repeatedly, it may affect the success of the implant therapy and the patient satisfaction. Factors that affect the frequency of prosthetic complications include: the implant-abutment connection, para-functional habits, cantilevers and the type of restoration. The treatment options for the clinician are limited but certain preventing measures during construction of the restoration may be helpful to overcome this clinical problem. PMID- 28556605 TI - Ionic Liquid/Metal-Organic Framework Composites: From Synthesis to Applications. AB - Metal-organic frameworks (MOFs) have been widely studied for different applications owing to their fascinating properties such as large surface areas, high porosities, tunable pore sizes, and acceptable thermal and chemical stabilities. Ionic liquids (ILs) have been recently incorporated into the pores of MOFs as cavity occupants to change the physicochemical properties and gas affinities of MOFs. Several recent studies have shown that IL/MOF composites show superior performances compared with pristine MOFs in various fields, such as gas storage, adsorption and membrane-based gas separation, catalysis, and ionic conductivity. In this review, we address the recent advances in syntheses of IL/MOF composites and provide a comprehensive overview of their applications. Opportunities and challenges of using IL/MOF composites in many applications are reviewed and the requirements for the utilization of these composite materials in real industrial processes are discussed to define the future directions in this field. PMID- 28556606 TI - Dinuclear Platinum(II) Complexes with Bone-Targeting Groups as Potential Anti Osteosarcoma Agents. AB - Osteosarcoma is the most common malignant bone tumor primarily affecting adolescents. Targeted platinum(II) complexes are promising candidates for overcoming the general toxicity of conventional platinum anticancer drugs. In this study four dinuclear platinum(II) complexes, {[cis-Pt(NH3 )2 Cl]2 (PD)} (NO3 )2 (1), {[cis-Pt(NH3 )2 Cl]2 (PDBP)} (NO3 )2 (2), {[cis-Pt(DACH)Cl]2 (PD)} (NO3 )2 (3), and {[cis-Pt(DACH)Cl]2 (PDBP)} (NO3 )2 (4) [PD=5,5'-carbonylbis(2-(2 (pyridin-2-yl)ethyl)isoindoline-1,3-dione), PDBP=tetraethyl (((bis(1,3-dioxo-2-(2 (pyridin-2-yl)ethyl)isoindolin-5-yl)methylene)amino) methylene)bis(phosphonate), DACH=1,2-diaminocyclohexane)], were designed and synthesized. The complexes were fully characterized by 1 H, 13 C, 195 Pt or 31 P NMR spectroscopy and HR-MS. ICP MS studies showed that considerable amounts of Pt accumulate in U2OS osteosarcoma cells. The interactions of the complexes with calf thymus DNA and plasmid pUC19 DNA were investigated using CD and gel electrophoresis, which indicated that the complexes can react with DNA. The in vitro cytotoxicity showed that 2 is the most potent complex towards U2OS cells. The cellular inhibition mode was examined by flow cytometry. Complex 2 kills U2OS cells predominately through an apoptotic pathway and arrests the cell cycle mainly in the G2 or M phase. The results demonstrate that dinuclear platinum(II) complexes with bone-targeting groups could be anticancer agents for osteosarcoma. PMID- 28556608 TI - Impact of a National Controlled Donation After Circulatory Death (DCD) Program on Organ Donation in the United Kingdom: A 10-Year Study. AB - Organ transplantation is the most successful treatment for some forms of organ failure, yet a lack of organs means many die on the waiting list. In the United Kingdom, the Organ Donation Taskforce was set up to identify barriers to organ donation and in 2008 released its first report (Organ Donation Taskforce Report; ODTR). This study assesses the success since the ODTR and examines the impact of the United Kingdom's controlled donation after circulatory death (DCD) program and the controversies surrounding it. There were 12 864 intended donation after brain death (DBD) or DCD donors from April 2004 to March 2014. When the 5 years preceding the ODTR was compared to the 5 years following, intended DCD donors increased 292% (1187 to 4652), and intended DBD donors increased 11% (3327 to 3698). Organs retrieved per intended DBD donor remained static (3.30 to 3.26), whereas there was a decrease in DCD (1.54 to 0.99) due to a large rise in donors who did not proceed to donation (325 to 2464). The majority of DCD donors who proceeded did so within 30 min from time of withdrawal. Our study suggests further work on converting eligible referrals to organ donation and exploring methods of converting DCD to DBD donors. PMID- 28556609 TI - Psychological impact of a genetic diagnosis on hearing impairment-An exploratory study. AB - OBJECTIVE: Genetic testing for hereditary hearing impairment has become more routinely available as a diagnostic tool in the outpatient clinic. However, little is known about the psychological impact of a genetic diagnosis. To evaluate this impact, an exploratory study was conducted. DESIGN: Prospectively, 48 individuals who underwent genetic testing for hereditary hearing impairment were included in this study. Study participants were asked to fill out the following questionnaires: Hospital Anxiety Depression Scale, Impact of Event Scale, Self-Efficacy 24, Illness Cognition Questionnaire and the Inventory for Social Reliance. Questionnaires were filled out on three occasions: before genetic testing, directly after counselling on either positive or negative test results, and six weeks thereafter. RESULTS: No significant differences were found between the group that received a genetic diagnosis for their hearing impairment and the group that did not. CONCLUSION: This study did not demonstrate differences between receiving a genetic diagnosis or not; however, special attention to psychological well-being should be offered to hearing-impaired patients who seek a genetic diagnosis for their hearing impairment. Additionally, the psychological impact of sensorineural hearing impairment might be greater than the impact of a genetic diagnosis itself. Based on the current exploratory study, there are no psychological reasons in favour of or against genetic testing for hereditary hearing impairment. PMID- 28556607 TI - Translational Modeling to Guide Study Design and Dose Choice in Obesity Exemplified by AZD1979, a Melanin-concentrating Hormone Receptor 1 Antagonist. AB - In this study, we present the translational modeling used in the discovery of AZD1979, a melanin-concentrating hormone receptor 1 (MCHr1) antagonist aimed for treatment of obesity. The model quantitatively connects the relevant biomarkers and thereby closes the scaling path from rodent to man, as well as from dose to effect level. The complexity of individual modeling steps depends on the quality and quantity of data as well as the prior information; from semimechanistic body composition models to standard linear regression. Key predictions are obtained by standard forward simulation (e.g., predicting effect from exposure), as well as non-parametric input estimation (e.g., predicting energy intake from longitudinal body-weight data), across species. The work illustrates how modeling integrates data from several species, fills critical gaps between biomarkers, and supports experimental design and human dose-prediction. We believe this approach can be of general interest for translation in the obesity field, and might inspire translational reasoning more broadly. PMID- 28556610 TI - VEGF release from a polymeric nanofiber scaffold for improved angiogenesis. AB - Angiogenesis plays a pivotal role in tissue engineering and regenerative medicine. This study aimed to develop an electrospun fiber scaffold that supports release of recombinant human vascular endothelial growth factor (rhVEGF) to enhance angiogenesis. Scaffolds composed of core-shell fibers were fabricated using co-electrospinning. The core solution was composed of polyethylene oxide and mixed with rhVEGF. The shell solution was composed of polycarpolactone, with 0.25, 1, and 3% of polyethylene glycol (PEG) to manipulate pore size on the shell. Pore size and density increased with higher PEG concentrations. Similarly, rhVEGF release was affected by PEG concentration: initial burst release was found in all scaffolds, followed by continuous 4 h release in 3% PEG and 18 h release in the 0.25 and 1% PEG polymeric scaffolds. Endothelial cell migration toward rhVEGF-incorporated polymeric scaffold was 80-fold higher as compared to VEGF free polymeric scaffold. In a subcutaneous mouse model, VEGF-incorporated polymeric scaffold stimulated cell migration into the scaffold within three days and significantly enhanced blood vessels formation within 14 days, whereas control scaffolds contained few vessels. In conclusion, the described novel scaffold represents a promising device for vascular tissue engineering, which may be of clinical significance in treating vascular deficient wounds. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2712-2721, 2017. PMID- 28556612 TI - Identification of a novel HLA-C*08 allele, HLA-C*08:01:20. AB - HLA-C*08:01:20 differs from C*08:01:01 by a single nucleotide substitution at position 93 of exon 2. PMID- 28556611 TI - Defining the minimal clinically important difference for olfactory outcomes in the surgical treatment of chronic rhinosinusitis. AB - BACKGROUND: Olfactory dysfunction is a common and defining symptom of chronic rhinosinusitis (CRS). Many measures of olfactory dysfunction in CRS are limited by scoring criteria defined within general populations with interpretations of statistical significance to infer clinically meaningful improvement. In this investigation we define a minimal clinically important difference (MCID) for the Brief Smell Identification Test (BSIT) in CRS patients electing endoscopic sinus surgery (ESS). METHODS: A multicenter cohort of 290 adult patients electing ESS for medically recalcitrant CRS were prospectively enrolled between March 2011 and June 2015 and completed BSIT evaluations before and after ESS. Distribution and anchor-based analytic approaches were utilized to define MCID values of the BSIT across patient cofactors. RESULTS: A total of 92 (?32%) patients were found to have preoperative olfactory dysfunction (BSIT <9), significantly associated with nasal polyposis (chi2 = 35.0; p < 0.001). The effect-size distribution-based approach identified 1.0 as a MCID criterion value between "small" and "medium" effect (range, 0.61-1.52) overall. Significant mean postoperative change (DeltaM) was reported for patients with olfactory dysfunction (DeltaM = 2.28; p < 0.001), both with (n = 54; DeltaM = 2.52; p < 0.001) and without (n = 38; DeltaM = 1.95; p < 0.001) nasal polyposis, significantly exceeding the MCID criterion. Anchor based approaches with regression modeling confirmed associations between MCID values and postoperative changes to olfactory-specific survey responses (p < 0.001). CONCLUSION: Clinically meaningful change in BSIT scores may be defined as an absolute value difference of at least 1.0 unit for heterogeneous patients electing ESS for CRS. Significantly exceeding this criterion may be restricted to CRS patients with baseline olfactory dysfunction, regardless of nasal polyposis. PMID- 28556614 TI - Preparation of arginine-modified reduced graphene oxide composite filled in an on line solid-phase extraction disk and its application in the analysis of heterocyclic aromatic amines. AB - An arginine-modified reduced graphene oxide composite was prepared in an on-line solid-phase extraction disk and coupled to high-performance liquid chromatography for the re-enrichment of heterocyclic aromatic amines. The synthetic composite presented an excellent adsorption capability because of the ultrahigh active surface area of graphene and the abundant alkaline groups of arginine. The adsorption capacity of it was 52.7 mg 2-amino-3-methyl-imidazo[4,5-f]-quinoline per gram, nearly twice that of threonine-modified reduced graphene oxide composite, glutamic acid modified reduced graphene oxide composite, and reduced graphene oxide. This on-line method was successfully applied to the detection of a series of heterocyclic aromatic amines in beef jerky. After clean-up and re enrichment of the on-line solid-phase extraction disk, the chromatographic background of the sample was low and the shape of chromatographic peaks was sharp. The method detection limit was in the range of 0.30-0.49 ng/g, and the recovery was in the range of 82.0-111.5%. PMID- 28556613 TI - Scale-up/Scale-down of microbial bioprocesses: a modern light on an old issue. AB - The bio-economy is in transit from innovation to commercialization. The bioprocess industry is expected to increasingly deliver bio-products to the market, in large amounts, at high quality and at competitive cost levels. This requires flawless start-up of new large-scale bioprocesses and continuous improvement of running processes. Fermentation scale-up and operation can benefit from recent advances in three areas: 1. computation-driven design of scale-down simulators, 2. omics-driven metabolic engineering and 3. sensing and understanding of population heterogeneity. Integration of these fields requires a unified computational approach, linked to big data and simulated reality frameworks, of which the contours are becoming visible today. PMID- 28556615 TI - Characteristics of germinal center-like structures in patients with Sjogren's syndrome. AB - AIM: To analyze the relationship between ectopic germinal centers (GCs) in the salivary glands and the clinical/laboratory characteristics of patients with Sjogren's syndrome (SS). METHODS: Retrospectively, 126 patients with primary SS (pSS) and 16 patients with secondary SS (sSS) were analyzed. Minor salivary gland biopsies were evaluated for the presence of GC-like morphology by hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining for CD21. Clinical and serological data were obtained from medical records. RESULTS: GC-like structures were observed in 36/126 (28.6%) pSS patients and 4/16 (25.0%) sSS patients. The mean inflammatory focus score of the gland was significantly higher in GC positive samples than in GC-negative ones in both pSS and sSS patients (P = 0.007 and 0.024, respectively). In pSS, significantly elevated titers of rheumatoid factor (RF)-IgM (P = 0.023) and antinuclear antibodies (ANA) (P = 0.036), increased levels of IgA (P = 0.012) and IgG (P = 0.017) were encountered in GC positive patients. The GC-positive group also presented higher prevalence of anti SSA antibodies, lower levels of white blood cells, higher levels of erythrocyte sedimentation rate and gamma-globulin, although not statistically significant. In sSS patients with ectopic GC formation, ANA titers were remarkably elevated. The anticyclic citrullinated peptide (anti-CCP)-IgG titers and the prevalence of antikeratin antibody (AKA)-IgG, antiperinuclear factor (APF)-IgG were also increased, yet not significantly. GCs were found to be associated with antibody and immunoglobulin production. CONCLUSION: This study indicates that SS patients with ectopic GCs have distinct features. Ectopic GC structures were particularly noted in patients with higher focus scores, and might play an essential role in sustaining antibody production as well as B cell activation. PMID- 28556616 TI - Fast-acting insulin aspart in Japanese patients with type 1 diabetes: Faster onset, higher early exposure and greater early glucose-lowering effect relative to insulin aspart. AB - INTRODUCTION: Fast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation with two added excipients (niacinamide and L-arginine) in order to obtain accelerated absorption after subcutaneous dosing. The present study compared the pharmacokinetic/pharmacodynamic characteristics of faster aspart vs IAsp in Japanese patients with type 1 diabetes. MATERIALS AND METHODS: In a randomized, double-blind, cross-over design, 43 participants were given faster aspart and IAsp (0.2 U/kg single dose) at two separate dosing visits. Frequent pharmacokinetic blood sampling was carried out, and pharmacodynamics were assessed using an automated euglycemic clamp lasting for a maximum of 12 h after dosing (target 5.5 mmol/L). RESULTS: Faster aspart showed onset of appearance approximately twice-as-fast vs IAsp (least squares means: 3.0 vs 7.1 min; estimated treatment difference -4.1 min, 95% confidence interval [CI]: -5.0, -3.2; P < 0.001) and onset of action occurring approximately 5 min earlier (20.2 vs 25.5 min; estimated treatment difference -5.3 min, 95% CI: -8.4, -2.2; P = 0.001). Within the first 30 min post-dose, both exposure (area under the curve [AUC]IAsp,0-30 min ) and glucose-lowering effect (AUCGIR,0-30 min ) were approximately twofold greater for faster aspart vs IAsp (P < 0.001 and P = 0.002, respectively). Bioavailability of faster aspart was similar to IAsp (AUCIAsp,0-t ; estimated treatment ratio 0.99, 90% CI: 0.96-1.02), whereas the total glucose lowering effect (AUCGIR,0-t ) was slightly lower for faster aspart vs IAsp (estimated treatment ratio 0.93, 95% CI: 0.87-0.99, P = 0.020). CONCLUSIONS: Faster aspart showed faster onset, higher early exposure and a greater early glucose-lowering effect relative to IAsp in Japanese patients with type 1 diabetes, in accordance with previous findings in Caucasian type 1 diabetes patients. PMID- 28556617 TI - Discovery of ectosymbiotic Endomicrobium lineages associated with protists in the gut of stolotermitid termites. AB - The genus Endomicrobium is a dominant bacterial group in the gut of lower termites, and most phylotypes are intracellular symbionts of gut protists. Here we report the discovery of Endomicrobium ectosymbionts of termite gut protists. We found that bristle-like Endomicrobium cells attached to the surface of spirotrichosomid protist cells inhabiting the termite Stolotermes victoriensis. Transmission electron microscopy revealed that a putative Endomicrobium cell likely attached to the protist surface via a protrusion from the tip of the bacterium. A phylotype, sharing 98.9% 16S rRNA sequence identity with the Endomicrobium ectosymbionts of the spirotrichosomid protists, was also found on the cell surface of the protist Trichonympha magna in the gut of the termite Porotermes adamsoni. We propose the novel species 'Candidatus Endomicrobium superficiale' for these bacteria. T. magna simultaneously harboured another Endomicrobium ectosymbiont that shared 93.5-94.2% 16S rRNA sequence identities with 'Ca. Endomicrobium superficiale'. Furthermore, Spirotrichonympha-like protists in P. adamsoni guts were associated with an Endomicrobium phylotype that possibly attached to the host flagella. A phylogenetic analysis suggested that these ectosymbiotic lineages have evolved multiple times from free-living Endomicrobium lineages and are relatively distant from the endosymbionts. Our results provide novel insights into the ecology and evolution of the Endomicrobium. PMID- 28556618 TI - High-Efficiency Perovskite Solar Cell Based on Poly(3-Hexylthiophene): Influence of Molecular Weight and Mesoscopic Scaffold Layer. AB - Here, we investigated the effect of the molecular weight (MW) of poly 3 hexylthiophene (P3HT) hole-transport material on the performance of perovskite solar cells (PSCs). We found that by increasing the MW the photovoltaic performances of the cells are enhanced leading to an improvement of the overall efficiency. P3HT-based PSCs with a MW of 124 kDa can achieve an overall average efficiency of 16.2 %, double with respect to the ones with a MW of 44 kDa. Opposite to spiro-OMeTAD-based PSCs, the photovoltaic parameters of the P3HT based devices are enhanced by increasing the mesoporous TiO2 layer thickness from 250 to 500 nm. Moreover, for a titania scaffold layer thickness of 500 nm, the efficiency of P3HT-based PSCs with high MW is larger than the spiro-OMeTAD based PSCs with the same scaffold layer thickness. Recombination reactions of the devices were also investigated by voltage decay and electrochemical impedance spectroscopy. We found that the relationship between P3HT MW and cell performance is related to the reduction of charge recombination and to the increase of the P3HT light absorption by increasing the MW. PMID- 28556619 TI - Enhanced process understanding and multivariate prediction of the relationship between cell culture process and monoclonal antibody quality. AB - This work investigates the insights and understanding which can be deduced from predictive process models for the product quality of a monoclonal antibody based on designed high-throughput cell culture experiments performed at milliliter (ambr-15(r) ) scale. The investigated process conditions include various media supplements as well as pH and temperature shifts applied during the process. First, principal component analysis (PCA) is used to show the strong correlation characteristics among the product quality attributes including aggregates, fragments, charge variants, and glycans. Then, partial least square regression (PLS1 and PLS2) is applied to predict the product quality variables based on process information (one by one or simultaneously). The comparison of those two modeling techniques shows that a single (PLS2) model is capable of revealing the interrelationship of the process characteristics to the large set product quality variables. In order to show the dynamic evolution of the process predictability separate models are defined at different time points showing that several product quality attributes are mainly driven by the media composition and, hence, can be decently predicted from early on in the process, while others are strongly affected by process parameter changes during the process. Finally, by coupling the PLS2 models with a genetic algorithm first the model performance can be further improved and, most importantly, the interpretation of the large dimensioned process-product-interrelationship can be significantly simplified. The generally applicable toolset presented in this case study provides a solid basis for decision making and process optimization throughout process development. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1368-1380, 2017. PMID- 28556621 TI - Measuring the aggregation of CHO cells prior to single cell cloning allows a more accurate determination of the probability of clonality. AB - The manufacturing process for biotherapeutics is closely regulated by the Food and Drug Administration (FDA), European Medicines Agency (EMA) and other regulatory agencies worldwide. To ensure consistency of the product of a manufacturing cell line, International Committee on Harmonization guidelines (Q5D, 1997) state that the cell substrate should be derived from a single cell progenitor, i.e., clonal.Cell lines in suspension culture may naturally revert to cell adhesion in the form of doublets, triplets and higher order structures of clustered cells. We can show evidence of a single colony from limiting dilution cloning or in semi-solid media, but we cannot determine the number of cells from which the colony originated. To address this, we have used the ViCELL(r) XR (Beckman Coulter, High Wycombe, UK) cell viability analyzer to determine the proportion of clusters of two or more cells in a sample of the cell suspension immediately prior to cloning. Here, we show data to define the accuracy of the ViCELL for characterizing a cell suspension and summarize the statistical model combining two or more rounds of cloning to derive the probability of clonality. The resulting statistical model is applied to cloning in semi-solid medium, but could equally be applied to a limiting dilution cloning process. We also describe approaches to reduce cell clusters to generate a cell line with a high probability of clonality from a CHO host lineage. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:593-601, 2018. PMID- 28556620 TI - Systematic Review of Quantitative Measures of Stakeholder Engagement. PMID- 28556622 TI - Predictors of Hospitalization, Length of Stay, and Cost of Care Among Adults With Dermatomyositis in the United States. AB - OBJECTIVE: To determine the prevalence and risk factors for hospitalization with dermatomyositis and assess inpatient burden of dermatomyositis. METHODS: Data on 72,651,487 hospitalizations from the 2002-2012 Nationwide Inpatient Sample, a 20% stratified sample of all acute-care hospitalizations in the US, were analyzed. International Classification of Diseases, Ninth Revision, Clinical Modification coding was used to identify hospitalizations with a diagnosis of dermatomyositis. RESULTS: There were 9,687 and 43,188 weighted admissions with a primary or secondary diagnosis of dermatomyositis, respectively. In multivariable logistic regression models with stepwise selection, female sex (logistic regression: adjusted odds ratio 2.05 [95% confidence interval (95% CI) 1.80, 2.34]), nonwhite race (African American: 1.68 [1.57, 1.79]; Hispanic: 2.38 [2.22, 2.55]; Asian: 1.54 [1.32, 1.81]; and multiracial/other: 1.65 [1.45, 1.88]), and multiple chronic conditions (2-5: 2.39 [2.20, 2.60] and >=6: 2.80 [2.56, 3.07]) were all associated with higher rates of hospitalization for dermatomyositis. The weighted total length of stay (LOS) and inflation-adjusted cost of care for patients with a primary inpatient diagnosis of dermatomyositis was 80,686 days and $168,076,970, with geometric means of 5.38 (95% CI 5.08, 5.71) and $11,682 (95% CI $11,013, $12,392), respectively. LOS and costs of hospitalization were significantly higher in patients with dermatomyositis compared to those without. Notably, race/ethnicity was associated with increased LOS (log-linear regression: adjusted beta [95% CI] for African American: 0.14 [0.04, 0.25] and Asian: 0.38 [0.22, 0.55]) and cost of care (Asian: 0.51 [0.36, 0.67]). CONCLUSION: There is a significant and increasing inpatient burden for dermatomyositis in the US. There appear to be racial differences, as nonwhites have higher prevalence of admission, increased LOS, and cost of care. PMID- 28556624 TI - A Quantitative Systems Physiology Model of Renal Function and Blood Pressure Regulation: Application in Salt-Sensitive Hypertension. AB - Salt-sensitivity (SS) refers to changes in blood pressure in response to changes in sodium intake. SS individuals are at greater risk for developing kidney disease, and also respond differently to antihypertensive therapies compared to salt-resistant (SR) individuals. In this study we used a systems pharmacology model of renal function (presented in a companion article) to evaluate the ability of proposed mechanisms to produce salt-sensitivity. The model reproduced previously published data on renal functional changes in response to salt-intake, and also predicted that glomerular pressure, a variable that is not easily evaluated clinically but is a key factor in renal injury, increases with salt intake in SS hypertension. We then used the model to generate mechanistic insight into the differential blood pressure and glomerular pressure responses to angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, and calcium channel blockers observed in SS and SR hypertension. PMID- 28556623 TI - Ultrasonography-driven combination antibiotic therapy with tigecycline significantly increases survival among patients with neutropenic enterocolitis following cytarabine-containing chemotherapy for the remission induction of acute myeloid leukemia. AB - Neutropenic enterocolitis (NEC) is an abdominal infection reported primarily in patients with acute myeloid leukemia (AML) following chemotherapy, especially cytarabine, a notable efficacious cytotoxic agent for AML remission. Specific data regarding the impact of different cytarabine schedules and/or antibacterial regimens for NEC are sparse. The aim of the study was to identify the predictors of outcome within 30 days of NEC onset. NEC episodes were retrospectively pinpointed among 440 patients with newly diagnosed AML hospitalized in our Institution, over a 10-year period, for receiving chemotherapy protocols with 100 6000 mg/m2 daily of cytarabine. Two subgroups, survivors versus nonsurvivors, were compared by using logistic regression analysis. NEC was documented in 100 of 420 (23.8%) analyzed patients: 42.5% had received high-dose cytarabine, whereas 19% and 15% intermediate-dose and standard-dose cytarabine, respectively (P < 0.001). The 30-day NEC attributable mortality rate was 23%. In univariate analysis, antileukemic protocols containing robust dosages of cytarabine were significantly associated with high mortality (P < 0.001); whereas, standard-dose cytarabine and prompt initiation (at the ultrasonographic appearance of intestinal mural thickening) of NEC therapy with antibiotic combinations including tigecycline were significantly associated with low mortality. In multivariate analysis, high-dose cytarabine-containing chemotherapy was the independent predictor of poor outcome (odds ratio [OR]: 0.109; 95% confidence interval [CI]: 0.032-0.364; P < 0.001), whereas ultrasonography-driven NEC therapy with antibiotic regimens including tigecycline was associated with a favorable outcome (OR: 13.161; 95% CI: 1.587-109.17; P = 0.017). Chemotherapy schedules with robust dosages of cytarabine for AML remission are associated with a high rate of NEC incidence and attributable. Vigorous antibacterial therapy, triggered off pathologic ultrasonographic findings, with drug combinations which have broad antimicrobial coverage and good gut penetration, specifically those also including tigecycline, may be effective in improving 30-day survival rate after NEC onset. PMID- 28556626 TI - Media development for large scale Agrobacterium tumefaciens culture. AB - A chemically defined media was developed for growing Agrobacterium tumefaciens at large scale for commercial production of recombinant proteins by transient expression in plants. Design of experiments was used to identify major and secondary effects of ten media components: sucrose, ammonium sulfate ((NH4 )2 SO4 ), magnesium sulfate heptahydrate (MgSO4 *7H2 O), calcium chloride dihydrate (CaCl2 *2H2 O), iron (II) sulfate heptahydrate (FeSO4 *7H2 O), manganese (II) sulfate monohydrate (MnSO4 *H2 O), zinc sulfate heptahydrate (ZnSO4 *7H2 O), sodium chloride (NaCl), potassium chloride (KCl) and a sodium/potassium phosphate buffer (Na2 HPO4 /KH2 PO4 ). Calcium and zinc were found to have no detectable impact on biomass concentration or transient expression level, and concentrations of the other components that maximized final biomass concentration were determined. The maximum specific growth rate of Agrobacterium strain C58C1 pTFS40 in this media was 0.33 +/- 0.01 h-1 and the final biomass concentration after 26 h of batch growth in shake flasks was 2.6 g dry cell weight/L. Transient expression levels of the reporter protein GUS following infiltration of a recombinant Agrobacterium strain C58C1 into N. benthamiana were comparable when the strain was grown in the defined media, Lysogeny Broth (LB) media, or yeast extract-peptone (YEP) media. In LB and YEP media, free amino acid concentration was measured at three points over the course of batch growth of Agrobacterium strain C58C1 pTFS40; results indicated that l-serine and l-asparagine were depleted from the media first, followed by l-alanine and l-glutamic acid. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1218-1225, 2017. PMID- 28556625 TI - Suppression of a methionine synthase by calmodulin under environmental stress in the entomopathogenic fungus Beauveria bassiana. AB - Methionine synthase (MetE, EC 2.1.1.14) catalyses the final step in the methionine biosynthetic pathway. Methionine biosynthesis plays a major role in protein biogenesis and is the source of S-adenosyl methionine (SAM), the universal donor of methyl groups. In this study, we demonstrated that BbMetE acts as a typical MetE enzyme in the entomopathogenic fungus Beauveria bassiana. In addition, we found that BbMetE binds to calmodulin (CaM) in vitro and in vivo. The functional role of CaM binding to BbMetE was to negatively regulate BbMetE activity in B. bassiana. Our proton-nuclear magnetic resonance data revealed that CaM inhibitor W-7 increases methionine content in B. bassiana, suggesting that CaM negatively regulates the BbMetE activity. Environmental stress stimuli such as salt, H2 O2 and heat suppressed BbMetE activity in B. bassiana. W-7 reversed this effect, suggesting that the inhibitory mechanism is mediated through stimulation of CaM activity. Therefore, this work suggests that BbMetE plays an important role in methionine biosynthesis, which is mediated by environmental stress stimuli via the CaM signalling pathway. PMID- 28556627 TI - A Mathematical Model to Predict HIV Virological Failure and Elucidate the Role of Lymph Node Drug Penetration. AB - Preventing virological failure following HIV treatment remains a difficult task that is further complicated by the emergence of drug resistance. We have developed a mathematical model able to explain and predict HIV virological outcomes for various compounds and patients' drug intake patterns. Compared to current approaches, this model considers, altogether, drug penetration into lymph nodes, a refined adherence representation accounting for the propensity for long drug holidays, population pharmacokinetic and pharmacodynamic variability, drug interaction, and crossresistance. In silico results are consistent with clinical observations for treatment with efavirenz, efavirenz in association with tenofovir DF and emtricitabine, or boosted darunavir. Our findings indicate that limited lymph node drug penetration can account for a large proportion of cases of virological failure and drug resistance. Since a limited amount of information is required by the model, it can be of use in the process of drug discovery and to guide clinical treatment strategies. PMID- 28556629 TI - In vitro methanol production from methyl coenzyme M using the Methanosarcina barkeri MtaABC protein complex. AB - Methanol:coenzyme M methyltransferase is an enzyme complex composed of three subunits, MtaA, MtaB, and MtaC, found in methanogenic archaea and is needed for their growth on methanol ultimately producing methane. MtaABC catalyzes the energetically favorable methyl transfer from methanol to coenzyme M to form methyl coenzyme M. Here we demonstrate that this important reaction for possible production of methanol from the anaerobic oxidation of methane can be reversed in vitro. To this effect, we have expressed and purified the Methanosarcina barkeri MtaABC enzyme, and developed an in vitro functional assay that demonstrates MtaABC can catalyze the energetically unfavorable (DeltaG degrees = 27 kJ/mol) reverse reaction starting from methyl coenzyme M and generating methanol as a product. Demonstration of an in vitro ability of MtaABC to produce methanol may ultimately enable the anaerobic oxidation of methane to produce methanol and from methanol alternative fuel or fuel-precursor molecules. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1243-1249, 2017. PMID- 28556628 TI - Tris-base buffer: a promising new inhibitor for cancer progression and metastasis. AB - Neutralizing tumor external acidity with oral buffers has proven effective for the prevention and inhibition of metastasis in several cancer mouse models. Solid tumors are highly acidic as a result of high glycolysis combined with an inadequate blood supply. Our prior work has shown that sodium bicarbonate, imidazole, and free-base (but not protonated) lysine are effective in reducing tumor progression and metastasis. However, a concern in translating these results to clinic has been the presence of counter ions and their potential undesirable side effects (e.g., hypernatremia). In this work, we investigate tris(hydroxymethyl)aminomethane, (THAM or Tris), a primary amine with no counter ion, for its effects on metastasis and progression in prostate and pancreatic cancer in vivo models using MRI and bioluminescence imaging. At an ad lib concentration of 200 mmol/L, Tris effectively inhibited metastasis in both models and furthermore led to a decrease in the expression of the major glucose transporter, GLUT-1. Our results also showed that Tris-base buffer (pH 8.4) had no overt toxicity to C3H mice even at higher doses (400 mmol/L). In conclusion, we have developed a novel therapeutic approach to manipulate tumor extracellular pH (pHe) that could be readily adapted to a clinical trial. PMID- 28556630 TI - Posterior wall left ventricular aneurysm repair. AB - Posterior wall aneurysms are a relatively rare form of left ventricular aneurysm that can sometimes involve the mitral valve. This tutorial illustrates the technical aspects of posterior wall left ventricular aneurysm repair. PMID- 28556632 TI - Multi-vessel small thoracotomy coronary artery bypass using in situ bilateral internal thoracic arteries and right gastroepiploic artery. AB - We present an innovative method of minimally invasive total arterial revascularization on a beating heart, using in situ bilateral internal thoracic arteries and laparoscopically harvested in situ right gastroepiploic artery. The safety and feasibility of this technique have been established. PMID- 28556634 TI - Uniportal VATS for treatment of bullous lung disease. AB - This tutorial shows the resection of a bulla by uniportal video assisted thoracoscopic surgery in bullous lung disease. This disease is a benign condition requiring treatment in cases of severe dyspnea, spontaneous secondary pneumothorax, repeated infection, hemoptysis, and an increase in bulla size. The uniportal VATS approach results in less pain, better cosmoses, and a quicker recovery for the patient. PMID- 28556635 TI - [The hospitalized morbidity of the population older than working age of the Russian Federation]. AB - The article presents the distribution of patients older than working age, retired from the hospital, analyzed the hospitalized morbidity by classes of diseases and separate nosology in the Russian Federation for the period 2010-2014 years (according to the form of Federal statistical observation No 14). During the study period, the number of persons of retirement age, people released from hospital care, increased by 13,45 % reported a slight increase in the rate of hospital morbidity by 0,14 %. The main reasons for treatment in hospital organizations are diseases of the circulatory system, neoplasms, diseases of the digestive system, respiratory system, eye and adnexa, etc. The average duration of stay on the bed of patients older than working age in hospitals were analysed accordingly classes of diseases. Over 5 years the indicator decreased by 1,3 days (from 14,2 to 12,9 days). PMID- 28556636 TI - [Trends of population aging in the Republic of Sakha (Yakutia): socio-demographic aspect]. AB - The scale and the signs of population aging in the Republic of Sakha (Yakutia), having expressed gender differences, have been defined. In the course of the analysis it have been revealed that the decline in mortality and life expectancy growth, migratory outflow of young population, reducing the number of children led to an increase in the number of older persons. It was found that the increase and redistribution of the dependency rate on the working population in the direction of older people acts as a consequence of the aging process. The survey of the employment behaviour of the elderly population of the Republic showed that the main activity motives of elderly are instrumental and social. PMID- 28556637 TI - [Length telomere leukocytes as ageing markers and risk factors for age-related diseases in humans]. AB - The purpose of the research was studying of leukocyte telomere length association with age, sex, risk factors for age-related diseases in Russian people of pre retirement and retirement age. By quantitative real-time PCR method we studied the leukocyte telomere length in 398 men (56,3+/-7,2 years) and 365 women (56,6+/ 7,1 years) selected from a population sample of 45-69 year-old residents of the Oktyabrsky and Kirovsky districts of Novosibirsk (9 400 people). The selection was formed in the course of work on the international project HAPIEE. As a result, an inverse correlation of telomere length with age (r=-0,159, r<0,001), with the ratio waist / hips (r=-0,107, p=0,003) was found out. The average length of telomeres in women significantly more than in men, p=0,031.The correlation of telomere length in males with weight (r=0,140, p=0,005), waist size (r=0,111, p=0,027) was found out. In women, there is an inverse correlation of telomere length with a waist size (r=-0,127, p=0,015), the ratio of waist / hips (r= 0,141, p=0,007). The length of telomeres is an inverse correlation with correlation with quantity of the cigarettes smoked (r=-0,121, r=0,024). The length of telomeres leukocytes correlates with age, smoking, and a number of phenotypical signs. In men with the family anamnesis burdened by malignancies leucocytes telomere length was found to be greater than in men without such anamnesis. PMID- 28556638 TI - [Role of PLAT, PKHD1L1, STK38L and TEAD1 genes Alu-polymorphism for longevity]. AB - The distribution of allele and genotype frequencies of Alu(I/D)-polymorphic sites in PLAT (TPA25), PKHD1L1 (Yb8AC702), STK38L (Ya5ac2145) i TEAD1 (Ya5ac2013) genes was first characterized in the ethnically homogeneous group (Tatars from the Republic of Bashkortostan, Russia), and was established (found) the association of each gene polymorphism with age. The study group consisted of 1580 unrelated individuals aged between 21 and 109 years, including 204 long-livers. It was found that STK38L*I/D genotype had positive association with longevity in the total group (OR=1,016, p=0,034). Long-lived women had a high probability of detection of PKHD1L1*I/I (OR=1,289, p=0,009), PLAT*D/D (OR=1,175, p=0,016) and TEAD1*I/I (OR=1,047, p=0,042) genotypes. PKHD1L1*I/D genotype was a significant factor in providing of male longevity (OR=1,713, p=0,030). Therefore, age dependent changes in genotype frequencies are specific for each studied gene. PMID- 28556639 TI - [Bioinformatic investigation of the involvement of candidate genes of cytokines in the formation of large myomatous nodes in women with uterine cancer in older age groups]. AB - The aim was to study bioinformatics involvement of candidate genes of cytokines in the formation of large fibroids in women with uterine cancer in older age groups. Genotyping of 15 molecular genetic markers cytokines was performed in 120 patients with uterine myoma with large myoma nodes and 107 patients with myoma nodes of small size. The study found that genetic risk factors for fibroids with large uterine fibroids are two combinations of genetic variants: G SDF-1, CC IL 1beta, A RANTES (OR=5,56) and A RANTES with genotype CC IL-1beta (OR=4,60). 12 of 15 polymorphic loci studied in various combinations (8 revealed significant combinations) have protective value in the formation of large fibroids with uterine cancer (OR=0,09-0,31). PMID- 28556640 TI - ["Protein of senility" CCL11, "protein of juvenility" GDF11 and their role in age related pathology]. AB - The paper presents the latest literature data on the structure and functions of "protein of juvenility" - CCL11 and "protein of senility" - GDF11. Chemokine CCL11 injected to young animals has been shown to lead to degenerative changes in the central nervous system (CNS), disturb cognitive functions and impede tissue regeneration. CCL11 concentration increases dramatically in schizophrenia, Alzheimer's disease, neuro-inflammatory disorders, cerebral malaria, drug addiction, as well as in atherosclerosis, periodontal disease, macular degeneration, cancer and other pathologies. In contrast to CCL11, differentiation growth factor 11 (GDF11), being administered to old mice, eliminates age associated hypertrophy of the heart, improves muscle tone and prevents degenerative changes in the CNS, improves cognitive functions and enhances tissue regeneration. Its concentration decreases in cardiovascular disease, osteoporosis, and other "diseases of old age". At the same time, the higher the GDF11 level in the blood, the milder myocardial infarction, stroke and other age related diseases of the cardiovascular system. PMID- 28556641 TI - [Age-related changes Kernogan's index of venous vessels hollow and parenchymatous organs at stages of a postnatal ontogenesis]. AB - Kernogan's index determination of hollow and parenchymatous organs' venous vessels was conducted on 80 men corpses of the three age groups. Average age of the investigated men corpses of the mature period is 27,8+/-4,2 years, elderly - 67,8+/-3,7 years, senile - 81,9+/-4,5 years. The age variability transformation of venous vessels bandwidth of lungs, kidneys, heart, stomach and ileum were obligate. It was revealed that the Kernogan's index of venous vessels changes can be equally detected at different age periods. While, with the obsolence, there is a gradual indicator's decline, which is mostly discerned in parenchymatous organs, while for the hollow organs transformations are less essentic. PMID- 28556642 TI - [Bilateral stenoses of carotids. The surgical treatment in acute period of ischemic stroke in patients of different age groups]. AB - The study included 138 patients who had 193 reconstructive operations on carotid arteries (CA) in the acute period of ischemic stroke. The 1st group included 22 patients with bilateral stenosis, age under 60 years; the 2nd group - 33 patients with a bilateral stenosis at the age more than 60 years; the 3rd group consisted of 83 patients with bilateral stenosis of the ipsilateral CA were operated in an acute period of ischemic stroke, but with contraindications and/or refused the surgery on the contralateral CA. Brain computer tomography, ultrasound duplex scanning of the CA with the assessment degree of stenosis and structure of plaques, also MSCT-AG of the head and neck vessels were performed for all patients. Cerebral oximeter was used for assessing adequate cerebral perfusion during cross-clamping of the CA. Indications for the installation of a temporary intraluminal shunt during cross-clamping of the CA performed according to the method. PMID- 28556643 TI - [Recent medical techniques for peripheral nerve repair: nerve guidance conduits update]. AB - The review deals with recent medical methods of reconstruction of peripheral nerve injuries, especially using the technology of nerve guidance conduits (NGCs), as well as scientific and applied prospects of further development of clinical and technical research in this area. In neurosurgery established techniques for the treatment of peripheral nerve injures include the matching and suturing of severed nerve fibers (however, it is important to avoid tension in gaps for effective regeneration of the nerve fiber), as well as allo/autologous nerve grafting for larger gaps (gold standard of repair). Unfortunately, this treatment is not always feasible in a number of clinical situations, has drawbacks and is associated with a potential risk of postoperative complications; in particular applying of donor transplants is complicated immunological incompatibility reactions. The use of implantable artificial tunneling device known as a nerve guidance conduit is an alternative method of reconstruction, contributing to the physiological regeneration of nerve fiber. The article describes technical engineering constructions - including by using various non- and biomaterials, liquid metals, light/laser, methods of electrospinning and microstereolithography - which are either commercially available or pre-tested and clinical studies detailing outcomes and reconstructive options. The review emphasizes that the further development of scientific research in the field of new materials and polymers, as well as techniques for the preparation and implantation of nerve conduits and their subsequent practical assessment is necessary for clinical medicine and rehabilitation. PMID- 28556644 TI - [Characteristics of inflammatory response in patients after senile cataract surgery]. AB - The aim of the work was to study prognostic value of some laboratory markers (anti-DNA antibodies, cell adhesive molecules, neopterin) in heriatric patients with exudative inflammation after cataract surgery. 12 in-patients with postoperative iridocyclitis and endophthalmitis were included. The assays were taken twice: after admission and before discharging. The follow-up period was 6 months. Preliminary data show that high serum levels of sVCAM, sICAM and anti-DNA antibodies, as well as very low levels of anti-DNA antibodies seems to be associated with poor outcomes in those patients (enucleation, blindness, lens extraction). Small cohort doesn't allow us to make strict conclusion about prognostic value of these laboratory markers. The study should be continued. PMID- 28556646 TI - [Clinical features of patients of older age groups with uterine myoma]. AB - The study analyzed 301 patients with uterine cancer at the age of 45 years and older and 304 patients with uterine myoma 45 years. It was found that patients with uterine myoma of the older age group (45 and older) have the following clinical features: overweight and thus increased BMI these women, a lower percentage of a family history of uterine cancer, a smaller percentage of infertility, a greater number of pregnancies, births, medical abortions, the high prevalence of diseases of the cardiovascular system and pathology of the cervix, large size fibroids and as a consequence more common compartment syndrome adjacent organs by myoma nodes (disuric disorders). PMID- 28556645 TI - [Age features of cytogenetic effects of spring-summer encephalitis among residents of northern western Siberia in connection with polymorphism for genes of glutathione-S-transferase]. AB - The aim of this work was a comparative study of the effects of spring diseases cytogenetic years of tick-borne encephalitis in elderly and young age due to differences in genes of glutathione-S-transferase. Surveyed by routine cytogenetics 120 patients with tick-borne encephalitis residents North of Tomsk region. We have taken in the study persons aged 20-35 years (Group 1) and 65-85 years old (Group 2). Material for study (buccal epithelium) was taken from each subject 3-5 times: 1st-2nd day after hospitalization, in 1 week, 1, 3 and 6 months. Tick-borne encephalitis infection causes a significantly large changes in cytogenetic regimens using buccal epithelium in the elderly than in younger patients. Restoring cytogenetic norms observed in a group of young in 3 months after hospitalization, in the elderly - in 6 months. When comparing cytogenetic effects of encephalitis shows: the young patients tick-borne encephalitis level by routine cytogenetics abnormal cells was significantly higher in carriers of inactive forms of gene GSTM1 (0)/GSTT1 (0) than containing active homozygous variants of these genes. Such patterns have not been noted in a group of elderly patients. PMID- 28556647 TI - [The problem of osteoporosis in patients with cardiovascular and broncho obstructive disease]. AB - The article deals with the problem of osteoporosis in patients with cardiovascular and broncho-obstructive disease. The risk factors and clinical functional features of osteoporosis are analyzed in patients with coronary heart disease, hypertension, chronic obstructive pulmonary disease, bronchial asthma. Indicators of bone mineral density in patients with cardiovascular and broncho obstructive disease on average meet the criteria for osteopenia. Most examinees had a high risk of osteoporotic fractures as a result of significant reduction in bone mineral density. The presence of osteoporosis in patients with cardiovascular and broncho-obstructive pathology from the point of co-morbidity results in a syndrome of mutual aggravation that determines the need for a comprehensive diagnosis, treatment and prevention. PMID- 28556648 TI - [Compensate restructuring of high cortical regulation of movement in aging at chronic cerebral ischemia]. AB - Dynamic praxis was tested in three groups: two groups of old responders with cognitive impairment of varying severity and one group of old responders sick of vascular dementia. These groups were compared. Methodological basis this research is Luriya's theory of system dynamic localization psychic functions. We found changes of dynamic praxis in aging. Motor acts some slow in Old responders with mild cognitive impairment. They compensate this deficit through laud speech, increase of latent period before motor act. Responders with cognitive impairment have motor perseverations, movement slowdown, which were more often at vascular dementia. They could not compensate motor deficits in fully. But same of them can compensate motor deficit after prompting or hit. PMID- 28556649 TI - [The role of a lysine residue in the antioxidant and dna-protective activity of oligopeptides]. AB - Oligopeptides present in the living cell were found to have antioxidative activity and to be involved in the regulation of antioxidant balance by interaction with the redox-dependent cellular signaling cascades. Experiments on animal models have shown that the introduction of oligopeptides causes geroprotective and adaptogenic effects. In the present work, we investigate the biological action of a number of synthetic oligopeptides using bacterial biosensors. This approach allows us to precisely estimate the antioxidant properties of the compounds without affecting their participation in regulatory cascades typical to eukaryotic cells. It has been shown that the ability of oligopeptides to protect cells from action of physical prooxidant factors (UV irradiation) is related to the presence of a lysine residue in the molecule. For chemical pro-oxidants (dioxidine), we have observed a similar, though less strict pattern. This effect also correlates with DNA-protective activity of the investigated oligopeptides. PMID- 28556651 TI - [Objectification feasibility stage dynamic control damage in patients elderly and senile with polytrauma]. AB - In this work the results of treatment of 116 patients with polytrauma older age groups was analysed, the comparison group consisted of 55 patients with multiple injuries aged 20 to 40 years. The objective of the study was the search of criteria of the objectification assess the severity of condition of patients of elderly and senile age with polytrauma on the basis of laboratory parameters and evaluation of the influence of concomitant somatic pathology on the level of lethality. We analysed the significance of each of the selected indicators and their entirety, thereby simplifying the formation of evidence-informed way to predict fatal outcome in patients of elderly and senile age with polytrauma. PMID- 28556650 TI - [Oxidative DNA damage in the pathogenesis of chronic obstructive pulmonary disease in older patients]. AB - Oxidative stress has long been recognized to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and aging, initiating oxidative damage of biomolecules. In this study the development of imbalances in the system of lipid peroxidation and increase the level of the marker of oxidative damage to DNA - 8-hydroxy-deoxyguanosine (8-ONdG) in patients with COPD and healthy individuals. Evaluation of the relationship between the parameters of the system of lipid peroxidation and the level of 8-ONdG allowed to drill down to different oxidative mechanisms in the pathogenesis of COPD in patients of middle or old age. PMID- 28556652 TI - [The use of speech audiometry in the practice of the geriatric center]. AB - The aim of the study was to evaluate a new test of speech audiometry while examining aged patients. 32 aged listeners from 60 to 88 years old were examined: 20 hearing aid (HA) users and 12 patients with normal hearing thresholds and mild cognitive impairment according to the results of the mini-mental state examination (MMSE). The speech audiometry consisted of the traditional polysyllabic words discrimination test and a new speech test with motor responses (Verbal Tasks and Motor Responses - VTMR); in both tests the signal was presented in background noise (polyphony) in free field. All listeners performed the VTMR test significantly better than the polysyllabic words discrimination test. In the group of hearing impaired patients the mean result in VTMR test was 73,2+/-29,2 % without HA and 88,6+/-20,5 % with it, in traditional test - 34,8+/-20,9 % without HA and 56+/-18,4 % with it. All patients of the group with normal hearing and mild cognitive impairment performed the VTMR test with 100 % result, their speech discrimination score in traditional test was 88+/-12 %. In the practice of the geriatric center the use of both the traditional speech audiometry and the new speech test with motor responses seems to be reasonable, that allows examining the auditory function in patients with significant deterioration of speech intelligibility or cognitive impairment. PMID- 28556653 TI - [Recovery form of the vertebral body in a transpedicular fixation at spine fractures associated with osteoporosis]. AB - We analyzed the correction indexes of posttraumatic deformation in 27 patients aged 61-76 years (62,9+/-1,4 years), when using an osteoplasty and transpedicular of fixation in respect of fractures of bodies vertebras of the thoracic and lumbar localization, associated with osteoporosis. Indicators of posttraumatic deformation the wedging index (WI) and the segmental kyphosis (SK) decreased at all patients. At the same time the minimally invasive (transcutaneous) operation allowed to achieve recovery of the lost anatomy and does not concede to results of open intervention. In group of patients with compression fractures decreased WI and SK, and in group with burst nature of damage only WI authentically decreased. Both indicators of deformation decreased at patients with T-criterion more than -3 SD, and only WI authentically decreased at patients with more expressed decrease in mineral density (T-criterion >-3). The received results show recovery of the lost anatomy, at the same time extent of correction depends on character fractures and the number of bone masses. PMID- 28556654 TI - [Assessment of skin photoaging in middle-aged and elder patients with non melanoma skin cancers]. AB - The development of methods of early detection of non-melanoma skin cancers, assessment of risk factors, including photoaging, by means of non-invasive techniques are the main research interests of modern dermato-oncology and gerontology. In our study we aim to investigate the range of clinical features of photoaging in 92 patients older than 50 years (50 patients had malignant epithelial skin tumors (actinic keratosis, basal cell carcinoma), to reveal risk factors for basal-cell carcinoma using adapted SCINEXA scale and to assess of the pathomorphological features of dermathoheliosis using reflectance confocal microscopy. The assessment of photoaging by means of SCINEXA with subsequent non invasive evaluation using reflectance confocal microscopy allows to evaluate the cumulative effect of the ultraviolet irradiation on the skin with objective criteria. That algorithm is perspective in terms of early detection of the risk factors of non-melanoma skin cancers. PMID- 28556655 TI - [Behavioral psychotherapy and citoftavin in the treatment of deforming coxarthrosis in elderly patients]. AB - The authors studied the efficiency of the expansion of the standard course of conservative therapy of deforming coxarthrosis by appointment Cytoflavin and behavioral therapy. The study was performed on 104 elderly patients. It was found that the addition of the existing scheme increases the effectiveness of therapeutic interventions, which manifests itself as the improvement of the mental and physical components of quality of life by reducing pain and increasing the functionality of some of the affected hip. At the heart of positive clinical effect is a decrease in processes of inflammation and reduction of tension of regulatory processes in the organism. Positive quality extra medical appointments was the absence of significant side effects when taken orally Cytoflavin requiring discontinuation of the drug, as well as the absence of failure patients from further sessions of behavioral therapy. PMID- 28556656 TI - [Psychophysiological determinants of perception of quality of life of gerontological patients with urolithiasis]. AB - The analysis of psychophysiological determinancy perception of life quality of gerontological patients with urolithiasis. The study was performed on 108 patients aged 60 to 76 years (51men, 57women). In order to determine the psychophysiological phenomenology of life survey was selected - before surgery, during the severe clinical manifestations of the disease. Research Methods "integrative anxiety test" (ICT 1997), "type attitude to the disease" (Tobol, 1987), total questionnaire WHOQOL-100. Types relationship to disease, in which anxiety is not significantly improved due to illness, causes higher levels of QOL (86,4+/-2,69) compared to the level of 70,1+/-4,28 points (p<0,001, r=-0,35) corresponding types of response in the presence of high anxiety. The presence of trait anxiety levels decreased quality of life in both sexes. In men, there was the highest level of determinism of the quality of life of their independence and physical ability; women - social relations and spiritual sphere. The lowest indicators of quality of life were observed in women and in patients with acute onset and complicated urolithiasis. PMID- 28556657 TI - [Demographic and social predictors of place of death in the group of elderly]. AB - Analysis of data from the 2814 Medical certificates of death was performed to reveal socio-demographic characteristics of citizens who died at elderly age, depending on the place of death and alcohol anamnesis. Divorced or single elderly people with lower educational status had greater odds ratio to die "on the street" or "at home" rather than in a "medical organization" (respectively to characteristics of demographic status and the structure of causes of death). Clinically verified diagnosis of "Mental and behavioral disorders due to alcohol" (F10) in anamnesis was not associated with the "choice" of place of death among elderly people. Obtained results can be used to develop the regional programs in the field of public health. PMID- 28556658 TI - [Analysis of catamnesis combatants and pensioners of the Ministry of internal Affairs with mental disorders]. AB - We analysed catamnesis of combatants and pensioners of the Ministry of internal Affairs (MIA) of Russia, dismissed in connection with the presence of mental disorder impeding further passage of service. It is shown that within three years after the dismissal of the combatants noted the negative clinical dynamics of mental state with a disability, the formation of a concomitant alcohol dependence. They have expressed social problems as divorce, do manual work low skilled or do not work, which requires improved approaches to providing them with medical psychological and social assistance, with regular observation. The establishment of mental health Centers in the departmental regional health units of the Ministry of internal Affairs of Russia on the basis of existing centres of psychophysiological diagnostics, system-monitoring the mental state of the combatants with mental disorders and improve the quality of provision of medical assistance. PMID- 28556659 TI - Covalent Surface Modification of Silicon Oxides with Alcohols in Polar Aprotic Solvents. AB - Alcohol-based monolayers were successfully formed on the surfaces of silicon oxides through reactions performed in polar aprotic solvents. Monolayers prepared from alcohol-based reagents have been previously introduced as an alternative approach to covalently modify the surfaces of silicon oxides. These reagents are readily available, widely distributed, and are minimally susceptible to side reactions with ambient moisture. A limitation of using alcohol-based compounds is that previous reactions required relatively high temperatures in neat solutions, which can degrade some alcohol compounds or could lead to other unwanted side reactions during the formation of the monolayers. To overcome these challenges, we investigate the condensation reaction of alcohols on silicon oxides carried out in polar aprotic solvents. In particular, propylene carbonate has been identified as a polar aprotic solvent that is relatively nontoxic, readily accessible, and can facilitate the formation of alcohol-based monolayers. We have successfully demonstrated this approach for tuning the surface chemistry of silicon oxide surfaces with a variety of alcohol containing compounds. The strategy introduced in this research can be utilized to create silicon oxide surfaces with hydrophobic, oleophobic, or charged functionalities. PMID- 28556660 TI - Chronology of CH...O Hydrogen Bonding from Molecular Dynamics Studies of the Phosphoric Acid-Catalyzed Allylboration of Benzaldehyde. AB - CH...O hydrogen bonds involving formyl groups have been invoked as a crucial factor controlling many asymmetric transformations. We conducted quasi-classical direct molecular dynamics simulations on the phosphoric acid-catalyzed allylboration of benzaldehyde to understand the synergy between the phosphoric acid OH...O hydrogen bond and the secondary CH...O formyl hydrogen bond as the reaction occurs. In the gas phase, both the CH...O and OH...O hydrogen bonds are enhanced from reactants to transition states. In toluene, the trend of H-bond enhancement is observed with a smaller magnitude because of solvent caging. The strength of the formyl hydrogen bond in the TS, a second CH...O interaction between the P?O oxygen and ortho-hydrogen of the phenyl ring and the OH...O hydrogen bond were determined using quantum mechanical calculations (4.6, 1.0, and 14.5 kcal mol-1, respectively). PMID- 28556661 TI - "Turn-on" Fluorescence Sensing and Discriminative Detection of Aliphatic Amines Using a 5-Fold-Interpenetrated Coordination Polymer. AB - A 5-fold-interpenetrated zinc-based coordination polymer can discriminately detect aliphatic amines through a fluorescence "turn-on" method. This compound can sense aliphatic amines in the solid state, solution state, and vapor phase. Theoretical calculations revealed that the ground-state dipole moment of the corresponding amines guides the order of enhancement. PMID- 28556662 TI - Polarity-Dependent Growth Rates of Selective Area Grown ZnO Nanorods by Chemical Bath Deposition. AB - Polarity is known to affect the growth and properties of ZnO single crystals and epitaxial films, but its effects are mostly unknown in ZnO nanorods. To leave polarity as the only varying parameter, ZnO nanorods are grown by chemical bath deposition under identical conditions and during the same run on O- and Zn-polar ZnO single crystals patterned by electron beam lithography with the same pattern consisting of 15 different domains. The resulting well-ordered O- and Zn-polar ZnO nanorod arrays with high structural uniformity are formed on all the domains. The comparison of their typical dimensions unambiguously reveals that Zn-polar ZnO nanorods have much higher growth rates than O-polar ZnO nanorods for all the hole diameter and period combinations. The distinct growth rates are explained in the framework of the surface reaction-/diffusive transport-limited elongation regime analysis, which yields a much larger surface reaction rate constant for Zn polar ZnO nanorods. The origin of the difference is attributed to polarity dependent dangling bond configurations at the top polar c-faces of ZnO nanorods, which may further be affected by polarity-dependent interactions with the ionic species in aqueous solution. These findings show the relevance of considering polarity as an important quantity in ZnO nanorods. PMID- 28556663 TI - Preparation of T-2-glucoronide with Rat Hepatic Microsomes and Its Use along with T-2 for Activation of the JAK/STAT Signaling Pathway in RAW264.7 Cells. AB - T-2 toxin (T-2), one of the most toxic trichothecene A-type mycotoxins, is biotransformed in animal tissues to modified T-2s (mT-2s) including T-2 glucuronide (T-2-GlcA). In this study, the optimal conditions for T-2-GlcA synthesis were established, and the JAK/STAT pathway in RAW264.7 cells was used to study the toxicity of T-2-GlcA. Because many mT-2 standards are not readily available, optimal conditions for T-2-GlcA synthesis in vitro were established by incubating T-2 with rat liver microsomes, UDPGA, and 0.2% Triton X-100 for 90 min. qRT-PCR and Western blot results showed 21- and 760-fold increases in IL-6 mRNA expression induced by T-2-GlcA and T-2, respectively. Similar differences were observed in JAK3, SOCS2/3, and CIS mRNA expression. T-2-GlcA induced a dose responsive decrease in STAT1 mRNA expression, whereas the result with T-2 was the opposite. Moreover, the phosphorylation of STAT3 induced by T-2-GlcA was higher than that by T-2, whereas the phosphorylation of STAT1 was to the contrary. Overall, the results show that T-2-GlcA was somewhat toxic, but activation of the JAK/STAT pathway in RAW264.7 was higher by T-2. PMID- 28556664 TI - Benchmarking Micropollutant Removal by Activated Carbon and Porous beta Cyclodextrin Polymers under Environmentally Relevant Scenarios. AB - The cost-effective and energy-efficient removal of organic micropollutants (MPs) from water and wastewater is challenging. The objective of this research was to evaluate the performance of porous beta-cyclodextrin polymers (P-CDP) as adsorbents of MPs in aquatic matrixes. Adsorption kinetics and MP removal were measured in batch and flow-through experiments for a mixture of 83 MPs at environmentally relevant concentrations (1 MUg L-1) and across gradients of pH, ionic strength, and natural organic matter (NOM) concentrations. Performance was benchmarked against a coconut-shell activated carbon (CCAC). Data reveal pseudo second-order rate constants for most MPs ranging between 1.5 and 40 g mg-1 min-1 for CCAC and 30 and 40000 g mg-1 min-1 for P-CDP. The extent of MP removal demonstrates slower but more uniform uptake on CCAC and faster but more selective uptake on P-CDP. Increasing ionic strength and the presence of NOM had a negative effect on the adsorption of MPs to CCAC but had almost no effect on adsorption of MPs to P-CDP. P-CDP performed particularly well for positively charged MPs and neutral or negatively charged MPs with McGowan volumes greater than 1.7 (cm3 mol 1)/100. These data highlight advantages of P-CDP adsorbents relevant to MP removal during water and wastewater treatment. PMID- 28556665 TI - Mechanics of Nanostructured Porous Silica Aerogel Resulting from Molecular Dynamics Simulations. AB - Silica aerogels are nanostructured, highly porous solids which have, compared to other soft materials, special mechanical properties, such as extremely low densities. In the present work, the mechanical properties of silica aerogels have been studied with molecular dynamics (MD) simulations. The aerogel model of 192 000 atoms was created with different densities by direct expansion of beta cristobalite and subjected to series of thermal treatments. Because of the high number of atoms and improved modeling procedure, the proposed model was more stable and showed significant improvement in the smoothness of the resulting stress-strain curves in comparison to previous models. Resulting Poisson's ratio values for silica aerogels lie between 0.18 and 0.21. The elasticity moduli display a power law dependence on the density, with the exponent estimated to be 3.25 +/- 0.1. These results are in excellent agreement with reported experimental as well as computational values. Two different deformation scenarios have been discussed. Under tension, the low-density aerogels were more ductile while the denser ones behaved rather brittle. In the compression simulations of low-density aerogels, deformation occurred without significant increase in stress. However, for high densities, atoms offer a higher resistance to the deformation, resulting in a more stiff response and an early densification. The relationship between different mechanical parameters has been found in the cyclic loading simulations of silica aerogels with different densities. The residual strain grows linearly with the applied strain (>=0.16) and can be approximated by a phenomenological relation epsilonp = 1.09epsilonmax - 0.12. The dissipation energy also varies with the compressive strain according to a power law with an exponent of 2.31 +/- 0.07. Moreover, the tangent modulus under cyclic loading varies exponentially with the compressive strain. The results of the study pave the way toward multiscale modeling of silica as well as reinforced silica aerogels. PMID- 28556666 TI - Field-Assisted Slow Magnetic Relaxation in a Six-Coordinate Co(II)-Co(III) Complex with Large Negative Anisotropy. AB - The reaction of Co(CH3COO)2.4H2O with the Schiff base ligand LH4 derived from o vanillin and tris(hydroxymethyl)aminomethane produces the dinuclear mixed-valence complex [CoIICoIII(LH2)2(CH3COO)(H2O)](H2O)3 (1), which has been investigated using IR spectroscopy, X-ray crystallography, temperature-dependent magnetic susceptibility, magnetization, HFEPR spectroscopy, and ac susceptibility measurements at various frequencies, temperatures, and external magnetic fields. The structure of 1 consists of neutral molecules in which two cobalt ions with distorted octahedral geometries, CoIIO6 and CoIIIN2O4, are bridged by two deprotonated -CH2O- groups of the two LH22- ligands. 1 completes a series with Cl, Br, NO3, and NCS anions published before by different authors. Low temperature HFEPR measurements reveal that the ground electronic state of the Co(II) center in 1 is a highly anisotropic Kramers doublet; the effective g values of 7.18, 2.97, and 1.96 are frequency-independent over the frequency ranges 200-630, 200-406, and 200-300 GHz for the highest, intermediate, and lowest geff values, respectively. The two lower values were not seen at higher frequencies because the magnetic field was not high enough. Temperature-dependent magnetic susceptibility and field-dependent magnetization data confirm high magnetic anisotropy of the easy axis type. Complex 1 behaves as a single-ion magnet under a small applied external field and demonstrates two relaxation modes that strongly depend on the applied static dc field. The observation of multiple relaxation pathways clearly distinguishes 1 from the Cl and Br analogues. PMID- 28556667 TI - Accelerometer-Measured Patterns of Shared Physical Activity Among Mother-Young Child Dyads. AB - BACKGROUND: Many mothers and young children are not meeting physical activity guidelines. Parent-child coparticipation in physical activity (ie, shared physical activity) provides opportunities for social modeling and might be associated with child physical activity. There is very little information about shared physical activity using objective measures. METHODS: Participants (N = 17 mother-young child dyads) completed a demographic survey and height/weight measurements, and wore a Bluetooth(r) accelerometer for 1 week. Accelerometers were initialized using the proximity function to yield both individual and proximity [a minute-by-minute log of whether the 2 accelerometers were in- or out of-range (~50 m or less)] data. Shared physical activity was calculated in MATLAB by overlaying individual and proximity accelerometer data. RESULTS: Mother-child dyads spent approximately 2 hours per day in shared time that was mostly shared sedentary activities. Less than 1% of shared minutes per day were spent in shared moderate to vigorous physical activity. CONCLUSIONS: Mothers and young children spent a small portion of their day in shared activities. Most mother-child shared time was spent in sedentary or light activities rather than moderate to vigorous physical activity. This method for objectively measuring shared physical activity provides novel information about the context in which physical activity occurs and could be used to understand patterns of physical activity among other dyads. PMID- 28556668 TI - A Novel Physical Activity and Sedentary Behavior Classification and Its Relationship With Physical Fitness in Spanish Older Adults: The PHYSMED Study. AB - BACKGROUND: As there is no gold-standard methodology to classify older people in relation to physical activity (PA) and sedentary behavior (SB), this paper aimed to propose a classification combining PA and SB. METHODS: Within a broader study, 433 subjects, aged 55 years and older (57% females) from Madrid and Majorca, were evaluated for PA and SB by means of validated questionnaires. Physical fitness was analyzed objectively using the EXERNET test battery. Cluster analyses were used to establish behavioral patterns, combining PA and SB. RESULTS: Males spent more time doing regular PA but less time walking and working at home than females (P < .001). Comparing the groups (inactive and high sedentary, inactive and low sedentary, active and high sedentary, and active and low sedentary), the worst aerobic endurance (P < .001) and lower body strength (P < .05) were obtained in males from both inactive groups. Agility was highest in the active and low sedentary group (P < .05). No significant differences were observed in females. CONCLUSIONS: The proposed classification is valid, as it classifies subjects according to their PA and SB, and outcomes are related to objectively measured fitness. It could facilitate the work of public health authorities, researchers, and physicians. PMID- 28556669 TI - Impact on Area-Level Physical Activity Following the Implementation of a Fitness Zone in Montevideo, Uruguay. AB - BACKGROUND: The aim of the study was to measure the level of physical activity (PA) of the users of an urban park before and after the installation of 2 fitness zones (FZs) and to assess the impact of that intervention on the users' level of PA. METHODS: The System for Observing Play and Recreation in Communities method was applied in the urban plaza Liber Seregni in Montevideo (Uruguay): 14 different areas were mapped and then recategorized as fitness (for PAs, including sports), green, and paved zones. Observations were made in the spring (Sep-Oct) of 2011 and 2014, before and after placing 2 FZs. Participation was analyzed by gender, year, mapped areas, and zones, and significant differences were assessed using the chi2 test. RESULTS: In total, 7342 individuals (4091 men and 3251 women) were observed. A greater number of people with intense PA could be seen in the FZ, with significant differences between 2011 (45%) and 2014 (70%; P < .05). CONCLUSION: This is the first longitudinal study on the impact of an intervention to increase the level of PA in public spaces in Uruguay. Higher intensity levels of PA and fewer sedentary people were observed after the installation of the FZ. PMID- 28556670 TI - Not Just Fun and Games: Toy Advertising on Television Targeting Children Promotes Sedentary Play. AB - OBJECTIVE: To examine the volume of television toy advertising targeting Canadian children and to determine if it promotes active or sedentary play, targets males or females more frequently, and has changed over time. METHODS: Data for toy/game advertising from 27 television stations in Toronto for the month of May in 2006 and 2013 were licensed from Neilsen Media Research (Montreal, Quebec, Canada). A content analysis was performed on all ads to determine what age group and gender were targeted and whether physical or sedentary activity was being promoted. Comparisons were made between 2006 and 2013. RESULTS: There were 3.35 toy ads/h/children's specialty station in 2013 (a 15% increase from 2006). About 88% of toy ads promoted sedentary play in 2013, a 27% increase from 2006 levels, while toy ads promoting active play decreased by 33%. In both 2006 and 2013, a greater number of sedentary toy ads targeted males (n = 1519, May 2006; n = 2030, May 2013) compared with females (n = 914, May 2006; n = 1619, May 2013), and between 2006 and 2013, these ads increased significantly for both males and females. CONCLUSION: Future research should explore whether such advertising influences children's preferences for activities and levels of physical activity. PMID- 28556671 TI - Imputing Accelerometer Nonwear Time When Assessing Moderate to Vigorous Physical Activity in Children. AB - BACKGROUND: A limitation of accelerometer measures of moderate to vigorous physical activity (MVPA) is nonwear time. Nonwear-time data is typically deleted prior to estimating MVPA. In this study, we used an approach that used sociodemographic, health, and time data to guide the imputation of nonwear-time data. We determined whether imputing nonwear-time data influences estimates of MVPA and the association between MVPA, body mass index, and blood pressure. METHODS: Seven days of accelerometer data were collected on 332 children aged 10 13 years. MVPA was estimated in a "nonimputed dataset," wherein nonwear-time data were deleted prior to estimating MVPA, and in an "imputed dataset," wherein nonwear-time data were imputed using sociodemographic and health characteristics of participants and time characteristics of the nonwear period prior to estimating MVPA. RESULTS: Nonwear time represented 7% of waking hours. Average MVPA estimates did not differ in the nonimputed and imputed datasets (56.8 vs 58.4 min/d). The strength of the relationship between MVPA and the 2 health outcomes did not differ in the nonimputed and imputed datasets. CONCLUSIONS: Studies achieving high accelerometer wear-time compliance can obtain MVPA estimates without substantial bias if they use the traditional approach of deleting nonwear-time data. PMID- 28556673 TI - Markers of Bone Health, Bone-Specific Physical Activities, Nutritional Intake, and Quality of Life of Professional Jockeys in Hong Kong. AB - Weight-making practices, regularly engaged in by horse racing jockeys, have been suggested to impair both physiological and mental health. This study aimed to assess bone health markers, nutritional intake, bone-specific physical activity (PA) habits, and quality of life of professional jockeys in Hong Kong (n = 14), with gender-, age-, and body mass index-matched controls (n = 14). Anthropometric measurements, serum hormonal biomarkers, bone mineral density, bone-specific PA habits, nutritional intake, and quality of life were assessed in all participants. The jockey group displayed significantly lower bone mineral density at both calcanei than the control group (left: 0.50 +/- 0.06 vs. 0.63 +/- 0.07 g/cm2; right: 0.51 +/- 0.07 vs. 0.64 +/- 0.10 g/cm2, both ps < .01). Thirteen of the 14 jockeys (93%) showed either osteopenia or osteoporosis in at least one of their calcanei. No significant difference in bone mineral density was detected for either forearm between the groups. The current bone-specific PA questionnaire score was lower in the jockey group than the control group (5.61 +/- 1.82 vs. 8.27 +/- 2.91, p < .05). Daily energy intake was lower in the jockeys than the controls (1,360 +/- 515 vs. 1,985 +/- 1,046 kcal/day, p < .01). No significant group difference was found for micronutrient intake assessed by the bone-specific food frequency questionnaire, blood hormonal markers, and quality of life scores. Our results revealed suboptimal bone conditions at calcanei and insufficient energy intake and bone-loading PAs among professional jockeys in Hong Kong compared with healthy age-, gender-, and body mass index-matched controls. Further research is warranted to examine the effect of improved bone-loading PAs and nutritional habits on the musculoskeletal health of professional jockeys. PMID- 28556672 TI - Faster Use and Fewer Failures with Needle-Free Nasal Glucagon Versus Injectable Glucagon in Severe Hypoglycemia Rescue: A Simulation Study. AB - BACKGROUND: During severe hypoglycemic episodes, people with diabetes depend on others to help with treatment. We compared needle-free nasal glucagon and commercially available injectable glucagon for ease of use by caregivers of people with diabetes and by others in treating simulated episodes of severe hypoglycemia. METHODS: Sixteen instructed caregivers and 15 noninstructed acquaintances administered nasal and injectable glucagon to manikins, simulating unconscious people with diabetes during severe hypoglycemia episodes. RESULTS: With nasal glucagon, 15 caregivers (94%) and 14 acquaintances (93%) administered a full dose (mean time 0.27 and 0.44 min, respectively). One caregiver and one acquaintance did not administer nasal glucagon because they did not fully depress the plunger on the device. Two caregivers deliberately administered both insulin and nasal glucagon, believing that insulin would also help the patient. With injectable glucagon, eight caregivers (50%) injected glucagon (mean time 1.89 min), but only two (13%) administered the full dose. Three acquaintances (20%) injected a partial dose of injectable glucagon (mean time 2.40 min); none gave a full dose. Errors included injecting diluent only, bending the needle, and injecting with an empty syringe. Two caregivers and one acquaintance injected insulin because they confused insulin with injectable glucagon. CONCLUSIONS: More than 90% of participants delivered full doses of nasal glucagon, while 13% and 0% of caregivers and acquaintances delivered full doses of injectable glucagon, indicating that nasal glucagon is easier for nonmedically trained people to administer. Thus, nasal glucagon has the potential to substantially improve treatment for patients experiencing a life-threatening episode of severe hypoglycemia. PMID- 28556674 TI - Implementation of Yoga Therapy into U.S. Healthcare Systems. PMID- 28556675 TI - A new modeling approach allowing prediction and comparison of the long-term outcomes of treatments for hemophilia B. AB - AIM: To develop a modeling approach to compare clinical outcomes of nonacog beta pegol to a standard-acting factor IX (FIX) product. METHODS: Regression analysis linked FIX activity to bleed rates. Pharmacokinetic parameters were used to estimate FIX activity over time. The probability of bleeds was estimated for both treatment arms. A Markov model estimated the presence of target joints and annualized bleed rates (ABRs). RESULTS: Higher FIX activity showed reduced ABRs (p < 0.001). Target joints resulted in higher bleed rates (p < 0.001). When FIX activity levels and bleed risks were applied to the Markov model, ABRs for nonacog beta pegol and its comparator were 2.40 and 6.36, respectively. CONCLUSION: This model provides a starting point for assessing the added value of new FIX products. PMID- 28556676 TI - Predictors of Postpartum Exercise According to Prepregnancy Body Mass Index and Gestational Weight Gain. AB - BACKGROUND: The study purposes were to examine (1) differences in postpartum exercise (EX) and related personal/psychological correlates in women according to prepregnancy weight and pregnancy gestational weight gain (GWG) status and (2) predictors of EX at 2 weeks, 2 months, and 6 months postpartum. METHODS: Participants (N = 891) were recruited at maternity hospitalization and completed interviews to assess EX (Leisure-Time Exercise Questionnaire) and personal correlates (demographics, anxiety/depressive symptoms) before/during pregnancy. Telephone interviews were conducted to assess postpartum EX/psychological correlates. Women were categorized according to prepregnancy weight (normal and overweight) and pregnancy GWG status (above or within weight gain guidelines): normal-above, normal-within, overweight-above, and overweight-within. RESULTS: Low levels of EX minutes were observed in all women with significant differences for strenuous EX minutes (overweight-within women had the lowest strenuous EX; normal-weight women had more strenuous EX than overweight women regardless of GWG). Correlates explained 14%-37% of the variance in postpartum EX; prepregnancy EX and pregnancy EX were strong determinants of early postpartum EX, and early postpartum EX predicted 6-month postpartum EX. Unique predictors of EX also emerged (eg, depressive symptoms for women with GWG above guidelines). CONCLUSIONS: These study findings highlight the benefits of EX before/during pregnancy for promoting postpartum EX and suggest tailoring postpartum EX interventions based on personal/psychological correlates to maximize effectiveness. PMID- 28556677 TI - A Review of Physical Activity Interventions Delivered via Facebook. AB - BACKGROUND: The use of social networking sites to deliver behavioral interventions is becoming more prevalent. The purpose of this review was to systematically evaluate the published research to determine the effectiveness of Facebook-delivered interventions for promoting physical activity behavior change. METHODS: A search of interventions delivered via Facebook (as the primary delivery method or part of a multifaceted intervention) in which physical activity was the primary or secondary outcome resulted in 8 studies for review. RESULTS: Overall, 87.5% of the Facebook interventions reported some type of significant physical activity behavior change (ie, interactions, main effects for time, differences between conditions); however, only 2 of these interventions found this change to be significantly better for the treatment group than the control group. CONCLUSION: Future researchers are encouraged to test the effectiveness of Facebook-delivered physical activity interventions with additional control groups that receive no aspects of the intervention within experimental study designs, more diverse samples, theory-based content with assessment of mediators of behavior change, direct observations of physical activity, and long-term follow-ups. Although based on a small sample of studies, Facebook appears to be a promising delivery method for physical activity interventions. PMID- 28556678 TI - Emerging drugs for urothelial (bladder) cancer. AB - INTRODUCTION: Metastatic urothelial carcinoma has been associated with poor prognosis and a median survival of approximately 12-14 months with standard therapy. Treatment options for decades have been limited to platinum based chemotherapy as first line with few therapeutic options available to the majority who will ultimately progress beyond platinum. Areas covered: This review focuses on the various targeted, antiangiogenic, chemotherapeutic and immunotherapeutic agents currently being developed for the treatment of urothelial carcinoma. Expert opinion: Incorporation of systemic immunotherapy into the treatment of urothelial carcinoma has already fundamentally changed the treatment of this disease. The landscape is rapidly changing and it is likely that immunotherapy will be incorporated into therapy in earlier disease states and in novel combinations. Outcomes in urothelial carcinoma have improved and likely to improve further with ongoing and future clinical research that is discussed in this review. PMID- 28556679 TI - Molecular Characterization and Risk Assessment of Bacillus cereus Sensu Lato Isolated from Ultrahigh-Temperature and Pasteurized Milk Marketed in Rio de Janeiro, Brazil. AB - The presence of Bacillus cereus in milk is a major concern in the dairy industry. In this study 27 Bacillus cereus sensu lato isolates from pasteurized and ultrahigh-temperature (UHT) milk (24 whole UHT and 4 pasteurized samples) collected at supermarket chains in Rio de Janeiro, Brazil, were evaluated to assess the potential risk for food poisoning. Toxigenic and virulence profiles were defined by gene-specific PCR. Affiliation to phylogenetic groups was assigned by panC sequencing. Microbiological analysis revealed the presence of B. cereus s.l. in eight (33.3%) brands (six brands of UHT and two brands of pasteurized milk). Twenty-seven isolates were recovered (13 B. cereus and 14 Bacillus thuringiensis ). Predominant toxigenic patterns were type I (contains all toxin genes except ces) and type II (does not contain cytK and ces), with seven (25.9%) isolates each. Predominant virulence patterns were type 2 (does not contain hlyII or shp) and type 3 (contains all virulence genes), with five (18.5%) isolates each. All isolates belonged to phylogenetic groups III and IV. Presence of hbl, piplc, and sph was associated with group IV isolates. Our results suggest that B. thuringiensis and B. cereus sensu stricto should be considered potential foodborne pathogens. Because the majority of the milk isolates studied have the potential to cause food poisoning because of the high prevalence of toxin and virulence genes and the specific phylogenetic group affiliations, these milk products can be potentially hazardous for human consumption. PMID- 28556680 TI - Efficacy of Gaseous Ozone Application during Vacuum Cooling against Escherichia coli O157:H7 on Spinach Leaves as Influenced by Bacterium Population Size. AB - Foodborne disease outbreaks associated with the consumption of fresh produce pose a threat to public health, decrease consumer confidence in minimally processed foods, and negatively impact the sales of these commodities. The aim of the study was to determine the influence of population size of inoculated pathogen on its inactivation by gaseous ozone treatment during vacuum cooling. Spinach leaves were spot inoculated with Escherichia coli O157:H7 at approximate initial populations of 108, 107, and 105 CFU/g. Inoculated leaves were vacuum cooled (28.5 inHg; 4 degrees C) in a custom-made vessel and then were subjected to a gaseous ozone treatment under the following conditions: 1.5 g of ozone per kg of gas mixture, vessel pressure at 10 lb/in2 gauge, 94 to 98% relative humidity, and 30 min of holding time at 9 degrees C. Treatment of the leaves, having the aforementioned inocula, decreased E. coli populations by 0.2, 2.1, and 2.8 log CFU/g, respectively, compared with the inoculated untreated controls. Additionally, spinach leaves were inoculated at 1.4 * 103 CFU/g, which approximates natural contamination level, and the small populations remaining after ozone treatment were quantified using the most-probable-number (MPN) method. Vacuum and ozone sequential treatment decreased this E. coli O157:H7 population to <3 MPN/g (i.e., greater than 3-log reduction). Resulting log reductions were greater (P < 0.05) at the lower rather than the higher inoculum levels. In conclusion, treatment of spinach leaves with gaseous ozone is effective against pathogen loads comparable to those found in naturally contaminated fresh produce, but efficacy decreases as inoculum level increases. PMID- 28556681 TI - Epidemiology of Shoulder Dislocations in High School and Collegiate Athletics in the United States: 2004/2005 Through 2013/2014. AB - BACKGROUND: Shoulder dislocations occur frequently in athletes across a variety of sports. This study provides an updated descriptive epidemiological analysis of shoulder dislocations among high school and college athletes and compares injury rates and patterns across these age groups. HYPOTHESIS: There would be no difference in injury rates/patterns between high school and college athletes. STUDY DESIGN: Descriptive epidemiology study. LEVEL OF EVIDENCE: Level 3. METHODS: Shoulder dislocation data from the High School Reporting Information Online (RIO) and the National Collegiate Athletic Association (NCAA) Injury Surveillance Program (ISP) databases were analyzed from the 2004/2005 through 2013/2014 (NCAA) or 2005/2006 through 2013/2014 (RIO) academic years in 11 different sports. Rate ratios (RRs) and injury proportion ratios (IPRs) were calculated to make comparisons between age groups. RESULTS: During the study period, 598 shoulder dislocations were reported during 29,249,482 athlete exposures (AEs) among high school athletes, for an overall shoulder dislocation rate of 2.04 per 100,000 AEs; 352 shoulder dislocations were reported during 13,629,533 AEs among college athletes, for an overall injury rate of 2.58 per 100,000 AEs. College athletes had a higher rate of shoulder dislocation than high school athletes (RR, 1.26; 95% CI, 1.11-1.44). However, the injury rate in football was lower in collegiate than high school athletes (RR, 0.52; 95% CI, 0.43-0.62). Surgery was performed to correct 28.0% of high school and 29.6% of college shoulder dislocations. Shoulder dislocations resulted in longer return-to play times than other shoulder injuries. CONCLUSION: Overall, shoulder dislocation rates were higher among collegiate than high school athletes. This may be due to greater contact forces involved in sports at higher levels of play, although the increased rate in high school football warrants additional research. CLINICAL RELEVANCE: Higher shoulder dislocation rates within collegiate athletics are likely due to the higher level of intensity at this level of play, with stronger and faster athletes resulting in more forceful collisions. PMID- 28556682 TI - Bouts of Vigorous Physical Activity and Bone Strength Accrual During Adolescence. AB - PURPOSE: We examined the influence of vigorous physical activity (VPA) bout frequency on bone strength accrual across adolescence, independent of total volume of VPA. METHODS: We measured VPA (6 metabolic equivalents; total volume and bout frequency <5 min in duration) annually using waist-worn accelerometers (ActiGraph GT1M) in 309 adolescents (9-20 y at baseline: 99, <13 y; 126, 13-18 y; 84, >18 y) over a maximum of 4 years. We applied finite element analysis to high resolution peripheral quantitative computed tomography scans of the distal tibia (8% site) to estimate bone strength (failure load; F.Load, Newtons). We fit a mixed effects model with maturity offset (years from age at peak height velocity) as a random effect and sex, ethnicity, tibia length, lean body mass, and VPA (volume and bout frequency) as fixed effects. RESULTS: VPA volume and bout frequency were positively associated with F.Load across adolescence; however, VPA volume did not predict F.Load once VPA bout frequency was included in the model. Participants in the upper quartile of VPA bout frequency (~33 bouts per day) had 10% (500 N) greater F.Load across adolescence compared with participants in the lowest quartile (~9 bouts per day; P = .012). Each additional daily bout of VPA was associated with 21 N greater F.Load, independent of total volume of VPA. CONCLUSION: Frequent VPA should be promoted for optimal bone strength accrual. PMID- 28556684 TI - Environmental and Behavioral Influences of Physical Activity in Junior High School Students. AB - BACKGROUND: Increasing access and opportunity for physical activity (PA) in schools are effective; however, not everyone experiences the same effects. Prompting and reinforcement may encourage more frequent participation in recreational PA during the school day. The purpose of this study was to investigate a lunchtime PA intervention on whole school PA participation and whether behavioral support enhanced these effects. METHODS: A modified reversal design compared an environmental and an environmental plus behavioral support intervention on lunchtime PA participation versus baseline levels in a suburban junior high school in the western United States (N = 1452). PA and related contextual data were collected using systematic observation. RESULTS: Significantly more girls and boys were observed in PA during the interventions compared with baseline phases (F2,1173 = 13.52, P < .0001, eta2 = .023; F2,1173 = 20.14, P < .0001, eta2 = .033, for girls and boys, respectively). There were no significant differences between the environmental phase and the environment plus behavioral support phase. CONCLUSION: Providing access and opportunity significantly increased the number of girls and boys observed in PA during a lunchtime program, with no additive effects of behavioral support. Further research into providing the individual-level contingencies at an institutional level is needed. PMID- 28556685 TI - Relationship Between Meeting 24-Hour Movement Guidelines and Cardiometabolic Risk Factors in Children. AB - BACKGROUND: The purpose of this study was to evaluate the relationship between adherence to pediatric 24-hour movement guidelines (moderate to vigorous physical activity, sedentary behavior, and sleep) and cardiometabolic risk factors. METHODS: The sample included 357 white and African American children aged 5-18 years. Physical activity, television viewing, and sleep duration were measured using questionnaires, and the 24-hour movement guidelines were defined as >=60 minutes per day of moderate to vigorous physical activity on >=5 days per week, <= 2 hours per day of television, and sleeping 9-11 hours per night (ages 5-13 y) or 8-10 hours per night (ages 14-18 y). Waist circumference, body fat, abdominal visceral and subcutaneous adipose tissue, blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, and glucose were measured in a clinical setting. RESULTS: A total of 26.9% of the sample met none of the guidelines, whereas 36.4%, 28.3%, and 8.4% of the sample met 1, 2, or all 3 guidelines, respectively. There were significant associations between the number of guidelines met and body mass index, visceral and subcutaneous adipose tissue, triglycerides, and glucose. There were no associations with blood pressure or high-density lipoprotein cholesterol. CONCLUSIONS: Meeting more components of the 24-hour movement guidelines was associated with lower levels of obesity and several cardiometabolic risk factors. Future efforts should consider novel strategies to simultaneously improve physical activity, sedentary time, and sleep in children. PMID- 28556686 TI - Dominance genetic and maternal effects for genetic evaluation of egg production traits in dual-purpose chickens. AB - 1. A study was conducted to study direct dominance genetic and maternal effects on genetic evaluation of production traits in dual-purpose chickens. The data set consisted of records of body weight and egg production of 49 749 Mazandaran fowls from 19 consecutive generations. Based on combinations of different random effects, including direct additive and dominance genetic and maternal additive genetic and environmental effects, 8 different models were compared. 2. Inclusion of a maternal genetic effect in the models noticeably improved goodness of fit for all traits. Direct dominance genetic effect did not have noticeable effects on goodness of fit but simultaneous inclusion of both direct dominance and maternal additive genetic effects improved fitting criteria and accuracies of genetic parameter estimates for hatching body weight and egg production traits. 3. Estimates of heritability (h2) for body weights at hatch, 8 weeks and 12 weeks of age (BW0, BW8 and BW12, respectively), age at sexual maturity (ASM), average egg weights at 28-32 weeks of laying period (AEW), egg number (EN) and egg production intensity (EI) were 0.08, 0.21, 0.22, 0.22, 0.21, 0.09 and 0.10, respectively. For BW0, BW8, BW12, ASM, AEW, EN and EI, proportion of dominance genetic to total phenotypic variance (d2) were 0.06, 0.08, 0.01, 0.06, 0.06, 0.08 and 0.07 and maternal heritability estimates (m2) were 0.05, 0.04, 0.03, 0.13, 0.21, 0.07 and 0.03, respectively. Negligible coefficients of maternal environmental effect (c2) from 0.01 to 0.08 were estimated for all traits, other than BW0, which had an estimate of 0.30. 4. Breeding values (BVs) estimated for body weights at early ages (BW0 and BW8) were considerably affected by components of the models, but almost similar BVs were estimated by different models for higher age body weight (BW12) and egg production traits (ASM, AEW, EN and EI). Generally, it could be concluded that inclusion of maternal effects (both genetic and environmental) and, to a lesser extent, direct dominance genetic effect would improve the accuracy of genetic evaluation for early age body weights in dual purpose chickens. PMID- 28556687 TI - Effects of Adolescent Sport Practice on Health Outcomes of Adult Amateur Endurance Cyclists: Adulthood Is Not Too Late to Start. AB - BACKGROUND: We investigated the effects of adolescent sport practice on the training, performance, and health outcomes of adult amateur endurance cyclists and compared health outcomes of 3 adult groups: amateur endurance cyclists who practiced sports during adolescence, amateur endurance cyclists who did not practice sports during adolescence, and inactive individuals. METHODS: In 859 (751 men and 108 women) adult cyclists and 718 inactive subjects (307 men and 411 women), we examined adolescent sport practice, current training status, quality of life, quality of sleep, anxiety and depression, and cardiometabolic risk: body mass index, physical activity, physical fitness, adherence to Mediterranean diet, and alcohol and tobacco consumption. RESULTS: Independent of gender, no significant differences in training, performance, or health outcomes were observed between amateur endurance cyclists who practiced sports during adolescence and those who did not. Independent of gender, cyclists reported significantly better health outcomes than inactive individuals in all variables, except depression. CONCLUSIONS: Training, performance, and health outcomes did not differ between adult amateur endurance cyclists who practiced sports during adolescence and those who did not, but their health outcomes were significantly improved compared with inactive individuals, except for depression. PMID- 28556688 TI - Severe and rapidly-progressive Lafora disease associated with NHLRC1 mutation: a case report. AB - Lafora disease (LD), also known as progressive myoclonic epilepsy-2 (EPM2), is a rare, fatal autosomal recessive disorder typically starting during adolescence in otherwise neurologically normal individuals. It is clinically characterized by insidious of progressive neurological features including seizures, action myoclonus, visual hallucination, ataxia and dementia. Mutations in the laforin (EPM2A) gene on chromosome 6q24 or in the malin gene (NHLRC1) on chromosome 6p22 are responsible of LD phenotype. Diagnostic workup includes genetic analysis as well as axillary skin biopsy with evidence of typical periodic acid-Schiff (PAS) positive polyglucosan inclusion bodies (Lafora bodies) in the apocrine glands and/or in the eccrine duct. Usually, genotype-phenotype correlations do not reveal substantial differences between patients carrying EPM2A and NHLRC1 mutations, but a few specific NHLRC1 mutations appear to correlate with a late onset and slow progressing LD. We report a case of LD due to compound heterozygote NHLRC1 mutation in an adolescent presenting with severe and atypical electro-clinical features, mimicking an autoimmune encephalopathy, and a rapidly progressive clinical course. PMID- 28556690 TI - Vitamin D Status and Muscle Function Among Adolescent and Young Swimmers. AB - Impaired muscle function has been coupled to vitamin D insufficiency in young women and in elderly men and women. Those living at Northern latitudes are at risk for vitamin D insufficiency due to low sun exposure which may be more pronounced among elite swimmers because of their indoor training schedules. We aimed to examine vitamin D status among young elite swimmers and evaluate the association between vitamin D status and muscle strength. Twenty-nine swimmers, 12 female and 17 male (16-24 years) residing at latitude 55-56 degrees N were studied in March and April. Blood samples were analyzed for serum 25 hydroxyvitamin D (s-25(OH)D) and hand-grip strength was measured as marker of muscle strength. Subjects' vitamin D and calcium intake were assessed by food frequency questionnaire and sun exposure and training status by questionnaires. Mean (+/- SD) s-25(OH)D was 52.6 +/- 18.3nmol/L among all swimmers. In 45% of the swimmers s-25(OH)D was below 50 nmol/L. Female swimmers had higher s-25(OH)D concentration than male swimmers (61.7 +/- 17,5 nmol/L vs. 46.2 +/- 16,5 nmol/L, p = .026). Among male swimmers, those with sufficient vitamin D status had higher hand grip strength than those with insufficient vitamin D status (50.6 +/- 6.4 kg vs. 41.1 +/- 7.8 kg, p = .02). Among Danish elite swimmers 45% had an insufficient vitamin D status during the spring; the prevalence being higher among male swimmers. Muscle strength was significantly higher in male swimmers with sufficient vitamin D status. PMID- 28556689 TI - Health-related quality of life data from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mantle cell lymphoma treated with ibrutinib versus temsirolimus. AB - Mantle cell lymphoma (MCL) is a rare, aggressive, incurable B-cell malignancy. Ibrutinib has been shown to be highly active for patients with relapsed/refractory (R/R) MCL. The RAY trial (MCL3001) was a phase 3, randomized, open-label, multicenter study that compared ibrutinib with temsirolimus in patients with R/R MCL. Active disease is frequently associated with impaired functional status and reduced well-being. Therefore, the current study employed two patient-reported outcome instruments, the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EQ-5D-5L, to assess symptoms, well-being, health status, and health-related quality of life of patients on treatment within the RAY trial. We found that patients on ibrutinib had substantial improvement in FACT-Lym subscale and total scores, and had improvement in EQ-5D-5L utility and VAS scores compared with temsirolimus patients, indicating a superior well-being. These improvements in well-being correlated with clinical response, indicating that better health-related quality of life was associated with decreased disease burden. PMID- 28556692 TI - War trauma and maternal-fetal attachment predicting maternal mental health, infant development, and dyadic interaction in Palestinian families. AB - Optimal maternal-fetal attachment (MFA) is believed to be beneficial for infant well-being and dyadic interaction, but research is scarce in general and among risk populations. Our study involved dyads living in war conditions and examined how traumatic war trauma associates with MFA and which factors mediate that association. It also modeled the role of MFA in predicting newborn health, infant development, mother-infant interaction, and maternal postpartum mental health. Palestinian women from the Gaza Strip (N = 511) participated during their second trimester (T1), and when their infants were 4 (T2) and 12 (T3) months. Mothers reported MFA (interaction with, attributions to, and fantasies about the fetus), social support, and prenatal mental health (post-traumatic stress disorder, depression, and anxiety) at T1, newborn health at T2, and the postpartum mental health, infant's sensorimotor and language development, and mother-infant interaction (emotional availability) at T3. Results revealed, first, that war trauma was not directly associated with MFA but that it was mediated through a low level of social support and high level of maternal prenatal mental health problems. Second, intensive MFA predicted optimal mother-reported infant's sensorimotor and language development and mother-infant emotional availability but not newborn health or maternal postpartum mental health. PMID- 28556691 TI - T1-weighted dynamic contrast-enhanced brain magnetic resonance imaging: A preliminary study with low infusion rate in pediatric patients. AB - Background The aim of this preliminary study is to evaluate the results of T1 weighted dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in pediatric patients at 1.5T, with a low peripheral intravenous gadoteric acid injection rate of 1 ml/s. Materials and methods Children with neurological symptoms were examined prospectively with conventional MRI and T1-weighted DCE MRI. An magnetic resonance perfusion analysis method was used to obtain time concentration curves (persistent pattern, type-I; plateau pattern, type-II; washout pattern, type-III) and to calculate pharmacokinetic parameters. A total of two radiologists manually defined regions of interest (ROIs) in the part of the lesion exhibiting the greatest contrast enhancement and in the surrounding normal or contralateral tissue. Lesion/surrounding tissue or contralateral tissue pharmacokinetic parameter ratios were calculated. Tumors were categorized by grade (I-IV) using the World Health Organization (WHO) Grade. Mann-Whitney testing and receiver-operating characteristic (ROC) curves were performed. Results A total of nine boys and nine girls (mean age 10.5 years) were included. Lesions consisted of 10 brain tumors, 3 inflammatory lesions, 3 arteriovenous malformations and 2 strokes. We obtained analyzable concentration-time curves for all patients (6 type-I, 9 type-II, 3 type-III). Ktrans between tumor tissue and surrounding or contralateral tissue was significantly different ( p = 0.034). Ktrans ratios were significantly different between grade I tumors and grade IV tumors ( p = 0.027) and a Ktrans ratio value superior to 0.63 appeared to be discriminant to determine a grade IV of malignancy. Conclusions Our results confirm the feasibility of pediatric T1-weighted DCE MRI at 1.5T with a low injection rate, which could be of great value in differentiating brain tumor grades. PMID- 28556693 TI - The Perception and Needs of Psychologists Toward Blended Care. AB - BACKGROUND: Blended care, meaning that online (Internet) components are used in combination with face-to-face contact, in mental health is increasingly encouraged, but research about the needs of psychologists is scarce. METHODS: We assessed the perceptions, design, and barriers toward blended care among members of the Dutch Association of Psychologists through an e-mailed survey. Mean scores (SD) and answer percentages were calculated. Mann-Whitney tests were performed to investigate differences between users and nonusers and primary- and secondary care professionals. RESULTS: Generally, psychologists (63% response rate) had a positive perception toward blended care and they intended to use it in future (M = 3.71, SD = 1.19). Users of blended care and secondary care professionals were more positive toward blended care than nonusers and primary care professionals. Online psychoeducation, diary forms, and exercises for different therapeutic approaches and communication technology configurations were most welcomed. Still, quite some barriers were mentioned before professionals would use blended care. CONCLUSIONS: Psychologists had a positive perception toward blended care, as long as attention is paid to the perceived barriers. Results of this survey could be used in the development of online components that correspond to the needs of professionals. Reviewing the needs of psychologists, e-health components of different therapeutic approaches, apart from cognitive behavioral therapy, are welcomed. Future research is necessary to gain insight in the (cost) effectiveness of blended care for different types of patients (e.g., transdiagnostic interventions) and of different therapeutic approaches. PMID- 28556756 TI - Peer Review Panel and Ad Hoc Reviewers for the Journal of Periodontology. PMID- 28556757 TI - 2016 Research Forum Poster Session and Competition: Winners. PMID- 28556755 TI - Effects of Exercise Training Alone on Depot-Specific Body Fat Stores in Youth: Review of Recent Literature. AB - The prevalence of childhood obesity has increased at an alarming rate. The increased obesity rate in pediatrics parallels the increased risks for developing metabolic abnormalities, such as insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease. In particular, the strong relationship between obesity and such health consequences is well explained by the excessive accumulation of depot-specific body adiposity, such as visceral adipose tissue, intrahepatic lipid content, intermuscular adipose tissue, and/or intramyocellular lipid content. Limited evidence suggests that both aerobic and resistance exercise alone, independent of weight loss, can be an effective therapeutic strategy for improving risk markers of metabolic abnormalities as well as inducing positive changes in depot-specific body adiposity in obese children and adolescents. However, the independent role of exercise alone (without calorie restriction) in body fat distribution is still unclear, and the results are less conclusive in pediatrics. In this brief review, the effects of aerobic and resistance exercise on depot-specific body adiposity changes in children and adolescents are discussed. PMID- 28556760 TI - Your New Editor. PMID- 28556759 TI - Potential Use of Ayahuasca in Grief Therapy. AB - The death of a loved one is ultimately a universal experience. However, conventional interventions employed for people suffering with uncomplicated grief have gathered little empirical support. The present study aimed to explore the potential effects of ayahuasca on grief. We compared 30 people who had taken ayahuasca with 30 people who had attended peer-support groups, measuring level of grief and experiential avoidance. We also examined themes in participant responses to an open-ended question regarding their experiences with ayahuasca. The ayahuasca group presented a lower level of grief in the Present Feelings Scale of Texas Revised Inventory of Grief, showing benefits in some psychological and interpersonal dimensions. Qualitative responses described experiences of emotional release, biographical memories, and experiences of contact with the deceased. Additionally, some benefits were identified regarding the ayahuasca experiences. These results provide preliminary data about the potential of ayahuasca as a therapeutic tool in treatments for grief. PMID- 28556761 TI - Accuracy of the Fitbit Zip for Measuring Steps for Adolescents With Visual Impairments. AB - Our purpose in this study was to document the criterion validity of the Fitbit Zip for measuring steps taken by youth with visual impairments (VI). A secondary purpose was to determine whether walking pace, mounting position, or relative position to the user's mobility device impacted the criterion validity of the device. Fourteen adolescent-aged individuals (Mage = 15.4; 13 male and 1 female) with VI participated in this study. Participants wore four Fitbit Zips at different mounting positions and completed two, 2-min walking trials while the lead investigator hand tallied steps. Measurement validity was analyzed using absolute percent error (APE), intraclass correlation coefficients estimated level of conformity, and paired samples t tests and Cohen's d effect sizes assessed APE relative to mounting positions. Results supported the use of the Fitbit Zip during regular-paced walking; however, caution must be used during activities exceeding regular walking speeds, as devices consistently underestimated steps. PMID- 28556762 TI - Evaluation of Game Performance in Elite Male Sitting Volleyball Players. AB - The aims of the current study were (a) to analyze the differences in game performances of sitting volleyball athletes representing the different types of disabilities and (b) to assess whether the seated position vertical reach is one of the crucial factors in the game performance level of sitting volleyball athletes. One hundred male athletes from various national teams participating in the European Championships in Sitting Volleyball (2009) took part in this study. The athletes were categorized according to type of disability and the results of the vertical reach in a seated position. Thirtysix games were analyzed using the Game Performance Sheet for Sitting Volleyball. Twenty-three game performance parameters were studied. In addition, the sum and effectiveness of attacks, blocks, block services, services, ball receiving, and defensive actions were calculated. The main results indicated significant differences between athletes with minimal disability and athletes with single amputations from above the knee in the level of defensive performances and the summation of defensive actions. There was also a significant difference between athletes in relation to their vertical reach during activity and attacking actions, blocks, and ball receiving. In addition, there were strong relationships between the players' vertical reach scores and their activity and effectiveness in sitting volleyball. In conclusion, the accuracy of the World Organization Volleyball for Disabled classification systems for sitting volleyball players was confirmed. There is a strong relationship between players' vertical reach and their effectiveness in sitting volleyball. PMID- 28556764 TI - In-Service Physical Educators' Experiences of Online Adapted Physical Education Endorsement Courses. AB - The purpose of this study was to investigate in-service physical education (PE) teachers' experiences during online adapted physical education (APE) graduate courses. Based on andragogy theory (adult learning theory) we employed a descriptive qualitative methodology using an explanatory case study design. The participants (6 female and 3 male) were in-service PE teachers enrolled in an online graduate APE endorsement program. Data collection included journal reflection reports and face-to-face interviews. A constant comparative method was used to interpret the data. Three interrelated themes emerged from the participants' narratives. The first theme, instructor communication, exposes the advantages and disadvantages the participants perceived regarding communication while enrolled in the online APE graduate courses. The second theme, bulletin board discussion experiences, described participants' perceptions of the use of the bulletin board discussion forum. Lastly, the final theme, assessment experiences, described how the participants learned knowledge and skills through online courses related to assessment and evaluation. PMID- 28556765 TI - Erratum: Bardid et al. (2016). AB - In the article by Bardid F., Huyben F., Deconinck F.J.A., De Martelaer K., Seghers J., & Lenoir M., "Convergent and Divergent Validity Between the KTK and MOT 4-6 Motor Tests in Early Childhood, " in Adapted Pyhsical Activity Quarterly, 33(1), the wrong DOI was printed. The DOI for this article is http://dx.doi.org/10.1123/APAQ.2014-0228. The online version has been corrected. PMID- 28556766 TI - Effects of B-Active2 on Balance, Gait, Stress, and Well-Being of Adults With Autism Spectrum Disorders and Intellectual Disability: A Controlled Trial. AB - Effects of B-Active2 (Enjoy Being Physically Active by Walking Safely: A Leisure Education Program) on the risk of falls, stress, and well-being of a sample of 44 adults with ASD (ages M = 36.88; SD =7.31) were examined using a controlled experimental trial. Given the relationship between physical activity and stress reduction to individual well-being, B-Active2 was developed as a multidimensional program involving leisure education and walking designed to create an enjoyable context in which adults with ASD learn about and engage in physical activity. All participants were evaluated on balance, gait, well-being, and stress at baseline and at 1 month postintervention by a team of therapists blind to study objectives. There was a significant difference postintervention on balance, F(1, 40) = 55.63, p < .001, eta2 = .58; gait, F(1, 40) = 23.58, p < .001, eta 2 =.37; and well-being, F(1, 40) = 34.16, p < .001, eta 2 = .47). No statistically significant effect was found for level of stress reduction, F(1, 40) = 0.27, n.s. Results of this study support the conclusion that B-Active2 is a viable leisure education program that promotes physical activity of adults with ASD and has positive effects on their well-being and risk of falls. PMID- 28556767 TI - Digest. PMID- 28556768 TI - Expert Users' Perceptions of Racing Wheelchair Design and Setup: The Knowns, Unknowns, and Next Steps. AB - This paper demonstrates how a qualitative methodology can be used to gain novel insights into the demands of wheelchair racing and the impact of particular racing chair configurations on optimal sport performance via engagement with expert users (wheelchair racers, coaches, and manufacturers). We specifically explore how expert users understand how wheels, tires, and bearings impact sport performance and how they engage, implement, or reject evidence-based research pertaining to these components. We identify areas where participants perceive there to be an immediate need for more research especially pertaining to the ability to make individualized recommendations for athletes. The findings from this project speak to the value of a qualitative research design for capturing the embodied knowledge of expert users and also make suggestions for "next step" projects pertaining to wheels, tires, and bearings drawn directly from the comments of participants. PMID- 28556769 TI - Health impact assessment for health promotion, education and learning. PMID- 28556770 TI - Case assignment in English-speaking children: a paired priming paradigm. AB - This study employed a paired priming paradigm to ask whether input features influence a child's propensity to use non-nominative versus nominative case in subject position, and to use non-nominative forms even when verbs are marked for agreement. Thirty English-speaking children (ages 2;6 to 3;7) heard sentences with pronouns that had non-contrasting case forms (e.g. Dad hugs it and it hugs Tigger) and it was hypothesized that these forms would lead to more errors (e.g. Him hugs Barney) in an elicited phrase more often than if the children heard contrasting case forms (e.g. Dad hugs us and we hug the doggie). Tense/agreement features were also examined in children's elicited productions. The findings were consistent with predictions, and supported the input ambiguity hypothesis of Pelham (2011). Implications for current accounts of the optional infinitive stage are discussed. PMID- 28556771 TI - On the inevitability of death. PMID- 28556772 TI - Faecalimonas umbilicata gen. nov., sp. nov., isolated from human faeces, and reclassification of Eubacterium contortum, Eubacterium fissicatena and Clostridium oroticum as Faecalicatena contorta gen. nov., comb. nov., Faecalicatena fissicatena comb. nov. and Faecalicatena orotica comb. nov. AB - Two bacterial strains, designated EGH7T and TSAH33, were isolated from human faeces and characterized by using a polyphasic taxonomic approach that included analysis of morphology, phenotypic and biochemical features, cellular fatty acid profiles and phylogenetic position based on 16S rRNA and hsp60 gene sequence analyses. The results of 16S rRNA gene sequence analysis indicated that these strains represented members of the family Lachnospiraceae and formed a monophyletic cluster near Eubacterium contortum JCM 6483T (95 % sequence similarity), Ruminococcus gnavus JCM 6515T (95 %), Clostridium oroticum JCM 1429T (95 %), Eubacterium fissicatena JCM 31501T (95 %) and Clostridium nexile JCM 31500T (94 %). The results of a hsp60 gene sequence analysis supported the phylogenetic tree based on the 16S rRNA gene sequence, with a sequence similarity value of between 77.9 and 84.8 % to the five strains listed above. The novel strains were obligately anaerobic, non-pigmented, non-spore-forming, non-motile, Gram-stain-positive cocco-bacilli. The strains formed characteristic umbilicated colonies on EG agar plates. The major cellular fatty acids were C18 : 1omega9c, C16 : 0 and C18 : 1omega9c dimethyl acetal (DMA). EGH7T and TSAH33 have DNA G+C contents of 46.9 and 45.5 mol%, respectively. On the basis of these data, strains EGH7T and TSAH33 represent a novel species of a novel genus, for which the name Faecalimonas umbilicata gen. nov., sp. nov. is proposed. The type strain of F. umbilicata is EGH7T (=JCM 30896T=DSM 103426T). PMID- 28556773 TI - Starmerella anomalae f.a., sp. nov., Starmerella asiatica f.a., sp. nov., Starmerella henanensis f.a., sp. nov. and Starmerella scarabaei f.a., sp. nov., four yeast species isolated from scarab beetles. AB - Eleven yeast strains representing four novel species of the genus Starmerella were isolated from scarabs beetles collected in Nanyang, Henan Province, Central China. Phylogenetic analysis using combined sequences of the D1/D2 domains of the large subunit (LSU) rRNA gene and the internal transcribed spacer (ITS) regions placed all the novel species in a clade distinct from the other known species in the clade representing the members of the genus Starmerella. These novel species differed from each other or their closest known species by more than 4.9 % nucleotide substitutions in the D1/D2 domains and by more than 9.1 % nucleotide substitutions in the ITS regions. The four novel species can also be separated from their closest relatives in terms of physiological characteristics. No asci or signs of conjugation were found in the novel species on the most common sporulation media. The novel species are designated as Starmerella anomalae f.a., sp. nov. (type strain NYNU 157145T=CICC 33094T=CBS 14178T), Starmerella asiatica f.a., sp. nov. (type strain NYNU 15782T=CICC 33089T=CBS 14173T), Starmerella henanensis f.a., sp. nov. (type strain NYNU 15766T=CICC 33088T=CBS 14172T) and Starmerella scarabaei f.a., sp. nov. (type strain NYNU 15821T=CICC 33090T=CBS 14174T). PMID- 28556774 TI - Functional MRI examination of empathy for pain in people with schizophrenia reveals abnormal activation related to cognitive perspective-taking but typical activation linked to affective sharing. AB - BACKGROUND: Schizophrenia is associated with important disturbances in empathy that are related to everyday functioning. Empathy is classically defined as including affective (sharing others' emotions) and cognitive (taking others' cognitive perspectives) processes. In healthy individuals, studies on empathy for pain revealed specific brain systems associated with these sets of processes, notably the anterior middle cingulate (aMCC) and anterior insula (AI) for affective sharing and the bilateral temporoparietal junction (TPJ) for the cognitive processes, but the integrity of these systems in patients with schizophrenia remains uncertain. METHODS: Patients with schizophrenia and healthy controls performed a pain empathy task while undergoing fMRI scanning. Participants observed pictures of hands in either painful or nonpainful situations and rated the level of pain while imagining either themselves (self) or an unknown person (other) in these situations. RESULTS: We included 27 patients with schizophrenia and 21 healthy controls in our analyses. For the pain versus no pain contrast, patients showed overall typical activation patterns in the aMCC and AI, with only a small part of the aMCC showing reduced activation compared with controls. For the other versus self contrast, patients showed an abnormal modulation of activation in the TPJ bilaterally (extending to the posterior superior temporal sulcus, referred to as the TPJ/pSTS). LIMITATIONS: The design included an unnecessary manipulation of the visual perspective that reduced the number of trials for analysis. The sample size may not account for the heterogeneity of schizophrenia. CONCLUSION: People with schizophrenia showed relatively intact brain activation when observing others' pain, but showed abnormalities when asked to take the cognitive perspectives of others. PMID- 28556775 TI - Glutamatergic deficit and schizophrenia-like negative symptoms: new evidence from ketamine-induced mismatch negativity alterations in healthy male humans. AB - BACKGROUND: Targeting the N-methyl-D-aspartate receptor (NMDAR) is a major translational approach for treating negative symptoms of schizophrenia. Ketamine comprehensively produces schizophrenia-like symptoms, such as positive, cognitive and negative symptoms in healthy volunteers. The amplitude of the mismatch negativity (MMN) is known to be significantly reduced not only in patients with schizophrenia, but also in healthy controls receiving ketamine. Accordingly, it was the aim of the present study to investigate whether changes of MMN amplitudes during ketamine administration are associated with the emergence of schizophrenia like negative symptoms in healthy volunteers. METHODS: We examined the impact of ketamine during an MMN paradigm with 64-channel electroencephalography (EEG) and assessed the psychopathological status using the Positive and Negative Syndrome Scale (PANSS) in healthy male volunteers using a single-blind, randomized, placebo-controlled crossover design. Low-resolution brain electromagnetic tomography was used for source localization. RESULTS: Twenty-four men were included in our analysis. Significant reductions of MMN amplitudes and an increase in all PANSS scores were identified under the ketamine condition. Smaller MMN amplitudes were specifically associated with more pronounced negative symptoms. Source analysis of MMN generators indicated a significantly reduced current source density (CSD) under the ketamine condition in the primary auditory cortex, the posterior cingulate and the middle frontal gyrus. LIMITATIONS: The sample included only men within a tight age range of 20-32 years. CONCLUSION: The MMN might represent a biomarker for negative symptoms in schizophrenia related to an insufficient NMDAR system and could be used to identify patients with schizophrenia with negative symptoms due to NMDAR dysfunction. PMID- 28556776 TI - HIF-1alpha is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium. AB - Hemodynamic forces regulate vascular functions. Disturbed flow (DF) occurs in arterial bifurcations and curvatures, activates endothelial cells (ECs), and results in vascular inflammation and ultimately atherosclerosis. However, how DF alters EC metabolism, and whether resulting metabolic changes induce EC activation, is unknown. Using transcriptomics and bioenergetic analysis, we discovered that DF induces glycolysis and reduces mitochondrial respiratory capacity in human aortic ECs. DF-induced metabolic reprogramming required hypoxia inducible factor-1alpha (HIF-1alpha), downstream of NAD(P)H oxidase-4 (NOX4) derived reactive oxygen species (ROS). HIF-1alpha increased glycolytic enzymes and pyruvate dehydrogenase kinase-1 (PDK-1), which reduces mitochondrial respiratory capacity. Swine aortic arch endothelia exhibited elevated ROS, NOX4, HIF-1alpha, and glycolytic enzyme and PDK1 expression, suggesting that DF leads to metabolic reprogramming in vivo. Inhibition of glycolysis reduced inflammation suggesting a causal relationship between flow-induced metabolic changes and EC activation. These findings highlight a previously uncharacterized role for flow induced metabolic reprogramming and inflammation in ECs. PMID- 28556779 TI - Anthropometric profile and diabetic foot risk: a cross-sectional study using thermography. AB - Diabetes is one of the greatest todays public health problems with enormous social and economic implications for society. Diabetic foot disorders represent a substantial economic burden with detrimental effects on quality of life with special impairment in physical domain. Early detection strategies of these complications should be implemented in order to avoid possible wounds, ulcerations and amputations. This work can be characterized as a cross-sectional study with an analytical approach. It involved 44 volunteers of both genders (22 women and 22 men; 66.70 +/- 6.26 years of age) with type 2 diabetes (diagnosed at 11.84 +/- 8.22 years), selected among the candidates to Diabetes em Movimento(r) (a community-based exercise program for patients with type 2 diabetes developed in the city of Vila Real, Portugal). Foot plantar thermal images were acquired through a high-resolution infrared camera (FLIR Systems Inc. Model SC2000; 320 * 240 pixels). Three regions of interest (ROI) were defined for evaluation: first finger, fifth finger and the heel. From the three pairs of ROIs evaluated, the higher temperature asymmetry was selected for diabetic foot risk analysis. The results showed the existence of a positive and significant association between BMI and fat mass with asymmetries in feet temperature. Three subjects with diabetes-related foot complications (ROIs higher temperature asymmetry >= 2.20 degrees C) were identified in the sample. All participants with detected diabetes related foot complications were obese (BMI >= 30 kg/m2) with high levels of body fat (>= 45%). It can be concluded that exist a positive association either of BMI (r=0.399, p=0.007) either of body fat percentage (r=0.432, p=0.003), with diabetic foot risk in patients with type 2 diabetes. PMID- 28556778 TI - How a brain keeps its cool. AB - Temperature-sensing neurons in the Drosophila brain cooperate with the central circadian clock to help regulate body temperature. PMID- 28556777 TI - The force-sensing peptide VemP employs extreme compaction and secondary structure formation to induce ribosomal stalling. AB - Interaction between the nascent polypeptide chain and the ribosomal exit tunnel can modulate the rate of translation and induce translational arrest to regulate expression of downstream genes. The ribosomal tunnel also provides a protected environment for initial protein folding events. Here, we present a 2.9 A cryo electron microscopy structure of a ribosome stalled during translation of the extremely compacted VemP nascent chain. The nascent chain forms two alpha-helices connected by an alpha-turn and a loop, enabling a total of 37 amino acids to be observed within the first 50-55 A of the exit tunnel. The structure reveals how alpha-helix formation directly within the peptidyltransferase center of the ribosome interferes with aminoacyl-tRNA accommodation, suggesting that during canonical translation, a major role of the exit tunnel is to prevent excessive secondary structure formation that can interfere with the peptidyltransferase activity of the ribosome. PMID- 28556780 TI - Theory of magnons in spin systems with Dzyaloshinskii-Moriya interaction. AB - We study in this paper magnetic properties of a system of quantum Heisenberg spins interacting with each other via a ferromagnetic exchange interaction J and an in-plane Dzyaloshinskii-Moriya interaction D. The non-collinear ground state due to the competition between J and D is determined. We employ a self-consistent Green'function theory to calculate the spin-wave spectrum and the layer magnetizations at finite T in two and three dimensions as well as in a thin film with surface effects. Analytical details and the validity of the method are shown and discussed. Numerical solutions are shown for realistic physical interaction parameters. Discussion on possible experimental verifications is given. PMID- 28556781 TI - Supine MRI for regional breast radiotherapy: imaging axillary lymph nodes before and after sentinel-node biopsy. AB - Regional radiotherapy (RT) is increasingly used in breast cancer treatment. Conventionally, computed tomography (CT) is performed for RT planning. Lymph node (LN) target levels are delineated according to anatomical boundaries. Magnetic resonance imaging (MRI) could enable individual LN delineation. The purpose was to evaluate the applicability of MRI for LN detection in supine treatment position, before and after sentinel-node biopsy (SNB). Twenty-three female breast cancer patients (cTis-3N0M0) underwent 1.5 T MRI, before and after SNB, in addition to CT. Endurance for MRI was monitored. Axillary levels were delineated. LNs were identified and delineated on MRI from before and after SNB, and on CT, and compared by Wilcoxon signed-rank tests. LN locations and LN-based volumes were related to axillary delineations and associated volumes. Although postoperative effects were visible, LN numbers on postoperative MRI (median 26 LNs) were highly reproducible compared to preoperative MRI when adding excised sentinel nodes, and higher than on CT (median 11, p < 0.001). LN-based volumes were considerably smaller than respective axillary levels. Supine MRI of LNs is feasible and reproducible before and after SNB. This may lead to more accurate RT target definition compared to CT, with potentially lower toxicity. With the MRI techniques described here, initiation of novel MRI-guided RT strategies aiming at individual LNs could be possible. PMID- 28556782 TI - Identification of interstitial-like defects in a computer model of glassy aluminum. AB - Computer simulation shows that glassy aluminum produced by rapid melt quenching contains a significant number of 'defects' similar to dumbbell (split) interstitials in the crystalline state. Although these 'defects' do not have any clear topological pattern as opposed to the crystal, they can be uniquely identified with the same properties which are characteristic of these defects in the crystalline structure, i.e. strong sensitivity to applied shear stress, specific local shear strain fields and distinctive low-/high-frequency peculiarities in the vibration spectra of 'defective' atoms. This conclusion provides new support for the interstitialcy theory, which was found to give consistent and verifiable explanations for a number of relaxation phenomena in metallic glasses and their relationship with the maternal crystalline state. PMID- 28556784 TI - Erratum. PMID- 28556785 TI - To Tax or Not to Tax Sugary Drinks? This Is the Question. PMID- 28556787 TI - Liver Failure in Early Infancy. PMID- 28556788 TI - An Improved Compressive Sensing and Received Signal Strength-Based Target Localization Algorithm with Unknown Target Population for Wireless Local Area Networks. AB - In this paper a two-phase compressive sensing (CS) and received signal strength (RSS)-based target localization approach is proposed to improve position accuracy by dealing with the unknown target population and the effect of grid dimensions on position error. In the coarse localization phase, by formulating target localization as a sparse signal recovery problem, grids with recovery vector components greater than a threshold are chosen as the candidate target grids. In the fine localization phase, by partitioning each candidate grid, the target position in a grid is iteratively refined by using the minimum residual error rule and the least-squares technique. When all the candidate target grids are iteratively partitioned and the measurement matrix is updated, the recovery vector is re-estimated. Threshold-based detection is employed again to determine the target grids and hence the target population. As a consequence, both the target population and the position estimation accuracy can be significantly improved. Simulation results demonstrate that the proposed approach achieves the best accuracy among all the algorithms compared. PMID- 28556789 TI - Characterization of Metabolite Profile in Phyllanthus niruri and Correlation with Bioactivity Elucidated by Nuclear Magnetic Resonance Based Metabolomics. AB - Phyllanthus niruri is an important medicinal plant. To standardize the extract and guarantee its maximum benefit, processing methods optimization ought to be amenable and beneficial. Herein, three dried P. niruri samples, air (AD), freeze (FD) and oven (OD), extracted with various ethanol to water ratios (0%, 50%, 70%, 80% and 100%) were evaluated for their metabolite changes using proton nuclear magnetic resonance (1H-NMR)-based metabolomics approach. The amino acids analysis showed that FD P. niruri exhibited higher content of most amino acids compared to the other dried samples. Based on principal component analysis (PCA), the FD P. niruri extracted with 80% ethanol contained higher amounts of hypophyllanthin and phenolic compounds based on the loading plot. The partial least-square (PLS) results showed that the phytochemicals, including hypophyllanthin, catechin, epicatechin, rutin, quercetin and chlorogenic, caffeic, malic and gallic acids were correlated with antioxidant and alpha-glucosidase inhibitory activities, which were higher in the FD material extracted with 80% ethanol. This report optimized the effect of drying and ethanol ratios and these findings demonstrate that NMR-based metabolomics was an applicable approach. The FD P. niruri extracted with 80% ethanol can be used as afunctional food ingredient for nutraceutical or in medicinal preparation. PMID- 28556790 TI - DNA Methylation Profiling of Human Prefrontal Cortex Neurons in Heroin Users Shows Significant Difference between Genomic Contexts of Hyper- and Hypomethylation and a Younger Epigenetic Age. AB - We employed Illumina 450 K Infinium microarrays to profile DNA methylation (DNAm) in neuronal nuclei separated by fluorescence-activated sorting from the postmortem orbitofrontal cortex (OFC) of heroin users who died from heroin overdose (N = 37), suicide completers (N = 22) with no evidence of heroin use and from control subjects who did not abuse illicit drugs and died of non-suicide causes (N = 28). We identified 1298 differentially methylated CpG sites (DMSs) between heroin users and controls, and 454 DMSs between suicide completers and controls (p < 0.001). DMSs and corresponding genes (DMGs) in heroin users showed significant differences in the preferential context of hyper and hypo DM. HyperDMSs were enriched in gene bodies and exons but depleted in promoters, whereas hypoDMSs were enriched in promoters and enhancers. In addition, hyperDMGs showed preference for genes expressed specifically by glutamatergic as opposed to GABAergic neurons and enrichment for axonogenesis- and synaptic-related gene ontology categories, whereas hypoDMGs were enriched for transcription factor activity- and gene expression regulation-related terms. Finally, we found that the DNAm-based "epigenetic age" of neurons from heroin users was younger than that in controls. Suicide-related results were more difficult to interpret. Collectively, these findings suggest that the observed DNAm differences could represent functionally significant marks of heroin-associated plasticity in the OFC. PMID- 28556792 TI - Two New Oxodolastane Diterpenes from the Jamaican Macroalga Canistrocarpus cervicornis. AB - The chemical investigation of the organic extract of Canistrocarpus cervicornis, collected at Drunken Man's Cay at Port Royal, Jamaica, has led to the isolation of two new dolastane diterpenes 4R-acetoxy-8S,9S-epoxy-14S-hydroxy-7-oxodolastane (1) and 4R-hydroxy-8S,9S-epoxy-14S-hydroxy-7-oxodolastane (2) and the previously isolated dolastane (4R,9S,14S)-4,9,14-trihydroxydolast-1(15),7-diene (3) as a major diterpene constituent. The structures of the new compounds were elucidated by extensive spectroscopic analyses. Compounds 1-3 were evaluated for their cytotoxicity against human tumor cell lines PC3 and HT29. The results revealed that the dolastane diterpenes (1-3) displayed moderate, concentration dependent, cytotoxicity. PMID- 28556791 TI - Significance of Phosphorylated Epidermal Growth Factor Receptor and Its Signal Transducers in Human Soft Tissue Sarcoma. AB - Abstract: Previous studies have shown that total epidermal growth factor receptor (EGFR) protein is highly expressed in soft tissue sarcoma (STS). We aimed to investigate the significance of phosphorylated-EGFR (pEGFR) and its activated downstream signal transducers in STS tissue samples. A tissue microarray comprising 87 STS samples was assessed for total EGFR, pEGFR and its phosphorylated signal transducers and expression was correlated with clinicopathlogical parameters including patient outcome. Although the expression of total EGFR was significantly associated with adverse STS histologic grade (p = 0.004) and clinical stage (p = 0.012) similar to pEGFR, phosphorylated protein kinase B (pAkt) and phosphorylated extracellular signal regulated kinase (pERK), it is not a prognostic factor for survival. By contrast, the expression of pEGFR is an independent factor for cancer specific survival, while pERK is an independent prognostic factor for both overall and cancer specific survival in STS (p < 0.05, Cox proportional hazard model and log-rank test) in addition to the recognised factors of tumour grade and clinical stage. pERK and pEGFR are new independent prognostic factors for overall and/or cancer specific survival in STS. The expression of EGFR/pEGFR, and their associated downstream signal transducers, was associated with STS progression, suggesting that EGFR downstream signalling pathways may jointly support STS cell survival. PMID- 28556794 TI - Formation of Conductive DNA-Based Nanowires via Conjugation of dsDNA with Cationic Peptide. AB - A novel conductive DNA-based nanomaterial, DNA-peptide wire, composed of a DNA core and a peripheral peptide layer, is presented. The electrical conductivity of the wire is found to be at least three orders in magnitude higher than that of native double-stranded DNA (dsDNA). High conductivity of the wires along with a better resistance to mechanical deformations caused by interactions between the substrate and electrode surface make them appealing for a wide variety of nanoelectronic and biosensor applications. PMID- 28556793 TI - Syntheses of Radioiodinated Pyrimidine-2,4,6-Triones as Potential Agents for Non Invasive Imaging of Matrix Metalloproteinases. AB - Dysregulated expression or activation of matrix metalloproteinases (MMPs) is observed in many kinds of live-threatening diseases. Therefore, MMP imaging for example with radiolabelled MMP inhibitors (MMPIs) potentially represents a valuable tool for clinical diagnostics using non-invasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. This work includes the organic chemical syntheses and in vitro evaluation of five iodinated barbiturate based MMPIs and the selection of derivative 9 for radiosyntheses of isotopologues [123I]9 potentially useful for MMP SPECT imaging and [124I]9 for MMP PET imaging. PMID- 28556795 TI - Perception of Organic Food Consumption in Romania. AB - This study provides insight into the attitude of Romanian consumers towards organic food. Furthermore, it examines the sustainable food production system in Romania from the perspective of consumer behavior. This study used a mathematical model of linear regression with the main purpose being to determine the best prediction for the dependent variable when given a number of new values for the independent variable. This empirical research is based on a survey with a sample of 672 consumers, which uses a questionnaire to analyze their intentions towards sustainable food products. The results indicate that a more positive attitude of consumers towards organic food products will further strengthen their purchasing intentions, while the status of the consumption of organic consumers will not affect their willingness to purchase organic food products. Statistics have shown that sustainable food consumption is beneficial for health, so it can also become a profitable business in Romania. Furthermore, food sustainability in Romania depends on the ability of an organic food business to adapt to the new requirements of green consumption. PMID- 28556797 TI - Small and Smaller-sRNAs and MicroRNAs in the Regulation of Toxin Gene Expression in Prokaryotic Cells: A Mini-Review. AB - Non-coding small RNAs (sRNAs) have been identified in the wide range of bacteria (also pathogenic species) and found to play an important role in the regulation of many processes, including toxin gene expression. The best characterized prokaryotic sRNAs regulate gene expression by base pairing with mRNA targets and fall into two broad classes: cis-encoded sRNAs (also called antisense RNA) and trans-acting sRNAs. Molecules from the second class are frequently considered as the most related to eukaryotic microRNAs. Interestingly, typical microRNA-size RNA molecules have also been reported in prokaryotic cells, although they have received little attention up to now. In this work we have collected information about all three types of small prokaryotic RNAs in the context of the regulation of toxin gene expression. PMID- 28556796 TI - Sugar-Binding Profiles of Chitin-Binding Lectins from the Hevein Family: A Comprehensive Study. AB - Chitin-binding lectins form the hevein family in plants, which are defined by the presence of single or multiple structurally conserved GlcNAc (N acetylglucosamine)-binding domains. Although they have been used as probes for chito-oligosaccharides, their detailed specificities remain to be investigated. In this study, we analyzed six chitin-binding lectins, DSA, LEL, PWM, STL, UDA, and WGA, by quantitative frontal affinity chromatography. Some novel features were evident: WGA showed almost comparable affinity for pyridylaminated chitotriose and chitotetraose, while LEL and UDA showed much weaker affinity, and DSA, PWM, and STL had no substantial affinity for the former. WGA showed selective affinity for hybrid-type N-glycans harboring a bisecting GlcNAc residue. UDA showed extensive binding to high-mannose type N-glycans, with affinity increasing with the number of Man residues. DSA showed the highest affinity for highly branched N-glycans consisting of type II LacNAc (N acetyllactosamine). Further, multivalent features of these lectins were investigated by using glycoconjugate and lectin microarrays. The lectins showed substantial binding to immobilized LacNAc as well as chito-oligosaccharides, although the extents to which they bound varied among them. WGA showed strong binding to heavily sialylated glycoproteins. The above observations will help interpret lectin-glycoprotein interactions in histochemical studies and glyco biomarker investigations. PMID- 28556798 TI - Loss of BAX by miR-365 Promotes Cutaneous Squamous Cell Carcinoma Progression by Suppressing Apoptosis. AB - Pro-apoptotic BCL2 associated X (BAX) is traditionally thought to be regulated by anti-apoptotic BCL-2 family members, like BCL2-like 1 (BCL-XL), at the protein level. However, the posttranscriptional regulation of BAX is under explored. In this study, we identified BAX as the novel downstream target of miR-365, which is supported by gain- and loss-of-function studies of onco-miR-365. Loss of BAX by either RNA interference or highly-expressed miR-365 in cells of cutaneous squamous cell carcinoma (CSCC) enhanced the tumor resistance against apoptosis, while repressing cell proliferation, migration, and invasiveness. In vivo experiment confirmed that BAX knockdown promotes the growth of CSCC xenografts. Collectively, our results find a miR-365-BAX axis for alleviating the pro apoptotic effects of BAX, which promotes CSCC development and may facilitate the generation of novel therapeutic regimens to the clinical treatment of CSCC. PMID- 28556799 TI - Impaired Insulin Signaling is Associated with Hepatic Mitochondrial Dysfunction in IR+/--IRS-1+/- Double Heterozygous (IR-IRS1dh) Mice. AB - Mitochondria play a pivotal role in energy metabolism, but whether insulin signaling per se could regulate mitochondrial function has not been identified yet. To investigate whether mitochondrial function is regulated by insulin signaling, we analyzed muscle and liver of insulin receptor (IR)+/--insulin receptor substrate-1 (IRS-1)+/- double heterozygous (IR-IRS1dh) mice, a well described model for insulin resistance. IR-IRS1dh mice were studied at the age of 6 and 12 months and glucose metabolism was determined by glucose and insulin tolerance tests. Mitochondrial enzyme activities, oxygen consumption, and membrane potential were assessed using spectrophotometric, respirometric, and proton motive force analysis, respectively. IR-IRS1dh mice showed elevated serum insulin levels. Hepatic mitochondrial oxygen consumption was reduced in IR-IRS1dh animals at 12 months of age. Furthermore, 6-month-old IR-IRS1dh mice demonstrated enhanced mitochondrial respiration in skeletal muscle, but a tendency of impaired glucose tolerance. On the other hand, 12-month-old IR-IRS1dh mice showed improved glucose tolerance, but normal muscle mitochondrial function. Our data revealed that deficiency in IR/IRS-1 resulted in normal or even elevated skeletal muscle, but impaired hepatic mitochondrial function, suggesting a direct cross-talk between insulin signaling and mitochondria in the liver. PMID- 28556802 TI - Multi-Site Simultaneous Time-Resolved Photometry with a Low Cost Electro-Optics System. AB - Sunlight reflected off of resident space objects can be used as an optical signal for astrometric orbit determination and for deducing geometric information about the object. With the increasing population of small satellites and debris in low Earth orbit, photometry is a powerful tool in operational support of space missions, whether for anomaly resolution or object identification. To accurately determine size, shape, spin rate, status of deployables, or attitude information of an unresolved resident space object, multi-hertz sample rate photometry is required to capture the relatively rapid changes in brightness that these objects can exhibit. OSCOM, which stands for Optical tracking and Spectral characterization of CubeSats for Operational Missions, is a low cost and portable telescope system capable of time-resolved small satellite photometry, and is field deployable on short notice for simultaneous observation from multiple sites. We present the electro-optical design principles behind OSCOM and light curves of the 1.5 U DICE-2 CubeSat and simultaneous observations of the main body of the ASTRO-H satellite after its fragmentation event. PMID- 28556801 TI - Heterogeneous Trajectories of Physical and Mental Health in Late Middle Age: Importance of Life-Course Socioeconomic Positions. AB - Drawing on life course and cumulative disadvantage theory, this study examines heterogeneous trajectories of functional limitations and depressive symptoms among late middle-aged individuals. This study used prospective data from 6010 adults, 51 to 64 years old, collected over a 12-year-period from the Health and Retirement Study. Considering the empirical proposition that several physical and mental trajectories may exist, Latent Class Growth Modeling was used. Five heterogeneous patterns of joint trajectories (Relatively healthy, Moderately improving, Steadily deteriorating, Steeply deteriorating, and Persistently high comorbid) were identified. Early life adversity was related to an increasing risk of declines in physical and mental health. The Persistently high comorbid class was characterized by a concentration of disadvantages over the life course. The development of public health interventions could help reduce co-existing physical and mental health problems, especially during late middle-age. PMID- 28556803 TI - Using Color, Texture and Object-Based Image Analysis of Multi-Temporal Camera Data to Monitor Soil Aggregate Breakdown. AB - Remote sensing has shown its potential to assess soil properties and is a fast and non-destructive method for monitoring soil surface changes. In this paper, we monitor soil aggregate breakdown under natural conditions. From November 2014 to February 2015, images and weather data were collected on a daily basis from five soils susceptible to detachment (Silty Loam with various organic matter content, Loam and Sandy Loam). Three techniques that vary in image processing complexity and user interaction were tested for the ability of monitoring aggregate breakdown. Considering that the soil surface roughness causes shadow cast, the blue/red band ratio is utilized to observe the soil aggregate changes. Dealing with images with high spatial resolution, image texture entropy, which reflects the process of soil aggregate breakdown, is used. In addition, the Huang thresholding technique, which allows estimation of the image area occupied by soil aggregate, is performed. Our results show that all three techniques indicate soil aggregate breakdown over time. The shadow ratio shows a gradual change over time with no details related to weather conditions. Both the entropy and the Huang thresholding technique show variations of soil aggregate breakdown responding to weather conditions. Using data obtained with a regular camera, we found that freezing-thawing cycles are the cause of soil aggregate breakdown. PMID- 28556800 TI - Disease Prevention: An Opportunity to Expand Edible Plant-Based Vaccines? AB - The lethality of infectious diseases has decreased due to the implementation of crucial sanitary procedures such as vaccination. However, the resurgence of pathogenic diseases in different parts of the world has revealed the importance of identifying novel, rapid, and concrete solutions for control and prevention. Edible vaccines pose an interesting alternative that could overcome some of the constraints of traditional vaccines. The term "edible vaccine" refers to the use of edible parts of a plant that has been genetically modified to produce specific components of a particular pathogen to generate protection against a disease. The aim of this review is to present and critically examine "edible vaccines" as an option for global immunization against pathogenic diseases and their outbreaks and to discuss the necessary steps for their production and control and the list of plants that may already be used as edible vaccines. Additionally, this review discusses the required standards and ethical regulations as well as the advantages and disadvantages associated with this powerful biotechnology tool. PMID- 28556804 TI - Smartphone-Based pH Sensor for Home Monitoring of Pulmonary Exacerbations in Cystic Fibrosis. AB - Currently, Cystic Fibrosis (CF) patients lack the ability to track their lung health at home, relying instead on doctor checkups leading to delayed treatment and lung damage. By leveraging the ubiquity of the smartphone to lower costs and increase portability, a smartphone-based peripheral pH measurement device was designed to attach directly to the headphone port to harvest power and communicate with a smartphone application. This platform was tested using prepared pH buffers and sputum samples from CF patients. The system matches within ~0.03 pH of a benchtop pH meter while fully powering itself and communicating with a Samsung Galaxy S3 smartphone paired with either a glass or Iridium Oxide (IrOx) electrode. The IrOx electrodes were found to have 25% higher sensitivity than the glass probes at the expense of larger drift and matrix sensitivity that can be addressed with proper calibration. The smartphone-based platform has been demonstrated as a portable replacement for laboratory pH meters, and supports both highly robust glass probes and the sensitive and miniature IrOx electrodes with calibration. This tool can enable more frequent pH sputum tracking for CF patients to help detect the onset of pulmonary exacerbation to provide timely and appropriate treatment before serious damage occurs. PMID- 28556805 TI - Corrosivity Sensor for Exposed Pipelines Based on Wireless Energy Transfer. AB - External corrosion was identified as one of the main causes of pipeline failures worldwide. A solution that addresses the issue of detecting and quantifying corrosivity of environment for application to existing exposed pipelines has been developed. It consists of a sensing array made of an assembly of thin strips of pipeline steel and a circuit that provides a visual sensor reading to the operator. The proposed sensor is passive and does not require a constant power supply. Circuit design was validated through simulations and lab experiments. Accelerated corrosion experiment was conducted to confirm the feasibility of the proposed corrosivity sensor design. PMID- 28556806 TI - Quality of Life in Women with Stage 1 Stress Urinary Incontinence after Application of Conservative Treatment-A Randomized Trial. AB - Stress urinary incontinence (SUI) influences quality of life in female patients. In this study, we used ICIQ LUTS QoL (The International Consultation Incontinence Questionnaire Lower Urinary Tract Symptoms quality of life) to determine the quality of life (QoL) in various domains in patients with stage 1 SUI. The study included 140 perimenopausal women subjected to urodynamic tests at the Department of Gynaecology, Endocrinology and Gynaecologic Oncology, Pomeranian Medical University, Police (Poland) in 2013-2015. The study subjects were divided into two groups, A and B. Each patient completed two questionnaires, an original survey developed by the authors and the validated ICIQ LUTS QoL. Two exercise programs, each lasting for 3 months and consisting of 4 weekly sessions, were recommended to the study subjects. The program for Group A included exercises for pelvic floor muscles (PFM) with simultaneous tension of the transverse abdominal muscle (TrA), and the program for Group B, PFM exercises without TrA tension. After completing the exercise programs, patients with stage 1 SUI, both from Group A and from Group B, showed a significant improvement in most QoL domains measured with ICIQ LUTS QoL. However, more beneficial effects of the training were observed in the group subjected to PFM exercises with TrA tension. PMID- 28556808 TI - Antinociceptive Effect of the Essential Oil from Croton conduplicatus Kunth (Euphorbiaceae). AB - Medicinal plants have been widely used in the treatment of chronic pain. In this study, we describe the antinociceptive effect of the essential oil from Croton conduplicatus (the EO 25, 50, and 100 mg/kg, i.p.), a medicinal plant native to Brazil. Antinociceptive activity was investigated by measuring the nociception induced by acetic acid, formalin, hot plate and carrageenan. A docking study was performed with the major constituents of the EO (E-caryophyllene, caryophyllene oxide, and camphor). The EO reduced nociceptive behavior at all doses tested in the acetic acid-induced nociception test (p < 0.05). The same was observed in both phases (neurogenic and inflammatory) of the formalin test. When the hot plate test was conducted, the EO (50 mg/kg) extended the latency time after 60 min of treatment. The EO also reduced leukocyte migration at all doses, suggesting that its antinociceptive effect involves both central and peripheral mechanisms. Pretreatment with glibenclamide and atropine reversed the antinociceptive effect of the EO on the formalin test, suggesting the involvement of KATP channels and muscarinic receptors. The docking study revealed a satisfactory interaction profile between the major components of the EO and the different muscarinic receptor subtypes (M2, M3, and M4). These results corroborate the medicinal use of C. conduplicatus in folk medicine. PMID- 28556809 TI - Frequency Domain Analysis of Sensor Data for Event Classification in Real-Time Robot Assisted Deburring. AB - Process monitoring using indirect methods relies on the usage of sensors. Using sensors to acquire vital process related information also presents itself with the problem of big data management and analysis. Due to uncertainty in the frequency of events occurring, a higher sampling rate is often used in real-time monitoring applications to increase the chances of capturing and understanding all possible events related to the process. Advanced signal processing methods are used to further decipher meaningful information from the acquired data. In this research work, power spectrum density (PSD) of sensor data acquired at sampling rates between 40-51.2 kHz was calculated and the corelation between PSD and completed number of cycles/passes is presented. Here, the progress in number of cycles/passes is the event this research work intends to classify and the algorithm used to compute PSD is Welch's estimate method. A comparison between Welch's estimate method and statistical methods is also discussed. A clear co relation was observed using Welch's estimate to classify the number of cycles/passes. The paper also succeeds in classifying vibration signal generated by the spindle from the vibration signal acquired during finishing process. PMID- 28556807 TI - The Effects of the Global Economic Recession and a Reduced Alcohol Tax on Hospitalizations Due to Alcohol-Attributed Diseases in Taiwan. AB - This study is to assess the effects of the 2008 economic crisis and a 2009 alcohol tax reduction on alcohol-related morbidity for men of different socioeconomic statuses in Taiwan. Admissions data for the period from 2007 to 2012 for men aged 24-59 years in 2007 was retrieved from the National Health Insurance Research Database. With stratification over three income levels, an interrupted time-series analysis examining the effects of the crisis and taxation reduction on incidence rates of hospitalization for alcohol-attributed diseases (AADs) was employed. The low income group showed a significant (p < 0.05) change in the rate of AAD-related hospitalizations in July 2008; specifically, an abrupt 7.11% increase that was then sustained for several months thereafter. In contrast, while the middle income group exhibited a significant 22.9% decline in the rate of AAD-related hospitalizations over the course of the crisis, that downward trend was gradual. The reduction of the alcohol tax resulted in increased rates of AADs among both the low and high income groups. The economic recession and the reduction of the alcohol tax resulted in an increased rate of AAD among low income men. PMID- 28556810 TI - Transtheoretical Model of Change during Travel Behavior Interventions: An Integrative Review. AB - This study aims to identify the relevant empirical work, to synthesize its findings, and to thus attain a general understanding of the application of the Transtheoretical Model (TTM) in transport behavior research. An integrative literature review was used to determine whether or not the implemented interventions impact the stages and processes of travel behavior change. Data was collected from different databases. English language articles published between 2002 and 2017 were included. After sequentially narrowing the search and removing duplicates, 53 relevant papers remained, 13 of which fulfilled the stated criteria of constituting a transport intervention study using the TTM as a reference frame. The final 13 studies were classified and categorized according to stages and processes in the TTM. Findings showed that none of the interventions met the method requirements for a proper evaluation of design and outcome measurement. Reporting did not follow a standardized structure desirable when enabling comparative analyses. Allowing for these shortcomings, it is inferred that positive travel behavior changes have been obtained during some interventions. Importantly, although it was stated that the empirical studies were based on the TTM, the included interventions were implemented irrespective of the individual's stage of change. For future research, it will be necessary to conduct evaluations of higher quality. PMID- 28556811 TI - Towards Targeting PI3K-Dependent Regulation of Gene Expression in Brain Cancer. AB - The PI3K pathway is one of the most highly perturbed cell signaling pathways in human cancer, including the most common malignant brain tumors, gliomas, where either activating mutations of positive pathway effectors or loss/inactivation of pathway inhibitors occurs. Knowledge of the precise transcription factors modulated by PI3K in tumor cells remains elusive but there are numerous PI3K responsive signaling factors, including kinases, which can activate many transcription factors. In the context of cancer, these transcription factors participate in the regulation of target genes expression networks to support cancer cell characteristics such as survival, proliferation, migration and differentiation. This review focuses on the role of PI3K signaling-regulated transcription in brain cancer cells from a series of recent investigations. A deeper understanding of this regulation is beginning to provide the hope of developing more sophisticated anti-cancer targeting approaches, where both upstream and downstream components of the PI3K pathway may be targeted by existing and novel drugs. PMID- 28556812 TI - Ultrafine Particle Distribution and Chemical Composition Assessment during Military Operative Trainings. AB - (1) Background: The assessment of airborne particulate matter (PM) and ultrafine particles (UFPs) in battlefield scenarios is a topic of particular concern; (2) Methods: Size distribution, concentration, and chemical composition of UFPs during operative military training activities (target drone launches, ammunition blasting, and inert bomb impact) were investigated using an electric low-pressure impactor (ELPI+) and a scanning electron microscope (SEM), equipped with energy dispersive spectroscopy (EDS); (3) Results: The median of UFPs, measured for all sampling periods and at variable distance from sources, was between 1.02 * 103 and 3.75 * 103 particles/cm3 for drone launches, between 3.32 * 103 and 15.4 * 103 particles/cm3 for the ammunition blasting and from 7.9 * 103 to 1.3 * 104 particles/cm3 for inert launches. Maximum peak concentrations, during emitting sources starting, were 75.5 * 106 and 17.9 * 106 particles/cm3, respectively. Particles from the drone launches were predominantly composed of silicon (Si), iron (Fe) and calcium (Ca), and those from the blasting campaigns by magnesium (Mg), sulphur (S), aluminum (Al), iron (Fe), barium (Ba) and silicon (Si); (4) Conclusions: The investigated sources produced UFPs with median values lower than other anthropogenic sources, and with a similar chemical composition. PMID- 28556813 TI - Cognitive-Motivational Determinants of Residents' Civic Engagement and Health (Inequities) in the Context of Noise Action Planning: A Conceptual Model. AB - The Environmental Noise Directive expects residents to be actively involved in localising and selecting noise abatement interventions during the noise action planning process. Its intervention impact is meant to be homogeneous across population groups. Against the background of social heterogeneity and environmental disparities, however, the impact of noise action planning on exposure to traffic-related noise and its health effects is unlikely to follow homogenous distributions. Until now, there has been no study evaluating the impact of noise action measures on the social distribution of traffic-related noise exposure and health outcomes. We develop a conceptual (logic) model on cognitive-motivational determinants of residents' civic engagement and health (inequities) by integrating arguments from the Model on household's Vulnerability to the local Environment, the learned helplessness model in environmental psychology, the Cognitive Activation Theory of Stress, and the reserve capacity model. Specifically, we derive four hypothetical patterns of cognitive motivational determinants yielding different levels of sustained physiological activation and expectancies of civic engagement. These patterns may help us understand why health inequities arise in the context of noise action planning and learn how to transform noise action planning into an instrument conducive to health equity. While building on existing frameworks, our conceptual model will be tested empirically in the next stage of our research process. PMID- 28556814 TI - Combined Treatment with Hyaluronic Acid and Mesalamine Protects Rats from Inflammatory Bowel Disease Induced by Intracolonic Administration of Trinitrobenzenesulfonic Acid. AB - Drugs such as mesalamine (5-ASA) are currently recommended for the treatment of inflammatory bowel disease (IBD). To reduce the frequency of their administration and improve their therapeutic effect, this study investigated the adhesion efficacy, wound healing promotion, and decrease in inflammation in ulcers in the colonic tissue of rats with colitis after combined treatment with hyaluronic acid (HA) and 5-ASA (IBD98-M). HA-fluoresceinamine (FL) conjugates successfully adhered to the mucosal layer and were conjugated in the vascular tissue. In addition, macroscopic and microscopic observations indicated that colonic injuries reduced significantly after treatment with IBD98-M. Compared with PBS and 5-ASA treatment alone, treatment with IBD98-M more effectively reduced bowel inflammation and promoted colonic mucosal healing in TNBS-induced colitis. IBD98 M treatment also reduced myeloperoxidase activity and the expression levels of cyclooxygenase 2 and tumor necrosis factor-alphain the colitis tissue. In conclusion, IBD98-M treatment strongly promoted wound healing in colonic injuries and significantly inhibited MPO activity in the inflamed colon tissue of rats. Combined treatment with HA and 5-ASA can accelerate wound healing and reduce inflammatory reaction in rat colitis. PMID- 28556815 TI - The Antidiabetic Mechanisms of Polyphenols Related to Increased Glucagon-Like Peptide-1 (GLP1) and Insulin Signaling. AB - Type-2 diabetes mellitus (T2DM) is an endocrine disease related to impaired/absent insulin signaling. Dietary habits can either promote or mitigate the onset and severity of T2DM. Diets rich in fruits and vegetables have been correlated with a decreased incidence of T2DM, apparently due to their high polyphenol content. Polyphenols are compounds of plant origin with several documented bioactivities related to health promotion. The present review describes the antidiabetic effects of polyphenols, specifically related to the secretion and effects of insulin and glucagon-like peptide 1 (GLP1), an enteric hormone that stimulates postprandial insulin secretion. The evidence suggests that polyphenols from various sources stimulate L-cells to secrete GLP1, increase its half-life by inhibiting dipeptidyl peptidase-4 (DPP4), stimulate beta-cells to secrete insulin and stimulate the peripheral response to insulin, increasing the overall effects of the GLP1-insulin axis. The glucose-lowering potential of polyphenols has been evidenced in various acute and chronic models of healthy and diabetic organisms. Some polyphenols appear to exert their effects similarly to pharmaceutical antidiabetics; thus, rigorous clinical trials are needed to fully validate this claim. The broad diversity of polyphenols has not allowed for entirely describing their mechanisms of action, but the evidence advocates for their regular consumption. PMID- 28556816 TI - Salmonid Jumping and Playing: Potential Cultural and Welfare Implications. AB - Salmonids of several species and other fishes can jump into the air from the water. This behavior has been used in net pen culture applications to control parasitic sea lice. The reasons that salmonids jump remain a topic for speculation. Research on these behaviors has focused on Atlantic salmon in net pen culture in Northwest Europe. Jumping in salmonids is a heterogeneous behavioral category with diverse functional outcomes. Additional research is needed from broad perspectives spanning indigenous and institutional science, cultural wisdom, and ethological direct observation. In theory and in practice, it is interesting that some salmonid jumping behavior may be a form of play. PMID- 28556817 TI - The Lateral Tracking Control for the Intelligent Vehicle Based on Adaptive PID Neural Network. AB - The intelligent vehicle is a complicated nonlinear system, and the design of a path tracking controller is one of the key technologies in intelligent vehicle research. This paper mainly designs a lateral control dynamic model of the intelligent vehicle, which is used for lateral tracking control. Firstly, the vehicle dynamics model (i.e., transfer function) is established according to the vehicle parameters. Secondly, according to the vehicle steering control system and the CARMA (Controlled Auto-Regression and Moving-Average) model, a second order control system model is built. Using forgetting factor recursive least square estimation (FFRLS), the system parameters are identified. Finally, a neural network PID (Proportion Integral Derivative) controller is established for lateral path tracking control based on the vehicle model and the steering system model. Experimental simulation results show that the proposed model and algorithm have the high real-time and robustness in path tracing control. This provides a certain theoretical basis for intelligent vehicle autonomous navigation tracking control, and lays the foundation for the vertical and lateral coupling control. PMID- 28556818 TI - Vital Sign Monitoring and Mobile Phone Usage Detection Using IR-UWB Radar for Intended Use in Car Crash Prevention. AB - In order to avoid car crashes, active safety systems are becoming more and more important. Many crashes are caused due to driver drowsiness or mobile phone usage. Detecting the drowsiness of the driver is very important for the safety of a car. Monitoring of vital signs such as respiration rate and heart rate is important to determine the occurrence of driver drowsiness. In this paper, robust vital signs monitoring through impulse radio ultra-wideband (IR-UWB) radar is discussed. We propose a new algorithm that can estimate the vital signs even if there is motion caused by the driving activities. We analyzed the whole fast time vital detection region and found the signals at those fast time locations that have useful information related to the vital signals. We segmented those signals into sub-signals and then constructed the desired vital signal using the correlation method. In this way, the vital signs of the driver can be monitored noninvasively, which can be used by researchers to detect the drowsiness of the driver which is related to the vital signs i.e., respiration and heart rate. In addition, texting on a mobile phone during driving may cause visual, manual or cognitive distraction of the driver. In order to reduce accidents caused by a distracted driver, we proposed an algorithm that can detect perfectly a driver's mobile phone usage even if there are various motions of the driver in the car or changes in background objects. These novel techniques, which monitor vital signs associated with drowsiness and detect phone usage before a driver makes a mistake, may be very helpful in developing techniques for preventing a car crash. PMID- 28556819 TI - Extraction of Rice Phenological Differences under Heavy Metal Stress Using EVI Time-Series from HJ-1A/B Data. AB - An effective method to monitor heavy metal stress in crops is of critical importance to assure agricultural production and food security. Phenology, as a sensitive indicator of environmental change, can respond to heavy metal stress in crops and remote sensing is an effective method to detect plant phenological changes. This study focused on identifying the rice phenological differences under varied heavy metal stress using EVI (enhanced vegetation index) time series, which was obtained from HJ-1A/B CCD images and fitted with asymmetric Gaussian model functions. We extracted three phenological periods using first derivative analysis: the tillering period, heading period, and maturation period; and constructed two kinds of metrics with phenological characteristics: date intervals and time-integrated EVI, to explore the rice phenological differences under mild and severe stress levels. Results indicated that under severe stress the values of the metrics for presenting rice phenological differences in the experimental areas of heavy metal stress were smaller than the ones under mild stress. This finding represents a new method for monitoring heavy metal contamination through rice phenology. PMID- 28556820 TI - Placebo by Proxy in Neonatal Randomized Controlled Trials: Does It Matter? AB - Placebo effects emerging from the expectations of relatives, also known as placebo by proxy, have seldom been explored. The aim of this study was to investigate whether in a randomized controlled trial (RCT) there is a clinically relevant difference in long-term outcome between very preterm infants whose parents assume that verum (PAV) had been administered and very preterm infants whose parents assume that placebo (PAP) had been administered. The difference between the PAV and PAP infants with respect to the primary outcome-IQ at 5 years of age-was considered clinically irrelevant if the confidence interval (CI) for the mean difference resided within our pre-specified +/-5-point equivalence margins. When adjusted for the effects of verum/placebo, socioeconomic status (SES), head circumference and sepsis, the CI was [-3.04, 5.67] points in favor of the PAV group. Consequently, our study did not show equivalence between the PAV and PAP groups, with respect to the pre-specified margins of equivalence. Therefore, our findings suggest that there is a small, but clinically irrelevant degree to which a preterm infant's response to therapy is affected by its parents' expectations, however, additional large-scale studies are needed to confirm this conjecture. PMID- 28556821 TI - A National Census of Birth Weight in Purebred Dogs in Italy. AB - Despite increasing professionalism in dog breeding, the physiological range of birth weight in this species remains unclear. Low birth weight can predispose to neonatal mortality and growth deficiencies in humans. To date, the influence of the morphotype on birth weight has never been studied in dogs. For this purpose, an Italian census of birth weight was collected from 3293 purebred pups based on maternal morphotype, size, body weight and breed, as well as on litter size and sex of pups. Multivariate analysis outcomes showed that birth weight (p < 0.001) and litter size (p < 0.05) increased with maternal size and body weight. Birth weight was also influenced by the maternal head and body shape, with brachycephalic and brachymorph dogs showing the heaviest and the lightest pups, respectively (p < 0.001). Birth weight decreased with litter size (p < 0.001), and male pups were heavier than females (p < 0.001). These results suggest that canine morphotype, not only maternal size and body weight, can affect birth weight and litter size with possible practical implications in neonatal assistance. PMID- 28556822 TI - Two Saporin-Containing Immunotoxins Specific for CD20 and CD22 Show Different Behavior in Killing Lymphoma Cells. AB - Immunotoxins (ITs) are hybrid proteins combining the binding specificity of antibodies with the cytocidal properties of toxins. They represent a promising approach to lymphoma therapy. The cytotoxicity of two immunotoxins obtained by chemical conjugation of the plant toxin saporin-S6 with the anti-CD20 chimeric antibody rituximab and the anti-CD22 murine antibody OM124 were evaluated on the CD20-/CD22-positive cell line Raji. Both ITs showed strong cytotoxicity for Raji cells, but the anti-CD22 IT was two logs more efficient in killing, probably because of its faster internalization. The anti-CD22 IT gave slower but greater caspase activation than the anti-CD20 IT. The cytotoxic effect of both immunotoxins can be partially prevented by either the pan-caspase inhibitor Z-VAD or the necroptosis inhibitor necrostatin-1. Oxidative stress seems to be involved in the cell killing activity of anti-CD20 IT, as demonstrated by the protective role of the H2O2 scavenger catalase, but not in that of anti-CD22 IT. Moreover, the IT toxicity can be augmented by the contemporary administration of other chemotherapeutic drugs, such as PS-341, MG-132, and fludarabine. These results contribute to the understanding of the immunotoxin mechanism of action that is required for their clinical use, either alone or in combination with other drugs. PMID- 28556823 TI - Belief Interval of Dempster-Shafer Theory for Line-of-Sight Identification in Indoor Positioning Applications. AB - Location data are among the most widely used contextual data in context-aware and ubiquitous computing applications. Numerous systems with distinct deployment costs and levels of positioning accuracy have been developed over the past decade for indoor positioning purposes. The most useful method focuses on the received signal strength (RSS) and provides a set of signal transmission access points. Furthermore, most positioning systems are based on non-line-of-sight (NLOS) rather than line-of-sight (LOS) conditions, and this cause ranging errors for location predictions. Hence, manually compiling a fingerprint database measuring RSS involves high costs and is thus impractical in online prediction environments. In our proposed method, a comparison method is derived on the basis of belief intervals, as proposed in Dempster-Shafer theory, and the signal features are characterized on the LOS and NLOS conditions for different field experiments. The system performance levels were examined with different features and under different environments through robust testing and by using several widely used machine learning methods. The results showed that the proposed method can not only retain positioning accuracy but also save computation time in location predictions. PMID- 28556826 TI - Corrigendum: The contemporary distribution of Trypanosoma cruzi infection in humans, alternative hosts and vectors. AB - This corrects the article DOI: 10.1038/sdata.2017.50. PMID- 28556825 TI - Modelling the role of groundwater hydro-refugia in East African hominin evolution and dispersal. AB - Water is a fundamental resource, yet its spatiotemporal availability in East Africa is poorly understood. This is the area where most hominin first occurrences are located, and consequently the potential role of water in hominin evolution and dispersal remains unresolved. Here, we show that hundreds of springs currently distributed across East Africa could function as persistent groundwater hydro-refugia through orbital-scale climate cycles. Groundwater buffers climate variability according to spatially variable groundwater response times determined by geology and topography. Using an agent-based model, grounded on the present day landscape, we show that groundwater availability would have been critical to supporting isolated networks of hydro-refugia during dry periods when potable surface water was scarce. This may have facilitated unexpected variations in isolation and dispersal of hominin populations in the past. Our results therefore provide a new environmental framework in which to understand how patterns of taxonomic diversity in hominins may have developed. PMID- 28556824 TI - Ancient Egyptian mummy genomes suggest an increase of Sub-Saharan African ancestry in post-Roman periods. AB - Egypt, located on the isthmus of Africa, is an ideal region to study historical population dynamics due to its geographic location and documented interactions with ancient civilizations in Africa, Asia and Europe. Particularly, in the first millennium BCE Egypt endured foreign domination leading to growing numbers of foreigners living within its borders possibly contributing genetically to the local population. Here we present 90 mitochondrial genomes as well as genome-wide data sets from three individuals obtained from Egyptian mummies. The samples recovered from Middle Egypt span around 1,300 years of ancient Egyptian history from the New Kingdom to the Roman Period. Our analyses reveal that ancient Egyptians shared more ancestry with Near Easterners than present-day Egyptians, who received additional sub-Saharan admixture in more recent times. This analysis establishes ancient Egyptian mummies as a genetic source to study ancient human history and offers the perspective of deciphering Egypt's past at a genome-wide level. PMID- 28556827 TI - RiceAtlas, a spatial database of global rice calendars and production. AB - Knowing where, when, and how much rice is planted and harvested is crucial information for understanding the effects of policy, trade, and global and technological change on food security. We developed RiceAtlas, a spatial database on the seasonal distribution of the world's rice production. It consists of data on rice planting and harvesting dates by growing season and estimates of monthly production for all rice-producing countries. Sources used for planting and harvesting dates include global and regional databases, national publications, online reports, and expert knowledge. Monthly production data were estimated based on annual or seasonal production statistics, and planting and harvesting dates. RiceAtlas has 2,725 spatial units. Compared with available global crop calendars, RiceAtlas is nearly ten times more spatially detailed and has nearly seven times more spatial units, with at least two seasons of calendar data, making RiceAtlas the most comprehensive and detailed spatial database on rice calendar and production. PMID- 28556828 TI - Interactive models of communication at the nanoscale using nanoparticles that talk to one another. AB - 'Communication' between abiotic nanoscale chemical systems is an almost unexplored field with enormous potential. Here we show the design and preparation of a chemical communication system based on enzyme-powered Janus nanoparticles, which mimics an interactive model of communication. Cargo delivery from one nanoparticle is governed by the biunivocal communication with another nanoparticle, which involves two enzymatic processes and the interchange of chemical messengers. The conceptual idea of establishing communication between nanodevices opens the opportunity to develop complex nanoscale systems capable of sharing information and cooperating. PMID- 28556829 TI - PCLO rs2522833-mediated gray matter volume reduction in patients with drug-naive, first-episode major depressive disorder. AB - Major depressive disorder (MDD) has been linked to differences in the volume of certain areas of the brain and to variants in the piccolo presynaptic cytomatrix protein (PCLO), but the relationship between PCLO and brain morphology has not been studied. A single-nucleotide polymorphism (SNP) in PCLO, rs2522833, is thought to affect protein stability and the activity of the hypothalamic pituitary-adrenal axis. We investigated the relationship between cortical volume and this SNP in first-episode, drug-naive patients with MDD or healthy control subjects. Seventy-eight participants, including 30 patients with MDD and 48 healthy control subjects, were recruited via interview. PCLO rs2522833 genotyping and plasma cortisol assays were performed, and gray matter volume was estimated using structural magnetic resonance images. Among the individuals carrying the C allele of PCLO rs2522833, the volume of the left temporal pole was significantly smaller in those with MDD than in healthy controls (family-wise error-corrected, P=0.003). No differences were detected in other brain regions. In addition, the C carriers showed a larger volume reduction in the left temporal pole than those in the individuals with A/A genotype (P=0.0099). Plasma cortisol levels were significantly higher in MDD-affected C-carriers than in the healthy control C carriers (12.76+/-6.10 vs 9.31+/-3.60 nm, P=0.045). We conclude that PCLO SNP rs2522833 is associated with a gray matter volume reduction in the left temporal pole in drug-naive, first-episode patients with MDD carrying the C-allele. PMID- 28556831 TI - Sex differences in recent first-onset depression in an epidemiological sample of adolescents. AB - Prior studies provide limited and contradictory evidence regarding sex differences in the incidence of depression during adolescence, a critical period for development of the disorder. Data from six consecutive years (2009-2014) of a national survey of US adolescents aged 12-17 (N=101 685) are used to characterize sex differences in the incidence of depression by age and to compare recent first onset and persistent depression with respect to impairment, suicide attempts, conduct problems and academic functioning. Projecting from age-specific incidence proportions, the cumulative incidence of depression between the ages of 12 and 17 is 13.6% among male and 36.1% among female subjects. The sex difference in incidence is significant at the age of 12 years (5.2% in female versus 2.0% in male subjects, P<0.0001), and it is significantly larger at ages of 13 through 17 years than at the age of 12 years (P-values<0.05). Depression-related impairment is lower in recent first-onset than in persistent depression among female but not among male subjects. The prevalence of conduct problems and poor academic functioning is higher in both recent first-onset and persistent depression relative to those with no depression for both male and female subjects. The incidence of depression during adolescence is higher than that suggested by prior studies based on retrospective recall. Contrary to prior studies, evidence suggests that the sex difference in depression originates during childhood and grows in magnitude during adolescence. High levels of impairment, suicide attempts, conduct problems and poor academic functioning argue against a 'wait and see' approach to clinical treatment of recent first-onset depression. PMID- 28556832 TI - Genetic susceptibility to cardiovascular disease and risk of dementia. AB - Several studies have shown cardiovascular disease (CVD) to be associated with dementia, but it is not clear whether CVD per se increases the risk of dementia or whether the association is due to shared risk factors. We tested how a genetic risk score (GRS) for coronary artery disease (CAD) affects dementia risk after CVD in 13 231 Swedish twins. We also utilized summarized genome-wide association data to study genetic overlap between CAD and Alzheimer's disease (AD), and additionally between shared risk factors and each disease. There was no direct effect of a CAD GRS on dementia (hazard ratio 0.99, 95% confidence interval (CI): 0.98-1.01). However, the GRS for CAD modified the association between CVD and dementia within 3 years of CVD diagnosis, ranging from a hazard ratio of 1.59 (95% CI: 1.05-2.41) in the first GRS quartile to 1.91 (95% CI: 1.28-2.86) in the fourth GRS quartile. Using summary statistics, we found no genetic overlap between CAD and AD. We did, however, find that both AD and CAD share a significant genetic overlap with lipids, but that the overlap arose from clearly distinct gene clusters. In conclusion, genetic susceptibility to CAD was found to modify the association between CVD and dementia, most likely through associations with shared risk factors. PMID- 28556830 TI - Adolescence is the starting point of sex-dichotomous COMT genetic effects. AB - The catechol-o-methyltransferase (COMT) genetic variations produce pleiotropic behavioral/neuroanatomical effects. Some of these effects may vary among sexes. However, the developmental trajectories of COMT-by-sex interactions are unclear. Here we found that extreme COMT reduction, in both humans (22q11.2 deletion syndrome COMT Met) and mice (COMT-/-), was associated to cortical thinning only after puberty and only in females. Molecular biomarkers, such as tyrosine hydroxylase, Akt and neuronal/cellular counting, confirmed that COMT-by-sex divergent effects started to appear at the cortical level during puberty. These biochemical differences were absent in infancy. Finally, developmental cognitive assessment in 22q11DS and COMT knockout mice established that COMT-by-sex dichotomous effects in executive functions were already apparent in adolescence. These findings uncover that genetic variations severely reducing COMT result in detrimental cortical and cognitive development selectively in females after their sexual maturity. This highlights the importance of taking into account the combined effect of genetics, sex and developmental stage. PMID- 28556834 TI - Developmental regulation of SMN expression: pathophysiological implications and perspectives for therapy development in spinal muscular atrophy. AB - Spinal muscular atrophy (SMA), the predominant form of motoneuron disease in children and young adults is caused by loss of function of the SMN protein. On the basis of a disrupted splice acceptor site in exon 7, transcripts from a second SMN gene in humans called SMN2 cannot give rise to SMN protein at sufficient levels for maintaining function of motoneurons and motor circuits. First clinical trials with Spinraza/Nusinersen, a drug that counteracts disrupted splicing of SMN2 transcripts, have shown that elevating SMN levels can successfully interfere with motoneuron dysfunction. This review summarizes current knowledge about the pathophysiological alterations in Smn-deficient motoneurons, which lead to defective neuromuscular transmission and altered spinal circuit formation. Both pathological mechanisms are important targets for therapeutic intervention. However, the developmental time window when therapeutic interventions ideally should start is not known. Endogenous SMN expression both from SMN1 and SMN2 genes is high at early developmental stages and declines progressively in humans and mice. Thus, therapeutic SMN upregulation should start just before SMN declines below a critical threshold, and before irreversible defects occur at neuromuscular junctions and in spinal circuits. Previous results indicate that loss of Smn function leads to synaptic dysfunction during a stage of neuromuscular development when synaptic strength determines which synapses are maintained or not. This time window appears as an important target for therapy, which possibly could be supported by additional strategies that strengthen synaptic transmission. PMID- 28556833 TI - Blockade of interleukin-6 receptor in the periphery promotes rapid and sustained antidepressant actions: a possible role of gut-microbiota-brain axis. AB - Depression is a common, severe and chronic psychiatric disease. Although the currently available antidepressants have been used in the treatment of depression, their beneficial effects are limited. Accumulating evidence suggests that pro-inflammatory cytokines such as interleukin-6 (IL-6) have an important role in the pathogenesis of depression. This study was undertaken to examine whether anti-mouse IL-6 receptor antibody (MR16-1) induces antidepressant effects in a social defeat stress model. Intravenous injection of MR16-1 induced rapid onset and long-lasting antidepressant effects in susceptible mice after social defeat stress through its anti-inflammatory actions. In contrast, intracerebroventricular injection of MR16-1 induced no antidepressant effects in susceptible mice. Furthermore, treatment with MR16-1 could significantly normalize alterations in the expression of synaptic proteins (postsynaptic density protein 95 and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 1) and dendritic spine density in the brain regions of susceptible mice. Gut microbiota analysis using 16S ribosomal RNA gene sequencing showed that MR16 1 significantly improved decreased Firmicutes/Bacteroidetes ratio in susceptible mice. It also significantly improved decreased levels of Oscillospira in susceptible mice. These findings suggest that peripheral IL-6 has a key role in the pathogenesis of depression and that the blockade of IL-6 receptor in the periphery might have rapid-onset and long-lasting antidepressant effects by normalizing the altered composition of gut microbiota in susceptible mice after social defeat stress. Therefore, the blockade of IL-6 receptor in the periphery shows promise as a novel therapeutic approach for depressed patients with higher IL-6 blood levels. PMID- 28556835 TI - Drug-seeking motivation level in male rats determines offspring susceptibility or resistance to cocaine-seeking behaviour. AB - Liability to develop drug addiction is heritable, but the precise contribution of non-Mendelian factors is not well understood. Here we separate male rats into addiction-like and non-addiction-like groups, based on their incentive motivation to seek cocaine. We find that the high incentive responding of the F0 generation could be transmitted to F1 and F2 generations. Moreover, the inheritance of high incentive response to cocaine is contingent on high motivation, as it is elicited by voluntary cocaine administration, but not high intake of cocaine itself. We also find DNA methylation differences between sperm of addiction-like and non addiction-like groups that were maintained from F0 to F1, providing an epigenetic link to transcriptomic changes of addiction-related signalling pathways in the nucleus accumbens of offspring. Our data suggest that highly motivated drug seeking experience may increase vulnerability and/or reduce resistance to drug addiction in descendants. PMID- 28556848 TI - Pilot study of risk factors associated with cardiovascular disease in northern and southern Cameroonians. AB - AIM: The aim of the study was to evaluate whether the risk factors for cardiovascular disease (CVD) are similar in the northern and southern regions of Cameroon. METHODS: The participants answered a questionnaire concerning their lifestyle. Anthropometric and blood pressure measurements were evaluated in 192 individuals and biochemical parameters in 50 randomly selected volunteers. RESULTS: Northerners displayed low alcohol and tobacco consumption, little practice of sport but physically demanding professions, and consumption of soybean, refined palm and other polyunsaturated oils. Southerners consumed alcohol, practiced sport, had intellectually based professions, and consumed crude and refined palm oils. Waist circumference and body mass index were higher in the southerners compared to the northerners. Blood glucose levels, and systolic and diastolic blood pressures were higher among the northerners than the southerners. Among the southerners, there were positive correlations between total cholesterol levels and systolic or diastolic blood pressure, low-density lipoprotein cholesterol and blood glucose levels or diastolic blood pressure, triglyceride levels and systolic blood pressure. CONCLUSION: Providing region adapted, health-related advice for northern and southern Cameroonians would contribute to reducing risk factors for CVD. PMID- 28556849 TI - Effects of age on systemic inflamatory response syndrome and results of coronary bypass surgery. AB - BACKGROUND: Coronary artery bypass (CAB) surgery triggers systemic inflammatory response syndrome (SIRS) via several mechanisms. Moreover, age is directly correlated with SIRS. We evaluated the effect of age on SIRS and postoperative outcome after CAB surgery. METHODS: We retrospectively reviewed the records of 229 patients who had undergone CAB surgery. The patients were divided into three groups according to age: group 1, < 40 years (n = 61); group 2, 40-75 years (n = 83); and group 3, > 75 years old (n = 85). Pre- and peri-operative data were assessed in all patients. SIRS was diagnosed according to the criteria established by Boehme. RESULTS: The average pre-operative EuroSCORE value in group 3 was higher than in the other groups and body surface areas were significantly lower in group 3 than in the other groups (p < 0.05). The postoperative SIRS rates were 68.9% in group 1, 84.3% in group 2 and 91.8% in group 3 (group 1 vs group 3; p < 0.05). Mortality rates were not significantly different between the groups (p > 0.05). The predictive factors for SIRS were age, EuroSCORE rate, on-pump CAB surgery and intra-aortic balloon pump use. CONCLUSIONS: Age was an important risk factor for SIRS during the postoperative period after CAB. PMID- 28556851 TI - Perceptions of radiation safety training among interventionalists in South Africa. AB - Exposure to ionising radiation may have deterministic and stochastic health effects, which include skin changes, chromosomal aberrations, cataracts and carcinomas. Formalised training in radiation safety and protection improves knowledge on the subject and facilitates greater compliance in safety practices. This qualitative study included 54 interventionalists (adult and paediatric cardiologists, and interventional radiologists). The participants were purposively selected and interviewed to explore their perceptions about radiation safety. A thematic analysis of the transcripts was done using a deductive and inductive approach. Findings showed participating cardiologists had less knowledge about radiation safety than participating radiologists. Cardiologists reported little or no formal training on radiation safety and did not display a culture of radiation safety. There was no consensus on how the training gap should be addressed. There is a perceived need to change and enhance the radiation safety culture among interventionists, and the participants proffered some ideas. These included the need for re-curricularisation of cardiologists' training to create awareness of radiation safety practices. PMID- 28556850 TI - Clinical profile, management and outcomes of patients with pulmonary embolism: a retrospective tertiary centre study in Angola. AB - OBJECTIVE: Pulmonary embolism (PE) is a potentially fatal disease. In Angola, few data are available on its occurrence. The aim of the study was to characterise the clinical profile, management and outcomes of patients with PE. METHODS: A retrospective observational study was conducted at the Girassol Clinic in Luanda, Angola. The medical records of patients admitted to the intensive care unit were analysed from 2011 to 2015. RESULTS: Fifty patients were included and the median age was 50.5 +/- 17.8 years. Dyspnoea and immobilisation for more than 72 hours were the most frequently seen risk factors at admission; 28% of the patients had massive PE, 36% sub-massive PE, 28% were haemodynamically unstable at admission and 30% had a very high risk of mortality. The in-hospital mortality rate was 20%. CONCLUSIONS: The clinical characteristics of our patients were similar to those described in the literature. The high prevalence of patients with very high risk at admisson highlights the need to investigate the cause of worst cardiovascular disease outcomes in Africans. PMID- 28556854 TI - Correction. PMID- 28556852 TI - Role of melatonin in glucose uptake by cardiomyocytes from insulin-resistant Wistar rats. AB - AIM: Melatonin supplementation reduces insulin resistance and protects the heart in obese rats. However, its role in myocardial glucose uptake remains unknown. This study investigated the effect of short-term melatonin treatment on glucose uptake by cardiomyocytes isolated from obese and insulin-resistant rats. METHODS: Cardiomyocytes were isolated from obese rats fed a high-calorie diet for 16 to 23 weeks, their age-matched controls, as well as young control rats aged four to eight weeks. After incubation with melatonin with or without insulin, glucose uptake was initiated by the addition of 2-deoxy-D- [3H] glucose and measured after 30 minutes. Additional control and obese rats received melatonin in the drinking water (4 mg/kg/day) for the last six weeks of feeding (20 weeks) and glucose uptake was determined in isolated cardiomyocytes after incubation with insulin. Intraperitoneal glucose tolerance and biometric parameters were also measured. RESULTS: Obese rats (fed for more than 20 weeks) developed glucose intolerance. Cardiomyocytes isolated from these obese rats had a reduced response to insulin-stimulated glucose uptake (ISGU) (p < 0.05). Melatonin administration in vitro had no effect on glucose uptake per se. However, it increased ISGU by cardiomyocytes from the young rats (p < 0.05), while having no effect on ISGU by cardiomyocytes from the older control and obese groups. Melatonin in vivo had no significant effect on glucose tolerance, but it increased basal (p < 0.05) and ISGU by cardiomyocytes from the obese rats (50.1 +/- 1.7 vs 32.1 +/- 5.1 pmol/mg protein/30 min, p < 0.01). CONCLUSION: These data suggest that short-term melatonin treatment in vivo but not in vitro improved glucose uptake and insulin responsiveness of cardiomyocytes in obesity and insulin-resistance states. PMID- 28556853 TI - Evaluation of Renal Calculi Passage While Riding a Roller Coaster. PMID- 28556858 TI - Effects of Osteopathic Manipulative Therapy on Pain and Mood Disorders in Patients With High-Frequency Migraine. AB - Context: The substantial functional impairment associated with migraine has both physical and emotional ramifications. Mood disorders are often comorbid in patients with migraine and are known to adversely affect migraine activity. Objectives: To explore the effects of osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) on pain and mood disorders in patients with high-frequency migraine. Methods: Retrospective review of the medical records of patients with high-frequency migraine who were treated with OMTh at the Headache Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia from 2011 to 2015. Clinical assessments were made using the Headache Disability Inventory (HDI), the Headache Impact Test (HIT-6), the Hamilton Depression Rating Scale (HDRS), and the State-Trait Anxiety Inventory (STAI) forms X-1 and X-2. Results: Medical records of 11 patients (6 women; mean age, 47.5 [7.8] years) with a diagnosis of high-frequency migraine who participated in an OMTh program met the inclusion criteria and were included in the study. When the questionnaire scores obtained at the first visit (T0) and after 4 OMTh sessions (T1) were compared, significant improvement in scores were observed on STAI X-2 (T0: 43.18 [2.47]; T1: 39.45 [2.52]; P<.05), HIT-6 (T0: 63 [2.20]; T1: 56.27 [2.24]; P<.05), and HDI (T0: 58.72 [6.75]; T1: 45.09 [7.01]; P<.05). Conclusion: This preliminary study revealed that patients with high frequency migraine and comorbid mood disorders showed significant improvement after four 45-minute OMTh sessions. Further investigation into the effects of OMTh on pain and mood disorders in patients with high-frequency migraine is needed. PMID- 28556857 TI - Emergency Health Care Professionals' Understanding of the Costs of Care in the Emergency Department. AB - Background: Efficiency and fiscal responsibility are important to the equal, safe, and effective delivery of care in the emergency department, where all presenting patients must be evaluated for emergent conditions. Health care professionals' understanding of the costs of care is a first step to developing rational approaches for the efficient distribution of the finite resources hospitals and emergency departments have at their disposal to reduce costs to patients and health care systems. Objective: To determine emergency department health care professionals' knowledge of the costs to patients of routine care delivered in the emergency department. Methods: An internet-based survey of currently practicing emergency medicine health care professionals with various levels of training (physicians, residents, physician assistants, and nurse practitioners) was conducted to evaluate their ability to identify the cost of care for 3 common presentations to the emergency department: abdominal pain, dyspnea, and sore throat. Results: Four hundred forty-one emergency medicine health care professionals participated. In the 3 cases presented, correct costs were determined by 43.0%, 32.0%, and 40.1% of participants, respectively. Geographic region was not related to cost determination. Larger institution size was related to greater cost chosen (P=.01). Higher level of training was significantly correlated with perceived understanding of cost (P<.001); however, it was not related to accurate cost assessment in this study. Conclusion: Emergency medicine health care professionals have an inadequate understanding of the costs associated with care routinely provided in the emergency department. PMID- 28556859 TI - One Health: Children, Waterfowl, and Lead Exposure in Northwestern Nigeria. AB - The One Health concept focuses on the interrelationship between the health of humans, animals, and the environment. There is a delicate balance among these relationships, and when an imbalance exists, the effects can be catastrophic. Such an imbalance occurred in 2010, when elevated lead exposure in rural communities in northwestern Nigeria resulted in the deaths of an estimated 400 children younger than 5 years in a 12-month period. Before the children became ill, waterfowl began to die in great numbers, a connection that would not be realized until much later. This review covers toxicodynamics and the neurotoxic effects of lead in the developing central nervous system, the role that animals can play in recognizing lead exposure and contamination, and environmental sources of lead exposure. The experiences in Nigeria may be especially pertinent to the emerging problems associated with lead exposure and poisoning in the United States. PMID- 28556860 TI - Bridging the Gap: An Osteopathic Primary Care-Centered Approach to Duchenne Muscular Dystrophy. AB - Duchenne muscular dystrophy (DMD) is a deadly and incurable disease typically diagnosed in early childhood. Presently, the delay between a caregiver's initial concern and the primary care physician obtaining creatine kinase levels-the most important screening test-is more than a year. It is imperative to diagnose DMD as soon as possible because early treatment has the potential to double the patient's lifespan. In addition, because of geographic and economic disadvantages, multidisciplinary DMD treatment centers are not readily available to all patients. Therefore, the challenge of early diagnosis and treatment coordination rests with the primary care physician. The present review provides osteopathic primary care physicians with current and relevant information regarding DMD diagnosis and management. PMID- 28556861 TI - Osteopathic Medical Students Entering Family Medicine and Attitudes Regarding Osteopathic Manipulative Treatment: Preliminary Findings of Differences by Sex. AB - Context: Factors distinguishing osteopathic physicians from their allopathic counterparts include the use of osteopathic manipulative treatment (OMT), application of osteopathic principles and practice (OPP), and a greater likelihood of entering primary care, specifically family medicine (FM). In the United States, the percentage of entering osteopathic medical students who were female rose from 14.3% in fall 1977 to 44.3% in fall 2015. Objectives: To investigate the perspectives of female osteopathic medical students as they relate to osteopathic distinctiveness. Methods: Students at the West Virginia School of Osteopathic Medicine who were eligible to participate in graduation exercises in 2014 or 2015 were asked to complete the school's standard Exit Survey. The research team chose 5 items from the survey to include in the current analysis. Sex had been self-identified at admission, and residency in first postgraduate year was categorized as FM or other specialty. Graduates entering a transitional year or traditional internship were removed from analysis. Results: Analysis was conducted for 308 of the 375 students (82%) expected to graduate in 2014 or 2015. chi2 analysis found no difference by sex in the number of graduates entering FM residencies vs other specialties (P=.727). Statistically significant differences were found in 2 survey items: "Use of OMT will enhance my practice" (P=.005) and "What emphasis do you believe OMT will have in your practice?" (P<.001). Graduating female students responded more favorably to OMT on both items. For the latter item, 91.4% of female and 80.3% of male students indicated OMT would have at least some role in their practices. Sex differences remained after statistically controlling for entry into FM. Conclusion: Female graduating osteopathic medical students were more likely to report that OMT will have at least some role in their practices. Future studies of the attitudes and practice patterns of osteopathic physicians should analyze for differences by sex. PMID- 28556862 TI - Therapeutic Hypothermia to Treat a Newborn With Perinatal Hypoxic-Ischemic Encephalopathy. AB - Hypoxic-ischemic encephalopathy is caused by neonatal asphyxia and can lead to mortality or long-term neurodevelopmental morbidity in neonates. Therapeutic hypothermia (TH) is one of the few effective ways to manage mitigating neurologic sequelae. The authors describe the case of a neonate who had a perinatal hypoxic insult and sustained no long-term sequelae after being treated with TH. It is important that osteopathic physicians who provide obstetric and gynecologic, perinatal, and emergency medical care are able to recognize a perinatal hypoxic event, understand the stratification of hypoxic-ischemic encephalopathy risk factors, and implement early TH protocols. PMID- 28556863 TI - Use of the Fascial Distortion Model to Evaluate a Limp in a Child. AB - Pediatric limp is a relatively common condition in primary care and can be challenging to diagnose and manage. Common causes of painful pediatric limp include transient synovitis, septic arthritis, osteomyelitis, and trauma. The authors present the case of an 11-year-old girl with a painful limp and anterior ankle pain of unclear origin. Osteopathic structural examination revealed a somatic dysfunction known as continuum distortion, 1 of 6 fascial alterations identified in the fascial distortion model. Myofascial release was applied, providing rapid, complete resolution of symptoms. This case demonstrates that osteopathic physicians may consider the fascial distortion model framework when identifying causes of pain in patients. PMID- 28556864 TI - Asynchronous Bilateral Ovarian Torsion. PMID- 28556865 TI - Abruptio Placentae. PMID- 28556867 TI - Voicing Ageism in Nursing Home Dementia Care. AB - Elderspeak (i.e., infantilizing communication) is a common form of ageism that has been linked to resistiveness to care in nursing home residents with dementia. Nursing home staff use elderspeak by modifying speech with older residents based on negative stereotypes, which results in patronizing communication that provides a message of incompetence. The purpose of the current secondary analysis was to describe communication practices used by nursing home staff that reflect ageism. Transcripts of 80 video recordings of staff-resident communication collected during nursing home care activities were re-analyzed to identify specific elderspeak patterns, including diminutives, collective pronouns, tag questions, and reflectives. Elderspeak was used in 84% of transcripts, and specifically during bathing, dressing, oral care, and other activities. Collective pronoun substitution occurred most frequently-in 69% of recorded conversations. Subgroup analysis of the inappropriate terms of endearment found that "honey"/"hon" and "sweetheart"/"sweetie" were most commonly used. [Journal of Gerontological Nursing, 43(9), 16-20.]. PMID- 28556866 TI - Model for Risk-Based Screening of Diabetic Retinopathy in People With Newly Diagnosed Type 2 Diabetes Mellitus. AB - Purpose: The purpose of this study was to evaluate the role of inflammatory/lipid markers and potential risk factors for diabetic retinopathy (DR) development in newly diagnosed patients with type 2 diabetes mellitus (T2DM). Methods: Participants in this study were 1062 patients with newly diagnosed T2DM. Demographic and clinical data of patients were collected. Assessment of DR status was performed using digital two-field photography. In addition, HbA1c (%), lipid profile, and urinary albumin were measured at recruitment. The following inflammatory markers were also measured: serum C-reactive protein, white blood cells, platelet, adiponectin, IL-4, IL-6, IL-10, vascular endothelial growth factor, tumor necrosis factor-alpha (TNF-alpha), IL-1b, IL-1 receptor antagonist (IL-1RA), and monocyte chemotactic protein-1. Univariate and multivariate analyses of the association of various potential risk factors and DR were conducted. Results: Univariate analysis showed that male sex, any cardiovascular event, and HbA1c were positively associated with DR, while IL-1RA, IL-1b, IL-6, and TNF-alpha were significantly negatively associated with presence of DR in the cohort. Risk factors that remained significantly associated with DR presence at the multivariate analysis were male sex, any cardiovascular event, HbA1c, and IL 1RA. Conclusions: Our study demonstrated that HbA1c levels, male sex, and previous cardiovascular events were risk factors for presence of DR in people with newly diagnosed T2DM, while IL-1RA seemed to have a protective role. The prevalence of DR in our population was 20.2%, reflecting current practice. Our findings may contribute to future risk-based modelling of screening for DR. PMID- 28556868 TI - Peripheral Inflammatory Biomarkers and Cognitive Decline in Older Adults With and Without Alzheimer's Disease: A Systematic Review. AB - Peripheral inflammatory biomarkers may play an important role in the cognitive decline of aging and incidence of Alzheimer's disease (AD); however, data from epidemiological studies present conflicting findings. The purpose of the current review was to systematically determine the current state of the science on the association between peripheral inflammatory biomarkers and cognitive decline. Articles published from January 1, 2006 to October 28, 2016 were searched using the Medline and Embase databases. Nine studies met inclusion criteria (two examined participants with AD dementia and seven examined participants without dementia). Although a wide range of peripheral inflammatory biomarkers was examined, C-reactive protein and interleukin 6 were the most studied. Findings show conflicting results for the association between peripheral inflammatory biomarkers and cognitive decline. Peripheral inflammation may harm and help the brain, and therefore, the challenge of modulating immunity will be to find ways of fine tuning inflammation to delay, prevent, or treat AD. [Journal of Gerontological Nursing, 43(12), 53-60.]. PMID- 28556869 TI - What Do Family Members Really Want When Older Adults Transition to a Nursing Home? AB - The purpose of the current study was to explore family members' perceptions of supports received during the transition experience of their older adult family member into a nursing home. In this exploratory, descriptive, qualitative study, interviews were conducted with six family members during the initial 6-month period following admission of the older adult family members. One overarching theme was found: importance of recognizing and supporting the personhood of older adult family members. Implications for how older adults' personhood can be supported are described. [Journal of Gerontological Nursing, 43(11), 9-14.]. PMID- 28556870 TI - Person-Centered Dementia Care in the Community: A Perspective From the United Kingdom. AB - Dementia is a global concern. Although effort is being put toward finding a cure, many advances have been made in ensuring excellence in dementia care. In the United Kingdom, the concept of person-centered dementia care has transformed what is expected for individuals with dementia. Now embraced in national policy in the United Kingdom, it was pioneered by Thomas Kitwood and Kathleen Bredin and driven by a concern for the quality of care for individuals with dementia in care homes. The purpose of the current article is to describe key concepts of Kitwood's pioneering work in person-centered dementia care and to use them to inform current community-based supports and services for individuals with dementia in their own homes, whether alone or with family carers. [Journal of Gerontological Nursing, xx(x), xx-xx.]. PMID- 28556871 TI - Nursing Work in Long-Term Care: An Integrative Review. AB - Evidence suggests that delivery of good nursing care in long-term care (LTC) facilities is reflected in nurses' descriptions of the factors and structures that affect their work. Understanding the contemporary nature of nursing work in aged care will influence policies for improving current work structures in this practice setting. The current review aims to present a contemporary perspective of RNs' work in LTC facilities. A comprehensive search and purposeful selection of the literature was conducted using CINAHL, PubMed, Medline, Scopus, and Google Scholar databases. Nine studies were eligible for review. Common themes revealed that nursing work in aged care settings is characterized by RNs providing indirect care tasks-primarily care coordination, engaging in non-nursing activities, and having an expanded and overlapping role. As care providers, aged care RNs do not always provide direct care as part of their nursing work. The scope of RN work beyond its clinical nature or performance of non-nursing tasks adds complexity in clarifying RN work roles in aged care. [Journal of Gerontological Nursing, 43(11), 41-49.]. PMID- 28556872 TI - Medication Adherence Interventions for Older Adults With Heart Failure: A Systematic Review. AB - Medication adherence is crucial in patients with heart failure; however, the rate of medication nonadherence in the heart failure population is 50%, making it a significant problem. The purpose of the current review was to summarize intervention studies designed to improve medication adherence in older adults with heart failure. A search was conducted to locate randomized controlled trials or quasi-experimental studies that tested interventions to improve medication adherence in patients 45 or older with heart failure. Five of eight studies (63%) showed a statistically significant improvement in medication adherence in intervention groups. Five of these six studies used a combination of educational, behavioral, and affective interventions, and focused on medication adherence alone versus multiple health behaviors. Interventions using combined approaches and focusing only on medication adherence show the most promise for future studies. [Journal of Gerontological Nursing, 43(10), 37-45.]. PMID- 28556873 TI - Nurses' Perceptions and Management of Urinary Incontinence in Hospitalized Older Adults: An Integrative Review. AB - Urinary incontinence (UI) is a geriatric syndrome affecting older adults in long term and acute hospital care. Most research has focused on nurses' perceptions of UI in long-term care and community settings rather than acute hospital settings. The purpose of the current integrative review was to understand nurses' perceptions and use of continence strategies for hospitalized older adults. Literature published from 1996-2016 was reviewed. Critical appraisal of the articles by two researchers yielded 10 articles that described nine studies. Findings revealed that nurses lack knowledge or motivation to thoroughly assess UI in older adults, often focusing on containment strategies (e.g., adult briefs) rather than conducting an assessment and promoting continence. More education about UI assessment, management, and research is needed to improve nursing care of hospitalized older adults. [Journal of Gerontological Nursing, 43(10), 46 55.]. PMID- 28556874 TI - Nurses' Experience With and Perception of Barriers to Promoting Mobility in Hospitalized Older Adults: A Descriptive Study. AB - The purpose of the current study was to examine nurses' barriers, including knowledge, attitude, and external barriers, to promoting physical activity in hospitalized older adults. Differences between the perceptions of barriers based on nurses' experience were also examined. A behavioral framework classifying nurse knowledge, nurse attitude, and external barriers was used for the study. Eighty-five nurses were recruited from two community-based hospitals in the Pacific Northwest. The findings suggest that nurses with varying levels of experience perceive a variety of barriers to promoting mobility in hospitalized older adults. Nurses with <=5 years of experience perceived that they may lack knowledge and training to safely mobilize hospitalized patients and make appropriate referrals to therapists. Nurses' attitudes revealed that they collectively viewed the promotion of mobility as a priority, but novice nurses did not. Further, some nurses deferred the responsibility to promote mobility to other disciplines. [Journal of Gerontological Nursing, 43(11), 22-29.]. PMID- 28556875 TI - Nonpharmacological Treatments for Post-Stroke Depression: An Integrative Review of the Literature. AB - Stroke is the fifth leading cause of death and the number one cause of long-term disability. Seventy-five percent of annual stroke victims are older than 65. Post stroke depression (PSD) is a common consequence of stroke, with the estimated prevalence ranging from 25% to 79%. Although several studies have investigated the impact of pharmacological interventions on PSD, there is a significant gap in knowledge regarding the efficacy of nonpharmacological measures for treatment of PSD. The purpose of the current integrative literature review was to synthesize the state of knowledge on selected nonpharmacological treatments for PSD and present findings regarding the efficacy of investigated treatments. Twenty-one studies published from 1992-2016 were identified and synthesized. Results indicated that studies demonstrating improvement in depressive symptoms included ecosystem-focused therapy, life review therapy, problem solving therapy, meridian acupressure, repetitive transcranial magnetic stimulation, music therapy, exercise, light therapy, motivational interviewing, and robotic-assisted neurorehabilitation. [Res Gerontol Nurs. 2017; 10(4):182-195.]. PMID- 28556877 TI - ? PMID- 28556876 TI - Comparison of Two Cognitive Training Programs With Effects on Functional Activities and Quality of Life. AB - The aim of the current study was to compare the effectiveness of two types of cognitive training in 60 older adults with mild cognitive impairment by assessing the impact on functional activities, quality of life (QOL), and various cognitive functions. The primary outcomes were functional activity level and QOL. The secondary outcome was cognitive examination. Group assignment was random. Group A (n = 30) underwent CogniPlus, a computer-based, cognitive training. Group B (n = 30) underwent classical group-based cognitive training. Both programs comprised two 30-minute sessions per week for 10 weeks. After training, group A had better QOL (p < 0.001, effect size [ES] = 0.69) and better attention (increased load score, p < 0.05, ES = -0.23; errors, p < 0.001, ES = -0.47); however, there were no group differences in functional activity level. Group A demonstrated larger improvements in QOL and attention than group B (i.e., classical cognitive training), but the transfer to functional activities was the same between groups. [Res Gerontol Nurs. 2017; 10(4):172-180.]. PMID- 28556878 TI - [Gene editing - which values should govern?]. PMID- 28556879 TI - ? PMID- 28556880 TI - ? PMID- 28556881 TI - [The Social Insurance Agency and the health care system must be able to evolve together]. PMID- 28556883 TI - ? PMID- 28556882 TI - ? PMID- 28556884 TI - ? PMID- 28556885 TI - ? AB - Venous thromboembolism prophylaxis in medical patients at Sahlgrenska University Hospital A hospitalized medical patient with risk factors has a 5-15 % risk of venous thromboembolism (VTE). Nonetheless thromboprophylaxis is largely underused. Our aim was to establish the proportion of high risk patients at Sahlgrenska University Hospital receiving thromboprophylaxis and to examine the 3 month incidence of VTE and bleeding. 198 patients were included and risk stratified according to American College of Chest Physician guidelines. 12 % of high risk patients without and 26 % with increased bleeding risk received pharmacological thromboprophylaxis, as did 8 % of the patients without increased risk of VTE. VTE events occurred in 4.5 % of high risk patients, none received prophylaxis. Bleeding occurred in 5.8 % of those with increased bleeding risk. There is a need to improve thromboprophylaxis use to enhance patient safety and quality of care, for instance by issuing local guidelines. PMID- 28556886 TI - Clarifying the link between cannabis use and risk for psychosis. PMID- 28556887 TI - COMT Val158Met and MTHFR C677T moderate risk of schizophrenia in response to childhood adversity. AB - OBJECTIVE: Mesolimbic dopamine sensitization has been hypothesized to be a mediating factor of childhood adversity (CA) on schizophrenia risk. Activity of catechol-O-methyltransferase (COMT) Val158Met increases mesolimbic dopamine signaling and may be further regulated by methylenetetrahydrofolate reductase (MTHFR) C677T. This study investigates the three-way interaction between CA, COMT, and MTHFR. METHODS: We conducted a nested case-control study on individuals born after 1981, linking population-based registers to study the three-way interaction. We included 1699 schizophrenia cases and 1681 controls, and used conditional logistic regression to report incidence rate ratios (IRRs). RESULTS: Childhood adversity was robustly associated with schizophrenia. No main genetic effects were observed. MTHFR C677T increased schizophrenia risk in a dose dependent manner per MTHFR T allele (P = 0.005) consequent upon CA exposure. After inclusion of the significant (P = 0.03) COMT * MTHFR * CA interaction, the risk was further increased per high-activity COMT Val allele. Hence, exposed COMT Val/Val and MTHFR T/T carriers had an IRR of 2.76 (95% CI, 1.66-4.61). Additional adjustments for ancestry and parental history of mental illness attenuated the results with the interaction being only marginally significant. CONCLUSION: MTHFR C677T and COMT Val158Met interact with CA to increase risk of schizophrenia. PMID- 28556888 TI - Comments regarding "Four cases of mucous membrane pemphigoid with clinical features of oral lichen planus" and on the utility of immunofluorescence. PMID- 28556889 TI - Involvement of M2 macrophages in the pathomechanisms of multicentric reticulohistiocytosis. PMID- 28556891 TI - Mobile Phones in the Bedroom: Trajectories of Sleep Habits and Subsequent Adolescent Psychosocial Development. AB - Mobile phones are an essential part of an adolescent's life, leading them to text, phone, or message into the night. Longitudinal latent growth models were used to examine relations between changes in adolescent night-time mobile phone use, changes in sleep behavior, and changes in well-being (depressed mood, externalizing behavior, self-esteem, and coping) for 1,101 students (43% male) between 13 and 16 years old. Both night-time mobile phone use and poor sleep behavior underwent positive linear growth over time. Increased night-time mobile phone use was directly associated with increased externalizing behavior and decreased self-esteem and coping. Changes in sleep behavior mediated the relation between early changes in night-time mobile phone use and later increases in depressed mood and externalizing behavior and later declines in self-esteem and coping. PMID- 28556890 TI - Recent progress in relapsed multiple myeloma therapy: implications for treatment decisions. AB - The availability of novel therapies for the treatment of multiple myeloma has had a dramatic impact on the depth of response that can be expected on initial treatment. Despite these advances, disease relapse remains inevitable in most patients and brings with it a different set of priorities for therapy. The most recent wave of novel agents may have a particular impact in the relapsed setting. In this review, we examine the evidence currently available from clinical trials for the use of novel agents, particularly in the formation of triplet therapy. We consider data supporting the addition of the proteasome inhibitors carfilzomib and ixazomib, or the monoclonal antibodies elotuzumab or daratumumab, to a treatment backbone of lenalidomide and dexamethasone. The clinical data set is less well developed for the addition of a third agent to the combination of bortezomib and dexamethasone; nonetheless, data are presented supporting the addition of the histone deacetylase inhibitor panobinostat, or elotuzumab or daratumumab. While acknowledging the lack of head-to-head data on which to base comparisons between the numerous regimens, we collate the latest data in order to provide a basis on which to make clinical decisions in this rapidly advancing field. PMID- 28556892 TI - A novel method to analyse in vivo the physiological state and cell viability of phototrophic microorganisms by confocal laser scanning microscopy using a dual laser. AB - Phototrophic microorganisms are very abundant in extreme environments, where are subjected to frequent and strong changes in environmental parameters. Nevertheless, little is known about the physiological effects of these changing environmental conditions on viability of these microorganisms, which are difficult to grow in solid media and have the tendency to form aggregates. For that reason, it is essential to develop methodologies that provide data in short time consuming, in vivo and with minimal manipulating the samples, in response to distinct stress conditions. In this paper, we present a novel method using Confocal Laser Scanning Microscopy and a Dual Laser (CLSM-DL) for determining the cell viability of phototrophic microorganisms without the need of either staining or additional use of image treating software. In order to differentiate viable and nonviable Scenedesmus sp. DE2009 cells, a sequential scan in two different channels was carried out from each same xyz optical section. On the one hand, photosynthetic pigments fluorescence signal (living cells) was recorded at the red channel (625- to 785-nm fluorescence emission) exciting the samples with a 561-nm laser diode, and an acousto-optic tunable filter (AOTF) of 20%. On the other hand, nonphotosynthetic autofluorescence signal (dead cells) was recorded at the green channel (500- to 585-nm fluorescence emission) using a 405-nm UV laser, an AOTF of 15%. Both types of fluorescence signatures were captured with a hybrid detector. The validation of the CLSM-DL method was performed with SYTOX green fluorochrome and electron microscopic techniques, and it was also applied for studying the response of distinct light intensities, salinity doses and exposure times on a consortium of Scenedesmus sp. DE2009. PMID- 28556893 TI - A component-by-component characterisation of high-risk atherosclerotic plaques by multiphoton microscopic imaging. AB - AIMS: Atherosclerotic plaques vulnerable to rupture are almost always inflamed, and carry a large lipid core covered by a thin fibrous cap. The other components may include neovascularisation, intraplaque haemorrhage and spotty calcification. In contrast, stable plaques are characterised by a predominance of smooth muscle cells and collagen, and lipid core is usually deep seated or absent. This study is a proof of principle experiment to evaluate the feasibility of multiphoton microscopy (MPM) to identify aforementioned plaque components. METHODS AND RESULTS: MPM is a nonlinear optical technique that allows imaging based on intrinsic tissue signals including autofluorescence and higher-order scattering. In our study, MPM imaging was performed on morphologically diverse aortic and coronary artery plaques obtained during autopsy. Various histologically verified plaque components including macrophages, cholesterol crystals, haemorrhage, collagen and calcification were recognised by MPM. CONCLUSIONS: Recognition of the distinct signatures of various plaque components suggests that MPM has the potential to offer next-generation characterisation of atherosclerotic plaques. The higher lateral resolution (comparable to histology) images generated by MPM for identifying plaque components might complement larger field of view and greater imaging depth currently available with optical coherence tomography imaging. As the next step MPM would need to be evaluated for intact vessel imaging ex vivo and in vivo. PMID- 28556894 TI - Analysis of precursors to multiply controlled problem behavior: A replication. AB - We replicated Fritz, Iwata, Hammond, and Bloom (2013) by evaluating the efficacy of an experimental methodology to identify precursors to aggression displayed by an adolescent with autism spectrum disorder. Using their trial-based precursor analysis, we identified seven precursors to aggression. Next, we compared the outcomes of separate precursor and aggression functional analyses and showed that both precursors and aggression were multiply controlled by the same variables. PMID- 28556896 TI - Associations Between Sexting Behaviors and Sexual Behaviors Among Mobile Phone Owning Teens in Los Angeles. AB - The implications of teen sexting for healthy development continue to concern parents, academics, and the general public. Using a probability sample of high school students (N = 1,208) aged 12-18, the prevalence of sexting, associations with sexting, and associations between sexing and sexual activity were assessed. Seventeen percent both sent and received sexts, and 24% only received sexts. Sending and receiving sexts were positively associated with each other and both behaviors were associated with having peers who sext. Lifetime reports of sexual intercourse, anal sex, oral sex, and recent unprotected sex were positively associated with reports of texting 300 or more times per day, only receiving sexts, and both sending and receiving sexts. PMID- 28556895 TI - A pharmacokinetic-pharmacodynamic model predicting tumour growth inhibition after intermittent administration with the mTOR kinase inhibitor AZD8055. AB - BACKGROUND AND PURPOSE: AZD8055 is a potent orally available mTOR kinase inhibitor with in vitro and in vivo antitumour activity against a range of tumour types. Preclinical studies showed that AZD8055 induced a dose-dependent pharmacodynamic effect in xenograft models in vivo, but a lack of understanding of the relative contributions of the maximum inhibition of the biomarkers and the duration of inhibition to the antitumour effect, limited the rational design of experiments to optimize the dose and schedules of treatment. EXPERIMENTAL APPROACH: In this study, a mathematical modelling approach was developed to relate pharmacodynamics and antitumour activity using preclinical data generated in mice bearing U87-MG xenografts. KEY RESULTS: Refinement and validation of the model was carried out in a panel of additional human tumour xenograft models with different growth rates and different sensitivity to AZD8055 (from partial growth inhibition to regression). Finally, the model was applied to accurately predict the efficacy of high, intermittent dosing schedules of AZD8055. CONCLUSIONS AND IMPLICATIONS: Overall, this new model linking pharmacokinetics, pharmacodynamic biomarkers and efficacy across several tumour xenografts with different sensitivity to AZD8055 was able to identify the optimal dose and route of administration to maximize the antitumour efficacy in preclinical models and its potential for translation into man. PMID- 28556897 TI - Claims for compensation after injuries related to airway management: a nationwide study covering 15 years. AB - BACKGROUND: Securing the airway is one of the most important responsibilities in anaesthesia. Injuries related to airway management can occur. Analysis from closed claims can help to identify patterns of injury, risk factors and areas for improvement. METHODS: All claims to The Norwegian System of Compensation to Patients from 1 January 2001 to 31 December 2015 within the medical specialty of anaesthesiology were studied. Data were extracted from this database for patients and coded by airway management procedures. RESULTS: Of 400 claims for injuries related to airway management, 359 were classified as 'non-severe' and 41 as 'severe'. Of the severe cases, 37% of injuries occurred during emergency procedures. Eighty-one claims resulted in compensation, and 319 were rejected. A total of ?1,505,344 was paid to the claimants during the period. Claims of dental damage contributed to a numerically important, but financially modest, proportion of claims. More than half of the severe cases were caused by failed intubation or a misplaced endotracheal tube. CONCLUSION: Anaesthesia procedures are not without risk, and injuries can occur when securing the airway. The most common injury was dental trauma. Clear patterns of airway management that resulted in injuries are not apparent from our data, but 37% of severe cases were related to emergency procedures which suggest the need for additional vigilance. Guidelines for difficult intubation situations are well established, but adherence to such guidelines varies. Good planning of every general anaesthesia should involve consideration of possible airway problems and assessment of pre-existing poor dentition. PMID- 28556898 TI - Hemoglobin Concentration Influences N-Terminal Pro B-Type Natriuretic Peptide Levels in Hospitalized Older Adults with and without Heart Failure. AB - OBJECTIVES: To investigate the relationship between hemoglobin and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentration in hospitalized older adults with or without a diagnosis of heart failure (HF). DESIGN: Cross-sectional study based on retrospective hospital records review. SETTING: Geriatric acute care ward. PARTICIPANTS: Individuals aged 65 and older (N = 226; mean age 81.1), with (n = 104) and without (n = 122) a diagnosis of HF. MEASUREMENTS: Information was collected on demographic characteristics, comorbidities, and laboratory and echocardiographic data. The relationship between hemoglobin and NT-proBNP was evaluated using linear regression models adjusted for potential confounders. RESULTS: A negative association was found between NT-proBNP and hemoglobin (beta = -0.226, P < .001). The regression coefficient was -0.114 (P = .04) in the subsample with HF and -0.191 (P < .001) in the subsample without HF. After adjustment for potential confounders, the inverse association between hemoglobin and NT-proBNP was confirmed in the whole sample (beta = -0.182, P < .001), in those with HF (beta = -0.136, P = .007), and in those without HF (beta = -0.165, P = .003). CONCLUSION: Hemoglobin concentration should be taken into account in the interpretation of NT-proBNP in hospitalized older adults, especially those without HF. PMID- 28556899 TI - The measure and mismeasure of reciprocity in heterostylous flowers. AB - The goal of biological measurement is to capture underlying biological phenomena in numerical form. The reciprocity index applied to heterostylous flowers is meant to measure the degree of correspondence between fertile parts of opposite sex on complementary (inter-compatible) morphs, reflecting the correspondence of locations of pollen placement on, and stigma contact with, pollinators. Pollen of typical heterostylous flowers can achieve unimpeded fertilization only on opposite-morph flowers. Thus, the implicit goal of this measurement is to assess the likelihood of 'legitimate' pollinations between compatible morphs, and hence reproductive fitness. Previous reciprocity metrics fall short of this goal on both empirical and theoretical grounds. We propose a new measure of reciprocity based on theory that relates floral morphology to reproductive fitness. This method establishes a scale based on adaptive inaccuracy, a measure of the fitness cost of the deviation of phenotypes in a population from the optimal phenotype. Inaccuracy allows the estimation of independent contributions of maladaptive bias (mean departure from optimum) and imprecision (within-population variance) to the phenotypic mismatch (inaccuracy) of heterostylous morphs on a common scale. We illustrate this measure using data from three species of Primula (Primulaceae). PMID- 28556900 TI - Vitamin D and mental health: optimizing in the midst of the complexity. PMID- 28556901 TI - Impact of an Individual Mandate and Other Health Reforms on Dependent Coverage for Adolescents and Young Adults. AB - OBJECTIVE: To determine the effect of state-level dependent coverage expansion (DCE) with and without other state health reforms on exit from dependent coverage for adolescents and young adults (AYA). DATA SOURCES: Administrative longitudinal data for 131,542 privately insured AYA in Massachusetts (DCE with other reforms) versus Maine and New Hampshire (DCE without other reforms) across three periods: prereform (1/00-12/06), poststate reform (1/07-9/10), and postfederal reform (10/10-12/12). STUDY DESIGN: A difference-in-differences estimator was used to determine the rate of exit from dependent coverage, age at exit from dependent coverage, and re-uptake of dependent coverage among AYA in states with comprehensive reforms versus DCE only. PRINCIPAL FINDINGS: Implementation of DCE with other reforms was significantly associated with a 23 percent reduction in exit from dependent coverage among AYA compared to the reduction observed for DCE alone. Additionally, comprehensive reforms were associated with over two additional years of dependent coverage for the average AYA and a 33 percent increase in the odds of regaining dependent coverage after a prior loss. CONCLUSIONS: Findings suggest that an individual mandate and other reforms may enhance the effect of DCE in preventing loss of coverage among AYA. PMID- 28556902 TI - Comparison of the prognostic values of selected inflammation based scores in patients with medullary thyroid carcinoma: A pilot study. AB - BACKGROUND: The significance of inflammation based scores including the neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index (PNI), and plasma fibrinogen remains unclear in medullary thyroid carcinoma (MTC). We aimed to compare the prognostic value of these scores. METHODS: Seventy-eight patients newly diagnosed as MTC with operation in our institution from May 2009 to September 2016 were retrospectively evaluated. Receiver operating characteristic (ROC) curves and Kaplan-Meier analyses were calculated to compare the prognostic value of these scores. RESULTS: Increased PLR was predictive of lymph node metastasis (AUC = 0.644, P = 0.022), capsule invasion (AUC = 0.666, P = 0.007), advanced tumor stages (AUC = 0.657, P = 0.011), and recurrence (AUC = 0.655, P = 0.049). Increased fibrinogen was predictive of lymph node metastasis (AUC = 0.669, P = 0.006) and capsule invasion (AUC = 0.631, P = 0.038). Reduced PNI was predictive of recurrence (AUC = 0.655, P = 0.049). Kaplan-Meier analyses and Cox regression analysis revealed that PLR was a significant predictor for recurrence. CONCLUSIONS: PLR, fibrinogen, and PNI are all predictive. Specially, PLR is superior to other inflammation based scores in terms of prognostic ability. PMID- 28556903 TI - Outcome summaries of latency-based functional analyses conducted in hospital inpatient units. AB - Latency-based functional analysis (FA) may be a viable alternative to the standard, rate-based, FA when frequently evoking problem behavior is not advisable. We conducted 18 latency-based FAs of the problem behavior of children diagnosed with autism in inpatient hospital settings and identified functional relations during 44.4% (8 of 18) of latency-based FAs. Implications for conducting FAs of severe problem behavior are discussed. PMID- 28556904 TI - Diagnostic application of a capture based NGS test for the concurrent detection of variants in sequence and copy number as well as LOH. AB - Whole exome sequencing (WES) has made the identification of causative SNVs/InDels associated with rare Mendelian conditions increasingly accessible. Incorporation of softwares allowing CNVs detection into the WES bioinformatics pipelines may increase the diagnostic yield. However, no standard protocols for this analysis are so far available and CNVs in non-coding regions are totally missed by WES, in spite of their possible role in the regulation of the flanking genes expression. So, in a number of cases the diagnostic workflow contemplates an initial investigation by genomic arrays followed, in the negative cases, by WES. The opposite workflow may also be applied, according to the familial segregation of the disease. We show preliminary results for a diagnostic application of a single next generation sequencing panel permitting the concurrent detection of LOH and variations in sequences and copy number. This approach allowed us to highlight compound heterozygosity for a CNV and a sequence variant in a number of cases, the duplication of a non-coding region responsible for sex reversal, and a whole chromosome isodisomy causing reduction to homozygosity for a WFS1 variant. Moreover, the panel enabled us to detect deletions, duplications, and amplifications with sensitivity comparable to that of the most widely used array CGH platforms. PMID- 28556906 TI - A dissimilar biosimilar? Lichenoid drug eruption induced by an infliximab biosimilar. AB - The advent of therapeutic antibodies, or biological medications, has transformed the treatment of many inflammatory diseases in dermatology. Recently, the development of biosimilars, biological drugs that are highly similar in quality, safety and efficacy to approved biologics, has changed this landscape. Although biosimilars are not identical to their reference product, they are required to have the same mechanism of action, route of administration, dosage form and strength as the reference product. This also leads to the possibility that subtle differences in the activity of these biosimilars can lead to differing clinical responses. We report the first case of a lichenoid eruption induced by a biosimilar to infliximab after switching from infliximab. Several days after initial infusion of the biosimilar, the patient developed a pruritic papulosquamous eruption that was biopsied to reveal a lichenoid drug eruption. Possible mechanisms for lichenoid drug eruptions as a result of tumour necrosis factor-alpha inhibitor administration are discussed, along with reasons why such a reaction may occur with a biosimilar but not the original, reference product. This case report calls attention to the unique differences between biosimilars and biological medications that a clinician should consider prior to prescribing these medications. PMID- 28556905 TI - Working memory load impairs the evaluation of behavioral errors in the medial frontal cortex. AB - Early error monitoring in the medial frontal cortex enables error detection and the evaluation of error significance, which helps prioritize adaptive control. This ability has been assumed to be independent from central capacity, a limited pool of resources assumed to be involved in cognitive control. The present study investigated whether error evaluation depends on central capacity by measuring the error-related negativity (Ne/ERN) in a flanker paradigm while working memory load was varied on two levels. We used a four-choice flanker paradigm in which participants had to classify targets while ignoring flankers. Errors could be due to responding either to the flankers (flanker errors) or to none of the stimulus elements (nonflanker errors). With low load, the Ne/ERN was larger for flanker errors than for nonflanker errors-an effect that has previously been interpreted as reflecting differential significance of these error types. With high load, no such effect of error type on the Ne/ERN was observable. Our findings suggest that working memory load does not impair the generation of an Ne/ERN per se but rather impairs the evaluation of error significance. They demonstrate that error monitoring is composed of capacity-dependent and capacity-independent mechanisms. PMID- 28556907 TI - Challenges describing motor profiles in alternating hemiplegia of childhood. PMID- 28556908 TI - Hydrophilic interaction anion exchange for separation of multiply modified neutral and anionic Dictyostelium N-glycans. AB - The unusual nature of the N-glycans of the cellular slime mould Dictyostelium discoideum has been revealed by a number of studies, primarily based on examination of radiolabeled glycopeptides but more recently also by MS. The complexity of the N-glycomes of even glycosylation mutants is compounded by the occurrence of anionic modifications, which also present an analytical challenge. In this study, we have employed hydrophilic interaction anion exchange (HIAX) HPLC in combination with MALDI-TOF MS/MS to explore the anionic N-glycome of the M31 (modA) strain, which lacks endoplasmic reticulum alpha-glucosidase II, an enzyme conserved in most eukaryotes including Homo sapiens. Prefractionation with HIAX chromatography enabled the identification of N-glycans with unusual oligo alpha1,2-mannose extensions as well as others with up to four anionic modifications. Due to the use of hydrofluoric acid treatment, we were able to discriminate isobaric glycans differing in the presence of sulphate or phosphate on intersected structures as opposed to those carrying GlcNAc-phosphodiesters. The latter represent biosynthetic intermediates during the pathway leading to formation of the methylphosphorylated mannose epitope, which may have a similar function in intracellular targeting of hydrolases as the mannose-6-phosphate modification of lysosomal enzymes in mammals. In conclusion, HIAX in combination with MS is a highly sensitive approach for both fine separation and definition of neutral and anionic N-glycan structures. PMID- 28556909 TI - Altered post-capillary and collecting venular reactivity in skeletal muscle with metabolic syndrome. AB - KEY POINTS: With the development of the metabolic syndrome, both post-capillary and collecting venular dilator reactivity within the skeletal muscle of obese Zucker rats (OZR) is impaired. The impaired dilator reactivity in OZR reflects a loss in venular nitric oxide and PGI2 bioavailability, associated with the chronic elevation in oxidant stress. Additionally, with the impaired dilator responses, a modest increase in adrenergic constriction combined with an elevated thromboxane A2 production may contribute to impaired functional dilator and hyperaemic responses at the venular level. For the shift in skeletal muscle venular function with development of the metabolic syndrome, issues such as aggregate microvascular perfusion resistance, mass transport and exchange within with capillary networks, and fluid handling across the microcirculation are compelling avenues for future investigation. ABSTRACT: While research into vascular outcomes of the metabolic syndrome has focused on arterial/arteriolar and capillary levels, investigation into venular function and how this impacts responses has received little attention. Using the in situ cremaster muscle of obese Zucker rats (OZR; with lean Zucker rats (LZR) as controls), we determined indices of venular function. At ~17 weeks of age, skeletal muscle post-capillary venular density was reduced by ~20% in LZR vs. OZR, although there was no evidence of remodelling of the venular wall. Venular tone at ~25 MUm (post capillary) and ~75 MUm (collecting) diameter was elevated in OZR vs. LZR. Venular dilatation to acetylcholine was blunted in OZR vs. LZR due to increased oxidant stress-based loss of nitric oxide bioavailability (post-capillary) and increased alpha1 - (and alpha2 -) mediated constrictor tone (collecting). Venular constrictor responses in OZR were comparable to LZR for most stimuli, although constriction to alpha1 -adrenoreceptor stimulation was elevated. In response to field stimulation of the cremaster muscle (0.5, 1, 3 Hz), venular dilator and hyperaemic responses to lower frequencies were blunted in OZR, but responses at 3 Hz were similar between strains. Venous production of TxA2 was higher in OZR than LZR and significantly higher than PGI2 production in either following arachidonic acid challenge. These results suggest that multi-faceted alterations to skeletal muscle venular function in OZR may contribute to alterations in upstream capillary pressure profiles and the transcapillary exchange of solutes and water under conditions of metabolic syndrome. PMID- 28556910 TI - Effects of trait anger, driving anger, and driving experience on dangerous driving behavior: A moderated mediation analysis. AB - To explore the effect of anger behind the wheel on driving behavior and accident involvement has been the subject of many studies. However, few studies have explored the interaction between anger and driving experience on dangerous driving behavior. This study is a moderated mediation analysis of the effect of trait anger, driving anger, and driving experience on driving behavior. A sample of 303 drivers was tested using the Trait Anger Scale (TAS), the Driving Anger Scale (DAS), and the Dula Dangerous Driving Index (DDDI). The results showed that trait anger and driving anger were positively correlated with dangerous driving behavior. Driving anger partially mediated the effect of trait anger on dangerous driving behavior. Driving experience moderated the relationship between trait anger and driving anger. It also moderated the effect of driving anger on dangerous driving behavior. These results suggest that drivers with more driving experience may be safer as they are not easily irritated during driving. PMID- 28556911 TI - A comparison of the lubrication behavior of whey protein model foods using tribology in linear and elliptical movement. AB - : Lubrication is an important factor in the sensory evaluation of food products. Tribology provides a theoretical framework and instrumental methods for evaluating frictional properties between two moving surfaces and the lubrication behavior of products between these surfaces. Relating frictional measurements to sensory properties detected during oral processing requires careful and pertinent choices in surface materials and testing conditions. The aims of this study were to investigate: (a) differences in lubrication behavior of a range of food textures and (b) the differences between linear and elliptical movement and added saliva to understand the contribution of food structure to friction. Six whey protein model food samples, ranging in texture from fluid to semisolid to soft solid, were analyzed using a pin on disk tribometer to determine the coefficient of friction (COF) across a range of sliding speeds. The samples were analyzed in their initial form and post-oral processing (n = 4) in both linear and elliptical movements. Elliptical movement slightly decreased coefficients of friction and extended the shape of the friction curve. Increases in test food viscosity decreased the COF but differences in viscosity were not apparent when test foods were mixed with saliva. Data correction for viscosity shifted the friction curves horizontally, indicating that lubrication had a greater impact upon friction than viscosity. This study provides initial insights for further comparison of linear and elliptical movement with a variety of sample compositions. PRACTICAL APPLICATIONS: Sensory perception of smoothness and creaminess are often major contributors to overall hedonic food liking and are a major reason why products high in fat and sugar are more highly preferred over other foods. These parameters are influenced by friction and lubrication between the tongue, palate, teeth, food products, and saliva during oral processing. Tribology provides an instrumental method to evaluate friction between moving surfaces that mimic oral surfaces and the lubrication behavior of foods. Trends in frictional measurements can be correlated with sensory ratings of the same foods to better understand why preferences exist for certain foods or food compositions and how to effectively improve the acceptability and enjoyment of healthier foods. PMID- 28556913 TI - Bilingual Infants Demonstrate Advantages in Learning Words in a Third Language. AB - Prior research suggests that bilingualism may endow infants with greater phonological flexibility. This study investigated whether this flexibility facilitates word learning in additional languages (n = 96). Experiment 1 compared 18- to 20-month-old monolingual (English) and bilingual (English/Mandarin) infants on their ability to learn words distinguished by click consonants from a Southern African language, Ndebele. English-Mandarin bilingual infants were sensitive to Ndebele click contrasts, but monolingual English infants were not. In Experiments 2a and 2b, we investigated whether enhanced bilingual sensitivity extended to analogous nonlinguistic labels: hand claps and finger snaps. Although discriminated by infants, neither group distinguished words labeled by hand claps and finger snaps. Results suggest that bilingual infants' sustained openness to non native contrast may facilitate the uptake of words in distant languages. PMID- 28556912 TI - Farnesyltransferase inhibitor FTI-277 inhibits PD-L1 expression on septic spleen lymphocytes and promotes spleen lymphocyte activation. AB - Farnesyltransferase inhibitors have been tested in clinical trials for the treatment of tumours. In sepsis, the binding of programmed death 1 (PD-1) to programmed death ligand 1 (PD-L1) promotes lymphocyte apoptosis and decreases cytokine expression, thus affecting survival rates. The PD-1/PD-L1 pathway plays an important role in chronic viral infection, bacterial infection and sepsis. However, the precise immunosuppressive and anti-inflammatory functions of this pathway remain poorly understood. In our previous study, the induction of sepsis by caecal ligation and puncture (CLP) resulted in increased farnesyltransferase activity and farnesylated protein levels in the spleen relative to sham treatment. However, the effect of inhibition of farnesyltransferase activity on overall survival rates in patients with sepsis and the specific signalling pathway involved remain to be investigated. In this study, mice with CLP-induced sepsis were treated with farnesyltransferase inhibitor (FTI-277), and PD-L1 expression on septic spleen lymphocytes was examined. Flow cytometric analysis revealed that PD-L1 is expressed constitutively on lymphocytes and that PD-L1 protein expression was up-regulated strongly following CLP. FTI-277 down regulated PD-L1 mRNA and protein expression on septic spleen lymphocytes in a dose-dependent manner. This effect was associated closely with nuclear factor kappa B (NF-kappaB). In addition, the significant damping effect of FTI-277 on the PD-L1 signal promoted interferon (IFN)-gamma secretion, interleukin (IL)-2 production and splenocyte proliferation in response to anti-CD3+ CD28+ antibodies in mice. Furthermore, FTI-277 reduced spleen lymphocyte apoptosis in septic mice. Therefore, FTI-277 regulates spleen lymphocyte activity via the PD-L1 signalling pathway, with significant anti-inflammatory effects attributable to suppression of the NF-kappaB pathway. Farnesyltransferase represents a valuable therapeutic target for the treatment of sepsis. PMID- 28556914 TI - Model-based bootstrapping when correcting for measurement error with application to logistic regression. AB - When fitting regression models, measurement error in any of the predictors typically leads to biased coefficients and incorrect inferences. A plethora of methods have been proposed to correct for this. Obtaining standard errors and confidence intervals using the corrected estimators can be challenging and, in addition, there is concern about remaining bias in the corrected estimators. The bootstrap, which is one option to address these problems, has received limited attention in this context. It has usually been employed by simply resampling observations, which, while suitable in some situations, is not always formally justified. In addition, the simple bootstrap does not allow for estimating bias in non-linear models, including logistic regression. Model-based bootstrapping, which can potentially estimate bias in addition to being robust to the original sampling or whether the measurement error variance is constant or not, has received limited attention. However, it faces challenges that are not present in handling regression models with no measurement error. This article develops new methods for model-based bootstrapping when correcting for measurement error in logistic regression with replicate measures. The methodology is illustrated using two examples, and a series of simulations are carried out to assess and compare the simple and model-based bootstrap methods, as well as other standard methods. While not always perfect, the model-based approaches offer some distinct improvements over the other methods. PMID- 28556915 TI - A microbially derived tyrosine-sulfated peptide mimics a plant peptide hormone. AB - The biotrophic pathogen Xanthomonas oryzae pv. oryzae (Xoo) produces a sulfated peptide named RaxX, which shares similarity to peptides in the PSY (plant peptide containing sulfated tyrosine) family. We hypothesize that RaxX mimics the growth stimulating activity of PSY peptides. Root length was measured in Arabidopsis and rice treated with synthetic RaxX peptides. We also used comparative genomic analyses and reactive oxygen species burst assays to evaluate the activity of RaxX and PSY peptides. Here we found that a synthetic sulfated RaxX derivative comprising 13 residues (RaxX13-sY), highly conserved between RaxX and PSY, induces root growth in Arabidopsis and rice in a manner similar to that triggered by PSY. We identified residues that are required for activation of immunity mediated by the rice XA21 receptor but that are not essential for root growth induced by PSY. Finally, we showed that a Xanthomonas strain lacking raxX is impaired in virulence. These findings suggest that RaxX serves as a molecular mimic of PSY peptides to facilitate Xoo infection and that XA21 has evolved the ability to recognize and respond specifically to the microbial form of the peptide. PMID- 28556918 TI - A Ten-year Study of Suicides from a Rural/Suburban County. AB - This study will discuss trends in suicide data compiled over 10 years in Dutchess County, NY, from 2004 to 2013. These data were based on reporting and examination standards recommended by the National Association of Medical Examiners and Department of Justice death investigation standards. Almost 300 cases were analyzed in terms of the deceased's gender, age, race, method of suicide, and weapon used. Results from this study agree with other reports showing significant differences for method of death both in terms of age and gender, with men more likely to choose firearms and women more likely to choose overdose. Furthermore, older persons were more likely to commit suicide by firearms, and the younger persons were more likely to commit suicide by overdose. However, other areas, such as method of suicide, differ from national statistics. PMID- 28556919 TI - Ethical living: relinking ethics and consumption through care in Chile and Brazil. AB - Mainstream conceptualizations of 'ethical consumption' equate the notion with conscious, individual, market-mediated choices motivated by ethical or political aims that transcend ordinary concerns. Drawing on recent sociology and anthropology of consumption literature on the links between ordinary ethics and ethical consumption, this article discusses some of the limitations of this conceptualization. Using data from 32 focus groups conducted in Chile and Brazil, we propose a conceptualization of ethical consumption that does not centre on individual, market-mediated choices but understands it at the level of practical outcomes, which we refer to as different forms of 'ethical living'. To do that, we argue, we need to depart from the deontological understanding of ethics that underpins mainstream approaches to ethical consumption and adopt a more consequentialist view focusing on ethical outcomes. We develop these points through describing one particular ordinary moral regime that seemed to be predominant in participants' accounts of ethics and consumption in both Chile and Brazil: one that links consumption and ethics through care. We show that the moral regime of care leads to 'ethical outcomes', such as energy saving or limiting overconsumption, yet contrary to the mainstream view of ethical consumption emphasizing politicized choice expressed through markets, these result from following ordinary ethics, often through routines of practices. PMID- 28556917 TI - Decreased relapsed rate and treatment-related mortality contribute to improved outcomes for pediatric acute myeloid leukemia in successive clinical trials. AB - BACKGROUND: Outcomes for children with acute myeloid leukemia (AML) have improved over the past 20 years even though the medications used for induction therapy have not changed. METHODS: This study analyzed data from patients with AML who were enrolled in successive protocols (AML97 and AML02) to determine the contributors to the improved outcomes of the latter clinical trial. RESULTS: There were significant improvements in 5-year overall survival (48.9% vs 71.2%; P < .0001) and event-free survival (43.5% vs 61.8%; P = .002) from AML97 to AML02. The 5-year cumulative incidence of early death (ED)/treatment-related mortality (TRM) was reduced for patients treated in AML02 (18.5% vs 7.9%; P = .007). Although the overall incidence of refractory disease (6.5% vs 5.6%; P = .736) and relapse (29.3% vs 21.0%; P = .12) did not differ between the 2 studies, patients with low-risk AML who were treated in AML02 had a reduced incidence of relapse (27.3% vs 8.8%; P = .036). CONCLUSIONS: The improved outcomes of the AML02 trial resulted from improved disease control for low-risk patients and overall decreased ED/TRM. These results emphasize the importance of supportive-care measures throughout chemotherapy courses and hematopoietic cell transplantation and the value of treatment intensity for patients with low-risk AML while underscoring the need for novel therapy, rather than increased therapy intensity, for children with high-risk AML. Cancer 2017;123:3791-3798. (c) 2017 American Cancer Society. PMID- 28556916 TI - Intestinal dysbiosis and probiotic applications in autoimmune diseases. AB - In humans, a complex interaction between the host immune system and commensal microbiota is required to maintain gut homeostasis. In this symbiotic relationship, the microbiota provides carbohydrate fermentation and digestion, vitamin synthesis and gut-associated lymphoid tissue development, as well as preventing colonization by pathobionts, whereas the host offers a niche and nutrients for the survival of the microbiota. However, when this mutualistic relationship is compromised and an altered interaction between immune cells and microorganisms occurs, the gut microbiota may cause or contribute to the establishment of infectious diseases and trigger autoimmune diseases. Researchers have made efforts to clarify the role of the microbiota in autoimmune disease development and find new therapeutic approaches to treat immune-mediated diseases. However, the exact mechanisms involved in the dysbiosis and breakdown of the gut epithelial barrier are currently unknown. Here, we provide a general overview of studies describing gut microbiota perturbations in animal models of autoimmune diseases, such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. Moreover, we include the main studies concerning dysbiosis in humans and a critical discussion of the existing data on the use of probiotics in these autoimmune diseases. PMID- 28556920 TI - AMPK activator acadesine fails to alleviate isoniazid-caused mitochondrial instability in HepG2 cells. AB - Isoniazid (INH) is a first-line antituberculosis drug that is adversely associated with hepatotoxicity. Recently, impairment of mitochondrial homeostasis involved in this side effect has been noticed. Mitochondrial homeostasis is achieved by the balance between the generation of functional mitochondria by biogenesis and elimination of dysfunctional mitochondria by autophagy. AMP activated protein kinase (AMPK) can maintain mitochondrial stability through positive control of these two processes. In this study, we showed that AMPK activator acadesine (AICAR) alleviated INH-caused impairment of mitochondrial biogenesis by activation of silent information regulator two ortholog 1 (SIRT1) peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC1 alpha) pathway in HepG2 cells. However, mitochondrial instability and apoptosis were caused by AICAR along with an unexpected decrease in INH-induced cytoprotective autophagy. Therefore, AICAR failed to alleviate INH-caused mitochondrial instability in HepG2 cells due to its inhibitory effect on autophagy induced by INH. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28556922 TI - Perceptually accurate display of two greyscale images as a single colour image. AB - Life scientists often desire to display the signal from two different molecular probes as a single colour image, so as to convey information about the probes' relative concentrations as well as their spatial corelationship. Traditionally, such colour images are created through a merge display, where each greyscale signal is assigned to different channels of an RGB colour image. However, human perception of colour and greyscale intensity is not equivalent. Thus, a merged image display conveys to the typical viewer only a subset of the absolute and relative intensity information present in and between two greyscale images. The Commission Internationale de l'Eclairage L*a*b* colour space (CIELAB) has been designed to specify colours according to the perceptually defined quantities of hue (perceived colour) and luminosity (perceived brightness). Here, we use the CIELAB colour space to encode two dimensions of information about two greyscale images within these two perceptual dimensions of a single colour image. We term our method a Perceptually Uniform Projection display and show using biological image examples how these displays convey more information about two greyscale signals than comparable RGB colour space-based techniques. PMID- 28556921 TI - Membrane-bound Dickkopf-1 in Foxp3+ regulatory T cells suppresses T-cell-mediated autoimmune colitis. AB - Induction of tolerance is a key mechanism to maintain or to restore immunological homeostasis. Here we show that Foxp3+ regulatory T (Treg) cells use Dickkopf-1 (DKK-1) to regulate T-cell-mediated tolerance in the T-cell-mediated autoimmune colitis model. Treg cells from DKK-1 hypomorphic doubleridge mice failed to control CD4+ T-cell proliferation, resulting in CD4 T-cell-mediated autoimmune colitis. Thymus-derived Treg cells showed a robust expression of DKK-1 but not in naive or effector CD4 T cells. DKK-1 expression in Foxp3+ Treg cells was further increased upon T-cell receptor stimulation in vitro and in vivo. Interestingly, Foxp3+ Treg cells expressed DKK-1 in the cell membrane and the functional inhibition of DKK-1 using DKK-1 monoclonal antibody abrogated the suppressor function of Foxp3+ Treg cells. DKK-1 expression was dependent on de novo protein synthesis and regulated by the mitogen-activated protein kinase pathway but not by the canonical Wnt pathway. Taken together, our results highlight membrane bound DKK-1 as a novel Treg-derived mediator to maintain immunological tolerance in T-cell-mediated autoimmune colitis. PMID- 28556923 TI - Antiarrhythmic properties of ivabradine in an experimental model of Short-QT- Syndrome. AB - The If channel inhibitor ivabradine is recommended for treatment of chronic heart failure. However, ivabradine also inhibits human ether-a-go-go (hERG) mediated potassium currents. The aim of the present study was to assess the electrophysiologic effects of ivabradine in an experimental model of short-QT syndrome. Twelve rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, pinacidil, an IK-ATP channel opener, was infused (1 MUmol/L). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a significant abbreviation of QT interval (-32 ms, P<.05) and shortening of action potential duration at 90% of repolarization (APD90; -22 ms, P<.05). The shortening of ventricular repolarization was accompanied by a reduction of effective refractory period (ERP; -20 ms, P<.05). Thereafter, hearts were additionally treated with ivabradine (5 MUmol/L) leading to an increase of QT interval (+31 ms, P<.05), APD90 (+15 ms, P<.05) as well as of ERP (+38 ms, P<.05) and post-repolarization refractoriness (PRR, +33 ms, P<.05) as compared with sole pinacidil infusion. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in 3 of 12 hearts (6 episodes). After application of 1 MUmol/L pinacidil, 6 of 12 hearts were inducible (22 episodes). Additional infusion of 5 MUmol/L ivabradine led to a significant suppression of VF. Only two episodes could be induced in 1 of 12 hearts. In the present study ivabradine reversed the electrophysiologic effects of pharmacologically simulated short-QT syndrome. Ivabradine demonstrated antiarrhythmic properties based on an increase of both ERP and PRR. PMID- 28556924 TI - Determination and risk assessment of naturally occurring genotoxic and carcinogenic alkenylbenzenes in nutmeg-based plant food supplements. AB - A risk assessment of nutmeg-based plant food supplements (PFS) containing different alkenylbenzenes was performed based on the alkenylbenzene levels quantified in a series of PFS collected via the online market. The estimated daily intake (EDI) of the alkenylbenzenes amounted to 0.3 to 312 MUg kg-1 body weight (bw) for individual alkenylbenzenes, to 1.5 to 631 MUg kg-1 bw when adding up the alkenylbenzene levels assuming equal potency, and to 0.4 to 295 MUg kg-1 bw when expressed in safrole equivalents using toxic equivalency factors (TEFs). The margin of exposure approach (MOE) was used to evaluate the potential risks. Independent of the method used for the intake estimate, the MOE values obtained were generally lower than 10000 indicating a priority for risk management. When taking into account that PFS may be used for shorter periods of time and using Haber's rule to correct for shorter than lifetime exposure it was shown that limiting exposure to only 1 or 2 weeks would result in MOE values that would be, with the presently determined levels of alkenylbenzenes and proposed uses of the PFS, of low priority for risk management (MOE > 10000). It is concluded that the results of the present paper reveal that nutmeg-based PFS consumption following recommendations for daily intake especially for longer periods of time raise a concern. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28556925 TI - Period Prevalence and Reporting Rate of Needlestick Injuries to Nurses in Iran: A Systematic Review and Meta-Analysis. AB - The purpose of this systematic review and meta-analysis was to provide a precise estimate of the period prevalence of needlestick injuries (NSI) among nurses working in hospitals in Iran and the reporting rate of NSI to nurse managers. We searched both international (PubMed, Scopus and the Institute for Scientific Information) and Iranian (Scientific Information Database, Iranmedex and Magiran) scientific databases to find studies published from 2000 to 2016 of NSI among Iranian nurses. The following keywords in Persian and English were used: "needle stick" or "needle stick" or "needlestick," with and without "injury" or "injuries," "prevalence" or "frequency," "nurses" or "nursing staff," and "Iran." In a sample of 21 articles with 6,480 participants, we estimated that the overall 1-year period prevalence of NSI was 44% (95% confidence interval [CI], 35-53%) among Iranian nurses. The overall 1-year period prevalence of reporting NSI to nurse managers was 42% (95% CI, 33-52%). In meta-regression analysis, sample size, mean age, years of experience, and gender ratio were not associated with prevalence of NSI or reporting rate. The year of data collection was positively associated with period prevalence of NSI (p < .05), but not with the period prevalence of reporting NSI to nurse managers. Results indicated a high NSI period prevalence and low NSI reporting rate among nurses in Iran. Thus, effective interventions are required in hospitals in Iran to reduce the prevalence and increase the reporting rate of NSI. (c) 2017 Wiley Periodicals, Inc. PMID- 28556926 TI - Emergence of MPLW515 mutation in a patient with CALR deletion: Evidence of secondary acquisition of MPL mutation in the CALR clone. AB - Myeloproliferative neoplasms are characterized by transduction pathway recognized as mutually exclusive molecular abnormalities such as BCR-ABL translocation, JAK2V617F or JAK2 exon 12 mutations, MPL w515, and CALR mutations. However, in some rare cases, associations of such mutations are found in 1 patient. This can be related to 2 pathologies (at least 2 different clones harboring 2 mutations) or associated mutations in 1 clone. We describe here such an association of CALR and MPL mutations in a patient harboring the second mutation in a subclone during the phenotypic evolution of the myeloproliferative neoplasms. PMID- 28556927 TI - The biomechanical, chemical and physiological adaptations of the eggs of two Australian megapodes to their nesting strategies and their implications for extinct titanosaur dinosaurs. AB - Megapodes are galliform birds endemic to Australasia and unusual among modern birds in that they bury their eggs for incubation in diverse substrates and using various strategies. Alectura lathami and Leipoa ocellata are Australian megapodes that build and nest in mounds of soil and organic matter. Such unusual nesting behaviours have resulted in particular evolutionary adaptations of their eggs and eggshells. We used a combination of scanning electron microscopy, including electron backscatter diffraction and energy-dispersive X-ray spectroscopy, to determine the fine structure of the eggshells and micro-CT scanning to map the structure of pores. We discovered that the surface of the eggshell of A. lathami displays nodes similar to those of extinct titanosaur dinosaurs from Transylvania and Auca Mahuevo egg layer #4. We propose that this pronounced nodular ornamentation is an adaptation to an environment rich in organic acids from their nest mound, protecting the egg surface from chemical etching and leaving the eggshell thickness intact. By contrast, L. ocellata nests in mounds of sand with less organic matter in semiarid environments and has eggshells with weakly defined nodes, like those of extinct titanosaurs from AM L#3 that also lived in a semiarid environment. We suggest the internode spaces in both megapode and titanosaur species act as funnels, which concentrate the condensed water vapour between the nodes. This water funnelling in megapodes through the layer of calcium phosphate reduces the likelihood of bacterial infection by creating a barrier to microbial invasion. In addition, the accessory layer of both species possesses sulphur, which reinforces the calcium phosphate barrier to bacterial and fungal contamination. Like titanosaurs, pores through the eggshell are Y shaped in both species, but A. lathami displays unique mid-shell connections tangential to the eggshell surface and that connect some adjacent pores, like the eggshells of titanosaur of AM L#4 and Transylvania. The function of these interconnections is not known, but likely helps the diffusion of gases in eggs buried in environments where occlusion of pores is possible. PMID- 28556928 TI - Using Alkylate Components for Classifying Gasoline in Fire Debris Samples. AB - The characteristic that discriminates gasoline from other ignitable liquids is that it contains high-octane blending components. This study elaborates on the idea that the presence of gasoline in fire debris samples should be based on the detection of known high-octane blending components. The potential of the high octane blending component alkylate as a characteristic feature for gasoline detection and identification in fire debris samples is explored. We have devised characteristic features for the detection of alkylate and verified the presence of alkylate in a large collection of gasoline samples from petrol stations in the Netherlands. Alkylate was detected in the vast majority of the samples. It is demonstrated that alkylate can be detected in fire debris samples that contain traces of gasoline by means of routine GC-MS methods. Detection of alkylate, alongside other gasoline blend components, results in a more solid foundation for gasoline detection and identification in fire debris samples. PMID- 28556929 TI - Obstetric outcomes following fertility-preserving management of gynecologic malignancies. PMID- 28556930 TI - Nurses' Unique Opportunity to Promote Patient Engagement in Prenatal Care. AB - AIM: To report an analysis of the concept of patient engagement in prenatal care. BACKGROUND: Engagement in health care has been widely discussed but vaguely defined. Patients benefit more from their health care when they are fully engaged in their care. Patient engagement in prenatal care is an important element of prenatal care utilization that has not been analyzed, standardized as a concept, or measured. DESIGN: Concept analysis. DATA SOURCES: CINAHL, MEDLINE, PsycINFO databases, and the internet were searched for literature published in English with a focus on peer-reviewed journals from disciplines of business, allied health sciences, health administration, psychology, and nursing, focusing on the period of 2010-2015. METHODS: Hybrid version of the Walker and Avant concept analysis method (2011). RESULTS: This concept analysis provides 4 defining attributes of patient engagement in prenatal care and a table of related empirical referents of engagement. These elements offer a foundation for further nursing scholarship toward measurement and evaluation of patient engagement in prenatal care. CONCLUSION: Patient engagement in prenatal care represents a human response to a health condition. Efforts to increase patient engagement in health care are best addressed by the nursing profession through continued research and intervention development. PMID- 28556932 TI - A systematic review of the association between consumption of sugar-containing beverages and excess weight gain among children under age 12. AB - OBJECTIVE: A systematic review was conducted to address this clinical question: Does consumption of (non-dairy) sugar-containing beverages (SCBs) among children under age 12 result in excess weight gain? METHODS: The authors searched four databases for controlled trials (randomized and non-randomized) and cohort studies published in English through March 29, 2016: PubMed, EMBASE, Cochrane Database of Systematic Reviews, CINAHL. Initial and full-text screening, data abstraction, and risk of bias assessment were performed independently and in duplicate. RESULTS: Thirty-eight studies met inclusion criteria for this systematic review. One was a randomized controlled trial, and 37 were cohort studies. Though the results of these studies were mixed, the majority demonstrated a statistically significant positive association between SCB consumption in children under age 12 and total adiposity and central adiposity. In contrast, most studies that assessed 100 percent fruit juice consumption only with either total adiposity or central adiposity did not support an association. Among only children under age 5 at baseline, no studies examined central adiposity, but nearly all studies examining SCBs and total adiposity, and a majority examining only fruit juice consumption, demonstrated a statistically significant positive association. CONCLUSION: Our results support a statistically significant positive association between SCBs and total and central adiposity among children under age 12. This association is most consistent for total adiposity among children <5. Our results for 100 percent fruit juice only suggest differences by age, as most studies among those < 12 were negative but most among those <5 were positive. PMID- 28556931 TI - Quantification of carbamylated albumin in serum based on capillary electrophoresis. AB - Protein carbamylation, a nonenzymatic posttranslational modification promoted during uremia, is linked to a poor prognosis. In the present study, carbamylation of serum albumin was assayed using the symmetry factor on a capillary electrophoresis instrument (Helena V8). The symmetry factor has been defined as the distance from the center line of the peak to the back slope, divided by the distance from the center line of the peak to the front slope, with all measurements made at 10% of the maximum peak height. Serum albumin, creatinine, and urea concentrations were assayed using routine methods, whereas uremic toxins were determined using HPLC. In vitro carbamylation induced a marked albumin peak asymmetry. Reference values for the albumin symmetry factor were 0.69-0.92. In kidney patients, albumin peak asymmetry corresponded to the chronic kidney disease stage (p < 0.0001). The symmetry factor correlated well with serum urea (r = -0.5595, p < 0.0001) and creatinine (r = -0.5986, p < 0.0001) concentrations. Several protein-bound uremic toxins showed a significant negative correlation with the symmetry factor. Morphology of the albumin fraction was not affected by presence of glycated albumin and protein-bound antibiotics. In conclusion, the presented method provides a simple, practical way for monitoring protein carbamylation. PMID- 28556934 TI - A quantitative systematic review of the effects of training interventions on enhancing the competence of nursing staff in managing challenging patient behaviour. AB - AIMS: This systematic quantitative review identifies and summarizes the current knowledge and effects of training interventions for managing patients' challenging behaviour. BACKGROUND: Challenging behaviour is an acknowledged worldwide healthcare problem and its management can have a huge impact on quality of care. Evidence-based training interventions that focus on managing challenging behaviour are needed, but few tools for the systematic evaluation of these interventions are currently offered. DESIGN: A quantitative systematic review following the 2008 Centre for Reviews and Dissemination guidelines. DATA SOURCES: CINAHL, Scopus, PsycInfo, PubMed and Cochrane were searched using the same terms for papers published in English from 2005-2015. REVIEW METHODS: Studies were assessed for quality and risk of bias, according to the Cochrane Effective Practice and Organisation of Care Group criteria. A narrative summary was conducted. RESULTS: We included 17 studies and evaluated 16 training interventions. Interventions were classified into four key themes: disengagements, communication, controlling behavioural symptoms and restrictive measures. Our review showed that interventions were more likely to decrease violent incident rates and increase staff confidence than change staff attitudes or increase knowledge. The elements of competence used to manage challenging behaviour were measured unilaterally. The evidence provided by studies was largely weak. CONCLUSION: The variety of measurements used in the studies made comparing the effectiveness of the training interventions difficult. An individual's competence to manage challenging behaviour needs to be defined and a comprehensive scale for evaluating competence is also needed. Patient safety should be included in future evaluations. PMID- 28556935 TI - Values, virtues and initiatives-time for a conversation. PMID- 28556933 TI - Heterotypic endosomal fusion as an initial trigger for insulin-induced glucose transporter 4 (GLUT4) translocation in skeletal muscle. AB - KEY POINTS: Comprehensive imaging analyses of glucose transporter 4 (GLUT4) behaviour in mouse skeletal muscle was conducted. Quantum dot-based single molecule nanometry revealed that GLUT4 molecules in skeletal myofibres are governed by regulatory systems involving 'static retention' and 'stimulus dependent liberation'. Vital imaging analyses and super-resolution microscopy based morphometry demonstrated that insulin liberates the GLUT4 molecule from its static state by triggering acute heterotypic endomembrane fusion arising from the very small GLUT4-containing vesicles in skeletal myofibres. Prior exposure to exercise-mimetic stimuli potentiated this insulin-responsive endomembrane fusion event involving GLUT4-containing vesicles, suggesting that this endomembranous regulation process is a potential site related to the effects of exercise. ABSTRACT: Skeletal muscle is the major systemic glucose disposal site. Both insulin and exercise facilitate translocation of the glucose transporter glucose transporter 4 (GLUT4) via distinct signalling pathways and exercise also enhances insulin sensitivity. However, the trafficking mechanisms controlling GLUT4 mobilization in skeletal muscle remain poorly understood as a resuly of technical limitations. In the present study, which employs various imaging techniques on isolated skeletal myofibres, we show that one of the initial triggers of insulin induced GLUT4 translocation is heterotypic endomembrane fusion arising from very small static GLUT4-containing vesicles with a subset of transferrin receptor containing endosomes. Importantly, pretreatment with exercise-mimetic stimuli potentiated the susceptibility to insulin responsiveness, as indicated by these acute endomembranous activities. We also found that AS160 exhibited stripe-like localization close to sarcomeric alpha-actinin and that insulin induced a reduction of the stripe-like localization accompanying changes in its detergent solubility. The results of the present study thus provide a conceptual framework indicating that GLUT4 protein trafficking via heterotypic fusion is a critical feature of GLUT4 translocation in skeletal muscles and also suggest that the efficacy of the endomembranous fusion process in response to insulin is involved in the benefits of exercise. PMID- 28556936 TI - Parasagittal fractures of the proximal phalanx in Thoroughbred racehorses in the UK: Outcome of repaired fractures in 113 cases (2007-2011). AB - BACKGROUND: Thirty years have elapsed since the last published review of outcome following fracture of the proximal phalanx in Thoroughbred racehorses in the UK and contemporary results are needed to be able to advise of expected outcome. OBJECTIVES: Collect and analyse outcome data following repair of fractures of the proximal phalanx in Thoroughbred racehorses in the UK. STUDY DESIGN: Retrospective case series. METHODS: Case records of all Thoroughbred racehorses admitted to Newmarket Equine Hospital for evaluation of a parasagittal fracture of the proximal phalanx during a 5 years period were reviewed. Follow-up data regarding racing careers was collected for horses that underwent repair. Following exclusion of outliers, cases with incomplete data sets and comminuted fractures, mixed effect logistic regression was used to identify variables affecting returning to racing and odds ratios and confidence intervals calculated. RESULTS: Of 113 repaired cases, fracture configurations included short incomplete parasagittal (n = 12), long incomplete parasagittal (n = 86), complete parasagittal (n = 12) and comminuted (n = 3). A total of 54 (48%) cases raced after surgery. Horses that fractured at 2 years of age had increased odds of racing following surgery than those older than 2 years of age (OR 1.34; 95% CI 1.13-1.59, P = 0.002). Horses sustaining short incomplete parasagittal fractures had increased odds of racing following surgery compared with those with complete parasagittal fractures (OR 2.62; 95% CI 1.36-5.07, P = 0.006). No horses with comminuted fractures returned to racing. MAIN LIMITATIONS: Data are relevant only to Thoroughbred racehorses in the UK. CONCLUSIONS: Approximately half of the cases in this series raced following surgical repair. More 2-year-old horses raced following surgery, but this likely reflects horses, specifically older horses, passing out of training from unrelated factors. Fracture configuration affects odds of racing, which is relevant to owners when deciding on treatment. PMID- 28556937 TI - Abnormal Fetal Findings Associated With a Global Sphericity Index of the 4 Chamber View Below the 5th Centile. AB - OBJECTIVES: The purpose of this study was to evaluate the global sphericity index (GSI) of the 4-chamber view and correlate the results with abnormal ultrasound findings. METHODS: The epicardial end-diastolic basal-apical length (BAL) and transverse length (TL) of the 4-chamber view were measured to compute the GSI (BAL/TL) in 200 control fetuses between 20 and 40 weeks' gestation. Three hundred study fetuses were prospectively examined between 17 and 39 weeks' gestation. The GSI, Z score, and centile were computed for each of the fetuses. RESULTS: The GSI (1.233; SD, 0.0953) in the control fetuses was independent of gestational age. Eighteen percent of the study fetuses (55 of 300) had a GSI below the 5th centile (<1.08), of whom 96% (53 of 55) had additional abnormal ultrasound findings. Fetuses with an estimated fetal weight below the 10th centile had a significantly (P < .05) higher rate of an umbilical artery Doppler pulsatility index above the 95th centile (27% versus 17.7%), a middle cerebral artery Doppler pulsatility index below the 5th centile (27% versus 0%), an abnormal cerebroplacental ratio (27% versus 4.5%), and an amniotic fluid index of less than 5 cm (36% versus 9%). The TL was significantly increased compared with the BAL in fetuses with cardiac dysfunction, irrespective of the estimated fetal weight. CONCLUSIONS: An abnormal GSI below the 5th centile is associated with abnormal fetal ultrasound findings. PMID- 28556938 TI - Superiority of magnetic resonance imaging over conventional radiography in the early diagnosis of psoriatic arthritis. PMID- 28556939 TI - A case of Fanconi syndrome due to a deferasirox overdose and a trial of plasmapheresis. AB - WHAT IS KNOWN AND OBJECTIVE: Deferasirox has nephrotoxic effects in the context of chronic therapy. This case report illustrates proximal tubular dysfunction (Fanconi syndrome) due to an acute deferasirox overdose. CASE DESCRIPTION: In response, we trialled plasmapheresis to eliminate the drug. Deferasirox levels were obtained in the context of three rounds of plasmapheresis. Given the half life model of decay, we concluded that plasmapheresis may not have been successful. The patient ultimately recovered normal tubular function after 2 months. WHAT IS NEW AND CONCLUSION: This report is the first to describe acute deferasirox-induced nephrotoxicity, and the application of plasmapheresis that, ultimately, did not change the typical time to recovery. PMID- 28556940 TI - Three TOB1-related YABBY genes are required to maintain proper function of the spikelet and branch meristems in rice. AB - YABBY genes play important roles in the development of lateral organs such as leaves and floral organs in Angiosperms. However, the function of YABBY genes is poorly understood in monocots. We focused on three rice (Oryza sativa) YABBY genes, TONGARI-BOUSHI (TOB1, TOB2, TOB3), which are closely related to Arabidopsis (Arabidopsis thaliana) FILAMENTOUS FLOWER (FIL). To elucidate the function of these YABBY genes, we employed a reverse genetic approach. TOB genes were expressed in bract and lateral organ primordia, but not in meristems. RNAi knockdown of TOB2 or TOB3 in the tob1 mutant caused abnormal spikelet development. Furthermore, simultaneous knockdown of both TOB2 and TOB3 in tob1 affected not only spikelet, but also inflorescence development. In severe cases, the inflorescences comprised naked branches without spikelets. Analysis of inflorescence development at an early stage showed that the observed phenotypic defects were closely associated with a failure to initiate and maintain reproductive meristems. These results indicate that the TOB genes regulate the maintenance and fate of all reproductive meristems. It is likely that the function of FIL/TOB clade YABBY genes has been conserved between Arabidopsis and rice to maintain the proper function of meristems, even though these genes are expressed in lateral organ primordia. PMID- 28556942 TI - The elusive ettringite under the high-vacuum SEM - a reflection based on natural samples, the use of Monte Carlo modelling of EDS analyses and an extension to the ettringite group minerals. AB - Ettringite, Ca6 Al2 (SO4 )3 (OH)12 .26H2 O, or C6 AS-3 H32 as it is known in cement chemistry notation, is a major phase of interest in cement science as an hydration product and in polluted soil treatment since its structure can accommodate with many hazardous cations. Beyond those anthropogenic features, ettringite is first of all a naturally occurring mineral (although rare). An example of its behaviour under the scanning electron microscope and during energy dispersive spectroscopy (EDS) qualitative analysis is presented, based on the study of natural ettringite crystals from the N'Chwaning mine in South Africa. Monte Carlo modelling of the electron-matter interaction zone at various voltages is presented and confronted with actual, observed beam damage on crystals, which burst at the analysis spot. Finally, theoretical energy dispersive spectroscopy spectra for all the ettringite group minerals have been computed as well as Monte Carlo modelling of the electron-matter interaction zone. The knowledge of the estimation of the size of this zone may thus be helpful for the understanding of energy dispersive spectroscopy analysis in cement pastes or ettringite-remediated soils. PMID- 28556941 TI - The buffering capacity of stems: genetic architecture of nonstructural carbohydrates in cultivated Asian rice, Oryza sativa. AB - Harnessing stem carbohydrate dynamics in grasses offers an opportunity to help meet future demands for plant-based food, fiber and fuel production, but requires a greater understanding of the genetic controls that govern the synthesis, interconversion and transport of such energy reserves. We map out a blueprint of the genetic architecture of rice (Oryza sativa) stem nonstructural carbohydrates (NSC) at two critical developmental time-points using a subpopulation-specific genome-wide association approach on two diverse germplasm panels followed by quantitative trait loci (QTL) mapping in a biparental population. Overall, 26 QTL are identified; three are detected in multiple panels and are associated with starch-at-maturity, sucrose-at-maturity and NSC-at-heading. They tag OsHXK6 (rice hexokinase), ISA2 (rice isoamylase) and a tandem array of sugar transporters. This study provides the foundation for more in-depth molecular investigation to validate candidate genes underlying rice stem NSC and informs future comparative studies in other agronomically vital grass species. PMID- 28556943 TI - Infected mediastinal bronchogenic cyst successfully treated by endoscopic ultrasound-guided fine-needle aspiration drainage through the esophagus. PMID- 28556944 TI - Queer signs: The women of the British projective test movement. AB - As queer history is often hidden, historians must look for "signs" that hint at queer lives and experiences. When psychologists use projective tests, the search for queer signs has historically been more literal, and this was especially true in the homophobic practices of Psychology in the mid-twentieth century. In this paper, I respond to Elizabeth Scarborough's call for more analytic history about the lesser known women in Psychology's history. By focusing on British projective research conducted by lesbian psychologist June Hopkins, I shift perspective and consider, not those who were tested (which has been historically more common), but those who did the testing, and position them as potential queer subjects. After briefly outlining why the projective test movement is ripe for such analysis and the kinds of queer signs that were identified using the Rorschach ink blot test in the mid-twentieth century, I then present June Hopkins' (1969, 1970) research on the "lesbian personality." This work forms a framework upon which I then consider the lives of Margaret Lowenfeld, Ann Kaldegg, and Effie Lillian Hutton, all of whom were involved in the British projective test movement a generation prior to Hopkins. By adopting Hopkins' research to frame their lives, I present the possibility of this ambiguous history being distinctly queer. PMID- 28556946 TI - Dexmedetomidine protects mice against myocardium ischaemic/reperfusion injury by activating an AMPK/PI3K/Akt/eNOS pathway. AB - Acute myocardial ischaemia/reperfusion (MIR) injury leads to severe arrhythmias and has a high rate of lethality. In the present study, we aim to determine the effect of dexmedetomidine (Dex) on heart injury parameters following MIR surgery. We examined the effects of Dex on heart function parameters and infarct size following MIR surgery. Proinflammatory cytokines, oxidative products and anti oxidative enzymes in the myocardium were measured to evaluate the anti inflammatory and anti-oxidative effects of Dex. The role of the adenosine 5' monophosphate (AMP)-activated protein kinase (AMPK)/phosphatidylino-sitol 3 kinase (PI3k)/Akt/endothelial nitric oxide synthase (eNOS) pathway was investigated using their inhibitors. The alteration of haemodynamic parameters, histopathological results, and infarct size caused by MIR was attenuated by Dex. The interleukine-1 beta (IL-1beta), IL-6, tumour necrosis factor-a (TNF-alpha) and myeloperoxidase (MPO) were all significantly decreased. Anti-oxidative enzymes superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) were restored by Dex. Oxidative products8-OHdG, MDA and protein carbonyl were all decreased by Dex (P<.05). Dex activated AMPK expression, eNOS and Akt phosphorylation. The influence of Dex on cardiac function was reversed by the inhibitors of the eNOS, AMPK and PI3K/Akt pathways. These results indicate that Dex protected the cardiac functional, histological changes, inflammation and oxidative stress induced by MIR. Our results present a novel signalling mechanism that Dex protects MIR injury by activating an AMPK/PI3K/Akt/eNOS pathway. PMID- 28556947 TI - On the applicability of density functional theory to manganese-based complexes with catalytic activity toward water oxidation. AB - The present contribution assesses the performance of several popular and accurate density functionals, namely B3LYP, BP86, M06, MN12L, mPWPW91, PBE0, and TPSSh toward manganese-based coordination complexes. These compounds show promising properties toward application to catalytic water oxidation. Although manganese with N- and O-biding ligands tends to give rise to high spin complexes, the results show that BP86, mPWPW91, and specially MN12L, tend to yield low-spin complexes. The usage of these functionals for such compounds is, thus, discouraged. All the functionals considered deliver accurate geometries. The present results show, however, that B3LYP delivers geometries deviating from experimental values when compared to the other functionals of the set. M06, PBE0, and TPSSh deliver geometries of similar accuracy, PBE0 outstanding slightly with respect to the other two. (c) 2017 Wiley Periodicals, Inc. PMID- 28556945 TI - Leukemia/lymphoma-related factor (LRF) exhibits stage- and context-dependent transcriptional controls in the oligodendrocyte lineage and modulates remyelination. AB - Leukemia/lymphoma-related factor (LRF), a zinc-finger transcription factor encoded by Zbtb7a, is a protooncogene that regulates differentiation in diverse cell lineages, and in the CNS, its function is relatively unexplored. This study is the first to examine the role of LRF in CNS pathology. We first examined LRF expression in a murine viral model of spinal cord demyelination with clinically relevant lesion characteristics. LRF was rarely expressed in oligodendrocyte progenitors (OP) yet, was detected in nuclei of the majority of oligodendrocytes in healthy adult CNS and during remyelination. Plp/CreERT :Zbtb7afl/fl mice were then used with cuprizone demyelination to determine the effect of LRF knockdown on oligodendrocyte repopulation and remyelination. Cuprizone was given for 6 weeks to demyelinate the corpus callosum. Tamoxifen was administered at 4, 5, or 6 weeks after the start of cuprizone. Tamoxifen-induced knockdown of LRF impaired remyelination during 3 or 6-week recovery periods after cuprizone. LRF knockdown earlier within the oligodendrocyte lineage using NG2CreERT :Zbtb7afl/fl mice reduced myelination after 6 weeks of cuprizone. LRF knockdown from either the Plp/CreERT line or the NG2CreERT line did not significantly change OP or oligodendrocyte populations. In vitro promoter assays demonstrated the potential for LRF to regulate transcription of myelin-related genes and the notch target Hes5, which has been implicated in control of myelin formation and repair. In summary, in the oligodendrocyte lineage, LRF is expressed mainly in oligodendrocytes but is not required for oligodendrocyte repopulation of demyelinated lesions. Furthermore, LRF can modulate the extent of remyelination, potentially by contributing to interactions regulating transcription. PMID- 28556948 TI - Two cases of Mycobacterium marinum infection on the upper limbs. PMID- 28556949 TI - Does early-life family income influence later dental pain experience? A prospective 14-year study. AB - BACKGROUND: The aim of this study was to investigate the association between early-life family income and dental pain experience from childhood to early adulthood. METHODS: Data came from a 14-year prospective study (1991/1992 2005/2006) carried out in South Australia, which included children and adolescents aged 4-17 years (N = 9875) at baseline. The outcome was dental pain experience obtained at baseline, 14 years later in adulthood and at a middle point of time. The main explanatory variable was early-life family income collected at baseline. RESULTS: The prevalence of dental pain was 22.8% at baseline, 19.3% at 'middle time' and 39.3% at follow up. The proportion of people classified as 'poor' at baseline was 27.7%. Being poor early in life was significantly associated with dental pain at 14-year follow up (odds ratio = 1.45; 95% confidence interval = 1.27-1.66). CONCLUSIONS: Early-life relative poverty is associated with more frequent dental pain across the 14-year follow up and may be a key exposure variable for later dental conditions. PMID- 28556950 TI - The radiosynthesis of novel PI3K inhibitor , 8-ethoxy-2-(4-[18 F]fluorophenyl)-3 nitro-2H-chromene (18 F-EFPNC). AB - 8-ethoxy-2-(4-[18 F]fluorophenyl)-3-nitro-2H-chromene(18 F-EFPNC)was preparated through nucleophilic substitution reaction of the precursor 8-ethoxy -2-[(4 -N, N, N-trimethylammonium triflate)phenyl]-3-nitro-2H-chromene and nuclide [18 F] fluorination. The best radiosynthesis condition was obtained via [18 F] fluorination substitution reaction between [18 F] and 18 mg of the precursor in dimethyl sulfoxide(DMSO) at 150 degrees C for 5 min after the radiosynthesis method was optimized.The decay-corrected radiochemical yields(DCRY) of 18 F-EFPNC were 38.5% with total synthesis time of 45 min.The radiochemical purity of 18 F EFPNC was more than 95% by Thin-layer chromatography(TLC) analysis.The test of 18 F-EFPNC's radiochemical stability showed it was stable at room temperature for up to 2 h.The above results demonstrated that the radiosynthesis method of 18 F EFPNC was feasible. PMID- 28556951 TI - The human mast cell line-1 cell membrane chromatography coupled with HPLC-ESI MS/MS method for screening potentical anaphylactic components from chuanxinlian injection. AB - Chuanxinlian injection is a traditional Chinese medicine injection widely used in China to treat sore throat, cough and dysentery, although a high occurrence of severe adverse reactions has been reported in clinical practice in recent years. In the present study, a human mast cell line-1 cell membrane chromatography coupled with HPLC-ESI-MS/MS method was established to screen and identify potentical anaphylactic components in chuanxinlian injection, and the dehydroandrographolide was identified as a potential anaphylactic component. In vitro anaphylactic assay showed that intracellular Ca2+ concentration clearly increased under dehydroandrographolide (100 MUm) treatment. beta-Hexosaminidase and histamine release in human mast cell line-1 cells were both markedly enhanced with increased concentrations of dehydroandrographolide, confirming the anaphylactic activity of dehydroandrographolide. The application for chuanxinlian injection in this study suggested that the developed human mast cell line-1 cell membrane chromatography coupled with HPLC-ESI-MS/MS system may be effective and rapid for screening the potentical anaphylactic components from complex samples. PMID- 28556952 TI - A miniaturized sensor for detection of formaldehyde fumes. AB - A miniaturized chemical sensor is here described for the analysis of environmental pollutants (VOC: volatile organic chemicals). It is used for remote detection of formaldehyde (FA) fumes in the atmosphere, and is based on the redox reaction between FA and silver nitrate. The sensor is worn as a bracelet and the data acquired are transferred via a Bluetooth channel to a smartphone. A dedicated software transforms the signal from a grey to a color scale. The signal response has been assessed over low (20 to 120 ppb) as well as higher (1-15 ppm range) levels. The sensor has been applied to monitor potential FA fumes of some artwork in the Summer Palace in Beijing and the modifications induced by FA treatment on a precious Stradivarius violin. The performance of this novel sensor is compared with a commercial apparatus widely adopted, namely the Honeywell MultiRAE Lite wireless portable multi-gas monitor (pumped model). PMID- 28556953 TI - Novel biallelic SZT2 mutations in 3 cases of early-onset epileptic encephalopathy. AB - The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, biallelic SZT2 mutations were found in 7 patients (from 5 families) presenting with epileptic encephalopathy with dysmorphic features and/or non-syndromic intellectual disabilities. In this study, we identified by whole-exome sequencing compound heterozygous SZT2 mutations in 3 patients with early-onset epileptic encephalopathies. Six novel SZT2 mutations were found, including 3 truncating, 1 splice site and 2 missense mutations. The splice-site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealed a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of the 2 cases. Interestingly, in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size. PMID- 28556955 TI - Complete reversal of bone marrow fibrosis after parathyroidectomy for secondary hyperparathyroidism. PMID- 28556954 TI - Transcatheter arterial embolization in normal canine liver. AB - OBJECTIVE: To determine the effects of selective transcatheter arterial embolization (TAE) in the normal canine liver. STUDY DESIGN: Experimental study. ANIMALS: Adult Beagle dogs (n = 5). METHODS: Gelatin sponge particles (GSPs) were injected through a microcatheter for selective embolization of the left hepatic artery in normal dogs. Computed tomography (CT) and histology were performed during an 8-week observation period; biochemical analysis data were obtained during a 12-week observation period after TAE. RESULTS: Embolization was successful in all dogs and did not induce any change in the clinical appearance of dogs. Postoperative CT was consistent with recanalization of the artery within 2 weeks of embolization in all dogs. Hepatic enzyme levels increased temporarily after embolization but gradually returned to normal ranges. Histological examinations did not differ between treated and untreated liver tissues. CONCLUSION: TAE appears safe in normal dogs observed for 12 weeks. Arterial recanalization seems to occur within 2 weeks after injection of GSPs in the left hepatic artery. IMPACT/CLINICAL RELEVANCE: Selective TAE of the hepatic artery was well tolerated in normal dogs. Selective TAE may be applicable to canine hepatocellular carcinoma. PMID- 28556956 TI - Prognostic value of p21-activated kinase 4 in resected pancreatic cancer. AB - Resectable pancreatic cancer has a high recurrence rate after curative surgery. Biomarkers are needed for distinguishing patients who may benefit from curative resection. In this study, we sought to analyze the prognostic value of p21 activated kinase 1 (PAK1), p21-activated kinase 4 (PAK4), human equilibrative nucleoside transporter 1 (hENT1), and thymidylate synthase (TS) in surgically resected pancreatic ductal adenocarcinomas. A total of 160 pancreatic cancer patients who underwent surgery with curative intent were retrospectively reviewed. Tissue microarrays were constructed and immunohistochemical stains were performed for PAK1, PAK4, hENT1, and TS. The absence of PAK4 expression in pancreatic adenocarcinomas was associated with poorer histologic differentiation (p < 0.001), shorter overall survival [hazard ratio (HR) = 2.86, 95% confidence interval (CI) 1.43-5.71; p = 0.003], and disease-free survival (HR = 2.29, 95% CI: 1.11-4.74; p = 0.025) on univariate analyses. In addition, more frequent venous invasion and lymph node metastases were seen in PAK4-negative tumors although not statistically significant. PAK1, hENT1, and TS expression status did not have significant influences on patient survival. In conclusion, PAK4 of the markers tested in this study may be a potential prognostic biomarker for pancreatic adenocarcinomas. PMID- 28556957 TI - Increased frequency of bronchiolar histotypes in lung carcinomas associated with idiopathic pulmonary fibrosis. AB - AIMS: The association between lung cancer and idiopathic pulmonary fibrosis (IPF) is well known, but the significance of this association is poorly understood. Bronchiolar honeycomb cysts have been proposed as possible precursors for the development of carcinoma, but limited evidence in support of this hypothesis is available. The aim of this study was to investigate this hypothesis analysing a series of carcinomas arising in IPF by immunohistochemistry. METHODS AND RESULTS: Thirty-three lung carcinomas arising in patients with IPF were analysed with a panel of immunohistochemical markers. The antibodies included those against pneumocyte markers [thyroid transcription factor 1 (TTF1), napsin-A, and surfactant protein A], the goblet cell marker mucin 5AC, markers of basal/squamous cell differentiation [cytokeratin (CK) 5/6 and DeltaN-p63], and markers related to enteric differentiation (CDX2, mucin 2, CK20, and villin). A series of 100 consecutive lung adenocarcinomas arising in smokers without IPF were investigated as controls. All carcinomas arising in IPF patients were peripherally located on imaging analysis. The diagnoses were: eight squamous cell carcinomas, 20 adenocarcinomas, three small-cell carcinomas (including one composite small-cell carcinoma and adenocarcinoma), and two large-cell carcinomas. Among adenocarcinomas, a 'pneumocyte' profile (TTF1/napsin-A/SPA1 triple-positive) was observed in seven of 20 (35% versus 84% in non-IPF controls, P = 0.0001). The remaining 13 adenocarcinomas (65%) showed rare histotypes: four invasive mucinous adenocarcinomas (20% in IPF patients versus 1% in non-IPF controls, P = 0.002), seven tumours (35%) that were characterized by variable expression of markers of enteric differentiation, and two tumours (10%) that showed a peculiar basaloid component. CONCLUSIONS: The immunohistochemical characterization of carcinomas arising in IPF patients shows striking divergence from that in non-IPF smokers. The prevalence of rare entities showing bronchiole related markers is in line with the hypothesis that these tumours arise from transformed small airways in honeycomb lung areas where abnormal bronchiolar proliferation takes place. PMID- 28556958 TI - Downregulation of androgen receptors by NaAsO2 via inhibition of AKT-NF-kappaB and HSP90 in castration resistant prostate cancer. AB - BACKGROUND: Androgen and androgen receptor (AR) play essential roles in the development and maintenance of prostate cancer. The recently identified AR splice variants (AR-Vs) have been considered as a plausible mechanism for the primary resistance against androgen deprivation therapy (ADT) in castration-resistant prostate cancer (CRPC). Sodium meta-arsenite (NaAsO2 ; KML001; Kominox), a trivalent arsenical, is an orally bioavailable and water soluble, which is currently in phase I/II clinical trials for the treatment of prostate cancer. It has a potent anti-cancer effect on prostate cancer cells and xenografts. The aim of this study was to examine the effect of NaAsO2 on AR signaling in LNCaP and 22Rv1 CRPC cells. METHODS: We used hormone-sensitive LNCaP cells, hormone insensitive 22Rv1 cells, and CRPC patient-derived primary cells. We analyzed anti cancer effect of NaAsO2 using real-time quantitative reverse transcription-PCR, Western blotting, immunofluorescence staining and CellTiter Glo(r) luminescent assay. Statistical evaluation of the results was performed by one-way ANOVA. RESULTS: NaAsO2 significantly reduced the translocation of AR and AR-Vs to the nucleus as well as their level in LNCaP and 22Rv1 cells. Besides, the level of the prostate-specific antigen (PSA), downstream target gene of AR, was also decreased. This compound was also an effective modulator of AKT-dependent NF kappaB activation which regulates AR. NaAsO2 significantly inhibited phosphorylation of AKT and expression and nuclear translocation of NF-kappaB. We then investigated the effect of NaAsO2 on AR stabilization. NaAsO2 promoted HSP90 acetylation by down-regulating HDAC6, which reduces the stability of AR in prostate cancer cells. CONCLUSIONS: Here, we show that NaAsO2 disrupts AR signaling at multiple levels by affecting AR expression, stability, and degradation in primary tumor cell cultures from prostate cancer patients as well as CRPC cell lines. These results suggest that NaAsO2 could be a novel therapeutics for prostate cancer. PMID- 28556959 TI - Exacerbation of allopurinol-induced drug reaction with eosinophilia and systemic symptoms by teicoplanin: A case report. AB - WHAT IS KNOWN AND OBJECTIVE: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially life-threatening drug reaction. Allopurinol is one of the most frequently reported drugs accounting for DRESS syndrome development. In contrast to allopurinol, DRESS syndrome induced by teicoplanin has not been reported frequently. CASE DESCRIPTION: A 50-year-old woman was admitted to receive FLAG chemotherapy regimen (fludarabine, cytarabine (high-dose Ara-C), granulocyte colony-stimulating factor) for relapsed acute lymphoblastic leukaemia (ALL) treatment. Allopurinol was initiated at a dose of 300 mg per day 48 hours before chemotherapy regimen initiation, for tumour lysis syndrome prophylaxis. Seven days after allopurinol initiation, the patient presented with fever, dyspnoea, shortening of breath, facial oedema, generalized pruritus, erythema and macular rash affecting the face, abdomen, trunk, upper and lower limbs and an elevation in hepatic enzymes. Allopurinol was immediately discontinued and intravenous hydrocortisone was started concomitantly alongside other supportive measures. About 72 hours later, pruritus, erythema and rash were ameliorated and abnormalities in liver tests were improved. Afterwards, teicoplanin administration led to severe deterioration of pruritus, erythema and rash; subsequently, serum alanine aminotransferase increased again and episodes of worsening dyspnea occurred. Signs of hypersensitivity reaction were reduced by discontinuation of teicoplanin and supportive care. WHAT IS NEW AND CONCLUSION: We report a case of allopurinol-induced DRESS syndrome, which was exacerbated by administration of teicoplanin. It can be suggested that the administration of drugs with high possibility of hypersensitivity reactions should be avoided during the acute phase of DRESS syndrome. PMID- 28556960 TI - The cellular character of liquefaction degeneration in oral lichen planus and the role of interferon gamma. AB - BACKGROUND: Oral lichen planus (OLP) is a T-cell-mediated chronic inflammatory oral mucosal disease of unknown etiology, and liquefaction degeneration in the basal keratinocytes is one of the specific histological changes. However, the understanding of liquefaction degeneration is still very limited, and how does it affect the prognosis of LP is largely unknown. Therefore, the objective of this study was to clarify the intrinsic change behind the liquefaction degeneration in lichen planus and to evaluate the effect of the OLP-typical cytokine, IFN-gamma, on these changes. MATERIALS AND METHODS: Biopsies were collected from patients with OLP; immunochemistry staining was performed to analyze E-cadherin, vimentin, CK19, beta1 integrin, nestin, STAT1, and STAT3 expression. Primary oral epithelial cells were cultured in vitro, and 20 ng/mL IFN-gamma was applied to assay the effect on epithelial cells. RESULTS: E-cadherin expression was decreased but vimentin expression was increased in the OLP epithelial cells that undergo liquefaction degeneration, showing the typical epithelial-mesenchymal transition (EMT) alteration. In vitro research showed that the OLP-typical cytokine, IFN-gamma, possesses EMT-inducing ability, and the primary oral epithelial cells stimulated by IFN-gamma acquired some properties of cancer stem cells, expressing more beta1 integrin, alpha6 integrin, and nestin. In addition, the major downstream mediator of IFN-gamma receptor, STAT1, was expressed more intensive and extensive with the malignant transition of OLP. CONCLUSION: Liquefaction degeneration in oral lichen planus is an EMT phenomenon, the IFN gamma may be the main inducer, and IFN-gamma signaling might be implicated in malignant transition of OLP. PMID- 28556961 TI - Hydroxychloroquine affects bone resorption both in vitro and in vivo. AB - We recently showed that patients with primary Sjogren syndrome (pSS) have significantly higher bone mineral density (BMD) compared to healthy controls. The majority of those patients (69%) was using hydroxychloroquine (HCQ), which may have favorable effects on BMD. The aim of the study was to evaluate whether HCQ modulates osteoclast function. Osteoclasts were cultured from PBMC-sorted monocytes for 14 days and treated with different HCQ doses (controls 1 and 5 MUg/ml). TRAP staining and resorption assays were performed to evaluate osteoclast differentiation and activity, respectively. Staining with an acidification marker (acridine orange) was performed to evaluate intracellular pH at multiple timepoints. Additionally, a fluorescent cholesterol uptake assay was performed to evaluate cholesterol trafficking. Serum bone resorption marker beta CTx was evaluated in rheumatoid arthritis patients. HCQ inhibits the formation of multinuclear osteoclasts and leads to decreased bone resorption. Continuous HCQ treatment significantly decreases intracellular pH and significantly enhanced cholesterol uptake in mature osteoclasts along with increased expression of the lowdensity lipoprotein receptor. Serum beta-CTx was significantly decreased after 6 months of HCQ treatment. In agreement with our clinical data, we demonstrate that HCQ suppresses bone resorption in vitro and decreases the resorption marker beta-CTx in vivo. We also showed that HCQ decreases the intracellular pH in mature osteoclasts and stimulates cholesterol uptake, suggesting that HCQ induces osteoclastic lysosomal membrane permeabilization (LMP) leading to decreased resorption without changes in apoptosis. We hypothesize that skeletal health of patients with increased risk of osteoporosis and fractures may benefit from HCQ by preventing BMD loss. PMID- 28556963 TI - Prediction of 30-year cardiovascular disease risk in psoriatic population. PMID- 28556964 TI - Psychopathy and Mortality. AB - It is not known how mortality differs between psychopathic and nonpsychopathic individuals. We linked data from subjects having been in forensic mental examinations at Niuvanniemi Hospital during 1984-1993 to the data from the National Death Registry to estimate the association between psychopathy and mortality. One hundred psychopathic individuals scoring 25 or higher in the PCL-R scale were followed up for 20-30 years. Two control groups were used as follows: 178 offenders scoring less than 25 on the PCL-R, and sample of general population drawn from the Finnish National Statistics database. Results reveal that psychopaths die younger than the general population, and the causes of death are more violent than in the nonpsychopath control group. There was a significant positive correlation between PCL-R score and mortality, and the mortality among psychopaths was about fivefold when compared with general population. PMID- 28556965 TI - Attachment Security and Developmental Patterns of Growth in Executive Functioning During Early Elementary School. AB - Despite the extensive research demonstrating the importance of child executive functioning (EF) for school adjustment, little longitudinal work has formally examined developmental change in EF during the early school years. Based on a sample of 106 mother-child dyads, the current longitudinal study investigated patterns of growth in child performance on three executive tasks between kindergarten (Mage = 6 years) and Grade 3 (Mage = 9 years), and the predictive role of earlier mother-child attachment security in these patterns. The results suggest that early elementary school is a period of significant developmental improvement in child EF, although child performance on different EF tasks follows distinct trajectories across time. The study also provides evidence for a sustained relation between children's early attachment security and their ongoing acquisition of executive skills. PMID- 28556962 TI - Treatment of spontaneous preterm labour with retosiban: a phase II pilot dose ranging study. AB - AIMS: The aims of the present study were to investigate the maternal, fetal and neonatal safety and tolerability, pharmacodynamics and pharmacokinetics of intravenous (IV) retosiban in pregnant women with spontaneous preterm labour (PTL) between 340/7 and 356/7 weeks' gestation. METHODS: In parts A and B of a three-part, double-blind, placebo-controlled, multicentre study, women were randomized 3:1 (Part A) or 2:1 (Part B) to either 12-h IV retosiban followed by a single dose of oral placebo (R-P) or 12-h IV placebo followed by single-dose oral retosiban (P-R). RESULTS: A total of 29 women were randomized; 20 to R-P and nine to P-R. An integrated analysis found that adverse events were infrequent in mothers/newborns and consistent with events expected in the population under study or associated with confounding factors. Retosiban was rapidly absorbed after oral administration, with an observed half-life of 1.45 h. Efficacy analyses included 19 women. While not statistically significant, those receiving R-P more frequently achieved uterine quiescence in 6 h (R-P, 63%; 95% credible interval [CrI]: 38, 84; P-R, 43%; 95% CrI: 12, 78) and more achieved a reduction of >=50% in uterine contractions in 6 h (R-P, 63%; 95% CrI: 38, 84; P-R, 29%; 95% CrI: 4, 64). The number of days to delivery was increased in women receiving R-P (median 26 days for R-P vs. 13 days for P-R). CONCLUSIONS: Intravenous retosiban has a favourable safety and tolerability profile and might prolong pregnancies in women with PTL. The study provides the rationale and dosing strategy for further evaluation of the efficacy of retosiban in the treatment of PTL. PMID- 28556966 TI - Effects of sample processing and storage on the integrity of cell-free miRNAs in maternal plasma. AB - BACKGROUND: Cell-free fetal miRNAs have been identified as potential biomarkers for fetal abnormalities and/or placental function. Factors affecting the stability of cell-free fetal miRNA samples (type of collection tube and time interval between sampling and analysis) have not previously been reported. METHODS: Blood from pregnant women (n = 12, 18 +/- 4 weeks' gestation) was collected into two types of tube (EDTA and RNA BCT) and was stored at different temperatures for up to 72 h. Expression of seven apparently placental specific miRNAs was then measured to compare the effects of sampling and storage. These miRNAs were also assessed in non-pregnant women (n = 9). RESULTS: The quantity of miRNA extracted was not affected by time or tube. Three miRNAs (miR-518b, miR-525 and miR-526a*) were measureable only in pregnant women, but miR-518b was not always present. Detailed study of the two pregnancy specific miRNAs showed no effect of tube type at 4 h. However, variability in miRNA level was observed with increased time and was significant for one miRNA in the BCT tube at >48 h (p < 0.005). CONCLUSION: Some cffmiRNAs are placental specific, and these samples are stable when analyzed within 48 h of collection in either tube type. (c) 2017 John Wiley & Sons, Ltd. PMID- 28556968 TI - Worldwide hemisphere-dependent lean in Cook pines. PMID- 28556969 TI - Metabolic profiling of quercetin in rats using ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry. AB - Quercetin, a kind of major flavonoid found in many traditional chinese medicines, is an effective substance for treatments such as lowering blood lipids. However, the studies on quercetin have been mainly focused on its pharmacological effect; the treatment of diseases on a material basis, particularly the metabolites derived from quercetin in vivo, has not been evaluated. In this study, we determined the levels, distributions and types of quercetin's metabolites in plasma, urine, feces and bile of rats after a single oral administration of quercetin at a dose of 80 mg/kg, using ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS). A total of 36 metabolites of quercetin were identified, including 11 metabolites in plasma, 34 metabolites in urine, 12 metabolites in feces and 21 metabolites in bile. The results showed that phase I metabolites were reduction metabolites and phase II metabolites mainly included glucuronidation, sulfation and methylation metabolites. These results provide important information on the metabolism of quercetin, which will be helpful for its further development and utilization. PMID- 28556967 TI - Teriparatide Treatment Improves Bone Defect Healing Via Anabolic Effects on New Bone Formation and Non-Anabolic Effects on Inhibition of Mast Cells in a Murine Cranial Window Model. AB - Investigations of teriparatide (recombinant parathyroid hormone [rPTH]) as a potential treatment for critical defects have demonstrated the predicted anabolic effects on bone formation, and significant non-anabolic effects on healing via undefined mechanisms. Specifically, studies in murine models of structural allograft healing demonstrated that rPTH treatment increased angiogenesis (vessels <30 MUm), and decreased arteriogenesis (>30 MUm) and mast cell numbers, which lead to decreased fibrosis and accelerated healing. To better understand these non-anabolic effects, we interrogated osteogenesis, vasculogenesis, and mast cell accumulation in mice randomized to placebo (saline), rPTH (20 MUg/kg/2 days), or the mast cell inhibitor sodium cromolyn (SC) (24 MUg/kg/ 2days), via longitudinal micro-computed tomography (MUCT) and multiphoton laser scanning microscopy (MPLSM), in a critical calvaria defect model. MUCT demonstrated that SC significantly increased defect window closure and new bone volume versus placebo (p < 0.05), although these effects were not as great as rPTH. Interestingly, both rPTH and SC have similar inhibitory effects on arteriogenesis versus placebo (p < 0.05) without affecting total vascular volume. MPLSM time course studies in untreated mice revealed that large numbers of mast cells were detected 1 day postoperation (43 +/- 17), peaked at 6 days (76 +/- 6), and were still present in the critical defect at the end of the experiment on day 30 (20 +/- 12). In contrast, angiogenesis was not observed until day 4, and functional vessels were first observed on 6 days, demonstrating that mast cell accumulation precedes vasculogenesis. To confirm a direct role of mast cells on osteogenesis and vasculogenesis, we demonstrated that specific diphtheria toxin-alpha deletion in Mcpt5-Cre-iDTR mice results in similar affects as SC treatment in WT mice. Collectively, these findings demonstrate that mast cells inhibit bone defect healing by stimulating arteriogenesis associated with fibrotic scaring, and that an efficacious non-anabolic effect of rPTH therapy on bone repair is suppression of arteriogenesis and fibrosis secondary to mast cell inhibition. (c) 2017 American Society for Bone and Mineral Research. PMID- 28556970 TI - Topical treatment of all-trans retinoic acid inhibits murine melanoma partly by promoting CD8+ T-cell immunity. AB - All-trans retinoic acid (atRA), the main biologically active metabolite of vitamin A, has been implicated in immunoregulation and anti-cancer. A recent finding that vitamin A could decrease the risk of melanoma in humans indicates the beneficial role of atRA in melanoma. However, it remains unknown whether topical application of atRA could inhibit melanoma growth by influencing tumour immunity. We demonstrate topical application of tretinoin ointment (atRA as the active ingredient) effectively inhibited B16F10 melanoma growth. This is accompanied by markedly enhanced CD8+ T-cell responses, as evidenced by significantly increased proportions of effector CD8+ T cells expressing granzyme B, tumour necrosis factor-alpha, or interferon-gamma, and Ki67+ proliferating CD8+ T cells in atRA-treated tumours compared with vaseline controls. Furthermore, topical atRA treatment promoted the differentiation of effector CD8+ T cells in draining lymph nodes (DLN) of tumour-bearing mice. Interestingly, atRA did not affect tumoral CD4+ T-cell response, and even inhibited the differentiation of interferon-gamma-expressing T helper type 1 cells in DLN. Importantly, we demonstrated that the tumour-inhibitory effect of atRA was partly dependent on CD8+ T cells, as CD8+ T-cell depletion restored tumour volumes in atRA-treated mice, which, however, was still significantly smaller than those in vaseline-treated mice. Finally, we demonstrated that atRA up-regulated MHCI expression in B16F10 cells, and DLN cells from tumour-bearing mice had a significantly higher killing rate when culturing with atRA-treated B16F10 cells. Hence, our study demonstrates that topical atRA treatment effectively inhibits melanoma growth partly by promoting the differentiation and the cytotoxic function of effector CD8+ T cells. PMID- 28556972 TI - Comparing anger, anger expression, life stress and social support between Korean female nursing and general university students. AB - AIMS: To compare anger, anger expression, life stress and social support among female students at a nursing university and a general university and to examine factors affecting anger in each group. BACKGROUND: University students typically experience constant stress resulting from factors like academic requirements, personal relationships and career decisions; this tends to promote anger. Particularly, nursing students' anger can negatively affect the quality of care that they provide, and also their mental health. Therefore, anger management of nursing students is very important in the training and development of future nurses. Nursing education needs to confirm factors associated with anger of nursing students compared with general university students to develop specific intervention programs for decreasing their anger levels. DESIGN: A descriptive, cross-sectional design was used. METHODS: Participants were 286 female students (146 from a nursing university and 140 from a general university); they completed self-report surveys examining anger, anger expression, life stress and social support. A stepwise multiple regression analysis was done to identify factors affecting anger. Data were collected from 15 May-10 June 2016. RESULTS/FINDINGS: In the stepwise multiple regression analysis, we entered three anger expression factors, eight life stress factors and social support as explanatory variables; factors affecting anger among nursing students were anger-out and same-sex peer relationship stress. In general university students, anger-out, anger-control and anger-in were identified as factors affecting anger. CONCLUSION: Becoming proficient in beneficial anger expression techniques and reducing stress from same-sex peer relationships will reduce anger among female nursing students. PMID- 28556974 TI - Eosinophilic granulomatosis with polyangiitis followed by venous thromboembolism resulting in severe cutaneous ulcers. PMID- 28556971 TI - Low-level laser therapy (780 nm) combined with collagen sponge scaffold promotes repair of rat cranial critical-size defects and increases TGF-beta, FGF-2, OPG/RANK and osteocalcin expression. AB - The aim of this study was to evaluate the effect of collagen sponge scaffold (CSS) implantation associated with low-level laser therapy (LLLT) on repairing bone defects. A single 5-mm cranial defect was surgically created in forty Wistar rats, which then received one of the following four interventions (n = 10 per group): no treatment (G0); bone defect implanted with collagen sponge scaffold (CSS) alone (G1); defect treated with low-level laser therapy (LLLT) (wavelength 780 nm; total energy density 120 J/cm2 ; power 50 mW) alone (G2); and CSS associated with LLLT treatment (G3). After surgery, animals in each group were euthanized at 21 days and 30 days (n = 5 per euthanasia time group). Bone formation was monitored by X-ray imaging analysis. Biopsies were collected and processed for histological analysis and immunohistochemical evaluation of transforming growth factor-beta (TGF-beta), fibroblast growth factor-2 (FGF-2), osteoprotegerin (OPG) and receptor activator of nuclear factor k (RANK). Osteocalcin (OCN) was detected by immunofluorescence analysis. Compared to the G0 group, defects in the 30-day G3 group exhibited increased bone formation, both by increase in radiopaque areas (P < 0.01) and by histomorphometric analysis (P < 0.001). The histopathological analysis showed a decreased number of inflammatory cells (P < 0.001). The combined CCS + LLLT (G3) treatment also resulted in the most intense immunostaining for OPG, RANK, FGF-2 and TGF-beta, and the most intense and diffuse OCN immunofluorescent labelling at 30 days postsurgery (G3 vs. G0 group, P < 0.05). Therefore, the use of CCS associated with LLLT could offer a synergistic advantage in improving the healing of bone fractures. PMID- 28556973 TI - Primary cutaneous perivascular epithelioid cell tumor (PEComa): Five new cases and review of the literature. AB - PEComas represent a family of uncommon mesenchymal tumors composed of "perivascular epithelioid cells" with a distinct immunophenotype that typically shows both myogenic and melanocytic differentiation. The PEComa family includes angiomyolipoma (AML), clear cell "sugar" tumor of the lung and extra pulmonary sites, lymphangioleiomyomatosis and clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres. Very rarely, PEComas may arise in the skin. Primary cutaneous PEComas typically display a dermal proliferation of epithelioid cells with pale, clear, or granular pink cytoplasm arranged in nests and trabecula with an intervening arborizing network of delicate capillaries. Primary cutaneous PEComas have a lower frequency of myogenic marker expression than their deep soft tissue and visceral counterparts. They also often express strong diffuse CD10, leading to potential confusion with metastatic renal cell carcinoma. Most cases behave indolently. We report 5 additional cases of this rare entity. All showed classic histologic features and expression of either HMB 45 and/or Melan-A/MART-1. Four cases were tested for myogenic markers (2 were positive & 2 were negative). Three cases were tested for CD10 (all 3 were positive). All of our cases with clinical follow-up behaved indolently. Table 1 provides a summary of findings for all 5 cases in our series. PMID- 28556975 TI - Successful endoscopic closure of gastrocutaneous fistulas using a combination of polyethylene glycolic acid mesh and the Funada-style gastropexy device. PMID- 28556976 TI - Exploring the radiosynthesis and in vitro characteristics of [68 Ga]Ga-DOTA Siglec-9. AB - Vascular adhesion protein 1 is a leukocyte homing-associated glycoprotein, which upon inflammation rapidly translocates from intracellular sources to the endothelial cell surface. It has been discovered that the cyclic peptide residues 283-297 of sialic acid-binding IgG-like lectin 9 (Siglec-9) "CARLSLSWRGLTLCPSK" bind to vascular adhesion protein 1 and hence makes the radioactive analogues of this compound ([68 Ga]Ga-DOTA-Siglec-9) interesting as a noninvasive visualizing marker of inflammation. Three different approaches to the radiosynthesis of [68 Ga]Ga-DOTA-Siglec-9 are presented and compared with previously published methods. A simple, robust radiosynthesis of [68 Ga]Ga-DOTA-Siglec-9 with a yield of 62% (non decay-corrected) was identified, and it had a radiochemical purity >98% and a specific radioactivity of 35 MBq/nmol. Furthermore, the protein binding and stability of [68 Ga]Ga-DOTA-Siglec-9 were analyzed in vitro in mouse, rat, rabbit, pig, and human plasma and compared with in vivo pig results. The plasma in vitro protein binding of [68 Ga]Ga-DOTA-Siglec-9 was the lowest in the pig followed by rabbit, human, rat, and mouse. It was considerably higher in the in vivo pig experiments. The in vivo stability in pigs was lower than the in vitro stability. Despite considerable species differences, the observed characteristics of [68 Ga]Ga-DOTA-Siglec-9 are suitable as a positron emission tomography tracer. PMID- 28556977 TI - Testing plant use of mobile vs immobile soil water sources using stable isotope experiments. AB - We tested for isotope exchange between bound (immobile) and mobile soil water, and whether there is isotope fractionation during plant water uptake. These are critical assumptions to the formulation of the 'two water worlds' hypothesis based on isotope profiles of soil water. In two different soil types, soil-bound water in two sets of 19-l pots, each with a 2-yr-old avocado plant (Persea americana), were identically labeled with tap water. After which, one set received isotopically enriched water whereas the other set received tap water as the mobile phase water. After a dry down period, we analyzed plant stem water as a proxy for soil-bound water as well as total soil water by cryogenic distillation. Seventy-five to 95% of the bound water isotopically exchanged with the mobile water phase. In addition, plants discriminated against 18 O and 2 H during water uptake, and this discrimination is a function of the soil water loss and soil type. The present experiment shows that the assumptions for the 'two water worlds' hypothesis are not supported. We propose a novel explanation for the discrepancy between isotope ratios of the soil water profile and other water compartments in the hydrological cycle. PMID- 28556978 TI - Giant pyogenic granuloma of the finger in an HIV-positive patient. PMID- 28556979 TI - Nursing care of patients with chronic liver diseases: Time for action. PMID- 28556981 TI - Effect of bariatric surgery treatment on lower urinary tract symptoms. PMID- 28556980 TI - Acne: morphologic and vascular study of lesions and surrounding skin by means of optical coherence tomography. AB - BACKGROUND: Acne vulgaris is a disease of the pilosebaceous unit, characterized by hyper-keratinization process, comedos formation and inflammatory reactions. OBJECTIVE: The definition of the morphology and the vascularization of acne lesions by means of dynamic optical coherence tomography (D-OCT), to non invasively define the alterations occurring during the acne development and patient therapeutic management. METHODS: A set of standardized clinical pictures and D-OCT images were acquired from 114 acne lesions of 31 volunteers, presenting mild to moderate acne and evaluated by experts. Fifteen patients treated with oral antibiotics were followed during time at 0, 20, 40, and 60 days. RESULTS: Optical coherence tomography enabled to identify vascular and morphological aspects characterizing different types of acne lesions. Oral antibiotic treatment improved the morphologic features and decreased the digitally reconstructed vascular signal during time. CONCLUSION: The characterization of acne lesions and the identification of vascular pattern in acne lesions through D-OCT, corresponding to blood vessel dilation and inflammatory associated hyper vascularization, may have important clinical consequences in the assessment of acne severity, therapeutic decisions and treatment efficacy monitoring. PMID- 28556982 TI - N-Heterocyclic Vinylidene-Stabilized Phosphorus Biradicaloid. AB - Four-membered biradicaloid compounds containing a N2 E2 (E=main group element) framework have been thoroughly investigated; however, the synthesis of stable analogues with a C2 P2 skeleton remains a challenge. Base-mediated double C-H functionalization of IPr=CH2 (1) (IPr=C[N(2,6-iPr2 -C6 H3 )CH]2 ) with PCl3 affords [{(IPr)CP}2 Cl]Cl (2) as a royal blue solid. Treatment of 2 with KC8 yields the stable phosphorus biradicaloid [(IPr)CP]2 (3) featuring a four membered C2 P2 ring. Compound 3 is diamagnetic and shows sharp and temperature independent NMR resonances, revealing its singlet biradicaloid nature. The stability of 3 is attributed to the sigma- and pi-electron-donating property of the N-heterocyclic vinylidene [(IPr)C] group. PMID- 28556984 TI - The emerging role of anti-CD25 directed therapies as both immune modulators and targeted agents in cancer. AB - CD25 (also termed IL2RA) forms one component of the high-affinity heterotrimeric interleukin 2 (IL2) receptor on activated T cells. Its affinity for IL2 and cellular function are tightly regulated and vary in different cell types. The high frequency of CD25 on the surface of many different haematological tumour cells is now well established and, apart from its prognostic significance, CD25 may be present on leukaemic stem cells and enable oncogenic signalling pathways in leukaemic cells. Additionally, high CD25 expression in activated circulating immune cells and Tregs is a factor that has already been exploited by IL2 immunotherapies for treatment of tumours and autoimmune disease. The relative clinical safety and efficacy of administering anti-CD25 radioimmunoconjugates and immunotoxins in various haematological tumour indications has been established and clinical trials of a novel CD25-directed antibody drug conjugate are underway. PMID- 28556985 TI - Does centre experience matter? PMID- 28556983 TI - PINK1 regulates mitochondrial trafficking in dendrites of cortical neurons through mitochondrial PKA. AB - Mitochondrial Protein Kinase A (PKA) and PTEN-induced kinase 1 (PINK1), which is linked to Parkinson's disease, are two neuroprotective serine/threonine kinases that regulate dendrite remodeling and mitochondrial function. We have previously shown that PINK1 regulates dendrite morphology by enhancing PKA activity. Here, we show the molecular mechanisms by which PINK1 and PKA in the mitochondrion interact to regulate dendrite remodeling, mitochondrial morphology, content, and trafficking in dendrites. PINK1-deficient cortical neurons exhibit impaired mitochondrial trafficking, reduced mitochondrial content, fragmented mitochondria, and a reduction in dendrite outgrowth compared to wild-type neurons. Transient expression of wild-type, but not a PKA-binding-deficient mutant of the PKA-mitochondrial scaffold dual-specificity A Kinase Anchoring Protein 1 (D-AKAP1), restores mitochondrial trafficking, morphology, and content in dendrites of PINK1-deficient cortical neurons suggesting that recruiting PKA to the mitochondrion reverses mitochondrial pathology in dendrites induced by loss of PINK1. Mechanistically, full-length and cleaved forms of PINK1 increase the binding of the regulatory subunit beta of PKA (PKA/RIIbeta) to D-AKAP1 to enhance the autocatalytic-mediated phosphorylation of PKA/RIIbeta and PKA activity. D-AKAP1/PKA governs mitochondrial trafficking in dendrites via the Miro 2/TRAK2 complex and by increasing the phosphorylation of Miro-2. Our study identifies a new role of D-AKAP1 in regulating mitochondrial trafficking through Miro-2, and supports a model in which PINK1 and mitochondrial PKA participate in a similar neuroprotective signaling pathway to maintain dendrite connectivity. PMID- 28556986 TI - Characteristics of highly rated leadership in nursing homes using item response theory. AB - AIM: To identify characteristics of highly rated leadership in nursing homes. BACKGROUND: An ageing population entails fundamental social, economic and organizational challenges for future aged care. Knowledge is limited of both specific leadership behaviours and organizational and managerial characteristics which have an impact on the leadership of contemporary nursing home care. DESIGN: Cross-sectional. METHOD: From 290 municipalities, 60 were randomly selected and 35 agreed to participate, providing a sample of 3605 direct-care staff employed in 169 Swedish nursing homes. The staff assessed their managers' (n = 191) leadership behaviours using the Leadership Behaviour Questionnaire. Data were collected from November 2013 - September 2014, and the study was completed in November 2016. A two-parameter item response theory approach and regression analyses were used to identify specific characteristics of highly rated leadership. RESULTS: Five specific behaviours of highly rated nursing home leadership were identified; that the manager: experiments with new ideas; controls work closely; relies on subordinates; coaches and gives direct feedback; and handles conflicts constructively. The regression analyses revealed that managers with social work backgrounds and privately run homes were significantly associated with higher leadership ratings. CONCLUSION: This study highlights the five most important leadership behaviours that characterize those nursing home managers rated highest in terms of leadership. Managers in privately run nursing homes and managers with social work backgrounds were associated with higher leadership ratings. Further work is needed to explore these behaviours and factors predictive of higher leadership ratings. PMID- 28556987 TI - Data presentation options to manage variability in physical activity research. AB - This paper presents seven tactics for managing the variability evident in some physical activity data. High levels of variability in daily step-count data from pedometers or accelerometers can make typical visual inspection difficult. Therefore, the purpose of the current paper is to discuss several strategies that might facilitate the visual interpretation of highly variable data. The seven strategies discussed in this paper are phase mean and median lines, daily average per week, weekly cumulative, proportion of baseline, 7-day moving average, change point detection, and confidence intervals. We apply each strategy to a data set and discuss the advantages and disadvantages. PMID- 28556989 TI - Weight-based dosing of alemtuzumab: an ounce of prevention? PMID- 28556990 TI - The relationship between anxiety-depression status and psychosocial adjustments in the patients undergoing liver transplantation. PMID- 28556991 TI - Determining the relative strengths of aromatic and aliphatic C-H???X hydrogen bonds in imidazolium ionic liquids through measurement of H/D isotope effects on 19 F nuclear shielding. AB - The relative strengths of aromatic and aliphatic C-H???X hydrogen bonds in imidazolium ionic liquids were investigated through measurement of H/D isotope effects on the 19 F nuclear shielding of deuterated isotopologues of 1-n-butyl-3 methylimidazolium hexafluorophosphate and tetrafluoroborate ([C4 mim]PF6 and [C4 mim]BF4 ). Delta19 F(H,D) values ranging from 9.7 to 49.7 ppb were observed for [C4 mim]PF6 isotopologues, while for the [C4 mim]BF4 series these went from 26.2 to 83.8 ppb. Our findings indicate that the interactions between the fluorinated anions and protons on the C-1' and C-1" position of the N-alkyl sidechains are comparable to, and in some cases stronger than, those involving protons on the aromatic ring, underscoring the role that these weak interionic forces have on the local ordering of imidazolium salts in the liquid state. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28556988 TI - Laparoscopic ischemic conditioning of the stomach increases neovascularization of the gastric conduit in patients undergoing esophagectomy for cancer. AB - BACKGROUND AND OBJECTIVES: Gastric ischemic preconditioning has been proposed to improve blood flow and reduce the incidence of anastomotic complications following esophagectomy with gastric pull-up. This study aimed to evaluate the effect of prolonged ischemic preconditioning on the degree of neovascularization in the distal gastric conduit at the time of esophagectomy. METHODS: A retrospective review of a prospectively maintained database identified 30 patients who underwent esophagectomy. The patients were divided into three groups: control (no preconditioning, n = 9), partial (short gastric vessel ligation only, n = 8), and complete ischemic preconditioning (left and short gastric vessel ligation, n = 13). Microvessel counts were assessed, using immunohistologic analysis to determine the degree of neovascularization at the distal gastric margin. RESULTS: The groups did not differ in age, gender, BMI, pathologic stage, or cancer subtype. Ischemic preconditioning durations were 163 +/- 156 days for partial ischemic preconditioning, compared to 95 +/- 50 days for complete ischemic preconditioning (P = 0.2). Immunohistologic analysis demonstrated an increase in microvessel counts of 29% following partial ischemic preconditioning (P = 0.3) and 67% after complete ischemic preconditioning (P < 0.0001), compared to controls. CONCLUSIONS: Our study indicates that prolonged ischemic preconditioning is safe and does not interfere with subsequent esophagectomy. Complete ischemic preconditioning increased neovascularization in the distal gastric conduit. PMID- 28556993 TI - Protein contact dermatitis induced by cabbage with recurrent symptoms after oral intake. PMID- 28556992 TI - Management of sulfonylurea-treated monogenic diabetes in pregnancy: implications of placental glibenclamide transfer. AB - The optimum treatment for HNF1A/HNF4A maturity-onset diabetes of the young and ATP-sensitive potassium (KATP ) channel neonatal diabetes, outside pregnancy, is sulfonylureas, but there is little evidence regarding the most appropriate treatment during pregnancy. Glibenclamide has been widely used in the treatment of gestational diabetes, but recent data have established that glibenclamide crosses the placenta and increases risk of macrosomia and neonatal hypoglycaemia. This raises questions about its use in pregnancy. We review the available evidence and make recommendations for the management of monogenic diabetes in pregnancy. Due to the risk of stimulating increased insulin secretion in utero, we recommend that in women with HNF1A/ HNF4A maturity-onset diabetes of the young, those with good glycaemic control who are on a sulfonylurea per conception either transfer to insulin before conception (at the risk of a short-term deterioration of glycaemic control) or continue with sulfonylurea (glibenclamide) treatment in the first trimester and transfer to insulin in the second trimester. Early delivery is needed if the fetus inherits an HNF4A mutation from either parent because increased insulin secretion results in ~800-g weight gain in utero, and prolonged severe neonatal hypoglycaemia can occur post-delivery. If the fetus inherits a KATP neonatal diabetes mutation from their mother they have greatly reduced insulin secretion in utero that reduces fetal growth by ~900 g. Treating the mother with glibenclamide in the third trimester treats the affected fetus in utero, normalising fetal growth, but is not desirable, especially in the high doses used in this condition, if the fetus is unaffected. Prospective studies of pregnancy in monogenic diabetes are needed. PMID- 28556994 TI - Hyperglycaemia in pregnant rats causes sex-related vascular dysfunction in adult offspring: role of cyclooxygenase-2. AB - NEW FINDINGS: What is the central question of this study? Hyperglycaemia during pregnancy induces vascular dysfunction and hypertension in male offspring. Given that female offspring from other fetal programming models are protected from the effects of fetal insult, the present study investigated whether there are sex differences in blood pressure and vascular function in hyperglycaemia-programmed offspring. What is the main finding and its importance? We demonstrated that hyperglycaemia in pregnant rats induced vascular dysfunction and hypertension only in male offspring. We found sex differences in oxidative stress and cyclooxygenase-2-derived prostanoid production that might underlie the vascular dysfunction. These differences, particularly in resistance arteries, may in part explain the absence of hypertension in female offspring born to hyperglycaemic dams. Exposure to maternal hyperglycaemia induces hypertension and vascular dysfunction in adult male offspring. Given that female offspring from several fetal programming models are protected from the effects of fetal insult, in this study we analysed possible differences relative to sex in blood pressure and vascular function in hyperglycaemia-programmed offspring. Hyperglycaemia was induced on day 7 of gestation (streptozotocin, 50 mg kg-1 ). Blood pressure, acetylcholine and phenylephrine or noradrenaline responses were analysed in the aorta and mesenteric resistance arteries of 3-, 6- and 12-month-old male and female offspring. Thromboxane A2 release was analysed with commercial kits and superoxide anion (O2- ) production by dihydroethidium-emitted fluorescence. Male but not female offspring of hyperglycaemic dams (O-DR) had higher blood pressure than control animals (O-CR). Contraction in response to phenylephrine increased and relaxation in response to acetylcholine decreased only in the aorta from 12 month-old male O-DR and not in age-matched O-CR. Contractile and vasodilator responses were preserved in both the aorta and mesenteric resistance arteries from female O-DR of all ages. Pre-incubation with tempol, superoxide dismutase, indomethacin, NS-398, furegrelate or SQ29548 decreased contraction in response to phenylephrine and potentiated relaxation in response to acetylcholine in 12-month old male O-DR aorta. In this artery, thromboxane A2 release and O2- generation were greater in O-DR than O-CR groups. In conclusion, exposure to hyperglycaemia in utero results in sex-specific and age-dependent hypertension. The fact that vascular function is preserved in female O-DR may in part explain the absence of hypertension in this group. In contrast, the peripheral artery dysfunction associated with increased cyclooxygenase-2-derived production of vasoconstrictor prostanoids could underlie the increased blood pressure in male O-DR. PMID- 28556995 TI - Synthesis and Characterization of Bromoaluminate Ionic Liquids. AB - Twelve bromoaluminate based ionic liquids (ILs) were synthesized and characterized by IR, Raman, and NMR spectroscopy, as well as single crystal X-ray diffraction in part. Their principal physicochemical properties including melting points, conductivities, viscosities, and densities were determined and compared with related ILs. The influence of the cation and anion on the physicochemical properties are discussed. The [AlBr4 ]- based salts are-with one exception-solid at room temperature, while the compounds based on the anion [Al2 Br7 ]- are liquid at room temperature. The liquid salts show low viscosities (49-139 mPa s), medium to high conductivities (0.76-3.53 mS cm-1 ) and high densities (1.82-2.04 g cm-3 ) at 28 degrees C. Furthermore, we showed aluminum electrodeposition from Lewis acidic ILs based on AlBr3 and 1-hexyl-3-methylimidazolium bromide and investigated the stability range of various formulations. PMID- 28556996 TI - Semi-high-throughput isolation and N-glycan analysis of human fibrinogen using monolithic supports bearing monoclonal anti-human fibrinogen antibodies. AB - Fibrinogen (FIB) is a secretory glycoprotein synthesized by hepatocytes that has a key role in blood clotting. Its glycosylation has not been studied in detail and little is known about the biological variability of FIB N-glycosylation, mainly due to the lack of fast, simple, and robust approaches to purify FIB from blood plasma samples. In recent years, customised chromatographic monoliths have been used for a variety of biological applications due to their unique characteristics. Here we describe development and optimisation of monolithic supports bearing monoclonal anti-human fibrinogen antibodies in a single column as well as in multi-well plate formats with high FIB specificity and binding capacity for fast immunoaffinity purification of FIB from human blood samples. The developed semi-high-throughput workflow has been successfully applied for FIB immunoaffinity isolation and subsequent ultra performance liquid chromatography N glycosylation analysis in ten healthy human individuals, demonstrating the potential of monolithic supports in glycomics studies. PMID- 28556997 TI - Response to early repeat celiotomy in horses after a surgical treatment of jejunal strangulation. AB - OBJECTIVE: To determine the outcome after early repeat celiotomy in horses operated for jejunal strangulation. STUDY DESIGN: Retrospective case series. ANIMALS: Horses (n = 22) that underwent repeat celiotomy for postoperative reflux (POR) and/or postoperative colic (POC) that did not improve within 48 hours from onset after initial surgical treatment of strangulating jejunal lesions by jejunojejunostomy (n = 14) or no resection (n = 8). METHODS: Medical records were reviewed for clinical signs, duration of signs before repeat surgery, surgical findings and treatment, and outcome. Survival was documented by phone call at long-term follow-up. The influence of POC and POR on timing of surgery were analyzed. Long-term survival was examined by Kaplan-Meier analyses. RESULTS: Repeat celiotomy was performed at a median of 57 hours after initial surgery and 16.5 hours from onset of signs, and earlier in horses with POC compared with POR (P < .05). A total of 3/22 horses were euthanatized under anesthesia. A total of 9 of 11 horses with initial jejunojejunostomy required resection of the original anastomosis due to anastomotic complications. In 8 horses without resection, second surgery included resection (4) or decompression (4). Repeat celiotomy was successful in 13/16 horses with POR. Repeat celiotomy eliminated POC in all horses (n = 9). A total of 19 horses were recovered from anesthesia and all survived to discharge. Incisional infections were diagnosed in 13/17 horses where both surgeries were performed through the same ventral median approach, and hernias developed in 4/13 infected incisions. Median survival time was 90 months. CONCLUSION: Repeat celiotomy can eliminate signs of POR and/or POC, and the additional surgery does not appear to aggravate POR. Criteria for repeat celiotomy in this study could provide guidelines for managing POC and POR after surgery for jejunal strangulation. PMID- 28556998 TI - Sometimes Less is More: Establishing the Core Symptoms of PTSD. AB - Historically, the symptoms of posttraumatic stress disorder (PTSD) have garnered attention and controversy due to symptom overlap with other disorders. To improve diagnostic specificity, researchers have proposed to reformulate PTSD symptoms into a parsimonious set of core criteria. The core symptoms consisted of recurrent distressing dreams or flashbacks; internal or external avoidance; and hypervigilance or exaggerated startle. The purpose of this study was to examine a previously proposed set of "core" PTSD criteria in identifying cases of PTSD within a veteran sample. Veterans (N = 383) presenting to a Veterans Affairs (VA) Medical Center PTSD clinic for psychological services were assessed using the Clinician Administered PTSD Scale for DSM-5 (CAPS-5). A logistic regression analysis revealed that the core criteria accurately identified 79% of veterans with PTSD (OR = 11.57). Findings support a parsimonious set of core criteria in the assessment and diagnosis of PTSD. Future studies should replicate these findings in diverse, nonveteran samples. PMID- 28556999 TI - Helical Oligonaphthodioxepins Showing Intense Circularly Polarized Luminescence (CPL) in Solution and in the Solid State. AB - A series of oligonaphthodioxepins was synthesized, revealing a helically arranged octamer, (R,R,R,R,R,R,R)-3, which showed intense circularly polarized luminescence (CPL) both in solution and in the solid state. The fluorescence quantum yields (PhiFL ) in solution and in the solid state were 0.90 and 0.22, respectively, and the glum values in solution and in the solid state were +2.2*10 3 and +7.0*10-3 , respectively. This is one of the highest solid-state CPL glum values yet reported. The high PhiFL and glum values were due to the rigidity, as well as to the fact that (R,R,R,R,R,R,R)-3 was a non-planar molecule. Moreover, (R,R,R,R,R,R,R)-3 was highly stable both chemically and stereochemically. PMID- 28557001 TI - Assessment of in vitro inhibitory activity of hydrogen peroxide on the growth of Malassezia pachydermatis and to compare its efficacy with commercial ear cleaners. AB - Otitis caused by Malassezia pachydermatis is generally a common and recurrent disease in canine clinical pathology. The increased incidence of fungal resistant to antifungal in both humans and pets is a cause for concern and is associated with the indiscriminate use of antifungals. Finding the most effective disinfectants and antifungals has become essential. To evaluate the in vitro inhibitory activity of hydrogen peroxide on the growth of M. pachydermatis and compare its efficacy with commercial ear cleaners. The test for sensitivity to antimicrobials was carried out following the indications of the CLSI document M44 A2. The comparative results demonstrated that hydrogen peroxide 1.5% showed excellent results for growth inhibition of M. pachydermatis, followed by Epiotic(r) and MalAcetic(r) , the lowest result was for Otoclean(r) . PMID- 28557000 TI - Clinical Trials in Veterinary Medicine: A New Era Brings New Challenges. AB - Randomized clinical trials (RCTs) are among the most rigorous ways to determine the causal relationship between an intervention and important clinical outcome. Their use in veterinary medicine has become increasingly common, and as is often the case, with progress comes new challenges. Randomized clinical trials yield important answers, but results from these studies can be unhelpful or even misleading unless the study design and reporting are carried out with care. Herein, we offer some perspective on several emerging challenges associated with RCTs, including use of composite endpoints, the reporting of different forms of risk, analysis in the presence of missing data, and issues of reporting and safety assessment. These topics are explored in the context of previously reported veterinary internal medicine studies as well as through illustrative examples with hypothetical data sets. Moreover, many insights germane to RCTs in veterinary internal medicine can be drawn from the wealth of experience with RCTs in the human medical field. A better understanding of the issues presented here can help improve the design, interpretation, and reporting of veterinary RCTs. PMID- 28557003 TI - Exchanging narratives-A qualitative study of peer support among surgical lung cancer patients. AB - AIM AND OBJECTIVE: The aim of this study was to examine how hospitalised, surgical lung cancer patients experience talking to a former patient, and how the former patient experiences the role as supportive. BACKGROUND: During hospitalisation, patients often create a community in which they can engage with fellow patients. The exchange of experiences with others in a similar situation might increase opportunities for support and complement nursing care, but there is a need for more evidence and understanding on the topic. DESIGN: The methodological framework is based on the French philosopher Paul Ricoeur's text interpretation theory. Qualitative interviews were conducted with nine patients, including a peer informant, using a narrative structure. The analysis was conducted on three levels: (i) naive reading, (ii) structural analysis and (iii) critical interpretation . RESULTS: Four themes were developed from the analysis of the interviews: Exchanging emotional thoughts is easier with a peer; Talking to a peer reduces loneliness; Being ambiguous about a relationship with fellow patients; and Being the main person in the conversation with a peer. Sharing stories about having similar symptoms and undergoing similar journeys predominated, and the key feature of the contact between patients was the commonality of their stories. CRITICAL INTERPRETATION AND CONCLUSION: Telling one's story to a former patient, and thereby creating a joint, common story, is the essence of this study. The support received in this process can be empowering because knowledge of the illness experience is shared and increased. This can help create new coping strategies. The contact with a former patient offered a way to confirm one's thoughts and to find a way out of the illness perspective, by seeing how the former patient had recovered. RELEVANCE TO CLINICAL PRACTICE: The nursing field faces challenges in the relational aspect of caring because of ever greater efficient and shortened hospital stays; therefore, the peer support concept is becoming increasingly relevant. Patient peers offer each other their own perspectives, and it is important to raise awareness of the value of this and incorporate it into patient stays in hospital. PMID- 28557002 TI - Mammalian target of rapamycin complex 1 signalling is essential for germinal centre reaction. AB - The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that has been shown to be essential for the differentiation and function of various immune cells. Earlier in vitro studies showed that mTOR signalling regulates B-cell biology by supporting their activation and proliferation. However, how mTOR signalling temporally regulates in vivo germinal centre B (GCB) cell development and differentiation into short-lived plasma cells, long-lived plasma cells and memory cells is still not well understood. In this study, we used a combined conditional/inducible knock-out system to investigate the temporal regulation of mTOR complex 1 (mTORC1) in the GCB cell response to acute lymphocytic choriomeningitis virus infection by deleting Raptor, a main component of mTORC1, specifically in B cells in pre- and late GC phase. Early Raptor deficiency strongly inhibited GCB cell proliferation and differentiation and plasma cell differentiation. Nevertheless, late GC Raptor deficiency caused only decreases in the size of memory B cells and long-lived plasma cells through poor maintenance of GCB cells, but it did not change their differentiation. Collectively, our data revealed that mTORC1 signalling supports GCB cell responses at both early and late GC phases during viral infection but does not regulate GCB cell differentiation into memory B cells and plasma cells at the late GC stage. PMID- 28557004 TI - Identification of beta-chain of Fo F1 -ATPase in apoptotic cell population induced by Microplitis bicoloratus bracovirus and its role in the development of Spodoptera litura. AB - Two physiological changes of Spodoptera litura parasitized by Microplitis bicoloratus are hemocyte-apoptosis and retarded immature development. beta-Chain of Fo F1 -ATPase was found from a S. litura transcriptome. It belongs to a conserved P-loop NTPase superfamily, descending from a common ancestor of Lepidopteran clade. However, the characterization of beta-chain of ATPase in apoptotic cells and its involvement in development remain unknown. Here, the ectopic expression and endogenous Fo F1 -ATPase beta-chain occurred on S. litura cell membrane: in vivo, at the late stage of apoptotic hemocyte, endogenous Fo F1 -ATPase beta-chain was stably expressed during M. bicoloratus larva development from 4 to 7 days post-parasitization; in vitro, at an early stage of pre apoptotic Spli221 cells by infecting with M. bicoloratus bracovirus particles, the proteins were speedily recover expression. Furthermore, endogenous Fo F1 ATPase beta-chain was localized on the apoptotic cell membrane. RNA interference (RNAi) of Fo F1 -ATPase beta-chain led to significantly decreased head capsule width. This suggested that Fo F1 -ATPase beta-chain positively regulated the development of S. litura. The RNAi effect on the head capsule width was enhanced with parasitism. Our research found that Fo F1 -ATPase beta-chain was expressed and localized on the cell membrane in the apoptotic cells, and involved in the development of S. litura. PMID- 28557007 TI - Simultaneous determination of ginsenoside Rb1, ginsenoside Rg1, paeoniflorin, albiflorin and oxypaeoniflorin in rat plasma by liquid chromatography-tandem mass spectrometry: Application to a pharmacokinetic study of wen-Yang-Huo-Xue soft capsule. AB - A simple and sensitive HPLC-MS/MS method was developed and fully validated for simultaneous determination of ginsenoside Rb1, ginsenoside Rg1, paeoniflorin, albiflorin and oxypaeoniflorin in rat plasma. Plasma samples were pretreated with protein precipitation using acetonitrile. The chromatographic separation was carried out on a C18 column with a gradient mobile phase consisting of acetonitrile and water (containing 0.1% formic acid). All analytes and digoxin (internal stand, IS) were quantitated through electrospray ionization in negative ion multiple reaction monitoring mode. All calibration curves exhibited good linearity (r > 0.9960) over a wide concentration range for all components. The intra-day and inter-day precisions (RSD) at three different levels were all <12.0% and the accuracies (RE) ranging from -6.1 to 6.2%. The extraction recoveries of the five compounds ranged from 89.2 to 97.1%. The validated method was successfully applied in a comparative pharmacokinetic study of Wen-Yang-Huo Xue soft capsule (WYHXSC) in rats. Compared with single pure component, the exposure of the investigated components, except for oxypaeoniflorin, increased after oral administration of WYHXSC in rats, which suggested a synergistic effects between the herbs in the WYHXSC preparations. PMID- 28557006 TI - Neutral processes forming large clones during colonization of new areas. AB - In species reproducing both sexually and asexually clones are often more common in recently established populations. Earlier studies have suggested that this pattern arises due to natural selection favouring generally or locally successful genotypes in new environments. Alternatively, as we show here, this pattern may result from neutral processes during species' range expansions. We model a dioecious species expanding into a new area in which all individuals are capable of both sexual and asexual reproduction, and all individuals have equal survival rates and dispersal distances. Even under conditions that favour sexual recruitment in the long run, colonization starts with an asexual wave. After colonization is completed, a sexual wave erodes clonal dominance. If individuals reproduce more than one season, and with only local dispersal, a few large clones typically dominate for thousands of reproductive seasons. Adding occasional long distance dispersal, more dominant clones emerge, but they persist for a shorter period of time. The general mechanism involved is simple: edge effects at the expansion front favour asexual (uniparental) recruitment where potential mates are rare. Specifically, our model shows that neutral processes (with respect to genotype fitness) during the population expansion, such as random dispersal and demographic stochasticity, produce genotype patterns that differ from the patterns arising in a selection model. The comparison with empirical data from a post-glacially established seaweed species (Fucus radicans) shows that in this case, a neutral mechanism is strongly supported. PMID- 28557008 TI - Influence of TNF-alpha inhibitors and fumaric acid esters on male fertility in psoriasis patients. AB - OBJECTIVE: Is there any influence of a therapy with TNF-alpha inhibitors or fumaric acid esters and of disease activity status on male fertility and sperm quality in patients with psoriasis? METHODS: In this monocentric, open-label, prospective study, semen samples were collected from patients receiving either TNF-alpha inhibitors or fumaric acid esters for moderate-to-severe plaque psoriasis. Semen was analysed at baseline before onset of the systemic therapy and monitored every 3 months under therapy. Sperm parameters were assessed according to the current WHO definitions. RESULTS: In total, 101 semen specimens from 27 patients were obtained. Mean Psoriasis Area and Severity Index (PASI) score at baseline was 11.05. Only 14.8% of patients showed a normozoospermia without any other abnormal seminal values. 85.2% of patients had at least one sperm/seminal abnormality, including two patients showing an azoospermia. Interestingly, 48.1% showed sperm parameters indicative of genital tract inflammation. Therapy with TNF-alpha inhibitors or fumaric acid esters did not have any negative effects on relevant sperm parameters such as mean total sperm number, sperm concentration, total and progressive motility. No major gonadal dysfunction was observed in any patient. CONCLUSION: At baseline, many patients with psoriasis showed abnormal semen/sperm parameters and remarkably elevated leukocytes and values of seminal polymorphonuclear elastase, indicating a genital tract inflammation. Thus, genital tract inflammation may represent an important comorbidity of psoriasis, little attention paid to so far. Regarding treatment with TNF-alpha inhibitors or fumaric acid esters, no major negative (side-) effects on sperm quality were observed. PMID- 28557009 TI - Drug concentration and antidrug antibodies in patients with psoriasis treated with adalimumab or etanercept. PMID- 28557005 TI - Sarcopenia in Alcoholic Liver Disease: Clinical and Molecular Advances. AB - Despite advances in treatment of alcohol use disorders that focus on increasing abstinence and reducing recidivism, alcoholic liver disease (ALD) is projected to be the major cause of cirrhosis and its complications. Malnutrition is recognized as the most frequent complication in ALD, and despite the high clinical significance, there are no effective therapies to reverse malnutrition in ALD. Malnutrition is a relatively imprecise term, and sarcopenia or skeletal muscle loss, the major component of malnutrition, is primarily responsible for the adverse clinical consequences in patients with liver disease. It is, therefore, critical to define the specific abnormality (sarcopenia) rather than malnutrition in ALD, so that therapies targeting sarcopenia can be developed. Skeletal muscle mass is maintained by a balance between protein synthesis and proteolysis. Both direct effects of ethanol (EtOH) and its metabolites on the skeletal muscle and the consequences of liver disease result in disturbed proteostasis (protein homeostasis) and consequent sarcopenia. Once cirrhosis develops in patients with ALD, abstinence is unlikely to be effective in completely reversing sarcopenia, as other contributors including hyperammonemia, hormonal, and cytokine abnormalities aggravate sarcopenia and maintain a state of anabolic resistance initiated by EtOH. Cirrhosis is also a state of accelerated starvation, with increased gluconeogenesis that requires amino acid diversion from signaling and substrate functions. Novel therapeutic options are being recognized that are likely to supplant the current "deficiency replacement" approach and instead focus on specific molecular perturbations, given the increasing availability of small molecules that can target specific signaling components. Myostatin antagonists, leucine supplementation, and mitochondrial protective agents are currently in various stages of evaluation in preclinical studies to prevent and reverse sarcopenia, in cirrhosis in general, and ALD, specifically. Translation of these data to human studies and clinical application requires priority for allocation of resources. PMID- 28557010 TI - Rapid amyloid-beta oligomer and protofibril accumulation in traumatic brain injury. AB - Deposition of amyloid-beta (Abeta) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Abeta deposition including monomeric Abeta40, Abeta42 and Abeta oligomers/protofibrils, Abeta species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Abeta40 and Abeta42, as well as Abeta oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 +/- 19 years) due to life threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Abeta40 and Abeta42 were not elevated by TBI. The levels of Abeta oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE epsilon3/4; n = 4) had increased levels of Abeta oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Abeta42 (P < 0.05) compared to APOE epsilon3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Abeta aggregates (commonly referred to as Abeta plaques) in three TBI patients, all of whom were APOE epsilon3/4 carriers. We conclude that soluble intermediary Abeta aggregates form rapidly after TBI, especially among APOE epsilon3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI. PMID- 28557011 TI - Costs and savings of parenting interventions: results of a systematic review. AB - BACKGROUND: This systematic review of economic evaluations of universal preventative or targeted treatment parenting interventions that aim to enhance parent-infant interaction is primarily intended to inform decision makers who have to make difficult spending decisions, especially at a time of reduced spending allocations. A synthesis of available costs and savings about parenting interventions that set out to enhance parent-infant interaction is presented. This topic is important specifically in view of the UK Governments' emphasis on the equalities agenda and the early years. The benefits of positive early life experiences, which include good parent-infant interaction, are far reaching and may be positively correlated with improved educational, health and well-being outcomes and reduced criminality. METHODS: A literature search was undertaken using on-line indexing databases between 2004 and 2014 that included the search terms 'parent', 'infant', 'interaction', 'cost benefit analysis' and their synonyms. RESULTS: Despite existing economic studies generally focusing upon targeted short-run outcomes, significant savings were observed in the included studies. Parenting interventions could save the health service around L2.5k per family over 25 years and could save the criminal justice system over L145k per person over the life course. In light of the escalating costs of remedial services, these potential savings may provide the UK and other governments with a robust incentive to invest in early years parenting interventions. CONCLUSIONS: Parenting interventions can be economically efficient and return savings on investment. Moreover, and one might argue as a moral imperative of democratic societies, population health can be improved and health inequalities reduced. An important debate is needed about early years policy, to include acknowledgement of the differences between UK and international healthcare systems and the potential savings from the synergistic and spin-off effects of early years interventions to inform decision-making to fund and implement appropriate action. PMID- 28557012 TI - Four-dimensional ultrasound guidance for pelvic floor Botulinum toxin-A injection in chronic pelvic pain: a novel technique. AB - OBJECTIVE: Botulinum toxin-A (BoNT-A) is used in the treatment of pelvic floor muscle overactivity associated with chronic pelvic pain (CPP) when conservative methods such as physiotherapy are not effective or appropriate. Traditional injection techniques require finger-guided palpation of pelvic floor muscles with concurrent insertion of the needle. The aim of this study was to describe a novel technique for the injection of BoNT-A into the pelvic floor musculature using four-dimensional ultrasound (4D-US) guidance. METHODS: Thirty-one BoNT-A injections were performed using the new technique between October 2013 and January 2016, on women scheduled to have BoNT-A injection for pelvic floor muscle overactivity and CPP. The pelvic floor was assessed by 4D-US. A test injection of saline was performed to confirm location of the needle, then BoNT-A was injected into the muscle under ultrasound guidance, using 4D-US to confirm that the fluid expanded and tracked along muscle fibers. RESULTS: The saline test confirmed correct location of the needle following a median of 1 (range, 1-3) attempt at needle placement. In all 31 instances, satisfactory injection of BoNT-A, with 4D US confirmation of fluid expansion within the muscle body, was performed. CONCLUSIONS: Injection of BoNT-A under 4D-US guidance is feasible and allows accurate placement into the target muscle in women with pelvic floor muscle overactivity associated with CPP. This technique may provide a safer alternative to finger-guided methods, owing to a lower likelihood of operator needle-stick injury. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28557013 TI - Unravelling the complexity and redundancy of carbon catabolic repression in Pseudomonas fluorescens SBW25. AB - The two-component system CbrAB is the principal regulator for cellular metabolic balance in Pseudomonas fluorescens SBW25 and is necessary for growth on many substrates including xylose. To understand the regulatory linkage between CbrAB and genes for xylose utilization (xut), we performed transposon mutagenesis of DeltacbrB to select for Xut+ suppressors. This led to identification of crc and hfq. Subsequent genetic and biochemical analysis showed that Crc and Hfq are key mediators of succinate-provoked carbon catabolite repression (CCR). Specifically, Crc/Hfq sequentially bind to mRNAs of both the transcriptional activator and structural genes involved in xylose catabolism. However, in the absence of succinate, repression is relieved through competitive binding by two ncRNAs, CrcY and CrcZ, whose expression is activated by CbrAB. These findings provoke a model for CCR in which it is assumed that crc and hfq are functionally complementary, whereas crcY and crcZ are genetically redundant. Inactivation of either crcY or crcZ produced no effects on bacterial fitness in laboratory media, however, results of mathematical modelling predict that the co-existence of crcY and crcZ requires separate functional identity. Finally, we provide empirical evidence that CCR is advantageous in nutrient-complex environments where preferred carbon sources are present at high concentrations but fluctuate in their availability. PMID- 28557014 TI - A narrative evaluation of a community-based nurse navigation role in an urban at risk community. AB - AIMS: To explore community members' stories of their experiences with a Nurse Navigator programme serving an urban neighbourhood and primary care practice to address persistent health and social barriers adversely affecting health equity and well-being. BACKGROUND: In response to striking health and social inequalities existing across neighbourhoods in a large southern city in Ontario, Canada, a pilot programme was designed to improve health and social outcomes in a specific "at-risk" neighbourhood. The programme includes nurse-led navigation support for individuals and families and networking to facilitate improved service integration at a systems level. DESIGN: A narrative inquiry approach based on the Three-Dimensional Narrative Inquiry Space method, as described by Clandinin & Connelly (Narrative inquiry: Experience and story in qualitative research, ). METHODS: A thematic analysis of nine community members' life stories from narrative semi-structured interviews (January-June 2014) in conjunction with field notes, observations and documents. Participants' life stories created a common narrative of the experience of navigation in a community setting. FINDINGS: There were four main themes: "opening the door"; "more than just a conversation"; "making connections"; and "on a new trajectory". Participants valued the development of a therapeutic relationship, which optimized social inclusion, barrier reduction and connectivity to supportive health and social services. CONCLUSIONS: The relational process of navigation as an antecedent to barrier reduction has direct implications for programme development, continuing education of navigators and quality improvement of existing navigation services. Study findings have implications for development of navigation competencies for nurses working with priority populations to address health inequities. PMID- 28557015 TI - Palestinian community perceptions of do-not-resuscitation order for terminally Ill patients: A qualitative study. AB - AIM AND OBJECTIVES: To illustrate the Palestinian community's views, opinions and stances about the concept of do-not-resuscitate for terminally ill patients. BACKGROUND: Do-not-resuscitate orders are practised in many countries worldwide, but there is no consensus on their practice in the Middle East. Do-not resuscitate orders may be applied for terminally ill paediatric patients. Some studies have been conducted describing people's experiences with these do-not resuscitate orders. However, few studies have considered community perspectives on do-not-resuscitate orders for terminally ill patients in Palestine. DESIGN: A descriptive-qualitative design was adopted. METHODS: A purposive sample of 24 participants was interviewed, with consideration of demographical characteristics such as age, gender, education and place of residency. The participants were recruited over a period of 6 months. Individual semistructured interviews were utilised. These interviews were transcribed and analysed using thematic analysis. FINDINGS: Significantly, the majority of the participants did not know the meaning of do-not-resuscitate and thought that removal of life-sustaining devices and do-not-resuscitate were the same concept. Most of the interviewees adopted stances against do-not-resuscitate orders. Several factors were suggested to influence the decision of accepting or rejecting the do-not-resuscitate order. The majority of the participants mentioned religion as a major factor in forming their viewpoints. The participants expressed different views regarding issuing a law regarding do-not-resuscitate orders. CONCLUSION: Our findings provide a unique understanding that there is a general misunderstanding among our participants regarding the do-not-resuscitate order. Further research with policymakers and stakeholders is still required. PMID- 28557016 TI - Recurrence patterns of retroperitoneal leiomyosarcoma and impact of salvage surgery. AB - BACKGROUND: Optimal treatment strategies for retroperitoneal leiomyosarcoma (RPLMS), particularly recurrent disease, are unknown. METHODS: We searched the tumor registry at The University of Texas MD Anderson Cancer Center (MDACC) to identify patients with RPLMS treated between 1994 and 2013. RESULTS: We identified 172 patients with a diagnosis of a RPLMS. Among the 85 patients who underwent complete resection included in the survival analysis, the median overall survival (OS) was 8.3 years (95% confidence interval [CI], 5.7-12.3), 5 year local recurrence rate was 21%, and 5-year distant metastasis rate was 47%. Among 114 patients who experienced recurrence, patients who underwent salvage surgery for recurrent disease had longer OS after recurrence than patients who did not undergo salvage surgery (median survival after recurrence 5.6 vs 3.3 years, 3-year OS rates after recurrence 72.6% vs 58.1%, HR 0.402 [95%CI, 0.243 0.666]; P = 0.0004). Whether salvage surgery was performed for local or distant recurrence was not associated with OS. Patients who had a longer disease-free interval (>=12 months) had better progression-free survival after salvage surgery than those who had a shorter interval (HR, 0.437 [95%CI, 0.244-0.783]; P = 0.0055). CONCLUSIONS: We recommend that salvage surgery be considered for selected patients with local or distant recurrence of RP LMS. PMID- 28557018 TI - Tunable Ligand Effects on Ruthenium Catalyst Activity for Selectively Preparing Imines or Amides by Dehydrogenative Coupling Reactions of Alcohols and Amines. AB - Selective dehydrogenative synthesis of imines from a variety of alcohols and amines was developed by using the ruthenium complex [RuCl2 (dppea)2 ] (6 a: dppea=2-diphenylphosphino-ethylamine) in the presence of catalytic amounts of Zn(OCOCF3 )2 and KOtBu, whereas the selective dehydrogenative formation of amides from the same sources was achieved by using another ruthenium complex, [RuCl2 {(S)-dppmp}2 ] [6 d: (S)-dppmp=(S)-2-((diphenylphosphenyl)methyl)pyrrolidine], in the presence of catalytic amounts of Zn(OCOCF3 )2 and potassium bis(trimethylsilyl)amide (KHMDS). Our previously reported ruthenium complex, [Ru(OCOCF3 )2 (dppea)2 ] (8 a), was the catalyst precursor for the imine synthesis, whereas [Ru(OCOCF3 )2 {(S)-dppmp}2 ] (8 d), which was derived from the treatment of 6 d with Zn(OCOCF3 )2 and characterized by single-crystal X-ray analysis, was the pre-catalyst for the amide formation. Control experiments revealed that the zinc salt functioned as a reagent for replacing chloride anions with trifluoroacetate anions. Plausible mechanisms for both selective dehydrogenative coupling reactions are proposed based on a time-course study, Hammett plot, and deuterium-labeling experiments. PMID- 28557017 TI - Novel compounds targeting the enterohemorrhagic Escherichia coli type three secretion system reveal insights into mechanisms of secretion inhibition. AB - Anti-virulence (AV) compounds are a promising alternative to traditional antibiotics for fighting bacterial infections. The Type Three Secretion System (T3SS) is a well-studied and attractive AV target, given that it is widespread in more than 25 species of Gram-negative bacteria, including enterohemorrhagic E. coli (EHEC), and as it is essential for host colonization by many pathogens. In this work, we designed, synthesized and tested a new series of compounds that block the functionality of the T3SS of EHEC. Affinity chromatography experiments identified the primary target of the compounds as the T3SS needle pore protein EspD, which is essential for effector protein translocation into host cells. These data were supported by mechanistic studies that determined the coiled-coil domain 1 of EspD as a key compound-binding site, thereby preventing correct assembly of the T3SS complex on the cell surface. However, binding of inhibitors to EspD or deletion of EspD itself did not result in transcriptional down regulation of effector proteins. Instead, we found the compounds to exhibit dual functionality by also down-regulating transcription of the entire chromosomal locus encoding the T3SS, further demonstrating their desirability and effectiveness. PMID- 28557019 TI - Development of a validated UPLC-MS/MS method for determination of humantenmine in rat plasma and its application in pharmacokinetics and bioavailability studies. AB - Humantenmine (HMT), the most toxic compound isolated from Gelsemium elegans Benth, is a well-known active herbal compound. A rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to estimate the absolute oral bioavailability of HMT in rats. Quantification was performed by multiple reaction monitoring using electrospray ionization operated in positive ion mode with transitions of m/z 327.14 -> m/z 296.19 for HMT and m/z 323.20 -> m/z 236.23 for gelsemine (internal standard, IS). The linear range of the calibration curve was 1-256 nmol/L, with a lower limit of quantification at 1 nmol/L. The accuracy of HMT ranged from 89.39 to 107.5%, and the precision was within 12.24% (RSD). Excellent recovery and negligible matrix effect were observed. HMT remained stable during storage, preparation and analytical procedures. The pharmacokinetics of HMT in rats showed that HMT reached the concentration peak at 12.50 +/- 2.74 min with a peak concentration of 28.49 +/- 6.65 nmol/L, and the corresponding area under the concentration-time curve (AUC0-t ) was 1142.42 +/- 202.92 nmol/L min after 200 MUg/kg HMT was orally administered to rats. The AUC0-t of HMT given at 20 MUg/kg by tail vein administration was 1518.46 +/- 192.24 nmol/L min. The calculated absolute bioavailability of HMT was 7.66%. PMID- 28557021 TI - Effects of high amylose corn starch and microbial transglutaminase on the textural and microstructural properties of wheat flour composite gels at high temperatures. AB - : Textural and microstructural properties of composite gels (CGs), along with wheat flour and high amylose corn starch (Hylon VII) mixed with microbial transglutaminase (MTGase) at different levels and temperatures were investigated. The results showed by increasing Hylon starch content, the firmness increased and adhesiveness decreased. Indeed, high level of amylose and cross-linking formed by MTGase enhanced the gel elasticity and reduced adhesiveness. Moreover, MTGase had more effect on the firmness and provided more cross-linked intermolecular gel structures at high temperatures. By adding MTGase to the CG, the lowest peak viscosity and final viscosity were found for 15% of Hylon starch. As the more Hylon content in the CG, the more water solubility index was particularly obtained at high temperature. Scanning electron microscopy (SEM) results showed that MTGase and Hylon starch addition enhanced the structure. The differences in SEM of CG were reflected the pasting properties of the gels. Consequently, MTGase treated gels can withstand high temperature as well as maintain the overall structure of the samples gels. Therefore, the increment of Hylon to the CG gels supplied tighter, stronger, and denser protein network which were formed by MTGase cross-linking within the network of starch and proteins. PRACTICAL APPLICATIONS: Although, transglutaminase was practically used in the production of noodles and pasta in Japan, but there is little academic and industrial knowledge concerning its utilization in the pasta or noodles. Moreover, long shelf-life noodle/pasta products have become popular in the Japanese market and in the emergency conditions like as floods or earthquake, but they can be stored for at least 5 months by applying heat treatment at 95C. Here, high amylose corn starch as a resistant starch, wheat flour, and microbial transglutaminase (MTGase) were selected as the main components in the composite gel (CG) systems to elucidate the effects of MTGase and Hylon on the texture, microstructure, and pasting behavior of CGs at high temperatures to produce long-life noodle/pasta products (about 2 years) through retort processing. PMID- 28557020 TI - First-time fathers' postnatal experiences and support needs: A descriptive qualitative study. AB - AIM: To explore first-time fathers' postnatal experiences and support needs in the early postpartum period. BACKGROUND: The postnatal period is a stressful transition period for new fathers. It is imperative to understand their needs and experiences to provide appropriate support for them. The majority of previous studies were based in Western countries and explored fathers' needs during pregnancy and childbirth, with few studies conducted in the postnatal period. In Singapore, a multiracial society with differing paternal cultural values from its Western counterparts, there is considerable need to examine the experiences and needs of first-time fathers. DESIGN: A descriptive qualitative design was used. METHODS: Data were collected from November 2015-January 2016. Fifteen first-time fathers were recruited from two postnatal wards of a public hospital, using a purposive sampling method. A semi-structured interview guide was used to conduct face-to-face interviews. A thematic analysis was conducted and ethics approval was sought for this study. RESULTS: Four overarching themes and seventeen subthemes were generated. The four overarching themes were: (1) No sense of reality to sense of responsibility; (2) Unprepared and challenged; (3) Support: needs, sources, experience and attitude; and (4) Future help for fathers. CONCLUSION: Fathers undergo a transition phase where they have unmet support needs during the early postnatal period. Understanding and addressing these needs may facilitate smooth transition to fatherhood. This study's findings can be used to involve fathers and design future supportive educational programs to promote positive parenting experiences and family dynamics. PMID- 28557022 TI - Missing binary outcomes under covariate-dependent missingness in cluster randomised trials. AB - Missing outcomes are a commonly occurring problem for cluster randomised trials, which can lead to biased and inefficient inference if ignored or handled inappropriately. Two approaches for analysing such trials are cluster-level analysis and individual-level analysis. In this study, we assessed the performance of unadjusted cluster-level analysis, baseline covariate-adjusted cluster-level analysis, random effects logistic regression and generalised estimating equations when binary outcomes are missing under a baseline covariate dependent missingness mechanism. Missing outcomes were handled using complete records analysis and multilevel multiple imputation. We analytically show that cluster-level analyses for estimating risk ratio using complete records are valid if the true data generating model has log link and the intervention groups have the same missingness mechanism and the same covariate effect in the outcome model. We performed a simulation study considering four different scenarios, depending on whether the missingness mechanisms are the same or different between the intervention groups and whether there is an interaction between intervention group and baseline covariate in the outcome model. On the basis of the simulation study and analytical results, we give guidance on the conditions under which each approach is valid. (c) 2017 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID- 28557023 TI - Muscular workload of veterinary students during simulated open and laparoscopic surgery: A pilot study. AB - OBJECTIVE: To compare upper extremity muscle activity and workload between simulated open surgery, multiple port laparoscopic surgery (MLS), and single incision laparoscopic surgery (SLS) techniques in veterinary students. STUDY DESIGN: Pilot study. POPULATION: Veterinary students (n = 10) from years 1 to 4. METHODS: Bipolar skin surface electrodes were fixed bilaterally to the forearm flexor, forearm extensor, biceps brachii, triceps brachii, and upper trapezius muscles. Electromyography data were recorded during one repetition of 2 simulated surgical exercises via open surgery, MLS, and SLS. Participants completed a validated workload survey after each simulated surgical technique. Muscle activity and perceived workload were compared between surgical techniques with 1 way ANOVAs and Fisher's LSD post hoc tests. RESULTS: Muscle activity during peg transfer was higher with MLS and SLS compared to simulated open surgery in the right and left forearm extensors (both P < .0001), right (P < .0001) and left biceps (P = .0005), right triceps (P = .0004), and right upper trapezius muscles (P = .0211). Similar results were found for the right and left forearm extensors (both P < .0001), right (P = .0381) and left (P = .0147) forearm flexors, right biceps (P < .0001), and right triceps (P = .0004) during a simulated suture task. Participants found laparoscopic techniques more mentally demanding, physically demanding, complex, and stressful compared to a simulated open surgical technique. CONCLUSION: In veterinary students, average muscle activity and perceived workload were highest using MLS and SLS compared to an open surgical technique when performing simulated surgical exercises in a laparoscopic box trainer. PMID- 28557025 TI - Birth weight and childhood size in a national sample of 6- to 11-year-old children. AB - The extent to which body size (stature, weight, or weight-for-stature) in later childhood is related to birth weight for normal-weight, full-term infants was explored using data from a national sample of U.S. children examined in Cycle II of the National Health Examination Survey, 1963-65. Standardized measurements of stature and weight from 4,689 white singletons ages 6-11 years were linked with birth certificate information. There were small but consistent positive associations of attained stature and weight with birth weight. The Body Mass Index (BMI), a measure of weight in proportion to stature, was also positively related to birth weight, although not as consistently, suggesting that the greater attained weight of higher birth weight children may be related to increased adiposity as well as to greater stature. However, simulations of the effect of an across-the-board increase in birth weight by 100 g or 200 g showed a negligible expected increase in the number of children with high BMI values. These findings indicate that birth weight is directly or indirectly a factor related to growth in childhood, but that upward shifts in the distribution of birth weight would have little effect on the prevalence of childhood obesity. (c) 1995 Wiley-Liss, Inc This article is a US Government work and, as such, is in the public domain in the United States of America. . PMID- 28557024 TI - A DFT Study on the Stabilization of the B=B Triple Bond in a Metallaborocycle: Contrasting Electronic Structures of Boron and Carbon Analogues. AB - The electronic structure of (eta5 -Cp)2 Zr(NH2 -BB-NH2 ) (3 b) suggests that it could be a candidate for having a boron-boron triple bond in the cyclic system; however, computational studies shows that 3 b is a very high energy isomer on its potential energy surface. Replacement of amines with tricoordinate nucleophilic boron groups (eta5 -Cp)2 Zr[B(PH3 )2 -BB-B(PH3 )2 ] (3 c) reduces the relative energy dramatically. The B=B triple bond arises through the donation of two electrons from the metal fragment, ZrCp2 , to the in-plane pi-bonding orbital of the central B-B unit. Strong sigma-donating and chelating bis-phosphine ligands (Me2 P(CH2 )n PMe2 ), which stabilize donor-acceptor bonding interaction in gem diborene L2 B-BBr2 (10), would be a good choice along the synthetic path towards 3 d, (eta5 -Cp)2 Zr[B4 (Me2 P(CH2 )3 PMe2 )2 ]. A comparison of the energetics of the reaction leading to a cyclic boryne system (3 d), with the linear boryne isomer [(B2 NHCPh )2 ] shows that the angle strain from cyclization is compensated by stabilization from the metal. PMID- 28557026 TI - Growth of a national sample of Israeli children: Are local standards needed? AB - Statures and weights of two national samples of Jewish children, from 9-15 months and 7-10 years of age, and their birth weights were studied, based on personal records (n = 7,532 and 4,638 respectively). Comparison with the National Center for Health Statistics (NCHS) median indicated that the median birth weight of the population is similar to the reference population. At both ages, males and females were slightly lighter and shorter than the reference data. Although the differences are small, <25% of the respective standard deviations for weight and stature, they are statistically significant due to the large sample sizes. The magnitude of the difference, however, has no biological meaningfulness. Jewish children of Asian and African origin have lower weights and statures at 8.75 years of age than Jewish children of European or American origin. The maximal differences between the ethnic groups are 1.4 kg and 2.5 cm in males after adjusting for maternal education, age, and birth order. The similar growth of Israeli children relative to NCHS reference data suggests that their growth is relatively unconstrained. The NCHS data are thus the reference of choice for the Israeli Jewish population. The small difference between ethnic groups, the continuously changing ethnic composition, and the homogenization of the population over time justify use of one standard for the heterogeneous Israeli population. Worldwide migration in the 1990s, considerable immigration to Israel, and heterogeneous gene pools in most countries make the construction of local standards irrelevant. (c) 1995 Wiley-Liss, Inc. PMID- 28557027 TI - Population differences in cardiovascular reactivity to the cold pressor test. AB - The interaction of race and climatic adaptation on patterns of cardiovascular reactivity among young adult males was examined. Malay and Chinese subjects living in a tropical climate in the Orient and Caucasians living in a sub tropical climate in North America were investigated. The cold pressor test with hand immersion in cold water was used as the stressor. Systolic and diastolic blood pressures, cardiac frequency, cardiac output, and stroke volume were measured. The results provided limited evidence for absence of differences in cardiac reactivity among racial groups and for greater vascular reactivity in the Caucasians. Cold immersion also elicited differential responses which could be partially attributed to differences in acclimatizations status. (c) 1995 Wiley Liss, Inc. PMID- 28557028 TI - Secular trend in the age at menarche in Haiti. AB - Trends in age at menarche of 10,563 pregnant Haitian women enrolled in a longitudinal study of maternal mortality are examined. Mean recalled age at menarche for adult women in the sample was 15.37 years. However, there was a clear decline in mean menarcheal ages from the oldest to the youngest women, with a mean rate of decline for adult women of 0.36 years per decade. Mean menarcheal age was higher in each age group of rural women than for women in the metropolitan Port-au-Prince area; the rate of decline for adult rural women (0.37 years per decade) was nonsignificantly higher than that for adult metropolitan women (0.30 years per decade). The data suggest a secular decline in age at menarche in Haiti, as well as a continuing disparity between metropolitan and rural women. A declining age at menarche has important implications for fertility and reproductive health in Haiti, and may reflect a gradual improvement in health and nutritional status. (c) 1995 Wiley-Liss, Inc. PMID- 28557029 TI - Reply. PMID- 28557030 TI - Aging of metacarpal density at midshaft and proximal end. AB - Aging of bone density of the second metacarpal at midshaft (compact bone) and the proximal end (trabecular bone) was compared in 114 men and 115 women, 30-98 years of age. The microdensitometric (MD) pattern of the bone at both sites, area (Sigma GS) and midheight (GSmid), were measured in standardized aluminun equivalents (SAE). In both sexes, Sigma GS and GSmid showed a greater deviation at the proximal end than at midshaft. There was a significant correlation between both sites for each parameter. Pattern area was significantly greater at the proximal end than at midshaft(P ? 0.01), but the relation was reversed for GSmid. At both sites, Sigma GS and GSmid decreased gradually with age in both sexes, especially after 69 years in women. Each parameter showed a significant negative linear regression with age at both sites in women and at midshaft in men. In both sexes, the slope of the regression curve of Sigma GS with age was significantly steeper at the proximal end than at midshaft. In women, the estimated rate of decline was 0.90% and 0.56% for Sigma GS, and 1.20% and 0.73% for GSmid per year at the proximal end and midshaft, respectively. The bone density loss with age may be slightly greater in trabecular than in compact bone. (c) 1995 Wiley-Liss, Inc. PMID- 28557031 TI - Lipids and apoproteins in relation to participation in organized sport activities and pubertal development in boys. AB - This study considers changes in the plasma lipid and apoprotein profiles of boys in relation to participation in organized sport activities and to testosterone (T) levels. Fifty boys, aged 9.9 +/- 0.6 years (mean +/- S.D.), participated in the study. During a 3 year follow-up, the following measurements were taken twice a year: stature, weight, and skinfolds. Blood samples for lipids and apoproteins and sex hormone levels, and information on participation in sport activities were also obtained. No relationship was found between participation in organized sport activities and high density lipoprotein cholesterol (HDL-C) or apoprotein A-I (apo A-I). The changes of the profile over time in more active boys (participation rate > 3 hr/wk) were similar to those of less active boys (participation rate < 1 hr/wk) (MANOVA, repeated measures, not significant.) Consistent relationships between sex hormones and lipids and apoproteins were restricted to T with total cholesterol (TC), HDL-C, and apo A-I, respectively. The common variance ranged from 5.8% (rT,TC ) to 18.5% (rT,HDL-C ) (P ? 0.05.) When the boys who reached advanced puberty during the follow-up period (n = 21) were studied apart from those who did not (n =29), differences were found in TC, apo A-I, and HDL-C, TC decreased from 4.6 +/- 0.65 to 4.3 +/- 0.58 mmol/l in the more advanced pubertal boys, and increased from 4.6 +/- 0.90 to 4.8 +/- 0.79 mmol/l in the others; apo A-I decreased from 185 +/- to 28.3 to 156 +/- 20.4 mg/dl and from 179 +/- 20.6 to 176 +/- 27.7 mg/dl, respectively (MANOVA, repeated measures, P ? 0.05) HDL-C was lower in advanced pubertal boys at the end of follow-up (1.4 +/- 0.33 and 1.7 +/- 0.38 mmol/l, respectivel; P ? 0.05). The lack of a relationship with regular physical activity may be due to the high levels of HDL-C and apo A-I at the begining of the study. On the other hand, the effect of the increasing T levels on HDL-C and apo A-I may have overwhelmed the presumed effect of regular physical activitiy. (c) 1995 Wiley-Liss, Inc. PMID- 28557032 TI - Impact of seasonal variation in food availability and disease stress on the health status of nomadic Turkana children: A longitudinal analysis of morbidity, immunity, and nutritional status. AB - The possible influence of seasonal variations in rainfall, resource availability, and morbidity on immune function and nutritional status was examined in a longitudinal study of 54 nomadic Turkana children, 6 months to 10 years of age. The highly seasonal nature of rainfall in the arid semidesert environment of the Turkana District, northwestern Kenya, was associated with varying levels of animal milk production and meat and blood consumption. Despite significant seasonal variation in rainfall and food availability, the nutritional status of Turkana children, assessed through various anthropometric indicators, showed only moderate, if any, decline in the dry season. Rather, the data indicated that Turkana Children suffer from chronic mild-to-moderate malnutrition. In addition, analyses of cellular immunocompetence of the children, recognized to be a functional index of nutritional status, revealed extremely high levels of immunosuppression Year-round. Significant monthly variation in the levels of acute respiratory and gastrointestinal infections among children were found, although averages across seasons were not significantly different and did not correspond with fluctuations in rainfall or resources availability. Instead, periodic spikes in the prevalence of morbidity occurred against an already high level of infectious endemicity. The results indicate that food availability is not likely to be the sole determinant of nutritional status and that infection may be an important contribtor to the high levels of nutritional and immunological stress among nomadic Turkana Children. (c) 1995 Wiley-Liss, Inc. PMID- 28557033 TI - Letters: To the editor. PMID- 28557034 TI - Hypovitaminosis A: A model for sudden infant death syndrome. AB - The cause of sudden infant death syndrome (SIDS) is unknown. It is the leading cause of death from age one month to one year in North America. The purpose of this essay is to generate some testable hypotheses as to the cause of SIDS by drawing attention to distinct epidemiological parallels between SIDS and a newly recognized form of enamel hypoplasia, termed localized hypoplasia of the primary canine tooth (LHPC), which has been attributed to vitamin A deficiency. LHPC and SIDS share a common epidemiological profile: winter seasonality, occurrence at 3 5 months, and affecting apparently healthy children, but with increased incidence in socio economically disadvantaged families particularly racial/ethnic minorities (except Hispanics who show a reduced incidence), previously compromised infant health, less prenatal counselling, and less breastfeeding. Vitamin A has pervasive functions throughout the body including bone growth and maintenance of epithelial membranes. It is proposed that SIDS is due in part to hypovitaminosis A through one of several mechanisms: imbalanced basicranial growth producing mechanical constriction on the respiratory nerves passing through the jugular foramen; or through compromised myelination and/or maturation of the brain stem and cranial nerves involved in respiration; or through pharyngeal collapse due to mandibular undergrowth; or dysfunction of hypoxia sensitive epithelial cells in the trachea. It is recommended that assay of hypoxia-sensitive epithelial cells in the trachea. It is recommended that assay of the retinyl ester content of the liver of SIDS victims be included in autopsy protocol. (c) 1995 Wiley-Liss, Inc. PMID- 28557035 TI - Conservative scoring and exclusion of the phenomenon of interest in linear enamel hypoplasia studies. AB - Conservative criteria are generally employed to select only "sufficiently large" linear enamel defects to be scored as linear enamel hypopasias (LEHs), a practice that excludes enamel defects below arbitrarily selected size thresholds. A question arising is, are such practices likely to exclude small, yet authentic(i.e., physiological stress induced) LEH? The permanent maxillary and mandibular first and second incisors, canines, and first premolars on dental casts (n = 532) form a contemporary Canadian farming commune were scored for LEH, with linear defects being categorized by both breadth and width to yeild the scores A (smallest), B, C, and D (largest). Relative frequencies were calculated as the percent prevalence of each score per tooth divided by the highest percent prevalence exhibited by any tooth in the same dental arch. The intertooth patters of the relative frequencies were tested for concordance. Secondly, assuming that different researchers employ different scoring criteria, tests for concordance of mean n of LEHs/tooth were conducted using data from four different reports as a second test for intertooth concordance of various-sized defects. Substantial concordance was obseved between A, B, C, and D (Kandall's coefficient of concordance, W = .65, P <.005) and in the interstudy comparison (W = .67, P <.01). Because it is unlikely that defects of varying sizes would have similar intertooth distributions if they did not have similar etiologies, it may be inferred that all of the defects observed, even the very small defects, A, are variants of the same phenomenon, LEH. (c) 1995 Wiley-Liss, Inc. PMID- 28557036 TI - Elizabeth Smithgall Watts-Parrish (1941-1994). PMID- 28557037 TI - Seasonality and child morbidity in rural Bangladesh. AB - This study examined seasonal variation in the impact of infection on child nutritional status. Maternal reports of child illness were examined in relation to monthly changes in weight, weight-for-age, and midupper arm circumference (MUAC) of children aged 2-6 years of age. The greatest deterioration in short term nutritional status was associated with episodes of fever, followed by episodes of diarrhea and respiratory infections. The monsoon season was associated with the highest prevalence of fever, respiratory infection, and diarrheal diseases. Irrespective of the prevalence of infection, the relationship between infection and nutritional status varied across seasons. Weight loss and decreases in MUAC associated with infection in the dry and monsoon seasons were statistically significantly greater than those in the winter months. The observed seasonal variation in morbidity is an important consideration for studies of infection and malnutrition in children. (c) 1995 Wiley-Liss, Inc. PMID- 28557038 TI - Prognostic performance of several anthropometric indicators for predicting low and insufficient birth weight. AB - Weight gain and several anthropometric indicators were studied in a sample of 181 pregnant women. The period considered ranged from the 12th to the 34th weeks of gestation. Changes in all of the attributes were calculated and related to a birth weight below 3,000 g. Optimal cut-off points for each indicator were defined as those which minimize a loss functioin which depends on the rates of false positive and false negatives. The independent predictive capacity of each attribute was assessed by means of sensitivity, specificity, positive and negative predictive values, relative risk, and two "measures of detectability" associated to the ROC (relative operating characteristic) curve of the attribute. A logistic regression model was fitted by searching for the best combination of indicators. The individual predictive capacities of the attributes were considerably improved when they were combined into a logistic equation. (c) 1995 Wiley-Liss, Inc. PMID- 28557039 TI - P. C. Mahalnobis's contributions to biometry. PMID- 28557040 TI - Estimates of aging and secular changes using total arm length. AB - Stature, total arm length, and subischial length were studied in a cross sectional sample of 387 working (career women) and 460 nonworking women (housewives), 20-75 years of age, from one endogamous group, the Khatris. Statural decrease due to aging was separated from secular effects by using total arm length, which was least affected by aging. The rate of loss in stature due to aging was 0.142 cm/year in the working women and 0.140 cm/year in the nonworking women. Both estimates are significantly different from zero. After adjusting stature for estimated aging effects, the resulting secular estimates were 0.004 cm/year in working women and 0.01 cm/year for nonworking women, both of which do not significantly differ from zero. (c) 1995 Wiley-Liss, Inc. PMID- 28557041 TI - Modified cuckoo search algorithm in microscopic image segmentation of hippocampus. AB - Microscopic image analysis is one of the challenging tasks due to the presence of weak correlation and different segments of interest that may lead to ambiguity. It is also valuable in foremost meadows of technology and medicine. Identification and counting of cells play a vital role in features extraction to diagnose particular diseases precisely. Different segments should be identified accurately in order to identify and to count cells in a microscope image. Consequently, in the current work, a novel method for cell segmentation and identification has been proposed that incorporated marking cells. Thus, a novel method based on cuckoo search after pre-processing step is employed. The method is developed and evaluated on light microscope images of rats' hippocampus which used as a sample for the brain cells. The proposed method can be applied on the color images directly. The proposed approach incorporates the McCulloch's method for levy flight production in cuckoo search (CS) algorithm. Several objective functions, namely Otsu's method, Kapur entropy and Tsallis entropy are used for segmentation. In the cuckoo search process, the Otsu's between class variance, Kapur's entropy and Tsallis entropy are employed as the objective functions to be optimized. Experimental results are validated by different metrics, namely the peak signal to noise ratio (PSNR), mean square error, feature similarity index and CPU running time for all the test cases. The experimental results established that the Kapur's entropy segmentation method based on the modified CS required the least computational time compared to Otsu's between-class variance segmentation method and the Tsallis entropy segmentation method. Nevertheless, Tsallis entropy method with optimized multi-threshold levels achieved superior performance compared to the other two segmentation methods in terms of the PSNR. PMID- 28557042 TI - Enhancing the Catalytic Activity of Zeolitic Imidazolate Framework-8-Derived N Doped Carbon with Incorporated CeO2 Nanoparticles in the Oxygen Reduction Reaction. AB - Incorporation of CeO2 nanoparticles into the cavity of zeolitic imidazolate framework-8 (ZIF-8) was followed by high-temperature pyrolysis to generate CeO2 @N-doped carbon materials. Introduction of the CeO2 nanoparticles greatly enhanced the catalytic activity of the ZIF-8-derived carbon materials in the oxygen reduction reaction (ORR) owing to the presence of Ce3+ and oxygen vacancies with high content of chemisorbed oxygen in CeO2 and the well-maintained skeleton of the original ZIF-8 with uniform mesoporous structure. The material treated at 900 degrees C (CeO2 @N-C-900) showed excellent ORR catalytic activity in both acidic and alkaline electrolyte. The ORR onset and half-wave potentials of CeO2 @N-C-900 were 1.003 and 0.908 V versus RHE, respectively, in 0.1 m KOH aqueous solution, which are comparable to those of Pt/C catalysts. Furthermore, it exhibited much better stability and methanol crossover tolerance than Pt/C, indicative of its good potential for applications in energy conversion. PMID- 28557043 TI - A psychological intervention programme for patients with breast cancer under chemotherapy and at a high risk of depression: A randomised clinical trial. AB - AIMS AND OBJECTIVES: To develop a nurse-led psychological intervention programme and to evaluate its effects on psychological distress and quality of life in patients with breast cancer undergoing chemotherapy and at a high risk of depression. BACKGROUND: Depression is common among patients with breast cancer undergoing chemotherapy. Psychological intervention programmes that improve psychological distress and quality of life have previously been lacking in South Korea. DESIGN: This was a pre- and post-test randomised controlled trial. METHODS: The nurse-led psychological intervention programme comprised seven weekly counselling sessions delivered face to face and telephonically. These aimed to provide emotional support to patients and to enable them to express their feelings. Patients at a high risk of depression were recruited from an oncology outpatient clinic in a university hospital. Sixty participants were evenly and randomly allocated to either the intervention group or the control group. The effects of the intervention on psychological distress (mood disturbance, anxiety and depression) and quality of life were examined using linear mixed models. RESULTS: Compared with the control group, the intervention group reported significantly lower mood disturbance, anxiety and depression and showed an improved global health status and physical, role and emotional functions. They also reported fewer symptoms such as fatigue, nausea/vomiting, pain and insomnia. CONCLUSIONS: Our nurse-led psychological intervention programme might reduce patients' uncertainty and encourage them to be proactive and self-controllable. RELEVANCE TO CLINICAL PRACTICE: Nurse-led psychological intervention programmes should be implemented to reduce psychological distress and improve quality of life in patients with breast cancer, particularly those at a high risk of depression. PMID- 28557045 TI - Dermoscopy in assisting the diagnosis of linear porokeratosis. PMID- 28557046 TI - Decisions to limit or withdraw treatment in young adults with melanoma. PMID- 28557044 TI - Timing of food introduction and development of food sensitization in a prospective birth cohort. AB - BACKGROUND: The effect of infant feeding practices on the development of food allergy remains controversial. We examined the relationship between timing and patterns of food introduction and sensitization to foods at age 1 year in the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study. METHODS: Nutrition questionnaire data prospectively collected at age 3, 6, 12, 18, and 24 months were used to determine timing of introduction of cow's milk products, egg, and peanut. At age 1 year, infants underwent skin prick testing to cow's milk, egg white, and peanut. Logistic regression models were fitted to assess the impact of timing of food exposures on sensitization outcomes, and latent class analysis was used to study patterns of food introduction within the cohort. RESULTS: Among 2124 children with sufficient data, delaying introduction of cow's milk products, egg, and peanut beyond the first year of life significantly increased the odds of sensitization to that food (cow's milk adjOR 3.69, 95% CI 1.37-9.08; egg adjOR 1.89, 95% CI 1.25-2.80; peanut adjOR 1.76, 95% CI 1.07-3.01). Latent class analysis produced a three-class model: early, usual, and delayed introduction. A pattern of delayed introduction, characterized by avoidance of egg and peanut during the first year of life, increased the odds of sensitization to any of the three tested foods (adjOR 1.78, 95% CI 1.26-2.49). CONCLUSIONS: Avoidance of potentially allergenic foods during the first year of life significantly increased the odds of sensitization to the corresponding foods. PMID- 28557047 TI - Prevention of alloimmunization during pregnancy by prednisone and immunoglobulin G-What is the evidence? PMID- 28557048 TI - Elucidation of Compatibility Interactions of Traditional Chinese Medicines: In Vitro Absorptions Across Caco-2 Monolayer of Coptidis Rhizoma and Euodiae Fructus in Zuojin and Fanzuojin Formulas as A Case. AB - Traditional Chinese medicines are often combined as formulae and interact with each other. As for Coptidis Rhizoma (CR) and Euodiae Fructus (EF), the most classical compatibilities were Zuojin (ZJF) and Fanzuojin formulas (FZJF) with reverse mixture ratios and opposite effects. To compare in vitro absorption interactions between CR and EF, bidirectional transports across Caco-2 cell monolayer of extracts of two formulas and equivalent single herbs were studied. Eighteen alkaloids from CR and EF were determined by liquid chromatography coupled to tandem mass spectrometry. Parameter apparent permeability coefficient (Papp ) and efflux rate (ER) values showed that most alkaloids were well or moderately absorbed and six quaternary protoberberine alkaloids from CR had obvious efflux. ZJF compatibilities reduced both Papp BL->AP and ER values of three indole alkaloids, and increased ER values of two quinolone alkaloids from EF. FZJF compatibilities obviously affected the bidirectional Papp values of CR alkaloids, weakened ERs of five protoberberines from CR and enlarged ERs of two quinolones from EF. Conclusions were drawn that different compatibility ratios of CR and EF led to different interactions on the in vitro absorption of alkaloids. The results may provide a good reference for interaction studies on the compatibilities of traditional Chinese medicines. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28557049 TI - Left Dorsolateral Prefrontal Cortex rTMS in Alleviating MTBI Related Headaches and Depressive Symptoms. AB - OBJECTIVE: Persistent mild traumatic brain injury related headache (MTBI-HA) represents a neuropathic pain state. This study tested the hypothesis that repetitive transcranial magnetic stimulation (rTMS) at the left prefrontal cortex can alleviate MTBI-HA and associated neuropsychological dysfunctions. METHODS AND MATERIALS: Veterans with MTBI-HA were randomized to receive four sessions of either real (REAL group) or sham (SHAM group) high frequency rTMS delivered at 10 Hz, 80% of resting motor threshold and 2000 pulses per session at >24 and <72 hours apart. Pre-treatment, post-treatment 1-week and 4-week headache and neuropsychological assessments were conducted. RESULTS: Twenty nine out of forty four consented subjects completed the study. A two-factor (visit * treatment) repeated measures ANOVA showed a significant (p = 0.002, F = 11.63, df = 1) interaction for the average daily persistent headache intensity with the REAL group exhibiting a significant (p < 0.0001) average reduction (+/-SD) of 25.3 +/- 16.8% and 23.0 +/- 17.7% reduction in their numerical rating scale at the one week and four-week post-treatment assessments in comparison to <1 +/- 11.7% and 2.3 +/- 14.5% reduction found in the SHAM group. In addition, a significant (p < 0.01) 50% and 57% reduction was found in the prevalence of persistent headache in the REAL group at the one-week and four-week assessments in comparison to 7% and 20% reduction found in the SHAM group. Furthermore, the REAL group demonstrated a significant (p = 0.033) improvement (from 22.3 +/- 6.4 at pre-treatment to 19.0 +/- 5.0 at post-treatment one-week) in the Hamilton Rating Scale for Depression score, while the SHAM group's score remained largely unchanged (from 25.33 +/- 8.43 to 24.64 +/- 5.03) in the same time frame. This trend of improvement, although not statistically significant, continues to the post-treatment four-week assessment. CONCLUSION: A short-course rTMS at the left DLPFC can alleviate MTBI HA symptoms and provide a transient mood enhancing benefit. Further studies are required to establish a clinical protocol balancing both treatment efficacy and patient compliance. PMID- 28557050 TI - Evaluation of sources of variation on in vitro fermentation kinetics of feedstuffs in a gas production system. AB - The aim of this study was to evaluate the effect of different sources of variation in gas production technique on the in vitro gas production kinetics of feedstuffs. Triplicates of commercial concentrate, grass silage, grass hay and grass pasture were incubated in three experiments: experiment 1 assessed two agitation methods; experiment 2 evaluated different rumen inocula (pooled or different donor cows for each incubation run); and experiment 3 used Goering-Van Soest or Mould buffers for media preparation. Gas production data were fitted into the Michaelis-Menten model and then subjected to analysis of variance. Gas production (GP) at 48 h and asymptote gas production (A) were lower when bottles were continuously under horizontal movement. Time to produce half and 75% of A, and A were affected by rumen inocula, while buffer type affected time to produce half and 25% of A and GP. No interactions between substrates and sources of variation were observed, suggesting that the effects of substrates on GP parameters were not modified. It is concluded that comparison of numerical data from in vitro experiments that follow different protocols must be done carefully. However, the ranking of different substrates is more robust and less affected by the sources of variation. PMID- 28557051 TI - When people with dementia are perceived as witches. Consequences for patients and nurse education in South Africa. AB - AIMS AND OBJECTIVES: To explore and describe the link between culture and dementia care with the focus on the influence of the belief in dementia as witchcraft and people with dementia as witches. BACKGROUND: In South Africa, especially in townships and rural areas, dementia is often perceived as connected to witchcraft rather than to disease. Persons labelled as witches-mostly older women-may be bullied, ostracised, beaten, stoned, burned, even killed. METHOD: One strand of findings from a larger international study is presented with in depth qualitative interviews of one close family member and seven nurses caring for patients with severe dementia in nursing homes in Tshwane in South Africa. A hermeneutic analytic approach was used. RESULTS: Two main themes are found, namely "Belief in witchcraft causing fear of persons with dementia" and "Need of knowledge and education." Fear of and violence towards people with dementia are based on the belief that they are witches. Some of the nurses had also held this belief until they started working with patients with dementia. There is a great need for education both among healthcare workers and the populace. DISCUSSION: The "witch" belief prevents seeking professional help. As nursing homes tend to be private and expensive, professional dementia care is virtually unattainable for the poor. Dementia needs a more prominent place in nursing curricula. Nurses as educators need to know the local culture and language to be accepted in the various communities. They need to visit families affected by dementia, give awareness talks in churches, schools and clinics and facilitate support groups for carers of people with dementia in the local language. CONCLUSION: Improved nurses' education in gerontology and geriatric care is needed. Trained specialist nurses may work as mediators and help eradicate the witchcraft beliefs connected to severe dementia. PMID- 28557052 TI - Investigating the use of tie-over dressing after skin grafting. AB - Tie-over bolster dressing after skin grafting can prolong operative time, and cause hematoma and seroma formation because of uneven pressure application. To describe the possibility of discontinuing the use of tie-over dressing, we carried out a retrospective comparative study of patients who underwent skin grafting at an institution between January 2009 and December 2014. We investigated and compared the take rate, healing period, wound infection rate and hematoma formation rate for the tie-over dressing group and the non-tie-over dressing group. Among 266 patients, 148 and 118 patients were included in the tie over dressing group and non-tie-over dressing group, respectively. There were no significant differences between the take rate, healing period, wound infection rate and hematoma formation rate for the two groups. Multivariate analysis showed that the complete graft take rate was not significantly influenced by tie-over dressing, age, sex, graft site, graft procedure and skin graft diameter. Although the use of tie-over dressing might remain necessary on sites with a free margin, including the eyelids, lips or nostrils, because of the difficulty in using tape fixation, the present study showed that alternative dressing with polyurethane foam is also useful in most cases of skin grafting. PMID- 28557054 TI - Alpha- and Beta-Diastereoisomers of Phenylcobalamin from Cobalt-Arylation with Diphenyliodonium Chloride. AB - Organometallic aryl-cobalamins are B12 -derivatives featuring properties of potential 'B12 antivitamins'. Herein, we describe a new method for the preparation of aryl-cobalamins using versatile diaryliodonium salts as arylation agents. Formate or sodium borohydride reduction of aquocobalamin in presence of diphenyliodonium chloride furnished Cobeta -phenyl-cobalamin PhCbl in a roughly 3:1 to 1:1 ratio with its coordination isomer alphaPhCbl, a first representative 'base-off' Coalpha -aryl-cobalamin. The new structures were secured by detailed spectroscopic analysis, supplemented by an X-ray crystal structure analysis of PhCbl. Both types of coordination isomers of the aryl-cobalamins promise to be useful molecular tools in biomedical and biological studies. PMID- 28557053 TI - A novel streptococcal cell-cell communication peptide promotes pneumococcal virulence and biofilm formation. AB - Streptococcus pneumoniae (pneumococcus) is a major human pathogen. It is a common colonizer of the human respiratory track, where it utilizes cell-cell communication systems to coordinate population-level behaviors. We reasoned that secreted peptides that are highly expressed during infection are pivotal for virulence. Thus, we used in silico pattern searches to define a pneumococcal secretome and analyzed the transcriptome of the clinically important PMEN1 lineage to identify which peptide-encoding genes are highly expressed in vivo. In this study, we characterized virulence peptide 1 (vp1), a highly expressed Gly Gly peptide-encoding gene in chinchilla middle ear effusions. The vp1 gene is widely distributed across pneumococcus as well as encoded in related species. Studies in the chinchilla model of middle ear infection demonstrated that VP1 is a virulence determinant. The vp1 gene is positively regulated by a transcription factor from the Rgg family and its cognate SHP (short hydrophobic peptide). In vitro data indicated that VP1 promotes increased thickness and biomass for biofilms grown on chinchilla middle ear epithelial cells. Furthermore, the wild type biofilm is restored with the exogenous addition of synthetic VP1. We conclude that VP1 is a novel streptococcal regulatory peptide that controls biofilm development and pneumococcal pathogenesis. PMID- 28557056 TI - Spinal SET7/9 may contribute to the maintenance of cancer-induced bone pain in mice. AB - Cancer-induced bone pain (CIBP) profoundly influences patients' quality of life. Exploring the mechanisms by which CIBP occurs is essential for developing efficacious therapies. Various studies have shown that proinflammatory factors were involved in CIBP. SET domain containing lysine methyltransferase 7/9 (SET7/9) may modulate the expression of NF-kappaB-dependent proinflammatory genes in vitro. However, whether SET7/9 may participate in the maintenance of CIBP remains unknown. In this study, NCTC 2472 cells were inoculated into the intramedullary space of the femur to establish a mouse model of CIBP. Upregulation of spinal SET7/9 expression was related to pain behaviours in tumour inoculated mice. Intrathecal cyproheptadine (10 or 20 nmol) attenuated response to painful stimuli in a dose-dependent manner. Moreover, there was a concomitant decrease in spinal SET7/9 and RANTES expression. The antinociceptive effects of cyproheptadine were abolished by pre-intrathecal administration of SET 7/9 (0.2 MUg) for 30 minutes before intrathecal cyproheptadine (20 nmol) administration. These results indicated that spinal SET7/9 may contribute to the maintenance of CIBP in mice. Hence, targeting of spinal SET7/9 might be a useful alternative therapy for the treatment of CIBP. PMID- 28557055 TI - Time-efficient and flexible design of optimized multishell HARDI diffusion. AB - PURPOSE: Advanced diffusion magnetic resonance imaging benefits from collecting as much data as is feasible but is highly sensitive to subject motion and the risk of data loss increases with longer acquisition times. Our purpose was to create a maximally time-efficient and flexible diffusion acquisition capability with built-in robustness to partially acquired or interrupted scans. Our framework has been developed for the developing Human Connectome Project, but different application domains are equally possible. METHODS: Complete flexibility in the sampling of diffusion space combined with free choice of phase-encode direction and the temporal ordering of the sampling scheme was developed taking into account motion robustness, internal consistency, and hardware limits. A split-diffusion-gradient preparation, multiband acceleration, and a restart capacity were added. RESULTS: The framework was used to explore different parameters choices for the desired high angular resolution diffusion imaging diffusion sampling. For the developing Human Connectome Project, a high-angular resolution, maximally time-efficient (20 min) multishell protocol with 300 diffusion-weighted volumes was acquired in >400 neonates. An optimal design of a high-resolution (1.2 * 1.2 mm2 ) two-shell acquisition with 54 diffusion weighted volumes was obtained using a split-gradient design. CONCLUSION: The presented framework provides flexibility to generate time-efficient and motion-robust diffusion magnetic resonance imaging acquisitions taking into account hardware constraints that might otherwise result in sub-optimal choices. Magn Reson Med 79:1276-1292, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28557057 TI - Unraveling complex molecular transformations of N-beta-alanyldopamine that account for brown coloration of insect cuticle. AB - RATIONALE: N-beta-Alanyldopamine (NBAD) and N-acetyldopamine (NADA) are catecholamines that are used by insects as sclerotizing precursors to harden their cuticle. They share a common pathway utilizing the same set of sclerotizing enzymes. Yet, cuticles using NBAD are brown, while cuticles using NADA are colorless. To identify the cause of this major unresolved color difference, molecular transformations of NBAD with cuticular enzymes were investigated. METHODS: Reactions of NBAD and NADA with native cuticle isolated from the wandering stages of Sarcophaga bullata larvae as well as the reactions of NBAD with cuticular sclerotization enzymes - phenoloxidase, quinone isomerase and quinone methide isomerase - were investigated using UV-Vis spectroscopy, high performance liquid chromatography (HPLC), and mass spectrometry (MS). In addition, the reactivity of enzymatically generated NBAD quinone was investigated by MS. RESULTS: Reactions of NBAD with sclerotizing enzymes isolated from Sarcophaga bullata larvae generate colorless products such as N-beta alanylnorepinephrine, N-beta-alanylarterenone, dehydro NBAD, the benzodioxan dimers of dehydro NBAD and other minor adducts, the same kind of compounds generated by NADA reaction with cuticular enzymes. However, oxidation of NBAD produces colored quinone adducts, in addition. NADA, which lacks the amino group, did not produce these quinone adducts. CONCLUSIONS: LC/MS analysis of the reaction mixture of NBAD-cuticular enzyme reactions reveals the novel production of colored quinone adducts that are not possible for NADA. Therefore, our results suggest that the brown coloration of cuticle formed through NBAD crosslinking is likely due to the formation and accumulation of NBAD quinone and its adducts, while NADA quinone adducts tend not to form during NADA crosslinking, producing a nearly colorless cuticle. PMID- 28557058 TI - Thoracic paravertebral blockade in breast surgery: Is pneumothorax an appreciable concern? A review of over 1000 cases. AB - There has been a substantial increase in ambulatory day-case breast surgery in recent decades. This has been largely due to improvements in anesthetic procedures and pre-emptive analgesia. Thoracic paravertebral blockade (TPVB) is increasing in popularity, though concerns over iatrogenic injury remain, especially pneumothorax. The purpose of this study was to conduct a review of the incidence of pneumothorax following TPVB prior to breast surgery. Data from of a consecutive series of patients having TPVB prior to breast surgery between 2009 and 2014 were reviewed. TPVB were used prior to unilateral and bilateral procedures. Medical records were retrospectively assessed for any complication including pleural punctures, pneumothorax, hypotension, bradycardia as well as signs and symptoms of local anesthetic toxicity. 1152 patients underwent a total of 1322 TPVB injections (982 unilateral and 340 bilateral). Clinically significant hypotension and/or bradycardia occurred in 26 patients (2.2%). Two patients (0.17%) had a suspected toxicity from the local anesthetic. Incidence of pleural puncture was 0.6% (n=9) and pneumothorax 0.26% (n=3). All pneumothoraxes were managed conservatively. There was no statistical difference in complication rates in those that had unilateral vs bilateral TPVB or those that had ultrasound guidance (P=.09). Good pre-emptive analgesia is pertinent to prevent acute postoperative pain. TPVB have been shown to be successful in reducing rescue analgesia. This study shows TPVB is a well-tolerated procedure, with a low associated incidence of iatrogenic injury and complication. PMID- 28557059 TI - Effects of taurine on plasma glucose concentration and active glucose transport in the small intestine. AB - Taurine lowers blood glucose levels and improves hyperglycemia. However, its effects on glucose transport in the small intestine have not been investigated. Here, we elucidated the effect of taurine on glucose absorption in the small intestine. In the oral glucose tolerance test, addition of 10 mmol/L taurine suppressed the increase in hepatic portal glucose concentrations. To investigate whether the suppressive effect of taurine occurs via down-regulation of active glucose transport in the small intestine, we performed an assay using the everted sac of the rat jejunum. Addition of taurine to the mucosal side of the jejunum suppressed active glucose transport via sodium-glucose cotransporter 1 (SGLT1). After elimination of chloride ions from the mucosal solution, taurine did not show suppressive effects on active glucose transport. These results suggest that taurine suppressed the increase in hepatic portal glucose concentrations via suppression of SGLT1 activity in the rat jejunum, depending on chloride ions. PMID- 28557060 TI - Epidermal growth factor receptor and anaplastic lymphoma kinase testing and mutation prevalence in patients with advanced non-small cell lung cancer in Switzerland: A comprehensive evaluation of real world practices. AB - In order to improve outcomes, identification of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) genes has become crucial in advanced non-small-cell lung cancer (NSCLC). The aim of the present study is to analyse time trends and frequency of testing, factors affecting testing as well as prevalence of mutations in the Swiss population. We analysed EGFR and ALK testing in a cohort of patients with newly diagnosed metastasised non-squamous NSCLC in the catchment area of the cancer registry Eastern Switzerland in the years 2008-2014. We analysed prevalence of mutations and studied clinicopathological characteristics and survival of tested and non-tested patients and of patients with and without mutations. Among 718 patients identified, 11% (51/447) harboured an EGFR mutation in the exons 18, 19 or 21 and further 12% (31/265) showed a positive test result for ALK rearrangements. In non smokers the proportions of mutations were 31% and 23% respectively. Testing rates increased over time and reached 79% in 2014. We observed significantly lower testing rates and poorer survival in elderly, patients with limited life expectancy and patients treated at hospitals not involved in clinical research. Outcomes can be further improved in a considerable proportion of patients with advanced non-squamous NSCLC. PMID- 28557061 TI - Classification of Involuntary Movements in Dogs: Myoclonus and Myotonia. AB - Myoclonus is a sudden brief, involuntary muscle jerk. Of all the movement disorders, myoclonus is the most difficult to encapsulate into any simple framework. On the one hand, a classification system is required that is clinically useful to aid in guiding diagnosis and treatment. On the other hand, there is need for a system that organizes current knowledge regarding biological mechanisms to guide scientific research. These 2 needs are distinct, making it challenging to develop a robust classification system suitable for all purposes. We attempt to classify myoclonus as "epileptic" and "nonepileptic" based on its association with epileptic seizures. Myotonia in people may be divided into 2 clinically and molecularly defined forms: (1) nondystrophic myotonias and (2) myotonic dystrophies. The former are a group of skeletal muscle channelopathies characterized by delayed skeletal muscle relaxation. Many distinct clinical phenotypes are recognized in people, the majority relating to mutations in skeletal muscle voltage-gated chloride (CLCN1) and sodium channel (SCN4A) genes. In dogs, myotonia is associated with mutations in CLCN1. The myotonic dystrophies are considered a multisystem clinical syndrome in people encompassing 2 clinically and molecularly defined forms designated myotonic dystrophy types 1 and 2. No mutation has been linked to veterinary muscular dystrophies. We detail veterinary examples of myotonia and attempt classification according to guidelines used in humans. This more precise categorization of myoclonus and myotonia aims to promote the search for molecular markers contributing to the phenotypic spectrum of disease. Our work aimed to assist recognition for these 2 enigmatic conditions. PMID- 28557062 TI - Substance-related psychopathology and aggressiveness in a nightlife holiday resort: Results from a pilot study in a psychiatric inpatient unit in Ibiza. AB - OBJECTIVES: We aimed to describe a sample of subjects admitted to a psychiatric unit after the intake of psychoactive substances for recreational purposes. METHODS: Between June and September 2015, 49 subjects were included. Sociodemographic characteristics and psychopathological aspects were investigated, and urine samples for further analysis were collected. Three subgroups (cannabinoids, stimulants, and depressors users) were identified, according to the structured interview regarding substance use and urinalysis. RESULTS: Level of aggressiveness was found to be significantly higher (p < .05) in the cannabinoids subgroup. Self-reported symptom severity was comparable among groups, but trends could be identified: SCL-90 results showed a prevalence of anxiety symptoms among depressors users, hostility or aggression in the tetrahydrocannabinol subgroup, and psychoticism in the stimulants subgroup. CONCLUSIONS: The use of psychoactive substances was be characterised by poly-use of both traditional and novel substances. The presence of aggressiveness emerged as a main feature associated with the use of cannabis and other cannabinoids. Binge drinking and sleep deprivation also represented a relevant component in almost all the evaluated subjects. PMID- 28557063 TI - Theory versus practice, bacteriological efficiency versus personal habits: A bacteriological and user acceptability evaluation of filtering tools for people who inject drugs. AB - INTRODUCTION AND AIMS: People who inject drugs (PWID) are exposed to associated viral, bacterial and fungal risks. These risks can be reduced by filtration. Large disparities in the quality of filtration exist between the various available filters. This paper compares both performance and user acceptability of three filters for drug injection (cotton filters, Sterifilt(r) and wheel filters) by combining epidemiological and bacteriological analyses. DESIGN AND METHODS: A cross-sectional epidemiological study (ANRS-Coquelicot) using time-location sampling combined with the generalised weight sampling method was conducted among 985 PWID in France. Two filtration-based bacteriological studies of 0.20- and 0.45-MUm wheel filters, Sterifilt filters and cotton filters were also conducted. RESULTS: The bacteriological study highlighted the value of using wheel filters with a porosity of less than 0.5 MUm, as they limit the risk of bacterial and fungal infection. The results of this study clearly highlight a distinction between the efficiency of Sterifilt and wheel filters, the latter being more effective. Our epidemiological study highlighted that the use of cotton filters is widespread and routine, but is the subject of much criticism among PWID. Sterifilt is not widely used, and its adoption is slow. Finally, the wheel filter remains a largely untested tool. DISCUSSION AND CONCLUSIONS: Low product retention and ease of use are the two most important factors for filters for PWID. Bacterial and fungal risk filtration is less important. It is essential to educate PWID about the benefits of wheel filters. [Jauffret-Roustide M, Chollet A, Santos A, Benoit T, Pechine S, Duplessy C, Bara J-L, Levi Y, Karolak S, Nefau T. Theory versus practice, bacteriological efficiency versus personal habits: A bacteriological and user acceptability evaluation of filtering tools for people who inject drugs. Drug Alcohol Rev 2018;37:106-115]. PMID- 28557064 TI - Quantitative assessment of wound healing using high-frequency ultrasound image analysis. AB - PURPOSE: We aimed to develop a method for quantitative assessment of wound healing in ulcerated diabetic feet. METHODS: High-frequency ultrasound (HFU) images of 30 wounds were acquired in a controlled environment on post-debridement days 7, 14, 21, and 28. Meaningful features portraying changes in structure and intensity of echoes during healing were extracted from the images, their relevance and discriminatory power being verified by analysis of variance. Relative analysis of tissue healing was conducted by developing a features-based healing function, optimised using the pattern-search method. Its performance was investigated through leave-one-out cross-validation technique and reconfirmed using principal component analysis. RESULTS: The constructed healing function could depict tissue changes during healing with 87.8% accuracy. The first principal component derived from the extracted features demonstrated similar pattern to the constructed healing function, accounting for 86.3% of the data variance. CONCLUSION: The developed wound analysis technique could be a viable tool in quantitative assessment of diabetic foot ulcers during healing. PMID- 28557065 TI - Lactate dehydrogenase predicts combined progression-free survival after sequential therapy with abiraterone and enzalutamide for patients with castration resistant prostate cancer. AB - BACKGROUND: An array of clinical issues remains to be resolved for castration resistant prostate cancer (CRPC), including the sequence of drug use and drug cross-resistance. At present, no clear guidelines are available for the optimal sequence of use of novel agents like androgen-receptor axis-targeted (ARAT) agents, particularly enzalutamide, and abiraterone. METHODS: This study retrospectively analyzed a total of 69 patients with CRPC treated with sequential therapy using enzalutamide followed by abiraterone or vice versa. The primary outcome measure was the comparative combined progression-free survival (PFS) comprising symptomatic and/or radiographic PFS. Patients were also compared for total prostate-specific antigen (PSA)-PFS, overall survival (OS), and PSA response. The predictors of combined PFS and OS were analyzed with a backward stepwise multivariate Cox model. RESULTS: Of the 69 patients, 46 received enzalutamide first, followed by abiraterone (E-A group), and 23 received abiraterone, followed by enzalutamide (A-E group). The two groups were not significantly different with regard to basic data, except for hemoglobin values. In a comparison with the E-A group, the A-E group was shown to be associated with better combined PFS in Kaplan-Meier analysis (P = 0.043). Similar results were obtained for total PSA-PFS (P = 0.049), while OS did not differ between groups (P = 0.62). Multivariate analysis demonstrated that pretreatment lactate dehydrogenase (LDH) values and age were significant predictors of longer combined PFS (P < 0.05). Likewise, multivariate analysis demonstrated that pretreatment hemoglobin values and performance status were significant predictors of longer OS (P < 0.05). CONCLUSIONS: The results of this study suggested the A-E sequence had longer combined PSA and total PSA-PFS compared to the E-A sequence in patients with CRPC. LDH values in sequential therapy may serve as a predictor of longer combined PFS. PMID- 28557066 TI - Purification and functional characterization of lectin with phenoloxidase activity from the hemolymph of cockroach, Periplaneta americana. AB - Lectins also identified as hemagglutinins are multivalent proteins and on account of their fine sugar-binding specificity play an important role in immune system of invertebrates. The present study was carried out on the hemolymph lectin of cockroach, Periplaneta americana with appropriate screening and purification to understand its molecular as well as functional nature. The lectin from the hemolymph was purified using ion-exchange chromatography. The approximate molecular weight of purified lectin was 340 kDa as determined by FPLC analysis. Rabbit erythrocytes were highly agglutinated with purified lectin from the hemolymph of P. americana. The hemagglutination activity (HA) of lectin was specifically inhibited by fucose. Glycoproteins also inhibited the HA activity of lectin. The amino acid sequences of the purified lectin revealed homology with amino acid sequences of allergen proteins from P. americana. Purified lectin showed the highest phenoloxidase activity against dopamine. The activators such as exogenous proteases and LPS from Escherichia coli and Salmonella minnesota significantly enhanced the PO activity of the purified lectin. Besides, the presence of copper and hemocyanin conserved domain in the purified lectin provided a new facet that insects belonging to the ancient clade such as cockroaches retained some traces of evolutionary resemblance in possessing lectin of ancient origin. PMID- 28557067 TI - Anxiety and depression in Spanish-speaking Latina cancer patients prior to starting chemotherapy. AB - OBJECTIVE: Anxiety and depression can substantially impact the life of a cancer patient, but literature on emotional distress in the Hispanic cancer population is sparse. Additionally, the influence of psychosocial variables including age, acculturation, and spiritual well-being on emotional distress in this population remains unclear. The purpose of the present report was to assess the prevalence of anxiety and depression in Spanish-speaking Latina cancer patients preparing to begin chemotherapy and to explore the predictors and correlates of these outcomes. METHODS: Participants were 198 Spanish-speaking Latina cancer patients who completed measures of anxiety, depression, acculturation, and spiritual well being prior to starting chemotherapy. RESULTS: Prevalence of clinically significant anxious symptomatology was 52%, and prevalence of clinically significant depressive symptomatology was 27%. Longer time since diagnosis and less acculturation predicted more severe anxiety, while longer time since diagnosis, less acculturation, and older age predicted more severe depression (Ps < .05). In multivariable analyses, only time since diagnosis emerged as a significant predictor of anxiety and depression when accounting for the influence of other variables. Greater spiritual well-being was correlated with both less severe anxiety and less severe depression (Ps < .001). CONCLUSIONS: The present findings document the high prevalence of emotional distress, particularly anxiety, in this patient population prior to chemotherapy initiation and identify several demographic and clinical factors associated with increased risk for heightened distress. Additionally, these findings suggest that interventions to address distress in this patient population would benefit from including components that seek to improve patients' spiritual well-being. PMID- 28557069 TI - On the long-range relativistic effects in the 15 N NMR chemical shifts of halogenated azines. AB - Long-range beta- and gamma-relativistic effects of halogens in 15 N NMR chemical shifts of 20 halogenated azines (pyridines, pyrimidines, pyrazines, and 1,3,5 triazines) are shown to be unessential for fluoro-, chloro-, and bromo derivatives (1-2 ppm in average). However, for iodocontaining compounds, beta- and gamma-relativistic effects are important contributors to the accuracy of the 15 N calculation. Taking into account long-range relativistic effects slightly improves the agreement of calculation with experiment. Thus, mean average errors (MAE) of 15 N NMR chemical shifts of the title compounds calculated at the non relativistic and full 4-component relativistic levels in gas phase are accordingly 7.8 and 5.5 ppm for the range of about 150 ppm. Taking into account solvent effects within the polarizable continuum model scheme marginally improves agreement of computational results with experiment decreasing MAEs from 7.8 to 7.4 ppm and from 5.5 to 5.3 ppm at the non-relativistic and relativistic levels, respectively. The best result (MAE: 5.3 ppm) is achieved at the 4-component relativistic level using Keal and Tozer's KT3 functional used in combination with Dyall's relativistic basis set dyall.av3z with taking into account solvent effects within the polarizable continuum solvation model. The long-range relativistic effects play a major role (of up to dozen of parts per million) in 15 N NMR chemical shifts of halogenated nitrogen-containing heterocycles, which is especially crucial for iodine derivatives. This effect should apparently be taken into account for practical purposes. PMID- 28557068 TI - Purification of glucose-6-phosphate dehydrogenase from rat (Rattus norvegicus) erythrocytes and inhibition effects of some metal ions on enzyme activity. AB - Glucose-6-phosphate dehydrogenase (G6PD) is the first enzyme on which the pentose phosphate pathway was checked. In this study, purification of a G6PD enzyme was carried out by using rat erythrocytes with a specific activity of 13.7 EU/mg and a yield of 67.7 and 155.6-fold by using 2',5'-ADP Sepharose-4B affinity column chromatography. For the purpose of identifying the purity of enzyme and molecular mass of the subunit, a sodium dodecyl sulfate-polyacrylamide gel electrophoresis was carried out. The molecular mass of subunit was calculated 56.5 kDa approximately. Then, an investigation was carried out regarding the inhibitory effects caused by various metal ions (Fe2+ , Pb2+ , Cd2+ , Ag+ , and Zn2+ ) on G6PD enzyme activities, as per Beutler method at 340 nm under in vitro conditions. Lineweaver-Burk diagrams were used for estimation of the IC50 and Ki values for the metals. Ki values for Pb+2 , Cd+2 , Ag+ , and Zn+2 were 113.3, 215.2, 19.4, and 474.7 MUM, respectively. PMID- 28557070 TI - Color and Power Doppler Sonography for Pneumothorax Detection. AB - The use of B- and M-mode sonography for detection of pneumothorax has been well described and studied. It is now widely incorporated by sonographers, emergency physicians, trauma surgeons, radiologists, and critical care specialists worldwide. Lung sonography can be performed rapidly at the bedside or in the prehospital setting. It is more sensitive, specific, and accurate than plain chest radiography. The use of color and power Doppler sonography as an adjunct to B- and M-mode imaging for detection of pneumothorax has been described in a small number of studies and case reports but is much less widely known or used. Color and power Doppler imaging may be used for confirmation of the presence or absence of lung sliding detected with B-mode sonography. In this article, we examine the physics behind Doppler sonography as it applies to the lung, technique, an actual case, and the past literature describing the use of color and power Doppler sonography for the detection of pneumothorax. PMID- 28557072 TI - An anthropogenetic study on the Oromo and Amhara of central Ethiopia. AB - Blood samples from members of the Oromo and Amhara ethnic groups of central Ethiopia were tested for 10 erythrocyte protein systems: ACP1, ADA, AK1, CA2, ESD, G6PD, GLO1, HBbeta, PGD, and PGM1. Differences between the two samples were relatively slight and not statistically significant. Gene frequency distributions were then analyzed in the context of the genetics of the African and Arabian peoples. Considering the erythrocyte enzyme data, the Oromo and Amhara appear quite similar to Europoids (particularly to the South Arabians) and considerably different from the Negritic peoples. There is evidence for close genetic affinity among the Cushitic- and Semitic-speaking population groups of the Horn. Admixture between Europoid and Negritic populations seems to have been the main microevolutionary factor in generating the present day Cushitic (and Semitic) speaking group of eastern Africa. The results are consistent with the hypothesis, supported by historical and linguistic evidence, for a common origin of these groups from a Cushitic-speaking group living in eastern Africa. (c) 1996 Wiley Liss, Inc. PMID- 28557071 TI - Single-step isolation of embelin using high-performance countercurrent chromatography and determination of the fatty acid composition of seeds of Embelia schimperi. AB - Embelin (2,5-dihydroxy-3-undecyl-p-benzoquinone) is known for its potent anthelmintic activity, but also for wound-healing, antidiabetic, anticonvulsant, antitumour, anti-inflammatory, analgesic, hepatoprotective, antioxidant, antibacterial and antispermatogenic activities. A high-performance countercurrent chromatography method was developed for the purification of embelin from an extract of the seeds of Embelia schimperi fruit. The optimized solvent system (n hexane-ethylacetate-ethanol-water, 7:3:7:3) resulted in the isolation of 13.9 mg of embelin, directly from 100 mg of crude extract, in a single step within a short time (40 min). Although the compound appeared to be completely pure when analysed by ultra-performance liquid chromatography (UPLC) with photo diode array detection, the purity was established as ~90% by UPLC-mass spectrometry. Furthermore, we report the fatty acid composition of the seeds of E. schimperi fruit. Nine fatty acids were quantified from the fruit seed extract by gas chromatography-mass spectrometry, with linoleic (46.4%), palmitic (21.5%) and oleic (19.6%) acids making up the largest proportions. PMID- 28557073 TI - Fat areas on the extremities in normal weight and overweight children and adolescents: Comparison between age-related and weight-related changes in adiposity. AB - The purpose of the study was to compare changes in fat distribution in association with obesity and puberty in adolescent boys and girls. Fat areas at the ulnar, triceps, thigh, and calf regions were measured in normal weight prepubertal children (P) and adolescents (N), and overweight adolescents (O). There were significant differences in fat areas at the four sites between N and O of both sexes, especially in the proximal extremities (triceps, thigh) in boys. On the other hand, fat areas on the extremities of N boys and girls were not significantly different from those of P children except for thigh fat area in girls. It is suggested that pubertal maturation in girls, but not in boys, is associated with increased adiposity on the legs, particularly in the proximal regions, and that there are sex differences between changes in fat distribution associated with puberty and obesity. (c) 1996 Wiley-Liss, Inc. PMID- 28557074 TI - Relationship between behavior and energy expenditure in 12-week-old infants. AB - In order to apply current international recommendations of basing energy requirements on energy expenditures (FAO/WHO/UNU [1985] Energy and Protein Requirements WHO: Geneva) to infants, it is first necessary to ascertain which aspects of infant physical activity significantly influence energy expenditure. The relationship between behavioral activity and energy expenditure was, therefore, investigated in 12 week infants. Behavior was assessed using activity diaries, temperament questionnaires, and actometers. Total energy expenditure and the energy cost of physical activity were estimated using the doubly labelled water method and indirect calorimetry. Certain aspects of behavior correlated significantly with the energy cost of physical activity. Behavior thus exerts a significant effect on energy expenditure in 12 week infants. (c) 1996 Wiley-Liss, Inc. PMID- 28557075 TI - Maximal aerobic power in children and adolescents of Beijing, China. AB - The maximal aerobic power of 463 Chinese children and adolescents, 10-19 years, is described. The absolute values of maximal oxygen intake (VO2 max) in boys and girls were 1.75-3.26 and 1.44-2.10 L/min, respectively. Relative values of VO2 max per unit stature (VO2 max/stature) were 12.35-19.42 ml/cm.min for boys and 10.18-13.42 ml/cm.min for girls, values per unit weight (VO2 max/weight) were 48.60-56.59 ml/kg.min for boys and 39.34-45.56 ml/kg.min for girls, and values per estimated unit lean body mass (VO2 max/lean-body-mass) were 58.98-65.28 ml/kg.min for boys and 54.90-59.04 ml/kg.min for girls. Maximal values of oxygen pulse (VO2 max/HRmax) were 8.58-16.67 ml/beat for boys and 6.88-10.35 ml/beat for girls. In early adolescence, VO2 max, VO2 max/stature, and VO2 max/HRmax increased with chronological age, but the increment was less in girls. In contrast, VO2 max/weight and VO2 max/LBM did not increase with age in boys and girls. All indicators of VO2 max were lager in boys than in girls. (c) 1996 Wiley Liss, Inc. PMID- 28557076 TI - Relationship between adult stature and timing of the pubertal growth spurt. AB - Various literature report that little or no correlation exists between adult stature (AS) and the timing of the pubertal growth spurt in stature. No direct linear relationship between AS and age at peak height velocity (PHV) was evident in the Hiroshima Growth Study sample. However, the partial correlation between AS and age at PHV was negative when stature at PHV was controlled. That is, AS and age at PHV negatively correlate with each other so that the older the age at PHV, the lower the AS when stature at PHV is statistically controlled. This is clearly shown by the scatter diagrams of AS and age at PHV. There is a similar relationship between AS and age at takeoff (or age at minimum height velocity). The stature increment during adolescence negatively correlates with age at PHV, and the stature increment highly correlates with length of adolescence. (c) 1996 Wiley-Liss, Inc. PMID- 28557077 TI - Age at menarche in Peruvian girls at sea level and at high altitude: Effect of ethnic background and socioeconomic status. AB - The objective of the present study was to determine median age at menarche using the status quo method and the independent effects of ethnic background and socioeconomic status on the age at menarche in Peruvian girls from two distinct levels at altitude: Lima (150 m) and Cerro de Pasco (4,340 m). The sample included 503 girls from Lima and 625 girls from Cerro de Pasco, ages 10-18 years. Ethnic background was determined by four parental surnames. Subjects were classified as Quechua when one or more surnames were from Quechua origin and Spanish when four surnames were from Spanish origin. Socioeconomic status was determined using a socioeconomic index score and subjects were classified as belonging to the middle-low, low, or very low class. Median age at menarche was calculated by survival analysis using the Life Table Method with a 95% Confidence Interval (CI). Among Quechua and Spanish girls, age at menarche occurred later at high altitude than at sea level. Median ages at menarche for the overall groups were 13.08 (12.91-13.25, 95% CI) years in Lima and 14.33 (14.17-14.48, 95% CI) years in Cerro de Pasco (P < 0.0001). Socioeconomic status had no significant effect on menarcheal age (P > 0.05). Controlling socioeconomic status in the design, median age at menarche was still higher at high altitude than at sea level (P < 0.05). After logistic regression analysis, an effect on age at menarche of chronological age and place of residence was observed, but not by ethnic background, socioeconomic status and not by interactions of age and place of residence, age and socioeconomic status, place of residence and socioeconomic status, place of residence and ethnic background, or socioeconomic status and ethnic background. Thus later age at menarche observed in girls at high altitude is not due the differences in ethnicity or socioeconomic status. (c) 1996 Wiley Liss, Inc. PMID- 28557079 TI - Familial aggregation of subcutaneous fat patterning: Principal components of skinfolds in the Quebec family study. AB - Familial resemblance was examined for each of the principal components arising from an analysis of six skinfolds (triceps, biceps, subscapular, abdominal, suprailiac, and medial calf) measured in 1,237 participants of the Quebec Family Study. Most of the phenotypic variance among the skinfolds (83%) was accounted for by the first two principal components. Examination of the skinfold loadings on each principal component, as well as intraindividual cross-trait correlations with other body composition and fat pattern measures (body mass index; total fat mass and fat-free mass estimated from body density obtained through underwater weighing; the sum of six skinfolds; and the ratio of trunk to extremity skinfolds) support the interpretation of the first component as a general measure of adiposity and the second component as a trunk-extremity contrast. Parent-child and sibling correlations for each of the two principal components indicate that familial effects reach 46% (general) and 52% (trunk-extremity). Although the eigenvalues for the remaining four principal components (accounting for 17% of the variance) are <1.0, it is noteworthy that each exhibits significant familial resemblance (31-60%). Further, the intraindividual correlations for the additional four components with the other body size indicators are quite low, suggesting that they capture somewhat different aspects of relative fat distribution. (c) 1996 Wiley-Liss, Inc. PMID- 28557078 TI - Conicity: A new index of body fat distribution-what does it tell us? AB - "Conicity" (C) is an index of body fat distribution which expresses an individuals waist circumference relative to the circumference of a cylinder generated with that persons weight and height assuming a constant for body density (Valdez [1991] J. Clin. Epidemiol. 44:955-956). The more central a person is in fat distribution, the higher the value of C. In a pilot study of cardiovascular reactivity and dimensions of anger and hostility in 60 African-, Anglo-, and Hispanic-American adolescents, anthropometry and sexual maturation were determined to assess their mediating influence on the relation between anger and cardiovascular risk. The concurrent validity of three indices of body fat distribution was explored: conicity(C), waist/hip ratio (WHR), and central/peripheral skinfold ratio (C/P) by assessing their association with cardiovascular variables (CV) and other anthropometrics. Anthropometry included height, weight, fat mass estimated from bioelectrical impedance, four circumferences, and skinfolds. Maturation variables included menarche in girls, testes size in boys, and pubic hair in both sexes. Cardiovascular variables included resting diastolic and systolic blood pressures and heart rate, and the same three variables after recovery from a step test. The boys and girls were 15 16 years of age, and there were equal numbers in each sex/ethnic group. Partial correlations accounting for height (which was affected by ethnicity) and maturation stratified by gender are reported. C was more strongly related to CV risk in boys and girls than the other indices or the body mass index. Least related to CV risk was C/P, correlated only weakly to central skinfold fat. C and WHR are highly related (0.85) yet differ in important respects in both sexes: C is more closely related to body fat (0.62-0.66) and fat mass (0.53-0.77) than the WHR (respective correlations: 0.54-0.55 and 0.43-0.66). Thus, C relates not only to body shape but also to body fat. Indices of central fat such as circumference and skinfold ratios, may "over-correct" for total fatness and thus miss important aspects of risk prediction. Conicity may be a useful indicator of body fat distribution in studies of adolescents. (c) 1996 Wiley-Liss, Inc. PMID- 28557080 TI - Kinship by isonymy and by gene frequencies: A comparison of population structures at different hierarchical population levels. AB - A comparison of population structures based on isonymy and on gene frequencies (ABO, Rh, Kell) was conducted for a sample of 28,205 individuals residing in three different provinces (Lucca, Massa Carrara, La Spezia) in northwest Italy, on the basis of both chronological and spatial subgroupings. Relationships between and within population subsamples were measured by means of kinship coefficients. The aim of this study was focused on kinship decay with geographic distance, associated with the great difference in location and variability between isonymic and genetic data. The analysis was carried out by Rst statistics and regression analysis to test the fit of the isolation by distance models. Further, the R matrices were converted into a distance measure, and Mantel's permutation test was used to assess the correlation across isonymy, genetic, and geographic matrices. Whereas estimates of Rst and isolation by distance parameters obtained from genetic and surname data pointed to a roughly comparable basic pattern of spatial differentiation in both chronological periods, the absolute values differ substantially. Both Rst and a isolation by distance parameters estimated from genetic data were higher than those from surnames, indicating greater local isolation by genetic analysis. The standard errors of b obtained from surname data were much smaller than those computed from genetic data, indicating that the kinship by isonymy coefficients fit Malecot's model better than the kinship coefficients estimated by the genetic data. Squared correlation coefficients among geographic, surname, and genetic distance matrices supported the above interpretations. The strong localization of surnames, the different level of variability in surname and gene frequency data, and random variations (due to the number of alleles considered) seem to be the main reasons for the observed differences between the two data sets. (c) 1996 Wiley-Liss, Inc. PMID- 28557081 TI - Admixture and relationships of the population of Jacobina, Bahia, Brazil. AB - As part of the Cornell-Bahia project on leishmaniasis, the people of Jacobina in the state of Bahia in northeastern Brazil were studied for five genetic polymorphisms: ABO blood groups, hemoglobin variants, PGM1, 6PGD, and adenylate kinase. A maximum likelihood method of calculation of frequency of genes for these traits indicates that the ancestry of the people is 45% African, 43% Portuguese, and 12% Brazilian Indian. This estimate is similar to previous estimates of admixture in the people of northeastern Brazil, except for more African and less Caucasian ancestry. Previous distance relationships, based upon physical traits only, showed the population of Jacobina to be similar to Seminole Indians of Florida and equally distant from Whites and Blacks. While not strictly comparable, the genetic and morphologic pictures of relationships are compatible and show concordance with surnames. The presence of Hemoglobin C and the frequencies of alleles of PGM1 and 6PGD in the Jacobina population are consistent with the greater importation of Africans into Brazil from Costa de Mina on the Guinea Coast than from Angola. (c) 1996 Wiley-Liss, Inc. PMID- 28557082 TI - Activity reduction as an adaptive response to seasonal hunger. AB - This paper investigates whether physical activity and productive work effort are reduced in response to nutritional stress during hunger seasons by examining patterns of association between nutritional status and both physical activity and behavior patterns among Lese horticulturists of northeast Zaire. Three predictions are derived and tested: (1) reduction of physical activity will not occur until after significant depletion of body energy stores, (2) reduction of physical activity will be correlated with weight loss and with loss of lean body mass, and (3) less essential activities will be curtailed prior to more essential activities. Anthropometric dimensions and behavioral observations were taken during the 31/2 month 1991 Lese hunger season. Among men with a BMI <18.5 kg/m2 and among men with summed skinfolds (SSF) below the median, physical activity level was negatively correlated with percentage loss of body weight and percentage loss of upper arm muscle area (UAMA), while there were no significant correlations in men above these thresholds, supporting predictions 1 and 2. Among women, there was no significant association between nutritional stress and physical activity level. However, patterns of association between nutritional stress and activity budgets suggested that activities that were not essential for short-term survival were curtailed in response to nutritional stress. Among men with SSF below the median, farmwork was negatively correlated with percentage loss of UAMA and positively correlated with minimum SSF, supporting a cycle model of seasonal hunger. (c) 1996 Wiley-Liss, Inc. PMID- 28557083 TI - Path analysis of risk factors leading to premature birth. AB - The present study tested whether various sociodemographic, anthropometric, behavioral, and medical/physiological factors act in a direct or indirect manner on the risk of prematurity using path analysis on a sample of Israeli births. The path model shows that medical complications, primarily toxemia, chorioammionitis, and a previous low birth weight delivery directly and significantly act on the risk of prematurity as do low maternal pregnancy weight gain and ethnicity. Other medical complications, including chronic hypertension, preclampsia, and placental abruption, although significantly correlated with prematurity, act indirectly on prematurity through toxemia. The model further shows that the commonly accepted sociodemographic, anthropometric, and behavioral risk factors act by modifying the development of medical complications that lead to prematurity as opposed to having a direct effect on premature delivery. (c) 1996 Wiley-Liss, Inc. PMID- 28557084 TI - Cytogenetics of autosomal fragile sites: A Basque population study. AB - Population cytogenetic data on autosomal fragile sites show differences among different ethnic groups. The Basques are an ancient population; their origin is not exactly known and many studies using several traits have shown peculiarities in the Basques. This is the first study about the incidence of autosomal fragile sites in a healthy Basque sample. The results show interindividual variability, no sex differences at a global level, but differences for some fragile sites. Compared with other populations, a higher incidence of rare autosomal fragile sites has been demonstrated (8%). (c) 1996 Wiley-Liss, Inc. PMID- 28557085 TI - Ulceration on an old cervical operative scar: Post-surgical pyoderma gangrenosum induced by recent mastectomy. PMID- 28557086 TI - Secular changes in the stature and weight of Taiwanese children, 1964-1988. AB - Secular changes in mean statures and body weights of nationally representative samples of school children from Taiwan, republic of china, between 1964 and 1988 are described. The trend is for continuous increase in both measures from 1964 through 1988, and the more recent data suggest that the positive secular trend is continuing more so in males than in females. Estimated ages at peak height velocity (PHV) and peak weight velocity (PWV), based on the Preece-Baines model I applied to the cross-sectional means, decline linearly in both sexes at about 0.04 yr/yr and 0.05 yr/yr, respectively. Chinese children in Taiwan, Republic of China, are, on average, heavier than Chinese children from the People's Republic of china, but differences in mean statures are negligible. Chinese children in Taiwan mature about 0.5 to 0.7 year earlier (estimated ages at PHV) than those in the People's Republic of China. Estimated rates of secular change in stature tend to be slightly greater in chinese children from the People's Republic of China between the 1950s and 1985 than in Chinese children from Taiwan, Republic of China, between 1964 and 1988. In contrast, estimated rates of secular change in body weight are greater in children from Taiwan than in children from the People's Republic of China. (c) 1995 Wiley-Liss, Inc. PMID- 28557087 TI - Demography in biological anthropology: Human population structure and evolution. AB - The fact of human evolution is evident in the biological variation caused by the pattern of lines of descent. Theories of human evolution are the explanations of the fertility and mortality differentials that determine patterns of variation at the subspecific level. Migrations also influence the patterns. Because human beings plan migrations and marriages, theories relying solely on selective advantage and gene diffusion do not fully account for the observed patterns. These patterns can be interpreted through time and space as dense thickets of descent lines, often clustered into local fascicles held together by inbreeding. The patterns of descent lines are thus punctuated by births, sometimes ended by extinction of lines, but marked also by rich interconnections of the fascicles by filaments that represent marital migration. The patterns are neither solely of racial isolates nor of simple diffusion, but are the result of the complex sociocultural events that influence genetic demography, a field of study that some of Ed Hunt's work foreshadowed. (c) 1995 Wiley-Liss, Inc. PMID- 28557088 TI - Dissociation between skinfold thickness changes and growth of adipose tissue volume in children and youth. AB - The purpose of this investigation was to determine whether there is a divergence in the relationship between skinfold thickness and an adipose tissue volume (ATV) corresponding to the same segment of the body during growth. Anthropometric data from the cross-sectional Coquitlam Growth Study (COGRO) were used to estimate the ATV of the arm, calf, thigh, and trunk in 6- to 18 years old girls (n = 458) and boys (n = 487). Assuring a cylindrical shape for body segments, ATV was calculated by subtracting an inner cylinder of muscle, bone, and residual from the total cylindrical volume of a given segment. Combined graphical analysis of both skinfold growth and growth of ATV reveals that a decrease in skinfold can occur without a concomitant decrease in its corresponding regional ATV. This happens more dramatically in boys than in girls, and in the limbs than in the trunk. This suggests that exaggerated growth in length and/or muscle girth cause a "spreading" and "thinning" of the adipose tissue layer, which does not necessarily reflect fat loss. The meaning of changes in skinfold thicknesses during growth thus needs evaluation. (c) 1995 Wiley-Liss, Inc. PMID- 28557089 TI - Sexual dimorphism in modern Japanese crania. AB - The Japanese population has gone through significant micro-evolutionary changes during the last half century. One approach to quantify these changes is an osteometric analysis of sexual variation in the skeleton. The present study evaluates sexual dimorphism in modern Japanese cranial dimensions. Comprehensive osteometric data were obtained from 84 modern Japanese skeletons of known sex and age at death from the dissecting room collection at Jikei Medical University, Tokyo. The remains were macerated between 1960 and 1970 and thus are from individuals who lived through World War II. A total of 16 cranial dimensions were subjected to SPSS-X discriminant function analysis. Using 11 measurements of the cranium, five dimensions were selected by the stepwise discriminant methods, including bigonial breadth. In a second stepwise function using 11 cranial measurements, seven contributed to the function. In both functions, mastoid height was selected first and prediction accuracy averaged 84%. Because of its significant contribution, a function was calculated from mastoid height alone. This produced an average of 74% prediction accuracy. In general, width dimensions better reflected differences between the sexes. The accuracy of correct classification from the Jikei sample was slightly lower than those of earlier Japanese populations. The results of this study also suggested that sexual dimorphism in Japanese crania may have decreased as a result of an increase in size of females. (c) 1995 Wiley-Liss, Inc. PMID- 28557090 TI - A special tribute in honor of Edward Eyre Hunt, Jr. PMID- 28557091 TI - Growth in stature in early, average, and late maturing children of the Caracas mixed-longitudinal study. AB - A sample of 113 boys and 101 girls of the Caracas Mixed-Longitudinal Study was grouped into early, average, and late maturers according to selected cut-off points of the 10th and 90th centiles for age at peak height velocity (APHV). Individual curves were fitted with the cubic spline function, in which height velocity corresponds to the first derivative. Age at menarche (AM) was estimated by recall in a longitudinal context. Differences between groups were assessed with F and t-tests. Girls were approximately 2 years earlier than boys in APHV and thus significantly shorter; their estimated PHV was also significantly lower. APHV in boys and girls occurred 0.4-0.6 years earlier than in European children, which is consistent with a faster tempo of growth of Venezuelan youth. The three maturity groups differed significantly in timing, stature, and AM. Early maturers were taller than average maturers, and the latter were taller than late maturers with maximal differences between the extreme groups at ages 13-14 in boys and 11 12 in girls. Early maturers grew at a faster rate than average maturers, and the latter grew at a faster rate than late maturers up to 13 years in boys and 10-11 years in girls. Despite difficulties encountered in the analysis of mixed-linked longitudinal data, meaningful growth differences were found between maturity groups of urban Venezuelan children. (c) 1995 Wiley-Liss, Inc. PMID- 28557092 TI - Associations between maternal and fetal serum levels of immune activation markers and fetal growth. AB - During pregnancy, signs of maternal immunologic sensitization to fetal HLA and other fetoplacental alloantigens are often detectable in peripheral blood. Presumbly, this in part reflects immune activity at the maternal-fetal interface. This response may involve activation of maternal T cells, which stimulate placental growth via lymphokine production. To shed light on this mechanism, data on placental weight, neonatal anthropometry, gestational age, fetomaternal HLA relationships (reflecting a potential for HLA allosensitization), and serum levels of three immune activation markers in maternal and cord blood were collected in a sample of 61 primiparous women and their neonates. The activation markers were soluble CD8 antigen (sCD8), interleukin-2 receptor (sIL-2R), and beta-2 microglobulin (beta2 m). Mean fetal and maternal sCD8 and beta2 m levels, and mean fetal sIL-2R levels were significantly higher than published norms. Fetal means for all three markers exceeded maternal means, and both sIL-2R and beta2 m were highly correlated between mother and fetus. This suggests that fetal sIL-2R and beta2 m levels result in part from transport or diffusion from the maternal compartment. No associations were found between fetomaternal HLA relationships, activation markers, and placental weight. The difference between the fetal and maternal beta2 m value was significantly correlated with birth weight, controlling for chest circumference and crown-heel length. Associations between birth weight and fetomaternal HLA relationships could not be interpreted with certainty. These findings suggest that maternal immune activation and diffusion or transport of beta2 m into fetal compartment enhances fetal growth in fat-free body mass. (c) 1995 Wiley-Liss, Inc. PMID- 28557093 TI - Stature and stature distribution in recent West German and historic samples of Italian and Dutch conscripts. AB - Based on the standard for the natural distribution of stature obtained from 11,851,168 West German conscripts (born in 1938-1971), stature and stature distribution were investigated in historic samples of Italian (born 1854-1963) and Dutch (drafts of 1863-1970) conscripts. Both stature and stature distribution in the historic Italian and Dutch samples showed a variety of characteristic deviations from the natural stature distribution of the modern populations, which strongly suggest that there are at least two developmental periods that are sensitive to socioeconomic events with regard to final stature. Environmental disasters during pregnancy and the first year of life lead to a ubiquitous reduction of mean stature in the total cohort affected. This is obvious in Italians born in 1945, who are 3.7 mm shorter than those born in 1944, and 7.9 mm shorter than those born in 1946. An even stronger suppression of final stature by more than 12 mm is obvious in Italians born in 1899 and 1900. Stature distribution, however, is influenced by environmental factors during adolescence. Particularly small persons become numerous during periods of war and economic depression. This is evident in the 19th century Dutch and Italian samples, and during the early 1920s. Changes in developmental tempo seem unlikely to cause these effects. (c) 1995 Wiley-Liss, Inc. PMID- 28557094 TI - Effects of religion, economics, and geography on genetic structure of Fogo Island, Newfoundland. AB - The population structure of Fogo Island, Newfoundland is described using geography, religious affiliation, economic factors (such as the presence of a fish-packing plant), and genetic markers. Five different analytic methods, R matrix analysis, rii VS. mean per locus heterozygosity, predicted kinship (phi), mean first passage time, and Mantel matrix comparisons, were applied to the Fogo Island genetic and demographic data. The results suggest that geography plays a role on Fogo Island in the distribution of genes, while religion, ethnicity, and economic factors play less significant roles. The communities with fish-packing plants and tourism serve as migratory "sinks" for Fogo islanders seeking employment. Reproductively, the most isolated village on Fogo Island is Tilting, and this is reflected in its genetic uniqueness, initially caused by Irish settlement and subsequently the action of stochastic processes. (c) 1995 Wiley Liss, Inc. PMID- 28557095 TI - Secular changes in the stature, weight, and age at maximum growth increments of urban Chinese girls from the 1950s to 1985. AB - This study focuses on changes in the stature, weight, and age at maximum increments in Chinese urban girls 7-17 years of age between the 1950s and 1985. The data come from anthropometric surbeys in the 1950s, 1960s, 1970s, and 1985 in 17 Chinese cities. An overall increasing trend is apparent for stature and weight. The average increments are 1.91 cm and 0.57 kg per decade for 7 year olds, 3.43 cm per decade for 11 year olds, 2.11 kg per decade for 13 year olds, and 1.27 cm and 0.73 kg per decade for 17 year olds. Girls in 1985 attained peak growth earlier, by 1.08 years or 0.04 year/decade, than girls in the generation 30 years earlier. Specific comprisons of changes in body size and age at maximum increments during 1950-1960, 1960-1970, and 1970-1985 are also reported, and the results are compared with those of other countries or groups. (c) 1995 Wiley Liss, Inc. PMID- 28557096 TI - Secular changes in the stature and mass of Western Australian secondary school children. AB - Anthropometric data for 4,683 Western Australian secondary school chidren from the metropolitan area of Perth, Western Australia, were compared with figures compiled in 1940 from the same area. In the 44 year period, the average stature of 12- to 18-year-old males increased by approximately 4% in each 1 year age band and average body mass increased by 15%. Over the same period, girls of similar age showed stature increases with a mean value of 2% for each 1 year age group and average mass increases of 11%. The magnitude of the secular increase declined with age from 12 to 17 years. Standard deviations for the 1940 data were not presented; hence, the statistical significance of any difference between mean values could not be established. The body mass index (BMI) estimates from 1940 were lower at all ages for both sexes than the actual BMI data from 1984. (c) 1995 Wiley-Liss, Inc. PMID- 28557097 TI - Sex ratio of livebirths in Micronesia. AB - A growing body of data extends Hunt's earlier findings from Yap to suggest a characteristic Micronesian pattern of highly masculinized secondary sex ratios. Using materials from an extensive family record register for pre-World War II Guam, it is now possible to examine parental age and birth order effects in a Micronesian population in which the overall sex ratio of livebirths to 3,406 formally wed and fertile couples was 109.6. In contrast to the results of most studies among Euroamerican groups, secondary sex ratios on Guam were significantly higher for higher order births and for paternal age at last recorded birth to older couples. This apparent anomaly is resolved, however, and James' hypothesis of human sex ratio determination is supported when universalistic assumptions of declinin coital frequencies with spousal age and marital duration are replaced by more appropriate and population-specific ethnodemographic information. (c) 1995 Wiley-Liss, Inc. PMID- 28557098 TI - Subsistence patterns and blood pressure variation in two rural Caboclo communities of Marajo Island, Para, Brazil. AB - Blood pressure (BP) increases with age in westernized societies, is higher in men, and is correlated with the body mass index (BMI). Traditional societies present more variable patterns of BP. In 1991, BP and anthropometric data from two "Caboclo" (rural populations of mixed ancestry) groups from Marajo Island, Brazil, were collected: The Paricatuba group, (N = 20;12 women), with a subsistence base of fishing, collection of palm fruits, and traditional gardening; and the Praia Grande group (N = 26; 14 women), where subsistence is based on mechanized agriculture. In Paricatuba, mean BP is 109/74 mmHg in men and 101/70 mmHg in women. There are no significant differences between BP of men and women, and systolic blood pressure (SBP) increases with age. Both SBP and diastolic blood pressure (DBP) are associated with weight, but only DBP is associated with the BMI, while SBP is associated with stature. In Praia Grande, mean BP is 120/76 mmHg in men and 118/70 mmHg in women, with no significant differences between the sexes. In Praia Grande, SBP is higher than in Paricatuba, and both SBP and DBP are associated with age. Compared with urban groups, both Caboclo samples have low BP. Still, differences in BP and body habitus between the two groups support a hypothesis that degree of westernization influences mean levels of BP in rural Amazonian populations. Further, the results also may be interpreted as suggesting that associations of sex, age, and BMI with BP, commonly reported in urban samples, are a byproduct of westernization rather than a result of genetic factors. (c) 1995 Wiley-Liss, Inc. PMID- 28557099 TI - Age assessment of the Spitalfields cemetery population by rib phase analysis. AB - Accurate paleodemographic reconstruction depends in large part on the ability to estimate age at death from the skeleton. Thus, it is important to evaluate the reliability of standards utilized for this assessment. The rib phase technique has proven to be one of the most consistently reliable means of determining age in modern human adults. A recent study also demonstrated that this method can be applied to Neandertals because they exhibit the same pattern of age-related change. However, the efficacy of the rib phases in aging archaeological populations of anatomically modern humans has not been systematically examined. Therefore, the purpose of this paper is to determine if ribs from the 16th to 18th century Spitalfields cemetery population (with church records of age at death) manifest a morphological aging pattern similar to that found in the recent specimens upon which the rib phase standards are based. Age was assessed on a sample of 87 individuals using only the sternal ends of the ribs without access to the rest of the skeleton or records of age and sex. Results indicated that Spitalfields ribs exhibit essentially the same aging patterns found in the ribs of modern Whites. Overall, the demographic profile generated from the ribs produced a good approximation of this sample in both range and distribution. Error was in the direction of underaging, and results for males were better than for females. The present findings indicate that the rib can be considered a reliable site for age estimation in archaeological populations. (c) 1995 Wiley Liss, Inc. PMID- 28557100 TI - Staff perspectives: What is the function of adult mental health day hospital programs? AB - : WHAT IS KNOWN ON THE SUBJECT?: Psychiatric day hospital (DH) treatment has been offered since the 1930s and is appropriate for individuals experiencing intense psychiatric symptoms without requiring 24-hour inpatient care. No empirical research has examined the specific purpose of DH treatment from the perspectives of healthcare providers within these programs. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This study was the first to address the question of the purpose and function of DH treatment from the outlook of frontline workers within this setting, and confirmed anecdotal observations that DH treatment provides an alternative to intensive psychiatric care, and also operates as "bridge" between these intensive services and purely outpatient treatment. Additional information emerged, such as the importance of the name of DH programs avoiding connotations of illness, the benefits and skills that draw patients to these programs, and challenges that staff and patients experience within DH programs (e.g. short length of treatment, barriers to treatment access). WHAT ARE THE IMPLICATIONS FOR PRACTICE?: This information can enhance curriculum development within these settings. For example, given the importance of skill building, it is essential to integrate the provision of skill building and coping strategies within these settings. In addition, given that the name of the setting can impact staff (and perhaps service users as well), ensuring that the name of such program highlight wellness and recovery may enable a different type of therapeutic community to develop within these settings. ABSTRACT: Introduction Despite the benefits of psychiatric day hospitals (DH), research has not addressed staff perspectives of these programs' effectiveness and barriers. Aim To elucidate staff perceptions of Adult Mental Health DH programs at two hospitals in Canada, allowing for improved programming, enhanced structure and increased understanding of DH settings within the continuum of care. Method Twenty-five DH staff members completed semi structured qualitative interviews. Two independent coders applied content analysis to achieve data saturation. Results Four major themes emerged: (1) program purpose and function, (2) what is in a name, (3) perceived patient motivation, and (4) room for improvement. Discussion Findings highlighted the importance of a multidisciplinary team delivering education and skill-focused interventions. Services were cited as "bridging" different mental health settings. Challenges included barriers to treatment access and inadequate length of treatment. Implications for Practice Understanding the function and purpose of this treatment service may enhance service delivery by enabling programs to integrate identified key ingredients. Providers can also note treatment duration and consider how to best use that time. Finally, language used within a DH setting appears to impact staff delivering services, and may also alter patients' understanding of the services they will receive and purpose of the program. PMID- 28557101 TI - The association between interval from acceptance to first-time donation, missed first appointment and future donation behaviour. AB - BACKGROUND AND OBJECTIVES: We examined the association of the interval between the date an individual is accepted for blood donation and the date of first donation (IFD-interval, index-to-first-time donation interval) and missed first appointment with future donation behaviour among new donors. These two variables have not been analysed in previous studies of donation behaviour among new donors. METHODS: Categories were generated for age (18-29 vs 30-65 years), missed appointment status (no-show vs same-day cancellation) and the IFD-interval [short (<=median time) vs long (>median time)]. Accepted donors (n = 807) were followed for 19 months. Outcome measures were first-appointment attendance rates, return rates among first-time donors and the proportion of experienced donors, defined as those who gave >=5 donations. RESULTS: In logistic regression analyses, high no-show rates were significantly associated with decreased likelihood of first time donation. Long IFD-intervals were significantly associated with decreased likelihood of returning for a second donation among first-time donors. Experienced donors, compared to novice donors, were more likely to be male than female, older than younger and with shorter vs longer IFD-intervals. CONCLUSIONS: No-show and long IFD-intervals may be behavioural markers of low levels of motivation for making the first donation and for returning for a second donation, respectively. PMID- 28557102 TI - Oncologic safety of cervical nerve preservation in neck dissection for head and neck cancer. AB - BACKGROUND: Although the functional merits of preserving cervical nerves in neck dissection for head and neck cancer have been reported, the oncologic safety has not yet been determined. Therefore, the purpose of this study was to evaluate the safety of cervical nerve preservation. METHODS: A retrospective chart review was performed on patients with head and neck cancer who had been treated by neck dissection between 2009 and 2014 at Kyoto Medical Center. Management of cervical nerves and clinical results were analyzed. RESULTS: A total of 335 sides of neck dissection had been performed in 222 patients. Cervical nerves were preserved in 175 neck sides and resected in 160 sides. The 5-year overall survival (OS) rate calculated by the Kaplan-Meier method was 71%. The 5-year neck control rate was 95% in cervical nerve preserved sides and 89% in cervical nerve resected sides. CONCLUSION: Preserving cervical nerves in neck dissection is oncologically safe in selected cases. PMID- 28557103 TI - Family involvement in timely detection of changes in health of nursing homes residents: A qualitative exploratory study. AB - AIMS AND OBJECTIVES: To explore family perspectives on their involvement in the timely detection of changes in their relatives' health in UK nursing homes. BACKGROUND: Increasingly, policy attention is being paid to the need to reduce hospitalisations for conditions that, if detected and treated in time, could be managed in the community. We know that family continue to be involved in the care of their family members once they have moved into a nursing home. Little is known, however, about family involvement in the timely detection of changes in health in nursing home residents. DESIGN: Qualitative exploratory study with thematic analysis. METHODS: A purposive sampling strategy was applied. Fourteen semi-structured one-to-one interviews with family members of people living in 13 different UK nursing homes. Data were collected from November 2015-March 2016. RESULTS: Families were involved in the timely detection of changes in health in three key ways: noticing signs of changes in health, informing care staff about what they noticed and educating care staff about their family members' changes in health. Families suggested they could be supported to detect timely changes in health by developing effective working practices with care staff. CONCLUSION: Families can provide a special contribution to the process of timely detection in nursing homes. Their involvement needs to be negotiated, better supported, as well as given more legitimacy and structure within the nursing home. RELEVANCE TO CLINICAL PRACTICE: Families could provide much needed support to nursing home nurses, care assistants and managers in timely detection of changes in health. This may be achieved through communication about their preferred involvement on a case-by-case basis as well as providing appropriate support or services. PMID- 28557104 TI - Large variability in CO2 and N2 O emissions and in 15 N site preference of N2 O from reactions of nitrite with lignin and its derivatives at different pH. AB - RATIONALE: Chemodenitrification is an important N2 O source in soil; however, knowledge about the production of CO2 and N2 O from abiotic nitrite-SOM reactions, especially the N2 O isotopic signatures (intramolecular 15 N site preference (SP), and delta15 Nbulk and delta18 O values), is quite limited at present. METHODS: N2 O and CO2 emissions from chemical reactions of nitrite with lignin products were determined with gas chromatography, and their response surfaces as a function of pH from 3 to 6 and nitrite concentration from 0.1 to 0.5 mM were explored with polynomial regression. The intramolecular 15 N distribution of N2 O, as well as delta15 Nbulk and delta18 O values, were measured with an isotope ratio mass spectrometer coupled to an online pre concentration unit. The variability in N2 O SP values was tested from pH 3 to 5, and for nitrite concentrations from 0.3 to 0.5 mM. RESULTS: Both CO2 and N2 O emissions varied largely with pH and the structure of lignin products. The highest N2 O emission occurred at pH 4-5 in 4-hydroxy-3,5-dimethoxybenzaldehyde and 4-hydroxy-3,5-dimethoxybenzoic acid treatments, and at pH 3 in the treatments with lignin, 4-hydroxy-3-methoxybenzaldehyde, 4-hydroxy-3-methoxybenzoic acid, 4 hydroxybenzaldehyde, and 4-hydroxybenzoic acid. A wide range of N2 O SP values (11.9-37.40/00), which was pH dependent and not distinguishable from microbial pathways, was observed at pH 3-5. The delta15 Nbulk and delta18 O values of N2 O were both in a similar range to that reported for fungal denitrification and bacterial denitrification. CONCLUSIONS: These results present the first characterization of the isotopic composition of N2 O from chemodenitrification in pure chemical assays. Chemical reactions of nitrite with lignin are pH-dependent and associated with substantial CO2 and N2 O emissions. The SP values of N2 O derived from chemodenitrification were neither distinguishable from the biotic pathways nor remained stable with varying pH. Therefore, the use of N2 O isotopic signatures for source partitioning is restricted when chemodenitrification is contributing significantly to N2 O emission. PMID- 28557105 TI - Major response to pembrolizumab in two patients with locally advanced cutaneous squamous cell carcinoma. PMID- 28557106 TI - Clinical feasibility of pre-operative neurodevelopmental assessment of infants undergoing open heart surgery. AB - AIM: Assessing the neurodevelopmental status of infants with congenital heart disease before surgery provides a means of identifying those at heightened risk of developmental delay. This study aimed to investigate factors impacting clinical feasibility of pre-operative neurodevelopmental assessment of infants undergoing early open heart surgery. METHODS: Infants who underwent open heart surgery prior to 4 months of age participated in this cross-sectional study. The Test of Infant Motor Performance and Prechtl's Assessment of General Movements were undertaken on infants pre-operatively. When assessments could not be undertaken, reasons were ascribed to either infant or environmental circumstances. Demographic data and Aristotle scores were compared between groups of infants who did or did not undergo assessment. Binary logistic regression was used to explore associations. RESULTS: A total of 60 infants participated in the study. Median gestational age was 38.78 weeks (interquartile range: 36.93-39.72). Of these infants, 37 (62%) were unable to undergo pre-operative assessment. Twenty-four (40%) could not complete assessment due to infant-related factors and 13 (22%) due to environmental-related factors. For every point increase in the Aristotle Patient-Adjusted Complexity score, the infants likelihood of being unable to undergo assessment increased by 35% (odds ratio: 0.35; 95% confidence interval: 1.03-1.77, P = 0.03). CONCLUSION: Over half of the infants undergoing open heart surgery were unable to complete pre-operative neurodevelopmental assessment. The primary reason for this was infant-related medical instability. Findings suggest further research is warranted to investigate whether the Aristotle Patient-Adjusted Complexity score might serve as an indicator to inform developmental surveillance with this medically fragile cohort. PMID- 28557107 TI - Case of linear immunoglobulin A/immunoglobulin G bullous dermatosis showing immunoglobulin G reactivity with the 120-kDa LAD-1. PMID- 28557108 TI - Thromboelastography (TEG) or thromboelastometry (ROTEM) to monitor haemostatic treatment versus usual care in adults or children with bleeding. PMID- 28557109 TI - Identification of two secondary acyltransferases of lipid A in Pseudomonas putida KT2442. AB - AIMS: Identify the secondary acyltransferases of lipid A in Pseudomonas putida. METHODS AND RESULTS: Two homologues of Escherichia coli acyltransferase LpxL, encoded by PP_0063 and PP_1735, exist in P. putida. Pseudomonas putida mutant strains KWZ001 and KWZ002 were constructed by deleting the genes PP_0063 and PP_1735 respectively. Lipid A species were isolated from P. putidaKT2442, KWZ001 and KWZ002, respectively, and analysed by using electrospray ionization/mass spectrometry (ESI/MS). The results suggest that both PP_0063 and PP_1735 encode secondary acyltransferase of lipid A in P. putida. To further study the site specificity of these two acyltransferases, PP_0063, PP_1735 and Escherichia coli lpxL were overexpressed in KWZ001 and KWZ002 respectively. Lipid A species isolated from these recombinant strains were analysed by using ESI/MS, and the results suggest that the acyltransferase encoded by PP_0063 catalyses the addition of the 2-OH-C12:0 chain at the 2-position and the acyltransferase encoded by PP_1735 catalyses the addition of the C12:0 chain to the 2'-position of lipid A in P. putida. CONCLUSION: The two acyltransferases encoded by PP_0063 and PP_1735, respectively, are responsible for the site-specific additions of the two secondary acyl chains at the 2- and 2'-positions of lipid A in P. putida. SIGNIFICANCE AND IMPACT OF THE STUDY: Understanding the lipid A structure variation in P. putida might provide new clues for the survival of P. putida under various stress conditions. PMID- 28557111 TI - Tetranitromethane: A Nightmare of Molecular Flexibility in the Gaseous and Solid States. AB - After numerous attempts over the last seven decades to obtain a structure for the simple, highly symmetric molecule tetranitromethane (C(NO2 )4 , TNM) that is consistent with results from diffraction experiments and spectroscopic analysis, the structure has now been determined in the gas phase and the solid state. For the gas phase, a new approach based on a four-dimensional dynamic model for describing the correlated torsional dynamics of the four C-NO2 units was necessary to describe the experimental gas-phase electron diffraction intensities. A model describing a highly disordered high-temperature crystalline phase was also established, and the structure of an ordered low-temperature phase was determined by X-ray diffraction. TNM is a prime example of molecular flexibility, bringing structural methods to the limits of their applicability. PMID- 28557110 TI - Dose-escalation study evaluating pegylated interferon alpha-2a in patients with cutaneous T-cell lymphoma. AB - BACKGROUND: This open-label, multicenter, dose-escalation study evaluated the safety, tolerability, and efficacy of subcutaneous pegylated (40 kD) interferon alpha-2a (PEG-IFN alpha-2a) in patients with cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: PEG-IFN alpha-2a was administered subcutaneously at 180 (n = 4), 270 (n = 6), or 360 MUg (n = 3) once weekly for 12 weeks. Efficacy was assessed by the proportion of patients with complete response (CR) or partial response (PR). RESULTS: PEG-IFN alpha-2a was generally well tolerated, with a moderate number of reductions or withholding of doses because of adverse events (AEs) (25% (n = 1), 66% (n = 4), and 0% (n = 0) in the 180-, 270-, and 360 MUg/week groups, respectively). The only dose-limiting toxicity was a grade 3 elevation of liver enzymes in the 270-MUg dose group. The most common AEs were fatigue, acute flu-like symptoms, and hepatic toxicity. The major response rate (CR or PR) was 50% in the 180-MUg group (CR, 50%; PR, 0%), 83% in the 270-MUg group (CR, 67%; PR, 17%), and 66% in the 360-MUg group (CR, 33%; PR, 33%). CONCLUSION: PEG-IFN alpha-2a at doses up to 360 MUg once weekly was well tolerated in patients with CTCL up to the highest dose group and showed good response rates. Due to their good tolerance even in high doses, they might be an option for patients not tolerating standard IFN-alpha preparations. However, for this purpose and to evaluate comparability between standard and PEG-IFN larger clinical trials are needed, alone and in combination with oral photochemotherapy (PUVA). PMID- 28557113 TI - Governing citizens and health professionals at a distance: A critical discourse analysis of policies of intersectorial collaboration in Danish health-care. AB - It is widely recognised that the delivery of services across health-care sectors faces multiple challenges related to incoherence in patient pathways. There are multiple reasons for this incoherence, which are often dealt with through national legislation and policy-making. This paper discusses policies as powerful actors and explores how effects of a concrete policy are adapted for intersectorial collaboration in Danish health-care. The paper is based on a critical discourse analysis of a central policy document in Danish health-care known as the 'Health Agreements'. Using Fairclough's three-dimensional model for discourse analysis, we explored the document to clarify the construction of actors participating in intersectorial collaboration. The analysis revealed the Health Agreement as a 'negotiated text', appearing as an overriding document legitimising one possible discourse regarding the premises of intersectorial collaboration. The premises of intersectorial collaboration are maintained through a specific presentation of actors leaving little room for discussion, where professionals are constructed as actors who are expected to develop ways of collaborating according to the Triple Aim approach in order to promote productivity and efficiency. Furthermore, this presentation constructs citizens and patients as active, participating individuals who consciously prioritise and act with the purpose of controlling their life situation. PMID- 28557112 TI - Effect of androgen deprivation therapy on sexual function and bother in men with prostate cancer: A controlled comparison. AB - OBJECTIVES: The adverse sexual effects of androgen deprivation therapy (ADT) on men with prostate cancer have been well described. Less well known is the relative degree of sexual dysfunction and bother associated with ADT compared to other primary treatment modalities such as radical prostatectomy. We sought to describe the trajectory and relative magnitude of changes in sexual function and bother in men on ADT and to examine demographic and clinical predictors of ADT's adverse sexual effects. METHODS: Prostate cancer patients treated with ADT (n = 60) completed assessments of sexual function and sexual bother 3 times during a 1 year period after the initiation of ADT. Prostate cancer patients treated with radical prostatectomy only and not receiving ADT (n = 85) and men with no history of cancer (n = 86) matched on age and education completed assessments at similar intervals. RESULTS: Androgen deprivation therapy recipients reported worsening sexual function and increasing bother over time compared to controls. Effect sizes for the differences in sexual function were large to very large, and for bother were small to very large. Age younger than 83 years predicted relatively poorer sexual function, and age younger than 78 years predicted greater sexual bother at 12 months in men on ADT compared to men not on ADT. CONCLUSIONS: Most men on ADT for prostate cancer will never return to baseline levels of sexual function. Interventions focused on sexual bother over function and designed to help couples build and maintain satisfying relationship intimacy are likely to more positively affect men's psychological well-being while on ADT than medical or sexual aids targeting sexual dysfunction. PMID- 28557114 TI - Herpes zoster-related aseptic meningitis and encephalomeningitis: A single faculty retrospective case study. PMID- 28557115 TI - James A. Gavan (1916-1994). PMID- 28557116 TI - Age at menarche as an indicator of the socioeconomic situation of rural girls in Poland in 1967, 1977, and 1987. AB - Village girls, 9.5-18.5 years of age, inhabiting various regions of Poland, were surveyed in 1967 (n = 7,886), 1977 (n = 7,771), and 1987 (n = 11,479). Based on the source of income of the families, three groups were identified: farmers, farmer-workers, and nonfarmers. The girls were also divided on the basis of the number of children in the family and education of their fathers. In all three surveys, the earliest age at menarche was observed in girls from the nonfarmer group and the latest in girls from the farmer group. In 1987 the ages at menarche were 13.27 +/- 0.03 years and 13.58 +/- 0.04 years, respectively. The rapid acceleration of menarcheal age (0.64 year) between 1967 and 1977 was halted, and perhaps, reversed from 1977 to 1987 (-0.06 year), reflecting the severe social and economic crisis in Poland. The later menarcheal ages observed in the last decade occur mainly among girls from families with four and five children. Girls from better educated rural families were more affected by the crisis than girls from families in which fathers have only an elementary or vocational training education. (c) 1995 Wiley-Liss, Inc. PMID- 28557117 TI - Inbreeding effects on reproductive outcome among seven tribes of Andhra Pradesh, India. AB - The effects of inbreeding on reproductive outcome in terms of fertility and mortality were analyzed in seven tribal populations from Andhra Pradesh, India. The effect on mortality at both prenatal and prereproductive postnatal stages was further verified after estimating genetic load by an exponential regression model. Relatively higher fertility and mortality rates were recorded among consanguineous marriages than nonconsanguineous unions in the majority of tribes. The regression analysis indicated a positive, nonsignificant association between inbreeding and mortality in five tribes. Low B/A ratios were found in five tribes. (c) 1995 Wiley-Liss, Inc. PMID- 28557118 TI - Effect of drink pattern and solar radiation on thermoregulation and fluid balance during exercise in chronically heat acclimatized children. AB - The purposes of this study were to examine the thermoregulatory and body fluid balance responses in chronically heat acclimatized children, i.e., indigenous to a tropical climate, during exercise in four outdoor conditions and the effects of dehydration on their thermoregulatory response. Nine children (age = 13.3 +/- 1.9 yr, VO2 max = 45.5 +/- 9.2 ml . kg-1 . min-1 ) cycled at 60% VO2 max each under four conditions: sun exposure voluntary drinking (SuVD), sun exposure forced drinking (SuFD), shaded voluntary drinking (ShVD), and shaded forced drinking (ShFD). Exercise sessions consisted of four 20-min exercise bouts alternating with 25-min rest periods. Globe temperature and the WBGT index were higher during SuVD and SuFD compared to ShVD and ShFD (P < 0.05). The change in rectal temperature, metabolic heat production, and heat storage did not differ among the conditions. Total water intake (% IBW) was higher during SuFD (4.1 +/- 0.01) and ShFD (3.7 +/- 0.1) compared to SuVD (2.1 +/- 0.1) and ShVD (1.0 +/- 0.1) and during SuVD compared to ShVD (P < 0.05). Sweating rate (L . hr-1 ) was higher during SuFD (0.7 +/- 0.1) and ShFD (0.6 +/- 0.1) compared to SuVD (0.5 +/- 0.1) and ShVD (0.4 +/- 0.1) (P < 0.05). Total fluid loss did not differ among conditions (SuVD = 1.7 +/- 0.4; SuFD = 1.5 +/- 0.4; ShVD = 2.1 +/- 0.2; ShFD = 1.3 +/- 0.3). Results indicate that when exercising in a tropical climate, chronically heat acclimatized children demonstrate mild voluntary dehydration and adequate heat dissipation. (c) 1995 Wiley-Liss, Inc. PMID- 28557119 TI - Stability of somatotypes: A longitudinal study of Belgian children age 6 to 17 years. AB - The purpose of this study was to investigate the stability of somatotypes in Belgian children and adolescents, 52 boys and 30 girls, followed longitudinally from 6 to 17 years of age. The anthropometric Heath-Carter somatotypes, with a stature correction for endomorphy, were estimated at 1-year intervals. Mean somatotypes were most different between the earliest and oldest ages in both boys and girls. For boys, the means from 9 to 13 years and from 14 to 17 years did not differ. Means were 2-4-21/2, 21/2-4-4, and 2-4-4 at 6, 12, and 17 years, respectively. The scatter of somatotypes about their means was smallest at 6-8 years and greatest at 11-13 years in both boys and girls (P <0.05). For girls, the mean somatotypes from 8 or 9 years through adolescence were not different, although they tended to become more meso-endomorphic. Means were 2-41/2-21/2, 3-4 31/2, and 31/2-31/2-3 at 6, 12, and 17 years, respectively. The average migratory distance for boys was 6.4 (range = 3.7-12.9) and 7.8 (3.9-21.8) for girls. Many subjects had changes that were three to four times greater than others. Boys were lower in ectomorphy at 6-8 years than at older ages, while girls were higher in mesomorphy at 6 than at 12-17 years (P <.05). Interage partial correlations for each component were highest (r2 ? .49) between adjacent years, but were poor to moderate as time intervals increased. The findings of this longitudinal study confirm and further define the instability of somatotypes previously observed in cross-sectional studies of Belgian children and adolescents. (c) 1995 Wiley-Liss, Inc. PMID- 28557120 TI - Precision of the one- versus two-handed method of skinfold measurement in the obese. AB - Skinfolds at five anatomic sites were measured on 47 subjects in a study of gallbladder disease in Starr County, Texas, by two methods, one and two handed. A comparison was made of the two methods as to bias and precision. There were statistically significant but biologically unimportant differences (on the order of 1-2 mm) at four of the five sites. At three of these, the two-handed method gave larger values (lower thigh, triceps, and subscapular), and at the other site (medial calf) this method produced smaller values on average. Measurement precision was improved using the two-handed method at three of the five sites, significantly so for the triceps skinfold. Measuring skinfolds with two hands improves the precision of measurement for some skinfold sites in obese individuals. It does not introduce important and systematic biases across skinfold sites. Adoption of this technique should be used when circumstances outweigh the cost of involving an extra observer in the measurement of skinfold thickness, such as when precision is very important and when subjects are obese. (c) 1995 Wiley-Liss, Inc. PMID- 28557122 TI - Sickle cell gene in Central India: Kinship and geography. AB - A wide range of variation (0.00-0.14) in the frequencies of the HbS allele has been observed among 16 tribes of Orissa, Madhya Pradesh, and Maharashtra. A significant excess of SS individuals over that expected under Hardy-Weinberg equilibrium was observed among 6 of 16 populations. These populations belong to three linguistic groups and have history of heterogeneous origins. A geographical cline of increase in HbS allele frequency from east to west is apparent. This pattern can largely be explained by differential migration. The kinship coefficient (rij ) and paired FST do not show any significant correleation up to 250 km of geographical distance but beyond this distance they show an inverse releationship with increasing geographic distance. Hemoglobin levels between individuals with betaS allele and with normal HbA individuals do not differ in these. (c) 1995 Wiley-Liss, Inc. PMID- 28557121 TI - Relationships of physical fitness, fatness, and lifestyle indicators with blood iron in children and adults. AB - The associations between physical fitness, fatness, activity level, dietary intake and smoking, with indicators of blood iron status are considered in 1,216 children and adults of the Quebec Family Study, 612 males and 604 females, classified into six age groups: 10-14, 15-19, 35-39, 40-44, 45-49, and 50-54 years. Physical fitness was determined as power output at a heart rate of 150 beats per min on a cycle ergometer (PWC150 ) and as strength of the knee extensor muscles. Fatness was estimated with the body mass index (BMI) and the sum of six skinfolds. Activity level and dietary intake were assessed with three-day records. Hemoglobin concentration (Hb), hematocrit (Hct), and serum ferritin of males were greater (P < 0.001) than those of females in all age groups except 10 14 years. Serum ferritin of boys and girls (10-19 years) was significantly lower than in adults. There were no clear relationships between Hb, Hct, and serum ferritin with activity level, physical fitness and body composition. However, smoking was positively correlated with Hb (P < 0.01) and Hct (P < 0.001) in all age groups, except adult females 35-39 years. Using a multiple correlation procedure, the independent variables of the study accounted for about 9% (adult males), 11% (boys), 11% (adult females), and 5% (girls) of the variance in serum ferritin. Thus, activity level, nutritional intake, physical fitness and body fat are only marginally related to blood iron status in this population. (c) 1995 Wiley-Liss, Inc. PMID- 28557123 TI - Coca chewing among high altitude natives: Work and muscular efficiencies of nonhabitual chewers. AB - The leaves of the coca plant (Erythroxylum sp.) have long been chewed by natives of the highland Andes. Folk belief is that the mild stimulant effect is indispensable as an ergogenic aid for strenuous work activities in a high altitude environment. This study explored the exercise responses of 23 nonhabitual coca chewing males who were asked to pedal a bicycle ergometer through a series of submaximal and maximal workloads both with and without coca chewing. The protocol of the exercise test was specifically designed to allow for the determination of work and muscular efficiencies during to submaximal work. The subjects showed no differences between the coca and control work protocols for VO2 max (1/min), VCO2 max (1/min), or maximal work output (watts). Further, there were no differences between coca and control work protocols in oxygen saturation (%), pulmonary ventilation (1/min), or respiratory exchange ratio (VCO2 /VO2 ) at any level of work. Coca chewing caused subjects to have a higher heart rate (bpm) and lower oxygen pulse (ml/beat) for most submaximal workloads and higher ventilatory equivalents (VE/VO2 and VE/VCO2 ) above 50% of VO2 max. Although there was a tendency for higher gross efficiencies (GE) during the coca exercise test at lower relative work levels, between 30-40% of the VO2 max, this difference did not reach significance. Mean net efficiency (NE) was higher (P=0.018) at a relative work level of ~32% of the VO2 max for exercise with coca (23.2% vs. 20.8%). This difference was not apparent at any other work level. The mean delta efficiency (DE) was significantly lower (P = 0.012) for exercise with coca (26.7%) than for exercise without coca (28.2%). These efficiency differences suggest a muscle metabolic effect for coca chewing at low workloads whereby less oxygen is consumed by the muscle to perform a given work task. Howeve, given the difficulty of interpreting efficiency values, it is not entirely clear if the differences are indicative of a work performance benefit for coca chewing. (c) 1995 Wiley-Liss, Inc. PMID- 28557124 TI - A comparison of physical fitness between Igloolik inuit and Volochanka nGanasan. AB - Physical characteristics, muscle strength, and predicted aerobic power were compared in two circumpolar populations aged 20-49 years at different stages in acculturation to a "modern" sedentary life-style: the Inuit of Igloolik (110 males, 80 females tested in 1989-90) and the nGanasan of Volochanka (29 males, 25 females tested in 1992-3). Both populations show short stature but normal body mass. Skinfold thicknesses (average of triceps, subscapular, and suprailiac) of the male Inuit (mean 10-11 mm, rising with age to 15 mm) are now much greater than in previous surveys, reflecting adoption of a mechanized, sedentary life style. Recent estimates from Siberia suggest continuing substantial daily energy expenditures by the men but not the women of this region, and averaged values for the three skinfolds in the nGanasan males (mean 7-8 mm) are still low. In women, both Inuit (mean skinfolds 15 mm, rising to 29 mm with age) and nGanasan (mean 19 mm, rising to 25 mm) are now relatively obese. Compared to the nGanasan, male Inuit have greater handgrip force (probably due to snowmobile operation), but poorer knee extension strength (probably because they now do little walking through snow). In contrast, older nGanasan women have less knee extension strength than the Inuit (probably because the latter still carry babies on their backs). The aerobic power of both Inuit and nGanasan (mean of 48, declining with age to 38-40ml/[kg.min] in males, mean of 38-45 declining with age to 33-37 ml/[kg.min] in females) still corresponds to that of a moderately active urban population. (c) 1995 Wiley-Liss, Inc. PMID- 28557126 TI - Parity, adiposity, and body fat distribution among Hispanic women. AB - The relationship between parity and body fat distribution was investigated in a sample of 1,590 Mexican American, 411 Cuban American, and 657 Puerto Rican women, aged 20-74 years. Participants were interviewed and examined as part of the Hispanic Health and Nutrition Examination Survey, a cross-sectional study of a representative sample of Hispanic populations residing in the United States. In each ethnic group, there was an increase with greater parity in overall body fat (body mass index [BMI], or triceps plus subscapular skinfolds), central vs. peripheral skinfold thicknesses (subscapular/triceps ratio), and upper vs. lower body skinfold thicknesses (subscapular/calf ratio). These positive associations remained after adjusting for age, income, marital status, smoking, menopausal status, and education. They were statistically significant only in the Mexican American group. After controlling for the BMI, the association between parity and the subscapular/ calf ratio remained significant in Mexican Americans, suggesting a relationship between parity and upper body fat distribution independent of body size. (c) 1995 Wiley-Liss, Inc. PMID- 28557125 TI - Comparative study of statural growth in Spanish populations. AB - Regional differences in the growth of Spanish children were studied by fitting the Preece-Baines Model I to cross-sectional stature data. The function parameters and derived biological variables were used to compare children from seven different studies. Regional differences in growth are interpreted as a result of a geographic variation among Spanish provinces in demographic, public health and nutritional conditions. There are differences between urban samples depending on region. Adult stature (h1 ) and the pattern of growth differ between urban and rural populations from the interior lands. Males from urban Extremadura, Barcelona and the Basque Country show the tallest adult statures. Adult statures of males from Segovia, Extremadura emigrants and Cuenca are not only the lowest, but the growth pattern shows delay in estimated ages at take-off and PHV compared to the other populations. Estimated age at PHV is later for all male samples compared to Vizcaya, except for the sample of Barcelona-I. Females from Barcelona-II, Segovia and the Basque Country show the tallest adult statures (h1 ). All of the female samples, except that of urban Extremadura, have an earlier estimated age at PHV compared to the sample from Vizcaya. (c) 1995 Wiley Liss, Inc. PMID- 28557127 TI - Fourteen year changes in adiposity and blood pressure in American Samoan adults. AB - A cohort of 194 American Samoan adults with no history of antihypertensive treatment was seen at two times, 14 years apart, 1976 and 1990. Anthropometric and blood pressure (BP) data in 1976 and 1990, and the chages, were described and correlated within age (<40 and ?40 years) and sex groups. These Samoans are characterized by massive adiposity and body mass, as well as high prevalence and incidence of overweight and hypertension. The younger group had a notable mean increase in the body mass index (BMI) and fatness over 14 years, whereas only younger females had BP increases. Among older females there were small negative mean chages, and in older males small positive mean changes in BMI and skinfolds. In both older males and females, systolic BP increased markedly with little mean change in diastolic BP. There was substantial heterogeneity around the mean chages in all sex-age groups. Adiposity in 1976, assessed by the BMI and skinfolds, was positively related to follow-up BP in all groups except older males. Chages in adiposity were positively related to chages in BP in all groups. Multiple regression analyses showed that change in BMI and age were positively related to 1990 BP after adjustment for baseline BP. (c) 1995 Wiley-Liss, Inc. PMID- 28557129 TI - Recreational stimulants, herbal, and spice cannabis: The core psychobiological processes that underlie their damaging effects. AB - AIMS: Recreational drugs are taken for their positive mood effects, yet their regular usage damages well-being. The psychobiological mechanisms underlying these damaging effects will be debated. METHODS: The empirical literature on recreational cannabinoids and stimulant drugs is reviewed. A theoretical explanation for how they cause similar types of damage is outlined. RESULTS: All psychoactive drugs cause moods and psychological states to fluctuate. The acute mood gains underlie their recreational usage, while the mood deficits on withdrawal explain their addictiveness. Cyclical mood changes are found with every central nervous system stimulant and also occur with cannabis. These mood state changes provide a surface index for more profound psychobiological fluctuations. Homeostatic balance is altered, with repetitive disturbances of the hypothalamic-pituitary-adrenal axis, and disrupted cortisol-neurohormonal secretions. Hence, these drugs cause increased stress, disturbed sleep, neurocognitive impairments, altered brain activity, and psychiatric vulnerability. Equivalent deficits occur with novel psychoactive stimulants such as mephedrone and artificial "spice" cannabinoids. These psychobiological fluctuations underlie drug dependency and make cessation difficult. Psychobiological stability and homeostatic balance are optimally restored by quitting psychoactive drugs. CONCLUSIONS: Recreational stimulants such as cocaine or MDMA (3.4-methylenedioxymethamphetamine) and sedative drugs such as cannabis damage human homeostasis and well-being through similar core psychobiological mechanisms. PMID- 28557128 TI - Detection of gastric atrophy by circulating pepsinogens: A comparison of three assays. AB - BACKGROUND: Circulating levels of pepsinogens have been used in high gastric cancer-risk Asian and European populations to triage endoscopic evaluation for more severe pathology. There are different analytic methods with uncertain correlations. We therefore compared diagnostic performance of three commonly used pepsinogen assays to detect histologically confirmed gastric atrophy. METHODS: We tested plasma samples from adult patients with (n=50) and without (n=755) moderate or severe gastric corpus atrophy, as determined histologically by consensus of three expert pathologists. A single laboratory measured pepsinogens I (PgI) and II (PgII) using commercially available assays: two ELISA assays produced by Biohit (Finland) and Vector Best (Russia), and a latex agglutination assay from Eiken (Japan). Quantitative correlations were assessed by Spearman statistics. Receiver operating characteristic (ROC) curves vs histological diagnosis were calculated using both the manufacturers' and optimized cutoffs. RESULTS: Pepsinogen levels were highly correlated among the assays (pairwise Rhos: PgI>=0.84, PgII>=0.87; all P-values<.01). Based on manufacturers' cutoffs, sensitivities, specificities and areas under the ROC curve for detecting moderate to severe histological corpus atrophy by PgI/PgII were 44%/91%/0.70, 56%/84%/0.76, and 52%/90%/0.77 for Biohit, Vector Best and Eiken, respectively. Cutoffs optimized by ROC or data mining analyses did not substantially improve test performance. CONCLUSIONS: Commercial assays for pepsinogen have good relative agreement but are imperfect tests for clinical diagnosis of gastric atrophy. IMPACT: Pepsinogen testing alone does not provide sufficient information for gastric cancer risk stratification. Future investigations should focus on other potential markers, in combination with pepsinogens. PMID- 28557130 TI - Female sexual pain: Epidemiology and genetic overlap with chronic widespread pain. AB - BACKGROUND: Increased tender spots and lowered general pain thresholds have been observed in patients with dyspareunia. Based on this, the aim of the study was to compare the co-occurrence of female sexual pain across various pain populations and to further explore the aetiological structure underlying sexual pain by dissecting the genetic and environmental covariation among sexual pain, chronic widespread pain (CWP) and the previously reported psychological correlates of anxiety sensitivity and depression. METHODS: A multivariate twin study including 1489 female twin individuals (246 full MZ pairs, 187 full DZ pairs and 623 whose co-twin did not participate). Main outcomes measures included self-reported diagnosis of osteoarthritis and rheumatoid arthritis, and validated questionnaires for the assessment of sexual pain, CWP, depression and anxiety sensitivity. RESULTS: Sexual pain showed a small but statistically significant correlation with CWP (r = 0.08; p < 0.05), anxiety sensitivity (r = 0.15, p < 0.001) and depression (r = 0.09, p < 0.01). The heritability of sexual pain was found to be 31%. Multivariate variance component analysis revealed a genetic factor common among CWP, depression, anxiety sensitivity and sexual pain, and a second genetic factor shared between anxiety sensitivity and sexual pain only. We further detected genetic and environmental factors unique to sexual pain, explaining 24.01% and 67.24%, respectively, of the phenotypic variance. CONCLUSIONS: Our findings suggest some overlap between sexual pain and CWP and point towards a shared but complex psychophysiological aetiology underlying sexual pain. Results further highlight the influence of specific environmental and contextual stressors in the development and maintenance of sexual pain. SIGNIFICANCE: Sexual pain shares a common genetic aetiology with chronic widespread pain and the frequently reported psychological comorbidities of depression and anxiety. Overall this suggests a complex psychophysiological aetiology underlying chronic pain conditions. The high proportion of variance in sexual pain explained by environmental factors further highlights the importance of specific environmental and contextual stressors in the development and maintenance of the condition. PMID- 28557131 TI - Tuberous breast and predisposition to breast deformity in consanguineous. AB - Tuberous breast deformity is a pathologic condition of the breast consisting of a constricting ring at the breast base, reduction in the volume of the breast parenchyma, and herniation of breast tissue through the nipple-areola complex with areola enlargement. This pathology is generally congenital and has an unknown etiopathogenesis. We report the first observation of tuberous breast deformity in consanguineous. This report suggests the potential role of a genetic base in the development of this deformity. Between May 2008 and March 2011, we observed six female patients from two different families, aged between 18 and 55 years, affected by tuberous breast deformity. The breast deformity was characterized by breast asymmetry in all six cases. Four patients underwent surgery to correct the deformity. Standardized objective measurements of breast and chest were taken. A Visual Analog Scale was used to evaluate patients' and physicians' satisfaction. The first three patients were consanguineous; two were first cousins, and the third was second cousin with one of the above. The other three patients were also from the same family: two sisters and their mother. According to Von Heimburg's classification, the patients presented different degrees of breast deformity. In all operated cases, a good esthetic result with a high satisfaction (average visual analog scale score 9) was achieved. The results remained stable over time and no revisions were needed after the 1-year follow up. The possibility of a parental consanguinity for breast deformities such tuberous breast has never been described in the literature. This report suggests the possible genetic role in the development of tuberous breast deformity. Further studies and genetic tests are required to prove this hypothesis. PMID- 28557132 TI - Playing it safe: Patron safety strategies and experience of violence in night time entertainment districts. AB - INTRODUCTION AND AIMS: Incidences of violence are elevated in night-time entertainment districts. Research suggests that safety-related behavioural strategies adopted while drinking can reduce negative alcohol-related outcomes. The current study investigates the use of safety strategies and its association with experiences of violence among patrons from the general population. DESIGN AND METHODS: Patron interviews (N = 3949) were conducted in and around licenced venues in Newcastle (New South Wales) and Geelong (Victoria) during peak trading hours (Friday and Saturday, 21:00-01:00 h). Participants (mean age = 24.3, SD = 5.8; male 54.4%) were asked to report what measures, if any, they used to keep safe when drinking and whether they had been involved in a violent incident in the last 12 months. RESULTS: After controlling for patron demographics and location, the use of multiple (more than one) safety strategies was significantly associated with reduced odds of involvement in a violent incident (odds ratio = 0.64, 95% confidence interval 0.49-0.85, P = 0.002). Significant gender differences were observed in the number and type of safety strategies reported. DISCUSSION AND CONCLUSIONS: Increasing the number of safety-related behaviours during drinking occasions is associated with a small but significant reduction in experiencing alcohol-related harms, such as violence. [Zhou J, Droste N, Curtis A, Zinkiewicz L, Miller P. Playing it safe: Patron safety strategies and experience of violence in night-time entertainment districts. PMID- 28557133 TI - Pharmacological and Toxicological Effects of Catha edulis F. (Khat). AB - Khat chewing is deeply rooted in the culture and tradition of communities in khat belt countries, and its consumption is spread to other countries through the suitcase trade. The aim of this article is to review current knowledge on the chemistry, social, pharmacology and toxicology of khat and its use. Khat produces effect invariably in every system, which is harmful or beneficial in some instances. Harmful effects are observed in heavy users, although firm evidence is lacking. Chewing khat acutely elicits states of euphoria, which is followed by low mood. Khat contains alkaloids with psychostimulant properties, but the effect cannot be totally explained by these alkaloids. It is also not clear whether the effect produced in some organs like liver could be attributed to khat or pesticides sprayed during farming. Although the evidence indicates that khat has adverse effects in most organs, our understanding of the complex interaction between use and effect is incomplete, and causal relationships have not yet been described. Moreover, khat has positioned itself well in the social, economic and political arena. Thus, a multidisciplinary research is required to understand the different dimensions and come up with ways that maximize the benefit while minimizing the risk. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28557134 TI - TGFbeta pathway deregulation and abnormal phospho-SMAD2/3 staining in hereditary cerebral hemorrhage with amyloidosis-Dutch type. AB - Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is an early onset hereditary form of cerebral amyloid angiopathy (CAA) pathology, caused by the E22Q mutation in the amyloid beta (Abeta) peptide. Transforming growth factor beta1 (TGFbeta1) is a key player in vascular fibrosis and in the formation of angiopathic vessels in transgenic mice. Therefore, we investigated whether the TGFbeta pathway is involved in HCHWA-D pathogenesis in human postmortem brain tissue from frontal and occipital lobes. Components of the TGFbeta pathway were analyzed with quantitative RT-PCR. TGFbeta1 and TGFbeta Receptor 2 (TGFBR2) gene expression levels were significantly increased in HCHWA-D in comparison to the controls, in both frontal and occipital lobes. TGFbeta-induced pro-fibrotic target genes were also upregulated. We further assessed pathway activation by detecting phospho-SMAD2/3 (pSMAD2/3), a direct TGFbeta down-stream signaling mediator, using immunohistochemistry. We found abnormal pSMAD2/3 granular deposits specifically on HCHWA-D angiopathic frontal and occipital vessels. We graded pSMAD2/3 accumulation in angiopathic vessels and found a positive correlation with the CAA load independent of the brain area. We also observed pSMAD2/3 granules in a halo surrounding occipital vessels, which was specific for HCHWA-D. The result of this study indicates an upregulation of TGFbeta1 in HCHWA D, as was found previously in AD with CAA pathology. We discuss the possible origins and implications of the TGFbeta pathway deregulation in the microvasculature in HCHWA-D. These findings identify the TGFbeta pathway as a potential biomarker of disease progression and a possible target of therapeutic intervention in HCHWA-D. PMID- 28557135 TI - Labor prediction based on the expression patterns of multiple genes related to cervical maturation in human term pregnancy. AB - PROBLEM: This study explored the possibility of evaluating cervical maturation using swabbed cervical cell samples at term pregnancy, and aimed to develop a novel approach to predict labor onset. METHOD OF STUDY: Women with uncomplicated pregnancies (n=117 from 62 women at term pregnancy) were recruited. Messenger RNA expression levels of cervical cells for ten genes were quantified by qPCR. Principal component analysis (PCA) was conducted, and principal components that significantly contributed to the prediction of days to delivery were determined. RESULTS: PCA demonstrated that 76% of the expression information from the ten genes can be represented by three principal components (PC1-3). By the multiple regression analysis, PC2 and Bishop score but not PC1 or PC3 were significant variables in the prediction of days to delivery. CONCLUSION: These findings support the concurrent assessment of multiple gene activities in cervical cells as a promising approach to predict the initiation of labor. PMID- 28557136 TI - Rhodium-Catalyzed Silylative and Germylative Cyclization with Dehydrogenation Leading to 9-Sila- and 9-Germafluorenes: A Combined Experimental and Computational Mechanistic Study. AB - Stoichiometric amounts of oxidants are widely used as promoters (hydrogen acceptors) in dehydrogenative silylation of C-H bonds. However, the present study demonstrates that silylative and germylative cyclization with dehydrogenation can proceed efficiently, even without hydrogen acceptors. The combination of [RhCl(cod)]2 and PPh3 was effective for both transformations, and allowed a reduction in reaction temperature compared with our previous report. Monitoring of the reactions revealed that both transformations had an induction period for the early stage, and that the rate constant of dehydrogenative germylation was greater than that of dehydrogenative silylation. Competitive reactions in the presence of 3,3-dimethyl-1-butene indicated that the ratio of dehydrogenative metalation and hydrometalation was affected by reaction temperature when a hydrosilane or hydrogermane precursor was used. Further mechanistic insights of oxidant-free dehydrogenative silylation, including the origin of these unique reactivities, were obtained by density functional theory studies. PMID- 28557137 TI - Modulation of CD11c+ lung dendritic cells in respect to TGF-beta in experimental pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a deadly, progressive lung disease with very few treatment options till now. Bleomycin-induced pulmonary fibrosis (BIPF) is a commonly used mice model in IPF research. TGF-beta1 has been shown to play a key role in pulmonary fibrosis (PF). Dendritic cell (DC) acts as a bridge between innate and adaptive immune systems. The coexistence of chronic inflammation sustained by mature DCs with fibrosis suggests that inflammatory phenomenon has key importance in the pathogenesis of pulmonary fibrosis. Here, we investigated the modulation of DCs phenotypic maturation, accumulation in lung tissue, and expression of other lung DC subsets in respect to TGF-beta in PF. First, we established BIPF model in mice and blocked TGF-beta expression by the use of inhibitor SB431542. Accumulation of lung CD11c+ DCs is significantly higher in both inflammatory and fibrotic phases of the disease but that percentages got reduced in the absence of TGF-beta. TGF-beta initiates up-regulation of costimulatory molecules CD86 and CD80 in the inflammatory phases of the disease but not so at fibrotic stage. Expression of lung DC subset CD11c+CD103+ is significantly increased in inflammatory phase and also in fibrotic phase of BIPF. Blocking of TGF-beta causes decreased expression of CD11c+CD103+ DCs. Another important lung DC subset CD11c+CD11b+ expression is suppressed by the absence of TGF-beta after bleomycin administration. CD11c+CD103+ DCs might have anti inflammatory as well as anti-fibrotic nature in PF. All these data demonstrate differential modulation of CD11c+ lung DCs by TGF-beta in experimental PF. PMID- 28557138 TI - Multiple placental surface cysts with intracystic hemorrhaging: A case report and review of the literature. AB - A placental surface cyst is a cystic mass arising from the surface of the placenta. It is seldom complicated by intracystic hemorrhaging and the clinical importance of this kind of case is unclear. Therefore, we present a case of a placental surface cyst with intracystic hemorrhaging. A 29-year-old multiparous woman was diagnosed with multiple placental surface cysts with threatened preterm birth and fetal growth restriction on ultrasonography at 26 gestational weeks (GW). At 31 GW, the hemorrhage was identified inside the cyst. At 32 GW, she presented with placental abruption, and emergency cesarean section was performed. Both the mother and her baby survived. Placental surface cysts up to 77 * 65 mm in diameter containing old hemorrhages were discovered, and pathological examination revealed hemosiderin and fibrin deposition. Pregnancy with a placental surface cyst with intracystic hemorrhaging may have the potential for severe obstetric complications. PMID- 28557139 TI - Functional assignment of multiple ESCRT-III homologs in cell division and budding in Sulfolobus islandicus. AB - The archaea Sulfolobus utilizes the ESCRT-III-based machinery for cell division. This machinery comprises three proteins: CdvA, Eukaryotic-like ESCRT-III and Vps4. In addition to ESCRT-III, Sulfolobus cells also encode three other ESCRT III homologs termed ESCRT-III-1, -2 and -3. Herein, we show that ESCRT-III-1 and 2 in S. islandicus REY15A are localized at midcell between segregating chromosomes, indicating that both are involved in cell division. Genetic analysis reveals that escrt-III-2 is indispensable for cell viability and cells with reduced overall level of ESCRT-III-1 exhibit growth retardation and cytokinesis defect with chain-like cell morphology. In contrast, escrt-III-3 is dispensable for cell division. We show that S. islandicus REY15A cells generate buds when infected with S. tengchongensis spindle shaped-virus 2 (STSV2) or when ESCRT-III 3 is over-expressed. Interestingly, Deltaescrt-III-3 cells infected with STSV2 do not produce buds. These results suggest that ESCRT-III-3 plays an important role in budding. In addition, cells over-expressing the C-terminal truncated mutants of ESCRT-III, ESCRT-III-1 and ESCRT-III-2 are maintained predominantly at the early, late, and membrane abscission stages of cell division respectively, suggesting a crucial role of the ESCRTs at different stages of membrane ingression. Intriguingly, intercellular bridge and midbody-like structures are observed in cells over-expressing MIM2-truncated mutant of ESCRT-III-2. PMID- 28557140 TI - Diet quality of children post-liver transplantation does not differ from healthy children. AB - Little has been studied regarding the diets of children following LTX. The study aim was to assess and compare dietary intake and DQ of healthy children and children post-LTX. Children and adolescents (2-18 years) post-LTX (n=27) and healthy children (n=28) were studied. Anthropometric and demographic data and two 24-hour recalls (one weekend; one weekday) were collected. Intake of added sugar, HFCS, fructose, GI, and GL was calculated. DQ was measured using three validated DQ indices: the HEI-C, the DGI-CA, and the DQI-I. Although no differences in weight-for-age z-scores were observed between groups, children post-LTX had lower height-for-age z-scores than healthy children (P<.01). With the exception of vitamin B12, no significant differences in energy and macronutrient (protein, carbohydrate, and fat), added sugar, HFCS, fructose, GI, GL, and micronutrient intakes and DQ indices (HEI-C, DGI-CA, and DQI-I) between groups were observed (P>.05). The majority of children in both groups (>40%) had low DQ scores. No significant interrelationships between dietary intake, anthropometric, and demographic were found (P>.05). Both healthy and children post-LTX consume diets with poor DQ. This has implications for risk of obesity and metabolic dysregulation, particularly in transplant populations on immunosuppressive therapies. PMID- 28557141 TI - Evaluating the accuracy of theoretical one-bond 13 C?13 C scalar couplings and their ability to predict structure in a natural product. AB - This study explores the feasibility of using a combination of experimental and theoretical 1-bond 13 C?13 C scalar couplings (1 JCC ) to establish structure in organic compounds, including unknowns. Historically, n JCC and n JCH studies have emphasized 2 and 3-bond couplings, yet 1 JCC couplings exhibit significantly larger variations. Moreover, recent improvements in experimental measurement and data processing methods have made 1 JCC data more available. Herein, an approach is evaluated in which a collection of theoretical structures is created from a partial nuclear magnetic resonance structural characterization. Computed 1 JCC values are compared to experimental data to identify candidates giving the best agreement. This process requires knowledge of the error in theoretical methods, thus the B3LYP, B3PW91, and PBE0 functionals are evaluated by comparing to 27 experimental values from INADEQUATE. Respective errors of +/-1.2, +/-3.8, and +/ 2.3 Hz are observed. An initial test of this methodology involves the natural product 5-methylmellein. In this case, only a single candidate matches experimental data with high statistical confidence. This analysis establishes the intramolecular hydrogen-bonding arrangement, ring heteroatom identity, and conformation at one position. This approach is then extended to hydroheptelidic acid, a natural product not fully characterized in prior studies. The experimental/theoretical approach proposed herein identifies a single best-fit structure from among 26 candidates and establishes, for the first time, 1 configuration and 3 conformations to complete the characterization. These results suggest that accurate and complete structural characterizations of many moderately sized organic structures (<800 Da) may be possible using only 1 JCC data. PMID- 28557142 TI - Reaction Acceleration in Thin Films with Continuous Product Deposition for Organic Synthesis. AB - Thin film formats are used to study the Claisen-Schmidt base-catalyzed condensation of 6-hydroxy-1-indanone with substituted benzaldehydes and to compare the reaction acceleration relative to the bulk. Relative acceleration factors initially exceeded 103 and were on the order of 102 at steady state, although the confined volume reaction was not electrostatically driven. Substituent effects were muted compared to those in the corresponding bulk and microdroplet reactions and it is concluded that the rate-limiting step at steady state is reagent transport to the interface. Conditions were found that allowed product deposition from the thin film to occur continuously as the reaction mixture was added and as the solvent evaporated. Yields of 74 % and production rates of 98 mg h-1 were reached in a very simple experimental system that could be multiplexed to greater scales. PMID- 28557143 TI - Liver stiffness reduction correlates with histological characteristics of hepatitis C patients with sustained virological response. AB - BACKGROUND & AIMS: We investigated the correlation between histological characteristics and changes in liver stiffness (LS) in patients with sustained virological response (SVR) using acoustic radiation force impulse (ARFI) elastography. METHODS: In this prospective study, we enrolled 176 hepatitis C patients with SVR who underwent ARFI elastography and liver biopsy before antiviral treatment, and serial ARFI elastography at the end of treatment (EOT) and at 24 weeks after the EOT. To compare the long-term changes in LS in patients with SVR using ARFI elastography, another group of 140 patients who had undergone paired biopsy after achieving SVR was included. RESULTS: Mean LS values were 1.60+/-0.63 m/s, 1.48+/-0.56 m/s and 1.37+/-0.62 m/s at baseline, EOT and 24 weeks after EOT, respectively, P<.001. Higher inflammatory activity at baseline was associated with an improvement in LS at the EOT, with an odds ratio of 1.940. Significant fibrosis at baseline was associated with an improvement in LS at 24 weeks after the EOT, with an odds ratio of 2.617. Among patients in the paired biopsy group with baseline fibrosis stage identical to the ARFI group, LS values at 24 weeks after the EOT did not show any difference with values at 5 years after EOT. CONCLUSIONS: Pre-treatment histological characteristics influence LS reduction after SVR is achieved. PMID- 28557144 TI - Cross-cultural variation in the association between family's socioeconomic status and adolescent alcohol use. AB - INTRODUCTION AND AIMS: This study estimates cross-country variation in socioeconomic disparities in adolescent alcohol use and identifies country-level characteristics associated with these disparities. DESIGN AND METHODS: The association between socioeconomic status (family wealth and parental education) and alcohol use (lifetime use and episodic heavy drinking) of 15- to 16-year-olds from 32 European countries was investigated. Country-level characteristics were national income, income inequality and per capita alcohol consumption. Multilevel modelling was applied. RESULTS: Across countries, lifetime use was lower in wealthy than in less wealthy families (odds ratio [OR](girls) = 0.95, OR(boys) = 0.94). The risk of episodic heavy drinking, in contrast, was higher for children from wealthier families (OR(girls) = 1.04, OR(boys) = 1.08) and lower when parents were highly educated (ORs = 0.95-0.98). Socioeconomic disparities varied substantially between countries. National wealth and income inequality were associated with cross-country variation of disparities in lifetime use in few comparisons, such that among girls, the (negative) effect of family wealth was greatest in countries with unequally distributed income (OR = 0.86). Among boys, the (negative) effect of family wealth was greatest in low-income countries (OR = 1.00), and the (positive) effect of mothers' education was greatest in countries with high income inequality (OR = 1.11). DISCUSSION AND CONCLUSIONS: Socioeconomic disparities in adolescent alcohol use vary across European countries. Broad country-level indicators can explain this variation only to a limited extent, but results point towards slightly greater socioeconomic disparities in drinking in countries of low national income and countries with a high income inequality. [Gomes de Matos E, Kraus L, Hannemann T-V, Soellner R, Piontek D. Cross-cultural variation in the association between family's socioeconomic status and adolescent alcohol use. PMID- 28557146 TI - Coordination-Supported Imidazolate Networks: Water- and Heat-Stable Mesoporous Polymers for Catalysis. AB - The poor water stability of most porous coordination polymers (PCPs) or metal organic frameworks (MOFs) is widely recognized as a barrier hampering their practical applications. Here, a facile and scalable route to prepare metal containing polymers with a good stability in boiling water (100 degrees C, 24 h) and air (up to 390 degrees C) is presented. The bifunctional 1-vinylimidazole (VIm) with a coordinating site and a polymerizable organic group is introduced as the building block. This core strategy includes the synthesis of a rigid monomer with four VIm branches through a coordination process at room temperature, followed by a radical polymerization. We refer to this material as coordination supported imidazolate networks (CINs). Interestingly, CINs are composed of rich mesopores from 2-15 nm, as characterized by low-energy (60 kV) STEM-HAADF images. In particular, the stable CINs illustrate a high turnover frequency (TOF) of 779 h-1 in the catalytic oxidation of phenol with H2 O as the green solvent. PMID- 28557145 TI - Salvage surgery for oropharyngeal squamous cell carcinomas: A retrospective study from 2005 to 2013. AB - BACKGROUND: In the case of a locoregional recurrence of oropharyngeal squamous cell carcinoma, the curative standard of care is surgery. Our main purpose of this study was to determine the preoperative prognostic factors that would allow us to select the patients on whom we could expect good results with salvage surgery. METHODS: We conducted a monocentric retrospective study from 2005 to 2013. It included all patients treated for a recurrence of oropharyngeal squamous cell carcinoma with surgery. Their initial treatment included radiotherapy. RESULTS: Fifty-two patients were included. Poor prognostic factors for survival were the cT status (P = .0039) and local recurrences versus secondary localizations in irradiated areas (P = .016) and a relapse less than a year after the end of the initial treatment (P = .050). Recurrence-free survival was 19% at 5 years. Twenty-nine percent of patients presented local complications, which were mainly fistulas and hemorrhaging at the surgical site. CONCLUSION: According to the high morbimortality, it is important to carefully select the right patients for surgery. PMID- 28557147 TI - Promoting a patient-centred approach in clinical consultations: Summary of a Cochrane review. PMID- 28557149 TI - A qualitative and quantitative evaluation of the peptide characteristics of microwave- and ultrasound-assisted digestion in discovery and targeted proteomic analyses. AB - RATIONALE: Fast digestion methods can dramatically accelerate enzyme digestion and increase the throughput of proteomic analysis. However, the peptide characteristics of fast digestion methods and their performance in discovery and targeted proteomic analysis must be systematically evaluated. METHODS: Three digestion methods, including overnight digestion, microwave-assisted protein enzymatic digestion (MAPED), and high-intensity focused ultrasonic-assisted enzymatic digestion (HIFUSAED), in trypsin or in trypsin/Lys-C were comprehensively compared in both discovery and targeted proteomics analysis using the HeLa cell proteome. In discovery proteomic analysis, the highest numbers of peptides and proteins were identified when the sample was digested via the MAPED method with trypsin/Lys-C. RESULTS: The fast digestion methods showed a higher mis-cleavage rate and a lower semi-tryptic rate than the overnight digestion method. In both label-free quantitative analysis and targeted proteomic analysis, both fully cleaved peptides (FCPs) and mis-cleaved peptides (MCPs) from the fast digestion methods and the overnight digestion method showed good reproducibility if they showed good abundance. CONCLUSIONS: When both the FCPs and MCPs were included in the analysis, the MAPED with trypsin/Lys-C method showed the best results for both discovery proteomic analysis and relative quantitative targeted proteomic analysis. These results will be beneficial for the application of fast digestion methods to proteomics. PMID- 28557148 TI - The impact of recipient BKV shedding before transplant on BKV viruria, DNAemia, and nephropathy post-transplant: A prospective study. AB - We previously demonstrated that detectable BKV replication in donor urine pretransplant was significantly associated with post-transplant recipient BKV viremia. In this 4-year prospective study, we assessed whether recipient BKV replication pretransplant was associated with post-transplant viremia/BKV nephropathy. We studied 220 primary adult and pediatric organ transplant recipients for 490 person-years and 2100 clinical visits. BKV viruria was detectable in 28 (16%), 26 adults and two children; and viremia in none pretransplant. Post-transplant viruria occurred in all recipients with pretransplant BKV viruria, significantly more than in recipients without pretransplant viruria on univariate (P<.005) and multivariate analysis including type of organ transplanted and immunosuppression type (P .008). Time to post transplant viruria was significantly shorter in recipients with pretransplant viruria (P .01). By univariate and multivariate analysis, BKV viruria in recipients pretransplant did not impact post-transplant BKV viremia (P=.97 and .97, respectively) even when stratified by type of organ transplant (kidney P=.6; liver P=.5). The peak serum and urine BKV PCR post-transplant were not significantly different in patients with pretransplant BKV viruria and no one developed BK nephropathy. In conclusion, recipient BKV viruria prior to transplant predicts post-transplant viruria but not viremia or BKV nephropathy. PMID- 28557150 TI - Characterization of CD34-deficient myofibroblastomas of the breast. AB - Mammary myofibroblastoma is a benign spindle cell tumor that can show variable morphologic patterns and lines of differentiation. Diffuse and strong immunohistochemical expression of CD34 is a characteristic of myofibroblastoma and greatly aids in confirming a diagnosis. Myofibroblastoma has been shown to belong to a family of CD34-positive tumors with similar morphology that show a deletion of 13q14, which includes RB1 and FOXO1A genes. The purpose of this study was to better understand a subset of myofibroblastomas that is characteristically CD34-deficient by immunohistochemistry. Six myofibroblastomas were studied by immunohistochemistry and fluorescence in situ hybridization (FISH) for RB1. Patients included five women and one man, aged 41-85 years (median, 52.5). Tumor size ranged from 0.4 to 1.5 cm (mean, 0.95). Tumors showed spindle cell morphology in five cases and epithelioid features in one case. Two tumors showed complete lack of CD34 staining. The remaining showed weak focal or weak patchy CD34 staining. Dichotomous staining was seen in one case with CD34-positive spindle cell areas and CD34-negative myxoid areas. All six tumors showed ER expression, five of six showed desmin expression, and four of six showed bcl-2 positivity. Two of six (33.3%) tumors showed deletion of RB1 by FISH, including one that showed loss of Rb immunohistochemical staining. Myofibroblastomas uncommonly show absent/focal expression of CD34, a potential diagnostic pitfall, particularly in small samples. Characteristic staining with other immunohistochemical markers is seen which can aid in confirming the diagnosis. These tumors may harbor deletion of RB1, similar to CD34-positive myofibroblastomas, and this deletion may not correlate with loss of Rb by immunohistochemistry. PMID- 28557151 TI - Feeding regulation by neuropeptide Y on Asian corn borer Ostrinia furnacalis. AB - The Asian Corn Borer Ostrinia furnacalis is a major agricultural pest. In this study, a full-length neuropeptide Y (npy) gene in O. furnacalis was sequenced and cloned from cDNA library, which contains an ORF of 273 bp by encoding 90 amino acid residues. The mature OfurNPY is composed of 29 amino acids with amidation in C-terminal. The spatiotemporal expression analysis showed that npy highest expression level was in the midgut of the fifth instar larvae (the gluttony period). When the expression of npy was knocked down by feeding or injecting dsNPY, larval food consumption, body size, and body weight were significantly inhibited compared to controls. These results indicate that NPY is an important regulator in the control of feeding of O. furnacalis. PMID- 28557152 TI - Quantified discordant placental echogenicity in twin anemia-polycythemia sequence (TAPS) and middle cerebral artery peak systolic velocity. AB - OBJECTIVE: To quantify sonographic placental echogenicity in twin anemia polycythemia sequence (TAPS) and to correlate it with middle cerebral artery peak systolic velocity (MCA-PSV) measurements. METHODS: We performed a retrospective search for consecutive TAPS cases between 16 and 36 weeks of gestation (MCA-PSV > 1.5 multiples of the median (MoM) in the anemic donor and < 1.0 MoM in the polycythemic recipient) in our database of monochorionic twin gestations from January 2007 until December 2016. In cases for which ultrasound images showing the donor's and the recipient's part of the placenta were available, echogenicity for both twins was quantified by image processing. MCA-PSV Doppler values of both fetuses were correlated to their respective placental echogenicity. Placental thickness of both twins was also measured. RESULTS: Of 756 cases with MCA-PSV measurements identified from the database, 36 (4.8%) had TAPS; of these, 23 had TAPS combined with twin-twin transfusion syndrome and 13 showed isolated TAPS. Placental echogenicity could be quantified in 28 pregnancies. Mean +/- SD placental echogenicity of donor twins was significantly higher than that of recipients (138.7 +/- 22.8 vs 77.9 +/- 37.0; P < 0.0001). Furthermore, a significant positive correlation was found between placental echogenicity and MCA PSV MoM (R = 0.67, P < 0.0001). Mean placental thickness of donor twins (n = 20) was significantly higher than that of recipients (49.3 mm +/- 13.4 vs 25.4 mm +/- 10.1; P < 0.0001). CONCLUSIONS: Echogenicity of the placental share in recipient and donor twins with TAPS correlates with MCA-PSV values. Quantification of sonographic placental echogenicity may help to determine the severity of TAPS in monochorionic twins. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28557153 TI - Genomic evaluation using SNP- and haplotype-based genomic relationship matrices in a closed line of Duroc pigs. AB - A simulation analysis and real phenotype analysis were performed to evaluate the impact of three different relationship matrices on heritability estimation and prediction accuracy in a closed-line breeding of Duroc pigs. The numerator relationship matrix (NRM), single nucleotide polymorphism (SNP)-based genomic relationship matrix (GRM) (GS ), and haplotype-based GRM (GH ) were applied in this study. We used PorcineSNP60 genotype array data (38 114 SNPs) of 831 Duroc pigs with four selection traits. In both heritability estimation and prediction accuracy, the accuracy depended on the number of animals with records. For heritability estimation, a large difference in the results among three relationship matrices was not shown, but the trend of the estimated heritabilities between GRMs, that is GS < GH , was shown in this population. For the accuracy of prediction values in test animals, the accuracies of prediction values obtained by two GRMs were higher than that by the NRM in this population. The accuracies obtained by GRMs using animals with no records were lower than that by the NRM using animals with their performance records, but were close to that by the NRM using animals with full-sib testing records. PMID- 28557155 TI - Tumour-stage mycosis fungoides regressing with milia and pustules after total skin electron beam therapy. PMID- 28557156 TI - Toward Hyperpolarized 19 F Molecular Imaging via Reversible Exchange with Parahydrogen. AB - Fluorine-19 has high NMR detection sensitivity-similar to that of protons-owing to its large gyromagnetic ratio and high natural abundance (100 %). Unlike protons, however, fluorine-19 (19 F) has a negligible occurrence in biological objects, as well as a more sensitive chemical shift. As a result, in vivo 19 F NMR spectroscopy and MR imaging offer advantages of negligible background signal and sensitive reporting of the local molecular environment. Here we report on NMR hyperpolarization of 19 F nuclei using reversible exchange reactions with parahydrogen gas as the source of nuclear spin order. NMR signals of 3 fluoropyridine were enhanced by ~100 fold, corresponding to 0.3 % 19 F nuclear spin polarization (at 9.4 T), using about 50 % parahydrogen. While future optimization efforts will likely significantly increase the hyperpolarization levels, we already demonstrate the utility of 19 F hyperpolarization for high resolution hyperpolarized 19 F imaging and hyperpolarized 19 F pH sensing. PMID- 28557157 TI - Validation of methods for predicting adult stature in Turkish girls. AB - The original or revised methods for prediction of adult stature of Tanner Whitehouse (TW), Roche-Wainer-Thissen (RWT), and Bayley-Pinneau (BP) were validated in a mixed longitudinal study of Turkish girls, 9-14 years of age. Comparison of 727 estimations of 102 girls showed that the RWT'93 revision is an improvement over the original method by reducing the standard deviation, and absolute median and mean of residuals. The TW'83 (3v) method, by dropping the variable midparent stature, was reduced in accuracy before age 12. The addition of the previous annual increment in stature improved the predictions, while further addition of the increment in skeletal age did not. In relation to overall accuracy and reliability, BP (0.75) and TW'75 (0.73) had the highest R2 values, while RWT'75 had the lowest (0.55). Regarding individual consistency of multiple predictions, the RWT methods ranked best and TW'83 relatively poorest. Systematic errors found in Turkish girls were similar to those found in French, Swiss, and Finnish girls. (c) 1995 Wiley-Liss, Inc. PMID- 28557154 TI - A meta-analysis of the relationship between socioeconomic status and executive function performance among children. AB - The relationship between childhood socioeconomic status (SES) and executive function (EF) has recently attracted attention within psychology, following reports of substantial SES disparities in children's EF. Adding to the importance of this relationship, EF has been proposed as a mediator of socioeconomic disparities in lifelong achievement and health. However, evidence about the relationship between childhood SES and EF is mixed, and there has been no systematic attempt to evaluate this relationship across studies. This meta analysis systematically reviewed the literature for studies in which samples of children varying in SES were evaluated on EF, including studies with and without primary hypotheses about SES. The analysis included 8760 children between the ages of 2 and 18 gathered from 25 independent samples. Analyses showed a small but statistically significant correlation between SES and EF across all studies (rrandom = .16, 95% CI [.12, .21]) without correcting for attenuation owing to range restriction or measurement unreliability. Substantial heterogeneity was observed among studies, and a number of factors, including the amount of SES variability in the sample and the number of EF measures used, emerged as moderators. Using only the 15 studies with meaningful SES variability in the sample, the average correlation between SES and EF was small-to-medium in size (rrandom = .22, 95% CI [.17, .27]). Using only the six studies with multiple measures of EF, the relationship was medium in size (rrandom = .28, 95% CI [.18, .37]). In sum, this meta-analysis supports the presence of SES disparities in EF and suggests that they are between small and medium in size, depending on the methods used to measure them. PMID- 28557159 TI - Growth faltering and catch-up growth in relation to environmental change in children of a disadvantaged community from Guatemala City. AB - The extent and persistence of stunting and growth status across a 10-year period, and their relationship to changes in the home environment, have been analyzed using data from a 10-year longitudinal study of three birth cohorts, seen initially at 3, 5, and 7 years and examined annually thereafter. The children came from an economically disadvantaged community located on the periphery of Guatemala City. The sample used in the analysis consisted of 271 subjects with complete growth and SES data over a 10-year period. Stunting was high initially, with 43.5% of the sample displaying USNCHS height z-scores < -2.0 at the first examination. Growth status at the first visit was a significant predictor of status after 10 years. The odds ratio for stunting in adolescence if stunted in early childhood was 18.39. Characteristics of the household at the first visit were a significant determinant of height, weight, estimated arm muscle, the triceps skinfold, and the BMI at the last visit, after adjusting for confounding variables. Changes in household status between the first and last visits were associated with greater growth increments in height and weight but not in the BMI, triceps skinfold, or estimated arm muscle circumference. These analyses have demonstrated that improved growth status during adolescence relative to status 10 years earlier (a form of catch-up growth) was attributable to two factors: first, for the sample as a whole there was a general improvement in growth status with a mean change in height-and weight-for-age z-scores of 0.218 and 0.420, respectively; second, the change in household score from first to last visit was a significant determinant of growth increment over that period, but only in the case of height and weight. Thus, while the early environment is a powerful determinant of later growth status, some catch-up growth can be identified both as a general systemic response as well as a response to changing environmental conditions. (c) 1995 Wiley-Liss, Inc. PMID- 28557158 TI - Red cell enzymes and plasma protein polymorphisms in the population of Cabo Verde (West Africa). AB - The genetic polymorphism of six red cell enzymes (ADA, AK1, ALAD, ESD, GLO1, and PGD) and 10 plasma proteins (AHSG, BF, F13A, F13B, GC, HP, ORM, PLG, TBG, and TF) is analyzed in a sample of 268 unrelated individuals from Cabo Verde (West Africa). The population of Cabo Verde was founded in the 15th century (1462), on the basis of a great number of slaves brought from the West African coast and a few Europeans, mainly from Portugal. The frequencies found in Cabo Verde for the majority of the markers are intermediate between those reported for Africans and Europeans. Further, the presence of alleles which are rarely or never seen in Blacks, but are common in Caucasians, suggest a substantial contribution of Europeans to the gene pool of the population of Cabo Verde. (c) 1995 Wiley-Liss, Inc. PMID- 28557160 TI - The human biology association. PMID- 28557161 TI - Rate of skeletal maturation in relation to secondary sexual development during female adolescence. AB - The relationship between rate of skeletal maturation (interval from capping of hand epiphyses to fusion of radius) and rate of secondary sexual development was studied in a longitudinal sample of 76 normal Turkish girls. The interval from capping to fusion correlated inversely and significantly with the stage of secondary sexual development (SSD) attained at capping. It is concluded that the rate of skeletal maturation and expected growth after the onset of capping are not constant and depend on the stage of secondary sexual characteristic development, the former being shorter with more advanced sexual maturation. (c) 1995 Wiley-Liss, Inc. PMID- 28557162 TI - Comparative study of physiological and anthropometric characteristics of high and low productivity workers in northern West Bengal, India. AB - Lung functiion, selected hematological traits, blood pressures, and anthropometric dimensions were measured on adult Oraon tea garden laborers of both sexes from two tea gardens of Jaipaiguri district, northern West Bengal, India. The laborers were classified into two groups on the basis of work output or productivity, measured in terms of the quantity of green leaves plucked per day. The groups were similar in income, dietary pattern, and self-reported morbidity. Relationships between the measured variables and productivity were evaluated. The results show several significant relationships, but do not conclusively demonstrate that the independent variables under study have any effects on work output. (c) 1995 Wiley-Liss, Inc. PMID- 28557163 TI - Basal metabolic rate of inuit. AB - Basal metabolic rates (BMR) at the end of the winter of 1981-1982 were determined in both Inuit and subjects of European ancestry resident in Igloolik, N.W.T. (69 degrees 40'N, 81 degrees W). Values for the Inuit sample (22 females, 14-53 years, and 30 males, 14-70 years) exceeded published body surface area norms by some 16-18%; they also exceeded the body mass norms of Schofield (1985) by 9-10%. In contrast, readings on the six subjects of European ancestry, obtained by the same observer, using the same Douglas bag technique, agreed closely with both sets of published norms. When data were expressed per unit of lean body mass, values were again 10-12% higher in the Inuit. Concomitant recordings of heart rate did not suggest that the BMRs of the Inuit subjects were increased by anxiety. Contrary to findings in the subjects of European ancestry, BMRs appeared to be higher in the elderly than in young and middle-age Inuit. This could reflect two consequences of a more traditional lifestyle among the older members of the Igloolik population: greater exposure to a very cold external environment, and greater consumption of "country" foods rich in protein and fat. (c) 1995 Wiley-Liss, Inc. PMID- 28557164 TI - Human biology association 1994/1995 members list. PMID- 28557165 TI - Anthropometric indicators of nutritional status and level of mortality. AB - The strength of the relationship between several anthropometric indicators of nutritional status, or more generally, standard of living, with overall mortality at the population level is compared. The anthropometic indicators examined include height, weight, weight-for-height, and weight-for-height2 at various ages. The results demonstrate that height is most closely associated with the level of mortality. Weight-for height2 , in contrast, has the weakest association with mortality. Of the ages examined, age 6 consistently has the strongest relationship with the level of mortality, whereas birthweight and adult measures have the lowest associations with the overall level of mortality, although the results for birthweight may be an artifact of biased data. Curiously, there is little or no sex difference in the slope of the relationship between anthropometric measure and level of mortality after correcting for smaller size and longer life expectancies of females compared to males. Overall, the anthropometric indicators are very highly correlated with mortality, exceeding 0.85 in some cases. This suggests that anthropometric dimensions may be a useful source of corroborative information when attempting to estimate demographic rates for populations where the demographic data are suspect. (c) 1995 Wiley-Liss, Inc. PMID- 28557167 TI - Haptoglobin and birth weight in a Bengalee population. AB - A close relationship between birth weight and synthesis of haptoglobin was found in a study of cord blood derived from newborns. Newborn infants with detectable haptoglobin types showed, on average, significantly higher birth weight than those without detectable haptoglobin types under normal conditions. (c) 1995 Wiley-Liss, Inc. PMID- 28557166 TI - Genetic estimation of the humoral responses to several infectious agents. AB - Heritabilities of antibody levels to measles, rubella, and mumps were estimated in 88 MZ and DZ twin pairs. The contribution of genetic factors in phenotypic antibody levels to measles was somewhat lower than environmental factors in both sexes (h2 = 0.450 and 0.459). A significantly stronger genetic than environmental control of anti-mumps antibody levels was evident in both sexes, but more so in females (h2 = 0.882) than in males (h2 = 0.626). The genetic determination of anti-rubella antibodies was also significantly higher in girls (h2 = 0.833), while environmental determination was greater in boys (h2 = 0.350). (c) 1995 Wiley-Liss, Inc. PMID- 28557168 TI - Age at menarche: Relationships to socioeconomic status, growth rate in stature and weight, and skeletal and sexual maturation. AB - A sample of 114 girls from low-middle and highest socioeconomic levels of Istanbul were followed at 6-month intervals for 7-9 years during adolescence. Results pertaining to age of menarche and its relationship to growth and maturation are presented. No significant difference was found for the occurrence of menarche in relation to season. The age of menarche was 6.6 months earlier in daughters compared to their mothers, but the variation between mothers and daughters was great. In the lower socioeconimic class, age of menarche was significantly later, 12.5 years in the high and 13.4 years in the lower class. Later menarche in the lower class was related to lower rates of growth in stature and weight, and of skeletal and sexual maturation. There was no significant correlation between age at menarche and stature and weight attained at menarche. Those with a faster rate of growth reached menarche early and the height velocity continued to be faster. The median stages of secondary sexual characteristics at menarche were 4 for breast and pubic hair, and 3 for axillary hair. The stage of development at menarche did not differ significantly with age of menarche and social class. Menarche occurred 2.4 years after the appearance of pubic hair, 2.0 years after the appearance of the breast bud, and 1.4 years after the appearance of axillary hair, and the ages at which the secondary sexual characters appeared correlated significantly with the age of menarche. Skeletal age at menarche was 13.0 +/- 0.69 years. Age of menarche correlated best with the age at which fusion of the second and first distal phalanges occurred. The percentage of adult height attained at menarche correlated significantly with the age of menarche. Regression equations and standard errors are presented to aid in the prediction of the age at menarche from other variables related to menarche. PMID- 28557169 TI - Delicate changes of bioapatite mineral in pig femur with addition of dietary xylooligosaccharide: Evidences from Raman spectroscopy and ICP. AB - Bone mineral is strongly correlated with performance and health of animal bodies. The mineral bioapatite (BAp) is the dominant component in bone tissue. This study investigated mineralogical changes of BAp in pig femur by Raman spectroscopy and inductively coupled plasma optical emission spectrometry (ICP-OES). The pigs had been raised with various xylooligosaccharide (XOS) additions at two stages of growth (growing and fattening periods). The results show that XOS can decrease the degree of carbonate substitution for PO4 in BAp mineral and improve the mineral's crystallinity. ICP data is consistent with the Raman results, that is the low solubility of bone BAp for pigs fed with XOS. Additionally, the effect of XOS is much better in the growing period (before 65 kg) than in the fattening period (after 65 kg). Moreover, the high addition of XOS (within the range of 0.1 0.5 g/kg) would be appropriate to improve the crystallinity of bone BAp. This study sheds light on applying Raman and ICP techniques to investigate the delicate changes of mineral in pig bones undergoing different managements. PMID- 28557170 TI - Phenolic compounds inhibit the aldose reductase enzyme from the sheep kidney. AB - Aldose reductase (AR) is the key enzyme for the polyol pathway and responsible for sorbitol accumulation during the hyperglycemia. The present article focuses on the role of phenol, pyrogallol, hydroquinone, resorcinol, catechol, and phloroglucinol in in vitro inhibition of AR. For this purpose, AR was purified from the sheep kidney with 5.33 EU mg-1 specific activity and 0.64% yield using several chromatographic methods. Various concentrations of the compounds were tested on in vitro AR activity. IC50 values were found for phenol, pyrogallol, hydroquinone, resorcinol, catechol, and phloroglucinol as 6.5, 1.13, 5.45, 2.21, 1.8, and 2.09 mM, respectively, and their Ki constant was calculated as 3.45 +/- 0.92, 0.96 +/- 0.28, 3.07 +/- 0.46, 1.59 +/- 0.43, 2.5 +/- 0.35, and 2.54 +/- 0.45 mM, respectively. Pyrogallol showed better inhibitory effect compared to the other compounds. The inhibition mechanisms of all compounds were noncompetitive. In the presents study, in vitro AR inhibition was examined by the phenolic compounds. PMID- 28557171 TI - Efficacy and feasibility of antidepressants for the prevention of migraine in adults: a meta-analysis. AB - BACKGROUND AND PURPOSE: Migraine has greatly impacted the quality of life for migraineurs and was ranked as the seventh highest specific cause of disability worldwide in 2012. Because of the role of serotonin in migraine mechanisms, antidepressants have been used in the prevention of migraine. However, the role of antidepressants for migraine prophylaxis in adults has not been completely established. Our aim was systematically to assess the efficacy and feasibility of antidepressants for the prevention of migraine in adults based on currently available literature. METHODS: A comprehensive search of databases was conducted including the Cochrane, PubMed, Web of Science and Embase databases from inception to July 2016. Randomized controlled trials that assigned adults with a clinical diagnosis of migraine to antidepressant or placebo treatment were included. The primary outcome was the reduction of migraine frequency or index. RESULTS: Overall, 16 randomized controlled trials including 1082 participants were identified. Antidepressants had a significant advantage over placebo in reducing the migraine frequency or index of adults with a standardized mean difference of -0.79 [95% confidence interval (CI) -1.13 to -0.45, P < 0.00001]. Patients receiving antidepressant therapy were more likely to experience an at least 50% reduction of headache burden than those receiving placebo (28.9% vs. 20.2%; risk ratio 1.40; 95% CI 0.97-2.02; P = 0.07). However, antidepressants were less well tolerated than placebo because of some adverse events (risk ratio 1.74, 95% CI 1.05-2.89, P = 0.03). CONCLUSIONS: Antidepressants are effective in the prophylaxis of migraine in adults, but the level of evidence for antidepressants except for amitriptyline seems to be quite shaky. PMID- 28557172 TI - Deubiquitinase Usp18 prevents cellular apoptosis from oxidative stress in liver cells. AB - Deubiquitinases (DUBs) deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate their activity and stability. They play different cellular functions such as cell cycle regulation, DNA repair, and early embryogenesis. Additionally, studies have demonstrated that some DUBs are the signaling targets of cellular stress such as oxidative stress. Reactive oxygen species are generated during normal mitochondrial oxidative metabolism and proper cellular mechanism could protect the cell from the oxidative stress. However, there are limited studies that specifically focus on the role of DUBs in oxidative stress, and thus the underlying protective mechanism by DUBs is not yet known. The report here, for the first time, applied the mouse-specific DUB RT2 Profiler PCR array to identify DUBs that are responsive to oxidative stress. Out of the tested 83 DUBs, 15 of them were found to be differentially expressed. Among them, Usp18 was found to be induced with a dose- and time-dependent manner of oxidative stress. In functional studies, depletion of Usp18 could stimulate the p53 and caspase 3 protein levels. In addition, knockdown of Usp18 could lead to the reduced cell viability and increased in apoptotic cell death under oxidative stress. Collectively, Usp18 protects the cells from oxidative stress-induced apoptosis which may be through the regulation of p53 and caspase 3. PMID- 28557174 TI - Polyunsaturated C-Glycosidic 4-Hydroxy-2-pyrone Derivatives: Total Synthesis Shows that Putative Orevactaene Is Likely Identical with Epipyrone A. AB - Orevactaene and epipyrone A were previously thought to comprise the same polyunsaturated tail but notably different C-glycosylated 4-hydroxy-2-pyrone head groups. Total synthesis now shows that the signature bicyclic framework assigned to orevactaene is a chimera; the compound is almost certainly identical with epipyrone A, whose previously unknown stereochemistry has also been established during this study. Key to success was the ready formation of the bicyclic core of putative orevactaene by a sequence of two alkyne cycloisomerization reactions using tungsten and gold catalysis. Equally important was the flexibility in the assembly process gained by the use of heterobimetallic polyunsaturated modules whose termini could be selectively and consecutively addressed in a practical one pot cross-coupling sequence. PMID- 28557173 TI - A Fluorescent RNA Forced-Intercalation Probe as a Pan-Selective Marker for Influenza A Virus Infection. AB - The influenza A virus (IAV) genome is segmented into eight viral ribonucleoproteins, each expressing a negatively oriented viral RNA (vRNA). Along the infection cycle, highly abundant single-stranded small viral RNAs (svRNA) are transcribed in a segment-specific manner. The sequences of svRNAs and of the vRNA 5'-ends are identical and highly conserved among all IAV strains. Here, we demonstrate that these sequences can be used as a target for a pan-selective sensor of IAV infection. To this end, we used a complementary fluorescent forced intercalation RNA (IAV QB-FIT) probe with a single locked nucleic acid substitution to increase brightness. We demonstrated by fluorescence in situ hybridization (FISH) that this probe is suitable and easy to use to detect infection of different cell types by a broad variety of avian, porcine, and human IAV strains, but not by other influenza virus types. IAV QB-FIT also provides a useful tool to characterize different infection states of the host cell. PMID- 28557175 TI - Psoriasis in patients with mycosis fungoides: a clinicopathological study of 25 patients. AB - BACKGROUND: It has been reported that patients with psoriasis are at increased risk for developing lymphoma including cutaneous T-cell lymphomas (CTCL). However, the comorbidity and the histopathologic correlation of psoriasis and mycosis fungoides (MF) have been less studied. OBJECTIVE: The objective of this study was to investigate the relation between MF and psoriasis. METHODS: We retrospectively reviewed and re-evaluated all MF cases diagnosed and followed in a 16-year period who carried both MF and psoriasis diagnoses. RESULTS: Forty-one of 321 MF patients was the rate of psoriasis' comorbidity according to medical records. Twenty-five patients (7.8%) finally met the inclusion criteria. The rest were excluded due to inadequate evidence. Twenty patients had psoriatic lesions at the time of MF diagnosis. In 23 patients, there was histological confirmation of both diseases. Six patients (24%) were diagnosed with folliculotropic MF, two were diagnosed with pustular psoriasis, and six patients were affected by palmoplantar and nail psoriasis. In four patients, there was a very short time interval between MF and psoriasis diagnosis. Fourteen patients with psoriasis had been previously treated with immunomodulatory regimens. Interestingly, in eight patients, typical histological findings of both diseases were detected in the same biopsy specimen. CONCLUSION: Our results support the opinion that the association between psoriasis and MF does exist. It is most possibly related to the chronic lymphocyte stimulation that occurs during psoriasis that eventually leads to a dominant clone and the evolution to CTCL. Our study suggests that apart from cases of early MF, which are being indeed misdiagnosed as psoriasis, there is another group of patients, where psoriasis truly coexists with - or even progresses to - MF. PMID- 28557178 TI - Impact of etiology and duration of pain on pharmacological treatment effects in painful polyneuropathy. AB - BACKGROUND: The pharmacological treatments for painful polyneuropathy have not changed much for more than a decade, and less than half of the patients obtain adequate pain relief with first line treatments. Therefore, patient-specific factors which could predict drug response are searched for. METHODS: We analysed data from four published, randomized, controlled trials of drugs in painful polyneuropathy to see if diabetic etiology and duration of neuropathic pain had an impact on drug efficacy. The studies had a cross-over design, and had nearly similar outcome recordings as well as a thorough baseline registration of symptoms, signs and quantitative sensory testing. 244 patient records of drug effect distributed over treatments with three antidepressants (imipramine, venlafaxine, escitalopram) and two anticonvulsants (pregabalin, oxcarbazepine) were analysed. RESULTS: Diabetes as etiology of polyneuropathy had no impact on the effect of antidepressants (imipramine, venlafaxine, escitalopram), but there was a significant interaction with treatment effect on anticonvulsants with better effects in diabetics (0.86 NRS points, p = 0.021) with most pronounced interaction for oxcarbazepine (1.47 NRS points, p = 0.032). There was an interaction between duration of neuropathic pain and treatment with antidepressants with better effect with duration less than 3 years (0.62 NRS points, p = 0.036), whereas anticonvulsants tended to work best with duration of pain for more than 3 years. CONCLUSION: Despite the small sample size and limited number of drugs included this study suggests that diabetic etiology of polyneuropathy may impact on the efficacy of anticonvulsants, and duration of neuropathic pain may impact on the efficacy of antidepressants. SIGNIFICANCE: This study found that duration of pain appears to have an impact on the effect of antidepressants in neuropathic pain and that diabetes as etiology for painful polyneuropathy appears to influence pain relief obtained with anticonvulsants. PMID- 28557177 TI - Dealing with end of life-New graduated nurse experiences. AB - AIMS AND OBJECTIVES: This article explores the perceptions of new graduate nurses around their readiness for practice when faced with death and dying within the workplace, particularly in rural hospital and community nursing settings. BACKGROUND: An essential consideration for nurses in the care of people with life limiting illness is the extent of their preparation for this area of practice. Nurses need to be aware of a multitude of compounding factors that will influence how and where the person is cared for. Despite significant literature about how to provide end of life education to undergraduate nurses there is little in the literature that explores the experiences of new graduate nurses. DESIGN: This paper reports on a qualitative interpretative study with data collected in seven semi-structured interviews. METHOD: Participants were invited to be interviewed with an online mail-out to Alumni who had graduated between 1-2 years earlier. A thematic analysis of the interviews was then conducted. RESULTS: Four themes emerged from the thematic analysis of the interviews. These were; the role of the new graduate in palliative care, preparation for palliative care in undergraduate nursing curricula, readiness for dealing with death and dying, and gaps in educational preparation. CONCLUSIONS: While palliative care is viewed as an important aspect of undergraduate nursing education, it is recognised as an area of practice that undergraduate nurses feel they are not adequately prepared for. This study identifies the need to incorporate skills such as having conversations and communicating effectively with patients and families experiencing end of life issues. RELEVANCE TO CLINICAL PRACTICE: Graduate nurses feel they are not adequately prepared for end of life care which demonstrates the need for quality end of life care education in undergraduate nursing curricula. PMID- 28557176 TI - Genetic variations at the human growth hormone receptor (GHR) gene locus are associated with idiopathic short stature. AB - GH plays an essential role in the growing child by binding to the growth hormone receptor (GHR) on target cells and regulating multiple growth promoting and metabolic effects. Mutations in the GHR gene coding regions result in GH insensitivity (dwarfism) due to a dysfunctional receptor protein. However, children with idiopathic short stature (ISS) show growth impairment without GH or GHR defects. We hypothesized that decreased expression of the GHR gene may be involved. To test this, we investigated whether common genetic variants (microsatellites, SNPs) in regulatory regions of the GHR gene region were associated with the ISS phenotype. Genotyping of a GT-repeat microsatellite in the GHR 5'UTR in a Montreal ISS cohort (n = 37 ISS, n = 105 controls) revealed that the incidence of the long/short (L/S) genotype was 3.3* higher in ISS children than controls (P = 0.04, OR = 3.85). In an Italian replication cohort (n = 143 ISS, n = 282 controls), the medium/short (M/S) genotype was 1.9* more frequent in the male ISS than controls (P = 0.017, OR = 2.26). In both ISS cohorts, logistic regression analysis of 27 SNPs showed an association of ISS with rs4292454, while haplotype analysis revealed specific risk haplotypes in the 3' haploblocks. In contrast, there were no differences in GT genotype frequencies in a cohort of short stature (SS) adults versus controls (CARTaGENE: n = 168 SS, n = 207 controls) and the risk haplotype in the SS cohort was located in the most 5' haploblock. These data suggest that the variants identified are potentially genetic markers specifically associated with the ISS phenotype. PMID- 28557179 TI - Cancer patients' perceptions of quality-of-care attributes-Associations with age, perceived health status, gender and education. AB - AIMS AND OBJECTIVES: The aim of this study was to explore the associations between patients' gender, education, health status in relation to assessments of patient-centred quality and individuality in care and trust in nurses for those <65 (working age) and >=65 years (older people). BACKGROUND: Patients' assessments of the quality of care they receive are essential for the development of the provision of patient care and services. Previous studies have revealed age of the patient is associated with their assessment of care quality attributes. DESIGN: The study employed a cross-sectional, multicultural comparative survey design. METHODS: The data were collected using questionnaires among hospitalised cancer patients (N = 876, n = 599, 68%) in four European countries: Greece, Cyprus, Sweden and Finland. The data were divided into two subgroups based on age (cut point 65 years) and were analysed statistically. RESULTS: Cancer patients' age, gender and level of education were not related to their assessments of care quality attributes: person-centred care quality, individuality in care and trust in nurses. Subgroup analysis of the older adults and those of working age showed clear associations with patients' assessments of quality-of-care attributes and perceived health status. The lower the perceived health status, the lower the assessment of care quality attributes. DISCUSSION: The results suggest that the cancer itself is the strongest determinant of the care delivered, rather than any patient characteristics, such as age, education or gender. Perceived health status, in association with cancer patient assessments of care quality attributes, may be useful in the development of patient-centred, individualised care strategies alongside a stronger focus on people instead of cancer-care related processes and duties. CONCLUSIONS: Health status was the only factor associated with cancer patients' assessments of care quality attributes. Cancer itself may be the strongest determinant of the care quality perceptions, rather than any patient characteristics. RELEVANCE TO CLINICAL PRACTICE: The findings of this study have implications for cancer care professionals in terms of patient assessment and care planning. The measures may be useful in assessing quality of cancer nursing care. PMID- 28557181 TI - "I don't want to look like an AIDS victim": A New Zealand case study of facial lipoatrophy. AB - The development of antiretroviral (ARV) drugs to treat HIV has turned what was once a death sentence into a chronic disorder. However, a focus on absence of disease in the form of an undetectable viral load and the dismissal of the so called "cosmetic" complications of the disease ignores perceptions of health and well-being of those living with HIV. Facial lipoatrophy is a stigmatising side effect of treatment for HIV as it betrays the presence of the virus within the body. The study took a longitudinal qualitative approach, interviewing 11 people twice over a period of 1 year on their experience of living with HIV. Two participants were given cameras and asked to take photos which represented what it was like for them to live with this condition and were interviewed four times at four monthly intervals. This paper looks at one man's struggle to conceal or veil his facial lipoatrophy. His story is presented in the form of "selfies" and extracts from in-depth interviews. It tells of an emotional (ongoing) journey of frustration, anger, excitement, depression and resignation which had a profound effect on his sense of social and psychological well-being. This suggests a more holistic approach to treating people living with HIV is needed. While an undetectable viral load is indeed vital, it should not be seen as the only essential outcome of treatment. PMID- 28557182 TI - Large Stokes Shift Ionic-Liquid Dye. AB - We have incorporated the dye N-methyl-6-oxyquinolone [6MQz] in its protonated form as a cation into an ionic liquid (IL) and thus to synthesize an IL dye. The IL dye N-methyl-6-hydroxyquinolinium bis(trifluoromethylsulfonyl) imide [6MQc][NTf2 ] was characterized by NMR, ATR IR spectroscopy and X-ray crystallography. The fluorescence of the IL dye has a large Stokes shift of Deltalambda=116 nm and a quantum yield of phiF =0.56 in acetonitrile. Characteristic solvent dependent shifts can be detected in the emission spectra. In other ILs, acetonitrile and THF we observe a bathochromic shift of up to 28 nm compared to the pure IL dye at 467 nm. For stronger polar solvents the fluorescence signals are strongly red-shifted to 650 nm indicating proton transfer to the solvent molecules in the excited state. This underlines the importance of the IL building block [MQc]+ as photo acid. PMID- 28557180 TI - Targeting G Protein-Coupled Receptors by Capture Compound Mass Spectrometry: A Case Study with Sertindole. AB - Unbiased chemoproteomic profiling of small-molecule interactions with endogenous proteins is important for drug discovery. For meaningful results, all protein classes have to be tractable, including G protein-coupled receptors (GPCRs). These receptors are hardly tractable by affinity pulldown from lysates. We report a capture compound (CC)-based strategy to target and identify GPCRs directly from living cells. We synthesized CCs with sertindole attached to the CC scaffold in different orientations to target the dopamine D2 receptor (DRD2) heterologously expressed in HEK 293 cells. The structure-activity relationship of sertindole for DRD2 binding was reflected in the activities of the sertindole CCs in radioligand displacement, cell-based assays, and capture compound mass spectrometry (CCMS). The activity pattern was rationalized by molecular modelling. The most-active CC showed activities very similar to that of unmodified sertindole. A concentration of DRD2 in living cells well below 100 fmol used as an experimental input was sufficient for unambiguous identification of captured DRD2 by mass spectrometry. Our new CCMS workflow broadens the arsenal of chemoproteomic technologies to close a critical gap for the comprehensive characterization of drug-protein interactions. PMID- 28557185 TI - Chemically Tailoring the Dopant Emission in Manganese-Doped CsPbCl3 Perovskite Nanocrystals. AB - Doping in perovskite nanocrystals adopts different mechanistic approach in comparison to widely established doping in chalcogenide quantum dots. The fast formation of perovskites makes the dopant insertions more competitive and challenging. Introducing alkylamine hydrochloride (RNH3 Cl) as a promoting reagent, precise controlled doping of MnII in CsPbCl3 perovskite nanocrystals is reported. Simply, by changing the amount of RNH3 Cl, the Mn incorporation and subsequent tuning in the excitonic as well as Mn d-d emission intensities are tailored. Investigations suggested that RNH3 Cl acted as the chlorinating source, controlled the size, and also helps in increasing the number of particles. This provided more opportunity for Mn ions to take part in reaction and occupied the appropriate lattice positions. Carrying out several reactions with varying reaction parameters, the doping conditions are optimized and the role of the promoting reagent for both doped and undoped systems are compared. PMID- 28557184 TI - Electronic Structure and Magnetic Anisotropy of an Unsaturated Cyclopentadienyl Iron(I) Complex with 15 Valence Electrons. AB - The 15 valence-electron iron(I) complex [CpAr Fe(IiPr2 Me2 )] (1, CpAr =C5 (C6 H4 -4-Et)5 ; IiPr2 Me2 =1,3-diisopropyl-4,5-dimethylimidazolin-2-ylidene) was synthesized in high yield from the FeII precursor [CpAr Fe(MU-Br)]2 . 57 Fe Mossbauer and EPR spectroscopic data, magnetic measurements, and ab initio ligand field calculations indicate an S= 3/2 ground state with a large negative zero field splitting. As a consequence, 1 features magnetic anisotropy with an effective spin-reversal barrier of Ueff =64 cm-1 . Moreover, 1 catalyzes the dehydrogenation of N,N-dimethylamine-borane, affording tetramethyl-1,3-diaza-2,4 diboretane under mild conditions. PMID- 28557183 TI - Extracellular vesicles do not contribute to higher circulating levels of soluble LRP1 in idiopathic dilated cardiomyopathy. AB - Idiopathic dilated cardiomyopathy (IDCM) is a frequent cause of heart transplantation. Potentially valuable blood markers are being sought, and low density lipoprotein receptor-related protein 1 (LRP1) has been linked to the underlying molecular basis of the disease. This study compared circulating levels of soluble LRP1 (sLRP1) in IDCM patients and healthy controls and elucidated whether sLRP1 is exported out of the myocardium through extracellular vesicles (EVs) to gain a better understanding of the pathogenesis of the disease. LRP1 alpha chain expression was analysed in samples collected from the left ventricles of explanted hearts using immunohistochemistry. sLRP1 concentrations were determined in platelet-free plasma by enzyme-linked immunosorbent assay. Plasma derived EVs were extracted by size-exclusion chromatography (SEC) and characterized by nanoparticle tracking analysis and cryo-transmission electron microscopy. The distributions of vesicular (CD9, CD81) and myocardial (caveolin 3) proteins and LRP1 alpha chain were assessed in SEC fractions by flow cytometry. LRP1 alpha chain was preferably localized to blood vessels in IDCM compared to control myocardium. Circulating sLRP1 was increased in IDCM patients. CD9- and CD81-positive fractions enriched with membrane vesicles with the expected size and morphology were isolated from both groups. The LRP1 alpha chain was not present in these SEC fractions, which were also positive for caveolin-3. The increase in circulating sLRP1 in IDCM patients may be clinically valuable. Although EVs do not contribute to higher sLRP1 levels in IDCM, a comprehensive analysis of EV content would provide further insights into the search for novel blood markers. PMID- 28557186 TI - The role of intrinsically disordered C-terminal region of FliK in substrate specificity switching of the bacterial flagellar type III export apparatus. AB - The bacterial flagellar export switching machinery consists of a ruler protein, FliK, and an export switch protein, FlhB and switches substrate specificity of the flagellar type III export apparatus upon completion of hook assembly. An interaction between the C-terminal domain of FliK (FliKC ) and the C-terminal cytoplasmic domain of FlhB (FlhBC ) is postulated to be responsible for this switch. FliKC has a compactly folded domain termed FliKT3S4 (residues 268-352) and an intrinsically disordered region composed of the last 53 residues, FliKCT (residues 353-405). Residues 301-350 of FliKT3S4 and the last five residues of FliKCT are critical for the switching function of FliK. FliKCT is postulated to regulate the interaction of FliKT3S4 with FlhBC , but it remains unknown how. Here we report the role of FliKCT in the export switching mechanism. Systematic deletion analyses of FliKCT revealed that residues of 351-370 are responsible for efficient switching of substrate specificity of the export apparatus. Suppressor mutant analyses showed that FliKCT coordinates FliKT3S4 action with the switching. Site-directed photo-cross-linking experiments showed that Val-302 and Ile-304 in the hydrophobic core of FliKT3S4 bind to FlhBC . We propose that FliKCT may induce conformational rearrangements of FliKT3S4 to bind to FlhBC . PMID- 28557187 TI - Automated high throughput analysis of antiretroviral drugs in dried blood spots. AB - For therapeutic drug monitoring in remote settings, dried blood spots (DBS) are particularly advantageous, as blood sample collection and handling is uncomplicated. The aim of this study was to develop and validate an automated extraction method for the analysis of nevirapine, efavirenz and lopinavir in DBS samples. Automated extraction was performed with methanol : water (70 : 30 v/v), using a DBS-MS 500 autosampler coupled to a liquid chromatography tandem mass spectrometry system. The autosampler used digital images of each DBS to position the extraction head, sprayed 10 MUl of internal standard onto each DBS and extracted a 4-mm disc (O) from the centre of each spot by unilateral flow using 25-MUl extraction solvent. The analytes were baseline separated on a pentafluorophenyl column and analysed by using electrospray ionization with multiple reaction monitoring in positive polarity mode for nevirapine and lopinavir and in negative mode for efavirenz. The method was linear between 10 and 10 000 ng/ml for all analytes. Automated sample extraction resulted in consistent recoveries (nevirapine: 70 +/- 6%, efavirenz: 63 +/- 11% and lopinavir: 60 +/- 10%) and matrix effects between different donors and concentration levels. Intra-day and inter-day accuracy and precision deviations were <=15%. Manual and automated extractions of DBS samples collected within the framework of an adherence assessment study in rural Tanzania showed good agreements with deviations of less than 10%. Our study highlights that therapeutic drug monitoring samples obtained in the resource-constrained setting of rural Africa can be reliably determined by automated extraction of DBS. Overall, automatization improved method sensitivity and facilitates analysis of large sample numbers. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28557188 TI - Descending aorta to right atrial fistula. AB - Here, we report a four-day old neonate presenting with cardiovascular collapse secondary to a descending aorta to right atrial fistula. Echocardiography was suggestive of the diagnosis and confirmed with computed tomographic (CT) imaging. The fistula was successfully occluded via cardiac catheterization using an Amplatzer Vascular Plug II implanted from the right atrial aspect. This report includes the first CT imaging of this extremely rare congenital defect as well as detailing the first successful transcatheter occlusion of this particular lesion. PMID- 28557189 TI - Phage applications for improving food safety and infection control in Egypt. AB - AIMS: The study investigated the use of bacteriophages to control bacterial contamination of chicken skin, eggs, tomatoes and meat. METHODS AND RESULTS: Experiments were performed to test the host ranges and killing potential of two isolated phages, ZCSE1 and ZCEC1, with hosts Salmonella and Escherichia coli respectively. The efficacy of both phages was determined by comparing the viable counts of recovered bacteria from treatment and phage-free control samples. In vitro experiments showed that phage ZCSE1 was able to reduce the numbers of Salmonella enterica ATCC 25566 to below 4.0 log10 CFU per ml (3.4 log10 CFU per ml reduction) in 240 min postinfection and phage ZCEC1 reduced the number of E. coli ATCC 8739 to undetectable levels (6.45 log10 CFU per ml reduction) during the first hour of infection at 37 degrees C. When applied to chicken skin and the surface of eggs, phage ZCSE1 treatment reduced the number of S. enterica ATCC 25566 by 2 log10 and to undetectable levels (<2.0 log10 CFU per ml), for skin and eggs respectively (P < 0.005). The administration of ZCEC1 phage to meat and tomatoes reduced the number of E. coli to below 2.0 log10 CFU per ml 1 day after treatment. CONCLUSIONS: The administration of these phages to meat and tomatoes reduced the numbers of E. coli and Salmonella significantly in tested foods. SIGNIFICANCE AND IMPACT OF THE STUDY: The results suggest that phages could be effective treatments for pathogenic bacteria in food relevant contexts in Egypt. PMID- 28557190 TI - Utility of the maximum standardized uptake value on positron emission tomography for predicting therapeutic effect in recurrent gynecological malignancies: A preliminary study. AB - AIM: The maximum standardized uptake value (SUVmax) of primary tumors in positron emission tomography can be used to predict prognosis in various cancers, but its significance in recurrent tumors remains unclear. In the present study, we evaluated the utility of the SUVmax for predicting therapeutic effects in recurrent gynecological malignancies. METHODS: From February 2012 to July 2014, patients with recurrent gynecological cancer who were treated with chemotherapy or radiotherapy were enrolled in this study. The SUVmax of recurrent lesions before treatment were compared to the therapeutic effects. RESULTS: Fifty patients with recurrent gynecological cancer were enrolled. The mean SUVmax was significantly higher in patients with stable disease/progressive disease than in patients who achieved complete remission/partial remission (13.24 +/- 9.78 vs 8.61 +/- 5.34, P = 0.039). In patients who were administered chemotherapy, the SUVmax was significantly higher in those with stable disease/progressive disease than in those who achieved complete remission/partial remission (13.24 +/- 9.78 vs 8.61 +/- 5.34, P = 0.0392) as well as those administered radiotherapy or concurrent chemoradiation therapy (18.15 +/- 3.25 vs 11.33 +/- 3.98, P = 0.0073). In ovarian cancer patients administered chemotherapy, when the cut-off value of the SUVmax was set as 6.94, the sensitivity and specificity of predicting therapeutic effects were 0.75 and 0.846, respectively. CONCLUSION: Although the number of enrolled cases was small, our study revealed that the SUVmax in recurrent gynecological tumors might predict therapeutic effects. If the SUVmax is relatively high, multimodal therapy, including surgical removal, should be considered. PMID- 28557192 TI - The Quebec experience in promoting healthy lifestyles and preventing obesity: how can we do better? AB - Over the last years, many actions have been implemented in the Canadian province of Quebec to prevent health issues related to diet, physical activity and obesity. As a new public health programme is being launched, the 'How can we do better?' project aimed to identify priority areas for further action. An exhaustive search led to identify 166 interventions rolled out in Quebec between 2006 and 2014. We compared it with evidence-based recommendations. Findings were challenged during a 2-d deliberative forum gathering 25 key stakeholders. At the crossroads of these analyses, 50 proposals emerged to sustain/bolster current efforts or to implement new initiatives. Specific improvements were recommended, e.g. about food supply quality monitoring, healthy food accessibility and affordability, physical activity promotion through land use policies, schools and childcare facilities retrofit and urban planning. Crosscutting proposals stress the importance to implement a new governmental prevention strategy and to reinforce evaluation at all levels. This call for action takes place at a critical period for political commitment and should be maintained until and after curbing the prevalence of obesity and related diseases. Although Quebec-focused, 'How can we do better?' project outcomes may be informative for other jurisdictions, and the methods may be inspiring for those interested in combining knowledge syntheses and deliberative processes to inform decision makers in a limited time frame. PMID- 28557191 TI - Effect of increasing monensin sodium levels in diets with virginiamycin on the finishing of Nellore cattle. AB - This study evaluated the effect of increasing levels of monensin sodium (MON) in diets with virginiamycin (VM) on the finishing of feedlot cattle. Two hundred and eighty intact male Nellore cattle (348 +/- 32 kg body weight, 22 months) received one of the following five diets: control diet (without additives); diet containing VM (25 mg per kg dry matter) combined with 0 (MON0), 10 (MON10), 20 (MON20) or 30 (MON30) mg MON per kg dry matter. During adaptation (28 days), the MON0 diet increased dietary net energy for maintenance and gain compared to the control diet (P = 0.04). The combination of additives linearly reduced dry matter intake, body weight and average daily gain (P < 0.01). Considering the total study period (110 days), there was a trend of greater net energy intake for maintenance (P = 0.09) and hot carcass weight (P = 0.06) for animals fed MON0 compared to the control diet. The combination of additives linearly reduced dry matter intake (P = 0.04) and linearly increased gain : feed and dietary net energy for maintenance and gain (P < 0.01). The combination of VM with MON at a dose of 30 mg/kg dry matter is recommended for Nellore feedlot cattle because it improves the efficiency of energy utilization. PMID- 28557193 TI - Binary Encoding of Random Peptide Sequences for Selective and Differential Antimicrobial Mechanisms. AB - Binary encoding of peptide sequences into differential antimicrobial mechanisms is reported. Such sequences are random in composition, but controllable in chain length, are assembled from the same two amino acids, but differ in the stereochemistry of one. Regardless of chirality, the sequences lyse bacteria including the "superbugs" methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Sequences with the same chirality, so called homochiral sequences, assemble into antimicrobial pores and form contiguous helices that are biologically promiscuous and hemolytic. By contrast, heterochiral sequences that lack such persistence selectively attack bacterial membranes without oligomerizing into visible pores. These results offer a mechanistic rationale for designing membrane-selective and sequence-independent antimicrobials. PMID- 28557194 TI - alpha-Quaternary Mannich Bases through Copper-Catalyzed Amination-Induced 1,2 Rearrangement of Allylic Alcohols. AB - A novel copper-catalyzed amination-induced 1,2-rearrangement reaction of allylic alcohols has been developed under simple and mild conditions. The commercially available N-fluorobenzenesulfonimide (NFSI) is employed as an amination reagent. In this transformation, not only alkyl, but also aryl substituents can efficiently undergo 1,2-carbon atom migration, thereby providing an efficient and powerful route to prepare a wide range of alpha-quaternary Mannich bases. The reaction features a broad substrate scope, operational simplicity, and excellent practicality. PMID- 28557195 TI - Allelopathic Effects, Physiological Responses and Phenolic Compounds in Litter Extracts of Juniperus rigidaSieb. et Zucc. AB - The allelopathic effects of Juniperus rigida litter aqueous extract (LE) on wheat and Pinus tabuliformis were studied, as well as the physiological responses to the extract. High concentration LE (0.10 g Dw/ml) significantly inhibited the seed germination and seedling growth in receptor plants. The chlorophyll content and root activity in the wheat seedlings were reduced significantly across all treatments; however, those were more prominently reduced at high concentration (0.10 g Dw/ml) but received little stimulation at low concentration (0.025 g Dw/ml) in P. tabuliformis. The content of malonaldehyde (MDA) increased with increasing concentrations of LE, except at 0.025 g Dw/ml. Activities of antioxidant enzymes (POD, CAT and SOD) in receptor plants were all significantly inhibited at high concentrations but stimulated at low concentrations. These results demonstrate that the aqueous extract from J. rigida litter has allelopathic potential. Various phenolic compounds were identified in litter aqueous extract and litter ethanol extract by HPLC. The phenolic compound content in the aqueous extract was significantly lower than that in the ethanol extract. Chlorogenic acid and podophyllotoxin were the predominant phenolic compounds in both types of litter extracts. These findings suggest that the seed germination and seedling growth of P. tabuliformis and wheat would be inhibited when planted near large amounts J. rigida litter. PMID- 28557196 TI - The influence of pubertal maturation on antisaccade performance. AB - Adolescence is a period characterized by continued improvements in inhibitory control, and this persisting immaturity is believed to interact with affective/motivational behavior to generate the impulsive and risk-taking behavior evidenced at this time. Puberty is a central event of adolescence that has been shown to influence affective/motivational behavior. However, despite plausible mechanisms by which puberty might influence inhibitory control, researchers have yet to test this possibility rigorously. Thus, we designed a study to examine the unique role of pubertal maturation, independent of age, in the development of inhibitory control. In order to minimize age-related variability while maximizing pubertal status variability, we recruited 78 participants (34 F) whose ages narrowly spanned the mean age of gonadarche for each sex (F: ages 11-13, M: ages 12-14). Two complementary measures were used to assess pubertal status: (1) circulating blood serum testosterone and estradiol levels reflecting internal manifestations of pubertal maturation, and (2) Tanner staging by a trained nurse reflecting pubertal maturation's external manifestations. Inhibitory control was assessed using the antisaccade task, and findings were adjusted for the potential effect of age. Results revealed no association between testosterone levels and error rates or response latencies in either sex. In girls, estradiol levels were not associated with error rates, but were associated with faster response latencies. There was similarly no association between Tanner status and error rates, although girls in more advanced pubertal stages showed faster response latencies. Power analyses indicate that findings of a lack of association did not reflect limited statistical power. Thus, in a study designed to isolate the effects of pubertal maturation independent of age, both external and internal indices of pubertal maturation converged to indicate that age-related improvements in cold antisaccade performance are independent of pubertal maturation. PMID- 28557197 TI - Impaired immune function in children and adults with Fanconi anemia. AB - BACKGROUND: Fanconi anemia (FA) is a rare genetic disorder characterized by genome instability, bone marrow failure, and cancer predisposition. Previously, small studies have reported heterogeneous immune dysfunction in FA. PROCEDURE: We performed a detailed immunologic assessment in a large FA cohort who have not undergone bone marrow transplantation or developed malignancies. Comprehensive quantitative and functional immunologic assessment of 29 FA individuals was compared to healthy age-matched controls. RESULTS: Compared to non-FA persons of similar ages, FA individuals showed lower absolute total B cells (P < 0.001), lower memory B cells (P < 0.001), and decreased IgM (P < 0.001) but normal IgG. NK cells (P < 0.001) and NK cytotoxicity (P < 0.001) were decreased. CD4+ T cells were decreased (P = 0.022), while CD8+ T cell and absolute T-cell numbers were comparable. Cytotoxic T cells (P < 0.003), and antigen proliferation response to tetanus (P = 0.019) and candida (P = 0.019), were diminished in FA. Phytohemagglutinin responses and plasma cytokines were normal. Within FA subjects, adults and older children (>=10 years) exhibited higher CD8+ T cells than younger children (P = 0.004). Documented atypical infections were infrequent, although oral human papilloma virus (HPV) prevalence was higher (31% positive) in FA. CONCLUSIONS: Overall, these results demonstrate a high rate of significant humoral and cellular immune dysfunction. Continued longitudinal study of immune function is critical to understand evolution with age, bone marrow failure, and cancer development. PMID- 28557199 TI - Hepatobiliary and Pancreatic: Hepatic and mesenteric aneurysms with biloma formation. PMID- 28557200 TI - Gastrointestinal: An unusual opportunistic infection mimicking lymphoma in a patient receiving Infliximab for Crohn's disease. PMID- 28557201 TI - Gastrointestinal: Crohn's disease in the terminal ileum with an ileo-ileal fistula: Radiologic-pathologic correlation. PMID- 28557202 TI - Gastrointestinal: Multiparametric hybrid 18-FDG PET/MRI evaluation of gastric adenocarcinoma. PMID- 28557203 TI - Gastrointestinal: Unusual spontaneous esophageal intramural dissection. PMID- 28557198 TI - Genetic engineering of grass cell wall polysaccharides for biorefining. AB - Grasses represent an abundant and widespread source of lignocellulosic biomass, which has yet to fulfil its potential as a feedstock for biorefining into renewable and sustainable biofuels and commodity chemicals. The inherent recalcitrance of lignocellulosic materials to deconstruction is the most crucial limitation for the commercial viability and economic feasibility of biomass biorefining. Over the last decade, the targeted genetic engineering of grasses has become more proficient, enabling rational approaches to modify lignocellulose with the aim of making it more amenable to bioconversion. In this review, we provide an overview of transgenic strategies and targets to tailor grass cell wall polysaccharides for biorefining applications. The bioengineering efforts and opportunities summarized here rely primarily on (A) reprogramming gene regulatory networks responsible for the biosynthesis of lignocellulose, (B) remodelling the chemical structure and substitution patterns of cell wall polysaccharides and (C) expressing lignocellulose degrading and/or modifying enzymes in planta. It is anticipated that outputs from the rational engineering of grass cell wall polysaccharides by such strategies could help in realizing an economically sustainable, grass-derived lignocellulose processing industry. PMID- 28557204 TI - Anti-adhesive effects of a newly developed two-layered gelatin sheet in dogs. AB - AIM: Adhesion after pelvic surgery causes infertility, ectopic pregnancy, and ileus or abdominal pain. The materials currently available for clinical use are insufficient. The purpose of this study was to develop an anti-adhesive material that overcomes the limitations of conventional anti-adhesive agents. METHODS: The adhesion prevention effects of three methods - a two-layered sheet composed of gelatin film and gelatin sponge, Seprafilm and INTERCEED - were evaluated in 37 dogs. Anti-adhesive effects were investigated macroscopically and microscopically in a cauterized uterus adhesion model. Cell growth on the materials in vitro using human peritoneal mesothelial cells, fibroblasts and uterine smooth muscle cells were also evaluated. RESULTS: The two-layered gelatin sheet had significantly superior anti-adhesive effects compared to the conventional materials (Seprafilm and INTERCEED). A single-cell layer of mature mesothelium formed three weeks after surgery in the gelatin group. Peritoneum regeneration in the Seprafilm and INTERCEED groups was delayed and incomplete in the early phase. Little inflammation around the materials occurred and cell growth was significantly proliferated with the gelatin sheet. CONCLUSION: The anti-adhesive effects of a two-layered gelatin sheet were superior to conventional agents in a cauterized canine uterus model, demonstrating early regeneration of the peritoneum, little inflammation and material endurance. The newly developed two layered gelatin sheet is a useful option as an anti-adhesive agent for deeply injured and hemorrhagic sites. PMID- 28557205 TI - Stereochemical Alignment in Triphospha[3]ferrocenophanes. AB - A series of triphospha[3]ferrocenophanes of the type Fe(C5 H4 -PtBu)2 PX with X=H, F, Cl, Br, I, NEt2 , tBu has been prepared and characterized by heteronuclear NMR spectroscopy and X-ray crystallography. Despite having three stereogenic centers, the selective formation of a reduced number of diastereomers (either one or two) has been observed for these ferrocenophanes. Theoretical calculations revealed that the inversion of the central stereogenic center inverts the frontier orbital sequence leading to either an iron or a phosphorus centered HOMO depending on the respective diastereomer. CV measurements supported these results. For the all-tert-butyl substituted [3]ferrocenophane Fe(C5 H4 )2 (PtBu)3 a chiral staggered conformation has been found in the solid state which differs substantially from the only other all-organo substituted [3]ferrocenophane, Fe(C5 H4 )2 (PPh)3 . PMID- 28557206 TI - Anthropological approaches to the study of sex differences in blood pressure. PMID- 28557207 TI - Usefulness of a stature-based standard of skinfold thickness, especially for short children. AB - Skinfold thicknessess (SFT) were measured at ulnar, triceps, subscapular and suprailiac sites in 730 boys and 724 girls (age 3-12 years) whose stature ranged from 100 to 150 cm and whose weight was within +/-20% of the average. Means and standard deviation (SD) were calculated after logarithmic transformation of the original skinfold readings to demonstrate stature-based standards of SFT in Japanese children. The means of SFT exhibited nadirs (boys/ girls: ulnar 5.1/5.9 mm, triceps 7.9/9.5 mm, subscapular 4.9/6.1 mm, suprailiac 4.5/6.2 mm) in subjects 110-115 cm tall except for ulnar SFT in girls. SFT values increased as children increased in stature. Standard deviations of SFT at the four sites in short children (staturte < mean -1 SD) were estimated using the stature-based standard as well as an age-based standard. Susms of the SDs assessed by the age based standard were significantly smaller than those assessed by the stature based standard in boys (P < 0.05) and girls (P < 0.01) with short stature, suggesting that SFT in short children was falsely understimated by the age-based standard. Thus, the stature-based standard is beneficial for the assessment of SFT, especially in children whose stature is below the mean --1 SD. (c) 1995 Wiley-Liss, Inc. PMID- 28557208 TI - High altitude and hypertension during pregnancy. AB - Hypertensive complications of pregnancy are more common at high than low altitudes. Hypertension in pregnancy is associated with increased maternal and fetal morbidity and mortality; thus natural selection may be operating against women who develop the disorder and their infants. It has long been hypothesized that chronic hypoxia due to residence at high altitude predisposes women to develop hypertension during pregnancy. Prior studies indicate that maternal adaptation to pregnancy is altered by residence at high altitude such that some physiological characteristics of women pregnant at high altitude resemble those of women who develop hypertension during pregnancy at low altitude. This paper reviews data from studies, conducted over the past decade, which support a relationship between chronic hypoxia and hypertension during pregnancy. The results suggest that both the requirements for successful adaptation to high altitude, as well as the effect of lowered PO2 during pregnancy, may contribute to the development of hypertension during pregnancy. (c) 1995 Wiley-Liss, Inc. PMID- 28557209 TI - Use of cortisol as a stress marker: Practical and theoretical problems. AB - Human biologists have shown increasing interest in the use of cortisol as an objective marker of stress in recent years. This paper reviews both practical and theoretical problems raised by this approach. The methodology of cortisol assessment using urine, saliva, and plasma is considered. There are many practical problems involved in obtaining good measures of cortisol, although the availability of salivary assays offers a promising way forward. Theoretical issues are of greater concern. Results of laboratory studies led to the hypothesis that cortisol is elevated when an individual is distressed. However, relatively little work has been done on cortisol variation in "real life," and the results of such studies do not, in general, conform to this hypothesis. It is concluded that the determinants of cortisol variation are not well understood. For example, cortisol level may be as much influenced by positive emotions as by negative emotions usually identified with stress. Further documentation of cortisol variation in everyday life is needed, and at present it is premature to use cortisol level as a marker of stress. (c) 1995 Wiley-Liss, Inc. PMID- 28557210 TI - Plasma lipids in two indigenous Arctic populations with low risk for cardiovascular diseases. AB - The distribution of plasma lipids and their sociodemographic and metabolic correlates were investigated in two Arctic indigenous populations based on two health surveys conducted during 1990-1991 among adults in eight Inuit communities in the Keewatin region of the Northwest Territories, Canada (n = 387), and in four communities in the Chukotka region in the Russian Far North (n = 362). For comparison, data from the Canadian Heart Health Survey were used. The age-sex specific mean total and low-density lipoprotein (LDL)-cholesterol levels among Inuit in northern Canada either do not differ significantly from the Canadian national population, or, in the case of younger Inuit women, are higher than in Canadians. This represents a temporal change from the results of earlier studies. Chukotka Natives tend to have the lowest total cholesterol (TC) and LDL values of the three populations. The two indigenous populations still enjoy considerably lower levels of triglycerides (TG) and higher levels of high density lipoprotein (HDL) cholesterol than observed in Canada, with the exception of younger Inuit women whose mean TG levels are not significantly different from those of Canadians. The proportion of individuals at risk for ischemic heart disease because of high TG (>=2.3 mmol/L) is 20% among Canadian men but only 2% and 0% among the Arctic Natives, and 11% among Canadian women compared to 6% and 3% in the Keewatin and Chukotka regions, respectively. Such sociodemographic factors as education and marital status do not have a substantial and consistent effect on plasma lipid levels. Women with higher education have lower HDL (in Keewatin) and higher TG (in Chukotka), significant only at the 0.10 level. Among Chukotka men those who reported a lineage without nonindigenous admixture have a higher HDL level (P = 0.048). No difference between the admixed and nonadmixed can be found in the Keewatin. Smoking status has no significant effect on any of the lipid fractions in either population. The two Arctic populations demonstrate an association of some plasma lipids with blood pressure and indices of obesity and central fat patterning commonly observed in other populations. However, plasma glucose does not increase in tandem with increasing levels of lipids, contrary to that observed in the general Canadian population. (c) 1995 Wiley-Liss, Inc. PMID- 28557211 TI - Body fat and fat distribution in relation to sex differences in blood pressure. AB - The extent to which the relationship between body fat and blood pressure either differs by sex or explains sex differences in blood pressure is examined. Estimates of the relationship of blood pressure to several measures of adiposity in men and women were obtained from a systematic review of the literature and tests of whether these relationships differ by sex were performed. Analysis of covariance (controlling for age and race) was used for both casual and ambulatory blood pressure in the Cornell Worksite Blood Pressure Study (N = 276). In general, most adiposity measures were significantly related to casual and ambulatory blood pressure in men and women. Subscapular skinfold thickness and body mass index exhibited the strongest associations. The vast majority of adiposity/blood pressure associations were not significantly different for men and women. Finally, sex differences in adiposity did not account for much of the sex difference observed in blood pressure. (c) 1995 Wiley-Liss, Inc. PMID- 28557212 TI - Head circumference for Mexican American infants and young children from the Hispanic health and nutrition examination survey (HHANES 1982-1984): Comparisons with Whites and Blacks from NHANES II (1976-1980). AB - This study presents descriptive statistics for head circumference in Mexican American children 6 months to 7 years of age using data from the Hispanic Health and Nutrition Examination Survey (HHANES, 1982-1984) and compares these statistics with national estimates of head circumference for non-Hispanic White children and non-Hispanic Black children from the Second National Health and Nutrition Examination Survey (NHANES II, 1976-1980). Head circumference was measured in the same standardized fashion in the two surveys. The patterns of change with age in means and in empirical percentiles were similar for both genders and for all three ethnic groups. Values for head circumference increased with age, but the rate of increase became less as age advanced. Analyses indicated that at 1, 2, and 4 years of age, mean values for head circumferences for non-Hispanic White boys were significantly larger than those for Mexican American boys. The differences in mean values for head circumferences ranged from 0.7 to 1.1 cm. Because ethnic differences in head circumferences are small in magnitude, ethnic-specific sets of reference data for head circumference are not needed for clinical evaluation of Mexican Americans, non-Hispanic Whites, and non Hispanic Blacks. Further analyses may be necessary when additional information from NHANES III allows the calculation of the 5th and 95th percentiles for Black and Mexican American children with small confidence limits. (c) 1995 Wiley-Liss, Inc. PMID- 28557213 TI - Thoughts on gender-related research: Models, myths, and medicine. AB - Gender-related research directed to hypertension and coronary artery disease (CAD) is discussed in terms of the one-sex and two-sex models. Gender "blind" research on the two conditions has resulted in questionable treatment regimes for women. In addition, the biomedical myth of CAD as a male disease has also perpetuated less-than-optimal treatment. Finally, the role of amount and distribution of body fat in the development of hypertension and CAD should be considered within an evolutionary framework. Body fatness in women has been of evolutionary survival value and current standards for ideal weight and risk for disease have to take this into account. (c) 1995 Wiley-Liss, Inc. PMID- 28557214 TI - Prevalence of hepatitis B virus markers in several institutions for the mentally handicapped in the autonomous community of Madrid. AB - In order to determine the prevalence of hepatitis B virus (HBV) markers, 400 patients were studied: 134 residents of an institution (RI) for the mentally retarded and 266 under non-residential care (NRC). In the residential institutions, all markers were absent in 69 (65.7%) of 105 patients with Down syndrome and 20 (69.0%) of 29 clients without Down syndrome. In the NRC clients, 167 (85.6%) of 195 patients with Down syndrome and 65 (91.5%) of 71 clients with other mental defects (psychologically and physically handicapped, autism) had negative tests for HBV markers. The prevalence of the hepatitis B surface antigen (HBsAg) was higher in institutionalized mentally retarded (RI) and older patients (21+ years). Examination of 195 Down patients revealed a higher frequency (1.4 times) of surface antigen carriers as strictly matched non-Down syndrome cases (point prevalences 14.2% and 10.3%, respectively). The higher prevalence in affected cases appears to be primarily associated with a longer persistence of antigenemia. Results related to the sex of the patients were less clear. Neither affected nor non-affected patients showed significant differences in prevalence among males and females. (c) 1995 Wiley-Liss, Inc. PMID- 28557215 TI - Sex differences in the response of blood pressure to modernization. AB - Sex and age differences in the incidence of hypertension and blood pressure (BP) levels and their concomitants are examined among the Manus of Papua New Guinea in the context of modernization. For Manus men, BP increases directly with both degree of modernization and duration of migration to the local towns and larger cities of Papua New Guinea, accompanied by similar increases in body mass and subcutaneous fat. For Manus women, however, although body mass and fatness increase along the modernization continuum, BP does not. Risk for hypertension (140/90 mm Hg) was increased fourfold among men who resided in town (adjusted odds ratio [AOR] = 4.4, 95% confidence interval [CI] 1.5-13.2) and also among those who were in the highest tertile of fatness (AOR = 4.1, 95% CI 1.6-10.4). Among women, older age (>=45) alone significantly increased risk tenfold (AOR = 10.5, 95% CI 1.7-66.8). Using a Mantel-Haenszel chi2 , a meta-analysis of sex and age differences in relative risk for hypertension (160/95 mm Hg) among 20 Pacific populations, 9 traditional living and 11 undergoing modernization, was performed. While young men showed increased risk in modernizing populations (summary relative risk [SRR] = 1.34, 95% CI 1.12-1.60), older men had significantly reduced risk for hypertension compared with women in both traditional (SRR = 0.46, 95% CI 0.33-0.64) and modernizing groups (SRR = 0.70, 95% CI 0.59-0.84). This crossover between the sexes with advancing age is also evident for BP levels in a larger sample of societies and suggests a biological basis for hypertension risk. (c) 1995 Wiley-Liss, Inc. PMID- 28557216 TI - Re-examination of secular change in adult Irish stature. AB - Data from a large cross-sectional study conducted in the 1930s were used to examine secular changes in adult stature in post-Famine Ireland. The sample consists of 4061 males and 804 females, who were 30 years of age or older at the time of measurement (mostly in 1935). The Himes-Mueller method was used to adjust stature for the effects of aging so that secular change could be assessed. The linear regression of adjusted stature on year of birth was significant for both males and females, and there was no significant difference in slopes between the sexes. These results show an increase in stature of approximately 0.35-0.40 cm per decade, which is not that different from increases found in other studies of 19th century European populations. No significant curvilinearity was detected. These results show that an earlier analysis of a much smaller portion of the sample was biased due to small numbers. (c) 1995 Wiley-Liss, Inc. PMID- 28557217 TI - Long-term pharmacologic treatment of women with hypertension. AB - As reviewed in "Hypertension in Women: What is Really Known?" (Women's Caucus Working Group on Women's Health of the Society of General Internal Medicine [1991] Ann Intern Med 115:287-293), the published literature reveals that hypertension frequently occurs in women and that only some prospective studies have defined specific benefits and risks of long-term pharmacologic treatment. Major U.S. epidemiologic studies show the incidence of hypertension to very between 20% and 50% of the population. It is more common among Afro-Americans than White Americans. Frequency increases with aging. Several studies of at least 3 years duration that have focused on the use of diuretics and B blockers are reviewed: Hypertension Detection and Follow-Up Program (HDFP), Medical Research Council (MRC), MRC trial in the treatment of older adults (MRC-Older), and isolated systolic hypertension in the elderly (SHEP). Both diuretics and B blockers generally lower blood pressure, and decrease stroke incidence and mortality. Diuretics seem to be more effective and better tolerated than B blockers. Long-term studies of newer antihypertensive agents do not yet exist. The sexual side effects of drugs have only been studied to a limited degree in women. (c) 1995 Wiley-Liss, Inc. PMID- 28557218 TI - Racial admixture in a Mestizo population from Mexico City. AB - Seven genetic systems were used to investigate the racial composition of a sample from a low-income Mexico City Mestizo group, finding estimates of 0.590, 0.348, and 0.062 of Indian, White, and Black ancestry, respectively. The results are similar to another Mexico City group studied previously and to several Mestizo populations from different parts of the country. The one thing in common in all these groups is low socioeconomic status. There is only one report suggesting that Mexico City Mestizos have around 70% White ancestry, and there is reason to believe the sample was taken from a high socioeconomic group. It is suggested that low socioeconomic Mexican Mestizo groups are characterized by a high Indian ancestry, above 50%. (c) 1995 Wiley-Liss, Inc. PMID- 28557219 TI - Effects of sex, age, weight, and heredity on blood pressure in baboons. AB - Using data on a population of 498 pedigreed baboons, the effects of several covariates, including sex, age, weight, and subspecies, on arterial blood pressures were studied. Females had significantly higher systolic and diastolic arterial blood pressure than males. Both systolic and diastolic arterial blood pressures increased significantly with increasing weight, and for diastolic pressure, the increase was significantly greater in females than in males. Systolic arterial blood pressure significantly decreased with increasing age and the decrease was larger in males. There were significant differences in arterial blood pressures that corresponded with degree of subspecies admixture. (c) 1995 Wiley-Liss, Inc. PMID- 28557220 TI - Maternal/offspring birth month concordance in a Pacific island population. AB - Analyses of 13,863 births occurring on Guam before 1942 reveal statistically significant concordance of maternal and offspring birth months, accounting for over 17% of recorded births. A secular change by maternal birth year in month of highest concordance level coincides with changing public health measures over this historical period. Together with observed birth order effects, showing decreasing concordance values with increasing birth order rank, these findings suggest an immunological component of observed birth seasonality patterns. The potential effects of maternal-fetal immunological interactions merit greater consideration in birth seasonality studies among historical and anthropological populations. (c) 1995 Wiley-Liss, Inc. PMID- 28557221 TI - Gender differences and similarities in effects of nonpharmacologic approaches to the treatment of mild hypertension. AB - TAIM, the Trial of Antihypertensive Interventions and Management, studied the effects of dietary sodium restriction or weight reduction, alone and in combination with low-dose diuretic or beta blocker on blood pressure after 6 months. The responses to these interventions of men compared to women are presented for those persons randomized to placebo drug. Men undergoing a weight reduction intervention were able to lose more weight (5.9 kg) than women (3.1 kg), P ? 05. Men also had a greater percentage of wright loss and a greater reduction in body mass index (BMI), although not significantly so. Weight loss was correlated to a decrease in triglycerides (r = 0.37), but not in cholesterol. The weight-reduction intervention lowered triglycerides more in men (-81 mg/dl) than in women(-21 mg/dl; P = .008). There were no sex differences in abiility to reduce sodium or increase potassium for those in the sodium restriction group. Both men and women decreased their sodium to the same extent by 36 mmol/day and 25 mmol, respectively, and increased their potassium by 13 mmol and 11 mmol, respectively. Blood pressure response at 6 months was greater in men than in women on weight reduction (a drop in diastolic pressure of -11 mmHg in men and 7 mmHg in women, P =.04). Sodium restriction had a similar effect on blood pressure in both sexes, and among men resulted in a significantly smaller reduction in blood pressure than did weight reduction. (c) 1995 Wiley-Liss, Inc. PMID- 28557222 TI - Distal versus proximal electrode placement in the prediction of total body water and extracellular water from multifrequency bioelectrical impedance. AB - In 48 normal weight subjects, 25 females and 23 males, body impedance was measured at multiple frequencies. Two different electrode placements were used, one the commonly used distal electrode placement, in which the source electrodes are on the dorsal sides of the hand and foot and the sensor electrodes are on ankle and wrist, and a second placement, in which the sensor electrodes are placed more proximally, at the knee and elbow. Theoretically a proximal electrode placement could result in more precise estimates of body water compartments. Total body water (TBW) and extracellular water (ECW) were determined using deuterium oxide dilution and bromide dilution, respectively. The aim of the study was to investigate whether proximal electrode placement results in a more precise estimation of TBW and ECW using multifrequency impedance analysis. Correlation coefficients of impedance and the impedance index stature2 /impedance) with TBW and ECW were not or were only slightly higher using proximal impedance values, resulting in slight improvement of the estimation error for TBW (0.13 kg) and ECW (0.04 kg). The differences between measured and predicted values (residuals) of TBW and ECW were not correlated with TBW and ECW, but they were correlated with body fat and body water distribution (ECW/TBW). These correlations did not differ between distal and proximal impedance measurements. It is concluded that proximal impedance measurements do not substantially improve the prediction of body water compartments. (c) 1995 Wiley-Liss, Inc. PMID- 28557224 TI - China productivity project: General description and analysis of productivity. AB - The amount of work that people do is a focal point of human life, an outcome with extraordinarily complex roots. The physical task itself, the natural setting, biological work capacity, and behavioral patterns presumably condition productivity. This paper presents a model by which work output of Chinese cycle haulers was investigated, and outlines investigative techniques including work physiology, health assessment, cold response, and ethnography of the workplace and home. The objective is to explain variation in work done on a daily, monthly, and seasonal basis. This paper also quantifies work output, or productivity, using long-term pay records as measures of productivity. While pay records, which show statistically normal distributions, serve as the primary dependent variable in the analysis, field observations and experiments offer supplementary data on the behaviors that produce work output. In a sample of 48 men, various measures of biological capacity and behaviors, such as motivation, predict overall productivity regardless of season. Since mean daily pay and monthly pay have different predictors, there is much individual choice in how many days per month one works. (c) 1995 Wiley-Liss, Inc. PMID- 28557225 TI - Frequency of haplotypes in the beta globin gene cluster in a selected sample of the mexican population. AB - Five polymorphic restriction enzyme sites in the beta globin gene cluster (HindIII Ggamma-Hind III Agamma-, Ava IIINV-2 beta-and Hpa I and Bam HI 3'beta globin gene) were studied in individuals from 13 families: 13 homozygote patients for sickle cell anemia, two double heterozygotes (one SC and one S/betaThal ), 35 AS heterozygotes (23 parents and 12 siblings), one father (A/betaThal ), and three normal siblings. In addition, 17 normal unrelated Mexican subjects were studied. All subjects were from the state of Veracruz on the coast of the Gulf of Mexico. The Southern blot technique was used. Fifteen haplotypes were identified in the 142 chromosomes. Five were the most frequent: two haplotypes, (+-+++) (52.4%) and (--+-+) (19.0%) were associated with betaS chromosomes; two haplotypes, (--+++) (38.2%) and (---++) (19.7%), were linked with betaA chromosomes, and the fifth (--++-) was present in both types of chromosomes. Haplotype (+-+++) corresponded to the Bantu or Senegal type. With Hinc II analysis after PCR amplification in both the 5' and 3' regions of the psibeta globin gene, it was possible to distinguish between these African types, as in the former both restriction sites are absent. This analysis was done in 23 betaS and 10 betaA subjects. All betaS chromosomes disclosed the Bantu type, while betaA were similar to Caucasians. Bantu and Benin haplotypes have been found with high frequency in African populations, indicating the great influence of African genes in the population of the Mexican coasts. In addition, two previously unidentified haplotypes were found: (++--+) and (-++++). These can be explainded by crossing-over events and/or by new mutations. (c) 1995 Wiley-Liss, Inc. PMID- 28557226 TI - 20th Annual Meeting Human Biology Council. PMID- 28557227 TI - Relationship between frame size and fatness in children and adolescents. AB - In order to evaluate variation in body fatness by category of frame size (small, medium, and large) during growth, a sample of 7,286 Cuban children and adolescents (3,721 males, 3,565 females) 5-20 years was surveyed. Fatness was estimated from skinfold thicknesses at four sites: subscapular, triceps, suprailiac, and posterior calf. Elbow breadth was used as an estimate of frame size. Generally, the larger the frame size, the greater the amount of subcutaneous fat regardless of age and sex. The results suggest that in the assessment of obesity and its associated risk, in children and youth, frame size, given by categories of elbow breadth, should be taken into account. (c) 1995 Wiley-Liss, Inc. PMID- 28557228 TI - Do type B women have more offspring?: An instance of asymmetrical selection at the ABO blood group locus. PMID- 28557229 TI - Bio-impedance analysis for estimation of total body potassium, total body water, and fat-free mass in white, black, and Asian adults. AB - Bio-impedance analysis (BIA) measurements have been used to predict components of body composition. Their validation is required for populations varying in race, sex, and age. In 371 Whites, 182 Blacks and 225 Asians, single-frequency BIA at 50 kHz (RJL-100) resistance and reactance measurements were correlated with same day measurements of total body water (TBW) by THO dilution, total body potassium (TBK) by whole body 40 K counting, and fat-free mass (FFM) by dual-photon absorptiometry. BIA correlation coefficients with TBW, TBK, FFM, and fat varied by sex and race for all measured body composition components. The highest correlation was for FFM, and the lowest was for fat mass. Prediction equations were further improved by including age, stature, and weight for each of the study cohorts. The SEE for predictions were in the ranges of 5-6, 6-8, and 7-10% of measured FFM, TBW, and TBK, respectively. BIA was effective in predicting body composition when subjects are specified by age, sex, stature, weight, and race for subjects from 18 to 94 years of age. (c) 1995 Wiley-Liss, Inc. PMID- 28557230 TI - Gene frequencies and admixture estimates for ABO, Rho (D), and MN blood groups in persons with mono- and polyphletic surnames in monterrey, N.L., Mexico. AB - A sample of 3,211 males and females insured by the Instituto Mexicano del Seguro Social (I.M.S.S.) residing in the Monterrey Metropolitan Area (MMA), northeastern Mexico, were selected by their monophyletic or polyphyletic surnames. ABO, Rho (D), and MN blood groups were determined, and phenotype and gene frequencies were estimated to study the genetic variation among populations with these surnames, to estimate the genetic contribution from their most important ancestral populations, both Spanish and Mexican Indians, and to compare genetic structure with other populations that have been reported from this MMA and other urban centers in Mexico with the hypothesis that the persons with monophyletic surnames are the closest descendants of the founders, who colonized the MMA between 1577 and 1596, and that they still conserve some degree of genetic isolation. The results indicate that the selected persons with monophyletic surnames are the closest to the Spanish, supporting the above hypothesis; on the other hand, persons with polyphyletic surnames are the closet to other Mestizo populations from central Mexico and the Mexican Indians. Hybrid persons with one monophyletic and one polyphyletic surname are closer to the monophyletics due to the fact that 90% of these polyphyletics originated in northeastern Mexico. It is concluded that, at present, the Mestizo population from the MMA is integrated by two subpopulations, one with monophyletic and the other with polyphyletic surnames. It is suggested that due to an increase in migration in Mexico, the Mestizo genetic structure of the MMA population will slowly become more uniform. (c) 1995 Wiley-Liss, Inc. PMID- 28557231 TI - Energy cost of physical activity in twelve week old infants. AB - The energy cost of physical activity has long remained the component of energy expenditure most difficult to quantify. Measurement of total energy expenditure (TEE) in free-living infants by the doubly-labelled water method permits a new approach. The energy cost of activity was estimated in 12 week infants as the difference between TEE and the sum of minimal metabolic rate, the energy cost of tissue synthesis, and thermogenesis. No differences were found between the sexes or between breast-fed and formula-fed infants. However, the cost of activity was substantially higher than previously assumed. The approach is more suitable for use with groups rather than individuals. (c) 1995 Wiley-Liss, Inc. PMID- 28557232 TI - Worker motivation and productivity in chinese (beijing) tricycle haulers: Integrating social and biological variables. AB - Ethnographic assessment of worker lifestyle and motivation was paired with measurement of health, maximum oxygen uptake, anthropometry, and cold response to predict productivity in order to determine how well behavioral ratings and biological rankings of worker capacity predict actual productivity. The subjects were Chinese laborers hauling heavy loads on a cycle by human power during a Beijing winter. Worker productivity was measured as pay for unit of work done. This paper reports the ethnographic methods and results. Worker health was assessed through a physical examination including vital signs, echocardiogram (ECG), nutrition, hemoglobin, and hematocrit. Worker motivation was assessed during 10 weeks of participant observation, extensive interview, and a visit to the worker's household. Motivation was rated using a rank-order comparison of all 50 workers from lowest to highest. Other observational ratings (household assets, demands on worker, and health of household members) were completed at the time of the home visit using five-point scales. (c) 1995 Wiley-Liss, Inc. PMID- 28557233 TI - Genetic affinities between the migrant and parental populations of fishermen, East coast, India. AB - Genetic affinities between the migrant groups of fishermen from Puri and their parental counterparts in the Southern areas were examined using 11 genetic loci: four blood groups, five red cell enzymes, and two serum proteins. The samples for the parental populations (about 430 subjects) were drawn from 34 villages spread along the 400 km coast in Ganjam district of Orissa and the contiguous Srikakulam, Vishakhapatnam, and East Godavari districts of Andhra Pradesh. Significant departures between the migrant groups and their parental counterparts were observed at some loci, although the configuration of interpopulation distances among the migrants mimicked that of the parental populations. While the observed differences may be due to a founder effect and subsequent random genetic drift in at least two of the three small populations, given high child mortality and the systematic nature of differences observed, the role of selection cannot be totally ruled out. (c) 1995 Wiley-Liss, Inc. PMID- 28557234 TI - Manuscript reviewers. PMID- 28557235 TI - Modulating the Kinetics of Nanoparticle Adsorption for Simple and High-Yield Fabrication of Plasmonic Heterostructures as SERS Substrates. AB - This work reports scalable, low-cost, and simple fabrication of plasmonic heterostructures consisting of gold nanoparticles (NPs) of different sizes to generate intense hot-pots over large areas to serve as substrates for molecular sensing in SERS applications. Our approach involves assembly of massively available colloidal gold NPs on substrates functionalized with end-grafted poly(ethylene glycol) (PEG) brushes without need for any sophisticated tools and post-modification of the particles and substrates. From real-time monitoring of the adsorption process by using a quartz crystal microbalance, we identified that the cyclic deposition of citrate-stabilized gold NPs on PEG brushes is an effective approach to modulate the kinetics of particle adsorption and greatly improves the surface coverage leading to reduced inter-particle distances. Cyclic deposition of NPs differing in size leads to placement of the small particles in close proximity of the large ones, yielding hot-spots as a consequence of the unique type of interaction between PEG chains and gold NPs. Assembly of heterostructures (60 nm+40 nm and 60 nm+20 nm) at optimized conditions resulted in strong SERS effects with enhancement factors as high as ~2.0*106 and enabled detection of rhodamine 6G molecules in concentrations as low as 1 nm. The cyclic deposition of NPs also results in increase of the water contact angle without need for any post-modification of the substrate, resulting in ~30 fold increase in the Raman intensity of aqueous molecules. The insights gained on the adsorption of gold NPs together with the simplicity of the presented approach show great promise for surface assembly of colloidal NPs for a broad range of applications. PMID- 28557236 TI - Using action research to develop midwives' skills to support women with perinatal mental health needs. AB - AIMS AND OBJECTIVES: The aim of the research was to identify and develop midwives' skills to support women with mental health needs during pregnancy, using an action research approach. BACKGROUND: A review of perinatal mental health services in a large Dublin maternity unit revealed a high number of referred women who 'did not attend' the perinatal mental health service with few guidelines in place to support midwives in identifying and referring women for specialist help. DESIGN: Action research using cooperative inquiry involved a mental health nurse specialist and a team of midwives, who were drawn to each other in mutual concern about an area of practice. METHODS: Data were gathered from three Cooperative Inquiry meetings, which incorporated one main Action Research Cycle of constructing, planning, taking and evaluating action. Data were analysed using a thematic content analysis framework. RESULTS: Participants experienced varying levels of uncertainty about how to support women with perinatal mental health needs. Cooperative inquiry supported participants in making sense of how they understood perinatal mental health and how they managed challenges experienced when caring for women with perinatal mental health issues. Participants developed a referral pathway, highlighted the significance of education to support women with perinatal mental health issues and identified the value of using open questions to promote conversation with pregnant women about mental health. CONCLUSIONS: Midwives value education and support to identify and refer women at risk of perinatal mental health issues. Cooperative inquiry, with a focus on action and shared reflection, facilitated the drawing together of two professional groups with diverse knowledge bases to work together to develop practice in an area of mutual concern. RELEVANCE TO CLINICAL PRACTICE: Perinatal mental health is a significant public health issue and midwives need support to make psychosocial assessments and to negotiate access to specialist services where available and when required. PMID- 28557238 TI - An integrated review of the correlation between critical thinking ability and clinical decision-making in nursing. AB - AIMS AND OBJECTIVES: To explore whether there is a correlation between critical thinking ability and clinical decision-making among nurses. BACKGROUND: Critical thinking is currently considered as an essential component of nurses' professional judgement and clinical decision-making. If confirmed, nursing curricula may be revised emphasising on critical thinking with the expectation to improve clinical decision-making and thus better health care. DESIGN: Integrated literature review. METHODS: The integrative review was carried out after a comprehensive literature search using electronic databases Ovid, EBESCO MEDLINE, EBESCO CINAHL, PROQuest and Internet search engine Google Scholar. Two hundred and 22 articles from January 1980 to end of 2015 were retrieved. All studies evaluating the relationship between critical thinking and clinical decision making, published in English language with nurses or nursing students as the study population, were included. No qualitative studies were found investigating the relationship between critical thinking and clinical decision-making, while 10 quantitative studies met the inclusion criteria and were further evaluated using the Quality Assessment and Validity Tool. As a result, one study was excluded due to a low-quality score, with the remaining nine accepted for this review. RESULTS: Four of nine studies established a positive relationship between critical thinking and clinical decision-making. Another five studies did not demonstrate a significant correlation. The lack of refinement in studies' design and instrumentation were arguably the main reasons for the inconsistent results. CONCLUSIONS: Research studies yielded contradictory results as regard to the relationship between critical thinking and clinical decision-making; therefore, the evidence is not convincing. Future quantitative studies should have representative sample size, use critical thinking measurement tools related to the healthcare sector and evaluate the predisposition of test takers towards their willingness and ability to think. There is also a need for qualitative studies to provide a fresh approach in exploring the relationship between these variables uncovering currently unknown contributing factors. RELEVANCE TO CLINICAL PRACTICE: This review confirmed that evidence to support the existence of relationships between critical thinking and clinical decision-making is still unsubstantiated. Therefore, it serves as a call for nurse leaders and nursing academics to produce quality studies in order to firmly support or reject the hypothesis that there is a statistically significant correlation between critical thinking and clinical decision-making. PMID- 28557239 TI - The neuroprotective effect of mesenchymal stem cells on an experimentally induced model for multiple sclerosis in mice. AB - Multiple sclerosis (MS) is a chronic autoimmune demyelinating neurodegenerative central nervous system disorder. The aim of the present study was to investigate the prophylactic effect exerted by the one-time intraperitoneal injection of mesenchymal stem cells (MSCs) 1 * 106 and 14-day intraperitoneal injection of methylprednisolone (MP) 40 mg/kg in an experimental autoimmune encephalomyelitis (EAE). EAE was induced by intradermal injection of rat spinal cord homogenate with complete Freund's adjuvant in Swiss mice. Results of MSCs and MP-treated mice showed a significantly milder disease and fewer clinical scores compared to control mice. They suppressed tumor necrosis factor-alpha and myeloperoxidase and increased interleukin 10, whereas thiobarbituric acid reactive substances and nitric oxide brain contents were reduced to comparable levels between treatment groups. Brain content of GSH was significantly higher in MSCs-treated mice than control mice. It is evident that MSCs have relevant prophylactic effect in an animal model of MS and might represent a valuable tool for stem cell based therapy in MS. PMID- 28557237 TI - Disorders of sex development (DSD): Clinical service delivery in the United States. AB - Following the principles of care recommended in the 2006 Consensus Statement on Disorders of Sex Development (DSD), along with input from representatives of peer support and advocacy groups, this study surveyed DSD clinical management practices at healthcare facilities in the United States. DSD are congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical. Facilities providing care for patients with DSD were targeted for participation. Specialty providers completed a survey with questions in six broad categories: Institution Information, Nomenclature and Care Guidelines, Interdisciplinary Services, Staff and Community Education, DSD Management, and Research. Twenty-two of 36 targeted sites (61%) participated. Differences were observed between sites with regard to what conditions were considered to be DSD. All sites reported some degree of involvement of pediatric urology and/or surgery and pediatric endocrinology in the care of DSD patients. Gynecology and neonatology were most frequently not represented. Wide variation was observed across sites in continuing education standards, obtaining informed consent for clinical procedures, and in specific clinical management practices. This survey is the first to assess DSD clinical management practices in the United States. The findings establish a baseline of current practices against which providers delivering care to these patients and their families can benchmark their efforts. Such surveys also provide a practical framework for collaboration in identifying opportunities for change that enhance health and quality of life outcomes for patients and families affected by DSD. PMID- 28557240 TI - Selective outcome reporting in obesity clinical trials: a cross-sectional review. AB - Selective outcome reporting is a form of bias resulting from discrepancies between outcomes presented in a trial's registration and the published report. We investigate this selective bias in obesity clinical trials. A PubMed search was conducted to identify randomized controlled trials (RCTs) published in four obesity journals from 2013 to 2015. Primary, secondary and tertiary outcomes were recorded for each trial and compared to pre-specified outcomes in each trial's registration. Of the 392 identified articles, 142 were included in the final analysis; 22 (15%) RCTs demonstrated major outcome discrepancies between registration and publication: No primary outcomes were demoted to a secondary or tertiary outcome; 14 (36.84%) primary outcomes were omitted; 14 (36.84%) primary outcomes were added: 5 (13.16%) secondary outcomes were upgraded to primary outcomes; and timing of assessment for a primary outcome changed 5 (13.16%) times. Out of the 63 prospectively registered studies, 53 had no discrepancies. A total of 76 of the studies (29.80%) were unregistered or did not have an associated registration number. Our results suggest that selective outcome reporting may be a concern in obesity clinical trials. As selective outcome reporting may distort clinical findings and limit outcomes in systematic reviews, we encourage trialists and journal editors to work towards solutions to mitigate this issue. PMID- 28557241 TI - Enantioselective Reaction of 2H-Azirines with Phosphite Using Chiral Bis(imidazoline)/Zinc(II) Catalysts. AB - The first highly enantioselective nucleophilic addition reaction of phosphites with 2H-azirines has been developed. The reaction was applied to various 3 substituted 2H-azirines using novel chiral bis(imidazoline)/ZnII catalysts to afford products in good yield with high enantioselectivity. The transformation of the obtained optically active aziridines showed that 2H-azirines act as either alpha,beta- or beta,beta-dicarbocationic amine synthons. PMID- 28557242 TI - Unexpected Complications of Novel Deep Brain Stimulation Treatments: Ethical Issues and Clinical Recommendations. AB - BACKGROUND: Innovative neurosurgical treatments present a number of known risks, the natures and probabilities of which can be adequately communicated to patients via the standard procedures governing obtaining informed consent. However, due to their novelty, these treatments also come with unknown risks, which require an augmented approach to obtaining informed consent. OBJECTIVE: This paper aims to discuss and provide concrete procedural guidance on the ethical issues raised by serious unexpected complications of novel deep brain stimulation treatments. APPROACH: We illustrate our analysis using a case study of the unexpected development of recurrent stereotyped events in patients following the use of deep brain stimulation (DBS) to treat severe chronic pain. Examining these unexpected complications in light of medical ethical principles, we argue that serious complications of novel DBS treatments do not necessarily make it unethical to offer the intervention to eligible patients. However, the difficulty the clinician faces in determining whether the intervention is in the patient's best interests generates reasons to take extra steps to promote the autonomous decision making of these patients. CONCLUSION AND RECOMMENDATIONS: We conclude with clinical recommendations, including details of an augmented consent process for novel DBS treatment. PMID- 28557243 TI - The use of electronic health records for psychiatric phenotyping and genomics. AB - The widespread adoption of electronic health record (EHRs) in healthcare systems has created a vast and continuously growing resource of clinical data and provides new opportunities for population-based research. In particular, the linking of EHRs to biospecimens and genomic data in biobanks may help address what has become a rate-limiting study for genetic research: the need for large sample sizes. The principal roadblock to capitalizing on these resources is the need to establish the validity of phenotypes extracted from the EHR. For psychiatric genetic research, this represents a particular challenge given that diagnosis is based on patient reports and clinician observations that may not be well-captured in billing codes or narrative records. This review addresses the opportunities and pitfalls in EHR-based phenotyping with a focus on their application to psychiatric genetic research. A growing number of studies have demonstrated that diagnostic algorithms with high positive predictive value can be derived from EHRs, especially when structured data are supplemented by text mining approaches. Such algorithms enable semi-automated phenotyping for large scale case-control studies. In addition, the scale and scope of EHR databases have been used successfully to identify phenotypic subgroups and derive algorithms for longitudinal risk prediction. EHR-based genomics are particularly well-suited to rapid look-up replication of putative risk genes, studies of pleiotropy (phenomewide association studies or PheWAS), investigations of genetic networks and overlap across the phenome, and pharmacogenomic research. EHR phenotyping has been relatively under-utilized in psychiatric genomic research but may become a key component of efforts to advance precision psychiatry. PMID- 28557244 TI - Acetazolamide Inhibits the Level of Tyrosinase and Melanin: An Enzyme Kinetic, In Vitro, In Vivo, and In Silico Studies. AB - Melanin is the major factor that determines skin color and protects from ultraviolet radiation. In present study we evaluated the anti-melanogenesis effect of acetazolamide (ACZ) using four different approaches: enzyme kinetic, in vitro, in vivo and in silico. ACZ demonstrated significant inhibitory activity (IC50 7.895 +/- 0.24 MUm) against tyrosinase as compared to the standard drug kojic acid (IC50 16.84 +/- 0.64 MUm) and kinetic analyses showed that ACZ is a non-competitive inhibitor without cytotoxic effect. In in vitro experiments, A375 human melanoma cells were treated with 20 or 40 MUm of ACZ with or without 50 MUm of l-DOPA. Western blot results showed that ACZ significantly (P < 0.05) decreased the expression level of tyrosinase at 40 MUm. Zebrafish embryos were treated with 10, 20 or 40 MUm of ACZ and of positive control kojic acid. At 72 h of treatment with ACZ and kojic acid, ACZ significantly (P < 0.001) decreased the embryos pigmentation to 40.8% of untreated embryos at the dose of 40 MUm of ACZ while kojic acid decreased only 25.0% of pigmentation at the same dose of kojic acid. In silico docking were performed against tyrosinase using PyRx tool. Docking studies suggested that His244, Asn260 and His85 are the major interacting residues in the binding site of the protein. In conclusion, our results suggest that ACZ is a good candidate for the inhibition of melanin and it could be used as a lead for developing the drugs for hyperpigmentary disorders and skin whitening. PMID- 28557245 TI - Everolimus in pregnancy: Case report and literature review. AB - There have been few reports on the effects of everolimus on the fetus, but none of six infants with documented everolimus exposure in utero had congenital malformations. A 32-year-old nulliparous woman on everolimus (5.0 mg/day) for renal angiomyolipoma (AML) due to tuberous sclerosis complex (TSC) was found to be pregnant at gestational week (GW) 7-5/7, at which time everolimus was withheld. To control AML in this patient, transarterial embolization was performed in the right and left kidneys at GW 21 and 24, respectively, and everolimus was reinitiated at GW 25. The patient gave birth at GW 37 to a normally formed infant weighing 3057 g, but who had cardiac tumors thought to be rhabdomyomas due to inherited TSC. Thus, although data are still limited, everolimus may be promising with respect to teratogenicity. Everolimus concentration in the maternal and umbilical cord blood at birth was 1.1 ng/mL and 1.0 ng/mL, respectively. PMID- 28557248 TI - Ponatinib-induced widespread ichthyosiform eruption. PMID- 28557246 TI - Extended calorie restriction suppresses overall and specific food cravings: a systematic review and a meta-analysis. AB - BACKGROUND: Multiple studies have concluded that calorie restriction for at least 12 weeks is associated with reduced food cravings, while others have shown that calorie restriction may increase food cravings. We addressed this ambiguity in a systematic review and meta-analysis. METHODS: We searched for studies conducted on subjects with obesity, implemented calorie restriction for at least 12 weeks and measured food cravings pre-intervention and post-intervention. Our final eight studies mostly used the Food Craving Inventory. Other comparable methods were converted to a similar scale. We used the duration >=12 weeks, but closest to 16 weeks for studies with multiple follow-ups and performed DerSimonian-Laird random-effects meta-analyses using the 'metafor' package in r software. RESULTS: Despite heterogeneity across studies, we observed reductions in pooled effects for overall food cravings (-0.246 [-0.490, -0.001]) as well as cravings for sweet (-0.410 [-0.626, -0.194]), high-fat (-0.190 [-0.343, -0.037]), starchy (-0.288 [ 0.517, -0.058]) and fast food (-0.340 [-0.633, -0.048]) in the meta-analysis. Baseline body weight, type of intervention, duration, sample size and percentage of female subjects explained the heterogeneity. CONCLUSIONS: Calorie restriction is associated with reduced food cravings supporting a de-conditioning model of craving reductions. Our findings should ease the minds of clinicians concerned about increased cravings in patients undergoing calorie restriction interventions. PMID- 28557247 TI - European consensus on the concepts and measurement of the pathophysiological neuromuscular responses to passive muscle stretch. AB - BACKGROUND AND PURPOSE: To support clinical decision-making in central neurological disorders, a physical examination is used to assess responses to passive muscle stretch. However, what exactly is being assessed is expressed and interpreted in different ways. A clear diagnostic framework is lacking. Therefore, the aim was to arrive at unambiguous terminology about the concepts and measurement around pathophysiological neuromuscular response to passive muscle stretch. METHODS: During two consensus meetings, 37 experts from 12 European countries filled online questionnaires based on a Delphi approach, followed by plenary discussion after rounds. Consensus was reached for agreement >=75%. RESULTS: The term hyper-resistance should be used to describe the phenomenon of impaired neuromuscular response during passive stretch, instead of for example 'spasticity' or 'hypertonia'. From there, it is essential to distinguish non-neural (tissue-related) from neural (central nervous system related) contributions to hyper-resistance. Tissue contributions are elasticity, viscosity and muscle shortening. Neural contributions are velocity dependent stretch hyperreflexia and non-velocity dependent involuntary background activation. The term 'spasticity' should only be used next to stretch hyperreflexia, and 'stiffness' next to passive tissue contributions. When joint angle, moment and electromyography are recorded, components of hyper-resistance within the framework can be quantitatively assessed. CONCLUSIONS: A conceptual framework of pathophysiological responses to passive muscle stretch is defined. This framework can be used in clinical assessment of hyper-resistance and will improve communication between clinicians. Components within the framework are defined by objective parameters from instrumented assessment. These parameters need experimental validation in order to develop treatment algorithms based on the aetiology of the clinical phenomena. PMID- 28557249 TI - Dendritic Mesoporous Silica Nanoparticles for pH-Stimuli-Responsive Drug Delivery of TNF-Alpha. AB - Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic immune stimulatory cytokine and natural endotoxin that can induce necrosis and regression in solid tumors. However, systemic administration of TNF-alpha is not feasible due to its short half-life and acute toxicity, preventing its widespread use in cancer treatment. Dendritic mesoporous silica nanoparticles (DMSN) are used coated with a pH-responsive block copolymer gate system combining charged hyperbranched polyethylenimine and nonionic hydrophilic polyethylenglycol to encapsulate TNF alpha and deliver it into various cancer cell lines and dendritic cells. Half maximal effective concentration (EC50 ) for loaded TNF-alpha is reduced by more than two orders of magnitude. Particle stability and premature cargo release are assessed with enzyme-linked immunosorbent assay. TNF-alpha-loaded particles are stable for up to 5 d in medium. Tumor cells are grown in vitro as 3D fluorescent ubiquitination-based cell cycle indicator spheroids that mimic in vivo tumor architecture and microenvironment, allowing real-time cell cycle imaging. DMSN penetrate these spheroids, release TNF-alpha from its pores, preferentially affect cells in S/G2/M phase, and induce cell death in a time- and dose-dependent manner. In conclusion, DMSN encapsulation is demonstrated, which is a promising approach to enhance delivery and efficacy of antitumor drugs, while minimizing adverse side effects. PMID- 28557250 TI - Decreased endothelial function and increased subclinical heart failure in women several years after pre-eclampsia. AB - OBJECTIVES: Pre-eclampsia (PE) is associated with both postpartum endothelial dysfunction and asymptomatic structural heart alterations consistent with heart failure Stage B (HF-B). In this study, we assessed the relationship between endothelial function, measured by flow-mediated dilation (FMD), and HF-B in women with a history of PE. METHODS: This was an observational study in which 67 formerly pre-eclamptic women (>= 4 years postpartum) and 37 healthy parous controls were assessed ultrasonographically for cardiac function and geometry, as well as for endothelial function by means of brachial artery FMD. HF-B was diagnosed as left ventricular hypertrophy (left ventricular mass index (LVMi) > 95 g/m2 ), concentric remodeling (relative wall thickness > 0.42 and LVMi <= 95 g/m2 ), mild systolic dysfunction (left ventricular ejection fraction > 40% and < 55%) or asymptomatic valvular disease. Cardiovascular and metabolic syndrome variables were compared between women with history of PE and controls, as well as between those in the formerly pre-eclamptic group who had HF Stage A, HF-B or no HF. Logistic regression analysis was performed to assess the associations of FMD with PE, metabolic syndrome risk factors and obstetric parameters. RESULTS: The prevalence of HF-B amongst formerly pre-eclamptic women was three-fold higher than that observed for controls (25% vs 8%, P < 0.05), while FMD was lower in formerly pre-eclamptic women compared with controls (6.12% vs 8.22%, P < 0.01); history of PE remained associated independently with lower FMD after adjusting for metabolic syndrome risk factors and obstetric parameters (beta, -1.88; 95% CI, -3.59 to -0.18). However, HF-B did not relate to low FMD in formerly pre eclamptic women. CONCLUSIONS: Years after pregnancy, formerly pre- eclamptic women have lower FMD and have HF-B more often compared with healthy parous controls. Nonetheless, HF-B was not related to reduced FMD. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28557251 TI - Evidence for the association of Epstein-Barr Virus in breast cancer in Indian patients using in-situ hybridization technique. AB - Epstein-Barr Virus (EBV) is etiologically linked to Burkitt lymphoma (BL), nasopharyngeal carcinoma, post-transplant lymphomas, Hodgkin disease, and possibly other tumors. However, the association of oncogenic EBV with breast carcinoma (BC) is still controversial and a matter of debate. We aimed to study the presence of EBV genome in BC cases in Indian patients and its association with the clinicopathological features. The formalin fixed paraffin embedded tissues from 83 women with primary invasive BC were studied for the presence of EBV by in-situ hybridization (ISH) technique for Epstein-Barr Virus Encoded RNA (EBER) with appropriate controls. Correlation of EBER-ISH positivity with clinicopathological features was performed using Fisher exact test and P<.05 was considered as significant. Eighty-three BC cases were comprised of 47 (56.5%) triple negative breast cancers (TNBC), 17 (20.5%) hormone positive and 19 (22.9%) HER2 positive cases. Of 83 cases, 25 cases (30.1%) were positive for EBER-ISH test. The positivity was restricted to the tumor cells and not seen in the surrounding breast lobules. EBER-ISH positivity was statistically associated with larger tumor size (52.6% in >5 cm tumors vs 19.3% in <=5 cm; P=.014) and with TNBCs (21/47 [44.7%] in TNBCs vs 4/36 [11.1%] in non-TNBCs; P=.001). A possible causal association of EBV in BC cases in Indian patients is suggested by high frequency of EBER-ISH positivity noted in our study. This might have therapeutic significance because of the possible role of EBV specific cytotoxic T cells in targeting EBV associated tumor cells and can be considered as a potential targeted therapy. To the best of our knowledge, this is the first study from India to address this issue using EBER-ISH technique. PMID- 28557252 TI - A case study integrating CBT with narrative therapy externalizing techniques with a child with OCD: How to flush away the Silly Gremlin. A single-case experimental design. AB - PROBLEM: Evidence exists for the use of cognitive behavioral therapy (CBT) combined with externalizing techniques from narrative therapy for pediatric obsessive compulsive disorder (OCD); however, no research gives a detailed account of what the externalizing process looks like in session or how it is incorporated into conceptualization. Literature is appraised with respect to the referral, assessment, formulation, intervention and outcome. METHODS: The case describes a 10-year-old boy who was referred with severe OCD. The evidence-based CBT model for OCD in child and adolescent populations was applied to the case. This was integrated with the externalizing technique from narrative therapy. Using these models, a shared formulation of the difficulties was developed, and created a new narrative. The intervention was assessed using the single-case experimental design. FINDINGS AND CONCLUSIONS: On all but one routine outcome measure positive clinically significant changes were made, and the young person managed to reach his therapeutic goals. Gains maintained over a month follow-up period. The use of externalizing was an effective and developmentally appropriate intervention and is discussed further. The case highlighted the need for more research detailing externalizing processes. PMID- 28557253 TI - Mitochondrial DNA polymorphism in three Brazilian Indian tribes. AB - The first 360 base pairs of the mitochondrial DNA (mtDNA) major noncoding region from 82 individuals affiliated with the Brazilian Xavante, Zoro and Gaviao tribes were sequenced. A total of 14 different lineages were observed, the largest number (8) being found among the Zoro. The latter share five lineages with the Gaviao (who are their neighbors and are culturally similar to them), but only one with the Xavante. The lineages can be grouped into four clusters, previously identified by other authors. The 9 base pair deletion characteristic of Asian and Pacific populations occurs in 32% of the individuals, whose mtDNA was classified in five lineages, all grouped in one of the four clusters. Nucleotide diversity, as evaluated by three indices, are not much different from those observed in Indians from Central and North America, despite the fact that the Xavante consistently show lower numbers. These results do not confirm previous generalizations about the genetic diversity of Amerindians, and the need for additional studies in this system is stressed. (c) 1996 Wiley-Liss, Inc. PMID- 28557254 TI - Changes in somatotype during growth in Chinese youth 7-18 years of age. AB - Heath-Carter anthropometric somatotypes were calculated for 7,710 Chinese youths (4,434 boys and 3,276 girls), 7-18 years of age in the context of sex and age differences in distributions during adolescence. Age-specific trends are characterized by a consistent increase in endomorphy in girls and generally stable mesomorphy in boys. Somatotypes are consistently dominant in mesomorphy in boys and in endomorphy in girls across all ages. Somatotype distributions in the 13 somatotype categories of Heath-Carter somatochart appear to be broader in girls than in boys, and is more influenced by age in girls than in boys. Comparisons with other Asian samples and with Canadian youth suggest racial/ethnic variation in somatotype. (c) 1996 Wiley-Liss, Inc. PMID- 28557255 TI - Dermatoglyphics of inhabitants of Alberche/Tormes valley (Sierra de Gredos Central Spain): I. Finger pattern types and pattern intensity. AB - The incidence of dermatoglyphic finger patterns and pattern intensity in a sample of school children from the Alberche/Tormes valley (northern slope of the Sierra de Gredos, Central Spain) are described. Significant bilateral differences for the overall finger pattern incidence are found in both sexes. The differences between sexes are also statistically significant, except for the left hand. The Pattern Intensity Index significantly differs between hands of males only, and the sex differences are not significant. Variation ranges for fingertip patterns and pattern intensity were constructed using published data of 69 male and 62 female series drawn from the whole of the Iberian Peninsula. The overall incidence of fingertip patterns and the Pattern Intensity Index locate the studied population near the middle of the corresponding variation ranges. The only exception is the case of arches, for which Alberche/Tormes is close to the minimum value of the range of variation. A more detailed comparison of 10 male and 10 female series from the Spanish northern and southern plateaus and from the Spanish region of Extremadura was done with R-matrix analysis. The series compared include those from the northern slope (Alberche/Tormes valley, this study) and the southern slope (Tietar valley) of the Sierra de Gredos. The observed degree of dermatoglyphic differentiation between these two series may be explained by taking into account both the role of the Sierra de Gredos as a biological barrier limiting gene flow and the evolutionary stability of dermatoglyphics. (c) 1996 Wiley-Liss, Inc. PMID- 28557257 TI - Energy expenditure at rest and during activities: A comparison between young and elderly women. AB - Energy expenditure at rest (resting metabolic rate, RMR) and during several activities was measured in 20 young (age 19-27 years) and 19 elderly (age 65-78 years) females. Fat-free mass (FFM) was estimated by means of a four compartment model which accounted for variability in water and bone mineral in the FFM. RMR was lower (P < 0.05) in the elderly (mean +/- SE 3.55 +/- 0.05 kJ/min) compared to the younger females (3.92 +/- 0.09 kJ/min). However, after correction for differences in FFM between the groups, RMR was 3.71 +/- 0.07 kJ/min and 3.77 +/- 0.06 kJ/min for the elderly and young, respectively, and the difference was not significant. Energy expenditure (EE) during several activities, standing with arm movement, bicycling at 25 Watts, and walking at 3 km/h, were not different between the two groups. However, the physical activity ratios (PAR) for the activities were higher (P < 0.05) in the elderly (1.61 +/- 0.03, 3.29 +/- 0.07, 4.11 +/- 0.16, respectively) than in the young (1.47 +/- 0.03, 2.93 +/- 0.05, 3.58 +/- 0.14, respectively). EE due to physical activity alone (total EE minus RMR) was significantly higher for all activities in the elderly, except for walking at fixed speed of 3 km/h. After correction for the lower relative FFM in the elderly, differences between age groups disappeared. EE for walking 500 m at an individually selected speed was higher in the elderly, although they selected a lower walking speed. Differences between young and elderly decreased when step frequency was taken into account. It is concluded that EE due to physical activity in elderly women is higher than in younger females, but that the differences in EE due to physical activity are largely attributable to differences in body composition. (c) 1996 Wiley-Liss, Inc. PMID- 28557256 TI - Biologic risk factors for low birthweight in Al Ain, United Arab Emirates. AB - A prospective study of biological factors for low birthweight (LBW) among UAE nationals in the Al Ain Medical District was undertaken from 15 January 1992 to 14 January 1993, using a case control method. All 293 mothers of LBW infants and an equal number of mothers of the next normal weight infants born after the LBW infant were studied. Of the 3,485 live births, 293 (8.4%) were LBW (less than 2,500 g). Maternal age less than 25 years, lighter weight at booking, nulliparity, first cousin marriage and short interpregnancy interval (IPI) of 3 months or less significantly increased the risk of LBW in this population. After adjusting for other biologic confounders, only low maternal weight and short IPI significantly increased the risk of LBW. Modification of these biologic risk factors would help to reduce the incidence of LBW among the UAE population. (c) 1996 Wiley-Liss, Inc. PMID- 28557258 TI - Reference data for arm muscle and arm adipose tissue areas in Mexican Americans from the Hispanic Health and Nutrition Examination survey (HHANES 1982-1984): Comparisons with whites and blacks from NHANES II (1976-1980). AB - Data for arm muscle area (AMA) and arm adipose tissue area (AATA) from 3695 Mexican American children 6 months to 18 years of age included in HHANES (1982 1984) were used to obtain age-and gender-specific means and selected percentiles. These statistics were compared with those for non-Hispanic white and non-Hispanic black children from NHANES II (1976-1980). In comparison with non-Hispanic white and non-Hispanic black children, the Mexican American children tended to have smaller means and percentile values for AMA but larger values for AATA. There was considerable sexual dimorphism in AMA and AATA. Within each population, boys tended to have larger means and percentile values for AMA than girls, and girls tended to have larger values for AATA than boys. Within each population of boys, there was a prepubescent gain in AATA, followed by a midpubescent loss, and then an increase near the middle of the second decade. This "fat wave" pattern was not noticeable in girls. Population differences in age- and gender-specific mean values for AMA and AATA were small. Few statistically significant differences were observed; these were no more common than would occur by chance. Therefore, population-specific reference data for AMA and AATA may not be needed for the clinical evaluation of Mexican Americans, non-Hispanic blacks, and non-Hispanic whites. (c) 1996 Wiley-Liss, Inc. PMID- 28557259 TI - Prediction of total body water and fatness from anthropometry: Importance of skinfold measurements. AB - Prediction equations for total body water (TBW) generally use weight and height as predictors, but their ability may be limited because they implicitly assume a constancy of TBW among individuals of similar body size. The objective of this study was to evaluate the relative importance of anthropometric dimensions in predicting TBW and body composition. TBW determined by doubly labeled water (DLW) dilution techniques was used as the frame of reference in 23 healthy Aymara subjects, 4-65 years, in a rural community of the Bolivian Andes. Predictive performances of anthropometric variables for TBW were examined with multiple regression analyses. The generated equations were tested for cross-validity, using published data for U.S. adults. The resulting errors were compared with those of the published prediction equations of Mellits and Cheek (M&C) and Durnin and Womersley (D&W). The simplified prediction equation using weight and the triceps skinfold (Eq-A1:R2 = 0.989, SEE = 1.041 L) and that using weight and the triceps and subscapular skinfolds (Eq-A2: R2 = 0.990, SEE = 1.020 L) had better R2 and smaller SEE than those using any combination of variables, weight, height, age, and sex. In the cross-validation sample, Eq-A1 and Eq-A2 demonstrated higher precision than the D&W and M&C equations. Evaluated by the method of Bland and Altman (mean difference +/- 2SD), prediction errors for fat mass and fat percent were 0.2 +/- 2.8 kg and 0.4 +/- 5.2% in Eq-A2, 1.1 +/- 3.5 kg, and 1.8 +/- 6.1% in Eq-A1, -2.4 +/- 3.6 kg and -3.4 +/- 5.1% in D&W, and -2.3 +/- 7.6 kg and -2.6 +/- 10.3% in M&C. Significant underestimation of fat mass and sex differences in the biases were observed with D&W and M&C (P < 0.05), but not with Eq-A2. By including skinfold measurements, a single prediction equation for TBW was valid for males and females across different population samples. (c) 1996 Wiley-Liss, Inc. PMID- 28557260 TI - Growth studies in Jena, Germany: Historical background and secular changes in stature and weight in children 7-14 years. AB - Anthropological investigations have been performed on Jena school children since 1880. The report summarizes the background of the surveys and then considers secular changes in stature and body weight since 1880. The stature of Jena school children shows a major increase over 105 years, ranging from 9.7% to 12.8% in girls and from 9.4% to 14.6% in boys. Changes in estimated growth rates are evident, especially in the preschool ages. Corresponding secular increases in weight between 1880 and 1985 range from 20.7% to 50.4%. Data during and after times of war suggest that females appear to react to changing living conditions more quickly than boys. On the other hand, the smaller variation in the stature of girls suggests more homogeneous and perhaps better buffered growth in girls. Estimated semiannual increments in stature and weight between 1880 and 1985 indicate an increase in the intensity of growth during school age in both sexes and acceleration of the pubertal growth spurt, especially in boys. The average decrease in weight in both sexes between 1932 and 1944 should be emphasized. This is the result of the poor nutritional conditions during the Second World War. Girls show a greater reduction in mean values than boys. (c) 1996 Wiley-Liss, Inc. PMID- 28557261 TI - Precision of measuring body fat distribution in adolescent African American girls from the 'healthy growth study'. AB - Precision estimates are given for anthropometric assessment of body fat distribution in participants (n = 86) of the Healthy Growth Study (total n = 154). This five year longitudinal study explored the psychosocial and biologic influences on activity levels in urban adolescent African American girls. The basic anthropometric data include height, weight, four body and limb circumferences, and five skinfold measurements. It is proposed that ratio indices of body fat distribution are likely to have poorer precisions than the single variables which they comprise, and that ratios based on skinfolds may be particularly sensitive to this problem. The precision of the body mass index (BMI) and principal components of skinfold fatness and fat distribution are also considered. Precisions were greater than 0.95 (intraclass correlation from a random-effects analysis of variance) for most anthropometric dimensions and indices, including the BMI and the first principal component of fatness. However, three of the five skinfolds had lower precisions (0.84-0.93). In contrast, the precisions of all indices of body fat distribution were 0.90 or less (range: 0.57 0.87 skinfold ratios; 0.83-0.90 circumference ratios). Of the ratios, conicity was most stable at 0.90 for repeated measures by both the same and different observers. A second principal component of central fat did not have precisions noticeably better than skinfold ratios (0.79-0.82). Indices of fat distribution may have lower reliabilities than the single variables that they comprise, because errors may be compounded when dividing one variable by another or in linear combinations of measurements other than the first principal component. This problem should be taken into account in clinical and epidemiologic investigations of body fat distribution. (c) 1996 Wiley-Liss, Inc. PMID- 28557262 TI - Basal metabolic rate and dietary seasonality among Tibetan nomads. AB - The results of 51 overnight measurements of basal metabolic rate (BMR) in a sample of pastoral nomads resident permanently in Phala, Tibet Autonomous Region, China, are reported. Past studies demonstrated a culturally driven seasonality of diet, with very low summer and very high winter caloric intake. The study was designed to test the hypothesis that the ability of Phala nomads to subsist on low caloric intake for several summer months without signs of malnutrition is explained by lower summer BMR. However, BMR measurements of 40 nomads 13-69 years of age during the summer and remeasurement of 11 nomads during the winter of 1993 provide no evidence for low summer BMR to compensate for the low summer caloric intake. BMR in both seasons is within the normal range predicted by international equations. The BMR of males does not differ from that of females, and the BMR of females averages 7% higher than predicted. Anthropometric evidence reveals that the Phala nomads accumulate body fat during the winter. It is inferred that this may buffer the summer period of low intake. The pattern of subcutaneous fat accumulation in winter, moreover, may afford slight improvement in physiological cold insulation during the severe winters as a consequence of depositing winter fat on the trunk rather than on the periphery. Thus, the dietary seasonality in Phala is a stress that elicits fluctuation in fat energy stores but not BMR. (c) 1996 Wiley-Liss, Inc. PMID- 28557263 TI - Double-Layered Plasmonic-Magnetic Vesicles by Self-Assembly of Janus Amphiphilic Gold-Iron(II,III) Oxide Nanoparticles. AB - Janus nanoparticles (JNPs) offer unique features, including the precisely controlled distribution of compositions, surface charges, dipole moments, modular and combined functionalities, which enable excellent applications that are unavailable to their symmetrical counterparts. Assemblies of NPs exhibit coupled optical, electronic and magnetic properties that are different from single NPs. Herein, we report a new class of double-layered plasmonic-magnetic vesicle assembled from Janus amphiphilic Au-Fe3 O4 NPs grafted with polymer brushes of different hydrophilicity on Au and Fe3 O4 surfaces separately. Like liposomes, the vesicle shell is composed of two layers of Au-Fe3 O4 NPs in opposite direction, and the orientation of Au or Fe3 O4 in the shell can be well controlled by exploiting the amphiphilic property of the two types of polymers. PMID- 28557264 TI - Duration of dual antiplatelet therapy following drug-eluting stent implantation: A systemic review and meta-analysis of randomized controlled trials with longer follow up. AB - OBJECTIVE: To evaluate the long term efficacy and safety of long duration DAPT (L DAPT) compared to short duration DAPT (S-DAPT) after drug-eluting stent (DES) implantation. METHODS: We searched Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials (RCTs) assessing the clinical impact of L-DAPT versus S-DAPT after DES and have mean follow up period of at least 2 years or longer. Primary end point was stent thrombosis (ST). Secondary endpoints were all-cause mortality, cardiac mortality, myocardial infarction (MI), target vessel revascularization (TVR), thrombolysis in myocardial infarction (TIMI) major bleeding and stroke. Event rates were compared using a random effects model. RESULTS: We identified five RCTs in which 19,760 patients were randomized to S-DAPT (N = 9,810) and L-DAPT (n = 9,950), respectively. Compared with L-DAPT, S-DAPT was associated with higher rate of MI (odds ratio [OR] 1.48, 95% confidence interval [CI] [1.04, 2.10]). There were no significant differences between S-DAPT and L-DAPT in terms of all cause mortality, cardiac mortality, ST, TVR or stroke (OR 0.90, 95% CI [0.73, 1.12]; OR 1.02, 95% CI [0.80, 1.30]; OR 1.59, 95% CI [0.77, 3.27]; OR 0.87 95% CI [0.67, 1.14]; and OR 1.08 95% CI [0.81, 1.46], respectively). However, rate of TIMI major bleeding was significantly lower with S-DAPT compared to L-DAPT (OR 0.64, 95% CI [0.41, 0.99]). CONCLUSIONS: In the present analysis of RCTs with longer follow up (2 years or longer), S-DAPT compared with L-DAPT, was associated with higher rate of MI and lower rate of major bleeding without any significant difference in the rates of all cause mortality, cardiac mortality, ST, TVR, and stroke. PMID- 28557266 TI - Human biology association guide to graduate programs and graduate training in human biology. AB - The Human Biology Council Executive Committee decided at its 1993 meeting that a guide to graduate programs in human biology would be very useful for students seeking graduate training and for faculty advising such students. Therefore, information on graduate training opportunities was requested from each member of the Human Biology Council in Fall 1993 and followup requests were made in spring 1994. The responses summarized below attest to the multidisciplinary nature and the international scope of the discipline. The Human Biology Association (formerly, the Human Biology Council) plans to update the guide periodically. Please contact the compiler of this version, Prof. Cynthia M. Beall with additions and comments. (c) 1996 Wiley-Liss, Inc. PMID- 28557265 TI - Pharmacokinetic Properties of Memantine after a Single Intraperitoneal Administration and Multiple Oral Doses in Euploid Mice and in the Ts65Dn Mouse Model of Down's Syndrome. AB - Memantine is a drug approved for the treatment of moderate-to-severe Alzheimer's disease (AD), and there is ongoing research on the potential expansion of its clinical applicability. Published data on the pharmacokinetics of memantine in the mouse are still incomplete, particularly for chronic administration regimens and mouse models of specific genetic disorders. Down's syndrome (DS) is a genetic disorder known to affect multiple organs and systems, with the potential to alter significantly drug pharmacokinetics. Here, we describe a simple, efficient and sensitive GC/MS-based procedure for the determination of memantine concentrations in murine blood and tissue samples. We analysed pharmacokinetic properties of memantine, particularly its distribution in blood, brain and liver in the Ts65Dn mouse model of DS and euploid F1 hybrid mice after single intraperitoneal administrations of increasing doses of this drug. We also determined steady-state memantine concentrations in plasma, brain and liver after chronic oral administration of this drug in adult male Ts65Dn mice, euploid littermate controls and nursing or pregnant Ts65Dn mice. Our results revalidated the acute dose of memantine used in previously published work, determined the appropriate amount of memantine to be mixed into mouse chow to achieve steady and pharmacologically relevant plasma and tissue levels of this drug and demonstrated that memantine can be transferred from mother to offspring via maternal milk and placenta. Most of these findings are potentially applicable not only to the study of DS but also to other neurodevelopmental and neurodegenerative disorders. PMID- 28557268 TI - Abstracts of the 21st Annual Meeting of the Human Biology Association Durham, North Carolina April 8-10, 1996. PMID- 28557267 TI - Baseline dietary intake and physical activity of Japanese American men in relation to glucose tolerance at 5-year follow-up. AB - Japanese American men (n = 124), with normal glucose tolerance (NGT, n = 69) or impaired glucose tolerance (IGT, n = 55) at baseline, were studied for effects of baseline dietary intake and physical activity on glucose tolerance at baseline and at 5-year follow-up. At baseline, both NGT and IGT men with positive family history of diabetes (FH) showed high intakes of animal fat and protein, but only the NGT men countered this with high levels of energy expenditure. In the total sample at 5-year follow-up, 2-hour plasma glucose was significantly related to intake of animal fat (AF), partial correlation r = 0.32, P < 0.001, adjusted for total energy intake, age, self-reported health, body mass index, FH, and baseline glucose tolerance category. Energy expenditure (EE) was not related to 5-year 2 hour plasma glucose in the total sample, but displayed a relationship with 5-year 2-hour plasma glucose in those IGT (r = -0.27, P < 0.05), but not in those NGT at baseline, and in those with positive FH (r = -0.33, P < 0.05), but not in those with negative FH. Additionally, AF showed a relationship to 5-year 2-hour plasma glucose only for those in the lowest (r = 0.37, P < 0.05) and middle (r = 0.33, P < 0.05) tertiles, but not in the highest tertile of EE. For baseline IGT men, 5 year 2-hour plasma glucose was related to "high vs. low risk" categories of AF intake and EE, but only in men with a positive FH (AF >= 25 vs. < 25 g/day: 180.1 +/- 38.6 vs. 143.6 +/- 39.7 mg/dl, P = 0.048; EE <= 2,000 kcal/week vs. > 2,000 kcal/week, 189.9 +/- 39.2 vs. 150.8 +/- 37.4 mg/dl, P = 0.028; with risk categories combined, i.e., both high, mixed, both low: 192.0 +/- 41.3, 165.4 +/- 28.4, 139.4 +/- 40.9 mg/dl, P = 0.045, linear trend, P = 0.014). Thus, high AF intake and low EE may have long-range detrimental effects on glucose tolerance, especially for those with IGT and positive FH. (c) 1996 Wiley-Liss, Inc. PMID- 28557269 TI - Early childhood growth of Chachi Amerindians and Afro-Ecuadorians in Northwest Ecuador. AB - This study compares the growth of Chachi Amerindian and Afro-Ecuadorian children living in the tropical forest of northwest Ecuador. Measurements of height and weight were taken on 148 Chachi and 148 Afro-Ecuadorian children under 5 years of age. Triceps and subscapular skinfolds, arm circumference, chest circumference, and sitting height were measured on a subsample of children. Socioeconomic information was collected from the households of 145 children, and a general socioeconomic index was derived. Afro-Ecuadorian children are substantially taller than Chachi children, with significant differences in height for age z scores in most age groups. On the other hand, Chachi children tend to have greater weight for height z-scores, with significant differences in some age groups. The greater weight for height of Chachi children may be related to their larger trunks. Estimates of body composition suggest that Afro-Ecuadorian children may have somewhat better nutritional status than Chachi children, but this does not appear to fully account for the greater height of Afro-Ecuadorian children. The socioeconomic index is positively correlated with all anthropometric dimensions, but even after controlling for the socioeconomic index, Afro-Ecuadorian children are significantly taller than Chachi children. These findings raise the possibility of genetic differences in growth potential between the two groups. (c) 1996 Wiley-Liss, Inc. PMID- 28557270 TI - Human biology association abstracts. PMID- 28557271 TI - Growth of postmenarcheal girls from three ethnic groups. AB - Documentation of normal growth in late adolescence has been limited to a few studies using largely white participants. Annual growth rates of 668 high school girls who had already achieved menarche were determined for stature, sitting height, and knee height measured using the Knee Height Measuring Device (KHMD), an instrument with superior reliability. The sample was 61.4% white, 16.8% Puerto Rican, 15.7% African American, and 6.1% girls of other ethnic backgrounds. Median growth rate was 1.5 cm/year for stature, 1.1 cm/year for sitting height, and 2.7 mm/year for knee height in the first full year after menarche, and >80% of all girls grew in at least one dimension. Growth in stature (>=1 cm) continued for 64% of girls 1 full year after menarche and for 31% of girls 2 years after menarche, and growth in knee height (>=1 mm) continued in >45% of girls up to 5 completed years past menarche. Whites, African Americans, and Puerto Ricans showed small but significant differences in amounts of postmenarcheal growth in the dimensions measured. African-American girls grew less in stature and sitting height than other groups, whereas Puerto Rican girls grew significantly more in sitting height and significantly less in knee height than other ethnic groups. These findings demonstrate that, as documented in other studies of postmenarcheal growth, there is substantial growth after menarche in most girls. The most sensitive measures indicate that small amounts of growth persist >5 years after menarche. Appreciation of this phenomenon needs to be communicated to clinicians who generally assume that growth ceases at/or just after menarche. (c) 1996 Wiley Liss, Inc. PMID- 28557272 TI - Further genetic variability of the VNTR D1S80 (pMCT118): Correspondence analysis studies. AB - A population genetic study of the VNTR D1S80 (pMCT118 locus) in 206 individuals from the Galician population in Spain was carried out. PCR amplified DNA were electrophoresed in horizontal polyacrylamide gels and subsequently were visualized by silver staining. Up to 19 alleles in 56 different genotypes were found. This report describes a new allele tentatively named T11 that defines the lower limit of repeats reported for this VNTR. A family study demonstrates autosomal codominant inheritance of this allele. Levels of heterozygosity indexes are about 80%. No significant deviations from Hardy-Weinberg equilibrium were observed, using the allele binning method (P > 0.3 in all cases). Correspondence analysis shows the usefulness of D1S80 alleles in the genetic profiling of human populations, with the alleles 16, 17, 21, 29, and 31 being of particular interest at different levels of analysis. (c) 1996 Wiley-Liss, Inc. PMID- 28557273 TI - Determinants of growth in body length from birth to 6 years of age: A longitudinal study of Lublin children. AB - The effect of determinants of growth in body length from birth to 6 years of age were studied in a longitudinal sample of 59 male and 70 female infants from Lublin, Poland. Structural equation modeling (SEM) was used to study the effects of gender of the child, occupation of the parents, the educational level of the parents, per capita income, the stature of the parents, and the weight of the mother on body length at birth and at 1, 2, 3, and 6 years of age. Significant sex differences in length were observed at birth and during the first 2 years of postnatal life, but not in the period between 3 and 6 years of age. Socioeconomic status (SES), expressed as a latent variable in the SEM, was not related to body length at birth but was significantly related to body length during infancy and, to a lesser extent, to body length during childhood. Paternal stature was not related to body length at birth and during infancy, but was significantly related to body length from 3 years onwards. Maternal stature was significantly related to body length at birth and at 1 year of age, but not thereafter, while maternal weight was significantly related to body length at birth only. (c) 1996 Wiley Liss, Inc. PMID- 28557274 TI - Fat-free mass as a determinant of left ventricular mass in children: The Muscatine Study. AB - To assess the relationship of somatic growth to heart growth, associations were examined among body composition, blood pressure, androgens, sexual maturation, and left ventricular mass (LVM) during early puberty in 123 children, 7-12 years of age. All subjects underwent anthropometry, random-zero blood pressure measurements, hormone determination of androgens, physician's examination to determine sexual maturation, and echocardiographic examinations. Subjects then repeated these procedures 1 year later. Data were examined cross-sectionally (year 1, year 2) and longitudinally (Delta = year 2 minus year 1). The strongest correlations with LVM were among weight and fat-free mass (FFM) (r = 0.60 to 0.83). In males, cross-sectional predictors of LVM were FFM and stage of sexual maturation (r2 = 0.49 to 0.65). Delta LVM was best predicted in males by Delta testosterone and Delta weight (r2 = 0.22). In females, FFM was the strongest cross-sectional predictor of LVM (r2 = 0.70). Delta LVM was best predicted in females by Delta FFM and Delta height (r2 = 0.27). When males and females were pooled, gender did not predict LVM in any of the models. The results suggest that FFM is an important predictor of LVM in circumpubertal children. Boys and girls do not significantly differ in LVM once normalized for FFM. (c) 1996 Wiley-Liss, Inc. PMID- 28557275 TI - Four-year comparative effectiveness of bare-metal and everolimus-eluting stents in New York. AB - OBJECTIVES: To study four-year outcomes for patients receiving either bare-metal stents (BMS) or everolimus-eluting stents (EES) and to evaluate the comparative effectiveness of BMS versus EES in six "off-label" and two "high-risk" patient subgroups. BACKGROUND: BMS and EES (a second generation of drug-eluting stent) are used in contemporary practice to treat coronary artery disease. However, little is known about long-term comparative effectiveness between BMS and EES. METHODS: Using the New York State (NYS) cardiac registries, statewide hospital discharge data, the National Death Index, and the U.S. Census file, we assessed four-year outcomes of BMS versus EES in patients receiving either BMS or EES from July 2008 through December 2009. The outcomes included all-cause mortality, acute myocardial infarction (AMI), target-lesion PCI (TLPCI), and target-vessel coronary artery bypass graft (TVCABG) surgery for a follow-up period of four years (median follow-up of 3.6 years). We compared 9,290 propensity score matched pairs with further adjustment using Cox proportional hazards regression. RESULTS: Compared with patients receiving BMS, patients receiving EES had a lower rate of four-year mortality (adjusted hazard ratio : 0.58, 95% confidence interval : 0.54-0.63), AMI (AHR: 0.68, 95% CI: 0.61-0.76), TLPCI (AHR: 0.67, 95% CI: 0.60-0.75), and TVCABG (AHR, 0.53, 95% CI: 0.43-0.65). For "off-label" and "high risk" subgroups, EES was associated with decreased mortality and generally better AMI, TLPCI, and TVCABG outcomes relative to BMS. CONCLUSIONS: Compared with BMS use, EES use was associated with better four-year outcomes. PMID- 28557276 TI - Evolving trends in head and neck cancer epidemiology: Ontario, Canada 1993-2010. AB - BACKGROUND: Given the dramatic changes in global head and neck cancer epidemiology, the purpose of this study was to present the findings of our investigation on patterns of head and neck cancer incidence/survival within the province of Ontario, Canada. METHODS: Temporal variations in age/sex adjusted incidence and survival were analyzed for all incident head and neck cancer cases (n = 20 781) managed within Ontario from 1993-2010. RESULTS: From 1993-2010, the incidence of oropharyngeal (average annual percentage change [AAPC] 4.56%; P < .001) and salivary gland (AAPC 4.99%; P < .001) carcinomas increased, whereas oral cavity (AAPC -1.44%; P < .001) and laryngeal/hypopharyngeal (AAPC -3.20%; P < .001) carcinomas declined, and nasopharyngeal carcinoma (NPC) remained static (AAPC 0.28%; P = .72). A general trend for improved 5-year overall survival (OS), was observed for all tumor sites. CONCLUSION: Consistent with previous studies, our results suggest a simultaneous decline in tobacco-associated and increase in human papillomavirus (HPV)-mediated carcinomas. The rising incidence of salivary malignancy and improvement in 5-year OS are novel findings, in need of future investigation. PMID- 28557277 TI - Rumen microbiota and dietary fat: a mutual shaping. AB - Although fat content in usual ruminant diets is very low, fat supplements can be given to farm ruminants to modulate rumen activity or the fatty acid (FA) profile of meat and milk. Unsaturated FAs, which are dominant in common fat sources for ruminants, have negative effects on microbial growth, especially protozoa and fibrolytic bacteria. In turn, the rumen microbiota detoxifies unsaturated FAs (UFAs) through a biohydrogenation (BH) process, transforming dietary UFAs with cis geometrical double-bonds into mainly trans UFAs and, finally, into saturated FAs. Culture studies have provided a large amount of data regarding bacterial species and strains that are affected by UFAs or involved in lipolysis or BH, with a major focus on the Butyrivibrio genus. More recent data using molecular approaches to rumen microbiota extend and challenge these data, but further research will be necessary to improve our understanding of fat and rumen microbiota interactions. PMID- 28557278 TI - Auditory access, language access, and implicit sequence learning in deaf children. AB - Developmental psychology plays a central role in shaping evidence-based best practices for prelingually deaf children. The Auditory Scaffolding Hypothesis (Conway et al., 2009) asserts that a lack of auditory stimulation in deaf children leads to impoverished implicit sequence learning abilities, measured via an artificial grammar learning (AGL) task. However, prior research is confounded by a lack of both auditory and language input. The current study examines implicit learning in deaf children who were (Deaf native signers) or were not (oral cochlear implant users) exposed to language from birth, and in hearing children, using both AGL and Serial Reaction Time (SRT) tasks. Neither deaf nor hearing children across the three groups show evidence of implicit learning on the AGL task, but all three groups show robust implicit learning on the SRT task. These findings argue against the Auditory Scaffolding Hypothesis, and suggest that implicit sequence learning may be resilient to both auditory and language deprivation, within the tested limits. A video abstract of this article can be viewed at: https://youtu.be/EeqfQqlVHLI [Correction added on 07 August 2017, after first online publication: The video abstract link was added.]. PMID- 28557279 TI - Development of a novel hollow-fiber liquid-phase microextraction based on oil-in salt and its comparison with conventional one. AB - A novel hollow-fiber liquid-phase microextraction based on oil-in-salt was proposed and introduced for the simultaneous extraction and enrichment of the main active compounds of hesperidin, honokiol, shikonin, magnolol, emodin, and beta,beta'-dimethylacrylshikonin in a formula of Zi-Cao-Cheng-Qi decoction and the single herb, Fructus Aurantii Immaturus, Cortex Magnoliae Officinalis, Radix et Rhizoma, and Lithospermum erythrorhizon, composing the formula prior to their analysis by high-performance liquid chromatography. The results obtained by the proposed procedure were compared with those obtained by conventional hollow-fiber liquid-phase microextraction, and the proposed procedure mechanism was described. In the procedure, a hollow-fiber segment was first immersed in organic solvent to fill the solvent in the fiber lumen and wall pore, and then the fiber was again immersed into sodium chloride solution to cover a thin salt membrane on the fiber wall pore filling organic solvent. Under the optimum conditions, the enrichment factors of the analytes were 0.6-109.4, linearities were 0.002-12 MUg/mL with r2 >= 0.9950, detection limits were 0.6-12 ng/mL, respectively. The results showed that oil-in-salt hollow-fiber liquid-phase microextraction is a simple and effective sample pretreatment procedure and suitable for the simultaneous extraction and concentration of trace-level active compounds in traditional Chinese medicine. PMID- 28557280 TI - CD8 expression in B chronic lymphocytic leukemia: A case of immuno-phenotypic aberrancy. AB - : Immuno-phenotyping forms an integral part of laboratory work up of Chronic lymphocytic leukemia (CLL). Aberrant antigen expressions are a known phenomenon in leukemic blasts, however cross lineage antigen expression is rarely seen in mature B cell leukemia, the reported percentages varying from 1% to 3% in Europe and North America. CASE DETAILS: We report a case of Rai stage 1 CLL showing aberrant expression of CD8 on flow cytometry. The patient had stable disease at a follow up of 9 months with no requirement of initiation of treatment. DISCUSSION: CD8 expression in CLL is rare and approximately 120 cases have been reported from Western population. To the best of our knowledge, this is the first case to be reported from India. The prognostic significance has been variably reported from favorable to poor. At present, our case reflects the phenotypic heterogeneity of leukemia. Long term follow up and evaluation of more cases is required to predict the prognostic role in our patient population. (c) 2017 International Clinical Cytometry Society. PMID- 28557281 TI - AgHalo: A Facile Fluorogenic Sensor to Detect Drug-Induced Proteome Stress. AB - Drug-induced proteome stress that involves protein aggregation may cause adverse effects and undermine the safety profile of a drug. Safety of drugs is regularly evaluated using cytotoxicity assays that measure cell death. However, these assays provide limited insights into the presence of proteome stress in live cells. A fluorogenic protein sensor is reported to detect drug-induced proteome stress prior to cell death. An aggregation prone Halo-tag mutant (AgHalo) was evolved to sense proteome stress through its aggregation. Detection of such conformational changes was enabled by a fluorogenic ligand that fluoresces upon AgHalo forming soluble aggregates. Using 5 common anticancer drugs, we exemplified detection of differential proteome stress before any cell death was observed. Thus, this sensor can be used to evaluate drug safety in a regime that the current cytotoxicity assays cannot cover and be generally applied to detect proteome stress induced by other toxins. PMID- 28557282 TI - Delayed diagnosis of subcutaneous dirofilariasis following a mosquito bite sustained in Germany. PMID- 28557283 TI - Halogen-Bonding-Mediated and Controlled Cationic Polymerization of Isobutyl Vinyl Ether: Expanding the Catalytic Scope of 2-Iodoimidazolium Salts. AB - Metal-free initiating systems for living cationic polymerizations are desirable from the viewpoint of environmentally benign polymer synthesis. We describe here the development of a halogen-bonding-mediated and controlled cationic polymerization of isobutyl vinyl ether (IBVE) using 2-iodoimidazolium salts as an organocatalyst. Due to the ionic nature of the catalysts, the polymerization should be performed in CH2 Cl2 . The HCl-adduct of IBVE was the most suitable initiator, and the polymerization was carried out at -10 degrees C under the catalyst concentration of 10 mm to suppress alcohol elimination from the polymer chain. The addition of a small amount of nBu4 NCl (0.02 equivalent) was effective to accomplish the controlled cationic polymerization and obtain polyIBVE, having the molecular weight distribution below 1.3. PMID- 28557285 TI - Annular atrophic lichen planus: a rare clinical entity. PMID- 28557284 TI - RPA3 is a potential marker of prognosis and radioresistance for nasopharyngeal carcinoma. AB - Radioresistance-induced residual and recurrent tumours are the main cause of treatment failure in nasopharyngeal carcinoma (NPC). Thus, the mechanisms of NPC radioresistance and predictive markers of NPC prognosis and radioresistance need to be investigated and identified. In this study, we identified RPA3 as a candidate radioresistance marker using RNA-seq of NPC samples. In vitro studies further confirmed that RPA3 affected the radiosensitivity of NPC cells. Specifically, the overexpression of RPA3 enhanced radioresistance and the capacity for DNA repair of NPC cells, whereas inhibiting RPA3 expression sensitized NPC cells to irradiation and decreased the DNA repair capacity. Furthermore, the overexpression of RPA3 enhanced RAD51 foci formation in NPC cells after irradiation. Immunohistochemical assays in 104 NPC specimens and 21 normal epithelium specimens indicated that RPA3 was significantly up-regulated in NPC tissues, and a log-rank test suggested that in patients with NPC, high RPA3 expression was associated with shorter overall survival (OS) and a higher recurrence rate compared with low expression (5-year OS rates: 67.2% versus 86.2%; 5-year recurrence rates: 14.8% versus 2.3%). Moreover, TCGA data also indicated that high RPA3 expression correlated with poor OS and a high recurrence rate in patients with head and neck squamous cell carcinoma (HNSC) after radiotherapy. Taken together, the results of our study demonstrated that RPA3 regulated the radiosensitivity and DNA repair capacity of NPC cells. Thus, RPA3 may serve as a new predictive biomarker for NPC prognosis and radioresistance to help guide the diagnosis and individualized treatment of patients with NPC. PMID- 28557286 TI - Incidence and predictors of massive bleeding in children undergoing liver transplantation: A single-center retrospective analysis. AB - BACKGROUND: Liver transplantation represents a major surgery involving a highly vascular organ. Reports defining the scope of bleeding in pediatric liver transplants are few. AIMS: We conducted a retrospective analysis of liver transplants performed at our pediatric tertiary care center to quantify blood loss, blood product utilization, and to determine predictors for massive intraoperative bleeding. METHODS: Pediatric patients who underwent isolated liver transplantation at Boston Children's Hospital between 2011 and 2016 were included. The amount of blood product transfused in the perioperative period and the incidence of postoperative complications were reported. Univariable and multivariable logistic regressions were used to determine predictors for massive bleeding, defined as estimated blood loss exceeding one circulating blood volume within 24 hours. RESULTS: Sixty-eight children underwent liver transplantation during the study period and were included in the analysis. Multivariable logistic regression analysis identified the following independent predictors of massive bleeding: preoperative hemoglobin level <8.5 g/dL (OR 11.09, 95% CI 1.87-65.76), INR >1.5 (OR 11.62, 95% CI 2.36-57.26), platelet count <100 109 /L (OR 7.92, 95% CI 1.46-43.05), and surgery duration >600 minutes (OR 6.97, 95% CI 0.99-48.92). CONCLUSIONS: Pediatric liver transplantation is associated with substantial blood loss and a significant blood product transfusion burden. A 43% incidence of massive bleeding is reported. Further efforts are needed to improve bleeding management in this high-risk population. PMID- 28557287 TI - Epidemiology and clinical features of inflammatory retinal vascular occlusions: pooled data from two tertiary-referral institutions. AB - IMPORTANCE: In a subset of patients with retinal vasculitis, there is occlusion of blood flow through the retinal vessels. These eyes are at high risk of sight threatening complications. BACKGROUND: To characterize epidemiology, clinical course, treatment and outcomes of occlusive retinal vasculitis (ORV). DESIGN: Retrospective study PARTICIPANTS: Seventy-seven uveitis patients with ORV at two large tertiary-care institutions (the USA and India). METHODS: Out of 2438 patients screened, 346 patients were diagnosed with retinal vasculitis of which 77 patients (96 eyes) were diagnosed with ORV. Patients with ORV (capillary, arteriolar and/or venular) were further analysed. Diagnostic criteria for occlusive vasculitis included (i) absence of blood flow in vessels (arterioles, venules and/or capillaries), (ii) capillary non-perfusion areas and/or arteriolar venous anastomosis and (iii) intraretinal haemorrhages, cotton-wool spots or vitreous haemorrhage. MAIN OUTCOME MEASURES: Best-corrected visual acuity, treatment and complications. RESULTS: The mean age was 32.09 +/- 13.51 years. Most common aetiologies were tuberculosis and Adamantiades-Behcet's disease in India and systemic lupus erythematosus in the USA. Best-corrected visual acuity improved from 0.38 +/- 0.30 logMAR (20/48 Snellen equivalent) (baseline) to 0.25 +/- 0.30 (20/35 Snellen equivalent) at final visit (P < 0.0001). Vitreous haemorrhage was seen in 31.08% eyes. Pars plana vitrectomy was performed in 12.16% eyes. Therapy with systemic steroids was required in 78.48% patients. In addition, 46.75% patients required immunomodulators and/or biologics. CONCLUSIONS: Occlusive retinal vasculitis is caused by heterogeneous group of uveitides depending upon the geographic location. It is imperative to identify eyes with ORV as they are predisposed to complications requiring aggressive therapy. PMID- 28557289 TI - How do late terminations of pregnancy affect comparisons of stillbirth rates in Europe? Analyses of aggregated routine data from the Euro-Peristat Project. AB - OBJECTIVE: To describe how terminations of pregnancy at gestational ages at or above the limit for stillbirth registration are recorded in routine statistics and to assess their impact on comparability of stillbirth rates in Europe. DESIGN: Analysis of aggregated data from the Euro-Peristat project. SETTING: Twenty-nine European countries. POPULATION: Births and late terminations in 2010. METHODS: Assessment of terminations as a proportion of stillbirths and derivation of stillbirth rates including and excluding terminations. MAIN OUTCOME MEASURES: Stillbirth rates overall and excluding terminations. RESULTS: In 23 countries, it is possible to assess the contribution of terminations to stillbirth rates either because terminations are rare occurrences or because they can be distinguished from spontaneous stillbirths. Where terminations were reported, they accounted for less than 1.5% of stillbirths at 22+ weeks in Denmark, between 13 and 22% in Germany, Italy, Hungary, Finland and Switzerland, and 39% in France. Proportions were much lower at 24+ weeks, with the exception of Switzerland (7.4%) and France (39.2%). CONCLUSIONS: Terminations represent a substantial proportion of stillbirths at 22+ weeks of gestation in some countries. Countries where terminations occur at 22+ weeks should publish rates with and without terminations in order to improve international comparisons and the policy relevance of stillbirth statistics. TWEETABLE ABSTRACT: For valid comparisons of stillbirth rates, data about late terminations of pregnancy are needed. PMID- 28557288 TI - The EF-1alpha promoter maintains high-level transgene expression from episomal vectors in transfected CHO-K1 cells. AB - In our previous study, we demonstrated that episomal vectors based on the characteristic sequence of matrix attachment regions (MARs) and containing the cytomegalovirus (CMV) promoter allow transgenes to be maintained episomally in Chinese hamster ovary (CHO) cells. However, the transgene expression was unstable and the number of copies was low. In this study, we focused on enhancers, various promoters and promoter variants that could improve the transgene expression stability, expression magnitude (level) and the copy number of a MAR-based episomal vector in CHO-K1 cells. In comparison with the CMV promoter, the eukaryotic translation elongation factor 1 alpha (EF-1alpha, gene symbol EEF1A1) promoter increased the transfection efficiency, the transgene expression, the proportion of expression-positive clones and the copy number of the episomal vector in long-term culture. By contrast, no significant positive effects were observed with an enhancer, CMV promoter variants or CAG promoter in the episomal vector in long-term culture. Moreover, the high-expression clones harbouring the EF-1alpha promoter tended to be more stable in long-term culture, even in the absence of selection pressure. According to these findings, we concluded that the EF-1alpha promoter is a potent regulatory sequence for episomal vectors because it maintains high transgene expression, transgene stability and copy number. These results provide valuable information on improvement of transgene stability and the copy number of episomal vectors. PMID- 28557290 TI - Repetitive ventricular tachycardia in a syncopal child: Cause or incidental finding ? AB - A 15-year-old girl suffered recurrent syncopal episodes during 7 years. Events were precipitated by exercise or emotional stress, leading to the diagnosis of reflex syncope. Exercise testing induced recurrent salvos of nonsustained right ventricular outflow tract tachycardia. This arrhythmia is often asymptomatic, reflex syncope is very frequent and both causes are related to the same triggering situations. It was therefore essential to obtain recordings during syncopal events and to observe the clinical evolution under effective treatment in order to make the right diagnosis. PMID- 28557291 TI - Single-Site Active Cobalt-Based Photocatalyst with a Long Carrier Lifetime for Spontaneous Overall Water Splitting. AB - An active and stable photocatalyst to directly split water is desirable for solar energy conversion. However, it is difficult to accomplish overall water splitting without sacrificial electron donors. Herein, we demonstrate a strategy via constructing a single site to simultaneously promote charge separation and catalytic activity for robust overall water splitting. A single Co1 -P4 site confined on g-C3 N4 nanosheets was prepared by a facile phosphidation method, and identified by electron microscopy and X-ray absorption spectroscopy. This coordinatively unsaturated Co site can effectively suppress charge recombination and prolong carrier lifetime by about 20 times relative to pristine g-C3 N4 , and boost water molecular adsorption and activation for oxygen evolution. This single site photocatalyst exhibits steady and high water splitting activity with H2 evolution rate up to 410.3 MUmol h-1 g-1 , and quantum efficiency as high as 2.2 % at 500 nm. PMID- 28557292 TI - In Response: The Contribution of the Emergency Department to Opioid Pain Reliever Misuse and Diversion: A Critical Review. PMID- 28557293 TI - Does Confinement Always Lead to Thermodynamically and/or Kinetically Favorable Reactions? A Case Study using Diels-Alder Reactions within ExBox+4 and CB[7]. AB - The impact of geometrical confinement on the thermodynamic as well as kinetic aspects of a model cycloaddition reaction between 1,3-butadiene and ethylene have been investigated based on density functional theory calculations. To this end, organic hosts ExBox+4 and cucurbit[7]uril (CB[7]) were used to impose confinement effects on the reactants, transition state (TS), and product involved in the reaction. The results suggest that the shape of the host and thereby the nature of the confining regime dictates the thermodynamic outcome of the reaction. The reaction becomes thermodynamically more spontaneous inside CB[7] as compared with that in either ExBox+4 or in the "unconfined" gaseous state. Furthermore, the rate constant associated with the reaction increases manifold inside CB[7]. Atoms in a-molecule, noncovalent interaction, natural bond orbital, as well as energy decomposition analyses suggest that the close geometrical proximity of the reactants inside CB[7] as well as extra stabilization of the TS in the encapsulated state may dictate the outcome. PMID- 28557294 TI - A mechanism for NaV 1.5 downregulation and sodium current decrease in heart failure. PMID- 28557295 TI - Study of the inhibitory effects on TNF-alpha-induced NF-kappaB activation of IMD0354 analogs. AB - Nuclear factor-kappaB (NF-kappaB) is an important nuclear transcription factor which regulates pro-inflammatory cytokines such as TNF-alpha, IL-6. Its role as immunoregulatory mediator makes it an attractive target in the development of treatments for inflammatory and autoimmune diseases. In this study, we synthesized derivatives of IMD0354, a known inhibitor for NF-kappaB, in attempt to understand the effect of benzanilide substitutions on its activity. The inhibition of these analogs on NF-kappaB activation was analyzed by luciferase assay. The inhibition of IKKbeta phosphorylation and pro-inflammatory cytokines was determined by Western blot and real-time PCR. The structure activity relationships showed that the hydroxyl group on IMD0354 is a critical moiety that resulting in the inhibition of NF-kappaB. Derivatives 1m, 2b, and 2c were shown to inhibit pro-inflammatory cytokine production at low concentration. These newly synthesized compounds may be useful for the treatment of chronic inflammatory disorders or for cancer prevention. PMID- 28557296 TI - Bottom-Up Construction of Porous Organic Frameworks with Built-In TEMPO as a Cathode for Lithium-Sulfur Batteries. AB - Two redox-active porous organic frameworks (POFs) with a built-in radical moiety (TEMPO) and hierarchical porous structures were synthesized through a facile bottom-up strategy and studied as cathode materials for lithium-sulfur (Li-S) batteries. The sulfur loading in these two POFs reached 61 %, benefitting from their large pore volumes. Owing to the highly dense docking sites of TEMPO, sulfur could be covalently immobilized within the porous networks and efficiently inhibit the shuttle effect, thereby significantly improving the cycling performance. The composites TPE-TEMPO-POF-S (TPE=tetraphenylethene) deliver a capacity in excess of 470 mAh g-1 after 200 cycles with a coulombic efficiency of around 100 % at a current rate of 0.1 C. Furthermore, TEMPO-POFs with sulfur embedded showed excellent rate capability with limited capacity loss at rates of 0.1-1 C. PMID- 28557298 TI - The insights of a visually impaired student. PMID- 28557297 TI - Correlation of Cup Inclination Angle with Liner Wear for Metal-on-polyethylene in Hip Primary Arthroplasty. AB - OBJECTIVES: The relationship between cup inclination angle and liner wear is controversial. Most authors in the published literature agree that the ideal cup inclination is associated with lower inner wear; however, some disagree. All previous studies did not control for femoral head diameter and inclination, so it is difficult to assess the relative or synergistic effects of cup angle on outcomes. METHODS: We retrospectively reviewed 154 patients (171 hips) with primary total hip arthroplasties performed from 2001 to 2004. All surgeries had been performed by the same physician team. A posterior approach was applied in all patients. All prostheses were non-cemented cups with a 28-mm metal head. Inclusion criteria included that the radiographic material was not completed or lost for primary or last follow up. Patients were divided into four groups according to different cup inclination angle. There were 108 hips with inclination angles below 50 degrees ; 35 hips with angles between 50 degrees and 55 degrees ; 17 hips with angles between 55 degrees and 60 degrees ; and 11 hips with angles greater than 60 degrees . An immediate postoperative radiograph was compared with a follow-up radiograph. Clinical and radiographic data were collected on standardized hip evaluation forms preoperatively, 6 months after surgery and at yearly follow-up visits. Radiographs were digitized and enlarged 100%. After the radiographs were digitized, polyethylene wear rates and acetabular cup abduction were measured on all patients with Cavas 15.0 software. The results were analyzed using Student's two-tailed paired t-test with SPSS 11.5. RESULTS: The preoperative mean Harris hip score improved from 45.36 to 93.5 points 10 years after surgery. No acetabular component was revised for aseptic loosening. Three patients (three hips) had to undergo bone grafting and a lined arthroplasty for severe osteolysis around the acetabular component. The rate of implant survival at 10 years with respect to loosening was 100%. The mean liner wear rate was 0.135 mm/year in cups with inclination angles below 50 degrees , 0.144 mm/year between 50 degrees and 55 degrees , 0.260 mm/year between 55 degrees and 60 degrees , and 0.403 mm/year when the angle was greater than 60 degrees . Liner wear increased when the cup angle was larger than 55 degrees (P < 0.05). CONCLUSIONS: For metal-on-polyethylene prostheses, liner wear correlates with cup inclination angle larger than 55 degrees . The ideal abduction angle for metal-on-polyethylene prostheses is less than 55 degrees . PMID- 28557299 TI - Internet-based guided self-help for posttraumatic stress disorder (PTSD): Randomized controlled trial. AB - BACKGROUND: There are numerous barriers that limit access to evidence-based treatment for posttraumatic stress disorder (PTSD). Internet-based guided self help is a treatment option that may help widen access to effective intervention, but the approach has not been sufficiently explored for the treatment of PTSD. METHODS: Forty two adults with DSM-5 PTSD of mild to moderate severity were randomly allocated to internet-based self-help with up to 3 h of therapist assistance, or to a delayed treatment control group. The internet-based program included eight modules that focused on psychoeducation, grounding, relaxation, behavioural activation, real-life and imaginal exposure, cognitive therapy, and relapse prevention. The primary outcome measure was reduction in clinician-rated traumatic stress symptoms using the clinician administered PTSD scale for DSM-V (CAPS-5). Secondary outcomes were self-reported PTSD symptoms, depression, anxiety, alcohol use, perceived social support, and functional impairment. RESULTS: Posttreatment, the internet-based guided self-help group had significantly lower clinician assessed PTSD symptoms than the delayed treatment control group (between-group effect size Cohen's d = 1.86). The difference was maintained at 1-month follow-up and dissipated once both groups had received treatment. Similar patterns of difference between the two groups were found for depression, anxiety, and functional impairment. The average contact with treating clinicians was 21/2 h. CONCLUSIONS: Internet-based trauma-focused guided self help for PTSD is a promising treatment option that requires far less therapist time than current first line face-to-face psychological therapy. PMID- 28557300 TI - Diversity and ecology of and biomineralization by magnetotactic bacteria. AB - Magnetotactic bacteria (MTB) biomineralize intracellular, membrane-bounded crystals of magnetite (Fe3 O4 ) and/or greigite (Fe3 S4 ) called magnetosomes. MTB play important roles in the geochemical cycling of iron, sulfur, nitrogen and carbon. Significantly, they also represent an intriguing model system not just for the study of microbial biomineralization but also for magnetoreception, prokaryotic organelle formation and microbial biogeography. Here we review current knowledge on the ecology of and biomineralization by MTB, with an emphasis on more recent reports of unexpected ecological and phylogenetic findings regarding MTB. In this study, we conducted a search of public metagenomic databases and identified six novel magnetosome gene cluster containing genomic fragments affiliated with the Deltaproteobacteria and Gammaproteobacteria classes of the Proteobacteria phylum, the Nitrospirae phylum and the Planctomycetes phylum from the deep subseafloor, marine oxygen minimum zone, groundwater biofilm and estuary sediment, thereby extending our knowledge on the diversity and distribution of MTB as well deriving important information as to their ecophysiology. We point out that the increasing availability of sequence data will facilitate researchers to systematically explore the ecology and biomineralization of MTB even further. PMID- 28557301 TI - Factors influencing the quality of life of haemodialysis patients according to symptom cluster. AB - AIMS AND OBJECTIVES: To identify the characteristics in each symptom cluster and factors influencing the quality of life of haemodialysis patients in Korea according to cluster. BACKGROUND: Despite developments in renal replacement therapy, haemodialysis still restricts the activities of daily living due to pain and impairs physical functioning induced by the disease and its complications. DESIGN: Descriptive survey. Two hundred and thirty dialysis patients aged >18 years. They completed self-administered questionnaires of Dialysis Symptom Index and Kidney Disease Quality of Life instrument-Short Form 1.3. METHODS: To determine the optimal number of clusters, the collected data were analysed using polytomous variable latent class analysis in R software (poLCA) to estimate the latent class models and the latent class regression models for polytomous outcome variables. Differences in characteristics, symptoms and QOL according to the symptom cluster of haemodialysis patients were analysed using the independent t test and chi-square test. The factors influencing the QOL according to symptom cluster were identified using hierarchical multiple regression analysis. RESULTS: Physical and emotional symptoms were significantly more severe, and the QOL was significantly worse in Cluster 1 than in Cluster 2. The factors influencing the QOL were spouse, job, insurance type and physical and emotional symptoms in Cluster 1, with these variables having an explanatory power of 60.9%. Physical and emotional symptoms were the only influencing factors in Cluster 2, and they had an explanatory power of 37.4%. CONCLUSIONS: Mitigating the symptoms experienced by haemodialysis patients and improving their QOL require educational and therapeutic symptom management interventions that are tailored according to the characteristics and symptoms in each cluster. RELEVANCE TO CLINICAL PRACTICE: The findings of this study are expected to lead to practical guidelines for addressing the symptoms experienced by haemodialysis patients, and they provide basic information for developing nursing interventions to manage these symptoms and improve the QOL of these patients. PMID- 28557304 TI - Device-associated thrombus formation after left atrial appendage occlusion. PMID- 28557302 TI - Dynamic changes and prognostic value of pulmonary congestion by lung ultrasound in acute and chronic heart failure: a systematic review. AB - AIMS: Pulmonary congestion is an important finding in patients with heart failure (HF) that can be quantified by lung ultrasound (LUS). We conducted a systematic review to describe dynamic changes in LUS findings of pulmonary congestion (B lines) in HF and to examine the prognostic utility of B-lines in HF. METHODS AND RESULTS: We searched online databases for studies conducted in patients with chronic or acute HF that used LUS to assess dynamic changes or the prognostic value of pulmonary congestion. We included studies in adult populations, published in English, and conducted in >=25 patients. Of 1327 identified studies, 13 (25-290 patients) met the inclusion criteria: six reported on dynamic changes in LUS findings (438 patients) and seven on the prognostic value of B-lines in HF (953 patients). In acute HF, B-line number changed within as few as 3 h of HF treatment. In acute HF, >=15 B-lines on 28-zone LUS at discharge identified patients at a more than five-fold risk for HF readmission or death. Similarly, in ambulatory patients with chronic HF, >=3 B-lines on five- or eight-zone LUS marked those at a nearly four-fold risk for 6-month HF hospitalization or death. CONCLUSIONS: Lung ultrasound findings change rapidly in response to HF therapy. This technique may represent a useful and non-invasive method to track dynamic changes in pulmonary congestion. Furthermore, residual congestion at the time of discharge in acute HF or in ambulatory patients with chronic HF may identify those at high risk for adverse events. PMID- 28557303 TI - Simultaneous fermentation of cellulose and current production with an enriched mixed culture of thermophilic bacteria in a microbial electrolysis cell. AB - An enriched mixed culture of thermophilic (60 degrees C) bacteria was assembled for the purpose of using cellulose to produce current in thermophilic microbial electrolysis cells (MECs). Cellulose was fermented into sugars and acids before being consumed by anode-respiring bacteria (ARB) for current production. Current densities (j) were sustained at 6.5 +/- 0.2 A m-2 in duplicate reactors with a coulombic efficiency (CE) of 84 +/- 0.3%, a coulombic recovery (CR) of 54 +/- 11% and without production of CH4 . Low-scan rate cyclic voltammetry (LSCV) revealed a mid-point potential (Eka ) of -0.17 V versus SHE. Pyrosequencing analysis of the V4 hypervariable region of 16S rDNA and scanning electron microscopy present an enriched thermophilic microbial community consisting mainly of the phylum Firmicutes with the Thermoanaerobacter (46 +/- 13%) and Thermincola (28 +/- 14%) genera occupying the biofilm anode in high relative abundance and Tepidmicrobium (38 +/- 6%) and Moorella (11 +/- 8%) genera present in high relative abundance in the bulk medium. The Thermoanaerobacter (15 +/- 16%) and Brevibacillus (21 +/- 30%) genera were also present in the bulk medium; however, their relative abundance varied by reactor. This study indicates that thermophilic consortia can obtain high CE and CR, while sustaining high current densities from cellulose in MECs. PMID- 28557305 TI - Diversity of Polyhydroxynaphthoquinone Pigments in North Pacific Sea Urchins. AB - Using high-performance liquid chromatography with diode-array detection and mass spectrometry (HPLC-DAD/MS) we investigated the composition of polyhydroxynaphthoquinone (PHNQ) pigments from sea urchins Strongylocentrotus pallidus, St. polyacanthus, St. droebachiensis, Brisaster latifrons and Echinarachnius parma, collected in the Sea of Okhotsk and the Bering Sea. Identification of PHNQ pigments from sea urchins St. polyacanthus, B. latifrons, and E. parma was performed for the first time. Among the usual PHNQ pigments, mono- and dimethoxy derivatives of spinochrome E, not previously found in other sea urchins, were discovered in St. polyacanthus and St. droebachiensis. In St. droebachiensis, two monomethoxy derivatives of echinochrome A were detected, isolated previously from only tropical sea urchins. It was found that the composition and total content of pigments of St. droebachiensis depends on the collection area of the sea urchins and its depth and varies from 88 to 331 MUg/g of dry shells. Sea urchins St. pallidus, B. latifrons and E. parma had average values for PHNQ pigment content, approximately 30 MUg/g, and St. polyacanthus had a low PHNQ content, 13 MUg/g. PMID- 28557307 TI - Pervasive yet nonuniform contributions of Dcp2 and Cnot7 to maternal mRNA clearance in zebrafish. AB - mRNA degradation is a fundamental biological process that erases transcribed genetic information from cells. During maternal-to-zygotic transition of animal development, thousands of maternal mRNAs are degraded by multiple mechanisms including microRNAs and codon-mediated decay. Enzymatic requirements for maternal mRNA clearance, however, are not fully understood. Here, we analyzed a contribution of the decapping enzyme Dcp2 to maternal mRNA clearance in zebrafish by over-expressing catalytically inactive Dcp2 and performing RNA-seq analysis. As expected, Dcp2 had a widespread role in maternal mRNA clearance. Interestingly, each mRNA showed differential dependency on Dcp2-mediated decapping and Cnot7-mediated deadenylation for degradation. Correlation analysis identified several mRNA features that were associated with the observed differential dependency. Our results show pervasive yet nonuniform contributions of the decapping enzyme Dcp2 and the deadenylase Cnot7 to maternal mRNA clearance. PMID- 28557308 TI - Discovery of a new intravacuolar protein required for the autophagy, development and virulence of Beauveria bassiana. AB - High proportions of hypothetical proteins exist in genomic databases of fungi, including putative secretory proteins (PSPs) likely involved in fungal invasion and virulence. Here we characterize one of many PSPs revealed in the previous transcriptome of Beauveria bassiana (a fungal insect pathogen) infecting a global lepidopteran pest and name it vacuole-localized protein 4 (VLP4) because this small, domain-lacking protein (22.96 kDa) was specifically localized in the vacuoles of hyphal cells. Deletion of VLP4 resulted in repression of almost all genes acting in autophagy and central development pathways. Consequently, the deletion mutant formed no autophagosome in hyphal vacuoles and displayed severe defects in aerial conidiation. conidial hydrophobicity to the insect surface, and secretion of cuticle-degrading Pr1 proteases required for normal cuticle infection. Blastospore formation was inhibited in the submerged mutant culture mimic to insect haemolymph, and formation of hyphal bodies in vivo was delayed. The fungal virulence was attenuated in the absence of VLP4. These phenotypic defects were well restored by targeted gene complementation. Our findings unveil a vital role of VLP4 in B. bassiana and call attention to many more PSPs for new insights into the interactions of fungal insect pathogens with insects. PMID- 28557309 TI - Dermatoscopy of confluent and reticulated papillomatosis (Gougerot-Carteaud syndrome). PMID- 28557306 TI - SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer. AB - Oncogenic signalling via Ca2+ -activated K+ channels of intermediate conductance (SK4, also known as KCa 3.1 or IK) has been implicated in different cancer entities including breast cancer. Yet, the role of endogenous SK4 channels for tumorigenesis is unclear. Herein, we generated SK4-negative tumours by crossing SK4-deficient (SK4 KO) mice to the polyoma middle T-antigen (PyMT) and epidermal growth factor receptor 2 (cNeu) breast cancer models in which oncogene expression is driven by the retroviral promoter MMTV. Survival parameters and tumour progression were studied in cancer-prone SK4 KO in comparison with wild-type (WT) mice and in a syngeneic orthotopic mouse model following transplantation of SK4 negative or WT tumour cells. SK4 activity was modulated by genetic or pharmacological means using the SK4 inhibitor TRAM-34 in order to establish the role of breast tumour SK4 for cell growth, electrophysiological signalling, and [Ca2+ ]i oscillations. Ablation of SK4 and TRAM-34 treatment reduced the SK4 generated current fraction, growth factor-dependent Ca2+ entry, cell cycle progression and the proliferation rate of MMTV-PyMT tumour cells. In vivo, PyMT oncogene-driven tumorigenesis was only marginally affected by the global lack of SK4, whereas tumour progression was significantly delayed after orthotopic implantation of MMTV-PyMT SK4 KO breast tumour cells. However, overall survival and progression-free survival time in the MMTV-cNeu mouse model were significantly extended in the absence of SK4. Collectively, our data from murine breast cancer models indicate that SK4 activity is crucial for cell cycle control. Thus, the modulation of this channel should be further investigated towards a potential improvement of existing antitumour strategies in human breast cancer. PMID- 28557310 TI - Larynx motion considerations in partial larynx volumetric modulated arc therapy for early glottic cancer. AB - INTRODUCTION: To assess laryngeal motion in early glottic cancer in order to determine safe margins for partial larynx volumetric modulated arc therapy (PL VMAT), and to quantify dosimetric advantages of PL-VMAT. METHODS: This prospective study included T1-2N0 glottic cancers treated with whole larynx VMAT (WL-VMAT). Pre- and mid-treatment 4D-computed tomography (4D-CT) and dynamic magnetic resonance imaging (MRI) allowed for assessment of larynx swallowing and respiratory motion. For 10 patients with lateralized lesions, PL-VMAT plans were calculated using margins derived from 4D-CT analysis. RESULTS: Twenty patients were accrued from 2014 to 2016. Mean amplitude of larynx swallowing excursion was 23 mm and 6 mm in the superior and anterior directions, respectively. Mean respiratory motion reached 4 mm and 2 mm in superior-inferior and antero posterior directions, respectively. Pre-treatment 4D-CT analysis identified one patient with planning CT acquired during swallowing. Mid-treatment 4D-CT revealed larynx shift relative to vertebrae in 30% of cases. PL-VMAT allowed for significant reduction of mean doses to ipsilateral carotid, contralateral carotid, thyroid gland, contralateral arytenoid and larynx. Using 8 mm internal margin for PL-VMAT, swallowing resulted in clinical target volume excursion beyond 95% isodose line during <=1.5% of total treatment time in all patients. CONCLUSION: Although swallowing motion is rare, rapid and easily suppressed by patients, there is a risk of systematic miss-targeting if planning CT is acquired during swallowing. Larynx position shift relative to vertebrae occurs in 1/3 of patients over the course of radiotherapy. With soft-tissue image guidance and margins accounting for respiratory motion, PL-VMAT allows safe reduction of dose to organs at risk. PMID- 28557311 TI - Late Incomplete stent apposition is associated with late/very late stent thrombosis: A meta-analysis. AB - BACKGROUND: There is a lingering controversy in the current literature about the impact of late incomplete stent apposition (LISA) on clinical outcomes, especially stent thrombosis (ST). Therefore, we aimed to synthesize the available evidence evaluating the association between LISA and adverse clinical outcomes. METHODS: We systematically searched electronic databases for studies reporting clinical outcomes in patients with and without LISA. Relevant study characteristics and clinical outcomes were extracted. Incidence rate ratios (IRR) and 95% Confidence Interval (CI) were computed. Sensitivity analyses were done. RESULTS: Sixteen studies with 4,946 patients; 666 patients with 20,035 patient months follow up with LISA and 4,280 patients with 121,855 patient-months follow up without LISA were included. The estimated prevalence of LISA at follow up was 16% (95% CI 12-20%). The incidences of late/very late ST (IRR = 4.81, 95% CI 2.68 8.62) and myocardial infarction (MI) (IRR = 3.09, 95% CI 1.72-5.55) were significantly higher in the LISA group compared to patients without LISA. Subset analysis of studies reporting Academic Research Consortium definitive/probable ST (IRR = 4.98; 95% CI 2.51-9.89) and acquired LISA (IRR = 3.67, 95% CI 1.5-9.0) similarly showed increased risk of late/very late ST. The results of sensitivity analyses were consistent. There was no difference in cardiac death and target lesion revascularization. CONCLUSION: The presence of LISA at a follow up of 6-18 months after stent implantation is associated with a higher risk of late/very late ST and MI. Additional studies are required to establish a cause and effect, and inform the management strategy. (c) 2017 Wiley Periodicals, Inc. PMID- 28557313 TI - Efficacy of radiation dose reduction due to real-time monitoring and visualization of peak skin dose during coronary angiography and percutaneous coronary intervention. AB - OBJECTIVES: This study assessed that the use of real-time monitoring and visualization of peak skin dose could reduce radiation dose during coronary angiography (CAG) and percutaneous coronary intervention (PCI). BACKGROUND: Exposure to ionizing radiation has dose related effects including skin damage. Reducing the radiation exposure is important during CAG and PCI. The skin dose tracking system (DTS) has a real-time monitor of radiation peak skin dose. METHODS: A total of 323 consecutive patients who underwent CAG and PCI between September 2014 and June 2015 were enrolled. Patients were classified into with DTS group (CAG alone in 104 and PCI in 57 patients) or without DTS group (CAG alone in 106 and PCI in 56 patients). RESULTS: There was no significant difference in reference air kerma between CAG alone with and without DTS groups. Reference air kerma with DTS group during PCI was lower than without DTS group (204.6 +/- 141.1 mGy vs. 294.2 +/- 237.4 mGy, P = 0.016). Moreover, kerma area product (17.8 +/- 13.0 Gycm2 vs. 25.2 +/- 19.3 Gycm2 , P = 0.019) and number of cine runs (12.8 +/- 5.0 vs. 15.5 +/- 6.5, P = 0.013) with DTS group were lower than without DTS group. Multiple regression analysis showed increased reference air kerma was associated with male gender, body mass index and type B2/C lesion. Conversely, DTS correlated with decreased reference air kerma. CONCLUSIONS: The use of DTS could reduce radiation dose during PCI. Real-time radiation monitoring and visualization of peak skin dose was effective for the patients with PCI. PMID- 28557312 TI - A novel HLA-G allele, HLA-G*01:01:01:07, was identified in a Chinese patient with Posner-Schlossman syndrome. AB - A novel HLA-G allele, HLA-G*01:01:01:07, was identified in a Chinese patient with Posner-Schlossman syndrome. PMID- 28557314 TI - Estradiol and progesterone influence on influenza infection and immune response in a mouse model. AB - PROBLEM: Influenza infection severity may be mediated by estradiol and/or progesterone. METHOD OF STUDY: An exploratory study was designed to evaluate 17 beta-estradiol and progesterone on influenza infection and examine immune mediated response in a mouse model. Inoculation with placebo or mouse-adapted H1N1 influenza virus occurred. Treatment groups included 17-beta-estradiol, progesterone, ovariectomy, and pregnancy. Mice were assessed for morbidity and mortality. Toll-like receptor gene studies and airspace cell differentials were performed. RESULTS: Onset of morbidity was earlier and morbidity duration greater for progesterone. Absence of morbidity/mortality and overall survival was greater for 17-beta-estradiol. Airspace cell differentials suggest improved immune cell recruitment for 17-beta-estradiol. Pregnant mouse data demonstrate significant mortality during the period of increased progesterone. Select immune cell markers demonstrate patterns of regulation that may promote proper immune response to influenza infection for 17-beta-estradiol. CONCLUSION: Estradiol may play a protective and progesterone a detrimental role in the pathophysiology of influenza infection. PMID- 28557316 TI - Role of disease in energy balance in children. AB - Nutritional stress can be caused by increased energy demands or inadequate caloric intake. In the absence of food shortage, disease is often a significant contributory factor in promoting nutritional stress. In children, the interaction of nutrition and disease is more difficult to assess than in adults because deficits in growth and development have both a determining and consequential role in defining energy needs. This paper presents a framework for examining the role of disease in energy balance in children and gives three examples of disease energy balance interactions. Resting and total energy expenditure (REE and TEE) and growth and body composition were measured in children with spastic quadriplegic cerebral palsy (SQCP) and cystic fibrosis (CF) and compared to normal children. Different patterns of energy balance emerged, with REE and TEE being lower in children with SQCP, and REE being higher in children with CF compared to controls. Clinical evaluations of REE in patients evaluated for failure-to-thrive and obesity indicated substantial variability in energy requirements relative to predicted values. These disease models demonstrate that the effect of disease on energy balance in children is diverse. Further studies quantifying the components of energy balance are needed to understand the mechanisms of nutritional adaptation during growth and development under the broad range of human conditions. (c) 1996 Wiley-Liss, Inc. PMID- 28557317 TI - Energetics and population ecology of Siberian herders. AB - Methodological advances now permit human biologists to more effectively monitor energy dynamics in traditional societies. This study examines the nutritional ecology and energetics of semisubsistence herders of Siberia (Evenki) during a single season of their annual cycle (late summer). Total energy expenditure (TEE) among adults, as measured by daily heart-rate monitoring, is greater in Evenki men (TEE = 11.9 +/- 2.8 MJ/d in men and 8.8 +/- 2.1 MJ/d in women; P < 0.001), a pattern that reflects the current division of labor under collectivized herding systems. Energy intakes are also greater among men (13.4 +/- 5.6 vs. 8.5 +/- 3.4 MJ/d; P < 0.01), and are, on average, sufficient to meet daily needs in both sexes. The Evenki appear to be in energy balance at the population level during the late summer (per capita energy intake = 9.0 +/- 5.5 MJ/person/d; per capita requirements = 8.6 MJ/person/d); however, only small changes in food availability and/or energy expenditure are necessary to shift the population into negative balance during the winter. Primary sources of dietary energy include reindeer meat and other animal products (25-30%), foraged plant foods (10-15%), and nonlocal products (55-65%), such as flour, rice, and sugar. The anthropometric data indicate that the Evenki grow slowly and have small adult body size. Women are relatively heavier and fatter than men, and show a centripetal pattern of fat distribution. Evenki males appear to be undergoing a secular trend in stature, while no such increases are evident in females. These gender differences may reflect the differential impact to the changes associated with collectivization. Reduced metabolic requirements (due to declining activity and fertility levels), along with greater food availability, are likely to be responsible for the higher rates of obesity among Evenki women. (c) 1996 Wiley-Liss, Inc. PMID- 28557318 TI - Energetics, lifestyles, and nutritional adaptation: An introduction. PMID- 28557315 TI - Salience network response to changes in emotional expressions of others is heightened during early adolescence: relevance for social functioning. AB - Adolescence is a unique developmental period when the salience of social and emotional information becomes particularly pronounced. Although this increased sensitivity to social and emotional information has frequently been considered with respect to risk behaviors and psychopathology, evidence suggests that increased adolescent sensitivity to social and emotional cues may confer advantages. For example, greater sensitivity to shifts in the emotions of others is likely to promote flexible and adaptive social behavior. In this study, a sample of 54 children and adolescents (age 8-19 years) performed a delayed match to-sample task for emotional faces while undergoing fMRI scanning. Recruitment of the anterior cingulate and anterior insula when the emotion of the probe face did not match the emotion held in memory followed a quadratic developmental pattern that peaked during early adolescence. These findings indicate meaningful developmental variation in the neural mechanisms underlying sensitivity to changes in the emotional expressions. Across all participants, greater activation of this network for changes in emotional expression was associated with less social anxiety and fewer social problems. These results suggest that the heightened salience of social and emotional information during adolescence may confer important advantages for social behavior, providing sensitivity to others' emotions that facilitates flexible social responding. PMID- 28557319 TI - Total energy expenditure in young children. AB - Measurement of total energy expenditure (TEE) in young children is now possible without interfering with or influencing lifestyle. Such data allow direct comparison with recommendations for energy requirements which have hitherto been based on measurements of energy intake. Evaluation of the current world data of measured TEE in children aged 1-6 years shows a consistent pattern despite originating from different laboratories. Data from 225 children reveal that energy expenditure is, on average, about 20% below current international recommendations. It is postulated that the reduction is probably due to changes in levels of habitual activity, which may have potentially important effects on health, and which need to be monitored carefully. (c) 1996 Wiley-Liss, Inc. PMID- 28557320 TI - Physical activity, energy stores, and seasonal energy balance among men and women in Nepali households. AB - The relationships among initial energy stores (body mass index), energy turnover (physical activity levels), and seasonal energy balance (weight changes) were examined in subsistence agropastoralists in rural Nepal. The population experiences no actual food shortage, but has a seasonal increase in physical activity levels, which are moderately heavy in early winter and very heavy in the monsoon season [men, 1.88 and 2.22 * basal metabolic rate (BMR); women, 1.77 and 2.01 * BMR in the respective seasons]. Repeated anthropometry in 1982 (29 men and 34 women), 1983 (29 men and 29 women), 1991 (22 men and 48 women), and 1993 (48 men and 72 women) showed a consistent interannual pattern of significant but modest seasonal weight change (<4% of initial values) and remarkable interindividual variation (men, -5.6 to 5.6 kg; women, -5.6 to 4.8 kg). Thinner individuals showed no significant change in body weight or workloads, and sustained high levels of total energy expenditure throughout the year. Heavier individuals lost weight (men -2.7 kg, women -0.9 kg) and increased total energy expenditure by 23% over the same period. Elements of lifestyle, especially during the season of less constraining workloads, allow for the continuation of hard work or taking a respite for nutritional recovery. The nature of household labor organization, featuring a highly flexible distribution of tasks, also contributes to the relatively short-term, reversible changes in energy balance in this population. (c) 1996 Wiley-Liss, Inc. PMID- 28557321 TI - Physical activity and correlates of estimated energy expenditure in Taiwanese adolescents 12-14 years of age. PMID- 28557322 TI - Energetics, adaptation, and adaptability. AB - Energy capture and conversion are fundamental to human existence, and over the past three decades biological anthropologists have used a number of approaches which incorporate energetics measures in studies of human population biology. Human groups can vary enormously in their energy expenditure. This review considers evidence for genetic adaptation and presents models for physiological adaptability to reduced physiological energy availability and/or negative energy balance. In industrialized populations, different aspects of energy expenditure have been shown to have a genetic component, including basal metabolic rate, habitual physical activity level, mechanical efficiency of work performance, and thermic effect of food. Metabolic adaptation to low energy intakes has been demonstrated in populations in both developing and industrialized nations. Thyroid hormone-related effects on energy metabolic responses to low physiological energy availability are unified in a model, linking energetic adaptability in physical activity and maintenance metabolism. Negative energy balance has been shown to be associated with reduced reproductive function in women experiencing seasonal environments in some developing countries. Existing models relating negative energy balance to menstrual or ovulatory function are largely descriptive, and do not propose any physiological mechanisms for this phenomenon. A model is proposed whereby reduced physiological energy availability could influence ovulatory function via low serum levels of the amino acid aspartate and reduced sympathetic nervous system activity. (c) 1996 Wiley-Liss, Inc. PMID- 28557323 TI - Physical activity patterns and anthropometric changes in Senegalese women observed over a complete seasonal cycle. AB - This study describes the habitual physical activity of a group of women in Northern Senegal who are involved in a hydroagricultural development program and assesses its consequences for their nutritional status. A group of 30 women was followed on three occasions during a complete agricultural cycle. At each visit, activities were observed and timed over periods of 3 and 2 consecutive days. Anthropometric dimensions were taken at each visit, with a follow-up 1 year later. The women were divided into three groups according to reproductive status: pregnant (P), lactating (L), and nonpregnant, nonlactating (NPNL). The P group showed a gain in weight and body mass index only starting with the second trimester of pregnancy. During the postpartum stage, indices of arm muscle mass were lower than those measured prior to pregnancy. The L and NPNL groups did not show any changes in anthropometric indices during the cycle. Activity intensity levels among the women did not change from one visit to another. The levels could be classified as moderate to heavy intensity according to the FAO/WHO/UNU criteria. Overall the NPNL group was more active than the P group, with the latter increasing rest time and light activity at the onset of pregnancy. The time spent on subsistence activities outside of the household varied from one visit to the next according to the demand for agricultural labor. Estimated energy expenditure of the women was compatible with their physiological state; however, increased participation of P and L women in agricultural work, especially work related to rice cultivation, could have a negative impact on their nutritional status. (c) 1996 Wiley-Liss, Inc. PMID- 28557324 TI - Behavioral quality and caloric intake in Malagasy children relative to international growth references. AB - Anthropometric, 3-day food weighing, and 2-day time allocation surveys were used in the 1990-1991 dry and wet seasons to examine the recommended international child growth references for weight/height (W/H). The sample included forty 6- to 9-year-old girls and boys from a slash-and-burn horticultural community near Ranomafana National Park in the southeastern Malagasy rain forest. Positional behavior, location, and various productive and social activities were related to anthropometric status, caloric intake, and gender. Sitting activities increased while energetic manual chores and prone activity decreased when W/H was below -1 to -1.5 SD of the international NCHS reference. However, running play and some of the locations that children use decreased more when W/H approached -2.5 or -3 SD, or when caloric intake was below about one half of the international recommendation. The latter anthropometric and dietary levels did not necessarily occur in the same children, suggesting that anthropometric surveillance alone may not identify children at risk. Moral thresholds of socially tolerable behavior relative to growth status and common statistically based cutoffs for growth status vary, which prompts questions about the appropriate level at which to target health programs. (c) 1996 Wiley-Liss, Inc. PMID- 28557325 TI - Issues in the measurement of energy intake for free-living human populations. AB - Energy intake is the most difficult component of energy balance to measure. All known methods are subject to considerable error, both random error and bias. High variability within and between subjects means that sampling is important to increase reliability. Further, the fact that true intakes are unknown means that some outside measure of validity is desirable as a check on the accuracy of recording of habitual intake. This report examines food intake for populations where expenditure has been measured by doubly labeled water. For 21 populations where aggregate data have been reported, intake came within one megajoule (MJ) of expenditure in about one-half of the cases. In seven populations where individual intake and expenditure were noted, reported intakes did not differ from measured expenditure for four groups, but differed significantly for two groups of African farm women and one group of obese volunteers. Individuals also differed in ranking of intake and expenditure, with intake able to predict the rank of expenditure only for one group of German students. Energy intake data are important for both ecological and epidemiological studies but are poor measures to use in estimating energy balance. (c) 1996 Wiley-Liss, Inc. PMID- 28557326 TI - Energy expenditures of urban Colombian girls and women. AB - Anthropometry, basal metabolic rate (BMR), and resting energy expenditure (RMR) measured by indirect calorimetry and total daily energy expenditure (TDEE) by the minute-by-minute heart rate (HR) method have been studied in 52 school-aged girls 6-16 years and 46 nonpregnant, nonlactating women 19-43 years of age. BMR, RMR, and TDEE increased with age in children, reaching approximate adult values by 15 years. TDEE averaged 9.29 +/- 2.32 MJ/d in women 19-43 years. The ratio RMR/BMR averaged 1.27 +/- 0.29 across all age groups. TDEE/BMR varied from 1.41 +/- 0.28 to 1.62 +/- 0.37 in the girls and averaged 1.78 +/- 0.43 in adults. Application of empirical equations to estimates of BMR showed that those of Schofield gave values of +3.1% (P = 0.03) and of Henry and Rees -3.8% (P = 0.052) of measured BMR (Schofield [1985] Hum Nutr Clin Nutr 39C [Suppl 1]:5-41; Henry and Rees [1991] Eur J Clin Nutr 45:177-185). The pattern of daily energy expenditure is highly variable across age groups during the awake portion of the day (0700-2000 hours). In the averaged data of women at home, there is a gradual increase in the morning, a decline at noon, followed by some increase in the early afternoon and decline in late afternoon and early evening. (c) 1996 Wiley-Liss, Inc. PMID- 28557327 TI - Energy intake and energy expenditure in the elderly. AB - This review briefly examines the effects of aging on resting metabolic rate, thermic effect of a meal, and the energy expenditure of physical activity. Thereafter, the effects of advancing age on total daily energy expenditure as assessed from doubly labeled water studies are examined. The paucity of studies in this area and the small sample sizes preclude definitive conclusions regarding daily energy requirements in the elderly. The rationale underlying measurement of daily energy expenditure to determine energy requirements in older individuals is presented. Evidence is provided that older individuals frequently underreport daily energy intake, and this underreporting is more pronounced in older women with higher levels of body fat. The effects of aerobic and resistance training on resting metabolic rate and total daily energy expenditure are then examined. Both forms of training increase resting metabolic rate due to increases in sympathetic nervous system activity. Lastly, procedures to normalize body size dependent data are discussed. (c) 1996 Wiley-Liss, Inc. PMID- 28557328 TI - The biology of everyday living. AB - The need for documenting details of lifestyle is argued, particularly from the results of studying the everyday life of Oxfordshire villagers. Relationships between lifestyle and well-being are sought through examination of characteristics of sleep and stress hormone excretion. It is concluded that although epinephrine and cortisol outputs show many relationships with lifestyle in various populations, they are poor measures of well-being. Sleep latency, however, seems to be a component of well-being. Well-being is seen as an important component of health and thus of the quality-of-life history. (c) 1996 Wiley-Liss, Inc. PMID- 28557329 TI - Measurement and interpretation issues in laboratory and field studies of energy expenditure. AB - The methods for measuring energy expenditure in the laboratory and the field are described and critically appraised and the criteria for reliable and valid measurements identified. Variation and adaptation in the energy costs of activities and the total daily energy expenditure are considered in the context of discriminating between what is variation and adaptation and what is honest error. This involves issues of comparative energetics and standardization and oxygen uptake kinetics, which are frequently neglected or ignored. The energetics of physical work, where many of the problems arise, are examined. It is technically feasible to measure energy expenditure with high accuracy, but the methods required, calorimeter rooms and doubly labelled water, are not widely available or applicable. The field methods, the factorial method of diary record of activities and their energy costs, and the heart rate methods are of acceptable accuracy for groups but less so for individuals. When using energy costs from the literature, as has been common in human biology, several problems arise. The sample sizes are small and of unknown provenance, and there is no information on variability or on whether the values are based on continuous or intermittent work. The problem of how to allow for differences in size and composition has been tackled with convenience rather than concepts. It is recommended that isometric scaling, using kcal/kg, be avoided and allometric scaling by, e.g., analysis of covariance, be used to remove the effects of size and composition. In investigations of variation and adaptation in the efficiency of work, the effects of oxygen uptake kinetics and of anaerobic metabolism must be considered. (c) 1996 Wiley-Liss, Inc. PMID- 28557330 TI - Predicting the Solvent Effect on Esterification Kinetics. AB - It is well known that solvents influence reaction kinetics. The classical concentration-based kinetic modeling is unable to describe these effects. In this work, the reaction kinetics was studied for the esterifications of acetic acid and propionic acid with ethanol at 303.15 K. It was found that the reactant ratio as well as the applied solvents (acetonitrile, tetrahydrofurane, dimethylformamide) significantly affect the reaction rate. The thermodynamic model PC-SAFT was applied to account for the interactions between the reacting species and the solvents via activity coefficients. This allowed the identification of solvent-independent kinetic constants and the prediction of the solvent effect on reaction kinetics in almost quantitative agreement with experimental data. The presented approach shows the importance of taking into account thermodynamic non-idealities and significantly reduces experimental effort for finding the best solvent candidate for a given target reaction. PMID- 28557331 TI - Understanding the Effect of Surface Chemistry of Mesoporous Silica Nanorods on Their Vaccine Adjuvant Potency. AB - Mesoporous silica nanoparticles are reported as adjuvants in nanovaccines in generating robust antigen-specific immunity. However, the effect of surface chemistry in initiating and modulating the immune response remains largely unexplored. In this study, mesoporous silica nanorods (MSNRs) are modified with ?NH2 and ?C18 groups to investigate the influence of surface functional groups (?OH, ?NH2 , and ?C18 ) on their adjuvant efficacy. It is found that compared to ?OH and ?NH2 groups, the hydrophobic ?C18 modification significantly enhances antigen uptake by antigen presenting cells and endosomal-lysosomal escape in vitro, dendritic cells, and macrophages maturation ex vivo, and elicits secretion of interferon-gamma level and antibody response in immunized mice. Moreover, bare MSNR and MSNR?NH2 exhibit T-helper 2 biased immune response, while MSNR?C18 shows a T-helper 1 biased immune response. These findings suggest that the surface chemistry of nanostructured adjuvants has profound impact on the immune response, which provides useful guidance for the design of effective nanomaterial based vaccines. PMID- 28557332 TI - Impact of contrast exposure from computed tomography angiography on acute kidney injury after neonatal cardiopulmonary bypass surgery. AB - OBJECTIVE: Acute kidney injury (AKI) is a frequent complication after cardiopulmonary bypass (CBP) for cardiac surgery in neonates. It is unclear if exposure to computed tomography angiography (CTA) in the preoperative period increases the risk of AKI. We hypothesized a short interval between CTA and CPB surgery would be associated with higher rates of AKI in infants. DESIGN: In this single center retrospective review of patients between 2012 and 2015, neonates less than one month old were analyzed if they had CTA prior to cardiac surgery with CPB. Baseline, demographic, fluid balance, and laboratory data was analyzed. AKI was staged according to KDIGO criteria. RESULTS: Fifty-six neonates were analyzed. AKI developed in 42 (75%) of patients; severe AKI (KDIGO stages 2 and 3) occurred in 18 (32%). Patient characteristics were similar at baseline and at time of CTA between those with and without severe AKI. Patients with severe AKI had longer CPB time, lower postoperative urine output, higher peak serum creatinine, and longer hospital length of stay. When considering intervals between CTA and CPB surgery <=1 day (n = 19), <=3 days (n = 28), and >3 days (n = 28); there was no difference in AKI incidence nor postoperative outcomes among these three interval cohorts. CONCLUSION: Routine exposure to CTA and CPB surgery in close succession does not appear to increase the risk of AKI after neonatal cardiac surgery. Though other risks need to be weighed (eg, sedation, intubation, radiation exposure), this result may enable more liberal utilization of CTA for preoperative surgical planning of congenital heart operations in patients with unclear or complex anatomy. PMID- 28557333 TI - Controlling the alpha/gamma-Reactivity of Vinylogous Ketone Enolates in Organocatalytic Enantioselective Michael Reactions. AB - The first regio-, diastereo-, and enantioselective direct Michael reaction of beta,gamma-unsaturated ketones with nitroolefins is enabled by Bronsted base/hydrogen-bonding bifunctional catalysis. A squaramide-substituted tertiary amine catalyzes the reaction of a broad range of beta,gamma-unsaturated ketones to proceed at the alpha-site exclusively, giving rise to adducts with two consecutive tertiary carbon stereocenters in diastereomeric ratios of up to >20:1 and enantioselectivities generally in the 90-98 % ee range. PMID- 28557335 TI - Identification, evolution and functional characterization of two Zn CDF-family transporters of the ectomycorrhizal fungus Suillus luteus. AB - Two genes, SlZnT1 and SlZnT2, encoding Cation Diffusion Facilitator (CDF) family transporters were isolated from Suillus luteus mycelium by genome walking. Both gene models are very similar and phylogenetic analysis indicates that they are most likely the result of a recent gene duplication event. Comparative sequence analysis of the deduced proteins predicts them to be Zn transporters. This function was confirmed by functional analysis in yeast for SlZnT1. SlZnT1 was able to restore growth of the highly Zn sensitive yeast mutant Deltazrc1 and localized to the vacuolar membrane. Transformation of Deltazrc1 yeast cells with SlZnT1 resulted in an increased accumulation of Zn compared to empty vector transformed Deltazrc1 yeast cells and equals Zn accumulation in wild type yeast cells. We were not able to express functional SlZnT2 in yeast. In S. luteus, both SlZnT genes are constitutively expressed whatever the external Zn concentrations. A labile Zn pool was detected in the vacuoles of S. luteus free-living mycelium. Therefore we conclude that SlZnT1 is indispensable for maintenance of Zn homeostasis by transporting excess Zn into the vacuole. PMID- 28557334 TI - Pleiotrophin, a target of miR-384, promotes proliferation, metastasis and lipogenesis in HBV-related hepatocellular carcinoma. AB - Hepatitis B virus (HBV) infection plays a crucial role and is a major cause of hepatocellular carcinoma (HCC) in China. microRNAs (miRNAs) have emerged as key players in hepatic steatosis and carcinogenesis. We found that down-regulation of miR-384 expression was a common event in HCC, especially HBV-related HCC. However, the possible function of miR-384 in HBV-related HCC remains unclear. The oncogene pleiotrophin (PTN) was a target of miR-384. HBx inhibited miR-384, increasing PTN expression. The PTN receptor N-syndecan was highly expressed in HCC. PTN induced by HBx acted as a growth factor via N-syndecan on hepatocytes and further promoted cell proliferation, metastasis and lipogenesis. PTN up regulated sterol regulatory element-binding protein 1c (SREBP-1c) through the N syndecan/PI3K/Akt/mTORC1 pathway and the expression of lipogenic genes, including fatty acid synthesis (FAS). PTN-mediated de novo lipid synthesis played an important role in HCC proliferation and metastasis. PI3K/AKT and an mTORC1 inhibitor diminished PTN-induced proliferation, metastasis and lipogenesis. Taken together, these data strongly suggest that the dysregulation of miR-384 could play a crucial role in HBV related to HCC, and the target gene of miR-384, PTN, represents a new potential therapeutic target for the prevention of hepatic steatosis and further progression to HCC after chronic HBV infection. PMID- 28557337 TI - A reappraisal of the proposed metabolic and antioxidant actions of butylated hydroxytoluene (BHT) in the liver. AB - Butylated hydroxytoluene (BHT) was investigated for its metabolic actions in the perfused rat liver. Contrary to what is expected from an uncoupler, BHT up to 500 MUM did not stimulate oxygen uptake nor did it inhibit gluconeogenesis from lactate. Transformation of fructose into glucose was also not affected by BHT; only lactate production was slightly increased at the concentration of 100 MUM. The uncoupling effect of BHT in isolated mitochondria was confirmed, but only at concentrations above 10 MUM; uncoupling at lower concentrations, 10-9 to 10-6 M, could not be confirmed. BHT, however, increased reactive oxygen species (ROS) production in isolated mitochondria, starting at the concentration of 10-8 M. This is the opposite of what can be expected from a compound with proven ex vivo antioxidant action. One cannot exclude the possibility that, in mitochondria, stimulation of ROS production rather than uncoupling could be the most significant effect of BHT. PMID- 28557336 TI - In response to Sharing different perspectives to understand asbestos-induced carcinogenesis: A comment to Jiang et al. (2016) by Alessandro Francesco Gualtieri (2017). PMID- 28557339 TI - Direct Zinc(II)-Catalyzed Enantioconvergent Additions of Terminal Alkynes to alpha-Keto Esters. AB - The addition of terminal alkynes to racemic beta-stereogenic alpha-keto esters was achieved in high levels of stereoselectivity, affording versatile tertiary propargylic alcohols containing two stereocenters. This environmentally benign enantioconvergent reaction proceeds with perfect atom economy, requires no solvent, and is catalyzed by a non-toxic zinc salt. The alkyne moiety can be leveraged in downstream transformations including hydrogenation to the corresponding saturated tertiary alcohol, which represents the product of a formal enantioconvergent aliphatic nucleophile addition. PMID- 28557338 TI - Coronary sinus lead delay index for optimization of coronary sinus lead placement. AB - AIM: Optimization of coronary sinus (CS) lead position to the latest activated left ventricular (LV) area is important to increase cardiac resynchronization therapy (CRT) response. We aimed to detect the relationship between coronary sinus lead delay index (CSDI) and echocardiographic, electrocardiographic response to CRT treatment. METHODS: We prospectively included 137 consecutive patients with heart failure (HF) diagnosis, QRS >= 120 ms, left bundle branch block (LBBB), New York Heart Association score (NYHA) II-IV, LV ejection fraction (LVEF) <35% and scheduled for CRT (84 male, 53 female; mean age 65.1 +/- 10.1 years). Echocardiographic CRT response was defined as >=15% reduction in LV end systolic volume (LVESV). CS lead sensing delay was calculated as the time interval from the onset of surface QRS wave to the onset of depolarization wave recorded from the CS lead by using the CS pacing lead as a bipolar electrode. CSDI was calculated by dividing the CS lead sensing delay by the QRS duration. RESULTS: LVESV reduction was associated with baseline QRS width (r = .257, p = .002), QRS narrowing (r = .396, p < .001), CSDI (r = .357, p < .001), and NT proBNP (r = -0.213, p = .022) in bivariate analysis. In logistic regression analysis, CSDI was found to be only independent parameter for predicting significant LVESV reduction (Beta = 0.318, p < .001). CSDI was also found to be significantly associated with LVEF increase (r = .244, p = .004) and QRS narrowing (r = .178, p = .046). CONCLUSION: CSDI may be used as a marker to predict the favorable response to CRT. It may be useful to integrate CSDI to CRT implantation procedure in order to minimize nonresponders. PMID- 28557341 TI - Over-expression of mutated ZmDA1 or ZmDAR1 gene improves maize kernel yield by enhancing starch synthesis. AB - Grain weight and grain number are important crop yield determinants. DA1 and DAR1 are the ubiquitin receptors that function as the negative regulators of cell proliferation during development in Arabidopsis. An arginine to lysine mutant at amino acid site 358 could lead to the da1-1 phenotype, which results in an increased organ size and larger seeds. In this study, the mutated ZmDA1 (Zmda1) and mutated ZmDAR1 (Zmdar1) driven by the maize ubiquitin promoter were separately introduced into maize elite inbred line DH4866. The grain yield of the transgenic plants was 15% greater than that of the wild-type in 3 years of field trials due to improvements in the grain number, weight and starch content. Interestingly, the over-expression of Zmda1 and Zmdar1 promoted kernel development, resulting in a more developed basal endosperm transfer cell layer (BETL) than WT and enhanced expression of starch synthase genes. This study suggests that the over-expression of the mutated ZmDA1 or ZmDAR1 genes improves the sugar imports into the sink organ and starch synthesis in maize kernels. PMID- 28557343 TI - Progression of early repolarization patterns at a four year follow-up in a female flight crew population: Implications for aviation medicine. AB - BACKGROUND: To assess the prevalence, the appearance, and the distribution, as well as the fluctuation over time of early repolarization patterns after four years in a female population derived from the French aviation sector. METHODS: This was a retrospective longitudinal study from 1998 to 2010 of a population of female employees who received a full clinical examination and an electrocardiogram (ECG) upon their recruitment and after a period of four years. RESULTS: A total of 306 women were included (average of 25.87 +/- 3.3 years of age). The prevalence of early repolarization was 9.2%. The most common appearance was J-point slurring for 64.3% (i.e. 20/28 subjects) that occurred in the inferior leads for 28.6% (i.e. 8/28 subjects). After four years, the prevalence was 7.5%, with a regression of this aspect in five of the subjects. There were no changes in the ECG in terms of the distribution and the appearance among the 23 subjects for whom the aspect persisted. Over the course of this four year period all of the subjects remained asymptomatic. CONCLUSIONS: Early repolarization in this largely physically inactive female population was common, and it fluctuated over time. At present, no particular restrictions can be placed on asymptomatic flight crew who exhibit this feature in the absence of a prior medical history for heart disease. PMID- 28557340 TI - TrkA is a binding partner of NPM-ALK that promotes the survival of ALK+ T-cell lymphoma. AB - Nucleophosmin-anaplastic lymphoma kinase-expressing (NPM-ALK+ ) T-cell lymphoma is an aggressive neoplasm that is more commonly seen in children and young adults. The pathogenesis of NPM-ALK+ T-cell lymphoma is not completely understood. Wild-type ALK is a receptor tyrosine kinase that is physiologically expressed in neural tissues during early stages of human development, which suggests that ALK may interact with neurotrophic factors. The aberrant expression of NPM-ALK results from a translocation between the ALK gene on chromosome 2p23 and the NPM gene on chromosome 5q35. The nerve growth factor (NGF) is the first neurotrophic factor attributed to non-neural functions including cancer cell survival, proliferation, and metastasis. These functions are primarily mediated through the tropomyosin receptor kinase A (TrkA). The expression and role of NGF/TrkA in NPM-ALK+ T-cell lymphoma are not known. In this study, we tested the hypothesis that TrkA signaling is upregulated and sustains the survival of this lymphoma. Our data illustrate that TrkA and NGF are expressed in five NPM-ALK+ T cell lymphoma cell lines and TrkA is expressed in 11 of 13 primary lymphoma tumors from patients. In addition, we found evidence to support that NPM-ALK and TrkA functionally interact. A selective TrkA inhibitor induced apoptosis and decreased cell viability, proliferation, and colony formation of NPM-ALK+ T-cell lymphoma cell lines. These effects were associated with downregulation of cell survival regulatory proteins. Similar results were also observed using specific knockdown of TrkA in NPM-ALK+ T-cell lymphoma cells by siRNA. Importantly, the inhibition of TrkA signaling was associated with antitumor effects in vivo, because tumor xenografts in mice regressed and the mice exhibited improved survival. In conclusion, TrkA plays an important role in the pathogenesis of NPM ALK+ T-cell lymphoma, and therefore, targeting TrkA signaling may represent a novel approach to eradicate this aggressive neoplasm. PMID- 28557342 TI - Morphologic characterization of residual DNA methylation in the gastric mucosa after Helicobacter pylori eradication. AB - Residual DNA methylation in the gastric mucosa after Helicobacter pylori (H. pylori) eradication may have a role in gastric carcinogenesis. We examined the association between morphologic features and promoter methylation status of non neoplastic gastric mucosa especially after H. pylori eradication. A total of 140 gastric specimens from 99 participants who had at least 6 months of post eradication period were examined. The magnifying narrow-band imaging (NBI) endoscopic feature of gastric mucosa was divided into two types: restored-small, round pits, accompanied with honeycomb-like subepithelial capillary networks; atrophic-well-demarcated oval or tubulovillous pits with clearly visible coiled or wavy vessels. Methylation status of five candidate genes (MYOD1, SLC16A12, IGF2, RORA, and PRDM5) were examined by bisulfite pyrosequencing. The atrophic type, informative endoscopic features of intestinal metaplasia, demonstrated higher methylation levels in all five genes compared to the restored type (all P < 0.0001). In the restored type, methylation levels were significantly lower among the samples with longer post-eradication period (for all genes, P < 0.0001), which was not observed in atrophic type (for all genes, P > 0.1). Multivariate analysis demonstrated that atrophic type or presence of intestinal held an independent factor for hyper methylation (odds ratio: 24.69, 95% confidence interval: 6.95-87.76, P < 0.0001). The atrophic type by the magnifying NBI and presence of intestinal metaplasia are the morphologic characteristics of residual DNA methylation of after H. pylori eradication, regardless of the post eradication period and it might be considered as the epigenetic irreversible point with H. pylori eradication. PMID- 28557344 TI - Transseptal transcatheter mitral valve-in-valve: A step by step guide from preprocedural planning to postprocedural care. AB - Transcatheter mitral valve replacement has been successfully performed with the use of aortic transcatheter heart valves in hundreds of patients worldwide with severe dysfunction of a degenerated mitral bioprosthesis and high surgical risk for repeat operation. The delivery approach in the vast majority of the mitral valve-in-valve procedures has been transapical. Although the transseptal approach may be more technically challenging, it is less invasive and may be preferred by patients. Data from case series and a large international registry suggest that patients treated with transseptal mitral valve-in-valve have faster recovery, more improvement in left ventricular ejection fraction and possibly lower mortality compared with patients treated with transapical approach. A prospective clinical trial, the MITRAL trial (Mitral Implantation of TRAnscatheter vaLves) is evaluating the safety and feasibility of transvenous transseptal mitral valve-in valve. The experience from this trial has allowed us to improve our procedural approach. In anticipation of a wider adoption of the transseptal approach for mitral valve-in-valve, we describe our current method step-by-step from planning the procedure through postprocedural management. This is an evolving technique that has changed with experience and the transition to newer generation transcatheter heart valve devices. We discuss the use of cardiac computed tomography for planning the procedure including transseptal puncture and valve size selection, provide procedural and technical tips, and discuss postprocedural care. PMID- 28557345 TI - Maintaining quality of care for very influential patients. PMID- 28557346 TI - Do the nodules detected in chest X-rays always indicate a disease of lung parenchyma? PMID- 28557347 TI - In vitro site-specific recombination mediated by the tyrosine recombinase XerA of Thermoplasma acidophilum. AB - In organisms with circular chromosomes, such as bacteria and archaea, an odd number of homologous recombination events can generate a chromosome dimer. Such chromosome dimers cannot be segregated unless they are converted to monomers before cell division. In Escherichia coli, dimer-to-monomer conversion is mediated by the paralogous XerC and XerD recombinases at a specific dif site in the replication termination region. Dimer resolution requires the highly conserved cell division protein/chromosome translocase FtsK, and this site specific chromosome resolution system is present or predicted in most bacteria. However, most archaea have only XerA, a homologue of the bacterial XerC/D proteins, but no homologues of FtsK. In addition, the molecular mechanism of XerA mediated chromosome resolution in archaea has been less thoroughly elucidated than those of the corresponding bacterial systems. In this study, we identified two XerA-binding sites (dif1 and dif2) in the Thermoplasma acidophilum chromosome. In vitro site-specific recombination assays showed that dif2, but not dif1, serves as a target site for XerA-mediated chromosome resolution. Mutational analysis indicated that not only the core consensus sequence of dif2, but also its flanking regions play important roles in the recognition and recombination reactions mediated by XerA. PMID- 28557348 TI - The toxic mode of action of cyclic lipodepsipeptide fusaricidins, produced by Paenibacillus polymyxa, toward mammalian cells. AB - AIMS: Toxigenic strains of Paenibacillus polymyxa were isolated from buildings connected with the symptoms of ill health. Our aim was to identify the toxic compounds of Paenibacillus polymyxa and to describe their toxic actions. METHODS AND RESULTS: The toxins of Paenibacillus polymyxa were purified and analysed by HPLC and mass spectrometry. Toxic fusaricidins A and B, and LI-F05a with mass ions at m/z 883.7, 897.6 and 897.6, respectively, were found. The cytotoxicity of purified fusaricidins A and B was measured using boar sperm, porcine tubular kidney epithelial cells and murine fibroblasts. The ion channel forming properties of fusaricidins were studied using the black lipid membrane (BLM) technique. Fusaricidins A and B depolarized the mitochondria of boar sperm, porcine tubular kidney epithelial cells and murine fibroblasts at concentrations of 0.5-1 MUg ml-1 and caused nuclear fragmentation and induced apoptosis at concentrations of 2.5-5 MUg ml-1 . Furthermore, fusaricidins A and B induced K+ permeating single channels. CONCLUSIONS: It was concluded that fusaricidins were toxic to mitochondria and induced apoptosis in mammalian cells. It was proposed that the observed toxicity of fusaricidins is due their ion channel forming properties. SIGNIFICANCE AND IMPACT OF THE STUDY: This paper revealed, for the first time, the mode of action of Paenibacillus polymyxa fusaricidins toxins towards mammalian cells. Fusaricidins, due to their potassium ionophoricity and mitochondria depolarizing impacts, may have contributed to the health damage observed at sites where the producer strains were isolated at high density. PMID- 28557349 TI - Synthesis and Deprotection of Biodegradably and Thermally Protected Dinucleoside 2',5'-Monophosphate Prodrug Model of 2-5A. AB - Protected dinucleoside-2',5'-monophosphate has been prepared to develop a prodrug strategy for 2-5A. The removal of enzymatically and thermally labile 4 (acetylthio)-2-(ethoxycarbonyl)-3-oxo-2-methylbutyl phosphate protecting group and enzymatically labile 3'-O-pivaloyloxymethyl group was followed at pH 7.5 and 37 degrees C by HPLC from the fully protected dimeric adenosine-2',5' monophosphate 1 used as a model compound for 2-5A. The desired unprotected 2',3' O-isopropylideneadenosine-2',5'-monophosphate (9) was observed to accumulate as a major product. Neither the competitive isomerization of 2',5'- to a 3',5'-linkage nor the P-O5' bond cleavage was detected. The phosphate protecting group was removed faster than the 3'-O-protection and, hence, the attack of the neighbouring 3'-OH on phosphotriester moiety did not take place. PMID- 28557350 TI - Interactive effects of seasonal drought and elevated atmospheric carbon dioxide concentration on prokaryotic rhizosphere communities. AB - Global change models indicate that rainfall patterns are likely to shift towards more extreme events concurrent with increasing atmospheric carbon dioxide concentration ([CO2 ]). Both changes in [CO2 ] and rainfall regime are known to impact above- and belowground communities, but the interactive effects of these global change drivers have not been well explored, particularly belowground. In this experimental study, we examined the effects of elevated [CO2 ] (ambient + 240 ppm; [eCO2 ]) and changes in rainfall patterns (seasonal drought) on soil microbial communities associated with forest ecosystems. Our results show that bacterial and archaeal communities are highly resistant to seasonal drought under ambient [CO2 ]. However, substantial taxa specific responses to seasonal drought were observed at [eCO2 ], suggesting that [eCO2 ] compromise the resistance of microbial communities to extreme events. Within the microbial community we were able to identify three types of taxa specific responses to drought: tolerance, resilience and sensitivity that contributed to this pattern. All taxa were tolerant to seasonal drought at [aCO2 ], whereas resilience and sensitivity to seasonal drought were much greater in [eCO2 ]. These results provide strong evidence that [eCO2 ] moderates soil microbial community responses to drought in forests, with potential implications for their long-term persistence and ecosystem functioning. PMID- 28557351 TI - The highly pleiotropic gene SLC39A8 as an opportunity to gain insight into the molecular pathogenesis of schizophrenia. AB - There is a long way from the initial discovery of a genome-wide significant signal to mechanistic understanding of the association. Identification of the gene and causal polymorphism usually requires an extensive additional effort. The schizophrenia genome-wide significant locus at 4q24 may be a rare exception to this pattern. As discussed in this review, the association at this locus is most probably driven by a functional missense variant at the metal cations transporter SLC39A8. The variant, rs13107325, is almost exclusive of European populations and is one of the most pleiotropic variants of the genome, being associated at genome wide significant level with several additional traits, such as body mass index, Crohn's disease, blood pressure related-traits, and serum levels of manganese, N terminal pro-B-type natriuretic peptide and HDL-cholesterol. SLC39A8 seems to be subject to recent natural selection in Europeans. It is almost ubiquitously expressed and its physiological role is beginning to be elucidated, mainly in relation to immunity. This manuscript presents arguments in favor of the rs13107325 variant as the functional variant responsible for the association of this locus with schizophrenia, reviews the genetic associations with this gene, the evidences of natural selection on the gene, and the known aspects about its structure and physiological functions. Finally, some hypotheses about putative mechanisms for its association with schizophrenia are presented based on this knowledge, including impaired immunity/inflammation, interference with glutamatergic neurotransmission, homeostasis of essential metals in brain, such as iron, zinc or manganese, or neurotoxicity by heavy metals, such as cadmium or lead. PMID- 28557352 TI - Effect of N-acetylcysteine on motivation, seeking and relapse to ethanol self administration. AB - Alcohol use disorder is a chronic and highly relapsing disorder, characterized by a loss of control over alcohol consumption and craving. Several studies suggest a key role of glutamate in this disorder. In recent years, the modulation of cystine/glutamate exchange via the xc- system has emerged as a new therapeutic alternative for reducing the excitatory glutamatergic transmission observed after ethanol self-administration in both rats and humans. The objective of this study was to determine whether a treatment with N-acetylcysteine (NAC), a cystine prodrug, could reduce ethanol self-administration, ethanol-seeking behavior and reacquisition of ethanol self-administration. Male Long Evans rats were trained to self-administer 20 percent ethanol in operant cages for several weeks. Once the consumption surpassed 1 g of ethanol/kg body weight/15 minutes, the effect of an acute intraperitoneal injection of NAC (0, 25, 50 or 100 mg/kg) 1 hour before the beginning of each test was evaluated on different aspects of the operant self administration behavior. We demonstrated antimotivational properties of NAC (100 mg/kg), as ethanol-reinforced responding was reduced in a fixed ratio (-35 percent) and in a progressive ratio schedule (-81 percent). NAC also reduced ethanol-seeking behavior (-77 percent) evaluated as extinction responding in a single extinction session. NAC was able to reduce reacquisition in rats that were abstinent for 17 days, while NAC had no effect on ethanol relapse in rats previously exposed to six extinction sessions. Overall, our results demonstrate that NAC limits motivation, seeking behavior and reacquisition in rats, making it a potential new treatment for the maintenance of abstinence. PMID- 28557354 TI - Modeling liver electrical conductivity during hypertonic injection. AB - Metastases in the liver frequently grow as scattered tumor nodules that neither can be removed by surgical resection nor focally ablated. Previously, we have proposed a novel technique based on irreversible electroporation that may be able to simultaneously treat all nodules in the liver while sparing healthy tissue. The proposed technique requires increasing the electrical conductivity of healthy liver by injecting a hypersaline solution through the portal vein. Aiming to assess the capability of increasing the global conductivity of the liver by means of hypersaline fluids, here, it is presented a mathematical model that estimates the NaCl distribution within the liver and the resulting conductivity change. The model fuses well-established compartmental pharmacokinetic models of the organ with saline injection models used for resuscitation treatments, and it considers changes in sinusoidal blood viscosity because of the hypertonicity of the solution. Here, it is also described a pilot experimental study in pigs in which different volumes of NaCl 20% (from 100 to 200 mL) were injected through the portal vein at different flow rates (from 53 to 171 mL/minute). The in vivo conductivity results fit those obtained by the model, both quantitatively and qualitatively, being able to predict the maximum conductivity with a 14.6% average relative error. The maximum conductivity value was 0.44 second/m, which corresponds to increasing 4 times the mean basal conductivity (0.11 second/m). The results suggest that the presented model is well suited for predicting on liver conductivity changes during hypertonic saline injection. PMID- 28557353 TI - Generation of carbamoyl phosphate synthetase 1 reporter cell lines for the assessment of ammonia metabolism. AB - Both primary hepatocytes and stem cells-derived hepatocyte-like cells (HLCs) are major sources for bioartificial liver (BAL). Maintenance of hepatocellular functions and induction of functional maturity of HLCs are critical for BAL's support effect. It remains difficult to assess and improve detoxification functions inherent to hepatocytes, including ammonia clearance. Here, we aim to assess ammonia metabolism and identify ammonia detoxification enhancer by developing an imaging strategy. In hepatoma cell line HepG2, and immortalized hepatic cell line LO2, carbamoyl phosphate synthetase 1 (CPS1) gene, the first enzyme of ammonia-eliminating urea cycle, was labelled with fluorescence protein via CRISPR/Cas9 system. With the reporter-based screening approach, cellular detoxification enhancers were selected among a collection of 182 small molecules. In both CPS1 reporter cell lines, the fluorescence intensity is positively correlated with cellular CPS1 mRNA expression, ammonia elimination and secreted urea, and reflected ammonia detoxification in a dose-dependent manner. Surprisingly, high-level CPS1 reporter clones also reserved many other critical hepatocellular functions, for example albumin secretion and cytochrome 450 metabolic functions. Sodium phenylbutyrate and resveratrol were identified to enhance metabolism-related gene expression and liver-enriched transcription factors C/EBPalpha, HNF4alpha. In conclusion, the CPS1-reporter system provides an economic and effective platform for assessment of cellular metabolic function and high-throughput identification of chemical compounds that improve detoxification activities in hepatic lineage cells. PMID- 28557355 TI - Screening methods for obstructive sleep apnoea in severely obese pregnant women. AB - Obstructive sleep apnoea (OSA) is an often-overlooked diagnosis, more prevalent in the obese population. Screening method accuracy, uptake and hence diagnosis is variable. There is limited data available regarding the obese pregnant population; however, many studies highlight potential risks of apnoeic episodes to mother and foetus, including hypertension, diabetes and preeclampsia. A total of 162 women with a body mass index (BMI) >= 35 were recruited from a tertiary referral hospital in the northwest of England. They were invited to attend three research antenatal clinics, completing an Epworth Sleepiness Scale (ESS) questionnaire at each visit. A monitor measuring the apnoea hypopnoea index (AHI) was offered at the second visit. Data taken from consent forms, hospital notes and hospital computer records were collated and anonymized prior to statistical analysis. A total of 12.1% of women had an ESS score of >10, suggesting possible OSA. Rates increased throughout pregnancy, although unfortunately, the attrition rate was high; 29.0% of women used the RUSleeping (RUS) meter, and only one (2.1%) met pre-specified criteria for OSA (AHI >= 15). This individual had OSA categorized as severe and underwent investigations for preeclampsia, eventually delivering by emergency caesarean section due to foetal distress. The accuracy of the ESS questionnaire, particularly the RUS monitor, to screen for OSA in the pregnant population remains unclear. Further research on a larger sample size using more user-friendly technology to confidently measure AHI would be beneficial. There are currently no guidelines regarding screening for OSA in the obese pregnant population, yet risks to both mother and foetus are well researched. PMID- 28557356 TI - Enabling Fast Pseudo-2D NMR Spectral Acquisition for Broadband Homonuclear Decoupling: The EXACT NMR Approach. AB - Pseudo-2D NMR spectroscopy provides a means of acquiring broadband homonuclear decoupled spectra useful for structural characterization of complex molecules. However, data points concatenated in the direct dimension in these experiments are acquired over incremented time periods-leading to long acquisition times with no sensitivity benefits due to the absence of signal averaging between scans. Herein, the concept of EXACT NMR spectroscopy ("burst" non-uniform sampling of data points) is explored in pseudo-2D experiments with results revealing little or no loss in spectral quality or signal intensity despite the acceleration of acquisition-up to 400 % in some cases. PMID- 28557358 TI - Evidence for Central Sensitization in Patients with Temporomandibular Disorders: A Systematic Review and Meta-analysis of Observational Studies. AB - OBJECTIVES: Several authors have evaluated different pain measurements, including quantitative sensory testing (QST), temporal summation (TS), and conditioned pain modulation (CPM) in order to determine the presence of central sensitization (CS) and its influence on patients with temporomandibular disorders (TMD). Since there are no convincing studies about this topic, the purpose of this study was to conduct a review of the studies involving CS-related measures in TMD patients. METHODS: A meta-analysis of case-control and cohort/cross sectional studies was conducted. Standardized mean differences (SMD) and 95% confidence intervals (CIs) were calculated for relevant QST outcomes and pooled in a meta-analysis using the random effects model. Twenty-two studies (eleven case-control and eleven cross sectional studies) met the inclusion criteria; eight were included in the meta analysis (five cross-sectional and three case-control). Patients with TMD had decreased pressure pain thresholds in both trigeminal (five studies; n = 1,985; SMD = -1.55, 95% CI -2.23 to -0.77; P < 0.01) and remote areas (five studies; n = 1,985; SMD = -1.92, 95% CI -2.95 to -0.89; P < 0.01). When analyzing for thermal hyperalgesia (hot and cold pain thresholds), differences were not found in trigeminal areas or remote areas in patients with TMD. The TS qualitative analysis showed strong evidence of spinal hyperexcitability for mechanically evoked pain. CONCLUSION: These meta-analyses support the existence of differences in widespread pressure pain sensitivity in patients with TMD when compared with asymptomatic subjects. Spinal and central hyperexcitability can be found in TMD patients as shown by an increase in mechanical TS. PMID- 28557357 TI - Imaging Endogenous Metal Ions in Living Cells Using a DNAzyme-Catalytic Hairpin Assembly Probe. AB - DNAzymes are a promising platform for metal ion detection, and a few DNAzyme based sensors have been reported to detect metal ions inside cells. However, these methods required an influx of metal ions to increase their concentrations for detection. To address this major issue, the design of a catalytic hairpin assembly (CHA) reaction to amplify the signal from photocaged Na+ -specific DNAzyme to detect endogenous Na+ inside cells is reported. Upon light activation and in the presence of Na+ , the NaA43 DNAzyme cleaves its substrate strand and releases a product strand, which becomes an initiator that trigger the subsequent CHA amplification reaction. This strategy allows detection of endogenous Na+ inside cells, which has been demonstrated by both fluorescent imaging of individual cells and flow cytometry of the whole cell population. This method can be generally applied to detect other endogenous metal ions and thus contribute to deeper understanding of the role of metal ions in biological systems. PMID- 28557359 TI - Aromatic-Imide-Based Thermally Activated Delayed Fluorescence Materials for Highly Efficient Organic Light-Emitting Diodes. AB - Aromatic-imide-based thermally activated delayed fluorescence (TADF) materials with a twisted donor-acceptor-donor skeleton were efficiently synthesized and exhibited excellent thermal stability and high photoluminescence quantum yields. The small DeltaEST value (<0.1 eV) along with the clear temperature-dependent delayed component of their transient photoluminescence (PL) spectra demonstrated their excellent TADF properties. Moreover, the performance of organic light emitting diodes in which TADF materials AI-Cz and AI-TBCz were used as dopants were outstanding, with external quantum efficiencies up to 23.2 and 21.1 %, respectively. PMID- 28557360 TI - Success of capture of toads improved by manipulating acoustic characteristics of lures. AB - BACKGROUND: Management of invasive vertebrates is a crucial component of conservation. Trapping reproductive adults is often effective for control, and modification of traps may greatly increase their attractiveness to such individuals. Cane toads (Rhinella marina) are invasive, and males use advertisement vocalisations to attract reproductive females. In amphibians, including toads, specific structural parameters of calls (e.g. dominant frequency and pulse rate) may be attractive to females. Some cane toad traps use an artificial advertisement vocalisation to attract toads. We determined whether variation of the call's parameters (volume, dominant frequency and pulse rate) could increase the capture rate of gravid females. RESULTS: Overall, traps equipped with loud calls (80 dB at 1 m) caught significantly more toads, and proportionally more gravid females, than traps with quiet calls (60 dB at 1 m), and traps with low dominant frequency calls caught more gravid females than traps with median frequency calls. Traps with high pulse rate calls attracted more females than traps with low pulse rate calls. Approximately 91% of the females trapped using a low frequency and high pulse rate combination call were gravid, whereas in traps using a call with population median parameters only approximately 75% of captured females were gravid. CONCLUSION: Calls that indicated large-bodied males (low frequency) with high energy reserves (high pulse rate) are often attractive to female anurans and were effective lures for female toads in our study. The design of future trapping regimes should account for behavioural preferences of the target sex. (c) 2017 Society of Chemical Industry. PMID- 28557361 TI - Diketopyrrolopyrrole-Porphyrin Based Conjugated Polymers for Ambipolar Field Effect Transistors. AB - Porphyrin-based molecules have been widely used in dye-sensitized solar cells and bulk heterojunction solar cells, but their application in field-effect transistors (FETs) is limited. In this work, two conjugated polymers based on diketopyrrolopyrrole and porphyrin units were developed for FETs. The polymers exhibit extra-low band gap with energy levels close to -4.0 eV and -5.0 eV due to the strong electron-donating and withdrawing ability of porphyrin and diketopyrrolopyrrole. With additionally high crystalline properties, ambipolar charge carrier transports with a hole mobility of 0.1 cm2 V-1 s-1 in FETs were realized in these polymers, representing the highest performance in solution processed FETs based on porphyrin unit. PMID- 28557362 TI - Longitudinal study of quality of life in advanced cancer patients on home parenteral nutrition. AB - Since there is little knowledge regarding the quality of life (QoL) of cancer patients on home parenteral nutrition (HPN), we planned a prospective, longitudinal, double-center study to investigate the changes of QoL in these patients. One hundred and eleven adult cancer patients who were candidates for HPN following the indications of the European guidelines were consecutively enrolled. For QoL analysis, EORTC QLQ-C30 questionnaires were filled at the HPN start and after 1, 2, 3, and 4 months, and scores changes over time were analyzed according to the univariate mixed-effects linear model for repeated measures. Most patients had gastrointestinal cancers, were severely malnourished, and were in stage IV; two-thirds were still receiving oncologic treatments. Median weight loss over 3 months and body mass index were 11.7% and 20.7, respectively. Median survival was 4.7 (1-42) months; 67 and 34% of patients survived 3 and 6 months, respectively. Global QoL, physical functioning, role functioning, emotional functioning, appetite loss, and fatigue scores had a statistically significant trend over time (P < 0.001, P < 0.001, P = 0.007, P < 0.001, P = 0.004, P = 0.022, respectively). At the univariate analyses, the determinants significantly associated with changes in trend over time for physical, role, and emotional functioning were oncologic treatments (P < 0.001, P = 0.014, P = 0.040, respectively) and for appetite loss they were weight loss and Karnofsky performance status (P = 0.003, P = 0.023, respectively). Global QoL, physical, role, and emotional functioning improved during HPN even in advanced cancer patients on oncologic treatments. PMID- 28557363 TI - Localized Chemical Remodeling for Live Cell Imaging of Protein-Specific Glycoform. AB - Live cell imaging of protein-specific glycoforms is important for the elucidation of glycosylation mechanisms and identification of disease states. The currently used metabolic oligosaccharide engineering (MOE) technology permits routinely global chemical remodeling (GCM) for carbohydrate site of interest, but can exert unnecessary whole-cell scale perturbation and generate unpredictable metabolic efficiency issue. A localized chemical remodeling (LCM) strategy for efficient and reliable access to protein-specific glycoform information is reported. The proof-of-concept protocol developed for MUC1-specific terminal galactose/N acetylgalactosamine (Gal/GalNAc) combines affinity binding, off-on switchable catalytic activity, and proximity catalysis to create a reactive handle for bioorthogonal labeling and imaging. Noteworthy assay features associated with LCM as compared with MOE include minimum target cell perturbation, short reaction timeframe, effectiveness as a molecular ruler, and quantitative analysis capability. PMID- 28557365 TI - Carotid artery stenting in clinical practice depending on patient age. AB - BACKGROUND: The age-dependent outcome of carotid artery stenting (CAS) outside of randomized controlled trials is largely unknown. Therefore, we assessed acute and long-term results of CAS in a single-center real-world registry. METHODS: All symptomatic and asymptomatic patients who consecutively underwent CAS were enrolled into the present analysis. The population was divided into three groups dependent on patients' age (<65, 65-74, and >=75 years). RESULTS: Between 1999 and 2015, a total of 878 patients (24%, <65 years; 40%, 65-74 years; and 36%, >=75 years) underwent CAS. The rate of the primary endpoint (30-day composite of death, stroke, and myocardial infarction [MACCE] plus long-term ipsilateral stroke) was higher in patients aged >=75 years compared to the middle-age group (hazard ratio [HR] 2.30, confidence interval [CI] 1.22-4.36; P = 0.001). Similarly, the rate of the stroke endpoint (30-day any stroke plus long-term ipsilateral stroke) was higher in patients aged >=75 years compared to patients aged 65-74 years (HR 2.03, CI 1.01-4.10; P = 0.04). There was no significant age dependent difference of the primary endpoint and stroke endpoint in the subset of asymptomatic patients. Furthermore, age had no influence on the risk of stroke beyond the periprocedural period. CONCLUSIONS: Patients aged >=75 years had poorer outcomes after CAS compared to younger patients. Importantly, age did not influence the outcome in asymptomatic patients and the risk for stroke beyond the periprocedural period. PMID- 28557364 TI - Supine awake oximetry as a screening tool for daytime hypercapnia in super-obese patients. AB - BACKGROUND: Evidence-based screening tools are required for detection of daytime hypercapnia in high-risk patient populations. AIMS: To determine the validity of supine awake oximetry as a test for daytime hypercapnia and severe sleep disordered breathing (SDB) in super-obese patients. METHODS: This was a cross sectional diagnostic test evaluation of super-obese adults (body mass index >50 kg/m2 ) presenting to Liverpool Hospital, Australia, between 2009 and 2015 for diagnostic polysomnography (PSG) and arterial blood gas measurement. Supine awake oxygen saturation (SpO2 ) was determined using oximetry measurements from the first three awake epochs of raw PSG data. Sensitivity and specificity of SpO2 for detecting patients with daytime hypercapnia (PaCO2 >45 mmHg) and severe SDB (respiratory disturbance index (RDI) >30 events/h) were assessed at various cut off points and displayed using a receiver operating characteristic (ROC) curve. Area under the ROC curve and positive and negative predictive values (PPV and NPV) in the present patient population were derived. RESULTS: Of 52 patients, 23 (44%) had daytime hypercapnia. SpO2 measured awake in the supine position was associated with the presence of daytime hypercapnia but not with the presence of severe SDB. Overall, awake supine SpO2 <91.2% had 34.8% sensitivity, 96.6% specificity and 88.8% PPV, and SpO2 <96.7% had 87.0% sensitivity, 20.7% specificity and 66.7% NPV for the presence of daytime hypercapnia. CONCLUSION: Awake supine oximetry is an easily performed test that may have novel use in identifying patients at high risk of respiratory failure. Future studies are required to evaluate prospectively its role in screening patients at risk of daytime hypercapnia. PMID- 28557367 TI - Septic keratitis in dogs, cats, and horses in Switzerland: associated bacteria and antibiotic susceptibility. AB - OBJECTIVE: To evaluate the most common bacterial pathogens associated with septic keratitis in veterinary patients from Switzerland. The second objective was to analyze antibiotic susceptibility test results of the identified bacterial pathogens. The third objective was to evaluate potential breed predispositions to septic keratitis. PROCEDURES: Two hundred and fifty-five cultures and antibiotic susceptibility reports from dogs, cats, and horses with septic keratitis that were presented to the University of Zurich Veterinary Medical Teaching Hospital between 2009 and 2013 were reviewed. Odds ratios for the risk of having a septic keratitis were estimated for all dog and cat breeds compared to the general nonbrachycephalic hospital population. RESULTS: Ninety-six, 29, and 31 positive cultures were obtained from 89 canine, 28 feline, and 29 equine eyes, respectively. Repeat sampling accounted for the differences in numbers. Negative culture results were obtained in 50, 31, and 18 cases. Staphylococci and streptococci accounted for 66% of the isolates in dogs and 80% of the isolates in cats and horses. Staphylococcus spp. had a higher percentage of fluoroquinolone resistant isolates compared to previous reports. Brachycephalic breeds had elevated odds ratios for the presence of septic keratitis. CONCLUSION: Identified bacterial pathogens and their prevalence as well as the elevated odds ratios for septic keratitis in brachycephalics are roughly consistent with previous studies. Based on systemic breakpoint data, resistance to commonly used topical antibiotics, including the second-generation fluoroquinolones, was found. PMID- 28557366 TI - Radiosensitization by BRAF inhibitors. AB - BACKGROUND: Increased skin toxicity during combination therapy with a BRAF inhibitor and radiation therapy has recently been reported. MATERIAL AND METHODS: We present seven melanoma patients with non-resectable stage III or IV disease and concomitant treatment with a BRAF inhibitor and radiation therapy. RESULTS: In all patients, combination therapy yielded a good local response. Only two patients, both on vemurafenib, showed severe radiation dermatitis (CTCAE grade 3/4) after one and two weeks, respectively, resulting in interruption of BRAF inhibitor treatment. The respective cumulative radiation dose was 10 Gy and 35 Gy. The remaining vemurafenib patients displayed only mild radiation dermatitis CTCAE grade 2; the only dabrafenib patient CTCAE grade 1. In one patient, recall dermatitis was diagnosed 14 days after completion of radiation therapy with a cumulative dose of 30 Gy. CONCLUSIONS: Severe skin toxicity caused by BRAF inhibitor-induced radiosensitization is not common and usually amenable to treatment. Thus, combination treatment should remain a therapeutic option, especially in melanoma patients characterized by aggressive tumor growth. Although there is an increased risk of skin toxicity during combination therapy, it is usually well tolerated by most patients. Sequential - instead of simultaneous - treatment does not seem to prevent such toxicity reactions. PMID- 28557368 TI - Strategic framework improves access to stroke reperfusion across the state of Victoria Australia. AB - BACKGROUND: In 2010, rapid access to stroke thrombolysis centres was limited in some regional areas in the Australian state of Victoria. These results, and planning for endovascular clot retrieval (ECR), have led to the implementation of strategies by the Victorian Stroke Clinical Network, the Victorian Stroke Telemedicine Program and local health services to improve state-wide access. AIMS: To examine whether access to stroke reperfusion services (thrombolysis and ECR) in regional Victoria have subsequently improved. METHODS: The locations of suspected stroke patients attended by ambulance in 2015 were mapped, and drive times to the nearest reperfusion services were calculated. We then calculated the proportion of cases with transport times within: (i) 60 min to thrombolysis centres; and (ii) 180 min to two ECR centres designated to receive regional patients. Statistical comparisons to existing 2010 data were made. RESULTS: In 2015, Ambulance Victoria attended 16 418 cases of suspected stroke (2.9% of all emergency calls), of whom 4597 (28%) were located in regional Victoria. Compared to 2010, a greater proportion of regional suspected stroke patients in 2015 were located within 60 min of a thrombolysis centre by road (77-95%, P < 0.001). A 3-h road travel time to the two ECR centres is currently possible for 88% of regional patients. CONCLUSION: A strategic and region-specific approach has resulted in improved access by road transport to reperfusion therapies for stroke patients across Victoria. PMID- 28557369 TI - Medical mishap as a cause of non-resolving pneumonia. AB - A 15-year old boy was referred for evaluation of fever, productive cough, and recurrent/persistent right lower lobe (RLL) pneumonia of 1-month duration. Chest computed tomography scan showed RLL consolidation, with minimal pleural effusion and a liver abscess with sharp borders, containing a solid calcification in the lower portion. History revealed acute appendicitis with laparoscopic appendectomy 6 months prior to presentation, during which a fecalith dropped to the peritoneal cavity. Following laparoscopically guided drainage of the abscess the patient improved. Herein we describe a rare case of non-resolving RLL pneumonia secondary to pyogenic liver abscess caused by dropped appendicolith. PMID- 28557370 TI - Hybrid and fully-etched surface implants in periodontally healthy patients: A comparative retrospective study on marginal bone loss. AB - BACKGROUND: Human studies on implants with the same design but with different surfaces are lacking at the present time. PURPOSE: The aim of this study was to compare the survival rate of and marginal bone loss (MBL) around 2 types of implants with the same design, but with different surfaces: fully "sandblasted and double-etched" (SDE) implants and hybrid (H) implants, with an apical SDE surface and a coronal machined-surface. MATERIALS AND METHODS: The SDE- and H surfaces were previously analyzed under SEM and profilometer. Implants were placed in partially edentulous periodontally healthy patients requiring single implant-restoration, in either mandible or maxilla, with cement-retained prosthetic restoration. Twelve months after prosthetic loading, MBL in relation to prosthetic abutment height (AH), calculated radiographically, was statistically analyzed. RESULTS: SEM and profilometer analyses revealed no differences between the SDE-surfaces of either SDE- or H-implants. Transverse ridges and grooves characterized the machined portion of H-implants, clearly influencing the profilometer analysis. In 75 patients, 37 SDE and 38 H-implants were placed and all functioned completely after 12 months. In both SDE- and H groups, MBL had a significant inverse relationship with AH, with greater intercept and negative slope for SDE-group and intersection of the 2 regression lines at AH = 2 mm. CONCLUSIONS: A 100% survival rate was recorded for SDE- and H implants placed in pristine bone of periodontally healthy patients; MBL was limited and similar in both SDE- and H-groups; the higher the prosthetic AH, the lesser the MBL around implants; H-implants could reduce bone loss most effectively with abutments lower than 2 mm, realistically exploitable on thin biotypes; SDE-implants could reduce bone loss most effectively with abutments greater than 2 mm, realistically exploitable on thick biotypes. PMID- 28557372 TI - Laparoscopic sigmoidectomy combined with uterus excision for colouterine fistula caused by sigmoid colon diverticulitis: A case report. AB - A case of colouterine fistula caused by colonic diverticulitis that was successfully treated laparoscopically is presented. A 74-year-old woman visited us with lower abdominal discomfort and vaginal excretion with minor fecal contamination. Mild tenderness was observed in her lower abdomen. Blood examinations revealed elevated white blood cell count and C-reactive protein. Sigmoid colon diverticulitis was revealed on CT, and her condition was diagnosed as colouterine fistula. Hinchey classification was stage I. After 2 weeks of conservative therapy, her symptoms were reduced, and the white blood cell count and C-reactive protein level decreased. However, fecal contaminated vaginal excretion continued. The patient underwent laparoscopic sigmoidectomy combined with uterus excision, and she has been in good health for the 3 years since the operation. Although colouterine fistula is usually treated with open surgery, patients with controlled and well-localized inflammation may be good candidates for a laparoscopic approach. PMID- 28557374 TI - Introduction: 2016 Rumelhart Prize Issue Honoring Dedre Gentner. PMID- 28557373 TI - PTEN inhibits replicative senescence-induced MMP-1 expression by regulating NOX4 mediated ROS in human dermal fibroblasts. AB - The biological function of NADPH oxidase (NOX) is the generation of reactive oxygen species (ROS). ROS, primarily arising from oxidative cell metabolism, play a major role in both chronological ageing and photoageing. ROS in extrinsic and intrinsic skin ageing may be assumed to induce the expression of matrix metalloproteinases. NADPH oxidase is closely linked with phosphatidylinositol 3 OH kinase (PI3K) signalling. Protein kinase C (PKC), a downstream molecule of PI3K, is essential for superoxide generation by NADPH oxidase. However, the effect of PTEN and NOX4 in replicative-aged MMPs expression has not been determined. In this study, we confirmed that inhibition of the PI3K signalling pathway by PTEN gene transfer abolished the NOX-4 and MMP-1 expression. Also, NOX 4 down-expression of replicative-aged skin cells abolished the MMP-1 expression and ROS generation. These results suggest that increase of MMP-1 expression by replicative-induced ROS is related to the change in the PTEN and NOX expression. PMID- 28557375 TI - Identifying metrics of success for transitional care practices in childhood cancer survivorship: A qualitative study of survivorship providers. AB - BACKGROUND: Long-term survival in childhood cancer is excellent. Most survivors will have a therapy-related chronic condition, yet very few receive survivor focused care as they transition from adolescence to young adulthood. The purpose of this study is to identify indicators of success in current transitional care practices for young adult survivors of childhood cancer as defined by all members of survivorship care teams. PROCEDURE: An exploratory, phenomenologic qualitative study was conducted with key informants from medical teams involved in transitional care of childhood cancer survivors. Data were collected through phone interviews with providers from both pediatric and adult care settings. RESULTS: A multidisciplinary study sample of 29 participants from three institutions identified two major themes with multiple subthemes. The first major theme was that providers must be good communicators, and it emphasized the importance of having good relationships throughout the transition of care to optimize effective communication. The second major theme was that models of care must include well-established partners throughout the healthcare system that promote accessible subspecialty care with streamlined referrals and patient navigation services. CONCLUSIONS: From the perspective of experienced pediatric- and adult-centered providers at three different institutions delivering life-long transitional care for childhood cancer survivors, the optimal model of care must be built around facilitating communication among all key stakeholders and emphasizing patient-friendly services that minimize patient stressors. PMID- 28557371 TI - Genetic engineering of Trichoderma reesei cellulases and their production. AB - Lignocellulosic biomass, which mainly consists of cellulose, hemicellulose and lignin, is the most abundant renewable source for production of biofuel and biorefinery products. The industrial use of plant biomass involves mechanical milling or chipping, followed by chemical or physicochemical pretreatment steps to make the material more susceptible to enzymatic hydrolysis. Thereby the cost of enzyme production still presents the major bottleneck, mostly because some of the produced enzymes have low catalytic activity under industrial conditions and/or because the rate of hydrolysis of some enzymes in the secreted enzyme mixture is limiting. Almost all of the lignocellulolytic enzyme cocktails needed for the hydrolysis step are produced by fermentation of the ascomycete Trichoderma reesei (Hypocreales). For this reason, the structure and mechanism of the enzymes involved, the regulation of their expression and the pathways of their formation and secretion have been investigated in T. reesei in considerable details. Several of the findings thereby obtained have been used to improve the formation of the T. reesei cellulases and their properties. In this article, we will review the achievements that have already been made and also show promising fields for further progress. PMID- 28557377 TI - Wet-AMD on a Chip: Modeling Outer Blood-Retinal Barrier In Vitro. AB - Choroidal neovascularization (CNV) in the retinal pigment epithelium (RPE) choroid complex constituting outer blood retinal barrier (oBRB) is a critical pathological step in various ophthalmic diseases, which results in blindness, such as wet type age-related macula degeneration. Current in vitro experimental models using petri dishes or transwell are unable to study CNV morphogenesis. Here, a unique organotypic eye-on-a-chip model is described that mimics the RPE choroid complex in vitro. This model consists of an RPE monolayer and adjacent perfusable blood vessel network, which is supporting barrier function of oBRB. The intact barrier function of the RPE-choroid complex is reconstituted while maintaining important structural features. Further, this model can successfully mimic the pathogenesis of CNV especially in terms of morphogenesis, which is penetrating angiogenic sprouts from pre-existing choroidal vessels that result in breakdown of RPE monolayer. The alleviation of the pathological angiogenesis can be modeled with bevacizumab, a clinical drug for CNV treatment. It is believed that this model can be used to aid in the development of advanced in vitro eye drug evaluation in conjunction with animal models. PMID- 28557376 TI - Comparison between tapered and cylindrical implants in the posterior regions of the mandible: A prospective, randomized, split-mouth clinical trial focusing on implant stability changes during early healing. AB - BACKGROUND: Companies affirm that tapered implants show adequate initial stability, while their installation in the lower arch is uncommon in clinical practice. PURPOSE: To compare the clinical outcomes of tapered and cylindrical implants and to study their effect on bone site characteristics and peri-implant health during healing. MATERIALS AND METHODS: The implant site dimensions were assessed by linear measurements using CBCT prior to the installation of 40 implants in the posterior mandible (20 tapered and 20 cylindrical). The bone type was registered during drilling via the surgeon's tactile perception, following the classification of Lekholm and Zarb. Primary stability (PS) was determined by the insertion torque (IT) and the implant stability quotient (ISQ). Secondary stability (SS) and the peri-implant health was monitored for 3 months through the visible plaque index (VPI), the peri-implant inflammation (PI), the probing depth index (PDI), and the gingival bleeding index (GBI). Significant differences were investigated with t-tests for independent samples, chi-square tests or Fisher's exact test. Pearson's correlation test was used to investigate the relationship between the bone site characteristics and PS (IT and ISQ), as well as the relationships between IT and ISQ for each implant type. RESULTS: Tapered and cylindrical implants showed no significant differences for any outcome variable (P > .05). A significant decrease in ISQ was observed after 7 days of healing (P = .0002), followed by a gradual increase beginning at 21 days (P = .0010) until the last follow-up time at 90 days (P = .0319). The cortical height was correlated with IT; while medullary bone dimensions were correlated with the PS as evidenced by the ISQ values. The insertion torque was significantly correlated with the PS only for the cylindrical dental implants. CONCLUSIONS: Tapered and cylindrical implants have similar biological behavior during the healing process. Bone site characteristics can influence insertion torque and implant stability. PMID- 28557378 TI - Lasting effects of early life stress in mice: interaction of maternal environment and infant genes. AB - In the mouse, a powerful paradigm of early life stress, infant maternal separation (IMS), can trigger emotional and cognitive dysfunctions in adulthood similar to those found in humans with a history of childhood adversity. The magnitude of IMS effects differs among diverse inbred strains suggesting an interaction between the genetic background of pups and the maternal care they received. Here, we investigated this interaction with studies on reciprocal F1 hybrid mice of the stress-susceptible Balb/c and the resilient C57Bl/6 strains that were either raised by Balb/c mothers (low maternal care) or by C57Bl/6 mothers (higher maternal care) with or without IMS exposure. The ultrasonic vocalization response to isolation was recorded from infant F1 pups, and their emotional, executive cognitive and epigenetic phenotypes were assessed in adulthood. These studies showed that, regardless of the maternal care received, the emotional phenotype of F1 hybrids was not significantly affected by IMS exposure. However, F1 pups raised by Balb/c (but not C57Bl/6) mothers during IMS exposure exhibit deficits in working memory and attention-set-shifting in adulthood. They also exhibit reduced histone deacetylase 1 levels at promotors of brain-derived neurotrophic factor and early growth response 2 genes, and abnormally high induction of expression of these genes during cognitive testing. As one of affected genes was previously shown to associate with the Balb/c and the other with the C57Bl/6 genetic background, these findings indicate that both parental alleles interact with the maternal environment to modulate the cognitive and epigenetic phenotypes of F1 mice exposed to the IMS. PMID- 28557380 TI - Lipid and Phenolic Constituents from Seeds of Hypericum perforatum L. and Hypericum tetrapterum Fr. and their Antioxidant Activity. AB - Seeds of Hypericum perforatum and H. tetrapterum were extracted with dichloromethane and methanol and investigated by chromatographic and mass spectrometric methods. Both species yielded a fatty oil fraction amounting to 30.5% and 18.0% of the seed weight, respectively. Linoleic acid (C18:2n-6) was shown to be the predominant fatty acid constituent. Moreover, xanthone derivatives, i.e. tetrahydroxyxanthones (THX), xanthone-glycosides and xanthone sulfonates, were assigned in methanolic extracts. For structure elucidation, one representative xanthone, namely 1,3,6,7-THX, was synthesized and analyzed via HPLC-DAD/MSn and GC/MS. Total THX contents were quantitated applying a validated HPLC-DAD method, resulting in 1.25 g/kg (H. perforatum) and 0.27 g/kg (H. tetrapterum), respectively. Moreover, the free radical scavenging capacity of the methanol extracts was tested using the DPPH antioxidant assay. Both, H. perforatum (IC50 = 8.7 mg/l) and 1,3,6,7-THX (IC50 = 3.0 mg/l), exhibited good DPPH free radical scavenging activity compared to Trolox (IC50 = 6.6 mg/l). PMID- 28557381 TI - Predicting frequent emergency department visits among children with asthma using EHR data. AB - OBJECTIVE: For children with asthma, emergency department (ED) visits are common, expensive, and often avoidable. Though several factors are associated with ED use (demographics, comorbidities, insurance, medications), its predictability using electronic health record (EHR) data is understudied. METHODS: We used a retrospective cohort study design and EHR data from one center to examine the relationship of patient factors in 1 year (2013) and the likelihood of frequent ED use (>=2 visits) in the following year (2014), using bivariate and multivariable statistics. We applied and compared several machine-learning algorithms to predict frequent ED use, then selected a model based on accuracy, parsimony, and interpretability. RESULTS: We identified 2691 children. In bivariate analyses, future frequent ED use was associated with demographics, co morbidities, insurance status, medication history, and use of healthcare resources. Machine learning algorithms had very good AUC (area under the curve) values [0.66-0.87], though fair PPV (positive predictive value) [48-70%] and poor sensitivity [16-27%]. Our final multivariable logistic regression model contained two variables: insurance status and prior ED use. For publicly insured patients, the odds of frequent ED use were 3.1 [2.2-4.5] times that of privately insured patients. Publicly insured patients with 4+ ED visits and privately insured patients with 6+ ED visits in a year had >=50% probability of frequent ED use the following year. The model had an AUC of 0.86, PPV of 56%, and sensitivity of 23%. CONCLUSION: Among children with asthma, prior frequent ED use and insurance status strongly predict future ED use. PMID- 28557379 TI - Exploring bacterial interspecific interactions for discovery of novel antimicrobial compounds. AB - Recent studies indicated that the production of secondary metabolites by soil bacteria can be triggered by interspecific interactions. However, little is known to date about interspecific interactions between Gram-positive and Gram-negative bacteria. In this study, we aimed to understand how the interspecific interaction between the Gram-positive Paenibacillus sp. AD87 and the Gram-negative Burkholderia sp. AD24 affects the fitness, gene expression and the production of soluble and volatile secondary metabolites of both bacteria. To obtain better insight into this interaction, transcriptome and metabolome analyses were performed. Our results revealed that the interaction between the two bacteria affected their fitness, gene expression and the production of secondary metabolites. During interaction, the growth of Paenibacillus was not affected, whereas the growth of Burkholderia was inhibited at 48 and 72 h. Transcriptome analysis revealed that the interaction between Burkholderia and Paenibacillus caused significant transcriptional changes in both bacteria as compared to the monocultures. The metabolomic analysis revealed that the interaction increased the production of specific volatile and soluble antimicrobial compounds such as 2,5-bis(1-methylethyl)-pyrazine and an unknown Pederin-like compound. The pyrazine volatile compound produced by Paenibacillus was subjected to bioassays and showed strong inhibitory activity against Burkholderia and a range of plant and human pathogens. Moreover, strong additive antimicrobial effects were observed when soluble extracts from the interacting bacteria were combined with the pure 2,5-bis(1-methylethyl)-pyrazine. The results obtained in this study highlight the importance to explore bacterial interspecific interactions to discover novel secondary metabolites and to perform simultaneously metabolomics of both, soluble and volatile compounds. PMID- 28557382 TI - Parental pre-pregnancy obesity and the risk of offspring weight and body mass index change from childhood to adulthood. AB - The purpose of this study was to examine the association of parental pre pregnancy weight and body mass index (BMI) on offspring weight and BMI change from childhood to adulthood. We analysed BMI data from a subsample of parents (n = 1494) from the Mater-University of Queensland Study of Pregnancy cohort that started in the early 1980s in Brisbane, Australia: data were collected at pre pregnancy and then also for offspring at 5, 14 and 21-year follow-ups. Multiple regression for continuous outcomes and multinomial regression for categorical outcomes were performed. A total of 14.7% of offspring experienced BMI change from normal at 5 years to overweight or obese (OW/OB) at 14 years, 15.3% of normal at 14 years to OW/OB at 21 years and 22.8% from normal at 5 years to OW/OB at 21 years. Overall, the strength of the association of parental BMI with offspring BMI was stronger as offspring become older. Pre-pregnancy parental BMI differentially impacts offspring OW/OB across the life course. For every unit increase in paternal and maternal BMI z-score, offspring BMI z-score increased, on average, by between 0.15% (kg m-2 ) and 0.24% (kg m-2 ) throughout all three stages of life when both parents were OW/OB; these associations were stronger than with one parent. Parental pre-pregnancy BMI and OW/OB is a strong predictor of offspring weight and BMI change from early life to adulthood. PMID- 28557383 TI - Editorial for Issue 2 in 2017. PMID- 28557384 TI - [Transcription factor p53 and skin aging]. AB - The review is devoted to an actual problem of cosmetics in gerontology, one of molecular aspects of skin aging. Cell renewal processes slow down with aging, and the proliferation apoptosis ratio shifts towards cell death. One of the most pivotal apoptotic markers is the transcription factor p53. p53 protein expression in the skin keratinocytes increases under the influence of ultraviolet radiation. Wherein when exposed to ultraviolet radiation mutant forms of p53 have been revealed in 70 % of keratinocytes. On the one hand, suppression of p53 expression decreases apoptosis in skin cells that slows down the process of aging. On the other hand, it promotes the development of tumors in the skin. Thus, maintaining the physiological balance of p53 expression in skin cells is important for the basic and practical cosmetic medicine in gerontology. In addition, p53 protein may be used as a functionality marker of skin cells when administered with geroprotective cosmetic means and instrumental cosmetology methods. PMID- 28557385 TI - [Telomere-telomerase system in aging, norm and pathology (literature review)]. AB - This literature review presents results of research showing association between functional activity of the telomere-telomerase system and mental cognitive and emotional processes in normal and various pathological states: chronic stress, depression, bipolar disorder, schizophrenia, mild cognitive impairment and dementia in aging. It also refers to age-specific, psycho-social, economic, immunological, genetic and epigenetic factors that influence these relationships. PMID- 28557386 TI - [Studying of the factors influencing biological age of long-livers of Almaty]. AB - The article presents the results of a study of centenarians (25 patients older than 90 years) residents of Almaty, suffering from coronary artery disease (CAD) of different severity, for the purpose of definition of biological age of CAD and identify factors influencing aging process. Significant positive correlation between the thickness of an intragastric partition and indexes of chronological age, due biological age was defined. We assume that the hypertrophy of walls of a left ventricle (LV) is the main morphological indicator of an aging of cardiovascular system. PMID- 28557387 TI - [Metabolic and hormonal indices in rats with prolonged model of metabolic syndrome induced by high-carbohydrate and high-fat diet]. AB - To develop the approaches for the prevention and treatment of metabolic syndrome (MS), a pathological state widespread in modern population, that involves a complex of metabolic and functional disorders, appropriate animal models of MS are required. One of these models is induced by the consumption of combined high carbohydrate and high-fat (HC/HF) diet consisting of excess amount of easily digestible carbohydrates and saturated fats. At the same time, the character, temporal dynamics and severity of metabolic abnormalities in MS induced by HC/HF diet are still poorly understood. The aim of work was the characterization of metabolic changes in Wistar rats with MS induced by 10- and 15-week HC/HF diet that includes the consumption of 30% sucrose solution (instead of drinking water) and food rich in saturated fats. Rats that received HC/HF diet for 15 weeks had a number of features characteristic of MS, such as increased body weight and content of abdominal fat, hyperglycemia, hyperinsulinaemia, impaired glucose tolerance, insulin resistance, dyslipidemia, as well as the markers of impaired function of the cardiovascular system (hyperhomocysteinemia, the reduced level of vasodilator nitric oxide, the increased concentration of vasoconstrictor endothelin 1). In rats, which were on the diet for 10 weeks, the metabolic abnormalities were less pronounced, indicating an insufficiency of 10-week duration of HC/HF diet for MS induction. Thus, the model of MS induced by 15-week HC/HF diet has the characteristic features that allow for extrapolation of the obtained data to similar pathologic changes in human, and can be used to study the etiology and pathogenesis of MS and the search of effective ways of MS prevention and treatment. PMID- 28557388 TI - [Effect of genetically coded amino acids and their precursors carboxylic acids on the cellular proliferation in the organotypic culture of spleen in young and old rats]. AB - Effect of carboxylic acids - structurally related to amino acids, on the proliferation activity of the cells in organotypic cultures of rat spleen was first studied. It was found that almost all aliphatic carboxylic acids have stimulating effects on proliferative activity of cells in young and old rats. In contrast only 3 from 14 active amino acids in young rats were able stimulate proliferation, but 11 amino acids inhibited it. In the old rats a number of the active amino acids was decreased until 4, an inhibiting effect was observed in 3 of them. Thus, the carboxylic acids are able to stimulate the regeneration processes in the immune tissue both in the young and old organisms. This fact can be a base for the research of new medical substances for the stimulation of the immunogenesis by the aging. PMID- 28557389 TI - [Role of ceramide in reduction of the cardiolipin content in the heart during aging]. AB - The close correlation between ceramide accumulation and cardiolipin content decrease in cardiomyocytes, mitochondrial dysfunction and heart failure was well documented. Taking into account that ceramide can alter the cardiolipin metabolism the purpose of the present study was to determine the role of ceramide in age-dependent decline of cardiolipin content in rat heart tissue. In the present work the puberty young, adult and old (3-, 12-, 24-, 30- and 34-month old) Wistar male rats were used. It has been shown, that cardiolipin content significantly decreased, while content of cardiolipin precursor, phosphatidic acid, increased during aging. Doxorubicin injection to the rats or isolated heart perfusion with the C16-ceramide-conteined buffer induced ceramide accumulation and cardiolipin level drop in the heart of 3-month-old rats. Treatment of 24 month-old rats with inhibitors of acid sphingomyelinase, melipramine and zoledronic acid, decreased the ceramide level and increased the cardiolipin content in the heart. The results obtained clearly demonstrated that the age related ceramide accumulation is closely associated with the loss of cardiolipin content and may lead to mitochondrial dysfunction in the heart at old age. Acid sphingomyelinase and cardiolipin metabolism can be important targets for treatment of age-dependent heart pathology. PMID- 28557390 TI - [The battery of tests for behavioral phenotyping of aging animals in the experiment]. AB - The purpose of the study was to develop a battery of tests to study social and cognitive impairments for behavioral phenotyping of aging experimental animals with physiological neurodegeneration. Object of the study were outbred CD1 mice in the following groups: 1st group - 12-month old male mice (physiological aging); 2nd group - 2-month old male mice (control group). Social recognition test, elevated plus maze test (EPM), open field test, light-dark box test, and Fear conditioning protocol were used to estimate the neurological status of experimental animals. We found that aging male mice in a contrast to young ones have demonstrated lower social interest to female mice in the social recognition task. EPM and light-dark box tests showed increased level of anxiety in the group of aged mice comparing to the control group. Fear conditioning protocol revealed impairment of associative learning and memory in the group of aged mice, particularly, fear memory consolidation was dramatically suppressed. Analysis of behavioral factors, social interactions and anxiety level in the experimental mice has confirmed age-related neurodegeneration in the 1st group. We found that the most informative approach to identifying neurological impairments in aging mice (social interaction deficit, limitation of interests, increased level of anxiety) should be based on the open field test light-dark box test, and Fear conditioning protocol. Such combination allows obtaining new data on behavioral alterations in the age-associated of neurodegeneration and to develop novel therapeutic strategies for the treatment of age-related brain pathology. PMID- 28557391 TI - [Age features peripheral link erythron rats and its status with experimental cardiosclerosis]. AB - Studied the performance of the peripheral unit erythrone rats aged 4 months (1st group) 12 months (2nd group) and 24 months (3rd group). Each age group (n=20) consisted of 10 intact animals and 10 animals c postinfarction cardiosclerosis (PICS). In the group of animals 24 months of age was showed an increase in the number of erythrocytes in the absence of difference in the amount of reticulocytes. Expressed anisocytosis and decrease in hemoglobin synthesis in animals of this age group suggests that the age-related disorders maturation of erythroid cells. The development of post-infarction myocardial remodeling has not affected polycythemia typical for animals of older age group. At the same time a significant increase in the reticulocyte count of peripheral blood smears was observed for this group of animals. Development of PICS for animals extreme age groups leads to a smoothing interage differences, noted in the animals in the intact condition. PMID- 28557392 TI - [Melatonin as a molecular marker of age-related pathologies]. AB - The review has described melatonin as a prognostic marker of invasive and non invasive diagnostic of organism aging time and age-related pathology. Decreasing of melatonin level in buccal cells has correlated with patient age. Melatonin level in patients with Alzheimer disease has decreased. Melatonin level in blood plasma has correlated with severity of menopausal syndrome. Melatonin secretion in enterocytes increased during gastric ulcer. In oncology patients was described changes of 6-COMT - metabolite of melatonin in urine in dependent of histology type and stage of disease. Thus, melatonin is the molecular marker, which characterized integral processes in neuro-immuno-endocrine system and can be verified by non-invasive methods in peripheral tissues and biological fluids of organism. PMID- 28557393 TI - [Melatonin as a marker of the grade of cardiac disorders during cachexia development in oncological patients of different ages]. AB - We have examined 103 patients at the age from 28 to 78 with the newly diagnosed oncological disease at stages II-IV before the beginning of anticancer treatment. The identification of the signs of the cachexia syndrome and its stage (pre cachexia, cachexia) were carried out in the accordance with the CASCO criteria (2011) and taking into the account the age of the patients. The cardiovascular infringements were found to be comorbid to the oncological disease significantly more often in patients with signs of cachexia syndrome on the pre-cachexia stage and the total index of cardiovascular disorders in oncological patients increases with the severity of cachexia. In the course of the cachexia symptoms development the significant decline of melatonin excretion level (evaluated by the excretion of its main metabolite 6-sulfatoximelatonin level - aMT6s) in oncological patients was noted. The lowest changes in aMT6s levels were observed in patients older than 60 years, referred to the group of pre-cachexia, which may indicate the heterogeneity of the investigated groups as a result of the combination of manifestations of geriatric syndromes and cancer pathology. The possibility of false-positive diagnosis of pre-cachexia due to a combination of polygenic metabolic and age-related changes in elderly patients should be taken into account. Therefore, evaluation of melatonin excretion can be recommended as an additional marker in diagnosis and differential diagnosis of cachexia syndrome particularly in geriatric patients. A significant correlation between the occurrence and/or worsening of cardiac disease in cancer patients, cachexia symptoms and reduced level of aMT6s were revealed. PMID- 28557394 TI - [Age-related changes of peripheral nerve system and muscles of the limbs in healthy persons]. AB - Our aim was to present and analyze age-related changes of peripheral nerves and muscles of limbs on a huge population of healthy persons of different ages. Persons aged from 2 months to 87 years were studied by conduction studies (EMG) during the period 2009-2016 years in Scientific Research Institute of Children's Infection. Data of those 1 121confirmed healthy was included in our study. Conduction along n. Medianus, n. Ulnaris, n. Musculocutaneus, n. Axillaris, n. Facialis, n. Tibialis, n. Peroneus et n. Femoralis was registered, with latency and amplitude of compound muscle action potential (CMAP) being analyzed. There were significant differences on latencies and amplitudes of CMAPs between different age groups. Significant lengthening of CMAP latency was registered in older age groups. We marked CMAP amplitude increase from the early childhood until adolescence and later it dropped in persons aged 55 years old and older. These changes may reflect, concerning latency, the lengthening of the peripheral nerves in the age 0-25 years, and later on age-related slowing of conduction starting from 55 years. Amplitude of CMAP may rise with the growing of muscles and drop in later life with age-related muscle atrophy and fibrous changes. PMID- 28557395 TI - [Analysis of the clinical efficacy of fasetoplasty method for the treatment of facet syndrome at lumbar spine in patients with middle and old age group]. AB - The aim of the study was to analyze results of using of fasetoplasty method in the treatment of facet-syndrome at lumbar spine in patients with middle and old age groups. The study included 227 patients older than 65 years with degenerative dystrophic diseases of the lumbosacral spine and the clinical manifestations in the form of a facet syndrome, which in the period from 2010 to 2013 years made fasetoplasty prosthesis of synovial fluid. To assess the clinical effectiveness of using a visual analogue scale of pain (VAS) and a questionnaire for patients with back problems in Oswestry. The dynamic assessment was performed within the time frame to 30 months after surgery. The study found that the puncture facet joints with intra-articular injections of the prosthesis of the synovial fluid - "fasetoplasty" is an effective minimally invasive treatment for facet syndrome, caused by degenerative-dystrophic lesions facet joints of lumbar spine, allowing early and late postoperative periods to conduct sustained a significant decrease in the level of pain and improve the quality of life in a group of elderly patients. PMID- 28557396 TI - [Age peculiarities in prostate cancer detection based on the prostate-specific antigen and its alterations control]. AB - Data on epidemiology of a prostate cancer are presented in article, high prevalence and body height of a case rate cause relevance of researches on this oncopathology. It is shown that the number augmentation for the first time of the taped cases is bound including to the program of a screening of inspection of men by determination of level of prostates-specific antigen (PSA). Modern diagnostic methods of identification of modifications of PSA, possessing larger sensitivity and specificity concerning a prostate cancer are lit. The attention to change of level of PSA depending on age is focused that needs to be considered at diagnostics of malignant neoplasms of a prostate. PMID- 28557397 TI - [Study into ratios of mineral metabolism in patients of different age groups suffering from osteoarthritis of the knee]. AB - A study has been made into indicators of electrolyte composition and phosphatase activity of blood serum, urine and synovial fluid of the patients belonging to different age groups and going through compensated, subcompensated and decompensated stages of osteoarthritis of the knee. Changes in parameters of mineral metabolism have been detected related to the progress of the disease. The most obvious alteration was discovered in patients of the second age group having the subcompensated osteoarthritis stage. Elderly patients at the decompensated stage showed shifts of indicators of the bone remodeling. PMID- 28557398 TI - [Characteristic of the cognitive evoked potentials at elderly people with cognitive decline]. AB - Results of research of cognitive visual evoked potentials at elderly women with various level of cognitive decline are shown in article. Both relevance of the early diagnostics of cognitive disorders and expedience of using of methods of functional neurovisualization to reveal higher cortical dysfunctions are shown also. To appraise cognitive functions we applied express-method of evaluating of cognitive functions during normal aging. According to results of this test two groups were created: the 1st - women without cognitive disorders, the 2nd - with mild cognitive impairment. The evoked potentials were registered for all participants with using of 128-channel system GES-300. Latency of P300-wave and reaction time were calculated. According to temporary characteristics of P300 wave it has been revealed that the group with cognitive decline differed in longer latent period in centro-temporo-parietal area of the left hemisphere, and also longer reaction time. However, latency of P300 in central-parietal areas of the right hemisphere was less than one at persons of the control group. These changes reflect dysfunction of structures of a medial temporal lobe which is expressed mainly by the memory disorders. PMID- 28557399 TI - [The role of free-radical oxidation for patogenesis of chronic generalization periodontitis in elderly age patients]. AB - In old aged patients with chronic generalized periodontitis and cardiovascular diseases the level lipoperoxidation increased and antioxidation protection decreased in saliva and blood. After the course of treatment myocardial ischemia and diseases chronic periodontal inflammation the level of lipoperoxidation was changed insignificant accompanied with decreased of TBK-active substance in saliva and blood. Change of nitric oxide after by treatment was depended it initial level before treatment and often had an opposite orientation. PMID- 28557400 TI - [The effectiveness of hearing aids in elderly people]. AB - The analysis of factors which influence on the hearing aid efficacy in elderly with presbycusis is presented in the article. 125 patients from 60 to 90 years old with moderate to severe hearing loss, hearing aid users, were examined. The audiology examination included standard methods as well as tests evaluating central auditory pathways processing. According to the results of speech audiometry in free field low efficacy of hearing aid is revealed in 21 % patients. The main factor that decreases hearing aid benefit is the presence of central auditory processing disorders, the additional one is poor technical characteristics of a hearing aid. To increase hearing aid benefit in elderly the correction of central auditory processing disorders, rational hearing aid fitting according to individual features of auditory system and help in adaptation to hearing aid using are required. PMID- 28557401 TI - [Personal response to disease at paresthesia oral mucosa]. AB - A study related to the disease in 39 (7 men and 32 women) people aged 61-86 years, suffering from paresthesia oral mucous membranes (POMM). To determine the type of relationship to the patient's illness was used clinical test method which employs a clinical-psychological typology of relationship to the patient's illness. It was found that for patients with middle and old age (69,2 %), suffering from severe and moderate POMM severity of pathology characteristic intrapsychic focus of personal response to the disease, is caused due to the presence of a constant burning sensation in the mouth, often accompanied by the syndrome of "dry mouth" violation of social adaptation of patients. For the older age groups suffering POMM, which proceeded in a light, at least moderate disease severity (28,2 %) is characteristic orientation interpsychic personal response to the disease, also causes disturbances of social adaptation of patients. The obtained information about the type of relationship the patients of elderly and senile age, suffering POMM show that to achieve a positive therapeutic outcome and successful rehabilitation is necessary to change their existing inadequate response to disease, it is possible by attracting clinical pharmacologist and (or) the therapist. PMID- 28557403 TI - [Improved management of patients in the detection of fluid in the uterine cavity during ultrasound examination of small pelvis in postmenopausal women]. AB - In carrying out preventive ultrasound in postmenopausal often reveals the presence of fluid in the uterine cavity and exhibiting as serozometra, whereby the patient is sent to the gynecological hospital to perform hysteroscopy. The analysis of 55 case histories of patients with serozometra treated in gynecological departments of Volgograd 2013-2015 years. The findings suggest that serozometra the majority (82,4 %) of the cases is not accompanied by endometrial pathology , thus intrauterine intervention was performed unfounded. In identifying serozometra advisable dynamic observation, followed by the need to address the issue of hysteroscopy. PMID- 28557402 TI - [Dosed walking efficacy in the complex correction of cognitive impairment in elderly patients]. AB - The dosed walking efficacy with including the cognitive training as the component of complex therapy of mild and moderate dementia was examined in elderly patients with the probable Alzheimer's disease and mixed dementia. It was stated that dosed walking with cognitive training interventions improved cognitive performance in patients with probable Alzheimer's disease to a greater extent as compared to a single medical therapy and patients with mixed dementia probably due to severe structural changes of the brain. Female patients showed more advantageous health outcome. PMID- 28557404 TI - [The presence of anti-allergic antihistamines for consumers in older age groups]. AB - The work investigated the availability of the antihistamines for consumers aged 45 years and older. The main factors reducing accessibility: self-healing, low frequency of references to the doctor if you have allergic reactions, failure to comply with medical appointments, low level of awareness about the use and side effects. PMID- 28557405 TI - [Indicators of comorbidity in chronic broncho-obstructive pathology]. AB - We studied the problem of comorbidity in hospitalized patients with chronic obstructive pulmonary disease (COPD) and bronchial asthma (control group). When conducting correlation and regression analysis also showed the existence of a close direct relationship between the comorbidity index and age in patients with chronic broncho-obstructive pathology. Summary comorbidity index, patients with chronic obstructive pulmonary disease significantly more than in 2 times differ from those of the comparison group. There was revealed the increase of the comorbidity index with an increase in the severity of chronic obstructive pulmonary disease, as well as the weighting of the forecast mortality within 3 years in COPD compared with bronchial asthma. PMID- 28557411 TI - Initiation of Targeted Nanodrug Delivery in Vivo by a Multifunctional Magnetic Implant. AB - Implant-mediated targeted drug delivery without an external magnetic field is very challenging. In this work, we report targeted nanodrug delivery initiated by a Fe3O4/poly(lactic-co-glycolic acid) implant scaffold with high magnetism. The implant scaffold is biocompatible and durable. It effectively attracts nanodrugs to its surface, thus killing cancer cells. These findings provide a proof of concept for the magnetic implant-directed nanodrug targeting without the need for an external magnetic field. This approach may further facilitate more precise medical treatments. PMID- 28557412 TI - Image-Guided Hydrogen Gas Delivery for Protection from Myocardial Ischemia Reperfusion Injury via Microbubbles. AB - Cardiomyocyte death induced by ischemia-reperfusion is a major cause of morbidity and mortality worldwide. Hydrogen (H2), as an antioxidant, has been shown to have great potential in preventive and therapeutic applications against lethal injury that occurs from ischemia-reperfusion. However, H2 is sparingly soluble in water, resulting in its poor bioavailability in blood and damaged tissues. Here, we have developed an ultrasound-visible H2 delivery system by loading H2 inside microbubbles (H2-MBs) to prevent myocardial ischemia-reperfusion injury. Using this system, the concentration of H2 in unit volume can be greatly improved under normal temperature and pressure conditions. H2-MBs can be visually tracked with ultrasound imaging systems and can effectively release their therapeutic gas. In vivo systemic delivery of H2-MBs in myocardial ischemic rats at the start of reperfusion resulted in a significant reduction of infarct size and pathological remodeling. Further analysis showed that this approach markedly inhibited cardiomyocyte apoptosis and reduced myocardial inflammation and oxidant damage in myocardial ischemia-reperfusion rats. These results indicate that H2-MBs are a promising visual delivery system for H2-based therapeutic applications. PMID- 28557413 TI - Manufacturing Te/PEDOT Films for Thermoelectric Applications. AB - In this work, flexible Te films have been synthesized by electrochemical deposition using PEDOT [poly(3,4-ethylenedioxythiophene)] nanofilms as working electrodes. The Te electrodeposition time was varied to find the best thermoelectric properties of the Te/PEDOT double layers. To show the high quality of the Te films grown on PEDOT, the samples were analyzed by Raman spectroscopy, showing the three Raman active modes of Te: E1, A1, and E2. The X-ray diffraction spectra also confirmed the presence of crystalline Te on top of the PEDOT films. The morphology of the Te/PEDOT films was studied using scanning electron microscopy, showing a homogeneous distribution of Te along the film. Also an atomic force microscope was used to analyze the quality of the Te surface. Finally, the electrical conductivity and the Seebeck coefficient of the Te/PEDOT films were measured as a function of the Te deposition time. The films showed an excellent thermoelectric behavior, giving a maximum power factor of about 320 +/- 16 MUW m-1 K-2 after 2.5 h of Te electrochemical deposition, a value larger than that reported for thin films of Te. Qualitative arguments to explain this behavior are given in the discussion. PMID- 28557414 TI - Enhanced Cycle Stability of Rechargeable Li-O2 Batteries by the Synergy Effect of a LiF Protective Layer on the Li and DMTFA Additive. AB - Li metal is an ideal anode for rechargeable Li-O2 batteries because of its large theoretical capacity (3860 mAh g-1). However, problems with the growth of dendrites and reaction with electrolytes and moisture during cycling have prevented its practical application. Herein, we report that the use of a 2 wt % N,N-dimethyltrifluoroacetamide (DMTFA) additive in a dimethyl sulfoxide (DMSO) electrolyte with a LiF layer on the Li anode allows for good cycling performance in Li-O2 batteries. Indeed, a Li-O2 cell with a multiwalled carbon nanotube (MWCNT) cathode, 1.0 M LiNO3/DMTFA + DMSO (2:98 v/v) electrolyte, and a LiF layer on the Li anode could be cycled 92 times at a current density of 1000 mA g-1 with a 1000 mAh g-1. PMID- 28557415 TI - Ab Initio Modeling of Electrolyte Molecule Ethylene Carbonate Decomposition Reaction on Li(Ni,Mn,Co)O2 Cathode Surface. AB - Electrolyte decomposition reactions on Li-ion battery electrodes contribute to the formation of solid electrolyte interphase (SEI) layers. These SEI layers are one of the known causes for the loss in battery voltage and capacity over repeated charge/discharge cycles. In this work, density functional theory (DFT) based ab initio calculations are applied to study the initial steps of the decomposition of the organic electrolyte component ethylene carbonate (EC) on the (1014) surface of a layered Li(Nix,Mny,Co1-x-y)O2 (NMC) cathode crystal, which is commonly used in commercial Li-ion batteries. The effects on the EC reaction pathway due to dissolved Li+ ions in the electrolyte solution and different NMC cathode surface terminations containing adsorbed hydroxyl -OH or fluorine -F species are explicitly considered. We predict a very fast chemical reaction consisting of an EC ring-opening process on the bare cathode surface, the rate of which is independent of the battery operation voltage. This EC ring-opening reaction is unavoidable once the cathode material contacts with the electrolyte because this process is purely chemical rather than electrochemical in nature. The -OH and -F adsorbed species display a passivation effect on the surface against the reaction with EC, but the extent is limited except for the case of OH bonded to a surface transition metal atom. Our work implies that the possible rate-limiting steps of the electrolyte molecule decomposition are the reactions on the decomposed organic products on the cathode surface rather than on the bare cathode surface. PMID- 28557416 TI - Hot-Chemistry Structural Phase Transformation in Single-Crystal Chalcogenides for Long-Life Lithium Ion Batteries. AB - Tuned chalcogenide single crystals rooted in sulfur-doped graphene were prepared by high-temperature solution chemistry. We present a facile route to synthesize a rod-on-sheet-like nanohybrid as an active anode material and demonstrate its superior performance in lithium ion batteries (LIBs). This nanohybrid contains a nanoassembly of one-dimensional (1D) single-crystalline, orthorhombic SnS onto two-dimensional (2D) sulfur-doped graphene. The 1D nanoscaled SnS with the rodlike single-crystalline structure possesses improved transport properties compared to its 2D hexagonal platelike SnS2. Furthermore, we blend this hybrid chalcogenide with biodegradable polymer composite using water as a solvent. Upon drying, the electrodes were subjected to heating in vacuum at 150 degrees C to induce polymer condensation via formation of carboxylate groups to produce a mechanically robust anode. The LIB using the as-developed anode material can deliver a high volumetric capacity of ~2350 mA h cm-3 and exhibit superior cycle stability over 1500 cycles as well as a high capacity retention of 85% at a 1 C rate. The excellent battery performance combined with the simplistic, scalable, and green chemistry approach renders this anode material as a very promising candidate for LIB applications. PMID- 28557417 TI - Pseudocapacitive Characteristics of Low-Carbon Silicon Oxycarbide for Lithium-Ion Capacitors. AB - Lithium-ion capacitors (LICs) and lithium-ion batteries (LIBs) are important energy storage devices. As a material with good mechanical, thermal, and chemical properties, low-carbon silicon oxycarbide (LC-SiOC), a kind of silicone oil derived SiOC, is of interest as an anode material, and we have examined the electrochemical behavior of LC-SiOC in LIB and LIC devices. We found that the lithium storage mechanism in LC-SiOC, prepared by pyrolysis of phenyl-rich silicon oil, depends on an oxygen-driven rather than a carbon-driven mechanism within our experimental scope. An investigation of the electrochemical performance of LC-SiOC in half- and full-cell LIBs revealed that LC-SiOC might not be suitable for full-cell LIBs because it has a lower capacity (238 mAh g-1) than that of graphite (290 mAh g-1) in a cutoff voltage range of 0-1 V versus Li/Li+, as well as a substantial irreversible capacity. Surprisingly, LC-SiOC acts as a pseudocapacitive material when it is tested in a half-cell configuration within a narrow cutoff voltage range of 0-1 V versus Li/Li+. Further investigation of a "hybrid" supercapacitor, also known as an LIC, in which LC-SiOC is coupled with an activated carbon electrode, demonstrated that a power density of 156 000 W kg-1 could be achieved while maintaining an energy density of 25 Wh kg-1. In addition, the resulting capacitor had an excellent cycle life, holding ~90% of its energy density even after 75 000 cycles. Thus, LC SiOC is a promising active material for LICs in applications such as heavy-duty electric vehicles. PMID- 28557418 TI - Enhancing Photocatalytic Activity of Graphitic Carbon Nitride by Codoping with P and C for Efficient Hydrogen Generation. AB - The generation of clean hydrogen gas from photocatalytic water splitting by using graphitic carbon nitride (g-C3N4) as the photocatalyst has attracted considerable research interest. For practical applications, however, the photocatalytic activity of g-C3N4 needs to be further improved by, for example, band gap engineering through heteroatom doping. In this study, we found that doping of carbon nitride with carbon and phosphorus (P) could tune energy level of the conduction band. Subsequent hydrothermal treatment led to an increase in the specific surface area from 24.9 up to 141.1 m2 g-1, which was accompanied by increasing C concentration of the resultant C, P-doped g-C3N4 to reduce the hole electron recombination and enhance the conductivity. Consequently, the C, P codoped g-C3N4 (i.e., CPCN-1*) exhibited a much enhanced photocatalytic activity for efficient generation of H2 by photocatalytic water splitting under visible light irradiation (1493.3 MUmol g-1 h-1-about 9.7 times enhancement from that of bulk g-C3N4). PMID- 28557420 TI - Enhancing the Properties of Conductive Polymer Hydrogels by Freeze-Thaw Cycles for High-Performance Flexible Supercapacitors. AB - We report that a postsynthesis physical process (freeze-thaw cycles) can reform the microstructure of conductive polymer hydrogels from clustered nanoparticles to interconnected nanosheets, leading to enhanced mechanical and electrochemical properties. The polyaniline-poly(vinyl alcohol) hydrogel after five freeze-thaw cycles (PPH-5) showed remarkable tensile strength (16.3 MPa), large elongation at break (407%), and high electrochemical capacitance (1053 F.g-1). The flexible supercapacitor based on PPH-5 provided a large capacitance (420 mF.cm-2 and 210 F.g-1) and high energy density (18.7 W.h.kg-1), whose robustness was demonstrated by its 100% capacitance retention after 1000 galvanostatic charge-discharge cycles or after 1000 mechanical folding cycles. The outstanding performance enables PPH-5 based supercapacitor as a promising power device for flexible electronics, which also demonstrates the merit of freeze-thaw cycles for enhancing the performance of functional hydrogels. PMID- 28557419 TI - PEGylated GdF3:Fe Nanoparticles as Multimodal T1/T2-Weighted MRI and X-ray CT Imaging Contrast Agents. AB - Contrast agents for multimodal imaging are in high demand for cancer diagnosis. To date, integration of T1/T2-weighted magnetic resonance imaging (MRI) and X-ray computed tomography (CT) imaging capabilities in one system to obtain an accurate diagnosis still remains challenging. In this work, biocompatible PEGylated GdF3:Fe nanoparticles (PEG-GdF3:Fe NPs) were reasonable designed and synthesized as multifunctional contrast agents for efficient T1/T2-weighted MRI and X-ray CT multimodal imaging. Owing to the enhanced permeability and retention effect in vivo, strong T1 contrast, evident T2 contrast, and X-ray CT signals in a tumor lesion can be observed after intravenous injection of PEG-GdF3:Fe NPs. Therefore, PEG-GdF3:Fe NPs could be used as potential multimodal contrast agents for cancer diagnosis. PMID- 28557422 TI - Guest Induced Strong Cooperative One- and Two-Step Spin Transitions in Highly Porous Iron(II) Hofmann-Type Metal-Organic Frameworks. AB - The synthesis, crystal structure, magnetic, calorimetric, and Mossbauer studies of a series of new Hofmann-type spin crossover (SCO) metal-organic frameworks (MOFs) is reported. The new SCO-MOFs arise from self-assembly of FeII, bis(4 pyridyl)butadiyne (bpb), and [Ag(CN)2]- or [MII(CN)4]2- (MII = Ni, Pd). Interpenetration of four identical 3D networks with alpha-Po topology are obtained for {Fe(bpb)[AgI(CN)2]2} due to the length of the rod-like bismonodentate bpb and [Ag(CN)2]- ligands. The four networks are tightly packed and organized in two subsets orthogonally interpenetrated, while the networks in each subset display parallel interpenetration. This nonporous material undergoes a very incomplete SCO, which is rationalized from its intricate structure. In contrast, the single network Hofmann-type MOFs {Fe(bpb)[MII(CN)4]}.nGuest (MII = Ni, Pd) feature enhanced porosity and display complete one-step or two-step cooperative SCO behaviors when the pores are filled with two molecules of nitrobenzene or naphthalene that interact strongly with the pyridyl and cyano moieties of the bpb ligands via pi-pi stacking. The lack of these guest molecules favors stabilization of the high-spin state in the whole range of temperatures. However, application of hydrostatic pressure induces one- and two-step SCO. PMID- 28557423 TI - Systematic Investigation of Controlled Nanostructuring of Mn12 Single-Molecule Magnets Templated by Metal-Organic Frameworks. AB - This is the first systematic study exploring metal-organic frameworks (MOFs) as platforms for the controlled nanostructuring of molecular magnets. We report the incorporation of seven single-molecule magnets (SMMs) of general composition [Mn12O12(O2CR)16(OH2)4], with R = CF3 (1), (CH3)CCH2 (2), CH2Cl (3), CH2Br (4), CHCl2 (5), CH2But (6), and C6H5 (7), into the hexagonal channel pores of a mesoporous MOF host. The resulting nanostructured composites combine the key SMM properties with the functional properties of the MOF. Synchrotron-based powder diffraction with difference envelope density analysis, physisorption analysis (surface area and pore size distribution), and thermal analyses reveal that the well-ordered hexagonal structure of the host framework is preserved, and magnetic measurements indicate that slow relaxation of the magnetization, characteristic of the corresponding Mn12 derivative guests, occurs inside the MOF pores. Structural host-guest correlations including the bulkiness and polarity of peripheral SMM ligands are discussed as fundamental parameters influencing the global SMM@MOF loading capacities. These results demonstrate that employing MOFs as platforms for the nanostructuration of SMMs is not limited to a particular host-guest system but potentially applicable to a multitude of other molecular magnets. Such fundamental findings will assist in paving the way for the development of novel advanced spintronic devices. PMID- 28557421 TI - Cu(I) Disrupts the Structure and Function of the Nonclassical Zinc Finger Protein Tristetraprolin (TTP). AB - Tristetraprolin (TTP) is a nonclassical zinc finger (ZF) protein that plays a key role in regulating inflammatory response. TTP regulates cytokines at the mRNA level by binding to AU-rich sequences present at the 3'-untranslated region, forming a complex that is then degraded. TTP contains two conserved CCCH domains with the sequence CysX8CysX5CysX3His that are activated to bind RNA when zinc is coordinated. During inflammation, copper levels are elevated, which is associated with increased inflammatory response. A potential target for Cu(I) during inflammation is TTP. To determine whether Cu(I) binds to TTP and how Cu(I) can affect TTP/RNA binding, two TTP constructs were prepared. One construct contained just the first CCCH domain (TTP-1D) and serves as a peptide model for a CCCH domain; the second construct contains both CCCH domains (TTP-2D) and is functional (binds RNA) when Zn(II) is coordinated. Cu(I) binding to TTP-1D was assessed via electronic absorption spectroscopy titrations, and Cu(I) binding to TTP-2D was assessed via both absorption spectroscopy and a spin filter/inductively coupled plasma mass spectrometry (ICP-MS) assay. Cu(I) binds to TTP-1D with a 1:1 stoichiometry and to TTP-2D with a 3:1 stoichiometry. The CD spectrum of Cu(I)-TTP-2D did not exhibit any secondary structure, matching that of apo-TTP-2D, while Zn(II)-TTP-2D exhibited a secondary structure. Measurement of RNA binding via fluorescence anisotropy revealed that Cu(I)-TTP-2D does not bind to the TTP-2D RNA target sequence UUUAUUUAUUU with any measurable affinity, while Zn(II)-TTP-2D binds to this site with nanomolar affinity. Similarly, addition of Cu(I) to the Zn(II)-TTP-2D/RNA complex resulted in inhibition of RNA binding. Together, these data indicate that, while Cu(I) binds to TTP-2D, it does not result in a folded or functional protein and that Cu(I) inhibits Zn(II)-TTP 2D/RNA binding. PMID- 28557424 TI - Carbon Dioxide as a Traceless Caramelization Promotor: Preparation of Prebiotic Difructose Dianhydrides (DFAs)-Enriched Caramels from d-Fructose. AB - Activation of a concentrated solution of d-fructose with carbonic acid, generated from carbon dioxide, induces the formation of difructose dianhydrides (DFAs) and their glycosylated derivatives (glycosyl-DFAs), a family of prebiotic oligosaccharides. Under optimized conditions, up to 70% of the active DFA species were obtained from a highly concentrated solution of fructose, avoiding the filtration step and contamination risk associated with the current procedures that employ heterogeneous catalysis with acid ion-exchange resins. The optimized CO2-promoted preparation of DFA-enriched caramel described here has been already successfully scaled up to 150 kg of d-fructose for nutritional studies, showing that implementation of this process is possible at a larger scale. PMID- 28557425 TI - Crystal Structure and Lithium Diffusion Pathways of a Potential Positive Electrode Material for Lithium-Ion Batteries: Li2VIII(H0.5PO4)2. AB - A new potentially interesting material as a positive electrode for lithium-ion batteries, Li2VIII(H0.5PO4)2, was obtained by hydrothermal synthesis. Its crystal structure was solved thanks to single-crystal X-ray diffraction. This material is isostructural to Li2FeIII(PO4)(HPO4) and also closely related to Li2FeII(SO4)2. It can be described as a VO6 octahedron sharing corners with six PO4 tetrahedra to form a 3D framework. One oxygen atom of each phosphate group is unshared with a vanadium octahedron and as such linked to a hydrogen atom. The arrangement of these polyhedra generates large channels running along [100] in which lithium cations are located. The close structural relationship between Li2FeIII(PO4)(HPO4) and Li2FeII(SO4)2 allows one to investigate, by comparison, the effect of the hydrogen atoms lying on lithium diffusion pathways. PMID- 28557426 TI - Sodium Diisopropylamide: Aggregation, Solvation, and Stability. AB - The solution structures, stabilities, physical properties, and reactivities of sodium diisopropylamide (NaDA) in a variety of coordinating solvents are described. NaDA is stable for months as a solid or as a 1.0 M solution in N,N dimethylethylamine (DMEA) at -20 degrees C. A combination of NMR spectroscopic and computational studies show that NaDA is a disolvated symmetric dimer in DMEA, N,N-dimethyl-n-butylamine, and N-methylpyrrolidine. Tetrahydrofuran (THF) readily displaces DMEA, affording a tetrasolvated cyclic dimer at all THF concentrations. Dimethoxyethane (DME) and N,N,N',N'-tetramethylethylenediamine quantitatively displace DMEA, affording doubly chelated symmetric dimers. The trifunctional ligands N,N,N',N",N"-pentamethyldiethylenetriamine and diglyme bind the dimer as bidentate rather than tridentate ligands. Relative rates of solvent decompositions are reported, and rate studies for the decomposition of THF and DME are consistent with monomer-based mechanisms. PMID- 28557427 TI - Metabolomics Approach To Evaluate a Baltic Sea Sourced Diet for Cultured Arctic Char (Salvelinus alpinus L.). AB - Aqua feeds traditionally rely on fishmeal as a protein source, which is costly and unsustainable. A new feed was formulated in the study with Baltic Sea sourced decontaminated fishmeal, Mytilus edulis and Saccharomyces cerevisiae, and given to Arctic char (Salvelinus alpinus) for ten months. The diet-induced changes on metabolic profile in fish plasma, liver, and muscle were studied relative to a fishmeal-based standard diet by using a 1H NMR-based metabolomics approach. Fish fed the test diet had higher content of betaine and lower levels of trimethylamine-N-oxide and aromatic amino acids in plasma or tissues, which were mainly caused by the diet. The metabolomics results are useful to understand the mechanism of lower body mass, smaller Fulton's condition factor, and a tendency of less lipid content observed in fish fed the test diet. Thus, modifications on the dietary levels of these compounds in the feed are needed to achieve better growth performance. PMID- 28557428 TI - Oxime-Based and Catalyst-Free Dynamic Covalent Polyurethanes. AB - Polyurethanes (PUs) have many applications resulting from their preeminent properties, but being commonly used toxic catalysts, and the lack of processability for PU thermosets cause limitations. Herein, we report a new class of the PU-like dynamic covalent polymers, poly(oxime-urethanes) (POUs), which are prepared from the uncatalyzed polyaddition of multifunctional oximes and hexamethylene diisocyanate (HDI) at ambient temperature. Kinetics studies reveal that almost complete polymerization (~99% conversion) can be achieved in 3 h at 30 degrees C in dichloromethane (DCM), the most effective among the solvents evaluated, producing linear POUs with comparable molecular weights to the catalyzed PUs. We find that the oxime-carbamate structures are reversible at about 100 degrees C through oxime-enabled transcarbamoylation via a thermally dissociative mechanism. The cross-linked POUs based on oxime-carbamate bonds show efficient catalyst-free healable/recyclable properties. Density functional theory (DFT) calculations suggest that the fast oxime-urethanation and the mild thermoreversible nature are mediated by the characteristic nitrone tautomer of the oxime. Given widespread urethane-containing materials, POUs are of promising potential in applications because of the excellent mechanical performances, facile preparation, and dynamic property without using catalysts. PMID- 28557429 TI - Comparative Proteome Analysis between High Lipid-Producing Strain Mucor circinelloides WJ11 and Low Lipid-Producing Strain CBS 277.49. AB - Mucor circinelloides is one of few oleaginous fungi that produces a useful oil rich in gamma-linolenic acid, but it usually only produces <25% total lipid. Nevertheless, we isolated a new strain WJ11 that can produce up to 36% lipid of cell dry weight. In this study, we have systematically analyzed the global changes in protein levels between the high lipid-producing strain WJ11 and the low lipid-producing strain CBS 277.49 (15%, lipid/cell dry weight) at lipid accumulation phase through comparative proteome analysis. Proteome analysis demonstrated that the branched-chain amino acid and lysine metabolism, glycolytic pathway, and pentose phosphate pathway in WJ11 were up-regulated, while the activities of tricarboxylic acid cycle and branch point enzyme for synthesis of isoprenoids were retarded compared with CBS 277.49. The coordinated regulation at proteome level indicate that more acetyl-CoA and NADPH are provided for fatty acid biosynthesis in WJ11 compared with CBS 277.49. PMID- 28557431 TI - Probabilistic Generation of Mass Spectrometry Molecular Abundance Variance for Case and Control Replicates. AB - Shotgun differential mass spectrometry, the untargeted discovery of statistically significant differences between two or more samples, is a popular application with potential to advance biomarker detection, disease diagnostics, and other health objectives. Although many methods have been proposed, few have been quantitatively evaluated. The lack of ground truth data for shotgun difference detection limits quantitative evaluation and algorithmic advancement. While public mass-spectrometry data sets of single samples abound, data sets with more than one sample are rare, and data sets with the thousands of samples necessary to capture the complexity of real world populations are nonexistent due to technological and cost limitations. We present MSabundanceSIM, novel software for simulating any number of molecular samples based on one or a few real world data sets. The software uses a probabilistic model to generate case and control populations, with intuitive user parameters for tuning. We demonstrate variability by comparing to a real world data set over a range of abundances with differing biological and experimental variation coefficients. MSabundanceSIM is implemented in Ruby, is freely available, requires no external dependencies, and is suitable for a range of applications. PMID- 28557430 TI - Identification of a Water-Soluble Indirubin Derivative as Potent Inhibitor of Insulin-like Growth Factor 1 Receptor through Structural Modification of the Parent Natural Molecule. AB - Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3'-position have been extensively investigated, but the impact of substituents in 5'-position is not equally well-studied. Here, we report the synthesis of new indirubin 3'- and 5' derivatives in the search of water-soluble indirubins by introducing basic centers. Antiproliferative activity of all compounds in tumor cells was evaluated along with kinase inhibition of selected compounds. The results show the 3' position to tolerate large substituents without compromising activity, whereas bulk and rigid substituents in 5'-position appear unfavorable. Screening molecular targets of water-soluble 3'-oxime ethers revealed 6ha as preferential inhibitor of insulin-like growth factor 1 receptor (IGF-1R) in a panel of 22 protein kinases and in cells. Consistently, 6ha inhibited tumor cell growth in the NCI 60 cell line panel and induced apoptosis. The results indicate that the 5'-position provides limited space for chemical modifications and identify 6ha as a potent water-soluble indirubin-based IGF-1R inhibitor. PMID- 28557432 TI - Self-Assembled TEMPO Cellulose Nanofibers: Graphene Oxide-Based Biohybrids for Water Purification. AB - Nanocellulose, graphene oxide (GO), and their combinations there off have attracted great attention for the application of water purification recently because of their unique adsorption capacity, mechanical characteristics, coordination with transition metal ions, surface charge density, and so on. In the current study, (2,2,6,6-tetramethylpiperidine-1-oxylradical) (TEMPO)-mediated oxidized cellulose nanofibers (TOCNF) and GO sheets or graphene oxide nanocolloid (nanoGO) biohybrids were prepared by vacuum filtration method to obtain self assembled adsorbents and membranes for water purification. The porous biohybrid structure, studied using advanced microscopy techniques, revealed a unique networking and self-assembling of TOCNF, GO, and nanoGO, driven by the morphology of the GO phase and stabilized by the intermolecular H-bonding between carboxyl groups and hydroxyl groups. The biohybrids exhibited a promising adsorption capacity toward Cu(II) due to TOCNF and formed a unique "arrested state" in water because of ionic cross-linking between adsorbed Cu(II) and the negatively charged TOCNF and GO phase. The mechanical performance of the freestanding biohybrid membranes investigated using PeakForce Quantative NanoMechanics characterization confirmed the enhanced modulus of the hybrid membrane compared to that of the TOCNF membrane. Besides, the TOCNF+nanoGO membrane shows unique hydrolytic stability and recyclability even under several cycles of adsorption and desorption and strong sonication. This study shows that TOCNF and nanoGO hybrids can generate new water-cleaning membranes with synergistic properties because of their high adsorption capacity, flexibility, hydrolytic stability, and mechanical robustness. PMID- 28557433 TI - Ligand-Mediated and Enzyme-Directed Precise Targeting and Retention for the Enhanced Treatment of Glioblastoma. AB - Glioblastoma (GBM), one of the most lethal cancers, remains as a hard task to handle. The major hurdle of nanostructured therapeutic agents comes from the limited retention at the GBM site and poor selectivity. In this study, we reported dual-functional gold nanoparticles (AuNPs) to figure out the biological barrier and improve their accumulation in GBM. The nanoparticles, AuNP-A&C-R, were composed of two functional particles: one was Ala-Ala-Asn-Cys-Asp (AK) and R8-RGD-comodified AuNPs (AuNP-AK-R) and the other was 2-cyano-6-amino benzothiazole and R8-RGD-comodified AuNPs (AuNP-CABT-R). AuNP-A&C-R could aggregate in the presence of legumain, resulting in a size increase from 41.4 +/- 0.6 to 172.9 +/- 10.2 nm after 8 h incubation. After entering the circulatory system, AuNP-A&C-R actively targeted the integrin alphavbeta3 receptor on blood brain barrier (BBB), mediated transcytosis of particles across BBB, and then targeted the receptor on the GBM cells. Once AuNP-A&C-R entered into GBM, they formed further aggregates with increased size extracellularly or intracellularly because of the overexpressed legumain, which in turn blocked their backflow to the bloodstream or limited their exocytosis by cells. In vivo optical imaging demonstrated that AuNP-A&C-R were efficiently delivered to the GBM site and retained with high selectivity. We further confirmed that AuNP-A&C-R acquired a higher accumulation at the GBM site than AuNP-A&C and AuNP-R because of the synergistic effect. More importantly, the doxorubicin (DOX)-loaded AuNP-A&C-R showed an improved chemotherapeutic effect to C6 GBM-bearing mice, which significantly prolonged the median survival time by 1.22-fold and 1.27-fold compared with the DOX-loaded AuNP-A&C and the DOX-loaded AuNP-R, respectively. These results suggested that the dual-functional nanoplatform is promising for the GBM treatment. PMID- 28557435 TI - Cross-linked Collagen Hydrogel Matrix Resisting Contraction To Facilitate Full Thickness Skin Equivalents. AB - Full-thickness skin equivalents are gathering increased interest as skin grafts for the treatment of large skin defects or chronic wounds or as nonanimal test platforms. However, their fibroblast-mediated contraction and poor mechanical stability lead to disadvantages toward their reproducibility and applicability in vitro and in vivo. To overcome these pitfalls, we aimed to chemically cross-link the dermal layer of a full-thickness skin model composed of a collagen type I hydrogel. Using a noncytotoxic four-arm succinimidyl glutarate polyethylene glycol (PEG-SG), cross-linking could be achieved in cell seeded collagen hydrogels. A concentration of 0.5 mg of PEG-SG/mg of collagen led to a viability comparable to non-cross-linked collagen hydrogels and no increased release of intracellular lactate dehydrogenase. Cross-linked collagen hydrogels were more mechanically stable and less prone to enzymatic degradation via collagenase when compared with non-cross-linked collagen hydrogels. Remarkably, during 21 days, cross-linked collagen hydrogels maintain their initial surface area, whereas standard dermal models contracted up to 50%. Finally, full-thickness skin equivalents were generated by seeding human epidermal keratinocytes on the surface of the equivalents and culturing these equivalents at an air-liquid interface. Immunohistochemical stainings of the cross-linked model revealed well defined epidermal layers including an intact stratum corneum and a dermal part with homogeneously distributed human dermal fibroblasts. These results indicate that cross-linking of collagen with PEG-SG reduces contraction of collagen hydrogels and thus increases the applicability of these models as an additional tool for efficacy and safety assessment or a new generation of skin grafts. PMID- 28557436 TI - Highly Sensitive Telomerase Assay Insusceptible to Telomerase and Polymerase Chain Reaction Inhibitors for Cervical Cancer Screening Using Scraped Cells. AB - A sensitive telomerase assay based on asymmetric-polymerase chain reaction (A PCR) on magnetic beads and subsequent application of cycling probe technology, STAMC, which is insusceptible to DNase and PCR inhibitors, was for the first time applied to clinical specimens in addition to a conventional telomeric repetitive amplification protocol (TRAP). The electrophoresis results showed that an increase in scraped cervical cancer cells not only reduced TRAP products but also increased smaller products, suggesting the unreliability of TRAP for clinical samples. To achieve the required sensitivity of STAMC for clinical application, the sequence and concentration conditions were explored for the forward and reverse primers for A-PCR, which resulted in a detection limit of only two HeLa cells with 1 MUM TS primer (5'-AATCCGTCGAGCAGAGTT-3') and 0.04 MUM ACX primer (5' GCGCGGCTTACCCTTACCCTTACCCTAACC-3'). Under the same primer conditions, the fluorescence signal of STAMC increased as scraped cervical cancer cells increased despite showing a negligible intensity for benign tumors. Furthermore, STAMC showed no signal for a cervical cancer patient treated with irradiation therapy. These results indicate that STAMC is useful for not only cervical cancer screening but also investigating the effect of cancer treatments such as radiation therapy and drug administration. PMID- 28557434 TI - Dual Targeting of WEE1 and PLK1 by AZD1775 Elicits Single Agent Cellular Anticancer Activity. AB - Inhibition of the WEE1 tyrosine kinase enhances anticancer chemotherapy efficacy. Accordingly, the WEE1 inhibitor AZD1775 (previously MK-1775) is currently under evaluation in clinical trials for cancer in combination with chemotherapy. AZD1775 has been reported to display high selectivity and is therefore used in many studies as a probe to interrogate WEE1 biology. However, AZD1775 also exhibits anticancer activity as a single agent although the underlying mechanism is not fully understood. Using a chemical proteomics approach, we here describe a proteome-wide survey of AZD1775 targets in lung cancer cells and identify several previously unknown targets in addition to WEE1. In particular, we observed polo like kinase 1 (PLK1) as a new target of AZD1775. Importantly, in vitro kinase assays showed PLK1 and WEE1 to be inhibited by AZD1775 with similar potency. Subsequent loss-of-function experiments using RNAi for WEE1 and PLK1 suggested that targeting PLK1 enhances the pro-apoptotic and antiproliferative effects observed with WEE1 knockdown. Combination of RNAi with AZD1775 treatment suggested WEE1 and PLK1 to be the most relevant targets for mediating AZD1775's anticancer effects. Furthermore, disruption of WEE1 by CRISPR-Cas9 sensitized H322 lung cancer cells to AZD1775 to a similar extent as the potent PLK1 inhibitor BI-2536 suggesting a complex crosstalk between PLK1 and WEE1. In summary, we show that AZD1775 is a potent dual WEE1 and PLK1 inhibitor, which limits its use as a specific molecular probe for WEE1. However, PLK1 inhibition makes important contributions to the single agent mechanism of action of AZD1775 and enhances its anticancer effects. PMID- 28557437 TI - Differentiating Physicochemical Properties between Addictive and Nonaddictive ADHD Drugs Revealed by Molecular Dynamics Simulation Studies. AB - Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed mental disorder of children and adolescents. Although psychostimulants are currently the first-line drugs for ADHD, their highly addictive profile raises great abuse concerns. It is known that psychostimulants' addictiveness is largely attributed to their interaction with dopamine transporter (DAT) and their binding modes in DAT can thus facilitate the understanding of the mechanism underlining drugs' addictiveness. However, no DAT residue able to discriminate ADHD drugs' addictiveness is identified, and the way how different drug structures affect their abuse liability is still elusive. In this study, multiple computational methods were integrated to differentiate binding modes between approved psychostimulants and ADHD drugs of little addictiveness. As a result, variation in energy contribution of 8 residues between addictive and nonaddictive drugs was observed, and a reduction in hydrophobicity of drugs' 2 functional groups was identified as the indicator of drugs' addictiveness. This finding agreed well with the physicochemical properties of 8 officially reported controlled substances. The identified variations in binding mode can shed light on the mechanism underlining drugs' addictiveness, which may thus facilitate the discovery of improved ADHD therapeutics with reduced addictive profile. PMID- 28557438 TI - Anti-inflammatory and Antibacterial Effects of Covalently Attached Biomembrane Mimic Polymer Grafts on Gore-Tex Implants. AB - Expanded polytetrafluoroethylene (ePTFE), also known as Gore-Tex, is widely used as an implantable biomaterial in biomedical applications because of its favorable mechanical properties and biochemical inertness. However, infection and inflammation are two major complications with ePTFE implantations, because pathogenic bacteria can inhabit the microsized pores, without clearance by host immune cells, and the limited biocompatibility can induce foreign body reactions. To minimize these complications, we covalently grafted a biomembrane-mimic polymer, poly(2-methacryloyloxylethyl phosphorylcholine) (PMPC), by partial defluorination followed by UV-induced polymerization with cross-linkers on the ePTFE surface. PMPC grafting greatly reduced serum protein adsorption as well as fibroblast adhesion on the ePTFE surface. Moreover, the PMPC-grafted ePTFE surface exhibited a dramatic inhibition of the adhesion and growth of Staphylococcus aureus, a typical pathogenic bacterium in ePTFE implants, in the porous network. On the basis of an analysis of immune cells and inflammation related factors, i.e., transforming growth factor-beta (TGF-beta) and myeloperoxidase (MPO), we confirmed that inflammation was efficiently alleviated in tissues around PMPC-grafted ePTFE plates implanted in the backs of rats. Covalent PMPC may be an effective strategy for promoting anti-inflammatory and antibacterial functions in ePTFE implants and to reduce side effects in biomedical applications of ePTFE. PMID- 28557439 TI - Spin-Polarized Tunneling through Chemical Vapor Deposited Multilayer Molybdenum Disulfide. AB - The two-dimensional (2D) semiconductor molybdenum disulfide (MoS2) has attracted widespread attention for its extraordinary electrical-, optical-, spin-, and valley-related properties. Here, we report on spin-polarized tunneling through chemical vapor deposited multilayer MoS2 (~7 nm) at room temperature in a vertically fabricated spin-valve device. A tunnel magnetoresistance (TMR) of 0.5 2% has been observed, corresponding to spin polarization of 5-10% in the measured temperature range of 300-75 K. First-principles calculations for ideal junctions result in a TMR up to 8% and a spin polarization of 26%. The detailed measurements at different temperature, bias voltages, and density functional theory calculations provide information about spin transport mechanisms in vertical multilayer MoS2 spin-valve devices. These findings form a platform for exploring spin functionalities in 2D semiconductors and understanding the basic phenomena that control their performance. PMID- 28557440 TI - Construction of Injectable Double-Network Hydrogels for Cell Delivery. AB - Herein we present a unique method of using dynamic cross-links, which are dynamic covalent bonding and ionic interaction, for the construction of injectable double network (DN) hydrogels, with the objective of cell delivery for cartilage repair. Glycol chitosan and dibenzaldhyde capped poly(ethylene oxide) formed the first network, while calcium alginate formed the second one, and in the resultant DN hydrogel, either of the networks could be selectively removed. The moduli of the DN hydrogel were significantly improved compared to that of the parent single network hydrogels and were tunable by changing the chemical components. In situ 3D cell encapsulation could be easily performed by mixing cell suspension to the polymer solutions and transferred through a syringe needle before sol-gel transition. Cell proliferation and mediated differentiation of mouse chondrogenic cells were achieved in the DN hydrogel extracellular matrix. PMID- 28557441 TI - Tyrosinase-Mediated Surface Coimmobilization of Heparin and Silver Nanoparticles for Antithrombotic and Antimicrobial Activities. AB - Thrombus and infections are the most common causes for the failure of medical devices, leading to higher hospitalization costs and, in some cases, patient morbidity. It is, therefore, necessary to develop novel strategies to prevent thrombosis and infection caused by medical devices. Herein, we report a simple and a highly efficient strategy to impart antithrombotic and antimicrobial properties to substrates, by simultaneously immobilizing heparin and in situ synthesized silver nanoparticles (Ag NPs) via a tyrosinase-catalyzed reaction. This consists of tyrosinase-oxidized phenolic groups of a heparin derivative (heparin-grafted tyramine, HT) to catechol groups, followed by immobilizing heparin and inducing the in situ Ag NP formation onto poly(urethane) (PU) substrates. The successful immobilization of both heparin and in situ Ag NPs on the substrates was confirmed by analyses of water contact angles, XPS, SEM, and AFM. The sustained silver release and the surface stability were observed for 30 days. Importantly, the antithrombotic potential of the immobilized surfaces was demonstrated by a reduction in fibrinogen absorption, platelet adhesion, and prolonged blood clotting time. Additionally, the modified PU substrates also exhibited remarkable antibacterial properties against both Gram-positive and Gram negative bacteria. The results of this work suggest a useful, effective, and time saving method to improve simultaneous antithrombotic and antibacterial performances of a variety of substrate materials for medical devices. PMID- 28557442 TI - Dry and Direct Deposition of Aerosol-Synthesized Single-Walled Carbon Nanotubes by Thermophoresis. AB - Single-walled carbon nanotubes (SWCNTs) show great potential as an active material in electronic and photonic devices, but their applicability is currently limited by shortcomings in existing deposition methods. SWCNTs can be dispersed from liquid solutions; however, their poor solubility requires the use of surfactants and ultrasonication, causing defects and degradation in device performance. Likewise, the high temperatures required by their chemical vapor deposition growth limit substrates on which SWCNTs can be directly grown. Here, we present a systematic study of the direct deposition of pristine, aerosol synthesized SWCNTs by thermophoresis. The density of the deposited nanotube film can be continuously adjusted from individual, separated nanotubes to multilayer thin films by changing the deposition time. Depending on the lateral flow inside the thermophoretic precipitator, the angular distribution of the deposited SWCNT film can be changed from uniform to nonuniform. Because the substrate is kept at nearly ambient temperature, deposition can be thus carried out on practically any flat substrate with high efficiencies close to unity. The thermophoretic terminal velocity of SWCNTs, determined by aerosol loss measurements, is found to be approximately one-third of the usual prediction in the free molecular regime and shows a weak dependence on the nanotube diameter. As a demonstration of the applicability of our technique, we have used thermophoretic deposition in the fabrication of carbon nanotube thin-film transistors with uniform electrical properties and a high, over 99.5%, yield. PMID- 28557443 TI - Synthesis of Heterocycle-Containing 9,9-Diarylfluorenes Using Superelectrophiles. AB - A superacid-promoted method for the synthesis of 9,9-diarylfluorenes is described. The chemistry involves cyclizations and arylations with biphenyl substituted heterocyclic ketones and a mechanism is proposed involving superelectrophilic intermediates. The key reactive intermediates-dicationic and trication fluorenyl cations have been observed by low-temperature NMR and the mechanism has been further studied using DFT calculations. PMID- 28557444 TI - Complex and Hierarchical 2D Assemblies via Crystallization-Driven Self-Assembly of Poly(l-lactide) Homopolymers with Charged Termini. AB - Poly(l-lactide) (PLLA)-based nanoparticles have attracted much attention with respect to applications in drug delivery and nanomedicine as a result of their biocompatibility and biodegradability. Nevertheless, the ability to prepare PLLA assemblies with well-defined shape and dimensions is limited and represents a key challenge. Herein we report access to a series of monodisperse complex and hierarchical colloidally stable 2D structures based on PLLA cores using the seeded growth, "living-crystallization-driven self-assembly" method. Specifically, we describe the formation of diamond-shaped platelet micelles and concentric "patchy" block co-micelles by using seeds of the charge-terminated homopolymer PLLA24[PPh2Me]I to initiate the sequential growth of either additional PLLA24[PPh2Me]I or a crystallizable blend of the latter with the block copolymer PLLA42-b-P2VP240, respectively. The epitaxial nature of the growth processes used for the creation of the 2D block co-micelles was confirmed by selected area electron diffraction analysis. Cross-linking of the P2VP corona of the peripheral block in the 2D block co-micelles using Pt nanoparticles followed by dissolution of the interior region in good solvent for PLLA led to the formation of novel, hollow diamond-shaped assemblies. We also demonstrate that, in contrast to the aforementioned results, seeded growth of the unsymmetrical PLLA BCPs PLLA42-b-P2VP240 or PLLA20-b-PAGE80 alone from 2D platelets leads to the formation of diamond-fiber hybrid structures. PMID- 28557446 TI - Total Synthesis of Isohericerin, Isohericenone, and Erinacerin A: Development of a Copper-Catalyzed Methylboronation of Terminal Alkynes. AB - Efficient and concise approaches for the synthesis of three bioactive natural products, isohericerin, isohericenone, and erinacerin A, are described in this paper. The key reactions employed include a Mannich reaction with commercially available hydroxybenzoate and subsequent one-pot lactamization to afford the common precursor isoindolinone in 3 steps and a Suzuki-Miyaura coupling reaction to connect geranyl side chains to the isoindolinone core. In addition, the mild and efficient synthesis of the C5'-oxidized geranyl side unit of isohericenone is enabled by developing a highly regioselective and efficient method for the Cu catalyzed methylboronation of functionalized terminal alkynes. PMID- 28557445 TI - Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure. AB - The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of riociguat in other cardiovascular indications is limited by its short half-life, necessitating a three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure-activity relationships and were able to decrease oxidative metabolism significantly. These studies resulting in the discovery of once daily sGC stimulator vericiguat (compound 24, BAY 1021189), currently in phase 3 trials for chronic heart failure, are now reported. PMID- 28557447 TI - Use of a 700 MHz NMR Microcryoprobe for the Identification and Quantification of Exogenous Carbon in Compounds Purified by Preparative Capillary Gas Chromatography for Radiocarbon Determinations. AB - Preparative capillary gas chromatography (PCGC) is the central technique used for the purification of volatile or semivolatile organic compounds for radiocarbon analysis using accelerator mass spectrometry (AMS). While thicker film columns offer efficient separations, cyclic poly(dimethylsiloxanes) (PDMS) derived from the column's stationary phase have been highlighted as a potential source of contaminant carbon in "trapped" compounds. The PDMS CH3 groups are of "infinite" radiocarbon age due to the fossil carbon origin of the feedstock used in production. Hence, column bleed, if present at sufficiently high concentrations, would shift the radiocarbon ages of trapped compounds to older ages. Quantification of the column bleed in trapped samples, however, is extremely challenging and up to now has only been achieved through indirect 14C determinations of chromatographic blanks, which are used for post 14C determination "corrections". As part of wider investigations aimed at better understanding the chemical nature of contamination in compound-specific 14C determinations, herein, we report a rigorous approach to column bleed identification and quantification. Using reference fatty acid methyl esters (FAMEs), 1H nuclear magnetic resonance spectroscopy (NMR), employing a 700 MHz instrument equipped with a 1.7 mm microcryoprobe optimized for 1H observation, was able to detect low submicrogram amounts of low molecular weight compounds (<500 Da). Direct quantification of PCGC "trapped" FAMEs was achieved based on the recorded 1H NMR spectra. Gravimetrically prepared calibration mixtures of cyclic PMDSs and FAMEs showed column bleed abundance to be below 0.03% w/w of the "trapped" FAMEs, which would lead to a maximum shift in radiocarbon age of <3 years toward older values. We therefore conclude that column bleed contamination has a negligible effect on the 14C determination of FAMEs prepared using the chromatographic method described. The 1H NMR analysis also revealed the absence of other protonated carbon-containing components that would affect radiocarbon determinations at the precisions achievable by AMS. PMID- 28557448 TI - Nonclassical Single-State Reactivity of an Oxo-Iron(IV) Complex Confined to Triplet Pathways. AB - C-H bond activation mediated by oxo-iron (IV) species represents the key step of many heme and nonheme O2-activating enzymes. Of crucial interest is the effect of spin state of the FeIV(O) unit. Here we report the C-H activation kinetics and corresponding theoretical investigations of an exclusive tetracarbene ligated oxo iron(IV) complex, [LNHCFeIV(O)(MeCN)]2+ (1). Kinetic traces using substrates with bond dissociation energies (BDEs) up to 80 kcal mol-1 show pseudo-first-order behavior and large but temperature-dependent kinetic isotope effects (KIE 32 at 40 degrees C). When compared with a topologically related oxo-iron(IV) complex bearing an equatorial N-donor ligand, [LTMCFeIV(O) (MeCN)]2+ (A), the tetracarbene complex 1 is significantly more reactive with second order rate constants k'2 that are 2-3 orders of magnitude higher. UV-vis experiments in tandem with cryospray mass spectrometry evidence that the reaction occurs via formation of a hydroxo-iron(III) complex (4) after the initial H atom transfer (HAT). An extensive computational study using a wave function based multireference approach, viz. complete active space self-consistent field (CASSCF) followed by N-electron valence perturbation theory up to second order (NEVPT2), provided insight into the HAT trajectories of 1 and A. Calculated free energy barriers for 1 reasonably agree with experimental values. Because the strongly donating equatorial tetracarbene pushes the Fe-dx2-y2 orbital above dz2, 1 features a dramatically large quintet-triplet gap of ~18 kcal/mol compared to ~2-3 kcal/mol computed for A. Consequently, the HAT process performed by 1 occurs on the triplet surface only, in contrast to complex A reported to feature two state-reactivity with contributions from both triplet and quintet states. Despite this, the reactive FeIV(O) units in 1 and A undergo the same electronic-structure changes during HAT. Thus, the unique complex 1 represents a pure "triplet-only" ferryl model. PMID- 28557450 TI - Does Synergism in Microscopic Polarity Correlate with Extrema in Macroscopic Properties for Aqueous Mixtures of Dipolar Aprotic Solvents? AB - Aqueous mixtures of dipolar aprotic solvents (acetonitrile, gamma-valerolactone, gamma-butyrolactone, tetrahydrofuran, 1,4-dioxane, acetone, pyridine, N-methyl-2 pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide) show synergism in microscopic polarity and extrema in macroscopic viscosity (eta) and molar excess enthalpy (HE) in water-rich compositions that correlate with solvent functional group electrostatic basicity (beta2H). Microscopic polarities of aqueous solvent mixtures were estimated by measuring the spectral shift (lambdamax) of 4-nitroaniline with UV-vis spectroscopy at 25 degrees C. Dynamic viscosities (eta) and densities were measured for eight aqueous dipolar aprotic mixtures over the full range of compositions at (25 to 45) degrees C. The lambdamax, eta, and HE values of the aqueous mixtures showed a linear trend with increasing electrostatic basicity of the solvent functional groups that is attributed to the size and strength of the hydration shell of water. Density functional theory (DFT) calculations were performed for 1:3 complexes (solvent: (H2O)3) and it was found that aqueous mixtures with high basicity have high binding energies and short hydrogen bonding distances implying that the size and strength of the hydration shell of water is proportional to functional group basicity. Consideration of functional group basicity of dipolar aprotic solvents allows one to relate synergism in microscopic polarity to extrema in macroscopic properties for a wide range of aqueous dipolar aprotic solvent mixtures. PMID- 28557449 TI - Antimalarial Activities of Alkyl Cyclohexenone Derivatives Isolated from the Leaves of Poupartia borbonica. AB - Bioactivity-guided fractionation of the ethyl acetate extract of the leaves of Poupartia borbonica led to the isolation of three new alkyl cyclohexenone derivatives 1-3, and named Poupartone A-C. The structures of the new compounds were elucidated by 1D and 2D NMR spectroscopic data analysis and MS, whereas calculated and experimental ECD spectra were used to define the absolute configurations. These compounds were active against 3D7 and W2 Plasmodium falciparum strains with IC50 values between 0.55 and 1.81 MUM. In vitro cytotoxicity against WI38 human fibroblasts and the human cervical cancer cell line HeLa (WST-1 assay) showed that these compounds were also cytotoxic, but no hemolytic activity was observed for the extract and pure compounds. An in vivo antimalarial assay was performed on the major cyclohexenone using P. berghei infected mice at a dose of 15 mg/kg/day ip. The assay revealed growth inhibition of 59.1 and 69.5% at days 5 and 7 postinfection, respectively, although some toxicity was observed. Zebrafish larvae were used as a model to determine the type of toxicity, and the results showed cardiac toxicity. The methanol extract was also studied, and it displayed moderate antiplasmodial properties in vitro. This extract contained the known flavonoids, quercetin, 3'-O hydroxysulfonylquercetin, quercitrin, and isoquercitrin as well as ellagic acid, which showed high to low activity against the 3D7 P. falciparum strain. PMID- 28557451 TI - Enantioselective Cycloaddition of Styrenes with Aldimines Catalyzed by a Chiral Magnesium Potassium Binaphthyldisulfonate Cluster as a Chiral Bronsted Acid Catalyst. AB - A chiral magnesium potassium binaphthyldisulfonate cluster, as a chiral Bronsted acid catalyst, was shown to catalyze an enantioselective cycloaddition of styrenes with aldimines for the first time. The strong Bronsted acidity of the catalyst precursors, which might dissolve drying agents and take up the leached Mg2+ and K+, serendipitously led to good enantioselectivity. Mechanistic aspects were supported by X-ray and ESI-MS analysis of the catalyst and a kinetics study of the reaction. Useful transformations to optically active 1,3-amino alcohols on a gram scale were also demonstrated. PMID- 28557452 TI - Photoreactions of Porphyrins Initiated by Deep Ultraviolet Single Photons. AB - The newly built 177 nm all-solid-state deep ultraviolet (DUV) laser photoionization mass spectrometer finds a unique advantage to identify porphyrins that bear ionization energies close to 7.0 eV. We observed dramatic selectivity of tetraphenylporphyrins (TPPs) pertaining to varied photochemical processes initiated by the DUV laser excitation. Single-photon ionization was found dominant for 2H-TPP resulting in a fragmentation-free mass spectrum; photoinduced dehydrogenation was observed for zinc TPP, but both dehydrogenation and demetalation are noted for copper TPP. Along with first-principle calculations, we demonstrate how the photoinduced reactions vary with residual energies of photoionization, highest occupied molecular orbital-lowest unoccupied molecular orbital gaps, donor-acceptor orbital overlaps, single-step barriers, and whether or not there is a major process of structural rearrangement. It is demonstrated that the rotation of benzene ring under proper laser radiation prompts dehydrogenation process; also, metallo-TPPs do not support direct demetalation, but it is selectively accomplishable along with dehydrogenation and successive hydrogenation processes. These findings not only provide insights into the hydrogen atom transfer in porphyrins initiated by ultraviolet laser but also suggest promising applications of the DUV laser in designed synthesis and chemical modification of porphyrins. PMID- 28557453 TI - Coating Nanoparticles with Plant-Produced Transferrin-Hydrophobin Fusion Protein Enhances Their Uptake in Cancer Cells. AB - The encapsulation of drugs to nanoparticles may offer a solution for targeted delivery. Here, we set out to engineer a self-assembling targeting ligand by combining the functional properties of human transferrin and fungal hydrophobins in a single fusion protein. We showed that human transferrin can be expressed in Nicotiana benthamiana plants as a fusion with Trichoderma reesei hydrophobins HFBI, HFBII, or HFBIV. Transferrin-HFBIV was further expressed in tobacco BY-2 suspension cells. Both partners of the fusion protein retained their functionality; the hydrophobin moiety enabled migration to a surfactant phase in an aqueous two-phase system, and the transferrin moiety was able to reversibly bind iron. Coating porous silicon nanoparticles with the fusion protein resulted in uptake of the nanoparticles in human cancer cells. This study provides a proof of-concept for the functionalization of hydrophobin coatings with transferrin as a targeting ligand. PMID- 28557454 TI - Galvanic Corrosion of Lead by Iron (Oxyhydr)Oxides: Potential Impacts on Drinking Water Quality. AB - Lead exposure via drinking water remains a significant public health risk; this study explored the potential effects of upstream iron corrosion on lead mobility in water distribution systems. Specifically, galvanic corrosion of lead by iron (oxyhydr)oxides was investigated. Coupling an iron mineral cathode with metallic lead in a galvanic cell increased lead release by 531 MUg L-1 on average-a 9-fold increase over uniform corrosion in the absence of iron. Cathodes were composed of spark plasma sintered Fe3O4 or alpha-Fe2O3 or field-extracted Fe3O4 and alpha FeOOH. Orthophosphate immobilized oxidized lead as insoluble hydroxypyromorphite, while humic acid enhanced lead mobility. Addition of a humic isolate increased lead release due to uniform corrosion by 81 MUg L-1 and-upon coupling lead to a mineral cathode-release due to galvanic corrosion by 990 MUg L-1. Elevated lead in the presence of humic acid appeared to be driven by complexation, with 208Pb and UV254 size-exclusion chromatograms exhibiting strong correlation under these conditions (R2average = 0.87). A significant iron corrosion effect was consistent with field data: lead levels after lead service line replacement were greater by factors of 2.3-4.7 at sites supplied by unlined cast iron distribution mains compared with the alternative, lined ductile iron. PMID- 28557455 TI - Host-Guest Interaction between Corona[n]arene and Bisquaternary Ammonium Derivatives for Fabricating Supra-Amphiphile. AB - The interactions between a host, water-soluble corona[n]arene (S6-CAP), and a series of guests, bisquaternary ammonium derivatives (CnDAs), in water, were investigated. The host and guest can form 1:1 host-guest complex. Their binding constants decrease as the alkyl length of CnDAs increases, which can be tunable ranging from 103 to 106 M-1. The binding processes are mainly entropy-driven, while the enthalpy changes also play an important role in enhancing the host guest interactions. In addition, a supra-amphiphile was fabricated with S6-CAP and a normal surfactant bearing bisquaternary ammonium (C4R). The S6-CAP.C4R complex forms micellar aggregates in water, and the system possesses better assembling activity and dilution stability than its building block C4R. This study enriches the families of supra-amphiphiles with a new architecture, and employing such a supra-amphiphile in biofunctional materials is highly anticipated. PMID- 28557456 TI - Met349 Mutations Enhance the Activity of 1,4-alpha-Glucan Branching Enzyme from Geobacillus thermoglucosidans STB02. AB - 1,4-alpha-Glucan branching enzyme (GBE, EC 2.4.1.18) is used to increase the number of alpha-1,6 branch points in starch and glycogen. On the basis of a multiple sequence alignment of the GBEs from a variety of bacteria, residue 349 (Geobacillus thermoglucosidans STB02 numbering) in region III is generally methionine in bacteria with higher identity, while it is threonine or serine in bacteria with lower identity. Four mutants (M349T, M349S, M349H, and M349Y) were constructed by site-directed mutagenesis and characterized. M349T and M349S showed 24.5% and 21.1% increases in specific activity compared with that of wild type GBE, respectively. In addition, M349T and M349S displayed 24.2% and 17.6% enhancements in the alpha-1,6-glycosidic linkage ratio of potato starch samples, respectively. However, M349Y displayed a significant reduction in activity. Moreover, the mutations at M349 have a negligible effect on substrate specificity. Thus, M349T and M349S are more suitable for industrial applications than wild-type GBE. PMID- 28557457 TI - Oxazolidinones and 2,5-Dihydrofurans via Zinc-Catalyzed Regioselective Allenylation Reactions of l-alpha-Amino Aldehydes. AB - The simultaneous control of diastereoselectivity and regioselectivity in Zn catalyzed allenylation reactions of N-protected l-alpha-amino aldehydes is reported. A reversal in diastereoselectivity could be realized by variation of the alpha-amino aldehyde protecting groups. A range of 1-allenyl-2-amino alcohols were obtained with excellent regioselectivity and converted to oxazolidinones and dihydrofurans. Many of which could be isolated as single diastereoisomers and without significant erosion of ee, making this a practical catalytic synthesis of highly functionalized heterocycles. PMID- 28557459 TI - Phonon-Assisted Two-Photon Interference from Remote Quantum Emitters. AB - Photonic quantum technologies are on the verge of finding applications in everyday life with quantum cryptography and quantum simulators on the horizon. Extensive research has been carried out to identify suitable quantum emitters and single epitaxial quantum dots have emerged as near-optimal sources of bright, on demand, highly indistinguishable single photons and entangled photon-pairs. In order to build up quantum networks, it is essential to interface remote quantum emitters. However, this is still an outstanding challenge, as the quantum states of dissimilar "artificial atoms" have to be prepared on-demand with high fidelity and the generated photons have to be made indistinguishable in all possible degrees of freedom. Here, we overcome this major obstacle and show an unprecedented two-photon interference (visibility of 51 +/- 5%) from remote strain-tunable GaAs quantum dots emitting on-demand photon-pairs. We achieve this result by exploiting for the first time the full potential of a novel phonon assisted two-photon excitation scheme, which allows for the generation of highly indistinguishable (visibility of 71 +/- 9%) entangled photon-pairs (fidelity of 90 +/- 2%), enables push-button biexciton state preparation (fidelity of 80 +/- 2%) and outperforms conventional resonant two-photon excitation schemes in terms of robustness against environmental decoherence. Our results mark an important milestone for the practical realization of quantum repeaters and complex multiphoton entanglement experiments involving dissimilar artificial atoms. PMID- 28557458 TI - Design and Discovery of N-(2-Methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4 yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers. AB - RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model. PMID- 28557460 TI - Unveiling the Catalytic Origin of Nanocrystalline Yttrium Ruthenate Pyrochlore as a Bifunctional Electrocatalyst for Zn-Air Batteries. AB - Zn-air batteries suffer from the slow kinetics of oxygen reduction reaction (ORR) and/or oxygen evolution reaction (OER). Thus, the bifunctional electrocatalysts are required for the practical application of rechargeable Zn-air batteries. In terms of the catalytic activity and structural stability, pyrochlore oxides (A2[B2-xAx]O7-y) have emerged as promising candidates. However, a limited use of A-site cations (e.g., lead or bismuth cations) of reported pyrochlore catalysts have hampered broad understanding of their catalytic effect and structure. More seriously, the catalytic origin of the pyrochlore structure was not clearly revealed yet. Here, we report the new nanocrystalline yttrium ruthenate (Y2[Ru2 xYx]O7-y) with pyrochlore structure. The prepared pyrochlore oxide demonstrates comparable catalytic activities in both ORR and OER, compared to that of previously reported metal oxide-based catalysts such as perovskite oxides. Notably, we first find that the catalytic activity of the Y2[Ru2-xYx]O7-y is associated with the oxidations and corresponding changes of geometric local structures of yttrium and ruthenium ions during electrocatalysis, which were investigated by in situ X-ray absorption spectroscopy (XAS) in real-time. Zn-air batteries using the prepared pyrochlore oxide achieve highly enhanced charge and discharge performance with a stable potential retention for 200 cycles. PMID- 28557461 TI - Perfluoropolyethers: Development of an All-Atom Force Field for Molecular Simulations and Validation with New Experimental Vapor Pressures and Liquid Densities. AB - A force field for perfluoropolyethers (PFPEs) based on the general optimized potentials for liquid simulations all-atom (OPLS-AA) force field has been derived in conjunction with experiments and ab initio quantum mechanical calculations. Vapor pressures and densities of two liquid PFPEs, perfluorodiglyme (CF3-O-(CF2 CF2-O)2-CF3) and perfluorotriglyme (CF3-O-(CF2-CF2-O)3-CF3), have been measured experimentally to validate the force field and increase our understanding of the physical properties of PFPEs. Force field parameters build upon those for related molecules (e.g., ethers and perfluoroalkanes) in the OPLS-AA force field, with new parameters introduced for interactions specific to PFPEs. Molecular dynamics simulations using the new force field demonstrate excellent agreement with ab initio calculations at the RHF/6-31G* level for gas-phase torsional energies (<0.5 kcal mol-1 error) and molecular structures for several PFPEs, and also accurately reproduce experimentally determined densities (<0.02 g cm-3 error) and enthalpies of vaporization derived from experimental vapor pressures (<0.3 kcal mol-1). Additional comparisons between experiment and simulation show that polyethers demonstrate a significant decrease in enthalpy of vaporization upon fluorination unlike related molecules (e.g., alkanes and alcohols). Simulation suggests this phenomenon is a result of reduced cohesion in liquid PFPEs due to a reduction in localized associations between backbone oxygen atoms and neighboring molecules. PMID- 28557462 TI - Coherent Interlayer Tunneling and Negative Differential Resistance with High Current Density in Double Bilayer Graphene-WSe2 Heterostructures. AB - We demonstrate gate-tunable resonant tunneling and negative differential resistance between two rotationally aligned bilayer graphene sheets separated by bilayer WSe2. We observe large interlayer current densities of 2 and 2.5 MUA/MUm2 and peak-to-valley ratios approaching 4 and 6 at room temperature and 1.5 K, respectively, values that are comparable to epitaxially grown resonant tunneling heterostructures. An excellent agreement between theoretical calculations using a Lorentzian spectral function for the two-dimensional (2D) quasiparticle states, and the experimental data indicates that the interlayer current stems primarily from energy and in-plane momentum conserving 2D-2D tunneling, with minimal contributions from inelastic or non-momentum-conserving tunneling. We demonstrate narrow tunneling resonances with intrinsic half-widths of 4 and 6 meV at 1.5 and 300 K, respectively. PMID- 28557463 TI - Synthesis of Dual-Size Cellulose-Polyvinylpyrrolidone Nanofiber Composites via One-Step Electrospinning Method for High-Performance Air Filter. AB - Dual-size nanofibers consisting of a random mixture of nano- and submicron-size nanofibers are promising structures for specific applications such as air filters because of their increased specific surface area and low pressure drop. Synthesis of dual-size nanofibers using one-step electrospinning was reported here for the first time. The formation of well-mixed nano- and submicron-size cellulose polyvinylpyrrolidone nanofiber composites was accomplished utilizing the physical properties of TEMPO-oxidized cellulose nanofibers (i.e., high thixotropy and high magnitude of zeta potential) and tuning the charge of the polymer jet, which influences the formation and shape of Taylor cone, and Coulombic explosion. The dual-size nanofibers were then spun on the surface of a HEPA filter to obtain a multilayer air filter. Aerosol filtration measurements show that this multilayer air filter has an incredibly high performance, shown by the high quality factor (Qf), 0.117 Pa-1, which is 10 times the Qf of commercial HEPA filters. PMID- 28557464 TI - Halide Ion-Induced Switching of Gold Nanozyme Activity Based on Au-X Interactions. AB - The influence of halide ion on the peroxidase activity of protein-modified gold nanoparticles (AuNPs) has been explored, based on the Au-X interaction directed binding of halide ion to AuNPs. Due to different Au-X interactions, halide has been demonstrated to display different switching behaviors to the catalytic activity of protein-modified AuNPs. Presented is the finding that iodide can rapidly inhibit the enzyme activity of CM-AuNP nanozyme effectively. Iodide mediated irreversible inhibition is due not to I--induced aggregation of AuNP but to the Au-I bond-induced blocking of active sites of AuNP nanozyme. I- switching efficiency was found to be strongly dependent on the surface density of modifiers and the intrinsic property of the modifier. Similar to iodide, bromide can also inhibit the enzyme activity effectively, but its inhibition behavior is reversible. Due to the weak Au-Cl interaction, chloride has no influence on the enzyme activity of CM-AuNP at low ion concentration and exhibits weak activity inhibition at high ion concentration. Fluoride shows no influence on the activity of gold nanozyme due to the absence of Au-F interaction. Our results have improved a profound understanding of anion-mediated AuNP nanozyme activity because of their interfacial interaction and provided guidance in the further utilization of nanozyme in numerous areas. PMID- 28557465 TI - Inverted Hysteresis in CH3NH3PbI3 Solar Cells: Role of Stoichiometry and Band Alignment. AB - J-V hysteresis in perovskite solar cells is known to be strongly dependent on many factors ranging from the cell structure to the preparation methods. Here we uncover one likely reason for such sensitivity by linking the stoichiometry in pure CH3NH3PbI3 (MAPbI3) perovskite cells with the character of their hysteresis behavior through the influence of internal band offsets. We present evidence indicating that in some cells the ion accumulation occurring at large forward biases causes a temporary and localized increase in recombination at the MAPbI3/TiO2 interface, leading to inverted hysteresis at fast scan rates. Numerical semiconductor models including ion accumulation are used to propose and analyze two possible origins for these localized recombination losses: one based on band bending and the other on an accumulation of ionic charge in the perovskite bulk. PMID- 28557466 TI - A fully conditional specification approach to multilevel imputation of categorical and continuous variables. AB - Specialized imputation routines for multilevel data are widely available in software packages, but these methods are generally not equipped to handle a wide range of complexities that are typical of behavioral science data. In particular, existing imputation schemes differ in their ability to handle random slopes, categorical variables, differential relations at Level-1 and Level-2, and incomplete Level-2 variables. Given the limitations of existing imputation tools, the purpose of this manuscript is to describe a flexible imputation approach that can accommodate a diverse set of 2-level analysis problems that includes any of the aforementioned features. The procedure employs a fully conditional specification (also known as chained equations) approach with a latent variable formulation for handling incomplete categorical variables. Computer simulations suggest that the proposed procedure works quite well, with trivial biases in most cases. We provide a software program that implements the imputation strategy, and we use an artificial data set to illustrate its use. (PsycINFO Database Record PMID- 28557467 TI - Thanks coefficient alpha, we'll take it from here. AB - Empirical studies in psychology commonly report Cronbach's alpha as a measure of internal consistency reliability despite the fact that many methodological studies have shown that Cronbach's alpha is riddled with problems stemming from unrealistic assumptions. In many circumstances, violating these assumptions yields estimates of reliability that are too small, making measures look less reliable than they actually are. Although methodological critiques of Cronbach's alpha are being cited with increasing frequency in empirical studies, in this tutorial we discuss how the trend is not necessarily improving methodology used in the literature. That is, many studies continue to use Cronbach's alpha without regard for its assumptions or merely cite methodological articles advising against its use to rationalize unfavorable Cronbach's alpha estimates. This tutorial first provides evidence that recommendations against Cronbach's alpha have not appreciably changed how empirical studies report reliability. Then, we summarize the drawbacks of Cronbach's alpha conceptually without relying on mathematical or simulation-based arguments so that these arguments are accessible to a broad audience. We continue by discussing several alternative measures that make less rigid assumptions which provide justifiably higher estimates of reliability compared to Cronbach's alpha. We conclude with empirical examples to illustrate advantages of alternative measures of reliability including omega total, Revelle's omega total, the greatest lower bound, and Coefficient H. A detailed software appendix is also provided to help researchers implement alternative methods. (PsycINFO Database Record PMID- 28557469 TI - Using implicit association tests in age-heterogeneous samples: The importance of cognitive abilities and quad model processes. AB - Implicit association tests (IATs) are increasingly used to indirectly assess people's traits, attitudes, or other characteristics. In addition to measuring traits or attitudes, IAT scores also reflect differences in cognitive abilities because scores are based on reaction times (RTs) and errors. As cognitive abilities change with age, questions arise concerning the usage and interpretation of IATs for people of different age. To address these questions, the current study examined how cognitive abilities and cognitive processes (i.e., quad model parameters) contribute to IAT results in a large age-heterogeneous sample. Participants (N = 549; 51% female) in an age-stratified sample (range = 12-88 years) completed different IATs and 2 tasks to assess cognitive processing speed and verbal ability. From the IAT data, D2-scores were computed based on RTs, and quad process parameters (activation of associations, overcoming bias, detection, guessing) were estimated from individual error rates. Substantial IAT scores and quad processes except guessing varied with age. Quad processes AC and D predicted D2-scores of the content-specific IAT. Importantly, the effects of cognitive abilities and quad processes on IAT scores were not significantly moderated by participants' age. These findings suggest that IATs seem suitable for age-heterogeneous studies from adolescence to old age when IATs are constructed and analyzed appropriately, for example with D-scores and process parameters. We offer further insight into how D-scoring controls for method effects in IATs and what IAT scores capture in addition to implicit representations of characteristics. (PsycINFO Database Record PMID- 28557470 TI - The visibility of social class from facial cues. AB - Social class meaningfully impacts individuals' life outcomes and daily interactions, and the mere perception of one's socioeconomic standing can have significant ramifications. To better understand how people infer others' social class, we therefore tested the legibility of class (operationalized as monetary income) from facial images, finding across 4 participant samples and 2 stimulus sets that perceivers categorized the faces of rich and poor targets significantly better than chance. Further investigation showed that perceivers categorize social class using minimal facial cues and employ a variety of stereotype-related impressions to make their judgments. Of these, attractiveness accurately cued higher social class in self-selected dating profile photos. However, only the stereotype that well-being positively relates to wealth served as a valid cue in neutral faces. Indeed, neutrally posed rich targets displayed more positive affect relative to poor targets and perceivers used this affective information to categorize their social class. Impressions of social class from these facial cues also influenced participants' evaluations of the targets' employability, demonstrating that face-based perceptions of social class may have important downstream consequences. (PsycINFO Database Record PMID- 28557468 TI - Differentiating the everyday emotion dynamics of borderline personality disorder from major depressive disorder and bipolar disorder. AB - A major barrier to the understanding of emotion dynamics in borderline personality disorder (BPD) lies in its substantial comorbidity with major depressive disorder (MDD) and bipolar disorder (BD). Whereas BPD has often been characterized in terms of dynamic emotional processes, including instability, reactivity, and inertia, its substantial comorbidity with MDD and BD makes it difficult to discern the specificity of these dynamics. To differentiate the emotion dynamics of BPD from those of MDD and BD, an experience sampling study of 38 participants with BPD, 15 participants with MDD, 14 participants with BD, and 62 healthy controls obtained reports of interpersonal challenges and emotions 5 times daily for 2 weeks. Interpersonal challenges included rejection, betrayal, abandonment, offense, disappointment, and self-image challenge; emotions included anger, excitement, guilt, happiness, irritability, and shame. Multilevel analyses revealed that heightened interpersonal reactivity of guilt and shame and heightened inertia of shame were relatively specific to BPD. These findings could not be accounted for by the presence of current MDD or BD. By contrast, heightened instability of anger and irritability and heightened inertia of irritability appeared to be largely transdiagnostic. Implications for clinical assessment, research, and theory are discussed. (PsycINFO Database Record PMID- 28557471 TI - The double-edged sword of leader charisma: Understanding the curvilinear relationship between charismatic personality and leader effectiveness. AB - This study advanced knowledge on charisma by (a) introducing a new personality based model to conceptualize and assess charisma and by (b) investigating curvilinear relationships between charismatic personality and leader effectiveness. Moreover, we delved deeper into this curvilinear association by (c) examining moderation by the leader's level of adjustment and by (d) testing a process model through which the effects of charismatic personality on effectiveness are explained with a consideration of specific leader behaviors. Study 1 validated HDS charisma (Hogan Development Survey) as a useful trait-based measure of charisma. In Study 2 a sample of leaders (N = 306) were assessed in the context of a 360-degree development center. In line with the too-much-of-a good-thing effect, an inverted U-shaped relationship between charismatic personality and observer-rated leader effectiveness was found, indicating that moderate levels are better than low or high levels of charisma. Study 3 (N = 287) replicated this curvilinear relationship and further illustrated the moderating role of leader adjustment, in such a way that the inflection point after which the effects of charisma turn negative occurs at higher levels of charisma when adjustment is high. Nonlinear mediation modeling further confirmed that strategic and operational leader behaviors fully mediate the curvilinear relationship. Leaders low on charisma are less effective because they lack strategic behavior; highly charismatic leaders are less effective because they lack operational behavior. In sum, this work provides insight into the dispositional nature of charisma and uncovers the processes through which and conditions under which leader charisma translates into (in)effectiveness. (PsycINFO Database Record PMID- 28557472 TI - Openness to experience and culture-openness transactions across the lifespan. AB - We examined the life span development of openness to experience and tested whether change in this personality trait was associated with change in cultural activity, such as attending the opera or visiting museums. Data came from the Dutch Longitudinal Internet Study for the Social Sciences panel, which includes 5 personality assessments across a 7-year period of a nationally representative sample of 7,353 individuals, aged 16 to 95 years. Latent growth curve analyses indicated that on average, openness remained relatively stable in emerging adulthood before declining in midlife and old age. At each stage of life, there were significant individual differences in openness development, and changes in openness were correlated with changes in cultural activity. Autoregressive cross lagged analyses indicated that increases in cultural activity precipitated increases in openness, and vice versa. These culture-openness transactions held across different age and education groups and when controlling for household income. We found less consistent codevelopmental associations between cultural activity and the other Big Five traits. We discuss the implications of these results for personality development theory and the role of cultural investment in personality trait change. (PsycINFO Database Record PMID- 28557473 TI - Vocational interests by gender and race 10 years after spinal cord injury. AB - OBJECTIVE: To examine and compare vocational interests as a function of gender and race among 247 participants with spinal cord injury (SCI) approximately 10 years after SCI onset utilizing the 2004 edition of the Strong Interest Inventory (SII). RESEARCH METHOD: For this cross-sectional analysis nested within a prospective cohort study, data were collected via mail and analyzed at a medical university in the Southeastern United States. Among the 563 adults with traumatic SCI initially enrolled during inpatient rehabilitation at a specialty hospital, 247 met current study eligibility criteria and completed the SII approximately 10 years postinjury. The SII is a 291-item measure of vocational interests. RESULTS: Male participants scored highest on the Realistic theme and females scored highest on the Social theme. White participants scored highest on the Realistic theme, whereas Black participants scored highest on the Conventional theme. Differences in vocational interests by gender were seen on two of the six General Occupational Themes (GOT; Realistic and Social) and 12 of the 30 Basic Interest Scales (BIS). Race differences were observed on the Enterprising and Conventional GOT and 11 of 30 BIS. CONCLUSIONS: For both female and Black participants, interests are more physically compatible with employment post-SCI than male and White participants. Yet, employment rates in White males with SCI are greater than those of female and Black individuals with SCI. These data suggest further research on factors influencing gender and racial disparities in employment among those with SCI is indicated. (PsycINFO Database Record PMID- 28557474 TI - Adolescents' body image trajectories: A further test of the self-equilibrium hypothesis. AB - The self-equilibrium hypothesis underlines the importance of having a strong core self, which is defined as a high and developmentally stable self-concept. This study tested this hypothesis in relation to body image (BI) trajectories in a sample of 1,006 adolescents (Mage = 12.6, including 541 males and 465 females) across a 4-year period. The results supported the self-equilibrium hypothesis among 3 profiles of adolescents, all characterized by matching BI levels and stability: (a) High (48.0%); (b) Increasing (34.1%); and (c) Decreasing (17.9%). Boys presented higher levels of BI, and the quality of relationships with peers and parents predicted initially more desirable trajectories across gender. By the end of the study, more positive academic outcomes were associated with the Decreasing profile, lower internalizing problems with the High profile, and lower externalizing problems with the High and the Increasing profiles. (PsycINFO Database Record PMID- 28557476 TI - Repeated computerized cognitive testing: Performance shifts and test-retest reliability in healthy young adults. AB - Many longitudinal studies entail repeated computerized cognitive testing. However, few of the measures frequently employed for assessing cognitive changes have been examined for within- and between-day retest effects over multiple time points. To address gaps in the repeated cognitive assessment literature, in the current study 20 male undergraduate students completed a computerized cognitive battery 6 times over 3 testing days, each 1 week apart. Performance shifts and test-retest reliability (TRR) varied for different measured variables. Reaction times (RTs) on tasks designed to measure inhibition, switching, and selective attention generally showed good TRR, and few or only gradual improvements over time, suggesting that these measures are suitable for use in repeated testing, and that the inclusion of brief familiarization periods sufficed to resolve initial practice effects. Similar findings were observed for both accuracy and speed on a 2-back working memory task. In contrast, RTs on a basic visuomotor task showed worsening performance across time (likely reflecting boredom effects) and poor TRR, suggesting unsuitability for measuring change in cognitive performance. Cost scores designed to assess inhibition, switching, and selective attention showed poor TRR, as did scoring metrics from visuospatial short-term and working memory tasks (Corsi block paradigm). This low reliability suggests that these scores may not be suitable for use in repeated assessment, and calls into question their validity as measures of the specified cognitive functions. Researchers planning studies entailing computerized assessment of cognitive functioning in healthy young adults should consider the current results when selecting suitable cognitive tasks and measures. (PsycINFO Database Record PMID- 28557475 TI - Early social behaviors and the trajectory of peer victimization across the school years. AB - Research has established that long-term exposure to peer victimization is associated with higher levels of emotional and behavioral maladjustment. Yet, relatively little is known regarding predictors of stable versus declining victimization across extended periods of time. To fill this knowledge gap, the present study used latent growth curve modeling to examine the separate and unique contributions of 3 early social behaviors in 2nd grade (aggression, anxious solitude, and prosocial behavior) to victimization across 2nd to 8th grade. Five hundred and 76 youth (M = 7.96 years, SD = .34) reported their level of exposure to victimization once a year from 2nd to 8th grade, and their teachers rated each youth on the 3 social behaviors in 2nd grade. When examined separately, the analyses revealed that (a) all 3 social behaviors contributed to 2nd-grade victimization; (b) anxious solitude and prosocial behavior contributed to the trajectory of victimization differently for boys and girls; and (c) aggression and anxious solitude contributed to significantly different levels of 8th-grade victimization in girls. Of interest, some effects were stronger in boys during elementary school and others were stronger in girls after the transition to middle school. When examined simultaneously, aggression remained the only significant predictor of 2nd-grade victimization; both anxious solitude and prosocial behavior uniquely predicted the trajectory of victimization, and aggression and anxious solitude uniquely predicted 8th-grade victimization in girls. Results are discussed with regard to prevention of prolonged victimization, with attention to gender differences. (PsycINFO Database Record PMID- 28557477 TI - Multivariate normative comparisons for neuropsychological assessment by a multilevel factor structure or multiple imputation approach. AB - Neuropsychologists administer neuropsychological tests to decide whether a patient is cognitively impaired. This clinical decision is made by comparing a patient's scores to those of healthy participants in a normative sample. In a multivariate normative comparison, a patient's entire profile of scores is compared to scores in a normative sample. Such a multivariate comparison has been shown to improve clinical decision making. However, it requires a multivariate normative data set, which often is unavailable. To obtain such a multivariate normative data set, the authors propose to aggregate healthy control group data from existing neuropsychological studies. As not all studies administered the same tests, this aggregated database will contain substantial amounts of missing data. The authors therefore propose two solutions: multiple imputation and factor modeling. Simulation studies show that factor modeling is preferred over multiple imputation, provided that the factor model is adequately specified. This factor modeling approach will therefore allow routine use of multivariate normative comparisons, enabling more accurate clinical decision making. (PsycINFO Database Record PMID- 28557478 TI - Assessment of emotion processing skills in acquired brain injury using an ability based test of emotional intelligence. AB - Social and emotional problems are commonly reported after moderate to severe acquired brain injury (ABI) and pose a significant barrier to rehabilitation. However, progress in assessment of emotional skills has been limited by a lack of validated measurement approaches. This study represents the first formal psychometric evaluation of the use of the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) V2.0 as a tool for assessing skills in perceiving, using, understanding and managing emotions following ABI. The sample consisted of 82 participants aged 18-80 years in the postacute phase of recovery (2 months-7 years) after moderate to severe ABI. Participants completed the MSCEIT V2.0 and measures of cognition and mood. Sociodemographic and clinical variables were collated from participant interview and medical files. Results revealed deficits across all MSCEIT subscales (approximately 1 SD below the normative mean). Internal consistency was adequate at overall, area, and branch levels, and MSCEIT scores correlated in expected ways with key demographic, clinical, cognitive, and mood variables. MSCEIT performance was related to injury severity and clinician rated functioning after ABI. Confirmatory factor analysis favored a 3-factor model of EI due to statistical redundancy of the Using Emotions branch. Overall, these findings suggest that the MSCEIT V2.0 is sensitive to emotion processing deficits after moderate to severe ABI, and can yield valid and reliable scores in an ABI sample. In terms of theoretical contributions, our findings support a domain-based, 3-factor approach for characterizing emotion-related abilities in brain-injured individuals. (PsycINFO Database Record PMID- 28557479 TI - Development and validation of an Overreporting Scale for the Personality Inventory for DSM-5 (PID-5). AB - Our aim in the current study was to develop a validity scale for the Personality Inventory for DSM-5 (PID-5) to detect noncredible overreported responding. To this end, we used a rare symptoms approach and identified extreme response options on PID-5 items that were infrequently endorsed by students in 3 different university samples (N = 1,370) and in a psychiatric patient sample (N = 194). The resulting 10-item scale (the PID-5-ORS) produced adequate-to-good estimates of internal reliability and was significantly correlated with the Minnesota Multiphasic Personality Inventory-2 Restructued Form (MMPI-2-RF) overreporting validity scales, providing evidence of concurrent validity. The criterion validity of the PID-5-ORS was demonstrated in an analog simulation design study. More specifically, university students instructed to overreport (n = 80) scored substantially higher on the PID-5-ORS relative to both a group of genuine psychiatric patients and students instructed to complete the PID-5 under standard (honest) instructions (n = 161); the effect size magnitudes associated with these differences were large. Classification accuracy analyses further revealed that high scores on the PID-5-ORS were associated with high specificity (and thus, low rates of false positive classifications) in differentiating overreporters from genuine patients, with sensitivity being somewhat weaker. (PsycINFO Database Record PMID- 28557481 TI - A within-person examination of the ideal-point response process. AB - Ideal-point processes assume that individuals engage in introspective comparisons when responding to self-reported typical traits such as personality, affect, and attitudes. Although this type of response process is fundamentally a within person phenomenon, past research has relied on between-person data using item response theory (IRT) model comparisons to draw inferences about the appropriateness of ideal-point response processes. However, between-person data may not necessarily be indicative of within-person processes. Across 2 studies, the authors used a paired comparison paradigm to examine whether within-person responses conform to an ideal-point response process (vs. a dominance response process). The authors found that an ideal-point response process more accurately describes within-person responses to personality, attitude, and affect constructs compared to a dominance response process. They additionally found that verbal ability and conscientiousness moderate both ideal and dominance response processes; individuals high on conscientiousness or high on verbal ability are more likely to engage in more precise introspective comparisons. (PsycINFO Database Record PMID- 28557480 TI - Patient-reported outcome measures in Huntington disease: Quality of life in neurological disorders (Neuro-QoL) social functioning measures. AB - Social functioning is an essential but poorly understood component of health related quality of life (HRQOL) for people with Huntington disease (HD). We report on the psychometric properties of 2 Neuro-QoL patient-reported outcome measures to assess social functioning in HD. Persons with prodromal (n = 198) or manifest HD (n = 195 early and n = 117 late) completed Neuro-QoL Ability to Participate in Social Roles and Activities, and Satisfaction with Social Roles and Activities. Items from 2 generic HRQOL patient-reported outcome measures were used to create a social functioning composite score; items from the Unified Huntington's Disease Rating Scale and Problem Behaviors Assessment Scale were used to create a clinician-rated composite score of social function. Internal consistencies for the scores on the Neuro-QoL measures were excellent (> .88). Computer adaptive test administration had some advantages over computer administered static Short Forms. Validity was supported by significant associations between the scores on the Neuro-QoL measures and other self- and clinician-reports of social function. Individuals with prodromal HD had better social functioning than the manifest HD groups; individuals with late-HD had less satisfaction and ability to participate in social roles and activities than the other 2 groups. Neuro-QoL provides brief, reliable scores of social functioning that measure ability to participate in, and satisfaction with, social roles and activities in persons with prodromal and manifest HD. In addition, test score interpretations of these measures support their validity in people with prodromal and manifest HD. These measurement tools add breadth to treatment outcome measures in HD and can increase understanding of the social implications of living with HD. (PsycINFO Database Record PMID- 28557482 TI - Assessing hyperactivation and deactivation strategies of the caregiving behavioral system: Psychometric studies of the Portuguese version of the Caregiving System Scale. AB - According to attachment theory, the main goal of the caregiving behavioral system is to relieve others' distress and promote their health and welfare. This is accomplished through a set of caregiving behaviors that are the primary strategy of this system. However, some individuals develop nonoptimal or secondary strategies (hyperactivation or deactivation). The Caregiving System Scale (CSS) is a self-report measure that assesses these nonoptimal caregiving strategies. This study examined the factor structure of the Portuguese version of the CSS using a bifactor model and a 2-factor correlated model; it also examined validity evidence for CSS scores in relation to other relevant variables. The sample comprised 417 women from the general population who completed the CSS, with a subsample of 124 women completing additional measures of attachment, mental representations of caregiving, compassion, and difficulties in emotional regulation. The bifactor model showed the best fit to the data, supporting an orthogonal and reliable 2-factor structure (Hyperactivation and Deactivation). This model also suggested that the Hyperactivation scale is multidimensional. With regard to the validity evidence for the CSS, the results showed that individuals engaged in volunteering activities presented lower levels of deactivation than those who were not engaged in these activities. The CSS scores also correlated as expected with the other measures. In conclusion, this study supports the utilization of Deactivation and Hyperactivation subscales as 2 statistically distinct constructs and demonstrates that the Portuguese version is an adequate measure of nonoptimal caregiving strategies. (PsycINFO Database Record PMID- 28557483 TI - Emotional flexibility: Development and application of a scale in adolescent earthquake survivors. AB - OBJECTIVE: Coping flexibility is strongly associated with individuals' well-being when coping with trauma. However an instrument to measure emotional flexibility, a specific type of coping flexibility, is yet to be developed. The present study reported the development and validation of a Self-Administered Inventory on emotional flexibility. The study also explored the relationship between emotional flexibility and psychological well-being in adolescents who had experienced the 2008 Sichuan earthquake in China. METHOD: A sample of 327 adolescents from Beijing was recruited for item development and preliminary validation. Another sample of 941 middle school students from areas affected by the Sichuan earthquake was recruited for further validation and examination of its relationship with psychological well-being. Exploratory factor analysis and confirmatory factor analysis were used to examine the construct validity of the scale. The criterion validity of the measure was assessed using Pearson's correlation coefficient. RESULTS: The Emotional Flexibility Scale comprises 10 items covering 3 dimensions, namely tuning of positive emotions, emotion communication, and tuning of negative emotions. Emotional flexibility was positively correlated with cognitive flexibility and psychological well-being. CONCLUSIONS: The Emotional Flexibility Scale provides a brief, reliable, and valid measure of emotion regulation ability of adolescents faced with disasters. (PsycINFO Database Record PMID- 28557484 TI - Understanding the early support needs of survivors of traumatic events: The example of severe injury survivors. AB - OBJECTIVE: In the aftermath of a potentially traumatic event, people may experience a range of mental health outcomes, including subclinical symptoms and distress. There is growing evidence that trauma survivors with subclinical symptoms are at increased risk of developing later psychiatric disorders, and this is especially the case with severe injury survivors. There is a need to develop evidence-based, early, brief interventions for those who are at risk of developing trauma-related psychopathology. To date, interventions for this at risk group have largely been derived from expert consensus. This study therefore aimed to understand the early psychosocial difficulties and perceived needs from the perspective of trauma survivors to further inform intervention development. METHOD: Forty-three survivors of a serious injury, identified as high risk for developing trauma-related psychopathology, were interviewed and qualitative methods (Thematic Analysis) were used to synthesize the data gathered. RESULTS: Participants described 5 main stressors: trauma-related psychological reactions, relationship stress, unsatisfactory services and support systems, reduced functioning, and negative thoughts and emotions in relation to recovery. In addition, participants described 3 main factors that were helpful in recovery: positive coping, professional support, and social support. CONCLUSIONS: These findings can inform posttrauma intervention development for those at risk of later psychological symptoms. In particular, the results support approaches focusing on promoting activity, supporting social relationships, stress and arousal management, and cognitive restructuring. In addition, future interventions might helpfully target rumination, worry, and reexperiencing symptoms. (PsycINFO Database Record PMID- 28557485 TI - Positive adaptations for trauma and healing (PATH), a pilot study of group therapy with Latino youth. AB - OBJECTIVE: This study examines the acceptability and preliminary efficacy of Positive Adaptations for Trauma and Healing (PATH), a manualized treatment for Latino youth and their caregivers. PATH is a culturally adapted program that incorporates a trauma model, positive psychology, and resilience. METHOD: Latino youth (N = 16) recruited from an urban community clinic participated in PATH with their caregiver. Pre- and postintervention measures on trauma symptoms, resilience, depression, caregiver's view of their youth's well-being, and positive and negative emotions were gathered. Following the intake meetings (1 to 3), the families participated in 10 90-minute weekly group sessions (total of 3 groups). Caregiver groups were conducted in Spanish, and youth in English. RESULTS: At pretest, 56% of the youth endorsed clinically significant symptoms on the UCLA PTSD Index (M = 34.2, SD = 11.2); the percentage dropped to 0% at posttest (M = 17.3, SD = 7.6). Youth reported pre- to posttest reductions on the Child Depression Inventory (mean difference [Mdiff] = 7.3; p = .004) and externalizing (Mdiff = 6.1; p < .001) and internalizing (Mdiff = 9.4; p < .001) behaviors on the caregiver-reported Child Behavior Checklist. Overall, there was high treatment engagement (93% attendance over 10 weeks). CONCLUSION: This novel treatment engaged a community-based Latino sample. The results suggest high acceptability and significant reduction in trauma symptoms and associated symptoms. This study included a small number of participants and results should be interpreted with caution. Future iterations will target larger number of participants to further assess feasibility. (PsycINFO Database Record PMID- 28557486 TI - Memory consolidation of attended information is optional: Comment on Jiang et al. (2016). AB - Attribute amnesia is a phenomenon in which information about a stimulus that was just recently used to perform a task is poorly remembered in a surprise test (Chen & Wyble, 2015a). In a recent article by Jiang, Shupe, Swallow, and Tan (2016), this effect was replicated but with an additional priming measure that revealed some carryover memory for the information that participants had trouble explicitly reporting on the surprise trial. Their work invites a discussion of the underlying cause of attribute amnesia by suggesting that the surprise question caused an overwriting of working memory contents. Although we agree that overwriting may be partially responsible for the inability to report, data from other experiments have suggested that a failure to consolidate a robust memory of the attended information is a major cause of the amnesia. We discuss experimental evidence supporting the theory that memory consolidation of attended information is an optional process that can be selectively evoked by task requirements. (PsycINFO Database Record PMID- 28557487 TI - How memory is tested influences what is measured: Reply to Wyble and Chen (2017). AB - In this response to Wyble and Chen's (2017) commentary on attribute amnesia, we hope to achieve several goals. First, we clarify how our view diverges from that described by Wyble and Chen. We argue that because the surprise memory test is disruptive, it is an insensitive tool for measuring the persistence of recently attended target attributes in memory. Second, we identify points of agreement between our view and that of Wyble and Chen. Like them, we believe that the strength of a mental representation is a critical factor in determining whether the representation persists long enough to be used in a surprise recognition task. We also agree that consolidation is one means of strengthening this representation. Finally, we suggest questions that should be addressed to clarify the factors that determine whether attended information can be reported in a surprise memory test. (PsycINFO Database Record PMID- 28557488 TI - Lying upside-down: Alibis reverse cognitive burdens of dishonesty. AB - The cognitive processes underlying dishonesty, especially the inhibition of automatic honest response tendencies, are reflected in response times and other behavioral measures. Here we suggest that explicit false alibis might have a considerable impact on these cognitive operations. We tested this hypothesis in a controlled experimental setup. Participants first performed several tasks in a preexperimental mission (akin to common mock crime procedures) and received a false alibi afterward. The false alibi stated alternative actions that the participants had to pretend to have performed instead of the actually performed actions. In a computer-based inquiry, the false alibi did not only reduce, but it even reversed the typical behavioral effects of dishonesty on response initiation (Experiment1) and response execution (Experiment 2). Follow-up investigations of response activation via distractor stimuli suggest that false alibis automatize either dishonest response retrieval, the inhibition of the honest response, or both (Experiments 3 and 4). This profound impact suggests that false alibis can override actually performed activities entirely and, thus, documents a severe limitation for cognitive approaches to lie detection. (PsycINFO Database Record PMID- 28557489 TI - Beyond opponent coding of facial identity: Evidence for an additional channel tuned to the average face. AB - Face identity can be represented in a multidimensional space centered on the average. It has been argued that the average acts as a perceptual norm, with the norm coded implicitly by balanced activation in pairs of channels that respond to opposite extremes of face dimensions (two-channel model). In Experiment 1 we used face identity aftereffects to distinguish this model from a narrow-band multichannel model with no norm. We show that as adaptors become more extreme, aftereffects initially increase sharply and then plateau. Crucially there is no decrease, ruling out narrow-band multichannel coding, but consistent with a two channel norm-based model. However, these results leave open the possibility that there may be a third channel, tuned explicitly to the norm (three-channel model). In Experiment 2 we show that alternating adaptation widens the range identified as the average whereas adaptation to the average narrows the range, consistent with the three-channel model. Explicit modeling confirmed the three-channel model as the best fit for the combined data from both experiments. However, a two channel model with decision criteria allowed to vary between adapting conditions, also provided a very good fit. These results support opponent, norm-based coding of face identity with additional explicit coding of the norm. (PsycINFO Database Record PMID- 28557490 TI - Combined effects of form- and meaning-based predictability on perceived clarity of speech. AB - The perceptual clarity of speech is influenced by more than just the acoustic quality of the sound; it also depends on contextual support. For example, a degraded sentence is perceived to be clearer when the content of the speech signal is provided with matching text (i.e., form-based predictability) before hearing the degraded sentence. Here, we investigate whether sentence-level semantic coherence (i.e., meaning-based predictability), enhances perceptual clarity of degraded sentences, and if so, whether the mechanism is the same as that underlying enhancement by matching text. We also ask whether form- and meaning-based predictability are related to individual differences in cognitive abilities. Twenty participants listened to spoken sentences that were either clear or degraded by noise vocoding and rated the clarity of each item. The sentences had either high or low semantic coherence. Each spoken word was preceded by the homologous printed word (matching text), or by a meaningless letter string (nonmatching text). Cognitive abilities were measured with a working memory test. Results showed that perceptual clarity was significantly enhanced both by matching text and by semantic coherence. Importantly, high coherence enhanced the perceptual clarity of the degraded sentences even when they were preceded by matching text, suggesting that the effects of form- and meaning-based predictions on perceptual clarity are independent and additive. However, when working memory capacity indexed by the Size-Comparison Span Test was controlled for, only form-based predictions enhanced perceptual clarity, and then only at some sound quality levels, suggesting that prediction effects are to a certain extent dependent on cognitive abilities. (PsycINFO Database Record PMID- 28557491 TI - The average facial expression of a crowd influences impressions of individual expressions. AB - People can accurately assess the "mood of a crowd" by rapidly extracting the average intensity of all the individual expressions, when the crowd consists of a set of faces comprising different expressions of the same individual. Here, we investigate the processes involved when people judge the expression intensity of individual faces that appear in the context of a more naturalistic crowd of different individuals' faces. We show that judgments of the intensity of happy and angry expressions for individual faces are biased toward the group mean expression intensity, even when the faces are all different individuals. In a second experiment, we demonstrate that this bias is not due to a generic tendency to endorse intermediate intensity expressions more frequently than more extreme intensity expressions. Together, these findings suggest that people integrate ensemble information about the group average expression when they make judgments of individual faces' expressions. (PsycINFO Database Record PMID- 28557492 TI - Decision-making training reduces the attentional blink. AB - Practice or training on a particular task often yields gains for the trained task; however, the extent to which these benefits generalize to other stimuli/tasks is contentious. It has been suggested that behavioral decision making/response selection training may enhance temporal visual attention, as measured using the attentional blink (AB) paradigm. Here, we show that AB can indeed be reduced through response selection training, which requires repeatedly performing a speeded decision-making task. Training gains garnered by this approach transferred to distinct AB measures, but not to unrelated measures of visual search and multitasking ability. Moreover, these changes were still evident 2 weeks after training completion. Crucially, training on 2 active control tasks-visual search and motion discrimination-did not elicit similar gains. Such malleability of temporal visual attention via response selection training offers tantalizing prospects for future cognitive enhancement endeavors. (PsycINFO Database Record PMID- 28557493 TI - Are goal states represented during kinematic imitation? AB - A number of studies have shown that observation of another person's actions can modulate one's own actions, such as when 2 individuals cooperate in order to complete a joint task. However, little is known about whether or not direct matching of specific movements is modulated by the goals of the actions observed. In a series of 7 experiments, we employed an action observation paradigm in which 2 coactors sat opposite each other and took turns to reach out to targets presented on a shared workspace. Importantly, coactors performed either the same goal at the reached-to location or a different goal. Although results consistently showed that the reaching action of 1 individual slows the observer's reaching action to the same spatial location, the effect was not modulated according to the adopted goals of coactors. These findings challenge the notion that the processes involved in the imitation of specific movements code for the action goals of those movements. (PsycINFO Database Record PMID- 28557494 TI - Identifying the locus of compatibility-based backward crosstalk: Evidence from an extended PRP paradigm. AB - The backward crosstalk effect (BCE) in dual tasking means that characteristics of Task 2 of 2 subsequently performed tasks influence Task 1 performance. This observation indicates that certain features of the second response are already activated to some degree before the first response is selected. Therefore, the BCE challenges bottleneck models, which assume that Task 2 response selection does not begin until Task 1 response selection is finished. Instead, an extended model with a capacity-unlimited response activation stage prior to the bottleneck as the locus of the BCE was suggested. To determine the exact locus of the BCE within the stages of task processing, 5 experiments were carried out. Experiments 1 to 4 were psychological refractory period-like experiments with 3 subsequent tasks. A prebottleneck locus of the BCE was ruled out in Experiments 1 to 3 by using the locus of slack logic. Additionally, a postbottleneck locus of the BCE was ruled out in Experiment 4 by using the effect propagation logic. To further support this latter conclusion, Experiment 5 applied a go-signal manipulation. Taken together, the results of all 5 experiments strongly suggest that the BCE has its locus in the capacity-limited stage, which contradicts the widely accepted notion that a capacity-unlimited stage of response activation preceding response selection proper is the locus of the BCE. (PsycINFO Database Record PMID- 28557495 TI - Working memory load and the retro-cue effect: A diffusion model account. AB - Retro-cues (i.e., cues presented between the offset of a memory array and the onset of a probe) have consistently been found to enhance performance in working memory tasks, sometimes ameliorating the deleterious effects of increased memory load. However, the mechanism by which retro-cues exert their influence remains a matter of debate. To inform this debate, we applied a hierarchical diffusion model to data from 4 change detection experiments using single item, location specific probes (i.e., a local recognition task) with either visual or verbal memory stimuli. Results showed that retro-cues enhanced the quality of information entering the decision process-especially for visual stimuli-and decreased the time spent on nondecisional processes. Further, cues interacted with memory load primarily on nondecision time, decreasing or abolishing load effects. To explain these findings, we propose an account whereby retro-cues act primarily to reduce the time taken to access the relevant representation in memory upon probe presentation, and in addition protect cued representations from visual interference. (PsycINFO Database Record PMID- 28557496 TI - Perceptual surprise aides inhibitory motor control. AB - Neurophysiological studies of cortico-motor excitability have shown that unexpected sounds are followed by motor inhibition. In a recent study, Leiva, Parmentier, Elchlepp, and Verbruggen (2015) derived a prediction from these findings: unexpected, task-irrelevant sounds should increase the ability to withhold motor responses in a Go/NoGo task. Contrary to that prediction, they found that playing unexpected sounds before NoGo-stimuli decreased the likelihood of successful motor inhibition. However, we here argue that the relative timing of unexpected events relative to NoGo-related motor activity is key. Cortico motor inhibition can be found only until ~150 ms after the onset of unexpected sounds. Therefore, since Leiva et al. (2015) placed their sounds 200 ms prior to NoGo-stimuli, the inhibitory influence of unexpected sounds may have fully abated before the critical inhibitory period. Consequently, we here repeated their study, with 1 key change: task-irrelevant sounds were presented 50 ms after NoGo stimulus onset, which ensures that cortico-motor inhibition takes place when motor inhibition is needed. Across 4 experiments, this changed timing produced the results predicted by the previous cortico-motor suppression findings: More responses were successfully withheld after unexpected sounds. These data provide new evidence for the fact that unexpected events can engage an inhibitory control process and benefit motor inhibition. (PsycINFO Database Record PMID- 28557497 TI - You said you would! The predictability of other's behavior from their intentions determines predictive biases in action perception. AB - The perception of an action is shifted farther along the observed trajectory if the observer has prior knowledge of the actor's intention. This intention-action prediction effect is explained by predictive perception models, wherein sensory input is interpreted in light of expectancies. This study altered the precision of the prediction by varying the predictability of the action from the intention, to increase/decrease the predictive perceptual bias. Participants heard an actor state an intention ("I'll take it"/"I'll leave it") before the actor reached or withdrew from an object, thus confirming or contradicting the intention. The intention was predictive of the action (75% congruency) for one group and counterpredictive (25%) for another. The action disappeared midmovement and participants estimated the disappearance position. The intention-action prediction effect was greater if the intention was predictive than if counterpredictive. However, participants needed to explicitly know the predictability rates (Experiments 1 and 3). No group differences emerged when both groups believed the intention was nonpredictive (Experiment 2a), nor when a nonpredictive intention was believed to be (counter)predictive (Experiment 2b). The perception of others behavior is determined by its predictability from their intentions, and the precision of our social predictions is adapted to individual differences in behavior. (PsycINFO Database Record PMID- 28557498 TI - Perceived control and voice handicap in patients with voice disorders. AB - OBJECTIVE: The purpose of the study was to replicate and extend previous research on the relation between perceived present control and voice handicap and to further examine the psychometric properties of a present control scale adapted for patients with voice disorders (Misono, Meredith, Peterson, & Frazier, 2016). METHOD: Sample 1 consisted of 1,129 patients recruited from a voice disorder clinic who completed measures of perceived present control, distress, and voice handicap in the clinic. Sample 2 consisted of 62 patients from the same clinic who completed measures of present control, distress, voice handicap, and general control beliefs online at baseline and measures of present control and voice handicap again 3 weeks later (n = 59). RESULTS: With regard to the psychometric properties of the voice-adapted present control scale, alpha coefficients were above .80 and the 3-week test-reliability coefficient was .69. There was mixed support for the hypothesized 1-factor structure of the scale. In Sample 1, present control was more strongly associated with lower voice handicap than was distress and accounted for significant variance in voice handicap controlling for distress. In Sample 2, present control at baseline predicted later voice handicap, controlling for general control beliefs and distress. CONCLUSIONS: Present control appears to be a promising target for adjunctive interventions for patients with voice disorders. An evidence-based online present control intervention (Hintz, Frazier, & Meredith, 2015) is being adapted for this patient population. (PsycINFO Database Record PMID- 28557500 TI - Do the effects of working memory training depend on baseline ability level? AB - There is a debate about the ability to improve cognitive abilities such as fluid intelligence through training on tasks of working memory capacity. The question addressed in the research presented here is who benefits the most from training: people with low cognitive ability or people with high cognitive ability? Subjects with high and low working memory capacity completed a 23-session study that included 3 assessment sessions, and 20 sessions of training on 1 of 3 training regiments: complex span training, running span training, or an active-control task. Consistent with other research, the authors found that training on 1 executive function did not transfer to ability on a different cognitive ability. High working memory subjects showed the largest gains on the training tasks themselves relative to the low working memory subjects-a finding that suggests high spans benefit more than low spans from training with executive function tasks. (PsycINFO Database Record PMID- 28557499 TI - The Dietary Inflammatory Index, shift work, and depression: Results from NHANES. AB - OBJECTIVES: Abnormal physiology (e.g., inflammation), brought on by environmental exposures (e.g., diet or shift work [SW]), can affect numerous bodily systems, including the brain, and may be associated with depressive symptomatology. The study examined the associations between SW and depressive symptoms and diet related inflammation (estimated by the Dietary Inflammatory Index [DII]) and depressive symptoms. Additionally, diet was examined as a mediator between SW and depressive symptoms. METHOD: Data were obtained from the U.S. National Health and Nutrition Examination Survey (Centers for Disease Control and Prevention, 2013). SW data were based on self-report. Dietary data were collected using 24-hr dietary recalls for DII calculation. Depressive symptoms were defined using a cut point of 10 (moderate) on the Patient Health Questionnaire-9 (PHQ-9). Logistic regression was used to estimate odds ratios and 95% confidence intervals (95% CI) for depressive symptoms by SW and DII quartiles. RESULTS: DII scores were associated with depressive symptoms among women. Women in DII quartile 4 were 30% more likely to report depressive symptoms than women in quartile 1 (95% CI [1.00 1.68]). There was no association between symptoms and SW when using a PHQ-9 cut point of 10. When using a cut-point of 5 (mild depressive symptoms), those working any form of SW were more likely to suffer from mild symptoms than day workers (odds ratio = 1.22; 95% CI [1.04-1.43]). There was some evidence for mediation by the DII between SW and depressive symptoms. CONCLUSIONS: Future longitudinal studies should examine effects of reductions in inflammation through diet on depressive symptoms, especially among shift workers, to elucidate the role of diet on depression among these groups. (PsycINFO Database Record PMID- 28557501 TI - Support from the morphological family when unembedding the stem. AB - Recent research investigating embedded stem priming effects with the masked priming paradigm and pseudoword primes (e.g., quickify-quick) has shown that priming effects can be obtained even when the embedded target word is followed by a non-morphological ending (e.g., quickald-quick). Here we examine the specific nature of such priming effects by testing whether they are modulated by morphological family size. We reasoned that if the effects are driven by pre lexical orthographic processing then they should not be influenced by the family size of the embedded target word. On the contrary, we found that embedded words having several morphologically related family members (e.g., serpentoche-SERPENT [English: snakerel-SNAKE]-serpents, serpentin, serpentine, serpenter, serpentant) generated greater priming than embedded words having only the plural form in the morphological family (e.g., dauphingri-DAUPHIN [English: dolphinald-DOLPHIN]). We therefore conclude that embedded stem priming is at least partly driven by processing at the level of lexical and morpho-semantic representations. (PsycINFO Database Record PMID- 28557502 TI - Common modality effects in immediate free recall and immediate serial recall. AB - In 2 experiments, participants were presented with lists of between 2 and 12 words for either immediate free recall (IFR) or immediate serial recall (ISR). Auditory recall advantages at the end of the list (modality effects) and visual recall advantages early in the list (inverse modality effects) were observed in both tasks and the extent and magnitude of these effects were dependent upon list length. Both tasks displayed modality effects with short lists that were large in magnitude but limited to the final serial position, consistent with those observed in the typically short lists used in ISR, and both tasks displayed modality effects with longer lists that were small in magnitude and more extended across multiple end-of-list positions, consistent with those observed in the typically longer lists used in IFR. Inverse modality effects were also observed in both tasks at early list positions on longer lengths. Presentation modality did not affect where recall was initiated, but modality effects were greatest on trials where participants initiated recall with the first item. We argue for a unified account of IFR and ISR. We also assume that the presentation modality affects the encoding of all list items, and that modality effects emerge due to the greater resistance of auditory items to output interference. (PsycINFO Database Record PMID- 28557503 TI - Fast or frugal, but not both: Decision heuristics under time pressure. AB - Heuristics are simple, yet effective, strategies that people use to make decisions. Because heuristics do not require all available information, they are thought to be easy to implement and to not tax limited cognitive resources, which has led heuristics to be characterized as fast-and-frugal. We question this monolithic conception of heuristics by contrasting the cognitive demands of two popular heuristics, Tallying and Take-the-Best. We contend that heuristics that are frugal in terms of information usage may not always be fast because of the attentional control required to implement this focus in certain contexts. In support of this hypothesis, we find that Take-the-Best, while being more frugal in terms of information usage, is slower to implement and fares worse under time pressure manipulations than Tallying. This effect is then reversed when search costs for Take-the-Best are reduced by changing the format of the stimuli. These findings suggest that heuristics are heterogeneous and should be unpacked according to their cognitive demands to determine the circumstances a heuristic best applies. (PsycINFO Database Record PMID- 28557504 TI - Does the acquisition of spatial skill involve a shift from algorithm to memory retrieval? AB - Performance on verbal and mathematical tasks is enhanced when participants shift from using algorithms to retrieving information directly from memory (Siegler, 1988a). However, it is unknown whether a shift to retrieval is involved in dynamic spatial skill acquisition. For example, do athletes mentally extrapolate the trajectory of the ball, or do they retrieve the future location from memory? To examine this question, 2 experiments were conducted using a task paradigm similar to the game Pong-a ball was launched from 1 side of the screen and participants attempted to position a paddle to intercept the ball. In Experiment 1, participants responded to a limited number of repeated trajectories. During the learning phase, the response deadline was near the paddle. During the difficult phase, the response deadline was closer to the launch point. During the critical phase, novel trajectories were introduced at the difficult response deadline. If participants are using a retrieval strategy by the critical phase, performance should be significantly worse on the novel trajectories, whereas if they are using an algorithmic strategy, performance on the novel trials should be similar to performance on the repeated trajectories. In Experiment 2, half the participants followed an experimental paradigm similar to Experiment 1 and half experienced all novel trajectories throughout the task. Our results were consistent with a shift from algorithmic processing to retrieval-participants performed significantly better on repeated trajectories relative to novel trajectories. Furthermore, retrieval strategies enhance performance above and beyond what is gained by practicing the algorithm alone. (PsycINFO Database Record PMID- 28557505 TI - Interaction between social categories in the composite face paradigm. AB - The composite face paradigm (Young, Hellawell, & Hay, 1987) is widely used to demonstrate holistic perception of faces (Rossion, 2013). In the paradigm, parts from different faces (usually the top and bottom halves) are recombined. The principal criterion for holistic perception is that responses involving the component parts of composites in which the parts are aligned into a face-like configuration are slower and less accurate than responses to the same parts in a misaligned (not face-like) format. This is often taken as evidence that seeing a whole face in the aligned condition interferes with perceiving its separate parts, but it remains unclear to what extent the composite face effect also reflects contributions from other potential sources of interference. We present a new variant of the paradigm involving composites created from top and bottom parts of familiar faces drawn from orthogonal social categories of gender and occupation. This allows us to examine the contributions of differences in relatively visual properties (gender) or relatively semantic properties (occupation) to composite interference and to measure whether variation in a task irrelevant category (e.g., differences in gender across the parts of the composite when the task is to categorize the occupation of one of the parts) will influence the size of the composite effect. Our findings show that the composite face effect can be modulated by task-irrelevant social categories and that this interference is primarily visual in nature because the influence of face gender is more direct and more consistent than the influence of occupation. (PsycINFO Database Record PMID- 28557506 TI - "A psychometric investigation of gender differences and common processes across borderline and antisocial personality disorders": Correction to Chun et al. (2017). AB - Reports an error in "A psychometric investigation of gender differences and common processes across borderline and antisocial personality disorders" by Seokjoon Chun, Alexa Harris, Margely Carrion, Elizabeth Rojas, Stephen Stark, Carl Lejuez, William V. Lechner and Marina A. Bornovalova (Journal of Abnormal Psychology, 2017[Jan], Vol 126[1], 76-88). In the article, there were two errors in the article's supplemental material. The supplemental material stated, "In each case, if the relaxed model fit significantly better than the baseline model (i.e., DeltaX2> 3.84, Deltadf =2), then the item under investigation was flagged as noninvariant; otherwise the item was marked as invariant." The value for DeltaX2 should have been 5.99. The supplemental material also stated, "If there was no decrement in fit as a function of constraining a given item, the item in question was flagged as noninvariant." It should have stated that these items were flagged as invariant. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2016-53090 001.) The comorbidity between borderline personality disorder (BPD) and antisocial personality disorder (ASPD) is well-established, and the 2 disorders share many similarities. However, there are also differences across disorders: most notably, BPD is diagnosed more frequently in women and ASPD in men. We investigated if (a) comorbidity between BPD and ASPD is attributable to 2 discrete disorders or the expression of common underlying processes, and (b) if the model of comorbidity is true across sex. Using a clinical sample of 1,400 drug users in residential substance abuse treatment, we tested 3 competing models to explore whether the comorbidity of ASPD and BPD should be represented by a single common factor, 2 correlated factors, or a bifactor structure involving a general and disorder-specific factors. Next, we tested whether our resulting model was meaningful by examining its relationship with criterion variables previously reported to be associated with BPD and ASPD. The bifactor model provided the best fit and was invariant across sex. Overall, the general factor of the bifactor model significantly accounted for a large percentage of the variance in criterion variables, whereas the BPD and AAB specific factors added little to the models. The association of the general and specific factor with all criterion variables was equal for men and women. Our results suggest common underlying vulnerability accounts for both the comorbidity between BPD and AAB (across sex), and this common vulnerability drives the association with other psychopathology and maladaptive behavior. This in turn has implications for diagnostic classification systems and treatment. (PsycINFO Database Record PMID- 28557507 TI - Structural learning difficulties implicate altered hippocampal functioning in adults with autism spectrum disorder. AB - Structural learning is fundamental to the formation of cognitive maps that are necessary for learning, memory, and spatial navigation. It also enables successful navigation of the social world, which is something that individuals with autism spectrum disorder (ASD) find particularly difficult. To master these situations, a person needs to bind pieces of information to one another and to consider the context in which experiences happen. Such binding is a capacity of the hippocampus. Although altered hippocampal function has for long been suspected to play a role in the etiology of ASD, the relevant evidence has remained inconclusive because few behavioral tests that are known to specifically necessitate preserved hippocampal function have been employed in studies of ASD. To address this gap in the literature, a total sample of 57 pairs of age and ability matched ASD and comparison participants was divided into 3 subsamples who were asked either to complete structural learning, or 1 of 2 configural learning control tasks (biconditional discrimination and transverse patterning) drawn from animal research. As predicted, ASD adults demonstrated specific difficulty with structural learning but not with other forms of configural learning. These differences were not attributable to decreased attentional shifting or increased perseveration, which would have indicated atypical frontal modulation of hippocampal processes. Instead, the observations implicate atypical hippocampal functioning as the source of structural learning difficulties in ASD. The data suggest that disturbances in domain-general cognitive processes such as structural learning, caused by altered hippocampal function, play a critical role in the etiology of ASD. (PsycINFO Database Record PMID- 28557509 TI - Insomnia symptoms drive changes in suicide ideation: A latent difference score model of community adults over a brief interval. AB - Insomnia is robustly associated with suicidal behavior, but methodological limitations in existing studies hinder nuanced understanding of this relationship. The current study addressed these limitations by utilizing a longitudinal design and advanced statistical modeling. Participants who endorsed lifetime experience of suicidal behavior were recruited through Amazon's Mechanical Turk (N = 589) and completed self-report online surveys at 6 time points over a 15-day period. Latent difference score modeling was utilized to investigate whether levels and/or changes in insomnia symptoms drive subsequent changes in suicide ideation, or vice versa. Results revealed that previous level of insomnia symptoms was predictive of positive changes in suicide ideation (i.e., level of insomnia symptoms predicted lagged increases in suicide ideation). This relationship was not bidirectional (i.e., suicide ideation exerted no effects on insomnia symptoms). Additionally, only previous level, and not previous changes, in insomnia symptoms were predictive of changes in suicide ideation. Our results help clarify the nature of the relationship between insomnia symptoms and suicide ideation as one that is unidirectional, thereby offering evidence of insomnia symptoms as a variable risk factor for suicide ideation. These findings yield clinical implications, including the importance of screening for insomnia symptoms, and provide support for exploring the potential effectiveness of insomnia treatments to target suicide ideation. Moreover, our study design and methodology establish a foundation for more rigorous and nuanced investigations of imminent suicide risk in future studies, which can ultimately promote better clinical practice in the reduction of suicidal behavior. (PsycINFO Database Record PMID- 28557510 TI - Endorsing help for others that you oppose for yourself: Mind perception alters the perceived effectiveness of paternalism. AB - How people choose to help each other can be just as important as how much people help. Help can come through relatively paternalistic or agentic aid. Paternalistic aid, such as banning certain foods to encourage weight loss or donating food to alleviate poverty, restricts recipients' choices compared with agentic aid, such as providing calorie counts or donating cash. Nine experiments demonstrate that how people choose to help depends partly on their beliefs about the recipient's mental capacities. People perceive paternalistic aid to be more effective for those who seem less mentally capable (Experiments 1 and 2), and people therefore give more paternalistically when others are described as relatively incompetent (Experiment 3). Because people tend to believe that they are more mentally capable than are others, people also believe that paternalistic aid will be more effective for others than for oneself, effectively treating other adults more like children (Experiments 4a-5b). Experiencing a personal mental shortcoming-overeating on Thanksgiving-therefore increased the perceived effectiveness of paternalism for oneself, such that participants thought paternalistic antiobesity policies would be more effective when surveyed the day after Thanksgiving than the day before (Experiment 6). A final experiment demonstrates that the link between perceived effectiveness of aid and mental capacity is bidirectional: Those receiving paternalistic aid were perceived as less mentally capable than those receiving relatively agentic aid (Experiment 7). Beliefs about how best to help someone in need are affected by subtle inferences about the mind of the person in need. (PsycINFO Database Record PMID- 28557511 TI - The heart trumps the head: Desirability bias in political belief revision. AB - Understanding how individuals revise their political beliefs has important implications for society. In a preregistered study (N = 900), we experimentally separated the predictions of 2 leading theories of human belief revision desirability bias and confirmation bias-in the context of the 2016 U.S. presidential election. Participants indicated who they desired to win, and who they believed would win, the election. Following confrontation with evidence that was either consistent or inconsistent with their desires or beliefs, they again indicated who they believed would win. We observed a robust desirability bias individuals updated their beliefs more if the evidence was consistent (vs. inconsistent) with their desired outcome. This bias was independent of whether the evidence was consistent or inconsistent with their prior beliefs. In contrast, we found limited evidence of an independent confirmation bias in belief updating. These results have implications for the relevant psychological theories and for political belief revision in practice. (PsycINFO Database Record PMID- 28557508 TI - Neural markers of emotional face perception across psychotic disorders and general population. AB - There is considerable variation in negative and positive symptoms of psychosis, global functioning, and emotional face perception (EFP), not only in schizophrenia but also in other psychotic disorders and healthy individuals. However, EFP impairment and its association with worse symptoms and global functioning have been examined largely in the domain of schizophrenia. The present study adopted a dimensional approach to examine the association of behavioral and neural measures of EFP with symptoms of psychosis and global functioning across individuals with schizophrenia spectrum (SZ; N = 28) and other psychotic (OP; N = 29) disorders, and never-psychotic participants (NP; N = 21). Behavioral and functional MRI data were recorded as participants matched emotional expressions of faces and geometrical shapes. Lower accuracy and increased activity in early visual regions, hippocampus, and amygdala during emotion versus shape matching were associated with higher negative, but not positive, symptoms and lower global functioning, across all participants. This association remained even after controlling for group-related (SZ, OP, and NP) variance, dysphoria, and antipsychotic medication status, except in amygdala. Furthermore, negative symptoms mediated the relationship between behavioral and brain EFP measures and global functioning. This study provides some of the first evidence supporting the specific relationship of EFP measures with negative symptoms and global functioning across psychotic and never-psychotic samples, and transdiagnostically across different psychotic disorders. Present findings help bridge the gap between basic EFP-related neuroscience research and clinical research in psychosis, and highlight EFP as a potential symptom-specific marker that tracks global functioning. (PsycINFO Database Record PMID- 28557513 TI - Shocking action: Facilitative effects of punishing electric shocks on action control. AB - Four experiments examined motivational effects of response-contingent electric shocks on action initiation. Although the shock was unambiguously aversive for the individual in line with subjective and functional criteria, results showed that the shock-producing action was initiated faster relative to a response producing no shock. However, no facilitation effect was found when strong shocks were delivered, ruling out increased emotional arousal as an explanation. The action was initiated faster even when the response discontinued to generate a shock. Furthermore, a control experiment with affectively neutral vibrotactile stimulations at homologous sites showed an analogous response facilitation effect. Overall, the results contradict the widespread belief that a contingency with a punishing response effect is sufficient for a response suppression. Instead, the results suggest that punishing action effects can facilitate action initiation via anticipatory feedback processes. Implications for theories and applications of punishment are discussed. (PsycINFO Database Record PMID- 28557512 TI - The nature-disorder paradox: A perceptual study on how nature is disorderly yet aesthetically preferred. AB - Natural environments have powerful aesthetic appeal linked to their capacity for psychological restoration. In contrast, disorderly environments are aesthetically aversive, and have various detrimental psychological effects. But in our research, we have repeatedly found that natural environments are perceptually disorderly. What could explain this paradox? We present 3 competing hypotheses: the aesthetic preference for naturalness is more powerful than the aesthetic aversion to disorder (the nature-trumps-disorder hypothesis); disorder is trivial to aesthetic preference in natural contexts (the harmless-disorder hypothesis); and disorder is aesthetically preferred in natural contexts (the beneficial disorder hypothesis). Utilizing novel methods of perceptual study and diverse stimuli, we rule in the nature-trumps-disorder hypothesis and rule out the harmless-disorder and beneficial-disorder hypotheses. In examining perceptual mechanisms, we find evidence that high-level scene semantics are both necessary and sufficient for the nature-trumps-disorder effect. Necessity is evidenced by the effect disappearing in experiments utilizing only low-level visual stimuli (i.e., where scene semantics have been removed) and experiments utilizing a rapid scene-presentation procedure that obscures scene semantics. Sufficiency is evidenced by the effect reappearing in experiments utilizing noun stimuli which remove low-level visual features. Furthermore, we present evidence that the interaction of scene semantics with low-level visual features amplifies the nature-trumps-disorder effect-the effect is weaker both when statistically adjusting for quantified low-level visual features and when using noun stimuli which remove low-level visual features. These results have implications for psychological theories bearing on the joint influence of low- and high-level perceptual inputs on affect and cognition, as well as for aesthetic design. (PsycINFO Database Record PMID- 28557514 TI - Cost-effectiveness of a statewide falls prevention program in Pennsylvania: Healthy Steps for Older Adults. AB - OBJECTIVES: Pennsylvania's Department of Aging has offered a falls prevention program, "Healthy Steps for Older Adults" (HSOA), since 2005, with about 40,000 older adults screened for falls risk. In 2010 to 2011, older adults 50 years or older who completed HSOA (n = 814) had an 18% reduction in falls incidence compared with a comparison group that attended the same senior centers (n = 1019). We examined the effect of HSOA on hospitalization and emergency department (ED) treatment, and estimated the potential cost savings. STUDY DESIGN: Decision tree analysis. METHODS: The following were included in a decision-tree model based on a prior longitudinal cohort study: costs of the intervention, number of falls, frequency and costs of ED visits and hospitalizations, and self-reported quality of life of individuals in each outcome condition. A Monte Carlo probabilistic sensitivity analysis assigned appropriate distributions to all input parameters and evaluated model results over 500 iterations. The model included all ED and hospitalization episodes rather than just episodes linked to falls. RESULTS: Over 12 months of follow-up, 11.3% of the HSOA arm and 14.8% of the comparison group experienced 1 or more hospitalizations (P = .04). HSOA participants had less hospital care when matched for falls status. Observed values suggest expected costs per participant of $3013 in the HSOA arm and $3853 in the comparison condition, an average savings of $840 per person. Results were confirmed in Monte Carlo simulations ($3164 vs $3882, savings of $718). CONCLUSIONS: The savings of $718 to $840 per person is comparable to reports from other falls prevention economic evaluations. The advantages of HSOA include its statewide reach and integration with county aging services. PMID- 28557515 TI - Connected Care: improving outcomes for adults with serious mental illness. AB - OBJECTIVES: To evaluate the effectiveness of Connected Care-a care coordination effort of physical and behavioral health managed care partners in Pennsylvania-on acute service use among adult Medicaid beneficiaries with serious mental illness (SMI). STUDY DESIGN: We examined changes in service utilization using a difference-in-differences model, comparing study group with a comparison group, and conducted key informant interviews to better understand aspects of program implementation. METHODS: We compared the difference in service use rates between baseline year and 2-year intervention period for the Connected Care group (n = 8633) with the difference in rates for the comparison group (n = 10,514), confirming results using a regression adjustment. RESULTS: Mental health hospitalizations (per 1000 members per month) decreased for the Connected Care group from 41.1 to 39.6, while increasing for the comparison group from 33.8 to 37.2 (P = .04). All-cause readmissions within 30 days decreased nearly 10% for Connected Care while increasing slightly for the comparison group (P < .01), with a similar pattern observed for 60- and 90-day all-cause readmissions. No differences were observed in physical health hospitalizations, drug and alcohol admissions, or ED use. Data from qualitative stakeholder interviews illuminated facilitators and barriers of implementing Connected Care. CONCLUSIONS: Payer level healthcare information sharing can help identify members who could benefit from care coordination services, inform care management activities, and assist with pharmacy management. Results can inform state, health plan, and provider efforts around integration of care for individuals with SMI and improve care efficiencies and quality, which is especially important in this time of Medicaid expansion. PMID- 28557516 TI - Patients' success in negotiating out-of-network bills. AB - OBJECTIVES: Out-of-network (OON) care is one area where patients might be more likely to challenge their healthcare bills due to the high out-of-pocket costs and unexpected charges related to emergency care or hospital-affiliated providers. We aimed to determine whether, and under what circumstances, patients negotiate with either insurers or providers when services are billed OON and how often patients that do engage in negotiation are successful. STUDY DESIGN: Internet-based survey. METHODS: We conducted a 2011 Internet survey on OON care on a nationally representative sample of privately insured adults (n = 721). We considered whether patients would be more likely to negotiate OON charges by demographic characteristics and under several scenarios: emergency visits, bills from hospital-affiliated OON providers at in-network hospitals, and balance bills. RESULTS: We found patients negotiated 19% of OON bills, were successful in lowering their costs 56% of the time, and were more likely to be successful negotiating with providers compared with insurers (63% vs 37%; P <.01). Men were more likely than women to be successful in lowering their costs (76% vs 50%; P <.05). OON bills for emergencies, providers at in-network hospitals, and with a balance bill were more likely to be negotiated, although bills from providers at in-network hospitals and with balance bills were less likely to be successfully negotiated. CONCLUSIONS: Patients had low rates of success in negotiating OON bills for emergency care and for OON providers at in-network hospitals. Policy makers aiming to protect patients under these scenarios should consider policies that allow for an easily accessible, formal, and unbiased mediation process. PMID- 28557517 TI - Economic value of pharmacist-led medication reconciliation for reducing medication errors after hospital discharge. AB - OBJECTIVES: Medication discrepancies at the time of hospital discharge are common and can harm patients. Medication reconciliation by pharmacists has been shown to prevent such discrepancies and the adverse drug events (ADEs) that can result from them. Our objective was to estimate the economic value of nontargeted and targeted medication reconciliation conducted by pharmacists and pharmacy technicians at hospital discharge versus usual care. STUDY DESIGN: Discrete-event simulation model. METHODS: We developed a discrete-event simulation model to prospectively model the incidence of drug-related events from a hospital payer's perspective. The model assumptions were based on data published in the peer reviewed literature. Incidences of medication discrepancies, preventable ADEs, emergency department visits, rehospitalizations, costs, and net benefit were estimated. RESULTS: The expected total cost of preventable ADEs was estimated to be $472 (95% credible interval [CI], $247-$778) per patient with usual care. Under the base-case assumption that medication reconciliation could reduce medication discrepancies by 52%, the cost of preventable ADEs could be reduced to $266 (95% CI, $150-$423), resulting in a net benefit of $206 (95% CI, $73-$373) per patient, after accounting for intervention costs. A medication reconciliation intervention that reduces medication discrepancies by at least 10% could cover the initial cost of intervention. Targeting medication reconciliation to high risk individuals would achieve a higher net benefit than a nontargeted intervention only if the sensitivity and specificity of a screening tool were at least 90% and 70%, respectively. CONCLUSIONS: Our study suggests that implementing a pharmacist-led medication reconciliation intervention at hospital discharge could be cost saving compared with usual care. PMID- 28557518 TI - Benchmarking health-related quality-of-life data from a clinical setting. AB - OBJECTIVES: Health-related quality of life (HRQoL) is an important clinical outcome, yet there is little guidance for its interpretation in clinical settings. One approach would use benchmarking to contextualize HRQoL results. Our objective was to construct a nationally representative HRQoL benchmark for use with a clinical sample. STUDY DESIGN: Cross-sectional analysis of HRQoL scores from: 1) the 2011 Medical Expenditures Panel Survey (MEPS), a representative sample of the noninstitutionalized US population; and 2) outpatient academic and community cardiology clinics within a large health system in 2012 and 2013. METHODS: The 2011 MEPS includes 21,959 adults who completed the HRQoL measures; 414 reported visiting a cardiologist. Of 1945 outpatient index visits during the study period that were not for outpatient cardiac catheterization, 1434 patients completed the HRQoL measures. The primary outcome was the Short Form 6-Dimension questionnaire (SF-6D). The secondary outcomes were the Mental Component Summary score and the Physical Component Summary score. RESULTS: The local cardiology clinic sample was 42% female with a mean Charlson Comorbidity Index (CCI) score of 1.74. The MEPS subsample of cardiology patients more closely matched the local cardiology clinic sample (43% female; mean CCI score of 1.57) than the entire MEPS sample (52% female; mean CCI score of 0.62). SF-6D scores for the local cardiology clinic sample were significantly better, statistically and clinically, in 4 of 5 age strata than the MEPS subsample of cardiology patients. CONCLUSIONS: HRQoL benchmarks can be created from current public datasets. Subgroups in national samples may provide more valid benchmarks for clinical populations. PMID- 28557519 TI - Does Medicare Managed Care reduce racial/ethnic disparities in diabetes preventive care and healthcare expenditures? AB - OBJECTIVES: Large and persistent racial/ethnic disparities exist in diabetes care. Considering the rapid rate of growth of Medicare Managed Care (MMC) plans among minority populations, our aim was to investigate whether disparities in diabetes management and healthcare expenditures are smaller in MMC versus Medicare fee-for-service (MFFS) plans. We hypothesized that racial/ethnic disparities in diabetes care and in health expenditures would be less pronounced in MMC compared with MFFS plans. STUDY DESIGN: Nationally representative data from the 2006 to 2011 Medical Expenditure Panel Survey on white, African American, and Hispanic seniors with diabetes were analyzed. METHODS: We examined 4 measures of diabetes care-regular foot check, eye exam, cholesterol check, and flu vaccine-and total and out-of-pocket (OOP) healthcare expenditures. We implemented the Institute of Medicine's definition of disparity, applied propensity score weighting to adjust for potential differential selection, and used a difference-in-differences generalized linear framework to estimate outcome measures. RESULTS: For African Americans, MMC was associated with a $1183 (P <.036) reduction and a $547 (P <.001) increase in disparities in total and OOP healthcare expenditures, respectively. For Hispanics, disparities in foot exam, flu shot, and cholesterol check decreased by 5, 10, and 7 percentage points (P <.001); additionally, disparities in total and OOP healthcare expenditures were reduced by $3588 and $276 (P <.001), respectively. MMC plans spend less on everyone, including whites. CONCLUSIONS: Hispanic/white disparities in diabetes management and healthcare expenditures were smaller in MMC than in MFFS plans. African American/white disparities were not consistently larger in 1 setting than the other. PMID- 28557521 TI - Mortality following hip fracture in Chinese, Japanese, and Filipina women. PMID- 28557522 TI - Estimating the social value of G-CSF therapies in the United States. AB - OBJECTIVES: To provide a comprehensive estimate of the total social value (TSV) delivered by granulocyte-colony stimulating factor (G-CSF) therapies in the United States in 2014. STUDY DESIGN: Estimation of the TSV of G-CSF, based on a targeted literature review of pivotal studies. METHODS: A literature review was conducted to obtain estimates of the adverse outcomes associated with myelosuppressive chemotherapy-induced febrile neutropenia (FN) and the positive impacts of G-CSFs. We monetized each outcome into a set of mutually exclusive value components that were aggregated to estimate the TSV. To estimate the share of TSV captured by manufacturers, we estimated 2014 profits from G-CSF using measures of industry revenues and operating costs. RESULTS: In 2014, approximately 314,440 patients received G-CSFs. Compared with what they would have experienced without G-CSFs, these patients were less likely to be hospitalized or die from FN, incur reductions in chemotherapy relative dose intensity, receive antibiotics, miss work, or experience reduced health-related quality of life. We estimated the social value from fewer FN hospitalizations to be $770 million; from fewer FN-related deaths, $2.65 billion; from fewer deaths due to higher effective chemotherapy doses, $4.83 billion; from reductions in antibiotics, $2.3 million; from reductions in indirect costs, $230 million; and from improvements in health-related quality of life, $1.9 million. The estimated 2014 US TSV of G-CSFs was $8.5 billion. Industry profits associated with G-CSFs were estimated at $1.3 billion, accounting for approximately 15% of the TSV. CONCLUSIONS: Based on our calculations, the TSV generated by G-CSFs in the United States in 2014 was substantial, with the majority of this value accruing to patients. PMID- 28557520 TI - Periodic health examinations and missed opportunities among patients likely needing mental health care. AB - OBJECTIVES: Periodic health examinations (PHEs) are the most common reason adults see primary care providers. It is unknown if PHEs serve as a "safe portal" for patients with mental health needs to initiate care. We examined how physician communication styles impact mental health service delivery in PHEs. STUDY DESIGN: Retrospective observational study using audio-recordings of 255 PHEs with patients likely to need mental health care. METHODS: Mixed-methods examined the timing of a mental health discussion (MHD), its quality, and the relationship between MHD quality and physician practice styles. MHD quality was measured against evidence-based practices as a 3-level variable (evidence-based, perfunctory, or absent). Physician practice styles were measured by: visit length, verbal dominance, and elicitation of a patient's agenda. A generalized ordered logit model was used. RESULTS: Many patients came with mental health concerns, as over 50% of the MHDs occurred in the first 5 minutes of the visit. One-third of the 255 patients had an evidence-based MHD, another third had a perfunctory MHD, and the remaining had no MHD. MHD quality was significantly associated with physician communication styles. Visits with physicians who tend to spend more time with patients, fully elicit patients' agendas, and let patients talk (instead of being verbally dominant) were more likely to deliver evidence-based MHD. CONCLUSIONS: If done well, PHEs could be a safe portal for patients to seek mental health care, but most PHEs fell short. Improving PHE quality may require reimbursement for longer visits and coaching for physicians to more fully elicit patients' agendas and to listen more attentively. PMID- 28557523 TI - Postdischarge telephone calls by hospitalists as a transitional care strategy. AB - OBJECTIVES: To determine whether treating hospitalists can identify and address early postdischarge problems through a structured telephone call. STUDY DESIGN: Prospective cohort study. METHODS: We studied patients insured through a managed care program who were discharged from a general internal medicine service of a university-affiliated public safety net hospital (Denver Health Medical Center) between March 1, 2012, and October 31, 2013. The hospitalist who treated the patient during their hospitalization contacted them 48 to 72 hours after discharge and completed a structured telephone assessment. We assessed the type and frequency of problems identified, the proportion of calls in which problems were independently addressed by the hospitalist, the proportion referred for additional managed care services, and the duration of calls and subsequent care coordination. RESULTS: Treating hospitalists identified 1 or more problems in 74 of the 131 patients (56%) contacted. The most common categories of problems were: new or worsening symptoms (41%), difficulty accessing recommended follow-up care (21%), and medication issues (20%). Hospitalists independently managed the problems identified in 68% of the calls; additional services were required in 32%. Median time spent per call was 8 minutes (interquartile range, 5-12). CONCLUSIONS: Treating hospitalists identified problems in over half of patients contacted by telephone shortly after discharge, the largest proportion of which were new or worsening symptoms. Hospitalists were able to address the majority of problems identified through the single, brief telephone encounter without utilizing additional resources. PMID- 28557524 TI - A call for a statewide medication reconciliation program. AB - In the outpatient setting, it is exceedingly difficult to know what medications our patients have been prescribed and are taking. Each encounter with a specialist, hospital, or pharmacy can generate a change to a patient's list of medications, and in most systems, this information is not communicated back to the primary care practice's electronic health record-the exception being opiate prescriptions. Prescription drug monitoring programs in 48 states list every opiate prescription, the name of the prescriber, and the date and location the prescription was picked up. We propose that policy makers act to expand these programs to all medications, thus improving the likelihood that any provider prescribing a new medication would know what medicines their patient is already taking. PMID- 28557526 TI - Molecular Profiling of Malignant Pleural Effusion in Metastatic Non-Small-Cell Lung Carcinoma. The Effect of Preanalytical Factors. AB - RATIONALE: Non-small-cell lung cancer (NSCLC)-associated malignant pleural effusions (MPEs) are sometimes the only available specimens for molecular analysis. OBJECTIVES: This study evaluates diagnostic yield of NSCLC-associated MPE, its adequacy for molecular profiling and the potential influence of MPE volume/cellularity on the analytic sensitivity of our assays. METHODS: Molecular results of 50 NSCLC-associated MPE cases during a 5-year period were evaluated. Molecular profiling was performed on cell blocks and consisted of fluorescent in situ hybridization (FISH) for ALK gene rearrangements and the following sequencing platforms: Sanger sequencing (for EGFR) and high-throughput pyrosequencing (for KRAS and BRAF) during the first 4 years of the study period, and targeted next-generation sequencing performed thereafter. RESULTS: A total of 50 NSCLC-associated MPE cases were identified where molecular testing was requested. Of these, 17 cases were excluded: 14 cases (28%) due to inadequate tumor cellularity and 3 cases due to unavailability of the slides to review. A total of 27 out of 50 MPE cases (54%) underwent at least EGFR and KRAS sequencing and FISH for ALK rearrangement. Of the 27 cases with molecular testing results available, a genetic abnormality was detected in 16 cases (59%). The most common genetic aberrations identified involved EGFR ( 9 ) and KRAS ( 7 ). Six cases had ALK FISH only, of which one showed rearrangement. MPE volume was not associated with overall cellularity or tumor cellularity (P = 0.360). CONCLUSIONS: Molecular profiling of MPE is a viable alternative to testing solid tissue in NSCLC. This study shows successful detection of genetic aberrations in 59% of samples with minimal risk of false negative. PMID- 28557527 TI - Return to Play After Shoulder Instability Surgery in National Collegiate Athletic Association Division I Intercollegiate Football Athletes. AB - BACKGROUND: Recent attention has focused on the optimal surgical treatment for recurrent shoulder instability in young athletes. Collision athletes are at a higher risk for recurrent instability after surgery. PURPOSE: To evaluate variables affecting return-to-play (RTP) rates in Division I intercollegiate football athletes after shoulder instability surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Invitations to participate were made to select sports medicine programs that care for athletes in Division I football conferences (Pac-12 Conference, Southeastern Conference [SEC], Atlantic Coast Conference [ACC]). After gaining institutional review board approval, 7 programs qualified and participated. Data on direction of instability, type of surgery, time to resume participation, and quality and level of play before and after surgery were collected. RESULTS: There were 168 of 177 procedures that were arthroscopic surgery, with a mean 3.3-year follow-up. Overall, 85.4% of players who underwent arthroscopic surgery without concomitant procedures returned to play. Moreover, 15.6% of athletes who returned to play sustained subsequent shoulder injuries, and 10.3% sustained recurrent instability, resulting in reduction/revision surgery. No differences were noted in RTP rates in athletes who underwent anterior labral repair (82.4%), posterior labral repair (92.9%), combined anterior-posterior repair (84.8%; P = .2945), or open repair (88.9%; P = .9362). Also, 93.3% of starters, 95.4% of utilized players, and 75.7% of rarely used players returned to play. The percentage of games played before the injury was 49.9% and rose to 71.5% after surgery ( P < .0001). Athletes who played in a higher percentage of games before the injury were more likely to return to play; 91% of athletes who were starters before the injury returned as starters after surgery. Scholarship status significantly correlated with RTP after surgery ( P = .0003). CONCLUSION: The majority of surgical interventions were isolated arthroscopic stabilization procedures, with no statistically significant difference in RTP rates when concomitant arthroscopic procedures or open stabilization procedures were performed. Athletes who returned to play often played in a higher percentage of games after surgery than before the injury, and many played at the same or a higher level after surgery. PMID- 28557528 TI - Airway Closure in Acute Respiratory Distress Syndrome: An Underestimated and Misinterpreted Phenomenon. PMID- 28557525 TI - Human Milk Provision Experiences, Goals, and Outcomes for Teen Mothers with Low Birth-Weight Infants in the Neonatal Intensive Care Unit. AB - INTRODUCTION: Breastfeeding rates are virtually unknown for teen mothers whose low-birth-weight (LBW; <2500 gm) infants are hospitalized in the neonatal intensive care unit (NICU). The objective was to examine the infant feeding experiences, goals, and outcomes of teen mothers of LBW infants. METHODS: We conducted a multimethod study using a qualitative research design, survey, and infant medical records. The primary data source was individual interviews conducted with teen mothers of LBW infants hospitalized in a tertiary NICU. Content analysis and descriptive statistics were used for data analysis. RESULTS: All 15 teen mothers (12 black, 3 Hispanic) wanted what was best for their infants and initiated lactation by breast pump. However, maintaining lactation was challenging and the following barriers were identified: fear of being judged; body image issues; influence of the maternal grandmother; and disorganized thought processes about combining pumping with returning to school or work. Despite these barriers, 50% of the teen mothers met their goals for human milk provision at NICU discharge. CONCLUSION: Most of the teen mothers' lactation barriers reflected their adolescent developmental stage. Potential interventions are identified and include focus groups with teen mothers and maternal grandmothers and lactation support by NICU-based teen breastfeeding peer counselors. PMID- 28557529 TI - Oak wine barrel as an active vessel: A critical review of past and current knowledge. AB - We review the role of the oak barrel as an active vessel for wine maturation. We present a historical background to highlight that previously established aspects of processes occurring with wine inside the oak barrel are still without confirmation. We argue that recently published new findings on the topic are determining factors in defining the manner in which the oak barrel works with wine. Several studies have been published reviewing how the wine barrel functions as an active vessel that releases chemical compounds into the wine, improving its physical, chemical, and sensory properties. Nevertheless, there are hardly any studies that describe how a wine barrel functions as an active vessel. The present review details the main factors affecting the gas exchange capacity of the barrel, such as the pressure drop generated within the barrel, the formation of a headspace, the effect of wood anatomy, the different oxygen entry routes, the role of wood moisture content and soluble ellagitannins, and the effect of barrel toasting on cooperage. Finally, a hypothesis is proposed regarding the function of the barrel as an active vessel, which determines the manner in which it interacts with the wine that it contains during aging. PMID- 28557530 TI - Minding the Mind-Body Literature: Focusing on Veterans. PMID- 28557531 TI - Importance of short-term continuing care plan adherence on long-term outcomes among patients discharged from residential substance use treatment. AB - BACKGROUND: Patients adherent to their recommended treatment regimen demonstrate favorable outcomes. However, it is unclear whether there are specific short-term continuing care performance variables indicative of better long-term prognosis. OBJECTIVE: This study determined the impact of attendance at an outpatient appointment within 7 days post-discharge from residential treatment on 12-month outcomes. METHOD: Data were abstracted from electronic medical records for 275 patients (58.9% male) discharged from a single residential treatment program. All discharge plans included a 7-day outpatient appointment with a provider in their home community. Patients were dichotomized based on their attendance at the initial appointment to yield a re-engagement variable. Twelve-month outcomes included past 30-day and continuous abstinence rates, quality of life, and long term adherence to continuing care plans. RESULTS: Patients attending their initial outpatient appointment within 7 days of discharge evidenced better long term outcomes relative to patients who did not with respect to continuous abstinence (75.4% vs. 37.3%), past-30-day abstinence (92.0% vs. 70.6%), quality of life (94.2% vs. 78.4%), and adherence (66.4% vs. 9.8%). Re-engagement remained a significant predictor of continuous abstinence and quality of life at 12 months after controlling for 12-month adherence and relevant demographic characteristics. CONCLUSION: Treatment providers are encouraged to emphasize the relative importance of attending initial post-discharge appointments in achieving successful long-term outcomes. Allocation of resources to enhance engagement during residential treatment may be justified in that there may be value in actively encouraging patients to participate in continuing care activities, particularly shortly following discharge. PMID- 28557532 TI - An Experimental Model to Study the Impact of Lipid Oxidation on Contact Lens Deposition In Vitro. AB - PURPOSE: This study was to establish a controlled in vitro test system to study the effect of lipid oxidation on lipid deposition on contact lenses. METHODS: Fatty acids with varying degree of unsaturation were oxidized using the Fenton reaction. The degree of lipid oxidation and the lipid moieties formed during the oxidation were identified and estimated by various lipid staining techniques following separation with thin-layer chromatography, and by measuring thiobarbituric acid reactive substances or peroxides in solution. Two different silicone hydrogel-based contact lenses (Balafilcon A and Senofilcon A) were incubated with fatty acids laced with radioactive tracer oxidized to varying degrees, and the amount of lipid deposition was measured using unoxidized lipid samples as controls. RESULTS: The Fenton reaction together with the analytical methods to analyze the lipid oxidation can be used to control oxidation of lipids to a desired amount. In general, saturated fatty acids are not oxidized, the monounsaturated oleic acid produced peroxides while poly-unsaturated lipids initially produced peroxides and then fragmented into reactive aldehydes. Incubation with mildly oxidized lipids (most likely lipid peroxides) resulted in increased lipid deposition on Balafilcon A lenses compared to unoxidized lipids, but this was not observed for Senofilcon A lenses. Further oxidation of the lipids (carbon chain breakup) on the other hand resulted in diminished lipid deposition for both contact lens types. CONCLUSIONS: This study provides a method for inducing and controlling lipid oxidation so that the effect of lipid oxidation on contact lens binding can be compared. It could be shown that the degree of lipid oxidation has different effects on the lipid deposition on different contact lens types. PMID- 28557533 TI - Induced Cell Turnover: A Novel Therapeutic Modality for In Situ Tissue Regeneration. AB - Induced cell turnover (ICT) is a theoretical intervention in which the targeted ablation of damaged, diseased, and/or nonfunctional cells is coupled with replacement by partially differentiated induced pluripotent stem cells in a gradual and multiphasic manner. Tissue-specific ablation can be achieved using pro-apoptotic small molecule cocktails, peptide mimetics, and/or tissue-tropic adeno-associated virus-delivered suicide genes driven by cell type-specific promoters. Replenishment with new cells can be mediated by systemic administration of cells engineered for homing, robustness, and even enhanced function and disease resistance. Otherwise, the controlled release of cells can be achieved using implanted biodegradable scaffolds, hydrogels, and polymer matrixes. In theory, ICT would enable in situ tissue regeneration without the need for surgical transplantation of organs produced ex vivo, and addresses non transplantable tissues (such as the vasculature, lymph nodes, and the nervous system). This article outlines several complimentary strategies for overcoming barriers to ICT in an effort to stimulate further research at this promising interface of cell therapy, tissue engineering, and regenerative medicine. PMID- 28557534 TI - The Influence of Information Appraisals and Information Behaviors on the Acceptance of Health Information: A Study of Television Medical Talk Shows in South Korea. AB - As television medical talk shows have become an increasingly popular source of health information, it is important to understand the processes by which people come to accept, at times unconditionally, the information presented by these shows. Based on the heuristic-systematic model (HSM), this study explores the way by which individuals process health information from television medical talk shows. Specifically, this study examines the relationship between information exposure, information appraisals (e.g., appropriateness and incoherence), information behaviors (e.g., information seeking and sharing), and unconditional acceptance of health information. Results from a survey of 588 women in South Korean indicate that an individual's appraisal of information as being appropriate or incoherent influences unconditional acceptance of health information. Both types of information appraisals are positively associated with information seeking, which is negatively associated with unconditional acceptance of information. In contrast, neither of these appraisals have an impact on unconditional acceptance via information sharing. Notably, when information appraisals are not considered, information exposure is positively associated with information sharing, which is then positively associated with unconditional acceptance. Implications for health information consumers and practitioners are discussed. PMID- 28557535 TI - Peripapillary Atrophy in High Myopia. AB - PURPOSE: To evaluate peripapillary atrophy (PPA) in high myopia (HM) as a function of extent of myopia, axial length (AL), and age. METHODS: Medical records from patients (n = 88) seen in the Ophthalmology Department of the Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China, and diagnosed with high myopia (HM)-defined as spherical equivalent (SE) of >6.00 diopters (D) of myopia in either eye-were included in this study. Eyes were classified according to SE and age. For the SE classification, individual eyes (n = 169) were arranged as follows: groups A1 (SE -6.00to -9.00D), A2 (-9.25 to 16.50D), and A3 (-16.75 to -27.00D). For the age classification, eyes (n = 154) were arranged as follows: groups B1 (5-18 years old), B2 (18.1-40 years old), and B3 (40.1-69 years old). Outcome measures included correlation of areas of optic nerve head (ONH), PPA, and peripapillary chorioretinal atrophy (PCA) with SE, age, and AL. Morphological parameters were measured using the 1000-edition program of 3D-OCT 2000 ( http://eyecare.topcon.com.cn/index.php?optionid = 748&autoid = 8 ) clinical auto-analyzer module. RESULTS: Average areas-ONH (PPA, PCA)-in groups A1, A2, and A3 were 1.95 (2.05, 0.42), 2.42 (4.44, 1.39), and 2.52 (7.19, 3.64) mm2, respectively; average areas were 1.99 (1.40, 0.03), 2.49 (4.68, 1.92), and 2.28 (5.99, 2.78) mm2 in groups B1, B2, and B3, respectively. There were statistically significant differences among groups A1, A2, and A3 (F = 6.03, 18.91, 13.86, all p < 0.01), and among B1, B2, and B3 (F = 5.46, 21.89, 13.06, all p < 0.01). ONH correlated only with SE (r = -0.30, p < 0.01). PPA and PCA correlated with SE, age, and AL (PPA: r = -0.53, 0.47, 0.61; PCA: r = -0.42, 0.46, 0.48; all p < 0.01). CONCLUSIONS: PPA and PCA correlated with SE, age, and AL; ONH correlated with SE, may be with age. PMID- 28557536 TI - Preoperative Hand Decontamination in Ophthalmic Surgery: A Comparison of the Removal of Bacteria from Surgeons' Hands by Routine Antimicrobial Scrub versus an Alcoholic Hand Rub. AB - PURPOSE: The goal of this experiment was to evaluate and compare the antimicrobial efficacy of routine preoperative hand washing using commercial medicated sponge brushes versus an alcoholic hand rub, by comparing bacterial growth on ophthalmic surgeons' hands after application of each of these methods. METHODS: Twenty ophthalmic surgeons were recruited at the Hadassah-Hebrew University Medical Center in Jerusalem, Israel. Samples were collected twice from the hands of each surgeon after hand decontamination using two different protocols during routine surgical practice. The routine preparation consisted of a 3-minute surgical scrub using commercial brush-sponges incorporating either 4% chlorhexidine gluconate (CHG) or 1% povidone-iodine (PVP-I) formulations with detergent, followed by drying the hands with a sterile towel, while the 70% ethanol solution was applied for 60-seconds and allowed to air dry. Half of the group was randomly assigned to provide samples first after the routine method and the alcoholic solution a week later, and the other half of the group was sampled in the reverse order. Viable counts of bacteria were evaluated using a modified glove juice method. Bacterial colonies were enumerated after incubation for 24 hours and expressed as colony forming units (CFU)/mL for each pair of hands. RESULTS: Geometric mean counts were 1310 and 39 CFU/mL, in the routine and alcohol rub groups, respectively, representing a mean log10 reduction in 1.53. The difference between the paired bacterial counts for the routine versus the alcohol rub was statistically significant (p < 0.0001). There was no statistically significant difference between log10 reductions for CHG and PVP-I (p = 0.97). CONCLUSIONS: This study provides evidence that an alcohol rub protocol is more effective in reducing bacterial counts on hands than routine surgical hand preparation with PVP-I and CHG in a population of practicing ophthalmic surgeons in the operative clinical setting. Thus, it provides a safe alternative as a preoperative hand disinfection method. PMID- 28557538 TI - Attention-Deficit Hyperactivity and Obsessive-Compulsive Symptoms in Adult Patients With Primary Restless Legs Syndrome: Different Phenotypes of the Same Disease? AB - OBJECTIVES: To investigate the prevalence of attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) symptoms in adult patients with primary restless legs syndrome (RLS) and to determine the iron biological correlates of these comorbidities. PARTICIPANTS AND METHODS: We obtained demographic and clinical data from consecutive 105 outpatients with idiopathic RLS who answered validated questionnaires designed to assess the presence of ADHD and OCD symptoms. In these patients, iron blood parameters were routinely checked. RESULTS: Of the total sample, 42.86% of the patients with RLS showed symptoms reminiscent either of ADHD or OCD. Prevalence of ADHD and OCD symptoms was 27.62% and 7.62%, respectively. Compared to other groups, a significantly higher percentage of RLS patients with ADHD symptoms was on antidepressant (p = 0.012); and women with ADHD symptoms, either alone or combined with OCD symptoms, showed significant reduced ferritin concentrations compared to men with either isolated ADHD symptoms or with combined ADHD and OCD symptoms (p = 0.028 and p = 0.025, respectively). CONCLUSIONS: Our findings highlight the high prevalence of ADHD and OCD symptoms in adult patients with primary RLS and independently of serum iron stores decrease, except for women with ADHD symptoms either alone or in combination with OCD symptoms. This may suggest an overlapping neurobiological dopaminergic and serotoninergic dysfunction in ADHD, OCD, and RLS, and question the expression of different RLS phenotypes. The efficacy of dopamine agonists in these groups of patients should be questioned in future studies. PMID- 28557537 TI - Respectable Gentlemen and Street-Savvy Men: HIV Vulnerability in Sri Lanka. AB - In this article, I investigate how particular discourses surrounding class specific understandings of sexual behavior and female morality shape awareness and views of the disease and personal vulnerability. Although both groups belong to the working class, those employed by the transportation board consider themselves government servants and, therefore, "respectable gentlemen." Construction workers identify easily with their class position, recognizing and sometimes trying to live up to the stereotypes of free sexuality. These different perceptions directly affect their concern and awareness of risk factors for sexually transmissible infections and safe-sex practices. While the "respectable gentlemen" consider themselves invulnerable, the "street-savvy men" learned about risks and took precautions to prevent STIs. PMID- 28557539 TI - Construction and temporal behaviour study of multi RLC intense light pulses for dermatological applications. AB - Driving a flash lamp in an intense pulsed light system requires a high-voltage DC power supply, capacitive energy storage and a flash lamp triggering unit. Single, double, triple and quadruple-mesh discharge and triggering circuits were constructed to provide intense light pulses of variable energy and time durations. The system was treated as [Formula: see text] circuit in some cases and [Formula: see text] circuit in others with a light pulse profile following the temporal behaviour of the exciting current pulse. Distributing the energy delivered to one lamp onto a number of LC meshes permitted longer current pulses, and consequently increased the light pulse length. Positive results were obtained when using the system to treat skin wrinkles. PMID- 28557540 TI - Prediction of long-term survival in patients with metastatic gastrointestinal stromal tumor: analysis of a large, single-institution cohort. AB - BACKGROUND: A subset of patients with metastatic GIST become long-term survivors, and a more precise prediction of outcome could improve clinical decision-making. MATERIAL AND METHODS: One-hundred and thirty-three patients diagnosed with metastatic GIST from 1995 to 2013 were identified from the sarcoma database at Oslo University Hospital. Clinical data prospectively registered in the database were supplemented with retrospective review of medical records. Factors associated with survival were analyzed using Kaplan-Meier curves, log-rank test, univariate and multivariate Cox regression analyses. RESULTS: One-hundred and fifteen patients with metastatic GIST were included in the final study cohort. Median overall survival (OS) was 6.9 years (95% CI 5.6-8.3). Factors associated with long-term survival in univariate analysis were good baseline performance status (ECOG <=1; p < .001), young age (p = .022), oligometastatic disease (OMD) (<=3 metastases; p < .001), maximum tumor diameter <5 cm (p < .001), surgery for metastatic disease (p = .005), surgery of the primary tumor (p < .001), normal baseline hemoglobin level (p = .05), normal baseline albumin level (p = .001) and normal baseline neutrophil count (p = .03). On multivariate analysis, good performance status, small tumor diameter and, OMD were the factors associated with long-term survival. Five and 10-year OS for patients with OMD were 89% and 71%, respectively, compared to 38% and 20% for patients with polymetastatic disease (p < .001). CONCLUSIONS: In this single-institution cohort of patients, OMD was as a strong prognostic factor in patients with metastatic GIST. Patients with OMD had an outcome similar to patients with high-risk localized disease, and should be regarded as a separate category among patients with metastatic GIST. PMID- 28557541 TI - Tracking SBRT for liver tumors with a gimbaled linac system: a single institution experience. PMID- 28557542 TI - The efficacy of fractional carbon dioxide (CO2) laser combined with terbinafine hydrochloride 1% cream for the treatment of onychomycosis. AB - BACKGROUND: Although systemic and topical antifungal agents are widely used to treat onychomycosis, oral medications can cause adverse effects and the efficacy of topical agents is not satisfying. Currently, laser treatment has been studied for its efficacy in the treatment of onychomycosis. Our study was aimed to evaluate the efficacy of fractional carbon dioxide (CO2) laser treatment combined with terbinafine cream for 6 months in the treatment of onychomycosis and to analyze the influencing factors. METHODS: A total of 30 participants (124 nails) with clinical and mycological diagnosis of onychomycosis received fractional CO2 laser treatment at 2-week interval combined with terbinafine cream once daily for 6 months. The clinical efficacy rate (CER) was assessed from the percentage of fully normal-appearing nails or nails with <=5% abnormal appearance, and the mycological clearance rate (MCR) was assessed from the percentage of nails with negative fungal microscopy. RESULTS: The CER was evaluated at 3 time points: at the end of treatment (58.9%), at 1 month after the last treatment (63.5%), and at 3 months after the last treatment (68.5%). The MCRs at 1 month and 3 months after the last treatment were 77.4 and 74.2%, respectively. The evaluation of influencing factors showed significantly higher CER (p < 0.05) in nails of participants with age <50 years, distal lateral subungual onychomycosis (DLSO), superficial white onychomycosis (SWO), nail thickness <2 mm, affected first-to fourth finger/toenails, Trichophyton rubrum, and Trichophyton mentagrophytes. All participants experienced tolerable mild burning sensation during laser treatment, but there were no other adverse reactions reported. CONCLUSIONS: Fractional CO2 laser treatment combined with terbinafine cream for 6 months was an effective and safe method for the treatment of onychomycosis. There were 5 factors that positively influenced the treatment outcome: age, clinical type of onychomycosis, nail thickness, involved nail, and species of fungus. PMID- 28557544 TI - Safety Assessment of Oil from Pequi (Caryocar brasiliense Camb.): Evaluation of the Potential Genotoxic and Clastogenic Effects. AB - Genotoxic data of medicinal plants and functional foods are required as part of the risk assessment by international regulatory agencies. Due to its food consumption and ethnopharmacological relevance, pequi oil (Caryocar brasiliense Camb.) is one of these compounds to be studied. The aim of this study was to evaluate the cytotoxic, genotoxic, and clastogenic effects of the oil from the pulp of C. brasiliense (OPCB) in vivo and in vitro. Initially, the Artemia salina in vitro assay was conducted to determine the cells viability rate of different doses of the OPCB. Subsequently, comet assay (Organization for Economic Cooperation and Development, OECD 489) and micronucleus test (OECD 474) were performed in blood and bone marrow of Wistar rats treated orally with a 125, 250, 500, or 1000 mg/kg/bw of the OPCB for 4 weeks. The chemical analysis indicated the presence of beta-carotene and lycopene in the oil. In the A. salina test, all OPCB doses maintained cell viability rates statistically similar to the negative control. The in vivo tests performed showed that OPCB did not show significant genotoxic or clastogenic effects in cells analyzed with the four doses tested. Altogether, these results indicate that, under our experimental conditions, C. brasiliense fruit oil did not reveal genetic toxicity in rat cells. PMID- 28557543 TI - Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages. AB - RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by impaired clearance of pulmonary bacteria. OBJECTIVES: The effect of COPD on alveolar macrophage (AM) microbicidal responses was investigated. METHODS: AMs were obtained from bronchoalveolar lavage from healthy donors or patients with COPD and challenged with opsonized serotype 14 Streptococcus pneumoniae. Cells were assessed for apoptosis, bactericidal activity, and mitochondrial reactive oxygen species (mROS) production. A transgenic mouse line in which the CD68 promoter ensures macrophage-specific expression of human induced myeloid leukemia cell differentiation protein Mcl-1 (CD68.hMcl-1) was used to model the molecular aspects of COPD. MEASUREMENTS AND MAIN RESULTS: COPD AMs had elevated levels of Mcl-1, an antiapoptotic B-cell lymphoma 2 family member, with selective reduction of delayed intracellular bacterial killing. CD68.hMcl-1 AMs phenocopied the microbicidal defect because transgenic mice demonstrated impaired clearance of pulmonary bacteria and increased neutrophilic inflammation. Murine bone marrow derived macrophages and human monocyte-derived macrophages generated mROS in response to pneumococci, which colocalized with bacteria and phagolysosomes to enhance bacterial killing. The Mcl-1 transgene increased oxygen consumption rates and mROS expression in mock-infected bone marrow-derived macrophages but reduced caspase-dependent mROS production after pneumococcal challenge. COPD AMs also increased basal mROS expression, but they failed to increase production after pneumococcal challenge, in keeping with reduced intracellular bacterial killing. The defect in COPD AM intracellular killing was associated with a reduced ratio of mROS/superoxide dismutase 2. CONCLUSIONS: Up-regulation of Mcl-1 and chronic adaption to oxidative stress alter mitochondrial metabolism and microbicidal function, reducing the delayed phase of intracellular bacterial clearance in COPD. PMID- 28557545 TI - Sexual Risk and Protective Behaviors Among Reproductive-Aged Women in the United States. AB - BACKGROUND: In 2014, women represented 19% of HIV diagnoses in the United States. Of these, 78% were among black women and Latinas. Sexual risk behaviors-for example concurrent sex partnerships, nonmonogamous sex partners, and inconsistent condom use-are associated with increased HIV transmission and prevalence; these behaviors have been understudied, collectively, in women. METHODS: To examine HIV related sexual risk behaviors among sexually active women aged 18-44 years by race/ethnicity and over time, we used data from the 2006-2008, 2008-2010, and 2011-2013 cycles of the National Survey of Family Growth. We estimated weighted percentages and performed logistic regression to measure adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for associations between selected behaviors and sociodemographic covariates. RESULTS: Among 13,588 women, 1.1% reported concurrent sex partnerships, 10.3% reported male partners whom they perceived were nonmonogamous, and 21.1% reported using a condom at either last vaginal or anal sex. Black women (aPR = 1.52; CI = 1.36-1.71) and Latinas (aPR = 1.29; CI = 1.14-1.47) were more likely to report condom use at either last vaginal or anal sex compared with white women. However, black women were also more likely to report concurrent opposite-sex partnerships (aPR = 2.44; CI = 1.57 3.78) and perceived nonmonogamous sex partners (aPR = 1.33; CI = 1.14-1.56) compared with white women. CONCLUSIONS: Improved HIV behavioral risk-reduction strategies are needed for women. Black women could benefit from interventions that address partnership concurrency. For black women and Latinas, who are more likely to use condoms, further examination of broader social and structural factors as contributors to racial/ethnic gaps are warranted and vital for understanding and decreasing HIV-related disparities. PMID- 28557547 TI - Readiness to Use Psychoactive Substances Among Second-Generation Adolescent Immigrants and Perceptions of Parental Immigration-Related Trauma. AB - OBJECTIVES: This research explores the relationship between parental immigration related trauma and second-generation adolescent substance abuse. To examine this relationship, we focused on Ethiopian adolescents in Israel who are at risk for substance abuse. Many immigrants from Ethiopia experienced severe immigration trauma and research indicates the existence of transgenerational trauma transmission. The current research focuses on the connection between Ethiopian adolescents' perceptions of their parents' immigration trauma and their readiness to use psychoactive substances. DESIGN: Five hundred and ten second-generation Ethiopian adolescents (Israeli-born children of Ethiopian immigrants) filled out questionnaires examining socio-demographic characteristics, immigration impact and readiness to consume alcoholic beverages and use illegal drugs. RESULTS: Our findings show that readiness levels among Ethiopian adolescents to use psychoactive substances are relatively low, and that parental trauma only affects the readiness to consume alcohol. The levels of readiness to consume drugs were partially related to parental trauma. Conclusions/Importance: Transgenerational trauma transmission should be considered when implementing alcohol and substance abuse treatment and prevention policies among second generation immigrants. This should be done on all levels including personal, interpersonal and community levels. PMID- 28557546 TI - Inflammation-associated DNA methylation patterns in epithelium of ulcerative colitis. AB - Aberrant DNA methylation patterns have been reported in inflamed tissues and may play a role in disease. We studied DNA methylation and gene expression profiles of purified intestinal epithelial cells from ulcerative colitis patients, comparing inflamed and non-inflamed areas of the colon. We identified 577 differentially methylated sites (false discovery rate <0.2) mapping to 210 genes. From gene expression data from the same epithelial cells, we identified 62 differentially expressed genes with increased expression in the presence of inflammation at prostate cancer susceptibility genes PRAC1 and PRAC2. Four genes showed inverse correlation between methylation and gene expression; ROR1, GXYLT2, FOXA2, and, notably, RARB, a gene previously identified as a tumor suppressor in colorectal adenocarcinoma as well as breast, lung and prostate cancer. We highlight targeted and specific patterns of DNA methylation and gene expression in epithelial cells from inflamed colon, while challenging the importance of epithelial cells in the pathogenesis of chronic inflammation. PMID- 28557549 TI - Clinician-Targeted Mobile Apps in Palliative Care: A Systematic Review. AB - BACKGROUND: The availability of smartphone applications has increased rapidly including applications related to palliative care. The scope of these available apps has not been synthesized. OBJECTIVE: The purpose of this study was to identify and review available palliative care-related smartphone applications for clinicians. DESIGN: Smartphone application platform stores, for example, App Store iOS, Google Play Store, Windows App-Microsoft Store, and Blackberry World App store were searched (December 2016) using relevant key words. RESULTS: Forty six palliative care applications targeting clinicians were identified, including clinical guidelines (n = 17), advance care planning (n = 9), training materials in palliative care (n = 7), and pharmaceutical tools (n = 7), and platforms for distributing current palliative care news, articles, and opinions (n = 6). The majority of the applications were free and available in English. The most common platforms were Android and iOS. CONCLUSIONS: The number of palliative care apps targeting clinicians has increased dramatically for the past five years. However, many apps did not report adequate information to judge the evidence upon which the apps were based. PMID- 28557548 TI - Efficacy and Safety of a Chewable Methylphenidate Extended-Release Tablet in Children with Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVE: This phase 3, laboratory classroom study assessed the efficacy and safety of methylphenidate hydrochloride extended-release chewable tablets (MPH ERCT) compared with placebo in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Following a 6-week, open-label, dose-optimization period, children 6-12 years of age (n = 90) with ADHD were randomly assigned to double-blind MPH ERCT at the final optimized dose (20-60 mg/day) or placebo. After 1 week of double-blind treatment, efficacy was assessed predose and 0.75, 2, 4, 8, 10, 12, and 13 hours postdose in a laboratory classroom setting. The primary efficacy measure was the average of postdose Swanson, Kotkin, Agler, M Flynn, and Pelham (SKAMP) Rating Scale-Combined scores, analyzed using a mixed model, repeated-measures analysis. Secondary efficacy measures included Permanent Product Measure of Performance (PERMP) total number of problems attempted and total number of problems correct. Safety assessments included adverse event (AE) monitoring and the Columbia-Suicide Severity Rating Scale (C-SSRS). RESULTS: MPH ERCT treatment statistically significantly reduced the average of all postdose SKAMP-Combined scores versus placebo (least-squares mean difference [95% confidence interval], -7.0 [-10.9, -3.1]; p < 0.001). Statistically significant treatment differences in SKAMP-Combined scores were observed at 2 hours postdose through 8 hours postdose (p-values <0.001). Statistically significant differences between MPH ERCT and placebo in PERMP total number of problems attempted and total number of problems correct were observed at 0.75 hours postdose through 8 hours postdose (p-values <=0.049). Common AEs in the open-label period (>=5%) were decreased appetite, upper abdominal pain, mood swings, irritability, insomnia, upper respiratory tract infection (URTI), dysgeusia, and headache; URTI was the only AE reported by >1 subject receiving MPH ERCT in the double-blind period (placebo: URTI, contusion, wound, and initial insomnia). No suicidal ideation or behavior was reported on the C-SSRS at baseline or at any postbaseline assessment. CONCLUSIONS: MPH ERCT 20-60 mg significantly improved ADHD symptoms compared with placebo at 2 hours postdose through at least 8 hours postdose. MPH ERCT was generally safe and well tolerated, with a safety profile consistent with other MPH ER formulations. ClinicalTrials.gov Identifier: NCT01654250. www.clinicaltrials.gov/ct2/show/NCT01654250 . PMID- 28557550 TI - Identifying "Hitting Bottom" Among Individuals with Alcohol Problems: Development and Evaluation of the Noteworthy Aspects of Drinking Important to Recovery (NADIR). AB - BACKGROUND: Alcohol use disorder (AUD) is a costly public health concern; yet, many individuals with AUD never receive formal treatment. Prior studies have identified that "hitting bottom" may be an important factor in seeking treatment for AUD) and the notion that "hitting bottom" is necessary for recovery is commonly portrayed in the popular media. Yet, "hitting bottom" has never been formally operationalized. OBJECTIVES: The present article aimed to operationalize "hitting bottom." METHODS: A multiphase process was used to develop a measure of hitting bottom among individuals experiencing alcohol problems: The Noteworthy Aspects of Drinking Important to Recovery (NADIR). Psychometric evaluation of the measure was conducted using online data collected from individuals who identified as moderate to heavy drinkers (N = 597). RESULTS: The NADIR included five lower order dimensions and one higher-order dimension ("hitting bottom"), had strong concurrent validity with measures of alcohol use severity and alcohol-related problems, and was found to have excellent internal consistency reliability (alpha > 0.90). An overall summary score on the NADIR of 50+ (factor scores>0) differentiated individuals who had previously sought treatment for AUD and reported more excessive alcohol use compared to those with no treatment history and lower levels of alcohol use. Thus, the NADIR with a cutoff of 50 may be a good starting point for future researchers to test as a method to identify individuals who have hit bottom. Conclusions/Importance: The NADIR provides a viable operational definition of hitting bottom. Future research should evaluate the predictive validity of the NADIR. PMID- 28557551 TI - MAP-IT: A Practical Tool for Planning Complex Behavior Modification Interventions. AB - Health research often aims to prevent noncommunicable diseases and to improve individual and public health by discovering intervention strategies that are effective in changing behavior and/or environments that are detrimental to one's health. Ideally, findings from original research support practitioners in planning and implementing effective interventions. Unfortunately, interventions often fail to overcome the translational block between science and practice. They often ignore theoretical knowledge, overlook empirical evidence, and underrate the impact of the environment. Accordingly, sustainable changes in individual behavior and/or the environment are difficult to achieve. Developing theory driven and evidence-based interventions in the real world is a complex task. Existing implementation frameworks and theories often do not meet the needs of health practitioners. The purpose of this article is to synthesize existing frameworks and to provide a tool, the Matrix Assisting Practitioner's Intervention Planning Tool (MAP-IT), that links research to practice and helps practitioners to design multicomponent interventions. In this article, we use physical activity of older adults as an example to explain the rationale of MAP IT. In MAP-IT, individual as well as environmental mechanisms are listed and behavior change techniques are linked to these mechanisms and to intervention components. MAP-IT is theory-driven and evidence-based. It is time-saving and helpful for practitioners when planning complex interventions. PMID- 28557552 TI - Family Discord After Completion of an Outpatient Community Treatment Program Predicts Greater Substance Use During Follow-up. AB - BACKGROUND: It is reasonable to consider family discord after treatment as a potential target for a next-step intervention, since family discord is often comorbid with substance use disorders. OBJECTIVE: This study evaluated family discord after completing an initial course of treatment as a predictor of substance use and retention in the community treatment program during follow-up. METHOD: Patients were from two multisite randomized clinical trials implemented through the Clinical Trials Network of the National Institute on Drug Abuse. There were 315 participants from Study 1 (12-week posttreatment follow-up) and 295 participants from Study 2 (8-week posttreatment follow-up). Negative binomial and logistic regression were used to estimate days of substance use and odds of retention in the community treatment program at follow-up, respectively, from family discord status. RESULTS: Family discord was significantly associated with more days of substance use during the posttreatment follow-up period than those without family discord in both Study 1 (9.12 vs. 2.89 days, p =.0001) and Study 2 (5.58 vs. 2.83 days, p =.0062). Family discord was significantly associated with lower retention in the community treatment program at follow-up than those not reporting family discord in Study 1 (47.6% vs. 60.6%; p =.03), but not in Study 2 (55.3% vs. 64.9%; p =.11). CONCLUSION: Family discord after an initial course of treatment might be a clinically relevant predictor of substance use. There is mixed support for a conclusion that family discord is associated with lower retention in the community treatment program at follow-up. PMID- 28557553 TI - Decreased Odds of Injection Risk Behavior Associated With Direct Versus Indirect Use of Syringe Exchange: Evidence From Two California Cities. AB - BACKGROUND: While there is substantial evidence that syringe exchange programs (SEPs) are effective in preventing HIV among people who inject drugs (PWID), nearly all the evidence comes from PWID who obtain syringes from an SEP directly. Much less is known about the benefits of secondary exchange to PWID who get syringes indirectly from friends or acquaintances who visit an SEP for them. OBJECTIVES: We evaluated the effectiveness of direct versus indirect syringe exchange in reducing HIV-related high-risk injecting behavior among PWID in two separate studies conducted in Sacramento and San Jose, California, cities with quite different syringe exchange models. METHODS: In both studies associations between direct and indirect syringe exchange and self-reported risk behavior were examined with multivariable logistic regression models. Study 1 assessed effects of a "satellite" home-delivery syringe exchange in Sacramento, while Study 2 evaluated a conventional fixed-site exchange in San Jose. RESULTS: Multivariable analyses revealed 95% and 69% reductions, respectively, in high-risk injection associated with direct use of the SEPs in Sacramento and San Jose, and a 46% reduction associated with indirect use of the SEP in Sacramento. Conclusions/Importance: The very large effect of direct SEP use in Sacramento was likely due in part to home delivery of sterile syringes. While more modest effects were associated with indirect use, such use nevertheless is valuable in reducing the risk of HIV transmission of PWID who are unable or unwilling to visit a syringe exchange. PMID- 28557555 TI - Effect of obstructive sleep apnea on the response to hypertension therapy. AB - Obstructive sleep apnea (OSA) often precedes cardiovascular disease, partly due to treatment resistant hypertension. The nocturnal apneas of OSA trigger increased sympathetic nervous discharge during both sleep and wakefulness. Apneas also trigger cardiac release of the endogenous diuretic atrial natriuretic peptide. We hypothesized that treatment of the excess sympathetic nervous activity of OSA with a beta1 blocker would lower 24 h blood pressure (BP) more than diuretic therapy. Subjects with OSA associated hypertension received 2 weeks of placebo followed by the beta1 blocker nebivolol or hydrochlorothiazide (HCTZ) for 6 weeks in a blinded crossover study. BP, baroreflex sensitivity (BRS), heart rate variability (HRV), arterial reactivity, and stiffness were measured after placebo and each treatment. The beta1 blocker lowered clinic BP by -11/-8 mmHg, more than the -3/-1 effect of HCTZ (P < 0.01). The beta1 blocker lowered 24 h diastolic blood pressure (DBP) more than HCTZ. Although given at bedtime, neither drug increased BP dipping. Nebivolol increased HRV in the high-frequency band. Nebivolol did not alter BRS while HCTZ significantly diminished BRS compared to nebivolol (P < 0.01). Nebivolol increased flow-mediated brachial artery dilation when compared to HCTZ and slowed pulse wave velocity, indicating a decrease in arterial stiffness. Diuretic therapy failed to lower BP in OSA subjects and this might account for the frequent association of OSA with treatment resistant hypertension. However, blockade of the excess sympathetic nervous activity of OSA with a beta1 blocker lowered both clinic and 24 h DBP. PMID- 28557554 TI - Ten-Year Review of Perioperative Complications After Transurethral Resection of Bladder Tumors: Analysis of Monopolar and Plasmakinetic Bipolar Cases. AB - OBJECTIVES: To evaluate the rate of perioperative complications after plasmakinetic bipolar and monopolar transurethral resection of bladder tumor (BTURB and MTURB). In addition, the study identifies patient and procedure characteristics associated with early complications. PATIENTS AND METHODS: Retrospective review was conducted on patients undergoing transurethral resection of bladder tumor procedures at a single institution from 2003 to 2013 to assess the 30-day complication rates associated with BTURB and MTURB. RESULTS: Four hundred twenty-seven patients met inclusion criteria and underwent 586 procedures (379 BTURB and 207 MTURB). Baseline patient demographics, tumor stage, and tumor grade were similar in BTURB and MTURB cohorts. The overall complication rate was 34.3% for MTURB and 26.7% for BTURB. The most frequent complications were acute urinary retention (AUR) 11%, hematuria 8%, and urinary tract infection (UTI) 7%. There was no statistical difference in rates of AUR, hematuria, UTI, or readmission for continuous bladder irrigation or hemostasis procedures between BTURB and MTURB cohorts. There was a trend toward lower perforation rate during BTURB (2.6% vs 5.8%). In multivariate logistic regression analysis, MTURB, male gender, and large resections were predictive of overall complications. Male gender was associated with hematuria and AUR. Large bladder tumor resection size was also associated with increased risk of overall complications and AUR. CONCLUSION: BTURB was associated with a lower risk of overall complications, but there was no difference in the rate of hematuria in the two cohorts. Male gender and large tumor size are associated with higher risk of early complications. PMID- 28557556 TI - Regulating the Regulators in Attention-Deficit/Hyperactivity Disorder: A Genetic Association Study of microRNA Biogenesis Pathways. AB - Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent complex psychiatric disorders in children as well as adults. ADHD impacts not only the affected individuals but also their families and social and professional networks. The clinical and diagnostic criteria for ADHD remain imprecise, in part, due to lack of robust biomarkers. ADHD comprises multiple subsets of diseases that present a shared set of downstream clinical findings, while displaying extensive molecular heterogeneity. This calls for innovation in diagnostic strategies that can help establish an ADHD diagnosis unequivocally as well as guiding precision medicine in this common mental health disorder. No study has examined, to the best of our knowledge, the upstream regulation of miRNAs that impact the downstream final ADHD phenotype. The latter focus on putative genetic biomarkers that regulate the regulators and can be tested empirically, for example, through genetic association analyses of the biogenesis pathways for miRNAs that impact the ADHD phenotype. Hence, we report here polymorphic variation in 10 miRNA biogenesis pathway candidate genes, including RNASEN, DGCR8, XPO5, RAN, DICER1, TARBP2, AGO1, AGO2, GEMIN3, and GEMIN4, in a large sample from the Eastern Mediterranean region (N = 355; 191 cases and 164 controls). We found that AGO1 rs595961 was significantly associated with ADHD susceptibility (p < 0.05). While polymorphic variation in other miRNA biogenesis pathway genes did not display a significant association in the present sample, the observations reported herein on miRNA biogenesis variation offer a new avenue of research for innovation in biomarker discovery concerning ADHD and other complex psychiatric diseases with major global health burden. PMID- 28557559 TI - Aggressive Antimicrobial Initiation for Suspected Intensive Care Unit-Acquired Infection Is Associated with Decreased Long-Term Survival after Critical Illness. AB - BACKGROUND: The long-term significance of early and prolonged antibiotic use in critically ill patients is yet to be described. Several studies suggest that antimicrobial exposure may have as yet unrecognized long-term effects on clinically meaningful outcomes. Our group previously conducted a quasi experimental, before and after observational cohort study of hemodynamically stable surgical patients suspected of having an intensive care unit-acquired infection. This study demonstrated that aggressive initiation of antimicrobial therapy was associated with increased 30-day deaths. In a follow-up survival analysis, we hypothesized that aggressive antimicrobial treatment would not be a significant predictor of long-term death. METHODS: Survival data for the 201 patients included in the initial study were obtained from our clinical data repository. Univariable analysis, Kaplan-Meier, and Cox proportional hazards models were used. Survival was evaluated at one and four years. Age, gender, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and co morbidities were chosen a priori for potential inclusion in the model. Variables that met the model assumptions after testing were included in the final model. RESULTS: Follow-up data were available for 190 patients (95 in each group) representing 94.5% of the initial cohort. Twenty-four (25.3%) patients in the aggressive group had initial APACHE II scores of less than 15 compared with 13 (13.7%) patients in the conservative group (p = 0.04). There was a trend toward higher deaths in the aggressive group at four years (41.1% vs. 30.5%; p = 0.13). Kaplan-Meier analysis demonstrated a difference in survival at one year but not at four years. The Cox proportional hazards model showed a higher long-term death for patients in the aggressive antimicrobial group at both one and four years (hazard rate: 2.26 and 1.70, respectively). CONCLUSION: Aggressive initiation of antimicrobial therapy is independently associated with decreased long-term survival after critical illness. While further work is needed to confirm these findings, waiting for evidence of infection before initiation of antibiotic agents may be beneficial. PMID- 28557560 TI - A Retrospective Study of Peroral Endoscopic Full-Thickness Myotomy in Patients with Severe Achalasia. AB - OBJECTIVES: Selective circular myotomy (CM) is recommended in peroral endoscopic myotomy (POEM) for achalasia, but completeness of myotmoy is the prerequisite for excellent long-term results of conventional surgical myotomy. The aim of our study was to compare the efficacy and safety between peroral endoscopic full thickness and simple CM for the treatment of severe achalasia. MATERIALS AND METHODS: A total of 123 severe achalasia patients who underwent POEM from August 2011 to May 2013 were included. They were divided into circular or full-thickness myotomy (FTM) groups according to the depth of myotomy. Demographics, Eckardt score, procedure-related parameters, perioperative adverse events, pre- and postoperative esophageal diameter, esophageal manometry, and follow-up results were retrospectively collected and compared between the two groups. RESULTS: All the 123 patients underwent POEM successfully, and the mean operation time was significantly shorter in FTM group compared with CM group (57.4 +/- 8.2 minutes versus 63.2 +/- 12.3 minutes, P < .05). There was no significant difference between the two groups in terms of treatment success, pre- and postoperative Eckardt score, esophageal diameter, esophageal manometry, and perioperative adverse events (P > .05). Twenty-four-hour pH monitoring was performed in 19 patients (11 in FTM, 8 in CM). Although no statistical difference was detected in rate of abnormal esophageal acid exposure between groups, this rate was higher in FTM group than CM group (60% versus 40%, P > .05). CONCLUSION: Treatment efficacy in short-to-medium term are comparable between circular or FTM. FTM significantly reduce the operative duration, but it may increase potential risk of gastroesophageal reflux disease incidence. PMID- 28557558 TI - A Social Media Peer Group for Mothers To Prevent Obesity from Infancy: The Grow2Gether Randomized Trial. AB - BACKGROUND: Few studies have addressed obesity prevention among low-income families whose infants are at increased obesity risk. We tested a Facebook peer group intervention for low-income mothers to foster behaviors promoting healthy infant growth. METHODS: In this randomized controlled trial, 87 pregnant women (Medicaid insured, BMI >=25 kg/m2) were randomized to the Grow2Gether intervention or text message appointment reminders. Grow2Gether participants joined a private Facebook group of 9-13 women from 2 months before delivery until infant age 9 months. A psychologist facilitated groups featuring a curriculum of weekly videos addressing feeding, sleep, parenting, and maternal well-being. Feasibility was assessed using the frequency and content of participation, and acceptability using surveys. Maternal beliefs and behaviors and infant growth were assessed at birth, 2, 4, 6, and 9 months. Differences in infant growth between study arms were explored. We conducted intention-to-treat analyses using quasi-least-squares regression. RESULTS: Eighty-eight percent (75/85) of intervention participants (42% (36/85) food insecure, 88% (75/85) black) reported the group was helpful. Participants posted 30 times/group/week on average. At 9 months, the intervention group had significant improvement in feeding behaviors (Infant Feeding Style Questionnaire) compared to the control group (p = 0.01, effect size = 0.45). Intervention group mothers were significantly less likely to pressure infants to finish food and, at age 6 months, give cereal in the bottle. Differences were not observed for other outcomes, including maternal feeding beliefs or infant weight-for-length. CONCLUSIONS: A social media peer-group intervention was engaging and significantly impacted certain feeding behaviors in families with infants at high risk of obesity. PMID- 28557561 TI - In vivo anti-inflammatory activity of aqueous extract of Teucrium polium against carrageenan-induced inflammation in experimental models. AB - The aim of this study was to evaluate the anti-inflammatory activity of Teucrium polium (TP). Rats were divided into four groups: group 1 controls received standard diet; group 2 inflamed by carrageenan (Carr) (1% Carr); group 3 as reference inflamed with Carr and treated with Indometacine (Ind) (150 mg/kg bw) and group 4 inflamed with Carr and pre0treated with TP (5 g/L). Oedema volume was measured 1 h to 5 h after injection. Administration of TP or Ind decreased the levels of hematology parameters relative to Carr and reduced the volume of rats induced by Carr. TP reduced levels of CRP, fibrinogen compared to treated, a decrease in oxidative stress (LP) and AOPP with an increase in the levels of SOD, CAT, GPx and Vit C in skin and erythrocytes. Carr increased the levels of lipid peroxidation and decreased levels of antioxidant enzymatic and Vit C. Our results were confirmed by histological sections of skin. PMID- 28557557 TI - Subsequent Surgery After Revision Anterior Cruciate Ligament Reconstruction: Rates and Risk Factors From a Multicenter Cohort. AB - BACKGROUND: While revision anterior cruciate ligament reconstruction (ACLR) can be performed to restore knee stability and improve patient activity levels, outcomes after this surgery are reported to be inferior to those after primary ACLR. Further reoperations after revision ACLR can have an even more profound effect on patient satisfaction and outcomes. However, there is a current lack of information regarding the rate and risk factors for subsequent surgery after revision ACLR. PURPOSE: To report the rate of reoperations, procedures performed, and risk factors for a reoperation 2 years after revision ACLR. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 1205 patients who underwent revision ACLR were enrolled in the Multicenter ACL Revision Study (MARS) between 2006 and 2011, composing the prospective cohort. Two-year questionnaire follow-up was obtained for 989 patients (82%), while telephone follow-up was obtained for 1112 patients (92%). If a patient reported having undergone subsequent surgery, operative reports detailing the subsequent procedure(s) were obtained and categorized. Multivariate regression analysis was performed to determine independent risk factors for a reoperation. RESULTS: Of the 1112 patients included in the analysis, 122 patients (11%) underwent a total of 172 subsequent procedures on the ipsilateral knee at 2-year follow-up. Of the reoperations, 27% were meniscal procedures (69% meniscectomy, 26% repair), 19% were subsequent revision ACLR, 17% were cartilage procedures (61% chondroplasty, 17% microfracture, 13% mosaicplasty), 11% were hardware removal, and 9% were procedures for arthrofibrosis. Multivariate analysis revealed that patients aged <20 years had twice the odds of patients aged 20 to 29 years to undergo a reoperation. The use of an allograft at the time of revision ACLR (odds ratio [OR], 1.79; P = .007) was a significant predictor for reoperations at 2 years, while staged revision (bone grafting of tunnels before revision ACLR) (OR, 1.93; P = .052) did not reach significance. Patients with grade 4 cartilage damage seen during revision ACLR were 78% less likely to undergo subsequent operations within 2 years. Sex, body mass index, smoking history, Marx activity score, technique for femoral tunnel placement, and meniscal tearing or meniscal treatment at the time of revision ACLR showed no significant effect on the reoperation rate. CONCLUSION: There was a significant reoperation rate after revision ACLR at 2 years (11%), with meniscal procedures most commonly involved. Independent risk factors for subsequent surgery on the ipsilateral knee included age <20 years and the use of allograft tissue at the time of revision ACLR. PMID- 28557562 TI - Mesenchymal Stromal Cells as Anti-Inflammatory and Regenerative Mediators for Donor Kidneys During Normothermic Machine Perfusion. AB - There is great demand for transplant kidneys for the treatment of end-stage kidney disease patients. To expand the donor pool, organs from older and comorbid brain death donors, so-called expanded criteria donors (ECD), as well as donation after circulatory death donors, are considered for transplantation. However, the quality of these organs may be inferior to standard donor organs. A major issue affecting graft function and survival is ischemia/reperfusion injury, which particularly affects kidneys from deceased donors. The development of hypothermic machine perfusion has been introduced in kidney transplantation as a preservation technique and has improved outcomes in ECD and marginal organs compared to static cold storage. Normothermic machine perfusion (NMP) is the most recent evolution of perfusion technology and allows assessment of the donor organ before transplantation. The possibility to control the content of the perfusion fluid offers opportunities for damage control and reparative therapies during machine perfusion. Mesenchymal stromal cells (MSC) have been demonstrated to possess potent regenerative properties via the release of paracrine effectors. The combination of NMP and MSC administration at the same time is a promising procedure in the field of transplantation. Therefore, the MePEP consortium has been created to study this novel modality of treatment in preparation for human trials. MePEP aims to assess the therapeutic effects of MSC administered ex vivo by NMP in the mechanisms of injury and repair in a porcine kidney autotransplantation model. PMID- 28557563 TI - Comparison of Support for Breastfeeding Beyond 12 Months of Age from Conventional and Alternative Pediatric Primary Care Providers. AB - OBJECTIVE: Conventional medicine pediatric care providers (e.g., pediatricians) have been shown to be influential in women's decisions to initiate and sustain breastfeeding. Alternative pediatric care providers (e.g., naturopaths and chiropractors) may also provide breastfeeding support, but this has not been the subject of prior research. Our objective was to compare breastfeeding mothers' perceptions of support from these two provider types in a large sample of women who breastfed for more than 12 months. METHODS: We conducted a cross-sectional study of 49,091 U.S. women through online questionnaire distributed through peer breastfeeding groups. We used log-binomial regression to compare those who used an alternative pediatric healthcare provider to care for their child to those who used a conventional provider on perceptions of support and key factors influencing the decision to breastfeed for more than 12 months. RESULTS: Those who used an alternative provider were more likely to discuss breastfeeding (Adj RR = 1.25, 95% CI 1.17-1.33), feel comfortable discussing breastfeeding (Adj RR = 1.17; 95% CI 1.15-1.19), and feel supported by the provider (Adj RR = 1.25; 95% CI 1.23-1.28). However, providers' recommendations were not important factors in these women's decision to breastfeed beyond 12 months of age. CONCLUSIONS: Mothers who used an alternative care provider as their child's primary source of healthcare rated the provider's breastfeeding support more favorable than those who used a conventional provider (usually a pediatrician). Improving breastfeeding support may be one way to retain families in conventional pediatric primary care, and thereby, ensure children receive comprehensive, evidence-based care. PMID- 28557564 TI - Metabolic Syndrome Among Leukemia Survivors: Still Delineating the Risk. PMID- 28557565 TI - Contemporary Trends in Utilization and Perioperative Outcomes of Percutaneous Nephrolithotomy in the United States from 2003 to 2014. AB - PURPOSE: To investigate the contemporary trends and perioperative outcomes of percutaneous nephrolithotomy (PCNL) by using a population-based cohort. MATERIALS AND METHODS: Using the Premier Healthcare Database, we identified 225,321 patients in whom kidney/ureteral calculi were diagnosed and who underwent PCNL at 447 different hospitals across the United States from 2003 to 2014. Outcomes included 90-day postoperative complications (as classified by the Clavien-Dindo system), prolonged hospital length of stay, operating room time, blood transfusions, and direct hospital costs. Temporal trends were quantified by estimated annual percentage change (EAPC) by using least-squares linear regression analysis. Multivariable logistic regression was performed to identify predictors of outcomes. RESULTS: PCNL utilization rates initially increased from 6.7% (2003) to 8.9% (2008) (EAPC: +5.60%, p = 0.02), before plateauing at 9.0% (2008-2011), and finally declining to 7.2% in 2014 (EAPC: -4.37%, p = 0.02). Overall (Clavien >=1) and major complication (Clavien >=3) rates rose significantly (EAPC: +12.2% and +16.4%, respectively, both p < 0.001). Overall/major complication and blood transfusion rates were 23.1%/4.8% and 3.3%, respectively. Median operating room time and 90-day costs were 221 minutes (interquartile range [IQR] 4) and $12,734 (IQR $9419), respectively. Significant predictors of overall complications include higher Charlson comorbidity index (CCI) (CCI >=2: odds ratio [OR] 2.08, p < 0.001) and more recent year of surgery (2007-2010: OR 3.20, 2011-2014: OR 4.39, both p < 0.001). Higher surgeon volume was significantly associated with decreased overall (OR 0.992, p < 0.001) and major (OR 0.991, p = 0.01) complications. CONCLUSIONS: Our contemporary analysis shows a decrease in the utilization of PCNL in recent years, along with an increase in complication rates. Numerous patient, hospital, and surgical characteristics affect complication rates. PMID- 28557566 TI - Psychosocial Factors Are Associated with Quality of Life After Laparoscopic Antireflux Surgery. AB - BACKGROUND: Laparoscopic antireflux surgery (LARS) is the gold standard treatment for refractory gastroesophageal reflux disease (GERD). Traditional surgical outcomes following LARS are well described, but limited data exist regarding patient-reported outcomes. We aimed to identify preoperative characteristics that were independently associated with a high GERD health-related quality of life (GERD-HRQL) following LARS. METHODS: Clinical data from our single institution foregut surgery database were used to identify all patients with GERD who underwent primary LARS from June 2010 to November 2015. Electronic health record data were reviewed to extract patient characteristics, diagnostic study characteristics, and operative data. Postoperative GERD-HRQL data were obtained through telephone follow-up. Variables hypothesized a priori to be associated with high GERD-HRQL after LARS, which were significant at P <= .2 on bivariate analysis, were entered into a multivariable linear regression model with GERD HRQL as the outcome. RESULTS: The study included 248 patients; 69.0% were female, 56.9% were married, and 58.1% had concurrent atypical symptoms. The most commonly performed fundoplications were Nissen (44.8%), Toupet (41.3%), and Dor (14.1%), respectively. The median follow-up interval was 3.4 years. The telephone response rate was 60.1%. GERD-HRQL scores improved from 24.8 (SD +/-11.4) preoperatively to 3.0 (SD +/-5.9) postoperatively. 79.9% of patients were satisfied with their condition at follow-up. On multivariable analysis, being married (P = .04) and absence of depression (P = .02) were independently associated with a higher postoperative QoL. CONCLUSIONS: Strong social support and psychiatric well-being appear to be important predictors of a higher QoL following LARS. Optimizing social support and treating depression preoperatively and postoperatively may improve QoL outcomes for LARS patients. PMID- 28557567 TI - Gene expression of the concentration-sensitive sodium channel is suppressed in lipopolysaccharide-induced acute lung injury in mice. AB - PURPOSE: The concentration-sensitive sodium channel (NaC) is expressed in alveolar type II epithelial cells and pulmonary microvascular endothelial cells in mouse lungs. We recently reported that NaC contributes to amiloride insensitive sodium transport in mouse lungs (Respiratory Physiology & Neurobiology, 2016). However, details regarding its physiological role in the lung remain unknown. To examine whether NaC is involved in alveolar fluid clearance during an acute lung injury (ALI), we analyzed the relationship between NaC gene expression in the lung and the development of pulmonary edema in lipopolysaccharide (LPS)-induced ALI mice. METHODS: LPS-induced ALI mice were prepared by the intratracheal administration of LPS. Bronchoalveolar lavage (BAL) neutrophils and lung water content (LWCs) were used as a marker of ALI and pulmonary edema, respectively. NaC protein production in the lung was detected by immunoblotting and immunofluorescence. The gene expressions of NaC and the epithelial sodium channel (ENaC) of LPS-induced ALI mice were examined by quantitative RT-PCR over a time course of 14 days. RESULTS: The BAL neutrophil count increased until day 2 after LPS administration and had nearly recovered by day 6. LWCs in LPS-induced mice gradually increased until day 8 and had recovered by day 14. The expression of the NaC protein in the lungs of LPS-induced mice dramatically decreased from day 2 to day 6, but recovered by day 8. The mRNA expression of NaC decreased in the lung, as well as those for alpha-, beta-, and gamma-ENaC during ALI. Thus, NaC expression is suppressed during the development stage of pulmonary edema and then recovers in the convalescent phase. CONCLUSION: Our results suggest that suppression of the gene expression of NaC is involved in the development of pulmonary edema in ALI. PMID- 28557568 TI - A Grid-Based Nucleus Counting Method for Estimates of the Density of Superficial Conjunctival Cells from Impression Cytology Samples Taken from Normal Healthy Human Eyes. AB - PURPOSE: To develop and validate an easily procured objective estimate of the cell density of the superficial epithelial cells of the normal bulbar conjunctiva using conjunctival impression cytology (CIC). METHODS: From 20 healthy non contact lens-wearing young adults, CIC was undertaken off the nasal aspect of the exposed bulbar conjunctiva, the filters stained with Giemsa, and images taken at 200* that only included an all-but-contiguous monolayer of epithelial cells. These images were projected at 1000* magnification and an overlay drawn of the location of the stained nuclei, from which two types of analysis were undertaken using either 100 micron circular or square regions of interest (ROI). From the former, the distances between all nuclei were measured and the number of nuclei/circle calculated to establish uniformity of cell nuclei distribution as a necessary prerequisite to using a grid-based counting method. From the latter, the number of nuclei in each square grid was manually counted and the grid-by grid variability assessed. RESULTS: The average inter-nucleus distance was 16.1+/3.5 microns, with predictable positioning to successive nuclei in the circular ROI to give an estimated numerical density of 1944 +/- 237/sq mm. Counting of nuclei in grid squares yielded numbers between 12 and 42 to yield an estimated cell density of 2390 +/ 330 /sq mm, with repeat counts off grid square ROIs being predictably within +/-15%. CONCLUSIONS: These studies indicate that it should be fairly easy to use carefully selected CIC samples to make estimates of the density of the superficial conjunctival cells. Such a method should be useful and offer advantage over the subjective assignment of morphological grades to CIC samples which have been shown to be highly variable. PMID- 28557569 TI - The Global End-Diastolic Volume (GEDV) Could Be More Appropiate to Fluid Management Than Central Venous Pressure (CVP) During Closed Hyperthermic Intrabdominal Chemotherapy with CO2 Circulation. AB - BACKGROUND: Closed hyperthermic intraperitoneal chemotherapy (HIPEC) may increase abdominal pressure and effects of hemodynamic changes due to maintenance hyperthermia. Our aim was to analyze the safety and effectiveness of our closed technique with CO2 circulation in management fluid status and hemodynamic parameters by means of cardiac preload control measured by Global End Diastolic Values (GEDV) and a gas exchanger. MATERIAL AND METHODS: A Pilot Clinical Study that included 18 advanced ovarian cancer patients undergoing citoreductive surgery and HIPEC. We used a closed-perfusion system (PRS Combat(r)) that includes CO2 circulation and a gas exchanger. Transpulmonary thermodilutions and hemodynamic measurements (PiCCO2(r)) were performed after citoreductive surgery (Pre-HIPEC); At half time of the HIPEC (Intra-HIPEC); After HIPEC (Post-HIPEC). RESULTS: No significant hemodynamic measurements changes in the three thermodilutions values of Cardiac Index (CI) (p = 0.227), Global End Diastolic Values (GEVD) (p = 0.966), Stroke Volume Variation (SVV) (p = 0,884) and Systemic Vascular Resistance Index (SVRI) (p = 0.082). No correlation between central venous pressure (CVP) and GEDV (Pre-HIPEC: r = 0.164, p = 0.211; Intra-HIPEC: r = 0.015, p = 0.900; Post-HIPEC: r = 0.018, p = 0.890). There was better correlation between GEDV and CI (Pre-HIPEC: r = 0.432, p = 0.071; Intra-HIPEC: r = 0.418, p = 0.074; Post-HIPEC: r = 0.411, p = 0.080). CONCLUSIONS: Closed intrabdominal chemotherapy with CO2 circulation model may be a safe model for HIPEC by means of a gas exchanger. GEDV and its changes significantly correlated to CI, and not observed for CVP. GEDV values may be more appropriate for monitoring cardiac preload, blood loss limitation and to predict changes in intravascular volume status during intraperitoneal chemotherapy. PMID- 28557570 TI - Childhood Maltreatment, Emotional Lability, and Alcohol Problems in Young Adults At-Risk for ADHD: Testing Moderation and Moderated Moderation. AB - Childhood maltreatment and alcohol problems are common among young adults with attention-deficit hyperactivity disorder (ADHD). However, little is known about the degree to which maltreatment and alcohol problems are associated; potential pertinent mediating or moderating mechanisms, such as emotional lability; and whether this association varies by sex. We examined, in a sample of adults at risk for ADHD (N = 122, 37% male), the association between childhood maltreatment and alcohol problems, whether emotional lability mediated or moderated this association, and whether either role of emotional lability differed between men and women. Emotional lability moderated the association between emotional neglect and alcohol problems; maltreatment increased risk for alcohol problems for those scoring high tovery high on emotional lability, but not for those with very low moderate levels. The association between emotional abuse and alcohol problems depended both on emotional lability and sex; emotional abuse decreased the risk for alcohol problems among men very low/low on emotional lability, but not for men who were moderate to very high on emotional lability, or for women. These findings have implications for the way in which targeting maltreatment and emotional lability may be incorporated into prevention and intervention programs to prevent alcohol problems among men and women at risk for ADHD. PMID- 28557571 TI - In Vivo Efficacy of an Injectable Microsphere-Hydrogel Ocular Drug Delivery System. AB - PURPOSE: Demonstrate in vivo that controlled and extended release of a low dose of anti-vascular endothelial growth factor (anti-VEGF) from a microsphere hydrogel drug delivery system (DDS) has a therapeutic effect in a laser-induced rat model of choroidal neovascularization (CNV). METHODS: Anti-VEGF (ranibizumab or aflibercept) was loaded into poly(lactic-co-glycolic acid) microspheres that were then suspended within an injectable poly(N-isopropylacrylamide)-based thermo responsive hydrogel DDS.The DDS was shown previously to release bioactive anti VEGF for ~200 days. CNV was induced using an Ar-green laser. The four experimental groups were as follows: (i) non-treated, (ii) drug-free DDS, (iii) anti-VEGF-loaded DDS, and (iv) bolus injection of anti-VEGF. CNV lesion areas were measured based on fluorescein angiograms and quantified using a multi-Otsu thresholding technique. Intraocular pressure (IOP) and dark-adapted electroretinogram (ERG) were also obtained pre- and post-treatment (1, 2, 4, 8, and 12 weeks). RESULTS: The anti-VEGF-loaded DDS group had significantly smaller (60%) CNV lesion areas than non-treated animals throughout the study. A small transient increase in IOP was seen immediately after injection; however, all IOP measurements at all time points were within the normal range. There were no significant changes in ERG maximal response compared to pre-treatment measurements for the drug-loaded DDS, which suggests no adverse effects on retinal cellular function. CONCLUSIONS: The current study demonstrates that the DDS can effectively decrease laser-induced CNV lesions in a murine model. Controlled and extended release from our DDS achieved greater treatment efficacy using an order of magnitude less drug than what is required with bolus administration. This suggests that our DDS may provide a significant advantage in the treatment of posterior segment eye diseases. PMID- 28557573 TI - Putative mechanisms of kiwifruit on maintenance of normal gastrointestinal function. AB - Kiwifruit are recognized as providing relief from constipation and symptoms of constipation-predominant irritable bowel syndrome (IBS-C). However, the underlying mechanisms, specifically in regards to gastrointestinal transit time and motility, are still not completely understood. This review provides an overview on the physiological and pathophysiological processes underlying constipation and IBS-C, the composition of kiwifruit, and recent advances in the research of kiwifruit and abdominal comfort. Additionally, gaps in the research are highlighted and scientific studies of other foods with known effects on the gastrointestinal tract are consulted to find likely mechanisms of action. While the effects of kiwifruit fiber are well documented, observed increases in gastrointestinal motility caused by kiwifruit are not fully characterized. There are a number of identified mechanism that may be activated by kiwifruit compounds, such as the induction of motility via protease-activated signaling, modulation of microflora, changes in colonic methane status, bile flux, or mediation of inflammatory processes. PMID- 28557572 TI - Novel Assay Assessment of Oxidative Stress Biomarkers in Patients with Keratoconus: Thiol-Disulfide Homeostasis. AB - PURPOSE: To investigate systemic oxidative stress by evaluating thiol-disulfide homeostasis using a novel automated homeostasis assay in keratoconus patients. METHODS: Twenty-eight patients with keratoconus and 30 control subjects of a similar age and gender were enrolled in the present study. The native thiol, total thiol, and disulfide levels and the disulfide-native thiol, disulfide-total thiol, and native thiol-total thiol ratios were analyzed and compared between the keratoconus and control groups using a novel automatized spectrophotometric assay. RESULTS: The median serum native thiol value was 441.5 (362.6-488.1) in the keratoconus group and 467.8 (401.8-564.6) in the control subjects. The median serum total thiol value was 467.9 (375-580.6) in the keratoconus group and 503.3 (437.7-578.5) in the control subjects. The median serum disulfide value was 20.1 (6.2-46.3) in the keratoconus patients and 16.7 (1.1-20.8) in the controls. There were significant differences between the native thiol, total thiol, and disulfide levels of the keratoconus patients and controls (p = 0.001, p = 0.04, and p = 0.03, respectively) and the disulfide-native thiol, disulfide-total thiol, and native thiol-total thiol ratios of these two groups (p = 0.02, p = 0.01, and p = 0.001, respectively). We found no significant correlation between age and any of the thiol-disulfide parameters (p > 0.05 for all values). CONCLUSIONS: There is an imbalance in the systemic thiol-disulfide homeostasis in KC patients. This metabolic imbalance may play an important role in the pathogenesis of keratoconus; thus, it can be discussed in terms of the prevention, diagnosis, and the possible treatment for keratoconus. PMID- 28557575 TI - Key concepts in the national guidelines: "Suicide exposure" and "levels of care". AB - This article is an extended excerpt from the document Responding to Grief, Trauma, and Distress After a Suicide: U.S. National Guidelines, rewritten to emphasize, expand upon, and clarify two key, interrelated concepts introduced in the Guidelines. First, everyone exposed to a suicide fatality, regardless of their relationship to the deceased, may require support services to ameliorate the effects of that exposure. Second, a systemic response to suicide ought to be organized around three levels of care, designed and implemented strategically to meet people's immediate needs, their need for ongoing support, and any clinical treatment needs that arise from their exposure to the fatality. PMID- 28557574 TI - Hydrophobic Effect from Conjugated Chemicals or Drugs on In Vivo Biodistribution of RNA Nanoparticles. AB - Liver or other organ accumulation of drugs is one of the major problems that leads to toxicity and side effects in therapy using chemicals or other macromolecules. It has been shown that specially designed RNA nanoparticles can specifically target cancer cells, silence oncogenic genes, and stop cancer growth with little or no accumulation in the liver or other vital organs. It is well known that physical properties of nanoparticles such as size, shape, and surface chemistry affect biodistribution and pharmacokinetic profiles in vivo. This study examined how the hydrophobicity of chemicals conjugated to RNA nanoparticles affect in vivo biodistribution. Weaker organ accumulation was observed for hydrophobic chemicals after they were conjugated to RNA nanoparticles, revealing RNA's ability to solubilize hydrophobic chemicals. It was found that different chemicals conjugated to RNA nanoparticles resulted in the alteration of RNA hydrophobicity. Stronger hydrophobicity induced by chemical conjugates resulted in higher accumulation of RNA nanoparticles in vital organs in mice. This study provides new insights for handling drug insolubility, therapeutic toxicity, and organ clearance in drug development. PMID- 28557576 TI - Clinical work with suicide loss survivors: Implications of the U.S. postvention guidelines. AB - The loss of a loved one to suicide can present difficult challenges for suicide loss survivors (people bereaved by suicide) as well as for clinicians who would seek to help them. Building on the recommendations in the new document Responding to Grief, Trauma, and Distress after a Suicide: U.S. National Guidelines, this article provides an overview of clinical work with suicide loss survivors. It includes discussions of the common themes of suicide bereavement, the psychological tasks for integration of a suicide loss, and the options for providing grief therapy after a suicide. The article will be of value to caregivers who work with suicide loss survivors in counseling or therapeutic context. PMID- 28557577 TI - The next chapter for group B meningococcal vaccines. AB - The majority of invasive meningococcal disease (IMD) in the developed world is caused by capsular group B Neisseria meningitidis, however success with vaccination against organisms bearing this capsule has previously been restricted to control of geographically limited clonal outbreaks. As we enter a new era, with the first routine program underway to control endemic group B meningococcal disease for infants in the UK, it is timely to review the key landmarks in group B vaccine development, and discuss the issues determining whether control of endemic group B disease will be achieved. Evidence of a reduction in carriage acquisition of invasive group B meningococcal strains, after vaccination among adolescents, is imperative if routine immunization is to drive population control of disease beyond those who are vaccinated (i.e. through herd immunity). The need for multiple doses to generate a sufficiently protective response and reactogenicity remain significant problems with the new generation of vaccines. Despite these limitations, early data from the UK indicate that new group B meningococcal vaccines have the potential to have a major impact on meningococcal disease, and to provide new insight into how we might do better in the future. PMID- 28557578 TI - Pediatric Nurses' Perceptions of Medication Safety and Medication Error: A Mixed Methods Study. AB - This study aims to outline the current workplace culture of medication practice in a pediatric medical ward. The objective is to explore the perceptions of nurses in a pediatric clinical setting as to why medication administration errors occur. As nurses have a central role in the medication process, it is essential to explore nurses' perceptions of the factors influencing the medication process. Without this understanding, it is difficult to develop effective prevention strategies aimed at reducing medication administration errors. Previous studies were limited to exploring a single and specific aspect of medication safety. The methods used in these studies were limited to survey designs which may lead to incomplete or inadequate information being provided. This study is phase 1 on an action research project. Data collection included a direct observation of nurses during medication preparation and administration, audit based on the medication policy, and guidelines and focus groups with nursing staff. A thematic analysis was undertaken by each author independently to analyze the observation notes and focus group transcripts. Simple descriptive statistics were used to analyze the audit data. The study was conducted in a specialized pediatric medical ward. Four key themes were identified from the combined quantitative and qualitative data: (1) understanding medication errors, (2) the busy-ness of nurses, (3) the physical environment, and (4) compliance with medication policy and practice guidelines. Workload, frequent interruptions to process, poor physical environment design, lack of preparation space, and impractical medication policies are identified as barriers to safe medication practice. Overcoming these barriers requires organizations to review medication process policies and engage nurses more in medication safety research and in designing clinical guidelines for their own practice. PMID- 28557579 TI - Postvention is prevention-The case for suicide postvention. AB - There is now convincing empirical evidence that exposure to suicide increases the risk of subsequent suicide, as well as other negative mental health sequelae, in those who have been exposed. This article provides a review of this empirical evidence. It also concludes that this substantial evidence base makes the compelling case that all suicide prevention programs need to include postvention services as a direct form of suicide prevention with a population of people known to be at heightened risk for suicide themselves: suicide loss survivors. PMID- 28557580 TI - Assessment of Optic Nerve Head Pallor in Primary Open-Angle Glaucoma Patients and Healthy Subjects. AB - PURPOSE: To investigate optic nerve head (ONH) pallor quantitatively in patients with primary open-angle glaucoma (POAG) and in healthy subjects, and to examine the relationship to mean deviation in perimetry (MD), cup-disk ratio (CDR), and diameters of retinal vessels. METHODS: A total of 89 POAG patients (67.6 +/- 11.1 years) and 48 healthy subjects (63.3 +/- 14 years) were included. A dual-bandpass transmission filter was introduced in the illumination path of the fundus camera of the Dynamic Vessel Analyzer (Imedos Systems UG) and two monochromatic images at different wavelenghts (548 +/- 10 and 610 +/- 10 nm) were recorded simultaneously. ONH pallor was defined as the quotient of light reflection in both spectral channels. Pallor values were averaged over four fields which were positioned on the ONH. The mean of these measurements was calculated. In 47 of 89 POAG patients diameters of retinal vessels were determined peripapillary. RESULTS: In POAG, the ONH showed a significantly higher pallor value compared to healthy subjects (82.34 +/- 19.28 vs. 62.67 +/- 10.41, p < 0.001). ONH pallor was correlated to indicators used to estimate disease severity: MD (r = -0.565, p < 0.001) and CDR (r = 0.561, p < 0.001). The pallor value was associated to diameters of retinal arterioles (r = -0.313, p = 0.032) and venules (r = -0.397, p = 0.006). CONCLUSIONS: Pallor determined by this method was higher in POAG patients than in healthy subjects and increased in patients with advanced disease. ONH pallor might result from a reduced blood perfusion of the ONH or tissue atrophy accompanied by vessel obliteration in POAG. By measuring ONH pallor additional diagnostic information about the vitality of the neuroretinal rim might be gained in glaucoma patients. PMID- 28557581 TI - Quality of Life in Youth With Obstructive Sleep Apnea Syndrome (OSAS) Treated With Continuous Positive Airway Pressure (CPAP) Therapy. AB - OBJECTIVE/BACKGROUND: Improvement is sought for youth with obstructive sleep apnea syndrome (OSAS) who have poor quality of life (QoL), which resolves somewhat following treatment. One mitigating factor in improved QoL following treatment may be adherence to the CPAP protocol, which presents a barrier to most youth. This study explored relations between CPAP adherence and QoL in youth with OSAS. PARTICIPANTS: We recruited 42 youth-caregiver dyads in which youth between the ages of 8 and 16 years were diagnosed with OSAS and required CPAP use as part of their treatment plan. METHODS: Following diagnosis of OSAS requiring treatment with CPAP therapy, caregivers completed baseline measures of OSAS-specific QoL. The OSAS-specific QoL domains assessed included sleep disturbance, physical symptoms, emotional distress, daytime function, and caregiver concern. Families received routine CPAP care for three months, after which caregivers again completed measures of OSAS-specific QoL. Adherence data were collected from smartcards within the CPAP machine after three months of treatment. RESULTS: Fifteen youth were adherent to CPAP therapy and 10 were not adherent. CPAP adherent youth demonstrated significant changes in two domains of OSAS-specific QoL when compared to nonadherent youth: decreased sleep disturbance and decreased caregiver concern. CONCLUSIONS: CPAP adherence appears to be associated with positive changes in OSAS-specific QoL domains. It will be important for future research and clinical work to examine strategies for improving CPAP adherence in youth with OSAS. PMID- 28557582 TI - Surgeon Performance Predicts Early Continence After Robot-Assisted Radical Prostatectomy. AB - INTRODUCTION: There is limited, yet compelling evidence supporting the role of surgeon technical performance in influencing patient outcomes. To date, this concept has been underexplored in endourologic procedures. We hypothesized that a surgeon's technical performance plays a role in predicting an early return to continence after robot-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: We conducted a retrospective, matched case-control analysis of prospectively collected unedited RARP endoscopic videos performed by a single surgeon. A blinded observer with expertise in intraoperative video analysis evaluated clinically relevant steps of RARP using the global evaluative assessment of robotic skill (GEARS) and the generic error rating tool (GERT). The primary outcome was continence status at 3 months postoperatively, defined as patient use of less than or equal to a single precautionary pad. Mann-Whitney U tests examined differences in predictor variables between cases and controls, and multivariate analysis was conducted using binary logistic regression models. RESULTS: Twenty-four incontinent patients were matched for age, body mass index, preoperative International Prostate Symptoms Score, use of posterior/anterior hitch, prostate weight, and learning curve position. No statistically significant difference in errors between groups was observed using the GERT. On multivariate analysis, overall case GEARS score was independently predictive of 3-month continence status (odds ratios [OR] = 0.55, 95% confidence interval [CI] 0.33 0.91), as were urethrovesical anastomosis (OR = 0.70, 95% CI 0.50-0.97) and bladder neck GEARS scores (OR = 0.69, 95% CI 0.51-0.94). CONCLUSIONS: Our study generates the hypothesis that there may be a link between surgeon technical performance and functional outcomes in RARP. This relationship may have implications for the accreditation and training of future urologists and warrants further investigation. PMID- 28557583 TI - Human identity versus gender identity: The perception of sexual addiction among Iranian women. AB - This qualitative study was conducted to explore the images of personal identity from the perspective of women with sexual addiction. The data required for the study were collected through 31 in-depth interviews. Sensing a threat to personal identity, dissatisfaction with gender identity, dissociation with the continuum of identity, and identity reconstruction in response to threat were four of the experiences that were common among women with sexual addiction. Painful emotional experiences appear to have created a sense of gender and sexual conflict or weakness in these women and thus threatened their personal identity and led to their sexual addiction. PMID- 28557584 TI - NHS Gene Mutations in Ashkenazi Jewish Families with Nance-Horan Syndrome. AB - PURPOSE: To describe ocular and extraocular abnormalities in two Ashkenazi Jewish families with infantile cataract and X-linked inheritance, and to identify their underlying mutations. METHODS: Seven affected members were recruited. Medical history, clinical findings, and biometric measurements were recorded. Mutation analysis of the Nance-Horan syndrome (NHS) gene was performed by direct sequencing of polymerase chain reaction-amplified exons. RESULTS: An unusual anterior Y-sutural cataract was documented in the affected male proband. Other clinical features among examined patients included microcorneas, long and narrow faces, and current or previous dental anomalies. A nonsense mutation was identified in each family, including a previously described 742 C>T, p.(Arg248*) mutation in Family A, and a novel mutation 2915 C>A, p.(Ser972*) in Family B. CONCLUSIONS: Our study expands the repertoire of NHS mutations and the related phenotype, including newly described anterior Y-sutural cataract and dental findings. PMID- 28557585 TI - PET-CT guided SIB-IMRT combined with concurrent 5-FU/MMC for the treatment of anal cancer. AB - BACKGROUND: To evaluate local control (LC), survival and toxicity in anal cancer patients treated with intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy at a single institution. MATERIAL AND METHODS: From August 2010 to May 2015, 26 patients were treated at our institution with IMRT and concurrent 5 fluorouracil/mitomycin-C (5-FU/MMC) for localized squamous cell carcinoma of the anal canal (SCCAC). Radiotherapy (RT) with 50.4-60 Gy was delivered with a sequential boost in 31%, and a simultaneous-integrated boost (SIB-IMRT) in 69% of cases. Initial staging was based on PET-CT and MRI. Clinical measures of interest were the influence of PET-CT on staging and treatment planning, LC, disease free survival (DFS), overall survival (OS), colostomy free survival (CFS) and toxicities. RESULTS: Median age was 61 years, 22 patients (85%) were female, and no patient was HIV-positive. The proportion of patients with stage I, II, IIIA and IIIB disease was 15%, 35%, 23% and 27%, respectively. PET-CT modified the extent of nodal disease in 9/23 cases (39%) and lead to major changes in treatment planning in 4/23 patients (17%). MRI was more accurate at identifying T4 disease. RT was delivered at full dose in 26 patients (100%) and chemotherapy in 22/26 patients (85%). Two patients (7.7%) required RT breaks. Median follow-up was 35 months [IQR: 19-52]. The 2-year LC, DFS, OS and CFS were 100%, 100%, 100% and 92%. Acute grade >=3 dermatitis and diarrhea occurred in 73% and 8% of cases, respectively. Grade 3-4 neutropenia was seen in 10/23 patients (43%). Four patients (15%) developed chronic grade 2 GI toxicity. CONCLUSIONS: PET-CT provided additional information leading to major changes in treatment planning for 17% of patients. Considering our excellent outcomes, routine use of PET-CT as standard staging modality and IMRT planning procedure appears justified for patients with SCCAC. PMID- 28557587 TI - The Prevalence of and Factors Associated With Receiving Concurrent Controlled Substance Prescriptions. AB - BACKGROUND: Controlled substance prescription (CSP) use and abuse in the United States has become a public health epidemic. One common and dangerous indicator of abuse involves obtaining CSPs concurrently. OBJECTIVE: The objective of this study was to identify the prevalence and factors associated with individuals receiving potentially inappropriate concurrent CSPs. METHODS: This was a retrospective, cohort analysis using data from the 2013-2014 Texas prescription drug monitoring program (PDMP). Descriptive statistics and a multiple logistic regression analysis were conducted to examine the individual-level and prescription utilization factors associated with individuals obtaining concurrent CSPs. RESULTS: Among Texas residents, 1,640,015 individuals (6.10% of all Texas residents and 15.99% of all CSP utilizers) were identified with at least one concurrent CSP combination. Concurrent opioid prescriptions were found to be the most prevalent concurrent use combination (n = 1,574,572). Having prescriptions for opioids, being >=18 years of age, utilizing CSPs for >30 days, utilizing greater than one CSP, having a multiple provider episode, and traveling >25 miles to obtain CSPs were all statistically significant predictors of utilizing concurrent CSPs. CONCLUSION: The study findings indicate a high prevalence of individuals utilizing concurrent CSPs. This practice is concerning when considering that many overdose deaths result from the concurrent use of CSPs. Prescribers should utilize PDMPs to ensure that aberrant prescription drug behaviors, such as the use of concurrent opioids and benzodiazepines do not readily occur. PMID- 28557586 TI - Qualitative Study of Patients' and Caregivers' Perceptions and Information Preferences About Hospice. AB - OBJECTIVE: The goal of this study is to assess perceptions about hospice among patients with metastatic cancer and their caregivers (i.e., family and/or friends). DESIGN AND SETTING: We conducted semi-structured interviews with 16 adult patients with a prognosis <=12 months and 7 of their caregivers. The interviews focused on perceptions, knowledge, and information preferences about hospice. Two raters coded interviews independently (kappa > 0.85). We used a framework approach for data analysis. RESULTS: Participants showed variable gaps in understanding about hospice, including who would benefit from hospice care and the extent of services provided. They all perceived that hospice involves a psychological transition to accepting imminent death and often referred to hospice from a relatively cognitive distance, using hypothetical scenarios of others for whom hospice would be more relevant. Participants' attitudes about hospice reflected their concerns about suffering, loss of dignity, and death, as well as their perceived understanding of hospice services. These attitudes along with the psychological barriers to projecting a need for hospice and lack of knowledge were all perceived as important barriers to hospice utilization. All participants felt they needed more information about hospice, yet they were mixed regarding the optimal timing of this information. CONCLUSIONS: Study participants had misunderstandings about hospice and perceived end-of-life (EOL) concerns such as fear of suffering, loss of dignity, and death, as well as lack of knowledge as the main barriers to hospice utilization. Interventions are needed to educate patients and their families about hospice and to address their EOL concerns. PMID- 28557588 TI - The Impact of Respondent Burden on Current Drinker Rates. AB - BACKGROUND: Increasing response burden in alcohol surveys combined with filter questions to exclude abstainers, results in systematically missing data in questions on alcohol consumption as abstainers are not required to answer them. OBJECTIVES: The aim of the current study is to assess the impact of responder burden on current drinker rates in a large scale Australian survey. METHOD: 23,855 Australian adults completed the National Drug Strategy Household Survey in 2013 and answered increasingly complex questions on alcohol consumption. RESULTS: Although 80% of respondents stated that they had consumed alcohol in the past 12 months, the current drinker rate appears to be 78% excluding, or 74% including missing data if taken from the quantity frequency measure. When respondents are then asked to give more detailed responses in a graduated frequency measure, current drinker rates appear to be at 75% or 73%, excluding or including missing data. CONCLUSIONS: The rate of abstention in alcohol survey research is artificially inflated when more complex survey methods are used. Excluding missing data only partially corrects for this. Given that more sensitive analyses are usually performed on more detailed survey questions, rates of abstention and consumption should be adjusted to account for systematically missing data. PMID- 28557589 TI - Comparison of Intraocular Lens Position Change Following Two Different Implantation Techniques. AB - PURPOSE: To assess the decentration and tilt of one-piece foldable acrylic intraocular lens following two different intraocular lens implantation techniques. METHODS: This prospective, randomized clinical study conducted on 102 eyes of 91 patients who underwent cataract surgery between September 2015 and May 2016 at Ulucanlar Eye Training and Research Hospital, Ankara, Turkey. Intraocular lens implantations were performed with the help of an ophthalmic viscosurgical device or a hydroimplantation technique during surgery. The main outcomes, which were evaluated one day and one month after surgery, were corrected distant visual acuity, intraocular lens tilt, and decentration at the vertical and horizontal meridians. All outcomes were compared between and within implantation technique groups. RESULTS: Angle of tilt and decentration of intraocular lens at the vertical and horizontal meridians showed no significant change within the ophthalmic viscosurgical device and hydroimplantation groups during follow-up (p > 0.05 for all). However, intraocular lens at both meridians were significantly lower in the hydroimplantation group (Vertical: p = 0.004, Horizontal: p = 0.015), and intraocular lens decentration tilt at both meridians were significantly lower in the hydroimplantation group than in the ophthalmic viscosurgical device group (Vertical: p = 0.004, Horizontal: p = 0.039). Postoperative corrected distant visual acuity outcomes showed no difference between and within the groups during follow-up (p > 0.05 for all). CONCLUSIONS: The intraocular lens implantation technique had an important effect on intraocular lens position. The hydroimplantation technique induces central placement of one-piece foldable acrylic intraocular lenses postoperatively by reducing decentration and the angle of tilt. PMID- 28557590 TI - The Cannabis Information Helpline: Assessing Interest in the Medicinal Use of Cannabis in Australia. AB - BACKGROUND: The majority of Australians support a change in legislation to allow the use of cannabis for medical purposes. Despite strong public support, very little is known about the patterns of medicinal cannabis use among Australians. OBJECTIVES: This study aims to gain a better understanding of Australian medicinal cannabis users and their patterns of use. METHODS: The nature of calls to the Cannabis Information and Helpline (N = 15701), a free national service for Australians with concerns regarding cannabis use, were investigated to determine the number of calls made by those who inquired about the medicinal use of cannabis (N = 275) and the implied reasons for use among those who identify using cannabis in this way. RESULTS: The majority of medicinal cannabis inquirers mentioned cannabis to alleviate pain. Further, compared to other callers, medicinal cannabis inquirers were more likely to be male, unemployed, older, and have recently started using cannabis. CONCLUSIONS: These findings highlight the need for future research to better understand the issues faced by Australians regarding the use of cannabis for medicinal purposes and how they may be meaningfully addressed. Particular focus should be placed toward older, unemployed males. PMID- 28557592 TI - Ameloblastic Fibro-Odontoma of the Maxilla in a Pierre-Robin Sequence Patient. AB - INTRODUCTION: Pierre Robin sequence (PRS) is a rare disorder classically observed as a triad of features including micrognathia, glossoptosis, and upper airway obstruction. It is associated with a syndrome in about 60% of cases. While odontogenic tumors are common findings in patients with familial adenomatous polyposis and nevoid basal cell carcinoma syndromes, PRS has not been found to be consistently associated with any tumors of the jaw. CASE REPORT: The current report aims to describe a patient with PRS who presented with an extensive ameloblastic fibro-odontoma (AFO) of the maxilla. CONCLUSION: Continued observation for odontogenic tumors in PRS is necessary. PMID- 28557593 TI - Effects of low-level laser therapy on the modulation of tissue temperature and hyperalgesia following a partial Achilles tendon injury in rats. AB - The aim of the present study was to evaluate the effects of low-level laser therapy (LLLT) on the modulation of tissue temperature and hyperalgesia following a partial injury to the Achilles tendon in rats. Forty-five rats were randomly divided into three groups: a control group, a group treated with LLLT at a dose of 1.4 J (808 nm, 50 mW, 1.4 J), and a group treated with LLLT at a dose of 2.1 J (808 nm, 50 mW, 2.1 J). LLLT was administered to a single point immediately following the partial injury of the Achilles tendon. Tissue temperature and hyperalgesia were evaluated 6, 24, and 48 hours following the injury. Thus, a significant group-versus-time interaction was found for tissue temperature (F = 4.097, p = 0.001) and hyperalgesia (F = 106.605, p < 0.001), with a greater reduction in theses outcomes in the group that received LLLT at a dose of 2.1 J evaluated 48 hours after the injury. Therefore, LLLT at a wavelength of 808 nm and dose of 2.1 J administered immediately following a partial injury to the Achilles tendon led to a reduction in tissue temperature and hyperalgesia at the injury site in rats, especially 48 hours after injury. PMID- 28557591 TI - CD36 gene is associated with intraocular pressure elevation after intravitreal application of anti-VEGF agents in patients with age-related macular degeneration: Implications for the safety of the therapy. AB - BACKGROUND: The wet form of age-related macular degeneration (AMD) is characterized by pathological vascularization of the outer retinal layers. The condition responds to treatment with antibodies against vascular endothelial growth factor (VEGF), but the patients receiving such anti-VEGF therapy sometimes show undesirable acute short-term increases in the intraocular pressure (IOP). The cause of this adverse effect is unknown, and here, we are testing a hypothesis that it is related to CD36 gene polymorphisms. MATERIALS AND METHODS: A group of 134 patients with AMD were given three therapeutic doses of anti-VEGF antibody (ranibizumab) at monthly intervals. Their IOP was measured immediately before and 30 min after each injection. Patients' DNA was analyzed, and the changes in IOP were matched against seven polymorphisms of the CD36 gene. RESULTS: Three polymorphisms were found to be associated with increases in IOP: rs1049673 (p = 0.006), rs3211931 (p = 0.01), and rs1761667 (p = 0.043) at the time of the third injection only. Pronounced elevations (IOP > 25 mmHg) were associated with rs1049673 polymorphism: GC genotype (p < 0.01) and CC genotype (p < 0.05); both increasing the risk 2.6-fold, the presence of C-allele conferring a 1.5-fold greater risk and with rs3211931 polymorphism: AG genotype (p < 0.01) and GG genotype (p < 0.05); increasing the risk 2.6-fold (AG) and 2.7-fold (GG). CONCLUSIONS: CD36 receptor may be involved in mediating the effects of VEGF on IOP. The findings will help to identify the patients at risk of acutely elevated IOP following the anti-VEGF therapy. PMID- 28557594 TI - Inhalant Use and Mental Health Problems in Russian Juvenile Delinquents. AB - BACKGROUND: Inhalant use by children and adolescents has been linked to an increased risk of multiple drug use, mental health problems and antisocial behavior. OBJECTIVES: The purpose of this study was to examine the association between the frequency of inhalant use and psychiatric diagnoses among incarcerated delinquent youths in Russia. METHODS: A total of 370 incarcerated delinquents from a juvenile correction center in Northern Russia were assessed by means of a semi-structured psychiatric interview and by self-reports. RESULTS: Compared to non-users (N = 266), inhalant users (N = 104) reported higher rates of PTSD, early onset conduct disorder, ADHD, alcohol abuse and dependence, as well as higher levels of antisocial behavior, impulsiveness and more psychopathic traits. Frequent inhalant users also reported the highest rates of co-occurring psychopathology. CONCLUSIONS: Our findings suggest that inhalant use in delinquents is frequent and may require additional clinical measures to address the issue of psychiatric comorbidity. PMID- 28557596 TI - The Next Generation of Molecular Pathology is Here: Validation of Next-Generation Sequencing Technology for Clinical Molecular Testing Across Multiple Different Disciplines. PMID- 28557595 TI - Chondroblastoma: An Update. AB - Chondroblastoma is a rare primary bone tumor of young people that typically arises in the ends of the long bones. Radiologic investigations show a small, circumscribed, lytic lesion. The tumor is characterized histologically by the proliferation of chondroblasts along with areas of mature cartilage, giant cells, and occasionally, secondary aneurysmal bone cyst formation. Chondroblastoma, however, may also present with atypical features, such as prominent hemosiderin deposition, numerous giant cells, or the presence of a large aneurysmal bone cyst component. Malignant entities such as clear cell chondrosarcoma and chondroblastic osteosarcoma must also be considered. Recently, immunohistochemical stains such as DOG1 and SOX9 have been described in chondroblastoma, and K36M mutations in either the H3F3A or H3F3B genes have also been identified. While generally regarded as a benign entity, chondroblastoma manifests an intermediate type of behavior, given its ability to recur locally, and rarely, metastasize. PMID- 28557597 TI - Medicare's New Quality Payment Program Has Started-Are You Ready? PMID- 28557598 TI - Gastric Angiolipoma: A Rare Entity. AB - Angiolipoma is a benign tumor composed of adipose tissue and proliferating blood vessels that is commonly found in the subcutaneous tissue of the trunk and extremities. Gastric angiolipoma is a rare entity, and to the best of our knowledge, only 4 cases have been reported in the English-language literature thus far. These tumors may present as gastrointestinal bleeding and anemia or with obstructive symptoms. Accurate preoperative diagnosis is challenging because of nonspecific clinical symptoms and lack of specific findings on imaging studies. The correct diagnosis is usually made by histopathologic examination. The clinical significance lies in being aware of this rare entity in the stomach and distinguishing it from other benign and malignant gastric neoplasms that may be in the differential diagnosis. We herein discuss the clinical presentation, radiologic and histopathologic features, ancillary studies, differential diagnosis, and treatment and prognosis of this rare entity. PMID- 28557600 TI - Integration of Technical, Bioinformatic, and Variant Assessment Approaches in the Validation of a Targeted Next-Generation Sequencing Panel for Myeloid Malignancies. AB - CONTEXT: - Detection of variants in hematologic malignancies is increasingly important because of a growing number of variants impacting diagnosis, prognosis, and treatment response, and as potential therapeutic targets. The use of next generation sequencing technologies to detect variants in hematologic malignancies in a clinical diagnostic laboratory setting allows for efficient identification of routinely tested markers in multiple genes simultaneously, as well as the identification of novel and rare variants in other clinically relevant genes. OBJECTIVE: - To apply a systematic approach to evaluate and validate a commercially available next-generation sequencing panel (TruSight Myeloid Sequencing Panel, Illumina, San Diego, California) targeting 54 genes. In this manuscript, we focused on the parameters that were used to evaluate assay performance characteristics. DATA SOURCES: - Analytical validation was performed using samples containing known variants that had been identified previously. Cases were selected from different disease types, with variants in a range of genes. Panel performance characteristics were assessed and genomic regions requiring additional analysis or wet-bench approaches identified. CONCLUSIONS: - We validated the performance characteristics of a myeloid next-generation sequencing panel for detection of variants. The TruSight Myeloid Sequencing Panel covers more than 95% of target regions with depth greater than 500*. However, because of unique variant types such as large insertions or deletions or genomic regions of high GC content, variants in CEBPA, FLT3, and CALR required supplementation with non-next-generation sequencing assays or with informatics approaches to address deficiencies in performance. The use of multiple bioinformatics approaches (2 variant callers and informatics scripts) allows for maximizing calling of true positives, while identifying limitations in using either method alone. PMID- 28557599 TI - Validation of OncoPanel: A Targeted Next-Generation Sequencing Assay for the Detection of Somatic Variants in Cancer. AB - CONTEXT: - The analysis of somatic mutations across multiple genes in cancer specimens may be used to aid clinical decision making. The analytical validation of targeted next-generation sequencing panels is important to assess accuracy and limitations. OBJECTIVE: - To report the development and validation of OncoPanel, a custom targeted next-generation sequencing assay for cancer. DESIGN: - OncoPanel was designed for the detection of single-nucleotide variants, insertions and deletions, copy number alterations, and structural variants across 282 genes with evidence as drivers of cancer biology. We implemented a validation strategy using formalin-fixed, paraffin-embedded, fresh or frozen samples compared with results obtained by clinically validated orthogonal technologies. RESULTS: - OncoPanel achieved 98% sensitivity and 100% specificity for the detection of single-nucleotide variants, and 84% sensitivity and 100% specificity for the detection of insertions and deletions compared with single-gene assays and mass spectrometry-based genotyping. Copy number detection achieved 86% sensitivity and 98% specificity compared with array comparative genomic hybridization. The sensitivity of structural variant detection was 74% compared with karyotype, fluorescence in situ hybridization, and polymerase chain reaction. Sensitivity was affected by inconsistency in the detection of FLT3 and NPM1 alterations and IGH rearrangements due to design limitations. Limit of detection studies demonstrated 98.4% concordance across triplicate runs for variants with allele fraction greater than 0.1 and at least 50* coverage. CONCLUSIONS: - The analytical validation of OncoPanel demonstrates the ability of targeted next-generation sequencing to detect multiple types of genetic alterations across a panel of genes implicated in cancer biology. PMID- 28557601 TI - FDA Oversight of Laboratory-Developed Tests: Where Are We Now? PMID- 28557602 TI - Systemic Steroid Sparing Effect of Intravitreal Dexamethasone Implant in Chronic Noninfectious Uveitic Macular Edema. AB - PURPOSE: To evaluate the effectiveness and the systemic corticosteroid sparing effect of a single intravitreal dexamethasone (DEX) implant in patients with chronic noninfectious uveitic macular edema (UME). METHODS: Data from 22 eyes treated with DEX implant for UME related to systemic or ocular-confined noninfectious diseases were retrospectively analyzed. RESULTS: The mean systemic prednisone (or equivalent) dosage significantly decreased at 3- and 6-month follow-up evaluations compared to baseline (P = 0.002 and P = 0.01, respectively). Compared to baseline, central macular thickness values significantly decreased at 1-, 3-, and 6-month evaluations after the implantation (P < 0.0001). The mean best corrected visual acuity (BCVA) value gradually improved at 1-, 3-, and 6-month visits compared to baseline (P = 0.009, P = 0.0004, and P = 0.0001, respectively). At fluorescein angiography, active retinal vasculitis was identified in 11 (50%) eyes at baseline, 3 (13.6%) eyes at 1- and 3-month follow-up, and in 2 (9.1%) eyes at the last visit. Regarding side effects, 3/22 (13.6%) eyes presented a newly recognized intraocular hypertension at 1-month follow-up; however, intraocular pressure reverted to normal values within the 6-month follow-up in all cases. CONCLUSIONS: Treatment with intravitreal DEX implant in noninfectious uveitis allowed a significant corticosteroid sparing effect, a significant improvement in BCVA, and a prompt resolution of UME and vasculitis. No safety issues were observed. PMID- 28557603 TI - Genome-wide Methyl-Seq analysis of blood-brain targets of glucocorticoid exposure. AB - Chronic exposure to glucocorticoids (GCs) can lead to psychiatric complications through epigenetic mechanisms such as DNA methylation (DNAm). We sought to determine whether epigenetic changes in a peripheral tissue can serve as a surrogate for those in a relatively inaccessible tissue such as the brain. DNA extracted from the hippocampus and blood of mice treated with GCs or vehicle solution was assayed using a genome-wide DNAm platform (Methyl-Seq) to identify differentially methylated regions (DMRs) induced by GC treatment. We observed that ~70% of the DMRs in both tissues lost methylation following GC treatment. Of the 3,095 DMRs that mapped to the same genes in both tissues, 1,853 DMRs underwent DNAm changes in the same direction. Interestingly, only 209 DMRs (<7%) overlapped in genomic coordinates between the 2 tissues, suggesting tissue specific differences in GC-targeted loci. Pathway analysis showed that the DMR associated genes were members of pathways involved in metabolism, immune function, and neurodevelopment. Also, changes in cell type composition of blood and brain were examined by fluorescence-activated cell sorting. Separation of the cortex into neuronal and non-neuronal fractions and the leukocytes into T-cells, B-cells, and neutrophils showed that GC-induced methylation changes primarily occurred in neurons and T-cells, with the blood tissue also undergoing a shift in the proportion of constituent cell types while the proportion of neurons and glia in the brain remained stable. From the current pilot study, we found that despite tissue-specific epigenetic changes and cellular heterogeneity, blood can serve as a surrogate for GC-induced changes in the brain. PMID- 28557604 TI - Dapsone hydroxylamine-mediated alterations in human red blood cells from endometriotic patients. AB - Endometriosis, an estrogen-dependent chronic gynecological disease in women of reproductive age, is characterized by a systemic inflammation status involving also red blood cells (RBCs). In this study, we evaluated how the protein oxidative status could be involved in the worsening of RBC conditions due to dapsone intake in endometriotic women in potential treatment for skin or infection diseases. Blood samples from two groups of volunteers, control group (CG) and endometriosis patient group (PG), were analyzed for their content of band 3 tyrosine phosphorylation (Tyr-P) and high molecular weight aggregate (HMWA) in membranes, and glutathione (GSH) content and carbonic anhydrase (CA) activity in cytosol. In endometriotic patients, RBC showed the highest level of oxidative-related alterations both in membrane and cytosol. More interestingly, the addition of dapsone hydroxylamine (DDS-NHOH) could induce further increase of both membranes and cytosol markers, with an enhancement of CA activity reaching about 66% of the total cell enzyme amount. In conclusion, in PG the systemic inflammatory status leads to the inability of counteracting adjunctive oxidative stress, with a potential involvement of CA-related pathologies, such as glaucoma. Hence, the importance of the evaluation of therapeutic approaches worsening oxidative imbalance present in PG RBC is underlined. PMID- 28557606 TI - Decomposition of postural movements in individuals with mild TBI while reaching to intercept a moving virtual target. AB - The study analyzed postural and arm movement coordinations in patients with traumatic brain injury (TBI) while standing and reaching for a target moving in a 3D virtual environment. Thirteen individuals with mild TBI and 13 height, sex, and age-matched healthy control individuals were involved. While standing in front of the screen, the participants interacted with the projected environment by reaching for virtual targets. Coordination was analyzed as the percentage of reach-to-intercept cycle time during which their movement toward the target was decomposed with 0% indicating simultaneous motion in three planes or 100% indicating motion in one or two planes only. Decomposition was calculated for the postural movements (DIp), arm movements (DIa), and arm-postural coordination (DIa p). The latter index represented the percentage of reach-to-intercept cycle time during which either the posture or arm moved alone. DIp and DIa-p were larger in the TBI group compared to the control group (p < 0.01). In the TBI group, DIp and DIa-p correlated negatively with postural stability (r = - 0.71 and r = - 0.60; p < 0.01). Results suggest that individuals with TBI decompose postural and arm postural coordinations during a reach-to-intercept task. This may be either a result of impaired postural control or an effort to compensate for instability. These abnormalities should be taken into consideration while planning physical therapy programs for individuals after brain injury. PMID- 28557605 TI - Blood Glucose Control and Related Factors at a Camp for Korean Children and Adolescents with Type 1 Diabetes. AB - Data about Asian children and adolescents with type 1 diabetes are sparse. This study's objectives were to describe blood glucose (BG) levels and related factors at a camp for Korean children and adolescents with type 1 diabetes. This descriptive study was conducted January 8-10, 2015. The participants, 24 children and adolescents, were recruited for a 3-day residential diabetes camp. Data on 24 campers were analyzed. Their mean age was 13.4 (+/- 1.7) years; 44.4% were boys, and mean HgbA1c was 8.5% (+/- 1.4%). Results revealed that BG levels were maintained safely: The mean BG level during the 3-day stay was 171.1 (+/- 33.3) mg/dl. Multiple regression analysis showed that insulin adjustment for hyperglycemia (standardized beta = .426; t = 2.431; p = .030) and snacks for hypoglycemia (standardized beta = -.719; t = -3.723; p = .003) at the camp were the only independent contributors to mean BG levels during the 3-day study period. No demographic or clinical factor was found to be associated with the mean BG level. This is the first study of its kind to be conducted in an Asian population, presumably because the prevalence of type 1 diabetes in Asia is low and diabetes camps are a novel concept. Further research is recommended to assess the characteristics of campers (e.g., diet, activity levels, and cultural background) and to determine how the health outcomes of children and adolescents with type 1 diabetes are affected by camp programs. PMID- 28557607 TI - A Poisson Log-Normal Model for Constructing Gene Covariation Network Using RNA seq Data. AB - Constructing expression networks using transcriptomic data is an effective approach for studying gene regulation. A popular approach for constructing such a network is based on the Gaussian graphical model (GGM), in which an edge between a pair of genes indicates that the expression levels of these two genes are conditionally dependent, given the expression levels of all other genes. However, GGMs are not appropriate for non-Gaussian data, such as those generated in RNA seq experiments. We propose a novel statistical framework that maximizes a penalized likelihood, in which the observed count data follow a Poisson log normal distribution. To overcome the computational challenges, we use Laplace's method to approximate the likelihood and its gradients, and apply the alternating directions method of multipliers to find the penalized maximum likelihood estimates. The proposed method is evaluated and compared with GGMs using both simulated and real RNA-seq data. The proposed method shows improved performance in detecting edges that represent covarying pairs of genes, particularly for edges connecting low-abundant genes and edges around regulatory hubs. PMID- 28557608 TI - Substantial underreporting of anastomotic leakage after anterior resection for rectal cancer in the Swedish Colorectal Cancer Registry. AB - BACKGROUND: The causes and effects of anastomotic leakage after anterior resection are difficult to study in small samples and have thus been evaluated using large population-based national registries. To assess the accuracy of such research, registries should be validated continuously. MATERIAL AND METHODS: Patients who underwent anterior resection for rectal cancer during 2007-2013 in 15 different hospitals in three healthcare regions in Sweden were included in the study. Registry data and information from patient records were retrieved. Registered anastomotic leakage within 30 postoperative days was evaluated, using all available registry data and using only the main variable anastomotic insufficiency. With the consensus definition of anastomotic leakage developed by the International Study Group on Rectal Cancer as reference, validity measures were calculated. RESULTS: Some 1507 patients were included in the study. The negative and positive predictive values for registered anastomotic leakage were 96 and 88%, respectively, while the kappa-value amounted to 0.76. The false negative rate was 29%, whereas the false-positive rate reached 1.3% (the vast majority consisting of actual leaks, but occurring after postoperative day 30). Using the main variable anastomotic insufficiency only, the false-negative rate rose to 41%. CONCLUSIONS: There is considerable underreporting of anastomotic leakage after anterior resection for rectal cancer in the Swedish Colorectal Cancer Registry. It is probable that this causes an underestimation of the true effects of leakage on patient outcomes, and further quality control is needed. PMID- 28557609 TI - Myeloma-Derived Light Chain Paired with a Diagnostic Monoclonal Antibody Hinders Immunoassay Performance. AB - Monoclonal antibodies are widely used as the capture and detection reagents in diagnostic immunoassays. In the past, myeloma fusion partners expressing endogenous heavy and/or light chains were often used to generate hybridoma cell lines. As a result, mixed populations of antibodies were produced that can cause inaccurate test results, poor antibody stability, and significant lot-to-lot variability. We describe one such scenario where the P3U1 (P3X63Ag8U.1) myeloma fusion partner was used in the generation of a hybridoma producing protein induced vitamin K absence/antagonist-II (PIVKA II) antibody. The hybridoma produces three subpopulations of immunoglobulin as determined by ion exchange (IEx) chromatography that exhibit varying degrees of immunoreactivity (0%, 50%, or 100%) to the target antigen as determined by Surface Plasmon Resonance. To produce an antibody with the highest possible sensitivity and specificity, the antigen-specific heavy and light chain variable domains (VH and VL) were cloned from the hybridoma and tethered to murine IgG1 and kappa scaffolds. The resulting recombinant antibody was expressed in Chinese hamster ovary cells and is compatible for use in a diagnostic immunoassay. PMID- 28557610 TI - Genome Sequence of a Novel HIV-1 Circulating Recombinant Form (CRF79_0107) Identified from Shanxi, China. AB - We report a novel HIV-1 circulating recombinant form (CRF79_0107) from three epidemiologically unlinked patients through sexual contact in Shanxi province of China. This is the first second-generation circulating recombinant form identified in China. The breakpoint analysis of recombinants showed that CRF79_0107 was composed of CRF01_AE and CRF07_BC, with three CRF07_BC segments inserted into the CRF01_AE backbone. The emergence of CRF79_0107 increases the complexity of the HIV epidemic in China. PMID- 28557612 TI - Admittance to specialized palliative care (SPC) of patients with an assessed need: a study from the Danish palliative care database (DPD). AB - BACKGROUND: Admittance to specialized palliative care (SPC) has been discussed in the literature, but previous studies examined exclusively those admitted, not those with an assessed need for SPC but not admitted. The aim was to investigate whether admittance to SPC for referred adult patients with cancer was related to sex, age, diagnosis, geographic region or referral unit. MATERIAL AND METHODS: A register-based study with data from the Danish Palliative Care Database (DPD). From DPD we identified all adult patients with cancer, who died in 2010-2012 and who were referred to and assessed to have a need for SPC (N = 21,597).The associations were investigated using logistic regression models, which also evaluated whether time from referral to death influenced the associations. RESULTS: In the adjusted analysis, we found that admittance was higher for younger patients [e.g., 50-59 versus 80 + years: odds ratio (OR) = 2.03; 1.78 2.33]. There was lower odds of admittance for patients with hematological malignancies and patients from two regions: Capital Region of Denmark and Region of Southern Denmark. Lower admittance among men and patients referred from hospital departments was explained by later referral. CONCLUSIONS: In this first nationwide study of admittance to SPC among patients with a SPC need, we found difference in admittance according to age, diagnosis and region. This indicates that prioritization of the limited resources means that certain subgroups with a documented need have reduced likelihood of admission to SPC. PMID- 28557611 TI - Lamin A and microtubules collaborate to maintain nuclear morphology. AB - Lamin A (LA) is a critical structural component of the nuclear lamina. Mutations within the LA gene (LMNA) lead to several human disorders, most striking of which is Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disorder. HGPS cells are best characterized by an abnormal nuclear morphology known as nuclear blebbing, which arises due to the accumulation of progerin, a dominant mutant form of LA. The microtubule (MT) network is known to mediate changes in nuclear morphology in the context of specific events such as mitosis, cell polarization, nucleus positioning and cellular migration. What is less understood is the role of the microtubule network in determining nuclear morphology during interphase. In this study, we elucidate the role of the cytoskeleton in regulation and misregulation of nuclear morphology through perturbations of both the lamina and the microtubule network. We found that LA knockout cells exhibit a crescent shape morphology associated with the microtubule-organizing center. Furthermore, this crescent shape ameliorates upon treatment with MT drugs, Nocodazole or Taxol. Expression of progerin, in LA knockout cells also rescues the crescent shape, although the response to Nocodazole or Taxol treatment is altered in comparison to cells expressing LA. Together these results describe a collaborative effort between LA and the MT network to maintain nuclear morphology. PMID- 28557613 TI - Sustainable Development of Pathology in Sub-Saharan Africa: An Example From Ghana. AB - CONTEXT: - Pathology services are poorly developed in Sub-Saharan Africa. Komfo Anokye Teaching Hospital in Kumasi, Ghana, asked for help from the pathology department of the University Hospital of North Norway, Tromso. OBJECTIVE: - To reestablish surgical pathology and cytology in an African pathology department in which these functions had ceased completely, and to develop the department into a self-supporting unit of good international standard and with the capacity to train new pathologists. DESIGN: - Medical technologists from Kumasi were trained in histotechnology in Norway, they were returned to Kumasi, and they produced histologic slides that were temporarily sent to Norway for diagnosis. Two Ghanaian doctors received pathology training for 4 years in Norway. Mutual visits by pathologists and technologists from the 2 hospitals were arranged for the introduction of immunohistochemistry and cytology. Pathologists from Norway visited Kumasi for 1 month each year during 2007-2010. Microscopes and immunohistochemistry equipment were provided from Norway. Other laboratory equipment and a new building were provided by the Ghanaian hospital. RESULTS: - The Ghanaian hospital had a surgical pathology service from the first project year. At 11 years after the start of the project, the services included autopsy, surgical pathology, cytopathology, frozen sections, and limited use of immunohistochemistry, and the department had 10 residents at different levels of training. CONCLUSIONS: - A Ghanaian pathology department that performed autopsies only was developed into a self-supported department with surgical pathology, cytology, immunohistochemistry, and frozen section service, with an active residency program and the capacity for further development that is independent from assistance abroad. PMID- 28557615 TI - Trends in Diagnosis of Gleason Score 2 Through 4 Prostate Cancer in the National Cancer Database, 1990-2013. AB - CONTEXT: - The incidence of prostate cancer with Gleason scores 2 through 4 has been decreasing for decades, largely because of evolving criteria for Gleason scores, including the 2005 International Society of Urological Pathology recommendation that scores of 2 through 4 should rarely, if ever, be diagnosed based on needle biopsy. Whether trends in assigning Gleason scores 2 through 4 vary by facility type and patient characteristics is unknown. OBJECTIVE: - To assess trends in prostate cancer grading among various categories of treatment facilities. DESIGN: - Analyses of National Cancer Database records from 1990 through 2013 for 434 612 prostate cancers diagnosed by core needle biopsy, including multivariable regression for 106 331 patients with clinical T1c disease diagnosed from 2004 through 2013. RESULTS: - The proportion of prostate core needle biopsies with Gleason scores 2 through 4 declined from 11 476 of 53 850 (21.3%) (1990-1994) to 96 of 43 566 (0.2%) (2010-2013). The proportions of American Joint Committee on Cancer category T1c needle biopsies assigned Gleason scores 2 through 4 were 416 of 12 796 (3.3%) and 9 of 7194 (0.1%) during 2004 and 2013, respectively. Declines occurred earliest at National Cancer Institute designated programs and latest at community programs. A multivariable logistic model adjusting for patient demographic and clinical variables and restricted to T1c cancers diagnosed in needle biopsies from 2004 through 2013 showed that facility type is independently associated with the likelihood of cancers in such specimens being assigned Gleason scores of 2 through 4, with community centers having a statistically significant odds ratio of 5.99 relative to National Cancer Institute-designated centers. CONCLUSIONS: - These results strongly suggest differences in Gleason grading by pathologists practicing in different facility categories and variations in their promptness of adopting International Society of Urological Pathology recommendations. PMID- 28557616 TI - Analytic Validation of Immunohistochemistry Assays: New Benchmark Data From a Survey of 1085 Laboratories. AB - CONTEXT: - A cooperative agreement between the College of American Pathologists (CAP) and the United States Centers for Disease Control and Prevention was undertaken to measure laboratories' awareness and implementation of an evidence based laboratory practice guideline (LPG) on immunohistochemical (IHC) validation practices published in 2014. OBJECTIVE: - To establish new benchmark data on IHC laboratory practices. DESIGN: - A 2015 survey on IHC assay validation practices was sent to laboratories subscribed to specific CAP proficiency testing programs and to additional nonsubscribing laboratories that perform IHC testing. Specific questions were designed to capture laboratory practices not addressed in a 2010 survey. RESULTS: - The analysis was based on responses from 1085 laboratories that perform IHC staining. Ninety-six percent (809 of 844) always documented validation of IHC assays. Sixty percent (648 of 1078) had separate procedures for predictive and nonpredictive markers, 42.7% (220 of 515) had procedures for laboratory-developed tests, 50% (349 of 697) had procedures for testing cytologic specimens, and 46.2% (363 of 785) had procedures for testing decalcified specimens. Minimum case numbers were specified by 85.9% (720 of 838) of laboratories for nonpredictive markers and 76% (584 of 768) for predictive markers. Median concordance requirements were 95% for both types. For initial validation, 75.4% (538 of 714) of laboratories adopted the 20-case minimum for nonpredictive markers and 45.9% (266 of 579) adopted the 40-case minimum for predictive markers as outlined in the 2014 LPG. The most common method for validation was correlation with morphology and expected results. Laboratories also reported which assay changes necessitated revalidation and their minimum case requirements. CONCLUSIONS: - Benchmark data on current IHC validation practices and procedures may help laboratories understand the issues and influence further refinement of LPG recommendations. PMID- 28557614 TI - The Gold Standard Paradox in Digital Image Analysis: Manual Versus Automated Scoring as Ground Truth. AB - CONTEXT: - Novel therapeutics often target complex cellular mechanisms. Increasingly, quantitative methods like digital tissue image analysis (tIA) are required to evaluate correspondingly complex biomarkers to elucidate subtle phenotypes that can inform treatment decisions with these targeted therapies. These tIA systems need a gold standard, or reference method, to establish analytical validity. Conventional, subjective histopathologic scores assigned by an experienced pathologist are the gold standard in anatomic pathology and are an attractive reference method. The pathologist's score can establish the ground truth to assess a tIA solution's analytical performance. The paradox of this validation strategy, however, is that tIA is often used to assist pathologists to score complex biomarkers because it is more objective and reproducible than manual evaluation alone by overcoming known biases in a human's visual evaluation of tissue, and because it can generate endpoints that cannot be generated by a human observer. OBJECTIVE: - To discuss common visual and cognitive traps known in traditional pathology-based scoring paradigms that may impact characterization of tIA-assisted scoring accuracy, sensitivity, and specificity. DATA SOURCES: - This manuscript reviews the current literature from the past decades available for traditional subjective pathology scoring paradigms and known cognitive and visual traps relevant to these scoring paradigms. CONCLUSIONS: - Awareness of the gold standard paradox is necessary when using traditional pathologist scores to analytically validate a tIA tool because image analysis is used specifically to overcome known sources of bias in visual assessment of tissue sections. PMID- 28557617 TI - Analytic Validation of Immunohistochemical Assays: A Comparison of Laboratory Practices Before and After Introduction of an Evidence-Based Guideline. AB - CONTEXT: - Laboratories must demonstrate analytic validity before any test can be used clinically, but studies have shown inconsistent practices in immunohistochemical assay validation. OBJECTIVE: - To assess changes in immunohistochemistry analytic validation practices after publication of an evidence-based laboratory practice guideline. DESIGN: - A survey on current immunohistochemistry assay validation practices and on the awareness and adoption of a recently published guideline was sent to subscribers enrolled in one of 3 relevant College of American Pathologists proficiency testing programs and to additional nonsubscribing laboratories that perform immunohistochemical testing. The results were compared with an earlier survey of validation practices. RESULTS: - Analysis was based on responses from 1085 laboratories that perform immunohistochemical staining. Of 1057 responses, 65.4% (691) were aware of the guideline recommendations before this survey was sent and 79.9% (550 of 688) of those have already adopted some or all of the recommendations. Compared with the 2010 survey, a significant number of laboratories now have written validation procedures for both predictive and nonpredictive marker assays and specifications for the minimum numbers of cases needed for validation. There was also significant improvement in compliance with validation requirements, with 99% (100 of 102) having validated their most recently introduced predictive marker assay, compared with 74.9% (326 of 435) in 2010. The difficulty in finding validation cases for rare antigens and resource limitations were cited as the biggest challenges in implementing the guideline. CONCLUSIONS: - Dissemination of the 2014 evidence-based guideline validation practices had a positive impact on laboratory performance; some or all of the recommendations have been adopted by nearly 80% of respondents. PMID- 28557619 TI - Correction to: Gillies, N. A., et al., Fasting levels of insulin and amylin after acute pancreatitis are associated with pro-inflammatory cytokines. PMID- 28557618 TI - Microenvironment Tumor Metabolic Interactions Highlighted by qMSI: Application to the Tryptophan-Kynurenine Pathway in Immuno-Oncology. AB - Inhibition of NK and effector T-cell functions and activation of regulatory cell populations are the main immunosuppressive effects of indoleamine-2,3 dioxygenase1 (IDO1). By converting tryptophan (Trp) into kynurenine (Kyn), IDO1 is involved in the immune response homeostasis, and its dysregulated expression is described in immune-related pathologies, as tumors that hijack it to evade immune destruction. Thereby, IDO1 inhibitors are being developed to stimulate antitumor immune responses. Existing and standard quantitation methods of IDO1 substrate and metabolite(s) are based on the total level of Trp and its metabolites determined by liquid chromatography tandem mass spectrometry analysis in human plasma, cerebrospinal fluid, and brain. Here, we describe the detection, localization, and absolute quantitation of Trp and Kyn by quantitative mass spectrometry imaging (qMSI) in transfected murine tumor models expressing various levels of IDO1. Myeloid, glycolysis metabolic signatures, and correlation between IDO1 expression and Trp to Kyn conversion are also shown. High-definition IDO1 and GCN2 immunostainings overlaid with Kyn molecular images underline the tumor metabolism and heterogeneity. The development of immunotherapies such as IDO1 inhibitors requires a deep understanding of the immune system, the interplay of cancer cells, and biomarker characterization. Our data underline that qMSI allows the study of the spatial distribution and quantitation of endogenous immune metabolites for biology and pharmacology studies. PMID- 28557620 TI - The Rapid Recovery Progression Measure: A Brief Assessment of Biopsychosocial Functioning During Substance Use Disorder Recovery. AB - BACKGROUND: There is debate in the literature around how to measure outcomes in treatment and recovery from substance use disorder (SUD). Various constructs have been suggested as appropriate including "recovery capital" and "treatment progression." To contribute to this debate, the construct of "recovery progression" has been suggested by the authors, and a psychometric assessment, the Recovery Progression Measure (RPM). Although published psychometrics data have demonstrated the RPM to be reliable, at 36-item long, it may be too lengthy to complete in clinic environments. Therefore, a shorter version has been developed, the Rapid RPM. OBJECTIVES: To examine reliability, validity, sensitivity and specificity of the Rapid RPM via data from 9208 service users. METHODS: Data were collected from service users accessing the Breaking Free Online (BFO) treatment and recovery program, which has within its baseline assessment the six-item, 11-point Likert scale Rapid RPM. Psychometric properties were examined. RESULTS: Internal reliability of the Rapid RPM was excellent, alpha =.92. The Rapid RPM also had good concurrent and predictive validity, with baseline scores, and changes in scores to follow-up, being significantly associated with scores on standardized measures of common mental health sequela, severity of substance dependence and quality of life, and changes in self reported substance use. The Rapid RPM was also able to differentiate between participants scoring above thresholds on these measures for clinically relevant substance dependence and mental health difficulties. CONCLUSIONS: This study provides data to support reliability, validity, sensitivity and specificity of the Rapid RPM, indicating potential as a clinical tool. PMID- 28557621 TI - Military personnel compared to multiple suicide attempters: Interpersonal theory of suicide constructs. AB - The current study aimed to address the discrepancy between suicide rates in the military and general population by comparing facets of the interpersonal theory of suicide between civilians with multiple suicide attempts and U.S. military personnel. Military personnel exhibited higher levels of capability for suicide but lower levels of perceived burdensomeness and thwarted belongingness than civilian multiple attempters. When comparing only personnel endorsing ideation and civilian multiple attempters, the significant difference for capability remained, but the differences for perceived burdensomeness and thwarted belongingness became nonsignificant. Results suggest the emergence of ideation places personnel at a greater risk for suicide than many civilian multiple attempters. PMID- 28557622 TI - Efficacy of seat-mounted thoracic side airbags in the German vehicle fleet. AB - OBJECTIVE: Thoracic side airbags (tSABs) deploy within close proximity to the occupant. Their primary purpose is to provide a protective cushion between the occupant and the intruding door. To date, various field studies investigating their injury mitigation has been limited and contradicting. The research develops efficacy estimations associated for seat-mounted tSABs in their ability to mitigate injury risk from the German collision environment. METHODS: A matched cohort study using German In-Depth Accident Study (GIDAS) data was implemented and aims to investigate the efficacy of seat-mounted tSAB units in preventing thoracic injury. Inclusion in the study required a nearside occupant involved in a lateral collision where the target vehicle exhibited a design year succeeding 1990. Collisions whereby a tSAB deployed were matched on a 1:n basis to collisions of similar severity where no airbag was available in the target vehicle. The outcome of interest was an incurred bodily or thoracic regional injury. Through conditional logistic regression, an estimated efficacy value for the deployed tSAB was determined. RESULTS: A total of 255 collisions with the deployed tSAB matched with 414 collisions where no tSAB was present. For the given sample, results indicated that the deployed tSAB was not able to provide an unequivocal benefit to the occupant thoracic region, because individuals exposed to the deployed tSAB were at equal risk of injury (Thorax Maximum Abbreviated Injury Scale (Tho.MAIS)2+ odds ratio [OR] = 1.04, 95% confidence interval [CI], 0.41-2.62; Tho.MAIS3+ OR = 1.15, 95% CI, 0.41-3.18). When attempting to isolate an effect for skeletal injuries, a similar result was obtained. Yet, when the tSAB was coupled with a head curtain airbag, a protective effect became apparent, most noticeable for head/face/neck (HFN) injuries (OR = 0.59, 95% CI, 0.21-1.65). CONCLUSION: The reduction in occupant HFN injury risk associated with the coupled tSAB and curtain airbag may be attributable to its ability to provide coverage over previous mechanisms of injury. Yet, the sole presence of the tSAB showed no ability to provide additional benefit for the occupant's thoracic region. Future work should identify mechanisms of injury in tSAB cases and attempt to quantify improvements in the vehicle's ability to resist intrusion. PMID- 28557623 TI - Developmental Competence and Epigenetic Profile of Porcine Embryos Produced by Two Different Cloning Methods. AB - The "Dolly" based cloning (classical nuclear transfer, [CNT]) and the handmade cloning (HMC) are methods that are nowadays routinely used for somatic cloning of large domestic species. Both cloning protocols share several similarities, but differ with regard to the required in vitro culture, which in turn results in different time intervals until embryo transfer. It is not yet known whether the differences between cloned embryos from the two protocols are due to the cloning methods themselves or the in vitro culture, as some studies have shown detrimental effects of in vitro culture on conventionally produced embryos. The goal of this study was to unravel putative differences between two cloning methods, with regard to developmental competence, expression profile of a panel of developmentally important genes and epigenetic profile of porcine cloned embryos produced by either CNT or HMC, either with (D5 or D6) or without (D0) in vitro culture. Embryos cloned by these two methods had a similar morphological appearance on D0, but displayed different cleavage rates and different quality of blastocysts, with HMC embryos showing higher blastocyst rates (HMC vs. CNT: 35% vs. 10%, p < 0.05) and cell numbers per blastocyst (HMC vs. CNT: 31 vs. 23 on D5 and 42 vs. 18 on D6, p < 0.05) compared to CNT embryos. With regard to histone acetylation and gene expression, CNT and HMC derived cloned embryos were similar on D0, but differed on D6. In conclusion, both cloning methods and the in vitro culture may affect porcine embryo development and epigenetic profile. The two cloning methods essentially produce embryos of similar quality on D0 and after 5 days in vitro culture, but thereafter both histone acetylation and gene expression differ between the two types of cloned embryos. PMID- 28557624 TI - RNA-Guided Activation of Pluripotency Genes in Human Fibroblasts. AB - Specific activation of endogenous genes can be achieved by programmable artificial transcription factors (ATFs). In this study, we compared two artificial, programmable, clustered regularly interspaced short palindromic repeats (CRISPR)-based, ubiquitous transcription factors: deficient CRISPR associated protein 9 (dCas9)-VP64 (CRISPRa) alone, or a combination of dCas9-VP64 and MS2-P65-HSF1 [synergistic activation mediator (SAM) system] mediated activation of five pluripotency genes: KLF4 (K), LIN28 (L), MYC (M), OCT4 (O), and SOX2 (S) in human cells (HEK293T, HeLa, HepG2, and primary fibroblasts). Activation potential was monitored using a luciferase reporter system and we found that both CRISPRa and SAM can efficiently activate the proximal promoter of all five genes. We also observed that the guide RNA (gRNA) target sites and number of gRNAs have a major effect on gRNA-guided activation efficiency. Furthermore, increased activation efficiency (>3-folds) could be achieved by the SAM system compared to CRISPRa. In addition, we discovered that only the SAM system could efficiently activate LIN28, OCT4, and SOX2 expression (up to 100 folds compared to coexpression with a scrambled gRNA) in primary human fibroblasts. This SAM-mediated activation of LOS can be stably maintained for over 20 days in fibroblasts cultured in either fibroblasts or stem cell medium. However, when attempting to use the SAM-LOS activation as an approach for induced pluripotent stem cells-reprogramming, no embryonic stem-like colonies could be obtained from these SAM fibroblasts. In conclusion, our study showed that CRISPR/Cas9-based ATFs are potent to activate and maintain transcription of endogenous human pluripotent genes. However, future improvements of the system are still required to improve activation efficiency and cellular reprogramming using ATFs. PMID- 28557626 TI - Response Characteristics and Retinal Origin of the Photopic Negative Response of the Electroretinogram in Dogs. AB - PURPOSE: To investigate the response characteristics and retinal origin of the photopic negative response (PhNR) of the electroretinograms (ERGs) in dogs. METHODS: Photopic ERGs were elicited by white flash stimuli of different intensities under a steady white background illumination in four anesthetized dogs. These ERGs were also recorded in the same manner after intravitreal injection of tetrodotoxin (TTX). Additionally, retinal localization of voltage gated sodium channel Nav 1.6 was assessed by immunohistochemistry. RESULTS: The amplitude of the a-wave and the PhNR was increased as the stimulus intensity was raised, while the amplitude of the b-wave was peaked at the moderate stimulus intensity of 3.09 cd.s/m2. TTX greatly attenuated the PhNR, while the reduction in the b-waves and a-wave was mild or insignificant. Nav 1.6-expression was specifically detected on the retinal ganglion cells (RGCs). CONCLUSIONS: Our results are consistent with the PhNR primarily derived from the inner retina including RGCs in dogs, suggesting that the PhNR can be used to monitor function of these retinal components in dogs. PMID- 28557625 TI - A home-based body weight supported treadmill training program for children with cerebral palsy: A case series. AB - BACKGROUND AND PURPOSE: Contemporary approaches to the treatment of cerebral palsy (CP) advocate a task-specific approach that emphasizes repetition and practice of specific tasks. Recent studies suggest that body-weight-supported treadmill training (BWSTT) programs may be beneficial in clinical settings. The purposes of this case series were to explore the outcomes and feasibility of a home-based BWSTT program for three children with CP. CASE DESCRIPTION: Three children with CP at Gross Motor Function Classification System (GMFCS) Levels III or IV participated in this case series. Examination included the Functional Assessment Questionnaire (FAQ), the 10-meter walk test, the Gross Motor Function Measure (GMFM-66), and the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT). A harness system was used to conduct the BWSTT program over an 8-12 week period. OUTCOMES: All of the families reported enjoying the BWSTT program and found the harness easy to use. Participant 2 increased from a 2 to a 4 on the FAQ, while Participant 3 increased from a 6 to a 7. DISCUSSION: Two of the participants demonstrated post-intervention improvements in functional mobility. In addition to mobility outcomes, future research should explore the potential health benefits of a home-based BWSTT program. PMID- 28557627 TI - A Nonresponse Bias Analysis of the Health Information National Trends Survey (HINTS). AB - We conducted a nonresponse bias analysis of the Health Information National Trends Survey (HINTS) 4, Cycles 1 and 3, collected in 2011 and 2013, respectively, using three analysis methods: comparison of response rates for subgroups, comparison of estimates with weighting adjustments and external benchmarks, and level-of-effort analysis. Areas with higher concentrations of low socioeconomic status, higher concentrations of young households, and higher concentrations of minority and Hispanic populations had lower response rates. Estimates of health information seeking behavior were higher in HINTS compared to the National Health Interview Survey (NHIS). The HINTS estimate of doctors always explaining things in a way that the patient understands was not significantly different from the same estimate from the Medical Expenditure Panel Survey (MEPS); however, the HINTS estimate of health professionals always spending enough time with the patient was significantly lower than the same estimate from MEPS. A level-of-effort analysis found that those who respond later in the survey field period were less likely to have looked for information about health in the past 12 months, but found only small differences between early and late respondents for the majority of estimates examined. There is some evidence that estimates from HINTS could be biased toward finding higher levels of health information seeking. PMID- 28557628 TI - Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1. AB - Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in up to 7% of all APS1 patients, with immunoreactivity to pituitary tissue frequently reported. We aimed to isolate and identify specific pituitary autoantigens in patients with APS1. Immunoscreening of a pituitary cDNA expression library identified endothelin-converting enzyme (ECE)-2 as a potential candidate autoantigen. Immunoreactivity against ECE-2 was detected in 46% APS1 patient sera, with no immunoreactivity detectable in patients with other autoimmune disorders or healthy controls. Quantitative-PCR showed ECE-2 mRNA to be most abundantly expressed in the pancreas with high levels also in the pituitary and brain. In the pancreas ECE-2 was co-expressed with insulin or somatostatin, but not glucagon and was widely expressed in GH producing cells in the guinea pig pituitary. The correlation between immunoreactivity against ECE-2 and the major recognized clinical phenotypes of APS1 including hypopituitarism was not apparent. Our results identify ECE-2 as a specific autoantigen in APS1 with a restricted neuroendocrine distribution. PMID- 28557630 TI - The Exploitation of Low-Energy Electrons in Cancer Treatment. AB - Given the distinct characteristics of low-energy electrons (LEEs), particularly at energies less than 30 eV, they can be applied to a wide range of therapeutic modalities to improve cancer treatment. LEEs have been shown to efficiently produce complex molecular damage resulting in substantial cellular toxicities. Since LEEs are produced in copious amounts from high-energy radiation beam, including photons, protons and ions; the control of LEE distribution can potentially enhance the therapeutic radio of such beams. LEEs can play a substantial role in the synergistic effect between radiation and chemotherapy, particularly halogenated and platinum-based anticancer drugs. Radiosensitizing entities containing atoms of high atomic number such as gold nanoparticles can be a source of LEE production if high-energy radiation interacts with them. This can provide a high local density of LEEs in a cell and produce cellular toxicity. Auger-electron-emitting radionuclides also create a high number of LEEs in each decay, which can induce lethal damage in a cell. Exploitation of LEEs in cancer treatment, however, faces a few challenges, such as dosimetry of LEEs and selective delivery of radiosensitizing and chemotherapeutic molecules close to cellular targets. This review first discusses the rationale for utilizing LEEs in cancer treatment by explaining their mechanism of action, describes theoretical and experimental studies at the molecular and cellular levels, then discusses strategies for achieving modification of the distribution and effectiveness of LEEs in cancerous tissue and their associated clinical benefit. PMID- 28557629 TI - Comparative analysis of 12 different kits for bisulfite conversion of circulating cell-free DNA. AB - Blood circulating cell-free DNA (cfDNA) is becoming popular in the search of promising predictive and prognostic biomarkers. Among these biomarkers, cfDNA methylation markers have especially gained considerable attention. A significant challenge in the utilization of cfDNA methylation markers is the limited amount of cfDNA available for analyses; reportedly, bisulfite conversion (BSC) reduce cfDNA amounts even further. Nevertheless, few efforts have focused on ensuring high cfDNA conversion efficiency and recovery after BSC. To compare cfDNA recovery of different BSC methods, we compared 12 different commercially available BSC kits. We tested whether DNA recovery was affected by the molecular weight and/or quantity of input DNA. We also tested BSC efficiency for each kit. We found that recovery varied for DNA fragments of different lengths: certain kits recovered short fragments better than others, and only 3 kits recovered DNA fragments of <100 bp well. In contrast, DNA input amount did not seem to affect DNA recovery: for quantities spanning between 820 and ~25,000 genome equivalents per BSC, a linear relation was found between input and recovery amount. Overall, mean recovery ranged between 9 and 32%, with BSC efficiency of 97-99.9%. When plasma cfDNA was used as input for BSC, recovery varied from 22% for the poorest and 66% for the best performing kits, while conversion efficiency ranged from 96 to 100% among different kits. In conclusion, clear performance differences exist between commercially available BSC kits, both in terms of DNA recovery and conversion efficiency. The choice of BSC kit can substantially impact the amount of converted cfDNA available for downstream analysis, which is critical in a cfDNA methylation marker setting. PMID- 28557632 TI - An exploratory analysis of the notable activities of U.S. child death review teams. AB - Child death review teams (CDRTs) focus on the prevention of child deaths, but a comprehensive understanding of their activities is lacking. This exploratory study addressed this gap through a qualitative analysis of reported CDRT activities using the "spectrum of prevention" framework. We collected state-level CDRT reports published 2006-2015, recorded their activities (n = 193), and coded them using the "spectrum of prevention" framework. The highest percentage (64.2%) of activities was categorized under "fostering coalitions and networks." We recommend that CDRTs increase their reporting of activities so others can better understand their potential impact on preventing child deaths. PMID- 28557631 TI - The daily progress system: A proof of concept pilot study of a recovery support technology tool for outpatient substance abuse treatment. AB - BACKGROUND: Illicit substance use remains highly prevalent in the US, and epidemiological surveillance surveys estimate that in 2015, over 27 million individuals (10.1% of the US population) 12 years of age or older used illicit drugs in the past 30 days.1 Outpatient treatment delivered in community-based settings is the dominant modality for addiction treatment, typically involving weekly psychosocial counseling sessions in an individual and/or group format.2,3 Unfortunately, relapse and premature treatment discontinuation are quite common in outpatient treatment.3-5 Objectives: This is a pilot proof of concept feasibility study involving clients presenting for outpatient SUD treatment. This study sought to examine the feasibility and acceptability of the Daily Progress System (DPS), a telephone-based software program, using interactive voice response (IVR), designed to enhance quality care and improve client outcomes. METHODS: Individuals who presented at the participating treatment clinic, who met study eligibility criteria, and who provided written informed consent to participate were included in the study (N = 15; 53.3% females). Incentives were paid to participants for calls completed. RESULTS: Participants completed 65% of scheduled daily call-ins, representing 273 person-days of data on client cravings, mood, substance use, and involvement in recovery support activities. The average call duration was approximately 2 minutes and 42 seconds. There was a high degree of client and counselor acceptance and satisfaction using the system. Conclusions and Clinical Significance: Findings suggest that the DPS appears to be a feasible means of potentially addressing relapse and treatment engagement issues based on client and counselor engagement and satisfaction with the system. PMID- 28557633 TI - Implementing a School-Based Sleep Intervention in the First Year of Elementary School: Voices of the School Nurses as Intervention Deliverers. AB - OBJECTIVE/BACKGROUND: Elementary school nurses are an important component of health care systems. However, translational research of their role in interventions is limited. This study aimed to determine the feasibility, acceptability and sustainability of training the school nursing workforce to deliver a brief behavioral sleep intervention and the associated delivery costs. PARTICIPANTS: Twenty-four primary school nurses from the Victorian Department of Education and Training, Melbourne, Australia, involved in delivering the school based sleep intervention as part of the Sleep Well - Be Well trial participated in three surveys and a focus group over 30 months. METHODS: An embedded mixed methods design utilizing quantitative and qualitative data sources was used. RESULTS: Qualitative and quantitative evidence demonstrated training school nurses to deliver a brief sleep intervention was feasible and acceptable. Competence and confidence levels were maintained 12 months after the completion of intervention delivery demonstrating sustainability for this low cost model. Benefits of school nurses' participation in translational research projects were also identified. CONCLUSIONS: These findings highlight the potential for utilizing school nurses directly in interventions at the health and education interface. Further research is required to address the challenges of intervention implementation and to identify policy implications for other intervention opportunities which may exist. PMID- 28557634 TI - School Nurses on the Front Lines of Medicine: Uppers and Downers: The Approach to the Student With Altered Mental Status. AB - Although a student presenting with altered mental status due to substance use may occur infrequently in the school setting, it is of utmost importance to develop a differential diagnosis and to initiate stabilization of the student. This article describes the initial assessment and management of a student presenting with altered mental status, focusing on the differential diagnosis of altered mental status, on the varying presentations associated with common intoxications and ingestions, and on the screening tools available for the detection of depression and substance use. PMID- 28557635 TI - Adolescent Vaccines: Latest Recommendations, Addressing Barriers, and Improving Vaccine Rates. AB - The Advisory Committee on Immunization Practices recommends that the Tdap, HPV, and meningitis vaccines be administered to youth beginning between the ages of 11 and 12. The school nurse, knowledgeable about vaccine schedules and the rationale for the schedules, is in a unique position to advocate for all adolescent vaccines and their timely administration through addressing parent-guardian concerns and supporting other healthcare providers in completing the adolescent vaccines. This article reviews current recommendations for adolescent vaccinations and the actions needed to improve vaccination rates with a focus on Human Papillomavirus vaccine, the vaccine with the lowest completion rates among this age group. Additionally, school nurses are introduced to Middle School Health Starts Here, a program for school nurses designed to address the whole child as students progress from 5th grade to middle school. Public policy issues including school mandates, along with possible barriers to vaccine completion in adolescents, are discussed. PMID- 28557636 TI - Therapeutic Hypothermia and Temperature Management. PMID- 28557638 TI - Essentials in Return to Work Issues: A Tale of Two Shoulders. AB - Musculoskeletal disorders are common in the workplace and often respond to first aid treatment. Worker education combined with precise management of precautionary restrictions by occupational health nurses can decrease employees' recovery time and lower risk of complications. PMID- 28557637 TI - Situational Factors Associated With Burnout Among Emergency Department Nurses. AB - Emergency departments are high-stress environments for patients and clinicians. As part of the clinical team, nurses experience this stress daily and are subject to high levels of burnout, which has been shown to lead to hypertension, depression, and anxiety. Presence of these diseases may also contribute to burnout, creating a cycle of stress and illness. This prospective qualitative study used a phenomenological approach to better understand factors associated with burnout among emergency department nurses. Burnout manifests itself in multiple modes, can affect nurses' decisions to leave the profession, and must be addressed to mitigate the phenomenon. PMID- 28557640 TI - Workplace Violence Training Programs for Health Care Workers: An Analysis of Program Elements. AB - Commercial workplace violence (WPV) prevention training programs differ in their approach to violence prevention and the content they present. This study reviews 12 such programs using criteria developed from training topics in the Occupational Safety and Health Administration's (OSHA) Guidelines for Preventing Workplace Violence for Healthcare and Social Service Workers and a review of the WPV literature. None of the training programs addressed all the review criteria. The most significant gap in content was the lack of attention to facility specific risk assessment and policies. To fill this gap, health care facilities should supplement purchased training programs with specific training in organizational policies and procedures, emergency action plans, communication, facility risk assessment, and employee post-incident debriefing and monitoring. Critical to success is a dedicated program manager who understands risk assessment, facility clinical operations, and program management and evaluation. PMID- 28557641 TI - Implementation of Activity Sensor Equipment in the Homes of Chronic Obstructive Pulmonary Disease Patients. AB - INTRODUCTION: Telemedicine care models for managing advanced chronic obstructive pulmonary disease (COPD) may benefit from the addition of motion sensing, spirometry, and tablet-based symptom diary tracking. METHODS: We conducted a feasibility study of telemedicine in the home setting using multiple activity sensor monitoring equipment. Deployment and monitoring were supported by home health nurses with technical advice from the equipment makers as needed. Data analytics for motion sensing was provided by the research sponsor, but was not used for care decisions. On study intake, a health risk assessment, Quality of Life (SF-36) survey, and the St. George Respiratory Questionnaire were administered to assess patients' self-perception of quality of life, activities of daily life function, and difficulty living with COPD. RESULTS: Twenty-eight patients were enrolled and data were gathered for a minimum of 6 months and maximum of 9 months. The researchers demonstrated that augmentation of traditional telemedicine methods with motion sensing, spirometry, and symptom diaries appears feasible. The technical, process, logistics barriers, and solutions required for system deployment are described. The researchers demonstrated that augmentation of traditional telemedicine methods with motion sensing, spirometry, and symptom diaries appears feasible. CONCLUSIONS: Further exploration will be needed to determine the value of this information in preventing outcomes relevant to patients. PMID- 28557642 TI - Comparing the efficiency of Er,Cr:YSGG laser and diode laser on human beta defensin-1 and IL-1beta levels during the treatment of generalized aggressive periodontitis and chronic periodontitis. AB - BACKGROUND: The aim of this study is to determine the suitability of the Er,Cr:YSGG and 940 +/- 15-nm diode laser for the treatment of generalized aggressive periodontitis and chronic periodontitis by measuring the levels of human beta-defensin-1 and IL-1beta. PATIENTS AND METHODS: A total of 26 patients were included in this study. The study was designed as a "split-mouth" experiment. We performed scaling and root planing in the right maxillary quadrant, scaling and root planning + Er,Cr:YSGG laser in the left maxillary quadrant, scaling and root planning + 940 +/- 15-nm diode laser in the left mandibular quadrant, and only scaling and root planing in the right mandibular quadrant. The presence of human beta-defensin-1 and IL-1beta was analyzed with an ELISA. RESULTS: When the baseline and post-treatment human beta-defensin-1 levels and IL-1beta levels of the study groups were evaluated, a decrease in human beta defensin-1 and IL-1beta were observed in the quadrant where the Er,Cr:YSGG laser was applied in both the generalized aggressive periodontitis group and the chronic periodontitis group. CONCLUSIONS: The use of the Er,Cr:YSGG laser at non surgical periodontal treatment decreased both IL-1beta and human beta-defensin-1 levels. It is likely that Er,Cr:YSGG laser is more suitable for the treatment of generalized aggressive periodontitis and chronic periodontitis. PMID- 28557643 TI - Trends in the Prevalence of Severe Obesity and Bariatric Surgery Access: A State Level Analysis from 2011 to 2014. AB - BACKGROUND: Understanding what proportion of the eligible population is undergoing bariatric surgery at the state level provides critical insight into characterizing bariatric surgery access. We sought to describe statewide trends in severe obesity demographics and report bariatric surgery volume in Wisconsin from 2011 to 2014. METHODS: Self-reported data from the Behavioral Risk Factor Surveillance System (BRFSS) were used to calculate prevalence rates of severe obesity (class II and III) in Wisconsin. Bariatric surgery volume data were analyzed from the Wisconsin Hospital Association. A survey was sent to all American Society for Metabolic and Bariatric Surgery member bariatric surgeons in Wisconsin to assess perspectives on bariatric surgery access, insurance coverage, and referral processes. RESULTS: The prevalence of severe obesity in Wisconsin increased by 30% from 2011 to 2014 (10.4%-13.2%; P = .035); the odds of severe obesity nearly doubled for adults age 20-39 (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.3-3.0). During this time, the volume of bariatric surgery declined by 4.2%; (1432 to 1372; P < .001), whereas the rates of bariatric surgery per 1000 persons with severe obesity declined by 25.7% (3.5 to 2.6/1000). A majority (72%) of bariatric surgeon respondents felt bariatric surgery access either worsened or remained the same over the last 4 years. CONCLUSIONS: Severe obesity increased significantly in Wisconsin over a 4-year period, whereas bariatric surgery rates among severely obese persons have remained largely unchanged and are substantially below the national average. Combining the state level obesity survey data and bariatric surgery administrative data may be a useful approach for tracking bariatric surgery access throughout the United States. PMID- 28557645 TI - Corrigendum. PMID- 28557644 TI - Dietary and Supplemental Vitamin C and D on Symptom Severity and Physical Function in Knee Osteoarthritis. AB - Vitamins C and D have been associated with decreasing pain and increasing function but these associations are not definitive. This cross-sectional study explores what relationships supplemental and dietary intake of vitamins C and D have on pain severity and physical function in patients with knee osteoarthritis. Using data from the Osteoarthritis Initiative, we performed regression analyses to examine relationships between vitamins C and D, pain, and function. Dietary vitamin D and dietary vitamin C were divided into >90th, 50th-90th, and <50th percentile. The high percentile group for supplemental vitamin D was divided into >85th percentile, whereas the high percentile group for supplemental vitamin C was divided into >90th percentile. We found the 90th/85th percentile levels of dietary and supplemental vitamin D to be positively associated with pain (beta = 0.180; p = 0.028) and inversely related to physical function (beta = -0.150, p = 0.028), respectively. Daily intake of vitamin C showed no statistical significance. We found that supplementary vitamin D was strongly associated with lessened disability for knee OA patients. The unexpected finding that associated dietary vitamin D with greater knee pain merits further study. PMID- 28557646 TI - Spontaneous Blinking Kinematics in Patients Who Have Undergone Autogeneous Fascia Frontalis Suspension. AB - PURPOSE: To measure spontaneous blink metrics and brow motion in patients with congenital ptosis operated with frontalis slings with autogenous fascia lata. METHODS: An infrared three-dimensional video motion analyzer was employed to simultaneously measure brow motion and spontaneous blinks of 17 patients with congenital ptosis who underwent frontalis sling with autogenous fascia lata and a control group of equal number of healthy subjects. A customized software identified and quantified the amplitude and maximum velocity spontaneous blinks eyelid and brown motion during a 5-minute observation of a commercial movie. The corneal status of the patients with and without lagophthamos was evaluated with slit-lamp biomicroscopy with fluorescein staining. RESULTS: Lagophthalmos was detected on 13 (76.5%) patients. Out of these 3 (23%) showed signs of inferior superficial keratopathy despite the presence of normal (upwards) Bell's phenomenon in all of them. Blink rate was significantly diminished in the patients. The distribution of interblink time was similar in both groups. The mean amplitude of the down-phase of the patients' blinks was only 38% of the controls. The main sequence slope of the patients' blinks was abnormally low. In controls brow motion was a minute and random event no related to blinks. In the patients, the mean brow amplitude was five times higher than in controls reaching 45% of the blink amplitude. CONCLUSIONS: Spontaneous blink amplitude and velocity are severely impaired in patients with fascia lata autogenous slings. After surgery blinking amplitude is linearly related to the amplitude of brow motion. PMID- 28557647 TI - Epidermolysis Bullosa with Pyloric Atresia and Aplasia Cutis in a Newborn Due to Homozygous Mutation in ITGB4. AB - BACKGROUND: Epidermolysis bullosa with pyloric atresia (EB-PA) is an autosomal recessive disorder due to mutations in ITGA6 and/or ITGB4, resulting in altered expression of alpha6beta4 integrin. EB-PA can also occur with aplasia cutis. CASE REPORT: We present a newborn with EB-PA and aplasia cutis, born of consanguineous parents, with a homozygous c.3793+1G>A mutation affecting ITGB4, previously described only in the heterozygous state with other mutations. CONCLUSION: The previously unreported homozygous c.3793+1G>A mutation affecting ITGB4 causes a severe form of junctional epidermolysis bullosa with pyloric atresia and aplasia cutis. PMID- 28557648 TI - Ventral Hernia Repair: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: From the patient's perspective, a ventral hernia (VH) can cause pain, adversely affect function, increase size, cosmetically distort the abdomen, and incarcerate/strangulate abdominal contents. The only known "cure" for a VH is surgical repair. The aim of this study was to review systematically the published randomized controlled trials (RCTs) of the surgical care of VH. METHOD: A search of the Ovid, MEDLINE, EMBASE, and Cochrane databases was performed to obtain reports of RCTs on the use of mesh reinforcement in abdominal wall hernia repair. The outcomes assessed were hernia recurrence and surgical site infection (SSI). The overall quality of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). When feasible, based on assessment of heterogeneity, data were pooled and analyzed in a meta-analysis. RESULTS: Of the 10,349 titles screened, 25 articles (23 studies) met the search criteria. Evidence indicates that mesh reinforcement in clean cases can decrease hernia recurrence (number needed to treat = 7.9) but increase risk of SSI (number needed to harm = 27.8). Placing mesh in the sublay position (as opposed to the onlay or underlay position) may decrease the risk of hernia recurrence and SSI. CONCLUSIONS: Mesh reinforcement is recommended for all VH repairs in a clean case (high grade of evidence). Sublay mesh location may result in fewer recurrences and SSIs than onlay or inlay placement, but further study is needed to confirm this hypothesis (moderate grade of evidence). PMID- 28557650 TI - A pilot study of the efficacy of the POLARGEN(r) ultrahigh-frequency electric field (40.68 MHz) radiofrequency device in the treatment of facial contouring. AB - BACKGROUND: Various radiofrequency (RF) devices are used to treat skin laxity and face contouring, but few studies have examined ultrahigh-frequency (UHF) electric field (40.68 MHz) RF devices. OBJECTIVE: To evaluate the efficacy and safety of a UHF electric field (40.68 MHz) RF device for skin tightening and face contouring. METHODS: Ten patients each underwent four sessions of UHF electric field RF device treatment at 2-week intervals. Clinical improvement was evaluated with the patient satisfaction score using a six-point scale, and clinical photographs taken at every visit and 2 months after the RF treatment were assessed. Skin biopsies were obtained from one patient before the first treatment and immediately after the last treatment. Adverse reactions were recorded at every follow-up visit. RESULTS: All patients were women with a mean age of 51.7 +/- 7.2 years. The mean satisfaction score was 4.5 +/- 0.9 immediately after the last treatment session. Cheek, jawline, and neck enhancement and tightening were apparent in all patients. Side effects were minimal, and there were no burns or major complications. CONCLUSIONS: The UHF electric field RF device was effective for skin tightening and facial contouring, without significant adverse reactions. PMID- 28557649 TI - Sustained release docetaxel-incorporated lipid nanoparticles with improved pharmacokinetics for oral and parenteral administration. AB - The aim of this study was to develop docetaxel-incorporated lipid nanoparticles (DTX-NPs) to improve the pharmacokinetic behaviour of docetaxel (DTX) after oral and parenteral administration via sustained release. DTX-NPs were prepared by nanotemplate engineering technique with palmityl alcohol as a solid lipid and Tween-40/Span-40/Myrj S40 as a surfactants mixture. Spherical DTX-NPs below 100 nm were successfully prepared with a narrow particle size distribution, 96% of incorporation efficiency and 686 times increase in DTX solubility. DTX-NPs showed a sustained release over 24 h in phosphate-buffered saline and simulated gastric and intestinal fluids, while DTX-micelles released DTX completely within 12 h. The half-maximal inhibitory concentration (IC50) of DTX-NPs against human breast cancer MCF-7 cells was 1.9 times lower than that of DTX-micelles and DTX solution. DTX-NPs demonstrated 3.7- and 2.8-fold increase in the area under the plasma concentration-time curve compared with DTX-micelles after oral and parenteral administration, respectively. PMID- 28557651 TI - Effects of a New Hospital-Wide Surgical Consultation Protocol in Patients with Clostridium difficile Colitis. AB - BACKGROUND: Fulminant Clostridium difficile colitis (fCDC) occurs in 2%-8% of patients with CDC and carries a high death rate. Prompt operation may reduce death. Our aim was to determine whether a standardized hospital-wide protocol for surgical referral in CDC would result in earlier surgical consultation, earlier identification of patients who could benefit from surgical therapy, and reduced deaths from fCDC. METHODS: A multidisciplinary team developed consensus criteria for surgical consultation. Compliance was evaluated by prospective review of all inpatient CDC cases. Outcomes of the prospective cohort (POST) were compared to an historic control group (PRE). RESULTS: From November 1, 2010 to October 31, 2012, we identified 1,106 inpatients with CDC; 339 patients matched the consultation criteria, of whom 213 received a surgical consultation, resulting in an overall compliance rate of 62.8%. All those with fCDC received a surgical consultation, with a median time to surgical referral of three hours. Of 46 patients with fCDC, 11 (23.9%) died, compared with 34.8% in the historical control group (p = 0.15). The death rate was 14.7% in the POST group, when excluding patients with limitations of care and those transferred to our institution in a fulminant state. There was a shorter interval between admission and surgical intervention for those who required operation in the POST group three (1-11) days versus 1.5 (0-3) days, respectively, in the PRE and POST groups (p = 0.018), and a shorter adjusted median hospital length of stay (adjusted difference 9.0, 95% CI 2.2-12.3, p = 0.007) Conclusions: A hospital-wide protocol with established criteria for surgical consultation resulted in faster intervention and a shorter adjusted median hospital length of stay. The overall death rate for fCDC patients without limitations of life-sustaining treatment who presented to our emergency department or in whom fCDC developed while they were admitted to our hospital was 14.7%. PMID- 28557652 TI - Comparison of clomiphene citrate and letrozole for ovulation induction in women with polycystic ovary syndrome: a prospective randomized trial. AB - To compare the therapeutic efficacy of clomiphene citrate (CC) and letrozole (LE) on ovulation, pregnancy, and live birth in women with polycystic ovary syndrome (PCOS); and to ensure if LE can replace CC as the first-line therapy for ovulation induction in these women. This is a prospectively, randomized, controlled trial in the tertiary hospital. Two-hundred and sixty-eight anovulatory PCOS patients were treated by CC or CC plus metformin and LE or LE plus metformin for three continuous cycles or conception; their ovulation rates, pregnancy rates, and live birth rates were calculated and compared. No significant difference was noted among the four groups regarding to the baseline data of clinical manifestations, serum sex hormone levels, and serum insulin levels. A total of 240 patients completed the therapies. The ovulation rate was significantly higher in the group LE than the group CC; however, no significant difference was noted between the groups LE and CC, CC, and CC + MET, or LE and LE + MET in the pregnancy rate, abortion rate, and live birth rate. No birth defect was found in the total of 63 newborns. CC regimen was still recommended to be the first-line therapy of ovulation induction for PCOS. PMID- 28557654 TI - Executive summary and goals and objectives of the U.S. National Postvention Guidelines. AB - This preparatory article to a special issue of Death Studies on Responding to Grief, Trauma and Distress After a Suicide: U.S. National Guidelines reproduces the document's Executive Summary and Goals and Objectives. PMID- 28557653 TI - Efficient Transduction of Zebrafish Melanoma Cell Lines and Embryos Using Lentiviral Vectors. AB - The establishment of in vitro cultures of zebrafish cancer cells has expanded the potential of zebrafish as a disease model. However, the lack of effective methods for gene delivery and genetic manipulation has limited the experimental applications of these cultures. To overcome this barrier, we tested and optimized vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped lentiviral and retroviral vector transduction protocols. We show that lentivirus successfully and efficiently transduced zebrafish melanoma cell lines in vitro, allowing antibiotic selection, fluorescence-based sorting, and in vivo allotransplantation. In addition, injection of concentrated lentiviral particles into embryos and tumors established the feasibility of in vivo gene delivery. PMID- 28557655 TI - Tear Film Stability in Sjogren Syndrome Patients Treated with Hyaluronic Acid Versus Crosslinked Hyaluronic Acid-Based Eye Drops. AB - PURPOSE: To compare the stability of the tear film after instillation of eye drops containing hyaluronic acid (HA) or crosslinked hyaluronic acid (CLHA)-based in patients with Sjogren syndrome-related dry eye (SSDE). METHODS: Forty subjects were included in this study and were divided into 2 groups: the first group (control group) consisted of 20 healthy volunteers; the second group (study group) constituted of 20 suffering from SSDE; before and 5, 30, and 60 min after instillation of eye drops the surface regularity index (SRI) and surface asymmetry index (SAI) were registered. RESULTS: Comparing HA and CLHA, in the control group, SAI show statistically significant difference in the time 0 and in time 5, whereas there is no a statistically significant difference after 30 and 60 min from instillation. For SRI there is no statistically significant difference at any time. In SSDE group there is no statistically significant difference in the time 0 and 5, whereas there is a statistically significant difference after 60 min for SAI, and after 30 and 60 min for SRI from instillation. Both SRI and SAI in dry eyes were significantly greater than in control eyes (P < 0.05). CONCLUSION: Our study showed a better efficacy of CLHA compared with HA in maintaining the stability of the tear film in a patient suffering from SSDE. PMID- 28557656 TI - Type I membranous anomaly in Stickler syndrome. PMID- 28557657 TI - Off-Campus Residence as a Risk Factor for Heavy Drinking Among College Students. AB - BACKGROUND: College student alcohol use is a public health problem. OBJECTIVES: The aim of this study was to examine associations between residence and drinking behaviors among college students. We hypothesized that living off-campus independently or with peers would be associated with riskier drinking than living on-campus, and living with parents would be associated with less risky drinking than living on-campus. METHODS: We analyzed data from two separate studies conducted at two four-year universities in the Northeast. Study 1 examined data from 1286 students (57% female) attending a private university. In Study 2, analyses were replicated and extended with 2408 students (67% female) from a public university. We conducted regression analyses that controlled for age, race, gender, and class year to determine the unique association of residence on typical and peak drinking, frequency of heavy drinking, and alcohol-related consequences. RESULTS: In both samples, students living off-campus without parents reported more frequent alcohol consumption, larger drinking quantities, more frequent heavy drinking, and a greater number of alcohol-related consequences than students living on-campus (ps <.001). In Study 2, students living off-campus with their parents exhibited significantly fewer risky drinking behaviors than those living on-campus (ps <.001). CONCLUSIONS: Living off-campus either independently or with peers - is a risk factor for heavy drinking and consequences. This group exhibits more risky drinking behaviors and alcohol related consequences than students living on-campus, independent of age and class year. Therefore, students moving off-campus may be appropriate targets for alcohol misuse prevention programs. PMID- 28557658 TI - Distance Learning Course for Healthcare Professionals: Continuing Education in Tuberculosis. AB - BACKGROUND: Continuing education of healthcare workers (HCWs) is an essential strategy for the control of tuberculosis (TB) transmission, enabling HCWs in early detection and appropriate treatment of TB cases. METHODS: We developed a distance learning (DL) course on TB for nurses. We conducted a quasi-experimental before and after study to evaluate the DL community at the participant's learning level. In addition, to evaluate the DL community at the level of participant satisfaction, a cross-sectional study was carried out after the course. Nurses involved in active inpatient or outpatient care of patients were recruited to participate in the study. RESULTS: Sixty-six participants started and completed the course and they were included in the analysis. The overall mean pretest and post-test scores were 10.3 +/- 2.2 and 11.4 +/- 2.7, respectively. Participants increased their knowledge to a statistically significant degree (p < 0.0001). At baseline, the frequency of correct answers was very low in some questions: number of people infected by Mycobacterium tuberculosis in the world (10.6%); number of TB cases in Brazil (36.4%); contagiousness of latent TB infection (LTBI) (28.8%); and definition of active case finding (45.5%). Course feedback was mostly positive, with majority of users saying they were satisfied or totally satisfied. CONCLUSIONS: A brief DL course on TB was associated with some improvement in knowledge among nurses. The baseline knowledge was low regarding TB epidemiologic data, concepts on LTBI, and active case finding. This finding emphasizes the need to further improve the competencies and knowledge of nurses. PMID- 28557659 TI - Geminin Participates in Differentiation Decisions of Adult Neural Stem Cells Transplanted in the Hemiparkinsonian Mouse Brain. AB - Neural stem cells have been considered as a source of stem cells that can be used for cell replacement therapies in neurodegenerative diseases, as they can be isolated and expanded in vitro and can be used for autologous grafting. However, due to low percentages of survival and varying patterns of differentiation, strategies that will enhance the efficacy of transplantation are under scrutiny. In this article, we have examined whether alterations in Geminin's expression, a protein that coordinates the balance between self-renewal and differentiation, can improve the properties of stem cells transplanted in 6-OHDA hemiparkinsonian mouse model. Our results indicate that, in the absence of Geminin, grafted cells differentiating into dopaminergic neurons were decreased, while an increased number of oligodendrocytes were detected. The number of proliferating multipotent cells was not modified by the absence of Geminin. These findings encourage research related to the impact of Geminin on transplantations for neurodegenerative disorders, as an important molecule in influencing differentiation decisions of the cells composing the graft. PMID- 28557660 TI - Diagnosing Primary Squamous Cell Cancer of the Rectum in a Patient With HIV: A Case Report. PMID- 28557661 TI - Opioids in Cancer Pain: Right or Privilege? AB - Opioid analgesia is a mainstay of the treatment of cancer pain. Treatment of pain in patients with cancer with an ongoing substance abuse disorder can be difficult. We report the ethical challenges of treating a patient with cancer with a concomitant substance abuse disorder in an outpatient palliative care setting. We present an analysis of ethical considerations for the palliative care physician and strategies to aid in the successful treatment of such patients. We argue that there are select patients with cancer for whom exclusion from treatment with opioid therapy is warranted if their health is endangered by prescription of these medications. PMID- 28557662 TI - Trends Across the Night in Patronage, Intoxication, and Licensed Venue Characteristics in Five Australian Cities. AB - BACKGROUND: While alcohol-related harm is reportedly greater on weekend evenings, research investigating trends in the intoxication levels of patrons and factors that increase risk of harm over the night is lacking. OBJECTIVES: The aim was to observe trends over the course of the night for patron demographics, venue characteristics and patron intoxication. METHODS: Observations of licensed venues and patrons in night-time entertainment districts of five Australian cities were conducted. In total, 798 observations occurred between 9 pm and 2 am on Friday and Saturday nights across 61 unique bars, nightclubs, and pubs. Patron characteristics such as gender and percentage of patrons under 25 years of age were estimated. Measures of venue characteristics included number of patrons, percentage venue capacity, ease of patron movement, bar crowding, and time to service. Measures of intoxication included the percentage of patrons showing any signs of alcohol intoxication, percentage of patrons too intoxicated to remain in the venue, overall level of intoxication, and percentage of patrons showing signs of drug use. RESULTS: Patron capacity increased across the night, peaking at 11 pm in bars, and 1 am in nightclubs. Patron intoxication measures increased for all venue types across the night. Patrons showed more signs of drug use in nightclubs than other venue types. CONCLUSIONS: Increasing intoxication and decreasing patron numbers later in the night provides support for restricted trading hours and improved responsible service of alcohol policies. Specific venue types should be targeted to reduce drug use in the night-time economy. PMID- 28557663 TI - Dietary Supplement Intake and Associated Factors Among Gym Users in a University Community. AB - Dietary supplement intake and associated factors among gym users in a university community in Sharjah, United Arab Emirates (UAE), were assessed using a structured, self-administered questionnaire in this cross-sectional study. Adults (N = 320) from five gyms in the University City of Sharjah participated in this cross-sectional study. The prevalence of dietary supplement intake was 43.8%. Statistically significant associations were found between the use of dietary supplements and sex (47.7% males, 28.1% females; p = .006), as well as weight lifting (88.6% taking supplements vs. 11.4% not taking supplements; p < .001), favoring male gym users. The reasons attributed to the use of dietary supplements varied between the sexes. Male exercisers used supplements to increase or maintain muscles mass, strength, and power and to boost exercise recovery. Females mainly used dietary supplements to increase energy, maintain their health, and prevent nutrition deficiency. Overall, protein supplements (whey proteins [48.6%] and protein powder [45.7%]) were among the most-consumed dietary supplements, followed by multivitamins (38.6%), branched-chain amino acids (36.4%), caffeine (35.0%), and creatine (29.3%). A widespread use of Internet driven, self-prescribed dietary supplement intake was reported among gym users (60.7%). Only 12.8% of dietary supplement users sought information from dietitians. Practical implications suggest that gym instructors and coaches should be sufficiently trained to be able to provide accurate and scientifically sound information on dietary supplements to the exercisers in gyms in the university environment. PMID- 28557664 TI - Efficacy of Laser Photobiomodulation on Morphological and Functional Repair of the Facial Nerve. AB - OBJECTIVE: Evaluate the efficacy of low-level laser therapy (LLLT) on qualitative, quantitative, and functional aspects in the facial nerve regeneration process. MATERIALS AND METHODS: Forty-two male Wistar rats were used, randomly divided into a control group (CG; n = 10), in which the facial nerve without lesion was collected, and four experimental groups: (1) suture experimental group (SEG) and (2) fibrin experimental group (FEG), consisting of 16 animals in which the buccal branch of the facial nerve was sectioned on both sides of the face; an end-to-end epineural suture was performed on the right side, and a fibrin sealant was used on the left side for coaptation of the stumps; and (3) laser suture experimental group (LSEG) and (4) laser fibrin experimental group (LFEG), consisting of 16 animals that underwent the same surgical procedures as SEG and FEG with the addition of laser application at three different points along the surgical site (pulsed laser of 830 nm wavelength, optical output power of 30 mW, power density of 0.2586 W/cm2, energy density of 6.2 J/cm2, beam area of 0.116 cm2, exposure time of 24 sec per point, total energy per session of 2.16 J, and cumulative dose of 34.56 J). The animals were submitted to functional analysis (subjective observation of whisker movement) and the data obtained were compared using Fisher's exact test. Euthanasia was performed at 5 and 10 weeks postoperative. The total number and density of regenerated axons were analyzed using the unpaired t-test (p < 0.05). RESULTS: Laser therapy resulted in a significant increase in the number and density of regenerated axons. The LSEG and LFEG presented better scores in functional analysis in comparison with the SEG and FEG. CONCLUSIONS: LLLT enhanced axonal regeneration and accelerated functional recovery of the whiskers, and both repair techniques allowed the growth of axons. PMID- 28557665 TI - Contribution of physiologists to the identification of the humoral component of immunity in the 19th century. AB - The history of antimicrobial humoral immunity usually focuses on the works of the German school at the end of the 19th century, born in the tradition of chemistry and disinfection. Starting from an old quarrel of priority about serotherapy between Emil von Behring (1854-1917) and the French physiologists Charles Richet (1850-1935) and Jules Hericourt (1850-1938), we first confirm that the latter stated the principle of serotherapy in 1888 and put it into practice before the seminal Behring's article in 1890, observing several adverse effects of this new immunotherapy. We also find that researchers who can be considered heirs of the French school of Physiology founded by Claude Bernard (1813-1878) also investigated the field of humoral immunity in the 1870-1880s. Maurice Raynaud (1834-1881), Auguste Chauveau (1827-1917), and eventually Charles Richet applied the experimental method of Claude Bernard to the young field of microbiology, illustrating a movement called by Jacques Leonard "physiologization of the pasteurism." However, the contribution of physiologists in this field started before Louis Pasteur, leading to the conclusion that physiologists and chemists synergistically contributed to the birth of bacteriology and immunology. PMID- 28557667 TI - Real-Life Experience with Aflibercept and Ranibizumab in the Treatment of Newly Diagnosed Neovascular Age-Related Macular Degeneration over 24 Months. AB - PURPOSE: Comparative data appertaining to the long-term effects of Aflibercept or Ranibizumab in newly diagnosed cases of neovascular age-related macular degeneration (nAMD) over follow-up periods exceeding 12 months in clinical routine are scarce. METHODS: In this retrospective comparative analysis, a case series of patients with treatment-naive nAMD and requiring anti-vascular endothelial growth factor (VEGF) therapy in a routine clinical setting were treated with either Aflibercept [Afl (n = 106)] or Ranibizumab [Ran (n = 47)]. During the drug-loading phase, 3 monthly injections were administered. Thereafter, a treat-and-extend protocol was pursued for a maximum of 24 months. Ran was administered predominantly in eyes with classical lesions; Afl was administered in all others. The primary outcome parameters included anatomical and functional stability after 24 months. RESULTS: Patients were comparable regarding age, gender distribution, and lens status. Fewer patients presented with intraretinal fluid in the Afl- than in the Ran group at diagnosis (46.2% vs. 67.4%; P = 0.02), but not after the drug-loading phase. After the drug-loading phase, visual acuity [-4.2 letters (Afl) vs. -4.5 letters (Ran); P = 0.78] and the central foveal thickness remained stable. Linked to the lesion type, the number of scheduled clinical visits during the course of 24 months was higher for the Ran- than for the Afl group [11.9 +/- 4.7 visits (Ran) vs. 8.4 +/- 3.1 visits (Afl); P = 0.0005]. However, the total number of injections was similar [10.5 +/- 2.8 (Ran) vs. 11.7 +/- 3.6 (Afl); P = 0.06]. CONCLUSIONS: Based on tailoring according to the lesion type in cases of nAMD, the anatomical and the functional outcomes of treatment with either Afl or Ran were comparable for a maximum of 2 years. PMID- 28557668 TI - Dynamic interaction of a downward plane jet and a cough jet with respect to particle transmission: An analytical and experimental study. AB - A cough jet can travel beyond the breathing zone of the source person, and thus, infectious viral- and bacterial-laden particles can be transported from the source person to others in close proximity. To reduce the interpersonal transmission of coughed particles, the objective of this study was to analytically and experimentally investigate the performance of downward plane jets with various discharge velocities. Chamber measurements were conducted to examine the interaction between a transient cough jet (discharge velocities of 12 m/sec and 16 m/sec) and a steady downward plane jet (discharge velocities from 1.0-8.5 m/sec) with respect to the transport of and human exposure to coughed particles. The results show that a relatively high-speed cough can easily penetrate a downward plane jet with a discharge velocity of less than 6 m/sec. A downward plane jet with a discharge velocity of 8.5 m/sec can bend the cough jet to a certain extent. In this study, momentum comparison of the cough jet and the downward plane jet shows that the value of personal exposure to coughed particles depends on the ratio of jet momentums. The results show that when the two momentums are equivalent or if the downward plane jet has a greater momentum, the cough jet is deflected downward and does not reach the breathing zone of the target thermal dummy. Using the ratio of the two momentums, it may be estimated whether the transmission of a cough jet can be controlled. A trajectory model was developed based on the ratio of the two momentums of a cough jet and a downward jet and was validated using the experimental data. In addition, the predicted trajectory of the cough jet agreed well with the results from smoke visualization experiments. This model can be used to guide the design of downward plane jet systems for protection of occupants from coughed particles. PMID- 28557669 TI - Pedestrian fatality and impact speed squared: Cloglog modeling from French national data. AB - OBJECTIVE: The present study estimates pedestrians' risk of death according to impact speed when hit by a passenger car in a frontal collision. METHODS: Data were coded for all fatal crashes in France in 2011 and for a random sample of 1/20th of all road injuries for the same year and weighted to take into account police underreporting of mild injury. A cloglog model was used to optimize risk adjustment for high collision speeds. The fit of the model on the data was also improved by using the square of the impact speed, which best matches the energy dissipated in the collision. RESULTS: Modeling clearly demonstrated that the risk of death was very close to 1 when impact speeds exceeded 80 km/h. For speeds less than 40 km/h, because data representative of all crashes resulting in injury were used, the estimated risk of death was fairly low. However, although the curve seemed deceptively flat below 50 km/h, the risk of death in fact rose 2-fold between 30 and 40 km/h and 6-fold between 30 and 50 km/h. For any given speed, the risk of death was much higher for more elderly subjects, especially those over 75 years of age. These results concern frontal crashes involving a passenger car. Collisions involving trucks are far less frequent, but half result in the pedestrian being run over, incurring greater mortality. CONCLUSIONS: For impact speeds below 60 km/h, the shape of the curve relating probability of death to impact speed was very similar to those reported in recent rigorous studies. For higher impact speeds, the present model allows the curve to rise ever more steeply, giving a much better fit to observed data. The present results confirm that, when a pedestrian is struck by a car, impact speed is a major risk factor, thus providing a supplementary argument for strict speed limits in areas where pedestrians are highly exposed. PMID- 28557671 TI - Surviving suicide: A psychiatrist's journey. AB - This article is a personal narrative by Diane Roston, M.D. of the suicide of her husband, David, in 2008. It is a powerful and intimate recounting of her thoughts, emotions, and behaviors from the day of her husband's death, up to the present time, as she tries to cope with the shock, trauma, confusion, horror, and intense grief produced by this life-changing event. It also includes her thoughtful reflections on how this experience has changed her personal and her professional life and has led to a hard-won sense of meaning and acceptance of the death. PMID- 28557670 TI - Validity and reliability of the Moxy oxygen monitor during incremental cycling exercise. AB - INTRODUCTION: The Moxy is a novel, cutaneously placed muscle oxygen monitor which claims to measure local oxygen saturation (SmO2) and total haemoglobin (THb) using near-infrared spectroscopy. If shown to be reliable, its data storage and telemetric capability will be useful for assessing localised O2 usage during field-based exercise. This study investigated the reliability of the Moxy during cycling and assessed the correlations between its measurements, whole-body O2 consumption (VO2) and heart rate (HR). METHODS: Ten highly trained cyclists performed an incremental, step-wise cycling protocol on two occasions while wearing the Moxy. SmO2, THb, VO2 and HR were recorded in the final minute of each five-minute stage. Data were analysed using Spearman's Order-Rank Coefficient (SROC), Intraclass Correlation (ICC), and Coefficient of Variance (COV). Significance was set at p <= .05. RESULTS: SmO2 showed a 'strong' or 'very large' correlation between trials (SROC: r = 0.842-0.993, ICC: r = 0.773-0.992, p <= .01) and was moderately correlated with VO2 and HR (r = -0.71-0.73, p <= .01). SmO2 showed a moderate to high reliability at low intensities, but this decreased as relative exercise intensity increased. THb showed poor correlations between tests and with the other measured variables, but was highly reliable at all power outputs. CONCLUSIONS: The Moxy is a reliable device to measure SmO2 at low to moderate intensities, but at higher intensities, greater variation in measurements occurs, likely due to tissue ischaemia or increased movement artefacts due to more frequent muscular contractions. THb has low variation during exercise, and does not appear to be a valid indicator of muscle oxygenation. PMID- 28557666 TI - Factors Released from Endothelial Cells Exposed to Flow Impact Adhesion, Proliferation, and Fate Choice in the Adult Neural Stem Cell Lineage. AB - The microvasculature within the neural stem cell (NSC) niche promotes self renewal and regulates lineage progression. Previous work identified endothelial produced soluble factors as key regulators of neural progenitor cell (NPC) fate and proliferation; however, endothelial cells (ECs) are sensitive to local hemodynamics, and the effect of this key physiological process has not been defined. In this study, we evaluated adult mouse NPC response to soluble factors isolated from static or dynamic (flow) EC cultures. Endothelial factors generated under dynamic conditions significantly increased neuronal differentiation, while those released under static conditions stimulated oligodendrocyte differentiation. Flow increases EC release of neurogenic factors and of heparin sulfate glycosaminoglycans that increase their bioactivity, likely underlying the enhanced neuronal differentiation. Additionally, endothelial factors, especially from static conditions, promoted adherent growth. Together, our data suggest that blood flow may impact proliferation, adhesion, and the neuron-glial fate choice of adult NPCs, with implications for diseases and aging that reduce flow. PMID- 28557673 TI - College student grief, grief differences, family communication, and family satisfaction. AB - Although family grief communication has received solid research attention, few studies have examined how communication about grief differences among family members may relate to college students' grief experiences and family satisfaction. Online survey data were collected from emerging adults attending college (n = 335) at a large Midwestern university and analyzed using hierarchical multiple regressions. Findings indicated that family communication about grief differences was positively associated with family satisfaction but was not related to individual grief reactions. This study contributes to the understanding of family grief communication among college students and offers implications for student affairs personnel working with grieving college students. PMID- 28557672 TI - The Road to Language Learning Is Not Entirely Iconic: Iconicity, Neighborhood Density, and Frequency Facilitate Acquisition of Sign Language. AB - Iconic mappings between words and their meanings are far more prevalent than once estimated and seem to support children's acquisition of new words, spoken or signed. We asked whether iconicity's prevalence in sign language overshadows two other factors known to support the acquisition of spoken vocabulary: neighborhood density (the number of lexical items phonologically similar to the target) and lexical frequency. Using mixed-effects logistic regressions, we reanalyzed 58 parental reports of native-signing deaf children's productive acquisition of 332 signs in American Sign Language (ASL; Anderson & Reilly, 2002) and found that iconicity, neighborhood density, and lexical frequency independently facilitated vocabulary acquisition. Despite differences in iconicity and phonological structure between signed and spoken language, signing children, like children learning a spoken language, track statistical information about lexical items and their phonological properties and leverage this information to expand their vocabulary. PMID- 28557675 TI - Guest Editorial. PMID- 28557674 TI - Self-Hypnosis Classes to Enhance the Quality of Life of Breast Cancer Patients. AB - The Healing Skills Project, consisting of five, four-session self-hypnosis classes, was a pilot-study to evaluate the impact of self-hypnosis on the quality of life for breast cancer patients. The impact of self-hypnosis in women with breast cancer was measured using a self-report instrument, the Functional Assessment of Cancer Therapy-Breast, pre- and post-intervention (Brady, et al., 1997; Maratia, Cedillo, & Rejas, 2016). After employing the self-hypnosis interventions, statistically significant changes were noted on 16 of the 36 items, despite the small sample size (N = 23). In summary, participants reported significantly less trouble meeting the needs of their family; less side effects; felt less ill, sad, and nervous; had less worry about dying and their condition getting worse; less shortness of breath; less swelling or tenderness in their arms; and less worry about the effects of stress on their illness. Participants also reported being significantly more able to enjoy life and sleep well; enjoy the usual things they do for fun; more content with their quality of life; feeling more attractive and more like a woman. Additionally, on a brief evaluation of the intervention form 86% of the participants indicated that the self-hypnosis classes were very useful and 100% indicated that it contributed to a noticeably improved quality of life. The pilot study offers support for the value of teaching self-hypnosis to breast cancer patients. This article includes an outline of the protocol for the four-session self-hypnosis classes. PMID- 28557676 TI - Hypnosis Attitudes: Treatment Effects and Associations With Symptoms in Individuals With Cancer. AB - Attitudes about hypnosis are associated with hypnotic responsiveness. However, little is known about how hypnosis attitudes change with treatment and if those changes are associated with better outcomes. This study examined whether an intervention based on the Valencia Model of Waking Hypnosis combined with Cognitive-Behavioral Therapy changed attitudes about hypnosis in a sample of patients with a history of cancer. The results indicated that the intervention improved attitudes toward hypnosis, relative to a control intervention, and the improvements remained stable at 3-month follow-up. Analyses also showed that changes in some attitudes were associated with treatment-related improvements. The findings are consistent with the idea that attitudes about hypnosis play a role in hypnosis treatment outcome, supporting the importance of addressing such beliefs at the onset of and throughout treatment. PMID- 28557677 TI - Staying the Course: Using Hypnosis to Help Cancer Patients Navigate Their Illness. AB - Although sometimes maligned and often misunderstood, clinical hypnosis can be utilized as a powerful adjunct for the treatment of mind-body conditions, including cancer. Unlike customary medical regimens that treat diseases of the body and psychotherapies that address disorders of the psyche, hypnosis is a uniquely customizable multi-tool that can augment the treatment of both physical and emotional disorders as well as their complex interactions. This article presents a longitudinal, phase-oriented, clinical model that uses hypnosis in a series of sequential interventions that incorporate targeted suggestions to address the unfolding phases of the cancer continuum. Five such phases of the cancer patient's trajectory, along with their associated medical and psychological challenges, are conceptualized. Each phase is illustrated by case examples from the author's clinical practice and by a discussion of relevant hypnotic approaches. On the somatic level, the intrinsic capacities of hypnotic phenomena, paired with suggestions, can be harnessed to effect perceptual and functional changes to offer symptom relief, re-establishment of systemic homeostasis, amelioration of cellular chemistry, and the acceleration of tissue healing. In the psychological realm, hypnotic strategies can be used to provide a much needed continuity of emotional support, a sense of mastery and self-agency, emotional regulation, and behavioral change. PMID- 28557679 TI - Review of the International Literature. PMID- 28557678 TI - Cancer Palliation: Layered Hypnotic Approaches Mending Symptoms, Minding Hope, and Meaning. AB - Advanced cancer often produces significant symptoms such as pain, anxiety, insomnia, nausea, and cachexia; many symptoms require medication adjustments in dose and route of administration, and most patients have significant symptom burdens near the end of life. Treatment strategies that integrate mind-body approaches, such as hypnosis, to improve symptoms are increasingly being studied and utilized. The current article addresses the role for adjunctive hypnotic approaches to relieve suffering from pain and other symptoms, while fostering hope, even in the midst of advancing illness, similar to Snyder's (2002) metaphorical painting of "a personal rainbow of the mind" (p. 269). We describe specific clinical indications, technical modifications, and imagistic language used in formulating hypnotic suggestions in the face of illness progression. Furthermore, we specifically describe formulation of layered hypnotic suggestions with intent to intentionally weave suggestions to modify symptoms and link to suggestions to enhance hope and alter time perception. This approach offers the opportunity to transform an experience often defined by its losses to one in which hidden opportunities for growth and change emerge within this transitional life experience. PMID- 28557680 TI - Psychological Effects of Group Hypnotherapy on Breast Cancer Patients During Chemotherapy. AB - The purpose of this study was to evaluate the effect of group hypnotherapy on anxiety, depression, stress, self-esteem, optimism, and social support during chemotherapy, in patients with breast cancer, compared with a control group with standard medical care. Hypnotherapy consisted of 24 sessions that included suggestions to encourage relaxation, self-esteem, the resolution of past traumatic events, physical healing, and optimism. Results show that the hypnotherapy group significantly decreased anxiety, distress, increased self esteem, and optimism in the first 12 sessions. However, at the end of the 24 sessions, only self-esteem and optimism remained significant compared with the control group. The convenience of using hypnotherapy to encourage optimism and self-esteem in patients with breast cancer during chemotherapy treatment is discussed given its protective effect on health. PMID- 28557681 TI - Hypnosis in Cancer Care. AB - Cancer affects a growing proportion of the population as survival improves. The illness and its treatment brings a substantial burden of symptoms, including pain, anxiety, insomnia, and grief. Here, the uses of hypnosis in the treatment of these cancer-related problems will be reviewed. The utility of measuring hypnotizability in the clinical setting will be discussed. The current neurobiology of hypnotizability and hypnosis will be reviewed. Methods and results of using hypnosis for pain control in acute and chronic settings will be presented. Effects of hypnotic analgesia in specific brain regions associated with pain reduction, notably the dorsal anterior cingulate cortex and the somatosensory cortex, underlies its utility as a potent and side-effect free analgesic. Methods for helping those with cancer to better manage their anxiety, insomnia, and grief will be described. These involve facing disease-related stressors while dissociating the experience from somatic arousal. Given the serious complications of medications widely used to treat pain, anxiety, and insomnia, this article provides methods and an evidence base for wider use of techniques involving hypnosis in cancer care. Altering patients' perception of pain, disease-related stress, and anxiety can help change the reality of their life with cancer. PMID- 28557682 TI - An infant presenting with failure to thrive and hyperkalaemia owing to transient pseudohypoaldosteronism: case report. AB - A 3-month-old boy presented with failure to thrive and a history of a prenatally detected unilateral hydroureteronephrosis which was confirmed after birth. His growth and developmental milestones had been normal during the first 2 months but in the third month his appetite was poor with reduced intake but no vomiting. At presentation, his temperature was normal, there was mild dehydration and there was weight loss (his weight had decreased by 270 g in the past month). Haemoglobin was 11.9 g/dL, total white cell count 20.2 * 109/L (7-15) [neutrophils 30% (39-75) and lymphocytes 61% (16-47)], platelets 702 * 109/L (150 450), BUN12.1 mmol/L (2.1-16.1), serum creatinine 35.4 MUmol/L (15.0-37.1), sodium 126 mmol/L (135-144), potassium 6.8 mmol/L (3.6-4.8), chloride 88 mmol/L (98-106) and bicarbonate 14 mmol/L (19-24). Intravenous rehydration with sodium chloride 0.9% solution was commenced and he was transferred to the paediatric intensive care unit. A salt-wasting syndrome was suspected and a differential diagnosis included adrenal insufficiency, pseudohypoaldosteronism and congenital adrenal hyperplasia (owing to 21-hydroxylase deficiency). Urinalysis confirmed a urinary tract infection. Serum aldosterone was 3608 ng/dL (3.7-43.2), plasma renin activity > 38.9 pmol/L (<0.85), random cortisol 459 nmol/L (74-289), adrenocorticotropic hormone (ACTH) 6.01 pmol/L (1.32-6.60) and 17 hydroxyprogesterone 4.01 nmol/L (<3.2). Treatment of the urinary tract infection was followed by normalisation of serum electrolytes and other biochemical abnormalities, return of appetite and normal growth, which confirmed the diagnosis of transient pseudohypoaldosteronsim (TPHA). TPHA is discussed and insight provided to enable early recognition and adequate treatment of this rare clinical entity. PMID- 28557683 TI - Is There a Dose-Response Relationship between Tea Consumption and All-Cause, CVD, and Cancer Mortality? AB - BACKGROUND: A small change in tea consumption at population level could have large impact on public health. However, the health benefits of tea intake among Americans are inconclusive. OBJECTIVE: To evaluate the association between tea consumption and all-causes, cardiovascular disease (CVD) and cancer mortality in the Aerobics Center Longitudinal study (ACLS). METHODS: 11808 participants (20-82 years) initially free of CVD and cancers enrolled in the ACLS and were followed for mortality. Participants provided baseline self-report of tea consumption (cups/day). During a median follow-up of 16 years, 842 participants died. Of others, 250 died from CVD, and 345 died from cancer, respectively. A Cox proportional hazard model was used to produce hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Compared with participants consuming no tea, tea drinkers had a survival advantage ( Log-2 = 10.2, df = 3, P = 0.017); however, the multivariate hazard ratios (HRs) of all-cause mortality for those drinking 1-7, 8-14, and >14 cups/week were 0.95 (95% CI, 0.81-1.12), 1.00 (95% CI, 0.82-1.22), and 0.98 (95% CI, 0.76-1.25), respectively (P for linear trend = 0.83). The multivariate HR were 1.16 (95% CI, 0.86-1.56), 1.22 (95% CI, 0.85 1.76), and 0.94 (95% CI, 0.56-1.54) for CVD mortality (P for linear trend = 0.47), and 0.97 (95% CI, 0.75-1.25), 0.85 (95% CI, 0.60-1.16), and 0.94 (95% CI, 0.64-1.38) for cancer mortality (P for trend = 0.62). CONCLUSIONS: There were week or null relationships between tea consumption and mortality due to all cause, CVD disease or cancer were observed in ACLS. PMID- 28557685 TI - Corrigendum. PMID- 28557684 TI - Summaries of the Micronutrient Symposium of the 2016 Meeting of the American College of Nutrition. PMID- 28557686 TI - What Health Care Professionals Should Know about the Regulation and Safety of Dietary Supplements. PMID- 28557687 TI - Relating Therapist Characteristics to Client Engagement and the Therapeutic Alliance in an Adolescent Custodial Group Substance Misuse Treatment Program. AB - BACKGROUND: Client engagement in substance misuse treatment programs is directly associated with positive treatment outcomes. The nature of these programs means there are often difficulties engaging and retaining clients, but authors have consistently found a strong therapeutic alliance is associated with client engagement. While research has focused on the association between the alliance and engagement, the factors that influence the therapeutic alliance have received less attention. OBJECTIVE: To examine therapists' characteristics, namely therapists' stress and empathy levels, as potential predictors of client engagement and the therapeutic alliance, within an adolescent substance misuse group treatment program. METHOD: The sample included 84 adolescent clients and 14 therapists from a Secure Training Centre in England. Client engagement in the treatment program was observed, while self-reporting measures assessed the therapeutic alliance (client and therapist-rated), and therapists' stress and empathy levels. RESULTS: Multiple regression analysis revealed that therapists' stress levels negatively influenced the therapeutic alliance and had a curvilinear relationship with client engagement, indicating that stress is not exclusively negatively related to engagement. Although stress was found to negatively impact both cognitive and affective empathy, neither cognitive nor affective empathy were significantly related to client engagement or the therapeutic alliance. CONCLUSIONS: This study demonstrates the importance of therapist characteristics on client engagement and the therapeutic alliance. Within practice stress can have a positive impact on clients' engagement. Nevertheless, therapists may need additional support to deal with stress effectively. Therapists' empathy may too be fundamental to client engagement, but only it if is perceived by clients. PMID- 28557688 TI - Learning Recruits Neurons Representing Previously Established Associations in the Corvid Endbrain. AB - Crows quickly learn arbitrary associations. As a neuronal correlate of this behavior, single neurons in the corvid endbrain area nidopallium caudolaterale (NCL) change their response properties during association learning. In crows performing a delayed association task that required them to map both familiar and novel sample pictures to the same two choice pictures, NCL neurons established a common, prospective code for associations. Here, we report that neuronal tuning changes during learning were not distributed equally in the recorded population of NCL neurons. Instead, such learning-related changes relied almost exclusively on neurons which were already encoding familiar associations. Only in such neurons did behavioral improvements during learning of novel associations coincide with increasing selectivity over the learning process. The size and direction of selectivity for familiar and newly learned associations were highly correlated. These increases in selectivity for novel associations occurred only late in the delay period. Moreover, NCL neurons discriminated correct from erroneous trial outcome based on feedback signals at the end of the trial, particularly in newly learned associations. Our results indicate that task relevant changes during association learning are not distributed within the population of corvid NCL neurons but rather are restricted to a specific group of association-selective neurons. Such association neurons in the multimodal cognitive integration area NCL likely play an important role during highly flexible behavior in corvids. PMID- 28557689 TI - Functional Mechanisms Encoding Others' Direction of Gaze in the Human Nervous System. AB - The direction of others' gaze is a strong social signal to their intentions and future behavior. Pioneering electrophysiological research identified cell populations in the primate visual cortex that are tuned to specific directions of observed gaze, but the functional architecture of this system is yet to be precisely specified. Here, we develop a computational model of how others' gaze direction is flexibly encoded across sensory channels within the gaze system. We incorporate the divisive normalization of sensory responses-a computational mechanism that is thought to be widespread in sensory systems but has not been examined in the context of social vision. We demonstrate that the operation of divisive normalization in the gaze system predicts a surprising and distinctive pattern of perceptual changes after sensory adaptation to gaze stimuli and find that these predictions closely match the psychophysical effects of adaptation in human observers. We also find that opponent coding, broadband multichannel, and narrowband multichannel models of sensory coding make distinct predictions regarding the effects of adaptation in a normalization framework and find evidence in favor of broadband multichannel coding of gaze. These results reveal the functional principles that govern the neural encoding of gaze direction and support the notion that divisive normalization is a canonical feature of nervous system function. Moreover, this research provides a strong foundation for testing recent computational theories of neuropsychiatric conditions in which gaze processing is compromised, such as autism and schizophrenia. PMID- 28557690 TI - Consistent Neural Activity Patterns Represent Personally Familiar People. AB - How does the brain encode and organize our understanding of the people we know? In this study, participants imagined personally familiar others in a variety of contexts while undergoing fMRI. Using multivoxel pattern analysis, we demonstrated that thinking about familiar others elicits consistent fine-grained patterns of neural activity. Person-specific patterns were distributed across many regions previously associated with social cognition, including medial prefrontal, medial parietal, and lateral temporoparietal cortices, as well as other regions including the anterior and mid-cingulate, insula, and precentral gyrus. Analogous context-specific patterns were observed in medial parietal and superior occipital regions. These results suggest that medial parietal cortex may play a particularly central role in simulating familiar others, as this is the only region to simultaneously represent both person and context information. Moreover, within portions of medial parietal cortex, the degree to which person specific patterns were typically instated on a given trial predicted subsequent judgments of accuracy and vividness in the mental simulation. This suggests that people may access neural representations in this region to form metacognitive judgments of confidence in their mental simulations. In addition to fine-grained patterns within brain regions, we also observed encoding of both familiar people and contexts in coarse-grained patterns spread across the independently defined social brain network. Finally, we found tentative evidence that several established theories of person perception might explain the relative similarity between person-specific patterns within the social brain network. PMID- 28557691 TI - Different Electrophysiological Correlates of Visual Awareness for Detection and Identification. AB - Detecting the presence of an object is a different process than identifying the object as a particular object. This difference has not been taken into account in designing experiments on the neural correlates of consciousness. We compared the electrophysiological correlates of conscious detection and identification directly by measuring ERPs while participants performed either a task only requiring the conscious detection of the stimulus or a higher-level task requiring its conscious identification. Behavioral results showed that, even if the stimulus was consciously detected, it was not necessarily identified. A posterior electrophysiological signature 200-300 msec after stimulus onset was sensitive for conscious detection but not for conscious identification, which correlated with a later widespread activity. Thus, we found behavioral and neural evidence for elementary visual experiences, which are not yet enriched with higher-level knowledge. The search for the mechanisms of consciousness should focus on the early elementary phenomenal experiences to avoid the confounding effects of higher-level processes. PMID- 28557692 TI - The Role of the Primary Sensory Cortices in Early Language Processing. AB - The results of this magnetoencephalography study challenge two long-standing assumptions regarding the brain mechanisms of language processing: First, that linguistic processing proper follows sensory feature processing effected by bilateral activation of the primary sensory cortices that lasts about 100 msec from stimulus onset. Second, that subsequent linguistic processing is effected by left hemisphere networks outside the primary sensory areas, including Broca's and Wernicke's association cortices. Here we present evidence that linguistic analysis begins almost synchronously with sensory, prelinguistic verbal input analysis and that the primary cortices are also engaged in these linguistic analyses and become, consequently, part of the left hemisphere language network during language tasks. These findings call for extensive revision of our conception of linguistic processing in the brain. PMID- 28557693 TI - Magnocellular Bias in Exogenous Attention to Biologically Salient Stimuli as Revealed by Manipulating Their Luminosity and Color. AB - Exogenous attention is a set of mechanisms that allow us to detect and reorient toward salient events-such as appetitive or aversive-that appear out of the current focus of attention. The nature of these mechanisms, particularly the involvement of the parvocellular and magnocellular visual processing systems, was explored. Thirty-four participants performed a demanding digit categorization task while salient (spiders or S) and neutral (wheels or W) stimuli were presented as distractors under two figure-ground formats: heterochromatic/isoluminant (exclusively processed by the parvocellular system, Par trials) and isochromatic/heteroluminant (preferentially processed by the magnocellular system, Mag trials). This resulted in four conditions: SPar, SMag, WPar, and WMag. Behavioral (RTs and error rates in the task) and electrophysiological (ERPs) indices of exogenous attention were analyzed. Behavior showed greater attentional capture by SMag than by SPar distractors and enhanced modulation of SMag capture as fear of spiders reported by participants increased. ERPs reflected a sequence from magnocellular dominant (P1p, ?120 msec) to both magnocellular and parvocellular processing (N2p and P2a, ?200 msec). Importantly, amplitudes in one N2p subcomponent were greater to SMag than to SPar and WMag distractors, indicating greater magnocellular sensitivity to saliency. Taking together, results support a magnocellular bias in exogenous attention toward distractors of any nature during initial processing, a bias that remains in later stages when biologically salient distractors are present. PMID- 28557695 TI - Evidence- and practice-informed approach to implementing peer grief support after suicide systematically in the USA. AB - The landmark report, Responding to Grief, Trauma, and Distress After a Suicide: U.S. National Guidelines, identifies the suicide bereaved as an underserved population and recommends systematic development of peer grief support to help meet the needs of survivors of suicide loss. A widespread array of peer grief support after suicide (PGSS) services exists nationally, but only as a decentralized network of autonomous programs. Some research indicates that peer support is generally helpful to the suicide bereaved, a finding that is reinforced by a large body of emerging research showing that peer support is effective in mental illness and substance abuse recovery. The practice, study, growth, and refinement of peer support in those fields have generated viable ideas about the elements and principles of effective peer support-for individual practitioners and for programs and organizations-that could be used to guide the systematic implementation of PGSS. In addition, a comprehensive PGSS program (Tragedy Assistance Program for Survivors) that currently serves a large population-survivors of suicide in the military-could be a model for national PGSS systems development. Finally, there are several frameworks for systems development-zero suicide, consumer-operated services, recovery-oriented systems of care, and the consumer action research model-that could guide the expansion and increased effectiveness of PGSS in keeping with the Guidelines' recommendation. PMID- 28557694 TI - Targeted Temperature Management Effectiveness in the Elderly: Insights from a Large Registry. AB - Targeted temperature management (TTM) is recommended for all comatose adult out of-hospital cardiac arrest (OHCA) patients with shockable first documented rhythm. However, studies examining the use and benefits of TTM among patients aged 75 and older are lacking. Using the Cardiac Arrest Registry to Enhance Survival (CARES) dataset registry from 2013 to 2015. Study criteria included being 75 years of age or older, survival to hospital admission, and known in hospital mortality and CPC (Cerebral Performance Categories Scale) Scores. The study outcomes were in-hospital mortality and poor neurologic outcomes (CPC Scores 3 or 4) at hospital discharge among survivors. Hierarchical logistic regression and propensity score matching were used for multivariable adjustment. Two thousand nine hundred eighty-two patients met study inclusion criteria. One thousand three hundred fifty-seven (45.5%) received TTM in the admitting hospital. Receipt of TTM was more likely among men, those with a shockable first documented rhythm, and those with their event witnessed. There was no significant association with TTM and in-hospital mortality among patients with ventricular fibrillation (odds ratio [OR] = 0.88; 95% confidence interval [CI] [0.62-1.25]), p = 0.487 within the cohort. However, patients with a nonshockable first rhythm receiving TTM had higher odds of in-hospital mortality (p < 0.001). Propensity score results showed a modest association with TTM and increased mortality (OR) = 1.22, 95% CI [1.01-1.47]; p = 0.036 and no association with poor neurologic outcome (OR = 1.18; 95% CI [0.82-1.69]; p = 0.379) in the elderly. TTM is often provided to OHCA patients over age 75 though the benefits, particularly among nonshockable first documented rhythm patients are unclear. A randomized trial is needed to definitively answer who among OHCA event survivors aged 75 and older should receive this treatment. PMID- 28557696 TI - Comparative Cytogenetics of the Black Ghost Knifefish (Gymnotiformes: Apteronotidae): Evidence of Chromosomal Fusion and Pericentric Inversions in Karyotypes of Two Apteronotus Species. AB - The karyotype and chromosomal characteristics of Apteronotus albifrons and Apteronotus caudimaculosus collected from populations of two different large Brazilian river basins were analyzed by conventional and molecular cytogenetic techniques, to contribute to the differentiation and identification of the species in this genus. The diploid chromosome number was 2n = 24 for A. albifrons, but with difference in the karyotype structure and fundamental number values between two populations under study. In A. caudimaculosus, the diploid chromosome number was 2n = 26, which was classified as 22 metacentric (m), 2 submetacentric (sm), and 2 acrocentric (a) chromosomes. Heterochromatins were preferentially located in pericentromeric regions for both species. However, there are more C-banded chromosomes in A. caudimaculosus than A. albifrons. The sites of 18S DNA as revealed by fluorescence in situ hybridization (FISH) in the karyotypes of both species corresponded to sites revealed by Ag impregnation, although some additional 18S rDNA sites were observed in the genome of A. caudimaculosus. FISH with 5S rDNA-probe revealed interstitial sites on the m pair No. 1 for individuals of both A. albifrons populations, and in pericentromeric regions on the long arm of pair Nos. 5 and 9 in those of A. caudimaculosus. The karyotypes of A. albifrons and A. caudimaculosus indicated a reduction of 2n resulting from chromosomal fusion, as could be hypothesized from the presence of an interstitial telomere sequence in two chromosome pairs in karyotype of A. caudimaculosus. Thus, the present study demonstrated species-specific cytogenetic markers of otherwise morphologically very similar species A. albifrons and A. caudimaculosus. PMID- 28557697 TI - Bufotenine. PMID- 28557698 TI - The Herbal Connection: Herbs, Drug Abuse & Holistic Health. PMID- 28557699 TI - Peyote: The Divine Cactus. PMID- 28557700 TI - Marijuana Botany. An Advanced Study: The Propagation and Breeding of Distinctive Cannabis. PMID- 28557701 TI - Drugs, Alcohol and Sex. PMID- 28557702 TI - Cannabis in Costa Rica. A Study of Chronic Marijuana Use. PMID- 28557703 TI - Marihuana: The First Twelve Thousand Years. PMID- 28557704 TI - Putative Effects of Sex Hormones on Urinary Tract Infection. AB - Urinary tract infections affect mostly females. The infection and possible consequent ascent of bacteria is enhanced by various risk factors. Sex hormones regulate gene transcription implicated in immune cell development and maturation, in regulation of immune responses and immune signalling pathways. Limited knowledge is available; however, recent findings underline the importance of understanding the interactions between sex hormones and urinary tract infection to diminish the occurrence of complications related to this infection. This review summarizes and discusses the current knowledge on the correlation and impact of sex hormones on urinary tract infections. PMID- 28557705 TI - Moringa olifeira Lam. Stimulates Activation of the Insulin-Dependent Akt Pathway. Antidiabetic Effect in a Diet-Induced Obesity (DIO) Mouse Model. AB - We investigated the antidiabetic effect of Moringa olifeira Lam. in a diet induced obesity (DIO) mouse model. Six mice were randomly selected as normal controls. Moringa olifeira Lam. leaf extract at a dose of 200, 400 or 600 mg/kg body weight, glibenclamide (Glib) at the dose of 10 mg/kg (positive control) and distilled water at 10 ml/kg (control group) were administered orally by gastric intubation, and each group consisted of six mice. Insulinsensitive tissues (liver, skeletal muscle) were collected to investigate antidiabetic effects and examine the plant's molecular mechanisms. Moringa olifeira Lam. leaf extract prevented weight gain. It also reduced blood glucose in DIO mice. Glib and Moringa olifeira Lam. leaf extract, 400 mg/kg, treatments restored insulin levels towards normal values (P < 0.05 versus diabetic control group). Western immunoblot analysis of different tissues, collected at the end of the study, demonstrated that Moringa olifeira Lam. stimulated activation of the insulin dependent Akt pathway and increased the protein content of Glut 4 in skeletal muscle. The improvement of hepatic steatosis observed in DIO-treated mice was associated with a decrease in the hepatic content of SREBP-1, a transcription factor involved in de novo lipogenesis. The hepatic PPARalpha protein content in the plant extract- treated mice remained significantly higher than those of the control group (P < 0.05). In conclusion, this study provides the first evidence for direct action of Moringa olifeira Lam. on pancreatic beta-cells, enhancing glucose-stimulated insulin secretion. This correlated with hypoglycaemic effects in diabetic mice associated with restored levels of plasma insulin. PMID- 28557706 TI - Downregulation of p68 RNA Helicase (DDX5) Activates a Survival Pathway Involving mTOR and MDM2 Signals. AB - The DEAD box p68 RNA helicase (DDX5) is required to manipulate RNA structures implicated in mRNA/rRNA processing and transcript export, and acts as a co activator for a range of transcription factors. Previous research has indicated that p68 RNA helicase may also be important in tumour development. Wild-type HeLa and stable HeLa (clone 13) cell cultures containing RNAi-mediated depletion of p68 RNA helicase induced by doxycycline (DOX) were used to study how the p68 RNA helicase affects the mTOR cell signalling pathway. Relevant results were repeated using transient transfection with pSuper/pSuper-p68 RNA helicase, containing RNAi mediated depletion of p68 RNA helicase, to avoid DOX interference. Here we provide strong evidence for the participation of p68 RNA helicase in mTOR regulation. In detail, depletion of this helicase decreases cell growth and activates the mTOR/MDM2 cell survival mechanism, which ultimately leads to inhibition of the pro-apoptotic activity. p68 RNA helicase downregulation strongly stimulates 4E-BP1 phosphorylation, thereby provoking activation of cap dependent translation. In contrast, the IRES-dependent translation of c-myc is reduced when p68 RNA helicase is depleted, thus indicating that at least this specific translation requires p68 RNA helicase activity to manipulate the complex 5' end of this mRNA. Interestingly, p68 RNA helicase depletion decreases cell growth while activating the mTOR/MDM2 cell survival mechanism. As MDM2 is a known negative regulator of p53, we infer that the activation of the cell survival mechanism may result in inhibition of the pro-apoptotic factor p53. Finally, p68 RNA helicase depletion activates capdependent translation and inhibits c-MYC IRES mediated translation. PMID- 28557707 TI - Novel Mutation (T273R) in Thyroid Hormone Receptor beta Gene Provides Further Insight into Cryptic Negative Regulation by Thyroid Hormone. AB - Production of thyroid hormone is precisely regulated in a negative feed-back mechanism that depends critically on thyroid hormone receptor beta (TRbeta). This mechanism decreases production of thyrotropin- releasing hormone (TRH) and thyrotropin (TSH) in the hypothalamus and pituitary gland in response to high levels of circulating thyroid hormones (TH). Despite the wealth of accumulated knowledge, it is still not clear how exactly this negative regulation is executed. The syndrome of resistance to thyroid hormone (RTH), in which the levels of TH are not properly sensed, represents naturally occurring situations in which molecular components of this regulation are displayed and may be uncovered. TRbeta, which is central to this regulation, is in the majority of RTH cases mutated in a way that preserves some functions of the receptor. Approximately 150 different mutations in TRbeta have been identified to date. Here, we hypothesized that additional pathogenic mutations in TRbeta are likely to exist in human population and analysed clinical cases with suspected RTH. In keeping with our prediction, analysis of 17 patients from nine families led to identification of four presumed pathogenic mutations of TRbeta, including a previously unknown mutation, T273R. This suggests that threonine 273 is likely to be critical for the normal function of TRbeta, possibly due to its role in helix 12 mobility and interaction with coactivators, and thus supports the concept that TRbeta-dependent trans-activating function is necessary for the inhibition of TRH and TSH expression in response to elevated levels of TH. PMID- 28557708 TI - Spontaneously Hypertensive Rat Chromosome 2 with Mutant Connexin 50 Triggers Divergent Effects on Metabolic Syndrome Components. AB - Metabolic syndrome is a frequent condition with multifactorial aetiology. Previous studies indicated the presence of genetic determinants of metabolic syndrome components on rat chromosome 2 (RNO2) and syntenic regions of the human genome. Our aim was to further explore these findings using novel rat models. We derived the BN-Dca and BN-Lx.Dca congenic strains by introgression of a limited RNO2 region from a spontaneously hypertensive rat strain carrying a mutation in the Gja8 gene (SHR-Dca, dominant cataract) into the genomic background of Brown Norway strain and congenic strain BN-Lx, respectively. We compared morphometric, metabolic and cytokine profiles of adult male BN-Lx, BN-Dca and BN-Lx.Dca rats. We performed in silico comparison of the DNA sequences throughout RNO2 differential segments captured in the new congenic strains. Both BN-Dca and BN Lx.Dca showed lower total triacylglycerols and cholesterol concentrations compared to BN-Lx. Fasting insulin in BN-Dca was higher than in BN-Lx.Dca and BN Lx. Concentrations of several proinflammatory cytokines were elevated in the BN Dca strain, including IL-1alpha, IL-1beta, IFN-gamma and MCP-1. In silico analyses revealed over 740 DNA variants between BN-Lx and SHR genomes within the differential segment of the congenic strains. We derived new congenic models that prove that a limited genomic region of SHR-Dca RNO2 significantly affects lipid levels and insulin sensitivity in a divergent fashion. PMID- 28557709 TI - Influence of Cytochrome P450, ABC and SLC Gene Polymorphisms on Imatinib Therapy Outcome of Patients with Gastrointestinal Stromal Tumours (GIST). AB - The efficacy of imatinib-based therapy depends on the proteins involved in its metabolism and transportation. Therefore, the aim of our study was to investigate the possible correlation of selected P450, ABC and SLC polymorphic variants and the outcome of imatinib therapy. A total of 101 patients with advanced, KIT/PDGFRA(+) GIST treated with imatinib were enrolled to the study. DNA was extracted from peripheral blood samples and genotypes were determined by PCR-RFLP and direct sequencing. Deviation from the Hardy-Weinberg equilibrium was only observed for rs2740574. None of the studied SNPs was associated with GIST time to progression. No significant correlation between any specific variant and time to progression was found in the group with KIT exon 11 mutation. However, individuals of at least three potentially unfavourable genotypes presented significantly shorter time to progression in comparison to patients with two or less unfavourable genotypes. PMID- 28557710 TI - A Case-Control Study of Maternal Polybrominated Diphenyl Ether (PBDE) Exposure and Cryptorchidism in Canadian Populations. AB - BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are flame retardants found in North American household products during the past four decades. These chemicals leach out in dust as products age, exposing individuals daily through inhalation and ingestion. Animal studies suggest that PBDEs disrupt sex hormones and adversely affect development of the reproductive system. OBJECTIVES: In the present study, we examined whether there is a link between maternal hair PBDE concentrations and the risk of cryptorchidism (undescended testes) in male infants; testis descent is known to be dependent on androgens. METHODS: Full-term male infants were recruited through clinics in Montreal, Toronto, and London, Canada. Boys with cryptorchidism at 3-18 months of age (n=137) were identified by pediatric urologists and surgeons; similar-aged controls (n=158) had no genitourinary abnormalities as assessed by pediatricians. Eight BDE congeners (BDE-28, -47, -99, -100, -153, -154, -183, -209) were measured by GC-MS (gas chromatography-mass spectrometry) in maternal hair samples collected at the time of recruitment. RESULTS: The ?PBDE geometric mean for maternal hair was 45.35 pg/mg for controls and 50.27 pg/mg for cases; the concentrations of three BDEs (BDE-99, -100, and -154) were significantly higher in cases than controls in unadjusted models. In adjusted models, every 10-fold increase in the concentration of maternal hair BDE-99 [OR=2.53 (95% CI: 1.29, 4.95) or BDE-100 [OR=2.45 (95% CI: 1.31, 4.56)] was associated with more than a doubling in the risk of cryptorchidism. BDE-154 [OR=1.88 (95% CI: 1.08, 3.28) was also significant. CONCLUSIONS: Our results suggest that maternal exposure to BDE-99, 100, and -154 may be associated with abnormal migration of testes in the male fetus. This may be due to the anti-androgenic properties of the PBDEs. https://doi.org/10.1289/EHP522. PMID- 28557711 TI - Prenatal Residential Proximity to Agricultural Pesticide Use and IQ in 7-Year-Old Children. AB - BACKGROUND: Residential proximity to agricultural pesticide use has been associated with neural tube defects and autism, but more subtle outcomes such as cognition have not been studied. OBJECTIVES: We evaluated the relationship between prenatal residential proximity to agricultural use of potentially neurotoxic pesticides and neurodevelopment in 7-year-old children. METHODS: Participants included mothers and children (n=283) living in the agricultural Salinas Valley of California enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study. We estimated agricultural pesticide use within 1 km of maternal residences during pregnancy using a geographic information system, residential location, and California's comprehensive agricultural Pesticide Use Report data. We used regression models to evaluate prenatal residential proximity to agricultural use of five potentially neurotoxic pesticide groups (organophosphates, carbamates, pyrethroids, neonicotinoids, and manganese fungicides) and five individual organophosphates (acephate, chlorpyrifos, diazinon, malathion, and oxydemeton methyl) and cognition in 7-year-old children. All models included prenatal urinary dialkyl phosphate metabolite concentrations. RESULTS: We observed a decrease of 2.2 points [95% confidence interval (CI): -3.9, -0.5] in Full-Scale IQ and 2.9 points (95% CI: -4.4, -1.3) in Verbal Comprehension for each standard deviation increase in toxicity-weighted use of organophosphate pesticides. In separate models, we observed similar decrements in Full-Scale IQ with each standard deviation increase of use for two organophosphates (acephate and oxydemeton-methyl) and three neurotoxic pesticide groups (pyrethroids, neonicotinoids, and manganese fungicides). CONCLUSIONS: This study identified potential relationships between maternal residential proximity to agricultural use of neurotoxic pesticides and poorer neurodevelopment in children. https://doi.org/10.1289/EHP504. PMID- 28557712 TI - An Integrated Chemical Environment to Support 21st-Century Toxicology. AB - SUMMARY: Access to high-quality reference data is essential for the development, validation, and implementation of in vitro and in silico approaches that reduce and replace the use of animals in toxicity testing. Currently, these data must often be pooled from a variety of disparate sources to efficiently link a set of assay responses and model predictions to an outcome or hazard classification. To provide a central access point for these purposes, the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods developed the Integrated Chemical Environment (ICE) web resource. The ICE data integrator allows users to retrieve and combine data sets and to develop hypotheses through data exploration. Open-source computational workflows and models will be available for download and application to local data. ICE currently includes curated in vivo test data, reference chemical information, in vitro assay data (including Tox21TM/ToxCastTM high-throughput screening data), and in silico model predictions. Users can query these data collections focusing on end points of interest such as acute systemic toxicity, endocrine disruption, skin sensitization, and many others. ICE is publicly accessible at https://ice.ntp.niehs.nih.gov. https://doi.org/10.1289/EHP1759. PMID- 28557713 TI - Effects of Prenatal PM10 Exposure on Fetal Cardiovascular Malformations in Fuzhou, China: A Retrospective Case-Control Study. AB - BACKGROUND: Maternal exposure to ambient air pollution has been associated with an increased risk of congenital heart defects in offspring; however, the results are inconsistent. OBJECTIVES: We investigated whether there is an association between prenatal exposure to particulate matter with diameter <=10MUm (PM10) during early pregnancy and fetal cardiovascular malformations. METHODS: The gravidae from a hospital-based case-control study in Fuzhou, China, during 2007 2013 were assigned 10-d or 1-mo averages of daily PM10 using an air monitor-based inverse distance weighting method during early pregnancy. A total of 662 live birth or selectively terminated cases and 3,972 live-birth controls were enrolled. The exposure was considered as a categorical variable. A multivariable logistic regression model was constructed to quantify the adjusted odds ratios (aORs) of the exposure to PM10 and the risks of fetal cardiovascular malformations. RESULTS: PM10 levels were positively associated with the risks of atrial septal defect (aORs ranging from 1.29 to 2.17), patent ductus arteriosus [aORs = 1.54, 1.63; 95% confidence intervals (CIs): 1.17, 2.23; 1.06, 3.24], overall fetal cardiovascular malformations (aOR = 1.28; 95% CI: 1.03, 1.61), ventricular septal defect (aOR = 1.19; 95% CI: 1.00, 1.43), and tetralogy of Fallot (aOR = 1.44; 95% CI: 1.01, 2.19) in the various observed periods scaled by 10 d or 1 mo in the first and second gestation months. The strongest associations were observed for exposure to PM10 in the second quartile, whereas the associations were attenuated when higher concentrations of PM10 in the third and fourth quartiles of the exposure were evaluated. No correlations of PM10 levels with these cardiovascular malformations in the other time periods of gestation were observed. CONCLUSIONS: Our findings suggest some positive associations between maternal exposure to ambient PM10 during the first two months of pregnancy and fetal cardiovascular malformations. https://doi.org/10.1289/EHP289. PMID- 28557714 TI - Innovative Use of the Electronic Health Record to Support Harm Reduction Efforts. AB - BACKGROUND AND OBJECTIVES: Awareness of the impact of preventable harm on patients and families has resulted in extensive efforts to make our health care systems safer. We determined that, in our hospital, patients experienced 1 of 9 types of preventable harm approximately every other day. In an effort to expedite early identification of patients at risk and provide timely intervention, we used the electronic health record's (EHR) documentation to enable decision support, data capture, and auditing and implemented reporting tools to reduce rates of harm. METHODS: Harm reduction strategies included aggregating data to generate a risk profile for hospital-acquired conditions (HACs) for all inpatients. The profile includes links to prevention bundles and available care guidelines. Additionally, lists of patients at risk for HACs autopopulate electronic audit tools contained within Research Electronic Data Capture, and data from observational audits and EHR documentation populate real-time dashboards of bundle compliance. Patient population summary reports promote the discussion of relevant HAC prevention measures during patient care and unit leadership rounds. RESULTS: The hospital has sustained a >30% reduction in harm for 9 types of HAC since 2012. In 2014, the number of HACs with >80% bundle adherence doubled coincident with the progressive rollout of these EHR-based interventions. CONCLUSIONS: Existing EHR documentation and reporting tools may be effective adjuncts to harm reduction initiatives. Additional study should include an evaluation of scalability across organizations, ongoing bundle adherence, and individual tests of change to isolate interventions with the highest impact on our results. PMID- 28557715 TI - Amyloidosis Cutis Dyschromica, a Rare Cause of Hyperpigmentation: A New Case and Literature Review. AB - Amyloidosis cutis dyschromica is a rare form of primary cutaneous amyloidosis without systemic involvement and characterized by asymptomatic, progressive hyper and hypopigmentation. We present the first case of a patient with amyloidosis cutis dyschromica diagnosed previously elsewhere as having Addison disease with generalized hyperpigmentation of the skin. This case suggests that in patients presenting with asymptomatic cutaneous dyschromia a skin biopsy for histopathological examination should be considered. PMID- 28557716 TI - Unusual Fungal Lesion Presenting as a Neoplastic Pediatric Tongue Mass. AB - Tongue lesions in the pediatric population are rare. The differential diagnosis of these lesions is broad, and rapid growth of the lesion is concerning for a neoplastic process. We present a rare case of a fungal lesion mimicking a neoplastic growth in a 22-month-old girl. She underwent complete excision successfully. Full evaluation for benign and malignant neoplasms was negative. Tissue culture demonstrated growth of a rare Candida species to be the cause of the lesion. Postoperatively, she continues to do well, without regrowth 6 months later. This case reinforces the role of tissue culture when histology fails to demonstrate a diagnosis and emphasizes the need for efficient communication between the pediatrician, otolaryngologist, and pathologist for timely excision. PMID- 28557717 TI - Race and Obesity in Adolescent Hypertension. AB - BACKGROUND AND OBJECTIVES: The overall prevalence of essential hypertension in adolescents may be growing. Differences in blood pressure (BP) are well established in adults, but are less clear in adolescents. We hypothesize that the prevalence of hypertension differs by race/ethnicity among adolescents at school based screenings. METHODS: We performed school-based BP screening in over 20 000 adolescents from 2000 to 2015. Race/ethnicity was self-reported. Height and weight were measured to determine BMI, and BP status was confirmed on 3 occasions to diagnose sustained hypertension according to Fourth Working Group Report criteria. RESULTS: We successfully screened 21 062 adolescents aged 10 to 19 years (mean, 13.8 years). The final prevalence of sustained hypertension in all subjects was 2.7%. Obesity rates were highest among African American (3.1%) and Hispanic (2.7%) adolescents. The highest rate of hypertension was seen in Hispanic (3.1%), followed by African American (2.7%), white (2.6%), and Asian (1.7%) adolescents (P = .019). However, obese white adolescents had the highest prevalence of sustained hypertension (7.4%) compared with obese African American adolescents (4.5%, P < .001). At lower BMI percentiles (<60th percentile), Hispanic adolescents actually had the lowest predicted prevalence of hypertension among the 4 groups. CONCLUSIONS: The prevalence of hypertension varies among different race/ethnicities. Although obesity remains the strongest predictor of early hypertension, the strength of this relationship is intensified in Hispanic and white adolescents, whereas it is lessened in African American adolescents. PMID- 28557718 TI - Combination Clearance Therapy and Barbiturate Coma for Severe Carbamazepine Overdose. AB - A 15-year-old female subject presented comatose, in respiratory failure and shock, after the intentional ingestion of ~280 extended-release 200-mg carbamazepine tablets with a peak serum concentration of 138 ug/mL (583.74 umol/L). The patient developed clinical seizures and an EEG pattern of stimulus induced rhythmic, periodic, or ictal discharges, suggestive of significant cortical dysfunction. Due to the extremely high drug serum concentration and clinical instability, a combination of therapies was used, including lipid emulsion therapy, plasmapheresis, hemodialysis, continuous venovenous hemodiafiltration, and endoscopic intestinal decontamination. The patient's elevated serum lactate level with a high mixed venous saturation suggested possible mitochondrial dysfunction, prompting treatment with barbiturate coma to reduce cerebral metabolic demand. The serum carbamazepine concentration declined steadily, with resolution of lactic acidosis, no long-term end-organ damage, and return to baseline neurologic function. The patient was eventually discharged in her usual state of health. In the laboratory, we demonstrated in vitro that the active metabolite of carbamazepine hyperpolarized the mitochondrial membrane potential, supporting the hypothesis that the drug caused mitochondrial dysfunction. We thus successfully treated a life-threatening carbamazepine overdose with a combination of modalities. Future studies are required to validate this aggressive approach. The occurrence of mitochondrial dysfunction must be confirmed in patients with carbamazepine toxicity and the need to treat it validated. PMID- 28557719 TI - Community Poverty and Child Abuse Fatalities in the United States. AB - BACKGROUND AND OBJECTIVE: Child maltreatment remains a problem in the United States, and individual poverty is a recognized risk factor for abuse. Children in impoverished communities are at risk for negative health outcomes, but the relationship of community poverty to child abuse fatalities is not known. Our objective was to evaluate the association between county poverty concentration and rates of fatal child abuse. METHODS: This was a retrospective, cross sectional analysis of child abuse fatalities in US children 0 to 4 years of age from 1999 to 2014 by using the Centers for Disease Control and Prevention Compressed Mortality Files. Population and poverty statistics were obtained from US Census data. National child abuse fatality rates were calculated for each category of community poverty concentration. Multivariate negative binomial regression modeling assessed the relationship between county poverty concentration and child abuse fatalities. RESULTS: From 1999 to 2014, 11 149 children 0 to 4 years old died of child abuse; 45% (5053) were <1 year old, 56% (6283) were boys, and 58% (6480) were white. The overall rate of fatal child abuse was 3.5 per 100 000 children 0 to 4 years old. In the multivariate model, counties with the highest poverty concentration had >3 times the rate of child abuse fatalities compared with counties with the lowest poverty concentration (adjusted incidence rate ratio, 3.03; 95% confidence interval, 2.4-3.79). CONCLUSIONS: Higher county poverty concentration is associated with increased rates of child abuse fatalities. This finding should inform public health officials in targeting high-risk areas for interventions and resources. PMID- 28557721 TI - Enriched Medical Home Intervention Using Community Health Worker Home Visitation and ED Use. AB - BACKGROUND AND OBJECTIVES: Community health workers (CHWs) have great potential to extend medical home services and reduce emergent health care use, but evidence in pediatrics is scarce. We evaluated the impact of an existing enriched medical home intervention (EMHI) that directly integrates CHWs into emergency department (ED) visits and hospitalizations for pediatric ambulatory care-sensitive conditions (ACSCs). METHODS: The EMHI group in this prospective cohort study received home visits from trained CHWs to support adherence to recommended care; the comparison group received usual care (UC). Sociodemographic characteristics were compiled from the EMHI database, and ED and hospitalization information was extracted for study participants from a statewide database. The Wilcoxon signed rank test was used to compare ED data and the Wald test was used to compare hospitalization use for ACSCs between the intervention and UC groups after adjusting for different characteristics between groups by using propensity score matching method. RESULTS: The study sample included 922 children (225 intervention, 697 UC). After propensity score matching, the analytic sample included 450 children (225 intervention, 225 UC). After propensity score matching, the intervention group was significantly less likely than the UC group to visit the ED for an ACSC (18.2% vs 35.1%; P = .004). We found no differences in ACSC hospitalizations between the 2 groups. CONCLUSIONS: Our findings suggest that EMHIs using trained CHWs may be a cost-effective model to reduce preventable ED utilization, especially among vulnerable children. PMID- 28557720 TI - A Family-Centered Rounds Checklist, Family Engagement, and Patient Safety: A Randomized Trial. AB - BACKGROUND AND OBJECTIVES: Family-centered rounds (FCRs) have become standard of care, despite the limited evaluation of FCRs' benefits or interventions to support high-quality FCR delivery. This work examines the impact of the FCR checklist intervention, a checklist and associated provider training, on performance of FCR elements, family engagement, and patient safety. METHODS: This cluster randomized trial involved 298 families. Two hospital services were randomized to use the checklist; 2 others delivered usual care. We evaluated the performance of 8 FCR checklist elements and family engagement from 673 pre- and postintervention FCR videos and assessed the safety climate with the Children's Hospital Safety Climate Questionnaire. Random effects regression models were used to assess intervention impact. RESULTS: The intervention significantly increased the number of FCR checklist elements performed (beta = 1.2, P < .001). Intervention rounds were significantly more likely to include asking the family (odds ratio [OR] = 2.43, P < .05) or health care team (OR = 4.28, P = .002) for questions and reading back orders (OR = 12.43, P < .001). Intervention families' engagement and reports of safety climate were no different from usual care. However, performance of specific checklist elements was associated with changes in these outcomes. For example, order read-back was associated with significantly more family engagement. Asking families for questions was associated with significantly better ratings of staff's communication openness and safety of handoffs and transitions. CONCLUSIONS: The performance of FCR checklist elements was enhanced by checklist implementation and associated with changes in family engagement and more positive perceptions of safety climate. Implementing the checklist improves delivery of FCRs, impacting quality and safety of care. PMID- 28557722 TI - Improving Self-Regulation for Obesity Prevention in Head Start: A Randomized Controlled Trial. AB - OBJECTIVES: To determine the effect of an intervention to improve emotional and behavioral self-regulation in combination with an obesity-prevention program on the prevalence of obesity and obesity-related behaviors in preschoolers. METHODS: This was a cluster-randomized intervention trial in Head Start (HS) classrooms conducted in each of 4 academic years from 2011 to 2015. Participants (697 children; 49% boys; mean age: 4.1 +/- 0.5 years; 48% white, 30% African American, 12% Hispanic) were randomly assigned by classroom to 1 of 3 intervention arms: (1) HS + Preschool Obesity Prevention Series (POPS) + Incredible Years Series (IYS) (HS enhanced by the POPS [program targeting evidence-based obesity prevention behaviors] and the IYS [program to improve children's self regulation]), (2) HS+POPS, or (3) HS. Primary outcomes were changes in prevalence of obesity, overweight/obesity, BMI z score, and teacher-reported child emotional and behavioral self-regulation; secondary outcomes were dietary intake, outdoor play, screen time, and parent nutrition knowledge and nutrition self-efficacy. RESULTS: HS+POPS+IYS improved teacher-reported self-regulation compared with HS+POPS (P < .001) and HS (P < .001), but there was no effect on the prevalence of obesity (16.4% preintervention to 14.3% postintervention in HS+POPS+IYS versus 17.3% to 14.4% in HS+POPS [P = .54] versus 12.2% to 13.0% in HS [P = .33]). There was no effect of HS+POPS compared with HS alone (P = .16). There was no effect on other outcomes except for sugar-sweetened beverage intake (HS+POPS+IYS resulted in a greater decline than HS; P = .005). CONCLUSIONS: An intervention for parents and children to improve HS preschoolers' emotional and behavioral self-regulation in combination with an obesity-prevention curriculum did not reduce obesity prevalence or most obesity-related behaviors. PMID- 28557723 TI - Microcystic Lymphatic Malformation Successfully Treated With Topical Rapamycin. AB - Microcystic lymphatic malformations (MLM) are low-flow vascular malformations composed of multiple small cysts. MLM usually affect deep-lying structures, which makes their treatment even more difficult and complex. A novel and interesting treatment is rapamycin, a mammalian target of rapamycin inhibitor that when orally administrated has offered favorable results. However, until recently, topical rapamycin had not been used in the treatment of MLM. Case 1 is a girl aged 13 years with extensive MLM affecting the muscles in the right buttock. The patient had received frequent cycles of cryotherapy, but they had failed to control the associated symptoms. In the previous 12 months, the patient had reported greater discomfort, swelling, exudate, and superinfection of the affected region. Because no specific treatment has yet been approved for MLM, and as a step before the use of aggressive systemic or intralesional treatments, it was decided to initiate treatment with 1% rapamycin ointment. After 4 months of treatment, the patient presented a marked improvement, with a significant reduction of associated complications and no major side effects. Case 2 is a boy aged 5 years who underwent surgery for an intergluteal lipoblastoma at 3 weeks of life and developed a MLM on the scar 6 months afterward. The lesion showed slow growth and continuous exudation with frequent episodes of superinfection. Treatments with laser multiplex and intralesional bleomycin were performed unsuccessfully. In the previous 4 months, the patient had been treated with 1% rapamycin ointment with significant improvement and no side effects. PMID- 28557725 TI - Reduced Radiation in Children Presenting to the ED With Suspected Ventricular Shunt Complication. AB - BACKGROUND: Ventricular shunt complications in children can be severe and life threatening if not identified and treated in a timely manner. Evaluation for shunt obstruction is not without risk, including lifetime cumulative radiation as patients routinely receive computed tomography (CT) scans of the brain and shunt series (multiple radiographs of the skull, neck, chest, and abdomen). METHODS: A multidisciplinary team collaborated to develop a clinical pathway with the goal of standardizing the evaluation and management of patients with suspected shunt complication. The team implemented a low-dose CT scan, specifically tailored for the detection of hydrocephalus and discouraged routine use of shunt series with single-view radiographs used only when specifically indicated. RESULTS: There was a reduction in the average CT effective dose (millisievert) per emergency department (ED) encounter of 50.6% (confidence interval, 46.0-54.9; P <= .001) during the intervention period. There was a significant reduction in the number of shunt surveys obtained per ED encounter, from 62.4% to 5.32% (P < .01). There was no significant change in the 72-hour ED revisit rate or CT scan utilization rate after hospital admission. There were no reports of inadequate patient evaluations or serious medical events. CONCLUSIONS: A new clinical pathway has rapidly reduced radiation exposure, both by reducing the radiation dose of CT scans and eliminating or reducing the number of radiographs obtained in the evaluation of patients with ventricular shunts without compromising clinical care. PMID- 28557724 TI - Implementation of "Helping Babies Breathe": A 3-Year Experience in Tanzania. AB - OBJECTIVES: This first-ever country-level study assesses the implementation of the Helping Babies Breathe (HBB) program in 15 of Tanzania's mainland regions by measuring coverage, adoption and retention of provider skills, acceptability among providers, and barriers and challenges to at-scale implementation. METHODS: Longitudinal facility-level follow-up visits assessed provider resuscitation knowledge and skills in using objective structured clinical examinations and readiness of facilities to resuscitate newborns, in terms of birth attendants trained and essential equipment available and functional. Focus group discussions were held with providers to determine the acceptability, challenges, and barriers to implementation of the HBB program. RESULTS: Immediately after HBB training, 87.1% of providers passed the objective structured clinical examination. This number dropped to 79.4% at 4 to 6 weeks and 55.8% at 4 to 6 months (P < .001). Noting this fall-off in skills, the program implemented structured on-the-job training and supportive supervisory visits, which were associated with an improvement in skill retention. At long-term follow-up, >90% of facilities had bag-mask devices available to all beds in the labor and delivery ward, and 96% were functional. Overall, providers were highly satisfied with the HBB program but thought that the 1-day training used in Tanzania was too short, so they would welcome additional training and follow-up visits to reinforce skills. CONCLUSIONS: The HBB program in Tanzania has gained acceptability and shown success in equipping providers with neonatal resuscitation knowledge, skills, and supplies. However, assessing the program's impact on neonatal mortality has proven challenging. PMID- 28557726 TI - Modifiable Resilience Factors to Childhood Adversity for Clinical Pediatric Practice. AB - Childhood adversity is highly prevalent and associated with risk for poor health outcomes in childhood and throughout the life course. Empirical literature on resilience over the past 40 years has identified protective factors for traumatized children that improve health outcomes. Despite these empirical investigations of resilience, there is limited integration of these findings into proactive strategies to mitigate the impact of adverse childhood experiences. We review the state of resilience research, with a focus on recent work, as it pertains to protecting children from the health impacts of early adversity. We identify and document evidence for 5 modifiable resilience factors to improve children's long- and short-term health outcomes, including fostering positive appraisal styles in children and bolstering executive function, improving parenting, supporting maternal mental health, teaching parents the importance of good self-care skills and consistent household routines, and offering anticipatory guidance about the impact of trauma on children. We conclude with 10 recommendations for pediatric practitioners to leverage the identified modifiable resilience factors to help children withstand, adapt to, and recover from adversity. Taken together, these recommendations constitute a blueprint for a trauma-informed medical home. Building resilience in pediatric patients offers an opportunity to improve the health and well-being of the next generation, enhance national productivity, and reduce spending on health care for chronic diseases. PMID- 28557727 TI - Barriers to Pediatric Health Information Exchange. PMID- 28557728 TI - Improving Recruitment and Retention Rates in a Randomized Controlled Trial. AB - High recruitment and retention rates in randomized controlled trials are essential to ensure validity and broad generalizability. We used quality improvement methods, including run charts and intervention cycles, to achieve and sustain high recruitment and retention rates during the Hospital-To-Home Outcomes randomized controlled trial. This study is examining the effects of a single nurse-led home health care visit after discharge for an acute pediatric hospitalization. A total of 1500 participants were enrolled in the 15-month study period. For study recruitment, we assessed the percentage of patients who enrolled in the study among those randomly selected to approach (goal >=50%) and the percentage of patients who refused to enroll from those randomly selected to approach (goal <=30%). For intervention completion, we examined the percentage of patients who completed the home visit intervention among those randomized to receive the intervention (goal >=95%) were examined. Follow-up rates were tracked as the percentage of patients who completed the 14-day follow-up telephone survey (goal >=95%). The study goals for 2 of the 4 metrics were met and sustained, with statistically significant improvements over time in 3 metrics. The median enrollment rate increased from 50% to 59%, and the median refusal rate decreased from 37% to 32%. The median intervention completion rate remained unchanged at 88%. The 14-day follow-up completion median rate increased from 94% to 96%. These results indicate that quality improvement methods can be used within the scope of a large research study to achieve and sustain high recruitment and retention rates. PMID- 28557729 TI - Early Prediction Model of Patient Hospitalization From the Pediatric Emergency Department. AB - BACKGROUND AND OBJECTIVES: Emergency departments (EDs) in the United States are overcrowded and nearing a breaking point. Alongside ever-increasing demand, one of the leading causes of ED overcrowding is the boarding of hospitalized patients in the ED as they await bed placement. We sought to develop a model for early prediction of hospitalizations, thus enabling an earlier start for the placement process and shorter boarding times. METHODS: We conducted a retrospective cohort analysis of all visits to the Boston Children's Hospital ED from July 1, 2014 to June 30, 2015. We used 50% of the data for model derivation and the remaining 50% for validation. We built the predictive model by using a mixed method approach, running a logistic regression model on results generated by a naive Bayes classifier. We performed sensitivity analyses to evaluate the impact of the model on overall resource utilization. RESULTS: Our analysis comprised 59 033 patient visits, of which 11 975 were hospitalized (cases) and 47 058 were discharged (controls). Using data available within the first 30 minutes from presentation, our model identified 73.4% of the hospitalizations with 90% specificity and 35.4% of hospitalizations with 99.5% specificity (area under the curve = 0.91). Applying this model in a real-time setting could potentially save the ED 5917 hours per year or 30 minutes per hospitalization. CONCLUSIONS: This approach can accurately predict patient hospitalization early in the ED encounter by using data commonly available in most electronic medical records. Such early identification can be used to advance patient placement processes and shorten ED boarding times. PMID- 28557730 TI - Evaluating Serial Strategies for Preventing Wrong-Patient Orders in the NICU. AB - BACKGROUND: NICU patients have characteristics believed to increase their risk for wrong-patient errors; however, little is known about the frequency of wrong patient errors in the NICU or about effective interventions for preventing these errors. We conducted a quality improvement study to evaluate the frequency of wrong-patient orders in the NICU and to assess the effectiveness of an ID reentry intervention and a distinct naming convention (eg, "Wendysgirl") for reducing these errors, using non-NICU pediatric units as a comparator. METHODS: Using a validated measure, we examined the rate of wrong-patient orders in NICU and non NICU pediatric units during 3 periods: baseline (before implementing interventions), ID reentry intervention (reentry of patient identifiers before placing orders), and combined intervention (addition of a distinct naming convention for newborns). RESULTS: We reviewed >850 000 NICU orders and >3.5 million non-NICU pediatric orders during the 7-year study period. At baseline, wrong-patient orders were more frequent in NICU than in non-NICU pediatric units (117.2 vs 74.9 per 100 000 orders, respectively; odds ratio 1.56; 95% confidence interval, 1.34-1.82). The ID reentry intervention reduced the frequency of errors in the NICU to 60.2 per 100 000 (48.7% reduction; P < .001). The combined ID reentry and distinct naming interventions yielded an additional decrease to 45.6 per 100 000 (61.1% reduction from baseline; P < .001). CONCLUSIONS: The risk of wrong-patient orders in the NICU was significantly higher than in non-NICU pediatric units. Implementation of a combined ID reentry intervention and distinct naming convention greatly reduced this risk. PMID- 28557731 TI - The Concordance of Parent and Child Immunization. AB - BACKGROUND: A substantial body of work has related survey-based parental vaccine hesitancy to noncompliant childhood immunization. However little attention has been paid to the connection between parents' own immunization behavior and the immunizations their children receive. METHODS: Using the Oregon ALERT Immunization Information System, we identified adult caregiver-child pairs for children between 9 months and 17 years of age. The likelihood of adult-child concordance of influenza immunization per influenza season from 2010-2011 through 2014-2015 was assessed. The utility of adult immunization as a predictor was also assessed for other, noninfluenza recommended immunizations for children and adolescents. RESULTS: A total of 450 687 matched adult caregiver-child pairs were included in the study. The children of immunizing adults were 2.77 times more likely to also be immunized for seasonal influenza across all seasons (95% confidence interval, 2.74-2.79), with similar results applying within each season. Adult immunization status was also significantly associated with the likelihood of children and adolescents getting other noninfluenza immunizations, such as the human papillomavirus vaccine (HPV). When adults improved their own behavior from nonimmunizing to immunizing across influenza seasons, their children if not immunized in the previous season were 5.44 times (95% confidence interval, 5.35-5.53) more likely to become immunized for influenza. CONCLUSIONS: Children's likelihood of following immunization recommendations is associated with the immunization behavior of their parents. Encouraging parental immunization is a potential tool for increasing children's immunization rates. PMID- 28557733 TI - A 9-Day-Old With Weight Loss and Diarrhea. AB - A 9-day-old infant girl presented with diarrhea and weight loss of 19% since birth. She was born via spontaneous vaginal delivery at 39 weeks' gestation to a mother positive for group B Streptococcus who received adequate intrapartum prophylaxis. The infant was formula-fed every 2 to 3 hours with no reported issues with feeding or swallowing. The infant had nonmucoid watery stools ~5 to 15 times per day. Her family history was significant for hypertrophic cardiomyopathy in several of her family members. Her initial vital signs and physical examination were normal. Laboratory data on hospital admission showed a normal complete blood cell count, but her chemistry analysis revealed significant hypernatremia, hyperkalemia, metabolic acidosis, and acute kidney injury. Her hypernatremia was resistant to fluid management. In this article, we discuss the infant's hospital course, our clinical thought process, and how we arrived at our final diagnosis. PMID- 28557732 TI - Validation of the Pediatric Sedation State Scale. AB - OBJECTIVES: Development and validation of the Pediatric Sedation State Scale (PSSS) is intended to specifically meet the needs of pediatric procedural sedation providers to measure effectiveness and quality of care. METHODS: The PSSS content was developed through Delphi methods utilizing leading pediatric sedation experts and published guidelines on procedural sedation in children. Video clips were created and presented to study participants, who graded the state of patients during procedures by using the PSSS to evaluate inter- and intrarater reliability by determining the intraclass correlation coefficient. We also compared the PSSS to the Observational Scale of Behavioral Distress-revised during 4 clinically relevant phases of a laceration repair procedure. RESULTS: Six sedation states were defined for the PSSS. Each state was assigned a numerical value with higher numbers for increasing activity states. We included behaviors associated with adequate and inadequate sedation and adverse events associated with excessive sedation. Analysis of interrater and intrarater reliability revealed an intraclass correlation coefficient of 0.994 (95% confidence interval: 0.986-0.998) and 0.986 (95% confidence interval: 0.970 0.995), respectively. Criterion validity was confirmed with respect to the Observational Scale of Behavioral Distress-revised (Spearman r = 0.96). Construct validity was indicated by significant differences in PSSS scores (P < .001) between 4 phases of a procedure, each having a different degree of painful or distressing stimuli. CONCLUSIONS: The PSSS is a 6-point scale that is a valid measure of the effectiveness and quality of procedural sedation in children within the limits of the testing method used in this study. PMID- 28557734 TI - Disparities in Diagnosis and Treatment of Autism in Latino and Non-Latino White Families. AB - OBJECTIVES: To compare barriers to autism spectrum disorder (ASD) diagnosis and current ASD-related service use among non-Latino white (NLW) families and Latino families with English proficiency (L-EP) or limited English proficiency (L-LEP). METHODS: We conducted a mixed-mode survey of families of children with confirmed ASD seen at specialty clinics in 3 United States cities. Bivariate and multivariate analyses compared barriers to ASD diagnosis, current service use, and unmet therapy need among NLW, L-EP, and L-LEP families. RESULTS: Overall, barriers to ASD diagnosis were prevalent: families (n = 352) experienced a mean of 8 of 15 barriers to ASD diagnosis. The most prevalent barriers overall were "stress of diagnostic process," "parent knowledge about ASD," and "understanding medical system." Compared with NLW families, L-LEP families were more likely to experience barriers related to knowledge about ASD and trust in providers. Children in L-LEP families also had fewer current therapy hours and more unmet therapy needs than children in NLW families. L-EP families' barriers and treatment services use profile was more similar to NLW than to L-LEP families. CONCLUSIONS: English proficiency was an important marker for barriers to ASD diagnosis and treatment in Latinos. Increasing ASD-related knowledge and provider trust may decrease disparities in the diagnosis and treatment of ASD among US Latinos. PMID- 28557735 TI - Inpatient Hospital Factors and Resident Time With Patients and Families. AB - OBJECTIVES: To define hospital factors associated with proportion of time spent by pediatric residents in direct patient care. METHODS: We assessed 6222 hours of time-motion observations from a representative sample of 483 pediatric-resident physicians delivering inpatient care across 9 pediatric institutions. The primary outcome was percentage of direct patient care time (DPCT) during a single observation session (710 sessions). We used one-way analysis of variance to assess a significant difference in the mean percentage of DPCT between hospitals. We used the intraclass correlation coefficient analysis to determine within- versus between-hospital variations. We compared hospital characteristics of observation sessions with >=12% DPCT to characteristics of sessions with <12% DPCT (12% is the DPCT in recent resident trainee time-motion studies). We conducted mixed-effects regression analysis to allow for clustering of sessions within hospitals and accounted for correlation of responses across hospital. RESULTS: Mean proportion of physician DPCT was 13.2% (SD = 8.6; range, 0.2% 49.5%). DPCT was significantly different between hospitals (P < .001). The intraclass correlation coefficient was 0.25, indicating more within-hospital than between-hospital variation. Observation sessions with >=12% DPCT were more likely to occur at hospitals with Magnet designation (odds ratio [OR] = 3.45, P = .006), lower medical complexity (OR = 2.57, P = .04), and higher patient-to-trainee ratios (OR = 2.48, P = .05). CONCLUSIONS: On average, trainees spend <8 minutes per hour in DPCT. Variation exists in DPCT between hospitals. A less complex case mix, increased patient volume, and Magnet designation were independently associated with increased DPCT. PMID- 28557736 TI - Change of School Playground Environment on Bullying: A Randomized Controlled Trial. AB - OBJECTIVE: To investigate whether increasing risk and challenge in primary school playgrounds influences interactions between children. METHODS: In a 2-year cluster-randomized controlled trial, 8 control schools were asked to not change their play environment, whereas 8 intervention schools increased opportunities for risk and challenge (eg, rough-and-tumble play), reduced rules, and added loose parts (eg, tires). Children (n = 840), parents (n = 635), and teachers (n = 90) completed bullying questionnaires at baseline, 1 (postintervention), and 2 (follow-up) years. RESULTS: Intervention children reported higher odds of being happy at school (at 2 years, odds ratio [OR]: 1.64; 95% confidence interval [CI]: 1.20-2.25) and playing with more children (at 1 year, OR: 1.66; 95% CI: 1.29 2.15) than control children. Although intervention children indicated they were pushed/shoved more (OR: 1.33; 95% CI: 1.03-1.71), they were less likely to tell a teacher (OR: 0.69; 95% CI: 0.52-0.92) at 2 years. No significant group differences were observed in parents reporting whether children had "ever" been bullied at school (1 year: P = .23; 2 years: P = .07). Intervention school teachers noticed more bullying in break time at 1 year (difference in scores: 0.20; 95% CI: 0.06-0.34; P = .009), with no corresponding increase in children reporting bullying to teachers (both time points, P >= .26). CONCLUSIONS: Few negative outcomes were reported by children or parents, except for greater pushing/shoving in intervention schools. Whether this indicates increased resilience as indicated by lower reporting of bullying to teachers may be an unanticipated benefit. PMID- 28557737 TI - Antibiotic Prophylaxis for Urinary Tract Infection-Related Renal Scarring: A Systematic Review. AB - CONTEXT: Acute pyelonephritis may result in renal scarring. Recent prospective studies have shown a small benefit of antibiotic prophylaxis in preventing symptomatic and febrile urinary tract infections (UTIs), while being underpowered to detect any influence in prevention of renal damage. OBJECTIVES: Review of the literature and a meta-analysis to evaluate the effect of antibiotic prophylaxis on UTI-related renal scarring. DATA SOURCES: Medline, Embase, and Cochrane Controlled Trials Register electronic databases were searched for studies published in any language and bibliographies of identified prospective randomized controlled trials (RCTs) performed and published between 1946 and August 2016. STUDY SELECTION: Subjects 18 years of age or younger with symptomatic or febrile UTIs, enrolled in prospective RCTs of antibiotic prophylaxis where 99mTc dimercaptosuccinic acid scans were performed at entry into the study and at late follow-up to detect new scar formation. DATA EXTRACTION: The literature search, study characteristics, inclusion and exclusion criteria, and risk of bias assessment were independently evaluated by 2 authors. RESULTS: Seven RCTs (1427 subjects) were included in the meta-analysis. Our results show no influence of antibiotic prophylaxis in preventing renal scarring (pooled risk ratio, 0.83; 95% confidence interval, 0.55-1.26) as did a subanalysis restricted to those subjects with vesicoureteral reflux (pooled risk ratio, 0.79; 95% confidence interval, 0.51-1.24). LIMITATIONS: Limitations include the small number of studies, short duration of follow-up, and insufficient children with high-grade dilating reflux and/or renal dysplasia enrolled in the studies. CONCLUSIONS: Antibiotic prophylaxis is not indicated for the prevention of renal scarring after a first or second symptomatic or febrile UTI in otherwise healthy children. PMID- 28557738 TI - Cross-Sex Hormones and Metabolic Parameters in Adolescents With Gender Dysphoria. AB - BACKGROUND AND OBJECTIVES: The Endocrine Society states that adolescents with gender dysphoria may start cross-sex hormones. The goal of this study was to identify patterns in metabolic parameters in transgender adolescents receiving cross-sex hormones. METHODS: Data from adolescents aged 14 to 25 years seen in 1 of 4 clinical sites between 2008 and 2014 were retrospectively analyzed. Subjects were divided into affirmed male (female-to-male) patients taking testosterone and affirmed female (male-to-female) patients taking estrogen. Previously recorded measurements of blood pressure, BMI, testosterone, estradiol, prolactin, lipids, electrolytes, liver function tests, hemoglobin/hematocrit, and hemoglobin A1c were reviewed. These values were obtained from before the start of therapy, at 1 to 3 months after initiation, at 4 to 6 months, and at 6 months and beyond. Repeated measures analysis of variance models were used to evaluate changes over time. RESULTS: One hunderd and sixteen adolescents were included (72 female-to male subjects and 44 male-to-female subjects). Of the 72 subjects taking testosterone, a significant increase in hemoglobin/hematocrit levels and BMI, as well as a decrease in high-density lipoprotein level, was recorded at each visit. No significant changes in any other parameter tested were found. Of the 44 subjects taking estrogen, no statistically significant changes were noted in the measured metabolic parameters. CONCLUSIONS: Testosterone use was associated with increased hemoglobin and hematocrit, increased BMI, and lowered high-density lipoprotein levels; estrogen was associated with lower testosterone and alanine aminotransferase levels. Otherwise, cross-sex hormone administration in adolescents was not associated with significant differences in the selected metabolic parameters over time. PMID- 28557739 TI - Epidemiology of Cerebrospinal Fluid Cultures and Time to Detection in Term Infants. AB - BACKGROUND: Although meningitis is rare in previously healthy term infants, lumbar puncture is often performed to evaluate for source of illness. This study was performed to determine the time to detection for positive cerebrospinal fluid (CSF) cultures and to provide an update on the current epidemiology of bacterial meningitis in term infants. METHODS: This study was a multicenter, retrospective review of positive CSF cultures in infants <=90 days of age. Specimens were drawn in the emergency department or inpatient setting between January 2000 and December 2013. Cultures were deemed true pathogens or contaminant species based on the attending physician's treatment plan. Cultures from premature infants, an operative source, or those with significant medical history were excluded. RESULTS: A total of 410 positive CSF culture results were included, with 53 (12.9%) true pathogens and 357 (87.1%) contaminant species. The mean +/- SD time to detection for true pathogens was 28.6 +/- 16.8 hours (95% confidence interval, 24-33.2); for contaminant species, it was 68.1 +/- 36.2 hours (95% confidence interval, 64.3-71.9). Forty-three true-positive cases (81.1%) were positive in <=36 hours. The most common pathogen was group B Streptococcus (51%), followed by Escherichia coli (13%) and Streptococcus pneumoniae (9%). CONCLUSIONS: The majority of pathogenic bacteria in CSF exhibit growth within 36 hours. Most growth from CSF cultures in febrile infants is treated as contamination. The epidemiology of meningitis has remained constant, with group B Streptococcus as the predominant pathogen, despite changes noted in the epidemiology of bacteremia in this population. PMID- 28557740 TI - Validation of the Rapid Estimate for Adolescent Literacy in Medicine Short Form (REALM-TeenS). AB - BACKGROUND: This study was designed to develop and validate a brief adolescent health literacy assessment tool (Rapid Estimate of Adolescent Literacy in Medicine Short Form [REALM-TeenS]). METHODS: We combined datasets from 2 existing research studies that used the REALM-Teen (n = 665) and conducted an item response theory analysis. The correlation between scores on the original 66-item REALM-Teen and the proposed REALM-TeenS was calculated, along with the decision consistency across forms with respect to grade level assignment of each adolescent and coefficient alpha. The proposed REALM-TeenS was validated with original REALM-Teen data from a third independent study (n = 174). RESULTS: Items with the largest discriminations across the scale, from low to high health literacy, were selected for inclusion in REALM-TeenS. From those, a set of 10 items was selected that maintained a reasonable level of SE across ability estimates and correlated highly (r = 0.92) with the original REALM-Teen scores. The coefficient alpha for the 10-item REALM-TeenS was .82. There was no evidence of model misfit (root mean square error of approximation < 0.001). In the validation sample, REALM-TeenS scores correlated highly with scores on the original REALM-Teen (r = 0.92), and the decision consistency across both forms was 80%. In pilot testing, administration took ~20 seconds. CONCLUSIONS: The REALM-TeenS offers researchers and clinicians a brief validated screening tool that can be used to assess adolescent health literacy in a variety of settings. Scoring guidelines ensure that reading level assessment is appropriate by age and grade. PMID- 28557741 TI - An Innovative Collaborative Model of Care for Undiagnosed Complex Medical Conditions. PMID- 28557742 TI - Viral Features and Testing for Streptococcal Pharyngitis. AB - BACKGROUND AND OBJECTIVES: The Infectious Diseases Society of America recommends that clinicians forego testing for group A Streptococcal (GAS) pharyngitis in patients with clinical features of viral illness. The prevalence of viral features in patients tested for GAS pharyngitis is not known. The objectives of this study were as follows: to describe the prevalence of viral features in pediatric patients for whom rapid antigen detection tests (RADTs) for GAS pharyngitis are performed; and to compare the prevalence of GAS and the sensitivity of the RADT in patients with and without viral features. METHODS: This secondary analysis of data from a prospective cohort study included children aged 3 to 21 years for whom RADTs were performed for sore throat in an urban tertiary care emergency department. The primary outcome was the prevalence of viral features, defined as cough, rhinorrhea, oral ulcers/vesicles, and/or conjunctival injection. Secondary outcomes were the prevalence of GAS and sensitivity of the RADT; these outcomes were compared between patients with and without viral features. RESULTS: Overall, 63% (95% confidence interval [CI]: 57% 68%) of patients had at least 1 viral feature. The prevalence of GAS pharyngitis was higher in patients without viral features (42% [95% CI: 33%-51%]) than in patients with viral features (29% [95% CI: 23%-35%]) (P = .01). The sensitivity of the RADT was 84% (95% CI: 77%-91%) and was not significantly different in patients with and without viral features. CONCLUSIONS: Because many asymptomatic children are carriers of GAS, judicious use of laboratory testing for GAS pharyngitis remains an important target for antimicrobial stewardship. PMID- 28557743 TI - Understanding the Category B Recommendation for Serogroup B Meningococcal Vaccine. PMID- 28557744 TI - Beyond the Label: Steering the Focus Toward Safe and Effective Prescribing. PMID- 28557745 TI - Current Workforce of Pediatric Subspecialists in the United States. AB - BACKGROUND: Concerns exist regarding the adequacy of the pediatric subspecialty workforce in the United States. Data on practice patterns and job characteristics are necessary to help develop policies to ensure availability. METHODS: We performed survey data analysis of all pediatric subspecialists enrolled in Maintenance of Certification in 2013 and 2014, assessing demographic information, characteristics of current positions, plans for retirement, and satisfaction with allocation of professional and clinical responsibilities. Four logistic regression models examined the independent association of demographic variables collected along with variables of practice ownership and academic appointment with the outcome variables of pediatric subspecialists reporting match of desired with current actual professional duties, match of desired with current actual clinical responsibilities, current part-time employment, and expected age of retirement <65 years of age. RESULTS: Data from 5100 subspecialists were analyzed (response rate 87.2%). Most (83%; N = 4251) reported their current allocation of professional time was what they desired in their current position; similarly, 93% (N = 4755) reported likewise for clinical responsibilities. Differences by gender and years in subspecialty were evident, with women much more likely to work part time than men (odds ratio 6.22); those >20 years in practice were less likely to retire before the age of 65 compared with those <10 years in practice (odds ratio 0.33). CONCLUSIONS: This study is the largest to date of practicing pediatric subspecialists. Variation in work patterns found between genders, with time in practice, and between subspecialties suggests that future research should focus on these issues. PMID- 28557746 TI - Ethical Conduct of Research in Children: Pediatricians and Their IRB (Part 1 of 2). AB - As human experimentation continues to grow into an ever more complex and sophisticated endeavor, the relevant ethical and regulatory structures become more intricate. When pediatricians and general practitioners are invited by pharmaceutical companies to enroll their offices in a clinical trial or a multicenter observational study or when they develop their own research questions, they frequently find themselves at a loss in the human research environment. The legal and regulatory complexity may have an unintended deterring effect at a time when office-based high quality pediatric research is urgently needed to support evidence-based medicine. Unfortunately, in many instances, unaware practitioners become involved in low-risk research activities without knowing it and become entangled in legal, auditing, and compliance procedures. This paper, written in 2 parts, aims at providing a general guidance on the principles that regulate human research with a focus on pediatrics. Part 1 discusses the history, the legal framework, and the consent process and highlights some practical aspects of initial protocol submission, continued review, and institutional review board determinations with the main focus on multicenter clinical trials (industry-sponsored research). Part 2 focuses on pediatric research regulation, also known as subpart-D, and minimal risk research, which encompasses many research activities aimed at addressing questions that may emerge in pediatricians' practices (investigator-initiated research). PMID- 28557747 TI - Supplemental Iodide for Preterm Infants and Developmental Outcomes at 2 Years: An RCT. AB - BACKGROUND: The recommendation for enteral iodide intake for preterm infants is 30 to 40 MUg/kg per day and 1 MUg/kg per day for parenteral intake. Preterm infants are vulnerable to iodide insufficiency and thyroid dysfunction. The hypothesis tested whether, compared with placebo, iodide supplementation of preterm infants improves neurodevelopment. METHODS: A randomized controlled trial of iodide supplementation versus placebo in infants <31 weeks' gestation. Trial solutions (sodium iodide or sodium chloride; dose 30 MUg/kg per day) were given within 42 hours of birth to the equivalent of 34 weeks' gestation. The only exclusion criterion was maternal iodide exposure during pregnancy or delivery. Whole blood levels of thyroxine, thyrotropin, and thyroid-binding globulin were measured on 4 specific postnatal days. The primary outcome was neurodevelopmental status at 2 years of age, measured by using the Bayley Scales of Infant Development-III. The primary analyses are by intention-to-treat, and data are presented also for survivors. RESULTS: One thousand two hundred seventy-three infants (637 intervention, 636 placebo) were recruited from 21 UK neonatal units. One hundred thirty-one infants died, and neurodevelopmental assessments were undertaken in 498 iodide and 499 placebo-supplemented infants. There were no significant differences between the intervention and placebo groups in the primary outcome: mean difference cognitive score, -0.34, 95% confidence interval (CI) -2.57 to 1.89; motor composite score, 0.21, 95% CI -2.23 to 2.65; and language composite score, -0.05, 95% CI -2.48 to 2.39. There was evidence of weak interaction between iodide supplementation and hypothyroxinemic status in the language composite score and 1 subtest score. CONCLUSIONS: Overall iodide supplementation provided no benefit to neurodevelopment measured at 2 years of age. PMID- 28557748 TI - The Next 7 Great Achievements in Pediatric Research. AB - The "7 Great Achievements in Pediatric Research" campaign noted discoveries in the past 40 years that have improved child and adult health in the United States and around the globe. This article predicts the next 7 great pediatric research advancements, including new immunizations, cancer immunotherapy, genomic discoveries, identification of early antecedents of adult health, impact of specific social-environmental influences on biology and health, quality improvement science, and implementation and dissemination research to reduce global poverty. It is an extraordinary time of new research tools that include electronic health records, technological ability to manage big data and measure "omics," and new functional and structural imaging modalities. These tools will discern mechanisms leading to health and disease with new prevention targets and cures. This article further discusses the challenges and opportunities to accelerate these exciting pediatric research discoveries to improve the lives of children and the adults they will become. PMID- 28557749 TI - Cancer Risk After Pediatric Solid Organ Transplantation. AB - BACKGROUND: The effects of pediatric solid organ transplantation on cancer risk may differ from those observed in adult recipients. We described cancers in pediatric recipients and compared incidence to the general population. METHODS: The US transplant registry was linked to 16 cancer registries to identify cancer diagnoses among recipients <18 years old at transplant. Standardized incidence ratios (SIRs) were estimated by dividing observed cancer counts among recipients by expected counts based on the general population rates. Cox regression was used to estimate the associations between recipient characteristics and non-Hodgkin's lymphoma (NHL) risk. RESULTS: Among 17 958 pediatric recipients, 392 cancers were diagnosed, of which 279 (71%) were NHL. Compared with the general population, incidence was significantly increased for NHL (SIR = 212, 95% confidence interval [CI] = 188-238), Hodgkin's lymphoma (SIR = 19, 95% CI = 13-26), leukemia (SIR = 4, 95% CI = 2-7), myeloma (SIR = 229, 95% CI = 47-671), and cancers of the liver, soft tissue, ovary, vulva, testis, bladder, kidney, and thyroid. NHL risk was highest during the first year after transplantation among recipients <5 years old at transplant (SIR = 313), among recipients seronegative for Epstein-Barr virus (EBV) at transplant (SIR = 446), and among intestine transplant recipients (SIR = 1280). In multivariable analyses, seronegative EBV status, the first year after transplantation, intestine transplantation, and induction immunosuppression were independently associated with higher NHL incidence. CONCLUSIONS: Pediatric recipients have a markedly increased risk for many cancers. NHL constitutes the majority of diagnosed cancers, with the highest risk occurring in the first year after transplantation. NHL risk was high in recipients susceptible to primary EBV infection after transplant and in intestine transplant recipients, perhaps due to EBV transmission in the donor organ. PMID- 28557750 TI - Incidence and Prevalence of Childhood Epilepsy: A Nationwide Cohort Study. AB - BACKGROUND AND OBJECTIVES: Epilepsy affects 0.5% to 1% of children and is the most frequent chronic neurologic condition in childhood. Incidence rates appear to be declining in high-income countries. The validity of epilepsy diagnoses from different data sources varies, and contemporary population-based incidence studies are needed. METHODS: The study was based on the Norwegian Mother and Child Cohort Study. Potential epilepsy cases were identified through registry linkages and parental questionnaires. Cases were validated through medical record reviews and telephone interviews of parents. RESULTS: The study population included 112 744 children aged 3 to 13 years (mean 7.4 years) at end of registry follow-up (December 31, 2012). Of these, 896 had registry recordings and/or questionnaire reports of epilepsy. After validation, 587 (66%) met the criteria for an epilepsy diagnosis. The incidence rate of epilepsy was 144 per 100 000 person-years in the first year of life and 58 per 100 000 for ages 1 to 10 years. The cumulative incidence of epilepsy was 0.66% at age 10 years, with 0.62% having active epilepsy. The 309 children (34%) with erroneous reports of epilepsy from the registry and/or the questionnaires had mostly been evaluated for nonepileptic paroxysmal events, or they had undergone electroencephalography examinations because of other developmental or neurocognitive difficulties. CONCLUSIONS: Approximately 1 out of 150 children is diagnosed with epilepsy during the first 10 years of life, with the highest incidence rate observed during infancy. Validation of epilepsy diagnoses in administrative data and cohort studies is crucial because reported diagnoses may not meet diagnostic criteria for epilepsy. PMID- 28557751 TI - Grief and Burnout in the PICU. AB - Doctors and nurses who work in PICUs often deal with emotionally difficult events. These events take a toll. They can cause long-term psychological problems that, if not addressed, can impair the ability of doctors and nurses to care for patients in a competent and compassionate manner. Furthermore, effective treatment is available. But there is a paradox. To get treatment, one must acknowledge the problem. Acknowledgment of the problem may not be encouraged, or may be discouraged and stigmatized, in the intensive care culture. This article describes a case in which a physician has classic signs of overwhelming grief and burnout, and it discusses the appropriate response. PMID- 28557752 TI - Effectiveness of Vaccination During Pregnancy to Prevent Infant Pertussis. AB - BACKGROUND: Vaccination against pertussis during pregnancy is recommended to protect newborns, yet there is limited information about the effectiveness of maternal tetanus toxoid, reduced diphtheria toxoid, acellular pertussis (Tdap) vaccine before the first infant dose of diphtheria, tetanus and acellular pertussis (DTaP) vaccine and during the first year of life in infants who have received DTaP. METHODS: In a retrospective cohort study of infants born at Kaiser Permanente Northern California from 2010 to 2015, we estimated the effectiveness of maternal pertussis vaccination for protecting newborns against pertussis in the first 2 months of life and in the first year of life accounting for each infant DTaP dose. RESULTS: Among 148 981 newborns, the vaccine effectiveness of maternal Tdap was 91.4% (95% confidence interval [CI], 19.5 to 99.1) during the first 2 months of life and 69.0% (95% CI, 43.6 to 82.9) during the entire first year of life. The vaccine effectiveness was 87.9% (95% CI, 41.4 to 97.5) before infants had any DTaP vaccine doses, 81.4% (95% CI, 42.5 to 94.0) between doses 1 and 2, 6.4% (95% CI, -165.1 to 66.9) between doses 2 and 3, and 65.9% (95% CI, 4.5 to 87.8) after infants had 3 DTaP doses. CONCLUSIONS: Maternal Tdap vaccination was highly protective against infant pertussis, especially in the first 2 months of life. Even after infant DTaP dosing, there was evidence of additional protection from maternal Tdap vaccination for the first year of life. This study strongly supports the United States' current recommendation to administer Tdap during each pregnancy. PMID- 28557753 TI - Oral Corticosteroid Prescribing for Children With Asthma in a Medicaid Managed Care Program. AB - BACKGROUND AND OBJECTIVE: Short courses of oral corticosteroid (OCS) medication are recommended for treatment of moderate to severe asthma exacerbations. Concern has been raised about OCS overuse. Our objective is to describe rates of OCS dispensing among children with asthma and factors associated with variation in OCS dispensing. METHODS: Claims data for children 1 to <18 years of age with an asthma diagnosis between January 2011 and January 2016 were extracted from the computerized databases of Texas Children's Health Plan. RESULTS: In the years 2011 to 2015, 17.1% to 21.8% of children had an asthma diagnosis. In each of these years 42.1% to 44.2% of these children had >=1 OCS dispensing. OCS dispensing rates were higher for the children 1 to 4 years of age compared with older children. Repeated OCS dispensing was common, and was most common for children 1 to 4 years of age. Most children with an OCS dispensing (81%-83%) did not have other utilization suggesting poor asthma control (excessive beta-agonist refills, emergency department visit, or hospitalization for asthma). OCSs were less commonly prescribed to patients whose primary care provider was a board certified pediatrician compared with other types of primary care providers. There was large variation in OCS prescribing rates among pediatricians (15%-86%). There were minimal differences in asthma emergency department visits and no differences in hospitalization rates by the pediatrician's OCS dispensing rate quartile. CONCLUSIONS: The patterns of dispensing observed suggest substantial overprescribing of OCS for children with an asthma diagnosis. PMID- 28557754 TI - Implementing Education to Reduce Neonatal Mortality in Low-Resource Environments. PMID- 28557755 TI - Validation of New Quality Measures for Transitions Between Sites of Care. AB - BACKGROUND AND OBJECTIVE: Assessing and improving the quality of transitions to home from the emergency department (ED) or hospital is critical for patient safety. Our objective was to validate 8 newly developed caregiver-reported measures of transition quality. METHODS: This prospective observational study included 1086 caregiver survey respondents whose children had an ED visit (n = 523) or hospitalization (n = 563) at Seattle Children's Hospital in 2014. Caregivers were contacted to complete 2 surveys. The first survey included the newly developed transition quality measures and multiple validation measures including modified versions of Child Hospital Consumer Assessments of Healthcare Providers and Systems (HCAHPS) composites, assessing communication and discharge planning. The second survey (administered 30 days later) included questions about follow-up appointments and ED return visits and readmissions. Using multivariate regression, we examined associations between the newly developed transition quality measures and each validation measure. RESULTS: All transition quality measures were significantly associated with >=1 validation measures. The hospital to-home transition measure assessing whether discharge instructions were easy to understand, were useful, and contained necessary follow-up information had the largest association with the Child HCAHPS nurse-parent and doctor-parent communication composites (beta = 55.6; 95% confidence interval, 43 to 68.3; and beta = 48.3; 95% confidence interval, 36.3 to 60.3, respectively, scaled to reflect change associated with a 0 to 100 change in the transition measure score). CONCLUSIONS: Newly developed quality measures for pediatric ED- and hospital-to-home transitions were significantly and positively associated with previously validated measures of caregiver experience. These new measures may be useful for assessing and improving on the quality of ED- and hospital-to-home transitions. PMID- 28557756 TI - Factors Associated With Provider Burnout in the NICU. AB - BACKGROUND: NICUs vary greatly in patient acuity and volume and represent a wide array of organizational structures, but the effect of these differences on NICU providers is unknown. This study sought to test the relation between provider burnout prevalence and organizational factors in California NICUs. METHODS: Provider perceptions of burnout were obtained from 1934 nurse practitioners, physicians, registered nurses, and respiratory therapists in 41 California NICUs via a validated 4-item questionnaire based on the Maslach Burnout Inventory. The relations between burnout and organizational factors of each NICU were evaluated via t-test comparison of quartiles, univariable regression, and multivariable regression. RESULTS: Overall burnout prevalence was 26.7% +/- 9.8%. Highest burnout prevalence was found among NICUs with higher average daily admissions (32.1% +/- 6.4% vs 17.2% +/- 6.7%, P < .001), higher average occupancy (28.1% +/- 8.1% vs 19.9% +/- 8.4%, P = .02), and those with electronic health records (28% +/- 11% vs 18% +/- 7%, P = .03). In sensitivity analysis, nursing burnout was more sensitive to organizational differences than physician burnout in multivariable modeling, significantly associated with average daily admissions, late transfer proportion, nursing hours per patient day, and mortality per 1000 infants. Burnout prevalence showed no association with proportion of high-risk patients, teaching hospital distinction, or in-house attending presence. CONCLUSIONS: Burnout is most prevalent in NICUs with high patient volume and electronic health records and may affect nurses disproportionately. Interventions to reduce burnout prevalence may be of greater importance in NICUs with >=10 weekly admissions. PMID- 28557758 TI - Mid-Childhood Bone Mass After Exposure to Repeat Doses of Antenatal Glucocorticoids: A Randomized Trial. AB - BACKGROUND AND OBJECTIVE: Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity, but could have adverse effects on skeletal development. We assessed whether exposure to repeat antenatal betamethasone alters bone mass in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. METHODS: Women were randomized to a single dose of betamethasone or placebo, >=7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at <32 weeks' gestation. In this follow-up study, children underwent whole-body dual-energy radiograph absorptiometry at 6 to 8 years' corrected age. RESULTS: Of 212 eligible childhood survivors, 185 were studied (87%; 91 repeat betamethasone group; 94 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar whole-body bone mineral content (median repeat betamethasone: 553 g, interquartile range: 442-712 g; placebo: 567 g, interquartile range: 447-750 g; geometric mean ratio: 0.99; 95% confidence interval: 0.94-1.03, P = .55) and bone area (median repeat betamethasone 832 cm2, interquartile range: 693-963 cm2; placebo: 822 cm2, interquartile range: 710-1020 cm2; geometric mean ratio: 0.99, 95% confidence interval: 0.92-1.07, P = .75). CONCLUSIONS: Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not alter bone mass in mid-childhood. PMID- 28557757 TI - Influenza Vaccine Effectiveness Against Pediatric Deaths: 2010-2014. AB - BACKGROUND AND OBJECTIVES: Surveillance for laboratory-confirmed influenza associated pediatric deaths since 2004 has shown that most deaths occur in unvaccinated children. We assessed whether influenza vaccination reduced the risk of influenza-associated death in children and adolescents. METHODS: We conducted a case-cohort analysis comparing vaccination uptake among laboratory-confirmed influenza-associated pediatric deaths with estimated vaccination coverage among pediatric cohorts in the United States. Case vaccination and high-risk status were determined by case investigation. Influenza vaccination coverage estimates were obtained from national survey data or a national insurance claims database. We estimated odds ratios from logistic regression comparing odds of vaccination among cases with odds of vaccination in comparison cohorts. We used Bayesian methods to compute 95% credible intervals (CIs) for vaccine effectiveness (VE), calculated as (1 - odds ratio) * 100. RESULTS: From July 2010 through June 2014, 358 laboratory-confirmed influenza-associated pediatric deaths were reported among children aged 6 months through 17 years. Vaccination status was determined for 291 deaths; 75 (26%) received vaccine before illness onset. Average vaccination coverage in survey cohorts was 48%. Overall VE against death was 65% (95% CI, 54% to 74%). Among 153 deaths in children with underlying high-risk medical conditions, 47 (31%) were vaccinated. VE among children with high-risk conditions was 51% (95% CI, 31% to 67%), compared with 65% (95% CI, 47% to 78%) among children without high-risk conditions. CONCLUSIONS: Influenza vaccination was associated with reduced risk of laboratory-confirmed influenza-associated pediatric death. Increasing influenza vaccination could prevent influenza associated deaths among children and adolescents. PMID- 28557759 TI - Assessing Child Lead Poisoning Case Ascertainment in the US, 1999-2010. AB - OBJECTIVES: To compare prevalence estimates for blood lead level >=10.0 MUg/dL (elevated blood lead level [EBLL]) with numbers reported to the Centers for Disease Control and Prevention (CDC) for children 12 months to 5 years of age from 1999 to 2010 on a state-by-state basis. METHODS: State-specific prevalence estimates were generated based on the continuous NHANES according to newly available statistical protocols. Counts of case reports were based on the 39 states (including the District of Columbia) reporting to the CDC Childhood Lead Poisoning Prevention Program during the study period. Analyses were conducted both including and excluding states and years of nonreporting to the CDC. RESULTS: Approximately 1.2 million cases of EBLL are believed to have occurred in this period, but 607 000 (50%) were reported to the CDC. Including only states and years for which reporting was complete, the reporting rate was 64%. Pediatric care providers in 23 of 39 reporting states identified fewer than half of their children with EBLL. Although the greatest numbers of reported cases were from the Northeast and Midwest, the greatest numbers based on prevalence estimates occurred in the South. In southern and western states engaged in reporting, roughly 3 times as many children with EBLL were missed than were diagnosed. CONCLUSIONS: Based on the best available estimates, undertesting of blood lead levels by pediatric care providers appears to be endemic in many states. PMID- 28557760 TI - Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A Meta analysis. AB - CONTEXT: Recombinant human erythropoietin (rhEPO) is a promising pharmacological agent for neuroprotection in neonates. OBJECTIVE: To investigate whether prophylactic rhEPO administration in very preterm infants improves neurodevelopmental outcomes in a meta-analysis of randomized controlled trials (RCTs). DATA SOURCES: Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched in December 2016 and complemented by other sources. STUDY SELECTION: RCTs investigating the use of rhEPO in preterm infants versus a control group were selected if they were published in a peer-reviewed journal and reported neurodevelopmental outcomes at 18 to 24 months' corrected age. DATA EXTRACTION: Data extraction and analysis followed the standard methods of the Cochrane Neonatal Review Group. The primary outcome was the number of infants with a Mental Developmental Index (MDI) <70 on the Bayley Scales of Infant Development. Secondary outcomes included a Psychomotor Development Index <70, cerebral palsy, visual impairment, and hearing impairment. RESULTS: Four RCTs, comprising 1133 infants, were included in the meta-analysis. Prophylactic rhEPO administration reduced the incidence of children with an MDI <70, with an odds ratio (95% confidence interval) of 0.51 (0.31-0.81), P < .005. The number needed to treat was 14. There was no statistically significant effect on any secondary outcome. CONCLUSIONS: Prophylactic rhEPO improved the cognitive development of very preterm infants, as assessed by the MDI at a corrected age of 18 to 24 months, without affecting other neurodevelopmental outcomes. Current and future RCTs should investigate optimal dosing and timing of prophylactic rhEPO and plan for long-term neurodevelopmental follow-up. PMID- 28557762 TI - Maintenance of Certification and the Challenge of Professionalism. AB - Board certification has been part of the social contract in which physicians commit to maintaining up-to-date scientific knowledge and improving the quality of patient care. However, the maintenance of certification program has been controversial. This review summarizes the philosophical underpinnings, published literature, recent improvements, and future directions of the American Board of Pediatrics maintenance of certification program. PMID- 28557761 TI - Celiac Disease and Anorexia Nervosa: A Nationwide Study. AB - BACKGROUND AND OBJECTIVE: Previous research suggests an association of celiac disease (CD) with anorexia nervosa (AN), but data are mostly limited to case reports. We aimed to determine whether CD is associated with the diagnosis of AN. METHODS: Register-based cohort and case-control study including women with CD (n = 17 959) and sex- and age-matched population-based controls (n = 89 379). CD (villous atrophy) was identified through the histopathology records of Sweden's 28 pathology departments. Inpatient and hospital-based outpatient records were used to identify AN. Hazard ratios for incident AN diagnosis were estimated by using stratified Cox regression with CD diagnosis as a time-dependent exposure variable. In the secondary analyses, we used conditional logistic regression to estimate odds ratios for being diagnosed with AN before CD. RESULTS: Median age of CD diagnosis was 28 years. During 1 174 401 person-years of follow-up, 54 patients with CD were diagnosed with AN (27/100 000 person-years) compared with 180 matched controls (18/100 000 person-years). The hazard ratio for later AN was 1.46 (95% confidence interval [CI], 1.08-1.98) and 1.31 beyond the first year after CD diagnosis (95% CI, 0.95-1.81). A previous AN diagnosis was also associated with CD (odds ratio, 2.18; 95% CI, 1.45-3.29). Estimates remained largely unchanged when adjusted for socioeconomic characteristics and type 1 diabetes. CONCLUSIONS: The bidirectional association between AN diagnosis and CD warrants attention in the initial assessment and follow-up of these conditions because underdiagnosis and misdiagnosis of these disorders likely cause protracted and unnecessary morbidity. PMID- 28557763 TI - No Surprise: The Rate of Fatal Child Abuse and Neglect Fatalities Is Related to Poverty. PMID- 28557765 TI - Young Adults With Chronic Illness: How Can We Improve Transitions to Adult Care? PMID- 28557764 TI - The Promise of Early Childhood Self-Regulation for Obesity Prevention. PMID- 28557766 TI - Re: Time to Change NRP. PMID- 28557767 TI - The Importance of Contextual and Temporal Accuracy When Studying Novel Tobacco Products. PMID- 28557768 TI - Authors' Response. PMID- 28557769 TI - We Agree on the Importance of Contextual and Temporal Accuracy When Studying Novel Tobacco Products. PMID- 28557770 TI - Disaster Preparedness in Neonatal Intensive Care Units. AB - Disasters disproportionally affect vulnerable, technology-dependent people, including preterm and critically ill newborn infants. It is important for health care providers to be aware of and prepared for the potential consequences of disasters for the NICU. Neonatal intensive care personnel can provide specialized expertise for their hospital, community, and regional emergency preparedness plans and can help develop institutional surge capacity for mass critical care, including equipment, medications, personnel, and facility resources. PMID- 28557771 TI - Transplanting One Problem for Another. PMID- 28557772 TI - Celiac Disease and Anorexia Nervosa-An Association Well Worth Considering. PMID- 28557773 TI - Corticosteroids and Asthma: Too Much or Too Little? PMID- 28557774 TI - The Primary Care Pediatrician and the Care of Children With Cleft Lip and/or Cleft Palate. AB - Orofacial clefts, specifically cleft lip and/or cleft palate (CL/P), are among the most common congenital anomalies. CL/P vary in their location and severity and comprise 3 overarching groups: cleft lip (CL), cleft lip with cleft palate (CLP), and cleft palate alone (CP). CL/P may be associated with one of many syndromes that could further complicate a child's needs. Care of patients with CL/P spans prenatal diagnosis into adulthood. The appropriate timing and order of specific cleft-related care are important factors for optimizing outcomes; however, care should be individualized to meet the specific needs of each patient and family. Children with CL/P should receive their specialty cleft-related care from a multidisciplinary cleft or craniofacial team with sufficient patient and surgical volume to promote successful outcomes. The primary care pediatrician at the child's medical home has an essential role in making a timely diagnosis and referral; providing ongoing health care maintenance, anticipatory guidance, and acute care; and functioning as an advocate for the patient and a liaison between the family and the craniofacial/cleft team. This document provides background on CL/P and multidisciplinary team care, information about typical timing and order of cleft-related care, and recommendations for cleft/craniofacial teams and primary care pediatricians in the care of children with CL/P. PMID- 28557776 TI - The Breastfeeding-Friendly Pediatric Office Practice. AB - The landscape of breastfeeding has changed over the past several decades as more women initiate breastfeeding in the postpartum period and more hospitals are designated as Baby-Friendly Hospitals by following the evidence-based Ten Steps to Successful Breastfeeding. The number of births in such facilities has increased more than sixfold over the past decade. With more women breastfeeding and stays in the maternity facilities lasting only a few days, the vast majority of continued breastfeeding support occurs in the community. Pediatric care providers evaluate breastfeeding infants and their mothers in the office setting frequently during the first year of life. The office setting should be conducive to providing ongoing breastfeeding support. Likewise, the office practice should avoid creating barriers for breastfeeding mothers and families or unduly promoting infant formula. This clinical report aims to review practices shown to support breastfeeding that can be implemented in the outpatient setting, with the ultimate goal of increasing the duration of exclusive breastfeeding and the continuation of any breastfeeding. PMID- 28557775 TI - Nonemergency Acute Care: When It's Not the Medical Home. AB - The American Academy of Pediatrics (AAP) affirms that the optimal location for children to receive care for acute, nonemergency health concerns is the medical home. The medical home is characterized by the AAP as a care model that "must be accessible, family centered, continuous, comprehensive, coordinated, compassionate, and culturally effective." However, some children and families use acute care services outside the medical home because there is a perceived or real benefit related to accessibility, convenience, or cost of care. Examples of such acute care entities include urgent care facilities, retail-based clinics, and commercial telemedicine services. Children deserve high-quality, appropriate, and safe acute care services wherever they access the health care system, with timely and complete communication with the medical home, to ensure coordinated and continuous care. Treatment of children under established, new, and evolving practice arrangements in acute care entities should adhere to the core principles of continuity of care and communication, best practices within a defined scope of services, pediatric-trained staff, safe transitions of care, and continuous improvement. In support of the medical home, the AAP urges stakeholders, including payers, to avoid any incentives (eg, reduced copays) that encourage visits to external entities for acute issues as a preference over the medical home. PMID- 28557777 TI - An assessment of residents' and fellows' personal finance literacy: an unmet medical education need. AB - Objectives: This study aimed to assess residents' and fellows' knowledge of finance principles that may affect their personal financial health. Methods: A cross-sectional, anonymous, web-based survey was administered to a convenience sample of residents and fellows at two academic medical centers. Respondents answered 20 questions on personal finance and 28 questions about their own financial planning, attitudes, and debt. Questions regarding satisfaction with one's financial condition and investment-risk tolerance used a 10-point Likert scale (1=lowest, 10=highest). Of 2,010 trainees, 422 (21%) responded (median age 30 years; interquartile range, 28-33). Results: The mean quiz score was 52.0% (SD = 19.1). Of 299 (71%) respondents with student loan debt, 144 (48%) owed over $200,000. Many respondents had other debt, including 86 (21%) with credit card debt. Of 262 respondents with retirement savings, 142 (52%) had saved less than $25,000. Respondents' mean satisfaction with their current personal financial condition was 4.8 (SD = 2.5) and investment-risk tolerance was 5.3 (SD = 2.3). Indebted trainees reported lower satisfaction than trainees without debt (4.4 vs. 6.2, F (1,419) = 41.57, p < .001). Knowledge was moderately correlated with investment-risk tolerance (r=0.41, p < .001), and weakly correlated with satisfaction with financial status (r=0.23, p < .001). Conclusions: Residents and fellows had low financial literacy and investment-risk tolerance, high debt, and deficits in their financial preparedness. Adding personal financial education to the medical education curriculum would benefit trainees. Providing education in areas such as budgeting, estate planning, investment strategies, and retirement planning early in training can offer significant long-term benefits. PMID- 28557778 TI - PreScription: United States Pharmacopeia Chapter <800> Comments and Alternatives. PMID- 28557779 TI - Adventures in the Environmental World and Environmental Microbiology Sampling of Air for Pharmaceutical Sterile Compounding. AB - Chapter <797> issued by the United States Pharmacopeial Convention, Inc. is the standard for sterile compounding. It is designed to reduce the number of patient infections due to contaminated pharmaceutical preparation. This regulation applies to all staff who prepare compounded sterile preparations and all places where they are produced, including hospitals, clinics, pharmacies, and physician's offices. This article provides the history of environmental microbiology and provides a discussion on environmental microbiology sampling of air for pharmaceutical sterile compounding. PMID- 28557780 TI - Microbiologic Testing for 503A Sterile-Compounding Pharmacies. AB - Compounding pharmacists must ensure that the sterile preparations they dispense are free of microbiologic contamination. Working in a cleanroom under controlled conditions (proper differential air pressure, temperature, and humidity; acceptable levels of viable and nonviable airborne particles and surface counts, etc.) and testing the efficacy of cleaning and disinfecting practices via environmental monitoring (viable-air and surface testing, glove-fingertip-thumb testing, etc.) are essential to preparing contamination-free medications. Sterile compounding pharmacists must understand how to monitor their cleanroom environment and, if they perform testing in house, to interpret the results of simple microbiologic tests (a skill helpful even when tests are outsourced to a contract laboratory). In this article, which pertains to 503A sterile compounding, and is based on the current version of United States Pharmacopeia (USP) Chapter <797>, basic concepts in microbiology and the microbial tests that can be performed and interpreted in house and those that must be outsourced are discussed. Streamlining communication with contract laboratory personnel is reviewed. Requirements for an inhouse microbiology laboratory are presented, and the advantages and disadvantages of inhouse and outsourced testing are examined. A list of suggested reading is provided for easy reference. In a subsequent article, environmental monitoring and analysis will be addressed in detail. PMID- 28557781 TI - Management of Psoriasis with a XemaTop Topical Compounded Formula: A Case Report. AB - Skin conditions such as psoriasis and eczema negatively impact the patient's quality of life; the primary goal of topical treatments is to minimize the disease-specific symptoms. This case report discusses the management of two refractory psoriasis skin lesions in an adult male using a topical compounded formula. The psoriasis symptoms were assessed quantitatively using two validated research instruments, the Psoriasis Symptom Inventory, and an adapted Numeric Rating Scale. A qualitative assessment was also performed by evaluating the digital photographs taken by the patient during the course of treatment. The compounded formula containing zinc pyrithione, clobetasol propionate, and cyanocobalamin in the Professional Compounding Centers of America's proprietary base PCCA XemaTop, applied topically for three weeks, significantly reduced the patient's self-reported psoriasis symptoms and improved his overall condition by 81.2%. This successful case report is important evidence for healthcare professionals when considering new, innovative topical compounded formulas for managing skin conditions such as psoriasis and eczema. PMID- 28557782 TI - International Academy of Compounding Pharmacists Legislative/Regulatory Update. PMID- 28557783 TI - Basics of Compounding: 3D Printing--Pharmacy Applications, Part 2. AB - 3D printing is a standard tool in the automotive, aerospace, and consumer goods in industry and is gaining traction in pharmaceutical manufacturing, which has introduced a new element into dosage-form development. This article, which represents part 2 of a 3-part article on the topic of 3D printing, discusses the different technologies available for 3D printing. PMID- 28557784 TI - Basics of Sterile Compounding: Manipulating Peptides and Proteins. AB - Biopharmaceuticals contain primary and secondary structure, which offer few problems. It is the tertiary structure that causes problems, resulting in both physical and chemical stability issues. The thrust of this article is to share briefly what can be done to minimize these problems. PMID- 28557785 TI - Updated Stability Data for Midazolam, Oseltamivir Phosphate, and Propranolol Hydrochloride in SyrSpend SF and Minoxidil in Espumil. PMID- 28557786 TI - Absorption of Transdermal Fluoxetine Compounded in a Lipoderm Base Compared to Oral Fluoxetine in Client-owned Cats. AB - The objective of this study was to compare serum concentrations of transdermal fluoxetine compounded in Lipoderm base versus commercially available oral fluoxetine tablets. Sixteen clinically healthy, client-owned cats that were at least one year of age were enrolled. Cats weighed between three and seven kilograms, had no comorbidities, and were behavior medication naive. Cats were recruited from January 2016 through April 2016. Eight cats were assigned to each medication group based on owner preference. The cats received either oral (1 mg/kg) or transdermal (5 mg/kg; maximum 25 mg daily) fluoxetine compounded in a transdermal base (PCCA Lipoderm), administered daily for 60 days. Serum levels of fluoxetine and norfluoxetine were assessed as a surrogate for relative efficacy. Serum was collected and analyzed by high-performance liquid chromatography-mass spectrometry/mass spectrometry at baseline and days 5, 10, 30, 45, and 60 post drug start. Adverse effects were monitored during physical exams, speaking with owners, and laboratory analysis of liver function tests at baseline and days 5, 30, and 60 post-drug start. Serum fluoxetine concentrations significantly differed between the treatment groups at days 45 and 60 post-drug start. Norfluoxetine concentrations significantly differed at days 30, 45, and 60 post drug start. Blood concentrations of fluoxetine and norfluoxetine significantly differed between oral and transdermal routes after 30 days of treatment. Oral fluoxetine concentrations were consistently higher. Transdermal fluoxetine appeared to be well-tolerated, but a lack of knowledge regarding effective blood levels makes it unclear if a clinical effective response would be obtained at the blood concentrations achieved. PMID- 28557787 TI - Warfarin Personalized Dosage: Re-compounding for a More Suitable Therapy and Better Compliance. AB - Warfarin is still the most prescribed oral anticoagulant prescribed for the prophylaxis and treatment of thromboembolic events such as stroke, heart attack, embolism, and deep vein thrombosis. It is administered orally in the form of sodium salt as a tablet with a typical strength of 5 mg. The molecule has a narrow therapeutic index. As a consequence, the dosage must be individualized for each patient based on the patient response in terms of time of coagulation. Thus, warfarin represents an example of a drug whose dose needs to be tailored to individual requirements that are often changing and, therefore, constitute a paramount illustration of personalized medicine. The aim of the present work was to investigate to what extent the manual division of a warfarin tablet by the patient represents an issue in terms of dose accuracy and precision. A second goal was to demonstrate that possible problems stemming from the manual division of the warfarin tablet could be overcome by compounding a solid dosage form (e.g., a capsule) starting from the commercially available warfarin product. The results of the present study put into evidence the great inhomogeneity and discrepancy from the target dose obtained when commercially available warfarin tablets are manually divided in four parts. This represents a potential source of inefficacy of the anticoagulant activity, with increased risk of either bleeding or thromboembolic events. The proposed solution is effective and yet simple and economically affordable, in particular considering the cost of the possible hospitalizations related to therapy failure. PMID- 28557788 TI - Stability of Extemporaneously Prepared Hydroxychloroquine Sulfate 25-mg/mL Suspensions in Plastic Bottles and Syringes. AB - This study evaluated the stability of the antimalarial and anti-rheumatic drug hydroxychloroquine sulfate in two commercially available suspension vehicles, Oral Mix and Oral Mix SF (Medisca Pharmaceutique Inc.). Hydroxychloroquine sulfate (25 mg/mL) suspension was prepared, packaged in amber 50-mL polyethylene terephthalate bottles and amber 3-mL syringes, and stored at room temperature or at 4 degrees C. Samples were collected and analyzed over a 16-week period by high performance liquid chromatography with ultraviolet detection at 340 nm. Approximately 99.8% of the hydroxychloroquine remained at the conclusion of the study, with no observable difference between room temperature and refrigerated storage. Hydroxychloroquine sulfate is stable for at least 90 days in Medisca Oral Mix or Oral Mix SF suspension media at 25 degrees C and 4 degrees C. PMID- 28557789 TI - Stability of Alprazolam, Atropine Sulfate, Glutamine, Levofloxacin, Metoprolol Tartrate, Nitrofurantoin, Ondansetron Hydrochloride, Oxandrolone, Pregabaline, and Riboflavin in SyrSpend SF pH4 Oral Suspensions. AB - The objective of this study was to evaluate the stability of 10 commonly used active pharmaceutical ingredients compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend SF PH4): alprazolam 1.0 mg/mL, atropine sulfate 0.1 mg/mL, glutamine 250.0 mg/mL, levofloxacin 50.0 mg/mL, metoprolol tartrate 10.0 mg/mL, nitrofurantoin 2.0 mg/mL, ondansetron hydrochloride 0.8 mg/mL, oxandrolone 3.0 mg/mL, pregabaline 20.0 mg/mL, riboflavin 10.0 mg/mL. All suspensions were stored at both controlled refrigeration (2 degrees C to 8 degrees C) and controlled room temperature (20 degrees C to 25 degrees C). Stability was assessed by measuring the percent recovery at varying time points throughout a 90-day period. Active pharmaceutical ingredients quantification was performed by high-performance liquid chromatography via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredients + vehicle) was at least 90 days for all suspensions with regard to both temperatures. This suggests that the vehicle is stable for compounding active pharmaceutical ingredients from different pharmacological classes. PMID- 28557791 TI - Packing in protein cores. AB - Proteins are biological polymers that underlie all cellular functions. The first high-resolution protein structures were determined by x-ray crystallography in the 1960s. Since then, there has been continued interest in understanding and predicting protein structure and stability. It is well-established that a large contribution to protein stability originates from the sequestration from solvent of hydrophobic residues in the protein core. How are such hydrophobic residues arranged in the core; how can one best model the packing of these residues, and are residues loosely packed with multiple allowed side chain conformations or densely packed with a single allowed side chain conformation? Here we show that to properly model the packing of residues in protein cores it is essential that amino acids are represented by appropriately calibrated atom sizes, and that hydrogen atoms are explicitly included. We show that protein cores possess a packing fraction of [Formula: see text], which is significantly less than the typically quoted value of 0.74 obtained using the extended atom representation. We also compare the results for the packing of amino acids in protein cores to results obtained for jammed packings from discrete element simulations of spheres, elongated particles, and composite particles with bumpy surfaces. We show that amino acids in protein cores pack as densely as disordered jammed packings of particles with similar values for the aspect ratio and bumpiness as found for amino acids. Knowing the structural properties of protein cores is of both fundamental and practical importance. Practically, it enables the assessment of changes in the structure and stability of proteins arising from amino acid mutations (such as those identified as a result of the massive human genome sequencing efforts) and the design of new folded, stable proteins and protein protein interactions with tunable specificity and affinity. PMID- 28557793 TI - Stationary nano-SQUID: theoretical investigation and feasibility analysis. AB - The standard operation of a dc SQUID leads to oscillatory electric fields that emit electromagnetic radiation. We estimate the effect that this radiation could have on the measured sample. A stationary SQUID could be advantageous if the oscillation contribution to back action on the measured sample has to be avoided. We study a superconducting loop that encloses a magnetic flux, connected to a superconducting and to a normal electrode, when a fixed electric current between the electrodes flows across the loop. The considered circuit does not contain Josephson junctions. We find that in a very broad range of parameters the current flow converges to a stationary regime, i.e. the densities of normal current and of supercurrent become functions of position only, independent of time. The potential difference between the electrodes depends on the magnetic flux, so that measuring this voltage would provide information on the enclosed flux. The influence of thermal noise was estimated. The sizes of the voltage and of the power dissipation could be appropriate for the design of a practical fluxmeter. We found narrow ranges of flux at which the voltage varies sharply with the flux. PMID- 28557792 TI - The approximate entropy concept extended to three dimensions for calibrated, single parameter structural complexity interrogation of volumetric images. AB - Reconstructive volumetric imaging permeates medical practice because of its apparently clear depiction of anatomy. However, the tell tale signs of abnormality and its delineation for treatment demand experts work at the threshold of visibility for hints of structure. Hitherto, a suitable assistive metric that chimes with clinical experience has been absent. This paper develops the complexity measure approximate entropy (ApEn) from its 1D physiological origin into a three-dimensional (3D) algorithm to fill this gap. The first 3D algorithm for this is presented in detail. Validation results for known test arrays are followed by a comparison of fan-beam and cone-beam x-ray computed tomography image volumes used in image guided radiotherapy for cancer. Results show the structural detail down to individual voxel level, the strength of which is calibrated by the ApEn process itself. The potential for application in machine assisted manual interaction and automated image processing and interrogation, including radiomics associated with predictive outcome modeling, is discussed. PMID- 28557794 TI - Disentangling electron- and electric-field-induced ring-closing reactions in a diarylethene derivative on Ag(1 1 1). AB - Using scanning tunneling microscopy and spectroscopy we investigate the adsorption properties and ring-closing reaction of a diarylethene derivative (C5F 4Py) on a Ag(1 1 1) surface. We identify an electron-induced reaction mechanism, with a quantum yield varying from 10-14-10-9 per electron upon variation of the bias voltage from 1-2 V. We ascribe the drastic increase in switching efficiency to a resonant enhancement upon tunneling through molecular orbitals. Additionally, we resolve the ring-closing reaction even in the absence of a current passing through the molecule. In this case the electric-field can modify the reaction barrier, leading to a finite switching probability at 4.8 K. A detailed analysis of the switching events shows that a simple plate-capacitor model for the tip-surface junction is insufficient to explain the distance dependence of the switching voltage. Instead, describing the tip as a sphere is in agreement with the findings. We resolve small differences in the adsorption configuration of the closed isomer, when comparing the electron- and field induced switching product. PMID- 28557795 TI - Odd-frequency superconductivity induced in topological insulators with and without hexagonal warping. AB - We study the effect of the Fermi surface anisotropy on the odd-frequency spin triplet pairing component of the induced pair potential. We consider a superconductor/ ferromagnetic insulator (S/FI) hybrid structure formed on the 3D topological insulator (TI) surface. In this case three ingredients ensure the possibility of the odd-frequency pairing: (1) the topological surface states, (2) the induced pair potential, and (3) the magnetic moment of a nearby ferromagnetic insulator. We take into account the strong anisotropy of the Dirac point in topological insulators when the chemical potential lies well above the Dirac cone and its constant energy contour has a snowflake shape. Within this model, we propose that the S/FI boundary should be properly aligned with respect to the snowflake constant energy contour to have an odd-frequency symmetry of the corresponding pairing component and to insure the Majorana bound state at the S/FI boundary. For arbitrary orientation of the boundary, the Majorana bound state is absent. This provides a selection rule to the realization of Majorana modes in S/FI hybrid structures, formed on the topological insulator surface. PMID- 28557796 TI - Geometric decoherence of valley excitons in monolayer transition metal dichachogenides. AB - We study the effects of the Berry phases of the valley excitons in the monolayer transition metal dichalcogenides (TMDs) when the valley excitons are manipulated by an external terahertz field. We find that the decoherence of the valley degree of freedom of the valley excitons is spontaneously induced because of the different Berry phases of valley excitons accumulated along the opposite trajectories under the manipulation of the external field. It is called the geometric decoherence because it completely results from the geometric phases. The obvious phenomenon related to such spontaneous decoherence is the gradual decrement of the dipole moment matrix element of the valley exciton and consequently the decrement of the emitted signals after the valley excitons are recombined. Moreover, another effect due to the Berry phases is the giant Faraday rotation of the polarization of the emitted photons. Such imperfection of the valley degree of freedom is supposed to provide the potential limits of the valleytronics based on the TMDs optoelecronic devices. PMID- 28557797 TI - Pressure-induced insulator-metal transition in EuMnO3. AB - We study the influence of external pressure on the electronic and magnetic structure of EuMnO3 from first-principles calculations. We find a pressure induced insulator-metal transition at which the magnetic order changes from A type antiferromagnetic to ferromagnetic with a strong interplay with Jahn-Teller distortions. In addition, we find that the non-centrosymmetric E *-type antiferromagnetic order can become nearly degenerate with the ferromagnetic ground state in the high-pressure metallic state. This situation can be exploited to promote a magnetically-driven realization of a non-centrosymmetric (ferroelectric-like) metal. PMID- 28557798 TI - Thermal ablation of a confluent lesion in the porcine kidney with a clinically available MR-HIFU system. AB - : The incidence of small renal masses (SRMs) sized <4 cm has increased over the decades (as co-findings/or due to introduction of cross sectional imaging). Currently, partial nephrectomy (PN) or watchful waiting is advised in these patients. Ultimately, 80-90% of these SRMs require surgical treatment and PN is associated with a 15% complication rate. In this aging population, with possible comorbidities and poor health condition, both PN and watchful waiting are non ideal treatment options. This resulted in an increased need for early, non invasive treatment strategies such as MR-guided high intensity focused ultrasound (MR-HIFU). (i) To investigate the feasibility of creating a confluent lesion in the kidney using respiratory-gated MR-HIFU under clinical conditions in a pre clinical study and (ii) to evaluate the reproducibility of the MR-HIFU ablation strategy. Healthy pigs (n = 10) under general anesthesia were positioned on a clinical MR-HIFU system with integrated cooling. A honeycomb pattern of seven overlapping ablation cells (4 * 4 * 10 mm3, 450 W, <30 s) was ablated successively in the cortex of the porcine kidney. Both MR thermometry and acoustic energy delivery were respiratory gated using a pencil beam navigator on the contralateral kidney. The non-perfused volume (NPV) was visualized after the last sonication by contrast-enhanced (CE) T 1-weighted MR (T 1 w) imaging. Cell viability staining was performed to visualize the extent of necrosis. RESULTS: a median NPV of 0.62 ml was observed on CE-T 1 w images (IQR 0.58-1.57 ml, range 0.33-2.75 ml). Cell viability staining showed a median damaged volume of 0.59 ml (IQR 0.24-1.35 ml, range 0-4.1 ml). Overlooking of the false rib, shivering of the pig, and too large depth combined with a large heat-sink effect resulted in insufficient heating in 4 cases. The NPV and necrosed volume were confluent in all cases in which an ablated volume could be observed. Our results demonstrated the feasibility of creating a confluent volume of ablated kidney cortical tissue in vivo with MR-HIFU on a clinically available system using respiratory gating and near-field cooling and showed its reproducibility. PMID- 28557799 TI - Repeatability of dose painting by numbers treatment planning in prostate cancer radiotherapy based on multiparametric magnetic resonance imaging. AB - Dose painting by numbers (DPBN) refers to a voxel-wise prescription of radiation dose modelled from functional image characteristics, in contrast to dose painting by contours which requires delineations to define the target for dose escalation. The direct relation between functional imaging characteristics and DPBN implies that random variations in images may propagate into the dose distribution. The stability of MR-only prostate cancer treatment planning based on DPBN with respect to these variations is as yet unknown. We conducted a test-retest study to investigate the stability of DPBN for prostate cancer in a semi-automated MR only treatment planning workflow. Twelve patients received a multiparametric MRI on two separate days prior to prostatectomy. The tumor probability (TP) within the prostate was derived from image features with a logistic regression model. Dose mapping functions were applied to acquire a DPBN prescription map that served to generate an intensity modulated radiation therapy (IMRT) treatment plan. Dose calculations were done on a pseudo-CT derived from the MRI. The TP and DPBN map and the IMRT dose distribution were compared between both MRI sessions, using the intraclass correlation coefficient (ICC) to quantify repeatability of the planning pipeline. The quality of each treatment plan was measured with a quality factor (QF). Median ICC values for the TP and DPBN map and the IMRT dose distribution were 0.82, 0.82 and 0.88, respectively, for linear dose mapping and 0.82, 0.84 and 0.94 for square root dose mapping. A median QF of 3.4% was found among all treatment plans. We demonstrated the stability of DPBN radiotherapy treatment planning in prostate cancer, with excellent overall repeatability and acceptable treatment plan quality. Using validated tumor probability modelling and simple dose mapping techniques it was shown that despite day-to-day variations in imaging data still consistent treatment plans were obtained. PMID- 28557801 TI - A comprehensive model for x-ray projection imaging system efficiency and image quality characterization in the presence of scattered radiation. AB - This work proposes a method for assessing the detective quantum efficiency (DQE) of radiographic imaging systems that include both the x-ray detector and the antiscatter device. Cascaded linear analysis of the antiscatter device efficiency (DQEASD) with the x-ray detector DQE is used to develop a metric of system efficiency (DQEsys); the new metric is then related to the existing system efficiency parameters of effective DQE (eDQE) and generalized DQE (gDQE). The effect of scatter on signal transfer was modelled through its point spread function (PSF), leading to an x-ray beam transfer function (BTF) that multiplies with the classical presampling modulation transfer function (MTF) to give the system MTF. Expressions are then derived for the influence of scattered radiation on signal-difference to noise ratio (SDNR) and contrast-detail (c-d) detectability. The DQEsys metric was tested using two digital mammography systems, for eight x-ray beams (four with and four without scatter), matched in terms of effective energy. The model was validated through measurements of contrast, SDNR and MTF for poly(methyl)methacrylate thicknesses covering the range of scatter fractions expected in mammography. The metric also successfully predicted changes in c-d detectability for different scatter conditions. Scatter fractions for the four beams with scatter were established with the beam stop method using an extrapolation function derived from the scatter PSF, and validated through Monte Carlo (MC) simulations. Low-frequency drop of the MTF from scatter was compared to both theory and MC calculations. DQEsys successfully quantified the influence of the grid on SDNR and accurately gave the break-even object thickness at which system efficiency was improved by the grid. The DQEsys metric is proposed as an extension of current detector characterization methods to include a performance evaluation in the presence of scattered radiation, with an antiscatter device in place. PMID- 28557800 TI - Lateral variations of radiobiological properties of therapeutic fields of 1H, 4He, 12C and 16O ions studied with Geant4 and microdosimetric kinetic model. AB - As known, in cancer therapy with ion beams the relative biological effectiveness (RBE) of ions changes in the course of their propagation in tissues. Such changes are caused not only by increasing the linear energy transfer (LET) of beam particles with the penetration depth towards the Bragg peak, but also by nuclear reactions induced by beam nuclei leading to the production of various secondary particles. Although the changes of RBE along the beam axis have been studied quite well, much less attention has been paid to the evolution of RBE in the transverse direction, perpendicular to the beam axis. In order to fill this gap, we simulated radiation fields of 1H, 4He, 12C and 16O nuclei of 20 mm in diameter by means of a Geant4-based Monte Carlo model for heavy-ion therapy connected with the modified microdosimetric kinetic model to describe the response of normal ([Formula: see text] Gy) and early-responding ([Formula: see text] Gy) tissues. Depth and radial distributions of saturation-corrected dose-mean lineal energy, RBE and RBE-weighted dose are investigated for passive beam shaping and active beam scanning. The field of 4He has a small lateral spread as compared with 1H field, and it is characterised by a modest lateral variation of RBE suggesting the use of fixed RBE values across the field transverse cross section at each depth. Reduced uncertainties of RBE on the boundary of a 4He treatment field can be advantageous in a specific case of an organ at risk located in lateral proximity to the target volume. It is found that the lateral distributions of RBE calculated for 12C and 16O fields demonstrate fast variations in the radial direction due to changes of dose and composition of secondary fragments in the field penumbra. Nevertheless, the radiation fields of all four projectiles at radii larger than 20 mm can be characterized by a common RBE value defined by tissue radiosensitivity. These findings can help, in particular, in accessing the transverse homogeneity of radiation fields of ions used in studies in vitro. PMID- 28557802 TI - Negative differential resistance in armchair silicene nanoribbons. AB - Due to dimensional confinement of carriers and non-trivial changes in the electronic structure, novel tunable transport properties manifest in nanoscale materials. Here, we report using first-principles density functional theory and non-equilibrium Green's function formalism, the occurrence of negative differential resistance (NDR) in armchair silicene nanoribbons (ASNRs). Interestingly, NDR manifests only in pristine [Formula: see text] ASNRs, where [Formula: see text]. We show that the origin of such a novel transport phenomenon lies in the bias-induced changes in the density of states of this particular family of nanoribbons. With increasing width of the nanoribbons belonging to this family, the peak-to-valley ratios of current decrease due to the increase in the number of sub-bands leading to a reduction in NDR. NDR is possible not only in [Formula: see text] ASNRs, but also in mixed configurations of armchair and zigzag silicene nanoribbons. This universality of NDR along with its unprecedented width-induced tunability can be useful for silicene-based low-power logic and memory applications. PMID- 28557803 TI - Grueneisen-approach for the experimental determination of transient spin and phonon energies from ultrafast x-ray diffraction data: gadolinium. AB - We study gadolinium thin films as a model system for ferromagnets with negative thermal expansion. Ultrashort laser pulses heat up the electronic subsystem and we follow the transient strain via ultrafast x-ray diffraction. In terms of a simple Grueneisen approach, the strain is decomposed into two contributions proportional to the thermal energy of spin and phonon subsystems. Our analysis reveals that upon femtosecond laser excitation, phonons and spins can be driven out of thermal equilibrium for several nanoseconds. PMID- 28557804 TI - Enhancing the stiffness of vertical graphene sheets through ion beam irradiation and fluorination. AB - Many applications of graphene can benefit from the enhanced mechanical robustness of graphene-based components. We report how the stiffness of vertical graphene (VG) sheets is affected by the introduction of defects and fluorination, both separately and combined. The defects were created using a high-energy ion beam while fluorination was performed in a XeF2 etching system. After ion bombardment alone, the average effective reduced modulus (E r), equal to ~4.9 MPa for the as grown VG sheets, approximately doubled to ~10.0 MPa, while fluorination alone almost quadrupled it to ~18.4 MPa. The maximum average E r of ~32.4 MPa was achieved by repeatedly applying fluorination and ion bombardment. This increase can be explained by the formation of covalent bonds between the VG sheets due to ion bombardment, as well as the conversion from sp2 to sp3 and increased corrugation due to fluorination. PMID- 28557805 TI - Cancer cell death pathways caused by photothermal and photodynamic effects through gold nanoring induced surface plasmon resonance. AB - The different death pathways of cancer cells under the conditions of the photothermal (PT), effect, photodynamic (PD) effect, and their combination are evaluated. By incubating cells with Au nanoring (NRI) either linked with the photosensitizer, AlPcS, or not, the illumination of a visible continuous laser for exciting the photosensitizer or an infrared femtosecond laser for exciting the localized surface plasmon resonance of Au NRI, leads to various PT and PD conditions for study. Three different staining dyes are used for identifying the cell areas of different damage conditions at different temporal points of observation. The cell death pathways and apoptotic evolution speeds under different cell treatment conditions are evaluated based on the calibration of the threshold laser fluences for causing early-apoptosis (EA) and necrosis (NE) or late-apoptosis (LA). It is found that with the PT effect only, strong cell NE is generated and the transition from EA into LA is faster than that caused by the PD effect when the EA stage is reached within 0.5 h after laser illumination. By combining the PT and PD effects, in the first few hours, the transition speed becomes lower, compared to the case of the PT effect only, when both Au NRIs internalized into cells and adsorbed on cell membrane exist. When the Au NRIs on cell membrane is removed, in the first few hours, the transition speed becomes higher, compared to the case of the PD effect only. PMID- 28557806 TI - Analytical study of the edge states in the bosonic Haldane model. AB - We investigate the properties of magnon edge states in a ferromagnetic honeycomb spin lattice with a Dzialozinskii-Moriya interaction (DMI). We derive analytical expressions for the energy spectra and wavefunctions of the edge states localized on the boundaries. By introducing an external on-site potential at the outermost sites, we show that the bosonic band structure is similar to that of the fermionic graphene. We investigate the region in the momentum space where the bosonic edge states are well defined and we analyze the width of the edge state and their dependence with the DMI strength. Our findings extend the predictions using topological arguments and they allow size-dependent confirmation from possible experiments. PMID- 28557807 TI - Halide perovskite solar cells using monocrystalline TiO2 nanorod arrays as electron transport layers: impact of nanorod morphology. AB - This is the first report of a 17.6% champion efficiency solar cell architecture comprising monocrystalline TiO2 nanorods (TNRs) coupled with perovskite, and formed using facile solution processing without non-routine surface conditioning. Vertically oriented TNR ensembles are desirable as electron transporting layers (ETLs) in halide perovskite solar cells (HPSCs) because of potential advantages such as vectorial electron percolation pathways to balance the longer hole diffusion lengths in certain halide perovskite semiconductors, ease of incorporating nanophotonic enhancements, and optimization between a high contact surface area for charge transfer (good) versus high interfacial recombination (bad). These advantages arise from the tunable morphology of hydrothermally grown rutile TNRs, which is a strong function of the growth conditions. Fluorescence lifetime imaging microscopy of the HPSCs demonstrated a stronger quenching of the perovskite PL when using TNRs as compared to mesoporous/compact TiO2 thin films. Due to increased interfacial contact area between the ETL and perovskite with easier pore filling, charge separation efficiency is dramatically enhanced. Additionally, solid-state impedance spectroscopy results strongly suggested the suppression of interfacial charge recombination between TNRs and perovskite layer, compared to other ETLs. The optimal ETL morphology in this study was found to consist of an array of TNRs ~300 nm in length and ~40 nm in width. This work highlights the potential of TNR ETLs to achieve high performance solution processed HPSCs. PMID- 28557808 TI - Electrostatic wrapping of doxorubicin with curdlan to construct an efficient pH responsive drug delivery system. AB - The development of environmentally responsive drug delivery systems for the treatment of cancer has attracted particular interest in recent years. However, the enhancement of drug loading capacity and realization of pH-responsive drug delivery remain challenging. Herein, we employ carboxymethyl curdlan as a hydrophilic carrier to wrap doxorubicin (DOX) directly via electrostatic interaction. The sizes of the formed nanoparticles can be simply tuned by changing their feeding ratios. In particular, the nanoparticles are highly stable in aqueous solution without size variation. In vitro drug release and cytotoxicity assays illustrate that this delivery system can release DOX differentially under various environmental conditions and transport it into cell nuclei efficiently, with comparable therapeutic effect to the free drug. These results suggest that the carrying of antitumor drugs by polysaccharide via electrostatic interaction is a simple but effective way to construct a pH dependent drug delivery platform. PMID- 28557809 TI - Thermal isomerization of azobenzenes: on the performance of Eyring transition state theory. AB - The thermal [Formula: see text] (back-)isomerization of azobenzenes is a prototypical reaction occurring in molecular switches. It has been studied for decades, yet its kinetics is not fully understood. In this paper, quantum chemical calculations are performed to model the kinetics of an experimental benchmark system, where a modified azobenzene (AzoBiPyB) is embedded in a metal organic framework (MOF). The molecule can be switched thermally from cis to trans, under solvent-free conditions. We critically test the validity of Eyring transition state theory for this reaction. As previously found for other azobenzenes (albeit in solution), good agreement between theory and experiment emerges for activation energies and activation free energies, already at a comparatively simple level of theory, B3LYP/6-31G* including dispersion corrections. However, theoretical Arrhenius prefactors and activation entropies are in qualitiative disagreement with experiment. Several factors are discussed that may have an influence on activation entropies, among them dynamical and geometric constraints (imposed by the MOF). For a simpler model-[Formula: see text] isomerization in azobenzene-a systematic test of quantum chemical methods from both density functional theory and wavefunction theory is carried out in the context of Eyring theory. Also, the effect of anharmonicities on activation entropies is discussed for this model system. Our work highlights capabilities and shortcomings of Eyring transition state theory and quantum chemical methods, when applied for the [Formula: see text] (back-)isomerization of azobenzenes under solvent-free conditions. PMID- 28557810 TI - Using Quick Response Codes in the Classroom: Quality Outcomes. AB - With smart device technology emerging, educators are challenged with redesigning teaching strategies using technology to allow students to participate dynamically and provide immediate answers. To facilitate integration of technology and to actively engage students, quick response codes were included in a medical surgical lecture. Quick response codes are two-dimensional square patterns that enable the coding or storage of more than 7000 characters that can be accessed via a quick response code scanning application. The aim of this quasi experimental study was to explore quick response code use in a lecture and measure students' satisfaction (met expectations, increased interest, helped understand, and provided practice and prompt feedback) and engagement (liked most, liked least, wanted changed, and kept involved), assessed using an investigator-developed instrument. Although there was no statistically significant correlation of quick response use to examination scores, satisfaction scores were high, and there was a small yet positive association between how students perceived their learning with quick response codes and overall examination scores. Furthermore, on open-ended survey questions, students responded that they were satisfied with the use of quick response codes, appreciated the immediate feedback, and planned to use them in the clinical setting. Quick response codes offer a way to integrate technology into the classroom to provide students with instant positive feedback. PMID- 28557812 TI - Two patients with 19p13.2 deletion (Malan syndrome) involving NFIX and CACNA1A with overgrowth, developmental delay, and epilepsy. PMID- 28557813 TI - Diabetic Ketoacidosis as an Immune-related Adverse Event from Pembrolizumab in Non-Small Cell Lung Cancer. AB - Programmed cell death protein 1 pathway inhibitors are now routinely administered to patients with non-small cell lung cancer, and prompt recognition of immune related adverse events is critical to managing serious drug toxicities. Here, we describe a 66-year-old man with no known history of diabetes who presented with diabetic ketoacidosis after receiving 3 doses of pembrolizumab for lung adenocarcinoma. Autoimmune diabetes is a rare but potentially life-threatening complication of programmed cell death protein 1 inhibitors. PMID- 28557811 TI - The Prevalence of Posttraumatic Stress Disorder in Primary Care: A Systematic Review. AB - LEARNING OBJECTIVES: After participating in this activity, learners should be better able to:* Determine the prevalence of clinician-diagnosed posttraumatic stress disorder (PTSD) in primary care patients* Identify the prevalence of questionnaire-ascertained PTSD symptoms in primary care patients OBJECTIVE: Determine the prevalence of clinician-diagnosed PTSD and questionnaire ascertained PTSD symptoms in primary care patients. METHODS: A systematic review of the literature using the PRISMA method, searching MEDLINE, CINAHL, Cochrane Database, PsycINFO, EMBASE, Google Scholar, and relevant book chapter bibliographies. Studies that reported on the prevalence, including point or lifetime prevalence, of PTSD ascertained using diagnostic interviews or self report questionnaires, or from administrative data, among patients seen in primary care were deemed eligible for inclusion. We abstracted data on the PTSD assessment tool, the mean questionnaire scores/cutoff scores, the time period of PTSD symptoms, and PTSD prevalence reported. RESULTS: Of 10,614 titles screened, 41 studies were eligible for inclusion. The included studies assessed PTSD in a total of 7,256,826 primary care patients. The median point prevalence of PTSD across studies was 12.5%. The median point prevalence in the civilian population was 11.1%; in the special-risk population, 12.5%; and in veterans, 24.5%. The point prevalence of diagnostic interview-ascertained PTSD ranged from 2% to 32.5%, and the point prevalence of questionnaire-based substantial PTSD symptoms ranged from 2.9% to 39.1%. Lifetime prevalence of diagnostic interview ascertained PTSD ranged from 14.5% to 48.8%. The prevalence of PTSD in administrative data-based studies ranged from 3.5% to 29.2%. CONCLUSIONS: PTSD is common in primary care settings. Additional research on effective and generalizable interventions for PTSD in primary care is needed. PMID- 28557815 TI - Use of Paley Classification and SUPERankle Procedure in the Management of Fibular Hemimelia. AB - BACKGROUND: Fibular hemimelia is the most common deficiency involving the long bones. Paley classification is based on the ankle joint morphology, identifies the basic pathology, and helps in planning the surgical management. Reconstruction surgery encompasses foot deformity correction and limb length equalization. The SUPERankle procedure is a combination of bone and soft tissue procedures that stabilizes the foot and addresses all deformities. METHODS: We retrospectively reviewed 29 consecutive patients (29 limb segments), surgically treated between December 2000 and December 2014. Among the 29 patients, 27 were treated with reconstructive procedures. Type 1 (8 patients) cases were treated with only limb lengthening, and correction of tibial deformities. Type 2 (7 patients) cases were treated by distal tibial medial hemiepiphysiodesis or supramalleolar varus osteotomy. In type 3 (10 patients) cases, the foot deformity was corrected using the SUPERankle procedure. Type 4 (2 patients) cases were treated with supramalleolar osteotomy along with posteromedial release and lateral column shortening. In a second stage, limb lengthening was performed, using the Ilizarov technique. In the remaining 2 patients (type 3A and type 3C), amputation was performed using Syme technique as a first choice of treatment. RESULTS: The results were evaluated using Association for the Study and Application of Methods of Ilizarov scoring. Excellent results were obtained in 15 of 27 (55%) patients. Six (22%) patients had good results, 4 (14.8%) had fair results, and 2 (7%) had poor results. Mean limb length discrepancy at initial presentation was 3.55 cm (range: 2 to 5.5 cm) which significantly improved to 1.01 cm (range: 0 to 3 cm) after treatment (P=0.015). CONCLUSIONS: Our results and a review of the literature clearly suggest that limb reconstruction according to Paley classification, is an excellent option in the management of fibular hemimelia. Our 2-staged procedure (SUPERankle procedure followed by limb lengthening) helps in reducing the complications of limb lengthening and incidence of ankle stiffness. Performing the first surgery at an earlier age (below 5 y) plays a significant role in preventing recurrent foot deformities. LEVEL OF EVIDENCE: Level IV.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 without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0/. PMID- 28557814 TI - Significance of Frequencies, Compositions, and/or Antileukemic Activity of (DC stimulated) Invariant NKT, NK and CIK Cells on the Outcome of Patients With AML, ALL and CLL. AB - Invariant natural killer T (iNKT)/natural killer (NK)/cytokine-induced killer (CIK) cells are important for immune surveillance. (I) Novel combinations of antibody 6B11 (targeting the Valpha24-Jalpha18-invariant T-cell receptor) with CD4/CD8/CD1d/Valpha24 for iNKT subset detection and "T/NK cell-like"-iNKT subsets were defined. Compared with healthy peripheral blood mononuclear cells (MNC) (significantly) lower proportions of iNKT cells (6B11/6B11CD3/6B11CD161), NK cells (CD3CD56/CD3CD161), and CIK cells (CD3CD56/CD3CD161) were found in peripheral blood MNC from acute myeloid (AML)/acute myeloid, lymphoid (ALL)/chronic lymphoid leukemia (CLL) patients in acute disease stages. Subtyping of iNKT cells revealed (significantly) higher proportions of CD3 T cells and CD161 NK cells in AML/ALL/CLL expressing 6B11 compared with healthy MNC. Prognostic evaluations showed higher proportions of iNKT/NK/CIK cells in favorable AML subgroups (younger age, primary, no extramedullary disease, achievement/maintenance of complete remission) or adult ALL and CLL patients. (II) iNKT/NK/CIK cell frequencies increased after (vs. before) mixed lymphocyte cultures of T-cell-enriched immune reactive cells stimulated with MNC/whole blood with or without pretreatment with "cocktails" (dendritic cells generating methods/kits inducing blasts' conversion to leukemia-derived dendritic cells from AML patients). Individual "cocktails" leading to "highest" iNKT cell frequencies could be defined. Antileukemic blast lytic activity correlated significantly with frequencies of iNKT/NK/CIK cells. In summary healthy MNC show significantly more iNKT/NK/CIK cells compared with AML/ALL/CLL MNC, a shift in the iNKT cell composition is seen in healthy versus leukemic samples and iNKT/NK/CIK cell proportions in AML/ALL/CLL MNC samples correlate with prognosis. "Cocktail" treated AML blasts lead to higher iNKT/NK/CIK cell frequencies and samples with antileukemic activity show significantly higher frequencies of iNKT/NK/CIK cells. Proportions of iNKT/NK/CIK cells should regularly be evaluated in AML/ALL/CLL diagnosis panels for quantitative/prognostic estimation of individual patients' antileukemic potential and their role in dendritic cells/leukemia-derived dendritic cells triggered immune surveillance. PMID- 28557816 TI - Predicting Perioperative Transfusion in Elective Hip and Knee Arthroplasty: A Validated Predictive Model. AB - BACKGROUND: Preoperative anemia is a significant predictor of perioperative erythrocyte transfusion in elective arthroplasty patients. However, interactions with other patient and procedure characteristics predicting transfusion requirements have not been well studied. METHODS: Patients undergoing elective primary total hip arthroplasty or total knee arthroplasty at a tertiary hospital in Adelaide, South Australia, Australia, from January 2010 to June 2014 were used to identify preoperative predictors of perioperative transfusion. A logistic regression model was developed and externally validated with an independent data set from three other hospitals in Adelaide. RESULTS: Altogether, 737 adult patients in the derivation group and 653 patients in the validation group were included. Binary logistic regression modeling identified preoperative hemoglobin (odds ratio, 0.51; 95% CI, 0.43 to 0.59; P < 0.001 for each 1 g/dl increase), total hip arthroplasty (odds ratio, 3.56; 95% CI, 2.39 to 5.30; P < 0.001), and females 65 yr of age and older (odds ratio, 3.37; 95% CI, 1.88 to 6.04; P = 0.01) as predictors of transfusion in the derivation cohort. CONCLUSIONS: Using a combination of patient-specific preoperative variables, this validated model can predict transfusion in patients undergoing elective hip and knee arthroplasty. The model may also help to identify patients whose need for transfusion may be decreased through preoperative hemoglobin optimization. PMID- 28557818 TI - Posterior-only Hemivertebra Resection With Anterior Structural Reconstruction With Titanium Mesh Cage and Short Segmental Fusion for the Treatment of Congenital Scoliokyphosis: The Indications and Preliminary Results. AB - : MINI: Posterior hemivertebra resection with anterior structural reconstruction and short segmental fusion may be a reliable procedure for selected patients with scoliokyphosis due to a hemivertebra, providing good correction both on the coronal and sagittal planes, saving mobile segments with lower risk of implants failures. STUDY DESIGN: Perspective study. OBJECTIVES: To evaluate indications and preliminary results of posterior hemivertebra resection with anterior structural reconstruction with titanium mesh cage and short segmental fusion. SUMMARY OF BACKGROUND DATA: There exist a lot of reports on posterior hemivertebra resection for the early surgical intervention of congenital scoliosis because of hemivertebra. However, a few reports describe the procedure of the anterior structural reconstruction after posterior hemivertebra resection. METHODS: In this study, 18 selected children of mean age 5.4 years (range, 2-12 yrs) with scoliokyphosis because of hemivertebra were treated with posterior hemivertebra resection with anterior structural reconstruction and short segmental fusion. They were followed for an average of 37.1 (24-85) months. Radiograghs, operative reports, and patient charts were studied to evaluate the correction and complications. RESULTS: Average fused segments were 1.67 (1-3). The segmental scoliosis was 40.1 degrees before surgery, 4.1 degrees postsurgery, and 5.7 degrees at the latest the follow up. Moreover, the segmental kyphosis (difference to normal segmental alignment) was improved from 27.6 degrees to 3.9 degrees . The correction of the compensatory cranial and caudal curve was 74.7% and 82.4%. The trunk shift improved from 17.7 mm to 5.3 mm. No complications occurred until the latest follow up. CONCLUSION: Posterior hemivertebra resection with anterior structural reconstruction and short segmental fusion is a reliable procedure for selected patients with scoliokyphosis because of hemivertebra. A structural reconstruction is essential to the avoidance of overcorrection of the segmental scoliosis and resultant postoperative coronal imbalance with limited fused levels in some patients, increasing chances of short segmental fusion and saving mobile segments. As a fulcrum, anterior reconstruction with a titanium mesh cage could help to improve the correction of segmental kyphosis. Furthermore, the cage may help to stabilize the level of hemivertebra resection like a structural autograft, enhancing the postoperative stability and decreasing the stress of the pedicle and implants. LEVEL OF EVIDENCE: 4. PMID- 28557817 TI - Accuracy of Capillary and Arterial Whole Blood Glucose Measurements Using a Glucose Meter in Patients under General Anesthesia in the Operating Room. AB - BACKGROUND: The aim of this study was to evaluate the use of a glucose meter with surgical patients under general anesthesia in the operating room. METHODS: Glucose measurements were performed intraoperatively on 368 paired capillary and arterial whole blood samples using a Nova StatStrip (Nova Biomedical, USA) glucose meter and compared with 368 reference arterial whole blood glucose measurements by blood gas analyzer in 196 patients. Primary outcomes were median bias (meter minus reference), percentage of glucose meter samples meeting accuracy criteria for subcutaneous insulin dosing as defined by Parkes error grid analysis for type 1 diabetes mellitus, and accuracy criteria for intravenous insulin infusion as defined by Clinical and Laboratory Standards Institute guidelines. Time under anesthesia, patient position, diabetes status, and other variables were studied to determine whether any affected glucose meter bias. RESULTS: Median bias (interquartile range) was -4 mg/dl (-9 to 0 mg/dl), which did not differ from median arterial meter bias of -5 mg/dl (-9 to -1 mg/dl; P = 0.32). All of the capillary and arterial glucose meter values met acceptability criteria for subcutaneous insulin dosing, whereas only 89% (327 of 368) of capillary and 93% (344 of 368) arterial glucose meter values met accuracy criteria for intravenous insulin infusion. Time, patient position, and diabetes status were not associated with meter bias. CONCLUSIONS: Capillary and arterial blood glucose measured using the glucose meter are acceptable for intraoperative subcutaneous insulin dosing. Whole blood glucose on the meter did not meet accuracy guidelines established specifically for more intensive (e.g., intravenous insulin) glycemic control in the acute care environment. PMID- 28557819 TI - The Scholarly Influence of Orthopaedic Research According to Conventional and Alternative Metrics: A Systematic Review. AB - BACKGROUND: Researchers are experiencing an innovative shift toward online distribution of their work, and metrics related to online scholarly influence are gaining importance. Our objectives were to determine which types of online activity are most prevalent in orthopaedics, to identify associated factors, and to explore a complementary approach to measuring overall scholarly influence using online activity and conventional citations. METHODS: We performed a systematic review of randomized controlled trials of surgical or nonsurgical interventions in participants with, or at specific risk for, injuries and diseases of the musculoskeletal system. We collected data on online activity in social media, mainstream media, blogs, forums, and other sources from a commercial provider of alternative metric data for medical journals. We tested associations with use of negative binomial regression. RESULTS: We identified 1,697 trials, published between 2011 and 2014, that had a total of 12,995 conventional citations and 15,068 online mentions. The median number of online mentions of each trial was 2 (interquartile range, 0 to 5). Twitter (82%) and Facebook (13%) mentions were the most prevalent types of online activity. Counts of online mentions correlated with conventional citations (r = 0.11, p < 0.01) but accumulated more rapidly. Higher total counts of online mentions were consistently associated with longer time since publication, higher journal impact factor, higher author h-index values, and less risk of bias (p < 0.01 for each). We found the best model fit for a complementary approach by weighting citations and online mentions equally. CONCLUSIONS: Online activity in orthopaedics is dominated by activity on Twitter and Facebook and is associated with increasing time since publication, journal impact factor, and author h-index values, and less risk of bias. Institutions, publishers, funding agencies, and clinicians may consider a complementary approach to measuring scholarly influence that weights online mentions and conventional citations equally. PMID- 28557820 TI - Features of Resting-State Electroencephalogram Theta Coherence in Somatic Symptom Disorder Compared With Major Depressive Disorder: A Pilot Study. AB - OBJECTIVE: Somatic symptom disorder (SSD) often co-occurs with major depressive disorder (MDD). Both conditions share common psychobiological and biobehavioral characteristics, but little is known about differential patterns in brain function. In this study, we compared resting-state functional brain connectivity between SSD and MDD using quantitative electroencephalography. METHODS: Fifteen patients with SSD (SSD group), 15 patients with MDD (MDD group), and 15 healthy volunteers (healthy control [HC] group) participated in this study. Participants were assessed with quantitative electroencephalography using a 21-channel electroencephalogram system. Electroencephalogram coherence in the theta frequency range (3.5-7.5 Hz) was assessed between the following seven electrode pairs: Fp1 and Fp2, F7 and T3, F8 and T4, T5 and P3, P4 and T6, P3 and Pz, and Pz and P4. Differences in coherence between groups were analyzed using analysis of variance. RESULTS: Theta coherence between the F7 and T3 electrodes was lower in the SSD group than the MDD and HC groups (F(2,42) = 6.67, p = .0030). Theta coherence between the T5 and P3 electrodes was lower in the SSD and MDD groups than the HC group (F(2,42) = 5.65, p = .0067). Theta coherence between the Pz and P4 electrodes was lower in the SSD group than the MDD group (F(2,42) = 6.41, p = .0037). CONCLUSIONS: Both SSD and MDD patients commonly showed decreased functional connectivity within the left temporoparietal junction, which has neurophysiological implications for cognitive-attentional processing and social interaction. Frontostriatal circuit dysfunction affects processes that control perception and emotion, as well as misperception of somatosensory data in the parietal somatosensory area, and is more likely to be a neuropathology of SSD than MDD. PMID- 28557822 TI - Gut Microbiota and the Gut-Brain Axis: New Insights in the Pathophysiology of Metabolic Syndrome. AB - OBJECTIVE: Emerging preclinical evidence has shown that the bidirectional signaling between the gastrointestinal (GI) tract and the brain, the so-called gut-brain axis, plays an important role in both host metabolism and behavior. In this review, we discuss the potential mechanisms of the brain-gut axis in relation to the pathophysiology of metabolic syndrome. METHODS: A selective literature review was conducted to evaluate GI and brain interactions. RESULTS: Evidence suggests reduced microbial diversity in obesity and metabolic dysregulation. However, findings of microbiota composition in obese individuals are inconsistent, and the investigation of causality between gut microbiota and energy homeostasis is complex because multiple variables contribute to the gut microbiota composition. The microbial metabolites short chain fatty acids are found to exert numerous physiologic effects, including energy homeostasis through the regulation of GI hormones such as cholecystokinin, glucagon-like peptide 1, peptide tyrosine-tyrosine, and leptin. Preclinical studies show that modifying rodents' microbiota through fecal transplantation results in alterations of these GI hormones and subsequently an altered metabolism and behavior. However, whether and to what extent preclinical findings translate to human metabolism is unclear. CONCLUSIONS: One of the major limitations and challenges in this field of research is interindividual variability of the microbiome. Future research needs to combine recent insights gained into tracking the dynamics of the microbiome as well as the metabolic responses. Furthermore, advanced mapping of the human microbiome is required to investigate the metabolic implications of the gut-brain axis to develop targeted interventions for obesity and metabolic syndrome. PMID- 28557823 TI - Effect of the Eye Tracking System on the Reproducibility of Measurements Obtained With Spectral-domain Optical Coherence Tomography in Glaucoma. AB - PURPOSE: The purpose of this study was to evaluate whether the eye tracking system (ETS) improved the reproducibility of a single circle peripapillary retinal nerve fiber layer (RNFL) measurement acquired with spectral-domain optical coherence tomography (OCT). MATERIALS AND METHODS: The sample comprised 205 individuals divided into 2 groups according to intraocular pressure and visual field outcomes. A total of 100 healthy individuals and 105 patients with open-angle glaucoma underwent imaging of the optic nerve head with OCT 3 times during the same session and 2 additional times in subsequent sessions (30 days apart). Intraclass correlation coefficient (ICC), coefficient of variation, and test-retest variability were calculated for the RNFL thickness acquired with and without the ETS enabled, and compared. RESULTS: The glaucoma group mainly comprised patients with moderate glaucoma (mean deviation of standard automated perimetry, -6.73+/-6.2 dB). The RNFL thicknesses did not differ between acquisitions with or without the ETS activated and disabled. All ICCs were >0.9 in the control and glaucoma groups with or without the ETS activated. The best parameter in the intersession analysis (with ETS activated) was global RNFL thickness (ICC, 0.95; coefficient of variation, 2.7%; and test-retest variability, 2.87 MUm). The reproducibility and repeatability of RNFL measurements did not differ significantly between acquisitions with or without the ETS in either group. CONCLUSIONS: The reproducibility of peripapillary RNFL thicknesses acquired with OCT was excellent. The variability between OCT measurements did not decrease with the ETS activated. PMID- 28557824 TI - Orbital Cellulitis Following Uncomplicated Aqueous Shunt Surgery. PMID- 28557825 TI - Suture of Symptomatic YAG Laser Peripheral Iridotomies Following Phakic Intraocular Lens Implantation. AB - A 45-year-old woman complained of glare and photophobia after iris-fixated phakic intraocular lens (IFPIOL) implantation in her left eye. The patient underwent prophylactic laser peripheral iridotomies (LPIs) 2 days before surgery. The uncorrected visual acuity after surgery was 20/20 and the intraocular pressure was 14 mm Hg. The slit-lamp examination showed a well-centered IFPIOL and 2 LPIs at 10 and 2 o'clock partially covered by the upper lid. Twenty days after IFPIOL implantation, as symptoms persisted and were intolerable to the patient, we decide to suture iridotomies using a modified Siepser slip-knot technique. Postoperatively, visual acuity remains 20/20 and patient reported a complete disappearance of symptoms. No intraoperative and postoperative complications were noted. Experiencing glare and photophobia is a rare side effect due to LPI. Suture of iridotomies using a modified Siepser slip-knot technique can be considered a safe and effective procedure to solve this annoying complication. PMID- 28557826 TI - Intracorneal Hematoma After Ahmed Glaucoma Valve Implant Surgery. AB - Intracorneal hematoma or hemorrhagic descemet detachment is a rare phenomenon. It has been previously described after nonpenetrating glaucoma surgeries such as canaloplasty, viscocanalostomy, and deep sclerectomy. In this report, we describe a rare case of intracorneal hematoma as a yet nondocumented complication after Ahmed glaucoma valve implant surgery. PMID- 28557828 TI - Vitreous Occlusion of a Glaucoma Drainage Implant-Surgical Management. AB - Vitreous occlusion of a glaucoma drainage implant (GDI) can lead to failure of the device and severely elevated intraocular pressure. The pathophysiology of tube obstruction is related to central and anterior displacement of vitreous that is drawn into and condenses within the proximal lumen of the tube. This can occur from days to years following GDI surgery. Successful management of vitreous-tube obstruction generally requires manual removal of the condensed vitreous plug with end-grasping forceps. This technique achieves reversal of tube blockage and restoration of GDI function. Amputation of the incarcerated vitreous alone with vitrectomy or neodymium:yttrium-aluminum-garnet vitreolysis does not consistently restore GDI function and risks persistent intraluminal tube obstruction. PMID- 28557830 TI - Evaluation of the Efficacy and Safety of the New Susanna Glaucoma Drainage Device in Refractory Glaucomas: Short-term Results. PMID- 28557829 TI - Progressive Decrease of Peripapillary Angioflow Vessel Density During Structural and Visual Field Progression in Early Primary Open-angle Glaucoma. AB - PURPOSE: To present a case of early primary open-angle glaucoma in which retinal nerve fiber layer thickness (RNFLT), ganglion cell complex (GCC), and visual field progression were accompanied with significant progression of peripapillary angioflow vessel density (PAFD) measured with optical coherence tomographic angiography. METHODS: A 68-year-old female patient who was under topical intraocular pressure (IOP) lowering medication for 20 years for ocular hypertension of the right and preperimetric primary open-angle glaucoma of the left eye (with reproducible inferotemporal and superotemporal neuroretinal rim and RNFL loss) was prospectively imaged with the AngioVue OCT for RNFLT, GCC thickness, and PAFD, and investigated with the Octopus Normal G2 visual field test on the same days at 6-month intervals for 18 months, while the IOP of the left eye escaped from control. RESULTS: IOP of the left eye fluctuated between 14 and 30 mm Hg in the study period. RNFLT, GCC thickness, and peripapillary PAFD all decreased significantly (linear regression analysis, P=0.030, 0.040, and 0.020, respectively), and a significant 2.1 dB/y progression was seen for a superior visual field cluster. The RNFLT, peripapillary PAFD, and visual field of the right eye remained normal and unchanged. CONCLUSIONS: In our case IOP elevation, glaucomatous visual field conversion, and structural progression were accompanied with significant progressive decrease of peripapillary PAFD. The simultaneous thinning of RNFLT and GCC and decrease of peripapillary PAFD suggest that PAFD may potentially be an additional indicator of early progression in primary open-angle glaucoma. PMID- 28557831 TI - Female exposure to endocrine disrupting chemicals and fecundity: a review. AB - PURPOSE OF REVIEW: Endocrine disrupting chemicals (EDCs) have been known for their ability to interfere with aspects of hormone action resulting in adverse health consequences among animals and humans; however, the effects of EDCs on human fecundity have shown inconsistent findings. This review summarizes the most recent epidemiologic literature from humans on the potential effects of female exposure to nonpersistent EDCs, specifically bisphenol A (BPA), phthalates, parabens, and triclosan, on fecundity, measured by markers of reproductive hormones, markers of ovulation or ovarian reserve, IVF outcomes, and time-to pregnancy. RECENT FINDINGS: Although the epidemiologic literature on this topic is growing, the evidence supporting an association between female urinary concentrations of BPA, phthalates, parabens and triclosan, and fecundity remains unclear. The heterogeneous results could be due to methodological differences in recruitment populations (fertile vs. subfertile), study designs (prospective vs. retrospective), assessment of exposure (including differences in the number and timing of urine samples and differences in the analytical methods used to assess the urinary concentrations), residual confounding due to diet or other lifestyle factors, and coexposures to other chemicals. SUMMARY: At present, there is limited evidence to conclude that female exposure to nonpersistent EDCs affect fecundity in humans. Further studies focusing on exposure to mixtures of EDCs are needed. PMID- 28557832 TI - Serum Vascular Endothelial Growth Factor-A as a Prognostic Biomarker for Epithelial Ovarian Cancer. AB - BACKGROUND: Bevacizumab, which targets vascular endothelial growth factor (VEGF) A, has recently been proven to be effective for the treatment of epithelial ovarian cancer (EOC). Thus, interest in VEGF-A has increased. There are few reports on concomitant detection of both ligands and its soluble receptors in serum samples, and the significance of serum VEGF-A in EOC is unclear, unlike the situation with tissue samples. We conducted the present study to explore the levels of serum VEGF family and its receptors and to evaluate their utility as prognostic biomarkers. METHODS: A total of 128 patients with EOC, who were consecutively treated at Tottori University Hospital between 2006 and 2012, were included. Blood samples were collected before initial surgery. Serum concentrations of VEGF-A, VEGF-C, VEGFR-1, and VEGFR-2 were analyzed by enzyme linked immunosorbent assay. We also examined the mRNA and protein expression of VEGF-A in tumor tissue from 30 cases by real-time reverse transcription polymerase chain reaction and immunohistochemistry. RESULTS: The levels of VEGF-A in patients with stage III/IV disease were significantly higher than those with stage I/II disease (P = 0.0036). On the other hand, the level of VEGFR-2 in stage III/IV was significantly lower than that in stage I/II (P = 0.0026). With the cutoff value of VEGF/VEGFRs at the median level, the overall survival (OS) for patients with high VEGF-A levels was significantly lower than those with low levels (P = 0.015). Patients with high VEGFR-2 levels showed better prognosis than those with low VEGFR-2 levels (P = 0.023). Multivariate analysis revealed that International Federation of Gynecology and Obstetrics stage and serum VEGF-A were independent prognostic factors for OS [hazard ratio 2.01, 95% confidence interval (1.13-3.63), P = 0.017]. There was no significant correlation between mRNA or protein expression and serum levels of VEGF-A. CONCLUSIONS: Serum VEGF-A is an independent prognostic factor for OS in patients with EOC, implying that serum VEGF-A is a prognostic biomarker for EOC. Further study to validate the data is needed. PMID- 28557833 TI - Lymphovascular Space Invasion for Endometrial Cancer: Undertreatment and Overtreatment Risks: A Survey of the Spanish Gynecologic Oncology Group. AB - OBJECTIVE: The purpose of this study is to asses the impact of lymphovascular space invasion (LVSI) present in early-stage endometrial cancer, regarding its therapeutic management and prognosis knowledge, based on a survey among Spanish oncologic gynecologist. METHODS/MATERIALS: Between October and November 2014, the Young Spanish Onco-gynecologist Group carried out a survey to perform a cross sectional study about the management of LVSI. All active members in the oncology field of the Spanish Society of Gynecology and Obstetrics were invited to participate in the survey. RESULTS: Most respondents consider LVSI a bad prognosis factor for endometrial cancer (66%) and also consider that it should be included in the International Federation of Gynecology and Obstetrics classification (56%). Seventy-five percent of all gynecologists did not modify their surgical treatment. Regarding follow-up, 38% of the respondents do not change their surveillance, 28% modify it, and 31% reported any change only with additional factors. Forty-seven percent of respondents advise systemic treatment with chemotherapy.Data were dichotomized between less than or equal to 20 versus greater than 20 years of OB-GYN specialist and less than or equal to 5 versus greater than 5 years of main dedication to gynecology oncology, but it was not possible to show any significant differences among the groups. The response rate (34 individuals) was too low to expect any significant differences. CONCLUSIONS: Results suggest that LVSI remains a controversial issue in the management of patients with endometrial cancer. Acquiring a deeper knowledge and uniform criteria could avoid the risk of undertreatment and overtreatment in this group of patients with early-stage endometrial cancer. The identification of vascular pseudoinvasion is recommended, although the clinical and prognostic implications still need to be determined. PMID- 28557834 TI - Preoperative Serum Human Epididymis Protein 4 Levels in Early Stage Endometrial Cancer: A Prospective Study. AB - OBJECTIVE: The aim of the study was to evaluate the prognostic value of human epididymis protein 4 (HE4) and cancer antigen 125 markers with pathological prognostic factor to complete the preoperative clinical panel and help the treatment planning. METHODS: This prospective multicenter study was conducted in 2 gynecologic oncology centers between 2012 and 2014 (Institute for Maternal and Child Health IRCCS Burlo Garofolo in Trieste and Catholic University of the Sacred Heart in Rome, Italy). We enrolled 153 patients diagnosed with clinical early (International Federation of Gynecology and Obstetrics stages I-II) type I endometrial cancer. RESULTS: Human epididymis protein 4 levels seemed to be strictly related to age (P < 0.001) and menopausal status (P < 0.002). Compared with myometrial invasion (MI), the HE4 values were significantly higher in case of invasion of greater than 50% of the thickness: MI of greater than 50%, median of 94.85 pmol/L (38.3-820.8 pmol/L), versus MI of less than 50%, median of 65.65 pmol/L (25.1-360.2 pmol/L), (P < 0.001). The HE4 levels increase significantly with increasing tumor size: diameter of larger than 2 cm, median of 86.9 pmol/L (35.8-820.8 pmol/L), versus diameter of smaller than 2 cm, median of 52.2 pmol/L (33.3-146.8 pmol/L), (P < 0.001). In our population, HE4 did not correlate with the histological grade, endometrial cancer type I versus type II (P = 0.86), the lymphovascular infiltration (P = 0.12), and the cervical invasion (P = 0.6). We established a new variable, considering 3 high-risk tumor features: MI of greater than 50% and/or histological G3 and/or type II. Human epididymis protein 4 levels significantly increase in high-risk tumors (high risk HE4, 93.6 pmol/L vs low medium risk, 65.5 pmol/L; P < 0.001). CONCLUSIONS: A preoperative HE4 evaluation could help stratify patients with deep invasion and/or metastatic disease and is correlated with other relevant prognostic factors to be considered to tailor an adequate surgical strategy. PMID- 28557835 TI - Giant Ocular Surface Squamous Neoplasia Wrapping Whole Cornea. AB - We present a giant ocular surface squamous neoplasia (OSSN) measuring approximately 20*18 mm arising from the fornix and wrapping the entire 12 clock hours of the cornea. The surgical excision was performed with preservation of the corneal surface. A 3-mm clear margin was obtained all around the mass. The histopathology confirmed as moderately differentiated squamous cell carcinoma with clear margins. The postoperative period was uneventful, and a clear cornea without a residual scar with best corrected visual acuity of 20/20 was attained. A giant OSSN can demonstrate corneal invasion, making surgical excision both challenging and associated with complications such as subsequent scarring. Extended surgical intervention, chemotherapy, chemoreduction, and immunotherapy have been reported in giant OSSNs. However, we report a giant OSSN wrapping the entire 12 clock hours of the cornea that was managed with single surgery with complete corneal restoration. PMID- 28557836 TI - Histopathology of Failed Descemet Membrane Endothelial Transfer. AB - OBJECTIVES: To describe the postmortem histologic features after an unsuccessful Descemet membrane endothelial transfer (DMET) and assess any potential clinical implications. METHODS: Postmortem, an eye from a patient who previously underwent unsuccessful DMET for pseudophakic bullous keratopathy (PPBK) was harvested and processed for morphologic evaluation. RESULTS: Clinically and histologically, the host cornea showed evidence of diffuse stromal edema. Although the edges of the surgical descemetorhexis were well visualized, there was no evidence of endothelial migration or repopulation of the posterior stroma from any direction. A multilayered, retrocorneal membrane was present that appeared to originate from the trabecular meshwork. CONCLUSIONS: Descemet membrane endothelial transfer and "descemetorhexis alone" may be insufficient treatment for eyes operated on for PPBK, that is, eyes with a significantly depleted or dysfunctional endothelium. PMID- 28557840 TI - John J. Bonica: born 100 years ago. PMID- 28557837 TI - Unraveling the pathogenesis of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis through genetic, immunologic, and microbiologic discoveries: an update. AB - PURPOSE OF REVIEW: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is considered the most common periodic fever syndrome of childhood. Although it was first described three decades ago, the pathogenesis has been poorly understood. Recent studies on the heritability and immunology of the disorder have begun to shed light into the mechanisms of this autoinflammatory disorder. This review will focus on the pathogenesis of PFAPA, especially as it pertains to the genetic susceptibility, tonsillar immunology, and the role of the microbiome. RECENT FINDINGS: Recent literature provides insights into the heritability, potential genetic modifiers, and the immunologic and microbiological profile of the tonsils in this syndrome. SUMMARY: Evidence is mounting that PFAPA is inherited as a complex genetic disease. Furthermore, tonsillectomy is curative in the majority of patients, including those who do not meet the complete clinical criteria for PFAPA. The tonsils in PFAPA patients may exhibit unique immunologic and microbiological features. The goal of this review is to outline these new developments. PMID- 28557842 TI - Appropriate Use of Drug Testing in Clinical Addiction Medicine. PMID- 28557844 TI - Child deaths of undetermined intent: An analysis of circumstances using Illinois Violent Death Reporting System data. AB - BACKGROUND: There is little information available about the circumstances surrounding the deaths of children aged 0 to 14 years in which the manner of death is of undetermined intent. METHODS: We analyzed data collected in the Illinois Violent Death Reporting System to describe victim demographics, location of injury, seasonality, day of week, and circumstances surrounding the victims' deaths. RESULTS: From 2005 to 2010 in Cook County, Illinois, 192 cases were identified of children aged 0 to 14 years, in which the manner of death was of undetermined intent. The majority of cases were younger than 1 year (81%), male (62%), and non-Hispanic black (66%); occurred in the City of Chicago (65%); and also occurred most frequently during the months of May (15%) and July (13%) and on Sunday (19%). Circumstances of note were having information on the location of death available for the victim (90%); scene investigation was not performed/unknown/not documented (81%); and the victim not presenting with red petechiae (84%). By ethnicity, a lower proportion of Hispanic victims had parental drug information available compared with non-Hispanic victims (17% and 40%, respectively; p = 0.017); Hispanic victims were more likely than non Hispanic victims to have a documented acute illness at the time of injury leading to death (57% and 33%, respectively; p = 0.015). The availability of scene information and the successful contact of one or both parents of the victim following the victim's death varied by location. CONCLUSIONS: No public health surveillance system exists for the collection of this type of death. There is not enough information provided to develop an effective intervention. The systematic, thorough collection of information surrounding these deaths is necessary to pinpoint possible contributing mechanisms of death for these children. LEVEL OF EVIDENCE: Epidemiologic, level IV. PMID- 28557843 TI - Increased Reporting Accuracy of Alzheimer Disease Symptoms in Caribbean Hispanic Informants. AB - INTRODUCTION: Informant report of symptoms is essential for diagnosing and characterizing Alzheimer disease (AD). Differences in the perception and experience of dementia across ethnicities may influence informant report. Understanding such differences is critical given that among those with AD, Hispanics are disproportionately affected. METHODS: Cross-sectional analyses examined informant report of cognitive and functional symptoms in mild AD across white (n=107) and Caribbean Hispanic (n=71) informants. To explore its accuracy, informant report of symptoms was compared against objective measures of patient performance. RESULTS: Adjusted analyses revealed Hispanics reported more symptoms than white informants. Informant report of symptoms was inversely correlated with patients' global cognition in both ethnic groups. Only Hispanic report of symptoms was significantly associated with memory and language performance. DISCUSSION: Informant report of symptoms was associated with patients' global cognition, reflecting relatively accurate informant reports in both ethnic groups, and was stronger in Hispanics when examining memory and language. Such differences may reflect cultural caregiving practices and perceptions of dementia, having implications for diagnosis and treatment. PMID- 28557845 TI - Pediatric injury prevention programs: Identifying markers for success and sustainability. AB - BACKGROUND: Injury is the leading cause of death in children. Although many pediatric hospitals and trauma centers provide injury prevention (IP) programming, there is no national standard. This study aims to identify characteristics of a sustainable and successful IP program by querying programs affiliated with the Injury Free Coalition for Kids (IFCK). METHODS: The IFCK sites were sent a 30-question survey via e-mail. Questions focused on demographics, scope of IP activities, self-efficacy, and outcome measures including finances, academic productivity, and legislative advocacy. Counts and frequencies were calculated and compared using chi tests. RESULTS: The survey was completed by 38 (90.4%) of 42 sites. The majority were associated with a freestanding children's hospital (57.9%) and Level I pediatric trauma center (86.8%). Most programs (79%) had at least one dedicated full-time equivalent (FTE) staff. Research was most common on child passenger safety and teen driving. Nearly 30% of programs offered educational curricula to health care providers; these sites were more likely to have FTE support (p = 0.036). Steady sources of funding were identified for 60.5% of programs, with 47.8% citing their hospital as the primary source; 73% of respondents were confident in their program's capacity to sustain activities; these were more likely to be larger programs (p = 0.001) with steady sources of funding (p < 0.001). Despite 73.7% of sites having academic affiliations, 60.5% had 5 or fewer publications over the previous 5 years. In the prior 2 years, 55.3% of programs impacted legislative or policy changes. Funding, size of program, and FTE had no statistical correlation with research productivity or number of legislative/policy contributions. CONCLUSIONS: This study characterizes the variation among pediatric IP programs within IFCK sites, while highlighting the association between financial and FTE support from programs' institutions with sustainable IP programming. These results can assist programs in identifying differences in relation to their peers. PMID- 28557846 TI - Adolescent motor vehicle crash prevention through a trauma center-based intervention program. AB - : Traumatic injuries account for millions of emergency room visits and hospital admissions annually. Motor vehicle crashes (MVCs) remain a leading cause of mortality between the ages of 1 and 44 years. With the popularity of smart devices, drivers are ever more distracted on the road. Programs that educate drivers on safe actions and to raise awareness of the perils of drunk and distracted driving exist, but there are few data that demonstrate a reduction in motor vehicle injury rates. We sought to determine if the implementation of such a program in our community would impact the rates of MVCs. Assessing the effectiveness of the Save A Life Tour, a risk reduction program, this intervention was instituted at a single area high school. The numbers of adolescent drivers aged 16 to 21 years involved in MVCs treated at the regional Level I trauma center were compared over two time intervals and between two adjoining counties. The time intervals consisted of preintervention and postintervention surveillance, each over a period of 3 years. Using our trauma registry, we compared the incidence of MVC between the two counties and between the two age groups. The data were also compared with the incidence among these populations nationally. In the preintervention period, the number of adolescent MVCs treated from the catchment area was 166, and the number in the postintervention period was 105. This represented a risk reduction of 37% (p < 0.05). During the same intervals, the incidence in the nonintervention control catchment area increased by 12%. There was no significant change in the population aged 16 to 21 years over the time intervals in either area. These results suggest that ongoing educational intervention programs aimed at adolescent drunk and distracted driving can have an impact on these life threatening behaviors and on the incidence of MVCs. LEVEL OF EVIDENCE: Therapy, level IV. PMID- 28557847 TI - Two lives, one REBOA: Hemorrhage control for urgent cesarean hysterectomy in a Jehovah's Witness with placenta percreta. PMID- 28557849 TI - Monitoring Resistance Exercise Intensity Using Ratings of Perceived Exertion in Previously Untrained Patients With Prostate Cancer Undergoing Androgen Deprivation Therapy. AB - Fairman, CM, LaFountain, RL, Lucas, AR, and Focht, BC. Monitoring resistance exercise intensity using ratings of perceived exertion (RPE) in previously untrained patients with prostate cancer undergoing androgen deprivation therapy. J Strength Cond Res 32(5): 1360-1365, 2018-Exercise has been shown to be safe and effective for patients with prostate cancer (PrCa). The monitoring of resistance exercise (RE) intensity is an emerging area of interest in RE prescription. Rating of perceived exertion (RPE) is one of the most commonly used methods but has not yet been validated in this population. Thus, the purpose of this study was to examine the relationship between RPE and RE intensity in PrCa. Data for this study were abstracted from baseline upper- and lower-body strength assessments from 2 previous trials (Individual Diet and Exercise Adherence Pilot Trial; Livestrong, Austin, TX, USA) in our laboratory investigating functional outcomes in patients with PrCa undergoing androgen deprivation therapy (ADT). A total of 75 participants from both trials were included in this study. Ratings of perceived exertion corresponding to 50, 70, and 90% 1 repetition maximum (1RM) were extracted from the results of participants' upper- and lower-body 1RM strength tests. The changes in RPE across increasing intensities were assessed using separate univariate analysis of variance (ANOVA). For each ANOVA, RPE was used as the dependent variable and intensity (50, 70, and 90%) used as the fixed factor. A univariate ANOVA revealed a significant difference (p <= 0.05) among the RPE values for each intensity for both upper- and lower-body lifts. The results of our analyses suggest that RPE values rise linearly in response to increases in exercise intensity. Our study supports the concept that RPE may be a practical training tool to accurately estimate RE intensity in PrCa survivors undergoing ADT. Practitioners may consider using RPE to monitor and adjust RE intensity in this population. PMID- 28557850 TI - Compensatory Muscle Activation During Unstable Overhead Squat Using a Water filled Training Tube. AB - Glass, SC, and Albert, RW. Compensatory muscle activation during unstable overhead squat using a water-filled training tube. J Strength Cond Res 32(5): 1230-1237, 2018-The purpose of this study was to assess compensatory muscle activation of core and support muscle during an overhead squat using a water filled training tube. Eleven experienced weightlifting (age = 20.10 +/- 0.99, mass 89.17 +/- 6.88 kg) men completed 3, 30-second trials of an overhead squat using an 11.4 kg tube that was partially filled with water. A central valve allowed 3 conditions of water movement: 50% open, 100% open, and a stable(S), closed valve condition. Subjects completed 8-10 repetitions within each condition. Electromyographic (EMG) electrodes were placed over the belly of the vastus lateralis, deltoid, rectus abdominus, and paraspinal muscles and recorded during concentric and eccentric (ECC) phases. Integrated EMG were computed and converted to percent maximal voluntary contraction (%MVC). Compensatory activation was assessed using the natural log of the coefficient of variation of %MVC across repetitions. A 1-way repeated-measures analysis of variance across (phase, condition) was used. Significant compensatory muscle activation was seen in the deltoid muscle during ECC (100% open = 3.60 +/- 0.50 > stable LogCV = 3.06 +/- 0.45). In addition, paraspinal muscle activity was also more variable during the ECC phase (50% open LogCv = 3.28 +/- 0.26 > stable = 2.77 +/- 0.67). We conclude that the water-filled training tube induces compensatory muscle activation in the deltoid and paraspinal muscles during the ECC phase of the overhead squat. PMID- 28557851 TI - Decrements in Neuromuscular Performance and Increases in Creatine Kinase Impact Training Outputs in Elite Soccer Players. AB - Malone, S, Mendes, B, Hughes, B, Roe, M, Devenney, S, Collins, K, and Owen, A. Decrements in neuromuscular performance and increases in creatine kinase impact training outputs in elite soccer players. J Strength Cond Res 32(5): 1342-1351, 2018-The aim of the current investigation was to understand the impact of pretraining neuromuscular performance and creatine kinase (CK) status on subsequent training performance in elite soccer players. Thirty soccer players (age: 25.3 +/- 3.1 years; height: 183 +/- 7 cm; mass: 72 +/- 7 kg) were involved in this observational study. Each morning before training, players completed assessments for neuromuscular performance (countermovement jump; CMJ) and CK levels. Global positioning technology provided external load: total distance, high-speed distance, sprint distance, accelerations, decelerations, average metabolic power, explosive distance, and high metabolic power distance (>25.5 W.kg). Mixed-effect linear models revealed significant effects for CK and CMJ Z score on total high-speed distance, very high-speed distance, accelerations, decelerations, explosive distance, and maximal velocity. Effects are reported with 90% confidence limits. A CK Z-score of +1 corresponded to a -5.5 +/- 1.1, 3.9 +/- 0.5, -4.3 +/- 2.9%, -4.1 +/- 2.9%, -3.1 +/- 2.9%, and -4.6 +/- 1.9%, reduction in total high-speed distance, very high-speed distance, accelerations, decelerations, explosive distance, and maximal velocity, respectively. Countermovement jump Z-score of -1 corresponded to a -3.5 +/- 1.1, -2.9 +/- 0.5, 2.1 +/- 1.4, -5.3 +/- 2.9%, -3.8 +/- 2.9%, -1.1 +/- 2.9%, and -5.6 +/- 1.2% reduction in these external load measures. Magnitude-based analysis revealed that the practical size of the effect of a pretraining CMJ Z-score of -1 and CK Z score of +1 would have on total high-speed distance, very high-speed distance, high metabolic power distance (>25.5 W.kg), accelerations, decelerations, explosive distance, and maximal velocity was likely negative. The results of this study suggest that systematic pretraining monitoring of neuromuscular and muscle stress within soccer cohorts can provide coaches with information about the training output that can be expected from individual players during a training session. PMID- 28557852 TI - Analysis of High-Intensity Skating in Top-Class Ice Hockey Match-Play in Relation to Training Status and Muscle Damage. AB - Lignell, E, Fransson, D, Krustrup, P, and Mohr, M. Analysis of high-intensity skating in top-class ice hockey match-play in relation to training status and muscle damage. J Strength Cond Res 32(5): 1303-1310, 2018-We examined high intensity activities in a top-class ice-hockey game and the effect of training status. Male ice-hockey players (n = 36) from the National Hockey League participated. Match analysis was performed during a game and physical capacity was assessed by a submaximal Yo-Yo Intermittent Recovery Ice-hockey test, level 1 (YYIR1-IHSUB). Venous blood samples were collected 24-hour post-game to determine markers of muscle damage. Players performed 119 +/- 8 and 31 +/- 3 m.min of high intensity and sprint skating, respectively, during a game. Total distance covered was 4,606 +/- 219 m (2,260-6,749 m), of which high-intensity distance was 2042 +/ 97 m (757-3,026 m). Sprint-skating speed was 5-8% higher (p <= 0.05) in periods 1 and 2 vs. period 3 and overtime. Defensemen (D) covered 29% more (p <= 0.05) skating in total than forwards (F) and were on the ice 47% longer. However, F performed 54% more (p <= 0.05) high-intensity skating per minute than defensemen. Plasma creatine kinase (CK) was 338 +/- 45 (78-757) U.L 24-hour post-game. Heart rate loading during YYIR1-IHSUB correlated inversely (p <= 0.05) to the frequency of high-intensity skating bouts (r = -0.55) and V[Combining Dot Above]O2max (r = 0.85) and positively to post-game CK (r = 0.49; p <= 0.05). In conclusion, ice hockey is a multiple-sprint sport that provokes fatigue in the latter half of a game. Forwards perform more intense skating than defensemen. Moreover, high intensity game activities during top-class ice hockey are correlated with cardiovascular loading during a submaximal skating test. Taken together, training of elite ice-hockey players should improve the ability for repeated high intensity skating, and testing should include the YYIR1-IHSUB test as an indicator for ice-hockey-specific physical match performance. PMID- 28557853 TI - Influence of Maturation Stage on Agility Performance Gains After Plyometric Training: A Systematic Review and Meta-analysis. AB - Asadi, A, Arazi, H, Ramirez-Campillo, R, Moran, J, and Izquierdo, M. Influence of maturation stage on agility performance gains after plyometric training: a systematic review and meta-analysis. J Strength Cond Res 31(9): 2609-2617, 2017 Although plyometric training (PT) improves change of direction (COD) ability, the influence of age on COD gains after PT is unclear. Therefore, the aim of this systematic review was to identify the age-related pattern of improvement in COD ability after PT in youths. A computerized search within 6 databases was performed, selecting studies based on specific inclusion criteria: experimental trials published in English-language journals, PT focused on the lower-body, COD ability measurements reported before and after training, and male participants aged 10 to 18 years. Sixteen articles with a total of 30 effect sizes (ESs) in the experimental groups and 13 ESs in the control groups were included. For the analyses, subjects were categorized into 3 age groups: 10-12.9 years of age (PRE), 13-15.9 years of age (MID), and 16-18 years of age (POST). Independent of age, PT improved COD ability in youths (ES = 0.86, time gains [TG = -0.61]). However, a tendency toward greater COD ability gains was observed in older subjects (MID, ES = 0.95; POST, ES = 0.99) compared with younger subjects (PRE, ES = 0.68). Pearson product-moment correlation (r) indicated that 2-weekly sessions of PT-induced meaningful COD ability gains (for ES, r = 0.436; for TG, r = -0.624). A positive relationship was found between training intensity and ES (r = 0.493). In conclusion, PT improves COD ability in youths, with meaningfully greater effects in older youths. Two PT sessions per week, with 1,400 moderate intensity jumps for 7 weeks, seems to be an adequate dose. PMID- 28557854 TI - Short Term Effects of Resistance Training Modalities on Performance Measures in Male Adolescents. AB - This study compared the effects of seven weeks of bodyweight, mobility and resistance training programs on strength, power, and sprint times. Thirty-nine male adolescents (aged 14-15 years) were randomly assigned to one of two groups; bodyweight and mobility training (BMT) (n=25) or combined bodyweight, mobility and free weights training (CBT) (n=14). A physical education class (n=23) of similar age constituted a control group (CON). Both training groups performed two bodyweight and mobility training sessions per week and the CBT group performed two additional free-weight resistance exercise training sessions. Pre-testing and post-testing consisted of vertical and horizontal jump tests, 5- and 20-m sprint tests, 2 kg medicine ball throw test and maximal number of press ups. Small significant improvements (p <= 0.01) between pre-post measures were observed in the CBT group for 20 m (?2.4%; ES = -0.45) sprint time and horizontal jump distance (?4.2%; ES = 0.43). No significant differences existed between the groups when the mean changes were compared. Effect sizes demonstrated training improvements were in favour of the CBT group (for sprint times, horizontal jump distance and maximal press ups; ES = 0.35 to -1.35) compared to the BMT and CON groups and in favour of the BMT group (for sprint times and horizontal jump distance; ES =-0.33 to 0.34) compared to the CON group. Seven weeks of BMT and CBT can be beneficial for the development of physical performance capacities in untrained male adolescents. Increased training frequency with the addition of free-weights provided greatest training effects. PMID- 28557855 TI - Mean Velocity vs. Mean Propulsive Velocity vs. Peak Velocity: Which Variable Determines Bench Press Relative Load With Higher Reliability? AB - Garcia-Ramos, A, Pestana-Melero, FL, Perez-Castilla, A, Rojas, FJ, and Haff, GG. Mean velocity vs. mean propulsive velocity vs. peak velocity: which variable determines bench press relative load with higher reliability? J Strength Cond Res 32(5): 1273-1279, 2018-This study aimed to compare between 3 velocity variables (mean velocity [MV], mean propulsive velocity [MPV], and peak velocity [PV]): (a) the linearity of the load-velocity relationship, (b) the accuracy of general regression equations to predict relative load (%1RM), and (c) the between-session reliability of the velocity attained at each percentage of the 1-repetition maximum (%1RM). The full load-velocity relationship of 30 men was evaluated by means of linear regression models in the concentric-only and eccentric-concentric bench press throw (BPT) variants performed with a Smith machine. The 2 sessions of each BPT variant were performed within the same week separated by 48-72 hours. The main findings were as follows: (a) the MV showed the strongest linearity of the load-velocity relationship (median r = 0.989 for concentric-only BPT and 0.993 for eccentric-concentric BPT), followed by MPV (median r = 0.983 for concentric-only BPT and 0.980 for eccentric-concentric BPT), and finally PV (median r = 0.974 for concentric-only BPT and 0.969 for eccentric-concentric BPT); (b) the accuracy of the general regression equations to predict relative load (%1RM) from movement velocity was higher for MV (SEE = 3.80-4.76%1RM) than for MPV (SEE = 4.91-5.56%1RM) and PV (SEE = 5.36-5.77%1RM); and (c) the PV showed the lowest within-subjects coefficient of variation (3.50%-3.87%), followed by MV (4.05%-4.93%), and finally MPV (5.11%-6.03%). Taken together, these results suggest that the MV could be the most appropriate variable for monitoring the relative load (%1RM) in the BPT exercise performed in a Smith machine. PMID- 28557856 TI - CrossFit-based High Intensity Power Training Improves Maximal Aerobic Fitness and Body Composition: Retraction. PMID- 28557857 TI - Consumption of a 5-mg Melatonin Supplement Does Not Affect 32.2-km Cycling Time Trial Performance. AB - Brandenberger, KJ, Ingalls, CP, Rupp, JC, and Doyle, JA. Consumption of a 5-mg melatonin supplement does not affect 32.2-km cycling time trial performance. J Strength Cond Res 32(10): 2872-2877, 2018-Some studies suggest that exogenous melatonin supplementation may improve athletic performance in hot humid environments because of its precooling effect. However, melatonin is also consumed as a sleep aid for its depressive effects on the central nervous system (CNS), which may hinder performance. Therefore, this study was conducted to determine whether consuming a 5-mg supplement of melatonin would affect performance in a laboratory-simulated 32.2-km cycling time trial. The time trial was conducted in a thermoneutral environment to separate CNS depressive effects of the melatonin from the cooling effects. Trained male subjects (n = 10; V[Combining Dot Above]O2max = 62.7 +/- 6.3 ml.kg.min; age = 25.1 +/- 4.0 years; mass = 69.9 +/- 9.1 kg; height = 176.0 +/- 7.1 cm) performed three 32.2-km time trials on an electronically braked cycle ergometer. The first trial was a familiarization. During the 2 experimental trials, subjects received in a random order either a placebo or a 5-mg melatonin supplement 15 minutes before exercise in a double-blind, crossover design. Variables were measured before exercise and at 8-km intervals. The mean 32.2-km time trial completion times for the melatonin (64.94 +/- 5.95 minutes) and placebo (65.26 +/- 6.85 minutes) trials were not different (p = 0.682). The mean time trial power output for the melatonin (190.4 +/- 40.4 watts) and placebo (190.0 +/- 45.7 watts) trials was not different (p = 0.927). Rectal temperature was not significantly different for melatonin compared with placebo (p = 0.827). These results suggest that a 5-mg melatonin supplement administered 15 minutes before exercise does not measurably impact the performance of a 32.2-km cycling time trial in a thermoneutral environment. PMID- 28557858 TI - Effects of Combined Strength and Sprint Training on Lean Mass, Strength, Power and Sprint Performance in Masters Road Cyclists. AB - Strength and sprint training exercises are integral part of training in many younger endurance cyclists to improve cycling efficiency and sprinting ability. This study was undertaken to examine whether muscle and performance characteristics could be improved in endurance-trained masters cyclist by adding strength and sprint training stimuli into their training regimen. Twenty five masters road cyclists were assigned to a combined strength and sprint training group (CT; n=9, 53.5 +/- 9.3 years), a sprint training group (ST, n=7, 49.4 +/- 4.8 years) or a control group (CG, n=9, 56.9 +/- 8.6 years). Before and after the 12 week intervention, whole body lean mass (WBLM), total lower limb lean mass (LLLM), countermovement jump height (CMJ), peak isometric torque of quadriceps (QPT) and hamstring (HPT) muscles were examined. For evaluation of sport-specific performance, 10 second sprint cycling peak power (PP10), total 30 second work (TW), peak power output (PPO) and flying 200 meter time trial performance (TT) were assessed. No pre-training differences were observed between CT, ST and CG groups for any of the dependant variables. After training, a significant (p<0.05) between group difference was observed in TW between CT and CG groups. A significant effect of time (p<0.05) was observed for LLLM in CT and ST groups, and for TT in the CT group. These results suggest including strength and sprint exercises in training can increase lower limb lean mass and sprint performance in endurance trained masters road cyclists. Further research is warranted to find out an ideal pattern of training to maintain aerobic capabilities along with sprint performance in aging road cyclists. PMID- 28557859 TI - Beta-2 Adrenergic Receptor Genotype Influences Power Output in Healthy Subjects. AB - Kelley, EF, Johnson, BD, and Snyder, EM. Beta-2 adrenergic receptor genotype influences power output in healthy subjects. J Strength Cond Res 31(8): 2053 2059, 2017-The purpose of this study was to determine the effects of ADRB2 genotypes on muscle function (absolute power and relative power) in healthy subjects. We performed genotyping of the ADRB2 (amino acid 16) and high intensity, steady-state exercise on 77 healthy subjects (AA = 18, AG = 25, GG = 34). There were no differences between genotype groups in age, height, weight, or body mass index (BMI) (age = 28.9 +/- 5.7 years, 27.9 +/- 5.7 years, 29.2 +/- 5.9 years, height = 170.7 +/- 8.6 cm, 174.9 +/- 8.7 cm, 173.4 +/- 9.6 cm, weight = 68.5 +/- 13.0 kg, 75.0 +/- 12.9 kg, 74.4 +/- 12.9 kg, and BMI = 23.4 +/- 3.9, 24.4 +/- 2.9, 24.7 +/- 3.4, for AA, AG, and GG, respectively). The genotype groups differed significantly in watts, and watts/V[Combining Dot Above]O2 with heavy exercise (watts = 186.3 +/- 54.6, 237.8 +/- 54.4, 219.4 +/- 79.5, watts/V[Combining Dot Above]O2 = 0.08 +/- 0.006, 0.09 +/- 0.005, 0.08 +/- 0.006). There was a trend toward significance (p = 0.058) for W.kg (2.7 +/- 0.4, 3.2 +/- 0.5, 2.9 +/- 0.8, for AA, AG, and GG, respectively). These data suggest that genetic variation of the ADRB2 may influence relative strength in healthy subjects and may become an important genetic determinant of muscular strength and functional capacity in patients with diseases that result in a loss of muscle strength. PMID- 28557860 TI - Applying the ACSM Preparticipation Screening Algorithm to U.S. Adults: National Health and Nutrition Examination Survey 2001-2004. AB - PURPOSE: For most people, the benefits of physical activity far outweigh the risks. Research has suggested that exercise preparticipation questionnaires might refer an unwarranted number of adults for medical evaluation before exercise initiation, creating a potential barrier to adoption. The new American College of Sports Medicine (ACSM) prescreening algorithm relies on current exercise participation; history and symptoms of cardiovascular, metabolic, or renal disease; and desired exercise intensity to determine referral status. Our purpose was to compare the referral proportion of the ACSM algorithm to that of previous screening tools using a representative sample of U.S. adults. METHODS: On the basis of responses to health questionnaires from the 2001-2004 National Health and Nutrition Examination Survey, we calculated the proportion of adults 40 yr or older who would be referred for medical clearance before exercise participation based on the ACSM algorithm. Results were stratified by age and sex and compared with previous results for the ACSM/American Heart Association Preparticipation Questionnaire and the Physical Activity Readiness Questionnaire. RESULTS: On the basis of the ACSM algorithm, 2.6% of adults would be referred only before beginning vigorous exercise and 54.2% of respondents would be referred before beginning any exercise. Men were more frequently referred before vigorous exercise, and women were more frequently referred before any exercise. Referral was more common with increasing age. The ACSM algorithm referred a smaller proportion of adults for preparticipation medical clearance than the previously examined questionnaires. CONCLUSIONS: Although additional validation is needed to determine whether the algorithm correctly identifies those at risk for cardiovascular complications, the revised ACSM algorithm referred fewer respondents than other screening tools. A lower referral proportion may mitigate an important barrier of medical clearance from exercise participation. PMID- 28557861 TI - HeartMate 3 in Lowest INTERMACS Profile Cohort: The Swiss Experience. AB - New generation devices for long-term mechanical circulatory support are centrifugal pumps having fully magnetically levitated rotors to reduce blood trauma. Recently, the novel HeartMate 3 was cleared for clinical application in Switzerland. In two Swiss University Hospitals part of the "Lausanne-Geneva Transplantation Network," 10 consecutive patients in end-stage heart failure received the HeartMate 3 (Thoratec Corporation, Pleasanton, CA). Device implantation criteria were persistent low output syndrome despite optimal medical treatment. The primary end-point of the study was survival or transplantation to 90 days on the device. Five patients (50%) were in Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) class 1 and 2 (two were under venoarterial extracorporeal membrane oxygenation [VA-ECMO]), and five were in class 3 and 4. The indication was bridge-to-transplant in seven patients, and destination therapy in three. Two patients (20%) received concomitant aortic valve surgery. Four patients (40%) required temporary right ventricle support (tRVAD) for a mean of 8 +/- 1.5 days. Bleeding requiring surgical revision occurred in five (50%) patients, two during the tRVAD support. At the 90 day end point, survival was 90%, one (10%) died due to respiratory failure. Three (30%) experienced critical illness polyneuropathy. Two had body temperature over 38.5 degrees C for more than 7 days after implant, without infections. Two (20%) had late driveline infection. The pump allowed rapid improvement of patients' clinical conditions even in severely compromised patients. Postoperative bleeding occurred in the setting of anticoagulation. No hemolysis or pump thrombosis occurred. Fever occurred frequently but was not associated with mortality. Hemodynamic support was consistent over time without significant adverse events. PMID- 28557862 TI - Quantification of Postmembrane Gaseous Microembolization During Venoarterial Extracorporeal Membrane Oxygenation. AB - Prolonged use of venoarterial extracorporeal membrane oxygenation (VA ECMO) may be complicated by end-organ dysfunction. Although gaseous microemboli (GME) are thought to damage end organs during cardiopulmonary bypass, patient exposures to GME have not been well characterized during VA ECMO. We therefore performed an observational study of GME in adult VA ECMO patients, with correlation to clinical events during routine patient care. After institutional review board (IRB) approval, we used two Doppler probes to detect GME noninvasively in extracorporeal membrane oxygenation (ECMO) circuits on four patients for 15 hours total while also recording patient care events. We then conducted in vitro trials to compare Doppler signals with gold-standard measurements using an Emboli Detection and Classification EDAC quantifier (Luna Innnovations, Inc. Roanoke, VA) (Terumo Cardiovascular, Ann Arbor, MI) during simulated clinical interventions. Correlations between Doppler and EDAC data were used to estimate GME counts and volumes represented by clinical Doppler data. A total of 503 groups of Doppler peaks representing GME showers were observed, including 194 statistically larger showers during patient care activities containing 92% of total Doppler peaks. Intravenous injections accounted for an estimated 68% of GME and 88% of GME volume, whereas care involving movement accounted for an estimated 6% of GME and 3% of volume. Overall estimated embolic rates of 24,000 GME totaling 4 MUl/hr rivals reported GME rates during cardiopulmonary bypass. Numerous GME are present in the postmembrane circuit during VA ECMO, raising concern for effects on microcirculation and organ dysfunction. Strategies to detect and minimize GME may be warranted to limit embolic exposures experienced by VA ECMO patients. PMID- 28557864 TI - STELLATE NONHEREDITARY IDIOPATHIC FOVEOMACULAR RETINOSCHISIS: RESPONSE TO TOPICAL DORZOLAMIDE THERAPY. AB - PURPOSE: To report the clinical course of a patient presenting with stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR) in response to topical Dorzolamide treatment. METHODS: Case report, with multimodal imaging findings, including spectral domain optical coherence tomography and fluorescein angiography. Topical Dorzolamide Hydrochloride 2% drops were used three times per day in the affected eye. RESULTS: We identified a 27-years-old male patient who presented with 1-week history of decreased vision in his left eye. Spectral domain optical coherence tomography of the affected eye showed macular splitting of the inner plexiform layer and outer plexiform layer involving the fovea with no other evidence of a hereditary or acquired predisposing condition. The patient was started on the topical treatment for 6 months with visual improvement from 20/40 to 20/30 in the left eye, after which the decision to stop topical dorzolamide therapy was made. On 3 months of follow-up, visual acuity decreased back to 20/40 in the left eye with an increase in retinal thickening on spectral domain optical coherence tomography. Topical dorzolamide was restarted three times per day in the left eye. At 1-year point after restarting treatment, visual acuity was 20/20 in the left eye, with resolved inner plexiform layer and outer plexiform layer splitting on spectral domain optical coherence tomography in the left eye. CONCLUSION: Stellate nonhereditary idiopathic foveomacular retinoschisis can be a devastating problem causing decrease in vision. To the best of our knowledge, this is the first case in the literature to report the complete resolution of SNIFR in response to topical dorzolamide hydrochloride 2% therapy. Further prospective studies are vital to better elucidate our understanding of this new disease identity. PMID- 28557863 TI - Pediatric Extracorporeal Life Support Organization Registry International Report 2016. AB - The purpose of this report is to describe the international growth, outcomes, complications, and technology used in pediatric extracorporeal life support (ECLS) from 2009 to 2015 as reported by participating centers in the Extracorporeal Life Support Organization (ELSO). To date, there are 59,969 children who have received ECLS in the ELSO Registry; among those, 21,907 received ECLS since 2009 with an overall survival to hospital discharge rate of 61%. In 2009, 2,409 ECLS cases were performed at 157 centers. By 2015, that number grew to 2,992 cases in 227 centers, reflecting a 24% increase in patients and 55% growth in centers. ECLS delivered to neonates (0-28 days) for respiratory support was the largest subcategory of ECLS among children <18-years old. Overall, 48% of ECLS was delivered for respiratory support and 52% was for cardiac support or extracorporeal life support to support cardiopulmonary resuscitation (ECPR). During the study period, over half of children were supported on ECLS with centrifugal pumps (51%) and polymethylpentene oxygenators (52%). Adverse events including neurologic events were common during ECLS, a fact that underscores the opportunity and need to promote quality improvement work. PMID- 28557865 TI - The emerging role of proprotein convertase subtilisin/kexin type-9 inhibition in secondary prevention: from clinical trials to real-world experience. AB - PURPOSE OF REVIEW: The recent advent of a highly efficacious class of low-density lipoprotein cholesterol (LDL-C) lowering agents, the proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors, has transformed dyslipidaemia management in patients with cardiovascular disease as well as those with familial hypercholesterolemia. RECENT FINDINGS: Recent positive results of the landmark Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk cardiovascular outcome trial with evolocumab as an add-on to statin therapy demonstrate further reduction of cardiovascular events. Additional safety outcomes from this large randomized trial, as well as the EBBINGHAUS substudy, allay fears of neurocognitive disorder as an adverse effect of achieving very low LDL-C levels with these agents. SUMMARY AND IMPLICATIONS: Widespread clinical adoption of PCSK9 inhibitors will depend on the results from ongoing and planned cardiovascular efficacy and safety trials with PCSK9 inhibitors. In addition, understanding the practical challenges and barriers to usage of these injectable agents by high cardiovascular risk patients will also affect clinical adoption of this class of agents. Analysis of cost-benefit models, along with anticipated updates to practice guidelines for dyslipidaemia management are likely to strengthen the clinical utility of PCSK9 inhibitors. Importantly, the potency of this new class of agents provides a huge opportunity to extend further the 'lower LDL-C is better' hypothesis in an effort to reduce rates of cardiovascular morbidity and mortality on a population level. PMID- 28557866 TI - Imaging adult patients with discrete subvalvar aortic stenosis. AB - PURPOSE OF REVIEW: Distinction between discrete subvalvar aortic stenosis and other causes of left ventricular outflow obstruction has important implications for predicting natural history and guiding the timing and type of intervention. Imaging, primarily transthoracic echocardiography (TTE), plays a pivotal role in the diagnosis and management of adults with subvalvar aortic stenosis. RECENT FINDINGS: Most systematic research on imaging of subvalvar aortic stenosis has focused on echocardiography. TTE, especially two-dimensional imaging with color and spectral Doppler, remains the main modality for delineation of the anatomic and hemodynamic features of subvalvar stenosis, associated anomalies and involvement of accessory mitral valve attachments to the subaortic septum or abnormally placed papillary muscles. Transesophageal echocardiography may provide more detailed definition of left ventricular outflow tract anatomy, including the presence and extension of the obstructive subaortic fibroelastic tissue onto the aortic or mitral valve, especially in patients with poor transthoracic windows. The clinical role for advanced imaging technologies, including three-dimensional echocardiography, cardiac magnetic resonance and computed tomography, is evolving but, largely because of the adequacy of established imaging with TTE, remains relatively limited. SUMMARY: In the absence of other congenital heart defects or alternative indications (e.g. coronary angiography), TTE is usually adequate for the assessment of discrete subvalvar aortic stenosis in the adult. In specific clinical situations, supplemental imaging modalities can play an integral role in clinical decision making. PMID- 28557867 TI - Rapid Communication: Solution for the MEEK Glue Transfer Problem. AB - Meek micrografting permits wide expansion of skin grafts in true ratios from 3:1 to 9:1, as well as the utilization of poor donor sites. The proprietary glue critical to successful skin transference is unavailable in the United States. While the technique is widely employed worldwide, alternative glues resulted in poor skin transfer and frustrated use in American burn centers. The authors present their protocol resulting in effective MEEK skin transfer using Mastisol(r) adhesive: "The Rule of Sevens." 1) Soak the corks in normal saline for 7 minutes. 2) Then spread the grafts on the corks and mince with the MEEK machine. 3) Spray the epidermal surface of the micrograft-covered corks thoroughly with 7 pumps of Mastisol(r) from a distance of 7 inches (17.7 cm). 4) Allow the Mastisol(r) to dry for 7 minutes on the micrografts. 5) Apply the corks with the Mastisol(r)-imbued skin to the gauzes. Press firmly for 7 seconds. 6) Allow the skin to transfer from cork to gauze undisturbed for 7 minutes. Next, carefully remove the corks and expand the gauzes. Apply the micrograft-covered gauzes to excised and prepared wound beds and staple into position. 7) After 7 days, remove the gauzes, though the authors have left them in place for up to 21 days. This novel protocol provides reliable skin transfer and permits the modified MEEK technique to be a consistent part of our practice. The authors present this rapid communication to allow others to utilize this technique without the frustration of adhesive failure resulting in lost grafts. PMID- 28557868 TI - Application of Three - dimensional Wound Analyzer in the Small Wound Area Measurement during the Process of Wound Healing. AB - The objective of this study was to determinate the reliability of 3-dimensional wound analyzer (3-DWMD) in the wound area measurement for animal small area in the process of wound healing. Seven Sprague-Dawley rats were used to establish the skin defect model. And the wound area and time consumption were measured on days 0, 5, 10, 15 using 3-DWMD, investigators, and planimetry method. The measurement results using 3-DWMD and investigators were analyzed comparative with that using planimetry method separately. A total 46 wounds, including 32 irregular wounds and regular 14 wounds, were measured. No matter calculating the irregular wounds or the regular wounds, there was no significant difference between 3-DWMD group and planimetry group in measuring wound area (P > 0.05). However, a statistically significant difference was found in time-consuming for measuring wound area between 3-DWMD group and planimetry group (P < 0.001). The same result was found between investigator group and planimetry group (P < 0.001). The 3-DWMD would quickly and accurately obtain the wound area, and its measurement results were consistent with planimetry method. Therefore, such measuring equipment has clinical reference value for measuring precision area of the wound in the process of wound healing. PMID- 28557870 TI - In Situ Delivery of Fibrin-Based Hydrogels Prevents Contraction and Reduces Inflammation. AB - While early excision and grafting has revolutionized burn wound care, autologous split-thickness skin grafts are sometimes unavailable. Tissue-engineered skin substitutes have generated great interest but have proven inadequate. Therefore, the development of novel biomaterials to replace/augment skin grafting could improve burn patient outcomes. Herein, we establish the effects of debridement on deep-partial thickness burns and subsequently examine the effects of 3 different hydrogels on healing. Burns were created on the dorsum of pigs and 4 days after, the eschar was either left intact or debrided for treatment with collagen, PEGylated fibrinogen (PEG-fibrin) or PEGylated autologous platelet-free plasma (PEG-PFP) hydrogels. Wounds were photographed, scored, and biopsied for histology on postburn days 7, 10, 14, and 28. Compared with nondebrided wounds, debridement improved wound color and suppleness but accelerated contraction. Debridement also significantly reduced the number of neutrophils in the wound bed at days 10 and 14 postburn. Treatment with any hydrogel transiently mitigated contraction, with the PEG-fibrin group displaying less contraction on day 28. All hydrogels were visible histologically for up to 10 days, with significant cellular and blood vessel infiltration observed in PEG-fibrin hydrogels. Collagen and PEG-fibrin hydrogels reduced neutrophils and macrophages in surrounding granulation tissue on day 7, while PEG-fibrin hydrogels contained less immune cells. These data suggest that a single hydrogel application at the time of debridement has immunomodulatory properties that aid in wound healing. Ultimately, these hydrogels may be combined with other biomaterials, cells, or biologics for replacing/augmenting skin substitutes. PMID- 28557869 TI - A Prospective, Randomized, Controlled Trial Comparing the Outpatient Treatment of Pediatric and Adult Partial-Thickness Burns with Suprathel or Mepilex Ag. AB - Modern treatment of partial-thickness burns follows the paradigm of less frequent dressing changes to allow for undisturbed reepithelialization of the burn wound. We compared Mepilex Ag (M), a silver-impregnated foam dressing, and Suprathel (S), a DL-lactid acid polymer, in the outpatient treatment of partial-thickness burns in pediatric and adult patients. Patients were enrolled in a randomized, controlled, prospective clinical trial. We monitored time to reepithelialization, wound pain, discomfort during dressing changes, and treatment cost. Objective scar characteristics (elasticity, transepidermal water loss, hydration, and pigmentation) and subjective assessments (Patient and Observer Scar Assessment Scale) were measured at 1 month post burn. Data are presented as mean +/- SEM, and significance was accepted at P < 0.05. Sixty-two patients (S n = 32; M n = 30) were enrolled; age, sex, and burn size were comparable between the groups. Time to reepithelialization was not different between the groups (12 days; P = 0.75). Pain ratings were significantly reduced during the first 5 days after burn in the Suprathel group in all patients (P = 0.03) and a pediatric subgroup (P < 0.001). Viscolelasticity of burned skin was elevated compared with unburned skin in the Mepilex Ag group at 1 month post burn. Patients treated with Suprathel reported better overall scar quality (S: 2; M: 4.5; P < 0.001). The cost of treatment per square centimeter for Mepilex Ag was considerably lower than that of Suprathel. Both dressings are feasible and efficacious for the outpatient treatment of minor and selected moderate partial-thickness burns. Reduced pain, especially in a pediatric patient population, may be advantageous, despite increased treatment cost. PMID- 28557871 TI - Epidemiology and Outcomes of Auricular Burn Injuries. AB - Auricular burns represent a unique type of injury. The acute management and clinical course of these injuries can be different from other facial burns. There is a paucity of literature pertaining to the epidemiology and acute management of auricular burns. Most studies focus on deformity reconstruction. The aim of this study was to characterize the epidemiology, treatment, and outcomes of auricular burns. Data from all patients presenting to a regional burn center in a 4-year period were reviewed and those with auricular burns were identified. Demographic data, burn mechanism, insurance status, method of treatment, need for skin grafting, percentage graft-take, time to reepithelialization and incidence of deformity were reviewed. During the study period, 593 facial burns were evaluated and 132 (22%) sustained burns to the auricle. The most common mechanisms of injury were flame (65.1%) and scalding (22.5%). Auricular burns were mostly second degree (88%), involved both ears in 44%, and involved only the ventral aspect of the ear in 57%. The majority of patients healed well with conservative management; none suffered from chondritis. Of the 89 patients followed to healing, 1 patient (1.1%) received full-thickness skin grafts to the auricle, resulting in excellent graft-take. All other patients were managed nonoperatively, and none suffered from ear deformities. Auricular burns occur with surprising frequency in patients presenting to burn centers. Careful acute management of these injuries can eliminate development of chondritis and minimize the rate of deformity and need for reconstruction. The majority of wounds heal with conservative management, but time to reepithelialization can be prolonged. PMID- 28557872 TI - Learn to Focus in a World of Multitasking. AB - Case managers' days are hectic and unpredictable. This Editorial describes why multitasking may not be the best choice and identifies techniques and attitudes for smoothing out hectic days. PMID- 28557873 TI - Utilization of the Health Care System of Community Case Management Patients. AB - PURPOSE OF STUDY: The has reduced payments to hospitals that have excessive readmissions. This mandate has made it imperative for hospitals to implement a plan to manage readmissions and transitions of care for patients they serve. The purpose of this study was to ascertain whether an advanced practice, nurse-led, community-based model is effective in reducing acute health care utilization. PRIMARY PRACTICE SETTING: The community case management (CCM) program was created more than 20 years ago to assess and manage care of patients demanding frequent emergency department (ED) visits and frequent hospitalizations, by providing in home visits and care coordination by an advanced practice nurse or masters prepared nurse. METHODOLOGY AND SAMPLE: The charts of 307 patients who were referred to CCM were reviewed to assess their utilization of the health care system after referral. There were 2 groups of patients: those who accepted CCM services (N = 151) and those who refused CCM services (N = 156) upon referral. RESULTS: It was found that if patients accepted CCM services, they had 55% fewer visits to the ED and 61% fewer hospital admissions than patients who refused CCM services. Utilization of urgent care was decreased by 47% in the patients who accepted CCM services, but this decline was not statistically significant. IMPLICATION FOR CASE MANAGEMENT PRACTICE: The results of this study indicate that CCM is effective in decreasing hospital admissions and ED visits for the patients using CCM services. Implementing a CCM program could be an effective method for decreasing utilization of the hospital and ED by adult patients with at least 1 chronic disease. PMID- 28557874 TI - Partnerships in Transitions: Acute Care to Skilled Nursing Facility. AB - PURPOSE/OBJECTIVES: Older adults, in particular those discharged to skilled nursing facilities (SNFs), are at high risk for readmission. As part of a multifaceted approach to reduce readmissions, a community hospital initiated a 3 prong approach (Collaboration, Communication, and Competency) and partnered with regional SNFs. PRIMARY PRACTICE SETTINGS: El Camino Hospital, an independent, locally owned, not-for-profit district, acute care hospital in Northern California, and 11 participating SNFs in the same region. FINDINGS/CONCLUSIONS: Collaboration: The combined leadership team developed a case report form and instituted regular reviews of 7-day readmissions. Communication: Standardized form for transferring patients to SNFs, form for transfer from SNF to emergency department, and consent form to enable SNFs to administer antipsychotic medications were developed. Regular phone and video conferencing between clinicians at the hospital and receiving SNF were instituted. Competency: Educational series to recognize and intervene to prevent readmission, and mutual exchange of best practices among hospital and SNF staff, were instituted. Continued work among ECH and the participating SNFs has improved the flow of information in both directions; favorable results from the broader study to reduce readmissions hospital-wide provide support for these efforts. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Initiating collaboration with the SNFs is imperative in the changing health care landscape. Because of the complexity of the problem, acute care facilities and SNFs need to create a partnership to ensure smooth patient transition. Communication between care settings is essential in achieving optimum patient outcomes. PMID- 28557875 TI - Supporting the Support System: How Assessment and Communication Can Help Patients and Their Support Systems. AB - PURPOSE/OBJECTIVE: The benefits of having a support system, such as social relationships with close friends and family, have been well documented for patients with serious health issues. As scientific evidence has shown, individuals who have the lowest level of involvement in social relationships face a greater mortality risk. Support systems, however, are not infallible. Relationship stress can have a negative impact on people-patient and caregiver alike-behaviorally, psychosocially, and physiologically. The purpose of this article is to encourage case managers who take a patient-centered approach to also consider the existence and extent of the support system, as well as any stresses or tensions that are observable within the support system. Although the case manager is ethically obliged to advocate for the individual receiving case management services, that advocacy can be extended to the support system for the good of all. PRIMARY PRACTICE SETTINGS: This discussion applies to numerous case management practices and work settings including (but not limited to) hospital based case management, home health, geriatrics, catastrophic case management, mental health, palliative care, and end of life/hospice. FINDING/CONCLUSIONS: As part of the assessment phase of the case management process, case managers determine the extent of the patient's support system or social support network such as family and close friends. Although their advocacy is primarily for the patient receiving case management services, case managers also become aware of the needs of the support system members as they face their loved one's serious illness, severe injury, geriatric care demands, or end of life. Case managers can use their communication skills, especially motivational interviewing, with patients and their support systems to identify stresses and issues that can impact the pursuit of health goals. In addition, case managers ensure that individuals and their support systems are kept informed such as about the health condition, stage of disease, plan of care, treatment options, and care transition plan. IMPLICATIONS FOR CASE MANAGEMENT: Professional case managers expand their role as advocates, serving primarily the patients ("clients") who receive case management services and also members of the support system. By becoming more aware and sensitive to the needs of the support system, case managers help reduce stress on the support system, which can contribute to positive outcomes for patients ("clients"). PMID- 28557876 TI - Case Management Competence: Reframing What Defines Practice Excellence. PMID- 28557877 TI - Case Managers Facing Legal Challenges: Application of the Standards of Practice. PMID- 28557878 TI - Addressing the Needs of the Support System. PMID- 28557879 TI - Improving Patient Self-Care and Reducing Readmissions Through an Outpatient Heart Failure Case Management Program. PMID- 28557882 TI - General Psychiatric Management for Suicidal Patients, With Remarks on Chronicity: Contending With the Angel of Death. AB - Assessing, managing, and treating suicidal patients, particularly those with chronic suicidality, challenge clinical decision making and emotional self management in trainees and seasoned practitioners. Educators and trainees have noted needs for additional teaching materials in these areas. This article assists in addressing these gaps. We reviewed diagnostic and phenomenological characteristics encountered in acutely and chronically suicidal patients, their comprehensive assessment, general approaches to management, risk mitigation and safety planning, and psychological and biological interventions. Integrating information from research and clinical experience-based literature, we offer concise guidance on comprehensive psychiatric management for the varieties of acutely and chronically suicidal patients encountered in practice. By actively engaging suicidal patients and their families, systematically attending to warning signs, conducting risk mitigation and safety planning, and using psychological and biological treatments as indicated, clinicians are likely to reduce suicidal ideation, plans, and attempts in patients and might reduce completed suicides. PMID- 28557883 TI - Pancreatic Cancer and Depression: A Narrative Review. AB - Depression is a common concomitant of pancreatic cancer, and, because it often occurs before the cancer is diagnosed, its occurrence is likely to be intrinsic to the condition rather than a reaction to such a diagnosis. Because pancreatic cancer is associated with a very high mortality, its early detection is a key task. We therefore review relevant literature to determine whether the depression is prototypically distinctive and whether its identification might lead to earlier diagnosis of pancreatic cancer. We report on the epidemiology and prognosis of pancreatic cancer and on the prevalence, description, and possible mechanisms involved for the occurrence of any associated depressive state, before reviewing the comparative utility of depression in relation to other risk factors in aiding diagnosis. Published studies fail to identify any distinct depressive prototypic phenotype to depression associated with pancreatic cancer. Although it is a relatively common concomitant of pancreatic cancer, the utility of depression as a marker of the condition is not suggested from a key study evaluating its contribution in relation to other symptoms and risk factors. PMID- 28557884 TI - From Whom Do Student Veterans Seek Help?: Understanding the Roles of Professional, Informal, and Religious Sources. AB - The purpose of this brief report was to ascertain student veterans' patterns of help-seeking from professional, informal, and religious sources. In total, 350 veterans from an academic institution on the Gulf Coast completed assessments of help-seeking intentions from a range of potential sources in their communities. Analyses revealed that veterans had a neutral probability to seek help from professional sources (e.g., physicians and psychologists) but were likely to pursue informal sources (e.g., partner/spouse, friend) in a psychological/emotional crisis. However, when compared with their nonclinical counterparts, veterans with a probable need for treatment for PTSD and/or depression generally reported less probability to seek help from informal and religious sources. In addition, sex, ethnicity, and religious background each contributed a significant influence in shaping preferences for seeking help for psychological or emotional concerns. Given unmet mental health needs of student veterans, findings highlight the importance attending to help-seeking preferences in this growing population. PMID- 28557886 TI - Extrasensory Perception Experiences and Childhood Trauma. PMID- 28557885 TI - Patient, Provider, and System Factors Contributing to Patient Safety Events During Medical and Surgical Hospitalizations for Persons With Serious Mental Illness. AB - This study aimed to explore patient-, provider-, and system-level factors that may contribute to elevated risk of patient safety events among persons with serious mental illness (SMI). We conducted a medical record review of medical/surgical admissions in Maryland hospitals from 1994 to 2004 for a community-based sample of adults with SMI (N = 790 hospitalizations). We estimated the prevalence of multiple patient, provider, and system factors that could influence patient safety among persons with SMI. We conducted a case crossover analysis to examine the relationship between these factors and adverse patient safety events. Patients' mental status, level of consciousness, disease severity, and providers' lack of patient monitoring, delay/failure to seek consultation, lack of trainee supervision, and delays in care were positively associated with adverse patient safety events (p < 0.05). Efforts to reduce SMI related patient safety risks will need to be multifaceted and address both patient- and provider-level factors. PMID- 28557887 TI - Commentary on "Extrasensory Perception Experiences and Childhood Trauma". PMID- 28557888 TI - Foreword. PMID- 28557889 TI - Introduction to the Anatomy and Physiology of Pulmonary Circulation. AB - In the United States, venous thromboembolism is associated with high mortality and morbidity affecting as many as 900 000 people (1-2 per 1000) each year. Estimates suggest that 60 000 to 100 000 Americans die of deep venous thrombosis/pulmonary embolism and 10% to 30% die within 1 month of diagnosis, with sudden death being the first symptom in approximately 25% of population with pulmonary embolism. One-half of the patients with deep venous thrombosis will have postthrombotic syndrome, which includes swelling, pain, discoloration, and scaling in the affected limb. Approximately 33% of patients will have a recurrence within 10 years. It is important to understand the anatomy of the pulmonary circulation and the pathophysiology of the disease as it leads to understanding of the potential devastating clinical consequences. PMID- 28557890 TI - Pathogenesis and Epidemiology of Venous Thromboembolic Disease. AB - Venous thromboembolism is the formation of a blood clot in the vein. It mainly consists of 2 life-threatening conditions-deep venous thrombosis and pulmonary embolism. Deep venous thrombosis is a potentially dangerous condition with grave sequelae, the worst of which is pulmonary embolism. Venous thromboembolism can also lead to multiple other conditions with significant morbidity and mortality that include extension of thrombi, pulmonary hypertension, recurrence, and postthrombotic syndrome. An update on the epidemiology, etiology, and pathogenesis of venous thromboembolism will be reviewed in this article. PMID- 28557891 TI - Clinical Presentation and Risk Factors of Venous Thromboembolic Disease. AB - Venous thromboembolism (VTE) has a wide range of clinical presentations. Deep venous thrombosis may occur in upper or lower extremities or in visceral veins. Extremity deep venous thrombosis usually manifests with unilateral painful swelling in the limb, while visceral deep venous thrombosis manifestations vary on the basis of the involved organ. Pulmonary embolism classically manifests with sudden pleuritic chest pain and unexplained dyspnea. Superficial thrombophlebitis usually presents with acute inflammation around a palpable thrombosed superficial vein. Risk factors of VTE are either inherited or acquired. The inherited causes of VTE tend to be familial and more common in younger patients. The common acquired risk factors of VTE include previous history of venous thrombosis, immobilization, recent surgery or trauma, malignancy, and pregnancy. Identifying high-risk patients for VTE based on these risk factors is the cornerstone to provide the prophylactic treatment to prevent thrombotic events. PMID- 28557892 TI - Diagnostic Considerations of Venous Thromboembolic Disease. AB - Venous thromboembolism (VTE) includes deep venous thrombosis (DVT) and pulmonary embolism (PE). The clinical presentation of VTE is nonspecific and requires confirmatory testing. The most common diagnostic tool for DVT is duplex ultrasonography since it is a noninvasive test with high accuracy. Contrast venography is considered the gold standard modality to diagnose DVT, but it is an invasive test. Magnetic resonance venography and computed tomography venography are alternative diagnostic methods for DVT, which can be helpful in certain circumstances. Pulmonary embolism is commonly diagnosed by computed tomography pulmonary angiography. Ventilation perfusion scanning is an alternative imaging to diagnose PE in patients who cannot receive intravenous contrast. Pulmonary angiography is still the gold standard in the diagnosis of PE and is usually needed in specific conditions. D-dimer assay can be utilized in ruling VTE out in low-risk patients. Estimating the pretest clinical probability for having VTE is the key step in guiding the clinicians and nurses to the appropriate diagnostic method for patients with suspected DVT or PE. PMID- 28557893 TI - Prophylaxis for Venous Thromboembolism. AB - Venous thromboembolisms are major risk factors for many of our hospitalized patients. These events, however, can be prevented with prophylactic measurements when administered appropriately and on a timely basis. As patients are admitted, discharged, transferred, and scheduled for procedures on an hourly basis, anticoagulation and deep vein thrombosis prophylaxis are held or discontinued in anticipation for possible procedures. This results in delay of care and intervals where patients may not be covered with any prophylactic measurements. Similarly, alterations in clinical status can quickly change such as an increase in creatinine levels or the development of a new bleed, thus requiring a revision in their deep vein thrombosis prophylaxis. Nurses, therefore, play an integral role in not only administering the medicine but also routinely assessing the patients' clinical status and, therefore, their deep vein thrombosis prophylactic regimens as well. This article will review the indications, scoring systems, common prophylactic methods, and special populations at increased risks for venous thromboembolisms. PMID- 28557894 TI - Deep Venous Thrombosis of the Upper and Lower Extremity. AB - Upper and lower extremity deep venous thrombosis (DVT) is defined as a blood clot within the deep veins of the affected extremities. These blood clots can either occur spontaneously or be associated with specific risk factors. Regardless of the cause, DVT is associated with significant morbidity and mortality and has the potential for lethal complications. The most notable complication is the potential for development of pulmonary embolism from a lower extremity DVT. As studies have reported, more than 90% of acute pulmonary emboli arise from the proximal veins. Venous thromboembolism is also associated with a significant economic burden on the health care system and the individual patient. In this article, we review DVT of the upper and lower extremity including risk factors, signs and symptoms, diagnosis, and management. PMID- 28557895 TI - Venous Thromboembolism and Pulmonary Embolism Response Teams: An Overview. AB - Venous thromboembolism is a common disease with a wide array of signs and symptoms. It has been cited as the third leading cause of cardiovascular death, and if left untreated, it leads to death in 1 in 4 patients. Sophisticated diagnostic tools have allowed physician to become more accurate in diagnosing pulmonary embolism and deep vein thrombosis. The advent of new oral anticoagulants, the emergence of pulmonary embolism response teams, and protocols demonstrate recent achievements in the management of venous thromboembolism. The focus of this article is to discuss the treatment of venous thromboembolism. PMID- 28557896 TI - Advanced Therapies in Venous Thromboembolism. AB - Advanced therapies are available for both deep venous thrombosis and pulmonary embolism when anticoagulation alone is not sufficient to improve clinical outcomes. In some cases, clinical deterioration ensues despite anticoagulation, and this requires unique techniques that can ameliorate the clinical course. Such advancements are described in this upcoming article. PMID- 28557897 TI - Consequences of Venous Thromboembolism, Including Chronic Thromboembolic Pulmonary Hypertension. AB - Venous thromboembolism includes both deep vein thrombosis and pulmonary embolism. They pose a significant risk for morbidity and mortality. In an appropriate clinical setting, invasive interventions, including administration of thrombolytics, anticoagulation, and placement of vena cava filter, are warranted. Bleeding, postthrombotic syndrome, recurrence, and filter-associated complications are few of the complications of this disease. More recently, chronic thromboembolic pulmonary hypertension has gained clinical interest in patients with pulmonary embolism and has warranted close follow-up. PMID- 28557898 TI - Special Circumstances and Populations. AB - Venous thromboembolism is a condition that includes both deep venous thrombosis and pulmonary embolism. Venous thromboembolism disease can result because of a combination of risk factors, including patient-related, treatment-related, and, more specifically, cancer-related factors. It is not disease-specific or a population-specific disorder, but it is more prevalent in certain specialty populations. This article will cover those specialty populations including cancer, pregnancy, and athletes. PMID- 28557899 TI - Prognosis and Monitoring of VTE. AB - Venous thromboembolism (VTE) can present in a variety of different clinical settings and in a diverse, comorbid patient population, both of which will guide the clinician toward the appropriate therapeutic response. Patients who present with pulmonary embolism are at risk for hemodynamic instability, recurrence of VTE, cardiac comorbidities, and increased risk of overall mortality. Prognostication models have been clinically validated for risk stratification and prediction of mortality. Similar to pulmonary embolism, patients with deep vein thrombosis carry a higher risk of VTE recurrence and cardiac comorbidities. Consequently, VTE can be treated by a variety of methods such as anticoagulants or inferior vena cava filters, which bear their own risks and benefits. It is imperative that clinicians monitor patients for complications from VTE and the chosen therapy. PMID- 28557900 TI - Controversies in Venous Thromboembolism. AB - Numerous controversies exist in the diagnosis of venous thromboembolism despite all the guidelines that are currently available. Screening of malignancy in venous thromboembolism has been a debated issue, as it has not been shown to change mortality. Calf vein thrombosis is also a controversial topic, but evidence points to risk stratifying those patients. Overdiagnosis, most notably from the finding of subsegmental pulmonary embolism, ultimately requires evaluating the risk and benefit for each patient. In addition, treatment of upper extremity deep vein thrombosis is a challenging scenario that is quite common in clinical practice. Finally, postthrombotic syndrome may be reduced by graduated compression stockings, but their use has not been validated for preventive use at this time and is still being discussed. PMID- 28557901 TI - IMPROVING THE AGE-RELATED MACULAR DEGENERATION CONSTRUCT: A New Classification System. AB - Previous models of disease in age-related macular degeneration (AMD) were incomplete in that they did not encompass subretinal drusenoid deposits (pseudodrusen), subtypes of neovascularization, and polypoidal choroidal vasculopathy. In addition, Type 3 neovascularization starts in the retina and may not necessarily involve the choroid. As such, the term choroidal neovascularization is not appropriate for these eyes. The new aspects in the AMD construct are to include specific lipoprotein extracellular accumulations, namely drusen and subretinal drusenoid deposits, as early AMD. The deposition of specific types of deposit seems to be highly correlated with choroidal thickness and topographical location in the macula. Late AMD includes macular neovascularization or atrophy. The particular type of extracellular deposit is predictive of the future course of the patient. For example, eyes with subretinal drusenoid deposits have a propensity to develop outer retinal atrophy, complete outer retinal and retinal pigment epithelial atrophy, or Type 3 neovascularization as specific forms of late AMD. Given Type 3 neovascularization may never involve the choroid, the term macular neovascularization is suggested for the entire spectrum of neovascular disease in AMD. In contrast to older classification systems, the proposed system encompasses the relevant presentations of disease and more precisely predicts the future course of the patient. In doing so, the concept was developed that there may be genetic risk alleles, which are not necessarily the same alleles that influence disease expression. PMID- 28557902 TI - Cryopreserved Amniotic Membrane Improves Clinical Outcomes Following Microdiscectomy. AB - STUDY DESIGN: Prospective, randomized controlled trial. OBJECTIVE: To compare pain, physical/mental functional recovery and recurrent herniation for patients following lumbar microdiscectomy with and without the use of a cryopreserved amniotic tissue graft. SUMMARY OF BACKGROUND DATA: Although microdiscectomy procedures are routinely successful for patients with lumbar radiculopathy due to herniated disc disease, residual low back pain, and recurrent herniation remain unsolved clinical problems. METHODS: Following Investigated Review Board approval, 80 subjects were randomized in a 1:1 ratio to either receive cryopreserved amniotic (cAM) tissue or no tissue following elective lumbar microdiscectomy surgery. cAM grafts were applied to the annular defect at the conclusion of the procedure. Patients provided preoperative and postoperative clinical assessment data out to 24 months using the Oswestry Disability Index (ODI), Short Form-12 (SF-12) Health Survey, and Visual Analog Pain Scale for back and leg pain. Patients with symptomatic recurrent disc herniation were recorded. RESULTS: In total, 48 males and 32 females with an average age of 47.2 years were included. Mean ODI scores for subjects treated with cAM graft demonstrated statistically greater improvement at 6 weeks (14.49 vs. 21.82; P=0.05) and 24 months (6.62 vs. 14.40; P=0.02) compared with controls. Similarly, SF-12 Physical Component Scores demonstrated statistically greater gains in the cAM group at both the 6 weeks and 24 months. None of the subjects in the cAM graft group sustained a recurrent herniation at the same surgical level, whereas 3 patients in the control group sustained a recurrent herniation at the same surgical level, with 2 requiring fusion to manage persistent pain. CONCLUSIONS: The data demonstrate statistically superior clinical outcomes following lumbar microdiscectomy as measured by ODI and SF-12 (physical composite scale) and a lower rate of recurrent herniation with the use of a cAM tissue graft compared with traditional microdiscectomy. PMID- 28557903 TI - Functional Recovery Following Early Kyphoplasty Versus Conservative Management in Stable Thoracuolumbar Fractures in Parachute Jumpers: A Randomized Clinical Trial. AB - STUDY DESIGN: A randomized clinical trial. OBJECTIVE: To compare the functional recovery between early kyphoplasty and conservative care in paratroopers with stable thoracolumbar fractures. SUMMARY OF BACKGROUND DATA: Treatment of traumatic stable thoracolumbar fractures in young individuals is still a debate. Conservative management and kyphoplasty are options of therapy. But enough data are not available for supporting each. METHODS: We included 70 paratroopers with stable thoracolumbar fractures (A1 and A2 classification according to AOSpine thoracolumbar spine injury classification system) presenting <60 days after trauma and hyperintensity in T2-weighted magnetic resonance imaging. Old fractures and those requiring fixation were excluded. Patients were randomly assigned to 2 study groups to undergo percutaneous balloon kyphoplasty (n=34) or conservative care (n=36) by applying orthosis for 2 months. Patients were followed for 12 months and were evaluated clinically using visual analogue scale (VAS) and Oswestry disability index (ODI). RESULTS: The baseline characteristics were comparable between 2 study groups. The VAS score and ODI decreased significantly in both study groups after 12 months of treatment. The VAS score was significantly lower in kyphoplasty group after the intervention (P<0.001), 1 month (P<0.001), 3 months (P<0.001), 6 months (P<0.001), and 12 months (P<0.001) after the intervention. In addition, the ODI was significantly lower after the intervention (P<0.001), 1 month (P<0.001), 3 months (P<0.001), 6 months (P<0.001), and 12 months (P<0.001) after the intervention. Kyphoplasty was associated with shorter duration of returning to parachuting (P<0.001) and shorter duration of absence from work (P<0.001). CONCLUSIONS: Early kyphoplasty in stable thoracolumbar fractures after parachute jumping is associated with less pain, better functional recovery, less days of absence from work, and shorter duration of returning to parachuting. PMID- 28557904 TI - Characteristics of EEG Seizure-Onset Patterns Recorded From Subdural Electrodes Over MRI-Visible Frontal Focal Cortical Dysplasia Type IIb Lesions. AB - PURPOSE: Focal cortical dysplasia (FCD) is intrinsically epileptogenic, and an MRI-visible lesion typically constitutes the core part of the epileptogenic zone. We aimed to identify ictal EEG patterns that represent the epileptogenic zone by using subdural electrodes placed over the MRI-visible FCD lesion. METHODS: We selected seven patients with frontal lobe epilepsy caused by pathologically proven FCD type IIb who underwent preoperative intracranial EEG evaluation with subdural electrodes followed by resection surgery with seizure-free outcome. The characteristics of ictal EEG patterns, interictal/ictal high-frequency oscillations, and ictal direct current shifts from intracranial electrodes placed over the MRI-visible lesion were analyzed. RESULTS: Two seizure-onset patterns (low voltage fast activity and fast spike activity) were identified. Low voltage fast activity was seen in all patients with a lateral frontal lesion, and it was always preceded by preictal spikes. Fast spike activity occurred only in patients with a mesial frontal lesion. Interictal/ictal high-frequency oscillations and ictal direct current shifts were seen in all patients. CONCLUSIONS: The epileptogenic zone of frontal FCD type IIb may be characterized by EEG seizure onset patterns consisting of low voltage fast activity and fast spike activity accompanied by ictal high-frequency oscillations and ictal direct current shifts. Further study is needed to determine whether other seizure-onset patterns exist in patients with FCD type IIb. PMID- 28557905 TI - SSEP in Therapeutic Hypothermia Era. AB - PURPOSE: The reliability of somatosensory evoked potentials (SSEPs) in predicting outcome in comatose survivors of cardiac arrest treated with therapeutic hypothermia (TH) has been questioned. We investigated whether the absence of cortical (N20) responses was a reliable predictor of a nonawakening in the setting of TH. METHODS: A retrospective review was conducted in cardiac arrest survivors treated with TH admitted to a single tertiary care hospital from April, 2010 to March, 2013 who underwent SSEP testing at various time points after cardiac arrest. N20 responses were categorized as normal, present but abnormal, bilaterally absent, or inadequate for interpretation. Neurologic outcome was assessed at discharge by the Cerebral Performance Category Scale (CPC). RESULTS: Ninety-three SSEP studies were performed in 73 patients. Fourteen patients had absent N20 responses; all had poor outcome (CPC 4-5). Eleven patients had absent N20 s during hypothermia, three of whom had follow-up SSEPs after rewarming and cortical responses remained absent. Fifty-seven patients had N20 peaks identified and had variable outcomes. Evaluation of 1 or more N20 peaks was limited or inadequate in 11.4% of SSEPs performed during the cooling because of artifact. CONCLUSIONS: Somatosensory evoked potentials remain a reliable prognostic indicator in patients undergoing TH. The limited sample size of patients who had SSEP performed during TH and repeated after normothermia added to the effect of self-fulfilling prophecy limit the interpretation of the reliability of this testing when performed during cooling. Further prospective, multicenter, large scale studies correlating cortical responses in SSEPs during and after TH are warranted. Technical challenges are commonplace during TH and caution is advised in the interpretation of suboptimal recordings. PMID- 28557907 TI - Assessment Reconsidered: Finding the Balance Between Patient Safety, Student Ranking, and Feedback for Improved Learning. PMID- 28557906 TI - Ultrasound Imaging of Median Nerve Conduit in a Patient With Persistent Median Nerve Symptoms. AB - Peripheral nerve injury can be reconstructed using composite polymer nerve autografts, but the sonographic appearance of nerve wraps and conduits have not been well documented. This case report describes the sonographic findings in a 42 year-old woman with bilateral carpal tunnel syndrome status post nerve repair with a conduit. The cross-sectional area of the left median nerve was 24 mm at the carpal tunnel inlet and 5 mm at the forearm. The wrist to forearm ratio was 4.8. There was a hypoechoic space surrounding the nerve that was 1.8 to 1.9 mm thick and bordered by a thin, hyperechoic outer rim. On review of the operative record and consultation with her surgeon (DR), it was determined that this represented the 2-mm nerve wrap used in the last surgery. Inclusion of these structures with the median nerve measured a total area of 52 mm at its maximum. In describing this image, we hope to lay the foundation for describing the sonographic appearance of peripheral nerve repair. PMID- 28557908 TI - Emphasizing Primary Prevention in the Curriculum to Mitigate Prescription Drug Abuse. PMID- 28557909 TI - In Reply to Manion and Khan. PMID- 28557910 TI - Moving Towards a Mixed-Method Approach to Educational Assessments. PMID- 28557911 TI - More on Emotions in Medical Education and Practice. PMID- 28557912 TI - More on Emotions in Medical Education and Practice. PMID- 28557913 TI - It's Time to Increase Community Hospital-Based Health Research. PMID- 28557914 TI - Secondary Medical School Applications Place an Unfair Financial Burden on Middle- and Lower-Income Applicants. PMID- 28557915 TI - Using Video-Conference Interviews in the Residency Application Process. PMID- 28557916 TI - Streamlining the Medical School Admissions Process for Couples. PMID- 28557917 TI - The Ugly Truth About Multiple Mini-Interviews in Medical School Admissions. PMID- 28557918 TI - SOAP for Everyone: An Evolutionary Development of the Match. PMID- 28557919 TI - Medical School Admissions: An LGBTQ Perspective. PMID- 28557921 TI - Less Fantasy, More Reality: A Call for Humanistic Change in Medical School Admissions. PMID- 28557920 TI - The Match: A Numbers Game. PMID- 28557922 TI - Who Is a Medical Scientist Training Program Student? Interviewing for an MD-PhD as a "Nontraditional" Researcher. PMID- 28557923 TI - USMLE Step 1 "Score Creep" Adversely Affects Dual-Degree Students. PMID- 28557924 TI - New Medical Student Performance Evaluation Standards: Laudable but Inadequate. PMID- 28557925 TI - Assessment in Medical Education Focuses Too Narrowly on Test Scores. PMID- 28557926 TI - Clinical Skills in the Age of Google: A Call for Reform and Expansion of the USMLE Step 2 CS. PMID- 28557927 TI - Incorporating Formative Assessments Into the Preclerkship Lecture. PMID- 28557928 TI - Do "Good" Medical Students Really Make Good Doctors? PMID- 28557929 TI - Medical Students Call for Single-Payer National Health Insurance. PMID- 28557930 TI - Is It Time for Entrustable Professional Activities for Residency Program Directors? AB - Residency program directors (PDs) play an important role in establishing and leading high-quality graduate medical education programs. However, medical educators have failed to codify the position on a national level, and PDs are often not recognized for the significant role they play. The authors of this Commentary argue that the core entrustable professional activities (EPAs) framework may be a mechanism to further this work and define the roles and responsibilities of the PD position. Based on personal observations as PDs and communications with others in the academic medicine community, the authors used work in competency-based medical education to define a list of potential EPAs for PDs. The benefits of developing these EPAs include being able to define competencies for PDs using a deconstructive process, highlighting the increasingly important role PDs play in leading high-quality graduate medical education programs, using EPAs as a framework to assess PD performance and provide feedback, allowing PDs to focus their professional development efforts on the most important areas for their work, and helping guide the PD recruitment and selection processes. PMID- 28557932 TI - Humbled. PMID- 28557931 TI - What Matters More About the Interpersonal Reactivity Index and the Jefferson Scale of Empathy? Their Underlying Constructs or Their Relationships With Pertinent Measures of Clinical Competence and Patient Outcomes? AB - In their study published in this issue of Academic Medicine, Costa and colleagues confirmed the underlying constructs of the Interpersonal Reactivity Index (IRI) and the Jefferson Scale of Empathy (JSE) in medical students. The authors of this Commentary propose that in comparing two instruments that both purport to measure empathy, researchers or test users must pay close attention to the target populations, the conceptualizations of empathy, and the validity evidence in relation to pertinent criterion measures. The Commentary's authors draw attention to the fact that the IRI was developed for administration to the general population, whereas the JSE was developed specifically for administration to students and practitioners of health professions. Also, the author of the IRI conceptualized empathy as a combination of cognitive and emotional attributes, whereas the authors of the JSE defined empathy as a predominantly cognitive attribute. These differences are reflected in the content of the items, which determines the underlying constructs of the two instruments. The Commentary authors suggest that any empathy-measuring instrument in the context of health professions education and patient care requires the crucial evidence of significant relationships with indicators of clinical competence and positive patient outcomes. Such validity evidence is readily available for the JSE, and the Commentary authors recommend that researchers make efforts to provide pertinent validity support for any other instrument measuring empathy in health professionals-in-training and in-practice. PMID- 28557933 TI - Transforming Medical Assessment: Integrating Uncertainty Into the Evaluation of Clinical Reasoning in Medical Education. AB - In an age where practicing physicians have access to an overwhelming volume of clinical information and are faced with increasingly complex medical decisions, the ability to execute sound clinical reasoning is essential to optimal patient care. The authors propose two concepts that are philosophically paramount to the future assessment of clinical reasoning in medicine: assessment in the context of "uncertainty" (when, despite all of the information that is available, there is still significant doubt as to the best diagnosis, investigation, or treatment), and acknowledging that it is entirely possible (and reasonable) to have more than "one correct answer." The purpose of this article is to highlight key elements related to these two core concepts and discuss genuine barriers that currently exist on the pathway to creating such assessments. These include acknowledging situations of uncertainty, creating clear frameworks that define progressive levels of clinical reasoning skills, providing validity evidence to increase the defensibility of such assessments, considering the comparative feasibility with other forms of assessment, and developing strategies to evaluate the impact of these assessment methods on future learning and practice. The authors recommend that concerted efforts be directed toward these key areas to help advance the field of clinical reasoning assessment, improve the clinical care decisions made by current and future physicians, and have positive outcomes for patients. It is anticipated that these and subsequent efforts will aid in reaching the goal of making future assessment in medical education more representative of current-day clinical reasoning and decision making. PMID- 28557934 TI - Using Contribution Analysis to Evaluate Competency-Based Medical Education Programs: It's All About Rigor in Thinking. AB - Competency-based medical education (CBME) aims to bring about the sequential acquisition of competencies required for practice. Although it is being adopted in centers of medical education around the globe, there is little evidence concerning whether, in comparison with traditional methods, CBME produces physicians who are better prepared for the practice environment and contributes to improved patient outcomes. Consequently, the authors, an international group of collaborators, wrote this article to provide guidance regarding the evaluation of CBME programs.CBME is a complex service intervention consisting of multiple activities that contribute to the achievement of a variety of outcomes over time. For this reason, it is difficult to apply traditional methods of program evaluation, which require conditions of control and predictability, to CBME. To address this challenge, the authors describe an approach that makes explicit the multiple potential linkages between program activities and outcomes. Referred to as contribution analysis (CA), this theory-based approach to program evaluation provides a systematic way to make credible causal claims under conditions of complexity. Although CA has yet to be applied to medical education, the authors describe how a six-step model and a postulated theory of change could be used to examine the link between CBME, physicians' preparation for practice, and patient care outcomes.The authors argue that adopting the methods of CA, particularly the rigor in thinking required to link program activities, outcomes, and theory, will serve to strengthen understanding of the impact of CBME over time. PMID- 28557936 TI - Nutella. PMID- 28557935 TI - Constructing a Shared Mental Model for Faculty Development for the Core Entrustable Professional Activities for Entering Residency. AB - In 2014, the Association of American Medical Colleges identified 13 Core Entrustable Professional Activities for Entering Residency (Core EPAs), which are activities that entering residents might be expected to perform without direct supervision. This work included the creation of an interinstitutional concept group focused on faculty development efforts, as the processes and tools for teaching and assessing entrustability in undergraduate medical education (UME) are still evolving. In this article, the authors describe a conceptual framework for entrustment that they developed to better prepare all educators involved in entrustment decision making in UME. This framework applies to faculty with limited or longitudinal contact with medical students and to those who contribute to entrustment development or render summative entrustment decisions.The authors describe a shared mental model for entrustment that they developed, based on a critical synthesis of the EPA literature, to serve as a guide for UME faculty development efforts. This model includes four dimensions for Core EPA faculty development: (1) observation skills in authentic settings (workplace-based assessments), (2) coaching and feedback skills, (3) self-assessment and reflection skills, and (4) peer guidance skills developed through a community of practice. These dimensions form a conceptual foundation for meaningful faculty participation in entrustment decision making.The authors also differentiate between the UME learning environment and the graduate medical education learning environment to highlight distinct challenges and opportunities for faculty development in UME settings. They conclude with recommendations and research questions for future Core EPA faculty development efforts. PMID- 28557938 TI - Live and Let Live. PMID- 28557937 TI - Implementing an Entrustable Professional Activities Framework in Undergraduate Medical Education: Early Lessons From the AAMC Core Entrustable Professional Activities for Entering Residency Pilot. AB - In 2014, the Association of American Medical Colleges (AAMC) published a list of 13 Core Entrustable Professional Activities for Entering Residency (Core EPAs) that medical school graduates might be expected to perform, without direct supervision, on the first day of residency. Soon after, the AAMC commissioned a five-year pilot with 10 medical schools across the United States, seeking to implement the Core EPA framework to improve the transition from undergraduate to graduate medical education.In this article, the pilot team presents the organizational structure and early results of collaborative efforts to provide guidance to other institutions planning to implement the Core EPA framework. They describe the aims, timeline, and organization of the pilot as well as findings to date regarding the concepts of entrustment, assessment, curriculum development, and faculty development. On the basis of their experiences over the first two years of the pilot, the authors offer a set of guiding principles for institutions intending to implement the Core EPA framework. They also discuss the impact of the pilot, its limitations, and next steps, as well as how the pilot team is engaging the broader medical education community. They encourage ongoing communication across institutions to capitalize on the expertise of educators to tackle challenges related to the implementation of this novel approach and to generate common national standards for entrustment. The Core EPA pilot aims to better prepare medical school graduates for their professional duties at the beginning of residency with the ultimate goal of improving patient care. PMID- 28557939 TI - Greener, Brighter. PMID- 28557940 TI - Commentary on "Greener, Brighter". PMID- 28557941 TI - Finding a Path to Entrustment in Undergraduate Medical Education: A Progress Report From the AAMC Core Entrustable Professional Activities for Entering Residency Entrustment Concept Group. AB - PROBLEM: To better prepare graduating medical students to transition to the professional responsibilities of residency, 10 medical schools are participating in an Association of American Medical Colleges pilot to evaluate the feasibility of explicitly teaching and assessing 13 Core Entrustable Professional Activities for Entering Residency. The authors focused on operationalizing the concept of entrustment as part of this process. APPROACH: Starting in 2014, the Entrustment Concept Group, with representatives from each of the pilot schools, guided the development of the structures and processes necessary for formal entrustment decisions associated with students' increased responsibilities at the start of residency. OUTCOMES: Guiding principles developed by the group recommend that formal, summative entrustment decisions in undergraduate medical education be made by a trained group, be based on longitudinal performance assessments from multiple assessors, and incorporate day-to-day entrustment judgments by workplace supervisors. Key to entrustment decisions is evidence that students know their limits (discernment), can be relied on to follow through (conscientiousness), and are forthcoming despite potential personal costs (truthfulness), in addition to having the requisite knowledge and skills. The group constructed a developmental framework for discernment, conscientiousness, and truthfulness to pilot a model for transparent entrustment decision making. NEXT STEPS: The pilot schools are studying a number of questions regarding the pathways to and decisions about entrustment. This work seeks to inform meaningful culture change in undergraduate medical education through a shared understanding of the assessment of trust and a shared trust in that assessment. PMID- 28557942 TI - Beyond Selection: The Use of Situational Judgement Tests in the Teaching and Assessment of Professionalism. AB - PROBLEM: Professionalism is a critical attribute of medical graduates. Its measurement is challenging. The authors sought to assess final-year medical students' knowledge of appropriate professional behavior across a broad range of workplace situations. APPROACH: Situational judgement tests (SJTs) are used widely in applicant selection to assess judgement or decision making in work related settings as well as attributes such as empathy, integrity, and resilience. In 2014, the authors developed three 40-item SJTs with scenarios relevant to interns (first-year junior doctors) and delivered the tests to final year medical students to assess aspects of professionalism. As preparation, students discussed SJT-style scenarios; after the tests they completed an evaluation. The authors applied the Angoff method for the standard-setting process, delivered electronic individualized feedback reports to students post test, and provided remediation for students failing to meet the cut score. OUTCOMES: Evaluation revealed that the tests positively affected students' learning and that students accepted them as an assessment tool. Validity and reliability were acceptable. Implementation costs were initially high but will be recouped over time. NEXT STEPS: Recent improvements include changes to pass requirements, question revision based on reliability testing, and provision of detailed item-level feedback. Work is currently under way to expand the item bank and to introduce tests earlier in the course. Future research will explore correlation of SJT performance with other measures of professionalism and focus on the impact of SJTs on professionalism and interns' ability to deal with challenging workplace situations. PMID- 28557943 TI - Artist's Statement: Icon. PMID- 28557944 TI - Internal Medicine Residency Program Directors' Views of the Core Entrustable Professional Activities for Entering Residency: An Opportunity to Enhance Communication of Competency Along the Continuum. AB - PURPOSE: To examine internal medicine (IM) residency program directors' (PDs') perspectives on the Core Entrustable Professional Activities for Entering Residency (Core EPAs)-introduced into undergraduate medical education to further competency-based assessment-and on communicating competency-based information during transitions. METHOD: A spring 2015 Association of Program Directors in Internal Medicine survey asked PDs of U.S. IM residency programs for their perspectives on which Core EPAs new interns must or should possess on day 1, which are most essential, and which have the largest gap between expected and observed performance. Their views and preferences were also requested regarding communicating competency-based information at transitions from medical school to residency and residency to fellowship/employment. RESULTS: The response rate was 57% (204/361 programs). The majority of PDs felt new interns must/should possess 12 of the 13 Core EPAs. PDs' rankings of Core EPAs by relative importance were more varied than their rankings by the largest gaps in performance. Although preferred timing varied, most PDs (82%) considered it important for medical schools to communicate Core EPA-based information to PDs; nearly three-quarters (71%) would prefer a checklist format. Many (60%) would be willing to provide competency-based evaluations to fellowship directors/employers. Most (> 80%) agreed that there should be a bidirectional communication mechanism for programs/employers to provide feedback on competency assessments. CONCLUSIONS: The gaps identified in Core EPA performance may help guide medical schools' curricular and assessment tool design. Sharing competency-based information at transitions along the medical education continuum could help ensure production of competent, practice-ready physicians. PMID- 28557945 TI - How Entrustment Is Informed by Holistic Judgments Across Time in a Family Medicine Residency Program: An Ethnographic Nonparticipant Observational Study. AB - PURPOSE: Entrustment has mainly been conceptualized as delegating discrete professional tasks. Because residents provide most of their patient care independently, not all resident performance is visible to supervisors; the entrustment process involves more than granting discrete tasks. This study explored how supervisors made entrustment decisions based on residents' performance in a long-term family medicine training program. METHOD: A qualitative nonparticipant observational study was conducted in 2014-2015 at competency-based family medicine residency programs in the Netherlands. Seven supervisor-resident pairs participated. During two days, one researcher observed first-year residents' patient encounters, debriefing sessions, and supervisor resident educational meetings and interviewed them separately afterwards. Data were collected and analyzed using iterative, phenomenological inductive research methodology. RESULTS: The entrustment process developed over three phases. Supervisors based their initial entrustment on prior knowledge about the resident. In the ensuing two weeks, entrustment decisions regarding independent patient care were derived from residents' observed general competencies necessary for a range of health problems (clinical reasoning, decision making, relating to patients); medical knowledge and skills; and supervisors' intuition. Supervisors provided supervision during and after encounters. Once residents performed independently, supervisors kept reevaluating their decisions, informed by residents' overall growth in competencies rather than by adhering to a predefined set of tasks. CONCLUSIONS: Supervisors in family medicine residency training took a holistic approach to trust, based on general competencies, knowledge, skills, and intuition. Entrustment started before training and developed over time. Building trust is a mutual process between supervisor and resident, requiring a good working relationship. PMID- 28557946 TI - A Patient-Centered Approach to Developing Entrustable Professional Activities. AB - PURPOSE: The medical education community is rapidly accepting the use of entrustable professional activities (EPAs) as a means of assessing residents. Stakeholder engagement is advised in developing EPAs, but no studies have investigated the role of patient input. In this qualitative study, the authors investigated what patient input may add to designing a patient-centered EPA. METHOD: The authors chose "management of acute low back pain (LBP)" as a common, important clinical task on which to base the patient-centered EPA. In 2015, 14 patients who presented to a teaching hospital with acute LBP participated in semistructured interviews exploring their illness experience and expectations of doctors. Clinicians representing multiple disciplines participated in a focus group. The authors used the Framework Method to analyze data, identifying and developing themes, similarities, and differences between patient and clinician input. They used the findings to develop the EPA. Through an iterative procedure of data review and tracking data sources, they determined how patient and clinician input informed each EPA descriptor. RESULTS: Drawing from their firsthand experience of LBP, patients described unique expectations of trainees which directly informed EPA descriptors. For example, the authors primarily used patients' detailed descriptions of desirable and observable trainee behaviors to inform the required attitudes descriptor. CONCLUSIONS: Patients can provide unique contributions, complementary to those of clinicians, to EPAs. Consultations with patients led to the development of a patient-centered EPA, which aligned best clinical practice with patient expectations. Educators seeking to apply patient-centered care to EPA development could adopt a similar approach. PMID- 28557947 TI - Validity Evidence From Ratings of Pediatric Interns and Subinterns on a Subset of Pediatric Milestones. AB - PURPOSE: To investigate evidence for validity of faculty members' pediatric milestone (PM) ratings of interns (first-year residents) and subinterns (fourth year medical students) on nine subcompetencies related to readiness to serve as a pediatric intern in the inpatient setting. METHOD: The Association of Pediatric Program Directors Longitudinal Educational Assessment Research Network (APPD LEARN) and the National Board of Medical Examiners collaborated to investigate the utility of assessments of the PMs for trainees' performance. Data from 32 subinterns and 179 interns at 17 programs were collected from July 2012 through April 2013. Observers used several tools to assess learners. At each site, a faculty member used these data to make judgments about the learner's current developmental milestone in each subcompetency. Linear mixed models were fitted to milestone judgments to examine their relationship with learner's rank and subcompetency. RESULTS: On a 5-point developmental scale, mean milestone levels for interns ranged from 3.20 (for the subcompetency Work effectively as a member of a team) to 3.72 (Humanism) and for subinterns from 2.89 (Organize and prioritize care) to 3.61 (Professionalization). Mean milestone ratings were significantly higher for the Professionalism competency (3.59-3.72) for all trainees compared with Patient Care (2.89-3.24) and Personal and Professional Development (3.33-3.51). Mean intern ratings were significantly higher than mean subintern ratings for all nine subcompetencies except Professionalization, Humanism, and Trustworthiness. CONCLUSIONS: The PMs had a coherent internal structure and could distinguish between differing levels of trainees, which supports their validation for documenting developmental progression of pediatric trainees. PMID- 28557948 TI - Critical Deficiency Ratings in Milestone Assessment: A Review and Case Study. AB - PURPOSE: The Accreditation Council for Graduate Medical Education (ACGME) requires programs to report learner progress using specialty-specific milestones. It is unclear how milestones can best identify critical deficiencies (CDs) in trainee performance. Specialties developed milestones independently of one another; not every specialty included CDs within milestones ratings. This study examined the proportion of ACGME milestone sets that include CD ratings, and describes one residency program's experiences using CD ratings in assessment. METHOD: The authors reviewed ACGME milestones for all 99 specialties in November 2015, determining which rating scales contained CDs. The authors also reviewed three years of data (July 2012-June 2015) from the University of Cincinnati Medical Center (UCMC) internal medicine residency assessment system based on observable practice activities mapped to ACGME milestones. Data were analyzed by postgraduate year, assessor type, rotation, academic year, and core competency. The Mantel-Haenszel chi-square test was used to test for changes over time. RESULTS: Specialties demonstrated heterogeneity in accounting for CDs in ACGME milestones, with 22% (22/99) of specialties having no language describing CDs in milestones assessment. Thirty-three percent (63/189) of UCMC internal medicine residents received at least one CD rating, with CDs accounting for 0.18% (668/364,728) of all assessment ratings. The authors identified CDs across multiple core competencies and rotations. CONCLUSIONS: Despite some specialties not accounting for CDs in milestone assessment, UCMC's experience demonstrates that a significant proportion of residents may be rated as having a CD during training. Identification of CDs may allow programs to develop remediation and improvement plans. PMID- 28557949 TI - Surgical Trainee Feedback-Seeking Behavior in the Context of Workplace-Based Assessment in Clinical Settings. AB - PURPOSE: To investigate surgical trainee feedback-seeking behaviors-directly asking for feedback (inquiry) and observing and responding to situational clues (monitoring)-in the context of workplace-based assessment (WBA). METHOD: A hypothetical model of trainee feedback-seeking behavior was developed using existing literature. A questionnaire, incorporating previously validated instruments from organizational psychology, was distributed to general surgical trainees at 23 U.K. hospitals in 2012-2013. Statistical modeling techniques compared the data with 12 predetermined hypothetical relationships between feedback-seeking behaviors and predictive variables (goal orientation, supervisory style) through mediating variables (perceptions of personal benefits and costs of feedback) to develop a final model. RESULTS: Of 235 trainees invited, 178 (76%) responded. Trainees completed 48 WBAs/year on average, and 73% reported receiving feedback via WBA. The final model was of good fit (chi square/degree of freedom ratio = 1.620, comparative fit index = 0.953, root mean square error of approximation = 0.059). Modeled data showed trainees who perceive personal benefits to feedback use both feedback inquiry and monitoring to engage in feedback interactions. Trainees who seek feedback engage in using WBA. Trainees' goal orientations and perceptions of trainers' supervisory styles as supportive and instrumental are associated with perceived benefits and costs to feedback. CONCLUSIONS: Trainees actively engage in seeking feedback and using WBA. Their perceptions of feedback benefits and costs and supervisory style play a role in their feedback-seeking behavior. Encouraging trainees to actively seek feedback by providing specific training and creating a supportive environment for feedback interactions could positively affect their ability to seek feedback. PMID- 28557950 TI - Are Female Applicants Rated Higher Than Males on the Multiple Mini-Interview? Findings From the University of Calgary. AB - PURPOSE: The multiple mini-interview (MMI) improves reliability and validity of medical school interviews, and many schools have introduced this in an attempt to select individuals more skilled in communication, critical thinking, and ethical decision making. But every change in the admissions process may produce unintended consequences, such as changing intake demographics. In this article, two studies exploring gender differences in MMI ratings are reported. METHOD: Cumulative meta-analysis was used to compare MMI ratings for female and male applicants to the University of Calgary Cumming School of Medicine between 2010 and 2014. Multiple linear regression was then performed to explore gender differences in MMI ratings after adjusting for other variables, followed by a sensitivity analysis of the impact of varying the weight given to MMI ratings on the odds of females being ranked in the top 150 applicants for 2014. RESULTS: Females were rated higher than male applicants (standardized mean difference 0.21, 95% CI [0.11, 0.30], P < .001). After adjusting for other explanatory variables, there was a positive association between female applicant and MMI rating (regression coefficient 0.23 [0.14, 0.33], P < .001). Increasing weight assigned to MMI ratings was associated with increased odds of females being ranked in the top 150 applicants. CONCLUSIONS: In this single-center study, females were rated higher than males on the MMI, and the odds of a female applicant being offered a position increased as more weight was given to MMI ratings. Further studies are needed to confirm and explain gender differences in MMI ratings. PMID- 28557951 TI - Are Scores From NBME Subject Examinations Valid Measures of Knowledge Acquired During Clinical Clerkships? AB - PURPOSE: The National Board of Medical Examiners' Clinical Science Subject Examinations are a component used by most U.S. medical schools to determine clerkship grades. The purpose of this study was to examine the validity of this practice. METHOD: This was a retrospective cohort study of medical students at the Virginia Commonwealth University School of Medicine who completed clerkships in 2012 through 2014. Linear regression was used to determine how well United States Medical Licensing Examination Step 1 scores predicted Subject Examination scores in seven clerkships. The authors then substituted each student's Subject Examination standard scores with his or her Step 1 standard score. Clerkship grades based on the Step 1 substitution were compared with actual grades with the Wilcoxon rank test. RESULTS: A total of 2,777 Subject Examination scores from 432 students were included in the analysis. Step 1 scores significantly predicted between 23% and 44% of the variance in Subject Examination scores, P < .001 for all clerkship regression equations. Mean differences between expected and actual Subject Examination scores were small (<= 0.2 points). There was a match between 73% of Step 1 substituted final clerkship grades and actual final clerkship grades. CONCLUSIONS: The results of this study suggest that performance on Step 1 can be used to identify and counsel students at risk for poor performance on the Subject Examinations. In addition, these findings call into the question the validity of using scores from Subject Examinations as a high-stakes assessment of learning in individual clerkships. PMID- 28557952 TI - Measuring Medical Students' Empathy: Exploring the Underlying Constructs of and Associations Between Two Widely Used Self-Report Instruments in Five Countries. AB - PURPOSE: Understanding medical student empathy is important to future patient care; however, the definition and development of clinical empathy remain unclear. The authors sought to examine the underlying constructs of two of the most widely used self-report instruments-Davis's Interpersonal Reactivity Index (IRI) and the Jefferson Scale of Empathy version for medical students (JSE-S)-plus, the distinctions and associations between these instruments. METHOD: Between 2007 and 2014, the authors administered the IRI and JSE-S in three separate studies in five countries, (Brazil, Ireland, New Zealand, Portugal, and the United Kingdom). They collected data from 3,069 undergraduate medical students and performed exploratory factor analyses, correlation analyses, and multiple linear regression analyses. RESULTS: Exploratory factor analysis yielded identical results in each country, confirming the subscale structures of each instrument. Results of correlation analyses indicated significant but weak correlations (r = 0.313) between the total IRI and JSE-S scores. All intercorrelations of IRI and JSE-S subscale scores were statistically significant but weak (range r = -0.040 to 0.306). Multiple linear regression models revealed that the IRI subscales were weak predictors of all JSE-S subscale and total scores. The IRI subscales explained between 9.0% and 15.3% of variance for JSE-S subscales and 19.5% for JSE-S total score. CONCLUSIONS: The IRI and JSE-S are only weakly related, suggesting that they may measure different constructs. To better understand this distinction, more studies using both instruments and involving students at different stages in their medical education, as well as more longitudinal and qualitative studies, are needed. PMID- 28557953 TI - Using In-Training Evaluation Report (ITER) Qualitative Comments to Assess Medical Students and Residents: A Systematic Review. AB - PURPOSE: In-training evaluation reports (ITERs) constitute an integral component of medical student and postgraduate physician trainee (resident) assessment. ITER narrative comments have received less attention than the numeric scores. The authors sought both to determine what validity evidence informs the use of narrative comments from ITERs for assessing medical students and residents and to identify evidence gaps. METHOD: Reviewers searched for relevant English-language studies in MEDLINE, EMBASE, Scopus, and ERIC (last search June 5, 2015), and in reference lists and author files. They included all original studies that evaluated ITERs for qualitative assessment of medical students and residents. Working in duplicate, they selected articles for inclusion, evaluated quality, and abstracted information on validity evidence using Kane's framework (inferences of scoring, generalization, extrapolation, and implications). RESULTS: Of 777 potential articles, 22 met inclusion criteria. The scoring inference is supported by studies showing that rich narratives are possible, that changing the prompt can stimulate more robust narratives, and that comments vary by context. Generalization is supported by studies showing that narratives reach thematic saturation and that analysts make consistent judgments. Extrapolation is supported by favorable relationships between ITER narratives and numeric scores from ITERs and non-ITER performance measures, and by studies confirming that narratives reflect constructs deemed important in clinical work. Evidence supporting implications is scant. CONCLUSIONS: The use of ITER narratives for trainee assessment is generally supported, except that evidence is lacking for implications and decisions. Future research should seek to confirm implicit assumptions and evaluate the impact of decisions. PMID- 28557954 TI - Correlation of 18F-FDG PET/CT with pathological features and survival in primary breast cancer. AB - OBJECTIVE: The aim of this study was to determine the correlation between the primary tumor (PT) maximum standardized uptake value (SUVmax) and breast cancer prognostic factors, overall survival, and relapse-free survival on the basis of histopathological and molecular characteristics. PATIENTS AND METHODS: In this retrospective study, 436 female patients with breast cancer were evaluated following a pretreatment F-FDG PET/CT scan. The PT SUVmax and histopathological/molecular characteristics were determined from primary tumor tissues and analyzed using the Mann-Whitney U and Kruskal-Wallis tests. RESULTS: The median SUVmax of 436 PT was 10.1 (1.7-72). The PT SUVmax values were higher in ER- versus ER+ (P=0.001), PR- versus PR+ (P=0.001), Her2+ versus Her2- (P=0.01), Ki-67% of at least 20 versus Ki-67% of less than 20 (P<0.001), histological grade 3 versus grade 1-2 (P<0.001), nuclear pleomorphism score 3 versus score 1-2 (P<0.001), and mitotic score 3 versus score 1-2 patients (P<0.001). The lowest SUVmax levels were observed in the LumA group and the highest SUVmax levels were observed in the Her2 group (P<0.001). LumA patients with PR values greater than 20% had lower PT SUVmax values than the patients with PR values of 20% or less (P=0.023). The PT SUVmax was higher in patients with recurrence (P=0.03) and died related to disease (P<0.001) independent of time. CONCLUSION: The PT SUVmax showed a significant correlation with most of the prognostic factors and histopathological subtypes as a noninvasive tool. It is also usable in the prediction of tumor-related deaths or relapse independent of time. Our results could guide future studies to provide new histopathologic subtype definitions on the basis of new PR criteria. PMID- 28557956 TI - "Model for Early Allograft Function" Outperforms "Early Allograft Dysfunction" as a Predictor of Transplant Survival. AB - BACKGROUND: The Model of Early Allograft Function (MEAF) grades the severity of liver graft dysfunction. Unlike the categorical early allograft dysfunction (EAD) classification, MEAF is a continuous score, based on bilirubin, international normalized ratio, and alanine aminotransferase within 3 days posttransplant. METHODS: Multivariable regression models were used to validate the MEAF score in 660 liver-only transplants performed between 2000 and 2014. MEAF performance for prediction of transplant survival was compared with that of EAD in univariable and multivariable models by means of Harrell's c-indices, integrated discrimination improvement, and net reclassification improvement. RESULTS: Median donor and recipient age was 52 years (interquartile range [IQR], 41-62 years) and 58 years (IQR, 50-64 years), respectively. Model for End-Stage Liver Disease score was 15 (IQR, 11-21); cold ischemia time, 8.0 hours (IQR, 6.4-9.7 hours); MEAF, 4 (IQR, 3-6). EAD occurred in 182 (27.6%) cases. Transplant survival was 93%, 90%, and 88% at 3, 6, and 12 months. Both MEAF and EAD were independent predictors of transplant survival within 3, 6, and 12 months. MEAF outperformed EAD as predictor of transplant survival, either when used as a standalone parameter or when corrected for additional independent predictors of transplant survival. CONCLUSIONS: MEAF is a more accurate predictor of transplant loss than the commonly used EAD classification. As a continuous score grading graft dysfunction, MEAF provides additional, granulated information that could be used both clinically and as a surrogate endpoint of transplant survival in clinical trials. PMID- 28557957 TI - Plasma Exosomes From HLA-Sensitized Kidney Transplant Recipients Contain mRNA Transcripts Which Predict Development of Antibody-Mediated Rejection. AB - BACKGROUND: Sensitization to HLA remains a significant immunologic barrier to successful transplantation. Identifying immune mechanisms responsible for antibody-mediated rejection (AMR) is an important goal. Here, we explored the possibility of predicting the risk for AMR by measuring mRNA transcripts of AMR associated genes in plasma exosomes from kidney transplant patients. METHODS: Total RNA was extracted from exosomes purified from 152 ethylenediaminetetraacetic acid-plasma samples of 64 patients (18 AMR, 8 cell mediated rejection [CMR], 38 no rejection in desensitized [DES] and non-DES control groups) for reverse transcription into cDNA, preamplification and then real time quantitative polymerase chain reaction (qPCR) for 21 candidate genes. The mRNA transcript levels of each gene were calculated. Comparisons were made among 4 patient groups for each gene and also for a gene combination score based on selected genes. RESULTS: Among 21 candidate genes, we identified multiple genes (gp130, CCL4, TNFalpha, SH2D1B, CAV1, atypical chemokine receptor 1 [duffy blood group]) whose mRNA transcript levels in plasma exosomes significantly increased among AMR compared with CMR and/or control patients. A gene combination score calculated from 4 genes of gp130, SH2D1B, TNFalpha, and CCL4 was significantly higher in the AMR than the CMR (P < 0.0001) and no rejection control groups (P < 0.01 vs DES control, P < 0.05 vs non-DES control). CONCLUSIONS: Our results suggest that plasma exosomes may contain information indicating clinical conditions of kidney transplant patients. mRNA transcript profiles based on gp130, SH2D1B, TNFalpha, and CCL4 in plasma exosomes may be used to predict on-going and/or imminent AMR. PMID- 28557955 TI - Comparative Evaluation of alphaCD40 (2C10R4) and alphaCD154 (5C8H1 and IDEC-131) in a Nonhuman Primate Cardiac Allotransplant Model. AB - BACKGROUND: Specific blockade of T cell costimulation pathway is a promising immunomodulatory approach being developed to replace our current clinical immunosuppression therapies. The goal of this study is to compare results associated with 3 monoclonal antibodies directed against the CD40/CD154 T cell costimulation pathway. METHODS: Cynomolgus monkey heterotopic cardiac allograft recipients were treated with either IDEC-131 (humanized alphaCD154, n = 9), 5C8H1 (mouse-human chimeric alphaCD154, n = 5), or 2C10R4 (mouse-rhesus chimeric alphaCD40, n = 6) monotherapy using a consistent, comparable dosing regimen for 3 months after transplant. RESULTS: Relative to the previously reported IDEC-131 treated allografts, median survival time (35 +/- 31 days) was significantly prolonged in both 5C8H1-treated (142 +/- 26, P < 0.002) and 2C10R4-treated (124 +/- 37, P < 0.020) allografts. IDEC-131-treated grafts had higher cardiac allograft vasculopathy severity scores during treatment relative to either 5C8H1 (P = 0.008) or 2C10R4 (P = 0.0002). Both 5C8H1 (5 of 5 animals, P = 0.02) and 2C10R4 (6/6, P = 0.007), but not IDEC-131 (2/9), completely attenuated IgM antidonor alloantibody (alloAb) production during treatment; 5C8H1 (5/5) more consistently attenuated IgG alloAb production compared to 2C10R4 (4/6) and IDEC 131 (0/9). All evaluable explanted grafts experienced antibody-mediated rejection. Only 2C10R4-treated animals exhibited a modest, transient drop in CD20 lymphocytes from baseline at day 14 after transplant (-457 +/- 152 cells/MUL) compared with 5C8H1-treated animals (16 +/- 25, P = 0.037), and the resurgent B cells were primarily of a naive phenotype. CONCLUSIONS: In this model, CD154/CD40 axis blockade using IDEC-131 is an inferior immunomodulatory treatment than 5C8H1 or 2C10R4, which have similar efficacy to prolong graft survival and to delay cardiac allograft vasculopathy development and antidonor alloAb production during treatment. PMID- 28557958 TI - Appropriate Use of Drug Testing in Clinical Addiction Medicine. AB - : Biological drug testing is a tool that provides information about an individual's recent substance use. Like any tool, its value depends on using it correctly; that is, on selecting the right test for the right person at the right time. This document is intended to clarify appropriate clinical use of drug testing in addiction medicine and aid providers in their decisions about drug testing for the identification, diagnosis, treatment, and recovery of patients with, or at risk for, addiction. The RAND Corporation (RAND)/University of California, Los Angeles (UCLA) Appropriateness Method (RAM) process for combining scientific evidence with the collective judgment of experts was used to identify appropriate clinical practices and highlight areas where research is needed. Although consensus panels and expert groups have offered guidance on the use of drug testing for patients with addiction, very few addressed considerations for patients across settings and in different levels of care. This document will focus primarily on patients in addiction treatment and recovery, where drug testing is used to assess patients for a substance use disorder, monitor the effectiveness of a treatment plan, and support recovery. Inasmuch as the scope includes the recognition of addiction, which often occurs in general healthcare settings, selected special populations at risk for addiction visiting these settings are briefly included. PMID- 28557959 TI - How to Deliver a More Persuasive Message Regarding Addiction as a Medical Disorder. AB - : Many members of our field are frustrated that the public does not see addiction as a legitimate medical disorder which should be compassionately addressed as a health problem rather than a criminal justice problem. Although some attribute the disconnect to the public's lack of scientific knowledge or attachment to outdated moral views regarding substance use, this commentary suggests that the problem may well be our own messaging. We would be more persuasive if we acknowledged that addiction is different from most medical disorders because of its high negative externalities, and that this understandably makes the public more scared of and angry about addiction than they are about conditions like asthma, type II diabetes, and hypertension. Relatedly, because of the amount of violence and other crimes associated with addiction, we should acknowledge that the public's belief that law enforcement has an important role to play in responding to addiction has a rational basis. PMID- 28557960 TI - Accuracy of Diagnosis and International Classification of Diseases; Tenth Revision Coding for Alcohol Dependence, Alcohol Withdrawal, and Alcohol withdrawal Delirium Among Inpatients at a University Hospital. PMID- 28557961 TI - Urine Drug Testing in a Family Medicine Residency Practice. PMID- 28557962 TI - Response to Urine Drug Testing in a Family Residency Practice. PMID- 28557963 TI - [Inflammatory processes in the pathogenesis of acute coronary syndromes]. AB - Cardiovascular diseases, including acute coronary syndromes (ACS), are one of the most serious problems of modern medicine and therefore every year 4 million Europeans have died. It is now believed that elevated levels of inflammatory factors in the blood promotes the development cardiovascular events and chronic inflammation plays a key role in the pathogenesis of atherosclerosis. Intensively conducted research in many centers in the world can confirm the desirability of introducing anti-inflammatory therapy to standard drug therapy. The balance between pro- and anti-inflammatory processes affect the risk of developing ACS. PMID- 28557964 TI - Sex differences in venous stenosis and occlusion in patients with endocardial leads. AB - : Venous stenosis and occlusion (VSO) in the presence of endocardial leads constitute one of the complications of permanent cardiac pacing. At present there are no scientific reports on the influence of sex on the incidence of VSO. AIM: The aim of the study was to examine the influence of sex on the incidence of VSO in patients with earlier implanted endocardial leads in a single-center retrospective analysis. MATERIALS AND METHODS: The material consists of 284 records of consecutive patients admitted to hospital to undergo electrotherapy procedures. In all patients a contrast venography for ipsilateral venous confluence was performed before the procedure. Patients were divided into two groups according to sex criterion. Groups were compared concerning following parameters: demographic characteristics, cardiac implantable electronic device (CIED) characteristics, comorbidities, CHA2DS2-VASc score, selected risk factors for VSO. RESULTS: Group I consist of 101 females, whereas group II consist of 183 males. Both groups did not differ significantly for age, number of implanted endocardial leads and lead dwell time. In the cohort males were with significantly greater burden of morbidity, reflected by the mean result of CHA2DS2-VASc (P=0.0098). In males there was significantly more often chronic heart failure (P<0.0001), chronic obstructive pulmonary disease (P=0.0450) and tobacco use (P=0.0159). Males had more ICD implanted than females (P=0.0270). In the examine cohort 88 patients (31%) had VSO. There was no statistically significant difference in terms of presence of VSO between females and males (P=0.4685). The detailed analysis of the patients with VSO divided according to sex revealed higher morbidity in males. CONCLUSIONS: The equality of VSO incidence in groups of males and females along with the predominance of factors protecting against VSO in group of males support the assumption that female gender is a protective factor against the development of VSO, equally as known protective factors in males. PMID- 28557965 TI - The assessment of renal function in patients with newly diagnosed hypertension - the role of hyperuricemia as a risk factor for chronic kidney disease - preliminary study. AB - : For the last few years, the role of uric acid in the pathogenesis of the hypertension and chronic kidney disease has drawn attention due to the increasing prevalence of the aforementioned states. Uric acid (UA), formed as a result of purine metabolism, is subject in the renal proximal tubule to filtration, reabsorption and secretion. The mechanisms of deleterious effect of UA on the kidney involve endothelial damage and the increment of hydrostatic pressure in the glomerulus which in turn lead to hypertrophy and glomerulosclerosis. Moreover, abnormally elevated levels of uric acid results in the activation of renin-angiotensinaldosterone system and thus it may be associated with disturbances of water and electrolyte balance and the appearance of hypertension. AIM: The aim of this study was to assess the prevalence of hyperuricemia in patients with newly diagnosed hypertension and its effect on renal function. MATERIALS AND METHODS: This is a retrospective study including 315 hypertensive patients (157 women - 49.8% and 158 men - 50.2%, aged 39.3 +/- 14.0 years) hospitalized in the Department of Nephrology, Hypertension and Family Medicine, WAM University Hospital of Lodz (study group) and 181 individuals without hypertension (103 women - 56.9% and 78 men - 43.1%, aged 42.4 +/- 14.0) (control group). RESULTS: Hyperuricemia was observed in 6.7% of patients with newly diagnosed hypertension. A positive correlation between serum creatinine and uric acid (Spearman coefficient 0.426, p<0.0001) and negative correlation between uric acid and eGFR (Spearman coefficient -0.116, p =0.068) were demonstrated in this study. CONCLUSIONS: Patients with newly diagnosed hypertension have higher levels of uric acid in comparison to control group. Elevated levels of uric acid can influence the development of hypertension and aggravate hypertension-associated renal damage. PMID- 28557967 TI - [The assessment of the impact of rehabilitation on the pain intensity level in patients with herniated nucleus pulposus of the intervertebral disc]. AB - : Back pain may be caused by many factors. In many cases it is difficult to unambiguously determine a cause of the pathology, which can involve various structures in the spine. In this paper we will discuss the symptoms associated with the degenerative changes of the intervertebral disc, which involve, among others, its bulging, dislocation and pressure on the surrounding structures. These problems require an adequate clinical and imaging diagnostics in order to implement an appropriate treatment. In the first place, it should be based on the conservative methods (such as: pharmacotherapy, rehabilitation and lifestyle changes). Only in the absence of improvement it is recommended to consider a surgical treatment. AIM: The aim of the study is to assess the impact of rehabilitation on the pain intensity level in patients with herniated nucleus pulposus of the intervertebral disc. MATERIALS AND METHODS: The study was performed in 46 patients (age range: 19-85), including 26 women and 20 men. On the basis of imaging, all patients showed the presence of a slipped disc with disc herniation. The patients were treated conservatively. For pain assessment was used the The Laitinen Modified Questionnaire Indicators of Pain and The Visual- Analogue Scale. The results were statistically analyzed. RESULTS: The results clearly demonstrate the analgesic efficacy of specialized rehabilitation in the spinal pain syndrome in a discopathy with a spinal disc herniation of an intervertebral disc. CONCLUSIONS: The rehabilitation of patients with a back pain due to the presence of herniated nucleus pulposus has a significant analgesic effect. In the case of a presence of the herniated nucleus pulposus, the rehabilitation should be considered in a first place. If no improvement, a possible surgery should be considered. An important element of a conservative treatment is an effective rehabilitation, which is of vital economic importance, because a therapy including surgery usually requires subsequent rehabilitation and is much more expensive. PMID- 28557966 TI - [The usefulness of the scale before exercise and exercise to identify coronary artery disease by physiotherapists]. AB - : Myocardial ischemia can be assessed by ECG at rest or doing the stress test, which also serves to evaluate the results of cardiac rehabilitation. AIM: The aim of this study was to determine the usefulness of the scale before exercise and exercise to assess the risk of coronary heart disease and recognition by physiotherapists. MATERIALS AND METHODS: The study included three groups of people: 1. 65 patients with stable coronary heart disease (IHD), including 45 men and 20 women, ranging in age from 33 to 79 years, an average of 60.18 +/- 9.43 years who exercise test was positive; 2. 24 patients after myocardial infarction undergoing subsequent rehabilitation, including 20 men and 4 women, aged from 42 to 78 years, an average of 58.75 +/- 8.45 years; 3. 70 healthy subjects without ischemic heart disease, including 34 men and 36 women, ranging in age from 24 to 70 years, an average of 56.24 +/- 12.33 years. All healthy people and patients were hospitalized in the Department of Internal Medicine and Cardiac Rehabilitation, University Hospital im. WAM in Lodz. The study groups were assessed risk of coronary heart disease based on the result obtained in the scale before exercise and exercise. The results were statistically analyzed using Statistica version 12 (StatSoft, Poland). For the statistically significant level of p<0.05. RESULTS: Compared to healthy individuals in both the ischemic heart disease (p=0.04) and in the group treated with rehabilitation (p=0.03) results in a scale before stress was significant higher. Compared to healthy individuals, both in the group of ischemic heart disease (p <0.001) and in the group treated with rehabilitation (p<0.001) The results on a scale of exercise were significantly higher. CONCLUSIONS: The use of scale before exercise to assess the risk of coronary heart disease is useful for physical therapists in their professional practice. There legitimacy of the use of scale exercise for the initial diagnosis of coronary artery disease without knowing the interpretation of the ECG stress test. PMID- 28557968 TI - Medicine and Physiotherapy students: are they physically active? Comparative research on Spanish and German population. AB - : Despite the fact that regular physical activity is beneficial to human life, there are still more and more overweight and obese people throughout the world today. Healthy habits taken from home or socioeconomic situation are factors which might influence on regular physical activity. People who lead a healthy lifestyle in childhood are also active during adulthood. On the other hand academic life might promote less healthy lifestyle. AIM: The aim of the study was to assess and compare the level of physical activity of both German and Spanish students of Medicine and Physiotherapy. MATERIALS AND METHODS: The study involved 100 Spanish and 100 German students aged from 19 to 24 years. Based on Eurobarometer 72.3, the respondents were asked a set of questions regarding physical activity. The chi-squared test (chi2) and Mann-Whitney U test were used for the statistical analysis. RESULTS: The vast majority of students presented a normal BMI value, but it was not related to high physical activity. More than one third of all students seldom practised any sports. The Spanish students usually did some form of physical activity outdoors, whereas the German students exercised in a fitness centre. Lack of time was to the Medicine and Physiotherapy students the most significant factor that did not allow them to be more physically active. CONCLUSIONS: Medicine and Physiotherapy students should be more physically active in order to promote a good, healthy lifestyle model to society and there should be more physical activity education to encourage more students to practise sports. PMID- 28557969 TI - [Metabolic safety of antidepressant medicines]. AB - : Metabolic syndrome is a very serious health issue, not only from internal medicine's point of view. Patients suffering from overweight, arterial hypertension, lipids and carbohydrates metabolism disorders are also in the circle of interest of other areas of medicine, including psychiatry. Currently, one of key problems of pharmacotherapy is a comorbidity of metabolic syndrome and mental disorder. Depression is more common than schizophrenia. Despite the fact that in everyday clinical practice there are more patients with depression than schizophrenia, there is a bigger interest among scientists for metabolic syndrome after antipsychotic drugs than as an effect of use of antidepressant agents. AIM: The aim of an analysis was to review literature committed to influence of depression pharmacotherapy on development of metabolic syndrome. 169 results were provided, including 18 original publications. Final analysis consists of 9 that investigate correlation between antidepressive medicines use and metabolic syndrome development (but not its each individual component). RESULTS: In general, antidepressant pharmacotherapy is associated not only with increased risk of metabolic syndrome occurrence but also their worsening. However, it needs to be emphasized that there is a difference between antidepressants groups - tricyclic antidepressive medicines are the most commonly associated with risk of developing metabolic disorders, but also SNRIs and SSRIs are mentioned as significant contributors. Mechanisms of aforementioned changes are still unclear. However, their influence on histamine and serotonin pathways, which take part in regulation of i.e. food intake, is suggested. The search for mechanisms that are precisely responsible for metabolic changes continues, in hope of finding a way to avoid adverse effects of antidepressant medicines use. PMID- 28557970 TI - [The use of fascial distorsion model (FDM) in patient with limited mobility in the shoulder joint - a case report]. AB - : FDM is the anatomical model in which clinical signs in conjunction with the patient's body language allow to diagnose one or more of the six specific distortions of the fascial system described by the creator of the concept of FDM and doctor-osteopath Stephen Typaldos. AIM: The aim of the study is to present the use of therapy Fascial Distorsion Model to patient with limited mobility in the shoulder joint. A CASE REPORT: Here we report a 32 year old female patient with painful limitation of motion in the shoulder joint right continuing for three weeks. The patient is an office worker, three times a week swims. Pain appears periodicaly and only in certain ranges of motion of the right upper limb. In the functional study by FDM it is continuum distortion and triggerband distortion. Then the appropriate therapeutic techniques were used. CONCLUSIONS: The patient regained full range of motion in the shoulder joint after using FDM techniques without pain that prevented her making a move. During the test, the patient performed functional movements in the full range of movement without pain. Techniques of the FDM are an interesting complement workshop therapy which is treating limits in the range of motion and pain in the joints. PMID- 28557971 TI - [Travels and spreading of multi-resistant bacteria]. AB - The increasing number of international travel for tourism, business and for medical reasons rises the risk of spreading of multi-resistant bacteria. It has been shown that an intercontinental travel, mainly to Asia (Indian Subcontinent), promotes a colonization of the digestive tract, mainly by multi-resistant Enterobacteriaceae (MRE) and increases the risk of symptomatic infections caused by these agents. The colonization of the digestive tract by MRE is reported in 29 88% of travelers. It sustains 3 to 12 months, respectively in 10% and 2% of travelers. Risk factors for the acquisition of colonization with MRE include: travel duration and destination, treatment with betalactam antibiotics during the travel, the use of local medical services, including hospitalization, presence of gastrointestinal symptoms during the travel (mainly diarrhea), age >65 years. The need of the hospitalization during the travel increases the risk of colonization, but is not a prerequisite factor for the acquisition of the colonization, as cases of the MRE carriage are reported in patients who had never used medical services outside the country. It indicates other possible transmission routes, including food. In order to reduce the risk of MRE spreading, it is recommended to ask patients about a history of travel and treatment within the last 12 months. All patient who report such events and require hospitalization in their home countries should be microbiologically screened. Hospitalized patients colonized with multiple resistant bacteria require an isolation or cohortation. Educational activities related to the hand hygiene compliance should be performed. The risk of the home transmission of MRE is not high, it lasts for a short period (up to 3 months). Routine microbiological testing for all persons returning from an international or intercontinental travel is not recommended, neither microbiological screening among their households. PMID- 28557972 TI - High Expression of Phosphorylated Extracellular Signal-Regulated Kinase (ERK1/2) is Associated with Poor Prognosis in Newly Diagnosed Patients with Multiple Myeloma. AB - BACKGROUND Previous research has demonstrated that the extracellular signal regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway is commonly activated in multiple myeloma (MM) patients. However, the prognostic value of activation of the MEK/ERK signaling pathway in newly diagnosed patients with MM has not been reported. MATERIAL AND METHODS Expression levels of p-ERK1/2 protein in bone marrow biopsy specimens obtained from 60 newly diagnosed patients with MM were analyzed using immunohistochemistry, and classified into 3 groups: high p-ERK1/2 expression, low p-ERK1/2 expression, and negative group. Correlations between clinicopathological characteristics, including expression levels of p-ERK1/2 protein, progression-free survival (PFS), and overall survival (OS), were analyzed using univariate and multivariate analysis. RESULTS Phosphorylated-ERK1/2 protein was positive in 47 bone marrow specimens, including 19 specimens with high p-ERK1/2 expression and 28 specimens with low p-ERK1/2 expression. Univariate Kaplan-Meier analysis showed that in newly diagnosed patients with MM, high p-ERK1/2 expression, high ISS staging, serum creatinine (Scr) >=177 MUmol/l, serum beta2-microglobulin (beta2-MG) >=5.5 MUmol/l, and serum calcium (Ca) >=2.75 mmol/l were significantly associated with shorter OS and PFS. Additionally, high ECOG scores (score 2-4) were associated with shorter PFS in newly diagnosed patients with MM. Multivariate Cox regression analysis showed that in newly diagnosed patients with MM, high p-ERK1/2 expression was significantly associated with shorter OS and PFS. Additionally, in newly diagnosed patients with MM, serum Ca >=2.75 mmol/l was significantly associated with shorter PFS, and serum beta2-MG >=5.5 MUmol/l was significantly associated with shorter OS. CONCLUSIONS High p-ERK1/2 expression is an independent factor for poor prognosis in newly diagnosed patients with MM. PMID- 28557973 TI - Cerebrospinal Fluid Dissemination and Neoplastic Meningitis in Primary Brain Tumors. AB - BACKGROUND: Neoplastic meningitis, also known as leptomeningeal disease, affects the entire neuraxis. The clinical manifestations of the disease may affect the cranial nerves, cerebral hemispheres, or the spine. Because of the extent of disease involvement, treatment options and disease staging should involve all compartments of the cerebrospinal fluid (CSF) and subarachnoid space. Few studies of patients with primary brain tumors have specifically addressed treatment for the secondary complication of neoplastic meningitis. Therapy for neoplastic meningitis is palliative in nature and, rarely, may have a curative intent. METHODS: A review of the medical literature pertinent to neoplastic meningitis in primary brain tumors was performed. The complication of neoplastic meningitis is described in detail for the various types of primary brain tumors. RESULTS: Treatment of neoplastic meningitis is complicated because determining who should receive aggressive, central nervous system (CNS)-directed therapy is difficult. In general, the therapeutic response of neoplastic meningitis is a function of CSF cytology and, secondarily, of the clinical improvement in neurological manifestations related to the disease. CSF cytology may manifest a rostrocaudal disassociation; thus, consecutive, negative findings require that both lumbar and ventricular cytological testing are performed to confirm the complete response. Based on data from several prospective, randomized trials extrapolated to primary brain tumors, the median rate of survival for neoplastic meningitis is several months. Oftentimes, therapy directed at palliation may improve quality of life by protecting patients from experiencing continued neurological deterioration. CONCLUSIONS: Neoplastic meningitis is a complicated disease in which response to therapy varies by histology. Thus, survival rates after CNS-directed therapy will differ by the underlying primary tumor. Optimal therapy of neoplastic meningitis is poorly defined, and few guidelines exist to guide clinicians on the most appropriate choice of therapy. PMID- 28557974 TI - Oncolytic alphavirus SFV-VA7 efficiently eradicates subcutaneous and orthotopic human prostate tumours in mice. AB - BACKGROUND: Despite recent therapeutic and diagnostic advances, prostate cancer remains the second leading cause of cancer-related deaths among men in the Western world. Oncolytic viruses that replicate selectively in tumour cells represent a novel treatment candidate for these malignancies. METHODS: We analysed infectivity of avirulent Semliki Firest virus SFV-VA7 in human prostate cancer cell lines VCaP, LNCaP and 22Rv1 and in nonmalignant prostate epithelial cell line RWPE-1. Therapeutic potency of SFV-VA7 was evaluated in subcutaneous and orthotopic mouse LNCaP xenograft models. RESULTS: SFV-VA7 infected and killed the tested human prostate cancer cell lines irrespective of their hormone response status, while the nonmalignant prostate epithelial cell line RWPE-1 proved highly virus resistant. Notably, a single peritoneal dose of SFV-VA7 was sufficient to eradicate all subcutaneous and orthotopic LNCaP tumours. CONCLUSIONS: Our results indicate that SFV-VA7 is a novel, promising therapeutic virus against prostate cancer warranting further testing in early clinical trials. PMID- 28557975 TI - The differential expression of omega-3 and omega-6 fatty acid metabolising enzymes in colorectal cancer and its prognostic significance. AB - BACKGROUND: Colorectal cancer is a common malignancy and one of the leading causes of cancer-related deaths. The metabolism of omega fatty acids has been implicated in tumour growth and metastasis. METHODS: This study has characterised the expression of omega fatty acid metabolising enzymes CYP4A11, CYP4F11, CYP4V2 and CYP4Z1 using monoclonal antibodies we have developed. Immunohistochemistry was performed on a tissue microarray containing 650 primary colorectal cancers, 285 lymph node metastasis and 50 normal colonic mucosa. RESULTS: The differential expression of CYP4A11 and CYP4F11 showed a strong association with survival in both the whole patient cohort (hazard ratio (HR)=1.203, 95% CI=1.092-1.324, chi2=14.968, P=0.001) and in mismatch repair-proficient tumours (HR=1.276, 95% CI=1.095-1.488, chi2=9.988, P=0.007). Multivariate analysis revealed that the differential expression of CYP4A11 and CYP4F11 was independently prognostic in both the whole patient cohort (P=0.019) and in mismatch repair proficient tumours (P=0.046). CONCLUSIONS: A significant and independent association has been identified between overall survival and the differential expression of CYP4A11 and CYP4F11 in the whole patient cohort and in mismatch repair-proficient tumours. PMID- 28557977 TI - Akt as a target for cancer therapy: more is not always better (lessons from studies in mice). AB - The PI3K/Akt signalling pathway is one of the most frequently altered signalling networks in human cancers and has become an attractive target in anticancer therapy. Several drugs targeting this pathway are currently in different phases of clinical trials. However, accumulating reports suggest that adverse effects such as hyperglycaemia and hyperinsulinaemia accompany treatment with pan-PI3K and pan-Akt inhibitors. Thus, understanding the consequences of the systemic deletion or inhibition of Akt activity in vivo is imperative. Three Akt isoforms may individually affect different cancer cells in culture to varying degrees that could suggest specific targeting of different Akt isoforms for different types of cancer. However, the results obtained in cell culture do not address the consequences of Akt isoform inhibition at the organismal level and consequently fail to predict the feasibility of targeting these isoforms for cancer therapy. This review summarises and discusses the consequences of genetic deletions of Akt isoforms in adult mice and their implications for cancer therapy. Whereas combined Akt1 and Akt2 rapidly induced mortality, hepatic Akt inhibition induced liver injury that promotes hepatocellular carcinoma. These findings may explain some of the side effects exerted by pan-PI3K and pan-Akt inhibitors and suggest that close attention must be paid when targeting all Akt isoforms as a therapeutic intervention. PMID- 28557976 TI - Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia. AB - BACKGROUND: In B-cell precursor acute lymphoblastic leukaemia (B-ALL), the identification of additional genetic alterations associated with poor prognosis is still of importance. We determined the frequency and prognostic impact of somatic mutations in children and adult cases with B-ALL treated with Spanish PETHEMA and SEHOP protocols. METHODS: Mutational status of hotspot regions of TP53, JAK2, PAX5, LEF1, CRLF2 and IL7R genes was determined by next-generation deep sequencing in 340 B-ALL patients (211 children and 129 adults). The associations between mutation status and clinicopathological features at the time of diagnosis, treatment outcome and survival were assessed. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with overall survival (OS), event-free survival (EFS) and relapse rate (RR). RESULTS: A mutation rate of 12.4% was identified. The frequency of adult mutations was higher (20.2% vs 7.6%, P=0.001). TP53 was the most frequently mutated gene (4.1%), followed by JAK2 (3.8%), CRLF2 (2.9%), PAX5 (2.4%), LEF1 (0.6%) and IL7R (0.3%). All mutations were observed in B-ALL without ETV6-RUNX1 (P=0.047) or BCR-ABL1 fusions (P<0.0001). In children, TP53mut was associated with lower OS (5-year OS: 50% vs 86%, P=0.002) and EFS rates (5-year EFS: 50% vs 78.3%, P=0.009) and higher RR (5-year RR: 33.3% vs 18.6% P=0.037), and was independently associated with higher RR (hazard ratio (HR)=4.5; P=0.04). In adults, TP53mut was associated with a lower OS (5-year OS: 0% vs 43.3%, P=0.019) and a higher RR (5-year RR: 100% vs 61.4%, P=0.029), whereas JAK2mut was associated with a lower EFS (5-year EFS: 0% vs 30.6%, P=0.035) and a higher RR (5 year RR: 100% vs 60.4%, P=0.002). TP53mut was an independent risk factor for shorter OS (HR=2.3; P=0.035) and, together with JAK2mut, also were independent markers of poor prognosis for RR (TP53mut: HR=5.9; P=0.027 and JAK2mut: HR=5.6; P=0.036). CONCLUSIONS: TP53mut and JAK2mut are potential biomarkers associated with poor prognosis in B-ALL patients. PMID- 28557979 TI - Cas9 in action: no more known unknowns? PMID- 28557980 TI - E-scape: interactive visualization of single-cell phylogenetics and cancer evolution. PMID- 28557978 TI - Prevalence of somatic mitochondrial mutations and spatial distribution of mitochondria in non-small cell lung cancer. AB - BACKGROUND: Mitochondria are considered relevant players in many tumour entities and first data indicate beneficial effects of mitochondria-targeted antioxidants in both cancer prevention and anticancer therapies. To further dissect the potential roles of mitochondria in NSCLC we comprehensively analysed somatic mitochondrial mutations, determined the spatial distribution of mitochondrial DNA within complete tumour sections and investigated the mitochondrial load in a large-scale approach. METHODS: Whole mitochondrial genome sequencing of 26 matched tumour and non-neoplastic tissue samples extended by reviewing published data of 326 cases. Systematical stepwise real-time PCR quantification of mitochondrial DNA covering 16 whole surgical tumour sections. Immunohistochemical determination of the mitochondrial load in 171 adenocarcinoma and 145 squamous cell carcinoma. RESULTS: Our results demonstrate very low recurrences (max. 1.7%) and a broad distribution of 456 different somatic mitochondrial mutations. Large inter- and intra-tumour heterogeneity were seen for mitochondrial DNA copy numbers in conjunction with a correlation to the predominant histological growth pattern. Furthermore, tumour cells had significantly higher mitochondrial level compared to adjacent stroma, whereas differences between tumour entities were negligible. CONCLUSIONS: Non-evident somatic mitochondrial mutations and highly varying mitochondrial DNA level delineate challenges for the approach of mitochondria-targeted anticancer therapies in NSCLC. PMID- 28557981 TI - Unexpected mutations after CRISPR-Cas9 editing in vivo. PMID- 28557982 TI - Digenome-seq web tool for profiling CRISPR specificity. PMID- 28557983 TI - Organoids: a better in vitro model. PMID- 28557984 TI - AEDT: A new concept for ecological dynamics in the ever-changing world. AB - The important concept of equilibrium has always been controversial in ecology, but a new, more general concept, an asymptotic environmentally determined trajectory (AEDT), overcomes many concerns with equilibrium by realistically incorporating long-term climate change while retaining much of the predictive power of a stable equilibrium. A population or ecological community is predicted to approach its AEDT, which is a function of time reflecting environmental history and biology. The AEDT invokes familiar questions and predictions but in a more realistic context in which consideration of past environments and a future changing profoundly due to human influence becomes possible. Strong applications are also predicted in population genetics, evolution, earth sciences, and economics. PMID- 28557985 TI - Adaptation towards scale-free dynamics improves cortical stimulus discrimination at the cost of reduced detection. AB - Fundamental to the function of nervous systems is the ability to reorganize to cope with changing sensory input. Although well-studied in single neurons, how such adaptive versatility manifests in the collective population dynamics and function of cerebral cortex remains unknown. Here we measured population neural activity with microelectrode arrays in turtle visual cortex while visually stimulating the retina. First, we found that, following the onset of stimulation, adaptation tunes the collective population dynamics towards a special regime with scale-free spatiotemporal activity, after an initial large-scale transient response. Concurrently, we observed an adaptive tradeoff between two important aspects of population coding-sensory detection and discrimination. As adaptation tuned the cortex toward scale-free dynamics, stimulus discrimination was enhanced, while stimulus detection was reduced. Finally, we used a network-level computational model to show that short-term synaptic depression was sufficient to mechanistically explain our experimental results. In the model, scale-free dynamics emerge only when the model operates near a special regime called criticality. Together our model and experimental results suggest unanticipated functional benefits and costs of adaptation near criticality in visual cortex. PMID- 28557987 TI - Study of 2-aminoquinolin-4(1H)-one under Mannich and retro-Mannich reaction. AB - 2-Aminoquinolin-4(1H)-one was reacted with various primary/secondary amines and paraformaldehyde under Mannich reaction conditions. In the case of secondary amines, the reaction in N,N-dimethylformamide yielded expected Mannich products accompanied with 3,3'-methylenebis(2-aminoquinolin-4(1H)-one). Except these main products, the pyrimido[4,5-b]quinolin-5-one derivative was also identified as co product. The reaction with primary amines led to the formation of pyrimido[4,5 b]quinolin-5-ones. The Mannich reaction products were thermally unstable and afforded a mixture of bis-(2-aminoquinolin-4(1H)-one) and tris-(2-aminoquinolin 4(1H)-one) derivative, probably via reactive methylene species. This retro Mannich reaction was tested in reaction with indole and thiophenole as nucleophilles, and appropriate conjugates were formed. The mechanism of above discussed reactions in which 2-aminoquinolinone displays the nucleophilicity on C3 carbon as well as N2 nitrogen is discussed. PMID- 28557986 TI - Epitope mapping of recombinant Leishmania donovani virulence factor A2 (recLdVFA2) and canine leishmaniasis diagnosis using a derived synthetic bi epitope. AB - BACKGROUND: Leishmaniasis is one of the most important zoonotic diseases spread in Latin America. Since many species are involved in dog infection with different clinical manifestations, the development of specific diagnostic tests is mandatory for more accurate disease control and vaccine strategies. METHODOLOGY/PRINCIPAL FINDINGS: Seventy-five 15-mer peptides covering the sequence of recombinant Leishmania donovani virulence factor A2 (recLdVFA2) protein were prepared by Spot synthesis. Membrane-bound peptides immunoreactivity with sera from dogs immunized with recLdVFA2 and with a specific anti-recLdVFA2 monoclonal antibody allowed mapping of continuous B-cell epitopes. Five epitopes corresponding to the N-terminal region of recLdVFA2 (MKIRSVRPLVVLLVC, RSVRPLVVLLVCVAA, RPLVVLLVCVAAVLA, VVLLVCVAAVLALSA and LVCVAAVLALSASAE, region 1 28) and one located within the repetitive units (PLSVGPQAVGLSVG, regions 67-81 and 122-135) were identified. A 34-mer recLdVFA2-derived bi-epitope containing the sequence MKIRSVRPLVVLLVC linked to PLSVGPQAVGLSVG by a Gly-Gly spacer was chemically synthesized in its soluble form. The synthetic bi-epitope was used as antigen to coat ELISA plates and assayed with dog sera for in vitro diagnosis of canine visceral leishmaniasis (CVL). The assay proved to be highly sensitive (98%) and specific (99%). CONCLUSIONS/SIGNIFICANCE: Our work suggests that synthetic peptide-based ELISA strategy may be useful for the development of a sensitive and highly specific serodiagnosis for CVL or other parasitic diseases. PMID- 28557988 TI - Synergy of circulating miR-212 with markers for cardiovascular risks to enhance estimation of atherosclerosis presence. AB - Synergy of specific microRNAs (miRNAs) with cardiovascular risk factors to estimate atherosclerosis presence in ischemic stroke patients has not been investigated. The present study aimed to identify atherosclerosis-related circulating miRNAs and to evaluate interaction with other cardiovascular markers to improve the estimation of atherosclerosis presence. We performed a miRNA profiling study using serum of 15 patients with acute ischemic stroke who were classified by the presence of no (n = 8) or severe (n = 7) stenosis on intracranial and extracranial vessels, which identified miR-212, -372, -454, and 744 as miRNAs related with atherosclerosis presence. Of the 4 miRNAs, only miR 212 showed a significant increase in expression in atherosclerosis patients in a validation study (atherosclerotic patients, n = 32, non-atherosclerotic patients, n = 33). Hemoglobin A1c, a high-density lipoprotein cholesterol, and lipoprotein(a), both established risk markers, were independently related with atherosclerosis presence in the validation population. miR-212 enhanced the accuracy of atherosclerosis presence by the three existing markers (three markers, 78.5%; three markers+miR-212, 84.6%, P<0.05) and significantly added to the area under the receiver operating characteristic curve (three markers, 0.8258; three markers+miR-212, 0.8646, P<0.05). The inclusion of miR-212 increased the reclassification index calculated using net reclassification improvement (0.4527, P<0.05) and integrated discrimination improvement (0.0737, P<0.05). We identified circulating miR-212 as a novel marker of atherosclerosis. miR-212 enhanced the estimation of atherosclerosis presence in combination with hemoglobin A1c, high-density lipoprotein cholesterol, and lipoprotein(a). Thus, miR-212 is expected to improve the estimation of atherosclerosis using peripheral blood of patients. PMID- 28557990 TI - On the effects of alternative optima in context-specific metabolic model predictions. AB - The integration of experimental data into genome-scale metabolic models can greatly improve flux predictions. This is achieved by restricting predictions to a more realistic context-specific domain, like a particular cell or tissue type. Several computational approaches to integrate data have been proposed-generally obtaining context-specific (sub)models or flux distributions. However, these approaches may lead to a multitude of equally valid but potentially different models or flux distributions, due to possible alternative optima in the underlying optimization problems. Although this issue introduces ambiguity in context-specific predictions, it has not been generally recognized, especially in the case of model reconstructions. In this study, we analyze the impact of alternative optima in four state-of-the-art context-specific data integration approaches, providing both flux distributions and/or metabolic models. To this end, we present three computational methods and apply them to two particular case studies: leaf-specific predictions from the integration of gene expression data in a metabolic model of Arabidopsis thaliana, and liver-specific reconstructions derived from a human model with various experimental data sources. The application of these methods allows us to obtain the following results: (i) we sample the space of alternative flux distributions in the leaf- and the liver specific case and quantify the ambiguity of the predictions. In addition, we show how the inclusion of l1-regularization during data integration reduces the ambiguity in both cases. (ii) We generate sets of alternative leaf- and liver specific models that are optimal to each one of the evaluated model reconstruction approaches. We demonstrate that alternative models of the same context contain a marked fraction of disparate reactions. Further, we show that a careful balance between model sparsity and metabolic functionality helps in reducing the discrepancies between alternative models. Finally, our findings indicate that alternative optima must be taken into account for rendering the context-specific metabolic model predictions less ambiguous. PMID- 28557989 TI - Association between expansion of primary healthcare and racial inequalities in mortality amenable to primary care in Brazil: A national longitudinal analysis. AB - BACKGROUND: Universal health coverage (UHC) can play an important role in achieving Sustainable Development Goal (SDG) 10, which addresses reducing inequalities, but little supporting evidence is available from low- and middle income countries. Brazil's Estrategia de Saude da Familia (ESF) (family health strategy) is a community-based primary healthcare (PHC) programme that has been expanding since the 1990s and is the main platform for delivering UHC in the country. We evaluated whether expansion of the ESF was associated with differential reductions in mortality amenable to PHC between racial groups. METHODS AND FINDINGS: Municipality-level longitudinal fixed-effects panel regressions were used to examine associations between ESF coverage and mortality from ambulatory-care-sensitive conditions (ACSCs) in black/pardo (mixed race) and white individuals over the period 2000-2013. Models were adjusted for socio economic development and wider health system variables. Over the period 2000 2013, there were 281,877 and 318,030 ACSC deaths (after age standardisation) in the black/pardo and white groups, respectively, in the 1,622 municipalities studied. Age-standardised ACSC mortality fell from 93.3 to 57.9 per 100,000 population in the black/pardo group and from 75.7 to 49.2 per 100,000 population in the white group. ESF expansion (from 0% to 100%) was associated with a 15.4% (rate ratio [RR]: 0.846; 95% CI: 0.796-0.899) reduction in ACSC mortality in the black/pardo group compared with a 6.8% (RR: 0.932; 95% CI: 0.892-0.974) reduction in the white group (coefficients significantly different, p = 0.012). These differential benefits were driven by greater reductions in mortality from infectious diseases, nutritional deficiencies and anaemia, diabetes, and cardiovascular disease in the black/pardo group. Although the analysis is ecological, sensitivity analyses suggest that over 30% of black/pardo deaths would have to be incorrectly coded for the results to be invalid. This study is limited by the use of municipal-aggregate data, which precludes individual-level inference. Omitted variable bias, where factors associated with ESF expansion are also associated with changes in mortality rates, may have influenced our findings, although sensitivity analyses show the robustness of the findings to pre-ESF trends and the inclusion of other municipal-level factors that could be associated with coverage. CONCLUSIONS: PHC expansion is associated with reductions in racial group inequalities in mortality in Brazil. These findings highlight the importance of investment in PHC to achieve the SDGs aimed at improving health and reducing inequalities. PMID- 28557992 TI - Seasonal monitoring of deep-sea megabenthos in Barkley Canyon cold seep by internet operated vehicle (IOV). AB - Knowledge of the processes shaping deep-sea benthic communities at seasonal scales in cold-seep environments is incomplete. Cold seeps within highly dynamic regions, such as submarine canyons, where variable current regimes may occur, are particularly understudied. Novel Internet Operated Vehicles (IOVs), such as tracked crawlers, provide new techniques for investigating these ecosystems over prolonged periods. In this study a benthic crawler connected to the NEPTUNE cabled infrastructure operated by Ocean Networks Canada was used to monitor community changes across 60 m2 of a cold-seep area of the Barkley Canyon, North East Pacific, at ~890 m depth within an Oxygen Minimum Zone (OMZ). Short video transects were run at 4-h intervals during the first week of successive calendar months, over a 14 month period (February 14th 2013 to April 14th 2014). Within each recorded transect video megafauna abundances were computed and changes in environmental conditions concurrently measured. The responses of fauna to environmental conditions as a proxy of seasonality were assessed through analysis of abundances in a total of 438 video-transects (over 92 h of total footage). 7698 fauna individuals from 6 phyla (Cnidaria, Ctenophora, Arthropoda, Echinodermata, Mollusca, and Chordata) were logged and patterns in abundances of the 7 most abundant taxa (i.e. rockfish Sebastidae, sablefish Anoplopoma fimbria, hagfish Eptatretus stoutii, buccinids (Buccinoidea), undefined small crabs, ctenophores Bolinopsis infundibulum, and Scyphomedusa Poralia rufescens) were identified. Patterns in the reproductive behaviour of the grooved tanner crab (Chionnecetes tanneri) were also indicated. Temporal variations in biodiversity and abundance in megabenthic fauna was significantly influenced by variabilities in flow velocity flow direction (up or down canyon), dissolved oxygen concentration and month of study. Also reported here for the first time are transient mass aggregations of grooved tanner crabs through these depths of the canyon system, in early spring and likely linked to the crab's reproductive cycle. PMID- 28557991 TI - Socioeconomic indicators in epidemiologic research: A practical example from the LIFEPATH study. AB - BACKGROUND: Several social indicators have been used in epidemiological research to describe socioeconomic position (SEP) of people in societies. Among SEP indicators, those more frequently used are education, occupational class and income. Differences in the incidence of several health outcomes have been reported consistently, independently from the indicator employed. Main objectives of the study were to present the socioeconomic classifications of the social indicators which will be employed throughout the LIFEPATH project and to compare social gradients in all-cause mortality observed in the participating adult cohorts using the different SEP indicators. METHODS: Information on the available social indicators (education, own and father's occupational class, income) from eleven adult cohorts participating in LIFEPATH was collected and harmonized. Mortality by SEP for each indicator was estimated by Poisson regression on each cohort and then evaluated using a meta-analytical approach. RESULTS: In the meta analysis, among men mortality was significantly inversely associated with both occupational class and education, but not with father's occupational class; among women, the increase in mortality in lower social strata was smaller than among men and, except for a slight increase in the lowest education category, no significant differences were found. CONCLUSIONS: Among men, the proposed three level classifications of occupational class and education were found to predict differences in mortality which is consistent with previous research. Results on women suggest that classifying them through their sole SEP, without considering that of their partners, may imply a misclassification of their social position leading to attenuation of mortality differences. PMID- 28557993 TI - Local introduction and heterogeneous spatial spread of dengue-suppressing Wolbachia through an urban population of Aedes aegypti. AB - Dengue-suppressing Wolbachia strains are promising tools for arbovirus control, particularly as they have the potential to self-spread following local introductions. To test this, we followed the frequency of the transinfected Wolbachia strain wMel through Ae. aegypti in Cairns, Australia, following releases at 3 nonisolated locations within the city in early 2013. Spatial spread was analysed graphically using interpolation and by fitting a statistical model describing the position and width of the wave. For the larger 2 of the 3 releases (covering 0.97 km2 and 0.52 km2), we observed slow but steady spatial spread, at about 100-200 m per year, roughly consistent with theoretical predictions. In contrast, the smallest release (0.11 km2) produced erratic temporal and spatial dynamics, with little evidence of spread after 2 years. This is consistent with the prediction concerning fitness-decreasing Wolbachia transinfections that a minimum release area is needed to achieve stable local establishment and spread in continuous habitats. Our graphical and likelihood analyses produced broadly consistent estimates of wave speed and wave width. Spread at all sites was spatially heterogeneous, suggesting that environmental heterogeneity will affect large-scale Wolbachia transformations of urban mosquito populations. The persistence and spread of Wolbachia in release areas meeting minimum area requirements indicates the promise of successful large-scale population transformation. PMID- 28557994 TI - The societal cost of heroin use disorder in the United States. AB - OBJECTIVE: Heroin use in the United States has reached epidemic proportions. The objective of this paper is to estimate the annual societal cost of heroin use disorder in the United States in 2015 US dollars. METHODS: An analytic model was created that included incarceration and crime; treatment for heroin use disorder; chronic infectious diseases (HIV, Hepatitis B, Hepatitis C, and Tuberculosis) and their treatments; treatment of neonatal abstinence syndrome; lost productivity; and death by heroin overdose. RESULTS: Using literature-based estimates to populate the model, the cost of heroin use disorder was estimated to be $51.2 billion in 2015 US dollars ($50,799 per heroin user). One-way sensitivity analyses showed that overall cost estimates were sensitive to the number of heroin users, cost of HCV treatment, and cost of incarcerating heroin users. CONCLUSION: The annual cost of heroin use disorder to society in the United States emphasizes the need for sustained investment in healthcare and non healthcare related strategies that reduce the likelihood of abuse and provide care and support for users to overcome the disorder. PMID- 28557995 TI - Preparation and characterization of a novel silicon-modified nanobubble. AB - Nanobubbles (NBs) opened a new field of ultrasound imaging. There is still no practical method to control the diameter of bubbles. In this study, we developed a new method to control the size by incorporating of silicon hybrid lipids into the bubble membrane. The range of particle size of resulting NBs is between 523.02 +/- 46.45 to 857.18 +/- 82.90, smaller than the conventional microbubbles. The size of resulting NBs increased with the decrease in amount of silicon hybrid lipids, indicating the diameter of NBs can be regulated through modulating the ratio of silicon hybrid lipids in the bubble shell. Typical harmonic signals could be detected. The in vitro and in vivo ultrasound imaging experiments demonstrated these silicon-modified NBs had significantly improved ultrasound contrast enhancement abilities. Cytotoxicity assays revealed that these NBs had no obvious cytotoxicity to the 293 cell line at the tested bubble concentration. Our results showed that the novel NBs could use as nanoscale ultrasound contrast agents, providing the foundation for NBs in future applications including contrast-enhanced imaging and drug/gene delivery. PMID- 28557997 TI - How genetic variation is affected by geographic environments and ploidy level in Erianthus arundinaceus? AB - Erianthus arundinaceus is not only a candidate plant for sugarcane breeding programs, but also a potential bioenergy grass. Genetic variation that is affected by geographic environments and ploidy level is very important for the utilization of Erianthus arundinaceus. In this study, effects of geographic environments and ploidy level on genetic variation were studied through analyzing the genetic diversity, genetic similarity and cluster analysis of 46 E. arundinaceus materials from natural habitats in China by using 7 ISSRs and 15 SSRs. Results showed that: 1) Seven ISSRs generated total 66 bands, of which 77% were polymorphic bands, the Nei's genetic similarity coefficient of tested materials ranged from 0.642 to 0.904 with an average value of 0.765. Fifteen SSRs generated 138 bands, of which 81% were polymorphic bands, the Nei's genetic similarity coefficient of tested materials ranged from 0.634 to 0.963 with an average value of 0.802. The results indicated great genetic diversity existed in the tested materials. 2)The tested materials were clustered into 3 groups and 7 subgroups, which demonstrated a strong geographic effect on variation of the local E. arundinaceus, and weak relationship was found between genetic distance and geographic distance. Five tetraploid materials were not clustered together, and were clustered together with materials from similar geographical location. 3) The genetic variation and cluster results were affected by geographic landforms and environments, the gene flow was blocked by Ocean and mountains, and promoted by river. The effect of ploidy level on genetic variation was little. PMID- 28557998 TI - Hard real-time closed-loop electrophysiology with the Real-Time eXperiment Interface (RTXI). AB - The ability to experimentally perturb biological systems has traditionally been limited to static pre-programmed or operator-controlled protocols. In contrast, real-time control allows dynamic probing of biological systems with perturbations that are computed on-the-fly during experimentation. Real-time control applications for biological research are available; however, these systems are costly and often restrict the flexibility and customization of experimental protocols. The Real-Time eXperiment Interface (RTXI) is an open source software platform for achieving hard real-time data acquisition and closed-loop control in biological experiments while retaining the flexibility needed for experimental settings. RTXI has enabled users to implement complex custom closed-loop protocols in single cell, cell network, animal, and human electrophysiology studies. RTXI is also used as a free and open source, customizable electrophysiology platform in open-loop studies requiring online data acquisition, processing, and visualization. RTXI is easy to install, can be used with an extensive range of external experimentation and data acquisition hardware, and includes standard modules for implementing common electrophysiology protocols. PMID- 28557996 TI - The cell non-autonomous function of ATG-18 is essential for neuroendocrine regulation of Caenorhabditis elegans lifespan. AB - Dietary restriction (DR) and reduced insulin growth factor (IGF) signaling extend lifespan in Caenorhabditis elegans and other eukaryotic organisms. Autophagy, an evolutionarily conserved lysosomal degradation pathway, has emerged as a central pathway regulated by various longevity signals including DR and IGF signaling in promoting longevity in a variety of eukaryotic organisms. However, the mechanism remains unclear. Here we show that the autophagy protein ATG-18 acts cell non autonomously in neuronal and intestinal tissues to maintain C. elegans wildtype lifespan and to respond to DR and IGF-mediated longevity signaling. Moreover, ATG 18 activity in chemosensory neurons that are involved in food detection sufficiently mediates the effect of these longevity pathways. Additionally, ATG 18-mediated cell non-autonomous signaling depends on the release of neurotransmitters and neuropeptides. Interestingly, our data suggest that neuronal and intestinal ATG-18 acts in parallel and converges on unidentified neurons that secrete neuropeptides to regulate C. elegans lifespan through the transcription factor DAF-16/FOXO in response to reduced IGF signaling. PMID- 28557999 TI - Treatment of AKI in developing and developed countries: An international survey of pediatric dialysis modalities. AB - HYPOTHESIS: Acute kidney injury (AKI) is a common cause of morbidity and mortality worldwide, with a pediatric incidence ranging from 19.3% to 24.1%. Treatment of pediatric AKI is a source of debate in varying geographical regions. Currently CRRT is the treatment for pediatric AKI, but limitations due to cost and accessibility force use of adult equipment and other therapeutic options such as peritoneal dialysis (PD) and hemodialysis (HD). It was hypothesized that more cost-effective measures would likely be used in developing countries due to lesser resource availability. METHODS: A 26-question internet-based survey was distributed to 650 pediatric Nephrologists. There was a response rate of 34.3% (223 responses). The survey was distributed via pedneph and pcrrt email servers, inquiring about demographics, technology, resources, pediatric-specific supplies, and preference in renal replacement therapy (RRT) in pediatric AKI. The main method of analysis was to compare responses about treatments between nephrologists in developed countries and nephrologists in developing countries using difference-of-proportions tests. RESULTS: PD was available in all centers surveyed, while HD was available in 85.1% and 54.1% (p = 0.00), CRRT was available in 60% and 33.3% (p = 0.001), and SLED was available in 20% and 25% (p = 0.45) centers of developed and developing world respectively. In developing countries, 68.5% (p = 0.000) of physicians preferred PD to costlier therapies, while in developed countries it was found that physicians favored HD (72%, p = 0.00) or CRRT (24%, p = 0.041) in infants. CONCLUSIONS: Lack of availability of resources, trained physicians and funds often preclude standards of care in developing countries, and there is much development needed in terms of meeting higher global standards for treating pediatric AKI patients. PD remains the main modality of choice for treatment of AKI in infants in developing world. PMID- 28558000 TI - Working memory training in healthy young adults: Support for the null from a randomized comparison to active and passive control groups. AB - Training of working memory as a method of increasing working memory capacity and fluid intelligence has received much attention in recent years. This burgeoning field remains highly controversial with empirically-backed disagreements at all levels of evidence, including individual studies, systematic reviews, and even meta-analyses. The current study investigated the effect of a randomized six week online working memory intervention on untrained cognitive abilities in a community-recruited sample of healthy young adults, in relation to both a processing speed training active control condition, as well as a no-contact control condition. Results of traditional null hypothesis significance testing, as well as Bayesian factor analyses, revealed support for the null hypothesis across all cognitive tests administered before and after training. Importantly, all three groups were similar at pre-training for a variety of individual variables purported to moderate transfer of training to fluid intelligence, including personality traits, motivation to train, and expectations of cognitive improvement from training. Because these results are consistent with experimental trials of equal or greater methodological rigor, we suggest that future research re-focus on: 1) other promising interventions known to increase memory performance in healthy young adults, and; 2) examining sub-populations or alternative populations in which working memory training may be efficacious. PMID- 28558002 TI - Electroencephalogram-based decoding cognitive states using convolutional neural network and likelihood ratio based score fusion. AB - Electroencephalogram (EEG)-based decoding human brain activity is challenging, owing to the low spatial resolution of EEG. However, EEG is an important technique, especially for brain-computer interface applications. In this study, a novel algorithm is proposed to decode brain activity associated with different types of images. In this hybrid algorithm, convolutional neural network is modified for the extraction of features, a t-test is used for the selection of significant features and likelihood ratio-based score fusion is used for the prediction of brain activity. The proposed algorithm takes input data from multichannel EEG time-series, which is also known as multivariate pattern analysis. Comprehensive analysis was conducted using data from 30 participants. The results from the proposed method are compared with current recognized feature extraction and classification/prediction techniques. The wavelet transform support vector machine method is the most popular currently used feature extraction and prediction method. This method showed an accuracy of 65.7%. However, the proposed method predicts the novel data with improved accuracy of 79.9%. In conclusion, the proposed algorithm outperformed the current feature extraction and prediction method. PMID- 28558001 TI - Reverse epitope mapping of the E2 glycoprotein in antibody associated hepatitis C virus. AB - The humoral immune system responds to chronic hepatitis C virus (HCV) infection by producing neutralising antibodies (nAb). In this study we generated three HCV pseudoparticles in which E1E2 glycoprotein sequence was targeted by the host humoral immune system. We used patient derived virus free Fabs (VF-Fabs) obtained from HCV genotype 1a (n = 3), genotype 1b (n = 7) and genotype 3a (n = 1) for neutralisation of HCVpp produced in this study both individually and in combination. Based on the available anti-HCV monoclonal nAb mapping information we selected amino acid region 384-619 for conformational epitope mapping. Amongst our notable findings, we observed significant reduction in HCVpp infectivity (p<0.05) when challenged with a combination of inter genotype and subtype VF Fabs. We also identified five binding motifs targeted by patient derived VF-Fab upon peptide mapping, of which two shared the residues with previously reported epitopes. One epitope lies within an immunodominant HVR1 and two were novel. In summary, we used a reverse epitope mapping strategy to identify preferred epitopes by the host humoral immune system. Additionally, we have combined different VF-Fabs to further reduce the HCVpp infectivity. Our data indicates that combining the antigen specificity of antibodies may be a useful strategy to reduce (in-vitro) infectivity. PMID- 28558003 TI - The genetic diversity of commensal Escherichia coli strains isolated from non antimicrobial treated pigs varies according to age group. AB - This is the first report on the genetic diversity of commensal E. coli from pigs reared in an antibiotic free production system and belonging to different age groups. The study investigated the genetic diversity and relationship of 900 randomly collected commensal E. coli strains from non-antimicrobial treated pigs assigned to five different age groups in a Danish farm. Fifty-two unique REP profiles were detected suggesting a high degree of diversity. The number of strains per pig ranged from two to 13. The highest and the lowest degree of diversity were found in the early weaners group (Shannon diversity index, H' of 2.22) and piglets (H' of 1.46) respectively. The REP profiles, R1, R7 and R28, were the most frequently observed in all age groups. E. coli strains representing each REP profile and additional strains associated with the dominant profiles were subjected to PFGE and were assigned to 67 different genotypes. Whole genome sequence analysis of 52 isolates leading to unique REP profiles identified a high level of sequence variation. Six and six strains were assigned to sequence type ST10 and sequence type ST58, respectively. Virulence and antimicrobial resistance genes, as well as, genes associated with mobile genetic elements were commonly found among these commensal E. coli strains. Interestingly, strains yielding the three most common REP profiles clustered together in the SNPs phylogenetic tree, and such strains may represent the archetypal commensal E. coli in Danish pigs. PMID- 28558004 TI - Diagnostic potential of multimodal neuroimaging in posttraumatic stress disorder. AB - Despite accumulating evidence of physiological abnormalities related to posttraumatic stress disorder (PTSD), the current diagnostic criteria for PTSD still rely on clinical interviews. In this study, we investigated the diagnostic potential of multimodal neuroimaging for identifying posttraumatic symptom trajectory after trauma exposure. Thirty trauma-exposed individuals and 29 trauma unexposed healthy individuals were followed up over a 5-year period. Three waves of assessments using multimodal neuroimaging, including structural magnetic resonance imaging (MRI) and diffusion-weighted MRI, were performed. Based on previous findings that the structural features of the fear circuitry-related brain regions may dynamically change during recovery from the trauma, we employed a machine learning approach to determine whether local, connectivity, and network features of brain regions of the fear circuitry including the amygdala, orbitofrontal and ventromedial prefrontal cortex (OMPFC), hippocampus, insula, and thalamus could distinguish trauma-exposed individuals from trauma-unexposed individuals at each recovery stage. Significant improvement in PTSD symptoms was observed in 23%, 52%, and 88% of trauma-exposed individuals at 1.43, 2.68, and 3.91 years after the trauma, respectively. The structural features of the amygdala were found as major classifiers for discriminating trauma-exposed individuals from trauma-unexposed individuals at 1.43 years after the trauma, but these features were nearly normalized at later phases when most of the trauma exposed individuals showed clinical improvement in PTSD symptoms. Additionally, the structural features of the OMPFC showed consistent predictive values throughout the recovery period. In conclusion, the current study provides a promising step forward in the development of a clinically applicable predictive model for diagnosing PTSD and predicting recovery from PTSD. PMID- 28558006 TI - Pulse Doppler ultrasound as a tool for the diagnosis of chronic testicular dysfunction in stallions. AB - Testicular function is particularly susceptible to vascular insult, resulting in a negative impact on sperm production and quality of the ejaculate. A prompt diagnosis of testicular dysfunction enables implementation of appropriate treatment, hence improving fertility forecasts for stallions. The present research aims to: (1) assess if Doppler ultrasonography is a good tool to diagnose stallions with testicular dysfunction; (2) to study the relationship between Doppler parameters of the testicular artery and those of sperm quality assessed by flow cytometry and (3) to establish cut off values to differentiate fertile stallions from those with pathologies causing testicular dysfunction. A total of 10 stallions (n: 7 healthy stallions and n: 3 sub-fertile stallions) were used in this study. Two ejaculates per stallion were collected and preserved at 5 degrees C in a commercial extender. The semen was evaluated at T0, T24 and T48h by flow cytometry. Integrity and viability of sperm (YoPro(r)-1/EthD-1), mitochondrial activity (MitoTracker(r) Deep Red FM) and the DNA fragmentation index (Sperm Chromatin Structure Assay) were assessed. Doppler parameters were measured at three different locations on the testicular artery (Supratesticular artery (SA); Capsular artery (CA) and Intratesticular artery (IA)). The Doppler parameters calculated were: Resistive Index (RI), Pulsatility Index (PI), Peak Systolic Velocity (PSV), End Diastolic Velocity (EDV), Time Average Maximum Velocity (TAMV), Total Arterial Blood Flow (TABF) and TABF rate. The capsular artery was the most reliable location to carry out spectral Doppler assessment, since blood flow parameters of this artery were most closely correlated with sperm quality parameters. Significant differences in all the Doppler parameters studied were observed between fertile and subfertile stallions (p <= 0.05). The principal components analysis assay determined that fertile stallions are characterized by high EDV, TAMV, TABF and TABF rate values (high vascular perfusion). In contrast, subfertile stallions tend to present high values of PI and RI (high vascular resistance). The ROC curves revealed that the best Doppler parameters to predict sperm quality in stallions were: Doppler velocities (PSV, EDV and TAMV), the diameter of the capsular artery and TABF parameters (tissue perfusion parameters). Cut off values were established using a Youden's Index to identify fertile stallions from stallions with testicular dysfunction. Spectral Doppler ultrasound is a good predictive tool for sperm quality since correlations were determined among Doppler parameters and markers of sperm quality. Doppler ultrasonography could be a valuable diagnostic tool for use by clinical practitioners for the diagnosis of stallions with testicular dysfunction and could be a viable alternative to invasive procedures traditionally used for diagnosis of sub-fertility disorders. PMID- 28558005 TI - The pathogenic role of interleukin-22 and its receptor during UVB-induced skin inflammation. AB - Recent studies show that IL-22, a cytokine produced by activated CD4+ T cells and NK cells, plays a pathogenic role in acute and chronic skin diseases. While IL-22 is produced by immune cells, the expression of IL-22Ralpha, the functional subunit of IL-22R, is mostly restricted to non-hematopoietic cells in organs such as the skin and pancreas. Although it is well known that ultraviolet B (UVB) radiation induces skin inflammation, there have been no reports regarding the effect of UVB on the expression of IL-22Ralpha. This study investigated IL 22Ralpha expression and IL-22-mediated proliferation and pro-inflammatory cytokine production by UVB-irradiated keratinocytes. IL-22Ralpha was increased in HaCaT and primary human keratinocytes after UVB irradiation through the translocation of IL-22Ralpha from the cytosol to the membrane. This increase in the expression of IL-22Ralpha was mediated by the PI3K/Akt pathway. Moreover, the suppression of keratinocyte proliferation by UVB irradiation was inhibited by treatment with IL-22. At the same time, IL-22 increased the production of IL 1alpha, IL-6, and IL-18 in UVB-irradiated HaCaT cells and primary human keratinocytes. Finally, IL-22Ralpha expression was increased in UVB-irradiated human and mouse skin by immunohistochemistry. The increased expression of IL 22Ralpha therefore promotes keratinocyte proliferation and pro-inflammatory cytokine production during UVB-induced skin inflammation, suggesting that UVB facilitates skin inflammation by increasing the responsiveness of keratinocytes to IL-22. This study provides a new insight into UVB-induced skin inflammation and the regulation of related inflammatory skin diseases. PMID- 28558007 TI - The clinical significance of accompanying NME on preoperative MR imaging in breast cancer patients. AB - PURPOSE: To investigate the significance of accompanying NME in invasive ductal carcinoma (IDC) on preoperative MR imaging and assess the factors affecting the significance. METHODS: Between January 2015 and February 2016, 163 consecutive patients with IDC who underwent preoperative MR imaging and subsequent surgery were enrolled and reviewed. Index cancer mass size and total extent with accompanying NME on MR images was measured and compared with pathologic size. Positive NME was defined as pathological result of IDC or DCIS. To identify affecting factors associated with frequency of accompanying NME on MR and positive pathologic result, clinicopathologic features were compared between breast cancers with NME and without NME, and between breast cancers with positive NME and negative NME using the Student t-test or Chi-square test. RESULTS: Of the 163 invasive breast cancers, 123(75.5%) cancers presented as only mass feature and 40(24.5%) cancers had accompanying NME around the index mass. Of the 40 accompanying NME, 22 (55%) had positive pathologic results and 18 (45%) had negative results. The HER2 positive status was significantly associated with positive pathologic results of accompanying NME (P = .016). CONCLUSION: Accompanying NME on preoperative MR imaging showed malignant pathologic results in 55%. The HER2 positive IDC was more frequently accompanied by malignant NME. PMID- 28558008 TI - Expression of anaesthetic and analgesic drug target genes in excised breast tumour tissue: Association with clinical disease recurrence or metastasis. AB - BACKGROUND: Retrospective analyses suggest anaesthetic-analgesics technique during cancer surgery may affect recurrence/metastasis. This could involve direct effects of anaesthetic-analgesic drugs on cancer cells. While MU-opioid receptor over-expression in lung tumours is associated with greater metastasis, other anaesthetic-analgesic receptor targets in cancer recurrence/metastasis remain unexplored. Therefore, we evaluated the association between genetic expression of anaesthetic-analgesic receptor targets and recurrence/metastasis, using a repository of breast cancer gene expression and matching clinical data. METHODS: A list of 23 genes encoding for the most prominent anaesthetic-analgesic receptor targets was compiled. This was processed through BreastMark- an algorithm integrating gene expression data from ~17,000 samples and clinical data from >4,500 breast cancer samples. Gene expression data was dichotomized using disease free survival (survival without recurrence) and distant disease-free survival (survival without metastasis) as end points. Hazard ratios were calculated by Cox regression analysis. Enrichment for prognostic markers was determined by randomly choosing 23-member gene lists from all available genes, calculating how often >5 significant markers were observed and adjusting p-values for multiple testing. This was repeated 10,000 times and an empirical p-value calculated. RESULTS: Of 23 selected genes, 9 were significantly associated with altered rates of metastasis and 4 with recurrence on univariate analysis. Adjusting for multiple testing, 5 of these 9 genes remained significantly associated with metastasis, non with recurrence. This ratio of genes (5/23) was not significantly enriched for markers of metastasis (p = 0.07). CONCLUSION: Several anaesthetic-analgesic receptor genes were associated with metastatic spread in breast cancer. Overall there was no significant enrichment in prognostic markers of metastasis, although a trend was observed. PMID- 28558009 TI - Association between aqueous humor and vitreous fluid levels of Th17 cell-related cytokines in patients with proliferative diabetic retinopathy. AB - Inflammation is known to be involved in the progression of diabetic retinopathy. We have recently reported that vitreous levels of IL-4, IL-17A, IL-22, IL-31, and TNFalpha are higher than the respective serum levels in proliferative diabetic retinopathy (PDR) patients, and that vitreous levels of these cytokines are higher in PDR than in other non-inflammatory vitreoretinal diseases or uveitis associated with sarcoidosis. In the present study, we investigated inflammatory cytokines including Th17 cell-related cytokines in aqueous humor samples obtained from eyes with PDR, and analyzed the association between the aqueous humor and vitreous fluid levels of individual cytokines. The study group consisted of 31 consecutive type 2 diabetic patients with PDR who underwent cataract surgery and vitrectomy for vitreous hemorrhage and/or tractional retinal detachment. Undiluted aqueous humor was collected during cataract surgery, and then vitreous fluid was obtained using a 25G vitreous cutter inserted into the mid-vitreous cavity at the beginning of vitrectomy. IL-1beta, IL-4, IL-6, IL-10, IL-17A, IL 17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-gamma, soluble CD40 ligand (sCD40L), and TNFalpha levels in the aqueous humor and vitreous fluid were measured using a beads-array system. Although IL-17A was detected in the aqueous humor of eyes with PDR and the level correlated with IL-17A level in the vitreous fluid, both percent detectable and level of IL-17A in the aqueous humor were significantly lower than those in the vitreous fluid. Vitreous IL-17A level was related significantly to IL-10, IL-22, and TNFalpha levels in aqueous humor as well as in vitreous fluid, On the other hand, aqueous IL-17A level was not related significantly to aqueous or vitreous levels of IL-10, IL-22 or TNFalpha level. The present study demonstrated that IL-17A level and detectable rate in the aqueous humor of patients with PDR are markedly lower than those in the vitreous fluid and aqueous IL-17A does not correlate with vitreous levels of other cytokines, and hence should not be used as a surrogate for IL-17A in the vitreous fluid. PMID- 28558010 TI - Effect of meteorological factors and geographic location on methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci colonization in the US. AB - BACKGROUND: Little is known about the effect of meteorological conditions and geographical location on bacterial colonization rates particularly of antibiotic resistant Gram-positive bacteria. We aimed to evaluate the effect of season, meteorological factors, and geographic location on methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) colonization. METHODS: The prospective cohort included all adults admitted to 20 geographically-dispersed ICUs across the US from September 1, 2011 to October 4, 2012. Nasal and perianal swabs were collected at admission and tested for MRSA and VRE colonization respectively. Poisson regression models using monthly aggregated colonization counts as the outcome and mean temperature, relative humidity, total precipitation, season, and/or latitude as predictors were constructed for each pathogen. RESULTS: A total of 24,704 ICU-admitted patients were tested for MRSA and 24,468 for VRE. On admission, 10% of patients were colonized with MRSA and 12% with VRE. For MRSA and VRE, a 10% increase in relative humidity was associated with approximately a 9% increase in prevalence rate. Southerly latitudes in the US were associated with higher MRSA colonization, while northerly latitudes were associated with higher VRE colonization. In contrast to MRSA, the association between VRE colonization and latitude was observed only after adjusting for relative humidity, which demonstrates how this effect is highly driven by this meteorological factor. CONCLUSIONS: To our knowledge, we are the first to study the effect of meteorological factors and geographical location/latitude on MRSA and VRE colonization in adults. Increasing humidity was associated with greater MRSA and VRE colonization. Southerly latitudes in the US were associated with greater MRSA and less VRE. The effect of these factors on MRSA and VRE rates has the potential not only to inform patient management and treatment, but also infection prevention interventions. PMID- 28558012 TI - Simulation and experimental research on trans-media vehicle water-entry motion characteristics at low speed. AB - The motion characteristics of trans-media vehicles during the water-entry process were explored in this study in an effort to obtain the optimal water-entry condition of the vehicle for developing a novel, single control strategy integrating underwater non-control and in-air control. A water-entry dynamics model is established by combining the water-entry motion characteristics of the vehicle in uncontrolled conditions at low speed with time-varying parameters (e.g. buoyancy, added mass). A water-entry experiment is designed to confirm the effectiveness of the established model. After that, by comparing the experimental results with the simulated results, the model is further modified to more accurately reflect water-entry motion. The change laws of the vehicle's attitude and position during the water-entry process are also obtained by analyzing the simulation of the modified model under different velocity, angle, and angle of attack conditions. The results presented here have guiding significance for the future realization of reaching the stable underwater navigation state of the vehicle after water-entry process. PMID- 28558011 TI - Conserved properties of Drosophila Insomniac link sleep regulation and synaptic function. AB - Sleep is an ancient animal behavior that is regulated similarly in species ranging from flies to humans. Various genes that regulate sleep have been identified in invertebrates, but whether the functions of these genes are conserved in mammals remains poorly explored. Drosophila insomniac (inc) mutants exhibit severely shortened and fragmented sleep. Inc protein physically associates with the Cullin-3 (Cul3) ubiquitin ligase, and neuronal depletion of Inc or Cul3 strongly curtails sleep, suggesting that Inc is a Cul3 adaptor that directs the ubiquitination of neuronal substrates that impact sleep. Three proteins similar to Inc exist in vertebrates-KCTD2, KCTD5, and KCTD17-but are uncharacterized within the nervous system and their functional conservation with Inc has not been addressed. Here we show that Inc and its mouse orthologs exhibit striking biochemical and functional interchangeability within Cul3 complexes. Remarkably, KCTD2 and KCTD5 restore sleep to inc mutants, indicating that they can substitute for Inc in vivo and engage its neuronal targets relevant to sleep. Inc and its orthologs localize similarly within fly and mammalian neurons and can traffic to synapses, suggesting that their substrates may include synaptic proteins. Consistent with such a mechanism, inc mutants exhibit defects in synaptic structure and physiology, indicating that Inc is essential for both sleep and synaptic function. Our findings reveal that molecular functions of Inc are conserved through ~600 million years of evolution and support the hypothesis that Inc and its orthologs participate in an evolutionarily conserved ubiquitination pathway that links synaptic function and sleep regulation. PMID- 28558014 TI - Correction: Retinoic acid exacerbates chlorpyrifos action in ensuing adipogenic differentiation of C3H10T1/2 cells in a GSK3beta dependent pathway. AB - [This corrects the article DOI: 10.1371/journal.pone.0173031.]. PMID- 28558013 TI - Downregulation of SIRT1 signaling underlies hepatic autophagy impairment in glycogen storage disease type Ia. AB - A deficiency in glucose-6-phosphatase-alpha (G6Pase-alpha) in glycogen storage disease type Ia (GSD-Ia) leads to impaired glucose homeostasis and metabolic manifestations including hepatomegaly caused by increased glycogen and neutral fat accumulation. A recent report showed that G6Pase-alpha deficiency causes impairment in autophagy, a recycling process important for cellular metabolism. However, the molecular mechanism underlying defective autophagy is unclear. Here we show that in mice, liver-specific knockout of G6Pase-alpha (L-G6pc-/-) leads to downregulation of sirtuin 1 (SIRT1) signaling that activates autophagy via deacetylation of autophagy-related (ATG) proteins and forkhead box O (FoxO) family of transcriptional factors which transactivate autophagy genes. Consistently, defective autophagy in G6Pase-alpha-deficient liver is characterized by attenuated expressions of autophagy components, increased acetylation of ATG5 and ATG7, decreased conjugation of ATG5 and ATG12, and reduced autophagic flux. We further show that hepatic G6Pase-alpha deficiency results in activation of carbohydrate response element-binding protein, a lipogenic transcription factor, increased expression of peroxisome proliferator activated receptor-gamma (PPAR-gamma), a lipid regulator, and suppressed expression of PPAR-alpha, a master regulator of fatty acid beta-oxidation, all contributing to hepatic steatosis and downregulation of SIRT1 expression. An adenovirus vector-mediated increase in hepatic SIRT1 expression corrects autophagy defects but does not rectify metabolic abnormalities associated with G6Pase-alpha deficiency. Importantly, a recombinant adeno-associated virus (rAAV) vector-mediated restoration of hepatic G6Pase-alpha expression corrects metabolic abnormalities, restores SIRT1-FoxO signaling, and normalizes defective autophagy. Taken together, these data show that hepatic G6Pase-alpha deficiency-mediated down-regulation of SIRT1 signaling underlies defective hepatic autophagy in GSD Ia. PMID- 28558015 TI - Effects of TiO2 nanoparticles on wheat (Triticum aestivum L.) seedlings cultivated under super-elevated and normal CO2 conditions. AB - Concerns over the potential risks of nanomaterials to ecosystem have been raised, as it is highly possible that nanomaterials could be released to the environment and result in adverse effects on living organisms. Carbon dioxide (CO2) is one of the main greenhouse gases. The level of CO2 keeps increasing and subsequently causes a series of environmental problems, especially for agricultural crops. In the present study, we investigated the effects of TiO2 NPs on wheat seedlings cultivated under super-elevated CO2 conditions (5000 mg/L CO2) and under normal CO2 conditions (400 mg/L CO2). Compared to the normal CO2 condition, wheat grown under the elevated CO2 condition showed increases of root biomass and large numbers of lateral roots. Under both CO2 cultivation conditions, the abscisic acid (ABA) content in wheat seedlings increased with increasing concentrations of TiO2 NPs. The indolepropioponic acid (IPA) and jasmonic acid (JA) content notably decreased in plants grown under super-elevated CO2 conditions, while the JA content increased with increasing concentrations of TiO2 NPs. Ti accumulation showed a dose-response manner in both wheat shoots and roots as TiO2 NPs concentrations increased. Additionally, the presence of elevated CO2 significantly promoted Ti accumulation and translocation in wheat treated with certain concentrations of TiO2 NPs. This study will be of benefit to the understanding of the joint effects and physiological mechanism of high-CO2 and nanoparticle to terrestrial plants. PMID- 28558016 TI - High mortality due to sepsis in Native Hawaiians and African Americans: The Multiethnic Cohort. AB - BACKGROUND/OBJECTIVES: Sepsis is a severe systemic response to infection with a high mortality rate. A higher incidence has been reported for older people, in persons with a compromised immune system including cancer patients, and in ethnic minorities. We analyzed sepsis mortality and its predictors by ethnicity in the Multiethnic Cohort (MEC). SUBJECTS/METHODS: Among 191,561 white, African American, Native Hawaiian, Japanese American, and Latino cohort members, 49,347 deaths due to all causes and 345 deaths due to sepsis were recorded during follow up from 1993-96 until 2010. Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated and adjusted for relevant confounders. In addition, national death rates were analyzed to compare mortality by state. RESULTS: Age-adjusted rates of sepsis death were 5-times higher for Hawaii than Los Angeles (14.4 vs. 2.7 per 100,000). By ethnicity, Native Hawaiians had the highest rate in Hawaii (29.0 per 100,000) and African Americans in Los Angeles (5.2 per 100,000). In fully adjusted models, place of residence was the most important predictor of sepsis mortality (HR = 7.18; 95%CI: 4.37-11.81 Hawaii vs. Los Angeles). African Americans showed the highest risk (HR = 2.08; 95% CI: 1.16 3.75) followed by Native Hawaiians (HR = 1.88; 95% CI: 1.34-2.65) as compared to whites. Among cohort members with cancer (N = 49,794), the 2-fold higher sepsis mortality remained significant in Native Hawaiians only. The geographic and ethnic differences in the MEC agreed with results for national death data. CONCLUSIONS: The finding that African Americans and Native Hawaiians experience a higher mortality risk due to sepsis than other ethnic groups suggest ethnicity related biological factors in the predisposition of cancer patients and other immune-compromising conditions to develop sepsis, but regional differences in health care access and death coding may also be important. PMID- 28558018 TI - Yellow-Leaf 1 encodes a magnesium-protoporphyrin IX monomethyl ester cyclase, involved in chlorophyll biosynthesis in rice (Oryza sativa L.). AB - Magnesium-protoporphyrin IX monomethyl ester cyclase (MPEC) catalyzes the conversion of MPME to divinyl protochlorophyllide (DVpchlide). This is an essential enzyme during chlorophyll (Chl) biosynthesis but details of its function in rice are still lacking. Here, we identified a novel rice mutant yellow-leaf 1 (yl-1), which showed decreased Chl accumulation, abnormal chloroplast ultrastructure and attenuated photosynthetic activity. Map-based cloning and over-expression analysis suggested that YL-1 encodes a subunit of MPEC. The YL-1 protein localizes in chloroplasts, and it is mainly expressed in green tissues, with greatest abundance in leaves and young panicles. Results of qRT-PCR showed that Chl biosynthesis upstream genes were highly expressed in the yl-1 mutant, while downstream genes were compromised, indicating that YL-1 plays a pivotal role in the Chl biosynthesis. Furthermore, the expression levels of photosynthesis and chloroplast development genes were also affected. RNA-seq results futher proved that numerous membrane-associated genes, including many plastid membrane-associated genes, have altered expression pattern in the yl-1 mutant, implying that YL-1 is required for plastid membrane stability. Thus, our study confirms a putative MPME cyclase as a novel key enzyme essential for Chl biosynthesis and chloroplast membrane stability in rice. PMID- 28558019 TI - Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis. AB - The DEK oncogene is overexpressed in many human malignancies including at early tumor stages. Our reported in vitro and in vivo models of squamous cell carcinoma have demonstrated that DEK contributes functionally to cellular and tumor survival and to proliferation. However, the underlying molecular mechanisms remain poorly understood. Based on recent RNA sequencing experiments, DEK expression was necessary for the transcription of several metabolic enzymes involved in anabolic pathways. This identified a possible mechanism whereby DEK may drive cellular metabolism to enable cell proliferation. Functional metabolic Seahorse analysis demonstrated increased baseline and maximum extracellular acidification rates, a readout of glycolysis, in DEK-overexpressing keratinocytes and squamous cell carcinoma cells. DEK overexpression also increased the maximum rate of oxygen consumption and therefore increased the potential for oxidative phosphorylation (OxPhos). To detect small metabolites that participate in glycolysis and the tricarboxylic acid cycle (TCA) that supplies substrate for OxPhos, we carried out NMR-based metabolomics studies. We found that high levels of DEK significantly reprogrammed cellular metabolism and altered the abundances of amino acids, TCA cycle intermediates and the glycolytic end products lactate, alanine and NAD+. Taken together, these data support a scenario whereby overexpression of the human DEK oncogene reprograms keratinocyte metabolism to fulfill energy and macromolecule demands required to enable and sustain cancer cell growth. PMID- 28558020 TI - Assessment of psychological pain in suicidal veterans. AB - Psychological pain is a relatively understudied and potentially important construct in the evaluation of suicidal risk. Psychological pain also referred to as 'mental pain' or 'psychache' can be defined as an adverse emotional reaction to a severe trauma (e.g., the loss of a child) or may be associated with an illness such as depression. When psychological pain levels reach intolerable levels, some individuals may view suicide as the only and final means of escape. To better understand psychological pain, we previously developed and validated a brief self-rating 10-item scale, Mee-Bunney Psychological Pain Assessment Scale [MBP] in depressed patients and non-psychiatric controls. Our results showed a significant increase in psychological pain in the depressed patients compared to controls. We also observed a significant linear correlation between psychological pain and suicidality in the depressed patient cohort. The current investigation extends our study of psychological pain to a diagnostically heterogeneous population of 57 US Veterans enrolled in a suicide prevention program. In addition to the MBP, we administered the Columbia Suicide Severity Rating Scale (C-SSRS), Beck Depression Inventory (BDI-II), Beck Hopelessness Scale (BHS), and the Barratt Impulsiveness Scale (BIS-11). Suicidal patients scoring above a predetermined threshold for high psychological pain also had significantly elevated scores on all the other assessments. Among all of the evaluations, psychological pain accounted for the most shared variance for suicidality (C SSRS). Stepwise regression analyses showed that impulsiveness (BIS) and psychological pain (MBP) contributed more to suicidality than any of the other combined assessments. We followed patients for 15 months and identified a subgroup (24/57) with serious suicide events. Within this subgroup, 29% (7/24) had a serious suicidal event (determined by the lethality subscale of the C SSRS), including one completed suicide. Our results build upon our earlier findings and recent literature supporting psychological pain as a potentially important construct. Systematically evaluating psychological pain along with additional measures of suicidality could improve risk assessment and more effectively guide clinical resource allocation toward prevention. PMID- 28558017 TI - A dual-strategy expression screen for candidate connectivity labels in the developing thalamus. AB - The thalamus or "inner chamber" of the brain is divided into ~30 discrete nuclei, with highly specific patterns of afferent and efferent connectivity. To identify genes that may direct these patterns of connectivity, we used two strategies. First, we used a bioinformatics pipeline to survey the predicted proteomes of nematode, fruitfly, mouse and human for extracellular proteins containing any of a list of motifs found in known guidance or connectivity molecules. Second, we performed clustering analyses on the Allen Developing Mouse Brain Atlas data to identify genes encoding surface proteins expressed with temporal profiles similar to known guidance or connectivity molecules. In both cases, we then screened the resultant genes for selective expression patterns in the developing thalamus. These approaches identified 82 candidate connectivity labels in the developing thalamus. These molecules include many members of the Ephrin, Eph-receptor, cadherin, protocadherin, semaphorin, plexin, Odz/teneurin, Neto, cerebellin, calsyntenin and Netrin-G families, as well as diverse members of the immunoglobulin (Ig) and leucine-rich receptor (LRR) superfamilies, receptor tyrosine kinases and phosphatases, a variety of growth factors and receptors, and a large number of miscellaneous membrane-associated or secreted proteins not previously implicated in axonal guidance or neuronal connectivity. The diversity of their expression patterns indicates that thalamic nuclei are highly differentiated from each other, with each one displaying a unique repertoire of these molecules, consistent with a combinatorial logic to the specification of thalamic connectivity. PMID- 28558021 TI - Interactions of sclerostin with FGF23, soluble klotho and vitamin D in renal transplantation. AB - Relationships of Sclerostin, a bone anti-anabolic protein, with biomarkers of mineral bone disorders in chronic kidney disease are still unsettled, in particular in kidney transplant (KTR). In 80 KTR patients (31F/49M, 54.7+/-10.3 years) we studied the relationships of serum Sclerostin with eGFR, Calcium, Phosphate, Alkaline Phosphatase (AP), intact Parathyroid hormone (iPTH), soluble alpha-Klotho (sKlotho), intact Fibroblast Growth Factor 23 (iFGF23), 25 hydroxyvitamin D(25D) and 1,25-dihydroxyvitamin D (1,25D). Thirty healthy subjects (35.0+/-12.4 years, eGFR 109.1+/-14.1 ml /min/1,73m2) served as control for Sclerostin, iFGF23 and sKlotho. With a median eGFR of 46.3 mL/min/1.73m2 (IQR, 36.2-58.3) our KTR had median Sclerostin levels of 23.7 pmol/L (IQR: 20.8 32.8), not different from controls (26.6 pmol/L, IQR: 22.0-32.2; p = n.s). Sclerostin correlated negatively with AP (r = -.251; p = 0.023) and positively with iFGF23 (r = .227; p = 0.017) and 25D (r = .214; p = 0.025). Age-adjusted multiple regression analysis identified AP and 1,25D as negative and 25D and sKlotho as positive best predictors of Sclerostin. No correlation was evident with eGFR. The negative correlation with AP confirms the direct anti-anabolic role of Sclerostin. The associations either negative or positive with iFGF23, sKlotho, and vitamin D metabolites suggest also a modulatory role in mineral homeostasis. In particular, the associations with iFGF23 (positive) and 1,25D (negative) underline the relevant inhibitory action of Sclerostin on vitamin D activation. In conclusion, Sclerostin levels in KTR are normal and influenced more by bone turnover than by eGFR. Its involvement with other hormones of mineral homeostasis (FGF23/Klotho and Vitamin D) is part of the sophisticated cross-talk between bone and the kidney. PMID- 28558023 TI - Structural and functional dissection reveals distinct roles of Ca2+-binding sites in the giant adhesin SiiE of Salmonella enterica. AB - The giant non-fimbrial adhesin SiiE of Salmonella enterica mediates the first contact to the apical site of epithelial cells and enables subsequent invasion. SiiE is a 595 kDa protein composed of 53 repetitive bacterial immunoglobulin (BIg) domains and the only known substrate of the SPI4-encoded type 1 secretion system (T1SS). The crystal structure of BIg50-52 of SiiE revealed two distinct Ca2+-binding sites per BIg domain formed by conserved aspartate or glutamate residues. In a mutational analysis Ca2+-binding sites were disrupted by aspartate to serine exchange at various positions in the BIg domains of SiiE. Amounts of secreted SiiE diminish with a decreasing number of intact Ca2+-binding sites. BIg domains of SiiE contain distinct Ca2+-binding sites, with type I sites being similar to other T1SS-secreted proteins and type II sites newly identified in SiiE. We functionally and structurally dissected the roles of type I and type II Ca2+-binding sites in SiiE, as well as the importance of Ca2+-binding sites in various positions of SiiE. Type I Ca2+-binding sites were critical for efficient secretion of SiiE and a decreasing number of type I sites correlated with reduced secretion. Type II sites were less important for secretion, stability and surface expression of SiiE, however integrity of type II sites in the C-terminal portion was required for the function of SiiE in mediating adhesion and invasion. PMID- 28558024 TI - Maternal age and severe maternal morbidity: A population-based retrospective cohort study. AB - BACKGROUND: One of the United Nations' Millennium Development Goals of 2000 was to reduce maternal mortality by 75% in 15 y; however, this challenge was not met by many industrialized countries. As average maternal age continues to rise in these countries, associated potentially life-threatening severe maternal morbidity has been understudied. Our primary objective was to examine the associations between maternal age and severe maternal morbidities. The secondary objective was to compare these associations with those for adverse fetal/infant outcomes. METHODS AND FINDINGS: This was a population-based retrospective cohort study, including all singleton births to women residing in Washington State, US, 1 January 2003-31 December 2013 (n = 828,269). We compared age-specific rates of maternal mortality/severe morbidity (e.g., obstetric shock) and adverse fetal/infant outcomes (e.g., perinatal death). Logistic regression was used to adjust for parity, body mass index, assisted conception, and other potential confounders. We compared crude odds ratios (ORs) and adjusted ORs (AORs) and risk differences and their 95% CIs. Severe maternal morbidity was significantly higher among teenage mothers than among those 25-29 y (crude OR = 1.5, 95% CI 1.5-1.6) and increased exponentially with maternal age over 39 y, from OR = 1.2 (95% CI 1.2-1.3) among women aged 35-39 y to OR = 5.4 (95% CI 2.4-12.5) among women aged >=50 y. The elevated risk of severe morbidity among teen mothers disappeared after adjustment for confounders, except for maternal sepsis (AOR = 1.2, 95% CI 1.1-1.4). Adjusted rates of severe morbidity remained increased among mothers >=35 y, namely, the rates of amniotic fluid embolism (AOR = 8.0, 95% CI 2.7-23.7) and obstetric shock (AOR = 2.9, 95% CI 1.3-6.6) among mothers >=40 y, and renal failure (AOR = 15.9, 95% CI 4.8-52.0), complications of obstetric interventions (AOR = 4.7, 95% CI 2.3-9.5), and intensive care unit (ICU) admission (AOR = 4.8, 95% CI 2.0-11.9) among those 45-49 y. The adjusted risk difference in severe maternal morbidity compared to mothers 25-29 y was 0.9% (95% CI 0.7%-1.2%) for mothers 40-44 y, 1.6% (95% CI 0.7%-2.8%) for mothers 45-49 y, and 6.4% for mothers >=50 y (95% CI 1.7%-18.2%). Similar associations were observed for fetal and infant outcomes; neonatal mortality was elevated in teen mothers (AOR = 1.5, 95% CI 1.2-1.7), while mothers over 29 y had higher risk of stillbirth. The rate of severe maternal morbidity among women over 49 y was higher than the rate of mortality/serious morbidity of their offspring. Despite the large sample size, statistical power was insufficient to examine the association between maternal age and maternal death or very rare severe morbidities. CONCLUSIONS: Maternal age specific incidence of severe morbidity varied by outcome. Older women (>=40 y) had significantly elevated rates of some of the most severe, potentially life threatening morbidities, including renal failure, shock, acute cardiac morbidity, serious complications of obstetric interventions, and ICU admission. These results should improve counselling to women who contemplate delaying childbirth until their forties and provide useful information to their health care providers. This information is also useful for preventive strategies to lower maternal mortality and severe maternal morbidity in developed countries. PMID- 28558025 TI - Doxycycline potentiates antitumor effect of 5-aminolevulinic acid-mediated photodynamic therapy in malignant peripheral nerve sheath tumor cells. AB - Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneous disorders. Some NF1 patients develop benign large plexiform neurofibroma(s) at birth, which can then transform into a malignant peripheral nerve sheath tumor (MPNST). There is no curative treatment for this rapidly progressive and easily metastatic neurofibrosarcoma. Photodynamic therapy (PDT) has been developed as an anti-cancer treatment, and 5-aminolevulinic (ALA) mediated PDT (ALA-PDT) has been used to treat cutaneous skin and oral neoplasms. Doxycycline, a tetracycline derivative, can substantially reduce the tumor burden in human and animal models, in addition to its antimicrobial effects. The purpose of this study was to evaluate the effect and to investigate the mechanism of action of combined doxycycline and ALA-PDT treatment of MPNST cells. An 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay showed that the combination of ALA PDT and doxycycline significantly reduce MPNST survival rate, compared to cells treated with each therapy alone. Isobologram analysis showed that the combined treatment had a synergistic effect. The increased cytotoxic activity could be seen by an increase in cellular protoporphyrin IX (PpIX) accumulation. Furthermore, we found that the higher retention of PpIX was mainly due to increasing ALA uptake, rather than activity changes of the enzymes porphobilinogen deaminase and ferrochelatase. The combined treatment inhibited tumor growth in different tumor cell lines, but not in normal human Schwann cells or fibroblasts. Similarly, a synergistic interaction was also found in cells treated with ALA-PDT combined with minocycline, but not tetracycline. In summary, doxycycline can potentiate the effect of ALA-PDT to kill tumor cells. This increased potency allows for a dose reduction of doxycycline and photodynamic radiation, reducing the occurrence of toxic side effects in vivo. PMID- 28558027 TI - Capacity value of energy storage considering control strategies. AB - In power systems, energy storage effectively improves the reliability of the system and smooths out the fluctuations of intermittent energy. However, the installed capacity value of energy storage cannot effectively measure the contribution of energy storage to the generator adequacy of power systems. To achieve a variety of purposes, several control strategies may be utilized in energy storage systems. The purpose of this paper is to study the influence of different energy storage control strategies on the generation adequacy. This paper presents the capacity value of energy storage to quantitatively estimate the contribution of energy storage on the generation adequacy. Four different control strategies are considered in the experimental method to study the capacity value of energy storage. Finally, the analysis of the influence factors on the capacity value under different control strategies is given. PMID- 28558022 TI - Different features of Vdelta2 T and NK cells in fatal and non-fatal human Ebola infections. AB - BACKGROUND: Human Ebola infection is characterized by a paralysis of the immune system. A signature of alphabeta T cells in fatal Ebola infection has been recently proposed, while the involvement of innate immune cells in the protection/pathogenesis of Ebola infection is unknown. Aim of this study was to analyze gammadelta T and NK cells in patients from the Ebola outbreak of 2014 2015 occurred in West Africa, and to assess their association with the clinical outcome. METHODOLOGY/PRINCIPAL FINDINGS: Nineteen Ebola-infected patients were enrolled at the time of admission to the Ebola Treatment Centre in Guinea. Patients were divided in two groups on the basis of the clinical outcome. The analysis was performed by using multiparametric flow cytometry established by the European Mobile Laboratory in the field. A low frequency of Vdelta2 T-cells was observed during Ebola infection, independently from the clinical outcome. Moreover, Vdelta2 T-cells from Ebola patients massively expressed CD95 apoptotic marker, suggesting the involvement of apoptotic mechanisms in Vdelta2 T-cell loss. Interestingly, Vdelta2 T-cells from survivors expressed an effector phenotype and presented a lower expression of the CTLA-4 exhaustion marker than fatalities, suggesting a role of effector Vdelta2 T-cells in the protection. Furthermore, patients with fatal Ebola infection were characterized by a lower NK cell frequency than patients with non fatal infection. In particular, both CD56bright and CD56dim NK frequency were very low both in fatal and non fatal infections, while a higher frequency of CD56neg NK cells was associated to non fatal infections. Finally, NK activation and expression of NKp46 and CD158a were independent from clinical outcome. CONCLUSIONS/SIGNIFICANCES: Altogether, the data suggest that both effector Vdelta2 T-cells and NK cells may play a role in the complex network of protective response to EBOV infection. Further studies are required to characterize the protective effector functions of Vdelta2 and NK cells. PMID- 28558026 TI - Identification of function-regulating antibodies targeting the receptor protein tyrosine phosphatase sigma ectodomain. AB - Receptor tyrosine phosphatase sigma (RPTPsigma) plays an important role in the regulation of axonal outgrowth and neural regeneration. Recent studies have identified two RPTPsigma ligands, chondroitin sulfate proteoglycans (CSPGs) and heparan sulfate proteoglycans (HSPG), which can modulate RPTPsigma activity by affecting its dimerization status. Here, we developed a split luciferase assay to monitor RPTPsigma dimerization in living cells. Using this system, we demonstrate that heparin, an analog of heparan sulfate, induced the dimerization of RPTPsigma, whereas chondroitin sulfate increased RPTPsigma activity by inhibiting RPTPsigma dimerization. Also, we generated several novel RPTPsigma IgG monoclonal antibodies, to identify one that modulates its activity by inducing/stabilizing dimerization in living cells. Lastly, we demonstrate that this antibody promotes neurite outgrowth in SH-SY5Y cells. In summary, we demonstrated that the split luciferase RPTPsigma activity assay is a novel high-throughput approach for discovering novel RPTPsigma modulators that can promote axonal outgrowth and neural regeneration. PMID- 28558028 TI - Kidney volume measurement methods for clinical studies on autosomal dominant polycystic kidney disease. AB - BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), total kidney volume (TKV) is regarded as an important biomarker of disease progression and different methods are available to assess kidney volume. The purpose of this study was to identify the most efficient kidney volume computation method to be used in clinical studies evaluating the effectiveness of treatments on ADPKD progression. METHODS AND FINDINGS: We measured single kidney volume (SKV) on two series of MR and CT images from clinical studies on ADPKD (experimental dataset) by two independent operators (expert and beginner), twice, using all of the available methods: polyline manual tracing (reference method), free-hand manual tracing, semi-automatic tracing, Stereology, Mid-slice and Ellipsoid method. Additionally, the expert operator also measured the kidney length. We compared different methods for reproducibility, accuracy, precision, and time required. In addition, we performed a validation study to evaluate the sensitivity of these methods to detect the between-treatment group difference in TKV change over one year, using MR images from a previous clinical study. Reproducibility was higher on CT than MR for all methods, being highest for manual and semiautomatic contouring methods (planimetry). On MR, planimetry showed highest accuracy and precision, while on CT accuracy and precision of both planimetry and Stereology methods were comparable. Mid-slice and Ellipsoid method, as well as kidney length were fast but provided only a rough estimate of kidney volume. The results of the validation study indicated that planimetry and Stereology allow using an importantly lower number of patients to detect changes in kidney volume induced by drug treatment as compared to other methods. CONCLUSIONS: Planimetry should be preferred over fast and simplified methods for accurately monitoring ADPKD progression and assessing drug treatment effects. Expert operators, especially on MR images, are required for performing reliable estimation of kidney volume. The use of efficient TKV quantification methods considerably reduces the number of patients to enrol in clinical investigations, making them more feasible and significant. PMID- 28558029 TI - Association of anterior cruciate ligament injury with knee osteoarthritis and total knee replacement: A retrospective cohort study from the Taiwan National Health Insurance Database. AB - OBJECTIVE: This study aimed to support the potential protective role of anterior cruciate ligament (ACL) reconstruction against the development of osteoarthritis (OA). METHODS: In this retrospective cohort study, the long-term results of ACL reconstruction in Taiwan were evaluated based on data from the National Health Insurance Research Database (NHIRD). In total, 8,769 eligible cases were included from 11,921 ACL-injured patients. The cumulative incidence rates of OA and total knee replacement (TKR) were analyzed using the Kaplan-Meier estimator. Cox proportional hazards models were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of OA. RESULTS: There was a lower cumulative incidence of OA among ACL-reconstructed patients (271, 33.1%) than among non reconstructed patients (1,874, 40.3%; p < 0.001). Patients who underwent ACL reconstruction had a lower cumulative incidence of TKR during the follow-up period (0.6%) than the non-reconstructed patients (4.6%, p < 0.001). After adjusting for covariates, ACL-injured patients who underwent reconstruction within one month after ACL injury showed a significantly lower risk of OA than those who never underwent reconstruction (adjusted HR = 0.83, 95% CI = 0.69 0.99). CONCLUSIONS: These results indicate that ACL reconstruction might not provide complete protection from OA development after traumatic knee injury but does yield a lower cumulative incidence of OA development and TKR. Moreover, based on the present study, ACL-injured patients should undergo reconstruction as early as possible (within one month) to lower the risk of OA. PMID- 28558031 TI - The G2 checkpoint inhibitor CBP-93872 increases the sensitivity of colorectal and pancreatic cancer cells to chemotherapy. AB - CBP-93872 suppresses maintenance of DNA double-stranded break-induced G2 checkpoint, by inhibiting the pathway between ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) activation. To examine the potential use of CBP 93872 for clinical applications, we analyzed the synergistic effects of platinum containing drugs, oxaliplatin and cisplatin, pyrimidine antimetabolites, gemcitabine and 5-fluorouracil (5-FU), in combination with CBP-93872, on cell lethality in colorectal and pancreatic cancer cell lines. Treatment with CBP 93872 significantly increased cancer cell sensitivities to various chemotherapeutic agents tested through suppression of checkpoint activation. Our results thus reveal that combination treatment of CBP-93872 with known chemotherapeutic agents inhibits phosphorylation of ATR and Chk1, and induces cell death. PMID- 28558032 TI - The association of mannose-binding lectin 2 polymorphisms with outcome in very low birth weight infants. AB - OBJECTIVES: Studies on the influence of mannose-binding lectin (MBL) deficiency on infection susceptibility in preterm infants have yielded controversial results. We investigated the association of genotype-based MBL levels with outcome in very-low-birth weight infants (VLBWI). METHODS: We genotyped 3 genetic variants of MBL2 (rs1800450, rs1800451, rs5030737) in 6878 VLBWI. MBL plasma levels were categorized as normal (wild type, A/A), low (heterozygotes, A/O) or undetectable (homozygotes, O/O). Primary outcome was the effect of genotype-based MBL2 levels on blood-culture proven and clinical sepsis during primary stay in hospital. We also evaluated burden of infection within 24 months after discharge. RESULTS: We found no association between MBL levels and sepsis risk in the whole cohort. Infants without measurable MBL levels born between 32 0/7 to 36 6/7 weeks of gestation, however, had a higher rate of Gram-negative sepsis than infants with normal or reduced MBL levels. In a follow-up investigation at 24 months (n = 1070 infants), infants without measurable MBL levels suffered more frequently from stomatitis and urinary tract infection. CONCLUSIONS: In a large cohort of VLBWI MBL2 deficiency had no major impact on infection risk unless children were born between 32 0/7 and 36 6/7 weeks of gestation. PMID- 28558030 TI - Fine-scale variation in microclimate across an urban landscape shapes variation in mosquito population dynamics and the potential of Aedes albopictus to transmit arboviral disease. AB - Most statistical and mechanistic models used to predict mosquito-borne disease transmission incorporate climate drivers of disease transmission by utilizing environmental data collected at geographic scales that are potentially coarser than what mosquito populations may actually experience. Temperature and relative humidity can vary greatly between indoor and outdoor environments, and can be influenced strongly by variation in landscape features. In the Aedes albopictus system, we conducted a proof-of-concept study in the vicinity of the University of Georgia to explore the effects of fine-scale microclimate variation on mosquito life history and vectorial capacity (VC). We placed Ae. albopictus larvae in artificial pots distributed across three replicate sites within three different land uses-urban, suburban, and rural, which were characterized by high, intermediate, and low proportions of impervious surfaces. Data loggers were placed into each larval environment and in nearby vegetation to record daily variation in water and ambient temperature and relative humidity. The number of adults emerging from each pot and their body size and sex were recorded daily. We found mosquito microclimate to significantly vary across the season as well as with land use. Urban sites were in general warmer and less humid than suburban and rural sites, translating into decreased larval survival, smaller body sizes, and lower per capita growth rates of mosquitoes on urban sites. Dengue transmission potential was predicted to be higher in the summer than the fall. Additionally, the effects of land use on dengue transmission potential varied by season. Warm summers resulted in a higher predicted VC on the cooler, rural sites, while warmer, urban sites had a higher predicted VC during the cooler fall season. PMID- 28558033 TI - sourceR: Classification and source attribution of infectious agents among heterogeneous populations. AB - Zoonotic diseases are a major cause of morbidity, and productivity losses in both human and animal populations. Identifying the source of food-borne zoonoses (e.g. an animal reservoir or food product) is crucial for the identification and prioritisation of food safety interventions. For many zoonotic diseases it is difficult to attribute human cases to sources of infection because there is little epidemiological information on the cases. However, microbial strain typing allows zoonotic pathogens to be categorised, and the relative frequencies of the strain types among the sources and in human cases allows inference on the likely source of each infection. We introduce sourceR, an R package for quantitative source attribution, aimed at food-borne diseases. It implements a Bayesian model using strain-typed surveillance data from both human cases and source samples, capable of identifying important sources of infection. The model measures the force of infection from each source, allowing for varying survivability, pathogenicity and virulence of pathogen strains, and varying abilities of the sources to act as vehicles of infection. A Bayesian non-parametric (Dirichlet process) approach is used to cluster pathogen strain types by epidemiological behaviour, avoiding model overfitting and allowing detection of strain types associated with potentially high "virulence". sourceR is demonstrated using Campylobacter jejuni isolate data collected in New Zealand between 2005 and 2008. Chicken from a particular poultry supplier was identified as the major source of campylobacteriosis, which is qualitatively similar to results of previous studies using the same dataset. Additionally, the software identifies a cluster of 9 multilocus sequence types with abnormally high 'virulence' in humans. sourceR enables straightforward attribution of cases of zoonotic infection to putative sources of infection. As sourceR develops, we intend it to become an important and flexible resource for food-borne disease attribution studies. PMID- 28558036 TI - Correction: Blood type, ABO genetic variants, and ovarian cancer survival. AB - [This corrects the article DOI: 10.1371/journal.pone.0175119.]. PMID- 28558035 TI - Oscillating PDF in termini of circadian pacemaker neurons and synchronous molecular clocks in downstream neurons are not sufficient for sustenance of activity rhythms in constant darkness. AB - In Drosophila, neuropeptide Pigment Dispersing Factor (PDF) is expressed in small and large ventral Lateral Neurons (sLNv and lLNv), among which sLNv are critical for activity rhythms in constant darkness. Studies show that this is mediated by rhythmic accumulation and likely secretion of PDF from sLNv dorsal projections, which in turn synchronises molecular oscillations in downstream circadian neurons. Using targeted expression of a neurodegenerative protein Huntingtin in LNv, we evoke a selective loss of neuropeptide PDF and clock protein PERIOD from sLNv soma. However, PDF is not lost from sLNv dorsal projections and lLNv. These flies are behaviourally arrhythmic in constant darkness despite persistence of PDF oscillations in sLNv dorsal projections and synchronous PERIOD oscillations in downstream circadian neurons. We find that PDF oscillations in sLNv dorsal projections are not sufficient for sustenance of activity rhythms in constant darkness and this is suggestive of an additional component that is possibly dependent on sLNv molecular clock and PDF in sLNv soma. Additionally, despite loss of PERIOD in sLNv, their activity rhythms entrain to light/dark cycles indicating that sLNv molecular clocks are not necessary for entrainment. Under constant light, these flies lack PDF from both soma and dorsal projections of sLNv, and when subjected to light/dark cycles, show morning and evening anticipation and accurately phased morning and evening peaks. Thus, under light/dark cycles, PDF in sLNv is not necessary for morning anticipation. PMID- 28558034 TI - MicroRNA 26a (miR-26a)/KLF4 and CREB-C/EBPbeta regulate innate immune signaling, the polarization of macrophages and the trafficking of Mycobacterium tuberculosis to lysosomes during infection. AB - For efficient clearance of Mycobacterium tuberculosis (Mtb), macrophages tilt towards M1 polarization leading to the activation of transcription factors associated with the production of antibacterial effector molecules such as nitric oxide (NO) and proinflammatory cytokines such as interleukin 1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha). At the same time, resolution of inflammation is associated with M2 polarization with increased production of arginase and cytokines such as IL-10. The transcriptional and post transcriptional mechanisms that govern the balance between M1 and M2 polarization, and bacteria-containing processes such as autophagy and trafficking of Mtb to lysosomes, are incompletely understood. Here we report for the first time, that the transcription factor KLF4 is targeted by microRNA-26a (miR-26a). During Mtb infection, downregulation of miR-26a (observed both ex vivo and in vivo) facilitates upregulation of KLF4 which in turn favors increased arginase and decreased iNOS activity. We further demonstrate that KLF4 prevents trafficking of Mtb to lysosomes. The CREB-C/EBPbeta signaling axis also favors M2 polarization. Downregulation of miR-26a and upregulation of C/ebpbeta were observed both in infected macrophages as well as in infected mice. Knockdown of C/ebpbeta repressed the expression of selected M2 markers such as Il10 and Irf4 in infected macrophages. The importance of these pathways is substantiated by observations that expression of miR-26a mimic or knockdown of Klf4 or Creb or C/ebpbeta, attenuated the survival of Mtb in macrophages. Taken together, our results attribute crucial roles for the miR-26a/KLF4 and CREB-C/EBPbetasignaling pathways in regulating the survival of Mtb in macrophages. These studies expand our understanding of how Mtb hijacks host signaling pathways to survive in macrophages, and open up new exploratory avenues for host-targeted interventions. PMID- 28558038 TI - Impact of cigarette smoking on early complications after liver transplantation: A single-center experience and a meta-analysis. AB - BACKGROUND: While studies have shown that cigarette smoking has negative implications on the long-term outcome following liver transplantation, its role in early complications is inconclusive. METHODS: The clinical data of 162 consecutive adult patients who underwent elective liver transplantation from January, 2012 to March, 2016 were analyzed. Patients were defined as active smokers, ex-smokers, or non-smokers on the basis of documentation at the time of liver transplantation. The overall complications following liver transplantation were expressed as the comprehensive complication index (CCI). The specific complications such as the incidence of hepatic artery thrombosis, biliary complications, acute kidney injury were also assessed. A meta-analysis was carried out based on results from the present study and 11 published studies. RESULTS: We found that cigarette smoking was not associated with higher CCI scores and smokers did not have a higher risk for developing hepatic artery thrombosis, biliary complications, acute kidney injury after liver transplantation. Meta-analysis confirmed the null association between cigarette smoking and an increased incidence of hepatic artery thrombosis or biliary complications in liver transplant recipients. However, the pooled results showed a significantly higher risk of cardiovascular diseases and de-novo malignancies in smokers following liver transplantation. CONCLUSION: There is not enough evidence supporting an association between cigarette smoking and early mortality and morbidity after liver transplantation. However, smokers should still be encouraged to quit before and after liver transplantation due to the long-term health benefits of smoking cessation. PMID- 28558037 TI - Inhibition of chronic prostate inflammation by hyaluronic acid through an immortalized human prostate stromal cell line model. AB - Benign prostatic hyperplasia (BPH) is the most common urologic disease among elderly men. A well-established in vitro cell model is required to determine the therapeutic mechanism of BPH inflammation. In this study, we attempted to establish an immortalized human prostate stromal cell line by transfecting with HPV-16 E6/E7 and designated as ihPSC. No significant difference was found in fibroblast-like morphology between primary hPSC and ihPSC. The ihPSC possessed a significantly higher cell proliferation rate than primary hPSC. The prostate specific markers and proteins including cytoskeleton (alpha-SMA and vimentin) and smooth muscle (calponin), especially the androgen receptor (AR) were also examined in ihPSC, almost identical to the primary hPSC. To create an in vitro model featuring chronic prostatic inflammation, ihPSC was stimulated with IFN gamma+IL-17 and then treated with the high molecular weight hyaluronic acid hylan G-F 20 as an alternative strategy for inhibiting BPH inflammation. Hylan G-F 20 could dose-dependently diminish the inflammation-induced proliferation in ihPSC. The enhanced expressions of inflammatory molecules including IL-1beta, IL-6, IL 8, cyclooxygenase 2 (COX2), inducible nitrogen oxide synthase (iNOS), and Toll like receptor 4 (TLR4) were all abolished by hylan G-F 20. For inflammatory signaling, hylan G-F 20 can also diminish the IFN-gamma+IL-17-increased expression of iNOS and p65 in ihPSC. These findings suggest that ihPSC could provide a mechanism-based platform for investigating prostate inflammation. The hylan G-F 20 showed strong anti-inflammatory effects by decreasing inflammatory cytokines and signalings in the ihPSC, indicating its therapeutic potentials in BPH treatment in the future. PMID- 28558039 TI - Dynamic decomposition of spatiotemporal neural signals. AB - Neural signals are characterized by rich temporal and spatiotemporal dynamics that reflect the organization of cortical networks. Theoretical research has shown how neural networks can operate at different dynamic ranges that correspond to specific types of information processing. Here we present a data analysis framework that uses a linearized model of these dynamic states in order to decompose the measured neural signal into a series of components that capture both rhythmic and non-rhythmic neural activity. The method is based on stochastic differential equations and Gaussian process regression. Through computer simulations and analysis of magnetoencephalographic data, we demonstrate the efficacy of the method in identifying meaningful modulations of oscillatory signals corrupted by structured temporal and spatiotemporal noise. These results suggest that the method is particularly suitable for the analysis and interpretation of complex temporal and spatiotemporal neural signals. PMID- 28558040 TI - MicroRNA319-regulated TCPs interact with FBHs and PFT1 to activate CO transcription and control flowering time in Arabidopsis. AB - The transcription factor CONSTANS (CO) is a central component that promotes Arabidopsis flowering under long-day conditions (LDs). Here, we show that the microRNA319-regulated TEOSINTE BRANCHED/CYCLOIDEA/PCF (TCP) transcription factors promote photoperiodic flowering through binding to the CO promoter and activating its transcription. Meanwhile, these TCPs directly interact with the flowering activators FLOWERING BHLH (FBHs), but not the flowering repressors CYCLING DOF FACTORs (CDFs), to additively activate CO expression. Furthermore, both the TCPs and FBHs physically interact with the flowering time regulator PHYTOCHROME AND FLOWERING TIME 1 (PFT1) to facilitate CO transcription. Our findings provide evidence that a set of transcriptional activators act directly and additively at the CO promoter to promote CO transcription, and establish a molecular mechanism underlying the regulation of photoperiodic flowering time in Arabidopsis. PMID- 28558041 TI - Earlier occurrence and increased explanatory power of climate for the first incidence of potato late blight caused by Phytophthora infestans in Fennoscandia. AB - BACKGROUND: Late blight (caused by Phytophthora infestans) is a devastating potato disease that has been found to occur earlier in the season over the last decades in Fennoscandia. Up until now the reasons for this change have not been investigated. Possible explanations for this change are climate alterations, changes in potato production or changes in pathogen biology, such as increased fitness or changes in gene flow within P. infestans populations. The first incidence of late blight is of high economic importance since fungicidal applications should be typically applied two weeks before the first signs of late blight and are repeated on average once a week. METHODS: We use field observations of first incidence of late blight in experimental potato fields from five sites in Sweden and Finland covering a total of 30 years and investigate whether the earlier incidence of late blight can be related to the climate. RESULTS: We linked the field data to meteorological data and found that the previous assumption, used in common late blight models, that the disease only develops at relative humidity levels above 90% had to be rejected. Rather than the typically assumed threshold relationship between late blight disease development and relative humidity we found a linear relationship. Our model furthermore showed two distinct responses of late blight to climate. At the beginning of the observation time (in Sweden until the early 90s and in Finland until the 2000s) the link between climate and first incidence was very weak. However, for the remainder of the time period the link was highly significant, indicating a change in the biological properties of the pathogen which could for example be a change in the dominating reproduction mode or a physiological change in the response of the pathogen to climate. CONCLUSIONS: The study shows that models used in decision support systems need to be checked and re-parametrized regularly to be able to capture changes in pathogen biology. While this study was performed with data from Fennoscandia this new pathogen biology and late blight might spread to (or already be present at) other parts of the world as well. The strong link between climate and first incidence together with the presented model offers a tool to assess late blight incidence in future climates. PMID- 28558042 TI - Relationships of growth factors, proinflammatory cytokines, and anti-inflammatory cytokines with long-term clinical results of autologous bone marrow mononuclear cell transplantation in STEMI. AB - AIM: The aim of the study was to test the hypothesis suggesting that the pre intervention levels of proinflammatory cytokines, anti-inflammatory cytokines, and angiogenic growth factors predict the long-term clinical results of autologous bone marrow-derived mononuclear cell (ABMMC) transplantation in patients with primary ST elevation myocardial infarction (STEMI). METHODS AND RESULTS: From 2003 to 2006, a total of 62 patients with primary STEMI were enrolled in an open randomized study registered under the title ESTABOMA. Patients were randomized into two groups: group 1 included patients treated with percutaneous coronary intervention (PCI) and ABMMC transplantation (n = 28); group 2 comprised patients treated only with PCI (n = 34). Follow-up study was performed 7.96 +/- 0.96 years after STEMI and involved physical examination, six minute walk test, echocardiography, and determination of brain natriuretic peptide (BNP) levels. The total and cardiovascular mortality rates were higher in group 1 compared with group 2: 36% (n = 10) vs. 12% (n = 4) (p = 0.02) and 29% (n = 8) vs. 6% (n = 2) (p = 0.03), respectively. Lower levels of proinflammatory cytokines were observed in group 1 after PCI and ABMMC transplantation. Serum levels of FGF, VEGF, and IL-10, determined before PCI and ABMMC transplantation were prognostically significant long-term indicators of unfavorable course of CAD after STEMI. PMID- 28558044 TI - Correction: Creativity associated with the application of a motivational intervention programme for the teaching of dance at school and its effect on the both genders. AB - [This corrects the article DOI: 10.1371/journal.pone.0174393.]. PMID- 28558043 TI - Vaccination with a Leishmania infantum HSP70-II null mutant confers long-term protective immunity against Leishmania major infection in two mice models. AB - BACKGROUND: The immunization with genetically attenuated Leishmania cell lines has been associated to the induction of memory and effector T cell responses against Leishmania able to control subsequent challenges. A Leishmania infantum null mutant for the HSP70-II genes has been described, possessing a non-virulent phenotype. METHODOLOGY/PRINCIPAL FINDINGS: The L. infantum attenuated parasites (LiDeltaHSP70-II) were inoculated in BALB/c (intravenously and subcutaneously) and C57BL/6 (subcutaneously) mice. An asymptomatic infection was generated and parasites diminished progressively to become undetectable in most of the analyzed organs. However, inoculation resulted in the long-term induction of parasite specific IFN-gamma responses able to control the disease caused by a challenge of L. major infective promastigotes. BALB/c susceptible mice showed very low lesion development and a drastic decrease in parasite burdens in the lymph nodes draining the site of infection and internal organs. C57BL/6 mice did not show clinical manifestation of disease, correlated to the rapid migration of Leishmania specific IFN-gamma producing T cells to the site of infection. CONCLUSION/SIGNIFICANCE: Inoculation of the LiDeltaHSP70-II attenuated line activates mammalian immune system for inducing moderate pro-inflammatory responses. These responses are able to confer long-term protection in mice against the infection of L. major virulent parasites. PMID- 28558045 TI - A technique system for the measurement, reconstruction and character extraction of rice plant architecture. AB - This study developed a technique system for the measurement, reconstruction, and trait extraction of rice canopy architectures, which have challenged functional structural plant modeling for decades and have become the foundation of the design of ideo-plant architectures. The system uses the location-separation measurement method (LSMM) for the collection of data on the canopy architecture and the analytic geometry method for the reconstruction and visualization of the three-dimensional (3D) digital architecture of the rice plant. It also uses the virtual clipping method for extracting the key traits of the canopy architecture such as the leaf area, inclination, and azimuth distribution in spatial coordinates. To establish the technique system, we developed (i) simple tools to measure the spatial position of the stem axis and azimuth of the leaf midrib and to capture images of tillers and leaves; (ii) computer software programs for extracting data on stem diameter, leaf nodes, and leaf midrib curves from the tiller images and data on leaf length, width, and shape from the leaf images; (iii) a database of digital architectures that stores the measured data and facilitates the reconstruction of the 3D visual architecture and the extraction of architectural traits; and (iv) computation algorithms for virtual clipping to stratify the rice canopy, to extend the stratified surface from the horizontal plane to a general curved surface (including a cylindrical surface), and to implement in silico. Each component of the technique system was quantitatively validated and visually compared to images, and the sensitivity of the virtual clipping algorithms was analyzed. This technique is inexpensive and accurate and provides high throughput for the measurement, reconstruction, and trait extraction of rice canopy architectures. The technique provides a more practical method of data collection to serve functional-structural plant models of rice and for the optimization of rice canopy types. Moreover, the technique can be easily adapted for other cereal crops such as wheat, which has numerous stems and leaves sheltering each other. PMID- 28558046 TI - Alfalfa virus S, a new species in the family Alphaflexiviridae. AB - A new species of the family Alphaflexiviridae provisionally named alfalfa virus S (AVS) was discovered in alfalfa samples originating from Sudan. A complete nucleotide sequence of the viral genome consisting of 8,349 nucleotides excluding the 3' poly(A) tail was determined by high throughput sequencing (HTS) on an Illumina platform. NCBI BLAST searches revealed that the virus shares the greatest degree of sequence identity with members of the family Alphaflexiviridae, genus Allexivirus. The AVS genome contains six computationally predicted open reading frames (ORF) encoding viral replication protein, triple gene block protein 1 (TGB1), TGB2, TGB3-like protein, unknown 38.4 kDa protein resembling serine-rich 40 kDa protein characteristic for allexiviruses, and coat protein (CP). AVS lacks a clear 3' proximal ORF that encodes a nucleic acid binding protein typical for allexiviruses. The identity of the virus was confirmed by RT-PCR with primers derived from the HTS-generated sequence, dot blot hybridization with DIG-labeled virus-specific RNA probes, and Western blot analysis with antibodies produced against a peptide derived from the CP sequence. Transmission electron microscopic observations of the infected tissues showed the presence of filamentous particles similar to allexiviruses in their length and appearance. To the best of our knowledge, this is the first report on the identification of a putative allexivirus in alfalfa (Medicago sativa). The genome sequence of AVS has been deposited in NCBI GenBank on 03/02/2016 as accession No KY696659. PMID- 28558047 TI - Age-related changes in hand dominance and functional asymmetry in older adults. AB - The aim of the study was to investigate fine motor performance and ascertain age related changes in laterality between the dominant and non-dominant hand. A representative sample of 635 adults (144 males and 491 females) aged 50 years and over completed a test battery MLS (Motor Performance Series) to assess a broad range of hand functions. Functional asymmetry was observed in all four motor tests (postural tremor, aiming, tapping, and inserting long pins). Significant differences between the dominant and non-dominant hand were obtained in both sexes across all age groups, except in the oldest female group (age >70) for the aiming (number of hits and errors) and postural tremor (number of errors) tasks. These differences in age-related changes may be attributed to hemispheric asymmetry, environmental factors, or use-dependent plasticity. Conflicting evidence in the literature warrants additional research to better explain age related alterations of hand dominance and manual performance in old age. PMID- 28558049 TI - Tobacco control: Developing an innovative and effective global strategy. AB - In this month's editorial, the PLOS Medicine Editors discuss the campaign for World No Tobacco Day 2017. PMID- 28558048 TI - DEK protein level is a biomarker of CD138positive normal and malignant plasma cells. AB - Overexpression of DEK oncogene is associated with increased proliferation of carcinoma cells and it is observed in several solid tumors due to the amplification of the 6p22.3 chromosomal region where DEK locates. Although the same chromosomal amplification occurs in multiple myeloma (MM), a plasma cell neoplasm, whether the expression and the copy number of the DEK gene are affected in MM remains elusive. We show that despite the increased copy number in CD138positive MM cells (4 out of 41 MM samples), DEK mRNA expression was down regulated compared with that in CD138negative bone marrow (BM) cells of the same patients (P<0.0001). DEK protein was not detectable by immunohistochemistry (IHC) in CD138positive normal plasma cells or in malignant plasma cells of MM patients (n = 56) whereas it was widely expressed in normal and neoplastic B-cells. Stable knockdown or overexpression of DEK in CD138positive MM cell lines did not affect the proliferation and viability of the cells profoundly in the presence or absence of chemotherapeutic agent melphalan whereas knockdown of DEK moderately but significantly increased the expression level of CD138 (p<0.01). Decreased DEK expression in plasma cells suggests a potential role of this gene in plasma cell development and lack of detectable DEK protein by IHC could be used as a biomarker for normal and malignant plasma cells. PMID- 28558050 TI - Citizen science: A new perspective to advance spatial pattern evaluation in hydrology. AB - Citizen science opens new pathways that can complement traditional scientific practice. Intuition and reasoning often make humans more effective than computer algorithms in various realms of problem solving. In particular, a simple visual comparison of spatial patterns is a task where humans are often considered to be more reliable than computer algorithms. However, in practice, science still largely depends on computer based solutions, which inevitably gives benefits such as speed and the possibility to automatize processes. However, the human vision can be harnessed to evaluate the reliability of algorithms which are tailored to quantify similarity in spatial patterns. We established a citizen science project to employ the human perception to rate similarity and dissimilarity between simulated spatial patterns of several scenarios of a hydrological catchment model. In total, the turnout counts more than 2500 volunteers that provided over 43000 classifications of 1095 individual subjects. We investigate the capability of a set of advanced statistical performance metrics to mimic the human perception to distinguish between similarity and dissimilarity. Results suggest that more complex metrics are not necessarily better at emulating the human perception, but clearly provide auxiliary information that is valuable for model diagnostics. The metrics clearly differ in their ability to unambiguously distinguish between similar and dissimilar patterns which is regarded a key feature of a reliable metric. The obtained dataset can provide an insightful benchmark to the community to test novel spatial metrics. PMID- 28558051 TI - The disease burden of congenital toxoplasmosis in Denmark, 2014. AB - BACKGROUND: Congenital toxoplasmosis (CT) causes a substantial disease burden worldwide. The aim of this study was to estimate the disease burden of CT in Denmark, a developed country with free public healthcare and nationwide data available. METHODS: Using data primarily from two public health surveillance programmes conducted between 1992 and 2007, we estimated the incidence, occurrence of sequelae, mortality and the burden of disease in terms of disability-adjusted life years (DALYs) of CT in Denmark in 2014. FINDINGS: We estimated that 14 children were born with CT in 2014, of which six will have developed sequelae by the age of 12. CT resulted in a total disease burden of 123 DALYs (95% uncertainty interval [UI], 100-148), of which 78 (95% UI, 64-94) were due to foetal loss and 2 (95% UI, 1-3) were due to neonatal death; the remaining burden was due to moderate to severe life-long sequelae. A comparison of the estimated incidence of CT with the number of reported CT cases in 2008-2014 indicated that for each reported CT case, at least five other CT cases could be expected to have occurred and gone unreported. INTERPRETATION: Early onset, severity, and life-long duration of sequelae have a major effect on the disease burden of CT. Our data suggest that CT is under-diagnosed or under-reported in Denmark. The estimated disease burden and public health impact in Denmark is lower than in other European countries, highlighting the need for country specific studies. PMID- 28558052 TI - Pleistocene to holocene expansion of the black-belt cichlid in Central America, Vieja maculicauda (Teleostei: Cichlidae). AB - The distributions of many Northern Hemisphere organisms have been influenced by fluctuations in sea level and climatic conditions during Pleistocene interglacial periods. These cycles are associated with range contraction and refugia for northern-distributed organisms as a response to glaciers. However, lower sea levels in the tropics and sub-tropics created available habitat for expansion of the ranges of freshwater organisms. The goal of this study was to use ecological niche modeling to test the hypothesis of north to south range expansion of Vieja maculicauda associated with Pleistocene glacial cycles. Understanding the biogeography of this widespread species may help us better understand the geology and interconnectivity of Central American freshwaters. Occurrence data for V. maculicauda was based on georeferencing of all museum records of specimens recovered from FishNet2. General patterns of phylogeographic structure were assessed with mtDNA. Present day niche models were generated and subsequently projected onto paleoclimatic maps of the region during the Last Interglacial, Last Glacial Maximum, and mid-Holocene. Phylogenetic analysis of mtDNA sequence data showed no phylogeographic structure throughout the range of this widespread species. Present day niche models were congruent with the observed distribution of V. maculicauda in Central America. Results showed a lack of suitable freshwater habitat in northern Central America and Mexico during the Last Interglacial, with greatest range expansion during the Last Glacial Maximum and mid-Holocene. Results support the hypothesis of a north to south range expansion of V. maculicauda associated with glacial cycles. The wide distribution of this species compared to other closely related cichlids indicates the latter did not respond to the degree of V. maculicauda in expansion of their distributions. Future work aimed at comparisons with other species and modeling of future climatic scenarios will be a fruitful area of investigation. PMID- 28558054 TI - Correction: New function of aldoxime dehydratase: Redox catalysis and the formation of an expected product. AB - [This corrects the article DOI: 10.1371/journal.pone.0175846.]. PMID- 28558053 TI - Novel mRNA-specific effects of ribosome drop-off on translation rate and polysome profile. AB - The well established phenomenon of ribosome drop-off plays crucial roles in translational accuracy and nutrient starvation responses during protein translation. When cells are under stress conditions, such as amino acid starvation or aminoacyl-tRNA depletion due to a high level of recombinant protein expression, ribosome drop-off can substantially affect the efficiency of protein expression. Here we introduce a mathematical model that describes the effects of ribosome drop-off on the ribosome density along the mRNA and on the concomitant protein synthesis rate. Our results show that ribosome premature termination may lead to non-intuitive ribosome density profiles, such as a ribosome density which increases from the 5' to the 3' end. Importantly, the model predicts that the effects of ribosome drop-off on the translation rate are mRNA-specific, and we quantify their resilience to drop-off, showing that the mRNAs which present ribosome queues are much less affected by ribosome drop-off than those which do not. Moreover, among those mRNAs that do not present ribosome queues, resilience to drop-off correlates positively with the elongation rate, so that sequences using fast codons are expected to be less affected by ribosome drop-off. This result is consistent with a genome-wide analysis of S. cerevisiae, which reveals that under favourable growth conditions mRNAs coding for proteins involved in the translation machinery, known to be highly codon biased and using preferentially fast codons, are highly resilient to ribosome drop-off. Moreover, in physiological conditions, the translation rate of mRNAs coding for regulatory, stress-related proteins, is less resilient to ribosome drop-off. This model therefore allows analysis of variations in the translational efficiency of individual mRNAs by accounting for the full range of known ribosome behaviours, as well as explaining mRNA-specific variations in ribosome density emerging from ribosome profiling studies. PMID- 28558055 TI - Plasma levels of high-mobility group box 1 and soluble receptor for advanced glycation end products in primary antiphospholipid antibody syndrome patients. AB - INTRODUCTION: Many studies have demonstrated elevated circulating levels of high mobility group box 1 (HMGB1) and decreased circulating levels of soluble receptor for advanced glycation end products (sRAGE) in patients with autoimmune diseases. In the present study, we investigated plasma levels of both HMGB1 and sRAGE in primary antiphospholipid syndrome (pAPS) patients. METHODS: We prospectively recruited 11 pAPS patients, 17 antiphospholipid antibody (APA)-positive SLE patients without APS manifestations (APA+SLE) and 12 SLE patients with secondary APS (APS+SLE). We also recruited 10 healthy controls (HCs). Plasma levels of HMGB1 and sRAGE were determined using sandwich ELISA kits. In addition, plasma levels of HMGB1 were also determined using Western blot in 6 pAPS patients and 6 HCs. RESULTS: There was no significant difference in plasma levels of HMGB1 measured by ELISA among subgroups of the enrolled subjects. In addition, there was no significant difference in plasma levels of HMGB1 measured by Western blot between pAPS patients and HCs. On the other hand, we observed a trend toward lower plasma levels of sRAGE in APA+SLE or APS+SLE patients when compared with HCs. However, there was no significant difference in plasma levels of sRAGE between pAPS patients and HCs, or between APA+SLE patients and APS+SLE patients. CONCLUSION: There was no significant difference in plasma levels of sRAGE or HMGB1 between pAPS patients and HCs. Plasma levels of sRAGE/HMGB1 could not be utilized to differentiate between APA+SLE and APS+SLE patients. PMID- 28558057 TI - New thermoluminescence age estimates for the Nyos maar eruption (Cameroon Volcanic Line). AB - Nyos maar is located in the Cameroon Volcanic Line and generates a multitude of primary and secondary hazards to the local population. For risk assessment and hazard mitigation, the age of the Nyos maar eruption provides some vital information. Since previous dating efforts using a range of techniques resulted in vastly varying eruption ages, we applied thermoluminescence (TL) methods to obtain independent and direct chronological constraints for the time of maar formation. Target minerals were granitic quartz clasts contained in pyroclastic surge deposits. Thermoluminescence plateau results prove that heat and/or pressure during the phreatomagmatic eruption was sufficient to reset the inherited luminescence signal of granitic bedrock quartz. Parallel application of three TL measurement protocols to one of the two samples gave consistent equivalent doses for the quartz ultra-violet emission. Despite the robustness of our dose estimates, the assessment of the dose rate was accompanied by methodological challenges, such as estimation of the original size distribution of quartz grains in the pyroclastic deposits. Considering results from additional laboratory analyses to constrain these uncertainties, we calculate an average maximum TL age of 12.3 +/- 1.5 ka for the Nyos maar eruption. Based on these new data, a more solid risk assessment can be envisaged. PMID- 28558058 TI - Correction: A Long-Term Assessment of the Variability in Winter Use of Dense Conifer Cover by Female White-Tailed Deer. AB - [This corrects the article DOI: 10.1371/journal.pone.0065368.]. PMID- 28558056 TI - Hypoxia-inducible factor 1 alpha is a poor prognostic factor and potential therapeutic target in malignant peripheral nerve sheath tumor. AB - BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. Hypoxia-inducible factor 1 (HIF-1) plays a crucial role in the cellular response to hypoxia and regulates the expression of multiple genes involved in tumor progression in various cancers. However, the importance of the expression of HIF-1alpha in MPNSTs is unclear. METHODS: The expression of HIF-1alpha was examined immunohistochemically in 82 MPNST specimens. Cell culture assays of human MPNST cells under normoxic and hypoxic conditions were used to evaluate the impact of anti-HIF-1alpha-specific siRNA inhibition on cell survival. A screening kit was employed to identify small molecules that inhibited HIF-1alpha. RESULTS: The nuclear expression of HIF-1alpha was positive in 75.6% of MPNST samples (62/82 cases). Positivity for HIF-1alpha was a significant poor prognostic factor both in univariate (P = 0.048) and multivariate (P <= 0.0001) analyses. HIF-1alpha knockdown abrogated MPNST cell growth, inducing apoptosis. Finally, chetomin, an inhibitor of HIF-1alpha, effectively inhibited the growth of MPNST cells and induced their apoptosis. CONCLUSION: Inhibition of HIF-1alpha signaling is a potential treatment option for MPNSTs. PMID- 28558059 TI - Multivalent peptidic linker enables identification of preferred sites of conjugation for a potent thialanstatin antibody drug conjugate. AB - Antibody drug conjugates (ADCs) are no longer an unknown entity in the field of cancer therapy with the success of marketed ADCs like ADCETRIS and KADCYLA and numerous others advancing through clinical trials. The pursuit of novel cytotoxic payloads beyond the mictotubule inhibitors and DNA damaging agents has led us to the recent discovery of an mRNA splicing inhibitor, thailanstatin, as a potent ADC payload. In our previous work, we observed that the potency of this payload was uniquely tied to the method of conjugation, with lysine conjugates showing much superior potency as compared to cysteine conjugates. However, the ADC field is rapidly shifting towards site-specific ADCs due to their advantages in manufacturability, characterization and safety. In this work we report the identification of a highly efficacious site-specific thailanstatin ADC. The site of conjugation played a critical role on both the in vitro and in vivo potency of these ADCs. During the course of this study, we developed a novel methodology of loading a single site with multiple payloads using an in situ generated multi drug carrying peptidic linker that allowed us to rapidly screen for optimal conjugation sites. Using this methodology, we were able to identify a double cysteine mutant ADC delivering four-loaded thailanstatin that was very efficacious in a gastric cancer xenograft model at 3mg/kg and was also shown to be efficacious against T-DM1 resistant and MDR1 overexpressing tumor cell lines. PMID- 28558060 TI - Genomic structure, expression pattern, and functional characterization of transcription factor E2F-2 from black tiger shrimp (Penaeus monodon). AB - Transcription factor E2F-2 is a regulator of cell cycle. Researchers identified E2F-2 genes from yeasts to humans, but few reports investigated E2F-2 gene from black tiger shrimp. In the present study, we cloned E2F-2 gene from black tiger shrimp (Penaeus monodon). Full-length PmE2F-2 complementary DNA sequence measures 3,189 bp with an open reading frame of 1,371 bp. Complete PmE2F-2 genomic sequence (17,305 bp) of P. monodon contains nine exons, which are separated by eight introns. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis indicated that PmE2F-2 is highly expressed in hepatopancreas and ovaries of P. monodon. Highest PmE2F-2 expression levels were observed in stage III ovarian development of P. monodon. PmE2F-2 expression levels were significantly augmented in ovaries of P. monodon after 5-hydroxytryptamine injection and eyestalk ablation. RNA interference experiments were conducted to examine PmE2F 2, PmCDK2, and PmCyclin E expression profiles. PmE2F-2 was successfully knocked down in ovaries and hepatopancreas via double-stranded RNA (dsRNA)-E2F-2 injection. In the same organs, PmE2F-2 expression localization and level were investigated through in situ hybridization, which revealed consistent results with those of qRT-PCR. After dsRNA-E2F-2 injection, gonadosomatic index of shrimp was significantly lower than those following dsRNA-GFP and phosphate-buffered solution injections. Therefore, PmE2F-2 may be involved in ovarian maturation in P. monodon. PMID- 28558061 TI - Low versus high dose of antimony for American cutaneous leishmaniasis: A randomized controlled blind non-inferiority trial in Rio de Janeiro, Brazil. AB - BACKGROUND: Although high dose of antimony is the mainstay for treatment of American cutaneous leishmaniasis (ACL), ongoing major concerns remain over its toxicity. Whether or not low dose antimony regimens provide non-inferior effectiveness and lower toxicity has long been a question of dispute. METHODS: A single-blind, non-inferiority, randomized controlled trial was conducted comparing high dose with low dose of antimony in subjects with ACL treated at a referral center in Rio de Janeiro, an endemic area of Leishmania (Viannia) braziliensis transmission. The primary outcome was clinical cure at 360 days of follow-up in the modified-intention-to-treat (mITT) and per-protocol (PP) populations. Non-inferiority margin was 15%. Secondary objectives included occurrence of epithelialization, adverse events and drug discontinuations. This study was registered in ClinicalTrials.gov: NCT01301924. RESULTS: Overall, 72 patients were randomly assigned to one of the two treatment arms during October 2008 to July 2014. In mITT, clinical cure was observed in 77.8% of subjects in the low dose antimony group and 94.4% in the high dose antimony group after one series of treatment (risk difference 16.7%; 90% CI, 3.7-29.7). The results were confirmed in PP analysis, with 77.8% of subjects with clinical cure in the low dose antimony group and 97.1% in the high dose antimony group (risk difference 19.4%; 90% CI, 7.1-31.7). The upper limit of the confidence interval exceeded the 15% threshold and was also above zero supporting the hypothesis that low dose is inferior to high dose of antimony after one series of treatment. Nevertheless, more major adverse events, a greater number of adverse events and major adverse events per subject, and more drug discontinuations were observed in the high dose antimony group (all p<0.05). Interestingly, of all the subjects who were originally allocated to the low dose antimony group and were followed up after clinical failure, 85.7% achieved cure after a further treatment with local therapy or low dose of antimony. CONCLUSIONS: Compared with high dose, low dose of antimony was inferior at the pre-specified margin after one series of treatment of ACL, but was associated with a significantly lower toxicity. While high dose of antimony should remain the standard treatment for ACL, low dose antimony treatment might be preferred when toxicity is a primary concern. PMID- 28558062 TI - Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh. AB - BACKGROUND: AmBisome therapy for VL has an excellent efficacy and safety profile and has been adopted as a first-line regimen in Bangladesh. Second-line treatment options are limited and should preferably be given in short course combinations in order to prevent the development of resistant strains. Combination regimens including AmBisome, paromomycin and miltefosine have proved to be safe and effective in the treatment of VL in India. In the present study, the safety and efficacy of these same combinations were assessed in field conditions in Bangladesh. METHODS: The safety and efficacy of three combination regimens: a 5 mg/kg single dose of AmBisome + 7 subsequent days of miltefosine (2.5 mg/kg/day), a 5 mg/kg single dose of AmBisome + 10 subsequent days of paromomycin (15 mg/kg/day) and 10 days of paromomycin (15 mg/kg/day) + miltefosine (2.5 mg/kg/day), were compared with a standard regimen of AmBisome 15 mg/kg given in 5 mg/kg doses on days 1, 3 and 5. This was a phase III open label, individually randomized clinical trial. Patients from 5 to 60 years with uncomplicated primary VL were recruited from the Community Based Medical College Bangladesh (CBMC,B) and the Upazila Health Complexes of Trishal, Bhaluka and Fulbaria (all located in Mymensingh district), and randomly assigned to one of the treatments. The objective was to assess safety and definitive cure at 6 months after treatment. RESULTS: 601 patients recruited between July 2010 and September 2013 received either AmBisome monotherapy (n = 158), AmBisome + paromomycin (n = 159), AmBisome + miltefosine (n = 142) or paromomycin + miltefosine (n = 142). At 6 months post- treatment, final cure rates for the intention-to-treat population were 98.1% (95%CI 96.0-100) for AmBisome monotherapy, 99.4% (95%CI 98.2-100) for the AmBisome + paromomycin arm, 94.4% (95%CI 90.6-98.2) for the AmBisome + miltefosine arm, and 97.9% (95%CI 95.5-100) for paromomycin + miltefosine arm. There were 12 serious adverse events in the study in 11 patients that included 3 non-study drug related deaths. There were no relapses or PKDL up to 6 months follow-up. All treatments were well tolerated with no unexpected side effects. Adverse events were most frequent during treatment with miltefosine + paromomycin, three serious adverse events related to the treatment occurred in this arm, all of which resolved. CONCLUSION: None of the combinations were inferior to AmBisome in both the intention-to-treat and per-protocol populations. All the combinations demonstrated excellent overall efficacy, were well tolerated and safe, and could be deployed under field conditions in Bangladesh. The trial was conducted by the International Centre for Diarrhoeal Disease Research (ICDDR,B) and the Shaheed Suhrawardy Medical College (ShSMC), Dhaka, in collaboration with the trial sites and sponsored by the Drugs for Neglected Diseases initiative (DNDi). TRIAL REGISTRATION: ClinicalTrials.gov NCT01122771. PMID- 28558064 TI - Multispectral image fusion for illumination-invariant palmprint recognition. AB - Multispectral palmprint recognition has shown broad prospects for personal identification due to its high accuracy and great stability. In this paper, we develop a novel illumination-invariant multispectral palmprint recognition method. To combine the information from multiple spectral bands, an image-level fusion framework is completed based on a fast and adaptive bidimensional empirical mode decomposition (FABEMD) and a weighted Fisher criterion. The FABEMD technique decomposes the multispectral images into their bidimensional intrinsic mode functions (BIMFs), on which an illumination compensation operation is performed. The weighted Fisher criterion is to construct the fusion coefficients at the decomposition level, making the images be separated correctly in the fusion space. The image fusion framework has shown strong robustness against illumination variation. In addition, a tensor-based extreme learning machine (TELM) mechanism is presented for feature extraction and classification of two dimensional (2D) images. In general, this method has fast learning speed and satisfying recognition accuracy. Comprehensive experiments conducted on the PolyU multispectral palmprint database illustrate that the proposed method can achieve favorable results. For the testing under ideal illumination, the recognition accuracy is as high as 99.93%, and the result is 99.50% when the lighting condition is unsatisfied. PMID- 28558063 TI - Amino acid metabolites that regulate G protein signaling during osmotic stress. AB - All cells respond to osmotic stress by implementing molecular signaling events to protect the organism. Failure to properly adapt can lead to pathologies such as hypertension and ischemia-reperfusion injury. Mitogen-activated protein kinases (MAPKs) are activated in response to osmotic stress, as well as by signals acting through G protein-coupled receptors (GPCRs). For proper adaptation, the action of these kinases must be coordinated. To identify second messengers of stress adaptation, we conducted a mass spectrometry-based global metabolomics profiling analysis, quantifying nearly 300 metabolites in the yeast S. cerevisiae. We show that three branched-chain amino acid (BCAA) metabolites increase in response to osmotic stress and require the MAPK Hog1. Ectopic addition of these BCAA derivatives promotes phosphorylation of the G protein alpha subunit and dampens G protein-dependent transcription, similar to that seen in response to osmotic stress. Conversely, genetic ablation of Hog1 activity or the BCAA-regulatory enzymes leads to diminished phosphorylation of Galpha and increased transcription. Taken together, our results define a new class of candidate second messengers that mediate cross talk between osmotic stress and GPCR signaling pathways. PMID- 28558065 TI - Prediabetes is associated with the modulation of antigen-specific Th1/Tc1 and Th17/Tc17 responses in latent Mycobacterium tuberculosis infection. AB - Type 2 diabetes mellitus (DM) is associated with the down modulation of Th1, Th2 and Th17 responses in latent Mycobacterium tuberculosis infection but the role of prediabetes (PDM) in this setting is not well understood. To examine the role of CD4+ and CD8+ T cell cytokines in latent tuberculosis (LTB) with coincident PDM, we studied the baseline, mycobacterial, control antigen and mitogen-stimulated T cell cytokine responses in LTB individuals with (LTB-PDM; n = 20) or without (LTB NDM; n = 20) concomitant prediabetes. LTB-PDM is characterized by diminished frequencies of mono-and dual-functional CD4+ Th1 and Th17 cells and mono functional Th2 cells at baseline and/or following mycobacterial-antigen stimulation in comparison to LTB-NDM. LTB-PDM is also characterized by diminished frequencies of mono-functional CD8+ Tc1, Tc2 and Tc17 cells at baseline and/or following mycobacterial-antigen stimulation in comparison to LTB-NDM. LTB-PDM is therefore characterized by diminished frequencies of antigen-specific Th1/Tc1 and Th17/Tc17 cells, indicating that PDM is associated with alterations of the immune response in latent TB associated with compromised CD4+ and CD8+ T cell function. PMID- 28558066 TI - Gene expression analysis of rocket salad under pre-harvest and postharvest stresses: A transcriptomic resource for Diplotaxis tenuifolia. AB - Diplotaxis tenuifolia L. is of important economic value in the fresh-cut industry for its nutraceutical and sensorial properties. However, information on the molecular mechanisms conferring tolerance of harvested leaves to pre- and postharvest stresses during processing and shelf-life have never been investigated. Here, we provide the first transcriptomic resource of rocket by de novo RNA sequencing assembly, functional annotation and stress-induced expression analysis of 33874 transcripts. Transcriptomic changes in leaves subjected to commercially-relevant pre-harvest (salinity, heat and nitrogen starvation) and postharvest stresses (cold, dehydration, dark, wounding) known to affect quality and shelf-life were analysed 24h after stress treatment, a timing relevant to subsequent processing of salad leaves. Transcription factors and genes involved in plant growth regulator signaling, autophagy, senescence and glucosinolate metabolism were the most affected by the stresses. Hundreds of genes with unknown function but uniquely expressed under stress were identified, providing candidates to investigate stress responses in rocket. Dehydration and wounding had the greatest effect on the transcriptome and different stresses elicited changes in the expression of genes related to overlapping groups of hormones. These data will allow development of approaches targeted at improving stress tolerance, quality and shelf-life of rocket with direct applications in the fresh cut industries. PMID- 28558067 TI - Impact of insurance coverage on utilization of pre-exposure prophylaxis for HIV prevention. AB - Pre-exposure prophylaxis (PrEP) can reduce U.S. HIV incidence. We assessed insurance coverage and its association with PrEP utilization. We reviewed patient data at three PrEP clinics (Jackson, Mississippi; St. Louis, Missouri; Providence, Rhode Island) from 2014-2015. The outcome, PrEP utilization, was defined as patient PrEP use at three months. Multivariable logistic regression was performed to determine the association between insurance coverage and PrEP utilization. Of 201 patients (Jackson: 34%; St. Louis: 28%; Providence: 28%), 91% were male, 51% were White, median age was 29 years, and 21% were uninsured; 82% of patients reported taking PrEP at three months. Insurance coverage was significantly associated with PrEP utilization. After adjusting for Medicaid expansion and individual socio-demographics, insured patients were four times as likely to use PrEP services compared to the uninsured (OR: 4.49, 95% CI: 1.68 12.01; p = 0.003). Disparities in insurance coverage are important considerations in implementation programs and may impede PrEP utilization. PMID- 28558069 TI - Impact of environmental variables on Dubas bug infestation rate: A case study from the Sultanate of Oman. AB - Date palm cultivation is economically important in the Sultanate of Oman, with significant financial investment coming from both the government and from private individuals. However, a global infestation of Dubas bug (Ommatissus lybicus Bergevin) has impacted the Middle East region, and infestations of date palms have been widespread. In this study, spatial analysis and geostatistical techniques were used to model the spatial distribution of Dubas bug infestations to (a) identify correlations between Dubas bug densities and different environmental variables, and (b) predict the locations of future Dubas bug infestations in Oman. Firstly, we considered individual environmental variables and their correlations with infestation locations. Then, we applied more complex predictive models and regression analysis techniques to investigate the combinations of environmental factors most conducive to the survival and spread of the Dubas bug. Environmental variables including elevation, geology, and distance to drainage pathways were found to significantly affect Dubas bug infestations. In contrast, aspect and hillshade did not significantly impact on Dubas bug infestations. Understanding their distribution and therefore applying targeted controls on their spread is important for effective mapping, control and management (e.g., resource allocation) of Dubas bug infestations. PMID- 28558068 TI - Diagnostic accuracy of gadoxetic acid-enhanced MR for small hypervascular hepatocellular carcinoma and the concordance rate of Liver Imaging Reporting and Data System (LI-RADS). AB - BACKGROUND & AIMS: To assess diagnostic accuracy of gadoxetic acid-enhanced MR for small hypervascular hepatocellular carcinoma (HCC) detected by C-arm CT and concordance rate of Liver Imaging Reporting and Data System (LI-RADS). METHODS: In this retrospective study, we recruited 4,544 patients suspected of having HCC underwent C-arm CT from November 2008 to May 2013. Among these patients, gadoxetic acid-enhanced MR was performed in 167 patients with HCC (n = 379; 257 > 1 cm, 122 <= 1 cm). HCC was confirmed by MR, CT, or follow-up images. Two radiologists graded likelihood of HCC and assessed MR features. Jackknife alternative free-response receiver operating characteristic (JAFROC) analysis was performed. All HCCs were evaluated concordance rate of LI-RADS. RESULTS: Mean JAFROC figure of merit for large (>1-cm) HCC was 0.948, while that for small HCC was 0.787 with fair agreement (kappa = 0.409). Mean sensitivity and positive predictive value (PPV) were 91% and 90% for large HCC versus 63.0% and 79% for small HCC, respectively. Seventeen of 122 small HCCs (13.9%) were not visible on MR. Among 379 HCCs, 99 met LR-5, and 259 met LR-4. Common features for small HCC included arterial enhancement (81.9%), hepatobiliary phase hypointensity (80.3%), and delayed washout (72.9%). CONCLUSION: Diagnostic accuracy of gadoxetic acid enhanced MR imaging for small, hypervascular HCCs (Mean figure of merit = 0.787) was still low compared with large HCC (Mean figure of merit = 0.948). LR-5 and LR 4 covered 94% (358/379) of the HCCs. PMID- 28558070 TI - Vocalizations during post-conflict affiliations from victims toward aggressors based on uncertainty in Japanese macaques. AB - We investigated the use of vocalizations called "grunts," "girneys," and "coos" accompanied by post-conflict affiliative interaction between former opponents (reconciliation) in Japanese macaques (Macaca fuscata). Although reconciliation functions to repair bonds, such interactions sometimes entail risks of receiving further aggression. Vocalizations can be used at a distance from the former opponent; thus, we predict that vocalizations are used particularly by victims of a conflict, and are frequently used in situations of uncertainty when it is difficult for them to estimate whether the former opponent will resume aggression. In addition, we predict that vocalizations are effective in preventing further aggression. To test these hypotheses, we conducted observations of post-conflict and matched-control situations in female Japanese macaques living in a free-ranging group. We found that former opponents tended to be attracted to each other within the first minute following a conflict, thus demonstrating reconciliation behavior. Vocalizations were more frequently used by the victims in post-conflict interactions than under control situations; however, this tendency was not found in aggressors. When affiliation with the former opponent occurred, victims were more likely to use vocalizations towards less familiar opponents. These findings suggest that Japanese macaques used vocalizations more often when interacting with less predictable former opponents. Victims were more likely to receive aggression from former aggressors when engaged in affiliations with them than under no such affiliations. No significant differences were found in the probability of the victims receiving aggression, regardless of whether they used vocalizations; thus, whether the victim benefits from using vocalizations in these contexts remains unclear. Japanese macaques form despotic societies and therefore, further aggression was inevitable, to some degree, after a conflict. The use of vocalizations by a victim was found to depend on the nature of their relationship with the aggressor; however, the effectiveness of this behavior requires further investigation. PMID- 28558071 TI - Gene expression patterns induced at different stages of rhinovirus infection in human alveolar epithelial cells. AB - Human rhinovirus (HRV) is the common virus that causes acute respiratory infection (ARI) and is frequently associated with lower respiratory tract infections (LRTIs). We aimed to investigate whether HRV infection induces a specific gene expression pattern in airway epithelial cells. Alveolar epithelial cell monolayers were infected with HRV species B (HRV-B). RNA was extracted from both supernatants and infected monolayer cells at 6, 12, 24 and 48 hours post infection (hpi) and transcriptional profile was analyzed using Affymetrix GeneChip and the results were subsequently validated using quantitative Real-time PCR method. HRV-B infects alveolar epithelial cells which supports implication of the virus with LRTIs. In total 991 genes were found differentially expressed during the course of infection. Of these, 459 genes were up-regulated whereas 532 genes were down-regulated. Differential gene expression at 6 hpi (187 genes up regulated vs. 156 down-regulated) were significantly represented by gene ontologies related to the chemokines and inflammatory molecules indicating characteristic of viral infection. The 75 up-regulated genes surpassed the down regulated genes (35) at 12 hpi and their enriched ontologies fell into discrete functional entities such as regulation of apoptosis, anti-apoptosis, and wound healing. At later time points of 24 and 48 hpi, predominated down-regulated genes were enriched for extracellular matrix proteins and airway remodeling events. Our data provides a comprehensive image of host response to HRV infection. The study suggests the underlying molecular regulatory networks genes which might be involved in pathogenicity of the HRV-B and potential targets for further validations and development of effective treatment. PMID- 28558072 TI - Regulation of PI3K/Akt dependent apoptotic markers during b virus infection of human and macaque fibroblasts. AB - B virus (Macacine herpesvirus 1), a simplex virus endemic in macaques, causes encephalitis, encephalomyelitis, and death in 80% of untreated zoonotically infected humans with delayed or no treatment. Here we report a significant difference in PI3K/Akt-dependent apoptosis between B virus infected human and macaque dermal fibroblasts. Our data show that B virus infection in either human or macaque fibroblasts results in activation of Akt via PI3K and this activation does not require viral de novo protein synthesis. Inhibition of PI3K with LY294002 results in a significant reduction of viral titers in B virus infected macaque and human fibroblasts with only a modest difference in the reduction of virus titers between the two cell types. We, therefore, tested the hypothesis that B virus results in the phosphorylation of Akt (S473), which prevents apoptosis, enhancing virus replication in B virus infected macaque dermal fibroblasts. We observed markers of intrinsic apoptosis when PI3K activation of Akt was inhibited in B virus infected macaque cells, while, these apoptotic markers were absent in B virus infected human fibroblasts under the same conditions. From these data we suggest that PI3K activates Akt in B virus infected macaque and human fibroblasts, but this enhances virus replication in macaque fibroblast cells by blocking apoptosis. PMID- 28558073 TI - Hepatitis E virus persists in the presence of a type III interferon response. AB - The RIG-I-like RNA helicase (RLR)-mediated interferon (IFN) response plays a pivotal role in the hepatic antiviral immunity. The hepatitis A virus (HAV) and the hepatitis C virus (HCV) counter this response by encoding a viral protease that cleaves the mitochondria antiviral signaling protein (MAVS), a common signaling adaptor for RLRs. However, a third hepatotropic RNA virus, the hepatitis E virus (HEV), does not appear to encode a functional protease yet persists in infected cells. We investigated HEV-induced IFN responses in human hepatoma cells and primary human hepatocytes. HEV infection resulted in persistent virus replication despite poor spread. This was companied by a type III IFN response that upregulated multiple IFN-stimulated genes (ISGs), but type I IFNs were barely detected. Blocking type III IFN production or signaling resulted in reduced ISG expression and enhanced HEV replication. Unlike HAV and HCV, HEV did not cleave MAVS; MAVS protein size, mitochondrial localization, and function remained unaltered in HEV-replicating cells. Depletion of MAVS or MDA5, and to a less extent RIG-I, also diminished IFN production and increased HEV replication. Furthermore, persistent activation of the JAK/STAT signaling rendered infected cells refractory to exogenous IFN treatment, and depletion of MAVS or the receptor for type III IFNs restored the IFN responsiveness. Collectively, these results indicate that unlike other hepatotropic RNA viruses, HEV does not target MAVS and its persistence is associated with continuous production of type III IFNs. PMID- 28558074 TI - Individual expression features of GPX2, NQO1 and SQSTM1 transcript variants induced by hydrogen peroxide treatment in HeLa cells. AB - Pathway activity assessment-based approaches are becoming highly influential in various fields of biology and medicine. However, these approaches mostly rely on analysis of mRNA expression, and total mRNA from a given locus is measured in the majority of cases. Notably, a significant portion of protein-coding genes produces more than one transcript. This biological fact is responsible for significant noise when changes in total mRNA transcription of a single gene are analyzed. The NFE2L2/AP-1 pathway is an attractive target for biomedical applications. To date, there is a lack of data regarding the agreement in expression of even classical target genes of this pathway. In the present paper we analyzed whether transcript variants of GPX2, NQO1 and SQSTM1 were characterized by individual features of expression when HeLa cells were exposed to pro-oxidative stimulation with hydrogen peroxide. We found that all the transcripts (10 in total) appeared to be significantly individually regulated under the conditions tested. We conclude that individual transcripts, rather than total mRNA, are best markers of pathway activation. We also discuss here some biological roles of individual transcript regulation. PMID- 28558075 TI - A never-ending story: the steadily growing family of the FA and FA-like genes. AB - Among the chromosome fragility-associated human syndromes that present cancer predisposition, Fanconi anemia (FA) is unique due to its large genetic heterogeneity. To date, mutations in 21 genes have been associated with an FA or an FA-like clinical and cellular phenotype, whose hallmarks are bone marrow failure, predisposition to acute myeloid leukemia and a cellular and chromosomal hypersensitivity to DNA crosslinking agents exposure. The goal of this review is to trace the history of the identification of FA genes, a history that started in the eighties and is not yet over, as indicated by the cloning of a twenty-first FA gene in 2016. PMID- 28558076 TI - Functional Effects of Hyperthyroidism on Cardiac Papillary Muscle in Rats. AB - BACKGROUND: Hyperthyroidism is currently recognized to affect the cardiovascular system, leading to a series of molecular and functional changes. However, little is known about the functional influence of hyperthyroidism in the regulation of cytoplasmic calcium and on the sodium/calcium exchanger (NCX) in the cardiac muscle. OBJECTIVES: To evaluate the functional changes in papillary muscles isolated from animals with induced hyperthyroidism. METHODS: We divided 36 Wistar rats into a group of controls and another of animals with hyperthyroidism induced by intraperitoneal T3 injection. We measured in the animals' papillary muscles the maximum contraction force, speed of contraction (+df/dt) and relaxation ( df/dt), contraction and relaxation time, contraction force at different concentrations of extracellular sodium, post-rest potentiation (PRP), and contraction force induced by caffeine. RESULTS: In hyperthyroid animals, we observed decreased PRP at all rest times (p < 0.05), increased +df/dt and -df/dt (p < 0.001), low positive inotropic response to decreased concentration of extracellular sodium (p < 0.001), reduction of the maximum force in caffeine induced contraction (p < 0.003), and decreased total contraction time (p < 0.001). The maximal contraction force did not differ significantly between groups (p = 0.973). CONCLUSION: We hypothesize that the changes observed are likely due to a decrease in calcium content in the sarcoplasmic reticulum, caused by calcium leakage, decreased expression of NCX, and increased expression of a-MHC and SERCA2. PMID- 28558077 TI - Prenatal Diagnosis of Intracardiac Tumors. PMID- 28558078 TI - Testosterone and Voluntary Exercise, Alone or Together Increase Cardiac Activation of AKT and ERK1/2 in Diabetic Rats. AB - BACKGROUND: Impaired angiogenesis in cardiac tissue is a major complication of diabetes. Protein kinase B (AKT) and extracellular signal regulated kinase (ERK) signaling pathways play important role during capillary-like network formation in angiogenesis process. OBJECTIVES: To determine the effects of testosterone and voluntary exercise on levels of vascularity, phosphorylated Akt (P- AKT) and phosphorylated ERK (P-ERK) in heart tissue of diabetic and castrated diabetic rats. METHODS: Type I diabetes was induced by i.p injection of 50 mg/kg of streptozotocin in animals. After 42 days of treatment with testosterone (2mg/kg/day) or voluntary exercise alone or in combination, heart tissue samples were collected and used for histological evaluation and determination of P-AKT and P-ERK levels by ELISA method. RESULTS: Our results showed that either testosterone or exercise increased capillarity, P-AKT, and P-ERK levels in the heart of diabetic rats. Treatment of diabetic rats with testosterone and exercise had a synergistic effect on capillarity, P-AKT, and P-ERK levels in heart. Furthermore, in the castrated diabetes group, capillarity, P-AKT, and P-ERK levels significantly decreased in the heart, whereas either testosterone treatment or exercise training reversed these effects. Also, simultaneous treatment of castrated diabetic rats with testosterone and exercise had an additive effect on P-AKT and P-ERK levels. CONCLUSION: Our findings suggest that testosterone and exercise alone or together can increase angiogenesis in the heart of diabetic and castrated diabetic rats. The proangiogenesis effects of testosterone and exercise are associated with the enhanced activation of AKT and ERK1/2 in heart tissue. PMID- 28558079 TI - Prognostic Value of a New Marker of Ventricular Repolarization in Cirrhotic Patients. AB - BACKGROUND: There is still debate about the relationship between changes in ventricular repolarization on the surface electrocardiogram and cirrhosis severity. OBJECTIVE: To study the relationship between variables related to ventricular repolarization and the clinical severity of the cirrhotic disease. METHODS: We selected 79 individuals with hepatic cirrhosis, classified according to the Child-Pugh-Turcotte criteria (Child A, B, and C). We measured the QT and corrected QT (QTc) intervals, and the interval between the peak and the end of the T wave (TpTe), and we identified their minimum, maximum, and mean values in the 12-lead electrocardiogram. We also calculated the dispersion of the QT (DQT) and QTc (DQTc) intervals. RESULTS: In 12 months of clinical follow-up, nine subjects underwent hepatic transplantation (Child A: 0 [0%]; Child B: 6 [23.1%]; Child C: 3 [18.8%]; p = 0.04) and 12 died (Child A: 3 [12.0%]; Child B: 4 [15.4%]; Child C: 5 [31.3%]; p = 0.002). No significant differences were observed between the cirrhotic groups related to the minimum, maximum, and mean values for the QT, QTc, TpTe, DQT, and DQTc intervals. A minimum TpTe interval <= 50 ms was a predictor for the composite endpoints of death or liver transplantation with a sensitivity of 90% and a specificity of 57% (p = 0.005). In the Cox multivariate analysis, the Child groups and a minimum TpTe of <= 50 ms were independent predictors of the composite endpoints. CONCLUSION: The intervals QT, QTc, DQT, DQTc, and TpTe have similar distributions between different severity stages in cirrhotic disease. The TpTe interval proved to be a prognostic marker in subjects with cirrhosis, regardless of disease severity (NCT01433848). PMID- 28558080 TI - The Relation between Epicardial Fat Thickness and Prognostic Risk Scores. PMID- 28558082 TI - Analysis of the Use of Extracorporeal Circulation on the In-Hospital Outcomes of Dialytic Patients Who Underwent Myocardial Revascularization Surgery. AB - BACKGROUND: Myocardial revascularization surgery is the best treatment for dyalitic patients with multivessel coronary disease. However, the procedure still has high morbidity and mortality. The use of extracorporeal circulation (ECC) can have a negative impact on the in-hospital outcomes of these patients. OBJECTIVES: To evaluate the differences between the techniques with ECC and without ECC during the in-hospital course of dialytic patients who underwent surgical myocardial revascularization. METHODS: Unicentric study on 102 consecutive, unselected dialytic patients, who underwent myocardial revascularization surgery in a tertiary university hospital from 2007 to 2014. RESULTS: Sixty-three patients underwent surgery with ECC and 39 without ECC. A high prevalence of cardiovascular risk factors was found in both groups, without statistically significant difference between them. The group "without ECC" had greater number of revascularizations (2.4 vs. 1.7; p <0.0001) and increased need for blood components (77.7% vs. 25.6%; p <0.0001) and inotropic support (82.5% vs 35.8%; p <0.0001). In the postoperative course, the group "without ECC" required less vasoactive drugs, (61.5% vs. 82.5%; p = 0.0340) and shorter time of mechanical ventilation (13.0 hours vs. 36,3 hours, p = 0.0217), had higher extubation rates in the operating room (58.9% vs. 23.8%, p = 0.0006), lower infection rates (7.6% vs. 28.5%; p = 0.0120), and shorter ICU stay (5.2 days vs. 8.1 days; p = 0.0054) as compared with the group with ECC surgery. No difference in mortality was found between the groups. CONCLUSION: Myocardial revascularization with ECC in patients on dialysis resulted in higher morbidity in the perioperative period in comparison with the procedure without ECC, with no difference in mortality though. PMID- 28558081 TI - Stroke Prevention in Atrial Fibrillation: Focus on Latin America. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, with an estimated prevalence of 1-2% in North America and Europe. The increased prevalence of AF in Latin America is associated with an ageing general population, along with poor control of key risk factors, including hypertension. As a result, stroke prevalence and associated mortality have increased dramatically in the region. Therefore, the need for effective anticoagulation strategies in Latin America is clear. The aim of this review is to provide a contemporary overview of anticoagulants for stroke prevention. The use of vitamin K antagonists (VKAs, eg, warfarin) and aspirin in the prevention of stroke in patients with AF in Latin America remains common, although around one fifth of all AF patients receive no anticoagulation. Warfarin use is complicated by a lack of access to effective monitoring services coupled with an unpredictable pharmacokinetic profile. The overuse of aspirin is associated with significant bleeding risks and reduced efficacy for stroke prevention in this patient group. The non-VKA oral anticoagulants (NOACbs) represent a potential means of overcoming many limitations associated with VKA and aspirin use, including a reduction in the need for monitoring and a reduced risk of hemorrhagic events. The ultimate decision of which anticoagulant drug to utilize in AF patients depends on a multitude of factors. More research is needed to appreciate the impact of these factors in the Latin American population and thereby reduce the burden of AF-associated stroke in this region. PMID- 28558083 TI - Obesity and its Association with Food Consumption, Diabetes Mellitus, and Acute Myocardial Infarction in the Elderly. AB - BACKGROUND: Obesity affects a large part of elderly individuals worldwide and is considered a risk predictor for the development of chronic diseases such as cardiac diseases, the leading causes of death in the elderly population. OBJECTIVE: To investigate the prevalence of obesity and associated factors, with emphasis on the occurrence of other diseases and on food consumption in elderly individuals treated at the Brazilian Unified Health System (Sistema Unico de Saude, SUS). METHODS: Cross-sectional sampling study performed in the city of Goiania (Brazil) including elderly individuals (>= 60 years) receiving primary care. During home visits, we performed anthropometric measurements and applied a structured, standardized, and pre-tested questionnaire assessing socioeconomic, demographic and lifestyle conditions, occurrence of diseases, and food consumption. We performed multiple Poisson regression analysis using a hierarchical model and adopting a significance level of 5%. RESULTS: We evaluated 418 elderly patients with a mean age of 70.7 +/- 7 years. Their body mass indices had a mean value of 27.0 kg/m2 and were higher in women than in men (27.4 kg/m2 versus 26.1 kg/m2, respectively, p = 0.017). Obesity had a prevalence of 49.0%, a risk 1.87 times higher between the ages of 60-69 years and 70-79 years, and a rate 1.4 times higher among individuals with more than four morbidities. On multivariate analysis, the factors associated with obesity were age 60-69 and 70 79 years, inadequate consumption of whole-wheat grains and adequate consumption of fruit, musculoskeletal diseases, diabetes mellitus, and acute myocardial infarction. CONCLUSIONS: Obesity had a high prevalence in the evaluated elderly population and was associated with food consumption, musculoskeletal disease, diabetes mellitus, and acute myocardial infarction. PMID- 28558084 TI - Stent Placement in a Neonate with Sano Modification of the Norwood using Semi Elective Extracorporeal Membrane Oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) is a well-established tool of cardiopulmonary circulatory support for cardiopulmonary failure in children and adults. It has been used as a supportive strategy during interventional procedures in neonates with congenital heart disease. Herein, we describe a neonate with hypoplastic left heart syndrome who underwent stenting of the Sano shunt and left pulmonary artery after Norwood Sano operation using intra procedural ECMO support. The use of ECMO as a bridge to recovery might be a feasible and reasonably safe adjunctive approach in the treatment of complications in selective case of neonates having undergone the Norwood Sano procedure. PMID- 28558085 TI - Complete Treatment Versus Residual Lesion - Long-Term Evolution After Acute Coronary Syndrome. AB - INTRODUCTION: A recently published study raised doubts about the need for percutaneous treatment of nonculprit lesions in patients with acute coronary syndromes (ACS). METHODS: Retrospective, unicentric, observational study. OBJECTIVE: To analyze the long-term outcomes in patients undergoing treatment of the culprit artery, comparing those who remained with significant residual lesions in nonculprit arteries (group I) versus those without residual lesions in other coronary artery beds (group II). The study included 580 patients (284 in group I and 296 in group II) between May 2010 and May 2013. We obtained demographic and clinical data, as well as information regarding the coronary treatment administered to the patients. In the statistical analysis, the primary outcome included combined events (reinfarction/angina, death, heart failure, and need for reintervention). The comparison between groups was performed using the chi-square test and ANOVA. The long-term analysis was conducted with the Kaplan Meier method, with a mean follow-up of 9.86 months. RESULTS: The mean ages were 63 years in group I and 62 years in group II. On long-term follow-up, there was no significant difference in combined events in groups I and II (31.9% versus 35.6%, respectively, p = 0.76). CONCLUSION: The strategy of treating the culprit artery alone seems safe. In this study, no long-term differences in combined endpoints were observed between patients who remained with significant lesions compared with those without other obstructions. PMID- 28558086 TI - Acute Heart Failure Registry: Risk Assessment Model in Decompensated Heart Failure. AB - BACKGROUND: Heart failure (HF) is a highly prevalent syndrome. Although the long term prognostic factors have been identified in chronic HF, this information is scarcer with respect to patients with acute HF. despite available data in the literature on long-term prognostic factors in chronic HF, data on acute HF patients are more scarce. OBJECTIVES: To develop a predictor of unfavorable prognostic events in patients hospitalized for acute HF syndromes, and to characterize a group at higher risk regarding their clinical characteristics, treatment and outcomes. METHODS: cohort study of 600 patients admitted for acute HF, defined according to the European Society of Cardiology criteria. Primary endpoint for score derivation was defined as all-cause mortality and / or rehospitalization for HF at 12 months. For score validation, the following endpoints were used: all-cause mortality and / or readmission for HF at 6, 12 and 24 months. The exclusion criteria were: high output HF; patients with acute myocardial infraction, acute myocarditis, infectious endocarditis, pulmonary infection, pulmonary artery hypertension and severe mitral stenosis. RESULTS: 505 patients were included, and prognostic predicting factors at 12 months were identified. One or two points were assigned according to the odds ratio (OR) obtained (p < 0.05). After the total score value was determined, a 4-point cut off was determined for each ROC curve at 12 months. Two groups were formed according to the number of points, group A < 4 points, and group B = 4 points. Group B was composed of older patients, with higher number of comorbidities and predictors of the combined endpoint at 6, 12 and 24 months, as linearly represented in the survival curves (Log rank). CONCLUSIONS: This risk score enabled the identification of a group with worse prognosis at 12 months. PMID- 28558088 TI - Case 6 / 2016 - Heart Failure in a 23-Year-Old Male with a History of Illicit Drug Use. PMID- 28558087 TI - Executive Summary of the II Brazilian Guidelines for Atrial Fibrillation. PMID- 28558090 TI - Confusing Terminology-Neuroleptic Malignant Syndrome vs Malignant Hyperthermia. PMID- 28558091 TI - Long-Acting Reversible Contraception for Adolescents: A Review. AB - Importance: Adolescents have higher rates of unintended pregnancies than any other age group. Contraceptive implants and intrauterine devices (IUDs) are long acting reversible contraceptives (LARCs) that are known to be highly effective in preventing pregnancy. New devices have recently been approved for use in adolescents, yet pediatricians may be less familiar with how to counsel adolescents about implants and IUDs. Observations: LARC methods should be described in basic terms to adolescents, including hormone dose, method of insertion, and method of pregnancy prevention. Clinicians should appreciate the developmental stages of adolescents, discuss the most effective methods of contraception, and ensure confidentiality from their parents. Short-acting contraception methods (eg, oral contraceptives) can be used as a temporary bridge to provide coverage until a LARC method can be placed. The most common adverse effect of LARC is nuisance bleeding, which can be managed with short courses of oral contraceptives or nonsteroidal anti-inflammatory drugs. Conclusions and Relevance: LARC devices constitute first-line contraceptive methods for adolescents. All clinicians, including pediatricians, can counsel about LARC even before suggesting an oral contraceptive or another less effective contraceptive method. Effective, confidential communication with sensitive language to inform adolescents of the different types of LARC is necessary to normalize offering LARC as a contraceptive option and improve its uptake among adolescents. Special clinical populations can also be offered appropriate contraceptive options inclusive of LARC. PMID- 28558092 TI - Linking Amyloid-beta and Tau Deposition in Alzheimer Disease. PMID- 28558089 TI - Analysis of Heart Rate Variability Before and During Tilt Test in Patients with Cardioinhibitory Vasovagal Syncope. AB - BACKGROUND: Cardioinhibitory vasovagal response is uncommon during the tilt test (TT). Heart rate variability (HRV) by use of spectral analysis can distinguish patients with that response. OBJECTIVE: To compare the HRV in patients with cardioinhibitory vasovagal syncope (case group - G1) with that in patients without syncope and with negative response to TT (control group - G2). METHODS: 64 patients were evaluated (mean age, 36.2 years; 35 men) and submitted to TT at 70 degrees, under digital Holter monitoring. The groups were paired for age and sex (G1, 40 patients; G2, 24). RESULTS: In G1, 21 patients had a type 2A response and 19 had type 2B, with mean TT duration of 20.4 minutes. There was a greater low frequency (LF) component (11,6 versus 4,5 ms2, p=0.001) and a lower low/high frequency ratio in the supine position (3,9 versus 4,5 ms2, p=0.008) in G1, with no difference during TT between the groups. Applying the receiver operating characteristic curve for cardioinhibitory response, the area under the curve was 0.74 for the LF component in the supine position (p = 0.001). The following were observed for the cutoff point of 0.35 ms(2) for the LF component: sensitivity, 97.4%; specificity, 83.3%; positive predictive value, 85.3%; negative predictive value, 96.9%; and positive likelihood ratio, 5.8. CONCLUSION: HRV in the supine position allowed identifying patients with syncope and cardioinhibitory response with a high negative predictive value and likelihood ratio of 5.8. PMID- 28558093 TI - Variation in Emergency Department vs Internal Medicine Excess Charges in the United States. AB - Importance: Uninsured and insured but out-of-network emergency department (ED) patients are often billed hospital chargemaster prices, which exceed amounts typically paid by insurers. Objective: To examine the variation in excess charges for services provided by emergency medicine and internal medicine physicians. Design, Setting, and Participants: Retrospective analysis was conducted of professional fee payment claims made by the Centers for Medicare & Medicaid Services for all services provided to Medicare Part B fee-for-service beneficiaries in calendar year 2013. Data analysis was conducted from January 1 to July 31, 2016. Main Outcomes and Measures: Markup ratios for ED and internal medicine professional services, defined as the charges submitted by the hospital divided by the Medicare allowable amount. Results: Our analysis included 12 337 emergency medicine physicians from 2707 hospitals and 57 607 internal medicine physicians from 3669 hospitals in all 50 states. Services provided by emergency medicine physicians had an overall markup ratio of 4.4 (340% excess charges), which was greater than the markup ratio of 2.1 (110% excess charges) for all services performed by internal medicine physicians. Markup ratios for all ED services ranged by hospital from 1.0 to 12.6 (median, 4.2; interquartile range [IQR], 3.3-5.8); markup ratios for all internal medicine services ranged by hospital from 1.0 to 14.1 (median, 2.0; IQR, 1.7-2.5). The median markup ratio by hospital for ED evaluation and management procedure codes varied between 4.0 and 5.0. Among the most common ED services, laceration repair had the highest median markup ratio (7.0); emergency medicine physician review of a head computed tomographic scan had the greatest interhospital variation (range, 1.6-27.7). Across hospitals, markups in the ED were often substantially higher than those in the internal medicine department for the same services. Higher ED markup ratios were associated with hospital for-profit ownership (median, 5.7; IQR, 4.0-7.1), a greater percentage of uninsured patients seen (median, 5.0; IQR, 3.5-6.7 for >=20% uninsured), and location (median, 5.3; IQR, 3.8-6.8 for the southeastern United States). Conclusions and Relevance: Across hospitals, there is wide variation in excess charges on ED services, which are often priced higher than internal medicine services. Our results inform policy efforts to protect uninsured and out-of-network patients from highly variable pricing. PMID- 28558096 TI - Folic Acid for the Prevention of Neural Tube Defects. PMID- 28558094 TI - Hierarchical Organization of Tau and Amyloid Deposits in the Cerebral Cortex. AB - Importance: Abnormal accumulation of tau and amyloid-beta (Abeta) proteins in the human brain are 2 pathologic hallmarks of Alzheimer disease (AD). Because pathologic processes begin decades before the onset of the clinical manifestations, the study of the cortical distribution of early-stage pathologic alterations is critical in understanding the underpinnings of the disease. Objectives: To identify the in vivo brain spatial distributions of tau and Abeta deposits in a sample of cognitively normal participants in the Harvard Aging Brain Study, determine spatial patterns of pathologic alterations, and provide means for improved individual in vivo staging. Design, Setting, and Participants: Eighty-eight individuals from the general community underwent flortaucipir 18 T807 (18F-T807) and carbon 11-labeled Pittsburgh Compound B (11C-PiB) positron emission tomographic (PET) imaging. A voxel-level hierarchical clustering approach was used to obtain the main clustering partitions corresponding to the cortical distribution maps of 18F-T807 and 11C-PiB. Hierarchical relationships between areas of distinctive pathologic deposits were then studied. Using cerebellar gray reference, 18F-T807 data were expressed as standardized uptake value ratio, and 11C-PiB were given as distribution volume ratio. Main Outcomes and Measures: Main in vivo and hierarchically organized tau and Abeta deposits in the elderly brain. Results: Of the 88 study participants, 39 (44%) were men, with a mean (SD) age of 76.2 (6.2) years. The tau and Abeta maps both displayed optimal cortical partitions at 4 clusters. The tau deposits were grouped in the temporal lobe, distributed in heteromodal areas, medial and visual regions, and primary somatomotor cortex; the Abeta deposits were clustered in the heteromodal areas and rather patchy in distributed regions involving the primary cortices, medial structures, and temporal areas. Moreover, tau deposits in the temporal lobe and distributed heteromodal areas were tightly nested. Conclusions and Relevance: Tau and Abeta deposits in the elderly brain generally display well defined hierarchical cortical relationships as well as overlaps between the principal clusters of both pathologic alterations in the heteromodal association regions. These findings represent systematic, large-scale mechanisms of early AD pathology. PMID- 28558097 TI - Effectiveness of Childhood Obesity Treatment Through 20 Group Education Sessions Over 6 Months: Does the Attendance of a Child Matter? PMID- 28558095 TI - Economic Evaluation of Quality Improvement Interventions Designed to Prevent Hospital Readmission: A Systematic Review and Meta-analysis. AB - Importance: Quality improvement (QI) interventions can reduce hospital readmission, but little is known about their economic value. Objective: To systematically review economic evaluations of QI interventions designed to reduce readmissions. Data Sources: Databases searched included PubMed, Econlit, the Centre for Reviews & Dissemination Economic Evaluations, New York Academy of Medicine's Grey Literature Report, and Worldcat (January 2004 to July 2016). Study Selection: Dual reviewers selected English-language studies from high income countries that evaluated organizational or structural changes to reduce hospital readmission, and that reported program and readmission-related costs. Data Extraction and Synthesis: Dual reviewers extracted intervention characteristics, study design, clinical effectiveness, study quality, economic perspective, and costs. We calculated the risk difference and net costs to the health system in 2015 US dollars. Weighted least-squares regression analyses tested predictors of the risk difference and net costs. Main Outcomes and Measures: Main outcomes measures included the risk difference in readmission rates and incremental net cost. This systematic review and data analysis is reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Results: Of 5205 articles, 50 unique studies were eligible, including 25 studies in populations limited to heart failure (HF) that included 5768 patients, 21 in general populations that included 10 445 patients, and 4 in unique populations. Fifteen studies lasted up to 30 days while most others lasted 6 to 24 months. Based on regression analyses, readmissions declined by an average of 12.1% among patients with HF (95% CI, 8.3%-15.9%; P < .001; based on 22 studies with complete data) and by 6.3% among general populations (95% CI, 4.0%-8.7%; P < .001; 18 studies). The mean net savings to the health system per patient was $972 among patients with HF (95% CI, -$642 to $2586; P = .23; 24 studies), and the mean net loss was $169 among general populations (95% CI, -$2610 to $2949; P = .90; 21 studies), reflecting nonsignificant differences. Among general populations, interventions that engaged patients and caregivers were associated with greater net savings ($1714 vs $6568; P = .006). Conclusions and Relevance: Multicomponent QI interventions can be effective at reducing readmissions relative to the status quo, but net costs vary. Interventions that engage general populations of patients and their caregivers may offer greater value to the health system, but the implications for patients and caregivers are unknown. PMID- 28558100 TI - Association Between Gender Minority Status and Self-Reported Physical and Mental Health in the United States. PMID- 28558098 TI - Complex and Dynamic Chromosomal Rearrangements in a Family With Seemingly Non Mendelian Inheritance of Dopa-Responsive Dystonia. AB - Importance: Chromosomal rearrangements are increasingly recognized to underlie neurologic disorders and are often accompanied by additional clinical signs beyond the gene-specific phenotypic spectrum. Objective: To elucidate the causal genetic variant in a large US family with co-occurrence of dopa-responsive dystonia as well as skeletal and eye abnormalities (ie, ptosis, myopia, and retina detachment). Design, Setting, and Participants: We examined 10 members of a family, including 5 patients with dopa-responsive dystonia and skeletal and/or eye abnormalities, from a US tertiary referral center for neurological diseases using multiple conventional molecular methods, including fluorescence in situ hybridization and array comparative genomic hybridization as well as large-insert whole-genome sequencing to survey multiple classes of genomic variations. Of note, there was a seemingly implausible transmission pattern in this family due to a mutation-negative obligate mutation carrier. Main Outcomes and Measures: Genetic diagnosis in affected family members and insight into the formation of large deletions. Results: Four members were diagnosed with definite and 1 with probable dopa-responsive dystonia. All 5 affected individuals carried a large heterozygous deletion encompassing all 6 exons of GCH1. Additionally, all mutation carriers had congenital ptosis requiring surgery, 4 had myopia, 2 had retinal detachment, and 2 showed skeletal abnormalities of the hands, ie, polydactyly or syndactyly or missing a hand digit. Two individuals were reported to be free of any disease. Analyses revealed complex chromosomal rearrangements on chromosome 14q21-22 in unaffected individuals that triggered the expansion to a larger deletion segregating with affection status. The expansion occurred recurrently, explaining the seemingly non-mendelian inheritance pattern. These rearrangements included a deletion of GCH1, which likely contributes to the dopa responsive dystonia, as well as a deletion of BMP4 as a potential cause of digital and eye abnormalities. Conclusions and Relevance: Our findings alert neurologists to the importance of clinical red flags, ie, unexpected co occurrence of clinical features that may point to the presence of chromosomal rearrangements as the primary disease cause. The clinical management and diagnostics of such patients requires an interdisciplinary approach in modern clinical-diagnostic care. PMID- 28558099 TI - Association of Longitudinal Cognitive Decline With Amyloid Burden in Middle-aged and Older Adults: Evidence for a Dose-Response Relationship. AB - Importance: Presently, the clinical standard for reporting the results of an amyloid positron emission tomography scan is to assign a dichotomous rating of positive or negative for the presence of amyloid. In a 4-year longitudinal study, we investigated whether using a continuous measure of the magnitude of baseline amyloid burden would provide valuable information about the rate of future cognitive decline over the subsequent 4 years compared with a dichotomous measure in middle-aged and older adults. Objective: To examine whether a continuous, dose response relationship between amyloid burden and cognitive decline was present among middle-aged and older adults. Design, Setting, and Participants: This cohort study included 174 participants from the Dallas Lifespan Brain Study who were 40 to 89 years old at the beginning of the study, were cognitively normal at baseline (a Mini-Mental State Examination score of 26 or higher) with no history of neurological or psychiatric disorders, and had completed amyloid imaging ([18F]-florbetapir) at baseline and cognitive assessments at baseline and a 4 year follow-up. Continuous amyloid burden was measured as the mean cortical standardized uptake value ratio (SUVR) at baseline. Main Outcomes and Measures: Linear mixed models assessed the effect of increasing baseline amyloid over time (SUVR * time interaction) on episodic memory, reasoning, processing speed, vocabulary, and Mini-Mental State Examination performance. Age, sex, education, apolipoprotein epsilon4, and the random effect of intercepts were included as covariates. Results: The mean (SD) age for all participants (n = 174) was 66.44 (11.74) years, and 65 participants (37%) were men. The primary analyses yielded significant SUVR * time interactions in episodic memory, processing speed, vocabulary, and Mini-Mental State Examination performance, but not in reasoning performance. Higher baseline SUVR projected greater cognitive decline over 4 years. When controlling for variance related to a dichotomized positive/negative classification, most effects on cognition remained. Dichotomized amyloid status alone yielded fewer significant effects of amyloid on cognitive decline than continuous SUVR. Among amyloid-positive participants, increasing baseline SUVR predicted an increasing decline in episodic memory, but other effects on cognition were more limited. Finally, higher baseline amyloid burden among middle aged adults was related to changes in vocabulary, with the effect driven by 3 apolipoprotein epsilon4 homozygotes. Conclusions and Relevance: These results suggest that the magnitude of amyloid burden at baseline is associated with the rate of cognitive decline over 4 years and potentially provides important information about the rate of future cognitive decline that is not available from a dichotomous positive/negative categorization. PMID- 28558102 TI - The Troponin Cascade: A Teachable Moment. PMID- 28558101 TI - Evolving State-Based Contraceptive and Abortion Policies. PMID- 28558103 TI - What to Do Following Fibrinolysis for ST-Elevation Myocardial Infarction: Reappraising Routine Percutaneous Intervention. PMID- 28558105 TI - Confusing Terminology-Neuroleptic Malignant Syndrome vs Malignant Hyperthermia Reply. PMID- 28558106 TI - Characterizing the Source of Text in Electronic Health Record Progress Notes. PMID- 28558104 TI - Effect of Attendance of the Child on Body Weight, Energy Intake, and Physical Activity in Childhood Obesity Treatment: A Randomized Clinical Trial. AB - Importance: Family-based weight loss treatment (FBT) is considered the gold standard treatment for childhood obesity and is provided to the parent and child. However, parent-based treatment (PBT), which is provided to the parent without the child, could be similarly effective and easier to disseminate. Objective: To determine whether PBT is similarly effective as FBT on child weight loss over 24 months. Secondary aims evaluated the effect of these 2 treatments on parent weight loss, child and parent dietary intake, child and parent physical activity, parenting style, and parent feeding behaviors. Design, Setting, and Participants: Randomized 2-arm noninferiority trial conducted at an academic medical center, University of California, San Diego, between July 2011 and July 2015. Participants included 150 overweight and obese 8- to 12-year-old children and their parents. Interventions: Both PBT and FBT were delivered in 20 one-hour group meetings with 30-minute individualized behavioral coaching sessions over 6 months. Treatments were similar in content; the only difference was the attendance of the child. Main Outcomes and Measures: The primary outcome measure was child weight loss (body mass index [BMI] and BMI z score) at 6, 12, and 18 months post treatment. Secondary outcomes were parent weight loss (BMI), child and parent energy intake, child and parent physical activity (moderate to vigorous physical activity minutes), parenting style, and parent feeding behaviors. Results: One hundred fifty children (mean BMI, 26.4; mean BMI z score, 2.0; mean age, 10.4 years; 66.4% girls) and their parent (mean BMI, 31.9; mean age, 42.9 years; 87.3% women; and 31% Hispanic, 49% non-Hispanic white, and 20% other race/ethnicity) were randomly assigned to either FBT or PBT. Child weight loss after 6 months was -0.25 BMI z scores in both PBT and FBT. Intention-to treat analysis using mixed linear models showed that PBT was noninferior to FBT on all outcomes at 6-, 12-, and 18-month follow-up with a mean difference in child weight loss of 0.001 (95% CI, -0.06 to 0.06). Conclusions and Relevance: Parent-based treatment was as effective on child weight loss and several secondary outcomes (parent weight loss, parent and child energy intake, and parent and child physical activity). Parent-based treatment is a viable model to provide weight loss treatment to children. Trial Registration: Clinicaltrials.gov Identifier: NCT01197443. PMID- 28558107 TI - Folic Acid for the Prevention of Neural Tube Defects. PMID- 28558108 TI - Association of Prescription Drug Price Rebates in Medicare Part D With Patient Out-of-Pocket and Federal Spending. AB - The increasing cost of prescription drugs is a burden for patients and threatens the financial stability of the US health care system. Rebates are a form of price concession paid by a pharmaceutical manufacturer to the health plan sponsor or the pharmacy benefit manager working on the plan's behalf. Proponents argue that rebates result from vigorous negotiations that help lower overall drug costs. Critics argue that rebates have perversely increased the costs patients pay out of pocket, as well as the costs for Medicare as a whole. This special communication discusses how the availability of rebates for drugs covered by the Medicare Part D program may raise costs for patients and Medicare while increasing the profits of Part D plan sponsors and pharmaceutical manufacturers. Two policy alternatives are herein proposed that would reconfigure cost sharing to lower patient out-of-pocket costs and reduce cost shifting to Medicare. PMID- 28558110 TI - Safety leadership at construction sites: the importance of rule-oriented and participative leadership. AB - Objectives The construction industry accounted for >20% of all fatal occupational accidents in Europe in 2014. Leadership is an essential antecedent to occupational safety. The aim of the present study was to assess the influence of transformational, active transactional, rule-oriented, participative, and laissez faire leadership on safety climate, safety behavior, and accidents in the Swedish and Danish construction industry. Sweden and Denmark are similar countries but have a large difference in occupational accidents rates. Methods A questionnaire study was conducted among a random sample of construction workers in both countries: 811 construction workers from 85 sites responded, resulting in site and individual response rates of 73% and 64%, respectively. Results The results indicated that transformational, active transactional, rule-oriented and participative leadership predict positive safety outcomes, and laissez-faire leadership predict negative safety outcomes. For example, rule-oriented leadership predicts a superior safety climate (beta=0.40, P<0.001), enhanced safety behavior (beta=0.15, P<0.001), and fewer accidents [odds ratio (OR) 0.78, 95% confidence interval (95% CI) 0.62-0.98]. The effect of rule-oriented leadership on workers' safety behavior was moderated by the level of participative leadership (beta=0.10, P<0.001), suggesting that when rules and plans are established in a collaborative manner, workers' motivation to comply with safety regulations and participate in proactive safety activities is elevated. The influence of leadership behaviors on safety outcomes were largely similar in Sweden and Denmark. Rule-oriented and participative leadership were more common in the Swedish than Danish construction industry, which may partly explain the difference in occupational accident rates. Conclusions Applying less laissez-faire leadership and more transformational, active transactional, participative and rule-oriented leadership appears to be an effective way for construction site managers to improve occupational safety in the industry. PMID- 28558111 TI - Clinical Results of Minimally Invasive Spine Stabilization for Spinal Metastases. AB - The goal of the study was to evaluate minimally invasive palliative surgery and the effect of postoperative adjuvant therapy for metastatic spinal tumor with a limited vital prognosis. Of the 70 patients who underwent palliative surgery for metastatic spinal tumor at the authors' hospital between March 2012 and May 2016, thirty-three were treated with minimally invasive spine stabilization (MISt) using percutaneous pedicle screws (PPSs) and included in the current study. Of the 33 patients, 26 were men and 7 were women; mean age at surgery was 68.6 years. Intraoperatively, posterior decompression and fusion was performed in 17 (51.5%) patients and fusion only was performed in 16 (48.5%). Mean operative time was 202.5 minutes, mean intraoperative blood loss was 331.6 mL, and intraoperative blood loss was 1500 mL or greater in 2 (6.1%) patients. Median postoperative survival time determined using the Kaplan-Meier method was 11.0 months (95% confidence interval, 7.3-14.6). Regarding improvement of paralysis, neurological deficit was improved by at least 1 Frankel grade for 15 (45.5%) patients, and the number of ambulatory patients increased from 22 (66.7%) to 25 (75.8%). Postoperative adjuvant therapy included chemotherapy in 17 (51.5%) patients, radiotherapy in 21 (63.6%), and bone-modifying agent treatment in 25 (75.8%). The mean Barthel Index for activities of daily living improved from 53.5 preoperatively to 71.5 postoperatively. Discharge to home was possible for 23 (69.7%) patients. Activities of daily living for patients with metastatic spinal tumor were improved by minimally invasive palliative surgery with MISt using PPSs and postoperative adjuvant therapy. [Orthopedics. 2017; 40(4):e693-e698.]. PMID- 28558112 TI - Mid-term Results of Total Hip and Total Knee Arthroplasty in Patients With Human Immunodeficiency Virus. AB - With antiretroviral therapy, patients who are human immunodeficiency virus (HIV) positive are increasingly becoming candidates for total hip arthroplasty (THA) and total knee arthroplasty (TKA). Prior reports focus on perioperative complications, but longer-term outcomes remain unclear. The authors specifically analyzed clinical outcomes, perioperative complications, and survivorship free of periprosthetic joint infection (PJI) of THAs and TKAs in HIV-positive patients who had extended follow-up. A total of 21 HIV-positive patients who underwent 29 primary arthroplasties (14 THAs, 15 TKAs) from 1992 to 2012 were retrospectively reviewed. Mean age was 43 years and mean follow-up was 8 years. Mean perioperative CD4 cell count was 450 cells/mL; only 2 patients had perioperative CD4 cell counts less than 200 cells/mL. At mid-term follow-up, THAs and TKAs were reliable in improving function (mean postoperative Harris Hip Score: 87, P<.01; mean postoperative Knee Society Score: 83, P<.01). The rate of perioperative complications was high (17%). Patients with both hemophilia and HIV were at particular risk for complications at 33% (P=.04). Survivorship free of deep PJI was 100% in THAs at 10 years and 93% in TKAs at 10 years. Only 1 (7%) patient (1 TKA), who had a perioperative CD4 cell count of less than 200 cells/mL, was revised for deep PJI. In HIV-positive patients, both THAs and TKAs are reliable in alleviating pain and improving clinical function at mid-term follow-up. However, HIV-positive patients are at substantial risk of perioperative complications, especially with comorbid hemophilia. With antiretroviral therapy and maintained CD4 cell counts above 200 cells/mL, survivorship free of deep PJI approaches 100%. [Orthopedics. 2017; 40(4):e699-e702.]. PMID- 28558113 TI - Retrieval Analysis of Porous Titanium Glenoid Posts: An Evaluation of Osteointegration. AB - Glenoid component loosening is a commonly encountered complication of total shoulder replacements. Therefore, focus has been placed on glenoid fixation. Porous metal implants, which promote biological fixation through osteointegration, have provided an uncemented alternative to the traditional cemented implant. In this explantation study, the authors examined the bone ingrowth and ongrowth of a specific porous titanium glenoid peg. Six explanted polyethylene glenoid components with porous titanium-coated central pegs were identified in the authors' implant retrieval program via retrospective review. The retrieved implants were sectioned into thirds with a precision saw and underwent scanning electron microscopy for analysis of bone ingrowth and ongrowth. Bone ingrowth was calculated as bone volume fraction, or the fraction of available pore space filled with bone, whereas ongrowth was the percentage of the perimeter of the implant covered with bone. The 6 total shoulders included in the study were revised at an average of 16.3 months (range, 5-48 months) for instability secondary to subscapularis rupture, subscapularis rupture plus infection, or other rotator cuff tear. All glenoid components were grossly stable on retrieval and had an average of 23% bone ingrowth and 54% ongrowth. The preliminary results show that osteointegration into a porous titanium ingrowth glenoid component is possible in the short-term, even in the presence of an unfavorable biomechanical environment, such as instability and rotator cuff dysfunction, as well as infection. [Orthopedics. 2017; 40(4):e703-e707.]. PMID- 28558114 TI - Three-Dimensional Templating for Acetabular Component Alignment During Total Hip Arthroplasty. AB - Appropriate placement of the acetabular cup is an important determinant of implant stability and longevity. Malposition of acetabular cups negatively influences prosthesis survival and leads to an increased dislocation rate. The objective of the study was to determine the role of 3-dimensional templating in obtaining accurate acetabular component placement in total hip arthroplasty. In this computed tomography-based study, the authors identified 93 patients who underwent primary total hip arthroplasty with computer-assisted navigation. Using 3-dimensional planning, the authors templated the acetabular component at an inclination of 40 degrees and anteversion of 20 degrees . To classify acetabular cup coverage by bone, the acetabulum was used as a clock face with the center of the transverse acetabular ligament (TAL) as 6-o'clock. Analyses revealed that 72% of cups were uncovered between 9- to 1-o'clock for right hips. On the left side, 88% of cups were uncovered between 11- to 3-o'clock. Across all hips, 74% of cups had a 1-o'clock position at the most lateral aspect. Further analysis revealed that 46% of acetabular cups had a teardrop at the same level of the most inferior aspect of the cup, whereas only 37% of cups had a teardrop above the inferior aspect of the cup. Finally, the acetabular component was aligned with the TAL in 76% of hips, retroverted to the TAL in 16%, and anteverted to the TAL in 8%. The current study demonstrates a useful gross intraoperative reference tool to standardize cup position without the need for additional equipment and reliance on anatomical landmarks. [Orthopedics. 2017; 40(4):e708-e713.]. PMID- 28558115 TI - Comparison of Magnetic Resonance Imaging and Computed Tomography Scans of the Glenoid Version in Anterior Dislocation of the Shoulder. AB - The glenoid version is an important factor in the etiology of anterior dislocation of the shoulder and the planning of shoulder surgery. Few reports compare the magnetic resonance imaging (MRI) measurements of the glenoid version with those of computed tomography (CT). This study aimed to show that it is possible to use MRI instead of CT, which is accepted as the gold standard today for the evaluation of the glenoid version. A total of 55 patients with a history of 1 nonsurgically treated unilateral anterior dislocation of the shoulder who had both MRI and CT records for the dislocated shoulders constituted the study group. The glenoid version was measured in the axial plane on MRI and CT. Mean glenoid version measured by the observers was -1.6 degrees +/-4.7 degrees (95% confidence interval, -2.3 degrees to -0.8 degrees ) and -1.8 degrees +/-4.3 degrees (95% confidence interval, -2.5 degrees to -1.2 degrees ) by CT and MRI, respectively (P=.126). The evaluation of the CT and MRI measurements made by the 3 observers (X, Y, and Z) revealed no significant difference, as the P values of X CT - X MRI, Y CT - Y MRI, and Z CT - Z MRI were .550, .406, and .238, respectively. Interclass correlation among the 3 observers for CT and MRI was 0.996 and 0.981, respectively. The imaging methods of MRI and CT can be interchangeably used in the evaluation of the glenoid version in cases of anterior dislocation of the shoulder. [Orthopedics. 2017; 40(4):e687-e692.]. PMID- 28558116 TI - Sentinel Lymph Node Technique in Endometrial Cancer. AB - Importance: Endometrial cancer (EMCA) is the most common gynecologic malignancy, with an estimated 54,000 new cases and 10,000 deaths in the United States in 2015. Lymph node metastasis is the most significant prognostic factor in EMCA. Sentinel lymph node (SLN) mapping has become a well-accepted procedure in surgical oncology and may strike a balance between the risks and benefits of lymphadenectomy. Objective: The aim of this study was to review the current literature regarding the history, techniques, and clinical application of SLN mapping in EMCA. Evidence Acquisition: Evidence was obtained through systematic literature review through PubMed and ClinicalTrials.gov. Conclusions: Sentinel lymph node biopsy for EMCA is an accepted approach to the staging of this cancer; however, a consensus approach to the SLN biopsy technique and pathologic assessment is needed. Surgeons newly adopting the technique should proceed with caution and care to monitor outcomes. PMID- 28558117 TI - Gonadotropin-Releasing Hormone-Agonist Triggering and a Freeze-All Approach: The Final Step in Eliminating Ovarian Hyperstimulation Syndrome? AB - Importance: In vitro fertilization (IVF) has evolved dramatically in recent decades; however, clinical practices have been slow to adopt these advancements, particularly regarding final oocyte maturation and the timing of embryo transfer. Concerns still exist over the ability of gonadotropin-releasing hormone (GnRH) agonists and elective embryo cryopreservation to reduce the risk of ovarian hyperstimulation syndrome (OHSS) without compromising pregnancy outcomes. Objective: This review investigates IVF outcomes associated with GnRH-agonist triggering and elective embryo cryopreservation. The safety and efficacy of GnRH agonist triggering are compared with conventional human chorionic gonadotropin triggering, and frozen embryo transfers are weighed against fresh transfers. Evidence Acquisition: A literature search was conducted using OVID (MEDLINE) and PubMed databases. The search strategy included keywords such as "ovarian hyperstimulation syndrome or OHSS," "GnRH-agonist triggering," "cryopreservation or freeze-all," and "IVF outcomes." A total of 214 articles were considered for review. Results: Gonadotropin-releasing hormone agonist triggering reduces OHSS incidence without compromising oocyte retrieval and fertilization rates in donor and autologous cycles. However, GnRH-agonist triggering causes a luteal phase deficiency in autologous cycles, deleteriously compromising pregnancy rates. Elective embryo cryopreservation overcomes this deficiency, reducing the risk of OHSS and may improve neonatal and obstetric outcomes. Conclusions: Gonadotropin releasing hormone agonist triggering should be considered in all donor cycles. It should also be selectively considered in autologous cycles in combination with elective cryopreservation of all viable embryos. PMID- 28558118 TI - Mosquito-Borne Diseases as a Global Health Problem: Implications for Pregnancy and Travel. AB - Importance: Mosquitoes are the most common disease vectors worldwide. A combination of factors, including changes in public health policy, climate change, and global travel, has led to the resurgence and spread of these diseases in our modern world. Pregnant women are vulnerable to a number of these illnesses, and obstetricians are likely to encounter pregnant travelers who have been exposed. Objective: This review was conducted to summarize knowledge of mosquito-borne diseases and their relevance in pregnancy. This will allow obstetricians to provide proper advice regarding travel and prepare providers to recognize manifestations of these illnesses in the pregnant woman. Evidence Acquisition: A review of the current literature was performed to summarize the various manifestations of mosquito-borne illnesses in pregnant women and discuss obstetric outcomes and management of disease in pregnancy. Results: Mosquito borne illnesses usually manifest after a period of incubation lasting from days to weeks. Symptoms usually include a febrile illness but may be nonspecific and may masquerade as pregnancy-specific illnesses such as preeclampsia or HELLP (hemolysis, elevated liver enzyme levels, and low platelet levels); a large number of patients remain asymptomatic. Pregnancy-related outcomes include spontaneous abortion, intrauterine fetal demise, intrauterine transmission to the fetus, and congenital anomalies. Management during pregnancy is mainly supportive. Precautions against disease include protective clothing and insect repellents. Vaccines are either available or in development. Conclusions and Relevance: Mosquito-borne disease should be considered in pregnant women who present with a febrile illness and a relevant exposure history. Prompt recognition can allow supportive treatment to the mother and fetal resuscitation and surveillance. PMID- 28558119 TI - Structural dissimilarity sampling with dynamically self-guiding selection. AB - Structural dissimilarity sampling (SDS) has been proposed as an enhanced conformational sampling method for reproducing the structural transitions of a given protein. SDS consists of cycles of two steps: (1) Selections of initial structures with structural dissimilarities by referring to a measure. (2) Conformational resampling by restarting short-time molecular dynamics (MD) simulations from the initial structures. In the present study, an efficient measure is proposed as a dynamically self-guiding selection to accelerate the structural transitions from a reactant state to a product state as an extension to the original SDS. In the extended SDS, the inner product (IP) between the reactant and the snapshots generated by short-time MD simulations are evaluated and ranked according to the IPs at every cycle. Then, the snapshots with low IPs are selected as initial structures for the short-time MD simulations. This scheme enables one to choose dissimilar and distant initial structures from the reactant, and thus the initial structures dynamically head towards the product, promoting structural transitions from the reactant. To confirm the conformational sampling efficiency, the extended SDS was applied to maltodextrin binding protein (MBP), and we successfully reproduced the structural transition from the open to closed states with submicrosecond-order simulation times. However, a conventional long-time MD simulation failed to reproduce the same structural transition. We also compared the performance with that obtained by the ordinary SDS and other sampling techniques that have been developed by us to characterize the possible utility of the extended SDS for actual applications. (c) 2017 Wiley Periodicals, Inc. PMID- 28558120 TI - Development of a multisite model for Ni(II) ion in solution from thermodynamic and kinetic data. AB - Force-field parameters are developed for a multisite model of Ni(II) ions to be used in molecular dynamics simulations combined to enhanced sampling methods. The performances of two charge-partitioning schemes are validated by taking into account structural, thermodynamic, and kinetic observables. One of the two models, featuring partial charges on the dummy atoms only, matches both Ni(II) free energy of solvation and water exchange rates. Such model is particularly suited to study complexation events at a fully dynamic description. (c) 2017 Wiley Periodicals, Inc. PMID- 28558122 TI - Morphology-Conserved Transformations of Metal-Based Precursors to Hierarchically Porous Micro-/Nanostructures for Electrochemical Energy Conversion and Storage. AB - To meet future market demand, developing new structured materials for electrochemical energy conversion and storage systems is essential. Hierarchically porous micro-/nanostructures are favorable for designing such high performance materials because of their unique features, including: i) the prevention of nanosized particle agglomeration and minimization of interfacial contact resistance, ii) more active sites and shorter ionic diffusion lengths because of their size compared with their large-size counterparts, iii) convenient electrolyte ingress and accommodation of large volume changes, and iv) enhanced light-scattering capability. Here, hierarchically porous micro /nanostructures produced by morphology-conserved transformations of metal-based precursors are summarized, and their applications as electrodes and/or catalysts in rechargeable batteries, supercapacitors, and solar cells are discussed. Finally, research and development challenges relating to hierarchically porous micro-/nanostructures that must be overcome to increase their utilization in renewable energy applications are outlined. PMID- 28558121 TI - Early-life stress diminishes the increase in neurogenesis after exercise in adult female mice. AB - Exposure to early-life stress (ES) has long-lasting consequences for later cognition and hippocampal plasticity, including adult hippocampal neurogenesis (AHN), i.e., the generation of new neurons from stem/progenitor cells in the adult hippocampal dentate gyrus. We had previously demonstrated a sex-specific vulnerability to ES exposure; female mice exposed to ES from P2-P9 exhibited only very mild cognitive changes and no reductions in AHN as adult, whereas ES-exposed male mice showed impaired cognition closely associated with reductions in AHN. Given the apparent resilience of AHN to ES in females, we here questioned whether ES has also altered the capacity to respond to positive stimuli for neurogenesis. We therefore investigated whether exercise, known for its strong pro-neurogenic effects, can still stimulate AHN in adult female mice that had been earlier exposed to ES. We confirm a strong pro-neurogenic effect of exercise in the dorsal hippocampus of 8-month-old control female mice, but this positive neurogenic response is less apparent in female ES mice. These data provide novel insights in the lasting consequences of ES on hippocampal plasticity in females and also indicate that ES might lastingly reduce the responsiveness of the hippocampal stem cell pool, to exercise, in female mice. PMID- 28558123 TI - DLPNO-CCSD(T) scaled methods for the accurate treatment of large supramolecular complexes. AB - In this work, we present scaled variants of the DLPNO-CCSD(T) method, dubbed as (LS)DLPNO-CCSD(T) and (NS)DLPNO-CCSD(T), to obtain accurate interaction energies in supramolecular complexes governed by noncovalent interactions. The novel scaled schemes are based on the linear combination of the DLPNO-CCSD(T) correlation energies calculated with the standard (LoosePNO and NormalPNO) and modified (Loose2PNO and Normal2PNO) DLPNO-CCSD(T) accuracy levels. The scaled DLPNO-CCSD(T) variants provide nearly TightPNO accuracy, which is essential for the quantification of weak noncovalent interactions, with a noticeable saving in computational cost. Importantly, the accuracy of the proposed schemes is preserved irrespective of the nature and strength of the supramolecular interaction. The (LS)DLPNO-CCSD(T) and (NS)DLPNO-CCSD(T) protocols have been used to study in depth the role of the CH-pi versus pi-pi interactions in the supramolecular complex formed by the electron-donor truxene-tetrathiafulvalene (truxTTF) and the electron-acceptor hemifullerene (C30 H12 ). (NS)DLPNO CCSD(T)/CBS calculations clearly reveal the higher stability of staggered (dominated by CH-pi interactions) versus bowl-in-bowl (dominated by pi-pi interactions) arrangements in the truxTTF*C30 H12 heterodimer. Hemifullerene and similar carbon-based buckybowls are therefore expected to self-assemble with donor compounds in a richer way other than the typical concave-convex pi-pi arrangement found in fullerene-based aggregates. (c) 2017 Wiley Periodicals, Inc. PMID- 28558124 TI - Comparison of glass slides and various digital-slide modalities for cytopathology screening and interpretation. AB - BACKGROUND: Whole-slide imaging in cytology is limited when glass slides are digitized without z-stacks for focusing. Different vendors have started to provide z-stacking solutions to overcome this limitation. The Panoptiq imaging system allows users to create digital files combining low-magnification panoramic images with regions of interest (ROIs) that are imaged with high-magnification z stacks. The aim of this study was to compare such panoramic images with conventional whole-slide images and glass slides for the tasks of screening and interpretation in cytopathology. METHODS: Thirty glass slides, including 10 ThinPrep Papanicolaou tests and 20 nongynecologic cytology cases, were digitized with an Olympus BX45 integrated microscope with an attached Prosilica GT camera. ViewsIQ software was used for image acquisition and viewing. These glass slides were also scanned on an Aperio ScanScope XT at *40 (0.25 MUm/pixel) with 1 z plane and were viewed with ImageScope software. Digital and glass sides were screened and dotted/annotated by a cytotechnologist and were subsequently reviewed by 3 cytopathologists. For panoramic images, the cytotechnologist manually created digital maps and selected representative ROIs to generate z stacks at a higher magnification. After 3-week washout periods, panoramic images were compared with Aperio digital slides and glass slides. RESULTS: The Panoptiq system permitted fine focusing of thick smears and cell clusters. In comparison with glass slides, the average screening times were 5.5 and 1.8 times longer with Panoptiq and Aperio images, respectively, but this improved with user experience. There was no statistical difference in diagnostic concordance between all 3 modalities. Users' diagnostic confidence was also similar for all modalities. CONCLUSIONS: The Aperio whole-slide scanner with 1 z-plane scanning and the Panoptiq imaging system with z-stacking are both suitable for cytopathology screening and interpretation. However, ROI z-stacks do offer a superior mechanism for overcoming focusing problems commonly encountered with digital cytology slides. Unlike whole-slide imaging, the acquisition of representative z-stack images with the Panoptiq system requires a trained cytologist to create digital files. Cancer Cytopathol 2017;125:701-9. (c) 2017 American Cancer Society. PMID- 28558127 TI - Reliability and validity analyses are essential for questionnaire research. PMID- 28558125 TI - Privileged Structures Revisited. AB - Privileged structures inspire compound library design in medicinal chemistry. We performed a comprehensive analysis of 1.4 million bioactive compounds, with the aim of assessing the prevalence of certain molecular frameworks. We used the Shannon entropy formalism to quantify the promiscuity of the most frequently observed atom scaffolds across the annotated target families. This analysis revealed an apparent inverse relationship between hydrogen-bond-acceptor count of a scaffold and its potential promiscuity. The results further suggest that chemically easily accessible scaffolds can serve as templates for the generation of bespoke compound libraries with differing degrees of multiple target engagement, and heterocyclic, sp3 -rich frameworks are particularly suited for target-focused library design. The outcome of our study enables us to place some of the many narratives surrounding the concept of privileged structures into a critical context. PMID- 28558126 TI - Cell wall peptidolipids of Mycobacterium avium: from genetic prediction to exact structure of a nonribosomal peptide. AB - Mycobacteria have a complex cell wall structure that includes many lipids; however, even within a single subspecies of Mycobacterium avium these lipids can differ. Total lipids from an M. avium subsp. paratuberculosis (Map) ovine strain (S-type) contained no identifiable glycopeptidolipids or lipopentapeptide (L5P), yet both lipids are present in other M. avium subspecies. We determined the genetic and phenotypic basis for this difference using sequence analysis as well as biochemical and physico-chemical approaches. This strategy showed that a nonribosomal peptide synthase, encoded by mps1, contains three amino acid specifying modules in ovine strains, compared to five modules in bovine strains (C-type). Sequence analysis predicted these modules would produce the tripeptide Phe-N-Methyl-Val-Ala with a lipid moiety, termed lipotripeptide (L3P). Comprehensive physico-chemical analysis of Map S397 extracts confirmed the structural formula of the native L3P as D-Phe-N-Methyl-L-Val-L-Ala-OMe attached in N-ter to a 20-carbon fatty acid chain. These data demonstrate that S-type strains, which are more adapted in sheep, produce a unique lipid. There is a dose dependent effect observed for L3P on upregulation of CD25+ CD8 T cells from infected cows, while L5P effects were static. In contrast, L5P demonstrated a significantly stronger induction of CD25+ B cells from infected animals compared to L3P. PMID- 28558128 TI - Carbon-MEMS-Based Alternating Stacked MoS2 @rGO-CNT Micro-Supercapacitor with High Capacitance and Energy Density. AB - A novel process to fabricate a carbon-microelectromechanical-system-based alternating stacked MoS2 @rGO-carbon-nanotube (CNT) micro-supercapacitor (MSC) is reported. The MSC is fabricated by successively repeated spin-coating of MoS2 @rGO/photoresist and CNT/photoresist composites twice, followed by photoetching, developing, and pyrolysis. MoS2 @rGO and CNTs are embedded in the carbon microelectrodes, which cooperatively enhance the performance of the MSC. The fabricated MSC exhibits a high areal capacitance of 13.7 mF cm-2 and an energy density of 1.9 uWh cm-2 (5.6 mWh cm-3 ), which exceed many reported carbon- and MoS2 -based MSCs. The MSC also retains 68% of capacitance at a current density of 2 mA cm-2 (5.9 A cm-3 ) and an outstanding cycling performance (96.6% after 10 000 cycles, at a scan rate of 1 V s-1 ). Compared with other MSCs, the MSC in this study is fabricated by a low-cost and facile process, and it achieves an excellent and stable electrochemical performance. This approach could be highly promising for applications in integration of micro/nanostructures into microdevices/systems. PMID- 28558130 TI - Strigolactones, karrikins and beyond. AB - The plant hormones strigolactones are synthesized from carotenoids and signal via the alpha/beta hydrolase DWARF 14 (D14) and the F-box protein MORE AXILLARY GROWTH 2 (MAX2). Karrikins, molecules produced upon fire, share MAX2 for signalling, but depend on the D14 paralog KARRIKIN INSENSITIVE 2 (KAI2) for perception with strong evidence that the MAX2-KAI2 protein complex might also recognize so far unknown plant-made karrikin-like molecules. Thus, the phenotypes of the max2 mutants are the complex consequence of a loss of both D14-dependent and KAI2-dependent signalling, hence, the reason why some biological roles, attributed to strigolactones based on max2 phenotypes, could never be observed in d14 or in the strigolactone-deficient max3 and max4 mutants. Moreover, the broadly used synthetic strigolactone analog rac-GR24 has been shown to mimic strigolactone as well as karrikin(-like) signals, providing an extra level of complexity in the distinction of the unique and common roles of both molecules in plant biology. Here, a critical overview is provided of the diverse biological processes regulated by strigolactones and/or karrikins. These two growth regulators are considered beyond their boundaries, and the importance of the yet unknown karrikin-like molecules is discussed as well. PMID- 28558129 TI - Somatostatin depresses the excitability of subicular bursting cells: Roles of inward rectifier K+ channels, KCNQ channels and Epac. AB - The hippocampus is a crucial component for cognitive and emotional processing. The subiculum provides much of the output for this structure but the modulation and function of this region is surprisingly under-studied. The neuromodulator somatostatin (SST) interacts with five subtypes of SST receptors (sst1 to sst5 ) and each of these SST receptor subtypes is coupled to Gi proteins resulting in inhibition of adenylyl cyclase (AC) and decreased level of intracellular cAMP. SST modulates many physiological functions including cognition, emotion, autonomic responses and locomotion. Whereas SST has been shown to depress neuronal excitability in the subiculum, the underlying cellular and molecular mechanisms have not yet been determined. Here, we show that SST hyperpolarized two classes of subicular neurons with a calculated EC50 of 0.1 MUM. Application of SST (1 MUM) induced outward holding currents by primarily activating K+ channels including the G-protein-activated inwardly-rectifying potassium channels (GIRK) and KCNQ (M) channels, although inhibition of cation channels in some cells may also be implicated. SST-elicited hyperpolarization was mediated by activation of sst2 receptors and required the function of G proteins. The SST induced hyperpolarization resulted from decreased activity of AC and reduced levels of cAMP but did not require the activity of either PKA or PKC. Inhibition of Epac2, a guanine nucleotide exchange factor, partially blocked SST-mediated hyperpolarization of subicular neurons. Furthermore, application of SST resulted in a robust depression of subicular action potential firing and the SST-induced hyperpolarization was responsible for its inhibitory action on LTP at the CA1 subicilum synapses. Our results provide a novel cellular and molecular mechanism that may explain the roles of SST in modulation of subicular function and be relevant to SST-related physiological functions. PMID- 28558131 TI - An association between genetic variation in the glutamatergic system and suicide attempts in alcohol-dependent individuals. AB - BACKGROUND AND OBJECTIVES: Pathological alterations of glutamatergic systems were observed in neurodegenerative and psychiatric disorders. There is some evidence that this system may be involved in the genetic vulnerability to suicide. The aim of the present study was to analyze possible relationship between the GRIN2B polymorphism and suicidal behavior. We hypothesized that this genetic factor may be associated with suicide attempts in alcohol-dependent patients and with death by suicide. METHODS: To analyze the relationship between GRIN2B and suicide attempts, the selected rs2268115 polymorphism was genotyped in a sample of 345 alcohol-dependent individuals stratified by the history of suicide attempts. The second part of the study concerning suicide was based on a sample of 510 suicide victims and 450 controls. RESULTS: The frequency of rs2268115 G allele among alcohol-dependent patients with the history of suicide attempts was significantly higher than among non-suicidal alcohol-dependent individuals (OR = 1.45, p = .033). This association was more significant when analyzing alcohol-dependent patients only without co-occurring drug dependence (OR = 1.62, p = .021). The analyzed GRIN2B polymorphism was associated with a twofold increase in odds of a suicide attempt (OR = 2.01, p = .004). No relationships between rs2268115 and death by suicide were identified. DISCUSSION AND CONCLUSIONS: Our results suggest that glutamatergic system influence susceptibility to suicide attempts in alcohol dependent individuals. Suicidal behavior and alcohol dependence may share a common etiology related to the glutamatergic system. SCIENTIFIC SIGNIFICANCE: The major contribution of the present study is a novel finding of the possible association between GRIN2B rs2268115 polymorphism and suicide attempts in alcohol dependent individuals. (Am J Addict 2017;26:595-601). PMID- 28558133 TI - Loops and Cycles at Surfaces: The Unique Properties of Topological Polymer Brushes. AB - Grafting synthetic polymers to inorganic and organic surfaces to yield polymer "brushes" has represented a revolution in many fields of materials science. Polymer brushes provide colloidal stabilization to nanoparticles (NPs), prevent and/or regulate the adsorption of proteins on biomaterials, and significantly reduce friction when applied to two surfaces sheared against each other. Can the performance of polymer brushes as steric stabilizers and boundary lubricants be improved? The answer to this question encompasses the application of polymer grafts presenting different chain topologies, beyond linearity. In particular, grafted polymers forming loops and cycles at the surface have been recently demonstrated to enable the modulation of interfacial physicochemical properties, including nanomechanical and nanotribological, to an extent that is difficultly addressed by using their linear counterparts. Loop and cyclic polymer brushes provide enhanced steric stabilization to surfaces, increase their biopassivity and show superlubricious behavior. Their distinctive structure, the methods applied to fabricate them and their application in several technologically relevant fields of materials science are reviewed in this contribution. PMID- 28558134 TI - A Strategy to Design High-Density Nanoscale Devices utilizing Vapor Deposition of Metal Halide Perovskite Materials. AB - The demand for high memory density has increased due to increasing needs of information storage, such as big data processing and the Internet of Things. Organic-inorganic perovskite materials that show nonvolatile resistive switching memory properties have potential applications as the resistive switching layer for next-generation memory devices, but, for practical applications, these materials should be utilized in high-density data-storage devices. Here, nanoscale memory devices are fabricated by sequential vapor deposition of organolead halide perovskite (OHP) CH3 NH3 PbI3 layers on wafers perforated with 250 nm via-holes. These devices have bipolar resistive switching properties, and show low-voltage operation, fast switching speed (200 ns), good endurance, and data-retention time >105 s. Moreover, the use of sequential vapor deposition is extended to deposit CH3 NH3 PbI3 as the memory element in a cross-point array structure. This method to fabricate high-density memory devices could be used for memory cells that occupy large areas, and to overcome the scaling limit of existing methods; it also presents a way to use OHPs to increase memory storage capacity. PMID- 28558132 TI - The ratio of pericardial to subcutaneous adipose tissues is associated with insulin resistance. AB - OBJECTIVE: To examine the association between pericardial adipose tissue (PAT) and the ratio of PAT to subcutaneous adipose tissue (SAT) with insulin resistance in adults with and without type 1 diabetes (T1D). METHODS: Data for this report came from a substudy of the Coronary Artery Calcification in Type 1 Diabetes cohort (n = 83; 38 with T1D, 45 without T1D). Insulin resistance was measured by hyperinsulinemic-euglycemic clamp. Abdominal computed tomography (CT) was used to measure visceral adipose tissue (VAT) and SAT. PAT was measured from CT scans of the heart. RESULTS: PAT and the ratio of PAT to SAT was higher in males compared to females. After adjustment for demographics, diabetes, blood pressure and lipid factors, BMI, VAT, and log PAT/SAT ratio, log PAT was positively associated with the glucose infusion rate (GIR) in females only (beta = 3.36 +/- 1.96, P = 0.097, P for sex interaction = 0.055). Conversely, the log PAT/SAT ratio was significantly associated with decreased GIR in both males and females (beta = 2.08 +/- 1.03, P = 0.047, P for sex interaction = 0.768). CONCLUSIONS: A significant association between the PAT/SAT ratio and insulin resistance was found, independent of BMI, VAT, and PAT. These results highlight the importance of considering fat distribution independent of volume. PMID- 28558135 TI - Sub-Micron Polymeric Stomatocytes as Promising Templates for Confined Crystallization and Diffraction Experiments. AB - The possibility of using sub-micrometer polymeric stomatocytes is investigated to effectuate confined crystallization of inorganic compounds. These bowl-shaped polymeric compartments facilitate confined crystallization while their glassy surfaces provide their crystalline cargos with convenient shielding from the electron beam's harsh effects during transmission electron microscopy experiments. Stomatocytes host the growth of a single nanocrystal per nanocavity, and the electron diffraction experiments reveal that their glassy membranes do not interfere with the diffraction patterns obtained from their crystalline cargos. Therefore, it is expected that the encapsulation and crystallization within these compartments can be considered as a promising template (nanovials) that hold and protect nanocrystals and protein clusters from the direct radiation damage before data acquisition, while they are examined by modern crystallography methodologies such as serial femtosecond crystallography. PMID- 28558136 TI - Multiphoton Direct Laser Writing and 3D Imaging of Polymeric Freestanding Architectures for Cell Colonization. AB - The realization of 3D architectures for the study of cell growth, proliferation, and differentiation is a task of fundamental importance for both technological and biological communities involved in the development of biomimetic cell culture environments. Here we report the fabrication of 3D freestanding scaffolds, realized by multiphoton direct laser writing and seeded with neuroblastoma cells, and their multitechnique characterization using advanced 3D fluorescence imaging approaches. The high accuracy of the fabrication process (~200 nm) allows a much finer control of the micro- and nanoscale features compared to other 3D printing technologies based on fused deposition modeling, inkjet printing, selective laser sintering, or polyjet technology. Scanning electron microscopy (SEM) provides detailed insights about the morphology of both cells and cellular interconnections around the 3D architecture. On the other hand, the nature of the seeding in the inner core of the 3D scaffold, inaccessible by conventional SEM imaging, is unveiled by light sheet fluorescence microscopy and multiphoton confocal imaging highlighting an optimal cell colonization both around and within the 3D scaffold as well as the formation of long neuritic extensions. The results open appealing scenarios for the use of the developed 3D fabrication/3D imaging protocols in several neuroscientific contexts. PMID- 28558137 TI - Complete assignment of the 1 H NMR data and reassignment of 13 C NMR data of four spongian diterpenes. PMID- 28558138 TI - A long-term copper exposure in a freshwater ecosystem using lotic mesocosms: Invertebrate community responses. AB - A lotic mesocosm study was carried out in 20-m-long channels, under continuous, environmentally realistic concentrations of copper (Cu) in low, medium, and high exposures (nominally 0, 5, 25, and 75 MUg L-1 ; average effective concentrations <0.5, 4, 20, and 57 MUg L-1 respectively) for 18 mo. Total abundance, taxa richness, and community structure of zooplankton, macroinvertebrates, and emerging insects were severely affected at Cu treatment levels of 25 and 75 MUg L 1 . Some taxa were sensitive to Cu, including gastropods such as Lymnaea spp. and Physa sp., crustaceans such as Chydorus sphaericus, Gammarus pulex, and Asellus aquaticus, rotifers such as Mytilina sp. and Trichocerca sp., leeches such as Erpobdella sp., and the emergence of dipteran insects such as Chironomini. Other taxa appeared to be tolerant or favored by indirect effects, as in Chironimidae larvae, the emergence of Orthocladiinae, and the zooplankter Vorticella sp., which increased in the 25 and 75 MUg L-1 treatments. After approximately 8 mo of Cu exposure, the macroinvertebrate community in the high treatment was decimated to the point that few organisms could be detected, with moderate effects in the medium treatment, and very slight effects in the low-Cu treatment. Subsequently, most taxa in the high-Cu exposure began a gradual and partial recovery. By the end of the study at 18 mo, macroinvertebrate taxa richness was similar to control richness, although overall abundances remained lower than controls. After 18 mo of copper exposure, a no-observed-effect concentration at the community level for consumers was set at 5 MUg L-1 (4 MUg L-1 as average effective concentration), and a lowest-observed-effect concentration at 25 MUg L-1 (20 MUg L-1 as average effective concentration). Environ Toxicol Chem 2017;36:2698-2714. (c) 2017 SETAC. PMID- 28558139 TI - Safety and tolerability of surfactant nasal irrigation. AB - BACKGROUND: Abnormal mucus composition and bacterial biofilms are thought to contribute to the pathophysiology of rhinosinusitis. Addition of a mucoactive surfactant to saline irrigation solution has been hypothesized to address these factors. We evaluated the safety and tolerability of a reformulated surfactant in a sample of normal subjects. METHODS: A total of 33 volunteers were randomly assigned to receive either surfactant solution or buffered saline at baseline in a controlled crossover study design. Each subject underwent rhinoscopic exam and in-office smell testing via the 40-question smell identification test (SIT). Those with non-normosmic results or active rhinitis symptoms were excluded. Subjects were instructed to irrigate twice daily with the selected solution for 1 week while keeping a daily diary. For week 2, treatment was stopped. During week 3, each group switched to the other treatment. Exam, SIT, and degree of congestion were assessed after each phase. RESULTS: Use of surfactant led to a marginal reduction in mean SIT score of 1.5 points, which was statistically significant (p = 0.012). A clinically meaningful reduction in SIT score, defined as >=4 points, was observed in 18% (6/33) of subjects after surfactant vs 3% (1/33) after saline (p = 0.046). During the surfactant phase, moderate or severe congestion was reported in 29% (8/28) of subjects completing the diary. In contrast, only 6% (2/32) of subjects reported moderate congestion after the saline phase (p = 0.021). CONCLUSION: In normal volunteers, surfactant nasal irrigation may be associated with tolerability issues due to congestion. A subset may experience reduction in olfactory acuity that appears reversible. PMID- 28558140 TI - New oleanane saponins from the roots of Dendrobangia boliviana identified by LC SPE-NMR. PMID- 28558141 TI - Self-Powered, Flexible, and Solution-Processable Perovskite Photodetector Based on Low-Cost Carbon Cloth. AB - Flexible perovskite photodetectors are usually constructed on indium-tin-oxide coated polymer substrates, which are expensive, fragile, and not resistant to high temperature. Herein, for the first time, a high-performance flexible perovskite photodetector is fabricated based on low-cost carbon cloth via a facile solution processable strategy. In this device, perovskite microcrystal and Spiro-OMeTAD (hole transporting material) blended film act as active materials for light detection, and carbon cloth serves as both a flexible substrate and a conductive electrode. The as-fabricated photodetector shows a broad spectrum response from ultraviolet to near-infrared light, high responsivity, fast response speed, long-term stability, and self-powered capability. Flexible devices show negligible degradation after several tens of bending cycles and at the extremely bending angle of 180 degrees . This work promises a new technique to construct flexible, high-performance photodetectors with low cost and self powered capability. PMID- 28558142 TI - Dearomative Intramolecular (4+3) Cycloadditions of Arenes with Epoxy and Aziridinyl Enolsilanes. AB - An intramolecular (4+3) cycloaddition of epoxy and aziridinyl enolsilanes with benzene, naphthalene, and anthracene derivatives is reported. Highly functionalized polycyclic alcohols and amines are generated under relatively mild reaction conditions with yields up to 89 %. Optically enriched cycloadducts are obtained from cycloadditions of enantiomerically pure epoxides and aziridines. PMID- 28558144 TI - The Nature of Ion Conduction in Methylammonium Lead Iodide: A Multimethod Approach. AB - By applying a multitude of experimental techniques including 1 H, 14 N, 207 Pb NMR and 127 I NMR/NQR, tracer diffusion, reaction cell and doping experiments, as well as stoichiometric variation, conductivity, and polarization experiments, iodine ions are unambiguously shown to be the mobile species in CH3 NH3 PbI3 , with iodine vacancies shown to represent the mechanistic centers under equilibrium conditions. Pb2+ and CH3 NH3+ ions do not significantly contribute to the long range transport (upper limits for their contributions are given), whereby the latter exhibit substantial local motion. The decisive electronic contribution to the mixed conductivity in the experimental window stems from electron holes. As holes can be associated with iodine orbitals, local variations of the iodine stoichiometry may be fast and enable light effects on ion transport. PMID- 28558146 TI - Cyanine based Nanoprobes for Cancer Theranostics. AB - Cyanine dyes are greatly accredited in the development of non-invasive therapy that can "see" and "treat" tumor cells via imaging, photothermal and photodynamic treatment. However, these dyes suffer from poor pharmacokinetics inducing severe toxicity to normal cells, insufficient accumulation in tumor regions and rapid photobleaching when delivered in free forms. Nanoparticles engineered to encapsulate these compounds and delivering them into tumor regions have increased rapidly, however, so far, these nanoparticles (NPs) have not proved to be so effective to circumvent existing challenges. Newly designed multifunctional smart nanocarriers that can improve phototherapeutic properties of these dyes, co encapsulate multiple potent therapeutic compounds, and simultaneously overcome limitations related to tumor recurrence, metastases, limited intracellular uptake, and tumor hypoxia have potential to revolutionize modern paradigm of cancer therapy. Such cyanine based multifunctional nanocarriers integrating imaging and therapy in a single platform can effectively produce better clinical outcomes in cancer treatment. This review briefly summarizes recent advancements of cyanine nanoprobes that are currently used as imaging/phototherapeutic agents in unimodal/bimodal/trimodal cancer theranostics. Finally, we conclude this review by addressing challenges of pre-existing therapeutic systems and designs adopted to overcome them with a brief insight assimilating future perspective of emerging cyanine-based NPs in cancer theranostics. PMID- 28558143 TI - Parsing disease-relevant protein modifications from epiphenomena: perspective on the structural basis of SOD1-mediated ALS. AB - Conformational change and modification of proteins are involved in many cellular functions. However, they can also have adverse effects that are implicated in numerous diseases. How structural change promotes disease is generally not well understood. This perspective illustrates how mass spectrometry (MS), followed by toxicological and epidemiological validation, can discover disease-relevant structural changes and therapeutic strategies. We (with our collaborators) set out to characterize the structural and toxic consequences of disease-associated mutations and post-translational modifications (PTMs) of the cytosolic antioxidant protein Cu/Zn-superoxide dismutase (SOD1). Previous genetic studies discovered >180 different mutations in the SOD1 gene that caused familial (inherited) amyotrophic lateral sclerosis (fALS). Using hydrogen-deuterium exchange with mass spectrometry, we determined that diverse disease-associated SOD1 mutations cause a common structural defect - perturbation of the SOD1 electrostatic loop. X-ray crystallographic studies had demonstrated that this leads to protein aggregation through a specific interaction between the electrostatic loop and an exposed beta-barrel edge strand. Using epidemiology methods, we then determined that decreased SOD1 stability and increased protein aggregation are powerful risk factors for fALS progression, with a combined hazard ratio > 300 (for comparison, a lifetime of smoking is associated with a hazard ratio of ~15 for lung cancer). The resulting structural model of fALS etiology supported the hypothesis that some sporadic ALS (sALS, ~80% of ALS is not associated with a gene defect) could be caused by post-translational protein modification of wild-type SOD1. We developed immunocapture antibodies and high sensitivity top-down MS methods and characterized PTMs of wild-type SOD1 using human tissue samples. Using global hydrogen-deuterium exchange, X-ray crystallography and neurotoxicology, we then characterized toxic and protective subsets of SOD1 PTMs. To cap this perspective, we present proof-of-concept that post-translational modification can cause disease. We show that numerous mutations (N?D; Q?E), which result in the same chemical structure as the PTM deamidation, cause multiple diseases. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28558145 TI - Prevalence of Vector-Borne Pathogens in Southern California Dogs With Clinical and Laboratory Abnormalities Consistent With Immune-Mediated Disease. AB - BACKGROUND: Studies investigating the prevalence of vector-borne pathogens in southern California dogs are limited. Occult infections might be misdiagnosed as idiopathic immune-mediated disease. HYPOTHESIS/OBJECTIVES: (1) To determine the prevalence of vector-borne pathogens in southern California dogs with compatible clinical findings using PCR and serologic panels and (2) to determine whether testing convalescent samples and repeating PCR on acute samples using the same and different gene targets enhance detection. ANIMALS: Forty-two client-owned dogs with clinical signs of vector-borne disease presenting to specialty practices in San Diego County. METHODS: Combined prospective and retrospective observational study. Forty-two acute and 27 convalescent samples were collected. Acute samples were prospectively tested for antibodies to Rickettsia, Ehrlichia, Bartonella, Babesia, Borrelia, and Anaplasma species. PCR targeting Ehrlichia, Babesia, Anaplasma, hemotropic Mycoplasma, and Bartonella species was also performed. Retrospectively, convalescent samples were tested for the same organisms using serology, and for Ehrlichia, Babesia, Anaplasma, and Bartonella species using PCR. Acute samples were retested using PCR targeting Ehrlichia and Babesia species. RESULTS: Evidence of exposure to or infection with a vector borne pathogen was detected in 33% (14/42) of dogs. Ehrlichia and Babesia species were most common; each was identified in 5 dogs. Convalescent serologic testing, repeating PCR, and using novel PCR gene targets increased detection by 30%. CONCLUSIONS AND CLINICAL IMPORTANCE: Repeated testing using serology and PCR enhances detection of infection by vector-borne pathogens in dogs with clinical signs of immune-mediated disease. Larger prevalence studies of emerging vector borne pathogens in southern California dogs are warranted. PMID- 28558147 TI - Safety and efficacy of a bioabsorbable fluticasone propionate-eluting sinus dressing in postoperative management of endoscopic sinus surgery: a randomized clinical trial. AB - BACKGROUND: Postoperative wound healing after endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis (CRS) is an important factor in procedural success. Local steroids and separation of opposing mucosa are commonly implemented to optimize healing. A bioabsorbable, fluticasone propionate (FP) eluting implant, SinuBand FP, was assessed for its safety and efficacy when used in patients with CRS and nasal polyps, who were indicated for ESS including bilateral anterior and posterior ethmoidectomy. METHODS: A first-in-human, randomized, partially double-blind, single-tertiary-referral-center, controlled trial enrolling 30 patients receiving 2 of 3 treatments (1 per sinus, intrapatient control): SinuBand FP, SinuBand (without FP), or standard nasal pack (Merocel(r)). Primary outcome measures were local safety, ocular safety (intraocular pressure [IOP], lens opacity), and 24-hour urine cortisol. Secondary measures (evaluated by independent review of postoperative video endoscopies) were ethmoid inflammation, polyp score, adhesion formation, and Lund-Kennedy score. Patient-reported outcomes of postoperative pain, nasal congestion, and nasal discharge were collected. RESULTS: Of 30 enrolled patients (used for safety analysis), 27 patients completed the trial. SinuBand FP showed local safety, ocular safety, and no significant change in 24-hour urine cortisol. SinuBand FP showed a trend to do better concerning inflammation. Concerning polyp score SinuBand FP did significantly better compared to Merocel (p = 0.03). No significance compared to SinuBand without corticosteroids (p = 0.97). Adhesions were comparable across treatments. Patient reported pain was nominally lower in the SinuBand group. CONCLUSION: SinuBand FP was well tolerated and showed evidence of efficacy. A larger study is needed to further evaluate and confirm the benefits of SinuBand FP. PMID- 28558148 TI - Glucosamine has an antiallergic effect in mice with allergic asthma and rhinitis. AB - BACKGROUND: Glucosamine (GlcN) is generally used as a dietary supplement because of its antiinflammatory effects. We evaluated the antiallergic effect of GlcN in mice with allergic asthma and rhinitis. METHODS: Thirty-two mice were allocated equally into 4 groups (n = 8). In group A (control), we performed intraperitoneal/intranasal challenge using sterile saline. In group B (asthma/rhinitis), we used ovalbumin for intraperitoneal/intranasal challenge to induce allergic asthma and rhinitis. In groups C and D (GlcN treatment), mice were given 1% and 5% GlcN throughout the period of ovalbumin challenge, respectively. We measured serum total and ovalbumin-specific immunoglobulin E (IgE), cytokine titers (interleukin-1, -4, -5, -6, -10, and -17; tumor necrosis factor-alpha; and interferon-gamma), and the number of inflammatory cells (eosinophils, neutrophils, lymphocytes) in bronchoalveolar lavage (BAL) fluid. We also performed histopathologic examination of the lung and nasal cavity. Finally, we performed real-time polymerase chain reaction for the genes Bcl-2, EC-SOD, VEGF, caspase-3, Bax, COX-2, Hif-1alpha, and heme oxygenase-1. RESULTS: Compared with group B, group D had significant serum total and ovalbumin-specific IgE decreases after GlcN treatment (p < 0.05). Titers for IL-4, IL-5, IL-6, and IL-17 in BAL fluid were significantly decreased in group D (p < 0.05). Eosinophils in BAL fluid were significantly decreased in group D compared with group B (p < 0.05). Groups C and D showed significant improvement of inflammation compared with group B. Group D had significant downregulation of EC-SOD, Bax, Hif-1alpha, and heme oxygenase-1 compared with group B. CONCLUSION: GlcN had a significant antiallergic effect in mice with allergic asthma and rhinitis. PMID- 28558149 TI - Mandibulofacial dysostosis Bauru type: Refining the phenotype. AB - Mandibulofacial dysostosis (MFD) Bauru type (OMIM 604830) is a rare genetic condition characterized mainly by malar hypoplasia, orofacial cleft, and micrognathia. Here, we describe the clinical and radiographic sings of 13 individuals (12 female and 1 male) from eight unrelated kindreds with MFD Bauru type, including four previously reported cases, treated at the Hospital for Rehabilitation of Craniofacial Anomalies. The clinical phenotype was characterized by severe underdevelopment of mandible, midface hypoplasia, orofacial cleft, bitemporal narrowing, mild upper eyelid down slanting, high nasal bridge, thick and everted lower lip, minor ears abnormalities, and hearing loss. Radiographic aspects included downslanting of zygomatic arch, maxillary hypoplasia, microretrognathia, hypoplastic mandibular condyles, and ectopic external auditory canal. Recurrence was observed in two of eight families and the affected distribution pattern was compatible with autosomal dominant inheritance in one and autosomal recessive in another, indicating possible genetic heterogeneity for this condition. Clinical and radiographic findings in this report contribute to the delineation of this rare MFD. PMID- 28558151 TI - Accurate van der Waals force field for gas adsorption in porous materials. AB - An accurate van der Waals force field (VDW FF) was derived from highly precise quantum mechanical (QM) calculations. Small molecular clusters were used to explore van der Waals interactions between gas molecules and porous materials. The parameters of the accurate van der Waals force field were determined by QM calculations. To validate the force field, the prediction results from the VDW FF were compared with standard FFs, such as UFF, Dreiding, Pcff, and Compass. The results from the VDW FF were in excellent agreement with the experimental measurements. This force field can be applied to the prediction of the gas density (H2 , CO2 , C2 H4 , CH4 , N2 , O2 ) and adsorption performance inside porous materials, such as covalent organic frameworks (COFs), zeolites and metal organic frameworks (MOFs), consisting of H, B, N, C, O, S, Si, Al, Zn, Mg, Ni, and Co. This work provides a solid basis for studying gas adsorption in porous materials. (c) 2017 Wiley Periodicals, Inc. PMID- 28558150 TI - Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics. AB - BACKGROUND: Sacituzumab govitecan (IMMU-132), an antitrophoblastic cell-surface antigen (anti-Trop-2) humanized antibody-SN-38 conjugate, had encouraging efficacy in the phase 1 clinical trial. This report further examines the pharmacokinetics and safety of multiple cycles of IMMU-132 at doses of 8 or 10 mg/kg in patients with diverse advanced epithelial cancers. METHODS: Patients who had multiple prior therapies received IMMU-132 on days 1 and 8 of 21-day treatment cycles. Trop-2 staining of archived tumor specimens, clearance of IMMU 132 and its constituents (ie, immunoglobulin G [IgG], SN-38 [a camptothecin, the active component of irinotecan], and glucuronidated SN-38 [SN-38G]), antibody responses, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) levels were determined. Safety was assessed according to Common Terminology Criteria for Adverse Events version 4.0, and responses were assessed using Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Patients with diverse metastatic cancers who received IMMU-132 at 8 mg/kg (n = 81) and 10 mg/kg (n = 97) were examined. Trop-2 was positive in 93% of the available specimens. IMMU-132 cleared with a half-life of approximately 11 to 14 hours, reflecting the release of SN-38 from the conjugate; IgG cleared more slowly (half-life, approximately 103-114 hours). Most SN-38 in the serum (>95%) was bound to IgG. SN-38G concentrations were lower than SN-38 concentrations. Dose-limiting neutropenia after the first cycle was not correlated with SN-38 in serum or with UGT1A1 genotype. No antibody responses were detected. Objective responses were observed in several indications, including metastatic triple-negative breast cancer, confirming that 10 mg/kg produced an encouraging overall response. CONCLUSIONS: Sacituzumab govitecan has a predictable pharmacokinetic profile and manageable toxicity at doses of 8 and 10 mg/kg. With objective responses and a good therapeutic index at 10 mg/kg, this dose was chosen for future development. Cancer 2017;123:3843-3854. (c) 2017 American Cancer Society. PMID- 28558152 TI - Diabetic macular oedema: evidence-based treatment recommendations for Asian countries. AB - Diabetic macular oedema is the most common cause of diabetic retinopathy-induced vision loss. Efficacy of anti-vascular endothelial growth factor therapy in diabetic macular oedema has been demonstrated in randomized controlled trials. An Asian-specific guideline for diabetic macular oedema treatment is needed as patients in Asia tend to present with far more advanced disease than seen elsewhere in the world. Previous reviews of diabetic macular oedema management lacked a broader assessment of anti-vascular endothelial growth factor treatment choices and newer trials. Recent clinical trial data allow head-to-head comparisons between the different anti-vascular endothelial growth factor agents and treatment regimens. This review aims to summarize the clinical evidence related to various treatment regimens for clinicians, with a focus on anti vascular endothelial growth factor therapies, and to provide guidance on the treatment of diabetic macular oedema in Asian patients. PMID- 28558153 TI - Quantification of morusin using LC-MS in rat plasma: Application to a pharmacokinetic study. AB - A sensitive LC-MS method was developed for the quantification of morusin in rat plasma using praeruptorin C as internal standard. After extraction with diethyl ether, post-treatment samples were chromatographed on a Hypersil C18 column. An isocratic mobile phase consisting of methanol-water (70:30, v/v) was applied at a flow rate of 0.4 mL/min. Detection was performed via electrospray ionization source with positive ion mode using selected ion monitoring mode at m/z 443.1 for morusin and m/z 451.0 for IS. Acceptable linearity (r2 >= 0.99) was observed over the concentration range of 1.5-800 ng/mL. This method was successfully applied in the pharmacokinetics study of morusin in rats. PMID- 28558155 TI - Rational Design and Synthesis of Extremely Efficient Macroporous CoSe2 -CNT Composite Microspheres for Hydrogen Evolution Reaction. AB - Uniquely structured CoSe2 -carbon nanotube (CNT) composite microspheres with optimized morphology for the hydrogen-evolution reaction (HER) are prepared by spray pyrolysis and subsequent selenization. The ultrafine CoSe2 nanocrystals uniformly decorate the entire macroporous CNT backbone in CoSe2 -CNT composite microspheres. The macroporous CNT backbone strongly improves the electrocatalytic activity of CoSe2 by improving the electrical conductivity and minimizing the growth of CoSe2 nanocrystals during the synthesis process. In addition, the macroporous structure resulting from the CNT backbone improves the electrocatalytic activity of the CoSe2 -CNT microspheres by increasing the removal rate of generated H2 and minimizing the polarization of the electrode during HER. The CoSe2 -CNT composite microspheres demonstrate excellent catalytic activity for HER in an acidic medium (10 mA cm-2 at an overpotential of ~174 mV). The bare CoSe2 powders exhibit moderate HER activity, with an overpotential of 226 mV at 10 mA cm-2 . The Tafel slopes for the CoSe2 -CNT composite and bare CoSe2 powders are 37.8 and 58.9 mV dec-1 , respectively. The CoSe2 -CNT composite microspheres have a slightly larger Tafel slope than that of commercial carbon supported platinum nanoparticles, which is 30.2 mV dec-1 . PMID- 28558156 TI - Phosphoribosyl Pyrophosphate: A Molecular Vestige of the Origin of Life on Minerals. AB - In this contribution, we report the formation under prebiotic conditions of phosphoribosyl pyrophosphate (PRPP) as a molecular precursor in the one-pot synthesis of a canonical nucleotide, namely adenosine monophosphate (AMP) from its building blocks (KH2 PO4 or Pi , adenine, and d-ribose), on a fumed silica surface. The on-the-rocks approach has been successfully applied to the simultaneous phosphorylation and glycosylation of ribose. The one-pot formation mechanism of AMP involves a two-step pathway via an activated intermediate, namely PRPP, obtained by multiple ribose phosphorylations upon mild thermal activation. PMID- 28558154 TI - Theta-paced flickering between place-cell maps in the hippocampus: A model based on short-term synaptic plasticity. AB - Hippocampal place cells represent different environments with distinct neural activity patterns. Following an abrupt switch between two familiar configurations of visual cues defining two environments, the hippocampal neural activity pattern switches almost immediately to the corresponding representation. Surprisingly, during a transient period following the switch to the new environment, occasional fast transitions between the two activity patterns (flickering) were observed (Jezek, Henriksen, Treves, Moser, & Moser, ). Here we show that an attractor neural network model of place cells with connections endowed with short-term synaptic plasticity can account for this phenomenon. A memory trace of the recent history of network activity is maintained in the state of the synapses, allowing the network to temporarily reactivate the representation of the previous environment in the absence of the corresponding sensory cues. The model predicts that the number of flickering events depends on the amplitude of the ongoing theta rhythm and the distance between the current position of the animal and its position at the time of cue switching. We test these predictions with new analysis of experimental data. These results suggest a potential role of short term synaptic plasticity in recruiting the activity of different cell assemblies and in shaping hippocampal activity of behaving animals. PMID- 28558157 TI - Superacids Based on Pentafluoroorthotellurate Derivatives of Aluminum. AB - The new Lewis acid Al(OTeF5 )3 and its acetonitrile adduct CH3 CN->Al(OTeF5 )3 were obtained by a simple one-step synthesis in batches of up to 15 g. Al(OTeF5 )3 and the adduct were characterized by vibrational spectroscopy (IR, Raman) and quantum-chemical calculations. Furthermore, five different salts of the new weakly coordinating anion [Al(OTeF5 )4 ]- were prepared in a two-step procedure. [Ph4 P][Al(OTeF5 )4 ], Cs[Al(OTeF5 )4 ], [Ph3 C][Al(OTeF5 )4 ], as well as the protonated benzene derivatives [C9 H13 ][Al(OTeF5 )4 ] and [C6 H7 ][Al(OTeF5 )4 ] were characterized by low-temperature single-crystal X-ray diffraction and NMR spectroscopy. Arenium salts have rarely been characterized in the solid state and were synthesized in this work in a simplified fashion. PMID- 28558158 TI - Probing Bis-FeIV MauG: Isolation of Highly Reactive Radical Intermediates. AB - MauG is a diheme enzyme that utilizes two covalently bound c-type heme centers. We report here step-wise oxidations of a synthetic analogue of MauG in which two heme centers are bridged covalently through a flexible linker containing a pyrrole moiety. One- and two-electron oxidations produce monocation radical and dication diradical intermediates, respectively, which, being highly reactive, undergo spontaneous intramolecular rearrangement involving the pyrrole bridge itself to form indolizinium-fused chlorin-porphyrin and spiro-porphyrinato heterodimers. Unlike in MauG, where the two oxidizing equivalents produce the bis FeIV redox state, the synthetic analogue of the same, however, stabilizes two ferric hemes, each coupled with a porphyrin pi-cation radical. The present study highlights the possible role played by the bridge in the electronic communication. PMID- 28558159 TI - A foundation of ecology rediscovered: 100 years of succession on the William S. Cooper plots in Glacier Bay, Alaska. AB - Understanding plant community succession is one of the original pursuits of ecology, forming some of the earliest theoretical frameworks in the field. Much of this was built on the long-term research of William S. Cooper, who established a permanent plot network in Glacier Bay, Alaska, in 1916. This study now represents the longest-running primary succession plot network in the world. Permanent plots are useful for their ability to follow mechanistic change through time without assumptions inherent in space-for-time (chronosequence) designs. After 100-yr, these plots show surprising variety in species composition, soil characteristics (carbon, nitrogen, depth), and percent cover, attributable to variation in initial vegetation establishment first noted by Cooper in the 1916 1923 time period, partially driven by dispersal limitations. There has been almost a complete community composition replacement over the century and general species richness increase, but the effective number of species has declined significantly due to dominance of Salix species which established 100-yr prior (the only remaining species from the original cohort). Where Salix dominates, there is no establishment of "later" successional species like Picea. Plots nearer the entrance to Glacier Bay, and thus closer to potential seed sources after the most recent glaciation, have had consistently higher species richness for 100 yr. Age of plots is the best predictor of soil N content and C:N ratio, though plots still dominated by Salix had lower overall N; soil accumulation was more associated with dominant species. This highlights the importance of contingency and dispersal in community development. The 100-yr record of these plots, including species composition, spatial relationships, cover, and observed interactions between species provides a powerful view of long-term primary succession. PMID- 28558161 TI - 'Printability' of Candidate Biomaterials for Extrusion Based 3D Printing: State of-the-Art. AB - Regenerative medicine has been highlighted as one of the UK's 8 'Great Technologies' with the potential to revolutionize patient care in the 21st Century. Over the last decade, the concept of '3D bioprinting' has emerged, which allows the precise deposition of cell laden bioinks with the aim of engineering complex, functional tissues. For 3D printing to be used clinically, there is the need to produce advanced functional biomaterials, a new generation of bioinks with suitable cell culture and high shape/print fidelity, to match or exceed the physical, chemical and biological properties of human tissue. With the rapid increase in knowledge associated with biomaterials, cell-scaffold interactions and the ability to biofunctionalize/decorate bioinks with cell recognition sequences, it is important to keep in mind the 'printability' of these novel materials. In this illustrated review, we define and refine the concept of 'printability' and review seminal and contemporary studies to highlight the current 'state of play' in the field with a focus on bioink composition and concentration, manipulation of nozzle parameters and rheological properties. PMID- 28558160 TI - Randomized trial reveals that physical activity and energy expenditure are associated with weight and body composition after RYGB. AB - OBJECTIVE: This study investigated the associations of both physical activity time (PA) and energy expenditure (EE) with weight and fat mass (FM) loss in patients following Roux-en-Y gastric bypass (RYGB) surgery. METHODS: Ninety-six nondiabetic patients were included in this analysis. Post-RYGB patients were randomized in one of two treatments: A 6-month exercise training program (RYBG+EX) or lifestyle educational classes (RYGB). Body composition was assessed by dual-energy X-ray absorptiometry and computed tomography. Components of PA and EE were quantified by a multisensory device. Dose-response relationships of both PA and EE with weight loss and body composition were explored according to quartiles of change in steps per day. RESULTS: Patients in the highest quartiles of steps per day change lost more FM (3rd = -19.5 kg and 4th = -22.7 kg, P < 0.05) and abdominal adipose tissue (4th = -313 cm2 , P < 0.05), maintained skeletal muscle mass (3rd = -3.1 cm2 and 4th = -4.5 cm2 , P < 0.05), and had greater reductions in resting metabolic rate. Decreases in sedentary EE and increases in light EE and age were significant predictors of both Deltaweight and DeltaFM (R2 = 73.8% and R2 = 70.6%, respectively). CONCLUSIONS: Nondiabetic patients who perform higher, yet still modest, amounts of PA following RYGB have greater energy deficits and lose more weight and FM, while maintaining higher skeletal muscle mass. PMID- 28558162 TI - A numerical investigation and experimental verification of size effects in loaded bovine cortical bone. AB - In this paper, we present 2- and 3-dimensional finite element-based numerical models of loaded bovine cortical bone that explicitly incorporate the dominant microstructural feature: the vascular channel or Haversian canal system. The finite element models along with the representation of the microstructure within them are relatively simple: 2-dimensional models, consisting of a structured mesh of linear elastic planar elements punctuated by a periodic distribution of circular voids, are used to represent beam samples of cortical bone in which the channels are orientated perpendicular to the sample major axis, while 3 dimensional models, using a corresponding mesh of equivalent solid elements, represent those samples in which the canals are aligned with the axis. However, these models are exploited in an entirely novel approach involving the representation of material samples of different sizes and surface morphology. The numerical results obtained for the virtual material samples when loaded in bending indicate that they exhibit size effects not forecast by either classical (Cauchy) or more generalized elasticity theories. However, these effects are qualitatively consistent with those that we observed in a series of carefully conducted experiments involving the flexural testing of bone samples of different sizes. Encouraged by this qualitative agreement, we have identified appropriate model parameters, primarily void volume fraction but also void separation and matrix modulus by matching the computed size effects to those we observed experimentally. Interestingly, the parameter choices that provide the most suitable match of these effects broadly concur with those we actually observed in cortical bone. PMID- 28558163 TI - Arylthio- and Arylseleno-Substituted s-Heptazines. AB - In contrast to numerous thio- and selenocyanuric acid derivatives, sulfur- or selenium-containing s-heptazines have not been reported so far. Thio- and selenocyameluric acid esters were obtained by substitution reactions of s heptazine chloride C6 N7 Cl3 with aromatic thiols and selenophenol; the resultant white or yellow solids were stable in air. They were comprehensively characterized by elemental analysis, 1 H, 13 C NMR, and IR spectroscopy. The thiocyameluric acid phenyl ester (1, C6 N7 (S(C6 H5 ))3 ) and the corresponding selenium compound (7) formed co-crystals with mesitylene, which were analyzed by single-crystal X-ray diffraction. Both structures showed unusually large channels of ~12 A diameter. The thermal stability was measured by TGA (thermogravimetric analysis), and the flame retardancy of compound 1 was tested in PP by carrying out limiting oxygen index (LOI) measurements, which gave promising results. Quantum chemical calculations of the title compounds were performed to explain the observed properties and structural characteristics. PMID- 28558164 TI - Advanced solvent signal suppression for the acquisition of 1D and 2D NMR spectra of Scotch Whisky. AB - A simple and robust solvent suppression technique that enables acquisition of high-quality 1D 1 H nuclear magnetic resonance (NMR) spectra of alcoholic beverages on cryoprobe instruments was developed and applied to acquire NMR spectra of Scotch Whisky. The method uses 3 channels to suppress signals of water and ethanol, including those of 13 C satellites of ethanol. It is executed in automation allowing high throughput investigations of alcoholic beverages. On the basis of the well-established 1D nuclear Overhauser spectroscopy (NOESY) solvent suppression technique, this method suppresses the solvent at the beginning of the pulse sequence, producing pure phase signals minimally affected by the relaxation. The developed solvent suppression procedure was integrated into several homocorrelated and heterocorrelated 2D NMR experiments, including 2D correlation spectroscopy (COSY), 2D total correlation spectroscopy (TOCSY), 2D band-selective TOCSY, 2D J-resolved spectroscopy, 2D 1 H, 13 C heteronuclear single-quantum correlation spectroscopy (HSQC), 2D 1 H, 13 C HSQC-TOCSY, and 2D 1 H, 13 C heteronuclear multiple-bond correlation spectroscopy (HMBC). A 1D chemical-shift-selective TOCSY experiments was also modified. The wealth of information obtained by these experiments will assist in NMR structure elucidation of Scotch Whisky congeners and generally the composition of alcoholic beverages at the molecular level. PMID- 28558165 TI - Simultaneous Enhancement of Charge Separation and Hole Transportation in a TiO2 SrTiO3 Core-Shell Nanowire Photoelectrochemical System. AB - Efficient charge separation and transportation are key factors that determine the photoelectrochemical (PEC) water-splitting efficiency. Here, a simultaneous enhancement of charge separation and hole transportation on the basis of ferroelectric polarization in TiO2 -SrTiO3 core-shell nanowires (NWs) is reported. The SrTiO3 shell with controllable thicknesses generates a considerable spontaneous polarization, which effectively tunes the electrical band bending of TiO2 . Combined with its intrinsically high charge mobility, the ferroelectric SrTiO3 thin shell significantly improves the charge-separation efficiency (etaseparation ) with minimized influence on the hole-migration property of TiO2 photoelectrodes, leading to a drastically increased photocurrent density ( Jph ). Specifically, the 10 nm-thick SrTiO3 shell yields the highest Jph and etaseparation of 1.43 mA cm-2 and 87.7% at 1.23 V versus reversible hydrogen electrode, respectively, corresponding to 83% and 79% improvements compared with those of pristine TiO2 NWs. The PEC performance can be further manipulated by thermal treatment, and the control of SrTiO3 film thicknesses and electric poling directions. This work suggests a material with combined ferroelectric and semiconducting features could be a promising solution for advancing PEC systems by concurrently promoting the charge-separation and hole-transportation properties. PMID- 28558166 TI - Ordered Single-Crystalline Anatase TiO2 Nanorod Clusters Planted on Graphene for Fast Charge Transfer in Photoelectrochemical Solar Cells. AB - Achieving efficient charge transport is a great challenge in nanostructured TiO2 electrode-based photoelectrochemical cells. Inspired by excellent directional charge transport and the well-known electroconductibility of 1D anatase TiO2 nanostructured materials and graphene, respectively, planting ordered, single crystalline anatase TiO2 nanorod clusters on graphene sheets (rGO/ATRCs) via a facial one-pot solvothermal method is reported. The hierarchical rGO/ATRCs nanostructure can serve as an efficient light-harvesting electrode for dye sensitized solar cells. In addition, the obtained high-crystallinity anatase TiO2 nanorods in rGO/ATRCs possess a lower density of trap states, thus facilitating diffusion-driven charge transport and suppressing electron recombination. Moreover, the novel architecture significantly enhances the trap-free charge diffusion coefficient, which contributes to superior electron mobility properties. By virtue of more efficient charge transport and higher energy conversion efficiency, the rGO/ATRCs developed in this work show significant advantages over conventional rGO-TiO2 nanoparticle counterparts in photoelectrochemical cells. PMID- 28558167 TI - Microfluidic Production of Biodegradable Microcapsules for Sustained Release of Hydrophilic Actives. AB - Biodegradable microcapsules with a large aqueous lumen and ultrathin membrane are microfluidically designed for sustained release of hydrophilic bioactives using water-in-oil-in-water double-emulsion drops as a template. As a shell phase, an organic solution of poly(lactic-co-glycolic acid) is used, which is consolidated to form a biodegradable membrane. The encapsulants stored in the lumen are released over a long period of time as the membranes degrade. The period can be controlled in a range of -three to five months at neutral pH condition by adjusting membrane thickness, providing highly sustained release and potentially enabling the programed release of multiple drugs. At acidic or basic condition, the degradation is accelerated, leading to the release in the period of approximately two months. As the membrane is semipermeable, the microcapsules respond to the osmotic pressure difference across the membrane. The microcapsules are inflated in hypotonic condition and deflated in hypertonic condition. Both conditions cause cracks on the membrane, resulting in the fast release of encapsulants in a day. The microcapsules implanted in mice also show sustained release, despite the period is decreased to a month. It is believed that the microcapsules are promising for the in vivo sustained release of drugs for high and long-term efficacy. PMID- 28558168 TI - Importance of explicit smeared lone-pairs in anisotropic polarizable molecular mechanics. Torture track angular tests for exchange-repulsion and charge transfer contributions. AB - A correct representation of the short-range contributions such as exchange repulsion (Erep ) and charge-transfer (Ect ) is essential for the soundness of separable, anisotropic polarizable molecular mechanics potentials. Within the context of the SIBFA procedure, this is aimed at by explicit representations of lone pairs in their expressions. It is necessary to account for their anisotropic behaviors upon performing not only in-plane, but also out-of-plane, variations of a probe molecule or cation interacting with a target molecule or molecular fragment. Thus, Erep and Ect have to reproduce satisfactorily the corresponding anisotropies of their quantum chemical (QC) counterparts. A significant improvement of the out-of-plane dependencies was enabled when the sp2 and sp localized lone-pairs are, even though to a limited extent, delocalized on both sides of the plane, above and below the atom bearer but at the closely similar angles as the in-plane lone pair. We report calibration and validation tests on a series of monoligated complexes of a probe Zn(II) cation with several biochemically relevant ligands. Validations are then performed on several polyligated Zn(II) complexes found in the recognition sites of Zn metalloproteins. Such calibrations and validations are extended to representative monoligated and polyligated complexes of Mg(II) and Ca(II). It is emphasized that the calibration of all three cations was for each DeltaE contribution done on a small training set bearing on a limited number of representative N?, O?, and S? monoligated complexes. Owing to the separable nature of DeltaE, a secure transferability is enabled to a diversity of polyligated complexes. For these the relative errors with respect to the target DeltaE(QC) values are generally < 3%. Overall, the article proposes a full set of benchmarks that could be useful for force field developers. (c) 2017 Wiley Periodicals, Inc. PMID- 28558169 TI - Flexible and Responsive Chiral Nematic Cellulose Nanocrystal/Poly(ethylene glycol) Composite Films with Uniform and Tunable Structural Color. AB - The fabrication of responsive photonic structures from cellulose nanocrystals (CNCs) that can operate in the entire visible spectrum is challenging due to the requirements of precise periodic modulation of the pitch size of the self assembled multilayer structures at the length scale within the wavelength of the visible light. The surface charge density of CNCs is an important factor in controlling the pitch size of the chiral nematic structure of the dried solid CNC films. The assembly of poly(ethylene glycol) (PEG) together with CNCs into smaller chiral nematic domains results in solid films with uniform helical structure upon slow drying. Large, flexible, and flat photonic composite films with uniform structure colors from blue to red are prepared by changing the composition of CNCs and PEG. The CNC/PEG(80/20) composite film demonstrates a reversible and smooth structural color change between green and transparent in response to an increase and decrease of relative humidity between 50% and 100% owing to the reversible swelling and dehydration of the chiral nematic structure. The composite also shows excellent mechanical and thermal properties, complementing the multifunctional property profile. PMID- 28558170 TI - Collision-induced dissociation of phenethylamides: role of ion-neutral complexes. AB - RATIONALE: Phenethylamides are a large group of naturally occurring molecules found both in the plant and animal kingdoms. In addition, they are used as intermediates for the synthesis of pharmaceutically important dihydro- and tetrahydroisoquinolines. To enable efficient characterization of this class of molecules, a detailed mass spectrometric fragmentation study of a broad series of analogs was carried out. METHODS: The test compounds were synthesized using standard methods for amide bond formation. Low-energy high-resolution tandem mass spectra were acquired on a hybrid quadrupole/time-of-flight mass spectrometer using positive ion electrospray ionization. RESULTS: A total of 26 analogs were investigated in the study. Fragmentation of phenethylamides was found to proceed via intermediate ion-neutral complexes. The complexes can break down via multiple pathways including dissociation, proton transfer, Friedel-Crafts acylation, and single electron transfer. The relative contribution of each of these pathways strongly depends on the structure of the coupling amine and acid. CONCLUSIONS: A general scheme for the fragmentation of phenethylamides was developed. This study further extends the knowledge base of the ion-neutral complex by discovering Friedel-Crafts acylation as a novel reaction. The strong influence of minor structural modifications on the fragmentation patterns highlights the importance of testing many analogs in order to fully predict a fragmentation pattern of a particular class of molecules. PMID- 28558171 TI - Polynitro-Functionalized Dipyrazolo-1,3,5-triazinanes: Energetic Polycyclization toward High Density and Excellent Molecular Stability. AB - A new fused N-heterocyclic framework, dipyrazolo-1,3,5-triazinane, was synthesized and the physiochemical properties of its derivatives were investigated to evaluate the integrated energetic performance. In contrast to 1,3,5-trinitro-1,3,5-triazinane (RDX) featuring a distorted chair confirmation, polynitro-functionalized dipyrazolo-1,3,5-triazinanes have nearly planar backbones, thereby enhancing the density and thermal stability. Among these new energetic tricyclic compounds, 5 a and 12 show favorable crystal densities of 1.937 g cm-3 and 1.990 g cm-3 at 150 K, respectively, which rank highest in triazinane-based energetic compounds. Additionally, this synthetic approach was carried out to form seven-membered and eight-membered rings, giving rise to tetranitro dipyrazolo-1,3,5-triazepane (5 b) and tetranitro dipyrazolo-1,3,5 triazocane (5 c), respectively. PMID- 28558172 TI - Epoxy Matrices Modified by Green Additives for Recyclable Materials. AB - Epoxy-based thermosets are one of the most popular matrix materials in many industries, and significant environmental benefits can be obtained by developing a recyclable variant of this widely utilized material. Incorporation of a bio based disulfide additive within a commercial epoxy system leads to a cross-linked material that can be fractionated under mild and environmentally benign conditions. The material has been analyzed by FTIR and solid-state NMR. Furthermore, modified epoxy matrices with low additive concentrations are demonstrated to have similar mechanical and thermal properties compared to commercially available benchmarks. Thus, additive formulation and fractionation based on green chemistry principles have been demonstrated, and a recyclable epoxy matrix has been developed. PMID- 28558173 TI - Epidermal bladder cells confer salinity stress tolerance in the halophyte quinoa and Atriplex species. AB - Epidermal bladder cells (EBCs) have been postulated to assist halophytes in coping with saline environments. However, little direct supporting evidence is available. Here, Chenopodium quinoa plants were grown under saline conditions for 5 weeks. One day prior to salinity treatment, EBCs from all leaves and petioles were gently removed by using a soft cosmetic brush and physiological, ionic and metabolic changes in brushed and non-brushed leaves were compared. Gentle removal of EBC neither initiated wound metabolism nor affected the physiology and biochemistry of control-grown plants but did have a pronounced effect on salt grown plants, resulting in a salt-sensitive phenotype. Of 91 detected metabolites, more than half were significantly affected by salinity. Removal of EBC dramatically modified these metabolic changes, with the biggest differences reported for gamma-aminobutyric acid (GABA), proline, sucrose and inositol, affecting ion transport across cellular membranes (as shown in electrophysiological experiments). This work provides the first direct evidence for a role of EBC in salt tolerance in halophytes and attributes this to (1) a key role of EBC as a salt dump for external sequestration of sodium; (2) improved K+ retention in leaf mesophyll and (3) EBC as a storage space for several metabolites known to modulate plant ionic relations. PMID- 28558174 TI - SERS and SERRS Detection of the DNA Lesion 8-Nitroguanine: A Self-Labeling Modification. AB - Rapid and sensitive methods to detect DNA lesions are essential in order to understand their role in carcinogenesis and for potential diagnosis of cancers. The 8-nitroguanine DNA lesion, which is closely associated with inflammation induced cancers, has been characterized for the first time by surface-enhanced Raman spectroscopy (SERS). This lesion has been studied as the free base, as well as part of a dinucleotide and oligodeoxynucleotides (ODNs) at 5 different excitation wavelengths in the range 785-488 nm. All nitrated samples produced distinctly different spectra from their control guanine counterparts, with nitro bands being assigned by DFT calculations. Additional resonance enhancement was observed at the shorter excitation wavelengths, these SERRS measurements allowed the detection of one nitrated guanine in over 1,300 bases. In addition, SER(R)S can be used to detect whether the unstable lesion is covalently attached to the ODN or has been released by hydrolytic depurination. PMID- 28558175 TI - Capillary-Induced Ge Uniformly Distributed in N-Doped Carbon Nanotubes with Enhanced Li-Storage Performance. AB - Germanium (Ge) is a prospective anode material for lithium-ion batteries, as it possesses large theoretical capacity, outstanding lithium-ion diffusivity, and excellent electrical conductivity. Ge suffers from drastic capacity decay and poor rate performance, however, owing to its low electrical conductivity and huge volume expansion during cycling processes. Herein, a novel strategy has been developed to synthesize a Ge@N-doped carbon nanotubes (Ge@N-CNTs) composite with Ge nanoparticles uniformly distributed in the N-CNTs by using capillary action. This unique structure could effectively buffer large volume expansion. When evaluated as an anode material, the Ge@N-CNTs demonstrate enhanced cycling stability and excellent rate capabilities. PMID- 28558176 TI - Primary Vitreoretinal Lymphoma -- A Review. AB - Primary vitreoretinal lymphoma (PVRL) is the most common intraocular lymphoma occurring in the eye. It is a high-grade typically B-cell malignancy, arising in the retina, and is often associated with central nervous system (CNS) disease and thereby a poor prognosis. It needs to be distinguished from choroidal low-grade B cell lymphomas, which do not disseminate to the brain and have a good prognosis. Because of the rarity of PVRL, information is lacking regarding its true incidence, its geographical or ethnic variation, and underlying risk factors apart from immunosuppression associated with human immunodeficiency virus (HIV) and Epstein Barr virus. PVRL often presents masquerading as other intraocular diseases and is therefore often associated with diagnostic delays. This is compounded by the fragility of the neoplastic B cells, which hampers vitrectomy yields and pathological work-up. The latter includes cytomorphology and immunoprofiling, with adjunctive tests such as cytokine analysis, polymerase chain reaction for clonality, MYD88 mutational testing, and possibly bespoke next generation sequencing. Recent examinations of PVRL and CNS lymphoma (CNSL) using whole genome sequencing confirm that these tumors arise from activated postgerminal center cells, reflecting their aggressive course in most cases. The treatment of PVRL varies between centers and is dependent on presence or absence of concomitant CNS disease. The prognosis remains poor, and yet progress is steadily being made through international collaborative clinical trials. PMID- 28558177 TI - Is Floaterectomy Worth the Risks? PMID- 28558178 TI - Retinoblastoma: Update on Current Management. AB - Retinoblastoma is a rare cancer in children, where in less than a century of dire mortality there has been a cure in industrialized countries. Unfortunately, mortality remains high in emerging countries. The evolution of treatment makes it possible to go further by preserving the eyeball but this must not be done at the cost of the reappearance of metastases. Herein we outline the evolution of treatment from the beginning of the 20th century until the last recent evolutions, trying to imagine what could be the future treatments. In this pathology, the ophthalmologist is a doctor who must cure his patient and enucleation is considered a failure. This situation should not lead to shizophrenic situations where to keep an eye one would take risks with the life of the child. New international classifications, international prospective multicentric studies, and the search for blood biomarkers that can predict the risk of micrometastases could allow for better stratification of patients. PMID- 28558179 TI - Floaterectomy -- Risks, Safety, and Future. PMID- 28558180 TI - Neural Tumors of the Orbit -- What Is New? AB - Primary neural tumors of the orbit account for approximately 10% of all orbital tumors. Different tumor entities include meningiomas, optic nerve gliomas, neurofibromas, schwannomas, malignant peripheral nerve sheath tumors, and granular cell tumors. This review summarizes current concepts regarding epidemiology, clinical presentation, diagnosis, pathology, immunohistochemistry, prognosis, and treatment for neural tumors of the orbit based on the available literature. PMID- 28558181 TI - An Update on Intravitreal Aflibercept in Treating Macular Diseases. PMID- 28558182 TI - Posterior Pole and Peripheral Retinal Fibrovascular Proliferation in von Hippel Lindau Disease. AB - PURPOSE: To report the occurrence of fibrovascular proliferation (FVP) in the retina in von Hippel-lindau (VHl) patients and its association with prior treatment. DESIGN: A retrospective study. METHODS: A retrospective study of 101 VHL patients. Fundus photos were available for 28 patients. FVP was classified into peripheral and posterior pole. RESULTS: All 28 patients had retinal capillary hemangioblastomas (RCH) in 1 or both eyes; 15 patients were found to have FVP (group A), whereas 13 patients did not (group B). Mean age of patients in group A was 35 +/- 11.3 years and 36.6 +/- 13.8 in group B (P = 0.74). In group A, 27 eyes had RCH; 21 (77.77%) had FVP. In group B, 19 eyes had RCH. The number of treated eyes was significantly higher in group A (81.48%) than group B (42.1%) (P = 0.007). In group A, FVP was noted in the posterior pole in 9 eyes, in the periphery in 5 eyes, and 7 eyes developed both posterior pole and peripheral FVP. CONCLUSIONS: FVP can occur in the peripheral retina and in the posterior pole. There is a significant association between prior treatment of RCH and the occurrence of FVP. PMID- 28558183 TI - Ultrahigh Energy Density in SrTiO3 Film Capacitors. AB - Solid-state dielectric film capacitors with high-energy-storage density will further promote advanced electronic devices and electrical power systems toward miniaturization, lightweight, and integration. In this study, the influence of interface and thickness on energy storage properties of SrTiO3 (STO) films grown on La0.67Sr0.33MnO3 (LSMO) electrode are systematically studied. The cross sectional high resolution transmission electron microscopy reveals an ion interdiffusion layer and oxygen vacancies at the STO/LSMO interface. The capacitors show good frequency stability and increased dielectric constant with increasing STO thickness (410-710 nm). The breakdown strength (Eb) increases with decreasing STO thickness and reaches 6.8 MV/cm. Interestingly, the Eb under positive field is enhanced significantly and an ultrahigh energy density up to 307 J/cm3 with a high efficiency of 89% is realized. The enhanced Eb may be related to the modulation of local electric field and redistribution of oxygen vacancies at the STO/LSMO interface. Our results should be helpful for potential strategies to design devices with ultrahigh energy density. PMID- 28558184 TI - Dopamine Receptor D1 Agonism and Antagonism Using a Field-Effect Transistor Assay. AB - The field-effect transistor (FET) has been used in the development of diagnostic tools for several decades, leading to high-performance biosensors. Therefore, the FET platform can provide the foundation for the next generation of analytical methods. A major role of G-protein-coupled receptors (GPCRs) is in the transfer of external signals into the cell and promoting human body functions; thus, their principle application is in the screening of new drugs. The research community uses efficient systems to screen potential GPCR drugs; nevertheless, the need to develop GPCR-conjugated analytical devices remains for next-generation new drug screening. In this study, we proposed an approach for studying receptor agonism and antagonism by combining the roles of FETs and GPCRs in a dopamine receptor D1 (DRD1)-conjugated FET system, which is a suitable substitute for conventional cell-based receptor assays. DRD1 was reconstituted and purified to mimic native binding pockets that have highly discriminative interactions with DRD1 agonists/antagonists. The real-time responses from the DRD1-nanohybrid FET were highly sensitive and selective for dopamine agonists/antagonists, and their maximal response levels were clearly different depending on their DRD1 affinities. Moreover, the equilibrium constants (K) were estimated by fitting the response levels. Each K value indicates the variation in the affinity between DRD1 and the agonists/antagonists; a greater K value corresponds to a stronger DRD1 affinity in agonism, whereas a lower K value in antagonism indicates a stronger dopamine-blocking effect. PMID- 28558185 TI - Formation of Triboelectric Series via Atomic-Level Surface Functionalization for Triboelectric Energy Harvesting. AB - Triboelectric charging involves frictional contact of two different materials, and their contact electrification usually relies on polarity difference in the triboelectric series. This limits the choices of materials for triboelectric contact pairs, hindering research and development of energy harvest devices utilizing triboelectric effect. A progressive approach to resolve this issue involves modification of chemical structures of materials for effectively engineering their triboelectric properties. Here, we describe a facile method to change triboelectric property of a polymeric surface via atomic-level chemical functionalizations using a series of halogens and amines, which allows a wide spectrum of triboelectric series over single material. Using this method, tunable triboelectric output power density is demonstrated in triboelectric generators. Furthermore, molecular-scale calculation using density functional theory unveils that electrons transferred through electrification are occupying the PET group rather than the surface functional group. The work introduced here would open the ability to tune triboelectric property of materials by chemical modification of surface and facilitate the development of energy harvesting devices and sensors exploiting triboelectric effect. PMID- 28558186 TI - Li Electrochemical Tuning of Metal Oxide for Highly Selective CO2 Reduction. AB - Engineering active grain boundaries (GBs) in oxide-derived (OD) electrocatalysts is critical to improve the selectivity in CO2 reduction reaction (CO2RR), which is becoming an increasingly important pathway for renewable energy storage and usage. Different from traditional in situ electrochemical reduction under CO2RR conditions, where some metal oxides are converted into active metallic phases but with decreased GB densities, here we introduce the Li electrochemical tuning (LiET) method to controllably reduce the oxide precursors into interconnected ultrasmall metal nanoparticles with enriched GBs. By using ZnO as a case study, we demonstrate that the LiET-Zn with freshly exposed GBs exhibits a CO2-to-CO partial current of ~23 mA cm-2 at an overpotential of -948 mV, representing a 5 fold improvement from the OD-Zn with GBs eliminated during the in situ electro reduction process. A maximal CO Faradaic efficiency of ~91.1% is obtained by LiET Zn on glassy carbon substrate. The CO2-to-CO mechanism and interfacial chemistry are further probed at the molecular level by advanced in situ spectroelectrochemical technique, where the reaction intermediate of carboxyl species adsorbed on LiET-Zn surface is revealed. PMID- 28558187 TI - Compound Quantum Dot-Perovskite Optical Absorbers on Graphene Enhancing Short Wave Infrared Photodetection. AB - Colloidal quantum dots (QDs) combined with a graphene charge transducer promise to provide a photoconducting platform with high quantum efficiency and large intrinsic gain, yet compatible with cost-efficient polymer substrates. The response time in these devices is limited, however, and fast switching is only possible by sacrificing the high sensitivity. Furthermore, tuning the QD size toward infrared absorption using conventional organic capping ligands progressively reduces the device performance characteristics. Here we demonstrate methods to couple large QDs (>6 nm in diameter) with organometal halide perovskites, enabling hybrid graphene phototransistor arrays on plastic foils that simultaneously exhibit a specific detectivity of 5 * 1012 Jones and high video-frame-rate performance. PbI2 and CH3NH3I co-mediated ligand exchange in PbS QDs improves surface passivation and facilitates electronic transport, yielding faster charge recovery, whereas PbS QDs embedded into a CH3NH3PbI3 matrix produce spatially separated photocarriers leading to large gain. PMID- 28558188 TI - Porous Iron-Carboxylate Metal-Organic Framework: A Novel Bioplatform with Sustained Antibacterial Efficacy and Nontoxicity. AB - Sustained drug release plays a critical role in targeting the therapy of local diseases such as bacterial infections. In the present work, porous iron carboxylate metal-organic framework [MOF-53(Fe)] nanoparticles (NPs) were designed to entrap the vancomycin (Van) drugs. This system exhibited excellent chemical stability under acidic conditions (pH 7.4, 6.5, and 5.5) and much higher drug-loading capability because of the high porosity and large surface area of MOF NPs. The results showed that the drug-loading ratio of Van could reach 20 wt % and that the antibacterial ratio of the MOF-53(Fe)/Van system against Staphylococcus aureus could reach up to 90%. In addition, this MOF-53(Fe)/Van system exhibited excellent biocompatibility because of its chemical stability and sustained release of iron ions. Hence, these porous MOF NPs are a promising bioplatform not only for local therapy of bacterial infections but also for other biomedical therapies for tissue regeneration. PMID- 28558189 TI - Blending Homopolymers for Controlling the Morphology Transitions of Block Copolymer Nanorods Confined in Cylindrical Nanopores. AB - The microphase separation of block copolymers in confined geometries has been widely investigated over the last few decades. The controllability and versatility of the confinement-induced morphologies, however, are still difficult to be achieved because of the limited experimental parameters in the process of fabricating the confined nanostructures. In this work, we study the morphology transitions of lamellae-forming polystyrene-block-polydimethylsiloxane (PS-b PDMS) nanorods confined in the nanopores of anodic aluminum oxide (AAO) templates. The nanorods are formed by solvent-assisted template wetting, and the morphologies are compared to those in the bulk state. By blending PS-b-PDMS with homopolystyrene (hPS), the morphologies of the nanorods can be controlled because of the changes of the effective volume fractions. Special morphology transitions from concentric lamellar morphology, to multihelical morphology, and finally to spherical-like morphology are observed by increasing the weight ratios of hPS. hPS with different molecular weights is also applied to investigate the effect of hPS on the morphologies of the PS-b-PDMS/hPS blend nanostructures. The unusual morphologies are further confirmed by a selective removal process, which also generates nanochannels for possible refilling with functional materials. PMID- 28558190 TI - Broadband Cooling Spectra of Hot Electrons and Holes in PbSe Quantum Dots. AB - Understanding cooling of hot charge carriers in semiconductor quantum dots (QDs) is of fundamental interest and useful to enhance the performance of QDs in photovoltaics. We study electron and hole cooling dynamics in PbSe QDs up to high energies where carrier multiplication occurs. We characterize distinct cooling steps of hot electrons and holes and build up a broadband cooling spectrum for both charge carriers. Cooling of electrons is slower than of holes. At energies near the band gap we find cooling times between successive electronic energy levels in the order of 0.5 ps. We argue that here the large spacing between successive electronic energy levels requires cooling to occur by energy transfer to vibrational modes of ligand molecules or phonon modes associated with the QD surface. At high excess energy the energy loss rate of electrons is 1-5 eV/ps and exceeds 8 eV/ps for holes. Here charge carrier cooling can be understood in terms of emission of LO phonons with a higher density-of-states in the valence band than the conduction band. The complete mapping of the broadband cooling spectrum for both charge carriers in PbSe QDs is a big step toward understanding and controlling the cooling of hot charge carriers in colloidal QDs. PMID- 28558192 TI - Tunable Magnetism and Transport Properties in Nitride MXenes. AB - Two-dimensional materials with intrinsic and robust ferromagnetism and half metallicity are of great interest to explore the exciting physics and applications of nanoscale spintronic devices, but no such materials have been experimentally realized. In this study, we predict several M2NTx nitride MXene structures that display these characteristics based on a comprehensive study using a crystal field theory model and first-principles simulations. We demonstrate intrinsic ferromagnetism in Mn2NTx with different surface terminations (T = O, OH, and F), as well as in Ti2NO2 and Cr2NO2. High magnetic moments (up to 9 MUB per unit cell), high Curie temperatures (1877 to 566 K), robust ferromagnetism, and intrinsic half-metallic transport behavior of these MXenes suggest that they are promising candidates for spintronic applications, which should stimulate interest in their synthesis. PMID- 28558193 TI - Influence of Size and Shape on the Anatomical Distribution of Endotoxin-Free Gold Nanoparticles. AB - The transport and the delivery of drugs through nanocarriers is a great challenge of pharmacology. Since the production of liposomes to reduce the toxicity of doxorubicin in patients, a plethora of nanomaterials have been produced and characterized. Although it is widely known that elementary properties of nanomaterials influence their in vivo kinetics, such interaction is often poorly investigated in many preclinical studies. The present study aims to evaluate the actual effect of size and shape on the biodistribution of a set of gold nanoparticles (GNPs) after intravenous administration in mice. To this goal, quantitative data achieved by inductively coupled plasma mass spectrometry and observational results emerging from histochemistry (autometallography and enhanced dark-field hyperspectral microscopy) were combined. Since the immune system plays a role in bionano-interaction we used healthy immune-competent mice. To keep the immune surveillance on the physiological levels we synthesized endotoxin-free GNPs to be tested in specific pathogen-free animals. Our study mainly reveals that (a) the size and the shape greatly influence the kinetics of accumulation and excretion of GNPs in filter organs; (b) spherical and star-like GNPs showed the same percentage of accumulation, but a different localization in liver; (c) only star-like GNPs are able to accumulate in lung; (d) changes in the geometry did not improve the passage of the blood brain barrier. Overall, this study can be considered as a reliable starting point to drive the synthesis and the functionalization of potential candidates for theranostic purposes in many fields of research. PMID- 28558194 TI - Adaptive Chitosan Hollow Microspheres as Efficient Drug Carrier. AB - Smart drug carrier with function-oriented adaptations is highly desired due to its unique properties in medical applications. Herein, adaptive chitosan hollow microspheres (CHM) are fabricated by employing interfacial Schiff-base bonding reaction. Hydrophilic macromolecules of glycol chitosan are fixed at the oil/water interface through numerous hydrophobic small molecules of borneol 4 formylbenzoate, forming the CHM with a positively charged surface and lipophilic cavity. These CHM have an average size of 400-1000 nm after passing through the 0.22 MUm apertures of filter paper. This phenomenon combined with SEM measurements demonstrates its remarkable shape-adaptive behavior. Furthermore, the CHM present a pH-dependence of structural stability. When pH value reduces from 7.06 to 5.01, the CHM begin to lose their integrity. All those characteristics make the CHM an intelligent drug carrier, especially for water insoluble anticancer drugs, paclitaxel (PTX) in particular. Both cell uptake and cell cytotoxicity assays suggest that the PTX-loaded CHM are highly efficient on HepG2 and A549 cells. Therefore, rather than most of the traditional materials, these adaptive CHM show great potential as a novel drug carrier. PMID- 28558195 TI - "In Water": Organocatalyzed Diastereoselective Multicomponent Reactions toward 2 Azapyrrolizidine Alkaloid Scaffolds. AB - Synthesis of the 2-aza analogues of pyrrolizidine and spirooxindole-2 azapyrrolizidine hybrid, a spiro-tetracyclic scaffold possessing multiple contiguous stereocenters, by an exclusive regio-, chemo-, and diastereoselective multicomponent reaction in water is reported. This logical and didactical tactic has integrated the principles of an ideal organic synthesis, privileged substructure-based diversity-oriented synthesis, and biology-oriented synthesis to access hybrid heterocyclic scaffolds. PMID- 28558196 TI - Supersnowflakes: Stepwise Self-Assembly and Dynamic Exchange of Rhombus Star Shaped Supramolecules. AB - With the goal of increasing the complexity of metallo-supramolecules, two rhombus star-shaped supramolecular architectures, namely, supersnowflakes, were designed and assembled using multiple 2,2':6',2"-terpyridine (tpy) ligands in a stepwise manner. In the design of multicomponent self-assembly, ditopic and tritopic ligands were bridged through Ru(II) with strong coordination to form metal organic ligands for the subsequent self-assembly with a hexatopic ligand and Zn(II). The combination of Ru(II)-organic ligands with high stability and Zn(II) ions with weak coordination played a key role in the self-assembly of giant heteroleptic supersnowflakes, which encompassed three types of tpy-based organic ligands and two metal ions. With such a stepwise strategy, the self-sorting of individual building blocks was prevented from forming the undesired assemblies, e.g., small macrocycles and coordination polymers. Furthermore, the intra- and intermolecular dynamic exchange study of two supersnowflakes by NMR and mass spectrometry revealed the remarkable stability of these giant supramolecular complexes. PMID- 28558197 TI - Evolution of Luminescent Supramolecular Lanthanide M2nL3n Complexes from Helicates and Tetrahedra to Cubes. AB - Lanthanide-containing molecules have many potential applications in material science and biology, that is, luminescent sensing/labling, MRI, magnetic refrigeration, and catalysis among others. Coordination-directed self-assembly has shown great power in the designed construction of well-defined supramolecular systems. However, application of this strategy to the lanthanide edifices is challenging due to the complicated and greatly labile coordination numbers and geometries for lanthanides. Here we demonstrate a sensitive structural switching phenomenon during the stereocontrolled self-assembly of a group of Ln2nL3n (Ln for lanthanides, L for organic ligands, and n = 1, 2, 4) compounds. Systematic variation of the offset distances between the two chelating arms on the bis(tridentate) ligands dictated the final outcomes of the lanthanide assembly, ranging from Ln2L3 helicates and Ln4L6 tetrahedra to Ln8L12 cubes. Remarkably, the borderline case leading to the formation of a mixture of the helicate and the tetrahedron was clearly revealed. Moreover, the concentration-dependent self assembly of an unprecedented cubic Ln8L12 complex was also confirmed. The luminescent lanthanide cubes can serve as excellent turn-off sensors in explosives detection, featuring high selectivity and sensitivity toward picric acid. All complexes were confirmed by NMR, ESI-TOF-MS, and single crystal X-ray diffraction studies. Our results provide valuable design principles for the coordination self-assembly of multinuclear functional lanthanide architectures. PMID- 28558198 TI - Engineered CRISPR Systems for Next Generation Gene Therapies. AB - An ideal in vivo gene therapy platform provides safe, reprogrammable, and precise strategies which modulate cell and tissue gene regulatory networks with a high temporal and spatial resolution. Clustered regularly interspaced short palindromic repeats (CRISPR), a bacterial adoptive immune system, and its CRISPR associated protein 9 (Cas9), have gained attention for the ability to target and modify DNA sequences on demand with unprecedented flexibility and precision. The precision and programmability of Cas9 is derived from its complexation with a guide-RNA (gRNA) that is complementary to a desired genomic sequence. CRISPR systems open-up widespread applications including genetic disease modeling, functional screens, and synthetic gene regulation. The plausibility of in vivo genetic engineering using CRISPR has garnered significant traction as a next generation in vivo therapeutic. However, there are hurdles that need to be addressed before CRISPR-based strategies are fully implemented. Some key issues center on the controllability of the CRISPR platform, including minimizing genomic-off target effects and maximizing in vivo gene editing efficiency, in vivo cellular delivery, and spatial-temporal regulation. The modifiable components of CRISPR systems: Cas9 protein, gRNA, delivery platform, and the form of CRISPR system delivered (DNA, RNA, or ribonucleoprotein) have recently been engineered independently to design a better genome engineering toolbox. This review focuses on evaluating CRISPR potential as a next generation in vivo gene therapy platform and discusses bioengineering advancements that can address challenges associated with clinical translation of this emerging technology. PMID- 28558199 TI - Global Kinetic Mechanism of Microsomal Glutathione Transferase 1 and Insights into Dynamic Enzyme Activation. AB - Microsomal glutathione transferase 1 (MGST1) has a unique ability to be activated, <=30-fold, by modification with sulfhydryl reagents. MGST1 exhibits one-third-of-the-sites reactivity toward glutathione and hence heterogeneous binding to different active sites in the homotrimer. Limited turnover stopped flow kinetic measurements of the activated enzyme allowed us to more accurately determine the KD for the "third" low-affinity GSH binding site (1.4 +/- 0.3 mM). The rate of thiolate formation, k2 (0.77 +/- 0.06 s-1), relevant to turnover, could also be determined. By deriving the steady-state rate equation for a random sequential mechanism for MGST1, we can predict KM, kcat, and kcat/KM values from these and previously determined pre-steady-state rate constants (all determined at 5 degrees C). To assess whether the pre-steady-state behavior can account for the steady-state kinetic behavior, we have determined experimental values for kinetic parameters at 5 degrees C. For reactive substrates and the activated enzyme, data for the microscopic steps account for the global mechanism of MGST1. For the unactivated enzyme and more reactive electrophilic substrates, pre-steady state and steady-state data can be reconciled only if a more active subpopulation of MGST1 is assumed. We suggest that unactivated MGST1 can be partially activated in its unmodified form. The existence of an activated subpopulation (approximately 10%) could be demonstrated in limited turnover experiments. We therefore suggest that MSGT1 displays a preexisting dynamic equilibrium between high- and low-activity forms. PMID- 28558200 TI - Multiplexed Lipid Bilayers on Silica Microspheres for Analytical Screening Applications. AB - Most druggable targets are membrane components, including membrane proteins and soluble proteins that interact with ligands or receptors embedded in membranes. Current target-based screening and intermolecular interaction assays generally do not include the lipid membrane environment in presenting these targets, possibly altering their native structure and leading to misleading or incorrect results. To address this issue, an ideal assay involving membrane components would (1) mimic the natural membrane environment, (2) be amenable to high-throughput implementation, and (3) be easily multiplexed. In a step toward developing such an ideal target-based analytical assay for membrane components, we present fluorescently indexed multiplexed biomimetic membrane assays amenable to high throughput flow cytometric detection. We build fluorescently multiplexed biomimetic membrane assays by using varying amounts of a fluorescently labeled lipid, NBD-DOPE [1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(7-nitro-2-1,3 benzoxadiazol-4-yl)], incorporated into a phospholipid membrane bilayer supported on 3 MUm silica microspheres. Using flow cytometry, we demonstrate this multiplexed approach by measuring specific affinity of two well-characterized systems, the fluorescently labeled soluble proteins cholera toxin B subunit-Alexa 647 and streptavidin-PE/Cy5, to membranes containing different amounts of ligand targets of these proteins, GM1 and biotin-DOPE, respectively. This work will enable future efforts in developing highly efficient biomimetic assays for interaction analysis and drug screening involving membrane components. PMID- 28558201 TI - Geochemical Interactions of Plutonium with Opalinus Clay Studied by Spatially Resolved Synchrotron Radiation Techniques. AB - Plutonium plays an important role within nuclear waste materials because of its long half-life and high radiotoxicity. The aim of this study was to investigate with high spatial resolution the reactivity of the more oxidized forms of Pu(V,VI) within Opalinus Clay (OPA) rock, a heterogeneous, natural argillaceous rock considered as a potential repository host. A combination of synchrotron based X-ray microprobe and bulk techniques was used to study the spatial distribution and molecular speciation of Pu within OPA after diffusion and sorption processes. Microscopic chemical images revealed a pronounced impact of geochemical heterogeneities concerning the reactivity of the natural barrier material. Spatially resolved X-ray absorption spectroscopy documented a reduction of the highly soluble Pu(V,VI) to the less mobile Pu(IV) within the argillaceous rock material, while bulk investigations showed second-shell scattering contributions, indicating an inner-sphere sorption of Pu on OPA components. Microdiffraction imaging identified the clay mineral kaolinite to play a key role in the immobilization of the reduced Pu. The findings provide strong evidence that reduction and immobilization do not occur as linked processes on a single reactive phase but as decoupled, subsequent, and spatially separated reactions involving different phases of the OPA. PMID- 28558202 TI - Effect of MultiSubstitution on the Thermoelectric Performance of the Ca11 xYbxSb10-yGez (0 <= x <= 9; 0 <= y <= 3; 0 <= z <= 3) System: Experimental and Theoretical Studies. AB - The Zintl phase solid-solution Ca11-xYbxSb10-yGez (0 <= x <= 9; 0 <= y <= 3; 0 <= z <= 3) system with the cationic/anionic multisubstitution has been synthesized by molten Sn metal flux and arc-melting methods. The crystal structure of the nine title compounds were characterized by both powder and single-crystal X-ray diffractions and adopted the Ho11Ge10-type structure with the tetragonal space group I4/mmm (Z = 4, Pearson Code tI84). The overall isotypic structure of the nine title compounds can be illustrated as an assembly of three different types of cationic polyhedra sharing faces with their neighboring polyhedra and the three-dimensional cage-shaped anionic frameworks consisting of the dumbbell shaped Sb2 units and the square-shaped Sb4 or (Sb/Ge)4 units. During the multisubstitution trials, interestingly, we observed a metal-to-semiconductor transition as the Ca and Ge contents increased in the title system from Yb11Sb10 to Ca9Yb2Sb7Ge3 (nominal compositions) on the basis of a series of thermoelectric property measurements. This phenomenon can be elucidated by the suppression of a bipolar conduction of holes and electrons via an extra hole-carrier doping. The tight-binding linear muffin-tin orbital calculations using four hypothetical structural models nicely proved that the size of a pseudogap and the magnitude of the density of states at the Fermi level are significantly influenced by substituting elements as well as their atomic sites in a unit cell. The observed particular cationic/anionic site preferences, the historically known abnormalities of atomic displacement parameters, and the occupation deficiencies of particular atomic sites are further rationalized by the QVAL value criterion on the basis of the theoretical calculations. The results of SEM, EDS, and TGA analyses are also provided. PMID- 28558203 TI - beta-Cyclodextrin Polymer Network Sequesters Perfluorooctanoic Acid at Environmentally Relevant Concentrations. AB - Per- and poly fluorinated alkyl substances (PFASs), notably perfluorooctanoic acid (PFOA), contaminate many ground and surface waters and are environmentally persistent. The performance limitations of existing remediation methods motivate efforts to develop effective adsorbents. Here we report a beta-cyclodextrin (beta CD)-based polymer network with higher affinity for PFOA compared to powdered activated carbon, along with comparable capacity and kinetics. The beta-CD polymer reduces PFOA concentrations from 1 MUg L-1 to <10 ng L-1, at least 7 times lower than the 2016 U.S. EPA advisory level (70 ng L-1), and was regenerated and reused multiple times by washing with MeOH. The performance of the polymer is unaffected by humic acid, a component of natural organic matter that fouls activated carbons. These results are promising for treating PFOA contaminated water and demonstrate the versatility of beta-CD-based adsorbents. PMID- 28558204 TI - Development and Application of Synthetic Affinity Ligands for the Purification of Ferritin-Based Influenza Antigens. AB - A recently developed novel recombinant influenza antigen vaccine has shown great success in preclinical studies in ferrets and mice. It provides broader protection, and is efficient to manufacture compared to the conventional trivalent influenza vaccines (TIV). Each strain of the recombinant antigen has a constant self-assembled bacterial ferritin core which, if used as a target for affinity chromatography, could lead to a universal purification method. Ferritin in silico models were used to explore potential target binding sites against ligands synthesized by the four-component Ugi reaction. Two ligands, SJ047 and SJ055, were synthesized in solution, characterized by 1H, 13C, and 2D NMR spectroscopy, and subsequently immobilized on the PEG-functionalized beads. Ligands SJ047 and SJ055 displayed apparent Kd values of 2.04 * 10-7 M and 1.91 * 10-8 M, respectively, against the ferritin. SJ047 and SJ055-functionalized resins were able to purify hemagglutinin (New Caledonia)-ferritin expressed in a crude Human Embryonic Kidney (HEK) cell supernatant in a single step to a purity of 85 +/- 0.5% (97 +/- 1% yield) and 87.5 +/- 0.5% (95.5 +/- 1.5% yield), respectively. Additionally, SJ047 and SJ055-functionalized resins purified the recombinant antigens when spiked at known concentrations into HEK supernatants. All three strains, hemagglutinin (New Caledonia)-ferritin, hemagglutinin (California) ferritin, and hemagglutinin (Singapore)-ferritin were purified, thereby offering an ideal alternate platform for affinity chromatography. Following elution from the affinity adsorbents, absorbance at 350 nm showed that there was no aggregation of the recombinant antigens and dynamic light scattering studies further confirmed the structural integrity of the recombinant antigen. The use of Ugi ligands coupled to a PEG-spacer arm to target the ferritin core of the strain is entirely novel and provides an efficient purification of these recombinant antigens. This approach represents a potentially universal method to purify any ferritin-based vaccine. PMID- 28558205 TI - Ruthenium-Catalyzed Urea Synthesis by N-H Activation of Amines. AB - Activation of the N-H bond of amines by a ruthenium pincer complex operating via "amine-amide" metal-ligand cooperation is demonstrated. Catalytic formyl C-H activation of N,N-dimethylformamide (DMF) is observed in situ, which resulted in the formation of CO and dimethylamine. The scope of this new mode of bond activation is extended to the synthesis of urea derivatives from amines using DMF as a carbon monoxide (CO) surrogate. This catalytic protocol allows the synthesis of simple and functionalized urea derivatives with liberation of hydrogen, devoid of any stoichiometric activating reagents, and avoids the direct use of fatal CO. The catalytic carbonylation occurred at low temperature to provide the formamide; a formamide intermediate was isolated. The consecutive addition of different amines provided unsymmetrical urea compounds. The reactions are proposed to proceed via N-H activation of amines followed by CO insertion from DMF and with liberation of dihydrogen. PMID- 28558206 TI - Inhibition Potential of Cycloartane-Type Glycosides from the Roots of Cimicifuga dahurica against Soluble Epoxide Hydrolase. AB - A phytochemical assay-guided fractionation of the 95% ethanol extract of Cimicifuga dahurica roots afforded 29 9,19-cycloartane triterpenoid glycosides, including the new cimiricasides A-F (1-6). The structures of 1-6 were established using contemporary NMR methods and from the HRESIMS data, and the sugar moiety in each case was confirmed by acid hydrolysis and subsequent GC/MS analysis. Compounds 2, 4, 5, 7-9, 18, 25, and 29 showed soluble epoxide hydrolase inhibitory effects with IC50 values of 0.4 +/- 0.1 to 24.0 +/- 0.2 MUM. The compounds were analyzed by enzyme kinetic studies to explore the binding mode between the ligand and receptor. Compounds 4 (mixed type), 8, 18, and 29 (noncompetitive type) bound to a preferred allosteric site, while compounds 2, 5, 7, 9, and 25 had competitive interactions at the active site. The binding mechanism of selected inhibitors was investigated using molecular docking and dynamics simulations. PMID- 28558207 TI - Structure and Stability of a Copper(II) Lactate Complex in Alkaline Solution: a Case Study by Energy-Dispersive X-ray Absorption Spectroscopy. AB - Energy-dispersive X-ray absorption spectroscopy was applied, aimed at solving the problem of the structure and stability of a copper(II) lactate complex in alkaline solution, used as a precursor for the electrodeposition of Cu2O. The application of multiple scattering calculations to the simulation of the X-ray absorption near-edge structure part of the spectra allowed an accurate resolution of the structure: the copper(II) cation is surrounded by four lactate ions in a distorted tetrahedral environment, with the lactate anions acting as monodentate ligands. This results in an atomic arrangement where copper is surrounded by four oxygen atoms located at quite a short distance (ca. 1.87 A) and four oxygen atoms located quite far apart (ca. 3.1-3.2 A). The complex was finally found to be stable in a wide range of applied potentials. PMID- 28558208 TI - Design and Characterization of DNA Strand-Displacement Circuits in Serum Supplemented Cell Medium. AB - The functional stability and lifetimes of synthetic molecular circuits in biological environments are important for long-term, stable sensors or controllers of cell or tissue behavior. DNA-based molecular circuits, in particular DNA strand-displacement circuits, provide simple and effective biocompatible control mechanisms and sensors, but are vulnerable to digestion by nucleases present in living tissues and serum-supplemented cell culture. The stability of double-stranded and single-stranded DNA circuit components in serum supplemented cell medium and the corresponding effect of nuclease-mediated degradation on circuit performance were characterized to determine the major routes of degradation and DNA strand-displacement circuit failure. Simple circuit design choices, such as the use of 5' toeholds within the DNA complexes used as reactants in the strand-displacement reactions and the termination of single stranded components with DNA hairpin domains at the 3' termini, significantly increase the functional lifetime of the circuit components in the presence of nucleases. Simulations of multireaction circuits, guided by the experimentally measured operation of single-reaction circuits, enable predictive realization of multilayer and competitive-reaction circuit behavior. Together, these results provide a basic route to increased DNA circuit stability in cell culture environments. PMID- 28558209 TI - Aminopolymer Mobility and Support Interactions in Silica-PEI Composites for CO2 Capture Applications: A Quasielastic Neutron Scattering Study. AB - Composite gas sorbents, formed from an active polymer phase and a porous support, are promising materials for the separation of acid gases from a variety of gas streams. Significant changes in sorption performance (capacity, rate, stability etc.) can be achieved by tuning the properties of the polymer and the nature of interactions between polymer and support. Here we utilize quasielastic neutron scattering (QENS) and coarse-grained molecular dynamics (MD) simulations to characterize the dynamic behavior of the most commonly reported polymer in such materials, poly(ethylenimine) (PEI), both in bulk form and when supported in a mesoporous silica framework. The polymer chain dynamics (rotational and translational diffusion) are characterized using two neutron backscattering spectrometers that have overlapping time scales, ranging from picoseconds to a few nanoseconds. Two modes of motion are detected for the PEI molecule in QENS. At low energy transfers, a "slow process" on the time scale of ~200 ps is found and attributed to jump-mediated, center-of-mass diffusion. A second, "fast process" at ~20 ps scale is also found and is attributed to a locally confined, jump-diffusion. Characteristic data (time scale and spectral weight) of these processes are compared to those characterized by MD, and reasonable agreement is found. For the nanopore-confined PEI, we observe a significant reduction in the time scale of polymer motion as compared to the bulk. The impacts of silica surface functionalization and of polymer fill fraction in the silica pores (controlling the portion of polymer molecules in contact with the pore walls), are both studied in detail. Hydrophobic functionalization of the silica leads to an increase of the PEI mobility above that in native silanol-terminated silica, but the dynamics are still slower than those in bulk PEI. Sorbents with faster PEI dynamics are also found to be more efficient for CO2 capture, possibly because sorption sites are more accessible than those in systems with slower PEI dynamics. Thus, this work supports the existence of a link between the affinity of the support for PEI and the accessibility of active sorbent functional groups. PMID- 28558210 TI - Excited-State Dynamics of 2-(2'-Hydroxyphenyl)benzothiazole: Ultrafast Proton Transfer and Internal Conversion. AB - One of the most widely studied model systems for excited-state proton transfer (ESPT) is the 2-(2'-hydroxyphenyl)benzothiazole (HBT) molecule. This compound undergoes ultrafast ESPT followed by internal conversion to return to the ground state. In the present work, we simulate the nonadiabatic photochemistry of HBT using ab initio multiple spawning (AIMS) nuclear dynamics and a complete active space configuration interaction (CASCI) method in conjunction with wave function in-DFT embedding to obtain ground- and excited-state potential surfaces on-the fly. Our simulation predicts ultrafast ESPT with a time constant of 48-54 fs and an excited-state lifetime of 1.7-1.8 ps. Following proton transfer, HBT becomes trapped in a metastable keto structure on the S1 state. Eventually, the molecule begins to twist and proceeds toward a seam of intersection with the ground state where internal conversion is highly efficient. PMID- 28558211 TI - Coumarin-Appended Stable Fluorescent Self-Complementary Quadruple-Hydrogen-Bonded Molecular Duplexes. AB - In this paper we report a coumarin-conjugated self-assembling system adorned with valuable features such as high duplex stability and a built-in fluorophore, which would augment its application potential. This system forms a highly stable molecular duplex in a nonpolar solvent (Kdim > 1.9 * 107 M-1 in CDCl3). Due to the fluorescent property of coumarin, these new structural motifs may find potential application in material chemistry and supramolecular chemistry. PMID- 28558212 TI - Thermal Decomposition Mechanism for Ethanethiol. AB - The thermal decomposition of ethanethiol was studied using a 1 mm * 2 cm pulsed silicon carbide microtubular reactor, CH3CH2SH + Delta -> Products. Unlike previous studies these experiments were able to identify the initial ethanethiol decomposition products. Ethanethiol was entrained in either an Ar or a He carrier gas, passed through a heated (300-1700 K) SiC microtubular reactor (roughly <=100 MUs residence time) and exited into a vacuum chamber. Within one reactor diameter the gas cools to less than 50 K rotationally, and all reactions cease. The resultant molecular beam was probed by photoionization mass spectroscopy and IR spectroscopy. Ethanethiol was found to undergo unimolecular decomposition by three pathways: CH3CH2SH -> (1) CH3CH2 + SH, (2) CH3 + H2C?S, and (3) H2C?CH2 + H2S. The experimental findings are in good agreement with electronic structure calculations. PMID- 28558213 TI - Phthalocyanines and Tetrapyrazinoporphyrazines with Two Cationic Donuts: High Photodynamic Activity as a Result of Rigid Spatial Arrangement of Peripheral Substituents. AB - High photodynamic activity was observed for hexadeca-cationic zinc, magnesium, and metal-free phthalocyanines (Pcs) and tetrapyrazinoporphyrazines with EC50 values as low as 5 nM (MCF-7 cells) for the best compound; this activity was several times better than that of clinically established photosensitizers verteporfin, temoporfin, S3AlOHPc, or protoporphyrin IX. This lead compound was characterized by low dark toxicity (TC50 = 369 MUM), high efficiency against other cell lines (HCT 116 and HeLa), and possible activation by light above 680 nm. The excellent photodynamic activity resulted from the rigid spatial arrangement of the quaternized triazole moieties above and below the Pc core, as confirmed by X-ray crystallography. The triazole moieties thus formed two "cationic donuts" that protected the hydrophobic core against aggregation in water. The lysosomes were found to be the site of subcellular localization and were consequently the primary targets of photodynamic injury, resulting in predominantly necrotic cell death. PMID- 28558214 TI - Substitution Effects on the Photoinduced Charge-Transfer Properties of Novel Perylene-3,4,9,10-tetracarboxylic Acid Derivatives. AB - We report here the synthesis and photophysical study of a series of electron donor-acceptor molecules, in which electron-donating 4-methoxyphenoxy groups are attached to the 1,7-bay positions of four different perylene tetracarboxylic acid derivatives, namely, perylene tetraesters 1, perylene monoimide diesters 2, perylene bisimides 3, and perylene monobenzimidazole monoimides 4. These perylene derivatives are used because of their increasing order of electron-accepting capability upon moving from 1 to 4. Two additional donor-acceptor molecules are synthesized by linking electron-donating 4-methoxyphenyl groups to the imide position of perylene monoimide diester 2 and perylene bisimide 3. The motivation for this study is to achieve a good control over the photoinduced charge-transfer (CT) process in perylene-based systems by altering the position of electron donors and tuning the electron deficiency of perylene core. A comprehensive study of the photophysical properties of these molecules has shown a highly systematic trend in the magnitude of CT as a function of increased electron deficiency of the perylene core and solvent polarity. Importantly, just by changing the attachment of electron-donating group from "bay" to "imide" position, we are able to block the CT process. This implies that the positioning of the electron donor at the perylene core strongly influences the kinetics of the photoinduced CT process. In these compounds, the CT process is characterized by the quenching of fluorescence and singlet excited-state lifetimes as compared to model compounds bearing non-electron-donating 4-tert-butylphenoxy groups. Transient absorption spectroscopy did not reveal spectra of CT states. This most likely implies that the CT state is not accumulated, because of the faster charge recombination. PMID- 28558215 TI - Effect of Different Silage Storing Conditions on the Oxygen Concentration in the Silo and Fermentation Quality of Rice. AB - We investigated the effects of different silage storing conditions on the oxygen concentration in the silo and fermentation quality of rice (Oryza sativa L.). Forage rice was ensiled in bottles (with or without space at the bottlemouth, with solid or pinhole cap, and with oxygen scavenger, ethanol transpiration agent, oxygen scavenger and ethanol transpiration agent, or no adjuvant) and stored for 57 days. The oxygen concentration decreased with the addition of the oxygen scavenger and increased with that of the ethanol transpiration agent. The oxygen scavenger facilitated silage fermentation and fungus generation, whereas the ethanol transpiration agent suppressed silage fermentation and fungus generation. However, the combined use of the oxygen scavenger and ethanol transpiration agent facilitated silage fermentation and also suppressed fungus generation. Overall, this study revealed the negative effects of oxygen on the internal silo and the positive effects of the combined use of the oxygen scavenger and ethanol transpiration agent on silage fermentation quality. PMID- 28558216 TI - Effect of Substituents on the Bond Strength of Air-Stable Dicyanomethyl Radical Thermochromes. AB - A series of substituted aryl dicyanomethyl radicals were synthesized, and the bonding thermodynamic parameters for self-dimerization were determined from van't Hoff plots obtained from variable-temperature electron paramagnetic resonance and ultraviolet-visible spectroscopy. At low temperatures, the radicals dimerize, but the colored, air-stable free radicals return upon heating. Heating and cooling cycles (5-95 degrees C) can be repeated without radical degradation and with striking thermochromic behavior. We find a linear free energy relationship between the Hammett para substituent parameter and the dimerization equilibrium constant, with para electron-donating substituents leading to a weaker bond and electron-withdrawing substituents leading to stronger bonds, following a captodative effect. Density functional theory investigations [B98D/6-31+G(d,p)] reveal that the dimers prefer a slip-stacked geometry and feature elongated bonds. PMID- 28558217 TI - Probing Co-Assembly of Supramolecular Photocatalysts and Polyelectrolytes Using Isothermal Titration Calorimetry. AB - The creation of renewable fuels to replace dwindling fossil energy resources is one of the greatest challenges facing the scientific community. Generating H2 fuel from water is a carbon-neutral strategy that demonstrates great promise. Photocatalysts of the molecular architecture [{(TL)2Ru(BL)}2RhX2]5+ (BL = bridging ligand, TL = terminal ligand, X = halide) catalyze the formation of H2 in deoxygenated organic solvents but are limited by poor performance in air saturated aqueous solutions. Addition of the water-soluble polyelectrolyte poly(sodium 4-styrenesulfonate) (PSS) was recently shown as being a promising new strategy to increase efficiency and stability of H2 evolving photocatalysts in air-saturated aqueous solutions. Herein we investigate intermolecular interactions between Ru,Rh,Ru photocatalysts and water-soluble polyelectrolytes using isothermal titration calorimetry (ITC). ITC studies provide insight into the thermodynamic forces that drive assembly of PSS-photocatalyst aggregates and give new evidence for the intermolecular forces that lead to increased photocatalytic efficiency. PMID- 28558218 TI - Catalytic Aerobic Chemoselective alpha-Oxidation of Acylpyrazoles en Route to alpha-Hydroxy Acid Derivatives. AB - Catalytic aerobic chemoselective alpha-oxidation of acylpyrazoles is described. Acylpyrazoles, carboxylic acid oxidation state substrates, were efficiently oxidized under aerobic conditions using TEMPO as an oxygenating agent. The mild catalytic conditions of the present catalysis were amenable to late-stage alpha oxidation of various pharmaceutical agents and natural products, leading to previously unreported alpha-hydroxy acid derivatives in short steps. Preliminary mechanistic studies revealed that in situ generated copper(II) peroxo species served as a Lewis acid/Bronsted base cooperative catalyst. PMID- 28558219 TI - Correction to "New Insights into Peptide-Silver Nanoparticle Interaction: Deciphering the Role of Cysteine and Lysine in the Peptide Sequence". PMID- 28558220 TI - Carboxylate Anions Accelerate Pyrrolidinopyridine (PPy)-Catalyzed Acylation: Catalytic Site-Selective Acylation of a Carbohydrate by in Situ Counteranion Exchange. AB - Acylpyridinium ions have been known as catalytically active species in acylation reactions catalyzed by 4-dimethylaminopyridine and its analogues. Acylpyridinium carboxylates were found to be 800-1300 times more reactive than the corresponding acylpyridinium chlorides. A catalytic cycle was developed, in which acylpyridinium carboxylates were generated by in situ counteranion exchange from the acylpyridinium chlorides. A catalyst loading as low as 0.01 mol % and catalyst turnover number of up to 6700 were achieved for site-selective acylation of a carbohydrate. PMID- 28558221 TI - Magnesium Catalysis Mediated Tetrazoles in Desymmetrization Reaction of Aziridines. AB - A magnesium-catalyzed asymmetric ring-opening reaction of aziridines with substituted tetrazoles is reported. The current protocol proceeds smoothly and gives the corresponding desymmetrization products in high yields and good enantioselectivities. A new chiral ligand was synthesized from azetidine and (R) BINOL and was employed in the current in situ generated magnesium catalyst. The Mg(II)-mediated desymmetrization reaction could be performed on gram scale under mild conditions and was transformed to chiral alkyl amines by a deprotection process. PMID- 28558222 TI - Structural Contraction of Zeolitic Imidazolate Frameworks: Membrane Application on Porous Metallic Hollow Fibers for Gas Separation. AB - Positive thermal expansion coefficients (TECs) of 52 * 10-6 and 35 * 10-6 K-1 were experimentally calculated in the -116 to 250 degrees C range for the III phases of zeolitic imidazolate frameworks (ZIF) ZIF-9(Co) and ZIF-7(Zn), respectively, by means of the unit cell dimensions and volume of the materials in the monoclinic crystal system calculated from the XRD patterns. The unit cell dimensions and volume showed a significant expansion phenomenon as the temperature increased, by as much as 5.5% for ZIF-9-III in the studied range. To exploit the advantages of such thermal behavior, a new approach to the fabrication of ZIF-9-III membranes on thin, flexible, and highly porous nickel hollow fiber (Ni HF) supports by a versatile and easy-controllable microfluidic setup is herein reported. These Ni HF supports result from the sintering of 25 MUm Ni particles and display very positive mechanical properties and bending resistance. As compared to the traditional polymer-based HF membranes, the ZIF metal-supported membrane exhibited good durability and robustness throughout its operation in a wide temperature range and after heating and cooling cycles. These benefits derive from (1) the pore-plugging membrane configuration resulting from the high porosity of the support and (2) the similarity between the TECs of the ZIF and the metallic support, both positive, which enhances their mutual compatibility. An increase in the H2/CO2 separation selectivity at low temperatures (as high as 22.2 at -10 degrees C, along with 102 GPU permeance of H2) was achieved, in agreement with the structural variations observed in the ZIF material. PMID- 28558223 TI - Engineered Assimilation of Exogenous and Endogenous Formate in Escherichia coli. AB - Decoupling biorefineries from land use and agriculture is a major challenge. As formate can be produced from various sources, e.g., electrochemical reduction of CO2, microbial formate-assimilation has the potential to become a sustainable feedstock for the bioindustry. However, organisms that naturally grow on formate are limited by either a low biomass yield or by a narrow product spectrum. The engineering of a model biotechnological microbe for growth on formate via synthetic pathways represents a promising approach to tackle this challenge. Here, we achieve a critical milestone for two such synthetic formate-assimilation pathways in Escherichia coli. Our engineering strategy involves the division of the pathways into metabolic modules; the activity of each module-providing at least one essential building block-is selected for in an appropriate auxotrophic strain. We demonstrate that formate can serve as a sole source of all cellular C1 compounds, including the beta-carbon of serine. We further show that by overexpressing the native threonine cleavage enzymes, the entire cellular glycine requirement can be provided by threonine biosynthesis and degradation. Together, we confirm the simultaneous activity of all pathway segments of the synthetic serine-threonine cycle. We go beyond the formate bioeconomy concept by showing that, under anaerobic conditions, formate produced endogenously by pyruvate formate-lyase can replace exogenous formate. The resulting prototrophic strain constitutes a substantial rewiring of central metabolism in which C1, glycine, and serine metabolism proceed via a unique set of pathways. This strain can serve as a platform for future metabolic-engineering efforts and could further pave the way for investigating the plasticity of metabolic networks. PMID- 28558224 TI - Designed Tetrapeptide Interacts with Tubulin and Microtubule. AB - Microtubules regulate eukaryotic cell functions, which have tremendous implication in tumor progression. Thus, the design of novel approaches for controlling microtubule function is extremely important. In this manuscript, a novel tetrapeptide Ser-Leu-Arg-Pro (SLRP) has been designed and synthesized from a small peptide library consisting of 14 tetrapeptides, which perturbs microtubule function through interaction in the "anchor region". We have studied the role of peptides on microtubule function on a chemically functionalized 2D platform. Interestingly, we have found that SLRP binds with tubulin and inhibits the kinesin-driven microtubule motility on a kinesin-immobilized chemically functionalized 2D platform. Further, this peptide modulator interacts with intracellular tubulin/microtubule and depolymerizes the microtubule networks. These interesting findings of perturbation of microtubule function both on engineered platforms and inside the cell by this small peptide modulator inspired us to study the effect of this tetrapeptide on cancer cell proliferation. We found that the novel tetrapeptide modulator causes moderate cytotoxicity to the human breast cancer cell (MCF-7 cell), induces the apoptotic death of MCF-7 cell, and activates the tumor suppressor proteins p53 and cyclin-dependent kinase inhibitor 1 (p21). To the best of our knowledge, this is the shortest peptide discovered, which perturbs microtubule function both on an engineered 2D platform and inside the cell. PMID- 28558225 TI - Can CF3-Functionalized La@C60 Be Isolated Experimentally and Become Superconducting? AB - Superconducting behavior even under harsh ambient conditions is expected to occur in La@C60 if it could be isolated from the primary metallofullerene soot when functionalized by CF3 radicals. We use ab initio density functional theory calculations to compare the stability and electronic structure of C60 and the La@C60 endohedral metallofullerene to their counterparts functionalized by CF3. We found that CF3 radicals favor binding to C60 and La@C60 and have identified the most stable isomers. Structures with an even number m of radicals are energetically preferred for C60 and structures with odd m for La@C60 due to the extra charge on the fullerene. This is consistent with a wide HOMO-LUMO gap in La@C60(CF3)m with odd m, causing extra stabilization in the closed-shell electronic configuration. CF3 radicals are both stabilizing agents and molecular separators in a metallic crystal, which could increase the critical temperature for superconductivity. PMID- 28558226 TI - Boosting Biexciton Collection Efficiency at Quantum Dot-Oxide Interfaces by Hole Localization at the Quantum Dot Shell. AB - Harvesting multiexcitons from semiconductor quantum dots (QDs) has been proposed as a path toward photovoltaic efficiencies beyond the Shockley-Queisser limit. Although multiexciton generation efficiencies have been quantified extensively in QD structures, the challenge of actually collecting multiple excitons at electrodes-a prerequisite for high-efficiency solar cell devices-has received less attention. Here, we demonstrate that multiexciton collection (MEC) at the PbS QD/mesoporous SnO2 interface can be boosted 5-fold from ~15 to reach ~80% quantum yield, by partial localization of holes in a QD molecular capping shell. The resulting weakened Coulombic interactions give rise to reduced Auger recombination rates within the molecularly capped QDs, so that biexciton Auger relaxation, competing with MEC, is strongly suppressed. These results not only highlight the importance of surface chemistry and energetics at QD/ligand interfaces for multiexciton extraction but also provide clear design principles for realizing the benefits of MEG in sensitized systems exploited in solar cells and fuel geometries. PMID- 28558227 TI - Imidazolium Ionic Liquid Mediates Black Phosphorus Exfoliation while Preventing Phosphorene Decomposition. AB - Forthcoming applications in electronics and optoelectronics make phosphorene a subject of vigorous research efforts. Solvent-assisted exfoliation of phosphorene promises affordable delivery in industrial quantities for future applications. We demonstrate, using equilibrium, steered and umbrella sampling molecular dynamics, that the 1-ethyl-3-methylimidazolium tetrafluoroborate [EMIM][BF4] ionic liquid is an excellent solvent for phosphorene exfoliation. The presence of both hydrophobic and hydrophilic moieties, as well as substantial shear viscosity, allows [EMIM][BF4] simultaneously to facilitate separation of phosphorene sheets and to protect them from getting in direct contact with moisture and oxygen. The exfoliation thermodynamics is moderately unfavorable, which indicates that an external stimulus is necessary. Unexpectedly, [EMIM][BF4] does not coordinates phosphorene by pi-electron stacking with the imidazole ring. Instead, the solvation proceeds via hydrophobic side chains, while polar imidazole rings form an electrostatically stabilized protective layer. The simulations suggest that further efforts in solvent engineering for phosphorene exfoliation should concentrate on use of weakly coordinating ions and grafting groups that promote stronger dispersion interactions and on elongation of nonpolar chains. PMID- 28558228 TI - Switchable Complexation between (O-Methyl)6-2,6-helic[6]arene and Protonated Pyridinium Salts Controlled by Acid/Base and Photoacid. AB - Complexation between (O-methyl)6-2,6-helic[6]arene and protonated pyridinium salts was investigated by 1H NMR, ESI-MS, and calculations. It was found that the host and the tested guests could form stable complexes and the binding and release process of the guests in the complexes could be reversibly controlled by acid-base stimulus. Notably, the switchable complexation could also be efficiently controlled by light stimulus in the presence of protonated merocyanine 1-MEH. PMID- 28558229 TI - Catalytic Dyad in the SGNH Hydrolase Superfamily: In-depth Insight into Structural Parameters Tuning the Catalytic Process of Extracellular Lipase from Streptomyces rimosus. AB - SrLip is an extracellular enzyme from Streptomyces rimosus (Q93MW7) exhibiting lipase, phospholipase, esterase, thioesterase, and tweenase activities. The structure of SrLip is one of a very few lipases, among the 3D-structures of the SGNH superfamily of hydrolases, structurally characterized by synchrotron diffraction data at 1.75 A resolution (PDB: 5MAL ). Its crystal structure was determined by molecular replacement using a homology model based on the crystal structure of phospholipase A1 from Streptomyces albidoflavus (PDB: 4HYQ ). The structure reveals the Rossmann-like 3-layer alphabetaalpha sandwich fold typical of the SGNH superfamily stabilized by three disulfide bonds. The active site shows a catalytic dyad involving Ser10 and His216 with Ser10 OgammaH...NepsilonHis216, His216-NdeltaH...O?C-Ser214, and Gly54-NH...Ogamma Ser10 hydrogen bonds essential for the catalysis; the carbonyl oxygen of the Ser214 main chain acts as a hydrogen bond acceptor ensuring the orientation of the His216 imidazole ring suitable for a proton transfer. Molecular dynamics simulations of the apoenzyme and its complex with p-nitrophenyl caprylate were used to probe the positioning of the substrate ester group within the active site and its aliphatic chain within the binding site. Quantum-mechanical calculations at the DFT level revealed the precise molecular mechanism of the SrLip catalytic activity, demonstrating that the overall hydrolysis is a two-step process with acylation as the rate-limiting step associated with the activation free energy of DeltaG?ENZ = 17.9 kcal mol-1, being in reasonable agreement with the experimental value of 14.5 kcal mol-1, thus providing strong support in favor of the proposed catalytic mechanism based on a dyad. PMID- 28558230 TI - Synthesis, Characterization, and Reactivity of Thermally Stable Anhydrous Quaternary Ammonium Fluorides. AB - The synthesis and properties of a new class of anhydrous quaternary ammonium fluorides, based on the rigid skeleton azabicyclo[2.2.2]octane, is described. Compounds 2a-d were easily prepared by passing the corresponding ammonium iodides over fluoride-based resin followed by drying their hydrated form at 100 or 140 degrees C under reduced pressure. The stability (experimental and theoretical study), solubility, reactivity, and characterization by solution and solid-state MAS NMR are discussed. PMID- 28558232 TI - Transparent Carbon Ultramicroelectrode Arrays for the Electrochemical Detection of a Bacterial Warfare Toxin, Pyocyanin. AB - Pyocyanin is a virulence factor produced as a secondary metabolite by the opportunistic human pathogen, Pseudomonas aeruginosa. Fast and direct detection of pyocyanin is of importance as it could provide important insights regarding P. aeruginosa's virulence mechanisms. Here, we present an electrochemical sensing platform of redox-active pyocyanin using transparent carbon ultramicroelectrode arrays (T-CUAs), which were made using a previously reported simple fabrication process ( Duay et al. Anal. Chem. 2015 , 87 , 10109 ). Square-wave voltammetry was used to quantify pyocyanin concentrations on T-CUAs with and without chitosan gold nanoparticles (CS/GNP) and planar transparent macroelectrodes (T-Macro). The response time (RT), limit of detection (LOD), and linear dynamic range (LDR) differ for each electrode type due to subtle influences in how the detectable signal varies in relation to the charging time and resistive and capacitive noise. In general lower LODs can be achieved at the consequence of smaller LDRs. The LOD for T-Macro was 0.75 +/- 0.09 MUM with a LDR of 0.75-25 MUM, and the LOD for the CS/GNP 1.54 T-CUA was determined to be 1.6 +/- 0.2 MUM with a LDR of 1 100 MUM, respectively. The LOD for the 1.54T-CUA with a larger LDR of 1-250 MUM was 1.0 +/- 0.3 MUM. These LODs and LDRs fall within the range of PYO concentrations for a variety of in vitro and in vivo cellular environments and offer promise of the application of T-CUAs for the quantitative study of biotoxins, quorum sensing, and pathogenesis. Finally, we demonstrate the successful use of T-CUAs for the electrochemical detection of pyocyanin secreted from P. aeruginosa strains while optically imaging the cells. The secreted pyocyanin levels from two bacterial strains, PA11 and PA14, were measured to have concentrations of 45 +/- 5 and 3 +/- 2 MUM, respectively. PMID- 28558233 TI - Cationic Copper Hydride Clusters Arising from Oxidation of (Ph3P)6Cu6H6. AB - Transfer of the first electron from (Ph3P)6Cu6H6 to Cp*2Fe+ is fast (k > 106 L.mol-1.s-1). Transfer of a second electron to the same oxidant has a much lower thermodynamic driving force and is considerably slower, with k = 9.29(4) * 103 L.mol-1.s-1. The second oxidation leads to the formation of [(Ph3P)6Cu6H5]+. The structure of [(Ph3P)6Cu6H5]+ has been confirmed by its conversion back to (Ph3P)6Cu6H6 and by microanalysis; X-ray diffraction shows that the complex is a bitetrahedron in the solid state. [(Ph3P)6Cu6H5]+ can also be prepared by treating (Ph3P)6Cu6H6 with MeOTf. With less than 1 equiv of Cp*2Fe+ as oxidant, (Ph3P)6Cu6H6 gives [(Ph3P)7Cu7H6]+ as the major product; X-ray diffraction shows a Cu6 octahedron with one face capped by an additional Cu. [(Ph3P)7Cu7H6]+ can also be prepared by treating (Ph3P)6Cu6H6 with [Cu(CH3CN)4]+ (along with 1 equiv of Ph3P), and can be converted back to (Ph3P)6Cu6H6 with base/H2. PMID- 28558234 TI - Sulfur-Driven Iron Reduction Coupled to Anaerobic Ammonium Oxidation. AB - A new biogeochemical pathway has been suggested to be present in terrestrial ecosystems, linking the nitrogen and iron cycles via ferric iron reduction coupled to anaerobic ammonium oxidation. However, the underlying microbiological process has not been demonstrated to date. Here we report a stable consortium, HJ 4, composed of Anaerospora hongkongensis (85%) and facultative anaerobe, Comamonadaceae (15%), which can process ferrihydrite reduction coupled to anaerobic ammonium oxidation driven by sulfur redox cycling. In this process, A. hongkongensis reduces elemental sulfur, sulfite, and polysulfides to sulfide, which fuels ferrihydrite reduction. Sulfide, elemental sulfur, sulfite, and polysulfides serve as electron shuttles, completing the sulfur cycle between A. hongkongensis and ferrihydrite. In addition, Comamonadaceae shows ammonium oxidation potential under aerobic conditions, with nitrite as the main product. We inferred that Comamonadaceae mediates simultaneous nitrification denitrification coupled to iron redox cycling through nitrate/nitrite-dependent ferrous oxidation under anaerobic conditions. Hence, we discovered a novel pathway for ferric iron reduction coupled to ammonium oxidation, highlighting the key role of electron shuttles and nitrate/nitrite-dependent ferrous oxidation in this process. The biogeochemical cycling of sulfur, iron, and nitrogen could be coupled in aquatic and terrestrial ecosystems. PMID- 28558235 TI - Tissue Uptake, Distribution, and Elimination of Perfluoroalkyl Substances in Juvenile Perch through Perfluorooctane Sulfonamidoethanol Based Phosphate Diester Dietary Exposure. AB - Perfluorooctane sulfonamidoethanol based phosphate diester (SAmPAP) is a potential perfluorooctanesulfonate (PFOS) precursor. To examine whether SAmPAP exposure would result in fish contamination by perfluoroalkyl and polyfluoroalkyl substances (PFASs), juvenile Eurasian perch were dietarily exposed to this compound (dosed group) or exposed to the same tank water but fed control feed (control group). SAmPAP and metabolites were monitored in the muscle, liver, and serum during the 45-day exposure phase and 35-day depuration phase. SAmPAP was only detected in the dosed group and the absorption efficiency (0.04-2.25%) was very low, possibly related to its low bioavailability in the gastrointestinal tract, steric constraints in crossing biological membranes, and clearing by enterohepatic circulation. Although SAmPAP was biotransformed and eliminated at a slow rate (t1/2 > 18 days), its biomagnification factor was low. The observed metabolites in fish were N-ethyl perfluorooctane sulfonamidoacetic acid, perfluorooctane sulfonamidoacetic acid, perfluorooctane sulfonamide, and PFOS. Considering that SAmPAP was the only source of PFASs in the tanks, the occurrence of metabolites indicates that SAmPAP could be biotransformed in fish and contribute to PFOS bioaccumulation. However, levels of metabolites were not significantly different in the dosed and control groups, indicating that metabolite excretion followed by re-exposure to these metabolites from water was the main uptake route. PMID- 28558237 TI - Meeting Proceedings, 2017 Cornell University Baker Symposium-Quo Vadis: The Boundless Trajectories of Chemical Biology. PMID- 28558238 TI - Analysis of the Magnetic Exchange Interactions in Yttrium(III) Complexes Containing Nitronyl Nitroxide Radicals. AB - We report a combined theoretical and experimental investigation of the exchange interactions governing the magnetic behavior of a series of nitronyl nitroxide (NIT)-based Y(III) complexes, i.e., Y(hfac)3(NIT-R)2 with R = PhOPh (1), PhOEt (2), and PhOMe (3a, 3b). Even though some of these complexes or their Dy(III) parents were previously described in the literature [ Zhao et al. Transition Met. Chem. 2006 , 31 , 593 ; Bernot et al. J. Am. Chem. Soc. 2009 , 131 , 5573 ], their synthesis procedure as well as their structural and magnetic properties were completely reconsidered. Depending on the nature of R and the crystallization conditions, Y(hfac)3(NIT-R)2 units can be organized as supramolecular dimers or linear or orthogonal chains. Such structural diversity within the series induces extremely different magnetic behaviors. The observed behaviors are rationalized by state-of-the-art wave function-based quantum chemical approaches (CASSCF/DDCI) that demonstrate the existence of not only effective intramolecular interactions between the NIT-R radical ligands of an isolated Y(hfac)3(NIT-R)2 molecule but also intermolecular interactions between NIT-R moieties belonging to different Y(hfac)3(NIT-R)2 units. These results are supported by the use of spin Hamiltonian models going beyond the basic Bleaney Bowers formalism to properly fit the experimental magnetic data. Finally, the microscopic mechanisms behind the evidenced intramolecular exchange interactions are elucidated through the inspection of the calculated wave functions. In particular, whereas the role of Y orbitals was already proposed, we herein demonstrate the contribution of the hfac- ancillary ligands in mediating the magnetic interactions between the NIT radicals. PMID- 28558231 TI - X-ray Scattering Studies of Protein Structural Dynamics. AB - X-ray scattering is uniquely suited to the study of disordered systems and thus has the potential to provide insight into dynamic processes where diffraction methods fail. In particular, while X-ray crystallography has been a staple of structural biology for more than half a century and will continue to remain so, a major limitation of this technique has been the lack of dynamic information. Solution X-ray scattering has become an invaluable tool in structural and mechanistic studies of biological macromolecules where large conformational changes are involved. Such systems include allosteric enzymes that play key roles in directing metabolic fluxes of biochemical pathways, as well as large, assembly line type enzymes that synthesize secondary metabolites with pharmaceutical applications. Furthermore, crystallography has the potential to provide information on protein dynamics via the diffuse scattering patterns that are overlaid with Bragg diffraction. Historically, these patterns have been very difficult to interpret, but recent advances in X-ray detection have led to a renewed interest in diffuse scattering analysis as a way to probe correlated motions. Here, we will review X-ray scattering theory and highlight recent advances in scattering-based investigations of protein solutions and crystals, with a particular focus on complex enzymes. PMID- 28558236 TI - Identification of a Conserved Histidine As Being Critical for the Catalytic Mechanism and Functional Switching of the Multifunctional Proline Utilization A Protein. AB - Proline utilization A from Escherichia coli (EcPutA) is a multifunctional flavoenzyme that oxidizes proline to glutamate through proline dehydrogenase (PRODH) and Delta1-pyrroline-5-carboxylate dehydrogenase (P5CDH) activities, while also switching roles as a DNA-bound transcriptional repressor and a membrane-bound catabolic enzyme. This phenomenon, termed functional switching, occurs through a redox-mediated mechanism in which flavin reduction triggers a conformational change that increases EcPutA membrane binding affinity. Structural studies have shown that reduction of the FAD cofactor causes the ribityl moiety to undergo a crankshaft motion, indicating that the orientation of the ribityl chain is a key element of PutA functional switching. Here, we test the role of a conserved histidine that bridges from the FAD pyrophosphate to the backbone amide of a conserved leucine residue in the PRODH active site. An EcPutA mutant (H487A) was characterized by steady-state and rapid-reaction kinetics, and cell-based reporter gene experiments. The catalytic activity of H487A is severely diminished (>50-fold) with membrane vesicles as the electron acceptor, and H487A exhibits impaired lipid binding and in vivo transcriptional repressor activity. Rapid reaction kinetic experiments demonstrate that H487A is 3-fold slower than wild type EcPutA in a conformational change step following reduction of the FAD cofactor. Furthermore, the reduction potential (Em) of H487A is ~40 mV more positive than that of wild-type EcPutA, and H487A has an attenuated ability to catalyze the reverse PRODH chemical step of reoxidation by P5C. In this process, significant red semiquinone forms in contrast to the same reaction with wild-type EcPutA, in which facile two-electron reoxidation occurs without the formation of a measurable amount of semiquinone. These results indicate that His487 is critically important for the proline/P5C chemical step, conformational change kinetics, and functional switching in EcPutA. PMID- 28558240 TI - Mitsunobu Reaction Using Basic Amines as Pronucleophiles. AB - A novel protocol for extending the scope of the Mitsunobu reaction to include amine nucleophiles to form C-N bonds through the utilization of N-heterocyclic phosphine-butane (NHP-butane) has been developed. Both aliphatic alcohols and benzyl alcohols are suitable substrates for C-N bond construction. Various acidic nucleophiles such as benzoic acids, phenols, thiophenol, and secondary sulfonamide also provide the desired products of esters, ethers, thioether, and tertiary sulfonamide with 43-93% yields. Importantly, C-N bond-containing pharmaceuticals, Piribedil and Cinnarizine, have been synthesized in one step from the commercial amines under this Mitsunobu reaction system. PMID- 28558239 TI - L-Pyroglutamic Sulphonamide as Hydrogen-Bonding Organocatalyst: Enantioselective Diels-Alder Cyclization to Construct Carbazolespirooxindoles. AB - Hydrogen-bonding organocatalysts L-pyroglutamic sulphonamides were readily synthesized for the first time by fully exploiting the potentials of L pyroglutamic acid. The newly designed catalyst was successfully applied in catalyzing asymmetric Diels-Alder cyclization of methyleneindolinones with 2 vinyl-1H-indoles to efficiently assemble carbazolespirooxindoles in excellent stereoselectivity (up to 99% ee, >20:1 dr) and yields (up to 99%). Mechanistic studies disclosed that the well-designed hydrogen-bonding modes between L pyroglutamic sulphonamide and substrates were crucial for stereocontrol in the cyclization. PMID- 28558241 TI - Diastereoselectivity of Azido-Ugi Reaction with Secondary Amines. Stereoselective Synthesis of Tetrazole Derivatives. AB - The diastereoselectivity of azido-Ugi reaction with cyclic amines was investigated. It was found that the reaction with alpha-substituted five- to seven-membered cyclic amines proceeds very efficiently to provide high control of diastereoselectivity (<=100% de) under mild conditions. Target tetrazole-derived products were isolated in excellent yields (<=98%). The reaction has a broad scope in terms of its amine, aldehyde, and isocyanide nature. It was found that the diastereoselectivity of the reaction depends on the ring size of the starting cyclic amines. More rigid piperidines provided the highest selectivity of the reaction. Using benzyl isocyanide, the prepared N-benzyl tetrazoles can be deprotected by hydrogenolysis to form the corresponding NH tetrazoles in high yields. PMID- 28558242 TI - Copper-Catalyzed Cross-Dehydrogenative N2-Coupling of NH-1,2,3-Triazoles with N,N -Dialkylamides: N-Amidoalkylation of NH-1,2,3-Triazoles. AB - An efficient copper-catalyzed C-N bond formation by N-H/C-H cross-dehydrogenative coupling (CDC) between NH-1,2,3-triazoles and N,N-dialkylamides has been developed. The method provided N-amidoalkylated 1,2,3-triazoles with moderate to high yields, and the reactions showed high N2-selectivities when 4,5 disubstituted NH-1,2,3-triazoles served as the substrates. PMID- 28558243 TI - Ion Transport Mechanisms in Liquid-Liquid Interface. AB - Interfacial liquid-liquid ion transport is of crucial importance to biotechnology and industrial separation processes including nuclear elements and rare earths. A water-in-oil microemulsion is formulated here with density and dimensions amenable to atomistic molecular dynamics simulation, facilitating convergent theoretical and experimental approaches to elucidate interfacial ion transport mechanisms. Lutetium(III) cations are transported from the 5 nm diameter water pools into the surrounding oil using an extractant (a lipophilic ligand). Changes in ion coordination sphere and interactions between the interfacial components are studied using a combination of synchrotron X-ray scattering, spectroscopy, and atomistic molecular dynamics simulations. Contrary to existing hypotheses, our model system shows no evidence of interfacial extractant monolayers, but rather ions are exchanged through water channels that penetrate the surfactant monolayer and connect to the oil-based extractant. Our results highlight the dynamic nature of the oil-water interface and show that lipophilic ion shuttles need not form flat monolayer structures to facilitate ion transport across the liquid-liquid interface. PMID- 28558244 TI - Rhodium(III)-Catalyzed Annulation of Pyridinones with Alkynes via Double C-H Activation: A Route to Functionalized Quinolizinones. AB - A Rh(III)-catalyzed oxidative annulation of pyridin-2(1H)-ones with alkynes via double C-H activation to produce highly functionalized 4H-quinolizin-4-ones is disclosed. This reaction features easily available starting materials, simple manipulation, a relatively wide substrate scope, and good functional group tolerance. The application of this protocol is demonstrated by the synthesis of a known fluorescent quinolizino[3,4,5,6-ija]quinolinium salt. PMID- 28558245 TI - Electron to Adsorbate Energy Transfer in Nanoparticles: Adsorption Site, Size, and Support Matter. AB - Confinement of hot electrons in metal nanoparticles (NPs) is expected to lead to increased reactivity in heterogeneous catalysis. NP size as well as support may influence molecule-NP coupling. Here, we use ultrafast nonlinear vibrational spectroscopy to follow energy transfer from hot electrons generated in Pd NP/MgO/Ag(100) to chemisorbed CO. Photoexcitation and photodesorption occur on an ultrashort time scale and are selective according to adsorption site. When the MgO layer is thick enough, it becomes NP size-dependent. Hot electron confinement within NPs is unfavorable for photodesorption, presumably because its dominant effect is to increase relaxation to phonons. An avenue of research is open where NP size and support thickness, photon energy, and molecular electronic structure will be tuned to obtain either molecular stability or reactivity in response to photon excitation. PMID- 28558247 TI - Sublimation Entropy and Dissociation Constants Prediction by Quantitative Evaluation of Molecular Mobility in Crystals. AB - Prediction of binding free energies (or dissociation constants) is a crucial challenge for computational biochemistry. One of the main problems here consists in fast and accurate evaluation of binding entropy, which is far more time consuming than evaluation of binding enthalpy. Here, we offer a fast and rather accurate approach to evaluate the sublimation entropy (i.e., entropy of binding of a vapor molecule to a crystal, taken with the opposite sign) from the average range of molecular movements in the solid state. To estimate this range (and the corresponding amplitude), we considered equilibrium sublimation of small organic molecules from molecular crystals. The calculations were based on experimental data on the sublimation enthalpy, pressure of saturated vapor, and structural characteristics of the molecule in question. The resulting average amplitude (0.17 +/- 0.01 A) of molecular movements in crystals was used to predict sublimation entropies and dissociation constants for sublimation of 28 molecular crystals. The results of these predictions are in close agreement with experimental values. PMID- 28558246 TI - Buffers Strongly Modulate Fibrin Self-Assembly into Fibrous Networks. AB - Fibrin is a plasma protein with a central role in blood clotting and wound repair. Upon vascular injury, fibrin forms resilient fibrillar networks (clots) via a multistep self-assembly process, from monomers, to double-stranded protofibrils, to a branched network of thick fibers. In vitro, fibrin self assembly is sensitive to physicochemical conditions like the solution pH and ionic strength, which tune the strength of the noncovalent driving forces. Here we report a surprising finding that the buffer-which is necessary to control the pH and is typically considered to be inert-also significantly influences fibrin self-assembly. We show by confocal microscopy and quantitative light scattering that various common buffering agents have no effect on the initial assembly of fibrin monomers into protofibrils but strongly hamper the subsequent lateral association of protofibrils into thicker fibers. We further find that the structural changes are independent of the molecular structure of the buffering agents as well as of the activation mechanism and even occur in fibrin networks formed from platelet-poor plasma. This buffer-mediated decrease in protofibril bundling results in a marked reduction in the permeability of fibrin networks but only weakly influences the elastic modulus of fibrin networks, providing a useful tuning parameter to independently control the elastic properties and the permeability of fibrin networks. Our work raises the possibility that fibrin assembly in vivo may be regulated by variations in the acute-phase levels of bicarbonate and phosphate, which act as physiological buffering agents of blood pH. Moreover, our findings add a new example of buffer-induced effects on biomolecular self-assembly to recent findings for a range of proteins and lipids. PMID- 28558248 TI - Ruthenium(II)-Catalyzed C-H Alkynylation of Weakly Coordinating Benzoic Acids. AB - C-H alkynylations with weakly coordinating acids were accomplished by the aid of an expedient ruthenium(II) catalysis manifold. The user-friendly C-H alkynylation occurred under mild conditions with the weak base K2CO3. The versatility of the ruthenium(II) catalysis was reflected by providing step-economical access to phthalides as well as enabling unprecedented decarboxylative ortho-C-H alkynylations. PMID- 28558249 TI - Reaction Mechanism of Cu(I)-Mediated Reductive CO2 Coupling for the Selective Formation of Oxalate: Cooperative CO2 Reduction To Give Mixed-Valence Cu2(CO2*-) and Nucleophilic-Like Attack. AB - A dinuclear, Cu(I)-catalyzed reductive CO2 coupling reaction was recently developed to selectively yield a metal-oxalate product through electrochemical means, instead of the usual formation of carbonate and CO ( Science 2010 , 327 , 313 ). To shed light on the mechanism of this important and unusual reductive coupling reaction, extensive and systematic density functional theory (DFT) calculations on several possible pathways and spin states were performed in which a realistic system up to 164 atoms was adopted. Our calculations support the observation that oxalate formation is energetically more favorable than the formation of carbonate and CO products in this cationic Cu(I) complex. Spatial confinement of the realistic catalyst (a long metal-metal distance) was found to further destabilize the carbonate formation, whereas it slightly promotes oxalate formation. Our study does not support the proposed diradical coupling mechanism. Instead, our calculations suggest a new mechanism in which one CO2 molecule is first reduced cooperatively by two Cu(I) metals to give a new, fully delocalized mixed-valence Cu2I/II(CO2*-) radical anion intermediate (analogues to Type 4 Cu center, CuA), followed by further partial reduction of the metal-ligated CO2 molecule and (metal-mediated) nucleophilic-like attack on the carbon atom of an incoming second CO2 molecule to afford the dinuclear Cu(II)-oxalate product. Overall, our proposed reaction mechanism involves a closed-shell reactant as well as two open-shell transition states and products. The effects of size, charge, and catalyst metal on the oxalate formation were also investigated and compared. PMID- 28558250 TI - Direct NMR Monitoring of Phase Separation Behavior of Highly Supersaturated Nifedipine Solution Stabilized with Hypromellose Derivatives. AB - We investigated the phase separation behavior and maintenance mechanism of the supersaturated state of poorly water-soluble nifedipine (NIF) in hypromellose (HPMC) derivative solutions. Highly supersaturated NIF formed NIF-rich nanodroplets through phase separation from aqueous solution containing HPMC derivative. Dissolvable NIF concentration in the bulk water phase was limited by the phase separation of NIF from the aqueous solution. HPMC derivatives stabilized the NIF-rich nanodroplets and maintained the NIF supersaturation with phase-separated NIF for several hours. The size of the NIF-rich phase was different depending on the HPMC derivatives dissolved in aqueous solution, although the droplet size had no correlation with the time for which NIF supersaturation was maintained without NIF crystallization. HPMC acetate and HPMC acetate succinate (HPMC-AS) effectively maintained the NIF supersaturation containing phase-separated NIF compared with HPMC. Furthermore, HPMC-AS stabilized NIF supersaturation more effectively in acidic conditions. Solution 1H NMR measurements of NIF-supersaturated solution revealed that HPMC derivatives distributed into the NIF-rich phase during the phase separation of NIF from the aqueous solution. The hydrophobicity of HPMC derivative strongly affected its distribution into the NIF-rich phase. Moreover, the distribution of HPMC-AS into the NIF-rich phase was promoted at lower pH due to the lower aqueous solubility of HPMC-AS. The distribution of a large amount of HPMC derivatives into NIF-rich phase induced the strong inhibition of NIF crystallization from the NIF-rich phase. Polymer distribution into the drug-rich phase directly monitored by solution NMR technique can be a useful index for the stabilization efficiency of drug-supersaturated solution containing a drug-rich phase. PMID- 28558251 TI - Omega-3 Use in Psychiatry: Evidence-Based or Elegance-Based? AB - Use of omega-3 in psychiatric practice is on the rise. It has been used in diverse indications, notably mood disorders, schizophrenia, dementia, borderline personality, and neurodevelopmental disorders, with varying levels of evidence base. Here, the author sheds some light on the therapeutic potential of omega-3 as an appealing addition to psychopharmacological armamentarium. PMID- 28558252 TI - The effect of exercise intensity and excess postexercise oxygen consumption on postprandial blood lipids in physically inactive men. AB - Reductions in postprandial lipemia have been observed following aerobic exercise of sufficient energy expenditure. Increased excess postexercise oxygen consumption (EPOC) has been documented when comparing high- versus low-intensity exercise. The contribution of EPOC energy expenditure to alterations in postprandial lipemia has not been determined. The purpose of this study was to evaluate the effects of low- and high-intensity exercise on postprandial lipemia in healthy, sedentary, overweight and obese men (age, 43 +/- 10 years; peak oxygen consumption, 31.1 +/- 7.5 mL.kg-1.min-1; body mass index, 31.8 +/- 4.5 kg/m2) and to determine the contribution of EPOC to reductions in postprandial lipemia. Participants completed 4 conditions: nonexercise control, low-intensity exercise at 40%-50% oxygen uptake reserve (LI), high-intensity exercise at 70% 80% oxygen uptake reserve (HI), and HI plus EPOC re-feeding (HI+EERM), where the difference in EPOC energy expenditure between LI and HI was re-fed in the form of a sports nutrition bar (Premier Nutrition Corp., Emeryville, Calif., USA). Two hours following exercise participants ingested a high-fat (1010 kcals, 99 g sat fat) test meal. Blood samples were obtained before exercise, before the test meal, and at 2, 4, and 6 h postprandially. Triglyceride incremental area under the curve was significantly reduced following LI, HI, and HI+EERM when compared with nonexercise control (p < 0.05) with no differences between the exercise conditions (p > 0.05). In conclusions, prior LI and HI exercise equally attenuated postprandial triglyceride responses to the test meal. The extra energy expended during EPOC does not contribute significantly to exercise energy expenditure or to reductions in postprandial lipemia in overweight men. PMID- 28558253 TI - Sugar sulfates are not hydrolyzed by the acid-inducible sulfatase AslA from Salmonella enterica Enteritidis NalR and Kentucky 3795 at pH 5.5. AB - The open reading frames SEN0085 and SeKA_A4361, from Salmonella enterica serovar Enteritidis NalR and serovar Kentucky 3795, respectively, corresponding to the acid-inducible sulfatase gene aslA from Salmonella enterica serovar Typhimurium, were previously suggested by microarray analysis to be differentially expressed under acid conditions. However, growth and enzyme activity tests in the present study demonstrated that both wild-type strains exhibited sulfatase activity with 4-nitrophenyl sulfate and 5-bromo-4-chloro-3 indolyl sulfate at pH 5.5. The acid sulfatase does not appear to be involved in sugar sulfate, tyrosine sulfate, 4 hydroxy-3-methoxyphenylglycol sulfate, heparin sulfate, or chondroitin sulfate hydrolysis at pH 5.5. Adhesion and invasion assays did not reveal differences between the serotypes and their corresponding aslA deletion mutants. Thus, the role and substrate(s) of AslA, a protein unique to salmonella and encoded in all sequenced Salmonella strains, remain elusive. PMID- 28558254 TI - Sensing the cold: TRP channels in thermal nociception. PMID- 28558255 TI - Anti-Inflammatory Subfractions Separated from Acidified Chloroform Fraction of Fenugreek Seeds (Trigonella foenum-graecum L.). AB - Considering the side effects of current anti-inflammatory drugs, novel therapeutic agents are desired. We have succeeded in separating flavonoid-rich fractions with anti-inflammatory effect from fenugreek seeds (Trigonella foenum graecum L.). In this work, we aimed to carry out further fractionation to find active anti-inflammatory subfractions. Trigonelline content of the plant was determined by spectrophotometric method. Fenugreek seeds were extracted consecutively with petroleum ether, acidified chloroform (ACC), alkaline chloroform (AKC), methanol, and water. ACC fraction, which had exhibited the highest anti-inflammatory effect, was further fractionated using column chromatography. Obtained subfractions were evaluated using carrageenan-induced paw edema (CIPE) method. Animals were pretreated by test compounds, and after 30 minutes edema was induced by subcutaneous injection of 100 ul of 1% w/v carrageenan into the right paw of animals. Volume difference of both paws was measured at different times after carrageenan injection. The concentration of trigonelline was determined as 16.2%. ACC fraction inhibited paw edema significantly in comparison to control (p < .05). Four subfractions (dry weight percentage basis) were selected for pharmacological study. F3 subfraction exhibited the greatest inhibition at 15 mg/kg (p < .001). ACC fraction and F4 significantly inhibited paw edema at doses of 5, 10, and 15 mg/kg (p < .001). Phytochemical studies indicated the presence of flavonoids in ACC and active subfractions. Further separation can lead to finding active components from active subfractions, which probably belong to flavonoid phytochemicals. Considering the gastroprotective effect of fenugreek, we hope the separated fractions also would be free of gastrointestinal side effects. PMID- 28558256 TI - [Case Formulation in Early Psychosis: What are the Tools for Teamwork?] PMID- 28558257 TI - Selection and Evaluation of Indexes Commonly Used to Determine Contamination with T-2 Toxin in Pacific White Shrimp Litopenaeus vannamei by the Grey Relational Method. AB - The objectives of the present study were to evaluate the effects of different concentrations of the mycotoxin T-2 toxin in feed on muscle performance in the Pacific white shrimp Litopenaeus vannamei, evaluate indexes of physiological variables that indicate T-2 toxin contamination in the shrimp using the grey relational method, and determine the dose-response relationships between T-2 toxin and the indexes. Of the 6 physical, 7 biochemical, and 17 nutritional indexes examined, the values of the grey relational coefficients were highest for the hepatopancreas: body weight ratio (HBR), alanine aminotransferase (ALT) activity, and serine (SER) content (0.83, 0.68, and 0.82, respectively). Therefore, the HBR, ALT activity, and SER content were selected as appropriate indexes for contamination of Pacific white shrimp muscle with T-2 toxin. Based on their dose-response relationship curves, mean effective doses of 1.45, 1.69, and 1.33 mg of T-2 toxin/kg of feed were obtained for the HBR, ALT activity, and SER content, respectively. These results offer technical reference points for the evaluation and control of T-2 toxin in shrimp feed. Received April 28, 2016; accepted April 9, 2017. PMID- 28558258 TI - Antitumoral effect of vanadium compounds in malignant melanoma cell lines. AB - In this study we evaluated the anticancer activity against malignant melanoma (MM) of four different vanadium species: the inorganic anion vanadate(V) (indicated with VN), and three oxidovanadium(IV) complexes, [VIVO(dhp)2] where dhp- is the anion 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate (indicated with VS2), [VIVO(mpp)2] where mpp- is 1-methyl-3-hydroxy-4(1H)-pyridinonate (indicated with VS3), and [VIVO(ppp)2] where ppp- is 1-phenyl-2-methyl-3-hydroxy-4(1H) pyridinonate (indicated with VS4). The antitumor effects of these compounds were studied against two different MM cell lines (A375 and CN-mel) and a fibroblast cell line (BJ) as normal control. All tested V compounds exert antiproliferative activity on MM cells in a dose dependent manner (IC50 ranges from 2.4MUM up to 14MUM) being A375 the most sensitive cell line. VN and VS2 were the two most active compounds against A375 (IC50 of 4.7 and 2.6MUM, respectively), causing apoptosis and cell cycle block. The experimental data indicate that the cell cycle arrest occurs at different phases for the two V species analyzed (G2 checkpoint for VN and G0/G1 for VS2), showing the importance of the chemical form in determining their mechanism of action. These results add more insights into the landscape of vanadium versatility in biological systems and into its role as a potential cancer therapeutic agent. PMID- 28558259 TI - Exploring the concept of continuous midwifery-led care and its dimensions in the prenatal, perinatal, and postnatal periods in Iran (Kashan). AB - AIM: to explore the concept of continuous care and its dimensions in the prenatal, perinatal, and postnatal periods based on the experiences of midwives, gynaecologists, obstetricians, pregnant women and their husbands. DESIGN: a qualitative study that was part of a large scale action research which aimed to develop, use and test a continuous midwifery-led care model. Data collection and analysis were performed concurrently through undertaking semi-structured interviews and using the conventional content analysis approach. SETTING: healthcare centres and hospitals affiliated to Kashan University of Medical Sciences, Kashan, Iran. PARTICIPANTS: 21 women following a recent pregnancy, five husbands, 18 midwives, and five physicians who had different official positions. FINDINGS: the participants' experiences revealed five concepts for continuous midwifery-led care which included continuity, the process of care, education and informing, management, and professionalism. Each of these five concepts consisted of several categories. CONCLUSION AND IMPLICATION FOR PRACTICE: according to the study participants, continuous midwifery-led prenatal, perinatal, and postnatal care is a multidimensional and important concept. Given the differences in the health infrastructures of different countries as well as the unique characteristics of pregnancy, higher priorities are recommended to be given to continuous midwifery-led care and its dimensions. PMID- 28558260 TI - Antimicrobial resistance and plasmid replicons in Yersinia enterocolitica strains isolated in Brazil in 30 years. AB - Some studies evaluated the resistance profile of the Y. enterocolitica strains isolated in diverse countries. However, in Brazil the isolation and the study of Y. enterocolitica are not common and therefore information about the antimicrobial resistance profile of this species in this country is scarce. Therefore, the aim of this study was to evaluate the antimicrobial resistance of Y. enterocolitica of biotypes 1A, 2 and 4 isolated from clinical and non-clinical sources between 1979 and 2012, in Brazil. This study showed that some Yersinia enterocolitica of different biotypes remain susceptible to antimicrobials used for gastroenteritis treatment. Moreover, neither acquired resistance genes nor diversity of plasmids replicons were found; however, variation in the in vitro intrinsic resistant pattern was detected, except the non-resistance to cefoxitin in all strains. Notwithstanding, due to epidemiological link between Y. enterocolitica and the pork production chain, monitoring plasmid acquired resistance in Y. enterocolitica could also be considered for antimicrobial resistance control purposes and food safety measures. PMID- 28558261 TI - Regulating urban surface runoff through nature-based solutions - An assessment at the micro-scale. AB - Urban development leads to changes of surface cover that disrupt the hydrological cycle in cities. In particular, impermeable surfaces and the removal of vegetation reduce the ability to intercept, store and infiltrate rainwater. Consequently, the volume of stormwater runoff and the risk of local flooding rises. This is further amplified by the anticipated effects of climate change leading to an increased frequency and intensity of heavy rain events. Hence, urban adaptation strategies are required to mitigate those impacts. A nature based solution, more and more promoted in politics and academia, is urban green infrastructure as it contributes to the resilience of urban ecosystems by providing services to maintain or restore hydrological functions. However, this poses a challenge to urban planners in deciding upon effective adaptation measures as they often lack information on the performance of green infrastructure to moderate surface runoff. It remains unclear what type of green infrastructure (e.g. trees, green roofs), offers the highest potential to reduce discharge volumes and to what extent. Against this background, this study provides an approach to gather quantitative evidence on green infrastructure's regulation potential. We use a micro-scale scenario modelling approach of different variations of green cover under current and future climatic conditions. The scenarios are modelled with MIKE SHE, an integrated hydrological simulation tool, and applied to a high density residential area of perimeter blocks in Munich, Germany. The results reveal that both trees and green roofs increase water storage capacities and hence reduce surface runoff, although the main contribution of trees lies in increasing interception and evapotranspiration, whereas green roofs allow for more retention through water storage in their substrate. With increasing precipitation intensities as projected under climate change their regulating potential decreases due to limited water storage capacities. The performance of both types stays limited to a maximum reduction of 2.4% compared to the baseline scenario, unless the coverage of vegetation and permeable surfaces is significantly increased as a 14.8% reduction is achieved by greening all roof surfaces. We conclude that the study provides empirical support for the effectiveness of urban green infrastructure as nature-based solution to stormwater regulation and assists planners and operators of sewage systems in selecting the most effective measures for implementation and estimation of their effects. PMID- 28558262 TI - The short-term effect of particulate matter on cardiorespiratory drug prescription, as a proxy of mild adverse events. AB - INTRODUCTION AND AIMS: The association between particulate matter < 10um in aerodynamic diameter (PM10) and mild disease episodes, not leading to hospitalization or death, has been rarely investigated. We studied the short-term effect of PM10 on purchases of specific cardiorespiratory medications, as proxies of mild episodes, in 7 small- and medium-sized cities of Northern Italy, during 2005-2006. MATERIALS AND METHODS: We extracted information on purchased prescriptions from healthcare administrative databases, and we obtained daily PM10 concentrations from fixed monitoring stations. We applied a time-stratified case-crossover design, using the time-series of antidiabetic drugs purchases to control for confounding due to irregularities in daily purchase frequencies. RESULTS: During the warm season, we estimated a delayed (lags 2-6) increased risk of buying glucocorticoid (4.53%, 95% Confidence Interval (CI): 2.62, 6.48) and adrenergic inhalants (1.66%, 95% CI: 0.10, 3.24), following an increment (10MUg/m3) in PM10 concentration. During the cold season, we observed an immediate (lags 0-1) increased risk of purchasing antiarrhythmics (0.76%; 95% CI: 0.16, 1.36) and vasodilators (0.72%; 95% CI: 0.30, 1.13), followed by a risk reduction (lags 2-6), probably due to harvesting. CONCLUSIONS: Focusing on drug purchases, we reached sufficient statistical power to study PM10 effect outside large urban areas and conclude that short-term increments in PM10 concentrations might cause mild cardiorespiratory disease episodes. PMID- 28558264 TI - Positive Expression of Programmed Death Ligand 1 in Peritumoral Liver Tissue is Associated with Poor Survival after Curative Resection of Hepatocellular Carcinoma. AB - BACKGROUND: Recurrence or metastasis of hepatocellular carcinoma (HCC) is mainly intrahepatic after curative resection, demonstrating that the peritumoral environment is important but often neglected. Programmed death ligand 1 (PD-L1) in intratumoral liver tissues is a poor prognosis factor whose impact is removed after curative resection. However, PD-L1 expression remains in the peritumoral liver tissues and its distribution and prognostic value are still not clear. METHODS: We assessed the expression of PD-L1 by immunohistochemistry in peritumoral liver tissues from 90 HCC patients who underwent curative hepatectomy. The results were validated in an independent cohort of additional 90 HCC patients. RESULTS: We found PD-L1 positive expression in 31.11% (28/90) of peritumoral tissues. Peritumoral PD-L1 expression was associated with a significantly worse overall survival (OS) (P=.000) and disease-free survival (DFS) (P=.001) compared to the negative expression group. Additionally, peritumoral PD-L1 positivity significantly correlated with vascular invasion and a lower albumin level (<=35 g/L). Univariate and multivariate Cox regression models both revealed peritumoral PD-L1 as an independent prognostic factor for OS (HR=2.853, P=.002) and DFS (HR=2.362, P=.003). The prognostic value of PD-L1 positivity was validated in the independent data set. CONCLUSIONS: Our data suggest PD-L1 expression in peritumoral hepatocytes is an independent prognostic factor for OS and DFS. This implies that future anti-cancer therapy should target not only residual tumor cells but also the "soil" for promoting tumor growth. Peritumoral PD-L1 could be a good target for adjuvant therapy after hepatectomy. PMID- 28558263 TI - The role of traffic noise on the association between air pollution and children's lung function. AB - Although it has been shown that traffic-related air pollution adversely affects children's lung function, few studies have examined the influence of traffic noise on this association, despite both sharing a common source. Estimates of noise exposure (Ldn, dB), and freeway and non-freeway emission concentrations of oxides of nitrogen (NOx, ppb) were spatially assigned to children in Southern California who were tested for forced vital capacity (FVC, n=1345), forced expiratory volume in 1s, (FEV1, n=1332), and asthma. The associations between traffic-related NOx and these outcomes, with and without adjustment for noise, were examined using mixed effects models. Adjustment for noise strengthened the association between NOx and reduced lung function. A 14.5mL (95% CI -40.0, 11.0mL) decrease in FVC per interquartile range (13.6 ppb) in freeway NOx was strengthened to a 34.6mL decrease after including a non-linear function of noise (95% CI -66.3, -2.78mL). Similarly, a 6.54mL decrease in FEV1 (95% CI -28.3, 15.3mL) was strengthened to a 21.1mL decrease (95% CI -47.6, 5.51) per interquartile range in freeway NOx. Our results indicate that where possible, noise should be included in epidemiological studies of the association between traffic-related air pollution on lung function. Without taking noise into account, the detrimental effects of traffic-related pollution may be underestimated. PMID- 28558265 TI - Preparation and Identification of HER2 Radioactive Ligands and Imaging Study of Breast Cancer-Bearing Nude Mice. AB - OBJECTIVE: A micro-molecule peptide TP1623 of 99mTc-human epithelial growth factor receptor 2 (HER2) was prepared and the feasibility of using it as a HER2 positive molecular imaging agent for breast cancer was evaluated. METHODS: TP1623 was chemically synthesized and labeled with 99mTc. The labeling ratio and stability were detected. HER2 expression levels of breast cancer cells (SKBR3 and MDA-MB-231) and cell binding activity were measured. Biodistribution of 99mTC TP1623 in normal mice was detected. SKBR3/MDA-MB-231-bearing nude mice models with high/low expressions of HER2 were established. Tumor tissues were stained with hematoxylin-eosin (HE) and measured by immunohistochemistry to confirm the formation of tumors and HER2 expression. SPECT imaging was conducted for HER2 overexpressing SKBR3-bearing nude mice. The T/NT ratio was calculated and compared with that of MDA-MB-231-bearing nude mice with low HER2 expression. The competitive inhibition image was used to discuss the specific binding of 99mTc- TP1623 and the tumor. RESULTS: The labeling ratio of 99mTc-TP1623, specific activity, and radiochemical purity (RCP) after 6 h at room temperature were (97.39 +/- 0.23)%, (24.61 +/- 0.06) TBq/mmol, and (93.25 +/- 0.06)%, respectively. HER2 of SKBR3 and MDA-MB-231 cells showed high and low expression levels by immunohistochemistry, respectively. The in vitro receptor assays indicated that specific binding of TP1623 and HER2 was retained. Radioactivity in the brain was always at the lowest level, while the clearance rate of blood and the excretion rate of the kidneys were fast. HE staining showed that tumor cells were observed in SKBR3- and MDA-MB-231-bearing nude mice, with significant heteromorphism and increased mitotic count. The imaging of mice showed that targeted images could be made of 99mTc-TP1623 in high HER2-expressing tumors, while no obvious development was shown in tumors in low HER2-expressing nude mice. No development was visible in tumors in competitive inhibition of imaging, which indicates the combination of 99mTc-TP1623 and tumor was mediated by HER2. CONCLUSION: High labeling ratio and specific activity of 99mTc-TP1623 is successfully prepared; it is a molecular imaging agent for HER2-positive tumors that has potential applicative value. PMID- 28558266 TI - Neurobiological mechanisms of state-dependent learning. AB - State-dependent learning (SDL) is a phenomenon relating to information storage and retrieval restricted to discrete states. While extensively studied using psychopharmacological approaches, SDL has not been subjected to rigorous neuroscientific study. Here we present an overview of approaches historically used to induce SDL, and highlight some of the known neurobiological mechanisms, in particular those related to inhibitory neurotransmission and its regulation by microRNAs (miR). We also propose novel cellular and circuit mechanisms as contributing factors. Lastly, we discuss the implications of advancing our knowledge on SDL, both for most fundamental processes of learning and memory as well as for development and maintenance of psychopathology. PMID- 28558268 TI - Identification of in situ flower volatiles from kiwifruit (Actinidia chinensis var. deliciosa) cultivars and their male pollenisers in a New Zealand orchard. AB - In situ flower volatiles from six kiwifruit cultivars (Actinidia chinensis var. deliciosa); 'Hayward', 'Chieftain', 'M56', 'Zes007' (Green11), 'M36', and 'M43' were collected by dynamic headspace sampling. Forty-five compounds were detected in the headspace of the flowers, with straight chain hydrocarbons and terpenes accounting for >98% of the volatiles emitted quantitatively across the six cultivars. Of these hydrocarbons, (3Z,6Z,9Z)-heptadecatriene is reported for the first time from a floral source while (8Z)-hexadecene and (9Z)-nonadecene are reported for the first time from kiwifruit flowers. All three hydrocarbons were verified by synthesis. Quantitative comparison of the six honey bee perceived compounds from the headspace of the cultivars showed that the males 'M36' and 'M43' closely matched the female cultivar Green11 that they are used to pollinate. Males 'M56' and 'Chieftain' were not as closely matched to the female cultivar 'Hayward' that they are used to pollinate. The male 'M56' in particular differed significantly from the female 'Hayward' in four of the six honey bee perceived compounds. PMID- 28558269 TI - White matter pathways mediate parental effects on children's reading precursors. AB - Previous studies have shown that the link between parental and offspring's reading is mediated by the cognitive system of the offspring, yet information about the mediating role of the neurobiological system is missing. This family study includes cognitive and diffusion MRI (dMRI) data collected in 71 pre readers as well as parental reading and environmental data. Using sequential path analyses, which take into account the interrelationships between the different components, we observed mediating effects of the neurobiological system. More specifically, fathers' reading skills predicted reading of the child by operating through a child's left ventral white matter pathway. For mothers no clear mediating role of the neural system was observed. Given that our study involves children who have not yet learned to read and that environmental measures were taken into account, the paternal effect on a child's white matter pathway is unlikely to be only driven by environmental factors. Future intergenerational studies focusing on the genetic, neurobiological and cognitive level of parents and offspring will provide more insight in the relative contribution of parental environment and genes. PMID- 28558267 TI - Neural immunoglobulin superfamily interaction networks. AB - The immunoglobulin superfamily (IgSF) encompasses hundreds of cell surface proteins containing multiple immunoglobulin-like (Ig) domains. Among these are neural IgCAMs, which are cell adhesion molecules that mediate interactions between cells in the nervous system. IgCAMs in some vertebrate IgSF subfamilies bind to each other homophilically and heterophilically, forming small interaction networks. In Drosophila, a global 'interactome' screen identified two larger networks in which proteins in one IgSF subfamily selectively interact with proteins in a different subfamily. One of these networks, the 'Dpr-ome', includes 30 IgSF proteins, each of which is expressed in a unique subset of neurons. Recent evidence shows that one interacting protein pair within the Dpr-ome network is required for development of the brain and neuromuscular system. PMID- 28558270 TI - Ictal ipsilateral sweating in focal epilepsy. PMID- 28558272 TI - Emotion dysregulation and peer drinking norms uniquely predict alcohol-related problems via motives. AB - This study examined the relationships between emotion dysregulation, peer drinking norms, drinking motives, and alcohol-related outcomes among 435 college students. We examined the mediating roles of drinking motives when predicting alcohol consumption and related problems from the subscales of the Difficulties in Emotion Regulation Scale (DERS; Gratz and Roemer, 2004) via negative and positive reinforcement models. First, we hypothesized that individuals who lack in emotion regulation strategies or have difficulties in accepting negative emotions are more likely to drink to cope. Additionally, we hypothesized that individuals who act impulsively or become distracted when upset as well as those with higher peer drinking norms are more likely to drink for social and enhancement motives. The results of the path model indicated that limited access to emotion regulation strategies significantly predicted alcohol-related problems via both depression and anxiety coping motives, but did not predict alcohol consumption. Nonacceptance of emotional responses was not significantly associated with coping motives. Impulsivity had a significant direct relationship with alcohol problems. Difficulty in engaging in goal-directed behaviors predicted both enhancement and social motives, but only enhancement motives in turn predicted consumption. Norms indirectly predicted problems via enhancement motives and consumption. The results indicated that using alcohol to reduce negative or to increase positive emotions increases alcohol consumption and alcohol-related problems. Overall, results advance our understanding of the mechanisms of increased alcohol use and problems among college students. PMID- 28558271 TI - The effects of social contact on cocaine intake in female rats. AB - BACKGROUND: Studies conducted in male rats report that social contact can either facilitate or inhibit drug intake depending on the behavior of social partners. The purpose of the present study was to: (1) examine the effects of social contact on cocaine intake in female rats, (2) examine the behavioral mechanisms by which social contact influences cocaine intake, and (3) examine whether the estrous cycle moderates the effects of social contact on cocaine intake. METHODS: Female rats were assigned to either isolated or pair-housed conditions in which a social partner either had access to cocaine (cocaine partner) or did not have access to cocaine (abstinent partner). Pair-housed rats were tested in custom built operant conditioning chambers that allowed both rats to be tested simultaneously in the same chamber. RESULTS: Rats housed with a cocaine partner self-administered more cocaine than isolated rats and rats housed with an abstinent partner. A behavioral economic analysis indicated that these differences were driven by a greater intensity of cocaine demand (i.e., greater intake at lower unit prices) in rats housed with a cocaine partner. Multivariate modeling revealed that the estrous cycle did not moderate the effects of social contact on cocaine intake. CONCLUSIONS: These findings indicate that: (1) social contact influences cocaine self-administration in females in a manner similar to that reported in males, (2) these effects are due to differences in the effects of social contact on the intensity of cocaine demand, and (3) these effects are consistent across all phases of the estrous cycle. PMID- 28558273 TI - Evolution of multiple quantum coherences with scaled dipolar Hamiltonian. AB - In this article, we introduce a pulse sequence which allows the monitoring of multiple quantum coherences distribution of correlated spin states developed with scaled dipolar Hamiltonian. The pulse sequence is a modification of our previous Proportionally Refocused Loschmidt echo (PRL echo) with phase increment, in order to verify the accuracy of the weighted coherent quantum dynamics. The experiments were carried out with different scaling factors to analyze the evolution of the total magnetization, the time dependence of the multiple quantum coherence orders, and the development of correlated spins clusters. In all cases, a strong dependence between the evolution rate and the weighting factor is observed. Remarkably, all the curves appeared overlapped in a single trend when plotted against the self-time, a new time scale that includes the scaling factor into the evolution time. In other words, the spin system displayed always the same quantum evolution, slowed down as the scaling factor decreases, confirming the high performance of the new pulse sequence. PMID- 28558274 TI - Active control of the spatial MRI phase distribution with optimal control theory. AB - This paper investigates the use of Optimal Control (OC) theory to design Radio Frequency (RF) pulses that actively control the spatial distribution of the MRI magnetization phase. The RF pulses are generated through the application of the Pontryagin Maximum Principle and optimized so that the resulting transverse magnetization reproduces various non-trivial and spatial phase patterns. Two different phase patterns are defined and the resulting optimal pulses are tested both numerically with the ODIN MRI simulator and experimentally with an agar gel phantom on a 4.7T small-animal MR scanner. Phase images obtained in simulations and experiments are both consistent with the defined phase patterns. A practical application of phase control with OC-designed pulses is also presented, with the generation of RF pulses adapted for a Magnetic Resonance Elastography experiment. This study demonstrates the possibility to use OC-designed RF pulses to encode information in the magnetization phase and could have applications in MRI sequences using phase images. PMID- 28558275 TI - Heat and mortality for ischemic and hemorrhagic stroke in 12 cities of Jiangsu Province, China. AB - BACKGROUND: Little evidence exists on the relationship between heat and subtypes of stroke mortality, especially in China. Moreover, few studies have reported the effect modification by individual characteristics on heat-related stroke mortality. In this study, we aimed to evaluate the effect of heat exposure on total, ischemic, and hemorrhagic stroke mortality and its individual modifiers in 12 cities in Jiangsu Province, China during 2009 to 2013. METHODS: We first used a distributed lag non-linear model with quasi-Poisson regression to examine the city-specific heat-related total, ischemic, and hemorrhagic stroke mortality risks at 99th percentile vs. 75th percentile of daily mean temperature in the whole year for each city, while adjusting for long-term trend, season, relative humidity, and day of the week. Then, we used a random-effects meta-analysis to pool the city-specific risk estimates. We also considered confounding by air pollution and effect modification by gender, age, education level, and death location. RESULTS: Overall, the heat-related mortality risk in 12 Jiangsu cities was 1.54 (95%CI: 1.44 to 1.65) for total stroke, 1.63 (95%CI: 1.48 to 1.80) for ischemic stroke, and 1.36 (95%CI: 1.26 to 1.48) for hemorrhagic stroke, respectively. Estimated total, ischemic, and hemorrhagic stroke mortality risks were higher for women versus men, older people versus younger people, those with low education levels versus high education levels, and deaths that occurred outside of hospital. Air pollutants did not significantly influence the heat related stroke mortality risk. CONCLUSIONS: Heat exposure significantly increased both ischemic and hemorrhagic stroke mortality risks in Jiangsu Province, China. Females, the elderly, and those with low education levels are particularly vulnerable to this effect. PMID- 28558276 TI - Next-generation sequencing identification of pathogenic bacterial genes and their relationship with fecal indicator bacteria in different water sources in the Kathmandu Valley, Nepal. AB - Bacteriological analysis of drinking water leads to detection of only conventional fecal indicator bacteria. This study aimed to explore and characterize bacterial diversity, to understand the extent of pathogenic bacterial contamination, and to examine the relationship between pathogenic bacteria and fecal indicator bacteria in different water sources in the Kathmandu Valley, Nepal. Sixteen water samples were collected from shallow dug wells (n=12), a deep tube well (n=1), a spring (n=1), and rivers (n=2) in September 2014 for 16S rRNA gene next-generation sequencing. A total of 525 genera were identified, of which 81 genera were classified as possible pathogenic bacteria. Acinetobacter, Arcobacter, and Clostridium were detected with a relatively higher abundance (>0.1% of total bacterial genes) in 16, 13, and 5 of the 16 samples, respectively, and the highest abundance ratio of Acinetobacter (85.14%) was obtained in the deep tube well sample. Furthermore, the blaOXA23-like genes of Acinetobacter were detected using SYBR Green-based quantitative PCR in 13 (35%) of 37 water samples, including the 16 samples that were analyzed for next generation sequencing, with concentrations ranging 5.3-7.5logcopies/100mL. There was no sufficient correlation found between fecal indicator bacteria, such as Escherichia coli and total coliforms, and potential pathogenic bacteria, as well as the blaOXA23-like gene of Acinetobacter. These results suggest the limitation of using conventional fecal indicator bacteria in evaluating the pathogenic bacteria contamination of different water sources in the Kathmandu Valley. PMID- 28558277 TI - Cytotoxicity and genotoxicity of anticancer drug residues and their mixtures in experimental model with zebrafish liver cells. AB - Anticancer drugs enter aquatic environment predominantly via hospital and municipal wastewater effluents where they may, due to their genotoxic potential, cause adverse environmental effects even at very low doses. In this study we evaluated cytotoxic and genotoxic potential of two widely used anticancer drugs, cyclophosphamide (CP) and ifosfamide (IF) as individual compounds and in a complex mixture together with 5-fluorouracil (5-FU) and cisplatin (CDDP) because these four drugs have been frequently detected in an oncological ward effluents. As an experimental model we used zebrafish liver cell (ZFL) line. The cytotoxicity was determined with the MTS assay and genotoxicity with the comet assay and cytokinesis block micronucleus (CBMN) assay that measure the formation of DNA strand breaks and genomic instability, respectively. CP and IF exerted low cytotoxicity towards ZFL cells. Both compounds induced DNA strand breaks and genomic instability, however at relatively high concentrations that are not relevant for the contamination of aquatic environment. The mixture of CP, IF, 5 FU and CDDP was tested at maximal detected concentrations of each drug as determined in the effluents from the oncological ward. The mixture was not cytotoxic and did not induce genomic instability, but it induced significant increase in the formation of DNA strand breaks at concentrations of individual compounds that were several orders of magnitude lower from those that were effective when tested as individual compounds. The results indicate that such mixtures of anticancer drugs may pose a threat to aquatic organisms at environmentally relevant concentrations and contribute to the accumulating evidence that it is not always possible to predict adverse effects of complex mixtures based on the toxicological data for individual compounds. PMID- 28558278 TI - Mayfly and fish species identification and sex determination in bleak (Alburnus alburnus) by MALDI-TOF mass spectrometry. AB - Besides food quality control of fish or cephalopods, the novel mass spectrometry (MS) approaches could be effective and beneficial methods for the investigation of biodiversity in ecological research. Our aims were to verify the applicability of MALDI-TOF MS in the rapid identification of closely related species, and to further develop it for sex determination in phenotypically similar fish focusing on the low mass range. For MALDI-TOF MS spectra analysis, ClinProTools software was applied, but our observed classification was also confirmed by Self Organizing Map. For verifying the wide applicability of the method, brains from invertebrate and vertebrate species were used in order to detect the species related markers from two mayflies and eight fish as well as sex-related markers within bleak. Seven Ephemera larvae and sixty-one fish species related markers were observed and nineteen sex-related markers were identified in bleak. Similar patterns were observed between the individuals within one species. In contrast, there were markedly diverse patterns between the different species and sexes visualized by SOMs. Two different Ephemera species and male or female fish were identified with 100% accuracy. The various fish species were classified into 8 species with a high level of accuracy (96.2%). Based on MS data, dendrogram was generated from different fish species by using ClinProTools software. This MS based dendrogram shows relatively high correspondence with the phylogenetic relationships of both the studied species and orders. In summary, MALDI-TOF MS provides a cheap, reliable, sensitive and fast identification tool for researchers in the case of closely related species using mass spectra acquired in a low mass range to define specific molecular profiles. Moreover, we presented evidence for the first time for determination of sex within one fish species by using this method. We conclude that it is a powerful tool that can revolutionize ecological and environmental research. PMID- 28558279 TI - Incidence of gastrointestinal illness following wet weather recreational exposures: Harmonization of quantitative microbial risk assessment with an epidemiologic investigation of surfers. AB - We modeled the risk of gastrointestinal (GI) illness associated with recreational exposures to marine water following storm events in San Diego County, California. We estimated GI illness risks via quantitative microbial risk assessment (QMRA) techniques by consolidating site specific pathogen monitoring data of stormwater, site specific dilution estimates, literature-based water ingestion data, and literature based pathogen dose-response and morbidity information. Our water quality results indicated that human sources of contamination contribute viral and bacterial pathogens to streams draining an urban watershed during wet weather that then enter the ocean and affect nearshore water quality. We evaluated a series of approaches to account for uncertainty in the norovirus dose-response model selection and compared our model results to those from a concurrently conducted epidemiological study that provided empirical estimates for illness risk following ocean exposure. The preferred norovirus dose-response approach yielded median risk estimates for water recreation-associated illness (15 GI illnesses per 1000 recreation events) that closely matched the reported epidemiological results (12 excess GI illnesses per 1000 wet weather recreation events). The results are consistent with norovirus, or other pathogens associated with norovirus, as an important cause of gastrointestinal illness among surfers in this setting. This study demonstrates the applicability of QMRA for recreational water risk estimation, even under wet weather conditions and describes a process that might be useful in developing site-specific water quality criteria in this and other locations. PMID- 28558280 TI - Parameter estimation of hydrologic models using a likelihood function for censored and binary observations. AB - Observations of a hydrologic system response are needed to accurately model system behaviour. Nevertheless, often very few monitoring stations are operated because collecting such reference data adequately and accurately is laborious and costly. It has been recently suggested to use observations not only from dedicated flow meters but also from simpler sensors, such as level or event detectors, which are available more frequently but only provide censored information. Binary observations can be considered as extreme censoring. It is still unclear, however, how to use censored observations most effectively to learn about model parameters. To this end, we suggest a formal likelihood function that incorporates censored observations, while accounting for model structure deficits and uncertainty in input data. Using this likelihood function, the parameter inference is performed within the Bayesian framework. We demonstrate the implementation of our methodology on a case study of an urban catchment, where we estimate the parameters of a hydrodynamic rainfall-runoff model from binary observations of combined sewer overflows. Our results show, first, that censored observations make it possible to learn about model parameters, with an average decrease of 45% in parameter standard deviation from prior to posterior. Second, the inference substantially improves model predictions, providing higher Nash-Sutcliffe efficiency. Third, the gain in information largely depends on the experimental design, i.e. sensor placement. Given the advent of Internet of Things, we foresee that the plethora of censored data promised to be available can be used for parameter estimation within a formal Bayesian framework. PMID- 28558281 TI - Optimization of sulfate removal from brackish water by membrane capacitive deionization (MCDI). AB - Removal of sulfate from water is an environmental challenge faced by many industrial sectors as most existing options are inefficient, costly or unsustainable. The situation is further complicated by the typical coexistence of other ions. In this work, the feasibility of sulfate removal from brackish water by single-pass constant-current membrane capacitive deionization (MCDI) under reverse-current desorption was investigated. Results revealed that sulfate is preferentially removed from the aqueous solution by MCDI compared to chloride. Equivalent circuits of the MCDI system during adsorption and desorption were proposed and the dynamic variation of cell voltage and charging voltage at different adsorption currents was satisfactorily elucidated. Optimization studies were conducted with attention given to discussing the effects of four operating parameters, i.e., adsorption current, pump flow rate, ending cell voltage and desorption current, on three performance indicators (i.e., water recovery, energy consumption and sorption ratio of sulfate to chloride) on the premise of maintaining the effluent sulfate concentration below the specified threshold of 300 mg L-1. Water recovery-energy consumption mapping and sorption ratio of sulfate to chloride-energy consumption mapping indicated that the combination of a lower adsorption current and a lower matching pump flow rate which reduced the effluent sulfate concentration to 300 mg L-1 was more favorable in practical applications. An appropriately small ending cell voltage was advantageous while a trade-off between water recovery and energy cost was required in optimizing the desorption current. PMID- 28558282 TI - Can stress biomarkers predict preterm birth in women with threatened preterm labor? AB - BACKGROUND: Preterm birth is a major paediatric challenge difficult to prevent and with major adverse outcomes. Prenatal stress plays an important role on preterm birth; however, there are few stress-related models to predict preterm birth in women with Threatened Preterm Labor (TPL). OBJECTIVE: The aim of this work is to study the influence of stress biomarkers on time until birth in TPL women. METHODS: Eligible participants were pregnant women between 24 and 31 gestational weeks admitted to the hospital with TPL diagnosis (n=166). Stress related biomarkers (alpha-amylase and cortisol) were determined in saliva samples after TPL diagnosis. Participants were followed-up until labor. A parametric survival model was constructed based on alpha-amylase, cortisol), TPL gestational week, age, parity, and multiple pregnancy. The model was adjusted using a logistic distribution and it was implemented as a nomogram to predict the labor probability at 7- and 14-day term. RESULTS: The time until labor was associated with cortisol (p=0.001), gestational week at TPL diagnosis (p=0.004), and age (p=0.02). Importantly, high cortisol levels at TPL diagnosis were predictive of latency to labor. Validation of the model yielded an optimum corrected AUC value of 0.63. CONCLUSIONS: High cortisol levels at TPL diagnosis may have an important role in the preterm birth prediction. Our statistical model implemented as a nomogram provided accurate predictions of individual prognosis of pregnant women. PMID- 28558283 TI - Potassium and zinc increase tolerance to salt stress in wheat (Triticum aestivum L.). AB - Potassium and zinc are essential elements in plant growth and metabolism and plays a vital role in salt stress tolerance. To investigate the physiological mechanism of salt stress tolerance, a pot experiment was conducted. Potassium and zinc significantly minimize the oxidative stress and increase root, shoot and spike length in wheat varieties. Fresh and dry biomass were significantly increased by potassium followed by zinc as compared to control C. The photosynthetic pigment and osmolyte regulator (proline, total phenolic, and total carbohydrate) were significantly enhanced by potassium and zinc. Salt stress increases MDA content in wheat varieties while potassium and zinc counteract the adverse effect of salinity and significantly increased membrane stability index. Salt stress decreases the activities of antioxidant enzymes (superoxide dismutase, catalase and ascorbate peroxidase) while the exogenous application of potassium and zinc significantly enhanced the activities of these enzymes. A significant positive correlation was found of spike length with proline (R2 = 0.966 ***), phenolic (R2 = 0.741*) and chlorophyll (R2 = 0.853**). The MDA content showed significant negative correlation (R2 = 0.983***) with MSI. It is concluded that potassium and zinc reduced toxic effect of salinity while its combine application showed synergetic effect and significantly enhanced salt tolerance. PMID- 28558284 TI - Characterization of PM2.5 exposure concentration in transport microenvironments using portable monitors. AB - Recently, portable monitors have been increasingly used to quantify air pollutant concentrations at high spatiotemporal resolution. A sampling campaign was conducted to measure the fine particulate matter (PM2.5) and carbon monoxide (CO) exposure concentrations in transport microenvironments (TMEs) in Hong Kong in January and June 2015 using TSI DustTrak and Q-Trak portable monitors. The objectives were to: (1) calibrate DustTrak and Q-Trak; (2) evaluate variability between seasons and microenvironments; (3) estimate indoor/outdoor relationships; and (4) determine minimum sample size. Calibration equations, obtained through side-by-side measurement against stationary reference methods in winter and summer, were applied to correct the measured PM2.5 data set. In general, PM2.5 concentrations in all TMEs were significantly higher in winter than in summer. The mean PM2.5 concentration in winter was lower for underground sections of the Mass Transit Railway (MTR) metro system (31 MUg/m3) than for other TMEs, whereas in summer TMEs had mean PM2.5 concentrations in the range of 10-15 MUg/m3, with above-ground MTR train as an exception, at 23 MUg/m3. PM2.5 concentrations measured in TMEs were strongly correlated with nearby air quality monitoring stations (AQMSs) measurements in winter, but in summer there was little correlation. The minimum sample size estimates varied more among TMEs in summer versus winter because of the differences in PM2.5 concentration distributions related to changes in ambient PM2.5 concentrations and ventilation practices. This study provides a feasible protocol on the calibration and application of portable monitors in TME air quality measurement and develops a method for estimating minimum sample size. PMID- 28558285 TI - Enhancing the interpretation of in vitro bioaccessibility data by using computer controlled scanning electron microscopy (CCSEM) at the individual particle level. AB - The adverse health effects resulting from exposure to contaminated soil on internally displaced populations in Mitrovica, Kosovo can be determined by how the potentially harmful elements are bound in the soils. Certainly this was the case for Pb, present at concentrations ranging from 624 to 46,900 mg/kg, and at bioaccessibilities ranging <5% to nearly 90%. To assess why the soil Pb might differ so markedly in terms of its bioaccessibility, computer controlled scanning electron microscopy (CCSEM) was employed to determine how the Pb was associated with other elements at the individual particle (IP) level in soils from the area. It was found that the Pb-bearing particle types were, for the most part, different in each sample. We consider these differences as the main control on Pb bioaccessibility in these soils. Pb solubility at the IP level was evaluated by examining Pb-particles from these soils in the electron microscope before and after successive immersions in a simulated gastric fluid. This analysis (differential IP analysis) confirmed the CCSEM characterization that Pb associated with other higher atomic number elements (Fe, Zn, Cu and Ni) was less soluble than when it was present as isolated phases (e.g., as carbonate) or when it was bound with lower atomic number elements (Na, Al, Si, K, Ca). The heterogeneity in solubility and composition of the Pb-particles suggested that the Pb originated from a range of different anthropogenic activities. The nature of these different anthropogenic activities created the wide differences in Pb bioaccessibilty by producing Pb bound in many different forms in the soil particles. This type of Pb-particle characterization highlights the role CCSEM analysis, and IP acid extraction, can play in providing supporting evidence alongside bioaccessibility data for applications in human health risk assessment and management of contaminated soil. PMID- 28558286 TI - Interactions between polystyrene microplastics and marine phytoplankton lead to species-specific hetero-aggregation. AB - To understand the fate and impacts of microplastics (MP) in the marine ecosystems, it is essential to investigate their interactions with phytoplankton as these may affect MP bioavailability to marine organisms as well as their fate in the water column. However, the behaviour of MP with marine phytoplanktonic cells remains little studied and thus unpredictable. The present study assessed the potential for phytoplankton cells to form hetero-aggregates with small micro polystyrene (micro-PS) particles depending on microalgal species and physiological status. A prymnesiophycea, Tisochrysis lutea, a dinoflagellate, Heterocapsa triquetra, and a diatom, Chaetoceros neogracile, were exposed to micro-PS (2 MUm diameter; 3.96 MUg L-1) during their growth culture cycles. Micro PS were quantified using an innovative flow-cytometry approach, which allowed the monitoring of the micro-PS repartition in microalgal cultures and the distinction between free suspended micro-PS and hetero-aggregates of micro-PS and microalgae. Hetero-aggregation was observed for C. neogracile during the stationary growth phase. The highest levels of micro-PS were "lost" from solution, sticking to flasks, with T. lutea and H. triquetra cultures. This loss of micro-PS sticking to the flask walls increased with the age of the culture for both species. No effects of micro-PS were observed on microalgal physiology in terms of growth and chlorophyll fluorescence. Overall, these results highlight the potential for single phytoplankton cells and residual organic matter to interact with microplastics, and thus potentially influence their distribution and bioavailability in experimental systems and the water column. PMID- 28558287 TI - FIB based fabrication of an operative Pt/HfO2/TiN device for resistive switching inside a transmission electron microscope. AB - Recent advances in microelectromechanical systems (MEMS) based chips for in situ transmission electron microscopy are opening exciting new avenues in nanoscale research. The capability to perform current-voltage measurements while simultaneously analyzing the corresponding structural, chemical or even electronic structure changes during device operation would be a major breakthrough in the field of nanoelectronics. In this work we demonstrate for the first time how to electrically contact and operate a lamella cut from a resistive random access memory (RRAM) device based on a Pt/HfO2/TiN metal-insulator-metal (MIM) structure. The device was fabricated using a focused ion beam (FIB) instrument and an in situ lift-out system. The electrical switching characteristics of the electron-transparent lamella were comparable to a conventional reference device. The lamella structure was initially found to be in a low resistance state and could be reset progressively to higher resistance states by increasing the positive bias applied to the Pt anode. This could be followed up with unipolar set/reset operations where the current compliance during set was limited to 400 uA. FIB structures allowing to operate and at the same time characterize electronic devices will be an important tool to improve RRAM device performance based on a microstructural understanding of the switching mechanism. PMID- 28558288 TI - Pulsed-voltage atom probe tomography of low conductivity and insulator materials by application of ultrathin metallic coating on nanoscale specimen geometry. AB - We present a novel approach for analysis of low-conductivity and insulating materials with conventional pulsed-voltage atom probe tomography (APT), by incorporating an ultrathin metallic coating on focused ion beam prepared needle shaped specimens. Finite element electrostatic simulations of coated atom probe specimens were performed, which suggest remarkable improvement in uniform voltage distribution and subsequent field evaporation of the insulated samples with a metallic coating of approximately 10nm thickness. Using design of experiment technique, an experimental investigation was performed to study physical vapor deposition coating of needle specimens with end tip radii less than 100nm. The final geometries of the coated APT specimens were characterized with high resolution scanning electron microscopy and transmission electron microscopy, and an empirical model was proposed to determine the optimal coating thickness for a given specimen size. The optimal coating strategy was applied to APT specimens of resin embedded Au nanospheres. Results demonstrate that the optimal coating strategy allows unique pulsed-voltage atom probe analysis and 3D imaging of biological and insulated samples. PMID- 28558289 TI - Toxicity of triphenyltin on the development of retinal axons in zebrafish at low dose. AB - The impacts of triphenyltin (TPT) on ecological health are of particular concern due to the unexpectedly high levels found in wild fish around the world. Here, zebrafish embryos were exposed to TPT via in ovo nano-injection to study its toxicity on the development of retinal axons in fish. Lipophilic dye labeling revealed obvious defects in retinal axon development in larvae with normally shaped eyes, with incidences of 0, 1.08%, 2.66%, 4.26%, and 6.85% observed in the control, 0.8, 4.0, 20.0, and 100ng TPT-Cl/g wet weight (ww) exposure groups, respectively, showing a dose-dependent increase. Since the lowest observable effective concentration of TPT to induce retinal axon development defects was 0.8ng TPT-Cl/g ww, which is lower than the concentrations in wild fish eggs, this defect would occur in wild fish larvae. Alterations in the expressions of pax6 and ephrinBs, which regulate the establishment of retinal polarity, were correlated with defect incidence. Expression levels of the CYP26A1 gene and protein were significantly up-regulated in all exposure groups compared with the control, which may lead to significant decreases in concentrations of all-trans retinoic acid (atRA). Such a disruption of RA metabolism would, at least partly, contribute to the incidence of developmental defects in retinal axons. This study is the first to report that TPT can interfere with development of retinal axons in fish at low dose. PMID- 28558290 TI - Nitrogen/sulfur-doping of graphene with cysteine as a heteroatom source for oxygen reduction electrocatalysis. AB - Heteroatom-doped graphene have encouraged intensive research as promising metal free oxygen reduction reaction (ORR) electrocatalysts but the correlation between the precursor material and final ORR activity remains unclear. In this work a serial of nitrogen/sulfur (N/S)-doped graphene catalysts were synthesized by modifying graphene oxide (GO) with cysteine as a N/S source and sequential thermal annealing. It is disclosed that the cysteine-GO reaction time shows a significant influence on the ORR activity of N/S-doped graphene. A unique process of oxidation-induced in situ disulfide formation is further found to be involved in the synthesis of optimal N/S-doped graphene, which displays ORR activity superior to commercial Pt/C in alkaline media. This work suggests that the heteroatom source itself and careful optimization of reaction conditions are critical to obtain high performance doped-graphene electrocatalyst. PMID- 28558291 TI - Versatile polyvinylidene fluoride hybrid ultrafiltration membranes with superior antifouling, antibacterial and self-cleaning properties for water treatment. AB - Novel ultrafiltration membranes with both superior antibacterial and self cleaning properties were fabricated. By using a non-solvent induced phase separation method (NIPS), N-halamine epoxide and siloxane were grafted onto the multi-walled carbon nanotubes (N-Si-MWNTs) to fabricate polyvinylidene fluoride (PVDF) hybrid membranes. The membrane morphology was observed under a field emission scanning electron microscopy. The results demonstrated that the PVDF hybrid membranes had an asymmetrical structure, and their hydraulic permeability was evidently enhanced with the addition of modified MWNTs. When compared with the primitive PVDF membrane, the hybrid membranes presented improved surface hydrophilicity. After three ultrafiltration-regeneration cycles with bovine serum albumin as model biofoulant and pure water as detergent, the PVDF hybrid membranes exhibited a high flux recovery ratio (FRR). Furthermore, when compared with other membranes, the membrane containing N-Si-MWNTs displayed the highest FRR value of above 96.5% after the entire fouling and cleaning experiment. The fabricated PVDF/N-Si-MWNTs hybrid membranes had excellent antibacterial efficacy, presenting maximum antibacterial efficacy of 98.0% and 95.6% against Staphylococcus aureus and Escherichia coli, respectively. Thus, the PVDF/N-Si MWNTs membranes fabricated in this study are environment-friendly with both benign antibacterial and self-cleaning properties. PMID- 28558292 TI - Tunable adhesion of superoleophilic/superhydrophobic poly (lactic acid) membrane for controlled-release of oil soluble drugs. AB - Superhydrophobic membranes with tunable adhesion have attracted intense interests for various engineering applications. In this work, superhydrophobic sustainable poly (lactic acid) (PLA) porous membrane with tunable adhesive force from 101MUN to 29MUN was successfully fabricated via one-step phase separation method. The incorporation of Perfluoro-1-decene (PFD) into the PLLA/PDLA membrane via the in situ polymerization can facilely tune the PLLA/PDLA stereocomplex crystallization during phase inversion, which consequently caused the unique morphology blooming evolution from bud to full-blown state. The resulted membrane showed tunable pore size, porosity, surface area, surface roughness and superhydrophobicity, which enabled the membrane with controlled-release of oil soluble drugs. PMID- 28558294 TI - Justification bias in self-reported disability: New evidence from panel data. AB - The relationship between health and work is frequently investigated using self assessments of disability from social surveys. The complication is that respondents may overstate their level of disability to justify non-employment and welfare receipt. This study provides new evidence on the existence and magnitude of justification bias by exploiting a novel feature of a large longitudinal survey: each wave respondents are asked identical disability questions twice; near the beginning and end of the face-to-face interview. Prior to answering the second disability question, respondents are asked a series of questions that increase the salience of their employment and welfare circumstances. Justification bias is identified by comparing the variation between the two measures within-individuals over time, with the variation in employment status over time. Results indicate substantial and statistically significant justification bias; especially for men and women who receive disability pensions. PMID- 28558293 TI - Blood-brain barrier peptide shuttles. AB - Brain delivery is hampered by the presence of the blood-brain barrier (BBB), a natural defence of the brain that protects it and allows the entrance of nutrients by several mechanisms. Taking advantage of these mechanisms is an opportunity to treat brain related diseases. Among the different alternatives, BBB peptide shuttles are gaining attention to increase brain delivery of therapeutics. The most recent advances in the field are analysed here. PMID- 28558295 TI - The effect of spending cuts on teen pregnancy. AB - In recent years, English local authorities have been forced to make significant cuts to devolved expenditure. In this paper, we examine the impact of reductions in local expenditure on one particular public health target: reducing rates of teen pregnancy. Contrary to predictions made at the time of the cuts, panel data estimates provide no evidence that areas which reduced expenditure the most have experienced relative increases in teenage pregnancy rates. Rather, expenditure cuts are associated with small reductions in teen pregnancy rates, a result which is robust to a number of alternative specifications and tests for causality. Underlying socio-economic factors such as education outcomes and alcohol consumption are found to be significant predictors of teen pregnancy. PMID- 28558296 TI - Corrigendum to "LNA aptamer based multi-modal, Fe3O4-saturated lactoferrin (Fe3O4 bLf) nanocarriers for triple positive (EpCAM, CD133, CD44) colon tumour targeting and NIR, MRI and CT imaging" [Biomaterials 71C (2015) 84-99]. PMID- 28558297 TI - MRI-sensitive contrast agent with anticoagulant activity for surface camouflage of transplanted pancreatic islets. AB - Pancreatic islet implantation in the liver is a promising approach for diabetes therapy. However, 70% of the islet mass fails to be engrafted in the liver due to the instant blood-mediated inflammatory reactions (IBMIR) resulting from direct contact between islet cells and the bloodstream. To overcome this issue, direct monitoring is very important for establishing prognosis after islet cell therapy. Here we established a new type of MR contrast agent with anticoagulant activity via heparin-immobilized superparamagnetic iron oxide (HSPIO). The HSPIO was chemically conjugated onto islet surface ex vivo without damage of their viability and functionality. The conjugated HSPIO nanoparticles onto islet surface could attenuate IBMIR in vitro and in vivo. The HSPIO-conjugated islets could cure the blood glucose levels of diabetes animals after implantation. In addition, the HSPIO nanoparticles were well maintained on the transplanted islets for a long time during modulation of inflammation. Also, they allowed for stable visualization of the implanted islet cells for more than 150 days without reduction of the MRI signal. Furthermore, when HSPIO itself was intraportally injected, it was rapidly eliminated without accumulation in the liver, suggesting that HSPIO nanoparticles could only track the immobilized islet. Collectively, this HSPIO nanoparticle having MRI sensitivity and anticoagulant activity could be utilized for successful islet implantation. PMID- 28558298 TI - Facile endothelium protection from TNF-alpha inflammatory insult with surface topography. AB - Adverse events triggered by the direct contact between blood and synthetic materials constitute a sincere shortcoming of cardiovascular implant technology. A well-connected autologous endothelium, generated through the process of endothelialization, impedes such interaction and endows the implant luminal interface with optimal protection. The endothelialization of artificial substrates is the result of a complex interplay between endothelial cells (ECs), surface topography, and flow-generated wall shear stress (WSS). This is however tainted by the pro-inflammatory signaling, typical of cardiovascular patients, which compromises endothelial integrity and survival. Here, we challenge human endothelial monolayers with the pro-inflammatory factor TNF-alpha under realistic WSS conditions. In these experimental settings we demonstrate that the simple contact between ECs and an optimized surface geometry can inhibit NF-kB activation downstream of TNF-alpha yielding increased stability of VE-Cadherin mediated cell-to-cell junctions and of focal adhesions. Therefore the here presented topographic modification can be implemented on a range of artificial substrates enabling their endothelialization under supra-physiological flow and in the presence of pro-inflammatory insults. These new findings constitute an important step toward achieving the full hemocompatibility of cardiovascular implants. PMID- 28558299 TI - Ligands of toll-like receptors 2/4 differentially alter markers of inflammation, adhesion and angiogenesis by monocytes from women with pre-eclampsia in co culture with endothelial cells. AB - Pre-eclampsia (PE) is characterized by an exaggerated systemic inflammatory response and generalized endothelial dysfunction. We have recently demonstrated that fibrinogen, an endogenous ligand of Toll-like receptor (TLR) 4, activates monocytes from women with pre-eclampsia (Al-ofi et al., 2014). Using an experimental co-culture model of primary human monocytes (derived from 9 women with PE (GA=33.18+/-5.8) and 9 normotensive pregnant women, NP (GA=33.15+/-4.0)) and human umbilical venous endothelial cells (HUVECs), we compared the effects of fibrinogen and lipopolysaccharide (LPS, bacterial ligand to TLR4) on the expression levels of inflammatory cytokines (IL-6 and IL-1beta), chemokines (IL-8 and MCP-1), and anti-angiogenic factor (soluble fms-like tyrosine kinase-1,sFLT 1), as well as the soluble vascular cell adhesion molecule-1 (sVCAM-1). Cytokines, VEGF and sVCAM-1 were measured in the supernatant media by cytometric array. The levels of sFLT-1 were measured by ELISA. Fibrinogen induced greater expression levels of IL-1beta and VCAM-1 from PE HUVEC-monocyte co-culture than from NP HUVEC-monocyte co-culture (P<0.05), similar to the effects of LPS. In contrast, unlike LPS, fibrinogen suppressed IL-6, IL-8, MCP-1 and sFLT-1 production by co-cultures that included PE monocytes compared to those with NP monocytes (P<0.05). In conclusion, fibrinogen promotes monocyte-endothelial cell adhesion and angiogenesis and suppresses the expression of some inflammatory markers in pre-eclampsia. Although the physiological implications of these intriguing observations are unclear our findings suggest that fibrinogen contributes to the regulation of cell adhesion, angiogenesis and inflammation by mechanisms not wholly dependent on TLR4 stimulation. PMID- 28558300 TI - Urine cadmium levels and albuminuria in a general population from Spain: A gene environment interaction analysis. AB - BACKGROUND: The interaction of cadmium with genes involved in oxidative stress, cadmium metabolism and transport pathways on albuminuria can provide biological insight on the relationship between cadmium and albuminuria at low exposure levels. OBJECTIVES: We tested the hypothesis that specific genotypes in candidate genes may confer increased susceptibility to cadmium exposure. METHODS: Cadmium exposure was estimated by inductively coupled plasma mass spectrometry (ICPMS) in urine from 1397 men and women aged 18-85years participating in the Hortega Study, a representative sample of a general population from Spain. Urine albumin was measured by automated nephelometric immunochemistry. Abnormal albuminuria was defined as urine albumin greater than or equal to 30mg/g. RESULTS: The weighted prevalence of abnormal albuminuria was 6.3%. The median level of urine cadmium was 0.39 (IQR, 0.23-0.65) MUg/g creatinine. Multivariable-adjusted geometric mean ratios of albuminuria comparing the two highest to the lowest tertile of urine cadmium were 1.62 (95% CI, 1.43-1.84) and 2.94 (95% CI, 2.58-3.35), respectively. The corresponding odds ratios of abnormal albuminuria were 1.58 (0.83, 3.02) and 4.54 (2.58, 8.00). The association between urine cadmium and albuminuria was observed across all participant subgroups evaluated including participants without hypertension, diabetes or chronic kidney disease. We observed Bonferroni corrected statistically significant interactions between urine cadmium levels and polymorphisms in gene SLC30A7 and RAC1. CONCLUSIONS: Increasing urine cadmium concentrations were cross-sectionally associated with increased albuminuria in a representative sample of a general population from Spain. Genetic variation in oxidative stress and cadmium metabolism and transport genes may confer differential susceptibility to potential cadmium effects. PMID- 28558301 TI - Crop bioaccumulation and human exposure of perfluoroalkyl acids through multi media transport from a mega fluorochemical industrial park, China. AB - Significant quantities of perfluoroalkyl acids (PFAAs) are released to the environment from fluorochemical manufacturing processes through wastewater discharge and air emission in China, which may lead to human exposure and health risks through crop bioaccumulation from PFAAs-contaminated soil and irrigation water. This paper systematically studied the distribution and transport of PFAAs in agricultural soil, irrigation water and precipitation, followed by crop bioaccumulation and finally human exposure of PFAAs within a 10km radius around a mega-fluorochemical industrial park (FIP). Hotspots of contamination by PFAAs were found near the FIP and downstream of the effluent discharge point with the maximum concentrations of 641ng/g in agricultural soil, 480ng/g in wheat grain, 58.8ng/g in maize grain and 4,862ng/L in precipitation. As the distance increased from the FIP, PFAAs concentrations in all media showed a sharp initial decrease followed by a moderate decline. Elevated PFAA concentrations in soil and grains were still present within a radius of 10 km of the FIP. The soil contamination was associated with the presence of PFAAs in irrigation water and precipitation, and perfluorooctanoic acid (PFOA) was the dominant PFAA component in soil. However, due to bioaccumulation preference, short-chain perfluoroalkyl carboxylic acids (PFCAs), especially perfluorobutanoic acid (PFBA), became the major PFAA contaminants in grains of wheat and maize. The bioaccumulation factors (BAFs) for both grains showed a decrease with increasing chain length of PFAAs (approximately 0.5 log decrease per CF2 group). Compared to maize grain, wheat grain showed higher BAFs, possibly related to its higher protein content. The PFCA (C4-C8) concentrations (on a log10 basis) in agricultural soil and grain were found to show a linear positive correlation. Local human exposure of PFOA via the consumption of contaminated grains represents a health risk for local residents, especially for toddlers and children. PMID- 28558302 TI - Anti-inflammatory effect of epigallocatechin gallate in a mouse model of ovalbumin-induced allergic rhinitis. AB - Currently, a variety of studies have demonstrated that green tea has anti allergic properties, and the major polyphenolic compound, epigallocatechin gallate (EGCG), plays a significant role. Some research indicates that EGCG reduces the production and expression of allergy-related substances. Therefore, EGCG has a potential effect of reducing allergic rhinitis (AR). In this study, the effect of EGCG on allergic rhinitis in an ovalbumin (OVA)-induced mouse model was investigated. After administration of EGCG, the number of sneezes and the occurrence of nasal rubbing were significantly decreased, the concentrations of immunoglobulin E (IgE) and histamine were suppressed in AR mouse serum, the levels of interleukin (IL)-1beta, IL-4, and IL-6 were reduced in AR mice nasal lavage fluid (NLF), and the nasal mucosa mRNA and protein expression of cyclooxygenase 2 (COX-2), IL-1beta, IL-4, and IL-6 were inhibited. The data indicate that EGCG has a beneficial effect of reducing allergic rhinitis. PMID- 28558304 TI - Sedentary behavior and musculoskeletal pain: a five-year longitudinal Icelandic study. PMID- 28558303 TI - Colorectal tumors are enriched with regulatory plasmablasts with capacity in suppressing T cell inflammation. AB - Inflammation plays a critical role in the initiation of colorectal cancer but is also required to mediate antitumor immunity in established tumors. Therefore, identifying the cellular and molecular components in colorectal tumors is necessary for the understanding of tumor progression and the development of novel treatment strategies. In this study, we demonstrated that a specific subtype of regulatory B cells, the CD19loCD27hi plasmablasts, was enriched in the colorectal tumor microenvironment. This CD19loCD27hi plasmablast subset presented high interleukin 10 (IL-10) expression but not transforming growth factor-beta (TGF beta) secretion. Phenotypically, the tumor-infiltrating IL-10+ CD19loCD27hi plasmablasts presented lower CD24, CD38, and IgA, and higher Tim-1 and IgG expression compared to the IL-10- CD19loCD27hi plasmablasts. The tumor infiltrating IL-10+ CD19loCD27hi plasmablasts were found to be gut-homing due to their higher expression of alpha4beta7 while peripheral blood B cells did not show the same characteristic. When cocultured with autologous T cells, CD19loCD27hi plasmablasts demonstrated potent activity in suppressing interferon gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) expression but did not promote Foxp3 expression. Overall, this study demonstrate that in colorectal cancer, CD19loCD27hi plasmablasts make up a large percentage in tumor infiltrating lymphocytes and possess potent immunoregulatory functions, and thus could be utilized in future therapeutic strategies. PMID- 28558305 TI - Synthesis and characterization of metal oxides (CeO2, CuO, NiO, Mn3O4, SnO2 and ZnO) nanoparticles as photo catalysts for degradation of textile dyes. AB - The progress of the enriched photocatalytic degradation predominantly depends on materials fabrication. In the recent times, the outcomes of nanomaterials show extraordinary efficiency due to its shape and size. In this connection, the present work concentrates on the fabrication of single digit metal oxides (CeO2, CuO, NiO, Mn3O4, SnO2 and ZnO) through precipitation method. The structural information of different metal oxides (MOs) and their crystallite size were estimated via XRD analysis and their consistent results revealed that the crystalline sizes of the prepared metal oxide were exhibited in nano size. The morphology and dimension of the synthesized MOs were identified through FE-SEM and TEM techniques. The FE-SEM images were apparently defined that the actual morphology of each metal oxide expresses different dimension due to nucleation and growth process. The result of UV-vis absorption spectra was helped to identify the band gap of MOs and a suitable light for photocatalytic irradiation. Additionally, the synthesized single digit MOs nanoparticles were magnificently applied for the degradation of methyl orange and methylene blue under UV light irradiation. PMID- 28558306 TI - User fees across ecosystem boundaries: Are SCUBA divers willing to pay for terrestrial biodiversity conservation? AB - While ecological links between ecosystems have been long recognised, management rarely crosses ecosystem boundaries. Coral reefs are susceptible to damage through terrestrial run-off, and failing to account for this within management threatens reef protection. In order to quantify the extent to that coral reef users are willing to support management actions to improve ecosystem quality, we conducted a choice experiment with SCUBA divers on the island of Bonaire, Caribbean Netherlands. Specifically, we estimated their willingness to pay to reduce terrestrial overgrazing as a means to improve reef health. Willingness to pay was estimated using the multinomial, random parameter and latent class logit models. Willingness to pay for improvements to reef quality was positive for the majority of respondents. Estimates from the latent class model determined willingness to pay for reef improvements of between $31.17 - $413.18/year, dependent on class membership. This represents a significant source of funding for terrestrial conservation, and illustrates the potential for user fees to be applied across ecosystem boundaries. We argue that such across-ecosystem-boundary funding mechanisms are an important avenue for future investigation in many connected systems. PMID- 28558307 TI - Electrophysiological signals associated with fluency of different levels of processing reveal multiple contributions to recognition memory. AB - Processing fluency appears to influence recognition memory judgements, and the manipulation of fluency, if misattributed to an effect of prior exposure, can result in illusory memory. Although it is well established that fluency induced by masked repetition priming leads to increased familiarity, manipulations of conceptual fluency have produced conflicting results, variously affecting familiarity or recollection. Some recent studies have found that masked conceptual priming increases correct recollection (Taylor & Henson, 2012), and the magnitude of this behavioural effect correlates with analogous fMRI BOLD priming effects in brain regions associated with recollection (Taylor, Buratto, & Henson, 2013). However, the neural correlates and time-courses of masked repetition and conceptual priming were not compared directly in previous studies. The present study used event-related potentials (ERPs) to identify and compare the electrophysiological correlates of masked repetition and conceptual priming and investigate how they contribute to recognition memory. Behavioural results were consistent with previous studies: Repetition primes increased familiarity, whereas conceptual primes increased correct recollection. Masked repetition and conceptual priming also decreased the latency of late parietal component (LPC). Masked repetition priming was associated with an early P200 effect and a later parietal maximum N400 effect, whereas masked conceptual priming was only associated with a central-parietal maximum N400 effect. In addition, the topographic distributions of the N400 repetition priming and conceptual priming effects were different. These results suggest that fluency at different levels of processing is associated with different ERP components, and contributes differentially to subjective recognition memory experiences. PMID- 28558308 TI - Age predicts cytokine kinetics and innate immune cell activation following intranasal delivery of IFNgamma and GM-CSF in a mouse model of RSV infection. AB - Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in young children and is further associated with increased healthcare utilization and cost of care in the first years of life. Severe RSV disease during infancy has also been linked to the later development of allergic asthma, yet there remains no licensed RSV vaccine or effective treatment. Pre-clinical and clinical studies have shown that disease severity and development of allergic asthma are associated with differences in cytokine production. As a result, stimulation of the innate host immune response with immune potentiators is gaining attention for their prospective application in populations with limited immune responses to antigenic stimuli or against pathogens for which vaccines do not exist. Specifically, macrophage-activating cytokines such as interferon gamma (IFNgamma) and granulocyte colony-stimulating factor (GM-CSF) are commercially available immune potentiators used to prevent infections in patients with chronic granulomatous disease and febrile neutropenia, respectively. Moreover, an increasing number of reports describe the protective function of IFNgamma and GM CSF as vaccine adjuvants. Although a positive correlation between cytokine production and age has previously been reported, little is known about age dependent cytokine metabolism or immune activating responses in infant compared to adult lungs. Here we use a non-compartmental pharmacokinetic model in naive and RSV-infected infant and adult BALB/c mice to determine the effect of age on IFNgamma and GM-CSF elimination and innate cell activation following intranasal delivery. PMID- 28558310 TI - Estimating sibling spillovers in health: Evidence on symptoms. AB - This paper estimates the sibling spillover effect in health symptoms using a sample of US adolescents from the National Longitudinal Study of Adolescent Health dataset. The research design of this paper is to restrict the sample to sibling pairs who are separated between schools, where one enters high school and the other middle school. Because of school separation, sibling pairs face independent health shocks from own school peers. The identification strategy further exploits variations in individual health across symptoms to control for unobserved individual heterogeneity, which flexibly partials out family correlated effects. Estimation results show that the sibling spillover effect is large as a one-standard-deviation increase in one sibling's frequency of developing a stomach ache or a loss of appetite increases the other sibling's frequency of having the same symptom by about 55% of a standard deviation. Further investigation suggests that the effect is not due to spillovers in drinking alcohol or depression, but probably due to the spread of contagious illnesses like the stomach flu. PMID- 28558311 TI - Prevalence of the number of cusps and occlusal groove patterns of the mandibular molars in a Saudi Arabian population. AB - A dental trait in humans can be a valuable diagnostic tool in anthropological studies for classifying and characterizing different ethnic groups. Many studies have attempted to relate the prevalence of dental morphologies with different factors. Several variations, such as variations in the size, number of cusps, and groove pattern, have been observed in the mandibular molars of diverse populations. The morphological features of the occlusal surfaces of the mandibular molars have been described by Gregory and Hellman. To date, no studies have been reported in the literature regarding the frequency and expression of different types of cusps and the occlusal groove patterns in a Saudi Arabian population. The present study aimed to determine the prevalence of different occlusal morphologies (number of cusps and occlusal groove patterns) of the permanent mandibular first and second molar in a Saudi population and to correlate its importance in forensics, if any. The results of this study showed that the most frequent occlusal configurations were the 5-cusp pattern seen in 85% (136 teeth) and the 4-cusp pattern seen in 11% (18 teeth) of the mandibular first molars, bilaterally. Regarding the mandibular second molars, the 4-cusp form was the most common occlusal configuration, seen in 82% (132 teeth), followed by the 5-cusps type, seen in approximately 16% (26 teeth), bilaterally. Statistically significant (P value = 0.001) differences were noted for the permanent mandibular first and second molars between male and female subjects in all cusp and groove patterns ("Y" and "+" patterns). Similarly, significant differences (P value = 0.001) were found between the unilateral and bilateral presence of different cusp and groove patterns, both in the mandibular first and second molars. The present study showed that the groove pattern in the mandibular first molars was very different when compared to other populations. The cusp and groove patterns of the mandibular second molars were similar to those of the East African and Iranian populations. The results of this study may be used in forensics. Thus, the outcomes of this study may be helpful in both anthropological and clinical dental research. PMID- 28558309 TI - Reduced frequency of murine cytomegalovirus retinitis in C57BL/6 mice correlates with low levels of suppressor of cytokine signaling (SOCS)1 and SOCS3 expression within the eye during corticosteroid-induced immunosuppression. AB - AIDS-related human cytomegalovirus retinitis remains a leading cause of blindness worldwide. We compared two C57BL/6 mouse models of experimental murine cytomegalovirus (MCMV) retinitis for intraocular expression of suppressors of cytokine signaling (SOCS)1 and SOCS3, host proteins that are inducible negative feedback regulators of cytokine signaling. These mouse models differed in method of immune suppression, one by retrovirus-induced immune suppression (MAIDS) and the other by corticosteroid-induced immune suppression. Following subretinal injection of MCMV to induce retinitis, intraocular SOCS1 and SOCS3 were only mildly stimulated, and often without significance, within MCMV-infected eyes during the progression of MCMV retinitis in corticosteroid-immunosuppressed mice, contrary to MCMV-infected eyes of mice with MAIDS that showed significant high stimulation of SOCS1 and SOCS3 expression in agreement with previous findings. Frequency and severity of retinitis as well as amounts of intraocular infectious MCMV in corticosteroid-immunosuppressed mice were also unexpectedly lower than values previously reported for MAIDS animals during MCMV retinitis. These data reveal a major difference between two mouse models of experimental MCMV retinitis and suggest a possible link between the amplitude of SOCS1 and SOCS3 stimulation and severity of disease in these models. PMID- 28558312 TI - Distinct influences of affective and cognitive factors on children's non-verbal and verbal mathematical abilities. AB - Individual differences in children's math performance have been associated with math anxiety, attention problems, working memory (WM), and reading skills, but the mechanisms by which these factors jointly contribute to children's math achievement are unknown. Here, we use structural equation modeling to characterize the relation between these factors and their influence on non-verbal Numerical Operations (NO) and verbal Math Reasoning (MR) in 330 children (M=8.34years). Our findings indicate that WM plays a central role in both non verbal NO and verbal MR, whereas math anxiety and reading comprehension have unique and more pronounced influences on MR, compared to NO. Our study elucidates how affective and cognitive factors distinctly influence non-verbal and verbal mathematical problem solving. PMID- 28558313 TI - Fertility affects asymmetry detection not symmetry preference in assessments of 3D facial attractiveness. AB - Consistent with theories from evolutionary psychology, facial symmetry correlates with attractiveness. Further, the preference for symmetrical faces appears to be affected by fertility in women. One limitation of previous research is that faces are often symmetrically lit front-views and so symmetry can be assessed using 2D pictorial information. Another limitation is that two-alternative-forced-choice (2afc) tasks are often used to assess symmetry preference and these cannot distinguish between differences in preference for symmetry and differences in ability of asymmetry detection. The current study used three tasks to assess the effects of facial symmetry: attractiveness ratings, 2afc preference and asymmetry detection. To break the link between 2D pictorial symmetry and facial symmetry, 3D computer generated heads were used with asymmetrical lighting and yaw rotation. Facial symmetry correlated with attractiveness even under more naturalistic viewing conditions. Path analysis indicates that the link between fertility and 2afc symmetry preference is mediated by asymmetry detection not increased preference for symmetry. The existing literature on symmetry preference and attractiveness is reinterpreted in terms of differences in asymmetry detection. PMID- 28558314 TI - Flexion synergy overshadows flexor spasticity during reaching in chronic moderate to severe hemiparetic stroke. AB - OBJECTIVE: Pharmaceutical intervention targets arm flexor spasticity with an often-unsuccessful goal of improving function. Flexion synergy is a related motor impairment that may be inadvertently neglected. Here, flexor spasticity and flexion synergy are disentangled to determine their contributions to reaching dysfunction. METHODS: Twenty-six individuals participated. A robotic device systematically modulated shoulder abduction loading during ballistic reaching. Elbow muscle electromyography data were partitioned into windows delineated by elbow joint velocity allowing for the separation of synergy- and spasticity related activation. RESULTS: Reaching velocity decreased with abduction loading (p<0.001) such that velocity was 30% slower when lifting the arm at 50% of abduction strength compared to when arm weight was supported. Abnormal flexion synergy increased with abduction loading (p<0.001) such that normalized activation ranged from a median (interquartile range) of 0.07 (0.03-0.12) when arm weight was supported to 0.19 (0.12-0.40) when actively lifting (large effect size, d=0.59). Flexor spasticity was detected during reaching (p=0.016) but only when arm weight was supported (intermediate effect size, d=0.33). CONCLUSION: Flexion synergy is the predominant contributor to reaching dysfunction while flexor spasticity appears only relevant during unnaturally occurring passively supported movement. SIGNIFICANCE: Interventions targeting flexion synergy should be leveraged in future stroke recovery trials. PMID- 28558315 TI - Macrodactylia lipomatosa with fibrolipomatous hamartomas: Macroscopic and ultrasound clues. PMID- 28558316 TI - Heart rate changes according to the complexity of motor events in REM sleep behavior disorder. PMID- 28558317 TI - Changes in resting-state directed connectivity in cortico-subcortical networks correlate with cognitive function in Parkinson's disease. AB - OBJECTIVE: The pathophysiological mechanisms underlying Parkinson's disease (PD) related cognitive decline and conversion to PD dementia are poorly understood. In the healthy human brain, stable patterns of posterior-to-anterior cortical information flow have recently been demonstrated in the higher frequency bands using magnetoencephalography (MEG). In this study we estimated PD-related changes in information flow patterns, as well as the contribution of subcortical regions. METHODS: Resting-state MEG recordings were acquired in moderately advanced PD patients (n=34; mean Hoehn and Yahr-stage 2.5) and healthy controls (n=12). MEG signals were projected to both cortical and subcortical brain regions, following which we estimated the balance between incoming and outgoing information flow per region. RESULTS: In PD patients, compared to controls, preferential beta band information outflow was significantly higher for the basal ganglia and frontotemporal cortical regions, and significantly lower for parieto-occipital regions. In addition, in patients, low preferential information outflow from occipital regions correlated with poor global cognitive performance. CONCLUSION: In the PD brain, a shift in balance towards more anterior-to-posterior beta band information flow takes place and is associated with poorer cognitive performance. SIGNIFICANCE: Our results indicate that a reversal of the physiological posterior to-anterior information flow may be an important mechanism in PD-related cognitive decline. PMID- 28558318 TI - A new near-lossless EEG compression method using ANN-based reconstruction technique. AB - Compression algorithm is an essential part of Telemedicine systems, to store and transmit large amount of medical signals. Most of existing compression methods utilize fixed transforms such as discrete cosine transform (DCT) and wavelet and usually cannot efficiently extract signal redundancy especially for non stationary signals such as electroencephalogram (EEG). In this paper, we first propose learning-based adaptive transform using combination of DCT and artificial neural network (ANN) reconstruction technique. This adaptive ANN-based transform is applied to the DCT coefficients of EEG data to reduce its dimensionality and also to estimate the original DCT coefficients of EEG in the reconstruction phase. To develop a new near lossless compression method, the difference between the original DCT coefficients and estimated ones are also quantized. The quantized error is coded using Arithmetic coding and sent along with the estimated DCT coefficients as compressed data. The proposed method was applied to various datasets and the results show higher compression rate compared to the state-of-the-art methods. PMID- 28558319 TI - Spotting L3 slice in CT scans using deep convolutional network and transfer learning. AB - In this article, we present a complete automated system for spotting a particular slice in a complete 3D Computed Tomography exam (CT scan). Our approach does not require any assumptions on which part of the patient's body is covered by the scan. It relies on an original machine learning regression approach. Our models are learned using the transfer learning trick by exploiting deep architectures that have been pre-trained on imageNet database, and therefore it requires very little annotation for its training. The whole pipeline consists of three steps: i) conversion of the CT scans into Maximum Intensity Projection (MIP) images, ii) prediction from a Convolutional Neural Network (CNN) applied in a sliding window fashion over the MIP image, and iii) robust analysis of the prediction sequence to predict the height of the desired slice within the whole CT scan. Our approach is applied to the detection of the third lumbar vertebra (L3) slice that has been found to be representative to the whole body composition. Our system is evaluated on a database collected in our clinical center, containing 642 CT scans from different patients. We obtained an average localization error of 1.91+/-2.69 slices (less than 5 mm) in an average time of less than 2.5 s/CT scan, allowing integration of the proposed system into daily clinical routines. PMID- 28558320 TI - Raman evidence for presence of high-temperature ferromagnetic clusters in magnetodielectric compound Ba-doped La2NiMnO6. AB - Magnetodielectric ferromagnetic semiconductors are key materials because of their applications in spintronic devices; they can be used to control the magnetic properties by applying electric fields. La2NiMnO6 emerged as an important magnetodielectric ferromagnetic semiconductor because of its high Curie temperature near room temperature. Recently Ba doped was successfully used to improve magnetic properties in La2NiMnO6, originating partially ordered systems with different ordering degrees but presenting same Tc=280K. However, the influence of Ba doping on the temperature dependent vibrational properties of the system was not investigated. To investigate the Ba doping influence on temperature dependent phonon spectra in La2NiMnO6, we used Raman Spectroscopy to probe the symmetric stretching mode behavior in the range from 10 to 600K. Remarkable softenings were detected in the phonon behavior due to spin phonon coupling, at several different temperatures, much above Tc. The FWHM dependence with temperature rules out magnetostriction effects. The phonon softenings are the largest reported so far for the RE2NiMnO6 systems and also indicate that Ba doping induces ordering in the Ni/Mn sites. The temperature discordance in characteristic softening onset of the spin phonon coupling are related to ferromagnetic short range clusters due the presence of Ni3+, Mn3+ oxidation states. PMID- 28558321 TI - Raman spectroscopy for the evaluation of the effects of different concentrations of Copper on the chemical composition and biological activity of basil essential oil. AB - The present study is performed to evaluate the effect of different concentrations of Cu as fertilizer on the chemical composition of basil essential oil and its biological activity including antioxidant and antifungal activities by employing Raman spectroscopy. Moreover, the effect of Cu is also determined on the vegetative growth and essential oil yield. Both, antifungal and antioxidant activities were found to be maximum with essential oils obtained at 0.04mg/l concentration of Cu fertilizer. The results of the GC-MS and Raman spectroscopy have revealed that the linalool and estragole are found to be as a major chemical compound in basil essential oil. The Raman spectral changes associated with these biological components lead to the conclusion that estragole seems to have dominating effect in the biological activities of the basil essential oil as compared to linalool although the latter is observed in greater concentration. PMID- 28558322 TI - Spectroscopic properties of Sm3+ ions doped Alkaliborate glasses for photonics applications. AB - A new series of Sm3+ doped alkaliborate glasses have been prepared by melt quenching technique and their structural and spectroscopic properties were analysed employing XRD, FTIR, optical absorption, photoluminescence and decay spectral measurements in order to explore their suitability for photonic applications. The amorphous nature have been confirmed through XRD analysis and the FTIR spectra reveal the presence of fundamental stretching and bending vibrations of the borate networks in the prepared glasses. From the absorption peak positions, bonding parameter (delta) values were calculated to examine the nature of the metal-ligand bond. The optical band gap (Eopt) corresponds to the direct and indirect allowed transitions and the Urbach energies (DeltaE) were calculated from the absorption spectra to understand the electronic band structure of the studied glasses. The Judd-Ofelt (JO) intensity parameters Omegalambda (lambda=2, 4 and 6) were determined to explore the symmetry of the ligand environment around the Sm3+ ions in the studied glasses. The luminescence spectra exhibit four emission bands in the visible region due to the 4G5/2 >6H5/2, 6H7/2, 6H9/2 and 6H11/2 transitions. The radiative parameters such as transition probability (A), stimulated emission cross-section (sigmaPE), branching ratios (betaR) and radiative lifetime (tauR) have been determined from the luminescence spectra using JO theory to ensure the suitability of the studied glasses for optoelectronic applications. The luminescence spectra were characterized through CIE 1931 chromaticity diagram to examine the dominant emission color of the studied glasses. The lifetime values of the Sm3+ doped studied glasses pertaining to the 4G5/2 excited level have been determined through decay curve measurements and the non-exponential decay curves were fitted to the Inokuti-Hirayama model to analyze the energy transfer mechanism between the nearby Sm3+ ions. The obtained results were discussed and compared with the similar reported glasses. PMID- 28558323 TI - "A boy, being a victim, nobody really buys that, you know?": Dynamics of sexual violence against boys. AB - The aim of this study was to present the dynamics of sexual violence against boys. Interviews were conducted with four male victims of sexual abuse between the ages of six and 10, as well as four psychologists employed in the health care system and involved in the treatment of sexually abused boys. Results were examined using thematic content analysis, based on six deductively identified themes corresponding to the following stages of sexual violence against children and adolescents: preparation, episodes, silencing, narratives, repression and overcoming. The results suggested that proximity between victims and offenders, who were mostly adolescent boys, was a facilitator of abuse. The interviews also revealed that victims faced significant levels of disbelief and discrimination. Lastly, the findings pointed to the importance of protective actions and of the system itself, though all practitioners perceived the latter as flawed and unprepared to handle cases involving sexually abused boys. These findings underscore the social invisibility of sexual violence against boys, due to the low number of referrals as well as the disbelief and discrimination, which permeates the management of these cases. PMID- 28558324 TI - Coping styles in youth exposed to maltreatment: Longitudinal patterns reported by youth in foster care. AB - Coping styles in youth living in foster care with a history of maltreatment were examined to determine the nature and stability of self-reported coping behavior over time. Participants included 542 (time 1), 377 (time 2), and 299 (time 3) youth ages 8-22 years (M=13.28years, SD=3.04). Using the Behavioral Inventory of Strategic Control, a dimensional, continuous measure of coping, across four possible coping styles endorsed in reference to specific potentially stressful situations, the results indicated that direct action coping was the most frequently endorsed or preferred style for more than 50% of the sample at each time point. A number of youth endorsed using more than one coping style, indicating some flexibility in the approach to coping when problems occur. Although most youth endorsed a preferred style, coping style endorsed did vary somewhat over time. The coping style endorsed also varied depending on the type of problem referenced, but no statistically significant differences were noted across situations, including social, academic, general, and foster-specific situations. Effects for age were also examined and the results indicated no significant differences across the age range for type of coping most commonly endorsed. The present study is the first large-scale, longitudinal assessment of coping styles in youth in foster care and the results suggest that coping is not a simple, categorical-only construct and the implications for the endorsement of the direct approach for youth in foster care along with the other findings are discussed. PMID- 28558325 TI - Migration and arsenic adsorption study of starch-modified Fe-Ce oxide on a silicon-based micromodel observation platform. AB - Iron materials have shown great potential to remediate arsenic (As) contaminated sites. It's very important to reveal the reaction process between iron materials and As from the perspective of pore scale, but relevant research was inadequate. In order to directly investigate the migration and As adsorption mechanism of starch-modified Fe-Ce oxide in pore scale, a silicon-based micromodel observation platform was established in this study. The results of Charge coupled Device images showed that the sedimentation surface area of SFC occupied about 57.02% of the large porosity zone, but only 23.27% of the small porosity zone. To further reveal the 3D distribution of Fe and As elements inside the pore network, Laser Induced Breakdown Spectroscopy was introduced. The results revealed that less As was adsorbed as less SFC intruded in the small porosity zone. When the large porosity zone was blocked by SFC, a permeability barrier was created to adsorb As from upstream. This study also explored the effect of particle size reduction on SFC migration, and found it might be a better candidate for more SFC penetrated into small porosity zone. Combined with various high-resolution and sensitivity detection methodologies, more colloidal migration mechanisms can be investigated using this technology in the future. PMID- 28558326 TI - Preparation, characterization and thermal risk evaluation of dihydroxylammonium 5, 5'-bistetrazole-1, 1'-diolate based polymer bonded explosive. AB - Dihydroxylammonium 5,5'- bistetrazole-1,1'-diolate (TKX-50) was used to prepare TKX-50-based polymer bonded explosive (PBX) for the first time in this study. The thermal stabilities and the kinetic parameters of TKX-50 and TKX-50-based PBX were compared via Differential Scanning Calorimetry (DSC), Thermal Gravity Differential Thermal Gravity (TG-DTG) and Accelerating Rate Calorimeter (ARC). Furthermore, in order to know about their thermal safeties comprehensively, an advanced thermal analysis program based on Friedman method was employed to calculate the thermal safety parameters for TKX-50 and its PBX. With its help, two important safety parameters (time to maximum rate under adiabatic conditions (TMRad) and self-accelerating decomposition temperature (SADT)) for the two energetic materials were calculated and discussed. Finally, based on the safety parameters, effects of storage conditions and ambient temperatures on the thermal explosions of TKX-50 and TKX-50-based PBX were further studied by using finite element analysis (FEA). PMID- 28558327 TI - d-Alanine 2, Leucine 5 Enkephaline (DADLE)-mediated DOR activation augments human hUCB-BFs viability subjected to oxidative stress via attenuation of the UPR. AB - Human mesenchymal stem cells (hMSCs) although being potent in repairing injured or ischemic tissues, their success regarding tissue-regenerative approaches are hindered by the paucity in their viability. The elevated levels of reactive oxygen species (ROS) in damaged sites provoke the pernicious effects of donor MSC survival. In the present study, the effect of delta-opioid receptor (DOR) activation on human umbilical cord-blood borne fibroblasts (hUCB-BFs) survival under oxidative stress (H2O2) was evaluated. Oxidative stress which is known to trigger pathological conditions of the unfolded protein response (UPR) leads to endoplasmic reticulum stress. Upon its activation by D-Alanine 2, Leucine 5 Enkephaline (DADLE, selective DOR agonist) in hUCB-BFs under oxidative stress, a significant down regulation (~2 folds) of key UPR genes was observed as determined by qPCR, Thioflavin-T protein aggregation assay and western blot analysis. Concomitantly, the oxidative stress-mediated cell-death was ameliorated and the viable-cells' percentage was enhanced following DOR activation. The intracellular ROS production upon H2O2 treatment as determined by CM-H2DCFDA staining was repressed, the anti-apoptotic marker Bcl-2 was upregulated along with a significant suppression in the expression levels of pro-apoptotic proteins Bax and Bad upon DOR activation. Upon subsequent treatment with naltrindole, the effects of DADLE-induced cytoprotection were reverted significantly. These results propound the role of DADLE-mediated DOR-activation on improvement of the viability, which might succour successful hUCB-BFs transplants and greatly absolve the inefficacy of tissue-specific engineered transplants. PMID- 28558328 TI - Microscopic evaluation of the ventricular tissue using stereological and Voronoi tessellation methods: Application on doxorubicin-induced cardiotoxicity in rats. AB - There is limited quantitative microscopic information concerning the three dimensional arrangement of cardiomyocytes and microvessels in cardiotoxic condition. The aim of this study was to evaluate the cardiac tissue of rats under different experimental conditions using modern second-order stereology and Voronoi tessellation techniques to show the spatial arrangement of the cardiomyocytes and microvessels. Sprague-Dawley rats were randomly divided into two groups (n=6). The control group received PBS and the doxorubicin (DOX) group received 4mg/kg DOX on days 1, 8, 15, and 22. On the 24th day, the left ventricle was sectioned and prepared according to the "orientator" method for microscopically evaluations. The "covariance functions" were plotted using "linear dipole probes". Polygonal tessellation of the ventricles was also diagrammed using ImageJ software. The plotting the covariance curves of the cardiomyocytes and microvessels forming the "gaps" by slopped down, crossing the reference line and rose again. In the control group, the gaps were placed at 35 40MUm and 14-16MUm for the cardiomyocytes and microvessels, respectively. In the cardiotoxic group, the curves demonstrated larger gaps in comparison with the normal hearts, indicating repulsion of these structures. The curves of the cross correlation function of the cardiomyocytes-microvessels also demonstrated the cardiomyocytes and microvessels were not normally correlated after the toxicity. Evaluation of Voronoi tessellations for the cardiomyocytes nuclei and microvessels in the normal and cardiotoxic groups showed that the areas of polygons in the normal heart were placed in the smaller range, while the areas fell in a larger range in the cases of cardiotoxicity. Stereological and Voronoi Tessellation methods showed that ventricular tissue lost its normal spatial arrangement in doxorubicin-induced cardiotoxicity in rats. PMID- 28558329 TI - Risk stratification of women with false-positive test results in mammography screening based on mammographic morphology and density: A case control study. AB - BACKGROUND: The long-term risk of breast cancer is increased in women with false positive (FP) mammography screening results. We investigated whether mammographic morphology and/or density can be used to stratify these women according to their risk of future breast cancer METHODS: We undertook a case-control study nested in the population-based screening programme in Copenhagen, Denmark. We included 288 cases and 288 controls based on a cohort of 4743 women with at least one FP-test result in 1991-2005 who were followed up until 17 April 2008. Film-based mammograms were assessed using the Breast Imaging-Reporting and Data System (BI RADS) density classification, the Tabar classification, and two automated techniques quantifying percentage mammographic density (PMD) and mammographic texture (MTR), respectively. The association with breast cancer was estimated using binary logistic regression calculating Odds Ratios (ORs) and the area under the receiver operating characteristic (ROC) curves (AUCs) adjusted for birth year and age and invitation round at the FP-screen RESULTS: Significantly increased ORs were seen for BI-RADS D(density)2-D4 (OR 1.94; 1.30-2.91, 2.36; 1.51-3.70 and 4.01; 1.67-9.62, respectively), Tabar's P(pattern)IV (OR 1.83; 1.16-2.89), PMD Q(quartile)2-Q4 (OR 1.71; 1.02-2.88, 1.97; 1.16-3.35 and 2.43; 1.41-4.19, respectively) and MTR Q4 (1.97; 1.12-3.46) using the lowest/fattiest category as reference CONCLUSION: All four methods, capturing either mammographic morphology or density, could segregate women with FP-screening results according to their risk of future breast cancer - using already available screening mammograms. Our findings need validation on digital mammograms, but may inform potential future risk stratification and tailored screening strategies. PMID- 28558330 TI - Spray-dried adjunct cultures of autochthonous non-starter lactic acid bacteria. AB - Spray-drying of lactic cultures provides direct-to-vat starters, which facilitate their commercialization and use. However, this process may alter the metabolic activity and deteriorate technological features. In this work, we assessed the influence of spray-drying on the survival and aroma production of two strains of mesophilic lactobacilli: Lactobacillus paracasei 90 and Lactobacillus plantarum 91, which have already been characterized as good adjunct cultures. The spray drying was carried out using a laboratory scale spray and the dried cultures were monitored during the storage for the survival rate. The dried cultures were applied to two cheese models: sterile cheese extract and miniature soft cheese. The influence on the carbohydrate metabolism and the production of organic acids and volatile compounds was determined. Both strains retained high levels of viable counts in the powder after drying and during the storage at 5 degrees C for twelve months. In addition, they also remained at high level in both cheese models during incubation or ripening. Similar profiles of carbohydrate fermentation and bioformation of volatile compounds were observed in the cheese extracts for each of the strains when tested as both fresh and dried cultures. In addition, the ability of Lb. paracasei 90 to increase the production of acetoin and diacetyl remarkably in cheese models was also confirmed for the spray-dried culture. PMID- 28558331 TI - Impact of thistle rennet from Carlina acanthifolia All. subsp. acanthifolia on bacterial diversity and dynamics of a specialty Italian raw ewes' milk cheese. AB - Caciofiore della Sibilla is an Italian specialty soft cheese manufactured with Sopravissana raw ewes' milk and thistle rennet prepared with young fresh leaves and stems of Carlina acanthifolia All. subsp. acanthifolia, according to an ancient tradition deeply rooted in the territory of origin (mountainous hinterland of the Marche region, Central Italy). In this study, the impact of thistle rennet on the bacterial dynamics and diversity of Caciofiore della Sibilla cheese was investigated by applying a polyphasic approach based on culture and DNA-based techniques (Illumina sequencing and PCR-DGGE). A control cheese manufactured with the same batch of ewes' raw milk and commercial animal rennet was analyzed in parallel. Overall, a large number of bacterial taxa were identified, including spoilage, environmental and pro-technological bacteria, primarily ascribed to Lactobacillales. Thistle rennet was observed clearly to affect the early bacterial dynamics of Caciofiore della Sibilla cheese with Lactobacillus alimentarius/paralimentarius and Lactobacillus plantarum/paraplantarum/pentosus being detected in the phyllosphere of C. acanthifolia All., thistle rennet and curd obtained with thistle rennet. Other bacterial taxa, hypothetically originating from the vegetable coagulant (Enterococcus faecium, Lactobacillus brevis, Lactobacillus delbrueckii, Leuconostoc mesenteroides/pseudomesenteroides), were exclusively found in Caciofiore della Sibilla cheese by PCR-DGGE. At the end of the maturation period, Illumina sequencing demonstrated that both cheeses were dominated by Lactobacillales; however curd and cheese produced with thistle rennet were co dominated by Lactobacillus and Leuconostoc, whereas Lactoccous prevailed in curd and cheese produced with commercial animal rennet followed by Lactobacillus. Differences in the bacterial composition between the two cheeses at the end of their maturation period were confirmed by PCR-DGGE analysis. PMID- 28558332 TI - Nitrate simultaneously enhances lipid and protein accumulation in developing yellow lupin cotyledons cultured in vitro, but not under field conditions. AB - The research was conducted on yellow lupin (Lupinus luteus L.) mature seeds, developing cotyledons, developing pods, and seedlings. The main storage compound in yellow lupin seeds is protein, whose content may reach up to 45%. Oil content in seeds of yellow lupin is about 6%. In such protein-storing seeds there is a strong negative relationship between accumulation of storage lipid and protein. An increase in protein content causes a decrease in lipid level, and vice versa. However, simultaneous increase in lipid and protein content is possible in developing lupin cotyledons (the main storage organs of lupin seeds) cultured in vitro. Such an effect was obtained by feeding the cotyledons with nitrate (35mM). The same positive relationship in storage lipid and protein accumulation was also obtained in developing lupin pods fed with nitrate (35mM), detached from the mother plant, and maintained under quasi in vitro conditions. Fertilization of lupin plants with nitrate under field conditions (40 or 80kgNha-1 applied before sowing, at the nodulation stage or at the flowering and pod formation stage) did not cause significant changes in lipid and protein contents in mature seeds. Experiments performed on lupin seedlings cultivated hydroponically showed that nitrate added to the medium was accumulated mainly in roots, and at a remarkably lower level in shoots. We hypothesize that the lack of stimulatory effect of nitrate on storage lipid and protein accumulation in seeds under field conditions is due to inefficient transport of nitrate from the root to developing pods in lupin plants. This causes that the level of nitrate inside the developing lupin seeds is not elevated under field conditions. PMID- 28558333 TI - Novel NO-releasing plumbagin derivatives: Design, synthesis and evaluation of antiproliferative activity. AB - A series of plumbagin/NO donor hybrids were designed, synthesized and evaluated in vitro against triple negative breast cancer (MDA-MB-231), hepatocellular (HepG2) and lung (A549) carcinoma cells. Most furoxan-based plumbagin derivatives exhibited significantly superior potency compared to their parent compound. Noticeably, MDA-MB-231 cells are the most sensitive to these furoxan-based plumbagin derivatives as evidenced by IC50 values ranging from 1.24 to 5.20 MUM. Besides, NO released amounts detection of all hybrids suggested that in most cases, the antiproliferative activities were positively correlated with the levels of intracellular NO release in MDA-MB-231 cells. The most active compound (11a) also possessed higher chemical stability at different pHs (6.0, 7.4 and 8.0) than plumbagin. Together, the above promising results warrant the future potential of plumbagin/NO hybrids as the lead compounds against triple negative breast cancer deserving further research. PMID- 28558334 TI - Design, synthesis and evaluation of aromatic heterocyclic derivatives as potent antifungal agents. AB - To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (1), a series of aromatic heterocyclic derivatives were designed, synthesized and evaluated for in vitro antifungal activity. Many of the target compounds showed good inhibitory activity against Candida albicans and Cryptococcus neoformans. In particular, the isoxazole nuclei were more suited for improving the activity against Aspergillus spp. Among these compounds, 2-F substituted analogues 23g and 23h displayed the most remarkable in vitro activity against Candida spp., C. neoformans, A. fumigatus and fluconazole-resistant C.alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and voriconazole. Notably, the compounds 23g and 23h exhibited low inhibition profiles for various isoforms of human cytochrome P450 and excellent blood plasma stability. PMID- 28558336 TI - Psychometric properties of the Chinese Internet Gaming Disorder Scale. AB - To develop a consensus on the definition and measurement of Internet gaming disorder (IGD), several recent studies have used the DSM-5's proposed criteria for IGD as the basis in scale construction. This study contributes to this emerging consensus by developing and validating a new Chinese Internet Gaming Disorder Scale (C-IGDS) based on the DSM-5 criteria. A representative sample of Hong Kong community adults (n=502, 50% men, mean age=37.1, age range=18-60) was recruited for a telephone survey with random digit dialing. Various statistical techniques were used to assess the psychometric properties of the C-IGDS. The C IGDS had good reliability (Cronbach's alpha=0.91) and structural validity (CFA model fit: RMSEA=0.027, CFI=0.991, TLI=0.988) in our sample. Moderate to moderately strong correlations with depressive symptoms (r=0.617, p<0.001), social anxiety symptoms (r=0.366, p<0.001), and gaming hours (r=0.412, p<0.001) supported the criterion validity of the C-IGDS. In addition, the C-IGDS exhibited strict measurement invariance for sex and at least strong measurement invariance for age. In addition to providing the first Chinese scale for measuring IGD based on the DSM-5's proposed criteria, this study provides empirical support for the validity of these diagnostic criteria as the basis for a universal measure of IGD. Most important, this study is the first to reveal the criteria's measurement invariance, thereby indicating their suitability for use with diverse demographic groups. PMID- 28558335 TI - Risk is still relevant: Time-varying associations between perceived risk and marijuana use among US 12th grade students from 1991 to 2016. AB - BACKGROUND: Perceived risk of harm has long been a key preventive factor for adolescent marijuana use. However, in recent years, perceived risk has decreased markedly and marijuana use has increased only slightly, leading to new questions about their association. This study investigates the magnitude and stability of the US adolescent marijuana risk/use association from 1991 to 2016, overall and by gender and race/ethnicity. METHODS: Self-reported data on past 12-month marijuana use, perceived risk of regular marijuana use, gender, and race/ethnicity were obtained from 275,768 US 12th grade students participating in the nationally representative Monitoring the Future study. Time-varying effect modeling (TVEM) was used to examine the marijuana risk/use association over time. RESULTS: Both before and after controlling for gender and race/ethnicity, perceived risk was a strong protective factor against adolescent marijuana use. The magnitude of the great risk/use association strengthened for Hispanic students; remained generally stable over time for 12th graders overall, males, females, and White students; and weakened for Black students. The magnitude of the moderate risk/use association strengthened for 12th graders overall, males, females, White and Hispanic students, but did not continue to strengthen for Black students from 2005 onwards. In general, marijuana use prevalence decreased over time within all levels of perceived risk. CONCLUSIONS: Perceived risk remains a strong protective factor for adolescent marijuana use, and the protective association for moderate risk (vs. no/slight risk) is actually increasing over time. Results suggest that accurate and credible information on the risks associated with marijuana use should remain a key component of prevention efforts. PMID- 28558337 TI - Relationship between substance use and attitudes towards seeking professional psychological help among veterans filing PTSD claims. AB - INTRODUCTION: Veterans in distress often do not seek mental health treatment, even when such services are available. Substance use may further undermine treatment-seeking, given its association with negative treatment views. This study examined attitudes towards seeking psychological help in a sample of veterans diagnosed with posttraumatic stress disorder (PTSD), with and without co occurring substance use disorders (SUD). METHODS: Altogether, 143 male OEF/OIF veterans filing service-connected benefits claims for PTSD completed the Attitudes Towards Seeking Professional Psychological Help-Short Form (ATSPPH-SF) and other baseline assessments. Treatment attitudes were compared among veterans with (n=34) and without (n=109) SUD using ANCOVA, controlling for demographic covariates. Post-hoc ANCOVA compared means on the two ATSPPH-SF subscales: Openness to Seeking Treatment, and Value/Need in Seeking Treatment. RESULTS: Overall, ATSPPH-SF scores were similar to those reported in other samples of young men. Controlling for demographic covariates, veterans with co-occurring SUD held significantly less favorable attitudes towards seeking help than veterans without comorbid SUD. In subscale analyses, valuation of treatment was significantly lower among veterans with SUDs, but openness towards treatment was not. CONCLUSIONS: Substance-using veterans' lower valuation of treatment may reflect opinions that problems resolve on their own, psychotherapy is ineffective, or concerns that SUDs complicate treatment. Thus an approach towards engaging these veterans in treatment that addresses a general skepticism towards the value of psychological help is warranted. PMID- 28558339 TI - Regulation the morphology of cationized gold nanoparticles for effective gene delivery. AB - Recent research indicated that the morphology of nanoparticles could result in distinct biological behaviors, thus played an important role in designing efficient gene delivery systems. Among them, gold nanoparticles (AuNPs) with various shapes were widely studied due to the good biocompatibility and easy modification ability. Our recent research indicated that polyethyleneimine-g bovine serum albumin (BSA-PEI) as non-viral gene vector showed good colloid stability and high transfection efficiency. In this work, BSA-PEI was utilized to modify gold nanospheres (AuNSs) and gold nanorods (AuNRs) to investigate the influence of the morphology on gene delivery. Both AuNS@BSA-PEI and AuNR@BSA-PEI nanoparticles condensed DNA effectively at N/P ratio above 5 and maintained spherical or rod-like morphology respectively. Due to the higher surface charge density at the tips, the rod-like gene complexes were prone to use the tips to contact with cell membrane, which facilitated to be uptaked by HepG2 cells. The endocytosis inhibition experiments showed some differences in the endocytic pathway. Gene transfection experiment showed that the rod-like complexes had almost 100-fold higher of transfection level than that of spherical complexes at the N/P ratio of 20. This work provided a potential strategy for further design of gene vectors with improved transfection results by adjusting the morphology of gene vectors. PMID- 28558338 TI - The challenge of sustainability in healthcare systems: Frequency and cost of inappropriate patterns of breast cancer care (the E.Pic.A study). AB - OBJECTIVES: In a context of decreasing economic health resources and a rise in health needs, it is urgent to face this sustainability crisis through the analysis of healthcare expenditures. Wastages, deriving from inappropriate interventions, erode resources which could be reallocated to high-value activities. To identify these areas of wastages, we developed a method for combining and analyzing data from multiple sources. Here we report the preliminary results of a retrospective cohort study evaluating the performance of breast cancer (BC) care at IRST, an Italian cancer institute. MATERIALS AND METHODS: Four data sources gathered in a real-world setting (a clinical database, two administrative databases and a cancer registry) were linked. Essential Key Performance Indexes (KPIs) in the pattern of BC diagnosis (KPI 1 and 2) and treatment (KPI 3 and 4) based on current guidelines were developed by a board of professionals. The costs of inappropriate examinations were associated with the diagnostic KPIs. RESULTS: We found that 2798 patients treated at IRST from January 2010 to June 2016 received a total of 2516 inappropriate examinations accounting for ? 573,510.80. Linkage from multiple routine healthcare data sources is feasible: it allows the measurement of important KPIs specifically designed for BC care, and the identification of areas of low-value use of the resources. CONCLUSION: If systematically applied, this method could help provide a complete picture of inappropriateness and waste, redirect these resources to higher-value interventions for patients, and fill the gap between proper use of the resources and the best clinical results. PMID- 28558340 TI - Dynamic changes of flavonoids in Abelmoschus manihot different organs at different growth periods by UPLC-MS/MS. AB - Abelmoschus manihot (Linn.) Medicus has been clinically used to treat chronic kidney disease, oral ulcers, burns, and dysmenorrhea in China for many centuries. The major pharmacologically-active components of A. manihot are flavonoids. In this study, a rapid and highly sensitive UPLC-MS/MS analysis method was established and successfully applied to the simultaneous determination of five major flavonoids (rutin, hyperoside, isoquercitrin, quercetin, and myricetin) in different parts of A. manihot harvested at ten growth periods. Under the optimized chromatographic conditions, good separation for five target components was obtained on an Acquity UPLC BEH C18 column within 18min. The total contents of the five investigated flavonoids in A. manihot roots, stems, leaves and flowers ranged from 2.86 to 123.7MUg/g, 46.39 to 141.0MUg/g, 929.4 to 3096MUg/g, and 10,150 to 19,390MUg/g, respectively, indicating that the total flavonoids in the four parts could be mainly arranged in a decreasing order as flower>leaf>stem>root. The peak of total flavonoids in flowers and leaves appeared at G8 and G9, respectively. These results will be helpful for the determination of the suitable harvest time of A. manihot and the improvement of the utility value of the disused parts. PMID- 28558341 TI - Understanding the GPCR biased signaling through G protein and arrestin complex structures. AB - G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and are important drug targets for many human diseases. The determination of the 3-D structure of GPCRs and their signaling complexes has promoted our understanding of GPCR biology and provided templates for structure based drug discovery. In this review, we focus on the recent structure work on GPCR signaling complexes, the beta2-adrenoreceptor-Gs and the rhodopsin-arrestin complexes in particular, and highlight the structural features of GPCR complexes involved in G protein- and arrestin-mediated signal transduction. The crystal structures reveal distinct structural mechanisms by which GPCRs recruit a G protein and an arrestin. A comparison of the two complex structures provides insight into the molecular mechanism of functionally selective GPCR signaling, and a structural basis for the discovery of G protein- and arrestin-biased treatments of human diseases related to GPCR signal transduction. PMID- 28558342 TI - The measurement properties of pediatric observational pain scales: A systematic review of reviews. AB - BACKGROUND: Valid observational pain scales are needed to assess pain and ensure sufficient treatment of pain in children that lack the verbal ability to self report pain. Published reviews attempt to synthesize results from primary studies validating these scales and based on the findings recommendations may be given, for example which pain scales are the most appropriate for use in different pediatric populations. OBJECTIVES: The aims of this review were to describe how systematic reviews have evaluated and recommended observational pain scales for use in children aged 0-18 years and appraise the evidence underlying these recommendations. DESIGN: Systematic review of reviews. DATA SOURCES: The Cochrane Library, PubMed/MEDLINE, CINAHL, Web of Science, and PsychINFO were searched from inception to September 2016. Reference lists and gray literature were searched for additional studies. REVIEW METHODS: Study selection and data extraction were performed by two reviewers independently with a disagreement procedure in place. Methodological quality or study validity was measured using the Assessment of Multiple Systematic Reviews checklist and risk of bias or internal validity was measured using the Risk of Bias in Systematic Reviews tool. The review protocol was registered with PROSPERO: registration number CRD42016035264. RESULTS: Twelve reviews met the inclusion criteria. Together; they included 65 different observational pain scales for use in children, of which 28 were recommended at least once. Face, Legs, Activity, Cry, Consolability/revised version of Face, Legs, Activity, Cry, Consolability, COMFORT/COMFORT behavioral scale and Children's Hospital of Eastern Ontario Pain Scale were evaluated and recommended most frequently. Few of the included reviews assessed the methodological quality of the studies included in the review. The narrative analysis consisted mostly of a reiteration of the results from the primary studies. In general, more recent reviews showed a lower risk of bias than older ones. CONCLUSIONS: Included reviews exhibited low quality of evidence; thus, their recommendations regarding pain scales for use in clinical practice or research with children that lack the verbal ability to self-report pain should be interpreted with caution. PMID- 28558344 TI - Experimental study and biomechanical characterization for the passive small intestine: Identification of regional differences. AB - This article reports regional differences in the inflation/extension properties and the no-load and zero-stress geometry, serving as the reference state for defining the multiaxial response, within and across the individual duodenum, jejunum, and ileum of the small intestine of middle-aged rats in the normal condition. The descriptive/predictive capacity of three phenomenological models, regularly appearing in the biomechanics literature, to characterize the anisotropic response of intestinal tissue was investigated in terms of best-fit parameters. Our inflation/extension results showed that the pressure-radius relationship was nonlinear, dissimilar to the near-constant, linear force pressure relationship at all axial stretches, suggesting an energetically favorable response in the entire loading range. The geometrical results showed that small intestinal dimensions were greatest in the proximal duodenum and smallest in the proximal jejunum, unlike the opening angle and circumferential residual strains that were less spatially variable; contrasting previous findings on relatively immature animals. The quadratic and exponential model was the most suitable descriptor of the passive pseudo-elastic response for the entire loading range from all regions, while the four- and seven-parameter exponential models afforded good data representations at the physiologic loading range primarily. The stress-strain and material characterization results showed progressive softening in the axial direction within the duodenum and jejunum, unlike the ileum that stiffened axially towards the caecum. Much remains to be learned as regards regional variations in biomechanical properties and the adaptive response during aging, but the reported data provide input for a quantitative analysis of physiological functions, mechanobiology, and clinical interventions, e.g. small intestine-repair device interaction. PMID- 28558343 TI - Interconnectivity imaged in three dimensions: Nano-particulate silica-hydrogel structure revealed using electron tomography. AB - We have used Electron Tomography (ET) to reveal the detailed three-dimensional structure of particulate hydrogels, a material category common in e.g. controlled release, food science, battery and biomedical applications. A full understanding of the transport properties of these gels requires knowledge about the pore structure and in particular the interconnectivity in three dimensions, since the transport takes the path of lowest resistance. The image series for ET were recorded using High-Angle Annular Dark Field Scanning Transmission Electron Microscopy (HAADF-STEM). We have studied three different particulate silica hydrogels based on primary particles with sizes ranging from 3.6nm to 22nm and with pore-size averages from 18nm to 310nm. Here, we highlight the nanostructure of the particle network and the interpenetrating pore network in two and three dimensions. The interconnectivity and distribution of width of the porous channels were obtained from the three-dimensional tomography studies while they cannot unambiguously be obtained from the two-dimensional data. Using ET, we compared the interconnectivity and accessible pore volume fraction as a function of pore size, based on direct images on the nanoscale of three different hydrogels. From this comparison, it was clear that the finest of the gels differentiated from the other two. Despite the almost identical flow properties of the two finer gels, they showed large differences concerning the accessible pore volume fraction for probes corresponding to their (two-dimensional) mean pore size. Using 2D pore size data, the finest gel provided an accessible pore volume fraction of over 90%, but for the other two gels the equivalent was only 10-20%. However, all the gels provided an accessible pore volume fraction of 30 40% when taking the third dimension into account. PMID- 28558345 TI - Post-operative unilateral internuclear ophthalmoplegia following basilar pneumocephalus after resection of C1 intradural extramedullary tumor. PMID- 28558346 TI - Incidental gastric accessory spleen during laparoscopic sleeve gastrectomy. AB - INTRODUCTION: Bariatric surgery has shown to produce the most predictable and tangible results for weight loss, with laparoscopic sleeve gastrectomy's being the most popular one of them. However, the occurrence of previously undiagnosed diseases can be encountered during bariatric operations. The work has been reported in line with the SCARE criteria. CASE PRESENTATION: This is the case of a 54year old morbidly obese female, presenting to our hospital for a laparoscopic sleeve gastrectomy. During her procedure, it was discovered that she has an accessory spleen on the fundus of her stomach. The decision was made to resect it with the specimen of the stomach for histopathalogical examination. CONCLUSION: Incidental findings during routine bariatric surgery are a common occurance, and therefore prompt and effective intra-op management is key to the prognosis of the patient. Accessory spleens, although uncommon, tend to be asymptomatic. However, if undiagnosed, could present with dangerous consequences. PMID- 28558347 TI - Total hip prosthesis complication, periprosthetic infection with external fistulizing due to Enterobacter cloacae complex multiple drugs resistance: A clinical case report. AB - INTRODUCTION: The Enterobacter cloacae is a microorganism found in the intestinal flora of the majority of animals, including humans. Primary infections caused by E. cloacae are rare in immunocompetent patients, but are very common in hospital settings in newborns and immunocompromised patients, and can be aggravated by the insurgence of antibiotic resistance. The incidence of periprosthetic hip infections is just below 2%. CASE PRESENTATION: A 76year old woman with multiple comorbidities underwent surgical implantation of intermediary total hip prosthesis of the left hip, in a different health facility, in February 2014, after the basicervical fracture of the upper femur extremity due to trauma. After an episode of dislocation of the prosthetic implant, in September 2014, she underwent a surgical operation to implant the acetabular component. A month later not in our facility, following a re-hospitalization for the dislocation of the arthroprosthesis, an infection from E. cloacae complex was discovered. After 2 years of chronic infection she came to our attention; the clinical picture featured coxalgia and secreting fistula in the surgical wound. Following a specific antibiotic therapy, carried out intravenously over the course of a month, we decided to intervene removing the left hip arthroprosthesis and placing an antibiotic spacer following the direction deduced from the antibiogram study of August 2016. CONCLUSION: The patient was hospitalized in our facility and 2 months later she underwent another operation to remove the antibiotic spacer and to place a new total hip arthroprosthesis. Multiple swabs showed the complete healing from the infection, which was confirmed a couple of months later. PMID- 28558348 TI - A pilot-scale study on the start-up of partial nitrification-anammox process for anaerobic sludge digester liquor treatment. AB - Treatment of sludge digester liquor was successfully accomplished using a pilot scale partial nitrification-anammox (PN/A) reactor with a nitrogen removal rate (NRR) of 1.23kgN/m3/d. A stable and efficient PN process was attained by controlling the concentration of free ammonia (0.7-8.4mg/L) and free nitrous acid (0.02-1.0mg/L). The application of hydroxylamine played a vital role in the reactivation of anammox bacteria. The bacteria exhibited improved granule properties at a specific input power between 0.065 and 0.097kW/m3, and achieved a specific anammox activity (SAA) of 1.01kgN/kgVSS/d on day 148. From day 0 to 120, the heme c content in the granules increased from 0.42+/-0.1 to 5.77+/ 1.0umol/gVSS, with a corresponding increase in NRRs and SAAs. High-throughput sequencing techniques revealed that the dominant anammox bacterial genus was Candidatus Brocadia. These conclusions provide valuable information for the full scale treatment of sludge digester liquor. PMID- 28558349 TI - Role and multi-scale characterization of bamboo biochar during poultry manure aerobic composting. AB - The objective of the present study was to study the changes in compost particle and its relationship with other physicochemical process during aerobic composting employing 5%, 10%, 20% or 0% biochar. Changes of physicochemical and biological parameters and gases emissions indicated that appropriate biochar addition improved both degradation rate and final degree of the organic matter and simultaneously reduced CO2, CH4, N2O and NH3 emissions. Beneficial properties like stability and high porosity of biochar could optimize composting environment, accelerate the process of composting and facilitate microbial growth during the thermophilic composting stage, with increases of 1.3*1010 to 1.5*1011cfu/g. Analysis of microstructure characterization of the changes in compost particle indicated that biochar amended contributed to better degradation of compost particle with smaller sizes and a higher degree of looseness. Ultimately, 10% biochar addition optimized organic matter degradation, while reducing ammonia and greenhouse gas emissions and costs. PMID- 28558350 TI - Phosphate adsorption and precipitation on calcite under calco-carbonic equilibrium condition. AB - Phosphate (PO43-) removal on calcite often entails two processes: adsorption and precipitation. Separating these two processes is of great importance for assessment of PO43- stability after removal. Thus, this study was aimed at finding a critical range of conditions for separating these two processes in calco-carbonic equilibrium, by adjusting PO43- concentration, reaction time and pH. PO43- removal kinetic results showed that: (I) At pH7.7, PO43- removal was mainly by adsorption at initial PO43- concentration <=2.2 mg L-1 and reaction time <=24 h, with dominant precipitation occurring at initial PO43- concentration >=3 mg L-1 after 24 h reaction; (II) At pH8.3, adsorption was the key removal process at initial PO43- concentration <=7.5 mg L-1 and reaction time <=24 h, whereas precipitation was observed at initial PO43- concentration of 10 mg L-1 after 24 h reaction, (III) At pH 9.1 and 10.1, PO43- removal mechanism was mainly by adsorption at initial PO43- concentration <=10 mg L-1 within 24 h reaction. Based on the kinetic results, it is suggested that PO43- precipitation will occur after 24 h reaction when saturation index of amorphous calcium phosphate is between 1.97 and 2.19. Besides, increasing PO43- concentration does not cause a continuous decline of PO43- removal percentage. Moreover, experimental removal data deviated largely from the theoretical adsorption value by CD-MUSIC model. These indicate occurrence of precipitation which is in agreement with the kinetic result. Therefore our study will provide fundamental reference information for better understanding of phosphorous stabilization after removal by calcite. PMID- 28558351 TI - Spatio-temporal variations of PM2.5 emission in China from 2005 to 2014. AB - With the rapid development of economy, air pollution has become increasingly serious nowadays in China, especially for the PM2.5. In this paper, the Spatio temporal variations of PM2.5 emission over the past decade, from 2005 to 2014, were researched by cartograms. Meanwhile, a complex network technology was adopted to study the spatial auto-correlation of PM2.5 emission. The results showed that every province in China suffered a disparate increment in PM2.5 emission during the past ten years and also indicated that provinces in the same region had a huge influence on each other. There were three sectors including the thermal power, biomass burning and building materials that constituted the major sources of PM2.5 emission and they had different changing trends. There existed a dramatic difference in the east and west of China considering that the amount of PM2.5 was closely related to gross domestic product (GDP) and population. With higher GDP and population, eastern provinces emitted the most amount of PM2.5. Normalization results proposed that most of the provinces were PM2.5 exporting provinces in the southeast of China while most in the northwest were importing provinces. This study can help the policy-makers understand the distribution characteristics of PM2.5 emission and propose the effective strategy to mitigate the pollution of haze. PMID- 28558352 TI - Humic supramolecular structures have polar surfaces and unpolar cores in native soil. AB - It was the aim of our study to prove the hypothesis that humic substances (HS) in native soil are spatially arranged in descending order of polarity, meaning that highly polar supramolecular subunits shield less polar subunits against the free soil solution and form layers of descending polarity. To address this aim, we consecutively extracted humic substances from soil with 8 M (HS1), 4 M (HS2), 2 M (HS3), 1 M (HS4) and 0.5 M LiCl (HS5) solution in 0.2 M LiOH after Cu2+ adsorption in batch soil column experiments. Adsorption was performed for 1, 10 and 60 min with concentrations ranging from 9.5 to 110 mg L-1 Cu2+ in 0.02 M CaCl2 solution. We assumed that high ionic strength facilitates extraction of most polar organic compounds, with polarity of the extracted HS decreasing with decreasing ionic strength, and that Cu extracted together with the successive HS solely formed coordination complexes, facilitating its use as a tracer for organic matter studies. We hypothesized a delayed Cu adsorption on the less polar fractions in case of spatial shielding due to interception on overlying fractions, and a concurrent Cu adsorption in case of random spatial arrangement. It was concluded that humic substances are shielded against each other in the order of descending polarity of the supramolecular subunits (free soil solution | HS1 | HS2 | HS3 | HS4 | HS5). PMID- 28558353 TI - Antiangiogenic activity of PLGA-Lupeol implants for potential intravitreal applications. AB - Uncontrolled angiogenesis is directly associated with ocular diseases such as macular degeneration and diabetic retinopathy. Implantable polymeric drug delivery systems have been proposed for intravitreal applications and in the present work, we evaluated the antiangiogenic potential of PLGA ocular implants loaded with the triterpene lupeol using in vitro and in vivo models. The drug/polymer physiochemical properties of the lupeol-loaded PLGA were validated as functionally similar using differential scanning calorimetry, Fourier transform infrared spectroscopy, and scanning electron microscopy. Interestingly, in an in vitro culture system, lupeol (100MUg/mL and 250MUg/mL) was capable to inhibited the proliferation as well as the migration of Human Umbilical Vein Endothelial Cells (HUVEC), without interfering in cell viability, promoting a significant reduction in the percentage of vessels (39.41% and 44.12%, respectively), compared with the control group. In vivo test, by using the chorioallantoic membrane (CAM) model, lupeol-loaded PLGA ocular implants showed antiangiogenic activity comparable to the FDA-approved anti-VEGF antibody Bevacizumab. Overall, our results suggest lupeol-loaded PLGA ocular implants were able to inhibit the angiogenic process by impairing both proliferation and migration of endothelial cells. PMID- 28558354 TI - Anthocyanin-rich Riceberry bran extract attenuates gentamicin-induced hepatotoxicity by reducing oxidative stress, inflammation and apoptosis in rats. AB - Liver plays an important role in the detoxification and metabolic elimination of various drugs and harmful substances. The damaging effects on the liver tissue treated with gentamicin are multi-factorial and their mechanisms remain unclear. This study aimed to investigate the possible protective effects of anthocyanin rich Riceberry bran extract on gentamicin-induced hepatotoxicity in rats. Riceberry bran extract was given by oral administration 30min before gentamicin injection for 15 consecutive days. Serum levels of liver marker enzymes, AST and ALT, were significantly elevated and the total serum protein level was markedly reduced in gentamicin-treated rats. Gentamicin injection led to the significant increase in hepatic MDA level and decrease SOD expression. Liver inflammation and apoptosis were observed in gentamicin-treated rats as indicated by the increases in NF-kappaB, TNF-alphaR1, COX2, and iNOS, caspase-3, Bax, and decrease in Bcl-XL expressions. Riceberry bran extract significantly prevented gentamicin-induced the elevations of serum AST, ALT and the reduction of serum total protein. These were related to the inhibition of oxidative stress, inflammation and apoptosis in Riceberry bran extract treatment. These findings suggest that anthocyanin-rich Riceberry bran extract can prevent liver dysfunction and damage induced by gentamicin, possibly through its antioxidant, anti-inflammatory and anti apoptotic effects. PMID- 28558356 TI - Puerarin suppresses LPS-induced breast cancer cell migration, invasion and adhesion by blockage NF-kappaB and Erk pathway. AB - BACKGROUND: Chronic inflammation is a major risk factor for the development and metastatic progression of breast cancer. Puerarin has long been used as traditional Chinese medicine, which possesses manifold physiological activities, including anti-inflammation and anti-cancer activities. However, its anti-cancer metastasis activity in breast cancer cell inflammation-mediated have not been studied. METHODS: Cell viability was detected with Cell Counting Kit (CCK)-8. Transwell migration and invasion assay were performed to evaluate cell migration and invasion, respectively. Enzyme-linked immunosorbent assay (ELISA) was conducted to analysis the expression of inflammatory factor. In addition, mRNA and protein levels of related cytokines were determined by qRT- PCR assay and western blot analysis, respectively. RESULTS: In this study, puerarin significantly inhibited lipopolysaccharide (LPS)-induced MCF-7 and MDA-MB-231 cell migration, invasion and adhesion. The mRNA and protein levels revealed that puerarin treatment effectively negated the expression of CCR7, CXCR4, MMP-2, MMP 9, ICAM and VCAM in LPS- activated MCF-7 and MDA-MB-231 cells. Further, the expression of inflammatory factor TNF-alpha and IL-6 in cell culture supernatant remarkably reduced. Finally, the result indicated that puerarin abrogated the NF kappaB activation in breast cancer cells stimulated by LPS, which is mediated through inhibition of phosphorylation of p65 and IkappaBalpha. Also, puerarin inhibited phosphorylation of Erk in breast cancer cells LPS-induced. CONCLUSIONS: This present study revealed that puerarin might be a novel therapeutic drug for breast cancer treatment. PMID- 28558355 TI - Apocynin prevented inflammation and oxidative stress in carbon tetra chloride induced hepatic dysfunction in rats. AB - BACKGROUND: Liver fibrosis is a leading pathway to cirrhosis and a global clinical issue. Oxidative stress mediated tissue damage is one of the prime causes of hepatic dysfunction and fibrosis. Apocynin is one of many strong antioxidants. OBJECTIVE: To evaluate the effect of apocynin in the CCl4 administered hepatic dysfunction in rats. METHODS: Female Long Evans rats were administered with CCl4 orally (1mL/kg) twice a week for 2 weeks and were treated with apocynin (100mg/kg). Both plasma and liver tissues were analyzed for alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase activities. Oxidative stress parameters were also measured by determining malondialdehyde (MDA), nitric oxide (NO), myeloperoxidase (MPO), advanced protein oxidation product (APOP). In addition, antioxidant enzyme activities such as superoxide dismutase (SOD) and catalase activities in plasma and liver tissues were analyzed. Moreover, inflammation and tissue fibrosis were confirmed by histological staining of liver tissue sections. RESULTS: Apocynin significantly reduced serum AST, ALT, and ALP activities in carbon tetrachloride treated rats. It also exhibited a considerable reduction of the oxidative stress markers (MDA, MPO, NO, and APOP level) which was elevated due to CCl4 administration in rats. Apocynin treatment also restored the catalase and superoxide dismutase activity in CCl4 treated rats. Histological analysis of liver sections revealed that apocynin prevented inflammatory cells infiltration and fibrosis in CCl4 administered rats. CONCLUSION: These results suggest that apocynin protects liver damage induced by CCl4 by inhibiting lipid peroxidation and stimulating the cellular antioxidant system. PMID- 28558357 TI - Long non-coding RNA HOXA11-AS functions as a competing endogenous RNA to regulate ROCK1 expression by sponging miR-124-3p in osteosarcoma. AB - Long non-coding RNAs (lncRNAs) have been strongly associated with various types of cancer. this study was to explore the critical role of lncRNA HOXA11-AS in osteosarcoma (OS) progression. Briefly, we should that the expression of HOXA11 AS was upregulated in OS tissues and cell lines. The high expression of HOXA11-AS was associated with advanced clinical stage, distant metastasis and poor overall survival of OS. In addition, We found that HOXA11-AS silencing suppressed OS cells proliferation, invasion and induced cell arrest in G0/G1 phase. Furthermore, our data showed that HOXA11-AS acts as an endogenous sponge by directly binding miR-124-3p, and decreasing the expression of miR-124-3p. Moreover, we found that HOXA11-AS may regulate tumor progression by affecting miR 124-3p targets, and ROCK1 expression. To conclude, our study helps to elucidate the effectiveness of HOXA11-AS promotion on OS cell proliferation and metastasis. A better understanding of interaction mechanism between HOXA11-AS-miR-124-3p ROCK1 signaling axis may be a step forward in the development of new therapeutic strategies for the treatment of OS. PMID- 28558358 TI - SCL-90-R emotional distress ratings in substance use and impulse control disorders: One-factor, oblique first-order, higher-order, and bi-factor models compared. AB - To fully understand the dimensionality of an instrument in a certain population, rival bi-factor models should be routinely examined and tested against oblique first-order and higher-order structures. The present study is among the very few studies that have carried out such a comparison in relation to the Symptom Checklist-90-R. In doing so, it utilized a sample comprising 2593 patients with substance use and impulse control disorders. The study also included a test of a one-dimensional model of general psychological distress. Oblique first-order factors were based on the original a priori 9-dimensional model advanced by Derogatis (1977); and on an 8-dimensional model proposed by Arrindell and Ettema (2003)-Agoraphobia, Anxiety, Depression, Somatization, Cognitive-performance deficits, Interpersonal sensitivity and mistrust, Acting-out hostility, and Sleep difficulties. Taking individual symptoms as input, three higher-order models were tested with at the second-order levels either (1) General psychological distress; (2) 'Panic with agoraphobia', 'Depression' and 'Extra-punitive behavior'; or (3) 'Irritable-hostile depression' and 'Panic with agoraphobia'. In line with previous studies, no support was found for the one-factor model. Bi-factor models were found to fit the dataset best relative to the oblique first-order and higher order models. However, oblique first-order and higher-order factor models also fit the data fairly well in absolute terms. Higher-order solution (2) provided support for R.F. Krueger's empirical model of psychopathology which distinguishes between fear, distress, and externalizing factors (Krueger, 1999). The higher order model (3), which combines externalizing and distress factors (Irritable hostile depression), fit the data numerically equally well. Overall, findings were interpreted as supporting the hypothesis that the prevalent forms of symptomatology addressed have both important common and unique features. Proposals were made to improve the Depression subscale as its scores represent more of a very common construct as is measured with the severity (total) scale than of a specific measure that purports to measure what it should assess symptoms of depression. PMID- 28558359 TI - Large-scale assessment of myxomatosis prevalence in European wild rabbits (Oryctolagus cuniculus) 60years after first outbreak in Spain. AB - Myxomatosis is a viral disease that affects European rabbits (Oryctolagus cuniculus) worldwide. In Spain, populations of wild rabbits drastically decreased in the 1950s after the first outbreak of myxomatosis. Since that first appearance, it seems to be an annual epizootic in Spain with periodic outbreaks, predominantly in summer and autumn. Taking into account rabbit population structure, abundance, and genetic lineage, this paper attempts to make a large scale characterization of myxomatosis seroprevalence based on the immune status of 29 rabbit populations distributed throughout Spain, where O. cuniculus cuniculus and O. c. algirus, the two known rabbit subspecies, naturally inhabit. A total of 654 samples were collected between 2003 and 2009, and seroprevalence of antibodies against Myxoma virus (MYXV) was determined. Overall, our results revealed that 53% of the rabbit samples were positive to antibodies against MYXV. Newborn and juvenile rabbits were the most susceptible animals to the virus, with 19% and 16% seropositivity for newborn and juveniles, respectively, while adult rabbits were the most protected, with 65% of seropositive samples. This suggests that prevalence is negatively related to the proportion of newborn and juvenile rabbits in a population. Our results also showed that seroprevalence against MYXV tended to be higher in high-abundance populations. In contrast, no differences were detected in seroprevalence between rabbit subspecies. This study confirms that >60years since first outbreak, myxomatosis is an endemic disease in Spain. Based on the results, the establishment of a myxomatosis surveillance protocol is proposed. PMID- 28558361 TI - Speciation of heavy metals in different grain sizes of Jiaozhou Bay sediments: Bioavailability, ecological risk assessment and source analysis on a centennial timescale. AB - Heavy metal contamination is an essential indicator of environmental health. In this work, one sediment core was used for the analysis of the speciation of heavy metals (Cr, Mn, Ni, Cu, Zn, As, Cd, and Pb) in Jiaozhou Bay sediments with different grain sizes. The bioavailability, sources and ecological risk of heavy metals were also assessed on a centennial timescale. Heavy metals were enriched in grain sizes of < 63um and were predominantly present in residual phases. Moreover, the mobility sequence based on the sum of the first three phases (for grain sizes of < 63um) was Mn > Pb > Cd > Zn > Cu >Ni > Cr > As. Enrichment factors (EF) indicated that heavy metals in Jiaozhou Bay presented from no enrichment to minor enrichment. The potential ecological risk index (RI) indicated that Jiaozhou Bay had been suffering from a low ecological risk and presented an increasing trend since 1940s owing to the increase of anthropogenic activities. The source analysis indicated that natural sources were primary sources of heavy metals in Jiaozhou Bay and anthropogenic sources of heavy metals presented an increasing trend since 1940s. The principal component analysis (PCA) indicated that Cr, Mn, Ni, Cu and Pb were primarily derived from natural sources and that Zn and Cd were influenced by shipbuilding industry. Mn, Cu, Zn and Pb may originate from both natural and anthropogenic sources. As may be influenced by agricultural activities. Moreover, heavy metals in sediments of Jiaozhou Bay were clearly influenced by atmospheric deposition and river input. PMID- 28558360 TI - Transfer of lead (Pb) in the soil-plant-mealybug-ladybird beetle food chain, a comparison between two host plants. AB - Contamination of soil with heavy metals has become an issue of concern on global scale. This study investigates the translocation of lead (Pb) along the soil - plant (eggplant and tomato) - mealybug (Dysmicoccus neobrevipes) - ladybird beetle (Cryptolaemus montrouzieri) food chain. Soil amendments used for this study were adjusted to 0, 25, 50 and 100mg/kg of Pb (w/w). The results revealed significantly higher transfer of Pb in tomato when compared to eggplant. Bio magnification of Pb (2-4 times) was observed for soil - root transfer whereas Pb was bio-minimized in later part of food chain (shoot - mealybug - ladybird transfer). A dose dependent increase in transfer of Pb across the multi-trophic food chain was observed for both host plants. A decrease in coefficients of Pb transfer (from root - shoot and shoot - mealybug) was observed with increase in Pb concentrations. Our results also showed removal of Pb from the bodies of ladybird beetle during metamorphosis. Further studies are required to explain the mechanisms or physiological pathways involved in the bio-minimization of Pb across the food chain. PMID- 28558362 TI - Node-controlled allocation of mineral elements in Poaceae. AB - Mineral elements taken up by the roots will be delivered to different organs and tissues depending on their requirements. In Poaceae, this selective distribution is mainly mediated in the nodes, which have highly developed and fully organized vascular systems. Inter-vascular transfer of mineral elements from enlarged vascular bundles to diffuse vascular bundles is required for their preferential distribution to developing tissues and reproductive organs. A number of transporters involved in this inter-vascular transfer processes have been identified mainly in rice. They are localized at the different cell layers and form an efficient machinery within the node. Furthermore, some these transporters show rapid response to the environmental changes of mineral elements at the protein level. In addition to the node-based transporters, distinct nodal structures including enlarged xylem area, folded plasma membrane of xylem transfer cells and presence of an apoplastic barrier are also required for the efficient inter-vascular transfer. Manipulation of node-based transporters will provide a novel breeding target to improve nutrient use efficiency, productivity, nutritional value and safety in cereal crops. PMID- 28558363 TI - Lifetime anxiety disorder and current anxiety symptoms associated with hastened depressive recurrence in bipolar disorder. AB - AIMS: To assess differential relationships between lifetime anxiety disorder/current anxiety symptoms and longitudinal depressive severity in bipolar disorder (BD). METHODS: Stanford BD Clinic outpatients enrolled during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation and followed with the STEP-BD Clinical Monitoring Form while receiving naturalistic treatment for up to two years. Baseline unfavorable illness characteristics/current mood symptoms and times to depressive recurrence/recovery were compared in patients with versus without lifetime anxiety disorder/current anxiety symptoms. RESULTS: Among 105 currently recovered patients, lifetime anxiety disorder was significantly associated with 10/27 (37.0%) demographic/other unfavorable illness characteristics/current mood symptoms/current psychotropics, hastened depressive recurrence (driven by earlier onset age), and a significantly (> two-fold) higher Kaplan-Meier estimated depressive recurrence rate, whereas current anxiety symptoms were significantly associated with 10/27 (37.0%) demographic/other unfavorable illness characteristics/current mood symptoms/current psychotropics and hastened depressive recurrence (driven by lifetime anxiety disorder), but only a numerically higher Kaplan-Meier estimated depressive recurrence rate. In contrast, among 153 currently depressed patients, lifetime anxiety disorder/current anxiety symptoms were not significantly associated with time to depressive recovery or depressive recovery rate. LIMITATIONS: American tertiary BD clinic referral sample, open naturalistic treatment. CONCLUSIONS: Research is needed regarding differential relationships between lifetime anxiety disorder and current anxiety symptoms and hastened/delayed depressive recurrence/recovery - specifically whether lifetime anxiety disorder versus current anxiety symptoms has marginally more robust association with hastened depressive recurrence, and whether both have marginally more robust associations with hastened depressive recurrence versus delayed depressive recovery, and related clinical implications. PMID- 28558364 TI - Structural and functional correlates of serum soluble IL-6 receptor level in patients with bipolar disorder. AB - OBJECTIVES: Inflammation is reported to play a crucial role in the pathogenesis of bipolar disorder (BD). Higher serum levels of soluble interleukin-6 receptor (sIL-6R), which forms a ligand-receptor complex with the potent proinflammatory cytokine IL-6, have been consistently observed in patients with BD. However, the effect of sIL-6R on neural structure and function remains unclear. This study investigated the association between serum sIL-6R levels and the structural and functional connectivity (FC) of the brain in patients with BD. METHODS: Seventy four stable patients with BD-I or BD-II were enrolled from the outpatient clinic. Structural and resting functional MRI and clinical evaluations were performed in all participants, and serum sIL-6R levels were measured. We used an automated surface-based method (FreeSurfer) to measure cortical thickness and a seed-based FC analysis to derive the FC map of the medial prefrontal cortex (mPFC), a key region implicated in the fronto-limbic disconnection hypothesis of BD. Brain-wise regression analyses of cortical thickness and FC mapping on IL-6 levels were performed using a general linear model. RESULTS: Higher sIL-6R levels were associated with a thinner cortex in the right middle temporal gyrus. Furthermore, higher sIL-6R levels were associated with increased FC between the mPFC and amygdala, pallidum, putamen, and insula and decreased FC between the mPFC and subgenual anterior cingulate cortex and frontal pole. CONCLUSION: The results evidence that higher serum inflammatory marker levels are associated with a severer deficit in structural and connectivity abnormalities implicated in BD. PMID- 28558365 TI - Reward anticipation revisited- evidence from an fMRI study in euthymic bipolar I patients and healthy first-degree relatives. AB - BACKGROUND: Symptomatic phases in bipolar disorder (BD) are hypothesized to result from a hypersensitive behavioral activation system (BAS) being sensitive to potential rewards. However, studies on the neuronal underpinnings of reward anticipation in BD are scarce with contradictory findings and possibly confounded by effects of dopaminergic medication, necessitating further research on dysfunctional motivation in BD. Moreover, its role as vulnerability marker for BD is unclear. METHODS: Functional imaging was conducted in 16 euthymic BD-I patients free from dopaminergic medication and 19 healthy first-degree relatives using a monetary incentive delay task and compared to parallelized control groups. Further, reward proneness, using the BIS/BAS questionnaire, and its relationship to neural reward anticipation was investigated. RESULTS: BD-I patients displayed greater anterior cingulate cortex (ACC) activity during reward anticipation and higher BIS total scores compared to controls, with a positive relationship between the two measures. There were no neural or self-report group differences between relatives and controls. LIMITATIONS: Due to the experimental design, the role of the ACC during receipt of reward remains unknown, sample sizes were rather small, and patients were not naive to dopaminergic drugs, making an exclusion of medication effects on findings impossible. CONCLUSIONS: Our findings give new insights on reward anticipation in BD. BD-I patients rated themselves as more risk avoidant and showed larger recruitment of the ACC rather than ventral striatum compared to controls during reward anticipation, possibly to down-regulate hyperactive limbic reward regions. This activation seems to be a consequence of rather than a vulnerability marker for the disorder. PMID- 28558366 TI - Antidepressant-induced hypomania/mania in patients with major depression: Evidence from the BRIDGE-II-MIX study. AB - BACKGROUND: The issue of antidepressant-induced mood switches to hypomania, mania, or mixed states within the course of mayor depressive disorder (MDD) has been a controversial topic. The present post-hoc analysis of the BRIDGE-II-MIX study focuses on the clinical features of patients with history of antidepressant induced hypomania/mania (AIHM) in a large international sample of patients with major depressive episode (MDE). METHODS: 2811 subjects with major depression were enrolled in this multicentre cross-sectional study. Current mixed symptoms, socio demographic and other clinical variables were collected and compared among MDD AIHM, MDD and BD patients. RESULTS: 475 patients out of 2811 had history of AIHM (16.90%). In the MDD-AIHM group, familiarity for BD and rates of atypical features and comorbid anxiety, eating and borderline personality disorders were similar to BD and significantly more frequent compared to MDD group. MDD-AIHM patients had more frequently more than 3 episodes and reported higher rates of treatment resistance, mood lability and irritability following treatment with antidepressants. Frequencies of depression with mixed features and (hypo)manic symptoms were similar in patients of MDD-AIHM and BD groups and significantly higher in both groups than in MDD. LIMITATIONS: there were widely varying rates of hospitalized patients across countries and the participating centres were not randomly selected. CONCLUSIONS: Our results strongly support the DSM-5 inclusion of MDD patients with AIHM within the rubric of bipolar disorder. Differences with other MDD and BD were also observed suggesting the possibility that MDD-AIHM may represent a specific sub-population, particularly sensitive to exogenous input from antidepressants. PMID- 28558367 TI - [Wirksamkeit und Vertraglichkeit eines homoopathischen Komplexmittels (Sinusitis Hevert SL) bei akuter, unkomplizierter Rhinosinusitis: Eine multizentrische, randomisierte, doppelblinde, placebokontrollierte Studie an erwachsenen Patienten]. AB - Hintergrund: In der vorliegenden Studie wurden die Wirksamkeit und Vertraglichkeit des homoopathischen Arzneimittels Sinusitis Hevert SL an Patienten mit akuter Rhinosinusitis untersucht. Methoden: In einer randomisierten, placebokontrollierten klinischen Studie wurden 314 Patienten mit bis zu 3 Tagen bestehenden Symptomen, leichtem bis moderatem Gesichtsschmerz und einem Major Rhinosinusitis Symptom Score (MRSS) >= 8 und <= 14 fur 15 Tage (Tag 0 erster Arztbesuch plus 14 Tage Behandlung) eingeschlossen und mit Sinusitis Hevert SL oder Placebo behandelt. Den primaren Endpunkt bildeten die Responderrate im MRSS (Reduktion >= 50%) bei der Abschlussvisite sowie die Rate der Remissionen (komplettes Abklingen aller 5 Hauptsymptome). Sekundare Zielkriterien bildeten die Einschatzung der Wirksamkeit durch den Prufer (auf einer 4-Punkte-Skala) und der Sino-Nasal Outcome Test 20 German Adapted Version (SNOT-20 GAV; Selbsterhebung durch die Patienten). Ergebnisse: 314 Patienten wurden in die Studie eingeschlossen. Davon wurden 308 mit der Studienmedikation behandelt: 153 mit Sinusitis Hevert SL und 155 mit Placebo. 265 Patienten schlossen die Studie vollstandig und valide ab (Valid Completers). Die MRSSpat Responderrate aller Patienten war fur Sinusitis Hevert SL nicht signifikant besser (85,6% vs. 80,6%; p = 0,243), die Rate der Remissionen war mit 31,4% fur Sinusitis Hevert SL und 37,4% fur Placebo in beiden Gruppen nicht signifikant unterschiedlich (p = 0,2641). In der sekundaren Completer-Analyse zeigte sich eine signifikante Differenz der Responderraten von 92,1% versus 83,5% zugunsten von Sinusitis Hevert SL (p = 0,032). Weiter war die Zeit bis zur Verbesserung der Rhinorrhoe signifikant kurzer (4,0 vs. 6,0 Tage; p = 0,040). Vor allem relevante nasale Symptome des SNOT-20 und die Lebensqualitat verbesserten sich unter Behandlung mit Sinusitis Hevert SL signifikant deutlicher. Schlussfolgerungen: Es zeigte sich in dieser Studie bei akuter Rhinosinusitis und hoher Placebo Ansprechrate keine Uberlegenheit fur Sinusitis Hevert SL in der Gesamtresponder- und Remissionsrate. Es fand sich ein Nutzen von Sinusitis Hevert SL in der Auswertung der Valid Completers fur die Response sowie fur spezifische Verbesserungen klinisch relevanter Symptome und die Abheilungsgeschwindigkeit der akuten Rhinosinusitis bei guter Vertraglichkeit. PMID- 28558368 TI - Molecular Imaging of Inducible VEGF Expression and Tumor Progression in a Breast Cancer Model. AB - BACKGROUND: Tumor derived vascular endothelial growth factor (VEGF) can stimulate proliferation and migration of endothelial cells and recruit endothelial progenitor cells into tumors for vascular formation via a paracrine manner. Now increasing evidence suggests that VEGF also serves as an autocrine factor promoting cell survival and tumor angiogenesis. Real time visualization of VEGF activity in the early stages of tumor formation using molecular imaging will provide unprecedented insight into the biological processes of cancer. METHODS: The mouse breast cancer cell line 4T1 was transfected with an inducible, bidirectional tetracycline (Bi-Tet) promoter driving VEGF and renilla luciferase (Rluc). This was used to quantitatively image conditional switching of VEGF by bioluminescence imaging (BLI) under the control of systemic administration of doxycycline. Simultaneously, 4T1 cells were labelled with the double fusion reporter gene (Fluc-eGFP) to establish a breast cancer model. RESULTS: We found that inducible VEGF could promote proliferation and attenuate apoptosis due to oxidative stress in an autocrine manner in vitro. In vivo studies revealed that induction of VEGF expression during early tumor development not only dramatically enhanced tumor growth but also increased tumor angiogenesis as visualized by BLI. Finally, immunohistochemistry staining confirmed that inducing VEGF expression promoted cell survival and tumor neovascularization. CONCLUSION: Together the inducible bidirectional tetracycline (Bi-Tet) co-expression system combined with the dual bioluminescence imaging (BLI) system provides a platform to investigate a target gene's role in the pathologic process of cancer and facilitates noninvasive monitoring of biological responses in real time. PMID- 28558369 TI - Long Non-Coding RNA Expression Profiling in Obesity Mice with Folic Acid Supplement. AB - BACKGROUND/AIMS: Obesity is a major contributor to the growing prevalence of metabolic and cardiovascular diseases. This study was designed to investigate the effect of folic acid (FA) on obese mice by detecting the genome-wide expression profile of lncRNAs and mRNAs in the heart. METHODS: Heart samples were collected from mice fed with standard diet (SD), high-fat diet (HFD) and high-fat diet with FA intake (HFDF). LncRNAs and mRNAs between HFD and HFDF group were analyzed by lncRNA microarray. Nine lncRNAs and mRNAs were validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Bioinformatics prediction was used to investigate the potential function of these differentially expressed lncRNAs. Co-expresson analysis was used to determine the transcriptional regulatory relationship of differentially expressed lncRNAs and mRNAs between two groups. RESULTS: The expression of 58,952 lncRNAs and 20,145 mRNAs in HFD and HFDF groups was profiled by using microarrays. Gene Ontology and pathway analyses indicated that the biological functions of differentially expressed mRNAs were related to inflammation, energy metabolism, and cell differentiation. Co-expression networks composed of lncRNAs and mRNAs were also constructed to investigate the potential regulatory roles of differentially expressed lncRNAs on mRNAs. LncRNAs, namely, NONMMUT033847, NONMMUT070811, and NONMMUT015327, were validated through qRT-PCR, and these lncRNAs may be important factors regulating inflammation, energy metabolism, and cell differentiation. The expression levels of Dnajb1, Egr2, Hba-a1, Il1beta, Cxcl2, and Tnfsf9 were significantly different between HFD and HFDF. CONCLUSIONS: Results suggested that FA may improve the cardiovascular function of obesity and contribute to those lncRNAs associated with inflammation and cell differentiation. In a nutshell, the present study identified a panel of lncRNAs and mRNAs that may be potential biomarkers or drug targets relevant to the high-fat diet related obesity. PMID- 28558370 TI - Genetic Polymorphisms and the Phenotypic Characterization of Individuals with Early Age-Related Macular Degeneration. AB - PURPOSE: While the importance of risk polymorphisms for the pathogenesis of age related macular degeneration (AMD) is well established, their impact on morphological and functional phenotypes is largely unclear. We aimed to characterize individual phenotypes in patients who were either homozygous for a risk allele in the CFH gene, ARMS2 gene, or both as compared to non-carriers. METHODS: Patients with early AMD (n = 85) were assessed during a follow-up examination of a prospective study (MARS) with multimodal diagnostics including SD-OCT and microperimetry. RESULTS: Compared to non-carriers, OCT scans revealed lower retinal thickness in patients homozygous for CFH or ARMS2, which was caused by a significantly reduced photoreceptor layer. The number and ultrastructure of drusen were also significantly different. CONCLUSIONS: These findings indicate that patients with risk alleles demonstrate distinct phenotypic differences of morphology and function as compared to non-carriers. In particular in the CFH group, a loss of photoreceptors occurred concomitantly with reduced retinal sensitivity. Further studies might help to better understand the pathophysiology. PMID- 28558371 TI - Early Effects of Dexamethasone Implant on Macular Morphology and Visual Function in Patients with Diabetic Macular Edema. AB - PURPOSE: To evaluate the early effects of dexamethasone implant in patients with diabetic macular edema (DME). METHODS: Eyes with DME were prospectively included in the study. Best-corrected visual acuity (BCVA) measurement, complete ophthalmic evaluation, and spectral-domain optical coherence tomography were performed at baseline and 1, 2, 3, 7, 14, 21, 28, 60, and 90 days after treatment. RESULTS: Twenty-three eyes of 20 patients were included in the study. Mean central retinal thickness (CRT) decreased rapidly after treatment (p < 0.0001, repeated measures ANOVA) from 511 MUm at baseline to 469 MUm after 1 day (p < 0.05), and 275 MUm (p < 0.01) at the end of the follow-up. BCVA gain (p < 0.0001, repeated measures ANOVA) was on average +2 ETDRS letters at day 1 (not significant), +9 letters from day 28 to day 90 (p < 0.01). CONCLUSION: Intravitreal dexamethasone implant showed an early and fast effect in reducing CRT and improving BCVA in DME patients. PMID- 28558373 TI - Joint CHEST-SGP Congress 2017. Basel, Switzerland, 7-9 June 2017: Abstracts. PMID- 28558374 TI - Development of an in vitro Test Procedure to Determine the Direct Infrared A Protection of Sunscreens and Non-Cosmetic Samples. AB - BACKGROUND: Every day human skin is exposed to infrared A (IRA) radiation as part of the natural sun rays. As IRA radiation accounts for around one third of the solar radiation, it has gained great attention concerning its effects on the human body and skin. In the past few years it has been discussed controversially whether IRA radiation (of solar origin) is harmful or not. Nonetheless, there are several sunscreens on the German market that claim IRA protection for themselves. AIMS: The present study seeks to find an experimental set-up and a test procedure for the determination and quantification of direct IRA protection (realized via reflection or absorption of the IRA radiation), since to our knowledge these do not yet exist. METHODS: In this study we proved the usability of a set-up consisting of a light source, an IRA-transmissible filter system and a sensor unit, for the determination and quantification of the IRA protection of cosmetic and non-cosmetic samples. RESULTS/CONCLUSION: The applicability of the IRA emission of the light source, the spectral detector, transmissivity of the filter systems and the sample carriers could be validated. This experimental set-up can be used as an in vitro test procedure for the determination of direct IRA protection. PMID- 28558372 TI - Dosage Calculation for Intravenous Thrombolysis of Ischemic Stroke: To Weigh or to Estimate. AB - BACKGROUND: Estimation is a widely used method of assessing the weight of patients with acute stroke. Because the dosage of tissue plasminogen activator (tPA) is weight-dependent, errors in estimation lead to incorrect dosing. METHODS: We installed a ground-level scale in the computed tomography (CT) suite of our hospital and also integrated a scale into the CT table of our Mobile Stroke Unit in order to prospectively assess the differences between reported, estimated, and measured weights of acute stroke patients. An independent rater asked patients to report their weight. The patients' weights were also estimated by the treating physician and measured with a scale. Differences between reported, estimated, and measured weights were analyzed statistically. RESULTS: For 100 consecutive patients, weighing was possible without treatment delays. Weights estimated by the physician diverged from measured weights by 10% or more for 27 patients and by 20% or more for 6 patients. Weights reported by the patient diverged from measured weights by 10% or more for 12 patients. Weights reported by the patients differed significantly less from measured weights (mean, 4.1 +/- 3.1 kg) than did weights estimated by the physician (5.7 +/- 4.4 kg; p = 0.003). CONCLUSION: This first prospective study of weight assessment in acute stroke shows that the use of an easily accessible scale makes it feasible to weigh patients with acute stroke without the treatment delay associated with additional patient transfers. Physicians' estimates of patients' weights demonstrated substantial aberrations from measured weights. Avoiding these deviations would improve the accuracy of tPA dosage. PMID- 28558375 TI - The Determinants of Quality of Life of Nursing Home Residents with Young-Onset Dementia and the Differences between Dementia Subtypes. AB - AIMS: The aims of this study are to (1) explore the determinants of quality of life (QoL) in nursing home residents with young-onset dementia (YOD), (2) investigate whether there are differences between dementia subtypes (Alzheimer dementia, vascular/mixed dementia, frontotemporal dementia, other) regarding these determinants, and (3) compare QoL profiles of YOD nursing home residents across dementia subtypes. METHODS: This cross-sectional study included 207 nursing home residents. Multilevel modeling was used to determine the relationships between QoL and neuropsychiatric symptoms (NPS), dementia severity, psychotropic drug use (PDU), dementia subtype, age, and gender. Additional multilevel models were used to compare aspects of QoL between dementia subtypes. RESULTS: Residents' QoL was negatively associated with advanced dementia, PDU, and NPS. In general, the relationships between the determinants and QoL were similar across the dementia subtypes. Aspects of QoL differed by dementia subtype. Residents with frontotemporal dementia showed less negative emotions, accepted more help and experienced better quality of relationships with professional caregivers, had a more positive self-image, felt more comfortable in the nursing home environment, and experienced lower quality of social relationships. CONCLUSIONS: Considering the high rates of NPS and PDU in YOD residents and their negative associations with QoL, we recommend emphasizing services to manage and reduce NPS and PDU in nursing home residents with YOD. Furthermore, our findings suggest accounting for differences in aspects of QoL by dementia subtype to address specific needs and thereby improve QoL. PMID- 28558377 TI - Addendum. PMID- 28558376 TI - Long-Term Outcomes of Patients with Central Precocious Puberty due to Hypothalamic Hamartoma after GnRHa Treatment: Anthropometric, Metabolic, and Reproductive Aspects. AB - BACKGROUND: Hypothalamic hamartoma (HH) represents the commonest cause of organic central precocious puberty (CPP). Follow-up of these patients in adulthood is scarce. OBJECTIVE: To describe the anthropometric, metabolic, and reproductive parameters of patients with CPP due to HH before and after treatment with gonadotropin-releasing hormone analog (GnRHa). METHODS: We performed a retrospective and cross-sectional study in a single tertiary center including 14 patients (7 females) with CPP due to HH. RESULTS: The mean duration of GnRHa treatment was 7.7 +/- 2.4 years in boys and 7.9 +/- 2.1 years in girls. GnRHa treatment was interrupted at the mean chronological age (CA) of 12.1 +/- 1.1 years in boys and 10.7 +/- 0.5 years in girls. At the last visit, the mean CA of the male and female patients was 21.5 +/- 3.2 and 24 +/- 3.9 years, respectively. Eleven of the 14 patients reached normal final height (FH) (standard deviation score -0.6 +/- 0.9 for males and -0.6 +/- 0.5 for females), all of them within the target height (TH) range. The remaining 3 patients had predicted height within the TH range. The mean body mass index and the percentage of body fat mass was significantly higher in females, with a higher prevalence of metabolic disorders. All patients presented normal gonadal function in adulthood, and 3 males fathered a child. CONCLUSION: All patients with CPP due to HH reached normal FH or near-FH. A higher prevalence of overweight/obesity and hypercholesterolemia was observed in the female patients. Finally, no reproductive disorder was identified in both sexes, indicating that HH per se has no deleterious effect on the gonadotropic axis in adulthood. PMID- 28558378 TI - Pial Arteriovenous Fistula and Capillary Malformation-Arteriovenous Malformation Associated with RASA1 Mutation: 2 Pediatric Cases with Successful Surgical Management. AB - We present case reports of 2 pediatric patients who were both found to have pial arteriovenous fistulas (AVFs) with subsequent genetic analysis revealing mutations in the RASA1 gene. Considering their family history of distinct cutaneous lesions, these mutations were likely inherited as opposed to de novo mutations. Patient 1 had large capillary malformations on the left side of the face and neck, associated with macrocephaly, and presented at the age of 32 months with speech delay, right-sided weakness, and focal seizures involving the right side of the body. Patient 2 presented with proptosis at the age of 9 months, but was otherwise neurologically intact. Given the chance for definitive single-stage control of vascular shunt (obviating chances for radiation exposure with endovascular treatment) and surgically accessible location of these intracranial lesions, both patients were treated with surgery with excellent clinical and radiological outcome. In general, given the high mortality secondary to severe congestive heart failure when treated conservatively, the goal of treatment in cortical AVF in young children, even when asymptomatic, is rapid control of the shunt. This was achieved successfully in our cases - both patients experienced significant symptomatic improvement following surgery and remained neurologically stable in the subsequent follow-up visits. PMID- 28558379 TI - SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families. AB - BACKGROUND: Autosomal recessive cerebellar ataxias (ARCA) are a complex group of neurodegenerative disorders with high clinical and genetic heterogeneity. In most cases, the cerebellar ataxia is not pure, and complicating clinical features such as pyramidal signs or extraneurological features are found. OBJECTIVE: To identify the genetic origin of the cerebellar ataxia for 3 consanguineous North African families presenting with ARCA. METHODS: Genome-wide high-density SNP genotyping and whole-exome sequencing were performed followed by Sanger sequencing for mutation confirmation. RESULTS: Two variants were identified in SLC25A46. Mutations in this gene have been previously associated with Charcot Marie-Tooth type 2 and optic atrophy. While the previously reported variant p.Arg340Cys seems to be consistently associated with the same clinical features such as childhood onset, optic atrophy, gait and speech difficulties, and wasting of the lower limbs, the patient with the novel mutation p.Trp160Ser did not present with optic atrophy and his ocular abnormalities were limited to nystagmus and saccadic pursuit. CONCLUSION: In this study, we report a novel variant (p.Trp160Ser) in SLC25A46 and we broaden the phenotypic spectrum associated with mutations in SLC25A46. PMID- 28558380 TI - Circulating Tumor Cells as a Biomarker in Pancreatic Ductal Adenocarcinoma. AB - BACKGROUND/AIMS: Circulating tumor cells (CTCs) are valuable in both basic research and clinical application for cancer management. In the current study, we evaluated the diagnostic value of CTCs in pancreatic ductal adenocarcinoma (PDAC). METHODS: In total, 143 blood samples from 95 consecutively diagnosed PDAC patients and 48 healthy donors were collected. Combined data from immunostaining of CD45, DAPI and fluorescence in situ hybridization (FISH) with chromosome 8 centromere (CEP8) probe were used to identify CTCs. Cells with features of CD45 /DAPI+/CEP8>2 were detected as CTCs. RESULTS: CTCs were classified as triploid, tetraploid and multiploid based on chromosome 8 copy number. CTC subtype composition was significantly different among groups. Both subtype number and total CTC number were significantly increased in PDAC patients, compared to healthy controls. Total CTC number had 75.8% sensitivity and 68.7% specificity at a cutoff value of 2 cells/3.2 mL. This study is the first to report that CTC subtype number is also useful in cancer diagnosis. Sensitivity was 53.7% and specificity was 85.4% at a cutoff point of 2 CTC subtypes. The diagnostic value of both total CTC number and CTC subtype number was a little poorer than CA199. CONCLUSIONS: Both CTC subtype and total CTC number may serve as potential biomarkers for PDAC. PMID- 28558381 TI - Aldolase B Overexpression is Associated with Poor Prognosis and Promotes Tumor Progression by Epithelial-Mesenchymal Transition in Colorectal Adenocarcinoma. AB - BACKGROUND: Glycolysis is considered to be the root of cancer development and progression, which involved a multi-step enzymatic reaction. Our study aimed at figuring out which glycolysis enzyme participates in the development of colorectal cancer and its possible mechanisms. METHODS: We firstly screened out Aldolase B (ALDOB) by performing qRT-PCR arrays of glycolysis-related genes in five paired liver metastasis and primary colorectal tissues, and further detected ALDOB protein with immunohistochemistry in tissue microarray (TMA) consisting of 229 samples from stage I-III colorectal cancer patients. CRISPR-Cas9 method was adopted to create knock out colon cancer cell lines (LoVo and SW480) of ALDOB. The effect of ALDOB on cell proliferation and metastasis was examined in vitro using colony formation assay as well as transwell migration and invasion assay, respectively. RESULTS: In TMA, there was 64.6% of samples demonstrated strong intensity of ALDOB. High ALDOB expression were associated with poor overall survival and disease-free survival in both univariate and multivariate regression analyses (P<0.05). In vitro functional studies of CCK-8 demonstrated that silencing ALDOB expression significantly (P<0.05) inhibited proliferation, migration and invasion of colon cancer cells. Mechanically, silencing ALDOB activated epithelial markers and repressed mesenchymal markers, indicating inactivation of ALDOB may lead to inhibition of epithelial-mesenchymal transition (EMT). CONCLUSION: Upregulation of ALDOB promotes colorectal cancer metastasis by facilitating EMT and acts as a potential prognostic factor and therapeutic target in colorectal cancer. PMID- 28558382 TI - ZNF750 Expression as a Novel Candidate Biomarker of Chemoradiosensitivity in Esophageal Squamous Cell Carcinoma. AB - OBJECTIVE: ZNF750, an epidermal differentiation regulator, has been suggested to act as a tumor suppressor of esophageal squamous cell carcinoma (ESCC). Although a correlation between the epidermal differentiation gene and resistance to chemoradiotherapy (CRT) has been posited, no data regarding the ZNF750 status in ESCC have been reported. The aim of the present study was to evaluate the relationship between ZNF750 expression and response to CRT in ESCC. METHODS: Eighty-seven patients who had been pathologically diagnosed with ESCC were evaluated in the present study. All patients underwent neoadjuvant CRT, followed by curative esophagectomy. The expression of ZNF750 in pretreatment biopsy samples was immunohistochemically investigated and compared to the histopathological effectiveness of CRT in surgical specimens. RESULTS: High expression of ZNF750 was closely correlated with good sensitivity to CRT (p = 0.016). A univariate analysis showed that high/intermediate expression of ZNF750 was a significant predictive factor for good sensitivity to CRT (p = 0.006). High/intermediate expression of ZNF750 (30% or more) remained an independent predictive factor for sensitivity to CRT in a multivariate analysis (p = 0.033). CONCLUSIONS: ZNF750 expression predicts sensitivity to CRT and can be a biomarker that reliably predicts the response of ESCC to CRT. PMID- 28558383 TI - Successful Liver Transplantation for Transient Abnormal Myelopoiesis-Associated Liver Failure. AB - Infants with Down syndrome (DS) are at risk of developing a transient abnormal myelopoiesis (TAM). TAM occasionally involves liver fibrosis, which can be fatal. The management of liver disease in TAM has not yet been established and is mainly supportive. We report an infant with DS and TAM who developed end-stage liver failure. Liver dysfunction progressed even after blast cells disappeared from the circulation. He underwent a living-donor liver transplantation at 56 days of life without surgical complications. The explanted liver showed atrophy and severe fibrosis without leukemic cell infiltration. The posttransplant course was favorable with no hematological abnormality. He is doing well 8 months after transplantation. To the best of our knowledge, this report is the first showing that liver transplantation might be a treatment option for TAM-related liver failure. PMID- 28558384 TI - Randomized Controlled Trial Comparing Different Single Doses of Intravenous Paracetamol for Placement of Peripherally Inserted Central Catheters in Preterm Infants. AB - BACKGROUND: The availability of a safe and effective pharmacological therapy to reduce procedural pain in preterm infants is limited. The effective analgesic single dose of intravenous paracetamol in preterm infants is unknown. Comparative studies on efficacy of different paracetamol doses in preterm infants are lacking. OBJECTIVES: To determine the analgesic effects of different single intravenous paracetamol doses on pain from peripherally inserted central catheter (PICC) placement in preterm infants. METHODS: In a blinded randomized controlled trial, the analgesic effects of 10-, 15-, and 20-mg/kg single-dose intravenous paracetamol before PICC placement were compared in neonates with a gestational age <32 weeks. Secondly, a separate age-matched nonrandomized control group receiving oral sucrose was included. Pain was assessed with the Premature Infant Pain Profile (PIPP) and the COMFORTneo score. Peak plasma concentrations of paracetamol were determined. RESULTS: A total of 60 patients were included in the paracetamol dose groups (median gestational age = 27.8, IQR: 25.7-29.2 weeks). PIPP scores were comparable: median = 8 (IQR: 6-10.5), 7 (IQR: 6-9), and 8 (IQR: 6-10) for the 10-, 15-, and 20-mg/kg paracetamol groups, respectively (p = 0.94). COMFORTneo scores were not statistically different between the different paracetamol dose groups (p = 0.35). All randomized subjects, except for 3 who received 10 mg/kg of paracetamol, had peak paracetamol concentrations >9 mg/L. PIPP (p = 0.78) and COMFORTneo (p = 0.08) scores were also comparable between paracetamol- and sucrose-treated patients. CONCLUSIONS: We found no analgesic benefit from intravenous paracetamol studied in different single doses over sucrose for PICC placement in preterm infants. Paracetamol is not a suitable analgesic for this procedure in preterm infants. PMID- 28558385 TI - Risk Factors for Overall Survival Outcome in Surgically Treated Human Papillomavirus-Negative and Positive Patients with Oropharyngeal Cancer. AB - INTRODUCTION: This study reports the oncological outcome of a non-selected series of patients with human papillomavirus(HPV)-positive and -negative oropharyngeal squamous cell carcinoma (OSCC) preferentially managed with upfront surgery. METHODS: Consecutive OSCC cases (n = 378) diagnosed from 2000 to 2010 in our department were evaluated for risk factors, HPV association, therapy and overall survival (OS). HPV status was determined by combined DNA and p16 testing, and treatment was defined as the first course of treatment with any kind of surgery (upfront surgery) or primary chemoradiotherapy. OS of HPV-associated and HPV negative patients was compared using Kaplan-Meier and multivariable Cox regression analyses. RESULTS: The majority of OSCC patients (215 of 361; 69.5%) received upfront surgery as first-line treatment in curative intent. The 5-year OS rate in patients with HPV-positive and HPV-negative tumors were 81.1 and 39.7%, respectively. Upfront surgery in HPV-negative (p < 0.001) and HPV-positive patients (p = 0.05) resulted in improved OS only in advanced stages. Multivariate analysis for patients revealed age in HPV-associated OSCC as an independent predictor for improved survival, and age, performance, N status and therapy as independent predictors in HPV-negative OSCC. CONCLUSIONS: Non-selected OSCC patients amenable to curative therapy show poor 5-year OS. The benefit of upfront surgery remains unclear. A younger patient age was the main factor for a better outcome in patients with HPV-associated OSCC. PMID- 28558391 TI - Breaking object correspondence across saccades impairs object recognition: The role of color and luminance. AB - Rapid saccadic eye movements bring the foveal region of the eye's retina onto objects for high-acuity vision. Saccades change the location and resolution of objects' retinal images. To perceive objects as visually stable across saccades, correspondence between the objects before and after the saccade must be established. We have previously shown that breaking object correspondence across the saccade causes a decrement in object recognition (Poth, Herwig, & Schneider, 2015). Color and luminance can establish object correspondence, but it is unknown how these surface features contribute to transsaccadic visual processing. Here, we investigated whether changing the surface features color-and-luminance and color alone across saccades impairs postsaccadic object recognition. Participants made saccades to peripheral objects, which either maintained or changed their surface features across the saccade. After the saccade, participants briefly viewed a letter within the saccade target object (terminated by a pattern mask). Postsaccadic object recognition was assessed as participants' accuracy in reporting the letter. Experiment A used the colors green and red with different luminances as surface features, Experiment B blue and yellow with approximately the same luminances. Changing the surface features across the saccade deteriorated postsaccadic object recognition in both experiments. These findings reveal a link between object recognition and object correspondence relying on the surface features colors and luminance, which is currently not addressed in theories of transsaccadic perception. We interpret the findings within a recent theory ascribing this link to visual attention (Schneider, 2013). PMID- 28558386 TI - Periodic Mechanical Stress INDUCES Chondrocyte Proliferation and Matrix Synthesis via CaMKII-Mediated Pyk2 Signaling. AB - BACKGROUND/AIMS: Periodic mechanical stress can promote chondrocyte proliferation and matrix synthesis to improve the quality of tissue-engineered cartilage. Although the integrin beta1-ERK1/2 signal cascade has been implicated in periodic mechanical stress-induced mitogenic effects in chondrocytes, the precise mechanisms have not been fully established. The current study was designed to probe the roles of CaMKII and Pyk2 signaling in periodic mechanical stress mediated chondrocyte proliferation and matrix synthesis. METHODS: Chondrocytes were subjected to periodic mechanical stress, proliferation was assessed by direct cell counting and CCK-8 assay; gene expressions were analyzed using quantitative real-time PCR, protein abundance by Western blotting. RESULTS: Mechanical stress, markedly enhanced the phosphorylation levels of Pyk2 at Tyr402 and CaMKII at Thr286. Both suppression of Pyk2 with Pyk2 inhibitor PF431396 or Pyk2 shRNA and suppression of CaMKII with CaMKII inhibitor KN-93 or CaMKII shRNA blocked periodic mechanical stress-induced chondrocyte proliferation and matrix synthesis. Additionally, either pretreatment with KN-93 or shRNA targeted to CaMKII prevented the activation of ERK1/2 and Pyk2 under conditions of periodic mechanical stress. Interestingly, in relation to periodic mechanical stress, in the context of Pyk2 inhibition with PF431396 or its targeted shRNA, only the phosphorylation levels of ERK1/2 were abrogated, while CaMKII signal activation was not affected. Moreover, the phosphorylation levels of CaMKII- Thr286 and Pyk2 Tyr402 were abolished after pretreatment with blocking antibody against integrinbeta1 exposed to periodic mechanical stress. CONCLUSION: Our results collectively indicate that periodic mechanical stress promotes chondrocyte proliferation and matrix synthesis through the integrinbeta1-CaMKII-Pyk2-ERK1/2 signaling cascade. PMID- 28558393 TI - Effect of allocentric landmarks on primate gaze behavior in a cue conflict task. AB - The relative contributions of egocentric versus allocentric cues on goal-directed behavior have been examined for reaches, but not saccades. Here, we used a cue conflict task to assess the effect of allocentric landmarks on gaze behavior. Two head-unrestrained macaques maintained central fixation while a target flashed in one of eight radial directions, set against a continuously present visual landmark (two horizontal/vertical lines spanning the visual field, intersecting at one of four oblique locations 11 degrees from the target). After a 100-ms delay followed by a 100-ms mask, the landmark was displaced by 8 degrees in one of eight radial directions. After a second delay (300-700 ms), the fixation point extinguished, signaling for a saccade toward the remembered target. When the landmark was stable, saccades showed a significant but small (mean 15%) pull toward the landmark intersection, and endpoint variability was significantly reduced. When the landmark was displaced, gaze endpoints shifted significantly, not toward the landmark, but partially (mean 25%) toward a virtual target displaced like the landmark. The landmark had a larger influence when it was closer to initial fixation, and when it shifted away from the target, especially in saccade direction. These findings suggest that internal representations of gaze targets are weighted between egocentric and allocentric cues, and this weighting is further modulated by specific spatial parameters. PMID- 28558392 TI - Illumination discrimination in real and simulated scenes. AB - Characterizing humans' ability to discriminate changes in illumination provides information about the visual system's representation of the distal stimulus. We have previously shown that humans are able to discriminate illumination changes and that sensitivity to such changes depends on their chromatic direction. Probing illumination discrimination further would be facilitated by the use of computer-graphics simulations, which would, in practice, enable a wider range of stimulus manipulations. There is no a priori guarantee, however, that results obtained with simulated scenes generalize to real illuminated scenes. To investigate this question, we measured illumination discrimination in real and simulated scenes that were well-matched in mean chromaticity and scene geometry. Illumination discrimination thresholds were essentially identical for the two stimulus types. As in our previous work, these thresholds varied with illumination change direction. We exploited the flexibility offered by the use of graphics simulations to investigate whether the differences across direction are preserved when the surfaces in the scene are varied. We show that varying the scene's surface ensemble in a manner that also changes mean scene chromaticity modulates the relative sensitivity to illumination changes along different chromatic directions. Thus, any characterization of sensitivity to changes in illumination must be defined relative to the set of surfaces in the scene. PMID- 28558394 TI - Disentangling vision and attention in multiple-object tracking: How crowding and collisions affect gaze anchoring and dual-task performance. AB - Previous studies of multiple-object tracking have shown that gaze behavior is affected by target collisions and target-distractor crowding. Therefore, in order to experimentally disentangle this collision-crowding confound, we examined events of target collisions with the bordering frame and crowding with distractors. We hypothesized that collisions are particularly demanding for covert attentional processing, whereas crowding particularly challenges peripheral vision. Results show that gaze is located closer to targets when they are crowded, as would be expected to reduce negative crowding effects by utilizing the higher spatial acuity of foveal vision. However, saccades, which interrupt visual information processing, were instead initiated as a function of target collisions with the bordering frame. Consequently, in a dual-task condition that required the detection of target changes, participants more frequently missed changes if they occurred in time intervals around a collision. Based on these results, superior performance should be expected if foveal gaze is optimally anchored among crowded targets and if potential target changes are monitored with peripheral vision. In addition to the implications for further laboratory research of multiple-object tracking, these findings are relevant to a multitude tasks that require the monitoring of several targets and the simultaneous detection of certain events in the visual periphery, as it is commonly the case, for instance, in sports. PMID- 28558395 TI - The perception of hazy gloss. AB - Most previous work on gloss perception has examined the strength and sharpness of specular reflections in simple bidirectional reflectance distribution functions (BRDFs) having a single specular component. However, BRDFs can be substantially more complex and it is interesting to ask how many additional perceptual dimensions there could be in the visual representation of surface reflectance qualities. To address this, we tested materials with two specular components that elicit an impression of hazy gloss. Stimuli were renderings of irregularly shaped objects under environment illumination, with either a single Ward specular BRDF component (Ward, 1992), or two such components, with the same total specular reflectance but different sharpness parameters, yielding both sharp and blurry highlights simultaneously. Differently shaped objects were presented side by side in matching, discrimination, and rating tasks. Our results show that observers mainly attend to the sharpest reflections in matching tasks, but they can indeed discriminate between single-component and two-component specular materials in discrimination and rating tasks. The results reveal an additional perceptual dimension of gloss-beyond strength and sharpness-akin to "haze gloss" (Hunter & Harold, 1987). However, neither the physical measurements of Hunter and Harold nor the kurtosis of the specular term predict perception in our tasks. We suggest the visual system may use a decomposition of specular reflections in the perception of hazy gloss, and we compare two possible candidates: a physical representation made of two gloss components, and an alternative representation made of a central gloss component and a surrounding halo component. PMID- 28558396 TI - [German Guideline for Idiopathic Pulmonary Fibrosis - Update on Pharmacological Therapies 2017]. AB - Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease with a median survival of 2 - 4 years after diagnosis. Since the publication of the German IPF guideline in 2013 new treatment trials have been published, necessitating an update of the pharmacological therapy of IPF. Different from the previous guideline, the GRADE system was discarded and replaced by the Oxford evidence classification system which allows a more differentiated judgement. The following pharmacological therapies were rated not suitable for the treatment of IPF patients (recommendation A; evidence 1-b): triple therapy with prednisolone, azathioprine and acetyl-cysteine; imatinib; ambrisentan; bosentan; macitentan. A less clear but still negative recommendation (B, 1-b) was attributed to the treatment of IPF with the phosphodiesterase-5-inhibitor sildenafil and acetyl cysteine monotherapy. In contrast to the international guideline antacid therapy as a general treatment for IPF was rated negative, based on conflicting results of recent analyses (recommendation C; evidence 4). An unanimous positive recommendation was granted for the antifibrotic drugs nintedanib and pirfenidone for the treatment of IPF (A, 1-a). For some open questions in the management of IPF patients for which firm evidence is lacking the guideline also offers recommendations based on expert consensus. PMID- 28558397 TI - [Endobronchial Dissemination of Metastatic Melanoma without Apparent Primary Tumor]. PMID- 28558398 TI - [Guidelines in Practice: The New S3 Guideline "Sleeping Disorders - Sleep-Related Abnormal Breathing"]. AB - Sleep related breathing disorders include central sleep apnea (CSA), obstructive sleep apnea (OSA), sleep-related hypoventilation, and sleep-related hypoxia. These disorders are frequent and growing in clinical relevance. The related chapter of the S3 guideline "Non-restorative sleep/Sleep disorders", published by the German Sleep Society (DGSM), has recently been updated in November 2016. Epidemiology, diagnostics, therapeutic procedures, and classification of sleep related disorders have been revised. Concerning epidemiology, a considerably higher mortality rate among pregnant women with OSA has been emphasized. With regards to diagnostics, the authors point out that respiratory polygraphy may be sufficient in diagnosing OSA, if a typical clinical condition is given. For CSA, recommendations were changed to diagnose CSA with low apnea rates present. Significant changes for treating CSA in patients with left ventricular dysfunction have been introduced. In addition, there is now to be differentiated between sleep-related hypoventilation and sleep-related hypoxaemia. Obesity hypoventilation syndrome is discussed in more detail. This article sums up and comments on the published changes. PMID- 28558399 TI - [Applicability of the Therapeutic Nursing Theory in Neurological (Early-) Rehabilitation into Nursing Practice - A Case Study]. AB - PURPOSE: The objective of the study is to describe how the theory of therapeutic nursing in neurological (early) rehabilitation can be transferred into nursing practice. MATERIALS AND METHODS: The theory was developed using the method of grounded theory by Glaser and Strauss. Open participatory observations (n=92) and episodic interviews (n=10) with nursing professionals and nursing auxiliaries were conducted in 5 inpatient rehabilitation clinics. Data analysis was performed using the constant comparative method by Glaser and Strauss. RESULTS: By means of a case study, the applicability of the theory into nursing practice with regard to the following care situations is described: (1) training for personal care, (2) therapeutic positioning, (3) oral hygiene, (4) training of sensory-motor perception and (5) counseling relatives. Consequently, the categories of the theory: (1) nursing care, (2) observation/perception, (3) communication, (4) autonomy and individual needs of patients and their relatives, (5) multi professional team and (6) prerequisites are transferred into the case scenario. CONCLUSIONS: The case study demonstrates how the therapeutic nursing theory in neurological (early-) rehabilitation can be transferred into nursing practice and reveals the complexity of nursing interventions. PMID- 28558400 TI - Transgastric retrograde endoscopic ultrasound sampling of a mediastinal mass in a patient with radiation-induced trismus. PMID- 28558401 TI - Endoscopic full-thickness resection of a non-lifting large laterally spreading flat colonic polyp. PMID- 28558402 TI - The use of clip anchoring to ensure safe transgastric puncture during endoscopic ultrasound-guided transmural drainage. PMID- 28558403 TI - First report of successful treatment of splenic artery pseudoaneurysm with endoscopic ultrasound-guided coil and glue. PMID- 28558404 TI - A benign colorectal lesion with amorphous pit (Kudo Vn) and avascular pattern (Sano's 3b): differential diagnosis with deep invasive adenocarcinoma. PMID- 28558405 TI - Endoscopic removal of an eroded magnetic sphincter augmentation device. PMID- 28558406 TI - West meets East: dynamic ERCP characterization of pancreaticobiliary maljunction without biliary dilation underlying extensive biliary tract cancer. PMID- 28558407 TI - Novel unroofing approach for incipient suprapapillary stone perforation causing papillary invagination ("the crescent sign"). PMID- 28558408 TI - Focusing on Patient Subcategories: When Could We Expect a Suboptimal Late Result after Coronary Endarterectomy? PMID- 28558409 TI - Reply by the Authors of the Original Article. PMID- 28558410 TI - French comment on article Extending magnifying NBI diagnosis of intestinal metaplasia in the stomach: the white opaque substance marker. PMID- 28558411 TI - French comment on article Risk factors for inadequate bowel preparation: a validated predictive score. PMID- 28558412 TI - French comment on article Dedicated Barrett's surveillance sessions managed by trained endoscopists improve dysplasia detection rate. PMID- 28558413 TI - Treatment of newly diagnosed Neuroblastoma after the end of clinical trials. PMID- 28558414 TI - Cystic Fibrosis Patient's best friend? Potential Transmission of Pseudomonas aeruginosa from a Dog. PMID- 28558415 TI - Obstacles to reducing plasma levels of uremic solutes by hemodialysis. AB - More intensive hemodialysis has provided limited clinical benefit. The lack of benefit may be due in part to the failure of intensive dialysis to reduce uremic solute levels in plasma. Two well-described factors limiting the reduction in these levels are the intermittency of dialysis treatment and the distribution of solutes in multiple body compartments. Efforts to increase the clearance of large solutes and protein-bound solutes have revealed two other considerations-the presence of nonrenal clearance and increases in solute generation. For beta2 microglobulin, a commonly measured large solute, nonrenal clearance limits reduction in its levels. For the bound solute p-cresol sulfate, an increase in generation appears to limit its reduction. A variety of factors likely determine the behavior of different solutes. More data on solute toxicity are needed as is better knowledge of solute kinetics. We will then be better able to design optimal therapeutic interventions. A combination of dialytic and nondialytic strategies may well be needed to reduce the plasma levels of toxic solutes and improve patients' health. PMID- 28558416 TI - Fast ultra-high-performance liquid chromatography with diode array and mass spectrometry method for determination of tadalafil drug substance and its impurities. AB - Tadalafil is used for the treatment of erectile dysfunction. Its related patents expired in 2016, and so related generic drug production is predicted to be increased. This work is focused on developing a fast ultra-high-performance liquid chromatography with diode array detection and/or mass spectrometry detection for the separation and determination of tadalafil and its impurities in pharmaceutical samples. A modern reversed-phase stationary phase with sub-2 MUm particle size, Zorbax StableBond Rapid Resolution High Definition with octylsilane chemically bonded phase to totally porous silica particles, was used for the solving this problem. Column temperature was set at 40 +/- 0.1 degrees C. A mobile phase consisting of acetonitrile and aqueous solution of 0.1% (v/v) trifluoroacetic acid for diode array detection detection and 0.05% (v/v) formic acid, both running at a flow rate of 0.62 mL/min, were used to achieve the required separation of all components within a 5 min run. The limit of detection was 3.5 MUg/L and the limit of quantification was 10.0 MUg/L for the method for both UV and MS detectors. Accurate mass spectra of tadalafil's related impurities are shown for advanced confirmation. The method is directly transferable to routine analysis of tadalafil in pharmaceutical and control laboratories. PMID- 28558417 TI - Imaging of Parathyroid Glands in End Stage Renal Disease. AB - Secondary hyperparathyroidism from chronic renal failure often requires a parathyroidectomy for correction. A successful parathyroidectomy often relies upon localization of all parathyroid tumors. Although most of the tumors are localized during a neck exploration, preoperative localization studies can help identify ectopic and supernumerary tumors. Three of the most common localization studies are radionuclide imaging, ultrasound, and CT scanning. Utility of these studies is strongly dependent on local institutional practice. PMID- 28558418 TI - Retraction statement: Mathematical-based modeling and prediction of the effect of external stimuli on human gait. PMID- 28558419 TI - Generation of recombinant bovine interferon tau in the human embryonic kidney cell line and its biological activity. AB - The objective of this study was to generate recombinant bovine interferon tau (rbIFNT) in mammalian hosts. The complementary DNA encoding bovine IFNT2 was cloned for the construction of pRcRSV-bIFNT2 expression vector. The expression vector was transfected to 293 cells. Transfected cells harboring expression vector were selected with G418. Highly expressing clonal line was adapted to serum-free suspension culture in a spinner flask. The recombinant protein had 24 kDa apparent molecular mass, suggesting being expressed as a glycoprotein, and was purified from serum-free conditioned medium by the combination of Diethylaminoethanol Sepharose ion exchange and Sephacryl S-200 HR gel filtration. A total of 7.3 mg rbIFNT was obtained from 13.5 L conditioned medium. Generated rbIFNT was biologically active in terms of antiviral activity measured by the plaque inhibition assay with Madin-Darby bovine kidney cells and the vesicular stomatitis virus. The recombinant protein was also utilized for immunization to raise antibodies in the rabbit. The generated antibody was capable of use in both Western blotting and the binding assay. The results in the present study suggest that a certain amount of rbIFNT is raised in mammalian hosts by using conventional plasmid vector and its antibody provides useful tools for studies in the biology of bovine IFNT. PMID- 28558420 TI - Understanding the drivers of extensive plant damage in boreal and Arctic ecosystems: Insights from field surveys in the aftermath of damage. AB - The exact cause of population dieback in nature is often challenging to identify retrospectively. Plant research in northern regions has in recent decades been largely focussed on the opposite trend, namely increasing populations and higher productivity. However, a recent unexpected decline in remotely-sensed estimates of terrestrial Arctic primary productivity suggests that warmer northern lands do not necessarily result in higher productivity. As large-scale plant dieback may become more frequent at high northern latitudes with increasing frequency of extreme events, understanding the drivers of plant dieback is especially urgent. Here, we report on recent extensive damage to dominant, short, perennial heath and tundra plant populations in boreal and Arctic Norway, and assess the potential drivers of this damage. In the High-Arctic archipelago of Svalbard, we recorded that 8-50% of Cassiope tetragona and Dryas octopetala shoots were dead, and that the ratios of dead shoots increased from 2014 to 2015. In boreal Norway, 38-63% of Calluna vulgaris shoots were dead, while Vaccinium myrtillus had damage to 91% of shoots in forested sites, but was healthy in non-forested sites. Analyses of numerous sources of environmental information clearly point towards a winter climate-related reason for damage to three of these four species. In Svalbard, the winters of 2011/12 and 2014/15 were documented to be unusually severe, i.e. insulation from ambient temperature fluctuation by snow was largely absent, and ground-ice enforced additional stress. In boreal Norway, the 2013/14 winter had a long period with very little snow combined with extremely low precipitation rates, something which resulted in frost drought of uncovered Calluna plants. However, extensive outbreaks of a leaf-defoliating geometrid moth were identified as the driver of Vaccinium mortality. These results suggest that weather and biotic extreme events potentially have strong impacts on the vegetation state of northern lands. PMID- 28558422 TI - Reflections on a boom: Perceptions of energy development impacts in the Bakken oil patch inform environmental science & policy priorities. AB - Ecosystems worldwide have been subject to new or intensified energy development facilitated by technologies such as horizontal drilling and hydraulic fracturing, activity that has generated concern for air, water, biotic, and social resources. Application of these technologies in the development of the Bakken oil patch has made it one of the most productive petroleum plays in North America, causing unprecedented landscape industrialization of otherwise rural, agricultural counties in western North Dakota. The region is isolated, and development impacts have not been well-studied. To identify concerns of citizens of the Bakken and determine how research and policy might support them, we conducted a two-part study: First, we held focus groups with resource management and community leaders in three major oil-producing counties. Second, we used an outline of the major concerns expressed by focus group members as a survey for landowners and farm/ranch operators. We found little relationship between survey respondents' reported categorization of energy impacts and actual land area impacted, suggesting factors such as attitude towards development, degree of compensation, and level of disturbance are relevant. Landowners agreed with focus groups on the nature of relationships between energy companies and locals and development impacts on infrastructure and communities; those reporting greater impacts tended to agree more strongly. But many specific problems described in focus groups were not widely reported in the survey, suggesting energy-community relationships can be improved through state-level public policy and respect from energy companies for locals and their way of life. Consideration of these concerns in future energy policy-both in the Bakken and worldwide-could reduce social tension, lessen environmental impact, and increase overall social, economic, and environmental efficiency in energy development. PMID- 28558421 TI - Phthalate metabolites in Norwegian mothers and children: Levels, diurnal variation and use of personal care products. AB - Exposure to phthalates has been associated with reproductive and developmental toxicity. Data on levels of these compounds in the Norwegian population is limited. In this study, urine samples were collected from 48 mothers and their children in two counties in Norway. Eleven different phthalate metabolites originating from six commonly used phthalates in consumer products were determined. Concentrations of phthalate metabolites were significantly higher in children compared to mothers except for mono-ethyl phthalate (MEP). The mothers provided several urine samples during 24hours (h) and diurnal variation showed that the concentrations in the morning urine samples (24-8h) were significantly higher than at other time-periods for most of the phthalate metabolites. Intraclass correlation coefficients (ICCs) for 24-hour time-period were in the range of 0.49-0.81. These moderate to high ICCs indicate that one spot urine sample can be used to estimate the exposure to phthalates. Since a significant effect of time of day was observed, it is still advisable to standardize the collection time point to reduce the variation. For the mothers, the use of personal care products (PCPs) were less associated with morning urine samples than early day (8-12h) and evening (16-24h) urine samples. The use of perfume and hair products were positively associated with the urinary concentrations of low molecular weight phthalates. Use of shower soap and shampoo were positively associated with urinary concentration of di(2-ethylhexyl) phthalate (DEHP) metabolites. For children, face cream use was positively associated with phthalate metabolites in the morning samples, and hand soap use was negatively associated with concentration of urinary DEHP metabolites in afternoon/evening samples. Since different PCPs were associated with the urinary phthalate metabolites in different time-periods during a day, more than one spot urine sample might be required to study associations between urinary phthalate metabolites and the use of PCPs. PMID- 28558423 TI - Public environmental awareness of water pollution from urban growth: The case of Zarjub and Goharrud rivers in Rasht, Iran. AB - Rivers in urban areas have been associated with water quality problems because of the practice of discharging untreated domestic and industrial waste into the water bodies. However, to what extent the public can identify specific environmental problems and whether people are ready to cope with potential risks is to a great extent unknown. Public environmental awareness of factors underpinning the pollution of rivers and approaches for reducing it were studied in Rasht City of Guilan Province in northern Iran, with Zarjub and Goharrud rivers as a case study. Data were collected from residents on the banks of the studied rivers using a questionnaire. Industrial areas, hospitals, and poultry farms were perceived as the main factors deteriorating water pollution of Zarjub and Goharrud rivers in Guilan Province. The discharge of urban sewage into the rivers was the second most important polluting factor. Most residents on the banks of Zarjub and Goharrud rivers showed high interest in the conservation of the environment. Overall, 62.7% of the residents had moderate, 20% had high, and 4% had very high environmental awareness. Families and mass media (TV and radio) were perceived of being the most important sources of information of family members concerning environmental awareness. According to the residents, the main approach for alleviating the pollution of Zarjub and Goharrud rivers were creating green spaces, dredging the rivers, establishing a water purifying system, and establishing a waste incinerator with a separation system (based on municipal planning). The public in the study area appeared well prepared to cope with the risks of water pollution, but further improving environmental awareness of the community can be a first step for preventing environmental degradation. The positive attitudes of the residents towards environmental conservation, the use of proper information sources, and practical training in the context of extension services can be effective in conserving water resources in urban areas. PMID- 28558424 TI - On the biophysical mechanism of sensing atmospheric discharges by living organisms. AB - Atmospheric electrical discharges during thunderstorms, and the related electromagnetic fields (EMFs)/waves called sferics, can be sensed by humans at long distances through a variety of symptoms, mainly headache, fatigue, etc. Up to today there is no explanation for this association. Sferics consist of partially polarized electromagnetic pulses with an oscillating carrier signal in the very low frequency (VLF) band and a pulse repetition frequency in the extremely low frequency (ELF) band. Their ELF intensity may reach ~5mV/m at global ranges, and ~0.5V/m at ~1000km from the lightning. The health symptoms associated with sferics are also associated with antennas of mobile telephony base stations and handsets, which emit radio frequency (RF) radiation pulsed on ELF, and expose humans at similar or stronger electric field intensities with sferics. According to the Ion Forced-Oscillation mechanism, polarized ELF EMFs of intensities down to 0.1-1mV/m are able to disrupt any living cell's electrochemical balance and function by irregular gating of electro-sensitive ion channels on the cell membranes, and thus initiate a variety of health symptoms, while VLF EMFs need to be thousands of times stronger in order to be able to initiate health effects. We examine EMFs from sferics in terms of their bioactivity on the basis of this mechanism. We introduce the hypothesis that stronger atmospheric discharges may reasonably be considered to be ~70% along a straight line, and thus the associated EMFs (sferics) ~70% polarized. We find that sferics mainly in the ELF band have adequate intensity and polarization to cause biological/health effects. We provide explanation for the effects of sferics on human/animal health on the basis of this mechanism. PMID- 28558425 TI - Production and consumption-based water dynamics: A longitudinal analysis for the EU27. AB - This paper investigates the relationship between economic development and water pressures using a global Multiregional Input-Output model (MRIO) dataset that takes into account the increasingly connected global supply chains underlying the economic systems. In particular, we analyse differences in water indicator outcomes by income level among European Union countries (EU27) from 1995 to 2008, focusing specifically on production and consumption-based water metrics for the member states. We use panel fixed effects regressions to study the dynamics of adjustment of water resources alongside controlling for individual country heterogeneity. Our main results indicate that the effects differ substantially depending on the approach used for measurement, especially when we conditioned on the country economic development, indicating opposite trajectories of water consumption and per capita gross domestic product (GDP). Furthermore, the analysis of the main components associated to water indicators highlight the role of water embodied in trade flows as the transmission mechanisms of the main effects. In particular, our estimates suggest that the growth path followed by the most developed areas in the EU27 is based on the externalisation of the environmental burden over the less developed European partners, and external developing countries. On the policy front, our findings call for the implementation of integrated water resources management, technological specific policies and the corresponding environmental regulation to combine the conservation of water ecosystems and sustainable economic growth at the national, supranational and global levels. PMID- 28558426 TI - Insights into mercury deposition and spatiotemporal variation in the glacier and melt water from the central Tibetan Plateau. AB - Long-term monitoring of global pollutant such as Mercury (Hg) in the cryosphere is very essential for understanding its bio-geochemical cycling and impacts in the pristine environment with limited emission sources. Therefore, from May 2015 to Oct 2015, surface snow and snow-pits from Xiao Dongkemadi Glacier and glacier melt water were sampled along an elevation transect from 5410 to 5678m a.s.l. in the central Tibetan Plateau (TP). The concentration of Hg in surface snow was observed to be higher than that from other parts of the TP. Unlike the southern parts of the TP, no clear altitudinal variation was observed in the central TP. The peak Total Hg (HgT) concentration over the vertical profile on the snow pits corresponded with a distinct yellowish-brown dust layer supporting the fact that most of the Hg was associated with particulate matter. It was observed that only 34% of Hg in snow was lost when the surface snow was exposed to sunlight indicating that the surface snow is less influenced by the post-depositional process. Significant diurnal variation of HgT concentration was observed in the river water, with highest concentration observed at 7pm when the discharge was highest and lowest concentration during 7-8am when the discharge was lowest. Such results suggest that the rate of discharge was influential in the concentration of HgT in the glacier fed rivers of the TP. The estimated export of HgT from Dongkemadi river basin is 747.43gyr-1, which is quite high compared to other glaciers in the TP. Therefore, the export of global contaminant Hg might play enhanced role in the Alpine regions as these glaciers are retreating at an alarming rate under global warming which may have adverse impact on the ecosystem and the human health of the region. PMID- 28558427 TI - A data-driven approach for the study of coagulation phenomena in waste lubricant oils and its relevance in alkaline regeneration treatments. AB - Coagulation phenomena can occur in certain types of waste lubricant oils (WLO) during regeneration processes involving alkaline treatments, causing plant shutdowns. In this context, this study addresses the nature of the compounds responsible for the coagulation phenomena after the alkaline treatment. For such, an empirical test was developed to assess the coagulation behaviour of WLO, consisting in the addition of KOH to the WLO followed by heating under stirring conditions. This test was performed on 133 samples and four coagulation classes were identified: A; B1; B2 and C. Moreover, a physicochemical characterization of WLO was carried out regarding viscosity at 40 degrees C, saponification number (SN), total acid number (TAN), surface tension, water content, elemental analysis and functional groups (FTIR). 56 samples of fresh lubricant oils for different applications were also characterized and their properties assessed and compared. Multivariate methods were applied to WLO to discriminate among coagulation classes based on FTIR spectra. It was found that coagulation classes A and B1 exhibit statistically similar patterns for all properties determined. Spectral discriminating analysis did not reveal discriminant peaks for class B1 samples, and the presence of specific additives was pointed as the possible factor underlying the increase in viscosity in this oils. Class B2 presents the absence of additives and oxidation products as differentiating features. In addition, B2 samples showed lower TAN SN, and lower concentration of some elements. Lubricants from gear or hydraulic applications can give rise to this class of WLO. Oils of Class C are mainly composed by synthetic ester type base oils, which hamper regeneration processes using alkaline pretreatments. In future studies, WLO type A and B1 can be classified as a single class. The coagulation phenomena classification becomes A - negative, B - precipitate formation and C - positive. PMID- 28558428 TI - Occurrence, abundance, and distribution of sulfonamide and tetracycline resistance genes in agricultural soils across China. AB - The prevalence and proliferation of antibiotic resistance genes (ARGs) have been identified as an emerging contaminant of concern and a crucial threat to public health worldwide. In this study, we carried out a nation-wide sampling campaign across China to investigate the distribution and abundances of 8 major ARGs in agricultural soils. The levels of sulfonamide (sul) and tetracycline (tet) resistance genes in China's agricultural soils ranged from 10-6-10-2 to 10-8-10-2 gene copies/16S rRNA gene copies, respectively. Northeast China is the hot-spot of ARGs, likely due to long-term wastewater irrigation in the area. Redundancy analysis was further performed to assess the influences of environmental variables on ARG abundances. Sulfonamide resistance genes displayed strong correlations with meteorological parameters (mean annual precipitation and temperature), and decreased from north to south. In comparison, tetracycline resistance genes were more closely related to soil organic matter and pH. Co selection between heavy metals and ARGs was significant among Cu, Hg and sulfonamide resistance genes. This study highlighted the current status of ARG contamination and their influencing factors in China's agricultural soils. Findings are valuable to identify effective management options for reducing the release of antibiotics and control ARG spread in the agriculture sector across the world. PMID- 28558429 TI - Workplace exposure and release of ultrafine particles during atmospheric plasma spraying in the ceramic industry. AB - Atmospheric plasma spraying (APS) is a frequently used technique to produce enhanced-property coatings for different materials in the ceramic industry. This work aimed to characterise and quantify the impact of APS on workplace exposure to airborne particles, with a focus on ultrafine particles (UFPs, <100nm) and nanoparticles (<50nm). Particle number, mass concentrations, alveolar lung deposited surface area concentration, and size distributions, in the range 10nm 20MUm were simultaneously monitored at the emission source, in the potential worker breathing zone, and in outdoor air. Different input materials (known as feedstock) were tested: (a) micron-sized powders, and (b) suspensions containing submicron- or nano-sized particles. Results evidenced significantly high UFP concentrations (up to 3.3*106/cm3) inside the spraying chamber, which impacted exposure concentrations in the worker area outside the spraying chamber (up to 8.3*105/cm3). Environmental release of UFPs was also detected (3.9*105/cm3, outside the exhaust tube). Engineered nanoparticle (ENP) release to workplace air was also evidenced by TEM microscopy. UFP emissions were detected during the application of both micron-sized powder and suspensions containing submicron- or nano-sized particles, thus suggesting that emissions were process- (and not material-) dependent. An effective risk prevention protocol was implemented, which resulted in a reduction of UFP exposure in the worker area. These findings demonstrate the potential risk of occupational exposure to UFPs during atmospheric plasma spraying, and raise the need for further research on UFP formation mechanisms in high-energy industrial processes. PMID- 28558430 TI - Spatiotemporal characteristics of PM2.5 and PM10 at urban and corresponding background sites in 23 cities in China. AB - Air pollution episodes in China are frequent and a more comprehensive understanding of pollution sources and impacts is needed to design appropriate strategies and set emission reduction targets. This study analyzes PM2.5 and PM10 concentrations measured in 23 cities at 178 urban sites and at 23 corresponding "urban contrast" sites in China with the goals of understanding spatial and temporal trends and quantifying the regional component of PM pollution. The contrast sites, located an average of 29km from cities in the upwind direction, are intended to represent "background" levels. Using daily measurements from April 2013 to March 2014, we assess compliance with air quality standards, PM2.5/PM10 ratios and urban "increments," defined as the increase in PM levels in the city compared to the contrast site. Spatial and temporal patterns at daily, monthly and annual levels are shown using distributions, correlations, spatial autocorrelation, and factor analyses. At the contrast sites, PM2.5 and PM10 concentrations averaged 56+/-26 and 91+/-44MUgm-3, respectively, and China's daily and annual average air quality standards were frequently exceeded. PM2.5 and PM10 concentrations in most cities exceeded levels at the corresponding contrast sites, but by an average of only 14+/-14 and 26+/-27MUgm-3, respectively. Seasonal changes in PM2.5 and PM10 concentrations and urban increments were striking, e.g., levels increased 2 to 3-fold in winter at several sites. The significance of exurban and regional sources of PM2.5 is demonstrated by the small urban increments, the strong correlations across broad regions, and the correlation between daily levels at city and contrast sites. These sources will require control to achieve air quality goals, in particular, the PM10 and PM2.5 targets announced by the Chinese government in 2013. PMID- 28558431 TI - Physiological and biochemical effects of nanoparticulate copper, bulk copper, copper chloride, and kinetin in kidney bean (Phaseolus vulgaris) plants. AB - It is essential to understand the interactions of engineered nanoparticles (ENPs) with additives used in agriculture and their impacts on crop plants. In this study, kidney bean (Phaseolus vulgaris) plants were grown in potting soil amended with either nano copper (nCu), bulk copper (bCu), or copper chloride (CuCl2) at 0, 50, and 100mg/kg, combined with 0, 10, or 100MUM of kinetin (KN). Plant growth, Cu, micro and macroelement concentrations, chlorophyll content, and enzymatic activity were examined in 55-day old plants. Results showed that root Cu content was at least 10-fold higher, compared to other tissues. Accumulation of Cu in roots was decreased by 100MUM KN up to 25%. A concentration-dependent increase of Cu content in leaves by Cu*KN was observed. Chlorophyll production was diminished by CuCl2+KN between 22 and 30%, showing a hormetic response. Catalase activity was repressed by 65% to 82% in bCu and CuCl2 treatments. From all essential elements, Ca, Mn, and P were reduced by 33% to 97% in bCu, CuCl2, and CuCl2+KN treatments. However, this did not impact stem elongation and tissue biomass that increased up to 55% under exposure to bCu and CuCl2. Our results demonstrate that KN combined with ionic Cu could have negative implications in kidney bean plants, since this combination impacted chlorophyll production and nutrient element accumulation. PMID- 28558432 TI - Bioaerosol sampling and detection methods based on molecular approaches: No pain no gain. AB - Bioaerosols are among the less studied particles in the environment. The lack of standardization in sampling procedures, difficulties related to the effect of sampling processes on the integrity of microorganisms, and challenges associated with the application of environmental microbiology analyses and molecular and culture methods frighten many young scientists. Every microorganism has its own particularities and acts differently when aerosolized in various conditions. Because the air is an extremely biologically diluted environment, it is necessary to concentrate its content before any analysis is performed. Challenges faced when applying molecular methods to air samples reveal the need for a better standardization of approaches for cell and nucleic acid recovery, the choice of genetic markers, and interpretation of data. This paper presents a few of the limits and difficulties tackled when molecular methods are applied to bioaerosols, suggests some improvements by specifying the critical stages that should be considered when studying the microbial ecology of bioaerosols, and provides thoughtful insights on how to overcome the challenges encountered. PMID- 28558433 TI - Testing the usefulness of 222Rn to complement conventional hydrochemical data to trace groundwater provenance in complex multi-layered aquifers. Application to the Ubeda aquifer system (Jaen, SE Spain). AB - The Ubeda aquifer system is a multi-layered aquifer intensively exploited for irrigation. It covers 1100km2 and consists of piled up sedimentary aquifer and aquitard layers from Triassic sandstones and clays at the bottom, to Jurassic carbonates (main exploited layer) in the middle, and Miocene sandstones and marls at the top. Flow network modification by intense exploitation and the existence of deep faults favour vertical mixing of waters from different layers and with distinct chemical composition. This induces quality loss and fosters risk of quantity restrictions. To support future groundwater abstraction management, a hydrogeochemical (major and some minor solutes) and isotopic (222Rn) study was performed to identify the chemical signatures of the different layers and their mixing proportions in mixed samples. The study of 134 groundwater samples allowed a preliminary identification of hydrochemical signatures and mixtures, but the existence of reducing conditions in the most exploited sector prevents the utility of sulphate as a tracer of Triassic groundwater in the Jurassic boreholes. The potential of 222Rn to establish isotopic signatures and to trace groundwater provenance in mixtures was tested. 222Rn was measured in 48 samples from springs and boreholes in most aquifer layers. At first, clear correlations were observed between 222Rn, Cl and SO4 in groundwater. Afterwards, very good correlations were observed between 222Rn and the chemical facies of the different layers established with End Member Mixing Analysis (EMMA). Using 222Rn as part of the signatures, EMMA helped to identify end-member samples, and to quantify the mixing proportions of water from the Triassic and the Deep Miocene layers in groundwater pumped by deep agricultural wells screened in the Jurassic. The incorporation of 222Rn to the study also allowed identifying the impact of irrigation returns through the association of moderate NO3, Cl, and Br contents with very low 222Rn activities. PMID- 28558435 TI - Tutorials and workshops. AB - Provides an abstract for each of the tutorial presentations and a brief professional biography of each presenter. The complete presentations were not made available for publication as part of the conference proceedings. PMID- 28558434 TI - Leaching of propellant compounds from munition residues may be controlled by sorption to nitrocellulose. AB - Sustainable management of military ranges requires effective assessment of surface mobility and leaching potential of propellant compounds (PCs). Previous studies have focused mostly on PCs' dissolution from fired residues and their sorption to soil components. This work investigated the potential role of nitrocellulose, a major component in propellants, in the binding of PCs to propellant residues. Sorption isotherms of military grade nitrocellulose for dissolved nitroglycerine (NG) or 2,4-dinitrotoluene (2,4-DNT) was measured in batch experiments and were determined to be SNG=102.39(+/-0.05)CNG0.916(+/-0.032) and S2,4-DNT=103.08(+/-0.01)C2,4-DNT0.668(+/-0.010) (S and C in mg/kgnitrocellulose and mg/Lwat, respectively). Solid-to-water partitioning for NG and 2,4-DNT was 100 times greater in propellant residues than in typical military ranges soils. Since nitrocellulose can sorb NG and 2,4-DNT up to 23 and 5% of its mass, respectively, it can slow down, through retarded diffusion, the leaching of PCs from fired residues over the typical composition ranges of common propellants. The slow leaching of PCs from propellant grains in column studies can be better interpreted by considering their sorptive interaction with nitrocellulose in addition to dissolution kinetics. With nitrocellulose as the carrying matrix, residue-bound PCs may migrate farther and persist longer in subsurface environment. PMID- 28558436 TI - Feature extraction employing fuzzy-morphological decomposition for detection and classification of mass on mammograms. AB - Mathematical Morphology is a theory of nonlinear processing extensively used in digital image processing. The computation effort, however, associated to Mathematical Morphology is usually large mainly because of high occurrence of conditional branches, due to use of intersection and union set operations. In terms of processing, it means the occurrence of maximum and minimum calculation. Mathematical Morphology, despite a relative large computational cost, is suitable to biomedical images applications, where both form and texture are essential in order to study anatomical deformities. We use detection and classification of mass in mammograms as a case study. The reason is that breast cancer is the leading cause of adult women by cancer worldwide. We propose a method inspired by series of wavelets for fuzzy-morphological decomposition in regions of interest on mammograms. Our decomposition employs nonlinear low-pass and high-pass filters based on openings and closings operations, which employ fuzzy-approximations. They replace conditional branches by arithmetic operators of subtraction and multiplication, computationally more efficient. We used 355 images of fatty breast tissue of IRMA database, with 233 normal instances, 66 benign, and 56 malignant cases. Classification was performed using SVM and ELM networks with modified kernels, in order to optimize accuracy rates, reaching 93.18%. PMID- 28558437 TI - Study Break: Precision Medicine: A New Revolution in Healthcare System PMID- 28558439 TI - Accuracy of Soluble Endoglin for Diagnosis of Preeclampsia and its Severity AB - Background: The use of biomarkers for diagnosis of Preeclampsia (PE), a life threatening pregnancy disorder, could reduce serious complications of this disease. In this study, we investigated dysregulation of endoglin (Eng) expression and diagnostic accuracy of soluble endoglin (sEng) in PE patients. Methods: For this case-control study, 26 mild and 15 severe preeclamptic women along with 20 normotensive controls were recruited. The expression level of Eng (the co-receptor of TGF-beta1) was evaluated using qRT-PCR. Also, the serum concentration of soluble Eng and expression of membranous Eng were determined by ELISA and immunohistochemistry. Results: A significant up-regulation in Eng mRNA and sEng levels was observed in PE patients versus normal controls. Immunohistochemistry (IHC) showed up-regulation of membranous Eng staining in syncytiotrophoblast and cytotrophoblast cells of PE patients. The serum levels of sEng were significantly increased in all patients (mild, sever, early- and late onset) as compared to healthy pregnant women (P?0.001). Receiver-operating characteristic (ROC) curve analysis revealed that sEng had the highest accuracy in distinguishing PE from normal pregnancies with cut-off value of 20.4, sensitivity of 92.1%, specificity of 90%, and area under the curve (AUC) of 0.94 (95% CI: 0.88-1.00). Conclusion: Our data showed that the up-regulation of Eng mRNA along with its membranous and soluble form in PE patients leads to defect in angiogenesis pathway. Also, the results of this study revealed sEng potential as a marker for diagnosis of PE and its severity. PMID- 28558440 TI - Chemical Composition and Antimicrobial Activities of Iranian Propolis AB - Background: With considering the importance of natural products for their remedial and therapeutic value, this research was aimed to analyze the chemical compositions and antimicrobial activity of four propolis samples from different areas of Iran (Chenaran, Taleghan, Morad Beyg, and Kalaleh) with various climates and flora. Methods: Ethanolic (70% EtOH) and dichlromethane (DCM) extracts of Iranian propolis were analyzed by gas chromatography-mass spectrometry (GC-MS) methods, and antimicrobial activity was evaluated against Candida albicans, Escherichia coli, and Staphylococcus aureus using disk diffusion antimicrobial method. Results: The results of GC-MS analysis showed the presence of fatty acids, flavonoids, terpenes, aromatic-aliphatic acids, and their related esters. The total flavonoids in DCM extract of Chenaran, Taleghan, Morad Beyg, and Kalaleh propolis were pinocembrin and pinostrobin chalcone. The common phenolic and terpene compounds detected in all four tested EtOH extracts were P-cumaric acid and dimethyl -1,3,5,6-tetramethyl-[1,3-(13C2)] bicycloce [5.5.0] dodeca 1,3,5,6,8,10-hexaene-9,10-dicarboxylate, respectively. The highest inhibitory diameter zone of the Iranian propolis against C. albicans, E. coli, and S. aureus was for DCM extract of Kalaleh propolis (13.33 mm), Morad Beyg propolis (12 mm), and Kalaleh (11.67 mm), respectively. Conclusion: Iranian propolis showed antimicrobial activities against C. albicans, E. coli, and S. aurous, perhaps due to the presence of flavonoids, phenolic acids, and terpenes as active components that can be used alone or in combination with the selected antibiotics to synergize antibiotic effect, as well as to prevent microbial resistance to available antimicrobial drugs. PMID- 28558441 TI - Validity of the InBody 520TM to predict metabolic rate in apparently healthy adults. AB - BACKGROUND: The present study seeks to assess the validity of the InBody 520TM device to predict RMR in apparently healthy adults relative to a metabolic cart (the standard, yet time-intensive, method for determining resting metabolic rate). METHODS: Twenty-six apparently healthy adults participated in the study. Predicted RMR (pRMR) was calculated by the InBody 520TM and measured RMR (mRMR) was determined by 30-minute gas analysis and ventilated hood system. Of the 78 measurement trials conducted, 64 yielded acceptable measurement trials. RESULTS: A Pearson product-moment correlation was used to determine the relationship between pRMR and mRMR (r=0.87, P<0.001). No significant difference existed between the pRMR (1650.89+/-295.96 kcal) and mRMR (1675.36+/-278.69 kcal) values (P=0.19). CONCLUSIONS: Study findings suggest that the InBody520TM provides valid measurements of RMR in apparently healthy adults and can be an effective and efficient method for collecting data in a clinical setting. PMID- 28558442 TI - Specific physiological and biomechanical performance in elite, sub-elite and in non-elite male team handball players. AB - BACKGROUND: Team handball is a dynamic sport game that is played professionally in numerous countries. However, knowledge about training and competition is based mostly on practical experience due to limited scientific studies. Consequently, the aims of our study were to compare specific physiological and biomechanical performance in elite, sub-elite and in non-elite male team handball players. METHODS: Thirty-six elite, sub-elite and non-elite male team handball players performed a game based performance test, upper-body and lower-body strength tests, 30-m sprint test, counter movement jump test and an incremental treadmill running test. RESULTS: Significant differences (P<0.05) were found for the peak oxygen uptake, heart rate, offense and defense time, jump height and ball velocity during the jump throw in the game based performance test, maximal oxygen uptake in the incremental treadmill running test as well as in maximal leg strength and leg explosive strength in the isometric strength test. CONCLUSIONS: Elite male players have an enhanced specific agility, a better throwing performance, a higher team handball specific oxygen uptake and higher leg strength compared to sub-elite and non-elite players. Based on these results we recommend that training in team handball should focus on game based training methods to improve performance in specific agility, endurance and technique. PMID- 28558443 TI - Effects of different durations of aerobic exercise on the cardiovascular health in untrained women: a meta-analysis and meta-regression. AB - INTRODUCTION: Women's cardiovascular health is a hot topic. Exercise intervention is an effective method to improve the cardiovascular functions. The aim of this study was to systematically assess effects of aerobic exercise at different durations on the cardiovascular health of untrained women. EVIDENCE ACQUISITION: Published articles from January 1989 to March 2016 were identified using electronic databases (PubMed, Cochrane Library, Embase and Web of Science) for randomized controlled trials. Weighted mean differences and 95% confidence intervals (CI) were calculated using fixed-effects and random-effects models. Meta-regression and subgroup analysis were performed to explore the possible heterogeneity. EVIDENCE SYNTHESIS: Data from 26 published studies with a total of 518 untrained women were identified. The subgroup analysis and meta-regression were performed according to age (under 40, and from 41 to 60 years old) and exercise durations. Maximal oxygen consumption significantly increased at short duration exercise (95% CI: -2.51 to -1.57; I2=0%) and mid-duration exercise (95% CI: -8.23 to -5.18; I2=0%). While HR (95% CI: 4.72 to 5.60; I2=0%) and SBP (95% CI: 5.55 to 7.52; I2=0%) significantly decreased at mid-duration exercise. Total cholesterol (N.=242, 95% CI: 0.07 to 0.16, I2=13%), HDL-C (N.=242, 95% CI: -0.11 to -0.06, I2=11%) and low-density lipoprotein cholesterol levels (N.=238, 95% CI: 0.07 to 0.16, I2=37%) significantly improved with short-duration, mid-duration and long-duration. CONCLUSIONS: Improvement of cardiovascular functions decreases with age in untrained women. Short-duration exercise has significant effects on aerobic capacity. Mid-duration exercise significantly improves on aerobic capacity, heart rate and systolic blood pressure. All the different durations of aerobic exercise improve the cholesterol metabolism. PMID- 28558444 TI - Blood flow patterns during incremental and steady-state aerobic exercise. AB - BACKGROUND: Endothelial shear stress (ESS) is a physiological stimulus for vascular homeostasis, highly dependent on blood flow patterns. Exercise-induced ESS might be beneficial on vascular health. However, it is unclear what type of ESS aerobic exercise (AX) produces. The aims of this study are to characterize exercise-induced blood flow patterns during incremental and steady-state AX. We expect blood flow pattern during exercise will be intensity-dependent and bidirectional. METHODS: Six college-aged students (2 males and 4 females) were recruited to perform 2 exercise tests on cycle-ergometer. First, an 8-12-min incremental test (test 1) where oxygen uptake (VO2), heart rate (HR), blood pressure (BP), and blood lactate (La) were measured at rest and after each 2-min step. Then, at least 48-hr. after the first test, a 3-step steady state exercise test (test 2) was performed measuring VO2, HR, BP, and La. The three steps were performed at the following exercise intensities according to La: 0-2 mmol/L, 2-4 mmol/L, and 4-6 mmol/L. During both tests, blood flow patterns were determined by high-definition ultrasound and Doppler on the brachial artery. These measurements allowed to determine blood flow velocities and directions during exercise. RESULTS: On test 1 VO2, HR, BP, La, and antegrade blood flow velocity significantly increased in an intensity-dependent manner (repeated measures ANOVA, P<0.05). Retrograde blood flow velocity did not significantly change during test 1. On test 2 all the previous variables significantly increased in an intensity-dependent manner (repeated measures ANOVA, P<0.05). CONCLUSIONS: These results support the hypothesis that exercise-induced ESS might be increased in an intensity-dependent way and blood flow patterns during incremental and steady state exercises include both antegrade and retrograde blood flows. PMID- 28558445 TI - The effect of beach volleyball training on muscle performance of indoor volleyball players. AB - BACKGROUND: Beach volleyball is frequently used as a conditioning activity for indoor volleyball players, but little information exists regarding any performance benefits when transitioning from sand to hard court. The present study examined the effect of 12 weeks beach volleyball training on muscle performance of indoor volleyball players. METHODS: Eleven athletes who completed an indoor volleyball season and were willing to train and compete at beach volleyball, participated in the study. Muscle endurance of knee extensors and plantar flexors (torque at 120 degrees .s-1 following 40 contractions), muscle strength of knee extensors/ flexors (60, 180, 300 degrees .s-1), dorsi/plantar flexors (torque at 60, 120, 180 degrees .s-1) trunk flexors (60, 90, 180 degrees .s-1) and power (squat [SJ] and countermovement [CMJ] jumps performed on sand and hard court surfaces) were assessed pre- and post-12 weeks of beach volleyball training. RESULTS: Knee extensors and plantar flexors endurance was higher post 12 weeks, as less torque decrease was found after 40 contractions for both muscle groups at post-12-week-time points. Knee extensors strength was higher post-12 weeks for 60 and 300 degrees .s-1, while dorsi flexors strength was higher post 12 weeks for all speeds. SJ and CMJ vertical jump height was improved when measured on sand and on hard court. CONCLUSIONS: Twelve weeks of systematic training and competition at beach volleyball can improve muscular endurance of lower limbs and jumping height in indoor volleyball players. More importantly, these improvements are transferrable to hard court, making beach volleyball a very attractive alternative for conditioning indoor volleyball players during the off-indoor volleyball season. PMID- 28558446 TI - Predicting playing status in professional water polo players: analysis by gender. AB - BACKGROUND: The aim of this study was twofold: firstly, to identify the characteristics of water polo players that discriminate between women and men based on specific playing positions; and secondly to develop a predicting model to identify the characteristics that are best suited to a given playing position based on gender. METHODS: The study included 130 professional water polo players. Anthropometric characteristics and throwing velocity were analyzed in different situations: no defender or goalkeeper, goalkeeper only and the players made three rapid arm movements and then threw the ball at maximum speed without further feinting with goalkeeper. Measured variables were compared according to gender and player position using discriminant analysis. RESULTS: The predictive model accurately classifies 71.1% of the male players using three variables (arm span, muscle mass Lee and penalty without goalkeeper), and 64.7% of the female players using three variables (triceps skinfold, biceps skinfold and anteroposterior chest breadth). CONCLUSIONS: The anthropometric characteristics and throwing velocity play an important role in identifying the different specific positions in male and female water polo players. In female players, the variables that were determinant in the predictive model, were those associated with body composition. PMID- 28558447 TI - Physical characteristics associated with neck pain and injury in rugby union players. AB - BACKGROUND: Neck pain and injury are common in rugby union. Physical characteristics predisposing players to neck injury are largely unknown. This study aimed to determine physical characteristics associated with neck pain and injury in rugby union players. METHODS: Semi-professional rugby union players (N.=142) underwent pre-season measurements including cervical active range of motion (AROM), strength, sensorimotor proprioception (joint position error), and anthropometry. A structured interview established previous neck injury history, current symptoms, playing position, competition level, age, and years playing rugby. Team physiotherapists and player telephone interviews identified players sustaining a neck injury during the competitive season (defined as any reported neck pain or neck injury). T-tests or Mann-Whitney U tests determined differences between neck injured and non-injured players. Logistic regression determined factors associated with neck injury history and incidence. RESULTS: Sixty-five (46%) players reported a previous neck injury; 11 (8%) sustained a neck injury during the competitive season. Player age (OR 1.14, 95% CI 1.03-1.25, P=0.009) was associated with neck injury history. Pre-season lateral flexion AROM was less in players sustaining a neck injury or reporting neck pain during the season (median left 23.6 degrees , IQR 21.8-26.2 degrees ; right 27.9 degrees , 23.6 32.5 degrees ) than in other players (left 34.8 degrees , 28.8-41.0 degrees , P<0.01; right 39.1 degrees , 28.9-48.1 degrees , P=0.03). Lateral flexion AROM was associated with increased risk of neck pain or injury (OR 0.82, 95%CI 0.71 0.94, P=0.005). CONCLUSIONS: Decreased cervical lateral flexion AROM may contribute to neck injury risk in rugby union players. However, few physical characteristics predicted neck injury incidence, suggesting additional factors should be explored to determine injury risk. PMID- 28558448 TI - [Transoral microsurgery for the treatment of pharyngeal and laryngeal malignancy]. PMID- 28558449 TI - [Transoral radiofrequency coblation surgery for the treatment of hypopharyngeal carcinoma]. AB - Objective: To explore the feasibility and effectiveness of transoral surgery (TOS) for the treatment of hypopharyngeal carcinoma by means of the radiofrequency coblation(RFC). Methods: Twenty-two patients with hypopharyngeal carcinoma who were treated with TOS using RFC during the years of 2010-2016 were enrolled. Among these patients, 15 suffered from pyriform sinus carcinoma, 4 suffered from postcricoid carcinoma, and 3 suffered from posterior hypopharyngeal wall carcinoma. According to the AJCC 2002 guideline, the tumor stages were T1N0M0 for 3 patients, T2N0M0 for 9 patients, T1N1M0 for 1 patient, T1N2M0 for 1 patient, T2N1M0 for 4 patients, and T2N2M0 for 4 patients respectively. All patients with N+ underwent concurrent neck dissection; 2 patients underwent concurrent prophylactic tracheotomy; 17 underwent post-operative radiotherapy for 50-66 Gy. The follow-up time was 6-72 months with a median 35 months.Two patients were lost to follow-up. Results: All patients except 2 underwent the TOS successfully, while the two patients were treated with open approach surgery due to unsure safe margin. Most patients returned to oral feeding within one week. Among the 18 patients with complete follow up data, 3 had the local recurrence of the tumor (16.7%) and one died due to local recurrence, multiple primary esophageal carcinoma, and distant metastasis 4 years after surgery (5.6%). According to the Kaplan-Meier method, the 5-years local control rate and survival rate were 57.8% and 67.5% respectively. All patients had no disorders in speech, swallowing and respiration during the follow up. Conclusions: The RFC can be applied in TOS for the treatments of hypopharyngeal carcinoma with high cutting efficiency and better control of intraoperative hemorrhage, which is useful in lowering the operation difficulty. The oncologic results are comparable to the open surgery with satisfactory postoperative organ function preservation. PMID- 28558450 TI - [Transoral coblation-assisted endoscopic minimally invasive surgery for superficial tongue base tumours]. AB - Objective: To introduce the method of transoral coblation-assisted endoscopic minimally invasive surgery for superficial tongue base tumour. Methods: A total of 15 patients treated with transoral coblation-assisted endoscopic minimally invasive surgery from Mar. 2006 to Aug. 2016 were retrospectively reviewed. There were 9 patients with malignant tumors, 6 patients with benign neoplasms. Adjuvant postoperative radiation therapy was applied in three cases of squamous cell carcinoma, neck was performed in four cases of cancer. One case of non-Hodgkin lymphoma received postoperative chemotherapy. Results: One case with ectopic thyroid gland was treated by subtotal resection and one case with squamous cell carcinoma changed into open surgery because of major lingual artery bleeding. The En bloc resection under edoscope was achieved in 92.86%(13/14)of patients. Fifteen cases of neoplasms were followed-up for 8-50 months(median 20 months), one patient with Cowden syndrome was lost to follow-up because of appendical carcinoid combined pulmonary metastasis, one patient with non-Hodgkin lymphoma died of recurrence in other head neck areas 2 years after chemotherapy. Conclusion: Transoral coblation-assisted endoscopic surgery can successfully treat for the patients with superficial tongue base tumours. PMID- 28558451 TI - [Treatment of glottic cancer involving the anterior commissure by transoral CO(2) laser surgery]. AB - Objective: To study the clinical outcome of transoral CO(2) laser surgery for glottic cancer involving the anterior commissure. Methods: Thirty-two cases of glottic cancer involving the anterior commissure treated by transoral CO(2) laser surgery between March 2009 and December 2013 were retrospectively reviewed. Among these cases, 27 were T1bM0M0, 5 were T2N0M0. All cases were followed-up for more than 3 years. Results: All the 32 cases were successfully treated. Perioperative complications included injuries in the soft palate mucosa(13/32, 40.63%), loose incisors(3/32, 9.38%) and subcutaneous emphysema in the neck(2/32, 6.25%). During the follow-up period, granulation was found in all cases. Three cases had local recurrence. Two patients treated by a secondary transoral CO(2) laser surgery and the other case had total laryngectomy, all three cases were followed up for 5 years without recurrence. Two cases had regional recurrence but no primary site recurrence. One patient was treated by neck dissection, and followed up for 5 years without recurrence. The other patient died of supraclavicular and mediastinal lymph node metastasis and lung metastasis 40 months after operation. The overall 5-year survival rate was 90.6%. There was no significant difference in survival rate between T1bN0M0(92.6%) and T2N0M0(80.0%) (Log Rank chi(2)=0.788, P=0.375). The overall 5-year local regional control rate was 84.4%. In T1bN0M0 lesions, the 5-year local regional control rate was 92.6%, which was significantly higher than that in T2N0M0 lesions(40.0%) (Log Rank chi(2)=9.504, P=0.002). Conclusion: With appropriate surgical indication, detailed preoperative evaluation, good surgical skill, transoral CO(2) laser surgery may achieve satisfactory outcome in the treatment of glottic cancer involving the anterior commissure. PMID- 28558452 TI - [Preliminary analysis of the effects of tailor-made notched music therapy on chronic idiopathic tinnitus]. AB - Objective: Tailor-made notched music was applied to alleviate the symptoms of chronic idiopathic tinnitus and compared its effectiveness with other existing sound treatment of tinnitus. Methods: Subjects (n=43; ears=75 )were recruited during June 2015 to October 2016 from the out-patients of our hospital. These patients had chronic (longer than 6months) and idiopathic tinnitus, with or without significant sensorineural hearing loss. In the prospective design, the patients were randomly divided into group A (treated with tailor-made notched music) and group B (treated with analogous sound masking), and received the treatment for 3 months. The tinnitus scale, tinnitus questionnaire and audiological findings were evaluated before treatment, and at one month and three months after treatment started. Results: After onemonth of treatment, the effective rate between the two groups was 40.9% and 42.9%, there was no significant difference between the two groups (chi(2)= 0.017, P=0.897). The average VAS for patients in group A showed more decrease in group A than in group B(VAS: 1.8 vs. 0.8, the percentage : 29.5% vs. 13.6%), but there was no significant difference between the two groups (t=-1.450, P=0.155). After 3 months of treatment, the effective rates were 68.2% and 23.8%, respectively. There was significant difference between the two groups (chi(2)= 8.503, P=0.004). The difference of the VAS scores between the two groups was statistically significant (t=-3.263, P=0.002), and the VAS score of group A was less.After 3 months of treatment, there was significant decreaseinthe average tinnitus loudness for patients in group A(t=5.569, P<0.01), and there was no significant changein group B(t=-0.953, P=0.374). There was also significant decreasein the scores of tinnitus handicap inventory (THI) (F=7.334, P<0.05), loudness visual analog scale (VAS) (F=20.48, P<0.001), and the proportion of patients with moderate to severe tinnitus(chi(2)=11.289, P<0.05) in the group A, and there was no significant change in group B(F=2.198, F=0.989, chi(2)=1.651; P=0.120, P=0.378, P=0.438>0.05). Conclusions: Our resultssuggest that long-term normalized listening to tailor-made notched music, can significantly reduce the perceived tinnitus loudness in varying degrees and improve the quality of life of patients. The effects and possible mechanism of this method were discussedin this paper. PMID- 28558453 TI - [Effects of noise competition on monosyllabic and disyllabic word perception in children]. AB - Objective: The purpose of the present study was to investigate the effects of noise competition on word perception in normal hearing (NH) children and children with cochlear implantation (CI). Methods: To estimate the contribution of noise competition on speech perception, word perception in speech-shaped noise(SSN)and 4-talker babble noise(BN) with Mandarin Lexical Neighborhood Test were performed in 80 NH children and 89 children with CI. Corrected perception percentages were acquired in each group. Results: Both signal to noise ratio (SNR) and noise type influenced the word perception. In NH group, corrected percentages of disyllabic word perception in SSN were 24.2%, 55.9%, 77.1%, 85.1% and 88.9% at -8, -4, 0, 4 and 8 dB SNR, corresponding corrected percentages of monosyllabic word were 13.9%, 39.5%, 60.1%, 68.8% and 80.1%, respectively. In BN noise, corrected percentages of disyllabic word were 2.4%, 24.3%, 55.6%, 74.3% and 86.2%, corresponding monosyllabic word were 2.3%, 20.8%, 47.2%, 61.1% and 74.8%, respectively. In CI group, corrected percentages of dissyllabic word in SSN and BN at 10 dB SNR were 65.5% and 58.1%, respectively. Corresponding monosyllabic word were 49.0% and 41.0%. For SNR=5 dB, corrected percentages of disyllabic word in SSN and BN were 50.0% and 38.1%, corresponding corrected percentages of monosyllabic word were 40.8% and 25.1%, respectively. Analysis indicated that the masking effect were significantly higher in BN compared with SSN. Conclusions: Noise competition influence word perception performance significantly. In specific, the influence of noise on word perception is bigger in children with CI than in NH children. The masking effect is higher in BN noise when compared with SSN. PMID- 28558454 TI - [Changing analysis of allergic rhinitis inhalant allergen spectrum in Xinjiang region]. AB - Objective: To investigate the aeroallergen spectrum in allergic rhinitis in Xinjiang area and analyze its relating factors. Methods: Skin prick test was carried out in 480 cases with allergic rhinitis using 20 inhaled allergens. The major change in recent years with allergic rhinitis and allergen distribution was compared.SPSS 17.0 software was used to analyze the data. Results: Among 480 cases, 406 showed positive reaction. The most common allergens found in patients were chenopodium (61.6%) and mugwort (44.1%), followed by willow(37.7%), maple(37.7%), poplar(30.3%), house dust mite(30.3%), plantain(29.8%), acacia(25.9%), dust mite maple(25.4%), and so on. The rate of positive reaction to only one allergen was 9.6%, of which 21 were mite allergens. The positiverate to allergensin male and female were 84.2% and 85.1%, the distribution of allergens in both sexes did not differ(chi(2)=0.001, P=0.978). The positiverate to allergens in patients aged 21 to 35 years old was 88.6%, in patients aged 36 to 54 years old was 78.4%, the difference was statistically significant(chi(2)=0.258, P<0.01). The positive rate to allergens in Kazakhs was slightly higher than that in other ethnic groups (91.7%). The positive rates to allergens in the Han, Uygur and other ethnic groups were 84.8%, 86.4% and 63.3% respectively, the difference was statistically significant(chi(2)=9.779, P=0.044). Seventy-five point four percent of all allergen-positive patients(306 cases) combined with asthma. Conclusions: The major allergen with allergic rhinitis is chenopodium. Among them, Kazakh allergic positive rate is higher than other ethnic groups. PMID- 28558455 TI - [Effect of intranasal excision on nasal vestibular cyst under nasal endoscopy]. AB - Objective: To observe the clinical effects of intranasal excision on nasal vestibular cyst under nasal endoscopy. Methods: Forty-two cases of nasal vestibular cyst diagnosed in the Department of Otorhinolaryngology Head and Neck Surgery, Tianjin Third Central Hospital between Feb. 2011 and Jan. 2016 were treated by intranasal excision under nasal endoscope. Results: All the 42 patients were cured without any complication. The rate of complete stripping was 78.6% (33/42), with operating time of (21.31+/-4.04) min and bleeding amount of (10.26+/-2.13) ml. During follow-up ranged from 6 months to 5 years, with the median follow-up time being 19.6 months, no post-operative recurrence and complication were found. Conclusion: Intranasal excision for nasal vestibular cyst under nasal endoscopy is an effective method, which can be widely used in hospitals. PMID- 28558456 TI - [Clinical efficacy of endoscopic nasopharyngectomy for initially diagnosed advanced nasopharyngeal carcinoma]. AB - Objective: To explore the clinical efficacy in patients who underwent endoscopic nasopharyngectomy for primary advanced nasopharyngeal carcinoma (NPC). Methods: Forty-five patients who underwent endoscopic nasopharyngectomy for primary advanced NPC encountered between Aug. 2007 and Sep. 2015 were retrospectively reviewed. Twenty-seven patients were male (60.0%), and 18 patients were female (40.0%), the ratio of male to female was 3?2. The median age was 53 years old (ranged from 13 to 75 years old). The median onset time was 5 months (ranged from 1 to 72 months). TNM stage: 16 cases were at stage III (35.6%), 29 at stage IV (64.4%); T3 16 cases (35.6%), T4 29 cases (64.4%); N0 38 cases (84.4%), N2 7 cases (15.6%). No patients were found to have distance metastasis. All patients underwent endoscopic resection of lesions. Postoperatively all the patients were treated with radiotherapy or chemoradiotherapy. Using SPSS 19.0 software, Kaplan Meier and Log-rank test were done for the assessmen of survival rate; Cox proportional hazards model was used for the univariate analysis of prognostic factors. Results: The median follow-up was 36 months (ranged from 6 to 97 months), with 36 cases surviving (80.0%), 9 cases died (20.0%); 15 cases relapsed (33.3%). The overall 1 year survival rates (SR), 3 year SR, 5 year SR was 90.6%, 81.0%, 76.0%, respectively. The survival univariate analysis indicated the recurrence and metastasis were correlated with the survival (chi(2) value was 16.644, 6.451, respectively, all P<0.05). Conclusion: The patients who undergo endoscopic nasopharyngectomy for primary advanced NPC have better survival rate with lower recurrent rate and metastatic rate. PMID- 28558457 TI - [Diagnostic value of enhanced CT/MRI for thyroid cartilage invasion by malignant tumor]. AB - Objective: To evaluate the values of enhanced CT and MRI for the diagnosis of thyroid cartilage invasion by laryngeal and hypopharyngeal cancer. Methods: One hundred and ninety-seven patients with primary laryngeal or hypopharyngeal cancer treated with surgery between January 2013 and December 2014 were included in this study. All patients underwent enhanced CT and MRI before surgery. With MRI using the techniques of fast recovery fast spin echo (FRFSE), spin echo echo planar imaging (SE-EPI) and diffusion weighted imaging (DWI), thyroid cartilage invasion was evaluated and the results of postoperative histopathological examination was used as a gold standard for the determination of thyroid cartilage invasion. The sensitivity, specificity, positive predictive value and negative predictive value of enhanced CT or MRI in detecting thyroid cartilage invasion by laryngeal and hypopharyngeal cancer were evaluated. Data were analyzed with SPSS17.0 software. Results: Among 197 patients, there were 35 cases with supraglottic laryngeal cancer, 92 cases with glottic laryngeal cancer, 9 cases with subglottic laryngeal cancer, and 61 cases with hypopharyngeal cancer. Postoperative pathologycal examinations showed that 63 (32.0%) of 197 patients had thyroid cartilage invasion by tumor. Based on TNM classification of AJCC (American Joint Commission for Cancer, 2010), there were 36 cases at T2 stage, 109 cases at T3 and 52 cases at T4; 117 cases with N0, 46 cases with N1 and 34 cases with N2. The sensitivity, specificity, positive predictive value and negative predictive value of CT for the detection of thyroid cartilage invasion were respectively 57%, 86%, 65% and 81%, and those of MRI were respectively 94%, 87%, 78% and 97%. Kappa values were 0.45 for CT and 0.77 for MRI in diagnosis of thyroid cartilage invasion, with statistically significant difference (chi(2)=6.78, P<0.05). Conclusion: MRI (FRFSE and SE-EPI DWI) has more advantages than CT in the diagnosis of thyroid cartilage invasion by laryngeal or hypopharyngeal cancer. PMID- 28558458 TI - [Clinical characteristics in children with cleft palate associated with middle ear cholesteatoma]. AB - Objective: To summarize the characteristics of children diagnosed as cleft palate associated with middle ear cholesteatoma. Methods: There were five middle ear cholesteatoma cases who had previously received cleft palate repairment surgery. All of the patients were followed up for 17 to 47 months. Median follow-up time was 31 months. Results: There were three males and two females with three to eleven years old , and the average of age was seven years and ten months. The time of cleft palate repairment surgery was from six months to four years, and the average age was one year and nine months. No history of grommet insertion. Three cases were unilateral choleateatoma (right ear in two cases and left ear in one case, of which two cases of contralateral ear with secretory otitis media) and two cases were bilateral choleateatoma. Five cases(seven ears) received surgeries. Radical mastoidectomy + canal wall down tympanoplasty were performed in three ears, in which we found stapes disappeared. Radical mastoidectomy + canal wall up tympanoplasty were performed in four ears, in which we found intact foot plate, with recurrence occurred in one case nine months after the first surgery. No recurrence occurred after the second canal wall down tympanoplasty. The postoperative average hearing thresholds of air conduction were improved in different degrees. Conclusions: There may be a relationship between cleft palate associated with middle ear cholesteatoma and no grommet insertion history. The incidence of bilateral cases is relatively high, and otitis media with effusion may occur because of poor Eustachian tube function in the unilateral cases. Choice of surgical methods should be decided basing on combination of decreasing the recrudescence and improving the hearing. PMID- 28558459 TI - [Clinical and pathological analyses of 154 patients with white lesion of vocal cord]. AB - Objective: To investigate the clinical and pathological features and prognosis of white lesion of vocal cord. Methods: One hundred and fifty-four cases of white lesion of vocal cord from January 2009 to February 2016 were retrospectively analysed. All the patients had undergone the resection of white lesion of vocal cord resection through retaining laryngoscope under general anesthesia with the specimens pathologically examined. Results: There were 148 males and 6 females in this study. The ages ranged from 36 to 83 years, and the median age was 54.5.There were 103(66.88%) long-term smokers, and 64(41.56%) long-term drinkers. Postoperative pathology showed that chronic mucosal inflammation in 19 cases (12.34%), squamous epithelial hyperplasia in 56 cases(36.36%), mild dysplasia in 25 cases(16.23%), moderate dysplasia in 34 cases(22.08%), severe dysplasia in 12 cases(7.79%), carcinoma in situ in 6 cases(3.90%), and invasive carcinoma in 2 cases(1.30%). The recurrence rate and canceration rate of chronic mucosal inflammation were 0. The recurrence rate of squamous epithelial hyperplasia was 10.71%, the canceration rate was 0.The recurrence rate of mild dysplasia was 8.00%, the canceration rate was 0. The recurrence rate of moderate dysplasia was 20.59%, the canceration rate was 8.82%. The recurrence rate of severe dysplasia was 25.00%, the canceration rate was 16.67%. Conclusions: White lesion of vocal cord is a predominantly male disease. Long-term smokering and drinking are one of common causes. The final diagnosis of white lesion of vocal cord relies on the pathology. Closed observation is necessary for theses dysplasia cases. The majority of which are benign, the operation effect is good. PMID- 28558460 TI - [Clinic features of laryngeal carcinosarcoma and sarcomatoid carcinoma]. AB - Objective: To investigate the clinic feature, pathology, therapy and prognosis of the sarcomatoid caricinoma or carcinosarcoma of the larynx. Methods: We reviewed the clinical records of 7 patients with laryngeal carcinosarcoma /sarcomatoid caricinoma who were treated at our hospital between June 1996 and August 2016. All patients were men (mean age, 65.9 years; range, 52 to 94 years). Among 7 patients, 6 had a history of smoking; 2 underwent radiotherapy; and 5 patients who didn't undergo radiotherapy complained of hoarseness. The glottis was the most frequent site of involvement. Most tumors exhibited a polypold or pedunculated gross morphology. Among the 5 patients who didn't undergo a radiotherapy, 2 were in stage I, 2 in stageII, and 1 in stage III. The other 2 cases underwent surgeries and radiotherapy were staged. Results: All 7 patients received surgeries, without lymph node metastasis. All the tumors were pathologically carcinosarcoma/sarcomatoid carcinoma. With immunohistochemistry examination, Vimetin was positive in all tumors, SMA positive in 3 tumors, S-100 positive in 1 tumors, but CD-68, HMB-45 or Myglobin was negative in all tumors. With follows-up from 3 months to 20 years, of 7 patients, 4 survived without recurrent, 1 dead, and 2 lost connection. Conclusions: Both of the carcinosarcoma and the sarcomatoid carcinoma of larynx contain pathologically carcinoma and sarcoma. Surgery is the best choice for laryngeal sarcomatoid carcinoma, and these patients without a undergoing radiotherapy before surgery or these with little sarcoma in tumors show better prognosis. PMID- 28558461 TI - [One case of conductive deafness caused by pulsatile tinnitus]. PMID- 28558462 TI - [Primary intraosseous squamous cell carcinoma arising from dentigerous cyst: a case report]. PMID- 28558463 TI - [Two cases of bronchogenic cyst]. PMID- 28558464 TI - [Use of minimally invasive surgical approach in the pharyngolaryngology]. PMID- 28558465 TI - Understanding Rate Acceleration and Stereoinduction of an Asymmetric Giese Reaction Mediated by a Chiral Rhodium Catalyst. AB - The surprising acceleration of the addition of electron-rich radicals to alpha,beta-unsaturated 2-acyl imidazoles by a chiral-at-metal rhodium catalyst is investigated. M06/Lanl2DZ (Rh),6-31G(d) calculations reproduce the observed rate acceleration and shed light on a catalyst design where a rigid chiral pocket with a steric interaction >5 A from the chiral metal center leads to the observed high stereoinduction. Analysis of the molecular orbitals of two key addition transition states emphasize the role of the catalyst as a Lewis acid without significant charge transfer. PMID- 28558466 TI - Regioselective Base-Mediated Cyclizations of Mono-N-acylpropargylguanidines. AB - A regioselective base-mediated cyclization of mono-N-acylpropargylguanidines is reported. A related Ag(I)-catalyzed hydroamination strategy was recently employed to yield N3-Cbz-protected ene-guanidines, which found utility in the synthesis of naamidine A. Herein, we report the base-catalyzed hydroamination of mono-N acylpropargylguanidines, which proceeds with the opposite regiochemistry to deliver isomerized N2-acyl-2-aminoimidazoles with broad substrate scope, circumventing the problematic regiospecific acylation of free 2-aminoimidazoles. PMID- 28558467 TI - Alginate Microcapsules Incorporating Hyaluronic Acid Recreate Closer in Vivo Environment for Mesenchymal Stem Cells. AB - The potential clinical application of alginate cell microencapsulation has advanced enormously during the past decade. However, the 3D environment created by alginate beads does not mimic the natural extracellular matrix surrounding cells in vivo, responsible of cell survival and functionality. As one of the most frequent macromolecules present in the extracellular matrix is hyaluronic acid, we have formed hybrid beads with alginate and hyaluronic acid recreating a closer in vivo cell environment. Our results show that 1% alginate-0.25% hyaluronic acid microcapsules retain 1.5% alginate physicochemical properties. Moreover, mesenchymal stem cells encapsulated in these hybrid beads show enhanced viability therapeutic protein release and mesenchymal stem cells' potential to differentiate into chondrogenic lineage. Although future studies with additional proteins need to be done in order to approach even more the extracellular matrix features, we have shown that hyaluronic acid protects alginate encapsulated mesenchymal stem cells by providing a niche-like environment and remaining them competent as a sustainable drug delivery system. PMID- 28558468 TI - Honeycomb Boron Allotropes with Dirac Cones: A True Analogue to Graphene. AB - We propose a series of planar boron allotropes with honeycomb topology and demonstrate that their band structures exhibit Dirac cones at the K point, the same as graphene. In particular, the Dirac point of one honeycomb boron sheet locates precisely on the Fermi level, rendering it as a topologically equivalent material to graphene. Its Fermi velocity (vf) is 6.05 * 105 m/s, close to that of graphene. Although the freestanding honeycomb B allotropes are higher in energy than alpha-sheet, our calculations show that a metal substrate can greatly stabilize these new allotropes. They are actually more stable than alpha-sheet sheet on the Ag(111) surface. Furthermore, we find that the honeycomb borons form low-energy nanoribbons that may open gaps or exhibit strong ferromagnetism at the two edges in contrast to the antiferromagnetic coupling of the graphene nanoribbon edges. PMID- 28558469 TI - Electrocatalytic Water Oxidation by a Homogeneous Copper Catalyst Disfavors Single-Site Mechanisms. AB - Deployment of solar fuels derived from water requires robust oxygen-evolving catalysts made from earth abundant materials. Copper has recently received much attention in this regard. Mechanistic parallels between Cu and single-site Ru/Ir/Mn water oxidation catalysts, including intermediacy of terminal Cu oxo/oxyl species, are prevalent in the literature; however, intermediacy of late transition metal oxo species would be remarkable given the high d-electron count would fill antibonding orbitals, making these species high in energy. This may suggest alternate pathways are at work in copper-based water oxidation. This report characterizes a dinuclear copper water oxidation catalyst, {[(L)Cu(II)]2 (MU-OH)2}(OTf)2 (L = Me2TMPA = bis((6-methyl-2-pyridyl)methyl)(2 pyridylmethyl)amine) in which water oxidation proceeds with high Faradaic efficiency (>90%) and moderate rates (33 s-1 at ~1 V overpotential, pH 12.5). A large kinetic isotope effect (kH/kD = 20) suggests proton coupled electron transfer in the initial oxidation as the rate-determining step. This species partially dissociates in aqueous solution at pH 12.5 to generate a mononuclear {[(L)Cu(II)(OH)]}+ adduct (Keq = 0.0041). Calculations that reproduce the experimental findings reveal that oxidation of either the mononuclear or dinuclear species results in a common dinuclear intermediate, {[LCu(III)]2-(MU O)2}2+, which avoids formation of terminal Cu(IV)?O/Cu(III)-O* intermediates. Calculations further reveal that both intermolecular water nucleophilic attack and redox isomerization of {[LCu(III)]2-(MU-O)2}2+ are energetically accessible pathways for O-O bond formation. The consequences of these findings are discussed in relation to differences in water oxidation pathways between Cu catalysts and catalysts based on Ru, Ir, and Mn. PMID- 28558470 TI - Flexible, Ultrathin, and High-Efficiency Electromagnetic Shielding Properties of Poly(Vinylidene Fluoride)/Carbon Composite Films. AB - In this study, we fabricated conductive poly(vinylidene fluoride) (PVDF)/carbon composites simply by dispersing multiwalled carbon nanotubes (MWCNTs) and graphene nanoplatelets into a PVDF solution. The electrical conductivity and the electromagnetic interference (EMI) shielding of the PVDF/carbon composites were increased by increasing the conductive carbon filler amounts. Moreover, we also found that the EMI shielding properties of the PVDF/CNT/graphene composites were higher than those of PVDF/CNT and PVDF/graphene composites. The mean EMI shielding values of PVDF/5 wt %-CNT, PVDF/10 wt %-graphene, and PVDF/CNT/graphene composite films with a thickness of 0.1 mm were 22.41, 18.70, and 27.58 dB, respectively. An analysis of the shielding mechanism showed that the main contribution to the EMI shielding came from the absorption mechanism, and that the EMI shielding could be tuned by controlling the films' thickness. The total shielding of the PVDF/CNT/graphene films increased from 21.90 to 36.46 dB as the thickness was increased from 0.06 mm to 0.25 mm. In particular, the PVDF/carbon composite films, with a thickness of 0.1 mm, achieved the highest specific shielding values of 1 310 dB cm2/g for the PVDF/5 wt %-CNT composite and 1 557 dB cm2/g for the PVDF/CNT/graphene composite, respectively. This was due to the ultrathin thickness. Our study provides the groundwork for an effective way to design flexible, ultrathin conductive polymer composite film for application in miniaturized electronic devices. PMID- 28558471 TI - Dual Recognition Element Lateral Flow Assay Toward Multiplex Strain Specific Influenza Virus Detection. AB - Different influenza virus strains have caused a number of recent outbreaks killing scores of people and causing significant losses in animal farming. Simple, rapid, sensitive, and specific detection of particular strains, such as a pandemic strain versus a previous seasonal influenza, plays a crucial role in the monitoring, controlling, and management of outbreaks. In this paper we describe a dual recognition element lateral flow assay (DRELFA) which pairs a nucleic acid aptamer with an antibody for use as a point-of-care platform which can detect particular strains of interest. The combination is used to overcome the individual limitations of antibodies' cross-reactivity and aptamers' slow binding kinetics. In the detection of influenza viruses, we show that DRELFA can discriminate a particular virus strain against others of the same subtype or common respiratory diseases while still exhibiting fast binding kinetic of the antibody-based lateral flow assay (LFA). The improvement in specificity that DRELFA exhibits is an advantage over the currently available antibody-based LFA systems for influenza viruses, which offer discrimination between influenza virus types and subtypes. Using quantitative real-time PCR (qRT-PCR), it showed that the DRELFA is very effective in localizing the analyte to the test line (consistently over 90%) and this is crucial for the sensitivity of the device. In addition, color intensities of the test lines showed a good correlation between the DRELFA and the qRT-PCR over a 50-fold concentration range. Finally, lateral flow strips with a streptavidin capture test line and an anti-antibody control line are universally applicable to specific detection of a wide range of different analytes. PMID- 28558473 TI - Theory of Mind and Empathy in Children With ADHD. AB - OBJECTIVE: The current study compared empathy and theory of mind (ToM) between children with ADHD and healthy controls, and assessed changes in ToM among children with ADHD following administration of methylphenidate (MPH). METHOD: Twenty-four children with ADHD (mean age = 10.3 years) were compared with 36 healthy controls. All children completed the interpersonal reactivity index (IRI), a self-reported empathy questionnaire, and performed the "faux-pas" recognition task (FPR). Children with ADHD performed the task with and without MPH. RESULTS: Children with ADHD showed significantly lower levels of self reported empathy on most IRI subscales. FPR scores were significantly lower in children with ADHD and were improved, following the administration of MPH, to a level equal to that found in healthy controls. CONCLUSION: Children with ADHD show impaired self-reported empathy and FPR when compared with healthy controls. Stimulants improve FPR in children with ADHD to a level equal to that in healthy controls. PMID- 28558474 TI - Development and Testing of a Measure of Caregiver Confidence in Medical Sign/Symptom Management. AB - Evaluation of efforts to support family caregivers of people with dementia in their daily medical management responsibilities requires a measure of caregiver self-efficacy (confidence). This article describes the development and psychometric properties of the Caregiver Confidence in Sign/Symptom Management (CCSM) scale, the only available instrument in this area. Measurement development included literature and expert panel review, cognitive testing, and field testing. The CCSM is a 25-item measure (alpha = .92) composed of confidence in relation to 4 subscales: knowledge of signs/symptoms (alpha = .83), management of cognitive signs/symptoms (alpha = .85), management of medical signs/symptoms (alpha = .87), and general medication management/responsiveness (alpha = .85), all of which relate to caregiver role strain. The CCSM is a reliable and valid instrument to assess caregiver confidence in sign/symptom management and is useful to determine caregiver needs and outcomes of related interventions. Additionally, it furthers understanding of the role of self-efficacy in caregiver quality of life. PMID- 28558475 TI - Protective effect of hydroalcoholic extract of Pistacia vera against gentamicin induced nephrotoxicity in rats. AB - PURPOSE: Pistacia vera is a plant of the family Anacardiaceae found in Central and West Asia. P. vera nut (Pistachio) possess multiple pharmacological effects such as antimicrobial, anti-hyperlipidemia, antioxidant and anti-inflammatory. This study is designed to evaluate the protective effect of the hydroalcoholic extract of pistachio on gentamicin-induced nephrotoxicity in rats. METHODS: Nephrotoxicity was induced in rats by intraperitoneal injection of gentamicin (100 mg/kg/day for 7 days). Hydroalcoholic extract of pistachio (10, 50 and 100 mg/kg/p.o) was administered for 7 days. The nephroprotective activity was evaluated by determining creatinine clearance, serum creatinine, urine volume, urine glucose and blood urea nitrogen (BUN) levels. The kidneys were processed for histopathological examinations and all specimens were examined for morphologic parameters involving tubular degeneration, tubular necrosis and tubule interstitial nephritis. RESULTS: Results showed a significant increase in the levels of serum creatinine, urine volume, urine glucose and BUN and decrease of creatinine clearance by gentamicin (GA) administration. Co-administration with pistachio extract showed reduction in the levels of serum creatinine, urine volume, urine glucose and BUN and increase of creatinine clearance in all doses but the most significant alteration was observed in doses of 100 mg/kg. Also, the nephroprotective effect of the GA was confirmed by the histological examination of the kidneys. CONCLUSION: The study revealed the nephroprotective effect of the hydroalcoholic extract of pistachio. These findings suggest that pistachio treatment may attenuate renal dysfunction and structural damage through the reduction of oxidative stress and inflammation in the kidney. PMID- 28558477 TI - Mitochondrial Glutathione: Regulation and Functions. AB - SIGNIFICANCE: Mitochondrial glutathione fulfills crucial roles in a number of processes, including iron-sulfur cluster biosynthesis and peroxide detoxification. Recent Advances: Genetically encoded fluorescent probes for the glutathione redox potential (EGSH) have permitted extensive new insights into the regulation of mitochondrial glutathione redox homeostasis. These probes have revealed that the glutathione pools of the mitochondrial matrix and intermembrane space (IMS) are highly reduced, similar to the cytosolic glutathione pool. The glutathione pool of the IMS is in equilibrium with the cytosolic glutathione pool due to the presence of porins that allow free passage of reduced glutathione (GSH) and oxidized glutathione (GSSG) across the outer mitochondrial membrane. In contrast, limited transport of glutathione across the inner mitochondrial membrane ensures that the matrix glutathione pool is kinetically isolated from the cytosol and IMS. CRITICAL ISSUES: In contrast to the situation in the cytosol, there appears to be extensive crosstalk between the mitochondrial glutathione and thioredoxin systems. Further, both systems appear to be intimately involved in the removal of reactive oxygen species, particularly hydrogen peroxide (H2O2), produced in mitochondria. However, a detailed understanding of these interactions remains elusive. FUTURE DIRECTIONS: We postulate that the application of genetically encoded sensors for glutathione in combination with novel H2O2 probes and conventional biochemical redox state assays will lead to fundamental new insights into mitochondrial redox regulation and reinvigorate research into the physiological relevance of mitochondrial redox changes. Antioxid. Redox Signal. 27, 1162-1177. PMID- 28558478 TI - Bacteria on Urine Microscopy Is Not Associated with Systemic Infection in Patients with Obstructing Urolithiasis. AB - INTRODUCTION: Determining whether bacterial presence in urine microscopy represents infection is important as ureteral stent placement is indicated in patients with obstructing urolithiasis and infection. We aim to investigate whether the presence of bacteria on urine microscopy is associated with other markers of infection in patients with obstructing urolithiasis presenting to the emergency room. METHODS: We performed a cross-sectional study of 199 patients with obstructing urolithiasis and divided patients into two groups according to the presence of bacteria on urine microscopy. The primary outcome was serum white blood cell count and secondary outcomes were objective fever, subjective fever, tachycardia, pyuria, and final urine culture. Univariate and multivariate analysis were used to assess whether the presence of bacteria on microscopy was associated with other markers of infection. RESULTS: The study included 72 patients in the bacteriuria group and 127 without bacteriuria. On univariate analysis, the presence of bacteria was not associated with leukocytosis, objective fever, or subjective fever, but it was associated with gender (p < 0.001), pyuria (p < 0.001), positive nitrites (p = 0.001), positive leukocyte esterase (p < 0.001), and squamous epithelial cells (p = 0.002). In a multilinear regression model including the presence of squamous cells, age, and sex, the presence of bacteriuria was not related to serum white blood cell count (coefficient -0.47; 95% confidence interval [CI] -1.1, 0.2; p = 0.17), heart rate (coefficient 0.85; 95% CI -2.5, 4.2; p = 0.62), presence of subjective or objective fever (odds ratio [OR] 1.5; 95% CI 0.8, 3.1; p = 0.18), or the presence of squamous epithelial cells (coefficient -4.4; 95% CI -10, 1.2; p = 0.12). However, the presence of bacteriuria was related to only the degree of pyuria (coefficient 16.4; 95% CI 9.6, 23.3; p < 0.001). CONCLUSIONS: Bacteria on urine microscopy is not associated with other markers of systemic infection and may largely represent a contaminant. Renal colic may be a risk factor for providing a contaminated urine specimen. PMID- 28558476 TI - Evaluation of Touchscreen Chambers To Assess Cognition in Adult Mice: Effect of Training and Mild Traumatic Brain Injury. AB - Cognitive impairments are often experienced after a mild traumatic brain injury (mTBI). In the clinical arena, neuropsychological assessments are used frequently to detect cognitive deficits. Animal models of mTBI, however, rely on an assortment of behavioral tasks to assess cognitive outcome. Computer-based touchscreen systems have been developed for rodents and are hypothesized to offer a translational approach to evaluate cognitive function because of the similarities of tasks performed in rodents to those implemented in humans. While these touchscreen systems have been used in pre-clinical models of neurodegenerative diseases and psychiatric disorders, their use in assessing cognitive impairment after mTBI has not been investigated. We hypothesized that mTBI would result in impaired cognitive performance on touchscreen tasks, particularly those with hippocampal-based learning components, including the paired associate learning (PAL) task and the location discrimination (LD) task. Adult male, C57BL/6 mice received a single impact-acceleration mTBI. We found that training mice before injury to perform to criteria is arduous and that performance is sensitive to many environmental variables. Despite extensive optimization and training, mice failed to perform better than chance in the PAL paradigm. Alternatively, mice demonstrated some capacity to learn in the LD paradigm, but only with the easier stages of the task. The mTBI did not affect performance in the LD paradigm, however. Thus, we concluded that under the conditions presented here, the PAL and LD touchscreen tasks are not robust outcome measures for the evaluation of cognitive performance in C57BL/6 mice after a single impact-acceleration mTBI. PMID- 28558479 TI - Mechanisms of Mitochondrial Redox Signaling in Psychosocial Stress-Responsive Systems: New Insights into an Old Story. AB - SIGNIFICANCE: Psychosocial stress is associated with alterations in serum glucocorticoids and cytokines, such as interleukin-6 (IL-6) and IL-1beta, which functionally interact. However, the molecular mechanisms and physiological relationship between the two systems within the context of stress exposure are not well characterized. Recent Advances: Extracellular IL-6, which stimulates the release of cortisol from the zona fasciculata of the adrenal cortex, mediates its intracellular effects by tyrosine phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3). Mitochondrial electron transfer reactions are involved in both STAT3-driven ATP production in oxidative respiration and adrenocortical steroid biosynthesis. CRITICAL ISSUES: The role of STAT3 in oxidative respiration and steroidogenesis suggests that it integrates both nuclear and mitochondrial actions, thereby preserving main steps of glucocorticoid biosynthesis in the adrenal gland under psychosocial stress. This review discusses the notion that these two pathways are together simultaneously involved in protection against chronic stressors. FUTURE DIRECTIONS: Linking the function of cytokines and main components of the hypothalamic-pituitary-adrenal (HPA) axis to molecular mechanisms of mitochondrial redox signaling will be essential for a better understanding of the relevant stress-responsive systems engaged in stress vulnerability. Antioxid. Redox Signal. 28, 760-772. PMID- 28558480 TI - Anorexia Nervosa and Functional Motor Symptoms: Two Faces of the Same Coin? AB - The aim of this study was to compare anorexia nervosa (AN) patients and functional motor symptoms (FMS) patients by assessing their variability in demographic and clinical characteristics, risk factors, precipitators, and family history. The authors assessed levels of depression and anxiety, alexithymia, dissociation, body awareness, self-objectification, and interoception in the two groups, using 20 healthy controls (HCs) as a control group for psychometric assessment and for interoception. Unexpectedly, no differences in the three groups were observed for the measures related to awareness of physical state, including body awareness, self-objectification, and interoceptive ability via the heartbeat task. However, the AN and FMS groups were not different from each other but were different from the HC group with regard to anxiety, depression, alexithymia, and dissociation. In light of the similarities found, these data support the hypothesis of a common etiology involving emotional dysfunction in both disorders. These findings suggest that AN and FMS may be disorders belonging to the same spectrum (where emotional dysregulation is a key feature) and that there exist potential opportunities for collaborative, integrated investigations of etiology, diagnosis, and management of these disorders. PMID- 28558482 TI - Low-Frequency rTMS Ameliorates Akathisia During Pregnancy. PMID- 28558481 TI - Correlates and Prevalence of Aggression at Six Months and One Year After First Time Traumatic Brain Injury. AB - Few studies have examined clinical correlates of aggression after first-time traumatic brain injury (TBI) within the first year after injury. The authors aimed to identify the rates of aggression at 6 and 12 months post-TBI and establish clinical and demographic correlates. A total of 103 subjects with first time TBI were seen within 12 months postinjury and evaluated for aggression. Post TBI social functioning and new-onset depression (within 3 months of the TBI) may serve as particularly important predictors for aggression within the first year of TBI, as these factors may afford intervention and subsequent decreased risk of aggression. PMID- 28558483 TI - Hydrogen Sulfide and Polysulfide Signaling. AB - Hydrogen sulfide (H2S) has been demonstrated to have physiological roles such as neuromodulation, vascular tone regulation, cytoprotection, oxygen sensing, inflammatory regulation, and cell growth. Recently, hydrogen polysulfides (H2Sn) have been found to be produced by 3-mercaptopyruvate sulfurtransferase and to regulate the activity of ion channels, tumor suppressers, and protein kinases. Furthermore, some of the effects previously reported to be mediated by H2S are now ascribed to H2Sn. Cysteine persulfide and cysteine polysulfide may also be involved in cellular redox regulation. The chemical interaction between H2S and nitric oxide (NO) can also produce H2Sn, nitroxyl, and nitrosopersulfide, suggesting their involvement in the reactions previously thought to be mediated by NO alone. This Forum focuses on and critically discusses the recent progress in the study of H2Sn, H2S, and NO as well as other per- or polysulfide species. Antioxid. Redox Signal. 00, 000-000. PMID- 28558484 TI - Confidence of IRB/REC Members in Their Assessments of Human Research Risk: A Study of IRB/REC Decision Making in Action. AB - Understanding how institutional review boards/research ethics committees (IRBs/RECs) perform risk/benefit assessment is important to help improve their function. In environmental ethics, uncertainty about potential outcomes and the precautionary principle play important roles in regulatory oversight but have received little attention in the context of human research ethics. We carried out an empirical study to gain insight into uncertainty by asking IRB/REC members about confidence in their risk assessments immediately after discussion of new protocols under review. Based on 12 meetings carried out by four IRBs/RECs over a 6-month period, we found a robust, inverse relationship between risk and confidence. As risk increased, confidence decreased. We detected different patterns of consensus between different IRBs/RECs and their members. Our study introduces a novel and relatively easy to implement approach to begin to understand IRB/REC decision making in real time that can be used within or across institutions. PMID- 28558485 TI - Intravenous alprostadil treatment compared to oral pentoxifylline treatment in outpatients with intermittent claudication - results of a randomised clinical trial. PMID- 28558486 TI - A Higher Ratio of Estradiol to Testosterone Is Associated with Autoimmune Thyroid Disease in Males. AB - BACKGROUND: Autoimmune thyroid disease (AITD) is highly prevalent. Although AITD is less common in males, it is unclear whether estradiol (E2) combined with total testosterone (T) contributes to the prevalence of AITD. This study evaluated the association between the E2/T ratio and the prevalence of AITD in males. METHODS: The data were obtained from a cross-sectional population-based study, the SPECT China study, 2014-2015. A total of 4109 males >=18 years of age were enrolled in this study. Participants underwent several checkups, which included assays of serum E2, T, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) levels, as well as thyroid ultrasonography (US). AITD was defined based on the presence of TPOAb and TgAb levels, and the presence of thyroid US findings. RESULTS: Overall, the prevalence of positivity for TPOAb and/or TgAb (TPO/TgAb[+]) was 11.02%, and the positivity for TPOAb and/or TgAb together with US (TPO/TgAb[+] and US[+]) was 4.58%. The E2/T ratio levels were significantly higher in the TPO/TgAb(+) group and the TPO/TgAb(+) and US(+) group (7.91 +/- 8.03 vs. 7.19 +/- 10.30, p = 0.003; 8.78 +/- 11.26 vs. 7.19 +/- 10.30, p = 0.001) compared to the TPO and TgAb(-) group. The prevalence of TPO/TgAb(+) and US(+) significantly increased with an increasing E2/T ratio (p = 0.013). Binary logistic analysis showed that increased E2/T ratio levels were associated with an increased risk of AITD (TPO/TgAb[+]: odds ratio = 1.35, p = 0.002; TPO/TgAb[+] and US[+]: odds ratio = 1.48, p = 0.006). CONCLUSIONS: AITD is highly prevalent in males in China. Higher E2/T ratios were significantly associated with AITD among males. Further studies will be needed to assess whether there is a causal relationship between E2/T ratios and AITD. PMID- 28558487 TI - Irreversible Electroporation Ablation of an Unresectable Fibrous Sarcoma With 2 Electrodes: A Case Report. AB - PURPOSE: To explore the safety and efficacy of irreversible electroporation ablation in unresectable fibrous sarcoma with 2 electrodes. METHODS: A 74-year old woman with unresectable retroperitoneal malignant fibrous sarcoma was treated with percutaneous irreversible electroporation. Four ablations were performed on the mass, which measured 7.3 * 7.0 * 7.5 cm, with 2 electrodes. RESULTS: A contrast-enhanced computed tomography scan 2 months postoperatively showed that the tumor had reduced to 5.1 * 4.0 * 5.2 cm, without obvious enhancement. Any adverse reactions were evaluated as level 1. CONCLUSION: In the short term, the treatment with 2 electrodes for fibrous sarcoma appears to be safe and effective. PMID- 28558489 TI - Ethical dilemmas during cardiac arrest incidents in the patient's home. AB - BACKGROUND: The majority (70%) of cardiac arrests in Sweden are experienced in the patient's home. In these situations, the ambulance nurses may encounter several ethical dilemmas. AIM: The aim was to investigate Swedish specialist ambulance nurses' experiences of ethical dilemmas associated with cardiac arrest situations in adult patients' homes. METHODS: Nine interviews were conducted with specialist ambulance nurses at four different ambulance stations in the southeast region of Sweden. Data were analysed using content analysis. Ethical considerations: Ethical principles mandated by the Swedish Research Council were carefully followed during the whole process. FINDINGS: Two main themes with six sub-themes were identified: The scene - creating a sheltered space for caring and Ethical decision-making. The results showed that ethical dilemmas might occur when trying to create a sheltered space to preserve the patients' integrity and dignity. A dilemma could be whether or not to invite significant others to be present during the medical treatment. Ethical decision-making was dependent on good communication and ethical reasoning among all parties. In certain situations, decisions were made not to commence or to terminate care despite guidelines. The decision was guided by combining the medical/nursing perspectives and ethical competence with respect to the human being's dignity and a will to do good for the patient. The nurses followed the voice of their heart and had the courage to be truly human. CONCLUSION: The ambulance nurses were guided by their ethos, including the basic motive to care for the patient, to alleviate suffering, to confirm the patient's dignity and to serve life and health. PMID- 28558488 TI - Psychoeducational intervention focused on healthy living improves psychopathological severity and lifestyle quality in psychiatric patients: preliminary findings from a controlled study. AB - BACKGROUND: Individuals with psychiatric disorders incur an increased risk of morbidity and mortality, with higher prevalence of cardio-metabolic risk factors s largely contributing to a significant reduction in life expectancy. OBJECTIVES: The aim of the present study was at evaluating the clinical effectiveness of an educational intervention targeting lifestyle habits in patients with mood and psychotic disorders. METHODS: Patients (n = 32) were randomly assigned to receive, in addition to the pharmacological treatment, either five sessions of group psychoeducation focused on healthy lifestyle or five sessions of a control group therapy. RESULTS: Both psychopathological severity (i.e. the brief psychiatric rating scale) and lifestyle quality (i.e. physical activity, sleep quality and adherence to the Mediterranean diet) improved significantly over time in patients who underwent specific psychoeducational sessions but not in the controls. CONCLUSIONS: These findings add to the accumulating evidence that educational interventions focused on lifestyle habits can ameliorate general and mental health in patients with psychiatric disorders and suggest that educational programs represent an effective non-pharmacological intervention to manage drug induced cardiometabolic disturbances. PMID- 28558490 TI - Changing Attitudes and Knowledge Toward SNAP Application. AB - PURPOSE: To examine effectiveness of an educational intervention on attitude and knowledge related to accessing and qualifying for the Supplemental Nutrition Assistance Program (SNAP). DESIGN: Cross-sectional survey. SETTING: Community sites (38) in North Carolina. PARTICIPANTS: Low-income adult participants who provided data (n = 558). INTERVENTION: Participants completed pre- and postsurveys for the 45-minute program. MEASURES: Theoretically based surveys measured knowledge requisite to the decision to apply for SNAP benefits. ANALYSIS: Paired sample t tests tested the hypothesis of "no difference" in postintervention knowledge. RESULTS: Knowledge gains were statistically significant on all questions ( P < .01) including the amount of food a minimum benefit could purchase, how to apply for SNAP, how the electronic benefit transfer card and benefits work, eligibility restrictions, and how to receive application assistance. Subsequent percentage change analyses revealed the strongest intervention effects to be how to apply and accessing application assistance. CONCLUSION: Effective theory-based programs can improve knowledge and dispel myths concerning SNAP participation among low-income participants. PMID- 28558491 TI - Vitamin D Status and Supplementation in Employer-Sponsored Wellness Program. AB - PURPOSE: To assess the response to information about vitamin D status by participants enrolled in employer-sponsored wellness programs. DESIGN: A self reported health risk assessment questionnaire was used to categorize vitamin D supplementation. PARTICIPANTS: A total of 50 209 participants of 12 employer sponsored wellness programs that included vitamin D testing and services provided by Quest Diagnostics in 2014 and 2015. MEASURES: Vitamin D status based on laboratory testing results and responses to vitamin D supplementation in a health risk assessment questionnaire for initial and subsequent years. RESULTS: Among 50 209 participants, 29% had deficient and 37% had suboptimal levels of vitamin D. Many participants appeared to act counter to their informed vitamin D status by starting supplements when vitamin D level was initially optimal (20%) or discontinuing supplements when vitamin D level was initially deficient (36%). Three-quarters of participants who had deficient or suboptimal vitamin D levels and were not taking supplements in 2014 continued not taking supplements in 2015. CONCLUSION: Deficient and suboptimal vitamin D levels remain prevalent in a working-age population. Many participants do not seem to be taking appropriate actions after receiving vitamin D testing results. Accordingly, employer sponsored wellness programs have an opportunity to better educate participants. PMID- 28558492 TI - E-Cigarette Advice to Patients From Physicians and Dentists in the United States. AB - PURPOSE: To report on adults' recall of discussion by physicians and dentists about e-cigarettes. DESIGN: A nationally representative cross-sectional survey (Internet and random digit dialing) in the United States. PARTICIPANTS: Adults who ever used e-cigarettes. MEASURES: Participant-reported discussion about the potential benefits and harms of e-cigarettes with their doctor, dentist, or child's doctor in the past 12 months. ANALYSIS: Fisher exact test for the analysis between benefits and harms for each type of provider and for rates of advice between provider types. RESULTS: Among the 3030 adults who completed the survey, 523 (17.2%) had ever used e-cigarettes. Of those who had seen their doctor, dentist, or child's doctor in the last year, 7.3%, 1.7%, and 10.1%, respectively, reported discussing potential harms of e-cigarettes. Conversely, 5.8%, 1.7%, and 9.3% of patients who had seen their doctor, dentist, or child's doctor in the last year reported that the clinician discussed the potential benefits of e-cigarettes. Each clinician type was as likely to discuss harms as benefits. Rates of advice were similar between doctors and child's doctors but lower for dentists. Rates were comparable when the analysis was limited to current e-cigarette users, participants with children, or those who reported using both e-cigarettes and combusted tobacco. CONCLUSIONS: Few physicians and dentists discuss either the harms or benefits of e-cigarettes with their patients. These data suggest an opportunity to educate, train, and provide resources for physicians and dentists about e-cigarettes and their use. PMID- 28558494 TI - Core Values of NAHN's Membership Committee. PMID- 28558493 TI - A Review of the Efficacy and Safety of Genvoya(r) (Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide) in the Management of HIV-1 Infection. AB - INTRODUCTION: This review evaluates the efficacy and safety of Genvoya(r) (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide [EVG/c/TAF/FTC]), a single-tablet regimen used for the management of HIV-1 infection. Phase II and III randomized clinical trials evaluate the efficacy and safety of EVG/c/TAF/FTC and tenofovir disoproxil fumerate (TDF)-containing arms; renal impairment, bone mineral density, metabolic effects, and other adverse events are topics explored within this review. METHODS: A MEDLINE with full text and PubMed literature search was conducted for the past 5 years, up to April 2016. RESULTS: Virologic suppression was similar between the EVG/c/TAF/FTC and TDF-containing groups (<50 copies/mL) at week 48. The bone mineral density in the hip and spine showed a significant reduction in the TDF-containing groups. The glomerular filtration rate increased in patients in the EVG/c/TAF/FTC arm and there were significant differences in total proteinuria, albuminuria, and tubular proteinuria in patients switching to EVG/c/TAF/FTC. The most common adverse events were diarrhea, nausea, and headache. DISCUSSION: The coformulated Genvoya regimen is well tolerated and effective in treatment-naive and virologically suppressed patients. Data seem to suggest it may also be effective and safe in patients with mild to moderate renal impairment. The lower-dosed single-tablet regimen has significantly reduced bone and renal side effects. PMID- 28558496 TI - Health Disparities and Hispanics. PMID- 28558495 TI - "It Feels Good to Know That Someone Cares". AB - INTRODUCTION: Diabetes is the leading cause of death in Hispanic communities. Self-management is an important part of diabetes care, and diabetes self management education (DSME) aims to teach the skills necessary for preventing and delaying complication. However, DSME is underutilized. The purpose of this study was to explore Hispanic adults' motivations for attending a DSME class to identify effective strategies for promoting class participation and retention. METHOD: Nineteen adults participated in seven focus groups conducted in Spanish. Discussions were audio-recorded, transcribed, and translated. Transcripts were content coded by two coders to create a thematic coding scheme. RESULTS: Five main themes emerged as motivations for attendance: (1) frustration with physiological changes, (2) desire to "do better" because of family experience with death/complications from diabetes, (3) free access to information that is unattainable elsewhere, (3) a way to take control, and (4) group setting offered valued emotional and informational support as well as peer support for those who were uncomfortable discussing diabetes with family or lived with family who do not support lifestyle changes. CONCLUSIONS: Gaining diabetes self-management knowledge only partly explains the perceived value of classes. Culturally relevant content and appealing to the social supportive aspects of groups may encourage participation. PMID- 28558497 TI - NAHN. PMID- 28558498 TI - From Systematic Review to Call for Action. AB - INTRODUCTION: Intimate partner violence (IPV) is a global public health and criminal justice concern with significant impacts; especially high rates are seen among rural Hispanic American (HA) communities, the fastest growing population in the United States. They experience additional barriers to care including extreme poverty, lesser education, gender norms, and language and immigration issues. METHOD: A systematic literature review was conducted using Cooper's framework to identify evidence supporting associations between interventions and prevention, reduction, and elimination of IPV among rural HA women. Searches conducted on databases including CINAHL, PubMed, Medline, Women's Studies International, MedicLatina, and JSTOR used the MeSH terms Hispanic Americans (Latino/a and Hispanic), domestic violence, and intimate partner violence. Selected studies were published between January 1, 2000, and January 1, 2014. RESULTS: Of the 617 yielded articles, only 6 met the inclusion criteria. Of these, none closely examined rurality or provided valid and reliable measures of outcomes, instead reporting program descriptions and suggested interventions. We identify key findings to guide program, screening, and tool development. CONCLUSION: Our study identifies a gap in knowledge, research, and effective practices and issues a call for action to create evidence-based tools to prevent, reduce, and eliminate IPV in these underserved populations. PMID- 28558499 TI - Parental Feeding Style and Pediatric Obesity in Latino Families. AB - INTRODUCTION: Pediatric obesity has become an epidemic in the United States. Previous research has shown that parenting factors related to feeding style affect child weight and that Latino families are especially at risk for pediatric obesity. The goal of the current study was to evaluate the relationship between parental feeding style and child body mass index (BMI) in Latino families. METHOD: Latino parents of children between the ages of 2 and 8 ( N = 124) completed a survey on parental feeding styles, acculturation, and demographics. The outcome variable was child BMI. RESULTS: Among respondents, 89% were mothers, 72% were overweight or obese, and 40% reported an indulgent feeding style. Children had a mean age of 59 months ( SD = 23.8) and a mean BMI z score of 0.77 ( SD = 1.14). A demanding parental feeding style was associated with lower child BMI z score, r = -.179, p < .05, and higher acculturation level, r = .213, p < .05. CONCLUSIONS: Findings from the current study can be used to inform health care practitioners of the need to use culturally sensitive interventions that consider parents' feeding behaviors. Future research is warranted in the area of ethnic variations of parenting and how these affect feeding and obesity in this highly vulnerable population. PMID- 28558500 TI - Influencing College and Higher Education Choices in Disadvantaged Hispanic High School Students Through a School-Based Health Club. AB - INTRODUCTION: Statistics representing professional health care providers do not adequately reflect the shift in the nation's diverse population. Latinos are significantly underrepresented at all levels of appropriate academic programs critical for entry to health profession careers. This project describes the implementation of a student-run, faculty-facilitated Future Nurse and Health Club at a school (with majority Latino students) to emphasize the importance of higher education in health care. Demographic and psychosocial profiles of club members were also developed to understand community needs. METHOD: The Future Nurse and Health Club was established in partnership with faculty and researchers representing a university-based nursing program, school officials, and community leaders. Both quantitative and qualitative data were collected from club members and their parents using a variety of techniques including questionnaires and focus groups. RESULTS: The findings of the study highlighted a variety of student and parent-related factors including poor lifestyle habits and perceptions of support that could potentially influence Latino high school students' interest and progress in health care-related higher education. CONCLUSION: A school-based health career club involving active participation of parents and students with support from health care professionals such as academic nursing faculty has the potential to simultaneously raise student interest in health-related careers and health needs of their community. PMID- 28558501 TI - Views on Exercise. AB - INTRODUCTION: There is a large prevalence of asthma, particularly among Hispanic children. Although physical activity is a good way to manage asthma, more Hispanic children with asthma lack activity than their healthy classmates. Given this, the purpose of this study was to explore the development of exercise perceptions in Hispanic children with asthma and to further develop an existing explanatory theory. METHOD: Grounded theory was the approach for the study. Grounded theory illuminated components of exercise perceptions from participants. Participants included Hispanic children with asthma, their families, and professionals who work with Hispanic children with asthma ( n = 29). RESULTS: Findings from this study supported the previously identified grounded theory called The Process of Creating Perceptions of Exercise. In addition, two new concepts ( cultural and peer influences) were identified that further explain the category of exercise influences. CONCLUSION: The revised theory can be used to assist in developing nursing interventions aimed at increasing exercise participation among Hispanic children with asthma. PMID- 28558503 TI - Hispanic Health Care International Author Guidelines. PMID- 28558502 TI - Six-Month Results From the Initial Randomized Study of the Ranger Paclitaxel Coated Balloon in the Femoropopliteal Segment. AB - PURPOSE: To evaluate the performance of the Ranger paclitaxel-coated balloon vs uncoated balloon angioplasty for femoropopliteal lesions. METHODS: Between January 2014 and October 2015, the prospective, randomized RANGER SFA study ( ClinicalTrials.gov identifier NCT02013193) enrolled 105 patients with symptomatic lower limb ischemia (Rutherford category 2-4) and stenotic lesions in the nonstented femoropopliteal segment at 10 European centers. Seventy-one patients (mean age 68+/-8 years; 53 men) were enrolled in the Ranger drug-coated balloon (DCB) arm and 34 patients (mean age 67+/-9 years; 23 men) were assigned to the control group. Six-month analysis included angiographic late lumen loss and safety and clinical outcomes assessments. RESULTS: Baseline characteristics of the DCB and control groups were similar, as were lesion lengths (68+/-46 vs 60+/ 48 mm; p=0.731), severity of calcification (p=0.236), and the prevalence of occlusions (34% vs 34%; p>0.999). At 6 months, late lumen loss was significantly less for the DCB group vs controls (-0.16+/-0.99 vs 0.76+/-1.4; p=0.002). The DCB group had significantly greater freedom from binary restenosis (92% vs 64%; p=0.005) and primary patency rates (87% vs 60%; p=0.014). Target lesion revascularization rates were 5.6% in the DCB group and 12% in the control group (p=0.475). No target limb amputations or device-related deaths occurred in either group. CONCLUSION: Six-month results suggest that Ranger DCB treatment effectively inhibited restenosis in symptomatic femoropopliteal disease, resulting in improved vessel patency and a low revascularization rate in the short term compared with uncoated balloon angioplasty. PMID- 28558505 TI - Chapter Presidents. PMID- 28558504 TI - 2016 Council of Business Advisor Members. PMID- 28558506 TI - Nursing Research: Contributions to Universal Health Care. PMID- 28558507 TI - How NAHN Nurses Advocate and Lead Change. PMID- 28558508 TI - Association Executive Board and Board of Directors. PMID- 28558509 TI - Examining Fall Recurrence Risk of Homebound Hispanic Older Adults Receiving Home Care Services. AB - INTRODUCTION: Unintentional falls and injuries is a major problem among older adults and the fourth cause of death in the United States. A previous fall event doubles the risk of recurrence and lessens the person's quality of life. Hispanic older adults have higher rates of disability and lower independent functioning due to poor medical health and risk for fall recurrence. Most fall studies focus on fall risk with few studies on fall recurrence in older adults receiving home health care services unrelated to fall incident. METHOD: A descriptive pilot study of 30 homebound Hispanic older adults receiving home care services who reported a fall within 3 months was conducted by a multidisciplinary team to evaluate risk of fall recurrence. RESULTS: A heightened risk for fall recurrence was identified with high number of chronic illnesses, high intake of medications, vision problems, and prevalence of urinary incontinence. CONCLUSION: Findings highlight significant number of intrinsic factors for fall risk recurrence and injuries in a Hispanic older adults population that is homebound and receiving home care services. A multidisciplinary evaluation and culturally appropriate interventions to lessen the risk of fall recurrence are recommended. PMID- 28558511 TI - HIV Testing Behaviors Among Latina Women Tested for HIV in Florida, 2012. AB - INTRODUCTION: Latina women in the United States (US) are not only disproportionately affected by human immunodeficiency virus (HIV) infection but also underuse HIV prevention services, such as HIV testing. METHOD: HIV testing events were examined to describe the HIV testing behaviors and test results among Latinas tested in 2012 at publicly funded sites in Florida, United States. Multivariable logistic regression was used to assess the demographic characteristics associated with reports of previous testing and positive HIV test results. RESULTS: Of the 184,037 testing events, 87,569 (45.6%) were among non Hispanic Blacks (NHBs), 47,926 (26.0%) non-Hispanic Whites (NHWs), 41,117 (22.3%) Latinas, 5,672 (3.1%) those with unknown race/ethnicity, and 1,753 (1.0%) other racial/ethnic groups. Compared to NHW and NHB women, Latinas testing for HIV were older (mean age = 32.1, NHW = mean age 30.3, NHB = mean age 30.0; p < .0001). Results indicated that women who reported previous HIV testing had decreased odds of being Latina (adjusted odds ratio = 0.90; 95% confidence interval [0.87, 0.94]). CONCLUSION: These findings indicate that Latinas are underusing HIV testing, and efforts are needed to increase the proportion of Latinas, especially younger Latinas, tested for HIV in Florida. PMID- 28558510 TI - Improving Family Communication. AB - INTRODUCTION: TeenSmart International harnesses the power and flexibility of technology to empower youth to take personal responsibility for their health and lifestyle choices. Access to the Internet via mobile phones is often cheaper than paying to connect to a wired broadband service, and in rural areas, mobile networks may be the only means of accessing the Internet. This study assessed the feasibility, acceptability, and impact of "cues to action" or brief motivating cell phone text messages to improve adolescent family communication and relationships. METHOD: A quasi-experimental design using a voluntary sample of 100 Nicaraguan youth at high risk for poor family communication participated. Pre and posttest quantitative measures using Student t statistical analysis, a focus group, and a participant testimony provided the evaluation evidence. RESULTS: Findings suggest that there are economic and motivational barriers to the use of text messages, but when barriers are eliminated, the behavioral results are positive. Youth who received two weekly text messages over a 6-month period demonstrated statistically significant improvements in family communication perceptions, attitudes, and behaviors, strengthening their family communications and relationships. CONCLUSION: Brief and personalized text messaging "cues to action" may be a cost-effective intervention to improve adolescent healthy lifestyle behaviors. PMID- 28558512 TI - Maternal Health of Undocumented Women With and Without Medicaid Access in Nebraska, 2007-2011. AB - INTRODUCTION: Four million infants are born in the United States to undocumented mothers. Nebraska granted Medicaid access to undocumented pregnant women from 1996 to 2010 and then discontinued access from 2010 to 2012. However, little is known about the maternal health of these undocumented women. The purpose of this study was to compare maternal health of undocumented women with and without access to Medicaid in Nebraska from 2007 to 2011. METHOD: A retrospective, longitudinal cohort design was conducted with 2007 to 2011 Nebraska birth certificate data. Study participants were 6,262 undocumented women. Groups of measures were created for demographics, prenatal, pregnancy, and delivery characteristics. Descriptive statistics were calculated and comparisons were conducted between women with and without access to Medicaid using chi-square and Student t tests. RESULTS: More than 60% of undocumented women had access to Medicaid, while 32% had no access to Medicaid. Undocumented women were predominately Hispanic (73.32%) and did not have a high school education (68.77%). The comparison of undocumented women with and without Medicaid revealed that women with Medicaid access had more than adequate prenatal care (17.86% vs. 14.80%) and a higher frequency of infant born with abnormal conditions (6.26% vs. 8.03%). Women without access to Medicaid more often had inadequate prenatal care (10.28% vs. 6.94%) and were obese prior to pregnancy (19.37% vs. 17.37%). CONCLUSIONS: Undocumented women who are prenatally obese and lack access to prenatal care may be at increased risk for poor maternal outcomes. PMID- 28558513 TI - Cues to Cervical Cancer Screening Among U.S. Hispanic Women. AB - INTRODUCTION: Hispanic women's cervical cancer rates are disproportionately high. Cues to cervical cancer screening (Cues to Action) are strategies to activate the decision-making process to get screened for cervical cancer. This study used the health belief model to examine which cues prompt Hispanic women to undergo cervical cancer screening and how perceptions could be potentiated by cues to cervical cancer screening. METHOD: A cross-sectional survey was conducted among Hispanic women 18 to 65 years old ( n = 220). Generalized linear modeling was used. RESULTS: Spanish media and reminders by mother and doctors were relevant cues. Generalized linear modeling showed cues to action modified significantly the predictive effect of Perceived Threats (i.e., Susceptibility, Severity), benefits, barriers, and self-efficacy on Hispanic women's cervical cancer screening behavior. "Mother told me" and Spanish media messages were significant covariates. CONCLUSION: Cues to Action influenced Hispanic's women participation in cervical cancer screening. Cues to Action increased the strength of the health belief model as an explanatory model, and must be considered in designing culturally appropriate cervical cancer screening interventions. PMID- 28558514 TI - In-vivo analysis of ankle joint movement for patient-specific kinematic characterization. AB - In this article, a method for the experimental in-vivo characterization of the ankle kinematics is proposed. The method is meant to improve personalization of various ankle joint treatments, such as surgical decision-making or design and application of an orthosis, possibly to increase their effectiveness. This characterization in fact would make the treatments more compatible with the specific patient's joint physiological conditions. This article describes the experimental procedure and the analytical method adopted, based on the instantaneous and mean helical axis theories. The results obtained in this experimental analysis reveal that more accurate techniques are necessary for a robust in-vivo assessment of the tibio-talar axis of rotation. PMID- 28558515 TI - Social Context and Value-Based Care: A Capabilities Approach for Addressing Health Disparities. AB - Racial disparities in health are persistent and pervasive in the United States. Researchers and policymakers have known for decades that access to health care is not sufficient for addressing health disparities because of the socially situated roots of the disparities. We argue that the lack of progress in alleviating health disparities is the result of a lack of overarching framework to guide both policymakers and researchers in their efforts. We propose Amartya Sen's capabilities approach as a theoretical framework that is expansive enough to address both the social context in which health occurs as well as the quality of health care provided. In this article, we use a subset of veterans receiving care from the Veterans Health Administration to review the theoretical concepts that link social inequalities with health disparities. Next, we provide empirical evidence of disparities in health based on race within the Veterans Health Administration, and we then provide a theoretical explanation for those disparities that exist at a system level. We close with a detailed examination of the applicability of the capabilities approach in addressing health disparities in the United States. PMID- 28558516 TI - Nurses Improve Their Communities' Health Where They Live, Learn, Work, and Play. AB - Nurses are often recognized for their volunteer efforts following disasters and international humanitarian crises. However, little attention is paid to the activities of nurses who promote a culture of health in their communities through local volunteer work. In this article, we describe nurses' perceptions of how they promote health in their communities through formal and informal volunteer work. Using 315 written responses to an open-ended question included in a 2016 survey of the career patterns of nurses in the U.S., we utilized conventional content analysis methods to code and thematically synthesize responses. Two broad categories of nurse involvement in volunteer activities arose from the participants' responses to the open-ended question, "Please tell us what you have done in the past year to improve the health of your community": 17% identified job-related activities, and 74% identified non-job-related activities. 9% of respondents indicated they do not participate in volunteer work. Job-related activities included patient education, educating colleagues, and "other" job related activities. Non-job-related activities included health-related community volunteering, volunteering related to a specific population or disease, family related volunteering, church activities, health fairs, raising or donating money, and travelling abroad for volunteer work. Nurses are committed to promoting a culture of health in their communities both at work and in their daily lives. Leveraging nurses' interest in volunteer work could improve the way nurses engage with their communities, expand the role of nurses as public health professionals, and foster the social desirability of healthful living. PMID- 28558517 TI - Nurse-Performed Endoscopy: Implications for the Nursing Profession in Australia. AB - Increasing demands for health care globally often lead to discussions about expanding the involvement of nurses in a range of nontraditional roles. Several countries have introduced nurse endoscopists as a means of easing the burden of demand for a range of endoscopic procedures. A shortage of medical staff in Australia combined with increasing demand for endoscopy led to the implementation of nurse endoscopists as a pilot program in the state of Queensland, where a nurse practitioner model was implemented, and Victoria, where an advanced practice model was used. This article will discuss the implementation of and responses from the nursing, medical, and policy community to nurse-performed endoscopy in this country. Regarding health policy, access to cancer screening may be improved by providing nurses with advanced training to safely perform endoscopy procedures. Moreover, issues of nurse credentialing and payment need to be considered appropriate to each country's health system model. PMID- 28558518 TI - Students' Beliefs About and Perceived Effectiveness of a Tobacco-Free Campus Policy. AB - Tobacco-free (TF) college campus policies have potential to be a high-impact tobacco control strategy. The purposes of the study presented here were to (a) determine the demographic and personal characteristics associated with students' beliefs about and perceived effectiveness of a TF campus policy and (b) assess whether tobacco use status and exposure to secondhand smoke (SHS) predicted beliefs and perceived effectiveness. Five thousand randomly selected students from a large southeastern university were invited by e-mail to participate in an online survey in April 2013, three and a half years after policy implementation. Students held positive beliefs about the policy (average rating 84% of the maximum possible score). Sixty-one percent believed that the policy was successful at reducing SHS exposure; and 40% thought the policy encouraged quitting. Males were less likely than females to believe the policy was effective in reducing SHS exposure and encouraging quitting. Lower undergraduates were more likely to perceive the policy as less effective in reducing SHS exposure; international students were more likely than domestic students to perceive the policy as more effective at encouraging quitting. Students most exposed to SHS were less likely to perceive the policy was effective. Compared with nonusers, those who smoked cigarettes were less likely to perceive the policy as effective in encouraging quitting. Tailored messaging regarding policy benefits are necessary. Perceived effectiveness of TF policies may be related to compliance with the policy and should be further investigated. Objective measures of effectiveness and tobacco use behaviors are needed to fully measure the success of TF campus policies. PMID- 28558519 TI - Medicaid for Newly Resettled Legal Immigrants. PMID- 28558520 TI - A Staged Approach to Educating Nurses in Health Policy. AB - Nurse leaders and health-care experts agree that nurses have a responsibility to address the health problems facing the nation by participating in health policy development. However, nurses have not fully realized their potential when it comes to engaging in health policy advocacy and leadership. Nurse leaders, professional nursing organizations, accrediting bodies, and the Institute of Medicine have all identified the need to educate nurses in heath policy. Valuable recommendations for content and learning activities in health policy have been made. We argue that nursing education in health policy and the many recommendations offered have been broad and overly ambitious. This article presents a proposal for a staged approach to educating nurses. This approach would tailor content to the role of the nurse at each level of nursing education. The focus of health policy content would progress from the organizational level to local, state, and finally national level health policies. The goal of this approach is to better prepare all levels of nursing students to participate in shaping effective health policies. PMID- 28558521 TI - What Is Known and Unknown About the Association Between Endometriosis and Sexual Functioning: A Systematic Review of the Literature. AB - It is well known that endometriosis is associated with an increase in the risk of deep dyspareunia, with potential negative effects on global female sexual functioning and couple relationship. The aims of this study were to review the literature on the impact of endometriosis on female sexual functioning and to suggest new avenues for future research and treatment strategies. An electronic database research was performed to identify all the studies on the relation between endometriosis and sexual functioning published in the period 2000 to 2016. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. After the screening process, a total of 9 studies investigating the relation between endometriosis and female sexual functioning were considered. Overall, these studies indicated that around two thirds of women with endometriosis have some form of sexual dysfunction not limited to deep dyspareunia. These findings suggest that the global sexual impact of endometriosis requires further investigation, focusing not only on pain during intercourse but also on psychological and relational dimensions, including partner's sexual functioning. Because sexual functioning is a complex, multidimensional phenomenon, the ideal treatment for endometriosis related sexual dysfunctions should be conducted by a multidisciplinary team composed of gynecologists, sexologists, and psychologists/psychotherapists. PMID- 28558522 TI - Saponin Extracts Induced Apoptosis of Endometrial Cells From Women With Endometriosis Through Modulation of miR-21-5p. AB - Among the several components in Korean red ginseng, the saponin components are known to have various pharmacologic activities. The objective of this study was to evaluate therapeutic effects of saponin extracts from Korean red ginseng on endometriosis and to identify microRNAs (miRNAs) associated with saponin treatment. This is an in vitro study which used human endometrial stromal cells (HESCs) obtained from patients who underwent laparoscopic surgery for endometriosis and other benign conditions. Human endometrial stromal cells were treated with saponin extracts, and microarray profiling was performed. Human endometrial stromal cells were then transfected with miRNAs identified in the profiling. After the saponin extract treatment, the expression of caspase 3 was significantly increased in HESCs. Microarray profiling revealed several miRNAs that were differentially expressed, and miR-21-5p was further validated. Expression of miR-21-5p was significantly upregulated in the endometrium of patients with endometriosis, compared with controls. Transfection of a miR-21-5p inhibitor significantly increased caspase 3 expression in HESCs. The apoptotic potential of saponin extracts and the miR-21-5p inhibitor were further validated in HESCs using flow cytometry analysis. In conclusions, treatment with saponin extracts significantly decreased the expression of miR-21-5p in HESCs from patients with endometriosis. Inhibition of miR-21-5p effectively increased the apoptotic potential of HESCs. These findings suggest that saponin extract treatment may have therapeutic potential for endometriosis via modulation of specific miRNAs. PMID- 28558524 TI - Mindfulness and Loving-Kindness Meditation. AB - An experiment involving 115 undergraduate students (74.8% females; mean age = 20.5 years, SD = 4.3) was conducted to explore effects of meditation on social connectedness, nature connectedness, and affect. Participants listened to one of three brief guided meditation Mp3 recordings via the internet, which involved mindfulness meditation (MM), loving-kindness meditation (LKM), or progressive muscle relaxation (active control group). Participants in the MM and LKM groups reported greater social and nature connectedness at post-test than those in the control group. There were no significant differences in connectedness between the MM and LKM groups, suggesting they are both effective for enhancing connectedness. There were no significant changes in negative or positive affect at post-test due to the interventions. Recommendations for future research are provided. PMID- 28558525 TI - Does Mind Wandering Mediate the Association Between Mindfulness and Negative Mood? A Preliminary Study. AB - The aim of this study was to assess the relationship between trait mindfulness and mood and to examine whether the relationship is mediated by mind wandering. Eighty-two individuals ( M age = 24.27 years, SD = 5.64, 18 men, 22%) completed a series of measures including the Five-Facet Mindfulness Questionnaire, the Profile of Mood States Questionnaire, and Meditation Breath Attention Exercise. Results showed that the level of mindfulness was significantly correlated with positive and negative mood, and the association between mindfulness and negative mood was mediated by mind wandering. This study indicated the important role of mind wandering in the relation between mindfulness and negative mood. Limitations and future research directions are discussed. PMID- 28558523 TI - Melatonin Treatment May Be Able to Restore Menstrual Cyclicity in Women With PCOS: A Pilot Study. AB - The objective of the study was to investigate the effects of 6 months of melatonin administration on clinical, endocrine, and metabolic features of women affected by polycystic ovary syndrome (PCOS). This is a prospective cohort study including 40 normal-weight women with PCOS between January and September 2016, enrolled in an academic research environment. Ultrasonographic pelvic examinations, hirsutism score evaluation, hormonal profile assays, oral glucose tolerance test, and lipid profile at baseline and after 6 months of melatonin administration were performed. Melatonin treatment significantly decreased androgens levels (free androgen index: P < .05; testosterone: P < .01; 17 hydroxyprogesterone: P < .01). Follicle-stimulating hormone levels significantly raised ( P < .01), and anti-Mullerian hormone serum levels significantly dropped after 6 months of melatonin treatment ( P < .01). No significant changes occurred in glucoinsulinemic and lipid parameters after treatment except a significant decrease of low-density lipoprotein cholesterol. Almost 95% of participants experienced an amelioration of menstrual cycles. Until now, only few data have been published about the role of melatonin in women with PCOS. This is the first study focused on the effects of exogenous oral melatonin administration on the clinical, endocrine, and metabolic characteristics of patients with PCOS. After 6 months of treatment, melatonin seems to improve menstrual irregularities and biochemical hyperandrogenism in women with PCOS through a direct, insulin independent effect on the ovary. Based on our results, melatonin could be considered a potential future therapeutic agent for women affected by PCOS. PMID- 28558526 TI - Profiles of Coping Strategies in Resilient Adolescents. AB - To understand how resilient adolescents adapt to adverse situations, this study examined resilient adolescents and their coping strategies. Resilience is the phenomenon characterized by good outcomes despite serious threats to adaptation and/or development. The current study aimed to identify the coping strategy profiles that distinguish a resilient group from three other groups-struggling, competent, and vulnerable-specifically to differentiate the resilient group from the competent group. Descriptive discriminant analysis results indicated that resilient adolescents simultaneously utilized not only problem-focused but also the emotion-focused coping strategies. The competent group primarily used problem focused coping, while the struggling group primarily used emotion-focused strategies. Finally, the vulnerable adolescents used neither problem-focused nor emotion-focused strategies. Practical implications of the results were discussed to guide professionals. PMID- 28558527 TI - Framing Effect in the Trolley Problem and Footbridge Dilemma. AB - The present study investigated the effect of dilemma type, framing, and number of saved lives on moral decision making. A total of 591 undergraduates, with a mean age of 20.56 (SD = 1.37) were randomly assigned to 12 groups on the basis of a grid of two dilemma types (the trolley problem or the footbridge dilemma) by three frames (positive, neutral, or negative frame) by two different numbers of workers (5 or 15 people). The main effects of dilemma type, frame, and number of saved workers were all significant. The interaction of dilemma type and number of saved workers and the interaction of the three independent factors were significant. Results indicated that moral judgment is affected by framing. Specifically, people were more inclined to utilitarianism in the positive or neutral frame and more inclined to intuitionism in the negative frame. Furthermore, this effect can be moderated by dilemma type and number of saved lives. Implications of our results are discussed. PMID- 28558528 TI - Are Sex Effects on Ethical Decision-Making Fake or Real? A Meta-Analysis on the Contaminating Role of Social Desirability Response Bias. AB - A meta-analysis of 143 studies was conducted to explore how the social desirability response bias may influence sex effects on ratings on measures of ethical decision-making. Women rated themselves as more ethical than did men; however, this sex effect on ethical decision-making was no longer significant when social desirability response bias was controlled. The indirect questioning approach was compared with the direct measurement approach for effectiveness in controlling social desirability response bias. The indirect questioning approach was found to be more effective. PMID- 28558529 TI - Equivalence and Bias in the South African Substance Use Contextual Risk Instrument. AB - This article forms part of a larger study that sought to develop and validate a scale to measure individual and contextual factors associated with adolescent substance use in low-socio-economic status South African communities. The scale was developed to inform the process of designing preventative interventions in these communities. This study assessed the construct equivalence and item bias across different language versions of the scale. Exploratory factor analysis, equality of reliabilities, and the Tucker's phi coefficient of congruence were employed to assess whether the two language versions were equivalent at a scale level. Differential item functioning analysis was conducted using ordinal logistic regression and the Mantel-Haenszel method at an item level. The findings revealed that there are significant differences between the two groups at a scale level. Items were flagged as presenting with moderate to large differential item functioning. The biased items have to be closely examined in order to decide how to address the bias. PMID- 28558530 TI - A Multisample Analysis of Psychometric Properties for the Malaysian Adapted Sport Anxiety Scale-2 Among Youth Athletes. AB - This study examined psychometric properties of a Malaysian-language Sport Anxiety Scale-2 (SAS-2) in three separate studies. Study 1 examined the criterion validity and internal consistency of SAS-2 among 119 developmental hockey players. Measures of trait anxiety and mood states along with digit vigilance, choice reaction time, and depth perception tests were administered. Regression analysis revealed that somatic anxiety and concentration disruption were significantly associated with sustained attention. Worry was significantly associated with depth perception but not sustained attention. Pearson correlation coefficients also revealed significant relationships between SAS-2 subscales and negative mood state dimensions. Study 2 examined the convergent and discriminant validity of SAS-2 by correlating it with state anxiety measured by the CSAI-2R. Significant positive relationships were obtained between SAS-2 subscales and somatic and cognitive state anxiety. Conversely, state self-confidence was negatively related to SAS-2 subscales. In addition, significant differences were observed between men and women in somatic anxiety. Study 3 examined the factorial validity of the Malaysian SAS-2 using confirmatory factor analysis in a sample of 539 young athletes. Confirmatory factor analysis results provided strong support for the SAS-2 factor structure. Path loadings exceeding 0.5 indicated convergent validity among the subscales, and low to moderate subscale intercorrelations provided evidence of discriminant validity. Overall, the results supported the criterion and construct validity of this Malaysian-language SAS-2 instrument. PMID- 28558531 TI - Psychometric Properties of the Multi-Affect Indicator in a Chinese Worker Sample. AB - The Multi-Affect Indicator is a new measure that assesses the core affect at work with 16 items. The current study examined the scale's psychometric properties in terms of internal consistency and composite reliability, factorial validity, convergent validity, and discriminant validity with a Chinese sample of 370 full time workers. The results demonstrated that Multi-Affect Indicator has high internal consistency and composite reliability and a correlated four-quadrant structure. Furthermore, three of its four subscales show adequate convergent validity. Thus, the Chinese version of the Multi-Affect Indicator behaves consistently with the original and can be used in future studies of core workplace affect in Chinese context. PMID- 28558532 TI - Development of a Short Self-Report Disability Questionnaire for Health Conditions. AB - For use in mental epidemiological survey research, a short self-report questionnaire measuring current disability is needed to assess the severity of health symptoms of respondents. A questionnaire, measuring current disability at the somatic, mental, and social domains in the environments of work, family (social) life, and leisure time was made along guidelines issued at the 54th World Health Assembly regarding the acceptance of the International Classification of Functioning, Disability and Health. This article presents the reliability and validity of the Self-Report Disability Questionnaire (SRDQ). A short self-report questionnaire was designed and completed by an adult population sample of a Dutch health region, participating in a mental health survey. The SRDQ measures current disability independent from disorder entity. The data show good reliability. Study outcomes confirm the validity of the SRDQ. Positive correlations were found between the score on the SRDQ and amount of medical and mental health consumption, as well as evidence for divergent validity. Positive correlations emerged with the number of symptoms on various mental health measures and psychiatric comorbidity. Nonretired respondents dependent on social services, elderly respondents, and low-educated respondents are populations commonly at risk, scoring higher on the SRDQ than other populations. The SRDQ is usable both as a disability screener and as an effect instrument for treatments and community interventions because its reliability and validity are found to be good. The combined use of the SRDQ with specific symptom screeners downsizes the proportion of persons who actually need help. PMID- 28558533 TI - Relationships Among Stress, Burnout, Athletic Identity, and Athlete Satisfaction in Students at Korea's Physical Education High Schools. AB - We tested the structural relationships between stress, burnout, athletic identity, and athlete satisfaction in student athletes attending Korea's physical education high schools and analyzed the differences between paths by ego resilience. Data were collected from student athletes at three Korean physical education high schools. Before data collection, each instruments' content validity was confirmed, and after data collection, construct validity was tested using factor analysis. The results were derived using reliability testing, descriptive statistics, correlation analyses, and structural equation modeling. After testing the final research model, the following results were obtained: (a) high levels of stress had a strong correlation with burnout and high levels of burnout was negatively related to athletic identity and athlete satisfaction; (b) in our model, burnout showed full mediation of the relationship between stress and athlete identity/athletic satisfaction; and PMID- 28558534 TI - Negative Life Events, Social Support, and Self-Efficacy in Anxious Adolescents. AB - Purpose To examine the prevalence and correlates of anxiety in a community sample of adolescents. Knowing the prevalence and characteristics of anxious adolescents is valuable to improve anxiety prevention strategies and interventions. Design Cross-sectional data about anxiety were collected via a school survey from a community sample of Norwegian adolescents aged 12-17 ( N = 1719). Methods Based on scores from the Spence Children's Anxiety Scale, the adolescents were categorized as not anxious or anxious. Logistic regression analysis was performed to access the impact of each factor on the likelihood that participants would report an elevated level of anxiety. Results A total of 22% of the adolescents were categorized as anxious. Female gender, experienced negative life events, low social support, and low self-efficacy were associated with elevated level of anxiety. Conclusions The high prevalence of anxiety in adolescents demonstrates the importance of improved prevention interventions targeting anxious adolescents. We argue that addressing is the responsibility of not only the individual adolescents and their families but also schools, school health services, and policy makers. School-based interventions that increase social support and self-efficacy would probably be particularly beneficial for anxious adolescents. PMID- 28558535 TI - Unpacking the Gender Differences on Mental Health. AB - Mental health studies show that women are likely to score higher on subjective well-being and higher on depression than men. To verify this, the present study collected a sample of 5648 undergraduates in 55 universities in China. Results showed that women reported higher optimism, gratitude, subjective well-being, and depression than men, and that optimism and gratitude mediated the relationship between gender and mental health (subjective well-being and depression). By its implication, women were more likely to be optimistic and grateful, and as such they tended to experience higher subjective well-being and depression simultaneously. This also implies that gender differences on mental health could also be a dispositional issue as well as a socialization one. PMID- 28558536 TI - Diverging Influences of Money Priming on Choice. AB - Prior research on money priming has suggested two seemingly contradicting findings. On the one hand, money has been shown to highlight the importance of cost saving, leading to the choice of a low-quality/low-price option. On the other hand, individuals primed with money as a symbol of social status, and capabilities may focus on social value of money, e.g., higher spending symbolizes higher status and prefer an option with high quality/high price. Current research proposes and demonstrates that whether money priming will lead different choices depends on the nature of the consumption context. Specifically, when the product is to be consumed privately, money priming will highlight the importance of cost, thus increasing the preference for lower price at a lower quality. However, when the product is to be consumed publicly, reversed pattern of consumer preference will be found. PMID- 28558537 TI - Self-Compassion and Confucian Coping as a Predictor of Depression and Anxiety in Impoverished Chinese Undergraduates. AB - The ability of self-compassion and Confucian coping to predict anxiety and depression were examined in impoverished Chinese undergraduate students. Three hundred and thirty impoverished undergraduates completed measures of self compassion, Confucian coping, depression, and anxiety. Results showed that higher self-compassion predicted lower depression and anxiety in impoverished undergraduates. Higher pro-setback thinking and responsibility thinking of Confucian coping were related with lower depression and anxiety. Higher fate thinking of Confucian coping was related with higher depression and anxiety. The predictive ability for depression and anxiety of self-compassion combined with fate thinking was better than self-compassion alone. Intervention to enhance self compassion and reduce fate thinking may be beneficial to mental health in impoverished undergraduates. PMID- 28558538 TI - Assessment of Undergraduates' Real-World Outcomes of Critical Thinking in Everyday Situations. AB - Critical thinking is a kind of "good" thinking that integrates a set of cognitive skills and dispositions to use those skills with knowledge to increase the chances of success in academic settings, job market, and daily life. The impact of critical thinking on life events, in face of everyday decisions and challenges, is still unclear, and further research is needed. In this exploratory study, a sample of 230 first-year students of a Bachelor's Degree or a Master's Degree in Portugal completed an experimental Portuguese version of the Real-World Outcomes, a self-report inventory measuring everyday negative life events that are mediated by a lack of critical thinking. Based on exploratory factor analysis results and theoretical premises, changes were made to the Portuguese version of the inventory that was administered, and items were aggregated into six dimensions, creating a new version that is more familiar to Portuguese young adults in college. This original proposal of the inventory presents six types of negative life events resulting from a lack of critical thinking: health neglect, mismanagement, slackness, poor impulse control, academic negligence, and rashness. Both limitations and future potentialities of this version are presented. PMID- 28558539 TI - Effects of Experience Abroad and Language Proficiency on Self-Efficacy Beliefs in Language Learning. AB - Experience abroad has been recognized as one of the best investments for second or foreign language learning. A lot of research has examined its impact on language learning from linguistic as well as non-linguistic perspectives. Nonetheless, literature on the relationships between and among experience abroad, language proficiency, and self-efficacy beliefs in language learning seems to still be cursory and thus the present study chose to focus on these aspects in more detail. To do so, 259 Korean English as a foreign language students answered the Questionnaire of English Self-Efficacy as well as completed a background questionnaire. Statistical analyses identified two underlying factors of self efficacy beliefs-production and comprehension-that helped analyze the data from a new perspective. Using this two-factor structure of self-efficacy, it was found that the combination of experience abroad and English proficiency were indeed related to these self-efficacy factors. In addition, the results indicate that students may have benefitted most in self-efficacy formation in production and comprehension aspects when they have four to six months of experience abroad. PMID- 28558540 TI - Full and Short Versions of the Coping Inventory for Stressful Situations and Social Problem-Solving Inventory-Revised. AB - Inadequate problem solving is associated with recidivism in sex offenders. However, the psychometric properties of two of the most widely used coping self report questionnaires, the Social Problem-Solving Inventory-Revised and Coping Inventory for Stressful Situations, have not been established for outpatient sex offenders. Using structural equation modeling, the present study aims to contribute to an empirically based decision as to which version of the Coping Inventory for Stressful Situations or Social Problem-Solving Inventory-Revised is best suited to use with forensic outpatient sex offenders. The sample consisted of 530 Dutch sex offenders treated in an outpatient forensic facility. Results support the use of the Coping Inventory for Stressful Situations-Short Form 20 for identifying problem-solving deficits among outpatient sex offenders, consequently facilitating the assessment of treatment needs. PMID- 28558541 TI - Predictors of Mental Health Symptoms, Automatic Thoughts, and Self-Esteem Among University Students. AB - University youth is a risk group regarding mental health, and many mental health problems are frequent in this group. Sociodemographic factors such as level of income and familial factors such as relationship with father are reported to be associated with mental health symptoms, automatic thoughts, and self-esteem. Also, there are interrelations between mental health problems, automatic thoughts, and self-esteem. The extent of predictive effect of each of these variables on automatic thoughts, self-esteem, and mental health symptoms is not known. We aimed to determine the predictive factors of mental health symptoms, automatic thoughts, and self-esteem in university students. Participants were 530 students enrolled at a university in Turkey, during 2014-2015 academic year. Data were collected using the student information form, the Brief Symptom Inventory, the Automatic Thoughts Questionnaire, and the Rosenberg Self-Esteem Scale. Mental health symptoms, self-esteem, perception of the relationship with the father, and level of income as a student significantly predicted automatic thoughts. Automatic thoughts, mental health symptoms, participation in family decisions, and age had significant predictive effects on self-esteem. Finally, automatic thoughts, self-esteem, age, and perception of the relationship with the father had significant predictive effects on mental health symptoms. The predictive factors revealed in our study provide important information to practitioners and researchers by showing the elements that need to be screened for mental health of university students and issues that need to be included in counseling activities. PMID- 28558542 TI - Examining the Temporal Development of Phonetic and Lexical Learning in Second Language. AB - The purpose of this study was to investigate how second-language (L2) learners lexically encode confusable phonemes. Given the inconsistency of previous studies on whether and if so how learners can establish separate lexical representations of confusable categories, we examined (1) how phonetic categorization and lexical encoding abilities were developed at the early stage of learning and (2) whether there are any differences in those abilities between the words with a sound pair from a corresponding native language (L1)-dominant category and those lacking such category. Native speakers of Korean learned Arabic words with these two types of sound pairs for four days and then their phonetic categorization and lexical processing abilities were evaluated in AXB discrimination and lexical decision tasks, respectively. The results showed that phonetic categorization of the words with a sound pair from an L1-dominant category developed very early. With success in their discrimination abilities, L2 learners began to overcome lexical competition from the words with such a sound pair. By contrast, learners showed poor sound discrimination and lexical encoding skills for words with a sound pair lacking an L1-dominant category. This suggests that (1) L2 learners' accurate phonetic categorization abilities are prerequisite to success in L2 lexical encoding and (2) lexical representations of the L2 words with confusable phonemes depend on the distinct types of sound category matchup between L1 and L2. PMID- 28558543 TI - Socializing Agents for Sport and Physical Activities in Teenage Students: Comparative Studies in Samples From Costa Rica, Mexico, and Spain. AB - The aim of this study is to analyze a set of socializing agents for sport and physical activities and to establish their relationship with leisure time sport and physical activities behaviors and practice patterns in samples of teenage students with different sociocultural backgrounds. The sample included 2168 students in their first year of secondary education, 423 of them being from Costa Rica, 408 from Mexico, and 1337 from Spain (1052 male students, 1037 female students, and 79 students who did not specify gender) aged 11-16 years old ( M = 12.49; SD = .81). A validated questionnaire with questions about leisure time sport and physical activities and socializing agents was used. Descriptive, inferential, and multinomial logistic regression analyses were carried out with SPSS 17.0 to compare all three countries. Costa Rica had the most active students, best friends' inactivity, and unsupportive parents being the agents predicting inactivity and a low level of sport and physical activities. Mexico has a high dropout rate and inactive students exceed active ones; no agent predicts inactivity or sport and physical activities pattern. Spain has the highest level of sport and physical activities practice, and parents, siblings, and friends are predicting agents of inactivity together with unsupportive parents and friends. PMID- 28558544 TI - Differences in Young Children's Peer Preference by Inhibitory Control and Emotion Regulation. AB - This study investigated differences in young children's peer preference by inhibitory control and emotion regulation. In Study 1, 66 preschoolers ( M = 5 years 11 months) were assessed for inhibitory control (IC), emotion regulation (ER), and peer preference. Stroop-like tasks (the black-white task and shine-rain task), the disappointing gift task, and a positive nomination measure were used as measures of IC, ER, and peer preference, respectively. The results of Study 1 showed that participants with high IC or high ER were popular with their peers in comparison to participants with low IC or low ER. Study 2 measured young children's ( N = 43, M = 6 years 1 month) ER by comparing social judgment between a condition that induces negative emotion and a condition that does not. The results of Study 2 showed that participants with high IC or high ER (who could select appropriate behaviors, even when negative emotion was induced) had many mutual relations with friends compared to participants with low IC or low ER. These data indicate the role of inhibitory control and emotion regulation in young children's peer preference. PMID- 28558545 TI - Development and Validation of a Comprehensive Work-Related Needs Measure. AB - In a work context, employees tend to gravitate toward situations that are most conducive to meeting their needs. The purpose of this research is threefold. First, we define and specify the psychological needs under investigation, briefly highlight extant research, and differentiate needs from other individual difference variables. Second, we demonstrate the limitations of one of the most highly cited psychological needs instruments and introduce a new needs model. Third, we develop and evaluate a multi-dimensional needs inventory using a multi study design. The strengths and limitations of the proposed and tested model are discussed, as are implications for future research. PMID- 28558546 TI - Experiencing Instigations and Trait Aggression Contribute to Harsh Parenting Behaviors. AB - Three studies (total N = 1777 parents) examined whether harsh parenting behaviors would increase when parents experienced an instigation and whether this increase would be especially pronounced for parents who were high in trait aggression. These predictions were tested both when parents' experience of an instigation was manipulated (Studies 1 and 2) and when parents' perceptions of their child's instigating behavior was reported (Study 3). Further, these predictions were tested across a variety of measures of parents' harsh behaviors: (1) asking parents to report their likelihood of behaving harshly (Study 1), (2) using proxy tasks for parents' inclinations to behave harshly (Study 2), and (3) having parents report their past child-directed behaviors, some of which were harsh (Study 3). Both child instigations and parents' trait aggression were consistently associated with parents' child-directed harsh behaviors. However, parents' trait aggression only moderated the extent to which the instigation was associated with their harsh parenting for self-reported physical harsh behaviors (Study 1). The results of the current studies demonstrate that both situational factors, such as experiencing an instigation, and individual difference variables, such as trait aggression, affect parents' likelihood to exhibit harsh behaviors, but found little evidence these factors interact. PMID- 28558547 TI - Examining the Priority Heuristic in Conditions of Resource Need Levels. AB - Within the domain of risky decision making, there are a number of predictive models which are consistent with the hypothesis that human minds are molded for specific behavioral patterns based on environmental cues. Two models are the priority heuristic and risk sensitive foraging. Using a modified version of the traditional risky choice gambles paradigm, a study was designed to tease apart specific predictions made by each of these two models. It was discovered that the best explanation for choice behavior was consistent with risk sensitive foraging. This was true for risky preferences in gambles. Also, decision time predictions from the priority heuristic were not supported. Collectively, this may show additional support for risk-sensitivity driving some human behaviors. It may also carve out the boundaries for the proper "ecology" of the priority heuristic. PMID- 28558548 TI - The Spanish Adaptation of the Sport Motivation Scale-II in Adolescent Athletes. AB - The aim of this study was to adapt and validate the Spanish version of the Sport Motivation Scale-II (S-SMS-II) in adolescent athletes. The sample included 766 Spanish adolescents (263 females and 503 males; average age = 13.71 +/- 1.30 years old). The methodological steps established by the International Test Commission were followed. Four measurement models were compared employing the maximum likelihood estimation (with six, five, three, and two factors). Then, factorial invariance analyses were conducted and the effect sizes were calculated. Finally, the reliability was calculated using Cronbach's alpha, omega, and average variance extracted coefficients. The five-factor S-SMS-II showed the best indices of fit (Cronbach's alpha .64 to .74; goodness of fit index .971, root mean square error of approximation .044, comparative fit index .966). Factorial invariance was also verified across gender and between sport federated athletes and non-federated athletes. The proposed S-SMS-II is discussed according to previous validated versions (English, Portuguese, and Chinese). PMID- 28558549 TI - What About the Different Shortened Versions of the Mindful Attention Awareness Scale? AB - Given the mixed conclusions on the psychometric properties of the Mindful Attention Awareness Scale (MAAS) and the variety of subsets of items identified as abbreviated forms, the current study aimed to (a) further investigate the performance of single items and different combinations of items of the MAAS from within an Item Response Theory framework, (b) to expand upon existing knowledge about the coverage of the construct of the scale and its shortened versions. A sample of 914 participants (67.6% women; mean age 23.28, SD = 4.77) completed the MAAS. To fulfill the second aim of the study, of the total sample, two subsamples ( N = 156 and N = 158, respectively) were administered a battery of self-report questionnaires. Analyses attested that four items of the MAAS have weak psychometric properties and that the reliability of the scale remains unchanged when these items are excluded. The relationships with several constructs (consciousness, present-time attitude, emotional intelligence, alexithymia, emotion regulation strategies, behavioral inhibition and activation, affect, anxiety, and depression) provided evidence that the scale adequately reflects the operationalization of the construct, although some facets of the construct are only partially covered. The current findings confirm that the MAAS might be slightly shortened without reducing its reliability and validity, but drastically abbreviated forms, such as the proposed five-item version, fail to maintain adequate psychometric properties. PMID- 28558550 TI - Lack of empathy from GPs could delay cancer diagnosis. AB - Older people with cancer symptoms are more likely to seek advice if their GP is a good listener, and doctors need to improve this skill, a study suggests. PMID- 28558551 TI - Pathophysiology, assessment and treatment of coronary heart disease in women. AB - Despite improvements in mortality rates, coronary heart disease (CHD) continues to be a leading cause of death in the UK. It has a long-standing reputation as a 'male disease', and although there has been an increased interest in and awareness of the disease, CHD in women remains understudied, under-diagnosed and undertreated. This article discusses the apparent disparity in pathophysiology, symptom presentation, risk factor profile, assessment, management and outcomes between men and women in relation to CHD and acute coronary syndrome, which is an acute manifestation of CHD. PMID- 28558552 TI - The patient who transformed motor neurone disease care. AB - In March 2015, Nursing Standard published a feature about a remarkable young man called Gordon Aikman. He had been diagnosed with motor neurone disease (MND) the previous year, aged 29, while working as director of research for the Better Together campaign, ahead of the Scottish independence referendum. The Scot, pictured, knew the prognosis wasn't good, and was determined to make the most of the time he had left. PMID- 28558553 TI - Year-long weight-loss classes could prevent more illnesses. AB - Offering year-long programmes of weight loss classes could prevent hundreds of additional cases of hypertension, diabetes and heart disease. PMID- 28558555 TI - Scientists map precise timings for the spread of cancer. AB - Scientists have established precise timings in the development of a patient's cancer for the first time, dating the stages of the disease's progression. PMID- 28558554 TI - Election 2017 Party policies and the future of the NHS. AB - Isn't this meant to be the Brexit election? Where does health fit in? Polls suggest the NHS is one of the key areas of concern for voters - possibly even more than Brexit. Labour would love this election to be all about the NHS, and has produced a raft of policies that should appeal to people working in it, including free car parking and an end to pay restraint. Labour leader Jeremy Corbyn has put the NHS at the heart of his campaign, promising an extra L37 billion for it by 2022. PMID- 28558556 TI - Chronic obstructive pulmonary disease. AB - A new report on chronic obstructive pulmonary disease by the British Lung Foundation criticises the lack of progress in tackling lung disease. PMID- 28558557 TI - Promoting healthy sleep. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article discussed the stages of sleep, the factors that may influence quality of sleep, and the effects of suboptimal sleep on patients and nurses. PMID- 28558558 TI - Three cups of espresso a day may halve prostate cancer risk. AB - Drinking more than three cups of Italian-style espresso coffee every day could halve the risk of prostate cancer in men. PMID- 28558559 TI - 'Keep everything in perspective'. AB - Sue Morgan MBE trained at the University Hospital of Wales in Cardiff as a general nurse and then as a sick children's nurse. She was a ward sister before becoming a Macmillan clinical nurse specialist for teenagers and young adults with cancer. PMID- 28558560 TI - Learning how to manage perinatal mental illness. AB - With more than one in ten women developing a mental health problem during pregnancy or in the first year afterwards, healthcare professionals need the skills to be able to support them effectively. PMID- 28558564 TI - RCN invites applications for credentialing scheme. AB - The RCN is launching its new credentialing programme for nurses working at an advanced level of practice, following a successful five-month trial. PMID- 28558566 TI - Nurse describes caring for Manchester bomb victims. AB - A senior surgical ward sister has spoken of the emotional night shift caring for those injured in the Manchester Arena attack. PMID- 28558567 TI - 'PJ paralysis' campaign gets patients up and trusts moving. AB - The aims of the #EndPJparalysis campaign are simple: get patients out of bed and dressed during the day, and then into chairs, activity rooms or to dining rooms for meals. Increased activity can help recovery, reduce muscle wastage, maintain independence and lead to patients being discharged sooner. PMID- 28558569 TI - Tracking devices could cut anxiety. AB - Leading nurse dementia expert June Andrews has revealed she has asked her family to put a tracking device under her skin if she develops symptoms in later years. PMID- 28558571 TI - Nurse used online translator to communicate during nursing home shifts. AB - A nurse with 'little understanding' of English relied on Google's online translator service while working at a nursing home in Wales, inspectors found. PMID- 28558572 TI - Student life - More prizes than pitfalls in organising a conference. AB - Most students and nurses will attend conferences but far fewer will tackle arranging and presenting one. PMID- 28558573 TI - Readers' panel - Does negative media coverage put young people off nursing? AB - Our experts consider a hot topic of the day. PMID- 28558574 TI - 'Nursing is at the heart of me'. AB - My path to mental health nursing started with some of my earliest memories of my family. As a young girl, we lived in a small village where my mother was everyone's best friend and a person to go to in difficult times. PMID- 28558575 TI - Keep unfit drivers off the road. AB - 'He'd be better off on a horse,' the patient's son told me. 'At least the horse can see where it's going.' PMID- 28558577 TI - Every country must commit to improving working conditions. AB - Global institutions understand the importance of the health workforce in improving healthcare and are worried about staff shortages. PMID- 28558576 TI - Age of uncertainty. AB - The impact of Brexit on the NHS and on nursing remains a 'known unknown'. We all agree it will have an impact, but we cannot agree yet what that impact will be. The 28 April report on Brexit by the Commons health committee does a good job of sorting out the facts from the speculation. The committee points to two other 'known unknowns' that complicate an assessment of UK nursing numbers after the referendum vote to leave the European Union (EU) last June. PMID- 28558578 TI - Look after yourself. AB - Nurses in all sectors are under pressure as they respond to the rising number of patients, often with multiple problems, and the complexities of care. It is therefore important to look after yourself, both in and outside of work. PMID- 28558579 TI - 'Cringeworthy' adverts proposed for recruitment campaign cause a stir. AB - Nurses expressed outrage at 'outdated stereotypes' used in adverts proposed for a recruitment campaign, after they were released in error. PMID- 28558580 TI - Assessing an individual's fitness to be interviewed in police custody. AB - Nurses working in police custody settings may be called on to assess a detainee's fitness to be interviewed by police, for example where the person is thought to have a mental disorder or vulnerability. This article outlines the role of the custody nurse in the fitness-to-interview assessment. This assessment is complex and multifaceted. It requires custody nurses to assess a detainee's medical, mental health, educational and social history, as well as any substance misuse. It should include a mental state examination and, where appropriate, a physical examination. Fitness-to-interview decisions should be rigorous to prevent miscarriages of justice or significant harm to detainees. Custody nurses should advocate for detainees who are mentally vulnerable and ensure appropriate safeguards are in place, where necessary. Further work is required to reduce the subjectivity of the fitness-to-interview assessment, along with increased investment in appropriate adult services. Equally, custody nurses working at this advanced level of practice require relevant postgraduate knowledge and skills. PMID- 28558581 TI - Dementia may affect care. AB - RCN Congress has resolved that nurses who have dementia should be allowed to continue working (news, 24 May). PMID- 28558582 TI - Problem Solving Through Precision Oncology Copson Ellen R Problem Solving Through Precision Oncology 256pp L39.95 Clinical Publishing 9781846921117 1846921112 [Formula: see text]. AB - Offering an interesting insight into cutting-edge cancer management, this book is timely given the focus on personalised medicine and the increasing number of targeted anti-cancer agents in development and clinical practice. PMID- 28558583 TI - Dementia nurses can carry on. AB - If the person with dementia feels they want to continue and their role can be supported, why not? PMID- 28558585 TI - BECCA. AB - Created by charity Breast Cancer Care, this app aims to help people with breast cancer adapt to life after hospital treatment ends. PMID- 28558586 TI - Nurse who encouraged patients to pray was 'rightfully dismissed', tribunal rules. AB - A nurse who told a patient he would have a better chance of surviving an operation if he prayed was rightly dismissed by her trust, an employment tribunal has ruled. PMID- 28558587 TI - It's unfair to push your beliefs. AB - It was right to dismiss Sarah Kuteh as she had been warned about pushing her views on people and patients had complained about her. PMID- 28558588 TI - No time to chat. AB - Patients do often say 'the nurses are always at the nurses' station chatting and not doing anything' (Hospital visitors' experiences at the nurses' station, evidence & practice, 19 April) but this is because they don't understand that so much has to be done on the computer, such as ordering blood tests, X-rays, documenting care and much more. PMID- 28558589 TI - Poor service is not acceptable. AB - The public perception of the nurses' station should not be dismissed. We need to look at this as a profession and work out how we can improve patients' and their relatives' experience in our own areas. PMID- 28558590 TI - Nurses go above and beyond. AB - The nurses who cared for people injured in the Manchester Arena attack dug deep and pulled together just like we always do and will continue to do. PMID- 28558591 TI - Throwing money at services is not enough. AB - The general election is an opportunity for a frank public debate on the future of our health and care system, which includes addressing the pressing issue of funding services adequately over the next few years. PMID- 28558592 TI - Develop your leadership style. AB - Nursing has evolved from the days when doctors directed nurses' every move. As a registered nurse, you now make autonomous decisions and are professionally accountable for your actions and omissions. PMID- 28558593 TI - Learning through leadership. AB - Almost 800,000 nasogastric tubes are used in the NHS each year. They are used regularly in children's nursing, particularly on neonatal units and children's wards over the winter bronchiolitis season. PMID- 28558594 TI - Manchester response reveals the spirit of our NHS staff. AB - As they always do in the nation's hour of need, nurses came to the rescue last week by responding so impressively to the terrorist attack in Manchester. Staff at eight hospitals were directly involved in caring for victims, while many more played their part by providing care and emotional support to the wider community of north-west England and beyond. PMID- 28558595 TI - Prayer is part of holistic care. AB - How very sad that Sarah Kuteh was dismissed for telling a patient with cancer he would have a better chance of surviving an operation if he prayed ( see news ). We say similar things all the time in the United States. I have been a nurse for more than 20 years and have never heard anything so sad. Holistic care should include physical, social, psychological and spiritual care. PMID- 28558596 TI - Chance meeting. AB - A nursing student who had cancer as a child has been reunited with the nurse who helped save her life. PMID- 28558597 TI - 'These nurses have made a terrible situation more bearable'. AB - I was diagnosed with secondary breast cancer in June last year. Unbelievably, my husband was diagnosed with terminal cancer in July. We had married that March. Now we both have just months to live. PMID- 28558598 TI - Body cameras could improve safety for staff and patients. AB - Violence, aggression and use of restraint could be reduced by equipping nursing staff with body-worn cameras, according to a study at a psychiatric unit. PMID- 28558599 TI - NMC's education plan swaps mentors for two new roles. AB - Mentors for nursing students could be replaced with supervisors and assessors as part of the 'radical' overhaul of nurse education by the Nursing and Midwifery Council (NMC). PMID- 28558600 TI - Bullying Policies across the Lifespan. PMID- 28558601 TI - Conducting Nursing Research to Advance and Inform Health Policy. AB - The primary roles of nurse scientists in conducting health policy research are to increase knowledge in the discipline and provide evidence for informing and advancing health policies with the goal of improving the health outcomes of society. Health policy research informs, characterizes, explains, or tests hypotheses by employing a variety of research designs. Health policy research focuses on improving the access to care, the quality and cost of care, and the efficiency with which care is delivered. In this article, we explain how nurses might envision their research in a policy process framework, describe research designs that nurse researchers might use to inform and advance health policies, and provide examples of research conducted by nurse researchers to explicate key concepts in the policy process framework. Health policies are well informed and advanced when nurse researchers have a good understanding of the political process. The policy process framework provides a context for improving the focus and design of research and better explicating the connection between research evidence and policy. Nurses should focus their research on addressing problems of importance that are on the healthcare agenda, work with interdisciplinary teams of researchers, synthesize, and widely disseminate results. PMID- 28558602 TI - How Activism Features in the Career Lives of Four Generations of Canadian Nurses. AB - Recent nursing research using a critical feminist lens challenges the prevailing view of political inertia in nursing. This comparative life history study using a critical feminist lens explores the relevance of activism with four generations of Canadian nurses. Purposeful sampling of Ontario nurses resulted in 40 participants who were diverse in terms of generation, practice setting, and activist practice. Interviews and focus groups were completed with the sample of Ontario registered nurses or undergraduate and graduate nursing students: 8 Generation X, 9 Generation Y (Millennials), 20 Boomers, and 3 Overboomers. Factors such as professional norms and personal and organizational supports shaped contradictory nursing activist identities, practices, and impacts. Gendered norms, organizational dynamics, and the political landscape influenced the meanings nurses attributed to critical incidents and influences that prompted activism inside and outside the workplace, shaping the transformative potential of nursing. Despite its limitations, the study has implications for creating professional and organizational supports for consideration of health politics and policy, and spaces for dialogue to support practice and research aligned with social justice goals. PMID- 28558603 TI - Social Media Awareness and Implications in Nursing Leadership. AB - Many nursing professionals-may be reluctant to engage in or are confused about appropriate use of social media in a clinical, research, or policy context. To address this issue, we developed a study to enhance nurse leaders' facility with social media in the context of a national professional meeting. This study examined a social media campaign at the 2015 American Academy of Nursing conference. The campaign was intended to bridge the gap between active social media users and nonusers attending the conference. Following a targeted social media campaign at the American Academy of Nursing 2015 Transforming Health, Driving Policy Conference, responses to the conference evaluation questions about social media were reviewed and analyzed. Overall, evaluations were positive about the campaign; however, some conference attendees were not aware of its various components. Despite perceived barriers to its use, there is significant curiosity about social media use among nurse leaders. With the engagement of these leaders, there may be opportunities to enhance social media use at professional meetings and to make broader use of this valuable tool throughout the nursing profession. PMID- 28558605 TI - Gender, Attitudes Toward War, and Masculinities in Japan. AB - Previous studies have argued that masculinity is linked to war. We conducted a web-based survey to examine relationships between gender, attitudes toward war, and masculinities within a sample of Japanese adults of both sexes ( N = 366). Our results indicated that while men were more likely than women to accept war, the relationship between attitudes toward war and masculinities was inconclusive. Moreover, the results suggested that favorable attitudes toward war among men could be attenuated by interpersonal orientations. Based on our findings, we recommend a reexamination of attitudes toward war within the Japanese population. PMID- 28558604 TI - Hospitals Known for Nursing Excellence Perform Better on Value Based Purchasing Measures. AB - It is well-established that hospitals recognized for good nursing care - Magnet hospitals - are associated with better patient outcomes. Less is known about how Magnet hospitals compare to non-Magnets on quality measures linked to Medicare reimbursement. The purpose of this study was to determine how Magnet hospitals perform compared to matched non-Magnet hospitals on Hospital Value Based Purchasing (VBP) measures. A cross-sectional analysis of three linked data sources was performed. The sample included 3,021 non-federal acute care hospitals participating in the VBP program (323 Magnets; 2,698 non-Magnets). Propensity score matching was used to match Magnet and non-Magnet hospitals with similar hospital characteristics. After matching, linear and logistic regression models were used to examine the relationship between Magnet status and VBP performance. After matching and adjusting for hospital characteristics, Magnet recognition predicted higher scores on Total Performance (Regression Coefficient [RC] = 1.66, p < 0.05), Clinical Processes (RC = 3.85; p < 0.01), and Patient Experience (RC = 6.33; p < 0.001). The relationships between Magnet recognition and the Outcome and Efficiency domains were not statistically significant. Magnet hospitals known for nursing excellence perform better on Hospital VBP measures. As healthcare systems adapt to evolving incentives that reward value, attention to nurses at the front lines may be central to ensuring high-value care for patients. PMID- 28558606 TI - Prevalence of Personality Disorders in a General Population Among Men and Women. AB - The aim of the present study is to establish the prevalence of personality disorders (PDs) in a healthy (nonclinical) Polish population, to examine sex difference in PDs, and to show the structure of clusters which PDs form with regard to men and women. A large sample of 1460 individuals of age between 18 and 65 years was examined. The Structured Clinical Interview for Axis II was used to obtain information on PDs, the Mini International Neuropsychiatric Interview to obtain information on other disorders, and an interview to record demographic data. Results show that approximately 9% of the sample had at least one PD (the overall rate is 8.9%) and rates on sex differences in PDs are similar to other European and North American countries. The most prevalent PDs are obsessive compulsive (9.6%), narcissistic (7%), and borderline (7%). Results show the considerable comorbidity of PDs which means that about 9% of the adult population have at least one PD and in fact they display features of many specific PDs. A factor analysis revealed that 12 PDs form different clusters in men and women. PMID- 28558607 TI - Presence of Meaning in Life and Search for Meaning in Life and Relationship to Health Anxiety. AB - The present study explored presence of meaning in life, search for meaning in life, and their correlation with health anxiety. The Meaning in Life Questionnaire and the Short Health Anxiety Inventory were completed by 753 individuals. Results indicated higher presence of meaning in life was associated with lower health anxiety, while the opposite was observed for search for meaning in life. Results also revealed an interaction between presence of meaning in life and search for meaning in life, where individuals with high search for meaning in life and high presence of meaning in life had lower health anxiety than those with high search for meaning in life and low presence of meaning in life. These findings suggest that presence of meaning in life and search for meaning in life are correlates of health anxiety. PMID- 28558609 TI - Reliability and Construct Validity of the Portuguese Version of the Psychological Capital Questionnaire. AB - The Psychological Capital Questionnaire (PCQ) is the most commonly used measure for assessing psychological capital in work settings. Although several studies confirmed its factorial validity, most validation studies only examined the four factor structure preconized by Luthans, Youssef, and Avolio, not attending to empirical evidence on alternative factorial structures. The present study aimed to test the psychometric properties of the Portuguese version of the PCQ, by using two independent samples (NS1 = 542; NS2 = 115) of Portuguese employees. We conducted a series of confirmatory factor analyses and found that, unlike previous findings, a five-factor solution of the PCQ best fitted the data. The evidence obtained also supported the existence of a second-order factor, psychological capital. The coefficients of internal consistency, as measured by Cronbach's alpha, were adequate and test-retest reliability suggested that the PCQ presented a lower stability than personality factors. Convergent validity, assessed with average variance extracted, revealed problems in the optimism subscale. The discriminant validity of the PCQ was confirmed by its correlations with Positive and Negative Affect and Big Five personality factors. Hierarchical regression analyses showed that this measure has incremental validity over personality and affect when predicting job performance. PMID- 28558608 TI - Impacts of Maximizing Tendencies on Experience-Based Decisions. AB - Previous research on risky decisions has suggested that people tend to make different choices depending on whether they acquire the information from personally repeated experiences or from statistical summary descriptions. This phenomenon, called as a description-experience gap, was expected to be moderated by the individual difference in maximizing tendencies, a desire towards maximizing decisional outcome. Specifically, it was hypothesized that maximizers' willingness to engage in extensive information searching would lead maximizers to make experience-based decisions as payoff distributions were given explicitly. A total of 262 participants completed four decision problems. Results showed that maximizers, compared to non-maximizers, drew more samples before making a choice but reported lower confidence levels on both the accuracy of knowledge gained from experiences and the likelihood of satisfactory outcomes. Additionally, maximizers exhibited smaller description-experience gaps than non-maximizers as expected. The implications of the findings and unanswered questions for future research were discussed. PMID- 28558610 TI - Adult Chinese as a Second Language Learners' Willingness to Communicate in Chinese: Effects of Cultural, Affective, and Linguistic Variables. AB - The present research explored the effects of cultural, affective, and linguistic variables on adult Chinese as a second language learners' willingness to communicate in Chinese. One hundred and sixty-two Chinese as a second language learners from a Chinese university answered the Willingness to Communicate in Chinese Scale, the Intercultural Sensitivity Scale, Chinese Speaking Anxiety Scale, Chinese Learning Motivation Scale, Use of Chinese Profile, as well as the Background Questionnaire. The major findings were as follows: (1) the Willingness to Communicate in Chinese Scales were significantly negatively correlated with Chinese Speaking Anxiety Scale but positively correlated with length of stay in China and (2) Chinese Speaking Anxiety Scale was a powerful negative predictor for the overall willingness to communicate in Chinese and the Willingness to Communicate in Chinese Scales, followed by length of stay in China, Chinese Learning Motivation Scale, interaction attentiveness, and Chinese proficiency level. Apparently, students' willingness to communicate in Chinese is largely determined by their Chinese Speaking Anxiety Scale level and length of stay in China, mediated by other variables such as Chinese proficiency level and intercultural communication sensitivity level. PMID- 28558611 TI - Self-Punishment Promotes Forgiveness in the Direct and Indirect Reciprocity Contexts. AB - Most previous studies regarding self-punishment have focused on the correlation between moral emotion and self-punishment. Only a few studies have attempted to understand self-punishment from the perspective of seeking forgiveness, and no study has yet directly tested whether wrongdoers' self-punishment promotes others to forgive the wrongdoers. In three studies, the participants judged the wrongdoers' self-punishment behaviors following an unfair allocation and reported the extent to which they forgave the wrongdoers. The results demonstrated that self-punishment did promote forgiveness in both the direct (Studies 1 and 2) and indirect reciprocity (Study 3) contexts. Consistent with costly signaling theory, the costlier the self-punishment was, the stronger the effect it had on forgiveness. Moreover, communicative self-punishment had a better effect than silent self-punishment when the cost was relatively high in the direct reciprocity studies. These findings can guide us regarding how to address a damaged relationship via self-punishment when compensation is not feasible or acceptable. PMID- 28558612 TI - Recognition of Facial Expressions by Urban Internet-Addicted Left-Behind Children in China. AB - Internet addition affects facial expression recognition of individuals. However, evidences of facial expression recognition from different types of addicts are insufficient. The present study addressed the question by adopting eye-movement analytical method and focusing on the difference in facial expression recognition between internet-addicted and non-internet-addicted urban left-behind children in China. Sixty 14-year-old Chinese participants performed tasks requiring absolute recognition judgment and relative recognition judgment. The results show that the information processing mode adopted by the internet-addicted involved earlier gaze acceleration, longer fixation durations, lower fixation counts, and uniform extraction of pictorial information. The information processing mode of the non addicted showed the opposite pattern. Moreover, recognition and processing of negative emotion pictures were relatively complex, and it was especially difficult for urban internet-addicted left-behind children to process negative emotion pictures in fine judgment and processing stage of recognition on differences as demonstrated by longer fixation duration and inadequate fixation counts. PMID- 28558613 TI - Work Engagement in South Korea. AB - This study aims to validate Korean versions of the 9-item Utrecht Work Engagement Scale, testing for its factor pattern validity through Exploratory Factor Analysis and Confirmatory Factor Analysis, reliability, and convergent and discriminant validity. The 9-item Utrecht Work Engagement Scale was translated according to the guidelines of the International Test Commission and tested with two Korean samples. First, the Exploratory Factor Analysis found that both two factor and three-factor solutions were viable options with the first sample. Second, comparison validations of these two solutions were tested by confirming the dimensionality of their structures through the Confirmatory Factor Analyses with the second sample, with the conclusion that the three-factor model solution was the most parsimonious model. Finally, the three-factor model of the 9-item Utrecht Work Engagement Scale was demonstrated to have good discriminant validity and convergent validity, as well as internal consistency of its subscales. PMID- 28558614 TI - Differentiating Between Donald Trump and Hillary Clinton Voters Using Facets of Right-Wing Authoritarianism and Social-Dominance Orientation. AB - Historically, much of the research on right-wing authoritarianism and social dominance orientation has proceeded from the assumption that they are unidimensional. Recently, researchers have begun to seriously consider the possibility that they are multidimensional in nature and should be measured as such. Several studies have examined the unique relationships between right-wing authoritarianism and social dominance orientation facets and social and political outcome measures of interest. However, there have been no efforts to include the full slate of right-wing authoritarianism and social dominance orientation facets as predictors in the same model. This is problematic when investigating the discriminant validity of these facets, given the potential empirical overlap among the facets both within and across scales. We included facets of right-wing authoritarianism and social dominance orientation as predictors of U.S. voters' intentions to vote for Hillary Clinton versus Donald Trump in the 2016 Presidential Election. Data were collected in September 2016. We found evidence for the discriminant validity of several of the right-wing authoritarianism and social dominance orientation facets. PMID- 28558615 TI - Religious Fundamentalism, Humor, and Treatment Outcomes in Individuals in Court Mandated Substance Abuse Outpatient Treatment. AB - The relationship between religious fundamentalism, humor, and psychological well being was examined with a sample of individuals ( n = 109) being treated for drug abuse in a court-mandated AA outpatient program. Three separate factors of religious fundamentalism were found through exploratory factor analysis of the Revised Religious Fundamentalism Scale, and these were named Righteous-Evil Worldview, True Religion, and Scriptural Literalism. Psychological well-being of individuals in court-mandated outpatient substance abuse treatment was found to be correlated with high levels of humor but not religious fundamentalism. Psychological well-being and humor were found to be related to satisfaction with services; no relationship was found between religious fundamentalism and satisfaction with services. One factor of religious fundamentalism, Scriptural Literalism, was found to be associated with high levels of depression and paranoia/hostility. Implications of these relationships for treatment and understanding of religious fundamentalism and psychological well-being are discussed. PMID- 28558616 TI - A Mediation Model for Ideas of Reference. AB - Ideas of reference are common in human beings, but they are frequent in certain psychopathological disorders, mainly those concerning the psychotic spectrum. The purpose of this study was to attempt to construct a model predicting the appearance of ideas of reference and to test the relationship of personality (based on the Gray model), emotional, and self-consciousness variables. Five hundred and seventy-four participants (287 patients with several different psychopathological diagnoses) filled in the Referential Thinking Scale (REF), the GHQ-28, the Self-Consciousness Scale (SCS-R), and the SPSRQ Scale. The resulting model found full mediation of sensitivity to punishment, sensitivity to reward, depression, and public self-consciousness between anxiety and ideas of reference, regardless of the group they were in (patients vs. nonpatients). This result, based on the appearance of anxiety symptomatology, explains 43% of the variance in scores, showing the presence of ideas of reference and therefore enables prediction of a set of vulnerabilities (established with self-reports) which could lead to a psychological state of high general pathological risk and proneness to psychosis in particular. PMID- 28558617 TI - Social Media Use and Episodic Heavy Drinking Among Adolescents. AB - : Objectives Little is known about the consequences of adolescent social media use. The current study estimated the association between the amount of time adolescents spend on social media and the risk of episodic heavy drinking. Methods A school-based self-report cross-sectional study including 851 Norwegian middle and high school students (46.1% boys). MEASURES: frequency and quantity of social media use. Frequency of drinking four or six (girls and boys, respectively) alcoholic drinks during a single day (episodic heavy drinking). The MacArthur Scale of Subjective Social Status, the Barratt Impulsiveness Scale - Brief, the Brief Sensation Seeking Scale, the Patient Health Questionnaire-9 items for Adolescents, the Strengths and Difficulties Questionnaire Peer Relationship problems scale, gender, and school grade. Results Greater amount of time spent on social media was associated with greater likelihood of episodic heavy drinking among adolescents ( OR = 1.12, 95% CI (1.05, 1.19), p = 0.001), even after adjusting for school grade, impulsivity, sensation seeking, symptoms of depression, and peer relationship problems. Conclusion The results from the current study indicate that more time spent on social media is related to greater likelihood of episodic heavy drinking among adolescents. PMID- 28558618 TI - Mechanisms Linking Ethical Leadership to Ethical Sales Behavior. AB - This study investigated the relationship between ethical leadership and ethical sales behavior. A total of 248 matched surveys with participant responses from insurance agents and their customers were collected. The insurance agents were asked to rate the ethical leadership of their leaders, the ethical climate in their organization, and their individual moral identity. Customers were asked to rate the perceived ethical sales behavior of the insurance agents. This empirical study utilized moderated mediation techniques to analyze the data. Results indicated that ethical climate mediated the relationship between ethical leadership and ethical sales behavior when moral identity was high, however, did not when moral identity was low. The research framework including contextual effects (i.e., ethical climate) and individual differences in moral judgment (i.e., moral identity) can provide a comprehensive picture of how ethical leadership influences ethical sales behavior. Theoretical and practical implications of these findings are also discussed. PMID- 28558619 TI - Mental Toughness in South African Youth. AB - Young people are particularly vulnerable to health risk behaviors and interpersonal violence, stimulating scholars' attention towards identifying factors that may reduce the likelihood that these actions will occur. Associated with positive outcomes in a variety of domains, mental toughness in young people might protect them from engaging in potentially deleterious interpersonal or health-risk behaviors, while potentially promoting positive psychological behaviors. Within this framework, the present study investigated the relationships between mental toughness, attitudes towards physical and psychological risk-taking, and trait forgiveness in a sample of 123 (males = 54, females = 69) South African youth ( M age = 23.97 years, SD = 4.46). Univariate and multivariate analyses indicated higher levels of mental toughness were associated with being more forgiving, ([Formula: see text] = .036), perceiving physical risk-taking more positively ([Formula: see text] = .062), but having more negative attitudes towards psychological risk-taking ([Formula: see text] = .036). These findings give credence to mental toughness as a psychological characteristic involved in youth risk-taking perceptions and interpersonal functioning. Future research might explore the integration of mental toughness into the development of future youth risk behavior interventions. PMID- 28558620 TI - Children With Developmental Coordination Disorder. AB - This study tested the effect of task-specific training of a perceptual ability for children with Developmental Coordination Disorder (DCD) compared to control children. A manual matching task (target location and pointing task) was used, which required the children to locate target pins either visually (seen target) or proprioceptively (felt target), while matching to the located target was always carried out without vision. Thirty-one children (11-12 years) were selected based on teacher statements regarding everyday motor skill performance, the DSM-IV criteria, and the Movement ABC test. Based on this, 10 children with obvious motor problems were placed in the DCD group (Trg-DCD), 9 children with no identified motor problems were placed in a training group (Trg-N), and 12 children also with no identified motor problems were placed in a control group. All the children were tested pre and post to training on a manual matching task. In the pretest, the children in the DCD group were significantly inferior to the control groups in the proprioceptive condition with both the preferred and nonpreferred hands. In the posttest, after the training periode was completed, the DCD subjects showed significant improvement in the proprioceptive condition for both preferred and nonpreferred hands. For the other groups, no significant training effects were observed across the training period. It is concluded that children in the DCD group may benefit from specific training of perceptual abilities, because they have motor control resources not exploited due to a lack of relevant experience. PMID- 28558621 TI - Physical Activity Levels and Well-Being in Older Adults. AB - The objective of this study was to identify the interconnectedness of different intensity levels of physical activity and psychological (life satisfaction and positive affect) and physical (physical health) well-being. Participants were from the National Study of Midlife in the United States with assessments in 2004 and aged 25 to 74 living in the United States were included in the analyses. We conducted bivariate correlations to examine significant relationships among the study variables. In addition, after multicollinearity among the independent variable was checked, a series of hierarchical regression analyses with physical health, positive affect, and life satisfaction as criterion variables were conducted. The results showed that light physical activities were positively associated with physical health and life satisfaction in summer, whereas light physical activities and all dependent variables were positively correlated in winter. Furthermore, engaging in moderate physical activities was positively related only with physical health. Meanwhile, vigorous physical activities were not associated with life satisfaction, physical health, and positive affect in summer and winter. PMID- 28558622 TI - Translation and Initial Validation of the Japanese Version of the Self-Beliefs Related to Social Anxiety Scale. AB - Cognitive models of social anxiety posit that there are several types of maladaptive beliefs responsible for persistent social anxiety. Although these beliefs are theoretically important, currently there is no validated measure of these beliefs in Japan. In the present study, we translated into Japanese a well validated measure of these beliefs, the Self-Beliefs Related to Social Anxiety (SBSA) Scale. The psychometric properties of the scale were also examined in two nonclinical samples ( ns = 401 and 30). Using confirmatory factor analysis, the Japanese version of the SBSA was found to have a correlated three-factor structure that consisted of "conditional beliefs," "unconditional beliefs," and "high standard beliefs." In addition, the Japanese version of the SBSA and its subscales demonstrated good internal consistency reliability and test-retest reliability. The Japanese version of the SBSA also demonstrated good convergent and divergent validity. Future applications of the Japanese version of the SBSA are discussed. PMID- 28558623 TI - Is Trypophobia a Phobia? AB - In the past 10 years, thousands of people have claimed to be affected by trypophobia, which is the fear of objects with small holes. Recent research suggests that people do not fear the holes; rather, images of clustered holes, which share basic visual characteristics with venomous organisms, lead to nonconscious fear. In the present study, both self-reported measures and the Preschool Single Category Implicit Association Test were adapted for use with preschoolers to investigate whether discomfort related to trypophobic stimuli was grounded in their visual features or based on a nonconsciously associated fear of venomous animals. The results indicated that trypophobic stimuli were associated with discomfort in children. This discomfort seemed to be related to the typical visual characteristics and pattern properties of trypophobic stimuli rather than to nonconscious associations with venomous animals. The association between trypophobic stimuli and venomous animals vanished when the typical visual characteristics of trypophobic features were removed from colored photos of venomous animals. Thus, the discomfort felt toward trypophobic images might be an instinctive response to their visual characteristics rather than the result of a learned but nonconscious association with venomous animals. Therefore, it is questionable whether it is justified to legitimize trypophobia. PMID- 28558624 TI - Contribution of Analyses on Triadic Relationships to Diagnostics and Treatment Planning in Developmental Psychopathology. AB - Recent clinical and theoretical research in the field of developmental psychopathology has focused on the importance of interactions in a child's development. The literature has investigated how children's early relationships contribute to the structure and expression of any subsequent psychological problems. The main focus of this pilot study is the application of the Lausanne Trilogue Play paradigm as part of psychodiagnostic assessments to elucidate family functioning in clinical settings. The research aims particularly to observe the characteristics of a family's interactions in the light of their child's psychopathological symptoms, based on a sample of 38 families with school age children referred to a Neuropsychiatry Unit for Children and Adolescents for emotional or behavioral problems. The children's psychopathological symptoms were assessed by administering the Child Behavior Check List to their parents. Triadic family interactions were observed using the Lausanne Trilogue Play procedure. Statistically significant relationships emerged between the family's interaction patterns and the child's externalizing and internalizing problems, suggesting an interdependence between these relational and individual factors in the development of the young person's psychopathology. The clinical and therapeutic implications of these findings are discussed. PMID- 28558625 TI - The Effects of Writing Anxiety and Motivation on EFL College Students' Self Evaluative Judgments of Corrective Feedback. AB - Feedback is regarded as a way to foster students' motivation and to ensure linguistic accuracy. However, mixed findings are reported in the research on written corrective feedback because of its multifaceted nature and its correlations with learners' individual differences. It is necessary, therefore, to conduct further research on corrective feedback from the student's perspective and to examine how individual differences in terms of factors such as writing anxiety and motivation predict learners' self-evaluative judgments of both teacher-corrected and peer-corrected feedback. For this study, 158 Taiwanese college sophomores participated in a survey that comprised three questionnaires. Results demonstrated that intrinsic motivation and different types of writing anxiety predicted English as foreign language learners' evaluative judgments of teacher and peer feedback. The findings have implications for English-writing instruction. PMID- 28558626 TI - An Update on Using the Range to Estimate sigma When Determining Sample Sizes. AB - In this research, we develop a strategy for using a range estimator of sigma when determining a sample size for estimating a mean. Previous research by Rhiel is extended to provide dn values for use in calculating a range estimate of sigma when working with sampling frames up to size 1,000,000. This allows the use of the range estimator of sigma with "big data." A strategy is presented for using the range estimator of sigma for determining sample sizes based on the dn values developed in this study. PMID- 28558627 TI - Interest Rate Demands and Television Viewing-Is a Single Exposure More Influential Than Routine Viewing? AB - This study examined the impact of media consumption, and particularly exposure to television, on decisions regarding interest rate demands. One hundred and fifty four participants were randomly divided into two groups: in the manipulation group, participants were exposed to a news clip about an Iranian nuclear attack on Israel, whereas in the control group, the participants were not exposed to the film. Both groups filled a questionnaires regarding their interest rate requirements in different situations, their media conception behaviors, and demographic questionnaires. Frequent routine viewing increased the interest rate demands only among participants in the manipulation group, but the manipulation itself did not have a significant effect on interest rate demands. The results are explained in terms of cultivation theory. PMID- 28558628 TI - The HEXACO Model of Personality and Risky Driving Behavior. AB - This research tested the association between the HEXACO personality model and risky driving behavior as well as the predictive power of the HEXACO model in explaining risky driving behavior compared with the Big Five model. In Sample 1, 227 undergraduate students completed measures of the HEXACO personality model, the Big Five model, and driving aggression. In Sample 2, 244 community respondents completed measures of the HEXACO personality model, the Big Five model, and driving styles. Results showed that the Honesty-Humility factor is an important addition to personality models that aim to explain risky driving behavior as being related to all forms of driving aggression as well as to maladaptive and adaptive driving styles and having incremental validity in predicting verbally aggressive expression, risky driving, high-velocity driving, and careful driving. Moreover, compared with the Big Five model, the HEXACO model had better predictive power of aggressive driving. PMID- 28558629 TI - Quinoline, Coumarin and Other Heterocyclic Analogs Based HIV-1 Integrase Inhibitors. AB - Human Immunodeficiency Virus Type 1 Integrase or HIV-1 integrase (IN) is a 288 amino acid protein that incorporates the retrotranscribed viral DNA into the host chromosomal DNA. Over the past 30 years, large number of derivatives have been evaluated for their inhibitory potential against IN. There is vast literature available which need to be collated to help scientists plan the future drug design. This review discusses the reports of past 25 years on analogs of quinoline, coumarin and other related heterocycles, which exhibit low micromolar inhibitory potency against IN. PMID- 28558630 TI - Leukopenia Associated with Risperidone Treatment. AB - Risperidone is an atypical antipsychotic agent that was originally approved by the United States Food and Drug Adminstration for the treatment of schizophrenia. There are many side effects that are frequently associated with the use of risperidone. These include weight gain, anxiety, extra-pyramidal side effects, and elevated prolactin levels. More infrequently, the use of risperidone has been linked to leukopenia. We will now present the case of a 66-year-old gentleman who developed leukopenia after the initiation of risperidone to control agitation due to delirium. We will review the previous cases of leukopenia associated with risperidone, and will review possible risk factors for the development of leukopenia, based on the reported cases. PMID- 28558631 TI - Ursolic Acid Mediates Hepatic Protection through Enhancing of anti-aging Biomarkers. AB - BACKGROUND: Age-associated loss of liver function has been recognized for decades. But, the mechanism driving liver regeneration and its decline with age remains elusive. OBJECTIVE: Hence, to support of our previous studies about anti aging effects of Ursolic Acid (UA), a compound which is extensively present in apple peels. The aim of this study is to address whether UA might alter sensors of the cell metabolic state such as SIRT1, SIRT6, PGC-1beta and Klotho proteins. METHODS: To evaluate the effect of UA on hepatic indicated proteins, mice were administrated with UA twice daily for 7 days. The involvements of these proteins in the UA-mediated effect harmony hepatic protection were investigated by immunofluorescence microscopy technique. RESULTS: Our findings clearly illustrated that UA enhanced SIRT1 (~ 5 +/- 0.2 folds) and SIRT6 (~ 8 +/- 0.5 folds) proteins levels in hepatic, p<0.001. In addition, the data showed that UA increased PGC-1beta (~ 7 +/- 0.4 folds) protein overexpression, p<0.001. Moreover, we showed that UA upregulated Klotho (~ 3.5 +/- 0.2 folds) protein in order to improve hepatic performance, p<0.01. CONCLUSION: Our results suggest that UA through increasing of SIRT1 up-regulation ameliorate reverse cholesterol transport, fatty acid use and oxidative stress defense. In addition, it seems that UA by enhancing of SIRT6 expression promotes cholesterol homeostasis through repressing SREBP1 and SREBP2. Reciprocally, UA might be involved in VLDL synthesis and exportation through PGC-1beta up-regulation. Finally, UA might be as key regulators of mineral homeostasis and bile acid/cholesterol metabolism, by inducing Klotho overexpression. PMID- 28558632 TI - Thyroglobulin Determination in Fine Needle Aspiration Biopsy Washout of Suspicious Lymph Nodes in Thyroid Carcinoma Follow up. AB - BACKGROUND: Differentiated thyroid carcinomas (DTCs) account for about 1% of all human malignancies. Cervical lymph nodes metastases and recurrences in the thyroid bed frequently occur. Furthermore, about 10-15% of patients develop distant metastases. Therefore, patients must undergo life-long follow-up. OBJECTIVE: The aim of this study was to evaluate the usefulness of Thyroglobulin measurement in FNAB washout (FNAB-Tg) in the detection of local metastasis in patients affected by or evaluated for thyroid cancer. MATERIALS AND METHODS: In a 3-year period, a total of 83 consecutive patients coming to our attention at the Ear-Nose-Throat (ENT) Outpatients Service of the National Cancer Research Center "Istituto Tumori Giovanni Paolo II" of Bari, Italy, because of the finding of one or more cervical lymph node(s), were enrolled in the study. After collection of the cytological specimen, the needle used for performing FNAB was then washed in 1 ml of normal saline. 89 FNAB washouts were collected from the same number of lymph nodes and subsequently investigated for Thyroglobulin levels using a sequential chemiluminescent-immunometric assay. RESULTS: Comparing the cytological or, when performed, histological diagnoses with the results of FNAB Tg, we found that in 24 cases of lymph node metastases from PTC (19 lymph nodes from patients at the first diagnoses and 5 lymph nodes from PTC patients in follow up) the mean level of Thyroglobulin was 1840.11 ng/ml; range: <0,2 to 11440 ng/ml. In the group of PTC patients (27 lymph nodes) with lymph nodes negative for metastatic involvement at cytology (i.e. no lymph node recurrence at follow-up), as well as in the cases of subjects without PTC and submitted to FNAB because of the appearance of lymph node(s) classified as reactive at cytology (37 lymph nodes), FNAB-Tg was lower than or equal to 0.2 ng/ml. As expected, the Thyroglobulin level was not detectable (< 0.2 ng/ml) also in a lymph node FNAB from a case of anaplastic thyroid carcinoma. CONCLUSION: In our study, FNAB-Tg was not detectable in all node negative patients showing, when considering together all the lymph node metastases, a 96% sensitivity and 100% specificity. PMID- 28558633 TI - Impact of Drug Metabolism/Pharmacokinetics and their Relevance Upon Salviabased Drug Discovery. AB - BACKGROUND: Salvia is the largest genus of family Lamiaceae and has nearly 1000 species. This genus produces several representative phytometabolites, e.g., diterpenoids and phenolic acids. The traditional uses in ethnomedicine and contemporary experimental studies have corroborated extensive therapeutic efficacy of Salvia plants. Drug metabolism and pharmacokinetic (DMPK) studies of Salvia natural products and their derivatives are indispensable in the optimization of lead compounds. New chemical entity with improved DMPK profiles is preferred. So far, there are few summaries concerning about the DMPK features of Salvia derived medicinal compounds. Tanshinones and Salvianolic acids raise concerns of herb-drug interaction. DMPK studies of various Salvia species, especially Salvia miltiorrhiza, are swiftly increasing. OBJECTIVE: Here, the latest awareness, as well as the gaps of the DMPK issues in drug development and clinical usage of Salvia compounds, was highlighted. CONCLUSION: Herb-herb interactions of Salvia-containing traditional Chinese medicine (TCM) medicine pair/formula significantly impact the PK/pharmacodynamic performance of compounds thereof, which may inspire researchers to develop novel herbal formula. While the absorption, distribution, metabolism, elimination and toxicity (ADME/T) of some tanshinones and Salvianolic acids have been outlined, DMPK studies should be extended to more compounds, Salvia species, and Salvia-containing formulations. In the context of systems pharmacology, the DMPK knowledgebase is expected to streamline the Salvia-based drug discovery and development. PMID- 28558635 TI - Recent Technology Development for the Biosynthesis of Human Milk Oligosaccharide. AB - BACKGROUND: Human milk oligosaccharide (HMO) is a third most abundant component in breast milk. HMOs are molecules naturally tailored to the need of an infant. They protect infants from diseases, foster healthy gastrointestinal systems, reinforce fledgling immune function, and promote early brain development. Supplement HMOs to infant formula, which lack this critical element, would substantially improve the function of formula. Overwhelming evidence also indicate that HMOs can be used for the treatment of arthritis and related autoimmune disease, and inhibition of bacteria adhesion or as potential prebiotics. The prospect of using HMO in these applications has stimulated worldwide interest in developing synthesis technology for these valuable products. METHODS: As the quantities extracted from human milk are limited, and chemical synthesis methods are time-consuming, costly, and complex, biotechnological approach, involving either enzyme catalysis or metabolically engineered bacteria is preferred. In this review, we highlight the most recent advances in the synthesis technologies, as disclosed in patents and patent applications, and analyze these technologies against those reported in literatures. CONCLUSION: Significant progress has been made over the past decade, especially in whole-cell biocatalysis for smaller HMOs. Significant challenges remain for larger and more complex HMOs. PMID- 28558636 TI - beta-Amyloid Upregulates Intracellular Clusterin but not Secretory Clusterin in Primary Cultured Neurons and APP Mice. AB - BACKGROUND: Previous studies have suggested that the expression of Abeta and clusterin is positively correlated. However, the causal relationship between Abeta and clusterin has not been exactly clarified. METHODS: In this study, primary hippocampal neurons were treated with Abeta42; clusterin mRNA and protein expression was assessed. Furthermore, we evaluated Abeta and clusterin protein expression in the brains of APP/PSEN1 mice, as well as serum clusterin concentration. RESULTS: We observed here that the exposure of primary hippocampal neurons to Abeta42 induced an overexpression of intracellular clusterin, but the level of clusterin in supernatants was not changed. Moreover, in APP/PSEN1 mice, there was a significant increase in intracellular clusterin in cortex and hippocampus, compared to age-matched WT mice, while serum clusterin level in APP/PSEN1 mice and in WT mice has no significant difference. CONCLUSION: Abeta42 upregulated intracellular clusterin, but secretory clusterin did not change. These findings reveal that clusterin is upregulated by Abeta and is responsive to AD pathology, although plasma clusterin concentration is not evidenced to be a stand-alone biomarker for AD. PMID- 28558638 TI - Heart Rate Variability Indexes in Dementia: A Systematic Review with a Quantitative Analysis. AB - BACKGROUND: Decreased heart rate variability (HRV) indexes indicate low vagal activity and may be associated with development of dementia. The neurodegenerative process is associated with the cardiovascular autonomic control. OBJECTIVE: The aim of this systematic review was to investigate the effect size (ES) magnitude of the HRV indexes in the evaluation of autonomic dysfunction in older persons with dementia. METHODS: PubMed (Medline), Web of Science, Scopus, Scielo, Lilacs, and APA Psycnet were consulted. Complete original articles published in English or Portuguese, investigating the association between autonomic dysfunction and dementia, using the HRV indexes were included. RESULTS: The search identified 97 potentially relevant articles. After screening the full text, eight articles were included in the qualitative analysis and six were included in the quantitative analysis. Almost all indexes showed a negative ES for all types of dementia and mild cognitive impairment. The most common frequency band of the power spectrum density function was the high frequency, which was reported by six studies. The meta-analysis of high frequency power in Alzheimer's disease group showed high heterogeneity and inconsistent results. CONCLUSION: The negative effect size suggests an autonomic dysfunction in all types of dementia as well as mild cognitive impairment. However, further analysis is necessary to support these results. PMID- 28558637 TI - The Cognitive Effects of Wearable Cameras in Mild Alzheimer Disease - An Experimental Study. AB - BACKGROUND: Wearable cameras are a new type of intervention aimed at stimulating memory in Alzheimer's disease (AD). Such passive external memory aids have started to be considered as alternatives to both more active external aids (such as writing in diaries, journals, and timetables) and to internal cognitive strategies (such as spaced retrieval, errorless learning). OBJECTIVE: In order to understand the benefits of these innovative devices for memory compensation, the present experiment examined the effectiveness of two memory training strategies: SenseCam, a wearable camera, a passive external memory aid and a memory training programme (MEMO+) created from tasks known to stimulate memory, in comparison with a control condition, a personal written diary. METHOD: Fifty-one patients with mild AD were randomly assigned to one of these three groups. Training lasted for six consecutive weeks, two sessions a week, one hour each, for all groups. Patients underwent a neuropsychological assessment at baseline, after treatment and at follow up (six months later). RESULTS: Groups showed non-significant differences at baseline. After treatment and at follow up, the SenseCam group had a superior autobiographical memory (AM) performance, compared to the Memo+ and Diary groups. The SenseCam and the Memo+ groups both showed improved episodic and semantic memory, and somewhat improved executive function. CONCLUSION: Our results suggest that passive memory training with SenseCam is a promising alternative to traditional memory training programs to help AD patients with autobiographical memory performance. PMID- 28558634 TI - Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery. AB - BACKGROUND: Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion. One such mechanism capitalizes on the body's natural defense against xenobiotics by increasing the rate of xenobiotic efflux and metabolic inactivation. Xenobiotic metabolism typically involves conversion of parent molecules to more soluble and easily excreted derivatives in reactions catalyzed by Phase I and Phase II drug metabolizing enzymes. METHODS: We performed a structured search of peer-reviewed literature on P450 (CYP) 3A, with a focus on CYP3A4 and CYP3A5. RESULTS: Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers. Such components include the pregnane X receptor (PXR), CYP3A4 and CYP3A5 enzymes. The CYP3A enzymes are a subset of the numerous enzymes that are transcriptionally activated following the interaction of PXR and many ligands. CONCLUSION: Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them. PMID- 28558639 TI - EDITORIAL: Current Views on Neurodegeneration: Computational to Clinical Research. PMID- 28558640 TI - Biosensors for Screening Kinase Inhibitors. AB - For successful drug discovery it is important to understand the fundamentals of the underlying causes and consequences of the diseases for which the drug is being developed. One such physiological process in eukaryotic cells is protein phosphorylation, which is the main post-translational modification of proteins responsible for the onset or progression of Alzheimer's disease, diabetes and various cancers. Protein phosphorylation is facilitated by kinases and inhibitors of kinases act as drugs in controlling or curing these diseases by reducing protein phosphorylation. This review discusses the technologies capable of detecting kinase activity and screening candidate compounds to identify novel inhibitors of protein kinases. PMID- 28558641 TI - High Incidence of Infections in HIV-positive Patients Treated for Lymphoproliferative Disorders. AB - BACKGROUND: Lymphoproliferative disorders are frequently diagnosed in HIV positive patients and severe infections may occur during antineoplastic treatments: the incidence and impact of such events are not well-characterized. OBJECTIVE: To describe the occurrence and mortality of incident infections in HIV positive individuals treated for lymphoproliferative disorders. METHODS: A retrospective study in HIV-positive adults with lymphoproliferative disorders (2000- 2012) who were hospitalised to receive antineoplastic chemotherapy; antimicrobial prophylaxis with alternate day co-trimoxazole (800/160 mg) was administered to all individuals. RESULTS: 103 patients were included: mostly males (81, 78.6%), Caucasians (101, 98.1%), with a median age of 43 years (39 51). Fifty-eight (56.3%) patients had non-Hodgkin's lymphoma (NHL), thirty-two (29.1%) had Hodgkin's lymphoma (HL) and ten patients (9.7%) had Burkitt's lymphoma (BL). Five year survival was 63.1%: the best survival rates were reported in HL (78.1%), followed by NHL (58.6%) and BL (50%). Forty-four patients (42.7%) developed 82 infections during follow up: identified causative agents were bacteria (35, 42.7%), viruses (28, 34.1%), mycobacteria (7, 8.5%), protozoa (7, 8.5%) and fungi (5, 6.1%). Cytomegalovirus infections (n=17, including 5 endorgan diseases) emerged 53 days after the diagnosis: multivariate analysis showed CD4+ cell count <100/uL as the only independently associated factor (p<0.001, aOR=23.5). Two factors were associated with mortality risk: an IPI/IPS score of >2 (p=0.004, aOR=6.55) and the presence of CMV disease (p=0.032, aOR=2.73). CONCLUSION: HIV positive patients receiving treatment for lymphoproliferative disorders suffer from a high incidence of infections and associated mortality risk. Tailored prophylactic strategies need to be considered in this setting. PMID- 28558642 TI - Ethanolic Extract of Berberis Vulgaris Fruits Inhibits the Proliferation of MCF-7 Breast Cancer Cell Line Through Induction of Apoptosis AB - BACKGROUND: As it is obvious, there is much documentation that shows the importance of breast cancer treatment in patients. High expressions of P53 and Bcl-2 are associated with breast cancer, which are reliable factors to follow up thebreast cancer. Berberis vulgaris is used as a traditional medicine in cancer. Despite of the fact that many researches have demonstrated its anti-cancer properties, there are no scientific documents to show its efficacy in detail in breast cancer. OBJECTIVE: Because of traditional use of B. vulgaris and little knowledge about its effects, our research was focused on determining the efficacy and toxicity of B. vulgaris. For this reason, we determined the efficacy of B. vulgaris on breast cancer cells. METHOD: As described in Method section, standard protocols including MTT assay and qPCR were performed to identify the effect of B. vulgaris ethanolic extract against breast cancer cells. RESULTS: Our results clearly demonstrated that 35 mg/ml had IC50 against 3t3 normal cells, and 9 mg/ml of B. vulgaris was effective against MCF-7 breast cancer cells. The results demonstrated that even at only 1 mg/ml concentration of B. vulgaris, crude extract was effective, 9 mg/ml and 12 mg/ml of extract had better anti-cancer activity compared with doxorubicin. CONCLUSION: Despite that the role of anticancer properties of B. vulgaris was clearly defined in some patents, our results demonstrated the potency of B. vulgaris against breast cancer, but further analysis should be performed to candidate this herb as an anti-breast cancer drug. PMID- 28558643 TI - Expression of Major Efflux Pumps in Fluconazole-Resistant Candida albicans. AB - INTRODUCTION: Resistance to azole antifungals is considered as a significant problem in Candida albicans infections. Several molecular mechanisms of fluconazole resistance including alterations in the gene encoding the target enzyme ERG11 or overexpression of efflux pump genes including CDR1, CDR2, MDR1, MDR2 and FLU1 have been reported. The aim of this study was to investigate overexpression of efflux pump genes including CDR1, CDR2, MDR1, MDR2 and FLU1 in fluconazole- resistant C. albicans. MATERIAL AND METHODS: In this study, a total of 97 clinical isolates of C. albicans were isolated from hospitalized children in Children medical center, an Iranian referral hospital. Fluconazole susceptibility testing of C. albicans was performed using the broth microdilution method according to the CLSI guideline. Expression of CDR1, CDR2, MDR1, MDR2 and FLU1 genes was measured using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) and 18SrRNA gene was used as a housekeeping gene. RESULTS: Among 97 C. albicans isolates, 5 strains were categorized as fluconazoleresistant. Overexpression of CDR1, CDR2 and MDR2 genes was found in all isolates. MDR1 overexpression was observed in four resistant isolates. None of the resistant strains displayed increases in FLU1 transcript levels. CONCLUSION: Overexpression of the CDR1, CDR2, MDR1 and MDR2 genes might play an important role in fluconazole-resistant C. albicans. No link between expression of FLU1 and fluconazole resistance was found. PMID- 28558644 TI - A Case of Subcutaneous Phaeohyphomycosis Associated with Leprosy. AB - BACKGROUND: Subcutaneous phaeohyphomycosis is an infection caused by melanized fungi and is increasingly reported among immunosuppressive patients. The most commonly cited etiologic agent is Exophiala jeanselmei, followed by Alternaria spp. We present a case of subcutaneous phaeohyphomycosis in a 48-yearold woman, with a history of lepromatous leprosy, using corticosteroid in immunosuppressive doses due to a type 2 repetitive reaction leprosy outbreak. RESULT AND DISCUSSION: The diagnosis was confirmed by fine-needle aspiration of the secretion, with subsequent direct mycological observations, culture and molecular analysis. The species agent was identified by culture and nucleotide sequences of ribosomal DNA as Exophiala dermatitidis. PMID- 28558645 TI - EDITORIAL: Recent Contributions of Medicinal Chemistry to Nano Drug Delivery Systems and Bio-Conjugates. PMID- 28558646 TI - Microevolution of the noble crayfish (Astacus astacus) in the Southern Balkan Peninsula. AB - BACKGROUND: The noble crayfish (Astacus astacus) displays a complex historical and contemporary genetic status in Europe. The species divergence has been shaped by geological events (i.e. Pleistocene glaciations) and humanly induced impacts (i.e. translocations, pollution, etc.) on its populations due to species commercial value and its niche degradation. Until now, limited genetic information has been procured for the Balkan area and especially for the southernmost distribution of this species (i.e. Greece). It is well known that the rich habitat diversity of the Balkan Peninsula offers suitable conditions for genetically diversified populations. Thus, the present manuscript revisits the phylogenetic relationships of the noble crayfish in Europe and identifies the genetic make-up and the biogeographical patterns of the species in its southern range limit. RESULTS: Mitochondrial markers (i.e. COI and 16S) were used in order to elucidate the genetic structure and diversity of the noble crayfish in Europe. Two of the six European haplotypic lineages, were found exclusively in Greece. These two lineages exhibited greater haplotypic richness when compared with the rest four (of "Central European" origin) while they showed high genetic diversity. Divergence time analysis identified that the majority of this divergence was captured through Pleistocene, suggesting a southern glacial refugium (Greece, southern Balkans). Furthermore, six microsatellite markers were used in order to define the factors affecting the genetic structure and demographic history of the species in Greece. The population structure analysis revealed six to nine genetic clusters and eight putative genetic barriers. Evidence of bottleneck effects in the last ~5000 years (due to climatic and geological events and human activities) is also afforded. Findings from several other research fields (e.g. life sciences, geology or even archaeology) have been utilized to perceive the genetic make-up of the noble crayfish. CONCLUSIONS: The southernmost part of Balkans has played a major role as a glacial refugium for A. astacus. Such refugia have served as centres of expansion to northern regions. Recent history of the noble crayfish in southern Balkans reveals the influence of environmental (climate, geology and/or topology) and anthropogenic factors. PMID- 28558647 TI - Hapl-o-Mat: open-source software for HLA haplotype frequency estimation from ambiguous and heterogeneous data. AB - BACKGROUND: Knowledge of HLA haplotypes is helpful in many settings as disease association studies, population genetics, or hematopoietic stem cell transplantation. Regarding the recruitment of unrelated hematopoietic stem cell donors, HLA haplotype frequencies of specific populations are used to optimize both donor searches for individual patients and strategic donor registry planning. However, the estimation of haplotype frequencies from HLA genotyping data is challenged by the large amount of genotype data, the complex HLA nomenclature, and the heterogeneous and ambiguous nature of typing records. RESULTS: To meet these challenges, we have developed the open-source software Hapl-o-Mat. It estimates haplotype frequencies from population data including an arbitrary number of loci using an expectation-maximization algorithm. Its key features are the processing of different HLA typing resolutions within a given population sample and the handling of ambiguities recorded via multiple allele codes or genotype list strings. Implemented in C++, Hapl-o-Mat facilitates efficient haplotype frequency estimation from large amounts of genotype data. We demonstrate its accuracy and performance on the basis of artificial and real genotype data. CONCLUSIONS: Hapl-o-Mat is a versatile and efficient software for HLA haplotype frequency estimation. Its capability of processing various forms of HLA genotype data allows for a straightforward haplotype frequency estimation from typing records usually found in stem cell donor registries. PMID- 28558648 TI - Geographical structure of endosymbiotic bacteria hosted by Bathymodiolus mussels at eastern Pacific hydrothermal vents. AB - BACKGROUND: Chemolithoautotrophic primary production sustains dense invertebrate communities at deep-sea hydrothermal vents and hydrocarbon seeps. Symbiotic bacteria that oxidize dissolved sulfur, methane, and hydrogen gases nourish bathymodiolin mussels that thrive in these environments worldwide. The mussel symbionts are newly acquired in each generation via infection by free-living forms. This study examined geographical subdivision of the thiotrophic endosymbionts hosted by Bathymodiolus mussels living along the eastern Pacific hydrothermal vents. High-throughput sequencing data of 16S ribosomal RNA encoding gene and fragments of six protein-coding genes of symbionts were examined in the samples collected from nine vent localities at the East Pacific Rise, Galapagos Rift, and Pacific-Antarctic Ridge. RESULTS: Both of the parapatric sister species, B. thermophilus and B. antarcticus, hosted the same numerically dominant phylotype of thiotrophic Gammaproteobacteria. However, sequences from six protein coding genes revealed highly divergent symbiont lineages living north and south of the Easter Microplate and hosted by these two Bathymodiolus mussel species. High heterogeneity of symbiont haplotypes among host individuals sampled from the same location suggested that stochasticity associated with initial infections was amplified as symbionts proliferated within the host individuals. The mussel species presently contact one another and hybridize along the Easter Microplate, but the northern and southern symbionts appear to be completely isolated. Vicariance associated with orogeny of the Easter Microplate region, 2.5-5.3 million years ago, may have initiated isolation of the symbiont and host populations. Estimates of synonymous substitution rates for the protein-coding bacterial genes examined in this study were 0.77-1.62%/nucleotide/million years. CONCLUSIONS: Our present study reports the most comprehensive population genetic analyses of the chemosynthetic endosymbiotic bacteria based on high-throughput genetic data and extensive geographical sampling to date, and demonstrates the role of the geographical features, the Easter Microplate and geographical distance, in the intraspecific divergence of this bacterial species along the mid ocean ridge axes in the eastern Pacific. Altogether, our results provide insights into extrinsic and intrinsic factors affecting the dispersal and evolution of chemosynthetic symbiotic partners in the hydrothermal vents along the eastern Pacific Ocean. PMID- 28558649 TI - Long-term leukocyte reconstitution in NSG mice transplanted with human cord blood hematopoietic stem and progenitor cells. AB - BACKGROUND: Humanized mice (hu mice) are based on the transplantation of hematopoietic stem and progenitor cells into immunodeficient mice and have become important pre-clinical models for biomedical research. However, data about their hematopoiesis over time are scarce. We therefore characterized leukocyte reconstitution in NSG mice, which were sublethally irradiated and transplanted with human cord blood-derived CD34+ cells at newborn age, longitudinally in peripheral blood and, for more detailed analyses, cross-sectionally in peripheral blood, spleen and bone marrow at different time points. RESULTS: Human cell chimerism and absolute human cell count decreased between week 16 and 24 in the peripheral blood of hu mice, but were stable thereafter as assessed up to 32 weeks. Human cell chimerism in spleen and bone marrow was maintained over time. Notably, human cell chimerism in peripheral blood and spleen as well as bone marrow positively correlated with each other. Percentage of B cells decreased between week 16 and 24, whereas percentage of T cells increased; subsequently, they levelled off with T cells clearly predominating at week 32. Natural killer cells, monocytes and plasmacytoid dendritic cells (DCs) as well as CD1c + and CD141+ myeloid DCs were all present in hu mice. Proliferative responses of splenic T cells to stimulation were preserved over time. Importantly, the percentage of more primitive hematopoietic stem cells (HSCs) in bone marrow was maintained over time. CONCLUSIONS: Overall, leukocyte reconstitution was maintained up to 32 weeks post-transplantation in our hu NSG model, possibly explained by the maintenance of HSCs in the bone marrow. Notably, we observed great variation in multi-lineage hematopoietic reconstitution in hu mice that needs to be taken into account for the experimental design with hu mice. PMID- 28558650 TI - Isolation, characterization and transcriptome analysis of a novel Antarctic Aspergillus sydowii strain MS-19 as a potential lignocellulosic enzyme source. AB - BACKGROUND: With the growing demand for fossil fuels and the severe energy crisis, lignocellulose is widely regarded as a promising cost-effective renewable resource for ethanol production, and the use of lignocellulose residues as raw material is remarkable. Polar organisms have important value in scientific research and development for their novelty, uniqueness and diversity. RESULTS: In this study, a fungus Aspergillus sydowii MS-19, with the potential for lignocellulose degradation was screened out and isolated from an Antarctic region. The growth profile of Aspergillus sydowii MS-19 was measured, revealing that Aspergillus sydowii MS-19 could utilize lignin as a sole carbon source. Its ability to synthesize low-temperature lignin peroxidase (Lip) and manganese peroxidase (Mnp) enzymes was verified, and the properties of these enzymes were also investigated. High-throughput sequencing was employed to identify and characterize the transcriptome of Aspergillus sydowii MS-19. Carbohydrate-Active Enzymes (CAZyme)-annotated genes in Aspergillus sydowii MS-19 were compared with those in the brown-rot fungus representative species, Postia placenta and Penicillium decumbens. There were 701CAZymes annotated in Aspergillus sydowii MS 19, including 17 cellulases and 19 feruloyl esterases related to lignocellulose degradation. Remarkably, one sequence annotated as laccase was obtained, which can degrade lignin. Three peroxidase sequences sharing a similar structure with typical lignin peroxidase and manganese peroxidase were also found and annotated as haem-binding peroxidase, glutathione peroxidase and catalase-peroxidase. CONCLUSIONS: In this study, the fungus Aspergillus sydowii MS-19 was isolated and shown to synthesize low-temperature lignin-degrading enzymes: lignin peroxidase (Lip) and manganese peroxidase (Mnp). These findings provide useful information to improve our understanding of low-temperature lignocellulosic enzyme production by polar microorganisms and to facilitate research and applications of the novel Antarctic Aspergillus sydowii strain MS-19 as a potential lignocellulosic enzyme source. PMID- 28558652 TI - Salivary epidermal growth factor correlates with hospitalization length in rotavirus infection. AB - BACKGROUND: The IFI27 interferon gene expression has been found to be largely increased in rotavirus (RV)-infected patients. IFI27 gene encodes for a protein of unknown function, very recently linked to epidermal proliferation and related to the epidermal growth factor (EGF) protein. The EGF is a low-molecular-weight polypeptide that is mainly produced by submandibular and parotid glands, and it plays an important physiological role in the maintenance of oro-esophageal and gastric tissue integrity. Our aim was to determine salivary EGF levels in RV infected patients in order to establish its potential relationship with IFI27 increased expression and EGF-mediated mucosal protection in RV infection. METHODS: We conducted a prospective comparative study using saliva samples from 27 infants infected with RV (sampled at recruitment during hospital admission and at convalescence, i.e. at least 3 months after recovery) and from 36 healthy control children. RESULTS: Median (SD) EGF salivary concentration was 777 (529) pg/ml in RV-infected group at acute phase and 356 (242) pg/m at convalescence, while it was 337 (119) pg/ml in the healthy control group. A significant association was found between EGF levels and hospitalization length of stay (P value = 0.022; r2 = -0.63). CONCLUSIONS: The salivary levels of EGF are significantly increased during the acute phase of natural RV infection, and relate to length of hospitalization. Further assessment of this non-invasive biomarker in RV disease is warranted. PMID- 28558651 TI - A user-friendly mathematical modelling web interface to assist local decision making in the fight against drug-resistant tuberculosis. AB - Multidrug-resistant and rifampicin-resistant tuberculosis (MDR/RR-TB) represent an important challenge for global tuberculosis (TB) control. The high rates of MDR/RR-TB observed among re-treatment cases can arise from diverse pathways: de novo amplification during initial treatment, inappropriate treatment of undiagnosed MDR/RR-TB, relapse despite appropriate treatment, or reinfection with MDR/RR-TB. Mathematical modelling allows quantification of the contribution made by these pathways in different settings. This information provides valuable insights for TB policy-makers, allowing better contextualised solutions. However, mathematical modelling outputs need to consider local data and be easily accessible to decision makers in order to improve their usefulness. We present a user-friendly web-based modelling interface, which can be used by people without technical knowledge. Users can input their own parameter values and produce estimates for their specific setting. This innovative tool provides easy access to mathematical modelling outputs that are highly relevant to national TB control programs. In future, the same approach could be applied to a variety of modelling applications, enhancing local decision making. PMID- 28558653 TI - Genome-wide association study of salt tolerance at the seed germination stage in rice. AB - BACKGROUND: Improving the salt tolerance of direct-seeding rice at the seed germination stage is a major breeding goal in many Asian rice-growing countries, where seedlings must often establish in soils with a high salt content. Thus, it is important to understand the genetic mechanisms of salt tolerance in rice and to screen for germplasm with salt tolerance at the seed germination stage. Here, we investigated seven seed germination-related traits under control and salt stress conditions and conducted a genome-wide association study based on the re sequencing of 478 diverse rice accessions. RESULTS: The analysis used a mixed linear model and was based on 6,361,920 single nucleotide polymorphisms in 478 rice accessions grouped into whole, indica, and non-indica panels. Eleven loci containing 22 significant salt tolerance-associated single nucleotide polymorphisms were identified based on the stress-susceptibility indices (SSIs) of vigor index (VI) and mean germination time (MGT). From the SSI of VI, six major loci were identified, explaining 20.2% of the phenotypic variation. From the SSI of MGT, five major loci were detected, explaining 26.4% of the phenotypic variation. Of these, seven loci on chromosomes 1, 5, 6, 11, and 12 were close to six previously identified quantitative gene loci/genes related to tolerance to salinity or other abiotic stresses. The strongest association region for the SSI of MGT was identified in a ~ 13.3 kb interval (15450039-15,463,330) on chromosome 1, near salt-tolerance quantitative trait loci controlling the Na+: K+ ratio, total Na+ uptake, and total K+ concentration. The strongest association region for the SSI of VI was detected in a ~ 164.2 kb interval (526662-690,854) on chromosome 2 harboring two nitrate transporter family genes (OsNRT2.1 and OsNRT2.2), which affect gene expression under salt stress. The haplotype analysis indicated that OsNRT2.2 was associated with subpopulation differentiation and its minor/rare tolerant haplotype was detected. CONCLUSIONS: These results provide valuable information for salt tolerance-related gene cloning and for understanding the genetic mechanisms of salt tolerance at the seed germination stage. This information will be useful to improve the salt tolerance of direct seeding rice varieties by genomic selection or marker-assisted selection. PMID- 28558654 TI - A pragmatic multi-center trial of goal-directed fluid management based on pulse pressure variation monitoring during high-risk surgery. AB - BACKGROUND: Intraoperative fluid therapy guided by mechanical ventilation-induced pulse-pressure variation (PPV) may improve outcomes after major surgery. We tested this hypothesis in a multi-center study. METHODS: The patients were included in two periods: a first control period (control group; n = 147) in which intraoperative fluids were given according to clinical judgment. After a training period, intraoperative fluid management was titrated to maintain PPV < 10% in 109 surgical patients (PPV group). We performed 1:1 propensity score matching to ensure the groups were comparable with regard to age, weight, duration of surgery, and type of operation. The primary endpoint was postoperative hospital length of stay. RESULTS: After matching, 84 patients remained in each group. Baseline characteristics, surgical procedure duration and physiological parameters evaluated at the start of surgery were similar between the groups. The volume of crystalloids (4500 mL [3200-6500 mL] versus 5000 mL [3750-8862 mL]; P = 0.01), the number of blood units infused during the surgery (1.7 U [0.9-2.0 U] versus 2.0 U [1.7-2.6 U]; P = 0.01), the fraction of patients transfused (13.1% versus 32.1%; P = 0.003) and the number of patients receiving mechanical ventilation at 24 h (3.2% versus 9.7%; P = 0.027) were smaller postoperatively in PPV group. Intraoperative PPV-based improved the composite outcome of postoperative complications OR 0.59 [95% CI 0.35-0.99] and reduced the postoperative hospital length of stay (8 days [6-14 days] versus 11 days [7-18 days]; P = 0.01). CONCLUSIONS: In high-risk surgeries, PPV-directed volume loading improved postoperative outcomes and decreased the postoperative hospital length of stay. TRIAL REGISTRATION: ClinicalTrials.gov Identifier; retrospectively registered- NCT03128190. PMID- 28558656 TI - Dissection of additive, dominance, and imprinting effects for production and reproduction traits in Holstein cattle. AB - BACKGROUND: Although genome-wide association and genomic selection studies have primarily focused on additive effects, dominance and imprinting effects play an important role in mammalian biology and development. The degree to which these non-additive genetic effects contribute to phenotypic variation and whether QTL acting in a non-additive manner can be detected in genetic association studies remain controversial. RESULTS: To empirically answer these questions, we analyzed a large cattle dataset that consisted of 42,701 genotyped Holstein cows with genotyped parents and phenotypic records for eight production and reproduction traits. SNP genotypes were phased in pedigree to determine the parent-of-origin of alleles, and a three-component GREML was applied to obtain variance decomposition for additive, dominance, and imprinting effects. The results showed a significant non-zero contribution from dominance to production traits but not to reproduction traits. Imprinting effects significantly contributed to both production and reproduction traits. Interestingly, imprinting effects contributed more to reproduction traits than to production traits. Using GWAS and imputation based fine-mapping analyses, we identified and validated a dominance association signal with milk yield near RUNX2, a candidate gene that has been associated with milk production in mice. When adding non-additive effects into the prediction models, however, we observed little or no increase in prediction accuracy for the eight traits analyzed. CONCLUSIONS: Collectively, our results suggested that non additive effects contributed a non-negligible amount (more for reproduction traits) to the total genetic variance of complex traits in cattle, and detection of QTLs with non-additive effect is possible in GWAS using a large dataset. PMID- 28558657 TI - Genome-wide identification of markers for selecting higher oil content in oil palm. AB - BACKGROUND: Oil palm (Elaeis guineensis, Jacq.) is the most important source of edible oil. The improvement of oil yield is currently slow in conventional breeding programs due to long generation intervals. Marker-assisted selection (MAS) has the potential to accelerate genetic improvement. To identify DNA markers associated with oil content traits for MAS, we performed quantitative trait loci (QTL) mapping using genotyping by sequencing (GBS) in a breeding population derived from a cross between Deli Dura and Ghana Pisifera, containing 153 F1 trees. RESULTS: We constructed a high-density linkage map containing 1357 SNPs and 123 microsatellites. The 16 linkage groups (LGs) spanned 1527 cM, with an average marker space of 1.03 cM. One significant and three suggestive QTL for oil to bunch (O/B) and oil to dry mesocarp (O/DM) were mapped on LG1, LG8, and LG10 in a F1 breeding population, respectively. These QTL explained 7.6-13.3% of phenotypic variance. DNA markers associated with oil content in these QTL were identified. Trees with beneficial genotypes at two QTL for O/B showed an average O/B of 30.97%, significantly (P < 0.01) higher than that of trees without any beneficial QTL genotypes (average O/B of 28.24%). QTL combinations showed that the higher the number of QTL with beneficial genotypes, the higher the resulting average O/B in the breeding population. CONCLUSIONS: A linkage map with 1480 DNA markers was constructed and used to identify QTL for oil content traits. Pyramiding the identified QTL with beneficial genotypes associated with oil content traits using DNA markers has the potential to accelerate genetic improvement for oil yield in the breeding population of oil palm. PMID- 28558655 TI - The common transcriptional subnetworks of the grape berry skin in the late stages of ripening. AB - BACKGROUND: Wine grapes are important economically in many countries around the world. Defining the optimum time for grape harvest is a major challenge to the grower and winemaker. Berry skins are an important source of flavor, color and other quality traits in the ripening stage. Senescent-like processes such as chloroplast disorganization and cell death characterize the late ripening stage. RESULTS: To better understand the molecular and physiological processes involved in the late stages of berry ripening, RNA-seq analysis of the skins of seven wine grape cultivars (Cabernet Franc, Cabernet Sauvignon, Merlot, Pinot Noir, Chardonnay, Sauvignon Blanc and Semillon) was performed. RNA-seq analysis identified approximately 2000 common differentially expressed genes for all seven cultivars across four different berry sugar levels (20 to 26 degrees Brix). Network analyses, both a posteriori (standard) and a priori (gene co-expression network analysis), were used to elucidate transcriptional subnetworks and hub genes associated with traits in the berry skins of the late stages of berry ripening. These independent approaches revealed genes involved in photosynthesis, catabolism, and nucleotide metabolism. The transcript abundance of most photosynthetic genes declined with increasing sugar levels in the berries. The transcript abundance of other processes increased such as nucleic acid metabolism, chromosome organization and lipid catabolism. Weighted gene co expression network analysis (WGCNA) identified 64 gene modules that were organized into 12 subnetworks of three modules or more and six higher order gene subnetworks. Some gene subnetworks were highly correlated with sugar levels and some subnetworks were highly enriched in the chloroplast and nucleus. The petal R package was utilized independently to construct a true small-world and scale-free complex gene co-expression network model. A subnetwork of 216 genes with the highest connectivity was elucidated, consistent with the module results from WGCNA. Hub genes in these subnetworks were identified including numerous members of the core circadian clock, RNA splicing, proteolysis and chromosome organization. An integrated model was constructed linking light sensing with alternative splicing, chromosome remodeling and the circadian clock. CONCLUSIONS: A common set of differentially expressed genes and gene subnetworks from seven different cultivars were examined in the skin of the late stages of grapevine berry ripening. A densely connected gene subnetwork was elucidated involving a complex interaction of berry senescent processes (autophagy), catabolism, the circadian clock, RNA splicing, proteolysis and epigenetic regulation. Hypotheses were induced from these data sets involving sugar accumulation, light, autophagy, epigenetic regulation, and fruit development. This work provides a better understanding of berry development and the transcriptional processes involved in the late stages of ripening. PMID- 28558658 TI - Therapeutic outcomes of endoscopic papillectomy for ampullary neoplasms: retrospective analysis of a multicenter study. AB - BACKGROUND: Endoscopic papillectomy (EP) is reported to be a relatively safe and reliable procedure for complete resection of ampullary neoplasms. The aim of this study was to evaluate the therapeutic outcomes and complications of EP for ampullary neoplasms. METHODS: A retrospective multicenter study was conducted with 5 participating centers from January 2007 to July 2014. A total of 104 patients who underwent EP for ampullary neoplasms were reviewed retrospectively. EP was performed by snare resection with or without submucosal lifting of the lesion. RESULTS: The mean age of patients was 60.5 +/- 12.1 years, and the male to-female ratio was 2.0:1. En bloc resection was possible in 94 patients (90.3%). A biliary and a pancreatic stent were placed after EP in 42 patients and in 60 patients, respectively. A pathologically incomplete resection was noted in 11 cases (10.6%), and 5 of these patients were treated with additional endoscopic procedure. Histology of resected specimens was as follows: low grade adenoma (43.2%), high grade adenoma (14.4%), adenocarcinoma (16.3%), hyperplastic polyp (7.7%), and others (18.4%). Of the 75 cases with low grade adenoma on biopsy specimen, 21.3% turned out to have high grade adenoma (12%) or adenocarcinoma (9.3%). Procedure-related complications occurred in 33 patients (31.7%); bleeding (18 cases, 17.3%), pancreatitis (16 cases, 15.4%), and perforation (8 cases, 7.7%). Pre-EP ERCP, saline lifting, sphincterotomy, biliary stenting, pancreatic stenting, specimen size, and cauterization were not related to post EP complications. Surgery was performed in 6 cases with pathological incomplete resection and 2 cases with complications after EP, and there were 2 cases of mortality due to complications. During follow-up endoscopy after initial success of EP, remnant tumors were found in 7 patients, one of whom underwent surgery and the others were treated endoscopically. Consequently, the overall endoscopic success rate of EP was 89.4%. CONCLUSIONS: Endoscopic papillectomy appears to be an effective treatment for ampullary neoplasms, and can be considered as an alternative to surgery. However, relatively high risk of procedure related complications is a problem that must be considered. PMID- 28558660 TI - Pneumonia caused by extensive drug-resistant Acinetobacter baumannii among hospitalized patients: genetic relationships, risk factors and mortality. AB - BACKGROUND: The clonal spread of multiple drug-resistant Acinetobacter baumannii is an emerging problem in China. We analysed the molecular epidemiology of Acinetobacter baumanni isolates at three teaching hospitals and investigated the risk factors, clinical features, and outcomes of hospital-acquired pneumonia caused by extensive drug-resistant Acinetobacter baumannii (XDRAB) infection in Guangzhou, China. METHODS: Fifty-two A. baumannii isolates were collected. Multilocus sequence typing (MLST) was used to assess the genetic relationships among the isolates. The bla OXA-51-like gene was amplified using polymerase chain reaction (PCR) and sequencing. The resistance phenotypes were determined using the disc diffusion method. A retrospective case-control study was performed to determine factors associated with XDRAB pneumonia. RESULTS: Most of the 52 A. baumannii isolates (N = 37, 71.2%) were collected from intensive care units (ICUs). The respiratory system was the most common bodily site from which A. baumannii was recovered (N = 45, 86.5%). Disc diffusion classified the isolates into 17 multidrug-resistant (MDR) and 35 extensively drug-resistant (XDR) strains. MLST grouped the A. baumannii isolates into 5 existing sequence types (STs) and 7 new STs. ST195 and ST208 accounted for 69.2% (36/52) of the isolates. The clonal relationship analysis showed that ST195 and ST208 belonged to clonal complex (CC) 92. According to the sequence-based typing (SBT) of the bla OXA-51 like gene, 51 A. baumannii isolates carried OXA-66 and the rest carried OXA-199. There were no significant differences with respect to the resistance phenotype between the CC92 and non-CC92 strains (P = 0.767). The multivariate analysis showed that the APACHE II score, chronic obstructive pulmonary disease (COPD) and cardiac disease were independent risk factors for XDRAB pneumonia (P < 0.05). The mortality rate of XDRAB pneumonia was high (up to 42.8%), but pneumonia caused by XDRAB was not associated with in-hospital mortality (P = 0.582). CONCLUSIONS: ST195 may be the most common ST in Guangzhou, China, and may serve as a severe epidemic marker. SBT of bla OXA-51-like gene variants may not result in sufficient dissimilarities to type isolates in a small-scale, geographically restricted study of a single region. XDRAB pneumonia was strongly related to systemic illnesses and the APACHE II score but was not associated with in hospital mortality. PMID- 28558661 TI - Uterus preserving surgery versus hysterectomy in the treatment of refractory postpartum haemorrhage in two tertiary maternity units in Cameroon: a cohort analysis of perioperative outcomes. AB - BACKGROUND: Little evidence exists on the efficacy and safety of the different surgical techniques used in the treatment of postpartum haemorrhage (PPH). We aimed to compare uterus preserving surgery (UPS) versus hysterectomy for refractory PPH in terms of perioperative outcomes in a sub-Saharan African country with a known high maternal mortality ratio due to PPH. METHODS: This was a retrospective cohort study comparing the perioperative outcomes of all women managed by UPS (defined as surgical interventions geared at achieving haemostasis while conserving the uterus) versus hysterectomy (defined as surgical resection of the uterus to achieve haemostasis) for PPH refractory to standard medical management in two tertiary hospitals in Cameroon from January 2004 to December 2014. We excluded patients who underwent hysterectomy after failure of UPS. Comparison was done using the Chi-square test or Fisher exact test where appropriate. Bonferroni adjustment of the p-value was performed in order to reduce the chance of obtaining false-positive results. RESULTS: We included 24 cases of UPS against 36 cases of hysterectomy. The indications of surgery were dominated by uterine rupture and uterine atony in both groups. Types of UPS performed were seven bilateral hypogastric artery ligations, seven hysterorraphies, six bilateral uterine artery ligations, three B-Lynch sutures and one Tsirulnikov triple ligation with an overall uterine salvage rate of 83.3%. Types of hysterectomies were 26 subtotal hysterectomies and 10 total hysterectomies. UPS was associated with maternal deaths (RR: 2.3; 95% CI: 1.38 3.93.; p: 0.0015) and postoperative infections (RR: 1.96; 95% CI: 1.1-3.49; p: 0.0215). The association of UPS with maternal death was not attenuated after Bonferroni correction. Hysterectomy had no statistically significant adverse outcome. CONCLUSION: Hysterectomy is safer than UPS in the management of intractable PPH in our setting. The choice of UPS as first-line surgical management of PPH in resource-limited settings should entail diligent anticipation of these adverse maternal outcomes in order to lessen the perioperative burden of PPH. PMID- 28558659 TI - The Cyprinodon variegatus genome reveals gene expression changes underlying differences in skull morphology among closely related species. AB - BACKGROUND: Understanding the genetic and developmental origins of phenotypic novelty is central to the study of biological diversity. In this study we identify modifications to the expression of genes at four developmental stages that may underlie jaw morphological differences among three closely related species of pupfish (genus Cyprinodon) from San Salvador Island, Bahamas. Pupfishes on San Salvador Island are trophically differentiated and include two endemic species that have evolved jaw morphologies unlike that of any other species in the genus Cyprinodon. RESULTS: We find that gene expression differs significantly across recently diverged species of pupfish. Genes such as Bmp4 and calmodulin, previously implicated in jaw diversification in African cichlid fishes and Galapagos finches, were not found to be differentially expressed among species of pupfish. Instead we find multiple growth factors and cytokine/chemokine genes to be differentially expressed among these pupfish taxa. These include both genes and pathways known to affect craniofacial development, such as Wnt signaling, as well as novel genes and pathways not previously implicated in craniofacial development. These data highlight both shared and potentially unique sources of jaw diversity in pupfish and those identified in other evolutionary model systems such as Galapagos finches and African cichlids. CONCLUSIONS: We identify modifications to the expression of genes involved in Wnt signaling, Igf signaling, and the inflammation response as promising avenues for future research. Our project provides insight into the magnitude of gene expression changes contributing to the evolution of morphological novelties, such as jaw structure, in recently diverged pupfish species. PMID- 28558662 TI - Evaluation of gene xpert for routine diagnosis of HIV-associated tuberculosis in Nigeria: A prospective cohort study. AB - BACKGROUND: Xpert MTB/Rif (Xpert) is described as a game changer in tuberculosis (TB) control. We evaluated the impact of Xpert on diagnosis, time to treatment, and treatment outcome among patients with HIV associated TB in Nigeria. METHODS: Adults with HIV being evaluated for pulmonary TB (PTB) were consecutively enrolled into the study cohort. At baseline, expectorated sputa were examined using Xpert and smear microscopy for Mycobacterium tuberculosis (MTB) and acid fast bacilli, respectively. Patients diagnosed with TB were followed-up until 6 months post TB diagnosis. TB was defined as sputum positive by smear microscopy, Xpert detection of MTB (bacteriologically confirmed case), or clinician diagnosed TB with initiation of full TB treatment (clinical diagnosis). Time to treatment was time from first clinic presentation for TB evaluation to initiation of TB treatment. We examined the proportion PTB patients with a positive Xpert result and compared time to TB treatment and outcome of TB treatment in patients based on sputum test results. RESULTS: A total of 310 adults with HIV were enrolled. The median CD4 cell count was 242 (interquartile range (IQR) 120-425) cells/mm3 and 88.1% were receiving antiretroviral therapy (ART). PTB was diagnosed in 76 (24.5%) patients, with 71 (93.4%) being bacteriologically confirmed. Among patients with PTB, 56 (73.7%) were Xpert positive. Median time to treatment was 5 (IQR 2-8) days and 12 (IQR 5-35) days in patient with and without Xpert positive results, respectively; p = 0.005. Overall 73.1% had symptom free survival at 6 months post PTB treatment initiation with no significant differences observed based on TB test method. 10 (14.9%) died within 6 months of TB treatment initiation. In analysis adjusted for age, sex, and mode of diagnosis (Xpert positive or negative), only ART use independently predicted mortality (AOR 0.10; 95% CI 0.01-0.93). CONCLUSION: The use of Xpert for routine care reduced time to PTB treatment, but did not improve survival in patients with HIV treated for susceptible PTB. PMID- 28558663 TI - Reasons for never and intermittent completion of colorectal cancer screening after receiving multiple rounds of mailed fecal tests. AB - BACKGROUND: Long-term adherence to colorectal cancer (CRC) screening is particularly important for fecal testing. Some U.S. studies report that only 25% of individuals repeat fecal testing annually. The purpose of this qualitative study was to identify barriers and facilitators reported by patients with suboptimal screening adherence to refine interventions for starting ongoing adherence to CRC screening. We also explored whether participants, particularly never screeners, would be willing to do a CRC screening blood test. METHODS: Forty-one patients who previously enrolled in the Systems of Support to Increase CRC Screening (SOS) trial were interviewed 4-5 years later. Participants were purposively selected to include men and women with diverse race/ethnicities who had either been inconsistent screeners or had never screened during the first three years of SOS despite receiving at least two rounds of mailed fecal tests. Two interviewers conducted 30-min telephone interviews using a semi-structured interview guide. An iterative thematic analysis approach was used. RESULTS: Themes related to screening barriers were more pervasive among never screeners including: (1) Avoidance (inattention, procrastination) (2) Concerns about handling stool; (3) Health concerns; (4) Fear of a cancer diagnosis or positive test results. Themes related to screening facilitators were more often mentioned by participants who screened at least once including: (1) Use of a simpler 1 sample fecal test; (2) Convenience of mailings and doing the test at home; (3) Salience of prevention, especially as one got older; and (4) Influence of recommendations from providers, family and friends. Participants had diverse preferences for the number (3 on average) and types (phone, mail, text) of screening reminders. Some participants did not prefer e-mail links to the patient shared electronic health record because of difficulties remembering their password. It was acceptable for a nurse or medical assistant not from their clinic to call them as long as that person was knowledgeable about their records and could communicate with their physician. Participants, especially never screeners, were generally very enthusiastic about the potential option of a CRC screening blood test. CONCLUSION: Future CRC screening programs should be designed to minimize these barriers and maximize facilitators to improve long term screening adherence. TRIAL REGISTRATION: Primary Funding Agency: The National Cancer Institute of the National Institutes of Health (R01CA121125). Registered at clinicaltrials.gov NCT00697047 . PMID- 28558664 TI - Numerical integration methods and layout improvements in the context of dynamic RNA visualization. AB - BACKGROUND: RNA visualization software tools have traditionally presented a static visualization of RNA molecules with limited ability for users to interact with the resulting image once it is complete. Only a few tools allowed for dynamic structures. One such tool is jViz.RNA. Currently, jViz.RNA employs a unique method for the creation of the RNA molecule layout by mapping the RNA nucleotides into vertexes in a graph, which we call the detailed graph, and then utilizes a Newtonian mechanics inspired system of forces to calculate a layout for the RNA molecule. The work presented here focuses on improvements to jViz.RNA that allow the drawing of RNA secondary structures according to common drawing conventions, as well as dramatic run-time performance improvements. This is done first by presenting an alternative method for mapping the RNA molecule into a graph, which we call the compressed graph, and then employing advanced numerical integration methods for the compressed graph representation. RESULTS: Comparing the compressed graph and detailed graph implementations, we find that the compressed graph produces results more consistent with RNA drawing conventions. However, we also find that employing the compressed graph method requires a more sophisticated initial layout to produce visualizations that would require minimal user interference. Comparing the two numerical integration methods demonstrates the higher stability of the Backward Euler method, and its resulting ability to handle much larger time steps, a high priority feature for any software which entails user interaction. CONCLUSION: The work in this manuscript presents the preferred use of compressed graphs to detailed ones, as well as the advantages of employing the Backward Euler method over the Forward Euler method. These improvements produce more stable as well as visually aesthetic representations of the RNA secondary structures. The results presented demonstrate that both the compressed graph representation, as well as the Backward Euler integrator, greatly enhance the run-time performance and usability. The newest iteration of jViz.RNA is available at https://jviz.cs.sfu.ca/download/download.html . PMID- 28558665 TI - The association between genetic polymorphisms of the interleukin-23 receptor gene and susceptibility to uveitis: a meta-analysis. AB - BACKGROUND: Uveitis is an eye inflammatory disease, which is sometimes associated with underlying systemic disease. Interleukin-23 plays an important role in autoimmune disease. The aim of this meta-analysis was to evaluate the association between the interleukin-23 receptor (IL-23R) and susceptibility to uveitis. METHODS: Published literature from PUBMED and EMBASE were retrieved. Seven studies were included in this meta-analysis, covering a total of 1309 cases of uveitis and 2400 controls. Meta-analyses were conducted on the associations between uveitisand rs7517847, rs17375018, and rs11209032 polymorphisms in the IL 23R gene. RESULTS: There were no significant associations between IL-23R polymorphisms and uveitis with regard to the following alleles: for G allele vs. T allele of rs7517847, OR 1.01, 95% CI 0.92-1.12, P = 0.83; for A allele vs. G allele of rs17375018, OR 0.68, 95% CI 0.47-0.99, P = 0.05; rs11209032 OR 1.12, 95% CI 0.84-1.51, P = 0.43. In contrast, there were significant associations between the AA + AG gene versus GG gene of rs17375018 and the AA gene versus AG + GG gene of rs11209032 polymorphism with uveitis (OR 0.59, 95% CI 0.35-0.99, P = 0.04; OR 1.32, 95% CI 1.10-1.59, P = 0.003). CONCLUSIONS: This meta-analysis suggests that each allele of IL-23R, including rs7519847, rs17375018 and rs11209032 was negatively associated with uveitis. However, homozygote models, including the rs17375018 GG genotype and rs11209032 AA genotype, were significantly associated with uveitis. PMID- 28558666 TI - Erratum to: gamma probe and ultrasound guided fine needle aspiration cytology of the sentinel node (GULF) trial - overview of the literature, pilot and study protocol. PMID- 28558667 TI - The meaning of labour pain: how the social environment and other contextual factors shape women's experiences. AB - BACKGROUND: The majority of women experience pain during labour and childbirth, however not all women experience it in the same way. In order to develop a more complete understanding of labour pain, this study aimed to examine women's experiences within the perspective of modern pain science. A more complete understanding of this phenomenon can then guide the development of interventions to enhance women's experiences and potentially reduce their need for pharmacological intervention. METHODS: A qualitative study was conducted using phenomenology as the theoretical framework. Data were collected from 21 nulliparous women, birthing at one of two large maternity services, through face to-face interviews and written questionnaires. Data were analysed using an Interpretative Phenomenological Analysis approach. RESULTS: The data from this study suggest that a determining factor of a woman's experience of pain during labour is the meaning she ascribes to it. When women interpret the pain as productive and purposeful, it is associated with positive cognitions and emotions, and they are more likely to feel they can cope. Alternatively, when women interpret the pain as threatening, it is associated with negative cognitions and emotions and they tend to feel they need help from external methods of pain control. The social environment seems particularly important in shaping a woman's pain experience by influencing her interpretation of the context of the pain, and in doing so can change its meaning. The context and social environment are dynamic and can also change throughout labour. CONCLUSION: A determining factor in a woman's experience of pain during labour is its perceived meaning which can then influence how the woman responds to the pain. The meaning of the pain is shaped by the social environment and other contextual factors within which it is experienced. Focussed promotion of labour pain as a productive and purposeful pain and efforts to empower women to utilise their inner capacity to cope, as well as careful attention to women's cognitions and the social environment around them may improve women's experiences of labour pain and decrease their need for pain interventions. PMID- 28558670 TI - Retirement and mental health: dose social participation mitigate the association? A fixed-effects longitudinal analysis. AB - BACKGROUND: Empirical evidence investigating heterogeneous impact of retirement on mental health depending on social backgrounds is lacking, especially among older adults. METHODS: We examined the impact of changes in working status on changes in mental health using Japanese community-dwelling adults aged >=65 years participating in the Japan Gerontological Evaluation Study between 2010 and 2013 (N = 62,438). Between-waves changes in working status ("Kept working", "Retired", "Started work", or "Continuously retired") were used to predict changes in depressive symptoms measured by the Geriatric Depression Scale. First-difference regression models were stratified by gender, controlling for changes in time varying confounding actors including equivalised household income, marital status, instrumental activities of daily living, incidence of serious illnesses and family caregiving. We then examined the interactions between changes in working status and occupational class, changes in marital status, and post retirement social participation. RESULTS: Participants who transitioned to retirement reported significantly increased depressive symptoms (beta = 0.33, 95% CI: 0.21-0.45 for men, and beta = 0.29, 95% CI: 0.13-0.45 for women) compared to those who kept working. Men who were continuously retired reported increased depressive symptoms (beta = 0.13, 95% CI: 0.05-0.20), whereas males who started work reported decreased depressive symptoms (beta = -0.20, 95% CI: -0.38--0.02). Men from lower occupational class (compared to men from higher class) reported more increase in depressive symptoms when continuously retired (beta = -0.16, 95% CI: -0.25--0.08). Those reporting recreational social participation after retirement appeared to be less influenced by transition to retirement. CONCLUSIONS: Retirement may increase depressive symptoms among Japanese older adults, particularly men from lower occupational class backgrounds. Encouraging recreational social participation may mitigate the adverse effects of retirement on mental health of Japanese older men. PMID- 28558668 TI - Combination of Helicobacter pylori infection and the interleukin 8 -251 T > A polymorphism, but not the mannose-binding lectin 2 codon 54 G > A polymorphism, might be a risk factor of gastric cancer. AB - BACKGROUND: Mannose-binding lectin (MBL) acts in the innate immune response to Helicobacter pylori. Interleukin 8 (IL-8) is a potent cytokine produced by gastric epithelial cells in response to H. pylori. We aimed to investigate whether polymorphisms in MBL2 and IL-8 influence susceptibility to H. pylori infection, and the associations of these polymorphisms with the risk of gastroduodenal diseases in a Korean population. METHODS: We consecutively enrolled 176 H. pylori-negative control subjects, 221 subjects with H. pylori positive non-atrophic gastritis, 52 mild atrophic gastritis (AG), 61 severe AG, 175 duodenal ulcer, and 283 gastric cancer (GC). Allele-specific PCR-RFLP was conducted for polymorphisms in MBL2 exon 1 (codon 52, 54, and 57) and IL-8 -251 T > A. IL-8 levels in gastric mucosal tissues and serum MBL levels were measured by enzyme-linked immunosorbent assay. RESULTS: MBL2 exon 1 polymorphic variants were found only in codon 54, and the allele frequencies did not differ significantly between the control and disease groups. Although serum MBL levels in codon 54 A/A mutants were markedly low, it did not influence susceptibility to H. pylori infection or the risk of gastroduodenal diseases. IL-8 levels were significantly different between T/T wild type, T/A heterozygote, and A/A mutant genotypes. IL-8 -251 A allele carriers (A/A + T/A) showed increased IL-8 levels, and were significantly associated with the risk of severe AG and GC. CONCLUSIONS: We suggest that a combination of H. pylori infection and the IL-8 -251 T > A polymorphism might increase the risk of severe AG and GC in a Korean population. PMID- 28558669 TI - Calretinin as a blood-based biomarker for mesothelioma. AB - BACKGROUND: Malignant mesothelioma (MM) is a deadly cancer mainly caused by previous exposure to asbestos. With a latency period up to 50 years the incidence of MM is still increasing, even in countries that banned asbestos. Secondary prevention has been established to provide persons at risk regular health examinations. An earlier detection with tumor markers might improve therapeutic options. Previously, we have developed a new blood-based assay for the protein marker calretinin. Aim of this study was the verification of the assay in an independent study population and comparison with the established marker mesothelin. METHODS: For a case-control study in men, a total of 163 cases of pleural MM and 163 controls were available from Australia, another 36 cases and 72 controls were recruited in Germany. All controls had asbestosis and/or plaques. Calretinin and mesothelin were determined by ELISA (enzyme-linked immunosorbent assay) in serum or plasma collected prior to therapy. We estimated the performance of both markers and tested factors potentially influencing marker concentrations like age, sample storage time, and MM subtype. RESULTS: Calretinin was able to detect all major subtypes except for sarcomatoid MM. Calretinin showed a similar performance in Australian and German men. At a pre-defined specificity of 95% the sensitivity of calretinin reached 71% and that of mesothelin 69%, when excluding sarcomatoid MM. At 97% specificity, the combination with calretinin increased the sensitivity of mesothelin from 66% to 75%. Sample storage time did not influence the results. In controls the concentrations of calretinin increased 1.87-fold (95% CI 1.10-3.20) per 10 years of age and slightly more for mesothelin (2.28, 95% CI 1.30-4.00). CONCLUSIONS: Calretinin could be verified as a blood-based marker for MM. The assay is robust and shows a performance that is comparable to that of mesothelin. Retrospective analyses would not be limited by storage time. The high specificity supports a combination of calretinin with other markers. Calretinin is specific for epithelioid and biphasic MM but not the rarer sarcomatoid form. Molecular markers like calretinin and mesothelin are promising tools to improve and supplement the diagnosis of MM and warrant further validation in a prospective study. PMID- 28558671 TI - Prevalence and determinants of unintended pregnancies amongst women attending antenatal clinics in Pakistan. AB - BACKGROUND: Unintended pregnancies are a global public health concern and contribute significantly to adverse maternal and neonatal health, social and economic outcomes and increase the risks of maternal deaths and neonatal mortality. In countries like Pakistan where data for the unintended pregnancies is scarce, studies are required to estimate its accurate prevalence and predictors using more specific tools such as the London Measure of Unplanned Pregnancies (LMUP). METHODS: We conducted a hospital based cross sectional survey in two tertiary care hospitals in Pakistan. We used a pre tested structured questionnaire to collect the data on socio-demographic characteristics, reproductive history, awareness and past experience with contraceptives and unintended pregnancies using six item the LMUP. We used Univariate and multivariate analysis to explore the association between unintended pregnancies and predictor variables and presented the association as adjusted odds ratios. We also evaluated the psychometric properties of the Urdu version of the LMUP. RESULTS: Amongst 3010 pregnant women, 1150 (38.2%) pregnancies were reported as unintended. In the multivariate analysis age < 20 years (AOR 3.5 1.1-6.5), being illiterate (AOR 1.9 1.1-3.4), living in a rural setting (1.7 1.2-2.3), having a pregnancy interval of = < 12 months (AOR 1.7 1.4-2.2), having a parity of >2 (AOR 1.4 1.2-1.8), having no knowledge about contraceptive methods (AOR 3.0 1.7-5.4) and never use of contraceptive methods (AOR 2.3 1.4-5.1) remained significantly associated with unintended pregnancy. The Urdu version of the LMUP scale was found to be acceptable, valid and reliable with the Cronbach's alpha of 0.85. CONCLUSIONS: This study explores a high prevalence of unintended pregnancies and important factors especially those related to family planning. Integrated national family program that provides contraceptive services especially the modern methods to women during pre-conception and post-partum would be beneficial in averting unintended pregnancies and their related adverse outcomes in Pakistan. PMID- 28558672 TI - Distinct genetic differentiation and species diversification within two marine nematodes with different habitat preference in Antarctic sediments. AB - BACKGROUND: Dispersal ability, population genetic structure and species divergence in marine nematodes are still poorly understood, especially in remote areas such as the Southern Ocean. We investigated genetic differentiation of species and populations of the free-living endobenthic nematode genera Sabatieria and Desmodora using nuclear 18S rDNA, internal transcribed spacer (ITS) rDNA, and mitochondrial cytochrome oxidase I (COI) gene sequences. Specimens were collected at continental shelf depths (200-500 m) near the Antarctic Peninsula, Scotia Arc and eastern side of the Weddell Sea. The two nematode genera co-occurred at all sampled locations, but with different vertical distribution in the sediment. A combination of phylogenetic (GMYC, Bayesian Inference, Maximum Likelihood) and population genetic (AMOVA) analyses were used for species delimitation and assessment of gene flow between sampling locations. RESULTS: Sequence analyses resulted in the delimitation of four divergent species lineages in Sabatieria, two of which could not be discriminated morphologically and most likely constitute cryptic species. Two species were recognised in Desmodora, one of which showed large intraspecific morphological variation. Both genera comprised species that were restricted to one side of the Weddell Sea and species that were widely spread across it. Population genetic structuring was highly significant and more pronounced in the deeper sediment-dwelling Sabatieria species, which are generally less prone to resuspension and passive dispersal in the water column than surface Desmodora species. CONCLUSIONS: Our results indicate that gene flow is restricted at large geographic distance in the Southern Ocean, which casts doubt on the efficiency of the Weddell gyre and Antarctic Circumpolar Current in facilitating circum-Antarctic nematode species distributions. We also show that genetic structuring and cryptic speciation can be very different in nematode species isolated from the same geographic area, but with different habitat preferences (surface versus deeper sediment layers). PMID- 28558673 TI - A randomized controlled trial to evaluate the impact of a geo-specific poster compared to a general poster for effecting change in perceived threat and intention to avoid drowning 'hotspots' among children of migrant workers: evidence from Ningbo, China. AB - BACKGROUND: Drowning among children of migrant workers is a major, though neglected public health issue in China. METHODS: A randomised controlled trial was used to examine the potential impact of viewing a preventive health poster with/without geo-located drowning events on perceptions of drowning risk among Chinese migrant children. A total of 752 children from three schools in Jiangbei district were selected by multi-stage sampling and randomly assigned to the intervention (n = 380) or control (n = 372). Multilevel models were used to analyse changes in responses to the following questions after viewing the assigned poster for 10 min: (1) "Do you believe that drowning is a serious health problem in Ningbo city?"; (2) "Do you believe that there are lots of drowning risk waters around you?"; (3) "Do you believe that the likelihood of your accessing a drowning-risk water is great?"; and (4) "Would you intend to avoid accessing to those drowning-risk waters when being exposed?" RESULTS: At baseline there were no significant differences between the intervention and control groups in perceptions of drowning risk or covariates. Following the intervention, participants that viewed the geo-specific poster were more likely to respond more favourably to the first three questions (p < 0.001) than those who viewed the standard poster. However, there was no substantive difference between the geo specific or standard poster in terms of changing intentions to avoid drowning hotspots (p = 0.214). CONCLUSIONS: Use of 'geo-located' information added value to the effectiveness of a drowning prevention poster for enhancing awareness of drowning hotspots among children of migrant workers. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-IOR-16008979 (Retrospectively registered) (The date of trial registration: Aug 5, 2016, the date of enrolment of the first participant: Nov 10, 2015). PMID- 28558674 TI - Learning rule sets from survival data. AB - BACKGROUND: Survival analysis is an important element of reasoning from data. Applied in a number of fields, it has become particularly useful in medicine to estimate the survival rate of patients on the basis of their condition, examination results, and undergoing treatment. The recent developments in the next generation sequencing open new opportunities in survival study as they allow vast amount of genome-, transcriptome-, and proteome-related features to be investigated. These include single nucleotide and structural variants, expressions of genes and microRNAs, DNA methylation, and many others. RESULTS: We present LR-Rules, a new algorithm for rule induction from survival data. It works according to the separate-and-conquer heuristics with a use of log-rank test for establishing rule body. Extensive experiments show LR-Rules to generate models of superior accuracy and comprehensibility. The detailed analysis of rules rendered by the presented algorithm on four medical datasets concerning leukemia as well as breast, lung, and thyroid cancers, reveals the ability to discover true relations between attributes and patients' survival rate. Two of the case studies incorporate features obtained with a use of high throughput technologies showing the usability of the algorithm in the analysis of bioinformatics data. CONCLUSIONS: LR-Rules is a viable alternative to existing approaches to survival analysis, particularly when the interpretability of a resulting model is crucial. Presented algorithm may be especially useful when applied on the genomic and proteomic data as it may contribute to the better understanding of the background of diseases and support their treatments. PMID- 28558677 TI - Measurement of special access to home visit nursing services among Japanese disabled elderly people: using GIS and claim data. AB - BACKGROUND: Home care service demands are increasing in Japan; this necessitates improved service allocation. This study examined the relationship between home visit nursing (HVN) service use and the proportion of elderly people living within 10 min' travel of HVN agencies. METHODS: The population of elderly people living within reach of HVN agencies for each of 17 municipalities in one low density prefecture was calculated using public data and geographic information systems. Multilevel logistic analysis for 2641 elderly people was conducted using medical and long-term care insurance claims data from October 2010 to examine the association between the proportion of elderly people reachable by HVNs and service usage in 13 municipalities. Municipality variables included HVN agency allocation appropriateness. Individual variables included HVN usage and demographic variables. RESULTS: The reachable proportion of the elderly population ranged from 0.0 to 90.2% in the examined municipalities. The reachable proportion of the elderly population was significantly positively correlated with HVN use (odds ratio: 1.938; confidence interval: 1.265-2.967). CONCLUSIONS: Residents living in municipalities with a lower reachable proportion of the elderly population are less likely to use HVN services. Public health interventions should increase the reachable proportion of the elderly population in order to improve HVN service use. PMID- 28558675 TI - Development of plant-produced protein body vaccine candidates for bluetongue virus. AB - BACKGROUND: Bluetongue is a disease of domestic and wild ruminants caused by bluetongue virus serotypes (BTV), which have caused serious outbreaks worldwide. Commercially available vaccines are live-attenuated or inactivated virus strains: these are effective, but there is the risk of reversion to virulence or reassortment with circulating strains for live virus, and residual live virus for the inactivated vaccines. The live-attenuated virus vaccines are not able to distinguish naturally infected animals from vaccinated animals (DIVA compliant). Recombinant vaccines are preferable to minimize the risks associated with these vaccines, and would also enable the development of candidate vaccines that are DIVA-compliant. RESULTS: In this study, two novel protein body (PB) plant produced vaccines were developed, Zera(r)-VP2ep and Zera(r)-VP2. Zera(r)-VP2ep contained B-cell epitope sequences of multiple BTV serotypes and Zera(r)-VP2 contained the full-length BTV-8 VP2 codon-optimised sequence. In addition to fulfilling the DIVA requirement, Zera(r)-VP2ep was aimed at being multivalent with the ability to stimulate an immune response to several BTV serotypes. Both these candidate vaccines were successfully made in N. benthamiana via transient Agrobacterium-mediated expression, and in situ TEM analysis showed that the expressed proteins accumulated within the cytoplasm of plant cells in dense membrane-defined PBs. The peptide sequences included in Zera(r)-VP2ep contained epitopes that bound antibodies produced against native VP2. Preliminary murine immunogenicity studies showed that the PB vaccine candidates elicited anti-VP2 immune responses in mice without the use of adjuvant. CONCLUSIONS: These proof of concept results demonstrate that Zera(r)-VP2ep and Zera(r)-VP2 have potential as BTV vaccines and their development should be further investigated. PMID- 28558676 TI - Association of calf circumference with insulin resistance and non-alcohol fatty liver disease: the REACTION study. AB - BACKGROUND: The feature of nonalcoholic fatty liver disease (NAFLD) is pathological excessive liver lipid accumulation of subjects who without history of alcohol abuse. Calf circumference is a proxy for lower-body fat and screening method for the identification of subjects with acatastatic lipid accumulation. The objective of this study was to examine the association between calf circumference and NAFLD. METHODS: The study was a cross-sectional analysis including 8850 middle-aged and elderly individuals. NAFLD was examined by hepatic ultrasound and without alcohol abuse and other liver diseases. Calf circumference was measured on the lower right leg at the point of maximal circumference. RESULTS: The mean of calf circumference were 35.7 cm for male and 34.6 cm for female (P < 0.001), respectively. Compared with the lowest calf circumference quartile, the odds ratio for NAFLD in the highest quartile was 2.73 (95% CI 2.34 3.19, P trend <0.001) after adjusted for potential cofounders. There were also significant positive correlation between calf circumference and HOMA-IR, liver enzyme levels and triglycerides. In addition, we found significant positive correlation of calf circumference with the HOMA-IR and fasting insulin level in overweight and obese subjects (BMI >= 24 kg/m2) but not in lean subjects (test for interaction: P both less than 0.001 for insulin and HOMA-IR). CONCLUSION: High calf circumference is significantly associated with elevated prevalence of NAFLD and increasing insulin resistance. PMID- 28558678 TI - High prevalence of sarcopenia among binge drinking elderly women: a nationwide population-based study. AB - BACKGROUND: Alcohol consumption is considered a risk factor for sarcopenia, but the association between alcohol consumption and the prevalence of sarcopenia has not been evaluated in detail. This study was to identify the relationship between alcohol drinking patterns and the prevalence of sarcopenia in the elderly Korean population. METHODS: The cross-sectional study was performed using data from the Korea National Health and Nutrition Examination Survey. Participants were excluded if they were under the age of 65, or if data was not available regarding skeletal muscle mass or dietary intake. After these exclusions, a total of 4020 participants (men: 1698; women: 2322) were analyzed in the present study. Sarcopenia is defined according to the criteria for the Asia Working Group for Sarcopenia (AWGS). Binge drinking was defined as consuming >=5 standard alcoholic drinks (>=4 drinks for women) consecutively on one occasion. This data was subcategorized into two groups based on presence of binge drinking: Social drinking (<=1 time/month) and binge drinking (>1 time/month). RESULTS: Women binge drinkers with weekly or daily consumption had 2.8 times higher prevalence of sarcopenia than social drinkers (Odds Ratio [OR] = 2.84; 95% Confidence Interval [CI] = 1.12-7.29). However, there were no associations between binge drinkers and sarcopenia in men. After adjusting for age, body mass index (BMI), energy intake, moderate physical activity, and energy intake, women binge drinkers with weekly or daily alcohol consumption had 3.9 times higher prevalence of sarcopenia than social drinkers (OR = 3.88; 95% CI = 1.33-11.36). CONCLUSIONS: The prevalence of sarcopenia in elderly women was related to binge drinking frequency and amounts of drinking after adjusting for covariates. Elderly Korean women who binge drink once or more per week may be associated with sarcopenia, as seen with the observed 3.9 times higher prevalence compared to social drinkers. PMID- 28558679 TI - Demonstration of biological activities of extracts from Isodon rugosus Wall. Ex Benth: Separation and identification of bioactive phytoconstituents by GC-MS analysis in the ethyl acetate extract. AB - BACKGROUND: Since long, natural sources have been explored for possible managements of various diseases. In this context, the study is designed to evaluate Isodon rugosus Wall. ex Benth for biological potentials including antibacterial, anthelmintic, insecticidal, anti-termites and anti-Pharaoh activities followed by GC-MS analysis of active fraction to identify various bioactive compounds. METHODS: I. rugosus was investigated against eight bacterial strains using well diffusion method and microdilution method with ceftriaxone as positive control. Similarly, the insecticidal activity was carried out against Tribolium castaneum, Rhyzopertha dominica, Monomorium pharaonis and Heterotermis indicola following contact toxicity method. Likewise, anthelmintic activity was performed against Ascaridia galli and Pherethima posthuma using albendazole as positive control, in which the paralysis and death times of the worms were observed. The GC-MS analysis of the most active solvent fraction was performed for identifications of various bioactive compounds. RESULTS: Among the tested samples of I. rugosus, flavonoids and ethyl acetate fraction exhibited high antibacterial activities. The crude saponins showed highest anthelmintic activity against Pherethima posthuma and Ascaridia galli with death times of 27.67 and 29.22 min respectively at concentrations of 40 mg/ml. In insecticidal activity, chloroform fraction and saponins exhibited notable results against R. dominica (60 and 70%) and T. castaneum (70 and 76%) at concentration of 200 mg/ml. In anti termite assay, all the plant samples showed overwhelming results, i.e. all the 25 termites were killed on the 3rd day. Similarly, in anti-Pharaoh activity, the chloroform, ethyl acetate and saponins fractions were most potent, each exhibiting LD50 of <0.1 mg/ml. In GC-MS analysis, total of 57 compounds were identified. Some of the bioactive compounds identified in GC-MS analysis are palmitic acid, hinokiol, alpha-amyrin, phytol, ethyl linolate, cyclohexanone, hinokione, methyl palmitate, ethyl palmitate and stigmasterol acetate. CONCLUSIONS: Based on our current results, it can be concluded that I. rugosus possess strong antibacterial, insecticidal and anthelmintic potentials having crude saponins and ethyl acetate as the most active fractions. The GC-MS analysis and biological assays reveal that ethyl acetate fraction is a suitable target for the isolation of diverse array of bioactive compounds. PMID- 28558681 TI - Enhanced knowledge of spontaneous reporting with structured educational programs in Korean community pharmacists: a cross-sectional study. AB - BACKGROUND: While spontaneous reporting (SR) is one of the important public health activities for community pharmacists to guard patients' safety, very few studies examined educational activities and its effects on knowledge about the SR system in Korea. This study described the association between knowledge of SR and educational activities targeting community pharmacists in Korea. METHODS: Self administered questionnaires were collected between September 1, 2014 and November 25, 2014. The questionnaires addressed sources of SR knowledge (structured educational programs, personal access to educational resources, and information by social network services) and knowledge about the Regional Pharmacovigilance Center designated for community pharmacists, the legal responsibility clause on the serious event reporting, and the reportable items. The association between the knowledge of SR and the educational activities was evaluated using analysis of variance or chi-squared tests. RESULTS: Overall, 766 questionnaires demonstrated that mean age and length of career in community pharmacies was 45.7 years and 15.9 years, respectively. A structured educational program was used in 63.1% of the participants followed by a personal access to educational resources (56.3%). An educational program offered by the Korean Pharmaceutical Association was the most frequently mentioned program (56.8%), and no regional disparity in the program between the metropolitan and rural areas was observed. Pharmacists who had personal access to educational resources identified SR knowledge contents less correctly than those who used a structured educational program or both (p < 0.01). In general, pharmacists' knowledge on reportable items was significantly lower with non-prescription drugs, nutritional supplements, and personal hygiene products as compared to their knowledge on prescription drugs, regardless of the type of education (p < 0.01). CONCLUSIONS: Knowledge regarding SR was more likely to increase when a structured educational program was used alone or in combination with other educational methods. Knowledge on reportable items should be reinforced during the continuing education process. PMID- 28558680 TI - Arginine supplementation modulates pig plasma lipids, but not hepatic fatty acids, depending on dietary protein level with or without leucine. AB - BACKGROUND: In the present study, the effect of arginine and leucine supplementation, and dietary protein level, were investigated in commercial crossbred pigs to clarify their individual or combined impact on plasma metabolites, hepatic fatty acid composition and mRNA levels of lipid sensitive factors. The experiment was conducted on fifty-four entire male pigs (Duroc * Pietrain * Large White * Landrace crossbred) from 59 to 92 kg of live weight. Each pig was randomly assigned to one of six experimental treatments (n = 9). The treatments followed a 2 * 3 factorial arrangement, providing two levels of arginine supplementation (0 vs. 1%) and three levels of basal diet (normal protein diet, NPD; reduced protein diet, RPD; reduced protein diet with 2% of leucine, RPDL). RESULTS: Significant interactions between arginine supplementation and protein level were observed across plasma lipids. While dietary arginine increased total lipids, total cholesterol, HDL-cholesterol, LDL cholesterol, VLDL-cholesterol and triacylglycerols in NPD, the inverse effect was observed in RPD. Overall, dietary treatments had a minor impact on hepatic fatty acid composition. RPD increased 18:1c9 fatty acid while the combination of leucine and RPD reduced 18:0 fatty acid. Arginine supplementation increased the gene expression of FABP1, which contributes for triacylglycerols synthesis without affecting hepatic fatty acids content. RPD, with or without leucine addition, upregulated the lipogenic gene CEBPA but downregulated the fat oxidation gene LPIN1. CONCLUSIONS: Arginine supplementation was responsible for a modulated effect on plasma lipids, which is dependent on dietary protein level. It consistently increased lipaemia in NPD, while reducing the correspondent metabolites in RPD. In contrast, arginine had no major impact, neither on hepatic fatty acids content nor on fatty acid composition. Likewise, leucine supplementation of RPD, regardless the presence of arginine, promoted no changes on total fatty acids in the liver. Ultimately, arginine, leucine and dietary protein reduction seem to be unrelated with fatty liver development. PMID- 28558682 TI - Anti-proliferative potential of Glucosamine in renal cancer cells via inducing cell cycle arrest at G0/G1 phase. AB - BACKGROUND: Renal cell carcinoma (RCC) is one of the most common types of cancer in urological system worldwide. Recently, the anticancer role of Glucosamine has been studied in many types of cancer. The aim of this study was to investigate the effects of Glucosamine on RCC. METHODS: The effects of Glucosamine on RCC cell proliferation and apoptosis were investigated by MTT assay and Annexin V FITC Apoptosis assay, respectively in vitro. Cell cycle was detected by flow cytometry after treatment with Glucosamine. Protein levels of several cell cycle associated markers were examined by Western Blot. RESULTS: Our data showed that Glucosamine significantly inhibited the proliferation of renal cancer 786-O and Caki-1 cells in a dose-dependent manner. Besides, Glucosamine treatment resulted in cell cycle arrest at G0/G1 phase in both cell lines. Meanwhile, the expression of several regulators that contribute to G1/S phased transition, such as Cyclin D1, CDK4 and CDK6, were significantly down-regulated with the up-regulation of cell cycle inhibitors, p21 and p53, after treatment with glucosamine. However, the apoptosis rate of RCC cells was down-regulated when treatment with Glucosamine at 1 mM and 5 mM, while up-regulated at 10 mM. CONCLUSIONS: Our findings indicated that Glucosamine inhibited the proliferation of RCC cells by promoting cell cycle arrest at G0/G1 phase, but not promoting apoptosis. The present results suggested that Glucosamine might be a potential therapeutic agent in RCC treatment in the future. PMID- 28558683 TI - Inhibition of biofilm formation in Mycobacterium smegmatis by Parinari curatellifolia leaf extracts. AB - BACKGROUND: Tuberculosis (TB) is a serious public health problem worldwide. Mycobacterium tuberculosis (M. tuberculosis) grows as drug tolerant pellicles. Agents that inhibit biofilm formation in M. tuberculosis have the potential to reduce the disease treatment period and improve the quality of tuberculosis chemotherapy. Parinari curatellifolia (P. curatellifolia) leaf extracts are claimed to treat symptoms similar to tuberculosis in ethnomedicinal practices. Mycobacterium smegmatis (M. smegmatis) is a surrogate organism used in antimycobacterial drug discovery assays. In this study, the effect of the leaf extracts of P. curatellifolia on M. smegmatis growth and biofilm formation was investigated in order to determine the basis of its use in traditional medicinal use. METHODS: Phytochemicals from P. curatellifolia leaves were prepared using a mixture of 50% dichloromethane (DCM): 50% methanol and by serial exhaustive extraction using different solvents of decreasing polarity. The solvents were used in the following order, hexane > dichloromethane > ethyl acetate > acetone >ethanol > methanol > water. The micro-broth dilution method was used as an antimycobacterial susceptibility test to screen for the extract that effectively inhibited M. smegmatis growth and biofilm formation. Biofilm quantification was performed by staining the biofilms with crystal violet and determining the amount of the stain using a spectrophotometer. In addition, the effects of combining the most active extract with kanamycin were also investigated. RESULTS: The minimum inhibitory concentrations (MIC) of the extracts were found to be 6.2 MUg/ml for the acetone extract, 12.5 MUg/ml for both the ethanol and the total extract and 50 MUg/ml for both the methanol and ethyl acetate extracts. The ethanol extract, dichloromethane extract and water extract were the only extracts that effectively inhibited biofilm formation in M. smegmatis. Combining the ethanol extract with kanamycin enhanced the effect of the ethanol extract in terms of inhibition of biofilm formation. CONCLUSIONS: P. curatellifolia leaves contain phytochemicals that have the potential to be used both as antimycobacterial and anti-biofilm formation compounds. PMID- 28558685 TI - Predictors of survival outcomes in native sub Saharan black men newly diagnosed with metastatic prostate cancer. AB - BACKGROUND: Though it is well established that black men are at higher risk of prostate cancer (PCa) very little is known about the disease in native sub Saharan black men. Newly diagnosed metastatic PCa patients treated with primary androgen deprivation therapy were identified and predictors of progression-free survival (PFS) assessed. METHODS: Patients diagnosed with metastatic PCa between 2010 and 2015 in a sub Saharan black population were included in the study. Primary outcome measure was PFS defined as time from primary androgen deprivation therapy to clinical progression or death. Demographic, clinical and PSA kinetic variables were evaluated for their prognostic power using Cox proportional hazard regression models. RESULTS: Seventy-nine patients met the eligibility criteria and were analyzed. Median age, median overall survival and PFS was 69 years, 40 months and 27 months respectively. A PSA nadir >4 ng/mL was found to predict an earlier clinical progression. Median PFS was shorter in those with PSA nadir >4 ng/mL (15 months) compared to those with PSA nadir <=4 ng/mL (29 months); log rank p value = 0.003. CONCLUSIONS: The PSA nadir achieved following primary androgen deprivation therapy predicts progression-free survival in sub Saharan black men newly diagnosed with metastatic PCa. PSA nadir >4 ng/mL was found to be associated with a more rapid clinical progression. PMID- 28558684 TI - Evaluating the accuracy of amplicon-based microbiome computational pipelines on simulated human gut microbial communities. AB - BACKGROUND: Microbiome studies commonly use 16S rRNA gene amplicon sequencing to characterize microbial communities. Errors introduced at multiple steps in this process can affect the interpretation of the data. Here we evaluate the accuracy of operational taxonomic unit (OTU) generation, taxonomic classification, alpha- and beta-diversity measures for different settings in QIIME, MOTHUR and a pplacer based classification pipeline, using a novel software package: DECARD. RESULTS: In-silico we generated 100 synthetic bacterial communities approximating human stool microbiomes to be used as a gold-standard for evaluating the colligative performance of microbiome analysis software. Our synthetic data closely matched the composition and complexity of actual healthy human stool microbiomes. Genus level taxonomic classification was correctly done for only 50.4-74.8% of the source organisms. Miscall rates varied from 11.9 to 23.5%. Species-level classification was less successful, (6.9-18.9% correct); miscall rates were comparable to those of genus-level targets (12.5-26.2%). The degree of miscall varied by clade of organism, pipeline and specific settings used. OTU generation accuracy varied by strategy (closed, de novo or subsampling), reference database, algorithm and software implementation. Shannon diversity estimation accuracy correlated generally with OTU-generation accuracy. Beta-diversity estimates with Double Principle Coordinate Analysis (DPCoA) were more robust against errors introduced in processing than Weighted UniFrac. The settings suggested in the tutorials were among the worst performing in all outcomes tested. CONCLUSIONS: Even when using the same classification pipeline, the specific OTU-generation strategy, reference database and downstream analysis methods selection can have a dramatic effect on the accuracy of taxonomic classification, and alpha- and beta diversity estimation. Even minor changes in settings adversely affected the accuracy of the results, bringing them far from the best-observed result. Thus, specific details of how a pipeline is used (including OTU generation strategy, reference sets, clustering algorithm and specific software implementation) should be specified in the methods section of all microbiome studies. Researchers should evaluate their chosen pipeline and settings to confirm it can adequately answer the research question rather than assuming the tutorial or standard-operating procedure settings will be adequate or optimal. PMID- 28558686 TI - Global identification, structural analysis and expression characterization of bHLH transcription factors in wheat. AB - BACKGROUND: Basic helix-loop-helix (bHLH) transcription factors (TFs), which are widely distributed in eukaryotic organisms, play crucial roles in plant development. However, no comprehensive analysis of the bHLH family in wheat (Triticum aestivum L.) has been undertaken previously. RESULTS: In this study, 225 bHLH TFs predicted from wheat using genomic and RNA sequencing data were subjected to identification, classification, phylogenetic reconstruction, conserved motif characterization, chromosomal distribution determination and expression pattern analysis. One basic region, two helix regions and one loop region were found to be conserved in wheat bHLH TFs. The bHLH proteins could be separated into four categories based on sequences in their basic regions. Neighbor-joining-based phylogenetic analysis of conserved bHLH domains from wheat, Arabidopsis and rice identified 26 subfamilies of bHLH TFs, of which 23 were found in wheat. A total of 82 wheat bHLH genes had orthologs in Arabidopsis (27 TFs), rice (28 TFs) and both of them (27 TFs). Seven tissue-specific bHLH TF clusters were identified according to their expression patterns in endosperm, aleurone, seedlings, heading-stage spikes, flag leaves, shoots and roots. Expression levels of six endosperm-specifically expressed TFs measured by qPCR and RNA-seq showed a good correlation. CONCLUSION: The 225 bHLH transcription factors identified from wheat could be classed into 23 subfamilies, and those members from the same subfamily with similar sequence motifs generally have similar expression patterns. PMID- 28558687 TI - Bibliometric analysis of worldwide scientific literature in mobile - health: 2006 2016. AB - BACKGROUND: The advancement of mobile technology had positively influenced healthcare services. An emerging subfield of mobile technology is mobile health (m-Health) in which mobile applications are used for health purposes. The aim of this study was to analyze and assess literature published in the field of m Health. METHODS: SciVerse Scopus was used to retrieve literature in m-Health. The study period was set from 2006 to 2016. ArcGIS 10.1 was used to present geographical distribution of publications while VOSviewer was used for data visualization. Growth of publications, citation analysis, and research productivity were presented using standard bibliometric indicators. RESULTS: During the study period, a total of 5465 documents were published, giving an average of 496.8 documents per year. The h-index of retrieved documents was 81. Core keywords used in literature pertaining to m-Health included diabetes mellitus, adherence, and obesity among others. Relative growth rate and doubling time of retrieved literature were stable from 2009 to 2015 indicating exponential growth of literature in this field. A total of 4638 (84.9%) documents were multi authored with a mean collaboration index of 4.1 authors per article. The United States of America ranked first in productivity with 1926 (35.2%) published documents. India ranked sixth with 183 (3.3%) documents while China ranked seventh with 155(2.8%) documents. VA Medical Center was the most prolific organization/institution while Journal of Medical Internet Research was the preferred journal for publications in the field of m-Health. Top cited articles in the field of m-Health included the use of mobile technology in improving adherence in HIV patients, weight loss, and improving glycemic control in diabetic patients. CONCLUSION: The size of literature in m-Health showed a noticeable increase in the past decade. Given the large volume of citations received in this field, it is expected that applications of m-Health will be seen into various health aspects and health services. Research in m-Health needs to be encouraged, particularly in the fight against AIDS, poor medication adherence, glycemic control in Africa and other low income world regions where technology can improve health services and decrease disease burden. PMID- 28558688 TI - High-quality genetic mapping with ddRADseq in the non-model tree Quercus rubra. AB - BACKGROUND: Restriction site associated DNA sequencing (RADseq) has the potential to be a broadly applicable, low-cost approach for high-quality genetic linkage mapping in forest trees lacking a reference genome. The statistical inference of linear order must be as accurate as possible for the correct ordering of sequence scaffolds and contigs to chromosomal locations. Accurate maps also facilitate the discovery of chromosome segments containing allelic variants conferring resistance to the biotic and abiotic stresses that threaten forest trees worldwide. We used ddRADseq for genetic mapping in the tree Quercus rubra, with an approach optimized to produce a high-quality map. Our study design also enabled us to model the results we would have obtained with less depth of coverage. RESULTS: Our sequencing design produced a high sequencing depth in the parents (248*) and a moderate sequencing depth (15*) in the progeny. The digital normalization method of generating a de novo reference and the SAMtools SNP variant caller yielded the most SNP calls (78,725). The major drivers of map inflation were multiple SNPs located within the same sequence (77% of SNPs called). The highest quality map was generated with a low level of missing data (5%) and a genome-wide threshold of 0.025 for deviation from Mendelian expectation. The final map included 849 SNP markers (1.8% of the 78,725 SNPs called). Downsampling the individual FASTQ files to model lower depth of coverage revealed that sequencing the progeny using 96 samples per lane would have yielded too few SNP markers to generate a map, even if we had sequenced the parents at depth 248*. CONCLUSIONS: The ddRADseq technology produced enough high-quality SNP markers to make a moderately dense, high-quality map. The success of this project was due to high depth of coverage of the parents, moderate depth of coverage of the progeny, a good framework map, an optimized bioinformatics pipeline, and rigorous premapping filters. The ddRADseq approach is useful for the construction of high-quality genetic maps in organisms lacking a reference genome if the parents and progeny are sequenced at sufficient depth. Technical improvements in reduced representation sequencing (RRS) approaches are needed to reduce the amount of missing data. PMID- 28558689 TI - Mortality in patients with HIV-1 and tuberculosis co-infection in Rio de Janeiro, Brazil - associated factors and causes of death. AB - BACKGROUND: Tuberculosis is the most frequent opportunistic infection and the leading cause of death among persons living with HIV in several low and middle income countries. Mortality rates during tuberculosis treatment and death causes among HIV-1/TB co-infected patients may differ based on the immunosuppression severity, timing of diagnosis and prompt initiation of tuberculosis and antiretroviral therapy. METHODS: This was a retrospective observational study conducted in the clinical cohort of patients with HIV-1/Aids of the National Institute of Infectious Diseases Evandro Chagas, Rio de Janeiro, Brazil. All HIV 1 infected patients who started combination antiretroviral therapy up to 30 days before or within 180 days after the start of tuberculosis treatment from 2000 to 2010 were eligible. Causes of death were categorized according to the "Coding Causes of Death in HIV" (CoDe) protocol. The Cox model was used to estimate the hazard ratio (HR) of selected mortality variables. RESULTS: A total of 310 patients were included. Sixty-four patients died during the study period. Mortality rate following tuberculosis treatment initiation was 44 per 100 person years within the first 30 days, 28.1 per 100 person-years within 31 and 90 days, 6 per 100 person-years within 91 and 365 days and 1.6 per 100 person-years after 365 days. Death probability within one year from tuberculosis treatment initiation was approximately 13%. In the adjusted analysis the associated factors with mortality were: CD4 <= 50 cells/mm3 (HR: 3.10; 95% CI: 1.720 to 5.580; p = 0.00); mechanical ventilation (HR: 2.81; 95% CI: 1.170 to 6.760; p = 0.02); and disseminated tuberculosis (HR: 3.70; 95% CI: 1.290 to 10.590, p = 0.01). Invasive bacterial disease was the main immediate cause of death (46.9%). CONCLUSION: Our results evidence the high morbidity and mortality among patients co-infected with HIV-1 and tuberculosis in Rio de Janeiro, Brazil. During the first year following tuberculosis diagnosis, mortality was the highest within the first 3 months, being invasive bacterial infection the major cause of death. In order to successfully intervene in this scenario, it is utterly necessary to address the social determinants of health contributing to the inequitable health care access faced by this population. PMID- 28558691 TI - The development and use of a molecular model for soybean maturity groups. AB - BACKGROUND: Achieving appropriate maturity in a target environment is essential to maximizing crop yield potential. In soybean [Glycine max (L.) Merr.], the time to maturity is largely dependent on developmental response to dark periods. Once the critical photoperiod is reached, flowering is initiated and reproductive development proceeds. Therefore, soybean adaptation has been attributed to genetic changes and natural or artificial selection to optimize plant development in specific, narrow latitudinal ranges. In North America, these regions have been classified into twelve maturity groups (MG), with lower MG being shorter season than higher MG. Growing soybean lines not adapted to a particular environment typically results in poor growth and significant yield reductions. The objective of this study was to develop a molecular model for soybean maturity based on the alleles underlying the major maturity loci: E1, E2, and E3. RESULTS: We determined the allelic variation and diversity of the E maturity genes in a large collection of soybean landraces, North American ancestors, Chinese cultivars, North American cultivars or expired Plant Variety Protection lines, and private company lines. The E gene status of accessions in the USDA Soybean Germplasm Collection with SoySNP50K Beadchip data was also predicted. We determined the E allelic combinations needed to adapt soybean to different MGs in the United States (US) and discovered a strong signal of selection for E genotypes released in North America, particularly the US and Canada. CONCLUSIONS: The E gene maturity model proposed will enable plant breeders to more effectively transfer traits into different MGs and increase the overall efficiency of soybean breeding in the US and Canada. The powerful yet simple selection strategy for increasing soybean breeding efficiency can be used alone or to directly enhance genomic prediction/selection schemes. The results also revealed previously unrecognized aspects of artificial selection in soybean imposed by soybean breeders based on geography that highlights the need for plant breeding that is optimized for specific environments. PMID- 28558690 TI - Profile and functional analysis of small RNAs derived from Aspergillus fumigatus infected with double-stranded RNA mycoviruses. AB - BACKGROUND: Mycoviruses are viruses that naturally infect and replicate in fungi. Aspergillus fumigatus, an opportunistic pathogen causing fungal lung diseases in humans and animals, was recently shown to harbour several different types of mycoviruses. A well-characterised defence against virus infection is RNA silencing. The A. fumigatus genome encodes essential components of the RNA silencing machinery, including Dicer, Argonaute and RNA-dependent RNA polymerase (RdRP) homologues. Active silencing of double-stranded (ds)RNA and the generation of small RNAs (sRNAs) has been shown for several mycoviruses and it is anticipated that a similar mechanism will be activated in A. fumigatus isolates infected with mycoviruses. RESULTS: To investigate the existence and nature of A. fumigatus sRNAs, sRNA-seq libraries of virus-free and virus-infected isolates were created using Scriptminer adapters and compared. Three dsRNA viruses were investigated: Aspergillus fumigatus partitivirus-1 (AfuPV-1, PV), Aspergillus fumigatus chrysovirus (AfuCV, CV) and Aspergillus fumigatus tetramycovirus-1 (AfuTmV-1, NK) which were selected because they induce phenotypic changes such as coloration and sectoring. The dsRNAs of all three viruses, which included two conventionally encapsidated ones PV and CV and one unencapsidated example NK, were silenced and yielded characteristic vsiRNAs together with co-incidental silencing of host fungal genes which shared sequence homology with the viral genomes. CONCLUSIONS: Virus-derived sRNAs were detected and characterised in the presence of virus infection. Differentially expressed A. fumigatus microRNA-like (miRNA-like) sRNAs and small interfering RNAs (siRNAs) were detected and validated. Host sRNA loci which were differentially expressed as a result of virus infection were also identified. To our knowledge, this is the first study reporting the sRNA profiles of A. fumigatus isolates. PMID- 28558692 TI - The feasibility and efficacy of implementing a focused cardiac ultrasound course into a medical school curriculum. AB - BACKGROUND: Teaching cardiac ultrasound to medical students in a brief course is a challenge. We aimed to evaluate the feasibility of teaching large groups of medical students the acquisition and interpretation of cardiac ultrasound images using a pocket ultrasound device (PUD) in a short, specially designed course. METHODS: Thirty-one medical students in their first clinical year participated in the study. All were novices in the use of cardiac ultrasound. The training consisted of 4 hours of frontal lectures and 4 hours of hands-on training. Students were encouraged to use PUD for individual practice. Finally, the students' proficiency in the acquisition of ultrasound images and their ability to recognize normal and pathological states were evaluated. RESULTS: Sixteen of 27 (59%) students were able to demonstrate all main ultrasound views (parasternal, apical, and subcostal views) in a six-minute test. The most obtainable view was the parasternal long-axis view (89%) and the least obtainable was the subcostal view (58%). Ninety-seven percent of students correctly differentiated normal from severely reduced left ventricular function, 100% correctly differentiated a normal right ventricle from a severely hypokinetic one, 100% correctly differentiated a normal mitral valve from a rheumatic one, and 88% correctly differentiated a normal aortic valve from a calcified one, while 95% of them correctly identified the presence of pericardial effusion. CONCLUSIONS: Training of medical students in cardiac ultrasound during the first clinical year using a short, focused course is feasible and enables students with modest ability to acquire the main transthoracic ultrasound views and gain proficiency in the diagnosis of a limited number of cardiac pathologies. PMID- 28558693 TI - Scrambling for access: availability, accessibility, acceptability and quality of healthcare for lesbian, gay, bisexual and transgender people in South Africa. AB - BACKGROUND: Sexual orientation and gender identity are social determinants of health for people identifying as lesbian, gay, bisexual and transgender (LGBT), and health disparities among sexual and gender minority populations are increasingly well understood. Although the South African constitution guarantees sexual and gender minority people the right to non-discrimination and the right to access to healthcare, homo- and transphobia in society abound. Little is known about LGBT people's healthcare experiences in South Africa, but anecdotal evidence suggests significant barriers to accessing care. Using the framework of the UN International Covenant on Economic, Social and Cultural Rights General Comment 14, this study analyses the experiences of LGBT health service users using South African public sector healthcare, including access to HIV counselling, testing and treatment. METHODS: A qualitative study comprised of 16 semi-structured interviews and two focus group discussions with LGBT health service users, and 14 individual interviews with representatives of LGBT organisations. Data were thematically analysed within the framework of the UN International Covenant on Economic, Social and Cultural Rights General Comment 14, focusing on availability, accessibility, acceptability and quality of care. RESULTS: All interviewees reported experiences of discrimination by healthcare providers based on their sexual orientation and/or gender identity. Participants recounted violations of all four elements of the UN General Comment 14: 1) Availability: Lack of public health facilities and services, both for general and LGBT-specific concerns; 2) Accessibility: Healthcare providers' refusal to provide care to LGBT patients; 3) Acceptability: Articulation of moral judgment and disapproval of LGBT patients' identity, and forced subjection of patients to religious practices; 4) Quality: Lack of knowledge about LGBT identities and health needs, leading to poor-quality care. Participants had delayed or avoided seeking healthcare in the past, and none had sought out accountability or complaint mechanisms within the health system. CONCLUSION: Sexual orientation and gender identity are important categories of analysis for health equity, and lead to disparities in all four dimensions of healthcare access as defined by General Comment 14. Discriminatory and prejudicial attitudes by healthcare providers, combined with a lack of competency and knowledge are key reasons for these disparities in South Africa. PMID- 28558694 TI - Accurate characterization of the IFITM locus using MiSeq and PacBio sequencing shows genetic variation in Galliformes. AB - BACKGROUND: Interferon inducible transmembrane (IFITM) proteins are effectors of the immune system widely characterized for their role in restricting infection by diverse enveloped and non-enveloped viruses. The chicken IFITM (chIFITM) genes are clustered on chromosome 5 and to date four genes have been annotated, namely chIFITM1, chIFITM3, chIFITM5 and chIFITM10. However, due to poor assembly of this locus in the Gallus Gallus v4 genome, accurate characterization has so far proven problematic. Recently, a new chicken reference genome assembly Gallus Gallus v5 was generated using Sanger, 454, Illumina and PacBio sequencing technologies identifying considerable differences in the chIFITM locus over the previous genome releases. METHODS: We re-sequenced the locus using both Illumina MiSeq and PacBio RS II sequencing technologies and we mapped RNA-seq data from the European Nucleotide Archive (ENA) to this finalized chIFITM locus. Using SureSelect probes capture probes designed to the finalized chIFITM locus, we sequenced the locus of a different chicken breed, namely a White Leghorn, and a turkey. RESULTS: We confirmed the Gallus Gallus v5 consensus except for two insertions of 5 and 1 base pair within the chIFITM3 and B4GALNT4 genes, respectively, and a single base pair deletion within the B4GALNT4 gene. The pull down revealed a single amino acid substitution of A63V in the CIL domain of IFITM2 compared to Red Jungle fowl and 13, 13 and 11 differences between IFITM1, 2 and 3 of chickens and turkeys, respectively. RNA-seq shows chIFITM2 and chIFITM3 expression in numerous tissue types of different chicken breeds and avian cell lines, while the expression of the putative chIFITM1 is limited to the testis, caecum and ileum tissues. CONCLUSIONS: Locus resequencing using these capture probes and RNA-seq based expression analysis will allow the further characterization of genetic diversity within Galliformes. PMID- 28558695 TI - Azithromycin and risk of COPD exacerbations in patients with and without Helicobacter pylori. AB - BACKGROUND: Helicobacter pylori (HP) infection is associated with reduced lung function and systemic inflammation in chronic obstructive pulmonary disease (COPD) patients. Azithromycin (AZ) is active against HP and reduces the risk of COPD exacerbation. We determined whether HP infection status modifies the effects of AZ in COPD patients. METHODS: Plasma samples from 1018 subjects with COPD who participated in the Macrolide Azithromycin (MACRO) in COPD Study were used to determine the HP infection status at baseline and 12 months of follow-up using a serologic assay. Based on HP infection status and randomization to either AZ or placebo (PL), the subjects were divided into 4 groups: HP+/AZ, HP-/AZ, HP+/PL, and HP-/PL. Time to first exacerbation was compared across the 4 groups using Kaplan-Meier survival analysis and a Cox proportional hazards model. The rates of exacerbation were compared using both the Kruskal-Wallis test and negative binomial analysis. Blood biomarkers at enrolment and at follow-up visits 3, 12, and 13 (1 month after treatment was stopped) months were measured. RESULTS: One hundred eighty one (17.8%) patients were seropositive to HP. Non-Caucasian participants were nearly three times more likely to be HP seropositive than Caucasian participants (37.4% vs 13.6%; p < 0.001). The median time to first exacerbation was significantly different across the four groups (p = 0.001) with the longest time in the HP+/AZ group (11.2 months, 95% CI; 8.4-12.5+) followed by the HP-/AZ group (8.0 months, 95% CI; 6.7-9.7). Hazard ratio (HR) for exacerbations was lowest in the HP+/AZ group after adjustment for age, sex, smoking status, ethnicity, history of peptic ulcer, dyspnea, previous hospital admission, GOLD grade of severity, and forced vital capacity (HR, 0.612; 95% CI, 0.442-0.846 vs HR, 0.789; 95% CI, 0.663-0.938 in the HP-/AZ group). Circulating levels of soluble tumor necrosis factor receptor-75 were reduced only in the HP+/AZ group after 3 months of AZ treatment (-0.87 +/- 0.31 MUg/L; p = 0.002); levels returned to baseline after discontinuing AZ. CONCLUSIONS: AZ is effective in preventing COPD exacerbations in patients with HP seropositivity, possibly by modulating TNF pathways related to HP infection. PMID- 28558697 TI - Does an electronic cognitive aid have an effect on the management of severe gynaecological TURP syndrome? A prospective, randomised simulation study. AB - BACKGROUND: Lack of familiarity with the content of current guidelines is a major factor associated with non-compliance by clinicians. It is conceivable that cognitive aids with regularly updated medical content can guide clinicians' task performance by evidence-based practices, even if they are unfamiliar with the actual guideline. Acute hyponatraemia as a consequence of TURP syndrome is a rare intraoperative event, and current practice guidelines have changed from slow correction to rapid correction of serum sodium levels. The primary objective of this study was to compare the management of a simulated severe gynaecological transurethral resection of the prostate (TURP) syndrome under spinal anaesthesia with either: an electronic cognitive aid, or with management from memory alone. The secondary objective was to assess the clinical relevance and participant perception of the usefulness of the cognitive aid. METHODS: Anaesthetic teams were allocated to control (no cognitive aid; n = 10) or intervention (cognitive aid provided; n = 10) groups. We identified eight evidence-based management tasks for severe TURP syndrome from current guidelines and subdivided them into acute heart failure (AHF)/pulmonary oedema tasks (5) and acute hyponatraemia tasks (3). Implementation of the treatment steps was measured by scoring task items in a binary fashion (yes/no). To assess whether or not the cognitive aid had prompted a treatment step, participants from the cognitive aid group were questioned during debriefing on every single treatment step. At the end of the simulation, session participants were asked to complete a survey. RESULTS: Teams in the cognitive aid group considered evidence-based treatment steps significantly more often than teams of the control group (96% vs. 50% for 'AHF/pulmonary oedema' p < 0.001; 79% vs. 12% for 'acute hyponatraemia' p < 0.001). Without the cognitive aid, performance would have been comparable across both groups. Nurses, trainees, and consultants derived equal benefit from the cognitive aid. CONCLUSIONS: The cognitive aid improved the implementation of evidence-based practices in a simulated intraoperative scenario. Cognitive aids with current medical content could help to close the translational gap between guideline publication and implementation in acute patient care. It is important that the cognitive aid should be familiar, in a format that has been used in practice and training. PMID- 28558696 TI - In-depth genome characterization of a Brazilian common bean core collection using DArTseq high-density SNP genotyping. AB - BACKGROUND: Common bean is a legume of social and nutritional importance as a food crop, cultivated worldwide especially in developing countries, accounting for an important source of income for small farmers. The availability of the complete sequences of the two common bean genomes has dramatically accelerated and has enabled new experimental strategies to be applied for genetic research. DArTseq has been widely used as a method of SNP genotyping allowing comprehensive genome coverage with genetic applications in common bean breeding programs. RESULTS: Using this technology, 6286 SNPs (1 SNP/86.5 Kbp) were genotyped in genic (43.3%) and non-genic regions (56.7%). Genetic subdivision associated to the common bean gene pools (K = 2) and related to grain types (K = 3 and K = 5) were reported. A total of 83% and 91% of all SNPs were polymorphic within the Andean and Mesoamerican gene pools, respectively, and 26% were able to differentiate the gene pools. Genetic diversity analysis revealed an average H E of 0.442 for the whole collection, 0.102 for Andean and 0.168 for Mesoamerican gene pools (F ST = 0.747 between gene pools), 0.440 for the group of cultivars and lines, and 0.448 for the group of landrace accessions (F ST = 0.002 between cultivar/line and landrace groups). The SNP effects were predicted with predominance of impact on non-coding regions (77.8%). SNPs under selection were identified within gene pools comparing landrace and cultivar/line germplasm groups (Andean: 18; Mesoamerican: 69) and between the gene pools (59 SNPs), predominantly on chromosomes 1 and 9. The LD extension estimate corrected for population structure and relatedness (r2SV) was ~ 88 kbp, while for the Andean gene pool was ~ 395 kbp, and for the Mesoamerican was ~ 130 kbp. CONCLUSIONS: For common bean, DArTseq provides an efficient and cost-effective strategy of generating SNPs for large-scale genome-wide studies. The DArTseq resulted in an operational panel of 560 polymorphic SNPs in linkage equilibrium, providing high genome coverage. This SNP set could be used in genotyping platforms with many applications, such as population genetics, phylogeny relation between common bean varieties and support to molecular breeding approaches. PMID- 28558699 TI - Incidence of and factors associated with catheter-related bloodstream infection in patients with advanced solid tumors on home parenteral nutrition managed using a standardized catheter care protocol. AB - BACKGROUND: Catheter-related bloodstream infections (CRBSIs) are associated with high morbidity and mortality as well as increased medical costs. Cancer patients, who are often immunocompromised, are susceptible to CRBSI while receiving home parenteral nutrition (HPN). We evaluated the incidence of and factors associated with CRBSIs in cancer patients undergoing HPN managed using a standardized catheter care protocol. METHODS: This is a retrospective cohort study of 335 cancer patients receiving HPN between January 2012 and July 2015. The primary outcome of interest was the incidence of CRBSI expressed as events per 1000 HPN days. HPN days were calculated from the start date with the home infusion provider until the discontinuation of HPN, or the removal of the venous access device (VAD), or the death of the patient. The VADs used were either peripherally inserted central catheters (PICCs) or a subcutaneous implanted port or tunneled central catheters (TCCs). Univariate Poisson regression analyses were used to determine the variables associated with CRBSIs. RESULTS: Of 335 patients, 193 were females and 142 were males. The most common cancer types were colorectal, pancreatic, ovarian and stomach. A total of 408 VADs in 335 patients were studied, covering a total of 29,403 HPN days. Of 408 VADs, 206 (50.5%) were ports, 191 (46.8%) were PICCs, and 7 (2.7%) were TCCs. The median duration of HPN was 54 days. A total of 16 CRBSI episodes were recorded (8 in ports, 7 in PICCs and 1 in TCCs). The median duration from the start of HPN to the development of CRBSI episodes was 43.5 days. The overall incidence of CRBSI per 1000 HPN days was 0.54 (95% confidence interval: 0.32-0.86). Upon univariate analysis, no variables were found to be statistically significantly associated with CRBSI incidence. CONCLUSIONS: We found a low rate of CRBSI following a standardized catheter maintenance protocol in a high-risk oncology population undergoing HPN. PMID- 28558698 TI - Role of human rhinovirus in triggering human airway epithelial-mesenchymal transition. AB - BACKGROUND: Structural changes in the airways, collectively referred to as airway remodeling, are a characteristic feature of asthma, and are now known to begin in early life. Human rhinovirus (HRV)-induced wheezing illnesses during early life are a potential inciting stimulus for remodeling. Increased deposition of matrix proteins causes thickening of the lamina reticularis, which is a well-recognized component of airway remodeling. Increased matrix protein deposition is believed to be due to the presence of increased numbers of activated mesenchymal cells (fibroblasts/myofibroblasts) in the subepithelial region of asthmatic airways. The origin of these increased mesenchymal cells is not clear, but one potential contributor is the process of epithelial-mesenchymal transition (EMT). We hypothesized that HRV infection may help to induce EMT. METHODS: We used the BEAS 2B human bronchial epithelial cells line, which uniformly expresses the major group HRV receptor, to examine the effects of stimulation with HRV alone, transforming growth factor-beta1 (TGF-beta1), alone, and the combination, on induction of changes consistent with EMT. Western blotting was used to examine expression of epithelial and mesenchymal phenotypic marker proteins and selected signaling molecules. Cell morphology was also examined. RESULTS: In this study, we show that two different strains of HRV, which use two different cellular receptors, are each capable of triggering phenotypic changes consistent with EMT. Moreover, both HRV serotypes synergistically induced changes consistent with EMT when used in the presence of TGF-beta1. Morphological changes were also most pronounced with the combination of HRV and TGF-beta1. Viral replication was not essential for phenotypic changes. The synergistic interactions between HRV and TGF-beta1 were mediated, at least in part, via activation of mitogen activated protein kinase pathways, and via induction of the transcription factor SLUG. CONCLUSIONS: These data support a role for HRV in the induction of EMT, which may contribute to matrix protein deposition and thickening of the lamina reticularis in airways of patients with asthma. PMID- 28558700 TI - Punicic acid: A striking health substance to combat metabolic syndromes in humans. AB - Punicic acid, a bioactive compound of pomegranate seed oil has gained wide attention for their therapeutic potential. Different studies conducted on animal and human models have revealed that punicic acid is very effective against various chronic diseases. Substantial laboratory works has been carried out to elaborate punicic acid effectiveness and mechanism of action in animals. The intention of this review article is to explore the facts about the clinical trials of punicic acid and to discuss different future strategies that can be employed to use it in human clinical trials. Although punicic acid may represent a novel therapeutic unconventional approach for some disorders, still further experimental studies are required to demonstrate its effects in human beings. PMID- 28558701 TI - Rapid reduction of malaria following introduction of vector control interventions in Tororo District, Uganda: a descriptive study. AB - BACKGROUND: In 2012, Tororo District had the highest malaria burden in Uganda with community Plasmodium prevalence of 48%. To control malaria in the district, the Ministry of Health introduced universal distribution of long lasting insecticide-treated nets (LLINs) in 2013 and added indoor residual spraying (IRS) in 2014. This study assessed malaria incidence, test positivity rates and outpatient (OPD) attendance due to malaria before and after vector control interventions. METHODS: This study was based on analysis of Health Management Information System (HMIS) secondary malaria surveillance data of 2,727,850 patient records in OPD registers of 61 health facilities from 2012 to 2015. The analysis estimated monthly malaria incidence for the entire population and also separately for <5- and >=5-year-olds before and after introduction of vector control interventions; determined laboratory test positivity rates and annual percentage of malaria cases in OPD. Chi square for trends was used to analyse annual change in malaria incidence and logistic regression for monthly reduction. RESULTS: Following universal LLINs coverage, the annual mean monthly malaria incidence fell from 95 cases in 2013 to 76 cases per 1000 in 2014 with no significant monthly reduction (OR = 0.99, 95% CI 0.96-1.01, P = 0.37). Among children <5 years, the malaria incidence reduced from 130 to 100 cases per 1000 (OR = 0.98, 95% CI 0.97-1.00, P = 0.08) when LLINs were used alone in 2014, but declined to 45 per 1000 in 2015 when IRS was combined with LLINs (OR = 0.94, 95% CI 0.91-0.996, P < 0.0001). Among individuals aged >=5 years, mean monthly malaria incidence reduced from 59 to 52 cases per 1000 (OR = 0.99, 95% CI 0.97 1.02, P = 0.8) when LLINs were used alone in 2014, but reduced significantly to 25 per 1000 in 2015 (OR = 0.91, 95% CI 0.88-0.94, P < 0.0001). Malaria test positivity rate reduced from 57% in 2013 to 30% (Chi = 15, P < 0.0001) in 2015. Slide positivity rate reduced from 45% in 2013 to 21% in 2015 (P = 0.004) while RDT positivity declined from 69 to 40%. CONCLUSIONS: A rapid reduction in malaria incidence was observed in Tororo District following the introduction of IRS in addition to LLINs. There was no significant reduction in malaria incidence following universal distribution of LLINs to communities before introduction of IRS. PMID- 28558702 TI - Background anaesthetic agents do not influence the impact of arginine vasopressin on haemodynamic states and cerebral oxygenation during shoulder surgery in the beach chair position: a prospective, single-blind study. AB - BACKGROUND: Administration of arginine vasopressin (AVP) is associated with reducing jugular venous (SjvO2) and regional cerebral (rScO2) oxygen saturation under propofol-remifentanil (P/R) anaesthesia. We determined whether background anaesthetics modulate the effect of AVP on cerebral oxygenation and haemodynamics. METHODS: We randomly allocated 60 adult patients scheduled for shoulder surgery in the beach chair position (BCP) into 4 groups, to receive either an intravenous bolus of saline (groups PR-S and SN-S) or 0.05 U/kg AVP (groups PR-AVP and SN-AVP) under P/R or sevoflurane-nitrous oxide (S/N) anaesthesia (n = 15 each). Haemodynamic variables, SjvO2 and rScO2 were measured. RESULTS: AVP significantly increased mean arterial blood pressure (MAP) and decreased rScO2 in either anaesthetic group. AVP also decreased SjvO2 in the P/R groups but not in the S/N groups. The AVP-treated groups showed higher MAP and cerebral desaturation (>20% rScO2 decrease from baseline), along with lower HR and rScO2 in the BCP than those in the saline-treated groups. In contrast, AVP did not affect SjvO2 values or the incidence of SjvO 2 < 50%. Baseline SjvO2 was lower and the magnitude of its reduction in the BCP was greater in the PR-AVP group than in the SN-AVP group, and the lowest SjvO2 values were 37 +/- 6 and 57 +/- 8%, respectively (P < 0.001). CONCLUSIONS: The choice of anaesthetic regimen did not affect cerebral oxygenation or haemodynamics of AVP in the BCP. However, the negative effect of AVP on cerebral oxygenation should be considered, especially under P/R anaesthesia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01687894 , registered on September 18, 2012. PMID- 28558703 TI - "Fibromyalgia and quality of life: mapping the revised fibromyalgia impact questionnaire to the preference-based instruments". AB - BACKGROUND: The revised version of the Fibromyalgia Impact Questionnaire (FIQR) is one of the most widely used specific questionnaires in FM studies. However, this questionnaire does not allow calculation of QALYs as it is not a preference based measure. The aim of this study was to develop mapping algorithm which enable FIQR scores to be transformed into utility scores that can be used in the cost utility analyses. METHODS: A cross-sectional survey was conducted. One hundred and 92 Spanish women with Fibromyalgia were asked to complete four general quality of life questionnaires, i.e. EQ-5D-5 L, 15D, AQoL-8D and SF-12, and one specific disease instrument, the FIQR. A direct mapping approach was adopted to derive mapping algorithms between the FIQR and each of the four multi attribute utility (MAU) instruments. Health state utility was treated as the dependent variable in the regression analysis, whilst the FIQR score and age were predictors. RESULTS: The mean utility scores ranged from 0.47 (AQoL-8D) to 0.69 (15D). All correlations between the FIQR total score and MAU instruments utility scores were highly significant (p < 0.0001) with magnitudes larger than 0.5. Although very slight differences in the mean absolute error were found between ordinary least squares (OLS) estimator and generalized linear model (GLM), models based on GLM were better for EQ-5D-5 L, AQoL-8D and 15D. CONCLUSION: Mapping algorithms developed in this study enable the estimation of utility values from scores in a fibromyalgia specific questionnaire. PMID- 28558705 TI - Disseminated cryptococcosis with recurrent multiple abscesses in an immunocompetent patient: a case report and literature review. AB - BACKGROUND: Cryptococcus neoformans is frequently present as an opportunistic pathogen mainly affecting immunocompromised populations. Disseminated C. neoformans infection in immunocompetent population is rare and usually involves lung and central nerve system. Cryptococcus from biologic samples can easily grow on routine fungal and bacterial culture media. Besides, cryptococcal latex agglutination test has been established as a reliable diagnostic tool with overall sensitivities of 93-100%. CASE PRESENTATION: We report a rare disseminated cryptococcosis case which presented with chronic recurrent multiple abscess in an immunocompetent male involving skin, lung, spine and iliac fossa without evidence of central nerve system involving. The results of serum cryptococcal latex agglutination tests and standard microbial cultures were negative. The patient underwent empirical anti-bacterial and anti-tuberculosis therapy which turned out to be effectless. Finally, bedside inoculation of the pus was carried out and revealed Cryptococcus neoformans, which was confirmed by polymerase chain reaction. After the administration of anti-fungal drugs including liposomal amphotericin B, the patient recovered from fever and paraplegia. CONCLUSIONS: This case reveals an uncommon pattern of disseminated C. neoformans infection in immunocompetent population presented with chronic multiple abscess and without central nerve system involving. Negative routine microbial cultures may not necessarily rule out cryptococcosis, especially in early stage. Besides, cryptococcal latex agglutination test does have a chance of false negative, which might be related with "capsule-deficiency". Moreover, this phenomenon could be related with low-grade virulence and relative long illness duration. PMID- 28558704 TI - Genome-wide network-based pathway analysis of CSF t-tau/Abeta1-42 ratio in the ADNI cohort. AB - BACKGROUND: The cerebrospinal fluid (CSF) levels of total tau (t-tau) and Abeta1 42 are potential early diagnostic markers for probable Alzheimer's disease (AD). The influence of genetic variation on these CSF biomarkers has been investigated in candidate or genome-wide association studies (GWAS). However, the investigation of statistically modest associations in GWAS in the context of biological networks is still an under-explored topic in AD studies. The main objective of this study is to gain further biological insights via the integration of statistical gene associations in AD with physical protein interaction networks. RESULTS: The CSF and genotyping data of 843 study subjects (199 CN, 85 SMC, 239 EMCI, 207 LMCI, 113 AD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed. PLINK was used to perform GWAS on the t-tau/Abeta1-42 ratio using quality controlled genotype data, including 563,980 single nucleotide polymorphisms (SNPs), with age, sex and diagnosis as covariates. Gene-level p-values were obtained by VEGAS2. Genes with p-value <= 0.05 were mapped on to a protein-protein interaction (PPI) network (9,617 nodes, 39,240 edges, from the HPRD Database). We integrated a consensus model strategy into the iPINBPA network analysis framework, and named it as CM-iPINBPA. Four consensus modules (CMs) were discovered by CM-iPINBPA, and were functionally annotated using the pathway analysis tool Enrichr. The intersection of four CMs forms a common subnetwork of 29 genes, including those related to tau phosphorylation (GSK3B, SUMO1, AKAP5, CALM1 and DLG4), amyloid beta production (CASP8, PIK3R1, PPA1, PARP1, CSNK2A1, NGFR, and RHOA), and AD (BCL3, CFLAR, SMAD1, and HIF1A). CONCLUSIONS: This study coupled a consensus module (CM) strategy with the iPINBPA network analysis framework, and applied it to the GWAS of CSF t-tau/Abeta1-42 ratio in an AD study. The genome-wide network analysis yielded 4 enriched CMs that share not only genes related to tau phosphorylation or amyloid beta production but also multiple genes enriching several KEGG pathways such as Alzheimer's disease, colorectal cancer, gliomas, renal cell carcinoma, Huntington's disease, and others. This study demonstrated that integration of gene-level associations with CMs could yield statistically significant findings to offer valuable biological insights (e.g., functional interaction among the protein products of these genes) and suggest high confidence candidates for subsequent analyses. PMID- 28558706 TI - Electronic applications for the CFQ-R scoring. AB - Patient reported outcomes (PROs) have become widely accepted outcome measures in cystic fibrosis (CF) and other respiratory diseases. The Cystic Fibrosis Questionnaire-Revised (CFQ-R) is the best validated and most widely used PRO for CF. Data collection can be time-intensive, and electronic platforms would greatly facilitate the feasibility, utility and accuracy of administration of the CFQ-R. Given that the CFQ-R is utilized in virtually all clinical trials worldwide and is increasingly integrated into clinical practice, we developed a software application that will help users to administer, score and save CFQ-R data for all versions. All codes are open access, which will enable other PRO users to design similar applications for other respiratory diseases, such as primary ciliary dyskinesia and non-CF bronchiectasis. PMID- 28558707 TI - Effect of the 2014 Clinical and Laboratory Standards Institute urine-specific breakpoints on cefazolin susceptibility rates at a community teaching hospital. AB - BACKGROUND: Enterobacteriaceae, which include Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, are identified as the infectious etiology in the majority of urinary tract infections (UTIs) in community hospitals across the United States. The minimum inhibitory concentration (MIC) is a useful tool when choosing an appropriate antibacterial agent. Recent changes to the 2014 Clinical and Laboratory Standards Institute (CLSI) guidelines included reporting a urine specific cefazolin breakpoint for enterobacteriaceae (susceptible <=16 mcg/mL). The purpose of this study was to determine the clinical and financial impact of implementing the 2014 CLSI urine-specific breakpoints for cefazolin in a community-based teaching hospital in the Southern U.S.A. METHODS: A retrospective review of patients hospitalized from January 1, 2010 through October 1, 2014 was performed. Patients that met inclusion criteria had a documented initial clinical isolate of E. coli, K. pneumoniae, or P. mirabilis from urine cultures during each year. Descriptive statistics and two-proportion test of hypothesis were used in the analysis to compare susceptibility rates before and after implementation of the updated CLSI breakpoints for cefazolin. RESULTS: A total of 190 clinical isolates from patients were included in the study. E. coli was the most common organism isolated (63.7%), followed by K. pneumoniae (22.1%), and P. mirabilis (14.2%). 86% of the included isolates were susceptible to cefazolin using the 2010 breakpoints. Implementation of the 2014 breakpoints did not significantly impact susceptibility results for E. coli, K. pneumoniae, or P. mirabilis. CONCLUSION: Modification of breakpoints did not significantly impact susceptibility rates of cefazolin. Substituting cefazolin may decrease the overall drug cost by 77.5%. More data is needed to correlate in vitro findings with clinical outcomes using cefazolin for UTIs. PMID- 28558709 TI - Beneficiaries' perceptions and reported use of unconditional cash transfers intended to prevent acute malnutrition in children in poor rural communities in Burkina Faso: qualitative results from the MAM'Out randomized controlled trial. AB - BACKGROUND: Acute malnutrition is a public health issue worldwide, and particularly in the Eastern region of Burkina Faso. Following a needs assessment, unconditional seasonal, multiannual cash transfers were implemented as a safety net to prevent childhood undernutrition. The objectives of this study were to explore the types of purchases made by beneficiaries of this cash transfer program and to understand the perceived effects of and changes induced by regular cash transfers in the daily lives of women, and at the household and community level. METHODS: The design of this study was a two-arm cluster randomized controlled trial. Qualitative data were collected each month during the cash transfer period for two years, leading to a total of more than 300 interviews and focus group discussions with various participants: beneficiary mothers, heads of households, mothers-in-law, co-wives, key members of the community, and participants of the control group. RESULTS: The two main types of expenses reported were food and health care for the child and the whole family. The program was also associated with positive perceived changes at the household level, mainly related to gender equality and improvement of women's status, and has promoted an increase in dignity and social integration of the poorest at the community level through cash sharing. Unexpected effects of this program included some women planning new pregnancies and some individuals not expecting the transfers to end. CONCLUSION: Although the transfers were unconditional, the cash was mainly used to improve the children's and households' food security and health, which correspond to two main underlying causes of undernutrition. Therefore, spending mainly in these areas can help to prevent undernutrition in children. TRIAL REGISTRATION: ClinicalTrials.gov , identifier: NCT01866124 , registered May 7, 2013. PMID- 28558708 TI - Circulating blood levels of IL-6, IFN-gamma, and IL-10 as potential diagnostic biomarkers in gastric cancer: a controlled study. AB - BACKGROUND: Gastric adenocarcinoma is the third most common cause of cancer associated death worldwide. Helicobacter pylori infection activates a signaling cascade that induces production of cytokines and chemokines involved in the chronic inflammatory response that drives carcinogenesis. We evaluated circulating cytokines and chemokines as potential diagnostic biomarkers for gastric cancer. METHODS: We included 201 healthy controls and 162 patients with distal gastric cancer who underwent primary surgical resection between 2009 and 2012 in Mexico City. The clinical and pathological data of patients were recorded by questionnaire, and the cancer subtype was classified as intestinal or diffuse. Pathological staging of cancer was based on the tumor-node-metastasis staging system of the International Union Against Cancer. Concentrations of IL-1beta, IL 6, TNF-alpha, IL-10, and MCP-1 in serum were measured using multiplex analyte profiling technology and concentrations of IL-8, IFN-gamma, and TGF-beta in plasma were measured using enzyme-linked immunosorbent assay. RESULTS: Levels of IL-1beta, IL-6, IFN-gamma, and IL-10 were significantly higher and that of MCP-1 was lower in gastric cancer patients compared with controls. No differences in IL 8 or TNF-alpha levels were observed between gastric cancer and controls. IFN gamma and IL-10 were significantly higher in both intestinal and diffuse gastric cancer, whereas IL-1beta and IL-6 were higher and TGF-beta lower only in intestinal gastric cancer; MCP-1 was lower only in diffuse gastric cancer. IFN gamma and IL-10 levels were significantly higher in early (I/II) and late stage (III/IV) gastric cancer; IL-1beta and IL-8 were higher and MCP-1 was lower only in late stage (IV) patients. Receiver-operating characteristic analysis showed that for diagnosis of GC, IL-6 had high specificity (0.97) and low sensitivity (0.39), IL-10 had moderate specificity (0.82) and low sensitivity (0.48), and IL 1beta and IFN-gamma showed low specificity (0.43 and 0.53, respectively) and moderate sensitivity (0.76 and 0.71, respectively). CONCLUSIONS: Increased levels of IL-6, IFN-gamma, and IL-10 might be useful as diagnostic biomarkers for GC; however, this needs to be confirmed with larger number of patients and with control groups other than blood donors, properly age paired. IL-1beta, IL-6, MCP 1, and TGF-beta differentiate intestinal from diffuse GC. IFN-gamma and IL-10 might be useful for diagnosis of early stage GC, and IL-1beta, IL-8, and MCP-1 for late stages of the disease. PMID- 28558710 TI - A metabolomic analytical approach permits identification of urinary biomarkers for Plasmodium falciparum infection: a case-control study. AB - BACKGROUND: Currently available diagnostic techniques of Plasmodium falciparum infection are not optimal for non-invasive, population-based screening for malaria. It was hypothesized that a mass spectrometry-based metabolomics approach could identify urinary biomarkers of falciparum malaria. METHODS: The study used a case-control design, with cases consisting of 21 adults in central Ethiopia with a diagnosis of P. falciparum infection confirmed with microscopy, and 25 controls of adults with negative blood smears for malaria matched on age and sex. Urinary samples were collected from these individuals during presentation at the clinic, and a second sample was collected from both cases and controls 4 weeks later, after the cases had received anti-malarial medication. The urine samples were screened for small molecule urinary biomarkers, using mass spectrometry based metabolomics analyses followed by multivariate analysis using principal component analysis and orthogonal partial least square-discriminant analysis. The chemical identity of statistically significant malaria biomarkers was confirmed using tandem mass spectrometry. RESULTS: The urinary metabolic profiles of cases with P. falciparum infection were distinct from healthy controls. After treatment with anti-malarial medication, the metabolomic profile of cases resembled that of healthy controls. Significantly altered levels of 29 urinary metabolites were found. Elevated levels of urinary pipecolic acid, taurine, N-acetylspermidine, N acetylputrescine and 1,3-diacetylpropane were identified as potential biomarkers of falciparum malaria. CONCLUSION: The urinary biomarkers of malaria identified have potential for the development of non-invasive and rapid diagnostic test of P. falciparum infection. PMID- 28558711 TI - Sarcoidosis as a rare cause for symmetrical giant bullous disease. AB - BACKGROUND: Sarcoidosis presents with typical clinic-radiological findings and shows histologically non-caseating granulomas. Pulmonary manifestations of sarcoidosis can be diverse, involving the intrathoracic lymph nodes and pulmonary parenchyma. CASE PRESENTATION: We here describe a case of a 35-year-old patient who presented with a history of exertion dyspnoea and coughing for the past 20 years. At the age of 15, she was exposed to smoke emanating from a fire. Later, she had exposure to mold for two years, and during her childhood, she had animals such as a cockatiel, dog, cat, gecko, and turtle. Computed tomography of the chest revealed symmetrical apical giant bullous lesions. Histology of the resected bullae showed prominent peribronchial fibrosis with non-necrotizing, non caseating granulomas and collaps of pulmonary lobules adjacent to the bulla. The absence of granulomatous infection and a markedly elevated CD4:CD8 ratio in bronchoalveolar lavage analysis suggested that the underlying process was sarcoidosis. CONCLUSION: In very rare cases, sarcoidosis can be associated with bilateral symmetrical apical giant bullous disease due to fibrotic and granulomatous changes resulting in a restriction of lung tissue. PMID- 28558712 TI - Molecular and immunological analyses of confirmed Plasmodium vivax relapse episodes. AB - BACKGROUND: Relapse infections resulting from the activation hypnozoites produced by Plasmodium vivax and Plasmodium ovale represent an important obstacle to the successful control of these species. A single licensed drug, primaquine is available to eliminate these liver dormant forms. To date, investigations of vivax relapse infections have been few in number. RESULTS: Genotyping, based on polymorphic regions of two genes (Pvmsp1F3 and Pvcsp) and four microsatellite markers (MS3.27, MS3.502, MS6 and MS8), of 12 paired admission and relapse samples from P. vivax-infected patients were treated with primaquine, revealed that in eight of the parasite populations in the admission and relapse samples were homologous, and heterologous in the remaining four patients. The patients' CYP2D6 genotypes did not suggest that any were poor metabolisers of primaquine. Parasitaemia tended to be higher in the heterologous as compared to the homologous relapse episodes as was the IgG3 response. For the twelve pro- and anti-inflammatory cytokine levels measured for all samples, only those of IL-6 and IL-10 tended to be higher in patients with heterologous as compared to homologous relapses in both admission and relapse episodes. CONCLUSIONS: The data from this limited number of patients with confirmed relapse episodes mirror previous observations of a significant proportion of heterologous parasites in relapses of P. vivax infections in Thailand. Failure of the primaquine treatment that the patients received is unlikely to be due to poor drug metabolism, and could indicate the presence of P. vivax populations in Thailand with poor susceptibility to 8-aminoquinolines. PMID- 28558713 TI - Understanding why cancer patients accept or turn down psycho-oncological support: a prospective observational study including patients' and clinicians' perspectives on communication about distress. AB - BACKGROUND: International standards prioritize introducing routine emotional distress screening in cancer care to accurately identify patients who most need psycho-oncological treatment, and ensure that patients can access appropriate supportive care. However, only a moderate proportion of distressed patients accepts referrals to or uses psycho-oncological support services. Predictors and barriers to psycho-oncological support service utilization are under-studied. We know little about how patients and oncologists perceive the discussions when oncologists assess psychosocial distress with a screening instrument. We aim to 1) assess the barriers and predictors of uptake of in-house psycho-oncological support along the distress screening pathway in cancer patients treated at a University Oncology Outpatient Clinic and, 2) determine how patients and clinicians perceive communication about psychosocial distress after screening with the Distress Thermometer. METHODS: This is a quantitative prospective observational study with qualitative aspects. We will examine medical and demographic variables, cancer patient self-reports of various psychological measures, and aspects of the patient-clinician communication as variables that potentially predict uptake of psycho-oncological support service. We will also assess the patients' reasons for accepting or refusing psycho-oncological support services. We assess at three points in time, based on paper-and-pencil questionnaires and two patient interviews during the study period. We will monitor outcomes (psycho-oncology service uptake) four months after study entry. DISCUSSION: The study will improve our understanding of characteristics of patients who accept or refuse psycho-oncological support, and help us understand how patients' and oncologists perceive communication about psychosocial distress, and referral to a psycho-oncologist. We believe this is the first study to focus on factors that affect uptake or rejection of psycho-oncological support services along the screening and referral pathway. The study 1) combines standard assessment with qualitative data collection, 2) embraces patient and oncologist perspectives, and, 3) focuses on patient-clinician communication about psychosocial issues raised by a standard screening instrument. Our results may improve routine practices and eliminate barriers to adequate health care, and make it easier to recognize patients with high distress levels who underuse the service. PMID- 28558714 TI - Feasibility and efficacy of a multi-factorial intervention to prevent falls in older adults with cognitive impairment living in residential care (ProF-Cog). A feasibility and pilot cluster randomised controlled trial. AB - BACKGROUND: Falls are common in people with dementia living in residential care. The ProF-Cog intervention was developed to address fall risk factors specific to this population. The aim of this study was to evaluate the safety, acceptability, and feasibility of the intervention and provide an estimate of its efficacy. METHODS: This was a cluster randomised controlled pilot study undertaken in care homes in London, UK. All permanent residents living in participating homes who were not terminally ill were invited to participate. The intervention included an assessment of falls risk factors followed by a tailored intervention which could include dementia care mapping, comprehensive geriatric assessment, occupational therapy input and twice-weekly exercise for 6 months as required to target identified risk factors. The control group received usual care without a falls risk assessment. Standing balance was the primary outcome. This and other outcome measures were collected at baseline and after 6 months. Falls were recorded for this period using incident reports. Changes were analysed using multi-level modelling. Adherence to the interventions, adverse events and trial feasibility were recorded. RESULTS: Nine care homes enrolled in the study with a total 191 participants (51% of those eligible); five homes allocated to the intervention with 103 participants, and four homes to the usual care control group with 88 participants. The intervention was safe with only one reported fall whilst undertaking exercise. Adherence to agreed recommendations on activity and the environment was modest (21 and 45% respectively) and to exercise was poor (41%). Balance scores (score range 0-49) analysed on 100 participants decreased by a mean of 3.9 in the control and 5.1 in the intervention groups, a non-significant difference (p = 0.9). In other measures, both groups declined equally and there was no difference in falls rates (IRR = 1.59 95%, CI 0.67-3.76). CONCLUSION: The intervention was safe but not clinically effective. Poor adherence suggests it was not an acceptable or feasible intervention. TRIAL REGISTRATION: ISRCTN00695885 . Registered 26th March 2013. PMID- 28558715 TI - Modern peptide biomarkers and echocardiography in cardiac healthy haemodialysis patients. AB - BACKGROUND: In this prospective study, we aimed to assess the haemodynamic changes before and after haemodialysis (HD) in cardiac healthy subjects on chronic HD by imaging methods and endocrine markers of fluid balance. METHODS: Mid-regional pro-atrial natriuretic peptide (MR-proANP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), vasopressin (AVP) and copeptin (CT proAVP), metanephrines and normetanephrines, renin and aldosterone, standard transthoracic echocardiography and diameter of vena cava inferior (VCID) were performed in 20 patients with end stage renal disease (CKD5D) before and after HD and were stratified in residual excretion (RE, less or more 0.5 l) and ultrafiltration rate (UF, less or more 2 l). RESULTS: Copeptin was significantly higher in patients before HD. Copeptin was inversely correlated with haemodialysis treatment adequacy (KT/v), RE and UF, but was not significantly influenced by age, gender and body mass index (BMI). MR-proANP was significantly reduced by haemodialysis by 27% and was inversely correlated with KT/v, but there was a significant influence by UF, RE, age, gender and BMI. NT-proBNP was significantly higher in patients before HD and was not influenced by RE and UF. Renin, aldosterone, metanephrines and normetanephrines did not demonstrate significant differences. Echocardiographic parameters and VCID were significantly correlated with RE, UF and copeptin. CONCLUSION: Modern biomarkers will provide cardiovascular risk assessment, but elimination (UF), RE and other factors may influence the serum concentrations, e.g. in patients with renal impairment. The interpretation will be limited by altered reference ranges, and will be restricted to individual courses combined with clinical and echocardiographic data. PMID- 28558716 TI - Development and validation of a Score for Preoperative Prediction of Obstructive Sleep Apnea (SPOSA) and its perioperative outcomes. AB - BACKGROUND: Postoperative respiratory complications (PRCs) are associated with significant morbidity, mortality, and hospital costs. Obstructive sleep apnea (OSA), often undiagnosed in the surgical population, may be a contributing factor. Thus, we aimed to develop and validate a score for preoperative prediction of OSA (SPOSA) based on data available in electronic medical records preoperatively. METHODS: OSA was defined as the occurrence of an OSA diagnostic code preceded by a polysomnography procedure. A priori defined variables were analyzed by multivariable logistic regression analysis to develop our score. Score validity was assessed by investigating the score's ability to predict non invasive ventilation. We then assessed the effect of high OSA risk, as defined by SPOSA, on PRCs within seven postoperative days and in-hospital mortality. RESULTS: A total of 108,781 surgical patients at Partners HealthCare hospitals (2007-2014) were studied. Predictors of OSA included BMI >25 kg*m-2 and comorbidities, including pulmonary hypertension, hypertension, and diabetes. The score yielded an area under the curve of 0.82. Non-invasive ventilation was significantly associated with high OSA risk (OR 1.44, 95% CI 1.22-1.69). Using a dichotomized endpoint, 26,968 (24.8%) patients were identified as high risk for OSA and 7.9% of these patients experienced PRCs. OSA risk was significantly associated with PRCs (OR 1.30, 95% CI 1.19-1.43). CONCLUSION: SPOSA identifies patients at high risk for OSA using electronic medical record-derived data. High risk of OSA is associated with the occurrence of PRCs. PMID- 28558717 TI - Timing of commencement of maintenance dialysis and mortality in young and older adults in Singapore. AB - BACKGROUND: The benefit of early dialysis initiation remains controversial with a paucity of data in Asians. Therefore, we undertook this study to investigate the association between timing of initiation of dialysis and mortality in Singapore. METHODS: The study used data from the Singapore Renal Registry database on 3286 patients with incident end-stage renal disease (ESRD) who commenced maintenance dialysis between January 2008 and December 2011. The data was further linked with the National Death Registry to acquire survival information until December 2013. We classified serum creatinine-based, estimated glomerular filtration rate (eGFR) by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at the start of dialysis into 3 categories: Early (>=10 ml/min/1.73m2), intermediate (5 to <10 ml/min/1.73m2) and late (<5 ml/min/1.73m2). RESULTS: In the unadjusted analysis, both early and intermediate dialysis initiation groups were at greater risk of death relative to late dialysis (Early: HR = 2.47; Intermediate: HR = 1.54). In the multivariate model, a significant interaction was detected between age and eGFR at dialysis initiation (p = 0.04). Adjusted mortality risk progressively increased with earlier initiation of dialysis for patients aged 18 54 years (p = 0.006) and aged 55 to 64 years (p < 0.001), and no statistically significant difference was observed for patients aged 65 years or older (p = 0.12). CONCLUSIONS: Early versus later initiation of dialysis was associated with significantly higher risk of mortality in Singapore's non-elderly population, and appeared to offer no survival advantage among the elderly. PMID- 28558718 TI - Lactic-fermented egg white reduced serum cholesterol concentrations in mildly hypercholesterolemic Japanese men: a double-blind, parallel-arm design. AB - BACKGROUND: Lactic-fermented egg white (LE), produced by lactic acid fermentation of egg white, is an easy-to-consume form of egg white. Here we assessed the effect of daily consumption of LE for 8 weeks on serum total cholesterol (TC) levels. METHODS: The study followed a double-blind, parallel-arm design and included 88 adult men with mild hypercholesterolemia (mean +/- standard error) serum TC levels, 229 +/- 1.6 mg/dL; range, 204-259 mg/dL). The subjects were randomly divided into three groups, which consumed LE containing 4, 6, or 8 g of protein daily for 8 weeks. Blood samples were collected before starting LE consumption (baseline) and at 4 and 8 weeks to measure serum TC and low-density lipoprotein cholesterol (LDL-C) levels. RESULTS: After 8 weeks of consumption, serum TC levels in the 8 g group decreased by 11.0 +/- 3.7 mg/dL, a significant decrease compared to baseline (p < 0.05) and a significantly greater decrease than for the 4 g group (3.1 +/- 3.4 mg/dL; p < 0.05). Serum LDL-C levels in the 8 g group decreased by 13.7 +/- 3.1 mg/dL, again a significant decrease compared with baseline (p < 0.05) and a significantly greater decrease than that for the 4 g group (2.1 +/- 2.9 mg/dL; p < 0.05). CONCLUSION: Consumption of LE for 8 weeks at a daily dose of 8 g of proteins reduced serum TC and LDL-C levels in men with mild hypercholesterolemia, suggesting this may be effective in helping to prevent arteriosclerotic diseases. TRIAL REGISTRATION: This clinical trial was retrospectively registered with the Japan Medical Association Center for Clinical Trials, (JMA-IIA00279; registered on 13/03/2017; https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRE02_04/JMACTRE02_04.aspx?kbn= &seqno=6530 ). PMID- 28558719 TI - Treatment adherence and perception in patients on maintenance hemodialysis: a cross - sectional study from Palestine. AB - BACKGROUND: Adherence to diet recommendations, fluid restriction, prescribed medications, and attendance at hemodialysis (HD) sessions are essential for optimal and effective treatment of patients with end-stage renal disease. No data regarding this issue are available from Palestine. Therefore, this study was carried out to assess adherence to diet, fluid restriction, medications, and HD sessions. METHODS: A cross-sectional study of HD patients at An-Najah National University Hospital was carried out during summer, 2016. Self-reported adherence behavior was obtained using a valid and reliable questionnaire (End-Stage Renal Disease Adherence Questionnaire: ESRD-AQ). Predialytic serum levels of potassium and phosphate were obtained as clinical indicator of diet and medication adherence respectively. In addition, interdialytic body weight (IDW) was also obtained from medical records and analyzed in relation to reported adherence of fluid restriction. RESULTS: A total of 220 patients answered all questions pertaining to ESRD-AQ. The mean age +/- standard deviation of participants was 56.82 +/- 14.51 years. Dietary adherence was observed in 24% while that of fluid restriction adherence was observed in 31% of studied patients. Reported adherence to HD sessions was 52% while that for medications was 81%. Overall, 122 (55.5%) patients had good adherence, 89 (40.5%) had moderate adherence, and 9 (4.1%) had poor adherence behavior. Male patients had significantly higher overall adherence scores than females (p = 0.034). A significant correlation between reported diet adherence and serum pre-HD potassium level (p < 0.01) was observed. A significant correlation between reported fluid restriction adherence and IDW (p < 0.01) was also found. However, no significant correlation between reported adherence and pre-HD phosphate level. There was significant correlation between overall perception and overall adherence score (p < 0.001). Counselling of patients regarding importance of adherence modalities was lowest for "staying for the entire dialysis time". Multivariate analysis indicated that elderly male patients who were city residents had higher odds of having higher adherence score. CONCLUSIONS: There was a good percentage of patients who had overall moderate or poor adherence. ESRD-AQ could be used to assess some aspects of HD adherence. Counselling and education of patients on HD are important to improve therapeutic outcome. PMID- 28558720 TI - Associations between transition to retirement and changes in dietary intakes in French adults (NutriNet-Sante cohort study). AB - BACKGROUND: Few studies have focused on the influence of retirement on dietary behaviors. Our study aimed at assessing the associations between transition to retirement and changes in dietary intake in French adults, particularly according to spousal retirement and baseline income. METHODS: This prospective study included 577 French participants from the NutriNet-Sante cohort who retired over a 5-year follow-up (2009-2014 or 2010-2015). At baseline and every year, dietary intakes were assessed using 24 h records. Repeated measures of dietary intake were analysed using mixed models adjusted for energy with random effects of time and period (before and after retirement) to assess changes following retirement for each gender. RESULTS: After retirement, intakes of saturated fatty acids and sodium increased in both genders. Women showed specific changes after retirement: decrease in the score of adherence to recommendations and in intakes of fruits, proteins, vitamins; increase in intakes of fatty sweet products. In men with the lowest income at baseline, specific changes in intake were associated with retirement such as decrease in intake of dairy products and increase in intake of lipids. CONCLUSIONS: Transition to retirement was associated with unhealthier dietary intakes. These results may help defining interventions during this vulnerable life-period. TRIAL REGISTRATION: This study was conducted according to guidelines laid down in the Declaration of Helsinki and all procedures were approved by the Institutional Review Board of the French Institute for Health and Medical Research (IRB Inserm No. 0000388FWA00005831) and the French Data Protection Authority (Commission Nationale Informatique et Libertes No. 908450 and No. 909216). Electronic informed consents were obtained from all participants. PMID- 28558721 TI - Extracellular heat shock protein 90alpha mediates HDM-induced bronchial epithelial barrier dysfunction by activating RhoA/MLC signaling. AB - BACKGROUND: The disruption and hyperpermeability of bronchial epithelial barrier are closely related to the pathogenesis of asthma. House dust mite (HDM), one of the most important allergens, could increase the airway epithelial permeability. Heat shock protein (Hsp) 90alpha is also implicated in the lung endothelial barrier dysfunction by disrupting RhoA signaling. However, the effect of extracellular Hsp90alpha (eHsp90alpha) on the bronchial epithelial barrier disruption induced by HDM has never been reported. METHODS: To investigate the involvement of eHsp90alpha in the bronchial epithelial barrier disruption induced by HDM, normal human bronchial epithelial cell line 16HBE14o- (16HBE) cells were treated by HDM, human recombinant (hr) Hsp90alpha and hrHsp90beta respectively and pretreated by1G6-D7, a specific anti-secreted Hsp90alpha monoclonal antibody (mAb). Hsp90alpha-silencing cells were also constructed. To further evaluate the role of RhoA signaling in this process, cells were pretreated by inhibitors of Rho kinase, GSK429286A and Y27632 2HCl. Transepithelial electrical resistance (TEER) and FITC-dextran flux (FITC-DX) were examined as the epithelial barrier function. Expression and localization of adherens junctional proteins E-cadherin and beta-catenin were evaluated by western blotting and immunofluorescence respectively. The level of eHsp90alpha was investigated by concentration and purification of condition media. RhoA activity was determined by using a Rho G LISA(r) RhoA activation assay kitTM biochem kit, and the phosphorylation of myosin light chain (MLC), the downstream signal molecule of RhoA, was assessed by western blotting. RESULTS: The epithelial barrier disruption and the loss of adherens junctional proteins E-cadherin and beta-catenin in cytomembrane were observed in HDM-treated 16HBE cells, paralleled with the increase of eHsp90alpha secretion. All of which were rescued in Hsp90alpha-silencing cells or by pretreating 16HBE cells with 1G6-D7. Also, 1G6-D7 suppressed RhoA activity and MLC phosphorylation induced by HDM. Furthermore, inhibitors of Rho kinase prevented and restored the airway barrier disruption. Consistently, it was hrHsp90alpha instead of hrHsp90beta that promoted barrier dysfunction and activated RhoA/MLC signaling in 16HBE cells. CONCLUSIONS: The eHsp90alpha mediates HDM-induced human bronchial epithelial barrier dysfunction by activating RhoA/MLC signaling, suggesting that eHsp90alpha is a potential therapeutic target for treatment of asthma. PMID- 28558722 TI - Phylogenomic analyses of Crassiclitellata support major Northern and Southern Hemisphere clades and a Pangaean origin for earthworms. AB - BACKGROUND: Earthworms (Crassiclitellata) are a diverse group of annelids of substantial ecological and economic importance. Earthworms are primarily terrestrial infaunal animals, and as such are probably rather poor natural dispersers. Therefore, the near global distribution of earthworms reflects an old and likely complex evolutionary history. Despite a long-standing interest in Crassiclitellata, relationships among and within major clades remain unresolved. METHODS: In this study, we evaluate crassiclitellate phylogenetic relationships using 38 new transcriptomes in combination with publicly available transcriptome data. Our data include representatives of nearly all extant earthworm families and a representative of Moniligastridae, another terrestrial annelid group thought to be closely related to Crassiclitellata. We use a series of differentially filtered data matrices and analyses to examine the effects of data partitioning, missing data, compositional and branch-length heterogeneity, and outgroup inclusion. RESULTS AND DISCUSSION: We recover a consistent, strongly supported ingroup topology irrespective of differences in methodology. The topology supports two major earthworm clades, each of which consists of a Northern Hemisphere subclade and a Southern Hemisphere subclade. Divergence time analysis results are concordant with the hypothesis that these north-south splits are the result of the breakup of the supercontinent Pangaea. CONCLUSIONS: These results support several recently proposed revisions to the classical understanding of earthworm phylogeny, reveal two major clades that seem to reflect Pangaean distributions, and raise new questions about earthworm evolutionary relationships. PMID- 28558723 TI - Body composition impacts appetite regulation in middle childhood. A prospective study of Norwegian community children. AB - BACKGROUND: Research suggests a role for both fat mass and muscle mass in appetite regulation, but the longitudinal relationships between them have not yet been examined in children. The present study therefore aimed to explore the prospective relationships between fat mass, muscle mass and the appetitive traits food responsiveness and satiety responsiveness in middle childhood. METHODS: Food responsiveness and satiety responsiveness were measured using the parent-reported Children's Eating Behavior Questionnaire in a representative sample of Norwegian 6 year olds, followed up at 8 and 10 years of age (n = 807). Body composition was measured by bioelectrical impedance. RESULTS: Applying a structural equation modeling framework we found that higher fat mass predicted greater increases in food responsiveness over time, whereas greater muscle mass predicted decreases in satiety responsiveness. This pattern was consistent both from ages 6 to 8 and from ages 8 to 10 years. CONCLUSIONS: Our study is the first to reveal that fat mass and muscle mass predict distinct changes in different appetitive traits over time. Replication of findings in non-European populations are needed, as are studies of children in other age groups. Future studies should also aim to reveal the underlying mechanisms. PMID- 28558724 TI - Feature selection for elderly faller classification based on wearable sensors. AB - BACKGROUND: Wearable sensors can be used to derive numerous gait pattern features for elderly fall risk and faller classification; however, an appropriate feature set is required to avoid high computational costs and the inclusion of irrelevant features. The objectives of this study were to identify and evaluate smaller feature sets for faller classification from large feature sets derived from wearable accelerometer and pressure-sensing insole gait data. METHODS: A convenience sample of 100 older adults (75.5 +/- 6.7 years; 76 non-fallers, 24 fallers based on 6 month retrospective fall occurrence) walked 7.62 m while wearing pressure-sensing insoles and tri-axial accelerometers at the head, pelvis, left and right shanks. Feature selection was performed using correlation based feature selection (CFS), fast correlation based filter (FCBF), and Relief-F algorithms. Faller classification was performed using multi-layer perceptron neural network, naive Bayesian, and support vector machine classifiers, with 75:25 single stratified holdout and repeated random sampling. RESULTS: The best performing model was a support vector machine with 78% accuracy, 26% sensitivity, 95% specificity, 0.36 F1 score, and 0.31 MCC and one posterior pelvis accelerometer input feature (left acceleration standard deviation). The second best model achieved better sensitivity (44%) and used a support vector machine with 74% accuracy, 83% specificity, 0.44 F1 score, and 0.29 MCC. This model had ten input features: maximum, mean and standard deviation posterior acceleration; maximum, mean and standard deviation anterior acceleration; mean superior acceleration; and three impulse features. The best multi-sensor model sensitivity (56%) was achieved using posterior pelvis and both shank accelerometers and a naive Bayesian classifier. The best single-sensor model sensitivity (41%) was achieved using the posterior pelvis accelerometer and a naive Bayesian classifier. CONCLUSIONS: Feature selection provided models with smaller feature sets and improved faller classification compared to faller classification without feature selection. CFS and FCBF provided the best feature subset (one posterior pelvis accelerometer feature) for faller classification. However, better sensitivity was achieved by the second best model based on a Relief-F feature subset with three pressure-sensing insole features and seven head accelerometer features. Feature selection should be considered as an important step in faller classification using wearable sensors. PMID- 28558725 TI - Benefits of local tumor excision and pharyngectomy on the survival of nasopharyngeal carcinoma patients: a retrospective observational study based on SEER database. AB - BACKGROUND: There is ongoing debate about surgery of primary site in nasopharyngeal carcinoma patients. METHODS: 3919 patients with nasopharyngeal carcinoma identified in the SEER registry between 2004 and 2013. The benefit of surgery of primary nasopharynx tumor site on overall and cancer-specific survival was assessed by risk-adjusted multivariate Cox proportional hazard regression and propensity score matching modeling. RESULTS: Surgery was marginally associated with better overall survival (hazard ratio (HR) = 0.816, 95% CI 0.656-1.015, p = 0.07) and cancer-specific survival (HR = 0.749, 95% CI 0.552-1.018, p = 0.06) in the propensity score model. Among 398 cases who underwent primary site surgery, 282 (70.85%) received local tumor excision and 79 (20.31%) received pharyngectomy. Local tumor excision and pharyngectomy had almost the same effect on survival in propensity score matching analysis. The benefit was significant in subgroups of white, age <60 year, and patients with T3, N1, M0, AJCC stage III, or moderately differentiated tumors. Further survival analysis showed surgery to promote survival in both radiotherapy and non-radiotherapy patients. CONCLUSION: This is the first population-based analysis using propensity score model to provide evidence of a positive impact of surgery on survival in nasopharyngeal carcinoma. Moreover, surgery demonstrated the significant benefit in subgroups of patients with specific clinical characteristics. PMID- 28558726 TI - Development and application of triple antibody sandwich enzyme-linked immunosorbent assays for begomovirus detection using monoclonal antibodies against Tomato yellow leaf curl Thailand virus. AB - BACKGROUND: Tomato yellow leaf curl Thailand virus, TYLCTHV, is a begomovirus that causes severe losses of tomato crops in Thailand as well as several countries in Southeast and East Asia. The development of monoclonal antibodies (MAbs) and serological methods for detecting TYLCTHV is essential for epidemiological studies and screening for virus-resistant cultivars. METHODS: The recombinant coat protein (CP) of TYLCTHV was expressed in Escherichia coli and used to generate MAbs against TYLCTHV through hybridoma technology. The MAbs were characterized and optimized to develop triple antibody sandwich enzyme-linked immunosorbent assays (TAS-ELISAs) for begomovirus detection. The efficiency of TAS-ELISAs for begomovirus detection was evaluated with tomato, pepper, eggplant, okra and cucurbit plants collected from several provinces in Thailand. Molecular identification of begomoviruses in these samples was also performed through PCR and DNA sequence analysis of the CP gene. RESULTS: Two MAbs (M1 and D2) were generated and used to develop TAS-ELISAs for begomovirus detection. The results of begomovirus detection in 147 field samples indicated that MAb M1 reacted with 2 begomovirus species, TYLCTHV and Tobacco leaf curl Yunnan virus (TbLCYnV), whereas MAb D2 reacted with 4 begomovirus species, TYLCTHV, TbLCYnV, Tomato leaf curl New Delhi virus (ToLCNDV) and Squash leaf curl China virus (SLCCNV). Phylogenetic analyses of CP amino acid sequences from these begomoviruses revealed that the CP sequences of begomoviruses recognized by the narrow-spectrum MAb M1 were highly conserved, sharing 93% identity with each other but only 72 81% identity with MAb M1-negative begomoviruses. The CP sequences of begomoviruses recognized by the broad-spectrum MAb D2 demonstrated a wider range of amino acid sequence identity, sharing 78-96% identity with each other and 72 91% identity with those that were not detected by MAb D2. CONCLUSIONS: TAS-ELISAs using the narrow-specificity MAb M1 proved highly efficient for the detection of TYLCTHV and TbLCYnV, whereas TAS-ELISAs using the broad-specificity MAb D2 were highly efficient for the detection of TYLCTHV, TbLCYnV, ToLCNDV and SLCCNV. Both newly developed assays allow for sensitive, inexpensive, high-throughput detection of begomoviruses in field plant samples, as well as screening for virus resistant cultivars. PMID- 28558727 TI - Examining differences in cognitive and affective theory of mind between persons with high and low extent of somatic symptoms: an experimental study. AB - BACKGROUND: Medically unexplained somatic symptoms are common, associated with disability and strongly related to depression and anxiety disorders. One interesting, but to date rarely tested, hypothesis is that deficits in both theory of mind (ToM) and emotional awareness may undergird the phenomenon of somatization. This study sought to investigate whether or not differences in ToM functioning and self-reported emotional awareness are associated with somatic symptoms in a sample from the general population. METHODS: The sample consisted of 50 healthy participants (37 females, 13 males) aged between 22 and 64 years (46.8 +/- 11.7) of whom 29 reported a high extent of somatic symptoms (HSR), whereas 21 reported a low extent of somatic symptoms (LSR) based on the 30 highest and lowest percentiles of the Symptom List norms. The participants' affective and cognitive ToM were assessed with two experimental paradigms by experimenters who were blind to the participants' group membership. In addition, self-reports regarding emotional awareness, alexithymia, depressive and anxiety symptoms and current affect were collected. RESULTS: In the experimental tasks, HSR showed lower affective ToM than LSR but the groups did not differ in cognitive ToM. Although HSR reported lower emotional awareness than LSR in the self-report measure, this group difference vanished when we controlled for anxiety and depression. Depression, anxiety, emotional awareness and alexithymia were correlated positively. CONCLUSIONS: The data supported the hypothesis that deficits in affective ToM are related to somatic symptoms. Neither cognitive ToM nor self-reported emotional awareness were associated with somatic symptoms. Self reported emotional awareness, alexithymia and symptoms of depression and anxiety shared a considerable amount of variance. PMID- 28558728 TI - The validity and psychometric properties of the Japanese version of the Compulsive Internet Use Scale (CIUS). AB - BACKGROUND: Prolonged Internet use is often associated with reduced social involvement and comorbid psychopathologies, including depression, anxiety, attention-deficit/hyperactivity disorder, and obsessive-compulsive disorder. Asian countries where Internet access is widely available have high reported levels of Internet addiction. As Internet use has changed drastically since concerns about Internet addiction were first raised, the results of recent studies may be inaccurate because the scales they employed to measure Internet addiction were formulated for different Internet usage from the present. It is thus necessary to develop more-up-to-date scales to assess problematic private use of the Internet. METHODS: The Compulsive Internet Use Scale (CIUS) was translated into Japanese. An online sample whose ages and sexes reflected that of the national population of Internet users was recruited to test the scale's reliability and validity. Correlations between the scale and Internet-related parameters (such as time spent online, motivation for going online, and applications used) and psychosocial factors (such as psychological distress symptoms and loneliness) were examined. Psychometric properties were examined by the split-half method using both exploratory and confirmatory factor analysis. Model fits were compared across gender. RESULTS: CIUS was found to have a high reliability and good concurrent, correlation and construct validity. Both exploratory and confirmatory factors revealed that the one-factor solution yielded a satisfactory result across gender. However, the three-factor structural model in which compulsiveness was gauged by "excessive absorption", "difficulty in setting priorities", and "mood regulation" gave the best fit of the model for the general population as well as across gender. CONCLUSIONS: Compulsive Internet behavior in Japan can be assessed in terms of absorption, priorities, and mood. CIUS is a valid scale for screening compulsive Internet behavior in the general Japanese population regardless of age and gender. PMID- 28558729 TI - High-throughput validation of ceRNA regulatory networks. AB - BACKGROUND: MicroRNAs (miRNAs) play multiple roles in tumor biology. Interestingly, reports from multiple groups suggest that miRNA targets may be coupled through competitive stoichiometric sequestration. Specifically, computational models predicted and experimental assays confirmed that miRNA activity is dependent on miRNA target abundance, and consequently, changes in the abundance of some miRNA targets lead to changes to the regulation and abundance of their other targets. The resulting indirect regulatory influence between miRNA targets resembles competition and has been dubbed competitive endogenous RNA (ceRNA). Recent studies have questioned the physiological relevance of ceRNA interactions, our ability to accurately predict these interactions, and the number of genes that are impacted by ceRNA interactions in specific cellular contexts. RESULTS: To address these concerns, we reverse engineered ceRNA networks (ceRNETs) in breast and prostate adenocarcinomas using context-specific TCGA profiles, and tested whether ceRNA interactions can predict the effects of RNAi-mediated gene silencing perturbations in PC3 and MCF7 cells._ENREF_22 Our results, based on tests of thousands of inferred ceRNA interactions that are predicted to alter hundreds of cancer genes in each of the two tumor contexts, confirmed statistically significant effects for half of the predicted targets. CONCLUSIONS: Our results suggest that the expression of a significant fraction of cancer genes may be regulated by ceRNA interactions in each of the two tumor contexts. PMID- 28558730 TI - Statutory retirement and changes in self-reported leisure-time physical activity: a follow-up study with three time-points. AB - BACKGROUND: Retirement is a key life event, which is associated with changes in physical activity, however, there is limited evidence with regard to changes in physical activity that take place in post-retirement years. The aim of this study was to examine how leisure-time physical activity changes shortly after the transition to retirement and during the post-retirement years. METHODS: The phase 1 data were collected in 2000-2002 (n = 8960, response rate 67%) among 40-60-year old employees of the City of Helsinki, Finland. Phase 2 was carried out in 2007 (n = 7332, response rate 83%) and phase 3 in 2012 (n = 6814, response rate 79%). Disability retirees and those under the age of 50 at baseline were excluded. This yielded 2902 participants. Most of the participants (79%) were women. The mean age of the participants was 54.4 in phase 1. Negative binomial models for repeated measurements with generalized estimating equations (GEE) were used to calculate the incidence rate ratios (IRR) and 95% confidence intervals (CI). These indicated the changes in time spent in self-reported leisure-time physical activity among the retired compared with the continuously employed. RESULTS: Of the participants, 851 retired on the grounds of old age during the first period (phases 1-2), and 948 during the second period (phases 2-3). Change in physical activity was positive among those who retired during the first (IRR = 1.10, 95% CI 1.04-1.17) and second (IRR = 1.10, 95% CI 1.04-1.16) periods compared to the continuously employed. During the second period, there was little difference between those who had retired during the first one (IRR = 0.96, 95% CI 0.91-1.02) and the continuously employed. CONCLUSIONS: The transition to statutory retirement was associated with an immediate increase in leisure-time physical activity, which nevertheless diminished during post-retirement years. PMID- 28558731 TI - Integration and activity of hospital-based palliative care consultation teams: the INSIGHT multicentric cohort study. AB - BACKGROUND: Hospital-based Palliative Care Consultation Teams (PCCTs) have a consulting role to specialist services at their request. Referral of patients is often late. Early palliative care in oncology has shown its effectiveness in improving quality of life, thereby questioning the "on request" model of PCCTs. Whether this evidence changed practice is unknown. This multicentre prospective cohort study aims to describe the activity and integration of PCCTs at the patient level. METHODS: For consecutive patients newly referred to participating PCCTs, the team collected the following data: circumstances of first referral, problems identified, number of interventions, patient's survival after first evaluation and place of death. RESULTS: Seventeen PCCTs based in university hospitals in Paris area, recruited 744 newly referred adult patients, aged 72 +/- 15 years, 52% males, and 504(68%) with cancer as primary diagnosis. After 6 months, 548(74%) had died. At first evaluation, 12% patients were outpatients, 88% were inpatients. Symptoms represented the main reasons for referral and problems identified; 79% of patients had altered performance status; 24% encountered the PCCT only once. Median survival (1st-3rd quartile) after first evaluation by the PCCT was 22 (5-82) days for overall patients, and respectively 31 (8-107) days and 9 (3-34) days for cancer versus noncancer patients (p < 0.0001). Place of death was acute care hospital for 51.7% patients, and home or Palliative Care Unit for 35%. Patients referred earlier died more often in PCU. CONCLUSION: The study provides original data showing a still late referral to the PCCTs in France. Cancer patients represent their predominant activity. The integrated palliative care model seems to emerge besides the "on request" model which originally characterised their missions. PMID- 28558732 TI - Safety and tolerability of Bifidobacterium longum subspecies infantis EVC001 supplementation in healthy term breastfed infants: a phase I clinical trial. AB - BACKGROUND: Historically, bifidobacteria were the dominant intestinal bacteria in breastfed infants. Still abundant in infants in developing nations, levels of intestinal bifidobacteria are low among infants in developed nations. Recent studies have described an intimate relationship between human milk and a specific subspecies of Bifidobacterium, B. longum subsp. infantis (B. infantis), yet supplementation of breastfed, healthy, term infants with this organism, has not been reported. The IMPRINT Study, a Phase I clinical trial, was initiated to determine the safety and tolerability of supplementing breastfed infants with B. infantis (EVC001). METHODS: Eighty mother-infant dyads were enrolled in either lactation support plus B. infantis supplementation (BiLS) or lactation support alone (LS). Starting with Day 7 postnatal, BiLS infants were fed 1.8-2.8 * 1010 CFU B. infantis EVC001 daily in breast milk for 21 days. Mothers collected fecal samples, filled out health questionnaires, and kept daily logs about their infants' feeding and gastrointestinal symptoms from birth until Day 61 postnatal. Safety and tolerability were determined from maternal reports. RESULTS: There were no differences in the mean gestational age at birth, weight 1 and 2 months postnatal, and breast milk intake between groups. The mean Log10 change in fecal Bifidobacterium from Day 6 to Day 28 was higher (p = 0.0002) for BiLS (6.6 +/- 2.8 SD) than for LS infants (3.5 +/- 3.5 SD). Daily stool number was higher (p < 0.005) for LS and lower (p < 0.05) for BiLS infants during supplementation than at Baseline. During supplementation, watery stools decreased and soft stools increased by 36% over baseline in BiLS infants (p < 0.05) with no significant changes in stool consistency for the LS infants. None of the safety and tolerability endpoints, including flatulence, bloody stool, body temperature, ratings of gastrointestinal symptoms, use of antibiotics or gas-relieving medications, infant colic, jaundice, number of illnesses, sick doctor visits, or diagnoses of eczema were different for the groups at any point. CONCLUSIONS: The B. infantis EVC001 supplement was safely consumed and well-tolerated. Stools were fewer and better formed in infants in the BiLS group compared with LS group. Adverse events were those expected in healthy infants and not different between groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT02457338 . Registered May 27, 2015. PMID- 28558734 TI - The effects of arthritis gloves on people with Rheumatoid Arthritis or Inflammatory Arthritis with hand pain: a study protocol for a multi-centre randomised controlled trial (the A-GLOVES trial). AB - BACKGROUND: Arthritis gloves are regularly provided as part of the management of people with rheumatoid arthritis (RA) and undifferentiated (early) inflammatory arthritis (IA). Usually made of nylon and elastane (i.e. Lycra(r)), these arthritis gloves apply pressure with the aims of relieving hand pain, stiffness and improving hand function. However, a systematic review identified little evidence supporting their use. We therefore designed a trial to compare the effectiveness of the commonest type of arthritis glove provided in the United Kingdom (Isotoner gloves) (intervention) with placebo (control) gloves (i.e. larger arthritis gloves providing similar warmth to the intervention gloves but minimal pressure only) in people with these conditions. METHODS: Participants aged 18 years and over with RA or IA and persistent hand pain will be recruited from National Health Service Trusts in the United Kingdom. Following consent, participants will complete a questionnaire booklet, then be randomly allocated to receive intervention or placebo arthritis gloves. Within three weeks, they will be fitted with the allocated gloves by clinical specialist rheumatology occupational therapists. Twelve weeks (i.e. the primary endpoint) after completing the baseline questionnaire, participants will complete a second questionnaire, including the same measures plus additional questions to explore adherence, benefits and problems with glove-wear. A sub-sample of participants from each group will be interviewed at the end of their participation to explore their views of the gloves received. The clinical effectiveness and cost effectiveness of the intervention, compared to placebo gloves, will be evaluated over 12 weeks. The primary outcome measure is hand pain during activity. Qualitative interviews will be thematically analysed. DISCUSSION: This study will evaluate the commonest type of arthritis glove (Isotoner) provided in the NHS (i.e. the intervention) compared to a placebo glove. The results will help occupational therapists, occupational therapy services and people with arthritis make informed choices as to the value of arthritis gloves. If effective, arthritis gloves should become more widely available in the NHS to help people with RA and IA manage hand symptoms and improve performance of daily activities, work and leisure. If not, services can determine whether to cease supplying these to reduce service costs. TRIAL REGISTRATION: ISRCTN Registry: ISRCTN25892131 Registered 05/09/2016. PMID- 28558733 TI - Towards a consensus definition of maternal sepsis: results of a systematic review and expert consultation. AB - BACKGROUND: There is a need for a clear and actionable definition of maternal sepsis, in order to better assess the burden of this condition, trigger timely and effective treatment and allow comparisons across facilities and countries. The objective of this study was to review maternal sepsis definitions and identification criteria and to report on the results of an expert consultation to develop a new international definition of maternal sepsis. METHODS: All original and review articles and WHO documents, as well as clinical guidelines providing definitions and/or identification criteria of maternal sepsis were included. A multidisciplinary international panel of experts was surveyed through an online consultation in March-April 2016 on their opinion on the existing sepsis definitions, including new definition of sepsis proposed for the adult population (2016 Third International Consensus Definitions for Sepsis and Septic Shock) and importance of different criteria for identification of maternal sepsis. The definition was agreed using an iterative process in an expert face-to-face consensus development meeting convened by WHO and Jhpiego. RESULTS: Standardizing the definition of maternal sepsis and aligning it with the current understanding of sepsis in the adult population was considered a mandatory step to improve the assessment of the burden of maternal sepsis by the expert panel. The literature review and expert consultation resulted in a new WHO consensus definition "Maternal sepsis is a life-threatening condition defined as organ dysfunction resulting from infection during pregnancy, child-birth, post-abortion, or post partum period". Plans are in progress to validate the new WHO definition of maternal sepsis in a large international population. CONCLUSION: The operationalization of the new maternal sepsis definition requires generation of a set of practical criteria to identify women with sepsis. These criteria should enable clinicians to focus on the timely initiation of actionable elements of care (administration of antimicrobials and fluids, support of vital organ functions, and referral) and improve maternal outcomes. PMID- 28558735 TI - Differential expression of microRNAs following cardiopulmonary bypass in children with congenital heart diseases. AB - BACKGROUND: Children with congenital heart defects (CHDs) are at high risk for myocardial failure after operative procedures with cardiopulmonary bypass (CPB). Recent studies suggest that microRNAs (miRNA) are involved in the development of CHDs and myocardial failure. Therefore, the aim of this study was to determine alterations in the miRNA profile in heart tissue after cardiac surgery using CPB. METHODS: In total, 14 tissue samples from right atrium were collected from patients before and after connection of the CPB. SurePrintTM 8 * 60K Human v21 miRNA array and quantitative reverse transcription-polymerase chain reaction (RT qPCR) were employed to determine the miRNA expression profile from three patients before and after connection of the CPB. Enrichment analyses of altered miRNA expression were predicted using bioinformatic tools. RESULTS: According to miRNA array, a total of 90 miRNAs were significantly altered including 29 miRNAs with increased and 61 miRNAs with decreased expression after de-connection of CPB (n = 3) compared to before CPB (n = 3). Seven miRNAs had been validated using RT-qPCR in an independent cohort of 11 patients. Enrichment analyses applying the KEGG database displayed the highest correlation for signaling pathways, cellular community, cardiovascular disease and circulatory system. CONCLUSION: Our result identified the overall changes of the miRNome in right atrium tissue of patients with CHDs after CPB. The differentially altered miRNAs lay a good foundation for further understanding of the molecular function of changed miRNAs in regulating CHDs and after CPB in particular. PMID- 28558736 TI - Scoping review of indicators and methods of measurement used to evaluate the impact of dog population management interventions. AB - BACKGROUND: Dogs are ubiquitous in human society and attempts to manage their populations are common to most countries. Managing dog populations is achieved through a range of interventions to suit the dog population dynamics and dog ownership characteristics of the location, with a number of potential impacts or goals in mind. Impact assessment provides the opportunity for interventions to identify areas of inefficiencies for improvement and build evidence of positive change. METHODS: This scoping review collates 26 studies that have assessed the impacts of dog population management interventions. RESULTS: It reports the use of 29 indicators of change under 8 categories of impact and describes variation in the methods used to measure these indicators. CONCLUSION: The relatively few published examples of impact assessment in dog population management suggest this field is in its infancy; however this review highlights those notable exceptions. By describing those indicators and methods of measurement that have been reported thus far, and apparent barriers to efficient assessment, this review aims to support and direct future impact assessment. PMID- 28558737 TI - Improving active case finding for tuberculosis in South Africa: informing innovative implementation approaches in the context of the Kharitode trial through formative research. AB - BACKGROUND: Tuberculosis (TB) is the leading infectious killer worldwide, with approximately 1.8 million deaths in 2015. While effective treatment exists, implementation of active case finding (ACF) methods to identify persons with active TB in a timely and cost-effective manner continues to be a major challenge in resource-constrained settings. Limited qualitative work has been conducted to gain an in-depth understanding of implementation barriers. METHODS: Qualitative research was conducted to inform the development of three ACF strategies for TB to be evaluated as part of the Kharitode cluster-randomised trial being conducted in a rural province of South Africa. This included 25 semi-structured in-depth interviews among 8 TB patients, 7 of their household members and 10 clinic health workers, as well as 4 focus group discussions (2 rural and 2 main town locations) with 6-8 participants each (n = 27). Interviews and focus group discussions explored the context, advantages and limitations, as well as the implications of three ACF methods. Content analysis was utilised to document salient themes regarding their feasibility, acceptability and potential effectiveness. RESULTS: Study participants (TB patients and community members) reported difficulty identifying TB symptoms and seeking care in a timely fashion. In turn, all stakeholder groups felt that more proactive case finding strategies would be beneficial. Clinic-based strategies (including screening all patients regardless of visit purpose) were seen as the most acceptable method based on participants' preference ranking of the ACF strategies. However, given the resource constraints experienced by the public healthcare system in South Africa, many participants doubted whether it would be the most effective strategy. Household outreach and incentive-based strategies were described as promising, but participants reported some concerns (e.g. stigma in case of household-based and ethical concerns in the case of incentives). Participants offered insights into how to optimise each strategy, tailoring implementation to community needs (low TB knowledge) and realities (financial constraints, transport, time off from work). CONCLUSIONS: Findings suggest different methods of TB ACF are likely to engage different populations, highlighting the utility of a comprehensive approach. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT02808507 ). Registered June 1, 2016. The participants in this formative study are not trial participants. PMID- 28558738 TI - Understanding knee osteoarthritis from the patients' perspective: a qualitative study. AB - BACKGROUND: No studies of Health Coach Interventions for knee OA sufferers that include patients' perspectives have been published. The study assesses current clinical practice and primary care professionals' advice from the patients' perspective, in order to obtain a participative design for a complex intervention based on coaching psychology. Moreover, wants to analyse the experiences, perceptions, cognitive evaluation, values, emotions, beliefs and coping strategies of patients with knee osteoarthritis, and secondly the impact of these factors in the Self-management of this condition. METHODS: It is an interpretative qualitative study. The study included patients with diagnosis of knee osteoarthritis (OA) from 4 primary health care centres in Barcelona. A theoretical sampling based on a prior definition of participants' characteristics was carried out. Ten semi-structured interviews with knee OA patients were carried out. A content thematic analysis was performed following a mixed-strategy text codification in Lazarus framework and in emerging codes from the data. RESULTS: The results are structured in two blocks: Experiences and perceptions of informants and Experiences of knee osteoarthritis according to the Lazarus model. Regarding experiences and perceptions of informants: Some participants reported that the information was mostly provided by health professionals. Informants know which food they should eat to lose weight and the benefits of weight loss. Moreover, participants explained that they like walking but that sometimes it is difficult to put into practice. Regarding experiences of knee osteoarthritis according Lazarus model: Cognitive evaluation is influenced by cognitive distortions such as obligation, guilt, dramatization and catastrophism. VALUES: Family is the value most associated with wellbeing. Helping others is another recurring value. Emotions: Most participants explain that they feel anxiety, irritability or sadness. Beliefs: To some, physiotherapy helps them feel less pain. However, others explain that it is of no use to them. Participants are aware of the association overweight- pain. Coping strategies: The strategies for coping with emotions aim to reduce psychological distress (anxiety, sadness, anger) and some are more active than others. CONCLUSIONS: The study highlights that patients with knee osteoarthritis require a person-centered approach that provides them with strategies to overcome the psychological distress caused by this condition. PMID- 28558739 TI - Similar cardiometabolic effects of high- and moderate-intensity training among apparently healthy inactive adults: a randomized clinical trial. AB - BACKGROUND: Metabolic syndrome (MetS) increases the risk of morbidity and mortality from cardiovascular disease, and exercise training is an important factor in the treatment and prevention of the clinical components of MetS. OBJECTIVE: The aim was to compare the effects of high-intensity interval training and steady-state moderate-intensity training on clinical components of MetS in healthy physically inactive adults. METHODS: Twenty adults were randomly allocated to receive either moderate-intensity continuous training [MCT group; 60 80% heart rate reserve (HRR)] or high-intensity interval training (HIT group; 4 * 4 min at 85-95% peak HRR interspersed with 4 min of active rest at 65% peak HRR). We used the revised International Diabetes Federation criteria for MetS. A MetS Z score was calculated for each individual and each component of the MetS. RESULTS: In intent-to-treat analyses, the changes in MetS Z-score were 1.546 (1.575) in the MCT group and -1.249 (1.629) in the HIT group (between-groups difference, P = 0.001). The average number of cardiometabolic risk factors changed in the MCT group (-0.133, P = 0.040) but not in the HIT group (0.018, P = 0.294), with no difference between groups (P = 0.277). CONCLUSION: Among apparently healthy physically inactive adults, HIT and MCT offer similar cardiometabolic protection against single MetS risk factors but differ in their effect on average risk factors per subject. Trial registration ClinicalTrials.gov NCT02738385 registered on March 23, 2016. PMID- 28558740 TI - Experiences with VHA care: a qualitative study of U.S. women veterans with self reported trauma histories. AB - BACKGROUND: Women veterans in the United States, particularly those with posttraumatic stress disorder (PTSD) or a history of military sexual assault, have unique health care needs, but their minority status in the US Veterans Health Administration (VHA) has led to documented healthcare disparities when compared to men. This study's objective was to obtain a richer understanding of the challenges and successes encountered by women veterans with self-reported service-related trauma histories (particularly those with a history of military sexual assault and/or posttraumatic stress symptomology) receiving VHA care. METHODS: Thirty-seven female Vietnam and post-Vietnam (1975-1998) era veterans were randomly selected from a cohort of PTSD disability benefit applicants to complete semi-structured interviews in 2011-2012. Grounded-theory informed procedures were used to identify interview themes; differences between veterans with and without a history of military sexual assault were examined through constant comparison. RESULTS: At the time of the interviews, many women believed that VHA was falling short of meeting women veterans' needs (e.g., lack of women only mental health programming). Also common, but particularly among those with a military sexual assault history, was the perception that VHA's environment was unwelcoming; being "surrounded by men" yielded emotions ranging from discomfort and mistrust to severe anxiety. A few veterans reported recent positive changes and offered additional suggestions for improvement. CONCLUSIONS: Findings suggest that while at the time of the interviews gains had been made in the delivery of gender-sensitive outpatient medical care, women veterans with a history of military sexual assault and/or posttraumatic stress symptomology perceived that they were not receiving the same quality of care as male veterans. PMID- 28558741 TI - Brain-Computer Interface application: auditory serial interface to control a two class motor-imagery-based wheelchair. AB - BACKGROUND: Certain diseases affect brain areas that control the movements of the patients' body, thereby limiting their autonomy and communication capacity. Research in the field of Brain-Computer Interfaces aims to provide patients with an alternative communication channel not based on muscular activity, but on the processing of brain signals. Through these systems, subjects can control external devices such as spellers to communicate, robotic prostheses to restore limb movements, or domotic systems. The present work focus on the non-muscular control of a robotic wheelchair. METHOD: A proposal to control a wheelchair through a Brain-Computer Interface based on the discrimination of only two mental tasks is presented in this study. The wheelchair displacement is performed with discrete movements. The control signals used are sensorimotor rhythms modulated through a right-hand motor imagery task or mental idle state. The peculiarity of the control system is that it is based on a serial auditory interface that provides the user with four navigation commands. The use of two mental tasks to select commands may facilitate control and reduce error rates compared to other endogenous control systems for wheelchairs. RESULTS: Seventeen subjects initially participated in the study; nine of them completed the three sessions of the proposed protocol. After the first calibration session, seven subjects were discarded due to a low control of their electroencephalographic signals; nine out of ten subjects controlled a virtual wheelchair during the second session; these same nine subjects achieved a medium accuracy level above 0.83 on the real wheelchair control session. CONCLUSION: The results suggest that more extensive training with the proposed control system can be an effective and safe option that will allow the displacement of a wheelchair in a controlled environment for potential users suffering from some types of motor neuron diseases. PMID- 28558742 TI - Generalised joint hypermobility and shoulder joint hypermobility, - risk of upper body musculoskeletal symptoms and reduced quality of life in the general population. AB - BACKGROUND: Generalised Joint Hypermobility (GJH) is a hereditary condition with an ability to exceed the joints beyond the normal range. The prevalence of GJH in the adult population and its impact on upper body musculoskeletal health and quality of life has mostly been studied in selected populations. The aims of this study were therefore, firstly to study the prevalence of GJH and GJH including shoulder hypermobility (GJHS), in the general Danish adult population; secondly to test the associations between GJH or GJHS and upper body musculoskeletal symptoms and health-related quality of life (HRQoL). METHODS: The study was cross sectional where 2072 participants, aged 25-65, randomly extracted from the Danish Civil Registration System), were invited to answer a questionnaire battery (Five Part Questionnaire for classification of GJH, Standardised Nordic Questionnaire for musculoskeletal symptoms, EuroQoL-5D for HRQoL). RESULTS: Totally 1006 (49%) participants responded. The prevalence of GJH and GJHS were 30% (n = 300) and 5% (n = 51), respectively. Compared with Non GJH (NGJH), participants with GJH and GJHS had Odds Ratio (OR) of 1.5-3.5 for upper body musculoskeletal symptoms within the last 12 months (mostly shoulders and hands/wrists). GJH and GJHS also had OR 1.6-4.4 for being prevented from usual activities, mostly due to shoulder and neck symptoms. Furthermore, GJH and GJHS had OR 2.2-3.1 for upper body musculoskeletal symptoms lasting for more than 90 days (neck, shoulders, hand/wrists), and 1.5-3.5 for reduced HRQoL (all dimensions, but anxiety/depression) compared with NGJH. Generally, most OR for GJHS were about twice as high as for those having GJH alone. CONCLUSIONS: GJH and GJHS are frequently self-reported musculoskeletal conditions in the Danish adult population. Compared with NGJH, GJH and especially GJHS, present with higher OR for upper body musculoskeletal symptoms, more severe symptoms and decreased HRQoL. PMID- 28558743 TI - Clinical and genetic characteristics of chinese patients with Birt-Hogg-Dube syndrome. AB - BACKGROUND: Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant disorder, the main manifestations of which are fibrofolliculomas, renal tumors, pulmonary cysts and recurrent pneumothorax. The known causative gene for BHD syndrome is the folliculin (FLCN) gene on chromosome 17p11.2. Studies of the FLCN mutation for BHD syndrome are less prevalent in Chinese populations than in Caucasian populations. Our study aims to investigate the genotype spectrum in a group of Chinese patients with BHD. METHODS: We enrolled 51 patients with symptoms highly suggestive of BHD from January 2014 to February 2017. The FLCN gene was examined using PCR and Sanger sequencing in every patient, for those whose Sanger sequencing showed negative mutation results, multiplex ligation-dependent probe amplification (MLPA) testing was conducted to detect any losses of large segments. MAIN RESULTS: Among the 51 patients, 27 had FLCN germline mutations. In total, 20 mutations were identified: 14 were novel mutations, including 3 splice acceptor site mutations, 2 different deletions, 6 nonsense mutations, 1 missense mutation, 1 small insertion, and 1 deletion of the whole exon 8. CONCLUSIONS: We found a similar genotype spectrum but different mutant loci in Chinese patients with BHD compared with European and American patients, thus providing stronger evidence for the clinical molecular diagnosis of BHD in China. It suggests that mutation analysis of the FLCN gene should be systematically conducted in patients with cystic lung diseases. PMID- 28558744 TI - Tocilizumab in the treatment of twelve cases with aa amyloidosis secondary to familial mediterranean fever. AB - BACKGROUND: There is no established treatment of AA amyloidosis, a long-term complication of various chronic inflammatory diseases associated with increased mortality, such as familial Mediterranian fever (FMF). Recently there are few reports pointing out that tocilizumab(TCZ), an anti IL-6 agent may be effective in AA amyloidosis resistant to conventional treatments. We report our data on the effect of TCZ in patients with FMF complicated with AA amyloidosis. METHODS: FMF patients with histologically proven AA amyloidosis, treated with TCZ (8 mg/kg per month) were followed monthly and the changes in creatinine, creatinine clearance, the amount of 24-hour urinary protein, erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) were noted throughout the treatment period. Adverse effects of the treatment were closely monitored. RESULTS: TCZ was given to 12 patients (6 F, 6 M) who also continued to receive colchicine (1.9 +/- 0.4 mg/day). Coexisting diseases were ankylosing spondylitis(4) and Crohn's disease(1). The mean age was 35.2 +/- 10.0 years and the mean follow-up on TCZ was 17.5 +/- 14.7 months. The renal functions remained stable (mean creatinine from 1.1 +/- 0.9 mg/dl to 1.0 +/- 0.6 mg/dl), while a significant decrease in acute phase response (the mean CRP from 18.1 +/- 19.5 mg/L to 5.8 +/- 7.1 mg/L and ESR from 48.7 +/- 31.0 mm/h to 28.7 +/- 28.3 mm/h) was observed and the mean 24-hour urinary protein excretion reduced from 6537.6 +/- 6526.0 mg/dl to 4745.5 +/- 5462.7 mg/dl. Two patients whose renal functions were impaired prior to TCZ therapy improved significantly on this regimen. No infusion reaction was observed. None of the patients experienced any FMF attack under TCZ treatment with the exception of 2, one of whom had less frequent attacks while the other had episodes of erysipelas-like erythema. CONCLUSiON: Tocilizumab improved the acute phase response and the renal function in this group of patients and was generally well tolerated. Besides improving the renal function TCZ seemed to control the recurrence of FMF attacks too. Further studies are warrented to test the efficacy and safety of TCZ in AA amyloidosis secondary to FMF as well as other inflammatory conditions. PMID- 28558745 TI - Knowledge, attitudes and behaviours related to dietary salt among adults in the state of Victoria, Australia 2015. AB - BACKGROUND: Information on consumer's knowledge, attitudes and behaviours (KABs) related to salt can be used to inform awareness and education campaigns and serve as a baseline measure to monitor changes in KABs over time. The aim of this study was to determine KABs related to salt intake among Victorian adults. METHODS: Cross-sectional survey conducted in Victorian adults aged 18-65 years. Participants were recruited from shopping centres located in Melbourne and Geelong and via online methods (Facebook and Consumer Research Panel) to complete an online survey assessing KABs related to dietary salt. Descriptive statistics (mean (SD) or n (%)) were used to report survey findings. RESULTS: A total of 2398 participants provided a valid survey (mean age 43 years (SD 13), 57% female). The majority (80%) were born in Australia and 63% were the main household grocery shopper. The majority (89%) were aware of the health risks associated with a high salt intake. Eighty three percent believed that Australians eat too much salt. Three quarters (75%) correctly identified salt from processed foods as being the main source of salt in the diet. Less than a third (29%) of participants believed their own individual salt intake exceeded dietary recommendations and only 28% could correctly identify the maximum recommended daily intake for salt. Just under half (46%) of participants were concerned about the amount of salt in food. Almost two thirds (61%) of participants believed that there should be laws which limit the amount of salt added to manufactured foods and 58% agreed that it was difficult to find lower salt options when eating out. CONCLUSIONS: The findings of this study serve as a baseline assessment of KABs related to salt intake in Victorian adults and can be used to assess changes in salt related KABs over time. Public concern about salt is low as many people remain unaware of their own salt intake. An increased awareness of the excessive amount of salt consumed and increased availability of lower salt foods are likely to reduce population salt intake. PMID- 28558746 TI - Characteristics of therapeutic alliance in musculoskeletal physiotherapy and occupational therapy practice: a scoping review of the literature. AB - BACKGROUND: Most conventional treatment for musculoskeletal conditions continue to show moderate effects, prompting calls for ways to increase effectiveness, including drawing from strategies used across other health conditions. Therapeutic alliance refers to the relational processes at play in treatment which can act in combination or independently of specific interventions. Current evidence guiding the use of therapeutic alliance in health care arises largely from psychotherapy and medicine literature. The objective of this review was to map out the available literature on therapeutic alliance conceptual frameworks, themes, measures and determinants in musculoskeletal rehabilitation across physiotherapy and occupational therapy disciplines. METHODS: A scoping review of the literature published in English since inception to July 2015 was conducted using Medline, EMBASE, PsychINFO, PEDro, SportDISCUS, AMED, OTSeeker, AMED and the grey literature. A key search term strategy was employed using "physiotherapy", "occupational therapy", "therapeutic alliance", and "musculoskeletal" to identify relevant studies. All searches were performed between December 2014 and July 2015 with an updated search on January 2017. Two investigators screened article title, abstract and full text review for articles meeting the inclusion criteria and extracted therapeutic alliance data and details of each study. RESULTS: One hundred and thirty articles met the inclusion criteria including quantitative (33%), qualitative (39%), mixed methods (7%) and reviews and discussions (23%) and most data came from the USA (23%). Randomized trials and systematic reviews were 4.6 and 2.3% respectively. Low back pain condition (22%) and primary care (30.7%) were the most reported condition and setting respectively. One theory, 9 frameworks, 26 models, 8 themes and 42 subthemes of therapeutic alliance were identified. Twenty-six measures were identified; the Working Alliance Inventory (WAI) was the most utilized measure (13%). Most of the therapeutic alliance themes extracted were from patient perspectives. The relationship between adherence and therapeutic alliance was examined by 26 articles of which 57% showed some correlation between therapeutic alliance and adherence. Age moderated the relationship between therapeutic alliance and adherence with younger individuals and an autonomy support environment reporting improved adherence. Prioritized goals, autonomy support and motivation were facilitators of therapeutic alliance. CONCLUSION: Therapeutic Alliance has been studied in a limited extent in the rehabilitation literature with conflicting frameworks and findings. Potential benefits described for enhancing therapeutic alliance might include better exercise adherence. Several knowledge gaps have been identified with a potential for generating future research priorities for therapeutic alliance in musculoskeletal rehabilitation. PMID- 28558747 TI - Weather and children's physical activity; how and why do relationships vary between countries? AB - BACKGROUND: Globally most children do not engage in enough physical activity. Day length and weather conditions have been identified as determinants of physical activity, although how they may be overcome as barriers is not clear. We aim to examine if and how relationships between children's physical activity and weather and day length vary between countries and identify settings in which children were better able to maintain activity levels given the weather conditions they experienced. METHODS: In this repeated measures study, we used data from 23,451 participants in the International Children's Accelerometry Database (ICAD). Daily accelerometer-measured physical activity (counts per minute; cpm) was matched to local weather conditions and the relationships assessed using multilevel regression models. Multilevel models accounted for clustering of days within occasions within children within study-cities, and allowed us to explore if and how the relationships between weather variables and physical activity differ by setting. RESULTS: Increased precipitation and wind speed were associated with decreased cpm while better visibility and more hours of daylight were associated with increased cpm. Models indicated that increases in these variables resulted in average changes in mean cpm of 7.6/h of day length, -13.2/cm precipitation, 10.3/10 km visibility and -10.3/10kph wind speed (all p < 0.01). Temperature showed a cubic relationship with cpm, although between 0 and 20 degrees C the relationship was broadly linear. Age showed interactions with temperature and precipitation, with the associations larger among younger children. In terms of geographic trends, participants from Northern European countries and Melbourne, Australia were the most active, and also better maintained their activity levels given the weather conditions they experienced compared to those in the US and Western Europe. CONCLUSIONS: We found variation in the relationship between weather conditions and physical activity between ICAD studies and settings. Children in Northern Europe and Melbourne, Australia were not only more active on average, but also more active given the weather conditions they experienced. Future work should consider strategies to mitigate the impacts of weather conditions, especially among young children, and interventions involving changes to the physical environment should consider how they will operate in different weather conditions. PMID- 28558748 TI - Use of ranitidine is associated with infections in newborns hospitalized in a neonatal intensive care unit: a cohort study. AB - BACKGROUND: The inhibition of gastric acid secretion with ranitidine is frequently prescribed off-label to newborns admitted to neonatal intensive care units (NICU). Some studies show that the use of inhibitors of gastric acid secretion (IGAS) may predispose to infections and necrotising enterocolitis (NEC), but there are few data to confirm this association. This study aimed to compare the rates of neonatal infections and NEC among preterm infants (<37 weeks gestation) hospitalised in a NICU exposed or not to treatment with ranitidine. METHODS: A retrospective cohort study was conducted with all consecutive preterm newborns admitted to a NICU between August-2014 and October-2015. The rates of infection, NEC, and death of newborns exposed or not to ranitidine were recorded. RESULTS: A total of 300 newborns were enrolled, of which 115 had received ranitidine and 185 had not. The two groups were similar with regard to the main demographic and clinical characteristics. Forty-eight (41.7%) of the 115 infants exposed to ranitidine and 49 (26.5%) of the 185 infants not exposed were infected (RR = 1.6, 95%CI 1.1-2.2, p = 0.006). The late onset (>48 h) blood culture positive infection rate was higher in the group exposed to ranitidine than in the untreated group (13.0% vs. 3.8%, p = 0.001). There was no significant association between the use of ranitidine and NEC (Bell stage >II) (p = 0.36). The mortality rate risk was 4-fold higher in infants receiving ranitidine (16.5% vs. 8.6%, p < 0.001). CONCLUSION: Ranitidine use in neonates was associated with an increased risk of infections and mortality, but not with NEC. PMID- 28558749 TI - A novel zoonotic Anaplasma species is prevalent in small ruminants: potential public health implications. AB - BACKGROUND: Tick-borne diseases currently represent an important issue for global health. A number of emerging tick-transmitted microbes continue to be discovered, and some of these are already identified as the cause of human infections. Over the past two decades, Anaplasma phagocytophilum is considered to be mainly responsible for human anaplasmosis. However, a novel zoonotic pathogen provisionally named "Anaplasma capra" has recently been identified in China. In this study, we did an active surveillance of A. capra in goats and sheep in different geographical regions of China. METHODS: The presence of A. capra was determined by nested PCR in 547 blood samples collected from goats and sheep from 24 counties distributed in 12 provinces in China. The molecular characterization of A. capra isolates in sheep and goats was achieved based on four conventional genetic markers (16S rRNA, gltA, groEL and msp4 genes). RESULTS: Anaplasma capra was identified in 75 of 547 animals, with an overall prevalence of 13.7%. The infection rates in the survey sites ranged from 0 to 78.6%, and were significantly different (P < 0.01). Phylogenetic analysis revealed that the isolates obtained from goats, sheep, Ixodes persulcatus ticks and humans create a separate clade within the genus Anaplasma and distinct from other recognized Anaplasma species. These findings indicated that these A. capra isolates possess the same molecular characteristics, suggesting that this organism could be a substantial health threat to both animals and humans. CONCLUSIONS: Anaplasma capra is an emerging tick-transmitted zoonotic pathogen. This novel Anaplasna species is widespread across China with an overall prevalence of 13.7% in goats and sheep with isolates indistinguishable from those found in humans. These findings warrant increased public health awareness for human anaplasmosis. PMID- 28558750 TI - Approach selection of radiofrequency catheter ablation for ventricular arrhythmias originating from the left ventricular summit: potential relevance of Pseudo Delta wave, Intrinsicoid deflection time, maximal deflection index. AB - BACKGROUND: Ventricular arrhythmias (VAs) originating from the left ventricular summit is a challenge for radiofrequency catheter ablation (RFCA). The present study aimed to investigate the appropriate RFCA strategy for VAs originating from the left ventricular summit. METHODS: Forty-five consecutive patients with VAs arising from the left ventricular summit were successfully ablated at our cardiac electrophysiology center and reviewed in the study. RESULTS: Thirty-two cases of VAs were eliminated in the left ventricular endocardium by retrograde transaortic (n = 22, 22/45, 48.9%) or antegrade transseptal (n = 10, 10/45, 22.2%) approaches, the other 13 cases were eliminated in the left ventricular epicardium by distal great cardiac vein (DGCV) approach (n = 13, 13/45, 28.9%). Though these VAs were similar in electrocardiographic (ECG) morphology, the pseudo delta waves (PDW), intrinsicoid deflection time (IDT), maximal deflection index (MDI) differed among them, PDW >53 ms, IDT > 74 ms, MDI > 0.45 strongly indicated that ablating left ventricular summit VAs by DGCV approach. During mean follow-up of 19.5 +/- 13.2 (range, 3-60) months, 2 (4.4%) patients experienced VAs recurrence. CONCLUSION: This retrospective study showed that VAs of left ventricular summit origin can be effectively cured with RFCA. For these VAs, prolonged PdW, IDT, MDI indicating RFCA by DGCV approach can be attempted firstly. PMID- 28558751 TI - A 14-day limit for bioethics: the debate over human embryo research. AB - BACKGROUND: This article explores the reasons in favour of revising and extending the current 14-day statutory limit to maintaining human embryos in culture. This limit is enshrined in law in over a dozen countries, including the United Kingdom. In two recently published studies (2016), scientists have shown that embryos can be sustained in vitro for about 13 days after fertilisation. Positive reactions to these results have gone hand in hand with calls for revising the 14 day rule, which only allows embryo research until the 14th day after fertilisation. MAIN TEXT: The article explores the most prominent arguments in favour of and against the extension of the 14-day limit for conducting research on human embryos. It situates these arguments within the history of the 14-day limit. I start by discussing the history of the 14-day limit in the United Kingdom and the reasons behind the decision to opt for a compromise between competing moral views. I then analyse the arguments that those who are generally in favour of embryo research put forward in support of extending the 14-day rule, namely (a) the argument of the beneficence of research and (b) the argument of technical feasibility (further explained in the article). I then show how these two arguments played a role in the recent approval of two novel techniques for the replacement of faulty mitochondrial DNA in the United Kingdom. Despite the popularity and widespread use of these arguments, I argue that they are ultimately problematic and should not be straightforwardly accepted (i.e. accepted without further scrutiny). I end by making a case for respecting value pluralism in the context of embryo research, and I present two reasons in favour of respecting value pluralism: the argument of public trust and the argument of democracy. CONCLUSION: I argue that 14-day limit for embryo research is not a valuable tool despite being a solution of compromise, but rather because of it. The importance of respecting value pluralism (and of respecting different views on embryo research) needs to be considered in any evaluation concerning a potential change to the 14-day rule. PMID- 28558753 TI - Medical students' career choices, preference for placement, and attitudes towards the role of medical instruction in Ethiopia. AB - BACKGROUND: In Ethiopia, the health care delivery and the system of medical education have been expanding rapidly. However, in spite of the expansion, no studies have been carried out among medical students to identify their career choices and attitudes towards the medical instruction. Therefore, this study aimed to fill the gap in evidence in these specific areas. METHODS: Pretested questionnaire was self-administered among fifth and sixth year medical students in six government owned medical schools in Ethiopia. A total of 959 students were involved in the study with a response rate of 82.2%. Career choices, intention where to work just after graduation, and attitudes towards medical instruction were descriptively presented. Binary logistic regression model was fitted to identify factors associated with the intention of medical students to work in rural and remote areas. RESULTS: Majority, (70.1%) of the medical students wanted to practice in clinical care settings. However, only a small proportion of them showed interest to work in rural and remote areas (21% in zonal and 8.7% in district/small towns). For most, internal medicine was the first specialty of choice followed by surgery. However, students showed little interest in obstetrics and gynecology, as well as in pediatrics and child health as their first specialty of choice. Medical students' attitudes towards their school in preparing them to work in rural and remote areas, to pursue their career within the country and to specialize in medical disciplines in which there are shortages in the country were low. The binary logistic regression model revealed that a significantly increased odds of preference to work in rural and remote areas was observed among males, those who were born in rural areas, the medical students of Addis Ababa University and those who had the desire to serve within the country. CONCLUSION: This study showed that Ethiopian medical schools are training medical workforce with preferences not to work in rural and remote places, and not to specialize in disciplines where there are shortages in the country. Thus, attention should be given to influence medical students' attitude to work in rural and remote locations and to specialize in diverse clinical specialties. PMID- 28558752 TI - Epigenomic and functional analyses reveal roles of epialleles in the loss of photoperiod sensitivity during domestication of allotetraploid cottons. AB - BACKGROUND: Polyploidy is a pervasive evolutionary feature of all flowering plants and some animals, leading to genetic and epigenetic changes that affect gene expression and morphology. DNA methylation changes can produce meiotically stable epialleles, which are transmissible through selection and breeding. However, the relationship between DNA methylation and polyploid plant domestication remains elusive. RESULTS: We report comprehensive epigenomic and functional analyses, including ~12 million differentially methylated cytosines in domesticated allotetraploid cottons and their tetraploid and diploid relatives. Methylated genes evolve faster than unmethylated genes; DNA methylation changes between homoeologous loci are associated with homoeolog-expression bias in the allotetraploids. Significantly, methylation changes induced in the interspecific hybrids are largely maintained in the allotetraploids. Among 519 differentially methylated genes identified between wild and cultivated cottons, some contribute to domestication traits, including flowering time and seed dormancy. CONSTANS (CO) and CO-LIKE (COL) genes regulate photoperiodicity in Arabidopsis. COL2 is an epiallele in allotetraploid cottons. COL2A is hypermethylated and silenced, while COL2D is repressed in wild cottons but highly expressed due to methylation loss in all domesticated cottons tested. Inhibiting DNA methylation activates COL2 expression, and repressing COL2 in cultivated cotton delays flowering. CONCLUSIONS: We uncover epigenomic signatures of domestication traits during cotton evolution. Demethylation of COL2 increases its expression, inducing photoperiodic flowering, which could have contributed to the suitability of cotton for cultivation worldwide. These resources should facilitate epigenetic engineering, breeding, and improvement of polyploid crops. PMID- 28558754 TI - Urinary TIMP-2 and IGFBP7 for the prediction of acute kidney injury following cardiac surgery. AB - BACKGROUND: Acute kidney injury (AKI) following cardiac surgery is common and associated with poor patient outcomes. Early risk assessment for development of AKI remains a challenge. The combination of urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) has been shown to be an excellent predictor of AKI following cardiac surgery, but reported studies are for predominately non-Asian populations. METHODS: Adult patients were prospectively enrolled at Zhongshan hospital in Shanghai, China. The primary analysis was prediction of AKI and stage 2-3 AKI by [TIMP-2]*[IGFBP7] measured 4 h after postoperative ICU admission assessed using receiver operating characteristic curve (ROC) analysis. Kinetics of [TIMP 2]*[IGFBP7] following ICU admission were also examined. RESULTS: We prospectively enrolled 57 cardiac surgery patients, of which 20 (35%) developed AKI and 6 (11%) developed stage 2-3 AKI. The area under the ROC curve (AUC) of [TIMP-2]*[IGFBP7] at 4 h after ICU admission was 0.80 (95% confidence interval (CI): 0.68-0.91) for development of AKI and 0.83 (95% CI: 0.69-0.96) for development of stage 2-3 AKI. Urinary [TIMP-2]*[IGFBP7] values at 4 h after ICU admission were significantly (P < 0.001) higher in patients who developed AKI than in patients who did not develop AKI (mean (standard error) of 1.08 (0.34) (ng/mL)2/1000 and 0.29 (0.05) (ng/mL)2/1000, respectively). The time-profile of [TIMP-2]*[IGFBP7] suggests the markers started to elevate by the time of ICU admission in patients who developed AKI and either decreased or remained flat in patients without AKI. CONCLUSION: The combination of urinary TIMP-2 and IGFBP7 4 h after postoperative ICU admission identifies patients at risk for developing AKI, not just stage 2-3 AKI following cardiac surgery. PMID- 28558755 TI - Evaluation of a species-specific C-reactive protein assay for the dog on the ABX Pentra 400 clinical chemistry analyzer. AB - BACKGROUND: A canine-specific immunoturbidimetric CRP assay, Gentian Canine CRP Immunoassay) with species-specific controls and calibrators was introduced and recently evaluated on the clinical chemistry analyzer Abbott Architect c4000 as well as on the Olympus AU600. Aims of our study were 1) to independently evaluate the canine-specific CRP assay on the ABX Pentra 400 clinical chemistry analyzer in comparison to the previously validated human-based immunoturbidimetric assay (Randox Canine CRP assay) and 2) to assess the impact of different sample types (serum versus heparinized plasma) on the results. Imprecision, accuracy, interference and the prozone effect were determined using samples from healthy and diseased dogs (n = 278). The Randox Canine CRP assay calibrated with canine specific control calibration material served as a reference method. Additionally, the impact of the sample type (serum and lithium heparin) was evaluated based on samples of healthy and diseased dogs (n = 49) in a second part of the study. RESULTS: Linearity was present for CRP concentrations ranging from 4 to 281 mg/l. For clinically relevant CRP concentrations of 7-281 mg/l, recovery ranged between 90 and 105% and intra- and inter-assay CVs ranged between 0.68% - 12.12% and 0.88% - 7.84%, respectively. CV was thus lower than 12.16%, i.e. the desired CV% based on biological variation. Interference was not present up to a concentration of 5 g/l hemoglobin, 800 mg/l bilirubin and 10 g/l triglycerides. No prozone effect occurred up to 676 mg/l CRP. Method comparison study revealed a Spearman's rank correlation coefficient of rs = 0.98 and a mean constant bias of 5.2%. The sample type had a significant (P = 0.008) but clinically not relevant impact on the results (median CRP of 30.9 mg/l in lithium heparin plasma versus 31.4 mg/l in serum). CONCLUSIONS: The species-specific Gentian Canine CRP Immunoassay reliably detects canine CRP on the ABX Pentra 400 clinical chemistry analyzer whereby both serum and heparin plasma can be used. The quality criteria reached on the Abbott Architect c4000 and Olympus AU600 could be met. PMID- 28558756 TI - Comparison of methods to identify long term care nursing home residence with administrative data. AB - BACKGROUND: To compare different methods for identifying a long term care (LTC) nursing home stay, distinct from stays in skilled nursing facilities (SNFs), to the method currently used by the Center for Medicare and Medicaid Services (CMS). We used national and Texas Medicare claims, Minimum Data Set (MDS), and Texas Medicaid data from 2011-2013. METHODS: We used Medicare Part A and B and MDS data either alone or in combination to identify LTC nursing home stays by three methods. One method used Medicare Part A and B data; one method used Medicare Part A and MDS data; and the current CMS method used MDS data alone. We validated each method against Texas 2011 Medicare-Medicaid linked data for those with dual eligibility. RESULTS: Using Medicaid data as a gold standard, all three methods had sensitivities > 92% to identify LTC nursing home stays of more than 100 days in duration. The positive predictive value (PPV) of the method that used both MDS and Medicare Part A data was 84.65% compared to 78.71% for the CMS method and 66.45% for the method using Part A and B Medicare. When the patient population was limited to those who also had a SNF stay, the PPV for identifying LTC nursing home was highest for the method using Medicare plus MDS data (88.1%). CONCLUSIONS: Using both Medicare and MDS data to identify LTC stays will lead to more accurate attribution of CMS nursing home quality indicators. PMID- 28558757 TI - Multiscalar cellular automaton simulates in-vivo tumour-stroma patterns calibrated from in-vitro assay data. AB - BACKGROUND: The tumour stroma -or tumour microenvironment- is an important constituent of solid cancers and it is thought to be one of the main obstacles to quantitative translation of drug activity between the preclinical and clinical phases of drug development. The tumour-stroma relationship has been described as being both pro- and antitumour in multiple studies. However, the causality of this complex biological relationship between the tumour and stroma has not yet been explored in a quantitative manner in complex tumour morphologies. METHODS: To understand how these stromal and microenvironmental factors contribute to tumour physiology and how oxygen distributes within them, we have developed a lattice-based multiscalar cellular automaton model. This model uses principles of cytokine and oxygen diffusion as well as cell motility and plasticity to describe tumour-stroma landscapes. Furthermore, to calibrate the model, we propose an innovative modelling platform to extract model parameters from multiple in-vitro assays. This platform provides a novel way to extract meta-data that can be used to complement in-vivo studies and can be further applied in other contexts. RESULTS: Here we show the necessity of the tumour-stroma opposing relationship for the model simulations to successfully describe the in-vivo stromal patterns of the human lung cancer cell lines Calu3 and Calu6, as models of clinical and preclinical tumour-stromal topologies. This is especially relevant to drugs that target the tumour microenvironment, such as antiangiogenics, compounds targeting the hedgehog pathway or immune checkpoint inhibitors, and is potentially a key platform to understand the mechanistic drivers for these drugs. CONCLUSION: The tumour-stroma automaton model presented here enables the interpretation of complex in-vitro data and uses it to parametrise a model for in-vivo tumour stromal relationships. PMID- 28558758 TI - FGF2/FGFR1 regulates autophagy in FGFR1-amplified non-small cell lung cancer cells. AB - BACKGROUND: Autophagy is a conserved catabolic process to degrade cellular organelles. The role of autophagy in cancer development is complex. Amplification of fibroblast growth factor receptor 1 (FGFR1) is one of the most frequent targets in lung squamous cell carcinoma (SQCC). Whether fibroblast growth factor 2 (FGF2)/FGFR1 contributes to the regulation of autophagy remains elusive. METHODS: Autophagic activity was evaluated by immunoblotting for microtubule associated protein 1 light chain 3 (LC3), formation of GFP-LC3 puncta, and monodansylcadaverine (MDC) staining. The effect of autophagy inhibition on cell survival was assessed by cell viability and apoptosis assays. RESULTS: We elucidated that FGFR1 activation suppressed autophagy. Pharmacological or genetic inhibition of FGFR1 by AZD4547 or FGFR1 short hairpin RNA (shRNA) induced autophagy in FGFR1-amplified non-small cell lung cancer (NSCLC) cells, H1581 and H520 cells. Mechanistic study revealed that the induction of autophagy by FGFR1 inhibition was mediated through inhibiting the ERK/MAPK pathway not by AKT pathway, accompanied by upregulation of beclin-1. Furthermore, activation of ERK/MAPK by transfection with a constitutively active MEK1 (caMEK1) construct or knockdown of beclin-1 by RNAi could attenuate autophagy induced by FGFR1 inhibition. Beclin-1 expression was inversely correlated with MEK1 phosphorylation. Inhibition of autophagy by beclin-1 silencing could enhance apoptosis after AZD4547 treatment in H1581 and H520 cells. High levels of LC3B mRNA was a marker of poor prognosis in NSCLC patients. CONCLUSIONS: Simultaneously inhibiting FGFR1 and autophagy could enhance cell death which should be further explored in vivo. PMID- 28558759 TI - The danish regions pediatric triage model has a limited ability to detect both critically ill children as well as children to be sent home without treatment - a study of diagnostic accuracy. AB - BACKGROUND: The Danish Regions Pediatric Triage model (DRPT) was introduced in 2012 and subsequent implemented in most Danish acute pediatric departments. The aim was to evaluate the validity of DRPT as a screening tool to detect both the most serious acute conditions and the non-serious conditions in the acute referred patients in a pediatric department. METHOD: The study was prospective observational, with follow-up on all children with acute referral to pediatric department from October to December 2015. The DRPT was evaluated by comparison to a predefined reference standard and to the actual clinical outcomes: critically ill children and children returned to home without any treatment. The sensitivity, specificity, positive predictive value, negative predictive value, accuracy and likelihood for positive and negative test were calculated. RESULTS: Five hundred fifty children were included. The DRPT categorized 7% very urgent, 28% urgent, 29% standard and 36% non-urgent. The DRPT was equal to the reference standard in 31% of the children (CI: 27-35%). DRPT undertriaged 55% of the children (CI: 51-59%) and overtriaged 14% of the children (CI: 11-17%). For the most urgent patients the sensitivity of DRPT was 31% (CI: 20-48%) compared to the reference standard and 20% (CI: 7-41) for critically ill. For children with non urgent conditions the specificity of DRPT was 66% (CI: 62-71%) compared to the reference standard and 68% (CI: 62-75%) for the children who went home with no treatment. In none of the analyses, the likelihood ratio of the negative test was less than 0.7 and the positive likelihood ratio only reached more than 5 in one of the analyses. DISCUSSION: This study is the first to evaluate the DRPT triage system. From the very limited validity studies of other well-established triage systems, it is difficult to judge whether the DRPT performs better or worse than the alternatives. The DRPT errs to the undertriage side. If the sensitivity is low, a number of the sickest children are undetected and this is a matter of concern. CONCLUSION: The DRPT is a triage tool with limited ability to detect the critically ill children as well as the children who can be returned to home without any treatment. TRIAL REGISTRATION: Not relevant. PMID- 28558760 TI - Ecological parameters of the (S)-9-methylgermacrene-B population of the Lutzomyia longipalpis complex in a visceral leishmaniasis area in Sao Paulo state, Brazil. AB - BACKGROUND: Visceral leishmaniasis (VL) is an important public health challenge in Brazil because of the high number of human and canine cases reported annually. Leishmania infantum is the etiological agent of VL and Lutzomyia longipalpis is its main vector. However, evidence suggests that this taxon constitutes a species complex. In Sao Paulo state, there are two populations of Lu. longipalpis, each secreting distinct pheromones, (S)-9-methylgermacrene-B and Cembrene 1; both have been associated with different patterns of VL transmission. The aim of the present study was to investigate the temporal distribution and natural infection of the (S)-9-methylgermacrene-B population of the Lu. longipalpis complex in a highly VL endemic area of Sao Paulo state to obtain information that may contribute to the surveillance of this zoonosis and to the planning of preventive and control measures. METHODS: The study was carried out in Panorama municipality, Sao Paulo State. Captures were made during 24 months in seven domiciles. The relation between sand fly abundance and climatic variables, temperature and humidity, was analyzed and natural infection by Leishmania spp. in sand fly females was investigated by nested PCR. RESULTS: A total of 4120 sand flies, with predominance of Lu. longipalpis (97.2%) were captured. The highest averages of sand flies/night/trap occurred in the rainy season (November-March) and a positive, significant correlation between sand fly abundance and the temperature and humidity 20 days before the capture days was found. Leishmania infantum DNA was detected in three out of 250 pools of females analyzed, giving an estimated minimum infection rate of 1.2%. CONCLUSION: The identification of the climatic association between the high abundance of the vector in this highly endemic VL focus constitutes a fundamental point for evaluating future vector and dog control measures and this information increases the data of VL foci in Sao Paulo state that could contribute to the public health authorities in planning prevention and control measures. The identification of natural infection by Le. infantum in Lu. longipalpis specimens reinforces the importance of entomological surveillance activities in this municipality. PMID- 28558761 TI - Production, characterization, and antifungal activity of a biosurfactant produced by Rhodotorula babjevae YS3. AB - BACKGROUND: Sophorolipids are one of the most promising glycolipid biosurfactants and have been successfully employed in bioremediation and various other industrial sectors. They have also been described to exhibit antimicrobial activity against different bacterial species. Nevertheless, previous literature pertaining to the antifungal activity of sophorolipids are limited indicating the need for further research to explore novel strains with wide antimicrobial activity. A novel yeast strain, Rhodotorula babjevae YS3, was recently isolated from an agricultural field in Assam, Northeast India. This study was primarily emphasized at the characterization and subsequent evaluation of antifungal activity of the sophorolipid biosurfactant produced by R. babjevae YS3. RESULTS: The growth kinetics and biosurfactant production by R. babjevae YS3 was evaluated by cultivation in Bushnell-Haas medium containing glucose (10% w/v) as the sole carbon source. A reduction in the surface tension of the culture medium from 70 to 32.6 mN/m was observed after 24 h. The yield of crude biosurfactant was recorded to be 19.0 g/l which might further increase after optimization of the growth parameters. The biosurfactant was characterized to be a heterogeneous sophorolipid (SL) with both lactonic and acidic forms after TLC, FTIR and LC-MS analyses. The SL exhibited excellent oil spreading and emulsifying activity against crude oil at 38.46 mm2 and 100% respectively. The CMC was observed to be 130 mg/l. The stability of the SL was evaluated over a wide range of pH (2-10), salinity (2-10% NaCl) and temperature (at 120 degrees C for time intervals of 30 up to 120 min). The SL was found to retain surface-active properties under the extreme conditions. Additionally, the SL exhibited promising antifungal activity against a considerably broad group of pathogenic fungi viz. Colletotrichum gloeosporioides, Fusarium verticilliodes, Fusarium oxysporum f. sp. pisi, Corynespora cassiicola, and Trichophyton rubrum. CONCLUSIONS: The study reports, for the first time, the biosurfactant producing ability of R. babjevae, a relatively lesser studied yeast. The persistent surface active properties of the sophorolipid in extreme conditions advocates its applicability in diverse environmental and industrial sectors. Further, antifungal activities against plant and human pathogens opens up possibilities for development of efficient and eco-friendly antifungal agents with agricultural and biomedical applications. PMID- 28558762 TI - Unmanipulated haploidentical stem cell transplantation in adults with acute lymphoblastic leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT. AB - BACKGROUND: Allogenic hematopoietic stem cell transplantation (allo-SCT) is the most effective post-remission treatment for adults with high-risk acute lymphoblastic leukemia (ALL). The aim of the study was to analyze results of unmanipulated haploidentical allo-SCT (haplo-SCT) for adults with ALL and to identify prognostic factors. METHODS: We performed a retrospective analysis on 208 adults transplanted in EBMT centers from 2007 to 2014. RESULTS: Median age at haplo-SCT was 32 years and median follow-up, 31 months. Forty-four percent of the patients were in first complete remission (CR1). Stem cell source was the bone marrow (BM) for 43% and peripheral blood (PB) for 57% of patients. Myeloablative conditioning (MAC) was used for 66% and reduced intensity regimen (RIC) for 34% of patients. GVHD prophylaxis was based on post-transplant cyclophosphamide (PT Cy) for 118 (57%) or on anti-thymocyte-globulin (ATG) for 90 (43%) plus standard prophylaxis. One hundred eighty-four (92%) patients achieved engraftment. Cumulative incidence (CI) of grade II-IV acute-graft-versus-host-disease (GVHD) was 31%, grade III-IV 11%, and chronic GVHD 29%. Non-relapse mortality (NRM) and relapse-incidence (RI) were 32 and 37%, respectively. Overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free-survival (GRFS) at 3 years were 33, 31, and 26%. For patients in CR1, OS, LFS, and GRFS were 52, 47, and 40%, respectively. Disease status was the main factor associated with transplant outcomes. Use of BM was independently associated with improvement in NRM, acute GVHD, GRFS, LFS, and OS. CONCLUSIONS: Unmanipulated haplo-SCT may be considered a valid option for adult patients with high-risk ALL lacking HLA identical donor preferably in early disease status. PMID- 28558763 TI - An analysis of policy success and failure in formal evaluations of Australia's national mental health strategy (1992-2012). AB - BACKGROUND: Heightened fiscal constraints, increases in the chronic disease burden and in consumer expectations are among several factors contributing to the global interest in evidence-informed health policy. The present article builds on previous work that explored how the Australian Federal Government applied five instruments of policy, or policy levers, to implement a series of reforms under the Australian National Mental Health Strategy (NMHS). The present article draws on theoretical insights from political science to analyse the relative successes and failures of these levers, as portrayed in formal government evaluations of the NMHS. METHODS: Documentary analysis of six evaluation documents corresponding to three National Mental Health Plans was undertaken. Both the content and approach of these government-funded, independently conducted evaluations were appraised. RESULTS: An overall improvement was apparent in the development and application of policy levers over time. However, this finding should be interpreted with caution due to variations in evaluation approach according to Plan and policy lever. Tabulated summaries of the success and failure of each policy initiative, ordered by lever type, are provided to establish a resource that could be consulted for future policy-making. CONCLUSIONS: This analysis highlights the complexities of health service reform and underscores the limitations of narrowly focused empirical approaches. A theoretical framework is provided that could inform the evaluation and targeted selection of appropriate policy levers in mental health. PMID- 28558764 TI - Elimination of Plasmodium falciparum malaria in Tajikistan. AB - Malaria was eliminated in Tajikistan by the beginning of the 1960s. However, sporadic introduced cases of malaria occurred subsequently probably as a result of transmission from infected mosquito Anopheles flying over river the Punj from the border areas of Afghanistan. During the 1970s and 1980s local outbreaks of malaria were reported in the southern districts bordering Afghanistan. The malaria situation dramatically changed during the 1990s following armed conflict and civil unrest in the newly independent Tajikistan, which paralyzed health services including the malaria control activities and a large-scale malaria epidemic occurred with more than 400,000 malaria cases. The malaria epidemic was contained by 1999 as a result of considerable financial input from the Government and the international community. Although Plasmodium falciparum constituted only about 5% of total malaria cases, reduction of its incidence was slower than that of Plasmodium vivax. To prevent increase in P. falciparum malaria both in terms of incidence and territory, a P. falciparum elimination programme in the Republic was launched in 200, jointly supported by the Government and the Global Fund for control of AIDS, tuberculosis and malaria. The main activities included the use of pyrethroids for the IRS with determined periodicity, deployment of mosquito nets, impregnated with insecticides, use of larvivorous fishes as a biological larvicide, implementation of small-scale environmental management, and use of personal protection methods by population under malaria risk. The malaria surveillance system was strengthened by the use of ACD, PCD, RCD and selective use of mass blood surveys. All detected cases were timely epidemiologically investigated and treated based on the results of laboratory diagnosis. As a result, by 2009, P. falciparum malaria was eliminated from all of Tajikistan, one year ahead of the originally targeted date. Elimination of P. falciparum also contributed towards speedy reduction of P. vivax incidence in Tajikistan. PMID- 28558765 TI - Sustentacular screw placement with guidance during ORIF of calcaneal fracture: an anatomical specimen study. AB - BACKGROUND: The sustentacular screw is essential to maintain the stability of the subtalar joint during ORIF (open reduction with internal fixation) of calcaneal fractures. Currently, the screw is still inserted based on surgeons' anatomical experiences and nearly 40% of screws are misplaced from the sustentaculum. Previous studies demonstrated some methods of sustentacular screw placement through anatomical measurements or navigation system. The purposes of this study are to design an assistant guidance device that can effectively improve the accuracy of sustentacular screw placement and to compare the accuracy of this technique with traditional screw placement based on experience. METHODS: A customized guidance device is designed, aiming to improve the accuracy of sustentacular screw placement. Twenty cadaveric specimens are used in the present study. Ten specimens are allocated into the guidance-assisted group, and others are included in the traditional screw insertion group. A total of 40 sustentacular screw placements are performed in each group. Fluoroscopic images are obtained after each screw placement. Only the screw that captures the sustentaculum both on the lateral and axial X-ray views was regarded as an accurate placement. RESULTS: The accuracy rate in the guidance-assisted group is 87.5% (35 out of 40 times of insertions) while in the traditional screw insertion group, the accuracy rate is 65% (26 out of 40 times of insertions). A significant difference is found between the two groups (p = 0.018). CONCLUSIONS: The guidance assisted technique is a convenient approach that can effectively improve the accuracy of sustentacular screw placement during the ORIF of calcaneal fractures. This study provides a novel technique that significantly facilitates sustentacular screw insertion and improves its accuracy. PMID- 28558766 TI - Prognostic analysis of radiation pneumonitis: carbon-ion radiotherapy in patients with locally advanced lung cancer. AB - BACKGROUND: Carbon-ion radiotherapy (CIRT) is a promising treatment for locally advanced non-small-cell lung cancer, especially for patients with inoperable lung cancer. Although the incidence of CIRT-induced radiation pneumonitis (RP) >= grade 2 ranges from 2.5 to 9.9%, the association between CIRT-induced RP and dosimetric parameters is not clear. Herein, we identified prognostic factors associated with symptomatic RP after CIRT for patients with non-small-cell lung cancer. METHODS: Clinical results of 65 patients treated with CIRT between 2000 and 2015 at the National Institute of Radiological Sciences were retrospectively analyzed. Clinical stage II B disease (TNM classification) was the most common stage among the patients (45%). The median radiation dose was 72 Gy (68-76) relative biological effectiveness (RBE) in 16 fractions. In cases involving metastatic lymph nodes, prophylactic irradiation of mediastinal lymph nodes was performed at a median dose of 49.5 Gy (RBE). The median follow-up was 22 months. RESULTS: Grade 2 and grade 3 RP occurred in 6 and 3 patients (9 and 5%), respectively. No patients developed grade 4 or 5 RP. Using univariate analysis, vital capacity as a percentage of predicted (%VC), forced expiratory volume in 1 s (FEV1), mean lung dose (MLD), volume of lung receiving >=5 Gy (RBE) (V5), V10, V20 and V30 were determined to be the significant predictive factors for >= grade 2 RP. The receiver operating characteristic (ROC) analysis revealed the cutoff values for %VC, FEV1, MLD, V5, V10, V20 and V30 for >= grade 2 RP, which were 86.9%, 1.16 L, 12.5 Gy (RBE), 28.8, 29.9, 20.1 and 15.0%, respectively. In addition, the multivariate analysis revealed that %VC <86.9% (odds ratio = 13.7; p = 0.0041) and V30 >= 15% (odds ratio = 6.1; p = 0.0221) were significant risk factors. CONCLUSIONS: Our study demonstrated the risk factors for >= grade 2 RP after carbon-ion radiotherapy for patients with locally advanced lung cancer. PMID- 28558767 TI - Combination of paclitaxel, bevacizumab and MEK162 in second line treatment in platinum-relapsing patient derived ovarian cancer xenografts. AB - Advanced ovarian cancer is very responsive to first line platinum therapy, however almost invariably it relapses with a resistant disease. We have reported that patient derived ovarian xenografts (PDXs), independently from the degree of the initial response to cisplatin (DDP), show a significantly lower response to a second DDP cycle. We here report the effect of new combination regimens containing a MEK inhibitor (MEK), bevacizumab (BEV) and paclitaxel (PTX) as second line therapy in platinum-relapsing PDXs.We selected three DDP-relapsing PDX models based on the presence of activation of the RAS/RAF/MEK/ERK axis, mutated p53, lack of PTEN expression and activation of the PI3K pathway. In all the selected xenograft models, the antitumor efficacy of the doublets can be summarized as PTX/BEV > BEV/MEK > PTX/MEK and the antitumor activity of the triple combination was higher than any double combination. All the different combinations were well tolerated. The present data corroborate the activity of bevacizumab in combination with chemotherapy for the treatment of relapsing ovarian tumors and suggest that the addition of another targeted agents (MEK inhibitor) can further increase the antitumor activity without any increase in toxicity. PDX models represent a useful model to test second line therapy after failure of DDP first line. PMID- 28558769 TI - A photoacoustic imaging reconstruction method based on directional total variation with adaptive directivity. AB - BACKGROUND: In photoacoustic tomography (PAT), total variation (TV) based iteration algorithm is reported to have a good performance in PAT image reconstruction. However, classical TV based algorithm fails to preserve the edges and texture details of the image because it is not sensitive to the direction of the image. Therefore, it is of great significance to develop a new PAT reconstruction algorithm to effectively solve the drawback of TV. METHODS: In this paper, a directional total variation with adaptive directivity (DDTV) model based PAT image reconstruction algorithm, which weightedly sums the image gradients based on the spatially varying directivity pattern of the image is proposed to overcome the shortcomings of TV. The orientation field of the image is adaptively estimated through a gradient-based approach. The image gradients are weighted at every pixel based on both its anisotropic direction and another parameter, which evaluates the estimated orientation field reliability. An efficient algorithm is derived to solve the iteration problem associated with DDTV and possessing directivity of the image adaptively updated for each iteration step. RESULTS AND CONCLUSION: Several texture images with various directivity patterns are chosen as the phantoms for the numerical simulations. The 180-, 90- and 30-view circular scans are conducted. Results obtained show that the DDTV-based PAT reconstructed algorithm outperforms the filtered back projection method (FBP) and TV algorithms in the quality of reconstructed images with the peak signal-to-noise rations (PSNR) exceeding those of TV and FBP by about 10 and 18 dB, respectively, for all cases. The Shepp-Logan phantom is studied with further discussion of multimode scanning, convergence speed, robustness and universality aspects. In-vitro experiments are performed for both the sparse-view circular scanning and linear scanning. The results further prove the effectiveness of the DDTV, which shows better results than that of the TV with sharper image edges and clearer texture details. Both numerical simulation and in vitro experiments confirm that the DDTV provides a significant quality improvement of PAT reconstructed images for various directivity patterns. PMID- 28558768 TI - Search for OIE-listed ruminant mycoplasma diseases in Afghanistan. AB - BACKGROUND: Little is known about the occurrence of important diseases of ruminants in Afghanistan because of the conflict affecting the country over the last 40 years. To address this discrepancy, ruminant herds in Afghanistan were screened for OIE-listed mycoplasma diseases, contagious bovine (CBPP) and caprine pleuropneumonias (CCPP). RESULTS: Of the 825 samples from 24 provinces tested for serological evidence of CBPP caused by Mycoplasma mycoides subsp.mycoides, 20 (3.4%) had ELISA values greater than the positive threshold of 50% though all were less than 55%. Repeat testing of these suspect sera gave values below 50. A smaller number of sera (330) from cattle in nine provinces were also tested by the rapid latex agglutination test (LAT) for CBPP, 10 of which were considered suspect. However, no positive bands were seen when immunoblotting was carried out on all sera that gave suspect results. Serological evidence of Mycoplasma bovis was detected in half of 28 herds in eight provinces. The cause of CCPP, M. capricolum subsp. capripneumoniae was not detected in any of the 107 nasal swabs and lung tissue collected from goats in seven provinces though sample handling and storage were not optimal. However, strong serological evidence was detected in goat herds in several villages near Kabul some of which were over 50% seropositive by LAT and ELISAs for CCPP; immunoblotting confirmed positive results on a selection of these sera. CONCLUSIONS: The data presented here provide a first assessment of the occurrence of the two OIE listed mycoplasma diseases in Afghanistan. From the results of the testing bovine sera from the majority of provinces there is no evidence of the presence of CBPP in Afghanistan. However the samples tested represented only 0.03% of the cattle population so a larger survey is required to confirm these findings. Serological, but not bacterial, evidence was produced during this investigation to show that CCPP is highly likely to be present in parts of Afghanistan. PMID- 28558770 TI - Leishmania LABCG1 and LABCG2 transporters are involved in virulence and oxidative stress: functional linkage with autophagy. AB - BACKGROUND: The G subfamily of ABC (ATP-binding cassette) transporters of Leishmania include 6 genes (ABCG1-G6), some with relevant biological functions associated with drug resistance and phospholipid transport. Several studies have shown that Leishmania LABCG2 transporter plays a role in the exposure of phosphatidylserine (PS), in virulence and in resistance to antimonials. However, the involvement of this transporter in other key biological processes has not been studied. METHODS: To better understand the biological function of LABCG2 and its nearly identical tandem-repeated transporter LABCG1, we have generated Leishmania major null mutant parasites for both genes (DeltaLABCG1-2). NBD-PS uptake, infectivity, metacyclogenesis, autophagy and thiols were measured. RESULTS: Leishmania major DeltaLABCG1-2 parasites present a reduction in NBD-PS uptake, infectivity and virulence. In addition, we have shown that DeltaLABCG1-2 parasites in stationary phase growth underwent less metacyclogenesis and presented differences in the plasma membrane's lipophosphoglycan composition. Considering that autophagy is an important process in terms of parasite virulence and cell differentiation, we have shown an autophagy defect in DeltaLABCG1-2 parasites, detected by monitoring expression of the autophagosome marker RFP ATG8. This defect correlates with increased levels of reactive oxygen species and higher non-protein thiol content in DeltaLABCG1-2 parasites. HPLC analysis revealed that trypanothione and glutathione were the main molecules accumulated in these DeltaLABCG1-2 parasites. The decrease in non-protein thiol levels due to preincubation with buthionine sulphoximide (a gamma-glutamylcysteine synthetase inhibitor) restored the autophagy process in DeltaLABCG1-2 parasites, indicating a relationship between autophagy and thiol content. CONCLUSIONS: LABCG1-2 transporters from Leishmania could be considered as phosphatidylserine and non protein thiol transporters. They probably accomplish transportation in conjunction with other molecules that are involved in oxidative stress, autophagy, metacyclogenesis and infectivity processes. The overall conclusion is that LABCG1-2 transporters could play a key role in Leishmania cell survival and infectivity. PMID- 28558771 TI - Assessment of the burden on caregivers of patients with mental disorders in Jeddah, Saudi Arabia. AB - BACKGROUND: Mental disorders are considered important public health problems not only to people with mental illness but also their caregivers. As is the case in many countries, the deinstitutionalization of mental health services in Saudi Arabia, has meant that informal caregivers are shouldering responsibilities for which they are not usually prepared; therefore, the current study was aimed at assessment of the burden on caregivers of people with mental illness. METHODS: Through a cross-sectional design, a sample of the caregivers of people with mental illness (n = 377) was selected randomly from a psychiatric hospital in Jeddah. An Arabic version of the Involvement Evaluation Questionnaire (IEQ) was used for collection of data. The data were analyzed on the subscale scores and the 27 items in two ways. First, we used the summed scores for the subscales based on the Likert scale (0-4) for univariate and multivariate statistical analyses, as recommended. We also used parametric statistics (t-tests, one-way ANOVA) because the IEQ subscale scores were fairly normally distributed. RESULTS: Males constituted more than one-half of the participating caregivers (55%), with a mean age of 36.6, SD = 11.4 years. As reported by the caregivers, most of the patients were males (62.7%) with a mean age of 33.8, SD = 13.7 years and a range of 17-90 years old. The total mean IEQ burden score of the caregivers was 38.4, SD = 17.5. "Tension" was significantly prominent among younger caregivers aged <=30 years. "Worrying" was significantly higher among caregivers living with their spouse and children and those living in families with relatively fewer members (<6 members). "Urging" was significantly higher among caregivers who are living with the patient in the same household and those who had been in close contact with the patient for 28 days in the four weeks prior to the study (13.4, SD = 6.8) p < 0.05. Meanwhile, "Urging" was also significantly higher among caregivers caring for mentally ill females (13.5, SD = 6.6) and those not receiving any kind of professional support (12.8, SD = 6.7). The overall burden and the subscale scores were highest among caregivers caring for a close relative such as a parent (44.1, SD = 17.6), son/daughter (39.1, SD = 12.9), sibling (37.1, SD = 18.6), or spouse (37.1, SD = 18.6) p < 0.05. CONCLUSION: Care for people with mental illness is burdensome for their caregivers, the magnitude of burden is potentially augmented by factors related to the patients and households. These factors should be considered when planning for preparing caregivers to cope with people with mental illness in Saudi Arabia. PMID- 28558772 TI - Predictive value of preoperative peripheral blood neutrophil/lymphocyte ratio for lymph node metastasis in patients of resectable pancreatic neuroendocrine tumors: a nomogram-based study. AB - BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) is one of the systemic inflammation markers, which has prognostic values in many types of tumor. However, hardly any research has reported the relationship between NLR and pancreatic neuroendocrine tumors (PanNETs). In this study, we aimed to evaluate the predictive value of the preoperative peripheral blood NLR on the clinical outcomes in patients of resectable PanNETs. METHODS: Ninety-five cases of PanNETs registered in the First Affiliated Hospital of Zhejiang University between March 2009 and May 2016 and underwent pancreatic surgery were included in this study. Univariate and multivariate analyses were applied to identify the prognostic factors for PanNETs. Prognostic nomogram and its calibration curve then used R (version 3.3.2) to predict lymph node (LN) metastasis. RESULTS: Among these 95 patients, 52 (54.7%) patients were diagnosed as grade 1 (G1) NET (mitotic count <2/10 HPF, Ki-67 <=2%), 32 (33.7%) as G2 NET (mitotic count 2-20/10 HPF, Ki-67 3 20%), and 11 (11.6%) as G3 NEC (mitotic count >20/10 HPF, Ki-67 >20%). Increased NLR was found to relate with advanced T stage, LN metastasis, tumor thrombus formation, and advanced grade (p < 0.05 for all). Multivariate logistic regression was performed and indicated that NLR (HR 6.74; p = 0.02) was an independent prognostic factor for LN metastasis. Furthermore, we developed a nomogram based on the combination of NLR, T stage, and grade for LN metastasis with a good discrimination ability with the AUC (area under the curve) of 0.885. This nomogram showed larger AUC than those using NLR (0.725), T stage (0.808), or grade (0.708) alone as a prognostic factor, which means this system achieved a more optional performance in predicting clinical outcomes. Finally, the Kaplan Meier curve indicated that the recurrence-free survival (RFS) of patients with high NLR (NLR >1.40, RFS 61.1 +/- 4.4 months) decreased significantly as compared with those of low NLR (NLR <=1.40, RFS 63.8 +/- 2.9 month, p < 0.05). CONCLUSIONS: The preoperative NLR is a potential independent predictor for LN metastasis and RFS. Our nomogram highlighted the important role of NLR in prognosis, which might be considered as a convenient indicator for lymph node metastasis, especially during the initial diagnosis for resectable PanNETs. PMID- 28558773 TI - Magnetic inductive phase shift: a new method to differentiate hemorrhagic stroke from ischemic stroke on rabbit. AB - BACKGROUND: The major therapy for ischemic stroke is thrombolytic treatment, but severe consequences occur when this method is used to treat hemorrhagic stroke. Currently, computed tomography and magnetic resonance imaging are used to differentiate between two types of stroke, but these two methods are ineffective for pre-hospital care. METHODS: We developed a new brain diagnostic device for rabbits based on electromagnetic induction to non-invasively differentiate two types of stroke. The device includes two coils and a phase difference measurement system that detects the magnetic inductive phase shift (MIPS) value to reflect the tissue's condition. The hemorrhage model was established through the injection of autologous blood into the internal capsule of a rabbit's brain. Ischemia was induced in the brain of a rabbit by bilateral carotid artery occlusion. Two types of animal models were measured with our device. RESULTS: The MIPS value gradually decreased with increasing injected blood and increased with ischemia time. The MIPS changes induced by the two types of strokes were exact opposites, and the absolute values of MIPS variation in the hemorrhagic and the ischemic groups were significantly larger than those of the normal control group (P < 0.05). CONCLUSIONS: The tested technique can differentiate ischemic stroke from hemorrhagic stroke on rabbit brain in a non-invasive, continuous, and bulk monitoring manner by using a simple and inexpensive apparatus. PMID- 28558774 TI - Gender-based disparities in the impact of adverse childhood experiences on adult health: findings from a national study in the Kingdom of Saudi Arabia. AB - BACKGROUND: Adverse Childhood Experiences (ACEs) have been linked to an increased risk of health and social problems throughout life. Studies on gender differences from developing countries are scarce. In this paper, we will examine gender variations in the types of reported ACEs and gender-specific relationships between cumulative ACEs and physical and mental health, and Risky Health Behaviors (RHB) in adulthood in the Kingdom of Saudi Arabia (KSA). METHODS: A cross sectional national study was conducted in all of the 13 regions in KSA in 2013 using the ACE- International Questionnaire (ACE-IQ). We used multivariate logistic regression to examine the relationship between 4 + ACEs and physical, mental health and RHBs for both men and women separately after adjusting for age, education, marital status and current employment. RESULTS: The total number of participants was 10,156 and women comprised 48% of the sample. The majority of respondents (80%) reported at least one ACE. Women had higher percentages of < =2 ACEs (65% vs 55%; p <0.05) while men were more likely to have 4+ ACEs (33% vs 25%; p < 0.05). When compared to participants with 0 ACE, men who reported 4+ ACEs were associated with the highest likelihood of using drugs (OR = 9.7; 95% CI: 6.4-14.5) and drinking alcohol (OR = 9.2; 95% CI: 6.3-13.6). On the other hand, women who experienced 4+ ACEs were associated with the highest likelihood of depression (OR = 7.0; 95% CI: 5.2-9.4), anxiety (OR = 6.4; 95% CI: 5.0-8.2) and other mental illnesses (OR = 7.4; 95% CI: 5.2-10.6). As for chronic diseases, abused men and women in childhood showed similarly a twofold increased risk of developing diabetes, hypertension, coronary heart disease and obesity when compared to non-abused participants. CONCLUSION: Findings highlight the need to consider gender specific differences in the development of preventive strategies to address ACEs in KSA. PMID- 28558775 TI - Fat content, fatty acid pattern and iron content in livers of turkeys with hepatic lipidosis. AB - BACKGROUND: The so-called "hepatic lipidosis" in turkeys is an acute progressive disease associated with a high mortality rate in a very short time. Dead animals show a massive fatty degeneration of the liver. The cause is still unclear. Previous findings suggest that there may be parallels to human non-alcoholic fatty liver disease. The object of the study was to examine the changes in the fat contents, the fatty acid composition and the iron content in livers of animals, which have died from hepatic lipidosis. METHODS: The conspicuous livers (n = 85) were collected from 20 flocks where the phenomenon of massive increased animal losses accompanied by marked macroscopically visible pathological liver steatosis suddenly occurred. For comparison and as a reference, livers (n = 16) of two healthy flocks were taken. Healthy and diseased flocks were fed identical diets concerning official nutrient recommendations and were operating under standardized, comparable conventional conditions. RESULTS: Compared to livers of healthy animals, in the livers of turkeys died from hepatic lipidosis there were found massively increased fat levels (130 +/- 33.2 vs. 324 +/- 101 g/kg dry matter-DM). In all fatty livers, different fatty acids concentrations were present in significantly increased concentrations compared to controls (palmitic acid: 104 g/kg DM, +345%; palmitoleic acid: 18.0 g/kg DM, + 570%; oleic acid: 115 g/kg DM, +437%). Fatty acids concentrations relevant for liver metabolism and inflammation were significantly reduced (arachidonic acid: 2.92 g/kg DM, -66.6%; eicosapentaenoic acid: 0.141 g/kg DM, -78.3%; docosahexaenoic acid: 0.227 g/kg DM, -90.4%). The ratio of certain fatty acids to one another between control and case livers changed analogously to liver diseases in humans (e.g.: C18:0/C16:0 - 0.913 against 0.311; C16:1n7/C16:0 - 0.090 against 0.165; C18:1/C18:0 - 0.938 against 4.03). The iron content in the liver tissue also increased massively (271 +/- 51.5 vs 712 +/- 214 mg/kg DM). CONCLUSION: The hepatic lipidosis has a massive impact on the lipid content, the lipid composition and the iron content in the liver. The character of the metabolic disorder includes parallels to the non-alcoholic steatohepatitis in humans. PMID- 28558776 TI - Association between Epicondylitis and Cardiovascular Risk Factors in Pooled Occupational Cohorts. AB - BACKGROUND: The pathophysiology of lateral epicondylitis (LE) is unclear. Recent evidence suggests some common musculoskeletal disorders may have a basis in cardiovascular disease (CVD) risk factors. Thus, we examined CVD risks as potential LE risks. METHODS: Workers (n = 1824) were enrolled in two large prospective studies and underwent structured interviews and physical examinations at baseline. Analysis of pooled baseline data assessed the relationships separately between a modified Framingham Heart Study CVD risk score and three prevalence outcomes of: 1) lateral elbow pain, 2) positive resisted wrist or middle finger extension, and 3) a combination of both symptoms and at least one resisted maneuver. Quantified job exposures, personal and psychosocial confounders were statistically controlled. Odds ratios (ORs) and 95% Confidence Intervals (CIs) were calculated. RESULTS: There was a strong relationship between CVD risk score and lateral elbow symptoms, resisted wrist or middle finger extension and LE after adjustment for confounders. The adjusted ORs for symptoms were as high as 3.81 (95% CI 2.11, 6.85), for positive examination with adjusted odds ratios as high as 2.85 (95% CI 1.59, 5.12) and for combined symptoms and physical examination 6.20 (95% CI 2.04, 18.82). Relationships trended higher with higher CVD risk scores. CONCLUSIONS: These data suggest a potentially modifiable disease mechanism for LE. PMID- 28558777 TI - Incidence of influenza virus infection among pregnant women: a systematic review. AB - BACKGROUND: The World Health Organization (WHO) considers pregnant women to be a risk group for severe influenza disease. We conducted a systematic review to evaluate influenza disease incidence in pregnant women in order to inform estimates of influenza vaccine impact for low-resource countries. METHODS: We performed electronic literature searches, targeting studies on the following outcomes in pregnant women: attack rate, hospitalization rate, intensive care unit admission rate, mortality rate, and disability-adjusted life years lost. Only original studies published in peer-reviewed journals that had laboratory confirmation for influenza virus infection and included population-based incidence rates with denominator data were included. We summarized study characteristics in descriptive tables and outcome-specific Forest plots. We generated summary incidence rates using random effects models and assessed statistical heterogeneity by visual examination of Forest plots, and by chi 2 and I2 tests. RESULTS: We identified 1543 articles, of which nine articles met the study inclusion criteria. Five were case series, three were cohort studies, and one was a randomized controlled trial. Eight studies were from high-income countries, and one was from an upper middle-income country. Six studies reported results for pandemic influenza, and three reported seasonal influenza. Statistical heterogeneity was high for all outcomes, and methodologies and duration of surveillance varied considerably among studies; therefore, we did not perform meta-analyses. CONCLUSIONS: Study quality was very low according to GRADE criteria. More data on influenza disease incidence in pregnant women, particularly in low- and middle-income countries and for seasonal influenza disease, are needed to inform public health decision-making. PMID- 28558778 TI - Test-retest reliability of mandibular morphology measurements on cone-beam computed tomography-synthesized cephalograms with random head positioning errors. AB - BACKGROUND: Cephalometric radiography has been used for orthodontic and surgical treatment planning and assessment, and for quantifying mandibular growth. However, it remains unclear how head positioning errors and the level of examiner experience affect the reliability of such morphometric measurements. The current study aimed to bridge the gap by determining the intra-, inter-rater, and inter session reliability of measurements of mandibular morphology with random head positioning errors as measured by a junior and a senior dentist. METHODS: Cone beam computed tomography data of twelve mandibles were obtained with each rotated randomly away from the neutral position within the range of +3 and -3 degrees along each of the anatomical axes to simulate six imaging trials. A synthetic cephalogram for each trial was obtained via a digitally reconstructed radiography (DRR) technique and eleven landmarks for twelve morphological parameters on the cephalogram were identified manually six times by a junior and a senior dentist. The procedure was repeated on another day within 5 days. Test-retest reliability was assessed in terms of an intra-class correlation coefficient (ICC) using a two way mixed-effects model. RESULTS: Good to very good intra-rater (senior: ICC > 0.92; junior: ICC > 0.78), inter-rater (ICC > 0.70 for most parameters) and inter session reliability (senior: ICC > 0.84; junior: ICC > 0.62) were found. Bland & Altman plots of inter-rater comparisons show that there were systematical biases between the examiners on most parameters, except for the distance between Gonion and Pogonion. CONCLUSIONS: The current results suggest that good to very good intra-rater, inter-rater and inter-session reliability can be achieved for most parameters with randomized head positioning errors; higher inter-session reliability can be achieved by more experienced examiners; and that long-term monitoring of mandibular growth based on cephalographic measurements should be made by the same more experienced examiner. The current DRR-based approach can be used to evaluate individual factors that affect the morphological measurements. PMID- 28558779 TI - "Are Thai children and youth sufficiently active? prevalence and correlates of physical activity from a nationally representative cross-sectional study". AB - BACKGROUND: Children and youth gain multiple health benefits from regular participation in physical activity (PA). However, in Thailand there is limited national data on children and youth's PA behaviors and recent reports suggest that Thai children and youth have low levels of PA. Furthermore, there is almost no data on the factors associated with inactivity to support the development of a Thai National PA Plan. The purpose of this paper is to investigate Thai children and youth's participation in PA and its correlates across sociodemographic characteristics and different PA domains. METHODS: This study applied a cross sectional study design with a multi-stage stratified cluster sampling. A national representative sample of 13,255 children and youth aged 6-17 years were used for data analysis. A previously validated questionnaire was used to assess PA prevalence. Logistic regression was conducted to examine the relationships of socio-demographic factors, and participation in different PA domains with overall PA. RESULTS: Only 23.4% of Thai children and youth met recommended levels of PA and there were large gender and regional differences. PA levels generally declined with age, although the level observed in the 10-13 year group was slightly higher than other year groups. A majority of children and youth engaged in a large number of different activities across PA domains. Sex, age, BMI, geographical regions, organized sports, participation in sport and recreational activities were significant predictors of meeting the global PA guidelines, whereas participation in physical education, active transport, and the number of screen time activities had no association. Girls were less likely to achieve sufficient PA levels (OR = 0.49, 95%CI; 0.45-0.54, p < 0.001), as were obese children (OR = 0.78, 95%CI; 0.64-0.94, p = 0.01), children living in the West (OR = 0.47, 95%CI; 0.38-0.59, p < 0.001), and those who did no participation in organized sports and sport/exercise activities, or minimal participation (1-2 activities) in recreational activities (OR = 0.79, 95%CI; 0.68-0.90, p < 0.001). CONCLUSIONS: The prevalence estimate of meeting the recommended guideline of sufficient PA in Thai children and youth is low, despite the high levels of engagement in a large number of PA. The results indicate that policy and interventions aimed at increasing PA are needed with special attention required to address specific groups less likely to meet the PA guideline. Strategies to promote a large volume of participation in all possible types of PA as part of Thai children and youth's daily life should be considered. PMID- 28558780 TI - Low-grade fibromyxoid sarcoma of the external anal sphincter: a case report. AB - BACKGROUND: Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft tissue tumor that has a tendency to grow in the deep soft tissue of the trunk and extremities. Despite its benign appearance, the tumor has a high recurrence rate and metastatic potential. LGFMS in the perineal space is rare, and only a few cases have been reported. We present the first case of LGFMS to be located at the external anal sphincter. CASE PRESENTATION: A 27-year-old male patient admitted to our Surgical Department with perianal pain and swollen for a year. The digital rectal examination revealed a perianal mass. Oral metronidazole and analgesia were prescribed on suspicion of perianal abscess failed to alleviate the symptom; hence, the patient was scheduled for surgery. Intraoperative diagnosis revealed an encapsulated tumor in the external anal sphincter that extended from the perianal region orally to the pararectal space. The results of immunohistochemistry (MUC4 staining) and FUS gene rearrangement by fluorescence in situ hybridization confirmed the diagnosis of LGFMS. CONCLUSIONS: This case is unique in terms of the location of the rare soft tissue tumor. Although LGFMS is considered low grade, its unpredictable behavior necessitates a long-term follow up. PMID- 28558781 TI - Reducing occupational sitting: Workers' perspectives on participation in a multi component intervention. AB - BACKGROUND: Office workers spend much of their time sitting, which is now understood to be a risk factor for several chronic diseases. This qualitative study examined participants' perspectives following their involvement in a cluster randomised controlled trial of a multi-component intervention targeting prolonged workplace sitting (Stand Up Victoria). The intervention incorporated a sit-stand workstation, individual health coaching and organisational support strategies. The aim of the study was to explore the acceptability of the intervention, barriers and facilitators to reducing workplace sitting, and perceived effects of the intervention on workplace culture, productivity and health-related outcomes. METHODS: Semi-structured interviews (n = 21 participants) and two focus groups (n = 7) were conducted with intervention participants at the conclusion of the 12 month trial and thematic analysis was used to analyse the data. Questions covered intervention acceptability, overall impact, barriers and facilitators to reducing workplace sitting, and perceived impact on productivity and workplace culture. RESULTS: Overall, participants had positive intervention experiences, perceiving that reductions in workplace sitting were associated with improved health and well-being with limited negative impact on work performance. While sit-stand workstations appeared to be the primary drivers of change, workstation design and limited suitability of standing for some job tasks and situations were perceived as barriers to their use. Social support from team leaders and other participants was perceived to facilitate behavioural changes and a shift in norms towards increased acceptance of standing in the workplace. CONCLUSIONS: Multi-component interventions to reduce workplace sitting, incorporating sit-stand workstations, are acceptable and feasible; however, supportive social and environmental conditions are required to support participant engagement. Best practice approaches to reduce workplace sitting should address the multiple levels of influence on behaviour, including factors that may act as barriers to behavioural change. PMID- 28558782 TI - Systematic literature review of reproductive outcome associated with residential proximity to polluted sites. AB - This study aims to assess the evidence on adverse pregnancy outcome associated with living close to polluted industrial sites, and identify the strengths and weaknesses of published epidemiological studies. A systematic literature search has been performed on all epidemiological studies published in developed countries since 1990, on the association between residential proximity to industrial sites (hazardous waste sites, industrial facilities and landfill sites) and adverse pregnancy outcome (low birth weight, preterm birth, small for gestational age, intrauterine growth retardation, infant mortality, congenital malformation). Based on 41 papers, our review reveals an excess risk of reproductive morbidity. However, no studies show significant excess risk of mortality including fetal death, neonatal or infant mortality and stillbirth. All published studies tend to show an increased risk of congenital abnormalities, yet not all are statistically significant. All but two of these studies revealed an excess risk of low birth weight. Results for preterm birth, small for gestational age and intrauterine growth retardation show the same pattern. There is suggestive evidence from the post-1990 literature that residential proximity to polluted sites (including landfills, hazardous waste sites and industrial facilities) might contribute to adverse reproductive outcomes, especially congenital malformations and low birth weight-though not mortality. This body of evidence has limitations that impede the formulation of firm conclusions, and new, well-focused studies are called for. The review findings suggest that continued strengthening of rules governing industrial emissions as well as industrial waste management and improved land use planning are needed. PMID- 28558783 TI - Clinical characteristics, predictors of immune reconstitution inflammatory syndrome and long-term prognosis in patients with Kaposi sarcoma. AB - OBJECTIVE: To investigate the predictive factors for the development of Kaposi sarcoma-related immune reconstitution inflammatory syndrome (KS-IRIS) and long term prognosis in patients starting combined antiretroviral therapy (cART). METHODS: We studied a retrospective-cohort of consecutive antiretroviral-naive patients with KS initiating cART from January 2005 to December 2011 and followed through June 2013. KS-IRIS was defined as >=2 of the following: abrupt increase in number of KS lesions, appearance or exacerbation of lung-opacities or lymphedema, concomitantly with an increase in CD4+ cell-count >=50 cells/mm3 and a decrease of >1 log in viral-load once started cART. We compared individuals who met KS-IRIS criteria with those that did not and described the long-term follow up. RESULTS: We included 89 patients, 88 males; 35 (39%) developed KS-IRIS at a median of 10 weeks (IQR 4-16). KS-IRIS patients had more pulmonary-involvement (60% vs. 16.6% of patients; p < 0.0001), eight died attributed to pulmonary-KS. Thrombocytopenia <100,000/mm3 at follow-up occurred in 36% of KS-IRIS vs. 4% in non-KS-IRIS patients (p = 0.0002), 45% KS-IRIS patients with thrombocytopenia died, non without KS-IRIS. Chemotherapy (bleomicyn-vincristine) was more frequently prescribed in KS-IRIS patients (88.6% vs. 29.6%) with no differences in outcome; 80% of all patients achieve KS complete remission, 52% of them never received chemotherapy. No difference between groups in the long-term follow-up (mean 52.4 +/- 27.4 months) was found, only one patient developed a secondary malignancy (1.12%). CONCLUSIONS: Lung-involvement was predictive of IRIS development. Thrombocytopenia in KS-IRIS patients at week 12 follow-up after cART initiation was associated with high mortality. Over a third of patients with KS achieve remission without chemotherapy. Individuals that survive the initial period of KS-IRIS adhere to cART had a good long-term prognosis. PMID- 28558784 TI - Hesperetin-5,7,3'-O-triacetate suppresses airway hyperresponsiveness in ovalbumin sensitized and challenged mice without reversing xylazine/ketamine-induced anesthesia in normal mice. AB - BACKGROUND: We recently reported that hesperetin-5,7,3'-O-triacetate (HTA) dually inhibited phosphodiesterase (PDE)3/4 with a therapeutic ratio of 20.8. The application and development of PDE4 inhibitors for treating asthma or COPD are limited by their side effects, such as nausea, vomiting and gastric hypersecretion. PDE4 inhibitors were reported to reverse xylazine/ketamine induced anesthesia in rats and triggered vomiting in ferrets. Thus the reversing effect of HTA on xylazine/ketamine-induced anesthesia in mice was studied to assess emetic effect of HTA. The aim of this study was to prove the therapeutic effect of HTA without vomiting effect at an effective dose for treating COPD. METHODS: Ten female BALB/c mice in each group were sensitized by ovalbumin (OVA) on days 0 and 14. On day 21, these mice were emphasized the sensitization by Freund's complete adjuvant. Mice were challenged by 1% OVA nebulization on days 28, 29, and 30. Airway hyperresponsiveness (AHR) was assessed on day 32 in each group, using the FlexiVent system to determine airway resistance (RL) and lung dynamic compliance (Cdyn) in anesthetized ovalbumin (OVA)-sensitized and challenged mice. Each group was orally administered HTA (10 ~ 100 MUmol/kg), roflumilast (1 and 5 mg/kg) or vehicles (controls) 2 h before and 6 and 24 h after OVA provocation. For comparison, sham-treated mice were challenged with saline instead of 1% OVA. The ability to reverse xylazine/ketamine-induced anesthesia by HTA or roflumilast for 3 h was determined in normal mice. We used roflumilast, a selective PDE4 inhibitor and bronchodilator for severe COPD approved by the US Food and Drug Administration, as a reference drug. RESULTS: In the results, HTA (100 MUmol/kg, p.o.) or roflumilast (5 mg/kg, p.o.) significantly suppressed all RL values of MCh at 0.78 ~ 25 mg/mL and enhanced Cdyn values of MCh at 3.125 ~ 25 mg/mL compared to OVA-sensitized and -challenged control mice. Orally administered 1, 3 or 10 mg/kg roflumilast, but not 30 or 100 MUmol/kg HTA, significantly reversed xylazine/ketamine-induced anesthesia. CONCLUSIONS: In contrast to roflumilast, HTA may ameliorate COPD but induce few side effects of nausea, vomiting and gastric hypersecretion at an effective dose for treating COPD, because HTA did not reverse xylazine/ketamine-induced anesthesia in mice. PMID- 28558785 TI - Clinical decisions surrounding genomic and proteomic testing among United States veterans treated for lung cancer within the Veterans Health Administration. AB - BACKGROUND: Current clinical guidelines recommend epidermal growth factor receptor (EGFR) mutational testing in patients with metastatic non-small cell lung cancer (NSCLC) to predict the benefit of the tyrosine kinase inhibitor erlotinib as first-line treatment. Proteomic (VeriStrat) testing is recommended for patients with EGFR negative or unknown status when erlotinib is being considered. Departure from this clinical algorithm can increase costs and may result in worse outcomes. We examined EGFR and proteomic testing among patients with NSCLC within the Department of Veterans Affairs (VA). We explored adherence to guidelines and the impact of test results on treatment decisions and cost of care. METHODS: Proteomic and EGFR test results from 2013 to 2015 were merged with VA electronic health records and pharmacy data. Chart reviews were conducted. Cases were categorized based on the appropriateness of testing and treatment. RESULTS: Of the 69 patients with NSCLC who underwent proteomic testing, 33 (48%) were EGFR-negative and 36 (52%) did not have documented EGFR status. We analyzed 138 clinical decisions surrounding EGFR/proteomic testing and erlotinib treatment. Most decisions (105, or 76%) were concordant with clinical practice guidelines. However, for 24 (17%) decisions documentation of testing or justification of treatment was inadequate, and 9 (7%) decisions represented clear departures from guidelines. CONCLUSION: EGFR testing, the least expensive clinical intervention analyzed in this study, was significantly underutilized or undocumented. The records of more than half of the patients lacked information on EGFR status. Our analysis illustrated several clinical scenarios where the timing of proteomic testing and erlotinib diverged from the recommended algorithm, resulting in excessive costs of care with no documented improvements in health outcomes. PMID- 28558786 TI - Lost in plasmids: next generation sequencing and the complex genome of the tick borne pathogen Borrelia burgdorferi. AB - BACKGROUND: Borrelia (B.) burgdorferi sensu lato, including the tick-transmitted agents of human Lyme borreliosis, have particularly complex genomes, consisting of a linear main chromosome and numerous linear and circular plasmids. The number and structure of plasmids is variable even in strains within a single genospecies. Genes on these plasmids are known to play essential roles in virulence and pathogenicity as well as host and vector associations. For this reason, it is essential to explore methods for rapid and reliable characterisation of molecular level changes on plasmids. In this study we used three strains: a low passage isolate of B. burgdorferi sensu stricto strain B31( NRZ) and two closely related strains (PAli and PAbe) that were isolated from human patients. Sequences of these strains were compared to the previously sequenced reference strain B31 (available in GenBank) to obtain proof-of principle information on the suitability of next generation sequencing (NGS) library construction and sequencing methods on the assembly of bacterial plasmids. We tested the effectiveness of different short read assemblers on Illumina sequences, and of long read generation methods on sequence data from Pacific Bioscience single-molecule real-time (SMRT) and nanopore (Oxford Nanopore Technologies) sequencing technology. RESULTS: Inclusion of mate pair library reads improved the assembly in some plasmids as did prior enrichment of plasmids. While cp32 plasmids remained refractory to assembly using only short reads they were effectively assembled by long read sequencing methods. The long read SMRT and nanopore sequences came, however, at the cost of indels (insertions or deletions) appearing in an unpredictable manner. Using long and short read technologies together allowed us to show that the three B. burgdorferi s.s. strains investigated here, whilst having similar plasmid structures to each other (apart from fusion of cp32 plasmids), differed significantly from the reference strain B31-GB, especially in the case of cp32 plasmids. CONCLUSION: Short read methods are sufficient to assemble the main chromosome and many of the plasmids in B. burgdorferi. However, a combination of short and long read sequencing methods is essential for proper assembly of all plasmids including cp32 and thus, for gaining an understanding of host- or vector adaptations. An important conclusion from our work is that the evolution of Borrelia plasmids appears to be dynamic. This has important implications for the development of useful research strategies to monitor the risk of Lyme disease occurrence and how to medically manage it. PMID- 28558788 TI - Comparison of the fecal bacterial microbiota of healthy and diarrheic foals at two and four weeks of life. AB - BACKGROUND: Diarrhea in foals affects up to 60% of foals during the first six months of life. The effect of diarrhea on the fecal bacterial microbiota in foals has not been investigated. Little is known on the fecal bacterial microbial richness and diversity of foals at a young age. The objective was to compare the fecal bacterial microbiota of healthy foals to foals with diarrhea at two and four weeks of life. METHODS: Fecal samples were collected from foals (n = 20) at 1-14 (T1) and 15-28 (T2) days of age and analyzed using high throughput sequencing. Differences in relative abundance of bacterial taxa, alpha diversity and beta diversity indices were assessed between age-matched foals with diarrhea (n = 9) and healthy foals (n = 11), and between time points. RESULTS: Differences in microbial community composition based on time point and health status were observed on all taxonomic levels. Of 117 enriched species in healthy foals at T2, 50 (48%) were Lachnospiraceae or Ruminococcaceae. The Chao richness index was increased in healthy foals at T2 compared to T1 (p = 0.02). Foals with diarrhea had a significantly lower richness index than non-diarrheic foals at T2 (p = 0.04). Diarrhea had an inconsistent effect, while time point had a consistent effect on microbial community structure. CONCLUSIONS: Preventative and therapeutic measures for diarrhea should focus on maintaining bacterial microbiota richness. Lachnospiraceae and Ruminococcaceae were underrepresented in foals with diarrhea. These should be evaluated further as potential therapeutic options. PMID- 28558787 TI - Airway exposure to multi-walled carbon nanotubes disrupts the female reproductive cycle without affecting pregnancy outcomes in mice. AB - BACKGROUND: The use of multiwalled carbon nanotubes (MWCNT) is increasing due to a growing use in a variety of products across several industries. Thus, occupational exposure is also of increasing concern, particularly since airway exposure to MWCNTs can induce sustained pulmonary acute phase response and inflammation in experimental animals, which may affect female reproduction. This proof-of-principle study therefore aimed to investigate if lung exposure by intratracheal instillation of the MWCNT NM-400 would affect the estrous cycle and reproductive function in female mice. RESULTS: Estrous cycle regularity was investigated by comparing vaginal smears before and after exposure to 67 MUg of NM-400, whereas reproductive function was analyzed by measuring time to delivery of litters after instillation of 2, 18 or 67 MUg of NM-400. Compared to normal estrous cycling determined prior to exposure, exposure to MWCNT significantly prolonged the estrous cycle during which exposure took place, but significantly shortened the estrous cycle immediately after the exposed cycle. No consistent effects were seen on time to delivery of litter or other gestational or litter parameters, such as litter size, sex ratio, implantations and implantation loss. CONCLUSION: Lung exposure to MWCNT interfered with estrous cycling. Effects caused by MWCNTs depended on the time of exposure: the estrous stage was particularly sensitive to exposure, as animals exposed during this stage showed a higher incidence of irregular cycling after exposure. Our data indicates that MWCNT exposure may interfere with events leading to ovulation. PMID- 28558789 TI - Repetitive reaching training combined with transcranial Random Noise Stimulation in stroke survivors with chronic and severe arm paresis is feasible: a pilot, triple-blind, randomised case series. AB - BACKGROUND: Therapy that combines repetitive training with non-invasive brain stimulation is a potential avenue to enhance upper limb recovery after stroke. This study aimed to investigate the feasibility of transcranial Random Noise Stimulation (tRNS), timed to coincide with the generation of voluntary motor commands, during reaching training. METHODS: A triple-blind pilot RCT was completed. Four stroke survivors with chronic (6-months to 5-years) and severe arm paresis, not taking any medications that had the potential to alter cortical excitability, and no contraindications to tRNS or MRI were recruited. Participants were randomly allocated to 12 sessions of reaching training over 4 weeks with active or sham tRNS delivered over the lesioned hemisphere motor representation. tRNS was triggered to coincide with a voluntary movement attempt, ceasing after 5-s. At this point, peripheral nerve stimulation enabled full range reaching. To determine feasibility, we considered adverse events, training outcomes, clinical outcomes, corticospinal tract (CST) structural integrity, and reflections on training through in-depth interviews from each individual case. RESULTS: Two participants received active and two sham tRNS. There were no adverse events. All training sessions were completed, repetitive practice performed and clinically relevant improvements across motor outcomes demonstrated. The amount of improvement varied across individuals and appeared to be independent of group allocation and CST integrity. CONCLUSION: Reaching training that includes tRNS timed to coincide with generation of voluntary motor commands is feasible. Clinical improvements were possible even in the most severely affected individuals as evidenced by CST integrity. TRIAL REGISTRATION: This study was registered on the Australian and New Zealand Clinical Trials Registry (ANZCTR) http://www.ANZCTR.org.au/ACTRN12614000952640.aspx . Registration date 4 September 2014, first participant date 9 September 2014. PMID- 28558790 TI - Challenges in transitioning adolescents and young adults with rheumatologic diseases to adult Care in a Developing Country - the Brazilian experience. AB - BACKGROUND: Transition guidelines and recommendations for developing countries are limited and best transition practices in young patients with chronic medical conditions have been poorly examined. This study evaluates transition practices from pediatric to adult rheumatology care in Brazil. METHODS: Practicing pediatric rheumatologists registered in the Brazilian Society of Rheumatology were e-surveyed with SurveyMonkey(r) using the Chira et al. questionnaire that had been used previously to evaluate transition practices of pediatric rheumatologists from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) in the USA and Canada. The questionnaire was modified to better address specific issues pertaining to the Brazilian health care system. RESULTS: Seventy six of 112 (68%) pediatric rheumatologists responded. Only 13% of the respondents reported that they had a well-established transition program and only 14% were satisfied with their current transition process. Eighty percent did not use any specific tools to assess transition readiness. While 43% of respondents considered 18 as the ideal transition age, only a third effectively transitioned their patients at that age while 48% did later. Major hurdles for a successful transition cited by the respondents included emotional attachment to the patients (95%) insufficient training in transition practice (87%), lack of devoted time for transition preparation and process (80%), lack of assistance by pediatric generalists, (77%), and lack of available adult subspecialists (75%). Sixty-seven percent of respondents stated that their program would need more tools/resources to facilitate transition and 59% believed that the development of specific guidelines would be useful to standardize and help with the transition process. CONCLUSIONS: Our study demonstrates that the identified challenges pertaining to transition in Brazilian patients are similar to those reported by pediatric rheumatologists in the United States and Canada. However, the current financial economic pressures affecting Brazil's health care system may force physicians to deprioritize non emergent care such as transition. A comprehensive understanding of transition issues specific to youth in developing countries and educating not only patients but also health care providers about the importance of a seamless transition process will support the development of transition guidelines and ensure better outcomes of pediatric subspecialty patients. PMID- 28558791 TI - Receptor tyrosine kinases play a significant role in human oligodendrocyte inflammation and cell death associated with the Lyme disease bacterium Borrelia burgdorferi. AB - BACKGROUND: In previous studies, human oligodendrocytes were demonstrated to undergo apoptosis in the presence of Borrelia burgdorferi under an inflammatory milieu. Subsequently, we determined that the MEK/ERK pathway played a significant role in triggering downstream inflammation as well as apoptosis. However, the identity of receptors triggered by exposure to B. burgdorferi and initiating signaling events was unknown. METHODS: In this study, we explored the role of several TLR and EGFR/FGFR/PDGFR tyrosine kinase pathways in inducing inflammation in the presence of B. burgdorferi, using siRNA and/or inhibitors, in MO3.13 human oligodendrocytes. Cell death and apoptosis assays were also carried out in the presence or absence of specific receptor inhibitors along with the bacteria to determine the role of these receptors in apoptosis induction. The expression pattern of specific receptors with or without B. burgdorferi was also determined. RESULTS: TLRs 2 and 5 had a minimal role in inducing inflammation, particularly IL-6 production. Rather, their effect was mostly inhibitory, with TLR2 downregulation significantly upregulating CXCL8, and CXCL (1,2,3) levels, and TLR5 likely having a similar role in CXCL8, CXCL(1,2,3), and CCL5 levels. TLR4 contributed mostly towards CCL5 production. On the other hand, inhibition of all three EGF/FGF/PDGF receptors significantly downregulated all five of the inflammatory mediators tested even in the presence of B. burgdorferi. Their inhibition also downregulated overall cell death and apoptosis levels. The expression pattern of these receptors, as assessed by immunohistochemistry indicated that the PDGFRbeta receptor was the most predominantly expressed receptor, followed by FGFR, although no significant differences were discernible between presence and absence of bacteria. Interestingly, inhibition of individual EGFR, FGFR, or PDGFR receptors did not indicate an individual role for any of these receptors in the overall downregulation of pathogenesis. Contrarily, suppression of FGFR signaling alone in the presence of bacteria significantly upregulated inflammatory mediator levels indicating that it might control an inhibitory pathway when triggered individually. CONCLUSIONS: Unlike TLRs, EGF/FGF/PDGF receptors collectively play a significant role in the inflammation and apoptosis of human oligodendrocytes as mediated by B. burgdorferi. It is likely that these three receptors need to be triggered simultaneously to achieve this effect. PMID- 28558792 TI - A diet change from dry food to beef induces reversible changes on the faecal microbiota in healthy, adult client-owned dogs. AB - BACKGROUND: Diet has a major influence on the composition of the gut microbiota, whose importance for gut health and overall well-being is increasingly recognized. Knowledge is limited regarding health implications, including effects on the faecal microbiota, of feeding a diet with high content of red meat to dogs, despite some owners' apparent preference to do so. The aim of this study was to evaluate how a diet change from commercial dry food to one with a high content of boiled minced beef and vice versa influenced the faecal microbiota, and short chain fatty acid profile in healthy, adult, client-owned dogs. RESULTS: The diet change influenced the faecal microbiota composition and diversity (Shannon diversity index). The most abundant OTUs in samples of dogs fed the dry food and high minced beef were affiliated with the species Faecalibacterium prausnitzii and Clostridia hiranonis respectively. The high minced beef diet apparently also influenced the short chain fatty acid profile, with increased isovaleric acid, as well as an increase in faecal pH. These effects were reversed when the commercial dry food was reintroduced in weeks 6 and 7. CONCLUSIONS: Results of this study can aid in the understanding of how diet changes influence the faecal microbiota and metabolite content on a short-term basis. Long-term studies are required to investigate potential implications for canine gut and general health. PMID- 28558793 TI - Is unemployment in young adulthood related to self-rated health later in life? Results from the Northern Swedish cohort. AB - BACKGROUND: Many studies have reported that unemployment has a negative effect on health. However, little is known about the long-term effect for those who become unemployed when they are young adults. Our aim was to examine how unemployment is related to long-term self-rated health among 30 year olds, with an emphasis on how health differs in relation to education level, marital status, previous health, occupation, and gender. METHODS: In the Northern Swedish Cohort, 1083 teenagers (~16 years old) were originally invited in 1981. Of these, 1001 participated in the follow-up surveys in 1995 and 2007. In our study, we included participants with either self-reported unemployment or activity in the labor force during the previous three years in the 1995 follow-up so long as they had no self-reported unemployment between the follow-up surveys. Labor market status was studied in relation to self-reported health in the 2007 follow-up. Information from the 1995 follow-up for education level, marital status, self reported health, and occupation were part of the statistical analyses. Analyses were stratified for these variables and for gender. Analyses were performed with logistic regression, G-computation, and a method based on propensity scores. RESULTS: Poor self-rated health in 2007 was reported among 43 of the 98 (44%) unemployed and 159 (30%) of the 522 employed subjects. Unemployment had a long term negative effect on health (odds ratio with logistic regression 1.74 and absolute difference estimates of 0.11 (G-computation) and 0.10 (propensity score method)). At the group level, the most pronounced effects on health were seen in those with upper secondary school as their highest education level, those who were single, low-level white-collar workers, and women. CONCLUSIONS: Even among those becoming unemployed during young adulthood, unemployment is related to a negative long-term health effect. However, the effect varies among different groups of individuals. Increased emphasis on understanding the groups for whom unemployment is most strongly related to ill health is important for future research so that efforts can be put towards those with the biggest need. Still, our results can be used as the basis for deciding which groups should be prioritized for labor-market interventions. PMID- 28558794 TI - Assessment of physical activity, capacity and nutritional status in elderly peritoneal dialysis patients. AB - BACKGROUND: This study aimed to evaluate the prevalence of sedentarism, and to assess physical capacity and nutritional status in a cohort of older patients on peritoneal dialysis (PD), with respect to age-matched non-dialysis CKD population, using highly accessible, simple methods, namely the Rapid Assessment of Physical activity (RAPA) test and the 30" Sit-to-stand (STS) test. METHODS: This cross-sectional multicenter study included 151 renal patients older than 60 years; 71 pts. (44 m, age 72 +/- 7 yrs) were on PD and 80 pts. (63 m, age 74 +/- 7 yrs) were affected by 3-4 stage CKD. RESULTS: The prevalence of sedentary/underactive patients was double of that of the active patients as assessed by RAPA test, both in the PD (65.3%) and in the CKD (67.5%) cohort. The 30"STS test showed a reduced physical performance in both groups: 84.5% of PD patients and 87.5% of CKD patients did not reach the expected number of stands by age and gender. A malnutrition-inflammation score (MIS) >= 6 occurred in 37 % of PD patients and in 2.5 % of CKD patients. In PD patients, an independent significant association was observed between 30"STS test and MIS (beta -0.510, p = 0.013), as well as between RAPA and MIS (beta -0.544, p = 003) and phase angle (beta -0.506, p = 0.028). CONCLUSIONS: A high prevalence of low- performance capacity and sedentarism has been detected among elderly patients on PD or with CKD stage 3-4. Apart from age, a condition of malnutrition-inflammation was the major determinant of poor physical activity and capacity in PD patients. Better body composition seems to be positively associated with physical activity in PD and with physical capacity in CKD patients. Routine clinical management should include a close evaluation of nutritional status and evaluation of physical activity and capacity which can be easily assessed by RAPA and 30"STS tests. PMID- 28558795 TI - Non-caloric sweetener provides magnetic resonance imaging contrast for cancer detection. AB - BACKGROUND: Image contrast enhanced by exogenous contrast agents plays a crucial role in the early detection, characterization, and determination of the precise location of cancers. Here, we investigate the feasibility of using a non nutritive sweetener, sucralose (commercial name, Splenda), as magnetic resonance imaging (MRI) contrast agent for cancer studies. METHODS: High-resolution nuclear magnetic-resonance spectroscopy and MR studies on sucralose solution phantom were performed to detect the chemical exchange saturation transfer (CEST) property of sucralose hydroxyl protons with bulk water (sucCEST). For the animal experiments, female Fisher rats (F344/NCR) were used to generate 9L-gliosarcoma model. MRI with CEST experiments were performed on anesthetized rats at 9.4 T MR scanner. Following the baseline CEST scans, sucralose solution was intravenously administered in control and tumor bearing rats. CEST acquisitions were continued during and following the administration of sucralose. Following the sucCEST, Gadolinium-diethylenetriamine pentaacetic acid was injected to perform Gd enhanced imaging for visualizing the tumor. RESULTS: The sucCEST contrast in vitro was found to correlate positively with the sucralose concentration and negatively with the pH, indicating the potential of this technique in cancer imaging. In a control animal, the CEST contrast from the brain was found to be unaffected following the administration of sucralose, demonstrating its blood brain barrier impermeability. In a 9L glioma model, enhanced localized sucCEST contrast in the tumor region was detected while the unaffected brain region showed unaltered CEST effect implying the specificity of sucralose toward the tumorous tissue. The CEST asymmetry plots acquired from the tumor region before and after the sucralose infusion showed elevation of asymmetry at 1 ppm, pointing towards the role of sucralose in increased contrast. CONCLUSIONS: We show the feasibility of using sucralose and sucCEST in study of preclinical models of cancer. This study paves the way for the potential development of sucralose and other sucrose derivatives as contrast agents for clinical MRI applications. PMID- 28558797 TI - Expression of signaling adaptor proteins predicts poor prognosis in pancreatic ductal adenocarcinoma. AB - BACKGROUND: Adaptor proteins bridge the gap between cell surface receptors and their downstream signaling elements. The clinicopathological and prognostic values of adaptor proteins remain poorly understood. The purpose of the present study was to explore the expression and prognostic value of three adaptor proteins: GRB2-associated binding protein 2 (GAB2), CRK-like protein (CRKL) and fibroblast growth factor receptor substrate 2 (FRS2) in pancreatic ductal adenocarcinoma (PDAC). METHODS: The expression of GAB2, CRKL, and FRS2 in 77 formalin fixed paraffin embedded (FFPE) samples from 77 PDAC patients, along with three paired fresh PDAC and matched normal tissues from 3 PDAC patients was analyzed by immunohistochemistry and western blot, respectively. The association between the expression of the three proteins and the clinicopathological factors of PDAC was assessed by chi 2 test. The correlation between the expression levels of the three proteins was analyzed by Spearman rank correlation analyses; Kaplan Meier survival analyses were also performed. RESULTS: IHC was successful in 75, 76, and 77 cases for GAB2, CRKL, and FRS2, respectively. Of which, the positive rate of GAB2, CRKL, and FRS2 protein expression was 40.00% (30/75), 53.95% (41/76) and 35.06% (27/77), respectively. The positive rate of GAB2, CRKL and FRS2 co-expression was 16.88% (13/77). Though there was no association between GAB2 expression, CRKL expression, FRS2 expression, GAB2/CRKL/FRS2 co-expression and the clinicopathological parameters of PDAC, positive correlations were observed between the expressions of the three proteins. Further, univariate survival analysis showed that positive expression of GAB2, CRKL and FRS2 and co expression of GAB2/CRKL/FRS2 of PDAC predicted poor clinical outcomes, and multivariate survival analysis suggested that positive expression of GAB2 and positive co-expression of GAB2/CRKL/FRS2 were independent prognostic factors for disease-free survival (DFS) and overall survival (OS), respectively. CONCLUSION: In conclusion, GAB2, CRKL, and FRS2 may be potential prognosticators and therapeutic targets for PDAC patients. PMID- 28558796 TI - Systems-based approach to examine the cytokine responses in primary mouse lung macrophages infected with low pathogenic avian Influenza virus circulating in South East Asia. AB - BACKGROUND: Influenza A virus (IAV) is a major public health concern, being responsible for the death of approximately half a million people each year. Zoonotic transmissions of the virus from swine and avian origin have occurred in the past, and can potentially lead to the em gergence of new IAV stains in fut ure pandemics. Pulmonary macrophages have been implicated in disease severity in the lower airway, and understanding the host response of macrophages infected with avian influenza viruses should provide new therapeutic strategies. RESULTS: We used a systems-based approach to investigate the transcriptome response of primary murine lung macrophages (PMF) infected with the mouse-adapted H1N1/WSN virus and low pathogenic avian influenza (LPAI) viruses H5N2 and H5N3. The results showed that the LPAI viruses H5N2 and H5N3 can infect PMF with similar efficiency to the H1N1/WSN virus. While all viruses induced antiviral responses, the H5N3 virus infection resulted in higher expression levels of cytokines and chemokines associated with inflammatory responses. CONCLUSIONS: The LPAI H5N2 and H5N3 viruses are able to infect murine lung macrophages. However, the H5N3 virus was associated with increased expression of pro -inflammatory mediators. A lthough the H5N3 virus it is capable of inducing high levels of cytokines that are associated with inflammation , this property is disti nct from its inability to efficiently replicate in a mammalian host. PMID- 28558798 TI - Effect of concrete slats, three mat types and out-wintering pads on performance and welfare of finishing beef steers. AB - BACKGROUND: The objective was to investigate the effect of placing mats on concrete slatted floors on performance, behaviour, hoof condition, dirt scores, physiological and immunological variables of beef steers, and to compare responses with animals on out-wintering pads. Continental crossbred beef steers [n = 360; mean (+/-SD) initial live weight 539 kg (42.2)] were blocked by breed and live weight and randomly assigned to one of five treatments; (1) Concrete slats alone, (2) Mat 1 (Natural Rubber structure) (Durapak Rubber Products), (3) Mat 2 (Natural rubber structure) (EasyFix), (4) Mat 3 (modified ethylene vinyl acetate (EVA) foam structure) and (5) Out-wintering pads (OWP's). RESULTS: Animals on the OWPs had a greater (P < 0.05) live weight gain (P < 0.05) compared with the slat and Mat 2 treatments: results for Mat 1 and Mat 3 were the same (P > 0.05) as the other treatments. Animals on the OWPs had reduced lying percentage time compared with all the other treatments. Dry matter (DM) intake was greater for animals on the OWPs compared with all the other treatments. Carcass weight, kill out proportion, carcass fat score, carcass composition score, FCR and physiological responses were similar (P > 0.05) among treatments. No incidence of laminitis was observed among treatments. The number of hoof lesions was greater on all mat types (P < 0.05) compared with concrete slats and OWP treatments. Dirt scores were greater (P < 0.05) for animals on OWPs when measured on days 42, 84, 105, 126 and 150 compared with animals on slats. CONCLUSIONS: Under the conditions adopted for the present study, there was no evidence to suggest that animals housed on bare concrete slats were disadvantaged in respect of animal welfare compared with animals housed on other floor types. It is concluded that the welfare of steers was not adversely affected by slats compared with different mat types or OWPs. PMID- 28558799 TI - Propagation of Tau aggregates. AB - Since 2009, evidence has accumulated to suggest that Tau aggregates form first in a small number of brain cells, from where they propagate to other regions, resulting in neurodegeneration and disease. Propagation of Tau aggregates is often called prion-like, which refers to the capacity of an assembled protein to induce the same abnormal conformation in a protein of the same kind, initiating a self-amplifying cascade. In addition, prion-like encompasses the release of protein aggregates from brain cells and their uptake by neighbouring cells. In mice, the intracerebral injection of Tau inclusions induced the ordered assembly of monomeric Tau, followed by its spreading to distant brain regions. Short fibrils constituted the major species of seed-competent Tau. The existence of several human Tauopathies with distinct fibril morphologies has led to the suggestion that different molecular conformers (or strains) of aggregated Tau exist. PMID- 28558801 TI - Astroglial-mediated remodeling of the interhemispheric midline during telencephalic development is exclusive to eutherian mammals. AB - The corpus callosum forms the major interhemispheric connection in the human brain and is unique to eutherian (or placental) mammals. The developmental events associated with the evolutionary emergence of this structure, however, remain poorly understood. A key step in callosal formation is the prior remodeling of the interhemispheric fissure by embryonic astroglial cells, which then subsequently act as a permissive substrate for callosal axons, enabling them to cross the interhemispheric midline. However, whether astroglial-mediated interhemispheric remodeling is unique to eutherian mammals, and thus possibly associated with the phylogenetic origin of the corpus callosum, or instead is a general feature of mammalian brain development, is not yet known. To investigate this, we performed a comparative analysis of interhemispheric remodeling in eutherian and non-eutherian mammals, whose lineages branched off before the evolution of the corpus callosum. Whole brain MRI analyses revealed that the interhemispheric fissure is retained into adulthood in marsupials and monotremes, in contrast to eutherians (mice), in which the fissure is significantly remodeled throughout development. Histological analyses further demonstrated that, while midline astroglia are present in developing marsupials, these cells do not intercalate with one another through the intervening interhemispheric fissure, as they do in developing mice. Thus, developing marsupials do not undergo astroglial mediated interhemispheric remodeling. As remodeling of the interhemispheric fissure is essential for the subsequent formation of the corpus callosum in eutherians, our data highlight the role of astroglial-mediated interhemispheric remodeling in the evolutionary origin of the corpus callosum. PMID- 28558800 TI - The influence of quality maternity waiting homes on utilization of facilities for delivery in rural Zambia. AB - BACKGROUND: Residential accommodation for expectant mothers adjacent to health facilities, known as maternity waiting homes (MWH), is an intervention designed to improve access to skilled deliveries in low-income countries like Zambia where the maternal mortality ratio is estimated at 398 deaths per 100,000 live births. Our study aimed to assess the relationship between MWH quality and the likelihood of facility delivery in Kalomo and Choma Districts in Southern Province, Zambia. METHODS: We systematically assessed and inventoried the functional capacity of all existing MWH using a quantitative facility survey and photographs of the structures. We calculated a composite score and used multivariate regression to quantify MWH quality and its association with the likelihood of facility delivery using household survey data collected on delivery location in Kalomo and Choma Districts from 2011-2013. RESULTS: MWH were generally in poor condition and composite scores varied widely, with a median score of 28.0 and ranging from 12 to 66 out of a possible 75 points. Of the 17,200 total deliveries captured from 2011-2013 in 40 study catchment area facilities, a higher proportion occurred in facilities where there was either a MWH or the health facility provided space for pregnant waiting mothers compared to those with no accommodations (60.7% versus 55.9%, p <0.001). After controlling for confounders including implementation of Saving Mothers Giving Life, a large-scale maternal health systems strengthening program, among women whose catchment area facilities had an MWH, those women with MWHs in their catchment area that were rated medium or high quality had a 95% increase in the odds of facility delivery than those whose catchment area MWHs were of poor quality (OR: 1.95, 95% CI 1.76, 2.16). CONCLUSIONS: Improving both the availability and the quality of MWH represents a potentially useful strategy to increasing facility delivery in rural Zambia. TRIAL REGISTRATION: The Zambia Chlorhexidine Application Trial is registered at Clinical Trials.gov (identifier: NCT01241318). PMID- 28558802 TI - Serum micro-rna profiles in patients with autosomal dominant polycystic kidney disease according to hypertension and renal function. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder with unclear disease mechanism. Currently, overt hypertension and increased renal volume are the best predictors of renal function. In this study, we assessed the usefulness of selected circulating microRNAs (miRs) to predict disease progress in a cohort with ADPKD. METHODS: Eighty ADPKD patients (44.6 +/- 12.7 years, 40% female, 65% hypertensive) and 50 healthy subjects (HS; 45.4 +/- 12.7, 44% female) were enrolled in the study. Serum levels of 384 miRs were determined by Biomark Real Time PCR. Groups were compared using the limma method with multiple-testing correction as proposed by Smyth (corrected p < 0.01 considered significant). RESULTS: Comparing ADPKD to HS, we found significant differences in blood levels of 18 miRs (3 more and 15 less abundant). Of these, miR-3907, miR-92a-3p, miR-25-3p and miR-21-5p all rose while miR-1587 and miR 3911 decreased as renal function declined in both cross-sectional and longitudinal analysis. Using ROC analysis, an increased baseline miR-3907 in the circulation predicted a > 10% loss of GFR over the following 12 months (cut-off >2.2 AU, sensitivity 83%, specificity 78%, area 0.872 [95% CI: 0.790-0.953, p < 0.001]). Adjusting for age and starting CKD stage using multiple binary logistic regression analysis did not abrogate the predictive value. CONCLUSION: Increased copy numbers of miR-3907 in the circulation may predict ADPKD progression and suggest pathophysiological pathways worthy of further study. PMID- 28558803 TI - Cross-cultural measurement invariance in the satisfaction with food-related life scale in older adults from two developing countries. AB - BACKGROUND: Nutrition is one of the major determinants of successful aging. The Satisfaction with Food-related Life (SWFL) scale measures a person's overall assessment regarding their food and eating habits. The SWFL scale has been used in older adult samples across different countries in Europe, Asia and America, however, there are no studies that have evaluated the cross-cultural measurement invariance of the scale in older adult samples. Therefore, we evaluated the measurement invariance of the SWFL scale across older adults from Chile and Ecuador. METHODS: Stratified random sampling was used to recruit a sample of older adults of both genders from Chile (mean age = 71.38, SD = 6.48, range = 60 92) and from Ecuador (mean age = 73.70, SD = 7.45, range = 60-101). Participants reported their levels of satisfaction with food-related life by completing the SWFL scale, which consists of five items grouped into a single dimension. Confirmatory factor analysis (CFA) was used to examine cross-cultural measurement invariance of the SWFL scale. RESULTS: Results showed that the SWFL scale exhibited partial measurement invariance, with invariance of all factor loadings, invariance in all but one item's threshold (item 1) and invariance in all items' uniqueness (residuals), which leads us to conclude that there is a reasonable level of partial measurement invariance for the CFA model of the SWFL scale, when comparing the Chilean and Ecuadorian older adult samples. The lack of invariance in item 1 confirms previous studies with adults and emerging adults in Chile that suggest this item is culture-sensitive. We recommend revising the wording of the first item of the SWFL in order to relate the statement with the person's life. CONCLUSIONS: The SWFL scale shows partial measurement invariance across older adults from Chile and Ecuador. A 4-item version of the scale (excluding item 1) provides the basis for international comparisons of satisfaction with food related life in older adults from developing countries in South America. PMID- 28558804 TI - Metofluthrin: investigations into the use of a volatile spatial pyrethroid in a global spread of dengue, chikungunya and Zika viruses. AB - BACKGROUND: Metofluthrin reduces biting activity in Aedes aegypti through the confusion, knockdown, and subsequent kill of a mosquito. A geographical spread in dengue, chikungunya, and Zika viruses, increases intervention demands. Response to a Zika outbreak may require a different strategy than dengue, as high-risk individuals, specifically pregnant women, need to be targeted. METHODS: In semi field conditions within a residential property in Cairns, Queensland, the impacts of metofluthrin on biting behaviour of free-flying Wolbachia-infected Ae. aegypti were evaluated. RESULTS: Mortality in Ae. aegypti exposed to metofluthrin over a 22 h period was 100% compared to 2.7% in an untreated room. No biting activity was observed in mosquitoes up to 5 m from the emanator after 10 min of metofluthrin exposure. Use of metofluthrin reduced biting activity up to 8 m, regardless of the host's proximity (near or far) to a dark harbourage area (HA) (P < 0.0001 and P = 0.006), respectively. In the presence or absence of the metofluthrin emanator, the host was most likely bitten when located immediately next to a HA (within 1 m) versus 8 m away from the HA (P = 0.006). The addition of a ceiling fan (0.8 m/s airflow) prevented all biting activity after 10 min of metofluthrin exposure. Previously unexposed Ae. aegypti were less likely to reach the host in a metofluthrin-treated room [Formula: see text]= 31%) compared to an untreated room ([Formula: see text]) (P < 0.0001). In a treated room, if the mosquito had not reached the host within 30 s, they never would. Upon activation, the time required for metofluthrin to infiltrate protected locations within a room causing knockdown in caged mosquitoes, required more time than exposed locations (P < 0.003); however exposed and protected locations do eventually reach equilibrium, affecting mosquitoes equally throughout the room. CONCLUSION: Metofluthrin is effective in interrupting indoor host-seeking in Ae. aegypti. Metofluthrin's efficacy is increased by centrally locating the emanator in the room, and by using a fan to increase airflow. Newly treated rooms may require a period of 2-4 h for sufficient distribution of the metofluthrin into protected locations where mosquitoes may be resting. PMID- 28558806 TI - A critical age: can we reliably measure frailty in critical care? PMID- 28558805 TI - Development of a 12-item short version of the HIV stigma scale. AB - BACKGROUND: Valid and reliable instruments for the measurement of enacted, anticipated and internalised stigma in people living with HIV are crucial for mapping trends in the prevalence of HIV-related stigma and tracking the effectiveness of stigma-reducing interventions. Although longer instruments exist, e.g., the commonly used 40-item HIV Stigma Scale by Berger et al., a shorter instrument would be preferable to facilitate the inclusion of HIV stigma in more and broader surveys. Therefore, the aim of this work was to develop a substantially shorter, but still valid, version of the HIV Stigma Scale. METHODS: Data from a psychometric evaluation of the Swedish 40-item HIV Stigma Scale were reanalysed to create a short version with 12 items (three from each of the four stigma subscales: personalised stigma, disclosure concerns, concerns with public attitudes and negative self-image). The short version of the HIV stigma scale was then psychometrically tested using data from a national survey investigating stigma and quality of life among people living with HIV in Sweden (n = 880, mean age 47.9 years, 26% female). RESULTS: The hypothesized factor structure of the proposed short version was replicated in exploratory factor analysis without cross loadings and confirmatory factor analysis supported construct validity with high standardised effects (>0.7) of items on the intended scales. The chi2 test was statistically significant (chi2 = 154.2, df = 48, p < 0.001), but alternate fit measures indicated acceptable fit (comparative fit index: 0.963, Tucker-Lewis index: 0.950 and root mean square error of approximation: 0.071). Corrected item total correlation coefficients were >0.4 for all items, with a variation indicating that the broadness of the concept of stigma had been captured. All but two aspects of HIV-related stigma that the instrument is intended to cover were captured by the selected items in the short version. The aspects that did not lose any items were judged to have acceptable psychometric properties. The short version of the instrument showed higher floor and ceiling effects than the full length scale, indicating a loss of sensitivity in the short version. Cronbach's alpha for the subscales were all >0.7. CONCLUSIONS: Although being less sensitive in measurement, the proposed 12-item short version of the HIV Stigma Scale has comparable psychometric properties to the full-length scale and may be used when a shorter instrument is needed. PMID- 28558808 TI - Gender differences in discharge dispositions of emergency department visits involving drug misuse and abuse-2004-2011. AB - BACKGROUND: Drug use-related visits to the emergency department (ED) can undermine discharge planning and lead to recurrent use of acute services. Yet, little is known about where patients go post discharge. We explored trends in discharge dispositions of drug-involved ED visits, with a focus on gender differences. METHODS: We extracted data from the 2004-2011 Drug Abuse Warning Network, a national probability sample of drug-related visits to hospital EDs in the U.S. We computed weighted multinomial logistic regression models to estimate discharge dispositions over time and to examine associations between gender and the relative risk of discharge dispositions, controlling for patient characteristics. RESULTS: The final pooled sample included approximately 1.2 million ED visits between 2004 and 2011. Men accounted for more than half (57.6%) of all ED visits involving drug misuse and abuse. Compared with women, men had a greater relative risk of being released to the police/jail, being referred to outpatient detox or other treatment, and leaving against medical advice than being discharged home. The relative risk of being referred to outpatient detox/drug treatment than discharged home increased over time for men versus women. CONCLUSIONS: Greater understanding of gender-based factors involved in substance-related ED visits and treatment needs may inform discharge planning and preventive interventions. PMID- 28558807 TI - Genome-wide DNA methylation at birth in relation to in utero arsenic exposure and the associated health in later life. AB - BACKGROUND: In utero arsenic exposure may alter fetal developmental programming by altering DNA methylation, which may result in a higher risk of disease in later life. We evaluated the association between in utero arsenic exposure and DNA methylation (DNAm) in cord blood and its influence in later life. METHODS: Genome-wide DNA methylation in cord blood from 64 subjects in the Taiwanese maternal infant and birth cohort was analyzed. Robust regressions were applied to assess the association of DNA methylation with in utero arsenic exposure. Multiple testing was adjusted by controlling false discovery rate (FDR) of 0.05. The DAVID bioinformatics tool was implemented for functional annotation analyses on the detected CpGs. The identified CpGs were further tested in an independent cohort. For the CpGs replicated in the independent cohort, linear mixed models were applied to assess the association of DNA methylation with low-density lipoprotein (LDL) at different ages (2, 5, 8, 11 and 14 years). RESULTS: In total, 579 out of 385,183 CpGs were identified after adjusting for multiple testing (FDR = 0.05), of which ~60% were positively associated with arsenic exposure. Functional annotation analysis on these CpGs detected 17 KEGG pathways (FDR = 0.05) including pathways for cardiovascular diseases (CVD) and diabetes mellitus. In the independent cohort, about 46% (252 out of 553 CpGs) of the identified CpGs showed associations consistent with those in the study cohort. In total, 11 CpGs replicated in the independent cohort were in the pathways related to CVD and diabetes mellitus. Via longitudinal analyses, we found at 5 out of the 11 CpGs methylation was associated with LDL over time and interactions between DNA methylation and time were observed at 4 of the 5 CpGs, cg25189764 (coeff = 0.157, p-value = 0.047), cg04986899 (coeff. For interaction [coeff.int] = 0.030, p-value = 0.024), cg04903360 (coeff.int = 0.026, p-value = 0.032), cg08198265 (coeff.int = -0.063, p-value = 0.0021), cg10473311 (coeff.int = -0.021, p-value = 0.027). CONCLUSION: In utero arsenic exposure was associated with cord blood DNA methylation at various CpGs. The identified CpGs may help determine pathological epigenetic mechanisms linked to in utero arsenic exposure. Five CpGs (cg25189764, cg04986899, cg04903360, cg08198265 and cg10473311) may serve as epigenetic markers for changes in LDL later in life. PMID- 28558809 TI - Genetic variation of mitochondrial genes among Echinococcus multilocularis isolates collected in western China. AB - BACKGROUND: Alveolar echinococcosis (AE) is a life-threatening human disease caused by Echinococcus multilocularis transmitted between rodents and dogs/foxes in the Northern Hemisphere. The study aims to identify the genetic variation of the parasite in AE patients from China. METHODS: E. multilocularis isolates were collected from wild small mammals (n = 6) and AE patients (n = 56) from western China. Genomic DNA was extracted from different tissue samples including paraffin tissue blocks, ethanol fixed tissues and frozen tissues surgically removed. Two mitochondrial gene fragments (526 bp for cob and 474 bp for nad2) of E. multilocularis were amplified and sequenced. RESULTS: The parasite fragment sequences of cob fragments from AE patients showed two haplotypes, and nad2 gene fragment sequences had four haplotypes. The gene sequences from Microtus sp. were 100% identical to the sequences of some isolates from AE patients. These haplotypes were distributed in both Qinghai and Xinjiang provinces. Alignment analysis with the sequences from the GenBank databases showed five genotypes including three Asian genotypes, one from Europe and one from North America. CONCLUSIONS: Most AE patients harbored the Asian genotype 1 which may be an indication of its relative frequency in the definitive hosts and the environment or of its pathogenicity to humans, which calls for further research. PMID- 28558810 TI - Varicella associated pneumoniae in a pediatric population. AB - BACKGROUND: Varicella pneumonia has been studied extensively in adults; it may also affect children and may require hospitalization. METHODS: We examined pneumonia complications in children hospitalized for varicella, over a 13 year period. RESULTS: Pneumonia occurred in 8.2% of children hospitalized for varicella. The median length of hospitalization was 6 days. No statistically significant difference in length of stay was detected between immunodepressed children and previously healthy children. The hospitalization was on average shorter in patients who started antiviral therapy within 24 h of varicella onset. None of the included patients had been previously immunized for varicella. CONCLUSIONS: Our results support the need for increased awareness of current varicella prevention recommendations among both immunocompetent and immunodepressed individuals. In children affected by varicella, prompt antiviral therapy may be indicated to reduce the number of days of hospitalization. PMID- 28558811 TI - Focal necrosis mimicking breast cancer following coronary bypass grafting. AB - BACKGROUND: Breast cancer can be diagnosed easily in most cases. However, occasionally, we are faced with some conditions that can mimic it. These may include inflammations, benign tumors, cysts, hematomas, or, more rarely, focal necrosis. CASE PRESENTATION: This report presents a case of focal breast necrosis following myocardial revascularization with the left internal mammary artery, which is a very rare condition, with only few cases described in the literature. The necrosis becomes usually apparent a few days or weeks after the surgery and is often coincidental with the dehiscence of sternotomy with necrosis of wound edges. As it mostly affects the skin, it can be easily recognized. Also, our patient developed a dehisced sternotomy shortly after the surgery but there were no obvious objective changes on the breast. The condition was first dominated only by non-specific subjective symptom-pain. Later, a lump in the breast occurred, when the sternotomy had already healed. Moreover, an enlarged lymph node was palpable in the axilla. Because of non-typical symptoms, the condition was suggestive of breast cancer for a relatively long time. The patient had suffered from a very strong pain until she was treated by mastectomy with a good clinical result. CONCLUSIONS: Mammary necrosis following the coronary artery bypass is rare. In most cases, it manifests on the skin shortly after the surgery concurrently with dehisced sternotomy, so it can be easily diagnosed. However, in sporadic cases, the symptoms may occur later and may mimic breast cancer. Our objective is to raise awareness of this rare condition. PMID- 28558812 TI - Introducing onsite antenatal syphilis screening in Burkina Faso: implementation and evaluation of a feasibility intervention tailored to a local context. AB - BACKGROUND: Although the advantages of introducing point of care testing for syphilis in antenatal care (ANC) are well documented, there is little evidence on how to address structural issues within health systems. A better understanding of how these interventions work in a range of settings and contexts is needed in order to overcome bottlenecks at health system level. To better understand the relationships between implementation and context we developed and implemented an intervention focused on integrating a rapid screening test for syphilis in ANC services in rural primary health care facilities in Burkina Faso. This manuscript describes the intervention and reports on feasibility and acceptability of the intervention, the facilitators and barriers to the implementation of this intervention and the likelihood that point of care test for syphilis will become routinely incorporated in practice. METHODS: In Kaya Health and Demographic Surveillance System (Kaya HDSS), all 7 primary healthcare facilities were selected for intervention in 2013. A participatory approach was used to design and implement an antenatal syphilis screening intervention. The Normalization Process Model (NPM) proposed by May et al. was adapted in order to identify barriers and facilitators and to explore the likelihood to become routinely incorporated in practice. Registers, Observations (n = 14 ANC 1) of interactions between patients and health workers during ANC and interviews with health workers (n = 14) were our data sources. RESULTS: An intervention that included onsite training, provision of supplies and medicines, quality control and supervision was implemented in 7 health facilities in 2013. Rapid syphilis test and treatment were delivered during ANC within the examination room with no specific additional mechanism regarding staff organization. The perceived barriers were lack of training of all staff, workload, stock-outs of consumables and lack of motivation of staff. Key facilitators included political environment, ease of use of test and acceptability to pregnant women. CONCLUSIONS: Onsite testing for antenatal syphilis is a feasible and acceptable intervention in ANC at primary health facility in Burkina Faso. The point-of care test for syphilis is more likely to be acceptable by health workers as routine service and incorporated as a normal practice. TRIAL REGISTRATION: The study was retrospectively registered on ClinicalTrials.gov under the Trial Registration Number NCT03156751 . PMID- 28558814 TI - Approach to growth hormone therapy in children with chronic kidney disease varies across North America: the Midwest Pediatric Nephrology Consortium report. AB - BACKGROUND: Growth impairment remains common in children with chronic kidney disease (CKD). Available literature indicates low level of recombinant human growth hormone (rhGH) utilization in short children with CKD. Despite efforts at consensus guidelines, lack of high-level evidence continues to complicate rhGH therapy decision-making and the level of practice variability in rhGH treatment by pediatric nephrologists is unknown. METHODS: Cross-sectional online survey electronically distributed to pediatric nephrologists through the Midwest Pediatric Nephrology Consortium and American Society of Pediatric Nephrology. RESULTS: Seventy three pediatric nephrologists completed the survey. While the majority (52.1%) rarely involve endocrinology in rhGH management, 26.8% reported that endocrinology managed most aspects of rhGH treatment in their centers. The majority of centers (68.5%) have a dedicated renal dietitian, but 20.6% reported the nephrologist as the primary source of nutritional support for children with CKD. Children with growth failure did not receive rhGH most commonly because of family refusal. Differences in initial work-up for rhGH therapy include variable use of bone age (95%), thyroid function (58%), insulin-like growth factor-1 (40%), hip/knee X-ray (36%), and ophthalmologic evaluation (7%). Most pediatric nephrologists (95%) believe that rhGH treatment improves quality of life, but only 24% believe that it improves physical function; 44% indicated that rhGH improves lean body mass. CONCLUSIONS: There is substantial variation in pediatric nephrology practice in addressing short stature and rhGH utilization in children with CKD. Hence, there may be opportunities to standardize care to study and improve growth outcomes in short children with CKD. PMID- 28558816 TI - Intraoperative electromyographic monitoring to optimize safe lumbar pedicle screw placement - a retrospective analysis. AB - BACKGROUND: The foremost concern of a surgeon during pedicle screw fixation is safety. Assistive modalities, especially intraoperative electromyographic monitoring (EMG) can function as an essential tool to recognize screw malposition that compromise neural integrity, so that the screws can be repositioned immediately rather than later. We intend to study the efficacy of intraoperative EMG monitoring to detect potential pedicle breach and evaluate whether reoperation rates were significantly reduced. METHODS: Retrospectively, patients who underwent posterior stabilization with pedicle screws for various pathologies were analysed and those with screws among L1-S1 levels were shortlisted. They were divided into two groups. Group 1 included patients in whom trigger EMG (t EMG) was used to confirm appropriate screw placement and Group 2 included those in whom it was not used. Responses to t-EMG and corresponding stimulation thresholds were recorded for Group 1 patients. The sensitivity and specificity of the test was calculated. Reoperation rates due to postoperative neurologic compromise caused by malpositioned screws were compared between both the groups. RESULTS: A total of 518 patients had 3112 pedicle screws between L1-S1 levels. Among Group 1 [n = 296; Screws = 1856], 145 screws (7.8%) showed a positive response for t-EMG at stimulation thresholds ranging between 2.6 to 19.8 mA. The sensitivity and specificity of t-EMG to diagnose potential pedicle breach was found to be 93.33% and 92.88% respectively. Only one patient among Group 1 required reoperation. However, among Group 2 [n = 222; screws = 1256], six patients required reoperation. This indicated a significant decrease in the number of malpositioned screws that caused neurological compromise [p = 0.02], leading to subsequent decrease in reoperation rates [p = 0.04] among Group 1 patients. CONCLUSIONS: Trigger EMG is well efficient in detecting potential pedicle screw breaches that might endanger neural integrity. In combination with palpatory and radiographic assessment, it will certainly aid safe and secure pedicle screw placement. It can also efficiently reduce reoperation rates due to neurologic compromise provoked by a malpositioned screw. PMID- 28558815 TI - Pathophysiology of chronic subdural haematoma: inflammation, angiogenesis and implications for pharmacotherapy. AB - Chronic subdural haematoma (CSDH) is an encapsulated collection of blood and fluid on the surface of the brain. Historically considered a result of head trauma, recent evidence suggests there are more complex processes involved. Trauma may be absent or very minor and does not explain the progressive, chronic course of the condition. This review focuses on several key processes involved in CSDH development: angiogenesis, fibrinolysis and inflammation. The characteristic membrane surrounding the CSDH has been identified as a source of fluid exudation and haemorrhage. Angiogenic stimuli lead to the creation of fragile blood vessels within membrane walls, whilst fibrinolytic processes prevent clot formation resulting in continued haemorrhage. An abundance of inflammatory cells and markers have been identified within the membranes and subdural fluid and are likely to contribute to propagating an inflammatory response which stimulates ongoing membrane growth and fluid accumulation. Currently, the mainstay of treatment for CSDH is surgical drainage, which has associated risks of recurrence requiring repeat surgery. Understanding of the underlying pathophysiological processes has been applied to developing potential drug treatments. Ongoing research is needed to identify if these therapies are successful in controlling the inflammatory and angiogenic disease processes leading to control and resolution of CSDH. PMID- 28558813 TI - Genome annotation for clinical genomic diagnostics: strengths and weaknesses. AB - The Human Genome Project and advances in DNA sequencing technologies have revolutionized the identification of genetic disorders through the use of clinical exome sequencing. However, in a considerable number of patients, the genetic basis remains unclear. As clinicians begin to consider whole-genome sequencing, an understanding of the processes and tools involved and the factors to consider in the annotation of the structure and function of genomic elements that might influence variant identification is crucial. Here, we discuss and illustrate the strengths and weaknesses of approaches for the annotation and classification of important elements of protein-coding genes, other genomic elements such as pseudogenes and the non-coding genome, comparative-genomic approaches for inferring gene function, and new technologies for aiding genome annotation, as a practical guide for clinicians when considering pathogenic sequence variation. Complete and accurate annotation of structure and function of genome features has the potential to reduce both false-negative (from missing annotation) and false-positive (from incorrect annotation) errors in causal variant identification in exome and genome sequences. Re-analysis of unsolved cases will be necessary as newer technology improves genome annotation, potentially improving the rate of diagnosis. PMID- 28558817 TI - Effects of exercise on brain activity during walking in older adults: a randomized controlled trial. AB - BACKGROUND: Physical activity may preserve neuronal plasticity, increase synapse formation, and cause the release of hormonal factors that promote neurogenesis and neuronal function. Previous studies have reported enhanced neurocognitive function following exercise training. However, the specific cortical regions activated during exercise training remain largely undefined. In this study, we quantitatively and objectively evaluated the effects of exercise on brain activity during walking in healthy older adults. METHODS: A total of 24 elderly women (75-83 years old) were randomly allocated to either an intervention group or a control group. Those in the intervention group attended 3 months of biweekly 90-min sessions focused on aerobic exercise, strength training, and physical therapy. We monitored changes in regional cerebral glucose metabolism during walking in both groups using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). RESULTS: All subjects completed the 3-month experiment and the adherence to the exercise program was 100%. Compared with the control group, the intervention group showed a significantly greater step length in the right foot after 3 months of physical activity. The FDG-PET assessment revealed a significant post-intervention increase in regional glucose metabolism in the left posterior entorhinal cortex, left superior temporal gyrus, and right superior temporopolar area in the intervention group. Interestingly, the control group showed a relative increase in regional glucose metabolism in the left premotor and supplemental motor areas, left and right somatosensory association cortex, and right primary visual cortex after the 3-month period. We found no significant differences in FDG uptake between the intervention and control groups before vs. after the intervention. CONCLUSION: Exercise training increased activity in specific brain regions, such as the precuneus and entorhinal cortices, which play an important role in episodic and spatial memory. Further investigation is required to confirm whether alterations in glucose metabolism within these regions during walking directly promote physical and cognitive performance. TRIAL REGISTRATION: UMIN-CTR ( UMIN000021829 ). Retrospectively registered 10 April 2016. PMID- 28558818 TI - MicroRNA-101a regulates microglial morphology and inflammation. AB - BACKGROUND: Microglia, as well as other tissue-resident macrophages, arise from yolk sac progenitors. Thus, it is likely that the central nervous system environment is critical for the acquisition of a distinct microglial phenotype. Several microRNAs that are enriched in the brain play crucial roles in brain development and may also play a role in the differentiation of microglia. METHODS: To track the differentiation of hematopoietic cells into microglia, lineage-negative bone marrow cells were co-cultured with astrocytes in the absence or presence of microRNAs or their inhibitors. Microglia-like cells were identified as small, round cells that were immunopositive for CD11b, Iba1, CX3CR1, and triggering receptor expressed on myeloid cells (TREM)-2. RESULTS: Five microRNAs (miR-101a, miR-139-3p, miR-214*, miR-218, and miR-1186) were identified as modifiers of the differentiation of bone marrow-derived microglia like cells. Among them, miR-101a facilitated the differentiation of bone marrow cells into microglia-like cells most potently. Small, round cells expressing CD11b, Iba1, CX3CR1, and TREM-2 were predominant in cells treated by miR-101a. miR-101a was abundantly expressed in non-microglial brain cells. Transfection of miR-101a into microglia significantly increased the production of IL-6 in response to LPS. Finally, miR-101a downregulated the expression of MAPK phosphatase-1. CONCLUSIONS: miR-101a, which is enriched in the brain, promotes the differentiation of bone marrow cells into microglia-like cells. PMID- 28558819 TI - Erratum to: Factors associated with hand joint destruction in Chinese patients with rheumatoid arthritis. PMID- 28558820 TI - Patients' views and needs about systemic sclerosis and its management: a qualitative interview study. AB - BACKGROUND: Systemic sclerosis (SSc) is a chronic connective-tissue disease responsible for reduced life expectancy, disability and a decreased quality of life. In order to optimize patients-physicians relationship and care strategy we aimed to survey views of patients on SSc and its management to reveal potential hurdles and improve health care strategies. METHODS: A qualitative study combined semi-structured interviews, focus groups, and a direct observation of an information session was performed between November 2008 and January 2009. RESULTS: Twenty-five patients with SSc were included. They encounter difficulties to have a clear representation of their disease. Physical, psychological, and social repercussions of SSc may lead to a psychological distress and different coping strategies, which widely differ among interviewed patients. Patients' views on their therapeutic journey and the management of their disease highlighted strong expectations about patient-physician relationship. These expectations were numerous, complex and sometimes ambivalent. Patients expected physicians to be human and attentive but also involved in research in the field and to provide psychological and affective support to help them to accept the uncertainty of disease evolution and lack of curative treatment. They also expected more individualized management, improvements in diagnosis and follow-up organization, more efforts in education and information, comprehensive behaviors and support from working colleagues and relatives, and increased funding from the health care system. CONCLUSIONS: Our results suggest that SSc management could be optimized, particularly with more attention to the patient-practitioner relationship. Patient profiles should be more precisely defined in terms of coping strategies and treatment preferences to propose more individualized options. PMID- 28558821 TI - Comparative evaluation of insertion torque and mechanical stability for self tapping and self-drilling orthodontic miniscrews - an in vitro study. AB - BACKGROUND: The aim of the present study was to evaluate the relationship between insertion torque and stability of miniscrews in terms of resistance against dislocation, then comparing a self-tapping screw with a self-drilling one. METHODS: Insertion torque was measured during placement of 30 self-drilling and 31 self-tapping stainless steel miniscrews (Leone SpA, Sesto Fiorentino, Italy) in synthetic bone blocks. Then, an increasing pulling force was applied at an angle of 90 degrees and 45 degrees , and the displacement of the miniscrews was recorded. RESULTS: The statistical analysis showed a statistically significant difference between the mean Maximum Insertion Torque (MIT) observed in the two groups and showed that force angulation and MIT have a statistically significant effect on miniscrews stability. For both the miniscrews, an angle of 90 degrees between miniscrew and loading force is preferable in terms of stability. CONCLUSIONS: The tested self-drilling orthodontic miniscrews showed higher MIT and greater resistance against dislocation than the self-tapping ones. PMID- 28558823 TI - First study conducted in Northern India that identifies group C rotavirus as the etiological agent of severe diarrhea in children in Delhi. AB - BACKGROUND: Group C Rotavirus (RVC) is an enteric pathogen responsible for acute gastroenteritis in children and adults globally. At present there are no surveillance studies on group C Rotaviruses in India and therefore their prevalence in India remains unknown. The present study aimed to evaluate group C rotavirus infection among <5 years old children hospitalized with acute gastroenteritis in New Delhi. METHODS: A total of 350 fecal specimens were collected during September 2013 to November 2014 from <5 years old diarrheal patients admitted at KSCH hospital, Delhi. The samples found negative for group A rotavirus (N = 180) by Enzyme immunoassay were screened for group C rotavirus by RT-PCR with VP6, VP7 and VP4 gene specific primers. The PCR products were further sequenced (VP6, VP7, VP4) and analyzed to ascertain their origin and G and P genotypes. RESULTS: Six out of 180 (group A rotavirus negative) samples were found positive for group C rotavirus by VP6 gene specific RT-PCR, of which 3 were also found positive for VP7 and VP4 genes. Phylogenetic analysis of VP7 and VP4 genes of these showed them to be G4 and P[2] genotypes. Overall, the nucleotide sequence data (VP6, VP7 and VP4) revealed a close relationship with the human group C rotavirus with no evidence of animal ancestry. Interestingly, the nucleotide sequence analysis of various genes also indicated differences in their origin. While the identity matrix of VP4 gene (n = 3) showed high amino acid sequence identity (97.60 to 98.20%) with Korean strain, the VP6 gene (n = 6) showed maximum identity with Nigerian strain (96.40 to 97.60%) and VP7 gene (n = 3) with Bangladeshi and USA strains. This is true for all analyzed samples. CONCLUSION: Our study demonstrated the group C rotavirus as the cause of severe diarrhea in young children in Delhi and provides insights on the origin of group C rotavirus genes among the local strains indicating their source of transmission. Our study also highlights the need for a simple and reliable diagnostic test that can be utilized to determine the disease burden due to group C rotavirus in India. PMID- 28558822 TI - Do outcomes reported in randomised controlled trials of joint replacement surgery fulfil the OMERACT 2.0 Filter? A review of the 2008 and 2013 literature. AB - BACKGROUND: It is not known, whether outcome reporting in trials of total joint arthroplasty in the recent years is adequate or not. Our objective was to assess whether outcomes reported in total joint replacement (TJR) trials fulfil the Outcome Measures in Rheumatology (OMERACT) Filter 2.0. METHODS: We systematically reviewed all TJR trials in adults, published in English in 2008 or 2013. Searches were conducted in the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE. Two authors independently applied the inclusion criteria for the studies, and any disagreement was resolved with a third review author. All outcome measures were abstracted using a pre-piloted standardised data extraction form and assessed for whether they mapped to one of the three OMERACT Filter 2.0 core areas: pathophysiological, life impact, and death. RESULTS: From 1635 trials identified, we included 70 trials (30 in 2008 and 40 in 2013) meeting the eligibility criteria. Twenty-two (31%) trials reported the three essential OMERACT core areas. Among the 27 hip replacement surgery trials and 39 knee replacement surgery trials included, 11 hip (41%) and nine knee (23%) trials reported all three essential OMERACT core areas. The most common outcome domains/measures were pain (20/27, 74%) and function (23/27, 85%) in hip trials and pain (26/39, 67%) and function (27/39, 69%) in knee trials. Results were similar for shoulder and hand joint replacement trials. CONCLUSIONS: We identified significant gaps in the measurement of OMERACT core outcome areas in TJR trials, despite the majority reporting outcome domains of pain and function. An international consensus of key stakeholders is needed to develop a core domain set for reporting of TJR trials. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014009216. PMID- 28558824 TI - The cruciferous Diplotaxis simplex: Phytochemistry analysis and its protective effect on liver and kidney toxicities, and lipid profile disorders in alloxan induced diabetic rats. AB - BACKGROUND: Type 2 diabetes mellitus is a prevalent systemic disease affecting an important proportion of the population worldwide. It has been suggested that excessive reactive oxygen species generation and therefore development of an oxidative stress status is a key factor leading to diabetic complications. Accordingly, it seems that medicinal plants can offer a wide range of new antidiabetic drugs. Diplotaxis simplex (Viv.) Spreng. (Brassicaceae) is an edible plant largely distributed in the Mediterranean region. D. simplex flowers display important in vitro antioxidant potential and inhibitory activity of the alpha glucosidase, a key enzyme linked to type 2 diabetes mellitus. In this paper, the antihyperglycemic potential of D. simplex flowers on diabetic rats were investigated. METHODS: Bioactive substances were determined by liquid chromatography-high resolution electrospray ionization mass spectrometry (LC HRESIMS) analysis. Animals were divided into four groups of six rats each: a normal control group, a diabetic control group, a diabetic group receiving flowers extract (200 mg/kg body mass) and a diabetic group receiving acarbose (10 mg/kg body mass) as standard drug. RESULTS: Many glycosides of rhamnetin, isorhamnetin, quercetin and kaempferol compounds were identified in the ethanolic flowers extract. Alloxan induced hyperglycemia, manifested by a significant (p < 0.05) increase in the blood glucose level as well as in serum alpha-amylase activity. Furthermore, diabetic rats exhibited oxidative stress, as evidenced by a decrease in antioxidant enzymes activities and an increase in lipid peroxidation level of the pancreas, liver and kidneys. Interestingly, the oral administration of D. simplex flowers extract during 30 days restored the glycemia, alpha-amylase activity, serum lipid profile and antioxidant enzymes. Moreover, the flowers extract exhibited a renal protective role by decreasing the urea and creatinine levels in diabetic rats serum. CONCLUSIONS: D. simplex flowers contained bioactive compounds that possess important antioxidant and hypoglycemic properties and protected pancreas, liver and kidneys against hyperglycemia damage. PMID- 28558825 TI - Does an 8-week home-based exercise program affect physical capacity, quality of life, sick leave, and use of psychotropic drugs in patients with pulmonary embolism? Study protocol for a multicenter randomized clinical trial. AB - BACKGROUND: The existing evidence base in pulmonary embolism (PE) is primarily focused on diagnostic methods, medical treatment, and prognosis. Only a few studies have investigated how everyday life is affected by PE, although many patients are negatively affected both physically and emotionally after hospital discharge. Currently, no documented rehabilitation options are available for these patients. We aim to examine whether an 8-week home-based exercise intervention can influence physical capacity, quality of life, sick leave, and use of psychotropic drugs in patients medically treated for PE. METHODS: One hundred forty patients with incident first-time PE will be recruited in five hospitals. After inclusion, patients will be randomly allocated to either the control group, receiving usual care, or the intervention group, who will be exposed to an 8-week home-based exercise program in addition to usual care. The intervention includes an initial individual exercise planning session with a physiotherapist, leading to a recommended exercise program of a minimum of three weekly training sessions of 30-60 minutes' duration. The patients have regular telephone contact with the physiotherapist during the 8-week program. At the time of inclusion, after 2 months, and after 6 months, the patients' physical capacity is measured using the Incremental Shuttle Walk test. Furthermore the patients' quality of life, sick leave, and use of psychotropic drugs is measured using self reported questionnaires. In both randomization arms, all follow-up measurements and visits will take place at the hospital from which the patient was discharged. Levels of eligibility, consent, adherence, and retention will be used as indicators of study feasibility. DISCUSSION: We expect that the home-based exercise program will improve the physical capacity and quality of life for the patients in the intervention group. The study will furthermore contribute significantly to the limited knowledge about the optimal rehabilitation of PE patients, and may thereby form the basis of future recommendations in this field. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02684721 . Registered on 20 January 2016. PMID- 28558826 TI - Critical care at the end of life: a population-level cohort study of cost and outcomes. AB - BACKGROUND: Despite the high cost associated with ICU use at the end of life, very little is known at a population level about the characteristics of users and their end of life experience. In this study, our goal was to characterize decedents who received intensive care near the end of life and examine their overall health care use prior to death. METHODS: This was a retrospective cohort study that examined all deaths in a 3-year period from April 2010 to March 2013 in Ontario, Canada. Using population-based health administrative databases, we examined healthcare use and cost in the last year of life. RESULTS: There were 264,754 individuals included in the study, of whom 18% used the ICU in the last 90 days of life; 34.5% of these ICU users were older than 80 years of age and 53.0% had more than five chronic conditions. The average cost of stay for these decedents was CA$15,511 to CA$25,526 greater than for those who were not admitted to the ICU. These individuals also died more frequently in hospital (88.7% vs 36.2%), and spent more time in acute-care settings (18.7 days vs. 10.5 days). CONCLUSIONS: We showed at a population level that a significant proportion of those with ICU use close to death are older, multi-morbid individuals who incur significantly greater costs and die largely in hospital, with higher rates of readmission, longer lengths of stay and higher rates of aggressive care. PMID- 28558827 TI - Early anti-inflammatory intervention ameliorates axial disease in the proteoglycan-induced spondylitis mouse model of ankylosing spondylitis. AB - BACKGROUND: Ankylosing spondylitis (AS) is characterised by immune-mediated arthritis and osteoproliferation, ultimately leading to joint ankylosis. Whether inflammation is necessary for osteoproliferation is controversial, fuelled by the unclear efficacy of anti-inflammatory treatments on radiographic progression. In proteoglycan-induced spondylitis (PGISp), a mouse model of AS, inflammation is the prerequisite for osteoproliferation as osteoproliferation was only observed following inflammation-driven intervertebral disc (IVD) destruction. We hypothesised that early intervention with a potent anti-inflammatory therapy would protect IVD integrity and consequently alter disease progression. METHODS: PGISp mice received vehicle or a combination of etanercept (ETN) plus prednisolone (PRD) therapy for 2 or 6 weeks initiated at an early disease stage. Peripheral arthritis was scored longitudinally. Spinal disease was assessed using a semi-quantitative histological scoring regimen including inflammation, joint destruction and excessive tissue formation. RESULTS: ETN + PRD therapy significantly delayed the onset of peripheral arthritis. IVD integrity was significantly protected when treatment was commenced in early disease. Six-weeks of treatment resulted in trends towards reductions in intervertebral joint damage and excessive tissue formation. IVD score distribution was dichotomized, likely reflecting the extent of axial disease at initiation of therapy. In the sub-group of mice with high IVD destruction scores, ETN + PRD treatment significantly reduced IVD destruction severity, inflammation and bone erosion and reduced cartilage damage and excessive tissue formation. CONCLUSIONS: Early intervention with anti-inflammatory treatment not only improved inflammatory symptoms but also ameliorated structural damage of spine in PGISp mice. This preclinical observation suggests that early anti-inflammatory intervention may slow radiographic progression in AS patients. PMID- 28558828 TI - Eprinomectin pour-on (EPRINEX(r) Pour-on, Merial): efficacy against gastrointestinal and pulmonary nematodes and pharmacokinetics in sheep. AB - BACKGROUND: The anthelmintic efficacy of the 0.5% w/v topical formulation of eprinomectin (EPN), EPRINEX(r) Pour-on (Merial) when administered at 1 mg/kg body weight was evaluated in sheep in two dose confirmation laboratory studies and one multicenter field study. In addition, the pharmacokinetics of EPN when administered at that dosage to adult sheep was determined. RESULTS: In the two dose confirmation studies, which included 10 sheep each, sheep treated with topical EPN had significantly (p < 0.05) fewer of the following nematodes than the untreated sheep with overall reduction of nematode counts by >99%: adult Dictyocaulus filaria, Haemonchus contortus, Teladorsagia circumcincta(pinnata/trifurcata), Trichostrongylus axei, T. colubriformis, T. vitrinus, Cooperia curticei, Nematodirus battus, Strongyloides papillosus, Chabertia ovina and Oesophagostomum venulosum, and inhibited fourth-stage Teladorsagia larvae. A total of 196 sheep harboring naturally acquired gastrointestinal nematode infections were included in the field efficacy study at two sites each in Germany (48 Merino x Ile de France lambs, 52 adult Merino females) and in Italy (adult male and female Bagnolese, Lacaune, Lacaune x Bagnolese, Bagnolese x Sarda sheep; 48 animals per site). Animals were blocked on pre-treatment body weight and within each block, one animal was randomly assigned to the control (untreated) group and three animals were randomly assigned to be treated with topical EPN. Examination of feces 14 days after treatment demonstrated that, relative to the controls, topical EPN-treated sheep had significantly (p < 0.0001) lower strongylid egg counts. Reduction was >=97% at each site and 98.6% across all sites. Pharmacokinetics of EPN following single treatment with topical EPN were determined in eight ~4.5 year old female Merino cross sheep based on the analysis of plasma samples which were collected from two hours to 21 days following treatment. The main pharmacokinetic parameters were: Cmax 6.20 +/- 1.71 ng/mL, AUClast 48.8 +/- 19.2 day*ng/mL, Tmax 3.13 +/- 2.99 days and T1/2 6.40 +/- 2.95 days. No treatment-related health problems or adverse drug events were observed in any study. CONCLUSION: These studies demonstrated 0.5% w/v EPN administered topically at 1 mg/kg body weight to be highly efficacious against a broad range of ovine gastrointestinal nematodes and D. filaria lungworms and well tolerated by sheep of different ages, breeds, gender and physiological status. PMID- 28558829 TI - Which bronchodilator reversibility criteria can predict severe acute exacerbation in chronic obstructive pulmonary disease patients? AB - BACKGROUND: It is unclear whether various bronchodilator reversibility (BDR) criteria affect the prognosis of chronic obstructive pulmonary disease (COPD). The aim of this study is to evaluate the impact of positive BDR defined according to various BDR criteria on the risk of severe acute exacerbation (AE) in COPD patients. METHODS: Patients from four prospective COPD cohorts in South Korea who underwent follow-up for at least 1 year were enrolled in this study. The assessed BDR criteria included the Global Initiative for Chronic Obstructive Lung Disease (GOLD), American Thoracic Society (ATS), American College of Chest Physicians, (ACCP), major criteria of the Spanish definition of asthma-COPD overlap syndrome (ACOS), criteria compatible with ACOS in the Global Initiative for Asthma (GINA), and European Respiratory Society (ERS). The rate of patients with severe AE who required hospitalization within 1 year due to BDR results according to each set of criteria was analyzed using logistic regression models. RESULTS: Among a total of 854 patients, the BDR-positive cases varied according to the criteria used. There was a 3.5% positive BDR rate according to GINA and a 29.9% rate according to the ATS criteria. Positive BDR according to the GOLD criteria was significantly associated with a decreased risk of severe AE (adjusted odds ratio (aOR) = 0.38; 95% Confidence interval (CI) = 0.15-0.93). This result remained statistically significant even in a sensitivity analysis that included only participants with a smoking history of at least 10 pack-years and in the analysis for the propensity score-matched participants. CONCLUSIONS: Among different criteria for positive BDR, the use of the GOLD ones was significantly associated with a decreased risk of severe AE in COPD patients. Increase use of ICS/LABA may have affected this relationship. PMID- 28558831 TI - Genetic diversity of Glossina fuscipes fuscipes along the shores of Lake Victoria in Tanzania and Kenya: implications for management. AB - BACKGROUND: Tsetse flies (Diptera: Glossinidae) are sole vectors for trypanosomiasis, which affect human health and livestock productivity in Africa. Little is known about the genetic diversity of Glossina fuscipes fuscipes, which is an important species in Tanzania and Kenya. The main objective of the study was to provide baseline data to determine the genetic variability and divergence of G. f. fuscipes in the Lake Victoria basin of Tanzania and Kenya in order to guide future vector control efforts in the region. FINDINGS: Two hundred and seventy five G. f. fuscipes from 8 sites along the shores of Lake Victoria were screened for genetic polymorphisms at 19 microsatellite loci. Samples were collected from two sites in Kenya and six sites in Tanzania. Four of the Tanzanian sites were located in the Rorya district, on the eastern shores of Lake Victoria, while the other two sites were from Ukerewe and Bukoba districts from the southern and western Lake Victoria shores, respectively. Four genetically distinct allopatric clusters were revealed by microsatellite analysis, which sorted the sampling sites according to geography, with sites separated by as little as ~65 km belonging to distinct genetic clusters, while samples located within ~35 km from each other group in the same cluster. CONCLUSION: Our results suggest that there is ongoing genetic admixture within sampling sites located ~35 km from each other, while sites located ~65 km apart are genetically isolated from each other. Similar patterns emerged from a parallel study on G. f. fuscipes analyzed from the Lake Victoria Uganda shores. From a control perspective these results suggest that for sites within the same genetic cluster, control efforts should be carried out in a coordinated fashion in order to avoid re-invasions. Future work should focus on better quantifying the extent and spatial patterns of the observed genetic discontinuities of the G. f. fuscipes populations along the Tanzanian shores. This will aid in their control by providing guidelines on the geographical extent of the area to be treated at the same time. PMID- 28558832 TI - In vitro quality evaluation of leading brands of ciprofloxacin tablets available in Bangladesh. AB - BACKGROUND: Ciprofloxacin is a broad-spectrum antibiotic that acts against a number of bacterial infections. The study was carried out to examine the in vitro quality control tests for ten leading brands of ciprofloxacin hydrochloride 500 mg tablet formulation, registered in Bangladesh by Directorate General of Drug Administration. The quality control parameters of ten different brands of ciprofloxacin hydrochloride 500 mg tablets were determined by weight variation, friability, hardness, disintegration, dissolution and assay tests. All the tablets were evaluated for conformity with United States Pharmacopoeia-National Formulary (USP-NF) and British Pharmacopoeia (BP) standards. RESULTS: Among ten brands of tablets Brand C had lower mean weight variation of 1.59% and Brand E had highest mean weight variation of 3.32%. For friability test Brand F had lowest mean friability (0.27%) and Brand G had highest mean friability (0.54%). Among ten brands mean lowest and highest hardness were founded in Brand G (4.49 kg/cm2) and Brand F (7.13 kg/cm2) respectively. The disintegration time for ten brands of ciprofloxacin tablet obtained were in the subsequent order: Brand G (8.19 min) < Brand C (9.25 min) < Brand E (9.61 min) < Brand D (10.11 min) < Brand B (11.07 min) < Brand A (12.15 min) < Brand H (13.68 min) < Brand I (14.59 min) < Brand J (16.32 min) < Brand F (17.49 min). Among ten brands for dissolution test mean percentages of drug release were not less than 80% in 45 min for four tablets (Brand E, 81.52%; Brand D, 86.44%; Brand G, 86.82% and Brand C, 94.12%), consequently they met BP standard and as per USP-NF standard six brands (Brand B, 75.62%; Brand A, 76.18%; Brand E, 81.52%; Brand D, 86.44%; Brand G, 86.82% and Brand C, 94.12%) had released not less than 75% drugs, so they also complied with the standard. The percentages of the drug content of the ten brands of ciprofloxacin tablet were obtained in the following sequence: Brand H (96.84%) < Brand J (97.34%) < Brand D (98.15%) < Brand I (98.47%) < Brand E (99.37%) < Brand F (100.28%) < Brand B (100.38%) < Brand A (100.54%) < Brand G (101.39%) < Brand C (101.46%). All of the brands met the BP and USP-NF specifications for assay. First-order, Higuchi and Korsmeyer-Peppas kinetics model fit for all of the mentioned ten brands. CONCLUSION: The present study revealed that all of the leading brands of this tablet met the quality control parameters as per pharmacopoeial specifications except dissolution test for four brands (Brand J, Brand H, Brand I, and Brand F). PMID- 28558830 TI - LincIN, a novel NF90-binding long non-coding RNA, is overexpressed in advanced breast tumors and involved in metastasis. AB - BACKGROUND: Recent genome-wide profiling by sequencing and distinctive chromatin signatures has identified thousands of long non-coding RNA (lncRNA) species (>200 nt). LncRNAs have emerged as important regulators of gene expression, involving in both developmental and pathological processes. While altered expression of lncRNAs has been observed in breast cancer development, their roles in breast cancer progression and metastasis are still poorly understood. METHODS: To identify novel breast cancer-associated lncRNA candidates, we employed a high density SNP array-based approach to uncover intergenic lncRNA genes that are aberrantly expressed in breast cancer. We first evaluated the potential value as a breast cancer prognostic biomarker for one breast cancer-associated lncRNA, LincIN, using a breast cancer cohort retrieved from The Cancer Genome Atlas (TCGA) Data Portal. Then we characterized the role of LincIN in breast cancer progression and metastasis by in vitro invasion assay and a mouse tail vein injection metastasis model. To study the action of LincIN, we identified LincIN interacting protein partner(s) by RNA pull-down experiments followed with protein identification by mass spectrometry. RESULTS: High levels of LincIN expression are frequently observed in tumors compared to adjacent normal tissues, and are strongly associated with aggressive breast cancer. Importantly, analysis of TCGA data further suggest that high expression of LincIN is associated with poor overall survival in patients with breast cancer (P = 0.044 and P = 0.011 after adjustment for age). The functional experiments demonstrate that knockdown of LincIN inhibits tumor cell migration and invasion in vitro, which is supported by the results of transcriptome analysis in the LincIN-knockdown cells. Furthermore, knockdown of LincIN diminishes lung metastasis in a mouse tail vein injection model. We also identified a LincIN-binding protein, NF90, through which overexpression of LincIN may repress p21 protein expression by inhibiting its translation, and upregulation of p21 by LincIN knockdown may be associated with less aggressive metastasis phenotypes. CONCLUSIONS: Our studies provide clear evidence to support LincIN as a new regulator of tumor progression-metastasis at both transcriptional and translational levels and as a promising prognostic biomarker for breast cancer. PMID- 28558833 TI - Reduction in clinically important deterioration in chronic obstructive pulmonary disease with aclidinium/formoterol. AB - BACKGROUND: 'Clinically important deterioration' (CID) is a composite endpoint measuring worsening of the key clinical features of chronic obstructive pulmonary disease (COPD), namely lung function, patient-reported outcomes, and exacerbations. ACLIFORM and AUGMENT were two 24-week, randomized, double-blind, phase III studies assessing twice-daily (BID) aclidinium bromide (AB) 400 MUg/formoterol fumarate (FF) 12 MUg. This pooled post-hoc analysis assessed the effects of AB/FF 400/12 MUg on both first and sustained CID events versus placebo and monotherapies in patients with moderate to severe COPD. METHODS: A first CID event was defined as the occurrence of a moderate/severe exacerbation or the worsening from baseline in >=1 of the following: trough forced expiratory volume in 1 second (FEV1; >=100 mL), Transition Dyspnea Index (TDI) focal score (>=1 unit), or St George's Respiratory Questionnaire (SGRQ) total score (>=4 units). A 'sustained' CID was defined as a worsening maintained at all subsequent visits from appearance to week 24 or a moderate/severe exacerbation at any time. CID events were assessed at three visits (weeks 4, 12, and 24); trough FEV1 was also measured at weeks 1 and 18. RESULTS: AB/FF 400/12 MUg reduced the risk of a first CID event by 45% versus placebo (hazard ratio [HR] 0.55, p < 0.001), 18% versus FF 12 MUg (HR 0.82, p < 0.01), and 15% versus AB 400 MUg (HR 0.85, p < 0.05). Similarly, AB/FF 400/12 MUg reduced the risk of a sustained CID event by 48% versus placebo (HR 0.52, p < 0.001) and 22% versus FF 12 MUg (HR 0.78, p < 0.01). AB/FF 400/12 MUg reduced the risk of a first or sustained CID event for all four components versus placebo (trough FEV1 and TDI, first and sustained CID, all p < 0.001; SGRQ first CID p < 0.001; SGRQ sustained CID, p < 0.01; exacerbations first and sustained CID, both p < 0.05) and TDI and SGRQ versus FF 12 MUg (TDI, first and sustained CID both p < 0.05; SGRQ first CID p < 0.01), and SGRQ versus AB 400 MUg (first CID, p < 0.05). CONCLUSIONS: AB/FF 400/12 MUg BID may provide greater airway stability and fewer exacerbations or deteriorations in lung function, health status, or dyspnea compared with placebo or monotherapies. TRIAL REGISTRATION: Clinicaltrials.gov NCT01462942 (ACLIFORM); registered 26 October 2011. Clinicaltrials.gov NCT01437397 (AUGMENT); registered 19 September 2011. PMID- 28558834 TI - Erratum to: Metazoan parasite communities: support for the biological invasion of Barbus barbus and its hybridization with the endemic Barbus meridionalis. PMID- 28558835 TI - A muscle-driven approach to restore stepping with an exoskeleton for individuals with paraplegia. AB - BACKGROUND: Functional neuromuscular stimulation, lower limb orthosis, powered lower limb exoskeleton, and hybrid neuroprosthesis (HNP) technologies can restore stepping in individuals with paraplegia due to spinal cord injury (SCI). However, a self-contained muscle-driven controllable exoskeleton approach based on an implanted neural stimulator to restore walking has not been previously demonstrated, which could potentially result in system use outside the laboratory and viable for long term use or clinical testing. In this work, we designed and evaluated an untethered muscle-driven controllable exoskeleton to restore stepping in three individuals with paralysis from SCI. METHODS: The self contained HNP combined neural stimulation to activate the paralyzed muscles and generate joint torques for limb movements with a controllable lower limb exoskeleton to stabilize and support the user. An onboard controller processed exoskeleton sensor signals, determined appropriate exoskeletal constraints and stimulation commands for a finite state machine (FSM), and transmitted data over Bluetooth to an off-board computer for real-time monitoring and data recording. The FSM coordinated stimulation and exoskeletal constraints to enable functions, selected with a wireless finger switch user interface, for standing up, standing, stepping, or sitting down. In the stepping function, the FSM used a sensor-based gait event detector to determine transitions between gait phases of double stance, early swing, late swing, and weight acceptance. RESULTS: The HNP restored stepping in three individuals with motor complete paralysis due to SCI. The controller appropriately coordinated stimulation and exoskeletal constraints using the sensor-based FSM for subjects with different stimulation systems. The average range of motion at hip and knee joints during walking were 8.5 degrees 20.8 degrees and 14.0 degrees -43.6 degrees , respectively. Walking speeds varied from 0.03 to 0.06 m/s, and cadences from 10 to 20 steps/min. CONCLUSIONS: A self-contained muscle-driven exoskeleton was a feasible intervention to restore stepping in individuals with paraplegia due to SCI. The untethered hybrid system was capable of adjusting to different individuals' needs to appropriately coordinate exoskeletal constraints with muscle activation using a sensor-driven FSM for stepping. Further improvements for out-of-the-laboratory use should include implantation of plantar flexor muscles to improve walking speed and power assist as needed at the hips and knees to maintain walking as muscles fatigue. PMID- 28558836 TI - Extraction of a specimen through an umbilical zigzag incision during laparoscopic surgery for endometrial cancer. AB - BACKGROUND: Though laparoscopic surgery has recently been applied in the treatment of early-stage endometrial cancer, the presence of a large uterus is a hindrance to specimen extraction from the abdominal cavity. We describe a laparoscopic surgical technique for endometrial cancer involving the extraction of the resected specimen through an umbilical zigzag incision. CASE PRESENTATION: A 63-year-old woman with endometrial cancer underwent a total hysterectomy and bilateral salpingo-oophorectomy that was performed laparoscopically. The surgical specimen was extracted through an umbilical zigzag incision. This umbilical zigzag incision created a larger fascial and peritoneal opening, facilitating the removal of the specimen. The final histopathologic results revealed stage 1A G1 endometrioid adenocarcinoma and multiple uterine leiomyomas. Three months after surgery, the wound in the umbilical region was inconspicuous, along with the inward movement of the umbilicus. CONCLUSIONS: A laparoscopic surgical technique for endometrial cancer involving the extraction of the specimen through an umbilical zigzag incision seems to reduce the difficulties associated with laparoscopic surgery and maintains cosmesis. Further analyses involving larger numbers of cases and long-term follow-up periods are warranted to evaluate this surgical method. PMID- 28558837 TI - Long-term clinical outcomes following treatment with alpha 1-proteinase inhibitor for COPD associated with alpha-1 antitrypsin deficiency: a look at the evidence. AB - Alpha-1 antitrypsin deficiency (AATD) is a common hereditary disorder caused by mutations in the SERPINA1 gene, which encodes alpha-1 antitrypsin (AAT; also known as alpha 1-proteinase inhibitor, A1-PI). An important function of A1-PI in the lung is to inhibit neutrophil elastase, one of various proteolytic enzymes released by activated neutrophils during inflammation. Absence or deficiency of A1-PI leads to an imbalance between elastase and anti-elastase activity, which results in progressive, irreversible destruction of lung tissue, and ultimately the development of chronic obstructive pulmonary disease with early-onset emphysema. AATD is under-diagnosed, patients can experience long delays before obtaining an accurate diagnosis, and the consequences of delayed diagnosis or misdiagnosis can be severe. Currently, A1-PI therapy is the only available treatment that addresses disease etiology in patients with AATD; however, demonstrating clinical efficacy of A1-PI therapy is challenging. In order to show therapeutic efficacy with traditional endpoints such as forced expiratory volume in one second and mortality, large sample sizes and longer duration trials are required. However, AATD is a rare, slow progressive disease, which can take decades to manifest clinically and recruiting sufficient numbers of patients into prolonged placebo-controlled trials remains a significant obstacle. Despite this, the Randomized, placebo-controlled trial of augmentation therapy in Alpha 1 Proteinase Inhibitor Deficiency (RAPID) and RAPID Extension trial, the largest clinical program completed to date, utilized quantitative chest computed tomography as a sensitive and specific measure of the extent of emphysema. Findings from the RAPID/RAPID Extension program definitively confirmed the benefits of A1-PI therapy in slowing disease progression and provided evidence of a disease-modifying effect of A1-PI therapy in patients with AATD. These findings suggest that the early introduction of treatment in patients with severe emphysema-related AATD may delay the time to death, lung transplantation or crippling respiratory complaints. In addition, there is now limited evidence that A1-PI therapy provides a gain of more than five life-years, supporting previous observations based on registry data. With the clinical efficacy of A1-PI therapy now demonstrated, further studies are required to assess long-term outcomes. PMID- 28558838 TI - Towards understanding the drivers of policy change: a case study of infection control policies for multi-drug resistant tuberculosis in South Africa. AB - BACKGROUND: Explaining policy change is one of the central tasks of contemporary policy analysis. In this article, we examine the changes in infection control policies for multi-drug resistant tuberculosis (MDR-TB) in South Africa from the time the country made the transition to democracy in 1994, until 2015. We focus on MDR-TB infection control and refer to decentralised management as a form of infection control. Using Kingdon's theoretical framework of policy streams, we explore the temporal ordering of policy framework changes. We also consider the role of research in motivating policy changes. METHODS: Policy documents addressing MDR-TB in South Africa over the period 1994 to 2014 were extracted. Literature on MDR-TB infection control in South Africa was extracted from PubMed using key search terms. The documents were analysed to identify the changes that occurred and the factors driving them. RESULTS: During the period under study, five different policy frameworks were implemented. The policies were meant to address the overwhelming challenge of MDR-TB in South Africa, contextualised by high prevalence of HIV infection, that threatened to undermine public health programmes and the success of antiretroviral therapy rollouts. Policy changes in MDR-TB infection control were supported by research evidence and driven by the high incidence and complexity of the disease, increasing levels of dissatisfaction among patients, challenges of physical, human and financial resources in public hospitals, and the ideologies of the political leadership. Activists and people living with HIV played an important role in highlighting the importance of MDR-TB as well as exerting pressure on policymakers, while the mass media drew public attention to infection control as both a cause of and a solution to MDR-TB. CONCLUSION: The critical factors for policy change for infection control of MDR-TB in South Africa were rooted in the socioeconomic and political environment, were supported by extensive research, and can be framed using Kingdon's policy streams approach as an interplay of the problem of the disease, political forces that prevailed and alternative proposals. PMID- 28558839 TI - NLRP3 inflammasome activation in murine macrophages caused by Neospora caninum infection. AB - BACKGROUND: Neospora caninum is an intracellular parasite that causes significant economic losses in cattle industry. Understanding the host resistance mechanisms in the innate immune response to neosporosis could facilitate the exploration of approaches for controlling N. caninum infection. The NLR inflammasome is a multiprotein platform in the cell cytoplasm and plays critical roles in the host response against microbes. METHODS: Neospora caninum-infected wild-type (WT) macrophages and Nlrp3 -/- macrophages, and inhibitory approaches were used to investigate inflammasome activation and its role in N. caninum infection. Inflammasome RT Profiler PCR Arrays were used to identify the primary genes involved in N. caninum infection. The expression of the sensor protein NLRP3, processing of caspase-1, secretion of IL-1beta and cell death were detected. Neospora caninum replication in macrophages was also assessed. RESULTS: Many NLR molecules participated in the recognition of N. caninum, especially the sensor protein NLRP3, and further study revealed that the NLRP3 distribution became punctate in the cell cytoplasm, which facilitated inflammasome activation. Inflammasome activation-mediated caspase-1 processing and IL-1beta cleavage in response to N. caninum infection were observed and were correlated with the time of infection and number of infecting parasites. LDH-related cell death was also observed, and this death was regarded as beneficial for the clearance of N. caninum. Treatment of N. caninum-infected macrophages with caspase-1, pan-caspase and NLRP3 inhibitors led to the impaired release of active IL-1beta and a failure to restrict parasite replication. And Neospora caninum infected peritoneal macrophages from Nlrp3-deficient mice displayed greatly decreased release of active IL-1beta and the failure of caspase-1 cleavage. CONCLUSIONS: The NLRP3 inflammasome can be activated in N. caninum-infected macrophages, and plays a protective role in the host response to control N. caninum. PMID- 28558840 TI - Health professionals' job satisfaction and associated factors at public health centers in West Ethiopia. AB - BACKGROUND: Human resources are vital for delivering health services, and health systems cannot function effectively without sufficient numbers of skilled, motivated, and well-supported health workers. Job satisfaction of health workers is important for motivation and efficiency, as higher job satisfaction improves both employee performance and patient satisfaction. Even though several studies have addressed job satisfaction among healthcare professionals in different part of the world, there are relatively few studies on healthcare professionals' job satisfaction in Ethiopia. METHODS: A facility-based cross-sectional study was conducted among health professionals working in health centers in April 2015 using self-administered structured questionnaires. All 322 health professionals working in 23 randomly selected public health centers were included. Factor scores were computed for the identified items by varimax rotation to represent satisfaction. Multivariate linear regression analysis was performed, and the effect of independent variables on the regression factor score quantified. RESULTS: Three hundred eight respondents participated with a response rate of 95.56%. The overall level of job satisfaction was 41.46%. Compensation (benefits) (beta 0.448 [95% CI 0.341 to 0.554]), recognition by management (beta 0.132 [95% CI 0.035 to 0.228]), and opportunity for development (beta 0.123 [95% CI 0.020 to 0.226]) were associated with job satisfaction. A unit increase in salary and incentives and recognition by management scores resulted in 0.459 (95% CI 0.356 to 0.561) and 0.156 (95% CI 0.065 to 0.247) unit increases in job satisfaction scores, respectively. CONCLUSIONS: The overall level of job satisfaction in health professionals was low. Salary and incentives, recognition by management, developmental opportunities, and patient appreciation were strong predictors of job satisfaction. PMID- 28558841 TI - Physical pain is common and associated with nonmedical prescription opioid use among people who inject drugs. AB - BACKGROUND: People who inject drugs (PWID) often have poor health and lack access to health care. The aim of this study was to examine whether PWID engage in self treatment through nonmedical prescription opioid use (NMPOU). We describe the prevalence and features of self-reported physical pain and its association with NMPOU. METHODS: PWID (N = 702) in San Francisco, California (age 18+) were recruited to complete interviewer administered surveys between 2011 and 2013. Multivariate logistic regression analysis was conducted to examine the associations among self-reported pain dimensions (past 24-h average pain, pain interference with functional domains) and NMPOU, controlling for age, sex, psychiatric illness, opioid substitution treatment, homelessness, street heroin use and unmet healthcare needs. RESULTS: Almost half of the sample reported pain, based on self-reported measures in the 24 h before their interview. The most common pain locations were to their back and lower extremities. Past 24-h NMPOU was common (14.7%) and associated with past 24 h average pain intensity on a 10 point self-rating scale (adjusted odds ratio [AOR] = 2.15, 95% confidence interval [CI] 1.21-3.80), and past 24 h pain interference with general activity (AOR 1.82 [95% CI 1.04-3.21]), walking ability (AOR 2.52 [95% CI 1.37-4.63]), physical ability (AOR 2.01 [95% CI 1.16-3.45]), sleep (AOR 1.98 [95% CI 1.13 3.48]) and enjoyment of life (AOR 1.79 [95% CI 1.02-3.15]). CONCLUSION: Both pain and NMPOU are common among PWID, and highly correlated in this study. These findings suggest that greater efforts are needed to direct preventive health and services toward this population. PMID- 28558842 TI - Natriuretic peptides improve the developmental competence of in vitro cultured porcine oocytes. AB - BACKGROUND: Natriuretic peptides (NPs), brain and C type NPs (BNP and CNP), were involved in the maintenance of porcine oocyte meiotic arrest. The present study investigated the effects of NPs on developmental competence of immature porcine oocytes with follicles of different sizes. METHODS: Follicular fluid NP levels were examined by radioimmunoassay. The developmental competence of porcine oocytes was evaluated by cleavage and blastocyst developmental rates after in vitro fertilization (IVF) or parthenogenetic activation (PA) of cumulus oocyte complexes (COCs), which were recovered from follicle with different sizes. NP levels were examined and classified according to the cleavage potential after IVF with COCs released from these follicles. RESULTS: The BNP and CNP concentrations were increased with follicular size in follicular fluid and sustained at the set ranges of 3.0 - 6.0 mm follicles compared to 6.1 - 8.0 mm follicles. The oocytes developed from 3.0 to 6.0 mm follicles demonstrated increased embryo cleavage and blastocyst ratios after IVF, with an increased follicle size (P < 0.05). Moreover, BNP and CNP significantly promoted the blastocyst developmental rates of 3.0 - 6.0 mm follicles, but could not improve the developmental competence of oocytes from 6.1 to 8.0 mm follicles due to low NP levels. The COCs from 3.0 to 4.0 mm follicles were pre-incubated in 100 ng/ml of BNP and CNP media for 20 h before regular in vitro maturation, which demonstrated 2 to 3 folds higher developmental competencies in both PA and IVF groups compared to respective controls (P < 0.01). CONCLUSIONS: The effects of BNP and CNP supplementation in the pre-maturation culture media (PMC) on porcine developmental competence from COCs in follicles of different sizes were different and improved the developmental competence of porcine oocytes from small antral follicle in vitro. PMID- 28558843 TI - The effectiveness of a de-implementation strategy to reduce low-value blood management techniques in primary hip and knee arthroplasty: a pragmatic cluster randomized controlled trial. AB - BACKGROUND: Perioperative autologous blood salvage and preoperative erythropoietin are not (cost) effective to reduce allogeneic transfusion in primary hip and knee arthroplasty, but are still used. This study aimed to evaluate the effectiveness of a theoretically informed multifaceted strategy to de-implement these low-value blood management techniques. METHODS: Twenty-one Dutch hospitals participated in this pragmatic cluster-randomized trial. At baseline, data were gathered for 924 patients from 10 intervention and 1040 patients from 11 control hospitals undergoing hip or knee arthroplasty. The intervention included a multifaceted de-implementation strategy which consisted of interactive education, feedback on blood management performance, and a comparison with benchmark hospitals, aimed at orthopedic surgeons and anesthesiologists. After the intervention, data were gathered for 997 patients from the intervention and 1096 patients from the control hospitals. The randomization outcome was revealed after the baseline measurement. Primary outcomes were use of blood salvage and erythropoietin. Secondary outcomes included postoperative hemoglobin, length of stay, allogeneic transfusions, and use of local infiltration analgesia (LIA) and tranexamic acid (TXA). RESULTS: The use of blood salvage (OR 0.08, 95% CI 0.02 to 0.30) and erythropoietin (OR 0.30, 95% CI 0.09 to 0.97) reduced significantly over time, but did not differ between intervention and control hospitals (blood salvage OR 1.74 95% CI 0.27 to 11.39, erythropoietin OR 1.33, 95% CI 0.26 to 6.84). Postoperative hemoglobin levels were significantly higher (beta 0.21, 95% CI 0.08 to 0.34) and length of stay shorter (beta -0.36, 95% CI -0.64 to -0.09) in hospitals receiving the multifaceted strategy, compared with control hospitals and after adjustment for baseline. Transfusions did not differ between the intervention and control hospitals (OR 1.06, 95% CI 0.63 to 1.78). Both LIA (OR 0.0, 95% CI 0.0 to 0.0) and TXA (OR 0.3, 95% CI 0.2 to 0.5) were significantly associated with the reduction in blood salvage over time. CONCLUSIONS: Blood salvage and erythropoietin use reduced over time, but not differently between intervention and control hospitals. The reduction in blood salvage was associated with increased use of local infiltration analgesia and tranexamic acid, suggesting that de-implementation is assisted by the substitution of techniques. The reduction in blood salvage and erythropoietin did not lead to a deterioration in patient-related secondary outcomes. TRIAL REGISTRATION: www.trialregister.nl, NTR4044. PMID- 28558844 TI - Radiation-related lymphopenia is associated with spleen irradiation dose during radiotherapy in patients with hepatocellular carcinoma. AB - BACKGROUND: The decrease in peripheral blood lymphocytes induced by radiation lessens the antitumour effect of the immune response, which might cause immunosuppression. We aimed to investigate the correlation between the decrease in peripheral blood lymphocytes during radiotherapy (RT) and the spleen irradiation dose in patients with hepatocellular carcinoma (HCC). METHODS: The subjects were 59 patients with HCC who had received RT from 2005 to 2014. The Min ALC (minimum value of absolute counts for peripheral blood lymphocytes) was collected from the routine workup for each patient prior to RT and weekly during RT. Spleen dose-volume variables, including the percentage of the organ volume receiving >= n Gy (Vn) and the mean spleen dose (MSD), were calculated using Eclipse treatment planning. Potential associations between dosimetric variables and the Min ALC were assessed by multiple linear regression analysis. RESULTS: Peripheral lymphocytes decreased during RT (P < 0.001). The Min ALC correlated with the MSD (P = 0.005), spleen V5 (P = 0.001), spleen V25 (P = 0.026) and spleen V30 (P = 0.018). Controlling for the Karnofsky performance status (KPS), sex, age, Child-Pugh grade, total dose and tumour stage, a multiple linear regression model with bootstrap analysis of 1000 replicates showed that only the spleen V5 was correlated with the decrease in the Min ALC (P < 0.05). According to the receiver-operating characteristic (ROC) curve analysis, the predictive cutoff values of the MSD, V5, V25 and V30 of the spleen for the Min ALC were 227.72 cGy, 17.84, 0.98 and 0.42%, respectively (P = 0.002, P = 0.004, P = 0.007 and P = 0.002, respectively). Furthermore, an MSD >= 227.72 cGy (OR = 14.39; 95% CI, 12.18 to 16.60) and V5 (OR = 7.99; 95% CI, 6.91 to 9.07) of the spleen significantly predicted the Min ALC. CONCLUSIONS: Higher spleen irradiation doses were significantly correlated with lower Min ALC during RT for HCC. V5 should be limited in clinical practice. Maximum sparing for spleen irradiation during RT is recommended to preserve peripheral blood lymphocytes, which may decrease immunosuppression. PMID- 28558845 TI - Metformin is not associated with lactic acidosis in patients with diabetes undergoing coronary artery bypass graft surgery: a case control study. AB - BACKGROUND: Metformin associated lactic acidosis (MALA) is a rare but lethal complication. There is no consensus regarding when to stop and resume metformin in patients who undergo coronary artery bypass grafting (CABG). This study aimed to determine if uninterrupted metformin administration in patients with diabetes undergoing CABG increases the risk of lactic acidosis. METHODS: Over a span of 12 months (2015-2016), 127 patients with type 2 diabetes underwent isolated CABG. Of those, 41 patients (32%) continued taking metformin and 86 patients (68%) took other antidiabetic agents. Patients taking metformin took the drug until the day of surgery and resumed taking it 3 h after extubation. RESULTS: There were no differences in clinical outcomes or complications between groups. Serial measurement of cardiac, liver, and kidney biomarkers were similar between groups. The mean peak lactic acid level was significantly higher in the non-metformin users (5.4 +/- 2.6 vs. 7.4 +/- 4.1 mmol/l; P = 0.001). Multivariable logistic regression analysis identified the need for vasopressor administration as an independent predictor of lactic acidosis (odds ratio: 7.3, 95% confidence interval: 2.5-20.6; P < 0.001). CONCLUSION: In the absence of risk factors associated with persistent lactic acidosis, such as shock or acute kidney or liver injury, continued peri-operative metformin administration was not associated with the occurrence of lactic acidosis in patients undergoing CABG. Elevated lactic acid levels seem to be directly related to tissue anoxia caused by escalating vasopressor support after surgery. PMID- 28558846 TI - Perioperative antibiotics in pediatric cardiac surgery: protocol for a systematic review. AB - BACKGROUND: Post-operative infections in pediatric cardiac surgery are an ongoing clinical challenge, with rates between 1 and 20%. Perioperative antibiotics remain the standard for prevention of surgical-site infections, but the type of antibiotic and duration of administration remain poorly defined. Current levels of practice variation through informal surveys are very high. Rates of antibiotic resistant organisms are increasing steadily around the world. METHODS/DESIGN: We will identify all controlled observational studies and randomized controlled trials examining prophylactic antibiotic use in pediatric cardiac surgery. Data sources will include MEDLINE, EMBASE, CENTRAL, and proceedings from recent relevant scientific meetings. For each included study, we will conduct duplicate independent data extraction, risk of bias assessment, and evaluation of quality of evidence using the GRADE approach. DISCUSSION: We will report the results of this review in agreement with the PRISMA statement and disseminate our findings at relevant critical care and cardiology conferences and through publication in peer-reviewed journals. We will use this systematic review to inform clinical guidelines, which will be disseminated in a separate stand-alone publication. STUDY REGISTRATION NUMBER: PROSPERO CRD42016052978C. PMID- 28558847 TI - Ultrasound characteristics of the mid-portion of the Achilles tendon in runners: a systematic review protocol. AB - BACKGROUND: Achilles tendinopathy is one of the most common overuse injuries in recreational and competitive runners, yet the clinical significance and frequency of abnormal sonographic characteristics in runners remains unclear. This paper presents a protocol for a systematic review which aims to assess existing literature which has employed ultrasonography to evaluate characteristics of the mid-portion of the Achilles tendon in runners. METHODS: An electronic literature search will be conducted using the following electronic databases: MEDLINE, CINAHL and SPORTDiscus. Studies published in English will be included if they evaluate ultrasound characteristics associated with mid-portion Achilles tendinopathy in runners. Methodological quality will be assessed using a scale adapted from the Newcastle-Ottawa Scale. DISCUSSION: This will be the first systematic review to summarise the existing evidence on ultrasound characteristics of the mid-portion of the Achilles tendon in recreational runners. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016050509. PMID- 28558848 TI - [Erythema nodosum as a reaction pattern: a broad spectrum of underlying causes]. AB - Erythema nodosum is a skin disorder that is characterised by the presence of painful erythematous nodules and plaques, mainly located on the shins. This disorder is associated with comorbidities and can be considered as an aspecific reaction pattern to a broad range of causes. However, an idiopathic variant also exists, which occurs in 22-72% of cases. Erythema nodosum is pre-eminently a skin disease which, due to its multifactorial pathogenesis, occurs in a wider field than dermatology alone. Therefore, knowledge of this disorder is important for all practicing physicians. To illustrate this we describe three patients with erythema nodosum attributable to different causes. PMID- 28558849 TI - [Characterisation of breast lesions with VTIQ elastography: a new elastography method to evaluate the stiffness of tissues]. AB - B-mode ultrasound is used as an adjunct to mammography to differentiate between benign and malignant breast lesions. An additional ultrasound technique is elastography which can evaluate the stiffness of tissues. It is believed that malignant lesions are generally stiffer than benign lesions. Virtual touch tissue Quantification (VTIQ) is a new elastography method for measuring the stiffness of tissue. Because this method does not depend on the degree of compression, measurements are reliable and reproducible. VTIQ - in combination with ultrasonography - has the potential to characterise abnormalities in more detail. Adding elastography to regular B-mode ultrasound improves the diagnostic specificity without loss of sensitivity. This suggests that VTIQ might change patient management and avoid unnecessary biopsies. However, further research involving a greater variety of abnormalities and larger study populations is indicated. PMID- 28558850 TI - [A girl with abdominal pain and haematomas on the belly]. AB - A 14-year-old girl with anorexia nervosa was referred to our paediatric hospital. She had a five-day history of severe abdominal pain. On abdominal sonography and MRI a duodenal wall hematoma was seen, correlating anatomically to abdominal bruises found on physical examination. The girl admitted to self-injury related to her eating disorder. PMID- 28558851 TI - [New biopsy at lung cancer progression: rational treatment of resistant lung cancer]. AB - Nowadays, patients with advanced non-small cell lung cancer harbouring a driver mutation undergo targeted treatment. This results in profound tumour responses but inevitably induces resistance after approximately 9 to 12 months. In this article we consider the importance and clinical implications of taking new biopsies to retrieve information regarding resistance mechanisms. There is a shift in the use of other modalities such as radiotherapy and surgery in patients with oligometastatic disease, producing long-lasting responses. This is illustrated by three different patient cases: one with an EGFR exon 21 mutation, obtaining a T790M mutation upon treatment; another with a BRAF V600 mutation initially treated with chemotherapy and later with targeted therapy; and, finally, a patient with an ALK translocation with progression on crizotinib treatment, responding to subsequent alectinib therapy. The latter developed oligometastatic disease that was treated with radiotherapy, resulting in a complete response for at least 2 years. PMID- 28558852 TI - [No glucocorticoids for treatment of sepsis; unless...]. AB - Steroids influence the immune response and blood pressure in patients with septic shock. Many trials have evaluated a putative positive effect of steroids as an adjuvant therapy in patients with sepsis and septic shock, with contradictory outcomes. As a consequence, the use of steroids in sepsis patients varies widely. A recently published randomized clinical trial has demonstrated that treatment with hydrocortisone does not delay or prevent progress to septic shock in patients with sepsis. Based on the current available data, the use of steroids in sepsis should be reserved for those patients who remain severely hemodynamic unstable after fluid resuscitation and vasopressor therapy, or those with a separate indication for steroid therapy. A corticotropin stimulation test to evaluate adrenal insufficiency is not useful. PMID- 28558853 TI - [Effectiveness of influenza vaccine in the Netherlands: predominant circulating virus type and vaccine match are important conditions]. AB - OBJECTIVE: To investigate the relationship between circulating influenza virus A types and subtypes and influenza B lineages, their match with the vaccine and the effectiveness of the influenza vaccine (IVE). DESIGN: Test negative case control study. METHOD: We used data from the Dutch Sentinel Practices of the Netherlands Institute for Health Services Research (NIVEL) Primary Care Database. Participating general practitioners took nose and throat swabs for viral studies from patients with influenza-like illness or another acute respiratory infection. Cases were those patients whose samples were positive for an influenza virus and controls were those whose samples were negative for influenza virus. We determined the IVE of 11 influenza seasons 2003/2004 to 2013/2014, for all seasons together and stratified by influenza virus type and to vaccine match or mismatch. RESULTS: Over all seasons, the IVE was 29% (95% CI:11-43). In seven of the 11 seasons there was a mismatch between vaccine and circulating virus type. The IVE was 40% (95% CI: 18-56) for those seasons in which there was a vaccine match, and 20% (95% CI: - 5-38) for seasons with a mismatch. When the influenza A/H3N2 virus was dominant, the IVE was 38% (95% CI: 14-55). The IVE against the influenza virus A/H1N1, A/H1N1/pdm09 and against both influenza B lineages was 77% (95% CI: 37-92), 47% (95% CI: 22-64) and 64% (95% CI: 50-74), respectively. CONCLUSION: The IVE was particularly low when there was a mismatch between the vaccine and the circulating virus type and when A/H3N2 was the dominant influenza subtype. PMID- 28558854 TI - Probiotic yogurt and acidified milk similarly reduce postprandial inflammation and both alter the gut microbiota of healthy, young men. AB - Probiotic yogurt and milk supplemented with probiotics have been investigated for their role in 'low-grade' inflammation but evidence for their efficacy is inconclusive. This study explores the impact of probiotic yogurt on metabolic and inflammatory biomarkers, with a parallel study of gut microbiota dynamics. The randomised cross-over study was conducted in fourteen healthy, young men to test probiotic yogurt compared with milk acidified with 2 % d-(+)-glucono-delta lactone during a 2-week intervention (400 g/d). Fasting assessments, a high-fat meal test (HFM) and microbiota analyses were used to assess the intervention effects. Baseline assessments for the HFM were carried out after a run-in during which normal milk was provided. No significant differences in the inflammatory response to the HFM were observed after probiotic yogurt compared with acidified milk intake; however, both products were associated with significant reductions in the inflammatory response to the HFM compared with the baseline tests (assessed by IL6, TNFalpha and chemokine ligand 5) (P<0.001). These observations were accompanied by significant changes in microbiota taxa, including decreased abundance of Bilophila wadsworthia after acidified milk (log 2-fold-change (FC)= 1.5, P adj=0.05) and probiotic yogurt intake (FC=-1.3, P adj=0.03), increased abundance of Bifidobacterium species after acidified milk intake (FC=1.4, P adj=0.04) and detection of Lactobacillus delbrueckii spp. bulgaricus (FC=7.0, P adj<0.01) and Streptococcus salivarius spp. thermophilus (FC=6.0, P adj<0.01) after probiotic yogurt intake. Probiotic yogurt and acidified milk similarly reduce postprandial inflammation that is associated with a HFM while inducing distinct changes in the gut microbiota of healthy men. These observations could be relevant for dietary treatments that target 'low-grade' inflammation. PMID- 28558855 TI - High-quality fish oil has a more favourable effect than oxidised fish oil on intermediate-density lipoprotein and LDL subclasses: a randomised controlled trial. AB - Fish oil (FO) supplementation reduces the risk of CVD. However, it is not known if FO of different qualities have different effects on lipoprotein subclasses in humans. We aimed at investigating the effects of oxidised FO and high-quality FO supplementation on lipoprotein subclasses and their lipid concentrations in healthy humans. In all, fifty-four subjects completed a double-blind randomised controlled intervention study. The subjects were randomly assigned to receive high-quality FO (n 17), oxidised FO (n 18) or high-oleic sunflower oil capsules (HOSO, n 19) for 7 weeks. The concentration of marine n-3 fatty acids was equal in high-quality FO and oxidised FO (1.6 g EPA+DHA/d). The peroxide value (PV) and anisidine value (AV) were 4 mEq/kg and 3 in high-quality FO and HOSO, whereas the PV and AV in the oxidised FO were 18 mEq/kg and 9. Blood samples were collected at baseline and end of study. NMR spectroscopy was applied for the analysis of lipoprotein subclasses and their lipid concentrations. High-quality FO reduced the concentration of intermediate-density lipoprotein (IDL) particles and large, medium and small LDL particles, as well as the concentrations of total lipids, phospholipids, total cholesterol, cholesteryl esters and free cholesterol in IDL and LDL subclasses compared with oxidised FO and HOSO. Hence, high-quality FO and oxidised FO differently affect lipid composition in lipoprotein subclasses, with a more favourable effect mediated by high-quality FO. In future trials, reporting the oxidation levels of FO would be useful. PMID- 28558856 TI - Incidence and Risk Factors for Community and Hospital Acquisition of Clostridium difficile Infection in the Tel Aviv Sourasky Medical Center. AB - OBJECTIVES To estimate the incidence and identified risk factors for community acquired (CA) and hospital-acquired (HA) Clostridium difficile infection (CDI) METHODS We conducted 2 parallel case-control studies at Tel Aviv Sourasky Medical Center from January 1, 2011, to December 31, 2014. We identified persons with CDI, determined whether infection was community or hospital acquired, and calculated incidence rates from 2007 to 2014. We collected demographic, clinical, and epidemiological information for CDI cases and hospitalized control cases and estimated the odds ratio with 95% confidence interval using conditional logistic regression. RESULTS In total, 1,563 CDI cases were identified in the study. The incidence rate of CA-CDI and HA-CDI increased by 1.6-fold and 1.2-fold, respectively, during 2012-2014. However, the incidence rate of CA-CDI was 0.84 per 100,000 (95% CI, 0.52-1.30), the rate for HA-CDI was 4.7 per 10,000 patient days (95% CI, 4.08-5.38), respectively, in 2014. We identified several factors as independent variables significantly associated with HA-CDI: functional disability, presence of nasogastric tube, antibiotic use, chemotherapy, infection by extended-spectrum beta-lactamases, and mean of albumin values. Risk factors independently associated with CA-CDI were close contact with a family member who had been hospitalized in the previous 6 months, inflammatory bowel disease, and home density index (adjusted odds ratio, 25.7; 95% confidence interval, 3.99 165.54; P=.001). CONCLUSIONS The identification of the main modifiable risk factors for HA-CDI (antibiotic exposure and hypoalbuminemia) and for CA-CDI (close contact with a family member who had been hospitalized in the previous 6 months) is likely to optimize prevention efforts; these factors are critical in preventing the spread of CDI. Infect Control Hosp Epidemiol 2017;38:912-920. PMID- 28558857 TI - How's Your Health at Home: Frail Homebound Patients Reported Health Experience and Outcomes. AB - We used a web-based mixed methods survey (HowsYourHealth - Frail) to explore the health of frail older (78% age 80 or older) adults enrolled in a home-based primary care program in Vancouver, Canada. Sixty per cent of eligible respondents participated, representing over one quarter (92/350, 26.2%) of all individuals receiving the service. Despite high levels of co-morbidity and functional dependence, 50 per cent rated their health as good, very good, or excellent. Adjusted odds ratios for positive self-rated health were 7.50, 95 per cent CI [1.09, 51.81] and 4.85, 95 per cent CI [1.02, 22.95] for absence of bothersome symptoms and being able to talk to family or friends respectively. Narrative responses to questions about end of life and living with illness are also described. Results suggest that greater focus on symptom management, and supporting social contact, may improve frail seniors' health. PMID- 28558858 TI - Adolescents from upper middle class communities: Substance misuse and addiction across early adulthood. AB - In this prospective study of upper middle class youth, we document frequency of alcohol and drug use, as well as diagnoses of abuse and dependence, during early adulthood. Two cohorts were assessed as high school seniors and then annually across 4 college years (New England Study of Suburban Youth younger cohort [NESSY Y]), and across ages 23-27 (NESSY older cohort [NESSY-O]; ns = 152 and 183 at final assessments, respectively). Across gender and annual assessments, results showed substantial elevations, relative to norms, for frequency of drunkenness and using marijuana, stimulants, and cocaine. Of more concern were psychiatric diagnoses of alcohol/drug dependence: among women and men, respectively, lifetime rates ranged between 19%-24% and 23%-40% among NESSY-Os at age 26; and 11%-16% and 19%-27% among NESSY-Ys at 22. Relative to norms, these rates among NESSY-O women and men were three and two times as high, respectively, and among NESSY-Y, close to one among women but twice as high among men. Findings also showed the protective power of parents' containment (anticipated stringency of repercussions for substance use) at age 18; this was inversely associated with frequency of drunkenness and marijuana and stimulant use in adulthood. Results emphasize the need to take seriously the elevated rates of substance documented among adolescents in affluent American school communities. PMID- 28558860 TI - Outil de sensibilisation des proches a la conduite automobile des aines. AB - This study aimed to explore the impact of an awareness tool for relatives of older drivers (OSCARPA) on i) their interest, openness and knowledge, ii) changes of abilities required for safe driving, and iii) utilization of compensatory strategies. A pre-experimental design with pretest (T0) and post-test (T1) eight to ten weeks after the intervention was realized with 45 relatives in contact with an older driver of 65 years old or older and who was driving at least once a week. Overall, the results demonstrated that OSCARPA increased i) interest, openness and knowledge of relatives (p<0.001), as well as their perceptions of ii) changes of abilities of older drivers (p=0.02), and iii) their utilization of compensatory strategies (p=0.001). Future studies would be relevant to further evaluate and increase the effectiveness of OSCARPA. PMID- 28558859 TI - Acute memory and psychotomimetic effects of cannabis and tobacco both 'joint' and individually: a placebo-controlled trial. AB - BACKGROUND: Cannabis and tobacco have contrasting cognitive effects. Smoking cannabis with tobacco is prevalent in many countries and although this may well influence cognitive and mental health outcomes, the possibility has rarely been investigated in human experimental psychopharmacological research. METHOD: The individual and interactive effects of cannabis and tobacco were evaluated in 24 non-dependent cannabis and tobacco smokers in a randomized, placebo-controlled, double-blind, 2 (cannabis, placebo) * 2 (tobacco, placebo) crossover design. Verbal memory (prose recall), working memory (WM) performance including maintenance, manipulation and attention (N-back), psychotomimetic, subjective and cardiovascular measures were recorded on each of four sessions. RESULTS: Cannabis alone impaired verbal memory. A priori contrasts indicated that tobacco offset the effects of cannabis on delayed recall. However, this was not supported by linear mixed model analysis. Cannabis load-dependently impaired WM. By contrast, tobacco improved WM across all load levels. The acute psychotomimetic effects and ratings of 'stoned' and 'dizzy' induced by cannabis were not altered by tobacco. Cannabis and tobacco had independent effects on increasing heart rate and interacting effects on increasing diastolic blood pressure. CONCLUSIONS: Relative to placebo, acute cannabis impaired verbal memory and WM. Tobacco enhanced performance on WM, independently of cannabis. Moreover, we found some preliminary evidence that tobacco may offset the effects of cannabis on delayed, but not immediate, verbal recall. In contrast, the psychotomimetic and subjective effects of cannabis were unaffected by tobacco co-administration. By reducing the cognitive impairment from cannabis, tobacco co-administration may perpetuate use despite adverse health consequences. PMID- 28558861 TI - Animal Board Invited Review: Comparing conventional and organic livestock production systems on different aspects of sustainability. AB - To sustainably contribute to food security of a growing and richer world population, livestock production systems are challenged to increase production levels while reducing environmental impact, being economically viable, and socially responsible. Knowledge about the sustainability performance of current livestock production systems may help to formulate strategies for future systems. Our study provides a systematic overview of differences between conventional and organic livestock production systems on a broad range of sustainability aspects and animal species available in peer-reviewed literature. Systems were compared on economy, productivity, environmental impact, animal welfare and public health. The review was limited to dairy cattle, beef cattle, pigs, broilers and laying hens, and to Europe, North America and New Zealand. Results per indicators are presented as in the articles without performing additional calculations. Out of 4171 initial search hits, 179 articles were analysed. Studies varied widely in indicators, research design, sample size and location and context. Quite some studies used small samples. No study analysed all aspects of sustainability simultaneously. Conventional systems had lower labour requirements per unit product, lower income risk per animal, higher production per animal per time unit, higher reproduction numbers, lower feed conversion ratio, lower land use, generally lower acidification and eutrophication potential per unit product, equal or better udder health for cows and equal or lower microbiological contamination. Organic systems had higher income per animal or full time employee, lower impact on biodiversity, lower eutrophication and acidification potential per unit land, equal or lower likelihood of antibiotic resistance in bacteria and higher beneficial fatty acid levels in cow milk. For most sustainability aspects, sometimes conventional and sometimes organic systems performed better, except for productivity, which was consistently higher in conventional systems. For many aspects and animal species, more data are needed to conclude on a difference between organic and conventional livestock production systems. PMID- 28558862 TI - First Results of the Swiss National Surgical Site Infection Surveillance Program: Who Seeks Shall Find. AB - OBJECTIVES To report on the results of the Swiss national surgical site infection (SSI) surveillance program, including temporal trends, and to describe methodological characteristics that may influence SSI rates DESIGN Countrywide survey of SSI over a 4-year period. Analysis of prospectively collected data including patient and procedure characteristics as well as aggregated SSI rates stratified by risk categories, type of SSI, and time of diagnosis. Temporal trends were analyzed using stepwise multivariate logistic regression models with adjustment of the effect of the duration of participation in the surveillance program for confounding factors. SETTING The study included 164 Swiss public and private hospitals with surgical activities. RESULTS From October 2011 to September 2015, a total of 187,501 operations performed in this setting were included. Cumulative SSI rates varied from 0.9% for knee arthroplasty to 14.4% for colon surgery. Postdischarge follow-up was completed in >90% of patients at 1 month for surgeries without an implant and in >80% of patients at 12 months for surgeries with an implant. High rates of SSIs were detected postdischarge, from 20.7% in colon surgeries to 93.3% in knee arthroplasties. Overall, the impact of the duration of surveillance was significantly and independently associated with a decrease in SSI rates in herniorraphies and C-sections but not for the other procedures. Nevertheless, some hospitals observed significant decreases in their rates for various procedures. CONCLUSIONS Intensive post-discharge surveillance may explain high SSI rates and cause artificial differences between programs. Surveillance per se, without structured and mandatory quality improvement efforts, may not produce the expected decrease in SSI rates. Infect Control Hosp Epidemiol 2017;38:697-704. PMID- 28558863 TI - Later School Start Times: What Informs Parent Support or Opposition? AB - STUDY OBJECTIVES: To investigate parental knowledge about adolescent sleep needs, and other beliefs that may inform their support for or objection to later school start times. METHODS: In 2014, we conducted a cross-sectional, Internet-based survey of a nationally representative sample of parents as part of the C.S. Mott Children's Hospital National Poll on Children's Health. Parents with teens aged 13-17 years reported their children's sleep patterns and school schedules, and whether the parents supported later school start times (8:30 am or later). Responses associated with parental support of later school start times were examined with logistic regression analysis. RESULTS: Overall, 88% of parents reported school start times before 8:30 am, and served as the analysis sample (n = 554). In this group, 51% expressed support for later school start times. Support was associated with current school start times before 7:30 am (odds ratio [OR] = 3.1 [95% confidence interval (CI) 1.2, 8.4]); parental opinion that their teen's current school start time was "too early" (OR = 3.8 [1.8, 7.8]); and agreement with American Academy of Pediatrics recommendations about school start times (OR = 4.7 [2.2, 10.1]). Support also was associated with anticipation of improved school performance (OR = 3.0 [1.5, 5.9]) or increased sleep duration (OR = 4.0 [1.8, 8.9]) with later school start times. Conversely, parents who anticipated too little time for after-school activities (OR = 0.5 [0.3, 0.9]) and need for different transportation plans (OR = 0.5 [0.2, 0.9]) were often less supportive. CONCLUSIONS: Parental education about healthy sleep needs and anticipated health benefits may increase their support for later school start times. Educational efforts should also publicize the positive experiences of communities that have made this transition, with regard to limited adverse effect on after-school activity schedules and transportation. PMID- 28558865 TI - Early Onset of Sleep-Disordered Breathing in Two Children With SEPN1-Related Myopathies. AB - ABSTRACT: Selenoprotein-related myopathy (SEPN1-RM) is a rare disease with a variable clinical presentation. The selenoprotein N1 gene (SEPN1) mutation causing this congenital muscular dystrophy was identified in 2001. Sleep disordered breathing (SDB) may occur in young patients with SEPN1-RM who are still able to walk. We report the cases of two children with SEPN1-RM who presented with SDB at the ages of 7 and 12 years and for whom long-term nocturnal noninvasive ventilation yielded significant improvement. Based on literature review and our current cases, it seems that there is no obvious relationship between the time since SDB onset and outcome of pulmonary function tests or limb muscle weakness. We therefore suggest that SDB should be systematically screened for in patients with SEPN1-RM, at regular intervals using nocturnal polysomnography. PMID- 28558864 TI - A Randomized Crossover Trial Comparing Autotitrating and Continuous Positive Airway Pressure in Subjects With Symptoms of Aerophagia: Effects on Compliance and Subjective Symptoms. AB - STUDY OBJECTIVES: To assess the benefit and tolerance of autotitrating positive airway pressure (APAP) versus continuous positive airway pressure (CPAP) in subjects who experience aerophagia. METHODS: This is the report of a prospective, two-week, double-blinded, randomized crossover trial set in an Australian clinical sleep laboratory in a tertiary hospital. Fifty-six subjects who reported symptoms of aerophagia that they attributed to CPAP were recruited. Full face masks were used by 39 of the 56 subjects recruited. Subjects were randomly and blindly allocated to either CPAP at their treatment recommended pressure or APAP 6-20 cm H2O, in random order. Subjects spent two weeks on each therapy mode. Therapy usage hours, 95th centile pressure, maximum pressure, 95th centile leak, and residual apnea-hypopnea index (AHI) were reported at the end of each two-week treatment period. Functional Outcome of Sleepiness Questionnaire, Epworth Sleepiness Scale, and visual analog scale to measure symptoms of aerophagia were also completed at the end of each 2-week treatment arm. RESULTS: The median pressure (P < .001) and 95th centile pressure (P < .001) were reduced with APAP but no differences in compliance (P = .120) and residual AHI were observed. APAP reduced the symptoms of bloating (P = .011), worst episode of bloating (P = .040), flatulence (P = .010), and belching (P = .001) compared to CPAP. There were no differences in Epworth Sleepiness Scale or Functional Outcome of Sleepiness Questionnaire outcomes between CPAP and APAP. CONCLUSIONS: APAP therapy reduces the symptoms of aerophagia while not affecting compliance when compared with CPAP therapy. CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry at https://www.anzctr.org.au, trial number ACTRN12611001250921. COMMENTARY: A commentary on this article appears in this issue on page 859. PMID- 28558866 TI - Potential Clinical Utility and Feasibility of Combined Left Atrial Appendage Closure and Positioning of Miniaturized Pacemaker Through a Single Right Femoral Vein Access. AB - This study assessed the clinical utility and feasibility of concomitant of combined left atrial appendage (LAA) closure and positioning of miniaturized pacemaker (Micra TPS). All consecutive patients who underwent VVI-PM implant from November 2015 to October 2016 were considered. VVI-PM implant was conducted either using transvenous approach or by positioning Micra TPS. In selected patients with concomitant contraindication to OAC, Micra TPS was combined with LAA occlusion ("combined approach"), performed in general anesthesia and guided by multimodality imaging; procedural and follow-up data of these specific patients were registered. Sixty patients were treated with VVI-PM implant. Six patients (10.0%) presented OAC contraindication, of which 4 (6.7%) were eligible for the "combined procedure"; 2 of 4 of these patients presented chronic hemodialysis-dependent renal failure. The combined approach was successful in all 4 patients without intra- or periprocedural complications. No adverse events linked to the combined approach occurred during mid-term follow-up (7.5, interquartile range 5.0 to 7.9 months). In conclusion, VVI-PM indication and concomitant contraindication to OAC is not uncommon; in selected patients, combined LAA closure and positioning of Micra TPS may be a feasible therapeutic option. PMID- 28558867 TI - Apigenin's anticancer properties and molecular mechanisms of action: Recent advances and future prospectives. AB - Cancer is a major health concern and leading burden on economy worldwide. An increasing effort is devoted to isolation and development of plant-derived dietary components as effective chemo-preventive products. Phytochemical compounds from natural resources such as fruits and vegetables are responsible for decreasing the risk of certain cancers among the consuming populations. Apigenin, a flavonoid phytochemical found in many kinds of fruits and vegetables, has been shown to exert significant biological effects, such as anti-oxidant, anti-inflammatory and most particularly anti-neoplastic properties. This review is intended to summarize the most recent advances in the anti-proliferative and chemo-preventive effects of apigenin in different cancer models. Analysis of the data from the studied cancer models has revealed that apigenin exerts its anti proliferative effects through multiple and complex pathways. This guided us to discover some controversial results about the exact role of certain molecular pathways such as autophagy in the anticancer effects of apigenin. Further, there were cumulative positive evidences supporting the involvement of certain pathways such as apoptosis, ROS and DNA damage and repair. Apigenin possesses a high potential to be used as a chemosensitizing agent through the up-regulation of DR5 pathway. According to these preclinical findings we recommend that further robust unbiased studies should consider the possible interactions between different molecular pathways. PMID- 28558868 TI - Anti-hyperuricemic and anti-inflammatory actions of vaticaffinol isolated from Dipterocarpus alatus in hyperuricemic mice. AB - The present study was designed to examine the anti-hyperuricemic and anti inflammatory effects and possible mechanisms of vaticaffinol, a resveratrol tetramer isolated from ethanol extracts of Dipterocarpus alatus, in oxonate induced hyperuricemic mice. At 1 h after 250 mg.kg-1 potassium oxonate was given, vaticaffinol at 20, 40, and 60 mg.kg-1 was intragastrically administered to hyperuricemic mice once daily for seven consecutive days. Vaticaffinol significantly decreased serum uric acid levels and improved kidney function in hyperuricemic mice. It inhibited hepatic activity of xanthine dehydrogenase (XDH) and xanthine oxidase (XOD), regulated renal mRNA and protein levels of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporter 1 (OAT1), organic cation transporter 1 (OCT1), OCT2, organic cation/carnitine transporter 1 (OCTN1), and OCTN2 in hyperuricemic mice. Moreover, vaticaffinol markedly down-regulated renal protein levels of NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like (ASC), and Caspase-1, resulting in the reduction of interleukin (IL)-1beta, IL-18, IL-6 and tumor necrosis factor-alpha (TNF alpha) levels in this animal model. Additionally, HPLC and LC-MS analyses clearly testified the presence of vaticaffinol in the crude extract. These results suggest that vaticaffinol may be useful for the prevention and treatment of hyperuricemia with kidney inflammation. PMID- 28558869 TI - Triptolide reduces prostate size and androgen level on testosterone-induced benign prostatic hyperplasia in Sprague Dawley rats. AB - Benign prostatic hyperplasia (BPH) is an age-related disease of unknown etiology, characterized by prostatic enlargement coincident with distinct alterations in tissue histology. In the present study, we investigated whether triptolide can prevent testosterone-induced prostatic hyperplasia in rats. Castration was performed via the scrotal route after urethane aesthesia. BPH was induced in experimental groups by daily subcutaneous injections of testosterone propionate (TP) for two weeks. Triptolide was administered daily by oral gavage at a dose of 100 and 50 MUg.kg-1 for 2 weeks, along with the TP injections. On day 14, the animals were humanely killed by cervical dislocation after aesthesia. Prostates were excised, weighed, and used for histological studies. Testosterone and dihydrotestosterone (DHT) levels in serum and prostate were measured. The results showed that triptolide significantly reduced the prostate weight, and the testosterone and DHT levels in both the serum and prostate. Histopathological examination also showed that triptolide treatment suppressed TP-induced prostatic hyperplasia. In conclusion, triptolide effectively inhibits the development of BPH induced by testosterone in a rat model. PMID- 28558870 TI - Synthesis and evaluation of 2-cyano-3, 12-dioxooleana-1, 9(11)-en-28-oate-13beta, 28-olide as a potent anti-inflammatory agent for intervention of LPS-induced acute lung injury. AB - The present study was designed to synthesize 2-Cyano-3, 12-dioxooleana-1, 9(11) en-28-oate-13beta, 28-olide (1), a lactone derivative of oleanolic acid (OA) and evaluate its anti-inflammatory activity. Compound 1 significantly diminished nitric oxide (NO) production and down-regulated the mRNA expression of iNOS, COX 2, IL-6, IL-1beta, and TNF-alpha in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Further in vivo studies in murine model of LPS-induced acute lung injury (ALI) showed that 1 possessed more potent protective effects than the well-known anti-inflammatory drug dexamethasone by inhibiting myeloperoxidase (MPO) activity, reducing total cells and neutrophils, and suppressing inflammatory cytokines expression, and thus ameliorating the histopathological conditions of the injured lung tissue. In conclusion, compound 1 could be developed as a promising anti-inflammatory agent for intervention of LPS-induced ALI. PMID- 28558871 TI - A lipophilic prodrug of Danshensu: preparation, characterization, and in vitro and in vivo evaluation. AB - Danshensu [3-(3, 4-dihydroxyphenyl) lactic acid, DSS], one of the significant cardioprotective components, is extracted from the root of Salvia miltiorrhiza. In the present study, an ester prodrug of Danshensu (DSS), palmitoyl Danshensu (PDSS), was synthesized with the aim to improve its oral bioavailability and prolong its half-life. The in vitro experiments were carried out to evaluate the physicochemical properties and stability of PDSS. Although the solubility of PDSS in water was only 0.055 mg.mL-1, its solubility in FaSSIF and FeSSIF reached 4.68 and 9.08 mg.mL-1, respectively. Octanol-water partition coefficient (log P) was increased from -2.48 of DSS to 1.90 of PDSS. PDSS was relatively stable in the aqueous solution in pH range from 5.6 to 7.4. Furthermore, the pharmacokinetics in rats was evaluated after oral administration of PDSS and DSS. AUC and t1/2 of PDSS were enhanced up to 9.8-fold and 2.2-fold, respectively, compared to that of DSS. Cmax was 1.67 +/- 0.11 MUg.mL-1 for PDSS and 0.81 +/- 0.06 MUg.mL-1 for DSS. Thus, these results demonstrated that PDSS had much higher oral bioavailability and longer circulation time than its parent drug. PMID- 28558872 TI - Nuclear magnetic resonance based metabolomic differentiation of different Astragali Radix. AB - Astragali Radix (AR) is one of the most popular herbal medicines in traditional Chinese medicine (TCM). Wild AR is believed to be of high quality, and substitution with cultivated AR is frequently encountered in the market. In the present study, two types of ARs (wild and cultivated) from Astragalus membranaceus (Fisch.) Bge. and A. membranaceus var. mongholicus (Bge.) Hsiao, growing in different regions of China, were analyzed by NMR profiling coupled with multivariate analysis. Results showed that both could be differentiated successfully and cultivation patterns or growing years might have greater impact on the metabolite compositions than the variety; the metabolites responsible for the separation were identified. In addition, three extraction methods were compared and the method (M1) was used for further analysis. In M1, the extraction solvent composed of water, methanol, and chloroform in the ratio of 1 : 1 : 2 was used to obtain the aqueous methanol (upper layer) and chloroform (lower layer) fractions, respectively, showing the best separation. The differential metabolites among different methods were also revealed. Moreover, the sucrose/glucose ratio could be used as a simple index to differentiate wild and cultivated AR. Meanwhile, the changes of correlation pattern among the differential metabolites of the two varieties were found. The work demonstrated that NMR-based non-targeted profiling approach, combined with multivariate statistical analysis, can be used as a powerful tool for differentiating AR of different cultivation types or growing years. PMID- 28558873 TI - Mechanism for ginkgolic acid (15 : 1)-induced MDCK cell necrosis: Mitochondria and lysosomes damages and cell cycle arrest. AB - Ginkgolic acids (GAs), primarily found in the leaves, nuts, and testa of ginkgo biloba, have been identified with suspected allergenic, genotoxic and cytotoxic properties. However, little information is available about GAs toxicity in kidneys and the underlying mechanism has not been thoroughly elucidated so far. Instead of GAs extract, the renal cytotoxicity of GA (15 : 1), which was isolated from the testa of Ginkgo biloba, was assessed in vitro by using MDCK cells. The action of GA (15 : 1) on cell viability was evaluated by the MTT and neutral red uptake assays. Compared with the control, the cytotoxicity of GA (15 : 1) on MDCK cells displayed a time- and dose-dependent manner, suggesting the cells mitochondria and lysosomes were damaged. It was confirmed that GA (15 : 1) resulted in the loss of cells mitochondrial trans-membrane potential (DeltaPsim). In propidium iodide (PI) staining analysis, GA (15 : 1) induced cell cycle arrest at the G0/G1 and G2/M phases, influencing on the DNA synthesis and cell mitosis. Characteristics of necrotic cell death were observed in MDCK cells at the experimental conditions, as a result of DNA agarose gel electrophoresis and morphological observation of MDCK cells. In conclusion, these findings might provide useful information for a better understanding of the GA (15 : 1) induced renal toxicity. PMID- 28558874 TI - Identification of C-geranylated flavonoids from Paulownia catalpifolia Gong Tong fruits by HPLC-DAD-ESI-MS/MS and their anti-aging effects on 2BS cells induced by H2O2. AB - The fruits of Paulownia catalpifolia Gong Tong are used as a Chinese folk herbal medicine for the treatment of enteritis, tonsillitis, bronchitis, and dysentery, etc. Our previous study has identified new C-geranylated flavanones with obvious anti-proliferative effects in lung cancer A549 cells. In the present study, a new C-geranylated flavone, paucatalinone C (1) and five known C-geranylated flavanones (2-6) were isolated. In addition, a total of 34 C-geranylated flavonoids were detected by HPLC-DAD-ESI-MS/MS coupling techniques from the CH2Cl2 extract of P. catalpifolia. Futhermore, anti-aging effects of isolated compounds were evaluated in vitro with premature senescent 2BS cells induced by H2O2. Phytochemical results indicated that P. catalpifolia was a natural resource of abundant C-geranylated flavonoids. Diplacone (3) and paucatalinone A (5) were the potent anti-aging agents in the premature senescent 2BS cells induced by H2O2 and the C-geranyl substituent may be an important factor because of its lipophilic character. PMID- 28558875 TI - Characterization and quantitation of aristolochic acid analogs in different parts of Aristolochiae Fructus, using UHPLC-Q/TOF-MS and UHPLC-QqQ-MS. AB - Aristolochiae Fructus, a Chinese herbal medicine derived from the fruit of Aristolochia contorta Bge., contains nephrotoxic aristolochic acid analogues (AAAs). According to ancient medical texts, various medicinal parts of the fruit of A. contorta were ever used. In order to reveal which part could be safely and effectively used, it is necessary to analyze the chemical profiles of different medicinal parts. Herein we compared the chemical compositions and determined aristolochic acid I (AA-I) and aristolochic acid II (AA-II) in the four parts viz. outer pericarp, inner pericarp, septum, and seed. Ultra-high performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) was applied for chemical profiling. Ultra-high performance liquid coupled with triple quadrupole mass spectrometry (UHPLC-QqQ-MS) was employed to quantify AA-I and AA-II in different parts. It was found that the chemical compositions of the four parts varied both qualitatively and quantitatively. A total of 10 AAAs, including 5 aristolochic acids and 5 aristolactams, together with 3 alkaloids, were unambiguously or tentatively identified by UHPLC-QTOF-MS. The quantitatively analytical results obtained by UHPLC-QqQ-MS showed that AA-I and AA-II exclusively accumulate in the seeds of A. contorta. These findings provide supporting data for the rational selection of medicinal parts. PMID- 28558876 TI - Chaotic home environment is associated with reduced infant processing speed under high task demands. AB - Early adversity has profound long-term consequences for child development across domains. The effects of early adversity on structural and functional brain development were shown for infants under 12 months of life. However, the causal mechanisms of these effects remain relatively unexplored. Using a visual habituation task we investigated whether chaotic home environment may affect processing speed in 5.5 month-old infants (n=71). We found detrimental effects of chaos on processing speed for complex but not for simple visual stimuli. No effects of socio-economic status on infant processing speed were found although the sample was predominantly middle class. Our results indicate that chaotic early environment may adversely affect processing speed in early infancy, but only when greater cognitive resources need to be deployed. The study highlights an attractive avenue for research on the mechanisms linking home environment with the development of attention control. PMID- 28558877 TI - mHealth for mental health in the Middle East: Need, technology use, and readiness among Palestinians in the West Bank. AB - Palestinians in the West Bank are at heightened risk for mental health problems. Limited availability of clinicians and a host of geopolitical, topographical, and infrastructural challenges create significant regional barriers to clinic-based care. The objective of this study was to examine whether mHealth approaches that leverage mobile phones for remote mental health treatment may be viable alternatives. We surveyed 272 Palestinian adults in urban, rural, and refugee camp settings. Most participants (93.4%) reported owning mobile phones. The penetration of mobile devices was high across all study sites. Males and females did not differ in their access to this resource. Among mobile phone owners, 79.9% had smartphones, 32.2% had basic mobile phones, and 12.2% owned both. Respondents reported having reliable access to electricity (99.6%) and Wi-Fi (80.9%). Almost all mobile phone owners (99.6%) reported using social media such as Facebook, WhatsApp, or Twitter. When asked to estimate the prevalence of mental health problems in the region, 61.4% of participants reported that over half of the people in their communities struggled with depression, posttraumatic stress, or auditory hallucinations. Most participants indicated that they would personally be interested in mHealth for Mental Health options such as bi-directional texting with clinicians (68.8%), smartphone applications (66.5%), unidirectional support texts (64.7%), or web-based interventions (64.0%). Given the Palestinian populations' broad access to technology and technological infrastructure, need for care, and openness to engage in mobile interventions, mHealth should be considered a promising strategy for mental health services in the West Bank. PMID- 28558878 TI - The neurobiology of depression: An integrated view. AB - Major Depressive Disorder (MDD) is one of the most common and debilitating mental disorders; however, its etiology remains unclear. This paper aims to summarize the major neurobiological underpinnings of depression, synthesizing the findings into a comprehensive integrated view. A literature review was conducted using Pubmed. Search terms included "depression" or "MDD" AND "biology", "neurobiology", "inflammation", "neurogenesis", "monoamine", and "stress". Articles from 1995 to 2016 were reviewed with a focus on the connection between different biological and psychological models. Some possible pathophysiological mechanisms of depression include altered neurotransmission, HPA axis abnormalities involved in chronic stress, inflammation, reduced neuroplasticity, and network dysfunction. All of these proposed mechanisms are integrally related and interact bidirectionally. In addition, psychological factors have been shown to have a direct effect on neurodevelopment, causing a biological predisposition to depression, while biological factors can lead to psychological pathology as well. The authors suggest that while it is possible that there are several different endophenotypes of depression with distinct pathophysiological mechanisms, it may be helpful to think of depression as one united syndrome, in which these mechanisms interact as nodes in a matrix. Depressive disorders are considered in the context of the RDoC paradigm, identifying the pathological mechanisms at every translational level, with a focus on how these mechanisms interact. Finally, future directions of research are identified. PMID- 28558879 TI - Psychosis and catatonia as presenting features of anti-N-methyl-D-aspartate (anti NMDA) receptor encephalitis. PMID- 28558880 TI - Cultural considerations in the diagnosis and treatment of schizophrenia: A case example from India. AB - Culture plays an important role in the presentation, help seeking, treatment and outcomes of psychiatric illnesses like schizophrenia. We report a case of paranoid schizophrenia in a 35-year-old lady, from South India, whose clinical presentation was influenced by various sociocultural factors. These cultural constructs were taken into consideration to formulate an acceptable and effective management plan. A detailed case description using a cultural formulation to highlight the etic and emic perspectives and challenges in treatment and management are discussed. PMID- 28558881 TI - Social anxiety and Internet socialization in Indian undergraduate students: An exploratory study. AB - BACKGROUND: Social Anxiety Disorder (SAD) is a globally prevalent, chronic, debilitating psychiatric disorder affecting youth. With comorbidities including major depression, substance abuse, lower educational and work attainment, and increased suicide risk, it has a significant public health burden. The objective of this study was to estimate the prevalence of SAD in urban Indian undergraduate students and to study their Facebook (FB) usage patterns. METHODS: In this exploratory cross-sectional study, 316 undergraduate students were screened for social anxiety using validated instruments, Social Interaction Anxiety Scale (SIAS) and Social Phobia Scale (SPS), and divided into two groups based on scores obtained. The groups were then compared with regards to behaviors and attitudes toward Facebook, obtained from a self-report questionnaire. RESULTS: SAD was estimated to be a significant, prevalent (7.8%) disorder in otherwise productive youth, and showed female preponderance. Higher specific social phobia scores were associated with the inability to reduce Facebook use, urges toward increasing use, spending more time thinking about Facebook, negative reactions to restricting use, and using it to forget one's problems. CONCLUSIONS: SAD was estimated to have a prevalence of 7.8% in our study, and was associated with stronger FB usage attitudes and patterns. We recommend that the relationship between social anxiety and Internet use be explored further, to study the possibility of Internet-based screening and intervention strategies having wider reach and appeal in socially anxious individuals. PMID- 28558882 TI - Validation of the Persian version of the Schizophrenia Cognition Rating Scale (SCoRS) in patients with schizophrenia. AB - The Schizophrenia Cognition Rating Scale (SCoRS) is an interview-based assessment of cognition that involves interviews with patients and informants. The SCoRS has shown good reliability, validity, and sensitivity to cognitive impairment in schizophrenia, with the advantage of brief administration and scoring time. The present study aimed to test the concurrent validity of the Persian version of the SCoRS. A group of 35 patients with schizophrenia and a group of 35 healthy controls received the Persian-SCoRS in the first session, and a standardized performance-based cognitive battery, the Brief Assessment of Cognition in Schizophrenia (BACS), in the second session.Our results indicated that the Persian version of the SCoRS was sensitive to cognitive impairment in the patients. The Persian SCoRS global rating was significantly associated with the composite score generated from the Persian version of the BACS and predicted functional outcomes as measured by Global Assessment of Functioning (GAF) and World Health Organization Quality of Life (WHO QOL). A Persian version of the SCoRS, an interview based measure of cognition that included informants, is related to cognitive performance and global functioning. PMID- 28558883 TI - Traumatic dimensions of hikikomori: A Foucauldian note. PMID- 28558884 TI - Exploring suicide risk factors among Japanese individuals: The largest case control psychological autopsy study in Japan. AB - This case-control psychological autopsy study explored suicide risk factors among Japanese individuals. We targeted 102 suicide completers over 20 years of age and 334 living controls matched to suicide cases by gender, age, and residential municipality in Japan. After controlling for other factors, we found significant associations between suicide and mental disorders, sleeping problems, and verbal communication of one's own death. We discuss the importance of sensitive responses to verbal expressions of suicidal ideation. PMID- 28558885 TI - Cortical surface area hyperexpansion in infants: A promising biomarker for autism spectrum disorder. PMID- 28558886 TI - Lipids, aggression, suicidality and impulsivity in drug-naive/drug-free patients of schizophrenia. AB - AIM: Present study aimed at determining lipid profiles in acutely symptomatic drug-naive/drug-free patients of schizophrenia, comparing them with healthy controls and exploring relationships between various lipid fractions, aggression, suicidality and impulsivity in this population. MATERIALS AND METHODS: This was a cross-sectional hospital-based study, comparing patients with schizophrenia (M=46, F=14; mean age 32.40+/-6.6 years; 48 drug-free for 10.50+/-9.2 weeks) with 60 age-sex matched healthy controls. Upon recruitment, fasting venous blood samples of all subjects were analysed for total cholesterol, HDL, LDL, VLDL and TG levels, and patients were rated on PANSS for symptom severity, Modified Overt Aggression Scale for aggression, Impulsivity Rating Scale for impulsivity and Scale for Suicide Ideation for suicidality. RESULTS: The socio-demographic characteristics of the patients were comparable to controls. In patients, total cholesterol, HDL and LDL levels were found to be significantly lower (p<0.01) than the control group. When explored further in patients, lower total cholesterol and LDL levels showed significant negative correlations with scores on impulsivity (p<0.01) and suicidality (p<0.05); and TG level showed a negative correlation with impulsivity (p<0.05). CONCLUSIONS: This study adds to a growing literature on a complex relationship between lipid fractions and impulsivity, suicidality and aggression in schizophrenia; providing interesting insights into the biochemical basis of human behaviour and confirming these in a developing world population. The implications are many, including a need to review judiciously the promotion of weight loss and cholesterol reduction programmes in constitutionally vulnerable population, at least during their acutely-symptomatic states. PMID- 28558887 TI - Treatment retention of risperidone long-acting injection in patients with early onset schizophrenia in Japan. PMID- 28558888 TI - Prevalence of metabolic syndrome among patients with depressive disorder admitted to a psychiatric inpatient unit: A comparison with healthy controls. AB - OBJECTIVE: This study aimed to compare the prevalence of metabolic syndrome (MS) among inpatients with depressive disorders and matched healthy controls. METHOD: One hundred fifty eight patients with depressive disorders and 52 age and gender matched healthy controls were assessed for the prevalence of MS using Common Criteria for MS. RESULTS: Prevalence of Metabolic syndrome among inpatients with depressive disorders was 44.3%, which was significantly higher than the healthy control group (17.3%). Increased waist circumference was the most common abnormality in both the groups. Prevalence of MS among patients with recurrent depression disorder (60.3%) was almost double that seen among those with first episode depression (32.6%). Compared to healthy controls, significantly greater proportion of patients with depressive disorders had increased blood pressure, abnormal fasting blood sugar, and HDL levels. Besides the prevalence of MS in 44.3% of patients with depressive disorders, another 46% of patients fulfilled one or two criteria of MS. Significant predictors of MS were being married, obese, greater age, higher weight, higher body mass index, and multiple episodes of depression. CONCLUSIONS: Nearly two-fifth of depressed patients have MS and another two-fifth of patients had one or two abnormalities in the MS criteria. The prevalence of MS among patients with depressive disorders is significantly higher than the healthy controls. Hence, patients with depressive disorders should be regularly evaluated for the presence of MS and other cardiovascular risk factors and appropriate management strategies must be instituted at the earliest. PMID- 28558889 TI - Strengthening American psychiatry - Diversity, leadership and Asian applicants for residency. PMID- 28558890 TI - Family accommodation in somatoform disorders-its effects on diagnosis and management: A case report. PMID- 28558891 TI - Mirror neuron activity in schizophrenia may remain unaffected by duration of untreated psychosis. PMID- 28558892 TI - Functional near infra-red spectroscopy (fNIRS) in schizophrenia: A review. AB - The research on the alterations in functional connectivity in schizophrenia has been facilitated by development of an array of functional neuroimaging techniques. Functional Near Infra Red Spectroscopy (fNIRS) is a novel diffuse optical neuromonitring method with its own advantages and limitations. The advantages of fNIRS have made it to be frequently used as a research tool by medical community in different settings. In fNIRS the property of haemoglobin to absorb near infrared light is used to measure brain activity. It provides the indirect measurement of the neuronal activity in the areas of interest. The advantage of fNIRS being less restrictive has made it to be used more commonly in the research of psychiatric disorders in general, schizophrenia in particular. The fNIRS studies on patients with schizophrenia have shown haemodynamic hypo activation primarily in the prefrontal cortex during various cognitive tasks. In this review, initially we have briefly explained the basic principles of fNIRS followed by detailed review of fNIRS findings in patients with schizophrenia. PMID- 28558893 TI - Are there differences in the mental health status of adolescents in Puducherry? AB - The present study assessed the mental health of adolescents in Puducherry, India. This cross-sectional study was conducted on 291 students (121 male and 170 female) in the 14-17year old age group, grades IX and XI. The students were recruited from private, public, co-ed and single sex schools. Along with a Structured Questionnaire, the Mental Health Inventory was administered. We sought to investigate as to whether there would be differences in mental health status of adolescents based on age, class, gender and other demographic variables. There were significant age differences with respect to global mental health, psychological distress, anxiety and loss of behavioural/emotional control. Family type-wise significant differences in global mental health, life satisfaction and loss of behavioural/emotional control were also found. Significant differences were observed with respect to global mental health, psychological well-being, positive effects, psychological distress and depression across socio-economic groups. Number of siblings also accounted for differences in anxiety and emotional ties. However, no significant gender differences were observed across mental health sub-scales. Results suggest the need for promotion of mental health awareness and intervention programs for adolescents, their parents and teachers. There is also a need for advocacy in children and adolescent rights regarding welfare, well-being and protection from violence. The objective is to enhance psychological well-being and reduce psychological distress in students across different social strata. PMID- 28558894 TI - Depression severity and quality of life of qualified and unqualified patients with a mood disorder for a research study targeting anhedonia in a clinical sample. AB - OBJECTIVE: To investigate the depression severity and quality of life of qualified and unqualified patients with a mood disorder for a research study based on anhedonia severity. METHODS: Diagnosis of major depressive disorder (MDD) or bipolar disorder (BPD) was ascertained with the MINI International Neuropsychiatric Interview. The severity of depression was measured with the 16 item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-16-SR), and Item 5, "feeling sad (sadness)," QIDS-16-SR Item 13, "change in general interest," was used to measure the severity of anhedonia. The quality of life was measured with the Quality of Life, Enjoyment and Satisfaction Questionnaire (Q LES-Q). RESULTS: Of 96 patients with MDD and 147 with bipolar I or II disorder, the severity rating on sadness and anhedonia was similar. The severities of anhedonia and sadness were highly correlated with R2 of >=0.91. Without considering depressive severity, 55% of patients would be eligible for a study if>=mild anhedonia was used as a severity criterion, but only 26% of patients eligible for a study if>=moderate anhedonia was used without considering substance use and medical comorbidities. If patients with >= moderate overall depressive symptoms were considered, 88.1% of patients would be eligible if>=mild anhedonia was required for a study, and 45.2% of patients would be eligible for a study if>=moderate anhedonia was required. For those who were unqualified for the study based on>=moderate anhedonia, about 1/3 had>=moderate overall depressive symptoms and less than 40% of maximum possible scores of Q-LES-Q. If only patients in remission based on overall depressive symptom severity were considered for a study of anhedonia, no patient would be eligible for the study. CONCLUSION: Depressive mood and anhedonia are highly correlated. Screening patients with a mood disorder and an overall moderate depressive severity is a cost-effective approach for a study targeting anhedonia, especially for a study requiring>=moderate severity of anhedonia. However, 1/3 of the unqualified patients will have>=moderate overall depressive symptoms and poor quality of life. PMID- 28558895 TI - Prevalence of depression and past suicide attempt in primary care. AB - BACKGROUND: It is known that persons who die by suicide commonly visit a primary care physician (PCP) shortly before the fatal act.There is little information on history of suicide attempt in depressed patients who consult PCPs for non-mental health indications.This information is important because past history of suicide attempt is a known predictor of future suicide risk. OBJECTIVE: To estimate the prevalence of depression among outpatients in primary care and to determine the prevalence and determinants of past suicide attempt among them. METHOD: This cross-sectional study was conducted in six primary care settings, both public and private, in Kerala, India. A psychiatrist evaluated adult outpatients (n=827), diagnosed depression using ICD-10 Diagnostic Criteria for Research, and elicited history of suicide attempt. RESULTS: Overall depression prevalence was 27.2% and was higher in women. Past suicide attempt was identified in 6.9% (95% CI, 5.17 8.63%) of all outpatients; higher in women (9.2%) than men (3.6%). Among the depressed, 21.3% had previously attempted suicide; while this figure was 1.5% in the non-depressed. The prevalence of current depression was 81% (severe depression, 61%) in patients reporting past suicide attempts. In univariate analyses, female gender, perceived financial stress, and being depressed were significantly associated with past suicide attempts. In multivariate analysis, current depression was the largest predictor of past suicide attempt (adjusted odds ratio, 14.3; 95% CI, 6.60-31.07). CONCLUSION: Depression and suicide attempt are both common in primary care. Depression is the single most important predictor of suicide attempt. PMID- 28558896 TI - Aripiprazole-induced neuroleptic malignant syndrome. PMID- 28558897 TI - A systematic review and quality assessment of psychological, pharmacological, and family-based interventions for hoarding disorder. AB - INTRODUCTION: Hoarding disorder (HD) affects at least 1.5% of the population and is considered to be hard to treat. The current study aimed to systematically review the treatments designed to improve HD symptoms and family impact. METHOD: Searches of PsycINFO, MEDLINE, EMBASE, and Web of Science were undertaken. Studies were included if: (i) the study evaluated an intervention for hoarding problems; (ii) outcome measures were reported; and (iii) study results were published in an indexed journal or were a published abstract from a professional/research conference. The quality of the studies was assessed using the Clinical Trials Assessment Measure (CTAM). RESULTS: Twenty studies, comprising 492 participants with clinically significant hoarding symptoms or HD and 21 relatives of individuals with HD, met inclusion criteria. Treatments reviewed included cognitive-behavior therapy, medication, cognitive remediation, and multi-component interventions for relatives. Most studies yielded statistically significant improvements in hoarding symptoms, although reductions were generally modest and many participants remained in the clinical range after treatment. According to the CTAM, most studies were judged to be of low methodological quality. CONCLUSIONS: HD is a chronic and highly burdensome condition for which efficacious treatments are needed. The current evidence base is somewhat limited and of low quality. Further research is needed to improve treatments, identify mechanisms of change, and increase the availability of evidence-based interventions for this group. PMID- 28558899 TI - Hyperprolactinemia with low dose of risperidone in a young female. PMID- 28558898 TI - Aripiprazole and impulse-control disorders in high-risk patients. AB - A case study demonstrating the association between aripiprazole and impulse control disorders and a call for caution when prescribing aripiprazole to high risk patients. PMID- 28558900 TI - Effect of CLU and PICALM polymorphisms on AD risk: A study from south India. AB - OBJECTIVES: To study the association of apolipoprotein E (APOE), Clusterin (CLU) and phosphatidylinositol binding clathrin assembly protein (PICALM) polymorphisms in Alzheimer's disease (AD) subjects compared to cognitively normal control subjects in an Indian population. METHODS: The study subjects included persons with AD (N=243) and age group matched healthy controls (N=164). All the AD subjects were evaluated using a standard protocol. DNA was isolated from whole blood. APOE (rs7412, rs429358), CLU (rs11136000) and PICALM (rs3851179) were genotyped. General linear model was used to test the association between the individual risk genotypes and AD. RESULTS: The presence of APOE epsilon4 was associated with AD after adjusting for age and gender (p<0.0001). There was no association observed with AD at both rs11136000 CLU (p=0.25) and rs3851179 PICALM (p=0.54). CONCLUSION: Our results confirmed a significant association of APOE epsilon4 carrier status with AD. No association was observed for CLU and PICALM with AD. This might be due to a different genetic background. There are no previous reports of these polymorphisms in an Indian cohort. Future Indian AD studies should investigate additional SNPs in a larger sample size in these genes. PMID- 28558901 TI - Associations of number and severity of depressive episodes with C-reactive protein and Interleukin-6. AB - BACKGROUND: Many researchers have found that the inflammatory process in the body and the brain may result in psychiatric disorders. Meta-analyses of cross sectional studies have reported increase in inflammatory markers in depression. However, the direction of the association remains unclear. AIMS: To compare the levels of C-reactive protein (CRP) and Interleukin-6 (IL-6) in depressed and healthy controls. To study the associations of these biomarkers with severity and number of depressive episodes. METHODS: A total of 72 subjects with major depression and 60 healthy controls were studied. CRP and IL-6 were measured in all subjects. RESULTS: No significant differences were noted between depressed patients and healthy controls with regard to CRP (p=0.29) and IL-6 (p=0.50). Those who were suffering from severe depression based on Beck's Depressive Inventory (BDI), were positively correlated with raised CRP (p=0.011) in comparison to patients with mild to moderate depression. Single and recurrent depressive disorder (RDD) were not associated with significant rise in CRP (p=0.866) and IL-6 (p=0.531). CONCLUSIONS: Severity of depression is correlated with elevated CRP but not with IL-6. No association found between number of depressive episodes and levels of CRP and IL-6. It is possible that immune dysregulation is not generally present in depression, but might be restricted to particular subgroups of depressed patients. Several factors that could influence the depression and inflammation relationship need further investigation. PMID- 28558902 TI - The prevalence of phantom vibration/ringing syndromes and their related factors in Iranian' students of medical sciences. AB - BACKGROUND AND AIM: Mobile phone abuse can cause pathologic stress that may lead to addictive behavior such as Phantom Vibration Syndrome (PVS) and Phantom Ringing Syndrome (PRS). The current study aimed to determine the PVS and PRS due to mobile phone use in students of Qom University of medical Sciences in Iran. DESIGN: Cross-sectional study. PARTICIPANTS: The participants were 380 students selected by proportional stratified random sampling method in each stratum. MEASUREMENTS: Data were collected by a self-administered questionnaire and analyzed by descriptive and analytic statistical methods including t-test, chi square and analysis of variance. FINDINGS: The prevalence of PVS and PRS due to mobile phones in students of medical sciences was estimated to be 54.3% and 49.3%, respectively. PVS was higher in female students than in males while the PRS was higher in male students. There was a significant relationship between PVS and using social networks such as Viber, WhatsApp, and Line. In addition, a significant association was observed between PVS and friend-finding, chatting and entertainment. CONCLUSION: Studies should be done in the future to assess the long-term complication of overusing mobile phones. In the current study, the prevalence of PVS and PRS in half of students is considerable. PMID- 28558903 TI - Exploration of food addiction in people living with schizophrenia. AB - The term food addiction (FA) denotes a concept among researchers and lay consumers as a behavioural phenotype related to excessive food consumption. In this study we examined the prevalence of FA using the validated Yale Food Addiction Scale (YFAS) as well as the dimensional symptom count. In addition, we explored associations between participant characteristics and FA diagnosis. Outpatients attending a clozapine clinic and possessing a diagnosis of schizophrenia were invited to complete an anonymous survey using the YFAS. Ninety three surveys were used to calculate the diagnostic YFAS criteria for FA. The prevalence of FA found in this sample was 26.9%. Among individuals who did not meet "diagnostic" criteria FA, 77.4% endorsed 3 or more symptoms but did not report distress or impairment. The most common food addiction symptom was a persistent desire or repeated unsuccessful attempts to cut down consumption (97.9%). The significant finding in association between individual's characteristics and diagnosis of FA was employment. Several factors related to reported results are postulated and discussed. The current study has found the prevalence of FA amongst people living with schizophrenia to be higher than the general populations but not as high as populations with disordered eating. PMID- 28558904 TI - Depression in diabetes mellitus-A comprehensive systematic review of literature from an Indian perspective. AB - : Diabetes and depression are rapidly growing chronic health conditions that have significant negative impact upon the physical, psychological, social and occupational functioning, quality of life and often leads to socio-economic burden. Presence of both these comorbid diseases results in various short term and long term complications and increases the mortality as compared to those with depression or diabetes alone. OBJECTIVES: Systematic review of the epidemiological data, risk factors and relationship between depression and glycaemic control among the Indian studies. METHODS: We searched Pubmed, Pubmed Central, Google Scholar and Directory of Open Access Journal (DOAJ) databases to identify relevant Indian studies. RESULTS: Substantial variation in the prevalence of depression in people with diabetes was found across the 41 selected studies; according to this review the range is 2% to 84% (T1DM - 2-7%; T2DM - 8% 84%). Correlates of depression in diabetic patients are advancing age, female gender, low literacy rate, burden of being from a lower socioeconomic status, rural domicile, marriage and duration of diabetes of >2years, diabetes related complications and poor glycaemic control. Sedentary life without adequate physical activities, lack of self-care are often the factors that precipitates depression in a T2DM patient and vice versa. CONCLUSION: According to this review, among Indian population there is a significant association between depression and diabetes. PMID- 28558905 TI - Correlates and predictors of antipsychotic drug polypharmacy in real-life settings: Results from a nationwide cohort study. AB - Reasons for using antipsychotic polypharmacy (APP) in routine clinical practice, despite a potentially unfavorable risk-benefit ratio, are poorly understood. This research aimed to determine (1) if severe courses of schizophrenia were associated with APP and (2) if a schizophrenia-related acute event would predict a switch to APP in the short term. Observational prospective data (at baseline and 6months) were drawn from a French nationwide cohort ("Cohorte Generale Schizophrenie"), which included 1859 inpatients and outpatients with schizophrenia. APP was defined as the prescription of >=2 antipsychotic drugs (there being different active substances). Early-onset schizophrenia, legal guardianship, higher lifetime maximal severity of illness and comorbid antisocial personality were used as proxies for severe courses of schizophrenia. Schizophrenia-related acute events included hospitalization and recent suicide attempts. Logistic regression models were used to determine (1) whether the use of APP at baseline (vs. monotherapy) was associated with a severe course of schizophrenia or not, independent of acute events, and (2) if a switch to APP at 6months (vs. remaining on monotherapy) was associated with acute events, independent of severe courses of schizophrenia. Increased odds of APP use at baseline were independently associated with legal guardianship (OR=1.6; 95%CI=1.3, 2.0) and higher lifetime maximum severity of illness (OR=1.3; 95%CI=1.2, 1.5). A switch to APP at 6months was predicted by a hospitalization occurring since baseline (OR=6.1; 95%CI=3.9, 9.4). In routine clinical practice, APP is more likely prescribed to patients with severe courses of illness, possibly indicating the difficulty to manage these patients. PMID- 28558906 TI - Carbamoylated azithromycin incorporated zirconia hybrid monolith for enantioseparation of acidic chiral drugs using non-aqueous capillary electrochromatography. AB - Carbamoylated derivatives of two antibiotics, namely, clindamycin phosphate (CLIP) and erythromycin (ERY) were successfully employed as co-precursors, in combination of zirconium tetrabutoxide as a precursor, to prepare chiral organic zirconia hybrid monoliths (i.e., CLIP-ZHMs and ERY-ZHMs, respectively) via a single-step in-situ sol-gel approach in our previous works. Their superiority over chiral organic-zirconia/silica monoliths, prepared by post-modification approach, in terms of better enantioresolution and enhanced stability inspired us to prepare ZHMs based on an another antibiotic, azithromycin (i.e., AZI-ZHMs). Monolithic columns were employed for capillary electrochromatographic enantioseparation of acidic chiral drugs in mobile phases consisting of acetonitrile (ACN) and methanol (MeOH) as organic modifiers, and acetic acid (AcOH) and triethylamine (TEA) as electrolytes. The effects of composition of mobile phase and applied voltage on chiral separation were investigated by using ketoprofen as a representative analyte. Baseline resolutions were obtained for six acidic drugs in mobile phase consisting of 80/20 (v/v) ACN/MeOH with 300mM AcOH and 10mM TEA at a 10kV applied voltage and 25 degrees C capillary temperature. The relative standard deviations for resolution values regarding column to column and batch to batch repeatability were less than 2.5% (for n=3) under optimized conditions, indicating satisfactory stability of the columns and reproducibility of the column preparation process. PMID- 28558907 TI - Cold-induced aqueous acetonitrile phase separation: A salt-free way to begin quick, easy, cheap, effective, rugged, safe. AB - Cooling a 1:1 (v/v) solution of acetonitrile and water at -16 degrees C is known to result in two clear phases. We will refer to this event as "cold-induced aqueous acetonitrile phase separation (CIPS)". On a molar basis, acetonitrile is 71.7% and 13.6% in the upper and lower phases, respectively, in our study. The phase separation proceeds as a descending cloud of microdroplets. At the convenient temperature (typical freezer) employed here the lower phase is rather resistant to solidification, although it emerges from the freezer as a solid if various insoluble matter is present at the outset. In a preliminary way, we replaced the initial (salting-out) step of a representative QuEChERS procedure with CIPS, applying this modified procedure ("CIPS-QuEChERS") to a homogenate of salmon (and partly to beef). Three phases resulted, where only the upper, acetonitrile-rich phase is a liquid (that is completely clear). The middle phase comprises ice and precipitated lipids, while the lower phase is the residual matrix of undissolved salmon or meat. Treating the upper phase from salmon, after isolation, with anhydrous MgSO4 and C18-Si (typical QuEChERS dispersive solid phase extraction sorbents), and injecting into a GC-MS in a nontargeted mode, gives two-fold more preliminary hits for chemicals, and also number of spiked pesticides recovered, relative to that from a comparable QuEChERS method. In part, this is because of much higher background signals in the latter case. Further study of CIPS-QuEChERS is encouraged, including taking advantage of other QuERChERS conditions. PMID- 28558909 TI - Introduction to the special issue on human competition. PMID- 28558908 TI - State-level geographic variation in prompt access to care for children after motor vehicle crashes. AB - BACKGROUND: Motor vehicle crashes (MVCs) are a principal cause of death in children; fatal MVCs and pediatric trauma resources vary by state. We sought to examine state-level variability in and predictors of prompt access to care for children in MVCs. MATERIALS AND METHODS: Using the 2010-2014 Fatality Analysis Reporting System, we identified passengers aged <15 y involved in fatal MVCs (crashes on US public roads with >=1 death, adult or pediatric, within 30 d). We included children requiring transport for medical care from the crash scene with documented time of hospital arrival. Our primary outcome was transport time to first hospital, defined as >1 or <=1 h. We used multivariable logistic regression to establish state-level variability in the percentage of children with transport time >1 h, adjusting for injury severity (no injury, possible injury, suspected minor injury, suspected severe injury, fatal injury, and unknown severity), mode of transport (emergency medical services [EMS] air, EMS ground, and non-EMS), and rural roads. RESULTS: We identified 18,116 children involved in fatal MVCs from 2010 to 2014; 10,407 (57%) required transport for medical care. Median transport time was 1 h (interquartile range: [1, 1]; range: [0, 23]). The percent of children with transport time >1 h varied significantly by state, from 0% in several states to 69% in New Mexico. Children with no injuries identified at the scene and crashes on rural roads were more likely to have transport times >1 h. CONCLUSIONS: Transport times for children after fatal MVCs varied substantially across states. These results may inform state-level pediatric trauma response planning. PMID- 28558910 TI - The PPII-to-alpha-helix transition of poly-l-lysine in methanol/water solvent mixtures accompanied by fibrillar self-aggregation: An influence of fluphenazine molecules. AB - Fourier-transform infrared, vibrational circular dichroism spectroscopy and transmission electron microscopy are used to follow the structural changes of pure and fluphenazine (FPh)-mixed poly-l-lysine (PLL) triggered by variations of the methanol to water ratio in solvent mixtures. FPh molecules are used as an effective psychotic drug but with a strong Parkinson's-related side effect. To answer the question whether FPh molecules can modify the fibril development, the PLL polypeptide was used as a model of alpha-helix- and PPII-rich fibrils. It was stated that the presence of FPh molecules did not inhibit the creation of both types of PLL fibrils with clustering features. The methanol-poor aqueous solutions promote the formation of extended polyproline II (PPII) helices; however, the methanol-rich aqueous solutions induce the development of alpha helices of both pure and FPh-mixed PLL. Unpredicted and interesting features of PLL fibrillogenesis are evidenced by the formation of uncommon fibrillar aggregates, which are developed in methanol/water solvents from PLL molecules rich in either alpha-helix or PPII structures. Possibility of PLL molecules to form beta-sheet-, alpha-helix- and PPII-rich fibrils demonstrating that fibrillogenesis is a common phenomenon, and fibrillar aggregates can be based on all of the basic protein secondary structures. PMID- 28558911 TI - Main photophysical properties of oxyblepharismin. AB - Oxyblepharismin is the photo-oxidized form of blepharismin, the chromophore responsible for the photophobic response of heterotrich ciliate Blepharisma japonicum, and represents a nice model for the study of photo-transduction. In this work, we focused on the photophysical characterization of OxyBP, in view of highlighting the main features related to excitation and emission. By a combined experimental and computational approach we identified the main features of absorption and fluorescence emission of the molecule in solvents of different properties, identifying the nature of transitions as well as the possible heterogeneity at ground/excited state. The thorough photophysical characterization of OxyBP is meant to provide the starting point for the elucidation of the photo-transduction pathway in vivo. PMID- 28558912 TI - Epidermolysis Bullosa Simplex Caused by Distal Truncation of BPAG1-e: An Intermediate Generalized Phenotype with Prurigo Papules. PMID- 28558914 TI - Numerical investigation of the early flight phase in ski-jumping. AB - The purpose of this study is to develop a numerical methodology based on real data from wind tunnel experiments to investigate the effect of the ski jumper's posture and speed on aerodynamic forces in a wide range of angles of attack. To improve our knowledge of the aerodynamic behavior of the ski jumper and his equipment during the early flight phase of the ski jump, we applied CFD methodology to evaluate the influence of angle of attack (alpha=14 degrees , 21.5 degrees , 29 degrees , 36.5 degrees and 44 degrees ) and speed (u=23, 26 and 29m/s) on aerodynamic forces in the situation of stable attitude of the ski jumper's body and skis. The standard k-omega turbulence model was used to investigate both the influence of the ski jumper's posture and speed on aerodynamic performance during the early flight phase. Numerical results show that the ski jumper's speed has very little impact on the lift and drag coefficients. Conversely, the lift and drag forces acting on the ski jumper's body during the early flight phase of the jump are strongly influenced by the variations of the angle of attack. The present results suggest that the greater the ski jumper's angle of inclination, with respect to the relative flow, the greater the pressure difference between the lower and upper parts of the skier. Further studies will focus on the dependency of the parameters with both the angle of attack alpha and the body-ski angle beta as control variables. It will be possible to test and optimize different ski jumping styles in different ski jumping hills and investigate different environmental conditions such as temperature, altitude or crosswinds. PMID- 28558913 TI - The International TREatment of ATopic Eczema (TREAT) Registry Taskforce: An Initiative to Harmonize Data Collection across National Atopic Eczema Photo- and Systemic Therapy Registries. PMID- 28558915 TI - Distal skeletal tibia assessed by HR-pQCT is highly correlated with femoral and lumbar vertebra failure loads. AB - Dual energy X-ray absorptiometry (DXA) is the standard for assessing fragility fracture risk using areal bone mineral density (aBMD), but only explains 60-70% of the variation in bone strength. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides 3D-measures of bone microarchitecture and volumetric bone mineral density (vBMD), but only at the wrist and ankle. Finite element (FE) models can estimate bone strength with 86-95% precision. The purpose of this study is to determine how well vBMD and FE bone strength at the wrist and ankle relate to fracture strength at the hip and spine, and to compare these relationships with DXA measured directly at those axial sites. Cadaveric samples (radius, tibia, femur and L4 vertebra) were compared within the same body. The radius and tibia specimens were assessed using HR-pQCT to determine vBMD and FE failure load. aBMD from DXA was measured at the femur and L4 vertebra. The femur and L4 vertebra specimens were biomechanically tested to determine failure load. aBMD measures of the axial skeletal sites strongly correlated with the biomechanical strength for the L4 vertebra (r=0.77) and proximal femur (r=0.89). The radius correlated significantly with biomechanical strength of the L4 vertebra for vBMD (r=0.85) and FE-derived strength (r=0.72), but not with femur strength. vBMD at the tibia correlated significantly with femoral biomechanical strength (r=0.74) and FE-estimated strength (r=0.83), and vertebral biomechanical strength for vBMD (r=0.97) and FE-estimated strength (r=0.91). The higher correlations at the tibia compared to radius are likely due to the tibia's weight bearing function. PMID- 28558916 TI - Microbiological diagnosis of biofilm-related infections. AB - Biofilm-related infections represent a serious health problem, accounting for 65- 80% of all infections. The infections are generally chronic and characterized by the persistence of the microorganism, due to the increased resistance of biofilms to both the immune system and antimicrobials. Biofilms can be located to almost every human body tissue and on exogenous devices such as catheters, pacemakers, prosthetic material, implants, urinary catheters, etc. Traditional antimicrobial susceptibility studies in clinical microbiology laboratories have lied on the study of planktonic form of microorganisms. However, this approach might lead to miss the biofilm characteristics and to a treatment failure. Microbiological diagnosis and antimicrobial susceptibility studies of biofilm-related infections are complex and, nowadays, represent a challenge that clinicians and microbiologists have to address as a team in the absence of consensus or standardized protocols. PMID- 28558917 TI - Urinary F2-isoprostanes and the risk of hypertension. AB - PURPOSE: There is strong biological plausibility for a causal role of reactive oxygen species in vascular pathology but no direct epidemiological evidence linking elevated reactive oxygen species levels to hypertension development. We examined cross-sectional and prospective associations between oxidative status (urinary F2-isoprostanes) and hypertension in the Insulin Resistance Atherosclerosis Study cohort (n = 831). METHODS: The cohort included non-Hispanic white, Hispanic, and non-Hispanic black individuals, with 252 (30%) having prevalent hypertension and 579 participants normotensive at baseline, 122 (21%) of whom developed hypertension during the 5-year follow-up. Four urinary F2 isoprostane isomers were quantified in baseline specimens using LC/MS-MS and were summarized as a composite index. Examined outcomes included hypertension status (yes/no), systolic (SBP) and diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP). RESULTS: Prevalent and incident hypertension were associated with greater age, Black race, impaired glucose tolerance, and greater BMI. F2-IsoP levels were lower among men and among non-Hispanic Blacks, were inversely associated with age, and were directly associated with BMI. No cross-sectional association was found between F2-isoprostanes and hypertension status (OR = 0.93, 0.77-0.12). Among the continuous measures of blood pressure only PP was associated with F2-isoprostanes at baseline (beta-coefficient = 0.99, 0.11-1.86). No prospective association was found between F2-isoprostanes and incident hypertension: OR = 0.98, 0.77-1.25. No prospective associations were found for systolic blood pressure and diastolic blood pressure, and pulse pressure. Mean arterial pressure showed an inverse association (beta-coefficient = -0.16, -0.31 to -0.01). CONCLUSIONS: Elevated F2-isoprostane levels do not increase the risk of hypertension. PMID- 28558918 TI - General phytoplasma detection by a q-PCR method using mycoplasma primers. AB - Phytoplasmas and mycoplasmas are bacteria belonging to the class Mollicutes. In this study, a fine tuning of quantitative polymerase chain reaction (qPCR) with a universal mycoplasma primer pair (GPO3F/MGSO) targeting the 16S rRNA gene was carried out on phytoplasmas. The dissociation curves of DNAs from Catharanthus roseus phytoplasma-infected micropropagated shoots and from phytoplasma field infected plant samples showed a single peak at 82.5 degrees C (+/-0.5) specifically detecting phytoplasmas belonging to several ribosomal groups. Assay specificity was determined with DNA of selected bacteria: 'Candidatus Liberibacter solanacearum', Xylella fastidiosa, Ralstonia solanacearum and Clavibacter michiganensis. No amplification curves were observed with any of these tested bacteria except 'Ca. L. solanacearum' that was amplified with a melting temperature at 85 degrees C. Absolute quantification of phytoplasma titer was calculated using standard curves prepared from serial dilutions of plasmids containing the cloned fragment GPO3F/MGSO from European stone fruit yellows phytoplasma. Phytoplasma copy number ranged from 106 to 103 according with the sample. The sensitivity evaluated comparing plasmid serial dilutions resulted 10-6 for conventional PCR and 10-7 for qPCR. The latter method resulted therefore able to detect very low concentrations of phytoplasma in plant material. PMID- 28558919 TI - Corrigendum to "Electric injury-induced Purkinje cell apoptosis in rat cerebellum: Histological and immunohistochemical stud" [J. Chem. Neuroanat., 81 (2017) 87-96]. PMID- 28558920 TI - Corrigendum to "Exercise-based cardiac rehabilitation in twelve European countries: Results of the European Cardiac Rehabilitation Registry" [Int. J. Cardiol. 228 (2017) 58-67]. PMID- 28558921 TI - Bronchial mucous gland adenoma: A rare tumor. PMID- 28558922 TI - The Role of Computed Tomography in the Diagnosis of Relapsing Polychondritis. PMID- 28558923 TI - Uncommon Variant of Scimitar Syndrome. PMID- 28558924 TI - The Future of Biololgical Markers in COPD. PMID- 28558925 TI - Core-needle biopsy in the diagnosis of lung cancer. PMID- 28558926 TI - Using PICO Methodology to Answer Questions About Smoking in COPD Patients. AB - The ALAT and SEPAR Treatment and Control of Smoking Groups have collaborated in the preparation of this document which attempts to answer, by way of PICO methodology, different questions on health interventions for helping COPD patients to stop smoking. The main recommendations are: (i)moderate-quality evidence and strong recommendation for performing spirometry in COPD patients and in smokers with a high risk of developing the disease, as a motivational tool (particularly for showing evidence of lung age), a diagnostic tool, and for active case-finding; (ii)high-quality evidence and strong recommendation for using intensive dedicated behavioral counselling and drug treatment for helping COPD patients to stop smoking; (iii)high-quality evidence and strong recommendation for initiating interventions for helping COPD patients to stop smoking during hospitalization with improvement when the intervention is prolonged after discharge, and (iv)high-quality evidence and strong recommendation for funding treatment of smoking in COPD patients, in view of the impact on health and health economics. PMID- 28558927 TI - In Vitro and In Vivo Evaluation of the Combination of Oscillating Positive Expiratory Pressure and Nebulization: A Randomized Cross-Over Study. PMID- 28558928 TI - NeuN immunoreactivity in the brain of Xenopus laevis. AB - Neuronal nuclear antigen (NeuN), discovered in mice brain cell nuclei by Mullen et al. (1992), is used as an excellent marker of post-mitotic neurons in vertebrates. In this study, the expression pattern of NeuN was examined in the Xenopus brain to explore phylogenetic differences in NeuN expression. Anti-NeuN antibody showed selective staining in mouse and Xenopus brain extracts, but the number and molecular weight of the bands differed in Western blotting analysis. In immunostaining, anti-NeuN antibody showed selective staining of neurons, but not glial cells, in the Xenopus brain. Most neurons, including olfactory bulb mitral cells and cerebellar Purkinjie cells, which show no immunoreactivity in birds/mammals, showed NeuN immunoreactivity in Xenopus. This study revealed that anti-NeuN antibody is a useful marker of post-mitotic neurons in amphibians, but it also stains neurons that show no reactivity in more derived animals. PMID- 28558929 TI - Agreement between heart failure patients and providers in assessing New York Heart Association functional class. AB - BACKGROUND: Uncertainty persists regarding whether patient assessment of New York Heart Association (NYHA) functional classification should be preferred over provider assessment among patients with heart failure (HF). OBJECTIVES: To compare patient against provider NYHA assessments, and both to distance walked on a 6-minute walk test (6MWT) among patients with HF. METHODS: In this prospective study, we enrolled 101 HF patients who self-assessed NYHA classification. Health care providers who were blinded to patient ratings of NYHA also rated NYHA. Patients completed a 6MWT according to a standardized protocol. We used Spearman coefficients (rs) to evaluate the correlations between variables. RESULTS: Patient- and provider-determined NYHA class were poorly correlated, but the relationship was statistically significant (rs = 0.40, p < 0.001). Patients consistently reported better NYHA class (class I: 72% vs 15%) than providers. Provider-determined NYHA had a stronger correlation with 6MWT distance (rs = 0.36, p < 0.001 vs. rs = -0.22, p = 0.03). Providers assigned a worse class to older patients who had comorbidity; patients with dyspnea and longer HF duration assigned themselves a worse class. CONCLUSION: Patients and providers exhibited poor agreement in NYHA assignment. PMID- 28558931 TI - Freeze-responsive regulation of MEF2 proteins and downstream gene networks in muscles of the wood frog, Rana sylvatica. AB - The wood frog survives frigid North American winters by retreating into a state of suspended animation characterized by the freezing of up to 65% of total body water as extracellular ice and displaying no heartbeat, breathing, brain activity, or movement. Physiological and biochemical adaptations are in place to facilitate global metabolic depression and protect against the consequences of whole body freezing. This study examined the myocyte enhancer factor 2 (MEF2) transcription factor family, proteins responsible for coordinating selective gene expression of a myriad of cellular functions from muscle development and remodelling to various stress responses. Immunoblotting, subcellular localization, and RT-PCR were used to analyze the regulation of MEF2A and MEF2C transcription factors and selected downstream targets under their control at transcriptional, translational, and post-translational levels in skeletal and cardiac muscles from control, frozen and thawed frogs. Both MEF2A/C proteins were freeze-responsive in skeletal muscle, displaying increases of 1.7-2 fold for phosphorylated MEF2AThr312 and MEF2CThr300 during freezing with an enrichment of nuclear phosphorylated MEF2 proteins (by 1.7-2.1 fold) observed as early as 4h post-freezing. Despite the reduced response of total and phosphorylated MEF2A/C protein levels observed in cardiac muscle, the MEF2 downstream gene targets (glucose transporter-4, calreticulin, and creatine kinase brain and muscle isozymes) displayed similar increases in transcript levels (1.7-4.8 fold) after 24h freezing in both muscle types. This study describes a novel freeze-responsive function for MEF2 transcription factors and further elaborates our understanding of the molecular mechanisms underlying natural freeze tolerance. This novel freeze-responsive regulation suggests a role for MEF2s and downstream genes in cryoprotectant glucose distribution, calcium homeostasis, and maintenance of energy reserves vital for successful freeze tolerance. PMID- 28558930 TI - The learning curve with a new cephalomedullary femoral nail. AB - INTRODUCTION: The Cephalomedullary Nail (CMN) (Zimmer, Warsaw) was introduced in 2010 as part of a multicenter trial to evaluate its performance. At one year the CMN had results in keeping with other intramedullary devices with good union rates and low complication rates. In the second and third years of use an increased rate of implant failure was observed, towards the higher end of the 1 5% nail breakage rate seen in other studies. This study aims to evaluate if there any common features in this cohort of patients. MATERIALS AND METHODS: This is a retrospective cohort study looking at patients who underwent femoral fracture fixation using the cephalomedullary nail between January 2011 and June 2014. The primary outcome measure was implant failure; secondary outcomes were; fracture reduction and bisphosphonate use. RESULTS: 201 patients were included (135 female, 66 male) with an average age of 81 years. Ten (5%) nail breakages occurred in the study period at an average of 39 weeks (24-92); 9 were 125 degrees nails 1 was a 130 degrees nail and all fractured at the lag screw junction. CONCLUSIONS: Implant failure is a recognised complication of intramedullary nailing in cases of non-union. The increased rate of implant failure in our department required a change to a 130 degrees CMN implant and a 3.2mm diameter guide wire for placement of the lag screw. We continue to monitor this difficult group of patients very closely. PMID- 28558932 TI - Bama miniature pigs' liver possess great heat tolerance through upregulation of Nrf2-mediated antioxidative enzymes. AB - The liver is one of the most crucial organs affected by high ambient temperature. Bama miniature pig show a heat tolerance in hot summer months. However, the physiological condition of liver under high ambient temperature has not been well elucidated in Bama miniature pig. Here we performed an experiment to investigate the effects of high ambient temperature on liver function, redox status and Nrf2 antioxidant pathway in Bama miniature pigs. Twelve pigs were randomly divided into two groups and separately exposed to the neutral temperature (NT, 25 degrees C) and high temperature (HT, 40 degrees C) for 8 days. The hepatic damage marker, such as total bilirubin (TBIL), alkaline phosphatase (AKP), gamma-glutamyl transpeptidas (gamma-GT), alanine transaminase (ALT) and aspartase transminase (AST), didn't reach statistical significance between NT and HT group. Moreover, abnormal observation of hepatic histology and hepatocyte ultrastructure were not detected in HT group. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) as well as glutathione (GSH) content, were dramatically increased after heat exposure. Heat treatment didn't increase hydrogen peroxide (H2O2) and malondialdehyde (MDA) concentrations. The expression of Nrf2-regulated genes, such as nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H: quinine oxidoreductase 1 (NQO1), superoxide dismutase 1 (SOD1), heme oxygenase-1 (HO-1) and glutamate cysteine ligase catalytic subunit (GCLC), were significantly increased in HT group. Nrf2 protein was accumulated in HT group through immunohistochemical analysis. The current data provide clear evidence that Bama miniature pigs' liver possess great capacity of heat tolerance, which related to activation of Nrf2 antioxidant pathway. PMID- 28558934 TI - Variation in rhinarium temperature indicates sensory specializations in placental mammals. AB - The rhinarium, a specialized nose-tip characterized by an area of naked and wet skin around the nostrils, is a typical mammalian structure. The type and amount of innervation suggests a sensory role and morphological diversity implies so far unidentified species-specific functional specializations. Rhinaria also vary in temperature and this may be related to the functions of these sensory organs. We performed a comparative study on rhinarium temperature in order to learn more about possible correlations with phylogeny and ecology. We have concentrated on terrestrial carnivorans and large herbivores, but also investigated a number of other species, some of them lacking typical rhinaria. We used infrared (IR) thermography to determine nose skin temperatures from safe distances and without interfering with the animals' behavior. In all groups studied, the temperature of the rhinarium/nose-tip decreased with decreasing ambient temperature. At all ambient temperatures, rhinarium temperature was lower, by 9-17 degrees C, in carnivorans compared to herbivores. Glires (rodents and lagomorphs), haplorrhine primates, and omnivorous Perisso- and Artiodactyla were intermediate. In strepsirrhine primates, rhinarium temperature was similar to ambient temperature. Our findings in Strepsirrhini are consistent with the hypothesis that their rhinaria have an indirect role in chemical communication. Warm rhinaria in herbivores suggest a tactile function, while the low skin temperatures on carnivoran rhinaria may make the skin particularly sensitive to warming. PMID- 28558933 TI - Effect of temperature and social environment on worker size in the ant Temnothorax nylanderi. AB - Warm temperatures decrease insect developmental time and body size. Social life could buffer external environmental variations, especially in large social groups, either through behavioral regulation and compensation or through specific nest architecture. Mean worker size and distribution of worker sizes within colonies are important parameters affecting colony productivity as worker size is linked to division of labor in insect societies. In this paper, we investigate the effect of stressful warm temperatures and the role of social environment (colony size and size of nestmate workers) on the mean size and size variation of laboratory-born workers in the small European ant Temnothorax nylanderi. To do so, we reared field-collected colonies under medium or warm temperature treatments after having marked the field-born workers and removed the brood except for 30 first instar larvae. Warm temperature resulted in the production of fewer workers and a higher adult mortality, confirming that this regime was stressful for the ants. T. nylanderi ants followed the temperature size rule observed in insects, with a decreased developmental time and mean size under warm condition. Social environment appeared to play an important role as we observed that (i) larger colonies buffered the effect of temperature better than smaller ones (ii) colonies with larger workers produced larger workers whatever the rearing temperature and (iii) the coefficient of variation of worker size was similar in the field and under medium laboratory temperature. This suggests that worker size variation is not primarily due to seasonal environmental fluctuations in the field. Finally, we observed a higher coefficient of variation of worker size under warm temperature. We propose that this results from a disruption of social regulation, i.e. the control of nestmate workers over developing larvae and adult worker size, under stressful conditions. PMID- 28558935 TI - Local muscle cooling does not impact expression of mitochondrial-related genes. AB - : Recovery that takes place in a cold environment after endurance exercise elevates PGC-1alpha mRNA whereas ERRalpha and NRF2 mRNA expression are inhibited. However, the effect of local skeletal muscle cooling on mitochondrial-related gene expression is unknown. PURPOSE: To determine the impact of local skeletal muscle cooling during recovery from an acute bout of exercise on mitochondrial related gene expression. METHODS: Recreationally-trained male cyclists (n=8, age 25+/-3 y, height 181+/-6cm, weight 79+/-8kg, 12.8+/-3.6% body fat, VO2peak 4.52+/ 0.88L.min-1 protocol) completed a 90-min variable intensity cycling protocol followed by 4h of recovery. During recovery, ice was applied intermittently to one leg (ICE) while the other leg served as a control (CON). Intramuscular temperature was recorded continuously. Muscle biopsies were taken from each vastus lateralis at 4h post-exercise for the analysis of mitochondrial-related gene expression. RESULTS: Intramuscular temperature was colder in ICE (26.7+/-1.1 degrees C) than CON (35.5+/-0.1 degrees C) throughout the 4h recovery period (p<0.001). There were no differences in expression of PGC-1alpha, TFAM, NRF1, NRF2, or ERRalpha mRNA between ICE and CON after the 4h recovery period. CONCLUSION: Local muscle cooling after exercise does not impact the expression of mitochondrial biogenesis-related genes compared to recovery from exercise in control conditions. When these data are considered with previous research, the stimuli for cold-induced gene expression alterations may be related to factors other than local muscle temperature. Additionally, different intramuscular temperatures should be examined to determine dose-response of mitochondrial related gene expression. PMID- 28558936 TI - Mitigating thermal effect of behaviour and microhabitat on the intertidal snail Littorina saxatilis (Olivi) over summer. AB - High shore intertidal ectotherms must withstand temperatures which are already close, at or beyond their upper physiological thermal tolerance. Their behaviour can provide a relief under heat stress, and increase their survival through thermoregulation. Here, we used infrared imaging to reveal the thermoregulatory behavioural strategies used by the snail Littorina saxatilis (Olivi) on different microhabitats of a high shore boulder field in Finistere (western France) in summer. On our study site, substrate temperature is frequently greater than L. saxatilis upper physiological thermal limits, especially on sun exposed microhabitats. To maintain body temperatures within their thermal tolerance window, withdrawn snails adopted a flat posture, or elevated their shells and kept appended to the rock on the outer lip of their aperture with dried mucous (standing posture). These thermal regulatory behaviours lowered snail body temperatures on average by 1-2 degrees C. Aggregation behaviour had no thermoregulatory effect on L. saxatilis in the present study. The occupation of biogenic microhabitats (barnacles) was associated with a 1 degrees C decrease in body temperatures. Barnacles and microhabitats that experienced low sun exposure, low thermal fluctuations and low thermal maxima, could buffer the heat extremes encountered at high shore level especially on sun exposed microhabitats. PMID- 28558937 TI - Numerical simulation of time fractional dual-phase-lag model of heat transfer within skin tissue during thermal therapy. AB - In this paper, we investigated the thermal behavior in living biological tissues using time fractional dual-phase-lag bioheat transfer (DPLBHT) model subjected to Dirichelt boundary condition in presence of metabolic and electromagnetic heat sources during thermal therapy. We solved this bioheat transfer model using finite element Legendre wavelet Galerkin method (FELWGM) with help of block pulse function in sense of Caputo fractional order derivative. We compared the obtained results from FELWGM and exact method in a specific case, and found a high accuracy. Results are interpreted in the form of standard and anomalous cases for taking different order of time fractional DPLBHT model. The time to achieve hyperthermia position is discussed in both cases as standard and time fractional order derivative. The success of thermal therapy in the treatment of metastatic cancerous cell depends on time fractional order derivative to precise prediction and control of temperature. The effect of variability of parameters such as time fractional derivative, lagging times, blood perfusion coefficient, metabolic heat source and transmitted power on dimensionless temperature distribution in skin tissue is discussed in detail. The physiological parameters has been estimated, corresponding to the value of fractional order derivative for hyperthermia treatment therapy. PMID- 28558938 TI - Effect of water temperature on reproductive performance and offspring quality of rare minnow, Gobiocypris rarus. AB - Water temperature plays a significant role in the reproductive processes of temperate fishes. In the present study, the effects of water temperature on the reproductive performance and offspring quality of rare minnow (Gobiocypris rarus) were evaluated by cultured parent fish at different temperature (18~30C) in a 2 month trial. The results revealed that rare minnows could spawn continuously within the range from 18C to 30C, and these at 24C and 27C spawned every 3-4 days. Batch size of rare minnow increased with increasing water temperature, while egg production increased with increasing water temperature and then decreased at 30C. High water temperature (30C) had significantly adverse effects on fertilization rate and hatching rate (P<0.05). It was found that the oocyte growth at 18C, 21C, and 30C were slower than those at 24C and 27C. Histologic analysis further showed that low temperature (18C and 21C) slowed down vitellogenesis and oocyte maturation, while high temperature (30C) had suppressive effects on oocyte maturation and ovulation. Based on present results, it was concluded that 24-27C was optimal breeding temperature for rare minnows and water temperature higher than 30C resulting from climate change would pose a threat to its wild populations. PMID- 28558939 TI - The Humboldt Penguin (Spheniscus humboldti) Rete Tibiotarsale - A supreme biological heat exchanger. AB - Humans are unable to survive low temperature environments without custom designed clothing and support systems. In contrast, certain penguin species inhabit extremely cold climates without losing substantial energy to self-heating (emperor penguins ambient temperature plummets to as low as -45 degrees C). Penguins accomplish this task by relying on distinct anatomical, physiological and behavioral adaptations. One such adaptation is a blood vessel heat exchanger called the 'Rete Tibiotarsale' - an intermingled network of arteries and veins found in penguins' legs. The Rete existence results in blood occupying the foot expressing a lower average temperature and thus the penguin loosing less heat to the ground. This study examines the Rete significance for the species thermal endurance. The penguin anatomy (leg and main blood vessels) is reconstructed using data chiefly based on the Humboldt species. The resulting model is thermally analyzed using finite element (COMSOL) with the species environment used as boundary conditions. A human-like blood vessel configuration, scaled to the penguin's dimensions, is used as a control for the study. Results indicate that the Rete existence facilitates upkeep of 25-65% of the species total metabolic energy production as compared with the human-like configuration; thus making the Rete probably crucial for penguin thermal endurance. Here, we quantitatively link for the first time the function and structure of this remarkable physiological phenotype. PMID- 28558940 TI - Hyperthermia enhances bortezomib-induced apoptosis in human white blood cancer cells. AB - At present, the current therapeutic strategy for apoptosis induction mainly relies on the administration of pharmacological apoptotic modulators. Apart from that, apoptosis can be induced by various external stimuli such as hyperthermia, ionizing radiation, and electric fields. Despite advantages, both physical and pharmacological approaches bear some limitations as well. The rationale of this study was to overcome the limitations by combining hyperthermia and apoptotic modulator 'bortezomib' (Velcade). Two types of human blood cancer cell lines were utilized: human leukemic monocyte lymphoma cell U937 line and peripheral blood mononuclear cells (PMBCs) derived from the patient diagnosed with acute myeloid leukemia. Prior to apoptosis experiments, cytotoxicity tests were performed at three types of temperature regimes (40 degrees , 42 degrees and 44 degrees C). We observed a gradual inhibition of cell viability correlating with an increase of temperature and drug concentration in both cell lines. However, there was no significant difference between sham group and groups of leukemic PMBCs treated by high temperature (44 degrees C) and bortezomib. In U937 cells, combined treatment by heat shock and bortezomib led to an increase the number of cells underwent the late apoptosis stage. At the same time, similar treatment of PMBCs resulted in the stimulation of early apoptosis. Our data suggest that combination of bortezomib and hyperthermia enhances apoptosis induction in human cancer white blood cells, indicating a therapeutic potential for blood cancer therapy. PMID- 28558941 TI - Effects of aripiprazole versus risperidone on brain activation during planning and social-emotional evaluation in schizophrenia: A single-blind randomized exploratory study. AB - Impaired function of prefrontal brain networks may be the source of both negative symptoms and neurocognitive problems in psychotic disorders. Whereas most antipsychotics may decrease prefrontal activation, the partial dopamine D2 receptor agonist aripiprazole is hypothesized to improve prefrontal function. This study investigated whether patients with a psychotic disorder would show stronger activation of prefrontal areas and associated regions after treatment with aripiprazole compared to risperidone treatment. In this exploratory pharmacological neuroimaging study, 24 patients were randomly assigned to either aripiprazole or risperidone. At baseline and after nine weeks treatment they underwent an interview and MRI session. Here we report on brain activation (measured with arterial spin labeling) during performance of two tasks, the Tower of London and the Wall of Faces. Aripiprazole treatment decreased activation of the middle frontal, superior frontal and occipital gyrus (ToL) and medial temporal and inferior frontal gyrus, putamen and cuneus (WoF), while activation increased after risperidone. Activation increased in the ventral anterior cingulate and posterior insula (ToL), and superior frontal, superior temporal and precentral gyrus (WoF) after aripiprazole treatment and decreased after risperidone. Both treatment groups had increased ventral insula activation (ToL) and middle temporal gyrus (WoF), and decreased occipital cortex, precuneus and caudate head activation (ToL) activation. In conclusion, patients treated with aripiprazole may need less frontal resources for planning performance and may show increased frontotemporal and frontostriatal reactivity to emotional stimuli. More research is needed to corroborate and extend these preliminary findings. PMID- 28558942 TI - Bone Margin Analysis for Benign Odontogenic Tumors. AB - With the potential exception of the case of ameloblastoma, information relevant to the exact tumor-bone interface and extent of bone invasion by the commonly encountered odontogenic tumors is lacking. These tumors are rare. Treatment rendered varies significantly. Although commonly accepted practices are recommended, scientific evidence is relatively lacking. Prospective multicenter studies from tertiary treatment centers are required for evidence-based guidelines. Until studies are available, the proposed linear bone resection margin for odontogenic tumors and the evaluation of its adequacy in tumor eradication will be based on the limited data available. PMID- 28558943 TI - Reply to Jae Heon Kim and Benjamin I. Chung's Letter to the Editor re: Julien Dagenais, Matthew J. Maurice, Pascal Mouracade, Onder Kara, Ercan Malkoc, Jihad J. Kaouk. Excisional Precision Matters: Understanding the Influence of Excisional Volume Loss on Renal Function After Partial Nephrectomy. Eur Urol 2017;72:168-70. PMID- 28558944 TI - What is a "Diagnostic Test Reference Range" Good for? PMID- 28558945 TI - Erratum. PMID- 28558946 TI - A Mouse Model of Cardiomyopathy Induced by Mutations in the Hemochromatosis HFE Gene. AB - BACKGROUND: The heart is 1 of the organs most affected by hereditary hemochromatosis (HH). The clinical impact of cardiomyopathy in patients with HH requires a particular diagnosis and less invasive treatments. We developed a model of cardiomyopathy in knockout (KO) mice for the high-Fe (HFE) gene and assessed left ventricular (LV) function and structure from 7-20 months. METHODS: Male wild-type (WT) heterozygous and KO SV129 mice for the HFE gene were used in this study. Twenty-four mice were used to assess LV function and structure by echocardiography at 7, 14, 18, and 20 months. Evaluations of LV function and structure and myocardial fibrosis were performed at 7 and 20 months. RESULTS: The percent decrease of LV thickness-to-radius ratio between 7 and 20 months was higher in KO mice compared with WT mice (-30.2% +/- 5.3% vs -10.5% +/- 4.9%; P < 0.01). The LV diameters were higher in old mice compared with young mice (+13% at end-diastole; +33% at end-systole; P < 0.001). The LV ejection fraction values were lower in KO mice compared with WT mice between 7 and 20 months. The highest difference was found at 14 months (60.0% +/- 7.6% vs 78.1% +/- 3.5%; P < 0.001). Myocardial fibrosis was higher in old KO mice compared with old WT mice (+55%; P < 0.001), and myocardial iron deposition was slightly increased in old KO mice compared with old WT mice (1.31% +/- 0.33% vs 0.84% +/- 0.22%; P = 0.056). CONCLUSIONS: The present mouse model has the potential to allow the determination of underlying mechanisms involved in the cardiomyopathy induced by HFE-related hemochromatosis. PMID- 28558947 TI - Hemochromatosis Protein (HFE) Knockout Mice As a Novel Model of Hemochromatosis: Implications for Study and Management of Iron-Overload Cardiomyopathy. PMID- 28558948 TI - Ultrasonic-assisted incorporation of nano-encapsulated omega-3 fatty acids to enhance the fatty acid profile of pork meat. AB - In this study, ultrasound was employed to enhance the diffusion of microencapsulated fatty acids into pork meat. Nanovesicles of fish oil composed of 42% EPA (eicosapentanoic acid) and 16% DHA (docosahexanoic acid) were prepared using two different commercial Pronanosome preparations (Lipo-N and Lipo-CAT; which yield cationic and non-cationic nanovesicles, respectively). The thin film hydration (TFH) methodology was employed for encapsulation. Pork meat (Musculus semitendinosus) was submerged in the nanovesicles suspension and subjected to ultrasound (US) treatment at 25kHz for either 30 or 60min. Samples were analysed for fatty acid composition using gas chromatography-flame ionisation (GC-FID). The content of long-chain PUFAs, especially omega-3, was found to increase following the US treatment which was higher for Lipo-CAT compared to Lipo-N nanovesicles. Samples subjected to Lipo-N had higher atherogenic and thrombogenic indices, indicating higher levels of saturated fatty acids compared to the Lipo CAT. The omega-6/omega-3 ratio in pork meat was significantly reduced following the US treatment, thus indicating an improved fatty acid profile of pork. PMID- 28558949 TI - Moderate statin treatment reduces prebeta-1 high-density lipoprotein levels in dyslipidemic patients. AB - BACKGROUND: Elevated plasma levels of prebeta-1 high-density lipoprotein (HDL), the principal acceptor of cholesterol effluxed from macrophages, are associated with increased risk of atherosclerotic coronary heart disease and myocardial infarction. OBJECTIVE: The objective of the study was to assess the effects on prebeta-1 HDL levels of 6-week moderate-dose statin treatment. METHODS: We studied 101 patients (mean age 52.7 years; 53.5% female; 63 with primary hypercholesterolemia; 38 with combined hyperlipidemia) before and after treatment with statins. Mean atorvastatin potency equivalence was 23.6 mg/d. Prebeta-1 HDL plasma levels were measured by immunofixation of agarose gels using anti apolipoprotein A-1 antibody. RESULTS: We observed a 42.0% reduction of low density lipoprotein cholesterol (181 +/- 56 vs 105 mg/dL, P < .001). Triglyceride (TG) levels decreased by 22.3% (157 vs 122 mg/dL, P < .001), HDL cholesterol levels remained similar (56.0 vs 57.1, P = NS). Levels of prebeta-1 HDL were significantly reduced by 17.9% after statin treatment (mean 11.4 vs 9.4 mg apoA 1/dL, P < .001). The magnitude of this decrease was similar with each of 3 statins (atorvastatin, simvastatin, and rosuvastatin). The decrease in prebeta-1 HDL was strongly associated with the decline in TG, but not with the decline in low-density lipoprotein cholesterol. CONCLUSIONS: The association of high prebeta 1 HDL with coronary heart disease identifies it as an inferential measure of the rate of cholesterol efflux from the artery wall. Our observations demonstrate a reduction of prebeta-1 HDL with statin therapy, partially reflecting the reduced TGs, and probably reflecting a direct beneficial impact on cholesterol efflux. PMID- 28558950 TI - Complement in renal transplantation: The road to translation. AB - Renal transplantation is the treatment of choice for patients with end-stage renal disease. The vital role of the complement system in renal transplantation is widely recognized. This review discusses the role of complement in the different phases of renal transplantation: in the donor, during preservation, in reperfusion and at the time of rejection. Here we examine the current literature to determine the importance of both local and systemic complement production and how complement activation contributes to the pathogenesis of renal transplant injury. In addition, we dissect the complement pathways involved in the different phases of renal transplantation. We also review the therapeutic strategies that have been tested to inhibit complement during the kidney transplantation. Several clinical trials are currently underway to evaluate the therapeutic potential of complement inhibition for the treatment of brain death-induced renal injury, renal ischemia-reperfusion injury and acute rejection. We conclude that it is expected that in the near future, complement-targeted therapeutics will be used clinically in renal transplantation. This will hopefully result in improved renal graft function and increased graft survival. PMID- 28558951 TI - Relationship among age, insulin resistance, and blood pressure. AB - The effect of age to modify the relationship between insulin resistance and hypertension is unclear. In this retrospective, cross-sectional study, median age was used to create two age groups (<52 vs. >=52 years), and comparisons were made of metabolic characteristics, including steady-state plasma glucose (SSPG) concentrations measured during the insulin suppression test to quantify insulin resistance. Individuals were stratified into SSPG tertiles and categorized as having normal blood pressure (BP), prehypertension, or hypertension. SSPG concentrations were similar in the two age groups (161 vs. 164 mg/dL). In the most insulin-resistant tertile, distribution of normal BP, prehypertension, and hypertension was equal in those aged <52 years, whereas in those aged >=52 years, prevalence of hypertension was increased approximately fivefold compared with those with normal BP. Multivariate regression analysis demonstrated significant interaction between age and SSPG in predicting systolic BP (P = .023). In stratified analysis, SSPG, but not age, was an independent predictor of systolic BP and diastolic BP in >=52 years group, whereas the reverse was true in the younger group. The adverse impact of insulin resistance on BP was accentuated in older individuals and may have a greater impact than further aging. PMID- 28558952 TI - Intra- and inter-rater reliability of neutral head position and target head position tests in patients with and without neck pain. AB - BACKGROUND: Cervical proprioception is a common term used in neck rehabilitation, and it is examined using neutral head position (NHP) and target head position (THP) tests. OBJECTIVE: To investigate intra- and inter-rater reliability of the NHP and THP tests in patients with neck pain and in healthy controls. METHODS: The intra-rater (between-day) and inter-rater (within-day) reliability of the NHP and THP tests were assessed in 36 patients with neck pain and 33 healthy subjects. NHP testing was evaluated in cervical extension, while THP testing was evaluated in six directions of cervical motion: cervical flexion, extension, side bending right, side bending left, rotation right, and rotation left. RESULTS: The intra-rater reliability for the NHP tests had intraclass correlation coefficient (ICC) values of 0.74-0.78 and a standard error of measurement (SEM) of 1.78-1.88; the THP tests had ICC values of 0.70-0.83 and SEM of 1.45-2.45. Likewise, inter rater reliability for NHP had ICC values of 0.74-0.79 and SEM of 1.79-1.87. For the THP test, the inter-rater reliability had ICC values of 0.62-0.84 and SEM of 1.50-2.23. CONCLUSION: Intra- and inter-rater reliability ranged from good to very good agreement both for NHP and for THP tests of cervical proprioception. PMID- 28558953 TI - Are heart rate dynamics in the transition from rest to submaximal exercise related to maximal cardiorespiratory responses in COPD? AB - BACKGROUND: Poor exercise capacity is an important negative prognostic marker in patients with chronic obstructive pulmonary disease (COPD). Heart rate variability (HRV) responses can indicate alterations in cardiac autonomic control. Nevertheless, it remains unclear whether these abnormalities are related to cardiorespiratory responses to exercise in these patients. OBJECTIVE: To evaluate whether HRV at rest and submaximal exercise are related to impaired cardiopulmonary responses to exercise in COPD patients. METHODS: Fifteen men (66.2+/-8.7 years) with COPD (FEV1: 55.1+/-19.2%) were assessed. The R-R interval (RRi) data collection was performed at rest (stand position) and during the six minute walk test (6MWT). All patients performed a symptom-limited cardiopulmonary exercise test on a cycle ergometer. The HRV changes from rest to submaximal exercise (Delta rest-6MWT) were calculated. RESULTS: We found significant correlations between low frequency (LF) and high frequency (HF) Delta rest-6MWT with Delta oxyhemoglobin saturation by pulse oximetry (r=-0.64 and r=0.65, respectively; p<0.05), minute ventilation/carbon dioxide output relationship from beginning to peak exercise (r=-0.52 and r=0.53, p<0.05), and exercise ventilatory power (r=0.52 and r=-0.53, p<0.05). Interestingly, there was a strong positive correlation (r=0.82, p<0.05) between six-minute walk distance (6MWD) and Delta LF/HF from rest to exercise. CONCLUSION: HRV analysis in the transition from rest to submaximal exercise is associated with exercise ventilatory and hemodynamic abnormalities in COPD patients. Rehabilitative strategies to improve HRV responses may provide an important tool to clinical practice in these patients. PMID- 28558954 TI - Diagnostic accuracy and cost analysis of the AlereTM i Influenza A&B near-patient test using throat swabs. AB - BACKGROUND: Clinical diagnostic sensitivity alone is inadequate in the diagnosis of influenza. Polymerase chain reaction (PCR) testing is sensitive but the inherent delays in result availability potentially prolong time to isolation and treatment. Until recently no near-patient test (NPT) has demonstrated adequate sensitivity for routine clinical use. AIM: To evaluate diagnostic accuracy, time to result availability, clinical impact, and cost consequences of AlereTM i Influenza A&B NPT (Alere Inc., Waltham, MA, USA) using off-label throat swabs. METHODS: Prospective, multi-centre [four UK National Health Service (NHS) hospitals], diagnostic accuracy cohort study with cost modelling. Throat swab samples from suspected influenza patients were tested for influenza using the reference standard of PCR; a second throat swab was tested using NPT. FINDINGS: A total of 827 participants were recruited; 589 were suitable for analysis: sensitivity was 75.8% [95% confidence interval (CI): 67.0-84.6]; specificity was 96.8% (95% CI: 95.2-98.3). Sensitivity varied between Sheffield (Northern General Hospital: 82.1%; Royal Hallamshire Hospital: 83.3%) and other sites (Doncaster Royal Infirmary: 71.4%; Newcastle's Royal Victoria Infirmary: 50.0%) whereas specificity was high (92-100%). Positive predictive value (PPV) was 81.2% (95% CI: 72.9-89.5) with negative predictive value 95.6% (95% CI: 93.9-97.4) with observed prevalence of 15.4%. Median time to result for PCR was 1.1 days (on-site laboratories) and 5.2 days (remote laboratories). Isolation findings: 75% influenza positive not isolated; 69% of isolated participants did not have influenza. For a cohort of 1000 participants, annual estimated non-diagnostic cost savings with NPT are L215,040. CONCLUSION: This first prospective study of the Alere i NPT using throat swabs demonstrates high specificity, high PPV during seasonal epidemics, and rapid result availability which could lead to substantial cost savings. PMID- 28558956 TI - Association between plasma BMP-2 and in-stent restenosis in patients with coronary artery disease. AB - OBJECTIVE: This study aimed to assess the association between plasma bone morphogenetic protein-2 (BMP-2) level and in-stent restenosis in patients with coronary artery disease. METHODS: A total of 96 patients who underwent percutaneous coronary intervention (PCI) and were followed up after PCI were enrolled in this study. 47 patients diagnosed with in-stent restenosis (ISR) were recruited to ISR group and 49 patients without ISR were recruited to Control group according to the results of coronary angiography (CAG). Baseline characteristic data were collected, and plasma BMP-2 level was evaluated. The results were analyzed using logistic regression. RESULTS: There were 47 patients in the ISR group and 49 patients in the Control group. Plasma levels of BMP-2 were higher in the ISR group than in the non-ISR group [20.96 (18.44, 27.05) pg/ml vs. 29.53 (25.03, 34.07) pg/ml, P<0.01]. Furthermore, the ISR group had significantly longer stent lengths and lower stent diameters than the Control group (P<0.01 and P<0.01, respectively). In multivariate analysis, BMP-2 level, diabetes, stent length and stent diameter were independently associated with ISR [odds ratio (OR)=1.11, 95% confidence interval (CI)=1.03-1.18, P<0.01; OR=4.75, 95% CI=(1.44-15.61), P=0.01; OR=1.06, 95% CI=(1.02-1.11), P<0.01; and OR=0.15, 95% CI=(0.02-0.95), P=0.04, respectively]. CONCLUSIONS: Increased BMP-2 levels were independently associated with ISR in patients with coronary artery disease. Plasma BMP-2 may be useful in predicting ISR. PMID- 28558957 TI - Maternal nutrition knowledge and child nutritional outcomes in urban Kenya. AB - We examine the link between maternal nutrition knowledge and nutritional outcomes of children and adolescents (5-18 years) measured in terms of height-for-age Z scores (HAZ). One particular focus is on the role of different types of nutrition knowledge. The analysis builds on household-level and individual-level data collected in urban Kenya in 2012 and 2015. Various regression models are developed and estimated. Results show that maternal nutrition knowledge - measured through an aggregate knowledge score - is positively associated with child HAZ, even after controlling for other influencing factors such as household living standard and general maternal education. However, disaggregation by type of knowledge reveals important differences. Maternal knowledge about food ingredients only has a weak positive association with child HAZ. For maternal knowledge about specific dietary recommendations, no significant association is detected. The strongest positive association with child HAZ is found for maternal knowledge about the health consequences of not following recommended dietary practices. These findings have direct relevance for nutrition and health policies, especially for designing the contents of educational campaigns and training programs. PMID- 28558955 TI - Seizures in Preterm Neonates: A Multicenter Observational Cohort Study. AB - BACKGROUND: The purpose of this study was to characterize seizures among preterm neonates enrolled in the Neonatal Seizure Registry, a prospective cohort of consecutive neonates with seizures at seven pediatric centers that follow the American Clinical Neurophysiology Society's neonatal electroencephalography monitoring guideline. STUDY DESIGN: Of 611 enrolled neonates with seizures, 92 (15%) were born preterm. Seizure characteristics were evaluated by gestational age at birth for extremely preterm (<28 weeks, N = 18), very preterm (28 to <32 weeks, N = 18), and moderate to late preterm (32 to <37 weeks, N = 56) and compared with term neonates. RESULTS: Hypoxic-ischemic encephalopathy (33%) and intracranial hemorrhage (27%) accounted for the etiology in more than half of preterm neonates. Hypothermia therapy was utilized in 15 moderate to late preterm subjects with encephalopathy. The presence of subclinical seizures, monotherapy treatment failure, and distribution of seizure burden (including status epilepticus) was similar in preterm and term neonates. However, exclusively subclinical seizures occurred more often in preterm than term neonates (24% vs 14%). Phenobarbital was the most common initial medication for all gestational age groups, and failure to respond to an initial loading dose was 63% in both preterm and term neonates. Mortality was similar among the three preterm gestational age groups; however, preterm mortality was more than twice that of term infants (35% vs 15%). CONCLUSIONS: Subclinical seizures were more common and mortality was higher for preterm than term neonates. These data underscore the importance of electroencephalographic monitoring and the potential for improved management in preterm neonates. PMID- 28558958 TI - Is Ep-CAM Expression a Diagnostic and Prognostic Biomarker for Colorectal Cancer? A Systematic Meta-Analysis. AB - BACKGROUND: Cancer stem cell (CSC) epithelial cell adhesion molecule (Ep-CAM) is frequently expressed in colorectal cancer (CRC). However, the clinical significance of Ep-CAM expression in CRC is not clear. This study evaluated whether Ep-CAM provided valuable insight as a molecular biomarker for CRC diagnosis and prognosis and the potential of Ep-CAM as a novel therapeutic target in CRC. METHODS: Publications were selected online using electronic databases. The pooled odds ratios (ORs) or hazard ratios (HRs) with their 95% confidence intervals (95% CIs), and the combined sensitivity, specificity, and area under the curve (AUC) were calculated and summarized. RESULTS: Eleven eligible articles published in English involving 4561 cases were analyzed in this study. Ep-CAM expression was significantly higher in CRC compared with normal controls, and its overexpression was negatively linked to tumor differentiation, tumor stage, vascular invasion, depth of tumor invasion, lymph node metastasis, distant metastasis, and tumor budding in CRC patients. The loss of Ep-CAM expression positively correlated with these characteristics. Multivariate analysis of loss of Ep-CAM expression correlated with a poor prognosis in disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). The pooled sensitivity, specificity and AUC values of Ep-CAM expression in patients with CRC vs. normal controls were 0.93, 0.90, and 0.94, respectively. CONCLUSIONS: The present findings suggest that Ep-CAM expression may be associated with CRC carcinogenesis, while the loss of Ep-CAM expression is correlated with the progression, metastasis, and poor prognosis of CRC. Ep-CAM expression may be a useful biomarker for the clinical diagnosis of CRC. PMID- 28558959 TI - The Transcriptional Landscape of p53 Signalling Pathway. AB - Although recent cancer genomics studies have identified a large number of genes that were mutated in human cancers, p53 remains as the most frequently mutated gene. To further elucidate the p53-signalling network, we performed transcriptome analysis on 24 tissues in p53+/+ or p53-/- mice after whole-body X-ray irradiation. Here we found transactivation of a total of 3551 genes in one or more of the 24 tissues only in p53+/+ mice, while 2576 genes were downregulated. p53 mRNA expression level in each tissue was significantly associated with the number of genes upregulated by irradiation. Annotation using TCGA (The Cancer Genome Atlas) database revealed that p53 negatively regulated mRNA expression of several cancer therapeutic targets or pathways such as BTK, SYK, and CTLA4 in breast cancer tissues. In addition, stomach exhibited the induction of Krt6, Krt16, and Krt17 as well as loricrin, an epidermal differentiation marker, after the X-ray irradiation only in p53+/+ mice, implying a mechanism to protect damaged tissues by rapid induction of differentiation. Our comprehensive transcriptome analysis elucidated tissue specific roles of p53 and its signalling networks in DNA-damage response that will enhance our understanding of cancer biology. PMID- 28558961 TI - A rare case of sarcoidosis in accessory spleen. PMID- 28558963 TI - Ecophysiological adaptations to variable salinity environments in the crab Hemigrapsus crenulatus from the Southeastern Pacific coast: Sodium regulation, respiration and excretion. AB - The estuarine crab Hemigrapsus crenulatus is a key benthic species of estuarine and intertidal ecosystems of the South Pacific, habitats that experience wide fluctuations in salinity. The physiological strategies that allow this crab to thrive under variable salinities, and how they change during the benthic stages of their life cycle, were evaluated under laboratory conditions. Oxygen consumption, ammonia excretion and the regulatory capacity of Na+ through the normal range of environmental salinities (i.e. 5, 10, 15, 20, 25, 30) were evaluated in three size classes, ranging from juveniles to adults. In all sizes, the oxygen consumption, ammonia excretion and regulatory capacity of Na+ decreased as salinity increased, with the highest values at 5 and the lowest values at 30 salinity. Bigger crabs showed a higher capacity to regulate Na+, as well as higher respiration and excretion rates compared to smaller crabs, suggesting that they are better equipped to exploit areas of the estuary with low salinity. Regardless of its size, H. crenulatus is a strong hyper regulator in diluted media (i.e. 5-20) while a conformer at salinities higher than 20. The regulatory capacity of Na+ was positively related with oxygen consumption and ammonia excretion rates. These relationships between sodium regulation, respiration and excretion are interpreted as adaptive physiological mechanisms that allow H. crenulatus to maintain the osmotic and bioenergetic balance over a wide range of environmental salinities. PMID- 28558962 TI - Galangin ameliorates cisplatin-induced nephrotoxicity by attenuating oxidative stress, inflammation and cell death in mice through inhibition of ERK and NF kappaB signaling. AB - Cisplatin is a chemotherapeutic agent widely used in the treatment of various cancers. However, cisplatin can induce nephrotoxicity and neurotoxicity, limiting its dosage and usage. Galangin, a natural flavonol, has been found to exhibit anti-oxidant and anti-inflammatory effects in vivo. Here, we investigated the effects of galangin on cisplatin-induced acute kidney injury (AKI) and its molecular mechanisms in mice. Galangin administration reduced the cisplatin induced oxidative stress by decreasing renal MDA and 3-NT formations. Galangin administration also increased renal anti-oxidative enzyme activities (SOD, GPx, and CAT) and GSH levels depleted by cisplatin. Furthermore, galangin administration inactivated stress-induced Nrf2 protein and its downstream products, HO-1 and GCLC. In terms of the inflammatory response, galangin administration reduced IkappaBalpha phosphorylation, NF-kappaB phosphorylation and nuclear translocation, and then inhibited cisplatin-induced secretions of pro inflammatory TNF-alpha, IL-1beta and IL-6. In addition, cisplatin-induced ERK and p38 phosphorylations were inhibited by galangin administration. In terms of cell death, galangin administration reduced levels of p53, pro-apoptotic Bax and activated caspase-3 to inhibit the cisplatin-induced apoptosis. Galangin administration also reduced the expression levels of RIP1 and RIP3 to inhibit cisplatin-induced RIP1/RIP3-dependent necroptosis. Therefore, galangin administration significantly ameliorates cisplatin-induced nephrotoxicity by attenuating oxidative stress, inflammation, and cell death through inhibitions of ERK and NF-kappaB signaling pathways. Galangin might be a potential adjuvant for clinical cisplatin therapy. PMID- 28558960 TI - Targeting PAR1: Now What? AB - Protease-activated receptors (PARs) are a ubiquitously expressed class of G protein-coupled receptors (GPCRs) that enable cells to respond to proteases in the extracellular environment in a nuanced and dynamic manner. PAR1 is the archetypal family member and has been the object of large-scale drug development programs since the 1990s. Vorapaxar and drotrecogin-alfa are approved PAR1 targeted therapeutics, but safety concerns have limited the clinical use of vorapaxar and questions regarding the efficacy of drotrecogin-alfa led to its withdrawal from the market. New understanding of mechanisms of PAR1 function, discovery of improved strategies for modifying PAR1 function, and identification of novel indications for PAR1 modulators have provided new opportunities for therapies targeting PAR1. In this review, we critically evaluate prospects for the next generation of PAR1-targeted therapeutics. PMID- 28558964 TI - Unravelling the interaction of pirenzepine, a gastrointestinal disorder drug, with calf thymus DNA: An in vitro and molecular modelling study. AB - Pirenzepine is an anti-ulcer agent which belongs to the anti-cholinergic group of gastrointestinal disorder drugs and functions as an M1 receptor selective antagonist. Drug-DNA interaction studies are of great significance as it helps in the development of new therapeutic drugs. It provides a deeper understanding into the mechanism through which therapeutic drugs control gene expression. Interaction of pirenzepine with calf-thymus DNA (Ct-DNA) was determined via a series of biophysical techniques. UV-visible absorption and fluorescence spectroscopy confirmed the formation of pirenzepine-Ct-DNA complex. The values of binding constant from various experiments were calculated to be in the order of 103 M-1 which is consistent with the groove binding mode. Various spectrofluorimetric experiments like competitive displacement of well known dyes with drug, iodide quenching experiments and the effect of Ct-DNA denaturation in presence of drug confirmed the binding of pirenzepine to the groove of Ct-DNA. The binding mode was further established by viscometric, circular dichroic and molecular modelling studies. Thermodynamic parameters obtained from isothermal titration calorimetric studies suggest that the interaction of pirenzepine with Ct-DNA is enthalpically driven. The value of TDeltaS and DeltaH calculated from calorimetric studies were found to be 4.3 kcal mol-1 and -2.54 kcal mol-1 respectively, indicating that pirenzepine-Ct-DNA complex is mainly stabilized by hydrophobic interaction and hydrogen bonding. The binding energy calculated was 7.5 kcal mol-1 from modelling studies which was approximately similar to that obtained by isothermal titration calorimetric studies. Moreover, the role of electrostatic interaction in the binding of pirenzepine to Ct-DNA cannot be precluded. PMID- 28558965 TI - The enzyme: Renalase. AB - Within the last two years catalytic substrates for renalase have been identified, some 10 years after its initial discovery. 2- and 6-dihydronicotinamide (2- and 6 DHNAD) isomers of beta-NAD(P)H (4-dihydroNAD(P)) are rapidly oxidized by renalase to form beta-NAD(P)+. The two electrons liberated are then passed to molecular oxygen by the renalase FAD cofactor forming hydrogen peroxide. This activity would appear to serve an intracellular detoxification/metabolite repair function that alleviates inhibition of primary metabolism dehydrogenases by 2- and 6-DHNAD molecules. This activity is supported by the complete structural assignment of the substrates, comprehensive kinetic analyses, defined species specific substrate specificity profiles and X-ray crystal structures that reveal ligand complexation consistent with this activity. This apparently intracellular function for the renalase enzyme is not allied with the majority of the renalase research that holds renalase to be a secreted mammalian protein that functions in blood to elicit a broad array of profound physiological changes. In this review a description of renalase as an enzyme is presented and an argument is offered that its enzymatic function can now reasonably be assumed to be uncoupled from whole organism physiological influences. PMID- 28558966 TI - Advanced Glycation End-Products Are Associated With the Presence and Severity of Paratonia in Early Stage Alzheimer Disease. AB - OBJECTIVE: Paratonia, a distinctive form of hypertonia in patients with dementia, causes loss of functional mobility in early stage dementia to severe contractures and pain in the late stages. The pathogenesis of paratonia is not well understood. Patients in early stage dementia with diabetes mellitus showed a significantly higher risk for the development of paratonia. Both Alzheimer disease and diabetes mellitus are related to higher concentrations of advanced glycation end-products (AGEs). The purpose of this study is to explore the association of AGEs with the prevalence and severity of paratonia in patients with Alzheimer disease. DESIGN: Observational longitudinal, 1-year follow-up cohort study with 3 assessments. SETTING: Day care centers for patients with dementia. PARTICIPANTS: A total of 144 community-dwelling patients with early stage Alzheimer or Alzheimer/vascular disease were recruited from 24 dementia day care centers in The Netherlands. MEASUREMENTS: The presence of paratonia (Paratonia Assessment Instrument), the severity of paratonia (Modified Ashworth Scale for paratonia), and AGE levels (AGE-reader). RESULTS: From the 144 participants (56.3% female and 43.7% male, with a mean [standard deviation] age of 80.7 [7.7] years), 118 participants were available for final follow-up. A significant association between AGE levels and the presence of paratonia (odds ratio 3.47, 95% confidence interval [CI] 1.87-6.44, P < .001) and paratonia severity (beta = 0.17, 95% CI 0.11-0.23, P < .001) was determined. In participants who developed paratonia and those with persistent paratonia throughout the study the AGE levels (95% CI -0.38 to -0.13, P < .001 and 95% CI 0.46 to -0.06, P = .012, respectively) and the severity of paratonia (95% CI 0.60 to -0.35, P < .001 and 95% CI -0.38 to -0.12, P < .001, respectively) significantly increased, whereas the AGE levels remained stable in those participants without paratonia. Notwithstanding, change in AGE levels was not significantly (P = .062) related to change in paratonia severity, mixed model analyses provided evidence for both a significant time and between participant effect of AGEs on paratonia severity. CONCLUSIONS: This study suggests that elevated AGE levels are a contributing factor to paratonia and its severity and could be the result of peripheral biomechanical changes reducing elasticity and increasing stiffness. These results provide a new perspective on paratonia and gives rise to further research whether paratonia could be postponed or movement stiffness can be improved by reducing AGE levels. PMID- 28558967 TI - The design, synthesis, and anti-inflammatory evaluation of a drug-like library based on the natural product valerenic acid. AB - The plant natural product, valerenic acid (1) was chosen as a desirable scaffold for the generation of a novel screening library due to its drug-like physicochemical parameters (such as LogP, hydrogen bond donor/acceptor counts, and molecular weight). An 11-membered amide library (2-12) was subsequently generated using parallel solution-phase synthesis and Ghosez's reagent. The chemical structures of all semi-synthetic analogues (2-12) were elucidated following analysis of the NMR, MS, UV and IR data. The structures of compounds 8 and 11 were also confirmed by X-ray crystallographic analysis. All library members were evaluated for their ability to inhibit the release of IL-8 and TNF alpha. Six analogues showed moderate activity in the IL-8 assay with IC50 values of 2.8-8.3MUM, while none of the tested compounds showed any significant effect on inhibiting TNF-alpha release. PMID- 28558968 TI - Ratiometric fluorescence imaging of nuclear pH in living cells using Hoechst tagged fluorescein. AB - Small-molecule fluorescent sensors that allow specific measurement of nuclear pH in living cells will be valuable for biological research. Here we report that Hoechst-tagged fluorescein (hoeFL), which we previously developed as a green fluorescent DNA-staining probe, can be used for this purpose. Upon excitation at 405nm, the hoeFL-DNA complex displayed two fluorescence bands around 460nm and 520nm corresponding to the Hoechst and fluorescein fluorescence, respectively. When pH was changed from 8.3 to 5.5, the fluorescence intensity ratio (F520/F460) significantly decreased, which allowed reliable pH measurement. Moreover, because hoeFL binds specifically to the genomic DNA in cells, it was applicable to visualize the intranuclear pH of nigericin-treated and intact living human cells by ratiometric fluorescence imaging. PMID- 28558969 TI - Pyrazolo[3,4-d]pyrimidines-loaded human serum albumin (HSA) nanoparticles: Preparation, characterization and cytotoxicity evaluation against neuroblastoma cell line. AB - Pyrazolo[3,4-d]pyrimidine derivatives 1-5, active as c-Src inhibitors, have been selected to be formulated as drug-loaded human serum albumin (HSA) nanoparticles, with the aim of improving their solubility and pharmacokinetic properties. The present study includes the optimization of a desolvation method-based procedure for preparing HSA nanoparticles. First, characterization by HPLC-MS and Dynamic Light Scattering (DLS) showed a good entrapment efficacy, a controllable particle size (between 100 and 200nm) and an optimal stability over time, confirmed by an in vitro drug release assay. Then, 1-4 and the corresponding NPs were tested for their antiproliferative activity against neuroblastoma SH-SY5Y cell line. Notably, 3-NPs and 4-NPs were identified as the most promising formulation showing a profitable balance of stability, small size and a similar activity compared to the free drugs in cell-based assays. In addition, albumin formulations increase the solubility of pyrazolo[3,4-d]pyrimidine avoiding the use of DMSO as solubilizing agent. PMID- 28558970 TI - New merosesquiterpenes from a Vietnamese marine sponge of Spongia sp. and their biological activities. AB - The investigation of the Vietnamese marine sponge Spongia sp. led to the isolation of three new sesquiterpene phenols, langconols A-C (1-3), and one new sesquiterpene hydroxyquinone, langcoquinone C (4), together with two known meroterpenoids (5 and 6). Their structures were determined on the basis of spectroscopic analyses and comparisons with published data. Furthermore, the antibacterial assays of the isolates 1-6 suggested that 4 and 6 had significant antibacterial activities against Bacillus subtilis and Staphylococcus aureus, with MICs ranging from 6.25 to 25.0uM, while 1 and 3 possessed significant antibacterial activities against B. subtilis with MICs of 12.5 and 25.0uM, respectively. In contrast, cytotoxic assays of the isolated compounds 1-6, as well as compounds 7-15 previously isolated from this sponge, indicated that 1 and the previously reported anti-B. subtilis and anti-S. aureus sesquiterpene phenol 9 lacked cytotoxic activities against three human cancer cell lines (A549, lung cancer; MCF7, breast cancer; HeLa, cervix cancer) and a human normal cell line (WI-38 fibroblast). PMID- 28558971 TI - Fused bi-heteroaryl substituted hydantoin compounds as TACE inhibitors. AB - We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series. PMID- 28558973 TI - Lipemia retinalis in an infant treated for retinopathy of prematurity. AB - Lipemia retinalis is an unusual ocular finding associated with hypertriglyceridemia. We report the case of an infant treated for retinopathy of prematurity who later developed lipemia retinalis, with triglyceride levels of 4736 mg/dl. There was a paradoxical worsening of hypertriglyceridemia with the use of medium chain triglyceride supplement. On discontinuing the supplement, the triglycerides level drastically dropped, and retinal vasculature returned to a normal hue. PMID- 28558972 TI - Structure-based identification of inhibitors targeting obstruction of the HIVgp41 N-heptad repeat trimer. AB - The viral protein HIVgp41 is an attractive and validated drug target that proceeds through a sequence of conformational changes crucial for membrane fusion, which facilitates viral entry. Prior work has identified inhibitors that interfere with the formation of a required six-helix bundle, composed of trimeric C-heptad (CHR) and N-heptad (NHR) repeat elements, through blocking association of an outer CHR helix or obstructing formation of the inner NHR trimer itself. In this work, we employed similarity-based scoring to identify and experimentally characterize 113 compounds, related to 2 small-molecule inhibitors recently reported by Allen et al. (Bioorg. Med. Chem Lett.2015, 25 2853-59), proposed to act via the NHR trimer obstruction mechanism. The compounds were first tested in an HIV cell-cell fusion assay with the most promising evaluated in a second, more biologically relevant viral entry assay. Of the candidates, compound #11 emerged as the most promising hit (IC50=37.81uM), as a result of exhibiting activity in both assays with low cytotoxicity, as was similarly seen with the known control peptide inhibitor C34. The compound also showed no inhibition of VSV-G pseudotyped HIV entry compared to a control inhibitor suggesting it was specific for HIVgp41. Molecular dynamics simulations showed the predicted DOCK pose of #11 interacts with HIVgp41 in an energetic fashion (per-residue footprints) similar to the four native NHR residues (IQLT) which candidate inhibitors were intended to mimic. PMID- 28558974 TI - Computational prediction of immune cell cytotoxicity. AB - Immunotoxicity, defined as adverse effects of xenobiotics on the immune system, is gaining increasing attention in the approval process of industrial chemicals and drugs. In-vivo and ex-vivo experiments have been the gold standard in immunotoxicity assessment so far, so the development of in-vitro and in-silico alternatives is an important issue. In this paper we describe a widely applicable, easy-to use computational approach which can serve as an initial immunotoxicity screen of new chemical entities. Molecular fingerprints describing chemical structure were used as parameters in a machine-learning approach based on the Naive-Bayes learning algorithm. The model was trained using blood-cell growth inhibition data from the NCI database and validated externally with several in-house and literature-derived data sets tested in cytotoxicity assays on different types on immune cells. Both cross-validations and external validations resulted in areas under the receiver operator curves (ROC/AUC) of 75% or higher. The classification of the validation data sets occurred with excellent specificities and fair to excellent selectivities, depending on the data set. This means that the probability of actual immunotoxicity is very high for compounds classified as immunotoxic, while the fraction of false negative predictions might vary. Thus, in a multistep immunotoxicity screening scheme, the classification as immunotoxic can be accepted without additional confirmation, while compounds classified as not immunotoxic will have to be subjected to further investigation. PMID- 28558975 TI - Critical review of the current literature on the safety of sucralose. AB - Sucralose is a non-caloric high intensity sweetener that is approved globally for use in foods and beverages. This review provides an updated summary of the literature addressing the safety of use of sucralose. Studies reviewed include chemical characterization and stability, toxicokinetics in animals and humans, assessment of genotoxicity, and animal and human feeding studies. Endpoints evaluated include effects on growth, development, reproduction, neurotoxicity, immunotoxicity, carcinogenicity and overall health status. Human clinical studies investigated potential effects of repeated consumption in individuals with diabetes. Recent studies on the safety of sucralose focused on carcinogenic potential and the effect of sucralose on the gut microflora are reviewed. Following the discovery of sweet taste receptors in the gut and studies investigating the activation of these receptors by sucralose lead to numerous human clinical studies assessing the effect of sucralose on overall glycemic control. Estimated daily intakes of sucralose in different population subgroups, including recent studies on children with special dietary needs, consistently find that the intakes of sucralose in all members of the population remain well below the acceptable daily intake. Collectively, critical review of the extensive database of research demonstrates that sucralose is safe for its intended use as a non-caloric sugar alternative. PMID- 28558976 TI - Chronic exposure to tumor necrosis factor in vivo induces hyperalgesia, upregulates sodium channel gene expression and alters the cellular electrophysiology of dorsal root ganglion neurons. AB - The goal of these studies was to investigate the links between chronic exposure to the pro-inflammatory cytokine tumor necrosis factor (TNF), hyperalgesia and the excitability of dorsal root ganglion (DRG) sensory neurons. We employed transgenic mice that constitutively express TNF (TNFtg mice), a well-established model of chronic systemic inflammation. At 6 months of age, TNFtg mice demonstrated increased sensitivity to both mechanical and thermal heat stimulation relative to aged-matched wild-type controls. These increases in stimulus-evoked behaviors are consistent with nociceptor sensitization to normal physiological stimulation. The mechanisms underlying nociceptor sensitization were investigated using single-cell analysis to quantitatively compare gene expression in small-diameter (<30MUm) DRG neurons. This analysis revealed the upregulation of mRNA encoding for tetrodotoxin-resistant (TTX-R) sodium (Na+) channels (Nav1.8, Nav1.9), Na+ channel beta subunits (beta1-beta3), TNF receptor 1 (TNFR1) and p38alpha mitogen-activated protein kinase in neurons of TNFtg mice. Whole-cell electrophysiology demonstrated a corresponding increase in TTX-R Na+ current density, hyperpolarizing shifts in activation and steady-state inactivation, and slower recovery from inactivation in the TNFtg neurons. Increased overlap of activation and inactivation in the TNFtg neurons produces inward Na+ currents at voltages near the resting membrane potential of sensory neurons (i.e. window currents). The combination of increased Na+ current amplitude, hyperpolarized shifts in Na+ channel activation and increased window current predicts a reduction in the action potential threshold and increased firing of small-diameter DRG neurons. Together, these data suggest that increases in the expression of Nav1.8 channels, regulatory beta1 subunits and TNFR1 contribute to increased nociceptor excitability and hyperalgesia in the TNFtg mice. PMID- 28558977 TI - Difference of recovery course of motor weakness according to state of corticospinal tract in putaminal hemorrhage. AB - OBJECTIVES: We investigated differences in recovery course of motor weakness according to the state of the corticospinal tract (CST) in putaminal hemorrhage, using diffusion tensor tractography (DTT). METHODS: We recruited 36 patients with complete weakness of the affected extremities at onset. The patients were classified into two groups according to the findings of DTT for the CST at chronic stage: group A- preserved integrity of the CST around the lesion, and group B- discontinued integrity of the CST. Motor function of the affected extremities was measured over a six month period using the Motricity Index (MI). RESULTS: The MI scores differed significantly each month, except at the onset, between group A and group B (p<0.05). In both groups, we observed significant increases between onset and one month, between one month and two months, between two month and three months, and between three months and four months (p<0.05). However, there were no significant increases after four months (p>0.05). The degree of difference between months was as follows: onset ~1 month, 1 month ~2months, 2 months ~3months, and 3 months ~4months. CONCLUSIONS: Patients with preserved integrity of the CST showed better motor function than patients with discontinued integrity of the CST. In both groups, significant motor recovery was achieved during the first four months after onset. In addition, the most rapid motor recovery occurred during the first month and then decreased gradually with the passage of time. PMID- 28558978 TI - The efficacy and safety of tofacitinib in Asian patients with moderate to severe chronic plaque psoriasis: A Phase 3, randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. OBJECTIVE: This study assessed tofacitinib efficacy and safety vs placebo in Asian patients with moderate to severe chronic plaque psoriasis. METHODS: Patients from China mainland, Taiwan, and Korea were randomized 2:2:1:1 to tofacitinib 5mg (N=88), tofacitinib 10mg (N=90), placebo->5mg (N=44), or placebo->10mg (N=44), twice daily (BID) for 52 weeks. Placebo-treated patients advanced to tofacitinib at Week 16. Co-primary efficacy endpoints: proportions of patients achieving Physician's Global Assessment (PGA) response ('clear' or 'almost clear') and proportion achieving >=75% reduction from baseline Psoriasis Area and Severity Index (PASI75) at Week 16. RESULTS: At Week 16, more patients achieved PGA and PASI75 responses with tofacitinib 5mg (52.3%; 54.6%) and 10mg (75.6%; 81.1%) BID vs placebo (19.3%; 12.5%; all p<0.0001). Of patients with a Week 16 response, 73.6% and 75.0% maintained PGA response, and 76.8% and 84.9% maintained PASI75 to Week 52 with tofacitinib 5mg and 10mg BID, respectively. Over 52 weeks, 2.2-4.5% of patients across treatment groups experienced serious adverse events, and 1.1 6.8% discontinued due to adverse events. CONCLUSION: Tofacitinib demonstrated efficacy vs placebo at Week 16 in Asian patients with moderate to severe plaque psoriasis; efficacy was maintained through Week 52. No unexpected safety findings were observed. [NCT01815424]. PMID- 28558980 TI - Diurnal variation in the pharmacokinetics and brain distribution of morphine and its major metabolite. AB - The pharmacokinetics and pharmacodynamics of drugs are influenced by daily fluctuations in physiological processes. The aim of this study was to determine the effect of dosing time on the pharmacokinetics and brain distribution of morphine. To this end, 4mg/kg morphine was administered intravenously to Wistar rats that were either pre-treated with vehicle or tariquidar and probenecid to inhibit processes involved in the active transport of morphine. Non-linear mixed effects modelling was used to describe the concentration-time profiles of morphine and its metabolite M3G in plasma and brain tissue. We found that the concentrations of morphine in the brain and of M3G in plasma depended on the time of day, which could be quantified by a 24-hour rhythm in the efflux of morphine from brain tissue back into the circulation, with the lowest efflux during the two light-dark phase transitions with a difference between peak and trough of 20%. The active processes involved in the clearance of morphine and its metabolite M3G from plasma also showed 24-hour variation with the highest value in the middle of the dark phase being 54% higher than the lowest value at the start of the light phase. Hence, time of day presents a considerable source of variation in the pharmacokinetics of morphine, which could be used to optimize the dosing strategy of morphine. PMID- 28558979 TI - Biocompatibility of hydrogel-based scaffolds for tissue engineering applications. AB - Recently, understanding of the extracellular matrix (ECM) has expanded rapidly due to the accessibility of cellular and molecular techniques and the growing potential and value for hydrogels in tissue engineering. The fabrication of hydrogel-based cellular scaffolds for the generation of bioengineered tissues has been based on knowledge of the composition and structure of ECM. Attempts at recreating ECM have used either naturally-derived ECM components or synthetic polymers with structural integrity derived from hydrogels. Due to their increasing use, their biocompatibility has been questioned since the use of these biomaterials needs to be effective and safe. It is not surprising then that the evaluation of biocompatibility of these types of biomaterials for regenerative and tissue engineering applications has been expanded from being primarily investigated in a laboratory setting to being applied in the multi-billion dollar medicinal industry. This review will aid in the improvement of design of non invasive, smart hydrogels that can be utilized for tissue engineering and other biomedical applications. In this review, the biocompatibility of hydrogels and design criteria for fabricating effective scaffolds are examined. Examples of natural and synthetic hydrogels, their biocompatibility and use in tissue engineering are discussed. The merits and clinical complications of hydrogel scaffold use are also reviewed. The article concludes with a future outlook of the field of biocompatibility within the context of hydrogel-based scaffolds. PMID- 28558981 TI - Natural lipids-based NLC containing lidocaine: from pre-formulation to in vivo studies. AB - In a nanotechnological approach we have investigated the use of natural lipids in the preparation of nanostructured lipid carriers (NLC). Three different NLC composed of copaiba oil and beeswax, sweet almond oil and shea butter, and sesame oil and cocoa butter as structural matrices were optimized using factorial analysis; Pluronic(r) 68 and lidocaine (LDC) were used as the colloidal stabilizer and model encapsulated drug, respectively. The optimal formulations were characterized by different techniques (IR-ATR, DSC, and TEM), and their safety and efficacy were also tested. These nanocarriers were able to upload high amounts of the anesthetic with a sustained in vitro release profile for 24h. The physicochemical stability in terms of size (nm), PDI, zeta potential (mV), pH, nanoparticle concentration (particles/mL), and visual inspection was followed during 12months of storage at 25 degrees C. The formulations exhibited excellent structural properties and stability. They proved to be nontoxic in vitro (cell viability tests with Balb/c 3T3 fibroblasts) and significantly improved the in vivo effects of LDC, over the heart rate of zebra fish larvae and in the blockage of sciatic nerve in mice. The results from this study support that the proper combination of natural excipients is promising in DDS, taking advantage of the biocompatibility, low cost, and diversity of lipids. PMID- 28558982 TI - Decrease in the incidence and in hospital mortality of community-acquired pneumonia among children in Spain (2001-2014). AB - OBJECTIVES: To describe trends in the incidence and outcomes of community acquired pneumonia (CAP) hospitalizations among Spanish children from 2001 to 2014 and to assess the effect of the pneumococcal vaccination (PCV) coverage in this period. METHODS: This study was conducted using the Spanish National Hospital Database from 2001 to 2014 including subjects <18years. We selected discharges with a primary diagnosis of CAP. Study variable included age, sex, comorbid conditions, procedures, isolated pathogens and hospital outcome variables. In order to estimate the effect of coverage of pneumococcal vaccination in hospitalizations for CAP, we used the number of commercialized doses of PCV (PCV7 PCV10, and PCV13) for each year. Incidence rates of admissions for CAP were calculated by dividing the number of admissions per year, sex, and age group by the corresponding number of people in that population group according to the census data. RESULTS: We identified 194,419 admissions for CAP. Incidence rate was highest among children younger than 2years and decreased significantly by 3.67% per year over the study period in this age group. Among children aged 2-4years incidence of CAP seem to decrease after year 2009. S. pneumoniae isolations decreased significantly over time but virus isolations increased. In children aged <2years and 2-4years increase in PVC was associated to a decrease in the incidence of CAP hospitalizations. Overall crude in hospital mortality following CAP fell significantly from 4.10/00 in 2001-2003 to 2.80/00 in 2012-2014. CONCLUSIONS: CAP incidence rates decreased significantly among children <2years of age from 2001 to 2014. S. pneumoniae isolations decreased significantly over time but virus isolations increased. In hospital mortality paralleling CAP fell significantly in children and adolescents from 2001 to 2014. Improvement in vaccination coverage seems to have a mitigating effect on hospitalizations and outcomes for CAP in children. PMID- 28558984 TI - Human immune responses against Shigella and enterotoxigenic E. coli: Current advances and the path forward. AB - Robust and well-established immunological assays and firm immune correlates of protection that can predict disease outcome and/or vaccine efficacy are essential to adequately assess human immune responses to infection and vaccination. The availability of reagents and calibrated controls is also critically important to standardize assays and generate comparable results among different laboratories. The workshop "Human Immune Responses against Shigella and ETEC: Current Advances and the Path Forward" held during the VASE meeting provided an opportunity to disseminate and discuss recent advances in the field of Shigella and ETEC immunology, identify research needs, and propose collaborative activities to advance the field. Four presentations featured current knowledge on humoral and cellular immune responses to Shigella and ETEC during infection and vaccination. A discussion followed on immunological methods relevant for clinical studies, immune parameters associated with protection, harmonization of assays among laboratories, and availability of reagents and standards. Specific recommendations proposed to facilitate "the path forward" included supporting communication among scientists, harmonization of assays and sharing of protocols, the creation of a repository of reagents and calibrated controls and distribution of such material to the research community, and expansion of exploratory studies to better understand the interactions between these pathogens and the human immune system and the ensuing responses. PMID- 28558986 TI - Tolerance of Orthotopic Ileal Neobladders to Radiotherapy: A Multi-institutional Retrospective Study. AB - BACKGROUND: The present retrospective study analyzed the tolerance of orthotopic ileal neobladders to radiotherapy by reviewing the acute and late toxicity in patients who underwent postoperative radiotherapy after radical cystectomy/cystoprostatectomy. MATERIALS AND METHODS: A multi-institutional database was created for patients who had undergone radical cystectomy/cystoprostatectomy and neobladder reconstruction, followed by adjuvant radiotherapy (RT). The patient and tumor characteristics were recorded. The RT data were reviewed to determine the treatment technique used, the radiation dose received by the neobladder, and acute and late toxicity evaluated using the Common Terminology Criteria for Adverse Events, version 4.0, scale. RESULTS: A total of 25 patients were included, with a median age of 64 years. Of the 25 patients, 18 received a dose of 45 to 50.4 Gy. The most common reasons for postoperative radiotherapy were close or positive surgical margins and pT3-pT4 or N+ disease. Ten patients underwent intensity modulated RT. All but 1 patient completed the RT course. Of the patients who completed their RT schedule, none had grade >= 3 acute gastrointestinal toxicity. One patient who received concurrent chemotherapy developed grade 3 acute genitourinary toxicity. Three patients reported late grade 1 genitourinary toxicity (frequency of urination, mild leakage at night), with no reports of chronic gastrointestinal toxicity. None of the patients experienced neobladder perforation, leak, or fistula. CONCLUSION: The use of moderate doses of pelvic RT (range, 45-50.4 Gy) was well tolerated among the 25 patients who underwent RT after cystoprostatectomy with orthotopic neobladder creation. This finding supports the use of postoperative RT to moderate doses in this patient population when clinically indicated. PMID- 28558985 TI - Factors associated with parental acceptance of seasonal influenza vaccination for their children - A telephone survey in the adult population in Germany. AB - INTRODUCTION: Influenza vaccination of children with underlying chronic diseases is currently recommended in Germany, but targeting all children constitutes an alternative approach to control seasonal influenza. To inform the modelling of vaccination impact and possible communication activities, we aimed to assess among parents the acceptance of universal childhood vaccination against seasonal influenza and possible modifiers. METHODS: We conducted a telephone survey in households in Germany using random digit dialing. We interviewed parents with children aged <18 years by constructing three hypothetical scenarios in subsequent order: (1) hearing about the influenza vaccination recommendation through the media, (2) the vaccine being recommended by a physician, and (3) being informed about the availability of the vaccine as a nasal spray. We calculated the proportion of parents who would immunize their child and used univariable and multivariable logistic regression to identify factors associated with influenza vaccination intention. RESULTS: Response was between 22 and 46%. Of 518 participants, 74% were female, mean age was 41.3 years. Participants had on average 1.6 children with a mean age of 8.9 years. In scenario 1, 52% of parents would immunize their child, compared to 64% in scenario 2 (p<0.01) and to 45% in scenario 3 (p=0.20). Factors independently associated with vaccination acceptance in scenario 1 were previous influenza vaccination of the child or parent (adjusted odds ratio [aOR] 4.5 and 8.6, respectively), perceived severity of influenza (aOR=5.1) and living in eastern Germany (aOR=2.4). CONCLUSION: If seasonal influenza vaccination was recommended for all children, more than half of the parents would potentially agree to immunize their child. Involving physicians in future information campaigns is essential to achieve high uptake. As intranasal vaccine administration is non-invasive and easily done, it remains unclear why scenario 3 was associated with low acceptance among parents, and the underlying reasons should be further explored. PMID- 28558983 TI - Enhancing global vaccine pharmacovigilance: Proof-of-concept study on aseptic meningitis and immune thrombocytopenic purpura following measles-mumps containing vaccination. AB - New vaccines designed to prevent diseases endemic in low and middle-income countries (LMICs) are now being introduced without prior record of utilization in countries with robust pharmacovigilance systems. To address this deficit, our objective was to demonstrate feasibility of an international hospital-based network for the assessment of potential epidemiological associations between serious and rare adverse events and vaccines in any setting. This was done through a proof-of-concept evaluation of the risk of immune thrombocytopenic purpura (ITP) and aseptic meningitis (AM) following administration of the first dose of measles-mumps-containing vaccines using the self-controlled risk interval method in the primary analysis. The World Health Organization (WHO) selected 26 sentinel sites (49 hospitals) distributed in 16 countries of the six WHO regions. Incidence rate ratios (IRR) of 5.0 (95% CI: 2.5-9.7) for ITP following first dose of measles-containing vaccinations, and of 10.9 (95% CI: 4.2-27.8) for AM following mumps-containing vaccinations were found. The strain-specific analyses showed significantly elevated ITP risk for measles vaccines containing Schwarz (IRR: 20.7; 95% CI: 2.7-157.6), Edmonston-Zagreb (IRR: 11.1; 95% CI: 1.4-90.3), and Enders'Edmonston (IRR: 8.5; 95% CI: 1.9-38.1) strains. A significantly elevated AM risk for vaccines containing the Leningrad-Zagreb mumps strain (IRR: 10.8; 95% CI: 1.3-87.4) was also found. This proof-of-concept study has shown, for the first time, that an international hospital-based network for the investigation of rare vaccine adverse events, using common standardized procedures and with high participation of LMICs, is feasible, can produce reliable results, and has the potential to characterize differences in risk between vaccine strains. The completion of this network by adding large reference hospitals, particularly from tropical countries, and the systematic WHO-led implementation of this approach, should permit the rapid post-marketing evaluation of safety signals for serious and rare adverse events for new and existing vaccines in all settings, including LMICs. PMID- 28558988 TI - Association of Distance to Treatment Facility With Survival and Quality Outcomes After Radical Cystectomy: A Multi-Institutional Study. AB - BACKGROUND: We sought to determine the effect of the travel distance on mortality and quality outcomes after radical cystectomy in a large multi-institutional cohort. PATIENTS AND METHODS: A total of 3957 patients who had undergone radical cystectomy for urothelial carcinoma at 6 North American tertiary care institutions were included. The association of travel distance with quality-of care endpoints, 90-day mortality, and long-term survival were evaluated. RESULTS: The median patient age was 69 years (interquartile range, 61-76 years), and most patients were men (80%). Most patients had clinical stage T2 (45.2%) and T1 (24.7%) tumors. The median distance to the treatment facility was 102.9 miles (interquartile range, 24-271 miles). Patients residing in the first quartile of travel distance to treatment facility (< 24 miles) had lower usage of neoadjuvant chemotherapy compared with patients in the fourth distance quartile (adjusted odds ratio, 1.58; 95% confidence interval, 1.22-2.05; P = .001). Patients in the first distance quartile were also less likely to experience a delay in time to cystectomy (> 3 months) compared with patients with a greater travel distance (adjusted odds ratio, 0.673; 95% confidence interval, 0.532-0.851). Distance to the treatment facility was not associated with 90-day mortality or cancer specific or all-cause mortality on multivariate analysis. CONCLUSION: Despite the potential health care disparities for bladder cancer patients residing distant to a regional surgical oncology facility, the study results suggest that the travel distance is not a barrier to appropriate oncologic care at regional tertiary care centers. PMID- 28558987 TI - Genomic Characterization of Renal Medullary Carcinoma and Treatment Outcomes. AB - BACKGROUND: Renal medullary carcinoma (RMC) is a rare and aggressive type of kidney cancer that primarily affects young adults with sickle cell trait; outcomes are poor despite treatment. Identifying molecular features of this tumor could provide biologic rationale for novel targeted therapies. The objective was to report on clinical outcomes with systemic therapy and characterize molecular features. PATIENTS AND METHODS: This was a retrospective analysis on 36 patients given a pathologic diagnosis of RMC at one institution from 1995 to 2015. Tumors were analyzed for expression of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1 (SMARCB1) through immunohistochemistry and for genomic alterations with fluorescence in situ hybridization for SMARCB1, and targeted next-generation sequencing. Time from initiation of therapy to progression of disease and overall survival were calculated using the Kaplan-Meier method. RESULTS: The median age in the cohort was 28 (range, 12-72) years, and all patients tested had sickle cell trait. Overall survival was 5.8 months (95% confidence interval [CI], 4.1-10.9) and for 12 patients who received platinum-based therapy, median progression-free survival was 2.5 months (95% CI, 1.2-not reached). A total of 10 available tumors underwent analysis with fluorescence in situ hybridization for SMARCB1; this revealed loss of heterozygosity with concurrent translocation in 8, and biallelic loss in 2. Next-generation targeted sequencing showed no recurring mutations. CONCLUSIONS: Outcome was generally poor in this cohort of patients with RMC. Uniform loss of SMARCB1 is a key molecular feature in this tumor and mechanism of loss appears to be mostly through translocations and deletions. PMID- 28558989 TI - Preoperative Cholesterol Level Is Associated With Worse Pathological Outcomes and Postoperative Survival in Localized Renal Cell Carcinoma Patients: A Propensity Score-Matched Study. AB - INTRODUCTION: Lipid metabolism has been suggested to be associated with clinical outcomes of renal cell carcinoma (RCC). In this study, we aimed to investigate the relationship between preoperative cholesterol level (PCL) and postoperative outcomes of patients with localized RCC. MATERIALS AND METHODS: We retrospectively analyzed the data of 5022 patients surgically treated for nonmetastatic RCC. According to the receiver operating curve of PCL for cancer specific mortality, we stratified the patients into 2 groups by using a cutoff value of 161 mg/dL. The propensity scores for having low PCL were calculated, and the low PCL group was matched with the high PCL group at a 1:2 ratio. The oncological profiles and postoperative survival of patients were compared. RESULTS: A low cholesterol level was significantly associated with adverse pathologic findings, such as higher pathologic stage (P < .001) and large tumor size (P = .002). Furthermore, the low cholesterol group showed significantly worse progression-free, cancer-specific, and overall survival (all P values < .001) compared with the high cholesterol group. Multivariate analysis exhibited a higher PCL as an independent predictor of better progression-free (P < .001), cancer-specific (P = .018), and overall survival (P = .001) after matching. Subgroup analysis according to tumor histology revealed that PCL had a significant relationship with patients' survival in clear cell RCC, but not in non-clear cell RCC. CONCLUSION: Decreased PCL was significantly associated with worse pathologic outcomes and also inferior postoperative survival in patients with localized RCC; however, those relationships were significant only in clear cell subtypes. PMID- 28558990 TI - Utilization of Pelvic Lymph Node Dissection for Patients With Low-Risk Prostate Cancer Treated With Robot-Assisted Radical Prostatectomy. AB - INTRODUCTION: Pelvic lymph node dissection (PLND) is not recommended for low-risk prostate cancer (PCa) patients. However, the rate of PLND in this population is unknown. METHODS: We queried the National Cancer Data Base for PCa patients who underwent robot-assisted radical prostatectomy from 2010 to 2013 and stratified them by D'Amico risk classification. We identified the frequency of PLND in low risk patients and identified factors associated with receipt of PLND. Further, we determined the number of lymph nodes evaluated (quality) and proportion of patients with detected nodal metastatic disease (utility) in each risk group. RESULTS: Of 51,971 patients with low-risk PCa who underwent robot-assisted radical prostatectomy, 19,059 (36.7%) received PLND. Predictors of PLND in low risk patients included rural residence (odds ratio [OR], 1.157; 95% confidence interval [CI], 1.009-1.327), treatment at an academic center (OR, 1.492; 95% CI 1.188-1.874), and high-volume facility (OR, 1.327; 95% CI, 1.078-1.633). The mean number of lymph nodes obtained in low-risk patients was lower than in intermediate/high-risk patients (4.74 vs. 5.86, P < .0001). Lymph node positivity was identified in 0.4% of low-risk patients and 4.6% of intermediate/high-risk patients. CONCLUSION: While PLND is not recommended for low-risk PCa by clinical practice guidelines, it was performed frequently (36.7%) in a large hospital based data set. PLND in this population was of lower quality (nodal yield) and had less utility of detecting nodal metastatic disease than PLND in intermediate/high-risk PCa. Treatment at a high-volume or academic center was associated with increased use of PLND. Reasons for the variation in practice patterns should be investigated to improve the value of PCa care. PMID- 28558991 TI - Variation in Locoregional Prostate Cancer Care and Treatment Trends at Commission on Cancer Designated Facilities: A National Cancer Data Base Analysis 2004 to 2013. AB - BACKGROUND: Contemporary treatment trends for prostate cancer show increased rates of active surveillance. However, nationwide applicability of these reports is limited. Additionally, the effect of Commission on Cancer facility type on prostate cancer treatment patterns is unknown. PATIENTS AND METHODS: We used the National Cancer Data Base to identify men diagnosed with prostate cancer, between 2004 and 2013. Our cohort was stratified on the basis of the National Comprehensive Cancer Network prostate cancer risk classes. Cochran-Armitage tests were used to evaluate temporal trends. Random effects hierarchical logit models were used to assess treatment variation at Commission on Cancer facility and institution level. RESULTS: In 825,707 men, utilization of radiation therapy declined and utilization of radical prostatectomy increased for all prostate cancer risk groups between 2004 and 2013 (P < .0001). Observation for low-risk prostate cancer increased from 16.3% in 2004 to 2005 to 32.0% in 2012 to 2013 (P < .0001). Significant treatment variation was observed on the basis of Commission on Cancer facility type. Across all risk groups, the lowest rates of radical prostatectomy and highest rates of external beam radiation therapy were observed in community cancer programs. The highest rates of observation for low-risk disease were observed in academic centers. Treatment variation according to institution ranged from 14% (95% confidence interval, 0.12-0.15) for androgen deprivation therapy up to 59% (95% confidence interval, 0.45-0.73) for cryotherapy. CONCLUSION: The increased utilization of observation in low-risk prostate cancer is an encouraging finding, which appears to be mainly derived by a decrease in radiotherapy utilization in this risk group. Regardless of tumor characteristics, significant variations in treatment modality exist among different facility types and institutions. PMID- 28558992 TI - Molecular surveillance of Theileria parasites of livestock in Oman. AB - BACKGROUND: Theileriosis is one of the most prevalent infectious diseases of livestock in the Arabian Peninsula, and causes high rates of mortality and morbidity in sheep and cattle. However, there is a paucity of information on the distribution of Theileria spp. over the whole region and their impact on different hosts. The present study carried out a country-wide molecular survey for Theileria spp. of livestock in Oman across four governorates. The aim of the survey was to define the prevalence of Theileria spp. in cattle, sheep and goats, highlight risk factors for infection and identify the main tick species involved in parasite transmission. MATERIAL AND METHODS: A total of 2020 animals were examined in the survey consisting of sheep [n=592], goats [n=981] and cattle [n=447]. All three species were raised and co-grazed on the same farms. Theileria parasites were detected using PCR-RFLP and RLB of the 18S rRNA gene. Cloning and sequencing of the 18S rRNA was carried out on 11 T. lestoquardi isolates from Ash Sharqiyah, and Ad-Dhahira governorates, and phylogenetic relationships were inferred using additional sequences of T. lestoquardi, T. annulata and T. ovis available in GenBank. RESULTS: Theileria spp. prevalence was 72.3%, 36.7% and 2.7% among cattle, sheep and goats, respectively. Strong similarity in results was obtained using RLB and PCR-RFLP for detection of Theileria spp. however, RLB detected a higher rate of mixed infection than PCR-RFPL (P<0.001). Theileria annulata was the only parasite detected in cattle, while sheep and goats carried T. ovis, T. lestoquardi and T. annulata as well as Theileria spp. OT1. Of the four Theileria spp. detected in small ruminants, overall T. ovis was most prevalent (sheep [33.4%], goats [2.0%]), whereas T. lestoquardi was less prevalent (sheep [22.0%], goats [0.5%]). A large proportion of infected sheep (19%) carried mixed infection of T. ovis and T. lestoquardi. However, single T. lestoquardi infections (3.0%) were less prevalent than T. ovis infections (14.5%). Risk of Theileria spp. infection was significantly higher for exotic breeds, relative to native breeds, of cattle (p=0.00002) and sheep (p=0.005). Phylogenetic analysis placed T. lestoquardi in Oman in the same clade as other T. lestoquardi strains isolated from the same regional area (Iraq and Iran). The main tick species, identified on the examined animals, Hyalomma anatolicum, was widely distributed and was found in all of the surveyed governorates. CONCLUSION: Theileria spp. are widespread in Oman with variable prevalence detected in different regions. Two economically important hosts, cattle and sheep are at high risk from virulent T. annulata and T. lestoquardi, respectively. The survey indicates extensive exposure to ticks and transmission of infection that has a significant economic impact. The higher prevalence of T. lestoquardi as mixed rather than single infection requires further investigation. PMID- 28558993 TI - Estradiol modulates the anorexic response to central glucagon-like peptide 1. AB - Estrogens suppress feeding in part by enhancing the response to satiation signals. Glucagon-like peptide 1 (GLP-1) acts on receptor populations both peripherally and centrally to affect food intake. We hypothesized that modulation of the central GLP-1 system is one of the mechanisms underlying the effects of estrogens on feeding. We assessed the anorexic effect of 0, 1, and 10MUg doses of GLP-1 administered into the lateral ventricle of bilaterally ovariectomized (OVX) female rats on a cyclic regimen of either 2MUg beta-estradiol-3-benzoate (EB) or oil vehicle 30min prior to dark onset on the day following hormone treatment. Central GLP-1 treatment significantly suppressed food intake in EB-treated rats at both doses compared to vehicle, whereas only the 10MUg GLP-1 dose was effective in oil-treated rats. To follow up, we examined whether physiologic-dose cyclic estradiol treatment influences GLP-1-induced c-Fos in feeding-relevant brain areas of OVX females. GLP-1 significantly increased c-Fos expression in the area postrema (AP) and nucleus of the solitary tract (NTS), and the presence of estrogens may be required for this effect in the paraventricular nucleus of the hypothalamus (PVN). Together, these data suggest that modulation of the central GLP-1 system may be one of the mechanisms by which estrogens suppress food intake, and highlight the PVN as a region of interest for future investigation. PMID- 28558995 TI - Cellular uptake of coagulation factor VIII: Elusive role of the membrane-binding spikes in the C1 domain. AB - Low density lipoprotein receptor-related protein 1 (LRP1) is involved in the catabolism of many ligands, including factor VIII (FVIII) and alpha-2 macroglobulin (alpha2M). Transfer of FVIII to LRP1 is currently believed to be preceded by pre-concentration on the cell surface, by interacting with a so far unidentified component. In the present study, we used confocal microscopy and flow cytometry to compare endocytosis of FVIII and alpha2M using U87MG cells. The results show that alpha2M is rapidly internalized and does not compete for LRP1 mediated internalization of FVIII. FVIII endocytosis did not occur in the presence of receptor-associated-protein (RAP), but FVIII remained visible as a striated fluorescent pattern at the cell borders. In the presence of Von Willebrand Factor (VWF), no FVIII was observed on or within the cells, suggesting that VWF blocks interaction with both cell surface and LRP1. The same dual inhibition has previously been observed for FVIII C1 domain directed monoclonal antibody KM33. Elimination of the KM33 epitope by replacing FVIII C1 residues 2091-2095 and 2155-2160 for the homologues from factor V (FV), however, did not impair FVIII endocytosis. These membrane spikes alone were insufficient for cellular uptake, because FV was neither internalized by U87MG cells nor capable of effectively competing for FVIII endocytosis. These results show that FVIII endocytosis is driven by interaction with LRP1, but at the same time involves the spikes in the C1 domain that have been implicated in lipid binding. PMID- 28558996 TI - Supramalleolar Osteotomy With Distraction Arthroplasty in Treatment of Varus Ankle Osteoarthritis With Large Talar Tilt Angle: A Case Report and Literature Review. AB - We treated a 57-year-old female with modified Takakura stage 3B varus ankle osteoarthritis. Her preoperative talar tilt angle was 21.3 degrees . The patient wished to avoid ankle joint arthrodesis or replacement. Therefore, medial opening wedge supramalleolar osteotomy with fibular osteotomy was used for her varus ankle osteoarthritis. Also, fixed medial distraction arthroplasty was performed to improve her talar tilt. After 3 months, the external device was removed, and the patient was allowed partial weightbearing and began full weightbearing 4 months postoperatively after the osteotomy site had reached bony union radiographically. At the 3-year follow-up visit, a radiograph showed the medial ankle joint space enlargement had been maintained. The talar tilt angle had decreased to 3.3 degrees , and the modified Takakura stage had improved to stage 1. The American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot scale score had improved from 26 points preoperatively to 85 points at 3 years postoperatively. Our findings suggested that good clinical and radiologic results can be achieved with supramalleolar osteotomy combined with distraction arthroplasty in the treatment of varus ankle osteoarthritis with a large talar tilt angle. PMID- 28558998 TI - Open Ankle Dislocation Without Fractures With Tibialis Posterior Tendon Interposition Through the Interosseous Space. AB - Open ankle dislocations without fracture are rare injuries. Dislocation or interposition of adjacent tendons are a rare associated feature of ankle fracture dislocation. We report an extremely unusual case of open ankle dislocation without fracture with concurrent tibialis posterior tendon interposition through the interosseous space that was detected incidentally on computed tomography. We highlight the clinical, radiologic, and intraoperative features to avoid missing similar diagnoses. PMID- 28558997 TI - Onychomatricoma: A Rare and Potentially Underreported Tumor of the Nail Matrix. AB - Onychomatricoma is a rare benign neoplasm of the nail matrix first described by Baran and Kint in 1992. Fewer than 80 cases of onychomatricoma have been described in the literature, 15 of which were initially misdiagnosed and treated as onychomycosis. We present the case of a 66-year-old male with thickening and linear xanthonychia of the hallux nail plate secondary to an onychomatricoma misdiagnosed as onychomycosis. Following biopsy for histopathologic analysis, the lesion and proximal nail matrix were surgically excised. At 12 months post excision, the patient remains asymptomatic without evidence of recurrence. The purpose of the present case report is to make foot and ankle surgeons more cognizant of the pathology, highlight the nonspecific clinical and radiologic findings, and emphasize the importance of interdisciplinary communication for an accurate clinicopathologic correlation and diagnosis of the lesion. Although rare, onychomatricoma should be considered in the differential diagnosis for patients presenting with onychomycosis failing to respond to antimycologic treatment. The clinical index of suspicion for onychomatricoma should increase when only a singular dystrophic nail is involved. Following diagnostic confirmation by histopathology, complete surgical excision is the treatment of choice. PMID- 28558999 TI - Massive Osteochondral Lesion of the Talus in a Skeletally Immature Patient Associated With a Tarsal Coalition and Valgus Hindfoot. AB - Rarely, osteochondral lesions of the talus occur without a history of trauma. Accurate interpretation of the mechanical load distributions onto the ankle leading to potential atraumatic cartilage damage must always be studied. The published data on the optimal treatment of talar osteochondral lesions in skeletally immature patients are scarce, especially when the lesions are associated with hindfoot malalignment. We describe the case of a pediatric female with an atraumatic osteochondral lesion of the talus associated with a talocalcaneal coalition and a valgus hindfoot, which we consider the first case to be reported. She presented with prolonged bilateral ankle pain and catching during gait of approximately 2 years' duration with a restricted range of motion, with the pain more excruciating in the right ankle. Radiographs revealed a large osteochondral lesion located at the lateral talar dome. The patient underwent partial osteochondral allograft transplantation, together with hindfoot realignment and coalition resection with a fat graft interposition. At the 2-year follow-up examination, the patient was free of pain in her right foot and ankle, with no signs of radiologic failure. PMID- 28558994 TI - PPARalpha-independent transcriptional targets of perfluoroalkyl acids revealed by transcript profiling. AB - Perfluoroalkyl acids (PFAAs) are ubiquitous and persistent environmental contaminants. Compounds such as perfluoroocanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonate (PFHxS) are readily found in the tissues of humans and wildlife. While PFOA and PFOS have been the subject of numerous studies since they were first described over a decade ago, less is known about the biological activity of PFHxS and PFNA. Most PFAAs are activators of peroxisome proliferator-activated receptor alpha (PPARalpha), although the biological effects of these compounds are likely mediated by other factors in addition to PPARalpha. To evaluate the effects of PFHxS and PFNA, male wild-type and Pparalpha-null mice were dosed by oral gavage with PFHxS (3 or 10mg/kg/day), PFNA (1 or 3mg/kg/day), or vehicle for 7days, and liver gene expression was evaluated by full-genome microarrays. Gene expression patterns were then compared to historical in-house data for PFOA and PFOS in addition to the experimental hypolipidemic agent, WY-14,643. While WY-14,643 altered most genes in a PPARalpha-dependent manner, approximately 11-24% of regulated genes in PFAA-treated mice were independent of PPARalpha. The possibility that PFAAs regulate gene expression through other molecular pathways was evaluated. Using data available through a microarray database, PFAA gene expression profiles were found to exhibit significant similarity to profiles from mouse tissues exposed to agonists of the constitutive activated receptor (CAR), estrogen receptor alpha (ERalpha), and PPARgamma. Human PPARgamma and ERalpha were activated by all four PFAAs in trans-activation assays from the ToxCast screening program. Predictive gene expression biomarkers showed that PFAAs activate CAR in both genotypes and cause feminization of the liver transcriptome through suppression of signal transducer and activator of transcription 5B (STAT5B). These results indicate that, in addition to activating PPARalpha as a primary target, PFAAs also have the potential to activate CAR, PPARgamma, and ERalpha as well as suppress STAT5B. PMID- 28559000 TI - Concordant testing results between various human papillomavirus assays in primary cervical cancer screening: systematic review. AB - OBJECTIVES: Human papillomavirus (HPV) assays are increasingly used for primary cervical screening and HPV-vaccination-effect monitoring. We undertook a systematic literature review to determine the concordance in positive test results (i.e. detection of HPV infections) between Hybrid Capture 2 (HC2) and other assays. METHODS: We searched PubMed, Embase and Scopus for studies of primary screening with HC2 and one or more assays, with cross-tabulated testing results for the assays. Two authors applied inclusion criteria and three authors extracted data from included studies. For each inter-assay comparison, we calculated the concordance by comparing the number of concordant samples with the number of samples that tested positive on at least one assay. RESULTS: Sixteen studies fulfilled inclusion criteria, comparing nine assays to HC2, and including 392 to 9451 patients each. The calculated concordance varied between 48% and 69% for HC2 and APTIMA, Cobas, Abbott RealTime, Cervista, GP5+/6+, CLART, BD HPV test, Amplicor and Linear Array, i.e. 31%-52% of all positive tests on any pair of compared assays were discordant. Although modest variation in the degree of concordance with HC2 was suggested for particular assays, the numbers of studies per assay were generally low. No pronounced systematic patterns were observed by study (e.g. liquid medium) or population characteristics. CONCLUSIONS: The ten commercially available assays do not detect the same HPV infections. Even in the most favourable case, the two assays provided discordant test results in 31% of all detected infections. PMID- 28559001 TI - Characterizing non-linear effects of hospitalisation duration on antimicrobial resistance in respiratory isolates: an analysis of a prospective nationwide surveillance system. AB - OBJECTIVES: Our objective was to systematically study the influence of length of hospital stay on bacterial resistance in relevant respiratory tract isolates. METHODS: Using prospective epidemiological data from the National Swiss Antibiotic Resistance Surveillance System, susceptibility testing results for respiratory isolates retrospectively retrieved from patients hospitalised between 2008 and 2014 were compiled. Generalized additive models were used to illustrate resistance rates relative to hospitalisation duration and to adjust for co variables. RESULTS: In all, 19 622 isolates of six relevant and predominant species were included. Resistance patterns for the predominant species showed a species-specific and antibiotic-resistance-specific profile in function of hospitalisation duration. The oxacillin resistance profile in Staphylococcus aureus isolates was constantly increasing (monophasic). The pattern of resistance to cefepime in Pseudomonas aeruginosa was biphasic with a decreasing resistance rate for the first 5 days of hospitalisation and an increase for days 6-30. A different biphasic pattern occurred in Escherichia coli regarding amoxicillin clavulanic acid resistance: odds/day increased for the first 7 days of hospitalisation and then remained stable for days 8-30. In the adjusted models epidemiological characteristics such as age, ward type, hospital type and linguistic region were identified as relevant co-variables for the resistance rates. The contribution of these confounders was specific to the individual species/antibiotic resistance models. CONCLUSIONS: Resistance rates do not follow a dichotomic pattern (early versus late nosocomial) as suggested by current hospital-acquired pneumonia treatment guidelines. Duration of hospitalisation rather appears to have a more complex and non-linear relationship with bacterial resistance in hospital-acquired pneumonia, also depending on host and environmental factors. PMID- 28559003 TI - Immunogenicity and safety of the 13-valent Pneumococcal Conjugate vaccine in 23 valent pneumococcal polysaccharide vaccine-naive and pre-immunized patients under treatment with chronic haemodialysis: a longitudinal quasi-experimental phase IV study. AB - OBJECTIVE: To benchmark the immunogenicity of pneumococcal conjugated vaccine (PCV-13) versus pneumococcal polysaccharide vaccine (PPV-23) in haemodialysis patients pre-vaccinated or not with PPV-23. METHODS: The study is a longitudinal quasi-experimental phase IV study in chronic haemodialysis patients aged >=50 years. Total (ELISA) and functional (opsonophagocytic assay) antibodies after pneumococcal vaccination were quantified at baseline, and after 28 and 365 days. Of 201 eligible patients, 155 were included. Patients were divided in four groups. PPV-23 naive patients were randomized to PPV-23 (40) or PCV-13 (40) vaccination. PPV-23-pre-vaccinated patients were categorized as being vaccinated more (40) or less (35) than 4 years before the study and all received PCV-13. RESULTS: Patients among the four groups had a significant ELISA antibody response for most serotypes that remained significant up to day 365 versus baseline. In PPV-23-naive patients, ELISA antibody titres were significantly higher among PCV 13 versus PPV-23 recipients for six serotypes (1.85-2.34-fold) after 28 days, and remained significantly higher for one serotype (6A, 1.57-fold) after 365 days. Following PCV-13 vaccination, increase in ELISA antibody titres was significantly higher among PPV-23-naive versus PPV-23-pre-vaccinated patients for 12 serotypes after 28 days (1.68-7.74-fold) and remained significantly higher in ten serotypes (1.44-3.29-fold) after 365 days. CONCLUSION: Immune response after PPV-23 and PCV 13 remains significant for at least 1 year in non-PPV-23-pre-vaccinated patients. Among vaccine-naive haemodialysis patients PCV-13 seems more immunogenic than PPV 23. Immune response to PCV-13 is weaker in PPV-23-pre-vaccinated compared with vaccine-naive patients. PMID- 28559002 TI - Assessment of the automated multiplex-PCR Unyvero i60 ITI(r) cartridge system to diagnose prosthetic joint infection: a multicentre study. AB - OBJECTIVES: Prosthetic joint infections (PJI) are responsible for significant morbidity and mortality and their number continues to rise. Their management remains complex, especially the microbiological diagnosis. Besides 'homemade' tests developed by several teams, new molecular biology methods are now available with different analytical performance and usability. METHODS: We studied the performances of one of these tests: ITI(r) multiplex PCR (mPCR) by the Curetis(r) company and compared it to either 'optimized' culture or 16S rRNA PCR. We performed a retrospective multicentre study to assess the contributions of mPCR in the diagnosis of PJI. We randomly selected 484 intraoperative specimens among 1252 of various types (biopsy, bone, tissue around the prosthesis, synovial fluid) from 251 patients in seven different hospitals. Each sample was treated according to the recommendations of the manufacturer. RESULTS: In all, 154 out of 164 (93.9%) samples negative in culture were negative with the mPCR. Among the 276 positive samples in culture, 251 (90.9%) were monomicrobial, of which 119 (47.4%) were positive with the mPCR, and 25 (9.1%) were polymicrobial, of which 12 (48%) were positive with the mPCR. The concordance rate of mPCR with culture was 58.1% (53.6%-62.7%) and the concordance rate with 16S rRNA PCR was 70.1% (65.5%-74.6%). CONCLUSION: This new standardized molecular test showed a lack of detection when the bacterial inoculum was low (number of positive media per sample and number of colonies per media) but can be useful when patients have received antibiotic therapy previously. PMID- 28559004 TI - The impact of self- and physician-administered cancer treatment on work productivity and healthcare utilization. AB - BACKGROUND: Lost productivity in the workplace represents a significant portion of the economic burden of cancer in the United States. Cancer treatments have historically been physician-administered, while recent innovations have led to the development of self-administered, usually oral, agents. Self-administered treatments have the potential to reduce healthcare utilization and time away from work, but the magnitude of these effects is unknown. OBJECTIVE: To compare the effects of self- and physician-administered cancer treatment on work productivity and health care utilization. METHODS: Cancer subtypes with self- and physician administered treatment options were selected. Patients with female breast, or lung or bronchus cancer diagnosed in 2004-2013 were identified in the Truven Health Analytics Commercial Claims and Encounters and Health and Productivity Management databases. Using multivariate regression models, work productivity and healthcare utilization were compared for patients receiving self- versus physician-administered treatment in the 12 months after initial diagnosis. Work productivity outcomes included the number of sick days and short-term disability claims. RESULTS: One month of self- versus physician-administered treatment significantly reduced cancer-related outpatient services, doctor visits, and infusions in the 12 months after initial diagnosis for both cancers of interest. In addition, breast and lung or bronchus cancer patients who received self administered treatment were less likely to have short-term disability claims, and breast cancer patients with non-metastatic disease who received self-administered treatment had significantly fewer sick days. CONCLUSIONS: Self-administered cancer treatment was associated with fewer cancer-related outpatient services and reduced time away from work compared to physician-administered cancer treatment. PMID- 28559005 TI - Tibial insertions of the anterior cruciate ligament and the anterior horn of the lateral meniscus: A histological and computed tomographic study. AB - BACKGROUND: A positional relationship between the anterior cruciate ligament (ACL) and the anterior horn of the lateral meniscus (AHLM) has not previously been a topic of interest in the literature because the AHLM is already known to be obviously adjacent to the ACL and is assumed as a lateral border. The objective of this study was to investigate the positional anatomic relationship between the ACL and AHLM by histological evaluation of sequential slices and computed tomography (CT) of the tibial insertion sites. HYPOTHESIS/PURPOSE: The ACL has a specific positional relationship with the AHLM and there is an identifiable distinct bony border between them. The position of the AHLM could be an important and useful landmark for accurate tibial tunnel positioning in anatomical ACL reconstruction. STUDY DESIGN: Descriptive laboratory study. METHODS: Twelve ACL-intact knees from embalmed cadavers were used in this study. Six knees were sectioned into four slices for histologic examination in the coronal planes parallel to the AHLM alignment. Before sectioning, these knees were subjected to three-dimensional (3-D) volume-rendering CT. Each of the four slices demonstrated the insertion area of the ACL relative to the position of the AHLM. Each histologic slice was compared with the corresponding CT image. Only histological examination in the sagittal planes was performed in the other six knees. RESULTS: The ACL fibres were broadly attached at the region anterior to the AHLM. However, the ACL and AHLM shared a clear border identifiable on the coronal CT images and appeared as a prominence of the bony ridge on the 3-D CT images. No dense ACL fibres were attached to the region posterior to the AHLM. Based on the histological data, the geometry of the ACL tibial insertion was L shaped along the AHLM. CONCLUSION: The ACL and AHLM have a specific positional relationship not only in the mediolateral direction but also anteroposteriorly. The AHLM serves not only as a lateral border, but also as a useful reference in an anterioposterior direction for tunnel positioning in ACL reconstruction. Specifically, the ACL fibres were found to be broadly attached onto the bony surface in the region anterior to the AHLM and there was no firm attachment of the ACL in the region posterior to the AHLM on the tibial side, which is useful in avoiding posterior tunnel placement. PMID- 28559007 TI - Comprehensive Qualitative Assessment of Urethral Stricture Disease: Toward the Development of a Patient Centered Outcome Measure. AB - PURPOSE: The primary objective of this study was to report what patients considered to be the most important symptoms, functions and impacts of urethral stricture disease. Patient and physician perspectives were correlated. MATERIALS AND METHODS: Patients were involved at each step of patient reported outcome measure development. We performed 1) qualitative semistructured concept elicitation interviews, 2) cognitive interviews, 3) prioritization interviews and 4) item prioritization by patients in regard to bother. A total of 22 reconstructive urologists ranked the items in regard to making treatment decisions. RESULTS: Patient qualitative interviews were done until no new information was gained (16 interviews) to reach concept saturation. A total of 40 items were generated from interview data. Urinary items predominated over sexually related content (34 vs 6). A review of published patient reported outcome measures revealed 10 legacy items that were not derived from the qualitative interviews. Two iterative rounds of cognitive interviews were performed in a separate cohort of 5 and 4 patients, respectively, to assess patient comprehension. Item prioritization was done in a separate cohort of 20 patients. The final instrument for validation included 31 items, of which 27 were new and 4 were legacy items. For the top 15 ranked items there was 53% agreement between patients and physicians. Patients were most worried about inability to urinate and urinary dribbling. CONCLUSIONS: We found multiple patient generated concepts related to urinary and sexual impact, function and symptoms. Patients and clinicians had a low agreement rate regarding item importance. PMID- 28559006 TI - ACL graft metabolic activity assessed by 18FDG PET-MRI. AB - BACKGROUND: To demonstrate the use of 18Fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) in combination (18FDG-PET) to assess the metabolic activity of ACL graft tissue and evaluate the utility of this technique for ligament imaging. METHODS: Twenty-one knees with intact ACL grafts in 19 patients at multiple time points following ACL reconstruction were recruited to participate. PET-MRI imaging was performed using a custom device to place knees in the same position for both studies. Images were co-registered for quantification of 18FDG-PET standardized uptake value (SUV) for the proximal, middle, and distal ACL was quantified. Signal in extra-articular muscle tissue in the index knee was also recorded as a control. Signal from each location was compared based on how far post-operative each knee was from ACL reconstruction (<6months, six to 12months, 12-24months, or >24months). RESULTS: Significant differences in 18FDG PET SUV between the four time points were observed in the proximal (p=0.02), middle (p=0.004), and distal (p=0.007) portions of the ACL graft. The greater than 24months group was noted to be different from other groups in each case. No difference in PET 18FDG SUV was noted in the extra articular muscle in the index knee in each time group (p=0.61). CONCLUSIONS: Metabolic activity was noted to be significantly lower in grafts imaged greater than two years post-reconstruction relative to those grafts that had been in place for shorter periods of time. PMID- 28559008 TI - Modelling mass transfer during venting/soil vapour extraction: Non-aqueous phase liquid/gas mass transfer coefficient estimation. AB - We investigate how the simulation of the venting/soil vapour extraction (SVE) process is affected by the mass transfer coefficient, using a model comprising five partial differential equations describing gas flow and mass conservation of phases and including an expression accounting for soil saturation conditions. In doing so, we test five previously reported quations for estimating the non aqueous phase liquid (NAPL)/gas initial mass transfer coefficient and evaluate an expression that uses a reference NAPL saturation. Four venting/SVE experiments utilizing a sand column are performed with dry and non-saturated sand at low and high flow rates, and the obtained experimental results are subsequently simulated, revealing that hydrodynamic dispersion cannot be neglected in the estimation of the mass transfer coefficient, particularly in the case of low velocities. Among the tested models, only the analytical solution of a convection dispersion equation and the equation proposed herein are suitable for correctly modelling the experimental results, with the developed model representing the best choice for correctly simulating the experimental results and the tailing part of the extracted gas concentration curve. PMID- 28559009 TI - Statins for primary prevention in active individuals; risks versus benefits? PMID- 28559010 TI - OpenMS - A platform for reproducible analysis of mass spectrometry data. AB - BACKGROUND: In recent years, several mass spectrometry-based omics technologies emerged to investigate qualitative and quantitative changes within thousands of biologically active components such as proteins, lipids and metabolites. The research enabled through these methods potentially contributes to the diagnosis and pathophysiology of human diseases as well as to the clarification of structures and interactions between biomolecules. Simultaneously, technological advances in the field of mass spectrometry leading to an ever increasing amount of data, demand high standards in efficiency, accuracy and reproducibility of potential analysis software. RESULTS: This article presents the current state and ongoing developments in OpenMS, a versatile open-source framework aimed at enabling reproducible analyses of high-throughput mass spectrometry data. It provides implementations of frequently occurring processing operations on MS data through a clean application programming interface in C++ and Python. A collection of 185 tools and ready-made workflows for typical MS-based experiments enable convenient analyses for non-developers and facilitate reproducible research without losing flexibility. CONCLUSIONS: OpenMS will continue to increase its ease of use for developers as well as users with improved continuous integration/deployment strategies, regular trainings with updated training materials and multiple sources of support. The active developer community ensures the incorporation of new features to support state of the art research. PMID- 28559011 TI - Protein tyrosine phosphatase sigma regulates autoimmune encephalomyelitis development. AB - Protein tyrosine phosphatases (PTPs) play essential roles in regulating signaling events in multiple cells by tyrosine dephosphorylation. One of them, PTPsigma, appears important in regulating function of plasmacytoid dendritic cells (pDC). Here we report that PTPsigma deletion in knockout mice and inhibition with a selective antagonist peptide exacerbated symptoms of experimental autoimmune encephalomyelitis (EAE) by enhancing axon and myelin damage in the spinal cord. PTPsigma-/- mice displayed pro-inflammatory profiles in the spinal cord and lymphoid organs following MOG peptide immunization. PTPsigma deletion promoted a pro-inflammatory phenotype in conventional DCs and directly regulated differentiation of CD4+ T cells. It also facilitated infiltration of T lymphocytes, activation of macrophages in the CNS and development of EAE. Therefore, PTPsigma is a key negative regulator in EAE initiation and progression, which acts by regulating functions of DCs, T cells, and other immune cells. PTPsigma may become an important molecular target for treating autoimmune disorders. PMID- 28559012 TI - Establishment and characterization of an oral tongue squamous cell carcinoma cell line from a never-smoking patient. AB - OBJECTIVE: The rising incidence of oral tongue squamous cell carcinoma (OTSCC) in patients who have never smoked and the paucity of knowledge of its biological behavior prompted us to develop a new cell line originating from a never-smoker. MATERIALS AND METHODS: Fresh tumor tissue of keratinizing OTSCC was collected from a 44-year-old woman who had never smoked. Serum-free media with a low calcium concentration were used in cell culture, and a multifaceted approach was taken to verify and characterize the cell line, designated UCSF-OT-1109. RESULTS: UCSF-OT-1109 was authenticated by STR DNA fingerprint analysis, presence of an epithelial marker EpCAM, absence of human papilloma virus (HPV) DNA, and SCC specific microscopic appearance. Sphere-forming assays supported its tumorigenic potential. Spectral karyotype (SKY) analysis revealed numerical and structural chromosomal abnormalities. Whole-exome sequencing (WES) identified 46 non synonymous and 13 synonymous somatic single-nucleotide polymorphisms (SNPs) and one frameshift deletion in the coding regions. Specifically, mutations of CDKN2A, TP53, SPTBN5, NOTCH2, and FAM136A were found in the databases. Copy number aberration (CNA) analysis revealed that the cell line loses chromosome 3p and 9p, but lacks amplification of 3q and 11q (as does HPV-negative, smoking-unrelated OTSCC). It also exhibits four distinctive focal amplifications in chromosome 19p, containing 131 genes without SNPs. Particularly, 52 genes showed >3- to 4-fold amplification and could be potential oncogenic drivers. CONCLUSION: We have successfully established a novel OTSCC cell line from a never-smoking patient. UCSF-OT-1109 is potentially a robust experimental model of OTSCC in never smokers. PMID- 28559014 TI - Comparison cisplatin with cisplatin plus 5FU in head and neck cancer patients received postoperative chemoradiotherapy. AB - PURPOSE: To compare the treatment outcomes and toxicity of both cisplatin and cisplatin plus 5FU chemotherapy in head and neck cancer patients who have received surgery, in addition to postoperative chemoradiotherapy. MATERIALS AND METHODS: From May 1991 to December 2012, a total of 113 head and neck cancer patients who received surgery, along with postoperative chemoradiotherapy were analyzed. The primary sites were oral cavity (86), oropharynx (17), hypopharynx (4), and larynx (6). Thirty-nine patients received cisplatin (P), while 74 patients received cisplatin plus 5FU (PF). The endpoints were overall survival (OS), local failure-free survival (LFFS), and distant metastasis-free survival (DMFS). RESULTS: The median follow up time was 43months, with a range of 4 222months. The 3-year rates of OS, LFFS, and DMFS were 62.1%, 71.3%, and 82.4%, respectively. The 3-year OS for P and PF were 71.3% and 57.5% (p=0.27). A multivariate analysis revealed that various chemotherapy regimens displayed no statistical difference for OS (Hazard Ratio [HR]=1.81; 95% Confidence Interval [CI]=0.963-3.408; p=0.065), LFFS (HR=0.98; 95% CI=0.458-2.127; p=0.973), and DMFS (HR=1.25; 95% CI=0.463-3.398; p=0.656). Grade 3 and 4 mucositis for P and PF group were 61.5% and 64.9%. A greater than grade 3 dermatitis for P and PF group were 7.7% and 14.9%. CONCLUSION: Postoperative chemoradiotherapy with cisplatin alone appeared to have higher 3-year OS and lower severe mucositis and dermatitis than cisplatin plus 5FU. PMID- 28559013 TI - Establishment and genomic characterization of primary salivary duct carcinoma cell line. AB - OBJECTIVES: To develop and characterize in vitro salivary duct carcinoma as a surrogate for functional studies. MATERIALS AND METHODS: Cells were dispersed from tumor tissue fragments under sterile conditions in RPMI media. Disassociated cells were cultivated, immortalized with hTERT and propagated for more than 100 passages. Morphologic, linage, cytogenetic and genomic analyses were performed on different passages of cell line and primary tumor. Soft agar growth was performed. RESULTS: Analysis of cytomorphologic features, growth characteristics and lineage specific markers expression confirmed the epithelial derivation and the neoplastic nature of the cell line. DNA STRs analysis showed identical match of both cell line and primary tumor. Cultivated cells expressed Androgen Receptor (AR), PTEN, and EFGR proteins and the AR-V7 isoform transcript. Comparative exome sequencing identified common mutated genes in both cell line and primary tumor. In-vitro colony formation of late passages is established. CONCLUSION: We report the development of the first human salivary duct carcinoma cell line (MDA-SDC-04) that retains critical biological and genomic features of the donor tumor. PMID- 28559015 TI - HLA traits linked to development of head and neck squamous cell carcinoma affect the progression-free survival of patients. AB - BACKGROUND: Personalized medicine and treatment stratification of patients with head and neck squamous cell carcinoma (HNSCC) today mostly ignore genetic heterogeneity in HNSCC but especially the patient's genetic background. We hypothesized that particular human leukocyte antigen (HLA) class I (HLA-A, B, Cw) and II proteins (DR, DQ) confer susceptibility for and influence development of HNSCC and may be prognostic factors for progression-free survival (PFS). METHODS: 90 consecutive HNSCC patients of the prospective observational cohort study LIFE treated between 08/2010 and 05/2011 at the University Leipzig underwent low resolution typing of HLA-A, B, Cw, DR, and DQ. Antigen and haplotype frequencies were compared to those in German blood donors. Effects on PFS were analyzed using Kaplan-Meier curves and Cox models. RESULTS: HNSCC patients had overall altered HLA-B frequencies (P<0.05); frequencies of B*44 were lower, those of B*13, B*52, and B*57 increased (P<0.05). Almost all other antigen frequencies showed no deviation. Homozygous HLA-Cw and DRB4 were frequent and associated with reduced PFS (P<0.05). Altered haplotype frequencies were common and particular haplotypes accompanied by differing PFS. B*13/Cw*06 carriers had poorest outcome (P=0.011). However, multivariate Cox proportional hazard models revealed 3 clinical covariates (localization oropharynx, loco-regional metastasis, and T4 category), HPV16-DNA positivity, and 10 HLA traits as independent predictors for PFS. CONCLUSIONS: The relevance of the genetic background of HNSCC patients calls for future research to clarify the role of HLA traits in HNSCC and if PFS depends on HLA. PMID- 28559016 TI - Critical roles of Wnt5a-Ror2 signaling in aggressiveness of tongue squamous cell carcinoma and production of matrix metalloproteinase-2 via DeltaNp63beta-mediated epithelial-mesenchymal transition. AB - OBJECTIVES: We previously showed that DeltaNp63beta, a splicing variant of DeltaNp63, mediated EMT and affected cell motility. DNA microarray was thus performed to elucidate the mechanism that DeltaNp63beta affects cell motility. As the results, Wnt5a was significantly down-regulated by DeltaNp63beta overexpression in tongue SCC cell line (SQUU-B) with EMT phenotype. MATERIALS AND METHODS: Seven OSCC cell lines were used. Expression of DeltaNp63, Wnt5a, its receptor Ror2, and matrix metalloproteinases (MMPs) were analyzed by RT-PCR, real time PCR, and western blotting, and gelatin zymography. Furthermore, we examined the effects of siRNA for Wnt5a or Ror2 and recombinant human Wnt5a (rhWnt5a) on motility of tongue SCC cells. Biopsy specimens from tongue SCC patients were used for immunohistochemical staining of Wnt5a and Ror2. RESULTS: Wnt5a and Ror2 were expressed only in SQUU-B cells without DeltaNp63 expression, and negatively associated with DeltaNp63 expression in other cells. DeltaNp63beta overexpression in SQUU-B cells decreased Wnt5a and Ror2 expression. By Wnt5a or Ror2 knockdown, cell motility was remarkably inhibited, but EMT markers expression was unaffected. MMP-2 expression and the activities inversely correlated with DeltaNp63 expression, and were inhibited by Wnt5a or Ror2 knockdown. Cell motility and MMP-2 activities were recovered by adding rhWnt5a in the cells with Wnt5a knockdown, but not in those with Ror2 knockdown. Moreover, immunohistochemical analyses in tongue SCC specimens found that high expression of Wnt5a or Ror2 was associated with poorer prognosis. CONCLUSION: Wnt5a-Ror2 signaling enhanced tongue SCC cell aggressiveness and promoted production of MMP 2 following DeltaNp63beta-mediated EMT. PMID- 28559017 TI - Ten-year survival outcomes for patients with nasopharyngeal carcinoma receiving intensity-modulated radiotherapy: An analysis of 614 patients from a single center. AB - OBJECTIVES: Intensity-modulated radiotherapy (IMRT) has been applied in nasopharyngeal carcinoma (NPC) for nearly twenty years, while little is known about the ten-year survival outcomes. This study aimed at evaluating the 10-year survival outcomes for patients with NPC receiving IMRT. MATERIALS AND METHODS: Data on 614 patients with newly diagnosed, non-disseminated NPC treated by IMRT between 2004 and 2008 were retrospectively reviewed. Survival outcomes stratified by tumor stage were compared. RESULTS: The median follow-up duration was 112.7months (range, 7.6-156.8months) for the entire cohort. The 10-year local relapse-free survival rates for T1, T2 and T3 were 94.2%, 92.5% and 91.4% (P>0.05), respectively, and significantly higher than that of T4 disease (79.3%, P<0.05 for all rates). As N category increased from N0 to N3, the 10-year distant metastasis-free survival rates significantly decreased accordingly (P<0.01 for all rates). Furthermore, the 10-year overall survival rates were 100%, 87.1%, 75.5% and 55.6% for stage I, II, III and IV, respectively (P<0.05 except stage I and II). Multivariate analysis established tumor stage and age as independent prognostic factors. Late toxicities were assessable for 495 (80.6%) patients and most were Grade I/II damages. Xerostomia (387 of 489, 79.1%) and hearing impairment (212 of 495, 42.8%) remained the most troublesome. CONCLUSION: IMRT could achieve satisfactory survival outcomes for NPC patients with acceptable late toxicities. However, distant control still remains poor, especially for patients with N3 disease. PMID- 28559018 TI - Outcome of recurrent and metastatic head and neck squamous cell cancer patients after first line platinum and cetuximab therapy. AB - OBJECTIVES: Second-line chemotherapy in recurrent and/or metastatic head and neck cancer (r/mHNSCC) patients showed dismal results with limited tumor response and reduced life expectancy. Outside of clinical trials, data on efficacy of second line treatment after first line anti-EGFR-AB combination therapy are not available. MATERIAL AND METHODS: Data regarding r/mHNSCC consecutive pts treated with cetuximab and platinum from 2009 to 2014 at our center were retrospectively collected. The analyses of response, Progression-Free Survival (PFS) and Overall Survival (OS), each evaluated starting from first and second-line treatment, were performed. Survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test. RESULTS: We identified 117 patients treated with first-line platinum and cetuximab-based therapy. Sixty-four (55%) patients did not receive second-line treatment due to worsening in performance status, 2 were not assessable for response thus 51 patients were included for analysis. Fifty-six percent were smokers/former smokers and 78% were male. Primary tumor sites were oropharynx (39%), oral cavity (31%), larynx/hypopharynx (24%) and others (6%). Regimens used in second-line were mostly monotherapies. Twenty-one % of the patients were treated within a clinical trial. Response rate (PR, CR) was 6% with 45% showing SD as best response. Median PFS was 2.2months (95%CI:1.5 2.8months) and OS 6.1months (95%CI:3.7-7.2months). CONCLUSIONS: Within our single center experience only half of the patients with r/mHNSCC were able to receive second-line treatment. Response rate was unsatisfactory, but median OS seems higher than previously reported in an anti-EGFR-AB naive population (Leon 2005). PMID- 28559019 TI - IL6 is associated with response to dasatinib and cetuximab: Phase II clinical trial with mechanistic correlatives in cetuximab-resistant head and neck cancer. AB - OBJECTIVE: Src family kinase (SFK) activation circumvents epidermal growth factor receptor (EGFR) targeting in head and neck squamous cell carcinoma (HNSCC); dual SFK-EGFR targeting could overcome cetuximab resistance. PATIENTS AND METHODS: We conducted a Simon two-stage, phase II trial of the SFK inhibitor, dasatinib, and cetuximab in biomarker-unselected patients with cetuximab-resistant, recurrent/metastatic HNSCC. Pre- and post-treatment serum levels of interleukin-6 (IL6) were measured by ELISA. HNSCC cell lines were assessed for viability and effects of IL6 modulation following dasatinib-cetuximab treatment. RESULTS: In the first stage, 13 patients were evaluable for response: 7 had progressive and 6 had stable disease (SD). Enrollment was halted for futility, and biomarker analysis initiated. Low serum IL6 levels were associated with SD (raw p=0.028, adjusted p=0.14) and improved overall survival (p=0.010). The IL6 classifier was validated in a separate trial of the same combination, but was unable to segregate survival risk in a clinical trial of cetuximab and bevacizumab suggesting serum IL6 may be specific for the dasatinib-cetuximab combination. Enhanced in vitro HNSCC cell death was observed with dasatinib-cetuximab versus single agent treatment; addition of IL6-containing media abrogated this effect. CONCLUSION: Clinical benefit and overall survival from the dasatinib-cetuximab combination were improved among patients with low serum IL6. Preclinical studies support IL6 as a modifier of dasatinib-cetuximab response. In the setting of clinical cetuximab resistance, serum IL6 is a candidate predictive marker specific for combined dasatinib-cetuximab. The trial was modified and redesigned as a biomarker-enriched Phase II study enrolling patients with undetectable IL6. PMID- 28559020 TI - Establishment and characterization of a clear cell odontogenic carcinoma cell line with EWSR1-ATF1 fusion gene. AB - OBJECTIVE: Clear cell odontogenic carcinoma (CCOC) is a rare malignant odontogenic tumor (MOT) characterized by sheets and lobules of vacuolated and clear cells. To understand the biology of CCOC, we established a new cell line, CCOC-T, with EWSR1-ATF1 fusion gene from a mandible tumor with distant metastasis and characterized this cell line. MATERIALS AND METHODS: To detect the EWSR1-ATF1 fusion gene, we used three CCOC cases, including the present case, by RT-PCR and FISH analysis. We characterized established CCOC-T cells by checking cell growth, invasion and the expression of odontogenic factors and bone-related factors. Moreover, the gene expression profile of CCOC-T cells was examined by microarray analysis. RESULTS: Histologically, the primary tumor was comprised of cords and nests containing clear and squamoid cells separated by fibrous septa. In addition, ameloblastomatous islands with palisaded peripheral cells were observed, indicating probable odontogenic origin. This tumor expressed the fusion gene EWSR1-ATF1, which underlies the etiology of hyalinizing clear cell carcinoma (HCCC) and potentially that of CCOC. We found a breakpoint in the EWSR1-ATF1 fusion to be the same as that reported in HCCC. Established CCOC-T cells grew extremely slowly, but the cells showed highly invasive activity. Moreover, CCOC-T cells expressed bone-related molecules, odontogenic factors, and epithelial mesenchymal transition (EMT)-related molecules. CONCLUSION: To the best of our knowledge, this is the first report on the establishment of a CCOC cell line. CCOC-T cells serve as a useful in vitro model for understanding the pathogenesis and nature of MOT. PMID- 28559021 TI - Human papillomavirus genotypes and risk of head and neck cancers: Results from the HeNCe Life case-control study. AB - OBJECTIVE: Human papillomaviruses (HPV) are changing dramatically the epidemiologic landscape of head and neck cancers (HNCs). Their role in the aetiology of these cancers varies widely among HNCs subsites, sex and geographical regions worldwide. We describe HPV prevalence and its association with HNCs risk overall and by anatomical subsite in a sample of Canadians. MATERIALS AND METHODS: The HeNCe Life study recruited 460 incident HNCs cases and 458 controls frequency-matched by age and sex from four Montreal hospitals in 2005-2013. We tested oral rinse and oral brush specimens for mucosal HPV genotypes. HPV positivity was categorized hierarchically as either negative, exclusively non-alpha-9 species types, alpha-9 types other than HPV16, and HPV16. We estimated odds ratios (OR) and 95% confidence intervals (CI) for the associations between HPV and HNCs using unconditional logistic regression, controlling for confounders. RESULTS: The prevalence of HPV infection among controls and cases was 14.5% and 41.2% in oral rinse and 3.1% and 24.4% in oral brush samples, respectively. HPV16 was the predominant genotype with an oral rinse and oral brush prevalence of 26.3% and 16.2% among cases and 2.4% and 0.2% among controls, respectively. HPV infection was associated with an increased risk of HNCs overall (OR=4.18; 95% CI, 2.94-5.95) and oropharyngeal cancer only (OR=10.3; 95% CI, 6.8-15.7). HNCs and oropharyngeal cancer were strongly associated with HPV16 (OR=18.1; 95% CI, 9.1-35.8, and OR=47.2; 95% CI, 23.1-96.6, respectively). CONCLUSION: HPV infection, particularly HPV16, was associated with an increased HNCs risk, most strongly for oropharyngeal cancers. PMID- 28559023 TI - The feasibility of contralateral lower neck sparing intensity modulation radiated therapy for nasopharyngeal carcinoma patients with unilateral cervical lymph node involvement. AB - OBJECTIVES: To investigate the feasibility of contralateral lower neck sparing intensity modulation radiated therapy (IMRT) for nasopharyngeal carcinoma patients (NPC) with unilateral cervical lymph node metastasis. MATERIALS AND METHODS: Retrospective review of 546 patients with unilateral cervical lymph node metastasis treated between November 2009 and February 2012 at one institution. All patients were staged using magnetic resonance imaging and received radical IMRT. Patients were classified into two groups: the inferior border of the negative neck irradiation field only covered Levels III to Va in Group 1; the inferior border covered entire neck down to Levels IV to Vb in Group 2. RESULTS: Median follow-up was 49.9months (range, 1.3-69.2months). Four-year overall survival (OS:89.3% vs. 88.9%, P=0.91), disease-free survival (DFS:81.7% vs. 81.0%, P=0.91), distant metastasis-free survival (DMFS:88.2% vs. 87.9%, P=0.95), local relapse-free survival (LRFS:96.7% vs. 94.7%, P=0.70) and nodal relapse-free survival (NRFS: 96.1% vs. 95.9%, P=0.94) were not significantly different between Group 1 and Group 2. Twenty-two patients developed cervical lymph node relapse; of whom 20/22 (91.0%) developed unilateral relapse within pretreatment positive neck. Only one patient developed out-of-field relapse, though this patient also relapsed within the neck irradiation field (Level II). No clinicopathological feature tested had significant prognostic value for NRFS in multivariate analysis. CONCLUSIONS: In the IMRT and MRI era, contralateral lower neck sparing IMRT seems to be feasible for NPC patients with unilateral cervical lymph node metastasis. PMID- 28559022 TI - Improving accuracy of RNA-based diagnosis and prognosis of oral cancer by using noninvasive methods. AB - RNA-based diagnosis and prognosis of squamous cell carcinoma has been slow to come to the clinic. Improvements in RNA measurement, statistical evaluation, and sample preservation, along with increased sample numbers, have not made these methods reproducible enough to be used clinically. We propose that, in the case of squamous cell carcinoma of the oral cavity, a chief source of variability is sample dissection, which leads to variable amounts of stroma mixed in with tumor epithelium. This heterogeneity of the samples, which requires great care to avoid, makes it difficult to see changes in RNA levels specific to tumor cells. An evaluation of the data suggests that, paradoxically, brush biopsy samples of oral lesions may provide a more reproducible method than surgical acquisition of samples for miRNA measurement. The evidence also indicates that body fluid samples can show similar changes in miRNAs with oral squamous cell carcinoma (OSCC) as those seen in tumor brush biopsy samples - suggesting much of the miRNA in these samples is coming from the same source: tumor epithelium. We conclude that brush biopsy or body fluid samples may be superior to surgical samples in allowing miRNA-based diagnosis and prognosis of OSCC in that they feature a rapid method to obtain homogeneous tumor cells and/or RNA. PMID- 28559024 TI - Prediction of distant metastases from nasopharyngeal carcinoma: Improved diagnostic performance of MRI using nodal volume in N1 and N2 stage disease. AB - PURPOSE: To determine if the magnetic resonance imaging (MRI) of the head and neck can predict distant metastases (DM) from nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: MRI examinations of 763 NPC patients were assessed for primary tumour stage (T), nodal stage (N), primary tumour volume (PTV) and total nodal volume (NV). The association between MRI and clinical parameters were examined in DM+ and DM- patients using logistic regression and for distant metastases free survival (DMFS) using cox regression. Optimum thresholds were assessed by receiver-operating characteristics analysis, and positive predictive value (PPV) and odds ratio (OR) calculated. RESULTS: Distant metastases were present in 181/763 NPC patients (23.7%). Higher N stage and NV were the independent predictors of DM (p<0.001 and 0.018 respectively) and poor DMFS (p=0.001 and 0.030 respectively). Addition of NV (threshold>=32.8cm3) to the N stage improved the PPVs and ORs for DM in stage N1 (from 18.9% to 31.8% and 5.613 to 11.133 respectively) and stage N2 (from 40.4% to 60.8% and 16.189 to 36.979 respectively) but not in stage N3 (68.3% to 68.6% and 51.385 to 52.052 respectively). CONCLUSION: MRI N stage and NV were independent predictors of DM and DMFS. The addition of NV in NPC patients with bulky N1 and N2 disease improved the ability of MRI to predict DM. PMID- 28559025 TI - Oncological outcome following de-intensification of treatment for stage I and II HPV negative oropharyngeal cancers with transoral robotic surgery (TORS): A prospective trial. AB - OBJECTIVE: This prospective study aimed to see long-term oncological outcome of Transoral Robotic Surgery as single modality treatment for cT1-T2 N0 HPV negative oropharyngeal malignancies. METHOD: From March 2013 to October 2015, 57 patients with early stage oropharyngeal carcinoma underwent Transoral robotic surgery (TORS) with neck dissection using daVinci(r) Surgical system. Patients were evaluated for disease free survival, overall survival, locoregional and distant metastasis. RESULTS: 57 patients (48 males and 9 females) underwent TORS for early stage oropharyngeal carcinoma. All patients underwent ipsilateral neck dissection and 12 patients underwent bilateral neck dissection. 49 patients with final histopathology suggestive of stage I and II disease did not received any adjuvant treatment. Mean age at presentation was 59.4years (37-88years). Most common site of involvement was the base of tongue (BOT) in 31 (54.8%) patients. Twenty-four (42.1%) patients were cT1 and 33 (57.9%) were cT2 at presentation. During follow-up, 2 (4.2%) patients recurred locoreginally and 1 (2.1%) patient had distant metastasis. Two patients expired due to causes other than malignancy. Forty-three (89.6%) patients were disease free on an average follow-up of 29months with an overall survival of 93.8% at mean follow-up of 29months. CONCLUSION: Transoral Robotic Surgery as a single modality treatment is a good option for cure in HPV negative early resectable oropharyngeal malignancies which are relatively unresponsive to radiation. TORS can be used to de-intensify the treatment of early stage oropharyngeal carcinoma and thus avoid the early and late toxicities associated with Radiotherapy/Chemoradiotherapy. PMID- 28559026 TI - Promotion of oral surgical wound healing using autologous mucosal cell sheets. AB - OBJECTIVES: Severe oral mucosal and tissue defects can lead to pain, infection, and later undesirable healing of scarring and adhesion, resulting in a poor quality of life. In vitro-engineered oral mucosal equivalents for covering such defects are an alternative to avoiding the donor site morbidity of conventional skin or tissue grafts. We examined the efficacy of our newly developed three dimensional mucosal cell sheets in an in vivo tongue wound model mimicking the surgical extirpation of tongue cancer. MATERIALS AND METHODS: Small oral mucosal and autologous fibrin samples were obtained from surgical patients and Sprague Dawley rats. The fibrin was mixed with fibroblasts and seeded with keratinocytes that had been primarily cultured for in vitro cell expansion. The three dimensional autologous cell sheets, cultured in air-lift interface inserts, were transplanted into deep wounds of the rat ventral tongue. Gross and microscopic findings of the postsurgical wounds were compared between wound control and cell sheet groups. RESULTS: The cell sheets were flexible, expandable, and easy to transfer, and had histological characteristics similar to that of the normal oral mucosa, with high p63 positivity. They promoted oral wound healing with earlier re-epithelialization and less fibrosis than that in the wound control. The cell sheet-healed tongue had similar histology to that of a normal tongue. CONCLUSIONS: Our engineered cell sheets have potential applicability for the rapid healing of oral mucosal and soft tissue defects, without scarring, adhesion, and functional deficits. CONDENSED ABSTRACT: The efficacy of in vitro engineered mucosal equivalents, using completely autologous mucosa and plasma, was examined. Transplantation of the autologous cell sheets into deep wounds of the rat ventral tongue promoted oral wound healing with earlier re epithelialization and less fibrosis than that in controls. Healed and normal tongues showed similar histology. PMID- 28559027 TI - Small cell carcinoma of the head and neck: An analysis of the National Cancer Database. AB - PURPOSE/OBJECTIVE(S): To evaluate treatment trends and overall survival of patients with small cell carcinoma of the head and neck region. MATERIALS/METHODS: Patients from 2004 to 2012 were identified from the National Cancer Database. Patient demographics and overall survival were analyzed. Multivariable analysis was used to identify predictors of survival. RESULTS: Among 347,252 head and neck patients a total of 1042 (0.3%) patients with small cell carcinoma were identified. 17% of patients were diagnosed as stage I/II, 61% as stage III/IVA/IVB and 22% as stage IVC disease. The distribution by anatomic site was 9% oral cavity, 12% oropharynx, 35% larynx, 4% hypopharynx, 10% nasopharynx and 30% nasal cavity and paranasal sinuses. The median overall survival by anatomical site was 20.8months for oral cavity, 23.7months for oropharynx, 17.9months for larynx/hypopharynx, 15.1months for nasopharynx and 36.4months for nasal cavity primary tumors. On multivariable analysis across stage, patients with nasal cavity and paranasal sinuses tumors had the best survival and patients with nasopharynx primaries had the worst survival. In stage I/II patients, type of treatment delivered resulted in no overall survival difference (p=0.78). In patients with locally advanced disease, there was no difference in survival between those treated with combined surgery, radiotherapy and chemotherapy compared to those treated only with radiotherapy and chemotherapy (p=0.46). The addition of radiotherapy to chemotherapy in the metastatic setting did not result in improved survival (p=0.14). CONCLUSIONS: Small cell carcinoma of the head and neck is a rare malignancy with a poor prognosis. The addition of surgery to radiotherapy and chemotherapy did not improve survival in patients with locally advanced disease. PMID- 28559029 TI - Coming Fast out of the Gate: Pacing and Productivity From a Resident Perspective. PMID- 28559028 TI - Establishing and applying nomograms based on the 8th edition of the UICC/AJCC staging system to select patients with nasopharyngeal carcinoma who benefit from induction chemotherapy plus concurrent chemoradiotherapy. AB - OBJECTIVES: The subgroups of patients with nasopharyngeal carcinoma (NPC) who benefit from induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) remain unclear. MATERIALS AND METHODS: We established prognostic nomograms for overall survival (OS) and disease-free survival (DFS), and validated the nomograms in 1230 patients with NPC and subgroup of 923 patients with locoregionally advanced NPC (LANPC). Three well-matched risk groups (i.e., low, intermediate and high risk) were created via recursive partitioning and 1-to-1 propensity score matching; IC+CCRT was compared with CCRT in each risk group. RESULTS: Histological type, T category, N category, plasma Epstein-Barr virus deoxyribonucleic acid (and the same factors plus age and neutrophil-lymphocyte ratio) were included in the nomograms for DFS (and OS). Both nomograms had higher c-indexes than the 7th edition staging system in both NPC/LANPC (all P values<=0.010). The nomogram for OS also had a higher c-index in LANPC than the 8th edition staging system (P-value=0.052). OS was significantly different between all three risk groups in the individualized risk stratification (all P values<0.001), while the 7th and 8th edition staging systems failed to clearly separate OS for stage II and III disease (P-value=0.415 and 0.347, respectively). IC+CCRT improved OS in intermediate and high risk patients with LANPC compared to CCRT alone (P-value<0.001 and P-value=0.002, respectively). CONCLUSION: These prognostic nomograms could accurately guide treatment of individual patients with NPC. IC+CCRT could improve OS for patients with LANPC at intermediate to high risk. PMID- 28559030 TI - The Effect of Utilization Review on Emergency Department Operations. AB - STUDY OBJECTIVE: Increasingly, hospitals are using utilization review software to reduce hospital admissions in an effort to contain costs. Such practices have the potential to increase the number of unsafe discharges, particularly in public safety-net hospitals. Utilization review software tools are not well studied with regard to their effect on emergency department (ED) operations. We study the effect of prospectively used admission decision support on ED operations. METHODS: In 2012, Los Angeles County + University of Southern California Medical Center implemented prospective use of computerized admission criteria. After implementation, only ED patients meeting primary review (diagnosis-based criteria) or secondary review (medical necessity as determined by an on-site emergency physician) were assigned inpatient beds. Data were extracted from electronic medical records from September 2011 through December 2013. Outcomes included operational metrics, 30-day ED revisits, and 30-day admission rates. Excluding a 6-month implementation period, monthly summary metrics were compared pre- and postimplementation with nonparametric and negative binomial regression methods. All adult ED visits, excluding incarcerated and purely behavioral health visits, were analyzed. The primary outcomes were disposition rates. Secondary outcomes were 30-day ED revisits, 30-day admission rate among return visitors to the ED, and estimated cost. RESULTS: Analysis of 245,662 ED encounters was performed. The inpatient admission rate decreased from 14.2% to 12.8%. Increases in discharge rate (82.4% to 83.4%) and ED observation unit utilization (2.5% to 3.4%) were found. Thirty-day revisits increased (20.4% to 24.4%), although the 30 day admission rate decreased (3.2% to 2.8%). Estimated cost savings totaled $193.17 per ED visit. CONCLUSION: The prospective application of utilization review software in the ED led to a decrease in the admission rate. This was tempered by a concomitant increase in ED observation unit utilization and 30-day ED revisits. Cost savings suggest that resources should be redirected to the more highly affected ED and ED observation unit, although more work is needed to confirm the generalizability of these findings. PMID- 28559031 TI - A Qualitative Analysis of Adolescent and Caregiver Acceptability of Universally Offered Gonorrhea and Chlamydia Screening in the Pediatric Emergency Department. AB - STUDY OBJECTIVE: We qualitatively explore adolescent and parent or guardian attitudes about benefits and barriers to universally offered gonorrhea and chlamydia screening and modalities for assessing interest in screening in the pediatric emergency department (ED). METHODS: A convenience sample of forty 14- to 21-year-olds and parents or guardians of adolescents presenting to an urban and community pediatric ED with any chief complaint participated in individual, semistructured, confidential interviews. Topics included support of universally offered gonorrhea and chlamydia screening, barriers and benefits to screening, and modalities for assessing interest in screening. Data were analyzed with framework analysis. RESULTS: Almost all adolescents (37/40; 93%) and parents (39/40; 98%) support offering ED gonorrhea or chlamydia screening. Benefits included earlier diagnosis and treatment, convenience and transmission prevention (cited by both groups), and improved education and long-term health (cited by parents/guardians). Barriers included concerns about confidentiality and cost (cited by both groups), embarrassment (cited by adolescents), and nondisclosure to parents or guardians (cited by parents/guardians). Adolescents preferred that the request for gonorrhea or chlamydia screening be presented in a private room, using tablet technology. Both groups noted that the advantages to tablets included confidentiality and adolescents' familiarity with technology. Adolescents noted that tablet use would address concerns about bringing up gonorrhea or chlamydia screening with clinicians, whereas parents or guardians noted that tablets might increase screening incidence but expressed concern about the lack of personal interaction. CONCLUSION: Universally offered gonorrhea and chlamydia screening in a pediatric ED was acceptable to the adolescents and parents or guardians in this study. Offering a tablet-based method to assess interest in screening may increase participation. PMID- 28559032 TI - Rib Fracture Diagnosis in the Panscan Era. AB - STUDY OBJECTIVE: With increased use of chest computed tomography (CT) in trauma evaluation, traditional teachings in regard to rib fracture morbidity and mortality may no longer be accurate. We seek to determine rates of rib fracture observed on chest CT only; admission and mortality of patients with isolated rib fractures, rib fractures observed on CT only, and first or second rib fractures; and first or second rib fracture-associated great vessel injury. METHODS: We conducted a planned secondary analysis of 2 prospectively enrolled cohorts of the National Emergency X-Radiography Utilization Study chest studies, which evaluated patients with blunt trauma who were older than 14 years and received chest imaging in the emergency department. We defined rib fractures and other thoracic injuries according to CT reports and followed patients through their hospital course to determine outcomes. RESULTS: Of 8,661 patients who had both chest radiograph and chest CT, 2,071 (23.9%) had rib fractures, and rib fractures were observed on chest CT only in 1,368 cases (66.1%). Rib fracture patients had higher admission rates (88.7% versus 45.8%; mean difference 42.9%; 95% confidence interval [CI] 41.4% to 44.4%) and mortality (5.6% versus 2.7%; mean difference 2.9%; 95% CI 1.8% to 4.0%) than patients without rib fracture. The mortality of patients with rib fracture observed on chest CT only was not statistically significantly different from that of patients with fractures also observed on chest radiograph (4.8% versus 5.7%; mean difference -0.9%; 95% CI -3.1% to 1.1%). Patients with first or second rib fractures had significantly higher mortality (7.4% versus 4.1%; mean difference 3.3%; 95% CI 0.2% to 7.1%) and prevalence of concomitant great vessel injury (2.8% versus 0.6%; mean difference 2.2%; 95% CI 0.6% to 4.9%) than patients with fractures of ribs 3 to 12, and the odds ratio of great vessel injury with first or second rib fracture was 4.4 (95% CI 1.8 to 10.4). CONCLUSION: Under trauma imaging protocols that commonly incorporate chest CT, two thirds of rib fractures were observed on chest CT only. Patients with rib fractures had higher admission rates and mortality than those without rib fractures. First or second rib fractures were associated with significantly higher mortality and great vessel injury. PMID- 28559033 TI - Refusal of Emergency Medical Treatment: Case Studies and Ethical Foundations. AB - Informed consent is an important component of emergency medical treatment. Most emergency department patients can provide informed consent for treatment upon arrival. Informed consent should also be obtained for emergency medical interventions that may entail significant risk. A related concept to informed consent is informed refusal of treatment. Patients may refuse emergency medical treatment during their evaluation and treatment. This article addresses important considerations for patients who refuse treatment, including case studies and discussion of definitions, epidemiology, assessment of decisional capacity, information delivery, medicolegal considerations, and alternative care plans. PMID- 28559034 TI - Shared Decisionmaking in the Emergency Department: A Guiding Framework for Clinicians. AB - Shared decisionmaking has been proposed as a method to promote active engagement of patients in emergency care decisions. Despite the recent attention shared decisionmaking has received in the emergency medicine community, including being the topic of the 2016 Academic Emergency Medicine Consensus Conference, misconceptions remain in regard to the precise meaning of the term, the process, and the conditions under which it is most likely to be valuable. With the help of a patient representative and an interaction designer, we developed a simple framework to illustrate how shared decisionmaking should be approached in clinical practice. We believe it should be the preferred or default approach to decisionmaking, except in clinical situations in which 3 factors interfere. These 3 factors are lack of clinical uncertainty or equipoise, patient decisionmaking ability, and time, all of which can render shared decisionmaking infeasible. Clinical equipoise refers to scenarios in which there are 2 or more medically reasonable management options. Patient decisionmaking ability refers to a patient's capacity and willingness to participate in his or her emergency care decisions. Time refers to the acuity of the clinical situation (which may require immediate action) and the time that the clinician has to devote to the shared decisionmaking conversation. In scenarios in which there is only one medically reasonable management option, informed consent is indicated, with compassionate persuasion used as appropriate. If time or patient capacity is lacking, physician directed decisionmaking will occur. With this framework as the foundation, we discuss the process of shared decisionmaking and how it can be used in practice. Finally, we highlight 5 common misconceptions in regard to shared decisionmaking in the ED. With an improved understanding of shared decisionmaking, this approach should be used to facilitate the provision of high-quality, patient-centered emergency care. PMID- 28559035 TI - External Defibrillator Damage Associated With Attempted Synchronized Dual-Dose Cardioversion. AB - The simultaneous use of 2 external defibrillators to administer either dual or sequential cardioversion or defibrillation for refractory cardiac arrhythmias is increasing in both the out-of-hospital and inhospital settings. Using 2 defibrillators to administer higher energy levels than can be achieved with a single defibrillator is considered off-label and is currently not part of published advanced cardiac life support guidelines. We report the first case in which the use of dual-dose cardioversion was associated with external defibrillator damage. Because defibrillator damage, especially if undetected, jeopardizes patient safety and off-label medical product use may void the manufacturer's warranty, this case should urge users to proceed with caution when contemplating this technique. PMID- 28559036 TI - Association of Out-of-Hospital Hypotension Depth and Duration With Traumatic Brain Injury Mortality. AB - STUDY OBJECTIVE: Out-of-hospital hypotension has been associated with increased mortality in traumatic brain injury. The association of traumatic brain injury mortality with the depth or duration of out-of-hospital hypotension is unknown. We evaluated the relationship between the depth and duration of out-of-hospital hypotension and mortality in major traumatic brain injury. METHODS: We evaluated adults and older children with moderate or severe traumatic brain injury in the preimplementation cohort of Arizona's statewide Excellence in Prehospital Injury Care study. We used logistic regression to determine the association between the depth-duration dose of hypotension (depth of systolic blood pressure <90 mm Hg integrated over duration [minutes] of hypotension) and odds of inhospital death, controlling for significant confounders. RESULTS: There were 7,521 traumatic brain injury cases included (70.6% male patients; median age 40 years [interquartile range 24 to 58]). Mortality was 7.8% (95% confidence interval [CI] 7.2% to 8.5%) among the 6,982 patients without hypotension (systolic blood pressure >=90 mm Hg) and 33.4% (95% CI 29.4% to 37.6%) among the 539 hypotensive patients (systolic blood pressure <90 mm Hg). Mortality was higher with increased hypotension dose: 0.01 to 14.99 mm Hg-minutes 16.3%; 15 to 49.99 mm Hg-minutes 28.1%; 50 to 141.99 mm Hg-minutes 38.8%; and greater than or equal to 142 mm Hg minutes 50.4%. Log2 (the logarithm in base 2) of hypotension dose was associated with traumatic brain injury mortality (adjusted odds ratio 1.19 [95% CI 1.14 to 1.25] per 2-fold increase of dose). CONCLUSION: In this study, the depth and duration of out-of-hospital hypotension were associated with increased traumatic brain injury mortality. Assessments linking out-of-hospital blood pressure with traumatic brain injury outcomes should consider both depth and duration of hypotension. PMID- 28559038 TI - Nonphysician Out-of-Hospital Rapid Sequence Intubation Success and Adverse Events: A Systematic Review and Meta-Analysis. AB - STUDY OBJECTIVE: Rapid sequence intubation performed by nonphysicians such as paramedics or nurses has become increasingly common in many countries; however, concerns have been stated in regard to the safe use and appropriateness of rapid sequence intubation when performed by these health care providers. The aim of our study is to compare rapid sequence intubation success and adverse events between nonphysician and physician in the out-of-hospital setting. METHODS: A systematic literature search of key databases including MEDLINE, EMBASE, and the Cochrane Library was conducted. Eligibility, data extraction, and assessment of risk of bias were assessed independently by 2 reviewers. A bias-adjusted meta-analysis using a quality-effects model was conducted for the primary outcomes of overall intubation success and first-pass intubation success and for adverse events when possible. RESULTS: Eighty-three studies were included in the meta-analysis. There was a 2% difference in successful intubation proportion for physicians versus nonphysicians, 99% (95% confidence interval [CI] 98% to 99%) versus 97% (95% CI 95% to 99%). A 10% difference in first-pass rapid sequence intubation success was noted between physicians versus nonphysicians, 88% (95% CI 83% to 93%) versus 78% (95% CI 65% to 89%). For airway trauma, bradycardia, cardiac arrest, endobronchial intubation, hypertension, and hypotension, lower prevalences of adverse events were noted for physicians. However, nonphysicians had a lower prevalence of hypoxia and esophageal intubations. Similar proportions were noted for pulmonary aspiration and emesis. Nine adverse events estimates lacked precision, except for endobronchial intubation, and 4 adverse event analyses showed evidence of possible publication bias. Consequently, no reliable evidence exists for differences between physicians and nonphysicians for adverse events. CONCLUSION: This analysis shows that physicians have a higher rapid sequence intubation first-pass and overall success, as well as mostly lower rates of adverse events for rapid sequence intubation in the out-of-hospital setting. Nevertheless, for all success and adverse events no firm conclusion for a difference could be drawn because of lack of precision of meta-analytic estimates or selective reporting. First-pass success could be an area in which to focus quality improvement strategies for nonphysicians. PMID- 28559040 TI - Are alpha-Blockers Beneficial for Outpatient Management of Uncomplicated Ureteric Stones? PMID- 28559037 TI - Repeated Emergency Medical Services Use by Older Adults: Analysis of a Comprehensive Statewide Database. AB - STUDY OBJECTIVE: The objective of this study is to characterize repeated emergency medical services (EMS) transports among older adults across a large and socioeconomically diverse region. METHODS: Using the North Carolina Prehospital Medical Information System, we analyzed the frequency of repeated EMS transports within 30 days of an index EMS transport among adults aged 65 years and older from 2010 to 2015. We used multivariable logistic regressions to determine characteristics associated with repeated EMS transport. RESULTS: During the 6 year period, EMS performed 1,711,669 transports for 689,664 unique older adults in North Carolina. Of these, 303,099 transports (17.7%) were followed by another transport of the same patient within 30 days. The key characteristics associated with an increased adjusted odds ratio of repeated transport within 30 days include transport from an institutionalized setting (odds ratio [OR] 1.42; 95% confidence interval [CI] 1.38 to 1.47), blacks compared with whites (OR 1.29; 95% CI 1.24 to 1.33), a dispatch complaint of psychiatric problems (OR 1.38; 95% CI 1.25 to 1.52), back pain (OR 1.35; 95% CI 1.26 to 1.45), breathing problems (OR 1.21; 95% CI 1.15 to 1.30), and diabetic problems (OR 1.14; 95% CI 1.06 to 1.22). Falls accounted for 15.6% of all transports and had a modest association with repeated transports (OR 1.07; 95% CI 1.00 to 1.14). CONCLUSION: More than 1 in 6 EMS transports of older adults in North Carolina are followed by a repeated transport of the same patient within 30 days. Patient characteristics and chief complaints may identify increased risk for repeated transport and suggest the potential for targeted interventions to improve outcomes and manage EMS use. PMID- 28559041 TI - Commentary on "Rehabilitation Outcomes Associated With Foreign Domestic Workers as Caregivers". AB - The purpose of this commentary is to illuminate the role of foreign domestic workers (FDW) as caregivers for patients undergoing rehabilitation in Asia. The authors of a published study in this issue of the Archives of Physical Medicine and Rehabilitation investigate the association between the characteristics of caregivers for patients recovering from sub-acute stroke and the rehabilitation outcomes of those patients in Singapore. The investigators examined over 4,000 caregivers and one of the findings showed that after controlling for characteristics of both caregivers and patients, there was a significant and negative association between having an FDW as a caregiver, compared to a spouse, and patient rehabilitation effectiveness. The inclusion of FDW's in this study is an important and understudied group of caregivers in the role of patient rehabilitation that is relatively new to the US, but common in other parts of the world. PMID- 28559039 TI - Geographic Variation in Use of Ambulance Transport to the Emergency Department. AB - STUDY OBJECTIVE: Evidence on variability in emergency medical services use is limited. We obtain national evidence on geographic variation in the use of ambulance transport to the emergency department (ED) among Medicare enrollees and assess the role of health status, socioeconomic status, and provider availability. METHODS: We used 2010 Medicare claims data for a random sample of 999,999 enrollees aged 66 years and older, and identified ambulance transport and ED use. The main outcome measures were number of ambulance transports to the ED per 100 person-years (ambulance transport rate) and proportion (percentage) of ED visits by ambulance transport by hospital referral regions. RESULTS: The national ambulance transport rate was 22.2 and the overall proportion of ED visits by ambulance was 36.7%. Relative to hospital referral regions in the lowest rate quartile, those in the highest quartile had a 75% higher ambulance transport rate (incidence rate ratio [IRR] 1.75; 95% confidence interval [CI] 1.69 to 1.81) and a 15.5% higher proportion of ED visits by ambulance (IRR 1.155; 95% CI 1.146 to 1.164). Adjusting for health status, socioeconomic status, and provider availability reduced quartile 1 versus quartile 4 difference in ambulance transport rate by 43% (IRR 1.43; 95% CI 1.38 to 1.48) and proportion of ED visits by ambulance by 7% (IRR 1.145; 95% CI 1.135 to 1.155). Among the 3 covariate domains, health status was associated with the largest variability in ambulance transport rate (30.1%), followed by socioeconomic status (12.8%) and provider availability (2.9%). CONCLUSION: Geographic variability in ambulance use is large and associated with variation in patient health status and socioeconomic status. PMID- 28559042 TI - Self-Assembled Core-Shell-Type Lipid-Polymer Hybrid Nanoparticles: Intracellular Trafficking and Relevance for Oral Absorption. AB - Lipid-polymer hybrid nanoparticles (NPs) are advantageous for drug delivery. However, their intracellular trafficking mechanism and relevance for oral drug absorption are poorly understood. In this study, self-assembled core-shell lipid polymer hybrid NPs made of poly(lactic-co-glycolic acid) (PLGA) and various lipids were developed to study their differing intracellular trafficking in intestinal epithelial cells and their relevance for oral absorption of a model drug saquinavir (SQV). Our results demonstrated that the endocytosis and exocytosis of hybrid NPs could be changed by varying the kind of lipid. A glyceride mixture (hybrid NPs-1) decreased endocytosis but increased exocytosis in Caco-2 cells, whereas the phospholipid (E200) (hybrid NPs-2) decreased endocytosis but exocytosis was unaffected as compared with PLGA nanoparticles. The transport of hybrid NPs-1 in cells involved various pathways, including caveolae/lipid raft-dependent endocytosis, and clathrin-mediated endocytosis and macropinocytosis, which was different from the other groups of NPs that involved only caveolae/lipid raft-dependent endocytosis. Compared with that of the reference formulation (nanoemulsion), the oral absorption of SQV-loaded hybrid NPs in rats was poor, probably due to the limited drug release and transcytosis of NPs across the intestinal epithelium. In conclusion, the intracellular processing of hybrid NPs in intestinal epithelia can be altered by adding lipids to the NP. However, it appears unfavorable to use PLGA-based NPs to improve oral absorption of SQV compared with nanoemulsion. Our findings will be essential in the development of polymer-based NPs for the oral delivery of drugs with the purpose of improving their oral absorption. PMID- 28559043 TI - Protein Adsorption to In-Line Filters of Intravenous Administration Sets. AB - Ensuring compatibility of administered therapeutic proteins with intravenous administration sets is an important regulatory requirement. A low-dose recovery during administration of low protein concentrations is among the commonly observed incompatibilities, and it is mainly due to adsorption to in-line filters. To better understand this phenomenon, we studied the adsorption of 4 different therapeutic proteins (2 IgG1s, 1 IgG4, and 1 Fc fusion protein) diluted to 0.01 mg/mL in 5% glucose (B. Braun EcoFlac; B. Braun Melsungen AG, Melsungen, Germany) or 0.9% sodium chloride (NaCl; Freeflex; Fresenius Kabi, Friedberg, Germany) solutions to 8 in-line filters (5 positively charged and 3 neutral filters made of different polymers and by different suppliers). The results show certain patterns of protein adsorption, which depend to a large extent on the dilution solution and filter material, and to a much lower extent on the proteins' biophysical properties. Investigation of the filter membranes' zeta potential showed a correlation between the observed adsorption pattern in 5% glucose solution and the filter's surface charge, with higher protein adsorption for the strongly negatively charged membranes. In 0.9% NaCl solution, the surface charges are masked, leading to different adsorption patterns. These results contribute to the general understanding of the protein adsorption to IV infusion filters and allow the design of more efficient compatibility studies. PMID- 28559044 TI - Aging-associated mitochondrial DNA mutations alter oxidative phosphorylation machinery and cause mitochondrial dysfunctions. AB - Our previous study generated a series of cybrids containing mitochondria of synaptosomes from mice at different ages. The following functional analysis on these cybrids revealed an age-dependent decline of mitochondrial function. To understand the underlying mechanisms that contribute to the age-related mitochondrial dysfunction, we focused on three cybrids carrying mitochondria derived from synaptosomes of the old mice that exhibited severe respiratory deficiencies. In particular, we started with a comprehensive analysis of mitochondrial genome by high resolution, high sensitive deep sequencing method. Compared with young control, we detected a significant accumulation of heteroplasmic mtDNA mutations. These mutations included six alterations in main control region that has been shown to regulate overall gene-expression, and four alterations in protein coding region, two of which led to significant changes in complex I subunit ND5 and complex III subunit CytB. Interestingly, a reduced mtDNA-encoded protein synthesis was associated with the changes in the main control region. Likewise, mutations in ND5 and CytB were associated with defects in assembly of respiratory complexes. Altogether, the identified age-dependent accumulation of mtDNA mutations in mouse brain likely contributes to the decline in mitochondrial function. PMID- 28559045 TI - Physical activity and frailty as indicators of cardiorespiratory reserve and predictors of surgical prognosis: General and digestive surgery population characterization. AB - INTRODUCTION: Frailty and low physical activity and cardiorespiratory reserve are related to higher perioperative morbimortality. The crucial step in improving the prognosis is to implement specific measures to optimize these aspects. It is critical to know the magnitude of the problem in order to implement preoperative optimization programmes. OBJECTIVE: To characterize surgical population in a university hospital. METHODS: All patients undergoing preoperative evaluation for abdominal surgery with admission were prospectively included during a 3-month period. Level of physical activity, functional capacity, frailty and emotional state were assessed using score tests. Additionally, physical condition was evaluated using 5 Times Sit-to-Stand Test. Demographic, clinical and surgical data were collected. RESULTS: One hundred and forty patients were included (60+/ 15yr-old, 56% male, 25% ASA III or IV). Forty-nine percent of patients were proposed for oncologic surgery and 13% of which had received neoadjuvant treatment. Seventy percent of patients presented a low functional capacity and were sedentary. Eighteen percent of patients were considered frail and more than 50% completed the 5 Times Sit-to-Stand Test at a higher time than the reference values adjusted to age and sex. Advanced age, ASA III/IV, sedentarism, frailty and a high level of anxiety and depression were related to a lower functional capacity. CONCLUSIONS: The surgical population of our area has a low functional reserve and a high index of sedentary lifestyle and frailty, predictors of postoperative morbidity. It is mandatory to implement preoperative measures to identify population at risk and prehabilitation programmes, considered highly promising preventive interventions towards improving surgical outcome. PMID- 28559046 TI - Ceftazidime-induced thrombocytopenia. AB - Ceftazidime is an antibiotic belonging to the group of third generation cephalosporins, frequently used in clinical practice for its broad antibacterial spectrum. A case report is presented on a 78-year-old man who entered the intensive care unit due to respiratory failure secondary to nosocomial pneumonia in the postoperative period of a laparoscopic hepatic bisegmentectomy for a hepatocarcinoma. It required invasive mechanical ventilation and was treated with ceftazidime, developing a progressive decrease in platelet count after the onset of this drug and after re-exposure to it, not coinciding with the introduction of other drugs. The adverse reaction was reported to the Spanish pharmacosurveillance system and according to the Naranjo algorithm the causal relationship was probable. Since no case of ceftazidime-induced thrombocytopenia was found in the literature, we consider knowledge of it relevant as an adverse effect to be taken into account given its potential severity, especially when it cannot be explained by other causes. PMID- 28559047 TI - Editorial Overview: Sense and react: how the innate immune system detects threats and generates protective responses. PMID- 28559048 TI - Endometriosis in Adolescent and Young Girls: Report on a Series of 55 Cases. AB - STUDY OBJECTIVE: The aim of this retrospective study was to evaluate endometriosis in adolescent and young girls and further to review the menstrual, reproductive characteristics, and risk factors. DESIGN AND SETTING: We reviewed the medical records of adolescent and young girls with endometriosis from 2 different countries. Data were collected and analyzed from charts of 900 patients with endometriosis. PARTICIPANTS AND INTERVENTIONS: Fifty-five female adolescents aged between 13 and 21 years (mean age 18.3 years) participated in our series. This study was conducted in the Obstetric and Gynecology Department of Venizeleio General Hospital of Crete and involved all patients diagnosed with endometriosis between 1996 and 2016. MAIN OUTCOME MEASURES: Statistical methods included chi2 and Mann-Whitney U test. RESULTS: Of 900 patients with endometriosis we found 55 female adolescents (6.1%). The mean age was 18.3 +/- 2.3 years, significantly younger compared with the advanced endometriosis patients (32.7 +/- 7.2; P < .001). Regarding the menstrual reproductive and others characteristics, we observed several differences in adolescent young girls compared with the advanced age endometriosis group. The factors associated with an increased risk for young women include age at menarche, dysmenorrhea, history of asthma, and a positive family history of endometriosis. Additionally, we report on 16 of 55 (32%) adolescent women with endometriosis and congenital malformations (P < .01) and 5 patients who were diagnosed with dry eye syndrome. CONCLUSION: There is an association between endometriosis in adolescent and young women and risk factors including early menarche, early onset of dysmenorrhea, history of asthma, previous surgical procedures, obstructive genital anomalies, and family history of endometriosis. PMID- 28559049 TI - Attenuation of thioacetamide-induced hepatocellular injury by short-term repeated injections associated with down-regulation of metabolic enzymes and relationship with MHC class II-presenting cells. AB - The liver is the primary organ participating in the metabolism of xenobiotics and is therefore an important target in the safety assessment of drugs, chemicals and environmental toxins. Drug-induced liver injury (DILI) has recently become widely recognized in human medicine as an adverse event. The progression of DILI often involves "damage-associated molecular patterns" (DAMPs) of gene and protein expression such as high-mobility group boxes (HMGBs), S100 proteins and heat shock proteins (Hsp). DAMPs are released from injured or necrotic cells and are bound to Toll-like receptors (TLRs) and modulate inflammatory reactions. Previously, in thioacetamide (TAA; 300mg/kg body weight, single injection) induced rat liver, we demonstrated that the expressions of DAMPs, TLR4 and major histocompatibility complex (MHC) class II were simultaneously increased, accompanied with progression of hepatocellular injury and inflammation. Here we investigated the association of DILI and DAMPs, TLRs and MHC class II by using rat livers repeated injections with TAA (100mg/kg body weight, once, three times). Two days after TAA single injection, centrilobular hepatocellular necrosis with infiltration of mononuclear cells was observed, being paralleled with increase in serum levels of aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP). However, two days after duplicate and triplicate injections, only mild degenerative change of hepatocytes and slight infiltration of mononuclear cells were seen in the affected centrilobular area. Serum levels of AST, ALT and ALP were also decreased to the same levels of control. mRNA expressions of DAMPs (HMGBs, S100A4 and Hsp 70-2), TLR4 and MHC class II tended to be increased only on single injection, although the number of MHC class II-positive cells in the centrilobular area was still increased on each examination point. The analysis of enzymes (CYP2E1 and Flavin monooxygenase (FMO) 3), which metabolize TAA in hepatocytes, showed a significant decrease in FMO3 on the duplicate and triplicate injections. Autophagy and regulatory T cells were not significantly changed for the attenuation of hepatocyte injury. Collectively, these results suggest that hepatocytes may adapt accumulation of the toxicant by changing their enzyme functions; furthermore, MHC class II cells, which still showed increased number in the duplicate and triplicate injections, may be related with protection from the toxicant. PMID- 28559050 TI - In vitro performance of near infrared light transillumination at 780-nm and digital radiography for detection of non-cavitated approximal caries. AB - OBJECTIVES: To evaluate the ability of a Near Infrared Light Transillumination (NILT) device to detect non-cavitated approximal caries lesions; and to compare its performance to Digital Radiography (DR). METHODS: Thirty human extracted premolars (sound to lesions into the outer one-third of dentin) were selected. Lesion depth was confirmed by micro-computed tomography (MU-CT). Teeth were mounted in a custom-made device to simulate approximal contact. DR and NILT (CariVuTM, DEXIS, LLC, Hatfield, PA, USA) examinations were performed and repeated by three trained and calibrated examiners. Sensitivity, specificity, area under ROC curve (Az), inter- and intra-class correlation coefficients (ICCs) for each method, and correlation among the methods were determined. RESULTS: ICCs for intra-/inter-examiner agreement were substantial for NILT (0.69/0.64), and moderate for DR (0.52/0.48). Sensitivity/specificity for NILT and DR were 0.68/0.93 and 0.50/0.64, respectively. Az for NILT was 0.81, while for DR it was 0.61. Spearman correlation coefficient with MU-CT for NILT (0.65, p<0.001) demonstrated moderate association, while that of DR suggested no association (0.19, p=0.289). CONCLUSION: Within the limitations of this in vitro study, NILT demonstrated a potential for early approximal caries detection. NILT and DR performed the same regarding the accuracy for non-cavitated approximal caries detection; however, NILT was superior to DR in terms of repeatability, agreement and correlation with MU-CT. CLINICAL SIGNIFICANCE: A commercial version of NILT was recently introduced as a non-irradiative adjunctive caries detection method. It uses near infrared (NIR) light at 780-nm to transilluminate teeth and captures live images from the occlusal surface. This study demonstrates that NILT can be used as an alternative to radiography for non-cavitated approximal caries detection. PMID- 28559051 TI - 8-Nitro-cGMP promotes bone growth through expansion of growth plate cartilage. AB - In endochondral ossification, growth of bones occurs at their growth plate cartilage. While it is known that nitric oxide (NO) synthases are required for proliferation of chondrocytes in growth plate cartilage and growth of bones, the precise mechanism by which NO facilitates these process has not been clarified yet. C-type natriuretic peptide (CNP) also positively regulate elongation of bones through expansion of the growth plate cartilage. Both NO and CNP are known to use cGMP as the second messenger. Recently, 8-nitro-cGMP was identified as a signaling molecule produced in the presence of NO in various types of cells. Here, we found that 8-nitro-cGMP is produced in proliferating chondrocytes in the growth plates, which was enhanced by CNP, in bones cultured ex vivo. In addition, 8-nitro-cGMP promoted bone growth with expansion of the proliferating zone as well as increase in the number of proliferating cells in the growth plates. 8 Nitro-cGMP also promoted the proliferation of chondrocytes in vitro. On the other hand, 8-bromo-cGMP enhanced the growth of bones with expansion of hypertrophic zone of the growth plates without affecting either the width of proliferating zone or proliferation of chondrocytes. These results indicate that 8-nitro-cGMP formed in growth plate cartilage accelerates chondrocyte proliferation and bone growth as a downstream molecule of NO. PMID- 28559053 TI - Peripapillar retinal hamartoma associated with tuberous sclerosis. Case report. AB - INTRODUCTION: Tuberous sclerosis is a rare multisystemic disease with an autosomal dominant inheritance pattern. There are few documented cases in the literature of retinal hamartomas (astrocytomas) with aggressive progression in the context of this disease. CASE REPORT: A report is presented on a case of a 31 year-old male with unknown history of ophthalmic or systemic conditions, who referred to a history of 6 months of blurred vision in his right eye. This was caused by a unilateral retinal hamartoma due to an undiagnosed tuberous sclerosis. DISCUSSION: Multidisciplinary management, with the cooperation of Internal Medicine and the Oncology Department, is needed in these cases, as well as genetic counselling for affected patients. Complications are directly related to increased tumour size. Treatment does not seem to have any influence on the natural history of the disease. PMID- 28559052 TI - The acute toxicity problem with some perfluorooctanes. PMID- 28559054 TI - Continuous monitoring of noise levels in the Gulf of Catania (Ionian Sea). Study of correlation with ship traffic. AB - Acoustic noise levels were measured in the Gulf of Catania (Ionian Sea) from July 2012 to May 2013 by a low frequency (<1000Hz) hydrophone, installed on board the NEMO-SN1 multidisciplinary observatory. NEMO-SN1 is a cabled node of EMSO-ERIC, which was deployed at a water depth of 2100m, 25km off Catania. The study area is characterized by the proximity of mid-size harbors and shipping lanes. Measured noise levels were correlated with the passage of ships tracked with a dedicated AIS antenna. Noise power was measured in the frequency range between 10Hz and 1000Hz. Experimental data were compared with the results of a fast numerical model based on AIS data to evaluate the contribution of shipping noise in six consecutive 1/3 octave frequency bands, including the 1/3 octave frequency bands centered at 63Hz and 125Hz, indicated by the Marine Strategy Framework Directive (2008/56/EC). PMID- 28559055 TI - Determination of sedimentation, diffusion, and mixing rates in coastal sediments of the eastern Red Sea via natural and anthropogenic fallout radionuclides. AB - The Red Sea is a unique ecosystem with high biodiversity in one of the warmest regions of the world. In the last five decades, Red Sea coastal development has rapidly increased. Sediments from continental margins are delivered to depths by advection and diffusion-like processes which are difficult to quantify yet provide invaluable data to researchers. Beryllium-7, lead-210 and ceseium-137 were analyzed from sediment cores from the near-coast Red Sea near Jeddah, Saudi Arabia. The results of this work are the first estimates of diffusion, mixing, and sedimentation rates of the Red Sea coastal sediments. Maximum chemical diffusion and particle mixing rates range from 69.1 to 380cm-2y-1 and 2.54 to 6.80cm-2y-1, respectively. Sedimentation rate is constrained to approximately 0.6cm/yr via multiple methods. These data provide baselines for tracking changes in various environmental problems including erosion, marine benthic ecosystem silting, and particle-bound contaminant delivery to the seafloor. PMID- 28559056 TI - Fate of microplastics and mesoplastics carried by surface currents and wind waves: A numerical model approach in the Sea of Japan. AB - A numerical model was established to reproduce the oceanic transport processes of microplastics and mesoplastics in the Sea of Japan. A particle tracking model, where surface ocean currents were given by a combination of a reanalysis ocean current product and Stokes drift computed separately by a wave model, simulated particle movement. The model results corresponded with the field survey. Modeled results indicated the micro- and mesoplastics are moved northeastward by the Tsushima Current. Subsequently, Stokes drift selectively moves mesoplastics during winter toward the Japanese coast, resulting in increased contributions of mesoplastics south of 39 degrees N. Additionally, Stokes drift also transports micro- and mesoplastics out to the sea area south of the subpolar front where the northeastward Tsushima Current carries them into the open ocean via the Tsugaru and Soya straits. Average transit time of modeled particles in the Sea of Japan is drastically reduced when including Stokes drift in the model. PMID- 28559057 TI - Synthesis and evaluation of c-di-4'-thioAMP as an artificial ligand for c-di-AMP riboswitch. AB - Cyclic-di-adenosine monophosphate (c-di-AMP) is a bacterial second messenger that binds to an RNA receptor called riboswitch and regulates its downstream genes involving cell wall metabolism, ion transport, and spore germination. Therefore, the c-di-AMP riboswitch can be a novel target of antibiotics. In this study, we synthesized c-di-4'-thioAMP (1), which possesses a sulfur atom instead of an oxygen atom in the furanose ring, as a candidate of a bioisoster for natural c-di AMP. The resulting 1 bound to the c-di-AMP riboswitch with a micromolar affinity (34.8MUM), and the phosphodiesterase resistance of 1 was >12-times higher than that of c-di-AMP. Thus, 1 can be considered to be a stable ligand against a c-di AMP riboswitch. PMID- 28559058 TI - Structure-activity relationships for flavone interactions with amyloid beta reveal a novel anti-aggregatory and neuroprotective effect of 2',3',4' trihydroxyflavone (2-D08). AB - Naturally-occurring flavonoids have well documented anti-aggregatory and neuroprotective properties against the hallmark toxic protein in Alzheimer's disease, amyloid beta (Abeta). However the extensive diversity of flavonoids has limited the insight into the precise structure-activity relationships that confer such bioactive properties against the Abeta protein. In the present study we have characterised the Abeta binding properties, anti-aggregatory and neuroprotective effects of a discreet set of flavones, including the recently described novel protein sumoylation inhibitor 2',3',4'-trihydroxyflavone (2-D08). Quercetin, transilitin, jaceosidin, nobiletin and 2-D08 were incubated with human Abeta1-42 for 48h in vitro and effects on Abeta fibrillisation kinetics and morphology measured using Thioflavin T (ThT) and electron microscopy respectively, in addition to effects on neuronal PC12 cell viability. Of the flavones studied, only quercetin, transilitin and 2-D08 significantly inhibited Abeta1-42 aggregation and toxicity in PC12 cells. Of those, 2-D08 was the most effective inhibitor. The strong anti-amyloid activity of 2-D08 indicates that extensive hydroxylation in the B ring is the most important determinant of activity against beta amyloid within the flavone scaffold. The lack of efficacy of jaceosidin and nobiletin indicate that extension of B ring hydroxylation with methoxyl groups result in an incremental loss of anti-fibrillar and neuroprotective activity, highlighting the constraint to vicinal hydroxyl groups in the B ring for effective inhibition of aggregation. These findings reveal further structural insights into anti-amyloid bioactivity of flavonoids in addition to a novel and efficacious anti-aggregatory and neuroprotective effect of the semi-synthetic flavone and sumoylation inhibitor 2',3',4'-trihydroxyflavone (2-D08). Such modified flavones may facilitate drug development targeting multiple pathways in neurodegenerative disease. PMID- 28559059 TI - Halogen-substituted catechol bisphosphates are potent and selective inhibitors of the transcription factor STAT5b. AB - The transcription factor STAT5b is an antitumor target. Recently, we presented the small molecules Stafib-1 and Stafib-2 as potent, selective inhibitors of the STAT5b SH2 domain. Here we report that halogen substitutions on the terminal phenyl ring of Stafib-1 and a close derivative are tolerated and specificity over the STAT5a SH2 domain is maintained, albeit with a slight reduction in activity. Our data demonstrate that the synthetic methodology used for generating Stafib-1 and Stafib-2 can be utilized to synthesize a small library of halogen-substituted derivatives, and extend the panel of catechol bisphosphate-based submicromolar and selective STAT5b inhibitors. PMID- 28559060 TI - Searching for novel N1-substituted benzimidazol-2-ones as non-nucleoside HIV-1 RT inhibitors. AB - Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent an integral part of the currently available combination antiretroviral therapy (cART) contributing to reduce the AIDS-mortality and turned the disease from lethal to chronic. In this context we recently reported a series of 6-chloro-1-(3 methylphenylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. In this paper, we describe the design and the synthesis of two novel series of benzimidazolone analogues in which the linker moiety between the phenyl ring and the sulfonyl group was modified and new small lipophilic groups on the benzyl sulfonyl pendant were introduced. All the new obtained compounds were evaluated as RT inhibitors and were also tested against RTs containing single amino acid mutations. Finally, molecular docking studies were performed in order to rationalize the observed activity of the most promising compound. PMID- 28559062 TI - Inhibitory effect of angiotensin (1-7) on angiotensin III-induced nociceptive behaviour in mice. AB - We have previously demonstrated that the intrathecal (i.t.) administration of angiotensin (Ang) II into mice produces a nociceptive behaviour consisting of scratching, biting and licking accompanied by the phosphorylation of p38 MAPK in the spinal cord, which was mediated through AT1 receptors. Both the p38 MAPK phosphorylation and subsequent nociceptive behaviour were attenuated by the i.t. co-administration of Ang (1-7), an N-terminal fragment of Ang II, that acted via Mas receptors. On the other hand, a C-terminal fragment of Ang II, namely Ang III, was also shown to induce a nociceptive behaviour by acting upon AT1 receptors on spinal astrocytes and neurons, and was found to be more potent than Ang II. However, the inhibitory effect of Ang (1-7) on the Ang III-induced nociceptive behaviour remains unclear. Thus, here we examined whether Ang (1-7) can attenuate the Ang III-induced nociceptive behaviour and activation of spinal p38 MAPK. The i.t. administration of Ang (1-7) (1-100fmol) dose-dependently attenuated the Ang III (1pmol)-induced nociceptive behaviour in mice. Moreover, the inhibitory effect of Ang (1-7) at a dose of 100fmol was prevented by A779 (30fmol), a Mas receptor antagonist. Western blot analysis showed that the phosphorylation of p38 MAPK induced by the i.t. administration of Ang III (1pmol) was also attenuated by Ang (1-7) (100fmol), and this inhibition was prevented by A779 (30fmol). Furthermore, we showed that in the lumbar superficial dorsal horn, Mas receptors are expressed in neurons and microglia but absent from astrocytes. Together, these results suggest that the i.t. administration of Ang (1-7) attenuates the nociceptive behaviour and accompanying p38 MAPK phosphorylation induced by Ang III, and that this effect is likely mediated through Mas receptors on spinal neurons. PMID- 28559061 TI - Neuropeptides: A promising target for treating seizures. AB - Seizures are serious neurological disorders affecting nearly 50 million people worldwide. Seizures are characterized by abnormal, repetitive and synchronised firing of the neurons which is produced as a result of imbalance in the levels of the excitatory and inhibitory neurotransmitters. Neuropeptides are found to regulate seizures by rectifying this imbalance. These neuropeptides are stored in the dense core synaptic vesicles, and are released on excitation. This review focuses on certain neuropeptides which can alleviate both, the effects of seizures as well as epileptogenesis. Thus making it an attractive target for the management of seizures. PMID- 28559063 TI - Natural History of Intracranial Absorbable Gelatin Powder. AB - This case report documents the natural history of intracranial absorbable gelatin powder. We depict the serial imaging of Surgifoam in the cavity of an intracranial hemorrhage cavity after surgical evacuation. PMID- 28559064 TI - Endoscopic Third Ventriculostomy for the Treatment of Hydrocephalus in a Pediatric Population with Myelomeningocele. AB - BACKGROUND: Hydrocephalus develops in up to 90% of patients born with myelomeningocele. Although endoscopic third ventriculostomy (ETV) is currently considered the preferred treatment for obstructive hydrocephalus, its results have been inconsistent in patients with myelomeningocele. This study focuses on clinical and radiologic outcomes of ETV in children with hydrocephalus related to myelomeningocele. METHODS: Medical records of 18 pediatric patients with myelomeningocele treated with ETV from 1998 to 2015 at the Centro Hospitalar Sao Joao (Porto, Portugal) were reviewed retrospectively. Patients' caregivers were contacted to evaluate their clinical manifestations before and after surgery regarding signs and symptoms of hydrocephalus and Chiari malformation. Control neuroradiologic imaging of 9 patients was obtained and analyzed. Success of ETV was defined by clinical resolution and radiologic confirmation. RESULTS: ETV was successful in 8 of 18 cases (44.4%). Groups of patients were compared according to age at the time of surgery, with a 40% (2/5) success rate in newborns and a 50% success rate (3/6) in children older than 1 year. Eight patients underwent ETV as a first option, with a 37.5% success rate. Ten patients underwent the procedure after previous ventriculoperitoneal shunt (VPS), 5 for malfunction and 5 for VPS infection with 60% and 40% success rates, respectively. Early postoperative complications occurred in 2 patients. CONCLUSIONS: ETV can be performed in patients with myelomeningocele and hydrocephalus with success rates of almost 50%. Prior VPS or VPS malfunction or infection do not contraindicate ETV. If possible, the procedure should be delayed until the patient is at least 1 month old. PMID- 28559065 TI - Primary Pituitary Fibrosarcoma with Previous Adenoma. AB - BACKGROUND: Pituitary sarcomas are rare clinical entities most often encountered as secondary neoplasms representing late sequelae of radiation therapy to the sellar region. Primary pituitary fibrosarcomas (PPFS), in contrast, are exceptionally rare tumors with very few cases described in the literature thus far. Herein, we present a case of PFFS and describe it in the context of the existing literature. CASE DESCRIPTION: A 39-year-old woman presented with 2 months of headaches and rapidly progressive vision loss. She was found to have a 2.7-cm pituitary mass and initially underwent transnasal transsphenoidal resection from which pathology confirmed a pituitary adenoma. Eight months after surgery, she represented with vision changes and a recurrent tumor that postoperatively was found to be a primary fibrosarcoma with embedded adenoma remnants. On post-hoc examination of her original pathologic specimen, a prominent fibrous tissue component was suspected to be the source of her fibrosarcoma. CONCLUSIONS: This is a rare case of PFFS that highlights the need for close surveillance in affected patients. Through this case, we review the existing literature and discuss both surgical management and aggressive adjuvant therapy of this rare disease entity. PMID- 28559066 TI - Status Epilepticus Secondary to Pseudonodular Hemorragic Occipital Lesion with Edema: "Non Semper Ea Sunt, Quae Videntur, Decipit Frons Prima Multos" (Things Are Not Always What They Seem; The First Appearance Deceives Many). AB - We report a case in which common radiologic images masked a rare case of supratentorial hemangioblastoma (HBL). Other peculiarities of this case are the clinical presentation with status epilepticus and the occurrence of a supratentorial HBL unrelated to von Hippel-Lindau syndrome. Based on clinical and radiologic findings, including massive cerebral edema and hemorrhagic presentation, our preoperative diagnosis was a cerebral metastasis. In this scenario, physicians must take into account the words of the Roman fabulist Phaedrus: "Non semper ea sunt, quae videntur, decipit frons prima multos" (things are not always what they seem; the first appearance deceives many). PMID- 28559067 TI - Chronic Subdural Hematoma in Women. AB - OBJECTIVE: Sex differences in various diseases recently have been recognized as an important factor in the approach to more efficient preventive and therapeutic medicine. We clarified sex differences in the clinical characteristics of chronic subdural hematoma (CSDH) by comparing men and women with CSDH, as there is a well known male predominance in the prevalence of CSDH. METHODS: Clinical factors and computed tomography findings were investigated retrospectively in 490 consecutive patients admitted to our hospital between 2006 and 2015 who were diagnosed with CSDH. RESULTS: On univariate analysis, women were significantly older than men (P < 0.05). In women, premorbid impaired activities of daily living, consciousness disturbance, acute-to-chronic subdural hematoma, and death as outcomes at discharge were significantly more frequent than in men (P < 0.05). In contrast, women had less frequent instances of good recovery and less alcohol intake (P < 0.05). Multivariate analysis demonstrated female sex as an independent predictor of consciousness disturbance at admission. Female sex also was identified as a predictor of death at discharge. CONCLUSIONS: We demonstrated sex differences in the clinical characteristics of CSDH. In the future, management of patients with CSDH with regard to sex differences in disease characteristics could be expected to improve the outcomes of women, which have been worse than in men. PMID- 28559068 TI - Vitom-3D for Exoscopic Neurosurgery: Initial Experience in Cranial and Spinal Procedures. AB - BACKGROUND: The authors describe the application of a new exoscope that offers 3 dimensional (3D) visualization in cranial and spinal neurosurgery in detail. METHODS: Five cranial and 11 spinal procedures were performed with a 3D exoscope. Instrument handling, repositioning of the exoscope, handling of the image control unit, the adjustment of magnification and focal length, the depth perception, the image quality, the illumination, and the comfort level of the posture during the procedure were assessed via a questionnaire. RESULTS: The following procedures were performed: Microvascular decompression (n = 1), craniotomy and tumor resection (n = 4), anterior cervical discectomy and fusion with cervical plating (n = 2), cervical laminectomy and lateral mass fixation (n = 1), shear cervical lateral mass osteosynthesis (n = 1), lumbar canal decompression (n = 1), transforaminal lumbar interbody fusion (n = 2), thoracic intraspinal extradural tumor resection (n = 1), and lumbar discectomy (n = 3). Instrument handling, the intraoperative repositioning and handling of the VITOM-3D, and the comfort level of the intraoperative posture was rated excellent in 100% of procedures. The image quality was rated equal to the operating microscope in 68.75% of procedures. None of the procedures had to be stopped because of technical problems. No surgical complications were noted that could be related to the use of the exoscope. CONCLUSIONS: The 3D-exoscopic system is safe and effective tool to perform spinal procedures and less demanding cranial procedures. The image quality and 3D visualization were comparable with the operating microscope. The technique harbors the unique advantage of excellent comfort for the involved surgical team during the procedure. PMID- 28559069 TI - Potential for Intrathecal Baclofen in Treatment of Essential Tremor. AB - INTRODUCTION: Essential tremor (ET) is the most common movement disorder of adults, affecting an estimated 7 million Americans. Symptoms of ET range from slightly noticeable to debilitating, with 1 cohort study finding 15% of patients were forced into early retirement. Additionally, depression has also been correlated with the severity of disability of ET. Treatment options include propranolol and primidone. Current treatment options are not very effective, with more than half (56.3%) of patients discontinuing medications because of no changes in symptoms. METHODS: Unfortunately, there is a relative void and controversy in the literature explaining ET pathophysiology; however, the gamma aminobutyric acid (GABA) hypothesis is the strongest. We conducted a PubMed search on 30 September 2015 with no time constraints using the search terms "essential tremor" and "baclofen," which resulted in a total of 5 articles. RESULTS: Neurohistopathologic studies have demonstrated decreased GABA-A and GABA B receptors in the cerebellar cortex of ET patients. GABA, the major inhibitory neurotransmitter in the central nervous system, is proposed to have an inhibitory effect on pacemaker output activity of the cerebello-thalamo-cortical pathway, with lower receptors resulting in decreased inhibition of baseline tremors. Tariq et al showed delayed onset and intensity of tremor with oral administration of R baclofen in a mouse model of ET. CONCLUSION: With a better side-effect profile and success in a physiologically related condition, we propose more clinical trials and research be carried out on intrathecal baclofen as a potential treatment option, especially drug refractory ET, so as to increase the quality of life of this patient population. PMID- 28559070 TI - Severe Traumatic Brain Injury at a Tertiary Referral Center in Tanzania: Epidemiology and Adherence to Brain Trauma Foundation Guidelines. AB - BACKGROUND: Severe traumatic brain injury (TBI) is a major cause of death and disability worldwide. Prospective TBI data from sub-Saharan Africa are sparse. This study examines epidemiology and explores management of patients with severe TBI and adherence to Brain Trauma Foundation Guidelines at a tertiary care referral hospital in Tanzania. METHODS: Patients with severe TBI hospitalized at Bugando Medical Centre were recorded in a prospective registry including epidemiologic, clinical, treatment, and outcome data. RESULTS: Between September 2013 and October 2015, 371 patients with TBI were admitted; 33% (115/371) had severe TBI. Mean age was 32.0 years +/- 20.1, and most patients were male (80.0%). Vehicular injuries were the most common cause of injury (65.2%). Approximately half of the patients (47.8%) were hospitalized on the day of injury. Computed tomography of the brain was performed in 49.6% of patients, and 58.3% were admitted to the intensive care unit. Continuous arterial blood pressure monitoring and intracranial pressure monitoring were not performed in any patient. Of patients with severe TBI, 38.3% received hyperosmolar therapy, and 35.7% underwent craniotomy. The 2-week mortality was 34.8%. CONCLUSIONS: Mortality of patients with severe TBI at Bugando Medical Centre, Tanzania, is approximately twice that in high-income countries. Intensive care unit care, computed tomography imaging, and continuous arterial blood pressure and intracranial pressure monitoring are underused or unavailable in the tertiary referral hospital setting. Improving outcomes after severe TBI will require concerted investment in prehospital care and improvement in availability of intensive care unit resources, computed tomography, and expertise in multidisciplinary care. PMID- 28559071 TI - Magnetic Resonance Spectroscopy Findings in Patients with Dural Arteriovenous Fistulas: Three Case Reports. AB - BACKGROUND: Magnetic resonance spectroscopy (MRS) is a potentially useful modality for evaluating brain metabolites in patients with dural arteriovenous fistula (dAVF). Here we describe a different pattern of MRS-based cerebral metabolism findings in patients with dAVF. CASE DESCRIPTIONS: We performed MRS in 3 patients with transverse sigmoid sinus dAVF associated with cortical venous reflux. In case 1, which was associated with vasogenic edema on T2-weighted magnetic resonance imaging (MRI), decreased preoperative N-acetylaspartate (NAA)/creatine (Cr) and myo-inositol (mIns)/Cr and increased lactate (Lac)/Cr ratios improved after treatment. In case 2, a decreased preoperative NAA/Cr ratio improved after treatment. These 2 patients presented with seizures. In case 3, the patient presented with headache and showed no metabolic changes on preoperative or postoperative MRS. CONCLUSIONS: Our results suggest that patients with dAVF can be classified based on a combination of metabolic and signal changes seen on T2-weighted MRI. MRS may allow significantly expanded evaluation of the metabolic changes associated with dAVF for appropriate classification and management. PMID- 28559072 TI - Risk Factors for Surgical Results of Hirayama Disease: A Retrospective Analysis of a Large Cohort. AB - OBJECTIVE: To explore risk factors affecting surgical results of Hirayama disease. METHODS: A retrospective analysis of 210 patients was performed to identify risk factors affecting surgical results of Hirayama disease by using univariate and multivariate analyses. A receiver operating characteristic curve and area under the curve were applied to evaluate the significant results of the multivariate analysis and the optimal reference value. RESULTS: The mean follow up period was 27.3 months (range, 14-45 months), and 194 patients with clinical and radiographic data completed the final follow-up. Multivariate analysis identified age of patients (cutoff value 22.5 years), duration of the disease (cutoff value 33 months), physiologic reflex, and pathologic reflex as independent risk factors for surgical results of Hirayama disease. The receiver operating characteristic curve analysis and area under the curve showed that good reference value was obtained for the risk factors. CONCLUSIONS: Age of patient, duration of the disease, physiologic reflex, and pathologic reflex are the main risk factors affecting surgical results of Hirayama disease. Receiver operating characteristic analysis shows that good reference value was obtained for the risk factors. PMID- 28559073 TI - A Meta-Analysis on the Clinical Significance of Redundant Nerve Roots in Symptomatic Lumbar Spinal Stenosis. AB - OBJECTIVE: Symptomatic lumbar spinal stenosis (LSS), which leads to severe socioeconomic consequences and places a heavy burden on global healthcare system, is a relatively frequent spine disorder. Redundant nerve roots (RNRs) are a relatively common finding in which slender, serpiginous, or tortuous nerve roots are found in the subarachnoid space of the lumbar spine. Previous studies that evaluated the prognostic assessment of RNRs in patients with symptomatic LSS are composed of doubtful results. Therefore, the clinical significance of RNRs in symptomatic LSS is still uncertain. The aim of this meta-analysis is a systematic assessment of the clinical significance of RNR syndrome in symptomatic LSS. METHODS: This study used a highly sensitive search strategy to identify all published studies in multiple databases up to January 1, 2017. All identified trials were systematically evaluated using specific inclusion and exclusion criteria. Cochrane methodology was also applied to the results of this study. RESULTS: This study identified 4 relevant studies involving 297 patients. Compared with a non-RNR group, the RNR group results included worse clinical outcomes that were assessed using the Japanese Orthopedic Association scores after surgery (weighted mean difference [WMD], -0.78; 95% confidence interval [CI], -1.26 to -0.29; P = 0.002; I2 = 0%), for recovery rate (WMD, -9.87; 95% CI, -15.07 to -4.67; P = 0.0002; I2 = 0%), and for older age (WMD, 2.51; 95% CI, 0.45 4.57; P = 0.02; I2 = 43%). CONCLUSIONS: RNR is an entity in association with symptomatic LSS, which may be viewed as a potentially powerful prognostic indicator of worse postoperative functional recovery for symptomatic LSS. PMID- 28559074 TI - Anterior Column Realignment has Similar Results to Pedicle Subtraction Osteotomy in Treating Adults with Sagittal Plane Deformity. AB - OBJECTIVE: Anterior column realignment (ACR) is a minimally invasive surgical technique used for the correction of adult sagittal plane deformity. ACR is performed via a minimally invasive lateral transpsoas approach with anterior longitudinal ligament release and hyperlordotic cage placement. The objective of this study was to compare radiographic outcomes and complications in patients treated by ACR or Pedicle subtraction osteotomy (PSO). METHODS: Patients who underwent ACR were matched with patients from a retrospective PSO dataset, by pelvic incidence, lumbar lordosis, and thoracic kyphosis. Inclusion criteria included pelvic incidence and lumbar lordosis mismatch > 10 degrees , pelvic tilt > 25 degrees , and/or C7 sagittal vertical axis >5 cm, and minimum 1-year follow up. RESULTS: All (n = 17) patients who underwent ACR underwent second-stage open posterior instrumented fusion. There were no differences in baseline demographic or radiographic parameters. Both groups were found to have significant improvement from preoperative to final follow-up for lumbar lordosis, T1 spinopelvic inclination, and T1 pelvic angle. Pelvic tilt did not improve with PSO (31 degrees to 28 degrees ) at final follow-up but did improve in ACR group (34 degrees to 25 degrees ). No differences were identified at 3-month or final follow-up for lumbar lordosis (51 degrees vs. 47 degrees ), pelvic tilt (25 degrees vs. 28 degrees ), and T1 pelvic angle (23 degrees vs. 24 degrees ). The group undergoing PSO achieved greater T1 spinopelvic inclination correction (8 degrees vs. 1.9 degrees ). Patients who underwent ACR had significantly less estimated blood loss than patients who underwent PSO (1.6 vs. 3.6 L, respectively), but no difference in the overall major complication rates was found (35.3% vs. 41.2%, respectively). CONCLUSIONS: ACR achieved similar radiographic results as PSO in a matched cohort with significantly less estimated blood loss and similar overall complication rate. PMID- 28559075 TI - Impact of Prehospital Transportation on Survival in Skiers and Snowboarders with Traumatic Brain Injury. AB - INTRODUCTION: Prehospital helicopter use and its impact on outcomes in snowboarders and skiers incurring traumatic brain injury (TBI) is unknown. The present study investigates the association of helicopter transport with survival of snowboarders and skiers with TBI, in comparison with ground emergency medical services (EMS), by using data derived from the National Trauma Data Bank (2007 2014). METHODS: Primary and secondary endpoints were defined as in-hospital survival and absolute risk reduction based upon number needed to transport (treat) respectively. Multivariable regression models including traditional logit model, model fitted with generalized estimating equations, and those incorporating results from propensity score matching methods were used to investigate the association of helicopter transport with survival compared with ground EMS. RESULTS: Of the 1018 snowboarders and skiers who met the criteria, 360 (35.4%) were transported via helicopters whereas 658 (64.6%) via ground EMS with a mortality rate of 1.7% and 1.5%, respectively. Multivariable log-binomial models demonstrated association of prehospital helicopter transport with increased survival (odds ratio 8.58; 95% confidence interval 1.09-67.64; P = 0.041; absolute risk reduction: 10.06%). This finding persisted after propensity score matching (odds ratio 24.73; 95% confidence interval 5.74-152.55; P < 0.001). The corresponding absolute risk reduction implies that approximately 10 patients need to be transported via helicopter to save 1 life. CONCLUSIONS: Based on our robust statistical analysis of retrospective data, our findings suggest prehospital helicopter transport improved survival in patients incurring TBI after snowboard- or ski-related falls compared with those transported via ground EMS. Policies directed at using helicopter services at remote winter resorts or ski or snowboarding locations should be implemented. PMID- 28559076 TI - Prenatal Diagnosis and Multimodal Neonatal Treatment of a Rare Pial Arteriovenous Fistula: Case Report and Review of the Literature. AB - BACKGROUND: Intracranial pial arteriovenous fistulas (PAVFs) are direct communications between the arterial and venous system of the brain, with the characteristic absence of a plexiform nidus, as seen in the classic cerebral arteriovenous malformations. These vascular malformations, usually occurring in the pediatric population, very rarely are diagnosed in utero, because of a lack of understanding of the condition and because they may be hard to visualize. CASE DESCRIPTION: We report a rare case of a mass-effect PAVF diagnosed with fetal magnetic resonance imaging, involving the right cerebral hemisphere, fed by a pericallosal artery and associated with a giant venous dilatation. The PAVF initially was managed by the endovascular embolization. The recruitment of a middle cerebral artery feeder and the rapidly enlarging size of the venous pouch with mass effect required subsequent surgery. CONCLUSIONS: The 2-stage multimodal treatment resulted in complete disappearance of the PAVF without complications. PMID- 28559078 TI - Risk Factors for Ventriculoperitoneal Shunt Dependency in Patients with Spontaneous Cerebellar Hemorrhage. AB - BACKGROUND: Hydrocephalus is a common complication after spontaneous cerebellar hemorrhage (CH). This study focused on predicting ventriculoperitorneal (VP) shunt dependency in patients with spontaneous CH. METHODS: Ninety-nine patients with spontaneous CH were evaluated in this retrospective study. A comparison between patients with and those without VP shunt dependency during hospitalization was made. RESULTS: VP shunt-dependent hydrocephalus developed in 19.2% of the patients (19 of 99). Comparison of neuroimaging findings on admission between the 2 patient groups identified large hematoma dimension (P < 0.001), large hematoma volume (P = 0.001), fourth ventricular degradation (P < 0.001), development of hydrocephalus (P < 0.001), and obliteration of the basal cisterns (P < 0.001) as significant risk factors for VP shunt-dependent hydrocephalus. Stepwise logistic regression analysis identified hydrocephalus on admission and maximum hematoma diameter on admission as independent risk factors for VP shunt dependency (P = 0.006 and 0.020, respectively). The adjusted risk of VP shunt dependency for patients with hydrocephalus on admission had an odds ratio of 37.04. Furthermore, an increase of 1 mm in the blood clot diameter on admission would increase the VP shunt dependency rate by 11.9%. The cutoff value of blood clot diameter on presentation was 36.15 mm (sensitivity, 84.2%; specificity, 85.0%). CONCLUSIONS: A patient with hydrocephalus on admission and a hematoma of larger size and dimension at the time of initial imaging is at elevated risk for VP shunt dependency. Repeat neuroimaging studies and careful clinical assessment are mandatory for high-risk patients to determine the presence of post-CH hydrocephalus. PMID- 28559077 TI - Incidence and Risk Factors of Postoperative Adjacent Segment Degeneration Following Anterior Decompression and Instrumented Fusion for Degenerative Disorders of the Cervical Spine. AB - OBJECTIVE: To explore incidence and risk factors of postoperative adjacent segment degeneration (ASD) following anterior decompression and instrumented fusion for degenerative disorders of the cervical spine. METHODS: Medical records from January 2005 to September 2011 of 283 patients were retrospectively reviewed. Patients were divided into 2 groups based on occurrence of ASD at follow-up: ASD group and no ASD group. To investigate risk for occurrence of ASD, 3 sets of factors were analyzed statistically: patient characteristics, surgical variables, and radiographic parameters. RESULTS: Postoperative ASD developed in 68 of 283 patients. There was no statistically significant difference between the 2 groups in patient characteristics or the surgical variables of surgical strategy, surgical time, and blood loss. The number of patients receiving 2-level spinal fusion was higher in the ASD group. Upper instrumented vertebra at C5 was more common in the ASD group. There was no difference between groups in all but 1 of the radiographic parameters; the plate-to-disc distance was much smaller in the ASD group. Logistic regression analysis revealed that upper instrumented vertebra at C5, plate-to-disc distance <3.0 mm, and 2-level anterior cervical fusion were independently associated with ASD. CONCLUSIONS: Patients with degenerative disorders of the cervical spine who receive 2-level cervical fusion and with upper instrumented vertebra at C5 are at high potential risk of ASD. PMID- 28559079 TI - Respiratory and Swallowing Outcomes Based on Aneurysm Location in 360 Patients with Subarachnoid Hemorrhage. AB - INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) may result in abnormal respiratory and swallowing function. We analyzed factors that may influence long term respiratory and swallowing function in aSAH patients and compared patients with anterior and posterior aneurysm locations. METHODS: We retrospectively reviewed 360 consecutive aSAH patients. We recorded location of the aneurysm and respiratory indices on admission, in-hospital adverse respiratory events, and the need for tracheostomy (for respiratory failure) or percutaneous endoscopic gastrostomy (PEG) tube (for prolonged dysphagia). Respiratory and swallowing function was also reviewed at 1 year and at most recent clinical follow-up. RESULTS: Aneurysms consisted of 293 described as anterior circulation (81.4%) and 67 described as posterior circulation (18.6%), including 31 patients with basilar artery aneurysms and 16 with posterior inferior cerebellar artery (PICA) aneurysms. There were no differences in oxygen saturation or PaO2:FiO2 ratio on admission, though patients with PICA aneurysms presented significantly more commonly with endotracheal intubation. PICA aneurysm patients had higher rates of tracheostomy and PEG tube dependence at 1 year in univariate analysis. Higher Hunt-Hess grade was a predictor of pneumonia and prolonged intubation, whereas older age and prolonged hospitalization were predictors of PEG placement in multivariate analysis. CONCLUSIONS: Ruptured anterior and posterior circulation aneurysms have similar rates of in-hospital respiratory and swallowing dysfunction. There was a higher rate of swallowing dysfunction in the posterior circulation aneurysm group compared with the anterior group at most recent follow up (12% vs. 2%, P = 0.035). Patients with PICA aneurysms demonstrated higher rates of tracheostomy and PEG, though the latter did not achieve statistical significance. PMID- 28559080 TI - Comparison of Stent-Assisted Coil Embolization and the Pipeline Embolization Device for Endovascular Treatment of Ophthalmic Segment Aneurysms: A Multicenter Cohort Study. AB - BACKGROUND: Stent-assisted coil embolization and flow diversion with the Pipeline embolization device (PED) are both effective endovascular treatment options for ophthalmic segment aneurysms (OSAs) of the internal carotid artery. Here we present a large comparative cohort study. METHODS: A multicenter, retrospective cohort comparison study of consecutively treated OSAs was conducted at 2 academic institutions in the United States comparing stent-coiling (between 2007 and 2015) and PED (between 2011 and 2016). RESULTS: A total of 62 of OSAs were treated with stent-coiling and 106 were treated with the PED. The stent-coiling-treated aneurysms were larger, although the maximum diameter was not significantly different between the 2 groups (P = 0.05). The median duration of follow-up was 22.5 months for the stent-coiling group and 8.7 months for the PED group (P = 0.0002). Complete occlusion at last follow-up was achieved in 75.9% of aneurysms in the stent-coiling group and in 81.1% of aneurysms in the PED group (P = 0.516). The retreatment rate was higher with stent-coiling, but the difference did not reach statistical significance (P = 0.062). A good functional outcome was achieved in 96.6% of patients in the stent-coiling group and in 94.7% of those in the PED group (P = 0.707). The rate of neurologic complications was 4.8% in the stent-coiling group and 9.4% in the PED group (P = 0.376). CONCLUSION: Stent coiling and the PED were equally effective for treating OSAs. There were no significant differences in terms of procedural complications, angiographic, functional, and visual outcomes. PED may be more favorable for multiple adjacent OSAs. PMID- 28559082 TI - Computed Tomography and Magnetic Resonance Imaging Parameters Associated with Poor Clinical Outcome in Spondylodiscitis. AB - BACKGROUND: Prognostic factors for the disease course of patients with spondylodiscitis have not been well studied. METHODS: The prognostic value of initial magnetic resonance imaging (MRI) and computed tomography imaging parameters was analyzed in 62 patients (47% women; mean age +/- SD, 71.6 +/- 9.6 years) with a confirmed diagnosis of spondylodiscitis. The disease course was separately evaluated during initial treatment response during hospitalization, relapse, and clinical short-term follow-up at 3 months. RESULTS: Overall CT findings graded as definitely inflammatory (P = 0.006), reduced disc height on MRI (P = 0.044) and fluid-equivalent hyperintensity of discs on T2 short tau inversion recovery-weighted sequences (P = 0.047) were associated with poor initial treatment response. High initial C-reactive protein value (>10.1 mg/dL) was associated with a higher relapse rate (P = 0.038). Risk factors for poor outcome were infection with low-virulence bacteria (P = 0.040) and overall MRI findings atypical for infection (P = 0.027). CONCLUSIONS: Compared with MRI, CT imaging parameters have a higher prognostic value regarding the disease course. Patients infected with low-virulence bacteria and atypical MRI findings are at higher risk for poor clinical outcome and thus warrant closer monitoring. PMID- 28559081 TI - Stemness Marker Detection in the Periphery of Glioblastoma and Ability of Glioblastoma to Generate Glioma Stem Cells: Clinical Correlations. AB - BACKGROUND: Recent studies suggested glioma stem cells (GSCs) are key contributors to therapeutic resistance of glioblastoma multiforme (GBM) and are responsible for GBM recurrence. METHODS: We characterized the phenotype of cancer cells in the core and periphery of 20 GBM tumors, correlating clinical outcome to the ability to form GSCs and distinguishing survival based on Ki-67 staining. RESULTS: Similar levels of methylguanine-deoxyribonucleic acid methyltransferase were found in the core and periphery of GBM tumors, whereas Ki-67 was reduced in the periphery. Similar levels of stemness markers in the periphery and in the core of all GBM cultures were found. Only cells expressing >30% SOX2 levels were able to produce neurospheres. Immunophenotypic analysis showed higher levels of stemness markers in GSC cultures than in all GBM primary cultures. GSC in vitro production and coexpression of Ki-67 >5% negatively correlated with outcome. CONCLUSIONS: Not all GBM cultures can generate GSCs, and this capacity is linked to >30% SOX2 levels. The ability to form spheres negatively correlated to survival, and the detection of >5% Ki-67 levels may be useful to identify patients at risk of disease progression. The presence of GSC-/SOX-2-/Ki-67- cells may be regarded as a new prognostic factor. The presence of stemness markers and methylguanine-deoxyribonucleic acid methyltransferase in the periphery of GBM tumors may be the reason for treatment failure and recurrence. Development of stem cell-targeted therapies and elaboration of more aggressive treatments represent an opportunity to eliminate the GBM source and the nidus of recurrence. PMID- 28559083 TI - Superior Petrosal Vein Sacrifice During Microvascular Decompression: Perioperative Complication Rates and Comparison with Venous Preservation. AB - OBJECTIVE: To investigate potential effect of sacrifice of the superior petrosal vein (SPV) on postoperative complications after microvascular decompression (MVD). METHODS: Retrospective review of 98 consecutive patients undergoing MVD of cranial nerve V was performed. Frequency of division of the SPV during surgery was recorded, and postoperative complications and imaging were recorded and analyzed. In patients with complications, the specific anatomic variation of the superior petrosal venous complex was noted. RESULTS: Of 98 patients undergoing MVD, 83 (84.7%) had sacrifice of the SPV at the time of surgery, 12 (12.2%) had the SPV preserved, and 3 (3.1%) were revision operations. Four patients (4.8%) had complications deemed to be attributable to venous insufficiency or congestion. These included sigmoid sinus thrombosis with coincident cerebellar hemorrhage, midbrain and pontine infarction, hemiparesis with midbrain and pontine edema, and facial paresis with ischemia in the middle cerebellar peduncle. None of the patients with preserved SPV were symptomatic or had imaging changes consistent with venous congestion. CONCLUSIONS: Sacrifice of the SPV is often performed during MVD. This is associated with a complication rate that is significant in frequency and severity compared with preserving the vein. SPV sacrifice should be limited to cases where it is deemed absolutely necessary for successful cranial nerve decompression. PMID- 28559084 TI - Letter to the editor regarding "Quantitative study of voice dysfunction after thyroidectomy". PMID- 28559087 TI - Not only limbs in atypical restless legs syndrome. AB - Restless legs syndrome (RLS) typically affects the limbs, but the involvement of other body parts has also been reported. In this essay, we critically review all literature reports of atypical RLS cases with unusual localizations. Applying the updated diagnostic criteria of the International restless legs syndrome study group (IRLSSG), which also consider symptoms localized outside of the lower limbs, a few of these atypical cases reported in the previous literature resulted in a definitive diagnosis of RLS. We also discuss the relationship between RLS and burning mouth syndrome (BMS) or restless genital syndrome (RGS). We conclude clinical sleep specialists should be aware of unusual RLS localizations because they respond to the usual treatment for RLS. All the IRLSSG diagnostic criteria should be applied in every suspected case, in order to establish a correct diagnosis of this disabling but treatable condition. PMID- 28559086 TI - Laparoscopic Intervention in Acute Crohn's Disease Involving an Ovary. AB - Crohn's disease (CD) is a chronic inflammatory disorder that may involve any part of the gastrointestinal tract. Acute manifestations in female internal reproductive organs are rare and have been described in only a few cases. A 27 year-old nulligravida woman diagnosed with CD presented with pelvic pain, fever, and a palpable mass (confirmed by ultrasound) in the right lower quadrant of the abdomen. She underwent diagnostic laparoscopy because of worsening symptoms suggestive of a tubo-ovarian abscess. The right adnexa were excised after adhesiolysis. Pathologic examination revealed an ovarian granuloma consistent with CD. This case shows that a laparoscopic approach is possible for active CD, with all the benefits of a minimally invasive approach. Although the involved ovary was removed, similar to previous reports using laparotomy, conservative therapy should be considered if preoperative diagnosis can be made. Improvements in preoperative diagnosis and development of management guidelines is critical for ovarian preservation and conservative treatment options. PMID- 28559088 TI - Additional value of left atrial appendage geometry and hemodynamics when considering anticoagulation strategy in patients with atrial fibrillation with low CHA2DS2-VASc scores. AB - BACKGROUND: Strokes occur in some patients with atrial fibrillation (AF), even when the CHA2DS2-VASc (congestive heart failure, hypertension, age >75 years, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age>65 years, female sex) score is low. OBJECTIVE: We sought to determine the factors defining the residual stroke risk in patients with AF and low CHA2DS2 VASc scores, with a particular focus on the hemodynamics and geometry of the left atrial appendage (LAA). METHODS: From February 1, 2008 to December 31, 2012, 66 consecutive patients with nonvalvular AF and a CHA2DS2-VASc score of 0 or 1 (except a point for the female sex) were enrolled. All patients were admitted with a diagnosis of acute ischemic stroke. The control group consisted of patients with nonvalvular AF without a history of stroke. RESULTS: The LAA orifice area was larger (4.35 +/- 1.51 cm2 vs 2.83 +/- 0.9 cm2; P < .001) and the LAA flow velocity was lower (41.9 +/- 22.7 cm/s vs 54.4 +/- 19.9 cm/s; P < .001) in the stroke group than in the control group. Low LAA flow velocity (<40 cm/s) and large LAA orifice area (>4 cm2) were independent predictors of stroke. Patients with an LAA flow velocity of <40 cm/s and an LAA orifice of >4.0 cm2 had a markedly higher odds ratio (odds ratio 10.9; 95% confidence interval 3.0-40.0; P < .001) of stroke than did those with preserved LAA flow velocity and smaller LAA orifice. CONCLUSION: Even in patients with low CHA2DS2-VASc scores, the presence of both decreased LAA flow velocity and increased LAA orifice size was associated with a high odds ratio of stroke. Future large prospective studies are needed to assess whether these patients should receive anticoagulants. PMID- 28559085 TI - Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. AB - PURPOSE: To devise a comprehensive multiplatform genetic testing strategy for inherited retinal disease and to describe its performance in 1000 consecutive families seen by a single clinician. DESIGN: Retrospective series. PARTICIPANTS: One thousand consecutive families seen by a single clinician. METHODS: The clinical records of all patients seen by a single retina specialist between January 2010 and June 2016 were reviewed, and all patients who met the clinical criteria for a diagnosis of inherited retinal disease were included in the study. Each patient was assigned to 1 of 62 diagnostic categories, and this clinical diagnosis was used to define the scope and order of the molecular investigations that were performed. The number of nucleotides evaluated in a given subject ranged from 2 to nearly 900 000. MAIN OUTCOME MEASURES: Sensitivity and false genotype rate. RESULTS: Disease-causing genotypes were identified in 760 families (76%). These genotypes were distributed across 104 different genes. More than 75% of these 104 genes have coding sequences small enough to be packaged efficiently into an adeno-associated virus. Mutations in ABCA4 were the most common cause of disease in this cohort (173 families), whereas mutations in 80 genes caused disease in 5 or fewer families (i.e., 0.5% or less). Disease-causing genotypes were identified in 576 of the families without next-generation sequencing (NGS). This included 23 families with mutations in the repetitive region of RPGR exon 15 that would have been missed by NGS. Whole-exome sequencing of the remaining 424 families revealed mutations in an additional 182 families, and whole-genome sequencing of 4 of the remaining 242 families revealed 2 additional genotypes that were invisible by the other methods. Performing the testing in a clinically focused tiered fashion would be 6.1% more sensitive and 17.7% less expensive and would have a significantly lower average false genotype rate than using whole exome sequencing to assess more than 300 genes in all patients (7.1% vs. 128%; P < 0.001). CONCLUSIONS: Genetic testing for inherited retinal disease is now more than 75% sensitive. A clinically directed tiered testing strategy can increase sensitivity and improve statistical significance without increasing cost. PMID- 28559089 TI - Endo-epicardial breakthrough: A tale of 2 sides. PMID- 28559090 TI - Effect of air removal with extracorporeal balloon inflation on incidence of asymptomatic cerebral embolism during cryoballoon ablation of atrial fibrillation. AB - BACKGROUND: Asymptomatic cerebral embolism (ACE) is sometimes detected after cryoballoon ablation of atrial fibrillation. The removal of air bubbles from the cryoballoon before utilization may reduce the rate of ACE. OBJECTIVE: This study aims to compare the incidence of ACE between a conventional and a novel balloon massaging method during cryoballoon ablation. METHODS: Of 175 consecutive patients undergoing initial cryoballoon ablation of paroxysmal atrial fibrillation, 60 (34.3%) patients underwent novel balloon massaging with extracorporeal balloon inflation in saline water (group N) before the cryoballoon was inserted into the body. The remaining 115 (65.7%) patients underwent conventional balloon massaging in saline water while the balloon remained folded (group C). Of those, 86 propensity score-matched patients were included. RESULTS: The baseline characteristics were similar between the 2 groups. In group N, even after balloon massaging in saline water was carefully performed, multiple air bubbles remained on the balloon surface when the cryoballoon was inflated in all cases. Postprocedural cerebral magnetic resonance imaging detected ACE in 14.0% of all patients. The incidence of ACE was significantly lower in group N than in group C (4.7% vs 23.3%; P = .01). According to multivariable analysis, the novel method was the sole factor associated with the presence of ACE (odds ratio 0.161; 95% confidence interval 0.033-0.736; P = .02). CONCLUSION: Preliminary removal of air bubbles in heparinized saline water with extracorporeal balloon inflation reduced the incidence of ACE. Since conventional balloon massaging failed to remove air bubbles completely, this novel balloon massaging method should be recommended before cryoballoon utilization. PMID- 28559091 TI - Triflusal in Patients With Aspirin Hypersensitivity Treated With Coronary Stent Implantation. PMID- 28559092 TI - Low health literacy and healthcare utilization among immigrants and non immigrants in Switzerland. AB - OBJECTIVE: This study aimed at investigating the association between functional health literacy and knowledge on when to seek medical help for potentially harmless (overutilization) or serious (underutilization) situations among immigrants and non-immigrants in Switzerland. METHODS: Data was collected among three immigrant groups and the native population (N=1146) in the German- and Italian-speaking part of Switzerland. Health literacy was assessed with the Short Test of Functional Health Literacy (S-TOFHLA) and three Brief Health Literacy Screeners. Over- and underutilization of healthcare services was assessed with items asking participants about when to seek medical help for minor, respectively major, physical symptoms. RESULTS: Immigrants were more likely to seek medical help when unwarranted (overutilization). Health literacy, when assessed with the S-TOFHLA, was significantly associated with over- and underutilization. Yet, once controlled for covariates, the association between health literacy and overutilization was negative. Immigration background and micro-cultural differences emerged as important predictors of utilization. CONCLUSIONS: Results suggest that functional health literacy is directly related to healthcare utilization. The effects might be amplified by (micro-)cultural differences. PRACTICE IMPLICATIONS: Healthcare providers should be aware of differences in health literacy and utilization patterns among different population groups. Communication between patients and providers should be literacy and culturally sensitive. PMID- 28559093 TI - The Lutonix(r) drug-coated balloon: A novel drug delivery technology for the treatment of vascular disease. AB - Local drug delivery of an anti-proliferative drug from balloon catheter systems to the site of arterial injury has been attempted repeatedly over the years with limited success in drug uptake and retention. Accessibility of the drug at the site is critical to combat the body's response to the procedural trauma of angioplasty. Recently, formulations have been designed which achieve delivery of therapeutic doses of the anti-proliferative drug paclitaxel to arteries with higher efficiency and longer tissue retention. These formulations succeed through formation of a drug reservoir in the artery wall enabling release after the initial angioplasty procedure. These formulations have become the cornerstone of several drug coated balloon (DCB) technologies which have found an initial, broad therapeutic application in the treatment of stenosis of the superficial femoral artery (SFA). DCBs achieve drug delivery while leaving no implant behind and represent a new class of combination products developed at the interface of engineering, chemistry and medical science. This review article summarizes the development of the LUTONIX(r) drug coated balloon catheter. The introduction of DCB technology has provided clinicians and patients with new SFA treatment options while ongoing clinical evidence in additional vascular beds is generated. PMID- 28559094 TI - [Fear of falling: Validation of a measurement tool in Chilean elderly living in the community]. AB - : INTRODUCCIoN: Fear of falling, with or without previous falls history, is a risk factor for decreased mobility, disability, as well as a decreased quality of life, and can trigger the self-restriction of activities with loss of independence and functionality. Validated tools for measuring the fear of falling in the Chilean population is a needed to detect those at risk. There are currently no validated instruments to measure this phenomenon in Chile. The aim of this study is to validate the Spanish version of the short "Falls Efficacy Scale-International" (FES-I) in an elderly population living in the community in Chile. MATERIAL AND METHOD: A cross-sectional study was performed using applications at baseline and 4 weeks. The short FES-I was translated using the back-translation method, evaluated by a panel of experts, and piloted in 10 older adults. After the pilot study, the final version was applied to a sample of 113 elderly persons. Data analysis used measures of central tendency, and reliability and confirmatory factor analysis was used. RESULTS: The Spanish version of the short FES-I showed good reliability and validity in an elderly Chilean population. CONCLUSIONS: This falls risks measurement tool can be used by clinicians and researchers in order to determine the magnitude of the problem and the impact of fear of falling on falls, functionality, and quality of life of the elderly who live in the community. PMID- 28559096 TI - [Heart failure: Does it matter which speciality treats it?] PMID- 28559095 TI - [Anxiety in a representative sample of the Spanish population over 50 years-old]. AB - INTRODUCTION: Anxiety is common throughout the ageing process. The objective of this study is to estimate the prevalence of anxiety in a representative sample of the Spanish population over 50 years-old. MATERIAL AND METHODS: The data of this study come from the Pilot Study developed within the Longitudinal Ageing Study in Spain (ELES), in which a representative sample of the non-institutionalised Spanish population was evaluated. An analysis was performed on the data of 1086 people who answered the question "I am now going to read a list with a series of diseases or health problems. I would like you to tell me if your doctor has diagnosed any of them". The tools used were a questionnaire consisting of 218 questions, along with standardised tests, such as the Spanish version of the Mini Mental State Examination. RESULTS: Anxiety was reported to have been diagnosed at some time in 14.3% of the sample. The prevalence was higher in women than in men (77.8 vs. 22.2%), decreasing with age, and related to different chronic diseases. CONCLUSIONS: The results show that the prevalence of anxiety throughout the lifespan is noticeable in people over 50 years, and should be taken into account, especially in the female population and in those with chronic diseases. PMID- 28559097 TI - Von Willebrand Disease type 2 in pregnancy - A critical clinical association. AB - Von Willebrand disease (vWD) is the most common inherited bleeding disorder. Its association with pregnancy is infrequent. Here we report three cases of vWD associated with pregnancy. The clinical features of this combination are very suggestive. However, difficulties are still encountered during the diagnosis process. The first case was diagnosed for the first time during the patient's second pregnancy despite several episodes of vaginal bleeding and suggestive clinical symptomatology. The second case was diagnosed during childhood and the patient was properly managed during this pregnancy. The third case was diagnosed at a pre-anesthesia consult, at 36 weeks gestation, before performing a cesarean section on request, despite a clinical suggestive symptomatology. All of the cases received prophylactic treatment with Haemate P(r) (CSL Behring, Marburg, Germay) 24hours before birth. No serious bleeding episodes were noticed during delivery or postpartum period. Two healthy babies were delivered from the cases Nos. 2 and 3. It is acknowledged that vaginal bleeding is common during first trimester of pregnancy. However, this study indicates that repeated bleeding episodes corroborated with a clinical suggestive symptomatology (epistaxis, heavy menstrual period, and easy bruising after minor trauma) should orient the diagnosis to vWD. PMID- 28559098 TI - Oral lichenoid dysplasia and exophytic oral verrucous hyperplasia: Mythical entities of oral pathology. PMID- 28559099 TI - Forecasting model for Pea seed-borne mosaic virus epidemics in field pea crops in a Mediterranean-type environment. AB - An empirical model was developed to forecast Pea seed-borne mosaic virus (PSbMV) incidence at a critical phase of the annual growing season to predict yield loss in field pea crops sown under Mediterranean-type conditions. The model uses pre growing season rainfall to calculate an index of aphid abundance in early-August which, in combination with PSbMV infection level in seed sown, is used to forecast virus crop incidence. Using predicted PSbMV crop incidence in early August and day of sowing, PSbMV transmission from harvested seed was also predicted, albeit less accurately. The model was developed so it provides forecasts before sowing to allow sufficient time to implement control recommendations, such as having representative seed samples tested for PSbMV transmission rate to seedlings, obtaining seed with minimal PSbMV infection or of a PSbMV-resistant cultivar, and implementation of cultural management strategies. The model provides a disease forecast risk indication, taking into account predicted percentage yield loss to PSbMV infection and economic factors involved in field pea production. This disease risk forecast delivers location-specific recommendations regarding PSbMV management to end-users. These recommendations will be delivered directly to end-users via SMS alerts with links to web support that provide information on PSbMV management options. This modelling and decision support system approach would likely be suitable for use in other world regions where field pea is grown in similar Mediterranean-type environments. PMID- 28559100 TI - Identification, transmission and genomic characterization of a new member of the family Caulimoviridae causing a flower distortion disease of Rudbeckia hirta. AB - A disease of Rudbeckia hirta (Black-eyed Susan), characterized by severe flower deformation, was observed in Minnesota during 2010-2016. A previously undescribed virus species, named Rudbeckia flower distortion virus (RuFDV, family Caulimoviridae, genus unassigned), was determined to be the causal agent of the disease. Symptoms induced by RuFDV infection resemble those characteristic of phytoplasma-induced diseases, but no phytoplasmas were detected in RuFDV-infected R. hirta. The virus, and the disease were transmitted readily by mechanical inoculation and by the aphid Myzus persicae, but only to R. hirta. Virions of RuFDV are icosahedral, 42-45nm in diameter, and contain a circular 8222bp dsDNA genome containing seven open reading frames (ORFs). The ORFs 2-6 have 28-52% amino acid sequence identity to the movement protein (MP), coat protein (CP), aspartic protease (AP), reverse transcriptase (RT) and RNase H, and translational transactivator (TA) domains of known caulimoviruses. The two remaining ORFs (1 and 7) have no significant amino acid sequence similarity to known viruses. Although the RuFDV ORF 6 is significantly truncated relative to those of other known caulimoviruses, neither this nor the concomitant absence of characteristic virus-encoded cytoplasmic inclusion bodies appears to adversely affect aphid transmission of this virus. Phylogenetic analysis based on the sequence of the RT region revealed no close relationship to known members of the family Caulimoviridae. Based on sequence similarity, genome organization and phylogenetic relatedness, RuFDV appears to be distinct from any currently recognized taxonomic grouping in the family Caulimoviridae. PMID- 28559101 TI - Bovine enzootic haematuria from consumption of Pteris deflexa and Pteris plumula in northwestern Argentina. AB - Bovine enzootic haematuria (BEH) is caused by prolonged ingestion of toxic principles of bracken fern, essentially by Pteridium spp. In northwestern Argentina, this disease has a great economic impact ant it is attributed a chronic consumption to Pteridium arachnoideum. This paper describes two endemic areas for enzootic hematuria due to the consumption of Pteris deflexa and Pteris plumula. Two areas where P. deflexa and P. plumula are endemic, but free of Pteridium species, were devised and seven farms were visited. The disease was confirmed based on the presence of clinically affected animals. In four necropsies bleeding neoplastic lesions were observed in the mucosa of the urinary bladder. At phytochemical analysis, both ptaquiloside and pterosin B were found in P. deflexa and P. plumula. Thus, the consumption of P. deflexa and P. plumula can also cause BEH. PMID- 28559102 TI - Biomechanical characteristics of the anatomic rectangular tunnel anterior cruciate ligament reconstruction with a bone-patellar tendon-bone graft. AB - PURPOSE: To clarify 1) the force sharing between two portions of BTB graft in anatomic rectangular tunnel (ART) reconstruction and 2) the knee stability in ART technique under anterior tibial load. METHODS: Eleven fresh cadaveric knees were used. First, anterior-posterior (A-P) laxity was measured with Knee Laxity Tester(r) in response to 134 N of A-P tibial load at 20 degrees on the normal knees. Then ART ACL reconstruction was performed with a BTB graft. For graft, the patellar bone plug and tendon portion was longitudinally cut into half as AM and PL portions. After the tibial bone plug was fixed at femoral aperture, AM/PL portions were connected to the tension-adjustable force gauges at tibial tubercle, and were fixed with 10 N to each portion at 20 degrees . Then the tension was measured 1) under anterior tibial load of 134 N at 0, 30, 60, and 90 degrees , and 2) during passive knee extension from 120 to 0 degrees . Next the graft tension was set at 0, 10, 20, 30, or 40 N at 20 degrees , and the A-P laxity was measured by applying A-P load of 134 N. By comparing the laxity for the normal knee, the tension to restore the normal A-P laxity (LMP) was estimated. RESULTS: The AM force was significantly smaller at 0 degrees and larger at 90 degrees than the PL force under anterior load, while the force sharing showed a reciprocal pattern. During knee extension motion, the tension of both portions gradually increased from around 5 N to 20-30 N with knee extended. And the LMP was 1.6 +/- 1.0 N with a range from 0.3 to 3.5 N. CONCLUSION: The pattern of force sharing was similar to that in the normal ACL in response to anterior tibial load and during passive knee extension motion. LMP in this procedure was close to the tension in the normal ACL. LEVEL OF EVIDENCE: Level IV, a controlled-laboratory study. PMID- 28559103 TI - Comparison of quantitative evaluation between cutaneous and transosseous inertial sensors in anterior cruciate ligament deficient knee: A cadaveric study. AB - BACKGROUND: Recently several authors have reported on the quantitative evaluation of the pivot-shift test using cutaneous fixation of inertial sensors. Before utilizing this sensor for clinical studies, it is necessary to evaluate the accuracy of cutaneous sensor in assessing rotational knee instability. To evaluate the accuracy of inertial sensors, we compared cutaneous and transosseous sensors in the quantitative assessment of rotational knee instability in a cadaveric setting, in order to demonstrate their clinical applicability. METHODS: Eight freshly frozen human cadaveric knees were used in this study. Inertial sensors were fixed on the tibial tuberosity and directly fixed to the distal tibia bone. A single examiner performed the pivot shift test from flexion to extension on the intact knees and ACL deficient knees. The peak overall magnitude of acceleration and the maximum rotational angular velocity in the tibial superoinferior axis was repeatedly measured with the inertial sensor during the pivot shift test. Correlations between cutaneous and transosseous inertial sensors were evaluated, as well as statistical analysis for differences between ACL intact and ACL deficient knees. RESULTS: Acceleration and angular velocity measured with the cutaneous sensor demonstrated a strong positive correlation with the transosseous sensor (r = 0.86 and r = 0.83). Comparison between cutaneous and transosseous sensor indicated significant difference for the peak overall magnitude of acceleration (cutaneous: 10.3 +/- 5.2 m/s2, transosseous: 14.3 +/- 7.6 m/s2, P < 0.01) and for the maximum internal rotation angular velocity (cutaneous: 189.5 +/- 99.6 deg/s, transosseous: 225.1 +/- 103.3 deg/s, P < 0.05), but no significant difference for the maximum external rotation angular velocity (cutaneous: 176.1 +/- 87.3 deg/s, transosseous: 195.9 +/- 106.2 deg/s, N.S). CONCLUSIONS: There is a positive correlation between cutaneous and transosseous inertial sensors. Therefore, this study indicated that the cutaneous inertial sensors could be used clinically for quantifying rotational knee instability, irrespective of the location of utilization. PMID- 28559104 TI - Fast co-pyrolysis of waste newspaper with high-density polyethylene for high yields of alcohols and hydrocarbons. AB - Waste newspaper (WP) was first co-pyrolyzed with high-density polyethylene (HDPE) using pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) to enhance the yields of alcohols and hydrocarbons. The effects of WP: HDPE feed ratio (100:0, 75:25, 50:50, 25:75, 0:100) and temperature (500-800 degrees C) on products distribution were investigated and the interaction mechanism during co-pyrolysis was also proposed. Maximum yields of alcohols and hydrocarbons reached 85.88% (feed ratio 50:50wt.%, 600 degrees C). Hydrogen supplements and deoxidation by HDPE and subsequently fragments recombination result in the conversion of aldehydes and ketones into branched hydrocarbons. Radicals from WP degradation favor the secondary crack for HDPE products resulting in the formation of linear hydrocarbons with low carbon number. Hydrocarbons with activated radical site from HDPE degradation were interacted with hydroxyl from WP degradation promoting the formation of linear long chain alcohols. Moreover, co-pyrolysis significantly enhanced condensable oil qualities, which were close to commercial diesel No. 0. PMID- 28559105 TI - Anti-inflammatory effect of the monoterpene myrtenol is dependent on the direct modulation of neutrophil migration and oxidative stress. AB - Myrtenol is a bicyclic monoterpene with anti-inflammatory properties. However, the mechanisms involved are partially unknown. Here, we investigated the effect of myrtenol during experimental chronic arthritis and the possible modulating activity of oxidative stress and neutrophil migration. Complete Freund's Adjuvant (CFA)-sensitized rats were treated with vehicle (1 mL/kg, po), myrtenol (12.5, 25 or 50 mg/kg, po), indomethacin (10 mg/kg, po) or dexamethasone (0.4 mg/kg) followed by intra-articular injection of CFA (0.5 mg/mL, 50 MUL per joint). Then, paw edema and articular incapacitation (paw elevation time) were evaluated for 14 days. On the last day, a blood concentration superoxide dismutase (SOD) and nitrite was determined. In another experimental setting, human neutrophils were incubated with vehicle (sterile saline, 1 mL) or myrtenol (10-100 ng/mL) and the in vitro chemotaxis to N-formylmethionine-leucyl-phenylalanine (fMLP) (10-7 M/well) was evaluated. In addition, antiinflammatory effect of myrtenol was investigated in carrageenan-induced peritonitis. We found that CFA induced a prominent paw swelling and incapacitation of the joint, which were significantly prevented by myrtenol (P < 0.05). In addition, blood accumulation nitrite was attenuated by myrtenol when compared with vehicle-treated CFA group (P < 0.05). Furthermore, plasma levels of SOD were significantly increased by myrtenol versus vehicle-treated CFA group (P < 0.05). Moreover, fMLP-triggered neutrophil chemotaxis and carrageenan-induced peritonitis were markedly prevented by myrtenol (P < 0.05). Therefore, myrtenol showed anti-inflammatory and antinociceptive effects on experimental chronic arthritis, which seems to be related to the direct modulation of neutrophil migration and antioxidant activity. PMID- 28559106 TI - Disregarding hearing loss leads to overestimation of age-related cognitive decline. AB - Aging is associated with cognitive and sensory decline. While several studies have indicated greater cognitive decline among older adults with hearing loss, the extent to which age-related differences in cognitive processing may have been overestimated due to group differences in sensory processing has remained unclear. We addressed this question by comparing younger adults, older adults with good hearing, and older adults with poor hearing in several cognitive domains: working memory, selective attention, processing speed, inhibitory control, and abstract reasoning. Furthermore, we examined whether sensory-related cognitive decline depends on cognitive demands and on the sensory modality used for assessment. Our results revealed that age-related cognitive deficits in most cognitive domains varied as a function of hearing loss, being more pronounced in older adults with poor hearing. Furthermore, sensory-related cognitive decline was observed across different levels of cognitive demands and independent of the sensory modality used for cognitive assessment, suggesting a generalized effect of age-related hearing loss on cognitive functioning. As most cognitive aging studies have not taken sensory acuity into account, age-related cognitive decline may have been overestimated. PMID- 28559107 TI - EvoDevo: Changes in developmental controls underlying the evolution of animal body plans. PMID- 28559109 TI - Real-time visualization of immune cell clearance of Aspergillus fumigatus spores and hyphae. AB - Invasive aspergillosis (IA) is a disease of the immunocompromised host and generally caused by the opportunistic fungal pathogen Aspergillus fumigatus. While both host and fungal factors contribute to disease severity and outcome, there are fundamental features of IA development including fungal morphological transition from infectious conidia to tissue-penetrating hyphae as well as host defenses rooted in mechanisms of innate phagocyte function. Here we address recent advances in the field and use real-time in vivo imaging in the larval zebrafish to visually highlight conserved vertebrate innate immune behaviors including macrophage phagocytosis of conidia and neutrophil responses post germination. PMID- 28559108 TI - The nitric oxide donor RuBPY does not induce in vitro cross-tolerance with acetylcholine. AB - PURPOSE: We have demonstrated that RuBPY induces hypotensive effect in hypertensive rats, promotes vasodilation at low concentrations, and presents low cytotoxicity. This study aimed to verify whether the NO donor RuBPY synthesized in our laboratory induces in vitro tolerance and cross-tolerance to acetylcholine (ACh) and sodium nitroprusside (SNP) in rat cava vein. METHODS: We compared the maximum relaxing effect (ME) and potency (pD2) of RuBPY and nitroglycerin (GTN) in cava vein rings. Exposure to RuBPY or GTN induced in vitro tolerance. Western Blotting helped to evaluate phosphorylation of endothelial nitric oxide synthase (NOS3/eNOS) at the Ser1177 activation site and at the Thr495 inactivation site and to determine the ratio between active eNOS dimers and inactive eNOS monomers. The NO and ROS ratio was assessed by flow citometry. RESULTS: RuBPY did not induce cross-tolerance with ACh, and this NO donor took longer to induce tolerance than GTN. Only GTN elicited phosphorylation of eNOS at Ser1177 and Thr495. In contrast to results obtained with pre-exposure to GTN, pre-exposure to RuBPY did not reduce the formation of NO. The O2- ratio increased in cells incubated with GTN. CONCLUSIONS: A major contribution of this work has been to evaluate the phenomenon of tolerance induced by GTN and by the new ruthenium complex RuBPY in a venous bed. RuBPY is more advantageous than GTN: RuBPY takes longer to induce tolerance, does not induce endothelial dysfunction or cross tolerance to ACh, and generates lower amount of ROS. PMID- 28559110 TI - Protein restriction affects sperm number but not sperm viability in male ants. AB - Sperm cells are costly to produce; diet should therefore affect sperm number and/or viability. In non-social insects and vertebrates, there is compelling evidence that diet influences sperm production. Less is known about this relationship in eusocial hymenopterans (all ants and some bees and wasps), whose mating systems impose unique selective pressures on sperm production. Males face physiological constraints: they acquire all of the resources they will use in future reproductive efforts as larvae and emerge from the pupal stage with a fixed, non-renewable amount of sperm. Furthermore, males die shortly after copulation, but their genetic material persists for years since their spermatozoa are stored in their mates' spermathecae. We examined the effects of protein restriction during larval development on sperm number and viability in the Argentine ant Linepithema humile. We also looked at its impact on male development, adult mass, and adult fluctuating asymmetry. We found that protein restriction during larval development significantly reduced sperm production, but not sperm viability. It did not affect the number of males reared, male mass, or male asymmetry. However, males from protein-restricted nests developed much more slowly than males from protein-supplemented nests. These results suggest investing in sperm quality and in somatic growth, which enhances a male's ability to disperse and find a mate, are critical to successful male reproduction. PMID- 28559111 TI - Pattern recognition receptors in grass carp Ctenopharyngodon idella: I. Organization and expression analysis of TLRs and RLRs. AB - Pattern recognition receptors (PRRs) play indispensable roles in the immune responses against invading pathogens. In the present study, we systematically identified and characterized Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) as well as their adaptors in grass carp (Ctenopharyngodon idella). A comprehensive analysis of BLAST and other bioinformatics methods showed that C. idella TLR family consist of 21 members and their adaptors contain four members. Phylogenetic analyses confirmed the existence of six TLR subfamilies (TLR1, 3, 4, 5, 7 and 11 subfamily) in C. idella and revealed their homologous relationships with other species. Most C. idella TLRs possess three typical structural features of TLR protein family: LRR, TM and TIR domains. Meanwhile, RLR family consist of three conserved members (RIG-I, MDA5 and LGP2) as well as two adaptors (IPS-1 and STING) in C. idella. mRNA expression analyses of TLRs, RLRs and their adaptors indicated that most members are sustainably expressed in multiple tissues before and after grass carp reovirus (GCRV) or Aeromonas hydrophila infection, while TLR9, TLR20a/b, TLR25, TIRAP, SARM1 and STING are transiently expressed in specific tissues. TLRs are transmembrane receptors with few introns, while RLRs are cytoplasmic receptors with plenty of introns. TLRs and RLRs interact with adaptors to perform their functions via various signaling pathways. In conclusion, this study systematically explores the characteristics of TLRs and RLRs in C. idella and provides evidence for the response patterns after viral and/or bacterial infection in vivo. These results contribute to studying the regulation mechanisms of TLR and RLR signaling pathways, and deeply understanding fish immune responses against pathogen infection. PMID- 28559112 TI - Investigation of polymorphic transitions of piracetam induced during wet granulation. AB - Piracetam was investigated as a model API which is known to exhibit a number of different polymorphic forms. It is freely soluble in water so the possibility exists for polymorphic transformations to occur during wet granulation. Analysis of the polymorphic form present during lab-scale wet granulation, using water as a granulation liquid, was studied with powder X-ray diffraction and Raman spectroscopy as off-line and inline analysis tools respectively. Different excipients with a range of hydrophilicities, aqueous solubilities and molecular weights were investigated to examine their influence on these solution-mediated polymorphic transitions and experimental results were rationalised using molecular modelling. Our results indicated that as an increasing amount of water was added to the as-received piracetam FIII, a greater amount of the API dissolved which recrystallised upon drying to the metastable FII(6.403) via a monohydrate intermediary. Molecular level analysis revealed that the observed preferential transformation of monohydrate to FII is linked with a greater structural similarity between the monohydrate and FII polymorph in comparison to FIII. The application of Raman spectroscopy as a process analytical technology (PAT) tool to monitor the granulation process for the production of the monohydrate intermediate as a precursor to the undesirable metastable form was demonstrated. PMID- 28559114 TI - A double blind randomized prospective study comparing prilocaine versus ropivacaine in upper eyelid blepharoplasty. PMID- 28559113 TI - Decreased contralateral breast volume after mastectomy, adjuvant chemotherapy, and anti-estrogen therapy, in particular in breasts with high density. AB - Adjuvant chemotherapy and anti-estrogenic therapy can result in decreased volume of the contralateral breast, following mastectomy for the treatment of breast cancer. However, no data on the effect of adjuvant therapy on contralateral breast volume have previously been reported. We aimed to evaluate the extent to which adjuvant therapy and differences in breast density contribute to decreased breast volume. We conducted a prospective cohort study, selecting 40 nonconsecutive patients who underwent immediate breast reconstruction with mastectomy and expander insertion followed by expander replacement. We measured the contralateral breast volume before each procedure. The extent of the change was analyzed with respect to adjuvant therapy and breast density measured by preoperative mammography. The greatest decrease in breast volume was 135.1 cm3. The decrease in breast volume was significantly larger in the adjuvant therapy (+) group, particularly in patients with high breast density, than in the adjuvant therapy (-) group. Significant differences between the chemotherapy (+), tamoxifen (+) group and the chemotherapy (-), tamoxifen (+) group were not found. Breast density scores had a range of 2.0-3.3 (mean: 2.8). In breast reconstruction, particularly when performed in one stage, preoperative mammography findings are valuable to plastic surgeons, and possible decreases in the contralateral breast volume due to adjuvant therapy, particularly in patients with high breast density, should be considered carefully. PMID- 28559115 TI - Methylation dictates PI.f-specific CYP19 transcription in human glial cells. AB - CYP19 is the single copy gene encoding for the estrogen synthetic enzyme aromatase. Alternate splicing of the promoter is the regulatory mechanism of this gene. In the brain, estrogen is synthesized in neuronal and glial cells and the gene is mainly regulated by the alternate promoter PI.f. The hormone produced in this vicinity has been associated with maintaining normal brain functions. Previously, epigenetic regulation has been shown in the promoters PII and I.3 of CYP19 in adipocytes. In the present study, the methylation of PI.f in CYP19 was examined in glial cells. Treatment of the hypomethylating agent 5-aza 2'deoxycytidine increased CYP19 mRNA species in U87 MG cells while little changes were observed in the other glia cell lines. As PI.f is also chiefly used in T98G cells with high expression of CYP19, the methylation statuses of the promoter in these two cell models were compared. Our results showed that treating U87 MG cells with 10 MUM 5-aza-2'deoxycytidine significantly induced a ~10-fold increase in CYP19 transcription and ~80% increase in aromatase activity. In contrast, the same treatment did not change either endpoint in T98G cells. Further investigation illustrated the CpGs in PI.f were differentially methylated in the two cell lines; 63% and 37% of the 14 CpG sites were methylated in U87 MG and T98G cells respectively. In conclusion, this study illustrated that the brain specific PI.f derived CYP19 expression can be regulated by DNA methylation. PMID- 28559116 TI - Uterine ERalpha epigenetic modifications are induced by the endocrine disruptor endosulfan in female rats with impaired fertility. AB - High ERalpha activity may disrupt the window of uterine receptivity, causing defective implantation. We investigated whether implantation failures prompted by endosulfan are associated with aberrant ERalpha uterine expression and DNA methylation status during the pre-implantation period. ERalpha-dependent target genes that play a crucial role in the uterine receptivity for embryo attachment and implantation were also investigated. Newborn female rats received corn oil (vehicle, Control), 6 MUg/kg/d of endosulfan (Endo6) or 600 MUg/kg/d of endosulfan (Endo600) on postnatal days (PND) 1, 3, 5, and 7. On PND90, females were made pregnant and on gestational day 5 (GD5, pre-implantation period) uterine samples were collected. ERalpha expression was assessed at protein and mRNA levels by immunohistochemistry and real time RT-PCR, respectively. ERalpha transcript variants mRNA containing alternative 5'-untranslated regions (5'UTRs) were also evaluated. We searched for predicted transcription factors binding sites in ERalpha regulatory regions and assessed their methylation status by Methylation-Sensitive Restriction Enzymes-PCR technique (MSRE-PCR). The expression of the ERalpha-dependent uterine target genes, i.e. mucin-1 (MUC-1), insulin-like growth factor-1 (IGF-1), and leukemia inhibitory factor (LIF), was assessed by real time RT-PCR. Both doses of endosulfan increased the expression of ERalpha and its transcript variants ERalpha-OS, ERalpha-O, ERalpha-OT and ERalpha-E1. Moreover, a decreased DNA methylation levels were detected in some ERalpha regulatory regions, suggesting an epigenetic up-regulation of it transcription. ERalpha overexpression was associated with an induction of its downstream genes, MUC-1 and IGF-1, suggesting that endosulfan might alter the uterine estrogenic pathway compromising uterine receptivity. These alterations could account, at least in part, for the endosulfan-induced implantation failures. PMID- 28559117 TI - Myxoid Adrenocortical Adenoma: A report of two cases and literature review. AB - Myxoid adrenocortical adenomas are uncommon. There were only 61 cases reports documented, and the tumors are tended to be misdiagnosed in virtue of being rare and distinctive histological features. Recently we encountered two myxoid adrenocortical adenoma cases of a 31-year-old Chinese woman and a 45-year-old Chinese man. The patients did not receive further treatment after surgery and were still alive after following up for 20 months. Myxoid adrenocortical adenomas is extremely rare. Recognition of this entity would be beneficial for pathologists to avoid msidiagnosis, and unnecessary treatment. PMID- 28559118 TI - Tumor regression grades, K-RAS mutational profile and c-MET in colorectal liver metastases. AB - INTRODUCTION: Recently TRG, necrosis grade and the rate of viable cancer cells of colorectal liver metastases were correlated with the response to chemotherapy treatments, whereas K-RAS mutations and c-MET over-expression were correlated with the prognosis. METHODS: 58 resection specimens were assessed for regression grades. Patients undergone neo-adjuvant treatments were compared to patients who underwent therapy exclusively adjuvantly. We investigated the K-RAS mutational profile, the c-MET over-expression along with patients' survivals curves. RESULTS: Patients undergone neo-adjuvant treatment presented significant higher fibrosis rates and lower rates of viable cells. 36.7% of the patients had a K-RAS mutation and the 26.7% presented c-MET over-expression, but these features did not correlate with patients' clinical/pathological data. Survival analysis documented that K-RAS WT patients presenting c-MET over-expression had worse outcomes. CONCLUSION: Fibrosis and the rate of viable cells significantly correlate with the response to chemotherapy treatments. c-MET is a promising marker in K-RAS WT patients. PMID- 28559120 TI - The emerging role of lawyers as addiction 'quasi-experts'. AB - This paper examines a discrete set of issues pertaining to the constitution of addiction in law. Based on qualitative interviews undertaken with lawyers in Australia and Canada, I examine how addiction figures in lawyers' daily practice. Drawing on ideas from science and technology studies scholars Sheila Jasanoff, Michael Lynch and Bruno Latour, and building on recent research I undertook on legal addiction veridiction, I explore the constitution of addiction 'facts' in law. I examine how and when lawyers claim to make decisions about addiction in the course of their legal practice. Lawyers report playing a central role in the making of decisions about addiction, at multiple stages of the legal process including: before taking cases on, while running cases in court, and while negotiating and/or settling cases. I argue that these decisions can be properly described as 'quasi-expert' determinations with important parallels to scientific, technological and medical claims often made in legal settings by more conventional 'expert witnesses'. I call these 'quasi-expert' decisions because they are decisions of the kind that might be assumed to be the purview of scientific or medical experts and because they have tangible implications for clients. Lawyers uniquely constitute addiction in unique ways, drawing on a combination of factors, including their own experience with and observations about addiction, the experiences of family members who have experienced alcohol and other drug problems, relevant legal concepts and frameworks, popular and scientific claims about addiction, emotions and values, including the gender politics of alcohol and other drug addiction. These addiction 'facts' can have a range of material and discursive effects, including potentially adverse implications for people characterised as 'addicts'. I conclude the paper with a discussion of some implications of these practices, and with reflections on how we might address these issues in future research. PMID- 28559119 TI - Clinicopathologic features and prognostic implications of MYBL2 protein expression in pancreatic ductal adenocarcinoma. AB - MYBL2 (B-MYB), a member of the MYB family of transcription factor genes, regulates the expression of genes in the process of tumorigenesis. Many studies have shown that MYBL2 is high expresssion in several human malignancies including pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC is still unclear. The present study is designed to investigate MYBL2 expression levels and prognostic significance in PDAC patients. We assessed MYBL2 expression level by immunohistochemistry in tumor tissues from 93 PDAC patients undergoing curative resection. The association of MYBL2 expression with clinicopathological parameters was evaluated by Pearson's chi-square (chi2) test, Fisher's exact test, and Spearman's rank. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of MYBL2 expression on survival. The expression of MYBL2 was significantly higher in PDAC cells compared with adjacent non-cancerous tissues (P=0.000). The overexpression of MYBL2 in the tumor tissues was significantly correlated with a higher T classification (p=0.002), peri-neural invasion (PNI) (p=0.013) and vital status (p=0.045). Kaplan-Meier analysis indicated that high MYBL2 expression was significantly associated with shorter overall survival times in PDAC patients. Moreover, univariate and multivariate analysis confirmed MYBL2 expression (P=0.010), histological grade (P=0.001) as independent prognostic factors in PDAC. These results suggested that overexpression of MYBL2 might serve as a novel prognostic biomarker in PDAC patients. PMID- 28559121 TI - Calpain-2/p35-p25/Cdk5 pathway is involved in the neuronal apoptosis induced by polybrominated diphenyl ether-153. AB - Polybrominated diphenyl ethers (PBDEs) have been demonstrated to induce neurotoxicity in experimental rats and mice, with neuronal apoptosis as one of the major mechanisms, however, the mechanisms underlying PBDEs-induced neuronal apoptosis remain unclear. In this study, we aimed to investigate the role of calpain/p35-p25/Cdk5 pathway in BDE-153-induced neuronal apoptosis in the hippocampus and primary neurons in rats. Results showed that compared to the controls, neuronal apoptosis was significantly increased in vivo and ex vivo, as manifested by the increased hippocampus TUNEL-positive cell rates, apoptotic neurons in Hoechst and AO/EB staining, and the increased LDH activity and percentage of Annexin V-positive cells in rat hippocampus and primary neurons. Calpain activity was significantly increased in all the BDE-153-treated groups in vivo and ex vivo when compared to non-treatment controls. In addition, we showed that calpain-2 accounted for the calpain activation instead of calpain-1, as demonstrated by the up-regulated mRNA and protein expressions in calpain-2 but not calpain-1. Activated calpain truncated p35 into p25, which resulted in the p25/Cdk5 formation and activation. Calpain inhibitor PD150606 or p25/Cdk5 inhibitor Roscovitine relieved neuronal apoptosis mainly via inhibiting the p25/Cdk5 activation. Overall, the findings suggested that calpain-2/p35-p25/Cdk5 pathway was involved in BDE-153-induced neuronal apoptosis, which provides novel insight into the mechanisms of PBDE neurotoxicity. PMID- 28559122 TI - Reprint of: Overview of avian toxicity studies for the Deepwater Horizon Natural Resource Damage Assessment. AB - The Oil Pollution Act of 1990 establishes liability for injuries to natural resources because of the release or threat of release of oil. Assessment of injury to natural resources resulting from an oil spill and development and implementation of a plan for the restoration, rehabilitation, replacement or acquisition of natural resources to compensate for those injuries is accomplished through the Natural Resource Damage Assessment (NRDA) process. The NRDA process began within a week of the Deepwater Horizon oil spill, which occurred on April 20, 2010. During the spill, more than 8500 dead and impaired birds representing at least 93 avian species were collected. In addition, there were more than 3500 birds observed to be visibly oiled. While information in the literature at the time helped to identify some of the effects of oil on birds, it was not sufficient to fully characterize the nature and extent of the injuries to the thousands of live oiled birds, or to quantify those injuries in terms of effects on bird viability. As a result, the US Fish and Wildlife Service proposed various assessment activities to inform NRDA injury determination and quantification analyses associated with the Deepwater Horizon oil spill, including avian toxicity studies. The goal of these studies was to evaluate the effects of oral exposure to 1-20ml of artificially weathered Mississippi Canyon 252 oil kg bw-1 day-1 from one to 28 days or one to five applications of oil to 20% of the bird's surface area. It was thought that these exposure levels would not result in immediate or short-term mortality but might result in physiological effects that ultimately could affect avian survival, reproduction and health. These studies included oral dosing studies, an external dosing study, metabolic and flight performance studies and field-based flight studies. Results of these studies indicated changes in hematologic endpoints including formation of Heinz bodies and changes in cell counts. There were also effects on multiple organ systems, cardiac function and oxidative status. External oiling affected flight patterns and time spent during flight tasks indicating that migration may be affected by short-term repeated exposure to oil. Feather damage also resulted in increased heat loss and energetic demands. The papers in this special issue indicate that the combined effects of oil toxicity and feather effects in avian species, even in the case of relatively light oiling, can significantly affect the overall health of birds. PMID- 28559123 TI - Biological dysrhythm in remitted bipolar I disorder. AB - BACKGROUND: Recent treatment guidelines support treatment of biological rhythm abnormalities as a part of treatment of bipolar disorder, but still, literature examining various domains (Sleep, Activity, Social, and Eating) of biological rhythm and its clinical predictors are less. OBJECTIVES: The main aim of our study is to compare various domains of biological rhythm among remitted bipolar I subjects and healthy controls. We also explored for any association between clinical variables and biological rhythm among bipolar subjects. METHODS: 40 subjects with Bipolar I disorder and 40 healthy controls who met inclusion and exclusion criteria were recruited for the study. Diagnoses were ascertained by a qualified psychiatrist using MINI 5.0. Sociodemographic details, biological rhythm (BRIAN-Biological Rhythm Interview of assessment in Neuropsychiatry) and Sleep functioning (PSQI- Pittsburgh Sleep Quality Index) were assessed in all subjects. RESULTS: Mean age of the Bipolar subjects and controls were 41.25+/ 11.84years and 38.25+/-11.25 years respectively. Bipolar subjects experienced more biological rhythm disturbance when compared to healthy controls (total BRIAN score being 34.25+/-9.36 vs 28.2+/-6.53) (p=0.002). Subsyndromal depressive symptoms (HDRS) had significant positive correlation with BRIAN global scores(r=0.368, p=0.02). Linear regression analysis showed that number of episodes which required hospitalization (beta=0.601, t=3.106, P=0.004), PSQI (beta=0.394, t=2.609, p=0.014), HDRS (beta=0.376, t=2.34, t=0.036) explained 31% of variance in BRIAN scores in remitted bipolar subjects. CONCLUSION: Biological rhythm disturbances seem to persist even after clinical remission of bipolar illness. More studies to look into the impact of subsyndromal depressive symptoms on biological rhythm are needed. PMID- 28559124 TI - Effect of an anaesthetic screening drape on vertical laminar airflow. AB - BACKGROUND: Effective operating room ventilation is required to reduce the risk of surgical site infection. Vertical laminar airflow from above the surgical field provides a source of 'ultra-clean' air, carrying contaminants away from the operative site. An anaesthetic screening drape is often used to shield the operative site from the anaesthetic team, and this defies the principles of vertical laminar airflow. METHODS: A mock theatre set-up for a total knee replacement was constructed with and without the use of an anaesthetic screening drape. A 10*10 grid was set up within the surgical canopy, and the downward air velocities were measured using a hot air anemometer. The average velocity and range of velocities at each grid point were measured in both set-ups. The range was used as the marker of turbulence. FINDINGS: Within the surgical canopy, the average downward air velocity was 0.35m/s. With the use of an anaesthetic screening drape, the mean downward air velocity in the area above the patient decreased from 0.36m/s to 0.29m/s (P=0.02). In the area immediately above the drape, the average velocity was 0.18m/s. Turbulent air currents were produced in the areas adjacent to the drape near to the mock surgical site. For the area above the patient, the range increased from an average of 0.034m/s to 0.05m/s (P=0.04). In the area directly above the drape, the average range was 0.08m/s. CONCLUSION: Use of an anaesthetic screening drape causes disruption to normal vertical laminar airflow. PMID- 28559125 TI - Respiratory-syncytial-virus- and rhinovirus-related bronchiolitis in children aged <2 years in an English district general hospital. AB - BACKGROUND: Bronchiolitis is the most common reason for hospitalization in young children. In addition to respiratory syncytial virus (RSV), other viruses have been increasingly implicated. Guidance on testing has also changed. AIMS: To compare clinicopathological outcomes in young children admitted with bronchiolitis due to RSV in comparison with rhinovirus (RV), and identify associated risk/epidemiological factors. METHODS: Children aged less than two years admitted to hospital with a clinical diagnosis of bronchiolitis with positive results for either RSV or RV were included in this study. Polymerase chain-reaction-negative cases using an extended respiratory virus panel served as a control group. Retrospective data were collected on sex, risk factors, respiratory support, intravenous fluids and antibiotics. Outcomes such as length of stay (LOS) and need for transfer to the high-dependency unit/paediatric intensive care unit were included. FINDINGS: Two hundred and twenty-seven out of 437 nasopharyngeal aspirate samples were positive for either RSV (N = 162) or RV (N = 65). The median age of cases was three months and 75% had at least one risk factor. Risk factors were higher in the RV group (P = 0.004). RV accounted for the majority of cases outside the RSV season (P < 0.01). RV-associated bronchiolitis had a longer LOS (more than seven days) (P < 0.05) and increased need for chest X-rays and/or antibiotics (P < 0.05). Use of intravenous fluids and respiratory support were higher in the RV group, but the difference was not significant. CONCLUSIONS: RV is the second most common pathogen associated with bronchiolitis and is isolated all year round. This may be important in those with risk factors resulting in prolonged LOS. Further research is necessary to establish the exact role of RV in this common condition, particularly outside the traditional RSV season. PMID- 28559127 TI - Effects of maternal hypoglycemia on fetal eye and skeleton development in rats. AB - The relationship between insulin-induced maternal hypoglycemia and teratogenicity was investigated in detail. We injected 4 different forms of insulin (insulin human, aspart, glargine, and detemir) subcutaneously at 1 or 2 dose levels to Sprague-Dawley rats from Days 6 to 11 of pregnancy, measured blood glucose levels, and conducted fetal examination. In the insulin human and aspart (low dose) groups, while severe hypoglycemia (approximately 50mg/dL) was seen, it lasted only 6h and no fetal anomalies were observed. Fetal axial skeleton anomalies were observed in the aspart (high dose) group, which exhibited intermediate-duration of severe hypoglycemia (9h). Eye and axial skeleton anomalies were observed in the glargine and detemir groups, which exhibited continuous severe hypoglycemia (>=9h). These results revealed that insulin induced maternal hypoglycemia caused fetal eye and skeleton anomalies and the causative key factors were duration of maternal severe hypoglycemia. PMID- 28559126 TI - Caring for a patient with rabies: implications of the Milwaukee protocol for infection control and public health measures. AB - This article discusses the infection control and public health measures taken whilst managing a case of laboratory-confirmed rabies, and the challenges faced in implementing these measures. Case management requires intensive multi disciplinary co-ordination. The Milwaukee protocol, which to date has five reported human rabies survivors associated with its use, has been suggested as a potential management pathway for human rabies. Consensus among hospital and public health clinicians would aid future deployment of this approach in selected cases. PMID- 28559128 TI - Performance of the modified Richmond Agitation Sedation Scale in identifying delirium in older ED patients. AB - BACKGROUND: Delirium in older emergency department (ED) patients is associated with severe negative patient outcomes and its detection is challenging for ED clinicians. ED clinicians need easy tools for delirium detection. We aimed to test the performance criteria of the modified Richmond Agitation Sedation Scale (mRASS) in identifying delirium in older ED patients. METHODS: The mRASS was applied to a sample of consecutive ED patients aged 65 or older by specially trained nurses during an 11-day period in November 2015. Reference standard delirium diagnosis was based on Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria, and was established by geriatricians. Performance criteria were computed. Analyses were repeated in the subsamples of patients with and without dementia. RESULTS: Of 285 patients, 20 (7.0%) had delirium and 41 (14.4%) had dementia. The sensitivity of an mRASS other than 0 to detect delirium was 0.70 (95% confidence interval, CI, 0.48; 0.85), specificity 0.93 (95% CI 0.90; 0.96), positive likelihood ratio 10.31 (95% CI 6.06; 17.51), negative likelihood ratio 0.32 (95% CI 0.16; 0.63). In the sub-sample of patients with dementia, sensitivity was 0.55 (95% CI 0.28; 0.79), specificity 0.83 (95% CI 0.66; 0.93), positive likelihood ratio 3.27 (95% CI 1.25; 8.59), negative likelihood ratio 0.55 (95% CI 0.28; 1.06). CONCLUSION: The sensitivity of the mRASS to detect delirium in older ED patients was low, especially in patients with dementia. Therefore its usefulness as a stand-alone screening tool is limited. PMID- 28559129 TI - One-step cross-genogroup multiplex RT-qPCR with an internal control system for the detection of infectious pancreatic necrosis virus (IPNV). AB - Infectious pancreatic necrosis virus (IPNV) causes great losses in fish hatcheries world-wide. The detection of IPNV can be challenging in certain circumstances, particularly due to low viral load and the genetic variability of this RNA virus. For the first time, this project created a quantitative triplex real-time reverse transcription PCR (RT-qPCR), including an endogenous control system, for specific, sensitive and rapid detection of IPNV in routine diagnostics. Multiple sequence alignment of 46 nucleotide sequences of the segment A genome obtained from the NCBI database allowed the design of two RT qPCR systems covering the IPNV genogroup 1 and genogroups 2-5, respectively. The completed triplex RT-qPCR including a salmonid-specific endogenous control showed high specificity and an analytical sensitivity of 20-40 oligonucleotide copies. Testing of dilution series of virus-loaded cell culture suspensions proved equality of the triplex RT-qPCR with virus detection in cell culture and a higher sensitivity than conventional RT-PCR in field samples. In comparative studies of a total of 77 field samples tested, 51 showed identical positive and 19 identical negative results in cell culture and the triplex RT-qPCR. However, seven other samples yielded positive results in the triplex RT-qPCR, but negative results in cell culture. PMID- 28559130 TI - Cholangiocarcinoma occurring in a patient with type 1 Gaucher disease treated with velaglucerase alfa enzyme replacement therapy: First case report. PMID- 28559131 TI - Response to gonadotrophins differs for gilts from female- and male-biased litters. AB - In several species, females masculinised by abnormal androgen exposure in utero have poor reproductive performance and gilts born into litters with a male bias are likely exposed to greater androgen concentrations prenatally than gilts born into female-biased litters. At 24h of age, piglet plasma testosterone concentrations in gilts from male-biased litters (>60% male; n=22) or female biased litters (>60% female; n=27) were not different. At 18 wks of age, all gilts received an injection of 400IU equine chorionic gonadotrophin plus 200IU human chorionic gonadotrophin to stimulate oestrus. Two weeks after the injection gilts were slaughtered and ovaries collected for determination of numbers of corpora lutea (CL). Compared to gilts from female-biased litters, gilts from male biased litters were more likely to ovulate (86.0% vs 59.5%, P=0.047) and had more CL (13.1+/-1.5 vs 7.2+/-1.7, P=0.015). The present data indicate an effect of birth litter sex-bias on pre-pubertal physiological development, possibly involving organisational effects at the ovarian cellular level impacting on future ovarian function. Potential impacts on subsequent fertility remain to be determined. PMID- 28559132 TI - Effect of reduced glutathione supplementation in semen extender on tyrosine phosphorylation and apoptosis like changes in frozen thawed Hariana bull spermatozoa. AB - To provide new insights into the mechanisms through which reduced glutathione (GSH) is able to protect spermatozoa, we tested the hypothesis that cryocapacitation and apoptosis like changes can contribute to the negative effect of freezing and thawing on bull spermatozoa, and that GSH prevent this damage. Having known protective effects of GSH in terms of a potent antioxidant, we evaluated capacitation, tyrosine phosphorylation and apoptosis like changes in bull spermatozoa after freezing and thawing in egg yolk tris glycerol extender containing (0.5m M-GSH-T1 & 1mM GSH-T2) and without GSH serving as the control (C). Forty ejaculates were collected from four Hariana bulls and were pooled due to non significant variations among the bull ejaculates for the evaluation of sperm attributes. Capacitation like changes, tyrosine phosphorylation, localization of tyrosine phosphorylated proteins, apoptosis like changes in terms of mitochondrial transmembrane potential and DNA fragmentation after final dilution, 4h of equilibration at 4 degrees C and 24h after freezing and thawing were evaluated. GSH supplementation at 0.5mM showed significant reduction in B- and AR- pattern spermatozoa during all stages of semen freezing and thawing. Immunoblot revealed six proteins which were tyrosine phosphorylated and protein of 30 and 75kDa (p30, p75) were the major tyrosine phosphorylted proteins. On further analysis, the p30 showed differential variation in intensity in all the three groups after freezing and thawing. Positive immune reactivity for tyrosine phosphorylated proteins was found in neck, middle piece and post-acrosomal regions of spermatozoa. Addition of 0.5mM GSH decreased percentage of spermatozoa showing fragmented DNA and increased the percentage of spermatozoa having high transmembrane mitochondrial potential (P<0.05). This study demonstrates that GSH favours survival of bull spermatozoa by interfering with apoptotic and cryocapacitation pathways, and thereby protects the spermatozoa from deleterious effects of cryopreservation. The findings of the study indicated that GSH at 0.5mM can be effectively used as an additive in bull semen extender for freezing and thawing. PMID- 28559133 TI - Medical image classification based on multi-scale non-negative sparse coding. AB - With the rapid development of modern medical imaging technology, medical image classification has become more and more important in medical diagnosis and clinical practice. Conventional medical image classification algorithms usually neglect the semantic gap problem between low-level features and high-level image semantic, which will largely degrade the classification performance. To solve this problem, we propose a multi-scale non-negative sparse coding based medical image classification algorithm. Firstly, Medical images are decomposed into multiple scale layers, thus diverse visual details can be extracted from different scale layers. Secondly, for each scale layer, the non-negative sparse coding model with fisher discriminative analysis is constructed to obtain the discriminative sparse representation of medical images. Then, the obtained multi scale non-negative sparse coding features are combined to form a multi-scale feature histogram as the final representation for a medical image. Finally, SVM classifier is combined to conduct medical image classification. The experimental results demonstrate that our proposed algorithm can effectively utilize multi scale and contextual spatial information of medical images, reduce the semantic gap in a large degree and improve medical image classification performance. PMID- 28559134 TI - Exosomes isolated from sera of mice fed Lactobacillus strains affect inflammatory cytokine production in macrophages in vitro. AB - Orally administered Lactobacillus strains, including L. plantarum No.14 and L. rhamnosus GG, reportedly reduce inflammatory cytokine production in mice. The present study tested our idea that circulating exosomes mediate the action of Lactobacillus strains. The lipopolysaccharide-induced production of TNF-alpha and IL-6 in vitro was attenuated in peritoneal exudate cells (PECs) isolated from C57BL/6N mice that had been fed L. plantarum No.14. When PECs were cultured for 24 h with exosomes isolated from the serum of mice fed L. plantarum No.14 or L. rhamnosus GG, accumulation of both TNF-alpha and of the corresponding mRNA was lowered. Growth in the presence of these exosomes also decreased the production of TNF-alpha and IL-6 by the murine macrophage cell line RAW264.7. In contrast, supplementation with exosome-depleted serum of mice fed L. plantarum No.14 or L. rhamnosus GG failed to affect the production of TNF-alpha and IL-6 by RAW264.7 cells. When PECs and RAW264.7 cells were cultured for 24 h with PKH67-labeled exosomes isolated from murine serum, fluorescent signal was observed inside the cells, suggesting that these cells incorporate serum exosomes. We propose that the anti-inflammatory activity of orally administered L. plantarum No.14 and L. rhamnosus GG is mediated, at least in part, by circulating exosomes. PMID- 28559135 TI - The NADPH-oxidase AtRbohI plays a positive role in drought-stress response in Arabidopsis thaliana. AB - As the major resource of reactive oxygen species (ROS), the NADPH oxidases (Rbohs) have been shown to play important roles in plant cells under normal growth and stress conditions. Although many family members of Rbohs were studied, little is known about the function of RbohI in Arabidopsis thaliana. Here, we report that exogenous ABA application decreases RbohI expression and mannitol significantly increases RbohI expression at transcript level. The RbohI transcripts were strongly detected in dry seeds and roots. The loss-of-function mutant rbohI exhibited sensitivity to ABA and mannitol stress during germination. Furthermore, the lateral root growth of rbohI was severely inhibited after treatment with mannitol stress. Overexpression of RbohI in Arabidopsis significantly improves the drought tolerance. Moreover, more H2O2 accumulated in RbohI overexpressors than in wild type plants in response to mannitol stress. Our conclusion is that AtRbohI functions in drought-stress response in Arabidopsis thaliana. PMID- 28559136 TI - Intradiencephalon injection of histamine inhibited the recovery of locomotor function of spinal cord injured zebrafish. AB - Human spinal cord injury (SCI) usually causes irreversible disability beneath the injured site due to poor neural regeneration. On the contrary, zebrafish show significant regenerative ability after SCI, thus is usually worked as an animal model for studying neuroregeneration. Most of the previous SCI studies focused on the local site of SCI, the supraspinal-derived signals were rarely mentioned. Here we showed that intradiencephalon injection of histamine (HA) inhibited the locomotor recovery in adult zebrafish post-SCI. Immunofluorescence results showed that intradiencephalon HA administration increased the activated microglia 3 days post injury (dpi), promoted the proliferation of radial glial cells at 7 dpi and affected the morphology of radial glial cells at 11 dpi. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) results showed that intradiencephalon HA administration also reduced the expression of neurotrophic factors including brain-derived neurotrophic factor (BDNF) and insulin-like growth factor1 (IGF-1) at the lesion site, however, had no effect on the expression of pro-inflammatory factors such as TNF-alpha and IL-1 beta. Hence, our data suggested that exogenous intradiencephalon HA retarded locomotor recovery in spinal cord injured zebrafish via modulating the repair microenvironment. PMID- 28559137 TI - Archaeal Lsm rings as stable self-assembling tectons for protein nanofabrication. AB - We have exploited the self-assembling properties of archaeal-derived protein Lsmalpha to generate new supramolecular forms based on its stable ring-shaped heptamer. We show that engineered ring tectons incorporating cysteine sidechains on obverse faces of the Lsmalpha7 toroid are capable of forming paired and stacked formations. A Cys-modified construct, N10C/E61C-Lsmalpha, appears to organize into disulfide-mediated tube formations up to 45 nm in length. We additionally report fabrication of cage-like protein clusters through conjugation of Cu2+ to His-tagged variants of the Lsmalpha7 tecton. These 400 kDa protein capsules are seen as cube particles with visible pores, and are reversibly dissembled into their component ring tectons by EDTA. The beta-rich Lsmalpha supramolecular assemblies described are amenable to further fusion modifications, or for surface attachment, so providing potential for future applications that exploit the RNA-binding capacity of Lsm proteins, such as sensing applications. PMID- 28559138 TI - Transcription factor FOXO1 promotes cell migration toward exogenous ATP via controlling P2Y1 receptor expression in lymphatic endothelial cells. AB - Sprouting migration of lymphatic endothelial cell (LEC) is a pivotal step in lymphangiogenic process. However, its molecular mechanism remains unclear including effective migratory attractants. Meanwhile, forkhead transcription factor FOXO1 highly expresses in LEC nuclei, but its significance in LEC migratory activity has not been researched. In this study, we investigated function of FOXO1 transcription factor associated with LEC migration toward exogenous ATP which has recently gathered attentions as a cell migratory attractant. The transwell membrane assay indicated that LECs migrated toward exogenous ATP, which was impaired by FOXO1 knockdown. RT-PCR analysis showed that P2Y1, a purinergic receptor, expression was markedly reduced by FOXO1 knockdown in LECs. Moreover, P2Y1 blockage impaired LEC migration toward exogenous ATP. Western blot analysis revealed that Akt phosphorylation contributed to FOXO1 dependent LEC migration toward exogenous ATP and its blockage affected LEC migratory activity. Furthermore, luciferase reporter assay and ChIP assay suggested that FOXO1 directly bound to a conserved binding site in P2RY1 promoter and regulated its activity. These results indicated that FOXO1 serves a pivotal role in LEC migration toward exogenous ATP via direct transcriptional regulation of P2Y1 receptor. PMID- 28559139 TI - Effects of phenylpropanoids on human organic anion transporters hOAT1 and hOAT3. AB - Human organic anion transporters hOAT1/SLC22A6 and hOAT3/SLC22A8 are highly expressed on the basolateral membrane of renal proximal tubules and mediate tubular uptake of anionic drugs from blood. They play an important role for drug disposition, and therefore close studies of their ligand recognition are important for drug therapy and development. In this study, we performed uptake experiments using HEK293 and fluorescent anion 6-carboxyfluorescein to asses the effects of phenylpropanoids on hOAT1 and hOAT3. We found that phenylpropanoids, 3 (4'-isopentenyloxyphenyl)-benzoic acid (IBA), 3-(4'-isopentenyloxy-3' methoxyphenyl)-benzoic acid (IMBA), and 3-(4'-geranyloxy-3'-methoxy phenyl) benzoic acid (GMBA) inhibited hOAT1 and hOAT3. The Ki values for hOAT1 were comparable to that of probenecid, a strong inhibitor of hOAT1 and hOAT3. While IBA demonstrated competitive inhibition, IMBA and GMBA showed mixed-type inhibition. After preincubation and washout, the inhibitory effects remained with IMBA and GMBA but not IBA, suggesting that the functional group at 3'-position is responsible for these differences. In conclusion, IBA, IMBA, and GMBA are inhibitors of hOAT1 and hOAT3. PMID- 28559140 TI - Bicarbonate alters cellular responses in respiration assays. AB - Metabolic assay buffers often omit bicarbonate, which is susceptible to alkalinisation in an open environment. Here, we assessed the effect of including bicarbonate in respirometry experiments. By supplementing HEPES-buffered media with low concentrations of bicarbonate, we found increased respiration in adipocytes and hepatocytes, but not myotubes. This was observed across multiple respirometry platforms and was independent of effects on enhanced insulin sensitivity, pH drift, or mitochondrial function. Permeabilised cell experiments suggest that bicarbonate increases substrate availability, likely by acting as a cofactor for carboxylase enzymes. This emphasises the importance of buffer choice in experimental biology. PMID- 28559141 TI - Establishment of a refined culture method for rat colon organoids. AB - BACKGROUND: Methods for the artificial three-dimensional (3D) culture of mouse and human small-intestinal and large-intestinal stem cells have been established with CD24+ or Paneth cell niches. In contrast, no studies have established stable 3D culture for rat colon stem cells. In this study, we established an advanced method for efficient rat colonic stem cell culture. METHODS: Using various tissue homogenates, we investigated the colonic organoid forming capacity under the TMDU protocol immediately adjacent to Ootani's 3D culture assembly in the same culture dish. Next, we examined whether the supernatant from the colon could be replaced by a colon homogenate. Finally, we identified the bioactive substances that were indispensable for efficient organoid culture using protein purification by three step column chromatography and proteomic analysis with a quantitative nanoflow liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: By combining Ootani's method with the TMDU protocol, we established a refined culture method for Lewis rat colon organoids, which we refer to as the modified TMDU protocol. Furthermore, we confirmed that PGE2 and galection-4 promoted rat colonic organoid formation. CONCLUSIONS: We established efficient rat colonic stem cell cultures in vitro. This success will contribute to the study of rat intestinal-disease models. PMID- 28559143 TI - Rectus femoris muscle atrophy and recovery caused by preoperative pretibial traction in femoral shaft fractures-comparison between traction period. AB - BACKGROUND: Skeletal traction is performed to temporarily stabilize fracture sites before surgery in patients with femoral fracture. To date, however, there is no study evaluating the difference in the degree of the recovery, of the muscle strength, as well as muscle atrophy following skeletal traction. The purpose of this study was to compare the degree of recovery of rectus femoris muscle strength after surgery in association with muscle atrophy by analyzing the duration of preoperative tibial traction, age and sex in patients with femoral fracture. HYPOTHESIS: Rectus femoris muscle atrophy will progress depending on the duration of preoperative tibial traction, age and sex in patients with femoral fracture. PATIENTS AND METHOD: Thirty-one patients who underwent preoperative pretibial skeletal traction and intramedullary nailing were divided into two groups according to the traction period: group A (n=12) with a duration of traction of <7 days (mean: 4.08+/-1.78 days) and group B (n=19) >=7 days (mean: 13.63+/-7.17 days). The degree of muscle atrophy and recovery were compared between the two groups, according to age and gender. The degree of muscle atrophy was measured by the difference in thickness of the rectus femoris between pre- and post-traction using ultrasound. The degree of muscle recovery was evaluated by the Q-setting and heel off time. Clinical outcome was evaluated by the non-union rate and Lysholm score. RESULTS: The degree of muscle atrophy was 0.99+/-0.14mm in group A and 2.22+/-0.11mm in group B (P<0.001). The Q setting time was 4.83+/-0.94 days in group A and 6.56+/-1.38 days in group B (P=0.001). Heel off time was also shorter in group A at 2.58+/-0.90 days, taking 3.72+/-1.27 days in group B (P=0.012). The recovery rate in the rectus femoris was significantly higher in group A than in group B (P<0.001). There was no significant difference in non-union rate between group A and B (P=0.672) but the mean Lysholm score at the last follow-up was significantly higher in group A than in group B (P=0.006). However, no significant differences were detected in the mean thickness of the rectus femoris, Q-setting, and heel off time between the different age and gender groups (P<0.05). CONCLUSIONS: The prolonged duration of preoperative skeletal traction indicates not only that the resulting disuse atrophy would progress further but also that the muscle atrophy would be accelerated more rapidly for shorter periods of time, based on a cut-off value of 7 days. In addition, the rate of rectus femoris muscle recovery and clinical outcomes were lower in patients undergoing traction for longer periods of time. This indicates that it would be effective for increasing the rate of the recovery and minimizing the occurrence of post surgical complications if surgeons could perform surgery at the earliest possible opportunity following traction, within seven days after the onset of trauma. LEVEL OF EVIDENCE: IV, retrospective cohort study. PMID- 28559142 TI - AG1296 enhances plaque stability via inhibiting inflammatory responses and decreasing MMP-2 and MMP-9 expression in ApoE-/- mice. AB - BACKGROUND: Atherosclerosis is a chronic process that progresses to unstable plaques. Plaque rupture leads to deleterious consequences such as acute coronary syndrome, thrombosis and stroke. AG1296 is a potent tyrosine kinase inhibitor which is able to block PDGF-PDGFR signaling pathway. This study aims to assess the effect of AG1296 on plaque stability and explore the potential mechanisms. METHODS: Atherosclerotic plaques were induced in carotid arteries in ApoE-/- mice by perivascular collar placement. All mice were randomly divided into PBS and AG1296 groups. 3 weeks after the surgery, the carotid arteries were harvested for histological analysis. RESULTS: In AG1296 group, plaque area decreased by 41.5% (p = 0.0041) and the contents of macrophages and lipids decreased by 43.5% (p = 0.0003) and 35.6% (p = 0.0032) respectively. The contents of smooth muscle cells increased by 22.3% (p = 0.0214) in AG1296 group. Vulnerable index decreased by 48.3% (p = 0.0002). The inflammation factors IL-6 and TNF- alpha decreased by 49.0% (p = 0.0008) and 51.8% (p < 0.0001) and matrix metalloproteinases MMP-2 and MMP-9 decreased by 54.1% (p = 0.0004) and 37.1% (p < 0.0001) in AG1296 group. M1 macrophage markers (MCP-1) were downregulated by 30.3% (p = 0.0007) and M2 macrophage markers (ARG-1) were increased by 55.2% (p = 0.0009) in AG1296 group. CONCLUSION: AG1296 inhibited the atherosclerotic plaque progression and enhanced plaque stability by inhibiting inflammatory responses, reducing the expression of matrix metalloproteinases and promoting macrophages from proinflammatory phenotype to anti-inflammatory phenotype. PMID- 28559145 TI - Fallen eyeball injury. PMID- 28559144 TI - Vascularised fibula or induced membrane to treat congenital pseudarthrosis of the Tibia: A multicentre study of 18 patients with a mean 9.5-year follow-up. AB - BACKGROUND: The objective of this study was to compare outcomes of two surgical techniques used to treat congenital pseudarthrosis of the tibia (CPT), the induced membrane technique (IM) and the transfer of the contralateral vascularised fibula (VF). HYPOTHESIS: The IM technique produces similar outcomes to those of VF grafting in terms of healing and function, while being simpler and having a lower complication rate. MATERIAL AND METHOD: This retrospective multicentre study included 18 patients with a mean age of 2.8 years at surgery. Among them, 11 had neurofibromatosis type 1 (NF1). The IM technique was used in 10 patients and VF grafting in 8 patients. Mean follow-up was 9.5 years (range: 5 15 years). RESULTS: The two groups showed no significant differences for healing or the occurrence of complications such as limb length discrepancy and residual malalignment. Two patients required amputation, one in each group. The mean number of surgical procedures per patient was 4.7 in the IM group and 5 in the VF group. DISCUSSION: Outcomes are similar with the two techniques. Although VF grafting theoretically involves a single stage, the mean number of surgical procedures was not lower than after the IM technique. The IM technique was associated with lower risks of complications and residual donor site abnormalities. Regardless of the reconstruction technique, the quality of the initial bone resection and internal fixation, particularly regarding alignment, is of the utmost importance. LEVEL OF EVIDENCE: IV, comparative retrospective study. PMID- 28559146 TI - Translation and adaptation of the Radiotherapy Edema Rating Scale to Brazilian Portuguese. AB - INTRODUCTION: Internal lymphedema is one of the sequelae of head and neck cancer treatment that can lead to varying degrees of swallowing, speech, and respiration alterations. The Radiotherapy Edema Rating Scale, developed by Patterson et al., is a tool used to evaluate pharyngeal and laryngeal edema. OBJECTIVE: To translate into Brazilian Portuguese, to culturally adapt and test this scale in patients undergoing treatment for head and neck cancer. METHODS: The process followed the international guidelines and translation steps by two head and neck surgeons and back-translation performed independently by two North-American natives. The final version of the test was evaluated based on the assessment of 18 patients by two head and neck surgeons and two speech therapists using the scales in Brazilian Portuguese. RESULTS: The translation and cultural adaptation were satisfactorily performed by the members of the committee in charge. CONCLUSION: The translation and adaptation into Brazilian Portuguese of the Radiotherapy Edema Rating Scale was successfully performed and showed to be easy to apply. PMID- 28559147 TI - Gluteus medius muscle metastasis of squamous cell carcinoma of larynx: a rare case. PMID- 28559148 TI - Leukocyte Breaching of Endothelial Barriers: The Actin Link. AB - Leukocyte transendothelial migration (TEM) takes place across micron-wide gaps in specific post-capillary venules generated by the transmigrating leukocyte. Because endothelial cells contain a dense cytoskeletal network, transmigrating leukocytes must overcome these mechanical barriers as they squeeze their nuclei through endothelial gaps and pores. Recent findings suggest that endothelial cells are not a passive barrier, and upon engagement by transmigrating leukocytes trigger extensive dynamic modifications of their actin cytoskeleton. Unexpectedly, endothelial contractility functions as a restrictor of endothelial gap enlargement rather than as a facilitator of gap formation as was previously suggested. In this review we discuss current knowledge regarding how accurately timed endothelial actin-remodeling events are triggered by squeezing leukocytes and coordinate leukocyte TEM while preserving blood vessel integrity. PMID- 28559149 TI - Chronic Lymphocytic Leukemia Patients With Deletion 11q Have a Short Time to Requirement of First-Line Therapy, But Long Overall Survival: Results of a Population-Based Cohort in British Columbia, Canada. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) patients with 11q22.3 deletion (11q-) have an aggressive clinical course, and thus selection of first-line therapy in this group is important. This study aimed to improve our understanding of real-world practice patterns and outcomes of CLL patients with 11q- in a population-based setting. PATIENTS AND METHODS: The British Columbia CLL Database was used to identify patients with 11q-. Overall survival (OS) and treatment-free survival (TFS) were assessed after adjustment for prognostic factors. RESULTS: Of 1044 patients in the database, 125 had 11q- (12%). Sixty-nine patients had 11q- identified before therapy initiation and had a median OS and TFS of 14.7 (95% confidence interval [CI], 11.3-18.1) and 2.5 (95% CI, 1.5-3.6) years. Patient with copresence of 11q- and deletion 17p had a markedly worse prognosis, with median OS of 4.9 versus 14.7 years (P < .001). Most treated patients (33 of 52) received fludarabine with or without rituximab (FR). Patients treated with FR had a median OS of 12.8 years (standard error, 1.0), which was not statistically different from those treated with alkylator-containing therapy (P = .35). CONCLUSION: Although median TFS of 11q- patients in this cohort was short at 2.5 years, OS remains long at 14.7 years, even when most patients received initial treatment without alkylators. PMID- 28559150 TI - Viral-induced Hemorrhagic Cystitis After Allogeneic Hematopoietic Stem Cell Transplant. AB - INTRODUCTION: Hemorrhagic cystitis (HC) is a well-recognized problem that is regularly observed after hematopoietic stem cell transplantation (HSCT). The published data does not report on the potential risk factors for the viral induced HC that might require prophylactic treatments. PATIENTS AND METHODS: We conducted a retrospective analysis of all adult patients who underwent allogeneic HSCT at Jules Bordet Institute between 1992 and 2013. Our institutional protocol consists in monitoring the patient for signs and symptoms of HC on a daily basis during the initial admission for HSCT, then once weekly after discharge until 2 months thereafter. RESULTS: HC was found in 64 patients, of whom 56 (87.5%) had viral-induced HC. The median time between HSCT and HC was 39.5 days (range, 1 2766 days); the median time between detection of a viral infection and HC was 32 days (range, 0-2752 days). In multivariate analysis, HC is correlated to the infection with the BK virus (hazard ratio, 6.0; 95% confidence interval, 5.03 6.90; P = .0001) and the adenovirus (hazard ratio, 4.93; 95% confidence interval, 4.06-5.80; P = .0003). The 5-year overall survival of patients with HC was 36%. The 5-year survival rates were not statistically different between patients with or without HC (25% vs. 39%; P = .20). CONCLUSION: The presence of the identified risk factors should prompt closer follow-up with screening tests and preventive measures for BK virus and adenovirus infections in patients undergoing HSCT. PMID- 28559151 TI - Generic Imatinib in Chronic Myeloid Leukemia: Survival of the Cheapest. AB - INTRODUCTION: The patent expiration of imatinib mesylate (Gleevec; Novartis) on February 1, 2016, has brought the focus back on generic versions of the drug, and an opportunity to provide a safe and cost-effective alternative. The objective of our study was to determine the molecular and cytogenetic responses, survival endpoints (event-free survival, failure-free survival, transformation-free survival, overall survival), and safety of innovator and generic brands of imatinib. MATERIALS AND METHODS: In this retrospective analysis, data from 1812 patients with chronic myeloid leukemia treated with frontline imatinib mesylate (innovator/generic) at a single institution between 2008 and 2014 is included. Of these, 445 were excluded owing to inadequate data and follow-up, and a further 156 were excluded as they were in either the accelerated phase or blast crisis at diagnosis. Thus, data from 1067 patients who were treated with Gleevec (Novartis), and 144 patients with Veenat (NATCO) were available for analysis, and included in the study. RESULTS: There was no significant difference in event-free survival (P = .05), failure-free survival (P = .07), transformation-free survival (P = .12), or overall survival (P = .24) between the 2 groups. The frequency of reported nonhematologic adverse events and hematologic adverse events was comparable between the study groups. CONCLUSION: The findings of the present study showed comparable efficacy and safety of the generic and innovator versions of imatinib in the treatment of patients with chronic myeloid leukemia. PMID- 28559153 TI - Valuing and embracing complexity: How an understanding of complex interventions needs to shape our evaluation capacities building initiatives. AB - This paper describes some of the main challenges of evaluating complex interventions, as well as the implications of such challenges for evaluation capacity building. It discusses lessons learned from a case study of an evaluation of Dancing with Parkinson's, an organization that provides dance classes to people with Parkinson's disease in Toronto, Canada. These implications are developed from a realist evaluation lens. Key lessons include the need to develop skills to understand program mechanisms and contexts, recognize multiple models of causality, apply mixed method designs, and ensure the successful scaling up and spread of an intervention. PMID- 28559152 TI - Anti-apoptotic activity of Japanese encephalitis virus NS5 protein in human medulloblastoma cells treated with interferon-beta. AB - BACKGROUND: Japanese encephalitis virus (JEV) non-structural protein 5 (NS5) exhibits type I interferon (IFN) antagonists, contributing to immune escape, and even inducing viral anti-apoptosis. This study investigated the anti-apoptotic mechanism of JEV NS5 protein on type I IFN-induced apoptosis of human medulloblastoma cells. METHODS: Vector control and NS5-expressing cells were treated with IFN-beta, and then harvested for analyzing apoptotic pathways with flow cytometry, Western blotting, subcellular localization, etc. RESULTS: Annexin V-FITC/PI staining indicated that IFN-beta triggered apoptosis of human medulloblastoma cells, but JEV NS5 protein significantly inhibited IFN-beta induced apoptosis. Phage display technology and co-immunoprecipitation assay identified the anti-apoptotic protein Hsp70 as a NS5-interacting protein. In addition, Western blotting demonstrated that NS5 protein up-regulated the Hsp70 expression, and reduced IFN-beta-induced phosphorylation of ERK2, p38 MAPK and STAT1. Hsp70 down-regulation by quercetin significantly recovered IFN-beta induced apoptosis of NS5-expressing cells, correlating with the increase in the phosphorylation of ERK2, p38 MAPK, and STAT1. Inhibiting the ATPase activity of Hsp70 by VER-155008 resulted in the elevated IFN-beta-induced apoptosis in vector control and NS5-expressing cells. CONCLUSIONS: The results indicated Hsp70 up regulation by JEV NS5 not only involved in type I IFN antagonism, but also responded to the anti-apoptotic action of JEV NS5 protein through the blocking IFN-beta-induced p38 MAPK/STAT1-mediated apoptosis. PMID- 28559154 TI - Mechanical CPR in refractory cardiac arrest may be practical, but injuries should be monitored: A concise meta-analysis. PMID- 28559155 TI - Ventricular fibrillation as initial rhythm in pediatric cardiac arrest by suicidal hanging. PMID- 28559156 TI - Dietary safety assessment of genetically modified rice EH rich in beta-carotene. AB - This 90-day study aimed to assess the dietary safety of transgenic rice EH which is rich in beta-carotene. Two experimental groups of Sprague-Dawley rats were fed diets containing 45% rice flour of Zhonghua 11 rice and transgenic rice EH rich in beta-carotene, respectively. The reference group was fed a diet containing standard feed nutrition. During the trial period, each rat was weighed and the food intake was recorded twice a week. Their behaviors were observed daily. In the end, blood samples were obtained from all anesthetized rats to measure the hematologic and serum chemistry indicators. Growth performance, anatomy and pathology of all organs in each group were analyzed. Although a few parameters were found to be statistically significantly different across groups, they were within the normal reference range for this breed and age of rats. Therefore, the changes were not considered to be diet related. The results revealed that the transgenic rice EH rich in beta-carotene was as nutritious as Zhonghua 11 rice and showed a lack of biologically meaningful unintended effects. PMID- 28559157 TI - Integrating habits and practices data for soaps, cosmetics and air care products into an existing aggregate exposure model. AB - In order to accurately assess aggregate exposure to a fragrance material in consumers, data are needed on consumer habits and practices, as well as the concentration of the fragrance material in those products. The present study describes the development of Phase 2 Creme RIFM model by expanding the previously developed Phase 1 model to include an additional six product types. Using subject matching algorithms, the subjects in the Phase 1 Creme RIFM database were paired with subjects in the SUPERB and BodyCare surveys based on age and gender. Consumption of the additional products was simulated to create a seven day diary allowing full data integration in a consistent format. The inhalation route was also included for air care and other products where a fraction of product used is inhaled, derived from the RIFM 2-box model. The expansion of the Phase 1 Creme RIFM model has resulted in a more extensive and refined model, which covers a broader range of product categories and now, includes all relevant routes of exposure. An evaluation of the performance of the model has been carried out in an accompanying publication to this one. PMID- 28559158 TI - Tissue and cellular biomechanics during corneal wound injury and repair. AB - : Corneal wound healing is an enormously complex process that requires the simultaneous cellular integration of multiple soluble biochemical cues, as well as cellular responses to the intrinsic chemistry and biophysical attributes associated with the matrix of the wound space. Here, we document how the biomechanics of the corneal stroma are altered through the course of wound repair following keratoablative procedures in rabbits. Further we documented the influence that substrate stiffness has on stromal cell mechanics. Following corneal epithelial debridement, New Zealand white rabbits underwent phototherapeutic keratectomy (PTK) on the right eye (OD). Wound healing was monitored using advanced imaging modalities. Rabbits were euthanized and corneas were harvested at various time points following PTK. Tissues were characterized for biomechanics with atomic force microscopy and with histology to assess inflammation and fibrosis. Factor analysis was performed to determine any discernable patterns in wound healing parameters. The matrix associated with the wound space was stiffest at 7days post PTK. The greatest number of inflammatory cells were observed 3days after wounding. The highest number of myofibroblasts and the greatest degree of fibrosis occurred 21days after wounding. While all clinical parameters returned to normal values 400days after wounding, the elastic modulus remained greater than pre-surgical values. Factor analysis demonstrated dynamic remodeling of stroma occurs between days 10 and 42 during corneal stromal wound repair. Elastic modulus of the anterior corneal stroma is dramatically altered following PTK and its changes coincide initially with the development of edema and inflammation, and later with formation of stromal haze and population of the wound space with myofibroblasts. Factor analysis demonstrates strongest correlation between elastic modulus, myofibroblasts, fibrosis and stromal haze thickness, and between edema and central corneal thickness. STATEMENT OF SIGNIFICANCE: Tissue biomechanics during the course of corneal wound healing is documented for the first time through atomic force microscopy, and is correlated with advanced clinical imaging and immunohistochemistry. Parameters obtained from the study are applied in a multivariate statistical model to cluster the data for better classification and monitor the wound repair process. Elastic modulus of the anterior corneal stroma is dramatically altered following wounding and correlates initially with the development of edema and inflammation, and later with formation of stromal haze and population of the wound space with myofibroblasts. Importantly, the occurrence of myofibroblasts is preceded by changes in tissue mechanics, which is important to consider in light of crosslinking procedures applied to treat corneal diseases. PMID- 28559159 TI - HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in a rat model of bone cancer pain by restoring MU opioid receptor in spinal cord. AB - Bone cancer pain (BCP) is a common complication with inadequate management in patients suffering from advanced cancer. Histone deacetylase inhibitors showed significant analgesic effect in multiple inflammatory and neuropathic pain models, but their effect in bone cancer pain has never been explored. In this study, we utilized a BCP rat model with intra-tibial inoculation of Walker 256 mammary gland carcinoma cells, which developed progressive mechanical hypersensitivity but not thermal hypersensitivity. Intrathecal application of trichostatin A (TSA), a classic pan-HDAC inhibitor, ameliorated tactile hypersensitivity and enhanced the analgesic effect of morphine in BCP rats. The analgesic effect of TSA was blocked by co-administration of CTAP, a specific MOR antagonist, confirming the involvement of mu-opioid receptor (MOR). A reduction of MOR expression was observed in the lumbar spinal cord of BCP rats and TSA treatment was able to partially reverse it. In vitro study in PC12 cells also demonstrated the dose-dependent enhancement of MOR expression by TSA treatment. Taking all into consideration, we could draw the conclusion that HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in BCP rats, probably by restoring MOR expression in spinal cord. PMID- 28559160 TI - Unrevealed part of myosin's powerstroke accounts for high efficiency of muscle contraction. AB - BACKGROUND: Myosin II, the motor protein driving muscle contraction, uses energy of ATP hydrolysis to produce movement along actin. The key step of energy transduction is the powerstroke, involving rotation of myosin's lever while myosin is attached to actin. Macroscopic measurements indicated high thermodynamic efficiency for energy conversion. However, single-molecule experiments indicated lower efficiency, provoking a long-standing discrepancy. METHODS: Based on the Fluctuation-Dissipation Theorem, we built a sufficiently detailed but low degree-of-freedom model reconstructing the entire mechanoenzymatic cycle. RESULTS: We show that a high axial stiffness of the lever during an initial, experimentally yet unrevealed part of the powerstroke results in a short-time, ratchet-like Kramers effect, and is responsible for the missing efficiency. The second part of the powerstroke is an Eyring-like relaxation that dominantly contributes to lever rotation, but produces only a minor part of the work. CONCLUSIONS: The model reveals the structural background of myosin's capability to function as a robust molecular engine and a very precise load sensor as well. Our model also suggests an explanation for the malfunction of myosins harboring mutations that lead to hypertrophic cardiomyopathies with most severe clinical prognosis. GENERAL SIGNIFICANCE: The model explains how a force transmitting device within a biological motor can enable high energetic efficiency. PMID- 28559161 TI - DNA metabarcoding to assess indoor fungal communities: Electrostatic dust collectors and Illumina sequencing. AB - DNA metabarcoding is increasingly being used to characterize the microbiological composition of both the indoor and outdoor environments of dwellings. Our study aimed to evaluate metabarcoding and bioinformatic analysis resulting from calibrated samples and samples collected by an electrostatic dust collector (EDC) in dwellings with no moisture problems. Thus, the fungal communities of 14 dwellings (eastern France, Franche-Comte region) were analyzed by Illumina MiSeq technology after amplification of the ITS2 region. Using the standard samples of 11 species of yeasts and molds allowed us to validate the Operational taxonomic units (OTU) assignment. These calibrated samples also showed a low amplification bias, a low rate of sequencing errors and the semi-quantitative nature of the technique. Only one species from the calibrated samples (Lichtheimia corymbifera) was less amplified probably due to the presence of two mismatches in its3 primer. EDC analysis identified 3594OTU with 75% of reads corresponding to 30 genera. The main genera are those usually found by culture techniques (Penicillium, Aspergillus and Cladosporium), but findings also indicate others less commonly isolated in culture such as Epicoccum, the fourth detected genus in our study. The type of heating systems was correlated with fungal diversity. We found less diversity in the dwellings with wood heating and larger quantities of Epicoccum nigrum verified by qPCR. DNA metabarcoding analysis applied to EDC seems promising. However, we think that it must be used along with qPCR, to obtain a more global view of microbial ecology and relative quantification of species of interest within communities. PMID- 28559162 TI - Identification of Cronobacter species by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry with an optimized analysis method. AB - Rapid and precise identification of Cronobacter species is important for foodborne pathogen detection, however, commercial biochemical methods can only identify Cronobacter strains to genus level in most cases. To evaluate the power of mass spectrometry based on matrix-assisted laser desorption/ionization time-of flight (MALDI-TOF MS) for Cronobacter species identification, 51 Cronobacter strains (eight reference and 43 wild strains) were identified by both MALDI-TOF MS and 16S rRNA gene sequencing. Biotyper RTC provided by Bruker identified all eight reference and 43 wild strains as Cronobacter species, which demonstrated the power of MALDI-TOF MS to identify Cronobacter strains to genus level. However, using the Bruker's database (6903 main spectra products) and Biotyper software, the MALDI-TOF MS analysis could not identify the investigated strains to species level. When MALDI-TOF MS analysis was performed using the combined in house Cronobacter database and Bruker's database, bin setting, and unweighted pair group method with arithmetic mean (UPGMA) clustering, all the 51 strains were clearly identified into six Cronobacter species and the identification accuracy increased from 60% to 100%. We demonstrated that MALDI-TOF MS was reliable and easy-to-use for Cronobacter species identification and highlighted the importance of establishing a reliable database and improving the current data analysis methods by integrating the bin setting and UPGMA clustering. PMID- 28559163 TI - A cost-saving strategy for processing isolated uropathogens in community-acquired urinary tract infections. AB - Outpatient urine samples are among the most commonly processed in a microbiology laboratory, which involves a high economic burden. The aim of this study was compare cost and efficiency to process uropathogens between MicroScan system (2010-2011) versus a chromogenic medium and the disk diffusion method (2013 2014). In the first period, a total 9918 bacterial populations were isolated from urine samples. Annual estimated costs during 2010 and 2011 for processing were EUR 53,818 and EUR 57,306, respectively (EUR 111,124 total). In the second period, a total 11,728 bacterial isolates were processed, with annual estimated costs of EUR 21,078 and EUR 23,248, respectively (EUR 44,326 total). We included the cost for a laboratory technician (252h worked per year), estimated at EUR 2500 per year. The mean estimated savings were EUR 66,797 (60%).The identification by chromogenic media and antibiotic susceptibility patterns by disk diffusion method was similar to MicroScan in both study periods. Only some isolated Citrobacter spp., Enterobacter spp., Morganella morganii, and Providencia spp. were misidentified. The strategy reported here did not affect the quality of the results and yielded substantial cost savings. PMID- 28559164 TI - Pomegranate seed oil influences the fatty acids profile and reduces the activity of desaturases in livers of Sprague-Dawley rats. AB - The aim of our study was to compare the influence of diet supplementation with pomegranate seed oil - as conjugated linolenic acids (CLnA) source, or conjugated linoleic acids (CLA) and to examine the mechanism of their activity. The content of fatty acids, levels of biomarkers of lipids' oxidation and the activity of key enzymes catalyzing lipids metabolism were measured. Obtained results revealed that conjugated fatty acids significantly decrease the activity of Delta5 desaturase (p=0.0001) and Delta6-desaturase (p=0.0008) and pomegranate seed oil reduces their activity in the most potent way. We confirmed that diet supplementation with pomegranate seed oil - a rich source of punicic acid leads to the increase of cis-9, trans-11 CLA content in livers (p=0.0003). Lack of side effects and beneficial influence on desaturases activity and fatty acids profile claim pomegranate seed oil to become interesting alternative for CLA as functional food. PMID- 28559165 TI - Protein tentacles. AB - Virus structures were among the earliest illustrations of how regulated protein assembly can proceed by folding of polypeptide-chain segments into complementary sites on partner proteins. I draw on Caspar's image of protein "tentacles" and his metaphor of SV40 pentamers as five-legged, aquatic organisms ("pentopuses") to suggest a helpful vocabulary. "Tentacular interactions" among component subunits organize most subcellular molecular machines. Their selective advantages include facile regulation of both assembly and disassembly by modifying enzymes and by folding chaperones. PMID- 28559166 TI - Cryo-FIB specimen preparation for use in a cartridge-type cryo-TEM. AB - Cryo-electron tomography (cryo-ET) is a well-established technique for studying 3D structural details of subcellular macromolecular complexes and organelles in their nearly native context in the cell. A primary limitation of the application of cryo-ET is the accessible specimen thickness, which is less than the diameters of almost all eukaryotic cells. It has been shown that focused ion beam (FIB) milling can be used to prepare thin, distortion-free lamellae of frozen biological material for high-resolution cryo-ET. Commercial cryosystems are available for cryo-FIB specimen preparation, however re-engineering and additional fixtures are often essential for reliable results with a particular cryo-FIB and cryo-transmission electron microscope (cryo-TEM). Here, we describe our optimized protocol and modified instrumentation for cryo-FIB milling to produce thin lamellae and subsequent damage-free cryotransfer of the lamellae into our cartridge-type cryo-TEM. PMID- 28559168 TI - Draft genome sequence of a CTX-M-15-producing Escherichia coli ST345 from commercial chicken meat in Brazil. AB - Escherichia coli, the main host of the CTX-M-15 extended-spectrum beta-lactamase (ESBL) enzyme, is widely distributed and exchanged between the environment, animals and humans. Therefore, identification of blaCTX-M-15-positive lineages in food has a significant impact on public health. In this regard, until the end of 1990s, ESBL-producing isolates were mainly associated with hospital-acquired infections, with a predominance of SHV- and TEM-type enzymes. In recent years, a new trend has been observed among ESBL-producers, where most isolates now harbour CTX-M-type, being further isolated from community-acquired infections. Nowadays, CTX-M-15 has been recognised as the most important ESBL variant, invading virtually all human and animal compartments, leading to a global pandemic. Thus, whilst the rapid emergence and dissemination of CTX-M-15 among E. coli isolates has generated a large genetic reservoir from which other members of the Enterobacteriaceae family can easily acquire this resistance gene, there are an increasing number of new reservoirs and transmission mechanisms that must be investigated. In this study, we present the draft genome sequence of a CTX-M-15 producing E. coli ST345 isolated from commercial chicken meat in Brazil. This draft genome can be used as a reference sequence for comparative analysis among CTX-M-15-producers. PMID- 28559167 TI - The stoichiometry of the TMEM16A ion channel determined in intact plasma membranes of COS-7 cells using liquid-phase electron microscopy. AB - TMEM16A is a membrane protein forming a calcium-activated chloride channel. A homodimeric stoichiometry of the TMEM16 family of proteins has been reported but an important question is whether the protein resides always in a dimeric configuration in the plasma membrane or whether monomers of the protein are also present in its native state within in the intact plasma membrane. We have determined the stoichiometry of the human (h)TMEM16A within whole COS-7 cells in liquid. For the purpose of detecting TMEM16A subunits, single proteins were tagged by the streptavidin-binding peptide within extracellular loops accessible by streptavidin coated quantum dot (QD) nanoparticles. The labeled proteins were then imaged using correlative light microscopy and environmental scanning electron microscopy (ESEM) using scanning transmission electron microscopy (STEM) detection. The locations of 19,583 individual proteins were determined of which a statistical analysis using the pair correlation function revealed the presence of a dimeric conformation of the protein. The amounts of detected label pairs and single labels were compared between experiments in which the TMEM16A SBP-tag position was varied, and experiments in which tagged and non-tagged TMEM16A proteins were present. It followed that hTMEM16A resides in the plasma membrane as dimer only and is not present as monomer. This strategy may help to elucidate the stoichiometry of other membrane protein species within the context of the intact plasma membrane in future. PMID- 28559169 TI - Spontaneous alternation: A potential gateway to spatial working memory in Drosophila. AB - Despite their ubiquity in biomedical research, Drosophila have yet to be widely employed as model organisms in psychology. Many complex human-like behaviors are observed in Drosophila, which exhibit elaborate displays of inter-male aggression and female courtship, self-medication with alcohol in response to stress, and even cultural transmission of social information. Here, we asked whether Drosophila can demonstrate behavioral indices of spatial working memory in a Y maze, a classic test of memory function and novelty-seeking in rodents. Our data show that Drosophila, like rodents, alternate their visits among the three arms of a Y-maze and spontaneously favor entry into arms they have explored less recently versus ones they have just seen. These findings suggest that Drosophila possess some of the information-seeking and working memory facilities mammals depend on to navigate through space and might be relevant models for understanding human psychological phenomena such as curiosity. PMID- 28559170 TI - Integration of contextual cues into memory depends on "prefrontal" N-methyl-D aspartate receptors. AB - Every learning event is embedded in a context, but not always does the context become an integral part of the memory; however, for extinction learning it usually does, resulting in context-specific conditioned responding. The neuronal mechanisms underlying contextual control have been mainly investigated for Pavlovian fear extinction with a focus on hippocampal structures. However, the initial acquisition of novel responses can be subject to contextual control as well, although the neuronal mechanisms are mostly unknown. Here, we tested the hypothesis that contextual control of acquisition depends on glutamatergic transmission underlying executive functions in forebrain areas, e.g. by shifting attention to critical cues. Thus, we antagonized N-methyl-D-aspartate (NMDA) receptors with 2-amino-5-phosphonovaleric acid (AP5) in the pigeon nidopallium caudolaterale, the functional analogue of mammalian prefrontal cortex, during the concomitant acquisition and extinction of conditioned responding to two different stimuli. This paradigm has previously been shown to lead to contextual control over extinguished as well as non-extinguished responding. NMDA receptor blockade resulted in an impairment of extinction learning, but left the acquisition of responses to a novel stimulus unaffected. Critically, when responses were tested in a different context in the retrieval phase, we observed that NMDA receptor blockade led to the abolishment of contextual control over acquisition performance. This result is predicted by a model describing response inclination as the product of associative strength and contextual gain. In this model, learning under AP5 leads to a change in the contextual gain on the learned association, possibly via the modulation of attentional mechanisms. PMID- 28559171 TI - Anatomical and technical predictors of perioperative clinical outcomes after carotid artery stenting. AB - BACKGROUND: A few other studies have reported the effects of anatomical and technical factors on clinical outcomes of carotid artery stenting (CAS). This study analyzed the effect of these factors on perioperative stroke/myocardial infarction/death after CAS. METHODS: This was a retrospective analysis of prospectively collected data of 409 of 456 patients who underwent CAS during the study period. A logistic regression analysis was used to determine the effects of anatomical and technical factors on perioperative stroke, death, and myocardial infarction (major adverse events [MAEs]). RESULTS: The MAE rate for the entire series was 4.7% (19 of 409), and the stroke rate was 2.2% (9 of 409). The stroke rate for asymptomatic patients was 0.46% (1 of 218; P = .01). The MAE rates for patients with transient ischemic attack (TIA) were 7% (11 of 158) vs 3.2% (8 of 251) for other indications (P = .077). The stroke rates for heavily calcified lesions were 6.3% (3 of 48) vs 1.2% (4 of 332) for mildly calcified/noncalcified lesions (P = .046). Differences in stroke and MAE rates regarding other anatomical features were not significant. The stroke rate for patients with percutaneous transluminal angioplasty (PTA) before embolic protection device (EPD) insertion was 9.1% (2 of 22) vs 1.8% (7 of 387) for patients without (P = .07) and 2.6% (9 of 341) for patients with poststenting PTA vs 0% (0 of 68) for patients without. The MAE rate for patients with poststenting PTA was 5.6% (19 of 341) vs 0% (0 of 68) for patients without (P = .0536). The MAE rate for patients with the ACCUNET (Abbott, Abbott Park, Ill) EPD was 1.9% (3 of 158) vs 6.7% (16 of 240) for others (P = .029). The differences between stroke and MAE rates for other technical features were not significant. A regression analysis showed that the odds ratio for stroke was 0.1 (P = .031) for asymptomatic indications, 13.7 (P = .014) for TIA indications, 6.1 (P = .0303) for PTA performed before EPD insertion, 1.7 for PTA performed before stenting, and 5.4 (P = .0315) for heavily calcified lesions. The MAE odds ratio was 0.46 (P = .0858) for asymptomatic indications, 2.1 for PTAs performed before EPD insertion, 2.2 for poststent PTAs, and 2.2 (P = .1888) for heavily calcified lesions. A multivariate analysis showed that patients with TIA had an odds ratio of stroke of 11.05 (P = .029). Patients with PTAs performed before EPD insertion had an OR of 6.15 (P = .062). Patients with heavily calcified lesions had an odds ratio of stroke of 4.25 (P = .0871). The MAE odds ratio for ACCUNET vs others was 0.27 (P = .0389). CONCLUSIONS: Calcific lesions and PTA before EPD insertion or after stenting were associated with higher stroke or MAE rates, or both. The ACCUNET EPD was associated with lower MAE rates. There was no correlation between other anatomical/technical variables and CAS outcome. PMID- 28559172 TI - Managing claudication in the community setting. AB - Advances made in medical management and treatment options in addressing lower extremity claudication and vascular disease have skyrocketed during the last decade. Given the recent advances in treatment options, there is often the perception within the medical community and general community that to get the most "cutting edge" treatment, one must go to an academic center or practitioner. The goal of this portion of the discussion is to explore the question of what differences in treatment options there are between a community practice and an academic practice within those members of the vascular surgery specialty. Are there really any differences in the types of treatments offered or availability of the different modalities, and what drives us as practitioners to one over the other? PMID- 28559173 TI - Surgeon, not institution, case volume is associated with limb outcomes after lower extremity bypass for critical limb ischemia in the Vascular Quality Initiative. AB - OBJECTIVE: Studies from large administrative databases have demonstrated associations between institutional case volume and outcomes after lower extremity bypass (LEB). We hypothesized that increased institutional and surgeon volume would be associated with improved outcomes after LEB. Using a national, prospectively collected clinical database, the objective of this study was to determine the effects of both surgeon and institutional volume on outcomes after LEB. METHODS: The Vascular Quality Initiative (VQI) was queried to identify all LEBs for critical limb ischemia or claudication between 2004 and 2014. Average annual case volume was calculated by dividing an institution's or surgeon's total LEB volume by the number of years they reported to the VQI. Institutional and surgeon volumes were analyzed as continuous variables to determine the impact of volume on major adverse cardiac events (MACEs), major adverse limb events (MALEs), graft patency, and amputation-free survival. Hierarchical regression models were used with cases clustered by surgeon and center. Time-dependent outcomes were evaluated with multivariable shared frailty Cox proportional hazards models. RESULTS: From 2004 to 2014, there were 14,678 LEB operations performed at 114 institutions by 587 surgeons. Average annual institutional volume ranged from 1.0 to 137.5 LEBs per year, with a median of 26.9 (interquartile range, 14-45.3). Average annual surgeon volume ranged from 1 to 52 LEBs per year with a median of 5.7 (interquartile range, 2.5-9.3). Institutional LEB volume was not associated with MACEs or MALEs or with loss of patency. However, average annual surgeon volume was independently associated with reduced MALEs and improved primary patency. Institutional and surgeon volume did not predict MACEs. CONCLUSIONS: In contradistinction to previous studies, there was no relationship in this study between institutional LEB volume and outcomes after LEB. However, greater average annual surgeon volume was associated with improved primary patency and decreased risk of MALEs. Open LEB remains a safe and effective procedure for limb salvage. Limb-related outcomes in critical limb ischemia and claudication will be optimized if surgeons maintain adequate volume of LEB. PMID- 28559175 TI - Rescue of failed endovascular aortic aneurysm repair using the fenestrated Anaconda device. AB - OBJECTIVE: Endovascular aortic aneurysm repair (EVAR) with a fenestrated device (FEVAR) allows an extension of the proximal sealing zone above the renal arteries to an adequate, healthier segment of the aorta. This feature makes FEVAR an option to treat patients with a diseased aortic neck or type Ia endoleak after EVAR. The aim of this investigation was to present a single-center experience with FEVAR for patients with an abdominal aortic endograft in situ compared with primary FEVAR. METHODS: A prospectively held database on FEVAR patients treated with the fenestrated Anaconda device (Vascutek/Terumo, Inchinnan, Scotland, United Kingdom) at our institution was screened for individuals who had previously undergone EVAR. RESULTS: Between April 1, 2013, and July 31, 2016, 94 fenestrated Anaconda devices were implanted at our institution. Twelve patients with prior EVAR were treated for pathology of the proximal neck: type I endoleak (n = 7), for stent migration with aneurysm progression but no visible endoleak (n = 2), and progressive aortic disease at the level of the visceral segment (n = 3). When redo cases and primary FEVARs were compared, primary technical success rates were 58.3% and 87.8% (P = .02) and primary functional success rates were 91.7% and 95.1%, respectively (P = .62). Perioperative rate of major deployment related (14.6% and 16.7%) and systemic complications (8.5% and 8.3%) as well as 30-day mortality (6.1% and 0%; P = .5) were comparable between groups. After an average follow-up interval of 10 months (range, 0-43 months), no late occlusions of connecting stents were observed. The late reintervention rates were 11.0% and 16.7%, respectively (P = .57). CONCLUSIONS: The risk of a failure to cannulate one or more visceral arteries through the respective fenestrations was increased in patients who had previously undergone EVAR. This is most likely caused by increased friction between the fenestrated endograft and the failing graft in situ, which may impair the adaption of the unsupported Anaconda device to the aortic wall. As a consequence, fenestrations may not line up perfectly at the respective openings of the visceral or renal arteries, and folding of the fabric may be increased, making cannulation of the fenestrations more difficult. PMID- 28559174 TI - Prospective, multicenter study of endovascular repair of aortoiliac and iliac aneurysms using the Gore Iliac Branch Endoprosthesis. AB - OBJECTIVE: The GORE EXCLUDER Iliac Branch Endoprosthesis (IBE; W. L. Gore and Associates, Flagstaff, Ariz) is an iliac branch stent graft system designed to preserve internal iliac artery perfusion during endovascular repair of aortoiliac aneurysms (AIAs) and common iliac artery (CIA) aneurysms (CIAAs). We report the 6 month primary end point results of the IBE 12-04 United States pivotal trial for endovascular treatment of AIAs and CIAAs using the IBE device. METHODS: The trial prospectively enrolled 63 patients with AIA or CIAA who underwent implantation of the IBE device at 28 centers in the United States from 2013 to 2015. All patients underwent placement of a single IBE device. Twenty-two patients (34.9%) with bilateral CIAs were enrolled after undergoing staged coil or plug embolization (21 of 22) or surgical revascularization (1 of 22) of the contralateral internal iliac artery. Follow-up at 30 days and 6 months included clinical assessment and computed tomography angiography evaluation as assessed by an independent core laboratory. The primary effectiveness end point was freedom from IBE limb occlusion and reintervention for type I or III endoleak and >=60% stenosis at 6 months, and the secondary effectiveness end point was freedom from new onset of buttock claudication on the IBE side at 6 months. RESULTS: Mean CIA diameter on the IBE side was 41.0 +/- 11.4 mm (range, 25.2-76.3 mm). There were no procedural deaths, and technical success, defined as successful deployment and patency of all IBE components and freedom from type I or III endoleak, was 95.2% (60 of 63). Data for 61 patients were available for primary and secondary effectiveness end point analysis. Internal iliac limb patency was 95.1% (58 of 61), and no new type I or III endoleaks or device migrations were observed at 6 months. The three patients with loss of internal iliac limb patency were asymptomatic, and freedom from new-onset buttock claudication on the IBE side was 100% at 6 months. New onset buttock claudication occurred on the non-IBE treatment side in six of 21 patients (28.6%) who underwent staged internal iliac artery coil embolization. CONCLUSIONS: These results confirm that the IBE device is effective at treating CIAAs and AIAs, maintaining blood flow into the internal iliac artery, and avoiding complications associated with internal iliac artery sacrifice. Follow-up will be continued for 5 years to establish the long-term durability of iliac aneurysm repair with the IBE device. PMID- 28559177 TI - Discussion. PMID- 28559176 TI - Results from multiple prospective single-center clinical trials of the off-the shelf p-Branch fenestrated stent graft. AB - OBJECTIVE: The purpose of this study was to report prospective data of an off-the shelf fenestrated endograft (Zenith p-Branch; Cook Medical, Bloomington, Ind) from four centers for the treatment of patients with pararenal abdominal aortic aneurysms. METHODS: Data were combined from four single-center investigational studies conducted in the United States and Europe. The p-Branch endograft consists of a proximal off-the-shelf component incorporating a scallop for the celiac artery, a superior mesenteric artery fenestration, and two conical pivot fenestrations to preserve flow to the renal vessels. The device is available in two configurations, a left renal fenestration at the same (configuration A) or lower (configuration B) longitudinal position than the right to accommodate varied anatomy of the patients. RESULTS: Between August 2011 and September 2015, 76 patients (82% male; mean age, 72 years; 65 elective and 11 emergent) were enrolled, with 55% implanted with option A and 45% with B. The device was deployed successfully in all patients, and stents were placed in all target vessels except in three cases (one elective, two emergent): a left kidney was sacrificed in one patient, and a right renal artery was left unstented in two patients during the index procedure. There was no 30-day mortality. During follow up (mean, 25 +/- 13 months), 10 late deaths occurred (6 elective, 4 emergent; none related to device or procedure), and there were no ruptures or conversions to open repair. Two patients experienced bowel ischemia; one case resolved with nonoperative treatment and one required superior mesenteric artery and celiac artery angioplasty and stent placement. Renal artery occlusion occurred in eight patients (11%) and was deemed procedure related in 63% (5/8) of these patients. Four of these were successfully intervened on with preservation of renal function. The overall renal insufficiency incidence was 7% (5/76). One patient developed renal failure requiring dialysis. CONCLUSIONS: Early results incorporating learning curves for physicians with a new device and delivery system indicate that the use of the Zenith p-Branch device is feasible and safe. Long-term follow-up is needed to assess the effectiveness and durability of this treatment strategy and to refine the indications for use. PMID- 28559178 TI - Investigation into drivers of cost of stenting for carotid stenosis. AB - OBJECTIVE: We aimed to identify factors associated with cost of carotid artery stenting (CAS). METHODS: Patient and hospital characteristics affecting cost of admission for CAS were identified using the Vizient national database of hospital reported outcomes. Patients who underwent CAS for either asymptomatic or symptomatic carotid stenosis were identified using surgical Medicare Severity Diagnosis Related Groups and appropriate International Classification of Diseases, Ninth Revision and Tenth Revision codes. RESULTS: There were 166 hospitals that reported outcomes from 7369 inpatient admissions for CAS. Each institution reported a mean value for cost related to patient care per admission for CAS; the average cost across all reporting institutions was $12,834.14 (standard error of the mean [SEM], 492.88). Institutions in the lowest 25th percentile with respect to frequency of intensive care unit admission after CAS had lower cost of admission than institutions above the 75th percentile ($10,971.30 [SEM, 460.67] vs $14,992.90 [964.29]; P = .002), without any differences in incidence of stroke during admission (2.2% [SEM, 0.3] vs 2.0% [0.4]; P = .877) or 30-day readmission (1.9% [SEM, 0.4] vs 2.5 [0.6]; P = .329). Admissions for patients with symptomatic stenosis were more expensive than those with asymptomatic stenosis ($20,462.10 [SEM, 819.93] vs $11,285.20 [347.11]; P < .001). Obesity was also associated with greater costs of admission ($14,176.20 [SEM, 597.13] vs $12,287.10 [395.73]; P < .001). CONCLUSIONS: Admission to an intensive care unit, symptomatic stenosis, and obesity were associated with increased costs in patients undergoing CAS. These data may aid in identifying opportunities to improve the cost-effectiveness of this procedure. PMID- 28559180 TI - Modulation of synaptic plasticity by short-term aerobic exercise in adult mice. AB - Physiological effects of different types, of continuous and interval aerobic training, have been largely described and studied in the adult man. It was previously indicated that interval training plays an important role in maximizing both peripheral muscle and central cardiorespiratory adaptations, permitting significant functional improvement even in healthy sedentary subjects. Since the outcome of different aerobic training trials on cognitive processes had never been evaluated, we compared, on an experimental mouse model, the effects of four training exercise protocols, named respectively C100, I100, C50 and I50 depending on the volume and on the type of training proposed, continuous or interval method. Therefore, to asses quantitative and qualitative functional changes, we analyzed several physical parameters before and after 6 weeks training in all four groups with respect to the control sedentary animals and we studied synaptic plasticity, by extracellular in vitro recordings, in hippocampal mouse slices, a region involved in learning and memory processes. We found that all four protocols of exercise applied in this study exerted positive effects on both physical and training parameters inducing weight augmentation, strength endurance and aerobic endurance increase, and potentiation of motor coordination. However, the improvement observed failed to induce an enhancement in synaptic plasticity in three out of four exercise protocols and only in the slices from mice trained with the interval 50% volume exercise the long term potentiation (LTP) increased with respect to the sedentary group. These findings suggest that motor activity exerts positive effects on cognitive processes provided that certain principles are respected, such as the training load and the elements of which it is composed, in order to plan the right quantitative and qualitative parameters and the appropriate recovery periods. PMID- 28559179 TI - Opioid receptors mediate the acquisition, but not the expression of mitragynine induced conditioned place preference in rats. AB - Mitragynine is the main psychoactive ingredient of the herbal drug preparation Kratom (Ketum), derived from the plant Mitragyna speciosa. Kratom is a widely abused drug in Southeast Asian and has a psychostimulant profile at low-medium doses, while high doses have opioidergic effects. Mitragynine was shown to possess opiate receptor affinity. However, its role in the behavioural effects of mitragynine is unclear. Here we asked whether the reinforcing effects of mitragynine are mediated by opiate receptors using a conditioned place preference (CPP) paradigm in rats. In the first experiment we tested the effects of the opiate receptor antagonist naloxone (0.1, 0.3 and 1.0mg/kg) on the acquisition of mitragynine (10mg/kg)-induced CPP. In the second experiment, we tested the involvement of opiate receptors in the expression of mitragynine-induced CPP in rats. We found that naloxone suppresses the acquisition of mitragynine-induced CPP. This effect was already evident at a dose of naloxone (0.1mg/kg) which, by itself, had no conditioned place aversion (CPA) effect. Higher doses of naloxone induced a CPA and blocked mitragynine-induced CPP. In contrast, naloxone had no effect on the expression of mitragynine-induced CPP. These findings suggest that the acquisition, but not the expression of the reinforcing effects of mitragynine is mediated by opiate receptors. PMID- 28559181 TI - Deletion of one allele of Mthfd1 (methylenetetrahydrofolate dehydrogenase 1) impairs learning in mice. AB - The MTHFD1 gene encodes for methylenetetrahydrofolate dehydrogenase 1, an enzyme that has an important role in folate-mediated one-carbon metabolism. In people, a single nucleotide polymorphism of this gene (1958G>A; rs2236225) is associated with increased risk for bipolar disorder and schizophrenia, neural tube and other birth defects. Mice homozygous for a loss of Mthfd1 via a gene-trap mutation are not viable, and heterozygotes, though they appear healthy, have metabolic imbalances in the folate- and choline-mediated 1-carbon metabolic pathways. In this study, we evaluated cognitive function in Mthfd1gt/+ male and female mice using a behavioral battery composed of eight different tests. We found that these mice display impaired cue-conditioned learning, while other behaviors remain intact. PMID- 28559182 TI - Time dependent effect of chronic embryonic exposure to ethanol on zebrafish: Morphology, biochemical and anxiety alterations. AB - Exposure to ethanol during critical period of development can cause severe impairments in the central nervous system (CNS). This study was conducted to assess the neurotoxic effects of chronic embryonic exposure to ethanol in the zebrafish, taking into consideration the time dependent effect. Two types of exposure regimen were applied in this study. Withdrawal exposure group received daily exposure starting from gastrulation until hatching, while continuous exposure group received daily exposure from gastrulation until behavioural assessment at 6dpf (days post fertilization). Chronic embryonic exposure to ethanol decreased spontaneous tail coiling at 24hpf (hour post fertilization), heart rate at 48hpf and increased mortality rate at 72hpf. The number of apoptotic cells in the embryos treated with ethanol was significantly increased as compared to the control. We also measured the morphological abnormalities and the most prominent effects can be observed in the treated embryos exposed to 1.50% and 2.00%. The treated embryos showed shorter body length, larger egg yolk, smaller eye diameter and heart edema as compared to the control. Larvae received 0.75% continuous ethanol exposure exhibited decreased swimming activity and increased anxiety related behavior, while withdrawal ethanol exposure showed increased swimming activity and decreased anxiety related behavior as compared to the respective control. Biochemical analysis exhibited that ethanol exposure for both exposure regimens altered proteins, lipids, carbohydrates and nucleic acids of the zebrafish larvae. Our results indicated that time dependent effect of ethanol exposure during development could target the biochemical processes thus leading to induction of apoptosis and neurobehavioral deficits in the zebrafish larvae. Thus it raised our concern about the safe limit of alcohol consumption for pregnant mother especially during critical periods of vulnerability for developing nervous system. PMID- 28559183 TI - Using concanavalinA as a spacer for immobilization of E. coli onto magnetic nanoparticles. AB - ConcanavalinA (conA) is a protein extracted from the concanavalin, which has specific recognition through mannose components on bacterial cell surfaces. A magnetic nanocarrier with the structure of a dopamine functionalized magnetic nanoparticles was grafted with conA, and was used for immobilization of recombinant Escherichia coli harboring glycerol dehydrogenase with the specific recognition between glycoconjugates and glycoprotein. The effect of various factors on the immobilization including temperature, pH, cell concentration and immobilization time were investigated. The highest immobilization yield of 91% was obtained under the conditions: enzyme/support 1.28mg/mg, pH 8.0, immobilization time 2h and temperature 4 degrees C. The obtained immobilized cell was characterized and exhibited higher thermal stability compared with the free cell. After ten cycles, the immobilized cell remained 62% initial activity. These results indicate that the cell immobilized onto conA-grafted nanoparticles by specific recognition of glycoconjugates and glycoprotein is a potential method for preparation of stable cell, and the immobilized cell showed perspective applications in the biocatalysis and biosensors. PMID- 28559184 TI - Morinda citrifolia lipid transfer protein 1 exhibits anti-inflammatory activity by modulation of pro- and anti-inflammatory cytokines. AB - Previous reports have demonstrated that a thermostable lipid transfer protein isolated from noni seeds (McLTP1; 9.4kDa) displays anti-nociceptive and anti inflammatory activities. This work aimed to investigate the underlying mechanisms of the anti-inflammatory activity of McLTP1 in mice. The protein was solubilised in sterile saline (0.9% NaCl) immediately before the treatment of mice by oral or intraperitoneal routes at doses of 8mg/kg. Given orally or intraperitoneally, McLTP1 significantly inhibited (p<0.05) cell migration in experimental models of carrageenan-induced peritonitis and the formation of paw oedema induced by carrageenan and dextran. Additionally, McLTP1 demonstrated the ability to significantly inhibit the production of the cytokines IL-1beta, IL-6, and TNF alpha (p<0.05) and to promote an increase in the production of the anti inflammatory cytokine IL-10. The treatment of mice with McLTP1 by the oral or i.p route reduced pancreatic injury and activities of amylase, lipase, and pancreatitis-associated lung injury. This study suggested that the observed anti inflammatory effects of McLTP1 can be related to modulation of pro- and anti inflammatory cytokine levels. PMID- 28559185 TI - Novel dendritic structure of alginate hybrid nanoparticles for effective anti viral drug delivery. AB - Lipid-polymer hybrid nanoparticles have recently gathered much attention as nanoplatforms for drug delivery applications due to their unique structural properties. In this study zidovudine (AZT) loaded hybrid nanoparticles of alginate (ALG) and stearic acid- poly ethylene glycol (SA-PEG) were synthesized. The structural characterization of drug loaded hybrid nanoparticles were studied using FT-IR spectroscopy, DLS and TEM analysis. These hybrid nanoparticles showed dendritic morphology and it can be used as an efficient carrier for zidovudine. In this drug loaded hybrid system of Alginate -Stearicacid/Poly (ethyleneglycol) Nanoparticles (ASNPs), AZT and alginate form the core wherein SA-PEG forms the external shell. We observed a dendritic morphology with internal voids and channels formed by the core molecule and the external shell forms the closed pack surface groups. The optimized formulation achieved a sub micron size of 407.67+/ 19.18nm with drug encapsulation of 83.18+/-1.22%, and surface potential of 42.53mV, and has significant stability for six months. Haemolysis and aggregation studies revealed that there were no lysis and aggregation in WBC, RBC and platelets. In-vitro cytotoxicity and cellular uptake of the nanoparticles in Glioma, Neuro2a and Hela cells showed that ASNPs are non toxic. The results indicate that the synthesized hybrid nanoparticles represent a potential carrier for zidovudine, thus possibly increasing zidovudine's efficiency as an anti-HIV drug. PMID- 28559186 TI - Multidrug ABC transporter Cdr1 of Candida albicans harbors specific and overlapping binding sites for human steroid hormones transport. AB - The present study examines the kinetics of steroids efflux mediated by the Candida drug resistance protein 1 (Cdr1p) and evaluates their interaction with the protein. We exploited our in-house mutant library for targeting the 252 residues forming the twelve transmembrane helices (TMHs) of Cdr1p. The screening revealed 65 and 58 residues critical for beta-estradiol and corticosterone transport, respectively. Notably, up to 83% critical residues for corticosterone face the lipid interface compared to 54% for beta-estradiol. Molecular docking identified a possible peripheral corticosterone-binding site made of 8/14 critical/non-critical residues between TMHs 3, 4 and 6. beta-estradiol transport was severely hampered by alanine replacements of Cdr1p core residues involving TMHs 2, 5 and 8, in a binding site made of 10/14 critical residues mainly shared with rhodamine 6G with which it competes. By contrast, TMH11 was poorly impacted, although being part of the core domain. Finally, we observed the presence of several contiguous stretches of 3-5 critical residues in TMHs 2, 5 and 10 that points to a rotation motion of these helices during the substrate transport cycle. The selective structural arrangement of the steroid-binding pockets in the core region and at the lipid-TMD interface, which was never reported before, together with the possible rotation of some TMHs may be the structural basis of the drug-transport mechanism achieved by these type II ABC transporters. PMID- 28559187 TI - Gap junction gene and protein families: Connexins, innexins, and pannexins. AB - Gap junction channels facilitate the intercellular exchange of ions and small molecules. While this process is critical to all multicellular organisms, the proteins that form gap junction channels are not conserved. Vertebrate gap junctions are formed by connexins, while invertebrate gap junctions are formed by innexins. Interestingly, vertebrates and lower chordates contain innexin homologs, the pannexins, which also form channels, but rarely (if ever) make intercellular channels. While the connexin and the innexin/pannexin polypeptides do not share significant sequence similarity, all three of these protein families share a similar membrane topology and some similarities in quaternary structure. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve. PMID- 28559188 TI - The flexible cytoplasmic loop 3 contributes to the substrate affinity of human monocarboxylate transporters. AB - Human monocarboxylate transporters (hMCTs/SLC16As) mediate the transport of small molecular weight monocarboxylates. Among hMCTs, hMCT1 exhibits high-affinity l lactate transport and broad substrate recognition, whereas hMCT4 shows highly specific substrate recognition and low-affinity l-lactate transport, indicating that hMCT1 and hMCT4 have different roles in the body. However, the molecular mechanism of transporter-mediated substrate transport remains unknown. The aim of this study is to identify the domain, which determines the substrate selectivity and affinity of hMCT1 and hMCT4. We constructed a chimera, hMCT4/1, in which the cytoplasmic loop 3 (TM6/7loop) region of hMCT4 was replaced by the corresponding region of hMCT1. Xenopus laevis oocyte heterologous expression system was used to characterize functional features of the chimera. We have demonstrated that the substrate affinity of hMCT1 and hMCT4 depends on the TM6/7loop. Non-conserved His237 residue in the TM6/7loop functions as a regulatory moiety of the substrate affinity. In contrast, the substrate selectivity of the transporters did not depend on the TM6/7loop, suggesting that the domain is not directly involved in substrate recognition. Our study provides important insights into the structures and functions of hMCT1 and hMCT4 transporters. These findings contribute to the development of novel hMCT1 and/or hMCT4 inhibitors as anticancer agents. PMID- 28559190 TI - Occipital, parietal, and frontal cortices selectively maintain task-relevant features of multi-feature objects in visual working memory. AB - Previous studies have shown that information held in visual working memory is represented in the occipital, parietal, and frontal cortices. However, less is known about whether the mnemonic information of multi-feature objects is modulated by task demand in the parietal and frontal regions. To address this question, we asked participants to remember either color or orientation of one of the two colored gratings for a delay. Using fMRI and an inverted encoding model, we reconstructed population-level, feature-selective responses in the occipital, parietal and frontal cortices during memory maintenance. We found that not only orientation but also color information can be maintained in higher-order parietal and frontal cortices as well as the early visual cortex when it was cued to be remembered. Conversely, neither the task-irrelevant feature of the cued object, nor any feature of the uncued object was maintained in the occipital, parietal, or frontal cortices. These results suggest a highly selective mechanism of visual working memory that maintains task-relevant features only. PMID- 28559191 TI - Hope and the brain: Trait hope mediates the protective role of medial orbitofrontal cortex spontaneous activity against anxiety. AB - As a central research topic in the field of positive psychology, hope refers to an individual's goal-oriented expectations that include both agency thinking (i.e., the motivation to initiate and sustain actions to achieve goals) and pathway thinking (i.e., the capacity to find ways toward goals). Evidence from many previous studies has shown the role of hope in protecting against anxiety. However, little is known about the neurobiological basis of hope and the underlying mechanism that how hope reduces anxiety in the brain. Here, we employed fractional amplitude of low-frequency fluctuations (fALFF) to investigate these issues in 231 high school students using resting-state functional magnetic resonance imaging (RS-fMRI). The whole-brain correlation analyses revealed that higher trait hope was related to lower fALFF in the bilateral medial orbitofrontal cortex (mOFC), which is involved in reward-related processing, motivation production, problem solving and goal-directed behaviors. Furthermore, mediation analyses suggested that trait hope acted as a mediator in the association between mOFC spontaneous activity and anxiety. These results persisted even after adjusting for the effects of positive and negative affect. Overall, this study provides the first evidence for functional brain substrates underlying trait hope and reveals a potential mechanism that trait hope mediates the protective role of spontaneous brain activity against anxiety. PMID- 28559193 TI - Effect of Stem Size and Fixation Method on Mechanical Failure After Revision Total Knee Arthroplasty. AB - BACKGROUND: Although the need for stemmed components is well accepted to improve mechanical survival in revision total knee arthroplasty (TKA), the ideal fixation method and stem design remain controversial. METHODS: We performed a retrospective review of 223 patients who underwent revision TKA in whom stemmed components had not been used previously and with a mean follow-up of 61.6 months, including 108 components with fully cemented stems and 316 components with "hybrid" press-fit stems. RESULTS: Based on a time to event model, risk for mechanical failure was equivalent for both cemented and hybrid stems (relative risk, 0.991; P = .98). Young age was the single greatest risk factor for mechanical failure (P = .006). Although there was a trend toward increased failure with cemented stems in patients aged <65 years, there was no significant difference in risk after accounting for covariates (relative risk, 1.4; P = .50). Intramedullary canal fill, not stem length or diameter, was the strongest predictor of failure with hybrid stems, and risk was reduced by 41.2% for each additional 10% canal fill. CONCLUSION: In conclusion, both cemented and hybrid modular stems are viable options in revision TKA. Surgeons should attempt to maximize canal filling of hybrid stems to obtain a solid press-fit. In addition, further studies are needed to evaluate the long-term survival of cemented stem fixation in young patients. PMID- 28559192 TI - Spatio-temporal TGV denoising for ASL perfusion imaging. AB - In arterial spin labeling (ASL) a perfusion weighted image is achieved by subtracting a label image from a control image. This perfusion weighted image has an intrinsically low signal to noise ratio and numerous measurements are required to achieve reliable image quality, especially at higher spatial resolutions. To overcome this limitation various denoising approaches have been published using the perfusion weighted image as input for denoising. In this study we propose a new spatio-temporal filtering approach based on total generalized variation (TGV) regularization which exploits the inherent information of control and label pairs simultaneously. In this way, the temporal and spatial similarities of all images are used to jointly denoise the control and label images. To assess the effect of denoising, virtual ground truth data were produced at different SNR levels. Furthermore, high-resolution in-vivo pulsed ASL data sets were acquired and processed. The results show improved image quality, quantitative accuracy and robustness against outliers compared to seven state of the art denoising approaches. PMID- 28559194 TI - Comparison of Perioperative Adverse Event Rates After Total Knee Arthroplasty in Patients With Diabetes: Insulin Dependence Makes a Difference. AB - BACKGROUND: Total knee arthroplasty (TKA) is an effective treatment option for patients with advanced osteoarthritis and has become one of the most frequently performed orthopedic procedures. With the increasing prevalence of diabetes mellitus (DM), the burden of its sequela and associated surgical complications has also increased. For these reasons, it is important to understand the association between DM and the rates of perioperative adverse events after TKA. METHODS: A retrospective cohort study was conducted using the American College of Surgeons National Surgical Quality Improvement Program database. Patients who underwent TKA between 2005 and 2014 were identified and characterized as having insulin-dependent DM (IDDM), non-insulin-dependent DM (NIDDM), or not having DM. Multivariate Poisson regression was used to control for demographic and comorbid factors and to assess the relative risks of multiple adverse events in the initial 30 postoperative days. RESULTS: A total of 114,102 patients who underwent TKA were selected (IDDM = 4881 [4.3%]; NIDDM = 15,367 [13.5%]; and no DM = 93,854 [82.2%]). Patients with NIDDM were found to be at greater risk for 2 of 17 adverse events studied relative to patients without DM. However, patients with IDDM were found to be at greater risk for 12 of 17 adverse events studied relative to patients without DM. CONCLUSION: In comparison with patients with NIDDM, patients with IDDM are at greater risk for many more perioperative adverse outcomes relative to patients without DM. These findings have important implications for patient selection, preoperative risk stratification, and postoperative expectations. PMID- 28559189 TI - The role of connexin and pannexin containing channels in the innate and acquired immune response. AB - Connexin (Cx) and pannexin (Panx) containing channels - gap junctions (GJs) and hemichannels (HCs) - are present in virtually all cells and tissues. Currently, the role of these channels under physiological conditions is well defined. However, their role in the immune response and pathological conditions has only recently been explored. Data from several laboratories demonstrates that infectious agents, including HIV, have evolved to take advantage of GJs and HCs to improve viral/bacterial replication, enhance inflammation, and help spread toxicity into neighboring areas. In the current review, we discuss the role of Cx and Panx containing channels in immune activation and the pathogenesis of several infectious diseases. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve. PMID- 28559196 TI - Quantifying Pelvic Motion During Total Hip Arthroplasty Using a New Surgical Navigation Device. AB - BACKGROUND: Accurate cup positioning is one of the most challenging aspects of total hip arthroplasty (THA). Undetected movement of the patient during THA surgery can lead to inaccuracies in cup anteversion and inclination, increasing the potential for dislocation and revision surgery. Investigations into the magnitude of patient motion during THA are not well represented in the literature. METHODS: We analyzed intraoperative pelvic motion using a novel navigation device used to assist surgeons with cup position, leg length, and offset during THA. This device uses an integrated accelerometer to measure motion in 2 orthogonal degrees of freedom. We reviewed the data from 99 cases completed between February and September 2016. RESULTS: The mean amount of pitch recorded per patient was 2.7 degrees (standard deviation, 2.2; range, 0.1 degrees -9.9 degrees ), whereas mean roll per patient was 7.3 degrees (standard deviation, 5.5; range, 0.3 degrees -31.3 degrees ). Twenty-one percent (21 of 99) of patients demonstrated pitch of >4 degrees . Sixty-nine percent (68 of 99) of patients demonstrated >4 degrees of roll, and 25% (25 of 99) of patients demonstrated roll of >=10 degrees . CONCLUSION: Our findings indicate that while the majority of intraoperative motion is <4 degrees , many patients experience significant roll, with a large proportion rolling >10 degrees . This degree of movement has implications for acetabular cup position, as failure to compensate for this motion can result in placement of the cup outside the planned safe zone, thus, increasing the potential for dislocation. Further study is warranted to determine the effect of this motion on cup position, leg length, and offset. PMID- 28559197 TI - Anteroposterior Rotational References of the Tibia for Medial Unicompartmental Knee Arthroplasty in Japanese Patients. AB - BACKGROUND: In unicompartmental knee arthroplasty (UKA), there is no consensus regarding how to determine the anteroposterior (AP) reference of the tibia. A number of surgeons in Japan perform the sagittal saw cut using the medial intercondylar ridge (MIR) of the tibia according to surgical manuals. However, there is no theoretical basis for this practice. METHODS: Preoperative computed tomography data from 32 lower limbs of 31 Japanese patients who received UKA were used. First, the angles between the surgical epicondylar axis and the MIR and the substitute AP (sAP) line connecting the medial border of the patellar tendon at the articular surface level and the medial intercondylar tubercle were measured. Next, the mediolateral (ML)/AP ratio of the tibial cut surface was measured when cut parallel to the MIR and sAP line. Finally, the ML/AP ratio of the tibial component was investigated in 4 contemporary UKA implants. RESULTS: The MIR and sAP line were externally rotated 94.9 degrees +/- 4.1 degrees and 90.4 degrees +/- 3.6 degrees relative to the surgical epicondylar axis, respectively. Compared with a cut parallel to the MIR, the mean ML/AP ratio of the cut surface was significantly larger, and the ML/AP ratio was closer to the ML/AP ratio of the components for a cut parallel to the sAP line. CONCLUSION: Obtaining the tibial AP orientation is one of the key steps not only in total knee arthroplasty but also in UKA. The sagittal cut referencing the sAP line provides better AP rotation and fitting of the tibia in UKA than referencing the MIR. PMID- 28559195 TI - Magnitude of Deformity Correction May Influence Recovery of Quadriceps Strength After Total Knee Arthroplasty. AB - BACKGROUND: Malalignment of the lower extremity is commonly seen in patients with severe osteoarthritis undergoing total knee arthroplasty (TKA) and is believed to play a role in quadriceps strength loss. Deformity correction is typically achieved through surgical techniques to provide appropriate ligamentous balancing. Therefore, this study examined the influence of change in lower extremity alignment on quadriceps strength outcomes after TKA. METHODS: Seventy three participants (36 male; mean age, 62 years; and mean body mass index, 29.7 kg/m2) undergoing primary unilateral TKA were used in this investigation. Before surgery and at 1 and 6 months after surgery, measures of isometric knee extensor strength, quadriceps activation, and long-standing plain films were collected. Using the films, measures of mechanical axis, distal femoral angle (DFA), proximal tibial angle, and patellofemoral angle were performed. Hierarchical linear regression was used to evaluate how change in alignment from baseline to 1 and 6 months influenced the change in quadriceps strength. RESULTS: DFA was found to significantly contribute to changes in quadriceps strength at 1 and 6 months after TKA above those contributed by associated covariates. None of the other measures of lower extremity alignment were found to contribute to quadriceps strength in this sample. CONCLUSION: Reductions in quadriceps strength experienced after TKA are likely to be influenced by changes in lower extremity alignment. Specifically, measures of DFA were found to significantly contribute to these changes. Future work is needed to prospectively examine measures of lower extremity alignment change and recovery after TKA. PMID- 28559199 TI - Commentary on "The effect of social media (#SoMe) on journal impact factor and parental awareness in paediatric urology". PMID- 28559198 TI - Modified Frailty Index Is an Effective Risk Assessment Tool in Primary Total Hip Arthroplasty. AB - BACKGROUND: Frailty is described as decreased physiological reserve and typically increasing with age. Hospitals are being penalized for reoperations and readmissions, which can affect reimbursement. The purpose of this study was to determine if the modified frailty index (MFI) could be used as a risk assessment tool for preoperative counseling and to make an objective decision on whether to perform total hip arthroplasty (THA) on a frail patient. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried by Current Procedural Terminology code for primary THA (27130) from 2005 to 2014. MFI was calculated using 11 variables extracted from the medical record. Bivariate analysis was performed for outcomes and complications, and the multiple logistic regression model was used to compare MFI with other predictors of readmission, any complication, and reoperation. RESULTS: A total of 51,582 patients underwent primary THA during the study period. MFI was a significant and stronger predictor than the American Society of Anesthesiologists class and age for readmission (odds ratio [OR], 14.72; 95% confidence interval [CI], 6.95 31.18; P < .001), any complication (OR, 3.63; 95% CI, 1.64-8.05; P = .002), and reoperation (OR, 8.78; 95% CI, 3.67-20.98; P < .001). As MFI increased, adverse discharge, any complication, readmission, reoperation, and mortality significantly increased (P < .001). Rates of systemic complications and length of stay significantly increased with increasing MFI. CONCLUSION: MFI is a simple and effective risk assessment tool to preoperatively counsel and make an objective decision on whether to perform THA on a frail patient. PMID- 28559200 TI - External Validation of the New International Association for the Study of Lung Cancer Tumor, Node, and Metastasis 8th Edition Staging System and Updated T Descriptors in Determining Prognosis for Patients With Non-Small Cell Lung Cancer Patients With N3 Disease. AB - OBJECTIVE: The objective of this study is to externally validate the 8th Edition of the Tumor, Node, and Metastasis staging system and its updated T descriptors in patients with non-small cell lung cancer with N3 disease. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database. Chi square test, Kaplan-Meier method, and Cox regression models were used in SPSS 23.0 (IBM Corp, Armonk, NY). RESULTS: A total of 7732 patients with non-small cell lung cancer with T1-4N3M0 disease from 1988 to 2013 were identified. A total of 1410 patients (18.2%) had T1N3 disease, 2491 patients (32.2%) had T2N3 disease, 1563 patients (20.2%) had T3N3 disease, and 2268 patients (29.3%) had T4N3 disease. The 5-year overall survival (OS) for the entire cohort was 8.4%. There was a significant difference in OS concerning T stage (T1N3: 10.8% vs. T2N3: 8.3% vs. T3N3: 8.1% vs. T4N3: 7.3%; P < .001). When stratified by the median age of patients (66 years), a significant difference in OS by stage of disease (IIIB vs. IIIC) was still observed in both the younger (P < .001) and older (P < .001) patient populations. A significant difference in disease specific survival (DSS) was observed by T stage (T1N3: 14.7% vs. T2N3: 11.6% vs. T3N3: 11.3% vs. T4N3: 9.7%; P < .001). On multivariate analysis, T stage, year of diagnosis, age, gender, histology, and receipt of radiotherapy remained independent prognostic factors for both OS and DSS. CONCLUSIONS: The 8th Edition of the Tumor, Node, and Metastasis staging system significantly stratifies both overall and DSS between stages IIIB and IIIC among those with N3 disease. However, small absolute differences in 5-year outcomes between T stage may suggest limited clinical relevance. PMID- 28559201 TI - Dysregulated miR-127-5p contributes to type II collagen degradation by targeting matrix metalloproteinase-13 in human intervertebral disc degeneration. AB - BACKGROUND: Intervertebral disc degeneration (IDD) is a chronic disease associated with the degradation of extracellular matrix (ECM). Matrix metalloproteinase (MMP)-13 is a major enzyme that mediates the degradation of ECM components. MMP-13 has been predicted to be a potential target of miR-127-5p. However, the exact function of miR-127-5p in IDD is still unclear. OBJECTIVE: We designed this study to evaluate the correlation between miR-127-5p level and the degeneration of human intervertebral discs and explore the potential mechanisms. METHODS: miR-127-5p levels and MMP-13 mRNA levels were detected by quantitative real-time polymerase chain reaction (qPCR). To determine whether MMP-13 is a target of miR-127-5p, dual luciferase reporter assays were performed. miR-127-5p mimic and miR-127-5p inhibitor were used to overexpress or downregulate miR-127 5p expression in human NP cells, respectively. Small interfering RNA (siRNA) was used to knock down MMP-13 expression in human NP cells. Type II collagen expression in human NP cells was detected by qPCR, western blotting, and immunofluorescence staining. RESULTS: We confirmed that miR-127-5p was significantly downregulated in nucleus pulposus (NP) tissue of degenerative discs and its expression was inversely correlated with MMP-13 mRNA levels. We reveal that MMP-13 may act as a target of miR-127-5p. Expression of miR-127-5p was inversely correlated with type II collagen expression in human NP cells. Moreover, suppression of MMP-13 expression by siRNA blocked downstream signaling and increased type II collagen expression. CONCLUSION: Dysregulated miR-127-5p contributed to the degradation of type II collagen by targeting MMP-13 in human IDD. Our findings highlight that miR-127-5p may serve as a new therapeutic target in IDD. PMID- 28559202 TI - Inhibitory effects of rosmarinic acid on pterygium epithelial cells through redox imbalance and induction of extrinsic and intrinsic apoptosis. AB - Pterygium is a common tumor-like ocular disease, which may be related to exposure to chronic ultraviolet (UV) radiation. Although the standard treatment for pterygium is surgical intervention, the recurrence rate of pterygium is high when no effective inhibitory drug is used after surgery. Rosmarinic acid (RA) is a polyphenol antioxidant with many biological activities, including anti-UV and anti-tumor properties. This study aimed to examine the inhibitory effects of RA on pterygium epithelial cells (PECs). Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay was used to examine the cell cytotoxicity of PECs after RA treatment. A fluorescent probe, DCFH-DA (2',7'-dichlorofluorescin diacetate), was stained with PECs to measure intracellular reactive oxygen species (ROS) levels. Antioxidant activity assays were used to measure the levels of superoxide dismutase (SOD) and catalase (CAT) in PECs. Western blot analysis was used to determine the protein expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), quinone acceptor oxidoreductase 1 (NQO1), and apoptosis associated proteins. RA significantly reduced the cell viability of the PECs. Treatment with RA remarkably increased the Nrf2 protein expression levels in the nucleus, HO-1 and NQO1 protein expression levels, and the activities of SOD and CAT. As a result, intracellular ROS levels in PECs were decreased. Additionally, the induction of extrinsic apoptosis on PECs by RA was associated with increasing expressions levels of Fas, Fas-associated protein with death domain (FADD), tumor necrosis factor-alpha (TNF-alpha), and caspase 8 protein. Moreover, the induction of intrinsic apoptotic cell death in PECs was confirmed through upregulation of cytochrome c, Bax, caspase 9, and caspase 3 and downregulation of Bcl-2 and pro caspase 3. Our study demonstrated that RA could inhibit the viability of PECs through regulation of extrinsic and intrinsic apoptosis pathways. Therefore, RA may have potential as a therapeutic medication for pterygium. PMID- 28559203 TI - Is antimicrobial photodynamic therapy an effective treatment for chronic periodontitis in diabetes mellitus and cigarette smokers: a systematic review and meta-analysis. AB - BACKGROUND: To determine whether treatment with antimicrobial photodynamic therapy (aPDT) as an adjunct to scaling and root planing (SRP) improves clinical, microbiological and immunological outcomes in type 2 diabetes mellitus (T2DM) and cigarette smokers with chronic periodontitis (CP). METHODS: Databases (MEDLINE, PubMed; Cochrane Central Register of Controlled Trials and Cochrane Oral Health Group Trials Register) were searched up to and including May 2017. The addressed PICO question was: "Does aPDT as an adjunct to SRP improves clinical, microbiological and immunological outcomes in T2DM and smokers with CP?" RESULTS: Six randomized clinical trials were included. All studies reporting clinical periodontal, microbiological, and immunological parameters showed that aPDT was effective in the treatment of CP in T2DM and smokers at follow up. When compared with SRP alone, none of the studies showed additional benefits of aPDT at follow up. Considering the effects of adjunctive aPDT as compared to SRP on clinical signs of CP in T2DM and smokers, no difference could be observed for all evaluated parameters (PD: Z=-0.81, P=0.41; CAL: Z=-0.19, P=0.84) except IL-1beta (Z=4.57, P<0.001). CONCLUSION: Due to limited evidence, it remains debatable whether aPDT as an adjunct to SRP is effective in improving clinical, microbiological and immunological outcomes compared to SRP alone in T2DM and smokers with CP. Further well-designed, large-scale clinical trials with microbiological parameters and long follow up periods are needed in order to assess the efficacy of adjunctive aPDT in T2DM and cigarette smokers with CP. PMID- 28559204 TI - Supine posture affects cortical plasticity in elderly but not young women during a word learning-recognition task. AB - The present research investigated the hypothesis that elderly and horizontal body position contribute to impair learning capacity. To this aim, 30 young (mean age: 23.2 years) and 20 elderly women (mean age: 82.8 years) were split in two equal groups, one assigned to the Seated Position (SP), and the other to the horizontal Bed Rest position (hBR). In the Learning Phase, participants were shown 60 words randomly distributed, and in the subsequent Recognition Phase they had to recognize them mixed with a sample of 60 new words. Behavioral analyses showed age-group effects, with young women exhibiting faster response times and higher accuracy rates than elderly women, but no interaction of body position with age group was found. Analysis of the RP component (250-270ms) revealed greater negativity in the left Occipital gyrus/Cuneus of both sitting age-groups, but significantly left-lateralized RP in left Lingual gyrus only in young bedridden women. Elderly hBR women showed a lack of left RP lateralization, the main generator being located in the right Cuneus. Young participants had the typical old/new effect (450-800ms) in different portions of left Frontal gyri/Uncus, whereas elderly women showed no differences in stimulus processing and its location. EEG alpha activity analyzed during a 3min resting state, soon after the recognition task, revealed greater alpha amplitude (i.e., cortical inhibition) in posterior sites of hBR elderly women, a result in line with their inhibited posterior RP. In elderly women the left asymmetry of RP was positively correlated with both greater accuracy and faster responses, thus pointing to a dysfunctional role, rather than a compensatory shift, of the observed right RP asymmetry in this group. This finding may have important clinical implications, with particular regard to the long-term side-effects of forced Bed Rest on elderly patients. PMID- 28559205 TI - Behavioral and electrophysiological correlates of cognitive control in ex-obese adults. AB - Impaired cognitive control functions have been documented in obesity. It remains unclear whether these functions normalize after weight reduction. We compared ex obese individuals, who successfully underwent substantial weight loss after bariatric surgery, to normal-weight participants on measures of resistance to interference, cognitive flexibility and response inhibition, obtained from the completion of two Stroop tasks, a Switching task and a Go/NoGo task, respectively. To elucidate the underlying brain mechanisms, event-related potentials (ERPs) in the latter two tasks were examined. As compared to controls, patients were more susceptible to the predominant but task-irrelevant stimulus dimension (i.e., they showed a larger verbal Stroop effect), and were slower in responding on trials requiring a task-set change rather than a task-set repetition (i.e., they showed a larger switch cost). The ERP correlates revealed altered anticipatory control mechanisms (switch positivity) and an exaggerated conflict monitoring response (N2). The results suggest that cognitive control is critical even in ex-obese individuals and should be monitored to promote weight loss maintenance. PMID- 28559207 TI - Corticosterone regulation in house sparrows invading Senegal. AB - What traits help organisms expand their ranges? Several behavioral and life history traits have been identified, but physiological and especially endocrinological factors have been minimally considered. Here, we asked whether steroid hormonal responses to stressors might be important. Previously, we found that corticosterone (CORT) responses to a standard restraint stressor were stronger at a range edge than at the core of the recent house sparrow (Passer domesticus) invasion of Kenya. In related work in the same system, we found that various behaviors (exploratory activity, responses to novelty, etc.) that are affected by CORT in other systems varied among sparrow populations in a manner that would suggest that CORT regulation directly influenced colonization success; birds at the range edge were less averse to novelty and more exploratory than birds from the core. Here, we asked whether the pattern in CORT regulation we observed in Kenya was also detectable in the more recent (~1970) and independent invasion of Senegal. We found, as in Kenya, that Senegalese range-edge birds mounted stronger CORT responses to restraint than core birds. We also found lower baseline CORT in range-edge than core Senegalese birds, but little evidence for effects of individual sex, body mass or body size on CORT. Follow-up work will be necessary to resolve whether CORT regulation in Senegal (and Kenya) actively facilitated colonization success, but our work implicates glucocorticoids as a mediator of range expansion success, making stress responses potentially useful biomarkers of invasion risk. PMID- 28559206 TI - Working hard for oneself or others: Effects of oxytocin on reward motivation in social anxiety disorder. AB - There is some evidence to suggest that oxytocin promotes social behavior, especially for disorders characterized by social dysfunction, such as social anxiety disorder (SAD). The goal of this study was to examine the effect of oxytocin on reward motivation in SAD. We tested whether oxytocin promotes prosocial, or antisocial, self-directed decisions, and whether its effects depended on social anxiety severity and attachment. Fifty-two males with SAD received 24 international units of oxytocin or placebo, and completed a reward motivation task that measured willingness to work for self vs. other monetary rewards. Although there was no main drug effect, social anxiety severity moderated the effect of oxytocin. Less socially anxious individuals who received oxytocin worked harder for other vs. own rewards, compared to high socially anxious individuals. Attachment did not moderate this effect. Among people with SAD, oxytocin enhances prosocial behaviors in individuals with relatively lower levels of social anxiety. National Institutes of Health ClinicalTrials.gov Registry #NCT01856530. https://clinicaltrials.gov/ct2/show/NCT01856530?term=oxytocin+pro-social&rank=2. PMID- 28559208 TI - Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms. AB - Cenani-Lenz syndactyly syndrome (CLSS; MIM-212780) is a rare autosomal recessive limb malformation characterized by complete osseous fusion of all fingers and toes, disorganization of phalangeal elements and severe shortening of the radius and ulna. It is occasionally associated with renal hypoplasia, oro-facial defects, scoliosis of the thoracic spine, hearing loss, and genital anomalies. Here we describe a consanguineous Pakistani kindred with a severe form of CLSS characterized by complete syndactyly and disorganization of fingers, oligo syndactyly of toes, shortening of limbs, frontal bossing, and hypoplasia/agenesis of left kidney. The affected individuals were additionally presented with short stature, cleft-lip and hypoplastic shoulder joint with restricted upper limb movement. A novel splice variant in LRP4 (c.316+1G > A) segregated with the phenotype in a five generations family. The mutation is predicted to add 29 non native amino acids with a premature termination, resulting in approximately 90% length reduction of the wild-type transcript. These findings not only further expand the phenotypic variability of CLSS but also indicate that early truncated and loss-of-function mutations in LRP4 lead to a more severe CLSS phenotype. PMID- 28559209 TI - Short post-weaning social isolation induces long-term changes in the dopaminergic system and increases susceptibility to psychostimulants in female rats. AB - Childhood and adolescence are sensitive periods of development, marked by high brain maturation and plasticity. Exposure to early life stress, such as social isolation, is able to prompt changes in sensitive brain circuitries, essentially in the mesolimbic dopaminergic system and increase the risk for addictive behaviors later in life. Post-weaning social isolation can stimulate the consumption of rewarding substances, like drugs of abuse and palatable foods. However, most studies analyze long periods of social isolation and very little is known about the effects of a brief social isolation in a sensitive period of development and its association with palatable food on the reward system sensitization. Furthermore, females are more susceptible to the reinforcing effect of drugs than males. Therefore, the aim of this study was to analyze the effects of a short post-weaning social isolation combined with a free access to a chronic high sugar diet (HSD) on the dopaminergic system, oxidative status and behavioral response to an amphetamine-like drug in adulthood. We used female Wistar rats that were socially isolated from post-natal days (PD) 21 to 35 and received free access to a HSD until PD 60. On PD 65, animals were submitted to a challenge with diethylpropion (DEP), an amphetamine-like drug and different responses were analyzed: locomotor activity, immmunocontent of dopamine related proteins, and the oxidative status in the striatum, before and after the DEP challenge. We showed that a short post-weaning social isolation (SI) increased the locomotor response to DEP, when compared with previous saline administration. Social isolation also increased dopamine transporter, tyrosine hydroxylase, and decreased dopamine D2 receptor immunocontent. Additionally, SI increased the overall oxidative status parameters after the challenge with DEP. Interestingly, the exposure to a HSD prevented the SI effects on locomotor response, but did not interfere in the dopaminergic parameters evaluated, despite having modified some oxidative parameters. This study showed for the first time that a short post weaning social isolation was able to induce long-term changes in the striatal dopaminergic system and increased the response to psychostimulants. These results emphasize the importance of stressful experiences during a short period of development on programming susceptibility to psychostimulants later in life. PMID- 28559211 TI - Effect of orlistat on plasma lipids and body weight: A systematic review and meta analysis of 33 randomized controlled trials. AB - Orlistat, an inhibitor of intestinal lipase, promotes body weight reduction. The lipid-lowering efficacy of orlistat is controversial and the effect of orlistat induced body weight reduction on lipid changes has not been explored in meta regression analyses. A systematic literature search was conducted to identify randomized controlled trials investigating the efficacy of orlistat on plasma total, low-density lipoprotein and high-density lipoprotein cholesterol, triglycerides and lipoprotein(a) levels. Thirty-three studies were included in the meta-analysis (5522 and 4210 participants in the orlistat therapy and control groups, respectively). Orlistat reduced body weight (weighted mean difference: 2.12, p <0.001), total-cholesterol (weighted mean difference: -0.30mmol/L, p <0.001), low-density lipoprotein cholesterol (weighted mean difference: 0.27mmol/L, p <0.001), high-density lipoprotein cholesterol (weighted mean difference: -0.034mmol/L, p <0.001) and triglyceride (weighted mean difference: 0.09mmol/L, p <0.001) concentrations, while no effect on lipoprotein(a) was observed. Total- and low-density lipoprotein cholesterol-lowering were associated negatively with duration of orlistat treatment and positively with body weight changes. In conclusion, Orlistat treatment slightly reduces cholesterol and triglyceride levels, but not lipoprotein(a) levels. Total- and low-density lipoprotein cholesterol levels reductions are more consistent in patients with greater body weight reduction and shorter duration of orlistat treatment. PMID- 28559210 TI - Cinnamaldehyde in diabetes: A review of pharmacology, pharmacokinetics and safety. AB - Cinnamaldehyde, one of the active components derived from Cinnamon, has been used as a natural flavorant and fragrance agent in kitchen and industry. Emerging studies have been performed over the past decades to evaluate its beneficial role in management of diabetes and its complications. This review highlights recent advances of cinnamaldehyde in its glucolipid lowering effects, its pharmacokinetics, and its safety by consulting the Pubmed, China Knowledge Resource Integrated, China Science and Technology Journal, National Science and Technology Library, Wanfang Data, and the Web of Science Databases. For the inquiries, keywords such as Cinnamon, cinnamaldehyde, property, synthesis, diabetes, obesity, pharmacokinetics, and safety were used in various combinations. Accumulating evidence supports the notion that cinnamaldehyde exhibits glucolipid lowering effects in diabetic animals by increasing glucose uptake and improving insulin sensitivity in adipose and skeletal muscle tissues, improving glycogen synthesis in liver, restoring pancreatic islets dysfunction, slowing gastric emptying rates, and improving diabetic renal and brain disorders. Cinnamaldehyde exerts these effects through its action on multiple signaling pathways, including PPARs, AMPK, PI3K/IRS-1, RBP4-GLUT4, and ERK/JNK/p38MAPK, TRPA1-ghrelin and Nrf2 pathways. In addition, cinnamaldehyde seems to regulate the activities of PTP1B and alpha-amylase. Furthermore, cinnamaldehyde has the potential of metalizing into cinnamyl alcohol and methyl cinnamate and cinnamic acid in the body. Finally, there is a potential toxicity concern about this compound. In summary, cinnamaldehyde supplementation is shown to improve glucose and lipid homeostasis in diabetic animals, which may provide a new option for diabetic intervention. To this end, further scientific evidences are required from clinical trials on its glucose regulating effects and safety. PMID- 28559212 TI - Evolution of foraging behaviour: Deep intra-generic genetic divergence between territorial and non-territorial southern African patellid limpets. AB - Southern Africa is a biodiversity hotspot of patellid limpets, with three genera (Helcion, Cymbula and Scutellastra) identified and described in the region. Scutellastra is the most diverse and most frequently studied of these and, along with Cymbula, includes species with territorial and non-territorial foraging behaviours. We used three mitochondrial markers (12S rRNA, 16S rRNA and COI) and one nuclear marker (ATPSbeta intron) to assess evolutionary relationships among species of Cymbula and Scutellastra with these two foraging behaviours and to identify which foraging mode is the more ancient. Maximum Likelihood and Bayesian Inference phylogenetic analyses revealed that the species sharing a foraging type are monophyletic in both genera. Territoriality is a derived character, as the clades with this foraging type are nested within a tree that otherwise comprises non-territorial taxa. These include Helcion, which was recovered as sister to the Cymbula/Scutellastra clade, and the next basal genus, Patella, which is ancestral to all southern African patellogastropods. Deep genetic divergence between the two foraging traits reflects strong adaptive effects of resource partitioning in the evolution of southern African patellid limpets. PMID- 28559213 TI - Phylogenomic analysis of integral diiron membrane histidine motif-containing enzymes in ciliates provides insights into their function and evolutionary relationships. AB - The Integral Membrane Histidine Motif-containing Enzymes (IMHME) are a class of binuclear non-heme iron proteins widely distributed among prokaryotes and eukaryotes. They are characterized by a conserved tripartite motif consisting of eight to ten histidine residues. Their known function is the activation of the dioxygen moiety to serve as efficient catalysts for reactions of hydroxylation, desaturation or reduction. To date most studies on IMHME were carried out in metazoan, phototrophic or parasitic organisms, whereas genome-wide analysis in heterotrophic free living protozoa, such as the Ciliophora phylum, has not been undertaken. In the seven fully sequenced genomes available we retrieved 118 putative sequences of the IMHME type, albeit with large differences in number among the ciliates: 11 sequences in Euplotes octocarinatus, 7 in Ichthyophthirius multifiliis, 13 in Oxytricha trifallax, 18 in Stylonychia lemnae, 25 in Tetrahymena thermophila, 31 in Paramecium tetraurelia and 13 in Pseudocohnilembus persalinus. The pool of putative sequences was classified in 16 orthologous groups from which 11 were related to fatty acid desaturase (FAD) and 5 to the fatty acid hydroxylase (FAH) superfamilies. Noteworthy, a large diversity on the number and type of FAD / FAH proteins were found among the ciliates, a feature that, in principle, may be attributed to peculiarities of the evolutionary process, such as gene expansion and reduction, but also to horizontal gene transfer, as we demonstrate in this work. We identified twelve putative enzymatic activities, from which four were newly assigned activities: sphingolipid Delta4 desaturase, omega3/Delta15 fatty acid desaturase, a large group of alkane 1 monooxygenases, and acylamide-delta-3(E)-desaturase, although unequivocal allocation would require additional experiments. We also combined the phylogenetics analysis with lipids analysis, thereby allowing the detection of two enzymatic activities not previously reported: a C-5 sterol desaturase in P. tetraurelia and a delta-9 fatty acid desaturase in Cohnilembus reniformis. The analysis revealed a significant lower number of FAD's sequences in the spirotrichea ciliates than in the oligohymenophorea, emphasizing the importance of fatty acids trophic transfer among aquatic organisms as a source of variation in metabolic activity, individual and population growth rates, and reproduction. PMID- 28559214 TI - Novel salicylic acid-based chemically crosslinked pH-sensitive hydrogels as potential drug delivery systems. AB - In this work, salicylic acid (SA), a non-steroidal anti-inflammatory, was chemically incorporated into hydrogel systems to achieve sustained SA release profiles. With its anti-inflammatory properties, sustained release of SA would be relevant for treating diseases such as diabetes and cancer. In this work, SA was chemically incorporated into hydrogel systems via covalent attachment to an itaconate moiety followed by UV-initiated crosslinking using acrylic acid and poly(ethylene glycol) diacrylate. The chemical composition of the hydrogel system was confirmed using FT-IR spectroscopy. The SA-based hydrogels were designed as pH-responsive hydrogels, collapsing at acidic pH (1.2) values and swelling at higher pH (7.4) values for gastrointestinal-specific delivery. The hydrogel systems exhibited a pH-dependent SA release profile: SA release was much slower at pH 1.2 compared to pH 7.4. Under acidic pH conditions, 30wt% SA was released after 24h, whereas 100wt% SA was released in a sustained manner within 24h in pH 7.4 PBS buffer. The pore structure of the gel networks were studied using SEM and exhibit appropriate pore sizes (15-60MUm) for physically encapsulating drugs. In addition, rheological studies of the hydrogels proved that these systems are mechanically strong and robust. Mucoadhesive behaviors were confirmed using a Texture Analyzer, the work of adhesion for the hydrogels was around 290 g.mm and the maximum detachment force was around 135g. The SA-based hydrogels demonstrate great potential for oral delivery of bioactives in combination with SA to treat serious diseases such as cancer and diabetes. PMID- 28559215 TI - Physicochemical characterization of pH-responsive and fusogenic self-assembled non-phospholipid vesicles for a potential multiple targeting therapy. AB - In order to obtain nanocarriers suitable for the delivery of drugs in the treatment of cancer, pH-responsive nanovesicles capable of facilitating fusion (fusogenic nanovesicles) were synthesized and then their physicochemical characteristics were modified. These nanovesicles were made by combining polysorbates having different physicochemical features with the aim of realizing multiple-targeting nanoformulations suitable for in vitro treatment of cancer cells. Tween21 and Tween80 were self-assembled at different molar concentrations resulting in pH-responsive fusogenic nanovesicles with an average size of less than 150nm, and a narrow size distribution (polydispersity index) value of less than 0.2. Hydrophobic and hydrophilic fluorescent probes were loaded inside the nanovesicles in order to study their pH-responsiveness and fusogenic properties and it was noted that this process did not modify their physicochemical features. The pH-responsiveness and fusogenic assay demonstrated that the nanovesicles containing Tween21 at different molar ratios were pH-responsive and interacted with a synthetic model of a biological membrane supplemented with Ca2+ in the incubation medium. Fifty percent (molar ratio) of Tween21 was replaced with Tween80, since Tween80 can promote the adsorption of apolipoproteins (A-E) onto the surfaces of nanovesicles without altering their pH-responsiveness or fusogenic properties. In fact this equivalent molar concentration of Tween21 and Tween80 also maintained their degree of interaction with the apolipoproteins (A E). Doxorubicin hydrochloride-loaded nanovesicles were synthesized and physicochemically characterized in order to obtain nanoformulations suitable for anticancer treatment. The therapeutic nanovesicles showed physicochemical properties similar to those of empty nanoformulations, and maintained pH responsiveness, fusogenic properties and targeting versus the apolipoproteins (A E). The doxorubicin hydrochloride was loaded into the nanovesicles using both passive and pH gradient remote loading procedures. The latter provided the nanovesicles with an entrapment efficiency percentage of over 30%, which was much higher than the 10% that was obtained using the passive loading procedure. The entrapment efficiency improved up to 60% for the nanovesicles made from the same molar concentration of Tween21 and Tween80. The anticancer activity of doxorubicin hydrochloride-loaded nanovesicles was further tested in vitro using human neuroblastoma (SH-SY5Y) cells which respond to treatment with this chemotherapeutic drug, but the nanovesicles carrying it must cross the BBB by means of specific receptors before the drug can provide a therapeutic effect in vivo. The anticancer activity of these doxorubicin hydrochloride-loaded nanovesicles was time- and dosage- dependent, and the surfactant components making up the nanoformulations was also a determining factor in the efficiency of their activity. These nanovesicles could provide innovative nanotherapeutics for potential in vitro multidrug targeting therapy. PMID- 28559216 TI - PLGA nanoparticles introduction into mitoxantrone-loaded ultrasound-responsive liposomes: In vitro and in vivo investigations. AB - A novel ultrasound-responsive liposomal system for tumor targeting was prepared in order to increase the antitumor efficacy and decrease serious side effects. In this paper, PLGA nanoparticles were used ultrasound-responsive agents instead of conventional microbubbles. The PLGA-nanoparticles were prepared by an emulsion solvent evaporation method. The liposomes were prepared by a lipid film hydration method. Particle size, zeta potential, encapsulation efficiency and drug loading capacity of the liposomes were studied by light scattering analysis and dialysis. Transmission electron microscopy (TEM) and atomic force microscope (AFM) were used to investigate the morphology of liposomes. The release in vitro was carried out in the pH 7.4 phosphate buffer solutions, as a result, liposome L3 encapsulating PLGA-nanoparticles displayed good stability under simulative physiological conditions and quickly responsive release under the ultrasound. The release in vivo was carried out on the rats, as a result, liposome L3 showed higher bioavailability than traditional intravenous injectable administration, and liposome L3 showed higher elimination ratio after stimulation by ultrasound than L3 without stimulation. Thus, the novel ultrasound-responsive liposome encapsulating PLGA-nanoparticles has a potential to be developed as a new drug delivery system for anti-tumor drug. PMID- 28559217 TI - In vitro and in vivo behavior of ground tadalafil hot-melt extrudates: How the carrier material can effectively assure rapid or controlled drug release. AB - Different types of ground hot-melt extrudates loaded with 10, 20 or 30 % of the poorly water-soluble drug tadalafil were prepared and characterized in vitro and in vivo (in rats). Soluplus was used as an amorphous carrier material, whereas mannitol and lactitol were studied as crystalline matrix formers. The systems were characterized using X-ray powder diffraction, thermogravimetric analysis coupled with quadruple mass spectrometry, differential scanning calorimetry, X ray computed microtomography, in vitro drug release measurements and monitoring of drug plasma levels upon oral administration to rats. The pure drug substance and physical mixtures of tadalafil with the carrier materials were used as references. Importantly, the bioavailability of this poorly water-soluble drug could be substantially increased with the proposed formulations, and the in vitro and in vivo release rates could be effectively adjusted by choosing the appropriate type of carrier material: Whereas mannitol-based ground hot-melt extrudates rapidly released the drug and led to an early rise in drug plasma concentrations, Soluplus-based systems released tadalafil more slowly, resulting in delayed plasma peaks. These behaviors could be explained by the rapid disintegration/dissolution of the porous mannitol-based formulations, whereas Soluplus significantly swelled and the dissolved drug had to diffuse through the polymeric network prior to release. Blending these formulations can be expected to allow providing elevated drug concentrations in vivo during prolonged periods of time upon one single administration with a rapid onset of drug action. PMID- 28559218 TI - Argpyrimidine-tagged rutin-encapsulated biocompatible (ethylene glycol dimers) nanoparticles: Application for targeted drug delivery in experimental diabetes (Part 2). AB - Diabetes mellitus is characterized by hyperglycemia and associated complications. However, long-term diabetes control is not often sustained by currently available therapeutic approaches. Research on nanoparticle-mediated drug delivery systems is in progress. Here we have tested a ligand (argpyrimidine)-tagged drug (rutin) encapsulated biocompatible (ethylene glycol dimers) nanoparticle for targeted drug delivery in streptozotocin-induced diabetic rats. Argpyrimidine, being an advanced glycation end product (AGE), directs the nanoparticles to interact with cell surface receptors of AGEs (RAGE) and delivers the drug into the cells. The bioflavonoid rutin possesses antihyperglycemic property, and has been used for nanocapsulation. Two doses of nanoparticles containing 20mg rutin/kg body weight were administered (i.v. at 7days interval) into streptozotocin-induced diabetic rats. Compared to free rutin, nanoparticle treatment appears to be significantly more effective in controlling the diabetogenic effects - hyperglycemia, hyperlipidemia, oxidative stress etc, including heart-associated complications. This approach may thus be explored for drug delivery in the treatment of diabetes mellitus. PMID- 28559219 TI - A Short Note About the Reconsideration of the Image of Bayezid II Darussifa. PMID- 28559220 TI - Salivary Gland Choristoma of the Larynx. PMID- 28559221 TI - Amoxycillin and Metronidazole Therapy for Helicobacter pylori Eradication: A 10 Year Trend in Turin, Italy. PMID- 28559223 TI - Dropout From an eHealth Intervention for Adults With Type 2 Diabetes: A Qualitative Study. AB - BACKGROUND: Adequate self-management is the cornerstone of type 2 diabetes treatment, as people make the majority of daily treatment measures and health decisions. The increasing prevalence of type 2 diabetes mellitus (T2DM) and the complexity of diabetes self-management demonstrate the need for innovative and effective ways to deliver self-management support. eHealth interventions are promoted worldwide and hold a great potential in future health care for people with chronic diseases such as T2DM. However, many eHealth interventions face high dropout rates. This led to our interest in the experiences of participants who dropped out of an eHealth intervention for adults with T2DM, based on the Guided Self-Determination (GSD) counseling method. OBJECTIVE: In this study, we aimed to explore experiences with an eHealth intervention based on GSD in general practice from the perspective of those who dropped out and to understand their reasons for dropping out. To the best of our knowledge, no previous qualitative study has focused on participants who withdrew from an eHealth self-management support intervention for adults with T2DM. METHODS: A qualitative design based on telephone interviews was used to collect data. The sample comprised 12 adults with type 2 diabetes who dropped out of an eHealth intervention. Data were collected in 2016 and subjected to qualitative content analysis. RESULTS: We identified one overall theme: "Losing motivation for intervention participation." This theme was illustrated by four categories related to the participants' experiences of the eHealth intervention: (1) frustrating technology, (2) perceiving the content as irrelevant and incomprehensible, (3) choosing other activities and perspectives, and (4) lacking face-to-face encounters. CONCLUSIONS: Our findings indicate that the eHealth intervention based on GSD without face-to-face encounters with nurses reduced participants' motivation for engagement in the intervention. To maintain motivation, our study points to the importance of combining eHealth with regular face-to-face consultations. Our study also shows that the perceived benefit of the GSD eHealth intervention intertwined with choosing to focus on other matters in complex daily lives are critical aspects in motivation for such interventions. This indicates the importance of giving potential participants tailored information about the aim, the content, and the effort needed to remain engaged in complex interventions so that eligible participants are recruited. Finally, motivation for engagement in the eHealth intervention was influenced by the technology used in this study. It seems important to facilitate more user-friendly but high-security eHealth technology. Our findings have implications for improving the eHealth intervention and to inform researchers and health care providers who are organizing eHealth interventions focusing on self-management support in order to reduce dropout rates. PMID- 28559222 TI - Mobile App Design, Development, and Publication for Adverse Drug Reaction Assessments of Causality, Severity, and Preventability. AB - BACKGROUND: Adverse drug reactions (ADRs) cause significant morbidity and mortality. Improved assessment of ADRs to identify the causal relationship, the severity, and the preventability will aid ADRs prevention or reduce patient burden. OBJECTIVE: The aim of this study was to develop mobile apps in assisting clinical decision in ADR assessments of causality, severity, and preventability using validated tools. The usability of the apps was assessed. METHODS: We designed mobile apps using validated assessment tools for ADRs. They are the Liverpool ADRs Causality Assessment Tool, Hartwig's Severity Assessment Scale, and the Modified Schumock and Thronton Preventability Scale. The apps were named "Adverse Drug ReactionCausality," "Adverse Drug ReactionSeverity," and "Adverse Drug RxnPreventability." A survey was conducted using the System Usability Scale (SUS) to assess the usability of the developed apps among health care professionals. RESULTS: These apps are available for download through Google Play Store for free since January 2015. From the survey, the mean SUS score was 70.9 based on 26 responses from the pediatric ward of Hospital Ampang, Malaysia. CONCLUSIONS: The developed apps received an overall acceptable usability among health care professionals. The usage of these apps will improve detection, assessment, and avoidance of future ADRs. They will also contribute to future research on ADRs, thus increasing drug safety. PMID- 28559224 TI - Uptake of an Incentive-Based mHealth App: Process Evaluation of the Carrot Rewards App. AB - BACKGROUND: Behavioral economics has stimulated renewed interest in financial health incentives worldwide. The Carrot Rewards app was developed as part of a public-private partnership to reward Canadians with loyalty points (eg, movies and groceries) for downloading the app, referring friends, and completing an average of 1 to 2 educational health quizzes per week ("micro-learning"), with long-term objectives of increasing health knowledge and encouraging healthy behaviors. OBJECTIVE: The main objective of this study was to evaluate uptake of a loyalty points-based mHealth app during the exclusive 3-month launch period in British Columbia (BC), Canada. The secondary aims were to describe the health and sociodemographic characteristics of users, as well as participation levels (eg, proportion of quizzes completed and friends referred). METHODS: The app was promoted via loyalty program email campaigns (1.64 million emails). Number of downloads and registrations (users enter age, gender, and valid BC postal code to register) were collected. Additional sociodemographics were inferred by linking postal codes with census data at the local health area (LHA) level. Health risk assessments were also deployed. Participation levels were collected over 3 months and descriptive data were presented. RESULTS: In 3 months, 67,464 individuals downloaded the app; in its first week, Carrot Rewards was the most downloaded health app in Canada. Among valid users (n=57,885; at least one quiz completed), the majority were female (62.96%; 36,446/57,885) and aged 18 to 34 years (54.34%; 31,459/57,885). More than half of the users (52.40%; 30,332/57,885) resided in LHAs where the median personal income was below the provincial average (Can $28,765). Furthermore, 64.42% (37,291/57,885) of users lived in metropolitan (ie, urban) LHAs, compared with 56.17% of the general BC population. The most prevalent risk factors were "not" meeting physical activity guidelines (72.70%; 31,765/43,692) and "not" getting the flu shot last year (67.69%; 30,286/44,739). Regarding participation, 60.05% (34,761/57,885) of users were classified as "very high" engagers (>75% quiz completion rate). CONCLUSIONS: Early results suggest that loyalty points may promote mHealth app uptake. The app was downloaded by younger females especially, and BC residents from higher and lower income regions were equally represented. Loyalty points appear to have driven participation throughout the inaugural 3-month period (ie, quiz completion). PMID- 28559226 TI - Physician's Perceptions of Telemedicine in HIV Care Provision: A Cross-Sectional Web-Based Survey. AB - BACKGROUND: Telemedicine, or electronic interactive health care consultation, offers a variety of benefits to both patients and primary care clinicians. However, little is known about the opinions of physicians using these modalities. OBJECTIVE: The aim of this study was to examine physician perceptions, including challenges, risks, and benefits of the use of telemedicine in human immunodeficiency virus (HIV) patient care. METHODS: A Web-based, self administered, anonymous, cross-sectional survey was sent to physicians known to be providing medical care to patients living with HIV in Ontario, Canada. Descriptive statistics and frequencies were used to examine physician perceptions and characteristics of participants. RESULTS: Among the 51 invited participants, 48 (94%) completed the survey. Sixty-two percent (29/47) of respondents reported that they used some form of telemedicine to care for HIV patients in their practice. Of the respondents who identified as having used telemedicine in their practice, telephone (86%, 25/29), email (69%, 20/29), and teleconsultation (24%, 7/29) were listed as frequent modalities used. A significant number of physicians (83%, 38/46) agreed that an obstacle to adopting telemedicine is their perception that this modality does not allow for a comprehensive assessment of their patients' health. In addition, 65% (28/43) of physicians agreed that patients may not feel adequately connected to them as a provider if they used telemedicine. However, 85% (39/46) of respondents believed that telemedicine could improve access and timeliness to care along with increasing the number of times physicians can interact with their patients. CONCLUSIONS: From the perceptions of physicians, telemedicine shows promise in the care of patients living with HIV. More than half of the respondents are already using telemedicine modalities. Whereas many physicians are concerned about their ability to fully assess the health of a patient via telemedicine, most physicians do see a need for it-to reduce patient travel times, reduce exposure to stigma, and improve efficiency and timely access to care. Challenges and risks such as technological gaps, confidentiality, and medicolegal concerns must be addressed for physicians to feel more comfortable using telemedicine. PMID- 28559225 TI - Home-Based HIV Testing and Counseling for Male Couples (Project Nexus): A Protocol for a Randomized Controlled Trial. AB - BACKGROUND: HIV prevalence remains high among men who have sex with men (MSM) in the United States, yet the majority of research has focused on MSM as individuals, not as dyads, and has discussed HIV risks primarily in the context of casual sex. Nexus is an online prevention program that combines home-based HIV testing and couples HIV testing and counseling (CHTC). It allows partners in dyadic MSM relationships to receive HIV testing and care in the comfort of their designated residence, via video-based chat. By using video-based technologies (eg, VSee video chat), male couples receive counseling and support from a remote online counselor, while testing for HIV at home. OBJECTIVE: This randomized control trial (RCT) aims to examine the effects of video-based counseling combined with home-based HIV testing on couples' management of HIV risk, formation and adherence to explicit sexual agreements, and sexual risk-taking. METHODS: The research implements a prospective RCT of 400 online-recruited male couples: 200 self-reported concordant-negative couples and 200 self-reported discordant couples. Couples in the control arm will receive one or two home-based HIV self-testing kits and will be asked to report their results via the study's website. Couples in the experimental arm will receive one or two home-based HIV self-testing kits and will conduct these tests together under the facilitation of a remotely located counselor during a prescheduled VSee-based video CHTC session. Study assessments are taken at baseline, as well as at 3- and 6-month follow-up sessions. RESULTS: Project Nexus was launched in April 2016 and is ongoing. To date, 219 eligible couples have been enrolled and randomized. CONCLUSIONS: Combining home-based HIV testing with video-based counseling creates an opportunity to expand CHTC to male couples who (1) live outside metro areas, (2) live in rural areas without access to testing services or LGBTQ resources, or (3) feel that current clinic-based testing is not for them (eg, due to fears of discrimination associated with HIV and/or sexuality). TRIAL REGISTRATION: ClinicalTrials.gov NCT02335138; https://clinicaltrials.gov/ct2/show/NCT02335138 (Archived by WebCite at http://www.webcitation.org/6qHxtNIdW). PMID- 28559227 TI - Human-Centered Design Study: Enhancing the Usability of a Mobile Phone App in an Integrated Falls Risk Detection System for Use by Older Adult Users. AB - BACKGROUND: Design processes such as human-centered design (HCD), which involve the end user throughout the product development and testing process, can be crucial in ensuring that the product meets the needs and capabilities of the user, particularly in terms of safety and user experience. The structured and iterative nature of HCD can often conflict with the necessary rapid product development life-cycles associated with the competitive connected health industry. OBJECTIVE: The aim of this study was to apply a structured HCD methodology to the development of a smartphone app that was to be used within a connected health fall risk detection system. Our methodology utilizes so called discount usability engineering techniques to minimize the burden on resources during development and maintain a rapid pace of development. This study will provide prospective designers a detailed description of the application of a HCD methodology. METHODS: A 3-phase methodology was applied. In the first phase, a descriptive "use case" was developed by the system designers and analyzed by both expert stakeholders and end users. The use case described the use of the app and how various actors would interact with it and in what context. A working app prototype and a user manual were then developed based on this feedback and were subjected to a rigorous usability inspection. Further changes were made both to the interface and support documentation. The now advanced prototype was exposed to user testing by end users where further design recommendations were made. RESULTS: With combined expert and end-user analysis of a comprehensive use case having originally identified 21 problems with the system interface, we have only seen and observed 3 of these problems in user testing, implying that 18 problems were eliminated between phase 1 and 3. Satisfactory ratings were obtained during validation testing by both experts and end users, and final testing by users shows the system requires low mental, physical, and temporal demands according to the NASA Task Load Index (NASA-TLX). CONCLUSIONS: From our observation of older adults' interactions with smartphone interfaces, there were some recurring themes. Clear and relevant feedback as the user attempts to complete a task is critical. Feedback should include pop-ups, sound tones, color or texture changes, or icon changes to indicate that a function has been completed successfully, such as for the connection sequence. For text feedback, clear and unambiguous language should be used so as not to create anxiety, particularly when it comes to saving data. Warning tones or symbols, such as caution symbols or shrill tones, should only be used if absolutely necessary. Our HCD methodology, designed and implemented based on the principles of the International Standard Organizaton (ISO) 9241-210 standard, produced a functional app interface within a short production cycle, which is now suitable for use by older adults in long term clinical trials. PMID- 28559228 TI - Who is More Likely to Use the Internet for Health Behavior Change? A Cross Sectional Survey of Internet Use Among Smokers and Nonsmokers Who Are Orthopedic Trauma Patients. AB - BACKGROUND: eHealth presents opportunities to provide population groups with accessible health interventions, although knowledge about Internet access, peoples' interest in using the Internet for health, and users' characteristics are required prior to eHealth program development. OBJECTIVE: This study surveyed hospital patients to examine rates of Internet use, interest in using the Internet for health, and respondent characteristics related to Internet use and interest in using the Internet for health. For patients who smoke, preferences for types of smoking cessation programs for use at home and while in hospital were also examined. METHODS: An online cross-sectional survey was used to survey 819 orthopedic trauma patients (response rate: 72.61%, 819/1128) from two public hospitals in New South Wales, Australia. Logistic regressions were used to examine associations between variables. RESULTS: A total of 72.7% (574/790) of respondents had at least weekly Internet access and more than half (56.6%, 357/631) reported interest in using the Internet for health. Odds of at least weekly Internet usage were higher if the individual was born overseas (OR 2.21, 95% CI 1.27-3.82, P=.005), had a tertiary education (OR 3.75, 95% CI 2.41-5.84, P<.001), or was a nonsmoker (OR 3.75, 95% CI 2.41-5.84, P<.001). Interest in using the Internet for health increased with high school (OR 1.85, 95% CI 1.09 3.15, P=.02) or tertiary education (OR 2.48, 95% CI 1.66-3.70, P<.001), and if household incomes were more than AUS $100,000 (OR 2.5, 95% CI 1.25-4.97, P=.009). Older individuals were less interested in using the Internet for health (OR 0.98, 95% CI 0.97-0.99, P<.001). CONCLUSIONS: Online interventions may be a potential tool for health care in this hospitalized population. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12614001147673; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366829&isReview= rue (Archived by WebCite at http://www.webcitation.org/6qg26u3En). PMID- 28559230 TI - Manchester doctors describe aftermath of bomb blast as NHS continues to treat casualties. PMID- 28559231 TI - Offending in theatre: the case of Ian Paterson. PMID- 28559232 TI - Junior doctor is struck off over false research claims. PMID- 28559229 TI - Design and Evaluation of a Computer-Based 24-Hour Physical Activity Recall (cpar24) Instrument. AB - BACKGROUND: Widespread access to the Internet and an increasing number of Internet users offers the opportunity of using Web-based recalls to collect detailed physical activity data in epidemiologic studies. OBJECTIVE: The aim of this investigation was to evaluate the validity and reliability of a computer based 24-hour physical activity recall (cpar24) instrument with respect to the recalled 24-h period. METHODS: A random sample of 67 German residents aged 22 to 70 years was instructed to wear an ActiGraph GT3X+ accelerometer for 3 days. Accelerometer counts per min were used to classify activities as sedentary (<100 counts per min), light (100-1951 counts per min), and moderate to vigorous (>=1952 counts per min). On day 3, participants were also requested to specify the type, intensity, timing, and context of all activities performed during day 2 using the cpar24. Using metabolic equivalent of task (MET), the cpar24 activities were classified as sedentary (<1.5 MET), light (1.5-2.9 MET), and moderate to vigorous (>=3.0 MET). The cpar24 was administered twice at a 3-h interval. The Spearman correlation coefficient (r) was used as primary measure of concurrent validity and test-retest reliability. RESULTS: As compared with accelerometry, the cpar24 underestimated light activity by -123 min (median difference, P difference <.001) and overestimated moderate to vigorous activity by 89 min (P difference <.001). By comparison, time spent sedentary assessed by the 2 methods was similar (median difference=+7 min, P difference=.39). There was modest agreement between the cpar24 and accelerometry regarding sedentary (r=.54), light (r=.46), and moderate to vigorous (r=.50) activities. Reliability analyses revealed modest to high intraclass correlation coefficients for sedentary (r=.75), light (r=.65), and moderate to vigorous (r=.92) activities and no statistically significant differences between replicate cpar24 measurements (median difference for sedentary activities=+10 min, for light activities=-5 min, for moderate to vigorous activities=0 min, all P difference >=.60). CONCLUSION: These data show that the cpar24 is a valid and reproducible Web-based measure of physical activity in adults. PMID- 28559233 TI - Recommendations for the Use of Mechanical Circulatory Support: Ambulatory and Community Patient Care: A Scientific Statement From the American Heart Association. PMID- 28559235 TI - Going format-free. PMID- 28559236 TI - An interview with Hiroshi Hamada. AB - Hiroshi Hamada is the Director of the RIKEN Center for Developmental Biology (CDB) in Kobe, Japan. His lab focusses on the establishment of left-right asymmetry in the mouse embryo, and the role of cilia in the symmetry-breaking event. Hiroshi's work has been recognised by various awards, including the Keio Medical Science Prize in 2014, and election as an EMBO Associate Member in 2016. We met with Hiroshi on a recent visit to the CDB, to talk about his career and current interests, and the prospects for developmental biology in Japan. PMID- 28559234 TI - Etiology and clinical presentation of birth defects: population based study. AB - Objective To assess causation and clinical presentation of major birth defects.Design Population based case cohort.Setting Cases of birth defects in children born 2005-09 to resident women, ascertained through Utah's population based surveillance system. All records underwent clinical re-review.Participants 5504 cases among 270 878 births (prevalence 2.03%), excluding mild isolated conditions (such as muscular ventricular septal defects, distal hypospadias).Main outcome measures The primary outcomes were the proportion of birth defects with a known etiology (chromosomal, genetic, human teratogen, twinning) or unknown etiology, by morphology (isolated, multiple, minors only), and by pathogenesis (sequence, developmental field defect, or known pattern of birth defects).Results Definite cause was assigned in 20.2% (n=1114) of cases: chromosomal or genetic conditions accounted for 94.4% (n=1052), teratogens for 4.1% (n=46, mostly poorly controlled pregestational diabetes), and twinning for 1.4% (n=16, conjoined or acardiac). The 79.8% (n=4390) remaining were classified as unknown etiology; of these 88.2% (n=3874) were isolated birth defects. Family history (similarly affected first degree relative) was documented in 4.8% (n=266). In this cohort, 92.1% (5067/5504) were live born infants (isolated and non-isolated birth defects): 75.3% (4147/5504) were classified as having an isolated birth defect (unknown or known etiology).Conclusions These findings underscore the gaps in our knowledge regarding the causes of birth defects. For the causes that are known, such as smoking or diabetes, assigning causation in individual cases remains challenging. Nevertheless, the ongoing impact of these exposures on fetal development highlights the urgency and benefits of population based preventive interventions. For the causes that are still unknown, better strategies are needed. These can include greater integration of the key elements of etiology, morphology, and pathogenesis into epidemiologic studies; greater collaboration between researchers (such as developmental biologists), clinicians (such as medical geneticists), and epidemiologists; and better ways to objectively measure fetal exposures (beyond maternal self reports) and closer (prenatally) to the critical period of organogenesis. PMID- 28559237 TI - Human embryo research and the 14-day rule. AB - In many jurisdictions, restrictions prohibit the culture of human embryos beyond 14 days of development. However, recent reports describing the successful maintenance of embryos in vitro to this stage have prompted many in the field to question whether the rule is still appropriate. This Spotlight article looks at the original rationale behind the 14-day rule and its relevance today in light of advances in human embryo culture and in the derivation of embryonic-like structures from human pluripotent stem cells. PMID- 28559238 TI - Epithelial cell behaviours during neurosensory organ formation. AB - Perception of the environment in vertebrates relies on a variety of neurosensory mini-organs. These organs develop via a multi-step process that includes placode induction, cell differentiation, patterning and innervation. Ultimately, cells derived from one or more different tissues assemble to form a specific mini-organ that exhibits a particular structure and function. The initial building blocks of these organs are epithelial cells that undergo rearrangements and interact with neighbouring tissues, such as neural crest-derived mesenchymal cells and sensory neurons, to construct a functional sensory organ. In recent years, advances in in vivo imaging methods have allowed direct observation of these epithelial cells, showing that they can be displaced within the epithelium itself via several modes. This Review focuses on the diversity of epithelial cell behaviours that are involved in the formation of small neurosensory organs, using the examples of dental placodes, hair follicles, taste buds, lung neuroendocrine cells and zebrafish lateral line neuromasts to highlight both well-established and newly described modes of epithelial cell motility. PMID- 28559240 TI - Getting MAD in meiosis. PMID- 28559241 TI - Growing a labyrinth with G9a. PMID- 28559239 TI - Escort cells generate a dynamic compartment for germline stem cell differentiation via combined Stat and Erk signalling. AB - Two different compartments support germline stem cell (GSC) self-renewal and their timely differentiation: the classical niche provides maintenance cues, while a differentiation compartment, formed by somatic escort cells (ECs), is required for proper GSC differentiation. ECs extend long protrusions that invade between tightly packed germ cells, and alternate between encapsulating and releasing them. How ECs achieve this dynamic balance has not been resolved. By combining live imaging and genetic analyses in Drosophila, we have characterised EC shapes and their dynamic changes. We show that germ cell encapsulation by ECs is a communal phenomenon, whereby EC-EC contacts stabilise an extensive meshwork of protrusions. We further show that Signal Transducer and Activator of Transcription (Stat) and Epidermal Growth Factor Receptor (Egfr) signalling sustain EC protrusiveness and flexibility by combinatorially affecting the activity of different RhoGTPases. Our results reveal how a complex signalling network can determine the shape of a cell and its dynamic behaviour. It also explains how the differentiation compartment can establish extensive contacts with germ cells, while allowing a continual posterior movement of differentiating GSC daughters. PMID- 28559242 TI - Wheat domestication: Q is the answer. PMID- 28559243 TI - Differential impact of water immersion on arterial blood flow and shear stress in the carotid and brachial arteries of humans. AB - Arterial shear stress is a potent stimulus to vascular adaptation in humans. Typically, increases in retrograde shear have been found to acutely impair vascular function while increases in antegrade shear enhance function. We hypothesized that blood flow and shear stress through the brachial and carotid arteries would change in a similar manner in response to water immersion, an intervention which modifies hemodynamics. Nine healthy young male subjects were recruited to undergo controlled water immersion in a standing upright position to the level of the right atrium in 30 degrees C water. Diameters were continuously and simultaneously recorded in the brachial and common carotid arteries along with mean arterial pressure (MAP), cardiac output (CO), and heart rate before, during, and after 10 min of immersion. MAP and CO increased during water immersion (baseline vs. 8-10 min; 80 +/- 9 vs. 91 +/- 12 mmHg; and 4.8 +/- 0.7 vs. 5.1 +/- 0.6 L/min, P < 0.01 and P < 0.05, respectively). We observed a differential regulation of flow and shear stress patterns in the brachial and carotid arteries in response to water immersion; brachial conductance decreased markedly in response to immersion (1.25 +/- 0.56 vs. 0.57 +/- 0.30 mL.min/mmHg, P < 0.05), whereas it was unaltered in the carotid artery (5.82 +/- 2.14 vs. 5.60 +/- 1.59). Our findings indicate that adaptations to systemic stimuli and arterial adaptation may be vessel bed specific in humans, highlighting the need to assess multiple vascular sites in future studies. PMID- 28559244 TI - Gene silencing and a novel monoallelic expression pattern in distinct CD177 neutrophil subsets. AB - CD177 presents antigens in allo- and autoimmune diseases on the neutrophil surface. Individuals can be either CD177-deficient or harbor distinct CD177neg and CD177pos neutrophil subsets. We studied mechanisms controlling subset restricted CD177 expression in bimodal individuals. CD177pos, but not CD177neg neutrophils, produced CD177 protein and mRNA. Haplotype analysis indicated a unique monoallelic CD177 expression pattern, where the offspring stably transcribed either the maternal or paternal allele. Hematopoietic stem cells expressed both CD177 alleles and silenced one copy during neutrophil differentiation. ChIP and reporter assays in HeLa cells with monoallelic CD177 expression showed that methylation reduced reporter activity, whereas demethylation caused biallelic CD177 expression. HeLa cell transfection with c Jun and c-Fos increased CD177 mRNA. Importantly, CD177pos human neutrophils, but not CD177neg neutrophils, showed a euchromatic CD177 promoter, unmethylated CpGs, and c-Jun and c-Fos binding. We describe epigenetic mechanisms explaining the two distinct CD177 neutrophil subsets and a novel monoallelic CD177 expression pattern that does not follow classical random monoallelic expression or imprinting. PMID- 28559245 TI - Temporal Transcriptomic and Proteomic Landscapes of Deteriorating Pancreatic Islets in Type 2 Diabetic Rats. AB - Progressive reduction in beta-cell mass and function comprise the core of the pathogenesis mechanism of type 2 diabetes. The process of deteriorating pancreatic islets, in which a complex network of molecular events is involved, is not yet fully characterized. We used RNA sequencing and tandem mass tag-based quantitative proteomics technology to measure the temporal mRNA and protein expression changes of pancreatic islets in Goto-Kakizaki (GK) rats from 4 to 24 weeks of age. Our omics data set outlines the dynamics of the molecular network during the deterioration of GK islets as two stages: The early stage (4-6 weeks) is characterized by anaerobic glycolysis, inflammation priming, and compensation for insulin synthesis, and the late stage (8-24 weeks) is characterized by inflammation amplification and compensation failure. Further time course analysis allowed us to reveal 5,551 differentially expressed genes, a large portion of which have not been reported before. Our comprehensive and temporal transcriptome and proteome data offer a valuable resource for the diabetes research community and for quantitative biology. PMID- 28559246 TI - Neprilysin Is Required for Angiotensin-(1-7)'s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1-2). AB - Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve beta-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1-7) by ACE2 and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that, although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1-7)-mediated GSIS. However, a more widely expressed islet peptidase, neprilysin, degrades angiotensin-(1-7) into several peptides. In neprilysin-deficient mouse islets, angiotensin-(1-7) and neprilysin-derived degradation products angiotensin-(1-4), angiotensin-(5-7), and angiotensin-(3-4) failed to enhance GSIS. Conversely, angiotensin-(1-2) enhanced GSIS in both neprilysin-deficient and wild-type islets. Rather than mediating this effect via activation of the G-protein-coupled receptor (GPCR) MasR, angiotensin-(1-2) was found to signal via another GPCR, namely GPCR family C group 6 member A (GPRC6A). In conclusion, in islets, intact angiotensin-(1-7) is not the primary mediator of beneficial effects ascribed to the ACE2/angiotensin-(1-7)/MasR axis. Our findings warrant caution for the concurrent use of angiotensin-(1-7) compounds and neprilysin inhibitors as therapies for diabetes. PMID- 28559247 TI - Mortality Associated with Bacteremia Due to Colistin-Resistant Klebsiella pneumoniae with High-Level Meropenem Resistance: Importance of Combination Therapy without Colistin and Carbapenems. AB - Combination therapy including colistin and a carbapenem has been found to be associated with lower mortality in the treatment of bloodstream infections (BSI) due to KPC-producing Klebsiella pneumoniae when the isolates show a meropenem or imipenem MIC of <16 mg/liter. However, the optimal treatment of BSI caused by colistin- and high-level carbapenem-resistant KPC-producing K. pneumoniae is unknown. A prospective cohort study including episodes of bacteremia caused by colistin-resistant and high-level meropenem-resistant (MIC >= 64 mg/liter) KPC producing K. pneumoniae diagnosed from July 2012 to February 2016 was performed. The impact of combination therapy on crude 30-day mortality was analyzed by Cox regression using a propensity score as a covariate to control for indication bias and in an inverse probability of treatment weighting (IPTW) cohort. The study sample comprised 104 patients, of which 32 (30.8%) received targeted monotherapy and 72 (69.2%) received targeted combination therapy; none of them received either colistin or a carbapenem. The 30-day crude mortality rate was 30.8% (43.8% in patients treated with monotherapy and 25% in patients receiving combination therapy). In the Cox regression analysis, 30-day mortality was independently associated with septic shock at BSI onset (hazard ratio [HR], 6.03; 95% confidence interval [CI], 1.65 to 21.9; P = 0.006) and admission to the critical care unit (HR, 2.87; 95% CI, 0.99 to 8.27; P = 0.05). Targeted combination therapy was associated with lower mortality only in patients with septic shock (HR, 0.14; 95% CI, 0.03 to 0.67; P = 0.01). These results were confirmed in the Cox regression analysis of the IPTW cohort. Combination therapy is associated with reduced mortality in patients with bacteremia due to colistin-resistant KPC producing K. pneumoniae with high-level carbapenem resistance in patients with septic shock. PMID- 28559248 TI - Structural Insights into TMB-1 and the Role of Residues 119 and 228 in Substrate and Inhibitor Binding. AB - Metallo-beta-lactamases (MBLs) threaten the effectiveness of beta-lactam antibiotics, including carbapenems, and are a concern for global public health. beta-Lactam/beta-lactamase inhibitor combinations active against class A and class D carbapenemases are used, but no clinically useful MBL inhibitor is currently available. Tripoli metallo-beta-lactamase-1 (TMB-1) and TMB-2 are members of MBL subclass B1a, where TMB-2 is an S228P variant of TMB-1. The role of S228P was studied by comparisons of TMB-1 and TMB-2, and E119 was investigated through the construction of site-directed mutants of TMB-1, E119Q, E119S, and E119A (E119Q/S/A). All TMB variants were characterized through enzyme kinetic studies. Thermostability and crystallization analyses of TMB-1 were performed. Thiol-based inhibitors were investigated by determining the 50% inhibitory concentrations (IC50) and binding using surface plasmon resonance (SPR) for analysis of TMB-1. Thermostability measurements found TMB-1 to be stabilized by high NaCl concentrations. Steady-state enzyme kinetics analyses found substitutions of E119, in particular, substitutions associated with the penicillins, to affect hydrolysis to some extent. TMB-2 with S228P showed slightly reduced catalytic efficiency compared to TMB-1. The IC50 levels of the new thiol-based inhibitors were 0.66 MUM (inhibitor 2a) and 0.62 MUM (inhibitor 2b), and the equilibrium dissociation constant (KD ) of inhibitor 2a was 1.6 MUM; thus, both were more potent inhibitors than l-captopril (IC50 = 47 MUM; KD = 25 MUM). The crystal structure of TMB-1 was resolved to 1.75 A. Modeling of inhibitor 2b in the TMB-1 active site suggested that the presence of the W64 residue results in T-shaped pi-pi stacking and R224 cation-pi interactions with the phenyl ring of the inhibitor. In sum, the results suggest that residues 119 and 228 affect the catalytic efficiency of TMB-1 and that inhibitors 2a and 2b are more potent inhibitors for TMB-1 than l-captopril. PMID- 28559249 TI - MK-8591 (4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine) Exhibits Potent Activity against HIV-2 Isolates and Drug-Resistant HIV-2 Mutants in Culture. AB - There is a pressing need to identify more effective antiretroviral drugs for HIV 2 treatment. Here, we show that the investigational compound MK-8591 (4'-ethynyl 2-fluoro-2'-deoxyadenosine [EFdA]) is highly active against group A and B isolates of HIV-2; 50% effective concentrations [EC50] for HIV-2 were, on average, 4.8-fold lower than those observed for HIV-1. MK-8591 also retains potent activity against multinucleoside-resistant HIV-2 mutants (EC50 <= 11 nM). These data suggest that MK-8591 may have antiviral activity in HIV-2-infected individuals. PMID- 28559251 TI - Frequent Tn2 Misannotation in the Genetic Background of rmtB. PMID- 28559250 TI - Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem Resistant Klebsiella pneumoniae Bacteremia. AB - There are no data comparing outcomes of patients treated with ceftazidime avibactam versus comparators for carbapenem-resistant Enterobacteriaceae infections. At our center, ceftazidime-avibactam treatment of carbapenem resistant Klebsiella pneumoniae bacteremia was associated with higher rates of clinical success (P = 0.006) and survival (P = 0.01) than other regimens. Across treatment groups, there were no differences in underlying diseases, severity of illness, source of bacteremia, or strain characteristics (97% produced K. pneumoniae carbapenemase). Aminoglycoside- and colistin-containing regimens were associated with increased rates of nephrotoxicity (P = 0.002). PMID- 28559252 TI - Occurrence of Plasmid- and Chromosome-Carried mcr-1 in Waterborne Enterobacteriaceae in China. AB - The aim of this study was to investigate the prevalence of the polymyxin resistance gene mcr-1 in Enterobacteriaceae from environmental water sources in Hangzhou, China. Colistin-resistant bacteria were isolated from environmental water samples using an enrichment broth culture method, were screened for mcr-1, and then were analyzed for the location and transferability of mcr-1 Isolates positive for mcr-1 were further examined to determine their susceptibility profiles and were screened for the presence of additional resistance genes. Twenty-three mcr-1-positive isolates (16 Escherichia coli, two Citrobacter freundii, two Klebsiella oxytoca, two Citrobacter braakii, and one Enterobacter cloacae) were isolated from 7/9 sampling locations; of those, eight mcr-1 positive isolates also contained beta-lactamase-resistance genes, eight contained qnrS, and 10 contained oqx No mcr-2-positive isolates were identified. The majority of isolates demonstrated a low to moderate level of colistin resistance. Transconjugation was successfully conducted from 14 of the 23 mcr-1-positive isolates, and mcr-1 was identified on plasmids ranging from 60 to 220 kb in these isolates. Conjugation and hybridization experiments revealed that mcr-1 was chromosome-borne in only three isolates. Pulsed-field gel electrophoresis showed that the majority of E. coli isolates belonged to different clonal lineages. Multilocus sequence typing analysis revealed that sequence type 10 (ST10) was the most prevalent, followed by ST181 and ST206. This study demonstrates the utility of enrichment broth culture for identifying environmental mcr-1-positive isolates. Furthermore, it highlights the importance of responsible agriculture and clinical use of polymyxins to prevent further widespread dissemination of polymyxin-resistant pathogens. PMID- 28559253 TI - Nucleotide Substrate Specificity of Anti-Hepatitis C Virus Nucleoside Analogs for Human Mitochondrial RNA Polymerase. AB - Nucleoside analog inhibitors (NAIs) are an important class of antiviral agents. Although highly effective, some NAIs with activity against hepatitis C virus (HCV) can cause toxicity, presumably due to off-target inhibition of host mitochondrial RNA polymerase (POLRMT). The in vitro nucleotide substrate specificity of POLRMT was studied in order to explore structure-activity relationships that can facilitate the identification of nontoxic NAIs. These findings have important implications for the development of all anti-RNA virus NAIs. PMID- 28559254 TI - Human Bile Reduces Antimicrobial Activity of Selected Antibiotics against Enterococcus faecalis and Escherichia coli In Vitro. AB - It has been known from previous studies that body fluids, such as cerebrospinal fluid, lung surfactant, and urine, have a strong impact on the bacterial killing of many anti-infective agents. However, the influence of human bile on the antimicrobial activity of antibiotics is widely unknown. Human bile was obtained and pooled from 11 patients undergoing cholecystectomy. After sterilization of the bile fluid by gamma irradiation, its effect on bacterial killing was investigated for linezolid (LZD) and tigecycline (TGC) against Enterococcus faecalis ATCC 29212. Further, ciprofloxacin (CIP), meropenem (MEM), and TGC were tested against Escherichia coli ATCC 25922. Time-kill curves were performed in pooled human bile and Mueller-Hinton broth (MHB) over 24 h. Bacterial counts (in CFU per milliliter after 24 h) of bile growth controls were approximately equal to MHB growth controls for E. coli and approximately 2-fold greater for E. faecalis, indicating a promotion of bacterial growth by bile for the latter strain. Bile reduced the antimicrobial activity of CIP, MEM, and TGC against E. coli as well as the activity of LZD and TGC against E. faecalis This effect was strongest for TGC against the two strains. Degradation of TGC in bile was identified as the most likely explanation. These findings may have important implications for the treatment of bacterial infections of the gallbladder and biliary tract and should be explored in more detail. PMID- 28559255 TI - A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers. AB - Influenza B can cause significant morbidity and mortality. MHAB5553A, a human monoclonal immunoglobulin G1 (IgG1) antibody that binds to a highly conserved region of the hemagglutinin protein of influenza B virus, is being examined as a novel therapeutic for the treatment of influenza B patients with severe disease. This phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of MHAB5553A. Twenty-six healthy male and female volunteers of >18 years of age were randomized into five cohorts receiving a single intravenous (i.v.) dose of 120, 1,200, 3,600, 8,400, or 10,800 mg MHAB5553A or placebo (four active:one placebo, except for the 120-mg cohort [4:2]). Subjects were followed for 120 days after dosing. No subject discontinued the study, no dose-limiting adverse events or serious adverse events were reported, and a maximum tolerated dose (MTD) was not defined. The most commonly reported adverse events were cold symptoms and headache; most were mild and occurred at a similar rate across all cohorts. MHAB5553A showed no relevant time- or dose-related changes in laboratory values or vital signs compared to the placebo. The observed serum PK was linear and generally dose proportional, and the observed nasal PK was nonlinear and generally non-dose proportional. MHAB5553A is generally well tolerated in healthy volunteers up to at least a single i.v. dose of 10,800 mg and demonstrated linear serum PK consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (This study has been registered at ClinicalTrials.gov under registration no. NCT02528903.). PMID- 28559256 TI - Aerosolized Polymyxin B for Treatment of Respiratory Tract Infections: Determination of Pharmacokinetic-Pharmacodynamic Indices for Aerosolized Polymyxin B against Pseudomonas aeruginosa in a Mouse Lung Infection Model. AB - Pulmonary administration of polymyxins is increasingly used for the treatment of respiratory tract infections caused by multidrug-resistant Gram-negative bacteria, such as those in patients with cystic fibrosis. However, there is a lack of pharmacokinetics (PK), pharmacodynamics (PD), and toxicity data of aerosolized polymyxin B to inform rational dosage selection. The PK and PD of polymyxin B following pulmonary and intravenous dosing were examined in neutropenic infected mice, and the data were analyzed by a population PK model. Dose fractionation study was performed for total daily doses between 2.06 and 24.8 mg base/kg of weight against Pseudomonas aeruginosa ATCC 27853, PAO1, and FADDI-PA022 (MIC of 1 mg/liter for all three strains). Histopathological examination of the lung was undertaken at 24 h posttreatment in both healthy and neutropenic infected mice. A two-compartment PK model was required for both epithelial lining fluid (ELF) and plasma drug exposure. The model consisted of central and peripheral compartments and was described by bidirectional first order distribution clearance. The ratio of the area under the curve to the MIC (AUC/MIC) was the most predictive PK/PD index to describe the antimicrobial efficacy of aerosolized polymyxin B in treating lung infections in mice (R2 of 0.70 to 0.88 for ELF and 0.70 to 0.87 for plasma). The AUC/MIC targets associated with bacteriostasis against the three P. aeruginosa strains were 1,326 to 1,506 in ELF and 3.14 to 4.03 in plasma. Histopathological results showed that polymyxin B aerosols significantly reduced lung inflammation and preserved lung epithelial integrity. This study highlights the advantageous PK/PD characteristics of pulmonary delivery of polymyxin B over intravenous administration in achieving high drug exposure in ELF. PMID- 28559257 TI - Etest and Sensititre YeastOne Susceptibility Testing of Echinocandins against Candida Species from a Single Center in Austria. AB - Candida species were tested for susceptibility to caspofungin, anidulafungin, and micafungin in order to evaluate the roles of Etest and Sensititre YeastOne in antifungal susceptibility testing for daily routines and to survey resistance. A total of 104 Candida species isolates detected from blood cultures were investigated. With EUCAST broth microdilution as the reference method, essential agreement (EA), categorical agreement (CA), very major errors (VME), major errors (ME), and minor (MIN) errors were assessed by reading MICs at 18, 24, and 48 h. By use of EUCAST broth microdilution and species-specific clinical breakpoints (CBPs), echinocandin resistance was not detected during the study period. Using EUCAST CBPs, MIC readings at 24 h for the Etest and Sensititre YeastOne resulted in CA levels of 99% and 93% for anidulafungin and 99% and 97% for micafungin. Using revised CLSI CBPs for caspofungin, CA levels were 92% and 99% for Etest and Sensititre YeastOne. The Etest proved an excellent, easy-to-handle alternative method for testing susceptibility to anidulafungin and micafungin. Due to misclassifications, the Etest is less suitable for testing susceptibility to caspofungin (8% of isolates falsely tested resistant). The CA levels of Sensititre YeastOne were 93% and 97% for anidulafungin and micafungin (24 h) by use of EUCAST CBPs and increased to 100% for both antifungals if CLSI CBPs were applied and to 100% and 99% if Sensititre YeastOne epidemiological cutoff values (ECOFFs) were applied. No one echinocandin could be demonstrated to be superior to another in vitro Since resistance was lacking among our Candida isolates, we cannot derive any recommendation from accurate resistance detection by the Etest and Sensititre YeastOne. PMID- 28559258 TI - In Vitro Efficacy of Moxidectin versus Ivermectin against Sarcoptes scabiei. AB - Moxidectin is under consideration for development as a treatment for human scabies. As some arthropods show decreased sensitivity to moxidectin relative to ivermectin, it was important to assess this for Sarcoptes scabieiIn vitro assays showed that the concentration of moxidectin required to kill 50% of mites was lower than that of ivermectin (0.5 MUM versus 1.8 MUM at 24 h; P < 0.0001). This finding provides further support for moxidectin as a candidate for the treatment of human scabies. PMID- 28559259 TI - Simkania negevensis, an Example of the Diversity of the Antimicrobial Susceptibility Pattern among Chlamydiales. AB - In past years, several Chlamydia-related bacteria have been discovered, including Simkania negevensis, the founding member of the Simkaniaceae family. We evaluated the antimicrobial susceptibility patterns of this emerging intracellular bacterium and highlighted significant differences, compared with related Chlamydiales members. S. negevensis was susceptible to macrolides, clindamycin, cyclines, rifampin, and quinolones. Importantly, unlike other Chlamydiales members, treatment with beta-lactams and vancomycin did not induce the formation of aberrant bodies, leading to a completely resistant phenotype. PMID- 28559260 TI - Unusual Escherichia coli PBP 3 Insertion Sequence Identified from a Collection of Carbapenem-Resistant Enterobacteriaceae Tested In Vitro with a Combination of Ceftazidime-, Ceftaroline-, or Aztreonam-Avibactam. AB - Carbapenemase-producing Enterobacteriaceae isolates (n = 110) from health care centers in central Indiana (from 2010 to 2013) were tested for susceptibility to combinations of avibactam (4 MUg/ml) with ceftazidime, ceftaroline, or aztreonam. MIC50/MIC90 values were 1/2 MUg/ml (ceftazidime-avibactam), 0.5/2 MUg/ml (ceftaroline-avibactam), and 0.25/0.5 MUg/ml (aztreonam-avibactam.) A beta-lactam MIC of 8 MUg/ml was reported for the three combinations against one Escherichia coli isolate with an unusual TIPY insertion following Tyr344 in penicillin binding protein 3 (PBP 3) as the result of gene duplication. PMID- 28559261 TI - The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques. AB - TP-271 is a novel, fully synthetic fluorocycline in development for complicated bacterial respiratory infections. TP-271 was active in vitro against a panel of 29 Francisella tularensis isolates, showing MICs against 50% and 90% of isolates of 0.25 and 0.5 MUg/ml, respectively. In a mouse model of inhalational tularemia, animals were exposed by aerosol to 91 to 283 50% lethal doses (LD50)/mouse of F. tularensis SCHU S4. Following 21 days of once-daily intraperitoneal dosing with TP-271 at 3, 6, 12, and 18 mg/kg of body weight/day, initiating at 24 h postchallenge, survival was 80%, 100%, 100%, and 100%, respectively. When treatment was initiated at 72 h postchallenge, survival was 89%, 100%, 100%, and 100% in the 3-, 6-, 12-, and 18-mg/kg/day TP-271 groups, respectively. No mice treated with the vehicle control survived. Surviving mice treated with TP-271 showed little to no relapse during 14 days posttreatment. In a nonhuman primate model of inhalational tularemia, cynomolgus macaques received an average aerosol exposure of 1,144 CFU of F. tularensis SCHU S4. Once-daily intravenous infusion with 1 or 3 mg/kg TP-271, or vehicle control, for 21 days was initiated within 6 h of confirmed fever. All animals treated with TP-271 survived to the end of the study, with no relapse during 14 days after the last treatment, whereas no vehicle control-treated animals survived. The protection and low relapse afforded by TP-271 treatment in these studies support continued investigation of TP-271 for use in the event of aerosolized exposure to F. tularensis. PMID- 28559262 TI - Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice. AB - Preliminary preclinical and observational studies suggest the potential utility of metformin as an adjunctive, host-directed agent for treatment of tuberculosis (TB). In this study, we sought to investigate the bactericidal and sterilizing activities of human-like exposures of metformin when given in combination with the first-line regimen against chronic tuberculosis in BALB/c mice. Mice receiving metformin adjunctive therapy had similar lung bacillary burdens with control mice during treatment, and the proportion of mice with microbiological relapse was similar between the two groups. PMID- 28559263 TI - Efficient Killing of Planktonic and Biofilm-Embedded Coagulase-Negative Staphylococci by Bactericidal Protein P128. AB - Coagulase-negative staphylococci (CoNS) are the major causative agents of foreign body-related infections, including catheter-related bloodstream infections. Because of the involvement of biofilms, foreign-body-related infections are difficult to treat. P128, a chimeric recombinant phage-derived ectolysin, has been shown to possess bactericidal activity on strains of Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). We tested the killing potential of P128 on three clinically significant species of CoNS, S. epidermidis, S. haemolyticus, and S. lugdunensis, under a variety of physiological conditions representing growing and nongrowing states. The MIC90 and minimum bactericidal concentration at which 90% of strains tested are killed (MBC90) of P128 on 62 clinical strains of CoNS were found to be 16 and 32 MUg/ml (0.58 and 1.16 MUM), respectively, demonstrating the bactericidal nature of P128 on CoNS strains. Serum showed a potentiating effect on P128 inhibition, as indicated by 4- to 32 fold lower MIC values observed in serum. P128 caused a rapid loss of viability in all CoNS strains tested. Persisters of CoNS that were enriched in the presence of vancomycin or daptomycin were killed by P128 at 1* the MIC in a rapid manner. Low concentrations of P128 caused a 2- to 5-log reduction in CFU in stationary-phase or poorly metabolizing CoNS cultures. P128 at low concentrations eliminated CoNS biofilms in microtiter plates and on the surface of catheters. Combinations of P128 and standard-of-care (SoC) antibiotics were highly synergistic in inhibiting growth in preformed biofilms. Potent activity on planktonic cells, persisters, and biofilms of CoNS suggests that P128 is a promising candidate for the clinical development of treatments for foreign-body-related and other CoNS infections. PMID- 28559265 TI - Hepatitis B Virus Capsid Assembly Modulators, but Not Nucleoside Analogs, Inhibit the Production of Extracellular Pregenomic RNA and Spliced RNA Variants. AB - The hepatitis B virus (HBV) core protein serves multiple essential functions in the viral life cycle, and antiviral agents that target the core protein are being developed. Capsid assembly modulators (CAMs) are compounds that target core and misdirect capsid assembly, resulting in the suppression of HBV replication and virion production. Besides HBV DNA, circulating HBV RNA has been detected in patient serum and can be associated with the treatment response. Here we studied the effect of HBV CAMs on the production of extracellular HBV RNA using infected HepaRG cells and primary human hepatocytes. Representative compounds from the sulfonamide carboxamide and heteroaryldihydropyrimidine series of CAMs were evaluated and compared to nucleos(t)ide analogs as inhibitors of the viral polymerase. The results showed that CAMs blocked extracellular HBV RNA with efficiencies similar to those with which they blocked pregenomic RNA (pgRNA) encapsidation, HBV DNA replication, and Dane particle production. Nucleos(t)ide analogs inhibited viral replication and virion production but not encapsidation or production of extracellular HBV RNA. Profiling of HBV RNA from both culture supernatants and patient serum showed that extracellular viral RNA consisted of pgRNA and spliced pgRNA variants with an internal deletion(s) but still retained the sequences at both the 5' and 3' ends. Similar variants were detected in the supernatants of infected cells with and without nucleos(t)ide analog treatment. Overall, our data demonstrate that HBV CAMs represent direct antiviral agents with a profile differentiated from that of nucleos(t)ide analogs, including the inhibition of extracellular pgRNA and spliced pgRNA. PMID- 28559264 TI - Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis. AB - Bisphosphonates are widely used for the treatment of bone disorders. These drugs also inhibit the growth of a variety of protozoan parasites, such as Toxoplasma gondii, the etiologic agent of toxoplasmosis. The target of the most potent bisphosphonates is the isoprenoid biosynthesis pathway enzyme farnesyl diphosphate synthase (FPPS). Based on our previous work on the inhibitory effect of sulfur-containing linear bisphosphonates against T. gondii, we investigated the potential synergistic interaction between one of these derivatives, 1-[(n heptylthio)ethyl]-1,1-bisphosphonate (C7S), and statins, which are potent inhibitors of the host 3-hydroxy-3-methyl glutaryl-coenzyme A reductase (3-HMG CoA reductase). C7S showed high activity against the T. gondii bifunctional farnesyl diphosphate (FPP)/geranylgeranyl diphosphate (GGPP) synthase (TgFPPS), which catalyzes the formation of FPP and GGPP (50% inhibitory concentration [IC50] = 31 +/- 0.01 nM [mean +/- standard deviation]), and modest effect against the human FPPS (IC50 = 1.3 +/- 0.5 MUM). We tested combinations of C7S with statins against the in vitro replication of T. gondii We also treated mice infected with a lethal dose of T. gondii with similar combinations. We found strong synergistic activities when using low doses of C7S, which were stronger in vivo than when tested in vitro We also investigated the synergism of several commercially available bisphosphonates with statins both in vitro and in vivo Our results provide evidence that it is possible to develop drug combinations that act synergistically by inhibiting host and parasite enzymes in vitro and in vivo. PMID- 28559267 TI - Penicillin Dried Blood Spot Assay for Use in Patients Receiving Intramuscular Benzathine Penicillin G and Other Penicillin Preparations To Prevent Rheumatic Fever. AB - Rheumatic heart disease (RHD) remains an important global health challenge. Administration of benzathine penicillin (BPG) every 3 to 4 weeks is recommended as a secondary prophylaxis to prevent recurrent episodes of acute rheumatic fever and subsequent RHD. Following intramuscular injection, BPG is hydrolyzed to penicillin G (benzylpenicillin). However, little is known of the pharmacokinetics (PK) of BPG in pediatric populations at high risk of RHD or of the pharmacokinetic-pharmacodynamic relationship between penicillin exposure and clinically relevant outcomes. Dried blood spot (DBS) assays can facilitate PK studies in situations where frequent venous blood sampling is logistically difficult. A liquid chromatography-mass spectroscopy assay for penicillin G in plasma and DBS was developed and validated. Application of the DBS assay for PK studies was confirmed using samples from adult patients receiving penicillin as part of an infection management plan. The limit of quantification for penicillin G in DBS was 0.005 mg/liter. Penicillin G is stable in DBS for approximately 12 h at room temperature (22 degrees C), 6 days at 4 degrees C, and >1 month at -20 degrees C. Plasma and DBS penicillin G concentrations for patients receiving BPG and penicillin G given via bolus doses correlated well and had comparable time concentration profiles. There was poor correlation for patients receiving penicillin via continuous infusions, perhaps as a result of the presence of residual penicillin in the peripherally inserted central catheter, from which the plasma samples were collected. The present DBS penicillin G assay can be used as a surrogate for plasma concentrations to provide valid PK data for studies of BPG and other penicillin preparations developed to prevent rheumatic fever and RHD. PMID- 28559266 TI - An Immunomodulatory Peptide Confers Protection in an Experimental Candidemia Murine Model. AB - Fungal Candida species are commensals present in the mammalian skin and mucous membranes. Candida spp. are capable of breaching the epithelial barrier of immunocompromised patients with neutrophil and cell-mediated immune dysfunctions and can also disseminate to multiple organs through the bloodstream. Here we examined the action of innate defense regulator 1018 (IDR-1018), a 12-amino-acid residue peptide derived from bovine bactenecin (Bac2A): IDR-1018 showed weak antifungal and antibiofilm activity against a Candida albicans laboratory strain (ATCC 10231) and a clinical isolate (CI) (MICs of 32 and 64 MUg . ml-1, respectively), while 8-fold lower concentrations led to dissolution of the fungal cells from preformed biofilms. IDR-1018 at 128 MUg . ml-1 was not hemolytic when tested against murine red blood cells and also has not shown a cytotoxic effect on murine monocyte RAW 264.7 and primary murine macrophage cells at the tested concentrations. IDR-1018 modulated the cytokine profile during challenge of murine bone marrow-derived macrophages with heat-killed C. albicans (HKCA) antigens by increasing monocyte chemoattractant protein 1 (MCP-1) and interleukin 10 (IL-10) levels, while suppressing tumor necrosis factor alpha (TNF-alpha), IL 1beta, IL-6, and IL-12 levels. Mice treated with IDR-1018 at 10 mg . kg-1 of body weight had an increased survival rate in the candidemia model compared with phosphate-buffered saline (PBS)-treated mice, together with a diminished kidney fungal burden. Thus, IDR-1018 was able to protect against murine experimental candidemia and has the potential as an adjunctive therapy. PMID- 28559268 TI - Circulation of blaKPC-3-Carrying IncX3 Plasmids among Citrobacter freundii Isolates in an Italian Hospital. AB - Colonizations due to carbapenem-resistant Enterobacteriaceae (CRE) are a source of antimicrobial resistance transmission in health care settings. Eleven Citrobacter freundii strains producing KPC-3 carbapenemase were isolated from rectal swabs during a 3-year surveillance program. blaKPC-3-carrying plasmids were found to belong to the IncX3 group in 9 of the 11 strains, and complete nucleotide sequences were obtained for 2 of them. Our results highlight the possible role of C. freundii as reservoir of resistance genes. PMID- 28559271 TI - Prevalence of Invasive Infections Due to Carbapenem-Resistant Enterobacteriaceae among Adult Patients in U.S. Hospitals. AB - This large-scale retrospective analysis (n = 60,551) of the Premier inpatient database (1 January 2011 to 31 December 2014) found an overall prevalence of carbapenem-resistant Enterobacteriaceae strains of 2.3% (range, 0.9% to 5.8% by geographic region) among patients with infections due to Enterobacteriaceae Ongoing monitoring and development of decision support tools/algorithms are needed for identification of high-risk patients. PMID- 28559269 TI - Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis. AB - Rifamycins exhibit concentration-dependent killing of Mycobacterium tuberculosis; higher exposures potentially induce better outcomes. We randomized 180 tuberculosis patients in Peru to receive rifampin at 10, 15, or 20 mg/kg/day. A total of 168 had noncompartmental pharmacokinetic analyses; 67% were sampled twice, and 33% were sampled six times. The doses administered were well tolerated. The median area under the concentration-time curve from 0 to 6 h (interquartile range) was 24.9 (17.6 to 32.1), 43.1 (30.3 to 57.5), or 55.5 (35.7 to 73.2) h . MUg/ml. The median maximum drug concentration in serum in the experimental arms reached the target of 8 MUg/ml. Continued investigation of higher rifampin doses is warranted. (This study has been registered at ClinicalTrials.gov under registration no. NCT01408914.). PMID- 28559270 TI - Efficacy of Rhesus Theta-Defensin-1 in Experimental Models of Pseudomonas aeruginosa Lung Infection and Inflammation. AB - Chronic airway infection and inflammation contribute to the progressive loss of lung function and shortened survival of patients with cystic fibrosis (CF). Rhesus theta defensin-1 (RTD-1) is a macrocyclic host defense peptide with antimicrobial and immunomodulatory activities. Combined with favorable preclinical safety and peptide stability data, RTD-1 warrants investigation to determine its therapeutic potential for treatment of CF lung disease. We sought to evaluate the therapeutic potential of RTD-1 for CF airway infection and inflammation using in vitro, ex vivo, and in vivo models. We evaluated RTD-1's effects on basal and Pseudomonas aeruginosa-induced inflammation in CF sputum leukocytes and CF bronchial epithelial cells. Peptide stability was evaluated by incubation with CF sputum. Airway pharmacokinetics, safety, and tolerance studies were performed in naive mice. Aerosolized RTD-1 treatment effects were assessed by analyzing lung bacterial burdens and airway inflammation using an established model of chronic P. aeruginosa endobronchial infection in CF (DeltaF508) mice. RTD-1 directly reduces metalloprotease activity, as well as inflammatory cytokine secretion from CF airway leukocyte and bronchial epithelial cells. Intrapulmonary safety, tolerability, and stability data support the aerosol administration route. RTD-1 reduced the bacterial lung burden, airway neutrophils, and inflammatory cytokines in CF mice with chronic P. aeruginosa lung infection. Collectively, these studies support further development of RTD-1 for treatment of CF airway disease. PMID- 28559272 TI - An Effective Antiviral Approach Targeting Hepatitis B Virus with NJK14047, a Novel and Selective Biphenyl Amide p38 Mitogen-Activated Protein Kinase Inhibitor. AB - Despite recent advances in therapeutic strategies against hepatitis B virus (HBV) infection, chronic hepatitis B remains a major global health burden. Recent studies have shown that targeting host factors instead of viral factors can be an effective antiviral strategy with low risk of the development of resistance. Efforts to identify host factors affecting viral replication have identified p38 mitogen-activated protein kinase (MAPK) as a possible target for antiviral strategies against various viruses, including HBV. Here, a series of biphenyl amides were synthesized as novel p38 MAPK selective inhibitors and assessed for their anti-HBV activities. The suppression of HBV surface antigen (HBsAg) production by these compounds was positively correlated with p38 MAPK-inhibitory activity. The selected compound NJK14047 displayed significant anti-HBV activity, as determined by HBsAg production, HBeAg secretion, and HBV production. NJK14047 efficiently suppressed the secretion of HBV antigens and HBV particles from HBV genome-transfected cells and HBV-infected sodium taurocholate cotransporting polypeptide-expressing human hepatoma cells. Furthermore, NJK14047 treatment resulted in a significant decrease of pregenomic RNA and covalently closed circular DNA (cccDNA) of HBV in HBV-harboring cells, indicating its ability to inhibit HBV replication. Considering that suppression of HBsAg secretion and elimination of cccDNA of HBV are the major aims of anti-HBV therapeutic strategies, the results suggested the potential use of these compounds as a novel class of anti-HBV agents targeting host factors critical for viral infection. PMID- 28559273 TI - First Detection of VIM-2 Metallo-beta-Lactamase-Producing Pseudomonas putida in Blattella germanica Cockroaches in an Algerian Hospital. PMID- 28559274 TI - A Lower Baseline CD4/CD8 T-Cell Ratio Is Independently Associated with Immunodiscordant Response to Antiretroviral Therapy in HIV-Infected Subjects. AB - We explored if baseline CD4/CD8 T-cell ratio is associated with immunodiscordant response to antiretroviral therapy in HIV-infected subjects. Comparing immunodiscordant and immunoconcordant subjects matched by pretreatment CD4 counts, we observed a lower pretreatment CD4/CD8 T-cell ratio in immunodiscordant subjects. Furthermore, pretreatment CD4/CD8 T-cell ratio, but not CD4 counts, correlated with the main immunological alterations observed in immunodiscordants, including increased regulatory T-cell (Treg) frequency and T-cell turnover related markers. Then, in a larger cohort, only baseline CD4/CD8 T-cell ratio was independently associated with immunodiscordance, after adjusting by the viral CXCR4-tropic HIV variants. Our results suggest that the CD4/CD8 T-cell ratio could be an accurate biomarker of the subjacent immunological damage triggering immunodiscordance. PMID- 28559275 TI - Urinary Concentrations of Colistimethate and Formed Colistin after Intravenous Administration in Patients with Multidrug-Resistant Gram-Negative Bacterial Infections. AB - Limited information is available on the urinary excretion of colistin in infected patients. This study aimed to investigate the pharmacokinetics of colistimethate sodium (CMS) and formed colistin in urine in patients with multidrug-resistant (MDR) Gram-negative bacterial infections. A pharmacokinetic study was conducted on 12 patients diagnosed with an infection caused by an extremely drug-resistant (XDR) P. aeruginosa strain and treated with intravenous CMS. Fresh urine samples were collected at 2-h intervals, and blood samples were collected predose (Cmin ss) and at the end of the CMS infusion (Cmax ss) for measurement of concentrations of CMS and formed colistin using high-performance liquid chromatography (HPLC). CMS urinary recovery was determined as the summed amount of CMS and formed colistin recovered in urine for each 2-h interval divided by the CMS dose. There were 12 enrolled patients, 9 of whom were male (75%). Data [median (range)] were as follows: age, 65.5 (37 to 86) years; colistimethate urinary recovery 0 to 6 h, 42.6% (2.9% to 72.8%); range of concentrations of colistin in urine, <0.1 to 95.4 mg/liter; Cmin ss and Cmax ss of colistin in plasma, 0.9 (<0.2 to 1.4) and 0.9 (<0.2 to 1.4) mg/liter, respectively. In 6/12 (50%) patients, more than 40% of the CMS dose was recovered in the urine within the first 6 h after CMS administration. This study demonstrated rapid urinary excretion of CMS in patients within the first 6 h after intravenous administration. In all but one patient, the concentrations of formed colistin in urine were above the MIC for the most predominant isolate of P. aeruginosa in our hospital. Future studies are warranted for optimizing CMS dosage regimens in urinary tract infection (UTI) patients. PMID- 28559276 TI - Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients. AB - The objectives of this study were to characterize the population pharmacokinetics (PK) of efavirenz (EFV) and 8-hydroxy-efavirenz (8OHEFV) in plasma and peripheral blood mononuclear cells (PBMCs) and to explore covariates affecting the PK parameters. Fifty-one patients had steady-state 0-to-24-h concentrations of EFV and 8OHEFV in plasma with corresponding concentrations in PBMCs, while 261 patients had one or two sparse concentrations at 16 +/- 1 h postdose at weeks 4 and/or 16. The pharmacogenetic markers CYP2B6*6, CYP3A5*3, CYP3A5*6, UGT2B7*2, ABCB1 (3435C->T, 3842A->G), OATP1B1*1B, and OATP1B1*5, the presence of a rifampin based antituberculosis (anti-TB) regimen, baseline body weight and organ function values, and demographic factors were explored as covariates. EFV concentration data were well described by a two-compartment model with first-order absorption (Ka ) and absorption lag time (Alag) (Ka = 0.2 h-1; Alag = 0.83 h; central compartment clearance [CLc/F] for CYP2B6*1/*1 = 18 liters/h, for CYP2B6*1/*6 = 14 liters/h, and for CYP2B6*6/*6 = 8.6 liters/h) and PBMCs as a peripheral compartment. EFV transfer from plasma to PBMCs was first order (CLp/F = 32 liters/h), followed by capacity-limited return (Vmax = 4,400 ng/ml/h; Km = 710 ng/ml). Similarly, 8OHEFV displayed a first-order elimination and distribution to PBMCs, with a capacity-limited return to plasma. No covariate relationships resulted in a significant explanation of interindividual variability (IIV) on the estimated PK parameters of EFV and 8OHEFV, except for CYP2B6*6 genotypes, which were consistent with prior evidence. Both EFV and 8OHEFV accumulated to higher concentrations in PBMCs than in plasma and were well described by first-order input and Michaelis-Menten kinetics removal from PBMCs. CYP2B6*6 genotype polymorphisms were associated with decreased EFV and 8OHEFV clearance. PMID- 28559278 TI - The p90 ribosomal S6 kinase-UBR5 pathway controls Toll-like receptor signaling via miRNA-induced translational inhibition of tumor necrosis factor receptor associated factor 3. AB - MicroRNAs (miRNAs) are small, noncoding RNAs that post-transcriptionally regulate gene expression. For example, miRNAs repress gene expression by recruiting the miRNA-induced silencing complex (miRISC), a ribonucleoprotein complex that contains miRNA-engaged Argonaute (Ago) and the scaffold protein GW182. Recently, ubiquitin-protein ligase E3 component N-recognin 5 (UBR5) has been identified as a component of miRISC. UBR5 directly interacts with GW182 proteins and participates in miRNA silencing by recruiting downstream effectors, such as the translation regulator DEAD-box helicase 6 (DDX6) and transducer of ERBB2,1/2,2 (Tob1/2), to the Ago-GW182 complex. However, the regulation of miRISC-associated UBR5 remains largely elusive. In the present study, we showed that UBR5 down regulates the levels of TNF receptor-associated factor 3 (TRAF3), a key component of Toll-like receptor signaling, via the miRNA pathway. We further demonstrated that p90 ribosomal S6 kinase (p90RSK) is an upstream regulator of UBR5. p90RSK phosphorylates UBR5 at Thr637, Ser1227, and Ser2483, and this phosphorylation is required for the translational repression of TRAF3 mRNA. Phosphorylated UBR5 co localized with GW182 and Ago2 in cytoplasmic speckles, which implies that miRISC is affected by phospho-UBR5. Collectively, these results indicated that the p90RSK-UBR5 pathway stimulates miRNA-mediated translational repression of TRAF3. Our work has added another layer to the regulation of miRISC. PMID- 28559277 TI - Cryptococcus neoformans ADS lyase is an enzyme essential for virulence whose crystal structure reveals features exploitable in antifungal drug design. AB - There is significant clinical need for new antifungal agents to manage infections with pathogenic species such as Cryptococcus neoformans Because the purine biosynthesis pathway is essential for many metabolic processes, such as synthesis of DNA and RNA and energy generation, it may represent a potential target for developing new antifungals. Within this pathway, the bifunctional enzyme adenylosuccinate (ADS) lyase plays a role in the formation of the key intermediates inosine monophosphate and AMP involved in the synthesis of ATP and GTP, prompting us to investigate ADS lyase in C. neoformans. Here, we report that ADE13 encodes ADS lyase in C. neoformans. We found that an ade13Delta mutant is an adenine auxotroph and is unable to successfully cause infections in a murine model of virulence. Plate assays revealed that production of a number of virulence factors essential for dissemination and survival of C. neoformans in a host environment was compromised even with the addition of exogenous adenine. Purified recombinant C. neoformans ADS lyase shows catalytic activity similar to its human counterpart, and its crystal structure, the first fungal ADS lyase structure determined, shows a high degree of structural similarity to that of human ADS lyase. Two potentially important amino acid differences are identified in the C. neoformans crystal structure, in particular a threonine residue that may serve as an additional point of binding for a fungal enzyme-specific inhibitor. Besides serving as an antimicrobial target, C. neoformans ADS lyase inhibitors may also serve as potential therapeutics for metabolic disease; rather than disrupt ADS lyase, compounds that improve the stability the enzyme may be used to treat ADS lyase deficiency disease. PMID- 28559280 TI - Crystal structure of the thioesterification conformation of Bacillus subtilis o succinylbenzoyl-CoA synthetase reveals a distinct substrate-binding mode. AB - o-Succinylbenzoyl-CoA (OSB-CoA) synthetase (MenE) is an essential enzyme in bacterial vitamin K biosynthesis and an important target in the development of new antibiotics. It is a member of the adenylating enzymes (ANL) family, which reconfigure their active site in two different active conformations, one for the adenylation half-reaction and the other for a thioesterification half-reaction, in a domain-alternation catalytic mechanism. Although several aspects of the adenylating mechanism in MenE have recently been uncovered, its thioesterification conformation remains elusive. Here, using a catalytically competent Bacillus subtilis mutant protein complexed with an OSB-CoA analogue, we determined MenE high-resolution structures to 1.76 and 1.90 A resolution in a thioester-forming conformation. By comparison with the adenylation conformation, we found that MenE's C-domain rotates around the Ser-384 hinge by 139.5 degrees during domain-alternation catalysis. The structures also revealed a thioesterification active site specifically conserved among MenE orthologues and a substrate-binding mode distinct from those of many other acyl/aryl-CoA synthetases. Of note, using site-directed mutagenesis, we identified several residues that specifically contribute to the thioesterification half-reaction without affecting the adenylation half-reaction. Moreover, we observed a substantial movement of the activated succinyl group in the thioesterification half-reaction. These findings provide new insights into the domain-alternation catalysis of a bacterial enzyme essential for vitamin K biosynthesis and of its adenylating homologues in the ANL enzyme family. PMID- 28559281 TI - Uridine monophosphate synthetase enables eukaryotic de novo NAD+ biosynthesis from quinolinic acid. AB - NAD+ biosynthesis is an attractive and promising therapeutic target for influencing health span and obesity-related phenotypes as well as tumor growth. Full and effective use of this target for therapeutic benefit requires a complete understanding of NAD+ biosynthetic pathways. Here, we report a previously unrecognized role for a conserved phosphoribosyltransferase in NAD+ biosynthesis. Because a required quinolinic acid phosphoribosyltransferase (QPRTase) is not encoded in its genome, Caenorhabditis elegans are reported to lack a de novo NAD+ biosynthetic pathway. However, all the genes of the kynurenine pathway required for quinolinic acid (QA) production from tryptophan are present. Thus, we investigated the presence of de novo NAD+ biosynthesis in this organism. By combining isotope-tracing and genetic experiments, we have demonstrated the presence of an intact de novo biosynthesis pathway for NAD+ from tryptophan via QA, highlighting the functional conservation of this important biosynthetic activity. Supplementation with kynurenine pathway intermediates also boosted NAD+ levels and partially reversed NAD+-dependent phenotypes caused by mutation of pnc 1, which encodes a nicotinamidase required for NAD+ salvage biosynthesis, demonstrating contribution of de novo synthesis to NAD+ homeostasis. By investigating candidate phosphoribosyltransferase genes in the genome, we determined that the conserved uridine monophosphate phosphoribosyltransferase (UMPS), which acts in pyrimidine biosynthesis, is required for NAD+ biosynthesis in place of the missing QPRTase. We suggest that similar underground metabolic activity of UMPS may function in other organisms. This mechanism for NAD+ biosynthesis creates novel possibilities for manipulating NAD+ biosynthetic pathways, which is key for the future of therapeutics. PMID- 28559279 TI - The UbiK protein is an accessory factor necessary for bacterial ubiquinone (UQ) biosynthesis and forms a complex with the UQ biogenesis factor UbiJ. AB - Ubiquinone (UQ), also referred to as coenzyme Q, is a widespread lipophilic molecule in both prokaryotes and eukaryotes in which it primarily acts as an electron carrier. Eleven proteins are known to participate in UQ biosynthesis in Escherichia coli, and we recently demonstrated that UQ biosynthesis requires additional, nonenzymatic factors, some of which are still unknown. Here, we report on the identification of a bacterial gene, yqiC, which is required for efficient UQ biosynthesis, and which we have renamed ubiK Using several methods, we demonstrated that the UbiK protein forms a complex with the C-terminal part of UbiJ, another UQ biogenesis factor we previously identified. We found that both proteins are likely to contribute to global UQ biosynthesis rather than to a specific biosynthetic step, because both ubiK and ubiJ mutants accumulated octaprenylphenol, an early intermediate of the UQ biosynthetic pathway. Interestingly, we found that both proteins are dispensable for UQ biosynthesis under anaerobiosis, even though they were expressed in the absence of oxygen. We also provide evidence that the UbiK-UbiJ complex interacts with palmitoleic acid, a major lipid in E. coli Last, in Salmonella enterica, ubiK was required for proliferation in macrophages and virulence in mice. We conclude that although the role of the UbiK-UbiJ complex remains unknown, our results support the hypothesis that UbiK is an accessory factor of Ubi enzymes and facilitates UQ biosynthesis by acting as an assembly factor, a targeting factor, or both. PMID- 28559282 TI - The higher plant plastid NAD(P)H dehydrogenase-like complex (NDH) is a high efficiency proton pump that increases ATP production by cyclic electron flow. AB - Cyclic electron flow around photosystem I (CEF) is critical for balancing the photosynthetic energy budget of the chloroplast by generating ATP without net production of NADPH. We demonstrate that the chloroplast NADPH dehydrogenase complex, a homolog to respiratory Complex I, pumps approximately two protons from the chloroplast stroma to the lumen per electron transferred from ferredoxin to plastoquinone, effectively increasing the efficiency of ATP production via CEF by 2-fold compared with CEF pathways involving non-proton-pumping plastoquinone reductases. By virtue of this proton-pumping stoichiometry, we hypothesize that NADPH dehydrogenase not only efficiently contributes to ATP production but operates near thermodynamic reversibility, with potentially important consequences for remediating mismatches in the thylakoid energy budget. PMID- 28559283 TI - Molecular dynamics simulations reveal the conformational dynamics of Arabidopsis thaliana BRI1 and BAK1 receptor-like kinases. AB - The structural motifs responsible for activation and regulation of eukaryotic protein kinases in animals have been studied extensively in recent years, and a coherent picture of their activation mechanisms has begun to emerge. In contrast, non-animal eukaryotic protein kinases are not as well understood from a structural perspective, representing a large knowledge gap. To this end, we investigated the conformational dynamics of two key Arabidopsis thaliana receptor like kinases, brassinosteroid-insensitive 1 (BRI1) and BRI1-associated kinase 1 (BAK1), through extensive molecular dynamics simulations of their fully phosphorylated kinase domains. Molecular dynamics simulations calculate the motion of each atom in a protein based on classical approximations of interatomic forces, giving researchers insight into protein function at unparalleled spatial and temporal resolutions. We found that in an otherwise "active" BAK1 the alphaC helix is highly disordered, a hallmark of deactivation, whereas the BRI1 alphaC helix is moderately disordered and displays swinging behavior similar to numerous animal kinases. An analysis of all known sequences in the A. thaliana kinome found that alphaC helix disorder may be a common feature of plant kinases. PMID- 28559286 TI - Successful treatment of pneumatosis intestinalis with associated pneumoperitoneum and ileus with hyperbaric oxygen therapy. AB - Pneumatosis intestinalis (PI), or the presence of air in the bowel wall, is a rare disorder that is associated with a variety of underlying diseases, including connective tissue disorders. PI presents on a spectrum from asymptomatic to bowel obstruction and acute abdomen. In general, treatment of PI consists of treating the underlying disease. Both normobaric and hyperbaric oxygen have been used to treat PI directly. Here we report a symptomatic scleroderma-related case of PI that responded clinically to hyperbaric oxygen therapy. This report adds to a growing body of literature supporting a role for hyperbaric oxygen therapy in symptomatic PI. PMID- 28559284 TI - The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/beta catenin pathway by inhibiting the proteasome. AB - UBE3A is a HECT domain E3 ubiquitin ligase whose dysfunction is linked to autism, Angelman syndrome, and cancer. Recently, we characterized a de novo autism-linked UBE3A mutant (UBE3AT485A) that disrupts phosphorylation control of UBE3A activity. Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear beta-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A. We also found that UBE3AT485A activates Wnt signaling to a greater extent in cells with low levels of ongoing Wnt signaling, suggesting that cells with low basal Wnt activity are particularly vulnerable to UBE3AT485A mutation. Ligase-dead UBE3A did not stimulate Wnt pathway activation. Overexpression of several proteasome subunits reversed the effect of UBE3AT485A on Wnt signaling. We also observed that subunits that interact with UBE3A and affect Wnt signaling are located along one side of the 19S regulatory particle, indicating a previously unrecognized spatial organization to the proteasome. Altogether, our findings indicate that UBE3A regulates Wnt signaling in a cell context-dependent manner and that an autism linked mutation exacerbates these signaling effects. Our study has broad implications for human disorders associated with UBE3A gain or loss of function and suggests that dysfunctional UBE3A might affect additional proteins and pathways that are sensitive to proteasome activity. PMID- 28559287 TI - Occult myeloproliferative neoplasms: not so occult any more. AB - Non-cirrhotic, non-malignant portal vein thrombosis (PVT) is commonly secondary to inherited or acquired prothrombotic states. However, even after extensive workup, 25% of patients with PVT have no apparent prothrombotic aetiology identified (idiopathic PVT). Inherited conditions include factor V Leiden, PT mutation and protein C/S/AT deficiency. Acquired conditions include APS, PNH and BCR-ABL 1-negative myeloproliferative neoplasms (MPN). BCR-ABL-1 negative MPNs are the most frequent underlying prothrombotic risk factor for PVT (15%-30%). However, peripheral blood counts often remain within normal ranges in these patients with MPN because of portal hypertension sequel. Despite suggestive features of MPN in bone marrow, these patients lack adequate diagnostic criteria and are classified as occult MPN. The discovery of recurrent molecular abnormalities such as CALR gene exon 9 mutation presented a crucial advance in the diagnosis of occult MPNs. In our patient, the diagnosis of MPN was made on this basis, despite lack of peripheral evidence of MPN. PMID- 28559285 TI - Hepatitis C virus induces a prediabetic state by directly impairing hepatic glucose metabolism in mice. AB - Virus-related type 2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV); however, the underlying molecular mechanisms remain unknown. Our aim was to unravel these mechanisms using FL-N/35 transgenic mice expressing the full HCV ORF. We observed that these mice displayed glucose intolerance and insulin resistance. We also found that Glut-2 membrane expression was reduced in FL-N/35 mice and that hepatocyte glucose uptake was perturbed, partly accounting for the HCV-induced glucose intolerance in these mice. Early steps of the hepatic insulin signaling pathway, from IRS2 to PDK1 phosphorylation, were constitutively impaired in FL-N/35 primary hepatocytes via deregulation of TNFalpha/SOCS3. Higher hepatic glucose production was observed in the HCV mice, despite higher fasting insulinemia, concomitant with decreased expression of hepatic gluconeogenic genes. Akt kinase activity was higher in HCV mice than in WT mice, but Akt-dependent phosphorylation of the forkhead transcription factor FoxO1 at serine 256, which triggers its nuclear exclusion, was lower in HCV mouse livers. These findings indicate an uncoupling of the canonical Akt/FoxO1 pathway in HCV protein-expressing hepatocytes. Thus, the expression of HCV proteins in the liver is sufficient to induce insulin resistance by impairing insulin signaling and glucose uptake. In conclusion, we observed a complete set of events leading to a prediabetic state in HCV transgenic mice, providing a valuable mechanistic explanation for HCV-induced diabetes in humans. PMID- 28559288 TI - David Oliver: Should practical quality improvement have parity of esteem with evidence based medicine? PMID- 28559289 TI - Generating minicorneal organoids from human induced pluripotent stem cells. AB - Corneal epithelial stem cells residing within the annular limbal crypts regulate adult tissue homeostasis. Autologous limbal grafts and tissue-engineered corneal epithelial cell sheets have been widely used in the treatment of various ocular surface defects. In the case of bilateral limbal defects, pluripotent stem cell (PSC)-derived corneal epithelial cells are now being explored as an alternative to allogeneic limbal grafts. Here, we report an efficient method to generate complex three-dimensional corneal organoids from human PSCs. The eye field primordial clusters that emerged from differentiating PSCs developed into whole eyeball-like, self-organized, three-dimensional, miniature structures consisting of retinal primordia, corneal primordia, a primitive eyelid-like outer covering and ciliary margin zone-like adnexal tissues in a stepwise maturation process within 15 weeks. These minicorneal organoids recapitulate the early developmental events in vitro and display similar anatomical features and marker expression profiles to adult corneal tissues. They offer an alternative tissue source for regenerating different layers of the cornea and eliminate the need for complicated cell enrichment procedures. PMID- 28559290 TI - A role for PFKFB3/iPFK2 in metformin suppression of adipocyte inflammatory responses. AB - Metformin improves obesity-associated metabolic dysregulation, but has controversial effects on adipose tissue inflammation. The objective of the study is to examine the direct effect of metformin on adipocyte inflammatory responses and elucidate the underlying mechanisms. Adipocytes were differentiated from 3T3 L1 cells and treated with metformin at various doses and for different time periods. The treated cells were examined for the proinflammatory responses, as well as the phosphorylation states of AMPK and the expression of PFKFB3/iPFK2. In addition, PFKFB3/iPFK2-knockdown adipocytes were treated with metformin and examined for changes in the proinflammatory responses. The following results were obtained from the study. Treatment of adipocytes with metformin decreased the effects of lipopolysaccharide on inducing the phosphorylation states of JNK p46 and on increasing the mRNA levels of IL-1beta and TNFalpha. In addition, treatment with metformin increased the expression of PFKFB3/iPFK2, but failed to significantly alter the phosphorylation states of AMPK. In PFKFB3/iPFK2-knockdown adipocytes, treatment with metformin did not suppress the proinflammatory responses as did it in control adipocytes. In conclusion, metformin has a direct effect on suppressing adipocyte proinflammatory responses in an AMPK-independent manner. Also, metformin increases adipocyte expression of PFKFB3/iPFK2, which is involved in the anti-inflammatory effect of metformin. PMID- 28559292 TI - Brucella abortus Induces a Warburg Shift in Host Metabolism That Is Linked to Enhanced Intracellular Survival of the Pathogen. AB - Intracellular bacterial pathogens exploit host cell resources to replicate and survive inside the host. Targeting these host systems is one promising approach to developing novel antimicrobials to treat intracellular infections. We show that human macrophage-like cells infected with Brucella abortus undergo a metabolic shift characterized by attenuated tricarboxylic acid cycle metabolism, reduced amino acid consumption, altered mitochondrial localization, and increased lactate production. This shift to an aerobic glycolytic state resembles the Warburg effect, a change in energy production that is well described in cancer cells and also occurs in activated inflammatory cells. B. abortus efficiently uses lactic acid as its sole carbon and energy source and requires the ability to metabolize lactate for normal survival in human macrophage-like cells. We demonstrate that chemical inhibitors of host glycolysis and lactate production do not affect in vitro growth of B. abortus in axenic culture but decrease its survival in the intracellular niche. Our data support a model in which infection shifts host metabolism to a Warburg-like state, and B. abortus uses this change in metabolism to promote intracellular survival. Pharmacological perturbation of these features of host cell metabolism may be a useful strategy to inhibit infection by intracellular pathogens.IMPORTANCEBrucella spp. are intracellular bacterial pathogens that cause disease in a range of mammals, including livestock. Transmission from livestock to humans is common and can lead to chronic human disease. Human macrophage-like cells infected with Brucella abortus undergo a Warburg-like metabolic shift to an aerobic glycolytic state where the host cells produce lactic acid and have reduced amino acid catabolism. We provide evidence that the pathogen can exploit this change in host metabolism to support growth and survival in the intracellular niche. Drugs that inhibit this shift in host cell metabolism inhibit intracellular replication and decrease the survival of B. abortus in an in vitro infection model; these drugs may be broadly useful therapeutics for intracellular infections. PMID- 28559291 TI - Interaction of Mycoplasma hominis PG21 with Human Dendritic Cells: Interleukin-23 Inducing Mycoplasmal Lipoproteins and Inflammasome Activation of the Cell. AB - Mycoplasma hominis lacks a cell wall, and lipoproteins anchored to the extracellular side of the plasma membrane are in direct contact with the host components. A Triton X-114 extract of M. hominis enriched with lipoproteins was shown to stimulate the production of interleukin-23 (IL-23) by human dendritic cells (hDCs). The inflammasome activation of the host cell has never been reported upon M. hominis infection. We studied here the interaction between M. hominis PG21 and hDCs by analyzing both the inflammation-inducing mycoplasmal lipoproteins and the inflammasome activation of the host cell. IL-23-inducing lipoproteins were determined using a sequential extraction strategy with two nondenaturing detergents, Sarkosyl and Triton X-114, followed by SDS-PAGE separation and mass spectrometry identification. The activation of the hDC inflammasome was assessed using PCR array and enzyme-linked immunosorbent assay (ELISA). We defined a list of 24 lipoproteins that could induce the secretion of IL-23 by hDCs, 5 with a molecular mass between 20 and 35 kDa and 19 with a molecular mass between 40 and 100 kDa. Among them, lipoprotein MHO_4720 was identified as potentially bioactive, and a synthetic lipopeptide corresponding to the N-terminal part of the lipoprotein was subsequently shown to induce IL-23 release by hDCs. Regarding the hDC innate immune response, inflammasome activation with caspase-dependent production of IL-1beta was observed. After 24 h of coincubation of hDCs with M. hominis, downregulation of the NLRP3-encoding gene and of the adaptor PYCARD-encoding gene was noticed. Overall, this study provides insight into both protagonists of the interaction of M. hominis and hDCs.IMPORTANCEMycoplasma hominis is a human urogenital pathogen involved in gynecologic and opportunistic infections. M. hominis lacks a cell wall, and its membrane contains many lipoproteins that are anchored to the extracellular side of the plasma membrane. In the present study, we focused on the interaction between M. hominis and human dendritic cells and examined both sides of the interaction, the mycoplasmal lipoproteins involved in the activation of the host cell and the immune response of the cell. On the mycoplasmal side, we showed for the first time that M. hominis lipoproteins with high molecular mass were potentially bioactive. On the cell side, we reported an activation of the inflammasome, which is involved in the innate immune response. PMID- 28559293 TI - A Conserved Metal Binding Motif in the Bacillus subtilis Competence Protein ComFA Enhances Transformation. AB - Genetic competence is a process in which cells are able to take up DNA from their environment, resulting in horizontal gene transfer, a major mechanism for generating diversity in bacteria. Many bacteria carry homologs of the central DNA uptake machinery that has been well characterized in Bacillus subtilis It has been postulated that the B. subtilis competence helicase ComFA belongs to the DEAD box family of helicases/translocases. Here, we made a series of mutants to analyze conserved amino acid motifs in several regions of B. subtilis ComFA. First, we confirmed that ComFA activity requires amino acid residues conserved among the DEAD box helicases, and second, we show that a zinc finger-like motif consisting of four cysteines is required for efficient transformation. Each cysteine in the motif is important, and mutation of at least two of the cysteines dramatically reduces transformation efficiency. Further, combining multiple cysteine mutations with the helicase mutations shows an additive phenotype. Our results suggest that the helicase and metal binding functions are two distinct activities important for ComFA function during transformation.IMPORTANCE ComFA is a highly conserved protein that has a role in DNA uptake during natural competence, a mechanism for horizontal gene transfer observed in many bacteria. Investigation of the details of the DNA uptake mechanism is important for understanding the ways in which bacteria gain new traits from their environment, such as drug resistance. To dissect the role of ComFA in the DNA uptake machinery, we introduced point mutations into several motifs in the protein sequence. We demonstrate that several amino acid motifs conserved among ComFA proteins are important for efficient transformation. This report is the first to demonstrate the functional requirement of an amino-terminal cysteine motif in ComFA. PMID- 28559294 TI - Bypassing the restriction system to improve transformation of Staphylococcus epidermidis. AB - Staphylococcus epidermidis is the leading cause of infections on indwelling medical devices worldwide. Intrinsic antibiotic resistance and vigorous biofilm production have rendered these infections difficult to treat and, in some cases, require the removal of the offending medical prostheses. With the exception of two widely-passaged isolates RP62A and 1457, the pathogenesis of infections caused by clinical S. epidermidis strains is poorly understood due to the strong genetic barrier that precludes efficient transformation of foreign DNA into clinical isolates. The difficulty in transforming clinical S. epidermidis isolates is primarily due to the type I and IV restriction modification systems which act as genetic barriers. Here, we showed that efficient plasmid transformation of clinical S. epidermidis isolates from clonal complexes 2, 10 and 89 could be realized by employing a plasmid artificial modification (PAM) in E. coli DC10B containing a Deltadcm mutation. This transformative technique should facilitate our ability to genetically modify clinical isolates of S. epidermidis and hence improve our understanding of its pathogenesis in human infections.ImportanceStaphylococcus epidermidis is a source of considerable morbidity worldwide. The underlying mechanisms contributing to the commensal and pathogenic lifestyles of S. epidermidis are poorly understood. Genetic manipulations of clinically relevant strains of S. epidermidis are largely prohibited due to the presence of a strong restriction barrier. With the introductions of the tools presented here, genetic manipulation has now become possible with clinically relevant S. epidermidis isolates, thus improving our understanding of S. epidermidis as a pathogen. PMID- 28559296 TI - Cysteine Biosynthesis Controls Serratia marcescens Phospholipase Activity. AB - Serratia marcescens causes health care-associated opportunistic infections that can be difficult to treat due to a high incidence of antibiotic resistance. One of the many secreted proteins of S. marcescens is the PhlA phospholipase enzyme. Genes involved in the production and secretion of PhlA were identified by screening a transposon insertion library for phospholipase-deficient mutants on phosphatidylcholine-containing medium. Mutations were identified in four genes (cyaA, crp, fliJ, and fliP) that are involved in the flagellum-dependent PhlA secretion pathway. An additional phospholipase-deficient isolate harbored a transposon insertion in the cysE gene encoding a predicted serine O acetyltransferase required for cysteine biosynthesis. The cysE requirement for extracellular phospholipase activity was confirmed using a fluorogenic phospholipase substrate. Phospholipase activity was restored to the cysE mutant by the addition of exogenous l-cysteine or O-acetylserine to the culture medium and by genetic complementation. Additionally, phlA transcript levels were decreased 6-fold in bacteria lacking cysE and were restored with added cysteine, indicating a role for cysteine-dependent transcriptional regulation of S. marcescens phospholipase activity. S. marcescenscysE mutants also exhibited a defect in swarming motility that was correlated with reduced levels of flhD and fliA flagellar regulator gene transcription. Together, these findings suggest a model in which cysteine is required for the regulation of both extracellular phospholipase activity and surface motility in S. marcescensIMPORTANCESerratia marcescens is known to secrete multiple extracellular enzymes, but PhlA is unusual in that this protein is thought to be exported by the flagellar transport apparatus. In this study, we demonstrate that both extracellular phospholipase activity and flagellar function are dependent on the cysteine biosynthesis pathway. Furthermore, a disruption of cysteine biosynthesis results in decreased phlA and flagellar gene transcription, which can be restored by supplying bacteria with exogenous cysteine. These results identify a previously unrecognized role for CysE and cysteine in the secretion of S. marcescens phospholipase and in bacterial motility. PMID- 28559298 TI - Phylogenetic and structural comparisons of the three types of methyl-coenzyme M reductase from Methanococcales and Methanobacteriales. AB - The phylogenetically diverse family of methanogenic archaea universally use methyl-coenzyme M reductase (MCR) for catalyzing the final methane-forming reaction step of the methanogenic energy metabolism. Some methanogens of the orders Methanobacteriales and Methanococcales contain two isoenzymes. Comprehensive phylogenetic analyses on the basis of all three subunits grouped MCRs from Methanobacteriales, Methanococcales and Methanopyrales into three distinct types: (1) MCRs from Methanobacteriales, (2) MCRs from Methanobacteriales and Methanococcales and (3) MCRs from Methanococcales. The first and second types contain MCR isoenzyme I and II from Methanothermobacter marburgensis, respectively; therefore, they were designated as MCR type I and type II and accordingly, the third one was designated as MCR type III. For comparison with the known MCR type I and type II structures, we determined the structure of MCR type III from Methanotorris formicicus and Methanothermococcus thermolithotrophicus As predicted, the three MCR types revealed highly similar overall structures and a virtually identical active site architecture reflecting the chemically challenging mechanism of methane formation. Pronounced differences were found at the protein surface with respect to loop geometries and electrostatic properties, which also involve the entrance of the active site funnel. In addition, the C-terminal end of the gamma-subunit is prolonged by an extra helix after helix gamma8 in MCR type II and type III, which is, however, differently arranged in the two MCR types. MCR types I, II and III share most of the post-translational modifications which appear to fine-tune the enzymatic catalysis. Interestingly, MCR type III lacks the methyl-cysteine but possesses in subunit alpha of M. formicicus a 6-hydroxy-tryptophan, which has been, so far, only found in the alpha-amanitin toxin peptide but not in proteins.IMPORTANCE Methyl-coenzyme M reductase (MCR) represents a prime target for the mitigation of methane releases. Phylogenetic analyses of MCR suggested several distinct sequence clusters; those from Methanobacteriales and Methanococcales were subdivided into three types: MCR type I from Methanobacteriales, MCR type II from Methanobacteriales and Methanococcales and the newly designated MCR type III exclusively from Methanococcales. We determined the first X-ray structures for an MCR type III. Detailed analyses only revealed substantial differences between the three types in the peripheral region. Identified subtle modifications and electrostatic profiles suggested enhanced substrate binding for MCR type III. In addition, MCR type III from Methanotorris formicicus contains 6-hydroxy tryptophan, a new post-translational modification that was, so far, only found in the alpha-amanitin toxin. PMID- 28559297 TI - Characterization of a Novel cis-3-Hydroxy-l-Proline Dehydratase and a trans-3 Hydroxy-l-Proline Dehydratase from Bacteria. AB - Hydroxyprolines, such as trans-4-hydroxy-l-proline (T4LHyp), trans-3-hydroxy-l proline (T3LHyp), and cis-3-hydroxy-l-proline (C3LHyp), are present in some proteins including collagen, plant cell wall, and several peptide antibiotics. In bacteria, genes involved in the degradation of hydroxyproline are often clustered on the genome (l-Hyp gene cluster). We recently reported that an aconitase X (AcnX)-like hypI gene from an l-Hyp gene cluster functions as a monomeric C3LHyp dehydratase (AcnXType I). However, the physiological role of C3LHyp dehydratase remained unclear. We here demonstrate that Azospirillum brasilense NBRC 102289, an aerobic nitrogen-fixing bacterium, robustly grows using not only T4LHyp and T3LHyp but also C3LHyp as the sole carbon source. The small and large subunits of the hypI gene (hypIS and hypIL, respectively) from A. brasilense NBRC 102289 are located separately from the l-Hyp gene cluster and encode a C3LHyp dehydratase with a novel heterodimeric structure (AcnXType IIa). A strain disrupted in the hypIS gene did not grow on C3LHyp, suggesting its involvement in C3LHyp metabolism. Furthermore, C3LHyp induced transcription of not only the hypI genes but also the hypK gene encoding Delta1-pyrroline-2-carboxylate reductase, which is involved in T3LHyp, d-proline, and d-lysine metabolism. On the other hand, the l-Hyp gene cluster of some other bacteria contained not only the AcnXType IIa gene but also two putative proline racemase-like genes (hypA1 and hypA2). Despite having the same active sites (a pair of Cys/Cys) as hydroxyproline 2-epimerase, which is involved in the metabolism of T4LHyp, the dominant reaction by HypA2 was clearly the dehydration of T3LHyp, a novel type of T3LHyp dehydratase that differed from the known enzyme (Cys/Thr).IMPORTANCE More than 50 years after the discovery of trans-4-hydroxy-l-proline (generally called l-hydroxyproline) degradation in aerobic bacteria, its genetic and molecular information has only recently been elucidated. l-Hydroxyproline metabolic genes are often clustered on bacterial genomes. These loci frequently contain a hypothetical gene(s), whose novel enzyme functions are related to the metabolism of trans-3-hydroxyl-proline and/or cis-3-hydroxyl-proline, a relatively rare l-hydroxyproline in nature. Several l-hydroxyproline metabolic enzymes show no sequential similarities, suggesting their emergence by convergent evolution. Furthermore, transcriptional regulation by trans-4-hydroxy-l-proline, trans-3-hydroxy-l-proline, and/or cis-3 hydroxy-l-proline significantly differs between bacteria. The results of the present study show that several l-hydroxyprolines are available for bacteria as carbon and energy sources and may contribute to the discovery of potential metabolic pathways of another hydroxyproline(s). PMID- 28559295 TI - Polyvalent Proteins, a Pervasive Theme in the Intergenomic Biological Conflicts of Bacteriophages and Conjugative Elements. AB - Intense biological conflicts between prokaryotic genomes and their genomic parasites have resulted in an arms race in terms of the molecular "weaponry" deployed on both sides. Using a recursive computational approach, we uncovered a remarkable class of multidomain proteins with 2 to 15 domains in the same polypeptide deployed by viruses and plasmids in such conflicts. Domain architectures and genomic contexts indicate that they are part of a widespread conflict strategy involving proteins injected into the host cell along with parasite DNA during the earliest phase of infection. Their unique feature is the combination of domains with highly disparate biochemical activities in the same polypeptide; accordingly, we term them polyvalent proteins. Of the 131 domains in polyvalent proteins, a large fraction are enzymatic domains predicted to modify proteins, target nucleic acids, alter nucleotide signaling/metabolism, and attack peptidoglycan or cytoskeletal components. They further contain nucleic acid binding domains, virion structural domains, and 40 novel uncharacterized domains. Analysis of their architectural network reveals both pervasive common themes and specialized strategies for conjugative elements and plasmids or (pro)phages. The themes include likely processing of multidomain polypeptides by zincin-like metallopeptidases and mechanisms to counter restriction or CRISPR/Cas systems and jump-start transcription or replication. DNA-binding domains acquired by eukaryotes from such systems have been reused in XPC/RAD4-dependent DNA repair and mitochondrial genome replication in kinetoplastids. Characterization of the novel domains discovered here, such as RNases and peptidases, are likely to aid in the development of new reagents and elucidation of the spread of antibiotic resistance.IMPORTANCE This is the first report of the widespread presence of large proteins, termed polyvalent proteins, predicted to be transmitted by genomic parasites such as conjugative elements, plasmids, and phages during the initial phase of infection along with their DNA. They are typified by the presence of multiple domains with disparate activities combined in the same protein. While some of these domains are predicted to assist the invasive element in replication, transcription, or protection of their DNA, several are likely to target various host defense systems or modify the host to favor the parasite's life cycle. Notably, DNA-binding domains from these systems have been transferred to eukaryotes, where they have been incorporated into DNA repair and mitochondrial genome replication systems. PMID- 28559299 TI - The Disulfide Bond Formation Pathway Is Essential for Anaerobic Growth of Escherichia coli. AB - Disulfide bonds are critical to the stability and function of many bacterial proteins. In the periplasm of Escherichia coli, intramolecular disulfide bond formation is catalyzed by the two-component disulfide bond forming (DSB) system. Inactivation of the DSB pathway has been shown to lead to a number of pleotropic effects, although cells remain viable under standard laboratory conditions. However, we show here that dsb strains of E. coli reversibly filament under aerobic conditions and fail to grow anaerobically unless a strong oxidant is provided in the growth medium. These findings demonstrate that the background disulfide bond formation necessary to maintain the viability of dsb strains is oxygen dependent. LptD, a key component of the lipopolysaccharide transport system, fails to fold properly in dsb strains exposed to anaerobic conditions, suggesting that these mutants may have defects in outer membrane assembly. We also show that anaerobic growth of dsb mutants can be restored by suppressor mutations in the disulfide bond isomerization system. Overall, our results underscore the importance of proper disulfide bond formation to pathways critical to E. coli viability under conditions where oxygen is limited.IMPORTANCE While the disulfide bond formation (DSB) system of E. coli has been studied for decades and has been shown to play an important role in the proper folding of many proteins, including some associated with virulence, it was considered dispensable for growth under most laboratory conditions. This work represents the first attempt to study the effects of the DSB system under strictly anaerobic conditions, simulating the environment encountered by pathogenic E. coli strains in the human intestinal tract. By demonstrating that the DSB system is essential for growth under such conditions, this work suggests that compounds inhibiting Dsb enzymes might act not only as antivirulents but also as true antibiotics. PMID- 28559300 TI - Rv3852 (H-NS) of Mycobacterium tuberculosis Is Not Involved in Nucleoid Compaction and Virulence Regulation. AB - A handful of nucleoid-associated proteins (NAPs) regulate the vast majority of genes in a bacterial cell. H-NS, the histone-like nucleoid-structuring protein, is one of these NAPs and protects Escherichia coli from foreign gene expression. Though lacking any sequence similarity with E. coli H-NS, Rv3852 was annotated as the H-NS ortholog in Mycobacterium tuberculosis, as it resembles human histone H1. The role of Rv3852 was thoroughly investigated by immunoblotting, subcellular localization, construction of an unmarked rv3852 deletion in the M. tuberculosis genome, and subsequent analysis of the resulting Deltarv3852 strain. We found that Rv3852 was predominantly present in the logarithmic growth phase with a decrease in protein abundance in stationary phase. Furthermore, it was strongly associated with the cell membrane and not detected in the cytosolic fraction, nor was it secreted. The Deltarv3852 strain displayed no growth defect or morphological abnormalities. Quantitative measurement of nucleoid localization in the Deltarv3852 mutant strain compared to that in the parental H37Rv strain showed no difference in nucleoid position or spread. Infection of macrophages as well as severe combined immunodeficient (SCID) mice demonstrated that loss of Rv3852 had no detected influence on the virulence of M. tuberculosis We thus conclude that M. tuberculosis Rv3852 is not involved in pathogenesis and is not a typical NAP. The existence of an as yet undiscovered Rv3852 ortholog cannot be excluded, although this role is likely played by the well-characterized Lsr2 protein.IMPORTANCEMycobacterium tuberculosis is the causative agent of the lung infection tuberculosis, claiming more than 1.5 million lives each year. To understand the mechanisms of latent infection, where M. tuberculosis can stay dormant inside the human host, we require deeper knowledge of the basic biology and of the regulatory networks. In our work, we show that Rv3852, previously annotated as H-NS, is not a typical nucleoid-associated protein (NAP) as expected from its initial annotation. Rv3852 from M. tuberculosis has neither influence on nucleoid shape or compaction nor a role in virulence. Our findings reduce the repertoire of identified nucleoid-associated proteins in M. tuberculosis to four transcription regulators and underline the importance of genetic studies to assign a function to bacterial genes. PMID- 28559302 TI - Margaret McCartney: The social care system has become inherently unsafe. PMID- 28559301 TI - Functional Interaction between the N and C Termini of NhaD Antiporters from Halomonas sp. Strain Y2. AB - Two NhaD-type antiporters, NhaD1 and NhaD2, from the halotolerant and alkaliphilic Halomonas sp. strain Y2, exhibit different physiological functions in regard to Na+ and Li+ resistance, although they share high sequence identity. In the present study, the truncation of an additional 4 C-terminal residues from NhaD2 or an exchange of 39 N-terminal residues between these proteins resulted in the complete loss of antiporter activity. Interestingly, combining 39 N-terminal residues and 7 C-terminal residues of NhaD2 (N39D2-C7) partially recovered the activity for Na+ and Li+ expulsion, as well as complementary growth following exposure to 300 mM Na+ and 100 mM Li+ stress. The recovered activity of chimera N39D2-C7 indicated that the N and C termini are structurally dependent on each other and function synergistically. Furthermore, fluorescence resonance energy transfer (FRET) analysis suggested that the N and C termini are relatively close in proximity which may account for their synergistic function in ion translocation. In the N-terminal region of N39D2-C7, the replacement of Glu38 with Pro abolished the recovered complementary and transport activities. In addition, this amino acid substitution in NhaD2 resulted in a drastically decreased complementation ability in Escherichia coli KNabc (level identical to that of NhaD1), as well as decreased activity and an altered pH profile.IMPORTANCE Limited information on NhaD antiporters supports speculation that these antiporters are important for resistance to high salinity and alkalinity. Moreover, only a few functional residues have been identified in NhaD antiporters, and there is limited literature on the molecular mechanisms of NhaD antiporter activity. The altered antiporter abilities of chimeras and mutants in this study implicate the functions of the N and C termini, especially Glu38, in pH regulation and ion translocation, and, most importantly, the essential roles of this negatively charged residue in maintaining the physiological function of NhaD2. These findings further our understanding of the molecular mechanism of NhaD antiporters for ion transport. PMID- 28559303 TI - TRPC1 is a differential regulator of hypoxia-mediated events and Akt signalling in PTEN-deficient breast cancer cells. AB - Hypoxia is a feature of the tumour microenvironment that promotes invasiveness, resistance to chemotherapeutics and cell survival. Our studies identify the transient receptor potential canonical-1 (TRPC1) ion channel as a key component of responses to hypoxia in breast cancer cells. This regulation includes control of specific epithelial to mesenchymal transition (EMT) events and hypoxia mediated activation of signalling pathways such as activation of the EGFR, STAT3 and the autophagy marker LC3B, through hypoxia-inducible factor-1alpha (HIF1alpha)-dependent and -independent mechanisms. TRPC1 regulated HIF1alpha levels in PTEN-deficient MDA-MB-468 and HCC1569 breast cancer cell lines. This regulation arises from effects on the constitutive translation of HIF1alpha under normoxic conditions via an Akt-dependent pathway. In further support of the role of TRPC1 in EMT, its expression is closely associated with EMT- and metastasis related genes in breast tumours, and is enhanced in basal B breast cancer cell lines. TRPC1 expression is also significantly prognostic for basal breast cancers, particularly those classified as lymph node positive. The defined roles of TRPC1 identified here could be therapeutically exploited for the control of oncogenic pathways in breast cancer cells. PMID- 28559304 TI - Transcription regulation mechanism of the syntaxin 1A gene via protein kinase A. AB - Syntaxin 1A (Stx1a) is primarily involved in the docking of synaptic vesicles at active zones in neurons. Its gene is a TATA-less gene, with several transcription initiation sites, which is activated by the binding of Sp1 and acetylated histone H3 (H3) in the core promoter region (CPR) through the derepression of class I histone deacetylase (HDAC). In the present study, to clarify the factor characterizing Stx1a gene expression via the protein kinase A (PKA) pathway inducing the Stx1a mRNA, we investigated whether the epigenetic process is involved in the Stx1a gene transcription induced by PKA signaling. We found that the PKA activator forskolin induced Stx1a expression in non-neuronal cells, FRSK and 3Y1, which do not endogenously express Stx1a, unlike PC12. HDAC8 inhibition by shRNA knockdown and specific inhibitors induced Stx1a expression in FRSK. The PKA inhibitor H89 suppressed HDAC8-Ser39 phosphorylation, H3 acetylation and Stx1a induction by forskolin in FRSK cells. Finally, we also found that forskolin led to the dissociation of HDAC8-CPR interaction and the association of Sp1 and Ac-H3 to CPR in FRSK. The results of the current study suggest that forskolin phosphorylates HDAC8-Ser39 via the PKA pathway and increases histone H3 acetylation in cells expressing HDAC8, resulting in the induction of the Stx1a gene. PMID- 28559305 TI - Biochemical and functional characterization of the human tissue kallikrein 9. AB - Human tissue kallikrein 9 (KLK9) is a member of the kallikrein-related family of proteases. Despite its known expression profile, much less is known about the functional roles of this protease and its implications in normal physiology and disease. We present here the first data on the biochemical characterization of KLK9, investigate parameters that affect its enzymatic activity (such as inhibitors) and provide preliminary insights into its putative substrates. We show that mature KLK9 is a glycosylated chymotrypsin-like enzyme with strong preference for tyrosine over phenylalanine at the P1 cleavage position. The enzyme activity is enhanced by Mg2+ and Ca2+, but is reversibly attenuated by Zn2+ KLK9 is inhibited in vitro by many naturally occurring or synthetic protease inhibitors. Using a combination of degradomic and substrate specificity assays, we identified candidate KLK9 substrates in two different epithelial cell lines [the non-tumorigenic human keratinocyte cells (HaCaT) and the tumorigenic tongue squamous carcinoma cells (SCC9)]. Two potential KLK9 substrates [KLK10 and midkine (MDK)] were subjected to further validation. Taken together, our data delineate some functional and biochemical properties of KLK9 for future elucidation of the role of this enzyme in health and disease. PMID- 28559306 TI - A helicase-independent activity of eIF4A in promoting mRNA recruitment to the human ribosome. AB - In the scanning model of translation initiation, the decoding site and latch of the 40S subunit must open to allow the recruitment and migration of messenger RNA (mRNA); however, the precise molecular details for how initiation factors regulate mRNA accommodation into the decoding site have not yet been elucidated. Eukaryotic initiation factor (eIF) 3j is a subunit of eIF3 that binds to the mRNA entry channel and A-site of the 40S subunit. Previous studies have shown that a reduced affinity of eIF3j for the 43S preinitiation complex (PIC) occurs on eIF4F dependent mRNA recruitment. Because eIF3j and mRNA bind anticooperatively to the 43S PIC, reduced eIF3j affinity likely reflects a state of full accommodation of mRNA into the decoding site. Here, we have used a fluorescence-based anisotropy assay to quantitatively determine how initiation components coordinate their activities to reduce the affinity of eIF3j during the recruitment of mRNA to the 43S PIC. Unexpectedly, we show that a full reduction in eIF3j affinity for the 43S PIC requires an ATP-dependent, but unwinding-independent, activity of eIF4A. This result suggests that in addition to its helicase activity, eIF4A uses the free energy of ATP binding and hydrolysis as a regulatory switch to control the conformation of the 43S PIC during mRNA recruitment. Therefore, our results define eIF4A as a universal initiation factor in cap-dependent translation initiation that functions beyond its role in RNA unwinding. PMID- 28559308 TI - Quantum critical scaling and fluctuations in Kondo lattice materials. AB - We propose a phenomenological framework for three classes of Kondo lattice materials that incorporates the interplay between the fluctuations associated with the antiferromagnetic quantum critical point and those produced by the hybridization quantum critical point that marks the end of local moment behavior. We show that these fluctuations give rise to two distinct regions of quantum critical scaling: Hybridization fluctuations are responsible for the logarithmic scaling in the density of states of the heavy electron Kondo liquid that emerges below the coherence temperature [Formula: see text], whereas the unconventional power law scaling in the resistivity that emerges at lower temperatures below [Formula: see text] may reflect the combined effects of hybridization and antiferromagnetic quantum critical fluctuations. Our framework is supported by experimental measurements on CeCoIn5, CeRhIn5, and other heavy electron materials. PMID- 28559310 TI - Disparate foundations of scientists' policy positions on contentious biomedical research. AB - What drives scientists' position taking on matters where empirical answers are unavailable or contradictory? We examined the contentious debate on whether to limit experiments involving the creation of potentially pandemic pathogens. Hundreds of scientists, including Nobel laureates, have signed petitions on the debate, providing unique insights into how scientists take a public stand on important scientific policies. Using 19,257 papers published by participants, we reconstructed their collaboration networks and research specializations. Although we found significant peer associations overall, those opposing "gain-of-function" research are more sensitive to peers than are proponents. Conversely, specializing in fields directly related to gain-of-function research (immunology, virology) predicts public support better than specializing in fields related to potential pathogenic risks (such as public health) predicts opposition. These findings suggest that different social processes might drive support compared with opposition. Supporters are embedded in a tight-knit scholarly community that is likely both more familiar with and trusting of the relevant risk mitigation practices. Opponents, on the other hand, are embedded in a looser federation of widely varying academic specializations with cognate knowledge of disease and epidemics that seems to draw more heavily on peers. Understanding how scientists' social embeddedness shapes the policy actions they take is important for helping sides interpret each other's position accurately, avoiding echo-chamber effects, and protecting the role of scientific expertise in social policy. PMID- 28559307 TI - Cortical neurons multiplex reward-related signals along with sensory and motor information. AB - Rewards are known to influence neural activity associated with both motor preparation and execution. This influence can be exerted directly upon the primary motor (M1) and somatosensory (S1) cortical areas via the projections from reward-sensitive dopaminergic neurons of the midbrain ventral tegmental areas. However, the neurophysiological manifestation of reward-related signals in M1 and S1 are not well understood. Particularly, it is unclear how the neurons in these cortical areas multiplex their traditional functions related to the control of spatial and temporal characteristics of movements with the representation of rewards. To clarify this issue, we trained rhesus monkeys to perform a center-out task in which arm movement direction, reward timing, and magnitude were manipulated independently. Activity of several hundred cortical neurons was simultaneously recorded using chronically implanted microelectrode arrays. Many neurons (9-27%) in both M1 and S1 exhibited activity related to reward anticipation. Additionally, neurons in these areas responded to a mismatch between the reward amount given to the monkeys and the amount they expected: A lower-than-expected reward caused a transient increase in firing rate in 60-80% of the total neuronal sample, whereas a larger-than-expected reward resulted in a decreased firing rate in 20-35% of the neurons. Moreover, responses of M1 and S1 neurons to reward omission depended on the direction of movements that led to those rewards. These observations suggest that sensorimotor cortical neurons corepresent rewards and movement-related activity, presumably to enable reward based learning. PMID- 28559309 TI - miR-183/96 plays a pivotal regulatory role in mouse photoreceptor maturation and maintenance. AB - MicroRNAs (miRNAs) are known to be essential for retinal maturation and functionality; however, the role of the most abundant miRNAs, the miR-183/96/182 cluster (miR-183 cluster), in photoreceptor cells remains unclear. Here we demonstrate that ablation of two components of the miR-183 cluster, miR-183 and miR-96, significantly affects photoreceptor maturation and maintenance in mice. Morphologically, early-onset dislocated cone nuclei, shortened outer segments and thinned outer nuclear layers are observed in the miR-183/96 double-knockout (DKO) mice. Abnormal photoreceptor responses, including abolished photopic electroretinography (ERG) responses and compromised scotopic ERG responses, reflect the functional changes in the degenerated retina. We further identify Slc6a6 as the cotarget of miR-183 and miR-96. The expression level of Slc6a6 is significantly higher in the DKO mice than in the wild-type mice. In contrast, Slc6a6 is down-regulated by adeno-associated virus-mediated overexpression of either miR-183 or miR-96 in wild-type mice. Remarkably, both silencing and overexpression of Slc6a6 in the retina are detrimental to the electrophysiological activity of the photoreceptors in response to dim light stimuli. We demonstrate that miR-183/96-mediated fine-tuning of Slc6a6 expression is indispensable for photoreceptor maturation and maintenance, thereby providing insight into the epigenetic regulation of photoreceptors in mice. PMID- 28559311 TI - Characterization of the scrambling domain of the TMEM16 family. AB - The TMEM16 protein family has 10 members, each of which carries 10 transmembrane segments. TMEM16A and 16B are Ca2+-activated Cl- channels. Several other members, including TMEM16F, promote phospholipid scrambling between the inner and outer leaflets of a cell membrane in response to intracellular Ca2+ However, the mechanism by which TMEM16 proteins translocate phospholipids in plasma membranes remains elusive. Here we show that Ca2+-activated, TMEM16F-supported phospholipid scrambling proceeds at 4 degrees C. Similar to TMEM16F and 16E, seven TMEM16 family members were found to carry a domain (SCRD; scrambling domain) spanning the fourth and fifth transmembrane segments that conferred scrambling ability to TMEM16A. By introducing point mutations into TMEM16F, we found that a lysine in the fourth transmembrane segment of the SCRD as well as an arginine in the third and a glutamic acid in the sixth transmembrane segment were important for exposing phosphatidylserine from the inner to the outer leaflet. However, their role in internalizing phospholipids was limited. Our results suggest that TMEM16 provides a cleft containing hydrophilic "stepping stones" for the outward translocation of phospholipids. PMID- 28559312 TI - Synchrony affects Taylor's law in theory and data. AB - Taylor's law (TL) is a widely observed empirical pattern that relates the variances to the means of groups of nonnegative measurements via an approximate power law: variance g ~ a [Formula: see text] mean gb , where g indexes the group of measurements. When each group of measurements is distributed in space, the exponent b of this power law is conjectured to reflect aggregation in the spatial distribution. TL has had practical application in many areas since its initial demonstrations for the population density of spatially distributed species in population ecology. Another widely observed aspect of populations is spatial synchrony, which is the tendency for time series of population densities measured in different locations to be correlated through time. Recent studies showed that patterns of population synchrony are changing, possibly as a consequence of climate change. We use mathematical, numerical, and empirical approaches to show that synchrony affects the validity and parameters of TL. Greater synchrony typically decreases the exponent b of TL. Synchrony influenced TL in essentially all of our analytic, numerical, randomization-based, and empirical examples. Given the near ubiquity of synchrony in nature, it seems likely that synchrony influences the exponent of TL widely in ecologically and economically important systems. PMID- 28559314 TI - Deciphering the landscape of host barriers to Listeria monocytogenes infection. AB - Listeria monocytogenes is a common food-borne pathogen that can disseminate from the intestine and infect multiple organs. Here, we used sequence tag-based analysis of microbial populations (STAMP) to investigate Lmonocytogenes population dynamics during infection. We created a genetically barcoded library of murinized Lmonocytogenes and then used deep sequencing to track the pathogen's dissemination routes and quantify its founding population (Nb) sizes in different organs. We found that the pathogen disseminates from the gastrointestinal tract to distal sites through multiple independent routes and that Nb sizes vary greatly among tissues, indicative of diverse host barriers to infection. Unexpectedly, comparative analyses of sequence tags revealed that fecally excreted organisms are largely derived from the very small number of L. monocytogenes cells that colonize the gallbladder. Immune depletion studies suggest that distinct innate immune cells restrict the pathogen's capacity to establish replicative niches in the spleen and liver. Finally, studies in germ free mice suggest that the microbiota plays a critical role in the development of the splenic, but not the hepatic, barriers that prevent L. monocytogenes from seeding these organs. Collectively, these observations illustrate the potency of the STAMP approach to decipher the impact of host factors on population dynamics of pathogens during infection. PMID- 28559315 TI - Historical climate controls soil respiration responses to current soil moisture. AB - Ecosystem carbon losses from soil microbial respiration are a key component of global carbon cycling, resulting in the transfer of 40-70 Pg carbon from soil to the atmosphere each year. Because these microbial processes can feed back to climate change, understanding respiration responses to environmental factors is necessary for improved projections. We focus on respiration responses to soil moisture, which remain unresolved in ecosystem models. A common assumption of large-scale models is that soil microorganisms respond to moisture in the same way, regardless of location or climate. Here, we show that soil respiration is constrained by historical climate. We find that historical rainfall controls both the moisture dependence and sensitivity of respiration. Moisture sensitivity, defined as the slope of respiration vs. moisture, increased fourfold across a 480 mm rainfall gradient, resulting in twofold greater carbon loss on average in historically wetter soils compared with historically drier soils. The respiration moisture relationship was resistant to environmental change in field common gardens and field rainfall manipulations, supporting a persistent effect of historical climate on microbial respiration. Based on these results, predicting future carbon cycling with climate change will require an understanding of the spatial variation and temporal lags in microbial responses created by historical rainfall. PMID- 28559313 TI - Arabidopsis JASMONATE-INDUCED OXYGENASES down-regulate plant immunity by hydroxylation and inactivation of the hormone jasmonic acid. AB - The phytohormone jasmonic acid (JA) is vital in plant defense and development. Although biosynthesis of JA and activation of JA-responsive gene expression by the bioactive form JA-isoleucine have been well-studied, knowledge on JA metabolism is incomplete. In particular, the enzyme that hydroxylates JA to 12-OH JA, an inactive form of JA that accumulates after wounding and pathogen attack, is unknown. Here, we report the identification of four paralogous 2 oxoglutarate/Fe(II)-dependent oxygenases in Arabidopsis thaliana as JA hydroxylases and show that they down-regulate JA-dependent responses. Because they are induced by JA we named them JASMONATE-INDUCED OXYGENASES (JOXs). Concurrent mutation of the four genes in a quadruple Arabidopsis mutant resulted in increased defense gene expression and increased resistance to the necrotrophic fungus Botrytis cinerea and the caterpillar Mamestra brassicae In addition, root and shoot growth of the plants was inhibited. Metabolite analysis of leaves showed that loss of function of the four JOX enzymes resulted in overaccumulation of JA and in reduced turnover of JA into 12-OH-JA. Transformation of the quadruple mutant with each JOX gene strongly reduced JA levels, demonstrating that all four JOXs inactivate JA in plants. The in vitro catalysis of 12-OH-JA from JA by recombinant enzyme could be confirmed for three JOXs. The identification of the enzymes responsible for hydroxylation of JA reveals a missing step in JA metabolism, which is important for the inactivation of the hormone and subsequent down-regulation of JA-dependent defenses. PMID- 28559316 TI - Electron localization in rod-shaped triicosahedral gold nanocluster. AB - Atomically precise gold nanocluster based on linear assembly of repeating icosahedrons (clusters of clusters) is a unique type of linear nanostructure, which exhibits strong near-infrared absorption as their free electrons are confined in a one-dimensional quantum box. Little is known about the carrier dynamics in these nanoclusters, which limit their energy-related applications. Here, we reported the observation of exciton localization in triicosahedral Au37 nanoclusters (0.5 nm in diameter and 1.6 nm in length) by measuring femtosecond and nanosecond carrier dynamics. Upon photoexcitation to S1 electronic state, electrons in Au37 undergo ~100-ps localization from the two vertexes of three icosahedrons to one vertex, forming a long-lived S1* state. Such phenomenon is not observed in Au25 (dimer) and Au13 (monomer) consisting of two and one icosahedrons, respectively. We have further observed temperature dependence on the localization process, which proves it is thermally driven. Two excited-state vibration modes with frequencies of 20 and 70 cm-1 observed in the kinetic traces are assigned to the axial and radial breathing modes, respectively. The electron localization is ascribed to the structural distortion of Au37 in the excited state induced by the strong coherent vibrations. The observed electron localization phenomenon provides unique physical insight into one-dimensional gold nanoclusters and other nanostructures, which will advance their applications in solar-energy storage and conversion. PMID- 28559317 TI - Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion. AB - Preexisting neutralizing antibodies (NAbs) against adeno-associated viruses (AAVs) pose a major, unresolved challenge that restricts patient enrollment in gene therapy clinical trials using recombinant AAV vectors. Structural studies suggest that despite a high degree of sequence variability, antibody recognition sites or antigenic hotspots on AAVs and other related parvoviruses might be evolutionarily conserved. To test this hypothesis, we developed a structure guided evolution approach that does not require selective pressure exerted by NAbs. This strategy yielded highly divergent antigenic footprints that do not exist in natural AAV isolates. Specifically, synthetic variants obtained by evolving murine antigenic epitopes on an AAV serotype 1 capsid template can evade NAbs without compromising titer, transduction efficiency, or tissue tropism. One lead AAV variant generated by combining multiple evolved antigenic sites effectively evades polyclonal anti-AAV1 neutralizing sera from immunized mice and rhesus macaques. Furthermore, this variant displays robust immune evasion in nonhuman primate and human serum samples at dilution factors as high as 1:5, currently mandated by several clinical trials. Our results provide evidence that antibody recognition of AAV capsids is conserved across species. This approach can be applied to any AAV strain to evade NAbs in prospective patients for human gene therapy. PMID- 28559318 TI - A mechanism for lipid binding to apoE and the role of intrinsically disordered regions coupled to domain-domain interactions. AB - Relative to the apolipoprotein E (apoE) E3 allele of the APOE gene, apoE4 strongly increases the risk for the development of late-onset Alzheimer's disease. However, apoE4 differs from apoE3 by only a single amino acid at position 112, which is arginine in apoE4 and cysteine in apoE3. It remains unclear why apoE3 and apoE4 are functionally different. Described here is a proposal for understanding the functional differences between these two isoforms with respect to lipid binding. A mechanism is proposed that is based on the full length monomeric structure of the protein, on hydrogen-deuterium exchange mass spectrometry data, and on the role of intrinsically disordered regions to control protein motions. It is proposed that lipid binds between the N-terminal and C terminal domains and that separation of the two domains, along with the presence of intrinsically disordered regions, controls this process. The mechanism explains why apoE3 differs from apoE4 with respect to different lipid-binding specificities, why lipid increases the binding of apoE to its receptor, and why specific residues are conserved. PMID- 28559321 TI - QnAs with Alta Charo and George Church. PMID- 28559320 TI - Visual cortex entrains to sign language. AB - Despite immense variability across languages, people can learn to understand any human language, spoken or signed. What neural mechanisms allow people to comprehend language across sensory modalities? When people listen to speech, electrophysiological oscillations in auditory cortex entrain to slow ([Formula: see text]8 Hz) fluctuations in the acoustic envelope. Entrainment to the speech envelope may reflect mechanisms specialized for auditory perception. Alternatively, flexible entrainment may be a general-purpose cortical mechanism that optimizes sensitivity to rhythmic information regardless of modality. Here, we test these proposals by examining cortical coherence to visual information in sign language. First, we develop a metric to quantify visual change over time. We find quasiperiodic fluctuations in sign language, characterized by lower frequencies than fluctuations in speech. Next, we test for entrainment of neural oscillations to visual change in sign language, using electroencephalography (EEG) in fluent speakers of American Sign Language (ASL) as they watch videos in ASL. We find significant cortical entrainment to visual oscillations in sign language <5 Hz, peaking at [Formula: see text]1 Hz. Coherence to sign is strongest over occipital and parietal cortex, in contrast to speech, where coherence is strongest over the auditory cortex. Nonsigners also show coherence to sign language, but entrainment at frontal sites is reduced relative to fluent signers. These results demonstrate that flexible cortical entrainment to language does not depend on neural processes that are specific to auditory speech perception. Low-frequency oscillatory entrainment may reflect a general cortical mechanism that maximizes sensitivity to informational peaks in time-varying signals. PMID- 28559319 TI - Myosin Va's adaptor protein melanophilin enforces track selection on the microtubule and actin networks in vitro. AB - Pigment organelles, or melanosomes, are transported by kinesin, dynein, and myosin motors. As such, melanosome transport is an excellent model system to study the functional relationship between the microtubule- and actin-based transport systems. In mammalian melanocytes, it is well known that the Rab27a/melanophilin/myosin Va complex mediates actin-based transport in vivo. However, pathways that regulate the overall directionality of melanosomes on the actin/microtubule networks have not yet been delineated. Here, we investigated the role of PKA-dependent phosphorylation on the activity of the actin-based Rab27a/melanophilin/myosin Va transport complex in vitro. We found that melanophilin, specifically its C-terminal actin-binding domain (ABD), is a target of PKA. Notably, in vitro phosphorylation of the ABD closely recapitulated the previously described in vivo phosphorylation pattern. Unexpectedly, we found that phosphorylation of the ABD affected neither the interaction of the complex with actin nor its movement along actin tracks. Surprisingly, the phosphorylation state of melanophilin was instead important for reversible association with microtubules in vitro. Dephosphorylated melanophilin preferred binding to microtubules even in the presence of actin, whereas phosphorylated melanophilin associated with actin. Indeed, when actin and microtubules were present simultaneously, melanophilin's phosphorylation state enforced track selection of the Rab27a/melanophilin/myosin Va transport complex. Collectively, our results unmasked the regulatory dominance of the melanophilin adaptor protein over its associated motor and offer an unexpected mechanism by which filaments of the cytoskeletal network compete for the moving organelles to accomplish directional transport on the cytoskeleton in vivo. PMID- 28559322 TI - Estimating the parameters of background selection and selective sweeps in Drosophila in the presence of gene conversion. AB - We used whole-genome resequencing data from a population of Drosophila melanogaster to investigate the causes of the negative correlation between the within-population synonymous nucleotide site diversity (piS ) of a gene and its degree of divergence from related species at nonsynonymous nucleotide sites (KA ). By using the estimated distributions of mutational effects on fitness at nonsynonymous and UTR sites, we predicted the effects of background selection at sites within a gene on piS and found that these could account for only part of the observed correlation between piS and KA We developed a model of the effects of selective sweeps that included gene conversion as well as crossing over. We used this model to estimate the average strength of selection on positively selected mutations in coding sequences and in UTRs, as well as the proportions of new mutations that are selectively advantageous. Genes with high levels of selective constraint on nonsynonymous sites were found to have lower strengths of positive selection and lower proportions of advantageous mutations than genes with low levels of constraint. Overall, background selection and selective sweeps within a typical gene reduce its synonymous diversity to ~75% of its value in the absence of selection, with larger reductions for genes with high KA Gene conversion has a major effect on the estimates of the parameters of positive selection, such that the estimated strength of selection on favorable mutations is greatly reduced if it is ignored. PMID- 28559324 TI - Bacteria exploit a polymorphic instability of the flagellar filament to escape from traps. AB - Many bacterial species swim by rotating single polar helical flagella. Depending on the direction of rotation, they can swim forward or backward and change directions to move along chemical gradients but also to navigate their obstructed natural environment in soils, sediments, or mucus. When they get stuck, they naturally try to back out, but they can also resort to a radically different flagellar mode, which we discovered here. Using high-speed microscopy, we monitored the swimming behavior of the monopolarly flagellated species Shewanella putrefaciens with fluorescently labeled flagellar filaments at an agarose-glass interface. We show that, when a cell gets stuck, the polar flagellar filament executes a polymorphic change into a spiral-like form that wraps around the cell body in a spiral-like fashion and enables the cell to escape by a screw-like backward motion. Microscopy and modeling suggest that this propagation mode is triggered by an instability of the flagellum under reversal of the rotation and the applied torque. The switch is reversible and bacteria that have escaped the trap can return to their normal swimming mode by another reversal of motor direction. The screw-type flagellar arrangement enables a unique mode of propagation and, given the large number of polarly flagellated bacteria, we expect it to be a common and widespread escape or motility mode in complex and structured environments. PMID- 28559323 TI - Contacts between the endoplasmic reticulum and other membranes in neurons. AB - Close appositions between the membrane of the endoplasmic reticulum (ER) and other intracellular membranes have important functions in cell physiology. These include lipid homeostasis, regulation of Ca2+ dynamics, and control of organelle biogenesis and dynamics. Although these membrane contacts have previously been observed in neurons, their distribution and abundance have not been systematically analyzed. Here, we have used focused ion beam-scanning electron microscopy to generate 3D reconstructions of intracellular organelles and their membrane appositions involving the ER (distance <=30 nm) in different neuronal compartments. ER-plasma membrane (PM) contacts were particularly abundant in cell bodies, with large, flat ER cisternae apposed to the PM, sometimes with a notably narrow lumen (thin ER). Smaller ER-PM contacts occurred throughout dendrites, axons, and in axon terminals. ER contacts with mitochondria were abundant in all compartments, with the ER often forming a network that embraced mitochondria. Small focal contacts were also observed with tubulovesicular structures, likely to be endosomes, and with sparse multivesicular bodies and lysosomes found in our reconstructions. Our study provides an anatomical reference for interpreting information about interorganelle communication in neurons emerging from functional and biochemical studies. PMID- 28559326 TI - Evidence for self-organization in determining spatial patterns of stream nutrients, despite primacy of the geomorphic template. AB - Nutrients in freshwater ecosystems are highly variable in space and time. Nevertheless, the variety of processes contributing to nutrient patchiness, and the wide range of spatial and temporal scales at which these processes operate, obfuscate how this spatial heterogeneity is generated. Here, we describe the spatial structure of stream nutrient concentration, quantify the relative importance of the physical template and biological processes, and detect and evaluate the role of self-organization in driving such patterns. We examined nutrient spatial patterns in Sycamore Creek, an intermittent desert stream in Arizona that experienced an ecosystem regime shift [from a gravel/algae-dominated to a vascular plant-dominated (hereafter, "wetland") system] in 2000 when cattle grazing ceased. We conducted high-resolution nutrient surveys in surface water along a 10-km stream reach over four visits spanning 18 y (1995-2013) that represent different successional stages and prewetland stage vs. postwetland state. As expected, groundwater upwelling had a major influence on nutrient spatial patterns. However, self-organization realized by the mechanism of spatial feedbacks also was significant and intensified over ecosystem succession, as a resource (nitrogen) became increasingly limiting. By late succession, the effects of internal spatial feedbacks and groundwater upwelling were approximately equal in magnitude. Wetland establishment influenced nutrient spatial patterns only indirectly, by modifying the extent of surface water/groundwater exchange. This study illustrates that multiple mechanisms interact in a dynamic way to create spatial heterogeneity in riverine ecosystems, and provides a means to detect spatial self-organization against physical template heterogeneity as a dominant driver of spatial patterns. PMID- 28559325 TI - Input timing for spatial processing is precisely tuned via constant synaptic delays and myelination patterns in the auditory brainstem. AB - Precise timing of synaptic inputs is a fundamental principle of neural circuit processing. The temporal precision of postsynaptic input integration is known to vary with the computational requirements of a circuit, yet how the timing of action potentials is tuned presynaptically to match these processing demands is not well understood. In particular, action potential timing is shaped by the axonal conduction velocity and the duration of synaptic transmission delays within a pathway. However, it is not known to what extent these factors are adapted to the functional constraints of the respective circuit. Here, we report the finding of activity-invariant synaptic transmission delays as a functional adaptation for input timing adjustment in a brainstem sound localization circuit. We compared axonal and synaptic properties of the same pathway between two species with dissimilar timing requirements (gerbil and mouse): In gerbils (like humans), neuronal processing of sound source location requires exceptionally high input precision in the range of microseconds, but not in mice. Activity-invariant synaptic transmission and conduction delays were present exclusively in fast conducting axons of gerbils that also exhibited unusual structural adaptations in axon myelination for increased conduction velocity. In contrast, synaptic transmission delays in mice varied depending on activity levels, and axonal myelination and conduction velocity exhibited no adaptations. Thus, the specializations in gerbils and their absence in mice suggest an optimization of axonal and synaptic properties to the specific demands of sound localization. These findings significantly advance our understanding of structural and functional adaptations for circuit processing. PMID- 28559327 TI - Deformable and conformal silk hydrogel inverse opal. AB - Photonic crystals (PhCs) efficiently manipulate photons at the nanoscale. Applying these crystals to biological tissue that has been subjected to large deformation and humid environments can lead to fascinating bioapplications such as in vivo biosensors and artificial ocular prostheses. These applications require that these PhCs have mechanical durability, deformability, and biocompatibility. Herein, we introduce a deformable and conformal silk hydrogel inverse opal (SHIO); the photonic lattice of this 3D PhC can be deformed by mechanical strain. This SHIO is prepared by the UV cross-linking of a liquid stilbene/silk solution, to give a transparent and elastic hydrogel. The pseudophotonic band gap (pseudo-PBG) of this material can be stably tuned by deformation of the photonic lattice (stretching, bending, and compressing). Proof of-concept experiments demonstrate that the SHIO can be applied as an ocular prosthesis for better vision, such as that provided by the tapeta lucida of nocturnal or deep-sea animals. PMID- 28559328 TI - Photoactivation mechanism of a carotenoid-based photoreceptor. AB - Photoprotection is essential for efficient photosynthesis. Cyanobacteria have evolved a unique photoprotective mechanism mediated by a water-soluble carotenoid based photoreceptor known as orange carotenoid protein (OCP). OCP undergoes large conformational changes in response to intense blue light, and the photoactivated OCP facilitates dissipation of excess energy via direct interaction with allophycocyanins at the phycobilisome core. However, the structural events leading up to the OCP photoactivation remain elusive at the molecular level. Here we present direct observations of light-induced structural changes in OCP captured by dynamic crystallography. Difference electron densities between the dark and illuminated states reveal widespread and concerted atomic motions that lead to altered protein-pigment interactions, displacement of secondary structures, and domain separation. Based on these crystallographic observations together with site-directed mutagenesis, we propose a molecular mechanism for OCP light perception, in which the photochemical property of a conjugated carbonyl group is exploited. We hypothesize that the OCP photoactivation starts with keto enol tautomerization of the essential 4-keto group in the carotenoid, which disrupts the strong hydrogen bonds between the bent chromophore and the protein moiety. Subsequent structural changes trapped in the crystal lattice offer a high resolution glimpse of the initial molecular events as OCP begins to transition from the orange-absorbing state to the active red-absorbing state. PMID- 28559330 TI - Positive association between population genetic differentiation and speciation rates in New World birds. AB - An implicit assumption of speciation biology is that population differentiation is an important stage of evolutionary diversification, but its significance as a rate-limiting control on phylogenetic speciation dynamics remains largely untested. If population differentiation within a species is related to its speciation rate over evolutionary time, the causes of differentiation could also be driving dynamics of organismal diversity across time and space. Alternatively, geographic variants might be short-lived entities with rates of formation that are unlinked to speciation rates, in which case the causes of differentiation would have only ephemeral impacts. By pairing population genetics datasets from 173 New World bird species (>17,000 individuals) with phylogenetic estimates of speciation rate, we show that the population differentiation rates within species are positively correlated with their speciation rates over long timescales. Although population differentiation rate explains relatively little of the variation in speciation rate among lineages, the positive relationship between differentiation rate and speciation rate is robust to species-delimitation schemes and to alternative measures of both rates. Population differentiation occurs at least three times faster than speciation, which suggests that most populations are ephemeral. Speciation and population differentiation rates are more tightly linked in tropical species than in temperate species, consistent with a history of more stable diversification dynamics through time in the Tropics. Overall, our results suggest that the processes responsible for population differentiation are tied to those that underlie broad-scale patterns of diversity. PMID- 28559329 TI - Antimalarials inhibit hematin crystallization by unique drug-surface site interactions. AB - In malaria pathophysiology, divergent hypotheses on the inhibition of hematin crystallization posit that drugs act either by the sequestration of soluble hematin or their interaction with crystal surfaces. We use physiologically relevant, time-resolved in situ surface observations and show that quinoline antimalarials inhibit beta-hematin crystal surfaces by three distinct modes of action: step pinning, kink blocking, and step bunch induction. Detailed experimental evidence of kink blocking validates classical theory and demonstrates that this mechanism is not the most effective inhibition pathway. Quinolines also form various complexes with soluble hematin, but complexation is insufficient to suppress heme detoxification and is a poor indicator of drug specificity. Collectively, our findings reveal the significance of drug-crystal interactions and open avenues for rationally designing antimalarial compounds. PMID- 28559331 TI - The POTRA domains of Toc75 exhibit chaperone-like function to facilitate import into chloroplasts. AB - Protein trafficking across membranes is an essential function in cells; however, the exact mechanism for how this occurs is not well understood. In the endosymbionts, mitochondria and chloroplasts, the vast majority of proteins are synthesized in the cytoplasm as preproteins and then imported into the organelles via specialized machineries. In chloroplasts, protein import is accomplished by the TOC (translocon on the outer chloroplast membrane) and TIC (translocon on the inner chloroplast membrane) machineries in the outer and inner envelope membranes, respectively. TOC mediates initial recognition of preproteins at the outer membrane and includes a core membrane channel, Toc75, and two receptor proteins, Toc33/34 and Toc159, each containing GTPase domains that control preprotein binding and translocation. Toc75 is predicted to have a beta-barrel fold consisting of an N-terminal intermembrane space (IMS) domain and a C terminal 16-stranded beta-barrel domain. Here we report the crystal structure of the N-terminal IMS domain of Toc75 from Arabidopsis thaliana, revealing three tandem polypeptide transport-associated (POTRA) domains, with POTRA2 containing an additional elongated helix not observed previously in other POTRA domains. Functional studies show an interaction with the preprotein, preSSU, which is mediated through POTRA2-3. POTRA2-3 also was found to have chaperone-like activity in an insulin aggregation assay, which we propose facilitates preprotein import. Our data suggest a model in which the POTRA domains serve as a binding site for the preprotein as it emerges from the Toc75 channel and provide a chaperone-like activity to prevent misfolding or aggregation as the preprotein traverses the intermembrane space. PMID- 28559334 TI - Response time in economic games reflects different types of decision conflict for prosocial and proself individuals. AB - Behavioral and neuroscientific studies explore two pathways through which internalized social norms promote prosocial behavior. One pathway involves internal control of impulsive selfishness, and the other involves emotion-based prosocial preferences that are translated into behavior when they evade cognitive control for pursuing self-interest. We measured 443 participants' overall prosocial behavior in four economic games. Participants' predispositions [social value orientation (SVO)] were more strongly reflected in their overall game behavior when they made decisions quickly than when they spent a longer time. Prosocially (or selfishly) predisposed participants behaved less prosocially (or less selfishly) when they spent more time in decision making, such that their SVO prosociality yielded limited effects in actual behavior in their slow decisions. The increase (or decrease) in slower decision makers was prominent among consistent prosocials (or proselfs) whose strong preference for prosocial (or proself) goals would make it less likely to experience conflict between prosocial and proself goals. The strong effect of RT on behavior in consistent prosocials (or proselfs) suggests that conflict between prosocial and selfish goals alone is not responsible for slow decisions. Specifically, we found that contemplation of the risk of being exploited by others (social risk aversion) was partly responsible for making consistent prosocials (but not consistent proselfs) spend longer time in decision making and behave less prosocially. Conflict between means rather than between goals (immediate versus strategic pursuit of self interest) was suggested to be responsible for the time-related increase in consistent proselfs' prosocial behavior. The findings of this study are generally in favor of the intuitive cooperation model of prosocial behavior. PMID- 28559333 TI - Auxin steers root cell expansion via apoplastic pH regulation in Arabidopsis thaliana. AB - Plant cells are embedded within cell walls, which provide structural integrity, but also spatially constrain cells, and must therefore be modified to allow cellular expansion. The long-standing acid growth theory postulates that auxin triggers apoplast acidification, thereby activating cell wall-loosening enzymes that enable cell expansion in shoots. Interestingly, this model remains heavily debated in roots, because of both the complex role of auxin in plant development as well as technical limitations in investigating apoplastic pH at cellular resolution. Here, we introduce 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) as a suitable fluorescent pH indicator for assessing apoplastic pH, and thus acid growth, at a cellular resolution in Arabidopsis thaliana roots. Using HPTS, we demonstrate that cell wall acidification triggers cellular expansion, which is correlated with a preceding increase of auxin signaling. Reduction in auxin levels, perception, or signaling abolishes both the extracellular acidification and cellular expansion. These findings jointly suggest that endogenous auxin controls apoplastic acidification and the onset of cellular elongation in roots. In contrast, an endogenous or exogenous increase in auxin levels induces a transient alkalinization of the extracellular matrix, reducing cellular elongation. The receptor-like kinase FERONIA is required for this physiological process, which affects cellular root expansion during the gravitropic response. These findings pinpoint a complex, presumably concentration dependent role for auxin in apoplastic pH regulation, steering the rate of root cell expansion and gravitropic response. PMID- 28559332 TI - Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations. AB - Mycobacterium tuberculosis (Mtb) encounters stresses during the pathogenesis and treatment of tuberculosis (TB) that can suppress replication of the bacteria and render them phenotypically tolerant to most available drugs. Where studied, the majority of Mtb in the sputum of most untreated subjects with active TB have been found to be nonreplicating by the criterion that they do not grow as colony forming units (cfus) when plated on agar. However, these cells are viable because they grow when diluted in liquid media. A method for generating such "differentially detectable" (DD) Mtb in vitro would aid studies of the biology and drug susceptibility of this population, but lack of independent confirmation of reported methods has contributed to skepticism about their existence. Here, we identified confounding artifacts that, when avoided, allowed development of a reliable method of producing cultures of >=90% DD Mtb in starved cells. We then characterized several drugs according to whether they contribute to the generation of DD Mtb or kill them. Of the agents tested, rifamycins led to DD Mtb generation, an effect lacking in a rifampin-resistant strain with a mutation in rpoB, which encodes the canonical rifampin target, the beta subunit of RNA polymerase. In contrast, thioridazine did not generate DD Mtb from starved cells but killed those generated by rifampin. PMID- 28559335 TI - Spontaneous formation of aligned DNA nanowires by capillarity-induced skin folding. AB - Although DNA nanowires have proven useful as a template for fabricating functional nanomaterials and a platform for genetic analysis, their widespread use is still hindered because of limited control over the size, geometry, and alignment of the nanowires. Here, we document the capillarity-induced folding of an initially wrinkled surface and present an approach to the spontaneous formation of aligned DNA nanowires using a template whose surface morphology dynamically changes in response to liquid. In particular, we exploit the familiar wrinkling phenomenon that results from compression of a thin skin on a soft substrate. Once a droplet of liquid solution containing DNA molecules is placed on the wrinkled surface, the liquid from the droplet enters certain wrinkled channels. The capillary forces deform wrinkles containing liquid into sharp folds, whereas the neighboring empty wrinkles are stretched out. In this way, we obtain a periodic array of folded channels that contain liquid solution with DNA molecules. Such an approach serves as a template for the fabrication of arrays of straight or wrinkled DNA nanowires, where their characteristic scales are robustly tunable with the physical properties of liquid and the mechanical and geometrical properties of the elastic system. PMID- 28559337 TI - Identification of the gene that codes for the sigma2 receptor. AB - The sigma2 receptor is an enigmatic protein that has attracted significant attention because of its involvement in diseases as diverse as cancer and neurological disorders. Unlike virtually all other receptors of medical interest, it has eluded molecular cloning since its discovery, and the gene that codes for the receptor remains unknown, precluding the use of modern biological methods to study its function. Using a chemical biology approach, we purified the sigma2 receptor from tissue, revealing its identity as TMEM97, an endoplasmic reticulum resident transmembrane protein that regulates the sterol transporter NPC1. We show that TMEM97 possesses the full suite of molecular properties that define the sigma2 receptor, and we identify Asp29 and Asp56 as essential for ligand recognition. Cloning the sigma2 receptor resolves a longstanding mystery and will enable therapeutic targeting of this potential drug target. PMID- 28559336 TI - AraC-like transcriptional activator CuxR binds c-di-GMP by a PilZ-like mechanism to regulate extracellular polysaccharide production. AB - Cyclic dimeric GMP (c-di-GMP) has emerged as a key regulatory player in the transition between planktonic and sedentary biofilm-associated bacterial lifestyles. It controls a multitude of processes including production of extracellular polysaccharides (EPSs). The PilZ domain, consisting of an N terminal "RxxxR" motif and a beta-barrel domain, represents a prototype c-di-GMP receptor. We identified a class of c-di-GMP-responsive proteins, represented by the AraC-like transcription factor CuxR in plant symbiotic alpha-proteobacteria. In Sinorhizobium meliloti, CuxR stimulates transcription of an EPS biosynthesis gene cluster at elevated c-di-GMP levels. CuxR consists of a Cupin domain, a helical hairpin, and bipartite helix-turn-helix motif. Although unrelated in sequence, the mode of c-di-GMP binding to CuxR is highly reminiscent to that of PilZ domains. c-di-GMP interacts with a conserved N-terminal RxxxR motif and the Cupin domain, thereby promoting CuxR dimerization and DNA binding. We unravel structure and mechanism of a previously unrecognized c-di-GMP-responsive transcription factor and provide insights into the molecular evolution of c-di GMP binding to proteins. PMID- 28559339 TI - Simple nuclear C*-algebras not isomorphic to their opposites. AB - We show that it is consistent with Zermelo-Fraenkel set theory with the axiom of choice (ZFC) that there is a simple nuclear nonseparable [Formula: see text] algebra, which is not isomorphic to its opposite algebra. We can furthermore guarantee that this example is an inductive limit of unital copies of the Cuntz algebra [Formula: see text] or of the canonical anticommutation relations (CAR) algebra. PMID- 28559340 TI - Microlayer source of oxygenated volatile organic compounds in the summertime marine Arctic boundary layer. AB - Summertime Arctic shipboard observations of oxygenated volatile organic compounds (OVOCs) such as organic acids, key precursors of climatically active secondary organic aerosol (SOA), are consistent with a novel source of OVOCs to the marine boundary layer via chemistry at the sea surface microlayer. Although this source has been studied in a laboratory setting, organic acid emissions from the sea surface microlayer have not previously been observed in ambient marine environments. Correlations between measurements of OVOCs, including high levels of formic acid, in the atmosphere (measured by an online high-resolution time-of flight mass spectrometer) and dissolved organic matter in the ocean point to a marine source for the measured OVOCs. That this source is photomediated is indicated by correlations between the diurnal cycles of the OVOC measurements and solar radiation. In contrast, the OVOCs do not correlate with levels of isoprene, monoterpenes, or dimethyl sulfide. Results from box model calculations are consistent with heterogeneous chemistry as the source of the measured OVOCs. As sea ice retreats and dissolved organic carbon inputs to the Arctic increase, the impact of this source on the summer Arctic atmosphere is likely to increase. Globally, this source should be assessed in other marine environments to quantify its impact on OVOC and SOA burdens in the atmosphere, and ultimately on climate. PMID- 28559338 TI - Superresolution microscopy reveals the three-dimensional organization of meiotic chromosome axes in intact Caenorhabditis elegans tissue. AB - When cells enter meiosis, their chromosomes reorganize as linear arrays of chromatin loops anchored to a central axis. Meiotic chromosome axes form a platform for the assembly of the synaptonemal complex (SC) and play central roles in other meiotic processes, including homologous pairing, recombination, and chromosome segregation. However, little is known about the 3D organization of components within the axes, which include cohesin complexes and additional meiosis-specific proteins. Here, we investigate the molecular organization of meiotic chromosome axes in Caenorhabditis elegans through STORM (stochastic optical reconstruction microscopy) and PALM (photo-activated localization microscopy) superresolution imaging of intact germ-line tissue. By tagging one axis protein (HIM-3) with a photoconvertible fluorescent protein, we established a spatial reference for other components, which were localized using antibodies against epitope tags inserted by CRISPR/Cas9 genome editing. Using 3D averaging, we determined the position of all known components within synapsed chromosome axes to high spatial precision in three dimensions. We find that meiosis-specific HORMA domain proteins span a gap between cohesin complexes and the central region of the SC, consistent with their essential roles in SC assembly. Our data further suggest that the two different meiotic cohesin complexes are distinctly arranged within the axes: Although cohesin complexes containing the kleisin REC-8 protrude above and below the plane defined by the SC, complexes containing COH-3 or -4 kleisins form a central core, which may physically separate sister chromatids. This organization may help to explain the role of the chromosome axes in promoting interhomolog repair of meiotic double-strand breaks by inhibiting intersister repair. PMID- 28559341 TI - Early 20th-century Arctic warming intensified by Pacific and Atlantic multidecadal variability. AB - With amplified warming and record sea ice loss, the Arctic is the canary of global warming. The historical Arctic warming is poorly understood, limiting our confidence in model projections. Specifically, Arctic surface air temperature increased rapidly over the early 20th century, at rates comparable to those of recent decades despite much weaker greenhouse gas forcing. Here, we show that the concurrent phase shift of Pacific and Atlantic interdecadal variability modes is the major driver for the rapid early 20th-century Arctic warming. Atmospheric model simulations successfully reproduce the early Arctic warming when the interdecadal variability of sea surface temperature (SST) is properly prescribed. The early 20th-century Arctic warming is associated with positive SST anomalies over the tropical and North Atlantic and a Pacific SST pattern reminiscent of the positive phase of the Pacific decadal oscillation. Atmospheric circulation changes are important for the early 20th-century Arctic warming. The equatorial Pacific warming deepens the Aleutian low, advecting warm air into the North American Arctic. The extratropical North Atlantic and North Pacific SST warming strengthens surface westerly winds over northern Eurasia, intensifying the warming there. Coupled ocean-atmosphere simulations support the constructive intensification of Arctic warming by a concurrent, negative-to-positive phase shift of the Pacific and Atlantic interdecadal modes. Our results aid attributing the historical Arctic warming and thereby constrain the amplified warming projected for this important region. PMID- 28559342 TI - Follistatin is critical for mouse uterine receptivity and decidualization. AB - Embryo implantation remains a significant challenge for assisted reproductive technology, with implantation failure occurring in ~50% of in vitro fertilization attempts. Understanding the molecular mechanisms underlying uterine receptivity will enable the development of new interventions and biomarkers. TGFbeta family signaling in the uterus is critical for establishing and maintaining pregnancy. Follistatin (FST) regulates TGFbeta family signaling by selectively binding TGFbeta family ligands and sequestering them. In humans, FST is up-regulated in the decidua during early pregnancy, and women with recurrent miscarriage have lower endometrial expression of FST during the luteal phase. Because global knockout of Fst is perinatal lethal in mice, we generated a conditional knockout (cKO) of Fst in the uterus using progesterone receptor-cre to study the roles of uterine Fst during pregnancy. Uterine Fst-cKO mice demonstrate severe fertility defects and deliver only 2% of the number of pups delivered by control females. In Fst-cKO mice, the uterine luminal epithelium does not respond properly to estrogen and progesterone signals and remains unreceptive to embryo attachment by continuing to proliferate and failing to differentiate. The uterine stroma of Fst cKO mice also responds poorly to artificial decidualization, with lower levels of proliferation and differentiation. In the absence of uterine FST, activin B expression and signaling are up-regulated, and bone morphogenetic protein (BMP) signals are impaired. Our findings support a model in which repression of activin signaling by FST enables uterine receptivity by preserving critical BMP signaling. PMID- 28559343 TI - Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase. AB - We explore the enzymatic mechanism of the reduction of glutathione disulfide (GSSG) by the reduced a domain of human protein disulfide isomerase (hPDI) with atomistic resolution. We use classical molecular dynamics and hybrid quantum mechanics/molecular mechanics calculations at the mPW1N/6 311+G(2d,2p):FF99SB//mPW1N/6-31G(d):FF99SB level. The reaction proceeds in two stages: (i) a thiol-disulfide exchange through nucleophilic attack of the Cys53 thiolate to the GSSG-disulfide followed by the deprotonation of Cys56-thiol by Glu47-carboxylate and (ii) a second thiol-disulfide exchange between the Cys56 thiolate and the mixed disulfide intermediate formed in the first step. The Gibbs activation energy for the first stage was 18.7 kcal.mol-1, and for the second stage, it was 7.2 kcal.mol-1, in excellent agreement with the experimental barrier (17.6 kcal.mol-1). Our results also suggest that the catalysis by protein disulfide isomerase (PDI) and thiol-disulfide exchange is mostly enthalpy-driven (entropy changes below 2 kcal.mol-1 at all stages of the reaction). Hydrogen bonds formed between the backbone of His55 and Cys56 and the Cys56-thiol result in an increase in the Gibbs energy barrier of the first thiol-disulfide exchange. The solvent plays a key role in stabilizing the leaving glutathione thiolate formed. This role is not exclusively electrostatic, because an explicit inclusion of several water molecules at the density-functional theory level is a requisite to form the mixed disulfide intermediate. In the intramolecular oxidation of PDI, a transition state is only observed if hydrogen bond donors are nearby the mixed disulfide intermediate, which emphasizes that the thermochemistry of thiol disulfide exchange in PDI is influenced by the presence of hydrogen bond donors. PMID- 28559344 TI - Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding. AB - Regulation of mRNA translation is a major control point for gene expression and is critical for life. Of central importance is the complex between cap-bound eukaryotic initiation factor 4E (eIF4E), eIF4G, and poly(A) tail-binding protein (PABP) that circularizes mRNAs, promoting translation and stability. This complex is often targeted to regulate overall translation rates, and also by mRNA specific translational repressors. However, the mechanisms of mRNA-specific translational activation by RNA-binding proteins remain poorly understood. Here, we address this deficit, focusing on a herpes simplex virus-1 protein, ICP27. We reveal a direct interaction with PABP that is sufficient to promote PABP recruitment and necessary for ICP27-mediated activation. PABP binds several translation factors but is primarily considered to activate translation initiation as part of the PABP-eIF4G-eIF4E complex that stimulates the initial cap-binding step. Importantly, we find that ICP27-PABP forms a complex with, and requires the activity of, eIF4G. Surprisingly, ICP27-PABP-eIF4G complexes act independently of the effects of PABP-eIF4G on cap binding to promote small ribosomal subunit recruitment. Moreover, we find that a cellular mRNA-specific regulator, Deleted in Azoospermia-like (Dazl), also employs the PABP-eIF4G interaction in a similar manner. We propose a mechanism whereby diverse RNA binding proteins directly recruit PABP, in a non-poly(A) tail-dependent manner, to stimulate the small subunit recruitment step. This strategy may be particularly relevant to biological conditions associated with hypoadenylated mRNAs (e.g., germ cells/neurons) and/or limiting cytoplasmic PABP (e.g., viral infection, cell stress). This mechanism adds significant insight into our knowledge of mRNA-specific translational activation and the function of the PABP eIF4G complex in translation initiation. PMID- 28559346 TI - Increased nitrous oxide emissions from Arctic peatlands after permafrost thaw. AB - Permafrost in the Arctic is thawing, exposing large carbon and nitrogen stocks for decomposition. Gaseous carbon release from Arctic soils due to permafrost thawing is known to be substantial, but growing evidence suggests that Arctic soils may also be relevant sources of nitrous oxide (N2O). Here we show that N2O emissions from subarctic peatlands increase as the permafrost thaws. In our study, the highest postthaw emissions occurred from bare peat surfaces, a typical landform in permafrost peatlands, where permafrost thaw caused a fivefold increase in emissions (0.56 +/- 0.11 vs. 2.81 +/- 0.6 mg N2O m-2 d-1). These emission rates match those from tropical forest soils, the world's largest natural terrestrial N2O source. The presence of vegetation, known to limit N2O emissions in tundra, did decrease (by ~90%) but did not prevent thaw-induced N2O release, whereas waterlogged conditions suppressed the emissions. We show that regions with high probability for N2O emissions cover one-fourth of the Arctic. Our results imply that the Arctic N2O budget will depend strongly on moisture changes, and that a gradual deepening of the active layer will create a strong noncarbon climate change feedback. PMID- 28559345 TI - Peripheral modifications of [Psi[CH2NH]Tpg4]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics. AB - Subsequent to binding pocket modifications designed to provide dual d-Ala-d-Ala/d Ala-d-Lac binding that directly overcome the molecular basis of vancomycin resistance, peripheral structural changes have been explored to improve antimicrobial potency and provide additional synergistic mechanisms of action. A C-terminal peripheral modification, introducing a quaternary ammonium salt, is reported and was found to provide a binding pocket-modified vancomycin analog with a second mechanism of action that is independent of d-Ala-d-Ala/d-Ala-d-Lac binding. This modification, which induces cell wall permeability and is complementary to the glycopeptide inhibition of cell wall synthesis, was found to provide improvements in antimicrobial potency (200-fold) against vancomycin resistant Enterococci (VRE). Furthermore, it is shown that this type of C terminal modification may be combined with a second peripheral (4 chlorobiphenyl)methyl (CBP) addition to the vancomycin disaccharide to provide even more potent antimicrobial agents [VRE minimum inhibitory concentration (MIC) = 0.01-0.005 MUg/mL] with activity that can be attributed to three independent and synergistic mechanisms of action, only one of which requires d-Ala-d-Ala/d Ala-d-Lac binding. Finally, it is shown that such peripherally and binding pocket modified vancomycin analogs display little propensity for acquired resistance by VRE and that their durability against such challenges as well as their antimicrobial potency follow now predictable trends (three > two > one mechanisms of action). Such antibiotics are expected to display durable antimicrobial activity not prone to rapidly acquired clinical resistance. PMID- 28559347 TI - Three classes of oxygen-dependent cyclase involved in chlorophyll and bacteriochlorophyll biosynthesis. AB - The biosynthesis of (bacterio)chlorophyll pigments is among the most productive biological pathways on Earth. Photosynthesis relies on these modified tetrapyrroles for the capture of solar radiation and its conversion to chemical energy. (Bacterio)chlorophylls have an isocyclic fifth ring, the formation of which has remained enigmatic for more than 60 y. This reaction is catalyzed by two unrelated cyclase enzymes using different chemistries. The majority of anoxygenic phototrophic bacteria use BchE, an O2-sensitive [4Fe-4S] cluster protein, whereas plants, cyanobacteria, and some phototrophic bacteria possess an O2-dependent enzyme, the major catalytic component of which is a diiron protein, AcsF. Plant and cyanobacterial mutants in ycf54 display impaired function of the O2-dependent enzyme, accumulating the reaction substrate. Swapping cyclases between cyanobacteria and purple phototrophic bacteria reveals three classes of the O2-dependent enzyme. AcsF from the purple betaproteobacterium Rubrivivax (Rvi.) gelatinosus rescues the loss not only of its cyanobacterial ortholog, cycI, in Synechocystis sp. PCC 6803, but also of ycf54; conversely, coexpression of cyanobacterial cycI and ycf54 is required to complement the loss of acsF in Rvi. gelatinosus These results indicate that Ycf54 is a cyclase subunit in oxygenic phototrophs, and that different classes of the enzyme exist based on their requirement for an additional subunit. AcsF is the cyclase in Rvi. gelatinosus, whereas alphaproteobacterial cyclases require a newly discovered protein that we term BciE, encoded by a gene conserved in these organisms. These data delineate three classes of O2-dependent cyclase in chlorophototrophic organisms from higher plants to bacteria, and their evolution is discussed herein. PMID- 28559348 TI - AP1G mediates vacuolar acidification during synergid-controlled pollen tube reception. AB - Double fertilization in angiosperms requires the delivery of immotile sperm through pollen tubes, which enter embryo sacs to initiate synergid degeneration and to discharge. This fascinating process, called pollen tube reception, involves extensive communications between pollen tubes and synergids, within which few intracellular regulators involved have been revealed. Here, we report that vacuolar acidification in synergids mediated by AP1G and V-ATPases might be critical for pollen tube reception. Functional loss of AP1G or VHA-A, encoding the gamma subunit of adaptor protein 1 or the shared component of two endomembrane V-ATPases, respectively, impaired synergid-controlled pollen tube reception and caused partial female sterility. AP1G works in parallel to the plasma membrane-associated receptor FERONIA in synergids, suggesting that synergid-mediated pollen tube reception requires proper sorting of vacuolar cargos by AP1G. Although AP1G did not mediate the targeting of V-ATPases, AP1G loss of function or the expression of AP1G-RNAi compromised vacuolar acidification mediated by V-ATPases, implying their genetic interaction. We propose that vacuolar acidification might represent a distinct cell-death mechanism specifically adopted by the plant phylum, which is critical for synergid degeneration during pollen tube reception. PMID- 28559349 TI - Dating rice remains through phytolith carbon-14 study reveals domestication at the beginning of the Holocene. AB - Phytolith remains of rice (Oryza sativa L.) recovered from the Shangshan site in the Lower Yangtze of China have previously been recognized as the earliest examples of rice cultivation. However, because of the poor preservation of macroplant fossils, many radiocarbon dates were derived from undifferentiated organic materials in pottery sherds. These materials remain a source of debate because of potential contamination by old carbon. Direct dating of the rice remains might serve to clarify their age. Here, we first validate the reliability of phytolith dating in the study region through a comparison with dates obtained from other material from the same layer or context. Our phytolith data indicate that rice remains retrieved from early stages of the Shangshan and Hehuashan sites have ages of approximately 9,400 and 9,000 calibrated years before the present, respectively. The morphology of rice bulliform phytoliths indicates they are closer to modern domesticated species than to wild species, suggesting that rice domestication may have begun at Shangshan during the beginning of the Holocene. PMID- 28559350 TI - Structural basis for ligand binding to an enzyme by a conformational selection pathway. AB - Proteins can bind target molecules through either induced fit or conformational selection pathways. In the conformational selection model, a protein samples a scarcely populated high-energy state that resembles a target-bound conformation. In enzymatic catalysis, such high-energy states have been identified as crucial entities for activity and the dynamic interconversion between ground states and high-energy states can constitute the rate-limiting step for catalytic turnover. The transient nature of these states has precluded direct observation of their properties. Here, we present a molecular description of a high-energy enzyme state in a conformational selection pathway by an experimental strategy centered on NMR spectroscopy, protein engineering, and X-ray crystallography. Through the introduction of a disulfide bond, we succeeded in arresting the enzyme adenylate kinase in a closed high-energy conformation that is on-pathway for catalysis. A 1.9-A X-ray structure of the arrested enzyme in complex with a transition state analog shows that catalytic sidechains are properly aligned for catalysis. We discovered that the structural sampling of the substrate free enzyme corresponds to the complete amplitude that is associated with formation of the closed and catalytically active state. In addition, we found that the trapped high-energy state displayed improved ligand binding affinity, compared with the wild-type enzyme, demonstrating that substrate binding to the high-energy state is not occluded by steric hindrance. Finally, we show that quenching of fast time scale motions observed upon ligand binding to adenylate kinase is dominated by enzyme substrate interactions and not by intramolecular interactions resulting from the conformational change. PMID- 28559352 TI - Tropical cyclone activity enhanced by Sahara greening and reduced dust emissions during the African Humid Period. AB - Tropical cyclones (TCs) can have devastating socioeconomic impacts. Understanding the nature and causes of their variability is of paramount importance for society. However, historical records of TCs are too short to fully characterize such changes and paleo-sediment archives of Holocene TC activity are temporally and geographically sparse. Thus, it is of interest to apply physical modeling to understanding TC variability under different climate conditions. Here we investigate global TC activity during a warm climate state (mid-Holocene, 6,000 yBP) characterized by increased boreal summer insolation, a vegetated Sahara, and reduced dust emissions. We analyze a set of sensitivity experiments in which not only solar insolation changes are varied but also vegetation and dust concentrations. Our results show that the greening of the Sahara and reduced dust loadings lead to more favorable conditions for tropical cyclone development compared with the orbital forcing alone. In particular, the strengthening of the West African Monsoon induced by the Sahara greening triggers a change in atmospheric circulation that affects the entire tropics. Furthermore, whereas previous studies suggest lower TC activity despite stronger summer insolation and warmer sea surface temperature in the Northern Hemisphere, accounting for the Sahara greening and reduced dust concentrations leads instead to an increase of TC activity in both hemispheres, particularly over the Caribbean basin and East Coast of North America. Our study highlights the importance of regional changes in land cover and dust concentrations in affecting the potential intensity and genesis of past TCs and suggests that both factors may have appreciable influence on TC activity in a future warmer climate. PMID- 28559351 TI - Positive impacts of early auditory training on cortical processing at an older age. AB - Progressive negative behavioral changes in normal aging are paralleled by a complex series of physical and functional declines expressed in the cerebral cortex. In studies conducted in the auditory domain, these degrading physical and functional cortical changes have been shown to be broadly reversed by intensive progressive training that improves the spectral and temporal resolution of acoustic inputs and suppresses behavioral distractors. Here we found older rats that were intensively trained on an attentionally demanding modulation-rate recognition task in young adulthood substantially retained training-driven improvements in temporal rate discrimination abilities over a subsequent 18-mo epoch-that is, forward into their older age. In parallel, this young-adult auditory training enduringly enhanced temporal and spectral information processing in their primary auditory cortices (A1). Substantially greater numbers of parvalbumin- and somatostatin-labeled inhibitory neurons (closer to the numbers recorded in young vigorous adults) were recorded in the A1 and hippocampus in old trained versus untrained age-matched rats. These results show that a simple form of training in young adulthood in this rat model enduringly delays the otherwise expected deterioration of the physical status and functional operations of the auditory nervous system, with evident training impacts generalized to the hippocampus. PMID- 28559353 TI - The impact of Last Glacial climate variability in west-European loess revealed by radiocarbon dating of fossil earthworm granules. AB - The characterization of Last Glacial millennial-timescale warming phases, known as interstadials or Dansgaard-Oeschger events, requires precise chronologies for the study of paleoclimate records. On the European continent, such chronologies are only available for several Last Glacial pollen and rare speleothem archives principally located in the Mediterranean domain. Farther north, in continental lowlands, numerous high-resolution records of loess and paleosols sequences show a consistent environmental response to stadial-interstadial cycles. However, the limited precision and accuracy of luminescence dating methods commonly used in loess deposits preclude exact correlations of paleosol horizons with Greenland interstadials. To overcome this problem, a radiocarbon dating protocol has been developed to date earthworm calcite granules from the reference loess sequence of Nussloch (Germany). Its application yields a consistent radiocarbon chronology of all soil horizons formed between 47 and 20 ka and unambiguously shows the correlation of every Greenland interstadial identified in isotope records with specific soil horizons. Furthermore, eight additional minor soil horizons dated between 27.5 and 21 ka only correlate with minor decreases in Greenland dust records. This dating strategy reveals the high sensitivity of loess paleoenvironments to Northern Hemisphere climate changes. A connection between loess sedimentation rate, Fennoscandian ice sheet dynamics, and sea level changes is proposed. The chronological improvements enabled by the radiocarbon "earthworm clock" thus strongly enhance our understanding of loess records to a better perception of the impact of Last Glacial climate changes on European paleoenvironments. PMID- 28559354 TI - RNA-seq reveals conservation of function among the yolk sacs of human, mouse, and chicken. AB - The yolk sac is phylogenetically the oldest of the extraembryonic membranes. The human embryo retains a yolk sac, which goes through primary and secondary phases of development, but its importance is controversial. Although it is known to synthesize proteins, its transport functions are widely considered vestigial. Here, we report RNA-sequencing (RNA-seq) data for the human and murine yolk sacs and compare those data with data for the chicken. We also relate the human RNA seq data to proteomic data for the coelomic fluid bathing the yolk sac. Conservation of transcriptomes across the species indicates that the human secondary yolk sac likely performs key functions early in development, particularly uptake and processing of macro- and micronutrients, many of which are found in coelomic fluid. More generally, our findings shed light on evolutionary mechanisms that give rise to complex structures such as the placenta. We identify genetic modules that are conserved across mammals and birds, suggesting these modules are part of the core amniote genetic repertoire and are the building blocks for both oviparous and viviparous reproductive modes. We propose that although a choriovitelline placenta is never established physically in the human, the placental villi, the exocoelomic cavity, and the secondary yolk sac function together as a physiological equivalent. PMID- 28559356 TI - Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice. AB - Thymic epithelial cells (TECs) provide crucial microenvironments for T-cell development and tolerance induction. As the regular function of the thymus declines with age, it is of fundamental and clinical relevance to decipher new determinants that control TEC homeostasis in vivo. Beyond its recognized tumor suppressive function, p53 controls several immunoregulatory pathways. To study the cell-autonomous role of p53 in thymic epithelium functioning, we developed and analyzed mice with conditional inactivation of Trp53 in TECs (p53cKO). We report that loss of p53 primarily disrupts the integrity of medullary TEC (mTEC) niche, a defect that spreads to the adult cortical TEC compartment. Mechanistically, we found that p53 controls specific and broad programs of mTEC differentiation. Apart from restraining the expression and responsiveness of the receptor activator of NF-kappaB (RANK), which is central for mTEC differentiation, deficiency of p53 in TECs altered multiple functional modules of the mTEC transcriptome, including tissue-restricted antigen expression. As a result, p53cKO mice presented premature defects in mTEC-dependent regulatory T cell differentiation and thymocyte maturation, which progressed to a failure in regular and regenerative thymopoiesis and peripheral T-cell homeostasis in the adulthood. Lastly, peripheral signs of altered immunological tolerance unfold in mutant mice and in immunodeficient mice that received p53cKO-derived thymocytes. Our findings position p53 as a novel molecular determinant of thymic epithelium function throughout life. PMID- 28559355 TI - Assessing human weaning practices with calcium isotopes in tooth enamel. AB - Weaning practices differ among great apes and likely diverged during the course of human evolution, but behavioral inference from the fossil record is hampered by a lack of unambiguous biomarkers. Here, we show that early-life dietary transitions are recorded in human deciduous tooth enamel as marked variations in Ca isotope ratios (delta44/42Ca). Using a sequential microsampling method along the enamel growth axis, we collected more than 150 enamel microsamples from 51 deciduous teeth of 12 different modern human individuals of known dietary histories, as well as nine enamel samples from permanent third molars. We measured and reconstructed the evolution of 44Ca/42Ca ratios in enamel from in utero development to first months of postnatal development. We show that the observed variations of delta44/42Ca record a transition from placental nutrition to an adult-like diet and that Ca isotopes reflect the duration of the breastfeeding period experienced by each infant. Typically, the delta44/42Ca values of individuals briefly or not breastfed show a systematic increase during the first 5-10 mo, whereas individuals with long breastfeeding histories display no measurable variation in delta44/42Ca of enamel formed during this time. The use of Ca isotope analysis in tooth enamel allows microsampling and offers an independent approach to tackle challenging questions related to past population dynamics and evolution of weaning practices in hominins. PMID- 28559357 TI - Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in thrombopoietin. AB - We report 5 individuals in 3 unrelated families with severe thrombocytopenia progressing to trilineage bone marrow failure (BMF). Four of the children received hematopoietic stem cell transplants and all showed poor graft function with persistent severe cytopenias even after repeated transplants with different donors. Exome and targeted sequencing identified mutations in the gene encoding thrombopoietin (THPO): THPO R99W, homozygous in affected children in 2 families, and THPO R157X, homozygous in the affected child in the third family. Both mutations result in a lack of THPO in the patients' serum. For the 2 surviving patients, improvement in trilineage hematopoiesis was achieved following treatment with a THPO receptor agonist. These studies demonstrate that biallelic loss-of-function mutations in THPO cause BMF, which is unresponsive to transplant due to a hematopoietic cell-extrinsic mechanism. These studies provide further support for the critical role of the MPL-THPO pathway in hematopoiesis and highlight the importance of accurate genetic diagnosis to inform treatment decisions for BMF. PMID- 28559362 TI - Receiving Providers' Perceptions on Information Transmission During Interfacility Transfers to General Pediatric Floors. AB - BACKGROUND: Pediatric patients can present to a medical facility and subsequently be transferred to a different hospital for definitive care. Interfacility transfers require a provider handoff across facilities, posing risks that may affect patient outcomes. OBJECTIVES: The goal of this study was to describe the thoroughness of information transmission between providers during interfacility transfers, to describe perceived errors in care at the posttransfer facility, and to identify potential associations between thoroughness of information transmission and perceived errors in care. METHODS: We performed an exploratory prospective cohort study on communication practices and patient outcomes during interfacility transfers to general pediatric floors. Data were collected from provider surveys and chart review. Descriptive statistics were used to summarize survey responses. Logistic regression was used to analyze the association of communication deficits with odds of having a perceived error in care. RESULTS: A total of 633 patient transfers were reviewed; 218 transport command physician surveys and 217 frontline provider surveys were completed. Transport command physicians reported higher proportions of key elements being included in the verbal handoff compared with frontline providers. The written key element transmitted with the lowest frequency was a summary document (65.2%), and 13% of transfers had at least 1 perceived error in care. Transfers with many deficits were associated with higher odds of having a perceived error in care. CONCLUSIONS: Information transmission during pediatric transfers is perceived to be inconsistently complete. Deficits in the verbal and written information transmission are associated with odds of having a perceived error in care. PMID- 28559360 TI - Circadian, Carbon, and Light Control of Expansion Growth and Leaf Movement. AB - We used Phytotyping4D to investigate the contribution of clock and light signaling to the diurnal regulation of rosette expansion growth and leaf movement in Arabidopsis (Arabidopsis thaliana). Wild-type plants and clock mutants with a short (lhycca1) and long (prr7prr9) period were analyzed in a T24 cycle and in T cycles that were closer to the mutants' period. Wild types also were analyzed in various photoperiods and after transfer to free-running light or darkness. Rosette expansion and leaf movement exhibited a circadian oscillation, with superimposed transients after dawn and dusk. Diurnal responses were modified in clock mutants. lhycca1 exhibited an inhibition of growth at the end of night and growth rose earlier after dawn, whereas prr7prr9 showed decreased growth for the first part of the light period. Some features were partly rescued by a matching T cycle, like the inhibition in lhycca1 at the end of the night, indicating that it is due to premature exhaustion of starch. Other features were not rescued, revealing that the clock also regulates expansion growth more directly. Expansion growth was faster at night than in the daytime, whereas published work has shown that the synthesis of cellular components is faster in the day than at nighttime. This temporal uncoupling became larger in short photoperiods and may reflect the differing dependence of expansion and biosynthesis on energy, carbon, and water. While it has been proposed that leaf expansion and movement are causally linked, we did not observe a consistent temporal relationship between expansion and leaf movement. PMID- 28559363 TI - Introduction: historical contexts to communicating mental health. AB - Contemporary discussions around language, stigma and care in mental health, the messages these elements transmit, and the means through which they have been conveyed, have a long and deep lineage. Recognition and exploration of this lineage can inform how we communicate about mental health going forward, as reflected by the 9 papers which make up this special issue. Our introduction provides some framework for the history of communicating mental health over the past 300 years. We will show that there have been diverse ways and means of describing, disseminating and discussing mental health, in relation both to therapeutic practices and between practitioners, patients and the public. Communicating about mental health, we argue, has been informed by the desire for positive change, as much as by developments in reporting, legislation and technology. However, while the modes of communication have developed, the issues involved remain essentially the same. Most practitioners have sought to understand and to innovate, though not always with positive results. Some lost sight of patients as people; patients have felt and have been ignored or silenced by doctors and carers. Money has always talked, for without adequate investment services and care have suffered, contributing to the stigma surrounding mental illness. While it is certainly 'time to talk' to improve experiences, it is also time to change the language that underpins cultural attitudes towards mental illness, time to listen to people with mental health issues and, crucially, time to hear. PMID- 28559364 TI - The presentation of mental disturbance in modern Scottish literature. AB - The subject of madness features throughout world literature, but the literature of modern Scotland appears to be especially preoccupied with it. This paper gives a brief overview of the ways in which madness is represented in modern Scottish literature and the different artistic functions it performs. It will consider the subject on a thematic basis. First, there are accounts by writers who have experienced mental turmoil themselves. Second, there is the theme of the 'Narrative of personal crisis' which depicts in fictional form an individual's journey through madness. Third, there is the theme of the 'Gothic or divided selves'. The fourth theme is that of the 'Female voice' and the last is that of 'Outsiders and holy fools', whose existence is to unsettle the beliefs of a wider society. PMID- 28559361 TI - Adaptor Protein-3-Dependent Vacuolar Trafficking Involves a Subpopulation of COPII and HOPS Tethering Proteins. AB - Plant vacuoles are versatile organelles critical for plant growth and responses to environment. Vacuolar proteins are transported from the endoplasmic reticulum via multiple routes in plants. Two classic routes bear great similarity to other phyla with major regulators known, such as COPII and Rab5 GTPases. By contrast, vacuolar trafficking mediated by adaptor protein-3 (AP-3) or that independent of the Golgi has few recognized cargos and none of the regulators. In search of novel regulators for vacuolar trafficking routes and by using a fluorescence based forward genetic screen, we demonstrated that the multispan transmembrane protein, Arabidopsis (Arabidopsis thaliana) PROTEIN S-ACYL TRANSFERASE10 (PAT10), is an AP-3-mediated vacuolar cargo. We show that the tonoplast targeting of PAT10 is mediated by the AP-3 complex but independent of the Rab5-mediated post-Golgi trafficking route. We also report that AP-3-mediated vacuolar trafficking involves a subpopulation of COPII and requires the vacuolar tethering complex HOPS. In addition, we have identified two novel mutant alleles of AP-3delta, whose point mutations interfered with the formation of the AP-3 complex as well as its membrane targeting. The results presented here shed new light on the vacuolar trafficking route mediated by AP-3 in plant cells. PMID- 28559365 TI - 'Trapped in the labyrinth': exploring mental illness through devised theatrical performance. AB - Mental health difficulties remain a major source of burden and distress for individuals, families, health and social care providers with stigma a key target for educational campaigns attempting to improve care pathways and access to support. Stigma is a multifaceted concept having a range of drivers including shame and is thought to act as a barrier to successful help seeking and engagement with support services. The current paper explores some of the salient themes that emerged from a British university drama project on the impact of symptoms and behaviours associated with a severe mental health condition on a young couple's relationship and reflects on the opportunities for connection with an audience provided by the medium and experience. It is suggested that enabling the impact of mental ill health to be explored in a protected environment such as theatre can allow for reflection and empathy to develop, with potential for positive impact on awareness understanding and stigma. Elements of the drama setting and narrative are explored, and analogies are made with the emerging literature on post-traumatic growth. PMID- 28559367 TI - 'She sits all day in the attitude depicted in the photo': photography and the psychiatric patient in the late nineteenth century. AB - The links between mental state and art in all its various forms and media have long been of interest to historians, critics, artists, patients and doctors. Photographs of patients constitute an extensive but largely unexplored archive that can be used to recover patient experience in the late nineteenth and early twentieth century. The camera and the photograph became tools to communicate information about mental ill health between doctors, their patients and their colleagues. They were published in textbooks and journals, exhibited, exchanged and pasted into medical case books alongside case notes. But they were also used by patients to communicate their own experiences, identity and sense of self. This article uses published and case book photographs from c. 1885-1910 to examine the networks of communication between different stakeholders and discourses. PMID- 28559366 TI - Heritage and Stigma. Co-producing and communicating the histories of mental health and learning disability. AB - University engagement with mental health services has traditionally been informed by the vocational and pedagogical links between the two sectors. However, a growth in the interest in public history and in the history of mental healthcare has offered new opportunities for those in the humanities to engage new audiences and to challenge perceptions about care in the past. The introduction of the 'impact agenda' and related funding streams has further encouraged academics to contribute to historical debates, and to those concerning current services. One such example of this is the Arts and Humanities Research Council funded Heritage and Stigma project at the University of Huddersfield, which was conceived to support mental health and learning disability charities in the exploration and dissemination of their own histories. Using this project as a case study, this paper will draw on primary source material to reflect on the opportunities and challenges of working in partnership with such groups. In particular, it will consider the need to address issues of stigma and exclusion in tandem with a critical understanding of the moves to 'community care' instigated by landmark legislation in the form of the 1959 Mental Health Act. Overall, it provides evidence of an inclusive, coproductive model of design and highlights the positive contribution to communicating mental health made by those based in the humanities. PMID- 28559368 TI - A crisis of meaning: can 'schizophrenia' survive in the 21st century? AB - Both within clinical and wider societal discourses, the term 'schizophrenia' has achieved considerable potency as a signifier, privileging particular conceptual frames for understanding and responding to mental distress. However, its status has been subject to instability, as it has lacked indisputable biological correlates that would anchor its place within the canon of medical diagnosis. Informed by a semiotic perspective, this paper focuses on its recent history: how 'schizophrenia' has been claimed, appropriated and contested-and how this connects with its earlier history of signification. It also explores how the dominance of this signifier has influenced the ways in which people with the diagnosis may find themselves constructed in their interactions with professionals, family and wider society, and hence how they may come to see themselves. It is argued that, from a point in the 1990s when 'schizophrenia' had achieved an almost iconic status, the term is now subject to greater instability, with concerns and challenges being raised from both within and outside psychiatry. On the one hand, this uncertainty has triggered a 'calls to arms' from those within the psychiatric establishment who see diagnoses such as 'schizophrenia' as crucial to their professional identity and status. On the other hand, this has created spaces for new conversations and alliances between elements within neurology, psychiatry, social work and other professions, and between these and service users. Some of these conversations are casting doubt on the validity and utility of 'schizophrenia' as a construct, and are beginning to posit alternative regimes of signification. PMID- 28559369 TI - If psychosis were cancer: a speculative comparison. AB - Recently, health policy in the UK has begun to engage with the concept of 'parity of esteem' between physical and mental healthcare. This has led one recent initiative to improve service provision for first episode psychosis, which aims to bring it into line with some of the principles underpinning good practice in cancer care. In this paper, we consider some of the metaphorical consequences of likening psychosis to cancer. While we find the comparison unhelpful for clinical purposes, we argue that it can be a helpful lens through which to examine service provision for psychosis in young people. Through this lens, specialist community based services would appear to compare reasonably well. Inpatient care for young people with psychosis, on the other hand, suffers very badly by comparison with inpatient facilities for teenage cancer care. We note some of the many positive features of inpatient cancer care for young adults, and-drawing upon previous research on inpatient psychiatric care-observe that many of these are usually absent from mental health facilities. We conclude that this metaphor may be a helpful rhetorical device for communicating the lack of 'parity of esteem' between mental and physical healthcare. This inequity must be made visible in health policy, in commissioning, and in service provision. PMID- 28559371 TI - Identity, law, policy and Communicating Mental Health. AB - This paper reflects on the special edition, Communicating Mental Health, from the perspective of a legal academic with an interest in the service user rights and in United Nations Convention on the Rights of Persons with Disabilities. It is argued that the special edition demonstrates the breadth of the medical model but also that the medical model remains firmly in place in academic understanding of mental disability. The paper questions what this means for identity formation of people with lived experience of mental disability and how we should conceptualise mental disability in the future. PMID- 28559370 TI - Listen and learn: engaging young people, their families and schools in early intervention research. AB - Recent policy guidelines highlight the importance of increasing the identification of young people at risk of developing mental health problems in order to prevent their transition to long-term problems, avoid crisis and remove the need for care through specialist mental health services or hospitalisation. Early awareness of the often insidious behavioural and cognitive changes associated with deteriorating mental well-being, however, is difficult, but it is vital if young people, their families and those who work with them are to be fully equipped with the skills to aid early help-seeking. Our early intervention research continues to highlight the necessity of engaging with and listening to the voices of young people, families and those who work with children and young people, in developing greater understanding of why some young people may be more at risk in terms of their mental health, and to provide children and young people with the best mental health support we can. Collaborative working with young people, their families and those who work with them has been an essential dimension of our youth mental health research in Birmingham, UK, enabling us to listen to the personal narratives of those with lived experience and to work alongside them. This paper highlights some of our key studies and how we have endeavoured to make intra-agency working successful at each stage of the research process through increasing use of digital and youth-informed resources to engage young people: a methodology which continues to inform, guide and develop our early intervention research and implementation. PMID- 28559373 TI - Correction to "Tramadol Metabolism to O-Desmethyl Tramadol (M1) and N-Desmethyl Tramadol (M2) by Dog Liver Microsomes: Species Comparison and Identification of Responsible Canine Cytochrome P450s". PMID- 28559372 TI - Transforming Growth Factor-beta Receptor III is a Potential Regulator of Ischemia Induced Cardiomyocyte Apoptosis. AB - BACKGROUND: Myocardial infarction (MI) is often accompanied by cardiomyocyte apoptosis, which decreases heart function and leads to an increased risk of heart failure. The aim of this study was to examine the effects of transforming growth factor-beta receptor III (TGFbetaR3) on cardiomyocyte apoptosis during MI. METHODS AND RESULTS: An MI mouse model was established by left anterior descending coronary artery ligation. Cell viability, apoptosis, TGFbetaR3, and mitogen-activated protein kinase signaling were assessed by methylthiazolyldiphenyl-tetrazolium bromide assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunofluorescence, electron microscopy, and Western blotting. Our results demonstrated that TGFbetaR3 expression in the border region of the heart was dynamically changed during MI. After stimulation with H2O2, TGFbetaR3 overexpression in cardiomyocytes led to increased cell apoptosis and activation of p38 signaling, whereas TGFbetaR3 knockdown had the opposite effect. ERK1/2 and JNK1/2 signaling was not altered by TGFbetaR3 modulation, and p38 inhibitor (SB203580) reduced the effect of TGFbetaR3 on apoptosis, suggesting that p38 has a nonredundant function in activating apoptosis. Consistent with the in vitro observations, cardiac TGFbetaR3 transgenic mice showed augmented cardiomyocyte apoptosis, enlarged infarct size, increased injury, and enhanced p38 signaling upon MI. Conversely, cardiac loss of function of TGFbetaR3 by adeno-associated viral vector serotype 9 TGFbetaR3 short hairpin RNA attenuated the effects of MI in mice. CONCLUSIONS: TGFbetaR3 promotes apoptosis of cardiomyocytes via a p38 pathway-associated mechanism, and loss of TGFbetaR3 reduces MI injury, which suggests that TGFbetaR3 may serve as a novel therapeutic target for MI. PMID- 28559374 TI - TARP gamma-2 Is Required for Inflammation-Associated AMPA Receptor Plasticity within Lamina II of the Spinal Cord Dorsal Horn. AB - In the brain, transmembrane AMPAR regulatory proteins (TARPs) critically influence the distribution, gating, and pharmacology of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. We found that the Type I TARP gamma-2 (stargazin) is present in lamina II of the superficial dorsal horn, an area involved in nociception. Consistent with the notion that gamma-2 is associated with surface AMPARs, CNQX, a partial agonist at AMPARs associated with Type I TARPs, evoked whole-cell currents in lamina II neurons, but such currents were severely attenuated in gamma-2-lacking stargazer (stg/stg) mice. Examination of EPSCs revealed the targeting of gamma-2 to be synapse-specific; the amplitude of spontaneously occurring miniature EPSCs (mEPSCs) was reduced in neurons from stg/stg mice, but the amplitude of capsaicin-induced mEPSCs from C-fiber synapses was unaltered. This suggests that gamma-2 is associated with AMPARs at synapses in lamina II but excluded from those at C-fiber inputs, a view supported by our immunohistochemical colabeling data. Following induction of peripheral inflammation, a model of hyperalgesia, there was a switch in the current-voltage relationships of capsaicin-induced mEPSCs, from linear to inwardly rectifying, indicating an increased prevalence of calcium-permeable (CP) AMPARs. This effect was abolished in stg/stg mice. Our results establish that, although gamma-2 is not typically associated with calcium-impermeable AMPARs at C-fiber synapses, it is required for the translocation of CP-AMPARs to these synapses following peripheral inflammation.SIGNIFICANCE STATEMENT In the brain, transmembrane AMPAR regulatory proteins (TARPs) critically determine the functional properties of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. An increase in the excitability of neurons within the superficial dorsal horn (SDH) of the spinal cord is thought to underlie heighted pain sensitivity. One mechanism considered to contribute to such long-lived changes is the remodeling of the ionotropic AMPA-type glutamate receptors that underlie fast excitatory synaptic transmission in the SDH. Here we show that the TARP gamma-2 (stargazin) is present in SDH neurons and is necessary in a form of inflammatory pain-induced plasticity, which involves an increase in the prevalence of synaptic calcium-permeable AMPARs. PMID- 28559376 TI - Scopolamine Impairs Appetitive But Not Aversive Trace Conditioning: Role of the Medial Prefrontal Cortex. AB - The muscarinic acetylcholine receptor is an important modulator of medial prefrontal cortex (mPFC) functions, such as the working memory required to bridge a trace interval in associative leaning. Aversive and appetitive trace conditioning procedures were used to examine the effects of scopolamine (0.1 and 0.5 mg/kg, i.p.) in male rats. Follow-up experiments tested the effects of microinfusion of 0.15 MUg of scopolamine (0.075 MUg of in 0.5 MUl/side) in infralimbic (IL) versus prelimbic regions of rat mPFC, in appetitive trace and locomotor activity (LMA) procedures. Systemic scopolamine was without effect in an aversive trace conditioning procedure, but impaired appetitive conditioning at a 2 s trace interval. This effect was demonstrated as reduced responding during presentations of the conditioned stimulus (CS) and during the interstimulus interval (ISI). There was no such effect on responding during food (unconditioned stimulus, US) responding or in the intertrial interval (ITI). In contrast, systemic scopolamine dose-relatedly increased LMA. Trace conditioning was similarly impaired at the 2 s trace (shown as reduced responding to the CS and during the ISI, but not during US presentations or in the ITI) after infusion in mPFC, whereas LMA was increased (after infusion in IL only). Therefore, our results point to the importance of cholinergic modulation in mPFC for trace conditioning and show that the observed effects cannot be attributed to reduced activity.SIGNIFICANCE STATEMENT Events are very often separated in time, in which case working memory is necessary to condition their association in "trace conditioning." The present study used conditioning variants motivated aversively with foot shock and appetitively with food. The drug scopolamine was used to block muscarinic acetylcholine receptors involved in working memory. The results show that reduced cholinergic transmission in medial prefrontal cortex (mPFC) impaired appetitive trace conditioning at a 2 s trace interval. However, scopolamine was without effect in the aversive procedure, revealing the importance of procedural differences to the demonstration of the drug effect. The finding that blockade of muscarinic receptors in mPFC impaired trace conditioning shows that these receptors are critical modulators of short-term working memory. PMID- 28559375 TI - Stable and Dynamic Coding for Working Memory in Primate Prefrontal Cortex. AB - Working memory (WM) provides the stability necessary for high-level cognition. Influential theories typically assume that WM depends on the persistence of stable neural representations, yet increasing evidence suggests that neural states are highly dynamic. Here we apply multivariate pattern analysis to explore the population dynamics in primate lateral prefrontal cortex (PFC) during three variants of the classic memory-guided saccade task (recorded in four animals). We observed the hallmark of dynamic population coding across key phases of a working memory task: sensory processing, memory encoding, and response execution. Throughout both these dynamic epochs and the memory delay period, however, the neural representational geometry remained stable. We identified two characteristics that jointly explain these dynamics: (1) time-varying changes in the subpopulation of neurons coding for task variables (i.e., dynamic subpopulations); and (2) time-varying selectivity within neurons (i.e., dynamic selectivity). These results indicate that even in a very simple memory-guided saccade task, PFC neurons display complex dynamics to support stable representations for WM.SIGNIFICANCE STATEMENT Flexible, intelligent behavior requires the maintenance and manipulation of incoming information over various time spans. For short time spans, this faculty is labeled "working memory" (WM). Dominant models propose that WM is maintained by stable, persistent patterns of neural activity in prefrontal cortex (PFC). However, recent evidence suggests that neural activity in PFC is dynamic, even while the contents of WM remain stably represented. Here, we explored the neural dynamics in PFC during a memory guided saccade task. We found evidence for dynamic population coding in various task epochs, despite striking stability in the neural representational geometry of WM. Furthermore, we identified two distinct cellular mechanisms that contribute to dynamic population coding. PMID- 28559378 TI - Parallel Regulation of Memory and Emotion Supports the Suppression of Intrusive Memories. AB - Intrusive memories often take the form of distressing images that emerge into a person's awareness, unbidden. A fundamental goal of clinical neuroscience is to understand the mechanisms allowing people to control these memory intrusions and reduce their emotional impact. Mnemonic control engages a right frontoparietal network that interrupts episodic retrieval by modulating hippocampal activity; less is known, however, about how this mechanism contributes to affect regulation. Here we report evidence in humans (males and females) that stopping episodic retrieval to suppress an unpleasant image triggers parallel inhibition of mnemonic and emotional content. Using fMRI, we found that regulation of both mnemonic and emotional content was driven by a shared frontoparietal inhibitory network and was predicted by a common profile of medial temporal lobe downregulation involving the anterior hippocampus and the amygdala. Critically, effective connectivity analysis confirmed that reduced amygdala activity was not merely an indirect consequence of hippocampal suppression; rather, both the hippocampus and the amygdala were targeted by a top-down inhibitory control signal originating from the dorsolateral prefrontal cortex. This negative coupling was greater when unwanted memories intruded into awareness and needed to be purged. Together, these findings support the broad principle that retrieval suppression is achieved by regulating hippocampal processes in tandem with domain specific brain regions involved in reinstating specific content, in an activity dependent fashion.SIGNIFICANCE STATEMENT Upsetting events sometimes trigger intrusive images that cause distress and that may contribute to psychiatric disorders. People often respond to intrusions by suppressing their retrieval, excluding them from awareness. Here we examined whether suppressing aversive images might also alter emotional responses to them, and the mechanisms underlying such changes. We found that the better people were at suppressing intrusions, the more it reduced their emotional responses to suppressed images. These dual effects on memory and emotion originated from a common right prefrontal cortical mechanism that downregulated the hippocampus and amygdala in parallel. Thus, suppressing intrusions affected emotional content. Importantly, participants who did not suppress intrusions well showed increased negative affect, suggesting that suppression deficits render people vulnerable to psychiatric disorders. PMID- 28559380 TI - Crossmodal Classification of Mu Rhythm Activity during Action Observation and Execution Suggests Specificity to Somatosensory Features of Actions. AB - The alpha mu rhythm (8-13 Hz) has been considered to reflect mirror neuron activity because it is attenuated by both action observation and action execution. The putative link between mirror neuron system activity and the mu rhythm has been used to study the involvement of the mirror system in a wide range of socio-cognitive processes and clinical disorders. However, previous research has failed to convincingly demonstrate the specificity of the mu rhythm, meaning that it is unclear whether the mu rhythm reflects mirror neuron activity. It also remains unclear whether mu rhythm suppression during action observation reflects the processing of motor or tactile information. In an attempt to assess the validity of the mu rhythm as a measure of mirror neuron activity, we used crossmodal pattern classification to assess the specificity of EEG mu rhythm response to action varying in terms of action type (whole-hand or precision grip), concurrent tactile stimulation (stimulation or no stimulation), or object use (transitive or intransitive actions) in 20 human participants. The main results reveal that above-chance crossmodal classification of mu rhythm activity was obtained in the central channels for tactile stimulation and action transitivity but not for action type. Furthermore, traditional univariate analyses applied to the same data were insensitive to differences between conditions. By calling into question the relationship between mirror system activity and the mu rhythm, these results have important implications for the use and interpretation of mu rhythm activity.SIGNIFICANCE STATEMENT The central alpha mu rhythm oscillation is a widely used measure of the human mirror neuron system that has been used to make important claims concerning cognitive functioning in health and in disease. Here, we used a novel multivariate analytical approach to show that crossmodal EEG mu rhythm responses primarily index the somatosensory features of actions, suggesting that the mu rhythm is not a valid measure of mirror neuron activity. Results may lead to the revision of the conclusions of many previous studies using this measure, and to the transition toward a theory of mu rhythm function that is more consistent with current models of sensory processing in the self and in others. PMID- 28559377 TI - Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in Abeta-Bearing Mice. AB - Hyperexcitable neuronal networks are mechanistically linked to the pathologic and clinical features of Alzheimer's disease (AD). Astrocytes are a primary defense against hyperexcitability, but their functional phenotype during AD is poorly understood. Here, we found that activated astrocytes in the 5xFAD mouse model were strongly associated with proteolysis of the protein phosphatase calcineurin (CN) and the elevated expression of the CN-dependent transcription factor nuclear factor of activated T cells 4 (NFAT4). Intrahippocampal injections of adeno associated virus vectors containing the astrocyte-specific promoter Gfa2 and the NFAT inhibitory peptide VIVIT reduced signs of glutamate-mediated hyperexcitability in 5xFAD mice, measured in vivo with microelectrode arrays and ex vivo brain slices, using whole-cell voltage clamp. VIVIT treatment in 5xFAD mice led to increased expression of the astrocytic glutamate transporter GLT-1 and to attenuated changes in dendrite morphology, synaptic strength, and NMDAR dependent responses. The results reveal astrocytic CN/NFAT4 as a key pathologic mechanism for driving glutamate dysregulation and neuronal hyperactivity during AD.SIGNIFICANCE STATEMENT Neuronal hyperexcitability and excitotoxicity are increasingly recognized as important mechanisms for neurodegeneration and dementia associated with Alzheimer's disease (AD). Astrocytes are profoundly activated during AD and may lose their capacity to regulate excitotoxic glutamate levels. Here, we show that a highly active calcineurin (CN) phosphatase fragment and its substrate transcription factor, nuclear factor of activated T cells (NFAT4), appear in astrocytes in direct proportion to the extent of astrocyte activation. The blockade of astrocytic CN/NFAT signaling in a common mouse model of AD, using adeno-associated virus vectors normalized glutamate signaling dynamics, increased astrocytic glutamate transporter levels and alleviated multiple signs of neuronal hyperexcitability. The results suggest that astrocyte activation drives hyperexcitability during AD through a mechanism involving aberrant CN/NFAT signaling and impaired glutamate transport. PMID- 28559381 TI - Learning Enhances Sensory Processing in Mouse V1 before Improving Behavior. AB - A fundamental property of visual cortex is to enhance the representation of those stimuli that are relevant for behavior, but it remains poorly understood how such enhanced representations arise during learning. Using classical conditioning in adult mice of either sex, we show that orientation discrimination is learned in a sequence of distinct behavioral stages, in which animals first rely on stimulus appearance before exploiting its orientation to guide behavior. After confirming that orientation discrimination under classical conditioning requires primary visual cortex (V1), we measured, during learning, response properties of V1 neurons. Learning improved neural discriminability, sharpened orientation tuning, and led to higher contrast sensitivity. Remarkably, these learning-related improvements in the V1 representation were fully expressed before successful orientation discrimination was evident in the animals' behavior. We propose that V1 plays a key role early in discrimination learning to enhance behaviorally relevant sensory information.SIGNIFICANCE STATEMENT Decades of research have documented that responses of neurons in visual cortex can reflect the behavioral relevance of visual information. The behavioral relevance of any stimulus needs to be learned, though, and little is known how visual sensory processing changes, as the significance of a stimulus becomes clear. Here, we trained mice to discriminate two visual stimuli, precisely quantified when learning happened, and measured, during learning, the neural representation of these stimuli in V1. We observed learning-related improvements in V1 processing, which were fully expressed before discrimination was evident in the animals' behavior. These findings indicate that sensory and behavioral improvements can follow different time courses and point toward a key role of V1 at early stages in discrimination learning. PMID- 28559379 TI - Neural Entrainment to the Beat: The "Missing-Pulse" Phenomenon. AB - Most humans have a near-automatic inclination to tap, clap, or move to the beat of music. The capacity to extract a periodic beat from a complex musical segment is remarkable, as it requires abstraction from the temporal structure of the stimulus. It has been suggested that nonlinear interactions in neural networks result in cortical oscillations at the beat frequency, and that such entrained oscillations give rise to the percept of a beat or a pulse. Here we tested this neural resonance theory using MEG recordings as female and male individuals listened to 30 s sequences of complex syncopated drumbeats designed so that they contain no net energy at the pulse frequency when measured using linear analysis. We analyzed the spectrum of the neural activity while listening and compared it to the modulation spectrum of the stimuli. We found enhanced neural response in the auditory cortex at the pulse frequency. We also showed phase locking at the times of the missing pulse, even though the pulse was absent from the stimulus itself. Moreover, the strength of this pulse response correlated with individuals' speed in finding the pulse of these stimuli, as tested in a follow up session. These findings demonstrate that neural activity at the pulse frequency in the auditory cortex is internally generated rather than stimulus driven. The current results are both consistent with neural resonance theory and with models based on nonlinear response of the brain to rhythmic stimuli. The results thus help narrow the search for valid models of beat perception.SIGNIFICANCE STATEMENT Humans perceive music as having a regular pulse marking equally spaced points in time, within which musical notes are temporally organized. Neural resonance theory (NRT) provides a theoretical model explaining how an internal periodic representation of a pulse may emerge through nonlinear coupling between oscillating neural systems. After testing key falsifiable predictions of NRT using MEG recordings, we demonstrate the emergence of neural oscillations at the pulse frequency, which can be related to pulse perception. These findings rule out alternative explanations for neural entrainment and provide evidence linking neural synchronization to the perception of pulse, a widely debated topic in recent years. PMID- 28559382 TI - Axonal Conduction Delays, Brain State, and Corticogeniculate Communication. AB - Thalamocortical conduction times are short, but layer 6 corticothalamic axons display an enormous range of conduction times, some exceeding 40-50 ms. Here, we investigate (1) how axonal conduction times of corticogeniculate (CG) neurons are related to the visual information conveyed to the thalamus, and (2) how alert versus nonalert awake brain states affect visual processing across the spectrum of CG conduction times. In awake female Dutch-Belted rabbits, we found 58% of CG neurons to be visually responsive, and 42% to be unresponsive. All responsive CG neurons had simple, orientation-selective receptive fields, and generated sustained responses to stationary stimuli. CG axonal conduction times were strongly related to modulated firing rates (F1 values) generated by drifting grating stimuli, and their associated interspike interval distributions, suggesting a continuum of visual responsiveness spanning the spectrum of axonal conduction times. CG conduction times were also significantly related to visual response latency, contrast sensitivity (C-50 values), directional selectivity, and optimal stimulus velocity. Increasing alertness did not cause visually unresponsive CG neurons to become responsive and did not change the response linearity (F1/F0 ratios) of visually responsive CG neurons. However, for visually responsive CG neurons, increased alertness nearly doubled the modulated response amplitude to optimal visual stimulation (F1 values), significantly shortened response latency, and dramatically increased response reliability. These effects of alertness were uniform across the broad spectrum of CG axonal conduction times.SIGNIFICANCE STATEMENT Corticothalamic neurons of layer 6 send a dense feedback projection to thalamic nuclei that provide input to sensory neocortex. While sensory information reaches the cortex after brief thalamocortical axonal delays, corticothalamic axons can exhibit conduction delays of <2 ms to 40-50 ms. Here, in the corticogeniculate visual system of awake rabbits, we investigate the functional significance of this axonal diversity, and the effects of shifting alert/nonalert brain states on corticogeniculate processing. We show that axonal conduction times are strongly related to multiple visual response properties, suggesting a continuum of visual responsiveness spanning the spectrum of corticogeniculate axonal conduction times. We also show that transitions between awake brain states powerfully affect corticogeniculate processing, in some ways more strongly than in layer 4. PMID- 28559385 TI - miR-214 promotes radioresistance in human ovarian cancer cells by targeting PETN. AB - Ovarian cancer is one of the leading causes of death among gynecological malignancies. Increasing evidence indicate that dysregulation of microRNAs (miRNAs) plays an important role in tumor radioresistance. The aim of the present study is to investigate whether microRNA-214 (miR-214) was involved in radioresistance of human ovarian cancer. Here, we showed that miR-214 was significantly up-regulated in ovarian cancer tissues and radioresistance ovarian cancer cell lines. Transfection of miR-214 agomir in radiosensitive ovarian cancer cell lines promoted them for resistance to ionizing radiation, whereas transfection of miR-214 antagomir in radioresistance ovarian cancer cell lines sensitized them to ionizing radiation again. Furthermore, we found miR-214 effectively promoted tumor radioresistance in xenograft animal experiment. Western blotting and quantitative real-time PCR demonstrated that miR-214 negatively regulated PTEN in radioresistance ovarian cancer cell lines and ovarian cancer tissues. Taken together, our data conclude that miR-214 contributes to radioresistance of ovarian cancer by directly targeting PTEN. PMID- 28559383 TI - Spatial Processing Is Frequency Specific in Auditory Cortex But Not in the Midbrain. AB - The cochlea behaves like a bank of band-pass filters, segregating information into different frequency channels. Some aspects of perception reflect processing within individual channels, but others involve the integration of information across them. One instance of this is sound localization, which improves with increasing bandwidth. The processing of binaural cues for sound location has been studied extensively. However, although the advantage conferred by bandwidth is clear, we currently know little about how this additional information is combined to form our percept of space. We investigated the ability of cells in the auditory system of guinea pigs to compare interaural level differences (ILDs), a key localization cue, between tones of disparate frequencies in each ear. Cells in auditory cortex believed to be integral to ILD processing (excitatory from one ear, inhibitory from the other: EI cells) compare ILDs separately over restricted frequency ranges which are not consistent with their monaural tuning. In contrast, cells that are excitatory from both ears (EE cells) show no evidence of frequency-specific processing. Both cell types are explained by a model in which ILDs are computed within separate frequency channels and subsequently combined in a single cortical cell. Interestingly, ILD processing in all inferior colliculus cell types (EE and EI) is largely consistent with processing within single, matched-frequency channels from each ear. Our data suggest a clear constraint on the way that localization cues are integrated: cortical ILD tuning to broadband sounds is a composite of separate, frequency-specific, binaurally sensitive channels. This frequency-specific processing appears after the level of the midbrain.SIGNIFICANCE STATEMENT For some sensory modalities (e.g., somatosensation, vision), the spatial arrangement of the outside world is inherited by the brain from the periphery. The auditory periphery is arranged spatially by frequency, not spatial location. Therefore, our auditory perception of location must be synthesized from physical cues in separate frequency channels. There are multiple cues (e.g., timing, level, spectral cues), but even single cues (e.g., level differences) are frequency dependent. The synthesis of location must account for this frequency dependence, but it is not known how this might occur. Here, we investigated how interaural-level differences are combined across frequency along the ascending auditory system. We found that the integration in auditory cortex preserves the independence of the different-level cues in different frequency regions. PMID- 28559384 TI - A Role for Auditory Corticothalamic Feedback in the Perception of Complex Sounds. AB - Feedback signals from the primary auditory cortex (A1) can shape the receptive field properties of neurons in the ventral division of the medial geniculate body (MGBv). However, the behavioral significance of corticothalamic modulation is unknown. The aim of this study was to elucidate the role of this descending pathway in the perception of complex sounds. We tested the ability of adult female ferrets to detect the presence of a mistuned harmonic in a complex tone using a positive conditioned go/no-go behavioral paradigm before and after the input from layer VI in A1 to MGBv was bilaterally and selectively eliminated using chromophore-targeted laser photolysis. MGBv neurons were identified by their short latencies and sharp tuning curves. They responded robustly to harmonic complex tones and exhibited an increase in firing rate and temporal pattern changes when one frequency component in the complex tone was mistuned. Injections of fluorescent microbeads conjugated with a light-sensitive chromophore were made in MGBv, and, following retrograde transport to the cortical cell bodies, apoptosis was induced by infrared laser illumination of A1. This resulted in a selective loss of ~60% of layer VI A1-MGBv neurons. After the lesion, mistuning detection was impaired, as indicated by decreased d' values, a shift of the psychometric curves toward higher mistuning values, and increased thresholds, whereas discrimination performance was unaffected when level cues were also available. Our results suggest that A1-MGBv corticothalamic feedback contributes to the detection of harmonicity, one of the most important grouping cues in the perception of complex sounds.SIGNIFICANCE STATEMENT Perception of a complex auditory scene is based on the ability of the brain to group those sound components that belong to the same source and to segregate them from those belonging to different sources. Because two people talking simultaneously may differ in their voice pitch, perceiving the harmonic structure of sounds is very important for auditory scene analysis. Here we demonstrate mistuning sensitivity in the thalamus and that feedback from the primary auditory cortex is required for the normal ability of ferrets to detect a mistuned harmonic within a complex sound. These results provide novel insight into the function of descending sensory pathways in the brain and suggest that this corticothalamic circuit plays an important role in scene analysis. PMID- 28559386 TI - Role of SDF-1alpha/CXCR4 signaling pathway in clinicopathological features and prognosis of patients with nasopharyngeal carcinoma. AB - The present study aims to explore the role of stromal cell-derived factor-1alpha (SDF-1alpha)/stromal cell-derived factor receptor-4 (CXCR4) signaling pathway to the clinicopathological features and prognosis of patients with nasopharyngeal carcinoma (NPC). From January 2009 to December 2010, 102 patients with NPC and 80 patients with chronic nasopharyngitis were enrolled for the study. Immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting were employed to determine the expressions of SDF 1alpha and CXCR4 proteins in NPC tissues and chronic nasopharyngitis tissues. Chi square test was conducted to analyze the associations of the expressions of SDF 1alpha and CXCR4 proteins with the clinicopathological features of NPC patients. Spearman rank correlation analysis was used to analyze the correlation between the SDF-1alpha protein expression and CXCR4 protein expression. The mRNA and protein expressions of SDF-1alpha and CXCR4 in NPC tissues were significantly higher than those in chronic nasopharyngitis tissues. The expressions of SDF 1alpha and CXCR4 proteins showed associations with T staging, N staging, tumor node metastasis (TNM) staging, skull base invasion, and cervical lymph node metastasis of NPC patients. Compared with NPC patients showing negative expressions of SDF-1alpha and CXCR4 proteins, those with positive expressions of SDF-1alpha and CXCR4 proteins had a significantly shorter survival time. SDF 1alpha protein, CXCR4 protein, EBV-IgG status, T staging, N staging, TNM staging, skull base invasion, and cervical lymph node metastasis were independent risk factors for the prognosis of NPC. The findings indicated that SDF-1alpha/CXCR4 signaling pathway might be associated with the clinicopathological features and prognosis of patients with NPC. PMID- 28559387 TI - Haemobilia due to hepatic artery pseudoaneurysm. AB - An 83-year-old woman with a history of hepaticoduodenostomy 20 years ago was admitted with upper gastrointestinal bleeding. Emergency upper gastrointestinal endoscopy revealed multiple blood clots over the stomach and first and second parts of the duodenum. The cannulation of the biliary tree with a flexible end viewing endoscope exposed the presence of blood clot inside biliary lumen and a semipedunculated polyp which, at first, appeared to be the cause of haemorrhage. A few days after polypectomy, patient was discharged home, however, was admitted again with massive bleeding and selective angiography demonstrated a pseudoaneurysm of left hepatic artery. Angioembolisation was performed and haemorrhage was stopped afterwards. PMID- 28559388 TI - Stress testing after percutaneous coronary interventions: a population-based study. AB - BACKGROUND: Routine stress testing is commonly used after percutaneous coronary intervention (PCI) to detect in-stent restenosis or suboptimal procedure results; however, recent studies suggest that such testing is rarely indicated. Our main objectives were to assess temporal trends in utilization of stress testing and to determine factors associated with its use. METHODS: We conducted an observational study involving all patients who had undergone PCI in Ontario, Canada, from Apr. 1, 2004, to Mar. 31, 2012. The main outcome was stress testing within 2 years after PCI. We constructed multivariable logistic regression models to determine factors associated with the use of stress tests. RESULTS: Our cohort consisted of 128 380 patients who underwent PCI procedures. The 2-year rate of stress testing declined significantly, from 68.1% among patients who underwent PCI in 2004 to 60.4% in 2012 (p < 0.001). Similar reductions were observed regardless of patients' risk of restenosis and type of stent received. Patients who were older or had diabetes mellitus, prior myocardial infarction, heart failure or other comorbidities were significantly less likely to undergo stress testing. In contrast, patients with higher income and those whose PCI was performed in a nonteaching hospital were significantly more likely to undergo stress testing. INTERPRETATION: We observed a decrease in the use of stress testing after PCI procedures over time. However, stress tests were not performed in accordance with patients' higher baseline risk of adverse outcomes or risk of restenosis. Instead, many nonclinical factors, such as patients' socioeconomic status and hospitals' teaching status, were associated with higher use of stress tests. PMID- 28559389 TI - Mineralocorticoid Receptor Deficiency in T Cells Attenuates Pressure Overload Induced Cardiac Hypertrophy and Dysfunction Through Modulating T-Cell Activation. AB - Although antagonists of mineralocorticoid receptor (MR) have been widely used to treat heart failure, the underlying mechanisms are incompletely understood. Recent reports show that T cells play important roles in pathologic cardiac hypertrophy and heart failure. However, it is unclear whether and how MR functions in T cells under these pathologic conditions. We found that MR antagonist suppressed abdominal aortic constriction-induced cardiac hypertrophy and decreased the accumulation and activation of CD4+ and CD8+ T cells in mouse heart. T-cell MR knockout mice manifested suppressed cardiac hypertrophy, fibrosis, and dysfunction compared with littermate control mice after abdominal aortic constriction. T-cell MR knockout mice had less cardiac inflammatory response, which was illustrated by decreased accumulation of myeloid cells and reduced expression of inflammatory cytokines. Less amounts and activation of T cells were observed in the heart of T-cell MR knockout mice after abdominal aortic constriction. In vitro studies showed that both MR antagonism and deficiency repressed activation of T cells, whereas MR overexpression elevated activation of T cells. These results demonstrated that MR blockade in T cells protected against abdominal aortic constriction-induced cardiac hypertrophy and dysfunction. Mechanistically, MR directly regulated T-cell activation and modulated cardiac inflammation. Targeting MR in T cells specifically may be a feasible strategy for more effective treatment of pathologic cardiac hypertrophy and heart failure. PMID- 28559390 TI - Long-Standing Problem of beta-Blocker-Elicited Hypoglycemia in Diabetes Mellitus. PMID- 28559392 TI - Renal Dysfunction Induced by Kidney-Specific Gene Deletion of Hsd11b2 as a Primary Cause of Salt-Dependent Hypertension. AB - Genome-wide analysis of renal sodium-transporting system has identified specific variations of Mendelian hypertensive disorders, including HSD11B2 gene variants in apparent mineralocorticoid excess. However, these genetic variations in extrarenal tissue can be involved in developing hypertension, as demonstrated in former studies using global and brain-specific Hsd11b2 knockout rodents. To re examine the importance of renal dysfunction on developing hypertension, we generated kidney-specific Hsd11b2 knockout mice. The knockout mice exhibited systemic hypertension, which was abolished by reducing salt intake, suggesting its salt-dependency. In addition, we detected an increase in renal membrane expressions of cleaved epithelial sodium channel-alpha and T53-phosphorylated Na+ Cl- cotransporter in the knockout mice. Acute intraperitoneal administration of amiloride-induced natriuresis and increased urinary sodium/potassium ratio more in the knockout mice compared with those in the wild-type control mice. Chronic administration of amiloride and high-KCl diet significantly decreased mean blood pressure in the knockout mice, which was accompanied with the correction of hypokalemia and the resultant decrease in Na+-Cl- cotransporter phosphorylation. Accordingly, a Na+-Cl- cotransporter blocker hydrochlorothiazide significantly decreased mean blood pressure in the knockout mice. Chronic administration of mineralocorticoid receptor antagonist spironolactone significantly decreased mean blood pressure of the knockout mice along with downregulation of cleaved epithelial sodium channel-alpha and phosphorylated Na+-Cl- cotransporter expression in the knockout kidney. Our data suggest that kidney-specific deficiency of 11beta-HSD2 leads to salt-dependent hypertension, which is attributed to mineralocorticoid receptor-epithelial sodium channel-Na+-Cl- cotransporter activation in the kidney, and provides evidence that renal dysfunction is essential for developing the phenotype of apparent mineralocorticoid excess. PMID- 28559393 TI - Healthy Vascular Aging. PMID- 28559391 TI - How Is the Brain Renin-Angiotensin System Regulated? PMID- 28559394 TI - Orthostatic Hypotension and Risk of Incident Dementia: Results From a 12-Year Follow-Up of the Three-City Study Cohort. AB - Several studies indicate a potential link between orthostatic hypotension (OH) and incident dementia but without substantial evidence to date. Our objective is to study the association between OH and dementia in a cohort of elderly individuals. To do so, baseline lying and standing blood pressure measurements were taken from 7425 subjects in the Three-City study. These subjects were then followed-up for 12 years. Cox proportional hazard models, adjusted for potential confounders, were used to estimate the risk of incident dementia according to OH status. Sensitivity analysis was performed using the so-called illness-death model, a specific statistical method which takes into account competitive risk with death. OH frequency was found to be around 13%, and 760 cases of dementia were diagnosed during follow-up. We observed significant associations between the presence of OH at baseline and the occurrence of dementia during the follow-up, with an increased risk of at least 25% observed regardless of the OH threshold and the statistical method used. In conclusion, there is an association between OH and dementia. Considering that OH is a common condition and is easy to measure, OH measurements could help to identify subjects with higher risk of dementia. Moreover, reducing OH could be a step to prevent conversion to dementia. PMID- 28559395 TI - Delayed Response to Antihypertension Medication: A Harbinger of Stroke, Heart Failure, and Vascular Disease. PMID- 28559396 TI - Oliver Smithies: A Remembrance. PMID- 28559397 TI - Cyclic Nucleotides Differentially Regulate Cx43 Gap Junction Function in Uterine Artery Endothelial Cells From Pregnant Ewes. AB - Cell-cell communication is dependent on GJ (gap junction) proteins such as Cx43 (connexin 43). We previously demonstrated the importance of Cx43 function in establishing the enhanced pregnancy vasodilatory phenotype during pregnancy in uterine artery endothelial cells from pregnant (P-UAEC) ewes. Cx43 is regulated by elevating cAMP and PKA (protein kinase A)-dependent Cx43 S365 phosphorylation associated trafficking and GJ open gating, which is opposed by PKC (protein kinase C)-dependent S368 phosphorylation-mediated GJ turnover and closed gating. However, the role of cyclic nucleotide-mediated signaling mechanisms that control Cx43 and GJ function in P-UAECs is unknown. We hypothesize that cAMP will mediate increases in S365 phosphorylation, thereby, enhancing GJ trafficking and open gating, while cGMP will stimulate S368, but not S365, phosphorylation to enhance GJ turnover and closed gating in P-UAECs. Treatment with 8-Bromo (8-Br)-cAMP signal significantly (P<0.05) increased nonphosphorylated S365 signal and total Cx43 phosphorylation, but not S368 phosphorylation, while 8-Br-cGMP significantly (P<0.05) increased Cx43 C-terminus-S365 signal, S368, and total Cx43 phosphorylation. Inhibition of PKA, but not PKG (protein kinase G), abrogated the 8-Br-cAMP-stimulated increase in nonphosphorylated S365 and total Cx43 phosphorylation and inhibited S368 below basal levels, whereas inhibition of PKG blocked (P<0.05) the 8-bromo-cGMP-stimulated rises in nonphosphorylated S365, total Cx43, and S368 phosphorylation levels in P-UAECs. Functional studies showed that 8-Br-cAMP increased dye transfer and sustained calcium bursts, while 8-Br cGMP decreased both. Thus, in P-UAECs, only 8-Br-cAMP and not 8-Br-cGMP effectively enhances nonphosphorylated S365 and total Cx43 expression that correspondingly reduces S368 phosphorylation, allowing increased GJ communication. This provides new insights into the regulatory mechanisms behind Cx43 function and GJ communication. PMID- 28559398 TI - Prevalence, Correlates, and Prognosis of Healthy Vascular Aging in a Western Community-Dwelling Cohort: The Framingham Heart Study. AB - Hypertension and increased vascular stiffness are viewed as inevitable parts of aging. To elucidate whether the age-related decrease in vascular function is avoidable, we assessed the prevalence, correlates, and prognosis of healthy vascular aging (HVA) in 3196 Framingham Study participants aged >=50 years. We defined HVA as absence of hypertension and pulse wave velocity <7.6 m/s (mean+2 SD of a reference sample aged <30 years). Overall, 566 (17.7%) individuals had HVA, with prevalence decreasing from 30.3% in people aged 50 to 59 to 1% in those aged >=70 years. In regression models adjusted for physical activity, caloric intake, and traditional cardiovascular disease (CVD) risk factors, we observed that lower age, female sex, lower body mass index, use of lipid-lowering drugs, and absence of diabetes mellitus were cross-sectionally associated with HVA (P<0.001 for all). A unit increase in a cardiovascular health score (Life's Simple 7) was associated with 1.55-fold (95% confidence interval, 1.38-1.74) age- and sex-adjusted odds of HVA. During a follow-up of 9.6 years, 391 CVD events occurred. In Cox regression models adjusted for traditional CVD risk factors, including blood pressure, HVA was associated with a hazard ratio of 0.45 (95% confidence interval, 0.26-0.77) for CVD relative to absence of HVA. Although HVA is achievable in individuals acculturated to a Western lifestyle, maintaining normal vascular function beyond 70 years of age is challenging. Although our data are observational, our findings support prevention strategies targeting modifiable factors and behaviors and obesity, in particular, to prevent or delay vascular aging and the associated risk of CVD. PMID- 28559399 TI - Heterogeneity in Early Responses in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). AB - Randomized trials of hypertension have seldom examined heterogeneity in response to treatments over time and the implications for cardiovascular outcomes. Understanding this heterogeneity, however, is a necessary step toward personalizing antihypertensive therapy. We applied trajectory-based modeling to data on 39 763 study participants of the ALLHAT (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial) to identify distinct patterns of systolic blood pressure (SBP) response to randomized medications during the first 6 months of the trial. Two trajectory patterns were identified: immediate responders (85.5%), on average, had a decreasing SBP, whereas nonimmediate responders (14.5%), on average, had an initially increasing SBP followed by a decrease. Compared with those randomized to chlorthalidone, participants randomized to amlodipine (odds ratio, 1.20; 95% confidence interval [CI], 1.10 1.31), lisinopril (odds ratio, 1.88; 95% CI, 1.73-2.03), and doxazosin (odds ratio, 1.65; 95% CI, 1.52-1.78) had higher adjusted odds ratios associated with being a nonimmediate responder (versus immediate responder). After multivariable adjustment, nonimmediate responders had a higher hazard ratio of stroke (hazard ratio, 1.49; 95% CI, 1.21-1.84), combined cardiovascular disease (hazard ratio, 1.21; 95% CI, 1.11-1.31), and heart failure (hazard ratio, 1.48; 95% CI, 1.24 1.78) during follow-up between 6 months and 2 years. The SBP response trajectories provided superior discrimination for predicting downstream adverse cardiovascular events than classification based on difference in SBP between the first 2 measurements, SBP at 6 months, and average SBP during the first 6 months. Our findings demonstrate heterogeneity in response to antihypertensive therapies and show that chlorthalidone is associated with more favorable initial response than the other medications. PMID- 28559400 TI - Risk of Cardiovascular Events in Patients With Diabetes Mellitus on beta Blockers. AB - Although the use of beta-blockers may help in achieving maximum effects of intensive glycemic control because of a decrease in the adverse effects after severe hypoglycemia, they pose a potential risk for the occurrence of severe hypoglycemia. This study aimed to evaluate whether the use of beta-blockers is effective in patients with diabetes mellitus and whether its use is associated with the occurrence of severe hypoglycemia. Using the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes) data, we performed Cox proportional hazards analyses with a propensity score adjustment. The primary outcome was the first occurrence of a cardiovascular event during the study period, which included nonfatal myocardial infarction, unstable angina, nonfatal stroke, and cardiovascular death. The mean follow-up periods (+/-SD) were 4.6+/-1.6 years in patients on beta-blockers (n=2527) and 4.7+/-1.6 years in those not on beta blockers (n=2527). The cardiovascular event rate was significantly higher in patients on beta-blockers than in those not on beta-blockers (hazard ratio, 1.46; 95% confidence interval, 1.24-1.72; P<0.001). In patients with coronary heart disease or heart failure, the cumulative event rate for cardiovascular events was also significantly higher in those on beta-blockers than in those not on beta blockers (hazard ratio, 1.27; 95% confidence interval, 1.02-1.60; P=0.03). The incidence of severe hypoglycemia was significantly higher in patients on beta blockers than in those not on beta-blockers (hazard ratio, 1.30; 95% confidence interval, 1.03-1.64; P=0.02). In conclusion, the use of beta-blockers in patients with diabetes mellitus was associated with an increased risk for cardiovascular events. PMID- 28559401 TI - Association Between Endometriosis and Hypercholesterolemia or Hypertension. AB - An altered hormonal or chronic systemic inflammatory milieu characterizing endometriosis may result in a higher risk of hypercholesterolemia and hypertension. Conversely, elevated low-density lipoprotein in hypercholesterolemia and chronic systemic inflammation resulting from hypertension may increase the risk of endometriosis. We assessed the association of laparoscopically confirmed endometriosis with hypercholesterolemia and hypertension in a large prospective cohort study. In 1989, 116 430 registered female nurses aged 25 to 42 completed the baseline questionnaire and were followed for 20 years. Multivariable Cox proportional hazards models were applied. In 1989, there were 4244 women with laparoscopically confirmed endometriosis and 91 554 women without. After adjusting for demographic, anthropometric, family history, reproductive, dietary, and lifestyle risk factors prospectively, comparing women with laparoscopically confirmed endometriosis to women without, the relative risks were 1.25 (95% confidence interval, 1.21-1.30) for development of hypercholesterolemia and 1.14 (95% confidence interval, 1.09 1.18) for hypertension. Conversely, the relative risks of developing laparoscopically confirmed endometriosis were 1.22 (95% confidence interval, 1.15 1.31) comparing women with hypercholesterolemia to women without and 1.29 (95% confidence interval, 1.18-1.41) comparing women with hypertension to women without. The strength of associations of laparoscopically confirmed endometriosis with hypercholesterolemia or hypertension was strongest among women aged <=40 and weakened as age increased (P values for interaction <0.001). We observed that ~45% of the associations between endometriosis and hypercholesterolemia and hypertension could be accounted for by treatment factors after endometriosis diagnosis, including greater frequency of hysterectomy/oophorectomy and earlier age for this surgery. In this large cohort study, laparoscopically confirmed endometriosis was prospectively associated with increased risk of hypercholesterolemia and hypertension. Conversely, hypercholesterolemia and hypertension were prospectively associated with higher risk of laparoscopically confirmed endometriosis. PMID- 28559402 TI - Findings May Lead to New Strategies for GVHD. AB - A new study in mice demonstrates that activating the RIG-I and STING signaling pathways, normally associated with antiviral immunity, can help protect the intestinal epithelium from damage caused by chemotherapy and radiation following stem cell transplantation. The findings may help in developing strategies to prevent graft-versus-host disease in patients with leukemia and other blood disorders. PMID- 28559403 TI - The Bordetella Bps Polysaccharide Is Required for Biofilm Formation and Enhances Survival in the Lower Respiratory Tract of Swine. AB - Bordetella bronchiseptica is pervasive in swine populations and plays multiple roles in respiratory disease. Additionally, B. bronchiseptica is capable of establishing long-term or chronic infections in swine. Bacterial biofilms are increasingly recognized as important contributors to chronic bacterial infections. Recently the polysaccharide locus bpsABCD has been demonstrated to serve a critical role in the development of mature biofilms formed by the sequenced laboratory strain of B. bronchiseptica We hypothesized that swine isolates would also have the ability to form mature biofilms and the bpsABCD locus would serve a key role in this process. A mutant containing an in-frame deletion of the bpsABCD structural genes was constructed in a wild-type swine isolate and found to be negative for poly-N-acetylglucosamine (PNAG)-like material by immunoblot assay. Further, the bpsABCD locus was found to be required for the development and maintenance of the three-dimensional structures under continuous-flow conditions. To investigate the contribution of the bpsABCD locus to the pathogenesis of B. bronchiseptica in swine, the KM22Deltabps mutant was compared to the wild-type swine isolate for the ability to colonize and cause disease in pigs. The bpsABCD locus was found to not be required for persistence in the upper respiratory tract of swine. Additionally, the bpsABCD locus did not affect the development of anti-Bordetella humoral immunity, did not contribute to disease severity, and did not mediate protection from complement-mediated killing. However, the bpsABCD locus was found to enhance survival in the lower respiratory tract of swine. PMID- 28559404 TI - Peripheral T-Cell Reactivity to Heat Shock Protein 70 and Its Cofactor GrpE from Tropheryma whipplei Is Reduced in Patients with Classical Whipple's Disease. AB - Classical Whipple's disease (CWD) is characterized by the lack of specific Th1 response toward Tropheryma whipplei in genetically predisposed individuals. The cofactor GrpE of heat shock protein 70 (Hsp70) from T. whipplei was previously identified as a B-cell antigen. We tested the capacity of Hsp70 and GrpE to elicit specific proinflammatory T-cell responses. Peripheral mononuclear cells from CWD patients and healthy donors were stimulated with T. whipplei lysate or recombinant GrpE or Hsp70 before levels of CD40L, CD69, perforin, granzyme B, CD107a, and gamma interferon (IFN-gamma) were determined in T cells by flow cytometry. Upon stimulation with total bacterial lysate or recombinant GrpE or Hsp70 of T. whipplei, the proportions of activated effector CD4+ T cells, determined as CD40L+ IFN-gamma+, were significantly lower in patients with CWD than in healthy controls; CD8+ T cells of untreated CWD patients revealed an enhanced activation toward unspecific stimulation and T. whipplei-specific degranulation, although CD69+ IFN-gamma+ CD8+ T cells were reduced upon stimulation with T. whipplei lysate and recombinant T. whipplei-derived proteins. Hsp70 and its cofactor GrpE are immunogenic in healthy individuals, eliciting effective responses against T. whipplei to control bacterial spreading. The lack of specific T-cell responses against these T. whipplei-derived proteins may contribute to the pathogenesis of CWD. PMID- 28559405 TI - Plasmodium berghei PIMMS2 promotes ookinete invasion of the Anopheles gambiae mosquito midgut. AB - Mosquito midgut stages of the malaria parasite present an attractive biological system to study host-parasite interactions and develop interventions to block disease transmission. Mosquito infection ensues upon oocyst development that follows ookinete invasion and traversal of the mosquito midgut epithelium. Here, we report the characterization of PIMMS2 (Plasmodium Invasion of Mosquito Midgut Screen candidate 2), a Plasmodium berghei protein with structural similarities to subtilisin-like proteins. PIMMS2 orthologs are present in the genomes of all plasmodia and are mapped between the subtilisin-encoding genes SUB1 and SUB3P. berghei PIMMS2 is specifically expressed in zygotes and ookinetes and is localized on the ookinete surface. Loss of PIMMS2 function through gene disruption by homologous recombination leads to normal development of motile ookinetes that exhibit severely impaired capacity to traverse the mosquito midgut and transform to oocysts. Genetic complementation of the disrupted locus with a mutated PIMMS2 allele reveals that amino acid residues corresponding to the putative subtilisin-like catalytic triad are important but not essential for the protein function. Our data demonstrate that PIMMS2 is a novel ookinete-specific protein that promotes parasite traversal of the mosquito midgut epithelium and establishment of mosquito infection. PMID- 28559406 TI - Efflux Transporter of Siderophore Staphyloferrin A in Staphylococcus aureus Contributes to Bacterial Fitness in Abscesses and Epithelial Cells. AB - The siderophores staphyloferrin A (SA) and staphyloferrin B (SB) of Staphylococcus aureus are essential for iron acquisition in the iron-restricted environment of the host, such as in subcutaneous abscesses. SA and SB are secreted by SfaA and SbnD transporters, respectively. To assess the further function of SfaA and SbnD in S. aureus fitness, we tested its effect on murine abscess models and intracellular replication in epithelial cells. Bacterial fitness in abscesses and in epithelial cells was studied, by comparing the parental strains RN6390 and MW2 and their DeltasfaA and DeltasbnD mutants using competition assays in a murine abscess model and invasion and replication assays with human lung adenocarcinoma cell line A549. In the murine abscess model using equal inocula of a DeltasfaA or DeltasbnD mutant and the wild-type RN6390 strain, the DeltasfaA mutant exhibited growth defects of 2.2-fold. Additionally, replication of the DeltasfaA mutant within A549 cells was decreased 3.0-fold. In complementation experiments, the DeltasfaA mutant carrying plasmid-borne sfaA restored the growth fitness in abscesses and epithelial cells. The DeltasbnD mutant, in contrast, showed no growth defect in either abscesses or epithelial cells. Our findings demonstrate that the efflux transporter of the siderophore SA contributes to the ability of S. aureus to replicate in abscesses and epithelial cells. Furthermore, fitness of S. aureus in these sites of replication is not compromised by the absence of transporter SbnD. PMID- 28559407 TI - Neutrophil elastase and IL17 expressed in the pig colon during Brachyspira hyodysenteriae infection synergistically with the pathogen induce increased mucus transport speed and production via MAPK3. AB - Brachyspira hyodysenteriae colonizes the pig colon resulting in mucoid hemorragic diarrhea and mucus layer changes. These changes are characterized by a disorganized mucus structure and a massive mucus induction with de novo expression of MUC5AC and increased production of MUC2. To investigate the mechanisms behind this altered mucin environment, we quantified the mRNA levels of mucin pathway genes and factors from the immune system in the colon of infected and control pigs, revealing upregulation of neutrophil elastase, SPDEF, FOXA3, MAPK3/ERK1, IL-17A, IL-1beta, IL-6 and IL-8 expression. Colonic mucus producing in vitro mucosal surfaces were treated with these factors along with B. hyodysenteriae infection and analyzed for their effect on mucin production. Neutrophil elastase and infection synergistically induced mucus production and transport speed, and IL-17A also had similar effects, both in the presence and absence of infection. A MAPK3/ERK1 inhibitor suppressed these effects. Therefore, we suggest that the SPDEF, FOXA3, and MAPK3/ERK1 signaling pathways are behind the transcriptional program regulating mucin biosynthesis in the colon during B. hyodysenteriae infection. In addition to furthering the knowledge of this economically important disease, this mechanism may be useful for the development of therapies aimed at conditions where enhancing mucus production may be beneficial, such as chronic inflammatory disorders of the colon. PMID- 28559408 TI - Social Network Structures of Breast Cancer Patients and the Contributing Role of Patient Navigators. AB - BACKGROUND: Minority women in the U.S. continue to experience inferior breast cancer outcomes compared with white women, in part due to delays in care delivery. Emerging cancer care delivery models like patient navigation focus on social barriers, but evidence demonstrating how these models increase social capital is lacking. This pilot study describes the social networks of newly diagnosed breast cancer patients and explores the contributing role of patient navigators. MATERIALS AND METHODS: Twenty-five women completed a one hour interview about their social networks related to cancer care support. Network metrics identified important structural attributes and influential individuals. Bivariate associations between network metrics, type of network, and whether the network included a navigator were measured. Secondary analyses explored associations between network structures and clinical outcomes. RESULTS: We identified three types of networks: kin-based, role and/or affect-based, or heterogeneous. Network metrics did not vary significantly by network type. There was a low prevalence of navigators included in the support networks (25%). Network density scores were significantly higher in those networks without a navigator. Network metrics were not predictive of clinical outcomes in multivariate models. CONCLUSION: Patient navigators were not frequently included in support networks, but provided distinctive types of support. If navigators can identify patients with poorly integrated (less dense) social networks, or who have unmet tangible support needs, the intensity of navigation services could be tailored. Services and systems that address gaps and variations in patient social networks should be explored for their potential to reduce cancer health disparities. IMPLICATIONS FOR PRACTICE: This study used a new method to identify the breadth and strength of social support following a diagnosis of breast cancer, especially examining the role of patient navigators in providing support. While navigators were only included in one quarter of patient support networks, they did provide essential supports to some individuals. Health care providers and systems need to better understand the contributions of social supports both within and outside of health care to design and tailor interventions that seek to reduce health care disparities and improve cancer outcomes. PMID- 28559409 TI - Association of Pre-Chemotherapy Peripheral Blood Pro-Inflammatory and Coagulation Factors with Physical Function in Women with Breast Cancer. AB - BACKGROUND: Pro-inflammatory and coagulation factors serve as biomarkers of aging and functional reserve. The purpose of this study was to determine if pro inflammatory (interleukin-6 [IL-6], C-reactive protein [CRP]), and coagulation (D dimer) factors were associated with pre-chemotherapy functional status in women with stage I-III breast cancer. PATIENTS AND METHODS: Prior to chemotherapy initiation in patients with stage I-III breast cancer, the following was captured: IL-6, CRP, D-dimer blood levels, and physical function measures including activities of daily living (ADL, subscale of Medical Outcomes Study Physical Health); instrumental activities of daily living (IADL, subscale of the Older Americans Resources and Services Program); Timed Up and Go (TUG); physician rated Karnofsky Performance Status (KPS); and self-rated KPS. The association of these biomarkers with physical function measures was evaluated. RESULTS: One hundred sixty patients (mean age 58.3 years, range 30-81 years) with stage I-III breast cancer (stages I [n = 34; 21.5%], II [n = 88; 55.7%], III [n = 36; 22.8%]) were enrolled. The group with poorest physical function (defined by ADL <70, IADL <14, and TUG >=10 seconds) had higher levels of IL-6 (p = .05), D-dimer (p = .0004), and CRP (p = .05). There was no significant association between these biomarkers and KPS. Patients with at least two biomarkers in the highest quartile were more likely to have poorer physical function (odds ration [OR] 18.75, p < .001). In multivariate analysis adjusting for age, stage, number of comorbidities, and body mass index, the association remained (OR 14.6, p = .002). CONCLUSION: Pre-chemotherapy biomarkers of aging are associated with poorer physical function among patients with breast cancer across the aging spectrum. The Oncologist 2017;22:1189-1196 IMPLICATIONS FOR PRACTICE: Commonly used physical function assessment tools may not reflect the diverse nature of physical function and risk for chemotherapy toxicity, particularly in older adults. No laboratory test reflects functional reserve. Pro-inflammatory and coagulation factors, such as IL-6, CRP, and D-dimer, can serve as biomarkers of aging and physical function; however, few studies have evaluated their utility in patients with cancer. This study was designed to understand the association between pre chemotherapy biomarkers and physical function in women with early stage breast cancer undergoing adjuvant chemotherapy. Results indicate that elevated pre chemotherapy levels in two of the three peripheral biomarkers are associated with the poorest physical function among patients with breast cancer across the aging spectrum. PMID- 28559410 TI - Case Report: Encephalitis, with Brainstem Involvement, Following Checkpoint Inhibitor Therapy in Metastatic Melanoma. AB - : Checkpoint inhibitors are increasingly being used in the treatment of malignant melanoma and other cancers. With the use of such therapies, autoimmune-mediated adverse events in the central and peripheral nervous system are likely to occur more frequently. We report a unique case of brainstem encephalitis with a sudden lethal outcome following ipilimumab and pembrolizumab therapy in a patient with malignant melanoma. The autopsy showed a diffuse nodular activation of microglia in the whole encephalon with prominent intraparenchymal and perivascular lymphocytic infiltration of the brainstem. Non-infectious brainstem encephalitis is a well-recognized subset of paraneoplastic encephalitis. Brainstem involvement is usually accompanied by a wide spectrum of signs and symptoms, which were not observed in this case. The timing of the clinical symptoms as well as the histopathological findings suggest an autoimmune-adverse event of ipilimumab and pembrolizumab administration rather than a paraneoplastic disorder. In the presence of neurological symptoms, immediate cessation of the immunotherapy and immunosuppressive therapy may lead to successful therapeutic intervention, as described in previous reports. Therefore, it is crucial that physicians are aware of the possible side effects of immunotherapies on the nervous system. IMPLICATIONS FOR PRACTICE: Metastatic melanoma patients treated with the anti CTLA-4 inhibitor ipilimumab have a high utilization of various types of health care services, such as inpatient hospital stays or doctor visits. There are differences across countries regarding patterns of health care utilization and economic burden of the disease. Health care services are used more frequently after patients experience progression of their disease. The study highlights that better therapies leading to durable response in patients with metastatic melanoma have the potential to decrease health care costs and patient burden in terms of hospitalizations and other health care services. PMID- 28559411 TI - Predictors of Disruptions in Breast Cancer Care for Individuals with Schizophrenia. AB - BACKGROUND: Patients with schizophrenia experience markedly increased breast cancer mortality, yet reasons for this disparity are poorly understood. We sought to characterize disruptions in breast cancer care for patients with schizophrenia and identify modifiable predictors of those disruptions. MATERIALS AND METHODS: We performed a medical record review of 95 patients with schizophrenia and breast cancer treated at an academic cancer center between 1993 and 2015. We defined cancer care disruptions as processes that interfere with guideline-concordant cancer care, including delays to diagnosis or treatment, deviations from stage appropriate treatment, and interruptions in treatment. We hypothesized that lack of psychiatric treatment at cancer diagnosis would be associated with care disruptions. RESULTS: Half of patients with schizophrenia experienced at least one breast cancer care disruption. Deviations in stage-appropriate treatment were associated with breast cancer recurrence at 5 years (p = .045). Patients without a documented psychiatrist experienced more delays (p = .016), without documented antipsychotic medication experienced more deviations (p = .007), and with psychiatric hospitalizations after cancer diagnosis experienced more interruptions (p < .0001). Independent of stage, age, and documented primary care physician, lack of documented antipsychotic medication (odds ratio [OR] = 4.97, 95% confidence interval [CI] = 1.90, 12.98) and psychiatric care (OR = 4.56, 95% CI = 1.37, 15.15) predicted cancer care disruptions. CONCLUSION: Disruptions in breast cancer care are common for patients with schizophrenia and are associated with adverse outcomes, including cancer recurrence. Access to psychiatric treatment at cancer diagnosis may protect against critical disruptions in cancer care for this underserved population. IMPLICATIONS FOR PRACTICE: Disruptions in breast cancer care are common for patients with schizophrenia, yet access to mental health treatment is rarely integrated into cancer care. When oncologists documented a treating psychiatrist and antipsychotic medication, patients had fewer disruptions in breast cancer care after adjusting for age, cancer stage, and access to primary care. Addressing psychiatric comorbidity at breast cancer diagnosis may increase the likelihood that patients with schizophrenia receive timely, stage-appropriate cancer treatment. Comanagement of schizophrenia and breast cancer at cancer diagnosis may be one key strategy to decrease inequities in cancer treatment and improve cancer survival in this underserved population. PMID- 28559412 TI - Complete Responses to Mitotane in Metastatic Adrenocortical Carcinoma-A New Look at an Old Drug. AB - PURPOSE: Based largely on reports that predate modern reporting standards, mitotane has been considered a systemic treatment option for both hormone control and antitumor control of metastatic adrenocortical cancer (ACC), although the therapeutic window is narrow. METHODS: We searched electronic medical records to identify patients with metastatic ACC treated and prescribed single-agent mitotane at Memorial Sloan Kettering Cancer Center from March 15, 1989-September 18, 2015. Reference radiologists reviewed all imaging and determined efficacy according to Response Evaluation Criteria in Solid Tumors 1.1. Patient demographics, toxicities, and treatment outcomes were reviewed. Next-generation sequencing was performed in selected cases. RESULTS: Thirty-six patients were identified. The mean age was 54 and 50% had functional tumors. Grade 3 or greater toxicities were documented in 16 out of 36 patients (44%) and 17% had documented long term adrenal insufficiency. Progression of the disease as the best response occurred in 30 out of 36 patients (83%) and one patient (3%) experienced clinical progression. Three patients achieved a complete response (CR) (8%), one patient achieved a partial response (3%), and one patient (3%) had stable disease after slow disease progression prior to initiation of therapy (durable for 6 months). All responders had nonfunctional tumors. Next-generation sequencing in two of the three CR patients was performed and failed to identify any novel alterations. CONCLUSION: In this retrospective series, mitotane had a low response rate and low tumor control rate; however, a disproportionately high complete response rate suggested it should be used in selected individuals. Adrenal insufficiency is common with mitotane use and aggressive treatment with steroid supplementation should be considered when appropriate to avoid excess toxicities. Biomarkers are desperately needed to further define this disease. IMPLICATIONS FOR PRACTICE: This is the first objective report of single-agent mitotane using modern objective criteria. Although the vast majority of patients did not respond (and toxicity was high), we identified a remarkable 8% complete response rate (i.e. cure) in biopsy proven stage IV adrenocortical cancer patients. Biomarkers are desperately needed for this rare disease. PMID- 28559413 TI - Targeting the Molecular Subtypes of Triple Negative Breast Cancer: Understanding the Diversity to Progress the Field. AB - : Triple negative breast cancers (TNBCs) represent 10%-20% of primary breast cancers, and despite having greater initial sensitivity to cytotoxic chemotherapy, patients with TNBCs have higher rates of distant metastasis and a poorer prognosis compared with patients with hormone receptor positive and/or human epidermal growth factor receptor 2 positive disease. TNBC has historically been treated as a single disease entity in targeted therapy trials, but advances in gene expression profiling and other molecular diagnostic techniques over the last decade have revealed considerable biologic heterogeneity within TNBCs, including subgroups with distinct, targetable aberrations. Such molecular heterogeneity explains, in part, the disappointing performance of targeted therapeutics in unselected TNBC. Here we discuss the history of gene expression profiling in breast cancer and its application in partitioning TNBCs into subtypes that may lead to more consistent therapeutic successes in this heterogeneous disease. IMPLICATIONS FOR PRACTICE: Triple negative breast cancers (TNBCs) have historically been regarded as a single entity in clinical trial design. Over the last decade, molecular characterization has revealed much heterogeneity in TNBCs, explaining in part the lackluster performance of targeted therapeutics in TNBCs as a group. In this article, we review the history of the molecular classification of breast cancer based on gene expression profiling and discuss its role in TNBCs. PMID- 28559415 TI - Should same day discharge general anaesthesia be a notifiable condition for being unfit to drive? PMID- 28559414 TI - Attitudes Toward Cancer and Cancer Patients in an Urban Iranian Population. AB - BACKGROUND: Because of the significant incidence and mortality of cancer in Iran, a Comprehensive National Cancer Control Program for the prevention and early detection of cancer was launched in 2007. However, cancer awareness and screening rates in Iran did not improve. This study aimed to evaluate public attitudes toward cancer and cancer patients in Iran. MATERIALS AND METHODS: We conducted a cross-sectional survey among 953 non-institutionalized individuals in Isfahan, Iran, from November 2014 to February 2015. We collected data on attitudes toward cancer in three domains (impossibility of recovery, cancer stereotypes, and discrimination), as well as questions on willingness to disclose a cancer diagnosis. RESULTS: Among all participants, 33.9% agreed that it is very difficult to regain one's health after a cancer diagnosis, 17.4% felt uncomfortable with a cancer patient, and 26.9% said that they would avoid marrying people whose family members had cancer. While 88.9% of study participants said that cancer patients deserve to be protected in society, 53.3% and 48.4% of participants agreed that they would not disclose a cancer diagnosis to neighbors and coworkers, respectively. CONCLUSION: Negative attitudes with respect to impossibility of recovery and discrimination toward cancer and cancer patients were common among urban Iranians. Most people would not disclose a cancer diagnosis to others in spite of advancements in cancer diagnosis and treatment, reflecting unfavorable attitudes toward cancer and cancer patients in society. Successful implementation of cancer awareness and prevention programs in Iran may require social changes based on adequate information on cancer and cancer patients. IMPLICATIONS FOR PRACTICE: Public attitudes toward cancer and cancer patients are an important factor affecting cancer control programs as well as quality of life and recovery of cancer patients. The issue has not been studied in Iran and the surrounding countries in the Middle East. This is the first report presented on the subject. These findings can be used by health policy makers, health managers, and clinicians for better practice. PMID- 28559419 TI - Correction to "Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine". PMID- 28559418 TI - Abnormal Global Longitudinal Strain Predicts Future Deterioration of Left Ventricular Function in Heart Failure Patients With a Recovered Left Ventricular Ejection Fraction. AB - BACKGROUND: Patients with recovery of left ventricular ejection fraction (LVEF) remain at risk for future deterioration of LVEF. However, there are no tools to risk stratify these patients. We hypothesized that global longitudinal strain (GLS) could predict sustained recovery within this population. METHODS AND RESULTS: We retrospectively identified 96 patients with a reduced LVEF <50% (screening echocardiogram), whose LVEF had increased by at least 10% and normalized (>50%) on evidence-based medical therapies (baseline echocardiogram). We examined absolute GLS on the baseline echocardiogram in relation to changes in LVEF on a follow-up echocardiogram. Patients with recovered LVEF had a wide range of GLS. The GLS on the baseline study correlated with the LVEF at the time of follow-up (r=0.33; P<0.001). The likelihood of having an LVEF >50% on follow-up increased by 24% for each point increase in absolute GLS on the baseline study (odds ratio, 1.24; P=0.001). An abnormal GLS (<=16%) at baseline had a sensitivity of 88%, a specificity of 46%, and an accuracy of 0.67 (P<0.001) as a predictor of a decrease in LVEF >5% during follow-up. A normal GLS (>16%) on the baseline study had a sensitivity of 47%, a specificity of 83%, and an accuracy of 0.65 (P=0.002) for predicting a stable LVEF (-5% to 5%) on follow-up. CONCLUSIONS: In patients with a recovered LVEF, an abnormal GLS predicts the likelihood of having a decreased LVEF during follow-up, whereas a normal GLS predicts the likelihood of stable LVEF during recovery. PMID- 28559416 TI - In vitro expansion of mouse primordial germ cell-like cells recapitulates an epigenetic blank slate. AB - The expansion of primordial germ cells (PGCs), the precursors for the oocytes and spermatozoa, is a key challenge in reproductive biology/medicine. Using a chemical screening exploiting PGC-like cells (PGCLCs) induced from mouse embryonic stem cells (ESCs), we here identify key signaling pathways critical for PGCLC proliferation. We show that the combinatorial application of Forskolin and Rolipram, which stimulate cAMP signaling via different mechanisms, expands PGCLCs up to ~50-fold in culture. The expanded PGCLCs maintain robust capacity for spermatogenesis, rescuing the fertility of infertile mice. Strikingly, during expansion, PGCLCs comprehensively erase their DNA methylome, including parental imprints, in a manner that precisely recapitulates genome-wide DNA demethylation in gonadal germ cells, while essentially maintaining their identity as sexually uncommitted PGCs, apparently through appropriate histone modifications. By establishing a paradigm for PGCLC expansion, our system reconstitutes the epigenetic "blank slate" of the germ line, an immediate precursory state for sexually dimorphic differentiation. PMID- 28559420 TI - Incremental Prognostic Use of Left Ventricular Global Longitudinal Strain in Asymptomatic/Minimally Symptomatic Patients With Severe Bioprosthetic Aortic Stenosis Undergoing Redo Aortic Valve Replacement. AB - BACKGROUND: With improved survival of patients undergoing primary bioprosthetic aortic valve replacement (AVR), reoperation to relieve severe prosthetic aortic stenosis (PAS) is increasing. Timing of redo surgery in asymptomatic/minimally symptomatic patients remains controversial. Left ventricular (LV) global longitudinal strain (GLS) is a marker of subclinical LV dysfunction. In asymptomatic/minimally symptomatic patients with severe PAS undergoing redo AVR, we sought to determine whether LV-GLS provides incremental prognostic use. METHODS AND RESULTS: We studied 191 patients with severe bioprosthetic PAS (63+/ 16 years, 58% men) who underwent redo AVR between 2000 and 2012 (excluding mechanical PAS, severe other valve disease transcatheter AVR, and LV ejection fraction <50%). Society of Thoracic Surgeons score was calculated. Standard echocardiography data were obtained. LV-GLS was measured on 2-, 3-, and 4-chamber views using velocity vector imaging. Severe PAS was defined as aortic valve area <0.8 cm2, mean aortic valve gradient >=40 mm Hg, and dimensionless index <0.25. A composite outcome of death and congestive heart failure admission was recorded. At baseline, mean Society of Thoracic Surgeons score, LV ejection fraction, mean aortic valve gradients, and right ventricular systolic pressure were 7+/-6, 58+/ 6%, 54+/-10 mm Hg and 40+/-14 mm Hg, whereas 50% had >2+ aortic regurgitation. Median LV-GLS was -14.2% (-11.4, -17.1%). At 4.2+/-3 years, 41 (22%) patients met the composite end point (2.5% deaths and 1% strokes at 30 days postoperatively). On multivariable Cox survival analysis, LV-GLS was independently associated with longer-term composite events (hazard ratio, 1.21; 95% confidence interval, 1.10 1.33), P<0.01. The C statistic for the clinical model (Society of Thoracic Surgeons score, degree of aortic regurgitation, and right ventricular systolic pressure) was 0.64 (95% confidence interval 0.54-0.79), P<0.001. Addition of LV GLS to the clinical model increased the C statistic significantly to 0.71 (95% confidence interval 0.58-0.81), P<0.001. CONCLUSIONS: In asymptomatic/minimally symptomatic patients with severe bioprosthetic PAS undergoing redo AVR, baseline LV-GLS provides incremental prognostic use over established predictors and could potentially aid in surgical timing and risk stratification. PMID- 28559417 TI - The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. AB - Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD-like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock-in mouse model for the disease-associated Trem2 p.T66M mutation. Consistent with a loss-of function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p.T66M mutation. Trem2 p.T66M knock-in mice show delayed resolution of inflammation upon in vivo lipopolysaccharide stimulation and cultured macrophages display significantly reduced phagocytic activity. Immunohistochemistry together with in vivo TSPO small animal positron emission tomography (MUPET) demonstrates an age-dependent reduction in microglial activity. Surprisingly, perfusion magnetic resonance imaging and FDG-MUPET imaging reveal a significant reduction in cerebral blood flow and brain glucose metabolism. Thus, we demonstrate that a TREM2 loss-of-function mutation causes brain-wide metabolic alterations pointing toward a possible function of microglia in regulating brain glucose metabolism. PMID- 28559421 TI - Challenge of Timing Redo Aortic Valve Replacement: Is There a Potential Role for Left Ventricular Global Longitudinal Strain? PMID- 28559422 TI - Comparison of corneal dynamic parameters and tomographic measurements using Scheimpflug imaging in keratoconus. AB - AIM: To compare the diagnostic ability of corneal tomography and corneal dynamic response measurements in normal and keratoconus eyes. METHODS: Consecutive patients with grade II-III keratoconus and age-matched normal subjects were recruited. Corneal imaging was performed using Pentacam (Oculus Optikgerate, Wetzlar, Germany) and Corvis (Oculus Optikgerate). A beta version of Corvis software was used with three additional parameters: maximal change of arc length, deformation amplitude (DA) ratio 1 and DA ratio 2. Diagnostic ability of both devices to differentiate normal and keratoconus eyes was evaluated using receiver operating characteristic (ROC) curves. The areas under the ROC curve (AUC) and partial AUC (pAUC) for specificity >=80% for each parameter of Corvis and final D value of Belin/Ambrosio Enhanced Ectasia Display (BAD) were compared. RESULTS: Forty-two eyes of 42 patients (21 patients with keratoconus and 21 normal subjects) were included. Both groups were age matched (p=0.760). The ROC analysis showed that the final D value of BAD had the highest AUC (0.994) and pAUC (0.194). Maximum inverse radius had the highest AUC (0.954) but a relatively lower pAUC (0.158), while DA ratio 2 had the second highest AUC (0.946) together with the highest pAUC (0.177) among Corvis parameters. There was no significant difference between AUC and pAUC of BAD compared with those of DA ratio 1 (p>=0.162) and DA ratio 2 (p>=0.208). CONCLUSIONS: The results of our study suggest that Corvis measurements have the potential to differentiate keratoconus and normal eyes. The diagnostic ability of novel parameters on Corvis was comparable to Pentacam. PMID- 28559423 TI - Hsc70 chaperone activity is required for the cytosolic slow axonal transport of synapsin. AB - Soluble cytosolic proteins vital to axonal and presynaptic function are synthesized in the neuronal soma and conveyed via slow axonal transport. Our previous studies suggest that the overall slow transport of synapsin is mediated by dynamic assembly/disassembly of cargo complexes followed by short-range vectorial transit (the "dynamic recruitment" model). However, neither the composition of these complexes nor the mechanistic basis for the dynamic behavior is understood. In this study, we first examined putative cargo complexes associated with synapsin using coimmunoprecipitation and multidimensional protein identification technology mass spectrometry (MS). MS data indicate that synapsin is part of a multiprotein complex enriched in chaperones/cochaperones including Hsc70. Axonal synapsin-Hsc70 coclusters are also visualized by two-color superresolution microscopy. Inhibition of Hsc70 ATPase activity blocked the slow transport of synapsin, disrupted axonal synapsin organization, and attenuated Hsc70-synapsin associations, advocating a model where Hsc70 activity dynamically clusters cytosolic proteins into cargo complexes, allowing transport. Collectively, our study offers insight into the molecular organization of cytosolic transport complexes and identifies a novel regulator of slow transport. PMID- 28559426 TI - Non-invasive fractional flow reserve using computed tomographic angiography: where are we now and where are we going? PMID- 28559425 TI - FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice. AB - The aim of the present study is to explore the molecular mechanism of fibroblast growth factor 21 (FGF21) in protecting against diabetic cardiomyopathy (DCM). Streptozotocin/high-fat diet (STZ/HFD) was used to induced diabetes in FGF21 deficient mice and their wild-type littermates, followed by evaluation of the difference in DCM between the two genotypes. Primary cultured cardiomyocytes were also used to explore the potential molecular mechanism of FGF21 in the protection of high glucose (HG)-induced cardiomyocyte injury. STZ/HFD-induced cardiomyopathy was exacerbated in FGF21 knockout mice, which was accompanied by a significant reduction in cardiac AMP-activated protein kinase (AMPK) activity and paraoxonase 1 (PON1) expression. By contrast, adeno-associated virus (AAV)-mediated overexpression of FGF21 in STZ/HFD-induced diabetic mice significantly enhanced cardiac AMPK activity, PON1 expression and its biological activity, resulting in alleviated DCM. In cultured cardiomyocytes, treatment with recombinant mouse FGF21 (rmFGF21) counteracted HG-induced oxidative stress, mitochondrial dysfunction, and inflammatory responses, leading to increased AMPK activity and PON1 expression. However, these beneficial effects of FGF21 were markedly weakened by genetic blockage of AMPK or PON1. Furthermore, inactivation of AMPK also markedly blunted FGF21-induced PON1 expression but significantly increased HG-induced cytotoxicity in cardiomyocytes, the latter of which was largely reversed by adenovirus-mediated PON1 overexpression. These findings suggest that FGF21 ameliorates DCM in part by activation of the AMPK-PON1 axis. PMID- 28559427 TI - Effects of altered sagittal trunk orientation on kinetic pattern in able-bodied walking on uneven ground. AB - Studies of disturbed human locomotion often focus on the dynamics of the gait when either posture, movement or surface is perturbed. Yet, the interaction effects of variation of trunk posture and ground level on kinetic behaviour of able-bodied gait have not been explored. For 12 participants we investigated the kinetic behaviour, as well as velocity and contact time, across four steps including an unperturbed step on level ground, pre-perturbation, perturbation (10 cm drop) and post-perturbation steps while walking with normal speed with four postures: regular erect, with 30 degrees , 50 degrees and maximal sagittal trunk flexion (70 degrees ). Two-way repeated measures ANOVAs detected significant interactions of posture*step for the second peak of the vertical ground reaction force (GRF), propulsive impulse, contact time and velocity. An increased trunk flexion was associated with a systematic decrease of the second GRF peak during all steps and with a decreased contact time and an increased velocity across steps, except for the perturbation step. Pre-adaptations were more pronounced in the approach step to the drop in regular erect gait. With increased trunk flexion, walking on uneven ground exhibited reduced changes in GRF kinetic parameters relative to upright walking. It seems that in trunk-flexed gaits the trunk is used in a compensatory way during the step-down to accommodate changes in ground level by adjusting its angle leading to lower variations in centre of mass height. Exploitation of this mechanism resembles the ability of small birds in adjusting their zig-zag-like configured legs to cope with changes in ground level. PMID- 28559424 TI - C-X-C Motif Chemokine Receptor 3 Splice Variants Differentially Activate Beta Arrestins to Regulate Downstream Signaling Pathways. AB - Biased agonism, the ability of different ligands for the same receptor to selectively activate some signaling pathways while blocking others, is now an established paradigm for G protein-coupled receptor signaling. One group of receptors in which endogenous bias is critical is the chemokine system, consisting of over 50 ligands and 20 receptors that bind one another with significant promiscuity. We have previously demonstrated that ligands for the same receptor can cause biased signaling responses. The goal of this study was to identify mechanisms that could underlie biased signaling between different receptor splice variants. The C-X-C motif chemokine receptor 3 (CXCR3) has two splice variants, CXCR3A and CXCR3B, which differ by 51 amino acids at its N terminus. Consistent with an earlier study, we found that C-X-C motif chemokine ligands 4, 9, 10, and 11 all activated G alphai at CXCR3A, while at CXCR3B these ligands demonstrated no measurable G alphai or G alphas activity. beta-arrestin (betaarr) was recruited at a reduced level to CXCR3B relative to CXCR3A, which was also associated with differences in betaarr2 conformation. betaarr2 recruitment to CXCR3A was attenuated by both G protein receptor kinase (GRK) 2/3 and GRK5/6 knockdown, while only GRK2/3 knockdown blunted recruitment to CXCR3B. Extracellular regulated kinase 1/2 phosphorylation downstream from CXCR3A and CXCR3B was increased and decreased, respectively, by betaarr1/2 knockout. The splice variants also differentially activated transcriptional reporters. These findings demonstrate that differential splicing of CXCR3 results in biased responses associated with distinct patterns of betaarr conformation and recruitment. Differential splicing may serve as a common mechanism for generating biased signaling and provides insights into how chemokine receptor signaling can be modulated post-transcriptionally. PMID- 28559429 TI - RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner. AB - Despite intensive investigations, mechanisms of liver cancer are not known. Here, we identified an important step of liver cancer, which is the neutralization of tumor suppressor activities of an RNA binding protein, CUGBP1. The translational activity of CUGBP1 is activated by dephosphorylation at Ser302. We generated CUGBP1-S302A knock-in mice and found that the reduction of translational activity of CUGBP1 causes development of a fatty liver phenotype in young S302A mice. Examination of liver cancer in diethylnitrosamine (DEN)-treated CUGBP1-S302A mice showed these mice develop much more severe liver cancer that is associated with elimination of the mutant CUGBP1. Searching for mechanisms of this elimination, we found that the oncoprotein gankyrin (Gank) preferentially binds to and triggers degradation of dephosphorylated CUGBP1 (de-ph-S302-CUGBP1) or S302A mutant CUGBP1. To test the role of Gank in degradation of CUGBP1, we generated mice with liver-specific deletion of Gank. In these mice, the tumor suppressor isoform of CUGBP1 is protected from Gank-mediated degradation. Consistent with reduction of CUGBP1 in animal models, CUGBP1 is reduced in patients with pediatric liver cancer. Thus, this work presents evidence that de-ph-S302-CUGBP1 is a tumor suppressor protein and that the Gank-UPS-mediated reduction of CUGBP1 is a key event in the development of liver cancer. PMID- 28559428 TI - Bypass of Activation Loop Phosphorylation by Aspartate 836 in Activation of the Endoribonuclease Activity of Ire1. AB - The bifunctional protein kinase-endoribonuclease Ire1 initiates splicing of the mRNA for the transcription factor Hac1 when unfolded proteins accumulate in the endoplasmic reticulum. Activation of Saccharomyces cerevisiae Ire1 coincides with autophosphorylation of its activation loop at S840, S841, T844, and S850. Mass spectrometric analysis of Ire1 expressed in Escherichia coli identified S837 as another potential phosphorylation site in vivo Mutation of all five potential phosphorylation sites in the activation loop decreased, but did not completely abolish, splicing of HAC1 mRNA, induction of KAR2 and PDI1 mRNAs, and expression of a beta-galactosidase reporter activated by Hac1i Phosphorylation site mutants survive low levels of endoplasmic reticulum stress better than IRE1 deletions strains. In vivo clustering and inactivation of Ire1 are not affected by phosphorylation site mutants. Mutation of D836 to alanine in the activation loop of phosphorylation site mutants nearly completely abolished HAC1 splicing, induction of KAR2, PDI1, and beta-galactosidase reporters, and survival of ER stress, but it had no effect on clustering of Ire1. By itself, the D836A mutation does not confer a phenotype. These data argue that D836 can partially substitute for activation loop phosphorylation in activation of the endoribonuclease domain of Ire1. PMID- 28559430 TI - Acetylation of Cavin-1 Promotes Lipolysis in White Adipose Tissue. AB - White adipose tissue (WAT) serves as a reversible energy storage depot in the form of lipids in response to nutritional status. Cavin-1, an essential component in the biogenesis of caveolae, is a positive regulator of lipolysis in adipocytes. However, molecular mechanisms of cavin-1 in the modulation of lipolysis remain poorly understood. Here, we showed that cavin-1 was acetylated at lysines 291, 293, and 298 (3K), which were under nutritional regulation in WAT. We further identified GCN5 as the acetyltransferase and Sirt1 as the deacetylase of cavin-1. Acetylation-mimetic 3Q mutants of cavin-1 augmented fat mobilization in 3T3-L1 adipocytes and zebrafish. Mechanistically, acetylated cavin-1 preferentially interacted with hormone-sensitive lipase and recruited it to the caveolae, thereby promoting lipolysis. Our findings shed light on the essential role of cavin-1 in regulating lipolysis in an acetylation-dependent manner in WAT. PMID- 28559433 TI - News Feature: Is theory about peopling of the Americas a bridge too far? PMID- 28559431 TI - DNA polymerase beta participates in mitochondrial DNA repair. AB - We have detected DNA polymerase beta (Polbeta), known as a key nuclear base excision repair (BER) protein, in mitochondrial protein extracts derived from mammalian tissue and cells. Manipulation of the N-terminal sequence affected the amount of Polbeta in the mitochondria. Using Polbeta fragments, mitochondrial specific protein partners were identified, with the interactors mainly functioning in DNA maintenance and mitochondrial import. Of particular interest was the identification of the proteins TWINKLE, SSBP1 and TFAM, all of which are mitochondria specific DNA effectors and are known to function in the nucleoid. Polbeta directly interacted with, and influenced the activity of, the mitochondrial helicase TWINKLE. Human kidney cells with Polbeta knock-out (KO) had higher endogenous mtDNA damage. Mitochondrial extracts derived from heterozygous Polbeta mouse tissue and KO cells had lower nucleotide incorporation activity. Mouse derived Polbeta null fibroblasts had severely affected metabolic parameters. Indeed, gene knockout of Polbeta caused mitochondrial dysfunction including reduced membrane potential and mitochondrial content. We show that Polbeta is a mitochondrial polymerase involved in mtDNA maintenance and is required for mitochondrial homeostasis. PMID- 28559435 TI - Taking distrust of science seriously: To overcome public distrust in science, scientists need to stop pretending that there is a scientific consensus on controversial issues when there is not. PMID- 28559436 TI - Hepatic FGF21 mediates sex differences in high-fat high-fructose diet-induced fatty liver. AB - The role of gender in the progression of fatty liver due to chronic high-fat high fructose diet (HFFD) has not been studied. The present investigation assessed whether HFFD induced hepatic perturbations differently between the sexes and examined the potential mechanisms. Male, female, and ovariectomized (OVX) Sprague Dawley rats were fed either a control diet or HFFD for 12 wk. Indexes of liver damage and hepatic steatosis were analyzed biochemically and histologically together with monitoring changes in hepatic gene and protein expression. HFFD induced a higher degree of hepatic steatosis in females, with significant increases in proteins involved in hepatic lipogenesis, whereas HFFD significantly induced liver injury, inflammation, and oxidative stress only in males. Interestingly, a significant increase in hepatic fibroblast growth factor 21 (FGF21) protein expression was observed in HFFD-fed males but not in HFFD-fed females. Ovarian hormone deprivation by itself led to a significant reduction in FGF21 with hepatic steatosis, and HFFD further aggravated hepatic fat accumulation in OVX rats. Importantly, estrogen replacement restored hepatic FGF21 levels and reduced hepatic steatosis in HFFD-fed OVX rats. Collectively, our results indicate that male rats are more susceptible to HFFD-induced hepatic inflammation and that the mechanism underlying this sex dimorphism is mediated through hepatic FGF21 expression. Our findings reveal sex differences in the development of HFFD-induced fatty liver and indicate the protective role of estrogen against HFFD-induced hepatic steatosis. PMID- 28559438 TI - Article-level assessment of influence and translation in biomedical research. AB - Given the vast scale of the modern scientific enterprise, it can be difficult for scientists to make judgments about the work of others through careful analysis of the entirety of the relevant literature. This has led to a reliance on metrics that are mathematically flawed and insufficiently diverse to account for the variety of ways in which investigators contribute to scientific progress. An urgent, critical first step in solving this problem is replacing the Journal Impact Factor with an article-level alternative. The Relative Citation Ratio (RCR), a metric that was designed to serve in that capacity, measures the influence of each publication on its respective area of research. RCR can serve as one component of a multifaceted metric that provides an effective data-driven supplement to expert opinion. Developing validated methods that quantify scientific progress can help to optimize the management of research investments and accelerate the acquisition of knowledge that improves human health. PMID- 28559439 TI - Stem cells: the new "model organism". AB - Human tissue culture cells have long been a staple of molecular and cell biology research. However, although these cells are derived from humans, they have often lost considerable aspects of natural physiological function. Here we argue that combined advances in genome editing, stem cell production, and organoid derivation from stem cells represent a revolution in cell biology. These advances have important ramifications for the study of basic cell biology mechanisms, as well as for the ways in which discoveries in mechanisms are translated into understanding of disease. PMID- 28559437 TI - Fibroblast growth factor 21: a regulator of metabolic disease and health span. AB - Fibroblast growth factor 21 (FGF21) is a potent endocrine regulator with physiological effects on glucose and lipid metabolism and thus garners much attention for its translational potential for the management of obesity and related metabolic syndromes. FGF21 is mainly expressed in several metabolically active tissue organs, such as the liver, adipose tissue, skeletal muscle, and pancreas, with profound effects and therapeutic relevance. Emerging experimental and clinical data point to the demonstrated metabolic benefits of FGF21, which include, but are not limited to, weight loss, glucose and lipid metabolism, and insulin sensitivity. In addition, FGF21 also acts directly through its coreceptor beta-klotho in the brain to alter light-dark cycle activity. In this review, we critically appraise current advances in understanding the physiological actions of FGF21 and its role as a biomarker of various metabolic diseases, especially type 2 diabetes mellitus. We also discuss the potentially exciting role of FGF21 in improving our health and prolonging our life span. This information will provide a fuller understanding for further research into FGF21, as well as providing a scientific basis for potentially establishing health care guidelines for this promising molecule. PMID- 28559440 TI - Bitter taste receptors as targets for tocolytics in preterm labor therapy. AB - Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity, with few prevention and treatment options. Uterine contraction is a central feature of PTB, so gaining new insights into the mechanisms of this contraction and consequently identifying novel targets for tocolytics are essential for more successful management of PTB. Here we report that myometrial cells from human and mouse express bitter taste receptors (TAS2Rs) and their canonical signaling components (i.e., G-protein gustducin and phospholipase C beta2). Bitter tastants can completely relax myometrium precontracted by different uterotonics. In isolated single mouse myometrial cells, a phenotypical bitter tastant (chloroquine, ChQ) reverses the rise in intracellular Ca2+ concentration ([Ca2+]i) and cell shortening induced by uterotonics, and this reversal effect is inhibited by pertussis toxin and by genetic deletion of alpha-gustducin. In human myometrial cells, knockdown of TAS2R14 but not TAS2R10 inhibits ChQ's reversal effect on an oxytocin-induced rise in [Ca2+]i Finally, ChQ prevents mouse PTBs induced by bacterial endotoxin LPS or progesterone receptor antagonist mifepristone more often than current commonly used tocolytics, and this prevention is largely lost in alpha-gustducin-knockout mice. Collectively, our results reveal that activation of the canonical TAS2R signaling system in myometrial cells produces profound relaxation of myometrium precontracted by a broad spectrum of contractile agonists, and that targeting TAS2Rs is an attractive approach to developing effective tocolytics for PTB management.-Zheng, K., Lu, P., Delpapa, E., Bellve, K., Deng, R., Condon, J. C., Fogarty, K., Lifshitz, L. M., Simas, T. A. M., Shi, F., ZhuGe, R. Bitter taste receptors as targets for tocolytics in preterm labor therapy. PMID- 28559441 TI - APMAP interacts with lysyl oxidase-like proteins, and disruption of Apmap leads to beneficial visceral adipose tissue expansion. AB - Adipocyte plasma membrane-associated protein (APMAP) has been described as an adipogenic factor in 3T3-L1 cells with unknown biochemical function; we therefore aimed to investigate the physiologic function of APMAP in vivo We generated Apmap knockout mice and challenged them with an obesogenic diet to investigate their metabolic phenotype. We identified a novel truncated adipocyte-specific isoform of APMAP in mice that is produced by alternative transcription. Mice lacking the full-length APMAP protein, the only isoform that is expressed in humans, have an improved metabolic phenotype upon diet-induced obesity, indicated by enhanced insulin sensitivity, preserved glucose tolerance, increased respiratory exchange ratio, decreased inflammatory marker gene expression, and reduced adipocyte size. At the molecular level, APMAP interacts with the extracellular collagen cross linking matrix proteins lysyl oxidase-like 1 and 3. On a high-fat diet, the expression of lysyl oxidase-like 1 and 3 is strongly decreased in Apmap-knockout mice, paralleled by reduced expression of profibrotic collagens and total collagen content in epididymal white adipose tissue, indicating decreased fibrotic potential. Together, our data suggest that APMAP is a novel regulator of extracellular matrix components, and establish that APMAP is a potential target to mitigate obesity-associated insulin resistance.-Pessentheiner, A. R., Huber, K., Pelzmann, H. J., Prokesch, A., Radner, F. P. W., Wolinski, H., Lindroos Christensen, J., Hoefler, G., Rulicke, T., Birner-Gruenberger, R., Bilban, M., Bogner-Strauss, J. G. APMAP interacts with lysyl oxidase-like proteins, and disruption of Apmap leads to beneficial visceral adipose tissue expansion. PMID- 28559443 TI - Colorectal cancer-initiating cells caught in the act. PMID- 28559442 TI - CXCL12alpha/SDF-1 from perisynaptic Schwann cells promotes regeneration of injured motor axon terminals. AB - The neuromuscular junction has retained through evolution the capacity to regenerate after damage, but little is known on the inter-cellular signals involved in its functional recovery from trauma, autoimmune attacks, or neurotoxins. We report here that CXCL12alpha, also abbreviated as stromal-derived factor-1 (SDF-1), is produced specifically by perisynaptic Schwann cells following motor axon terminal degeneration induced by alpha-latrotoxin. CXCL12alpha acts via binding to the neuronal CXCR4 receptor. A CXCL12alpha neutralizing antibody or a specific CXCR4 inhibitor strongly delays recovery from motor neuron degeneration in vivo Recombinant CXCL12alpha in vivo accelerates neurotransmission rescue upon damage and very effectively stimulates the axon growth of spinal cord motor neurons in vitro These findings indicate that the CXCL12alpha-CXCR4 axis plays an important role in the regeneration of the neuromuscular junction after motor axon injury. The present results have important implications in the effort to find therapeutics and protocols to improve recovery of function after different forms of motor axon terminal damage. PMID- 28559445 TI - Erratum for the Research Article: "The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response" by T. Okazaki, M. Higuchi, K. Takeda, K. Iwatsuki-Horimoto, M. Kiso, M. Miyagishi, H. Yanai, A. Kato, M. Yoneyama, T. Fujita, T. Taniguchi, Y. Kawaoka, H. Ichijo, Y. Gotoh. PMID- 28559444 TI - T-plastin is essential for basement membrane assembly and epidermal morphogenesis. AB - The establishment of epithelial architecture is a complex process involving cross talk between cells and the basement membrane. Basement membrane assembly requires integrin activity but the role of the associated actomyosin cytoskeleton is poorly understood. Here, we identify the actin-bundling protein T-plastin (Pls3) as a regulator of basement membrane assembly and epidermal morphogenesis. In utero depletion of Pls3 transcripts in mouse embryos caused basement membrane and polarity defects in the epidermis but had little effect on cell adhesion and differentiation. Loss-of-function experiments demonstrated that the apicobasal polarity defects were secondary to the disruption of the basement membrane. However, the basement membrane itself was profoundly sensitive to subtle perturbations in the actin cytoskeleton. We further show that Pls3 localized to the cell cortex, where it was essential for the localization and activation of myosin II. Inhibition of myosin II motor activity disrupted basement membrane organization. Our results provide insights into the regulation of cortical actomyosin and its importance for basement membrane assembly and skin morphogenesis. PMID- 28559449 TI - A little stress is good. AB - Acute psychological stress triggers signaling between sympathetic neurons and the spleen to protect against ischemic tissue damage. PMID- 28559450 TI - New connections: Manipulating NK cell responses. AB - Manipulating ligand interactions with the activating receptor NKG2D modulates natural killer cell responses. PMID- 28559451 TI - A disease-linked ULBP6 polymorphism inhibits NKG2D-mediated target cell killing by enhancing the stability of NKG2D ligand binding. AB - NKG2D (natural killer group 2, member D) is an activating receptor found on the surface of immune cells, including natural killer (NK) cells, which regulates innate and adaptive immunity through recognition of the stress-induced ligands ULBP1 (UL16 binding protein 1) to ULBP6 and MICA/B. Similar to class I human leukocyte antigen (HLA), these NKG2D ligands have a major histocompatibility complex-like fold and exhibit pronounced polymorphism, which influences human disease susceptibility. However, whereas class I HLA polymorphisms occur predominantly in the alpha1alpha2 groove and affect antigen binding, the effects of most NKG2D ligand polymorphisms are unclear. We studied the molecular and functional consequences of the two major alleles of ULBP6, the most polymorphic ULBP gene, which are associated with autoimmunity and relapse after stem cell transplantation. Surface plasmon resonance and crystallography studies revealed that the arginine-to-leucine polymorphism within ULBP0602 affected the NKG2D ULBP6 interaction by generating an energetic hotspot. This resulted in an NKG2D ULBP0602 affinity of 15.5 nM, which is 10- to 1000-fold greater than the affinities of other ULBP-NKG2D interactions and limited NKG2D-mediated activation. In addition, soluble ULBP0602 exhibited high-affinity competitive binding for NKG2D and partially suppressed NKG2D-mediated activation of NK cells by other NKG2D ligands. These effects resulted in a decrease in a range of NKG2D mediated effector functions. Our results reveal that ULBP polymorphisms affect the strength of human lymphocyte responses to cellular stress signals and may offer opportunities for therapeutic intervention. PMID- 28559452 TI - Noise exposure and auditory thresholds of German airline pilots: a cross sectional study. AB - OBJECTIVE: The cockpit workplace of airline pilots is a noisy environment. This study examines the hearing thresholds of pilots with respect to ambient noise and communication sound. METHODS: The hearing of 487 German pilots was analysed by audiometry in the frequency range of 125 Hz-16 kHz in varying age groups. Cockpit noise (free-field) data and communication sound (acoustic manikin) measurements were evaluated. RESULTS: The ambient noise levels in cockpits were found to be between 74 and 80 dB(A), and the sound pressure levels under the headset were found to be between 84 and 88 dB(A).The left-right threshold differences at 3, 4 and 6 kHz show evidence of impaired hearing at the left ear, which worsens by age.In the age groups <40/>=40 years the mean differences at 3 kHz are 2/3 dB, at 4 kHz 2/4 dB and at 6 kHz 1/6 dB.In the pilot group which used mostly the left ear for communication tasks (43 of 45 are in the older age group) the mean difference at 3 kHz is 6 dB, at 4 kHz 7 dB and at 6 kHz 10 dB. The pilots who used the headset only at the right ear also show worse hearing at the left ear of 2 dB at 3 kHz, 3 dB at 4 kHz and at 6 kHz. The frequency-corrected exposure levels under the headset are 7-11 dB(A) higher than the ambient noise with an averaged signal-to-noise ratio for communication of about 10 dB(A). CONCLUSIONS: The left ear seems to be more susceptible to hearing loss than the right ear. Active noise reduction systems allow for a reduced sound level for the communication signal below the upper exposure action value of 85 dB(A) and allow for a more relaxed working environment for pilots. PMID- 28559453 TI - Developing a framework for community-based sexual health interventions for youth in the rural setting: protocol for a participatory action research study. AB - INTRODUCTION: There is limited research examining community-based or multilevel interventions that address the sexual health of young people in the rural Australian context. This paper describes the Participatory Action Research (PAR) project that will develop and validate a framework that is effective for planning, implementing and evaluating multilevel community-based sexual health interventions for young people aged 16-24 years in the Australian rural setting. METHODS AND ANALYSIS: To develop a framework for sexual health interventions with stakeholders, PAR will be used. Three PAR cycles will be conducted, using semistructured one-on-one interviews, focus groups, community mapping and photovoice to inform the development of a draft framework. Cycle 2 and Cycle 3 will use targeted Delphi studies to gather evaluation and feedback on the developed draft framework. All data collected will be reviewed and analysed in detail and coded as concepts become apparent at each stage of the process. ETHICS AND DISSEMINATION: This protocol describes a supervised doctoral research project. This project seeks to contribute to the literature regarding PAR in the rural setting and the use of the Delphi technique within PAR projects. The developed framework as a result of the project will provide a foundation for further research testing the application of the framework in other settings and health areas. This research has received ethics approval from the Curtin University Human Research and Ethics Committee (HR96/2015). PMID- 28559454 TI - Patient-reported safety incidents in older patients with long-term conditions: a large cross-sectional study. AB - BACKGROUND: Increasing evidence suggests that patient safety is a serious concern for older patients with long-term conditions. Despite this, there is a lack of research on safety incidents encountered by this patient group. In this study, we sought to examine patient reports of safety incidents and factors associated with reports of safety incidents in older patients with long-term conditions. METHODS: The baseline cross-sectional data from a longitudinal cohort study were analysed. Older patients (n=3378 aged 65 years and over) with a long-term condition registered in general practices were included in the study. The main outcome was patient-reported safety incidents including availability and appropriateness of medical tests and prescription of wrong types or doses of medication. Binary univariate and multivariate logistic regression analyses were undertaken to examine factors associated with patient-reported safety incidents. RESULTS: Safety incidents were reported by 11% of the patients. Four factors were significantly associated with patient-reported safety incidents in multivariate analyses. The experience of multiple long-term conditions (OR=1.09, 95% CI 1.05 to 1.13), a probable diagnosis of depression (OR=1.36, 95% CI 1.06 to 1.74) and greater relational continuity of care (OR=1.28, 95% CI 1.08 to 1.52) were associated with increased odds for patient-reported safety incidents. Perceived greater support and involvement in self-management was associated with lower odds for patient-reported safety incidents (OR=0.95, 95% CI 0.93 to 0.97). CONCLUSIONS: We found that older patients with multimorbidity and depression are more likely to report experiences of patient safety incidents. Improving perceived support and involvement of patients in their care may help prevent patient-reported safety incidents. PMID- 28559455 TI - Association between childcare educators' practices and preschoolers' physical activity and dietary intake: a cross-sectional analysis. AB - INTRODUCTION: Childcare educators may be role models for healthy eating and physical activity (PA) behaviours among young children. This study aimed to identify which childcare educators' practices are associated with preschoolers' dietary intake and PA levels. METHODS: This cross-sectional analysis included 723 preschoolers from 50 randomly selected childcare centres in two Canadian provinces. All data were collected in the fall of 2013 and 2014 and analysed in the fall of 2015. PA was assessed using Actical accelerometers during childcare hours for 5 consecutive days. Children's dietary intake was measured at lunch on 2 consecutive days using weighed plate waste and digital photography. Childcare educators' nutrition practices (modelling, nutrition education, satiety recognition, verbal encouragement and not using food as rewards) and PA practices (informal and formal PA promotion) were assessed by direct observation over the course of 2 days, using the Nutrition and Physical Activity Self-Assessment for Child Care tool. Associations between educators' practices and preschoolers' PA and dietary intake were examined using multilevel linear regressions. RESULTS: Overall, modelling of healthy eating was positively associated with children's intake of sugar (beta=0.141, 95% CI 0.03 to 0.27), while calorie (beta=-0.456, 95% CI -1.46 to -0.02) and fibre intake (beta=-0.066, 95% CI -0.12 to -0.01) were negatively associated with providing nutrition education. Not using food as rewards was also negatively associated with fat intake (beta=-0.144, 95% CI -0.52 to -0.002). None of the educators' PA practices were associated with children's participation in PA. CONCLUSIONS: Modelling healthy eating, providing nutrition education and not using food as rewards are associated with children's dietary intake at lunch in childcare centres, highlighting the role that educators play in shaping preschoolers' eating behaviours. Although PA practices were not associated with children's PA levels, there is a need to reduce sedentary time in childcare centres. PMID- 28559456 TI - Can exercise suppress tumour growth in advanced prostate cancer patients with sclerotic bone metastases? A randomised, controlled study protocol examining feasibility, safety and efficacy. AB - INTRODUCTION: Exercise may positively alter tumour biology through numerous modulatory and regulatory mechanisms in response to a variety of modes and dosages, evidenced in preclinical models to date. Specifically, localised and systemic biochemical alterations produced during and following exercise may suppress tumour formation, growth and distribution by virtue of altered epigenetics and endocrine-paracrine activity. Given the impressive ability of targeted mechanical loading to interfere with metastasis-driven tumour formation in human osteolytic tumour cells, it is of equal interest to determine whether a similar effect is observed in sclerotic tumour cells. The study aims to (1) establish the feasibility and safety of a combined modular multimodal exercise programme with spinal isometric training in advanced prostate cancer patients with sclerotic bone metastases and (2) examine whether targeted and supervised exercise can suppress sclerotic tumour growth and activity in spinal metastases in humans. METHODS AND ANALYSIS: A single-blinded, two-armed, randomised, controlled and explorative phase I clinical trial combining spinal isometric training with a modular multimodal exercise programme in 40 men with advanced prostate cancer and stable sclerotic spinal metastases. Participants will be randomly assigned to (1) the exercise intervention or (2) usual medical care. The intervention arm will receive a 3-month, supervised and individually tailored modular multimodal exercise programme with spinal isometric training. Primary endpoints (feasibility and safety) and secondary endpoints (tumour morphology; biomarker activity; anthropometry; musculoskeletal health; adiposity; physical function; quality of life; anxiety; distress; fatigue; insomnia; physical activity levels) will be measured at baseline and following the intervention. Statistical analyses will include descriptive characteristics, t-tests, effect sizes and two-way (group * time) repeated-measures analysis of variance (or analysis of covariance) to examine differences between groups over time. The data set will be primarily examined using an intention-to-treat approach with multiple imputations, followed by a secondary sensitivity analysis to ensure data robustness using a complete cases approach. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Human Research Ethics Committee (HREC) of Edith Cowan University and the Sir Charles Gairdner and Osborne Park Health Care Group. If proven to be feasible and safe, this study will form the basis of future phase II and III trials in human patients with advanced cancer. To reach a maximum number of clinicians, practitioners, patients and scientists, outcomes will be disseminated through national and international clinical, conference and patient presentations, as well as publication in high-impact, peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: ACTRN 12616000179437. PMID- 28559457 TI - Violent injury predicts poor psychological outcomes after traumatic injury in a hard-to-reach population: an observational cohort study. AB - BACKGROUND: People who experience physical trauma face a range of psychosocial outcomes. These may be overlooked by busy clinicians. While some risk factors are understood, understanding of the psychological effects of violent injury remains limited, particularly in UK settings. This study compared psychological outcomes following interpersonal violence and accidental injury, including the persistence of psychological distress. METHODS: A questionnaire survey was carried out at two time points of patients admitted to a large teaching hospital in London between July 2012 and April 2014. Participants were consecutive adult patients admitted to the Royal London Hospital with traumatic injuries, with 219 participants at baseline. Follow-up survey was 8 months later (n=109). Standardised measures assessed post-traumatic stress symptoms (PTSS) (Acute Stress Disorder Scale and PTSD Checklist) and depressive symptoms (Hospital Anxiety and Depression Scale). RESULTS: PTSS and depressive symptoms affected 27% and 33%, respectively, at baseline. At 8 months, 27% and 31% reported these symptoms for PTSS and depressive symptoms, respectively. The repeated measures were assessed with multilevel models: after adjusting for demographic factors, patients with violent injury showed more PTSS (OR 6.27, 95% CI 1.90 to 20.66) and depressive symptoms (OR 3.12, 95% CI 1.08 to 8.99). CONCLUSIONS: There were high levels of psychological distress among traumatic injury patients. Violent injuries were associated with an increased risk of both post-traumatic and depressive symptoms. People vulnerable to distress would benefit from psychological support, and hospital admission provides a unique opportunity to engage hard-to-reach groups in interventions. PMID- 28559459 TI - Tamoxifen Acceptance and Adherence among Patients with Ductal Carcinoma In Situ (DCIS) Treated in a Multidisciplinary Setting. AB - Tamoxifen and other endocrine agents have proven benefits for women with ductal carcinoma in situ (DCIS), but low patient acceptance is widely reported. We examined factors associated with tamoxifen acceptance and adherence among DCIS patients who received a recommendation for therapy in a multidisciplinary setting. Using our institutional database, we identified women diagnosed with DCIS, 1998 to 2009, who were offered tamoxifen. We recorded data on demographics, tumor and therapy variables, tamoxifen acceptance, and adherence to therapy for >=4 years. Univariable and multivariable analyses were conducted using logistic regression to identify factors specific to each group that were related to acceptance and adherence. A total of 555 eligible women identified, of whom 369 were offered tamoxifen; 298 (81%) accepted, among whom 214 (72%) were adherent, 59 of 298 (20%) were nonadherent, and for 25 (8%), adherence was undetermined. After stepwise elimination in adjusted logistic regression models, acceptance of breast radiotherapy was associated with acceptance of tamoxifen [OR, 2.22; 95% confidence interval (CI), 1.26-3.90; P < 0.01], as was a medical oncology consultation (OR, 1.76; 95% CI, 0.99-3.15; P = 0.05). Insured patients were more likely to adhere to tamoxifen (OR, 6.03; 95% CI, 2.60-13.98; P < 0.01). The majority of nonadherent women (n = 38/56, 68%) discontinued the drug during the first year of treatment with 48 (86%) citing adverse effect(s) as the reason. In a multidisciplinary, tertiary care setting, we observed relatively high rates of acceptance and adherence of tamoxifen. Acceptance of tamoxifen and radiotherapy were associated, and adherence was influenced by insurance status.Key Message: Tamoxifen acceptance and adherence following resection of DCIS of the breast is related to acceptance of radiotherapy and may be improved by confirmation of the recommendation by a medical oncologist. Despite the low cost of tamoxifen, adherence to therapy is significantly impacted by lack of insurance; those who discontinue therapy report adverse effects as a major reason. Cancer Prev Res; 10(7); 389-97. (c)2017 AACR. PMID- 28559458 TI - Towards an optimal composition of general practitioners and nurse practitioners in out-of-hours primary care teams: a quasi-experimental study. AB - OBJECTIVES: To gain insights into the ability of general practitioners (GPs) and nurse practitioners (NPs) to meet patient demands in out-of-hours primary care by comparing the outcomes of teams with different ratios of practitioners. DESIGN: Quasi-experimental study. SETTING: A GP cooperative (GPC) in the Netherlands. INTERVENTION: Team 2 (1 NP, 3 GPs) and team 3 (2 NPs, 2 GPs) were compared with team 1 (4 GPs). Each team covered 35 weekend days. PARTICIPANTS: All 9503 patients who were scheduled for a consultation at the GPC through a nurse triage system. OUTCOME MEASURES: The primary outcome was the total number of consultations per provider for weekend cover between 10:00 and 18:00 hours. Secondary outcomes concerned the numbers of patients outside the NPs' scope of practice, patient safety, resource use, direct healthcare costs and GPs' performance. RESULTS: The mean number of consultations per shift was lower in teams with NPs (team 1: 93.9, team 3: 87.1; p<0.001). The mean proportion of patients outside NPs' scope of practice per hour was 9.0% (SD 6.7), and the highest value in any hour was 40%. The proportion of patients who did not receive treatment within the targeted time period was higher in teams with NPs (team 2, 5.2%; team 3, 8.3%) compared with GPs only (team 1 3.5%) (p<0.01). Team 3 referred more patients to the emergency department (14.7%) compared with team 1 (12.0%; p=0.028). In teams with NPs, GPs more often treated urgent patients (team 1: 13.2%, team 2: 16.3%, team 3: 21.4%; p<0.01) and patients with digestive complaints (team 1: 11.1%, team 2: 11.8%, team 3: 16.7%; p<0.01). CONCLUSIONS: Primary healthcare teams with a ratio of up to two GPs and two NPs provided sufficient capacity to provide care to all patients during weekend cover. Areas of concern are the number of consultations, delay in patient care and referrals to the emergency department. TRIAL REGISTRATION: NCT02407847. PMID- 28559460 TI - Development of a Cancer Risk Prediction Tool for Use in the UK Primary Care and Community Settings. AB - Several multivariable risk prediction models have been developed to asses an individual's risk of developing specific cancers. Such models can be used in a variety of settings for prevention, screening, and guiding investigations and treatments. Models aimed at predicting future disease risk that contains lifestyle factors may be of particular use for targeting health promotion activities at an individual level. This type of cancer risk prediction is not yet available in the UK. We have adopted the approach used by the well-established U.S.-derived "YourCancerRisk" model for use in the UK population, which allow users to quantify their individual risk of developing individual cancers relative to the population average risk. The UK version of "YourCancerRisk" computes 10 year cancer risk estimates for 11 cancers utilizing UK figures for prevalence of risk factors and cancer incidence. Because the prevalence of risk factors and the incidence rates for cancer are different between the U.S. and the UK population, this UK model provides more accurate estimates of risks for a UK population. Using an example of breast cancer and data from UK Biobank cohort, we demonstrate that the individual risk factor estimates are similar for the U.S. and UK populations. Assessment of the performance and validation of the multivariate model predictions based on a binary score confirm the model's applicability. The model can be used to estimate absolute and relative cancer risk for use in Primary Care and community settings and is being used in the community to guide lifestyle change. Cancer Prev Res; 10(7); 421-30. (c)2017 AACR. PMID- 28559463 TI - Development and Testing of a Bubble Bi-Level Positive Airway Pressure System. AB - BACKGROUND: Neonatal respiratory distress results in > 1 million annual deaths worldwide. Bubble CPAP is a simple, effective, and widely used therapy for infants in respiratory distress. In low-resource settings, more advanced respiratory support is limited by cost, technical expertise, and sporadic electricity. We sought to develop a safe, inexpensive, and simple solution to provide further respiratory support for these infants. METHODS: A standard bubble CPAP system was modified to provide 2 levels of positive airway pressure (bi level positive airway pressure) by attaching a novel device. To demonstrate reliability, the system was run with continuous pressure monitoring on full-term and preterm neonatal mannikins with pressure targets of 8/5 cm H2O and 15/5 cm H2O to simulate 2 different modes of noninvasive ventilation (NIV). RESULTS: At a ventilation rate set between 30 and 45 cycles/min, by adjusting the leak rate of the device, the following mean pressures +/- SD were demonstrated: term mannikin low-pressure NIV, 7.9 +/- 0.2/5.3 +/- 0.2 cm H2O; term mannikin high-pressure NIV, 15.1 +/- 0.1/6.1 +/- 0.1 cm H2O; preterm mannikin low-pressure NIV, 7.9 +/- 0.2/5.3 +/- 0.2 cm H2O; preterm mannikin high-pressure NIV, 16.5 +/- 0.4/5.1 +/- 0.1 cm H2O. CONCLUSIONS: The modified bubble CPAP system reliably provided alternating pressures similar to bi-level positive airway pressure modes of respiratory support in neonatal mannikins. The dual-pressure technology is a simple, single connection add-on that can readily be applied to existing bubble CPAP systems. PMID- 28559462 TI - Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis. AB - Purpose: We determined whether quantifying neuroblastoma-associated mRNAs (NB mRNAs) in bone marrow and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory neuroblastoma.Experimental Design: mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in bone marrow and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold, DeltaCt, for the geometric mean of genes from the TaqMan Low Density Array NB5 assay) and morphologically defined tumor cell percentage in bone marrow, 123I-meta iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between DeltaCt and progression-free survival (PFS).Results: NB-mRNA was detectable in 83% of bone marrow (185/223) and 63% (89/142) of blood specimens, and their DeltaCt values were correlated (Spearman r = 0.67, P < 0.0001), although bone marrow Ct was 7.9 +/- 0.5 Ct stronger than blood Ct When bone marrow morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of bone marrow samples. When all three were negative, NB-mRNA was detected in 55% (11/20) of bone marrow samples. Bone marrow NB-mRNA correlated with bone marrow morphology or MIBG positivity (P < 0.0001 and P = 0.007). Bone marrow and blood DeltaCt values correlated with PFS (P < 0.001; P = 0.001) even when bone marrow was morphologically negative (P = 0.001; P = 0.014). Multivariate analysis showed that bone marrow and blood DeltaCt values were associated with PFS independently of clinical disease and MYCN gene status (P < 0.001; P = 0.055).Conclusions: This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory neuroblastoma. Clin Cancer Res; 23(18); 5374-83. (c)2017 AACR. PMID- 28559464 TI - Smoke, Biomass Exposure, and COPD Risk in the Primary Care Setting: The PUMA Study. AB - BACKGROUND: The evidence indicates that risk factors other than smoking are important in the development of COPD. It has been postulated that less traditional risk factors (eg, exposure to coal and/or biomass smoke) may interact with smoking to further increase COPD risk. This analysis evaluated the effect of exposure to biomass and smoking on COPD risk in a primary care setting in Latin America. METHODS: Subjects attending routine primary care visits, >=40 y old, who were current or former smokers or were exposed to biomass smoke, completed a questionnaire and performed spirometry. COPD was defined as post-bronchodilator FEV1/FVC < 0.70 and the lower limit of normal. Smoking was defined by pack-years (<= 20, 20-30, or > 30), and biomass exposure was defined as an exposure to coal or wood (for heating, cooking, or both) for >= 10 y. RESULTS: One thousand seven hundred forty-three individuals completed the questionnaire, and 1,540 performed spirometry. Irrespective of COPD definition, approximately 40% of COPD subjects reported exposure to biomass versus 30% of those without COPD. A higher proportion of COPD subjects (post-bronchodilator FEV1/FVC < 0.70) than those without COPD smoked > 30 pack-years (66% vs 39%); similar results were found with the lower limit of normal definition. Analysis of exposure to biomass > 10 y plus smoking > 20 pack-years (reference was no exposure) found that tobacco smoking (crude odds ratio [OR] 4.50, 95% CI 2.73-7.41; adjusted OR 3.30, 95% CI 1.93 5.63) and biomass exposure (crude OR 3.66, 95% CI 2.00-6.73; adjusted OR 2.28, 95% CI 1.18-4.41) were risk factors for COPD, with smoking a possible confounder for the association between biomass and COPD (post-bronchodilator FEV1/FVC < 0.70); similar results were found with the lower limit of normal definition. CONCLUSIONS: Subjects with COPD from primary care had a higher exposure to biomass and smoking compared with non-COPD subjects. Smoking and biomass are both risk factors for COPD, but they do not appear to have an additive effect. PMID- 28559461 TI - The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non-Small Cell Lung Cancer. AB - Purpose: Resistance to VEGFR inhibitors is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). We investigated the cellular mechanisms mediating resistance of NSCLCs to VEGFR tyrosine kinase inhibitors.Experimental Design: We generated murine models of human NSCLC and performed targeted inhibition studies with the VEGFR TKIs cediranib and vandetanib. We used species specific hybridization of microarrays to compare cancer (human) and stromal (mouse) cell transcriptomes of TKI-sensitive and -resistant tumors. We measured tumor microvascular density and vessel tortuosity to characterize the effects of therapy on the tumor vascular bed. Circulating cytokine and angiogenic factor levels in patients enrolled in VEGFR TKI trials were correlated with clinical outcomes.Results: Murine xenograft models of human lung adenocarcinoma were initially sensitive to VEGFR TKIs, but developed resistance to treatment. Species specific microarray analysis identified increased expression of stromal-derived hepatocyte growth factor (HGF) as a candidate mediator of TKI resistance and its receptor, c-MET, was activated in cancer cells and tumor-associated stroma. A transient increase in hypoxia-regulated molecules in the initial response phase was followed by adaptive changes resulting in a more tortuous vasculature. Forced HGF expression in cancer cells reduced tumor sensitivity to VEGFR TKIs and produced tumors with tortuous blood vessels. Dual VEGFR/c-MET signaling inhibition delayed the onset of the resistant phenotype and prevented the vascular morphology alterations. In patients with cancer receiving VEGFR TKIs, high pretreatment HGF plasma levels correlated with poorer survival.Conclusions: HGF/c-MET pathway mediates VEGFR inhibitor resistance and vascular remodeling in NSCLC. Clin Cancer Res; 23(18); 5489-501. (c)2017 AACR. PMID- 28559465 TI - Reducing Unplanned Extubations in the NICU Following Implementation of a Standardized Approach. AB - BACKGROUND: Unplanned extubations (UEs) have been associated with increased ventilator days, risk of infection, cardiopulmonary resuscitation, and resuscitation medication usage. The UE rate in our level 4 NICU is lower than the national average. Efforts to further reduce UE events at our institution led an interdisciplinary group to define steps to eliminate UEs. Steps included: (1) requiring at least 2 care providers at the bedside for movement of an intubated subject; (2) standardizing head and endotracheal tube (ETT) position; (3) defining a set methodology for ETT securing; (4) introducing a postoperative handoff to improve communication; and (5) implementing a post-UE assessment tool. METHODS: A quality improvement initiative reviewed subjects and compared UE rates before (January 2013 to December 2013) and after (January 2014 to December 2014) implementation of UE prevention guidelines. A de-identified data set was used for analysis. RESULTS: 67 UE events were identified with 46 UE events at baseline in 2013 compared with 21 in 2014 post-implementation. This amounted to a 64% decrease in total UE events (from 46 to 21) (P < .001). Additionally, monthly UE rates decreased 50% (from 3.8 to 1.9), and UE events per 100 ventilator days decreased 53% (from 1.15 to 0.54). CONCLUSIONS: The development of standard guidelines to prevent UE and a quality review process to track UE provided important information for education and practice change. In our NICU, these changes have significantly improved the UE rate through improved teamwork, accountability, and communication. PMID- 28559466 TI - Inhaled Drug Therapy 2016: The Year in Review. AB - Some recent salient publications related to inhaled drug therapy are discussed. Unexpectedly, a 2.5-MUg once-daily dose of tiotropium (Respimat) had greater efficacy than the 5.0-MUg daily dose. Occurrence of a reverse dose response serves to caution us that administering more drug is not always beneficial. Small airway inflammation contributes to pathogenesis of asthma, especially severe asthma. However, there is no conclusive evidence that the use of small-particle aerosols to target small airways improves clinical outcomes in controlled clinical trials. Clinical outcomes of patients with symptomatic asthma have been better in "real-life" studies when fine-particle aerosols were compared with conventional (large-particle) aerosols. In subjects with COPD, the FLAME study indicates that a long-acting antimuscarinic agent/long-acting beta-agonist combination was superior to an inhaled corticosteroid/long-acting beta-agonist combination in preventing exacerbations. Another study in children with asthma and adults with asthma or COPD showed that peak inhalation flow must be considered in the context of the dry powder inhaler resistance. Investigators from the United Kingdom have shown modest success in replacing the defective cystic fibrosis transmembrane regulator gene in subjects with cystic fibrosis with a plasmid encoding the normal cystic fibrosis transmembrane regulator gene packaged within a non-viral vector. Also, inhaled antibiotics in patients with non-cystic fibrosis bronchiectasis and inhaled interferon-gamma in patients with idiopathic pulmonary fibrosis have shown encouraging results but are investigational at this time. Compared to combustion cigarettes, use of e cigarettes reduces exposure to carcinogens and volatile organic compounds. However, high levels of benzaldehyde in the vapor from cherry-flavored cigarettes raise concerns about the safety of some food flavorings in e-cigarettes. PMID- 28559467 TI - Effect of ARDS Severity and Etiology on Short-Term Outcomes. AB - BACKGROUND: We evaluated the outcome of subjects with ARDS in relation to etiology and severity in a retrospective cohort study of the ARDS Network randomized controlled trials. The primary outcome was 28-d mortality. The secondary outcomes were 60-d mortality and ventilator- and ICU-free days. For severity of ARDS, subjects were stratified according to PaO2/FIO2. The etiology of ARDS was classified into sepsis, pneumonia, aspiration, trauma, and others. RESULTS: A total of 2,914 subjects were included in these trials. Outcomes were modeled with multivariable regressions adjusted for baseline covariates, age, sex, race, Acute Physiology and Chronic Health Evaluation III (APACHE III), vasopressor use, modified lung injury score, diabetes mellitus, cancer status, body mass index, pre-ICU location, ICU location, and study. There was no statistically significant difference in 28-d mortality in relation to ARDS severity. Subjects with trauma, compared with other etiologies of ARDS, had significantly lower mortality at 28 d (odds ratio [OR] = 0.47, 95% CI 0.26-0.83, P = .01). Sixty-day mortality was significantly lower for trauma subjects and those with severe ARDS group (OR = 0.5, 95% CI 0.3-0.85, P = .01 and OR = 0.71, 95% CI 0.52-0.98, P = .034, respectively). There were statistically significantly more ICU-free days and ventilator-free days for the aspiration group (OR = 1.09, 95% CI 1.02-1.17, P = .01 and OR = 1.09, 95% CI 1.02-1.16, P = .01, respectively). There was no statistically significant difference in ICU-free days or ventilator-free days in relation to severity of ARDS. CONCLUSIONS: Severity of ARDS based on PaO2/FIO2 did not impact 28-d mortality, ventilator-free days, or ICU-free days. Among the etiologies of ARDS, trauma subjects had the lowest 28- and 60-d mortality, whereas subjects with aspiration had more ICU-free days and ventilator-free days. PMID- 28559468 TI - Severity of Hypoxemia and Other Factors That Influence the Response to Aerosolized Prostacyclin in ARDS. AB - BACKGROUND: ARDS is characterized by decreased functional residual capacity (FRC), heterogeneous lung injury, and severe hypoxemia. Tidal ventilation is preferentially distributed to ventilated alveoli. Aerosolized prostaglandin I2 exploits this pathophysiology by inducing local vasodilation, thereby increasing ventilation-perfusion matching and reducing hypoxemia. Therefore, aerosolized prostaglandin I2 efficacy may depend upon FRC. Both PaO2 /FIO2 and compliance of the respiratory system (CRS) are indirect signifiers of FRC and thus may partly determine the response to aerosolized prostaglandin I2. METHODS: We reviewed the records of 208 ARDS subjects who received aerosolized prostaglandin I2 and had arterial blood gases done before and after the initiation of therapy, without other ventilator manipulations. Subjects were grouped according to baseline PaO2 /FIO2 (lowest: < 60, intermediate: 60-90, highest: > 90 mm Hg) and CRS (< 20, 20 29, 30-39, and >= 40 mL/cm H2O) and by other factors, such as sepsis. Comparisons were analyzed by paired t tests, or Kruskal-Wallis and Dunn post-tests. Multivariate logistic regression modeling was done to determine which of 18 clinically relevant factors were most predictive for responding to aerosolized prostaglandin I2. alpha was set at .05. RESULTS: Mean PaO2 /FIO2 increased by 33 mm Hg (42%) upon initiation of prostaglandin I2, with a responder rate of 62%. PaO2 /FIO2 increased significantly in all oxygenation groups. The highest baseline PaO2 /FIO2 group had the greatest improvement and responder rate (51 +/- 63 mm Hg, and 82%). In addition, those with sepsis had a smaller improvement in PaO2 /FIO2 compared with those without sepsis (18 +/- 35 vs 40 +/- 55 mm Hg, P = .002). Both PaO2 /FIO2 and responder rate increased as CRS improved, but between group improvements were not as consistent. In the final model, the only factors that predicted a positive response to aerosolized prostaglandin I2 were baseline PaO2 /FIO2 (odds ratio 1.10 [1.004-1.205], P = .042) and CRS (odds ratio 1.04 [1.01-1.08], P = .02). CONCLUSIONS: Aerosolized prostaglandin I2 improves oxygenation in approximately 60% of ARDS cases. A favorable response was most strongly associated with baseline PaO2 /FIO2 and CRS. PMID- 28559469 TI - Physiological Requirements to Perform the Glittre Activities of Daily Living Test by Subjects With Mild-to-Severe COPD. AB - BACKGROUND: The Glittre activities of daily living (ADL) test is supposed to evaluate the functional capacity of COPD patients. The physiological requirements of the test and the time taken to perform it by COPD patients in different disease stages are not well known. The objective of this work was to compare the metabolic, ventilatory, and cardiac requirements and the time taken to carry out the Glittre ADL test by COPD subjects with mild, moderate, and severe disease. METHODS: Spirometry, Medical Research Council questionnaire, cardiopulmonary exercise test, and 2 Glittre ADL tests were evaluated in 62 COPD subjects. Oxygen uptake (VO2 ), carbon dioxide production, pulmonary ventilation, breathing frequency, heart rate, SpO2 , and dyspnea were analyzed before and at the end of the tests. Maximum voluntary ventilation, Glittre peak VO2 /cardiopulmonary exercise test (CPET) peak VO2 , Glittre VE/maximum voluntary ventilation, and Glittre peak heart rate/CPET peak heart rate ratios were calculated to analyze their reserves. RESULTS: Subjects carried out the Glittre ADL test with similar absolute metabolic, ventilatory, and cardiac requirements. Ventilatory reserve decreased progressively from mild to severe COPD subjects (P < .001 for Global Initiative for Chronic Obstructive Lung Disease [GOLD] 1 vs GOLD 2, P < .001 for GOLD 1 vs GOLD 3, and P < .001 for GOLD 2 vs GOLD 3). Severe subjects with COPD presented a significantly lower metabolic reserve than the mild and moderate subjects (P = .006 and P = .043, respectively) and significantly lower Glittre peak heart rate/CPET peak heart rate than mild subjects (P = .01). Time taken to carry out the Glittre ADL test was similar among the groups (P = .82 for GOLD 1 vs GOLD 2, P = .19 for GOLD 1 vs GOLD 3, and P = .45 for GOLD 2 vs GOLD 3). CONCLUSIONS: As the degree of air-flow obstruction progresses, the COPD subjects present significant lower ventilatory reserve to perform the Glittre ADL test. In addition, metabolic and cardiac reserves may differentiate the severe subjects. These variables may be better measures to differentiate functional performance than Glittre ADL time. PMID- 28559470 TI - Flow Decay: A Novel Spirometric Index to Quantify Dynamic Airway Resistance. AB - BACKGROUND: Dynamic airway resistance from obstructive disease causes a concavity in the mid-expiratory portion of the spirometric flow-volume loop. We developed a simple model to measure the exponential decay in air flow during forced exhalation to quantify the extent of dynamic airway obstruction and facilitate the detection of obstructive airway diseases clinically. METHODS: We calculated flow decay as the slope of volume versus ln(1/flow) in mid-exhalation. We derived the normal range in a derivation group of healthy volunteers in whom spirometry had been performed repeatedly. We validated the derived upper limit of normal (mean + 2 * SD) by using it to distinguish a separate group of healthy subjects (n = 25) from subjects with independently diagnosed reversible airway obstruction (n = 31) and subjects with obstruction, hyperinflation, and air trapping (n = 62). RESULTS: In the derivation group (n = 7), the mean +/- SD flow decay was 0.588 +/- 0.107 L-1 (upper limit of normal = 0.802 L-1). Flow decay in 23 of 25 healthy subjects in the validation group was below the upper limit of normal. In contrast, it was above the upper limit of normal in 29 of 31 subjects with reversible airway obstruction (sensitivity 94%, 95% CI 79-99%; specificity 92%, 95% CI 74-99%) and in 59 of 62 of subjects with obstruction, hyperinflation, and air trapping (sensitivity 92%, 95% CI 74-99%; specificity 95%, 95% CI 86-99%). CONCLUSIONS: Flow decay distinguished subjects with obstructive lung defects from healthy subjects. It is a straightforward representation of spirometry data that provides a reproducible index to quantify dynamic airway obstruction. PMID- 28559471 TI - Gas Exchange in the Prone Posture. AB - The prone posture is known to have numerous effects on gas exchange, both under normal conditions and in patients with ARDS. Clinical studies have consistently demonstrated improvements in oxygenation, and a multi-center randomized trial found that, when implemented within 48 h of moderate-to-severe ARDS, placing subjects in the prone posture decreased mortality. Improvements in gas exchange occur via several mechanisms: alterations in the distribution of alveolar ventilation, redistribution of blood flow, improved matching of local ventilation and perfusion, and reduction in regions of low ventilation/perfusion ratios. Ventilation heterogeneity is reduced in the prone posture due to more uniform alveolar size secondary to a more uniform vertical pleural pressure gradient. The prone posture results in more uniform pulmonary blood flow when compared with the supine posture, due to an anatomical bias for greater blood flow to dorsal lung regions. Because both ventilation and perfusion heterogeneity decrease in the prone posture, gas exchange improves. Other benefits include a more uniform distribution of alveolar stress, relief of left-lower-lobe lung compression by the heart, enhanced secretion clearance, and favorable right-ventricular and systemic hemodynamics. PMID- 28559472 TI - Spermatogonial deubiquitinase USP9X is essential for proper spermatogenesis in mice. AB - USP9X (ubiquitin-specific peptidase 9, X chromosome) is the mammalian orthologue of Drosophila deubiquitinase fat facets that was previously shown to regulate the maintenance of the germ cell lineage partially through stabilizing Vasa, one of the widely conserved factors crucial for gametogenesis. Here, we demonstrate that USP9X is expressed in the gonocytes and spermatogonia in mouse testes from newborn to adult stages. By using Vasa-Cre mice, germ cell-specific conditional deletion of Usp9x from the embryonic stage showed no abnormality in the developing testes by 1 week and no appreciable defects in the undifferentiated and differentiating spermatogonia at postnatal and adult stages. Interestingly, after 2 weeks, Usp9x-null spermatogenic cells underwent apoptotic cell death at the early spermatocyte stage, and then, caused subsequent aberrant spermiogenesis, which resulted in a complete infertility of Usp9x conditional knockout male mice. These data provide the first evidence of the crucial role of the spermatogonial USP9X during transition from the mitotic to meiotic phases and/or maintenance of early meiotic phase in Usp9x conditional knockout testes. PMID- 28559473 TI - Prenatal exposure to paracetamol/acetaminophen and precursor aniline impairs masculinisation of male brain and behaviour. AB - Paracetamol/acetaminophen (N-Acetyl-p-Aminophenol; APAP) is the preferred analgesic for pain relief and fever during pregnancy. It has therefore caused concern that several studies have reported that prenatal exposure to APAP results in developmental alterations in both the reproductive tract and the brain. Genitals and nervous system of male mammals are actively masculinised during foetal development and early postnatal life by the combined actions of prostaglandins and androgens, resulting in the male-typical reproductive behaviour seen in adulthood. Both androgens and prostaglandins are known to be inhibited by APAP. Through intrauterine exposure experiments in C57BL/6 mice, we found that exposure to APAP decreased neuronal number in the sexually dimorphic nucleus (SDN) of the preoptic area (POA) in the anterior hypothalamus of male adult offspring. Likewise, exposure to the environmental pollutant and precursor of APAP, aniline, resulted in a similar reduction. Decrease in neuronal number in the SDN-POA is associated with reductions in male sexual behaviour. Consistent with the changes, male mice exposed in uteri to APAP exhibited changes in urinary marking behaviour as adults and had a less aggressive territorial display towards intruders of the same gender. Additionally, exposed males had reduced intromissions and ejaculations during mating with females in oestrus. Together, these data suggest that prenatal exposure to APAP may impair male sexual behaviour in adulthood by disrupting the sexual neurobehavioral programming. These findings add to the growing body of evidence suggesting the need to limit the widespread exposure and use of APAP by pregnant women. PMID- 28559474 TI - A low-fat diet enriched in fish oil increased lipogenesis and fetal outcome of C57BL/6 mice. AB - There is clear evidence that nutritional strategy employed during pregnancy has profound influence on the offspring health outcomes. However, the effect of the quality and the quantity of maternal fat intake on maternal metabolic profile during different stages of pregnancy and its impact on pregnancy sustainability is not known. Female C57BL/6 mice (7 weeks old) were fed diets varying in the quantity of fat (5% vs 11%) for two weeks prior to mating and throughout pregnancy. The 5% fat diet was enriched with longer chain omega (n)-3 polyunsaturated fatty acids (PUFA) from fish oil. Maternal plasma and tissues were collected before mating and during pregnancy at days 6.5, 12.5 and 18.5. Plasma lipids, glucose, insulin, progesterone and estradiol levels were measured. Cholesterol efflux capacity of maternal plasma as well as the mRNA expression of placental steroidogenic acute regulatory protein and hepatic lipogenic genes (acetyl-CoA carboxylase-1, fatty acid synthase, diacylglycerol acyltransferase-2 and stearoyl-CoA desaturase-1) was determined. Feto-placental weight and fetuses sustained throughout gestation were recorded. A low-fat maternal diet enriched with n-3 PUFA increased maternal plasma triacylglycerol and the mRNA expression of rate-limiting lipogenic enzymes, along with increasing cholesterol efflux capacity (P < 0.05), likely to meet fetal lipid demand during pregnancy. Furthermore, diet enriched with longer chain n-3 PUFA increased the maternal plasma concentration of progesterone and estradiol during pregnancy (P < 0.05), which coincides with an increase in the number of fetuses sustained till day 18.5. These novel findings may be important when designing dietary strategies to optimize reproductive capability and pregnancy outcomes. PMID- 28559475 TI - Interplay of Plasma Membrane and Vacuolar Ion Channels, Together with BAK1, Elicits Rapid Cytosolic Calcium Elevations in Arabidopsis during Aphid Feeding. AB - A transient rise in cytosolic calcium ion concentration is one of the main signals used by plants in perception of their environment. The role of calcium in the detection of abiotic stress is well documented; however, its role during biotic interactions remains unclear. Here, we use a fluorescent calcium biosensor (GCaMP3) in combination with the green peach aphid (Myzus persicae) as a tool to study Arabidopsis thaliana calcium dynamics in vivo and in real time during a live biotic interaction. We demonstrate rapid and highly localized plant calcium elevations around the feeding sites of M. persicae, and by monitoring aphid feeding behavior electrophysiologically, we demonstrate that these elevations correlate with aphid probing of epidermal and mesophyll cells. Furthermore, we dissect the molecular mechanisms involved, showing that interplay between the plant defense coreceptor BRASSINOSTEROID INSENSITIVE-ASSOCIATED KINASE1 (BAK1), the plasma membrane ion channels GLUTAMATE RECEPTOR-LIKE 3.3 and 3.6 (GLR3.3 and GLR3.6), and the vacuolar ion channel TWO-PORE CHANNEL1 (TPC1) mediate these calcium elevations. Consequently, we identify a link between plant perception of biotic threats by BAK1, cellular calcium entry mediated by GLRs, and intracellular calcium release by TPC1 during a biologically relevant interaction. PMID- 28559476 TI - Noncanonical Alternative Polyadenylation Contributes to Gene Regulation in Response to Hypoxia. AB - Stresses from various environmental challenges continually confront plants, and their responses are important for growth and survival. One molecular response to such challenges involves the alternative polyadenylation of mRNA. In plants, it is unclear how stress affects the production and fate of alternative mRNA isoforms. Using a genome-scale approach, we show that in Arabidopsis thaliana, hypoxia leads to increases in the number of mRNA isoforms with polyadenylated 3' ends that map to 5'-untranslated regions (UTRs), introns, and protein-coding regions. RNAs with 3' ends within protein-coding regions and introns were less stable than mRNAs that end at 3'-UTR poly(A) sites. Additionally, these RNA isoforms were underrepresented in polysomes isolated from control and hypoxic plants. By contrast, mRNA isoforms with 3' ends that lie within annotated 5'-UTRs were overrepresented in polysomes and were as stable as canonical mRNA isoforms. These results indicate that the generation of noncanonical mRNA isoforms is an important feature of the abiotic stress response. The finding that several noncanonical mRNA isoforms are relatively unstable suggests that the production of non-stop and intronic mRNA isoforms may represent a form of negative regulation in plants, providing a conceptual link with mechanisms that generate these isoforms (such as alternative polyadenylation) and RNA surveillance. PMID- 28559479 TI - Modeling Human Myocardium Exposure to Doxorubicin Defines the Risk of Heart Failure from Low-Dose Doxorubicin. AB - The antitumor anthracycline, doxorubicin (DOX), can cause heart failure (HF) upon cumulative administration. Lowering the cumulative dose of DOX proved useful to minimize HF risk, and, yet, there is a growing concern that HF might occur after doses that were thought to be safe. Clinical trials that prospectively address such concerns are lacking. Because HF risk correlates with cardiac exposure to DOX, cumulative doses associated with HF risk were re-explored by modeling the accumulation of anthracycline pools in human myocardium. Ex vivo myocardial samples were used in vitro to simulate DOX rapid infusions. The accumulation of anthracycline pools was measured and incorporated into equations from which a risk versus dose curve was obtained. The experimental curve identified a 5% risk dose that was congruent with a previously reported clinical value (380 versus 400 mg/m2, respectively); however, 1-2% risk occurred after lower doses than reported. Simulations of gain-of-function polymorphism of carbonyl reductase 3, which converts DOX to its poorly diffusible alcohol metabolite, doxorubicinol (DOXOL), expanded anthracycline pools and caused 5% or 1-2% risk doses to decrease to 330 or 180-230 mg DOX/m2, respectively. These data show there is no safe dose of DOX. Diminishing cardiac exposure to circulating DOX may represent a cardioprotective strategy. We show that DOX slow infusions or liposomal DOX, which reduce cardiac exposure to DOX, caused formation of smaller anthracycline pools, did not generate DOXOL, increased the 5% risk dose to 750-800 mg/m2, and prevented HF risk aggravation by carbonyl reductase polymorphism. PMID- 28559480 TI - In Vitro and In Silico Characterization of Lemborexant (E2006), a Novel Dual Orexin Receptor Antagonist. AB - Orexin (hypocretin) neuropeptides have, among others, been implicated in arousal/sleep control, and antagonizing the orexin signaling pathway has been previously demonstrated to promote sleep in animals and humans. This mechanism opens up a new therapeutic approach to curb excessive wakefulness in insomnia disorder rather than to promote sleep-related signaling. Here we describe the preclinical pharmacological in vitro and in silico characterization of lemborexant ((1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3 fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide)), a dual orexin receptor antagonist (DORA), as a novel experimental therapeutic agent for the symptomatic treatment of insomnia disorder and compare its properties to two other DORAs, almorexant and suvorexant. Lemborexant binds to both orexin receptors and functionally inhibits them in a competitive manner with low nanomolar potency, without any species difference apparent among human, rat, and mouse receptors. Binding and dissociation kinetics on both orexin receptors are rapid. Lemborexant is selective for both orexin receptors over 88 other receptors, transporters, and ion channels of important physiologic function. In silico modeling of lemborexant into the orexin receptors showed that it assumes the same type of conformation within the receptor-binding pocket as suvorexant, the pi-stacked horseshoe-like conformation. PMID- 28559481 TI - Methylation dynamics during folliculogenesis and early embryo development in sheep. PMID- 28559482 TI - A Screen for rfaH Suppressors Reveals a Key Role for a Connector Region of Termination Factor Rho. AB - RfaH activates horizontally acquired operons that encode lipopolysaccharide core components, pili, toxins, and capsules. Unlike its paralog NusG, which potentiates Rho-mediated silencing, RfaH strongly inhibits Rho. RfaH is recruited to its target operons via a network of contacts with an elongating RNA polymerase (RNAP) and a specific DNA element called ops to modify RNAP into a pause- and NusG-resistant state. rfaH null mutations confer hypersensitivity to antibiotics and detergents, altered susceptibility to bacteriophages, and defects in virulence. Here, we carried out a selection for suppressors that restore the ability of a DeltarfaH mutant Escherichia coli strain to grow in the presence of sodium dodecyl sulfate. We isolated rho, rpoC, and hns suppressor mutants with changes in regions previously shown to be important for their function. In addition, we identified mutants with changes in an unstructured region that connects the primary RNA-binding and helicase domains of Rho. The connector mutants display strong defects in vivo, consistent with their ability to compensate for the loss of RfaH, and act synergistically with bicyclomycin (BCM), which has been recently shown to inhibit Rho transformation into a translocation competent state. We hypothesize that the flexible connector permits the reorientation of Rho domains and serves as a target for factors that control the motor function of Rho allosterically. Our results, together with the existing data, support a model in which the connector segment plays a hitherto overlooked role in the regulation of Rho-dependent termination.IMPORTANCE The transcription termination factor Rho silences foreign DNA, reduces antisense transcription, mediates surveillance of mRNA quality, and maintains genome integrity by resolving transcription-replication collisions and deleterious R loops. Upon binding to RNA, Rho undergoes a rate-limiting transition from an open "lock washer" state to a closed ring capable of processive translocation on, and eventually the release of, the nascent transcript. Recent studies revealed that Rho ligands, including its cofactor NusG and inhibitor bicyclomycin, control the ring dynamics allosterically. In this work, we used a genetic selection for suppressors of RfaH, a potent inhibitor of Rho, to isolate a new class of mutations in a flexible region that connects the primary RNA-binding and ATPase/translocase domains of Rho. We propose that the connector is essential for the modulation of Rho activity by different RNA sequences and accessory proteins. PMID- 28559477 TI - European Glaucoma Society Terminology and Guidelines for Glaucoma, 4th Edition - Chapter 3: Treatment principles and options Supported by the EGS Foundation: Part 1: Foreword; Introduction; Glossary; Chapter 3 Treatment principles and options. PMID- 28559483 TI - Endoplasmic Reticulum Stress Caused by Lipoprotein Accumulation Suppresses Immunity against Bacterial Pathogens and Contributes to Immunosenescence. AB - The unfolded protein response (UPR) is a stress response pathway that is activated upon increased unfolded and/or misfolded proteins in the endoplasmic reticulum (ER), and enhanced ER stress response prolongs life span and improves immunity. However, the mechanism by which ER stress affects immunity remains poorly understood. Using the nematode Caenorhabditis elegans, we show that mutations in the lipoproteins vitellogenins, which are homologs of human apolipoprotein B-100, resulted in upregulation of the UPR. Lipoprotein accumulation in the intestine adversely affects the immune response and the life span of the organism, suggesting that it could be a contributing factor to immunosenescence. We show that lipoprotein accumulation inhibited the expression of several immune genes encoding proteins secreted by the intestinal cells in an IRE-1-independent manner. Our studies provide a mechanistic explanation for adverse effects caused by protein aggregation and ER stress on immunity and highlight the role of an IRE-1-independent pathway in the suppression of the expression of genes encoding secreted proteins.IMPORTANCE Increased accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) leads to enhanced ER stress. However, the mechanism(s) by which ER stress affects immunity remain understudied. Using the nematode C. elegans, we showed that mutations in lipoproteins lead to their accumulation in the intestine, causing ER stress and adversely affecting the life span of the organisms and their resistance to pathogen infection. Our results indicate that the ER stress caused by lipoprotein accumulation significantly reduced the levels of expression of genes encoding secreted immune effectors, contributing to immunosenescence. It is known that ER stress may suppress gene expression via IRE-1, which is a sensor of ER stress. The novel mechanism uncovered in our study is IRE-1 independent, which highlights the role of a novel process by which ER stress suppresses innate immunity. PMID- 28559485 TI - Thermodynamic Basis of Molecular Diffusion through Cyanobacterial Septal Junctions. PMID- 28559484 TI - Finding the Needle in the Haystack-the Use of Microfluidic Droplet Technology to Identify Vitamin-Secreting Lactic Acid Bacteria. AB - Efficient screening technologies aim to reduce both the time and the cost required for identifying rare mutants possessing a phenotype of interest in a mutagenized population. In this study, we combined a mild mutagenesis strategy with high-throughput screening based on microfluidic droplet technology to identify Lactococcus lactis variants secreting vitamin B2 (riboflavin). Initially, we used a roseoflavin-resistant mutant of L. lactis strain MG1363, JC017, which secreted low levels of riboflavin. By using fluorescence-activated droplet sorting, several mutants that secreted riboflavin more efficiently than JC017 were readily isolated from the mutagenesis library. The screening was highly efficient, and candidates with as few as 1.6 mutations per million base pairs (Mbp) were isolated. The genetic characterization revealed that riboflavin production was triggered by mutations inhibiting purine biosynthesis, which is surprising since the purine nucleotide GTP is a riboflavin precursor. Purine starvation in the mutants induced overexpression of the riboflavin biosynthesis cluster ribABGH When the purine starvation was relieved by purine supplementation in the growth medium, the outcome was an immediate downregulation of the riboflavin biosynthesis cluster and a reduction in riboflavin production. Finally, by applying the new isolates in milk fermentation, the riboflavin content of milk (0.99 mg/liter) was improved to 2.81 mg/liter, compared with 0.66 mg/liter and 1.51 mg/liter by using the wild-type strain and the original roseoflavin-resistant mutant JC017, respectively. The results obtained demonstrate how powerful classical mutagenesis can be when combined with droplet based microfluidic screening technology for obtaining microorganisms with useful attributes.IMPORTANCE The food industry prefers to use classical approaches, e.g., random mutagenesis followed by screening, to improve microorganisms used in food production, as the use of recombinant DNA technologies is still not widely accepted. Although modern automated screening platforms are widely accessible, screening remains as a bottleneck in strain development, especially when a mild mutagenesis approach is applied to reduce the chance of accumulating unintended mutations, which may cause unwanted phenotypic changes. Here, we incorporate a droplet-based high-throughput screening method into the strain development process and readily capture L. lactis variants with more efficient vitamin secretion from low-error-rate mutagenesis libraries. This study shows that useful mutants showing strong phenotypes but without extensive mutations can be identified with efficient screening technologies. It is therefore possible to avoid accumulating detrimental mutations while enriching beneficial ones through iterative mutagenesis screening. Due to the low mutation rates, the genetic determinants are also readily identified. PMID- 28559486 TI - Mismatch Repair of DNA Replication Errors Contributes to Microevolution in the Pathogenic Fungus Cryptococcus neoformans. AB - The ability to adapt to a changing environment provides a selective advantage to microorganisms. In the case of many pathogens, a large change in their environment occurs when they move from a natural setting to a setting within a human host and then during the course of disease development to various locations within that host. Two clinical isolates of the human fungal pathogen Cryptococcus neoformans were identified from a collection of environmental and clinical strains that exhibited a mutator phenotype, which is a phenotype which provides the ability to change rapidly due to the accumulation of DNA mutations at high frequency. Whole-genome analysis of these strains revealed mutations in MSH2 of the mismatch repair pathway, and complementation confirmed that these mutations are responsible for the mutator phenotype. Comparison of mutation frequencies in deletion strains of eight mismatch repair pathway genes in C. neoformans showed that the loss of three of them, MSH2, MLH1, and PMS1, results in an increase in mutation rates. Increased mutation rates enable rapid microevolution to occur in these strains, generating phenotypic variations in traits associated with the ability to grow in vivo, in addition to allowing rapid generation of resistance to antifungal agents. Mutation of PMS1 reduced virulence, whereas mutation of MSH2 or MLH1 had no effect on the level of virulence. These findings thus support the hypothesis that this pathogenic fungus can take advantage of a mutator phenotype in order to cause disease but that it can do so only in specific pathways that lead to a mutator trait without a significant tradeoff in fitness.IMPORTANCE Fungi account for a large number of infections that are extremely difficult to treat; superficial fungal infections affect approximately 1.7 billion (25%) of the general population worldwide, and systemic fungal diseases result in an unacceptably high mortality rate. How fungi adapt to their hosts is not fully understood. This research investigated the role of changes to DNA sequences in adaption to the host environment and the ability to cause disease in Cryptococcus neoformans, one of the world's most common and most deadly fungal pathogens. The study results showed that microevolutionary rates are enhanced in either clinical isolates or in gene deletion strains with msh2 mutations. This gene has similar functions in regulating the rapid emergence of antifungal drug resistance in a distant fungal relative of C. neoformans, the pathogen Candida glabrata Thus, microevolution resulting from enhanced mutation rates may be a common contributor to fungal pathogenesis. PMID- 28559487 TI - A Toxin Involved in Salmonella Persistence Regulates Its Activity by Acetylating Its Cognate Antitoxin, a Modification Reversed by CobB Sirtuin Deacetylase. AB - Bacterial toxin-antitoxin systems trigger the onset of a persister state by inhibiting essential cellular processes. The TacT toxin of Salmonella enterica is known to induce a persister state in macrophages through the acetylation of aminoacyl-tRNAs. Here, we show that the TacT toxin and the TacA antitoxin work as a complex that modulates TacT activity via the acetylation state of TacA. TacT acetylates TacA at residue K44, a modification that is removed by the NAD+ dependent CobB sirtuin deacetylase. TacA acetylation increases the activity of TacT, downregulating protein synthesis. TacA acetylation altered binding to its own promoter, although this did not change tacAT expression levels. These claims are supported by results from in vitro protein synthesis experiments used to monitor TacT activity, in vivo growth analyses, electrophoretic mobility shift assays, and quantitative reverse transcription-PCR (RT-qPCR) analysis. TacT is the first example of a Gcn5-related N-acetyltransferase that modifies nonprotein and protein substrates.IMPORTANCE During host infection, pathogenic bacteria can modulate their physiology to evade host defenses. Some pathogens use toxin antitoxin systems to modulate a state of self-toxicity that can decrease their cellular activity, triggering the onset of a persister state. The lower metabolic activity of persister cells allows them to escape host defenses and antibiotic treatments. Hence a better understanding of the mechanisms used by pathogens to ingress and egress the persister state is of relevance to human health. PMID- 28559488 TI - Viral DNA Replication Orientation and hnRNPs Regulate Transcription of the Human Papillomavirus 18 Late Promoter. AB - The life cycle of human papillomaviruses (HPVs) is tightly linked to keratinocyte differentiation. Although expression of viral early genes is initiated immediately upon virus infection of undifferentiated basal cells, viral DNA amplification and late gene expression occur only in the mid to upper strata of the keratinocytes undergoing terminal differentiation. In this report, we show that the relative activity of HPV18 TATA-less late promoter P811 depends on its orientation relative to that of the origin (Ori) of viral DNA replication and is sensitive to the eukaryotic DNA polymerase inhibitor aphidicolin. Additionally, transfected 70-nucleotide (nt)-long single-strand DNA oligonucleotides that are homologous to the region near Ori induce late promoter activity. We also found that promoter activation in raft cultures leads to production of the late promoter-associated, sense-strand transcription initiation RNAs (tiRNAs) and splice-site small RNAs (spliRNAs). Finally, a cis-acting AAGTATGCA core element that functions as a repressor to the promoter was identified. This element interacts with hnRNP D0B and hnRNP A/B factors. Point mutations in the core prevented binding of hnRNPs and increased the promoter activity. Confirming this result, knocking down the expression of both hnRNPs in keratinocytes led to increased promoter activity. Taking the data together, our study revealed the mechanism of how the HPV18 late promoter is regulated by DNA replication and host factors.IMPORTANCE It has been known for decades that the activity of viral late promoters is associated with viral DNA replication among almost all DNA viruses. However, the mechanism of how DNA replication activates the viral late promoter and what components of the replication machinery are involved remain largely unknown. In this study, we characterized the P811 promoter region of HPV18 and demonstrated that its activation depends on the orientation of DNA replication. Using single-stranded oligonucleotides targeting the replication fork on either leading or lagging strands, we showed that viral lagging-strand replication activates the promoter. We also identified a transcriptional repressor element located upstream of the promoter transcription start site which interacts with cellular proteins hnRNP D0B and hnRNP A/B and modulates the late promoter activity. This is the first report on how DNA replication activates a viral late promoter. PMID- 28559489 TI - In Vivo Imaging of Influenza Virus Infection in Immunized Mice. AB - Immunization is the cornerstone of seasonal influenza control and represents an important component of pandemic preparedness strategies. Using a bioluminescent reporter virus, we demonstrate the application of noninvasive in vivo imaging system (IVIS) technology to evaluate the preclinical efficacy of candidate vaccines and immunotherapy in a mouse model of influenza. Sequential imaging revealed distinct spatiotemporal kinetics of bioluminescence in groups of mice passively or actively immunized by various strategies that accelerated the clearance of the challenge virus at different rates and by distinct mechanisms. Imaging findings were consistent with conclusions derived from virus titers in the lungs and, notably, were more informative than conventional efficacy endpoints in some cases. Our findings demonstrate the reliability of IVIS as a qualitative approach to support preclinical evaluation of candidate medical countermeasures for influenza in mice.IMPORTANCE Influenza A viruses remain a persistent threat to public health. Vaccination and immunotherapy are effective countermeasures for the control of influenza but must contend with antigenic drift and the risk of resistance to antivirals. Traditional preclinical efficacy studies for novel vaccine and pharmaceutical candidates can be time-consuming and expensive and are inherently limited in scope. In vivo imaging approaches offer the potential to noninvasively track virus replication in real time in animal models. In this study, we demonstrate the utility of bioluminescent imaging for tracking influenza virus replication in the lungs of immunized mice and also identify important factors that may influence the accurate interpretation of imaging results. Our findings support the potential of IVIS approaches to enhance traditional preclinical efficacy evaluation of candidate vaccines and human monoclonal antibodies for the prevention and treatment of influenza. PMID- 28559492 TI - Angiotensin Receptor Blockers Reduce Cardiovascular Events, Including the Risk of Myocardial Infarction. PMID- 28559493 TI - Angiotensin Receptor Blockers Do Not Reduce Risk of Myocardial Infarction, Cardiovascular Death, or Total Mortality: Further Evidence for the ARB-MI Paradox. PMID- 28559494 TI - Common Variants for Cardiovascular Disease: Clinical Utility Confirmed. PMID- 28559490 TI - ADAR RNA editing below the backbone. AB - ADAR RNA editing enzymes (adenosine deaminases acting on RNA) that convert adenosine bases to inosines were first identified biochemically 30 years ago. Since then, studies on ADARs in genetic model organisms, and evolutionary comparisons between them, continue to reveal a surprising range of pleiotropic biological effects of ADARs. This review focuses on Drosophila melanogaster, which has a single Adar gene encoding a homolog of vertebrate ADAR2 that site specifically edits hundreds of transcripts to change individual codons in ion channel subunits and membrane and cytoskeletal proteins. Drosophila ADAR is involved in the control of neuronal excitability and neurodegeneration and, intriguingly, in the control of neuronal plasticity and sleep. Drosophila ADAR also interacts strongly with RNA interference, a key antiviral defense mechanism in invertebrates. Recent crystal structures of human ADAR2 deaminase domain-RNA complexes help to interpret available information on Drosophila ADAR isoforms and on the evolution of ADARs from tRNA deaminase ADAT proteins. ADAR RNA editing is a paradigm for the now rapidly expanding range of RNA modifications in mRNAs and ncRNAs. Even with recent progress, much remains to be understood about these groundbreaking ADAR RNA modification systems. PMID- 28559491 TI - Antagonistic actions of two human Pan3 isoforms on global mRNA turnover. AB - Deadenylation is a fundamental process that regulates eukaryotic gene expression. Mammalian deadenylation exhibits biphasic kinetics, with the Pan2-Pan3 and Ccr4 Caf1 deadenylase complexes mediating the first and second phase, respectively; however, the significance of the biphasic nature of deadenylation in mRNA turnover remains unclear. In this study, we discovered that two distinct isoforms of human Pan3 display opposing properties necessary for coordinating the two phases of deadenylation. The shorter isoform (Pan3S) interacts more strongly with PABP than the longer isoform (Pan3L) does. Pan2 deadenylase activity is enhanced by Pan3S but suppressed by Pan3L. Knocking down individual Pan3 isoforms has opposing effects on the global poly(A) tail length profile, P-body formation, and different mRNA decay pathways. Transcriptome-wide analysis of Pan3 knockdown effects on mRNA turnover shows that depleting either Pan3 isoform causes profound and extensive changes in mRNA stability globally. These results reveal a new fundamental step governing mammalian mRNA metabolism. We propose that the first phase of deadenylation, coordinated through the interplay among the two Pan3 isoforms, Pan2, and PABP, represents a cytoplasmic mRNA maturation step important for proper mRNA turnover. PMID- 28559495 TI - Temporal Trends in Adverse Events After Everolimus-Eluting Bioresorbable Vascular Scaffold Versus Everolimus-Eluting Metallic Stent Implantation: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Bioresorbable coronary stents have been introduced into clinical practice to improve the outcomes of patients treated with percutaneous coronary intervention. The everolimus-eluting bioresorbable vascular scaffold (BVS) is the most studied of these stent platforms; however, recent trials comparing BVS with everolimus-eluting metallic stents (EES) raised concerns about BVS safety. We aimed to assess the efficacy and safety of BVS versus EES in patients undergoing percutaneous coronary intervention. METHODS: We searched Medline, Embase, the Cochrane Central Register of Controlled Trials, scientific sessions abstracts, and relevant Web sites for randomized trials with a follow-up of >=2 years investigating percutaneous coronary interventions with BVS versus EES. The primary outcomes of our analysis were definite/probable stent thrombosis (ST) and target lesion failure (TLF; device-oriented composite end point of cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization [TLR]). Secondary outcomes were target vessel myocardial infarction, TLR, and cardiac death. We calculated the risk estimates for main outcomes according to a fixed-effect model. RESULTS: We included 7 trials comprising data for 5583 patients randomized to receive either a BVS (n=3261) or an EES (n=2322). Median follow-up was 24 months (range, 24-36 months). Patients treated with BVS had a higher risk of definite/probable ST compared with patients treated with EES (odds ratio, 3.33; 95% confidence interval, 1.97-5.62; P<0.00001). In particular, patients with BVS had a higher risk of subacute, late, and very late ST, whereas the risk of acute ST was similar. Patients treated with BVS compared with EES had a higher risk at 2 years of TLF (odds ratio, 1.47; 95% confidence interval, 1.14-1.90; P=0.003), driven mainly by an increased risk of target vessel myocardial infarction (odds ratio, 1.73; 95% confidence interval, 1.31-2.28; P=0.0001; I2=0%) and of TLR (odds ratio, 1.27; 95% confidence interval, 1.00-1.62; P=0.05). Of importance, the risk of TLF and TLR for patients with BVS was higher between 1 and 2 years, whereas there was no difference in the first year. Risk of cardiac death was similar between the 2 groups. CONCLUSIONS: Our meta-analysis of randomized trials with a follow-up of >=2 years demonstrated a higher risk of ST and of TLF in patients treated with BVS compared with EES. Of note, BVS had a higher risk of subacute, late, and very late ST, whereas the risk of TLF and TLR was higher between 1 and 2 years. PMID- 28559497 TI - Highlights From the Circulation Family of Journals. PMID- 28559498 TI - 3D Printers Provide a Window into the Heart. PMID- 28559499 TI - The Revised Framingham Stroke Risk Profile in a Primary Prevention Population: The Rotterdam Study. PMID- 28559500 TI - Letter by Saritas Regarding Article, "Total Anomalous Pulmonary Venous Connection: The Current Management Strategies in a Pediatric Cohort of 768 Patients". PMID- 28559496 TI - Magnetic Resonance Imaging of Cardiovascular Function and the Brain: Is Dementia a Cardiovascular-Driven Disease? AB - The proximal aorta acts as a coupling device between heart and brain perfusion, modulating the amount of pressure and flow pulsatility transmitted into the cerebral microcirculation. Stiffening of the proximal aorta is strongly associated with age and hypertension. The detrimental effects of aortic stiffening may result in brain damage as well as heart failure. The resulting cerebral small vessel disease and heart failure may contribute to early cognitive decline and (vascular) dementia. This pathophysiological sequence of events underscores the role of cardiovascular disease as a contributory mechanism in causing cognitive decline and dementia and potentially may provide a starting point for prevention and treatment. Magnetic resonance imaging is well suited to assess the function of the proximal aorta and the left ventricle (eg, aortic arch pulse wave velocity and distensibility) as well as the various early and late manifestations of cerebral small vessel disease (eg, microbleeds and white matter hyperintensities in strategically important regions of the brain). Specialized magnetic resonance imaging techniques are explored for diagnosing preclinical changes in white matter integrity or brain microvascular pulsatility. PMID- 28559501 TI - Letter by Ghimire Regarding Article, "Total Anomalous Pulmonary Venous Connection: The Current Management Strategies in a Pediatric Cohort of 768 Patients". PMID- 28559502 TI - Response by Chen to Letters Regarding Article, "Total Anomalous Pulmonary Venous Connection: The Current Management Strategies in a Pediatric Cohort of 768 Patients". PMID- 28559503 TI - Letter by Karamasis et al Regarding Article, "Thrombus Aspiration in ST-Segment Elevation Myocardial Infarction: An Individual Patient Meta-Analysis: Thrombectomy Trialists Collaboration". PMID- 28559504 TI - Letter by Jurado-Roman et al Regarding Article, "Thrombus Aspiration in ST Segment-Elevation Myocardial Infarction: An Individual Patient Meta-Analysis: Thrombectomy Trialists Collaboration". PMID- 28559505 TI - Letter by Shah Regarding Article, "Thrombus Aspiration in ST-Segment-Elevation Myocardial Infarction: An Individual Patient Meta-Analysis: Thrombectomy Trialists Collaboration". PMID- 28559506 TI - Response by Jolly et al to Letters Regarding Article, "Thrombus Aspiration in ST Segment-Elevation Myocardial Infarction: An Individual Patient Meta-Analysis: Thrombectomy Trialists Collaboration". PMID- 28559507 TI - In defense of our patients. PMID- 28559508 TI - Contextualizing the first-round failure of the AHCA: down but not out. AB - On 8 November 2016 the American electorate voted Donald Trump into the Presidency and a majority of Republicans into both houses of Congress. Since many Republicans ran for elected office on the promise to 'repeal and replace' Obamacare, this election result came with an expectation that campaign rhetoric would result in legislative action on healthcare. The American Health Care Act (AHCA) represented the Republican effort to repeal and replace the Affordable Care Act (ACA). Key elements of the AHCA included modifications of Medicaid expansion, repeal of the individual mandate, replacement of ACA subsidies with tax credits, and a broadening of the opportunity to use healthcare savings accounts. Details of the bill and the political issues which ultimately impeded its passage are discussed here. PMID- 28559509 TI - Aneurysmal wall imaging in a case of cortical superficial siderosis and multiple unruptured aneurysms. AB - We report a case of interhemispheric and bifrontal cortical superficial siderosis in association with two intracranial aneurysms. The patient had no clinical history suggestive of aneurysm rupture, no feature of amyloid angiopathy or other apparent etiology for cortical siderosis. We performed high resolution brain MRI with dark blood T1 sequences before and after IV contrast injection. An anterior communicating aneurysm showed partial wall enhancement on the posterior wall whereas a left posterior communicating aneurysm did not. In the light of recent reports of the association of wall enhancement with unstable aneurysms, we considered wall enhancement to be a marker of inflammation and remodeling of the aneurysm wall, resulting in chronic hemorrhagic suffusion in the subarachnoid spaces. To our knowledge, this is the first report offering proof for a possible link between apparently unruptured aneurysms and cortical siderosis. PMID- 28559510 TI - Rapid detection of in vitro antituberculous drug resistance among smear-positive respiratory samples using microcolony detection-based direct drug susceptibility testing method. AB - BACKGROUND: With the rise in multidrug-resistant tuberculosis, there is a search for newer techniques that will rapidly detect drug-resistant Mycobacterium tuberculosis. Although molecular techniques can detect resistance, culture is still considered gold standard, especially in resource-limited settings where quick, cheap, and easy techniques are needed. The aim of the study was to evaluate microcolony method thin layer agar (TLA) for quick detection of resistance against the first- and second-line antituberculous drugs in clinical isolates. This was a cross-sectional study performed at Aga Khan University Hospital. MATERIAL AND METHODS: A total of 87 Z-N stain smear-positive pulmonary samples were received and indirect drug susceptibility test (ID-DST) was performed using Lowenstein-Jensen and mycobacteria growth indicator tube. Direct DST was performed using TLA on 7H10 agar. TLA was observed twice weekly under microscope for 4 weeks. Sensitivity, specificity, and accuracy were calculated for TLA using indirect susceptibility method as the gold standard. Level of agreement was calculated using Kappa score. RESULTS: TLA showed sensitivity of 89% and 95.2% for isoniazid and rifampicin, while for ethionamide, ofloxacin, and injectable aminoglycosides, it was 96.6%, 92.1%, and 100%, respectively. Specificity for the first-line drugs was >95% while second-line drugs ranged from 70% to 100%. Mean time to positivity was 10.2 days by TLA as compared to 43.1 days by ID-DST. CONCLUSIONS: TLA is a quick and reliable method in identifying resistance, especially in resource-limited settings. However, additional liquid culture can be set up as backup, especially in patients on therapy to avoid false negative results. PMID- 28559511 TI - Diagnostic performance of genoType(r) MTBDRplus line probe assay in bronchoalveolar lavage for pulmonary tuberculosis diagnosis in sputum scarce and smear-negative patients. AB - BACKGROUND: MTBDRplus line probe assay (LiPA) has been endorsed by the World Health Organization for pulmonary tuberculosis (TB) diagnosis. However, its value for Mycobacterium tuberculosis (MTB) detection in bronchoalveolar lavage (BAL) needs exploration. This study determined the diagnostic performance of MTBDRplus in BAL for MTB complex detection and isoniazid/rifampicin resistance in smear negative and sputum scarce patients. MATERIALS AND METHODS: Retrospective evaluation of data (January-December 2013) from patients who underwent bronchoscopy was done. Of these, patients with high TB suspicion with available data on acid-fast bacilli (AFB) smear/culture and MTBDRplus were selected. Results of MTBDRplus were compared with AFB smear/culture and drug susceptibility. Sensitivity and specificity of MTBDRplus was determined using TB culture as gold standard. RESULTS: Data on 383 patients who underwent bronchoscopy were collected. Of these, 154 previously untreated TB suspect patients that were either smear negative on sputum microscopy or sputum scarce were selected. Out of 154 patients, 11 were smear positive and 34 patients were AFB culture positive. MTBDRplus detected MTB in 23/34 cases, the sensitivity and specificity being 67.6% and 85% (P < 0.001) versus 32.4% and 100% (P < 0.001) compared to smear microscopy. All smear-positive cases (n = 11) were detected by MTBDRplus. There were no discrepancies between phenotypic drug susceptibility testing and LiPA for isoniazid and rifampicin resistance in patients. Two cases of multidrug-resistant TB were detected. CONCLUSION: MTBDRplus detected TB more rapidly and accurately than smear microscopy with significant accuracy for isoniazid and rifampicin resistance. Its use in clinical practice would lead to rapid detection and effective management. PMID- 28559512 TI - Atlantoaxial tuberculosis: Outcome analysis. AB - BACKGROUND: Tuberculous (TB) spondylitis occurs in <1% of patients with TB. Atlantoaxial involvement is extremely rare amounting to 0.3%-1% cases of TB spondylitis. The management of this entity has been fluctuating with time. Various classifications and management protocols have also evolved. We present our experience in managing this entity in 8 patients. MATERIALS AND METHODS: Retrospective follow-up study of eight patients with atlantoaxial TB over 2 years. They ranged in age from 14 to 33 years with male preponderance. Four required surgical intervention on initial presentation, 2 were successfully treated conservatively, and 2 had to undergo surgery after a trial of conservative management. All of them were started on antituberculous therapy (ATT) for 18 months. Patients were followed up for 8-29 months. RESULTS: Neck pain and restriction of neck movements were standard presenting features. All patients had pulmonary TB confirmed by sputum examination. Radiological investigations formed an integral part of the evaluation of disease, treatment plan, and prognosis. Improvement in symptoms has been documented in all eight. CONCLUSION: The involvement of the most mobile spinal segment and the potential cervicomedullary compression makes it a disease of utmost importance. Although ATT remains the mainstay of treatment, surgical intervention is needed for stabilizing the joint and decompressing the cervicomedullary junction. Strict adherence to medical advice and optimum surgical intervention tailored for each patient results in the successful management of the disease. PMID- 28559513 TI - Extrapulmonary tuberculosis in colombian children: Epidemiological and clinical data in a reference hospital. AB - BACKGROUND: The pediatric population is at increased risk of disseminated and extrapulmonary tuberculosis (TB). There is little information on children affected by this entity. The demographic, clinical, and outcome characteristics of the treatment of children with extrapulmonary TB, treated at a national reference institution between January 1, 2008, and December 31, 2016, are described and analyzed in this work. MATERIALS AND METHODS: This was a retrospective observational study. Cases of extrapulmonary TB were identified, and variables were collected based on each criterion used for diagnosis and treatment outcomes. A descriptive analysis of the variables collected was performed. RESULTS: Ninety-three cases were identified, of which 32 (34.4%) met the criteria for extrapulmonary TB. The mean age was 10.2 years (range 0.8-17 years), and the most frequent site of extrapulmonary TB was lymph node 40.6%, meningeal 21.9%, and ocular 18.8%. Bacteriological confirmation was obtained in 8 cases (25%) while the remaining 24 cases (75%) were classified as cases of clinically diagnosed TB. Two patients (6.2%) died during treatment although their decease was not attributable to TB. CONCLUSION: The clinical criterion was fundamental to establish the diagnosis. The microbiological isolation rate was low. Molecular biology tools increase bacteriological performance although their extended use is limited by cost. Regional multicenter studies are required to identify the target population and the tools necessary for timely management and treatment. PMID- 28559514 TI - Molecular typing of Mycobacterium Abscessus isolated from cystic fibrosis patients. AB - BACKGROUND: The possibility of inter-human transmission of Mycobacterium abscessus in cystic fibrosis centres has been recently hypothesized suggesting the need for the molecular characterization of strains isolated from such patients. MATERIALS AND METHODS: One hundred and forty one isolates of M. abscessus grown from sputum samples of 29 patients with cystic fibrosis were genotyped resorting to variable number of tandem repeats (VNTR) determination and whole genome sequencing (WGS). RESULTS: Out of 29 VNTR profiles, 15 were unique to the same number of patients while seven were shared by multiple patients. WGS showed that only two of the patients sharing common VNTR patterns were indeed infected by the same strain. The shared VNTR patterns were mostly present among the isolates of M. abscessus subsp. abscessus. CONCLUSION: As expected WGS showed a clearly higher discriminatory power in comparison with VNTR and appeared the only molecular epidemiology tool suitable to effectively discriminate the isolates of M. abscessus subsp. abscessus. PMID- 28559516 TI - Cholecalciferol for prophylaxis against antituberculosis therapy-induced liver disorders among naive patients with pulmonary tuberculosis: A randomized, comparative study. AB - BACKGROUND: Patients in countries endemic for chronic viral hepatitis are more vulnerable to antituberculosis therapy-induced liver disorders (ATT-LDs). The aim of this study was to explore the role of cholecalciferol in prophylaxis against ATT-LD among patients with pulmonary tuberculosis (TB) receiving ATT. MATERIAL AND METHODS: We conducted a hospital-based, prospective, randomized, comparative study which included 300 consecutive, naive patients with pulmonary TB eligible for ATT. The patients were randomly allocated to Group A (150 patients who received ATT) and Group B (150 patients who received ATT with cholecalciferol) who had clinical evaluation, laboratory investigations, and imaging studies. Statistical analysis used student's t-test and Chi-square test were used as appropriate to compare the variables between the study groups. RESULTS: The study population mean age was 35.6 +/- 15.3 years. The overall incidence rate of ATT-LD among the study population was 9.3%; the incidence rate was significantly higher among Group A patients compared to those of Group B (13.3 vs. 5.3%;P = 0.001). The onset of ATT-LD was significantly earlier among patients of Group A compared to those of Group B (31.4 vs. 58.7 days,P = 0.027), while the duration of ATT-LD was significantly longer among patients of Group A compared to those of Group B (34.8 vs. 16.9 days,P = 0.009). No adverse effects related to cholecalciferol use were observed. CONCLUSIONS: Adjuvant cholecalciferol supplementation may be protective against ATT-LD without extra adverse effects. Before recommending the routine use of cholecalciferol supplementation for prevention of ATT-LD, larger scale studies are recommended. PMID- 28559515 TI - In silico structure-based drug screening of novel antimycobacterial pharmacophores by DOCK-GOLD tandem screening. AB - BACKGROUND: Enzymes responsible for cell wall development in Mycobacterium tuberculosis are considered as potential targets of anti-tuberculosis (TB) agents. Mycobacterial cyclopropane mycolic acid synthase 1 (CmaA1) is essential for mycobacterial survival because of its critical role in synthesizing mycolic acids. MATERIALS AND METHODS: We screened compounds that were capable of interacting with the mycobacterial CmaA1 active site using a virtual compound library with an in silico structure-based drug screening (SBDS). Following the selection of such compounds, their antimycobacterial activity was examined. RESULTS: With the in silico SBDS, for which we also used DOCK-GOLD programs and screening methods that utilized the structural similarity between the selected active compounds, we identified two compounds with potent inhibitory effects on mycobacterial growth. The antimycobacterial effect of the compounds was comparable to that of isoniazid, which is used as a first-line anti-TB drug. CONCLUSION: The compounds identified through SBDS were expected to be a novel class of anti-TB pharmacophores. PMID- 28559517 TI - Characterization of pyrazinamide resistance in consecutive multidrug-resistant mycobacterium tuberculosis isolates in sweden between 2003 and 2015. AB - BACKGROUND: The first line anti-tuberculosis drug pyrazinamide (PZA) is important when treating PZA susceptible multidrug-resistant tuberculosis (MDR-TB). Several drug resistance surveys have however reported PZA resistance among a significant proportion of multidrug-resistant (MDR) cases and this undoubtedly highlights the need for accurate and reliable detection of PZA resistance. Unfortunately, the testing of PZA susceptibility is associated with technical difficulties and even though the introduction of pncA sequencing has helped to address this issue, misclassification may still occur. In this study, we determined the prevalence and characteristics of PZA resistance in Swedish MDR-TB strains. MATERIALS AND METHODS: 153 MDR-TB strains isolated in Sweden between 2003 and 2015 were analyzed for PZA resistance by considering both phenotypic and genotypic data. RESULTS: The phenotypic test showed that 58% of the multidrug-resistant isolates were PZA resistant and the correlation between phenotype and genotype was solid, although a small number of isolates deviate from the expected phenotypic genotypic pattern. CONCLUSION: The results indicate that the prevalence of pyrazinamide resistance among Swedish MDR cases is increasing. PMID- 28559518 TI - Epidemiology of extrapulmonary and disseminated tuberculosis in a tertiary care center in Oman. AB - BACKGROUND: The incidence of extrapulmonary and disseminated tuberculosis (TB) cases is increasing worldwide, and this growth significantly impacts TB-related morbidity and mortality. Little is known about the host risk factors for extrapulmonary and disseminated TB. In this study, we examined those risk factors. MATERIALS AND METHODS: We conducted a retrospective review of all TB cases admitted to Sultan Qaboos University Hospital from 2006 to 2015. We compared extrapulmonary TB (EPTB) cases with pulmonary and disseminated TB cases. We evaluated the risk factors associated with the development of extrapulmonary and disseminated TB using logistic regression analysis. RESULTS: We reviewed 260 TB cases, of which EPTB comprised 37%, PTB comprised 53%, and disseminated TB comprised 10%. The most common sites of infection in the EPTB group were the lymph nodes and the abdomen. Disseminated TB and TB meningitis were more common in expatriates than in Omanis. Patients with EPTB were less likely to smoke compared to a patient with PTB. Patients with disseminated TB had a higher mortality when compared to patients with EPTB (adjusted odds ratio [OR], 0.004; 95% confidence intervals [CI]: 0.001-0.054;P = 0.001) and PTB (adjusted OR, 0.022; 95% CI: 0.004-0.115;P = 0.001). Human immunodeficiency virus (HIV) was the main risk factor for patients with disseminated TB when compared to patients with extrapulmonary and PTB. CONCLUSION: The rates of extrapulmonary and disseminated TB in Oman are higher than what has been recognized. Expatriates, patients with HIV, and smokers are at high risk for disseminated TB. In these patients, suspected extrapulmonary sites should be evaluated and sampled to exclude disseminated TB. PMID- 28559519 TI - Phenotypic low-level isoniazid resistance as a marker to predict ethionamide resistance in Mycobacterium tuberculosis. AB - BACKGROUND: Tuberculosis is one of the most prevalent diseases in Pakistan. Pakistan has the highest burden of MDR-TB in the Eastern Mediterranean region. Ethionamide is an anti-tuberculous drug frequently used to treat MDR-TB. Its drug susceptibility testing is not easily available in resource limited settings. Since it acts on the same target protein as isoniazid (inhA protein encoded by inhA gene), we sought to find out if phenotypic isoniazid resistance can be a marker of ethionamide resistance. MATERIALS AND METHODS: This was a retrospective observational study conducted at the Aga Khan University hospital section of microbiology. Data was retrieved between 2011 to 2014 for all culture positive MTB strains. All culture positive MTB isolates with susceptibilities to isoniazid and ethionamide recorded were included in the study. Isoniazid and ethionamide susceptibilities were performed using agar proportion method on Middlebrook 7H10 agar. Rate of Ethionamide resistance between low-level isoniazid resistant, high level isoniazid resistant and isoniazid sensitive MTB was compared. RESULTS: A total of 11,274 isolates were included in the study. A statistically significant association (P < 0.001) was found between Ethionamide resistance and low-level isoniazid resistance (26.6%) as compared to high-level isoniazid resistance (8.85%) and isoniazid sensitivity (0.71%) in MTB strains. However this association was not seen in XDR-TB strains. CONCLUSION: Low level isoniazid resistance may be used as marker for phenotypic ethionamide resistance and hence guide clinicians' choice of antituberculous agent for MDR-TB in Pakistan. Further studies involving detection of genotypic association of isoniazid and ethionamide susceptibilities are needed before a final conclusion can be derived. PMID- 28559520 TI - Modified rifampin nanoparticles: Increased solubility with slow release Rate. AB - BACKGROUND: Recent advances in nanotechnology-based drug delivery system have been shown to improve either antibacterial efficacy or pharmacokinetics behavior.The aim of this study was to design a rifampin nanoparticle (RIF-NP) which has a high loading capacity with the slow release profile. MATERIAL AND METHODS: The designed chitosan/gelatin/lecithin (Chg/L) RIF-NPs were prepared by multilamellar vesicle. Thereafter, the particle size, zeta potential, morphology, and release rate were investigated. To optimize the loading capacity and release profiles, different concentrations of lecithin were used. RESULTS: Our results showed a correlation of lecithin concentration with size, zeta potential, and loading capacity of RIF-NPs. Increases in lecithin concentration (0.2-2.0 g) could cause a significant size reduction in NPs (250-150 nm); the amount of zeta potential (from 14 to 49 mV;P < 0.05) and loading capacity increases from 8% to 20% (P < 0.05). Designed NPs had slow drug release profile which was influenced by pH and lecithin concentration. The cumulative percentage of RIF released at pH 7.4 was approximately 93% up to 12 h. In overall, release profile was better than standard drug, even in various pH conditions (pH = 1, 3.4, and 7.4). The Chg/L RIF NPs may be considered as a promising drug nanocarrier. CONCLUSIONS: These NPs release RIF in slow and constant rate, which effectively might eliminate the bacilli and prevent the formation of RIF-resistant bacilli. PMID- 28559521 TI - Contribution of putative efflux pump genes to isoniazid resistance in clinical isolates of Mycobacterium tuberculosis. AB - BACKGROUND: Isoniazid (INH) resistance in Mycobacterium tuberculosis has been mainly attributed to mutations in katG (64%) and inhA (19%). However, 20%-30% resistance to INH cannot be explained by mutations alone. Hence, other mechanisms besides mutations may play a significant role in providing drug resistance. Here, we explored the role of 24 putative efflux pump genes conferring INH-resistance in M. tuberculosis. MATERIALS AND METHODS: Real-time expression profiling of the efflux pump genes was performed in five INH-susceptible and six high-level INH resistant clinical isolates of M. tuberculosis exposed to the drug. Isolates were also analyzed for mutations in katG and inhA. RESULTS: Four high-level INH resistant isolates (minimum inhibitory concentration [MIC] >=2.5 mg/L) with mutations at codon 315 (AGC-ACC) of katG showed upregulation of one of the efflux genes Rv1634, Rv0849, efpA, or p55. Another high-level INH-resistant isolate (MIC 1.5 mg/L), with no mutations at katG or inhA overexpressed 8/24 efflux genes, namely, Rv1273c, Rv0194, Rv1634, Rv1250, Rv3823c, Rv0507, jefA, and p55. Five of these, namely, Rv0194, Rv1634, Rv1250, Rv0507, and p55 were induced only in resistant isolates. CONCLUSION: The high number of efflux genes overexpressed in an INH-resistant isolate with no known INH resistance associated mutations, suggests a role for efflux pumps in resistance to this antituberculous agent, with the role of Rv0194 and Rv0507 in INH resistance being reported for the first time. PMID- 28559522 TI - pulmonary tuberculosis: A neglected risk factor for deep venous thrombosis. AB - A case of deep venous thrombosis (DVT) of the lower limb in the absence of known common risk factors and its link with underlying pulmonary tuberculosis is described in a young female patient. Possible underlying mechanisms and awareness regarding tuberculosis as a risk factor for DVT is also emphasized. PMID- 28559523 TI - The first report of two cases of fatal liver injury due to anti-tuberculosis drugs in the presence of alpha-1 antitrypsin deficiency. AB - Tuberculosis (TB) is a major global health problem. Awareness of liver injury due to anti-TB therapy is vital because fulminant hepatic failure is a devastating and often fatal condition without liver transplantation. Here, we report for the first time, two patients of fatal liver injury due to anti-TB drugs in the presence of alpha-1 antitrypsin deficiency. Based on the triad of rapid loss in hepatocyte function, the onset of hepatic encephalopathy, and absence of a prior history of liver disease, the diagnosis of acute liver failure was established. Both patients had low levels of serum alpha-1 antitrypsin, consistent with alpha 1 antitrypsin deficiency. Despite aggressive medical therapy and supportive care, patients developed multi-organ failure and died. It seems measuring the serum levels of alpha 1-antitrypsin before beginning anti-TB therapies is necessary, especially when there is emphysema or bronchiectasis. PMID- 28559524 TI - Isolated lytic bone lesion in tuberculosis. AB - Causes of lytic bone lesions include benign, malignant, and infectious processes. Lytic lesions due to tuberculosis (TB) may closely mimic those due to tumors such as bone cyst, osteoblastoma, osteosarcoma, and metastatic bone disease radiologically. Histopathology and culture help in definitive diagnosis and prompt management. We describe an immunocompetent patient with isolated lytic bone lesion in the distal part of ulna due to TB to make the readers aware of such unusual presentations of TB. PMID- 28559525 TI - Reactivation pulmonary tuberculosis in two patients treated with pirfenidone. AB - We report two cases of patients with biopsy-proven idiopathic pulmonary fibrosis (IPF) who were treated with new antifibrotic agent for pirfenidone for more than 12 months. Both cases developed cavitary pulmonary tuberculosis (TB) proven by positive sputum TB culture. Both cases were treated with standard anti-TB drugs for 9 months and had complete clinical and radiological resolution. To our knowledge, these are the first reported human cases of patients with IPF who have been on pirfenidone and developed cavitary pulmonary TB. PMID- 28559526 TI - Tenosynovitis: An unusual presentation of leprosy. AB - Tenosynovitis is an uncommon presentation of Type 1 reaction in leprosy. Herein, we report a case of bilateral tenosynovitis of wrist joints who after being unsuccessfully treated by a rheumatologist for several months, was finally diagnosed as a case of Hansen's disease (borderline lepromatous) with Type 1 reaction. PMID- 28559527 TI - Death caused by possible unrecognized (too Late Recognized) Mycobacterium gordonae infection in a patient with angioimmunoblastic T-cell lymphoma. AB - Here, we present possible death caused by Mycobacterium gordonae infection in a patient with angioimmunoblastic T-cell lymphoma. Our patient was severely immunocompromised in whom we suspect to an infection, but we did not have isolates until she died. After she died, we received a positive sputum culture of M. gordonae. We conclude that when having severely immunocompromised patients with suspicion of infection but without isolates we should always consider the saprophytic mycobacteria. These mycobacteria require a long period of isolation, but patients with these mycobacteria are potentially curable if appropriate treatment is applied for a sufficiently long period. PMID- 28559528 TI - Disseminated Mycobacterium avium complex in an immunocompetent host. AB - Disseminated Mycobacterium avium complex (DMAC) has historically been described in the immunocompromised. The current epidemiologic research suggests that the incidence of nontuberculous mycobacterial infections is increasing. We present a case of DMAC infection manifesting as hepatic granulomas in a 35-year-old immunocompetent female. This case suggests DMAC infection in a patient without traditional epidemiological risk factors. PMID- 28559529 TI - Tubercular infection of hydatid cyst. AB - Tubercular infection of hydatid cyst of the chest wall in an immunocompetent individual is rare. Immune modulation for symbiosis between host cells and the parasite - Echinococcus granulosus favors tubercular infection. In this case report, we describe a case of both these chronic diseases coexisting together, to present as chest wall mass. PMID- 28559530 TI - Performance of light-emitting diode-based fluorescence microscopy to diagnose tuberculosis in a rural hospital of ethiopia. PMID- 28559531 TI - Association between left atrial function assessed by speckle-tracking echocardiography and the presence of left atrial appendage thrombus in patients with atrial fibrillation. AB - OBJECTIVE: The aim of the study was to investigate whether the deformation of left atrium (LA) measured by speckle-tracking analysis (STE) is associated with the presence of LA appendage thrombus (LAAT) during non-valvular atrial fibrillation (AF). METHODS: Eighty-seven patients (mean age 67 years, 59% men) were included to retrospective cross-sectional study. On top of standard echocardiography we assessed: LA longitudinal systolic strain (LS), systolic (LSSR) and early diastolic strain rate (LESR) in four-chamber and twochamber apical views. All patients underwent transesophageal echocardiography disclosing LAAT in 36 (41%) patients. RESULTS: Subgroups with and without thrombi did not differ with regard to clinical characteristics. Univariate factors associated with LAAT were as follows: CH2ADS2-VASc Score, left ventricular ejection fraction (LVEF), LV mass, and STE measurements. In a multivariate model only LVEF (p=0.002), LS (p=0.02), LESR (p=0.008), and LSSR (p=0.045) were independently associated with LAAT presence. Moreover, LVEF and LA STE measurements provided incremental value over the CH2ADS2-VASc Score. CONCLUSION: Speckle-tracking TTE may be used to describe LA reservoir and conduit function during AF, allowing the identification of patients with higher risk of LAAT and providing incremental value over the CH2ADS2-VASc Score. PMID- 28559532 TI - "Desert" gene (Chr9p21) variants as novel markers for coronary artery disease. AB - OBJECTIVE: Previous reports have denoted to the possible link of Chr9p21 locus to the incidence of coronary artery disease (CAD). The entire core of chr9p21 is covered by "ANRIL" (Antisense noncoding RNA in INK4 Locus) and lies in a region that is free from any coding proteins; therefore, it is called the desert gene. The major objectives of this study were to examine the association of rs10757278 and rs2383206 SNPs on Chr9p21 with the incidence of CAD in the presence and absence of type 2 diabetes (T2D) in Egyptians and to correlate these genetic variants with several disease biomarkers (TC, CRP, and HbA1c). METHODS: The study subjects consisted of 150 subjects; 50 healthy controls and 100 patients that were divided into two groups; CAD patients and CAD T2D patients. The genotyping of SNPs was performed using qPCR. RESULTS: Genotype distribution for both SNPs were found to be significantly different (p=0.0009 for rs10757278 and p=0.001 for rs2383206) between patients and controls. The allele frequency was also different for rs10757278. CONCLUSION: The current study showed that rs10757278/rs2383206-G allele increases the risk for CAD in Egyptians. Moreover, AA variant appeared as a protective genotype. However, SNPs did not noticeably contribute in the elevation of TC, hs-CRP, and HbA1c in non-diabetic and diabetic CAD patients. PMID- 28559533 TI - Assessment of the association between the presence of fragmented QRS and the predicted risk score of sudden cardiac death at 5 years in patients with hypertrophic cardiomyopathy. AB - OBJECTIVE: It has been shown that the presence of fragmented QRS (fQRS) is associated with poor prognosis in many cardiovascular diseases and in patients with hypertrophic cardiomyopathy (HCM). However, no study has shown an association with the absolute risk score of sudden cardiac death. The aim of this study was to determine the relationship between QRS and the predicted risk score of sudden cardiac death at 5 years (HCM Risk-SCD) in HCM patients. METHODS: In total, 115 consecutive HCM patients were included in this prospective observational study. The patients were divided into two groups according to the presence [fQRS(+) group (n=65)] or absence [fQRS(-) group (n=50)] of fQRS on a 12 lead electrocardiogram (ECG). RESULTS: The HCM Risk-SCD (%) HCM Risk-SCD (>6%) values and some echocardiographic parameters, including ventricular extrasystole, ventricular tachycardia, cardiopulmonary resuscitation, implantable cardioverter defibrillator implantation, appropriate shock, and heart failure at the time of admission, were significantly higher in the fQRS(+) group than in the fQRS(-) group (all p<0.05). Both univariate and multivariate analyses revealed fQRS and New York Heart Association (NYHA) class as independent predictors of HCM Risk SCD. In a receiver operating characteristic (ROC) curve analysis, an HCM Risk-SCD value of >4 was identified as an effective cut-off point in fQRS for HCM. An HCM Risk-SCD value of >4 yielded a sensitivity of 77% and a specificity of 76%. CONCLUSION: fQRS is determined to be an independent high-risk indicator of HCM Risk-SCD. It seems to be associated with increased ventricular arrhythmias and some echocardiographic parameters. PMID- 28559534 TI - Granulocyte-Colony Stimulating Factor (G-CSF) Accelerates Wound Healing in Hemorrhagic Shock Rats by Enhancing Angiogenesis and Attenuating Apoptosis. AB - BACKGROUND Following severe trauma, treatment of cutaneous injuries is often delayed by inadequate blood supply. The aim of the present study was to determine whether granulocyte-colony stimulating factor (G-CSF) protects endothelial cells (ECs) and enhances angiogenesis in a rat model of hemorrhagic shock (HS) combined with cutaneous injury after resuscitation. MATERIAL AND METHODS The HS rats with full-thickness defects were resuscitated and randomly divided into a G-CSF group (200 MUg/kg body weight), a normal saline group, and a blank control group. Histological staining was to used estimate the recovery and apoptosis of skin. Apoptosis- and angiogenesis-related factors were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot (WB). Scratch assay, tube formation, and WB experiments were performed to verify the functional effects of G-CSF on HUVECs in vitro. RESULTS H&E staining and Masson trichrome staining showed earlier inflammation resolution and collagen synthesis in the G CSF-treated group. Angiogenesis-related factors were elevated at mRNA and protein levels. TUNEL staining suggested fewer apoptotic cells in the G-CSF group. The apoptotic-related factors were down-regulated and anti-apoptotic factors were up regulated in the G-CSF-treated group. Scratch assay and tube formation experiments revealed that G-CSF facilitated migration ability and angiogenic potential of HUVECs. The angiogenic and anti-apoptotic effects were also enhanced in vitro. CONCLUSIONS Our results suggest that G-CSF after resuscitation attenuates local apoptosis and accelerates angiogenesis. These findings hold great promise for improving therapy for cutaneous injury in severe trauma and ischemia diseases. PMID- 28559535 TI - Breast Implant-Associated Anaplastic Large Cell Lymphoma (ALCL): A Case Report. AB - BACKGROUND Anaplastic large cell lymphomas (ALCL) are a rare type of primary breast lymphoma. The association between breast implants and ALCL was first described in 1997 and since then 34-173 cases have been presented. The annual incidence of breast implant-associated ALCL (BI-ALCL) is 0.1-0.3 per 100 000 women who undergo breast reconstruction, and cases are often underreported due to the rarity of these tumors. BI-ALCL arises from the inflammatory T cells surrounding the fibrous capsule, and most tumors are in situ. CASE REPORT Here, we present the case of a 51-year-old woman with ALCL following bilateral silicone breast implants. The patient presented with breast enlargement and tenderness 9 years following reconstructive surgery. Imagining studies showed fluid collection surrounding the affected breast implant. Staging studies and histocytopathology examination confirmed the presence BI-ALCL without capsular invasion or metastasis. Complete surgical excision was performed. The patient continues to be in complete remission. CONCLUSIONS Due to the rarity of these tumors, establishing the diagnosis of BI-ALCL can be challenging and requires a multidisciplinary approach. Clinicians should be aware of the relationship between breast implants and BI-ALCL. PMID- 28559536 TI - Office paper decorated with silver nanostars - an alternative cost effective platform for trace analyte detection by SERS. AB - For analytical applications in portable sensors to be used in the point-of-need, low-cost SERS substrates using paper as a base, are an alternative. In this work, SERS substrates were produced on two different types of paper: a high porosity paper (Whatman no. 1); and a low porosity paper (commercially available office paper, Portucel Soporcel). Solutions containing spherical silver nanoparticles (AgNPs) and silver nanostars (AgNSs) were separately drop-casted on hydrophilic wells patterned on the papers. The porosity of the paper was found to play a determinant role on the AgNP and AgNS distribution along the paper fibres, with most of the nanoparticles being retained at the illuminated surface of the office paper substrate. The highest SERS enhancements were obtained for the office paper substrate, with deposited AgNSs. A limit of detection for rhodamine-6G as low as 11.4 +/- 0.2 pg could be achieved, with an analytical enhancement factor of ~107 for this specific analyte. The well patterning technique allowed good signal uniformity (RSD of 1.7%). Besides, these SERS substrates remained stable after 5 weeks of storage (RSD of 7.3%). Paper-induced aggregation of AgNPs was found to be a viable alternative to the classical salt-induced aggregation, to obtain a highly sensitive SERS substrates. PMID- 28559538 TI - When agreement-accepting free-riders are a necessary evil for the evolution of cooperation. AB - Agreements and commitments have provided a novel mechanism to promote cooperation in social dilemmas in both one-shot and repeated games. Individuals requesting others to commit to cooperate (proposers) incur a cost, while their co-players are not necessarily required to pay any, allowing them to free-ride on the proposal investment cost (acceptors). Although there is a clear complementarity in these behaviours, no dynamic evidence is currently available that proves that they coexist in different forms of commitment creation. Using a stochastic evolutionary model allowing for mixed population states, we identify non-trivial roles of acceptors as well as the importance of intention recognition in commitments. In the one-shot prisoner's dilemma, alliances between proposers and acceptors are necessary to isolate defectors when proposers do not know the acceptance intentions of the others. However, when the intentions are clear beforehand, the proposers can emerge by themselves. In repeated games with noise, the incapacity of proposers and acceptors to set up alliances makes the emergence of the first harder whenever the latter are present. As a result, acceptors will exploit proposers and take over the population when an apology-forgiveness mechanism with too low apology cost is introduced, and hence reduce the overall cooperation level. PMID- 28559537 TI - High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group. AB - To investigate safety and efficacy of high-dose chemotherapy followed by autologous stem cell transplantation (HCT-ASCT) in relapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL), we conducted a single-arm multicentre study for immunocompetent patients (<66 years) with PCNSL failing high-dose methotrexate)-based chemotherapy. Induction consisted of two courses of rituximab (375 mg/m2), high-dose cytarabine (2 * 3 g/m2) and thiotepa (40 mg/m2) with collection of stem cells in between. Conditioning for HCT-ASCT consisted of rituximab 375 mg/m2, carmustine 400 mg/m2 and thiotepa (4 * 5 mg/kg). Patients commenced HCT-ASCT irrespective of response after induction. Patients not achieving complete remission (CR) after HCT-ASCT received whole-brain radiotherapy. Primary end point was CR after HCT-ASCT. We enrolled 39 patients; median age and Karnofsky performance score are 57 years and 90%, respectively. About 28 patients had relapsed and 8 refractory disease. About 22 patients responded to induction and 32 patients commenced HCT-ASCT. About 22 patients (56.4%) achieved CR after HCT-ASCT. Respective 2-year progression-free survival (PFS) and overall survival (OS) rates were 46.0% (median PFS 12.4 months) and 56.4%; median OS not reached. We recorded four treatment-related deaths. Thiotepa based HCT-ASCT is an effective treatment option in eligible patients with r/r PCNSL. Comparative studies are needed to further scrutinise the role of HCT-ASCT in the salvage setting. PMID- 28559539 TI - In silico analyses of deleterious missense SNPs of human apolipoprotein E3. AB - ApoE3 is the major chylomicron apolipoprotein, binding in a specific liver peripheral cell receptor, allowing transport and normal catabolism of triglyceride-rich lipoprotein constituents. Point mutations in ApoE3 have been associated with Alzheimer's disease, type III hyperlipoproteinemia, atherosclerosis, telomere shortening and impaired cognitive function. Here, we evaluate the impact of missense SNPs in APOE retrieved from dbSNP through 16 computational prediction tools, and further evaluate the structural impact of convergent deleterious changes using 100 ns molecular dynamics simulations. We have found structural changes in four analyzed variants (Pro102Arg, Arg132Ser, Arg176Cys and Trp294Cys), two of them (Pro102Arg and Arg176Cys) being previously associated with human diseases. In all cases, except for Trp294Cys, there was a loss in the number of hydrogen bonds between CT and NT domains that could result in their detachment. In conclusion, data presented here could increase the knowledge of ApoE3 activity and be a starting point for the study of the impact of variations on APOE gene. PMID- 28559540 TI - rs9939609 FTO genotype associations with FTO methylation level influences body mass and telomere length in an Australian rural population. AB - BACKGROUND: The fat mass- and obesity-associated (FTO) gene influences energy homeostasis in humans. Although the obesity-related variant, rs9939609 has been replicated across a number of cohort studies, there remains significant variance and a low to modest association. Telomere length is another commonly reported obesity risk factor. We hypothesize understanding the associations between FTO rs9939609 with FTO methylation and telomere length will provide a more accurate assessment of obesity risk. METHODS: Overall, 942 participants free of diabetes or pre-diabetes were included in the retrospective study. Leukocyte genomic DNA was analyzed for rs9939609 genotyping, FTO gene methylation and leukocyte telomere length (LTL) measurement. RESULTS: In general linear models, rs9939609 AA genotypes were associated with increased fat percentage (3.15%, P=0.001), fat mass (4.16 kg, P=0.001), body mass index (BMI) (1.38, P=0.006) and waist circumference (3.35 cm, P=0.006), but not with FTO methylation or LTL in this overall population. However, when participants were stratified into higher and lower FTO methylation groups, the AA genotype possesses a 2.04-fold increased obesity risk in comparison to TT genotype (95%CI, 1.07-3.89, P=0.031) in participants with a higher FTO methylation level, but this association was absent in the lower FTO methylation sub-group. Moreover, AT and AA genotype carriers were associated with shorter LTL compared to TT carriers (P=0.020 and P=0.111, respectively) in the higher FTO methylation level group. However, this association was absent in the lower methylation group. Furthermore, FTO gene methylation level was significantly associated with LTL in the 942 samples (P=0.017). CONCLUSIONS: FTO rs9939609 is associated with obesity risk and LTL in this study, where this association is only observed at higher, but not lower, FTO methylation levels of participants. Our data suggest association of multiple factors, including FTO methylation level, may be involved in one of several mechanisms underlying the commonly reported obesity risk of this FTO polymorphism. PMID- 28559541 TI - Adiponectin deficiency rescues high-fat diet-induced hepatic injury, apoptosis and autophagy loss despite persistent steatosis. AB - : Background &aims:Low levels of adiponectin (APN), an adipose-derived adipokine, are associated with obesity and non-alcoholic steatohepatitis although its role in high-fat diet-induced hepatic injury and steatosis remains unclear. Here we hypothesized that APN deficiency alters fat diet-induced hepatic function. To this end, we examined the effect of APN deficiency on high-fat diet-induced hepatic injury, apoptosis and steatosis. METHODS: Adult wild type and APN knockout mice were fed a low- or high-fat diet for 20 weeks. Serum levels of liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholesterol, hepatic triglycerides, steatosis, pro-inflammatory cytokines, apoptosis and autophagy were examined. RESULTS: High-fat feeding led to elevated body (48.2%) and liver weights (18.8%), increased levels of ALT (87.8%), serum cholesterol (104.4%), hepatic triglycerides (305.6%) and hepatic fat deposition as evidenced by Oil Red O staining, along with a reduced AST/ALT ratio and unchanged AST. Although APN knockout itself did not affect hepatic function and morphology, it reconciled fat diet-induced hepatic injury (P<0.05 vs WT-HF group) without reversing changes in body and liver weights, serum cholesterol and hepatic steatosis. In addition, fat diet intake promoted AMPK phosphorylation, p62 accumulation and apoptosis, including elevated Bax and cleaved Caspase-3 and downregulated Bcl-2, along with suppressed phosphorylation of Akt, STAT3 and JNK, and the autophagy makers Atg7, Beclin-1 and LC3B (P<0.05 vs WT-LF group) without affecting hepatic interlelukin-6 and tumor necrosis factor-alpha levels, the effects were reversed or significantly attenuated by APN knockout (P<0.05 vs WT HF group). In vitro study using HepG2 cells revealed that STAT3 activation rescued palmitic acid-induced cell injury whereas STAT3 inhibition nullified APN knockdown-offered beneficial effects. CONCLUSIONS: Our results revealed that high fat diet intake promotes hepatic steatosis, apoptosis and interrupted autophagy. APN knockout elicits protective effect against hepatic injury possibly associated with autophagy regulation despite persistent hepatic steatosis. PMID- 28559543 TI - Comparative transcriptomic analysis indicates genes associated with local and systemic resistance to Colletotrichum graminicola in maize. AB - The hemibiotrophic fungus Colletotrichum graminicola may cause severe damage to maize, affecting normal development of the plant and decreasing grain yield. In this context, understanding plant defense pathways at the inoculation site and systemically in uninoculated tissues can help in the development of genetic engineering of resistance against this pathogen. Previous work has discussed the molecular basis of maize - C. graminicola interaction. However, many genes involved in defense have not yet been exploited for lack of annotation in public databases. Here, changes in global gene expression were studied in root, male and female inflorescences of maize under local and systemic fungal infection treatments, respectively. RNA-Seq with qPCR was used to indicate genes involved in plant defense. We found that systemic acquired resistance induction in female inflorescences mainly involves accumulation of salicylic acid (SA)-inducible defense genes (ZmNAC, ZmHSF, ZmWRKY, ZmbZIP and PR1) and potential genes involved in chromatin modification. Furthermore, transcripts involved in jasmonic acid (JA) and ethylene (ET) signaling pathways were also accumulated and may participate in plant immunity. Moreover, several genes were functionally re annotated based on domain signature, indicating novel candidates to be tested in strategies involving gene knockout and overexpression in plants. PMID- 28559544 TI - Characterization of meta-Cresol Purple for spectrophotometric pH measurements in saline and hypersaline media at sub-zero temperatures. AB - Accurate pH measurements in polar waters and sea ice brines require pH indicator dyes characterized at near-zero and below-zero temperatures and high salinities. We present experimentally determined physical and chemical characteristics of purified meta-Cresol Purple (mCP) pH indicator dye suitable for pH measurements in seawater and conservative seawater-derived brines at salinities (S) between 35 and 100 and temperatures (T) between their freezing point and 298.15 K (25 degrees C). Within this temperature and salinity range, using purified mCP and a novel thermostated spectrophotometric device, the pH on the total scale (pHT) can be calculated from direct measurements of the absorbance ratio R of the dye in natural samples as[Formula: see text] Based on the mCP characterization in these extended conditions, the temperature and salinity dependence of the molar absorptivity ratios and - [Formula: see text] of purified mCP is described by the following functions: e 1 = -0.004363 + 3.598 * 10-5 T, e 3/e 2 = -0.016224 + 2.42851 * 10-4 T + 5.05663 * 10-5(S - 35), and - [Formula: see text] = -319.8369 + 0.688159 S -0.00018374 S 2 + (10508.724 - 32.9599 S + 0.059082S 2) T-1 + (55.54253 - 0.101639 S) ln T -0.08112151T. This work takes the characterisation of mCP beyond the currently available ranges of 278.15 K <= T <= 308.15 K and 20 <= S <= 40 in natural seawater, thereby allowing high quality pHT measurements in polar systems. PMID- 28559542 TI - MARCH9-mediated ubiquitination regulates MHC I export from the TGN. AB - Given the heterogeneous nature of antigens, major histocompatibility complex class I (MHC I) intracellular transport intersects with multiple degradation pathways for efficient peptide loading and presentation to cytotoxic T cells. MHC I loading with peptides in the endoplasmic reticulum (ER) is a tightly regulated process, while post-ER intracellular transport is considered to occur by default, leading to peptide-bearing MHC I delivery to the plasma membrane. We show here that MHC I traffic is submitted to a previously uncharacterized sorting step at the trans Golgi network (TGN), dependent on the ubiquitination of its cytoplasmic tail lysine residues. MHC I ubiquitination is mediated by the E3 ligase membrane associated RING-CH 9 (MARCH9) and allows MHC I access to Syntaxin 6-positive endosomal compartments. We further show that MARCH9 can also target the human MHC I-like lipid antigen-presentation molecule CD1a. MARCH9 expression is modulated by microbial pattern exposure in dendritic cells (DCs), thus revealing the role of this ubiquitin E3 ligase in coordinating MHC I access to endosomes and DC activation for efficient antigen cross-presentation. PMID- 28559545 TI - Positive regulatory role of sound vibration treatment in Arabidopsis thaliana against Botrytis cinerea infection. AB - Sound vibration (SV), a mechanical stimulus, can trigger various molecular and physiological changes in plants like gene expression, hormonal modulation, induced antioxidant activity and calcium spiking. It also alters the seed germination and growth of plants. In this study, we investigated the effects of SV on the resistance of Arabidopsis thaliana against Botrytis cinerea infection. The microarray analysis was performed on infected Arabidopsis plants pre-exposed to SV of 1000 Hertz with 100 decibels. Broadly, the transcriptomic analysis revealed up-regulation of several defense and SA-responsive and/or signaling genes. Quantitative real-time PCR (qRT-PCR) analysis of selected genes also validated the induction of SA-mediated response in the infected Arabidopsis plants pre-exposed to SV. Corroboratively, hormonal analysis identified the increased concentration of salicylic acid (SA) in the SV-treated plants after pathogen inoculation. In contrast, jasmonic acid (JA) level in the SV-treated plants remained stable but lower than control plants during the infection. Based on these findings, we propose that SV treatment invigorates the plant defense system by regulating the SA-mediated priming effect, consequently promoting the SV-induced resistance in Arabidopsis against B. cinerea. PMID- 28559548 TI - Malignant melanoma: from cause to cure. PMID- 28559546 TI - Identification of oral cancer related candidate genes by integrating protein protein interactions, gene ontology, pathway analysis and immunohistochemistry. AB - In the recent years, bioinformatics methods have been reported with a high degree of success for candidate gene identification. In this milieu, we have used an integrated bioinformatics approach assimilating information from gene ontologies (GO), protein-protein interaction (PPI) and network analysis to predict candidate genes related to oral squamous cell carcinoma (OSCC). A total of 40973 PPIs were considered for 4704 cancer-related genes to construct human cancer gene network (HCGN). The importance of each node was measured in HCGN by ten different centrality measures. We have shown that the top ranking genes are related to a significantly higher number of diseases as compared to other genes in HCGN. A total of 39 candidate oral cancer target genes were predicted by combining top ranked genes and the genes corresponding to significantly enriched oral cancer related GO terms. Initial verification using literature and available experimental data indicated that 29 genes were related with OSCC. A detailed pathway analysis led us to propose a role for the selected candidate genes in the invasion and metastasis in OSCC. We further validated our predictions using immunohistochemistry (IHC) and found that the gene FLNA was upregulated while the genes ARRB1 and HTT were downregulated in the OSCC tissue samples. PMID- 28559547 TI - Comparison of ocular biometric measurements between a new swept-source optical coherence tomography and a common optical low coherence reflectometry. AB - The purpose of the current study was to compare the measurements between a new optical biometer based on swept-source optical coherence tomography (SS-OCT), the OA-2000 (Tomey, Japan), and an optical biometer based on optical low coherence reflectometry (OLCR), the Lenstar (Haag-Streit, Switzerland). Ninety-nine eyes of 99 healthy subjects were included. The axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), aqueous depth (AD), lens thickness (LT), keratometry (K) readings, including flat K (Kf), steep K (Ks), mean K (Km), astigmatism vectors J0, J45 at diameters of 2.5 and 3.0 mm, and white-to-white diameter (WTW) were measured three times each using both biometer in normal eyes by random sequence. Bland-Altman analysis showed good agreement between the SS OCT and OLCR devices for AL, AD, ACD, LT, with narrow 95% LoA (-0.05 to 0.07 mm, 0.09 to 0.10 mm, -0.10 to 0.09 mm, and -0.06 to 0.22 mm, respectively), and the P values of ACD were both >0.05. The CCT, Kf, Ks, Km, J0, J45 and WTW values provided by the OA-2000 were in good agreement with the Lenstar, and statistically significant differences were detected for some of them but not clinical differences. The agreement was excellent especially for AL. PMID- 28559549 TI - Re-exposure to nicotine-associated context from adolescence enhances alcohol intake in adulthood. AB - Alcohol and nicotine are the two most commonly-abused substances and are often used together. Nicotine enhances alcohol-drinking behaviors in humans and in animals, and was suggested to enhance the reinforcing properties of other reinforcers. Here, we show that nicotine-associated environment, rather than nicotine itself, enhances alcohol intake in rats. Adolescent rats received repeated intermittent injections of nicotine (0.4 mg/kg, i.p., 5 injections, every 3rd day) or saline. The injection was paired with their home cage, or with the subsequent alcohol self-administration context. Rats were then trained to self-administer 20% alcohol. Nicotine given in the home cage did not alter subsequent alcohol intake. However, pairing nicotine with the operant chamber during adolescence led to a long-lasting increased alcohol self-administration in adulthood, compared to nicotine pre-treatment in other contexts. This effect persisted 3 months after nicotine cessation, in a relapse test after abstinence. Furthermore, re-exposure to the nicotine-associated context in adult rats led to a decrease in glial cell line-derived neurotrophic factor (Gdnf) mRNA expression in the ventral tegmental area, an effect that leads to increased alcohol consumption, as we have previously reported. Our findings suggest that retrieval of nicotine-associated contextual memories from adolescence may gate alcohol intake in adulthood, with a possible involvement of GDNF. PMID- 28559551 TI - Ageing: A youthful reminder. PMID- 28559550 TI - Metabolic and transcriptional alternations for defense by interfering OsWRKY62 and OsWRKY76 transcriptions in rice. AB - Metabolomic and transcriptomic approaches were used to dissect the enhanced disease resistance in the plants harbouring a RNA interfering construct of OsWRKY62 and OsWRKY76 (dsOW62/76) genes. The primary metabolic pathways were activated in dsOW62/76 compared with wild-type (ZH17) plants, revealed by increased accumulation of amino acids and constituents of citric acid cycle etc. Contents of phenolic acids derived from phenylpropanoid pathway were elevated in dsOW62/76 plants. Importantly, phenolamides, conjugates of the phenolic acids with amines, were detected in large number and mostly at higher levels in dsOW62/76 compared with ZH17 plants; however, the free pools of flavonoids were mostly decreased in dsOW62/76. Salicylic acid (SA) and jasmonic acid (JA)/JA-Ile contents were increased in dsOW62/76 and knockout lines of individual OsWRKY62 and OsWRKY76 genes. Transcription of isochorismate synthase (OsICS1) gene was suppressed in dsOW62/76 and in MeJA-treated rice plants, whereas the transcription level of cinnamoyl-CoA hydratase-dehydrogenase (OsCHD) gene for beta-oxidation in peroxisome was increased. The calli with OsCHD mutation showed markedly decreased SA accumulation. These results indicate that OsWRKY62 and OsWRKY76 function as negative regulators of biosynthetic defense-related metabolites and provide evidence for an important role of phenylpropanoid pathway in SA production in rice. PMID- 28559555 TI - Zeroing in on neurodegenerative alpha-synuclein. PMID- 28559557 TI - Deal watch: Neurokinin 3 receptor antagonist revival heats up with Astellas acquisition. PMID- 28559559 TI - Birgitte Volck. PMID- 28559561 TI - Search for liquid biopsy grail points the way to drug discovery and development gems. PMID- 28559562 TI - Infectious disease: Peroxin inhibitor treats Trypanosoma infection. PMID- 28559564 TI - Efficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models. AB - Therapeutic concepts exploiting tumor-specific antibodies are often established in pre-clinical xenograft models using immuno-deficient mice. More complex therapeutic paradigms, however, warrant the use of immuno-competent mice, that more accurately capture the relevant biology that is being exploited. These models require the use of (surrogate) mouse or rat antibodies to enable optimal interactions with murine effector molecules. Immunogenicity is furthermore decreased, allowing longer-term treatment. We recently described controlled Fab arm exchange (cFAE) as an easy-to-use method for the generation of therapeutic human IgG1 bispecific antibodies (bsAb). To facilitate the investigation of dual targeting concepts in immuno-competent mice, we now applied and optimized our method for the generation of murine bsAbs. We show that the optimized combinations of matched point-mutations enabled efficient generation of murine bsAbs for all subclasses studied (mouse IgG1, IgG2a and IgG2b; rat IgG1, IgG2a, IgG2b, and IgG2c). The mutations did not adversely affect the inherent effector functions or pharmacokinetic properties of the corresponding subclasses. Thus, cFAE can be used to efficiently generate (surrogate) mouse or rat bsAbs for pre clinical evaluation in immuno-competent rodents. PMID- 28559565 TI - Anti-Aging Potentials of Methylene Blue for Human Skin Longevity. AB - Oxidative stress is the major cause of skin aging that includes wrinkles, pigmentation, and weakened wound healing ability. Application of antioxidants in skin care is well accepted as an effective approach to delay the skin aging process. Methylene blue (MB), a traditional mitochondrial-targeting antioxidant, showed a potent ROS scavenging efficacy in cultured human skin fibroblasts derived from healthy donors and from patients with progeria, a genetic premature aging disease. In comparison with other widely used general and mitochondrial targeting antioxidants, we found that MB was more effective in stimulating skin fibroblast proliferation and delaying cellular senescence. The skin irritation test, performed on an in vitro reconstructed 3D human skin model, indicated that MB was safe for long-term use, and did not cause irritation even at high concentrations. Application of MB to this 3D skin model further demonstrated that MB improved skin viability, promoted wound healing and increased skin hydration and dermis thickness. Gene expression analysis showed that MB treatment altered the expression of a subset of extracellular matrix proteins in the skin, including upregulation of elastin and collagen 2A1, two essential components for healthy skin. Altogether, our study suggests that MB has a great potential for skin care. PMID- 28559566 TI - Chaos as an intermittently forced linear system. AB - Understanding the interplay of order and disorder in chaos is a central challenge in modern quantitative science. Approximate linear representations of nonlinear dynamics have long been sought, driving considerable interest in Koopman theory. We present a universal, data-driven decomposition of chaos as an intermittently forced linear system. This work combines delay embedding and Koopman theory to decompose chaotic dynamics into a linear model in the leading delay coordinates with forcing by low-energy delay coordinates; this is called the Hankel alternative view of Koopman (HAVOK) analysis. This analysis is applied to the Lorenz system and real-world examples including Earth's magnetic field reversal and measles outbreaks. In each case, forcing statistics are non-Gaussian, with long tails corresponding to rare intermittent forcing that precedes switching and bursting phenomena. The forcing activity demarcates coherent phase space regions where the dynamics are approximately linear from those that are strongly nonlinear.The huge amount of data generated in fields like neuroscience or finance calls for effective strategies that mine data to reveal underlying dynamics. Here Brunton et al.develop a data-driven technique to analyze chaotic systems and predict their dynamics in terms of a forced linear model. PMID- 28559567 TI - Functional end-arterial circulation of the choroid assessed by using fat embolism and electric circuit simulation. AB - The discrepancy in the choroidal circulation between anatomy and function has remained unsolved for several decades. Postmortem cast studies revealed extensive anastomotic channels, but angiographic studies indicated end-arterial circulation. We carried out experimental fat embolism in cats and electric circuit simulation. Perfusion defects were observed in two categories. In the scatter perfusion defects suggesting an embolism at the terminal arterioles, fluorescein dye filled the non-perfused lobule slowly from the adjacent perfused lobule. In the segmental perfusion defects suggesting occlusion of the posterior ciliary arteries, the hypofluorescent segment became perfused by spontaneous resolution of the embolism without subsequent smaller infarction. The angiographic findings could be simulated with an electric circuit. Although electric currents flowed to the disconnected lobule, the level was very low compared with that of the connected ones. The choroid appeared to be composed of multiple sectors with no anastomosis to other sectors, but to have its own anastomotic arterioles in each sector. Blood flows through the continuous choriocapillaris bed in an end-arterial nature functionally to follow a pressure gradient due to the drainage through the collector venule. PMID- 28559569 TI - A framework for quantifying the extent of impact to plants from linear construction. AB - We present a novel framework that accurately evaluates the extent of a linear project's effect from the variability of the structure of the plant community while avoiding interference caused by pioneer species and invasive species. This framework was based on the change of dominant species in the plant community affected by construction. TWINSPAN classification and variation of the integrated importance value (IIV) of each plant species group were used to characterize the process of change in the structure of the plant community. Indicator species group and its inflection point were defined and used to judge the extent of the effects of pipelines. Our findings revealed that dominant species in the working area of the pipeline construction were different from the original plant communities. With the disturbance decreased, the composition and structure of the plant communities gradually changed. We considered the outer limit of the area affected by the construction to be the first area in which the plant community reached a steady state and was similar to the original community. The framework could be used in the post eco-environment impact assessment of linear construction to estimate the intensity of disturbance and recovery condition. PMID- 28559570 TI - Security of a kind of quantum secret sharing with entangled states. AB - We present a new collusion attack to a kind of quantum secret sharing schemes with entangled states. Using this attack, an unauthorized set of agents can gain access to the shared secret without the others' cooperation. Furthermore, we establish a general model for this kind of quantum secret sharing schemes and then give some necessary conditions to design a secure quantum secret sharing scheme under this model. PMID- 28559568 TI - Auxin regulates functional gene groups in a fold-change-specific manner in Arabidopsis thaliana roots. AB - Auxin plays a pivotal role in virtually every aspect of plant morphogenesis. It simultaneously orchestrates a diverse variety of processes such as cell wall biogenesis, transition through the cell cycle, or metabolism of a wide range of chemical substances. The coordination principles for such a complex orchestration are poorly understood at the systems level. Here, we perform an RNA-seq experiment to study the transcriptional response to auxin treatment within gene groups of different biological processes, molecular functions, or cell components in a quantitative fold-change-specific manner. We find for Arabidopsis thaliana roots treated with auxin for 6 h that (i) there are functional groups within which genes respond to auxin with a surprisingly similar fold changes and that (ii) these fold changes vary from one group to another. These findings make it tempting to conjecture the existence of some transcriptional logic orchestrating the coordinated expression of genes within functional groups in a fold-change specific manner. To obtain some initial insight about this coordinated expression, we performed a motif enrichment analysis and found cis-regulatory elements TBX1-3, SBX, REG, and TCP/site2 as the candidates conferring fold-change specific responses to auxin in Arabidopsis thaliana. PMID- 28559571 TI - Sex differences in the clinical characteristics and brain gray matter volume alterations in unmedicated patients with major depressive disorder. AB - This study was to explore the sex differences in clinical characteristics and brain gray matter volume (GMV) alterations in 29 male patients with major depressive disorder (MDDm), 53 female patients with MDD (MDDf), and in 29 male and 53 female matched healthy controls. Maps of GMV were constructed using magnetic resonance imaging data and compared between groups. We evaluated clinical symptoms using the Hamilton Rating Scale for Depression and obtained a total score and five syndrome scores. A two-factor ANCOVA model was specified using SPM8, with sex and diagnosis as the between-subject factors. We found that: (1) significant GMV increase in the left cerebellum and GMV reduction in the bilateral middle temporal gyrus and left ventral medial prefrontal gyrus occurred selectively in male patients, while the GMV reduction in the left lingual gyrus and dorsal medial prefrontal gyrus occurred selectively in female patients; (2) MDDf may have experienced more severe sleep disturbance than MDDm; and (3) the severity of sleep symptom could be predicted by the sex specific brain structural alterations in depressions. These findings suggest that sex specific anatomical alterations existed in MDD, and these alterations were associated with the clinical symptoms. PMID- 28559573 TI - Transcription: Paused means poised. PMID- 28559574 TI - Cytoplasmic movements outside the living cell. PMID- 28559572 TI - C-terminal fragments of the amyloid precursor protein in cerebrospinal fluid as potential biomarkers for Alzheimer disease. AB - This study assesses whether C-terminal fragments (CTF) of the amyloid precursor protein (APP) are present in cerebrospinal fluid (CSF) and their potential as biomarkers for Alzheimer's disease (AD). Immunoprecipitation and simultaneous assay by Western blotting using multiplex fluorescence imaging with specific antibodies against particular domains served to characterize CTFs of APP in human CSF. We demonstrate that APP-CTFs are detectable in human CSF, being the most abundant a 25-kDa fragment, probably resulting from proteolytic processing by eta secretase. The level of the 25-kDa APP-CTF was evaluated in three independent CSF sample sets of patients and controls. The CSF level of this 25-kDa CTF is higher in subjects with autosomal dominant AD linked to PSEN1 mutations, in demented Down syndrome individuals and in sporadic AD subjects compared to age-matched controls. Our data suggest that APP-CTF could be a potential diagnostic biomarker for AD. PMID- 28559575 TI - Autophagy: Membrane contacts lend a hand. PMID- 28559576 TI - Working Memory Requires a Combination of Transient and Attractor-Dominated Dynamics to Process Unreliably Timed Inputs. AB - Working memory stores and processes information received as a stream of continuously incoming stimuli. This requires accurate sequencing and it remains puzzling how this can be reliably achieved by the neuronal system as our perceptual inputs show a high degree of temporal variability. One hypothesis is that accurate timing is achieved by purely transient neuronal dynamics; by contrast a second hypothesis states that the underlying network dynamics are dominated by attractor states. In this study, we resolve this contradiction by theoretically investigating the performance of the system using stimuli with differently accurate timing. Interestingly, only the combination of attractor and transient dynamics enables the network to perform with a low error rate. Further analysis reveals that the transient dynamics of the system are used to process information, while the attractor states store it. The interaction between both types of dynamics yields experimentally testable predictions and we show that this way the system can reliably interact with a timing-unreliable Hebbian network representing long-term memory. Thus, this study provides a potential solution to the long-standing problem of the basic neuronal dynamics underlying working memory. PMID- 28559577 TI - Inhibition of DNA replication in Staphylococcus aureus by tegaserod. PMID- 28559578 TI - 5-O-Mycaminosyltylonolide antibacterial derivatives: design, synthesis and bioactivity. AB - Tylosin is a 16-membered macrolide broad-spectrum antibiotic that has an important role in veterinary medicine, active against Gram-positive and a restricted range of Gram-negative bacteria. We synthesized 15 types of tylosin related derivatives by chemical modification and evaluated them against mastitis pathogens. Among them, 20-deoxy-20-{N-methyl-N-[1-(3-quinolyl)-1H-1,2,3-triazol-4 yl]methylamino}-5-O-mycaminosyltylonolide 2f and 20-deoxy-20-{N-benzyl-N-[1-(3 quinolyl)-1H-1,2,3-triazol-4-yl]methylamino}-5-O-mycaminosyltylonolide 2k were found to not only expand their antibacterial impact to include Gram-negative bacteria, such as Escherichia coli and Klebsiella pneumoniae, but also to retain or increase antibacterial activity against Gram-positive bacteria, such as Staphylococcus aureus and Streptococcus uberis in comparison with the parent tylosin. PMID- 28559579 TI - NC1404, a novel derivative of Bleomycin with modified sugar moiety obtained during the preparation of Boningmycin. PMID- 28559580 TI - Cladomarine, a new anti-saprolegniasis compound isolated from the deep-sea fungus, Penicillium coralligerum YK-247. PMID- 28559581 TI - Synthesis and structure-activity relationships of novel lincomycin derivatives. Part 4: synthesis of novel lincomycin analogs modified at the 6- and 7-positions and their potent antibacterial activities. AB - To modify lincomycin (LCM) at the C-6 and the C-7 positions, we firstly prepared various substituted proline intermediates (7, 11-15 and 17). These proline intermediates were coupled with methyl 1-thio-alpha-lincosamide and tetrakis-O trimethylsilylation followed by selective deprotection of the TMS group at the 7 position gave a wide variety of key intermediates (23-27, 47 and 50). Then, we synthesized a variety of novel LCM analogs modified at the 7-position in application of the Mitsunobu reaction, an SN2 reaction, and a Pd-catalyzed cross coupling reaction. Compounds 34 and 35 (1'-NH derivatives) exhibited enhanced antibacterial activities against resistant pathogens with erm gene compared with the corresponding 1'-N-methyl derivatives (3 and 37). On the basis of reported SAR, we modified the 4'-position of LCM derivatives possessing a 5-(2 nitrophenyl)-1,3,4-thiadiazol-2-yl group at the C-7 position. Compound 56 showed significantly potent antibacterial activities against S. pneumoniae and S. pyogenes with erm gene, and its activities against S. pneumoniae with erm gene were improved compared with those of 34 and 57. Although we synthesized novel analogs by transformation of a C-7 substituent focusing on the 1'-demethyl framework to prepare very potent analogs 73 and 75, it was impossible to generate novel derivatives exhibiting stronger antibacterial activities against S. pneumoniae with erm gene compared with 56. PMID- 28559582 TI - Thalamic Bursts Down-regulate Cortical Theta and Nociceptive Behavior. AB - We tested the relation between pain behavior, theta (4-8 Hz) oscillations in somatosensory cortex and burst firing in thalamic neurons in vivo. Optically induced thalamic bursts attenuated cortical theta and mechanical allodynia. It is proposed that thalamic bursts are an adaptive response to pain that de synchronizes cortical theta and decreases sensory salience. PMID- 28559583 TI - Many-body Tunneling and Nonequilibrium Dynamics of Doublons in Strongly Correlated Quantum Dots. AB - Quantum tunneling dominates coherent transport at low temperatures in many systems of great interest. In this work we report a many-body tunneling (MBT), by nonperturbatively solving the Anderson multi-impurity model, and identify it a fundamental tunneling process on top of the well-acknowledged sequential tunneling and cotunneling. We show that the MBT involves the dynamics of doublons in strongly correlated systems. Proportional to the numbers of dynamical doublons, the MBT can dominate the off-resonant transport in the strongly correlated regime. A T 3/2-dependence of the MBT current on temperature is uncovered and can be identified as a fingerprint of the MBT in experiments. We also prove that the MBT can support the coherent long-range tunneling of doublons, which is well consistent with recent experiments on ultracold atoms. As a fundamental physical process, the MBT is expected to play important roles in general quantum systems. PMID- 28559584 TI - Close linkage between serum uric acid and cardiac dysfunction in patients with ischemic heart disease according to covariance structure analysis. AB - High serum uric acid (UA) level has been assumed to be a risk factor for left ventricular (LV) dysfunction; however, the precise relationship between these conditions has not been fully examined because many confounding factors are associated with UA level. We herein examined the precise relationship by proposing structural equation models. The study population consisted of 1432 cases with ischemic heart disease who underwent cardiac catheterization. Multiple regression analyses and covariance structure analyses were performed to elucidate the cause-and-effect relationship between UA level and LV ejection fraction (LVEF). A path model exploring the factors contributing to LVEF showed that high UA was a significant cause of reduced LVEF (P = 0.004), independent of other significant factors. The degree of atherosclerosis, as estimated by the number of diseased coronary vessels, was significantly affected by high UA (P = 0.005); and the number of diseased coronary vessels subsequently led to reduced LVEF (P < 0.001). Another path model exploring the factors contributing to UA level showed that LVEF was a significant cause of high UA (P = 0.001), while other risk factors were also independent contributing factors. This study clearly demonstrated that there was a close link between high UA and LV dysfunction, which was represented by possible cause-and-effect relationship. PMID- 28559585 TI - Ultrahigh-Q optomechanical crystal cavities fabricated in a CMOS foundry. AB - Photonic crystals use periodic structures to create frequency regions where the optical wave propagation is forbidden, which allows the creation and integration of complex optical functionalities in small footprint devices. Such strategy has also been successfully applied to confine mechanical waves and to explore their interaction with light in the so-called optomechanical cavities. Because of their challenging design, these cavities are traditionally fabricated using dedicated high-resolution electron-beam lithography tools that are inherently slow, limiting this solution to small-scale or research applications. Here we show how to overcome this problem by using a deep-UV photolithography process to fabricate optomechanical crystals in a commercial CMOS foundry. We show that a careful design of the photonic crystals can withstand the limitations of the photolithography process, producing cavities with measured intrinsic optical quality factors as high as Q i = (1.21 +/- 0.02) * 106. Optomechanical crystals are also created using phononic crystals to tightly confine the GHz sound waves within the optical cavity, resulting in a measured vacuum optomechanical coupling rate of g 0 = 2pi * (91 +/- 4) kHz. Efficient sideband cooling and amplification are also demonstrated since these cavities are in the resolved sideband regime. Further improvements in the design and fabrication process suggest that commercial foundry-based optomechanical cavities could be used for quantum ground state cooling. PMID- 28559587 TI - Urban eddy covariance measurements reveal significant missing NOx emissions in Central Europe. AB - Nitrogen oxide (NOx) pollution is emerging as a primary environmental concern across Europe. While some large European metropolitan areas are already in breach of EU safety limits for NO2, this phenomenon does not seem to be only restricted to large industrialized areas anymore. Many smaller scale populated agglomerations including their surrounding rural areas are seeing frequent NO2 concentration violations. The question of a quantitative understanding of different NOx emission sources is therefore of immanent relevance for climate and air chemistry models as well as air pollution management and health. Here we report simultaneous eddy covariance flux measurements of NOx, CO2, CO and non methane volatile organic compound tracers in a city that might be considered representative for Central Europe and the greater Alpine region. Our data show that NOx fluxes are largely at variance with modelled emission projections, suggesting an appreciable underestimation of the traffic related atmospheric NOx input in Europe, comparable to the weekend-weekday effect, which locally changes ozone production rates by 40%. PMID- 28559586 TI - Abeta42 pentamers/hexamers are the smallest detectable oligomers in solution. AB - Amyloid beta (Abeta) oligomers may play a decisive role in Alzheimer's disease related neurodegeneration, but their structural properties are poorly understood. In this report, sedimentation velocity centrifugation, small angle neutron scattering (SANS) and molecular modelling were used to identify the small oligomeric species formed by the 42 amino acid residue long isoform of Abeta (Abeta42) in solution, characterized by a sedimentation coefficient of 2.56 S, and a radius of gyration between 2 and 4 nm. The measured sedimentation coefficient is in close agreement with the sedimentation coefficient calculated for Abeta42 hexamers using MD simulations at uM concentration. To the best of our knowledge this is the first report detailing the Abeta42 oligomeric species by SANS measurements. Our results demonstrate that the smallest detectable species in solution are penta- to hexamers. No evidences for the presence of dimers, trimers or tetramers were found, although the existence of those Abeta42 oligomers at measurable quantities had been reported frequently. PMID- 28559588 TI - The mobility of small vacancy/helium complexes in tungsten and its impact on retention in fusion-relevant conditions. AB - Tungsten is a promising plasma facing material for fusion reactors. Despite many favorable properties, helium ions incoming from the plasma are known to dramatically affect the microstructure of tungsten, leading to bubble growth, blistering, and/or to the formation of fuzz. In order to develop mitigation strategies, it is essential to understand the atomistic processes that lead to bubble formation and subsequent microstructural changes. In this work, we use large-scale Accelerated Molecular Dynamics simulations to investigate small (N = 1,2) V N He M vacancy/helium complexes, which serve as the nuclei for larger helium bubble growth, over timescales reaching into the milliseconds under conditions typical of the operation of fusion reactors. These complexes can interconvert between different I L V N+L He M variants via Frenkel pair nucleation (leading to the creation of a additional vacancy/interstitial pair) and annihilation events; sequences of these events can lead to net migration of these embryonic bubbles. The competition between nucleation and annihilation produces a very complex dependence of the diffusivity on the number of heliums. Finally, through cluster dynamics simulations, we show that diffusion of these complexes provides an efficient pathway for helium release at fluxes expected in fusion reactors, and hence that accounting for the mobility of these complexes is crucial. PMID- 28559590 TI - Gut microbiota: Trust your gut - metformin and diabetes. PMID- 28559591 TI - Genetics: Novel causative genes for polycystic liver disease. PMID- 28559589 TI - Tuning the photoexcitation response of cyanobacterial Photosystem I via reconstitution into Proteoliposomes. AB - The role of natural thylakoid membrane housing of Photosystem I (PSI), the transmembrane photosynthetic protein, in its robust photoactivated charge separation with near unity quantum efficiency is not fundamentally understood. To this end, incorporation of suitable protein scaffolds for PSI incorporation is of great scientific and device manufacturing interest. Areas of interest include solid state bioelectronics, and photoelectrochemical devices that require bio abio interfaces that do not compromise the photoactivity and photostability of PSI. Therefore, the surfactant-induced membrane solubilization of a negatively charged phospholipid (DPhPG) with the motivation of creating biomimetic reconstructs of PSI reconstitution in DPhPG liposomes is studied. Specifically, a simple yet elegant method for incorporation of PSI trimeric complexes into DPhPG bilayer membranes that mimic the natural thylakoid membrane housing of PSI is introduced. The efficacy of this method is demonstrated via absorption and fluorescence spectroscopy measurements as well as direct visualization using atomic force microscopy. This study provides direct evidence that PSI confinements in synthetic lipid scaffolds can be used for tuning the photoexcitation characteristics of PSI. Hence, it paves the way for development of fundamental understanding of microenvironment alterations on photochemical response of light activated membrane proteins. PMID- 28559592 TI - Gut microbiota: Inulin regulates endothelial function: a prebiotic smoking gun? PMID- 28559593 TI - Sonochemical Synthesis of Sulfur Doped Reduced Graphene Oxide Supported CuS Nanoparticles for the Non-Enzymatic Glucose Sensor Applications. AB - Over the present material synthesis routes, the sonochemical route is highly efficient and comfortable way to produce nanostructured materials. In this way, the copper sulfide (CuS-covellite) and sulfur doped reduced graphene oxide (S rGO) nanocomposite was prepared by sonochemical method. Interestingly, the structure of the as-prepared S-rGO/CuS was changed from the covellite to digenite phase. Herein, the S-rGO was act as a mild oxidizer and liable for the structural transformations. These structural changes are sequentially studied by various physicochemical characterizations such as Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and Transmission electron microscopy (TEM). After scrupulous structural evaluations, the transformation of CuS phase was identified and documented. This oxidized CuS has an excellent electrocatalytic activity when compare to the bulk CuS. This S-rGO/CuS was further used for the determination of glucose and acquired good electrocatalytic performances. This S-rGO/CuS was exhibited a wide linear concentration range, 0.0001-3.88 mM and 3.88-20.17 mM, and a low-level detection limit of 32 nM. Moreover, we have validated the practicability of our developed glucose sensor in real biological samples. PMID- 28559594 TI - Cassava derivatives in ice cream formulations: effects on physicochemical, physical and sensory properties. AB - In the present study, the effects of derivatives of cassava, maltodextrin and bagasse, on the physicochemical, physical and sensory properties of ice creams were investigated. The content of cassava maltodextrin increased significantly the content of carbohydrate and total soluble solids and decreased lipids content. The effect of cassava bagasse was more pronounced than the maltodextrin on physical and sensory parameters. Increased percentage of cassava bagasse in formulation led to decrease of overrun, melting and luminosity, but increased hardness and unfreezable water. Sensory attributes were mainly influenced by cassava bagasse inclusion. The results suggested the potential use of cassava derivatives in ice cream formulations. Ice creams with low percentage of cassava bagasse (1.5) and intermediate values of cassava maltodextrin (3.65%) had good nutritional, technological and sensorial acceptance. PMID- 28559595 TI - Sensory, spectrometric (PTR-ToF-MS) and chemometric analyses to distinguish extra virgin from virgin olive oils. AB - Olive oil samples were obtained from six cultivars grown in different environments, and graded by chemical analyses as extra virgin (EVOOs). These were evaluated for flavors and off-flavors, and relative VOCs spectrum as determined by PTR-ToF-MS. A hierarchical clustering of Panel test data separated olive oil in three groups, one including the samples with perceived off-flavor (VOOs), regardless of cultivar and environment. The Pearson's correlation coefficients between the mass data from PTR-ToF-MS and the sensory characteristics perceived by the Panel test were determined. A mass-to-sensory attributes correlation index was calculated. A color-coded card was built up based on the intensities (ncps) of five selected protonated mass data that was able to distinguish EVOOs from VOOs olive oil samples. PMID- 28559596 TI - Evaluation of fatty acid profile, color characteristics, oxidative quality and stability of common Kilka (Clupeonella cultriventris caspia) oil obtained by various extraction techniques. AB - This study aimed to evaluate the impact of various oil extraction procedures on yield, color properties, fatty acid profile and oxidative stability of common Kilka (Clupeonella cultriventris caspia) oil. The supercritical fluid extraction (SFE) with carbon dioxide, than other techniques (wet reduction, ammonia and enzymatic extractions), showed the highest oil yield (96.94%), the best oxidative and color characteristics, with 0.68 mg KOH/g oil, 2.62 meq O2/kg oil, 6.5 and 5.36 in terms of acid value (AV), peroxide value (PV), yellowness and redness, respectively, and have the highest total of unsaturated fatty acids average (10.33), especially the omega-3 family. Furthermore, the oil obtained by SFE had the best oxidative parameters; AV, PV and thiobarbituric acid values, during the whole 90 days of storage time at 4 degrees C. Therefore, the SFE is the most effective procedure at obtaining the oil from common Kilka tissue than other methods studied in this research. PMID- 28559597 TI - The effects of egg albumin incorporation on quality attributes of pale, soft, exudative (PSE-like) turkey rolls. AB - Pale, soft, exudative (PSE-like) poultry phenomenon has been a growing problem in meat industry in terms of quality and economic losses, thus data is required to evaluate PSE raw material in product formulations. The aim of our study was to investigate the effects of egg albumin (EA) utilization on quality characteristics of PSE-like turkey rolls. Turkey Pectoralis major muscles were exposed to either 40 degrees C to stimulate typical processing causing PSE or 0 degrees C to reduce PSE and keep the muscles "normal". Turkey rolls were prepared in nine different formulations; using 100% normal (N), 50% normal + 50% PSE (NP) or 100% PSE meat (P). Treatments also included 0, 1 or 2% EA. Addition of EA increased protein content of all samples. L*, a* and b* values were affected by PSE level. Increased levels of PSE caused decreased processing yields, while EA incorporation increased processing yield of the samples. Addition of 1% EA increased water-holding capacity (WHC) of the samples, while higher level of EA (2%) caused decrement in the same. Addition of either 1% or 2% EA was effective in reducing purge loss in P samples. Texture profile analysis showed that EA addition rather had considerable effects on N samples. Sensory scores showed that 1% EA utilization has the potential to increase mostly the mouthfeel of PSE-like products. Results showed that EA could be used as a promising ingredient that improved overall quality of PSE-like turkey rolls. PMID- 28559598 TI - Preparation of mayonnaise from extracted plant protein isolates of chickpea, broad bean and lupin flour: chemical, physiochemical, nutritional and therapeutic properties. AB - This investigation was aimed to study the molecular, physico-chemical, and biofunctional health properties of mayonnaise prepared using proteins isolated from broad bean, lupin and chickpea flour. Proteins were isolated from chickpea (CPPI), broad bean (BBPI) and lupin (LPPI) flour and assessed for molecular, physico-chemical, biofunctional, and protein yield. The highest water holding capacity, foaming stability, emulsion stability as well as protein yield and protein content of 44.0, 70.8, 37.5, 81.2, and 36.4, respectively were observed for BBPI. Mayonnaise prepared from the isolated plant proteins was evaluated for chemical composition, molecular properties of the protein subunits, and potential nutraceutical properties. Preparation of mayonnaise using BBPI or a mixture of either BBPI and CPPI or BBPI and LPPI showed superior values for lightness and lowered values for redness. Mayonnaise prepared from either BBPI or the BBPI and CPPI mixture showed the best antioxidant, antihypertensive and antidiabetic properties. The present study results indicated that the use of the BBPI and CPPI mixture can be a novel technological approach for the development of a mayonnaise with improved health promoting properties. PMID- 28559599 TI - The development of low glycemic index cookie bars from foxtail millet (Setaria italica), arrowroot (Maranta arundinacea) flour, and kidney beans (Phaseolus vulgaris). AB - Wholegrain foods are becoming increasingly popular as a high fiber dietary supplement recommended for people with diabetes. In Indonesia, the incidence of diabetes mellitus has almost doubled recently and poses a significant health risk with the high prevalence of obesity and cardiovascular diseases. The present research aimed to develop cookie bars from foxtail millet, arrowroot flour, and kidney beans. The physical, chemical, and sensory properties were evaluated by selecting the best formula to test the glycemic index. Three formulae of cookie bars, which had different percentages of foxtail millet, kidney beans, and arrowroot flour were evaluated. The results showed that the three formulae (F1, F2, F3) had degrees Hue values of 53.77, 58.46, and 58.31, and breaking force of 8.37, 10.12, and 5.87 N, respectively. While all other nutritional content were significantly different between formulae, the total crude fat was not. The F2 cookie bar was selected and evaluated for the glycemic index because it has the best sensory properties, lowest total sugar and available carbohydrate content. F2 cookie bars that contain 15% foxtail millet, 15% arrowroot flour, and 30% of kidney beans have a glycemic index of 37.6 hence it could be classified as a low glycemic index cookie bar. In conclusion, our findings indicated that F2 cookie bars can be further developed as a suitable diabetic food since it has the best physico-chemical properties, sensory properties, and low glycemic index. PMID- 28559601 TI - Effect of fermented and unfermented buckwheat flour on functional properties of gluten-free muffins. AB - Selected functional properties of four types of gluten-free muffins made of unfermented and fermented (by Lactobacillus plantarum) buckwheat flour in comparison with control muffins made using commercial gluten-free corn flour were evaluated in this study. The proximate chemical composition, antioxidant capacity analysed by ABTS, photochemiluminescence and cyclic voltammetry assays, and inhibitory activity against protein glycation in vitro in BSA/Glu systems were investigated. The content of the total phenolic compounds, available lysine, furosine, free and total FIC, browning index and antioxidant capacity of buckwheat-enhanced gluten-free muffins were higher compared to the control samples. Gluten-free muffins made of the fermented buckwheat flour showed a significantly higher antioxidant capacity, an increased activity against AGEs formation and an increased available lysine content, as well as a higher FAST index and browning index as compared to the muffins obtained with unfermented buckwheat flour. The study showed that buckwheat flour fermented by L. plantarum could be used as an ingredient for improving the functional properties of gluten free muffins. PMID- 28559600 TI - Particularities of Syrah wines from different growing regions of Southern Brazil: grapevine phenology and bioactive compounds. AB - The aim of this study was to monitor the phenological parameters of grapevine (Vitis vinifera) of Syrah variety recently introduced in the region of Marari, Agua Doce, Campos Novos and Sao Joaquim, Santa Catarina State (SC), Brazil, and to characterize the phenolic composition and antioxidant activity of wines produced from this variety of the vintages 2010 and 2011. The adaptation of the grapevine to climate conditions of these grape growing regions of Southern Brazil for this variety has also been assessed. The climate variations occurring between the phenological cycles of grapevine of Syrah for each growing region influenced the phenological extension and heat accumulation of the grapevine. The wines showed significant levels of phenolic compounds and high antioxidant activity, while catechin, a potent antioxidant, was the main phenolic compound quantified in wines. Positive correlations between the phenolic compounds and antioxidant activity were observed. The principal component analysis confirmed the influence of the growing region and vintages on the phenolic composition of wines, indicating the importance of climate conditions. This study identified possible phenolic markers indicative of climatic influence. PMID- 28559602 TI - Influence of different flours and starches on gluten-free bread aroma. AB - The aim of this research was to study the effect of different gluten-free flours (yellow and white corn, rice, oat, teff, buckwheat, amaranth and quinoa) and starches (wheat, corn and potato) on the generation of volatile compounds in the fermented doughs and crumbs. Volatile compounds were analyzed by static headspace gas chromatography/mass spectrometry (SHS-GC/MS). Nine fermentation and lipid oxidation volatile compounds were evaluated, which were found to be the same from dough to crumb but vary in levels. Concentrations of compounds produced during fermentation were higher in doughs whereas those from lipid oxidation were higher in crumbs. The type of flour/starch affected the concentration of these volatile compounds. The proportions of ethanol and 2/3-methylbutanol (fermentation compounds) were higher in dough from yellow and white corn, rice and oat while the proportions of hexanal, 1-pentanol and 2,4-decadienal (lipid oxidation compounds) were higher in the doughs made with starches. The proportions of ethanol and 2/3-methylbutanol were higher in quinoa and amaranth crumbs whilst hexanal, 1-pentanol and 2,4-decadienal were higher in yellow and white corn crumbs. PMID- 28559603 TI - Octopus vulgaris protein hydrolysates: characterization, antioxidant and functional properties. AB - Composition, functional properties and in vitro antioxidant activities of octopus (Octopus vulgaris) protein hydrolysates (OPHs) were evaluated. OPHs were prepared by treatment with commercial Esperase (OPH-Esp), alkaline protease extract from Zebra blenny (Salaria basilica) (OPH-ZB) and enzyme preparation from Bacillus subtilis A26 (OPH-A26). OPHs showed different degrees of hydrolysis (DH from 17.6 to 21%), and hydrophobic/hydrophilic peptide ratio. The amino acid profiles of OPHs showed a high level of essential amino acids, and Lys was the most abundant amino acid. Enzymatic hydrolysis improved solubility significantly as well as emulsifying and foaming properties of octopus proteins. The emulsifying activity index of OPHs decreased with increasing concentrations. Conversely, the foaming abilities increased as the hydrolysate concentrations increased. For the antioxidant activities, five different in vitro assay systems were investigated. All hydrolysates displayed various degrees and dose dependant antioxidant activities. The highest DPPH scavenging activity and reducing power were achieved by OPH-A26. OPH-Esp displayed the highest ability to prevent the bleaching of beta-carotene, whereas OPH-ZB exhibited the highest protection against hydroxyl radical induced DNA breakage. The results suggested that OPHs could be used, as a promising source of functional peptides with antioxidant activities, to formulate functional foods. PMID- 28559604 TI - Effects of tempering (annealing), acid hydrolysis, low-citric acid substitution on chemical and physicochemical properties of starches of four yam (Dioscorea spp.) cultivars. AB - The effects of tempering (annealing), acid hydrolysis and low-citric acid substitution on chemical and physicochemical properties of starches of four Nigerian yam cultivars were investigated. Crude fat and protein contents of the native starches decreased significantly after the modifications, while nitrogen free extract increased significantly with acid hydrolysis and citric acid substitution. Acid hydrolysis and low-citric acid substitution reduced the least concentration for gel formation of the starches from 4 to 2% w/v, but tempering had no effect. Swelling power of the starches reduced significantly, and water solubility increased significantly at 75 and 85 degrees C, especially with acid hydrolysis and low-citric acid substitution. However, tempering significantly reduced starch solubility in the four cultivars. Paste clarity of starches of white (29.17%), water (18.90%), yellow (30.90%) and bitter (10.57%) yams reduced significantly with tempering to 14.43, 11.83, 16.93 and 7.27%, but increased significantly with acid hydrolysis to 41.40, 35.37, 28.77 and 32.33%, and low citric acid substitution to 36.60, 44.17, 50.67 and 14.33%, respectively. Pasting properties such as peak, trough, breakdown, final, and setback viscosities and peak time of native starches reduced significantly with acid hydrolysis and low citric acid substitution, however, tempering significantly increased their pasting temperature, peak time, setback and final viscosities. PMID- 28559605 TI - Antioxidant and iron-chelating properties of taxifolin and its condensation product with glyoxylic acid. AB - The condensation of taxifolin with glyoxylic acid was examined, and the properties of the resulting product were compared with those of taxifolin. The structure of the product was determined by NMR spectroscopy. The ability of the polyphenols to scavenge reactive oxygen species (ROS) was estimated by luminol dependent chemiluminescence. The iron-chelating and iron-reducing activities were studied using absorption spectrophotometry. It was shown that the condensation leads to the formation of a dimer consisting of two taxifolin units linked through a carboxymethine bridge at the C-6 and C-8 positions of the A ring. The dimer exhibited a somewhat higher ROS scavenging activity than taxifolin. The iron-binding capacity of the compounds was proportional to the number of polyphenol units. The iron-reducing ability of the dimer was lower than that of taxifolin. Thus, the dimer possessed a higher antioxidant activity than the parent flavonoid. The data obtained may be useful for a better understanding of processes occurring in foods and beverages and in a search for new active compounds. PMID- 28559606 TI - Enzymatic hydrolysis of whey and its analysis. AB - An attempt was made to hydrolyze proteins and lactose in whey to improve the nutritive value of this byproduct, and extend its application as an ingredient to healthy beverages. Flavourzyme in different concentrations was used at pH 7.0 to hydrolyze protein at 50 degrees C. pH stat method, SDS-PAGE and RP HPLC-MS were used to evaluate degree of protein hydrolysis, pattern of peptide formation and characterize smaller peptides in hydrolysate, respectively. Higher concentration of enzymes produced more number of small peptides. Protein hydrolysate was again hydrolyzed at 30 degrees C with beta-galactosidase at pH 5.5 to hydrolyze lactose. HPLC analysis indicated the degree of lactose hydrolysis and number of tri/poly saccharides formed due to varied enzyme concentration. Results from the experiment can be utilized to formulate healthy whey beverages for specific purpose. PMID- 28559607 TI - Seasonal variation in phytochemicals and nutraceutical potential of Begonia nelumbiifolia consumed in Puebla, Mexico. AB - Begonia nelumbiifolia is a traditional edible plant consumed and commercialized in the northern highlands of Puebla, Mexico. The present study reports the seasonal variation in proximate analysis as well as organic acids, carotenoids and flavonoids content in both leaves and stalks of this plant. The stalks contained low concentrations of protein (~3%), fiber (~1.5%) and nitrogen free extract (~0.26%) during the time of study. Both organs showed contents of oxalic acid (91-103 mg 100 g-1 FW), ascorbic acid (50-65 mg 100 g-1 FW), lutein (1-2.5 mg 100 g-1 FW), beta-carotene (1-3 mg 100 g-1 FW), quercetin (1.3-2.7 mg 100 g-1 DW) and rutin (0.5-1.7 mg 100 g-1 DW). Antioxidant activity against DPPH was observed by the stalk extracts from 30% methanol (IC50, 0.21-0.37 mg L-1), pure methanol (IC50, 0.14-0.21 mg L-1) and hexane: acetone (IC50, 0.77-1.21 mg L-1). In vitro anti-HMG-CoA reductase (IC50, 0.07-0.36 mg L-1) and anti-alpha glucosidase (IC50, 0.28-0.43 mg L-1) activities were observed in extracts from the edible stalks from pure methanol and 30% methanol. The leaf extracts from 30% methanol inhibited the growth of Pseudomonas syringae pv. tabaci TBR2004 (MIC, 254 ug mL-1), P. syringae pv. tomato DC3000 (MIC, 423 ug mL-1), P. syringae pv. glycinea (MIC, 605 ug mL-1) and Clavibacter michiganensis AB299158 (MIC, 162 ug mL-1). B. nelumbiifolia contained valuable phytochemicals associated to nutraceutical and biological properties. However, the consumption of the fresh stalks must be carefully considered because of the high oxalate content. PMID- 28559608 TI - The states of water in glutinous rice flour characterized by interpreting desorption isotherm. AB - Water content of glutinous rice flour were determined after equilibrium at water activity (aw) of 0.06-0.98 and temperature of 10, 20 and 30 degrees C. Distribution of water in different states and its evolution with aw were characterized using four composite models. Interactions of water molecules with solid matrix and themselves were further evaluated. The Park model was a more realistic and mechanism-based approach for describing water desorption of glutinous rice flour. Increased equilibrium water induced by lowering temperature existed mostly as strongly bound water with only a few parts as weakly bound water. The water-polymer thermodynamic incompatibility predominated the water mobility, and resulted in a rapid decrease of diffusion coefficient at aw > ~0.7. Water diffusivity behavior with aw suggested water clustering at high aw levels. The Zimm-Lundberg theory, Park model and Brown analysis all revealed that critical aw of water clustering was of 0.81-0.85, depending on temperature, but gave inconsistent prediction about mean cluster size. PMID- 28559609 TI - Effect of Opuntia ficus-indica flowers maceration on quality and on heat stability of olive oil. AB - This study was focused on the evaluation of the quality and the oxidative stability of olive oil added with Opuntia ficus-indica flowers. Two different amounts of O. ficus-indica flowers were considered 5 and 15% (w/w). The olive oils were evaluated towards their quality, fatty acids profile, total phenol contents and thermal properties by differential scanning calorimetry. The oxidative stability was also monitored by employing the Rancimat and the oven test based on accelerating the oxidation process during storage. The addition of O. ficus-indica flowers induced an increase in free acidity values and a variation in fatty acids profile of olive oils but values remained under the limits required for an extra-virgin olive oil. The obtained olive oils were nutritionally enriched due to the increase in their phenols content. The oxidative stability was generally improved, mainly in olive oil enriched with 5% Opuntia ficus-indica flowers. These findings proved that this enriched olive oil could be considered as a product with a greater added value. PMID- 28559610 TI - Distribution of phenolic compounds and antioxidant capacity in apples tissues during ripening. AB - The effect of variety and ripening stage on the distribution of phenolic compounds and in vitro antioxidant capacity of Gala, Fuji Suprema and Eva apples were evaluated. Hydroxycinnamic acids, flavonoids, flavanols, flavonols, dihydrochalcones and antioxidant activity (FRAP and DPPH) were assessed in the epicarp, mesocarp and endocarp of three varieties at three ripening stages (unripe, ripe and senescent). The Fuji Suprema variety distinguished by its content of flavonols at senescent stage, while Eva variety distinguished by its content of dihydrochalcones (unripe stage) and anthocyanins (ripe stage). In general, phenolic acids and flavonoids decreased with ripening in the epicarp and endocarp. However, in the mesocarp, the effect of ripening was related with the apple variety. Hierarchical cluster analysis confirmed the influence of ripening in the apple tissue. The evolution of these compounds during ripening occurred irregularly and it was influenced by the variety. PMID- 28559611 TI - A benign alternative process for efficient separation of pure commercially important flavonoid nutraceuticals from edible plants. AB - The present study signifies the development of a unique, optimized procedure for both selective determination and separation of different flavonoid nutraceuticals from edible plants. Totally ten different flavonoids were determined (HPLC-DAD) and isolated from five different plants using the developed process with a remarkable purity of 91-98% and recovery of 88-95%. Box-Behnken experimental design model yielded a optimized amount of 40.36 mg/g of AI extract (Pinostrobin) and 28.95 mg/g of AI extract (Baicalein) with a high correlation coefficient (0.98-0.99), indicating a good fit between the second order regression model and the experimental observations. The final purity of compounds through optimized process is 97.1% (Pinostrobin) and 93.5% (Baicalein) respectively. The optimized yields depicted a total recovery of 92% for pinostrobin, and 89% for Baicalein respectively. Thus, the developed process worked as a potential alternative which when statistically optimized results in a remarkable recovery of flavonoids from various plants. Being an environmentally friendly protocol the process could be useful in industrial separation of commercially important flavonoids widely applied in food industry. PMID- 28559612 TI - Effect of osmotic dehydration pretreatment and glassy state storage on the quality attributes of frozen mangoes under long-term storage. AB - Changes in the quality of frozen mango cuboids were investigated during long-term glassy state storage with and without osmotic dehydration pretreatment. The mango cuboids were dehydrated in mixed solutions (sucrose: glucose: fructose in a ratio of 3.6:1:3) of different concentrations (30, 40, and 50% (wt/wt)) prior to freezing and then stored at -55 degrees C (in the glassy state) for 6 months. The results revealed that compared with the untreated samples, osmotic pretreatment decreased total color difference (reduced by 15.6-62.3%), drip loss (reduced by 8.2-29.5%) and titration acidity (reduced by 1.3-9.4%), while increasing hardness (increased by 48.8-82.3%), vitamin C content (increased by 72.5-120.6%) and total soluble solids (increased by 21.8-53.7%) of frozen mangoes after 6 months. Dehydration with a sugar concentration of 40% was considered as the optimal pretreatment condition. In addition, a storage temperature of -55 degrees C provided better retention of quality than rubbery state storage at -18 degrees C. With prolonged storage time, the quality of frozen mangoes continued to change, even in the glassy state. However, the changes in quality of the osmotic-dehydrated samples were less than those of the untreated samples. The current work indicates that osmotic pretreatment and glassy state storage significantly improved the quality of frozen mangoes during long-term storage. PMID- 28559613 TI - Comparative analyses of prediction models for inactivation of Escherichia coli in carrot juice by means of pulsed electric fields. AB - This paper reports the prediction capacity of various microbial inactivation models to prefigure the bactericidal effect using pulsed electric field (PEF) on liquid food. The aim of study was to compare the various inactivation models based on accuracy and bias factor to find out the most accurate inactivation model for Escherichia coli present in carrot juice treated with PEF. In this study, E. coli suspended in carrot juice was treated with varying pulsed electric field strength for different intervals. The obtained data were utilized for the evaluation of parameters of Bigelow, Peleg, Hulsheger and Weibull inactivation models. Furthermore, secondary models were developed for Hulsheger and Weibull to predict the microbial inactivation at any level of field strength and treatment time. The secondary model for Hulsheger exhibits 5.8% error as compared to the Weibull model having 8.5% error in prediction of death kinetics of E. coli suspended in carrot juice by means of PEF. The comparative analysis of secondary models to forecast the unknown data set unveiled the superior functioning of Hulsheger model. PMID- 28559614 TI - Harvest date and storage effect on fruit size, phenolic content and antioxidant capacity of wild blueberries of NW Ontario, Canada. AB - Blueberries are eaten fresh or after storing at room temperature, refrigerator or freezer but little is known about changes in food values of wild blueberries due to harvest dates and storage conditions. The aim of this study was to investigate the effect of harvest date and storage conditions of wild blueberries on berry quality and health related chemistry. We analyzed Vaccinium angustifolium, V. angustifolium var. nigrum, and V. myrtilloides native to NW Ontario, Canada harvested early and late in the season for total phenol (TP), anthocyanin contents (AC), and soluble solids to titratable acidity ratio storing at room temperature, refrigerator and freezer temperature. We also determined their antioxidant content and activity (ORAC). Late harvest and low temperature storage significantly increased TP and AC for most genotypes. In V. myrtilloides TP increased by 50, 44 and 45% respectively at late harvest, 14 days refrigerator and 90 days freezer storage. It also had significantly higher ORAC (22 and 33%) than the other two genotypes. Wild blueberry pickers and consumers can optimize health benefits and quality attributes of blueberries by customizing harvest protocols and choice of cultivar and storage in household fridge and freezer. Blueberry storage, at household fridge and freezer temperature, does not reduce its health benefits. PMID- 28559616 TI - Response surface optimization of extraction protocols to obtain phenolic rich antioxidant from sea buckthorn and their potential application into model meat system. AB - In the present study, processing parameters for the extraction of phenolic rich sea buckthorn seed (SBTE) extract were optimised using response surface method and subjected for in vitro efficacy viz. total phenolic, ABTS, DPPH and SASA activity. The optimised model depicted MeOH as a solvent at 60% concentration level with a reaction time of 20 min and extracting temperature of 55 degrees C for the highest yield and total phenolic content. The efficacy of different concentration of obtained SBT was evaluated in raw ground pork as a model meat system on the basis of various physico-chemical, microbiological, sensory quality characteristics. Addition of 0.3% SBTE significantly reduced the lipid peroxidation (PV, TBARS and FFA) and improved instrumental colour (L*, a*, b*) attributes of raw ground pork during refrigerated storage of 9 days. Results concluded that SBTE at 0.3% level can successfully improve the oxidative stability, microbial, sensory quality attributes in the meat model system. PMID- 28559617 TI - Two isoforms of lipoxygenase from mature grains of pearl millet [Pennisetum glaucum (L.) R. Br.]: purification and physico-chemico-kinetic characterization. AB - This study describes the partial purification and characterization of lipoxygenase (LOX) from pearl millet mature grains of inbred HBL 0843-2. Two isoforms of LOX, i.e., LOX 1 and LOX 2, were purified using ammonium sulphate fractionation, gel filtration chromatography and ion exchange chromatography near homogeneity to 56 and 40 folds with yield of 28 and 24%, respectively. LOX 1 and LOX 2 having molecular masses of approximately 85 and 79 kDa, respectively were purified. LOX 1 and LOX 2 exhibited maximum activity at pH 4.5 and 4.8, respectively at 25 degrees C temperature. Both the isoforms, which showed thermostability up to 35 degrees C when incubated for 30 min, were stable at a pH range of 7-7.8. LOX 1 and LOX 2 had apparent Km value of 0.86 and 0.57 uM, respectively. Ascorbic acid and vitamin E inhibited 66-78 and 61-69% activity of LOX 1 and LOX 2, respectively but Na+, Zn2+ and K+ strongly inhibited the activity of these isozymes. The present information about lipoxygenase enzyme might be valuable in drafting the strategies for its inactivation, which in turn can obstruct the LOX damaging effects on food products during processing and storage. PMID- 28559615 TI - Screening of enzymatic activities within different enological non-Saccharomyces yeasts. AB - Ninety-seven non-Saccharomyces wine yeast strains belonging to ten different genera and species (Candida spp. and Criptococcus spp.; Debaryomyces hansenii, Lachancea thermotolerans, Metschnikowia pulcherrima, Pichia kluyveri, Sporidiobolus salmonicolor, Torulaspora delbrueckii, Williopsis pratensis and Zygosaccharomyces bailii) were screened for 13 enzymes related to wine aroma, color and clarity. Understanding the yeasts' influence in these wine characteristics provides a platform for selecting strains for their development as starter cultures and for the management of alcoholic fermentation. Most of the strains showed the presence of one or more enzymes of biotechnological interest. Our screening demonstrated several intraspecific differences within the yeast species investigated, indicating that strain selection is of great importance for their enological application, and also that some non-Saccharomyces that have not been thoroughly explored, may deserve further consideration. This research represents the first stage for selecting non-Saccharomyces strains to be used as a starter along with Saccharomyces cerevisiae to enhance some particular characteristics of wines. PMID- 28559619 TI - Evaluation of different hydrocolloids to improve dough rheological properties and bread quality of potato-wheat flour. AB - The aim of study was to investigate the effect of hydroxylpropylmethylcellulose (HPMC), arabic gum (AG), konjac glucomannan (KG) and apple pectin (AP) at 2% (w/w, potato-wheat flour basis) on the potato-wheat dough (the mass ratio was 1:1) rheological, fermentation and bread making properties. The tan delta of potato-wheat dough was significantly increased upon addition of adding HPMC which was close to wheat dough (0.531). Moreover, dough height during fermentation process was significantly improved on addition of hydrocolloids, with the order of HPMC (23.1 mm) > AP (19.3 mm) > AG (18.6 mm) > KG (13.6 mm). Protein bands of potato-wheat dough were pale in the presence of hydrocolloids, suggesting the formation of higher molecular weight aggregates formed between proteins hydrocolloids or proteins-proteins after fermentation process. Furthermore, HPMC significantly increased specific volume (from 1.45 to 2.22 ml/g), and hydrocolloids restricted the retrogradation of starch in potato-wheat breads. PMID- 28559618 TI - Identification of food preservative, stress relief compounds by GC-MS and HR-LC/Q TOF/MS; evaluation of antioxidant activity of Acalypha indica leaves methanolic extract (in vitro) and polyphenolic fraction (in vivo). AB - The present paper has been designed to evaluate phytochemical profile, in vitro free radical scavenging activity, cytotoxicity of methanolic extract and in vivo antioxidant activity of polyphenolic fraction of Acalypha indica leaves. Methanolic extract of A. indica leaves (MEAIL) contained rich amount of phenols, flavonoids and saponins. The GC-MS analysis of extract revealed 13 compounds, whereas HR-LC/Q-TOF/MS showed 87, and all were coincided with functional groups identified by FTIR. The extract showed good scavenging activity on DPPH, H2O2, hydroxyl radicals and metal ions. The Polyphenolic fraction induced the antioxidant enzymes in Diabetic rats. The extract also potentially showed cytotoxic (LC50: 140.02 ug/mL) activity against brine shrimp. Based on these analytical results, in vitro and in vivo experiments, it was concluded that the MEAIL has encompassed rich amount of polyphenols (antioxidants) and cytotoxic compounds for their respective activities. Polyphenolic fraction has the induction capacity to elevate cellular antioxidant enzymes in diabetic animals. PMID- 28559620 TI - Physical, microbiological and rheological properties of probiotic yogurt supplemented with grape extract. AB - In this study, yogurt was supplemented with 1.5 and 3.0 g L-1 of grape extract, inoculated culture containing Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus acidophilus and Bifidobacterium bb12 bifidum, fermented and stored at 4 degrees C. Acid production, microbial growth, gel strength, syneresis, rheological and sensory properties were studied. An increase in grape extract concentration extended fermentation time. Bacterial strains were found in at least 109 CFU100 g-1 of yogurt showing the possibility of probiotic yogurt production with grape extract. Gel strength decreased with increasing concentration of grape extract while syneresis increased. The addition of grape extract changed the dilatant behavior to a pseudoplastic behavior, decreased yield stress, whereas k values increased. Sensory attributes (color, flavor, taste, texture and appearance) didn't differ significantly. PMID- 28559621 TI - Physico-chemical, microstructural and rheological properties of camel-milk yogurt as enhanced by microbial transglutaminase. AB - Camel milk produces watery texture when it is processed to yogurt. Despite the extensive studies on microbial transglutaminase (MTGase) in dairy research, the effect of this enzyme on the properties of yogurt made from camel milk has not been studied. This study aims to investigate the impact of MTGase with and without bovine skimmed milk powder (SMP), whey protein concentrate (WPC),or beta lactoglobulin (beta-lg) on physico-chemical, rheological, microstructural, and sensory properties of camel-milk yogurt during 15 days of storage period. MTGase treatment markedly reduced the fermentation time of unfortified and SMP-fortified camel milk. The fortification of camel milk without MTGase failed to give set type yogurt. The treatment of unfortified milk with MTGase enormously improved the viscosity and the body of yogurt samples. Fortification of MTGase-treated milk impacted positively on the viscosity, the water holding capacity, and the density of the protein matrix in the gel microstructure, which were influenced by the type of dairy ingredients. All MTGase-treated yogurts differed from each other in hardness and adhesiveness values. Electrophoresis results showed that the susceptibility of the individual milk proteins to MTGase varied, and there were differences among the treatments toward the enzyme. SMP-fortified yogurt was the most accepted product. Generally, the addition of MTGase preparation at a concentration of 0.4%, simultaneously with starter culture, to fortified camel milk was considered an effective tool to solve the challenges of producing set type yogurt from this milk. PMID- 28559622 TI - The effects of certain enzymes on the rheology of dough and the quality characteristics of bread prepared from wheat meal. AB - This study was carried out to evaluate the effects of amyloglucosidase, glucose oxidase, hemicellulase (mainly consist of endo-1,4-beta-xylanase), cellulase, lipase, and the combination of phospholipase and hemicellulase (phospholipase + hemicellulase) on the extensographic properties of dough and the quality characteristics of bread prepared from wheat meal. The enzymes were added separately in two different amounts. The addition of glucose oxidase (at 0.0003 0.001%) caused a significant decrease in the resistance to extension, ratio of resistance to extensibility and energy values of the wheat meal dough compared with the control dough. The addition of hemicellulase (at 0.001-0.005%) and phospholipase + hemicellulase (at 0.0006-0.0009%) also improved the wheat meal dough rheology by reducing the resistance to extension and the ratio of resistance to extensibility. Glucose oxidase (at 0.0003-0.001%), hemicellulase (at 0.001-0.005%) and phospholipase + hemicellulase (at 0.0006-0.0009%) addition improved the specific volume of wheat meal bread compared with the control bread. Increasing the dosage of glucose oxidase from 0.0003 to 0.001% caused a further increase in the specific volume of wheat meal bread. The addition of hemicellulase (at 0.001-0.005%) caused a significant decrease in the baking loss and an increase in the moisture content of wheat meal bread compared with the control bread. The addition of amyloglucosidase (at 0.000875-0.001%), lipase (at 0.0002-0.001%) and cellulase (at 0.0003-0.0005%) did not considerably affected the dough rheological and the quality characteristics of wheat meal bread. PMID- 28559623 TI - Rheological properties of reduced fat ice cream mix containing octenyl succinylated pearl millet starch. AB - The octenyl succinyl anhydride (OSA) esterified pearl millet (Pennisetum typhoides) starch was evaluated as fat replacer in soft serve ice cream in comparison to other fat replacers viz. inulin, whey protein concentrate-70 and commercial starch. During temperature sweep test, the yield stress and flow behaviour index of un-pasteurized ice cream mixes increased as the temperature increased from 40 to 80 degrees C, while the consistency index decreased. Consistency index of aged ice cream mixes containing 2% fat replacer was higher as compared to mixes with 1% level. The aged ice cream mixes exhibited non Newtonian behaviour as flow behaviour index values were less than one. Apparent viscosity (at 50 s-1 shear rate) of control as well as ice cream mix containing 1% OSA-esterified pearl millet starch samples was 417 and 415 mPas, respectively and did not differ significantly. The overrun of the ice cream (with 5 and 7.5% fat) containing 1 and 2% of above fat replacers ranged between 29.7 and 34.3% and was significantly lower than control (40.3%). The percent melted ice cream was also low for the ice creams containing 2% of above fat replacers at 5% fat content as compared to control. However, sensory acceptability and rheological characteristics of reduced fat ice creams containing 1.0 and 2.0% OSA-esterified pearl millet starch were at par with other fat replacers under the study. Thus, OSA-esterified pearl millet starch has potential to be used as fat replacer in reduced fat ice cream. PMID- 28559624 TI - Characteristics and gelling properties of gelatin from goat skin as affected by drying methods. AB - Characteristics and gel properties of spray-dried goat skin gelatin (SDGG) and freeze-dried counterpart (FDGG) were determined, in comparison with commercial bovine gelatin (BG). SDGG gel had the similar gel strength to FDGG gel and their gel strengths were higher than that of BG gel. SDGG gel showed slightly higher a* and b* values as well as the higher solution turbidity than those of FDGG. Both SDGG and FDGG solutions could set at room temperature (25-28 degrees C) within 18.52-19.30 min and showed the gelling and melting temperatures of 25.14-25.23 and 34.09-34.18 degrees C, respectively. Gels from SDGG and FDGG had the denser structure with smaller voids than that from BG. Therefore, drying methods affected the characteristics and gel properties of gelatin from goat skin to some degree. PMID- 28559625 TI - Effect of soaking and single/two cycle high pressure treatment on water absorption, color, morphology and cooked texture of brown rice. AB - Water absorption, color, morphology and cooked texture of brown rice were evaluated after selected soaking (30-50 degrees C, 30 min) and high pressure treatment (HPT) (100-500 MPa; single or two cycle; total holding time 10 min). Water absorption ratio and lightness values of brown rice were increased by soaking and HPT. Hardness and gumminess values of cooked brown rice were reduced while springiness and cohesiveness were elevated by HPT. Scanning electron microscopy indicated that HPT improved the texture of brown rice by disrupting the structure of rice bran layer, which allowed easier water penetration into the rice grain during cooking. Moreover, the two cycle HPT resulted in lighter color and softer texture for cooked brown rice than single cycle HPT primarily caused by the more severe structural disruption of bran layer. Overall, two cycle HPT after soaking could potentially improve the quality of brown rice, taking about the same time as the single cycle HPT. Further, the quality improvements with the two cycle HPT were facilitated at lower pressure levels thereby providing better commercial processing opportunities. PMID- 28559626 TI - Optimization of antioxidant efficacy of a deflavored and decolorized rosemary extract: effect of carnosol content on the oxidative stability of paprika colored beef patties. AB - Considering the significance of natural antioxidants to preserve meat, the present study was undertaken to evaluate the efficacy of a deflavored and decolorised extract of rosemary (StabilRoseTM) for the production and preservation of naturally colored fresh meat. Oxidative rancidity of meat and color degradation of paprika oleoresin were exploited as model systems and compared with butylated hydroxyanisole (BHA). The results showed similar efficacy for 3% carnosic acid extract and BHA, with further enhancement in efficacy with respect to the carnosic acid content. A synergetic antioxidant effect of carnosol on carnosic acid content was also noticed to an extent of 1:1 (w/w) ratio, and further increase in carnosol content showed no improvement in the antioxidant efficacy. Finally, stabilized paprika and optimized rosemary extract containing carnosic acid and carnosol in 1:1 (w/w) ratio was successfully applied to produce naturally colored meat suitable for storage at 4 +/- 1 degrees C. PMID- 28559627 TI - Physico-chemical, functional and rheological properties of milk protein concentrate 60 as affected by disodium phosphate addition, diafiltration and homogenization. AB - Ultrafiltration and diafiltration of skim milk altered delicate salt equilibrium and composition of 5* UF retentate (5* UFR), and thus adversely affected the reconstitutional and functional properties of milk protein concentrate (MPC) powders. It might be due to interaction and aggregation of proteins during spray drying. Therefore, this study was envisaged to investigate the effect of disodium phosphate (DSP) addition, diafiltration and homogenization of retentates on physico-chemical, functional and rheological properties of MPC60 powders. Solubility of fresh control powder was significantly lower than MPC60-H powder; at par with that of MPC60-DSP and MPC60-Na-K, but remained minimum after 60 days of storage at 25 +/- 1 degrees C. The pH (6.6) adjustment of 5* UFR with DSP, significantly enhanced the dispersability, wettability, specific surface area (SSA), heat coagulation time (HCT), emulsification capacity and stability; buffer index of MPC60-DSP powder over control. Diafiltration of 5* UFR with NaCl and KCl, significantly (P < 0.05) decreased calcium content, but enhanced pH and mineral content of MPC60-Na-K powder. This treatment led to significant improvement in dispersability, SSA, emulsification capacity and stability, HCT and oil binding properties. Flowability, wettability, dispersability, HCT, foaming capacity, emulsification capacity and stability were also improved significantly in MPC60-H powder made from homogenized 5* UFR. Rheological behavior of reconstituted powder samples exhibited pseudoplastic behavior, best explained by Hershel Bulkley model. These MPC60 powders with improved functional properties can be used for the improvement of quality attributes of various food formulations. PMID- 28559628 TI - Responses of fresh-cut products of four mango cultivars under two different storage conditions. AB - Due to availability of minimally processed products, the consumption of fresh produce has increased over recent years. The present study has been undertaken with the objective of screening of four mango cultivars ('Kesar', 'Rajapuri', 'Totapuri' and 'Ladvo') for evaluating the consequences of minimal processing on their quality attributes under storage at two different temperatures (5 +/- 1 degrees C, 95% RH and 10 +/- 1 degrees C, 87% RH) up to 12 days. The result of the study revealed significant impacts of low temperature storage on the quality parameters of fresh-cut mango cultivars. The evaluated bioactive compounds such as total phenolics, vitamin C and carotenoids were better retained in the samples stored at 5 degrees C as compared with that of 10 degrees C. Moreover, the storage of fresh-cut mango cultivars at 5 degrees C showed lower water loss and microbial contamination. Sensory analyses revealed that the storage of fresh-cut mango cultivars at 10 degrees C influenced overall acceptability due to changes in their visual perception, though taste, odor and firmness were less affected. This study revealed a significant variation in the storability of fresh-cut mango cultivars with respect to the storage temperature. Among currently studied four cultivars of mango, slices of 'Totapuri' showed comparatively the least change in color, firmness and sensory properties during storage at 5 and 10 degrees C and it can be a potential cultivar for fresh-cut processing. PMID- 28559629 TI - Preparation and characterization of a novel edible film based on Alyssum homolocarpum seed gum. AB - In this study a novel biodegradable edible film based on Alyssum homolocarpum seed gum (AHSG) was fabricated and characterized. Glycerol at three levels (25, 35, and 45% based on dried AHSG) as plasticizer were added. The microstructure and barrier, electromagnetic, mechanical, and thermal properties of the film were characterized. Results showed that permeability to both oxygen and water vapor, increased as the plasticizer content increased from 25 to 45%. The mechanical properties of AHSG films were comparable to those of polysaccharide films. Results showed that the glycerol content significantly decreased the glass transition temperature of the film. The color measurement indicated that increasing the plasticizer content augmented the b* and L* values. Results of the field emission scanning electron microscopy revealed a uniform and smooth surface morphology and an absence of phase separation among the film compositions. The findings demonstrated that AHSG has the potential to fabricate edible films with enhanced quality characteristics. PMID- 28559630 TI - Investigation of process and product parameters for physicochemical properties of rice and mung bean (Vigna radiata) flour based extruded snacks. AB - PR 106 and SML 668 cultivars of rice and mung bean respectively, were studied for their potential to serve as a nutritious snack with improved protein quality and quantity. The effect of extrusion conditions, including feed moisture content (14 18%), screw speed (400-550 rpm) and barrel temperature (130-170 degrees C) on the physicochemical properties (bulk density, water absorption index (WAI), water solubility index (WSI) and hardness) was investigated. The replacement of rice flour at 30% level with mung bean flour for making extruded snacks was evaluated. Pasting temperature increased (84-93 degrees C) while peak viscosity (2768-408 cP), hold viscosity (2018-369 cP), breakdown (750-39 cP), setback (2697-622 cP) and final viscosity (4715-991 cP) decreased with increasing mung bean flour addition. Increasing feed moisture lowered the specific mechanical energy (SME), WAI and WSI of extrudates whereas increased bulk density and hardness. Higher screw speed had linear positive effect on SME of extruder and negative linear effect on WAI. Positive curvilinear quadratic effect of screw speed was also observed on WSI and density. Higher barrel temperature linearly decreased the SME, density and hardness of extrudates. Developed extrusion cooked rice-mung bean snacks with increased protein content and improved protein quality along with higher dietary fibre and minerals have good potential in effectively delivering the nutrition to the population. PMID- 28559631 TI - Effect of olive leaf extract rich in oleuropein on the quality of virgin olive oil. AB - Effect of olive leaf extract rich in oleuropein on the quality of virgin olive oil was investigated. After extracting the dried and ground olive leaves with the assistance of homogenizer, the dried extract was partially dissolved into the oil to increase the oxidative stability of the oil. A face central composite design through response surface methodology was used to investigate the effects of enrichment conditions (extract content, time and mixing speed) on the responses, total phenolic content and oleuropein concentration of the enriched olive oil. Furthermore, antioxidant activity of the oil was determined by 2,2'-azino-bis-(3 ethylbenzothiazoline-6-sulfonic acid) diammonium salt method. Additionally, oxidative stability of the enriched oil was assessed by the Rancimat method. Total carotenoid content, peroxide value, alpha-tocopherol and chlorophyll were also measured, respectively. Addition of 0.15% natural antioxidant increased the stability of the oil (~46%). The antioxidant capacity of the enriched oil was almost 2.5 times higher than that of the untreated oil. Furthermore, olive leaf extract improved the quality of the virgin olive oil with respect to tocopherol, carotenoid and chlorophyll contents and peroxide value, respectively. The leaf sampling was also performed both in the autumn and summer to evaluate the possible seasonal effects on phenolic profile in order to be careful for selecting the proper harvesting time to apply the extract into the oil. PMID- 28559632 TI - Achiote (Bixa orellana L.): a natural source of pigment and vitamin E. AB - Commercialization of agricultural products, including seeds and its derived products, represents an important economic source for developing countries. Natural colorants obtained from the seeds of achiote plant (annatto) have been used since pre-Hispanic times. Also, production of this crop has been important for Mayan cuisine. Annual world production of achiote seeds is approximately 14,500 tons (dry weight). Two thirds of the production is commercialized as dried seeds and the rest as colorant. Latin America produces 60% of the total world production, followed by Africa (27%) and Asia (12%). The main producers in Latin America are Peru, Brazil and Mexico. The purpose of the present paper is to review the most recent literature on Bixa orellana L. focusing on bixin, norbixin, tocotrienols and tocopherols biosynthesis, use and industrial applications of annatto extracts, as well as its nutraceutical potential and its benefits for human health. PMID- 28559633 TI - Studies on chemical composition of yellowfin tuna (Thunnus albacares, Bonnaterre, 1788) eye. AB - Chemical composition viz., fatty acids, amino acids and minerals of yellowfin tuna (Thunnus albacares) eye were analyzed for better utilization of fish processing discards. Analysis of fatty acids composition by gas chromatography mass spectrometry revealed the presence of polyunsaturated fatty acids namely docosahexaenoic acid, eicosapentaenoic acid, arachidonic acid and linoleic acid at the levels of 37.8, 7.1, 3.6 and 1.4%, respectively. The major available monounsaturated fatty acids, palmitoleic acid and oleic acid were present at the level of 17.9 and 18.3% respectively. Myristic acid was the dominant saturated fatty acid and occupied 2% of the total fatty acids. Amino acid analysis by high performance liquid chromatography showed that the tuna eye has a high concentration of glycine (19.24 mg/100 g) followed by glutamic acid (16 mg/100 g) and aspartic acid (12.76 mg/100 g). Analysis of mineral content of tuna eye showed the presence of higher sodium and lower copper content. The results revealed that yellowfin tuna eye could be used as a potential source of omega-3 fatty acids and essential amino acids. PMID- 28559640 TI - Is Colombia a Violent Country? PMID- 28559641 TI - Self-report health-related quality of life among children and adolescents from Bogota, Colombia. The FUPRECOL study. AB - OBJECTIVE: To describe by self-report the HRQoL among schoolchildren from Bogota, Colombia belonging to the FUPRECOL study. METHODS: A cross-sectional study in 3,245 children and 3,354 adolescents, between 9 and 17.9 years old, participated in the study. Spanish version of the EQ-5D-Y was self-assessment. Percentages of missing values and reported problems were calculated. The data was analyzed by measurement of central tendency stratified by age group, and to compare them to international references. RESULTS: A total of 58.3%, (n= 3,848) were women. In all ages, the HRQoL was higher in boys than in girls. To compare by sex, the dimensions of the EQ-5D-Y "feeling worried, sad or unhappy" and "having pain or discomfort", showed the highest frequency among women. Overall, our HRQoL were higher than South Africa, Germany and Italy references. CONCLUSION: The HRQoL was higher in boys than in girls The HRQoL. The dimensions of the EQ-5D-Y "feeling worried, sad or unhappy" and "having pain or discomfort", showed the highest frequency. The HRQoL by age and sex may be used in the evaluation of the health perceived among schoolchildren from Bogota. PMID- 28559642 TI - Metric properties of the "timed get up and go- modified version" test, in risk assessment of falls in active women. AB - OBJECTIVE: To analyse the metric properties of the Timed Get up and Go-Modified Version Test (TGUGM), in risk assessment of falls in a group of physically active women. METHODS: A sample was constituted by 202 women over 55 years of age, were assessed through a crosssectional study. The TGUGM was applied to assess their fall risk. The test was analysed by comparison of the qualitative and quantitative information and by factor analysis. The development of a logistic regression model explained the risk of falls according to the test components. RESULTS: The TGUGM was useful for assessing the risk of falls in the studied group. The test revealed two factors: the Get Up and the Gait with dual task. Less than twelve points in the evaluation or runtimes higher than 35 seconds was associated with high risk of falling. More than 35 seconds in the test indicated a risk fall probability greater than 0.50. Also, scores less than 12 points were associated with a delay of 7 seconds more in the execution of the test (p= 0.0016). CONCLUSIONS: Factor analysis of TGUGM revealed two dimensions that can be independent predictors of risk of falling: The Get up that explains between 64% and 87% of the risk of falling, and the Gait with dual task, that explains between 77% and 95% of risk of falling. PMID- 28559643 TI - Variability between Clarke's angle and Chippaux-Smirak index for the diagnosis of flat feet. AB - BACKGROUND: The measurements used in diagnosing biomechanical pathologies vary greatly. The aim of this study was to determine the concordance between Clarke's angle and Chippaux-Smirak index, and to determine the validity of Clarke's angle using the Chippaux-Smirak index as a reference. METHODS: Observational study in a random population sample (n= 1,002) in A Coruna (Spain). After informed patient consent and ethical review approval, a study was conducted of anthropometric variables, Charlson comorbidity score, and podiatric examination (Clarke's angle and Chippaux-Smirak index). Descriptive analysis and multivariate logistic regression were performed. RESULTS: The prevalence of flat feet, using a podoscope, was 19.0% for the left foot and 18.9% for the right foot, increasing with age. The prevalence of flat feet according to the Chippaux-Smirak index or Clarke's angle increases significantly, reaching 62.0% and 29.7% respectively. The concordance (kappa I) between the indices according to age groups varied between 0.25-0.33 (left foot) and 0.21-0.30 (right foot). The intraclass correlation coefficient (ICC) between the Chippaux-Smirak index and Clarke's angle was -0.445 (left foot) and -0.424 (right foot). After adjusting for age, body mass index (BMI), comorbidity score and gender, the only variable with an independent effect to predict discordance was the BMI (OR= 0.969; 95% CI: 0.940 0.998). CONCLUSION: There is little concordance between the indices studied for the purpose of diagnosing foot arch pathologies. In turn, Clarke's angle has a limited sensitivity in diagnosing flat feet, using the Chippaux-Smirak index as a reference. This discordance decreases with higher BMI values. PMID- 28559644 TI - Severe microscopic polyangiitis with unilateral vocal cord paralysis as initial manifestation. AB - CASE DESCRIPTION: A 16 year-old female who presented with initial ear, nose and throat manifestations who later progressed to severe renal disease, requiring hemodialysis after 11 months of unique laryngeal involvement. CLINICAL FINDINGS: Unilateral vocal cord paralysis without other symptoms or signs, but with positive perinuclear anti-neutrophil cytoplasmic antibodies (ANCA) and anti myeloperoxidase autoantibodies, followed an unfavorable course months later with rapidly progressive glomerulonephritis. Renal biopsy confirmed an ANCA-associated vasculitis. She was diagnosed with microscopic polyangiitis. TREATMENT AND OUTCOME: High-dose glucocorticoids, intravenous cyclophosphamide, plasma exchange and finally, hemodialysis and renal transplantation. CLINICAL RELEVANCE: In contrast to granulomatosis with polyangiitis (Wegener), ear, nose and throat manifestations in microscopic polyangiitis are uncommon, while involvement of the lungs and kidneys are usual. We present a case with an isolated rare involvement, which progressed to severe disease. This atypical case warns about laryngeal symptoms as initial manifestation of an anti-myeloperoxidase positive systemic vasculitides, and emphasizes the relevance of close observation when unexplained isolated conditions with accompanying evidence of autoimmunity, in this case high levels of specific autoantibodies, are present. PMID- 28559645 TI - Comorbidity between HTLV-1-associated adult T-cell lymphoma/leukemia and verrucous carcinoma: a case report. AB - BACKGROUND: Adult T-cell Leukemia/Lymphoma (ATLL) is classified as a peripheral CD4+ T-cell neoplasm caused by the human T-cell lymphotropic virus type 1 (HTLV 1). Typical symptoms are associated with leukemic infiltration; however, atypical and exaggerated manifestations of verrucous carcinoma have also been described. CASE REPORT: We present here the case of a patient with multiple skin lesions, ischemic necrosis in the hallux and lymphadenopathies. Biopsies were taken, which showed verrucous epidermal carcinoma and cutaneous lymphoma. Splenomegaly and adenopathy in mesentery, retro peritoneum and lymph node chains in the limbs were observed. Bone marrow examination showed findings compatible with T-cell leukemia/lymphoma; and it was ELISA positive for HTLV-1/2. TREATMENT AND OUTCOME: The patient had a good initial response to a CHOP scheme (cyclophosphamide, doxorubicin, vincristine and prednisone) with filgrastim. However, the patient had a relapse and died before the second cycle. CLINICAL RELEVANCE: Comorbidity could lead to the associated risk factors model. According to this model, secondary immunodeficiency caused by HTLV-1 may induce the development of verrucous carcinomas; alternatively, the disease could be due to a correlation between HTLV-1 and the human papillomavirus (HPV). PMID- 28559647 TI - Erratum: Preliminary Characterisation of Cognition and Social Cognition in Spinocerebellar Ataxia Types 2, 1, and 7. AB - [This corrects the article DOI: 10.3233/BEN-2010-0270.]. PMID- 28559646 TI - Assessing Cognitive Ability and Simulator-Based Driving Performance in Poststroke Adults. AB - Driving is an important activity of daily living, which is increasingly relied upon as the population ages. It has been well-established that cognitive processes decline following a stroke and these processes may influence driving performance. There is much debate on the use of off-road neurological assessments and driving simulators as tools to predict driving performance; however, the majority of research uses unlicensed poststroke drivers, making the comparability of poststroke adults to that of a control group difficult. It stands to reason that in order to determine whether simulators and cognitive assessments can accurately assess driving performance, the baseline should be set by licenced drivers. Therefore, the aim of this study was to assess differences in cognitive ability and driving simulator performance in licensed community-dwelling poststroke drivers and controls. Two groups of licensed drivers (37 poststroke and 43 controls) were assessed using several cognitive tasks and using a driving simulator. The poststroke adults exhibited poorer cognitive ability; however, there were no differences in simulator performance between groups except that the poststroke drivers demonstrated less variability in driver headway. The application of these results as a prescreening toolbox for poststroke drivers is discussed. PMID- 28559648 TI - Current concepts in the articular cartilage repair and regeneration. PMID- 28559649 TI - Tranexamic acid in total hip arthroplasty: A recursive cumulative meta-analysis of randomized controlled trials and assessment of publication bias. AB - INTRODUCTION: TXA has been evaluated in THA in several randomized controlled trials for the past 16 years. We attempted to evaluate the trends in the evidence using recursive cumulative meta-analysis and publication bias using Rosenthal and 'Trim and Fill' methods. METHODS: Electronic databases were searched for randomized controlled clinical trials comparing TXA with either placebo (or no TXA administration) or TXA, administered through different routes in patients with osteoarthritis or osteonecrosis of the hip who underwent THA. We considered the total number of patients requiring blood transfusion as the clinical outcome for both the analyses and used quality effects model for assessing the changes in the pooled estimates with addition of new clinical trial data. We also assessed the publication bias by plotting individual study estimates with the standard errors using Rosenthal and 'Trim and Fill'methods. RESULTS: A total of 20 studies were included. The pooled cumulative meta-analysis indicates that from 2014 the addition of estimate from new studies in the following years is only narrowing the confidence interval without any significant change in the point estimate. Rosenthal fail-safe-N for the comparisons of intravenous bolus TXA, intra operative and post-operative intravenous TXA and topical with control groups were 54, 6 and 16 respectively. Fail-safe-N for the combined intravenous and topical TXA with intravenous TXA alone was 13. CONCLUSION: Adequate evidence exists supporting the use of intravenous TXA in reducing the need for blood transfusion in THA. There is possible existence of small studies with null effects evaluating the use of TXA in THA. PMID- 28559650 TI - A numerical study on stress distribution across the ankle joint: Effects of material distribution of bone, muscle force and ligaments. AB - OBJECTIVE: The goal of this study is to develop a realistic three dimensional FE model of intact ankle joint. METHODS: Three dimensional FE model of the intact ankle joint was developed using computed tomography data sets. The effect of muscle force, ligaments and proper material property distribution of bone on stress distribution across the intact ankle joint was studied separately. RESULTS: Present study indicates bone material property, ligaments and muscle force have influence on stress distribution across the ankle joint. CONCLUSION: Proper bone material, ligaments and muscle must be considered in the computational model for pre-clinical analysis of ankle prosthesis. PMID- 28559652 TI - Mini-Review of the Chin-Shan Community Cardiovascular Cohort Study in Population Health Research in Taiwan. AB - Preventing and controlling non-communicable diseases (NCDs) is a growing global public health concern, and evidence-based data from population-based health studies are needed in order to develop appropriate public health policies for controlling NCDs. The Chin-Shan Community Cardiovascular Cohort (CCCC) study is a prospective cohort consisting of participants from one community in China in 1990 1991, and has provided substantial evidence-based data on domestic and global health issues in preventive cardiology fields. The present study is a mini-review of the CCCC study. In this review, we have described the historical background of the cardiovascular disease burden and related risk factors, especially lifestyle factors, subclinical disease markers, biomarkers and prediction models, and related international collaborative projects. In addition, this mini-review study provides a measure of insight into future plans for 21st century epidemiological research in cardiovascular diseases, suggesting possible areas of focus for future research. PMID- 28559651 TI - The 2017 Focused Update of the Guidelines of the Taiwan Society of Cardiology (TSOC) and the Taiwan Hypertension Society (THS) for the Management of Hypertension. AB - Hypertension (HT) is the most important risk factor for cardiovascular diseases. Over the past 25 years, the number of individuals with hypertension and the estimated associated deaths has increased substantially. There have been great debates in the past few years on the blood pressure (BP) targets. The 2013 European Society of Hypertension and European Society of Cardiology HT guidelines suggested a unified systolic BP target of 140 mmHg for both high-risk and low risk patients. The 2014 Joint National Committee report further raised the systolic BP targets to 150 mmHg for those aged >= 60 years, including patients with stroke or coronary heart disease, and raised the systolic BP target to 140 mmHg for diabetes. Instead, the 2015 Hypertension Guidelines of the Taiwan Society of Cardiology and the Taiwan Hypertension Society suggested more aggressive BP targets of < 130/80 mmHg for patients with diabetes, coronary heart disease, chronic kidney disease with proteinuria, and atrial fibrillation patients on antithrombotic therapy. Based on the main findings from the Systolic Blood Pressure Intervention Trial (SPRINT) and several recent meta-analyses, the HT committee members of the Taiwan Society of Cardiology and the Taiwan Hypertension Society convened and finalized the revised BP targets for management of HT. We suggested a new systolic BP target to < 120 mmHg for patients with coronary heart disease, chronic kidney disease with an eGFR of 20-60 ml/min/1.73 m2, and elderly patients aged >= 75 years, using unattended automated office BP measurement. When traditional office BP measurement is applied, we suggested BP target of < 140/90 mmHg for elderly patients with an age >= 75 years. Other BP targets with traditional office BP measurement remain unchanged. With these more aggressive BP targets, it is foreseeable that the cardiovascular events will decrease substantially in Taiwan. PMID- 28559653 TI - Clinical Characteristics of Patients Less than Forty Years Old with Coronary Artery Disease in Taiwan: A Cross-Sectional Study. AB - BACKGROUND: Coronary artery disease (CAD) rarely occurs in young adults. Our objective was to investigate the baseline characteristics and outcomes of young patients with CAD. METHODS: We retrospectively enrolled patients aged < 40 years of age who underwent coronary angiography in a tertiary hospital in Taiwan between 2002 and 2015. The baseline characteristics and in-hospital outcomes of patients with acute coronary syndrome (ACS) and occlusive CAD (stenotic lesions > 50%) were compared with those of patients without ACS and non-occlusive CAD, respectively. RESULTS: We enrolled 245 young patients including 131 (53.5%) with ACS and 178 with occlusive CAD. The median age of the patients was 36.08 years and the mean follow-up period was 4.84 years. Of all study subjects, 220 (89.8%) were men and 140 (57.1%) were current smokers; there was an overall in-hospital mortality rate of 3.3%. Furthermore, age, body mass index, smoking, total leukocyte count, neutrophil-to-lymphocyte ratio, total cholesterol, and low density lipoprotein were higher in patients with ACS and significant CAD than in those without ACS and nonstenotic CAD. Interestingly, triglyceride (TG) levels and the TG to high-density lipoprotein ratio were significantly higher in patients with ACS and occlusive CAD than in those without ACS and non-occlusive CAD. Logistic regression analysis revealed that smoking is an independent predictor of ACS and occlusive CAD. CONCLUSIONS: Our findings suggest that classical risk factors, obesity, and inflammation remain potent contributors to occlusive CAD and ACS in young adults in Taiwan. Efforts to prevent or minimize these risk factors, such as smoking cessation and aggressive lipid control, are necessary in young adults. PMID- 28559654 TI - Aortic Arch Calcification Associated with Cardiovascular Events and Death among Patients with Acute Coronary Syndrome. AB - BACKGROUND: To date, it remains unsettled whether aortic arch calcification (AAC) has prognostic value in patients with acute coronary syndrome. METHODS: From January 1 to December 31, 2013, a total of 225 patients with acute coronary syndrome (mean age 72 +/- 26 years, 75% male) were enrolled in this study. Patients admitted to the coronary care unit of a tertiary referral medical center under the preliminary diagnosis of acute coronary syndrome were retrospectively investigated. The primary endpoint was composite of long-term major adverse cardiovascular events. The secondary endpoints were 30-day and long-term all cause mortality. RESULTS: Of the 225 patients enrolled in this study, 143 had detectable AAC. Those who had AAC were older, with higher Killip classification and thrombolysis in myocardial infarction (TIMI) score with a lower probability of single vessel disease. Acute coronary syndrome patients with AAC had significantly higher 30-day mortality (17.3% vs. 7.1%, log-rank p = 0.02). During a mean follow-up period of 165 +/- 140 days (maximum 492 days), the calcification group had significantly increased cardiovascular deaths (27.6% vs. 11.2%, log rank p = 0.002), all-cause mortality (28.3% vs. 11.2%, log-rank p = 0.001) and composite endpoint of major adverse cardiovascular events (39.4% vs. 24.6%, log rank p = 0.01). After adjusting for age, gender, diabetes mellitus and hypertension, AAC was an independent risk factor for primary and secondary endpoints among patients with acute coronary syndrome. CONCLUSIONS: AAC provided valuable prognostic information on clinical outcomes in patients with acute coronary syndrome. However, different treatment strategies would be warranted for optimal risk reduction in such a population. PMID- 28559655 TI - Everolimus-Eluting Bioresorbable Vascular Scaffold in Real World Practice - A Single Center Experience. AB - BACKGROUND: Drug-eluting stents are widely used in coronary artery intervention. However, vessel caging and very late thrombotic events are of persistent and substantial concern. Bioresorbable vascular scaffolds (BVS) were developed to deliver vascular reparative therapy, by eliminating permanent mechanical restraint. However, data regarding its clinical performance is lacking. METHODS: After the BVS implantation procedure received national approval in May 2014, patients receiving BVS implantation until November 2014 in National Taiwan University Hospital (NTUH) were enrolled. Clinical variables, angiographic data, procedural details, and follow-up information were collected and compared with those receiving BVS at NTUH as part of the global ABSORB EXTEND trial. RESULTS: A total of 35 patients (38 target vessels) with 48 BVS implanted after approval were enrolled, as the "real-world practice" group. Data of the 34 patients (34 target vessels) with 37 BVS implanted in the ABSORB EXTEND trial were also obtained. Differences in lesion complexity (0% type B2/C lesion in ABSORB EXTEND, versus 23.7% in real-world, p = 0.007) and lesion length (20.9 +/- 6.1 mm in ABSORB EXTEND, versus 29.5 +/- 15.9 mm in real-world, p = 0.008) were noted. The ischemia-driven target vessel revascularization after an average of 732 days follow-up was 11.8% in the ABSORB EXTEND trial. However, there was no ischemia driven target lesion revascularization (TLR), no scaffold thrombosis, no myocardial infarction (MI), and no patients passed during the follow-up period. In real-world patients, there is 5.3% of MI, 2.6% ischemia-driven TLR, and 2.6% of non-fatal probable scaffold thrombosis. CONCLUSIONS: The use of BVS in real world practice is feasible, with clinical outcomes comparable to those in the ABSORB EXTEND trial. PMID- 28559656 TI - Local Intracoronary Infusion of Glycoprotein IIb/IIIa Inhibitors via a Perfusion Catheter versus Intracoronary Guiding Catheter Injection during Primary Percutaneous Coronary Intervention: A Pilot Observational Study. AB - BACKGROUND: Glycoprotein IIb IIIa inhibitors improved short- and long-term outcome when added to primary percutaneous coronary intervention (PPCI) in patients with ST-segment-elevation myocardial infarction (STEMI). We hypothesized that intracoronary eptifibatide infusion via a perfusion catheter improves angiographic and clinical outcome of patients with STEMI undergoing PPCI, versus conventional intracoronary bolus injection. METHODS: Prospectively, we enrolled 80 patients with acute STEMI and thrombolysis in myocardial infarction (TIMI) thrombus grade >= 2. Patients were assigned to receive eptifibatide (180 MUg) either via a dedicated coronary perfusion catheter (ClearWayTM) during PPCI (group I), or guiding catheter (group II). Assessment of TIMI thrombus grade, TIMI flow grade, and TIMI myocardial perfusion (TMP) grade was performed both at baseline and post- procedurally. The primary 'angiographic' endpoint was final TMP grade 0/1. The primary 'clinical' endpoint was a composite of cardiac death, non-fatal re-infarction, target vessel revascularization, and recurrent ischemia at 30-day follow-up. RESULTS: Mean age was 52.3 +/- 8.9 years (17.5% females). Clearance of visible thrombus (TIMI thrombus grade 0) at final angiogram was more frequent in group I. Additionally, both final TIMI flow grade 3 and final TMP grade 3 occurred more frequently in group I. The primary angiographic endpoint was more frequent in group II versus group I (17.5% versus 0%, respectively, p = 0.001). The primary clinical endpoint was more frequent in group II (20% versus 0%, respectively, p = 0.003). CONCLUSIONS: In patients with STEMI, intracoronary eptifibatide infusion via a perfusion catheter during PPCI improved immediate angiographic outcome, and reduced clinical events at 30-day follow-up, versus bolus injection via the guiding catheter. PMID- 28559658 TI - Platelet Endothelial Cell Adhesion Molecule-1 Gene Polymorphisms are Associated with Coronary Artery Lesions in the Chronic Stage of Kawasaki Disease. AB - BACKGROUND: Kawasaki disease is the most common cause of pediatric acquired heart disease. The role of platelet endothelial cell adhesion molecule-1 in the inflammatory process has been documented. To date, no report has investigated the relationship between coronary artery lesions of Kawasaki disease and platelet endothelial cell adhesion molecule-1 polymorphisms. METHODS: A total of 114 Kawasaki disease children with coronary artery lesions and 185 Kawasaki disease children without coronary artery lesions were recruited in this study. The TaqMan assay was conducted to identify the genotype in this case-control study. RESULTS: In three single nucleotide polymorphisms (Leu125Val, Ser563Asn, and Arg670Gly) of platelet endothelial cell adhesion molecule-1, we found that the Leu-Ser-Arg haplotype was associated with a significantly increased risk for coronary artery lesions in the chronic stage (odds ratio 3.05, 95% confidence interval 1.06-8.80, p = 0.039), but not for coronary artery lesions in the acute stage. Analysis based on the diplotypes of platelet endothelial cell adhesion molecule-1 also showed that Kawasaki disease with one or two alleles of Leu-Ser-Arg had a significantly increased risk of chronic coronary artery lesions (odds ratio 3.38, 95% confidence interval 1.11-10.28, p = 0.032) and had increased platelet counts after Kawasaki disease was diagnosed, as compared to those with other diplotypes. CONCLUSIONS: The haplotype of platelet endothelial cell adhesion molecule-1 Leu Ser-Arg might be associated with the increased platelet counts and the following risk of chronic coronary artery lesions in a dominant manner in Kawasaki disease. PMID- 28559657 TI - Epicardial Adipose Tissue Thickness and Carotid Intima-Media Thickness in Hemodialysis Patients. AB - BACKGROUND: It is well-known that cardiovascular risk and all-cause mortality is increased in hemodialysis patients. Epicardial fat thickness (EFT), which reflects visceral adiposity, has been suggested as a new cardiometabolic risk factor. The purpose of this study was to investigate EFT in hemodialysis patients. METHODS: A total of 144 consecutive patients (60 hemodialysis patients and 84 controls) were enrolled into the study, and patients with diabetes mellitus and cardiovascular diseases (CVD) were excluded. EFT was measured on the free wall of the right ventricle at end-diastole from the parasternal long-axis view by standard transthorasic 2D echocardiography. RESULTS: The groups were similar in terms of sex distribution, age, blood pressure, heart rate and frequencies of CAD risk factors including smoking status, family history of CAD and hypertension. There were no significant differences between the hemodialysis patients and controls in 2D echocardiographic parameters, including ejection fraction and biochemical parameters except low-density lipoprotein, high-density lipoprotein and c- reactive protein. Despite having lower body mass index, EFT levels were significantly higher in hemodialysis patients compared to the controls (8.0 +/- 2.2 mm vs. 5.8 +/- 1.9 mm; p < 0.01). In multivariate linear regression analysis we determined that hemodialysis patient status was found to be an independent predictor for both EFT (beta = 0. 700, p = 0.014) and carotid intima-media thickness (CIMT, beta = 0. 614, p = 0.047). CONCLUSIONS: Hemodialysis patients are independently associated with high EFT and CIMT. PMID- 28559659 TI - Shen-Yuan-Dan Capsule Inhibiting Inflammatory Reaction by Regulating Insulin Receptor Substrate 1/PI3K/Akt/NF-kappaB Signaling Pathway in Apoliprotein E Knockout Mice Fed with a High-Fat Diet. AB - BACKGROUND: Shen-Yuan-Dan Capsule (SYDC), a traditional Chinese medicine, is proposed to have the capacity to prevent angina pectoris. However, the effects and the related mechanisms of SYDC on atherosclerosis (AS) are still unknown. This study was designed to investigate the effects of SYDC on AS and inflammatory reaction in the apoliprotein E-knockout (ApoE-/-) mice fed with a high-fat diet. METHODS: Thirty eight-week-old male ApoE-/- mice were randomly divided into three groups (n = 10) 6 weeks after being fed with a high-fat diet: the control group, the lipitor group, and the SYDC group. The hearts were collected for hematoxylin and eosin (HE) or Van Gieson (VG) staining, and the aortas were collected for quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blotting. RESULTS: The data showed that the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), atherosclerotic indexes (AI) and the corrected areas of atherosclerotic plaque of the mice on SYDC group were significantly decreased compared with those of the mice in the control group (p < 0.01, p < 0.05). SYDC can significantly increase collagen proportion in plaques as compared to the untreated mice (p < 0.01). In addition, the messenger ribonucleic acid (mRNA) expressions of insulin receptor substrate 1 (IRS-1), PI3K, Akt, NF-kappaB and tumor necrosis factor-alpha (TNF-alpha) in the mice fed with a high-fat diet were significantly reduced by SYDC (p < 0.05, p < 0.01). CONCLUSIONS: SYDC can exert an anti-atherosclerotic effect on ApoE-/- mice fed with a high-fat diet. The action mechanism of SYDC was attributed to its ability to inhibit inflammatory reaction by regulating IRS-1/PI3K/Akt/NF-kappaB signaling pathway. PMID- 28559660 TI - Mean Platelet Volume as a Predictor of Heart Failure-Related Hospitalizations in Stable Heart Failure Outpatients with Sinus Rhythm. AB - BACKGROUND: In this study, we investigated the relationship between the mean platelet volume (MPV) with mortality and heart failure (HF)-related hospitalization in stable chronic HF outpatients with reduced ejection fraction (HFrEF) and with sinus rhythm (SR). METHODS: This retrospective cohort study included 197 consecutive stable chronic HFrEF outpatients with SR, who were admitted to our cardiology outpatient clinics for examination between January 2014 and January 2015. According to the receiver-operating characteristic curve analysis, the optimal cut-off value of MPV to predict HF-related hospitalization was > 9.1 fL. Patients were classified into two categories according to threshold MPV levels, as group I with MPV <= 9.1 fL and group II with MPV > 9.1 fL. RESULTS: The mean age of patients was 65 +/- 13 years. The mean follow-up duration was 10 +/- 3 months, and 44 patients (22%) succumbed to cardiovascular (CV) death. The rate of CV mortality was similar between the two groups (21% vs. 24%, p = 0.649). However, the rate of patients who experienced HF-related hospitalization was lower in group I compared with group II (41% vs. 87%, p < 0.001, respectively). Univariate analysis demonstrated associations of many clinical factors in addition to increased MPV > 9.1 fL with HF-related hospitalization; however, In the multivariate Cox proportional-hazards model, only increased MPV > 9.1 fL (HR: 2.895, 95% CI: 1.774-4.724, p < 0.001), systolic pulmonary artery pressure level (HR: 1.018, 95% CI: 1.001-1.036, p = 0.048) and pre-admission beta blocker use (HR: 0.517, 95% CI: 0.305-0.877, p = 0.014) remained associated with a risk of HF-related hospitalization. CONCLUSIONS: The mean platelet volume might be a useful parameter for risk stratification with regard to HF-related hospitalization in HFrEF outpatients with SR. PMID- 28559661 TI - Potential Screening for Cardiologist? PMID- 28559662 TI - The Relationship between Brachial-Ankle Pulse Wave Velocity and Depressive Symptoms among Patients with Coronary Artery Disease. AB - BACKGROUND: Noninvasive brachial-ankle pulse wave velocity (baPWV) is an index for arterial stiffness in coronary artery disease (CAD). Depression has been connected to increased adverse cardiac events and mortality among patients with CAD. The aim of this study was to investigate the relationship between arterial stiffness and depressive symptoms among patients with CAD. METHODS: Eighty-six patients with CAD were recruited. Demographic characteristics and Beck Depressive Inventory II scores were obtained from the study participants, and resting baPWV was measured by using a noninvasive device. Thereafter, the participants were divided into mild and severe arteriosclerosis groups according to baPWV values. RESULTS: After adjusting the age, use of beta-blockers, and left ventricular ejection fraction, there were higher somatic symptoms of depression in the severe arteriosclerosis group than those in the mild arteriosclerosis group, in particular concentration difficulty, changes in appetite, and fatigue. A multiple regression analysis indicated that baPWV was related to somatic symptoms of depression after adjusting the covariates of CAD risk factors. However, this association was not found between baPWV and cognitive symptoms of depression, and the total score of depression. CONCLUSIONS: This study supports the proposition that somatic symptom of depression was related to arterial stiffness among patients with CAD. PMID- 28559663 TI - Consecutive Sessions of Rescue Balloon Atrial Septostomy for an Idiopathic Pulmonary Arterial Hypertension Patient with Refractory Right Heart Failure - Usefulness of Intracardiac Echocardiography Guidance. AB - For idiopathic pulmonary artery hypertension (PAH) patients with end-stage right heart failure who received maximal medical therapy, balloon atrial septostomy (BAS) is recommended by most guidelines as a palliative therapy or a bridging treatment before lung transplantation. In this report, we described a 32-year-old woman with idiopathic PAH, who received maximal PAH-specific medical treatment, including intravenous prostacyclin, but still suffered from refractory right heart failure. The markedly enlarged right atrium (RA), high mean RA pressure of 23 mmHg, low systemic arterial oxygen saturation of 86% and concomitant pancytopenia all increased the patient's risk for BAS. We used intracardiac echocardiography (ICE) guidance to facilitate trans-septal puncture, and performed graded BAS four times within 7 months to stabilize the patient. Our case showed that with dedicated PAH treatment, an experienced structural heart interventionist and ICE guidance, BAS could be done safely even in a patient in unfavorable clinical and hemodynamic condition. PMID- 28559664 TI - How radiological findings can help or hinder patients' recovery in the rehabilitation management of patients with low back pain: what can clinicians do? PMID- 28559665 TI - Spinal mobilization vs conventional physiotherapy in the management of chronic low back pain due to spinal disk degeneration: a randomized controlled trial. AB - OBJECTIVES: The aim of the study was to examine the efficacy of spinal mobilization in subjects with low back pain (LBP) and associated spinal disk degeneration. METHODS: Seventy-five subjects suffering from chronic LBP (>3 months) were randomly allocated into 3 groups of 25 subjects each. Each group received five treatment sessions with the first group receiving manual therapy (MT) (spinal mobilization), the second a sham treatment, and the third conventional physiotherapy (CP) (stretching exercises, transcutaneous electrical nerve stimulation, and massage). Subjects were assessed for their pain intensity using the numerical pain rating scale and for their self-reported disability using the Oswestry and Roland-Morris Questionnaire at baseline and after the completion of the five treatment sessions. RESULTS: Paired t-tests showed a significant improvement for all outcome measures in the MT and CP group (p < 0.05). Analysis of covariance revealed that the MT group had significant improvement in all outcome measures in comparison with the sham and CP group (p < 0.05), whereas no significant difference was observed between the sham and CP group (p > 0.05). DISCUSSION: MT is preferable to CP in order to reduce the pain intensity and disability in subjects with chronic LBP and associated disk degeneration. The findings of this study may lead to the establishment of spinal mobilization as one of the most preferable approaches for the management of LBP due to disk degeneration. LEVEL OF EVIDENCE: 1b. PMID- 28559666 TI - Thrust joint manipulation utilization by U.S. physical therapists. AB - STUDY DESIGN: Online survey study. OBJECTIVE: To determine physical therapists' utilization of thrust joint manipulation (TJM) and their comfort level in using TJM between the cervical, thoracic, and lumbar regions of the spine. We hypothesized that physical therapists who use TJM would report regular use and comfort providing it to the thoracic and lumbar spines, but not so much for the cervical spine. BACKGROUND: Recent surveys of first professional physical therapy degree programs have found that TJM to the cervical spine is not taught to the same degree as to the thoracic and lumbar spines. METHODS: We developed a survey to capture the required information and had a Delphi panel of 15 expert orthopedic physical therapists review it and provide constructive feedback. A revised version of the survey was sent to the same Delphi panel and consensus was obtained on the final survey instrument. The revised survey was made available to any licensed physical therapists in the U.S.A. using an online survey system, from October 2014 through June 2015. RESULTS: Of 1014 responses collected, 1000 completed surveys were included for analysis. There were 478 (48%) males; the mean age of respondents was 39.7 +/- 10.81 years (range 24-92); and mean years of clinical experience was 13.6 +/- 10.62. A majority of respondents felt that TJM was safe and effective when applied to lumbar (90.5%) and thoracic (91.1%) spines; however, a smaller percentage (68.9%) felt that about the cervical spine. More therapists reported they would perform additional screening prior to providing TJM to the cervical spine than they would for the lumbar and thoracic spines. Therapists agreed they were less likely to provide and feel comfortable with TJM in the cervical spine compared to the thoracic and lumbar spines. Finally, therapists who are male; practice in orthopedic spine setting; are aware of manipulation clinical prediction rules; and have manual therapy certification, are more likely to use TJM and be comfortable with it in all three regions. CONCLUSION: Results indicate that respondents do not believe TJM for the cervical spine to be as safe and efficacious as that for the lumbar and thoracic spines. Further, they are more likely to perform additional screening, abstain from and do not feel comfortable performing TJM for the cervical spine. CLINICAL RELEVANCE: Our research reveals there is a discrepancy between utilization of TJM at different spinal levels. This research provides an opportunity to address variability in clinical practice among physical therapists utilizing TJM. PMID- 28559667 TI - Inter-rater reliability of the McKenzie System of Mechanical Diagnosis and Therapy in the examination of the knee. AB - OBJECTIVE: The McKenzie System of Mechanical Diagnosis and Therapy (MDT) is a widely used method of classification and management of musculoskeletal problems. Although MDT has been investigated for its reliability and efficacy in the management of spinal pain, few studies have evaluated the system when applying it to musculoskeletal problems in the extremities, in particular the knee. The purpose of this study was to investigate the inter-rater reliability of MDT when classifying clinical vignettes describing patients with musculoskeletal knee pain. METHODS: This study was divided into two phases. First, 10 clinicians experienced in the use of MDT were recruited to write a total of 60 clinical vignettes based upon the initial assessment of their past patients with knee pain. Second, six different MDT raters were recruited to rate 53 selected vignettes and reliability was determined using Fleiss Kappa. RESULTS: There was 'substantial agreement' among six MDT raters classifying the clinical vignettes into one of four categories (kappa = 0.72). There was no statistically significant difference between therapists with different levels of training. DISCUSSION: MDT demonstrated acceptable reliability among trained raters to classify clinical vignettes describing patients with musculoskeletal knee pain. To generalize the use of the system to more users, future research should continue to investigate the reliability of MDT using raters with lower levels of training and experience and assess reliability in real patients. LEVEL OF EVIDENCE: 5. PMID- 28559668 TI - Effect of leg dominance, gender and age on sensory responses to structural differentiation of straight leg raise test in asymptomatic subjects: a cross sectional study. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVES: To assess the effect of structural differentiation on sensory responses of asymptomatic individuals to standard neurodynamic tests of straight leg raise (SLR) and to evaluate the relevance of leg dominance, gender, and age. BACKGROUND: SLR test is a well-known neurodynamic test among physical therapists; no studies to date have investigated the influence of gender, age, and leg dominance to the sensory responses of this neurodynamic test and its structured differentiating maneuver. METHODS: Thirty (16 women) asymptomatic individuals enrolled in this study. Dominancy test was performed for each participant. Pain intensity using visual analogue scale (VAS), symptoms location in a body chart, nature of symptoms evoked, and hip range of motion (ROM) were recorded and compared at ankle neutral position (N-SLR) and dorsiflexion (DF-SLR) in both legs at the point of pain tolerance during SLR (P2). In addition, hip ROM was recorded at the onset of pain (P1). RESULTS: There was a statistically significant sex main effect for P1 and P2 between N-SLR and DF-SLR (p < 0.05). Mean hip ROM during the SLR was more than 10 degrees greater in women than men. There was no statistically significant interaction between leg dominance and age group in N-SLR, DF-SLR, and VAS. Pain intensity was moderate for each SLR test. Symptoms most often described were stretch (96.7%), followed by tightness (70%) in the posterior thigh and leg. CONCLUSIONS: SLR hip ROM is influenced by sex in asymptomatic individuals, leading to a greater hip ROM in SLR in women. Age and limb dominance are not relevant to SLR hip ROM or pain intensity. PMID- 28559669 TI - The effect of spinal position on sciatic nerve excursion during seated neural mobilisation exercises: an in vivo study using ultrasound imaging. AB - OBJECTIVES: Research has established that the amount of inherent tension a peripheral nerve tract is exposed to influences nerve excursion and joint range of movement (ROM). The effect that spinal posture has on sciatic nerve excursion during neural mobilisation exercises has yet to be determined. The purpose of this research was to examine the influence of different sitting positions (slump sitting versus upright-sitting) on the amount of longitudinal sciatic nerve movement during different neural mobilisation exercises commonly used in clinical practice. METHODS: High-resolution ultrasound imaging followed by frame-by-frame cross-correlation analysis was used to assess sciatic nerve excursion. Thirty four healthy participants each performed three different neural mobilisation exercises in slump-sitting and upright-sitting. Means comparisons were used to examine the influence of sitting position on sciatic nerve excursion for the three mobilisation exercises. Linear regression analysis was used to determine whether any of the demographic data represented predictive variables for longitudinal sciatic nerve excursion. RESULTS: There was no significant difference in sciatic nerve excursion (across all neural mobilisation exercises) observed between upright-sitting and slump-sitting positions (P = 0.26). Although greater body mass index, greater knee ROM and younger age were associated with higher levels of sciatic nerve excursion, this model of variables offered weak predictability (R2 = 0.22). DISCUSSION: Following this study, there is no evidence that, in healthy people, longitudinal sciatic nerve excursion differs significantly with regards to the spinal posture (slump-sitting and upright sitting). Furthermore, although some demographic variables are weak predictors, the high variance suggests that there are other unknown variables that may predict sciatic nerve excursion. It can be inferred from this research that clinicians can individualise the design of seated neural mobilisation exercises, using different seated positions, based upon patient comfort and minimisation of neural mechanosensitivity with the knowledge that sciatic nerve excursion will not be significantly influenced. PMID- 28559671 TI - The Contributions of Human Rights to Universal Health Coverage. PMID- 28559670 TI - Manual therapy and eccentric exercise in the management of Achilles tendinopathy. AB - : Chronic Achilles tendinopathy (AT) is an overuse condition seen among runners. Eccentric exercise can decrease pain and improve function for those with chronic degenerative tendon changes; however, some individuals have continued pain requiring additional intervention. While joint mobilization and manipulation has not been studied in the management in Achilles tendinopathy, other chronic tendon dysfunction, such as lateral epicondylalgia, has responded well to manual therapy (MT). Three runners were seen in physical therapy (PT) for chronic AT. They were prescribed eccentric loading exercises and calf stretching. Joint mobilization and manipulation was implemented to improve foot and ankle mobility, decrease pain, and improve function. Immediate within-session changes in pain, heel raise repetitions, and pressure pain thresholds (PPT) were noted following joint directed MT in each patient. Each patient improved in self-reported function on the Achilles tendon specific Victorian Institute for Sport Assessment questionnaire (VISA-A), pain levels, PPT, joint mobility, ankle motion, and single-leg heel raises at discharge and 9-month follow-up. The addition of MT directed at local and remote sites may enhance the rehabilitation of patients with AT. Further research is necessary to determine the efficacy of adding joint mobilization to standard care for AT. LEVEL OF EVIDENCE: Case series. Therapy, Level 4. PMID- 28559672 TI - Universal Health Coverage: A Return to Alma-Ata and Ottawa. PMID- 28559673 TI - Three Case Studies in Making Fair Choices on the Path to Universal Health Coverage. AB - The goal of achieving Universal Health Coverage (UHC) can generally be realized only in stages. Moreover, resource, capacity, and political constraints mean governments often face difficult trade-offs on the path to UHC. In a 2014 report, Making fair choices on the path to UHC, the WHO Consultative Group on Equity and Universal Health Coverage articulated principles for making such trade-offs in an equitable manner. We present three case studies which illustrate how these principles can guide practical decision-making. These case studies show how progressive realization of the right to health can be effectively guided by priority-setting principles, including generating the greatest total health gain, priority for those who are worse off in a number of dimensions (including health, access to health services, and social and economic status), and financial risk protection. They also demonstrate the value of a fair and accountable process of priority setting. PMID- 28559674 TI - What Do Core Obligations under the Right to Health Bring to Universal Health Coverage? AB - Can the right to health, and particularly the core obligations of states specified under this right, assist in formulating and implementing universal health coverage (UHC), now included in the post-2015 Sustainable Development Goals? In this paper, we examine how core obligations under the right to health could lead to a version of UHC that is likely to advance equity and rights. We first address the affinity between the right to health and UHC as evinced through changing definitions of UHC and the health domains that UHC explicitly covers. We then engage with relevant interpretations of the right to health, including core obligations. We turn to analyze what core obligations might bring to UHC, particularly in defining what and who is covered. Finally, we acknowledge some of the risks associated with both UHC and core obligations and consider potential avenues for mitigating these risks. PMID- 28559675 TI - Using the Right to Health to Promote Universal Health Coverage: A Better Tool for Protecting Non-Nationals' Access to Affordable Health Care? AB - Five years ago, the World Health Assembly adopted a resolution on universal health coverage, followed a year later by a resolution from the United Nations General Assembly. In these resolutions, states promised to deliver affordable health care for everyone, referring to notions of equity and human rights law, particularly a human right to health. However, the explosion of migration coupled with the post-2008 bleak economic climate have led societies worldwide to restrict, or at least challenge, the affordability of access to national health systems for non-nationals. It is in this light that the claims of universality made by universal health coverage should be challenged. This article, therefore, will question the effectiveness of this global health policy in guaranteeing access to affordable health care for non-nationals and will ask whether and how legal avenues such as the right to health should be used to address potential weaknesses. PMID- 28559676 TI - Closing the Gap Between Formal and Material Health Care Coverage in Colombia. AB - This paper explores Colombia's road toward universal health care coverage. Using a policy-based approach, we show how, in Colombia, the legal expansion of health coverage is not sufficient and requires the development of appropriate and effective institutions. We distinguish between formal and material health coverage in order to underscore that, despite the rapid legal expansion of health care coverage, a considerable number of Colombians-especially those living in poor regions of the country-still lack material access to health care services. As a result of this gap between formal and material coverage, an individual living in a rich region has a much better chance of accessing basic health care than an inhabitant of a poor region. This gap between formal and material health coverage has also resulted in hundreds of thousands of citizens filing lawsuits tutelas-demanding access to medications and treatments that are covered by the health system, but that health insurance companies-also known as EPS- refuse to provide. We explore why part of the population that is formally insured is still unable to gain material access to health care and has to litigate in order to access mandatory health services. We conclude by discussing the current policy efforts to reform the health sector in order to achieve material, universal health care coverage. PMID- 28559677 TI - Human Rights and the Political Economy of Universal Health Care: Designing Equitable Financing. AB - Health system financing is a critical factor in securing universal health care and achieving equity in access and payment. The human rights framework offers valuable guidance for designing a financing strategy that meets these goals. This article presents a rights-based approach to health care financing developed by the human right to health care movement in the United States. Grounded in a human rights analysis of private, market-based health insurance, advocates make the case for public financing through progressive taxation. Financing mechanisms are measured against the twin goals of guaranteeing access to care and advancing economic equity. The added focus on the redistributive potential of health care financing recasts health reform as an economic policy intervention that can help fulfill broader economic and social rights obligations. Based on a review of recent universal health care reform efforts in the state of Vermont, this article reports on a rights-based public financing plan and model, which includes a new business tax directed against wage disparities. The modeling results suggest that a health system financed through equitable taxation could produce significant redistributive effects, thus increasing economic equity while generating sufficient funds to provide comprehensive health care as a universal public good. PMID- 28559678 TI - Assessing Private Sector Involvement in Health Care and Universal Health Coverage in Light of the Right to Health. AB - The goal of universal health coverage is to "ensure that all people obtain the health services they need without suffering financial hardship when paying for them." There are many connections between this goal and the state's legal obligation to realize the human right to health. In the context of this goal, it is important to assess private actors' involvement in the health sector. For example, private actors may not always have the incentives to deal with externalities that affect the availability, accessibility, acceptability, and quality of health care services; they may not be in a position to provide "public goods"; or they may operate under imperfect information. This paper sets out to answer the question, what legal human rights obligations do states have in terms of regulating private sector involvement in health care? PMID- 28559680 TI - Interpreting the International Right to Health in a Human Rights-Based Approach to Health. AB - This article tracks the shifting place of the international right to health, and human rights-based approaches to health, in the scholarly literature and United Nations (UN). From 1993 to 1994, the focus began to move from the right to health toward human rights-based approaches to health, including human rights guidance adopted by UN agencies in relation to specific health issues. There is a compelling case for a human rights-based approach to health, but it runs the risk of playing down the right to health, as evidenced by an examination of some UN human rights guidance. The right to health has important and distinctive qualities that are not provided by other rights-consequently, playing down the right to health can diminish rights-based approaches to health, as well as the right to health itself. Because general comments, the reports of UN Special Rapporteurs, and UN agencies' guidance are exercises in interpretation, I discuss methods of legal interpretation. I suggest that the International Covenant on Economic, Social and Cultural Rights permits distinctive interpretative methods within the boundaries established by the Vienna Convention on the Law of Treaties. I call for the right to health to be placed explicitly at the center of a rights-based approach and interpreted in accordance with public international law and international human rights law. PMID- 28559679 TI - Case Study of an Aboriginal Community-Controlled Health Service in Australia: Universal, Rights-Based, Publicly Funded Comprehensive Primary Health Care in Action. AB - Universal health coverage provides a framework to achieve health services coverage but does not articulate the model of care desired. Comprehensive primary health care includes promotive, preventive, curative, and rehabilitative interventions and health equity and health as a human right as central goals. In Australia, Aboriginal community-controlled health services have pioneered comprehensive primary health care since their inception in the early 1970s. Our five-year project on comprehensive primary health care in Australia partnered with six services, including one Aboriginal community-controlled health service, the Central Australian Aboriginal Congress. Our findings revealed more impressive outcomes in several areas-multidisciplinary work, community participation, cultural respect and accessibility strategies, preventive and promotive work, and advocacy and intersectoral collaboration on social determinants of health-at the Aboriginal community-controlled health service compared to the other participating South Australian services (state-managed and nongovernmental ones). Because of these strengths, the Central Australian Aboriginal Congress's community-controlled model of comprehensive primary health care deserves attention as a promising form of implementation of universal health coverage by articulating a model of care based on health as a human right that pursues the goal of health equity. PMID- 28559681 TI - International Human Rights and the Mistreatment of Women During Childbirth. AB - International human rights bodies have played a critical role in codifying, setting standards, and monitoring human rights violations in the context of sexual and reproductive health and rights. In recent years, these institutions have developed and applied human rights standards in the more particular context of maternal mortality and morbidity, and have increasingly recognized a critical human rights issue in the provision and experience of care during and after pregnancy, including during childbirth. However, the international human rights standards on mistreatment during facility-based childbirth remain, in an early stage of development, focused largely on a discrete subset of experiences, such as forced sterilization and lack of access to emergency obstetric care. As a consequence, the range of mistreatment that women may experience has not been adequately addressed or analyzed under international human rights law. Identifying human rights norms and standards related to the full range of documented mistreatment is thus a first step towards addressing violations of human rights during facility-based childbirth, ensuring respectful and humane treatment, and developing a program of work to improve the overall quality of maternal care. This article reviews international human rights standards related to the mistreatment of women during childbirth in facility settings under regional and international human rights law and lays out an agenda for further research and action. PMID- 28559682 TI - Europe's Shifting Response to HIV/AIDS: From Human Rights to Risk Management. AB - Despite a history of championing HIV/AIDS as a human rights issue, and a rhetorical commitment to health as a human right, European states and institutions have shifted from a rights-based response to a risk management approach to HIV/AIDS since the economic recession of 2008. An interdisciplinary perspective is applied to analyze health policy changes at the national, regional, and global levels by drawing on data from key informant interviews, and institutional and civil society documents. It is demonstrated that, in the context of austerity measures, member states such as the UK and Greece reduced commitments to rights associated with HIV/AIDS; at the regional level, the EU failed to develop rights-based approaches to address the vulnerabilities and health care needs of key populations affected by HIV/AIDS, particularly migrants and sex workers; and at the global level, the EU backtracked on commitments to global health and is prioritizing the intellectual property rights of pharmaceutical companies over the human rights of people living with HIV/AIDS. The focus within and from the EU is on containment, efficiency, and cost reduction. The rights of those most affected are no longer prioritized. PMID- 28559683 TI - HIV and the Right to Health in Colombia. AB - The first Colombian to claim a judicially enforceable right to health was a gay man living with HIV, who in 1992 claimed a violation of his constitutional rights on account of being denied antiretroviral therapy. Since then, HIV activists have been at the forefront of advancing both the judicialization and social reconstruction of health as a human right. However, their role-and its implications today-has been sometimes overlooked in the study of Colombia's right to health. Based on semi-structured interviews with key stakeholders, we evaluate the HIV movement's effect on the progression of the right to health and resulting health care reform, and analyze the reform's success in addressing the needs of people living with HIV. While the landmark Constitutional Court decision T-760 and resulting health care reform are not the result of any one group, the HIV movement played a significant role in these developments, and its values are largely reflected in the country's new sociopolitical conceptualization of the right to health. However, the movement has faced division over the issue of generic medication availability and among subpopulations who have not been strongly represented or consistent beneficiaries of its successes. PMID- 28559684 TI - HIV, Hepatitis C, TB, Harm Reduction, and Persons Deprived of Liberty: What Standards Does International Human Rights Law Establish? AB - HIV, hepatitis C virus (HCV), and TB in prisons and other places of detention are serious public health concerns, with prevalence and incidence considerably higher than in the general community because of the overrepresentation of risky behavior, substandard conditions, overcrowding, people who inject drugs, and the wholly inadequate prevention, care, and treatment of these conditions, including the denial of harm reduction services. This is not only a severe public health crisis but also a serious human rights concern. This article works to clarify the standards established by human rights law with regards to HIV, HCV, TB, and harm reduction in prisons by examining international and regional case law, minimum standards on the treatment of prisoners and public health, as well as the work of UN treaty bodies, Special Rapporteurs, and prison monitoring bodies. It is imperative that urgent steps are taken to close the gap between human rights and public health standards on the one hand, and effective implementation in prison settings on the other. PMID- 28559685 TI - Reproductive Health Policy in Tunisia: Women's Right to Reproductive Health and Gender Empowerment. AB - Although Tunisia is regarded as a pioneer in the Middle East and North Africa in terms of women's status and rights, including sexual and reproductive health and rights, evidence points to a number of persisting challenges. This article uses the Health Rights of Women Assessment Instrument (HeRWAI) to analyze Tunisia's reproductive health policy between 1994 and 2014. It explores the extent to which reproductive rights have been incorporated into the country's reproductive health policy, the gaps in the implementation of this policy, and the influence of this policy on gender empowerment. Our results reveal that progress has been slow in terms of incorporating reproductive rights into the national reproductive health policy. Furthermore, the implementation of this policy has fallen short, as demonstrated by regional inequities in the accessibility and availability of reproductive health services, the low quality of maternal health care services, and discriminatory practices. Finally, the government's lack of meaningful engagement in advancing gender empowerment stands in the way as the main challenge to gender equality in Tunisia. PMID- 28559686 TI - Health for All? Sexual Orientation, Gender Identity, and the Implementation of the Right to Access to Health Care in South Africa. AB - The framework of health and human rights provides for a comprehensive theoretical and practical application of general human rights principles in health care contexts that include the well-being of patients, providers, and other individuals within health care. This is particularly important for sexual and gender minority individuals, who experience historical and contemporary systematical marginalization, exclusion, and discrimination in health care contexts. In this paper, I present two case studies from South Africa to (1) highlight the conflicts that arise when sexual and gender minority individuals seek access to a heteronormative health system; (2) discuss the international, regional, and national human rights legal framework as it pertains to sexual orientation, gender identity, and health; and (3) analyze the gap between legislative frameworks that offer protection from discrimination based on sexual orientation and gender identity and their actual implementation in health service provision. These case studies highlight the complex and intersecting discrimination and marginalization that sexual and gender minority individuals face in health care in this particular context. The issues raised in the case studies are not unique to South Africa, however; and the human rights concerns illustrated therein, particularly around the right to health, have wide resonance in other geographical and social contexts. PMID- 28559687 TI - Australia's Efforts to Improve Food Security for Aboriginal and Torres Strait Islander Peoples. AB - Australia is a wealthy country; however, available evidence suggests that food security among Aboriginal and Torres Strait Islander peoples has not yet been achieved. Aboriginal and Torres Strait Islander peoples living in remote, regional, and urban parts of Australia experience food insecurity for a number of reasons that usually include low income and a lack of access to affordable and healthy food. The much higher rate of illness and disease that this population experiences compared to non-indigenous Australians is directly related to food insecurity. This paper examines the food insecurity among Aboriginal and Torres Strait Islander peoples and recent Australian government efforts to combat this problem. The paper first considers what constitutes a human rights-based approach to achieving food security. Second, it describes the food insecurity that currently exists among Aboriginal and Torres Strait Islander peoples across the three pillars of food access, food availability, and food use. Third, the paper critically examines recent and current Australian government policy aimed at improving food security. The paper concludes with some reflections regarding how the Australian government can improve its efforts to achieve food security for Aboriginal and Torres Strait Islander peoples. PMID- 28559689 TI - Transforming Policy into Justice: The Role of Health Advocates in Mozambique. AB - Despite expanding policy commitments in many poor countries, health care is often a failure at the point of delivery. Lack of information, poor enforcement, and power dynamics prevent those whose rights have been violated from pursuing redress. In Mozambique, grassroots health advocates work to address this gap between policy and reality by blending approaches known as legal empowerment and social accountability. They raise awareness of health policy, support clients to seek redress for grievances, and facilitate problem-solving dialogues between communities and health facility staff. In three years we have seen communities begin to overcome a culture of silence. Twenty-one advocates and their clients have achieved redress to over a thousand grievances across 27 health facilities. These cases have resulted in improvements to access, infrastructure, and provider performance. Advocates have supported village health committees to transform themselves from collections of names on a list into active agents for change. Advocates should not be trained and left alone-they are most effective when integrated into a vertical team that provides continuous support and supervision, and that can engage higher levels of authority to solve tough cases. Aggregate data from cases handled by health advocates provides unique insight into how health policy is working in practice. We draw on that information to advocate for systemic changes that affect the entire country, like better policies for combatting bribery and stronger procedures for responding to grievances. We have found that legal empowerment and social accountability practices interact synergistically. Our preliminary experience suggests that when people are equipped to exercise their rights to health, even a poorly resourced system can improve. PMID- 28559688 TI - The Mental Health of Children and Parents Detained on Christmas Island: Secondary Analysis of an Australian Human Rights Commission Data Set. AB - This paper describes secondary analysis of previously unreported data collected during the 2014 Australian Human Rights Commission Inquiry into Children in Immigration Detention. The aim was to examine the mental health of asylum-seeking parents and children during prolonged immigration detention and to consider the human rights implications of the findings. The average period of detention was seven months. Data includes 166 Kessler 10 Scales (K10) and 70 Strengths and Difficulties Questionnaires (SDQ) for children aged 3-17 and parental concerns about 48 infants. Extremely high rates of mental disorder in adults and children resemble clinical populations. The K10 indicated severe co-morbid depression and anxiety in 83% of adults and 85.7% of teenagers. On the SDQ, 75.7% of children had a high probability of psychiatric disorder, with lower conduct and hyperactivity scores than clinic populations. Sixty-seven percent of parents had concerns about their infant's development. Correlations were not found between time detained or parent/child distress. Multiple human rights breaches are identified, including the right to health. This is further evidence of the profound negative consequences for adults and children of prolonged immigration detention. Methodological limitations demonstrate the practical and ethical obstacles to research with this population and the politicized implications of the findings. PMID- 28559690 TI - Terminal Patients and the Right to Refuse Medical Treatment in Argentina. AB - The right to health has many dimensions. On the one hand, it entails positive duties for states to protect the health of individuals. On the other, it encompasses patient decision making regarding personal health, an idea which is closely linked to the right to autonomy and the right to free development of the individual-that is, to dignity.1 This is why the informed consent of the patient and her right to make a choice according to her own values should be honored, even when her decision may seem irrational or imprudent. When patients are incapable of providing informed consent-for example, if the patient is unconscious-the law can authorize certain persons to act as a proxy on their behalf. In Argentina, the Patients' Rights Act (2009) as amended by the Death with Dignity Act (2012) states that if a patient is unable to provide informed consent, consent may be provided on her behalf by her close relatives, affinal kin, or legal guardian, in this order of preference.2 The Patients' Rights Act also permits patients to set up advance directives regarding health decisions to be made if they become terminally ill. In 2015, the Argentine Supreme Court of Justice discussed the scope of patient autonomy in the case D., M.A. s/ declaracion de incapacidad.3 This case presented a question that had yet to be explored by the court: how can we determine an unconscious patient's will if she does not have written advance directives concerning whether a life-sustaining medical treatment should be continued? This article examines the grounds of the Argentine Supreme Court's decision in D., M.A. First, we describe the case law that existed prior to D., M.A. Then, after explaining the facts of the case, we discuss the ruling and raise doubts about its scope.4. PMID- 28559691 TI - Lessons from Jonathan Mann: The Ten Commandments on Multidrug-Resistant TB. PMID- 28559692 TI - Moving the Debate Forward in Right to Health Litigation. PMID- 28559693 TI - On the Heterogeneity and Politics of the Judicialization of Health in Brazil. PMID- 28559694 TI - Galectin-3: a novel biomarker for the prognosis of heart failure. AB - Heart failure (HF) is still a global burden which carries substantial risk of morbidity and mortality. Thus, appropriate approach of diagnosis and layering the prognosis of HF are of great importance. In this paper we discuss and review a novel biomarker, which is called galectin-3 and already approved by Food and Drugs Administration (FDA) as a prediction tool for HF. Galectin-3, which is secreted by macrophages under the influence of mediators like osteopontin, has been known for its significant role in mediating cardiac fibrosis and inflammation. Numerous studies have shown galectin-3 as a novel prognostic biomarker with high predictive value for cardiovascular mortality and re hospitalization in HF patients. However, there are also other contradictive studies displayed galectin-3 inferiority against other existed HF prognostic biomarkers like NT-proBNP and ST2. Nevertheless, galectin-3 has some advantages such as more stability and resistance against hemodynamic loading and unloading state, and also it could act as an early indicator of cardiac fibrosis, ventricular remodeling, and renal impairment in HF patients. PMID- 28559695 TI - Therapy of the postinfectious irritable bowel syndrome: an update. AB - After acute infectious gastroenteritis, up to thirty percent of patients present prolonged gastrointestinal symptoms and a part of those affected patients can have the diagnostic criteria for postinfectious irritable bowel syndrome. Treatment is symptom directed rather than curative and includes agents prescribed for the treatment of irritable bowel syndrome in general. Prophylaxis or early treatment of acute bacterial diarrhea may reduce the risk of postinfectious irritable bowel syndrome development by reducing the occurrence, duration, and severity of the chronic inflammation and mucosal alterations (all these believed to play an important role in disease persistence). Probiotic treatment is effective in restoring the intestinal microbiota in patients with irritable bowel syndrome and in animal models there are improvements of postinfectious irritable bowel syndrome. Fecal microbiota transplantation seems to be one of the most effective methods of treating the postinfectious irritable bowel syndrome (with recurrent episodes) caused by Clostridium difficile. PMID- 28559696 TI - The determination factors of left-right asymmetry disorders- a short review. AB - Laterality defects in humans, situs inversus and heterotaxy, are rare disorders, with an incidence of 1:8000 to 1:10 000 in the general population, and a multifactorial etiology. It has been proved that 1.44/10 000 of all cardiac problems are associated with malformations of left-right asymmetry and heterotaxy accounts for 3% of all congenital heart defects. It is considered that defects of situs appear due to genetic and environmental factors. Also, there is evidence that the ciliopathies (defects of structure or function) are involved in development abnormalities. Over 100 genes have been reported to be involved in left-right patterning in model organisms, but only a few are likely to candidate for left-right asymmetry defects in humans. Left-right asymmetry disorders are genetically heterogeneous and have variable manifestations (from asymptomatic to serious clinical problems). The discovery of the right mechanism of left-right development will help explain the clinical complexity and may contribute to a therapy of these disorders. PMID- 28559698 TI - Changes observed in erythrocyte cells exposed to an alternating current. AB - BACKGROUND AND AIMS: Appliance of electric pulses induces red blood cells (RBCs) membrane poration, membrane aminophospholipid perturbation and alteration of the normal flip-flop process, resulting in various shape changes of the RBCs. We studied morphological and water permeability changes of RBCs bombarded with electrons in an alternating current circuit. METHODS: We used three venous blood samples of 100 mL and an alternating current device. The harvested blood was divided into four experimental sets to be used for various exposure times: 0 hours (control RBCs), 0.5h, 3h and 6h (electric-stimulated RBCs). Following the electric current each of the four sets were further divided into three samples: one for the assessment of the echinocytes/RBCs ratio, another for the electron microscopy study of ultrastructural changes induced by the alternating electrical current and a larger third one for determining water permeability of RCBs by 1H NMR spectroscopy and morphological measurements. RESULTS: There is a small but statistically significant effect of the RBC exposure to alternating electric current on cell diameters. Exposure to electric current is positively and strongly correlated with the percentage of echinocytes in a duration-dependent manner. There is a strong and statistically significant correlation between electric current exposure and permeability to water as measured by 1H-NMR spectroscopy. CONCLUSION: Following interactions between electric current and RBC membrane, certain modifications were observed in the erythrocyte structure. We attribute the increased cell size to a higher permeability to water and a decreased tonicity. This leads to the transformation of the RBCs into echinocytes. PMID- 28559697 TI - Quality of life in thyroid cancer patients: a literature review. AB - INTRODUCTION: Quality of life (QoL) has received increasing interest in the last years, especially in patients with cancer. This article aims to analyze a selection of medical research papers regarding the quality of life in patients with thyroid carcinoma. We overviewed the main QoL aspects derived from several studies and highlighted those less researched issues, which could represent a solid base for future clinical studies. METHOD: We used an integrative selection method of medical literature, choosing mostly "free access" studies, as it was considered that they could be easily viewed, searched and researched including by patients. RESULTS: After an integrative literature review, we selected 16 relevant studies. Patients with thyroid cancer have several factors influencing their QoL, with both physical and psychological impact. The decisive factors are the quality of the surgical act, radioiodine therapy, follow-up using rh-TSH vs. hormonal withdrawal, access to behavioral help and the relationship with their physician. CONCLUSION: We must understand the emotional impact of the cancer diagnosis on the patient and we must collaborate in order to help the patient restore the psychosomatic balance and to recover the quality of life. PMID- 28559699 TI - Pulmonary hypertension in patients with hepatic cirrhosis and portal hypertension. An echographic study. AB - AIM OF THE STUDY: The aim of the study is to determine the frequency of pulmonary hypertension in patients with hepatic cirrhosis and portal hypertension, to determine the possibility of an accurate ultrasound diagnosis of the characteristics of this complication. METHOD: 347 patients with liver cirrhosis consecutively hospitalized at Coltea Clinical Hospital were screened. 61 were excluded because of other possible causes of portal or pulmonary hypertension. All patients were investigated clinically and by abdominal and cardiac ultrasonography. RESULTS: Of the remaining 286 patients, 116 had portal hypertension, 27 of them (23%) having pulmonary hypertension. In this group we found a higher cardiac index and right atrial volume, higher pressures in the right atrium, suggesting a hyperdynamic state. Porto-pulmonary hypertension was found in only one patient. CONCLUSION: Echocardiography permits characterization of patients with cirrhosis and portal hypertension. PMID- 28559700 TI - Arterial stiffness: hemodialysis versus hemodiafiltration. AB - BACKGROUND AND AIMS: Arterial stiffness seems to be influenced by the dialysis method, but studies are sparse and the results discordant. High substitution volume online hemodiafiltration appears to have beneficial cardiovascular effects in dialysis patients, but its effects on arterial stiffness are not investigated. We aimed to analyze arterial stiffness parameters in high substitution volume post-dilution online hemodiafiltration and compare results to high-flux hemodialysis. METHODS: We studied arterial stiffness parameters using the oscillometric method (Arteriograph IrDA, TensioMed, Budapest, Hungary) in 23 non diabetic patients on high substitution volume online postdilution hemodiafiltration and 23 non-diabetic patients on high-flux hemodialysis. Dialysis vintage was at least 6 months in all subjects. RESULTS: Hemodiafiltration-treated patients showed a more favorable arterial stiffness profile. Pulse wave velocity was significantly higher in hemodialysis compared to hemodiafiltration patients (10.39+/-2.29 m/s vs 9.0+/-1.7 m/s, p=0.026). Augmentation indexes and the diastolic reflection area were also significantly elevated hemodialysis patients compared to hemodiafiltration patients. CONCLUSIONS: High substitution volume online postdilution hemodiafiltration could have a beneficial effect on arterial stiffness and should be assessed in properly sized controlled trials. PMID- 28559702 TI - Tubercular abdominal cocoon in children - a single centre study in remote area of northern India. AB - BACKGROUND: Amongst the numerous causes of intestinal obstruction listed in the literature, sclerosing encapsulating peritonitis also called Abdominal Cocoon (AC) is one of the rarest entities. Its characteristic feature is a thick fibrotic membrane encasing varying lengths of the small and large gut in a cocoon. In India, there is an increasing incidence of tuberculosis, especially in the rural areas. AIMS AND OBJECTIVES: The aim of this study was to investigate the clinical presentation and evaluate the operative findings of tuberculous AC. We also evaluated the outcomes and response to anti tuberculous treatment (ATT) in all the patients diagnosed with this condition. MATERIAL AND METHODS: This study was carried out at M.M. Institute of Medical Sciences and Research, Mullana, Ambala, India between April 2013 - March 2016 in the Department of Pediatric Surgery. This is a prospective study. A total of 17 patients diagnosed with abdominal cocoon secondary to tuberculosis have been included in the study. RESULTS: A total of 17 patients presented to the emergency ward with features of acute intestinal obstruction. The average age was 15.3 years (range 9 years to 16 years). There were 14 females and 3 males. All patients presented with abdominal pain, bilious vomiting, constipation and abdominal distention. The patients were operated in our hospital and relieved of their obstruction. Based on their operative findings and after histopathological confirmation, patients were given ATT. In the follow-up, all patients did well, without recurrence of tuberculosis or intestinal obstruction. CONCLUSION: Tuberculosis as a cause of childhood AC is rather common in developing countries and is potentially a fatal condition. A strong clinical suspicion, sonographic and computed tomography scan findings help establish a pre-operative diagnosis. Tuberculous AC has a strong prevalence in females. Surgery is the mainstay of treatment followed by anti-tuberculous drugs. PMID- 28559701 TI - Solid pseudopapillary tumor of the pancreas: clinical-pathological features and management of 13 cases. AB - BACKGROUND AND AIM: Solid pseudopapillary tumor (SPT) of the pancreas is a rare pathological condition, representing less than 3% of all exocrine pancreatic tumors. SPT usually occurs in young females, without notable symptoms, with a low malignant potential and excellent prognosis. METHOD: We conducted a retrospective study during the period January 2005 - January 2015. SPT patients admitted in our institution were reviewed by describing demographic data, clinico-pathologic and radiological features, therapeutic management and prognosis records. RESULTS: Thirteen patients with SPT were identified (10 females), with a median age of 30 years. The main clinical presentation was abdominal pain (92.3%). The tumor was mostly located in the body or tail of the pancreas (77%), and the mean size was 8.2 cm. Regarding the surgical approach there were 5 distal pancreatectomies with splenectomy, 3 body and tail pancreatectomies, 2 body and tail pancreatectomies with splenectomy, 2 pancreato-duodenectomy, 1 partial enucleation and of all only 2 partial resections. Postoperative hematoxylin- eosin staining and immunohistochemistry confirmed the diagnosis in all cases. None of the patients had lymph nodes metastases. Only one local invasion. There was one case of death due to postoperative complications. Four cases followed adjuvant systemic chemotherapy. The mean follow-up was 18 months, without evidence of recurrence during this period. CONCLUSION: SPT should always be considered in the differential diagnosis in young women with a pancreatic tumor. Complete surgical excision is the treatment of choice, and is usually curative. The decision to administer systemic therapy must be individualized. Malignant behavior and late recurrences mandates long-term follow-up for patients with SPT. PMID- 28559703 TI - The value of laboratory tests in the diagnosis of tuberculosis. AB - BACKGROUND AND AIM: In the last decades, the inhabitants of the Romanian region known as Jiu Valley underwent changes in their social and economic status which determined changes in behaviour and health, which influenced their general health condition. One of the consequences was the exacerbation of tuberculosis. In order to control this situation, there was a need to increase the efficiency of diagnosis. This optimization can be reached by a better detection of mycobacterium infection, optimal isolation of strains and identification of the resistance of strains to antituberculous drugs. METHODS: In order to identify the best diagnostic modality, we compared the efficacy of the classical bacteriological diagnosis, still performed in the field, to the modern methods of molecular biology. The study included two groups, one represented by 213 patients who were investigated using the classical bacteriological methods, and 49 who were diagnosed using the PCR method. RESULTS: The tuberculosis patients who have been evaluated only with the classical bacteriological methods where diagnosed as TB positive and treated according to the national guidelines, which are in agreement with the international guidelines. The PCR diagnostic methods had a superior diagnostic value compared to the traditional bacteriological method. CONCLUSIONS: The results revealed the superiority of the modern molecular biology methods based on PCR. However the bacteriological method remains useful in areas where PCR cannot be afforded. PMID- 28559704 TI - Endobronchial ultrasound - one year of experience in clinical practice. AB - BACKGROUND AND AIM: Endobronchial ultrasound (EBUS) is a recent minimally invasive, safe examination method for the mediastinum, with a good diagnostic precision. This method makes possible real time examination with transbronchial fine needle aspiration, diagnostic transbronchial needle aspiration (TBNA) and staging of non-small pulmonary tumors, as well as diagnosis of mediastinal and hilar adenopathies of various causes. METHODS: We present the experience of the Bronchoscopy Department of the Pulmonology Clinic of Cluj-Napoca with EBUS-TBNA as a tool for the diagnosis and staging of tumors in contact with the bronchial wall and mediastinal and hilar adenopathies of unknown etiology. During the period August 2014 - January 2016 we examined 152 patients with no direct or indirect signs of lung tumor in traditional bronchoscopy. Rapid on site evaluation (ROSE) was available for all patients. RESULTS: Our study is a retrospective study of 152 EBUS-TBNA examinations. The average age of our patients was 54.43 years and 64% came from urban and 36% from rural background. EBUS-TBNA brought the final histological confirmation (tumors, sarcoidosis, limphoma) in 82.8% of the cases. A tumor confirmation was obtained in 95% of the patients who were suspected of having tumor. For a better understanding of the importance of this method in the daily clinical practice we present a case of peripheral pulmonary neoplasm with mediastinal and hilar adenopathies, where the contribution of EBUS-TBNA to a rapid diagnosis was essential. CONCLUSION: By the introduction of this method in our country one year ago, we can diagnose patients with lung and mediastinal tumors, which cannot be diagnosed by traditional bronchoscopy. This brings a valuable contribution to the improvement of lung cancer staging and diagnostic. PMID- 28559705 TI - Choosing the scientific journal for publishing research work: perceptions of medical and dental researchers. AB - BACKGROUND AND AIM: With the increasing demand to publish due to 'publish or perish' culture among research and academic institutions, the choice of a journal for publishing scientific articles becomes very important. A publication with many citations and high impact factor can propel researchers in their academic careers. The aim of this study is to explore the perceptions of medical and dental researchers in India about the important criteria to consider while selecting scientific journals for publishing their research. METHODS: 206 faculty staff members from three medical and five dental institutions were selected through convenience sampling. The study participants completed a questionnaire with 24 closed ended questions on various factors related to journal selection for publication. Factors such as publication frequency, journal citation, indexing, peer-review, impact factor, publication fees, acceptance or rejection rate, publishing house, previous submission and online submission process were considered. The responses were recorded using a Likert scale. Cronbach's alpha as a measure of internal consistency or homogeneity was 0.909. Descriptive statistics and Mann-Whitney U test were employed for comparison of responses among study participants. RESULTS: The mean weight of 24 criteria on a scale of 0 to 4 varied between 2.13 and 3.45. The results showed that indexing of journal (3.45+/-0.74), online submission (3.24+/-0.83), impact factor (3.11+/-0.91), peer review process (3.0+/-1.02) and publication fees (2.99+/-1.11) were among the most important criteria to consider in journal selection. CONCLUSIONS: Of the 24 factors considered by health researchers for journal selection, the most important were Journal indexing, online submission, impact factor, peer-review and publication fees. Compared to dental researchers, medical researchers perceived open access and peer-review process as significantly more important criteria. PMID- 28559706 TI - Flap surgical techniques for incisional hernia recurrences. A swine experimental model. AB - BACKGROUND AND AIM: In the age of synthetic prostheses most of hernia studies include a careful examination of the various types of prosthesis, their characteristics and their repair indications. Biological prostheses are also beginning to draw attention. But in terms of recurrence especially for poor or developing countries, the discussion is different, due to their high cost which makes them difficult to afford. In this article we present new flap reconstruction techniques for the reconstruction of the abdominal wall versus mesh repair, applied on swine models, outline the results of each technique, and specify the indications for their use. METHODS: An experimental protocol using four swine models (PIC-FII-337 hybrid breed pigs), five months old, was conducted. All animal care and operative procedures were studied following the protocol approved by the Ethics Committee of the University of Medicine and Pharmacy resolution no. 281/2014 of the Department of Surgery of the University of Agricultural Sciences and Veterinary Medicine); the study was carried out between November 2015 and February 2016. The primary objective was to compare the effect of surgical strategies in the treatment of the abdominal wall defect using variable flaps versus mesh repair in a large-animal models. Physical examination and ultrasound imaging of the abdominal wall repair were done on determined periods, during one month. The complications occurring after the abdominal wall repair were edema, collections, superficial dehiscence an recurrences. RESULTS: No recurrences were reported at one month results, all seromas reported were solved over time by natural drainage. Superficial necrosis appeared in two swine models and superficial dehiscence occurred in one model, the perforator "plus" flap. Mesh infection was detected in the "onlay" swine model. CONCLUSIONS: In terms of recurrences, contaminated abdominal wall defects or other contraindications to the use of prosthetic materials, biological mesh repair or flap surgery are the only surgical options. Based on our findings and considering the high cost reported by the biological meshes use, flap surgery becomes the suitable treatment for such cases, allowing a good reconstruction of the abdominal wall. PMID- 28559707 TI - Formulation and evaluation of a water-in-oil cream containing herbal active ingredients and ferulic acid. AB - BACKGROUND AND AIMS: The main aims of the present study were to formulate an anti age cream based on vegetal ingredients and ferulic acid and to evaluate the physical characteristics and the efficacy of the cream. METHODS: The active ingredients were Centella asiatica oil, Spilanthes acmella oil, Zingiber officinale extract and ferulic acid. Formulation 1 (F1) was prepared using glyceryl stearate and Ceteareth-25(r) as emulsifiers and Formulation 2 (F2) using glyceryl stearate and potassium cetyl phosphate, all other ingredients remaining the same. The physical characterization of the creams was performed and the following parameters were analyzed: viscosity, oil droplet size, polydispersity index; also, texture analysis was performed. The anti-aging effect of the F2 was evaluated by assessing the cutaneous density before and after cream application using DUB-cutis(r) scanner. RESULTS: The mean diameter of oil drops was 10.26+/ 4.72 mm (F1) and 22.72+/-7.93 mm (F2) and the polydispersity index was 35.4% and 45.7%, respectively. The mean values for consistency were 594.7+/-10.3 g (F1) and 300.5+/-14.5 g (F2), the average values for adhesion were 15.61+/-0.8 mJ (F1) and 22.25+/-4.3 mJ (F2), for firmness were 51.2+/-0.8 g (F1) and 30.3+/-4.3 g (F2) and the spreadability had values between 72.63 mm2 (F1) and 73.3 mm2 (F2). In vivo study revealed that the mean values of the cutaneous density increased from 9.21+/-1.39 % to 12.50+/-1.44 % after 8 weeks of cream application. The herbal ingredients incorporated in the O/W cream base for the antioxidant activity and anti-wrinkle effect, induced changes of the cutaneous density, an important parameter which quantifies the regeneration process of the skin. CONCLUSIONS: An anti-age cream containing herbal active ingredients and ferulic acid with appropriate physical characteristics was obtained. In vivo study of clinical efficacy revealed a positive effect on skin density, which increased after 8 weeks of cream application. PMID- 28559708 TI - Effect of injection site pre-cooling on pain perception in patients attending a dental camp at Life Line Express: a split mouth interventional study. AB - BACKGROUND AND AIM: To determine the effect of pre-cooling injection site on pain perception in patients attending a dental camp at lifeline express, Habibganj. METHODS: A split mouth interventional study assessed the effect of pre cooling the injection site in patients (n=33) requiring bilateral buccal infiltration prior to extraction. One side of the patient's mouth received the intervention after the injection site was pre cooled with ice for 3 minutes along with topical Lidocaine, while the other mouth side of the same patient received only topical Lidocaine and served as control group. A structured proforma assessed the demographic characteristics and risk factors that influence pain perception in patients. Mann-Whitney U tests and Wicoxon rank sum test were used for statistical analysis. Statistical significance was defined at P<0.05. RESULTS: The results revealed a significant difference in pain perception between control and intervention group as assessed using both Heft-Parker Visual Analog Scale (median score 3.0 and 1.0) and Sound Eye Motor scale (median score=1.0 and 0.0) (P<0.01). For both the scales the assessed and self reported variables Gender, Location, Chief Complaint, Region and Arch were found to be statistically significant. CONCLUSION: Pre cooling injection site reduced pain perception in patients. PMID- 28559709 TI - Comparative radiographic assessment of a new bioceramic-based root canal sealer. AB - BACKGROUND AND AIMS: The aim of this study was to assess the radiopacity of two bioceramic-based root canal sealers, the conventional TotalFill BC sealer (FKG Dentaire Switzerland) and a new experimental filling material developed in collaboration with 'Raluca Ripan' Institute for Research in Chemistry, Cluj Napoca. METHODS: Five disc samples were prepared using both materials (10 mm diameter * 1 mm thickness), being subjected to digital radiography together with aluminum step wedges (1 to 12 mm in thickness), in accordance with ISO 6876: 2012. Radiopacity was determined by the computer analysis of the images obtained. Four different areas were selected for each sample, corresponding to a disk sample quadrant. Statistical analysis was performed using ANOVA. RESULTS: Both materials showed a radiopacity that was 3 mm greater than the equivalent thickness of aluminum. Total Fill BC showed greater radiopacity than the experimental material, but the differences were not statistically significant. CONCLUSIONS: Both materials comply with ISO 6876: 2012 recommendations on minimum radiopacity. PMID- 28559710 TI - Cutaneous nocardiosis manifesting as a frontal mass in a patient with giant cell arteritis. AB - We report the case of a subcutaneous abscess due to Nocardia spp. mimicking a spontaneous hematoma or an aneurysm of the temporal artery branch, in a giant cell arteritis patient treated with methylprednisolone and azathioprine. Ultrasonography, incision and drainage with cultures helped in the diagnosis. This case highlights the importance of considering rare pathogens in immunosuppressed patients, besides the more frequent disease complications. PMID- 28559711 TI - Biography of Professor Cornel Tiberiu Opris. Professional maturity. AB - Professor Cornel Tiberiu Opris was the founder and Chair of the Clinic and University Department of Oral and Maxillofacial Surgery in Cluj, after the Education Reform of 1948. The article illustrates how the founder of these institutions led a valiant struggle for obtaining and arranging a location for the newly established Faculty of Dentistry, within the Institute of Medicine and Pharmacy. Professor Cornel Tiberiu Opris established himself as the most prodigious researcher at the Faculty for over a quarter-century, until his retirement, introducing his original conception in the therapeutic and surgical field. He created in Cluj-Napoca a specialist medical school by imposing national prestige for the institution that he led. PMID- 28559712 TI - Lethal case of vipera bersus bite. PMID- 28559713 TI - History of Medicine between tradition and modernity. AB - History of medicine is an extensive and very complex science. In a simple and classical understanding, it has an informative and associative role. Although it is not easy for students to understand the multiple implications of the history of medicine, its importance becomes more evident during their academic formation. The students must be persuaded particularly about the ethical and cultural values that history of medicine has in their training. Furthermore, history of medicine participates in creating the necessary perspective for shaping the future of medicine in the next decades. This is, perhaps, the most interesting role that the history of medicine should play from the modern point of view of students and young physicians. This paper presents different ways of understanding the roles of the history of medicine regarded from the traditional perspective to the contemporary point of view. PMID- 28559714 TI - Practice patterns for herpes simplex keratitis: A survey of ophthalmologists in Gulf Coast countries. AB - PURPOSE: Herpes simplex is a common cause of visual disability, and there are published evidence-based guidelines for therapy. This survey aims to determine the preferred practice patterns of ophthalmologists in Gulf Coast Countries regarding herpetic eye disease, as well as identify areas of controversy or barriers to acceptance of evidence-based protocols. METHODS: Anonymous web-based survey of ophthalmologists in Saudi Arabia, Bahrain, the United Arab Emirates, and Oman. RESULTS: There were 48 responses to the survey. For a first episode of epithelial dendritic keratitis, 28.2% reported "observation" rather than specific therapy. The majority of respondents utilize oral or topical antiviral for epithelial keratitis, with oral antiviral being the most popular (43.6%). The majority also included a corticosteroid with antiviral for stromal keratitis (83.9%) or iritis (70.3%). Over 90% prescribe a prophylactic antiviral after keratoplasty for herpetic eye disease, although the length of therapy ranged widely from <6 months to indefinite. The perceived risk of recurrent disease was ranked as the most important factor when considering antiviral prophylaxis, followed by risk of adverse effects. Topical cyclosporine was utilized "never or almost never" by 76.9% of respondents. CONCLUSIONS: Most respondents report following evidence-based guidelines. There was less consensus in areas where there are remaining knowledge gaps, such as the length of antiviral prophylaxis after keratoplasty and the potential role for topical cyclosporine. PMID- 28559715 TI - Intrasession repeatability of pachymetry measurements with RTVue XR 100 optical coherence tomography in normal cornea. AB - PURPOSE: To assess intra-observer reproducibility and repeatability of corneal pachymetry measurements with RTVue XR-100 anterior segment optical coherence tomography (AS-OCT) in normal cornea. METHODS: Eighty-four eyes of 84 healthy volunteers were enrolled for this study. A single examiner performed 3 successive corneal pachymetry mappings with RTVue XR-100 AS -OCT in a single session. One eye was randomly selected for the analysis. Intrasession intraexaminer reproducibility and repeatability were calculated for the minimum corneal thickness (MCT), central corneal thickness (CCT, central 0-2 mm), pericentral (2 5 mm) and peripheral (5-6 mm) annular zones of cornea, in the pachymetry mapping protocol by intraclass correlation coefficient (ICC), coefficient of variation and test retest variability. RESULTS: The mean CCT was 497.08 +/- 32.83 um and MCT was 490.28 +/- 32.87 um. ICC was 0.994 for CCT and 0.983 for MCT in central 2 mm zone. ICC in the pericentral 2-5 mm zones and 5-6 mm zone was lower than that in central 2 mm zone, but were still over 0.961 in 2-5 mm zone and had ICC of 0.85 in 5-6 mm zone. CONCLUSION: In normal cornea, corneal thickness measurements produced highly repeatable pachymetry measurements at the central and paracentral zones (up to 6-mm diameter) which could be because of the high resolution and faster image acquisition with RTVue XR-100 OCT. PMID- 28559716 TI - Thickness of the retinal photoreceptor outer segment layer in healthy volunteers and in patients with diabetes mellitus without retinopathy, diabetic retinopathy, or diabetic macular edema. AB - PURPOSE: The purpose of this study was to investigate whether the severity of diabetic disease in the retina is paralleled by changes in the photoreceptor layer. METHODS: This cross-sectional study included healthy volunteers (30 volunteers, 60 eyes) and patients with diabetes (48 patients, 96 eyes). Each patient underwent a single session of spectral domain optical coherence tomography (OCT) in which each retina was imaged twice. On each OCT image, the thickness of the PROS layer was measured at the foveal center and at points 750 MUm temporal to and nasal to the center. For statistical analyses, OCT images were assigned to one of the following groups: healthy, diabetes without retinopathy (DM), diabetic retinopathy (DR), or diabetic retinopathy with macular edema (DME). RESULTS: The mean PROS thickness at the foveal center in the first and second-obtained OCT images was as follows: healthy, 38.5 MUm and 38.6 MUm; DM, 38.2 MUm and 38.2 MUm; DR, 35.6 MUm and 36.1 MUm; DME, 32.6 MUm and 32.6 MUm. In the first and second-obtained images, significant differences were found between the healthy group and DR and DME (p < 0.05 for all), between the DM group and the DME (p < 0.05 for all), and between the DR group and the DME group (p < 0.05 for all). No significant differences between groups were found at the nasal and temporal locations. CONCLUSION: The PROS layer at the foveal center was thinner in patients who had diabetic retinopathy or diabetic macular edema than both the healthy volunteers and diabetic patients without retinopathy. PMID- 28559717 TI - Serum vitamin D levels in Indian patients with retinal venous occlusions. AB - PURPOSE: To estimate serum vitamin D (25 OH D) level in patients of retinal vein occlusion (RVO) and compare it with age-matched controls. METHODS AND MATERIAL: Forty patients above 18 years of age with retinal vein occlusion and forty age matched controls underwent serum vitamin D (Vit D) level estimation using a standard protocol. Student's t test was used to analyse differences between the mean of two groups. RESULTS: The mean age in RVO and control group was 60.25 and 60.73 years respectively. The mean (+/-SD) level of vitamin D in RVO patients was 13.68 (+/-4.58) ng/mL (range 5.5-24.8), and the 95% CI of mean was 12.21-15.14 with SD 4.58 while in control group it was 23.03 (+/-2.89) ng/ml (range 18.4 30.1) with 95% CI of mean being 22.11-23.96 with SD 2.89 (p value of <0.005). While comparing the level of Vitamin D based on type of occlusion the mean level of Vit D in CRVO patients was 15.36 (SD 5.30) and in BRVO it was 12.77 (SD 3.96) which was statistically not significant (p = 0.08). The odds ratio calculated for RVO cases versus controls was 133.33 which was statistically significant (P < 0.05). CONCLUSIONS: There is a paucity of published literature on level of Vit D in RVO. This study shows significantly lower levels of serum vitamin D in Indian patients with retinal vein occlusion as compared to age matched controls. Establishment of this correlation has possible implications for prophylaxis or treatment of RVOs. PMID- 28559718 TI - Clinical presentation of retinoblastoma in Alexandria: A step toward earlier diagnosis. AB - OBJECTIVE: To evaluate the clinical presentation of retinoblastoma in Alexandria, Egypt, correlate the timing of accurate diagnosis with the presence of advanced disease and identify causes of delayed presentation. METHODS: Retrospective noncomparative single institution study reviews demographic and clinical data of all new children with retinoblastoma presenting to Alexandria Main University ocular oncology clinic (OOC) from January 2012 to June 2014. Diagnosis time was from initial parental complaint to retinoblastoma diagnosis and referral time was from retinoblastoma diagnosis to presentation to the Alexandria OCC. Delayed Diagnosis and referral were counted if >2 weeks. Advanced presentation is defined as clinical TNMH (8th edition) staging of cT2 or cT3 (international intraocular retinoblastoma classification group D or E) in at least one eye or the presence of extra-ocular disease (cT4). RESULTS: Seventy eyes of 47 children were eligible: 52% unilateral, 7% with family history and 96% presented with leukocorea. Sixty-four percent of children had advanced intraocular disease and none had extra-ocular disease. Delayed presentation occurred in 58% of children and was significantly associated with advanced disease in both unilaterally and bilaterally affected children (p = 0.003, 0.002 respectively). The delay in diagnosis was more in unilateral cases while the delay in referral was more in bilateral cases. The main cause of delayed presentation in unilateral retinoblastoma was misdiagnosis (30%) while parental shopping for second medical opinion (30%) was the main cause in bilateral children. CONCLUSIONS: Delayed diagnosis is a problem affecting retinoblastoma management. Better medical education and training, health education and earlier screening are recommended to achieve earlier diagnosis. PMID- 28559719 TI - Age related changes in corneal morphological characteristics of healthy Pakistani eyes. AB - PURPOSE: To determine the age related changes in corneal morphological characteristics in normal healthy adult Pakistani population. METHODS: Four hundred and sixty-four eyes of 232 healthy volunteers with ages between 10 and 80 years of either gender were included. Corneal endothelial cell density (CED), morphology and central corneal thickness (CCT) were evaluated in each subject with non-contact specular microscope (SP-3000 P, Topcon Corporation, Japan) and average of three readings per eye was used for final analysis. All the findings including demographic data, and corneal parameters were endorsed on a pre-devised proforma. RESULTS: Mean age of study population was 39.52 +/- 18.09 years with 123 (53%) males and 109 (47%) females. Mean CED of study population was 2722.67 +/- 349.67 cells/mm2, while mean CCT was 505.72 +/- 32.82 um. Corneal morphological parameters among various age groups showed statistically significant difference in all parameters (p < 0.01). Correlation statistics revealed that CED (r = -0.497, p < 0.01), CCT (r = -0.216, p < 0.01) and hexagonality (r = -0.397, p < 0.01) decreased significantly with increasing age, while average cell size (r = 0.492, p < 0.01) and CV of size (r = 0.454, p < 0.01) increased with age. CONCLUSION: This study showed that CED in Pakistani eyes was less than that reported in Chinese eyes, higher than Portuguese, Iranian and Indian eyes and comparable to the values in Turkish, Nigerian and Thai eyes. PMID- 28559720 TI - Magnitude of diabetes and hypertension among patients with Dry Eye Syndrome at a tertiary hospital of Riyadh, Saudi Arabia - A case series. AB - PURPOSE: To study the magnitude of chronic diseases among patients suffering from Dry Eye Syndrome (DES) and compare them with published findings in the literature. METHODS: Patients diagnosed in 2016 suffering from DES based on presenting symptoms and findings of ocular examination were included in this study. The demographic information included age and gender. Chronic diseases among them were identified through case records, assessment and ongoing medications. RESULTS: This case series had 62 patients (58% males) of DES. The mean age was 60.2 +/- 16.6 years. The prevalence of hypertension, dyslipidemia and diabetes among them was 48.5% (95% confidence interval (CI) 31.5-65.5), 55.9% (95% CI 40.1-71.7) and 47.1% (95% CI 29.8-64.4) respectively. The rate of thyroid diseases (16.2%), renal diseases (6.5%), and liver diseases (6.7%) was not significant in this series. CONCLUSIONS: This series in central Saudi Arabia suggests that the magnitude of chronic diseases such as diabetes, hypertension, obesity and dyslipidemia seems to be higher in patients with DES compared to the population. PMID- 28559721 TI - Non-pharmacological therapies for primary open angle glaucoma: A quasi experimental pilot study. AB - Purpose: One of the major causes of blindness is Primary open angle glaucoma (POAG) and it has only surgical treatment and lifelong use of medication. Hence many side effects arise. To overcome this, the drugless approach is in practice but the importance of Muscle Energy Technique (MET) and Myofacial (MFR) Release is not explored. Hence, our objective was to determine the effectiveness of MET and MFR on POAG. Methods: A total of 12 patients with POAG were recruited from the tertiary care teaching hospital through criteria based convenience sampling for the study. But nine patients with POAG completed the study. The age of the patient with POAG ranges from 15 to 30 years. MET and MFR were given to the patient for 30 min/day, six days/week for three weeks. Intraocular pressure (IOP) was assessed with Tonometer as dependent variable by Ophthalmologist. Pre and post treatment IOP change was established. Result: Pre IOP and Post are 23.1 +/- 1.9 mmHg and Post IOP is 20 +/- 1.4 mmHg respectively. The mean pre-post difference is 3.1 +/- 1.9 mmHg with significance difference of p = 0.002. Conclusion: MET and MFR reduce IOP. This proves to be one of the feasible and cost effective treatments in the management of POAG. Clinical Trial Registry: CTRI/2014/09/4986. PMID- 28559722 TI - Topical versus subconjunctival anti-vascular endothelial growth factor therapy (Bevacizumab, Ranibizumab and Aflibercept) for treatment of corneal neovascularization. AB - In order to evaluate the effect of topical and subconjunctival anti-vascular endothelial growth factor (anti-VEGF) therapy, Ranibizumab, Bevacizumab and Aflibercept as a therapy for corneal neovascularization (NV) treatment, the aim of this study was to review all data related to some of anti-VEGF as a promising therapies for corneal NV treatment. Corneal NV is a dangerous condition leading to a marked reduction in vision due to angiogenesis of abnormal vessels that block light. During the recent years, we have recognized new drug proliferation for corneal NV treatment. Recently, anti-VEGF therapies are one of the most important drugs used for corneal NV treatment. Several growth factors are involved in angiogenesis. The most important growth factor in corneal angiogenesis is VEGF. VEGF can be considered as key mediators in corneal angiogenesis. It is upregulated during corneal NV. In fact, anti-VEGF therapies have shown efficacy in attenuation of corneal NV in both animal models and clinical trials. A promising therapeutic success has been achieved using antibodies directed against VEGF. Bevacizumab has demonstrated efficacy and efficiency in the treatment of different neo-vascular ocular diseases and it has partially reduced corneal NV through different routes of administrations: topical, subconjunctival, and intraocular application. A similar efficacy to bevacizumab profiles in the treatment of neo-vascular age-related macular degeneration was induced by ranibizumab. Moreover, at worse levels of initial visual acuity of diabetic macular edema, aflibercept was more effective at improving vision. Anti-VEGF agents (Bevacizumab, Ranibizumab and Aflibercept) seem to have a higher efficiency and efficacy for corneal NV treatment. Both subconjunctival therapy and topical therapy of bevacizumab prohibit corneal NV, while early treatment with subconjunctival administration of ranibizumab may successfully reduce corneal NV. Therefore, establishment of safe doses is highly important before these drugs can be involved in the clinical setting. Further investigations and studies are highly warranted to adjust the dose and route of administration for the antibodies directed against VEGF to be the key therapeutic agents in the corneal NV treatment. PMID- 28559724 TI - Intra-ocular medulloepithelioma as a masquerade for PHPV and Panophthalmitis: a Diagnostic Dilemma. AB - A previously diagnosed child of persistent hyperplastic primary vitreous (PHPV) with painless blind eye remained clinically silent for about 3 years follow-up. The child suddenly presented as a case of orbital cellulitis and panopthalmitis with meningitis. No definite mass lesion was detected on ultrasonography, magnetic resonance imaging (MRI) and positron emission tomography (PET) scan. Histopathology of the enucleated eye revealed intra-ocular medulloepithelioma as the culprit of sterile panophthalmitis and orbital inflammation. PMID- 28559723 TI - Endogenous Brucella endophthalmitis: A case report. AB - Brucellosis may be associated with a wide range of ophthalmic manifestations including endophthalmitis, which is a sight-threatening condition that needs to be rapidly recognized and treated to avoid permanent visual loss. A 26-year-old female with a 6-month history of vision loss in the left eye was treated with high dose systemic corticosteroids and azathioprine with an initial misdiagnosis elsewhere. A dense vitreous haze with opacities at the posterior hyaloid and a wide area of retinochoroiditis led to the diagnosis of endogenous endophthalmitis at presentation to us. The vitreous sample and blood cultures demonstrated growth of Brucella melitensis. She received 6 months of systemic antibiotherapy, which resulted in resolution of inflammation; however, visual acuity remained poor due to irreversible damage. Infectious etiology, including brucellosis in endemic countries, has to be considered in the differential diagnosis before administering immunomodulatory therapy in patients with panuveitis of unknown origin. PMID- 28559725 TI - Green laser induced foveal cyst sustained in a recreational laser light show. AB - We report the case of a 9-year-old boy complained of visual loss in his right eye after watching green laser light show being hit by a ray of a laser at shopping center before five days ago. The laser had a maximum power rating of 30 mW (US Food and Drug Administration class IIIB). Best-corrected visual acuity in his right eye was 0.2 with Snellen at 5 days after the injury. Dilated fundoscopic examination demonstrated a macular hole appearance in the right eye. Spectral domain optical coherence tomography (OCT, Spectralis, Heidelberg Engineering, Heidelberg, Germany) demonstrates a steep fovea contour, a thickening of the macular edges, intraretinal cysts, disruption of the photoreceptor inner segment/outer segment layer and macular pseudohole formation. Central foveal thickness (515 um) was increased. Two months after the injury, the patient's visual acuity improved to 0.9 in the right eye without any ocular treatment. Spectral domain OCT revealed the closure of the macular hole with the resolution of the cystic spaces. At 6-months follow-up, visual function had fully recovered and macular assessment was normal. PMID- 28559726 TI - Ultra wide field imaging of coats like response in Leber's congenital amaurosis. PMID- 28559727 TI - What may lie beneath! PMID- 28559728 TI - Editor's Letter. PMID- 28559730 TI - General Characteristics and Treatment Possibilities of?Dairy Wastewater - A Review. AB - The milk processing industry is one of the world's staple industries, thus the treatment possibilities of dairy effluents have been attracting more and more attention. The purpose of the paper is to review contemporary research on dairy wastewater. The origin, categories, as well as liquid by-products and general indicators of real dairy wastewater are described. Different procedures applied for dairy wastewater management are summarised. Attention is focused on in factory treatment technologies with the emphasis on biological processes. Aerobic and anaerobic methods with both their advantages and disadvantages are discussed in detail. Consecutive anaerobic and aerobic systems are analysed, too. Finally, future research niches are identified. PMID- 28559729 TI - Biosynthesis of Oxytetracycline by Streptomyces rimosus:?Past, Present and Future Directions in the Development?of Tetracycline Antibiotics. AB - Natural tetracycline (TC) antibiotics were the first major class of therapeutics to earn the distinction of 'broad-spectrum antibiotics' and they have been used since the 1940s against a wide range of both Gram-positive and Gram-negative pathogens, mycoplasmas, intracellular chlamydiae, rickettsiae and protozoan parasites. The second generation of semisynthetic tetracyclines, such as minocycline and doxycycline, with improved antimicrobial potency, were introduced during the 1960s. Despite emerging resistance to TCs erupting during the 1980s, it was not until 2006, more than four decades later, that a third--generation TC, named tigecycline, was launched. In addition, two TC analogues, omadacycline and eravacycline, developed via (semi)synthetic and fully synthetic routes, respectively, are at present under clinical evaluation. Interestingly, despite very productive early work on the isolation of a Streptomyces aureofaciens mutant strain that produced 6-demethyl-7-chlortetracycline, the key intermediate in the production of second- and third-generation TCs, biosynthetic approaches in TC development have not been productive for more than 50 years. Relatively slow and tedious molecular biology approaches for the genetic manipulation of TC-producing actinobacteria, as well as an insufficient understanding of the enzymatic mechanisms involved in TC biosynthesis have significantly contributed to the low success of such biosynthetic engineering efforts. However, new opportunities in TC drug development have arisen thanks to a significant progress in the development of affordable and versatile biosynthetic engineering and synthetic biology approaches, and, importantly, to a much deeper understanding of TC biosynthesis, mostly gained over the last two decades. PMID- 28559731 TI - Developing a Molecular Identification Assay of Old Landraces for the Genetic Authentication of Typical Agro-Food Products: The Case Study of the Barley 'Agordino'. AB - The orzo Agordino is a very old local variety of domesticated barley (Hordeum vulgare ssp. distichum L.) that is native to the Agordo District, Province of Belluno, and is widespread in the Veneto Region, Italy. Seeds of this landrace are widely used for the preparation of very famous dishes of the dolomitic culinary tradition such as barley soup, bakery products and local beer. Understanding the genetic diversity and identity of the Agordino barley landrace is a key step to establish conservation and valorisation strategies of this local variety and also to provide molecular traceability tools useful to ascertain the authenticity of its derivatives. The gene pool of the Agordino barley landrace was reconstructed using 60 phenotypically representative individual plants and its genotypic relationships with commercial varieties were investigated using 21 pure lines widely cultivated in the Veneto Region. For genomic DNA analysis, following an initial screening of 14 mapped microsatellite (SSR) loci, seven discriminant markers were selected on the basis of their genomic position across linkage groups and polymorphic marker alleles per locus. The genetic identity of the local barley landrace was determined by analysing all SSR markers in a single multi-locus PCR assay. Extent of genotypic variation within the Agordino barley landrace and the genotypic differentiation between the landrace individuals and the commercial varieties was determined. Then, as few as four highly informative SSR loci were selected and used to develop a molecular traceability system exploitable to verify the genetic authenticity of food products deriving from the Agordino landrace. This genetic authentication assay was validated using both DNA pools from individual Agordino barley plants and DNA samples from Agordino barley food products. On the whole, our data support the usefulness and robustness of this DNA-based diagnostic tool for the orzo Agordino identification, which could be rapidly and efficiently exploited to guarantee the authenticity of local varieties and the typicality of food products. PMID- 28559732 TI - Effect of Temperature-Shift and Temperature-Constant Cultivation on the Monacolin K Biosynthetic Gene Cluster Expression in Monascus sp. AB - In this study, the effects of temperature-shift (from 30 to 25 degrees C) and temperature-constant (at 30 degrees C) cultivation on the mass of Monascus fuliginosus CG-6 mycelia and concentration of the produced monacolin K (MK) were monitored. The expression levels of the MK biosynthetic genes of M. fuliginosus CG-6 at constant and variable culture temperatures were analysed by real-time quantitative polymerase chain reaction (RT-qPCR). The total protein was collected and determined by liquid chromatography-electrospray ionisation with tandem mass spectrometry (LC-ESI-MS/MS). Results showed that the maximum mycelial mass in temperature-shift cultivation was only 0.477 g of dry cell mass per dish, which was lower than that in temperature-constant cultivation (0.581 g of dry cell mass per dish); however, the maximum concentration of MK in temperature-shift cultivation (34.5 ug/mL) was 16 times higher than that in temperature-constant cultivation at 30 degrees C (2.11 ug/mL). Gene expression analysis showed that the expression of the MK biosynthetic gene cluster at culture temperature of 25 degrees C was higher than that at 30 degrees C, which was similar to the trend of the MK concentration, except for individual MK B and MK C genes. Analysis of differential protein expression revealed that 2016 proteins were detected by LC ESI-MS/MS. The expression level of efflux pump protein coded by the MK I gene exhibited the same upregulated trend as the expression of MK I in temperature shift cultivation. Temperature-shift cultivation enhanced the expression of proteins in the secondary metabolite production pathway, but suppressed the expression of proteins involved in the mycelial growth. PMID- 28559733 TI - Three New Lactobacillus plantarum Strains in the Probiotic Toolbox against Gut Pathogen Salmonella enterica Serotype Typhimurium. AB - The benefits of probiotic bacteria have been widely explored. However, fermented foods and digestive system of humans and animals are an inexhaustible source of new potentially probiotic microorganisms. In this study we present three new Lactobacillus plantarum strains isolated from different dairy products: cow's cheese, sheep's cheese and whey. In order to determine the antibacterial activity of yet unexplored L. plantarum strains against Salmonella enterica serotype Typhimurium, in vitro competition and co-culture tests were done. Furthermore, adhesion of these strains to Caco-2 cells and their influence on the adhesion of Salmonella were tested. Results showed the potential probiotic activity of isolated strains. L. plantarum strains survived in the presence of 1% bile salts, they possessed acidification ability, antibacterial activity and significantly attenuated the growth of S. Typhimurium in brain heart infusion broth. All tested L. plantarum strains were able to adhere to Caco-2 cells and significantly impair the adhesion of S. Typhimurium. All three L. plantarum strains exhibited significant probiotic potential and anti-Salmonella activity; therefore, further testing on in vivo models should follow. PMID- 28559734 TI - Lactococci of Local Origin as Potential Starter Cultures?for Traditional Montenegrin Cheese Production. AB - The aim of this study is to characterise and examine the biochemical properties of 40 Lactococcus lactis strains isolated from indigenous Montenegrin dairy products in order to explore their potential to be used as starter cultures for producing typical Montenegrin cheese, such as 'bijeli sir', 'masni sir' and 'njeguski sir'. Their safety regarding the production of biogenic amines, the presence of antimicrobial resistance and the antibacterial activity against relevant pathogens and spoilage microorganisms has also been tested. Based on the characterisation, all strains belong to L. lactis ssp. lactis. Out of these 40 strains, 23 displayed rapid acidification ability and proteolysis. However, none of the strains exhibited the ability of lipid degradation. Most of the strains were not associated with any health risk investigated. Summing up, a large percentage (27.5%) of the tested strains showed good properties. These strains should be further examined for their possible application as specific starter cultures in the production of indigenous cheese in Montenegro. PMID- 28559735 TI - The Effect of Autochthonous Starter Culture, Sugars and Temperature on the Fermentation of Slavonian Kulen. AB - In this study, the effect of an isolated and well-characterised autochthonous starter culture, glucose and maltodextrin (w=0.8%) and temperatures of 12 and 20 degrees C on fermentation and quality of Slavonian kulen produced using the traditional technology and recipe were investigated. Physicochemical and microbiological analyses were carried out after 20 days of fermentation. Upon the completion of the production process (90 days), a sensory analysis was carried out. Furthermore, pH value was continuously measured throughout the twenty-day fermentation period. The addition of an autochthonous starter culture and sugars and different fermentation temperatures significantly (p<0.05) affected the instrumental colour and texture parameters of the Slavonian kulen. The fermentation was most intense in the samples with added autochthonous starter culture and 0.8% glucose, and fermented at 20 degrees C. Microbiological analysis showed that samples with added autochthonous starter culture and fermented at higher temperature contained a higher number of lactic acid bacteria and coagulase-negative staphylococci and were safe. Sensory evaluation confirmed the outcomes of physicochemical and microbiological analyses and showed differences among samples fermented at two different temperatures and with added glucose or maltodextrin and an autochthonous starter culture. PMID- 28559736 TI - Properties and Antioxidant Capacity of Anchovy (Engraulis encrasicholus) By Product Protein Films Containing Thyme Essential Oil. AB - In this study, some properties and antioxidant capacity of anchovy (Engraulis encrasicholus) by-product protein films with added 0.5, 1.0 and 1.5% of thyme essential oil were investigated. The films with thyme essential oil had higher elongation at break, water vapour permeability and oxygen permeability, lower solubility and tensile strength than control film (p<0.05). The incorporation of thyme essential oil affected transparency values of the films, but only the addition of 1.5% of thyme essential oil significantly reduced the transparency (p<0.05). In the film matrix, molecular organisation and intermolecular interaction were changed by thyme essential oil addition. The films with thyme essential oil had a heterogeneous surface and a relatively smooth cross-section structure. Slightly higher phase transition and lower glass transition temperatures were observed in films with thyme essential oil. The antioxidant capacity of the films was improved by incorporating thyme essential oil depending on its volume fraction. PMID- 28559737 TI - Optimisation of Microwave-Assisted Extraction of Pomegranate (Punica granatum L.) Seed Oil and Evaluation ?of Its Physicochemical and Bioactive Properties. AB - Pomegranate seed oil was extracted in a closed-vessel high-pressure microwave system. The characteristics of the obtained oil, such as fatty acid composition, free fatty acidity, total phenolic content, antioxidant activity and colour, were compared to those of the oil obtained by cold solvent extraction. Response surface methodology was applied to optimise extraction conditions: power (176-300 W), time (5-20 min), particle size (d=0.125-0.800 mm) and solvent to sample ratio (2:1, 6:1 and 10:1, by mass). The predicted highest extraction yield (35.19%) was obtained using microwave power of 220 W, particle size in the range of d=0.125 0.450 mm and solvent-to-sample ratio of 10:1 (by mass) in 5 min extraction time. Microwave-assisted solvent extraction (MASE) resulted in higher extraction yield than that of Soxhlet (34.70% in 8 h) or cold (17.50% in 8 h) extraction. The dominant fatty acid of pomegranate seed oil was punicic acid (86%) irrespective of the extraction method. Oil obtained by MASE had better physicochemical properties, total phenolic content and antioxidant activity than the oil obtained by cold solvent extraction. PMID- 28559738 TI - Differentiation of Commercial PDO Wines Produced in Istria (Croatia) According to Variety and Harvest Year Based on HS-SPME-GC/MS Volatile Aroma Compound Profiling. AB - To differentiate monovarietal wines made from native and introduced varieties in Istria (Croatia), samples of Malvazija istarska, Chardonnay and Muscat yellow from two harvest years (2013 and 2014) were subjected to headspace solid-phase microextraction and gas chromatographic/mass spectrometric analysis (HS-SPME GC/MS) of volatile aroma compounds. Significant effects of variety and harvest year were determined, but their interaction complicated the differentiation. Particular compounds were consistent as markers of variety in both years: nerol for Malvazija, ethyl cinnamate and a tentatively identified isomer of dimethylbenzaldehyde for Chardonnay, and terpenes for Muscat yellow. Wines from 2013 contained higher concentrations of the majority of important volatiles. A 100% correct differentiation of Malvazija istarska and Chardonnay wines according to both variety and harvest year was achieved by stepwise linear discriminant analysis. PMID- 28559739 TI - Polyphenols from Wine Lees as a Novel Functional Bioactive Compound in the Protection Against Oxidative Stress and Hyperlipidaemia. AB - The study examines the potential of wine industry by-product, the lees, as a rich mixture of natural polyphenols, and its physiological potential to reduce postprandial metabolic and oxidative stress caused by a cholesterol-rich diet in in vivo model. Chemical analysis of wine lees showed that their total solid content was 94.2%. Wine lees contained total phenols, total nonflavonoids and total flavonoids expressed in mg of gallic acid equivalents per 100 g of dry mass: 2316.6+/-37.9, 1332.5+/-51.1 and 984.1+/-28.2, respectively. The content of total anthocyanins expressed in mg of cyanidin-3-glucoside equivalents per 100 g of dry mass was 383.1+/-21.6. Antioxidant capacity of wine lees determined by the DPPH and FRAP methods and expressed in mM of Trolox equivalents per 100 g was 259.8+/-1.8 and 45.7+/-1.05, respectively. The experiment lasted 60 days using C57BL/6 mice divided in four groups: group 1 was fed normal diet and used as control, group 2 was fed normal diet with added wine lees, group 3 was fed high cholesterol diet (HCD), i.e. normal diet with the addition of sunflower oil, and group 4 was fed HCD with wine lees. HCD increased serum total cholesterol (TC) by 2.3-fold, triacylglycerol (TAG) by 1.5-fold, low-density lipoprotein (LDL) by 3.5 fold and liver malondialdehyde (MDA) by 50%, and reduced liver superoxide dismutase (SOD) by 50%, catalase (CAT) by 30% and glutathione (GSH) by 17.5% compared to control. Conversely, treatment with HCD and wine lees reduced TC and LDL up to 1.4 times more than with HCD only, with depletion of lipid peroxidation (MDA) and restoration of SOD and CAT activities in liver, approximating values of the control. HDL levels were unaffected in any group. Serum transaminase activity showed no hepatotoxic properties in the treatment with lees alone. In the proposed model, wine lees as a rich polyphenol source could be a basis for functional food products without alcohol. PMID- 28559740 TI - The Anti-Staphylococcus aureus Effect of Combined Echinophora platyloba Essential Oil and Liquid Smoke in Beef. AB - In the current study, the antibacterial effect of Echinophora platyloba essential oil and common liquid smoke (individually and in combination) against Staphylococcus aureus in beef meat samples is investigated. Using an automated microbiological growth analyser and the turbidimetric technique, the minimum inhibitory concentrations (MIC) and the minimum bactericidal concentrations (MBC) of the essential oil and liquid smoke were determined. Anti-S. aureus activity of essential oil and liquid smoke (individually and in combination) was defined by disk diffusion assay, generation time and cell constituent release. Apart from that, the interactions between these two compounds were measured by the checkerboard assay and by calculating the fractional inhibitory concentration (FIC) indices. Related MIC values of essential oil and smoke were found to be 7200 and 5500 mg/L, and MBC values were 8500 and 8000 mg/L, respectively. The conducted organoleptic assay showed that the addition of 0.05 g of essential oil and 0.6 g of liquid smoke to 100 g of meat samples did not have adverse effect on the overall acceptance. Weaker antibacterial effect against Staphylococcus aureus was observed when only Echinophora platyloba essential oil was used than when it was used in combination with liquid smoke. PMID- 28559741 TI - An Effective Method of Continuous Production of Erythritol from Glycerol by Yarrowia lipolytica MK1. AB - This study demonstrates the potential applicability of the UV mutant Yarrowia lipolytica MK1 for the valorisation of glycerol and erythritol production in a chemostat culture. The aim of this research is to investigate the optimal C:N ratio in the feeding medium in order to enhance erythritol production. The highest erythritol concentration, at 113.1 g/L with a volumetric erythritol production rate of 1.1 g/(L.h) and a yield of 0.57 g/g, was obtained in the feeding medium with a C:N ratio of 80:1. Moreover, no residual glycerol was observed in the culture broth during cultivation. The chemical composition of the biomass was analysed. The contents of lysine and threonine in the biomass protein amino acid profile were higher than those required by the FAO/WHO for fodder yeast. PMID- 28559742 TI - Assessment of Grape, Plum and Orange Synthetic Food Flavourings Using in vivo Acute Toxicity Tests. AB - The present study evaluates the acute toxicity of synthetic grape, plum and orange flavourings in root meristem cells of Allium cepa at the doses of 3.5, 7.0 and 14.0 mL/kg and exposure times of 24 and 48 h, and in bone marrow erythrocytes of mice treated orally for seven days with 0.5, 1.0, 2.0, 5.0 and 10.0 mL/kg of flavouring. The results of the plant test showed that grape, plum and orange flavourings, at both exposure times, inhibited cell division and promoted the formation of a significant number of micronuclei and mitotic spindle changes. These alterations were observed in at least one exposure time analysed, demonstrating a significant cytotoxic, genotoxic and mutagenic activity. In mouse bioassay, animals treated with 2.0, 5.0 and 10.0 mL/kg of flavouring died before the seventh day of treatment. The amounts of 0.5 and 1.0 mL/kg of the three additives were cytotoxic to erythrocytes, and treatment with the grape flavouring significantly induced the formation of micronucleated cells in the bone marrow of animals. Therefore, under the study conditions, the grape, plum and orange flavouring additives promoted significant toxicity to cells of the test systems used. PMID- 28559744 TI - Erratum to: Conference materials. 15th Congress of the Polish Society of Experimental and Clinical Immunology. Wroclaw 2014. AB - [This corrects the article on p. s13 in vol. 39.][This corrects the article on p. s23 in vol. 39.][This corrects the article on p. s11 in vol. 39.][This corrects the article on p. s19 in vol. 39.][This corrects the article on p. s1 in vol. 39.][This corrects the article on p. s13 in vol. 39.][This corrects the article on p. s24 in vol. 39.][This corrects the article on p. s24 in vol. 39.][This corrects the article on p. s11 in vol. 39.][This corrects the article on p. s13 in vol. 39.][This corrects the article on p. s12 in vol. 39.][This corrects the article on p. s12 in vol. 39.][This corrects the article on p. s33 in vol. 39.][This corrects the article on p. s21 in vol. 39.][This corrects the article on p. s22 in vol. 39.]. PMID- 28559743 TI - Adhesion of Candida spp. and Pichia spp. to Wooden Surfaces. AB - Yeast adhesion to and biofilm formation on surfaces is present in many different environments. In food industry, biofilms may be a source of contaminations, causing food spoilage and reducing quality of products. Candida and Pichia are two common yeast genera involved in the spoilage of some food products. The aim of this study is to assess the potential of Candida and Pichia species to adhere to two types of wooden surfaces (smooth and rough), one of the materials typical for the food processing industry, and investigate the influence of surface roughness of wood on the degree of yeast adhesion. The adhesion of the cells to the wooden surfaces was determined by rinsing them from the surface, followed by methylene blue staining, and quantification after imaging under microscope by automatic counting of viable cells. The results showed that all Candida and Pichia strains were able to adhere to the wooden surfaces in a species- and strain-dependent manner. On the other hand, our data indicated that adhesion by these yeasts was not significantly affected by the roughness of the wood surfaces. PMID- 28559745 TI - Cross-sectional examination of the association between shift length and hospital nurses job satisfaction and nurse reported quality measures. AB - BACKGROUND: Twenty-four hour nursing care involves shift work including 12-h shifts. England is unusual in deploying a mix of shift patterns. International evidence on the effects of such shifts is growing. A secondary analysis of data collected in England exploring outcomes with 12-h shifts examined the association between shift length, job satisfaction, scheduling flexibility, care quality, patient safety, and care left undone. METHODS: Data were collected from a questionnaire survey of nurses in a sample of English hospitals, conducted as part of the RN4CAST study, an EU 7th Framework funded study. The sample comprised 31 NHS acute hospital Trusts from 401 wards, in 46 acute hospital sites. Descriptive analysis included frequencies, percentages and mean scores by shift length, working beyond contracted hours and day or night shift. Multi-level regression models established statistical associations between shift length and nurse self-reported measures. RESULTS: Seventy-four percent (1898) of nurses worked a day shift and 26% (670) a night shift. Most Trusts had a mixture of shifts lengths. Self-reported quality of care was higher amongst nurses working <=8 h (15.9%) compared to those working longer hours (20.0 to 21.1%). The odds of poor quality care were 1.64 times higher for nurses working >=12 h (OR = 1.64, 95% CI 1.18-2.28, p = 0.003). Mean 'care left undone' scores varied by shift length: 3.85 (<=8 h), 3.72 (8.01-10.00 h), 3.80 (10.01-11.99 h) and were highest amongst those working >=12 h (4.23) (p < 0.001). The rate of care left undone was 1.13 times higher for nurses working >=12 h (RR = 1.13, 95% CI 1.06-1.20, p < 0.001). Job dissatisfaction was higher the longer the shift length: 42.9% (>=12 h (OR = 1.51, 95% CI 1.17-1.95, p = .001); 35.1% (<=8 h) 45.0% (8.01-10.00 h), 39.5% (10.01-11.99 h). CONCLUSIONS: Our findings add to the growing international body of evidence reporting that >=12 shifts are associated with poor ratings of quality of care and higher rates of care left undone. Future research should focus on how 12-h shifts can be optimised to minimise potential risks. PMID- 28559746 TI - Estimating outcomes and cost effectiveness using a single-arm clinical trial: ofatumumab for double-refractory chronic lymphocytic leukemia. AB - BACKGROUND: Ofatumumab (Arzerra(r), Novartis) is a treatment for chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab [double refractory (DR-CLL)]. Ofatumumab was licensed on the basis of an uncontrolled Phase II study, Hx-CD20-406, in which patients receiving ofatumumab survived for a median of 13.9 months. However, the lack of an internal control arm presents an obstacle for the estimation of comparative effectiveness. METHODS: The objective of the study was to present a method to estimate the cost effectiveness of ofatumumab in the treatment of DR-CLL. As no suitable historical control was available for modelling, the outcomes from non-responders to ofatumumab were used to model the effect of best supportive care (BSC). This was done via a Cox regression to control for differences in baseline characteristics between groups. This analysis was included in a partitioned survival model built in Microsoft(r) Excel with utilities and costs taken from published sources, with costs and quality-adjusted life years (QALYs) were discounted at a rate of 3.5% per annum. RESULTS: Using the outcomes seen in non-responders, ofatumumab is expected to add approximately 0.62 life years (1.50 vs. 0.88). Using published utility values this translates to an additional 0.30 QALYs (0.77 vs. 0.47). At the list price, ofatumumab had a cost per QALY of L130,563, and a cost per life year of L63,542. The model was sensitive to changes in assumptions regarding overall survival estimates and utility values. CONCLUSIONS: This study demonstrates the potential of using data for non-responders to model outcomes for BSC in cost-effectiveness evaluations based on single-arm trials. Further research is needed on the estimation of comparative effectiveness using uncontrolled clinical studies. PMID- 28559747 TI - Structure-Leveraged Methods in Breast Cancer Risk Prediction. AB - Predicting breast cancer risk has long been a goal of medical research in the pursuit of precision medicine. The goal of this study is to develop novel penalized methods to improve breast cancer risk prediction by leveraging structure information in electronic health records. We conducted a retrospective case-control study, garnering 49 mammography descriptors and 77 high frequency/low-penetrance single-nucleotide polymorphisms (SNPs) from an existing personalized medicine data repository. Structured mammography reports and breast imaging features have long been part of a standard electronic health record (EHR), and genetic markers likely will be in the near future. Lasso and its variants are widely used approaches to integrated learning and feature selection, and our methodological contribution is to incorporate the dependence structure among the features into these approaches. More specifically, we propose a new methodology by combining group penalty and [Formula: see text] (1 <= p <= 2) fusion penalty to improve breast cancer risk prediction, taking into account structure information in mammography descriptors and SNPs. We demonstrate that our method provides benefits that are both statistically significant and potentially significant to people's lives. PMID- 28559748 TI - A Preliminary Randomized Clinical Trial on the Effect of Cervicothoracic Manipulation Plus Supervised Exercises vs a Home Exercise Program for the Treatment of Shoulder Impingement. AB - OBJECTIVE: The purpose of this study was to investigate changes in pain, disability, and range of movement after cervicothoracic manipulation plus exercise therapy in individuals with unilateral shoulder impingement syndrome. METHODS: Forty-one patients (30 men, 11 women; aged 47 +/- 9) diagnosed with unilateral shoulder impingement syndrome attended 10 sessions for 5 weeks (2 sessions/wk). Eligible patients were randomly allocated to 2 study groups: cervicothoracic manipulation plus exercise therapy (n = 21) or home exercise program (n = 20). The outcomes measures included the visual analog scale (VAS); the Disabilities of the Arm, Shoulder, and Hand score; Shoulder Disability Questionnaire; subacromial impingement syndrome (Hawkins-Kennedy Test and Neer Test); and shoulder active range of motion (movements of flexion, extension, rotation, adduction, and abduction). Assessments were applied at baseline and 24 hours after completing 5 weeks of related interventions. RESULTS: After 5 weeks of treatment significant between-group differences were observed in the Disabilities of the Arm, Shoulder, and Hand score (P = .012); however, no statistically significant differences were achieved for Shoulder Disability Questionnaire (P = .061) and pain intensity (P = .859). Both groups improved with regard to disability and clinical tests for detecting subacromial impingement syndrome. CONCLUSIONS: This clinical trial suggests that cervicothoracic manipulative treatment with mobilization plus exercise therapy may improve intensity of pain and range of motion compared with the home exercise group alone; the home exercise group had significant changes for flexion, extension, adduction, and abduction, but not for external and internal rotation movement in patients with shoulder impingement. PMID- 28559749 TI - Effect of Mulligan Concept Lumbar SNAG on Chronic Nonspecific Low Back Pain. AB - OBJECTIVE: The purpose of this study was to investigate the outcomes of adding lumbar sustained natural apophyseal glide (SNAG) to a conventional therapy program for chronic nonspecific low back pain (LBP). METHODS: Forty-two participants with chronic nonspecific LBP were randomly divided into 2 groups. The study group (aged 27.1 +/- 8.3, 20 men, 3 women) received a conventional physical therapy program consisted of stretching and strengthening exercises plus SNAG (based on the Mulligan concept) on the affected lumbar levels, and the control group (aged 28.9 +/- 7.7, 13 men, 6 women) received the same conventional program without SNAG 3 times per week for 1 month. Outcome measures were repositioning error (the primary outcome), pain, and function measured by an isokinetic dynamometer, visual analog scale, and the Oswestry Disability Index. Measurements were recorded before and after the end of the treatment period. RESULTS: The comparison between pretreatment and posttreatment test scores indicated that both study and control groups had significant improvement in all dependent variables (P > .001). However, adding SNAG to the conventional program resulted in higher improvement in terms of repositioning error, pain, and function (P = .02, .002, .008) respectively. CONCLUSIONS: This preliminary study indicated improvement in both groups. Adding SNAG to conventional programs in the treatment of chronic nonspecific LBP may result in greater improvement of repositioning error, pain reduction, and improved function. PMID- 28559750 TI - Comparison of Supine and Prone Methods of Leg Length Inequality Assessment. AB - OBJECTIVE: The primary objective of the current study was to determine the reliability between methods of supine and prone leg length inequality (LLI) assessment. The secondary objective was to determine if the degree of examiner confidence affected the degree of intermethod agreement. METHODS: Two experienced doctors of chiropractic assessed 43 participants for LLI, one using a prone and the other a supine method. They stated whether they were confident or not confident in their findings. RESULTS: Kappa values for intermethod agreement were 0.16 for the full data set; 0.00 for the n = 20 subgroup with both examiners confident; 0.24 for the n = 18 subgroup with 1 examiner confident; and 0.55 for the n = 5 subgroup with neither examiner confident. Supine and prone measures exhibited slight agreement for the full data set, but no agreement when both examiners were confident. The moderate agreement with both examiners not confident may be an artifact of small sample size. CONCLUSIONS: This study found that supine and prone assessments for leg length inequality were not in agreement. Positioning the patient in the prone position may increase, decrease, reverse, or offset the observed LLI that is seen in the supine position. PMID- 28559751 TI - Analysis of Patient Outcomes Using the MyoKinesthetic System for the Treatment of Low Back Pain: A Case Series. AB - OBJECTIVE: The purpose of this case series was to test the feasibility of using the MyoKinesthetic (MYK) System as a treatment-based classification system and intervention for a sample of patients with low back pain. METHODS: This within subject intervention was completed in a university athletic training clinic. Nine participants (mean age: 31 years) with a primary complaint of LBP were evaluated and included. An athletic trainer performed the initial assessment, which contained the following components: patient history, palpation, range of motion testing, lower quarter neurologic screening, MYK System posture screen, orthopedic special tests, and baseline data for pain intensity, disability, and function. All participants were treated with the MYK System. The primary outcomes were pain, disability, function, active range of motion, posture, and global efficacy of treatment. RESULTS: The mean number of MYK treatments administered was 12.11 (SD = 6.25), and the mean number of days until discharge was 28.67 (SD = 9.38). A repeated-measures analysis of variance revealed statistically significant and clinically meaningful improvements in pain, disability, function, and posture from the initial evaluation to discharge and from the initial evaluation to a 1-month follow-up (P < .01). CONCLUSION: This study determined the feasibility of further evaluation of the MYK System as a treatment-based classification system and intervention for patients with low back pain. PMID- 28559752 TI - Clinical Validation of Pain Management Manipulative Therapy for Knee Osteoarthritis With the Squeeze-Hold Technique: A Case Series. AB - OBJECTIVE: The purpose of this case series was to describe the short-term and long-term clinical effects of a manual technique for treating osteoarthritis (OA) knee pain. METHODS: This study measured of the immediate effect and long-term effect by using a case series of different groups of subjects. Knee OA and activity restriction in patients were evaluated by using the Kellgren-Lawrence (K/L) Grading Scale and the Japanese Knee Osteoarthritis Measure (JKOM) index. In the intervention, lower limb muscles were squeezed by hand for 20 seconds. Each squeeze was performed for both lower limbs. Passive range-of-motion (ROM) exercise was performed on the knee joint. In one set of cases, immediate effects were measured after a one-time treatment with pretreatment and posttreatment outcome measures. Eleven people with knee OA participated in the study. On a visual analogue scale (VAS) for pain, muscle stiffness, and muscular hemodynamics for estimation of muscle blood flow were recorded before and after the squeeze hold treatment. In another set of cases, the treatment was given to all patients once a week for 6 months, and long-term effects were measured. Data on 5 subjects with knee OA were collected for 6 months after initial treatment. The VAS for pain and JKOM were recorded every month for 6 months. RESULTS: For immediate effects, the VAS was 69 +/- 21 mm before treatment and 26 +/- 22 mm after treatment. Muscle stiffness was 8.8 +/- 3.6 (absolute number) before treatment and 3.5 +/- 2.1 after treatment. Tissue (muscle) oxygen saturation was 60.1 +/- 5.7% before treatment and 65.3 +/- 4.8% after treatment. Total hemoglobin was 24.3 +/- 3.3 (absolute number) before treatment and 25 +/- 2.3 after treatment. A tendency for reduction in OA knee pain and muscle stiffness was observed, and a tendency for increase was observed in the blood flow in the muscle. For long-term effects in all 5 participants (any K/L grade, any JKOM score), OA knee pain and JKOM score improved gradually through 6 months. CONCLUSIONS: The participants in this case series showed improvement in pain and function. These findings indicate the feasibility of a larger study on the squeeze-hold intervention for OA knee pain. PMID- 28559753 TI - Photogrammetric Assessment of Upper Body Posture Using Postural Angles: A Literature Review. AB - OBJECTIVE: The purpose of this paper was to review the literature regarding the measurement properties of various angles used for postural assessment of the head, neck, shoulder, and thorax and to discuss the utility of these measures. METHODS: The inclusion criteria for this literature review were use of postural angles to assess posture, measurement of upper body posture, and research studies conducted in last 3 decades that had free full-text available online entirely in the English language. The exclusion criteria were review articles; studies involving subjects having obesity, visual problems, any history of surgery, respiratory, cardiovascular, neurologic, or congenital pathology or disease; and research studies in which postural angles were measured with respect to vertical only. The following databases were searched: PubMed Central, PubMed, ResearchGate, Springer Link, ScienceDirect, Google Scholar and Scielo through February 20, 2016. RESULTS: A total of 21 studies that were found to be best suited to explain the craniovertebral (CV) angle, sagittal head tilt, sagittal shoulder-C7 angle, coronal head tilt, coronal shoulder angle, and thoracic kyphosis angle were included in this review. Craniovertebral angle, sagittal head tilt, sagittal shoulder-C7 angle, coronal head tilt, and coronal shoulder angle possess moderate to high intrarater reliability. Craniovertebral angle, sagittal head tilt, sagittal shoulder-C7 angle and thoracic kyphosis angle possess high interrater reliability (except for sagittal head tilt when measured using the goniometer). Craniovertebral angle, sagittal head tilt, and sagittal shoulder-C7 angle have been proved to be valid measures of posture when compared with similar angles measured on radiographs. None of the studies reported intrarater reliability of thoracic kyphosis angle, interrater reliability of coronal head tilt and coronal shoulder angle, and validity of coronal angles and thoracic kyphosis angle. CONCLUSIONS: We found several reliable methods to measure the postures of the head, neck, shoulder, and thoracic regions by measuring the CV angle, sagittal head tilt, sagittal shoulder-C7 angle, and thoracic kyphosis angle, respectively. Standardization of methods for angular measurement is recommended so that there is uniformity among studies regarding camera height, participant-camera distance, and type of software to generate normative data for postural angles. PMID- 28559754 TI - Effectiveness of Manual Therapy Combined With Physical Therapy in Treatment of Patellofemoral Pain Syndrome: Systematic Review. AB - OBJECTIVES: The purpose of this study was to conduct a review of randomized controlled trials (RCTs) to determine the treatment effectiveness of the combination of manual therapy (MT) with other physical therapy techniques. METHODS: Systematic searches of scientific literature were undertaken on PubMed and the Cochrane Library (2004-2014). The following terms were used: "patellofemoral pain syndrome," "physical therapy," "manual therapy," and "manipulation." RCTs that studied adults diagnosed with patellofemoral pain syndrome (PFPS) treated by MT and physical therapy approaches were included. The quality of the studies was assessed by the Jadad Scale. RESULTS: Five RCTs with an acceptable methodological quality (Jadad >= 3) were selected. The studies indicated that MT combined with physical therapy has some effect on reducing pain and improving function in PFPS, especially when applied on the full kinetic chain and when strengthening hip and knee muscles. CONCLUSIONS: The different combinations of MT and physical therapy programs analyzed in this review suggest that giving more emphasis to proximal stabilization and full kinetic chain treatments in PFPS will help better alleviation of symptoms. PMID- 28559755 TI - Multimodal Chiropractic Care for Pain and Disability in a Patient Diagnosed With Ehlers-Danlos Syndrome-Hypermobility Type: A Case Report. AB - OBJECTIVE: The purpose of this article is to describe the clinical response to multimodal chiropractic treatment of a patient diagnosed with Ehlers-Danlos syndrome, hypermobility type (EDS-HT), and chronic pain. CLINICAL FEATURES: A 22 year-old woman presented with severe chronic neck and low back pain, headaches, and bilateral hand pain and stiffness. In addition to these pain complaints, the patient had a family history of EDS, weekly or daily recurring joint dislocations, and upper and lower extremity joint hypermobility. As a result of her significant history and examination findings, which met the Brighton and Villefranche criteria, she was diagnosed with EDS-HT. INTERVENTIONS AND OUTCOMES: Treatment primarily consisted of low force joint manipulative therapy and soft tissue therapy intermittently over 21 months concurrently with conventional and complementary medical care. Multiple outcome questionnaires were administered pragmatically at follow-up intervals of 3, 51/2, 81/2, 19, and 21 months, including but not limited to the Headache and Neck Disability Indices and the Oswestry Low Back Questionnaire. The patient had clinically meaningful improvements on the Neck Disability Index, the Headache Disability Index, and the Revised Oswestry after 3, 51/2, 81/2, and 21 months from baseline. CONCLUSION: This patient with EDS-HT had clinically meaningful decreases in disability, headache, and spine pain after a course of multimodal chiropractic care combined with conventional and complementary medical care. PMID- 28559756 TI - Multimodal Care in the Management of a Patient With Chronic Tendinopathy of the Biceps Femoris: A Case Report. AB - OBJECTIVE: The purpose of this case report was to describe the use of dry needling in conjunction with auricular acupuncture, core exercises, and light aerobic activity for treating chronic tendinopathy of the biceps femoris. CLINICAL FEATURES: A 30-year-old white female presented with chronic biceps femoris tendinopathy. The injury had occurred 18 months prior while training for a triathlon. Active stretching of her right biceps femoris while standing with her feet 6 inches apart aggravated the pain at the origin in the right tendon of the biceps femoris at 0 degrees of movement. INTERVENTION/OUTCOME: The combination of dry needling and auricular acupuncture with core rehabilitation exercises and light activity was employed. Alleviation of pain with full range of motion was achieved during hip extension, knee flexion, and standing biceps femoris stretch at the 11th, 16th, and 18th treatments. In addition, the patient also reported improvement in her symptoms, including night sweats, insomnia, anxiety, tension, and constipation. CONCLUSIONS: This patient's symptoms and function improved after 18 treatments of multimodal care. Dry needling employed simultaneously with auricular acupuncture, core exercises, and light activity could be considered a possible strategy for treating chronic tendinopathy. PMID- 28559757 TI - Validation of the OptoGait System for Monitoring Treatment and Recovery of Post Concussion Athletes. AB - OBJECTIVE: This study sought to investigate correlations between OptoGait motion analysis technology and 2 commonly used concussion assessment instruments, the Balance Evaluation Scoring System (BESS) and the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) computerized neurocognitive assessment software, to see if OptoGait might be a valid concussion assessment tool. METHODS: Twenty Division-1 college women varsity soccer players completed trials of 8 different conditions of the OptoGait test battery. Then participants completed the BESS and ImPACT tests. One hundred twenty-eight total spatiotemporal variables were recorded for each trial of OptoGait. Pearson's r correlations among these variables and BESS and ImPACT results were calculated, and pattern analysis was completed to evaluate for emergent patterns in the data. RESULTS: Correlations for the 8 OptoGait mean-score subtests were related to the balance double-leg foam test (BESS). Correlations for the 8 OptoGait mean-score subtests were related to the balance double-leg foam test (BESS), and correlations between OptoGait standard deviation measures and the balance tandem hard surface test (BESS) both indicated potentially significant patterns. No consistent patterns of correlation existed between the OptoGait variables and the ImPACT results. CONCLUSION: OptoGait conditions correlate at higher than predicted rates with subtests of the BESS instruments but not the ImPACT measures. PMID- 28559758 TI - Plasmacytoma of the Cervical Spine: A Case Study. AB - OBJECTIVE: The purpose of this case study is to describe the presentation of a patient with plasmacytoma. CLINICAL FEATURES: A 49-year-old man presented with progressive neck pain, stiffness, and dysphagia to a chiropractic office. A radiograph indicated a plasmacytoma at C3 vertebral body. The lesion was expansile and caused a mass effect anteriorly on the esophagus and posteriorly on the spinal cord. Neurologic compromise was noted with fasciculations and hypesthesia in the right forearm. The patient was referred to a neurosurgeon. INTERVENTION AND OUTCOME: Surgical resection of the tumor was performed with a vertebral body spacer and surrounding titanium cage. Bony fusion was initiated by inserting bone grafts from the iliac crests into the titanium cage. Additional laboratory analysis and advanced imaging confirmed that the plasmacytoma had progressed to multiple myeloma and radiation and chemotherapy were also necessary. CONCLUSION: A chiropractor recognized a large, expansile plasmacytoma in the C3 vertebral body and referred the patient for surgical care. This case suggests that all practitioners of manual medicine should provide a careful analysis of the patient's clinical presentation and, if clinically warranted, radiographic examination to determine neck or back pain is due to an underlying malignant condition. PMID- 28559759 TI - Chiropractic Care of a 10-Year-Old Boy With Nonorganic Gait Disorder: A Case Report. AB - OBJECTIVE: The purpose of this case report is to describe the multidisciplinary management of a boy with nonorganic gait disorder. CLINICAL FEATURES: A 10-year old boy presented to a chiropractic clinic having had a concussion 1 week prior. He presented with lower limb muscle weakness and ataxia while weight bearing. He was referred immediately to the emergency department, from which he was sent to a neurologist at a children's hospital. The neurologist's diagnosis was nonorganic gait disorder. INTERVENTION/OUTCOME: Treatment consisted of physiotherapy, occupational therapy, and a psychiatric assessment. Chiropractic care including manipulative therapy was initiated 6 months after diagnosis. After 1 year, the gait disorder was resolved. CONCLUSION: The addition of chiropractic care to conventional treatment may have been supportive in the recovery process for this patient. The condition required 1 year to resolve, with questions remaining as to whether the symptom resolution was a result of treatment or natural history. PMID- 28559760 TI - Reply to "Presumptive Late-Onset Ankylosing Spondylitis Simulating Osteoblastic Skeletal Metastasis in a Patient With a History of Prostate Carcinoma: A Diagnostic Challenge". PMID- 28559762 TI - Accurate Measurement of Financial Toxicity Is a Prerequisite to Finding a Remedy. PMID- 28559763 TI - Financial Toxicity of Cancer Drugs: Possible Remedies from an Ethical Perspective. AB - Spiraling costs of cancer treatments have become a major concern for the payers in the health care system and for individual patients suffering from the cancer drugs' financial toxicity. This article discusses possible solutions from an ethical perspective. First, it gives some orientation about what constitutes a fair price for innovative anticancer agents. While a definitive answer remains difficult, there are good reasons to enter into price negotiations with the pharmaceutical companies to align the price with the R&D costs and the added value of the product. Information about the drug's cost-effectiveness should be available, a fixed threshold, however, seems ethically problematic. Rather, a 'signal cost-effectiveness threshold' should indicate when the drug price requires special justification. Further strategies include an improved benefit assessment after market authorization by independent publicly financed studies, which will provide a valid basis for price negotiations and clinical decision making at the micro level. Last but not least, cancer treatments should be tailored not only to the biology of the tumor but also to the preferences of the patient. Primarily mandated by the respect for autonomy, promoting patient centered care has the potential to improve quality of care and enable a wise use of scarce health care resources. PMID- 28559761 TI - A systematic review of rye (Secale cereale L.) as a source of resistance to pathogens and pests in wheat (Triticum aestivum L.). AB - Wheat is globally one of the most important crops. With the current human population growth rate, there is an increasing need to raise wheat productivity by means of plant breeding, along with development of more efficient and sustainable agricultural systems. Damage by pathogens and pests, in combination with adverse climate effects, need to be counteracted by incorporating new germplasm that makes wheat more resistant/tolerant to such stress factors. Rye has been used as a source for improved resistance to pathogens and pests in wheat during more than 50 years. With new devastating stem and yellow rust pathotypes invading wheat at large acreage globally, along with new biotypes of pest insects, there is renewed interest in using rye as a source of resistance. Currently the proportion of wheat cultivars with rye chromatin varies between countries, with examples of up to 34%. There is mainly one rye source, Petkus, that has been widely exploited and that has contributed considerably to raise yields and increase disease resistance in wheat. Successively, the multiple disease resistances conferred by this source has been overcome by new pathotypes of leaf rust, yellow rust, stem rust and powdery mildew. However, there are several other rye sources reported to make wheat more resistant to various biotic constraints when their rye chromatin has been transferred to wheat. There is also development of knowledge on how to produce new rye translocation, substitution and addition lines. Here we compile information that may facilitate decision making for wheat breeders aiming to transfer resistance to biotic constraints from rye to elite wheat germplasm. PMID- 28559764 TI - Factors Affecting Concordance between Radiological and Histological Findings in Invasive Lobular Carcinoma - Experience from a National Cancer Centre. AB - BACKGROUND: Invasive lobular carcinoma (ILC) is characterized by an infiltrative discohesive growth pattern, making it difficult to accurately assess both clinically and by imaging studies. Despite favourable biological characteristics, challenges remain in the surgical treatment of ILC. We aimed to evaluate radiology/histology concordance and identify histological and biological parameters on core biopsies that may predict final tumour histology and guide surgical treatment decisions. PATIENTS AND METHODS: The radiology and histology reports for all newly diagnosed cases of ILC were analysed. The biopsy and resection histological slides for all the surgical cases were reviewed. RESULTS: 75 new cases of ILC were diagnosed over a 2-year period. 48 patients underwent surgery of whom 25% had 2 or more operations. There was discordance between radiological and histological tumour focality and tumour size in 35 and 40%, respectively. The correlation between radiology/histology discordance and E cadherin expression was statistically significant. However, the correlation between radiology/histology discordance and menopausal status, breast density, pattern of invasion, presence of lobular intraepithelial neoplasia (LIN), hormonal status, and Ki67 were not statistically significant. CONCLUSION: Histological and biological factors in ILC, with the exception of E-cadherin expression, do not seem to play a significant role in radiology/histology discordance. However, larger studies are needed to further corroborate these findings. PMID- 28559765 TI - Value of Digital Breast Tomosynthesis versus Additional Views for the Assessment of Screen-Detected Abnormalities - a First Analysis. AB - BACKGROUND: The purpose of this study was to countercheck the equivalence of single-view digital breast tomosynthesis (DBT) or DBT with additional views (DBT+AV) compared to traditional standard assessment by additional views (AV) in patients with a screen-detected abnormality. PATIENTS AND METHODS: Patients with a screen-detected abnormality were consecutively invited to obtain 1 single-view wide-angle DBT in addition to the indicated AV. The study was approved by the local ethics committee and by the Federal Office for Radiation Protection. RESULTS: This study is based on 311 lesions in 285 patients with a follow-up of > 2 years and/or biopsy. Counting BI-RADS 0 and 3 as positive calls, the sensitivity/specificity of DBT+AV versus DBT only versus AV only were 96.4/54.3%, 96.4/56.6%, and 90.9/42.2%, respectively. The specificities and BI-RADS classifications differed significantly (p < 0.01). AV appeared unnecessary in 88.8% of the cases. CONCLUSION: DBT appeared to be at least equivalent to AV for assessing indeterminate screen-detected lesions and could replace AV for most lesions. To obtain the extra information appears possible without increasing the overall radiation dose. Subsequent blinded reader studies are ongoing. PMID- 28559766 TI - Combining Virtual Touch Tissue Imaging and BI-RADS May Improve Solid Breast Lesion Evaluation. AB - BACKGROUND: Ultrasound elastography (UE) is a novel imaging method. The purpose of this study was to determine the utility of Virtual Touch tissue imaging in the evaluation of solid breast lesions. PATIENTS AND METHODS: 209 breast solid lesions in 192 patients that had been evaluated using ultrasound (US) and UE were reviewed and analyzed. RESULTS: The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for UE, US, and US plus UE in the differentiation of malignant from benign breast lesions were 80.8, 75.6, 77.9, 73.1, and 82.8% for UE, 87.2, 86.1, 86.6, 83.7, and 89.2% for US, and 92.5, 86.9, 89.5, 85.3, and 93.4% for US plus UE. There were significant differences between UE and US plus UE (all p < 0.05). Except for accuracy, there were no significant differences between UE and US or US and US plus UE (all p > 0.05). The area under the curve obtained from the ROC curve for UE, US, and US plus UE in differentiating malignant from benign lesions was 0.845, 0.884, and 0.922, respectively. CONCLUSION: The UE scoring system is not superior to BI-RADS in the sonographic evaluation of solid breast lesions. Combined use may improve the performance. PMID- 28559767 TI - St. Gallen/Vienna 2017: A Brief Summary of the Consensus Discussion about Escalation and De-Escalation of Primary Breast Cancer Treatment. AB - For the second time, the St. Gallen Consensus Conference on early breast cancer treatment standards took place in Vienna, Austria, where it will remain for the foreseeable future (next date: March 20-23, 2019). With the probably most prominent line-up of global breast cancer experts and more than 3,000 participants from over 100 countries, the 2017 St. Gallen/Vienna conference again was a huge success. A generation change took place with respect to the Conference Co-Chairpersons. Traditionally, the experts from all continents reviewed publications from the past 2 years, and discussed whether new diagnostic or therapeutic means were ready for routine everyday practice. This year, the conference's main theme was 'Escalating and Deescalating Treatment', and the traditional panel votings clarified a number of issues in this respect. Several subjects of all breast cancer modalities were further de-escalated (surgery: 'no ink on tumor' clearly confirmed as standard; resection within new limits after neoadjuvant systemic therapy; axillary dissection may also be avoided after mastectomy under certain circumstances; radiotherapy: hypofractionation is standard of care in breast conserving therapy; chemotherapy: can be avoided in low-risk patients). However, others were escalated: surgery: after neoadjuvant treatment and after mastectomy a positive sentinel node leads to axillary dissection; radiotherapy: regional nodes have to be irradiated in 4+ nodes situations; adjuvant therapy: bisphosphonates as standard for postmenopausal women. There was no clear panel opinion on the optimal use of multigenomic assays. As always, the panel recommendations are strictly opinion-based, and try to depict the 'usual' treatment for the 'average' patients. This rapid report by the editors-in-chief of Breast Care summarizes the results of the 2017 international panel votings with respect to loco-regional systemic treatment, and does not intend to replace the official St. Gallen Consensus publication. PMID- 28559768 TI - Intraoperative Radiotherapy of Breast Cancer and Its Biological Effects. AB - Conservative breast cancer surgery followed by radiation therapy is the standard treatment for this type of cancer. Numerous studies demonstrate that 90% of local recurrences after traditional surgery occur in the same quadrant as the primary cancer. The published data suggest that the wound healing process after surgery alters the area surrounding the original tumor and the modified microenvironment is more favorable for the tumor to recur. The majority of metastases within scar initiated much research, and the consequences of these studies led to clinical trials aimed at assessing whether localized radiotherapy, such as intraoperative radiotherapy (IORT), would be more effective in inhibiting formation of local recurrence than the standard postoperative whole breast radiotherapy. IORT involves irradiation of diseased tissue directly during surgery. The rationale for this approach is the fact that the increase in the radiation dose increases local tumor control, which is the primary goal of radiation therapy. The biological basis of this process are still not thoroughly understood. Gaining new knowledge about the recurrence formation at the molecular level could serve as a starting point for further analysis and to create an opportunity to identify new targets of therapy, and possibly new therapeutic agents. PMID- 28559770 TI - Erratum. AB - [This corrects the article on p. 432 in vol. 11.]. PMID- 28559769 TI - Next-Generation Sequencing Reveals a Nonsense Mutation (p.Arg364Ter) in MRE11A Gene in an Indian Patient with Familial Breast Cancer. AB - BACKGROUND: The MRN complex consisting of MRE11A-RAD50-NBS1 proteins is involved in the repair of double-strand breaks, and mutations in genes coding for the MRN complex have been identified in families with breast and ovarian cancer. CASE REPORT: In a BRCA-negative family with positive history of breast and endometrial cancer, next-generation sequencing-based panel testing identified a mutation in the MRE11A gene (NM_005590 c.1090C>T: p.Arg364Ter). This mutation results in a shorter mutated protein lacking 2 DNA binding domains (the GAR domain and the RAD50 binding site), abolishing the function of protein. CONCLUSION: This case provides insight into the role of the MRE11A gene in causing breast cancer susceptibility in families, and supports the use of multigene panel testing in cases with hereditary predisposition to breast cancer. PMID- 28559771 TI - CDK4/6 Inhibitors in the Treatment of Metastatic Breast Cancer. PMID- 28559774 TI - Geriatric Nutrition Risk Index is an Important Predictor of Cancer-Specific Survival, but not Recurrence-Free Survival, in Patients Undergoing Surgical Resection for Non-Metastatic Renal Cell Carcinoma. AB - BACKGROUND: The objective of this study was to assess the prognostic value of the Geriatric Nutrition Risk Index (GNRI), a simplified, objective screening parameter of nutrition-related risk for various pathological conditions, on patients with non-metastatic renal cell carcinoma (RCC) who underwent surgical resection. PATIENTS AND METHODS: This study included 432 consecutive patients with non-metastatic RCC who received complete surgical resection. The prognostic outcomes of these patients were evaluated focusing on the significance of GNRI, calculated from serum albumin and the body mass index. RESULTS: Of the 432 patients, 107 (24.8%) and 325 (75.2%) were classified into low (GNRI <= 98) and high (GNRI > 98) nutritional groups, respectively. Both recurrence-free survival and cancer-specific survival in the low nutritional group were significantly poorer compared with those in the high nutritional group. Despite the lack of independent significance as a predictor of recurrence-free survival, GNRI, in addition to microvascular invasion, appeared to be independently associated with cancer-specific survival on multivariate analysis. CONCLUSION: A low nutritional status evaluated by GNRI may have an unfavorable impact on postoperative cancer control, particularly cancer-specific survival, in non-metastatic RCC patients who received surgical resection. PMID- 28559773 TI - Neuroendocrine Testicular Tumors: A Systematic Review and Meta-Analysis. AB - PURPOSE: The purpose of this study is to study the main epidemiological, clinical, para clinical, pathological, therapeutic, and evolutionary features of patients with testicular neuroendocrine tumors (TNET). MATERIALS AND METHODS: Nine case series and sixteen case reports were identified by searching PubMed database and qualified for inclusion in this study. We added the data of one case treated in the department of urology in Habib Bourguiba Hospital in Sfax, to the published cases. RESULTS: A total of 132 cases were collected. Median age at diagnosis was 39 years old (range 10- 83 years). The most common presenting symptom was either a testicular mass or a swelling in 38.46% of cases. Carcinoid syndrome was documented in 10.60% of patients. The clinical examination revealed a palpable mass in 44.70% of patients. This mass was painless and firm in most cases. Serum tumor markers (beta-gonadotrophine chorionique humaine, alpha-feto protein, and lactate dehydrogenase) were within normal limits in all patients except in one case. Most testicular neuroendocrine tumors (76.52%) were primary and pure. The tumors were positive for chromogranin (100%), synaptophysin (100%) and cytokeratin (93.10%). Metastases were detected at time of diagnosis in eight cases (6.06%). The main treatment was radical orchiectomy performed in 127 patients (96.21%). The 5-year overall survival rate was 78.70% and the 5-year specific survival rate was 84.30%. CONCLUSION: The diagnosis of testicular carcinoids is based on the immunohistochemistry study. The treatment of choice for these tumors is radical orchiectomy. Somatostatin analogues were reported to be effective in patients with carcinoid syndrome. PMID- 28559772 TI - Classifying Hydroceles of the Pelvis and Groin: An Overview of Etiology, Secondary Complications, Evaluation, and Management. AB - INTRODUCTION: A hydrocele is defined as the pathological buildup of serous fluid in the pelvis and groin due to various etiologies such as diseases or trauma. It has distinct clinical manifestations, particularly discomfort and psychosocial distress. Understanding the anatomy, embryology, and physiology associated with hydrocele formation is crucial to understand its onset and progression. MATERIALS AND METHODS: A MEDLINE(r) search was conducted using keywords for the relevant classification of hydrocele and its etiology, complications, sexual barriers, evaluation, and management. RESULTS: Appropriately classifying the hydrocele as primary, secondary communicating, secondary noncommunicating, microbe-induced, inflammatory, iatrogenic, trauma-induced, tumor-induced, canal of Nuck, congenital, and giant is important for identifying the underlying etiology. Often this process is overlooked when the classification or etiology is too rare. A focused evaluation is important for this, so that timely management can be provided. We comprehensively review the classifications, etiology, and secondary complications of hydrocele. Pitfalls of current diagnostic techniques are explored along with recommended methods for accurate diagnosis and current treatment options. CONCLUSION: Due to the range of classifications and etiologies of hydrocele in the pelvis and groin, a deliberate differential diagnosis is essential to avoiding imminent life-threatening complications as well as providing the appropriate treatment. PMID- 28559775 TI - Post Prostatectomy Vesicourethral Stenosis or Bladder Neck Contracture with Concomitant Urinary Incontinence: Our Experience and Recommendations. AB - OBJECTIVES: To present our experience in the management of bladder neck contracture with concomitant post prostatectomy incontinence and to provide our recommendations based on the updated literature. MATERIALS AND METHODS: Between Jan 2010 and June 2015, 37 patients from our cohort of 341 patients with post prostatectomy incontinence were evaluated. Patient data were retrospectively collected. Patients with bladder neck contracture confirmed on flexible cystoscopy underwent subsequent rigid cystoscopy and deep endoscopic bladder neck incision (BNI). A follow up flexible cystoscopy would be performed 3 months later. If there was no recurrence of the bladder neck contracture, an artificial urethral sphincter (AUS) or a male sling was recommended. RESULTS: The mean age of patients was 68 years (range 59-77) and the mean BMI was 31 (range 21-41) kg/m2. Twenty-five (67.7%) patients had open prostatectomy and 12 (32.4%) patients had laparoscopic prostatectomy. Fourteen patients (37.8%) underwent adjuvant radiotherapy. Twenty-four (64.8%) patients had one BNI procedure, 8 (21.6%) patients had two procedures and 5 (13.5%) patients had more than 2 procedures. Twenty-one (91.3%) patients had AUS implantation and 2 (8.7%) patients had male sling placement. Besides, 85.7% of AUS and 50% of male sling patients managed to achieve successful outcomes with a mean follow up period of 13.1 months (range 2-33 months). CONCLUSION: Initial management with aggressive BNI followed by implantation of an AUS or male sling when bladder neck is stable is essential to achieve a satisfactory urinary continence outcome. PMID- 28559776 TI - Association between Serum Testosterone and PSA Levels in Middle-Aged Healthy Men from the General Population. AB - INTRODUCTION: The aim of the present study was to evaluate the association between serum testosterone and PSA levels in middle-aged healthy men from the general population. MATERIALS AND METHODS: Based on 119 healthy men from the general population, total testosterone and PSA levels were measured. Demographic data regarding BMI, waist-to-hip ratio, smoking, and alcohol consumption were also collected. Men were classified into two groups according to testosterone levels; hypogonadal (testosterone <= 12 nmol/l), and eugonadal (testosterone > 12 nmol/l). RESULTS: The mean age of the subjects was 55 years (range 46-60 years). No significant correlation between serum testosterone and PSA levels was found (p = 0.60). PSA levels were similar when compared between hypogonadal and eugonadal men (1.4 ug/l vs. 1.4 ug/l, p = 0.90). When using a multivariate analysis model adjusted for the age of the subjects, BMI, waist-to-hip ratio, smoking, and alcohol consumption, a positive significant association between testosterone and PSA levels was found (beta = 0.03, 95 % CI = 0.003-0.062, p = 0.03). CONCLUSION: Only after adjusted multivariate analysis, our results indicated that testosterone was associated with PSA levels in middle-aged healthy men. PMID- 28559777 TI - Microsurgical Subinguinal Varicocele Repair of Grade II-III Lesions Associated with Improvements of Testosterone Levels. AB - INTRODUCTION: The results of reports on the association between varicocele repair and testosterone levels were conflicting. The aim of the present study is, therefore, to investigate the impact of varicocele repair on testosterone levels. MATERIALS AND METHODS: The study is based on 20 men who experienced microsurgical subinguinal varicoceles repair because of chronic dull scrotal pain. All hormonal profiles available in the clinical records were reviewed. Follow-up evaluation was done at 1 and 12 months after surgery. Men were classified into groups based on the preoperative testosterone levels: euogonadal (serum levels of testosterone > 12 nmol/l), hypogonadal men (serum levels of testosterone <= 12 nmol/l). RESULTS: Microsurgical subinguinal varicocele repair was associated with a significant improvements of testosterone levels at 1 and 12 months after surgery as compared to the preoperative levels (13 nmol/l vs. 18 nmol/l, p = 0.03; 13 nmol/l vs. 15 nmol/l, p = 0.01). The same trend was seen in men who were classified as being hypogonadal (7.0 nmol/l vs. 15 nmol/l, p = 0.01; 7.0 nmol/l vs. 10 nmol/l, p = 0.02). No significant improvements in testosterone levels were observed in euogonadal men (p > 0.05). CONCLUSION: Microsurgical subinguinal varicocele repair was associated with a significant improvements of testosterone levels in men with grade II-III lesions and low preoperative testosterone values. PMID- 28559779 TI - Periurethral Gland Calculus Discovered on Workup for Dyspareunia. AB - A 55-year-old woman with a history of chronic dysuria in the absence of infection was found to have an unusual lesion below the urethral meatus. This was subsequently determined to be a periurethral gland containing a sizeable calculus. Pathologic analysis found the composition to be car bonate apatite (dahllite). Only one prior report of a female periurethral calculus has been noted in the English peer-reviewed literature. PMID- 28559778 TI - Magnetic Resonance Imaging in Hematospermia: Does It Increase Unnecessary Prostate Biopsy? AB - INTRODUCTION: Hematospermia is an uncommon presentation of prostate cancer. Following the introduction of MRI for patients with hematospermia we evaluated its use and effect on prostate biopsy and cancer detection rates. MATERIALS AND METHODS: Analysis of patients attending our outpatient department over 2 years was undertaken. Diagnostic workup included digital rectal examination and PSA. Those with abnormal findings or persisting symptoms were offered prostate biopsy. In the second year MRI became available for patients with hematospermia. Abnormal MRI or persisting symptoms were offered biopsy. We compared the frequency of prostate biopsy and cancer detection in patients undergoing MRI and those not having imaging. RESULTS: Forty-seven patients were referred with hematospermia. Nineteen patients did not undergo MRI; four received prostate biopsy with one adenocarcinoma found. Twenty-four patients had an MRI with 17 biopsies undertaken. Three biopsies revealed adenocarcinoma. In the MRI group 71% of patients underwent prostate biopsy but only 21% from the non-MRI group (p < 0.05). Prostate cancer detection rate in the MRI group was 18% whilst in the non MRI group was 25% (p = 0.7). CONCLUSIONS: Our findings indicate that caution should be used with MRI as it can lead to an increase in prostate biopsy with no change in cancer detection rate. PMID- 28559780 TI - Pancreatitis Induced by Cocaine. AB - Pancreatitis is one of the commonest diseases of the gastrointestinal tract, characterized by epigastric pain of moderate to severe intensity, which radiates to the back, elevation of pancreatic lipase and amylase enzymes, and changes in pancreatic parenchyma in imaging methods. The most common etiologies vary, generally the most frequent being biliary lithiasis and alcohol, followed by hypertriglyceridemia. Among the less frequent causes is drug-induced pancreatitis. We report a case of acute pancreatitis caused by cocaine, rarely described in literature. PMID- 28559781 TI - Pancreatic Squamous Cell Carcinoma. AB - Pancreatic squamous cell carcinoma (SCC) is a rare event. Here, we present a 56 year-old man with pancreatic SCC. Imaging methods demonstrated a hypodense mass at the head and trunk of the pancreas. Also, some lymphadenopathy has been seen around the pancreas and para-aorta. The mass created pressure and encasement on the celiac trunk, portal vein, and arteries of the liver and spleen. Endoscopic ultrasound showed a mass lesion of 45-37 mm (mixed echoic) at the trunk of the pancreas. Histological examination of the endoscopic ultrasound-guided fine needle aspiration specimen confirmed the diagnosis of SCC. The disease is highly aggressive, most often locally advanced or metastatic at diagnosis, and poorly responsive to treatment. It also has generally poor survival rates. PMID- 28559782 TI - Cholecystoparietal Fistula Revealed by an Epigastric Abscess. AB - Cholecystocutaneous fistula, the ultimate complication of abscessed or overlooked acute cholecystitis, is due to perforation of the gallbladder in the abdominal wall. The authors report an unusual case of cholecystoparietal fistula revealed by an epigastric abscess. Fistulography and modern imaging tools make the diagnosis easier. Surgery is the best available treatment. PMID- 28559783 TI - Long-Term Results of Serial Transverse Enteroplasty with Neovalve Creation for Extreme Short Bowel Syndrome: Report of Two Cases. AB - OBJECTIVE: The aim of this article was to determine whether serial transverse enteroplasty (STEP) and the creation of a new ileocecal valve in extreme short bowel syndrome (SBS) cases (<45 cm) is effective in intestinal adaptation and improvement of nutritional parameters and serum citrulline levels. PATIENTS AND METHODS: We present 2 cases of SBS treated with STEP. Enterectomy was performed for massive intestinal ischemia secondary to a gastrointestinal stromal tumor in the first case and to catastrophic antiphospholipid syndrome in the second. After enterectomy, the short residual bowel measured 34 cm in the first patient and 45 cm in the second. In both cases STEP, cholecystectomy, and gastrostomy were performed. In the first case a Brooke neovalve was created, and in the other the ileocecal valve was preserved. RESULTS: Both patients could finally be weaned off total parenteral nutrition (TPN) and gastrostomy feeding, maintaining a good nutritional status 1 year after surgery. CONCLUSIONS: In extreme SBS, a minimum length of 80-90 cm of functioning small bowel and an intact ileocecal valve are necessary. We plead for the use of STEP with preservation of the ileocecal valve or creation of a neovalve using the Brooke technique in order to achieve the ultimate goal, which is to wean patients off TPN. After a critical review of different surgical techniques, a treatment algorithm is proposed. PMID- 28559784 TI - Splenic Injury Following Endoscopic Retrograde Cholangiopancreatography: A Case Report and Literature Review. AB - Splenic injury following endoscopy is a rare but potentially fatal complication. While this has been found to occur more frequently after colonoscopy, splenic injury following endoscopic retrograde cholangiopancreatography (ERCP) remains highly uncommon since its first reported case in 1989. Indeed, there have been only 19 such cases reported in the English, German, and Spanish literature collectively over the past 27 years. We report on a 59-year-old woman who developed a peri-splenic haematoma diagnosed on abdominal computed tomography the day following ERCP and stenting for Mirizzi syndrome. The patient was treated conservatively and made a full recovery. We reviewed all cases of post-ERCP splenic injuries reported to date and discuss the published opinions on the likely mechanism of injury, predisposing factors, presenting features, investigation, and treatment options. Ultimately, patient outcome relies on clinical suspicion of this rare complication following ERCP. PMID- 28559785 TI - An Uncommon Cause of Small Bowel Bleeding from Appendiceal Carcinoma. AB - Massive hematochezia caused by a small bowel lesion is a rare entity. Currently, video capsule endoscopy and balloon-assisted enteroscopy are effective in identifying the source of small intestine bleeding. Herein, we report a case of small bowel bleeding caused by a nonmucinous appendiceal adenocarcinoma with ileal invasion which was detected by video capsule endoscopy and single-balloon endoscopy. Despite the advanced disease stage with hepatic and peritoneal metastases, as of September 2016 the patient has had 8 years' disease-free survival after surgical resection and chemotherapy. PMID- 28559786 TI - Recognition of Extraperitoneal Colonic Perforation following Colonoscopy: A Review of the Literature. AB - Colon perforation is an uncommon but serious complication of colonoscopy. It may occur as either intraperitoneal or extraperitoneal perforation or in combination. The majority of colonic perforations are intraperitoneal, causing air and intracolonic contents to leak into the peritoneal space. Rarely, colonic perforation can be extraperitoneal, leading to the passage of air into the retroperitoneal space causing pneumoretroperitoneum, pneumomediastinum, pneumopericardium, pneumothorax, and subcutaneous emphysema. A literature review revealed that 31 cases of extraperitoneal perforation exist, out of which 20 cases also reported concomitant intraperitoneal perforation. We report the case of a young female with a history of ulcerative colitis who developed combined intraperitoneal and extraperitoneal perforation after colonoscopy. We also report the duration of onset of symptoms, clinical features, imaging findings, site of leak, and treatment administered in previously reported cases of extraperitoneal colonic perforation. PMID- 28559787 TI - A 3D Computational Model of Transcutaneous Electrical Nerve Stimulation for Estimating Abeta Tactile Nerve Fiber Excitability. AB - Tactile sensory feedback plays an important role in our daily life. Transcutaneous electrical nerve stimulation (TENS) is widely accepted to produce artificial tactile sensation. To explore the underlying mechanism of tactile sensation under TENS, this paper presented a novel 3D TENS computational model including an active Abeta tactile nerve fiber (TNF) model and a forearm finite element model with the fine-layered skin structure. The conduction velocity vs. fiber diameter and strength-duration relationships in this combined TENS model matched well with experimental data. Based on this validated TENS model, threshold current variation were further investigated under different stimulating electrode sizes with varied fiber diameters. The computational results showed that the threshold current intensity increased with electrode size, and larger nerve fibers were recruited at lower current intensities. These results were comparable to our psychophysical experimental data from six healthy subjects. This novel 3D TENS model would further guide the floorplan of the surface electrodes, and the stimulating paradigms for tactile sensory feedback. PMID- 28559788 TI - Assessment of Motor Control during Three-Dimensional Movements Tracking with Position-Varying Gravity Compensation. AB - Active movements are important in the rehabilitation training for patients with neurological motor disorders, while weight of upper limb impedes movements due to muscles weakness. The objective of this study is to develop a position-varying gravity compensation strategy for a cable-based rehabilitation robot. The control strategy can estimate real-time gravity torque according to position feedback. Then, the performance of this control strategy was compared with the other two kinds of gravity compensation strategies (i.e., without compensation and with fixed compensation) during movements tracking. Seven healthy subjects were invited to conduct tracking tasks along four different directions (i.e., upward, forward, leftward, and rightward). The performance of movements with different compensation strategies was compared in terms of root mean square error (RMSE) between target and actual moving trajectories, normalized jerk score (NJS), mean velocity ratio (MVR) of main motion direction, and the activation of six muscles. The results showed that there were significant effects in control strategies in all four directions with the RMSE and NJS values in the following order: without compensation > fixed compensation > position-varying compensation and MVR values in the following order: without compensation < fixed compensation < position varying compensation (p < 0.05). Comparing with movements without compensation in all four directions, the activation of muscles during movements with position varying compensation showed significant reductions, except the activations of triceps and in forward and leftward movements, the activations of upper trapezius and middle parts of deltoid in upward movements and the activations of posterior parts of deltoid in all four directions (p < 0.05). Therefore, with position varying gravity compensation, the upper limb cable-based rehabilitation robotic system might assist subjects to perform movements with higher quality and improve the participation of robot-aided rehabilitation training. Further studies are needed to explore the effectiveness and clinic application across pathologies. PMID- 28559791 TI - Photogrammetry-Based Head Digitization for Rapid and Accurate Localization of EEG Electrodes and MEG Fiducial Markers Using a Single Digital SLR Camera. AB - The performance of EEG source reconstruction has benefited from the increasing use of advanced head modeling techniques that take advantage of MRI together with the precise positions of the recording electrodes. The prevailing technique for registering EEG electrode coordinates involves electromagnetic digitization. However, the procedure adds several minutes to experiment preparation and typical digitizers may not be accurate enough for optimal source reconstruction performance (Dalal et al., 2014). Here, we present a rapid, accurate, and cost effective alternative method to register EEG electrode positions, using a single digital SLR camera, photogrammetry software, and computer vision techniques implemented in our open-source toolbox, janus3D. Our approach uses photogrammetry to construct 3D models from multiple photographs of the participant's head wearing the EEG electrode cap. Electrodes are detected automatically or semi automatically using a template. The rigid facial features from these photo-based models are then surface-matched to MRI-based head reconstructions to facilitate coregistration to MRI space. This method yields a final electrode coregistration error of 0.8 mm, while a standard technique using an electromagnetic digitizer yielded an error of 6.1 mm. The technique furthermore reduces preparation time, and could be extended to a multi-camera array, which would make the procedure virtually instantaneous. In addition to EEG, the technique could likewise capture the position of the fiducial markers used in magnetoencephalography systems to register head position. PMID- 28559790 TI - Non-linear Analysis of Scalp EEG by Using Bispectra: The Effect of the Reference Choice. AB - Bispectral analysis is a signal processing technique that makes it possible to capture the non-linear and non-Gaussian properties of the EEG signals. It has found various applications in EEG research and clinical practice, including the assessment of anesthetic depth, the identification of epileptic seizures, and more recently, the evaluation of non-linear cross-frequency brain functional connectivity. However, the validity and reliability of the indices drawn from bispectral analysis of EEG signals are potentially biased by the use of a non neutral EEG reference. The present study aims at investigating the effects of the reference choice on the analysis of the non-linear features of EEG signals through bicoherence, as well as on the estimation of cross-frequency EEG connectivity through two different non-linear measures, i.e., the cross bicoherence and the antisymmetric cross-bicoherence. To this end, four commonly used reference schemes were considered: the vertex electrode (Cz), the digitally linked mastoids, the average reference, and the Reference Electrode Standardization Technique (REST). The reference effects were assessed both in simulations and in a real EEG experiment. The simulations allowed to investigated: (i) the effects of the electrode density on the performance of the above references in the estimation of bispectral measures; and (ii) the effects of the head model accuracy in the performance of the REST. For real data, the EEG signals recorded from 10 subjects during eyes open resting state were examined, and the distortions induced by the reference choice in the patterns of alpha-beta bicoherence, cross-bicoherence, and antisymmetric cross-bicoherence were assessed. The results showed significant differences in the findings depending on the chosen reference, with the REST providing superior performance than all the other references in approximating the ideal neutral reference. In conclusion, this study highlights the importance of considering the effects of the reference choice in the interpretation and comparison of the results of bispectral analysis of scalp EEG. PMID- 28559792 TI - Open-Source, Low Cost, Free-Behavior Monitoring, and Reward System for Neuroscience Research in Non-human Primates. AB - We describe a low-cost system designed to document bodily movement and neural activity and deliver rewards to monkeys behaving freely in their home cage. An important application is to studying brain-machine interface (BMI) systems during free behavior, since brain signals associated with natural movement can differ significantly from those associated with more commonly used constrained conditions. Our approach allows for short-latency (<500 ms) reward delivery and behavior monitoring using low-cost off-the-shelf components. This system interfaces existing untethered recording equipment with a custom hub that controls a cage-mounted feeder. The behavior monitoring system uses a depth camera to provide real-time, easy-to-analyze, gross movement data streams. In a proof-of-concept experiment we demonstrate robust learning of neural activity using the system over 14 behavioral sessions. PMID- 28559793 TI - Initial Validation for the Estimation of Resting-State fMRI Effective Connectivity by a Generalization of the Correlation Approach. AB - Resting-state functional MRI (rs-fMRI) is widely used to noninvasively study human brain networks. Network functional connectivity is often estimated by calculating the timeseries correlation between blood-oxygen-level dependent (BOLD) signal from different regions of interest (ROIs). However, standard correlation cannot characterize the direction of information flow between regions. In this paper, we introduce and test a new concept, prediction correlation, to estimate effective connectivity in functional brain networks from rs-fMRI. In this approach, the correlation between two BOLD signals is replaced by a correlation between one BOLD signal and a prediction of this signal via a causal system driven by another BOLD signal. Three validations are described: (1) Prediction correlation performed well on simulated data where the ground truth was known, and outperformed four other methods. (2) On simulated data designed to display the "common driver" problem, prediction correlation did not introduce false connections between non-interacting driven ROIs. (3) On experimental data, prediction correlation recovered the previously identified network organization of human brain. Prediction correlation scales well to work with hundreds of ROIs, enabling it to assess whole brain interregional connectivity at the single subject level. These results provide an initial validation that prediction correlation can capture the direction of information flow and estimate the duration of extended temporal delays in information flow between regions of interest ROIs based on BOLD signal. This approach not only maintains the high sensitivity to network connectivity provided by the correlation analysis, but also performs well in the estimation of causal information flow in the brain. PMID- 28559794 TI - Possible Function of Molecular Chaperones in Diseases Caused by Propagating Amyloid Aggregates. AB - The vast majority of neurodegenerative pathologies stem from the formation of toxic oligomers and aggregates composed of wrongly folded proteins. These protein complexes can be released from pathogenic cells and enthralled by other cells, causing the formation of new aggregates in a prion-like manner. By this mechanism, migrating complexes can transmit a disorder to distant regions of the brain and promote gradually transmitting degenerative processes. Molecular chaperones can counteract the toxicity of misfolded proteins. In this review, we discuss recent data on the possible cytoprotective functions of chaperones in horizontally transmitting neurological disorders. PMID- 28559789 TI - The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases. AB - The accumulation of misfolded proteins in the human brain is one of the critical features of many neurodegenerative diseases, including Alzheimer's disease (AD). Assembles of beta-amyloid (Abeta) peptide-either soluble (oligomers) or insoluble (plaques) and of tau protein, which form neurofibrillary tangles, are the major hallmarks of AD. Chaperones and co-chaperones regulate protein folding and client maturation, but they also target misfolded or aggregated proteins for refolding or for degradation, mostly by the proteasome. They form an important line of defense against misfolded proteins and are part of the cellular quality control system. The heat shock protein (Hsp) family, particularly Hsp70 and Hsp90, plays a major part in this process and it is well-known to regulate protein misfolding in a variety of diseases, including tau levels and toxicity in AD. However, the role of Hsp90 in regulating protein misfolding is not yet fully understood. For example, knockdown of Hsp90 and its co-chaperones in a Caenorhabditis elegans model of Abeta misfolding leads to increased toxicity. On the other hand, the use of Hsp90 inhibitors in AD mouse models reduces Abeta toxicity, and normalizes synaptic function. Stress-inducible phosphoprotein 1 (STI1), an intracellular co chaperone, mediates the transfer of clients from Hsp70 to Hsp90. Importantly, STI1 has been shown to regulate aggregation of amyloid-like proteins in yeast. In addition to its intracellular function, STI1 can be secreted by diverse cell types, including astrocytes and microglia and function as a neurotrophic ligand by triggering signaling via the cellular prion protein (PrPC). Extracellular STI1 can prevent Abeta toxic signaling by (i) interfering with Abeta binding to PrPC and (ii) triggering pro-survival signaling cascades. Interestingly, decreased levels of STI1 in C. elegans can also increase toxicity in an amyloid model. In this review, we will discuss the role of intracellular and extracellular STI1 and the Hsp70/Hsp90 chaperone network in mechanisms underlying protein misfolding in neurodegenerative diseases, with particular focus on AD. PMID- 28559795 TI - Voltage-Dependent Inhibition of Glycine Receptor Channels by Niflumic Acid. AB - Niflumic acid (NFA) is a member of the fenamate class of nonsteroidal anti inflammatory drugs. This compound and its derivatives are used worldwide clinically for the relief of chronic and acute pain. NFA is also a commonly used blocker of voltage-gated chloride channels. Here we present evidence that NFA is an efficient blocker of chloride-permeable glycine receptors (GlyRs) with subunit heterogeneity of action. Using the whole-cell configuration of patch-clamp recordings and molecular modeling, we analyzed the action of NFA on homomeric alpha1DeltaIns, alpha2B, alpha3L, and heteromeric alpha1beta and alpha2beta GlyRs expressed in CHO cells. NFA inhibited glycine-induced currents in a voltage dependent manner and its blocking potency in alpha2 and alpha3 GlyRs was higher than that in alpha1 GlyR. The Woodhull analysis suggests that NFA blocks alpha1 and alpha2 GlyRs at the fractional electrical distances of 0.16 and 0.65 from the external membrane surface, respectively. Thus, NFA binding site in alpha1 GlyR is closer to the external part of the membrane, while in alpha2 GlyR it is significantly deeper in the pore. Mutation G254A at the cytoplasmic part of the alpha1 GlyR pore-lining TM2 helix (level 2') increased the NFA blocking potency, while incorporation of the beta subunit did not have a significant effect. The Hill plot analysis suggests that alpha1 and alpha2 GlyRs are preferably blocked by two and one NFA molecules, respectively. Molecular modeling using Monte Carlo energy minimizations provides the structural rationale for the experimental data and proposes more than one interaction site along the pore where NFA can suppress the ion permeation. PMID- 28559796 TI - Presynaptic Membrane Receptors Modulate ACh Release, Axonal Competition and Synapse Elimination during Neuromuscular Junction Development. AB - During the histogenesis of the nervous system a lush production of neurons, which establish an excessive number of synapses, is followed by a drop in both neurons and synaptic contacts as maturation proceeds. Hebbian competition between axons with different activities leads to the loss of roughly half of the neurons initially produced so connectivity is refined and specificity gained. The skeletal muscle fibers in the newborn neuromuscular junction (NMJ) are polyinnervated but by the end of the competition, 2 weeks later, the NMJ are innervated by only one axon. This peripheral synapse has long been used as a convenient model for synapse development. In the last few years, we have studied transmitter release and the local involvement of the presynaptic muscarinic acetylcholine autoreceptors (mAChR), adenosine autoreceptors (AR) and trophic factor receptors (TFR, for neurotrophins and trophic cytokines) during the development of NMJ and in the adult. This review article brings together previously published data and proposes a molecular background for developmental axonal competition and loss. At the end of the first week postnatal, these receptors modulate transmitter release in the various nerve terminals on polyinnervated NMJ and contribute to axonal competition and synapse elimination. PMID- 28559798 TI - In situ RT-PCR Optimized for Electron Microscopy Allows Description of Subcellular Morphology of Target mRNA-Expressing Cells in the Brain. AB - In situ RT-PCR detects and amplifies mRNA (cDNA) while obtaining spatial information of gene expression. When the intended use is an ultrastructural analysis of morphology, the procedure may be technically challenging and quality of tissue dramatically altered by proteolytic digestion and extreme astringency and temperature conditions. We describe a low-damaging protocol of in situ RT-PCR combined to conventional electron microscopy that preserves fine morphology, increases sensitivity, and decreases costs and complexity associated to RNA probes. PMID- 28559797 TI - Regulation of the Hippocampal Network by VGLUT3-Positive CCK- GABAergic Basket Cells. AB - Hippocampal interneurons release the inhibitory transmitter GABA to regulate excitation, rhythm generation and synaptic plasticity. A subpopulation of GABAergic basket cells co-expresses the GABA/glycine vesicular transporters (VIAAT) and the atypical type III vesicular glutamate transporter (VGLUT3); therefore, these cells have the ability to signal with both GABA and glutamate. GABAergic transmission by basket cells has been extensively characterized but nothing is known about the functional implications of VGLUT3-dependent glutamate released by these cells. Here, using VGLUT3-null mice we observed that the loss of VGLUT3 results in a metaplastic shift in synaptic plasticity at Shaeffer's collaterals - CA1 synapses and an altered theta oscillation. These changes were paralleled by the loss of a VGLUT3-dependent inhibition of GABAergic current in CA1 pyramidal layer. Therefore presynaptic type III metabotropic could be activated by glutamate released from VGLUT3-positive interneurons. This putative presynaptic heterologous feedback mechanism inhibits local GABAergic tone and regulates the hippocampal neuronal network. PMID- 28559799 TI - The Effect of Serotonin-Targeting Antidepressants on Neurogenesis and Neuronal Maturation of the Hippocampus Mediated via 5-HT1A and 5-HT4 Receptors. AB - Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) specifically increase serotonin (5-HT) levels in the synaptic cleft and are widely used to treat mood and anxiety disorders. There are 14 established subtypes of 5-HT receptors in rodents, each of which has regionally different expression patterns. Many preclinical studies have suggested that the hippocampus, which contains abundant 5-HT1A and 5-HT4 receptor subtypes in the dentate gyrus (DG), is critically involved in the mechanisms of action of antidepressants. This review article will analyze studies demonstrating regulation of hippocampal functions and hippocampus-dependent behaviors by SSRIs and similar serotonergic agents. Multiple studies indicate that 5-HT1A and 5-HT4 receptor signaling in the DG contributes to SSRI-mediated promotion of neurogenesis and increased neurotrophic factors expression. Chronic SSRI treatment causes functions and phenotypes of mature granule cells (GCs) to revert to immature-like phenotypes defined as a "dematured" state in the DG, and to increase monoamine reactivity at the dentate-to-CA3 synapses, via 5-HT4 receptor signaling. Behavioral studies demonstrate that the 5-HT1A receptors on mature GCs are critical for expression of antidepressant effects in the forced swim test and in novelty suppressed feeding; such studies also note that 5-HT4 receptors mediate neurogenesis-dependent antidepressant activity in, for example, novelty suppressed feeding. Despite their limitations, the collective results of these studies describe a potential new mechanism of action, in which 5-HT1A and 5-HT4 receptor signaling, either independently or cooperatively, modulates the function of the hippocampal DG at multiple levels, any of which could play a critical role in the antidepressant actions of 5-HT-enhancing drugs. PMID- 28559800 TI - Key Metabolic Enzymes Underlying Astrocytic Upregulation of GABAergic Plasticity. AB - GABAergic plasticity is recognized as a key mechanism of shaping the activity of the neuronal networks. However, its description is challenging because of numerous neuron-specific mechanisms. In particular, while essential role of glial cells in the excitatory plasticity is well established, their involvement in GABAergic plasticity only starts to emerge. To address this problem, we used two models: neuronal cell culture (NC) and astrocyte-neuronal co-culture (ANCC), where we chemically induced long-term potentiation at inhibitory synapses (iLTP). iLTP could be induced both in NC and ANCC but in ANCC its extent was larger. Importantly, this functional iLTP manifestation was accompanied by an increase in gephyrin puncta size. Furthermore, blocking astrocyte Krebs cycle with fluoroacetate (FA) in ANCC prevented enhancement of both mIPSC amplitude and gephyrin puncta size but this effect was not observed in NC, indicating a key role in neuron-astrocyte cross-talk. Blockade of monocarboxylate transport with alpha-Cyano-4-hydroxycinnamic acid (4CIN) abolished iLTP both in NC and ANCC and in the latter model prevented also enlargement of gephyrin puncta. Similarly, blockade of glycogen phosphorylase with BAYU6751 prevented enlargement of gephyrin puncta upon iLTP induction. Finally, block of glutamine synthetase with methionine sulfoxide (MSO) nearly abolished mIPSC increase in both NMDA stimulated cell groups but did not prevent enlargement of gephyrin puncta. In conclusion, we provide further evidence that GABAergic plasticity is strongly regulated by astrocytes and the underlying mechanisms involve key metabolic enzymes. Considering the strategic role of GABAergic interneurons, the plasticity described here indicates possible mechanism whereby metabolism regulates the network activity. PMID- 28559801 TI - Parsing Heterogeneous Striatal Activity. AB - The striatum is an input channel of the basal ganglia and is well known to be involved in reward-based decision making and learning. At the macroscopic level, the striatum has been postulated to contain parallel functional modules, each of which includes neurons that perform similar computations to support selection of appropriate actions for different task contexts. At the single-neuron level, however, recent studies in monkeys and rodents have revealed heterogeneity in neuronal activity even within restricted modules of the striatum. Looking for generality in the complex striatal activity patterns, here we briefly survey several types of striatal activity, focusing on their usefulness for mediating behaviors. In particular, we focus on two types of behavioral tasks: reward-based tasks that use salient sensory cues and manipulate outcomes associated with the cues; and perceptual decision tasks that manipulate the quality of noisy sensory cues and associate all correct decisions with the same outcome. Guided by previous insights on the modular organization and general selection-related functions of the basal ganglia, we relate striatal activity patterns on these tasks to two types of computations: implementation of selection and evaluation. We suggest that a parsing with the selection/evaluation categories encourages a focus on the functional commonalities revealed by studies with different animal models and behavioral tasks, instead of a focus on aspects of striatal activity that may be specific to a particular task setting. We then highlight several questions in the selection-evaluation framework for future explorations. PMID- 28559802 TI - A CREB1 Gene Polymorphism (rs2253206) Is Associated with Prospective Memory in a Healthy Cohort. AB - Prospective memory (PM) is generally defined as remembering to perform intended actions in the future and is important for functioning in daily life. Cyclic adenosine monophosphate (cAMP) responsive element binding protein 1 (CREB1) plays an important role in cognitive functions. In this study, we hypothesized that genetic variation in the CREB1 gene is associated with PM. We genotyped a CREB1 promoter polymorphism rs2253206 and tested it for association with PM in 619 healthy subjects. PM performance was measured using the Prospective and Retrospective Memory Questionnaire (PRMQ), the Comprehensive Assessment of Prospective Memory (CAPM), and the Memory for Intentions Screening Test (MIST). Generalized linear model analysis was conducted for each PM test independently using different inheritance models to identify any associations (p < 0.05). After multiple testing adjustments, a significant association was found between the rs2253206 genotype and PM performance for CAPM instrumental activities of daily living measure (p = 0.016). These results suggest that the rs2253206 polymorphism in the CREB1 gene locus is associated with PM in healthy individuals and contributes to knowledge on the genetics of this particular type of memory. PMID- 28559803 TI - Aberrant Insula-Centered Functional Connectivity in Psychogenic Erectile Dysfunction Patients: A Resting-State fMRI Study. AB - Most previous studies exploring the neural mechanism of psychogenic erectile dysfunction (pED) focused on brain activity under tasks. We suggest that the resting brain activity is equally important in pED studies, in that the patterns of spontaneous neural activities is independent of modalities of sensory input, therefore providing substantial information regarding the central mechanism of pED. Our previous study reported the altered baseline activity in right anterior insula (aINS) in pED patients. Also, the insula is a pivotal region in sexual behavior, which is suggested to be able to directly mediate erection. Therefore, the current study employed resting-state fMRI to examine alterations in functional connectivity (FC) of the aINS comparing pED patients with matched control subjects. After rigorous participant inclusion procedure, 27 pED patients and 27 healthy male controls were enrolled. Our results elucidated the disrupted homogeneity within the right aINS and aberrant connection patterns between the right aINS and the right dorsolateral prefrontal cortex (dlPFC), as well as the right aINS and the right temporoparietal junction (TPJ) respectively in pED group, as compared with the healthy controls. In conclusion, our results demonstrated the aberrant insula-centered FC in pED, which may be related to the abnormal representation of internal bodily state or needs in pED patients and thus further affect the inhibitory control in the sexual context. We hope that these findings may shed new light on the understanding of the central mechanism of pED. PMID- 28559804 TI - Using Transcranial Direct Current Stimulation to Enhance Creative Cognition: Interactions between Task, Polarity, and Stimulation Site. AB - Creative cognition is frequently described as involving two primary processes, idea generation and idea selection. A growing body of research has used transcranial direct current stimulation (tDCS) to examine the neural mechanisms implicated in each of these processes. This literature has yielded a diverse set of findings that vary depending on the location and type (anodal, cathodal, or both) of electrical stimulation employed, as well as the task's reliance on idea generation or idea selection. As a result, understanding the interactions between stimulation site, polarity and task demands is required to evaluate the potential of tDCS to enhance creative performance. Here, we review tDCS designs that have elicited reliable and dissociable enhancements for creative cognition. Cathodal stimulation over the left inferior frontotemporal cortex has been associated with improvements on tasks that rely primarily on idea generation, whereas anodal tDCS over left dorsolateral prefrontal cortex (DLPFC) and frontopolar cortex has been shown to augment performance on tasks that impose high demands on creative idea selection. These results highlight the functional selectivity of tDCS for different components of creative thinking and confirm the dissociable contributions of left dorsal and inferior lateral frontotemporal cortex for different creativity tasks. We discuss promising avenues for future research that can advance our understanding of the effectiveness of tDCS as a method to enhance creative cognition. PMID- 28559806 TI - Computer-Based Training Programs for Older People with Mild Cognitive Impairment and/or Dementia. AB - Currently, due to the demographic trends, the number of aging population groups is dramatically rising, especially in developed countries. This trend causes serious economic and social issues, but also an increase of aging disorders such as mild cognitive impairment (MCI) or dementia in older population groups. MCI and dementia are connected with deterioration of cognitive functions. The aim of this mini review article is therefore to explore whether computer-based training programs might be an effective intervention tool for older people with MCI and/or dementia or not. The methods include a literature search in the world's acknowledged databases: Web of Science, Scopus, Science Direct, MEDLINE and Springer, and consequently, evaluation of the findings of the relevant studies. The findings from the selected studies are quite neutral with respect to the efficacy of the computer assisted intervention programs on the improvement of basic cognitive functions. On the one hand, they suggest that the computer-based training interventions might generate some positive effects on patients with MCI and/or dementia, such as the improvement of learning and short-term memory, as well as behavioral symptoms. On the other hand, these training interventions seem to be short-term, with small sample sizes and their efficacy was proved only in the half of the detected studies. Therefore more longitudinal randomized controlled trials (RCTs) are needed to prove the efficacy of the computer-based training programs among older individuals with MCI and/or dementia. PMID- 28559805 TI - Semantic Feature Training in Combination with Transcranial Direct Current Stimulation (tDCS) for Progressive Anomia. AB - We examined the effectiveness of a 2-week regimen of a semantic feature training in combination with transcranial direct current stimulation (tDCS) for progressive naming impairment associated with primary progressive aphasia (N = 4) or early onset Alzheimer's Disease (N = 1). Patients received a 2-week regimen (10 sessions) of anodal tDCS delivered over the left temporoparietal cortex while completing a language therapy that consisted of repeated naming and semantic feature generation. Therapy targets consisted of familiar people, household items, clothes, foods, places, hygiene implements, and activities. Untrained items from each semantic category provided item level controls. We analyzed naming accuracies at multiple timepoints (i.e., pre-, post-, 6-month follow-up) via a mixed effects logistic regression and individual differences in treatment responsiveness using a series of non-parametric McNemar tests. Patients showed advantages for naming trained over untrained items. These gains were evident immediately post tDCS. Trained items also showed a shallower rate of decline over 6-months relative to untrained items that showed continued progressive decline. Patients tolerated stimulation well, and sustained improvements in naming accuracy suggest that the current intervention approach is viable. Future implementation of a sham control condition will be crucial toward ascertaining whether neurostimulation and behavioral treatment act synergistically or alternatively whether treatment gains are exclusively attributable to either tDCS or the behavioral intervention. PMID- 28559807 TI - EEG and Eye Tracking Signatures of Target Encoding during Structured Visual Search. AB - EEG and eye tracking variables are potential sources of information about the underlying processes of target detection and storage during visual search. Fixation duration, pupil size and event related potentials (ERPs) locked to the onset of fixation or saccade (saccade-related potentials, SRPs) have been reported to differ dependent on whether a target or a non-target is currently fixated. Here we focus on the question of whether these variables also differ between targets that are subsequently reported (hits) and targets that are not (misses). Observers were asked to scan 15 locations that were consecutively highlighted for 1 s in pseudo-random order. Highlighted locations displayed either a target or a non-target stimulus with two, three or four targets per trial. After scanning, participants indicated which locations had displayed a target. To induce memory encoding failures, participants concurrently performed an aurally presented math task (high load condition). In a low load condition, participants ignored the math task. As expected, more targets were missed in the high compared with the low load condition. For both conditions, eye tracking features distinguished better between hits and misses than between targets and non-targets (with larger pupil size and shorter fixations for missed compared with correctly encoded targets). In contrast, SRP features distinguished better between targets and non-targets than between hits and misses (with average SRPs showing larger P300 waveforms for targets than for non-targets). Single trial classification results were consistent with these averages. This work suggests complementary contributions of eye and EEG measures in potential applications to support search and detect tasks. SRPs may be useful to monitor what objects are relevant to an observer, and eye variables may indicate whether the observer should be reminded of them later. PMID- 28559808 TI - Constructing Neuronal Network Models in Massively Parallel Environments. AB - Recent advances in the development of data structures to represent spiking neuron network models enable us to exploit the complete memory of petascale computers for a single brain-scale network simulation. In this work, we investigate how well we can exploit the computing power of such supercomputers for the creation of neuronal networks. Using an established benchmark, we divide the runtime of simulation code into the phase of network construction and the phase during which the dynamical state is advanced in time. We find that on multi-core compute nodes network creation scales well with process-parallel code but exhibits a prohibitively large memory consumption. Thread-parallel network creation, in contrast, exhibits speedup only up to a small number of threads but has little overhead in terms of memory. We further observe that the algorithms creating instances of model neurons and their connections scale well for networks of ten thousand neurons, but do not show the same speedup for networks of millions of neurons. Our work uncovers that the lack of scaling of thread-parallel network creation is due to inadequate memory allocation strategies and demonstrates that thread-optimized memory allocators recover excellent scaling. An analysis of the loop order used for network construction reveals that more complex tests on the locality of operations significantly improve scaling and reduce runtime by allowing construction algorithms to step through large networks more efficiently than in existing code. The combination of these techniques increases performance by an order of magnitude and harnesses the increasingly parallel compute power of the compute nodes in high-performance clusters and supercomputers. PMID- 28559809 TI - Fuchs Syndrome: Medical Treatment of 1 Case and Literature Review. AB - Fuchs syndrome is a particular type of erythema multiforme major; the lesions are only found on the mucosae and specifically affect oral, ocular, and genital mucosae. The cause is not always immediately apparent, which is why this pathology requires a rigorous, detailed clinical examination to eliminate a differential diagnosis. The severity of the symptoms, particularly of oral and ocular symptoms, requires immediate treatment. The treatment of this pathology requires a multiple-drug regime. Through a clinical case study, the objective of this work is to help guide practitioners when diagnosing and treating this pathology as no current consensus exists on these 2 subjects. The authors present the case of a 29-year-old patient who was suffering from a recurring outbreak of Fuchs syndrome, suspected of having been triggered by Mycoplasma pneumoniae. After completing the treatment program based on colchicine and prednisolone, the patient was relieved from pain and has not suffered from any further periodic eruptions of erythema multiforme. PMID- 28559810 TI - Atypical Clinical and Serological Manifestation of Pemphigus Vegetans: A Case Report and Review of the Literature. AB - Pemphigus vegetans (PVeg) is a rare variant of pemphigus vulgaris characterized by pustules and/or papillomatous vegetations, preferentially affecting intertriginous and periorificial areas. Exceptional manifestations may be misdiagnosed resulting in delayed diagnosis and treatment. Diagnosis is confirmed by immunofluorescence and detection of anti-desmoglein (Dsg) 3 and/or anti-Dsg1 antibodies. We herein report an unusual manifestation of PVeg. At the time of first presentation, lesions were restricted to the right ring finger's tip. Although mucous membranes were initially not affected, high levels of anti-Dsg3 antibodies were detected while anti-Dsg1 and anti-desmocollin (Dsc) 1, 2, and 3 antibodies were absent. To compare our immunological findings with previous reports, all accessible Anglophone literature published since December 1988 was evaluated. We identified 52 patients suffering from PVeg, 7 of these showed anti Dsg3 antibodies without any mucous membrane involvement. Notably, the detection of anti-Dsg1 and anti-Dsg3 antibodies does not necessarily correlate with the involvement of skin and/or mucous membranes. This might be due to more specific and complex antibody constellations in nonclassical or atypical pemphigus. PMID- 28559811 TI - Isolated Actinic Lichen Planus of the Lower Lip. AB - Oral lichen planus (LP) is a common manifestation in patients with LP; however, isolated lip LP is rare and may mimic other conditions such as lichenoid drug eruptions, actinic cheilitis, and early carcinoma in situ in the absence of typical skin lesions. Actinic lichen planus (ALP) is a variant of LP occurring on light-exposed areas in patients with dark skin. We report the case of a Chinese female with isolated ALP of the lower lip, mimicking herpes simplex infection at presentation. The presence of prognathism, involvement of the lower lip, and flares associated with sunlight reinforces the role of sun exposure in the development of this condition. PMID- 28559812 TI - Rapid Involution of Pustules during Topical Steroid Treatment of Acute Generalized Exanthematous Pustulosis. AB - Acute generalized exanthematous pustulosis (AGEP) is a dramatic generalized pustular rash of severe onset, which is considered a serious cutaneous adverse reaction to drugs. However, even though the clinical features are impressive and are often accompanied by systemic inflammation, it can be controlled quickly and safely by topical steroids subsequent to interruption of the offending drug. Here, we describe the management of a case and the evolution of the pustular rash. An elderly woman consulted with a generalized crop of 2-3 mm, nonfollicular pustules on erythematous background. In the 4 preceding weeks, she had been using amoxicillin/clavulanic acid for a bacterial implant infection and rivaroxaban. The clinical EuroSCAR criteria including the histology confirmed AGEP. Her medication was stopped and topical clobetasol propionate was used. Within 24 h, the development of new pustules ceased and the patient was discharged after 7 days of hospitalization with only a faint, diffuse erythema and focal desquamation remaining. This and many other cases in the literature suggest that topical steroids should be considered as a first-line treatment option, especially as systemic steroids themselves can sometimes induce generalized pustulosis. PMID- 28559813 TI - Interruption of Sneddon-Wilkinson Subcorneal Pustulation with Infliximab. AB - Subcorneal pustular dermatosis (SCPD, Sneddon-Wilkinson disease) is a rare chronic-relapsing skin disorder that typically manifests as flaccid sterile pustules without systemic symptoms. Although the accumulation of neutrophils is acknowledged to be a hallmark of SCPD, its exact pathomechanism is still not known. Several chemotactic factors have been implicated in neutrophil recruitment and invasion, including the proinflammatory cytokine TNF-alpha. These findings correspond well with clinical reports of successful off-label use of TNF blocking agents in cases that were refractory to first-line therapy, mostly with dapsone. We report the case of a 29-year-old male with atypical and severe manifestation of SCPD that resolved after a single dose of infliximab. Consolidation was observed 1 day after treatment and regression of skin lesions occurred after a few days. Residual scarring and postlesional hyperpigmentation was seen at a 2 month follow-up appointment. The patient was initiated on a daily maintenance therapy with dapsone, which led to a drop in hemoglobin and had to be stopped. Upon development of small, scaly lesions, a maintenance therapy with infliximab was started and the patient has had no recurrence to date. Anti-TNF agents present a promising option for patients affected by severe SCPD. We review the reports of similar cases in the literature to date. PMID- 28559814 TI - The Rare Case of Pemphigus Vegetans in Association with Malnutrition Children in the Multidisciplinary Management. AB - Pemphigus vegetans is a clinical variant of pemphigus vulgaris, accounting for 1 2% of all very rare pemphigus cases in children. The involvement of the oral mucosa in this disease is usually accompanied by severe pain that aggravates the patient's malnourished condition. Conversely, malnutrition may also reduce vulnerability towards autoimmune diseases. Although pemphigus vegetans has never been reported to develop in a child with marasmus before, we encountered a case of pemphigus vegetans in a severely malnourished patient. A 12-year-old boy in marasmic condition presented with painful, clear, fluid-filled blisters, accompanied by erosions, crusts, and vegetative lesions on almost all parts of the body. Histopathological examination of the lesions revealed a suprabasal cleft, and direct immunofluorescence staining showed deposits of immunoglobulin G in the epidermal intracellular spaces. The patient was treated with a multidisciplinary approach, and intravenous corticosteroid was administered for 2 weeks with an appropriate diet. There were significant improvements in the skin lesions and his nutritional status. Although pemphigus vegetans may occur in children with malnutrition, the underlying mechanism for the development of autoimmune diseases in malnutrition remains unclear. PMID- 28559815 TI - Pruritic Urticarial Papules and Plaques of Pregnancy Occurring Postpartum Treated with Intramuscular Injection of Autologous Whole Blood. AB - Pruritic urticarial papules and plaques of pregnancy (PUPPP) is one of the most common diseases associated with pregnancy. In most cases, the skin lesions develop in the third trimester of primigravidas. There are no systemic alterations seen in PUPPP; however, most patients report severe pruritus. A 34 year-old woman presented 1 week postpartum with typical clinical features of PUPPP. The patient showed good response to intramuscular injection of autologous whole blood with no adverse effects to the patient or her baby. Presentation of PUPPP in the postpartum period is rare. Conservative management with topical corticosteroids and oral antihistamines is commonly used to relieve pruritus. In severe cases, skin lesions and symptoms are controlled with a brief course of systemic corticosteroids. Investigation of new treatment options has been limited by patient concerns about the negative effects of medication on the fetus or breastfeeding. Intramuscular injection of autologous whole blood could be an alternative treatment option for PUPPP, especially for women who worry about the use of medications during pregnancy or breastfeeding. PMID- 28559816 TI - Pneumothorax during Pazopanib Treatment in Patients with Soft-Tissue Sarcoma: Two Case Reports and a Review of the Literature. AB - Pazopanib, a multitargeting tyrosine kinase inhibitor, has single-agent activity in patients with advanced soft-tissue sarcoma. Herein, we describe 2 cases of pneumothorax that occurred during pazopanib treatment in patients with soft tissue sarcoma. These 2 patients had multiple lung metastases. According to previous reports and our past experience, the risk of pneumothorax may be higher in patients with multiple lung metastases. Although a causal relationship is uncertain, the risk of pneumothorax when prescribing pazopanib for these patients should be considered. PMID- 28559818 TI - Infrared Thermography in Surgery of Newly Diagnosed Glioblastoma Multiforme: A Technical Case Report. AB - Infrared thermography (IRT) is a real-time non-contact diagnostic tool with a broad potential for neurosurgical applications. Here we describe the intraoperative use of this technique in a single patient with newly diagnosed glioblastoma multiforme (GBM). An 86-year-old female was admitted in the clinic with a 2-month history of slowly progressing left-sided paresis. Neuroimaging studies demonstrated an irregular space-occupying process consistent with a malignant glioma in the right fronto-temporo-insular region. An elective surgical intervention was performed by using 5-aminolevulinic acid fluorescence (BLUE 400, OPMI) and intraoperative IRT brain mapping (LWIR, 1.25 mRad IFOV, 0.05 degrees C NETD). After dura opening, the cerebral surface appeared inconspicuous. However, IRT revealed a significantly colder area (Deltat degrees 1.01 degrees C), well corresponding to the cortical epicenter of the lesion. The underlying tumor was partially excised and the histological result was GBM. Intraoperative IRT seems to be a useful technique for subcortical convexity brain tumor localization. Further studies with a large number of patients are needed to prove the reliability of this method in GBM surgery. PMID- 28559817 TI - Treatment Outcomes of Locally Advanced Squamous Cell Carcinoma of the Ethmoid Sinus Treated with Anterior Craniofacial Resection or Chemoradiotherapy. AB - We retrospectively analyzed 14 patients with locally advanced squamous cell carcinoma of ethmoid sinus (LASCC-ES) for the feasibility of anterior craniofacial resection (ACFR). Ethmoid cancer treatment comprised alternating chemoradiotherapy (ALCRT; n = 1), concomitant radiotherapy and intra-arterial cisplatin (RADPLAT; n = 4) and ACFR (n = 9). The 3- and 5-year overall survival (OS) rates of patients were 47.6 and 39.6%, respectively. The 3-year local control (LC) rates of chemoradiotherapy (CRT; ALCRT and RADPLAT) (n = 5) and ACFR (n = 9) groups were 0 and 66.7% (p = 0.012), respectively. The 3-year progression free survival (PFS) rate of the CRT and ACFR groups were 0 and 55.6% (p = 0.018), respectively. The 3-year OS rate of the CRT and ACFR groups were 0 and 76.2% (p = 0.005), respectively. Postoperative pathological examinations confirmed positive margins in 3 (33%) of 9 cases. The 3-year LC and PFS rates of cases (n = 3) with positive surgical margins were significantly poorer than those of cases (n = 6) with negative surgical margins. Although ACFR for LASCC-ES is a feasible treatment, cases with positive surgical margins were more prone to local relapse. Therefore, surgical safety margins should be thoroughly assessed. PMID- 28559819 TI - Two-Year Complete Remission of Diffuse Large B-Cell Lymphoma in an Immunological Nonresponder HIV-Infected Patient: Case Report. AB - INTRODUCTION: HIV-infected patients are affected significantly more frequently by all types of lymphoma, with diffuse large B-cell lymphoma (DLBCL) as the most prevalent histological type. Since the introduction of combination antiretroviral therapy (cART) morbidity and mortality of DLBCL has been markedly reduced, which is primarily interpreted as a result of the drug-mediated immune reconstitution. CASE REPORT: We present a previously healthy, 44-year-old HIV-infected man with DLBCL of the oral cavity, treated with immunochemotherapy and cART. During HIV directed treatment, despite the successful virologic response, a satisfactory immunological response was not achieved. However, the patient had a 2-year complete remission after first-line treatment of DLBCL. CONCLUSION: Response to cART strongly predicts outcome in patients with DLBCL. Close monitoring of HIV directed therapy efficacy, especially as to achievement of successful virologic response, independently associated with prolonged survival, is essential for estimating future DLBCL treatment strategies. PMID- 28559820 TI - Nivolumab Therapy for Synchronous ALK-Positive Lung Cancer and Gastric Cancer. AB - Nivolumab is an immune checkpoint inhibitor with demonstrated efficacy against several malignant tumors. Alterations in driver oncogenes such as EGFR and ALK are a poor prognostic factor in nivolumab therapy for non-small cell lung cancer (NSCLC), whereas a smoking history is a well-known, favorable prognostic factor. However, an efficacy of nivolumab therapy for multiple primary malignant tumors (MPMTs) has not been reported, and its efficacy for driver oncogene-positive NSCLC in smokers is unclear. Herein, we report the case of a patient with a history of heavy smoking who developed synchronous ALK-positive NSCLC and gastric cancer that responded to nivolumab therapy. A 76-year-old man who was a heavy smoker presented to our hospital with symptoms of hoarseness and dysphagia. He was ultimately diagnosed with ALK-positive advanced NSCLC. An ALK inhibitor (alectinib) was administered, and the lung cancer lesions showed improvement. The alectinib therapy was continued for 5 months. Thereafter, the lesions in the left lower lobe of the lung showed regrowth. During the same period, the patient experienced epigastric pain. Gastrointestinal endoscopy examination revealed gastric cancer. He was administered nivolumab to treat both the lung cancer and the gastric cancer. Two months later, both the lung lesions and the gastric lesions had diminished in size. Nivolumab therapy might be an effective therapy for synchronous MPMTs and NSCLC in heavy smokers, even if the lung cancer possesses driver oncogene mutations. PMID- 28559821 TI - Successful Treatment of Sudden Hepatitis Induced by Long-Term Nivolumab Administration. AB - Immune checkpoint inhibitors have drastically changed in the treatment of many kinds of malignancies, especially malignant melanoma. The focus of the recent experiments has not only been on their efficacy but also immune-related adverse events (irAEs). We report a case of fulminant hepatitis due to nivolumab. In this case, the patient had undergone long-term nivolumab therapy. He did not complain of any symptoms but his liver enzyme levels were extremely elevated (grade 4). We promptly decided to start oral corticosteroids in the patient. His liver function rapidly improved. The dose of corticosteroids was gradually reduced. Our case demonstrates that sudden onset fulminant hepatitis can occur despite the safe use of long-term nivolumab therapy. The irAE can improve rapidly with proper corticosteroid treatment. This report will be useful for the physicians who always use immune checkpoint inhibitors. PMID- 28559822 TI - Sarcoidosis-Lymphoma Syndrome Associated with Folliculotropic Peripheral T Cell Lymphoma Not Otherwise Specified. AB - Sarcoidosis is occasionally accompanied by hematologic malignancies, including cutaneous T-cell lymphoma, called sarcoidosis-lymphoma syndrome. Although the mechanism underlying the induction of lymphomas is still unknown, understanding the immunological background of sarcoidosis could help explain the possible mechanisms of the induction of lymphomas. In this report, we describe a case of sarcoidosis-lymphoma syndrome associated with folliculotropic peripheral T cell lymphoma not otherwise specified, which caused dense infiltration of CD30+ CD163+ tumor-associated macrophages (TAMs) only in the lesional skin. Our present case might suggest the significance of TAMs in developing sarcoid-lymphoma syndrome. PMID- 28559823 TI - Serum G-CSF May Be a More Valuable Biomarker than Image Evaluation in G-CSF Producing Urothelial Carcinoma: A Case Report. AB - Granulocyte colony-stimulating factor (G-CSF)-producing urothelial carcinomas (UCs) are rare and have a poor prognosis. According to the literature, treatment for G-CSF-producing UCs is very difficult. We experienced 2 cases of UC presenting with leukocytosis. In these cases, serum G-CSF levels were higher than the reference value with leukocytosis at diagnosis, and the resected specimens were positive for anti-G-CSF immunostaining. One case had a good prognosis and the other case died after 9 months from diagnosis. A change in serum G-CSF levels was reportedly an effective tumor marker in several reports. In the present cases, evaluation of serum G-CSF levels was found to be more sensitive than computerized tomography. The treatment and outcomes of UC-producing G-CSFs and the efficacy of serum G-CSF as a tumor marker are discussed based on our cases and a review of the literature. PMID- 28559824 TI - Microwave Ablation and Immune Activation in the Treatment of Recurrent Colorectal Lung Metastases: A Case Report. AB - We present a patient with colorectal metastases confined to the lungs and treated with multiple resections until this was not an option anymore, followed by stereotactic body radiation therapy until this option was drained. Then, the patient was successfully treated with multiple microwave ablations combined with immunological activation targeting the programmed cell death 1 receptor (PD-1), possibly instigating a powerful abscopal effect. Techniques, doses, and radiological findings are presented. PMID- 28559825 TI - Testicular Metastasis from Renal Cell Carcinoma: A Case Report and Review of the Literature. AB - Testicular metastases from renal cell carcinoma (RCC) are extremely rare. To the best of our knowledge, only 33 cases have been described in the literature. Most of the reported cases are of unilateral testicular metastasis from RCC. We report a case of metachronous ipsilateral testicular metastasis from RCC in a 78-year old man 6 years after nephrectomy. Scrotal ultrasonography showed a 4 * 5 cm mass in the right testis. Right inguinal orchiectomy was performed for diagnosis. Computed tomography revealed liver and lung metastases. First-line therapy with sunitinib was started in November 2016 for metastatic RCC. PMID- 28559826 TI - Spontaneous Tumor Lysis Syndrome in a Patient with Metastatic Small Cell Lung Cancer: A Case Report. AB - Tumor lysis syndrome is an oncologic emergency that usually occurs after chemotherapy in patients with hematologic malignancies. Tumor lysis syndrome is rare in cases of solid tumors, especially when it occurs spontaneously. Herein, we present a case of spontaneous tumor lysis syndrome in a 55-year-old woman who presented with dyspnea and was found to have extensive metastatic small cell lung cancer. She developed acute oliguric renal failure and multiple electrolyte abnormalities requiring hemodialysis. The findings of this case suggest that clinicians should maintain a high index of suspicion for patients with malignancies who demonstrate the classic symptom of laboratory abnormalities even in the absence of chemotherapy. PMID- 28559828 TI - Multisystem Disease, Including Eosinophilia and Progressive Hyper-Creatine-Kinase emia over 10 Years, Suggests Mitochondrial Disorder. AB - BACKGROUND: Eosinophilia has not been reported as a manifestation of a mitochondrial disorder (MID). Here, we report a patient with clinical features suggesting a MID and permanent eosinophilia, multisystem disease, and progressive hyper-creatine-kinase (CK)-emia for at least 10 years. MATERIALS AND METHODS: Methods applied included a clinical exam, blood chemical investigations, electrophysiological investigations, imaging, and invasive cardiological investigations. The patient was repeatedly followed up over several years. He required replacement cardiac surgery. RESULTS: In a 57-year-old male, eosinophilia was first detected at the age of 44 years and has remained almost constantly present until today. In addition to eosinophilia, he developed progressive hyper-CK-emia at the age of 47 years. His history was further positive for hepatopathy, hyperlipidemia, hypothyroidism, renal insufficiency, spontaneous Achilles tendon rupture, double vision, exercise intolerance, muscle aching, mild hypoacusis, sensory neuropathy, seizures, and mitral insufficiency/stenosis requiring valve replacement therapy, oral anticoagulation, and pacemaker implantation. Based on the multisystem nature of his abnormalities and permanent hyper-CK-emia, a MID was suspected. CONCLUSION: Eosinophilia can be associated with a MID with myopathy, possibly as a reaction to myofiber necrosis. If eosinophilia is associated with progressive hyper-CK-emia and multisystem disease, a MID should be suspected. PMID- 28559827 TI - Pure Amorphagnosia without Tactile Object Agnosia. AB - A 54-year-old female showed amorphagnosia without ahylognosia and tactile agnosia 40 days after the onset of right cerebral infarction. Her basic somatosensory functions were normal. The appreciation of substance qualities (hylognosia) was preserved, but the patient's inability to recognize the size and shape (morphagnosia) was confined to 2- and 3-dimensional shapes (amorphagnosia) in the left hand. However, the patient's ability to recognize real daily objects was well preserved. Brain MRI after admission showed ischemic lesions confined to the right pre- and postcentral gyri and the medial frontal cortex on DWI and FLAIR images. An analysis of SPECT images revealed that the most decreased areas were localized to the pre- and postcentral gyri, superior and inferior parietal lobules, supramarginal gyrus, and angular gyrus. Considering the previous reported cases, the responsible lesion for the impaired perception of hylognosia and morphagnosia may not necessarily be confined to the right hemisphere. To date, 5 reports (6 cases) of tactile agnosia have been published; 4 cases presented with both ahylognosia and amorphagnosia, while 1 presented with only amorphagnosia, and another showed amorphagnosia and mild ahylognosia. Our case is the first to present with only amorphagnosia without tactile agnosia. The mechanism for the well-preserved recognition of real objects may depend on the preserved hylognosia. Of note, there have been no reports showing only ahylognosia without amorphagnosia. Further studies are necessary to clarify whether or not patients with preserved hylognosia or morphagnosia retain the ability to perceive real objects. PMID- 28559829 TI - Early Thrombectomy of a Proximal Middle Cerebral Artery Occlusion Leading to Complete Recovery with No Infarct. AB - Many recent trials show the benefit of mechanical thrombectomy in acute ischemic stroke caused by thrombi lodged in large arteries. We report the case of a 55 year-old patient who developed sudden-onset right-sided hemiplegia and aphasia. Computed tomography angiography showed a thrombus in the M1 segment of the left middle cerebral artery. The thrombus was removed by mechanical thrombectomy 85 min after the onset of symptoms. A magnetic resonance imaging (MRI) scan showed no infarct, and the patient was discharged symptom free. To the best of our knowledge, this is the first report of thrombectomy of a symptomatic proximal middle cerebral artery occlusion leading to complete rescue, both clinically and radiologically assessed by MRI. Our case report shows that an early thrombectomy can provide an excellent outcome. PMID- 28559830 TI - Choreoathetosis Is a Possible Adverse Event of a Commonly Used Antibiotic. AB - BACKGROUND: Choreoathetosis (CAS) is attributed to a few neuropsychiatric drugs; however, it is scarcely reported with commonly used antibiotics. AIMS: To present a case of ceftriaxone (CTX)-induced CAS and to perform a literature review. SETTING: A medical teaching hospital. CASE HISTORY: An 83-year-old female with end stage renal disease was prescribed CTX 2 g/day intravenously and doxycycline (DXC) 200 mg/day orally for the treatment of acute community-acquired systemic infection. CAS developed 3 days after the administration of both drugs. Withdrawal of CTX and DXC yielded complete resolution of the CAS on the following day. Neither neurological adverse events related to DXC use nor pharmacological interaction between DXC and CTX was reported. Therefore, the CAS development was attributed to CTX. CONCLUSION: CTX as well as other beta-lactam antibiotics induce glutamate excess in the striatum and cerebral cortex, resulting in neurological hyperexcitability disorders. Dosage adjustment of these antibiotics in relation to the patients' renal clearance is warranted. PMID- 28559831 TI - Internal Carotid Artery Occlusion in Systemic Lupus Erythematosus as a Potential Mimicker of Multiple Sclerosis. AB - The diagnosis of neurological symptoms in patients with systemic lupus erythematosus (SLE) is often challenging, in part because they sometimes mimic features of multiple sclerosis (MS). Herein we report a case of a young female who presented with relapsing-remitting symptoms of unilateral visual loss and motor aphasia. Additionally, radiological findings revealed multiple white matter lesions on her brain that led to an initial diagnosis of MS based on the established diagnostic criteria. However, she was eventually diagnosed with neuropsychiatric SLE (NPSLE) presenting with extracranial internal carotid artery (ICA) occlusion. Her ICA occlusion had not been detected for 2 months until she underwent magnetic resonance angiography. Although exact underlying pathological mechanisms are unclear, both the ICA occlusion and MS-like brain white matter lesions could be attributed to SLE. This case demonstrated that both of these lesions can coexist in the same patient, suggesting that NPSLE with ICA occlusion can be a potential mimicker of MS, and vice versa. Care must be paid to avoid delay in the diagnosis. PMID- 28559832 TI - Chronic Autoimmune Meningoencephalitis and Periodic Fever Syndrome Treated with Anakinra. AB - We report the case of a 63-year-old male diagnosed with chronic autoimmune mediated meningoencephalitis and periodic cyclical fever syndrome. After 2 years of failed conventional treatment and recurrent hospitalizations, anakinra treatment (an interleukin-1 [IL-1] receptor antagonist) was trialed which resulted in full recovery. As evidenced by this case, anakinra can be used to treat chronic autoimmune meningitis, which can often be refractory to treatment. PMID- 28559833 TI - Acute Intravenous Calcium Antagonist for Suspected Hemiplegic Migraine - A Case Story. AB - Stroke mimics, like attacks of hemiplegic migraine, are challenging in acute stroke evaluation. We present a 28-year-old woman with a suspected hemiplegic migraine attack with left-sided hemiparalysis. Brain CT with perfusion imaging 1 h 54 min after symptom onset revealed hypoperfusion in the right hemisphere. The patient was treated with intravenous recombinant tissue plasminogen activator (rtPA) with no effect. After a subsequent intravenous verapamil infusion, the patient gained full motor function within 10 min. Brain magnetic resonance imaging (MRI) performed 5 h 46 min after symptom onset revealed diffusion restriction in the same area as the hypoperfusion on CT. There were no notable changes on T2 images. The patient stayed clinically in remission, except for reduced sensation for all modalities on the extremities on the left side. Although brain CT 24 h after symptom onset revealed an edema in the same area, an MRI performed 17 days later showed no new infarctions. Young patients with a history of migraine with aura admitted with symptoms of acute ischemic stroke are at risk of insufficient treatment. Calcium antagonists might be considered if there is no effect of first-line treatment with rtPA. PMID- 28559834 TI - Favourable Outcome in a 33-Year-Old Female with Acute Haemorrhagic Leukoencephalitis. AB - BACKGROUND: Acute haemorrhagic leukoencephalitis (AHLE) is a rare and rapidly fatal disease of unknown aetiology. There is a paucity of literature on the presentation and management of this rare disease. CASE DESCRIPTION: We report the case of a 33-year-old female presenting with headache and left-sided apraxia. Imaging revealed a right-sided white matter lesion with extensive cytotoxic oedema. Pathology was suggestive of AHLE. She underwent an open excisional biopsy and was treated with high-dose corticosteroids. Three months since symptom onset she remains clinically well with resolving apraxia and radiological appearance. CONCLUSION: This case may represent a milder spectrum of AHLE, which responded favourably to corticosteroids. PMID- 28559835 TI - Cytarabine Induced Acute Cerebellar Syndrome during Hyper-CVAD Treatment for B Cell Acute Lymphoblastic Leukemia. AB - Acute cerebellar syndrome can be caused by high doses of cytarabine, but it has not been described in patients with acute lymphoblastic leukemia (ALL) who received hyper-CVAD chemotherapy. Herein, we report two cases with histories of positive Philadelphia chromosome B-cell ALL who developed acute cerebellar syndrome after the exposure to relatively low doses of cytarabine in the second cycle of hyper-CVAD regimen. The cerebellar symptoms were attenuated by cytarabine discontinuation and administration of steroids. This case report provides detailed discussions on the treatments, the potential role of methotrexate in cytarabine-induced cerebellar syndrome, and the importance of carefully monitoring renal function during hyper-CVAD treatment. PMID- 28559836 TI - Unilateral Posterior Polymorphous Corneal Dystrophy Presented as Anisometropic Astigmatism: 3 Case Reports. AB - BACKGROUND: Posterior polymorphous corneal dystrophy (PPCD) is typically considered bilateral and asymptomatic. However, few case reports on patients with unilateral PPCD with asymmetric refractive error have mentioned anisometropic amblyopia development. In support of this, we report 3 cases of unilateral PPCD that presented as anisometropic astigmatism. Visual prognosis related to amblyopia development is discussed. CASE PRESENTATION: All 3 patients had a band lesion in the affected eye and a difference of at least 1.5 diopters in cylindrical refractive error between their eyes. The affected eye had a greater amount of astigmatism in all cases. Two patients (Cases 1 and 2) also had amblyopia in the affected eye. Case 1 was a 25-year-old male with a unilateral PPCD diagnosis and a band lesion involving the visual axis. Case 2 was an 11-year old boy diagnosed with unilateral PPCD. The boy was treated with occlusion and atropine therapy over a 2-year period. Case 3 was a 4-year-old girl diagnosed with unilateral PPCD. The girl had a 30-month history of corrective spectacle use and had no amblyopia. In all cases, the corneal endothelial cell count was lower in the affected eye than in the unaffected contralateral eye. CONCLUSIONS: Practitioners should closely monitor patients with unilateral PPCD for astigmatic anisometropia and amblyopia development. Visual prognosis for patients with unilateral PPCD may be related to lesion position, age at diagnosis, astigmatism severity, and early-childhood corrective spectacle use. PMID- 28559837 TI - Transient Esotropia in the Child: Case Report and Review of the Literature. AB - The aim of this report is to investigate the possible causes of acute acquired onset of transient esotropia (AATE) in children and to help to differentiate ophthalmoplegic migraine (OM) from accommodative spasm (AS). A case of an 8-year old Caucasian female affected by AATE and diplopia is described. The day before AATE onset, the patient complained of slight headache without nausea and vomiting, with spontaneous resolution. AATE diagnosis is challenging. The most likely ophthalmological causes of AATE are AS and OM. In these cases it is important to evaluate the presence of both a familial history of recurrent headaches and an AATE associated with migraine, ptosis, nausea, and vomiting. A full ophthalmological evaluation and a thorough refractive examination in cycloplegia are mandatory to exclude ophthalmological causes. PMID- 28559838 TI - Ten-Year Follow-Up after Bilateral Submacular Neovascular Membrane Removal in a Case of Autosomal Recessive Bestrophinopathy. AB - Herein, we report the case of an 8-year-old girl who presented in December 2000 with a submacular neovascular membrane in the right eye, with a clinical diagnosis of Best disease. At that time, she underwent pars plana vitrectomy (PPV) with removal of the subretinal choroidal neovascularization (CNV). Her vision improved from 20/200 to 20/25. Four years later, a new CNV developed in the other eye. Initially, she underwent unsuccessful photodynamic therapy. As her vision worsened, she underwent a second, this time successful, PPV with membrane removal in the left eye, with vision improving to 20/30. Ten years later, she returned complaining of vision loss over the last year. Her vision was 20/200 OU, and optical coherence tomography demonstrated very large intraretinal cystoid spaces resembling bilateral macular schisis. Four ranibizumab injections as well as dorzolamide eye drops were tried, both without success. Finally, she underwent PPV with internal limiting membrane peeling and gas-fluid exchange in the left eye. One month later, the macula appeared flat and vision had improved to 20/60. The same procedure was performed 1 year later for the right eye, with vision improving to 20/80. One year later, mild cystic spaces developed again in both eyes, although much smaller than previously observed. Her vision remained stable. PMID- 28559839 TI - Branch Retinal Vein Occlusion, Macular Ischemia, and Intravitreal Anti-VEGF Therapy. AB - PURPOSE: To report a case with ischemic macular edema (ME) due to an acute branch retinal vein occlusion (BRVO) which was treated with repeated intravitreal anti VEGF injections. METHODS: Retrospective case presentation. RESULTS: A 66-year-old female patient was treated with repeated intravitreal anti-VEGF injections due to ischemic ME following an acute BRVO. Over a period of 2.5 years best corrected visual acuity increased from 0.06 to 0.6 (decimal notation) accompanied by a reduction in central retinal thickness from 546 to 292 um. Overall 17 anti-VEGF injections were administered to treat repeated recurrence of ME. Macular ischemia did not worsen during this profound intravitreal anti-VEGF therapy. CONCLUSION: Intravitreal anti-VEGF therapy can be a beneficial treatment strategy even in ischemic ME following an acute BRVO. PMID- 28559840 TI - Limbal Stem Cell-Sparing Corneoscleroplasty with Peripheral Intralamellar Tuck: A New Surgical Technique for Keratoglobus. AB - PURPOSE: To describe the technique of limbal stem cell-sparing corneoscleroplasty for the management of advanced keratoglobus. METHODS: A patient with bilateral advanced keratoglobus, with best-corrected visual acuity of 20/400 in the right eye and 20/200 in the left eye, underwent limbal stem cell-sparing corneoscleroplasty of the right eye. Initially, a 360-degree limbal incision with 200-MUm depth was created, followed by a sublimbal tunnel dissection into the sclera, in order to conserve stem cells. Next, a limbus-to-limbus lamellar keratectomy at 200-MUm depth was performed. Meanwhile, a donor corneoscleral button with preserved endothelium of the central 8 mm was fashioned. Prior to suturing the donor corneoscleral graft using a modified suturing technique to cover its scleral component, a full-thickness trephination of 8-mm diameter was completed in the central host cornea. RESULTS: Reepithelialization occurred within the first week. No episodes of rejection, intraocular pressure spikes, or epithelial breakdown were observed postoperatively. At the 6-month follow-up, the patient had 20/70 best-corrected vision and a smooth cornea with regular astigmatism on topography. CONCLUSION: Limbal stem cell-sparing corneoscleroplasty is a single-step technique for restoring the structural integrity of the cornea in advanced keratoglobus while preserving the host limbal stem cells. PMID- 28559841 TI - Giant Orbital Melanoma in a Heroin Abuser. AB - PURPOSE: The aim of this report was to report a heroin abuser with nondiagnosed giant uveal melanoma infiltrating the orbit and prolapsing through the face. METHODS: We conducted a case report of the patient with giant melanoma. RESULTS: In March 2013, a 39-year-old male with bleeding from the right side of his face was taken to the Emergency Center of the University Hospital Bratislava by ambulance. The heroin abusing, homeless male who had never been treated before reported a 2-year history of a prolapsed, dark colored mass from his eye. Acute computed tomography confirmed a solid mass 20 * 20 cm prolapsing from the orbit. The patient rejected primary care, accepted only 1 transfusion and left the hospital. Two months later, he was admitted to the hospital due to anemia after many collapses. Liver metastasis was present. Surgical palliative therapy was not possible due to his general status. The patient started fractionated external radiotherapy with 8.0 Gy Co60. Histopathological examination of the biopsy specimen showed malignant melanoma of the epitheloid type G2-3. The patient died in December 2013. CONCLUSION: Extraorbital formation of a melanoma mass may progress to a giant volume, and without treatment, led to metastases in the liver and to death after 9 months in our patient with anemia. PMID- 28559842 TI - Cross-Sectional and Longitudinal Effects of CREB1 Genotypes on Individual Differences in Memory and Executive Function: Findings from the BLSA. AB - Purpose: Previously, we have shown that the SNP rs10932201 genotype of the cyclic AMP responsive element binding protein 1 gene (CREB1) contributes to individual differences in executive and memory function at the neural system and behavioral levels in healthy, young adults. However, longitudinal effects of CREB1 genotypes on cognition have not yet been addressed. Furthermore we were interested in replicating associations between CREB1 genotypes and human cognition in previous cross-sectional studies and explore whether APOE??4 status might modify these relations. Materials and Methods: We investigated whether common, independent tag SNPs within CREB1 (rs2253206, rs10932201, rs6785) influence individual differences in age-related longitudinal change and level of executive function and memory performance independent of baseline age, sex, APOE??4 status, and education. Our analysis included data from cognitively unimpaired older adults participating in the Baltimore Longitudinal Study of Aging. Eleven measures from six cognitive tests (sample sizes range 617-786) were analyzed using linear mixed effects and generalized estimating equations models. Mean baseline age ranged from 50 to 69 years and mean time of follow-up (interval) ranged from 8 to 22 years. Results: We found significant effects of all three CREB1 SNPs on performance level and/or longitudinal change in performance based on eight measures assessing semantic memory, episodic memory, or both executive function and semantic memory. SNP rs10932201 showed the most significant and largest effect (Cohen's d = -0.70, p < 0.01) on age-related longitudinal decline of semantic memory. Additionally, we show interactions between all three CREB1 SNPs and APOE??4 status on age-related longitudinal declines and levels of memory and executive function. Conclusion: Our results suggest that CREB1 genotypes independently and by interactions with APOE??4 status contribute to individual differences in cognitive aging. PMID- 28559843 TI - Altered Functional Connectivity of Cognitive-Related Cerebellar Subregions in Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common cause of dementia. Previous studies have found disrupted resting state functional connectivities (rsFCs) in various brain networks in the AD patients. However, few studies have focused on the rsFCs of the cerebellum and its sub-regions in the AD patients. In this study, we collected resting-state functional magnetic resonance imaging (rs-fMRI) data including 32 AD patients and 38 healthy controls (HCs). We selected two cognitive related subregions of the cerebellum as seed region and mapped the whole-brain rsFCs for each subregion. We identified several distinct rsFC patterns of the two cognitive-related cerebellar subregions: default-mode network (DMN), frontoparietal network (FPN), visual network (VN) and sensorimotor network (SMN). Compared with the controls, the AD patients showed disrupted rsFCs in several different networks (DMN, VN and SMN), predicting the impairment of the functional integration in the cerebellum. Notably, these abnormal rsFCs of the two cerebellar subregions were closely associated with cognitive performance. Collectively, we demonstrated the distinct rsFCs patterns of cerebellar sub regions with various functional networks, which were differentially impaired in the AD patients. PMID- 28559845 TI - Combating Sale of Counterfeit and Falsified Medicines Online: A Losing Battle. PMID- 28559844 TI - Impact of Dendrimers on Solubility of Hydrophobic Drug Molecules. AB - Adequate aqueous solubility has been one of the desired properties while selecting drug molecules and other bio-actives for product development. Often solubility of a drug determines its pharmaceutical and therapeutic performance. Majority of newly synthesized drug molecules fail or are rejected during the early phases of drug discovery and development due to their limited solubility. Sufficient permeability, aqueous solubility and physicochemical stability of the drug are important for achieving adequate bioavailability and therapeutic outcome. A number of different approaches including co-solvency, micellar solubilization, micronization, pH adjustment, chemical modification, and solid dispersion have been explored toward improving the solubility of various poorly aqueous-soluble drugs. Dendrimers, a new class of polymers, possess great potential for drug solubility improvement, by virtue of their unique properties. These hyper-branched, mono-dispersed molecules have the distinct ability to bind the drug molecules on periphery as well as to encapsulate these molecules within the dendritic structure. There are numerous reported studies which have successfully used dendrimers to enhance the solubilization of poorly soluble drugs. These promising outcomes have encouraged the researchers to design, synthesize, and evaluate various dendritic polymers for their use in drug delivery and product development. This review will discuss the aspects and role of dendrimers in the solubility enhancement of poorly soluble drugs. The review will also highlight the important and relevant properties of dendrimers which contribute toward drug solubilization. Finally, hydrophobic drugs which have been explored for dendrimer assisted solubilization, and the current marketing status of dendrimers will be discussed. PMID- 28559846 TI - Oncolytic Herpes Simplex Viral Therapy: A Stride toward Selective Targeting of Cancer Cells. AB - Oncolytic viral therapy, which makes use of replication-competent lytic viruses, has emerged as a promising modality to treat malignancies. It has shown meaningful outcomes in both solid tumor and hematologic malignancies. Advancements during the last decade, mainly genetic engineering of oncolytic viruses have resulted in improved specificity and efficacy of oncolytic viruses in cancer therapeutics. Oncolytic viral therapy for treating cancer with herpes simplex virus-1 has been of particular interest owing to its range of benefits like: (a) large genome and power to infiltrate in the tumor, (b) easy access to manipulation with the flexibility to insert multiple transgenes, (c) infecting majority of the malignant cell types with quick replication in the infected cells and (d) as Anti-HSV agent to terminate HSV replication. This review provides an exhaustive list of oncolytic herpes simplex virus-1 along with their genetic alterations. It also encompasses the major developments in oncolytic herpes simplex-1 viral therapy and outlines the limitations and drawbacks of oncolytic herpes simplex viral therapy. PMID- 28559847 TI - High Sensitivity of SIRT3 Deficient Hearts to Ischemia-Reperfusion Is Associated with Mitochondrial Abnormalities. AB - Aim: Sirtuins are NAD+-dependent deacetylases that regulate cell metabolism through protein acetylation/deacetylation, and SIRT3 is the major deacetylase among mitochondrial isoforms. Here, we elucidated the possible role of acetylation of cyclophilin D, a key regulator of the mitochondrial permeability transition pore (mPTP), in mitochondria-mediated cardiac dysfunction induced by ischemia-reperfusion (IR) in wild type (WT) and SIRT3 knockout (SIRT3-/-) mice. Materials and Methods: Isolated and Langendorff-mode perfused hearts of WT and SIRT3-/- mice were subjected to 25-min global ischemia followed by 60-min of reperfusion in the presence or absence of the mPTP inhibitor, sanglifehrin A (SfA). Results: Analysis of mitochondrial sirtuins demonstrated that SIRT3 deficiency upregulated SIRT4 with no effect on SIRT5 expression. Hearts of SIRT3 /- mice exhibited significantly less recovery of cardiac function at the end of IR compared to WT mice. Intact (non-perfused) SIRT3-/- hearts exhibited an increased rate of Ca2+-induced swelling in mitochondria as an indicator of mPTP opening. However, there was no difference in mPTP opening and cyclophilin D acetylation between WT and SIRT3-/- hearts subjected to IR injury. Ca2+ stimulated H2O2 production was significantly higher in SIRT3-/- mitochondria that was prevented by SfA. Superoxide dismutase activity was lower in SIRT3-/- heart mitochondria subjected to IR which correlated with an increase in protein carbonylation. However, mitochondrial DNA integrity was not affected in SIRT3-/- hearts after IR. Conclusion: SIRT3 deficiency exacerbates cardiac dysfunction during post-ischemic recovery, and increases mPTP opening and ROS generation without oxidative damage to mitochondrial proteins and DNA. PMID- 28559848 TI - Efficient Fetal-Maternal ECG Signal Separation from Two Channel Maternal Abdominal ECG via Diffusion-Based Channel Selection. AB - There is a need for affordable, widely deployable maternal-fetal ECG monitors to improve maternal and fetal health during pregnancy and delivery. Based on the diffusion-based channel selection, here we present the mathematical formalism and clinical validation of an algorithm capable of accurate separation of maternal and fetal ECG from a two channel signal acquired over maternal abdomen. The proposed algorithm is the first algorithm, to the best of the authors' knowledge, focusing on the fetal ECG analysis based on two channel maternal abdominal ECG signal, and we apply it to two publicly available databases, the PhysioNet non invasive fECG database (adfecgdb) and the 2013 PhysioNet/Computing in Cardiology Challenge (CinC2013), to validate the algorithm. The state-of-the-art results are achieved when compared with other available algorithms. Particularly, the F1 score for the R peak detection achieves 99.3% for the adfecgdb and 87.93% for the CinC2013, and the mean absolute error for the estimated R peak locations is 4.53 ms for the adfecgdb and 6.21 ms for the CinC2013. The method has the potential to be applied to other fetal cardiogenic signals, including cardiac doppler signals. PMID- 28559849 TI - Epigenetic DNA Methylation Mediating Octopus vulgaris Early Development: Effect of Essential Fatty Acids Enriched Diet. AB - The common octopus, Octopus vulgaris, is a good candidate for aquaculture but a sustainable production is still unviable due to an almost total mortality during the paralarvae stage. DNA methylation regulates gene expression in the eukaryotic genome, and has been shown to exhibit plasticity throughout O. vulgaris life cycle, changing profiles from paralarvae to adult stages. This pattern of methylation could be sensitive to small alterations in nutritional and environmental conditions during the species early development, thus impacting on its health, growth and survival. In this sense, a full understanding of the epigenetic mechanisms operating during O. vulgaris development would contribute to optimizing the culture conditions for this species. Paralarvae of O. vulgaris were cultured over 28 days post-hatching (dph) using two different Artemia sp. based diets: control and a long chain polyunsaturated fatty acids (LC-PUFA) enriched diet. The effect of the diets on the paralarvae DNA global methylation was analyzed by Methyl-Sensitive Amplification Polymorphism (MSAP) and global 5 methylcytosine enzyme-linked immunosorbent assay (ELISA) approaches. The analysis of different methylation states over the time revealed a global demethylation phenomena occurring along O. vulgaris early development being directly driven by the age of the paralarvae. A gradual decline in methylated loci (hemimethylated, internal cytosine methylated, and hypermethylated) parallel to a progressive gain in non-methylated (NMT) loci toward the later sampling points was verified regardless of the diet provided and demonstrate a pre-established and well defined demethylation program during its early development, involving a 20% of the MSAP loci. In addition, a differential behavior between diets was also observed at 20 dph, with a LC-PUFA supplementation effect over the methylation profiles. The present results show significant differences on the paralarvae methylation profiles during its development and a diet effect on these changes. It is characterized by a process of demethylation of the genome at the paralarvae stage and the influence of diet to favor this methylation loss. PMID- 28559851 TI - Estimating Neural Control from Concentric vs. Eccentric Surface Electromyographic Representations during Fatiguing, Cyclic Submaximal Back Extension Exercises. AB - Purpose: To investigate the differences in neural control of back muscles activated during the eccentric vs. the concentric portions of a cyclic, submaximal, fatiguing trunk extension exercise via the analysis of amplitude and time-frequency parameters derived from surface electromyographic (SEMG) data. Methods: Using back dynamometers, 87 healthy volunteers performed three maximum voluntary isometric trunk extensions (MVC's), an isometric trunk extension at 80% MVC, and 25 cyclic, dynamic trunk extensions at 50% MVC. Dynamic testing was performed with the trunk angular displacement ranging from 0 degrees to 40 degrees and the trunk angular velocity set at 20 degrees /s. SEMG data was recorded bilaterally from the iliocostalis lumborum at L1, the longissimus dorsi at L2, and the multifidus muscles at L5. The initial value and slope of the root mean square (RMS-SEMG) and the instantaneous median frequency (IMDF-SEMG) estimates derived from the SEMG recorded during each exercise cycle were used to investigate the differences in MU control marking the eccentric vs. the concentric portions of the exercise. Results: During the concentric portions of the exercise, the initial RMS-SEMG values were almost twice those observed during the eccentric portions of the exercise. The RMS-SEMG values generally increased during the concentric portions of the exercise while they mostly remained unchanged during the eccentric portions of the exercise with significant differences between contraction types. Neither the initial IMDF-SEMG values nor the time-course of the IMDF-SEMG values significantly differed between the eccentric and the concentric portions of the exercise. Conclusions: The comparison of the investigated SEMG parameters revealed distinct neural control strategies during the eccentric vs. the concentric portions of the cyclic exercise. We explain these differences by relying upon the principles of orderly recruitment and common drive governing motor unit behavior. PMID- 28559852 TI - Is Abdominal Fetal Electrocardiography an Alternative to Doppler Ultrasound for FHR Variability Evaluation? AB - Great expectations are connected with application of indirect fetal electrocardiography (FECG), especially for home telemonitoring of pregnancy. Evaluation of fetal heart rate (FHR) variability, when determined from FECG, uses the same criteria as for FHR signal acquired classically-through ultrasound Doppler method (US). Therefore, the equivalence of those two methods has to be confirmed, both in terms of recognizing classical FHR patterns: baseline, accelerations/decelerations (A/D), long-term variability (LTV), as well as evaluating the FHR variability with beat-to-beat accuracy-short-term variability (STV). The research material consisted of recordings collected from 60 patients in physiological and complicated pregnancy. The FHR signals of at least 30 min duration were acquired dually, using two systems for fetal and maternal monitoring, based on US and FECG methods. Recordings were retrospectively divided into normal (41) and abnormal (19) fetal outcome. The complex process of data synchronization and validation was performed. Obtained low level of the signal loss (4.5% for US and 1.8% for FECG method) enabled to perform both direct comparison of FHR signals, as well as indirect one-by using clinically relevant parameters. Direct comparison showed that there is no measurement bias between the acquisition methods, whereas the mean absolute difference, important for both visual and computer-aided signal analysis, was equal to 1.2 bpm. Such low differences do not affect the visual assessment of the FHR signal. However, in the indirect comparison the inconsistencies of several percent were noted. This mainly affects the acceleration (7.8%) and particularly deceleration (54%) patterns. In the signals acquired using the electrocardiography the obtained STV and LTV indices have shown significant overestimation by 10 and 50% respectively. It also turned out, that ability of clinical parameters to distinguish between normal and abnormal groups do not depend on the acquisition method. The obtained results prove that the abdominal FECG, considered as an alternative to the ultrasound approach, does not change the interpretation of the FHR signal, which was confirmed during both visual assessment and automated analysis. PMID- 28559850 TI - Innovative Perspective: Gadolinium-Free Magnetic Resonance Imaging in Long-Term Follow-Up after Kidney Transplantation. AB - Since the mid-1980s magnetic resonance imaging (MRI) has been investigated as a non- or minimally invasive tool to probe kidney allograft function. Despite this long-standing interest, MRI still plays a subordinate role in daily practice of transplantation nephrology. With the introduction of new functional MRI techniques, administration of exogenous gadolinium-based contrast agents has often become unnecessary and true non-invasive assessment of allograft function has become possible. This raises the question why application of MRI in the follow-up of kidney transplantation remains restricted, despite promising results. Current literature on kidney allograft MRI is mainly focused on assessment of (sub) acute kidney injury after transplantation. The aim of this review is to survey whether MRI can provide valuable diagnostic information beyond 1 year after kidney transplantation from a mechanistic point of view. The driving force behind chronic allograft nephropathy is believed to be chronic hypoxia. Based on this, techniques that visualize kidney perfusion and oxygenation, scarring, and parenchymal inflammation deserve special interest. We propose that functional MRI mechanistically provides tools for diagnostic work-up in long-term follow-up of kidney allografts. PMID- 28559853 TI - Proteogenomics Reveals Enriched Ribosome Assembly and Protein Translation in Pectoralis major of High Feed Efficiency Pedigree Broiler Males. AB - Background: In production animal agriculture, the cost of feed represents 60-70% of the total cost of raising an animal to market weight. Thus, development of viable biomarkers for feed efficiency (FE, g gain/g feed) to assist in genetic selection of breeding stock remains an important goal in commercial breeding programs. Methods: Global gene (cDNA microarray, RNAseq) and protein expression (shotgun proteomics) analyses have been conducted on breast muscle samples obtained from pedigree broiler males (PedM) exhibiting high and low FE phenotypes. Using the entire datasets (i.e., no cutoffs for significance or fold difference in expression) the number of genes or proteins that were expressed numerically higher or lower in the high FE compared to the low FE phenotype for key terms or functions, e.g., ribosomal, mitochondrial ribosomal, tRNA, RNA binding motif, RNA polymerase, small nuclear ribonucleoprotein, and protein tyrosine phosphatase, were determined. Bionomial distribution analysis (exact) was then conducted on these datasets to determine significance between numerically up or down expression. Results: Processes associated with mitochondrial proteome expression (e.g., mitochondrial ribosomal proteins, mitochondrial transcription, mitochondrial tRNA, and translation) were enriched in breast muscle from the high FE compared to the low FE pedigree male broiler phenotype. Furthermore, the high FE phenotype exhibited enrichment of ribosome assembly (e.g., RNA polymerase, mitochondrial and cytosolic ribosomes, small, and heterogeneous nuclear ribonucleoproteins), as well as nuclear transport and protein translation processes compared to the low FE phenotype. Quality control processes (proteosomes and autophagy) were also enriched in the high FE phenotype. In contrast, the low FE phenotype exhibited enrichment of cytoskeletal proteins, protein tyrosine phosphatases, and tyrosine kinases compared to the high FE phenotype. These results suggest that processes of mitochondrial and cytosolic ribosomal construction, activity, and protein translation would be enhanced in high FE breast muscle, and that phosphorylation of tyrosine moieties of proteins could be prolonged in the high compared to low FE phenotype. The results indicate the presence of a proteogenomic architecture that could enhance ribosome construction, protein translation, and quality control processes and contribute to the phenotypic expression of feed efficiency in this PedM broiler model. PMID- 28559854 TI - Deletion of Slc26a1 and Slc26a7 Delays Enamel Mineralization in Mice. AB - Amelogenesis features two major developmental stages-secretory and maturation. During maturation stage, hydroxyapatite deposition and matrix turnover require delicate pH regulatory mechanisms mediated by multiple ion transporters. Several members of the Slc26 gene family (Slc26a1, Slc26a3, Slc26a4, Slc26a6, and Slc26a7), which exhibit bicarbonate transport activities, have been suggested by previous studies to be involved in maturation-stage amelogenesis, especially the key process of pH regulation. However, details regarding the functional role of these genes in enamel formation are yet to be clarified, as none of the separate mutant animal lines demonstrates any discernible enamel defects. Continuing with our previous investigation of Slc26a1-/- and Slc26a7-/- animal models, we generated a double-mutant animal line with the absence of both Slc26a1 and Slc26a7. We showed in the present study that the double-mutant enamel density was significantly lower in the regions that represent late maturation-, maturation- and secretory-stage enamel development in wild-type mandibular incisors. However, the "maturation" and "secretory" enamel microstructures in double-mutant animals resembled those observed in wild-type secretory and/or pre-secretory stages. Elemental composition analysis revealed a lack of mineral deposition and an accumulation of carbon and chloride in double-mutant enamel. Deletion of Slc26a1 and Slc26a7 did not affect the stage-specific morphology of the enamel organ. Finally, compensatory expression of pH regulator genes and ion transporters was detected in maturation-stage enamel organs of double-mutant animals when compared to wild-type. Combined with the findings from our previous study, these data indicate the involvement of SLC26A1and SLC26A7 as key ion transporters in the pH regulatory network during enamel maturation. PMID- 28559855 TI - A Longitudinal Study on Attention Development in Primary School Children with and without Teacher-Reported Symptoms of ADHD. AB - Background: Prospective longitudinal studies are essential in characterizing cognitive trajectories, yet few of them have been reported on the development of attention processes in children. We aimed to explore attention development in normal children and children with attention deficit and hyperactivity disorder (ADHD) symptoms in a repeated measures design using the attention network test (ANT). Methods: The population sample included 2,835 children (49.6% girls) aged 7-11 years from 39 schools in Barcelona (Catalonia, Spain) who performed the ANT four times from January 2012 to March 2013. According to teacher ratings, 10.5% of the children presented ADHD symptoms. We performed multilevel mixed-effects linear regression models, adjusting for school and individual, to test the effects of age-related growth on the ANT networks: alerting, orienting and executive attention, and three measurements related to attentiveness: median of hit reaction time (HRT), hit reaction time standard error (HRT-SE) and variability. Results: We observed age-related growth in all the outcomes, except orienting. The curves were steeper at the younger groups, although for alertness the improvement was further at the oldest ages. Gender and ADHD symptoms interacted with age in executive attention, HRT and variability. Girls performed better in executive attention at young ages although boys reached females at around 10 years of age. For HRT, males showed faster HRT. However, girls had a more pronounced improvement and reached the levels of boys at age 11. Children with ADHD symptoms had significant differences in executive attention, HRT and variability compared to children without ADHD symptoms. Conclusions: We detected an ongoing development of some aspects of attention in primary school children, differentiating patterns by gender and ADHD symptoms. Our findings support the ANT for assessing attention processes in children in large epidemiological studies. PMID- 28559857 TI - Spanish Adaptation and Validation of the Outcome Questionnaire OQ-30.2. AB - This study assessed the psychometric properties of a Spanish version of the Shortened Outcome Questionnaire (OQ-30.2, Lambert et al., 2004) validated with a sample of 546 patients in an outpatient mental health clinic and 100 non-clinical adults in Chile. Our results show that this measure has similar normative data to the original measure, with a cutoff score for the Chilean population set at 43.36, and the reliable change index at 14. This Spanish OQ-30.2 has good internal consistency (alpha = 0.90), has concurrent validity with the Depressive, Anxious, and Somatoform disorders measuring scale (Alvarado and Vera, 1991), and is sensitive to change during psychotherapy. Consistent with previous studies, factorial analyses showed that both, the one-factor solution for a general scale and the three-factor solution containing three theoretical scales yielded poor fit estimates. Overall, our results are similar to past research on the OQ-45 and the OQ-30. The short version has adequate psychometric properties, comparable to those of the OQ-45, but provides a gain in application time that could be relevant in the setting of psychotherapy research with large samples, frequent assessments over time, and/or samples that may require more assistance completing items (e.g., low-literacy). We conclude that this measure will be a valuable instrument for research and clinical practice. PMID- 28559856 TI - A Nap But Not Rest or Activity Consolidates Language Learning. AB - Recent evidence suggests that a period of sleep after a motor learning task is a relevant factor for memory consolidation. However, it is yet open whether this also holds true for language-related learning. Therefore, the present study compared the short- and long-term effects of a daytime nap, rest, or an activity task after vocabulary learning on learning outcome. Thirty healthy subjects were divided into three treatment groups. Each group received a pseudo-word learning task in which pictures of monsters were associated with unique pseudo-word names. At the end of the learning block a first test was administered. Then, one group went for a 90-min nap, one for a waking rest period, and one for a resting session with interfering activity at the end during which a new set of monster names was to be learned. After this block, all groups performed a first re-test of the names that they initially learned. On the morning of the following day, a second re-test was administered to all groups. The nap group showed significant improvement from test to re-test and a stable performance onto the second re test. In contrast, the rest and the interference groups showed decline in performance from test to re-test, with persistently low performance at re-test 2. The 3 (GROUP) * 3 (TIME) ANOVA revealed a significant interaction, indicating that the type of activity (nap/rest/interfering action) after initial learning actually had an influence on the memory outcome. These data are discussed with respect to translation to clinical settings with suggestions for improvement of intervention outcome after speech-language therapy if it is followed by a nap rather than interfering activity. PMID- 28559859 TI - From Data to Truth in Psychological Science. A Personal Perspective. PMID- 28559858 TI - Parent-Toddler Behavior and Language Differ When Reading Electronic and Print Picture Books. AB - Little is known about the language and behaviors that typically occur when adults read electronic books with infants and toddlers, and which are supportive of learning. In this study, we report differences in parent and child behavior and language when reading print versus electronic versions of the same books, and investigate links between behavior and vocabulary learning. Parents of 102 toddlers aged 17-26 months were randomly assigned to read two commercially available electronic books or two print format books with identical content with their toddler. After reading, children were asked to identify an animal labeled in one of the books in both two-dimensional (pictures) and three-dimensional (replica objects) formats. Toddlers who were read the electronic books paid more attention, made themselves more available for reading, displayed more positive affect, participated in more page turns, and produced more content-related comments during reading than those who were read the print versions of the books. Toddlers also correctly identified a novel animal labeled in the book more often when they had read the electronic than the traditional print books. Availability for reading and attention to the book acted as mediators in predicting children's animal choice at test, suggesting that electronic books supported children's learning by way of increasing their engagement and attention. In contrast to prior studies conducted with older children, there was no difference between conditions in behavioral or off-topic talk for either parents or children. More research is needed to determine the potential hazards and benefits of new media formats for very young children. PMID- 28559860 TI - Postural Communication of Emotion: Perception of Distinct Poses of Five Discrete Emotions. AB - Emotion can be communicated through multiple distinct modalities. However, an often-ignored channel of communication is posture. Recent research indicates that bodily posture plays an important role in the perception of emotion. However, research examining postural communication of emotion is limited by the variety of validated emotion poses and unknown cohesion of categorical and dimensional ratings. The present study addressed these limitations. Specifically, we examined individuals' (1) categorization of emotion postures depicting 5 discrete emotions (joy, sadness, fear, anger, and disgust), (2) categorization of different poses depicting the same discrete emotion, and (3) ratings of valence and arousal for each emotion pose. Findings revealed that participants successfully categorized each posture as the target emotion, including disgust. Moreover, participants accurately identified multiple distinct poses within each emotion category. In addition to the categorical responses, dimensional ratings of valence and arousal revealed interesting overlap and distinctions between and within emotion categories. These findings provide the first evidence of an identifiable posture for disgust and instantiate the principle of equifinality of emotional communication through the inclusion of distinct poses within emotion categories. Additionally, the dimensional ratings corroborated the categorical data and provide further granularity for future researchers to consider in examining how distinct emotion poses are perceived. PMID- 28559861 TI - Does a Flatter General Gradient of Visual Attention Explain Peripheral Advantages and Central Deficits in Deaf Adults? AB - Individuals deaf from early age often outperform hearing individuals in the visual periphery on attention-dependent dorsal stream tasks (e.g., spatial localization or movement detection), but sometimes show central visual attention deficits, usually on ventral stream object identification tasks. It has been proposed that early deafness adaptively redirects attentional resources from central to peripheral vision to monitor extrapersonal space in the absence of auditory cues, producing a more evenly distributed attention gradient across visual space. However, little direct evidence exists that peripheral advantages are functionally tied to central deficits, rather than determined by independent mechanisms, and previous studies using several attention tasks typically report peripheral advantages or central deficits, not both. To test the general altered attentional gradient proposal, we employed a novel divided attention paradigm that measured target localization performance along a gradient from parafoveal to peripheral locations, independent of concurrent central object identification performance in prelingually deaf and hearing groups who differed in access to auditory input. Deaf participants without cochlear implants (No-CI), with cochlear implants (CI), and hearing participants identified vehicles presented centrally, and concurrently reported the location of parafoveal (1.4 degrees ) and peripheral (13.3 degrees ) targets among distractors. No-CI participants but not CI participants showed a central identification accuracy deficit. However, all groups displayed equivalent target localization accuracy at peripheral and parafoveal locations and nearly parallel parafoveal-peripheral gradients. Furthermore, the No-CI group's central identification deficit remained after statistically controlling peripheral performance; conversely, the parafoveal and peripheral group performance equivalencies remained after controlling central identification accuracy. These results suggest that, in the absence of auditory input, reduced central attentional capacity is not necessarily associated with enhanced peripheral attentional capacity or with flattening of a general attention gradient. Our findings converge with earlier studies suggesting that a general graded trade-off of attentional resources across the visual field does not adequately explain the complex task-dependent spatial distribution of deaf hearing performance differences reported in the literature. Rather, growing evidence suggests that the spatial distribution of attention-mediated performance in deaf people is determined by sophisticated cross-modal plasticity mechanisms that recruit specific sensory and polymodal cortex to achieve specific compensatory processing goals. PMID- 28559863 TI - Young Children's Understanding of Teaching and Learning and Their Theory of Mind Development: A Causal Analysis from a Cross-Cultural Perspective. AB - Children's understanding of the concepts of teaching and learning is closely associated with their theory of mind (ToM) ability and vital for school readiness. This study aimed to develop and validate a Preschool Teaching and Learning Comprehension Index (PTLCI) across cultures and examine the causal relationship between children's comprehension of teaching and learning and their mental state understanding. Two hundred and twelve children from 3 to 6 years of age from Hong Kong and the United States participated in study. The results suggested strong construct validity of the PTLCI, and its measurement and structural equivalence within and across cultures. ToM and PTLCI were significantly correlated with a medium effect size, even after controlling for age, and language ability. Hong Kong children outperformed their American counterparts in both ToM and PTLCI. Competing structural equation models suggested that children's performance on the PTLCI causally predicted their ToM across countries. PMID- 28559862 TI - Family Burden, Emotional Distress and Service Satisfaction in First Episode Psychosis. Data from the GET UP Trial. AB - Background: Literature has documented the role of family in the outcome of chronic schizophrenia. In the light of this, family interventions (FIs) are becoming an integral component of treatment for psychosis. The First Episode of Psychosis (FEP) is the period when most of the changes in family atmosphere are observed; unfortunately, few studies on the relatives are available. Objective: To explore burden of care and emotional distress at baseline and at 9-month follow-up and the levels of service satisfaction at follow-up in the two groups of relatives (experimental treatment EXP vs. treatment as usual TAU) recruited in the cluster-randomized controlled GET UP PIANO trial. Methods: The experimental treatment was provided by routine public Community Mental Health Centers (Italian National Health Service) and consisted of Treatment as Usual plus evidence-based additional treatment (Cognitive Behavioral Therapy for psychosis for patients, Family Intervention for psychosis, and Case Management). TAU consisted of personalized outpatient psychopharmacological treatment, combined with non specific supportive clinical management and informal support/educational sessions for families. The outcomes on relatives were assessed by the Involvement Evaluation Questionnaire (IEQ-EU), the General Health Questionnaire (GHQ-12), and the Verona Service Satisfaction Scale (VSSS-EU). Differences within and between groups were evaluated. Results: At baseline, 75 TAU and 185 EXP caregivers were assessed. In the experimental group 92% of relatives participated in at least 1 family session. At follow-up both groups experienced improvement in all IEQ and GHQ items, but caregivers belonging to the EXP arm experienced a significantly greater change in 10 IEQ items (mainly pertaining to the "Tension" dimension) and in GHQ items. Due to the low sample size, a significant effectiveness was only observed for 2 IEQ items and 1 GHQ-12 item. With respect to VSSS data at follow up, caregivers in the EXP arm experienced significantly greater satisfaction in 8 items, almost all pertaining to the dimensions "Relatives' Involvement" and "Professionals' Skills and Behavior." Conclusions: The Family intervention for psychosis delivered in the GET UP PIANO trial reduced family burden of illness and improved emotional distress and satisfaction with services. These results should encourage to promote FIs on caregivers of first-episode psychosis patients. PMID- 28559864 TI - The Development and Validation of the Online Shopping Addiction Scale. AB - We report the development and validation of a scale to measure online shopping addiction. Inspired by previous theories and research on behavioral addiction, the Griffiths's widely accepted six-factor component model was referred to and an 18-item scale was constructed, with each component measured by three items. The results of exploratory factor analysis, based on Sample 1 (999 college students) and confirmatory factor analysis, based on Sample 2 (854 college students) showed the Griffiths's substantive six-factor structure underlay the online shopping addiction scale. Cronbach's alpha suggested that the resulting scale was highly reliable. Concurrent validity, based on Sample 3 (328 college students), was also satisfactory as indicated by correlations between the scale and measures of similar constructs. Finally, self-perceived online shopping addiction can be predicted to a relatively high degree. The present 18-item scale is a solid theory-based instrument to empirically measure online shopping addiction and can be used for understanding the phenomena among young adults. PMID- 28559865 TI - Effects of Music on Agitation in Dementia: A Meta-Analysis. AB - Agitation is a common problem in patients suffering from dementia and encompasses a variety of behaviors such as repetitive acts, restlessness, wandering, and aggressive behaviors. Agitation reduces the probability of positive social interaction and increases the psychological and organizational burden. While medical interventions are common, there is need for complementary or alternative methods. Music intervention has been brought forward as a promising method to reduce agitation in dementia. While interventions, target groups and research designs differ, there has so far not been a systematic overview assessing the effect of music intervention for agitation in patients with dementia. A meta analysis was conducted in order to investigate possible effects of music interventions. Twelve studies met inclusion criteria. Music intervention had a medium overall effect on agitation in dementia, suggesting robust clinical relevance. While the moderate number of studies does not allow for further differentiation between sub-types of music intervention, the sub-group comparisons indicated promising pathways for future systematic reviews. This meta analysis is the first systematic and quantitative overview supporting clinically and statistically robust effects of music intervention on agitation in dementia. The analysis provides further arguments for this non-pharmacological approach and highlights needs for future systematic research reviews for the investigation of intervention types. PMID- 28559866 TI - How Do B-Learning and Learning Patterns Influence Learning Outcomes? AB - Learning Management System (LMS) platforms provide a wealth of information on the learning patterns of students. Learning Analytics (LA) techniques permit the analysis of the logs or records of the activities of both students and teachers on the on-line platform. The learning patterns differ depending on the type of Blended Learning (B-Learning). In this study, we analyse: (1) whether significant differences exist between the learning outcomes of students and their learning patterns on the platform, depending on the type of B-Learning [Replacement blend (RB) vs. Supplemental blend (SB)]; (2) whether a relation exists between the metacognitive and the motivational strategies (MS) of students, their learning outcomes and their learning patterns on the platform. The 87,065 log records of 129 students (69 in RB and 60 in SB) in the Moodle 3.1 platform were analyzed. The results revealed different learning patterns between students depending on the type of B-Learning (RB vs. SB). We have found that the degree of blend, RB vs. SB, seems to condition student behavior on the platform. Learning patterns in RB environments can predict student learning outcomes. Additionally, in RB environments there is a relationship between the learning patterns and the metacognitive and (MS) of the students. PMID- 28559867 TI - Response: Commentary: How to Make the Ghosts in my Bedroom Disappear? Focused Attention Meditation Combined with Muscle Relaxation (MR Therapy)-A Direct Treatment Intervention for Sleep Paralysis. PMID- 28559868 TI - Individual Alpha Peak Frequency in Ice Hockey Shooting Performance. AB - There are several important inter- and intra-individual variations in individual alpha peak frequency (IAPF) in the cognitive domain. The rationale for the present study was to extend the research on IAPF in the cognitive domain to IAPF in the sport domain. Specifically, the purpose of the present study was twofold: (a) to explore whether baseline IAPF is related to performance in an ice hockey shooting task and (b) to explore whether a shooting task has an effect on IAPF variability. The present investigation is one of the first studies to examine links between IAPF and sport performance. Study results did not show significant changes in IAPF when comparing baseline IAPF and pre- to post-task IAPF across three performance levels. The findings support previous literature in the cognitive domain suggesting that IAPF is a stable neurophysiological marker. Future research should consider the following methodological suggestions: (a) measuring IAPF during sport performance instead of at a resting state, (b) changing the pre-performance resting baseline instructions to take into account sport-specific mental preparation, PMID- 28559869 TI - Impression Management in the Job Interview: An Effective Way of Mitigating Discrimination against Older Applicants? AB - The increasingly aging population in most industrialized societies, coupled with the rather age-diverse current workforce makes discrimination against older employees a prevalent issue, especially in employment contexts. This renders research on ways for reducing this type of discrimination a particularly pressing concern. Drawing on theories of social identity and impression management, our research examines the role of impression management, aimed at refuting common older worker stereotypes, in diminishing bias against older job applicants during the job interview. The study consisted in an experimental hiring simulation conducted on a sample of 515 undergraduate students. Results show that older applicants who used impression management to contradict common older worker stereotypes were perceived as more hirable than those who did not. However, despite this positive effect, discrimination persisted: older applicants were consistently rated as less hirable than their younger counterparts when displaying the same IM behavior. Taken together, this research demonstrates that older job seekers can indeed ameliorate biased interview outcomes by engaging in impression management targeting common age stereotypes; however, it also shows that this strategy is insufficient for overcoming age discrimination entirely. The current study has important implications for theory, by expanding research on the use of impression management in mitigating age discrimination, as well as for practice, by offering older employees a hands-on strategy to reduce bias and stereotyping against them. PMID- 28559870 TI - Visual Representations of Sexual Violence in Online News Outlets. AB - To study visual representations of sexual violence, photographs accompanying German Internet news articles that appeared between January 2013 and March 2015 (N = 42) were subjected to thematic analysis. Two main themes, consisting of several sub-themes, emerged from the data. The first theme was "rape myths," illustrating a stereotypical view of sexual violence. It consisted of three sub themes: "beauty standards," referring to the fact that all women in our sample fit western beauty standards, "physical violence," as most images implied some form of physical violence, and finally "location," suggesting that rape only happens in secluded outdoor areas. These findings suggest that the images from our sample perpetuate certain rape myths. The second theme was "portrayal of victimhood," referring to the way victims of sexual violence were portrayed in photographs. The analysis of the sub-theme "passivity" showed that these portrayals fit a certain stereotype: the women were shown to be weak and helpless rather than individuals with agency and able to leave their status as a victim. Further sub-themes were "background," "organization of space," "camera perspective," and "lighting." We discuss these findings in relation to possibly reinforcing rape myths in society and as an issue in creating a biased perception of women who have experienced sexual violence. PMID- 28559871 TI - Abstracting Dance: Detaching Ourselves from the Habitual Perception of the Moving Body. AB - This work explores to what extent the notion of abstraction in dance is valid and what it entails. Unlike abstraction in the fine arts that aims for a certain independence from representation of the external world through the use of non figurative elements, dance is realized by a highly familiar object - the human body. In fact, we are all experts in recognizing the human body. For instance, we can mentally reconstruct its motion from minimal information (e.g., via a "dot display"), predict body trajectory during movement and identify emotional expressions of the body. Nonetheless, despite the presence of a human dancer on stage and our extreme familiarity with the human body, the process of abstraction is applicable also to dance. Abstract dance removes itself from familiar daily movements, violates the observer's predictions about future movements and detaches itself from narratives. In so doing, abstract dance exposes the observer to perceptions of unfamiliar situations, thus paving the way to new interpretations of human motion and hence to perceiving ourselves differently in both the physical and emotional domains. PMID- 28559872 TI - Positive fEMG Patterns with Ambiguity in Paintings. AB - Whereas ambiguity in everyday life is often negatively evaluated, it is considered key in art appreciation. In a facial EMG study, we tested whether the positive role of visual ambiguity in paintings is reflected in a continuous affective evaluation on a subtle level. We presented ambiguous (disfluent) and non-ambiguous (fluent) versions of Magritte paintings and found that M. Zygomaticus major activation was higher and M. corrugator supercilii activation was lower for ambiguous than for non-ambiguous versions. Our findings reflect a positive continuous affective evaluation to visual ambiguity in paintings over the 5 s presentation time. We claim that this finding is indirect evidence for the hypothesis that visual stimuli classified as art, evoke a safe state for indulging into experiencing ambiguity, challenging the notion that processing fluency is generally related to positive affect. PMID- 28559873 TI - New Strategies in the New Millennium: Servant Leadership As Enhancer of Service Climate and Customer Service Performance. AB - In a world in which customers are increasingly looking for solutions to their own concerns on how to make a better globalized world, new organizational strategies are emerging to approach the customer in the current third millennium. Servant leadership, which involves putting employees' needs first and serving the broader society, is emerging as a new strategic mechanism to approach the customer in line with the new social values-driven Marketing 3.0 era. Yet research has ignored the role and the various mechanisms servant leadership might utilize to improve customer service performance of their service units. Spanning 185 hotels located in Spain, a sample of 247 service units -in close contact with customers- was used to investigate whether servant leadership enhances customer service performance through shaping a service climate within the service unit. Results revealed that service climate mediates the positive influence of servant leadership on customer service performance. Managers can use these findings to note the value of leading the service unit in a servant friendly direction, which is better aligned with the new aspirations of customers today. PMID- 28559874 TI - Editorial: Infants' Understanding and Production of Goal-Directed Actions in the Context of Social and Object-Related Interactions. PMID- 28559875 TI - Beyond the Impasse - Reflections on Dissociative Identity Disorder from a Freudian-Lacanian Perspective. AB - Dissociative identity disorder (DID) is a widely contested diagnosis. The dominant posttraumatic model (PTM) considers early life trauma to be the direct cause of the creation of alter identities and assumes that working directly with alter identities should be at the core of the therapeutic work. The socio cognitive model, on the other hand, questions the validity of the DID diagnosis and proposes an iatrogenic origin of the disorder claiming that reigning therapeutic and socio-cultural discourses create and reify the problem. The author argues that looking at the underlying psychical dynamics can provide a way out of the debate on the veracity of the diagnosis. A structural conception of hysteria is presented to understand clinical and empirical observations on the prevalence, appearance and treatment of DID. On a more fundamental level, the concept of identification and the fundamental division of human psychic functioning are proposed as crucial for understanding the development and treatment of DID. PMID- 28559876 TI - Cognitive Investments in Academic Success: The Role of Need for Cognition at University. AB - Previous research has shown that Need for Cognition (NFC), the individual tendency to engage in and enjoy cognitive endeavors, contributes to academic performance. Most studies on NFC and related constructs have thereby focused on grades to capture tertiary academic success. This study aimed at a more comprehensive approach on NFC's meaning to success in university. We examined not only performance but also rather affective indicators of success. The current sample consisted of 396 students of different subjects with a mean age of 24 years (139 male). All participants took part in an online survey that assessed NFC together with school performance and further personality variables via self report. Success in university was comprehensively operationalized including performance, satisfaction with one's studies, and thoughts about quitting/changing one's major as indicators. The value of NFC in predicting tertiary academic success was examined with correlation analyses and path analysis. NFC significantly correlated with all success variables with the highest correlation for study satisfaction. Path analysis confirmed the importance of NFC for study satisfaction showing that NFC had a significant direct effect on study satisfaction and via this variable also a significant indirect effect on termination thoughts. This study clearly indicates that NFC broadly contributes to the mastery of academic requirements and that it is worthwhile to intensify research on NFC in the context of tertiary education. PMID- 28559877 TI - Poor Executive Functions among Children with Moderate-into-Severe Asthma: Evidence from WCST Performance. AB - Executive functions (EFs) measures of 27 asthmatic children, with general learning difficulties, were tested by using the Wisconsin card sorting test (WCST), and were compared to the performances of 30 non-asthmatic children with general learning difficulties. The results revealed that the asthmatic group has poor performance through all the WCST psychometric parameters and especially the perseverative errors one. The results were discussed in light of the postulation that poor EFs could be associated with the learning difficulties of asthmatic children. Neurophysiological framework has been suggested to explain the etiology of poor EFs among children with moderate into severe asthma. PMID- 28559878 TI - Attentional Capture to a Singleton Distractor Degrades Visual Marking in Visual Search. AB - Visual search is easier after observing some distractors in advance; it is as if the previewed distractors were excluded from the search. This effect is referred to as the preview benefit, and a memory template that visually marks the old locations of the distractors is thought to help in prioritizing the locations of newly presented items. One remaining question is whether the presence of a conspicuous item during the sequential shift of attention within the new items reduces this preview benefit. To address this issue, we combined the above preview search and a conventional visual search paradigm using a singleton distractor and examined whether the search performance was affected by the presence of the singleton. The results showed that the slope of reaction time as a function of set size became steeper in the presence of a singleton, indicating that the singleton distractor reduced the preview benefit. Furthermore, this degradation effect was positively correlated with the degree of conventional attentional capture to a singleton measured in a separate experiment with simultaneous search. These findings suggest that the mechanism of visual marking shares common attentional resources with the search process. PMID- 28559879 TI - Agrobacterium tumefaciens-Mediated Transformation of Pseudocercospora fijiensis to Determine the Role of PfHog1 in Osmotic Stress Regulation and Virulence Modulation. AB - Black Sigatoka disease, caused by Pseudocercospora fijiensis is a serious constraint to banana production worldwide. The disease continues to spread in new ecological niches and there is an urgent need to develop strategies for its control. The high osmolarity glycerol (HOG) pathway in Saccharomyces cerevisiae is well known to respond to changes in external osmolarity. HOG pathway activation leads to phosphorylation, activation and nuclear transduction of the HOG1 mitogen-activated protein kinases (MAPKs). The activated HOG1 triggers several responses to osmotic stress, including up or down regulation of different genes, regulation of protein translation, adjustments to cell cycle progression and synthesis of osmolyte glycerol. This study investigated the role of the MAPK encoding PfHog1 gene on osmotic stress adaptation and virulence of P. fijiensis. RNA interference-mediated gene silencing of PfHog1 significantly suppressed growth of P. fijiensis on potato dextrose agar media supplemented with 1 M NaCl, indicating that PfHog1 regulates osmotic stress. In addition, virulence of the PfHog1-silenced mutants of P. fijiensis on banana was significantly reduced, as observed from the low rates of necrosis and disease development on the infected leaves. Staining with lacto phenol cotton blue further confirmed the impaired mycelial growth of the PfHog1 in the infected leaf tissues, which was further confirmed with quantification of the fungal biomass using absolute- quantitative PCR. Collectively, these findings demonstrate that PfHog1 plays a critical role in osmotic stress regulation and virulence of P. fijiensis on its host banana. Thus, PfHog1 could be an interesting target for the control of black Sigatoka disease in banana. PMID- 28559883 TI - Relationship between Pyruvate Kinase Activity and Cariogenic Biofilm Formation in Streptococcus mutans Biotypes in Caries Patients. AB - Streptococcus mutans (MS) and its biotype I are the strains most frequently found in dental plaque of young children. Our results indicate that in children pyruvate kinase (PK) activity increases significantly in dental plaque, and this corresponds with caries progression. The MS strains isolated in this study or their main glycolytic metabolism connected with PK enzymes might be useful risk factors for studying the pathogenesis and target points of novel therapies for dental caries. The relationship between PK activity, cariogenic biofilm formation and selected biotypes occurrence was studied. S. mutans dental plaque samples were collected from supragingival plaque of individual deciduous molars in 143 subjects. PK activity was measured at different time points during biofilm formation. Patients were divided into two groups: initial stage decay, and extensive decay. Non-parametric analysis of variance and analysis of covariance were used to determine the connections between S. mutans levels, PK activity and dental caries biotypes. A total of 143 strains were derived from subjects with caries. Biotyping data showed that 62, 23, 50, and 8 strains were classified as biotypes I, II, III, IV, respectively. PK activity in biotypes I, II, and IV was significantly higher in comparison to that in biotype III. The correlation between the level of S. mutans in dental plaque and PK activity was both statistically significant (p < 0.05) and positive. The greater the level of S. mutans in the biofilm (colony count and total biomass), the higher the PK activity; similarly, a low bacterial count correlated with low PK activity. PMID- 28559882 TI - Bacterial Root Microbiome of Plants Growing in Oil Sands Reclamation Covers. AB - Oil sands mining in northern Alberta impacts a large footprint, but the industry is committed to reclaim all disturbed land to an ecologically healthy state in response to environmental regulations. However, these newly reconstructed landscapes may be limited by several factors that include low soil nutrient levels and reduced microbial activity. Rhizosphere microorganisms colonize plant roots providing hosts with nutrients, stimulating growth, suppressing disease and increasing tolerance to abiotic stress. High-throughput sequencing techniques can be used to provide a detailed characterization of microbial community structure. This study used 16S rRNA amplicon sequencing to characterize the bacterial root microbiome associated with annual barley (Hordeum vulgare) and sweet clover (Melilotus albus) growing in an oil sands reclamation area. Our results indicate that Proteobacteria dominated the endosphere, whereas other phyla such as Acidobacteria and Gemmatimonadetes were restricted to the rhizosphere, suggesting that plants have the ability to select for certain soil bacterial consortia. The bacterial community in the endosphere compartments were less rich and diverse compared to the rhizosphere. Furthermore, it was apparent that sweet clover plants were more selective, as the community exhibited a lower richness and diversity compared to barley. Members of the family Rhizobiaceae, such as Sinorhizobium and Rhizobium were mainly associated with clover, whereas Acholeplasma (wall-less bacteria transmitted by insects) was unique to barley. Genera from the Enterobacteriaceae family, such as Yersinia and Lentzea were also mostly detected in barley, while other genera such Pseudomonas and Pantoea were able to successfully colonize both plants. Endophytic bacterial profiles varied within the same plant species at different sampling locations; however, these differences were driven by factors other than slope positions or cover management. Our results suggest that bacterial endophytic communities of plants growing in land reclamation systems are a subset of the rhizosphere community and selection is driven by plant factors. PMID- 28559884 TI - Editorial: Emerging Tools for Emerging Symbioses-Using Genomics Applications to Studying Endophytes. PMID- 28559880 TI - Laccases: Production, Expression Regulation, and Applications in Pharmaceutical Biodegradation. AB - Laccases are a family of copper-containing oxidases with important applications in bioremediation and other various industrial and biotechnological areas. There have been over two dozen reviews on laccases since 2010 covering various aspects of this group of versatile enzymes, from their occurrence, biochemical properties, and expression to immobilization and applications. This review is not intended to be all-encompassing; instead, we highlighted some of the latest developments in basic and applied laccase research with an emphasis on laccase mediated bioremediation of pharmaceuticals, especially antibiotics. Pharmaceuticals are a broad class of emerging organic contaminants that are recalcitrant and prevalent. The recent surge in the relevant literature justifies a short review on the topic. Since low laccase yields in natural and genetically modified hosts constitute a bottleneck to industrial-scale applications, we also accentuated a genus of laccase-producing white-rot fungi, Cerrena, and included a discussion with regards to regulation of laccase expression. PMID- 28559885 TI - Occurrence and Variety of beta-Lactamase Genes among Aeromonas spp. Isolated from Urban Wastewater Treatment Plant. AB - Members of the genus Aeromonas that commonly occur in various aquatic ecosystems are taken into account as vectors spreading antibiotic resistance genes (ARGs) in the environment. In our study strains of Aeromonas spp. (n = 104) not susceptible to ampicillin were isolated from municipal sewage of different levels of purification - raw sewage, activated sludge and treated wastewater. The crucial step of the study was the identification of beta-lactamase resistance genes. The identified genes encode beta-lactamases from 14 families - blaTEM, blaOXA, blaSHV, blaCTX-M, blaMOX, blaACC, blaFOX, blaGES, blaPER, blaV EB, blaKPC, cphA, imiH, and cepH. There were no significant differences in number of identified ARGs between isolation points. BlaOXA, blaFOX variants and, characteristic for Aeromonas genus, metallo-beta-lactamase cphA-related genes were the most commonly identified types of beta-lactam resistance determinants. Moreover, we found four extended-spectrum beta-lactamases (blaSHV -11, blaCTX-M-27, blaCTX-M-98, and blaPER-4) - and seven AmpC (blaACC, blaFOX-2-like, blaFOX-3, blaFOX-4-like, blaFOX-9, blaFOX-10-like, and blaFOX-13-like) types and variants of genes that had never been found among Aeromonas spp. before. Five of the beta-lactamases families (blaTEM, blaOXA, blaFOX, blaV EB, and cphA) were identified in all three isolation sites, which supports the hypothesis that wastewater treatment plants (WWTPs) are hot spots of ARGs dissemination. The obtained ARGs sequences share high identity with previously described beta-lactamases, but new variants of those genes have to be considered as well. Characterization of antibiotic susceptibility was performed using disk the diffusion method with 12 different antibiotics according to CLSI guidelines. Over 60% of the strains are unsusceptible to cefepime and chloramphenicol and the majority of the strains have a multidrug resistance phenotype (68%). Finally, analysis of plasmid profiles among the resistant strains showed that 62% of the isolates from all three points of the WWTP carry plasmids of different sizes. Among some of the isolated plasmids blaFOX-4-like and blaGES genes have been found. To sum up, the results strongly suggest that Aeromonas spp. can be considered as agents of antibiotic resistance dissemination from wastewater to the natural environment. PMID- 28559887 TI - CRP Regulates D-Lactate Oxidation in Shewanella oneidensis MR-1. AB - Shewanella oneidensis MR-1 is a heterotrophic facultative anaerobe that respires using various organic and inorganic compounds. This organism has served as a model to study bacterial metabolic and regulatory systems that facilitate their survival in redox-stratified environments. The expression of many anaerobic respiratory genes in MR-1, including those for the reduction of fumarate, dimethyl sulfoxide, and metal oxides, is regulated by cyclic AMP receptor protein (CRP). However, relatively little is known about how this organism regulates the expression of catabolic enzymes catalyzing the oxidation of organic compounds, including lactate. Here, we investigated transcriptional mechanisms for the lldP (SO_1522) and dld (SO_1521) genes, which encode putative lactate permease and D lactate dehydrogenase, respectively, and demonstrate that CRP regulates their expression in MR-1. We found that a crp-deletion mutant of MR-1 (Deltacrp) showed impaired growth on D-lactate. Complementary expression of dld in Deltacrp restored the ability to grow on D-lactate, indicating that the deficient growth of Deltacrp on D-lactate is attributable to decreased expression of dld. In vivo transcription and in vitro electrophoretic mobility shift assays reveal that CRP positively regulates the expression of the lldP and dld genes by directly binding to an upstream region of lldP. Taken together, these results indicate that CRP is a global transcriptional regulator that coordinately regulates the expression of catabolic and respiratory pathways in MR-1, including D-lactate dehydrogenase and anaerobic terminal reductases. PMID- 28559886 TI - Global Diversity of Desert Hypolithic Cyanobacteria. AB - Global patterns in diversity were estimated for cyanobacteria-dominated hypolithic communities that colonize ventral surfaces of quartz stones and are common in desert environments. A total of 64 hypolithic communities were recovered from deserts on every continent plus a tropical moisture sufficient location. Community diversity was estimated using a combined t-RFLP fingerprinting and high throughput sequencing approach. The t-RFLP analysis revealed desert communities were different from the single non-desert location. A striking pattern also emerged where Antarctic desert communities were clearly distinct from all other deserts. Some overlap in community similarity occurred for hot, cold and tundra deserts. A further observation was that the producer consumer ratio displayed a significant negative correlation with growing season, such that shorter growing seasons supported communities with greater abundance of producers, and this pattern was independent of macroclimate. High-throughput sequencing of 16S rRNA and nifH genes from four representative samples validated the t-RFLP study and revealed patterns of taxonomic and putative diazotrophic diversity for desert communities from the Taklimakan Desert, Tibetan Plateau, Canadian Arctic and Antarctic. All communities were dominated by cyanobacteria and among these 21 taxa were potentially endemic to any given desert location. Some others occurred in all but the most extreme hot and polar deserts suggesting they were relatively less well adapted to environmental stress. The t-RFLP and sequencing data revealed the two most abundant cyanobacterial taxa were Phormidium in Antarctic and Tibetan deserts and Chroococcidiopsis in hot and cold deserts. The Arctic tundra displayed a more heterogenous cyanobacterial assemblage and this was attributed to the maritime-influenced sampling location. The most abundant heterotrophic taxa were ubiquitous among samples and belonged to the Acidobacteria, Actinobacteria, Bacteroidetes, and Proteobacteria. Sequencing using nitrogenase gene-specific primers revealed all putative diazotrophs were Proteobacteria of the orders Burkholderiales, Rhizobiales, and Rhodospirillales. We envisage cyanobacterial carbon input to the system is accompanied by nitrogen fixation largely from non-cyanobacterial taxa. Overall the results indicate desert hypoliths worldwide are dominated by cyanobacteria and that growing season is a useful predictor of their abundance. Differences in cyanobacterial taxa encountered may reflect their adaptation to different moisture availability regimes in polar and non-polar deserts. PMID- 28559888 TI - Transmission of Bamboo mosaic virus in Bamboos Mediated by Insects in the Order Diptera. AB - Bamboo mosaic virus (BaMV), a member of the genus Potexvirus, is the major threat to bamboo cultivation. Similar to most potexviruses, the transmission of BaMV by insect vectors has not been documented previously. However, field observations of BaMV disease incidences suggested that insect vectors might be involved. In this study, we aimed to investigate the possibility of insect-mediated transmission of BaMV among bamboo clumps, in order to provide further insights into the infection cycles of BaMV for the development of effective disease management measures. From the major insects collected from infected bamboo plantations, BaMV genomic RNAs were detected inside the bodies of two dipteran insects, Gastrozona fasciventris and Atherigona orientalis, but not in thrips (Scirtothrips dorsalis). Artificial feeding assays using green fluorescent protein-tagged BaMV virions revealed that BaMV could enter the digestive systems and survive in the regurgitant and excretion of the dipterans. BaMV RNA could be retained in the dipterans for up to 4 weeks. Insect-mediated transmission assays indicated that both dipterans could transmit BaMV to bamboo seedlings through artificially created wounds with low infection efficiency (14 - 41%), suggesting that the dipterans may mediate the transmission in a mechanical-like manner. These results demonstrated that dipterans with sponge-like mouthparts may also serve as vectors for at least one potexvirus, BaMV, among bamboo plants. The finding suggested that dipteran insect control should be integrated into the disease management measures against BaMV infections. PMID- 28559889 TI - Characterization of Lipopeptide Biosurfactants Produced by Bacillus licheniformis MB01 from Marine Sediments. AB - Antibiotic resistance has become one of the world's most severe problems because of the overuse of antibiotics. Antibiotic-resistant bacteria are more difficult to kill and more expensive to treat. Researchers have been studied on antibiotic alternatives such as antimicrobial peptides and lipopeptides. A functional bacteria MB01 producing lipopeptides which can be used as bacteriostat was isolated from the Bohai Sea sediments, which had been identified as Bacillus licheniformis by the morphological, physiological, and biochemical identification and 16s rDNA sequence. The lipopeptides produced by MB01 were determined to be cyclic surfactin homologs by LC-ESI-MS structural identification after crude extraction and LH-20 chromatography. [M+H]+m/z 994, 1008, 1022, and 1036 were all the characteristic molecular weight of surfactin homologs. CID analysis revealed that the molecular structure of the lipopeptides was Rn-Glu1-Leu/Ile2-Leu3-Val4 Asp5-Leu6-Leu/Ile7. The lipopeptides showed well resistance to UV light and the change of pH and temperature. PMID- 28559890 TI - Unexpected Transcripts in Tn7 orf19.2646 C. albicans Mutant Lead to Low Fungal Burden Phenotype In vivo. AB - The commensal fungus Candida albicans is the major cause of fungal systemic infection in immuno-compromised patients, with a mortality rate approaching 50% in the case of bloodstream infections. There is therefore a clear need to better understand fungal biology during infection to improve treatment. One of the particularities of C. albicans is its capacity to adapt to drastically diverse environments such as brain, bloodstream or gut. Adaptations to environmental change are mediated by transcription factors (TF) that modulate the expression of their target genes. Previous screening of a collection of Tn7 C. albicans TF mutants in vivo identified orf19.2646 as playing a crucial role in the ability of the fungus to survive within its host. Indeed, the orf19.2646 Tn7 interruption mutant strain displayed a reduced fungal burden compared to the wild-type strain. Surprisingly, an independent deletion mutant did not recapitulate the phenotype of the Tn7 interruption mutant. In the present study, we therefore investigated the difference between these two mutants and determined by performing a RACE analysis whether unexpected transcripts of the Tn7 mutant occurred. We found that two such transcripts upstream and downstream of the Tn7 insertion site were produced. The two transcripts were expressed in an orf19.2646 deletion mutant which displayed a significantly reduced fungal burden level compared to the wild type in G. mellonella. When the regions corresponding to these transcripts were deleted in the Tn7 mutants, the strains lacking both regions displayed a fungal burden similar to that of the wild-type strain. This study shows for the first time that mRNA transcription may occur downstream of a Tn7 sequence. In addition, these results demonstrated that the low fungal burden phenotype observed in the orf19.2646 Tn7 mutant is due to the presence of these two transcripts together participating to an unidentified virulence mechanism to be further elucidated. PMID- 28559891 TI - Systematic Optimization of Protein Secretory Pathways in Saccharomyces cerevisiae to Increase Expression of Hepatitis B Small Antigen. AB - Hepatitis B is a major disease that chronically infects millions of people in the world, especially in developing countries. Currently, one of the effective vaccines to prevent Hepatitis B is the Hepatitis B Small Antigen (HBsAg), which is mainly produced by the recombinant yeast Saccharomyces cerevisiae. In order to bring down the price, which is still too high for people in developing countries to afford, it is important to understand key cellular processes that limit protein expression. In this study, we took advantage of yeast knockout collection (YKO) and screened 194 S. cerevisiae strains with single gene knocked out in four major steps of the protein secretory pathway, i.e., endoplasmic-reticulum (ER) associated protein degradation, protein folding, unfolded protein response (UPR), and translocation and exocytosis. The screening showed that the single deletion of YPT32, SBH1, and HSP42 led to the most significant increase of HBsAg expression over the wild type while the deletion of IRE1 led to a profound decrease of HBsAg expression. The synergistic effects of gene knockout and gene overexpression were next tested. We found that simultaneously deleting YPT32 and overexpressing IRE1 led to a 2.12-fold increase in HBsAg expression over the wild type strain. The results of this study revealed novel genetic targets of protein secretory pathways that could potentially improve the manufacturing of broad scope vaccines in a cost-effective way using recombinant S. cerevisiae. PMID- 28559892 TI - Streptomyces colonosanans sp. nov., A Novel Actinobacterium Isolated from Malaysia Mangrove Soil Exhibiting Antioxidative Activity and Cytotoxic Potential against Human Colon Cancer Cell Lines. AB - Streptomyces colonosanans MUSC 93JT, a novel strain isolated from mangrove forest soil located at Sarawak, Malaysia. The bacterium was noted to be Gram-positive and to form light yellow aerial and vivid yellow substrate mycelium on ISP 2 agar. The polyphasic approach was used to determine the taxonomy of strain MUSC 93JT and the strain showed a range of phylogenetic and chemotaxonomic properties consistent with those of the members of the genus Streptomyces. Phylogenetic and 16S rRNA gene sequence analysis indicated that closely related strains include Streptomyces malachitofuscus NBRC 13059T (99.2% sequence similarity), Streptomyces misionensis NBRC 13063T (99.1%), and Streptomyces phaeoluteichromatogenes NRRL 5799T (99.1%). The DNA-DNA relatedness values between MUSC 93JT and closely related type strains ranged from 14.4 +/- 0.1 to 46.2 +/- 0.4%. The comparison of BOX-PCR fingerprints indicated MUSC 93JT exhibits a unique DNA profile. The genome of MUSC 93JT consists of 7,015,076 bp. The DNA G + C content was determined to be 69.90 mol%. The extract of strain MUSC 93JT was demonstrated to exhibit potent antioxidant activity via ABTS, metal chelating, and SOD assays. This extract also exhibited anticancer activity against human colon cancer cell lines without significant cytotoxic effect against human normal colon cells. Furthermore, the chemical analysis of the extract further emphasizes the strain is producing chemo-preventive related metabolites. Based on this polyphasic study of MUSC 93JT, it is concluded that this strain represents a novel species, for which the name Streptomyces colonosanans sp. nov. is proposed. The type strain is MUSC 93JT (= DSM 102042T = MCCC 1K02298T). PMID- 28559881 TI - Rodent Models of Invasive Aspergillosis due to Aspergillus fumigatus: Still a Long Path toward Standardization. AB - Invasive aspergillosis has been studied in laboratory by the means of plethora of distinct animal models. They were developed to address pathophysiology, therapy, diagnosis, or miscellaneous other concerns associated. However, there are great discrepancies regarding all the experimental variables of animal models, and a thorough focus on them is needed. This systematic review completed a comprehensive bibliographic analysis specifically-based on the technical features of rodent models infected with Aspergillus fumigatus. Out the 800 articles reviewed, it was shown that mice remained the preferred model (85.8% of the referenced reports), above rats (10.8%), and guinea pigs (3.8%). Three quarters of the models involved immunocompromised status, mainly by steroids (44.4%) and/or alkylating drugs (42.9%), but only 27.7% were reported to receive antibiotic prophylaxis to prevent from bacterial infection. Injection of spores (30.0%) and inhalation/deposition into respiratory airways (66.9%) were the most used routes for experimental inoculation. Overall, more than 230 distinct A. fumigatus strains were used in models. Of all the published studies, 18.4% did not mention usage of any diagnostic tool, like histopathology or mycological culture, to control correct implementation of the disease and to measure outcome. In light of these findings, a consensus discussion should be engaged to establish a minimum standardization, although this may not be consistently suitable for addressing all the specific aspects of invasive aspergillosis. PMID- 28559893 TI - Upregulation of Early and Downregulation of Terminal Pathway Complement Genes in Subcutaneous Adipose Tissue and Adipocytes in Acquired Obesity. AB - Inflammation is an important mediator of obesity-related complications such as the metabolic syndrome but its causes and mechanisms are unknown. As the complement system is a key mediator of inflammation, we studied whether it is activated in acquired obesity in subcutaneous adipose tissue (AT) and isolated adipocytes. We used a special study design of genetically matched controls of lean and heavy groups, rare monozygotic twin pairs discordant for body mass index (BMI) [n = 26, within-pair difference (Delta) in body mass index, BMI >3 kg/m2] with as much as 18 kg mean Deltaweight. Additionally, 14 BMI-concordant (BMI <3 kg/m2) served as a reference group. The detailed measurements included body composition (DEXA), fat distribution (MRI), glucose, insulin, adipokines, C3a and SC5b-9 levels, and the expression of complement and insulin signaling pathway related genes in AT and adipocytes. In both AT and isolated adipocytes, the classical and alternative pathway genes were upregulated, and the terminal pathway genes downregulated in the heavier co-twins of the BMI-discordant pairs. The upregulated genes included C1q, C1s, C2, ficolin-1, factor H, receptors for C3a and C5a (C5aR1), and the iC3b receptor (CR3). While the terminal pathway components C5 and C6 were downregulated, its inhibitor clusterin was upregulated. Complement gene upregulation in AT and adipocytes correlated positively with adiposity and hyperinsulinemia and negatively with the expression of insulin signaling-related genes. Plasma C3a, but not SC5b-9, levels were elevated in the heavier co-twins. There were no differences between the co-twins in BMI concordant pairs. Obesity is associated with increased expression of the early, but not late, complement pathway components and of key receptors. The twins with acquired obesity have therefore an inflated inflammatory activity in the AT. The results suggest that complement is likely involved in orchestrating clearance of apoptotic debris and inflammation in the AT. PMID- 28559894 TI - Multifactorial Modulation of Food-Induced Anaphylaxis. AB - Prevalence of food-induced anaphylaxis increases progressively and occurs in an unpredictable manner, seriously affecting the quality of life of patients. Intrinsic factors including age, physiological, and genetic features of the patient as well as extrinsic factors such as the intake of drugs and exposure to environmental agents modulate this disorder. It has been proven that diseases, such as mastocytosis, defects in HLA, or filaggrin genes, increase the risk of severe allergic episodes. Certain allergen families such as storage proteins, lipid transfer proteins, or parvalbumins have also been linked to anaphylaxis. Environmental factors such as inhaled allergens or sensitization through the skin can exacerbate or trigger acute anaphylaxis. Moreover, the effect of dietary habits such as the early introduction of certain foods in the diet, and the advantage of the breastfeeding remain as yet unresolved. Interaction of allergens with the intestinal cell barrier together with a set of effector cells represents the primary pathways of food-induced anaphylaxis. After an antigen cross-links the IgEs on the membrane of effector cells, a complex intracellular signaling cascade is initiated, which leads cells to release preformed mediators stored in their granules that are responsible for the acute symptoms of anaphylaxis. Afterward, they can also rapidly synthesize lipid compounds such as prostaglandins or leukotrienes. Cytokines or chemokines are also released, leading to the recruitment and activation of immune cells in the inflammatory microenvironment. Multiple factors that affect food-induced anaphylaxis are discussed in this review, paying special attention to dietary habits and environmental and genetic conditions. PMID- 28559895 TI - Autophagy Plays an Important Role in Anti-inflammatory Mechanisms Stimulated by Alpha7 Nicotinic Acetylcholine Receptor. AB - Alpha7 nicotinic acetylcholine receptor (alpha7nAChR) has been reported to alleviate neuroinflammation. Here, we aimed to determine the role of autophagy in alpha7nAChR-mediated inhibition of neuroinflammation and its underlying mechanism. Experimental autoimmune encephalomyelitis (EAE) mice and lipopolysaccharide-stimulated BV2 microglia were used as in vivo and in vitro models of neuroinflammation, respectively. The severity of EAE was evaluated with neurological scoring. Autophagy-related proteins (Beclin 1, LC3-II/I, p62/SQSTM1) were detected by immunoblot. Autophagosomes were observed using transmission electron microscopy and tandem fluorescent mRFP-GFP-LC3 plasmid was applied to test autophagy flux. The mRNA levels of interleukin-6 (IL-6), IL-1beta, IL-18, and tumor necrosis factor-alpha (TNF-alpha) were detected by real-time PCR. We used 3-methyladenine (3-MA) and autophagy-related gene 5 small interfering RNA (Atg5 siRNA) to block autophagy in vivo and in vitro, respectively. Activating alpha7nAChR with PNU282987 ameliorates EAE severity and spinal inflammatory infiltration in EAE mice. PNU282987 treatment also enhanced monocyte/microglia autophagy (Beclin 1, LC3-II/I ratio, p62/SQSTM1, colocalization of CD45- or CD68 positive cells with LC3) both in spinal cord and spleen from EAE mice. The beneficial effects of PNU282987 on EAE mice were partly abolished by 3-MA, an autophagy inhibitor. In vitro, PNU282987 treatment increased autophagy and promoted autophagy flux. Blockade of autophagy by Atg5 siRNA or bafilomycin A1 attenuated the inhibitory effect of PNU282987 on IL-6, IL-1beta, IL-18, and TNF alpha mRNA. Our results demonstrate for the first time that activating alpha7nAChR enhances monocyte/microglia autophagy, which suppresses neuroinflammation and thus plays an alleviative role in EAE. PMID- 28559896 TI - Climate Influences the Content and Chemical Composition of Foliar Tannins in Green and Senesced Tissues of Quercus rubra. AB - Environmental stresses not only influence production of plant metabolites but could also modify their resorption during leaf senescence. The production resorption dynamics of polyphenolic tannins, a class of defense compound whose ecological role extends beyond tissue senescence, could amplify the influence of climate on ecosystem processes. We studied the quantity, chemical composition, and tissue-association of tannins in green and freshly-senesced leaves of Quercus rubra exposed to different temperature (Warming and No Warming) and precipitation treatments (Dry, Ambient, Wet) at the Boston-Area Climate Experiment (BACE) in Massachusetts, USA. Climate influenced not only the quantity of tannins, but also their molecular composition and cell-wall associations. Irrespective of climatic treatments, tannin composition in Q. rubra was dominated by condensed tannins (CTs, proanthocyanidins). When exposed to Dry and Ambient*Warm conditions, Q. rubra produced higher quantities of tannins that were less polymerized. In contrast, under favorable conditions (Wet), tannins were produced in lower quantities, but the CTs were more polymerized. Further, even as the overall tissue tannin content declined, the content of hydrolysable tannins (HTs) increased under Wet treatments. The molecular composition of tannins influenced their content in senesced litter. Compared to the green leaves, the content of HTs decreased in senesced leaves across treatments, whereas the CT content was similar between green and senesced leaves in Wet treatments that produced more polymerized tannins. The content of total tannins in senesced leaves was higher in Warming treatments under both dry and ambient precipitation treatments. Our results suggest that, though climate directly influenced the production of tannins in green tissues (and similar patterns were observed in the senesced tissue), the influence of climate on tannin content of senesced tissue was partly mediated by the effect on the chemical composition of tannins. These different climatic impacts on leaves over the course of a growing season may alter forest dynamics, not only in decomposition and nutrient cycling dynamics, but also in herbivory dynamics. PMID- 28559898 TI - Silencing of Soybean Raffinose Synthase Gene Reduced Raffinose Family Oligosaccharides and Increased True Metabolizable Energy of Poultry Feed. AB - Soybean [Glycine max (L.) Merr.] is the number one oil and protein crop in the United States, but the seed contains several anti-nutritional factors that are toxic to both humans and livestock. RNA interference technology has become an increasingly popular technique in gene silencing because it allows for both temporal and spatial targeting of specific genes. The objective of this research is to use RNA-mediated gene silencing to down-regulate the soybean gene raffinose synthase 2 (RS2), to reduce total raffinose content in mature seed. Raffinose is a trisaccharide that is indigestible to humans and monogastric animals, and as monogastric animals are the largest consumers of soy products, reducing raffinose would improve the nutritional quality of soybean. An RNAi construct targeting RS2 was designed, cloned, and transformed to the soybean genome via Agrobacterium mediated transformation. Resulting plants were analyzed for the presence and number of copies of the transgene by PCR and Southern blot. The efficiency of mRNA silencing was confirmed by real-time quantitative PCR. Total raffinose content was determined by HPLC analysis. Transgenic plant lines were recovered that exhibited dramatically reduced levels of raffinose in mature seed, and these lines were further analyzed for other phenotypes such as development and yield. Additionally, a precision-fed rooster assay was conducted to measure the true metabolizable energy (TME) in full-fat soybean meal made from the wild-type or transgenic low-raffinose soybean lines. Transgenic low-raffinose soy had a measured TME of 2,703 kcal/kg, an increase as compared with 2,411 kcal/kg for wild-type. As low digestible energy is a major limiting factor in the percent of soybean meal that can be used in poultry diets, these results may substantiate the use of higher concentrations of low-raffinose, full-fat soy in formulated livestock diets. PMID- 28559897 TI - The Influence of the Plant Growth Regulator Maleic Hydrazide on Egyptian Broomrape Early Developmental Stages and Its Control Efficacy in Tomato under Greenhouse and Field Conditions. AB - Broomrapes (Phelipanche spp. and Orobanche spp.) are holoparasitic plants that cause tremendous losses of agricultural crops worldwide. Broomrape control is extremely difficult and only amino acid biosynthesis-inhibiting herbicides present an acceptable control level. It is expected that broomrape resistance to these herbicides is not long in coming. Our objective was to develop a broomrape control system in tomato (Solanum lycopersicum L.) based on the plant growth regulator maleic hydrazide (MH). Petri-dish and polyethylene-bag system experiments revealed that MH has a slight inhibitory effect on Phelipanche aegyptiaca seed germination but is a potent inhibitor of the first stages of parasitism, namely attachment and the tubercle stage. MH phytotoxicity toward tomato and its P. aegyptiaca-control efficacy were tested in greenhouse experiments. MH was applied at 25, 50, 75, 150, 300, and 600 g a.i. ha-1 to tomato foliage grown in P. aegyptiaca-infested soil at 200 growing degree days (GDD) and again at 400 GDD. The treatments had no influence on tomato foliage or root dry weight. The total number of P. aegyptiaca attachments counted on the roots of the treated plants was significantly lower at 75 g a.i. ha-1 and also at higher MH rates. Phelipanche aegyptiaca biomass was close to zero at rates of 150, 300, and 600 g a.i. ha-1 MH. Field experiments were conducted to optimize the rate, timing and number of MH applications. Two application sequences gave superior results, both with five split applications applied at 100, 200, 400, 700, and 1000 GDD: (a) constant rate of 400 g a.i. ha-1; (b) first two applications at 270 g a.i. ha-1 and the next three applications at 540 g a.i. ha 1. Based on the results of this study, MH was registered for use in Israel in 2013 with the specified protocol and today, it is widely used by most Israeli tomato growers. PMID- 28559900 TI - Isoflavone Malonyltransferases GmIMaT1 and GmIMaT3 Differently Modify Isoflavone Glucosides in Soybean (Glycine max) under Various Stresses. AB - Malonylated isoflavones are the major forms of isoflavonoids in soybean plants, the genes responsible for their biosyntheses are not well understood, nor their physiological functions. Here we report a new benzylalcohol O-acetyltransferase, anthocyanin O-hydroxycinnamoyltransferase, anthranilate N hydroxycinnamoyl/benzoyltransferase, deacetylvindoline 4-O-acetyltransferase (BAHD) family isoflavone glucoside malonyltransferase GmIMaT1, and GmIMaT3, which is allelic to the previously characterized GmMT7 and GmIF7MaT. Biochemical studies showed that recombinant GmIMaT1 and GmIMaT3 enzymes used malonyl-CoA and several isoflavone 7-O-glucosides as substrates. The Km values of GmIMaT1 for glycitin, genistin, and daidzin were 13.11, 23.04, and 36.28 MUM, respectively, while these of GmIMaT3 were 12.94, 26.67, and 30.12 MUM, respectively. Transgenic hairy roots overexpressing both GmIMaTs had increased levels of malonyldaidzin and malonylgenistin, and contents of daidzin and glycitin increased only in GmIMaT1-overexpression lines. The increased daidzein and genistein contents were detected only in GmIMaT3-overexpression lines. Knockdown of GmIMaT1 and GmIMaT3 reduced malonyldaidzin and malonylgenistin contents, and affected other isoflavonoids differently. GmIMaT1 is primarily localized to the endoplasmic reticulum while GmIMaT3 is primarily in the cytosol. By examining their transcript changes corresponding to the altered isoflavone metabolic profiles under various environmental and hormonal stresses, we probed the possible functions of GmIMaTs. Two GmIMaTs displayed distinct tissue expression patterns and respond differently to various factors in modifying isoflavone 7-O-glucosides under various stresses. PMID- 28559899 TI - Atmospheric CO2 Alters Resistance of Arabidopsis to Pseudomonas syringae by Affecting Abscisic Acid Accumulation and Stomatal Responsiveness to Coronatine. AB - Atmospheric CO2 influences plant growth and stomatal aperture. Effects of high or low CO2 levels on plant disease resistance are less well understood. Here, resistance of Arabidopsis thaliana against the foliar pathogen Pseudomonas syringae pv. tomato DC3000 (Pst) was investigated at three different CO2 levels: high (800 ppm), ambient (450 ppm), and low (150 ppm). Under all conditions tested, infection by Pst resulted in stomatal closure within 1 h after inoculation. However, subsequent stomatal reopening at 4 h, triggered by the virulence factor coronatine (COR), occurred only at ambient and high CO2, but not at low CO2. Moreover, infection by Pst was reduced at low CO2 to the same extent as infection by mutant Pst cor- . Under all CO2 conditions, the ABA mutants aba2 1 and abi1-1 were as resistant to Pst as wild-type plants under low CO2, which contained less ABA. Moreover, stomatal reopening mediated by COR was dependent on ABA. Our results suggest that reduced ABA levels at low CO2 contribute to the observed enhanced resistance to Pst by deregulation of virulence responses. This implies that enhanced ABA levels at increasing CO2 levels may have a role in weakening plant defense. PMID- 28559901 TI - Estimation of Wheat Plant Density at Early Stages Using High Resolution Imagery. AB - Crop density is a key agronomical trait used to manage wheat crops and estimate yield. Visual counting of plants in the field is currently the most common method used. However, it is tedious and time consuming. The main objective of this work is to develop a machine vision based method to automate the density survey of wheat at early stages. RGB images taken with a high resolution RGB camera are classified to identify the green pixels corresponding to the plants. Crop rows are extracted and the connected components (objects) are identified. A neural network is then trained to estimate the number of plants in the objects using the object features. The method was evaluated over three experiments showing contrasted conditions with sowing densities ranging from 100 to 600 seeds?m-2. Results demonstrate that the density is accurately estimated with an average relative error of 12%. The pipeline developed here provides an efficient and accurate estimate of wheat plant density at early stages. PMID- 28559902 TI - A Spectrophotometric Assay for Robust Viability Testing of Seed Batches Using 2,3,5-Triphenyl Tetrazolium Chloride: Using Hordeum vulgare L. as a Model. AB - A comparative analysis was carried out of published methods to assess seed viability using 2,3,5-triphenyltetrazolium chloride (TTC) based assays of seed batches. The tests were carried out on seeds of barley (Hordeum vulgare cv. Optic) as a model. We established that 10% [w/v] trichloroacetic acid (TCA)/methanol is superior to the acetone and methanol-only based methods: allowing the highest recovery of formazan and the lowest background optical density (OD) readings, across seed lots comprising different ratios of viable and dead seeds. The method allowed a linear-model to accurately capture the statistically significant relationship between the quantity of formazan that could be extracted using the method we developed and the seed temperature response, and seed viability as a function of artificially aged seed lots. Other quality control steps are defined to help ensure the assay is robust and these are reported in a Standard Operating Procedure. PMID- 28559903 TI - Expression of CdDHN4, a Novel YSK2-Type Dehydrin Gene from Bermudagrass, Responses to Drought Stress through the ABA-Dependent Signal Pathway. AB - Dehydrin improves plant resistance to many abiotic stresses. In this study, the expression profiles of a dehydrin gene, CdDHN4, were estimated under various stresses and abscisic acid (ABA) treatments in two bermudagrasses (Cynodon dactylon L.): Tifway (drought-tolerant) and C299 (drought-sensitive). The expression of CdDHN4 was up-regulated by high temperatures, low temperatures, drought, salt and ABA. The sensitivity of CdDHN4 to ABA and the expression of CdDHN4 under drought conditions were higher in Tifway than in C299. A 1239-bp fragment, CdDHN4-P, the partial upstream sequence of the CdDHN4 gene, was cloned by genomic walking from Tifway. Bioinformatic analysis showed that the CdDHN4-P sequence possessed features typical of a plant promoter and contained many typical cis elements, including a transcription initiation site, a TATA-box, an ABRE, an MBS, a MYC, an LTRE, a TATC-box and a GT1-motif. Transient expression in tobacco leaves demonstrated that the promoter CdDHN4-P can be activated by ABA, drought and cold. These results indicate that CdDHN4 is regulated by an ABA dependent signal pathway and that the high sensitivity of CdDHN4 to ABA might be an important mechanism enhancing the drought tolerance of bermudagrass. PMID- 28559904 TI - Genetic Architecture of Anther Extrusion in Spring and Winter Wheat. AB - Hybrid wheat breeding is gaining prominence worldwide because it ensures higher and more static yield than conventionally bred varieties. The cleistogamous floral architecture of wheat (Triticum aestivum L.) impedes anthers inside the floret, making it largely an inbreeder. For hybrid seed production, high anther extrusion is needed to promote cross pollination and to ensure a high level of pollen availability for the seed plant. This study, therefore, aimed at the genetic dissection of anther extrusion (AE) in panels of spring (SP), and winter wheat (WP) accessions by genome wide association studies (GWAS). We performed GWAS to identify the SNP markers potentially linked with AE in each panel separately. Phenotypic data were collected for 3 years for each panel. The average levels of Pearson's correlation (r) among all years and their best linear unbiased estimates (BLUEs) within both panels were high (r(SP) = 0.75, P < 0.0001;r(WP) = 0.72, P < 0.0001). Genotypic data (with minimum of 0.05 minor allele frequency applied) included 12,066 and 12,191 SNP markers for SP and WP, respectively. Both genotypes and environment influenced the magnitude of AE. In total, 23 significant (|log10(P)| > 3.0) marker trait associations (MTAs) were detected (SP = 11; WP = 12). Anther extrusion behaved as a complex trait with significant markers having either favorable or unfavorable additive effects and imparting minor to moderate levels of phenotypic variance (R2(SP) = 9.75-14.24%; R2 (WP) = 9.44-16.98%). All mapped significant markers as well as the markers within their significant linkage disequilibrium (r2 >= 0.30) regions were blasted against wheat genome assembly (IWGSC1+popseq) to find the corresponding genes and their high confidence descriptions were retrieved. These genes and their orthologs in Hordeum vulgare, Brachypodium distachyon, Oryza sativa, and Sorghum bicolor revealed syntenic genomic regions potentially involved in flowering related traits. Moreover, the expression data of these genes suggested potential candidates for AE. Our results suggest that the use of significant markers can help to introduce AE in high yielding varieties to increase cross fertilization rates and improve hybrid-seed production in wheat. PMID- 28559905 TI - Validation of Suitable Reference Genes for RT-qPCR Data in Achyranthes bidentata Blume under Different Experimental Conditions. AB - Real-time quantitative polymerase chain reaction (RT-qPCR) is a sensitive technique for gene expression studies. However, choosing the appropriate reference gene is essential to obtain reliable results for RT-qPCR assays. In the present work, the expression of eight candidate reference genes, EF1-alpha (elongation factor 1-alpha), GAPDH (glyceraldehyde 3-phosphate dehydrogenase), UBC (ubiquitin-conjugating enzyme), UBQ (polyubiquitin), ACT (actin), beta-TUB (beta-tubulin), APT1 (adenine phosphoribosyltransferase 1), and 18S rRNA (18S ribosomal RNA), was evaluated in Achyranthes bidentata samples using two algorithms, geNorm and NormFinder. The samples were classified into groups according to developmental stages, various tissues, stresses (cold, heat, drought, NaCl), and hormone treatments (MeJA, IBA, SA). Suitable combination of reference genes for RT-qPCR normalization should be applied according to different experimental conditions. In this study, EF1-alpha, UBC, and ACT genes were verified as the suitable reference genes across all tested samples. To validate the suitability of the reference genes, we evaluated the relative expression of CAS, which is a gene that may be involved in phytosterol synthesis. Our results provide the foundation for gene expression analysis in A. bidentata and other species of Amaranthaceae. PMID- 28559907 TI - SHB1/HY1 Alleviates Excess Boron Stress by Increasing BOR4 Expression Level and Maintaining Boron Homeostasis in Arabidopsis Roots. AB - Boron is an essential mineral nutrient for higher plant growth and development. However, excessive amounts of boron can be toxic. Here, we report on the characterization of an Arabidopsis mutant, shb1 (sensitive to high-level of boron 1), which exhibits hypersensitivity to excessive boron in roots. Positional cloning demonstrated that the shb1 mutant bears a point mutation in a gene encoding a heme oxygenase 1 (HO1) corresponding to the HY1 gene involved in photomorphogenesis. The transcription level of the SHB1/HY1 gene in roots is up regulated under excessive boron stimulation. Either overexpressing SHB1/HY1 or applying the HO1 inducer hematin reduces boron accumulation in roots and confers high boron tolerance. Furthermore, carbon monoxide and bilirubin, catalytic products of HO1, partially rescue the boron toxicity-induced inhibition of primary root growth in shb1. Additionally, the mRNA level of BOR4, a boron efflux transporter, is reduced in shb1 roots with high levels of boron supplementation, and hematin cannot relieve the boron toxicity-induced root inhibition in bor4 mutants. Taken together, our study reveals that HO1 acts via its catalytic by products to promote tolerance of excessive boron by up-regulating the transcription of the BOR4 gene and therefore promoting the exclusion of excessive boron in root cells. PMID- 28559906 TI - Drawing Links from Transcriptome to Metabolites: The Evolution of Aroma in the Ripening Berry of Moscato Bianco (Vitis vinifera L.). AB - Monoterpenes confer typical floral notes to "Muscat" grapevine varieties and, to a lesser extent, to other aromatic non-Muscat varieties. Previous studies have led to the identification and functional characterization of some enzymes and genes in this pathway. However, the underlying genetic map is still far from being complete. For example, the specific steps of monoterpene metabolism and its regulation are largely unknown. With the aim of identifying new candidates for the missing links, we applied an integrative functional genomics approach based on the targeted metabolic and genome-wide transcript profiling of Moscato Bianco ripening berries. In particular, gas chromatography-mass spectrometry analysis of free and bound terpenoid compounds was combined with microarray analysis in the skins of berries collected at five developmental stages from pre-veraison to over ripening. Differentially expressed metabolites and probes were identified in the pairwise comparison between time points by using the early stage as a reference. Metabolic and transcriptomic data were integrated through pairwise correlation and clustering approaches to discover genes linked with particular metabolites or groups of metabolites. These candidate transcripts were further checked for co localization with quantitative trait loci (QTLs) affecting aromatic compounds. Our findings provide insights into the biological networks of grapevine secondary metabolism, both at the catalytic and regulatory levels. Examples include a nudix hydrolase as component of a terpene synthase-independent pathway for monoterpene biosynthesis, genes potentially involved in monoterpene metabolism (cytochrome P450 hydroxylases, epoxide hydrolases, glucosyltransferases), transport (vesicle associated proteins, ABCG transporters, glutathione S-transferases, amino acid permeases), and transcriptional control (transcription factors of the ERF, MYB and NAC families, intermediates in light- and circadian cycle-mediated regulation with supporting evidence from the literature and additional regulatory genes with a previously unreported association to monoterpene accumulation). PMID- 28559909 TI - Differential Responses of Polyamines and Antioxidants to Drought in a Centipedegrass Mutant in Comparison to Its Wild Type Plants. AB - Centipedegrass (Eremochloa ophiuroides [Munro] Hack.) is an important warm-season turfgrass species with low turf maintenance requirements. However, our knowledge on physiological adaptation of centipedegrass to drought stress is limited. Physiological responses to drought in a gamma-ray-induced mutant 22-1 as compared with two wild type (WT) lines were analyzed for understanding of drought tolerance mechanism of centipedegrass. The mutant showed an elevated drought tolerance with higher levels of relative water content, net photosynthetic rate (A) and stomatal conductance (gs) and lower levels of ion leakage and malondialdehyde (MDA) under drought stress as compared with WT plants. A showed significant correlation with gs and MDA. Higher levels of antioxidant enzymes activities, non-enzyme antioxidants, and polyamines including putrescine (Put), spermidine (Spd), and spermine (Spm) were maintained in 22-1 than in WT plants. Superoxide dismutase (SOD), catalase (CAT), ascorbate-peroxidase (APX), and glutathione reductase (GR) activities and ascorbic acid (AsA) content were significantly correlated with both Put and Spd levels, and reduced glutathione level was correlated with Put during drought stress. Exogenous application of Put, Spd, and Spm increased drought tolerance and activities of SOD, CAT, APX, and GR in WT plants. The results suggest that higher levels of polyamines and antioxidant defense system are associated with the elevated drought tolerance in 22-1, which may improve protection on photosynthesis against drought induced oxidative damage. PMID- 28559908 TI - Association of Candidate Genes With Submergence Response in Perennial Ryegrass. AB - Perennial ryegrass is a popular cool-season grass species due to its high quality for forage and turf. The objective of this study was to identify associations of candidate genes with growth and physiological traits to submergence stress and recovery after de-submergence in a global collection of 94 perennial ryegrass accessions. Accessions varied largely in leaf color, plant height (HT), leaf fresh weight (LFW), leaf dry weight (LDW), and chlorophyll fluorescence (Fv/Fm) at 7 days of submergence and in HT, LFW and LDW at 7 days of recovery in two experiments. Among 26 candidate genes tested by various models, single nucleotide polymorphisms (SNPs) in 10 genes showed significant associations with traits including 16 associations for control, 10 for submergence, and 8 for recovery. Under submergence, Lp1-SST encoding sucrose:sucrose 1-fructosyltransferase and LpGA20ox encoding gibberellin 20-oxidase were associated with LFW and LDW, and LpACO1 encoding 1-aminocyclopropane-1-carboxylic acid oxidase was associated with LFW. Associations between Lp1-SST and HT, Lp6G-FFT encoding fructan:fructan 6G fructosyltransferase and Fv/Fm, LpCAT encoding catalase and HT were also detected under submergence stress. Upon de-submergence, Lp1-SST, Lp6G-FFT, and LpPIP1 encoding plasma membrane intrinsic protein type 1 were associated with LFW or LDW, while LpCBF1b encoding C-repeat binding factor were associated with HT. Nine significant SNPs in Lp1-SST, Lp6G-FFT, LpCAT, and LpACO1 resulted in amino acid changes with five substitutions found in Lp1-SST under submergence or recovery. The results indicated that allelic diversity in genes involved in carbohydrate and antioxidant metabolism, ethylene and gibberellin biosynthesis, and transcript factor could contribute to growth variations in perennial ryegrass under submergence stress and recovery after de-submergence. PMID- 28559910 TI - QTL Mapping of Adult-Plant Resistance to Leaf Rust in the Wheat Cross Zhou 8425B/Chinese Spring Using High-Density SNP Markers. AB - Wheat leaf rust is an important disease worldwide. Growing resistant cultivars is an effective means to control the disease. In the present study, 244 recombinant inbred lines from Zhou 8425B/Chinese Spring cross were phenotyped for leaf rust severities during the 2011-2012, 2012-2013, 2013-2014, and 2014-2015 cropping seasons at Baoding, Hebei province, and 2012-2013 and 2013-2014 cropping seasons in Zhoukou, Henan province. The population was genotyped using the high-density Illumina iSelect 90K SNP assay and SSR markers. Inclusive composite interval mapping identified eight QTL, designated as QLr.hebau-2AL, QLr.hebau-2BS, QLr.hebau-3A, QLr.hebau-3BS, QLr.hebau-4AL, QLr.hebau-4B, QLr.hebau-5BL, and QLr.hebau-7DS, respectively. QLr.hebau-2BS, QLr.hebau-3A, QLr.hebau-3BS, and QLr.hebau-5BL were derived from Zhou 8425B, whereas the other four were from Chinese Spring. Three stable QTL on chromosomes 2BS, 4B and 7DS explained 7.5 10.6%, 5.5-24.4%, and 11.2-20.9% of the phenotypic variance, respectively. QLr.hebau-2BS in Zhou 8425B might be the same as LrZH22 in Zhoumai 22; QLr.hebau 4B might be the residual resistance of Lr12, and QLr.hebau-7DS is Lr34. QLr.hebau 2AL, QLr.hebau-3BS, QLr.hebau-4AL, and QLr.hebau-5BL are likely to be novel QTL for leaf rust. These QTL and their closely linked SNP and SSR markers can be used for fine mapping, candidate gene discovery, and marker-assisted selection in wheat breeding. PMID- 28559911 TI - Comparative Analysis of Transcriptomes in Rhizophoraceae Provides Insights into the Origin and Adaptive Evolution of Mangrove Plants in Intertidal Environments. AB - Mangroves are woody plants that grow at the interface between land and sea in tropical and subtropical latitudes, where they exist in conditions of high salinity, extreme tides, strong winds, high temperatures, and muddy, anaerobic soils. Rhizophoraceae is a key mangrove family, with highly developed morphological and physiological adaptations to extreme conditions. It is an ideal system for the study of the origin and adaptive evolution of mangrove plants. In this study, we characterized and comprehensively compared the transcriptomes of four mangrove species, from all four mangrove genera, as well as their closest terrestrial relative in Rhizophoraceae, using RNA-Seq. We obtained 41,936-48,845 unigenes with N50 values of 982-1,185 bp and 61.42-69.48% annotated for the five species in Rhizophoraceae. Orthology annotations of Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Clusters of Orthologous Groups revealed overall similarities in the transcriptome profiles among the five species, whereas enrichment analysis identified remarkable genomic characteristics that are conserved across the four mangrove species but differ from their terrestrial relative. Based on 1,816 identified orthologs, phylogeny analysis and divergence time estimation revealed a single origin for mangrove species in Rhizophoraceae, which diverged from the terrestrial lineage ~56.4 million years ago (Mya), suggesting that the transgression during the Paleocene-Eocene Thermal Maximum may have been responsible for the entry of the mangrove lineage of Rhizophoraceae into intertidal environments. Evidence showed that the ancestor of Rhizophoraceae may have experienced a whole genome duplication event ~74.6 Mya, which may have increased the adaptability and survival chances of Rhizophoraceae during and following the Cretaceous-Tertiary extinction. The analysis of positive selection identified 10 positively selected genes from the ancestor branch of Rhizophoraceae mangroves, which were mainly associated with stress response, embryo development, and regulation of gene expression. Positive selection of these genes may be crucial for increasing the capability of stress tolerance (i.e., defense against salt and oxidative stress) and development of adaptive traits (i.e., vivipary) of Rhizophoraceae mangroves, and thus plays an important role in their adaptation to the stressful intertidal environments. PMID- 28559912 TI - Development of SSR Markers Based on Transcriptome Sequencing and Association Analysis with Drought Tolerance in Perennial Grass Miscanthus from China. AB - Drought has become a critical environmental stress affecting on plant in temperate area. As one of the promising bio-energy crops to sustainable biomass production, the genus Miscanthus has been widely studied around the world. However, the most widely used hybrid cultivar among this genus, Miscanthus * giganteus is proved poor drought tolerance compared to some parental species. Here we mainly focused on Miscanthus sinensis, which is one of the progenitors of M. * giganteus providing a comparable yield and well abiotic stress tolerance in some places. The main objectives were to characterize the physiological and photosynthetic respond to drought stress and to develop simple sequence repeats (SSRs) markers associated with drought tolerance by transcriptome sequencing within an originally collection of 44 Miscanthus genotypes from southwest China. Significant phenotypic differences were observed among genotypes, and the average of leaf relative water content (RWC) were severely affected by drought stress decreasing from 88.27 to 43.21%, which could well contribute to separating the drought resistant and drought sensitive genotype of Miscanthus. Furthermore, a total of 16,566 gene-associated SSRs markers were identified based on Illumina RNA sequencing under drought conditions, and 93 of them were randomly selected to validate. In total, 70 (75.3%) SSRs were successfully amplified and the generated loci from 30 polymorphic SSRs were used to estimate the genetic differentiation and population structure. Finally, two optimum subgroups of the population were determined by structure analysis and based on association analysis, seven significant associations were identified including two markers with leaf RWC and five markers with photosynthetic traits. With the rich sequencing resources annotation, such associations would serve an efficient tool for Miscanthus drought response mechanism study and facilitate genetic improvement of drought resistant for this species. PMID- 28559913 TI - Facilitation by a Spiny Shrub on a Rhizomatous Clonal Herbaceous in Thicketization-Grassland in Northern China: Increased Soil Resources or Shelter from Herbivores. AB - The formation of fertility islands by shrubs increases soil resources heterogeneity in thicketization-grasslands. Clonal plants, especially rhizomatous or stoloniferous clonal plants, can form large clonal networks and use heterogeneously distributed resources effectively. In addition, shrubs, especially spiny shrubs, may also provide herbaceous plants with protection from herbivores, acting as 'shelters'. The interaction between pre-dominated clonal herbaceous plants and encroaching shrubs remains unclear in thicketization grassland under grazing pressure. We hypothesized that clonal herbaceous plants can be facilitated by encroached shrubs as a 'shelter from herbivores' and/or as an 'increased soil resources' under grazing pressure. To test this hypothesis, a total of 60 quadrats were chosen in a thicket-grassland in northern China that was previously dominated by Leymus chinensis and was encroached upon by the spiny leguminous plant Caragana intermedia. The soil and plant traits beneath and outside the shrub canopies were sampled, investigated and contrasted with an enclosure. The soil organic matter, soil total nitrogen and soil water content were significantly higher in the soil beneath the shrub canopies than in the soil outside the canopies. L. chinensis beneath the shrub canopies had significantly higher plant height, single shoot biomass, leaf length and width than outside the shrub canopies. There were no significantly differences between plant growth in enclosure and outside the shrub canopies. These results suggested that under grazing pressure in a grassland undergoing thicketization, the growth of the rhizomatous clonal herbaceous plant L. chinensis was facilitated by the spiny shrub C. intermedia as a 'shelter from herbivores' more than through 'increased soil resources'. We propose that future studies should focus on the community- and ecosystem-level impacts of plant clonality. PMID- 28559914 TI - Changes in Cerebral Oxygenation Associated with Intradialytic Blood Transfusion in Patients with Severe Anemia Undergoing Hemodialysis. AB - BACKGROUND: Hemodialysis (HD) patients frequently suffer from severe anemia caused by various hemorrhagic disorders in addition to renal anemia. Intradialytic blood transfusion is sometimes performed; however, the cerebral oxygenation changes associated with this procedure remain unclear. METHODS: Sixteen HD patients with severe anemia who required intradialytic blood transfusion were included (12 men and 4 women; mean age, 64.8 +/- 9.8 years). Cerebral regional oxygen saturation (rSO2) was monitored using near-infrared spectroscopy, and cerebral fractional oxygen extraction (FOE) was calculated before and after HD. Twenty-five HD patients with well-maintained hemoglobin (Hb) levels were included as a control group. RESULTS: Cerebral rSO2 values were significantly lower in HD patients with severe anemia than in the control group (42.4 +/- 9.9 vs. 52.5 +/- 8.5%, p = 0.001). Following intradialytic blood transfusion (385 +/- 140 mL of concentrated red blood cells), Hb levels significantly increased (from 7.2 +/- 0.9 to 9.1 +/- 1.1 g/dL, p < 0.001), and cerebral rSO2 values significantly improved after HD (from 42.4 +/- 9.9 to 46.3 +/- 9.0%, p < 0.001). Cerebral FOE values before HD in patients with severe anemia were significantly higher than those in the control group (severe anemia, 0.56 +/- 0.10; controls, 0.45 +/- 0.08; p < 0.001). After HD with intradialytic blood transfusion, these values significantly decreased (0.52 +/- 0.09 after HD versus 0.56 +/- 0.10 before HD, p = 0.002). CONCLUSION: HD patients with severe anemia represented cerebral oxygen metabolism deterioration, which could be significantly improved by intradialytic blood transfusion. PMID- 28559915 TI - Combining Results from Distinct MicroRNA Target Prediction Tools Enhances the Performance of Analyses. AB - Target prediction is generally the first step toward recognition of bona fide microRNA (miRNA)-target interactions in living cells. Several target prediction tools are now available, which use distinct criteria and stringency to provide the best set of candidate targets for a single miRNA or a subset of miRNAs. However, there are many false-negative predictions, and consensus about the optimum strategy to select and use the output information provided by the target prediction tools is lacking. We compared the performance of four tools cited in literature-TargetScan (TS), miRanda-mirSVR (MR), Pita, and RNA22 (R22), and we determined the most effective approach for analyzing target prediction data (individual, union, or intersection). For this purpose, we calculated the sensitivity, specificity, precision, and correlation of these approaches using 10 miRNAs (miR-1-3p, miR-17-5p, miR-21-5p, miR-24-3p, miR-29a-3p, miR-34a-5p, miR 124-3p, miR-125b-5p, miR-145-5p, and miR-155-5p) and 1,400 genes (700 validated and 700 non-validated) as targets of these miRNAs. The four tools provided a subset of high-quality predictions and returned few false-positive predictions; however, they could not identify several known true targets. We demonstrate that union of TS/MR and TS/MR/R22 enhanced the quality of in silico prediction analysis of miRNA targets. We conclude that the union rather than the intersection of the aforementioned tools is the best strategy for maximizing performance while minimizing the loss of time and resources in subsequent in vivo and in vitro experiments for functional validation of miRNA-target interactions. PMID- 28559917 TI - Development of the nervous system in Platynereis dumerilii (Nereididae, Annelida). AB - BACKGROUND: The structure and development of the nervous system in Lophotrochozoa has long been recognized as one of the most important subjects for phylogenetic and evolutionary discussion. Many recent papers have presented comprehensive data on the structure and development of catecholaminergic, serotonergic and FMRFamidergic parts of the nervous system. However, relatively few papers contain detailed descriptions of the nervous system in Annelida, one of the largest taxa of Lophotrochozoa. The polychaete species Platynereis dumerilii has recently become one of the more popular model animals in evolutionary and developmental biology. The goal of the present study was to provide a detailed description of its neuronal development. The data obtained will contribute to a better understanding of the basic features of neuronal development in polychaetes. RESULTS: We have studied the development of the nervous system in P. dumerilii utilizing histo- and immunochemical labelling of catecholamines, serotonin, FMRFamide related peptides, and acetylated tubulin. The first neuron differentiates at the posterior extremity of the protrochophore, reacts to the antibodies against both serotonin and FMRFamide. Then its fibres run forwards along the ventral side. Soon, more neurons appear at the apical extreme, and their basal neurites form the basel structure of the developing brain (cerebral neuropil and circumesophageal connectives). Initial development of the nervous system starts in two rudiments: anterior and posterior. At the nectochaete stage, segmental ganglia start to differentiate in the anterior-to-posterior direction, and the first structures of the stomatogastric and peripheral nervous system appear. All connectives including the unpaired ventral cord develop from initially paired nerves. CONCLUSIONS: We present a detailed description of Platynereis dumerilii neuronal development based on anti-acetylated tubulin, serotonin, and FMRFamide-like immunostaining as well as catecholamine histofluorescence. The development of the nervous system starts from peripheral pioneer neurons at both the posterior and anterior poles of the larva, and their neurites form a scaffold upon which the adult central nervous system develops. The anterior-to-posterior mode of the ventral ganglia development challenges the primary heteronomy concept. Comparison with the development of Mollusca reveals substantial similarities with early neuronal development in larval Solenogastres. PMID- 28559918 TI - Geographical and temporal variation in environmental conditions affects nestling growth but not immune function in a year-round breeding equatorial lark. AB - BACKGROUND: Variation in growth and immune function within and among populations is often associated with specific environmental conditions. We compared growth and immune function in nestlings of year-round breeding equatorial Red-capped Lark Calandrella cinerea from South Kinangop, North Kinangop and Kedong (Kenya), three locations that are geographically close but climatically distinct. In addition, we studied growth and immune function of lark nestlings as a function of year-round variation in breeding intensity and rain within one location. We monitored mass, wing, and tarsus at hatching (day 1) and at 4, 7, and 10 days post-hatch, and we quantified four indices of immune function (haptoglobin, agglutination, lysis and nitric oxide) using blood samples collected on day 10. RESULTS: Nestling body mass and size at hatching, which presumably reflect the resources that females allocated to their eggs, were lowest in the most arid location, Kedong. Contrary to our predictions, nestlings in Kedong grew faster than nestlings in the two other cooler and wetter locations of South and North Kinangop. During periods of peak reproduction within Kedong, nestlings were heavier at hatching, but they did not grow faster over the first 10 days post hatch. In contrast, rainfall, which did not relate to timing of breeding, had no effect on hatching mass, but more rain did coincide with faster growth post hatch. Finally, we found no significant differences in nestling immune function, neither among locations nor with the year-round variation within Kedong. CONCLUSION: Based on these results, we hypothesize that female body condition determines nestling mass and size at hatching, but other independent environmental conditions subsequently shape nestling growth. Overall, our results suggest that environmental conditions related to food availability for nestlings are relatively unimportant to the timing of breeding in equatorial regions, while these same conditions do have consequences for nestling size and growth. PMID- 28559916 TI - Maternal sensitivity and social support protect against childhood atopic dermatitis. AB - BACKGROUND: Many studies have identified associations between qualities of maternal-child relationships and childhood asthma, but few have examined associations with childhood atopic dermatitis (AD), a common precursor to asthma. Moreover, maternal psychological distress, including prenatal and postnatal depression, anxiety and stress, may increase risk, while social support from partners may reduce risk for childhood AD. We sought to uncover the association between maternal-infant relationship qualities (maternal sensitivity towards infant behavioral signals, controlling behavior, and unresponsiveness) and child AD after accounting for risk (i.e., prenatal and postnatal maternal depression, anxiety and stress) and protective (i.e., social support) factors. METHODS: We conducted a secondary analysis of data collected on a subsample of 242 women and their infants enrolled during pregnancy in the ongoing Alberta Pregnancy Outcomes and Nutrition cohort study. Inclusion criteria required mothers to be >16 years of age, English speaking and <22 weeks gestational age at enrollment. Data on depression, anxiety and stress in the prenatal and postnatal periods and physician diagnosis of childhood AD at 18 months were gathered via maternal report. Maternal sensitivity, unresponsiveness and controlling behaviours were assessed via videotaped observations using the Child-Adult Relationship Experimental (CARE)-Index at 6 months of infant age. RESULTS: Higher maternal sensitivity, or the inability of the mother to appropriately understand and respond to infant needs based on behavioral signals, predicted reduced odds of AD independent of and in combination with low prenatal and postnatal anxiety and high paternal support. After adjustment, higher maternal controlling behaviours and unresponsiveness also predicted greater odds of AD. CONCLUSIONS: Low maternal sensitivity is a risk factor for childhood AD, independently and in combination with perinatal anxiety and low social support. Thus, interventions that improve maternal-infant relationship quality, especially sensitivity, reduce anxiety and improve social support from partners could reduce odds of childhood AD. PMID- 28559919 TI - Prevalence of latent tuberculosis infection among foreign students in Lubeck, Germany tested with QuantiFERON-TB Gold In-Tube and QuantiFERON-TB Gold Plus. AB - BACKGROUND: The tuberculosis (TB) incidence rate in foreign-born individuals has been increasing in Germany in recent years. Foreign students may be an important source of latent tuberculosis infection (LTBI) in low-incidence countries. In Germany, there are no guidelines for LTBI screening of foreign students. The aim of the study was to estimate LTBI prevalence and evaluate associated risk factors among foreign students in Germany. The second purpose of our study was to compare the results of the new generation of QuantiFERON-TB Gold Plus (QFT-Plus) to those of its predecessor QuantiFERON-TB Gold In-Tube (QFT-GIT). METHODS: This cross sectional study was conducted between February 2016 and March 2016. Foreign students and young professionals attending the university and higher education institutes in Lubeck, Germany were tested with QFT-Plus and QFT-GIT. Participants filled out a questionnaire for the purpose of LTBI risk assessment and analysis. Variables associated with a positive test result were analyzed using logistic regression. RESULTS: One hundred thirty four students participated in the study. The overall prevalence as regards positive results from both tests, QFT-Plus and QFT-GIT, was 9.7%, and the prevalence of positive QFT-Plus results was 8.2%. The main independent variables associated with a positive QFT-Plus result were a) being born in a high-incidence country (OR = 6.7, 95% CI: 1.3-34.3) and b) previous contact with a person with active TB (OR = 4.5, 95% CI: 1.1-18.3). Higher age (OR = 2.8, 95% CI: 0.7-11.3) and male gender (OR = 1.6, 95% CI: 0.4 6.7) showed a tendency toward positive QFT-Plus results but this was not statistically significant. Agreement between QFT-Plus and QFT-GIT results was kappa = 0.85, p < 0.001. CONCLUSIONS: The LTBI prevalence among foreign students was about 10%. We recommend implementing a policy whereby all foreign students are screened by means of a questionnaire about LTBI risk factors, so that only students with present risk factors are tested for LTBI. The agreement between the new QFT-Plus and the QFT-GIT (kappa = 0.85) was good. QFT-Plus might be used in the same format as its predecessor. PMID- 28559920 TI - Assessment of long-term cultivated human precision-cut lung slices as an ex vivo system for evaluation of chronic cytotoxicity and functionality. AB - BACKGROUND: Investigation of basic chronic inflammatory mechanisms and development of new therapeutics targeting the respiratory tract requires appropriate testing systems, including those to monitor long- persistence. Human precision-cut lung slices (PCLS) have been demonstrated to mimic the human respiratory tract and have potential of an alternative, ex-vivo system to replace or augment in-vitro testing and animal models. So far, most research on PCLS has been conducted for short cultivation periods (<=72 h), while analyses of slowly metabolized therapeutics require long-term survival of PCLS in culture. In the present study, we evaluated viability, physiology and structural integrity of PCLS cultured for up to 15 days. METHODS: PCLS were cultured for 15 days and various parameters were assessed at different time points. RESULTS: Structural integrity and viability of cultured PCLS remained constant for 15 days. Moreover, bronchoconstriction was inducible over the whole period of cultivation, though with decreased sensitivity (EC501d = 4 * 10-8 M vs. EC5015d = 4 * 10-6 M) and reduced maximum of initial airway area (1d = 0.5% vs. 15d = 18.7%). In contrast, even though still clearly inducible compared to medium control, LPS-induced TNF alpha secretion decreased significantly from day 1 to day 15 of culture. CONCLUSIONS: Overall, though long-term cultivation of PCLS need further investigation for cytokine secretion, possibly on a cellular level, PCLS are feasible for bronchoconstriction studies and toxicity assays. PMID- 28559921 TI - The gene family-free median of three. AB - BACKGROUND: The gene family-free framework for comparative genomics aims at providing methods for gene order analysis that do not require prior gene family assignment, but work directly on a sequence similarity graph. We study two problems related to the breakpoint median of three genomes, which asks for the construction of a fourth genome that minimizes the sum of breakpoint distances to the input genomes. METHODS: We present a model for constructing a median of three genomes in this family-free setting, based on maximizing an objective function that generalizes the classical breakpoint distance by integrating sequence similarity in the score of a gene adjacency. We study its computational complexity and we describe an integer linear program (ILP) for its exact solution. We further discuss a related problem called family-free adjacencies for k genomes for the special case of [Formula: see text] and present an ILP for its solution. However, for this problem, the computation of exact solutions remains intractable for sufficiently large instances. We then proceed to describe a heuristic method, FFAdj-AM, which performs well in practice. RESULTS: The developed methods compute accurate positional orthologs for genomes comparable in size of bacterial genomes on simulated data and genomic data acquired from the OMA orthology database. In particular, FFAdj-AM performs equally or better when compared to the well-established gene family prediction tool MultiMSOAR. CONCLUSIONS: We study the computational complexity of a new family-free model and present algorithms for its solution. With FFAdj-AM, we propose an appealing alternative to established tools for identifying higher confidence positional orthologs. PMID- 28559922 TI - Association of hepatitis status with surgical outcomes in patients with dual hepatitis B and C related hepatocellular carcinoma. AB - BACKGROUND: The conception that serological hepatitis markers determined surgical prognosis of hepatocellular carcinoma (HCC) associated with hepatitis B (HBV) or hepatitis C (HCV) has been well defined. However, little is known about the relationship between surgical outcomes and serological hepatitis markers in patients with dual HBV and HCV related HCC. METHODS: A retrospective analysis of the clinical data of 39 HCC patients with HBV-HCV coinfection who underwent curative hepatectomy between 2001 and 2011 was performed. HBV DNA quantification, expression of HBV antigens, anti-HCV signal-to-cutoff ratio (S/CO) and some clinicopathological characteristics were investigated to show the potential relationship among them and the surgical prognosis. RESULTS: The Cox proportional hazards model identified that HBV DNA quantification of 1,000 IU/mL or higher, HBeAg seropositivity, tumor size of greater than 5 cm, multiple tumors, and vascular invasion were risk factors for HCC prognosis. Thus, HBV DNA quantification, HBsAg level, HBeAg status and HCV-Ab level which may reveal the hepatitis status were further analyzed. The overall survival time in the group with high (>=1,000 IU/mL) HBV DNA quantification was significantly lower than the group with low (<1,000 IU/mL) HBV DNA quantification. Similarly, the high HBsAg level (>=1,000 IU/mL) was associated with poor survival compared with the low HBsAg level. Moreover, HBeAg seropositivity determined a higher cumulative risk for death. However, no significant difference was observed in overall survival time between the groups with low (<10.9 S/CO) and high (>=10.9 S/CO) HCV-Ab level. Compared to HCV-Ab high-level group, the serological HBsAg level was observed significantly higher in HCV-Ab low-level group. Furthermore, the data we analyzed showed these 4 serological hepatitis markers were not correlated with cumulative recurrence rate. On multivariate analysis, none of serological hepatitis markers was an independent prognostic factor for HCC patients with dual hepatitis B and C. CONCLUSION: Among HCC patients with HBV-HCV coinfection, those who with preoperatively high HBV DNA quantification or HBeAg seropositivity had a short survival time and served as poor survival indicators. Serological expression of HBV status rather than HCV status might potentially dominate the surgical outcomes of the Chinese HCC patients with HBV-HCV coinfection. PMID- 28559924 TI - Acceptance and commitment therapy universal prevention program for adolescents: a feasibility study. AB - BACKGROUND: There is a need to prevent anxiety and depression in young people and mindfulness contains important emotion regulation strategies. Acceptance and commitment therapy (ACT), a mindfulness-based therapy, has yet to be evaluated as a prevention program, but has demonstrated an ability to reduce symptoms of anxiety and depression in adult and adolescent populations. This study examines the feasibility of using an ACT-based prevention program in a sample of year 10 (aged 14-16 years) high school students from Sydney, Australia. METHODS: Participants were allocated to either their usual classes or to the ACT-based intervention. Participants were followed for a period of 5 months post intervention and completed the Flourishing Scale, Depression Anxiety Stress Scale, and a program evaluation questionnaire. Analyses were completed using intention-to-treat mixed models for repeated measures. RESULTS: The results indicated that the intervention was acceptable to students and feasible to administer in a school setting. There were no statistically significant differences between the conditions, likely due to the small sample size (N = 48). However, between-group effect sizes demonstrated small to large differences for baseline to post-intervention mean scores and medium to large differences for baseline to follow-up mean scores, all favouring the ACT-based condition. CONCLUSION: The results suggest that an ACT-based school program has potential as a universal prevention program and merits further investigation in a larger trial. Trial registration Australian New Zealand Clinical Trials Registry. Trial ID: ACTRN12616001383459. Registered 06/10/2016. Retrospectively registered. PMID- 28559923 TI - Prevalence and risk factors associated with sexually transmitted infections (STIs) among women of reproductive age in Swaziland. AB - BACKGROUND: Sexually transmitted infections (STIs) remain an important public health problem with approximately half a billion new cases annually among persons aged 15-49 years. Epidemiological data on STIs among women of reproductive age in Swaziland are limited. The availability of epidemiological data on STIs and associated risk factors in this population is essential for the development of successful prevention, diagnosis and management strategies in the country. The study aimed to determine the prevalence and risk factors associated with STIs. METHODS: A total of 655 women aged 15-49 years were systematically enrolled from five health facilities using a cross-sectional study design. Cervical specimen were tested using GeneXpert CT/NG Assays for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG), GeneXpertTV Assay for Trichomonas vaginalis (TV), and GeneXpert HPV Assays for hr-HPV. Blood samples were tested using Alere Determine HIV-1/2Ag/Ab Combo and Trinity Biotech Uni-Gold Recombigen HIV test for confirmation for HIV, and Rapid Plasma Reagin and TPHA test for confirmation for Treponema pallidum (syphilis). Genital warts were assessed prior to specimen collection. Survey weighted analyses were done to estimate the population burden of STIs. RESULTS: The four most common curable STIs: CT, NG, TV, Treponema pallidum (syphilis), as well as genital warts were considered in this study. The overall weighted prevalence of any of these five STIs was 19.4% (95% CI: 14.9 24.8), corresponding to 72 990 women with STIs in Swaziland. The estimated prevalences were 7.0% (95% CI: 4.1-11.2) for CT, 6.0% (95% CI: 3.8-8.8) for NG, 8.4% (95% CI: 5.4-12.8) for TV, 1.4% (95% CI: 1.1-10.2) for syphilis and 2.0% (95% CI: 1.0-11.4) for genital warts. The overall weighted HIV prevalence was 42.7% (95%CI: 35.7-46.2). Among hr-HPV positive women, 18.8% (95% CI: 13.1-26.3) had one STI, while 6.3% (95% CI: 3.3-11.7) had multiple STIs. Risk factors associated with STIs were being employed (OR = 2.2, 95% CI: 1.0-4.7), self employed (OR = 2.8, 95% CI: 1.5-5.5) and being hr-HPV positive (OR = 2.0, 95% CI: 1.3-3.1). Age (0.9, 95% CI: 0.8-0.9), being married (OR = 0.4, 95% CI: 0.3-0.7) and not using condoms with regular partners (OR = 0.5, 95% CI: 0.3-0.9) were inversely associated with STIs. CONCLUSION: STIs are highly prevalent among women of reproductive age in Swaziland. Thus, a comprehensive STIs screening, surveillance and treatment programme would be justified and could potentially lower the burden of STIs in the country. PMID- 28559926 TI - Genome-wide characterization of cellulases from the hemi-biotrophic plant pathogen, Bipolaris sorokiniana, reveals the presence of a highly stable GH7 endoglucanase. AB - BACKGROUND: Bipolaris sorokiniana is a filamentous fungus that causes spot blotch disease in cereals like wheat and has severe economic consequences. However, information on the identities and role of the cell wall-degrading enzymes (CWDE) in B. sorokiniana is very limited. Several fungi produce CWDE like glycosyl hydrolases (GHs) that help in host cell invasion. To understand the role of these CWDE in B. sorokiniana, the first step is to identify and annotate all possible genes of the GH families like GH3, GH6, GH7, GH45 and AA9 and then characterize them biochemically. RESULTS: We confirmed and annotated the homologs of GH3, GH6, GH7, GH45 and AA9 enzymes in the B. sorokiniana genome using the sequence and domain features of these families. Quantitative real-time PCR analyses of these homologs revealed that the transcripts of the BsGH7-3 (3rd homolog of the GH 7 family in B. sorokiniana) were most abundant. BsGH7-3, the gene of BsGH7-3, was thus cloned into pPICZalphaC Pichia pastoris vector and expressed in X33 P. pastoris host to be characterized. BsGH7-3 enzyme showed a temperature optimum of 60 degrees C and a pHopt of 8.1. BsGH7-3 was identified to be an endoglucanase based on its broad substrate specificity and structural comparisons with other such endoglucanases. BsGH7-3 has a very long half-life and retains 100% activity even in the presence of 4 M NaCl, 4 M KCl and 20% (v/v) ionic liquids. The enzyme activity is stimulated up to fivefold in the presence of Mn+2 and Fe+2 without any deleterious effects on enzyme thermostability. CONCLUSIONS: Here we reanalysed the B. sorokiniana genome and selected one GH7 enzyme for further characterization. The present work demonstrates that BsGH7-3 is an endoglucanase with a long half-life and no loss in activity in the presence of denaturants like salt and ionic liquids, and lays the foundation towards exploring the Bipolaris genome for other cell wall-degrading enzymes. PMID- 28559925 TI - Integrated analysis of 454 and Illumina transcriptomic sequencing characterizes carbon flux and energy source for fatty acid synthesis in developing Lindera glauca fruits for woody biodiesel. AB - BACKGROUND: Lindera glauca fruit with high quality and quantity of oil has emerged as a novel potential source of biodiesel in China, but the molecular regulatory mechanism of carbon flux and energy source for oil biosynthesis in developing fruits is still unknown. To better develop fruit oils of L. glauca as woody biodiesel, a combination of two different sequencing platforms (454 and Illumina) and qRT-PCR analysis was used to define a minimal reference transcriptome of developing L. glauca fruits, and to construct carbon and energy metabolic model for regulation of carbon partitioning and energy supply for FA biosynthesis and oil accumulation. RESULTS: We first analyzed the dynamic patterns of growth tendency, oil content, FA compositions, biodiesel properties, and the contents of ATP and pyridine nucleotide of L. glauca fruits from seven different developing stages. Comprehensive characterization of transcriptome of the developing L. glauca fruit was performed using a combination of two different next-generation sequencing platforms, of which three representative fruit samples (50, 125, and 150 DAF) and one mixed sample from seven developing stages were selected for Illumina and 454 sequencing, respectively. The unigenes separately obtained from long and short reads (201, and 259, respectively, in total) were reconciled using TGICL software, resulting in a total of 60,031 unigenes (mean length = 1061.95 bp) to describe a transcriptome for developing L. glauca fruits. Notably, 198 genes were annotated for photosynthesis, sucrose cleavage, carbon allocation, metabolite transport, acetyl-CoA formation, oil synthesis, and energy metabolism, among which some specific transporters, transcription factors, and enzymes were identified to be implicated in carbon partitioning and energy source for oil synthesis by an integrated analysis of transcriptomic sequencing and qRT PCR. Importantly, the carbon and energy metabolic model was well established for oil biosynthesis of developing L. glauca fruits, which could help to reveal the molecular regulatory mechanism of the increased oil production in developing fruits. CONCLUSIONS: This study presents for the first time the application of an integrated two different sequencing analyses (Illumina and 454) and qRT-PCR detection to define a minimal reference transcriptome for developing L. glauca fruits, and to elucidate the molecular regulatory mechanism of carbon flux control and energy provision for oil synthesis. Our results will provide a valuable resource for future fundamental and applied research on the woody biodiesel plants. PMID- 28559928 TI - Novel insight into the relationship between organic substrate composition and volatile fatty acids distribution in acidogenic co-fermentation. AB - BACKGROUND: Co-fermentation is an attractive technology for improving volatile fatty acids (VFAs) production by treatment of solid organic wastes. However, it remains unclear how the composition of different organic matters in solid waste influences the VFAs distribution, microbial community structure, and metabolic pathway during acidogenic co-fermentation. In this study, different organic wastes were added into waste activated sludge (WAS) as co-fermentation substrates to explore the impact of organic matter composition on VFAs pattern and the microbiological mechanism . RESULTS: Acetate was the most dominant VFA produced in all fermentation groups, making up 41.3-57.6% of the total VFAs produced during acidogenic co-fermentation under alkaline condition. With the increased addition of potato peel waste, the concentrations of propionate and valerate decreased dramatically, while ethanol and butyrate concentrations increased. The addition of food waste caused gradual decreases of valerate and propionate, but ethanol increased and butyrate was relatively stable. Some inconsistency was observed between hydrolysis efficiency and acidification efficiency. Our results revealed that starch was mainly responsible for butyrate and ethanol formation, while lipids and protein favored the synthesis of valerate and propionate. Microbial community analysis by high-throughput sequencing showed that Firmicutes had the highest relative abundance at phylum level in all fermentation groups. With 75% potato peel waste or 75% food waste addition to WAS, Bacilli (72.2%) and Clostridia (56.2%) were the dominant respective classes. In fermentation using only potato peel waste, the Bacilli content was 64.1%, while the Clostridia content was 53.6% in the food-only waste fermentation. CONCLUSIONS: Acetate was always the dominant product in acidogenic co-fermentation, regardless of the substrate composition. The addition of carbon-rich substrates significantly enhanced butyrate and ethanol accumulation, while protein-rich substrate substantially benefited propionate and valerate generation. Potato peel waste substantially favored the enrichment of Bacilli, while food waste dramatically increased Clostridia content in the sludge. PMID- 28559927 TI - Modeling the impact of high temperatures on microalgal viability and photosynthetic activity. AB - BACKGROUND: Culture collapse due to high temperatures can significantly impact the profitability of outdoor algal cultivation systems. The objective of this study was to model for the first time the impact of high temperatures on algal activity and viability. RESULTS: Viability measurements on Dunaliella salina cultures were based on cytometry with two fluorescent markers (erythrosine and fluorescein di-acetate), and photosynthetic activity was measured by Pulse Amplitude Modulation (PAM) fluorometry. Kinetic studies revealed that viability and activity losses during exposure to high temperatures could be described by a Weibull model. Both mortality and activity were shown to be functions of the thermal dose received by the algae, defined as the product of duration of exposure to high temperatures and an exponential function of temperature. Simulations at five climatic locations revealed that culture collapse due to high temperatures could impact productivity of D. salina in non-temperature-controlled outdoor photobioreactors by 35 and 40% in arid and Mediterranean climates, respectively. CONCLUSIONS: The model developed in this study can be used to forecast the impact of high temperatures on algal biofuel productivity. When coupled with models predicting the temperature of outdoor cultivation systems, this model can also be used to select the best combination of location, system geometry, and algal species to minimize the risks of culture collapse and therefore maximize biofuel productivity. PMID- 28559929 TI - Gene Set Enrichment Analyses: lessons learned from the heart failure phenotype. AB - BACKGROUND: Genetic studies for complex diseases have predominantly discovered main effects at individual loci, but have not focused on genomic and environmental contexts important for a phenotype. Gene Set Enrichment Analysis (GSEA) aims to address this by identifying sets of genes or biological pathways contributing to a phenotype, through gene-gene interactions or other mechanisms, which are not the focus of conventional association methods. RESULTS: Approaches that utilize GSEA can now take input from array chips, either gene-centric or genome-wide, but are highly sensitive to study design, SNP selection and pruning strategies, SNP-to-gene mapping, and pathway definitions. Here, we present lessons learned from our experience with GSEA of heart failure, a particularly challenging phenotype due to its underlying heterogeneous etiology. CONCLUSIONS: This case study shows that proper data handling is essential to avoid false positive results. Well-defined pipelines for quality control are needed to avoid reporting spurious results using GSEA. PMID- 28559931 TI - Soluble plasma proteins ST2 and CD163 as early biomarkers of nephropathy in Swedish patients with diabetes, 15-34 years of age: a prospective cohort study. AB - BACKGROUND: The aim of this study was to investigate plasma levels of sST2 and sCD163 to determine whether they at an early stage could predict development of diabetic nephropathy and/or diabetic retinopathy in patients at clinical onset. METHODS: Patients diagnosed with diabetes mellitus at age 15-34 years between 1987 and 1988 (n = 220) were included. Data such as BMI, smoking, HbA1c and islet cell antibodies were collected at time of diagnosis. Within the 10 year follow-up period, 112 patients (51%) developed following diabetes related complications; retinopathy (n = 91), nephropathy (n = 12) or both (n = 9). Plasma concentrations of sST2 and sCD163 were measured at time of diagnosis and levels compared between different complication groups. RESULTS: Plasma levels of sST2 were significantly higher in patients who later developed nephropathy (n = 21; 1012 [773-1493] pg/ml) compared to those who did not (n = 199; 723 [449-1084] pg/ml; p = 0.006). A tendency for higher plasma levels of sCD163 was observed but not statistically significant (p = 0.058). CONCLUSIONS: sST2 and sCD163 show promise as potential biomarkers for the development of nephropathy already at clinical onset. sST2 and/or sCD163 could possibly be part of a biomarker panel aimed to find patients at high risk of developing nephropathy. Both markers need to be investigated in a larger prospective study. PMID- 28559933 TI - Nuclear Medicine in the Era of Precision Medicine. PMID- 28559930 TI - Comparison of clinical and immunological findings in gnotobiotic piglets infected with Escherichia coli O104:H4 outbreak strain and EHEC O157:H7. AB - BACKGROUND: Shiga toxin (Stx) producing Escherichia coli (E. coli) (STEC) is the most frequent cause of diarrhoea-positive haemolytic uraemic syndrome (D + HUS) in humans. In 2011, a huge outbreak with an STEC O104:H4 strain in Germany highlighted the limited possibilities for causative treatment of this syndrome. The responsible STEC strain was found to combine Stx production with adherence mechanisms normally found in enteroaggregative E. coli (EAEC). Pathotypes of E. coli evolve and can exhibit different adhesion mechanisms. It has been shown previously that neonatal gnotobiotic piglets are susceptible for infection with STEC, such as STEC O157:H7 as well as for EAEC, which are considered to be the phylogenetic origin of E. coli O104:H4. This study was designed to characterise the host response to infection with the STEC O104:H4 outbreak strain in comparison to an STEC O157:H7 isolate by evaluating clinical parameters (scoring) and markers of organ dysfunction (biochemistry), as well as immunological (flow cytometry, assessment of cytokines/chemokines and acute phase proteins) and histological alterations (light- and electron microscopy) in a gnotobiotic piglet model of haemolytic uraemic syndrome. RESULTS: We observed severe clinical symptoms, such as diarrhoea, dehydration and neurological disorders as well as attaching-and-effacing lesions (A/E) in the colon in STEC O157:H7 infected piglets. In contrast, STEC O104:H4 challenged animals exhibited only mild clinical symptoms including diarrhoea and dehydration and HUS-specific/severe histopathological, haematological and biochemical alterations were only inconsistently presented by individual piglets. A specific adherence phenotype of STEC O104:H4 could not be observed. Flow cytometric analyses of lymphocytes derived from infected animals revealed an increase of natural killer cells (NK cells) during the course of infection revealing a potential role of this subset in the anti-bacterial activity in STEC disease. CONCLUSIONS: Unexpectedly, E. coli O104:H4 infection caused only mild symptoms and minor changes in histology and blood parameters in piglets. Outcome of the infection trial does not reflect E. coli O104:H4 associated human disease as observed during the outbreak in 2011. The potential role of cells of the innate immune system for STEC related disease pathogenesis should be further elucidated. PMID- 28559932 TI - Exploring the heterogeneity of neural social indices for genetically distinct etiologies of autism. AB - BACKGROUND: Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous disorder. Promising initiatives utilizing interdisciplinary characterization of ASD suggest phenotypic subtypes related to specific likely gene-disrupting mutations (LGDMs). However, the role of functionally associated LGDMs in the neural social phenotype is unknown. METHODS: In this study of 26 children with ASD (n = 13 with an LGDM) and 13 control children, we characterized patterns of mu attenuation and habituation as children watched videos containing social and nonsocial motions during electroencephalography acquisition. RESULTS: Diagnostic comparisons were consistent with prior work suggesting aberrant mu attenuation in ASD within the upper mu band (10-12 Hz), but typical patterns within the lower mu band (8-10 Hz). Preliminary exploration indicated distinct social sensitization patterns (i.e., increasing mu attenuation for social motion) for children with an LGDM that is primarily expressed during embryonic development. In contrast, children with an LGDM primarily expressed post embryonic development exhibited stable typical patterns of lower mu attenuation. Neural social indices were associated with social responsiveness, but not cognition. CONCLUSIONS: These findings suggest unique neurophysiological profiles for certain genetic etiologies of ASD, further clarifying possible genetic functional subtypes of ASD and providing insight into mechanisms for targeted treatment approaches. PMID- 28559934 TI - The Current Status of SPECT or SPECT/CT in South Korea. AB - The first step to nuclear medicine in Korea started with introduction of the gamma camera in 1969. Although planar images with the gamma camera give important functional information, they have the limitations that result from 2-dimensional images. Single-photon emission computed tomography (SPECT) due to its 3 dimensional image acquisition is superior to earlier planar gamma imaging in image resolution and diagnostic accuracy. As demand for a hybrid functional and anatomical imaging device has increased, integrated SPECT/CT systems have been used. In Korea, SPECT/CT was for the first time installed in 2003. SPECT/CT can eliminate many possible pitfalls on SPECT-alone images, making better attenuation correction and thereby improving image quality. Therefore, SPECT/CT is clinically preferred in many hospitals in various aspects. More recently, additional SPECT/CT images taken from the region with equivocal uptake on planar images have been helpful in making precise interpretation as part of their clinical workup in postoperative thyroid cancer patients. SPECT and SPECT/CT have various advantages, but its clinical application has gradually decreased in recent few years. While some researchers investigated the myocardial blood flow with cardiac PET using F-18 FDG or N-13 ammonia, myocardial perfusion SPECT is, at present, the radionuclide imaging study of choice for the risk stratification and guiding therapy in the coronary artery disease patients in Korea. New diagnostic radiopharmaceuticals for AD have received increasing attention; nevertheless, brain SPECT will remain the most reliable modality evaluating cerebral perfusion. PMID- 28559935 TI - Current Status and Future Direction of Nanomedicine: Focus on Advanced Biological and Medical Applications. AB - Nanotechnology is the engineering and manipulation of materials and devices with sizes in the nanometer range. Colloidal gold, iron oxide nanoparticles and quantum dot semiconductor nanocrystals are examples of nanoparticles, with sizes generally ranging from 1 to 20 nm. These nanotechnologies have been researched tremendously in the last decade and this has led to a new area of "nanomedicine" which is the application of nanotechnology to human health-care for diagnosis, monitoring, treatment, prediction and prevention of diseases. Recently progress has been made in overcoming some of the difficulties in the human use of nanomedicines. In the mid-1990s, Doxil was approved by the FDA, and now various nanoconstructs are on the market and in clinical trials. However, there are many obstacles in the human application of nanomaterials. For translation to clinical use, a detailed understanding is needed of the chemical and physical properties of particles and their pharmacokinetic behavior in the body, including their biodistribution, toxicity, and biocompatibility. In this review, we provide a broad introduction to nanomedicines and discuss the preclinical and clinical trials in which they have been evaluated. PMID- 28559936 TI - Salmonella-Mediated Cancer Therapy: Roles and Potential. AB - The use of bacteria for cancer therapy, which was proposed many years ago, was not recognized as a potential therapeutic strategy until recently. Technological advances and updated knowledge have enabled the genetic engineering of bacteria for their safe and effective application in the treatment of cancer. The efficacy of radiotherapy depends mainly on tissue oxygen levels, and low oxygen concentrations in necrotic and hypoxic regions are a common cause of treatment failure. In addition, the distribution of a drug is important for the therapeutic effect of chemotherapy, and the poor vasculature in tumors impairs drug delivery, limiting the efficacy of a drug, especially in necrotic and hypoxic regions. Bacteria-mediated cancer therapy (BMCT) relies on facultative anaerobes that can survive in well or poorly oxygenated regions, and it therefore improves the therapeutic efficacy drug distribution throughout the tumor mass. Since the mid 1990s, the number of published bacterial therapy papers has increased rapidly, with a doubling time of 2.5 years in which the use of Salmonella increased significantly. BMCT is being reevaluated to overcome some of the drawbacks of conventional therapies. This review focuses on Salmonella-mediated cancer therapy as the most widely used type of BMCT.2. PMID- 28559938 TI - Ratio of Mediastinal Lymph Node SUV to Primary Tumor SUV in 18F-FDG PET/CT for Nodal Staging in Non-Small-Cell Lung Cancer. AB - PURPOSE: Following determination of the maximum standardized uptake values (SUVmax) of the mediastinal lymph nodes (SUV-LN) and of the primary tumor (SUV-T) on 18F-FDG PET/CT in patients with non-small-cell lung cancer (NSCLC), the aim of the study was to determine the value of the SUV-LN/SUV-T ratio in lymph node staging in comparison with that of SUV-LN. METHODS: We retrospectively reviewed a total of 289 mediastinal lymph node stations from 98 patients with NSCLC who were examined preoperatively for staging and subsequently underwent pathologic studies of the mediastinal lymph nodes. We determined SUV-LN and SUV-R for each lymph node station on 18F-FDG PET/CT and then classified each station into one of three groups based on SUV-T (low, medium and high SUV-T groups). Diagnostic performance was assessed based on receiver operating characteristic (ROC) curve analysis, and the optimal cut-off values that would best discriminate metastatic from benign lymph nodes were determined for each method. RESULTS: The average of SUV-R of malignant lymph nodes was significantly higher than that of benign lymph nodes (0.79 +/- 0.45 vs. 0.36 +/- 0.23, P < 0.0001). In the ROC curve analysis, the area under the curve (AUC) of SUV-R was significantly higher than that of SUV-LN in the low SUV-T group (0.885 vs. 0.810, P = 0.019). There were no significant differences between the AUCs of SUV-LN and of SUV-R in the medium and high SUV-T groups. The optimal cut-off value for SUV-R in the low SUV-T group was 0.71 (sensitivity 87.5 %, specificity 85.9 %). CONCLUSIONS: The SUV-R performed well in distinguishing between metastatic and benign lymph nodes. In particular, SUV-R was found to have a better diagnostic performance than SUV-LN in the low SUV-T group. PMID- 28559937 TI - The Role of Nuclear Medicine in the Staging and Management of Human Immune Deficiency Virus Infection and Associated Diseases. AB - Human immune deficiency virus (HIV) is a leading cause of death. It attacks the immune system, thereby rendering the infected host susceptible to many HIV associated infections, malignancies and neurocognitive disorders. The altered immune system affects the way the human host responds to disease, resulting in atypical presentation of these disorders. This presents a diagnostic challenge and the clinician must use all diagnostic avenues available to diagnose and manage these conditions. The advent of highly active antiretroviral therapy (HAART) has markedly reduced the mortality associated with HIV infection but has also brought in its wake problems associated with adverse effects or drug interaction and may even modulate some of the HIV-associated disorders to the detriment of the infected human host. Nuclear medicine techniques allow non invasive visualisation of tissues in the body. By using this principle, pathophysiology in the body can be targeted and the treatment of diseases can be monitored. Being a functional imaging modality, it is able to detect diseases at the molecular level, and thus it has increased our understanding of the immunological changes in the infected host at different stages of the HIV infection. It also detects pathological changes much earlier than conventional imaging based on anatomical changes. This is important in the immunocompromised host as in some of the associated disorders a delay in diagnosis may have dire consequences. Nuclear medicine has played a huge role in the management of many HIV-associated disorders in the past and continues to help in the diagnosis, prognosis, staging, monitoring and assessing the response to treatment of many HIV-associated disorders. As our understanding of the molecular basis of disease increases nuclear medicine is poised to play an even greater role. In this review we highlight the functional basis of the clinicopathological correlation of HIV from a metabolic view and discuss how the use of nuclear medicine techniques, with particular emphasis of F-18 fluorodeoxyglucose, may have impact in the setting of HIV. We also provide an overview of the role of nuclear medicine techniques in the management of HIV-associated disorders. PMID- 28559939 TI - Comparison of Quantitative Methods on FDG PET/CT for Treatment Response Evaluation of Metastatic Colorectal Cancer. AB - PURPOSE: FDG PET is effective in treatment response evaluation of cancer. However, there is no standard method for quantitative evaluation of FDG PET, particularly regarding cytostatic drugs. We compared various FDG PET quantitative methods in terms of response determination. METHODS: A total of 39 refractory metastatic colorectal cancer patients who received a multikinase inhibitor treatment were included. Baseline and posttreatment FDG PET/CT scans were performed before and two cycles after treatment. Standardized uptake value (SUV) and total lesion glycolysis (TLG) values using various margin thresholds (30-70 % of maximum SUV with increment 10 %, twice mean SUV of blood pool, SUV 3.0, and SUV 4.0) were measured, with measurement target of the hottest lesion or a maximum of five hottest lesions. Treatment response by the PERCIST criteria was also determined. Predictive values of the PET indexes were evaluated in terms of the treatment response determined by the RECIST 1.1 criteria. RESULTS: The agreement rate was 38 % between response determined by the PERCIST and the RECIST criteria (kappa = 0.381). When patients were classified into disease control group (PR, SD) and non-control group (PD) by the RECIST criteria, percent changes of TLG with various margin thresholds (particularly, 30-50 % of maximum SUV) exhibited significant differences between the two groups, and high diagnostic power for the response by the RECIST criteria. TLG-based criteria, which used a margin threshold of 50 % of maximum SUV, exhibited a high agreement with the RECIST criteria compared with the PERCIST criteria (kappa = 0.606). CONCLUSION: In metastatic colorectal cancer, FDG PET/CT could be effective for treatment response evaluation by using TLG measured by margin thresholds of 30-50 % of maximum SUV. Further studies are warranted regarding the optimal cutoff values for this method. PMID- 28559940 TI - Clinical Significance of Pretreatment FDG PET/CT in MIBG-Avid Pediatric Neuroblastoma. AB - PURPOSE: 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging is well known to have clinical significance in the initial staging and response evaluation of the many kinds of neoplasms. However, its role in the pediatric neuroblastoma is not clearly defined. In the present study, the clinical significance of FDG-PET/computed tomography (CT) in 123I- or 131I metaiodobenzylguanidine (MIBG)-avid pediatric neuroblastoma was investigated. METHODS: Twenty patients with neuroblastoma who undertook pretreatment FDG PET/CT at our institute between 2008 and 2015 and showed MIBG avidity were retrospectively enrolled in the present study. Clinical information-including histopathology, and serum markers-and several PET parameters-including SUVmax of the primary lesion (Psuv), target-to-background ratio (TBR), metabolic tumor volume (MTV), and coefficient of variation (CV)-were analyzed. The prognostic effect of PET parameters was evaluated in terms of progression-free survival (PFS). RESULTS: Total 20 patients (4.5 +/- 3.5 years) were divided as two groups by disease progression. Six patients (30.0 %) experienced disease progression and one patient (5.0 %) died during follow-up period. There were not statistically significant in age, stage, MYCN status, primary tumor size, serum lactate dehydrogenase (LDH), neuron-specific enolase (NSE), and ferritin level between two groups with progression or no progression. However, Psuv (p = 0.017), TBR (p = 0.09), MTV (p = 0.02), and CV (p = 0.036) showed significant differences between two groups. In univariate analysis, PFS was significantly associated with Psuv (p = 0.021) and TBR (p = 0.023). CONCLUSIONS: FDG-PET parameters were significantly related with progression of neuroblastoma. FDG-PET/CT may have the potential as a valuable modality for evaluating prognosis in the patients with MIBG-avid pediatric neuroblastoma. PMID- 28559942 TI - High Prevalence of Thyroid Disease and Role of Salivary Gland Scintigraphy in Patients with Xerostomia. AB - PURPOSE: Although Sjogren's syndrome (SS) is the most common disease causing xerostomia, autoimmune thyroid diseases can also affect the salivary glands. The aim of our study was to estimate the prevalence of thyroid diseases (TD) in subjects with symptoms of xerostomia and evaluate the efficacy of salivary gland scintigraphy (SGS) in the detection of TD in patients with SS and without SS. METHODS: We retrospectively reviewed the SGS findings of 173 subjects (men:women, 29:144) with symptoms of xerostomia. Ejection fractions (EF) in the parotid and submandibular glands were calculated. Thyroid disease was diagnosed on the basis of the results of the visual assessment of tracer uptake in the thyroid gland on SGS images as well as serological thyroid function tests. RESULTS: Based on the American-European Criteria, 94 patients were diagnosed with SS. Hashimoto's thyroiditis was diagnosed in 63 patients, subacute thyroiditis in 23, subclinical hypothyroidism in five, and Graves' disease in one. There were significant differences in the EF values of the parotid and submandibular glands between patients with TD and those with undetermined diagnoses. CONCLUSIONS: More than half of patients with xerostomia exhibited TD. Thyroid assessment by SGS is feasible, and SGS appears to be useful for the patients with xerostomia caused by TD. SGS may be the first imaging modality capable of evaluating both salivary gland function and thyroid gland status in patients with xerostomia. This strategy would make the requirement for additional workup for thyroid disease. PMID- 28559943 TI - Unusual Contiguous Soft Tissue Spread of Advanced Malignant Mesothelioma Detected by FDG PET/CT. AB - Malignant pleural mesothelioma (MPM) is a tumor of mesodermal origin that arises from the serosa of the pleura, peritoneum, pericardium or tunica vaginalis. MPM is well known to have a poor prognosis with a median survival time of 12 months. Accurate diagnosis, staging and restaging of MPM are crucial with [18F] flurodeoxy-D-glucose positron emission tomography (FDG PET/CT) playing an increasingly important role. Here we report a case of MPM with unusual contiguous soft tissue spread of the tumor along the dermal and fascial planes characterized by PET/CT. Given that the loco-regional tumor in the thorax was under control on PET/CT, the death of the patient was most likely associated with physiologic or metabolic causes associated with an extra-thoracic tumor. PMID- 28559941 TI - Comparison of Two Different Segmentation Methods on Planar Lung Perfusion Scan with Reference to Quantitative Value on SPECT/CT. AB - PURPOSE: Until now, there was no single standardized regional segmentation method of planar lung perfusion scan. We compared planar scan based two segmentation methods, which are frequently used in the Society of Nuclear Medicine, with reference to the lung perfusion single photon emission computed tomography (SPECT)/computed tomography (CT) derived values in lung cancer patients. METHODS: Fifty-five lung cancer patients (male:female, 37:18; age, 67.8 +/- 10.7 years) were evaluated. The patients underwent planar scan and SPECT/CT after injection of technetium-99 m macroaggregated albumin (Tc-99 m-MAA). The % uptake and predicted postoperative percentage forced expiratory volume in 1 s (ppoFEV1%) derived from both posterior oblique (PO) and anterior posterior (AP) methods were compared with SPECT/CT derived parameters. Concordance analysis, paired comparison, reproducibility analysis and spearman correlation analysis were conducted. RESULTS: The % uptake derived from PO method showed higher concordance with SPECT/CT derived % uptake in every lobe compared to AP method. Both methods showed significantly different lobar distribution of % uptake compared to SPECT/CT. For the target region, ppoFEV1% measured from PO method showed higher concordance with SPECT/CT, but lower reproducibility compared to AP method. Preliminary data revealed that every method significantly correlated with actual postoperative FEV1%, with SPECT/CT showing the best correlation. CONCLUSION: The PO method derived values showed better concordance with SPECT/CT compared to the AP method. Both PO and AP methods showed significantly different lobar distribution compared to SPECT/CT. In clinical practice such difference according to different methods and lobes should be considered for more accurate postoperative lung function prediction. PMID- 28559944 TI - Giant Cell Tumor of the Rib: Two Cases of F-18 FDG PET/CT Findings. AB - We report two cases of giant cell tumor arising from the rib and their F-18 FDG PET/CT findings. The two patients complained of chest wall pain, and large lobulated soft tissue masses with intense FDG uptake were seen on F-18 FDG PET/CT. A malignant tumor such as osteosarcoma or chondrosarcoma was suspected due to the large size of the mass, bony destruction, and intense FDG uptake. En bloc resection was performed and final pathologic results revealed giant cell tumor of the rib. Giant cell tumor of the rib is very rare, and larger lesions with high FDG uptake can be misdiagnosed as an intrathoracic malignancy arising from the rib, pleura, or chest wall. PMID- 28559945 TI - Sensitive Detection of a Small Parathyroid Adenoma Using Fluorocholine PET/CT: A Case Report. AB - Primary hyperparathyroidism is caused by parathyroid adenoma in the majority of cases and diagnosis is usually made biochemically. Pre-surgical localization of parathyroid adenoma is essential to limit the extent of surgery and avoid missing them at ectopic sites. Anatomical and functional imaging are used for the localization, but may fail to identify the small and ectopic parathyroid adenoma. We present a case of small sized ectopic parathyroid adenoma at unusual location detected by F-18 fluorocholine (FCH) PET/CT, where other imaging modalities failed. The post-operative histopathology confirmed the diagnosis of ectopic parathyroid adenoma. PMID- 28559946 TI - F-18 FDG PET Findings for Vogt-Koyanagi-Harada Disease. AB - Vogt-Koyanagi-Harada disease is a rare multisystemic granulomatous autoimmune disorder affecting pigmented tissues such as the choroid, meninges, inner ear, and the skin. Neurologic symptoms are usually mild. Clinical manifestations include generalized muscle weakness, headache, meningismus, vertigo, decreased visual acuity, hearing loss and mental changes ranging from mild confusion to psychosis, hemiparesis, dysarthria, and aphasia. Seizures are very rare. We describe a case of 18F-fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET) and software-fused PET-magnetic resonance imaging (MRI) in Vogt-Koyanagi Harada disease with seizure. PMID- 28559947 TI - Visual and Quantitative Analysis of Cisternography for the Detection of Cerebrospinal Fluid Leakage. AB - We herein present a case of a 29-year-old man with clear rhinorrhea, which persisted for 8 years following a myringotomy. After cotton pledgets were placed in several different regions of the nasal cavity, cisternography using Tc-99m DTPA was performed to measure the radioactivity of each pledget. Cisternography showed subtle uptake in the nasal cavity. However, intense uptake was detected in the pledget placed in the right eustachian tube orifice, where the pledget:serum count ratio was 10.3:1. The patient underwent duroplasty and cranioplasty, and the rhinorrhea resolved. PMID- 28559948 TI - Bone Scintigraphy and Tenofovir-Induced Osteomalacia in Chronic Hepatitis B. AB - Tenofovir, used in the treatment of chronic hepatitis B and HIV, is known for its side effects on the kidneys and bones. We share interesting images of a patient with tenofovir-induced osteomalacia on Technetium-99 m hydroxymethyelene (Tc-99 m HDP) bone scintigraphy. Pattern recognition of this bone scintigraphy and correlation with the clinical history is essential to avoid misdiagnosis. PMID- 28559949 TI - Biopsy from Recurrent Lesion May Change Further Treatment Plan in Metastatic Breast Cancer. PMID- 28559950 TI - Erratum to: Incidental Findings of Intense Radioiodine Uptake in Struma Ovarii and Bilateral Non-Lactating Breast Simultaneously on Post-Ablation SPECT/CT for Papillary Thyroid Cancer. AB - [This corrects the article DOI: 10.1007/s13139-016-0459-0.]. PMID- 28559951 TI - Neurodynamic evaluation of hearing aid features using EEG correlates of listening effort. AB - In this study, we propose a novel estimate of listening effort using electroencephalographic data. This method is a translation of our past findings, gained from the evoked electroencephalographic activity, to the oscillatory EEG activity. To test this technique, electroencephalographic data from experienced hearing aid users with moderate hearing loss were recorded, wearing hearing aids. The investigated hearing aid settings were: a directional microphone combined with a noise reduction algorithm in a medium and a strong setting, the noise reduction setting turned off, and a setting using omnidirectional microphones without any noise reduction. The results suggest that the electroencephalographic estimate of listening effort seems to be a useful tool to map the exerted effort of the participants. In addition, the results indicate that a directional processing mode can reduce the listening effort in multitalker listening situations. PMID- 28559953 TI - Quantitative EEG evaluation for performance level analysis of professional female soccer players. AB - Quantitative electroencephalography (QEEG) was used to investigate the brain activity of Thai professional female soccer team players who exhibit high performance. The QEEGs of 29 players were recorded three times: twice before a competition (once a week) and a week after a competition. The results of the brain topographic map (absolute power) in the alpha frequency band and the brain connectivity (coherence) in the delta frequency bands represented their anxiety and decision-making levels, respectively. These phenomena occurred in the brain activities of the athletes, which could be used to predict their performances during the competition. Moreover, the value of the correlation coefficient between the brain activity ranking and average performance score revealed a moderate to good relationship (rs = .586, p = .001). These results support the association between brain activity and performance level during competition. PMID- 28559952 TI - Multivariate multi-scale weighted permutation entropy analysis of EEG complexity for Alzheimer's disease. AB - The complexity change of brain activity in Alzheimer's disease (AD) is an interesting topic for clinical purpose. To investigate the dynamical complexity of brain activity in AD, a multivariate multi-scale weighted permutation entropy (MMSWPE) method is proposed to measure the complexity of electroencephalograph (EEG) obtained in AD patients. MMSWPE combines the weighted permutation entropy and the multivariate multi-scale method. It is able to quantify not only the characteristics of different brain regions and multiple time scales but also the amplitude information contained in the multichannel EEG signals simultaneously. The effectiveness of the proposed method is verified by both the simulated chaotic signals and EEG recordings of AD patients. The simulation results from the Lorenz system indicate that MMSWPE has the ability to distinguish the multivariate signals with different complexity. In addition, the EEG analysis results show that in contrast with the normal group, the significantly decreased complexity of AD patients is distributed in the temporal and occipitoparietal regions for the theta and the alpha bands, and also distributed from the right frontal to the left occipitoparietal region for the theta, the alpha and the beta bands at each time scale, which may be attributed to the brain dysfunction. Therefore, it suggests that the MMSWPE method may be a promising method to reveal dynamic changes in AD. PMID- 28559954 TI - Route searching based on neural networks and heuristic reinforcement learning. AB - In this paper, an improved and much stronger RNH-QL method based on RBF network and heuristic Q-learning was put forward for route searching in a larger state space. Firstly, it solves the problem of inefficiency of reinforcement learning if a given problem's state space is increased and there is a lack of prior information on the environment. Secondly, RBF network as weight updating rule, reward shaping can give an additional feedback to the agent in some intermediate states, which will help to guide the agent towards the goal state in a more controlled fashion. Meanwhile, with the process of Q-learning, it is accessible to the underlying dynamic knowledge, instead of the need of background knowledge of an upper level RBF network. Thirdly, it improves the learning efficiency by incorporating the greedy exploitation strategy to train the neural network, which has been testified by the experimental results. PMID- 28559955 TI - A plausible neural circuit for decision making and its formation based on reinforcement learning. AB - A human's, or lower insects', behavior is dominated by its nervous system. Each stable behavior has its own inner steps and control rules, and is regulated by a neural circuit. Understanding how the brain influences perception, thought, and behavior is a central mandate of neuroscience. The phototactic flight of insects is a widely observed deterministic behavior. Since its movement is not stochastic, the behavior should be dominated by a neural circuit. Based on the basic firing characteristics of biological neurons and the neural circuit's constitution, we designed a plausible neural circuit for this phototactic behavior from logic perspective. The circuit's output layer, which generates a stable spike firing rate to encode flight commands, controls the insect's angular velocity when flying. The firing pattern and connection type of excitatory and inhibitory neurons are considered in this computational model. We simulated the circuit's information processing using a distributed PC array, and used the real time average firing rate of output neuron clusters to drive a flying behavior simulation. In this paper, we also explored how a correct neural decision circuit is generated from network flow view through a bee's behavior experiment based on the reward and punishment feedback mechanism. The significance of this study: firstly, we designed a neural circuit to achieve the behavioral logic rules by strictly following the electrophysiological characteristics of biological neurons and anatomical facts. Secondly, our circuit's generality permits the design and implementation of behavioral logic rules based on the most general information processing and activity mode of biological neurons. Thirdly, through computer simulation, we achieved new understanding about the cooperative condition upon which multi-neurons achieve some behavioral control. Fourthly, this study aims in understanding the information encoding mechanism and how neural circuits achieve behavior control. Finally, this study also helps establish a transitional bridge between the microscopic activity of the nervous system and macroscopic animal behavior. PMID- 28559956 TI - From abstract topology to real thermodynamic brain activity. AB - Recent approaches to brain phase spaces reinforce the foremost role of symmetries and energy requirements in the assessment of nervous activity. Changes in thermodynamic parameters and dimensions occur in the brain during symmetry breakings and transitions from one functional state to another. Based on topological results and string-like trajectories into nervous energy landscapes, we provide a novel method for the evaluation of energetic features and constraints in different brain functional activities. We show how abstract approaches, namely the Borsuk-Ulam theorem and its variants, may display real, energetic physical counterparts. When topology meets the physics of the brain, we arrive at a general model of neuronal activity, in terms of multidimensional manifolds and computational geometry, that has the potential to be operationalized. PMID- 28559957 TI - Global asymptotic stability of complex-valued neural networks with additive time varying delays. AB - In this paper, we extensively study the global asymptotic stability problem of complex-valued neural networks with leakage delay and additive time-varying delays. By constructing a suitable Lyapunov-Krasovskii functional and applying newly developed complex valued integral inequalities, sufficient conditions for the global asymptotic stability of proposed neural networks are established in the form of complex-valued linear matrix inequalities. This linear matrix inequalities are efficiently solved by using standard available numerical packages. Finally, three numerical examples are given to demonstrate the effectiveness of the theoretical results. PMID- 28559958 TI - Hereditary and non-hereditary branches of family eligible for BRCA test: cancers in other sites. AB - BACKGROUND: The analysis of relationships of BRCA alterations with cancer at sites other than breast/ovary may provide innovative information concerning BRCA pathogenic role and support additional clinical decisions. Aim of this study is to compare presence of cancers in other sites in members of hereditary (H) and not-hereditary (nH) branches of families of patients eligible to BRCA test. METHODS: We retrospectively analyzed the incidence of cancer in other sites in members of 136 families eligible for hereditary breast/ovarian cancer genetic counseling at Centro Studi Tumori Eredo-familiari of our Institute; we compared the frequency of other cancer types in 1156 members of the H-branch with respect to 1062 members of nH-Branch. The families belonging to a proband case and with informative members in at least three generation entered the present study. RESULTS: The frequency of other Cancers in members of H-branch was significantly higher than that in members of nH-branch (161 vs 75 cancers; p < 0.0001). In specific, members of H-branch had a significantly higher probability to have more lung cancer (38 vs 9;p < 0.0006), kidney cancer (23 vs 5;p < 0.0005), liver cancer (13 vs 3;p < 0.02) and larynx cancer (14 vs 4;p < 0.03). Interestingly, to belong to H-branch resulted significantly associated with a higher probability of lung cancer (OR 4.5; 2.15-9.38 95%C.I.), liver cancer (OR: 4.02; 1.14-14.15 95% C.I.) and larynx cancer (OR:3.4; 1.12-10.39 95%C.I.) independently from Gender and Age. CONCLUSIONS: Members belonging to the H-branch of families of patients eligible to BRCA test have a higher risk of tumors in lung, larynx and liver. Clinicians should consider the increased risk for these cancers to activate prevention/early diagnosis practices in members of families with breast/ovarian familial cancer syndrome. PMID- 28559959 TI - Traditional Chinese medicine for lipid metabolism disorders. AB - Dyslipidemia significantly contributes to the development of cardiovascular disease (CVD), which is the most common cause of morbidity and mortality in China. Statins are the first-line therapy for reducing LDL-C serum levels. However, they have adverse effects, which restrict their clinical application. Traditional Chinese medicine (TCM) preparations have been increasingly described for their beneficial effects in hyperlipidemic patients. Existing data show that the lipid-regulating effects of TCM may be related to: (1) inhibiting intestinal absorption of lipids; (2) reducing endogenous cholesterol synthesis; (3) regulating cholesterol transport; (4) promoting the excretion of cholesterol in the liver; (5) regulating transcription factors related to lipid metabolism. This study provides an overview of recent studies and elaborates the underlying mechanisms of lipid-regulation by TCM. PMID- 28559960 TI - Medicinal plants for the treatment of obesity: ethnopharmacological approach and chemical and biological studies. AB - Obesity is a global epidemic that has shown a steady increase in morbimortality indicators; it is considered a social problem and entails serious health risks. One of the alternatives in the treatment of obesity is the traditional use of medicinal plants, which supports the research and development of obesity phytotherapy. In this article, we provide information about ethnopharmacological species used to treat obesity, through an electronic search of the periodical databases Web of Science, Scopus, PubMed and Scielo, considering the period 1996 2015 and using the descriptors "plants for obesity", "ethnopharmacology for obesity" and "anti-obesity plants" in both Portuguese and English. We analyzed and organized data on 76 plant species, cataloged per the taxonomy, geographic distribution, botanical aspects, popular use, and chemical and biological studies of the listed plants. The anti-obesity effect of the cataloged species was reported, describing actions on the delay of fat absorption, suppression of enzymatic activities, mediation of lipid levels and increase of lipolytic effects, attributed mainly to phenolic compounds. Given these findings, ethnopharmacological approaches are relevant scientific tools in the selection of plant species for studies that demonstrate anti-obesity action. Deeper botanical, chemical, pre-clinical and clinical studies are particularly necessary for species that present phenolic compounds in their chemical structure. PMID- 28559961 TI - Autophagy inhibitor regulates apoptosis and proliferation of synovial fibroblasts through the inhibition of PI3K/AKT pathway in collagen-induced arthritis rat model. AB - BACKGROUND AND OBJECTIVE: Mounting studies have illustrated an important role of autophagy in various diseases, but few studies have reported its contribution to rheumatoid arthritis (RA) and the underlying mechanism was largely unknown. This study aimed to investigate whether autophagy inhibitors could regulate apoptosis and proliferation through PI3K/AKT pathway in RA. METHODS: RA animal model was established by collagen induction. General observations and degree of joint swelling were observed. Inflammatory response, cell survival related factors and apoptosis were also detected in synovial fibroblasts. In addition, cultured rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) were subjected to TNF alpha treatment in vitro, and TNF-alpha induced cell autophagy, synovial cell proliferation and apoptosis were detected. Moreover, cell cycle and cytokine secretion protein, along with the above parameters, were analyzed. RESULTS: Results from the animal model showed that autophagy inhibitors attenuated inflammatory reaction and synovial hyperplasia, while promoted synovial fibroblasts apoptosis. Meanwhile, inhibition of autophagy promoted cell apoptosis and reversed cell proliferation in vitro, also blocked cell in the G2/M arrest and reduced the S phase cells. Furthermore, we observed that inhibition of PI3K/AKT pathway reversed TNF-alpha mediated autophagy and cytokine secretion. CONCLUSION: autophagy inhibitors could mitigate inflammation response, inhibiting RA-FLS cell proliferation while promoting cell apoptosis by the PI3K/AKT pathway. PMID- 28559962 TI - Icariside II promotes the osteogenic differentiation of canine bone marrow mesenchymal stem cells via the PI3K/AKT/mTOR/S6K1 signaling pathways. AB - The aim of the present study was to investigate the osteogenic effects of icariside II (ICSII) on canine bone marrow mesenchymal stem cells (BMSCs) and the pathways by which these effects were induced. BMSCs were cultured and expanded to the fourth passage. The proliferative effects of ICSII were assessed using the cell counting kit-8 (CCK-8) assay. The osteogenic response to ICSII in BMSCs in vitro was examined by alkaline phosphatase (ALP) activity assays and Alizarin red staining. Using Western blot assays and real-time PCR (RT-PCR), we examined the expression of osteogenetic proteins/genes. We also evaluated changes in Akt and S6K1 phosphorylation levels, along with changes in the expression of osteogenesis proteins/genes after pretreatment with wortmannin (an inhibitor of phosphatidylinositol 3-kinase; PI3K) or rapamycin [a specific inhibitor of mammalian target of rapamycin (mTOR)] in the presence or absence of ICSII. Our results show that ICSII promotes the proliferation of BMSCs, while inhibiting ALP activity. We also found that calcium nodules form after BMSCs are treated with ICSII and osteogenetic medium for 21 days. ICSII significantly increased the expression of osteogenesis proteins/genes and elevated the phosphorylation levels of Akt and S6K1. Treatment with wortmannin or rapamycin attenuated the expression of p-Akt, p-S6K1, and osteogenesis proteins/genes. These results suggest that ICSII promotes the osteogenic differentiation of canine BMSCs via the PI3K/AKT/mTOR/S6K1 signaling pathways. PMID- 28559963 TI - Identification of miR-101-3p targets and functional features based on bioinformatics, meta-analysis and experimental verification in hepatocellular carcinoma. AB - BACKGROUND: MiR-101-3p has been reported to suppress invasion and metastasis in hepatocellular carcinoma (HCC) cells. However, the relevant mechanisms are still unclear. The research seeks to determine systematic value of miR-101-3p in HCC, and comprehensively summarize the predicted target genes as well as their potential function, pathways and networks in HCC. METHODS: The miR-101-1 profiles in 353 HCC patients from The Cancer Genome Atlas (TCGA) were analyzed. Meta analysis was performed to estimate relationship of miR-101 (including precursor and mature miR-101) with clinical features and prognosis in HCC. Further, the promising targets of miR-101-3p were predicted and followed with Gene Ontology (GO), pathway and network analysis. In addition, the functional impact of miR-101 3p was confirmed with in vitro experiments in HCC cells. RESULTS: In TCGA data, low-expression of miR-101-1 might be a diagnostic (AUC: 0.924, 95% CI: 0.894 0.953) and prognostic (HR=1.55) marker for HCC. Down-regulated miR-101-1 also correlated with poor differentiation, advanced TNM stage, lymph node metastasis and high AFP level of HCC. Meta-analysis revealed that miR-101 down-regulation were associated with poor prognosis, high AFP level and advanced TNM stage of HCC. Moreover, 343 hub genes were filtered and miR-101-3p may be involved in intracellular signaling cascade, transcription, metabolism and cell proliferation. Focal adhesion and pathways in cancer were also significantly enriched. In vitro experiments demonstrated that miR-101-3p inhibited proliferation and promoted apoptosis in HCC cells. CONCLUSIONS: MiR-101-1 may be a prospective biomarker for diagnosis and prognosis of HCC. Potential targets of miR-101-3p could regulate genesis and development of HCC. The data offers insights into biological significances and promising targets of miR-101-3p for further investigation and potential therapies in HCC. PMID- 28559964 TI - Expression and prognostic value of glutamate dehydrogenase in extrahepatic cholangiocarcinoma patients. AB - Glutamate dehydrogenase (GDH) produces a precursor to glutathione, an important molecule in maintaining cellular redox balance and the cancerous characteristics of tumor cells through intracellular signaling pathways. However, the underlying molecular mechanisms linking glutamate dehydrogenase and extrahepatic cholangiocarcinoma have not been elucidated yet. Herein, we examined GDH expression levels and evaluated its potential correlations with prognosis. Meanwhile, the therapeutic value of GDH targeting the Smad pathways in extrahepatic cholangiocarcinoma was explored. Immunohistochemical studies revealed that GDH expression level was correlated to CD34 expression, cellular differentiation, the presence or absence of capsular and vascular invasion, lymph node metastasis, neural invasion and patient age. Kaplan-Meier survival analysis and COX proportional hazards models demonstrated that the prognosis was closely associated with GDH expression, CD34 positivity, nerve infiltration and cell differentiation. GDH silencing significantly reduced the proliferation, migratory potential and invasive capability. We also demonstrated that GDH promoted cell proliferation and metastasis potentially through Smad-mediated induction of TGF beta signaling pathway. Therefore, GDH may be an important prognostic indicator and may provide a new target for novel treatments of extrahepatic cholangiocarcinoma. PMID- 28559965 TI - Brainstem injury associated with supratentorial lesions is revealed by electronystagmography of the cold caloric reflex test. AB - To explore the brainstem injury associated with supratentorial lesions, we conducted analysis of ICP levels and detected ENG parameters by using the cold caloric reflex test and histopathological examinations of the brainstem. Rat model of intracerebral hemorrhage was well-established in the study of supratentorial lesions of varying severities (n=210). Intracerebral pressure monitoring and electronystagmography of the cold caloric reflex test were simultaneously performed in animals. Apoptotic, immunohistochemical, and histopathological changes in different segments of the brainstem were investigated at various time intervals. Electronystagmography parameters were analyzed by cold caloric reflex test. The result showed that the increase of intracerebral pressure was correlated with lesion severity including elevating levels and rostral-caudal progression of neuronal apoptosis, demyelination, N methyl-D-aspartate cell receptor down-regulation (r=0.815), and histopathological changes. Mutiple discrimination analysis of electronystagmography parameters presented a diagnostic accuracy rate of 79.5% in localizing brainstem injury. In conclusion, our data demonstrated that electronystagmography monitoring along with the cold caloric reflex test performed a favorable effect on the estimation of brainstem injury in ICH rat model, which provided a potential bedside diagnostic tool to assess and predict the progress of supratentorial lesion patient in future. PMID- 28559966 TI - Wedelolactone from Eclipta alba inhibits lipopolysaccharide-enhanced cell proliferation of human renal mesangial cells via NF-kappaB signaling pathway. AB - Mesangial cells of glomerulus which could produce and degrade several ECMs, take part in the repair and update of mesangial matrix and GBM, regulate glomerular filtration rate, secret cytokines and phagocytose immune complexes contribute a lot to physiological functions and pathological reactions of glomerular. There inflammation response of abnormal proliferation induced by LPS could lead to renal damage. Herein, wedelolactone, an active chemical constituent extracted from leaves of Eclipta alba, was used to explore if it could be an effective inhibitor of the proliferative response of HRMCs. The effects of different concentration wedelolactone on the secretion of cytokines, cell viability and NF kappaB pathway were all detected by qPCR, western blotting and ELISA. The results indicated that wedelolactone could inhibit the abnormal proliferation of HRMCs via regulating the activity of several key members of NF-kappaB signaling pathway. PMID- 28559967 TI - Effect of activation of Toll-like receptor 7 in the inhibition of allergic asthma on a mouse model. AB - Targeting Toll-like receptor 7 (TLR7) is known to have a potential therapeutic effect on experimental allergic asthma, but the exact mechanism is incompletely understood. To investigate the potential therapeutic effect of TLR7 agonist (TLR7a) a new versatile TLR7 agonist conjugated to Der f 1 was synthesized and evaluated in vivo here. It was confirmed that the course of airway hyperresponsiveness (AHR) and eosinophilia of the TLR7a vaccine-treated mice were limited. Levels of specific IgG1, IgG2a and IgE antibodies of these mice were changed obviously compared with that of the model mice. The expression of T helper 2 cytokine, interleukin (IL)-4, production in bronchoalveolar lavage fluid (BALF) and splenocytes were significantly decreased, while the levels of IFN gamma, IL-12 and IL-10 were increased after the treatment of TLR7a vaccine. In addition, Muc5 expression and goblet cells were significantly decreased in the lung tissue of asthma model mice treated with TLR7a plus Der f 1. These results suggest that the TLR7a-Der f 1 vaccine exhibits interesting therapeutic potency in suppressing allergic asthma and could be used a new agent in the treatment of allergic diseases. PMID- 28559968 TI - PEA3 protects against gentamicin nephrotoxicity: role of mitochondrial dysfunction. AB - Toxin-induced nephrotoxicity is one of the major causes leading to the acute kidney injury (AKI). Among these nephrotoxic toxins, gentamicin can induce AKI with elusive mechanisms. Emerging evidence demonstrated that PEA3 (polyomavirus enhancer activator 3) contributed to the nephrogenesis, while its role in AKI remains unknown. Thus, this study was to investigate the role of PEA3 in gentamicin nephrotoxicity, as well as the underlying mechanisms. In rats, gentamicin treatment (200 mg/kg twice per day) for two days induced remarkable kidney injury with a peak damage on day 5 evaluated by the tubular injury score, proteinuria, and tubular injury markers of NGAL and KIM-1. In parallel with the tubular injury, PEA3 protein and mRNA expressions were significantly upregulated by gentamicin and peaked on day 5. To define the role of PEA3 in gentamicin nephrotoxicity, proximal tubule cells were transfected with PEA3 plasmid with or without gentamicin treatment (1 mg/ml). Notably, overexpression of PEA3 attenuated gentamicin-induced cell injury shown by the ameliorated cell apoptosis and NGAL and KIM-1 upregulation. Meantime, gentamicin caused severe mitochondrial dysfunction, which was largely normalized by PEA3 overexpression. In contrast, silencing PEA3 by a siRNA strategy further deteriorated gentamicin-induced cell apoptosis and mitochondrial dysfunction. In sum, PEA3 protected against gentamicin nephrotoxicity possibly via a mitochondrial mechanism. PMID- 28559969 TI - Escape of U251 glioma cells from temozolomide-induced senescence was modulated by CDK1/survivin signaling. AB - Temozolomide (TMZ) has been widely used in conjunction with radiotherapy for treating various types of cancers. However, tumor cells arrested in senescence due to TMZ administration can sometimes escape and become drug resistant. In the current study, the possible role of survivin in the senescence escape of TMZ treated glioma cells was comprehensively studied. The levels of survivin and CDK1 expression in a human glioma cell line (U251) were monitored, and cell apoptosis, cell cycle distribution, anchorage-independent growth, and senescence were studied in U251 cells in different degrees of senescence. To further investigate how survivin affects the TMZ-resistance of gliomas, we modulated the levels of survivin and CKD1 expression in TMZ-treated cells and then examined how the treated cells responded. The results showed that knockdown of the survivin gene increased the sensitivity of glioma cells to TMZ treatment by inducing senescent cells to become apoptotic. Moreover, after senescence was induced, expression of the survivin gene became suppressed, but survivin levels returned to normal after the cells had escaped from senescence. While down-regulation of the survivin gene in senescent and senescence-escaping U251 cells had no effect on cell apoptosis, cell cycle distribution, or senescence status, it dramatically reduced the anchorage-independent growth ability of the cells. Additionally, CDK1 was able to not only enhance the anchorage-independent growth ability of the cells, but also contribute to their further senescence escape by modulating the survivin and other pathways. In conclusion, the survivin gene was necessary for glioma cells to escape from and enter into senescence during treatment with TMZ. PMID- 28559970 TI - The lncRNA n340790 accelerates carcinogenesis of thyroid cancer by regulating miR 1254. AB - Long non-coding RNAs (lncRNAs) have been recently reported to be dysregulated and play a critical role in the progression of thyroid cancer. Here, we found that the lncRNA n340790 was highly expressed in human thyroid cancer tissues and was strongly correlated with the clinical characteristics of patients. There was a good prognostic value of n340790 for thyroid cancer. In vitro overexpression of n340790 promoted the development of thyroid cancer, while silencing n340790 inhibited this process. Additionally, n340790 accelerated the growth of thyroid cancer tumor in vivo. Furthermore, we discovered that n340790 could act as an endogenous sponge by directly binding to miR-1254 and downregulating miR-1254 expression. In addition, miR-1254 could inhibit the stimulatory effect of n340790 on the growth and invasion of thyroid cancer cells. In conclusion, n340790 promoted the development process of malignant thyroid cancer by regulating miR 1254, and targeting n340790 may be a promising strategy as a thyroid cancer therapy. PMID- 28559971 TI - Astragalus polysaccharides attenuates TNF-alpha-induced insulin resistance via suppression of miR-721 and activation of PPAR-gamma and PI3K/AKT in 3T3-L1 adipocytes. AB - Insulin resistance is associated with obesity and type 2 diabetes. The aim of this study was to explore the mechanism of how Astragalus Polysaccharides (APS) improves insulin resistance in 3T3-L1 adipocytes. A cell culture model of insulin resistance was established in mature 3T3-L1 adipocytes by treating them with TNF alpha, high glucose and insulin. Glucose uptake levels were detected in each group. To determine the mechanism by which APS improves insulin resistance in 3T3 L1 adipocytes, qRT-PCR was used to detect the expression of miR-721, and Western blots were used to detect the expression or activity of PPAR-gamma, PAKT, PI3K, AKT, and GLUT4. Immunostaining was used to detect the expression of GLUT4. We successfully madea model of insulin resistance in mature 3T3-L1 adipocytes. APS increased glucose uptake levels in insulin-resistant adipocytes in a dose- and time-dependent manner, and also increased insulin sensitivity. APS suppressed miR 721 with its target gene PPAR-gamma in a dose-dependent manner. miR-721 or PPAR inhibitor T0070907 inhibited the expressions of PPAR-gamma, pAKT, and GLUT4 and also reduced glucose accumulation. APS attenuated these miR-721- and PPAR-gamma induced changes. APS increased insulin sensitivity by attenuating the effects of miR-721. The PI3K inhibitor wortmannin reduced the APS-increased pAKT, glucose uptake, and GLUT4 levels, and also reduced those levels in the presence of insulin with or without APS. Taken together, our findings suggest that APS promotes glucose uptake and increases insulin sensitivity in 3T3-L1 adipocytes and may involve the miR-721-PPAR-gamma-PI3K/AKT-GLUT4 signaling pathway. These might be new therapeutic targets for treating insulin resistance in obesity and diabetes. PMID- 28559972 TI - FOXQ1 promotes cancer metastasis by PI3K/AKT signaling regulation in colorectal carcinoma. AB - Colorectal cancer is one of the major health problems, with invade surrounding tissues, and migrate to distant organs being the most critical concern, thus identified metastasis associated hallmarks and more efficacious treatment are urgently needed. It found that forkhead box q1 (FOXQ1) is aberrant expression in variety of human cancers and FOXQ1 is involved in oncogenic pathways. However, the role of FOXQ1 has been unexplored in colorectal cancer metastasis to date. Here, expression of FOXQ1 was higher in colorectal cancer tissue samples and cancer cell lines than in normal colorectal tissue and cell lines. Further research suggested that FOXQ1 positively regulated cell proliferation in colorectal cancer and down-regulation of CDK6, extracellular regulated protein kinases 1/2 (ERK1/2) and mammalian target of rapamycin (mTOR). In corresponding to this result, over-expression of FOXQ1 significantly promoted colorectal cancer growth in vivo. Moreover, down regulation of FOXQ1 expression in colorectal carcinoma cell HCT116 and LOVO strikingly inhibits tumor growth in vivo. Finally, FOXQ1-dependent inhibition of colorectal cancer cell migration and invasion and down-regulation of focal adhesion kinase (FAK), phosphatidyl inositol 3-kinase (PI3K) phosphorylation, AKT (v-akt murine thymoma viral oncogene) phosphorylation and matrix metalloproteinase-2/9 (MMP-2/9) expression. These integrated efforts have identified FOXQ1 as a tumor promoter and might provide promising approaches for colorectal cancer metastasis treatment. PMID- 28559973 TI - Research on the traditional Chinese medicine treating gastrointestinal motility in diabetic rats by improving biomechanical remodeling and neuroendocrine regulation. AB - Previous studies have demonstrated that TWA, a Chinese herbal medicine, could significantly improve the symptoms of patients with diabetic gastrointestinal dysfunction. However, the specific mechanism of regulating intestinal peristalsis has not been found. This study aimed to discover TWA's therapeutic mechanism for regulating intestinal motility. The intestinal propulsion rate of diabetic rats was significantly increased after treatment with TWA for 8 weeks. Aiming at the mechanical structure, biomechanical testing indicated that TWA can significantly decrease the no-load intestinal wall thickness, cross-sectional area, and angular spread in a zero-stress state. Notably, intestinal stress-strain curve shifted to the right, which indicated TWA can inhibit intestinal hyperplasia and hardening and improve biomechanical remodeling. Further study of the mechanism revealed that TWA significantly inhibited the expression of AGE in the villi, crypt, and muscle and RAGE in crypt and upregulated the expression of nerve regulator (PSD95, C-kit and SCF). Radioimmunoassay showed TWA treatment decreased levels of serum somatostatin and vasoactive intestinal peptide. Moreover, associations were found between the intestinal propulsion rate with the morphologic and biomechanical remodeling parameters, changes of nerve factors, and endocrine hormones. Morphologic and biomechanical remodeling of the intestinal wall are the pathologic basis of gastrointestinal dysfunction. TWA can benefit intestinal motility by improving biomechanical and morphologic remodeling and by regulating expression of neuroendocrine factors. The results showed that the effect of TWA was dose-dependent, the higher the dose, the greater is the improvement. Thus, traditional Chinese medicine might be a valuable tool for treating diabetic gastrointestinal dysfunction. PMID- 28559975 TI - Inhibition of glioblastoma growth and invasion by 125I brachytherapy in rat glioma model. AB - Development of the novel targeted therapies for glioblastoma multiforme is very important. Brachytherapy has been proven to provide a good alternative to surgical removal of the prostate, breast and cervix with reduced risk of certain long-term side effects. Thus, 125I brachytherapy was used to effect on the growth and invasion of glioma cells in vitro and in vivo. The inhibitory effect of 125I seeds on C6 cells proliferation was determined by MTT assay. A rat intracranial glioma model was established and the 125I seeds were implanted into the glioma area. CD31 expression was determined by immunohistochemical method to evaluate the angiogenesis. The DeltaPsim detection and cell invasion assays were performed to detect the mitochondrial-induced apoptosis and invasion signaling in tumor cells. 125I brachytherapy could significantly inhibit C6 rat glioma cells growth and reduce cell viability in vitro. The seeds implantation also inhibited tumor growth in the rat glioma model and improved survival rate. Analysis revealed that ROS production and the intrinsic mitochondrial pathway of apoptosis was activated by 125I brachytherapy. The HE staining results revealed that the rat glioma model treated with 125I seeds exhibited better defined tumor margins and fewer invasive cells to the lateral striatum compared with the untreated group. The comparison of expression of CD31 in treated or untreated groups was performed to show that the 125I brachytherapy has potential antiangiogenic activity. Meanwhile, 125I brachytherapy can inhibit the growth and invasion of glioma cells via decreasing the expression of MMP-2 and MMP-9. PMID- 28559974 TI - Melatonin prevents sleep deprivation-associated anxiety-like behavior in rats: role of oxidative stress and balance between GABAergic and glutamatergic transmission. AB - Sleep deprivation (SD) has been shown to induce anxiety-like behavior. Melatonin, an endogenous potent antioxidant, protects neurons from oxidative stress in many disease models. Here we investigated the effect of melatonin against SD-induced anxiety-like behavior and attempted to define the possible mechanisms involved. SD was induced in rats using modified multiple platform model. Melatonin (15 mg/kg) was administered to the rats via intraperitoneal injection. The elevated plus maze test, open field test and light-dark exploration were used to evaluate anxiety-like behavior. Serum corticosterone was measured to determine stress level. Malondialdehyde (MDA) level and superoxide dismutase (SOD) enzyme activity of amygdala and serum were performed to determine the level of oxidative stress. Levels of protein were detected by means of Western blot. The results showed that SD induces anxiety-like behavior, while melatonin treatment prevented these changes. Serum corticosterone also increased with SD but its levels were normalized by melatonin. In addition, melatonin reversed SD-induced changes in MDA and SOD in both of amygdala and serum. The results of Western blot showed that melatonin attenuated the up-regulation of NR2B-containing N-methyl-D aspartate receptors, GluR1 subunit of the alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor as well as phosphorylation of GluR1 at Ser831, and Ca2+/calmodulin-dependent protein kinase II-alpha in SD rats. Meanwhile, melatonin blocked the down-regulation of gamma-aminobutyric acid A-alpha-2 receptor. In conclusion, our results suggest that melatonin prevents anxiety-like behavior induced by SD. The possible mechanism may be attributed to its ability to reduce oxidative stress and maintain balance between GABAergic and glutamatergic transmission. PMID- 28559976 TI - Quantitative photoacoustic imaging for early detection of muscle ischemia injury. AB - Acute lower extremity ischemia is a limb-and life-threatening problem. The timing of clinical intervention is critical to achieving optimal outcomes. However, there has been a lack of effective techniques capable of evaluating muscle and limb damage. Microcirculatory injury is the initial pathological change during ischemic muscle injury. Here, we performed photoacoustic imaging (PAI) in real time to quantitatively detect the degree of microcirculatory injury of ischemic muscles in a rat model in which Evans blue (EB), which strongly binds to albumin in blood, was used as a nontoxic molecular PA probe. The right lower hind limbs of Sprague-Dawley (SD) rats were subjected to 2 or 3 hours of tourniquet-induced ischemia. Then, PA imaging of the tibialis anterior (TA) muscles in the anterior compartment was performed for 0-24 h after the release of compression. Twenty four hours after reperfusion, rats were euthanized and examined for pathology, edema and muscle viability. Imaging at 680 nm on rats revealed that there was significant signal enhancement in the TA muscles of the two injury groups compared to the control group, and the 3-h injury group had significantly higher PA signal intensity than the 2-h injury group at each time point. Histopathology results obtained from both the normal and the damaged muscles correlated well with the PAI findings. In conclusion, PA imaging is a promising modality for quantitatively detecting limb and muscle ischemic injury and may pave the road for further clinical application. PMID- 28559977 TI - Oxysophocarpine reduces oxygen-glucose deprivation-induced microglial activation and injury. AB - Microglial over-activation and apoptosis are associated with ischemic brain diseases. These processes may be hindered by oxysophocarpine (OSC) that generates anti-inflammatory and anti-apoptotic activities. However, the precise roles of OSC in microglial inflammation and apoptosis induced by oxygen-glucose deprivation/reoxygenation (OGD/R) remain unclear. In this study, we found that OSC reduced OGD/R-induced inflammation in BV-2 microglia. OSC elevated cell viability and prevented the release of lactate dehydrogenase. OSC downregulated cyclooxygenase 2 and inducible nitric oxide synthase and reduced the levels of inflammatory mediators, including tumor necrosis factor-alpha, interleukin (IL) 1beta, IL-6, monocyte chemoattractant protein-1, prostaglandin E2, and nitric oxide. OSC inhibited the expression of Toll-like receptor 4 (TLR4) and myeloid differentiation protein 88 (MyD88) and blocked the activation of nuclear factor (NF)-kappaB. In addition, OSC suppressed OGD/R-elicited BV-2 cell apoptosis, as indicated as follows: The restored mitochondrial membrane potential and the reduced caspase-3 activity; the decrease of Bax and cleaved caspase-3 and the increase of Bcl-2; the enhanced phosphorylation of Akt and mTOR. These results implied that OSC impedes OGD/R-induced inflammation and apoptosis of microglial cells. Therefore, OSC may be potentially used for ischemic stroke therapy. PMID- 28559978 TI - miR-143-3p targeting LIM domain kinase 1 suppresses the progression of triple negative breast cancer cells. AB - Breast cancer is the most common cancer in women worldwide. Triple-negative breast cancer is one of the most aggressive types of breast cancer as it has the worst clinical outcome for patients. microRNAs are a type of small non-coding RNA and play an important role in breast cancer. The purpose of this study was to explore the potential function and mechanism of miR-143-3p in triple-negative breast cancer (TNBC). MTT and colony formation assays, the effect of miR-143-3p modulation on MDA-MB-231 cell proliferation, revealed that increased miR-143-3p expression inhibited the proliferation of MDA-MB-231 TNBC cells. Moreover, miR 143-3p overexpression inhibited the movement of MDA-MB-231 TNBC cells in wound healing and transwell assays. To identify a potential miR-143-3p target, we investigated the effect of miR-143-3p modulation on LIMK1 expression level. Increased miR-143-3p expression caused a reduction in LIMK1 mRNA and protein, suggesting that LIMK1 is a target of miR-143-3p. In addition, dual-luciferase reporter assays showed that LIMK1 is a target gene of miR-143-3p. Flow cytometry analysis indicated that miR-143-3p arrested MDA-MB-231 TNBC cells at the G0/G1 phase. The TCGA (The Cancer Genome Atlas) database demonstrated that miR-143-3p was down-regulated in breast cancer tissues compared with normal breast tissues. These data demonstrated that miR-143-3p functioned as a suppressor gene in TNBC and that miR-143 targeted therapy may be a new strategy for TNBC treatment. PMID- 28559979 TI - A new comorbidity model and the common pathological mechanisms of migraine and epilepsy. AB - A bi-directional relationship between epilepsy and migraine has been widely reported in epidemiological and clinical studies, but the mechanisms of interaction between these disorders have not been fully examined using animal models. The aim of the present study was to develop a new comorbidity model of migraine and epilepsy. Nociception was induced by applying an inflammatory soup to the dura mater; this procedure resulted in nociception similar to that expressed in inflammatory disorders such as migraine. We showed that nociceptive behaviors (head rubbing, including with the forepaws and hindpaws) were significantly enhanced in comorbidity rats compared to sham-operation (Sham) rats, and these nociceptive behaviors were correlated with epilepsy-like behaviors. The plasma levels of calcitonin gene-related peptide (CGRP) significantly increased in the migraine group compared with the sham group, but CGRP did not further increase in comorbidity rats compared with migraine rats. C Fos immunoreactive area values were higher in the comorbidity group than in the migraine group in the trigeminal nucleus caudalis (Sp5C) area (P<0.05). There was no significant difference in HSP70 expression between the comorbidity group and the epilepsy group. The expression of brain-derived neurotrophic factor (BDNF) in the CA3 area of the hippocampus in the comorbidity group was significantly higher than that in the epilepsy group according to the immunohistochemical test (P<0.05). In conclusion, our findings indicate that pilocarpine-induced epilepsy exacerbates inflammatory nociception, which can aggravate seizure severity. Moreover, we established a new comorbidity model for migraine and epilepsy. PMID- 28559980 TI - All-trans-retinoic acid activates SDF-1/CXCR4/ROCK2 signaling pathway to inhibit chondrogenesis. AB - Recent studies have indicated that ATRA inhibits chondrogenesis and can lead to congenital clubfoot (CCF). The molecular mechanism of ATRA-induced chondrogenesis is not clear. As RhoA/ROCK and SDF-1/CXCR4 signaling play important molecular roles for a variety of cellular processes, we hypothesized that RhoA/ROCK2 and SDF-1/CXCR4 signaling are involved in ATRA-induced chondrogenesis in rat embryo hind limb bud mesenchymal cells (rEHBMCs). We found that ATRA dose-dependently inhibits proliferation and expression of chondrogenic transcription factors (SOX9 and COL2A1) in rEHBMCs. In contrast, ATRA increases the expression of ROCK2, SDF 1 and CXCR4. Pharmacological inhibition of ROCK signaling and SDF-1/CXCR4 signaling by Y27632 and AMD3100, respectively, resulted in elevated expression of SOX9 and COL2A1. In addition, we found that disturbing SDF-1/CXCR4 signaling by AMD3100 decreases ATRA-induced ROCK2 expression. In vivo studies we also confirm that SOX9 expression of early-stage cartilage progenitors in the proliferative zone and COL2A1 expression in prehypertrophic chondrocytes are decreased in ATRA treated rat embryo hind limb. Together, these results show that ATRA activates SDF-1/CXCR4/ROCK2 signaling to inhibit chondrogenesis to lead to CCF by suppressing differentiation through down-regulation of SOX9 and COL2A1 expression in rat embryo hind limb bud mesenchymal cells. PMID- 28559981 TI - Examination of histopathological changes of scalpel, monopolar, bipolar, and thermocautery applications in rat experimental circumcision model. AB - This study endeavors to analyze the effects of thermocautery, bipolar cautery, monopolar cautery, and the scalpel to show that the thermocautery is a safe device to be used in circumcision. Twenty-four rats were assigned to 4 different groups: the scalpel, thermocautery, bipolar cautery, and monopolar cautery groups. Circumcisions were performed using the scalpel, thermocautery, bipolar cautery, or monopolar cautery devices. The circumcised foreskin was removed for histopathological analysis. The circumcision techniques were compared in terms of the depth of injury on the prepuce. Wound healing on the 5th day on the circumcision plane was evaluated by using a grading scale from 0-4 and by comparing re-epithelization, granulation tissue, and collagen deposition. Blood samples were taken 1st hour after the operation and the 5th day, prior to the necropsy. The totals of the oxidant/anti-oxidant levels were determined. For statistical analyses, the SPSS packet program was used. Statistical significance was determined as a P value <0.05. The least trauma was with the scalpel which was comparable with the thermocautery in regard to depth of injury, epithelization, granulation tissue formation, and collagen buildup. Thermocautery group showed superior collagen proliferation compared with the monopolar cautery group, while being superior in epithelization and injury depth when compared with the bipolar cautery group. The use of thermocautery for circumcision has shown to be safe and resulted in better wound healing in rats with no apparent complications, and, if used in the human population, it may be a safe and effective technique. PMID- 28559982 TI - Long noncoding RNAs and novel inflammatory genes determined by RNA sequencing in human lymphocytes are up-regulated in permanent atrial fibrillation. AB - Atrial fibrillation (AF) is a common arrhythmia in clinical practice. Currently, approximately 33.5 million individuals are affected by AF globally. AF involves multiple complicated mechanisms which have not been fully investigated yet. RNA sequencing (RNAseq) is an outstanding method for investigation of diseases due to its high-throughput information. Here, RNAseq was applied to determine mRNA and long noncoding RNA (lncRNA) expression profiles in human lymphocytes from 6 permanent atrial fibrillation (pmAF) patients and 6 healthy controls. Quantitative real-time PCR (qRT-PCR) was applied to further validate 3 lncRNAs and 4 inflammatory mRNAs. It was discovered that there were numerous differentially-expressed mRNAs and lncRNAs between these two groups. GO analysis indicated that differentially-expressed mRNAs were mainly involved in native immunity, inflammation, signaling transduction and so forth, and they were also enriched in pathways like TNF signaling pathway, NF-kappa B signaling pathway, Toll-like receptor pathway and NOD-like receptor pathway. Moreover, co-expression network demonstrated that dysregulated mRNAs and lncRNAs in pmAF lymphocytes participated in inflammation, autophagy, mitochondrial functions, oxidative stress, etc. Further validation by qRT-PCR demonstrated mRNAs and lncRNAs were significantly higher in lymphocytes from pmAF patients compared with controls. In conclusion, mRNA and lncRNA expression profiles in lymphocytes are significantly different between pmAF and controls, differentially-expressed mRNAs and lncRNAs are involved in pathways closely associated with inflammation, oxidative stress, autophagy, cell apoptosis and collagen synthesis, suggesting lymphocytes might play indispensable roles in the development of pmAF. PMID- 28559983 TI - Feedback between E2F1 and CIP2A regulated by human papillomavirus E7 in cervical cancer: implications for prognosis. AB - Previously, we found that cancerous inhibitor of protein phosphatase 2A (CIP2A) plays a key role in the malignant transformation of cervical cancer. Here, we further explore whether and how CIP2A is regulated by human papillomavirus E7 (HPV E7) and the prognostic value of CIP2A in cervical cancer. We demonstrated a positive feedback loop between the E2F transcription factor 1 (E2F1) and CIP2A at the transcription level in HeLa and SiHa cells by real-time PCR and western blot analysis. The feedback, regulated by HPV E7, was further confirmed by their sub cellular co-expression seen on immunofluorescence and immunohistochemistry staining in vitro and in vivo. Moreover, CIP2A and E2F1 expression was greatly elevated in human cervical cancer tissue. CIP2A expression was tightly associated with tumor size, depth of invasion and lymph node metastasis in 184 cases of cervical cancer. Kaplan-Meier and Cox proportional-hazards regression analyses revealed poor overall and disease-free survival of patients with CIP2A-E2F1 co expression, and high CIP2A-E2F1 co-expression was an independent risk factor for overall survival of patients. Therefore, CIP2A-E2F1 expression might be a valuable indicator to predict outcome and guide personal treatment in cervical cancer. PMID- 28559984 TI - Ulcer healing effect of autologous mixed sheets consisting of fibroblasts and peripheral blood mononuclear cells in rabbit ischemic hind limb. AB - We developed mixed cell sheets consisting of fibroblasts and peripheral blood mononuclear cells that had high potency for secreting vascular endothelial growth factor. The purpose of this study was to confirm the therapeutic effects of mixed sheets in rabbits suffering from ulcers at the ischemic hind limbs. We used the ulcer model, which was constructed by implantation and sandwiching the skin between two magnets to be a representative of human refractory cutaneous ulcer. The ulcer healing rate of mixed cell sheets was higher than that of the control at an early stage of healing. The calf blood pressure and angiographic score, which were considered to reflect rough collateral blood flow, did not vary amongmixed cell sheets. However, through laser Doppler perfusion image, implantation of mixed cell sheets revealed a significant improvement in microvascular blood flow in the healed skin of the ischemic limb compared to trafermin, a recombinant human basic fibroblast growth factor, and the control. These results suggest that mixed cell may operate predominantly on the surface of the ischemic tissue by their angiogenic potency, thereby promoting healing of the ischemic ulcer. Mixed cell sheets could become a promising therapeutic material for refractory cutaneous ulcers. PMID- 28559985 TI - Peptide-modified chitosan hydrogels promote skin wound healing by enhancing wound angiogenesis and inhibiting inflammation. AB - Cutaneous wound healing following trauma is a complex and dynamic process involving multiple overlapping events following trauma. Two critical elements affecting skin wound healing are neovascularization and inflammation. A nascent vessel can provide nutrition and oxygen to a healing wound. Therefore, treatments strategies that enhance angiogenesis and inhibit inflammation can promote skin wound healing. Previous studies have shown that the SIKVAV peptide (Ser-Ile-Lys Val-Ala-Val) from laminin can promote angiogenesis in vitro. This study evaluated the effects of peptide SIKVAV-modified chitosan hydrogels on skin wound healing. We established skin wounds established in mice and treated them with SIKVAV modified chitosan hydrogels. H&E staining showed that peptide-modified chitosan hydrogels accelerated the reepithelialization of wounds compared with the negative and positive controls. Immunohistochemistry analysis demonstrated that more myofibroblasts were deposited at wounds treated with peptide-modified chitosan hydrogels that at those treated with negative and positive controls. In addition, peptide-modified chitosan hydrogels promoted angiogenesis as well as keratinocyte proliferation and differentiation, but inhibited inflammation in skin wounds. Taken together, these results suggest that SIKVAV-modified chitosan hydrogels are a promising treatment component for healing-impaired wounds. PMID- 28559986 TI - Severe traumatic hemorrhagic shock induces compromised immune barrier function of the mesenteric lymph node leading to an increase in intestinal bacterial translocation. AB - Critically ill patients have increased susceptibility to translocation of gut bacteria. However, the mechanisms are complicated and remain unclear, and the aim of this study was to explore these mechanisms. Rats exposed to different levels of shock were orally administrated with bioluminescent Citrobacter. We found that severe shock caused an increase in bacterial translocation to the visceral organs, such as liver, spleen and blood, compared with mild shock. Surprisingly, bacterial translocation to mesenteric lymph node (MLN) was unchanged between the two shock groups. Various methods, including flow cytometry, a co-culture model and western blots, were used to evaluate MLN-associated immune function. Specifically, we focused on mesenteric lymph node dendritic cells (MLN-DCs), the critical antigen presenting cells involved in the construction of the immune barrier in MLN. We also found that severe shock impaired the phenotypic maturation of MLN-DCs and induced a tolerogenic phenotype. Furthermore, co culture assays of DCs with naive CD4+ T cells showed that DCs subject to severe shock were more inclined to polarize native CD4+ T cells into Th2 and Treg cells. This study successfully reproduced the clinical phenomenon of severe shock resulting in increased bacterial translocation to extraintestinal tissues, and this may be related to the compromised immune barrier function of MLN, as maturation and function of MLN-DC's were badly impaired. PMID- 28559988 TI - MiR-31 is involved in the high glucose-suppressed osteogenic differentiation of human periodontal ligament stem cells by targeting Satb2. AB - Diabetes mellitus (DM) is a chronic metabolic disease that gives rise to impaired bone remodeling. Increasing evidences have shown that miRNAs are associated with osteogenic differentiation of stem cells. However, the underlying mechanism that links DM-induced HG conditions and impaired osteogenic differentiation capacity of periodontal ligament stem cells (PDLSCs) still remains unclear. In this study, we found that diabetic mice with increased miR-31 level in periodontal ligaments exhibited greater bone loss. In vitro, the high expression of miR-31 is associated with the impaired osteogenic differentiation ability of PDLSCs in high glucose environment. Furthermore, miR-31 inhibitors increased mineralized bone matrix formation and raised Runx2, Osx and OCN expression at both mRNA and protein levels. However, PDLSCs pretreated with miR-31 mimics decreased bone matrix formation and reduced Runx2, Osx and OCN expression level in high glucose microenvironment. Moreover, Satb2 was identified as a target of miR-31 which directly binds to its 3'-untranslated region. To further elucidate the effect of Satb2 in miR-31-mediated osteogenic differentiation, PDLSCs were transfected with Satb2 siRNA and miR-31 inhibitors. The results showed that Satb2 siRNA inhibited osteogenic differentiation of PDLSCs in HG, whereas miR-31 inhibitors reversed the repression of osteogenic differentiation in Satb2 siRNA transfected PDLSCs. Taken together, these results demonstrate that miR-31 is involved in the high glucose-suppressed osteogenic differentiation of PDLSCs by targeting Satb2. PMID- 28559987 TI - microRNA-383 mediates high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells by repressing peroxiredoxin 3. AB - Hyperglycemia-mediated damage to retinal pigment epithelial (RPE) cells plays a central role in the pathogenesis of diabetic retinopathy. Dysregulation of microRNA (miR)-383 modulates pancreatic beta cell survival in diabetes; however, its role in diabetic retinopathy remains unclear. In this study, we examined the expression of miR-383 in ARPE-19 human RPE cell lines after high glucose treatment and investigated its functions in high glucose-induced reactive oxygen species (ROS) generation and apoptotic responses. The downstream target gene that mediated the action of miR-383 was functionally characterized. It was found that high glucose induced a 2.4-fold increase in miR-383 abundance, compared to ARPE 19 cells treated with normal glucose. Overexpression of miR-383 inhibited cell viability and promoted apoptosis and ROS formation in ARPE-19 cells, which was coupled with deregulation of Bcl-2 and Bax. Peroxiredoxin 3 (PRDX3) expression was repressed by miR-383 in ARPE-19 cells. Restoration of PRDX3 counteracted miR 383-induced ROS generation and apoptosis, while silencing of PRDX3 phenocopied the detrimental effects of miR-383 on ARPE-19 cells. Delivery of anti-miR-383 inhibitors led to an increase of PRDX3 expression and prevented high glucose elicited ROS formation and apoptosis in ARPE-19 cells. Overall, miR-383 upregulation accounts for high glucose-induced oxidative stress and apoptosis in RPE cells by repressing PRDX3 expression. Targeting miR-383 may have therapeutic potential in the treatment of diabetic retinopathy. PMID- 28559989 TI - MicroRNA-142-5p promotes cell growth and migration in renal cell carcinoma by targeting BTG3. AB - PURPOSE: Some microRNA (miRNA) levels have been found to be dysregulated in cancer patients, suggesting the potential usefulness of miRNAs in cancer therapies. The purpose of this study was to investigate the expression of miR-142 5p in human renal cell carcinoma (RCC) and its potential role in tumor growth and metastasis. METHODS: The expression level of miR-142-5p in human RCC tissue and cell lines was determined by quantitative reverse transcription polymerase chain reaction analysis. MTT, colony formation, Transwell, and cell cycle assays were performed to explore the potential functions of miR-142-5p in human RCC cells. The potential target gene of miR-142-5p was identified and confirmed via luciferase reporter assays. RESULTS: miR-142-5p expression was elevated in RCC tissues and cell lines. Overexpression of miR-142-5p significantly promoted cell proliferation and colony formation and could prevent G1 phase arrest among RCC 786-O cells. Meanwhile, the migration potential of 786-O cells was greater than that of control cells. BTG3 was identified as a direct target of miR-142-5p, and re-expression of BTG3 reversed the miR-142-5p-induced cell proliferation. CONCLUSION: miR-142-5p promoted the proliferation and migration of RCC cells by targeting BTG3. With this potential onco-miRNA role in the progression of RCC, miR-142-5p may be a therapeutic target for the treatment of RCC. PMID- 28559990 TI - Macrophages activating chemokine (C-X-C motif) ligand 8/miR-17 cluster modulate hepatocellular carcinoma cell growth and metastasis. AB - Macrophages are a major component of tumor stroma and the infiltrated macrophages in malignant tumor tissues (as called tumor associated macrophages, TAM) play a pivotal role in hepatocellular carcinoma (HCC) progression. However, the molecular mechanisms of macrophages promoting HCC metastasis are poorly understood. The study was to investigate the effects of macrophages on liver cancer cell proliferation and metastasis through chemokine (C-X-C Motif) Ligand 8 (CXCL8). We found that macrophages activated by co-cultured liver cancer cells produced higher levels of CXCL8, which accelerated cell growth and metastasis. The expression of miR-18a and miR-19a (belonging to miR-17 cluster) increased in HCC cells by CXCL8 simulation and led to the enhancement of HCC cell proliferation and metastasis. In a conclusion, HCC cells and macrophages interaction promoted cancer cell proliferation and metastasis through the up regulation of CXCL8/miR-17 cluster. PMID- 28559991 TI - Exogenous MSCs ameliorate hypoxia/reoxygenation injury in renal tubular epithelial cells through JAK/STAT signaling pathway-mediated regulation of HMGB1. AB - This study was conducted to investigate the repair mechanism of hypoxia/reoxygenation injury (HRI) in renal tubular epithelial cells (HK-2) by exogenous mesenchymal stem cells (MSCs). The activation of the JAK/STAT pathway in HK-2 cells after HRI and treatment of MSCs, JAK inhibitor WP1066 and STAT inhibitor SOCS3 was investigated using Western blot analysis. HK-2 cells were transfected with siRNA STAT3 and analyzed for expression of STAT3, JAK2 and HMGB1 using fluorescence quantitative PCR and Western blot. Cell viability and apoptosis were analyzed using the MTT assay and flow cytometry. After HRI, the JAK/STAT pathway in HK-2 cells was activated, resulting in the upregulation of JAK1, JAK2, JAK3, p-JAK1, p-JAK2, p-JAK3, STAT1, STAT2, STAT3, p-STAT1, p-STAT2 and p-STAT3. After treatment with MSC conditioned medium (MSCs CM), WP1066, or SOCS, the expression of these proteins was significantly down-regulated. When the cells were transfected with siRNA STAT3, the expression of STAT3 at protein and mRNA levels and JAK2 and HMGB1 at mRNA level was down-regulated; the cell viability was reduced and apoptosis increased. It is concluded that exogenous MSCs reduce HRI of HK-2 cells by suppressing the JAK/STAT signaling pathway and down-regulating the expression of HMGB1. PMID- 28559992 TI - Delivery of adipose-derived mesenchymal stem cells attenuates airway responsiveness and inflammation in a mouse model of ovalbumin-induced asthma. AB - Adipose-derived mesenchymal stem cells (ADMSCs) possess immunomodulation property, yet their therapeutic potential in asthma is unclear. This study aimed to explore the effects of ADMSCs on airway hyperresponsiveness and inflammation in ovalbumin (OVA)-induced asthma models. The underlying mechanism(s) was also examined. BALB/c mice were sensitized with OVA on days 0, 7, and 14, followed by 8-week OVA challenge from day 22. ADMSCs were injected via tail vein on day 21. Animals were measured for airway responsiveness, lung pathology, IgE and cytokine levels in serum, cell composition in bronchoalveolar lavage fluid (BALF), gene expression in the lung, and regulatory T cells (Tregs). We found that delivery of ADMSCs decreased airway responsiveness and eosinophil counts in BALF and reduced infiltration of inflammatory cells and number of mucus-expressing goblet cells in the lung in OVA-challenged mice. OVA-evoked elevation of serum IgE levels and alteration of cytokine production in serum and BALF was significantly prevented by ADMSCs. In addition, administration of ADMSCs impaired the regulation of lung IL-10, Foxp3, IL-17, and RORgamma expression by OVA challenge and restored the percentage of CD4+CD25+Foxp3+ Tregs in the spleen. In conclusion, ADMSCs confer protection against OVA-induced airway hyperresponsiveness and inflammation, which is associated with induction of Tregs and restoration of immune homeostasis. These findings suggest that ADMSCs may have therapeutic implications for allergic asthma. PMID- 28559993 TI - Propofol inhibits cell proliferation and invasion in rheumatoid arthritis fibroblast-like synoviocytes via the nuclear factor-kappaB pathway. AB - Propofol is an anesthetic drug commonly used in the clinical practice. The aim of this study is to explore the effect of propofol on the aggressive behaviors of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs). Propofol treatment for 48 or 72 h significantly inhibited the viability of RA-FLSs, but a 24-h treatment did not produce cytotoxic effects. Propofol exposure for 48 h led to reduction of proliferation and induction of apoptosis in RA-FLSs, which was coupled with increased Bax and decreased Bcl-2 and survivin levels. Additionally, treatment with propofol for 24 h significantly suppressed the migration and invasion of RA-FLSs. Mechanistically, propofol inhibited nuclear factor-kappaB (NF-kappaB) activity. Overexpression of constitutively active NF-kappaB p65 reversed the inhibitory effects of propofol on RA-FLSs. Taken together, propofol exerts anti-proliferative and anti-invasive effects on RA-FLSs via the NF-kappaB pathway and may have therapeutic potential in treatment of RA. PMID- 28559994 TI - MiR-144-3p inhibits cell proliferation and induces apoptosis in multiple myeloma by targeting c-Met. AB - MicroRNA-144-3p (miR-144-3p) has been implicated in the development of many types of cancer. However, its role in multiple myeloma (MM) remains largely unknown. In this study, we found that miR-144-3p was downregulated in both MM cell lines and plasma from patients with MM. In vitro studies further showed that transfection of an miR-144-3p mimic into MM cells inhibited their proliferation and colony formation, and promoted cell cycle arrest at the G0/G1 phase and apoptosis. In addition, we found that miR-144-3p could directly target the 3'-untranslated region of cellular-mesenchymal to epithelial transition factor (c-MET) and suppress c-MET expression and its downstream signaling pathway (PI3K/AKT). Rescue experiments revealed that overexpression of c-MET partially reversed the inhibition effect of miR-144-3p in MM cells. In vivo studies confirmed that restoration of miR-144-3p suppressed tumor growth in xenograft nude mice by repressing c-MET. Overall, these findings demonstrate that miR-144-3p functions as a tumor suppressor in MM by targeting c-MET, suggesting that miR-144-3p might serve as a potential therapeutic target in MM. PMID- 28559995 TI - Cryptotanshinone reverses reproductive disturbances in rats with dehydroepiandrosterone-induced polycystic ovary syndrome. AB - Polycystic ovarian syndrome (PCOS), with a prevalence of 5-8%, is the most common endocrine disorder in women of reproductive age. Although cryptotanshinone (CRY) has been shown to effectively reverse reproductive disturbances, it remains poorly understood whether it can be used to treat PCOS. Here we used an established rat model of PCOS. Prepubertal female Sprague-Dawley rats were subcutaneously injected with dehydroepiandrosterone (DHEA) 60 mg/kg/day for 3 weeks. Those in the DHEA group were given normal saline, while the CRY group was given 27 mg/kg by gastrogavage for 3 weeks. DHEA-treated rats had irregular estrous cycles and significantly increased ovarian weight compared to control rats (P < 0.05), and 3 weeks of treatment with CRY in DHEA-treated rats significantly decreased ovarian weight (P < 0.05). CRY decreased the levels of testosterone, estradiol, and luteinizing hormone (LH) as well as the LH/follicle stimulating hormone ratio (P < 0.05). CRY decreased inhibin B and follistatin mRNA and protein expression but upregulated activin A mRNA and protein expression in the ovarian tissue of rats with PCOS (P < 0.05). These results suggest that CRY treatment could reverse reproductive disturbances in rats with PCOS. PMID- 28559996 TI - MicroRNA-199a-3p inhibits tumorigenesis of hepatocellular carcinoma cells by targeting ZHX1/PUMA signal. AB - BACKGROUND AND OBJECTIVE: MicroRNAs play an important role in cell proliferation, apoptosis, differentiation, and invasion by regulating the expression of various genes. For example, the downregulation of microRNA-199a-3p (miR-199a-3p) that is noted in numerous human malignancies, including hepatocellular carcinoma (HCC), results in a poor prognosis in patients with HCC. This finding suggests that miR 199a-3p overexpression in HCC could provide a new treatment approach. We explored this possibility by examining the effects of miR-199a-3p on the growth and apoptosis of HCC cells in vitro and vivo. METHODS: The miR-199a-3p signaling pathway was examined using ZHX1 (zinc-fingers and homeoboxes-1) or PUMA (a p53 upregulated modulator of apoptosis) siRNA transfection to determine the effects of miR-199a-3p on growth and apoptosis of HepG2 cells in vitro. A subcutaneously implanted tumor model of HepG2 cells in nude mice was used to assess the effects of miR-199a-3p on the signaling pathway and tumorigenesis development in vivo. RESULTS: miR-199a-3p inhibited growth and induced apoptosis of HepG2 cells in vitro. These effects were accompanied by upregulation of ZHX1 and PUMA. Targeting ZHX1 inhibited upregulation of PUMA after miR-199a-3p transfection. In addition, miR-199a-3p inhibited Bcl2 expression, but increased Bax and cleaved caspase-3 expression. Targeting PUMA or ZHX1 reversed the effect of miR-199a-3p, followed by upregulation of Bcl2 and downregulation of Bax and cleaved caspase-3, respectively. Furthermore, miR-199a-3p inhibited tumorigenesis of xenografts in nude mice. CONCLUSIONS: miRNA-199a-3p could effectively prevent primary tumor formation. The ability of this therapy to decrease tumorigenesis may be related toZHX1-dependent PUMA signals. PMID- 28559997 TI - Anticancer effect of PP31J isolated from Physalis pubescens L. in human cervical carcinoma cells. AB - Extracts derived from Physalis pubescens L. may function as cancer therapies. The pharmacological effects of PP31J on human cervical carcinoma cells (HeLa cells) were investigated in this study. HeLa cells were treated with PP31J, and then cell proliferation, apoptosis, and cell cycle distribution were measured using a cell counting kit-8 (CCK-8) assay and flow cytometry. Protein expression levels of regulators of cell apoptosis and cell cycle were also examined using western blotting. Our data show that PP31J inhibited the growth of HeLa cells. Significant growth inhibition compared to the vehicle-treated group was observed using a concentration of 5 MUM PP31J at 24, 48, and 72 h. PP31J also selectively arrested cell cycle progression in the G1 phase at 40 MUM (P < 0.05) and in the G2/M phase at 20 MUM (P < 0.01) and 40 MUM (P < 0.001). Our results further demonstrate a significant increase in cell apoptosis (P < 0.001) following PP31J treatment (10, 20, and 40 MUM). Immunoblotting data show that PP31J downregulated (P < 0.01) the expression of Bcl-xL and decreased (P < 0.05) the expression of Survivin and Cyclin D1 at 20 and 40 MUM. This study shows the anti-tumor activity of PP31J in HeLa cells and that the effects of PP31J on cell cycle distribution and apoptosis induction were partially attributed to the regulation of Cyclin D1, Survivin, and Bcl-xL. PMID- 28559999 TI - Hypoxia-inducible factor 1 alpha protects mesenchymal stem cells against oxygen glucose deprivation-induced injury via autophagy induction and PI3K/AKT/mTOR signaling pathway. AB - Mesenchymal stem cell (MSC) transplantation is a promising therapeutic strategy for myocardial infarction. The survival rate of the grafted MSCs is limited by the conditions of hypoxia and low nutrient levels. In this study, we investigated the role of hypoxia-inducible factor 1 alpha (Hif-1alpha) in oxygen-glucose deprivation (OGD)-induced injury in MSCs. Hif-1alpha was overexpressed or suppressed in MSCs by transfection with a Hif-1alpha expressing vector or Hif 1alpha-specific siRNA, respectively. Then MSCs were exposed to OGD, and the changes in cell viability, cell cycle distribution and apoptosis were respectively monitored by MTT assay and flow cytometry. Additionally, expression levels of Beclin1, LC3 I and LC3 II, as well phosphorylation of PI3K, AKT and mTOR were detected by RT-PCR and Western blotting. The results indicated that Hif 1alpha overexpression improved cell viability, reduced G1 phase cells accumulation, and suppressed apoptosis under OGD condition (P<0.05). Beclin1 expression and the LC3 II/LC3 I ratio were increased by Hif-1alpha overexpression, and were decreased by Hif-1alpha knock-down (P<0.05). In addition, PI3K, AKT and mTOR were inactivated by Hif-1alpha overexpression, and phosphorylated by Hif-1alpha knock-down (P<0.05). In conclusion, these data suggest that Hif-1alpha overexpression protects MSCs from OGD-induced injury via a mechanism in which autophagy and PI3K/AKT/mTOR pathway are implicated. PMID- 28560000 TI - Discoidin domain receptor 1 activity drives an aggressive phenotype in bladder cancer. AB - Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase which utilizes collagen as a ligand to regulate the interaction between cancer cells and tumor stroma. However, the clinical relevance of DDR1 expression in bladder cancer as well as its molecular regulation have not been previously investigated. Here, we assessed the role of DDR1 in bladder cancer. The DDR1 levels in bladder cancer specimens were examined by Western blot, compared to the paired adhesive normal controls. The effects of DDR1 were explored on both cell migration in bladder cancer cells and tumor growth as xenograft. We detected significant higher levels of DDR1 in bladder cancer tissues. Moreover, high levels of DDR1 were correlated with poor prognosis of corresponding patients. Both the in vitro cell invasiveness and in vivo tumor xenograft growth could be promoted by the overexpressed DDR1, while both of which could be inhibited after the depletion of DDR1. Furthermore, DDR1 increased the levels of ZEB1 and Slug, based on its effects on tumor invasion. In conclusion, DDR1 may promote the aggressiveness of bladder cancer cells and drive an aggressive phenotype in bladder cancer. PMID- 28559998 TI - A novel relationship for schizophrenia, bipolar and major depressive disorder Part 5: a hint from chromosome 5 high density association screen. AB - Familial clustering of schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD) was systematically reported (Aukes, M. F. Genet Med 2012, 14, 338-341) and any two or even three of these disorders could co-exist in some families. In addition, evidence from symptomatology and psychopharmacology also imply that there are intrinsic connections between these three major disorders. A total of 56,569 single nucleotide polymorphism (SNPs) on chromosome 5 were genotyped by Affymetrix Genome-Wide Human SNP array 6.0 on 119 SCZ, 253 BPD (type-I), 177 MDD patients and 1000 controls. Associated SNPs and flanking genes was screen out systematically, and cadherin pathway genes (CDH6, CDH9, CDH10, CDH12, and CDH18) belong to outstanding genes. Unexpectedly, nearly all flanking genes of the associated SNPs distinctive for BPD and MDD were replicated in an enlarged cohort of 986 SCZ patients (P <= 9.9E-8). Considering multiple bits of evidence, our chromosome 5 analyses implicated that bipolar and major depressive disorder might be subtypes of schizophrenia rather than two independent disease entities. Also, cadherin pathway genes play important roles in the pathogenesis of the three major mental disorders. PMID- 28560001 TI - Icariside II induces cell cycle arrest and apoptosis in human glioblastoma cells through suppressing Akt activation and potentiating FOXO3a activity. AB - Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, and currently chemotherapeutic options for GBM are very limited. Given the poor prognosis, the development of novel anti-GBM agents is quite urgent. Using two human glioma cells (U87 and A172 cells), we demonstrated that Icariside II (ICA II), an active flavonoid compound derived from Epimedium koreanum, could inhibit GBM cell growth in a dose dependent manner. Wound healing data suggested that ICA II also inhibited the migration of human glioma cells. Mechanistically, ICA II induced apoptosis and cell cycle arrest, and this cytotoxic effect was dependent on the reduction of Forkhead box O3a(FOXO3a) phosphorylation mediated by Akt and the enrichment of nuclear FOXO3a, which initiated the transcription of p21/p27. Importantly, the cytotoxic effect induced by ICA II could be reversed by silencing the expression of FOXO3a, suggesting the critical role of FOXO3a in this process. Taken together, we propose ICA II as a potential novel anti-GBM candidate with a mechanism of inhibiting cell proliferation and inducing apoptosis through suppressing Akt activation and potentiating FOXO3a activity. PMID- 28560003 TI - Glutamine with probiotics attenuates intestinal inflammation and oxidative stress in a rat burn injury model through altered iNOS gene aberrant methylation. AB - Severe burns may lead to intestinal inflammation and oxidative stress resulting in intestinal barrier damage and gut dysfunction. In the management of severe burns, therapies are needed to attenuate whole-body inflammatory responses and control the burden of oxidative stress. In this study, we evaluated the effects of oral glutamine (Gln) with probiotics on burn-induced intestinal inflammation and oxidative stress using a Wistar rat burn injury model. We then explored potential molecular mechanisms for the effects of glutamine and probiotics on intestinal tissue inflammation and oxidative stress. We found that glutamine and probiotics together significantly inhibited nitric oxide (NO) content; reduced levels of the inflammatory factors TNF-alpha, IL-6, and IL-8; and altered expression of oxidative stress factors including reactive oxygen species and superoxide dismutase. We found that the apoptotic proportion of intestinal epithelial cells in severely burned subjects was notably decreased following treatment with glutamine plus probiotics. We also found that glutamine and probiotics given together markedly reduced NO content by down-regulating the expression of iNOS in blood and intestinal tissue. These findings indicate that regulation of the iNOS gene plays a pivotal role in inflammation and oxidative stress in the response to severe burns in the Wistar rat. We then further investigated the mechanism by which combined therapy with glutamine and probiotics might reduce expression of iNOS and found that this treatment resulted in increased methylation of the iNOS gene. The methylation level of the iNOS gene was found to be regulated via differential expression of DNMT1 and Tet1. Collectively, our results suggest that combined therapy with glutamine and probiotics can markedly reduce the synthesis of NO, suppressing intestinal inflammation and oxidative stress in the Wistar rat burn injury model. PMID- 28560002 TI - Prostaglandin E1 protects coronary microvascular function via the glycogen synthase kinase 3beta-mitochondrial permeability transition pore pathway in rat hearts subjected to sodium laurate-induced coronary microembolization. AB - Prostaglandin E1 (PGE1) is used as a pretreatment for ischemia reperfusion injury in many biological systems. However, its value as a pretreatment for coronary microembolization (CME) is unknown. The goal of this study was to determine whether PGE1 would protect against CME. In a CME rat model, we observed microthrombi and early myocardial ischemia, with endothelium appearing exfoliated and mitochondria having irregular morphology and decreased internal complexity. The level of fibrinogen-like protein 2 prothrombinase was increased and superoxide dismutase and catalase levels were decreased. Moreover, mitochondria copy number and mitochondrial permeability transition pore (mPTP) opening were increased. Pretreatment with PGE1 (1 or 2 MUg/kg) significantly improved these cardiological deficits, acting via the glycogen synthase kinase 3beta (GSK-3beta) mPTP pathway. Unexpectedly, the phosphorylation of Akt at Ser473 decreased in the PGE1 at high dose. Overall, our findings suggested an important role for PGE1 in pretreatment of coronary microvascular dysfunction. PMID- 28560005 TI - Low-expression of TMEM100 is associated with poor prognosis in non-small-cell lung cancer. AB - Transmembrane protein 100 (TMEM100) was first identified as a transcript from the mouse genome. Recent studies have demonstrated that TMEM100 is involved in hepatocellular carcinoma (HCC) malignancy. However, the distribution and clinical significance of TMEM100 in non-small-cell lung carcinoma (NSCLC) remains poorly understood. This study aims to explore the significance of TMEM100 expression in NSCLC. We found that TMEM100 expression was significantly reduced in NSCLC tissues when compared with that in adjacent normal lung tissues (P<0.001). Kaplan Meier survival analysis showed that overall survival of patients with lower expressions of TMEM100 was significantly shorter (n=152, P<0.05). In addition, TMEM100 overexpression in NSCLC cell lines inhibited cell proliferation in vitro and in vivo. Transwell migration and invasion assay showed that TMEM100 significantly suppressed the migration and invasion of NSCLC cell lines. In contrast, knocking down TMEM100 promoted NSCLC proliferation and migration. Finally, we found that TMEM100 worked as a cancer suppressor gene mainly by inhibiting the TNF signaling pathway. In conclusion, TMEM100 acted as a tumor suppressor in NSCLC and may prove to be a potential prognostic biomarker and therapeutic target for NSCLC. PMID- 28560004 TI - Impact of impaired cardiac function on the progression of chronic kidney disease- -role of pharmacomodulation of valsartan. AB - Although chronic kidney disease (CKD) is known to aggravate cardiovascular disease in the setting of cardiorenal syndrome (CRS), the impact of impaired cardiac function on the progression of CKD has seldom been reported. This study tested the impact of acute myocardial infarction on a rodent CKD model and the therapeutic effect of valsartan in this setting. Adult male Sprague-Dawley rats (n = 50) equally divided into group 1 (sham control), group 2 (CKD induced by 5/6 nephrectomy), group 3 (AMI by ligation of left coronary artery), group 4 (CKD+AMI), group 5 (CKD+AMI+valsartan, orally 10 mg/kg/day). By day 60, kidney injury score, creatinine levels, and ratio of urine to creatinine were highest in group 4 and lowest in group 1, significantly higher in group 4 than those in groups 2 and 5, and significantly higher in group 5 than those in group 2 (all p < 0.001). Protein expressions of inflammation (IL-1beta/MMP-9), oxidative stress (NOX-1/NOX-2/oxidized protein, angiotensin-II receptor), apoptosis (Bax, cleaved caspase-3/PARP), fibrosis (Smad3/TGF-beta), and kidney injured (KIM-1/FSP-1) markers showed an identical pattern, whereas anti-fibrosis (Smad5/BMP-2) indices exhibited an opposite pattern compared to that of creatinine level among all groups (all p < 0.01). Cellular expressions of inflammation (CD14/CD68), DNA damage (gamma-H2AX, CD90/XRCC1) and proximal-renal tubule (KIM-1) biomarkers displayed an identical pattern, whereas podocyte-integrity markers (podocin/ZO 1/p-cadherin/synaptopodin) showed a pattern opposite to that of creatinine level among all groups (all p < 0.001). In a rodent CKD setting, renal function impairment and parenchymal damage further deteriorated after AMI but were suppressed following valsartan treatment. PMID- 28560006 TI - Fat tissue, a potential Schwann cell reservoir: isolation and identification of adipose-derived Schwann cells. AB - Schwann cells can be used to promote peripheral nerve repair. However, it is challenging to obtain abundant autologous Schwann cells without sacrificing nerve integrity. In this study, we isolated Schwann cells from murine inguinal adipose tissue and identified the cell phenotype and function in vivo and in vitro. Through H&E and immunofluorescence staining, we detected tiny nerve fibers and Schwann cells in adipose tissue. We evaluated the phenotype of spindle-shaped cells (Schwann cell-like cells, SCLCs) isolated from adipose tissue using immunofluorescence staining and real-time RT-PCR. The results showed that SCLCs expressed specific Schwann cell markers. Analysis of conditioned SCLC culture media showed that, similar to Schwann cells isolated from sciatic nerves, SCLCs secreted NGF and BDNF. SCLCs were harvested from CAG-EGFP transgenic mice and combined with silicone nerve conduits to repair sciatic nerve defects in wild type mice. Six months post-surgery, we found EGFP-positive SCLCs forming myelin sheaths in the same way as sciatic nerve-derived Schwann cells. This research indicates the existence of Schwann cells in adipose tissue and identifies the spindle-shaped cells isolated from adipose tissue as Schwann cells using in vitro and in vivo evaluations. Thus, SCLCs might be promising seed cells for peripheral nerve tissue engineering. PMID- 28560007 TI - Use of immune modulation by human adipose-derived mesenchymal stem cells to treat experimental arthritis in mice. AB - Rheumatoid arthritis is a chronic and systemic autoimmune disease characterized by inflammatory cell infiltration and joint erosion. Human adipose-derived mesenchymal stem cells (hASCs) have shown the capacity of suppressing effector T cell activation and inflammatory cytokine expression. We investigated whether hASCs play a therapeutic role in collagen-induced arthritis (CIA) by administering a single dose of hASCs in mice with established CIA. In vivo, a beneficial effect was observed following hASC infusion as shown by a marked decrease in the severity of arthritis. Human ASCs were detectable in the joints, and reduced levels of pro-inflammatory cytokines and increased levels of anti inflammatory cytokines were observed in the sera of the hASC-treated mice. Furthermore, hASC treatment induced the expansion of regulatory T cells (Tregs) both in the peripheral blood and in the spleen tissues. In vitro, hASCs downregulated the production of proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6 in mouse macrophages stimulated with lipopolysaccharide and inhibited the proliferation of human primary T cells in response to mitogens. Thus hASCs represent a novel and effective therapeutic strategy for RA. PMID- 28560008 TI - GC7 blocks epithelial-mesenchymal transition and reverses hypoxia-induced chemotherapy resistance in hepatocellular carcinoma cells. AB - Hypoxia is common in solid tumors and results in the activation of hypoxia response genes. Hypoxia-inducible factor-1alpha (HIF-1alpha) is thought to reflect major cellular adaptation to hypoxia and contributes to chemoresistance in various tumors including hepatocellular carcinoma (HCC). N1-guanyl-1,7 diaminoheptane (GC7) is an inhibitor which suppresses the active eukaryotic translation initiation factor 5A-2 (eIF5A2), preventing epithelial-mesenchymal transition (EMT) in chemoresistance. In this study, we investigated the role of GC7 in the therapeutic effect of doxorubicin in hypoxia in HCC. We utilized four types of HCC cell line (Huh7, Hep3B, SNU387 and SNU449) in this study. Western blot and immunofluorescence were used to detect expression of epithelial/mesenchymal markers for EMT evaluation and HIF-1alpha was knocked down using HIF-1alpha-siRNA. Hypoxia-induced EMT contributed to doxorubicin chemoresistance in HCC cells. Low concentrations of GC7 sensitized Huh7 and Hep3B to doxorubicin by reversing EMT. Knockdown of HIF-1alpha attenuated hypoxia induced EMT and abolished the unique feature of GC7. GC7 enhanced sensitivity to doxorubicin in HCC by reversing hypoxia-induced EMT via the HIF-1alpha-mediated signaling pathway. We suggest a new method of enhancing cytotoxicity of chemotherapy and improving the long-term survival rate in HCC. PMID- 28560009 TI - Analysis of different bicruciate-retaining tibial prosthesis design using a three dimension finite element model. AB - The recent interest in bicruciate-retaining prostheses has aimed to address the need for an implant that can mimic a natural knee. Arguments have always existed about survivorship, including loosening and subsidence, as well as tibial preparation in bicruciate-retaining tibial prostheses. The aim of this study was to investigate the biomechanics of a new modular design and other bicruciate retaining designs using a three-dimensional finite element model under different load conditions to discover which prosthesis was more suitable. We also evaluated related parameters (the third principal stress, shear stress, micromotion, and von Mises stresses) to compare the characteristics of different bicruciate retaining designs. The biomechanics of the bicruciate-retaining tibial prosthesis can be influenced by the style of the designed prosthesis and gait loading. The new modular design showed stability and moderated the third principal stress, leading to less shear stress and stress shield, suggesting that this type of design can avoid knee prosthesis loosening and subsidence. Therefore, the new design may be used as a more suitable prosthesis for future bicruciate-retaining implant application. PMID- 28560010 TI - Hyperbaric oxygen treatment attenuates neuropathic pain by elevating autophagy flux via inhibiting mTOR pathway. AB - Peripheral neuropathic pain is a complex disease, and treated based on underlying diseases. Emerging evidences suggest that hyperbaric oxygen alleviates neuropathic pain. However, its cellular and molecular mechanism on pain relief is unknown. We hypothesize that hyperbaric oxygen alleviates neuropathic pain via activating autophagy flux and inhibiting mTOR pathway. Hyperbaric oxygen effectively inhibited nerve injury induced autophagy impairment and mTOR pathway activation in a rat spinal nerve ligation (SNL) model. Moreover, intrathecal injection of rapamycin, an autophagy inducer, enhanced hyperbaric oxygen effect by further decreasing mTOR activity. In contrast, chloroquine, an autophagy inhibitor, counteracted hyperbaric oxygen analgesic effect. These findings indicate that hyperbaric oxygen attenuated neuropathic pain by increasing spinal autophagic flux via inhibiting mTOR pathway. Our study provides pre-clinical evidences in expediting hyperbaric oxygen become a safe clinical treatment of neuropathic pain. PMID- 28560011 TI - Peutz-Jeghers syndrome with early onset of pre-adolescent gynecomastia: a predigree case report and clinical and molecular genetic analysis. AB - This study reports a case of Peutz-Jeghers syndrome with early onset of gynecomastia, and discusses its clinical characteristics and genetic changes in a family. The clinical characteristics of a child diagnosed with Peutz-Jeghers syndrome in our hospital and his parents were summarized, and related genes were detected in the child and his parents. Furthermore, the therapeutic effect of letrozole was also observed. A five-year-and-three-month-old male patient visited a doctor due to "progressive painless enlargements at bilateral breast for more than two years". The mother of the patient had breast hyperplasia and ovarian cysts, had no hematemesis and hematochezia history, and had two 1-mm pigmented spots on the palm side of the left thumb. The father of the patient revealed no abnormalities. In the child, luteinizing hormone (LH) release peak induced by luteinizing hormone releasing hormone (LHRH) excitation testing was 0.29 U/l, and follicle stimulating hormone (FSH) peak was 0.41 U/l. Karyotype: 46, XY. Gene sequencing revealed a mutation c.658C>T in the serine threonine kinase 11 (STK11) gene in the child and this mother, while the child's father was normal. After one year of oral administration of letrozole, the boy's breasts reduced to stage B2, bone age was 10 years and eight months old, and DeltaBA/DeltaCA ratio was <1. The patient had early onset of pre-adolescent gynecomastia, had no obvious gastrointestinal symptoms, presented with a few pigmented spots in the skin mucosa, and was diagnosed with Peutz-Jeghers syndrome by genetic testing. Letrozole treatment can effectively control the development of breast and progression of bone age. PMID- 28560012 TI - RIZ1 negatively regulates ubiquitin-conjugating enzyme E2C/UbcH10 via targeting c Myc in meningioma. AB - RIZ1 has been considered as an important tumor suppressor gene. Our previous studies have already demonstrated that the expression of RIZ1 is closely related to the occurrence and development of meningioma. In addition, we also found that the expression of UbcH10 was related to the pathologic grade of meningioma which also affected the prognosis of these patients. However, we are lack of the understanding of the effect of UbcH10 on cell proliferation, cell apoptosis, cell cycle and other functions in meningioma cells. Besides, the regulation mechanism between RIZ1 and UbcH10 still remains unclear. In this study, we attempted to demonstrated that UbcH10 was a downstream target of RIZ1 and reported that UbcH10 silencing might negatively regulate cell proliferation, migration, invasion and promote apoptosis, which is similar to the cell phenotype that of over expressed RIZ1. Mechanistically, we proved that UbcH10 was a c-Myc target gene and that RIZ1 regulated UbcH10 expression in a c-Myc-dependent manner. For the first time, our study demonstrated that UbcH10 played a key role in the proliferation, metastasis and apoptosis of primary human malignant meningioma cells. In addition, the mechanism of RIZ1 regulating UbcH10 is also clear. Our study can also provide a potential target and new idea for the follow-up molecular intervention in clinical malignant meningiomas. PMID- 28560013 TI - Stromal cell-derived factor-1alpha and transforming growth factor-beta1 synergistically facilitate migration and chondrogenesis of synovium-derived stem cells through MAPK pathways. AB - The clinical translation of tissue engineering methods is confined by the limited external cell sources, which is hopefully to be addressed by the cell guidance approach as cytokine-induced homing and differentiation of the patients' autologous cells. Synovium-derived stem cells (SDSCs) are a potent cell source for cartilage restoration due to its intrinsic proximity and tissue-specific chondrogenic capacity. In this study, stromal cell-derived factor-1alpha (SDF 1alpha) in combination with transforming growth factor beta1 (TGF-beta1) were used to induce SDSCs migration and chondrogenesis in vitro. The migration capacity was evaluated by transwell assay and for chondrogenic evaluation, the expression of Sox9, ACAN and COL2A1 were assessed by quantitative RT-PCR while the expression of sulfated GAG and collagen II were evaluated by Alcian Blue stain and immunohistochemistry respectively. Our data showed that SDF-1alpha/CXC chemokine receptor 4 (CXCR4) was involved in SDSCs migration through phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. Exogenous TGF beta1 enhanced SDF-1alpha-induced SDSCs migration in a concentration and time dependent manner through CXCR4, evidenced as complete blockage by AMD3100, the CXCR4 antagonist and this effect was mediated by extracellular regulated protein kinases (ERK) activation. Moreover, the addition of SDF-1alpha augmented the TGF beta1-induced SDSCs chondrogenesis, evidenced by the increased pellet sizes and the expressions of COL 2A1, ACAN and Sox9. This effect was related to c-Jun N terminal kinase (JNK) activation. Collectively, these results suggest that SDF 1alpha and TGF-beta1 interacts with each other and synergistically enhance the SDSCs migration and chondrogenesis through MAPK pathways. PMID- 28560014 TI - The "Spinner" Illusion: More Dots, More Speed? AB - The perceived speed of a ring of equally spaced dots moving around a circular path appears faster as the number of dots increases (Ho & Anstis, 2013, Best Illusion of the Year contest). We measured this "spinner" effect with radial sinusoidal gratings, using a 2AFC procedure where participants selected the faster one between two briefly presented gratings of different spatial frequencies (SFs) rotating at various angular speeds. Compared with the reference stimulus with 4 c/rev (0.64 c/rad), participants consistently overestimated the angular speed for test stimuli of higher radial SFs but underestimated that for a test stimulus of lower radial SFs. The spinner effect increased in magnitude but saturated rapidly as the test radial SF increased. Similar effects were observed with translating linear sinusoidal gratings of different SFs. Our results support the idea that human speed perception is biased by temporal frequency, which physically goes up as SF increases when the speed is held constant. Hence, the more dots or lines, the greater the perceived speed when they are moving coherently in a defined area. PMID- 28560016 TI - A case of large cell neuroendocrine carcinoma of the bladder with prolonged spontaneous remission. AB - Large cell neuroendocrine carcinoma (LCNEC) of the urinary bladder are rare. We present a case of a 72-year-old man who presented with back pain and acute renal failure. Ultrasound showed a soft tissue mass in the base of the bladder causing bilateral ureteric obstruction. Subsequent biopsy of this mass demonstrated neuroendocrine carcinoma. He was commenced on neoadjuvant chemotherapy (carboplatin/etoposide) and proceeded to a radical cysto-prostatectomy. Histology revealed a LCNEC involving the bladder, T4a with invasion through to adipose tissue and posteriorly at perivesical resection margins. In addition, there was a Gleason score 9 prostatic adenocarcinoma, distinct from the neuroendocrine carcinoma. Following surgery, the patient developed gross local-regional recurrence and refused further systemic therapy. However, 1 year following referral to palliative care, a further CT-PET showed complete spontaneous remission of his disease. There are only few case reports of LCNEC of the urinary bladder therefore the pathogenesis and treatment protocol are still unclear. This case report highlights the unpredictable nature of this disease. PMID- 28560017 TI - An unusual case of traumatic bilateral hip dislocation without fracture. AB - Bilateral traumatic hip dislocations are extremely rare. Most of these are related to acetabular or proximal femoral fractures, consisting of complex lesions, and are rarely pure ligamentous injuries. Posterior dislocation is the most frequent. Some dislocations are accompanied by sciatic nerve palsy. The present case is a posterior bilateral hip dislocation with no other associated lesions, there are very few reports published with this clinical setting. The patient had good functional outcome. PMID- 28560015 TI - A mini review focused on the proangiogenic role of silicate ions released from silicon-containing biomaterials. AB - Angiogenesis is considered an important issue in the development of biomaterials for the successful regeneration of tissues including bone. While growth factors are commonly used with biomaterials to promote angiogenesis, some ions released from biomaterials can also contribute to angiogenic events. Many silica-based biomaterials have been widely used for the repair and regeneration of tissues, mainly hard tissues such as bone and tooth structure. They have shown excellent performance in bone formation by stimulating angiogenesis. The release of silicate and others (Co and Cu ions) has therefore been implicated to play critical roles in the angiogenesis process. In this short review, we highlight the in vitro and in vivo findings of angiogenesis (and the related bone formation) stimulated by the various types of silicon-containing biomaterials where silicate ions released might play essential roles. We discuss further the possible molecular mechanisms underlying in the ion-induced angiogenic events. PMID- 28560018 TI - Internal hernia after laparoscopic right hemicolectomy, report of a case. AB - Mesenteric defects are often not closed in laparoscopic colectomy. We herein report a case of an internal hernia projecting through a mesenteric defect following laparoscopy-assisted right hemicolectomy. A 74-year-old woman was hospitalized for the surgical treatment of double colon cancer. Preoperative colonoscopy demonstrated the presence of ascending colon and transverse colon cancers. A laparoscopic-assisted right hemicolectomy was performed. The mesenteric defect resulting from the colectomy was not closed. Three months after the surgery, the patient developed a bowel obstruction. Under a diagnosis of strangulated bowel obstruction, we performed a laparotomy, and found a necrotic small bowel, which had passed into the bursa omentalis through the mesenteric defect. We removed the necrotic small bowel and closed the mesenteric defect by suturing. The patient's postoperative course was uneventful. An internal hernia projecting through a mesenteric defect following laparoscopy-assisted right hemicolectomy developed a severe strangulated bowel obstruction. PMID- 28560019 TI - Post-transplantation nephroptosis causing recurrent episodes of acute renal failure and hypertension secondary to intermittent vascular torsion of intraperitoneal renal allograft. AB - Nephroptosis is a rare complication in renal transplantation, but one with significant associated risk. Due to non-specific clinical features, there may be a substantial delay in diagnosis and loss of the transplanted kidney due to renal pedicle thrombosis. We present a case of post-transplantation nephroptosis after simultaneous pancreas and kidney transplant, which resulted in accelerated hypertension and reversible acute kidney injury >1 year after transplantation. Prompt detection of this rare entity leading to expeditious surgical intervention is necessary to preserve viability of the renal allograft. PMID- 28560020 TI - Intracranial monodermal teratoma presenting with growing teratoma syndrome. AB - Intracranial teratomas are rare. We report a case of a purely monodermal teratoma manifesting as intracranial growing teratoma syndrome. To the best of our knowledge, this is the first report of such nature in the literature. PMID- 28560021 TI - 'Coexisting pituitary adenoma and suprasellar meningioma-a coincidence or causation effect: report of two cases and review of the literature'. AB - Coexistence of pituitary adenoma (PA) and another type of brain tumor is a very rare clinical scenario. Even though such a presentation can be an incidental event but a thorough review of the literature will be made to elucidate the possible mechanisms and treatment options in similar cases. Two cases of concomitant sellar and suprasellar/diaphragmatic tumors are reported. A 37-year old lady with prolactinoma and a suprasellar diaphragmatic meningioma and a 42 year-old acromegalic man with suprasellar/diaphragmatic meningioma and a PA. Both meningiomas were removed transcranially. The prolactinoma could be managed medically and the growth hormone secreting adenoma was removed trans sphenoidally. The visual problems and hormonal imbalances of both patients improved postoperatively. The literature is reviewed on this topic and the possible pathogenesis and management protocol of similar lesions are discussed. PMID- 28560022 TI - Combined TRAM flap with latissimus dorsi myocutaneous flap for reconstruction of a large breast post-radiation induced necrosis. AB - Radiation therapy is a critical component of breast cancer management following breast-conserving surgery. Post-radiation sequelae are greater in women with larger breasts, given the need for higher doses and dosing heterogeneity. The goal of breast reconstruction post-mastectomy is to improve the quality of life and add no more health risk. The optimal reconstruction should make the patient feel as natural as possible. Reconstruction of a large-sized breast with aesthetically satisfactory outcome poses a challenge to the breast surgeon. The breast of most Egyptian women is of a large volume with variable degrees of ptosis, thus it is difficult to reconstruct such a large-ptotic breast using an implant. We describe the successful reconstruction of a large-sized breast after radiation-induced necrosis using a combined transverse myocutaneous rectus abdominis flap and latissimus dorsi myocutaneous flap reconstruction. The combined use of both flaps offered a more natural breast reconstruction and avoided the use of any implants. PMID- 28560023 TI - Malrotation with midgut volvulus in an adult: a case report and review of the literature. AB - We report a case of a 53-year-old male who presented with acute onset right upper quadrant (RUQ) abdominal pain with investigations demonstrating malrotation causing midgut volvulus and subsequent intestinal obstruction. The patient was consented for an emergent operation and underwent an exploratory laparotomy. Operative findings included the presence of adhesive bands in the RUQ (Ladd's Band), volvulus of the mid-portion of the small bowel in a clockwise fashion and multiple intra-abdominal adhesions causing internal hernias. We subsequently performed a Ladd's procedure and the patient had an uneventful recovery with eventual discharge on postoperative day 8. This case report reviews the incidence of malrotation in adults. It also highlights the difficulty in diagnosing midgut volvulus in the adult population given the nonspecific, insidious symptoms therefore prompting awareness of its existence and a high degree of clinical suspicion. PMID- 28560024 TI - Neuroendocrine carcinoma as a rare cause of jejunal intussusception in an adult. Management and literature review. AB - Intussusception of the small bowel is an uncommon condition, with the majority of cases being observed during infancy. A number of points are responsible, with benign and malignant lesions of the small intestine being the most common. Herein, we present the case of a 75-year-old male patient with vague abdominal pain and black stool during defecation, who underwent surgery due to jejunal intussusception. Pathology report demonstrated a neuroendocrine carcinoma as the underlying cause for his condition, with no additional metastases during the initial diagnosis. Although a conservative approach for management of intussusception is viable, the possibility of gastric outlet obstruction and the presence of malignancy as the primary point usually lead to urgent surgery. In the case of malignancy, adjuvant chemotherapy or additional symptomatic therapy with close follow-up may be required depending on tumor's grade and aggressiveness. PMID- 28560025 TI - An unusual case of massive hematemesis caused by aorto-esophageal fistula due to mycotic aneurysm of mid-thoracic aorta in a patient without prior aortic instrumentation. AB - In the words of Sir William Osler: "There is no disease more conducive to clinical humility than aneurysms of the aorta". Here, we describe a case of a primary fistulous tract between a pseudoaneurysm sac and a portion of the mid thoracic esophagus leading to massive extravasation of blood causing hemorrhagic shock in a 71-year-old female. PMID- 28560026 TI - Conservative management of a traumatic common iliac venous pseudoaneurysm: a case report. AB - Limited evidence-based protocols exist regarding the management of venous pseudoaneurysms. Cases reports have documented surgical treatments including endovascular coil embolization or suture ligation in the setting of hemodynamic stability. Depending on the location of the venous injury, a more conservative approach to a stable pseudoaneurysm may be advantageous. This report describes a case of a patient who sustained a blunt traumatic common iliac vein pseudoaneurysm who was successfully managed non-operatively. PMID- 28560027 TI - Successful surgical employment of Impella recovery system for right ventricular failure after previous aortic valve replacement. AB - A 58-year-old woman underwent aortic valve replacement. On the second postoperative day the patient referred a sharply chest pain, and an emergent coronary angiography revealed total occlusion of the right coronary artery. An intra-aortic ballon pump was placed and the patient underwent emergent off-pump coronary revascularization of the right coronary artery. Five hours later, due to unstable hemodynamic the extracorporeal membrane oxygenation was implanted without improvement of the right ventricular (RV) function. Then we decided to implant the Impella Right Direct (RD). After 9 days of Impella's insertion the RV was recovered and the device was successfully explanted. After 16 days of Impella explanted the patient was discharged. This case suggest that implantation of Impella RD is clinically feasible, associated with hemodynamic improvement, and facilitate successful bridge-to-recovery in patients with post-cardiotomy RV failure due to myocardial infarction unresponsive to coronary artery bypass grafting, maximal medical therapy, contrapulsation and extracorporeal membrane oxygenation. PMID- 28560028 TI - Aortic rupture due to radiation injury successfully treated with thoracic endovascular aortic repair. AB - Thoracic endovascular aortic repair (TEVAR) has been reported to be an effective treatment option for aortic emergencies. However, there are few reports about TEVAR for aortic rupture due to radiation injury. A 54-year-old man presented with haemoptysis. He had a history of lung cancer, which had been treated with chemotherapy and radiation therapy (72 Gy/16 times) 3 years previously, and the cancer lesion did not progress. On chest radiography, pneumonia was suspected in the radiated lesion. However, after admission, he presented with back pain, progressive anaemia and hypotension. Enhanced computed tomography revealed extravasation of contrast medium in the distal aortic arch. He was diagnosed with aortic rupture due to radiation injury. TEVAR was performed. He was extubated one day after the operation, and the haemoptysis disappeared. He was discharged from the hospital without any complications. He is well 1 year after the surgery, without aortic disease progression or lung cancer recurrence. PMID- 28560029 TI - Is there a doctor in the house? Availability of Israeli physicians to the workforce. AB - BACKGROUND: Israeli policymakers have expressed serious concerns about being able to meet the growing demand for physician services. For this reason, the Israel Ministry of Health (MoH) undertook studies based on 2008 and then 2012 data to obtain an accurate assessment of the size, specialty mix, demographic and geographic composition of the physician workforce. This paper highlights the findings from these studies about the number and percentage of licensed physicians in Israel who were not available, were only partially available, or were about to leave the Israeli healthcare workforce. METHODS: The two studies cross-linked administrative files of the entire physician population in Israel. The two sources were the MoH registry of licensed physicians, which contains demographic, medical education and specialty information, and the Israel Tax Authority income file on employment data. A third source, used only for the study of 2008 data, was the CBS Population Census Data 2008 which was based on a large representative sample of the population (14%), along with the updated Population Registry, which provided data on physicians whose occupation was in medical care as well as the number of work-hours. By linking the files we could also assess the population of licensed Israeli physicians living abroad. RESULTS: Only 74% of licensed physicians of all ages in 2012 were active in the Israeli workforce. Of physicians under the age of 70, 87% were living and working in Israel. Female physicians tended to retire from the workforce earlier than males and were more likely to work fewer hours during their working years. The rate of physicians who worked longer hours declined in both genders as age rose. About 10% of licensees had been living abroad for at least a year and the majority of these were older. Approximately 7% of licensed physicians, ages 30-44, were abroad and most are presumed to be doing additional clinical training or gaining research experience. In some specialty fields young physicians were not replacing retirees at a compensatory rate; anesthesiologists, a specialty in short supply in Israel were more likely to be living abroad than other specialists. CONCLUSIONS: Assessment of the medical workforce pool and personnel planning require not just the number of licensed physicians but also information about the employment mix of license holders and their level of professional activity in Israel. For planning future workforce needs, it is important to keep in mind that the average female vs. male physician has lower clinical productivity due to shorter hours and earlier retirement and that a group of young physicians will predictably be abroad at any point in time; however major "brain drain" is not evident. Furthermore, extrapolating from the findings in the current studies, we believe that a potential shortage of physicians within Israel can be mitigated by better administrative support of physicians, use of physician extenders, and careful attention to improving physician satisfaction in certain specialties. PMID- 28560030 TI - Thoracolumbar epidural anaesthesia with 0.5% bupivacaine with or without methadone in goats. AB - BACKGROUND: Epidural anaesthesia is one of the most commonly used locoregional techniques in ruminants. The lumbosacral epidural technique is reasonably easy to perform and requires low volumes of local anaesthetic drug to allow procedures caudal to the umbilicus. However, surgical procedures in the flank of the animal would require an increased volume of drugs. The anaesthetized area provided by thoracic epidural technique is larger than the lumbosacral technique; however the former is rather challenging to perform. Therefore, access through lumbosacral area to introduce a catheter into the thoracolumbar space is a potential alternative to thoracic access. Epidural anaesthesia is achieved with local anaesthetics; opioids can be added to improve analgesia. This study aimed to evaluate the effects of 0.5% bupivacaine with or without methadone, administered through an epidural catheter inserted through the lumbosacral access and advanced to the thoracolumbar space, on thoracolumbar epidural anaesthesia in goats. METHODS: Six animals received two treatments each in a randomized crossover study: BUP treatment consisted of 0.5% bupivacaine (1 mL per each 10 cm of spine column; 1 +/- 0.2 mg/kg BW) and BMT treatment was the same; however 1 mL of bupivacaine was replaced by 1 mL (0.22 +/- 0.03 mg/kg BW) of methadone (10 mg/mL). The treatments were administered near to T11-T12 through an epidural catheter. Motor blockade and analgesia were evaluated by electrical stimulation. RESULTS: Heart rate, respiratory rate, ruminal motility and rectal temperature were evaluated before and after the treatment. Motor blockade was observed on both treatments, up to 6 h post-treatment. Analgesia was observed on BUP up to 4 h and on BMT up to 6 h post-treatment. Physiological values did not change at any moment. CONCLUSIONS: Bupivacaine-methadone combination promoted longer-lasting analgesia in goats compared to bupivacaine alone when administered through an epidural catheter into the thoracolumbar space. PMID- 28560032 TI - Transauricular intra-arterial and intravenous digital subtraction angiography for abdominal aortic aneurysm imaging in a rabbit model. AB - AIM: The aim of this study was to evaluate transauricular digital subtraction angiography (DSA) as an alternative to conventional intra-arterial DSA for rabbit abdominal aortic aneurysm (AAA). MATERIALS AND METHODS: AAA models were created in 8 New Zealand white rabbits by sewing vein patch. The diameters of aortic arteries were measured by DSA via ear vein and ear central artery. The common carotid artery (CCA) was exposed and cannulated for DSA as conventional angiography. Diameter size was measured and compared. RESULTS: Aortic diameters, tested by DSA via ear vein, ear central artery and CCA were 7.9 +/- 1.2 mm, 7.8 +/- 1.0 mm and 7.9 +/- 1.1 mm respectively, with no significant differences. Angiography via CCA as standard procedure, correlation in aneurysm neck diameter was r = 0.93 for IVDSA and r = 0.96 for angiography via central artery (P < 0.01); Correlation in AAA diameter was r = 0.99 for IVDSA and r = 0.99 for angiography via central artery (P < 0.0001). CONCLUSIONS: Transauricular DSA shows good correlation to conventional DSA, can be used repeatedly with less invasiveness, and suitable for rabbit AAA follow-up study. PMID- 28560033 TI - Comparison of outcome of VLCP versus PKEF in the treatment of AO type C2-3 distal radial fractures. AB - PURPOSES: Fractures of the distal radius are extremely common in adults. However, the optimal management remains controversial, especially in AO type C2-3 (Type23 C2 or C3 of distal radial fracture, according to AO classifications). The purpose of this study was to compare the results of the volar locking compression plate (VLCP) and percutaneous Kirschner-wires combined with external fixation (PKEF) in the treatment of the AO type C2-3 fractures. METHODS: From July 2012 to June 2015, 62 patients with AO type C2-3 fractures, treated by VLCP or PKEF, were included in this retrospective study. Patients were followed up at 3 months, 6 months after operation, and final follow up. Outcomes were assessed by radiographic features in all follow up and by DASH and Sarmiento's modification of the Gartland-Werley score at final follow up. RUSULTS: No significant difference was noted between these two groups in terms of volar inclination, ulnar angulation and ulnar variance. There was also no significant difference on DASH score between these two groups. However, according to the Sarmiento's modification of the Gartland-Werley scores, the scores was higher in VLCP group than the PKEF group, and ratings of excellent and good were lower in the VLCP group (P = 0.05). CONCLUSIONS: Both techniques could get satisfactory results in the treatment of AO type C2-3 fractures, but PKEF leads to better wrist function than VLCP . PMID- 28560034 TI - Spontaneous temporomandibular joint herniation into the external auditory canal through a patent foramen of Huschke: A case report. AB - Temporomandibular joint herniation (TMJ) can be caused by inflammation, trauma, tumor, or otologic procedures. However, spontaneous TMJ herniation can also occur as a result of a congenital bony defect in the external auditory canal (EAC), known as the patent foramen of Huschke (PFH), and occurs in 0.4% of the population. Herein, the authors present a case of spontaneous TMJ herniation through the PFH with clicking tinnitus. The patient underwent the surgical repair of bony defect in the EAC with placement of titanium mesh, and the symptom disappeared after surgery. They also review the relevant literature regarding this disease and discuss its embryologic development and clinical significance. PMID- 28560031 TI - Nuclear roles for cilia-associated proteins. AB - Cilia appear to be derived, evolutionarily, from structures present in the ancestral (pre-ciliary) eukaryote, such as microtubule-based vesicle trafficking and chromosome segregation systems. Experimental observations suggest that the ciliary gate, the molecular complex that mediates the selective molecular movement between cytoplasmic and ciliary compartments, shares features with nuclear pores. Our hypothesis is that this shared transport machinery is at least partially responsible for the observation that a number of ciliary and ciliogenesis-associated proteins are found within nuclei where they play roles in the regulation of gene expression, DNA repair, and nuclear import and export. Recognizing the potential for such nuclear roles is critical when considering the phenotypic effects that arise from the mutational modification of ciliary proteins. PMID- 28560035 TI - Completeness in clerking: The surgical admissions proforma. AB - BACKGROUND: The accessibility of surgical patient data is a key safety concern, and relies on efficient clerking and handovers. This project assessed whether the introduction of a surgical clerking proforma improved the recording of patient information in the surgical admissions unit (SAU) at Northwick Park Hospital. MATERIALS AND METHODS: Existing patient notes were assessed on content and ease of access, using two independent surveys conducted over a 5-day period. The first survey audited patient notes before (n = 28) and after (n = 23) the introduction of the proforma. It assessed whether key patient details were documented, in line with the 17 criteria set out in the Guidelines for Clinicians on Medical Records and Notes by The Royal College of Surgeons in England. The second survey questioned healthcare professionals before (n = 25) and after (n = 17) proforma implementation on the accessibility of patient data and coherency of patient notes. RESULTS: 5 of the 17 criteria showed significant differences post proforma implementation. Of these differences, the recording of height and occupation was most notable (p < 0.01). Medication history, weight and investigations also showed significant increases in documentation (p < 0.05). In all 3 questions asked to healthcare professionals, fewer healthcare professionals were required to revisit archived notes following proforma implementation (p < 0.05). CONCLUSION: Our study illustrates that a comprehensive surgical clerking proforma improves patient data documentation and saves healthcare professionals' time compared to the freehand clerking method. The implications of such work are far reaching, and if well implemented could allow a new reliable platform for further clinical audits. PMID- 28560036 TI - Barriers and motivations for health insurance subscription in Cape Coast, Ghana: a qualitative study. AB - BACKGROUND: One of the main objectives of the Ghana National Health Insurance Scheme, at its establishment in 2003, was to ease financial burden of the full cost recovery policy, particularly on the poor. However, currently, majority of the scheme's subscribers are individuals in the upper wealth quintile, as the poor in society rather have not subscribed. We explored the motivational factors as well as the barriers to health insurance subscription in the Cape Coast Metropolis of Ghana. METHODS: This study collected qualitative data from 30 purposively selected subscribers and non-subscribers to the National Health Insurance Scheme using an in-depth interview guide. RESULTS: Major motivational factors identified were; affordable health insurance premium, access to free drugs, and social security against unforeseen health challenges. Encouragement by friends, family members, and colleagues, was also found to motivate subscription to the health insurance. The major barriers to health insurance subscription included; long queues and waiting time, perceived poor quality of drugs, and negative attitude of service providers both at the healthcare facilities and the health insurance office. The study underscores the need for the National Health Insurance Authority to conduct intensive education to change the negative perception people have regarding the quality of health insurance drugs. Efforts should also be made to reduce the waiting time in accessing healthcare with the National Health Insurance Scheme card. This would motivate more people to subscribe or renew their membership. CONCLUSIONS: The implication of barriers found is that people may not subscribe to the scheme in subsequent years. This would, therefore, consequently defeat the objective of achieving universal healthcare coverage with the scheme. PMID- 28560037 TI - Instant velocity and consistency of emitted cloud change by the different levels of canister filling with Metered Dose Inhalers (MDIs), but not with Soft Mist Inhalers (SMIs): a bench study. AB - BACKGROUND: Inhalation is the preferred route for respiratory drug delivery, but several factors contribute to the variability of the respirable dose fraction. Instant velocity and the dynamic characteristics of the droplet cloud represent crucial factors. Aim was to measure and compare the instant velocity and the consistency of emitted cloud from five different MDIs (A - Salbutamol sulphate 100mcg, GSK; B - Salbutamol sulphate 100mcg, Valeas; C - Salmeterol xinafoate/Fluticasone propionate 25/125mcg, GSK; D - Formoterol fumarate/Bechlomethasone propionate 6/100mcg, Chiesi; E - Formoterol fumarate/Fluticasone dipropionate 5/125mcg, Mundipharma) and one SMI (Tiotropium bromide 5mcg, Boehringer Ingelheim), at different distance from the nozzle and canister filling. METHODS: Measurements were made at 90, 50, and 10% of canister filling, and at 5, 10, and 20 cm from the nozzle, for a total of 972 puffs. A high speed video photography protocol was adopted and high speed cameras (1.200 frames/sec.) were used. Data were acquired by means of specialized softwares. Temperature, humidity, and vibrations occurrence were strictly controlled during measurements. Statistics: Anova and p < 0.05 were accepted as the minimum significance level. RESULTS: MDIs generated different Instant velocities: MDI B generated the highest, while MDI A the lowest. As expected, velocity decreased in proportion to the distance from the nozzle. Except with MDI C, instant velocity decreased significantly over the first 50% of canister emptying, but dropped by >33% at 90% of emptying with all other MDIs (p < 0-037; p < 0.001; p < 0.005, and p < 0.001, respectively). Instant velocity was extremely lower (p < 0.001) and constant for all levels of canister filling (p = ns) with SMI. All MDIs had a very fast jet phase, ranging 0.01-0.03 s at 10 cm, and 0.03-0.05 s at 20 cm from the nozzle, without any significant difference from each other (p = ns). MDIs generated a cloud similarly tight (p = ns) at 10 and 20 cm from the nozzle, while it was extremely wider and constant with the SMI (p = 0-001). Also the cloud turbulence was minimized during the SMI emission. DISCUSSION AND CONCLUSIONS: MDIs are characterized by a substantial variability in both their instant velocity and consistency of the emitted cloud at different levels of canister filling. SMI generates a much slower soft mist cloud which is constantly homogeneous and independent of canister emptying. These peculiarities assessed at bench are suggesting a higher dose consistency and a much more effective therapeutic performance also in real life. PMID- 28560038 TI - Mutational status predicts the risk of thromboembolic events in lung adenocarcinoma. AB - BACKGROUND: Precision medicine promises to improve prognosis of patients affected by untreatable diseases. Patients with lung cancer (especially lung adenocarcinoma) bear an increased risk of VTE. Mutations in the EGFR and rearrangement in the ALK genes identify specific subgroups of patients. Aim of this study was to investigate the role of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutational status on the risk of venous thromboembolism (VTE) in lung adenocarcinoma. METHODS: A retrospective longitudinal design was used. Patients with lung adenocarcinoma diagnosed and undergoing a mutational analysis at the Karolinska University Hospital, Stockholm, Sweden between January 2009 and September 2015 were divided in three subgroups based on their mutational status (EGFR-, ALK-mutated, unexposed group). Event-free time for VTE was assessed using Cox regression analysis based on mutation status and treatment received. RESULTS: Three hundred-ten patients were included. A VTE occurred in 70 (22.6%) patients. Mutation of EGFR was associated with a decreased risk of VTE (HR 0.46, 95% CI 0.23-0.94). Treatment with tyrosine kinase inhibitors (TKI) reduced the risk of VTE compared to other treatment strategies not including TKI (HR 0.42, 95% CI 0.29-0.79). CONCLUSIONS: Our study suggests that patients with lung adenocarcinoma bearing a EGFR-mutation have a decreased risk of VTE compared with patients with other forms of lung adenocarcinoma. Targeted therapy with TKI alone or in combination with other treatments seems to reduce the risk of VTE compared to other treatments not including TKI. PMID- 28560039 TI - Percentile ranks and benchmark estimates of change for the Health Education Impact Questionnaire: Normative data from an Australian sample. AB - OBJECTIVE: Participant self-report data play an essential role in the evaluation of health education activities, programmes and policies. When questionnaire items do not have a clear mapping to a performance-based continuum, percentile norms are useful for communicating individual test results to users. Similarly, when assessing programme impact, the comparison of effect sizes for group differences or baseline to follow-up change with effect sizes observed in relevant normative data provides more directly useful information compared with statistical tests of mean differences and the evaluation of effect sizes for substantive significance using universal rule-of-thumb such as those for Cohen's 'd'. This article aims to assist managers, programme staff and clinicians of healthcare organisations who use the Health Education Impact Questionnaire interpret their results using percentile norms for individual baseline and follow-up scores together with group effect sizes for change across the duration of typical chronic disease self management and support programme. METHODS: Percentile norms for individual Health Education Impact Questionnaire scale scores and effect sizes for group change were calculated using freely available software for each of the eight Health Education Impact Questionnaire scales. Data used were archived responses of 2157 participants of chronic disease self-management programmes conducted by a wide range of organisations in Australia between July 2007 and March 2013. RESULTS: Tables of percentile norms and three possible effect size benchmarks for baseline to follow-up change are provided together with two worked examples to assist interpretation. CONCLUSION: While the norms and benchmarks presented will be particularly relevant for Australian organisations and others using the English language version of the Health Education Impact Questionnaire, they will also be useful for translated versions as a guide to the sensitivity of the scales and the extent of the changes that might be anticipated from attendance at a typical chronic disease self-management or health education programme. PMID- 28560041 TI - Severe acute asthma caused by Chlamydophila pneumoniae infection. AB - Asthma exacerbation is associated with respiratory infections, including those by viruses and atypical bacteria. We herein report a case of severe acute asthma in an adult caused by Chlamydophila pneumoniae (C. pneumoniae) infection. A 39-year old woman without a history of asthma reported to the emergency department with progressive worsening of cough, shortness of breath, and wheezing with low oxygen saturation. A computed tomography (CT) scan revealed patchy ground-glass opacity and bronchial wall thickening. She was treated with systemic corticosteroids, inhaled short-acting beta2 agonists, aminophylline, doripenem, and levofloxacin. Through successful treatment in the intensive care unit (ICU), her condition and the chest X-ray and CT findings improved. Chlamydophila pneumoniae infection was confirmed by elevated paired serum C. pneumoniae-specific IgA antibodies. Chlamydophila pneumoniae infection is an important cause of severe acute asthma. On CT, findings typical of C. pneumoniae pneumonia were noted. PMID- 28560040 TI - Spatially-segmented undersampled MRI temperature reconstruction for transcranial MR-guided focused ultrasound. AB - BACKGROUND: Volumetric thermometry with fine spatiotemporal resolution is desirable to monitor MR-guided focused ultrasound (MRgFUS) procedures in the brain, but requires some form of accelerated imaging. Accelerated MR temperature imaging methods have been developed that undersample k-space and leverage signal correlations over time to suppress the resulting undersampling artifacts. However, in transcranial MRgFUS treatments, the water bath surrounding the skull creates signal variations that do not follow those correlations, leading to temperature errors in the brain due to signal aliasing. METHODS: To eliminate temperature errors due to the water bath, a spatially-segmented iterative reconstruction method was developed. The method fits a k-space hybrid signal model to reconstruct temperature changes in the brain, and a conventional MR signal model in the water bath. It was evaluated using single-channel 2DFT Cartesian, golden angle radial, and spiral data from gel phantom heating, and in vivo 8-channel 2DFT data from a FUS thalamotomy. Water bath signal intensity in phantom heating images was scaled between 0-100% to investigate its effect on temperature error. Temperature reconstructions of retrospectively undersampled data were performed using the spatially-segmented method, and compared to conventional whole-image k-space hybrid (phantom) and SENSE (in vivo) reconstructions. RESULTS: At 100% water bath signal intensity, 3 *-undersampled spatially-segmented temperature reconstruction error was nearly 5-fold lower than the whole-image k-space hybrid method. Temperature root-mean square error in the hot spot was reduced on average by 27 * (2DFT), 5 * (radial), and 12 * (spiral) using the proposed method. It reduced in vivo error 2 * in the brain for all acceleration factors, and between 2 * and 3 * in the temperature hot spot for 2-4 * undersampling compared to SENSE. CONCLUSIONS: Separate reconstruction of brain and water bath signals enables accelerated MR temperature imaging during MRgFUS procedures with low errors due to undersampling using Cartesian and non-Cartesian trajectories. The spatially-segmented method benefits from multiple coils, and reconstructs temperature with lower error compared to measurements from SENSE reconstructed images. The acceleration can be applied to increase volumetric coverage and spatiotemporal resolution. PMID- 28560042 TI - Acetylcholinesterase and butyrylcholinesterase in cardiosurgical patients with postoperative delirium. AB - BACKGROUND: Patients in intensive care units (ICU) are often diagnosed with postoperative delirium; the duration of which has a relevant negative impact on various clinical outcomes. Recent research found a potentially important role of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in delirium of critically ill patients on non-surgical ICU or in non-cardiac-surgery patients. We tested the hypothesis that AChE and BChE have an impact on patients after cardiac surgery with postoperative delirium. METHODS: After obtaining approval from the local ethics committee, this mechanistic study gathered data of all 217 patients included in a randomized controlled trial testing non-pharmacological modifications of care in the cardiac surgical ICU to reduce delirium. Delirium was assessed with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and the Nursing Delirium Screening Scale (Nu-DESC) twice a day for the first 3 days after surgery. Further outcome variables were somatic laboratory parameters and variables regarding surgery, anesthesia, and postsurgical recovery. 10 MUl venous or arterial blood was drawn and AChE and BChE were determined with ChE check mobile from Securetec. RESULTS: Of 217 patients, 60 (27.6%) developed postsurgical delirium (POD). Patients with POD were older (p = 0.005), had anemia (p = 0.01), and worse kidney function (p = 0.006). Furthermore, these patients had lower intraoperative cerebral saturation (NIRS) (p < 0.001) and higher intraoperative need of catecholamines (p = 0.03). Delirious patients showed more inflammatory response (p < 0.001). AChE and BChE values were mainly inside the norm. Patients with values outside the norm did not have POD more often than others. Regarding AChE and BChE patients did not differ in having delirium or not (p > 0.10). CONCLUSIONS: Postoperative measurement of AChE and BChE did not discern between patients with and without POD. The effect of the cardiac surgical procedure on AChE and BChE remains unclear. Further studies with patients in cardiac surgery are needed to evaluate a possible combination of delirium and the cholinergic transmitter system. There might be possible interactions with AChE/BChE and blood products and the use of cardiopulmonary bypass, which should be investigated more intensively. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00006217. PMID- 28560043 TI - New and emerging chlamydial infections of creatures great and small. AB - Until recently, our knowledge of the host range and diversity of members of the Chlamydiaceae, obligate intracellular bacterial pathogens of humans and animals, was thought to be nearly complete. Aided by advances in molecular diagnostics, a new picture is emerging, however, that the host barriers may be looser than previously thought for many chlamydial species. While cross-host transmission of chlamydial species is a concern for animal health, new reports highlight an emerging zoonotic risk for several species associated with intensification of farming and the widespread popularity of companion animals. The description of an expanded cohort of new species within this family from avian and reptilian hosts has also highlighted how much we still have to learn about the biology and pathogenicity of the Chlamydiaceae as a whole. Reports emerging about these relatives of the traditional chlamydial pathogens are matched by the continued identification of novel Chlamydia-related bacteria in the phylum Chlamydiae, providing evidence that many may be pathogenic to humans or animals and pose a zoonotic or vector-borne risk. The review examines the new hosts described for well-characterized chlamydial veterinary pathogens, emerging novel chlamydial species and the potential for these to cause disease in their respective hosts. PMID- 28560044 TI - Decolorization of synthetic textile wastewater using electrochemical cell divided by cellulosic separator. AB - BACKGROUND: Annually, large quantities of dyes are produced and consumed in different industries. The discharge of highly colored textile effluents to the aquatic environments causes serious health problems in living organisms. This paper investigates the performance of each of the electro-oxidation and electro reduction pathways in the removal of reactive red 120 (RR120) from synthetic textile effluents using a novel electrochemical reactor. METHODS: In the current study, a two-compartment reactor divided by cellulosic separator was applied in batch mode using graphite anodes and stainless steel cathodes. Central Composite Design was used to design the experiments and find the optimal conditions. The operational parameters were initial dye concentration (100-500 mg L-1), sodium chloride concentration (2500-12,500 mg L-1), electrolysis time (7.5-37.5 min), and current intensity (0.06-0.3 A). RESULTS: The results showed that electro oxidation was much more efficient than electro-reduction in the removal of RR120. According to the developed models, current intensity was the most effective factor on the electro-oxidation of RR120 as well as in power consumption (Coefficients of 12.06 and 0.73, respectively). With regard to the dye removal through electro-reduction, electrolysis time (coefficient of 8.05) was the most influential factor. Under optimal conditions (RR120 = 200 mg.L-1, NaCl = 7914.29 mg.L-1, current intensity = 0.12 A, and reaction time = 30 min), the dye was removed as 99.44 and 32.38% via electro-oxidation and electro-reduction mechanisms, respectively, with consuming only 1.21 kwhm-3 of electrical energy. CONCLUSIONS: According to the results, electro-oxidation using graphite anodes in a cell divided by cellulosic separator is very efficient, compared to electro reduction, in the removal of RR120 from aqueous solutions. PMID- 28560045 TI - Correlation of neuter status and expression of heritable disorders. AB - BACKGROUND: Gonadectomy, or neutering, is a very common surgery for dogs having many positive effects on behavior, health, and longevity. There are also certain risks associated with neutering including the development of orthopedic conditions, cognitive decline, and a predisposition to some neoplasias. This study was designed specifically to identify if a correlation exists between neuter status and inherited conditions in a large aggregate cohort of dogs representing many different breeds. RESULTS: Neutered dogs were at less risk for early and congenital conditions (aortic stenosis, early onset cataracts, mitral valve disease, patent ductus arteriosus, portosystemic shunt, and ventricular septal defect) than intact dogs. Neutering was also associated with reduced risk of dilated cardiomyopathy and gastric dilatation volvulus in males. Neutering was significantly associated with an increased risk for males and females for cancers (hemangiosarcoma, hyperadrenocorticism, lymphoma, mast cell tumor, and osteosarcoma), ruptured anterior cruciate ligament and epilepsy. Intervertebral disk disease was associated with increased risk in females only. For elbow dysplasia, hip dysplasia, lens luxation, and patellar luxation neutering had no significant effect on the risk for those conditions. Neutering was associated with a reduced risk of vehicular injury, a condition chosen as a control. CONCLUSIONS: In this retrospective study, several conditions showed an increased risk associated with neutering whereas other conditions were less likely to be expressed in neutered dogs. The complexity of the interactions between neutering and inherited conditions underscores the need for reflective consultation between the client and the clinician when considering neutering. The convenience and advantages of neutering dogs that will not be included in a breeding program must be weighed against possible risk associated with neutering. PMID- 28560046 TI - A review of delivery room resuscitation in very low birth weight infants in a middle income country. AB - BACKGROUND: Advanced levels of delivery room resuscitation in very low birth weight infants are reported to be associated with death and complications of prematurity. In resource limited settings, the need for delivery room resuscitation is often used as a reason to limit care in these infants. METHODS: This was a review of delivery room resuscitation in very low birth weight infants born in a tertiary hospital in South Africa between 01 January 2013 and 30 June 2016. Outcomes included death and serious complications of prematurity. Advanced delivery room resuscitation was defined as the need for intubation, chest compressions or the administration of adrenaline. RESULTS: A total of 1511 very low birth weight infants were included in the study. The majority (1332/1511 (88.2%) required oxygen in the delivery room. Face mask ventilation was needed in 45.2% (683/1511). Advanced delivery room resuscitation was only required in 10.6% (160/1511). More than half the infants who required advanced delivery room resuscitation died (89/160; 55.6%). Advanced delivery room resuscitation was required in significantly more infants <1000 grams at birth than those infants >1000 grams (83/539 (15.4%) vs 77/972 (7.9%) p < 0.001). Advanced delivery room resuscitation was significantly associated with a 5 minute Apgar score < 6 (OR 13.8 (95%CI 8.6-22.0), supplemental oxygen at day 28 (OR 2.2 (95% CI 1.4-3.9), metabolic acidosis (OR 2.3 (95% CI 1.1-4.8) and death (OR 1.9 95% CI 1.1-3.3). Other serious complications of prematurity were not associated with advanced delivery room resuscitation. Mortality was increased in infants with a low admission temperature (35.1 degrees C (SD 0.92) vs 36.1 degrees C (SD 1.4) (p < 0.001). CONCLUSION: There was a high mortality rate associated with advanced delivery room resuscitation; however complications of prematurity were not increased in survivors..The need for advanced delivery room resuscitation alone should not be used as a predictor of poor outcome in very low birth weight infants. Survivors of advanced delivery room resuscitation should be afforded ventilatory support if required. Special care must be taken to avoid hypothermia in very low birth weight infants requiring resuscitation at birth. PMID- 28560047 TI - Effects of dexamethasone on progesterone and estrogen profiles and uterine progesterone receptor localization during pregnancy in Sahel goat in Semi-Arid region. AB - BACKGROUND: Despite the widespread use of dexamethasone in veterinary and human medicine, it is reported to cause some severe pregnancy related side effects like abortion in some animals. The mechanism of the response is not clear but seems to be related to interspecies and/or breed difference in response which may involve alterations in the concentrations of some reproductive hormones. METHODS: Twenty Sahel goats comprising 18 does and 2 bucks were used for this study. Pregnancies were achieved by natural mating after synchronization. Repeated dexamethasone injections were given at 0.25 mg/kg body weight. Blood samples were collected biweekly for hormonal assay. Uterine biopsies were harvested at days 28 and day 78 of gestation through caesarean section for immunohistochemical analysis using 3 pregnant does randomly selected from each group at each instant. Data were expressed as Means +/- Standard Deviations and analyzed using statistical soft ware package, GraphPad Instant, version 3.0 (2003) and progesterone receptor (PR) were scored semi-quantitatively. RESULTS: Dexamethasone treatments had no significant (p > 0.05) effect on progesterone and estrogen concentrations in pregnant Sahel goats but up regulated PR from 2+ to 3+ in second trimester. CONCLUSION: As dexamethasone adverse effect on placenta is an established fact, the lack of effect on progesterone level in this study may be due to the fact that unlike other species whose progesterone production during pregnancy is placenta - dependent, in goats is corpus luteum - dependent. Consequently dexamethasone adverse effect on placenta reported in literatures did not influence progesterone levels during pregnancy in Sahel goat. The up regulation of progesterone receptor (PR) in Sahel goat gravid uterus is a beneficial effects and that dexamethasone can safely be used in corpus luteum - dependent progesterone secreting pregnant animal species like Sahel goat and camel. Therefore source of progesterone secretions during pregnancy should be considered in clinical application of dexamethasone in pregnancy. PMID- 28560048 TI - The phylogenetic position of dicyemid mesozoans offers insights into spiralian evolution. AB - BACKGROUND: Obtaining phylogenomic data for enigmatic taxa is essential to achieve a better understanding of animal evolution. Dicyemids have long fascinated biologists because of their highly simplified body organization, but their life-cycles remain poorly known. Based on the discovery of the dicyemid DoxC gene, which encodes a spiralian peptide, it has been proposed that dicyemids are members of the Spiralia. Other studies have suggested that dicyemids may have closer affinities to mollusks and annelids. However, the phylogenetic position of dicyemids has remained a matter of debate, leading to an ambiguous picture of spiralian evolution. RESULTS: In the present study, newly sequenced transcriptomic data from Dicyema japonicum were complemented with published transcriptomic data or predicted gene models from 29 spiralian, ecdysozoan, and deuterostome species, generating a dataset (Dataset 1) for phylogenomic analyses, which contains 348 orthologs and 58,124 amino acids. In addition to this dataset, to eliminate systematic errors, two additional sub-datasets were created by removing compositionally heterogeneous or rapidly evolving sites and orthologs from Dataset 1, which may cause compositional heterogeneity and long-branch attraction artifacts. Maximum likelihood and Bayesian inference analyses both placed Dicyema japonicum (Dicyemida) in a clade with Intoshia linei (Orthonectida) with strong statistical support. Furthermore, maximum likelihood analyses placed the Dicyemida + Orthonectida clade within the Gastrotricha, while in Bayesian inference analyses, this clade is sister group to the clade of Gastrotricha + Platyhelminthes. CONCLUSIONS: Whichever the case, in all analyses, Dicyemida, Orthonectida, Gastrotricha, and Platyhelminthes constitute a monophyletic group that is a sister group to the clade of Mollusca + Annelida. Based on present phylogenomic analyses, dicyemids display close affinity to orthonectids, and they may share a common ancestor with gastrotrichs and platyhelminths, rather than with mollusks and annelids. Regarding spiralian phylogeny, the Gnathifera forms the sister group to the Rouphozoa and Lophotrochozoa, as has been suggested by previous studies; thus our analysis supports the traditional acoeloid-planuloid hypothesis of a nearly microscopic, non-coelomate common ancestor of spiralians. PMID- 28560049 TI - Measurement of refractive indices of tunicates' tunics: light reflection of the transparent integuments in an ascidian Rhopalaea sp. and a salp Thetys vagina. AB - BACKGROUND: Tunic is a cellulosic, integumentary matrix found in tunicates (Subphylum Tunicata or Urochordata). The tunics of some ascidian species and pelagic tunicates, such as salps, are nearly transparent, which is useful in predator avoidance. Transparent materials can be detected visually using light reflected from their surfaces, with the different refractive indices between two media, i.e., tunic and seawater, being the measure of reflectance. A larger difference in refractive indices thus provides a larger measure of reflectance. RESULTS: We measured the refractive indices of the transparent tunic of Thetys vagina (salp: Thaliacea) and Rhopalaea sp. (ascidian: Ascidiacea) using an Abbe refractometer and an ellipsometer to estimate the light reflection at the tunic surface and evaluate the anti-reflection effect of the nipple array structure on the tunic surface of T. vagina. At D-line light (lambda = 589 nm), the refractive indices of the tunics were 0.002-0.004 greater than seawater in the measurements by Abbe refractometer, and 0.02-0.03 greater than seawater in the measurements by ellipsometer. The refractive indices of tunics were slightly higher than that of seawater. According to the simulation of light reflection based on rigorous coupled wave analysis (RCWA), light at a large angle of incidence will be completely reflected from a surface when its refractive indices are smaller than seawater. Therefore, the refractive index of integument is important for enabling transparent organisms to remain invisible in the water column. CONCLUSION: In order to minimize reflectance, the refractive index should be similar to, but never smaller than, that of the surrounding seawater. The simulation also indicated that the presence or absence of a nipple array does not cause significant difference in reflectance on the surface. The nipple array on the tunic of the diurnal salp may have another function, such as bubble repellence, other than anti-reflection. PMID- 28560050 TI - Gamma knife radiosurgery for the treatment of uveal melanoma and uveal metastases. AB - BACKGROUND: This study retrospectively analyzed outcomes for patients undergoing gamma knife radiosurgery (GKR) for uveal melanoma (UM) and intraocular metastases. METHODS: Patients who underwent GKR for UM or intraocular metastases between 1/1/1990 and 6/1/2015 at Mayo Clinic, Rochester, MN, USA, were retrospectively analyzed. RESULTS: Eleven patients (11 eyes) had UM while seven patients (7 eyes) had intraocular metastases. Patients with UM were followed for a median of 19.74 +/- 10.4 months. Visual acuity (VA) logMAR 0.30 +/- 0.53 (Snellen 20/40) versus 0.40 +/- 0.97 (Snellen 20/50), tumor thickness (5.30 +/- 2.17 vs. 3.60 +/- 2.32 mm), were not significantly different between preoperative and postoperative measurements, respectively. Nine percent (1/11) patients required enucleation. Subsequently, no patients experienced metastases. Patients with intraocular metastases were followed for a median of 6.03 +/- 6.32 months. They did not have significant changes in VA (logMAR 0.30 +/- 0.59 vs. 0.30 +/- 1.57; Snellen 20/40 vs. 20/40) or tumor thickness (3.50 +/- 1.36 vs. 1.30 +/- 0.76 mm) postoperatively. Fourteen percent (1/7 patients) required enucleation. Complications experienced by patients with UM include radiation retinopathy (2/11), papillopathy (1/11), cystoid macular edema (1/11), vitreomacular traction (1/11), exudative retinal detachment (1/11). Patients with metastases had treatment complicated by recurrence (2/7). Dose to the margin, maximum dose of radiation, and clinical target volume did not correlate with post-procedural VA, risk of enucleation, or death in patients with either UM or patients with intraocular metastases. CONCLUSIONS: Visual outcomes were satisfactory for patients undergoing GKR without significant morbidity and without significant risk of enucleation or metastases. PMID- 28560052 TI - Genomic profile of a patient with triple negative essential thrombocythemia, unresponsive to therapy: A case report and literature review. AB - Clonal analysis of patients with triple negative myeloproliferative neoplasm (MPN) has provided evidence of additional aberrations, including epigenetic alterations. To discover such novel genetic aberrations, patients were screened through next-generation sequencing using a myeloid sequencing panel of 54 genes using a genetic analyser. Genetic variants in 28 genes, including TET2, BCOR, BCR, and ABL1 were identified in a triple negative essential thrombocythemia (ET) patient. The individual role of some of these variants in disease pathogenesis has yet to be studied. Somatic mutations in the same genes have been reported with variable frequencies in myeloid malignancies. However, no pathogenic impact of these variants could be found; therefore, long-term follow up of patients with genetic analysis of a large cohort and the use of whole genome sequencing is required to assess the effects of these variants. PMID- 28560051 TI - Choroidal vascular analysis in myopic eyes: evidence of foveal medium vessel layer thinning. AB - PURPOSE: To analyse morphologic features of the choroid in Non-pathological myopic eyes using spectral-domain (SD) optical coherence tomography (OCT). METHODS: Retrospective analysis of enhanced depth SD-OCT images of Non pathological myopic eyes in comparison with age-matched healthy controls was performed. Choroidal thickness (CT) and large choroidal vessel thickness (LCVT) were measured at the fovea, 750 um nasally from fovea (N750) and 750 um temporally (T750) from fovea. Medium choroidal vessel thickness (MCVT) was calculated by subtracting LCVT from CT. Choriocapillaris was encompassed by MCVT, given its reduced thickness. Linear regression analysis evaluated the relationship between age and axial with CT, LCVT and MCVT. RESULTS: The study group comprised 42 eyes of 31 patients (mean age 46.13 +/- 15.63; 15 females). Control group included 57 eyes of 34 patients (mean age of 42.3 +/- 15.29; 24 females). Mean axial length in myopic eyes and control group was 26.57 +/- 1.27 and 23.59 +/- 0.99 mm respectively. Myopic eyes showed significant thinning of MCVT and CT at all locations (p < 0.0001) compared to controls, unlike LCVT (p > 0.05). With each decade, thinning of up to 37 um in CT was noted along with thinning of LCVT (up to 22.6 um) and MCVT (up to 25 um). Each mm increase in axial length caused 38.2 um thinning of choroid along with LCVT (<10 um), however, MCVT showed more notable thinning (>30 um). CONCLUSION: Significant thinning of MCVT was noted in non-pathological myopic eyes in comparison to healthy subjects. It appears that MCVT has stronger relationship with age and axial length. PMID- 28560053 TI - Volatiles profiling in Ceratonia siliqua (Carob bean) from Egypt and in response to roasting as analyzed via solid-phase microextraction coupled to chemometrics. AB - Ceratonia siliqua is a legume tree of considerable commercial importance for the flavor and sweets industry cultivated mostly for its pods nutritive value and or several health benefits. Despite extensive studies on C. siliqua pod non-volatile metabolites, much less is known regarding volatiles composition which contributes to the flavor of its many food products. To gain insight into C. siliqua aroma, 31 volatile constituents from unroasted and roasted pods were profiled using headspace solid-phase micro extraction (HD-SPME) analyzed via quadruple mass spectrometer followed by multivariate data analyses. Short chain fatty acids amounted for the major volatile class at ca. (71-77%) with caproic acid (20%) and pentanoic acid (15-25%) as major components. Compared to ripe pod, roasted ripe pod was found less enriched in major volatile classes i.e., short chain fatty acids and aldehydes, except for higher pyranone levels. Volatiles mediating for unheated and hot carob fruit aroma is likely to be related to its (E) cinnamaldehyde and pyranone content, respectively. Such knowledge is expected to be the key for understanding the olfactory and taste properties of C. siliqua and its various commercial food products. PMID- 28560054 TI - Antibacterial activity against Streptococcus mutans and inhibition of bacterial induced enamel demineralization of propolis, miswak, and chitosan nanoparticles based dental varnishes. AB - Using natural products can be a cost-effective approach for caries prevention especially in low income countries where dental caries is highly prevalent and the resources are limited. Specially prepared dental varnishes containing propolis, miswak, and chitosan nanoparticles (CS-NPs) with or without sodium fluoride (NaF) were assessed for antibacterial effect against Streptococcus mutans (S. mutans) using disk diffusion test. In addition, the protective effect of a single pretreatment of primary teeth enamel specimens against in vitro bacterial induced enamel demineralization was assessed for 3 days. All natural products containing varnishes inhibited bacterial growth significantly better than 5% NaF varnish, with NaF loaded CS-NPs (CSF-NPs) showing the highest antibacterial effect, though it didn't significantly differ than those of other varnishes except miswak ethanolic extract (M) varnish. Greater inhibitory effect was noted with varnish containing freeze dried aqueous miswak extract compared to that containing ethanolic miswak extract, possibly due to concentration of antimicrobial substances by freeze drying. Adding natural products to NaF in a dental varnish showed an additive effect especially compared to fluoride containing varnish. 5% NaF varnish showed the best inhibition of demineralization effect. Fluoride containing miswak varnish (MF) and CSF-NPs varnish inhibited demineralization significantly better than all experimental varnishes, especially during the first 2 days, though CSF-NPs varnish had a low fluoride concentration, probably due to better availability of fluoride ions and the smaller size of nanoparticles. Incorporating natural products with fluoride into dental varnishes can be an effective approach for caries prevention, especially miswak and propolis when financial resources are limited. PMID- 28560056 TI - Maintaining a regular physical activity aggravates intramuscular tumor growth in an orthotopic liposarcoma model. AB - Today, care teams within cancer centers encourage patients to be physically active, after diagnosis, based on data obtained mainly from breast, colon and prostate cancer. Intriguingly, the impact of physical activity (PA) on intramuscular tumors (e.g. sarcomas) has not been specifically addressed and, thus, could be mistakenly confounded with other cancers. In this preclinical study we assessed the impact of PA on intramuscular liposarcoma (LS) evolution. Four-week-old nude male mice were active by voluntary running on wheels, for six weeks. Then, mice were divided into four groups with open or restricted access to wheels, which have received an orthotopic intramuscular injection of either vehicle or human LS, SW872, cells. Active mice presented ~1.5 fold increase in tumor mass, which was mainly due to higher cellular mitosis and proliferation. This bulging intramuscular tumor mass altered muscle function, as evidence by overall muscle strength and maximum running capacity. From a molecular point of view, active mice exhibited poor levels of Phospho-p38Thr180/Tyr182 and p21 content in tumors and also displayed low amounts of circulating insulin comparing to inactive counterparts. Insulin induced Phospho-p38Thr180/Tyr182 and p21 expression in SW872 cells, in vitro. The expression of p21 was regulated in a p38 dependent fashion, since inhibition of p38 activity abolished the up-regulation of p21. Our data suggest that insulin-dependent activation of p38 MAPK-p21 pathway is a possible mechanism responsible for delaying tumor growth in inactive mice. Clinically, patients with lower-extremities LS could be advised to reduce or minimize their levels of PA during the preoperative period. PMID- 28560057 TI - CEBPA-mediated upregulation of the lncRNA PLIN2 promotes the development of chronic myelogenous leukemia via the GSK3 and Wnt/beta-catenin signaling pathways. AB - Accumulating evidence has shown that long noncoding RNAs (lncRNAs) are significant regulators of multiple cellular processes, including the development of chronic myelocytic leukemia (CML). However, the mechanism of how the lncRNA PLIN2 affects CML development remains unclear. In this study, we aimed to investigate the potential roles of CEBPA-mediated upregulation of PLIN2 in the process of CML development by regulating the GSK3 and Wnt/beta-catenin signaling pathways. We found that both CEBPA and PLIN2 were expressed at significantly higher levels in CML. Simultaneously, we found that CEBPA upregulated the expression of PLIN2 and that there was a positive correlation between CEBPA and PLIN2 in CML patients. CEBPA promoted the progression of CML by upregulating PLIN2. We also found that PLIN2 increased the expression levels of AKT, p-AKT, GSK-3beta, beta-catenin and Axin2/Conductin as well as promoted the progression of CML via the GSK3 and Wnt/beta-catenin signaling pathways in vitro. Furthermore, we found that CEBPA-mediated upregulation of PLIN2 expression promotes tumor growth via GSK3 and Wnt/beta-catenin signaling in vivo. Therefore, our study provided a new theoretical basis for CML treatment through the CEBPA/PLIN2 axis. PMID- 28560055 TI - Revisiting the hallmarks of cancer. AB - The hallmarks of cancer described by Hanahan and Weinberg have proved seminal in our understanding of cancer's common traits and in rational drug design. Not free of critique and with understanding of different aspects of tumorigenesis coming into clearer focus in the recent years, we attempt to draw a more organized and updated picture of the cancer hallmarks. We define seven hallmarks of cancer: selective growth and proliferative advantage, altered stress response favoring overall survival, vascularization, invasion and metastasis, metabolic rewiring, an abetting microenvironment, and immune modulation, while highlighting some considerations for the future of the field. PMID- 28560058 TI - Flot2 promotes tumor growth and metastasis through modulating cell cycle and inducing epithelial-mesenchymal transition of hepatocellular carcinoma. AB - Flotillin-2 (Flot2) is a highly conserved and ubiquitously expressed protein that resides on the cytoplasmic side of the cell membrane within specific cholesterol rich microdomains. Some studies have reported that overexpression of Flot2 is related to cancer progression. However, the role of Flot2 in hepatocellular carcinoma (HCC) remains unclarified. In this study, we aim to explore the correlation between Flot2 expression and HCC progression and the underlying mechanism. In the present study, overexpression of Flot2 in HCC tissues and cell lines was detected, and forced overexpression of Flot2 significantly promoted the proliferation, migration, invasion and metastasis of HCC in vitro and in vivo by modulating cell cycle and inducing EMT, which was mediated via up-regulation of Twist as a result of Raf/MEK/ERK1/2 pathway activation. In contrast, silencing Flot2 expression inhibited these biological processes. Furthermore, high expression of Flot2 was significantly correlated with poor prognosis of HCC patients after curative resection and is an independent risk factor. In conclusion, Flot2 promoted tumor growth and metastasis of HCC through modulating cell cycle and inducing EMT. The expression of Flot2 may play a key role in HCC progression and may be regarded as a potential poor prognostic marker for HCC. PMID- 28560059 TI - The anti-protozoan drug nifurtimox preferentially inhibits clonogenic tumor cells under hypoxic conditions. AB - Tumor hypoxia is an independent prognostic indicator of tumor malignant progression and poor patient survival. Therefore, eradication of hypoxic tumor cells is of paramount importance for successful disease control. In this study, we have made a new discovery that nifurtimox, a clinically approved drug to treat Chagas disease caused by the parasitic protozoan trypanosomes, can function as a hypoxia-activated cytotoxin. We have found that nifurtimox preferentially kill clonogenic tumor cells especially under the hypoxic conditions of <=0.1% O2. Mechanistically, nifurtimox becomes activated after tumor cells enter into a fully hypoxic state, as shown by the stabilization of the Hypoxia-Inducible Factor 1alpha (HIF-1alpha). Nifurtimox specifically induces the formation of 53BP1 foci, a hallmark of DNA double-stranded breaks, in hypoxic tumor cells. Hypoxia-dependent activation of nifurtimox involves P450 (cytochrome) oxidoreductase. The anti-protozoan drug nifurtimox holds promise as a new hypoxia activated cytotoxin with the potential to preferentially eliminates severely hypoxic tumor cells. PMID- 28560060 TI - MicroRNA-365 inhibits ovarian cancer progression by targeting Wnt5a. AB - MicroRNA-365 (miR-365) has been reported to play an important role in tumorigenesis in many types of cancers; however, the role of miR-365 in the carcinogenesis of ovarian cancer remains unknown. In this study, we focused on the roles and underlying mechanisms of miR-365 in ovarian cancer. Here, we found that miR-365 expression level was significantly decreased in ovarian cancer tissues and cell lines, and that low miR-365 expression was negatively significantly associated with advanced stages as defined by the International Federation of Gynecology and Obstetrics (FIGO), histological grading, and lymph node metastasis. Further functional assays showed that transfection with a miR 365 mimic significantly decreased ovarian cancer cell proliferation, colony formation, migration, and invasion. In addition, Wnt5a was identified as a target gene of miR-365 in ovarian cancer by bioinformatic analysis, luciferase reporter assay, qPCR, and western blot. Wnt5a expression levels were upregulated and inversely correlated with miR-365 expression in ovarian cancer tissues (r = 0.638, P < 0.0001). Overexpression of Wnt5a could effectively reverse the miR-365 overexpression-induced suppression of proliferation and invasion in ovarian cancer cells. Additionally, in vivo studies utilizing a xenograft model demonstrated that overexpression of miR-365 could reduce tumor growth by repressing Wnt5a. Taken together, these findings suggest that miR-365 may be a promising candidate for therapeutic application in ovarian cancer treatment. PMID- 28560062 TI - miR-146b-5p regulates cell growth, invasion, and metabolism by targeting PDHB in colorectal cancer. AB - MiRNA have been found to play a role in a plethora of cellular processes of cancer cells such as cell apoptosis, cell proliferation, invasion, migration metabolism and stem cell differentiation. Dysregulation of miR-146b-5p has been documented in a variety of human malignancies. However, the biological functions and molecular mechanisms of miR-146b-5p in ovarian cancer remain unknown. In this study, our results show that miR-146b-5p was unregulated in colorectal cancer (CRC) tissues compared with the adjacent non-cancerous tissues. Ectopic overexpression of miR-146b-5p in CRC promoted cell growth, invasion and glycolysis, while knockdown of miR-146b-5p inhibited the growth, invasion and glycolysis of CRC cells. The oncogenic effect of miR-146b-5p is also confirmed in vivo. Mechanically, miR-146b-5p targets the 3'-UTR of pyruvate dehydrogenase B (PDHB) and exerts oncogenic effect. Overexpression of PDHB abolished the oncogenic effects of miR-146b-5p on the growth, invasion and glycolysis of CRC cells. Taken together, our results show that miR-146b-5p is an oncogenic miRNA in CRC which exerts its effect by directly targeting PDHB. PMID- 28560063 TI - CCR6+ B lymphocytes responding to tumor cell-derived CCL20 support hepatocellular carcinoma progression via enhancing angiogenesis. AB - BACKGROUND & AIMS: Different immune cells in tumor microenvironment shape tumor progression. CCL20 over-expression was reported as one of the "stemness" trait in TP53 mutated hepatocellular carcinoma (HCC). We aimed to understand the effect of CCL20 on HCC progression. METHODS: In two HCC cohort patients (n=95, n=85 respectively), serum CCL20 concentration was quantified by using ELISA. Expressions of CCL20 and CCR6 in 41 paired HCC tumor and adjacent non-tumor tissues were determined by quantitative Real-Time PCR, confirmed by immunohistochemistry (CCL20) or by flow cytometry analysis (CCR6). Chemotaxis of splenocytes or purified CD19+ B cells to tumor cell-derived CCL20, and angiogenesis of different CD19+ B subtypes responding to tumor cell-derived CCL20 were measured in vitro. H22 murine hepatoma cells were inoculated into immunocompetent or immunodeficient SCID mice, tumor growth and metastasis were monitored after the mice were treated with anti-CCL20 neutralizing antibody or depleted B cells by anti-CD20. RESULTS: Elevation of pretherapy serum CCL20 in HCC patients and increase of CCR6 expression in HCC tissues were closely associated with tumor metastasis and disease poor prognosis. In HCC tissues, CCL20 expression was positively correlated with CCR6 (R2 =0.3134, P=0.0002), and CCR6 was exclusively identified in tumor infiltrated immune cells. CD19+CD5+ B lymphocytes expressed higher CCR6, responded to tumor cell-derived CCL20 and enhanced angiogenesis in vitro. Neutralizing CCL20 activity in immunocompetent mice, not in SCID mice, attenuated tumor incidence, restrained tumor growth and distal metastasis. Tumor angiogenesis was significantly inhibited after CCL20 activity was blockade. In addition, inhibiting B lymphocyte infiltration into tumor mileum also attenuated tumor growth. CONCLUSIONS: Tumor cell-derived CCL20 interacts with CCR6 highly expressed CD19+CD5+ B cells, to promote HCC progression, which might be via enhancing angiogenesis. PMID- 28560065 TI - MicroRNA-338-3p inhibits thyroid cancer progression through targeting AKT3. AB - microRNA-338-3p (miR-338-3p) has been implicated in tumor development and progression in many types of cancers. However, the function and mechanism underlying the action of miR-383-3p in thyroid cancer remain unclear and were therefore investigated in this study by in vitro and in vivo experiments. We found that miR-338-3p was downregulated in thyroid cancer tissues and cell lines. miR-338-3p expression was significantly associated with the clinical stage and lymph node metastasis of thyroid cancer. Forced expression of miR-338-3p suppressed thyroid cancer cell proliferation, clonogenicity, migration, and invasion in vitro and inhibited tumorigenesis in a nude mouse xenograft model system. Moreover, AKT3, a known oncogene, was confirmed as a direct target of miR 383-3p in thyroid cancer cells, as evidenced by the fact that ectopic miR-383 expression suppressed AKT3 expression and its downstream pathway (AKT pathway). In addition, AKT3 silencing by siRNA mimicked the effect of ectopic miR-338-3p on the growth and invasion of thyroid cancer cells. In contrast, AKT3 overexpression attenuated the inhibitory effect induced by miR-338-3p overexpression in thyroid cancer cells. These results suggest that miR-338-3p functions as a novel tumor suppressor that blocks thyroid cancer cell growth through targeting AKT3. PMID- 28560064 TI - Fms related tyrosine kinase 1 (Flt1) functions as an oncogene and regulates glioblastoma cell metastasis by regulating sonic hedgehog signaling. AB - Studies have shown that the abnormal expression of Fms related tyrosine kinase 1 (Flt1) is associated with multiple malignancies, yet its role in glioblastoma pathology remains to be elucidated. In this study, we investigated the role of Flt1 in regulating proliferation, migration and invasion of glioblastoma cells by establishing glioblastoma cell strains with constitutively silenced or elevated Flt1 expression. We demonstrate that ectopic expression of Flt1 promotes glioblastoma cells migration, invasion through cell scratching and Transwell assays. Further study has indicated that Flt1 knockdown prevents the spread of glioblastoma cells in vivo. Conversely, we also show that suppression of Flt1 expression inhibits migration and invasion of glioblastoma cells. Finally, our findings demonstrate that Flt1 promotes invasion and migration of glioblastoma cells through sonic hedgehog (SHH) signaling pathway. Our study suggests that galectin-1 represents a crucial regulator of glioblastoma cells metastasis. Thus, the detection and targeted treatment of Flt1-expressing cancer serves as a new therapeutic target for glioblastoma. PMID- 28560066 TI - GalNAc-T6 in the relationship with invasion ability of endometrial carcinomas and prognostic significance. AB - O-glycosylation in the field of carcinogenesis has been a critical topic of concern for several decades. The abnormal function of enzymes catalyzing the first step of this process, named polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts) has been determined to play an important role in cancer development and metastasis. Accordingly, we investigated the expression of GalNAc-T6 in endometrial carcinoma and evaluated the relationship between invasion characteristics and the cellular level of GalNAc-T6. The results suggested that positive GalNAc-T6 expression is significantly associated with histological grade of tumors and myometrial invasion characteristic. In vitro experiments showed that the over expression of GalNAc-T6 had strong association with the decrease of endometrial cell invasiveness. Taken together, our data support the use of GalNAc T6 as a potential indicator of good prognosis and noninvasive tumor in patients with endometrial carcinoma. PMID- 28560061 TI - Understanding tumor anabolism and patient catabolism in cancer-associated cachexia. AB - Cachexia is a multifactorial paraneoplastic syndrome commonly associated with advanced stages of cancer. Cachexia is responsible for poor responses to antitumoral treatment and death in close to one-third of affected patients. There is still an incomplete understanding of the metabolic dysregulation induced by a tumor that leads to the appearance and persistence of cachexia. Furthermore, cachexia is irreversible, and there are currently no guidelines for its diagnosis or treatments for it. In this review, we aim to discuss the current knowledge about cancer-associated cachexia, starting with generalities about cancer as the generator of this syndrome, then analyzing the characteristics of cachexia at the biochemical and metabolic levels in both the tumor and the patient, and finally discussing current therapeutic approaches to treating cancer-associated cachexia. PMID- 28560067 TI - Inhibition of HIF-1alpha by PX-478 suppresses tumor growth of esophageal squamous cell cancer in vitro and in vivo. AB - The aim of this study is to investigate the clinical significance of hypoxia inducible factor-1alpha (HIF-1alpha) expression in esophageal squamous cell cancer (ESCC) and clarify the effects of PX-478, a selective HIF-1alpha inhibitor, on ESCC both in vitro and in vivo. HIF-1alpha, cyclooxygenase-2 (COX 2) and programmed death ligand-1 (PD-L1) were markedly overexpressed in ESCC tissue and associated with poorer survival. In vitro, both COX-2 and PD-L1 expression of ESCC cells were significantly induced by CoCl2 treatment, but inhibited by HIF-1alpha knock-down or PX-478 treatment. Furthermore, PX-478 significantly inhibited tumor cell proliferation by inhibiting the G2/M transition and promoting apoptosis of ESCC cells. In addition, inhibited epithelial-mesenchymal transition was observed after PX-478 treatment. In vivo, PX-478 significantly decreased tumor volume following subcutaneous implantation. Together, our results indicated that PX-478 had significant antitumor activity against HIF-1alpha over-expressing ESCC tumors in vitro and in vivo. These results opened up the possibility of inhibiting HIF-1alpha for targeted therapy of ESCC. PMID- 28560069 TI - The identification and validation of Trichosstatin A as a potential inhibitor of colon tumorigenesis and colon cancer stem-like cells. AB - Colon cancer is one of the most prevalent cancer types in developed countries. Metastasis and drug resistance are two contributing factors to the high mortality rate. Accumulating evidence suggest that cancer stem-like cells (CSCs) represents as a major contributor to these malignant features. Here, we identified and isolated colon cancer stem-like cells using side-population (SP) method from human colon cancer cell lines. SP colon cells demonstrate cancer stem-like cell properties including enhanced sphere-forming ability and resistance towards fluorouracil (5-FU). The CSC properties were associated with the increased expression level of major oncogenic and stem cell markers including beta-catenin, NF-kB, Akt/mTOR, KRAS and c-Myc. Trichostatin A (TSA), an antifungal antibiotic also a HDAC inhibitor, was found to function not only to decrease the expression of oncogenic markers but also the colon CSC properties. Importantly, TSA and 5-FU combined treatment synergistically suppressed colon cancer viability. Finally, in vivo results demonstrated that TSA alone and in combination with 5-FU effectively suppressed colon tumorigenesis. Collectively, this study provides preclinical evidence that TSA may function as a potential colon cancer therapeutic agent by targeting CSC and overcoming 5-FU resistance. PMID- 28560071 TI - The Changing Hospital Landscape: An Exploration of International Experiences. AB - The nature of hospital activity is changing in many countries, with some experiencing a broad trend towards the creation of hospital groups or chains and multi-hospital networks. This study seeks to contribute to the understanding of experiences in other countries about the extent to which different hospital "models" may provide lessons for hospital provision in England by means of a review of four countries: France, Germany, Ireland and the United States, with England included for comparison. We find that there has been a trend towards privatisation and the formation of hospital groups in France, Germany, and the United States although it is important to understand the underlying market structure in these countries explaining the drivers for hospital consolidation. Thus, and in contrast to the NHS, in France, Germany, and the United States, private hospitals contribute to the delivery of publicly funded healthcare services. There is limited evidence suggesting that different forms of hospital cooperation, such as hospital groups, networks or systems, may have different impacts on hospital performance. Available evidence suggests that hospital consolidation may lead to quality improvements as increased size allows for more costly investments and the spreading of investment risk. There is also evidence that a higher volume of certain services such as surgical procedures is associated with better quality of care. However, the association between size and efficiency is not clear-cut and there is a need to balance "quality risk" associated with low volumes and "access risk" associated with the closure of services at the local level. PMID- 28560068 TI - HDAC2 overexpression correlates with aggressive clinicopathological features and DNA-damage response pathway of breast cancer. AB - There are 18 lysine deacetylases, also known as histone deacetylases (HDACs), that remove acetyl groups from histone and non-histone proteins, thereby playing critical roles in numerous biological processes. In many human cancers, HDACs are dysregulated through mutation, altered expression, or inappropriate recruitment to certain loci. However, knowledge of the genomic and transcriptomic alterations and the clinical significance of most HDACs in breast cancer remain incomplete. We used TCGA and METABRIC datasets to perform comprehensive, integrated genomic and transcriptomic analyses of 18 HDAC genes in approximately 3000 primary breast cancers and identified associations among recurrent copy number alteration, gene expression, clinicopathological features, and patient survival. We found distinct patterns of copy number alteration and expression for each HDAC in breast cancer subtypes. We demonstrated that HDAC2 and SIRT7 were the most commonly amplified/overexpressed, and SIRT3 was most deleted/underexpressed, particularly in aggressive basal-like breast cancer. Overexpression of HDAC2 was significantly correlated with high tumor grade, positive lymph node status, and poor prognosis. The HDAC inhibitor mocetinostat showed anti-tumor effects in HDAC2-overexpressing basal-like breast cancer lines in vitro. Furthermore, HDAC2 expression was positively correlated with a set of DNA-damage response genes, notably RAD51. We revealed a potential mechanism by which HDAC2 regulates RAD51 expression-by indirect mediation through microRNAs, e.g., miR-182. HDAC inhibitors have emerged as a promising new class of multifunctional anticancer agents. Identifying which breast cancers or patients show HDAC deregulation that contributes to tumor development/progression might enable us to improve target cancer therapy. PMID- 28560072 TI - Health Sector Reform in the Kurdistan Region - Iraq: Financing Reform, Primary Care, and Patient Safety. AB - In 2010, the Kurdistan Regional Government asked the RAND Corporation to help guide reform of the health care system in the Kurdistan Region of Iraq. The overarching goal of reform was to help establish a health system that would provide high-quality services efficiently to everyone to prevent, treat, and manage physical and mental illnesses and injuries. This article summarizes the second phase of RAND's work, when researchers analyzed three distinct but intertwined health policy issue areas: development of financing policy, implementation of early primary care recommendations, and evaluation of quality and patient safety. For health financing, the researchers reviewed the relevant literature, explored the issue in discussions with key stakeholders, developed and assessed various policy options, and developed plans or approaches to overcome barriers and achieve stated policy objectives. In the area of primary care, they developed and helped to implement a new management information system. In the area of quality and patient safety, they reviewed relevant literature, discussed issues and options with health leaders, and recommended an approach toward incremental implementation. PMID- 28560070 TI - Clinical implications of c-maf expression in plasma cells from patients with multiple myeloma. AB - BACKGROUND: Multiple myeloma (MM) is a type of hematological malignancy with significant heterogeneity in clinical features and prognosis. Cytogenetic abnormalities are the major factors affecting patient outcomes. Studies have shown that immunohistochemistry (IHC)-based detection of cancer-related genes expression could be alternative indicators for the prognosis of MM. METHODS: Nuclear expression of c-maf protein in the bone marrow plasma cells of 128 multiple myeloma patients were examined by IHC, and its association with the clinicopathological features of MM patients was analyzed as well. RESULTS: Among the 128 patients, the positive rate of c-maf protein expression was up to 30.5%, which had no correlation with patient age, M protein type, Durie-Salmon staging system, the International Staging System, abnormal plasma cell ratio in the bone marrow, or the level of peripheral blood hemoglobin, serum calcium or lactate dehydrogenase. However, the c-maf-positive patients had a significantly higher rate of hypoproteinemia (p = 0.026) and higher serum beta2-microglobulin levels (>2500 MUg/L) (p = 0.007). Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on progression-free survival or overall survival was observed. CONCLUSION: Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on survival was observed. A further large-scale prospective study is required to verify these findings. PMID- 28560073 TI - Process Evaluation of the New Mexico Maternal, Infant, and Early Childhood Home Visiting Competitive Development Grant. AB - This article describes the evaluation of the New Mexico Home Visiting Competitive Development Grant, which sought to pilot test the use of implementation supports to improve the development and implementation of home visiting programs. Each community was to use Getting To Outcomes(r) (GTO) and ECHO(r) (Extension for Community Healthcare Outcomes) to support their work. The GTO framework promotes capacity for high-quality programming by specifying ten steps that practitioners should take and by providing support to complete those steps. ECHO involves specialists providing training and technical assistance via distance technology to community practitioners in rural areas to improve the quality of services. The grant was delayed, and the project's scope shifted significantly from the original plan. The evaluation documents significant challenges in meeting grant goals. A local team hired to facilitate GTO did not use it as designed, and no communities were trained in GTO. The coalitions that were developed operated with few resources or accountability, and made little progress on plans to enhance services. Only two of the four communities started home visiting after nearly a year and a half. ECHO was used with fidelity with those two programs. There was no change in the continuum of services to support children and families. Due to delays and lack of implementation of the proposed intervention, the evaluation was not able to assess the project's impact on child or family outcomes, nor did the project serve as a robust pilot test of the use of GTO and ECHO to improve home visiting implementation. PMID- 28560074 TI - The Role of Health Care Transformation for the Chinese Dream: Powering Economic Growth, Promoting a Harmonious Society. AB - After having successfully expanded health insurance coverage, China now faces the challenge of building an effective and efficient delivery system to serve its large and aging population. The country finds itself at a crossroads-it can emulate the models of Western countries with their well-known limitations, or embark on an ambitious endeavor to create an innovative and sustainable model. We recommend that China choose the second option and design and implement a health care system based on population health management principles and sophisticated health information technology. Taking this path could yield a triple dividend for China: Health care will contribute to the growth of service sector employment, stimulate domestic demand by unlocking savings, and enable China to export its health system development capabilities to other emerging economies, mirroring its success in building other critical infrastructure. These forces can help turn the Chinese Dream into a reality. PMID- 28560075 TI - Emergency Department Patient Experience of Care Survey: Development and Field Test. AB - The Centers for Medicare & Medicaid Services (CMS) have implemented Consumer Assessment of Healthcare Providers and Systems (CAHPS(r)) surveys to assess patient experience in a number of settings. Following CAHPS principles, RAND researchers designed and field tested an Emergency Department Patient Experience of Care Survey that consists of three survey instruments for use with adult patients who have visited the emergency department (ED). One instrument is for use with those patients who are discharged to the community following their ED visit; the other two are for use with those patients who are admitted to the hospital from the ED (one for use on its own and one to supplement an existing inpatient survey). The authors conducted a field test of these instruments in 12 hospitals in late 2013 and early 2014 and analyzed the resulting data from 4,101 ED patients. The analyses identified four composite measures (measures composed of responses to multiple survey questions) and ten measures that are each composed of a single survey question. As of September 2014, CMS plans to conduct additional testing on these instruments. PMID- 28560076 TI - Evaluation of the SAMHSA Primary and Behavioral Health Care Integration (PBHCI) Grant Program: Final Report. AB - Excess morbidity and mortality in persons with serious mental illness is a public health crisis. Numerous factors contribute to this health disparity, including illness and treatment-related factors, socioeconomic and lifestyle-related factors, and limited access to and poor quality of general medical care. Primary and Behavioral Health Care Integration (PBHCI), one of the Substance Abuse and Mental Health Services Administration's service grant programs, is intended to improve the overall wellness and physical health status of people with serious mental illness, including individuals with co-occurring substance use disorders, by making available an array of coordinated primary care services in community mental health and other community-based behavioral health settings where the population already receives care. This article describes the results of a RAND Corporation evaluation of the PBHCI grants program. The evaluation was designed to understand PBHCI implementation strategies and processes, whether the program leads to improvements in outcomes, and which program models and/or model features lead to better program processes and consumer outcomes. Results of the evaluation showed that PBHCI grantee programs were diverse, varying in their structures, procedures, and the extent to which primary and behavioral health care was integrated at the program level. Overall, PBHCI programs also served many consumers with high rates of physical health care needs, although total program enrollment was lower than expected. The results of a small, comparative effectiveness study showed that consumers served at PBHCI clinics (compared to those served at matched control clinics) showed improvements on some (e.g., markers of dyslipidemia, hypertension, diabetes) but not all of the physical health indicators studied (e.g., smoking, weight). Finally, we found that program features, such as clinic hours, regular staff meetings, and the degree of service integration, increased consumer access to integrated care, but that access to integrated care was not directly associated with improvements in physical health. Implications of the study results for programs and the broader field, plus options for future PBHCI-related research are discussed. PMID- 28560077 TI - Promoting Patient Safety Through Effective Health Information Technology Risk Management. AB - The potential for health information technology (IT) to improve health care delivery has been appreciated for decades, but "digitizing" health care can also introduce new risks and even harm. As the use of health IT has grown, these risks have become more apparent. The authors of this report evaluated the efforts of 11 hospitals and ambulatory practices to use an improvement strategy and tools developed to promote safe use of health IT and to diagnose, monitor, and mitigate health IT-related safety risks. Through interviews, the authors discovered that some health care organizations (especially hospitals) with expertise in process improvement were able to identify and begin to mitigate health IT-related safety risks, but in most others, awareness of these risks was limited (especially in ambulatory practices). The authors concluded that better tools like the recently released Safety Assurance Factors for EHR Resilience (SAFER) Guides are needed to help organizations optimize the safe use of health IT. However, health care organizations will require a better understanding of the safety risks posed by electronic health record (EHR) use to take full advantage of the SAFER Guides. There may also be a need for additional tools and metrics (and further usability studies of existing tools and metrics) to better support the needs of health care organizations as they increasingly rely on health IT to improve the quality and safety of patient care. PMID- 28560078 TI - Changes in Health Insurance Enrollment Since 2013: Evidence from the RAND Health Reform Opinion Study. AB - RAND's Health Reform Opinion Study (HROS) allows for an estimation of how many people have become enrolled in all sources of health care coverage since the implementation of the Affordable Care Act (ACA). The HROS is conducted using the RAND American Life Panel, a nationally representative panel of individuals who regularly participate in surveys; this particular analysis, is focused on respondents age 18-64. In addition to asking them about their opinions of the ACA, each month RAND collected information about enrollment in health insurance, including employer-sponsored insurance (ESI), Medicaid, Medicare, insurance purchased on a marketplace, and other insurance purchased on the individual market. This detailed information about insurance coverage combined with the fact that the same individuals were surveyed each month provides a unique ability to track how insurance coverage has changed since the major health insurance coverage provisions of the ACA took effect on January 1, 2014. The analysis presented here examines changes in health insurance enrollment between September 2013 and March 2014; overall, the authors estimate that 9.3 million more people have health care coverage in March 2014, lowering the uninsured rate from 20.5 percent to 15.8 percent. This increase in coverage is driven not only by enrollment in health insurance marketplace plans, but also by gains in ESI and Medicaid. Enrollment in ESI plans increased by 8.2 million and Medicaid enrollment increased by 5.9 million, although some individuals did lose coverage during this period. The authors also found that 3.9 million people are now covered through the state and federal marketplaces-the so-called insurance exchanges-and less than 1 million people who previously had individual-market insurance became uninsured during the period in question. While the survey cannot tell if this latter group lost their insurance due to cancellation or because they simply felt the cost was too high, the overall number is very small, representing less than 1 percent of people between the ages of 18 and 64. PMID- 28560079 TI - Beliefs Related to Mental Illness Stigma Among California Young Adults. AB - This study examines mental illness stigma and related beliefs among young adults in California, especially whether levels of stigma are higher or lower than those observed in older adults. PMID- 28560080 TI - A Case Study Evaluating the Fidelity of Suicide Prevention Workshops in California. AB - Reports on an evaluation of California suicide intervention training workshops to provide evidence that training is delivered with fidelity and adherence to the workshop's design, as well as with high quality. PMID- 28560081 TI - Evaluation of the California Mental Health Services Authority's Prevention and Early Intervention Initiatives: Progress and Preliminary Findings. AB - The California Mental Health Services Authority (CalMHSA) statewide Prevention and Early Intervention (PEI) program comprises three strategic initiatives: (1) reduction of stigma and discrimination toward those with mental illness, (2) prevention of suicide, and (3) improvement in student mental health. Community agencies serve as PEI program partners to perform activities intended to meet the goals of the initiatives. This article evaluates the progress of the PEI program partners in achieving their goals and establishes baseline population tracking of key risk factors and long-term outcomes targeted by the initiatives. Based on a model to assess the program partners' capacities and resources and a recent survey of California adults, this article shows that the partners have greatly expanded their abilities to launch numerous PEI activities and programs. PMID- 28560082 TI - An Examination of New York State's Integrated Primary and Mental Health Care Services for Adults with Serious Mental Illness. AB - The poor physical health of adults with serious mental illnesses is a public health crisis. Greater integration of mental health and primary medical care services at the clinic and system levels could address this need. In New York state, there are several ongoing initiatives that promote integrated care for adults with serious mental illness, provided or coordinated by community mental health center staff. This study examines three initiatives. Data were collected by RAND through site visits and surveys of mental health clinic administrators and associated professionals. Results showed that Primary and Behavioral Health Care Integration grantees developed infrastructure that supported a broad scope of primary and preventive health care services; these broad changes appeared to contribute to clinic-wide culture shifts toward integration and shared accountability for consumers' "whole person" health. Clinics participating in the Medicaid Incentive tended to implement only those services for which they could bill, which resulted in newly identified consumer physical health care needs but did not help consumers to connect to physical health care services. Finally, while administrators and providers were optimistic that Medicaid Health Homes have potential to improve access to care for adults with serious mental illness, the newness of the initiative made it difficult to assess the degree to which Health Home networks would meet these goals. We conclude with recommendations to state policymakers, clinical providers, and technical assistance providers and recommendations for future research, all designed to strengthen New York state's integrated care initiatives for adults with serious mental illness. PMID- 28560083 TI - Language Differences in California Adults' Exposure to Suicide Prevention Messaging, Confidence in One's Ability to Intervene with Someone at Risk, and Resource Preferences. AB - Assesses the results of a statewide survey to determine language differences among California adults' exposure to suicide prevention messaging, confidence to intervene with someone at risk of suicide, and resource preferences. PMID- 28560084 TI - Recommendations for Sustaining California's Statewide Mental Health Prevention and Early Intervention Programs. AB - Provides preliminary advice about which of the California Mental Health Services Authority's Prevention and Early Intervention activities seem most valuable to sustain or, in some cases, enhance. PMID- 28560085 TI - Developing a Research Strategy for Suicide Prevention in the Department of Defense: Status of Current Research, Prioritizing Areas of Need, and Recommendations for Moving Forward. AB - In response to the elevated rate of suicide among U.S. service members, a congressionally mandated task force recommended that the U.S. Department of Defense (DoD) create a unified, comprehensive strategic plan for suicide prevention research to ensure that DoD-funded studies align with DoD's goals. To help meet this objective, a RAND study cataloged the research funded by DoD and other entities that is directly relevant to military personnel, examined the extent to which current research maps to DoD's strategic research needs, and provided recommendations to ensure that proposed research strategies align with the national research strategy and integrate with DoD's data collection and program evaluation strategies. The study found that although DoD is one of the largest U.S. funders of research related to suicide prevention, its current funding priorities do not consistently reflect its research needs. The study indexed each of 12 research goals according to rankings of importance, effectiveness, cultural acceptability, cost, and learning potential provided by experts who participated in a multistep elicitation exercise. The results revealed that research funding is overwhelmingly allocated to prevention goals already considered by experts to be effective. Other goals considered by experts to be important and appropriate for the military context receive relatively little funding and have been the subject of relatively few studies, meaning that there is still much to learn about these strategies. Furthermore, DoD, like other organizations, suffers from a research-to-practice gap. The most promising results from studies funded by DoD and other entities do not always find their way to those responsible for implementing suicide prevention programs that serve military personnel. The RAND study recommended approaches to thoughtfully integrate the latest research findings into DoD's operating procedures to ensure that evidence-based approaches can benefit suicide prevention programs and prevent the further loss of lives to suicide. PMID- 28560086 TI - How Deployments Affect the Capacity and Utilization of Army Treatment Facilities. AB - The Army was concerned about how the Army Force Generation (ARFORGEN) cycle, established to provide a predictable process by which Army units deploy, reset, and train to become ready and available to deploy again, affected the lives of Army soldiers and their families. In particular, the Vice Chief of Staff of the Army asked RAND Arroyo Center to determine whether ARFORGEN resulted in ebbs and flows in the ability of Army military treatment facilities (MTFs) to provide medical care and respond to changes in family needs as soldiers and care providers deploy and return home. This concern is especially well-founded because military health research has shown that family members of service members utilize health care differently during deployment than when the soldier is at home. This study found that MTF capacity is not greatly affected when soldiers and care providers deploy, and that MTFs may be slightly less busy than when soldiers and care providers are both at home. In aggregate, family member access to health care does not appear to be impinged when soldiers deploy, and soldiers who did not deploy with their unit slightly increase their utilization of health care during those times. PMID- 28560087 TI - The Future of Public Health: A Horizon Scan. AB - Public Health England (PHE) commissioned RAND Europe to undertake a horizon scanning study exploring the future of public health and related scientific services. This work was intended to help inform thinking at the strategic level within PHE, firstly in relation to the wider vision of the Agency (which was only established in April 2013) and, secondly, in relation to the proposals for the creation of an integrated public health science hub. The study is based on a literature review, a brief Delphi exercise using the ExpertLens platform and key informant interviews with a range of PHE staff and external experts. It focuses on the different future public health science needs and the extent to which an integrated science hub could serve PHE as it evolves over the next twenty years. Thus, the study considers PHE's future remit and objectives in order that decisions about an integrated and co-located science hub be made in context and with reference to expert perceptions about the future. PMID- 28560088 TI - The Structural Genomics Consortium: A Knowledge Platform for Drug Discovery: A Summary. AB - The Structural Genomics Consortium (SGC) supports drug discovery efforts through a unique, open access model of public-private collaboration. This study presents the results of an independent evaluation of the Structural Genomics Consortium, conducted by RAND Europe with the Institute on Governance. The evaluation aimed to establish the role of the SGC within the wider drug discovery and PPP landscape, assessing the merits of the SGC open access model relative to alternative models of funding R&D in this space, as well as the key trends and opportunities in the external environment that may impact on the future of the SGC. It also established the incentives and disincentives for investment, strengths and weaknesses of the SGC's model, and the opportunities and threats the SGC will face in the future. This enabled us to assess the most convincing arguments for funding the SGC at present; important trade-offs or limitations that should be addressed in moving towards the next funding phase; and whether funders are anticipating changes either to the SGC or the wider PPP landscape. Finally, we undertook a quantitative analysis to ascertain what judgements can be made about the SGC's past and current performance track record, before unpacking the role of the external environment and particular actors within the SGC in developing scenarios for the future. PMID- 28560090 TI - Correction to: Biores Open Access 2016;5:137-145. AB - [This corrects the article DOI: 10.1089/biores.2016.0010.]. PMID- 28560089 TI - Characterization of a Murine Model of Bioequivalent Bladder Wound Healing and Repair Following Subtotal Cystectomy. AB - Previous work demonstrated restoration of a bioequivalent bladder within 8 weeks of removing the majority of the bladder (subtotal cystectomy or STC) in rats. The goal of the present study was to extend our investigations of bladder repair to the murine model, to harness the power of mouse genetics to delineate the cellular and molecular mechanisms responsible for the observed robust bladder regrowth. Female C57 black mice underwent STC, and at 4, 8, and 12 weeks post STC, bladder repair and function were assessed via cystometry, ex vivo pharmacologic organ bath studies, and T2-weighted magnetic resonance imaging (MRI). Histology was also performed to measure bladder wall thickness. We observed a time-dependent increase in bladder capacity (BC) following STC, such that 8 and 12 weeks post-STC, BC and micturition volumes were indistinguishable from those of age-matched non-STC controls and significantly higher than observed at 4 weeks. MRI studies confirmed that bladder volume was indistinguishable within 3 months (11 weeks) post-STC. Additionally, bladders emptied completely at all time points studied (i.e., no increases in residual volume), consistent with functional bladder repair. At 8 and 12 weeks post-STC, there were no significant differences in bladder wall thickness or in the different components (urothelium, lamina propria, or smooth muscle layers) of the bladder wall compared with age matched control animals. The maximal contractile response to pharmacological activation and electrical field stimulation increased over time in isolated tissue strips from repaired bladders but remained lower at all time points compared with controls. We have established and validated a murine model for the study of de novo organ repair that will allow for further mechanistic studies of this phenomenon after, for example, genetic manipulation. PMID- 28560091 TI - A mixed methods study of multiple health behaviors among individuals with stroke. AB - BACKGROUND: Individuals with stroke often have multiple cardiovascular risk factors that necessitate promoting engagement in multiple health behaviors. However, observational studies of individuals with stroke have typically focused on promoting a single health behavior. Thus, there is a poor understanding of linkages between healthy behaviors and the circumstances in which factors, such as stroke impairments, may influence a single or multiple health behaviors. METHODS: We conducted a mixed methods convergent parallel study of 25 individuals with stroke to examine the relationships between stroke impairments and physical activity, sleep, and nutrition. Our goal was to gain further insight into possible strategies to promote multiple health behaviors among individuals with stroke. This study focused on physical activity, sleep, and nutrition because of their importance in achieving energy balance, maintaining a healthy weight, and reducing cardiovascular risks. Qualitative and quantitative data were collected concurrently, with the former being prioritized over the latter. Qualitative data was prioritized in order to develop a conceptual model of engagement in multiple health behaviors among individuals with stroke. Qualitative and quantitative data were analyzed independently and then were integrated during the inference stage to develop meta-inferences. The 25 individuals with stroke completed closed-ended questionnaires on healthy behaviors and physical function. They also participated in face-to-face focus groups and one-to-one phone interviews. RESULTS: We found statistically significant and moderate correlations between hand function and healthy eating habits (r = 0.45), sleep disturbances and limitations in activities of daily living (r = - 0.55), BMI and limitations in activities of daily living (r = - 0.49), physical activity and limitations in activities of daily living (r = 0.41), mobility impairments and BMI (r = - 0.41), sleep disturbances and physical activity (r = - 0.48), sleep disturbances and BMI (r = 0.48), and physical activity and BMI (r = - 0.45). We identified five qualitative themes: (1) Impairments: reduced autonomy, (2) Environmental forces: caregivers and information, (3) Re-evaluation: priorities and attributions, (4) Resiliency: finding motivation and solutions, and (5) Negative affectivity: stress and self-consciousness. Three meta-inferences and a conceptual model described circumstances in which factors could influence single or multiple health behaviors. DISCUSSION: This is the first mixed methods study of individuals with stroke to elaborate on relationships between multiple health behaviors, BMI, and physical function. A conceptual model illustrates addressing sleep disturbances, activity limitations, self-image, and emotions to promote multiple health behaviors. We discuss the relevance of the meta-inferences in designing multiple behavior change interventions for individuals with stroke. PMID- 28560092 TI - Comparison in antioxidant and antitumor activities of pine polyphenols and its seven biotransformation extracts by fungi. AB - Microbial transformation can strengthen the antioxidant and antitumor activities of polyphenols. Polyphenols contents, antioxidant and antitumor activities of pine polyphenols and its biotransformation extracts by Aspergillus niger, Aspergillus oryzae, Aspergillus carbonarius, Aspergillus candidus, Trichodermas viride, Mucor wutungkiao and Rhizopus sp were studied. Significant differences were noted in antioxidant and antitumor activities. The highest antioxidant activities in Trolox equivalent antioxidant capacity (TEAC), DPPH radical scavenging activity, superoxide anion radical scavenging activity, hydroxyl radical scavenging activity, reducing power assay and antitumor activity against LoVo cells were biotransformation extract of Aspergillus carbonarius (BAC), biotransformation extract of Mucor wutungkiao (BMW), biotransformation extract of Aspergillus carbonarius (BAC), biotransformation extract of Aspergillus niger (BAN), biotransformation extract of Aspergillus oryzae (BAO) and BMW, respectively. Correlation analysis found that antioxidant and antitumor activities were associated with polyphenols contents and types of free radicals and tumors. A. carbonarius can make polyphenol oxidation, hydroxylation and methylation, and form new polyphenols. In conclusion, A. carbonarius, A. niger and M. wutungkiao are valuable microorganisms used for polyphenols biotransformation and enhance the antioxidant and antitumor activities of polyphenols. PMID- 28560093 TI - Invasive lionfish had no measurable effect on prey fish community structure across the Belizean Barrier Reef. AB - Invasive lionfish are assumed to significantly affect Caribbean reef fish communities. However, evidence of lionfish effects on native reef fishes is based on uncontrolled observational studies or small-scale, unrepresentative experiments, with findings ranging from no effect to large effects on prey density and richness. Moreover, whether lionfish affect populations and communities of native reef fishes at larger, management-relevant scales is unknown. The purpose of this study was to assess the effects of lionfish on coral reef prey fish communities in a natural complex reef system. We quantified lionfish and the density, richness, and composition of native prey fishes (0-10 cm total length) at sixteen reefs along ~250 km of the Belize Barrier Reef from 2009 to 2013. Lionfish invaded our study sites during this four-year longitudinal study, thus our sampling included fish community structure before and after our sites were invaded, i.e., we employed a modified BACI design. We found no evidence that lionfish measurably affected the density, richness, or composition of prey fishes. It is possible that higher lionfish densities are necessary to detect an effect of lionfish on prey populations at this relatively large spatial scale. Alternatively, negative effects of lionfish on prey could be small, essentially undetectable, and ecologically insignificant at our study sites. Other factors that influence the dynamics of reef fish populations including reef complexity, resource availability, recruitment, predation, and fishing could swamp any effects of lionfish on prey populations. PMID- 28560094 TI - Eumelanin and pheomelanin are predominant pigments in bumblebee (Apidae: Bombus) pubescence. AB - BACKGROUND: Bumblebees (Hymenoptera: Apidae: Bombus) are well known for their important inter- and intra-specific variation in hair (or pubescence) color patterns, but the chemical nature of the pigments associated with these patterns is not fully understood. For example, though melanization is believed to provide darker colors, it still unknown which types of melanin are responsible for each color, and no conclusive data are available for the lighter colors, including white. METHODS: By using dispersive Raman spectroscopy analysis on 12 species/subspecies of bumblebees from seven subgenera, we tested the hypothesis that eumelanin and pheomelanin, the two main melanin types occurring in animals, are largely responsible for bumblebee pubescence coloration. RESULTS: Eumelanin and pheomelanin occur in bumblebee pubescence. Black pigmentation is due to prevalent eumelanin, with visible signals of additional pheomelanin, while the yellow, orange, red and brown hairs clearly include pheomelanin. On the other hand, white hairs reward very weak Raman signals, suggesting that they are depigmented. Additional non-melanic pigments in yellow hair cannot be excluded but need other techniques to be detected. Raman spectra were more similar across similarly colored hairs, with no apparent effect of phylogeny and both melanin types appeared to be already used at the beginning of bumblebee radiation. DISCUSSION: We suggest that the two main melanin forms, at variable amounts and/or vibrational states, are sufficient in giving almost the whole color range of bumblebee pubescence, allowing these insects to use a single precursor instead of synthesizing a variety of chemically different pigments. This would agree with commonly seen color interchanges between body segments across Bombus species. PMID- 28560095 TI - A novel genus and cryptic species harboured within the monotypic freshwater crayfish genus Tenuibranchiurus Riek, 1951 (Decapoda: Parastacidae). AB - Identifying species groups is an important yet difficult task, with there being no single accepted definition as to what constitutes a species, nor a set of criteria by which they should be delineated. Employing the General Lineage Concept somewhat circumvents these issues, as this concept allows multiple concordant lines of evidence to be used as support for species delimitation, where a species is defined as any independently evolving lineage. Genetically diverse groups have previously been identified within the monotypic parastacid genus Tenuibranchiurus Riek, 1951, but no further investigation of this diversity has previously been undertaken. Analysis of two mitochondrial DNA gene regions has previously identified two highly divergent groups within this taxon, representing populations from Queensland (Qld) and New South Wales (NSW), respectively. Additional testing within this study of both mitochondrial and nuclear DNA through species discovery analyses identified genetically diverse groups within these regions, which were further supported by lineage validation methods. The degree of genetic differentiation between Qld and NSW populations supports the recognition of two genera; with Qld retaining the original genus name Tenuibranchiurus, and NSW designated as Gen. nov. until a formal description is completed. Concordance between the species discovery and lineage validation methods supports the presence of six species within Tenuibranchiurus and two within Gen. nov. The recognition of additional species removes the monotypy of the genus, and the methods used can improve species identification within groups of organisms with taxonomic problems and cryptic diversity. PMID- 28560096 TI - Interactions of 172 plant extracts with human organic anion transporter 1 (SLC22A6) and 3 (SLC22A8): a study on herb-drug interactions. AB - BACKGROUND: Herb-drug interactions (HDIs) resulting from concomitant use of herbal products with clinical drugs may cause adverse reactions. Organic anion transporter 1 (OAT1) and 3 (OAT3) are highly expressed in the kidney and play a key role in the renal elimination of substrate drugs. So far, little is known about the herbal extracts that could modulate OAT1 and OAT3 activities. METHODS: HEK293 cells stably expressing human OAT1 (HEK-OAT1) and OAT3 (HEK-OAT3) were established and characterized. One hundred seventy-two extracts from 37 medicinal and economic plants were prepared. An initial concentration of 5 ug/ml for each extract was used to evaluate their effects on 6-carboxylfluorescein (6-CF) uptake in HEK-OAT1 and HEK-OAT3 cells. Concentration-dependent inhibition studies were conducted for those extracts with more than 50% inhibition to OAT1 and OAT3. The extract of Juncus effusus, a well-known traditional Chinese medicine, was assessed for its effect on the in vivo pharmacokinetic parameters of furosemide, a diuretic drug which is a known substrate of both OAT1 and OAT3. RESULTS: More than 30% of the plant extracts at the concentration of 5 ug/ml showed strong inhibitory effect on the 6-CF uptake mediated by OAT1 (61 extracts) and OAT3 (55 extracts). Among them, three extracts for OAT1 and fourteen extracts for OAT3 were identified as strong inhibitors with IC50 values being <5 ug/ml. Juncus effusus showed a strong inhibition to OAT3 in vitro, and markedly altered the in vivo pharmacokinetic parameters of furosemide in rats. CONCLUSION: The present study identified the potential interactions of medicinal and economic plants with human OAT1 and OAT3, which is helpful to predict and to avoid potential OAT1- and OAT3-mediated HDIs. PMID- 28560098 TI - Sports training enhances visuo-spatial cognition regardless of open-closed typology. AB - The aim of this study was to investigate the effects of open and closed sport participation on visuo-spatial attention and memory performance among young adults. Forty-eight young adults-16 open-skill athletes, 16 closed-skill athletes, and 16 non-athletes controls-were recruited for the study. Both behavioral performance and event-related potential (ERP) measurement were assessed when participants performed non-delayed and delayed match-to-sample task that tested visuo-spatial attention and memory processing. Results demonstrated that regardless of training typology, the athlete groups exhibited shorter reaction times in both the visuo-spatial attention and memory conditions than the control group with no existence of speed-accuracy trade-off. Similarly, a larger P3 amplitudes were observed in both athlete groups than in the control group for the visuo-spatial memory condition. These findings suggest that sports training, regardless of typology, are associated with superior visuo-spatial attention and memory performance, and more efficient neural resource allocation in memory processing. PMID- 28560097 TI - pathVar: a new method for pathway-based interpretation of gene expression variability. AB - Identifying the pathways that control a cellular phenotype is the first step to building a mechanistic model. Recent examples in developmental biology, cancer genomics, and neurological disease have demonstrated how changes in the variability of gene expression can highlight important genes that are under different degrees of regulatory control. Simple statistical tests exist to identify differentially-variable genes; however, methods for investigating how changes in gene expression variability in the context of pathways and gene sets are under-explored. Here we present pathVar, a new method that provides functional interpretation of gene expression variability changes at the level of pathways and gene sets. pathVar is based on a multinomial exact test, or an asymptotic Chi-squared test as a more computationally-efficient alternative. The method can be used for gene expression studies from any technology platform in all biological settings either with a single phenotypic group, or two-group comparisons. To demonstrate its utility, we applied the method to a diverse set of diseases, species and samples. Results from pathVar are benchmarked against analyses based on average expression and two methods of GSEA, and demonstrate that analyses using both statistics are useful for understanding transcriptional regulation. We also provide recommendations for the choice of variability statistic that have been informed through analyses on simulations and real data. Based on the datasets selected, we show how pathVar can be used to gain insight into expression variability of single cell versus bulk samples, different stem cell populations, and cancer versus normal tissue comparisons. PMID- 28560099 TI - A retrospective analysis of postoperative hypokalemia in pituitary adenomas after transsphenoidal surgery. AB - BACKGROUND: Pituitary adenoma is one of the most common intracranial neoplasms, and its primary treatment is endoscopic endonasal transsphenoidal tumorectomy. Postoperative hypokalemia in these patients is a common complication, and is associated with morbidity and mortality. This study aimed to analyze the etiopathology of postoperative hypokalemia in pituitary adenomas after endoscopic transsphenoidal surgery. METHODS AND MATERIALS: This retrospective study included 181 pituitary adenomas confirmed by histopathology. Unconditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Repeated measures ANOVA was used to analyze change in serum potassium levels at different time points. RESULTS: Multiple Logistic regression analysis revealed that only ACTH-pituitary adenoma (OR = 4.92, 95% CI [1.18 20.48], P = 0.029) had a significant association with postoperative hypokalemia. Moreover, the overall mean serum potassium concentration was significantly lower in the ACTH versus the non-ACTH group (3.34 mmol/L vs. 3.79 mmol/L, P = 0.001). Postoperative hypokalemia was predominantly found in patients with ACTH-pituitary adenoma (P = 0.033). CONCLUSIONS: ACTH-pituitary adenomas may be an independent factor related postoperative hypokalemia in patients despite conventional potassium supplementation in the immediate postoperative period. PMID- 28560100 TI - The first reported ceratopsid dinosaur from eastern North America (Owl Creek Formation, Upper Cretaceous, Mississippi, USA). AB - Ceratopsids ("horned dinosaurs") are known from western North America and Asia, a distribution reflecting an inferred subaerial link between the two landmasses during the Late Cretaceous. However, this clade was previously unknown from eastern North America, presumably due to limited outcrop of the appropriate age and depositional environment as well as the separation of eastern and western North America by the Western Interior Seaway during much of the Late Cretaceous. A dentary tooth from the Owl Creek Formation (late Maastrichtian) of Union County, Mississippi, represents the first reported occurrence of Ceratopsidae from eastern North America. This tooth shows a combination of features typical of Ceratopsidae, including a double root and a prominent, blade-like carina. Based on the age of the fossil, we hypothesize that it is consistent with a dispersal of ceratopsids into eastern North America during the very latest Cretaceous, presumably after the two halves of North America were reunited following the retreat of the Western Interior Seaway. PMID- 28560101 TI - Restoring lepidopteran diversity in a tropical dry forest: relative importance of restoration treatment, tree identity and predator pressure. AB - Tropical dry forests (TDFs) have been widely transformed by human activities worldwide and the ecosystem services they provide are diminishing. There has been an urgent call for conservation and restoration of the degraded lands previously occupied by TDFs. Restoration experiences aim to recover species diversity and ecological functions. Different restoration strategies have been used to maximize plant performance including weeding, planting or using artificial mulching. In this investigation, we evaluated whether different restoration practices influence animal arrival and the reestablishment of biotic interactions. We particularly evaluated lepidopteran larvae diversity and caterpillar predation on plants established under different restoration treatments (mulching, weeding and control) in the Pacific West Coast of Mexico. This study corroborated the importance of plant host identity for lepidopteran presence in a particular area. Lepidopteran diversity and herbivory rates were not affected by the restoration treatment but they were related to tree species. In contrast, caterpillar predation marks were affected by restoration treatment, with a greater number of predation marks in control plots, while caterpillar predation marks among plant species were not significantly different. This study highlights the importance of considering the introduction of high plant species diversity when planning TDF restoration to maximize lepidopteran diversity and ecosystem functioning. PMID- 28560102 TI - Effectiveness of coral relocation as a mitigation strategy in Kane'ohe Bay, Hawai'i. AB - Coral reef restoration and management techniques are in ever-increasing demand due to the global decline of coral reefs in the last several decades. Coral relocation has been established as an appropriate restoration technique in select cases, particularly where corals are scheduled for destruction. However, continued long-term monitoring of recovery of transplanted corals is seldom sustained. Removal of coral from a navigation channel and relocation to a similar nearby dredged site occurred in 2005. Coral recovery at the donor site and changes in fish populations at the receiving site were tracked periodically over the following decade. Coral regrowth at the donor site was rapid until a recent bleaching event reduced coral cover by more than half. The transplant of mature colonies increased spatial complexity at the receiving site, immediately increasing fish biomass, abundance, and species that was maintained throughout subsequent surveys. Our research indicates that unlike the majority of historical accounts of coral relocation in the Pacific, corals transplanted into wave protected areas with similar conditions as the original site can have high survival rates. Data on long-term monitoring of coral transplants in diverse environments is central in developing management and mitigation strategies. PMID- 28560103 TI - Effects of arginine vasopressin on the urine proteome in rats. AB - Biomarkers are the measurable changes associated with a physiological or pathophysiological process. The content of urine frequently changes because it is not controlled by homeostatic mechanisms, and these alterations can be a source of biomarkers. However, urine is affected by many factors. In this study, vasoconstrictor and antidiuretic arginine vasopressin (AVP) were infused into rats using an osmotic pump. The rats' urinary proteome after one week of infusion was analyzed by label-free LC-MS/MS. A total of 408 proteins were identified; among these proteins, eight and 10 proteins had significantly altered expression in the low and high dose groups, respectively, compared with the control group using the one-way ANOVA analysis followed by post hoc analysis with the least significant difference (LSD) test or Dunnett's T3 test. Three differential proteins were described in prior studies as related to AVP physiological processes, and nine differential proteins are known disease biomarkers. Sixteen of the 17 differential proteins have human orthologs. These results suggest that we should consider the effects of AVP on urinary proteins in future urinary disease biomarker researches. The study data provide clues regarding underlying mechanisms associated with AVP for future physiological researches on AVP. This study provide a sensitive changes associated with AVP. However, the limitation of this result is that the candidate biomarkers should be further verified and filtered. Large clinical samples must be examined to verify the differential proteins identified in this study before these proteins are used as biomarkers for pathological AVP increased diseases, such as syndrome of inappropriate antidiuretic hormone secretion (SIADH). PMID- 28560104 TI - Construct validity and test-retest reliability of the International Fitness Scale (IFIS) in Colombian children and adolescents aged 9-17.9 years: the FUPRECOL study. AB - BACKGROUND: There is a lack of instruments and studies written in Spanish evaluating physical fitness, impeding the determination of the current status of this important health indicator in the Latin population, especially in Colombia. The aim of the study was two-fold: to examine the validity of the International Fitness Scale (IFIS) with a population-based sample of schoolchildren from Bogota, Colombia and to examine the reliability of the IFIS with children and adolescents from Engativa, Colombia. METHODS: The sample comprised 1,873 Colombian youths (54.5% girls) aged 9-17.9 years. We measured their adiposity markers (waist-to-height ratio, skinfold thickness, percentage of body fat and body mass index), blood pressure, lipids profile, fasting glucose, and physical fitness level (self-reported and measured). A validated cardiometabolic risk index score was also used. An age- and sex-matched subsample of 229 schoolchildren who were not originally included in the sample completed the IFIS twice for reliability purposes. RESULTS: Our data suggest that both measured and self-reported overall physical fitness levels were inversely associated with percentage of body fat indicators and the cardiometabolic risk index score. Overall, schoolchildren who self-reported "good" or "very good" fitness had better measured fitness levels than those who reported "very poor/poor" fitness (all p < 0.001). The test-retest reliability of the IFIS items was also good, with an average weighted kappa of 0.811. DISCUSSION: Our findings suggest that self-reported fitness, as assessed by the IFIS, is a valid, reliable, and health related measure. Furthermore, it can be a good alternative for future use in large studies with Latin schoolchildren from Colombia. PMID- 28560106 TI - A molecular phylogeny of the spiny lobster Panulirus homarus highlights a separately evolving lineage from the Southwest Indian Ocean. AB - Accurate species description in the marine environment is critical for estimating biodiversity and identifying genetically distinct stocks. Analysis of molecular data can potentially improve species delimitations because they are easily generated and independent, and yield consistent results with high statistical power. We used classical phylogenetic (maximum likelihood and Bayesian inference) and coalescent-based methods (divergence dating with fossil calibrations and coalescent-based species delimitation) to resolve the phylogeny of the spiny lobster Panulirus homarus subspecies complex in the Indo-West Pacific. Analyses of mitochondrial data and combined nuclear and mitochondrial data recovered Panulirus homarus homarus and Panulirus homarus rubellus as separately evolving lineages, while the nuclear data trees were unresolved. Divergence dating analysis also identified Panulirus homarus homarus and Panulirus homarus rubellus as two distinct clades which diverged from a common ancestor during the Oligocene, approximately 26 million years ago. Species delimitation using coalescent-based methods corroborated these findings. A long pelagic larval life stage and the influence of ocean currents on post-larval settlement patterns suggest that a parapatric mode of speciation drives evolution in this subspecies complex. In combination, the results indicate that Panulirus homarus rubellus from the Southwest Indian Ocean is a separately evolving lineage and possibly a separate species. PMID- 28560105 TI - The metabolic profile of a rat model of chronic kidney disease. AB - BACKGROUND: The kidney is always subjected to high metabolic demand. The aim of this study was to characterize metabolic profiles of a rat model of chronic kidney disease (CKD) with cardiorenal syndrome (CRS) induced by prolonged hypertension. METHODS: We used inbred male Dahl salt-sensitive (DS) rats fed an 8% NaCl diet from six weeks of age (high-salt; HS group) or a 0.3% NaCl diet as controls (low-salt; LS group). We analyzed function, pathology, metabolome, and the gene expression related to energy metabolism of the kidney. RESULTS: DS rats with a high-salt diet showed hypertension at 11 weeks of age and elevated serum levels of creatinine and blood urea nitrogen with heart failure at 21 weeks of age. The fibrotic area in the kidneys increased at 21 weeks of age. In addition, gene expression related to mitochondrial function was largely decreased. The levels of citrate and isocitrate increased and the gene expression of alpha ketoglutaratedehydrogenase and succinyl-CoA synthetase decreased; these are enzymes that metabolize citrate and isocitrate, respectively. In addition, the levels of succinate and acetyl Co-A, both of which are metabolites of the tricarboxylic acid (TCA) cycle, decreased. CONCLUSIONS: DS rats fed a high-salt diet were deemed a suitable model of CKD with CRS. Gene expression and metabolites related to energy metabolism and mitochondria in the kidney significantly changed in DS rats with hypertension in accordance with the progression of renal injury. PMID- 28560107 TI - Factors affecting genotyping success in giant panda fecal samples. AB - Fecal samples play an important role in giant panda conservation studies. Optimal preservation conditions and choice of microsatellites for giant panda fecal samples have not been established. In this study, we evaluated the effect of four factors (namely, storage type (ethanol (EtOH), EtOH -20 degrees C, 2-step storage medium, DMSO/EDTA/Tris/salt buffer (DETs) and frozen at -20 degrees C), storage time (one, three and six months), fragment length, and repeat motif of microsatellite loci) on the success rate of microsatellite amplification, allelic dropout (ADO) and false allele (FA) rates from giant panda fecal samples. Amplification success and ADO rates differed between the storage types. Freezing was inferior to the other four storage methods based on the lowest average amplification success and the highest ADO rates (P < 0.05). The highest microsatellite amplification success was obtained from either EtOH or the 2-step storage medium at three storage time points. Storage time had a negative effect on the average amplification of microsatellites and samples stored in EtOH and the 2-step storage medium were more stable than the other three storage types. We only detected the effect of repeat motif on ADO and FA rates. The lower ADO and FA rates were obtained from tri- and tetra-nucleotide loci. We suggest that freezing should not be used for giant panda fecal preservation in microsatellite studies, and EtOH and the 2-step storage medium should be chosen on priority for long-term storage. We recommend candidate microsatellite loci with longer repeat motif to ensure greater genotyping success for giant panda fecal studies. PMID- 28560108 TI - Storm effects on intertidal invertebrates: increased beta diversity of few individuals and species. AB - Climate change is predicted to lead to more extreme weather events, including changes to storm frequency, intensity and location. Yet the ecological responses to storms are incompletely understood for sandy shorelines, the globe's longest land-ocean interface. Here we document how storms of different magnitude impacted the invertebrate assemblages on a tidal flat in Brazil. We specifically tested the relationships between wave energy and spatial heterogeneity, both for habitat properties (habitat heterogeneity) and fauna (beta-diversity), predicting that larger storms redistribute sediments and hence lead to spatially less variable faunal assemblages. The sediment matrix tended to become less heterogeneous across the flat after high-energy wave events, whereas beta-diversity increased after storms. This higher beta-diversity was primarily driven by species losses. Significantly fewer species at a significantly lower density occurred within days to weeks after storms. Negative density and biomass responses to storm events were most prominent in crustaceans. Invertebrate assemblages appeared to recover within a short time (weeks to months) after storms, highlighting that most species typical of sedimentary shorelines are, to some degree, resilient to short term changes in wave energy. Given that storm frequency and intensity are predicted to change in the coming decades, identifying properties that determine resilience and recovery of ecosystems constitute a research priority for sedimentary shorelines and beyond. PMID- 28560109 TI - Within outlying mean indexes: refining the OMI analysis for the realized niche decomposition. AB - The ecological niche concept has regained interest under environmental change (e.g., climate change, eutrophication, and habitat destruction), especially to study the impacts on niche shift and conservatism. Here, we propose the within outlying mean indexes (WitOMI), which refine the outlying mean index (OMI) analysis by using its properties in combination with the K-select analysis species marginality decomposition. The purpose is to decompose the ecological niche into subniches associated with the experimental design, i.e., taking into account temporal and/or spatial subsets. WitOMI emphasize the habitat conditions that contribute (1) to the definition of species' niches using all available conditions and, at the same time, (2) to the delineation of species' subniches according to given subsets of dates or sites. The latter aspect allows addressing niche dynamics by highlighting the influence of atypical habitat conditions on species at a given time and/or space. Then, (3) the biological constraint exerted on the species subniche becomes observable within Euclidean space as the difference between the existing fundamental subniche and the realized subniche. We illustrate the decomposition of published OMI analyses, using spatial and temporal examples. The species assemblage's subniches are comparable to the same environmental gradient, producing a more accurate and precise description of the assemblage niche distribution under environmental change. The WitOMI calculations are available in the open-access R package "subniche." PMID- 28560110 TI - Isolation and characterization of microsatellite markers for Sturnira parvidens and cross-species amplification in Sturnira species. AB - BACKGROUND: Sturnira is one of the most species-rich genera in the Neotropics, and it is found from Mexico and the Lesser Antilles to Argentina. This genus forms a well-supported monophyletic clade with at least twenty-one recognized species, as well as several others under taxonomic review. Sturnira parvidens is a widespread frugivorous bat of the deciduous forests of the Neotropics, is highly abundant, and is a major component in fruit dispersal to regenerate ecosystems. METHODS: We used a technique based on Illumina paired-end sequencing of a library highly enriched for microsatellite repeats to develop loci for S. parvidens. We analyzed millions of resulting reads with specialized software to extract those reads that contained di-, tri-, tetra-, penta-, and hexanucleotide microsatellites. RESULTS: We selected and tested 14 polymorphic (di, tri, and tetra) microsatellites. All markers were genotyped on 26 different individuals from distinct locations of the distributional area of S. parvidens. We observed medium-high genetic variation across most loci, but only 12 were functionally polymorphic. Levels of expected heterozygosity across all markers were high to medium (mean HE = 0.79, mean HO = 0.72). We examined ascertainment bias in twelve bats of the genus, obtaining null/monomorphic/polymorphic amplifications. DISCUSSION: The Illumina paired-end sequencing system is capable of identifying massive numbers of microsatellite loci, while expending little time, reducing costs, and providing a large amount of data. The described polymorphic loci for S. parvidens in particular, and for the genus in general, could be suitable for further genetic analysis, including taxonomic inconsistencies, parentage/relatedness analysis, and population genetics assessments. PMID- 28560111 TI - Clonidine or remifentanil for adequate surgical conditions in patients undergoing endoscopic sinus surgery: a randomized study. AB - BACKGROUND: Deliberate hypotension is one way to achieve a bloodless surgical field in endoscopic sinus surgery (ESS). We compared two anaesthesia regimens to induce deliberate hypotension and attempted to determine the most efficient one. METHODS: Fifty-nine patients undergoing ESS were minimized into two groups. In the CLO group, patients received I.V. sufentanil 0.15 ug/kg together with I.V. clonidine 2-3 ug/kg. In the REMI group, patients received remifentanil at a rate of up to 1 ug/kg/min. Fromme scores were collected 15 min after the incision and at the end of the procedure. Mean arterial pressure readings (MAP), heart rate readings, time to eyes opening, time to extubation, pain scores, analgesic requirements, and oxygen needs were collected and compared. RESULTS: There were no significant differences in Fromme scores between the two groups. The averaged MAP from 15 min to the end of the procedure was significantly lower in the REMI group; these patients also received more ephedrine. Significantly fewer patients in the CLO group needed oxygen therapy to keep their Pulse Oximeter Oxygen Saturation within 3% of their preoperative values. Patients in this group also needed less piritramide in the recovery room, and their pain scores were lower at discharge from the recovery room. DISCUSSION: Although both anaesthesia regimens offered a similar quality of surgical field, this study suggests that clonidine had a better average safety profile. Furthermore, patients who received this regimen required fewer painkillers immediately after surgery. PMID- 28560112 TI - Genetic effects on life-history traits in the Glanville fritillary butterfly. AB - BACKGROUND: Adaptation to local habitat conditions may lead to the natural divergence of populations in life-history traits such as body size, time of reproduction, mate signaling or dispersal capacity. Given enough time and strong enough selection pressures, populations may experience local genetic differentiation. The genetic basis of many life-history traits, and their evolution according to different environmental conditions remain however poorly understood. METHODS: We conducted an association study on the Glanville fritillary butterfly, using material from five populations along a latitudinal gradient within the Baltic Sea region, which show different degrees of habitat fragmentation. We investigated variation in 10 principal components, cofounding in total 21 life-history traits, according to two environmental types, and 33 genetic SNP markers from 15 candidate genes. RESULTS: We found that nine SNPs from five genes showed strong trend for trait associations (p-values under 0.001 before correction). These associations, yet non-significant after multiple test corrections, with a total number of 1,086 tests, were consistent across the study populations. Additionally, these nine genes also showed an allele frequency difference between the populations from the northern fragmented versus the southern continuous landscape. DISCUSSION: Our study provides further support for previously described trait associations within the Glanville fritillary butterfly species across different spatial scales. Although our results alone are inconclusive, they are concordant with previous studies that identified these associations to be related to climatic changes or habitat fragmentation within the Aland population. PMID- 28560113 TI - The role of kelp crabs as consumers in bull kelp forests-evidence from laboratory feeding trials and field enclosures. AB - The Northern kelp crab (Pugettia producta) and the graceful kelp crab (Pugettia gracilis) are common primary consumers in bull kelp beds near the San Juan Islands (Salish Sea, NE Pacific). In this system, urchins (often considered the most voracious herbivores exerting top-down control on kelp beds) tend to remain sedentary because of the high availability of detrital macroalgae, but the extent to which kelp crabs consume kelp (and other food options) is largely unknown. I conducted four types of laboratory feeding experiments to evaluate kelp crab feeding patterns: (1) feeding electivity between bull kelp (Nereocystis luetkeana) and seven species of co-occurring local macroalgae; (2) feeding electivity on aged vs. fresh bull kelp; (3) feeding preference between N. luetkeana and small snails (Lacuna sp.); and (4) scaling of feeding rate with body size in P. producta and P. gracilis. In choice experiments, P. producta consumed greater mass of N. luetkeana than of other macroalgal species offered and elected to eat fresh bull kelp over aged. However, P. producta also consumed snails (Lacuna sp.), indicating more generalized feeding than previously suspected. Feeding rates for P. producta exceeded the expected 3/4 scaling rule of metabolic rates, indicating that larger P. producta may have a disproportionately large impact on bull kelp. A subtidal field experiment, designed to assess the influence of consumers on juvenile bull kelp net tissue gain, found that only fully enclosed (protected) bull kelp increased in wet mass and blade length. Herbivory by kelp crabs, among other consumers, is likely to play a previously unrecognized role in mediating the growth and survival of this annual kelp species within the Salish Sea. PMID- 28560114 TI - Differentiation of Bifidobacterium longum subspecies longum and infantis by quantitative PCR using functional gene targets. AB - BACKGROUND: Members of the genus Bifidobacterium are abundant in the feces of babies during the exclusively-milk-diet period of life. Bifidobacterium longum is reported to be a common member of the infant fecal microbiota. However, B. longum is composed of three subspecies, two of which are represented in the bowel microbiota (B. longum subsp. longum; B. longum subsp. infantis). B. longum subspecies are not differentiated in many studies, so that their prevalence and relative abundances are not accurately known. This may largely be due to difficulty in assigning subspecies identity using DNA sequences of 16S rRNA or tuf genes that are commonly used in bacterial taxonomy. METHODS: We developed a qPCR method targeting the sialidase gene (subsp. infantis) and sugar kinase gene (subsp. longum) to differentiate the subspecies using specific primers and probes. Specificity of the primers/probes was tested by in silico, pangenomic search, and using DNA from standard cultures of bifidobacterial species. The utility of the method was further examined using DNA from feces that had been collected from infants inhabiting various geographical regions. RESULTS: A pangenomic search of the NCBI genomic database showed that the PCR primers/probes targeted only the respective genes of the two subspecies. The primers/probes showed total specificity when tested against DNA extracted from the gold standard strains (type cultures) of bifidobacterial species detected in infant feces. Use of the qPCR method with DNA extracted from the feces of infants of different ages, delivery method and nutrition, showed that subsp. infantis was detectable (0-32.4% prevalence) in the feces of Australian (n = 90), South-East Asian (n = 24), and Chinese babies (n = 91), but in all cases at low abundance (<0.01-4.6%) compared to subsp. longum (0.1-33.7% abundance; 21.4-100% prevalence). DISCUSSION: Our qPCR method differentiates B. longum subspecies longum and infantis using characteristic functional genes. It can be used as an identification aid for isolates of bifidobacteria, as well as in determining prevalence and abundance of the subspecies in feces. The method should thus be useful in ecological studies of the infant gut microbiota during early life where an understanding of the ecology of bifidobacterial species may be important in developing interventions to promote infant health. PMID- 28560115 TI - Seasonal dispersal and longitudinal migration in the Relict Gull Larus relictus across the Inner-Mongolian Plateau. AB - The Relict Gull Larus relictus is a globally vulnerable species and one of the least known birds, so understanding its seasonal movements and migration will facilitate the development of effective conservation plans for its protection. We repeatedly satellite-tracked 11 adult Relict Gulls from the Ordos sub-population in Hongjian Nur, China, over 33 migration seasons and conducted extensive ground surveys. Relict Gulls traveled ~800 km between Hongjian Nur in northern China to the coast of eastern China in a predominantly longitudinal migration, following a clockwise loop migration pattern. The gulls migrated faster in spring (4 +/- 2 d) than in autumn (15 +/- 13 d) due to a time-minimization strategy for breeding, and they showed considerable between-individual variation in the timing of the autumn migration, probably due to differences in the timing of breeding. Gulls that made at least two round trips exhibited high flexibility in spring migration timing, suggesting a stronger influence of local environment conditions over endogenous controls. There was also high route flexibility among different years, probably due to variations in meteorological or habitat conditions at stopover sites. Relict Gulls stayed for a remarkably long time (234 +/- 17 d) on their major wintering grounds in Bohai Bay and Laizhou Bay, between which there were notable dispersals. Pre-breeding dispersals away from the breeding area were distinct, which seemed to be a strategy to cope with the degradation of breeding habitat at Hongjian Nur. Overwhelming lake shrinkage on the breeding ground and at stopover sites and loss of intertidal flats on the wintering grounds are regarded as the main threats to Relict Gulls. It is crucial to make protection administrations aware of the great significance of key sites along migration routes and to promote the establishment of protected areas in these regions. PMID- 28560116 TI - Infrared thermography applied to lower limb muscles in elite soccer players with functional ankle equinus and non-equinus condition. AB - Gastrocnemius-soleus equinus (GSE) is a foot-ankle complaint in which the extensibility of the gastrocnemius (G) and soleus muscles (triceps surae) and ankle are limited to a dorsiflexion beyond a neutral ankle position. The asymmetric forces of leg muscles and the associated asymmetric loading forces might promote major activation of the triceps surae, tibialis anterior, transverses abdominal and multifidus muscles. Here, we made infrared recordings of 21 sportsmen (elite professional soccer players) before activity and after 30 min of running. These recordings were used to assess temperature modifications on the gastrocnemius, tibialis anterior, and Achilles tendon in GSE and non-GSE participants. We identified significant temperature modifications among GSE and non-GSE participants for the tibialis anterior muscle (mean, minimum, and maximum temperature values). The cutaneous temperature increased as a direct consequence of muscle activity in GSE participants. IR imaging capture was reliable to muscle pattern activation for lower limb. Based on our findings, we propose that non invasive IR evaluation is suitable for clinical evaluation of the status of these muscles. PMID- 28560117 TI - A Comparison of Pattern Recognition Control and Direct Control of a Multiple Degree-of-Freedom Transradial Prosthesis. AB - With existing conventional prosthesis control (direct control), individuals with a transradial amputation use two opposing muscle groups to control each prosthesis motor. As component complexity increases, subjects must switch the prosthesis into different modes to control each component in sequence. Pattern recognition control offers the ability to control multiple movements in a seamless manner without switching. In this paper, three individuals with a transradial amputation completed a home trial to compare direct control and pattern recognition control of a multiple degree-of-freedom prosthesis. Outcome measures before and after the home trial, together with subject questionnaires, were used to evaluate functional control. Although small, this trial has implications for the implementation of pattern recognition in commercial control systems and for future research studies. PMID- 28560118 TI - Low-Cost Sensor System Design for In-Home Physical Activity Tracking. AB - An aging and more sedentary population requires interventions aimed at monitoring physical activity, particularly within the home. This research uses simulation, optimization, and regression analyses to assess the feasibility of using a small number of sensors to track movement and infer physical activity levels of older adults. Based on activity data from the American Time Use Survey and assisted living apartment layouts, we determined that using three to four doorway sensors can be used to effectively capture a sufficient amount of movements in order to estimate activity. The research also identified preferred approaches for assigning sensor locations, evaluated the error magnitude inherent in the approach, and developed a methodology to identify which apartment layouts would be best suited for these technologies. PMID- 28560119 TI - Collaborative Paradigm of Preventive, Personalized, and Precision Medicine With Point-of-Care Technologies. AB - Recent advances in biosensors, medical instrumentation, and information processing and communication technologies (ICT) have enabled significant improvements in healthcare. However, these technologies have been mainly applied in clinical environments, such as hospitals and healthcare facilities, under managed care by well-trained and specialized individuals. The global challenge of providing quality healthcare at affordable cost leads to the proposed paradigm of P reventive, Personalized, and Precision Medicine that requires a seamless use of technology and infrastructure support for patients and healthcare providers at point-of-care (POC) locations including homes, semi or pre-clinical facilities, and hospitals. The complexity of the global healthcare challenge necessitates strong collaborative interdisciplinary synergies involving all stakeholder groups including academia, federal research institutions, industry, regulatory agencies, and clinical communities. It is critical to evolve with collaborative efforts on the translation of research to technology development toward clinical validation and potential healthcare applications. This special issue is focused on technology innovation and translational research for POC applications with potential impact in improving global healthcare in the respective areas. Some of these papers were presented at the NIH-IEEE Strategic Conference on Healthcare Innovations and POC Technologies for Precision Medicine (HI-POCT) held at the NIH on November 9-10, 2015. The papers included in the Special Issue provide a spectrum of critical issues and collaborative resources on translational research of advanced POC devices and ICT into global healthcare environment. PMID- 28560120 TI - Efficacy Evaluation of SAVE for the Diagnosis of Superficial Neoplastic Lesion. AB - The detection of non-polypoid superficial neoplastic lesions using current standard of white light endoscopy surveillance and random biopsy is associated with high miss rate. The subtle changes in mucosa caused by the flat and depressed neoplasms often go undetected and do not qualify for further investigation, e.g., biopsy and resection, thus increasing the risk of cancer advancement. This paper presents a screening tool named the saliency-aided visual enhancement (SAVE) method, with an objective of highlighting abnormalities in endoscopic images to detect early lesions. SAVE is a hybrid system combining image enhancement and saliency detection. The method provides both qualitative enhancement and quantitative suspicion index for endoscopic image regions. A study to evaluate the efficacy of SAVE to localize superficial neoplastic lesion was performed. Experimental results for average overlap index >0.7 indicated that SAVE was successful to localize the lesion areas. The area under the receiver operating characteristic curve obtained for SAVE was 94.91%. A very high sensitivity (100%) was achieved with a moderate specificity (65.45%). Visual inspection showed a comparable performance of SAVE with chromoendoscopy to highlight mucosal irregularities. This paper suggests that SAVE could be a potential screening tool that can substitute the application of burdensome chromoendoscopy technique. SAVE method, as a simple, easy-to-use, highly sensitive, and consistent red flag technology, will be useful for early detection of neoplasm in clinical applications. PMID- 28560122 TI - Advanced Practice Clinician Training for Neurology. AB - BACKGROUND: The specialty of Neurology is faced with a fundamental problem of economics: supply and demand. The projected increase in provider supply is unlikely to keep up with projected increases in patient-care demand. Many large academic centers have used residents to meet this patient-care demand. However, the conflict between education of residents and patient-care needs has created a hindrance to both of those missions. Many specialties have been using advanced practice clinicians (APCs) to help address the need for patient care. In the setting of a residency program, this availability of APCs can help to alleviate patient-care demands for the resident and allow for better allocated educational time. Neurology has not historically been a popular choice for APCs and a standardized educational curriculum for a Neurology APC has not been established. METHODS: The authors share an example curriculum recently implemented for training new inpatient Neurology APCs. This curriculum includes a 12-week program complete with rotations through various subspecialties and proposes fundamental lecture topics for use in education. The authors share their expectations for clinical duties that evolve over the course of the 12-week program in conjunction with expectations for increasing clinical knowledge as well as efficiency in system utilization. CONCLUSION: The addition of APCs to support a busy inpatient Neurology practice has obvious beneficial implications but the integration and education of this new staff must be structured and well-designed to support the confidence of the APC in both their knowledge and their role as an indispensable member of the care team. PMID- 28560121 TI - Comparison of Different Analgesia Drug Regimens for Pain Control During Extracorporeal Shock Wave Lithotripsy for Renal Stones: A Randomized Control Study. AB - INTRODUCTION: With the increased use of extracorporeal shock wave lithotripsy (ESWL), the management of urolithiasis has become much convenient for the patients and the health care professionals alike. However, associated with the procedure is the common complaint of pain. No agreed upon pain management strategy has yet been developed for the procedure. We compared the effect of different analgesia drug regiments for pain control. METHODOLOGY: A randomised controlled trial was carried out in Shifa International Hospital from between July 2015 to January 2016. A total of 135 patients were divided into three groups; group A received 30 g lidocaine 2% gel applied locally on corresponding lumber area 30 minutes before the procedure, group B received oral naproxen sodium 550 mg 45 minutes before the procedure, and group C received both oral naproxen and lidocaine gel. Patients were supplemented with intravenous nalbuphine during the procedure. The pain was assessed with 0-10 visual analogue scale. Both pre-procedure and post-procedure pain score was measured. RESULTS: Among 135 patients, 105 (77.8%) were male and 29 (21.5%) were female with mean age of 38.7 +/- 1.31 years. There was no difference of mean pain score or need for supplemental intravenous nalbuphine between groups B and C but there was significantly decreased mean pain score and need for supplemental intravenous nalbuphine in groups B and C in comparison with group A. CONCLUSION: The use of oral naproxen sodium with or without the addition of lidocaine gel during ESWL is a promising option for pain management during the procedure with significant improvement in comparison with lidocaine gel alone. PMID- 28560123 TI - Use of Subdural Evacuating Port System Following Open Craniotomy with Excision of Native Dura and Membranes for Management of Chronic Subdural Hematoma. AB - An 86-year-old woman was admitted to the intensive care unit with a chronic subdural hematoma (CSDH) and rapid onset of worsening neurological symptoms. She was taken to the operating room for a mini-craniotomy for evacuation of the CSDH including excision of the dura and CSDH membrane. Postoperatively, a subdural evacuation port system (SEPS) was integrated into the craniotomy site and left in place rather than a traditional subdural catheter drain to evacuate the subdural space postoperatively. The patient had a good recovery and improvement of symptoms after evacuation and remained clinically well after the SEPS was removed. We offer the technique of dura and CSDH membrane excision plus SEPS drain as an effective postoperative alternative to the standard craniotomy leaving the native dura intact with traditional subdural drain that overlies the cortical surface of the brain in treating patients with CSDH. PMID- 28560124 TI - Multidrug Resistant Invasive Nontyphoidal Salmonella Isolated from and Masquerading Healed Tubercular Constrictive Pericarditis and Study of Virulence Markers. AB - Among the infectious causes of pericarditis are various bacteria, viruses, fungal and parasitic infections. The course disease may progress to a chronic constrictive pattern especially with tubercular etiology. Non-typhoidal Salmonella has rarely been reported as a cause of pericarditis. We describe here a case from which the pericardial fluid from an old case of tubercular pericarditis sent for culture to microbiology laboratory grew a Salmonella typhimurium. We studied the antibiotic resistance pattern, phage type and virulence factors playing a role in the invasive nature of the pathogen since no such study from pericardial fluid was found in the literature. The isolate was sensitive only to cephalosporins and it was untypable. It showed amplification for five fimbrial operons, three colonization factors, and other genes (pef operon), gog B(Gifsy-1 encoded effector), sseI (Gifsy-2 encoded effector), sodC ( the periplasmic [copper and zinc Cu, Zn ]-superoxide dismutase) & sopE (a guanine nucleotide exchange factors). The present case highlights the need for early detection of the exact causative agent and serovar in management, the likelihood of a different etiological agent other than the original to be kept in mind for timely management and the highly resistant pattern of non-typhoidal Salmonella (NTS) limiting the therapeutic options as in our case to only cephalosporins. The genes encoded from the NTS might be required for invasive cardiac manifestation in humans. PMID- 28560125 TI - Learning Microvascular Anastomosis in Low Socioeconomic Vascular Models During Residency. AB - Microvascular anastomosis procedure has become an essential practice for the management of most neurovascular diseases. Increasing use of neurosurgical techniques necessitates intensive laboratory training in microsurgery. Umbilical artery is used for quantifiable representation to set up microvascular anastomosis model for the beginners. These arteries are found to be between 4 and 5 mm in diameter. Chicken wings are set up as second anastomosis model. Five to six centimeter long brachial artery extracted from a chicken is measured approximately 1-2 mm in diameter. These arteries are practiced for end-to-end, end-to-side, or side-to-side anastomosis under the microscope. Umbilical cord and chicken wing model hold several advantages. These essentials are inexpensive, convenient to manage, and easy to obtain for educational purposes. They neither need detailed facilities for maintenance like in animal model nor any anesthetic prerequisite. Moreover, the diameter and structure of the material are identical to those of human cortical vessels. Low-cost laboratory training during residency is more relevant in source restraint areas. It has several added benefits in refining the procedural dexterity on anastomosing smaller size vessel identical to a cortical vessel of middle cerebral artery and distal branches of the superficial temporal artery. PMID- 28560126 TI - Transient Giant R Wave as a Marker for Ischemia in Unstable Angina. AB - Unstable angina is a clinical diagnosis that may present with or without electrocardiographic changes. The "giant R wave" on electrocardiogram has been reported as a manifestation of acute ischemia; however, it is a rare finding in current clinical practice. We describe a case of a patient with unstable angina and a transient "giant R wave" pattern with a culprit lesion in the right coronary artery. PMID- 28560127 TI - Naproxen and Diclofenac Attenuate Atorvastatin-induced Preconditioning of the Myocardium. AB - Statins reduce infarct size (IS) in ischemia-reperfusion injury of the myocardium. Inhibition of cyclooxygenase-2 (COX-2) attenuates this benefit. We investigated the effect of two widely used non-selective non-steroidal anti inflammatory drugs (NSAIDs) with different degree of anti-COX-2 activity on atorvastatin-mediated preconditioning. Wistar rats received oral atorvastatin (10 mg?kg-1?day-1), naproxen (10 mg?kg-1?day-1), diclofenac (8 mg?kg-1?day-1), atorvastatin+naproxen, atorvastatin+diclofenac or water for three days. Hearts were then excised and perfused in the Langendorff system. Area at risk (AR) and IS were determined after 30 min of regional ischemia and 120 min of reperfusion. Atorvastatin reduced IS by 51.3% compared with controls (14.7 +/- 3.9% vs. 30.2 +/- 4.6% of the AR; P < 0.001). Naproxen and diclofenac alone did not alter IS compared to control. Diclofenac completely abrogated atorvastatin-mediated protection of the myocardium. Naproxen significantly attenuated but did not eliminate the IS reducing the effect of atorvastatin when compared with controls (P = 0.038). The difference in IS between the atorvastatin+naproxen group and the atorvastatin+diclofenac group showed a strong trend in reaching statistical significance (P = 0.058), but was not found to be significant. Our results suggest relatively small, but noticeable differences among non-selective NSAIDs in their potential to attenuate statin-mediated preconditioning. PMID- 28560128 TI - Identification of aqueous access residues of the sodium half channel in transmembrane helix 5 of the Fo-a subunit of Propionigenium modestum ATP synthase. AB - The Fo-a subunit of the Na+-transporting FoF1 ATP synthase from Propionigenium modestum plays a key role in Na+ transport. It forms half channels that allow Na+ to enter and leave the buried carboxyl group on Fo-c subunits. The essential Arg residue R226, which faces the carboxyl group of Fo-c subunits in the middle of transmembrane helix 5 of the Fo-a subunit, separates the cytoplasmic side and periplasmic half-channels. To elucidate contributions of other amino acid residues of transmembrane helix 5 using hybrid FoF1 (Fo from P. modestum and F1 from thermophilic Bacillus PS3), 25 residues were individually mutated to Cys, and effects of modification with the SH-modifying agent N-ethylmaleimide (NEM) on ATP synthesis and hydrolysis activity were analyzed. NEM significantly inhibited ATP synthesis and hydrolysis as well as proton pumping activities of A214C, G215C, A218C, I223C (cytoplasmic side from R226), and N230C (periplasmic side from R226) mutants and inhibited ATP synthesis activity of the K219C mutant (cytoplasmic side from R226). Thus, these residues contribute to the integrity of the Na+ half channel, and both half channels are present in the Fo-a subunit. PMID- 28560129 TI - Existence of two O-like intermediates in the photocycle of Acetabularia rhodopsin II, a light-driven proton pump from a marine alga. AB - A spectrally silent change is often observed in the photocycle of microbial rhodopsins. Here, we suggest the presence of two O intermediates in the photocycle of Acetabularia rhodopsin II (ARII or also called Ace2), a light driven algal proton pump from Acetabularia acetabulum. ARII exhibits a photocycle including a quasi-equilibrium state of M, N, and O (M?N?O->) at near neutral and above pH values. However, acidification of the medium below pH ~5.5 causes no accumulation of N, resulting in that the photocycle of ARII can be described as an irreversible scheme (M->O->). This may facilitate the investigation of the latter part of the photocycle, especially the rise and decay of O, during which molecular events have not been sufficiently understood. Thus we analyzed the photocycle under acidic conditions (pH <= 5.5). Analysis of the absorbance change at 610 nm, which mainly monitors the fractional concentration changes of K and O, was performed and revealed a photocycle scheme containing two sequential O-states with the different molar extinction coefficients. These photoproducts, termed O1 and O2, may be even produced at physiological pH, although they are not clearly observed under this condition due to the existence of a long M-N-O equilibrium. PMID- 28560130 TI - Fatal haemorrhagic duodenal mucormycosis in a non-immunocompromised host: A case report. AB - Mucormycosis is an opportunistic infection caused by the fungi of the Mucorales order of the class Zygomycetes. Gastrointestinal mucormycosis is an uncommon, fatal condition accounting for only 7% of the cases. We present the case of a gastroduodenal mucormycosis presenting as recurrent massive hematemesis. We report this case to alert clinicians of this rare but fatal condition and to encourage further research into its pathogenesis and management. PMID- 28560131 TI - Fatal invasive aspergillosis caused by Aspergillus niger after bilateral lung transplantation. AB - Aspergillus niger is usually considered to be a low virulence fungus, not commonly reported to cause invasive infections. Invasive pulmonary aspergillosis due to Aspergillus niger was diagnosed in a 43-year-old woman following bilateral lung transplantation. Intravenous voriconazole failed to control progression of the disease. Despite salvage therapy with a combination of voriconazole and caspofungin for 23 days, the patient developed massive hemoptysis leading to death. The authors report the clinical features and treatment of this case. PMID- 28560132 TI - Arthroscopic Capsular Release of the Talocalcaneonavicular Joint. AB - Arthrofibrosis of the talocalcaneonavicular joint can follow talar neck fracture especially if anterior approaches have been used for fracture fixation. Capsular release of the talocalcaneonavicular joint is indicated if the painful hindfoot stiffness cannot be controlled with conservative treatment. Open capsular release of the talocalcaneonavicular joint demands extensive soft tissue dissection and hinders early postoperative mobilization exercise of the joint. The purpose of this technical note is to describe a minimally invasive approach of arthroscopic capsular release of the talocalcaneonavicular joint that is composed of arthroscopic release of the talonavicular joint and the anterior subtalar joint. This allows immediate postoperative mobilization of the joint. PMID- 28560133 TI - Arthroscopic Tarsometatarsal Arthrodesis. AB - Tarsometatarsal (Lisfranc) osteoarthritis can be a disabling condition and is commonly due to posttraumatic causes. Tarsometatarsal arthrodesis is indicated if the pain does not subdue with conservative treatment. Classically, this is performed as an open procedure. The purpose of this technical note is to describe a minimally invasive approach of arthroscopic arthrodesis of the involved tarsometatarsal joints. The arthroscopic procedure is performed through the junction portals of the involved articulation. It has the advantages of better cosmesis, less wound complication, less bone resection, and more thorough joint debridement. However, it is contraindicated if there is an associated significant foot deformity or shortening of the involved foot rays. PMID- 28560134 TI - Basics of Elbow Arthroscopy Part I: Surface Anatomy, Portals, and Structures at Risk. AB - As our knowledge and technology advance, the indications for elbow arthroscopy continue to grow rapidly. During this expansion, a number of new portals have been described and reported using variable nomenclature and location descriptions. Accordingly, a comprehensive review of these portals is warranted. Given the concern for potential iatrogenic injury to surrounding neurovascular structures, a discussion of these critical nerves and vessels is also timely. In this work, we review pertinent surface anatomy; portal nomenclature, locations, and utility; and review distances to the nearest structures at risk. PMID- 28560135 TI - Basics of Elbow Arthroscopy Part II: Positioning and Diagnostic Arthroscopy in the Supine Position. AB - The field of elbow arthroscopy has evolved significantly since the procedure was first introduced more than 30 years ago. As our knowledge and understanding grows, numerous technical modifications have been made to improve the safety and efficacy of elbow arthroscopy. One of the most significant modifications is the change from the supine hanging position to the supine-suspended position with the use of a mechanical arm holder. Currently, the supine-suspended and lateral decubitus positions are the 2 most commonly used techniques. In this work, we discuss the history of the supine position, provide key points for proper patient positioning, and detail the steps of diagnostic elbow arthroscopy. It is our hope that this work will serve as an up-to-date review and summary of the most critical components of this procedure for emerging elbow arthroscopists. PMID- 28560136 TI - Basics of Elbow Arthroscopy Part III: Positioning and Diagnostic Arthroscopy in the Lateral Decubitus Position. AB - In recent years, arthroscopy has gained popularity as a preferred treatment of a multitude of pathologies affecting the elbow. Since its initial description in 1985, many modifications have been made as our knowledge and technology have advanced. Currently, the majority of arthroscopic procedures are performed in either the lateral decubitus or supine suspended position. In this work, we discuss the history, patient positioning, and key steps for performing elbow arthroscopy in the lateral decubitus position. In addition to key steps, a number of strengths and limitations of this set up are discussed in detail. When properly executed, elbow arthroscopy can be performed in a safe and efficient manner with minimal risk to patients. PMID- 28560137 TI - Management of Rotator Cuff Defects After Calcific Tendinopathy Debridement Using a Bioinductive Collagen Implant. AB - The management of rotator cuff defects after arthroscopic debridement for calcific tendinitis can be a challenge for physicians. To date, treatment options have included debridement alone, in situ repairs of the tendon, or full-thickness takedown and repair. Each option, however, has been fraught with its own pitfalls and limitations. We propose a technique for the management of rotator cuff defects through the application of a bioinductive collagen implant that may allow for rapid tissue incorporation and regeneration. PMID- 28560138 TI - Arthroscopically Assisted Modified Jones Procedure. AB - The modified Jones procedure is the classic operative treatment of symptomatic clawed hallux. It is composed of transfer of the extensor hallucis longus tendon to the first metatarsal neck and fusion of the hallux interphalangeal joint. The purpose of this technical note is to report the technique of an arthroscopically assisted modified Jones procedure. This can be combined with other minimally invasive bone and soft-tissue procedures to correct all aspects of the complex cavus foot deformity. PMID- 28560139 TI - Arthroscopic Decompression of a Type III Subspine Impingement. AB - Extra-articular hip impingement refers to a variety of hip disorders causing pain and limited function in young, non-arthritic patients. Recently, there has been an increased focus on analyzing the degree of anterior inferior iliac spine (AIIS) dysmorphism and its correlation with subspine impingement (SSI), defined as abutment between a prominent distal aspect of the AIIS and the anterior aspect of the femoral head-neck junction. Arthroscopic decompression of the AIIS is recognized as an effective treatment for SSI. However, there may be some inherent risks of performing this procedure arthroscopically that require further investigation. PMID- 28560140 TI - Compression and Flip Test for Diagnosis of Unstable Acetabular Labral Tears Using a Peripheral Compartment Approach. AB - Assessment of integrity of the acetabular labrum is generally done via the central compartment under distraction of the femoral head from the acetabulum. With the technique of raising the extra-articular and peripheral compartment first, there is a need for testing the stability and function of the labrum from the peripheral side in a nondistracted position of the joint. The authors report on the compression and flip test (i.e., the flip test) for the detection of unstable, intrasubstance tears of the labrum or unstable chondrolabral separations. The test can be performed by compressing the labrum with blunt instruments. We grade the labral conditions as follows: grade 0 for firm resistance and elasticity to palpation, grade 1+ as easily compressed by the probe, grade 2+ for eversion of the body of the labrum under compression), and grade 1 for ossified, hard resistance without any elasticity and compressibility. This test can be performed directly after accessing the peripheral compartment through a 2-portal technique without extensive capsular work. PMID- 28560141 TI - The "Pull-Over" Technique for Arthroscopic Superior Capsular Reconstruction. AB - The management of irreparable rotator cuff tears is a difficult problem to deal with. The options include nonoperative route with anterior deltoid exercises, debridement with or without long head of biceps tenotomy, partial rotator cuff repair, tuberoplasty, muscle transfer, patch augmentation, biodegradable spacers, and reverse shoulder arthroplasty. None of these options are without their limitations. In recent years, arthroscopic superior capsular reconstruction has gained popularity as an alternative technique to address irreparable rotator cuff tears. Arthroscopic superior capsular reconstruction, however, is technically difficult. The purpose of this technical note is to describe a simple and reproducible technique for this procedure that addresses some of the challenges involved. PMID- 28560143 TI - Ultrasound for Treating Meniscocapsular Separation Together With Arthroscopy. AB - Magnetic resonance imaging (MRI) can be used to identify most types of meniscal tears; however, meniscocapsular separation of the medial meniscus can be difficult to identify with MRI. Here we present a technical note on the intrasurgical use of ultrasonography for the detection of meniscocapsular separation and confirmation of the beneficial effect of suturing on the stability of this lesion in a representative case of meniscocapsular separation that could be diagnosed with ultrasonography but not MRI preoperatively. Ultrasonography can detect meniscocapsular separation as a vertical low echoic area and be performed together with arthroscopy using the picture-in-picture function of the ultrasonography machine. Ultrasonography is an effective tool for diagnosing meniscocapsular separation and is helpful during arthroscopic surgery. PMID- 28560142 TI - Minimally Invasive Anterolateral Ligament Reconstruction of the Knee. AB - Anterior cruciate ligament (ACL) tears are among the most common knee injuries, and multiple reconstructive techniques have been described. However, studies frequently report an inability to duplicate native, dynamic knee function, particularly rotationally. This residual joint laxity that occasionally follows an ACL reconstruction can cause further problems post surgical intervention, including meniscal tears and especially late osteoarthritic change. Additionally, ACL graft retears are a concern, particularly in young patients. Although these undesired sequelae of ACL reconstruction could be a by-product of insufficient ACL reconstruction methods related to either graft placement or problems with graft healing and biology, it is also possible that failure to additionally address lateral extra-articular structures after ACL injury could play a role in the residual knee laxity of the affected knee. The purpose of this article is to show a minimally invasive technique for extra-articular anterolateral ligament reconstruction. PMID- 28560144 TI - Biceps Tenoscopy: Arthroscopic Evaluation of the Extra-articular Portion of the Long Head of Biceps Tendon. AB - The recent literature shows that imaging modalities, physical examination tests, and glenohumeral arthroscopy all have low sensitivities and specificities with respect to the diagnosis of the long head of biceps tendon pathology. Biceps tenoscopy is a strategy that aims to reduce the rate of missed diagnoses by improving visualization of the extra-articular part of the tendon. This is an area of predilection of pathology that is not adequately visualized with conventional arthroscopic techniques. This technical note presents the surgical technique for biceps tenoscopy. PMID- 28560145 TI - Using a Posterolateral Portal to Pass and Tie the Suture of the Inferior Anchor During Arthroscopic Bankart Repair. AB - Using a posterolateral portal in passing and tying the inferior knot allows good labral reduction and adequate capsular shift to treat anterior shoulder instability. In this technique, the most inferior anchor is placed through a low anterolateral portal. A penetrating grasper is introduced from a posterolateral portal situated 2 to 3 cm distal and lateral to the viewing portal. This portal is used to pass the 2 limbs of the anchor suture as inferior as possible through the labrum and capsule close to 6 o'clock position to form the 2 limbs of the first mattress suture. Finally, knot tying is performed through this posterolateral portal, thus allowing better superior shift of the capsulolabral tissue. The other 2 anchor sutures are passed and tied through the low anterolateral portal. PMID- 28560146 TI - Endobronchial primary large B-cell Non-Hodgkin lymphoma in HIV-infected patient in the Highly Active Antiretroviral Therapy era: Description of a case report. AB - We report an unusual case of endobronchial primary large B-cell Non Hodgkin Lymphoma in a HIV-infected patient in the course of effective Highly Active Antiretroviral Therapy (HAART). Diagnosis of large B-cell NHL was obtained by fibreoptic bronchoscopy (FOB) biopsies. Three cycles of R-CHOP chemotherapy (rituximab, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone) was performed and clinical and radiological remission was obtained after 3 cycles of therapy. PMID- 28560147 TI - Bosutinib induced pleural effusions: Case report and review of tyrosine kinase inhibitors induced pulmonary toxicity. AB - Tyrosine kinase inhibitors are known to cause pulmonary complications. We report a case of bosutinib related bilateral pleural effusions in a patient with chronic myeloid leukemia. Characteristics of the pleural fluid are presented. We also discuss other tyrosine kinase inhibitors induced pulmonary toxicities, including pulmonary hypertension and interstitial lung disease. PMID- 28560148 TI - Mesenchymal cystic hamartoma of the lung. AB - Mesenchymal cystic hamartoma, although first reported as early as 1980s, remains a very rare lung disease. There have been less than 20 cases reported to date. Mesenchymal cystic hamartoma usually has an indolent course, but it could potentially result in morbidity and mortality. Biopsy is needed to confirm the diagnosis because it is essential to rule out other possibilities including malignancy. PMID- 28560149 TI - Non-invasive ventilation in a pregnancy with severe pneumonia. AB - INTRODUCTION: Non-invasive ventilation (NIV) is not proven to be effective in treating respiratory failure in severe pneumonia. However, some clinicians nevertheless attempt NIV to indirectly deliver adequate oxygenation and avoid unnecessary endotracheal intubation. CASE PRESENTATION: In this article, we report the case of a 24-year-old woman at 32 weeks' gestation who presented with hypoxemic respiratory failure requiring mechanical ventilation. She was successfully managed by NIV. DISCUSSION: However, NIV must be managed by providers who are trained in mechanical ventilation. This is of the utmost importance in avoiding any delay should the patient's condition worsen and require endotracheal intubation. Moreover, in pregnant women, the severity of illness may progress quickly due to the immunosuppression inherent in these patients. CONCLUSION: Special attention should be given to the choices of invasive ventilation and NIV to manage community acquired pneumonia patients in third trimester. PMID- 28560150 TI - Amyloid positron emission tomography in sporadic cerebral amyloid angiopathy: A systematic critical update. AB - Sporadic cerebral amyloid angiopathy (CAA) is a very common small vessel disease of the brain, showing preferential and progressive amyloid-betadeposition in the wall of small arterioles and capillaries of the leptomeninges and cerebral cortex. CAA now encompasses not only a specific cerebrovascular pathological trait, but also different clinical syndromes - including spontaneous lobar intracerebral haemorrhage (ICH), dementia and 'amyloid spells' - an expanding spectrum of brain parenchymal MRI lesions and a set of diagnostic criteria - the Boston criteria, which have resulted in increasingly detecting CAA during life. Although currently available validated diagnostic criteria perform well in multiple lobar ICH, a formal diagnosis is currently lacking unless a brain biopsy is performed. This is partly because in practice CAA MRI biomarkers provide only indirect evidence for the disease. An accurate diagnosis of CAA in different clinical settings would have substantial impact for ICH risk stratification and antithrombotic drug use in elderly people, but also for sample homogeneity in drug trials. It has recently been demonstrated that vascular (in addition to parenchymal) amyloid-betadeposition can be detected and quantified in vivo by positron emission tomography (PET) amyloid tracers. This non-invasive approach has the potential to provide a molecular signature of CAA, and could in turn have major clinical impact. However, several issues around amyloid-PET in CAA remain unsettled and hence its diagnostic utility is limited. In this article we systematically review and critically appraise the published literature on amyloid PET (PiB and other tracers) in sporadic CAA. We focus on two key areas: (a) the diagnostic utility of amyloid-PET in CAA and (b) the use of amyloid-PET as a window to understand pathophysiological mechanism of the disease. Key issues around amyloid-PET imaging in CAA, including relevant technical aspects are also covered in depth. A total of six small-scale studies have addressed (or reported data useful to address) the diagnostic utility of late-phase amyloid PET imaging in CAA, and one additional study dealt with early PiB images as a proxy of brain perfusion. Across these studies, amyloid PET imaging has definite diagnostic utility (currently tested only in probable CAA): it helps rule out CAA if negative, whether compared to healthy controls or to hypertensive deep ICH controls. If positive, however, differentiation from underlying incipient Alzheimer's disease (AD) can be challenging and so far, no approach (regional values, ratios, visual assessment) seems sufficient and specific enough, although early PiB data seem to hold promise. Based on the available evidence reviewed, we suggest a tentative diagnostic flow algorithm for amyloid-PET use in the clinical setting of suspected CAA, combining early- and late-phase PiB-PET images. We also identified ten mechanistic amyloid-PET studies providing early but promising proof-of-concept data on CAA pathophysiology and its various manifestations including key MRI lesions, cognitive impairment and large scale brain alterations. Key open questions that should be addressed in future studies of amyloid-PET imaging in CAA are identified and highlighted. PMID- 28560151 TI - Auditory prediction errors as individual biomarkers of schizophrenia. AB - Schizophrenia is a complex psychiatric disorder, typically diagnosed through symptomatic evidence collected through patient interview. We aim to develop an objective biologically-based computational tool which aids diagnosis and relies on accessible imaging technologies such as electroencephalography (EEG). To achieve this, we used machine learning techniques and a combination of paradigms designed to elicit prediction errors or Mismatch Negativity (MMN) responses. MMN, an EEG component elicited by unpredictable changes in sequences of auditory stimuli, has previously been shown to be reduced in people with schizophrenia and this is arguably one of the most reproducible neurophysiological markers of schizophrenia. EEG data were acquired from 21 patients with schizophrenia and 22 healthy controls whilst they listened to three auditory oddball paradigms comprising sequences of tones which deviated in 10% of trials from regularly occurring standard tones. Deviant tones shared the same properties as standard tones, except for one physical aspect: 1) duration - the deviant stimulus was twice the duration of the standard; 2) monaural gap - deviants had a silent interval omitted from the standard, or 3) inter-aural timing difference, which caused the deviant location to be perceived as 90 degrees away from the standards. We used multivariate pattern analysis, a machine learning technique implemented in the Pattern Recognition for Neuroimaging Toolbox (PRoNTo) to classify images generated through statistical parametric mapping (SPM) of spatiotemporal EEG data, i.e. event-related potentials measured on the two dimensional surface of the scalp over time. Using support vector machine (SVM) and Gaussian processes classifiers (GPC), we were able classify individual patients and controls with balanced accuracies of up to 80.48% (p-values = 0.0326, FDR corrected) and an ROC analysis yielding an AUC of 0.87. Crucially, a GP regression revealed that MMN predicted global assessment of functioning (GAF) scores (correlation = 0.73, R2 = 0.53, p = 0.0006). PMID- 28560152 TI - Improved cerebral microbleeds detection using their magnetic signature on T2* phase-contrast: A comparison study in a clinical setting. AB - INTRODUCTION/PURPOSE: In vivo detection of cerebral microbleeds (CMBs) from T2* gradient recalled echo (GRE) magnitude image suffers from low specificity, modest inter-rater reproducibility and is biased by its sensitivity to acquisition parameters. New methods were proposed for improving this identification, but they mostly rely on 3D acquisitions, not always feasible in clinical practice. A fast 2D phase processing technique for computing internal field maps (IFM) has been shown to make it possible to characterize CMBs through their magnetic signature in routine clinical setting, based on 2D multi-slice acquisitions. However, its clinical interest for CMBs identification with respect to more common images remained to be assessed. To do so, systematic experiments were undertaken to compare the ratings obtained by trained observers with several image types, T2* magnitude, Susceptibility Weighted Imaging reconstructions (SWI) and IFM built from the same T2*-weighted acquisition. MATERIALS/METHODS: 15 participants from the MEMENTO multi-center cohort were selected: six subjects with numerous CMBs (20 +/- 6 CMBs), five subjects with a few CMBs (2 +/- 1 CMBs) and four subjects without CMB. 2D multi-slice T2* GRE sequences were acquired on Philips and Siemens 3T systems. After pilot experiments, T2* magnitude, Susceptibility Weighted Imaging (SWI) minimum intensity projection (mIP) on three slices and IFM were considered for the rating experiments. A graphical user interface (GUI) was designed in order to consistently display images in random order. Six raters of various background and expertise independently selected "definite" or "possible" CMBs. Rating results were compared with respect to a specific consensus reference, on both lesion and subject type points of view. RESULTS: IFM yielded increased sensitivity and decreased false positives rate (FPR) for CMBs identification compared to T2* magnitude and SWI-mIP images. Inter-rater variability was decreased with IFM when identifying subjects with numerous lesions, with only a limited increase in rating time. IFM thus appears as an interesting candidate to improve CMBs identification in clinical setting. PMID- 28560153 TI - Sexual dimorphism of volume reduction but not cognitive deficit in fetal alcohol spectrum disorders: A combined diffusion tensor imaging, cortical thickness and brain volume study. AB - Quantitative magnetic resonance imaging (MRI) has revealed abnormalities in brain volumes, cortical thickness and white matter microstructure in fetal alcohol spectrum disorders (FASD); however, no study has reported all three measures within the same cohort to assess the relative magnitude of deficits, and few studies have examined sex differences. Participants with FASD (n = 70; 30 females; 5-32 years) and healthy controls (n = 74; 35 females; 5-32 years) underwent cognitive testing and MRI to assess cortical thickness, regional brain volumes and fractional anisotropy (FA)/mean diffusivity (MD) of white matter tracts. A significant effect of group, age-by-group, or sex-by-group was found for 9/9 volumes, 7/39 cortical thickness regions, 3/9 white matter tracts, and 9/10 cognitive tests, indicating group differences that in some cases differ by age or sex. Volume reductions for several structures were larger in males than females, despite similar deficits of cognition in both sexes. Correlations between brain structure and cognitive scores were found in females of both groups, but were notably absent in males. Correlations within a given MRI modality (e.g. total brain volume and caudate volume) were prevalent in both the control and FASD groups, and were more numerous than correlations between measurement types (e.g. volumes and diffusion tensor imaging) in either cohort. This multi-modal MRI study finds widespread differences of brain structure in participants with prenatal alcohol exposure, and to a greater extent in males than females which may suggest attenuation of the expected process of sexual dimorphism of brain structure during typical development. PMID- 28560154 TI - Children with cerebral palsy have altered oscillatory activity in the motor and visual cortices during a knee motor task. AB - The neuroimaging literature on cerebral palsy (CP) has predominantly focused on identifying structural aberrations within the white matter (e.g., fiber track integrity), with very few studies examining neural activity within the key networks that serve the production of motor actions. The current investigation used high-density magnetoencephalography to begin to fill this knowledge gap by quantifying the temporal dynamics of the alpha and beta cortical oscillations in children with CP (age = 15.5 +/- 3 years; GMFCS levels II-III) and typically developing (TD) children (age = 14.1 +/- 3 years) during a goal-directed isometric target-matching task using the knee joint. Advanced beamforming methods were used to image the cortical oscillations during the movement planning and execution stages. Compared with the TD children, our results showed that the children with CP had stronger alpha and beta event-related desynchronization (ERD) within the primary motor cortices, premotor area, inferior parietal lobule, and inferior frontal gyrus during the motor planning stage. Differences in beta ERD amplitude extended through the motor execution stage within the supplementary motor area and premotor cortices, and a stronger alpha ERD was detected in the anterior cingulate. Interestingly, our results also indicated that alpha and beta oscillations were weaker in the children with CP within the occipital cortices and visual MT area during movement execution. These altered alpha and beta oscillations were accompanied by slower reaction times and substantial target matching errors in the children with CP. We also identified that the strength of the alpha and beta ERDs during the motor planning and execution stages were correlated with the motor performance. Lastly, our regression analyses suggested that the beta ERD within visual areas during motor execution primarily predicted the amount of motor errors. Overall, these data suggest that uncharacteristic alpha and beta oscillations within visuomotor cortical networks play a prominent role in the atypical motor actions exhibited by children with CP. PMID- 28560155 TI - Grey matter abnormalities in children and adolescents with functional neurological symptom disorder. AB - OBJECTIVE: Functional neurological symptom disorder refers to the presence of neurological symptoms not explained by neurological disease. Although this disorder is presumed to reflect abnormal function of the brain, recent studies in adults show neuroanatomical abnormalities in brain structure. These structural brain abnormalities have been presumed to reflect long-term adaptations to the disorder, and it is unknown whether child and adolescent patients, with illness that is typically of shorter duration, show similar deficits or have normal brain structure. METHOD: High-resolution, three-dimensional T1-weighted magnetic resonance images (MRIs) were acquired in 25 patients (aged 10-18 years) and 24 healthy controls. Structure was quantified in terms of grey matter volume using voxel-based morphometry. Post hoc, we examined whether regions of structural difference related to a measure of motor readiness to emotional signals and to clinical measures of illness duration, illness severity, and anxiety/depression. RESULTS: Patients showed greater volumes in the left supplementary motor area (SMA) and right superior temporal gyrus (STG) and dorsomedial prefrontal cortex (DMPFC) (corrected p < 0.05). Previous studies of adult patients have also reported alterations of the SMA. Greater SMA volumes correlated with faster reaction times in identifying emotions but not with clinical measures. CONCLUSIONS: The SMA, STG, and DMPFC are known to be involved in the perception of emotion and the modulation of motor responses. These larger volumes may reflect the early expression of an experience-dependent plasticity process associated with increased vigilance to others' emotional states and enhanced motor readiness to organize self-protectively in the context of the long-standing relational stress that is characteristic of this disorder. PMID- 28560156 TI - Neural signature of coma revealed by posteromedial cortex connection density analysis. AB - Posteromedial cortex (PMC) is a highly segregated and dynamic core, which appears to play a critical role in internally/externally directed cognitive processes, including conscious awareness. Nevertheless, neuroimaging studies on acquired disorders of consciousness, have traditionally explored PMC as a homogenous and indivisible structure. We suggest that a fine-grained description of intrinsic PMC topology during coma, could expand our understanding about how this cortical hub contributes to consciousness generation and maintain, and could permit the identification of specific markers related to brain injury mechanism and useful for neurological prognostication. To explore this, we used a recently developed voxel-based unbiased approach, named functional connectivity density (CD). We compared 27 comatose patients (15 traumatic and 12 anoxic), to 14 age-matched healthy controls. The patients' outcome was assessed 3 months later using Coma Recovery Scale-Revised (CRS-R). A complex pattern of decreased and increased connections was observed, suggesting a network imbalance between internal/external processing systems, within PMC during coma. The number of PMC voxels with hypo-CD positive correlation showed a significant negative association with the CRS-R score, notwithstanding aetiology. Traumatic injury specifically appeared to be associated with a greater prevalence of hyper connected (negative correlation) voxels, which was inversely associated with patient neurological outcome. A logistic regression model using the number of hypo-CD positive and hyper-CD negative correlations, accurately permitted patient's outcome prediction (AUC = 0.906, 95%IC = 0.795-1). These points might reflect adaptive plasticity mechanism and pave the way for innovative prognosis and therapeutics methods. PMID- 28560157 TI - Optimized classification of 18F-Florbetaben PET scans as positive and negative using an SUVR quantitative approach and comparison to visual assessment. AB - INTRODUCTION: Standardized uptake value ratios (SUVRs) calculated from cerebral cortical areas can be used to categorize 18F-Florbetaben (FBB) PET scans by applying appropriate cutoffs. The objective of this work was first to generate FBB SUVR cutoffs using visual assessment (VA) as standard of truth (SoT) for a number of reference regions (RR) (cerebellar gray matter (GCER), whole cerebellum (WCER), pons (PONS), and subcortical white matter (SWM)). Secondly, to validate the FBB PET scan categorization performed by SUVR cutoffs against the categorization made by post-mortem histopathological confirmation of the Abeta presence. Finally, to evaluate the added value of SUVR cutoff categorization to VA. METHODS: SUVR cutoffs were generated for each RR using FBB scans from 143 subjects who were visually assessed by 3 readers. SUVR cutoffs were validated in 78 end-of life subjects using VA from 8 independent blinded readers (3 expert readers and 5 non-expert readers) and histopathological confirmation of the presence of neuritic beta-amyloid plaques as SoT. Finally, the number of correctly or incorrectly classified scans according to pathology results using VA and SUVR cutoffs was compared. RESULTS: Composite SUVR cutoffs generated were 1.43 (GCER), 0.96 (WCER), 0.78 (PONS) and 0.71 (SWM). Accuracy values were high and consistent across RR (range 83-94% for histopathology, and 85-94% for VA). SUVR cutoff performed similarly as VA but did not improve VA classification of FBB scans read either by expert readers or the majority read but provided higher accuracy than some non-expert readers. CONCLUSION: The accurate scan classification obtained in this study supports the use of VA as SoT to generate site-specific SUVR cutoffs. For an elderly end of life population, VA and SUVR cutoff categorization perform similarly in classifying FBB scans as Abeta positive or Abeta-negative. These results emphasize the additional contribution that SUVR cutoff classification may have compared with VA performed by non-expert readers. PMID- 28560158 TI - Application and evaluation of NODDI in the cervical spinal cord of multiple sclerosis patients. AB - INTRODUCTION: There is a need to develop imaging methods sensitive to axonal injury in multiple sclerosis (MS), given the prominent impact of axonal pathology on disability and outcome. Advanced multi-compartmental diffusion models offer novel indices sensitive to white matter microstructure. One such model, neurite orientation dispersion and density imaging (NODDI), is sensitive to neurite morphology, providing indices of apparent volume fractions of axons (vin), isotropic water (viso) and the dispersion of fibers about a central axis (orientation dispersion index, ODI). NODDI has yet to be studied for its sensitivity to spinal cord pathology. Here, we investigate the feasibility and utility of NODDI in the cervical spinal cord of MS patients. METHODS: NODDI was applied in the cervical spinal cord in a cohort of 8 controls and 6 MS patients. Statistical analyses were performed to test the sensitivity of NODDI-derived indices to pathology in MS (both lesion and normal appearing white matter NAWM). Diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) analysis were also performed to compare with NODDI. RESULTS: A decrease in NODDI-derived vin was observed at the site of the lesion (p < 0.01), whereas a global increase in ODI was seen throughout white matter (p < 0.001). DKI-derived mean kurtosis (MK) and radial kurtosis (RK) and DTI-derived fractional anisotropy (FA) and radial diffusivity (RD) were all significantly different in MS patients (p < 0.02), however NODDI provided higher contrast between NAWM and lesion in all MS patients. CONCLUSION: NODDI provides unique contrast that is not available with DKI or DTI, enabling improved characterization of the spinal cord in MS. PMID- 28560159 TI - Williams syndrome-specific neuroanatomical profile and its associations with behavioral features. AB - Williams Syndrome (WS) is a rare genetic disorder with unique behavioral features. Yet the rareness of WS has limited the number and type of studies that can be conducted in which inferences are made about how neuroanatomical abnormalities mediate behaviors. In this study, we extracted a WS-specific neuroanatomical profile from structural magnetic resonance imaging (MRI) measurements and tested its association with behavioral features of WS. Using a WS adult cohort (22 WS, 16 healthy controls), we modeled a sparse representation of a WS-specific neuroanatomical profile. The predictive performances are robust within the training cohort (10-fold cross-validation, AUC = 1.0) and accurately identify all WS individuals in an independent child WS cohort (seven WS, 59 children with diverse developmental status, AUC = 1.0). The WS-specific neuroanatomical profile includes measurements in the orbitofrontal cortex, superior parietal cortex, Sylvian fissures, and basal ganglia, and variability within these areas related to the underlying size of hemizygous deletion in patients with partial deletions. The profile intensity mediated the overall cognitive impairment as well as personality features related to hypersociability. Our results imply that the unique behaviors in WS were mediated through the constellation of abnormalities in cortical-subcortical circuitry consistent in child WS and adult WS. The robustness of the derived WS-specific neuroanatomical profile also demonstrates the potential utility of our approach in both clinical and research applications. PMID- 28560160 TI - Application of calibrated fMRI in Alzheimer's disease. AB - Calibrated fMRI based on arterial spin-labeling (ASL) and blood oxygen-dependent contrast (BOLD), combined with periods of hypercapnia and hyperoxia, can provide information on cerebrovascular reactivity (CVR), resting blood flow (CBF), oxygen extraction fraction (OEF), and resting oxidative metabolism (CMRO2). Vascular and metabolic integrity are believed to be affected in Alzheimer's disease (AD), thus, the use of calibrated fMRI in AD may help understand the disease and monitor therapeutic responses in future clinical trials. In the present work, we applied a calibrated fMRI approach referred to as Quantitative O2 (QUO2) in a cohort of probable AD dementia and age-matched control participants. The resulting CBF, OEF and CMRO2 values fell within the range from previous studies using positron emission tomography (PET) with 15O labeling. Moreover, the typical parietotemporal pattern of hypoperfusion and hypometabolism in AD was observed, especially in the precuneus, a particularly vulnerable region. We detected no deficit in frontal CBF, nor in whole grey matter CVR, which supports the hypothesis that the effects observed were associated specifically with AD rather than generalized vascular disease. Some key pitfalls affecting both ASL and BOLD methods were encountered, such as prolonged arterial transit times (particularly in the occipital lobe), the presence of susceptibility artifacts obscuring medial temporal regions, and the challenges associated with the hypercapnic manipulation in AD patients and elderly participants. The present results are encouraging and demonstrate the promise of calibrated fMRI measurements as potential biomarkers in AD. Although CMRO2 can be imaged with 15O PET, the QUO2 method uses more widely available imaging infrastructure, avoids exposure to ionizing radiation, and integrates with other MRI-based measures of brain structure and function. PMID- 28560161 TI - Do managed bees drive parasite spread and emergence in wild bees? AB - Bees have been managed and utilised for honey production for centuries and, more recently, pollination services. Since the mid 20th Century, the use and production of managed bees has intensified with hundreds of thousands of hives being moved across countries and around the globe on an annual basis. However, the introduction of unnaturally high densities of bees to areas could have adverse effects. Importation and deployment of managed honey bee and bumblebees may be responsible for parasite introductions or a change in the dynamics of native parasites that ultimately increases disease prevalence in wild bees. Here we review the domestication and deployment of managed bees and explain the evidence for the role of managed bees in causing adverse effects on the health of wild bees. Correlations with the use of managed bees and decreases in wild bee health from territories across the globe are discussed along with suggestions to mitigate further health reductions in wild bees. PMID- 28560164 TI - Confirmation of a unique species of Giardia, parasitic in the quenda (Isoodon obesulus). AB - The 'quenda genotype' of Giardia was first identified in quenda (syn. southern brown bandicoots, Isoodon obesulus) in Western Australia in 2004. We aimed to formally describe this genotype as a species of Giardia, Giardia peramelis. Seventy five faecal samples positive for G. peramelis were obtained from quenda within the Statistical Division of Perth, Western Australia. These samples were used in morphological and molecular characterisation of G. peramelis. PCR amplification and sequencing was most successful at the 18S rRNA and ITS1-5.8s ITS2 loci. Phylogenetic analyses placed G. peramelis external to the 'Giardia duodenalis species complex' and Giardia microti. This confirmed the uniqueness of G. peramelis, warranting classification as a separate species of Giardia. Study findings suggest quenda are a natural host for G. peramelis. PMID- 28560165 TI - Draft genome of the oomycete pathogen Phytophthora cactorum strain LV007 isolated from European beech (Fagus sylvatica). AB - Phytophthora cactorum is a broad host range phytopathogenic oomycete. P. cactorum strain LV007 was isolated from a diseased European Beech (Fagus sylvatica) in Malmo, Sweden in 2016. The draft genome of P. cactorum strain LV007 is 67.81 Mb. It contains 15,567 contigs and 21,876 predicted protein-coding genes. As reported for other phytopathogenic Phytophthora species, cytoplasmic effector proteins including RxLR and CRN families were identified. The genome sequence has been deposited at DDBJ/ENA/GenBank under the accession NBIJ00000000. The version described in this paper is version NBIJ01000000. PMID- 28560162 TI - More than a rabbit's tale - Encephalitozoon spp. in wild mammals and birds. AB - Within the microsporidian genus Encephalitozoon, three species, Encephalitozoon cuniculi, Encephalitozoon hellem and Encephalitozoon intestinalis have been described. Several orders of the Class Aves (Passeriformes, Psittaciformes, Apodiformes, Ciconiiformis, Gruiformes, Columbiformes, Suliformes, Podicipediformes, Anseriformes, Struthioniformes, Falconiformes) and of the Class Mammalia (Rodentia, Lagomorpha, Primates, Artyodactyla, Soricomorpha, Chiroptera, Carnivora) can become infected. Especially E. cuniculi has a very broad host range while E. hellem is mainly distributed amongst birds. E. intestinalis has so far been detected only sporadically in wild animals. Although genotyping allows the identification of strains with a certain host preference, recent studies have demonstrated that they have no strict host specificity. Accordingly, humans can become infected with any of the four strains of E. cuniculi as well as with E. hellem or E. intestinalis, the latter being the most common. Especially, but not exclusively, immunocompromised people are at risk. Environmental contamination with as well as direct transmission of Encephalitozoon is therefore highly relevant for public health. Moreover, endangered species might be threatened by the spread of pathogens into their habitats. In captivity, clinically overt and often fatal disease seems to occur frequently. In conclusion, Encephalitozoon appears to be common in wild warm-blooded animals and these hosts may present important reservoirs for environmental contamination and maintenance of the pathogens. Similar to domestic animals, asymptomatic infections seem to occur frequently but in captive wild animals severe disease has also been reported. Detailed investigations into the epidemiology and clinical relevance of these microsporidia will permit a full appraisal of their role as pathogens. PMID- 28560166 TI - Small RNA-seq analysis in response to methyl jasmonate and abscisic acid treatment in Persicaria minor. AB - Persicaria minor (Kesum) is an important medicinal plant with high level of secondary metabolite contents, especially, terpenoids and flavonoids. Previous studies have revealed that application of exogenous phytohormone could increase secondary metabolite contents of the plant. MicroRNAs (miRNAs) are small RNAs that play important regulatory roles in various biological processes. In order to explore the possible role of miRNA in the regulation of these phytohormones signaling pathway and uncovering their potential correlation, we, for the first time, have generated the smallRNA library of Kesum plant. The library was developed in response to methyl jasmonate (MJ) and abscisic acid (ABA) treatment by using next-generation sequencing technology. Raw reads have been deposited to SRA database with the accession numbers, SRX2655642 and SRX2655643 (MJ-treated), SRXSRX2655644 and SRX2655645 (ABA-treated) and SRX2655646and SRX2655647 (Control). PMID- 28560167 TI - RNA-seq analysis of mangosteen (Garcinia mangostana L.) fruit ripening. AB - Mangosteen (Garcinia mangostana L.) is known for its delectable taste and contains high amount of xanthones which have been reported to possess anti cancer, anti-inflammatory and other bioactive properties. However, stage-specific regulation of mangosteen fruit ripening has never been studied in detail. We have performed a comparative transcriptomic analysis of three ripening stages (Stage 0, 2 and 6) of mangosteen. We have obtained a raw data from six libraries through Illumina HiSeq 4000. A total of ~ 40 Gb of raw data were generated. Clean reads of 650,887,650 (bp) were obtained from 656,913,570 (bp) raw reads. The raw transcriptome data were deposited to SRA database, with the BioProject accession number of PRJNA339916. These data will be beneficial for transcriptome profiling in order to study the regulation of mangosteen fruit ripening. The lack of a complete sequence database from this species impedes protein identification. These data sets provide a reference data for the exploration of novel genes or proteins to understand mangosteen fruit ripening behaviour. PMID- 28560169 TI - Small RNA sequencing for secondary metabolite analysis in Persicaria minor. AB - Persicaria minor (kesum) is an important medicinal plant and commonly found in southeast countries; Malaysia, Thailand, Indonesia, and Vietnam. This plant is enriched with a variety of secondary metabolites (SMs), and among these SMs, terpenoids are in high abundance. Terpenoids are comprised of many valuable biomolecules which have well-established role in agriculture and pharmaceutical industry. In P. minor, for the first time, we have generated small RNAs data sets, which can be used as tool in deciphering their roles in terpenoid biosynthesis pathways. Fungal pathogen, Fusarium oxysporum was used as elicitor to trigger SMs biosynthesis in P. minor. Raw reads and small RNA analysis data have already been deposited at GenBank under the accessions; SRX2645684 (Fusarium treated), SRX2645685 (Fusarium-treated), SRX2645686 (mock-infected), and SRX2645687 (mock-infected). PMID- 28560168 TI - Genome sequence of the oleaginous yeast Rhodotorula toruloides strain CGMCC 2.1609. AB - Most eukaryotic oleaginous species are yeasts and among them the basidiomycete red yeast, Rhodotorula (Rhodosporidium) toruloides (Pucciniomycotina) is known to produce high quantities of lipids when grown in nitrogen-limiting media, and has potential for biodiesel production. The genome of the CGMCC 2.1609 strain of this oleaginous red yeast was sequenced using a hybrid of Roche 454 and Illumina technology generating 13 * coverage. The de novo assembly was carried out using MIRA and scaffolded using MAQ and BAMBUS. The sequencing and assembly resulted in 365 scaffolds with total genome size of 33.4 Mb. The complete genome sequence of this strain was deposited in GenBank and the accession number is LKER00000000. The annotation is available on Figshare (doi:10.6084/m9.figshare.4754251). PMID- 28560170 TI - RNA-seq detects pharmacological inhibition of Epstein-Barr virus late transcription during spontaneous reactivation. AB - The stepwise and sequential expression of viral genes underlies progression of the infectious life cycle. The Epstein-Barr virus (EBV) is both a tractable model for elucidating principles of transcription as well as a global health threat. We describe an experimental protocol and bioinformatics pipeline for functional identification of EBV true late genes, the last step of transcription prior to virion packaging and egress. All data have been uploaded to the Gene Expression Omnibus under accession code GSE96689. The key improvement over previous approaches is leveraging the sensitivity of RNA-seq to detect gene expression changes during spontaneous reactivation. PMID- 28560171 TI - Pasteurella multocida chest wall abscess without wounds. PMID- 28560172 TI - A Case of Osteomyelitis of the toe caused by Coccidioidomycosis in a 17 year-old with Diabetes Insipidus. AB - We report a case of a 17-year-old male who presented with pain in his right first toe. His pain and swelling had worsened and x-rays of his foot revealed erosive changes of the great toe distal phalanx suggesting possible osteomyelitis. His co morbidities were morbid obesity and diabetes insipidus. He was admitted to the hospital, blood cultures were drawn, and he was started on vancomycin for presumed bacterial osteomyelitis. He underwent incision and drainage of the fluctuant abscess of the toe, where a culture of the wound was taken. Preliminary results grew fungi. Being located in an endemic area, he was started on anti fungal treatment for presumed disseminated coccidioidomycosis; culture was positive for Coccidiodes immitis. He also had serology positive for coccidioidomycosis titers. He had uneventful hospital stay and was discharged on long-term oral antifungal therapy. PMID- 28560173 TI - Severe interstitial pneumonia due to murine typhus in a patient returning from Bali. AB - Murine typhus has been increasingly reported as a cause of fever in returning travelers from Southeast Asia. We report a case of a previously healthy traveler returning from Bali with an non-specific febrile illness which quickly progressed to a severe form of interstitial pneumonia. After a careful epidemiological evaluation and laboratory analysis, murine typhus was diagnosed. PMID- 28560175 TI - Miliary tuberculosis with cerebral, liver, prostate and retroesophageal involvement. AB - Miliary tuberculosis results from the lymphohematogenous spread of Mycobacterium tuberculosis and it is a rare form of this disease. The most affected places are the lymph nodes, pleura, and osteoarticular system, but any organ can be involved. Currently the disease is still endemic in developing countries by its close association with poor living conditions and malnutrition. Other comorbidities, particularly infection by human immunodeficiency virus (HIV), diabetes mellitus, smoking and alcoholism are of great importance in the epidemiology of this disease. The authors describe the case of an adult man from Guinea-Bissau that has been residing in Portugal for the last few months, admitted with complaints of headache. He was submitted to a computerized tomography (CT) scan of the brain which showed multiple lesions. This led to further study and the diagnosis of a disseminated tuberculosis with cerebral, liver, prostate and retroesophageal involvement. He was started on anti tuberculosis therapy, achieving good results. PMID- 28560174 TI - Pediatric huaiyangshan virus infection: A case report with literature review. AB - To define the clinical manifestations and laboratory characteristics of pediatric severe fever with thrombocytopenia syndrome (SFTS) case caused by a novel bunyavirus. we retrospectively analyzed a pediatric case of viral SFTS in a 13 year old successfully managed and confirmed to be due to the novel bunyavirus now referred to as Huaiyangshan virus. A literature review of related cases was performed.Our pediatric case was a 13.3-year-old middle school student no underlying disease. Major clinical features included a fever with chills, headache, and dizziness. The patient's epidemiology showed he had close contact with his grandfather who had a confirmed, novel bunyavirus infection. Symptomatic theraphy were given at admission. The patient's temperature and platelet count returned to normal by days 7 and 10, respectively, and he was discharged from the hospital with an improved condition. A literature search was performed using "severe fever with thrombocytopenia syndrome" and "bunyavirus" as keywords, but few relevant reports were found. Novel bunyavirus infection can be transmitted through close contact. Confirmed cases should be kept in isolation. Clinical manifestations were characterized by aspecific symptoms, such as fever and chills. In some cases, platelet counts may remain normal in the early phase of the disease, and fever may not present throughout the entire illness period. Thus, misdiagnosis is possible. Surveillance and vigorous follow-up should be carried out in children with tick bites or in close contact with an index patient in high-risk areas during peak season. PMID- 28560176 TI - Wife to husband transmission of Ecthyma contagiosum (Orf). PMID- 28560163 TI - Public health significance of zoonotic Cryptosporidium species in wildlife: Critical insights into better drinking water management. AB - Cryptosporidium is an enteric parasite that is transmitted via the faecal-oral route, water and food. Humans, wildlife and domestic livestock all potentially contribute Cryptosporidium to surface waters. Human encroachment into natural ecosystems has led to an increase in interactions between humans, domestic animals and wildlife populations. Increasing numbers of zoonotic diseases and spill over/back of zoonotic pathogens is a consequence of this anthropogenic disturbance. Drinking water catchments and water reservoir areas have been at the front line of this conflict as they can be easily contaminated by zoonotic waterborne pathogens. Therefore, the epidemiology of zoonotic species of Cryptosporidium in free-ranging and captive wildlife is of increasing importance. This review focuses on zoonotic Cryptosporidium species reported in global wildlife populations to date, and highlights their significance for public health and the water industry. PMID- 28560178 TI - Letter to the Editors: Concerning "Divergent clinical outcomes of alpha glucosidase enzyme replacement therapy in two siblings with infantile-onset Pompe disease treated in the symptomatic or pre-symptomatic state" by Takashi et al. and Letter to the Editors by Ortolano et al. PMID- 28560177 TI - Dengue virus serotype 3 and Chikungunya virus co-infection in a traveller returning from India to Portugal, November 2016. AB - We report a case of a laboratory-confirmed Dengue and Chikungunya viruses co infection imported from India to Portugal in early November 2016. The patient developed fever, retro-orbital pain and generalized myalgia after returning from Delhi, Jaipur, Agra, Rishikesh, Goa and Mumbai. This case highlights the importance of these arboviruses to public health in India where high rates of co infection have been reported in the last few years, and demonstrates how challenging the laboratory diagnosis of imported co-infection cases can be in non endemic areas. PMID- 28560179 TI - The factors affecting lipid profile in adult patients with Mucopolysaccharidosis. AB - BACKGROUND: Mucopolysaccharidoses (MPS) are a group of rare inherited disorders characterized by abnormal accumulation of glycosaminoglycans (GAGs) within the myocytes and coronary arteries. Little is known about hyperlipidaemia as a potential cardiovascular risk factor in these patients. Baseline cholesterol data in adults are scarce. Therefore, the aim of this study was to analyse factors affecting lipid profile in different types of MPSs to determine if abnormalities in lipid profile contribute to the overall risk of cardiovascular disease. METHODS: Adult patients (above the age of 16) with MPS type I, II, III, IV and VI attending clinics in two Inherited Metabolic Disorders centres were included. Their lipid profile, lipoprotein (a), HbA1c, Glucose Tolerance Test (GTT), BMI and treatment type were extracted. Analysis included descriptive statistics and Student t-test. RESULTS: Eighty two patients with five MPS types (I, II, III, IV and VI) were included in the study; 29 were females (35%) and 53 were males (65%). BMI above 25 kg/m2 in all MPS types indicated that some patients were overweight for their height. Only one patient post-HSCT had diabetes. In 3 cases insulin was analysed during GTT and showed no insulin resistance despite raised BMI. Mean total cholesterol and LDL-cholesterol were below 5 mmol/L and 3 mmol/L, respectively, in five individual MPS types. Lipoprotein (a) was available for 6 MPS IV patients and was not significantly raised. CONCLUSIONS: MPS disorders are not associated with significant hypercholesterolaemia or diabetes mellitus despite increased BMI. Total cholesterol and LDL-cholesterol were within the targets for primary prevention for non-MPS population. Lipoprotein (a) is not a useful marker of cardiovascular disease in a small group of adult MPS IV patients irrespectively of treatment option. Whether long-term cardiovascular risk is dependent on lipid profile, diabetes, obesity or GAGs deposition within the organ system remains unanswered. PMID- 28560180 TI - Treatment of sugar processing industry effluent up to remittance limits: Suitability of hybrid electrode for electrochemical reactor. AB - Sugar industry is an oldest accommodates industry in the world. It required and discharges a large amount of water for processing. Removal of chemical oxygen demand and color through the electrochemical process including hybrid iron and aluminum electrode was examined for the treatment of cane-based sugar industry wastewater. Most favorable condition at pH 6.5, inter-electrode gap 20 mm, current density 156 A m-2, electrolyte concentration 0.5 M and reaction time 120 min, 90% COD and 93.5% color removal was achieved. The sludge generated after treatment has less organic contain, which can be used as manure in agricultural crops. Overall the electrocoagulation was found to be reliable, efficient and economically fit to treat the sugar industry wastewater. *Electrocoagulation method for sugar processing industry wastewater treatment Optimization of operating parameters for maximum efficiency.*Physicochemical analysis of sludge and scum.*Significance of hydride metal electrode for pollutant removal. PMID- 28560181 TI - A modified assay for the enumeration of ascaris eggs in fresh raw sewage. AB - Soil-transmitted helminths (STHs) pose a significant public health problem, infecting approximately 2 billion people globally. Despite relatively low prevalence in developed countries, the removal of STHs from wastewater remains crucial to allow the safe use of biosolids or recycled water for agriculture. Wastewater helminth egg count data can contribute to an assessment of the need for, or success of, a parasite management program. Although the World Health Organisation (WHO) has recommended a standard method for counting helminth eggs in raw sewage based on the method of Bailenger (Ayres et al., 1996), the method generally results in low percentage egg recoveries. Given the importance of determining the presence of STHs, it is essential to develop novel techniques that optimise the recovery rate of eggs from raw sewage. In the present study: *The method described by Bowman et al. (2003) was optimized for the concentration and enumeration of helminth eggs in raw sewage from municipal sewage treatment plants.*The method is simple and reproducible and recovers a greater percentage of helminth eggs compared to the WHO method. PMID- 28560182 TI - Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Treatment of Metastatic Non-Small Cell Lung Cancer, with a Focus on Afatinib. AB - Somatic epidermal growth factor receptor (EGFR) mutations are present in around 50% of Asian patients and in 10-15% of Caucasian patients with metastatic non small cell lung cancer (NSCLC) of adenocarcinoma histology. The first-generation EGFR-tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have demonstrated improved progression-free survival (PFS) and response rates but not overall survival (OS) benefit in randomized phase III trials when compared with platinum doublet chemotherapy. All patients treated with EGFR-TKIs will eventually develop acquired resistance to these agents. Afatinib, an irreversible ErbB family blocker, has shown in two randomly controlled trials in patients with EGFR activating mutations, a significant improvement in PFS and health-related quality of life when compared to platinum-based chemotherapy. Afatinib improved OS in patients with Del19 mutations. In patients having progressed on first-generation EGFR-TKIs, afatinib did lead to a clinical benefit. A randomly controlled trial showed that PFS was significantly superior with afatinib vs. erlotinib in patients with squamous NSCLC in the second-line setting. A phase IIb trial comparing afatinib and gefitinib in first-line EGFR positive NSCLC showed significantly improved PFS with afatinib but OS was not significantly improved. PMID- 28560183 TI - Outbreak by Hypermucoviscous Klebsiella pneumoniae ST11 Isolates with Carbapenem Resistance in a Tertiary Hospital in China. AB - Hypervirulent and multidrug resistant Klebsiella pneumoniae strains pose a significant threat to the public health. In the present study, 21 carbapenem resistant K. pneumoniae isolates (CRKP) were determined by the string test as hypermucoviscous K. pneumoniae (HMKP), with the prevalence of 15.0% (21/140) among CRKP, and 1.1% (21/1838) among all K. pneumoniae isolates. Among them, 7 (33.3%), and 1 (4.76%) isolate belonged to capsular serotype K20 and K2 respectively, while 13 (61.9%, 13/21) weren't successfully typed by capsular serotyping. All the 21 isolates were carbapenemase-producers and were positive for blaKPC-2. In addition to blaKPC-2, all the 21 isolates except one harbor blaSHV-11, and 15 carry extended-spectrum beta-lactamase gene blaCTX-M-65. The virulence-associated genes with more than 90% of positive rates among 21 isolates included ureA (100%, 21/21), wabG (100%, 21/21), fimH (95.2%, 20/21), entB (95.2%, 20/21), ycf (95.2%, 20/21), ybtS (95.2%, 20/21), and iutA (90.5%, 19/21). rmpA and aerobactin were found in 57.1% (12/21) isolates. Five sequence types (STs) were identified by multilocus sequence typing (MLST), including ST11 (11 K non capsule typable and 5 K20 isolates), ST268 (1 K20 isolate and 1 K-non capsule typable isolate), ST65 (1 K2 isolate), ST692 (1 K-non capsule typable isolate), and ST595, a novel sequence type (1 K-non capsule typable isolate). Pulsed-field gel electrophoresis (PFGE) results showed two major PFGE clusters, of which cluster A accounts for 6 ST11 isolates (28.6%) and cluster B includes 8 ST11 isolates (38.1%, 8/21). Ten and six ST11 isolates were isolated from 2014 and 2015, respectively, while 8 were isolated from the same month of December in 2014. Ten isolates were collected from the intensive care unit (ICU), and all except one belonged to ST11. Additional 4 ST11 isolates were collected from patients in non-ICU wards, who had more than 10 days of ICU stay history in 2014 prior to transfer to their current wards where the isolates were recovered. Taken together, the present study showed a hospital outbreak and dissemination of ST11 HMKP with carbapenem resistance caused by KPC-2. Effective surveillance and strict infection control strategies should be implemented to prevent outbreak by HMKP with carbapenem resistance in hospitals. PMID- 28560184 TI - Interaction between Plasmodium Glycosylphosphatidylinositol and the Host Protein Moesin Has No Implication in Malaria Pathology. AB - Glycosylphosphatidylinositol (GPI) anchor of Plasmodium falciparum origin is considered an important toxin leading to severe malaria pathology through stimulation of pro-inflammatory responses from innate immune cells. Even though the GPI-induced immune response is widely described to be mediated by pattern recognition receptors such as TLR2 and TLR4, previous studies have revealed that these two receptors are dispensable for the development of severe malaria pathology. Therefore, this study aimed at the identification of potential alternative Plasmodium GPI receptors. Herein, we have identified the host protein moesin as an interaction partner of Plasmodium GPI in vitro. Given previous reports indicating the relevance of moesin especially in the LPS-mediated induction of pro-inflammatory responses, we have conducted a series of in vitro and in vivo experiments to address the physiological relevance of the moesin Plasmodium GPI interaction in the context of malaria pathology. We report here that although moesin and Plasmodium GPI interact in vitro, moesin is not critically involved in processes leading to Plasmodium-induced pro-inflammatory immune responses or malaria-associated cerebral pathology. PMID- 28560185 TI - Deregulation of MicroRNAs in Gastric Lymphomagenesis Induced in the d3Tx Mouse Model of Helicobacter pylori Infection. AB - Helicobacter pylori infection is considered as an excellent model of chronic inflammation-induced tumor development. Our project focuses on gastric MALT lymphoma (GML) related to H. pylori infection and mediated by the chronic inflammatory process initiated by the infection. Recently, microRNAs (miRNAs) have emerged as a new class of gene regulators, which play key roles in inflammation and carcinogenesis acting as oncogenes or tumor suppressors. Their precise characterization in the development of inflammation and their contribution in regulating host cells responses to infection by H. pylori have been little explored. Our goal was to analyze the changes in miRNAs in a GML mouse model using BALB/c mice thymectomized at day 3 post-birth (d3Tx model) and to clarify their implication in GML pathogenesis. PCR array followed by RT-qPCR identified five miRNAs (miR-21a, miR-135b, miR-142a, miR-150, miR-155) overexpressed in the stomachs of GML-developing d3Tx mice infected by H. pylori. The analysis of their putative targets allowed us to identify TP53INP1, an anti proliferative and pro-apoptotic protein, as a common target of 4 of the 5 up regulated miRNAs. We postulate that these miRNAs may act in synergy to promote the development of GML. miR-142a was also overexpressed in mouse sera samples and therefore could serve as a diagnostic marker. In situ hybridization on gastric samples with miR-142a revealed a global up-regulation of this miRNA by the tumor microenvironment at the lymphoma stage. Dysregulation of miR-21a, miR-135b, miR 142a, miR-150, miR-155 could play a critical role in the pathogenesis of GML and might offer potential applications as therapeutic targets and novel biomarkers for this disease. PMID- 28560186 TI - Tracking Bioluminescent ETEC during In vivo BALB/c Mouse Colonization. AB - Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea worldwide. Adhesion to the human intestinal tract is crucial for colonization. ETEC adhesive structures have been extensively studied; however, colonization dynamics remain uncharacterized. The aim of this study was to track bioluminescent ETEC during in vivo infection. The promoter region of dnaK was fused with the luc gene, resulting in the pRMkluc vector. E. coli K-12 and ETEC FMU073332 strains were electroporated with pRMkluc. E. coli K-12 pRMkluc was bioluminescent; in contrast, the E. coli K-12 control strain did not emit bioluminescence. The highest light emission was measured at 1.9 OD600 (9 h) and quantified over time. The signal was detected starting at time 0 and up to 12 h. Streptomycin-treated BALB/c mice were orogastrically inoculated with either ETEC FMU073332 pRMkluc or E. coli K-12 pRMkluc (control), and bacterial colonization was determined by measuring bacterial shedding in the feces. ETEC FMU073332 pRMkluc shedding started and stopped after inoculation of the control strain, indicating that mouse intestinal colonization by ETEC FMU073332 pRMkluc lasted longer than colonization by the control. The bioluminescence signal of ETEC FMU073332 pRMkluc was captured starting at the time of inoculation until 12 h after inoculation. The bioluminescent signal emitted by ETEC FMU073332 pRMkluc in the proximal mouse ileum was located, and the control signal was identified in the cecum. The detection of maximal light emission and bioluminescence duration allowed us to follow ETEC during in vivo infection. ETEC showed an enhanced colonization and tropism in the mouse intestine compared with those in the control strain. Here, we report the first study of ETEC colonization in the mouse intestine accompanied by in vivo imaging. PMID- 28560187 TI - Which Health Cares Are Related to the Family Physician? A Critical Interpretive Synthesis of Literature. AB - BACKGROUND: This study provided the theoretical basis for program development through a new conceptualization of the concept of family physician related health care. METHODS: Critical interpretive synthesis (CIS) was used to carry out qualitative analysis and synthesis of the literature from 2006 until 2015. At the beginning of CIS, the search strategy was designed to access electronic databases such as CINAHL, Medline, Cochrane library, PsycINFO, Embase, EBMreviews, and Thomson scientific web of science database. The main review question was the clarification of the health care related to family physician in health system, which produced over related 750 articles; 60 articles related to the research objective were studied by purposive sampling. After identifying the main categories and sub-categories, synthesis of the contradictory findings in different studies was conducted. New concepts and relationships between concepts were created using CIS of documentation related to the place of family physician in health system. RESULTS: To define the original position of family physician in health system, clarify its related health care and determine its boundaries from other health care providers, and its use in the design and development of family physician's educational program, a frame of concepts related to the main concept and question was created. A more useful means of understanding family physician is offered by the synthetic constructs of this framework. CONCLUSION: The theoretical conceptualization of family physician position and duties in the health system can be an appropriate guide for educational program and curricula in our context. PMID- 28560188 TI - Life-course and Cohort Trajectories of Chronic Non-communicable Diseases Risk Factors in China. AB - BACKGROUND: NCDs are the leading disease burdens in China and the NCDs risk factors shifts have accelerated at an unprecedented scale over the past 30 years. The aim of this study was to analysis the natural trajectories of NCDs risk factors over the life course. METHODS: The large-scale longitudinal data from the CHNS includes nine rounds of surveys between 1989 and 2011. Overall, 145913 observations (29719 individuals) at multiple exams have been followed up over a 23-year period. The mixed-effects models with random intercepts were used to the characterize shifts in the distribution of these risk factors across the whole life course. RESULTS: During about 23 years observational period across all age bands, the mean AMC, UAC, TSF, BMI, WC, DBP, SD, DD, and PA trajectory all increased until a certain age. Then decreased in both gender, whereas SBP strictly increased across lifespan; and the secular trend in AMC and WC, SBP, DBP was greater in women than in men; younger generations had higher AMC, UAC, TSF, BMI, WC, WHR, WHtR, SBP, DBP levels across adulthood, whereas younger birth cohorts had lower SD, DD, and PA levels. CONCLUSION: We observed in a large and comprehensive longitudinal dataset that provided strong evidence of population wide secular shifts from childhood onwards, which suggests that promoting healthier lifestyles, body weight, blood pressure and enhancing the primary practitioner's capability should be required to reduce the burden of NCDs in China. PMID- 28560190 TI - Botulinum as a Toxin for Treating Post-herpetic Neuralgia. AB - BACKGROUND: We aimed to study the curative effects of botulinum A toxin (BTX-A) on the treatment of post-herpetic neuralgia (PNH). METHODS: We enrolled 58 PNH patients and treated them with hypodermic injection of BTX-A in Xiangyang No.1 People's Hospital, Hubei University of Medicine, Hubei, China. We measured and compared the Visual Analog Score (VAS), Neuropathy Pain Scale (NPS), Quality of Life Scale (SF-36) score, PNH seizure severity degree, seizure duration, frequency of attack and the use of painkillers before and after treatment. We used SPSS13 software package for statistical analysis. Values were expressed by mean+/- standard deviation. P<0.05 indicated a significant difference and P<0.01 indicated an obvious significant difference. RESULTS: Attack frequency, attack duration and attack severity were all significantly lower after treatment (P<0.01). The use of painkillers reduced after treatment (P<0.01) and we observed very few adverse reactions associated with BTX-A injection. CONCLUSION: The use of BTX-A for treating post-herpetic neuralgia produced very promising results with very few adverse reactions. BTX-A can be considered as a valid approach in the treatment of PNH, especially in patients that do not respond well to painkillers. PMID- 28560189 TI - Systematic Analysis of Palatal Rugae Pattern for Use in Human Identification between Two Different Populations. AB - BACKGROUND: Forensic odontology plays important role in identification of human remains in mass disasters such as air crash, tsunami, and accidents. Palatal rugae act as an ideal requisite for human identification as they are present in all victims and are resistant to changes such as aging and trauma. The study aimed to analyze differences in shape and number of palatal rugae in population from Andhra Pradesh and Telangana states. METHODS: This study was conducted in SIBAR institute of Dental Sciences, Guntur, India in 2012 on 200 subjects, gender matched and equally divided as 100 from Andhra Pradesh and 100 from Telangana states. Rugae were studied using Kapali.S classification. Association between rugae shape and gender variation between the two populations were tested by chi square analysis and student t-test. RESULTS: Average number of rugae was more (11.84+/-3.03) in subjects of Andhra Pradesh, compared to Telangana (9.50 +/ 1.65) population. Males of Andhra Pradesh showed significantly higher mean number of total rugae than in Telangana males. Distribution of total number of different rugae shapes in males and females of both the populations showed significant variation in wavy and circular rugae patterns. Wavy, curved and straight rugae were significantly higher in males and females of Andhra Pradesh compared to Telangana population. Telangana population showed significant increase in circular rugae. CONCLUSION: Our study revealed statistically significant variation in shape and total number of rugae between observed populations of Andhra Pradesh and Telangana states. PMID- 28560191 TI - Application of Fuzzy Logic in Oral Cancer Risk Assessment. AB - BACKGROUND: The mapping of the malignization mechanism is still incomplete, but oxidative stress is strongly correlated to carcinogenesis. In our research, using fuzzy logic, we aimed to estimate the oxidative stress related-cancerization risk of the oral potentially malignant disorders. METHODS: Serum from 16 patients diagnosed (clinical and histopathological) with oral potentially malignant disorders (Dept. of Cranio-Maxillofacial Surgery and Radiology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj Napoca, Romania) was processed fluorometric for malondialdehyde and proton donors assays (Dept. of Physiology,"Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania). The values were used as inputs, they were associated linguistic terms using MIN-MAX method and 25 IF-THEN inference rules were generated to estimate the output value, the cancerization risk appreciated on a scale from 1 to 10 - IF malondialdehyde is very high and donors protons are very low THEN the cancer risk is reaching the maximum value (Dept. of Industrial Engineering, Faculty of Managerial and Technological Engineering, University of Oradea, Oradea, Romania) (2012-2014). RESULTS: We estimated the cancerization risk of the oral potentially malignant disorders by implementing the multi-criteria decision support system based on serum malondialdehyde and proton donors' values. The risk was estimated as a concrete numerical value on a scale from 1 to 10 depending on the input numerical/linguistic value. CONCLUSION: The multi-criteria decision support system proposed by us, integrated into a more complex computerized decision support system, could be used as an important aid in oral cancer screening and establish future medical decision in oral potentially malignant disorders. PMID- 28560192 TI - Mutational Analysis of Mitochondrial tRNA Genes in Patients with Asthma. AB - BACKGROUND: Mitochondria are autonomous cellular organelles that oversee a variety of functions such as metabolism, energy production, calcium buffering, and cell fate determination. Most recently, mitochondrial dysfunction caused by mitochondrial mutations played important roles in the pathogenesis of asthma. However, the frequency of mitochondrial tRNA mutations in asthma is largely unknown. METHODS: Overall, 200 patients with asthma and 100 healthy control subjects were recruited between Jan 2015 and Dec 2015 at the Guangming New District People's Hospital, Shenzhen, Guangdong Province, China. We first performed PCR amplification of the mitochondrial tRNA genes and subsequently sequenced the PCR products, and we used the pathogenicity scoring system to evaluate the potential role of these mutations. RESULTS: Two patients carrying the tRNAThr G15927A mutation, three patients carrying the tRNAAla T5655C mutation and one patient carrying the tRNAGlu A14693G mutation, these mutations were absent in healthy controls. Moreover, these mutations located at positions highly conserved between different species, and may cause a failure in mitochondrial tRNA metabolism, consequently result in mitochondrial dysfunction that responsible for asthma. In addition, the pathogenicity scoring system showed that these mutations should be regarded as "pathogenic". CONCLUSION: Mitochondrial tRNA mutations caused the mitochondrial dysfunction may be involved in the pathogenesis of asthma. Thus, this study provided novel insight into the molecular mechanism underlying mitochondrial tRNA mutations in asthma. Moreover, screening for the mitochondrial tRNA mutations was advised for the diagnosis of patients with asthma. PMID- 28560193 TI - Comparative Evaluation of Heavy Metals in Patients with Rheumatoid Arthritis and Healthy Control in Pakistani Population. AB - BACKGROUND: Exposure to heavy metals in development of many diseases has been investigated previously, specially created by oxidative stress. The etiology of Rheumatoid arthritis (RA) is still not fully understood but oxidative stress created by heavy metals may have role in development of RA. The aim of present study was to compare serum level of heavy metals in RA and healthy control individuals. METHODS: Blood samples of 100 RA patients were collected from different hospitals in district Sargodha, Punjab, Pakistan and 100 control individuals from Dec 2013 to May 2014.The serum samples were analyzed for determination of Pb, Cd, Cr and Ni through Atomic absorption spectrophotometer (AA 6600 Shimadzu). RESULTS: Statistically highly significant difference was observed between RA patients and healthy control individuals for Pb, Cd, Cr, and Ni level (P<0.01). The difference between the means of both sexes was not significant for Pb and Cd concentrations (P>0.01). For Cr the difference between the means of both sexes was statistically not significant in RA +ve patients and highly significant difference was observed between both sexes in healthy control group (P<0.01). The difference between the means of both sexes for Ni was statistically non-significant in healthy control group while significant difference was observed between both sexes in RA +ve group (P<0.05). Statistically non-significant difference for Pb, Cd, Cr and Ni level was found among the all three age groups of RA and healthy control individuals (P>0.01). CONCLUSION: Concentration of heavy metals in serum samples of RA patients and healthy control individuals differ significantly, which shows that heavy metals may contributes towards development of RA. PMID- 28560194 TI - Short-term Effects of Catheter Pressure and Time Control in Vacuum Aspiration Abortion for Early High-risk Pregnancies. AB - BACKGROUND: We aimed to evaluate an approach to induced abortions during early pregnancies that controls the suction pressure and restricts the duration of the procedure. METHODS: Three hundred patients programmed for induced early pregnancy abortions, hospitalized in the Shandong Provincial Maternity & Child-care Hospital from October 2013 to October 2015, were enrolled. Patients were randomly assigned to either research or control group. In the research group, operation pressure was controlled at 400 mmHg and operation time in the uterine cavity was kept at less than 75 s. In the control group, pressure ranged from 400-500 mmHg. Clinical variables were recorded for each patient until the fourth month after surgery, correlation and multivariate analyses were carried. RESULTS: Compared with control group, anesthesia and intervention durations and the suction pressure were significantly lower and the endometrial thickness of the first late follicular phase after operation was significantly larger in the research group (P<0.05). In the first postoperative month, the number of patients who reported menstruation flow decreased by more than 1/3 of its normal volume was significantly lower than that in the control group (P<0.05). In the third postoperative month, the thickness of the late follicular phase endometrium was significantly larger than that in the control group (P<0.001). The mean intraoperative pressure and intrauterine operation duration both influenced the endometrial thickness of follicular phase. CONCLUSION: Controlling the suction pressure and time for vacuum aspiration abortions during early pregnancies can reduce the incidence of intrauterine adhesions and better protect the endometrium. PMID- 28560195 TI - Development and Psychometric Properties of Social Exclusion Questionnaire for Iranian Divorced Women. AB - BACKGROUND: Divorce, especially in women, could be assessed from socio-cultural perspective as well as psychological viewpoint. This assessment requires cultural adopted as well as valid and reliable questionnaire. This study aimed to develop and assess the psychometric properties of a questionnaire in order to address social consequences in Iranian divorced women. METHODS: This was an exploratory mixed method study conducted during 2012 to 2014. According to the grounded theory approach in the first phase, social exclusion was extracted as a core of understanding process in participants. Based on, 47 preliminary generated items reliability and validity were assessed. In the second phase, the divorced women were recruited from a safe community center in Tehran through convenience sampling. RESULTS: Exploratory factor analysis conducted on the questionnaires of 150 divorced women with mean age 41.76+/-8.49 yr, in that, indicated five dimensions, discriminative marital status, economic dependence on marital status, exclusionary marital status, and traumatic marital status health risks and, frightening marital status that jointly accounted for the 64% of the variance observed. An expert panel approved the face and content validity of the developed tool. The Cronbach's alpha coefficient and the Intra-class Correlation Coefficient were found to be 0.70 and 0.85, respectively. CONCLUSION: The present study provided a valid and reliable measure as Social Exclusion Questionnaire in Iranian divorced women (SEQ-IDW) to address social post-divorce consequences, which might help to improve women's social health. PMID- 28560196 TI - Psychometric Soundness of an Arabic Version of the Jefferson Scale of Attitude toward Physician and Nurse Collaboration (JSAPNC): A Preliminary Study. AB - BACKGROUND: The Jefferson Scale of Attitude toward Physician-Nurse Collaboration (JSAPNC) has been used to measure the attitude regarding collaboration between nurses and physicians. The aim of this preliminary study was to test the reliability and validity of an Arabic version of the questionnaire and adapt it for use in Palestine. METHODS: Forward-backward translation of guidelines provided in the literature was followed. Content validity was examined by nine health experts and reliability was assessed with Cronbach's coefficient alpha; test-retest reliability. Construct validity was explored with exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) by means of survey among 414 physicians and nurses worked at Shifa Medical Complex in the Gaza Strip in 2015. RESULTS: Response rate was 65% and Cronbach's coefficient alpha was 73.2 for the entire sample. Test-retest reliability was 0.79 measured by Pearson correlation. Factor analysis with Varimax rotation revealed four factors explained 60.5% of the variance in the responses labeled as physician-nurse collaboration, doctor's authority, Shared education and Nursing role in-patient care. Goodness of fit indices from the CFA showed a satisfactory model of fit; Comparative Fit Index (CFI) = 0.89; Root Mean Square Error of Approximation (RMSEA) = 0.06; Standardized Root Mean Square Residual (SRMR) = 0.03; and Hoelter index = 206. CONCLUSION: The Arabic version of JSAPNC is psychometrically sound tool with satisfactory measurement characteristics including validity and internal consistency reliability. Future research is required to replicate these findings with larger and representative sample. Generalization to Arab speaking countries can be considered but with caution. PMID- 28560197 TI - The Effect of Snail1 Gene Silencing by siRNA in Metastatic Breast Cancer Cell Lines. AB - BACKGROUND: Breast cancer is the most common diagnosed cancer among women in the world. Snail1 plays a role in the development of the invasive phenotypes of cancer, neural cell differentiation, cell division and apoptosis in tumor cells. Traces of snail1 in metastasis of breast cancer to bone are observed. The aim of this study was to investigate the effect of specific snail1 siRNAs on the proliferation, migration, induction of apoptosis and cell cycle arrest of MDA-MB 468 cells. METHODS: In 2015, this experimental study was performed on the MDA-MB 468 cell lines in Immunology Research Center, Tabriz University of Medical Sciences. After the design and construction of siRNA, transfection was performed with transfection reagent. The expression levels of mRNA and protein were measured by qRT-PCR and western blot analysis, respectively. The survival of cells was determined by using MTT assay cells, apoptosis using Tunel assay, Cell migration using scratch assay, Cell cycle analysis by Propidium Iodide (PI) DNA staining method using flow cytometry on the MDA-MB-468. RESULTS: Transfection with siRNA significantly suppressed the expression of snail1 gene in dose dependent manner after 48 h (P<0.0001). Surprisingly, treatment with snail1 siRNA arrested cell cycle in S phases (P<0.0001). Moreover, siRNA transfection had effects on breast adenocarcinoma cells and inhibited the migration (P<0.0001), proliferation (P<0.0001) and induced apoptosis (P<0.0016). CONCLUSION: The snail1 can be considered as a potent adjuvant in breast cancer therapy. PMID- 28560198 TI - Exploring Measures to Control Road Traffic Injuries in Iran: Key Informants Points of View. AB - BACKGROUND: Injuries and fatalities from road traffic Injuries are global public health concerns, and a major problem in the Iran. This study aimed to explore strategies to control road traffic Injuries (RTI) in Iran. METHODS: We conducted a qualitative study to explore possible ways to reduce the occurrence of road traffic Injuries in Iran in 2016. Interviewees were purposively sampled from various sectors due to multidisciplinary nature of RTIs. Participants were mainly representatives from the police, Ministry of Road, Municipal, emergency services and Ministry of Health. Besides, public health authorities, researchers, and university professors were interviewed. We conducted in-depth interviews using generic guides. Data was analyzed using MAXQDA 10 software. Through content analysis, we interpreted core themes relevant to the accomplishment of our study objectives. RESULTS: Themes that emerged from our study include; road traffic management, governance, education, improving accident database, enforcement, driving license restrictions, and construction of pedestrian overpass. CONCLUSION: This study revealed key informants' views regarding available and affordable solutions to reduce RTIs in Iran. Many applicable strategies are identified in the control of RTIs in Iran. Although some solutions such as highway construction and/or expanding rail transportation have been suggested as effective measures for reducing accident, but they are costly and may not be fully applied in developing countries like Iran. PMID- 28560199 TI - Emotional Intelligence in Patients with Spinal Cord Injury (SCI). AB - BACKGROUND: Spinal Cord Injury (SCI) is a devastating situation. Spinal Cord Injury affects functional, psychological and socioeconomic aspects of patients' lives. The ability to accomplish and explicate the one's own and other's feelings and emotions to spread over appropriate information for confirming thoughts and actions is defined as emotional intelligence (EI). The goal of this study was to evaluate depression and EI in SCI patients in comparison with healthy subjects. METHODS: One-hundred-ten patients with SCI and 80 healthy subjects between Aug 2014 and Aug 2015 were enrolled. The study was conducted in Imam Hospital, Tehran, Iran. All participants were asked to fill valid and reliable Persian version Emotional Quotient inventory (EQ-i) and Beck Depression Inventory (BDI). All data were analyzed using SPSS. Data were presented as Mean+/-SD for continuous or frequencies for categorical variables. Continuous variables compared by means of independent sample t-test. P-values less than 0.05 were considered as significant. RESULTS: Mean age of patients was 28.7 and mean age of controls was 30.2 yr. Spinal cord injury in 20 (18.3%) were at cervical level, in 83 (75.4%) were thoracic and in 7 (6.3%) were lumbar. Mean values of independence, stress tolerance, self-actualization, emotional Self-Awareness, reality testing, Impulse Control, flexibility, responsibility, and assertiveness were significantly different between cases and controls. Mean values of stress tolerance, optimism, self-regard, and responsibility were significantly different between three groups with different injury level. Most scales were not significantly different between male and female cases. CONCLUSION: Emotional intelligence should be considered in SCI cases as their physical and psychological health is affected by their illness. PMID- 28560200 TI - An Efficient Predictive Model for Myocardial Infarction Using Cost-sensitive J48 Model. AB - BACKGROUND: Myocardial infarction (MI) occurs due to heart muscle death that costs like human life, which is higher than the treatment costs. This study aimed to present an MI prediction model using classification data mining methods, which consider the imbalance nature of the problem. METHODS: We enrolled 455 healthy and 295 myocardial infarction cases of visitors to Shahid Madani Specialized Hospital, Khorramabad, Iran, in 2015. Then, a hybrid feature selection method included Weight by Relief and Genetic algorithm applied on the dataset to select the best features. After selection of the features, the metacost classifier applied on the sampled dataset. Metacost made a cost sensitive J48 model by assigning different costs ratios for misclassified cases; include 1:10, 1:50, 1:100, 1:150 and 1:200. RESULTS: After applying the model on the imbalanced dataset, the cost ratio 1:200 led to the best results in comparison to not using feature selection and cost sensitive model. The model achieved sensitivity, F measure and accuracy of 86.67%, 80% and 82.67%, respectively. CONCLUSION: Experiments on the real dataset showed that using the cost-sensitive method along with the hybrid feature selection method improved model performance. Therefore, the model considered a reliable Myocardial Infarction prediction model. PMID- 28560201 TI - A Comparative Study on Willingness to Pay for Breast Cancer and Osteoporosis Screening in Kerman, Southeastern Iran. AB - BACKGROUND: One of the economic evaluation techniques involves calculation of willingness to pay (WTP) for a service to find out the value of that service from the clients' perspective. This study estimated WTP for both breast cancer and osteoporosis screening and comparatively examined the contributing factors. In fact, the comparisons served to provide an exact analysis of individual attitudes and behaviors in relation to screening programs for cancers and other diseases. METHODS: This study was first designed in six scenarios several questionnaires concerning individual breast cancer and osteoporosis screening cases, and determined the WTP median in each scenario between people in Kerman Province of Iran in 2016. Then, the demand function for breast cancer and osteoporosis screening was formulated. Moreover, the factors contributing to WTP were examined through various scenarios in Stata and econometric techniques. RESULTS: The median and mean values of WTP in all the above scenarios were greater for breast cancer screening than for osteoporosis screening. Theoretically, the price assumed a minus sign whereas risk assumed a plus sign within the demand function formulated for both screening programs. Regarding the evaluated factors, age in breast cancer screening and risk of disease in osteoporosis screening were the major factors contributing to WTP. CONCLUSION: Breast cancer screening was more valuable than osteoporosis screening program from the perspective of the subjects. The programs can be successfully designed by concentrating on patients' age groups in breast cancer screening and high-risk patients in osteoporosis screening. PMID- 28560202 TI - Prevalence and Incidence of Multiple Sclerosis in Tehran, Iran. AB - BACKGROUND: Tehran is the capital of Iran with an increasing Multiple Sclerosis (MS) incidence. A retrospective population-based study was conducted to evaluate the status of MS prevalence and MS incidence trends in Tehran Province, Iran. METHODS: A population-based study was conducted from 1991 to 2014 in Tehran Province, the capital city of Iran based on Iranian MS Society (IMSS) registry system. A structured questionnaire design to cover the important epidemiological variables, related at the individual level for MS. A Monte Carlo Permutation method was utilized to test whether the apparent change in MS trends during 1991 2014 was statistically significant. RESULTS: MS incidence was significantly increased during our study period. The annual percent change (APC) was 12.8% in women during 1991 to 2004 and 12.5% in men during the same period. The point prevalence of MS was 101.39 per 100000 populations in 2014. The age-adjusted prevalence rates were 134.03 and for male patients were 42.45 per 100000. CONCLUSION: MS prevalence and incidence in Tehran are markedly rising, it is crucial to elucidate the causes of the increasing trends and implement efficient policies lowering disease burden. PMID- 28560203 TI - Comparison of Gene-expression Profiles between Normal and Periodontitis-affected Tissues. PMID- 28560204 TI - Socio-demographic Factors Associated with Inhabitants' View Related to Vaccines in Indonesia. PMID- 28560205 TI - Treadmill Measurement of Maximal Aerobic Capacity in Untrained Students Aged 9-18 Year. PMID- 28560206 TI - Dental Education and Oral Health Service in Iraq. PMID- 28560207 TI - Knowledge, Attitude, and Practices about Polio Vaccination of the Guardian in Super High-risk Areas of Gadap Town, Karachi, Pakistan. PMID- 28560209 TI - Basic Health Insurance Package in Iran: Revision Challenges. PMID- 28560208 TI - Challenges of Achieving Tuberculosis Elimination by 2050: A Need for More Attention in the TB Control Program in Iran. PMID- 28560210 TI - Determining the Requirements and Barriers for Using Barcode Technology in the Hospitals of Tabriz, Iran. PMID- 28560211 TI - Advanced Therapy Medicinal Products for Rare Diseases: State of Play of Incentives Supporting Development in Europe. AB - In 2008, the European Union introduced the Advanced Medicines Regulation aiming to improve regulation of advanced therapy medicinal products (ATMPs). We applied the ATMPs classification definitions in this Regulation to understand the link of this emerging group of medicinal products and the use of the Orphan Regulation. A total of 185 products that can be classified as ATMPs based on this Regulation have been submitted for orphan designation. Prior to its introduction in 2008, 4.5% of the products submitted for orphan designation met these criteria. This percentage went up to 15% after 2008. We analyzed several parameters associated with active ATMP ODDs focusing on sponsor type and EU-Member State origin, therapeutic area targeted, and ATMP classification [i.e., somatic cell therapy medicinal product, tissue-engineered product (TEP), or gene therapy medicinal product (GTMP)] and the use of regulatory services linked to incentives such as the use of protocol assistance (PA) and other Committees [Committee for Advanced Therapies (CAT) and the Pediatric Committee]. The aim here was to gain insight on the use of different services. The UK submits the largest number of ATMPs for ODD representing ~30% of the total to date. Few submissions have been received from central and Eastern European Member States as well as some of the larger Member States such as Germany (3.6%). ATMPs ODDs were primarily GTMPs (48.7%) and SCTMPs (43.3%). TEPs only represented 8% of all submissions for this medicinal class. This is different from non-ODDs ATMPs where GTMPs make only 20% of ATMPs. A total of 11.7% of ATMP ODDs had received formal CAT classification. A total of 29.8% of all orphan drug (OD) ATMPs requested PA. A total of 71.8% did not have an agreed pediatric investigation plan (PIP). Four products (Glybera one PA; Zalmoxis two; Holoclar one; Strimvelis three) have received a marketing authorization (MAA) and a 10-year market exclusivity. Strimvelis also completed their PIP, which was compliant and received the additional 2-year extension to their 10-year market exclusivity. One OD ATMP (Cerepro) received a negative opinion for MAA. The use of services linked to incentives offered by different legislations for ATMP ODDs is low, indicating a need for increasing awareness. PMID- 28560212 TI - Enhancing Human Cognition with Cocoa Flavonoids. AB - Enhancing cognitive abilities has become a fascinating scientific challenge, recently driven by the interest in preventing age-related cognitive decline and sustaining normal cognitive performance in response to cognitively demanding environments. In recent years, cocoa and cocoa-derived products, as a rich source of flavonoids, mainly the flavanols sub-class, have been clearly shown to exert cardiovascular benefits. More recently, neuromodulation and neuroprotective actions have been also suggested. Here, we discuss human studies specifically aimed at investigating the effects of acute and chronic administration of cocoa flavanols on different cognitive domains, such as executive functions, attention and memory. Through a variety of direct and indirect biological actions, in part still speculative, cocoa and cocoa-derived food have been suggested to possess the potential to counteract cognitive decline and sustain cognitive abilities, particularly among patients at risk. Although still at a preliminary stage, research investigating the relations between cocoa and cognition shows dose dependent improvements in general cognition, attention, processing speed, and working memory. Moreover, cocoa flavanols administration could also enhance normal cognitive functioning and exert a protective role on cognitive performance and cardiovascular function specifically impaired by sleep loss, in healthy subjects. Together, these findings converge at pointing to cocoa as a new interesting nutraceutical tool to protect human cognition and counteract different types of cognitive decline, thus encouraging further investigations. Future research should include complex experimental designs combining neuroimaging techniques with physiological and behavioral measures to better elucidate cocoa neuromodulatory properties and directly compare immediate versus long-lasting cognitive effects. PMID- 28560214 TI - Clinical and Histopathological Findings of Frontal Fibrosing Alopecia-Associated Lichen Planus Pigmentosus. AB - BACKGROUND: Frontal fibrosing alopecia (FFA) is a primary lymphocytic scarring alopecia occurring mainly in postmenopausal women. A range of facial lesions have been described in FFA, such as lichen planus (LP) pigmentosus, red dots, facial papules, and perifollicular and diffuse erythema. These lesions can be the first sign of FFA. LP pigmentosus is a rare variant of LP. The first description of LP pigmentosus associated with FFA (in 2012) reported 22 cases of LP pigmentosus among 44 cases of FFA affecting South African patients. METHODS: We reviewed 16 FFA patients with LP pigmentosus and the histopathological findings of the biopsy of LP pigmentosus in 9 patients. RESULTS: Most patients had intermediate skin phototypes (III-IV; n = 10; 62%). The age at onset of LP pigmentosus ranged from 30 to 60 years. The most common histopathological findings were epidermal atrophy, basal cell degeneration, interfollicular inflammatory infiltrate and melanophages, and perifollicular changes. Other findings not previously described in LP pigmentosus were inflammation and interface changes on sweat duct epithelia (acrosyringium and superior dermal duct), and lichenoid perisebaceitis. CONCLUSIONS: Histology of our cases confirmed previous findings and showed a high incidence of perifollicular involvement with occasional changes affecting sebaceous and sweat glands. PMID- 28560213 TI - Tetrabutylphosphonium Bromide Reduces Size and Polydispersity Index of Tat2:siRNA Nano-Complexes for Triticale RNAi. AB - Cell-penetrating peptides (CPPs) are short 8-30 amino-acid oligopeptides that act as effective transducers of macromolecular cargo, particularly nucleic acids. They have been implemented in delivering dsDNA, ssDNA, and dsRNA into animal and plant cells. CPPs and nucleic acids form nano-complexes that are often 100-300 nm in size but still effectively transit the cell membrane of animal cells, but are less effective with plant cells due to the plant cell wall. To overcome this obstacle, nano-complexes of the CPP Tat2 and various lengths of nucleic acid (21 mer siRNA duplex (dsRNA) to ~5.5 kb circular plasmid) were evaluated for size using dynamic light scattering (DLS), under conditions of increasing ionic strength (Ic) and addition of phase transfer catalyst salts (tetrabutylammonium bromide-TBAB and tetrabutylphosphonium bromide-TBPB) and sugars (maltose-mannitol solution). It was found that the combination of 21-mer siRNA:Tat2 complexes with TBPB produced small 10-20 nm diameter nano-complexes with a polydispersity index (PDI) of ~0.1. Furthermore, it was found that for each length of nucleic acid that a linear mathematical relationship existed between the theoretical volume of the nano-complex and the nucleic acid length. Next, nano-complex formulation was tested for its ability to carry small interfering RNA molecules into plant cells and to trigger silencing of phytoene desaturase (PDS) in Triticale leaves. RT qPCR showed 75% suppression of PDS, demonstrating that TBPB acts as an adjuvant in effecting the entry and efficacy of siRNA in young Triticale plants. PMID- 28560215 TI - Temporal Triangular Alopecia in Children: The Same Clinical Feature for Two Distinct Entities. PMID- 28560216 TI - A Painful Periungual Red Spot in a Patient with Onychodystrophy. PMID- 28560217 TI - Dermoscopy in the Evaluation of Nail Disorders. AB - Nail dermoscopy was initially used only in the assessment of nail pigmentation, but now it is widely utilized for the evaluation of many nail disorders. In daily practice, dermoscopy may confirm clinical diagnoses and guides in the management of nail diseases and treatments, permitting a better visualization of symptoms. Dry dermoscopy is required for evaluation of the nail plate surface, while gel as an interface is necessary for assessment of nail pigmentation and onycholysis, as well as for the evaluation of the distal nail margin. In this review, we describe the dermoscopic features of the most important nail disorders, looking at the different areas of the nail. Dermatoscopic changes that usually accompany specific nail diseases are also reviewed. PMID- 28560218 TI - Dermoscopic Analysis of Nevus Sebaceus of Jadassohn: A Study of 13 Cases. AB - BACKGROUND: Nevus sebaceus of Jadassohn (NSJ) is a complex cutaneous hamartoma with various clinical appearances. AIM: To describe different dermoscopic patterns of this nevus according to its evolutionary stages. METHODS: This was an analytical study of NSJ carried out in the Department of Dermatology at the University Hospital Hassan II, Fez, Morocco. RESULTS: Thirteen patients with a NSJ were enrolled in the study. Elevated verrucous plaques were noticed in 9 patients, homogeneous tumors were described in 2 NSJ, an alopecic patch was found in 1 case, and we had 1 case of malignant transformation into basal cell carcinoma. The dermoscopic aspects of NSJ described in our study were yellowish or brown globules aggregated in clusters on a yellow background. This pattern was significantly related to the first stage of an alopecic patch (p = 0.001). Whitish-yellow lobular aspect and grayish papillary appearance were significantly related to verrucous plaques (p = 0.003). Homogeneous yellow-whitish pattern was related to nodules (p = 0.005). CONCLUSION: The establishment of specific dermoscopic features of NSJ according to its evolutionary stages is important for its diagnosis and especially its monitoring in order to detect malignant transformation. PMID- 28560219 TI - Atypical Localization of Necrobiosis Lipoidica: Involvement of the Face and Scalp. PMID- 28560221 TI - Successful Treatment of Facial Papules in Frontal Fibrosing Alopecia with Oral Isotretinoin. PMID- 28560222 TI - A Birth Cohort Analysis to Study Dog Walking in Adolescence Shows No Relationship with Objectively Measured Physical Activity. AB - Physical inactivity during childhood and adolescence is a serious health concern. There are few studies of the activity undertaken by adolescents when walking with the family dog, and the effect of this on objectively measured physical activity levels. Objective measures of physical activity using accelerometers were recorded at age 11-12, 13-14, and 15-16 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) (ALSPAC, UK) birth cohort during the 2000s. Family pet ownership was collected retrospectively using a questionnaire at age 18 years, for the ages 7, 11, 13, and 15 years. In addition, approximate frequency per week of walks undertaken with dogs were also reported. Multilevel, multivariable modeling was used to investigate the relationship between dog ownership and dog walking status, and physical activity outcomes. There were a total of 4,373 complete data observations for use in 2,055 children. Reported participation in dog walking tended to increase during adolescence, as did dog ownership. The majority of who own dogs reported walking them either 2-6 times/week (range 39-46%) or never (range 27-37%). A small minority (7-8%) reported walking their dog every day. Most reported never walking any other dog either (94-87%). We found no evidence for an association between dog ownership or reported dog walking, and objectively measured physical activity (counts per minute, P = 0.3, or minutes of moderate-to-vigorous physical activity, P = 0.7) during adolescence. This study provides no evidence to support a relationship between adolescent dog ownership and physical activity, and demonstrates the importance of using objective activity measures and considering dog walking rather than just dog ownership. PMID- 28560224 TI - Volume and Quality in Visceral Medicine. PMID- 28560220 TI - Medical and Surgical Treatment of Hidradenitis Suppurativa: A Review. AB - Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease presenting with painful nodules, abscesses, sinus tracts, and scarring primarily affecting apocrine gland-rich intertriginous areas. HS prevalence ranges from 0.05 to 1%. The central pathogenic event in HS is believed to be the occlusion of the upper part of the folliculopilosebaceous unit, leading to the rupture of the sebofollicular canal with the consequent development of perifollicular lymphohistiocytic inflammation. The HS treatment choices are influenced by disease severity and its individual subjective impact, involving both medical and surgical interventions. However, given the chronic nature of HS, its destructive impact on social, working, and daily life of patients, its management is often frustrating for both the patient and physician. Hence, prompt and effective management strategies are urgently needed and a multidisciplinary approach is advocated. Therefore, in this article, we highlighted the main features of HS (clinical aspects, epidemiology, pathogenesis, diagnostic criteria, classifications, comorbidities, and treatments), so that awareness of this disease might be heightened in primary care physicians and surgeons, who may be the first health care providers to see patients with this disease owing to its characteristic clinical presentation (inflammatory nodules, abscesses, sinus tract, etc.). PMID- 28560223 TI - Epidemiological and Economic Evaluation of Alternative On-Farm Management Scenarios for Ovine Footrot in Switzerland. AB - Footrot is a multifactorial infectious disease mostly affecting sheep, caused by the bacteria Dichelobacter nodosus. It causes painful feet lesions resulting in animal welfare issues, weight loss, and reduced wool production, which leads to a considerable economic burden in animal production. In Switzerland, the disease is endemic and mandatory coordinated control programs exist only in some parts of the country. This study aimed to compare two nationwide control strategies and a no intervention scenario with the current situation, and to quantify their net economic effect. This was done by sequential application of a maximum entropy model (MEM), epidemiological simulation, and calculation of net economic effect using the net present value method. Building upon data from a questionnaire, the MEM revealed a nationwide footrot prevalence of 40.2%. Regional prevalence values were used as inputs for the epidemiological model. Under the application of the nationwide coordinated control program without (scenario B) and with (scenario C) improved diagnostics [polymerase chain reaction (PCR) test], the Swiss-wide prevalence decreased within 10 years to 14 and 5%, respectively. Contrary, an increase to 48% prevalence was observed when terminating the current control strategies (scenario D). Management costs included labor and material costs. Management benefits included reduction of fattening time and improved animal welfare, which is valued by Swiss consumers and therefore reduces societal costs. The net economic effect of the alternative scenarios B and C was positive, the one of scenario D was negative and over a period of 17 years quantified at CHF 422.3, 538.3, and -172.3 million (1 CHF = 1.040 US$), respectively. This implies that a systematic Swiss-wide management program under the application of the PCR diagnostic test is the most recommendable strategy for a cost-effective control of footrot in Switzerland. PMID- 28560225 TI - Minimum Volume Standards in Surgery - Are We There Yet? AB - The quality of surgery is directly dependent on the quantity, more specifically, on the number of operations performed at a given hospital as well as on the designated surgeon. This fact is supported by numerous studies and meta-analyses that will be presented in the following text. Most of the convincing data for complex procedures can be obtained from visceral (upper and lower gastrointestinal) surgery studies. Mortality of large oncological procedures, such as esophageal or pancreatic surgery, can be reduced by 50% if a certain number of interventions are guaranteed per year. Centralizing these operations performed by specialized surgeons is the key to success. This also ensures that the minimum volume amounts within a given hospital are well above the required levels, thus enabling to teach the necessary expertise step by step. The obligatory 'learning curve' for complex interventions cannot be completed within the framework of reference figures during residency training. Together, surgeons and their respective societies have introduced a proposal for efficient case oriented centralized surgery. Whether 'we are there yet' in surgery will depend in the end on how these efforts will be incorporated into administrative requirements and the guidelines that will then be implemented across the board. PMID- 28560226 TI - Dimensions of Quality and Their Increasing Relevance for Visceral Medicine in Germany. AB - BACKGROUND: 'Quality in medicine' is a term used in a broad sense. In this work the definition and dimensions of quality in medicine and the implementation of a measurement and reporting system in Germany are discussed. Existing applications are described and possible future effects are pointed out. METHODS: The ongoing process of implementing a quality reporting system into the German healthcare system is studied by publicly available legal texts, published reactions of stakeholders and publications of G-BA and IQTIG. Definitions of quality, dimensions of quality and quality measurement in medicine are studied by using textbooks as well as the world wide web and PubMed search. RESULTS: Donabedian's 'dimensions of quality' are fundamental in dealing with quality in medicine. Existing measurement and reporting systems have immanent strengths and weaknesses, as the definition of quality is affected by one's point of view. The legislator will have to decide which 'dimension of quality' is mandatory and how to measure it. CONCLUSION: Quality has become a control instrument with unforeseeable consequences. A clear definition of the used quality concept is as essential as the use of feasible measurement and reporting systems. The use of routine data could be an interesting option. PMID- 28560227 TI - Quality Indicators in Pancreatic Surgery: Lessons Learned from the German DGAV StuDoQ|Pancreas Registry. AB - BACKGROUND: Political and public interest in quality management in surgery is increasing. The German Society for General and Visceral Surgery (DGAV) established the DGAV StuDoQ, a nationwide registry for quality assessment in visceral surgery, with the organ-specific module DGAV StuDoQ|Pancreas. The first prerequisite for the measurement of quality is the definition of quality indicators. These can be related to risk factors which are also documented in the registry. METHODS: Quality indicators for pancreatic surgery were developed by review of the current literature and expert consensus. After ranking the potential quality indicators, three essential indicators for outcome quality were selected for further review of the literature. Current figures were extracted from the DGAV StuDoQ|Pancreas registry and the correlation with selected risk factors was tested. RESULTS: Three essential outcome quality indicators were selected: in-hospital mortality, TV30, and severe complications according to the Clavien-Dindo Classification. Preliminary data confirms the validity of risk factors included in the DGAV StuDoQ|Pancreas registry. CONCLUSION: Essential quality indicators were defined for pancreatic surgery. The DGAV StuDoQ|Pancreas constitutes a valid platform for risk-adjusted quality assessment in Germany. PMID- 28560228 TI - Influence of Hospital Volume Effects and Minimum Caseload Requirements on Quality of Care in Pancreatic Surgery in Germany. AB - INTRODUCTION: Numerous international studies have identified hospital volume as significant independent variable of death following pancreatic surgery. Most of these studies were limited to regions of countries or portions of a national population and did not include data on volume-outcome effects in Germany. METHODS: The Medline database was systematically searched to identify studies that analyzed volume-outcome relationships and effects of minimum caseload requirements on outcomes of pancreatic surgery in Germany. RESULTS: Recent observational studies utilizing German hospital discharge data confirmed that patients undergoing pancreatic surgery in Germany also have better outcomes when treated in facilities with high annual caseloads. Besides a decreased risk of in hospital mortality, there is also a reduced risk of 1-year mortality in high volume hospitals. In addition, there is evidence that adherence to already existing minimum caseload requirements reduces morbidity and mortality of pancreatic surgery in Germany. As a result of an insufficient centralization in the recent past, however, a large proportion of hospitals that perform pancreatic surgery still do not meet minimum caseload requirements. CONCLUSIONS: Specific measures (i.e. sanctions for failure to achieve minimum volumes) that initiate a sufficient centralization process without threatening patient access to surgical care are needed. PMID- 28560229 TI - Is There a Rationale for Structural Quality Assurance in Esophageal Surgery? AB - BACKGROUND: Advances regarding perioperative mortality rates and oncological outcomes after esophagectomy have been reported extensively by specialized high volume centers in Europe and the USA over the last decade. However, recent database analyses reveal that the perioperative mortality of esophagectomy remains high in these countries, indicating a discrepancy between surgical quality in baseline hospitals and specialized centers. METHODS: This article provides an overview over the existing literature on the correlation between structural quality, procedural volume, and surgical outcome in e- sophageal surgery. RESULTS: Structural, procedural and outcome measures can be used to assess the quality of surgical treatment and perioperative management. Surgical procedures on the esophagus for both benign and malignant diseases are rare and typically associated with high perioperative morbidity and mortality. Usually, direct outcome measures do not provide enough statistical power to actually identify differences in surgical quality between hospitals, making structural quality measures the only feasible parameter to compare the quality of e- sophageal surgery among different centers. Several analyses from different countries have shown a strong correlation between hospital volume and postoperative mortality. Data from countries in which esophageal surgery has been centralized indicate beneficial effects of a centralized health care system on postoperative mortality after esophagectomy. Additionally, only high-volume centers generally provide optimal preoperative and postoperative management and comprehensive access to modern multimodal treatment. In Germany, esophageal surgery is still decentralized, but hospitals performing complex esophageal procedures have to fulfill minimum caseload requirements of 10 cases per year. In practice, these requirements are not met by the majority of hospitals and a detrimental effect on the achieved surgical outcomes can be noted. CONCLUSION: Therefore, we conclude that structural quality assurance is crucial to further reduce postoperative morbidity after esophageal surgery and to improve long-term results. PMID- 28560230 TI - Minimum Volume Discussion in the Treatment of Colon and Rectal Cancer: A Review of the Current Status and Relevance of Surgeon and Hospital Volume regarding Result Quality and the Impact on Health Economics. AB - BACKGROUND: To answer the question whether minimum caseloads need to be stipulated in the German S3 (or any other) guidelines for colorectal cancer, we analyzed the current representative literature. The question is important regarding medical quality as well as health economics and policy. METHODS: A literature research was conducted in PubMed for papers concerning 'colon cancer' (CC), 'rectal cancer' (RC), and 'colorectal cancer' (CRC), with 'results', 'quality', and 'mortality' between the years 2000 and 2016 being relevant factors. We graded the recommendations as 'pro', 'maybe', or 'contra' in terms of a significant correlation between hospital volume (HV) or surgeon volume (SV) and treatment quality. We also listed the recommended numbers suggested for HV or SV as minimum caseloads and calculated and discussed the socio-economic impact of setting minimum caseloads for CRC. RESULTS: The correlations of caseloads of hospitals or surgeons turned out to be highly controversial concerning the influence of HV or SV on short- and long-term surgical treatment quality of CRC. Specialized statisticians made the point that the reports in the literature might not use the optimal biometrical analytical/reporting methods. A Dutch analysis showed that if a decision towards minimum caseloads, e.g. >50 for CRC resections, would be made, this would exclude a lot of hospitals with proven good treatment quality and include hospitals with a treatment quality below average. Our economic analysis envisioned that a yearly loss of EUR <830,000 might ensue for hospitals with volumes <50 per year. CONCLUSIONS: Caseload (HV, SV) definitely is an inconsistent surrogate parameter for treatment quality in the surgery of CC, RC, or CRC. If used at all, the lowest tolerable numbers but the highest demands for structural, process and result quality in the surgical/interdisciplinary treatment of CC and RC must be imposed and independently controlled. Hospitals fulfilling these demands should be medically and socio-economically preferred concerning the treatment of CC and RC patients. PMID- 28560231 TI - Arguments for and against Centralization in Oncologic Visceral Medicine. PMID- 28560232 TI - The Microbiome in Visceral Medicine: Inflammatory Bowel Disease, Obesity and Beyond. AB - It has become increasingly evident over the past two decades that the microbiota plays a nurturing role in the development of the immune system. This appears to be important since the amplitude of immune responses has a crucial regulatory function in homeostasis and the prevention of unwanted inflammation. Hence, a malfunctioning gut flora has been shown to play a key role in visceral medicine. Strong evidence demonstrates for example that intestinal inflammation can develop as a result of a dysregulated microbiota, deficient antimicrobial responses, and aberrant bacterial translocation into the bowel wall. In healthy individuals, the bacterial translocation is blocked by a single layer of highly specialized intestinal epithelial cells which forms a strong barrier that lines the gut wall. This structure is responsible for an efficient absorption of nutrients while keeping the luminal flora at bay. In susceptible individuals, for yet incompletely understood reasons, either defective epithelial barrier function or dysregulated microbial composition or microbial pathogens drive intestinal inflammation. Many therapeutic strategies focusing on the modulation of the microbiota have been proposed recently but future research including prospective human studies and gnotobiotic mouse models are still needed to evaluate the contribution and potential therapeutic value of individual bacteria to human health. PMID- 28560234 TI - Robotic single-site supracervical hysterectomy with manual morcellation: Preliminary experience. AB - AIM: To evaluate the feasibility, safety and peri- and postoperative outcomes of robotic single-site supracervical hysterectomy (RSSSH) for benign gynecologic disease. METHODS: We report 3 patients who received RSSSH for adenomyosis of the uterus from November 2015 to April 2016. We evaluated the feasibility, safety and outcomes among these patients. RESULTS: The mean surgical time was 244 min and the estimated blood loss was 216 mL, with no blood transfusion necessitated. The docking time was shortened gradually from 30 to 10 min. We spent 148 min on console operation. Manual morcellation time was also short, ranging from 5 to 10 min. The mean hospital stay was 5 d. Lower VAS pain score was also noted. There is no complication during or after surgery. CONCLUSION: RSSSH is feasible and safe, incurs less postoperative pain and gives good cosmetic appearance. The technique of in-bag, manual morcellation can avoid tumor dissemination. PMID- 28560235 TI - Ticagrelor therapy and atrioventricular block: Do we need to worry? AB - Ticagrelor is a potent, direct P2Y12 antagonist with rapid onset of action and intense platelet inhibition, indicated in patients with acute coronary syndromes (ACS). This drug is usually well tolerated, but some patients experience serious adverse effects: Major bleeding; gastrointestinal disturbances; dyspnoea; ventricular pauses > 3 s. Given the unexpected high incidence of bradyarrhythmias, a PLATO substudy monitored this side effect, showing that ticagrelor was associated with an increase in the rate of sinus bradycardia and sinus arrest compared to clopidogrel. This side effect was usually transient, asymptomatic and not associated with higher incidence of severe atrioventricular (AV) block or pacemaker needs. A panel of experts from Food and Drug Administration did not consider bradyarrhythmias a serious problem in clinical practice and, accordingly, current labeling of the drug does not give any precaution or contraindication regarding this issue. However, recently some articles have described ACS patients with high-degree, life-threatening, AV block requiring drug discontinuation and, in some cases, pacemaker implantation. In this paper, we describe and discuss five published case reports of severe AV block following ticagrelor therapy and two other cases managed in our Hospital. The analysis of literature suggests that, although rarely, ticagrelor can be associated with life-threatening AV block. Caution and careful monitoring are required especially in patients with already compromised conduction system and/or treated with AV blocking agents. Future studies, with long-term rhythm monitoring, would help to define the outcome of patients at higher risk of developing this complication. PMID- 28560233 TI - Evolution, current status and advances in application of platelet concentrate in periodontics and implantology. AB - Platelet concentrates (PC) [platelet-rich plasma (PRP) and platelet-rich fibrin (PRF)] are frequently used for surgical procedures in medical and dental fields, particularly in oral and maxillofacial surgery, plastic surgery and sports medicine. The objective of all these technologies is to extract all the elements from a blood sample that could be used to improve healing and promote tissue regeneration. Although leukocyte rich and leukocyte poor PRP's have their own place in literature, the importance of non-platelet components in a platelet concentrate remains a mystery. PC have come a long way since its first appearance in 1954 to the T-PRF, A-PRF and i-PRF introduced recently. These PC find varied applications successfully in periodontics and implant dentistry as well. However, the technique of preparation, standing time, transfer process, temperature of centrifuge, vibration, etc., are the various factors for the mixed results reported in the literature. Until the introduction of a proper classification of terminologies, the PC were known by different names in different countries and by different commercial companies which also created a lot of confusion. This review intends to clarify all these confusion by briefing the exact evolution of PC, their preparation techniques, recent advances and their various clinical and technical aspects and applications. PMID- 28560236 TI - Unusual presentation of nasopharyngeal carcinoma with rectal metastasis. AB - Nasopharyngeal carcinoma (NPC) is a rare tumour that mainly metastasizes in lymph nodes, bones, lungs and liver. Colorectal metastases of NPC are extremely rare phenomenon and associated with a poor prognosis. We reported here a case of NPC with rectal metastasis, we discussed the treatment modalities and the prognosis after reviewing the similar cases described in the literature. PMID- 28560237 TI - Elizabethkingia miricola: A rare non-fermenter causing urinary tract infection. AB - Elizabethkingia miricola (E. miricola) is a gram-negative non-fermentative bacterium which is rarely encountered. It is usually misidentified or considered as a contaminant in routine microbiology laboratories due to the limitations in conventional biochemical techniques. However, with the advent of the matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), the identification of non-fermenters has become easy and this has led to enhanced understanding of the clinical significance of these uncommonly isolated microorganisms. The genus Elizabethkingia has only two species E. meningoseptica and E. miricola. Both of these organisms are known to be multi-drug resistant and therefore, their accurate identification and antimicrobial susceptibility testing are necessary prior to the initiation of appropriate therapy. In the world literature till date, only 3 cases of sepsis caused by E. miricola have been reported. We present the first case of E. miricola association with urinary tract infection. PMID- 28560238 TI - High PD-1 expression on regulatory and effector T-cells in lung cancer draining lymph nodes. AB - The treatment of advanced nonsmall cell lung cancer (NSCLC) with PD-1/PD-L1 immune checkpoint inhibitors has improved clinical outcome for a proportion of patients. The current challenge is to find better biomarkers than PD-L1 immunohistochemistry (IHC) that will identify patients likely to benefit from this therapy. In this exploratory study we assessed the differences in T-cell subsets and PD-1 expression levels on T-cells in tumour-draining lymph nodes (TDLNs) and peripheral blood mononuclear cells (PBMCs). To evaluate this, flow cytometric analyses were performed on endobronchial ultrasound-guided (EBUS) fine needle aspirates (FNA) from TDLNs of patients with NSCLC, and the results were compared to paired PBMC samples. For a select number of patients, we were also able to obtain cells from a non-TDLN (NTDLN) sample. Our data show that the frequency of PD-1+ CD4+ and CD8+ T-cells, as well as the PD-1 expression level on activated regulatory T (aTreg) and CD4+ and CD8+ T-cells, are higher in TDLNs than in PBMCs and, in a small sub-analysis, NTDLNs. These elevated PD-1 expression levels in TDLNs may reflect tumour-specific T-cell priming and conditioning, and may serve as a predictive or early-response biomarker during PD 1 checkpoint blockade. PMID- 28560239 TI - Image reconstruction of oxidized cerebral cytochrome C oxidase changes from broadband near-infrared spectroscopy data. AB - In diffuse optical tomography (DOT), overlapping and multidistance measurements are required to reconstruct depth-resolved images of oxy- ([Formula: see text]) and deoxy- (HHb) hemoglobin concentration changes occurring in the brain. These can be considered an indirect measure of brain activity, under the assumption of intact neurovascular coupling. Broadband systems also allow changes in the redox state of cytochrome c oxidase (oxCCO) to be measured, which can be an important biomarker when neurovascular coupling is impaired. We used DOT to reconstruct images of [Formula: see text], [Formula: see text], and [Formula: see text] from data acquired with a broadband system. Four healthy volunteers were measured while performing a visual stimulation task (4-Hz inverting checkerboard). The broadband system was configured to allow multidistance and overlapping measurements of the participants' visual cortex with 32 channels. A multispectral approach was employed to reconstruct changes in concentration of the three chromophores during the visual stimulation. A clear and focused activation was reconstructed in the left occipital cortex of all participants. The difference between the residuals of the three-chromophore model and of the two-chromophore model (recovering only [Formula: see text] and [Formula: see text]) exhibits a spectrum similar to that of oxCCO. These results form a basis for further studies aimed to further optimize image reconstruction of [Formula: see text]. PMID- 28560240 TI - Mesoscale brain explorer, a flexible python-based image analysis and visualization tool. AB - Imaging of mesoscale brain activity is used to map interactions between brain regions. This work has benefited from the pioneering studies of Grinvald et al., who employed optical methods to image brain function by exploiting the properties of intrinsic optical signals and small molecule voltage-sensitive dyes. Mesoscale interareal brain imaging techniques have been advanced by cell targeted and selective recombinant indicators of neuronal activity. Spontaneous resting state activity is often collected during mesoscale imaging to provide the basis for mapping of connectivity relationships using correlation. However, the information content of mesoscale datasets is vast and is only superficially presented in manuscripts given the need to constrain measurements to a fixed set of frequencies, regions of interest, and other parameters. We describe a new open source tool written in python, termed mesoscale brain explorer (MBE), which provides an interface to process and explore these large datasets. The platform supports automated image processing pipelines with the ability to assess multiple trials and combine data from different animals. The tool provides functions for temporal filtering, averaging, and visualization of functional connectivity relations using time-dependent correlation. Here, we describe the tool and show applications, where previously published datasets were reanalyzed using MBE. PMID- 28560241 TI - Single-view geometric calibration for C-arm inverse geometry CT. AB - Accurate and artifact-free reconstruction of tomographic images requires precise knowledge of the imaging system geometry. A projection matrix-based calibration method to enable C-arm inverse geometry CT (IGCT) is proposed. The method is evaluated for scanning-beam digital x-ray (SBDX), a C-arm mounted inverse geometry fluoroscopic technology. A helical configuration of fiducials is imaged at each gantry angle in a rotational acquisition. For each gantry angle, digital tomosynthesis is performed at multiple planes and a composite image analogous to a cone-beam projection is generated from the plane stack. The geometry of the C arm, source array, and detector array is determined at each angle by constructing a parameterized three-dimensional-to-two-dimensional projection matrix that minimizes the sum-of-squared deviations between measured and projected fiducial coordinates. Simulations were used to evaluate calibration performance with translations and rotations of the source and detector. The relative root-mean square error in a reconstruction of a numerical thorax phantom was 0.4% using the calibration method versus 7.7% without calibration. In phantom studies, reconstruction of SBDX projections using the proposed method eliminated artifacts present in noncalibrated reconstructions. The proposed IGCT calibration method reduces image artifacts when uncertainties exist in system geometry. PMID- 28560242 TI - Segmented targeted least squares estimator for material decomposition in multibin photon-counting detectors. AB - We present a fast, noise-efficient, and accurate estimator for material separation using photon-counting x-ray detectors (PCXDs) with multiple energy bin capability. The proposed targeted least squares estimator (TLSE) is an improvement of a previously described A-table method by incorporating dynamic weighting that allows the variance to be closer to the Cramer-Rao lower bound (CRLB) throughout the operating range. We explore Cartesian and average-energy segmentation of the basis material space for TLSE and show that, compared with Cartesian segmentation, the average-energy method requires fewer segments to achieve similar performance. We compare the average-energy TLSE to other proposed estimators-including the gold standard maximum likelihood estimator (MLE) and the A-table-in terms of variance, bias, and computational efficiency. The variance and bias were simulated in the range of 0 to 6 cm of aluminum and 0 to 50 cm of water with Monte Carlo methods. The Average-energy TLSE achieves an average variance within 2% of the CRLB and mean absolute error of [Formula: see text]. Using the same protocol, the MLE showed variance within 1.9% of the CRLB ratio and average absolute error of [Formula: see text] but was 50 times slower in our implementations. Compared with the A-table method, TLSE gives a more homogenously optimal variance-to-CRLB ratio in the operating region. We show that variance in basis material estimates for TLSE is lower than that of the A-table method by as much as [Formula: see text] in the peripheral region of operating range (thin or thick objects). The TLSE is a computationally efficient and fast method for material separation with PCXDs, with accuracy and precision comparable to the MLE. PMID- 28560243 TI - Semiautomated biventricular segmentation in three-dimensional echocardiography by coupled deformable surfaces. AB - With the advancement of three-dimensional (3-D) real-time echocardiography in recent years, automatic creation of patient specific geometric models is becoming feasible and important in clinical decision making. However, the vast majority of echocardiographic segmentation methods presented in the literature focus on the left ventricle (LV) endocardial border, leaving segmentation of the right ventricle (RV) a largely unexplored problem, despite the increasing recognition of the RV's role in cardiovascular disease. We present a method for coupled segmentation of the endo- and epicardial borders of both the LV and RV in 3-D ultrasound images. To solve the segmentation problem, we propose an extension of a successful state-estimation segmentation framework with a geometrical representation of coupled surfaces, as well as the introduction of myocardial incompressibility to regularize the segmentation. The method was validated against manual measurements and segmentations in images of 16 patients. Mean absolute distances of [Formula: see text], [Formula: see text], and [Formula: see text] between the proposed and reference segmentations were observed for the LV endocardium, RV endocardium, and LV epicardium surfaces, respectively. The method was computationally efficient, with a computation time of [Formula: see text]. PMID- 28560244 TI - Toward real-time quantification of fluorescence molecular probes using target/background ratio for guiding biopsy and endoscopic therapy of esophageal neoplasia. AB - Multimodal endoscopy using fluorescence molecular probes is a promising method of surveying the entire esophagus to detect cancer progression. Using the fluorescence ratio of a target compared to a surrounding background, a quantitative value is diagnostic for progression from Barrett's esophagus to high grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). However, current quantification of fluorescent images is done only after the endoscopic procedure. We developed a Chan-Vese-based algorithm to segment fluorescence targets, and subsequent morphological operations to generate background, thus calculating target/background (T/B) ratios, potentially to provide real-time guidance for biopsy and endoscopic therapy. With an initial processing speed of 2 fps and by calculating the T/B ratio for each frame, our method provides quasireal-time quantification of the molecular probe labeling to the endoscopist. Furthermore, an automatic computer-aided diagnosis algorithm can be applied to the recorded endoscopic video, and the overall T/B ratio is calculated for each patient. The receiver operating characteristic curve was employed to determine the threshold for classification of HGD/EAC using leave-one-out cross-validation. With 92% sensitivity and 75% specificity to classify HGD/EAC, our automatic algorithm shows promising results for a surveillance procedure to help manage esophageal cancer and other cancers inspected by endoscopy. PMID- 28560245 TI - Assistive lesion-emphasis system: an assistive system for fundus image readers. AB - Computer-assisted diagnostic (CAD) tools are of interest as they enable efficient decision-making in clinics and the screening of diseases. The traditional approach to CAD algorithm design focuses on the automated detection of abnormalities independent of the end-user, who can be an image reader or an expert. We propose a reader-centric system design wherein a reader's attention is drawn to abnormal regions in a least-obtrusive yet effective manner, using saliency-based emphasis of abnormalities and without altering the appearance of the background tissues. We present an assistive lesion-emphasis system (ALES) based on the above idea, for fundus image-based diabetic retinopathy diagnosis. Lesion-saliency is learnt using a convolutional neural network (CNN), inspired by the saliency model of Itti and Koch. The CNN is used to fine-tune standard low level filters and learn high-level filters for deriving a lesion-saliency map, which is then used to perform lesion-emphasis via a spatially variant version of gamma correction. The proposed system has been evaluated on public datasets and benchmarked against other saliency models. It was found to outperform other saliency models by 6% to 30% and boost the contrast-to-noise ratio of lesions by more than 30%. Results of a perceptual study also underscore the effectiveness and, hence, the potential of ALES as an assistive tool for readers. PMID- 28560246 TI - Psychosis research in Asia: advantage from low prevalence of cannabis use. PMID- 28560247 TI - Enabling point-of-care testing and personalized medicine for schizophrenia. PMID- 28560248 TI - Personalized medicine for schizophrenia. PMID- 28560249 TI - Altered sulcogyral patterns of orbitofrontal cortex in a large cohort of patients with schizophrenia. AB - Abnormalities in prenatal brain development contribute to schizophrenia vulnerability. Orbitofrontal cortex sulcogyral patterns are largely determined during prenatal development, and four types of orbitofrontal cortex sulcogyral patterns have been classified in humans. Altered orbitofrontal cortex patterns have been reported in individuals with schizophrenia using magnetic resonance imaging; however, sample sizes of previous studies were small-medium effects for detection, and gender manifestation for orbitofrontal cortex sulcogyral patterns is unclear. The present study investigated orbitofrontal cortex patterns of 155 patients with schizophrenia and 375 healthy subjects. The orbitofrontal cortex sulcogyral pattern distributions of schizophrenia were significantly different compared with healthy subjects in the left hemisphere (chi2 = 14.55, p = 0.002). In female schizophrenia, post-hoc analyses revealed significantly decreased Type I expression (chi2 = 6.76, p = 0.009) and increased Type II expression (chi2 = 11.56, p = 0.001) in the left hemisphere. The present study suggested that female schizophrenia showed altered orbitofrontal cortex patterns in the left hemisphere, which may be related to neurodevelopmental abnormality. PMID- 28560250 TI - On discontinuing treatment in schizophrenia: a clinical conundrum. PMID- 28560251 TI - Effects of childhood and adolescence physical activity patterns on psychosis risk a general population cohort study. AB - Schizophrenia spectrum disorders are associated with high morbidity and mortality in somatic diseases. The risk factors of this excess mortality include, e.g., obesity, dietary factors, and physical inactivity, especially after the onset of psychosis, but there are limited early developmental data on these factors in individuals who later develop psychosis. A population-based cohort study "Cardiovascular Risk of Young Finns" started in 1980 with 3596 children and adolescents from six different age groups (3, 6, 9, 12, 15, and 18 years). Cardiovascular health parameters, including questionnaire of physical activity before first hospitalization (<=18 years), were studied in 1980, 1983, and 1986. All psychiatric diagnoses of the participants were derived from the Finnish Hospital Discharge Register up to the year 2012. We identified diagnostic groups of non-affective psychosis (n = 68, including a schizophrenia subgroup, n = 41), personality disorders (n = 43), affective disorders (n = 111), and substance related disorders (n = 49), based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed ition (DSM-IV). Groups were compared with controls with no psychiatric diagnoses (n = 3325). Sex, age, body mass index, birth weight, non preterm birth, and mother's mental disorders were included in the statistical model. Low physical activity in childhood and adolescence (9-18 years) independently predicted later development of non-affective psychosis. Lower physical activity index (relative risk 1.26 [1.1-1.5]), lower level of common activity during leisure time (relative risk 1.71 [1.2-2.5]), and non participation in sports competitions (relative risk 2.58 [1.3-5.3]) were associated with a higher risk for later non-affective psychosis (expressed as increase in relative risk per physical activity unit). The findings were even stronger for schizophrenia, but no such link was observed for other diagnoses. The cause of low physical activity in premorbid/prodromal phase is likely to be multifactorial, including deviant motor and cognitive development. The results provide a rationale for including exercise and physical activity interventions as a part of psychosis prevention programs. PMID- 28560252 TI - DNA methylation in schizophrenia in different patient-derived cell types. AB - DNA methylation of gene promoter regions represses transcription and is a mechanism via which environmental risk factors could affect cells during development in individuals at risk for schizophrenia. We investigated DNA methylation in patient-derived cells that might shed light on early development in schizophrenia. Induced pluripotent stem cells may reflect a "ground state" upon which developmental and environmental influences would be minimal. Olfactory neurosphere-derived cells are an adult-derived neuro-ectodermal stem cell modified by developmental and environmental influences. Fibroblasts provide a non neural control for life-long developmental and environmental influences. Genome wide profiling of DNA methylation and gene expression was done in these three cell types from the same individuals. All cell types had distinct, statistically significant schizophrenia-associated differences in DNA methylation and linked gene expression, with Gene Ontology analysis showing that the differentially affected genes clustered in networks associated with cell growth, proliferation, and movement, functions known to be affected in schizophrenia patient-derived cells. Only five gene loci were differentially methylated in all three cell types. Understanding the role of epigenetics in cell function in the brain in schizophrenia is likely to be complicated by similar cell type differences in intrinsic and environmentally induced epigenetic regulation. PMID- 28560255 TI - What if it was easier to prevent schizophrenia than to treat it? PMID- 28560256 TI - Schizophrenia genetics comes to translation. PMID- 28560253 TI - Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia. AB - The N-methyl-d-aspartate receptor hypofunction is one of the most prevalent models of schizophrenia. For example, healthy subjects treated with uncompetitive N-methyl-d-aspartate receptor antagonists elicit positive, negative, and cognitive-like symptoms of schizophrenia. Patients with anti-N-methyl-d-aspartate receptor encephalitis, which is likely caused by autoantibody-mediated down regulation of cell surface N-methyl-d-aspartate receptors, often experience psychiatric symptoms similar to schizophrenia initially. However, where and when N-methyl-d-aspartate receptor hypofunction occurs in the brain of schizophrenic patients is poorly understood. Here we review the findings from N-methyl-d aspartate receptor antagonist and autoantibody models, postmortem studies on N methyl-d-aspartate receptor subunits, as well as the global and cell-type specific knockout mouse models of subunit GluN1. We compare various conditional GluN1 knockout mouse strains, focusing on the onset of N-methyl-d-aspartate receptor deletion and on the cortical cell-types. Based on these results, we hypothesize that N-methyl-d-aspartate receptor hypofunction initially occurs in cortical GABAergic neurons during early postnatal development. The resulting GABA neuron maturation deficit may cause reduction of intrinsic excitability and GABA release, leading to disinhibition of pyramidal neurons. The cortical disinhibition in turn could elicit glutamate spillover and subsequent homeostatic down regulation of N-methyl-d-aspartate receptor function in pyramidal neurons in prodromal stage. These two temporally-distinct N-methyl-d-aspartate receptor hypofunctions may be complimentary, as neither alone may not be able to fully explain the entire schizophrenia pathophysiology. Potential underlying mechanisms for N-methyl-d-aspartate receptor hypofunction in cortical GABA neurons are also discussed, based on studies of naturally-occurring N-methyl-d-aspartate receptor antagonists, neuregulin/ErbB4 signaling pathway, and theoretical analysis of excitatory/inhibitory balance. PMID- 28560254 TI - Unravelling socio-motor biomarkers in schizophrenia. AB - We present novel, low-cost and non-invasive potential diagnostic biomarkers of schizophrenia. They are based on the 'mirror-game', a coordination task in which two partners are asked to mimic each other's hand movements. In particular, we use the patient's solo movement, recorded in the absence of a partner, and motion recorded during interaction with an artificial agent, a computer avatar or a humanoid robot. In order to discriminate between the patients and controls, we employ statistical learning techniques, which we apply to nonverbal synchrony and neuromotor features derived from the participants' movement data. The proposed classifier has 93% accuracy and 100% specificity. Our results provide evidence that statistical learning techniques, nonverbal movement coordination and neuromotor characteristics could form the foundation of decision support tools aiding clinicians in cases of diagnostic uncertainty. PMID- 28560257 TI - Generating testable hypotheses for schizophrenia and rheumatoid arthritis pathogenesis by integrating epidemiological, genomic, and protein interaction data. AB - Patients with schizophrenia and their relatives have reduced prevalence of rheumatoid arthritis. Schizophrenia and rheumatoid arthritis genome-wide association studies also indicate negative genetic correlations, suggesting that there may be shared pathogenesis at the DNA level or downstream. A portion of the inverse prevalence could be attributed to pleiotropy, i.e., variants of a single nucleotide polymorphism that could confer differential risk for these disorders. To study the basis for such an interrelationship, we initially compared lists of single nucleotide polymorphisms with significant genetic associations (p < 1e-8) for schizophrenia or rheumatoid arthritis, evaluating patterns of linkage disequilibrium and apparent pleiotropic risk profiles. Single nucleotide polymorphisms that conferred risk for both schizophrenia and rheumatoid arthritis were localized solely to the extended HLA region. Among single nucleotide polymorphisms that conferred differential risk for schizophrenia and rheumatoid arthritis, the majority were localized to HLA-B, TNXB, NOTCH4, HLA-C, HCP5, MICB, PSORS1C1, and C6orf10; published functional data indicate that HLA-B and HLA-C have the most plausible pathogenic roles in both disorders. Interactomes of these eight genes were constructed from protein-protein interaction information using publicly available databases and novel computational predictions. The genes harboring apparently pleiotropic single nucleotide polymorphisms are closely connected to rheumatoid arthritis and schizophrenia associated genes through common interacting partners. A separate and independent analysis of the interactomes of rheumatoid arthritis and schizophrenia genes showed a significant overlap between the two interactomes and that they share several common pathways, motivating functional studies suggesting a relationship in the pathogenesis of schizophrenia/rheumatoid arthritis. PMID- 28560259 TI - DNA methylation evidence against the accelerated aging hypothesis of schizophrenia. AB - The accelerated aging hypothesis of schizophrenia posits that physiological changes throughout the body that are associated with normal aging occur at an earlier age in individuals with schizophrenia. Testing this hypothesis has been limited by problems measuring biological age. Recently, a method using DNA methylation levels at 353 genomic sites to produce "DNA methylation age", an estimate of tissue biological age, was described and validated. We used this method to test the hypothesis in the postmortem superior temporal gyrus of 22 non psychiatric control and 22 schizophrenia subjects. DNA methylation age correlated with chronological age in both non-psychiatric control (r = 0.95, p < 0.0001) and schizophrenia subjects (r = 0.96, p < 0.0001). Age acceleration did not differ between non-psychiatric control and schizophrenia subjects (t = 1.27, p = 0.21). Our findings suggest there is no acceleration of brain aging in schizophrenia. Larger studies using samples from multiple brain regions and homogenous cell populations will be necessary to confirm these findings. PMID- 28560258 TI - Vulnerability to omega-3 deprivation in a mouse model of NMDA receptor hypofunction. AB - Several studies have found decreased levels of omega-3 polyunsaturated fatty acids in the brain and blood of schizophrenia patients. Furthermore, dietary omega-3 supplements may improve schizophrenia symptoms and delay the onset of first-episode psychosis. We used an animal model of NMDA receptor hypofunction, NR1KD mice, to understand whether changes in glutamate neurotransmission could lead to changes in brain and serum fatty acids. We further asked whether dietary manipulations of omega-3, either depletion or supplementation, would affect schizophrenia-relevant behaviors of NR1KD mice. We discovered that NR1KD mice have elevated brain levels of omega-6 fatty acids regardless of their diet. While omega-3 supplementation did not improve any of the NR1KD behavioral abnormalities, omega-3 depletion exacerbated their deficits in executive function. Omega-3 depletion also caused extreme mortality among male mutant mice, with 75% mortality rate by 12 weeks of age. Our studies show that alterations in NMDAR function alter serum and brain lipid composition and make the brain more vulnerable to dietary omega-3 deprivation. PMID- 28560260 TI - Science of recovery in schizophrenia research: brain and psychological substrates of personalized value. PMID- 28560262 TI - Decreased free d-aspartate levels are linked to enhanced d-aspartate oxidase activity in the dorsolateral prefrontal cortex of schizophrenia patients. AB - It is long acknowledged that the N-methyl d-aspartate receptor co-agonist, d serine, plays a crucial role in several N-methyl d-aspartate receptor-mediated physiological and pathological processes, including schizophrenia. Besides d serine, another free d-amino acid, d-aspartate, is involved in the activation of N-methyl d-aspartate receptors acting as an agonist of this receptor subclass, and is abundantly detected in the developing human brain. Based on the hypothesis of N-methyl d-aspartate receptor hypofunction in the pathophysiology of schizophrenia and considering the ability of d-aspartate and d-serine to stimulate N-methyl d-aspartate receptor-dependent transmission, in the present work we assessed the concentration of these two d-amino acids in the post-mortem dorsolateral prefrontal cortex and hippocampus of patients with schizophrenia and healthy subjects. Moreover, in this cohort of post-mortem brain samples we investigated the spatiotemporal variations of d-aspartate and d-serine. Consistent with previous work, we found that d-aspartate content was selectively decreased by around 30% in the dorsolateral prefrontal cortex, but not in the hippocampus, of schizophrenia-affected patients, compared to healthy subjects. Interestingly, such selective reduction was associated to greater (around 25%) cortical activity of the enzyme responsible for d-aspartate catabolism, d aspartate oxidase. Conversely, no significant changes were found in the methylation state and transcription of DDO gene in patients with schizophrenia, compared to control individuals, as well as in the expression levels of serine racemase, the major enzyme responsible for d-serine biosynthesis, which also catalyzes aspartate racemization. These results reveal the potential involvement of altered d-aspartate metabolism in the dorsolateral prefrontal cortex as a factor contributing to dysfunctional N-methyl d-aspartate receptor-mediated transmission in schizophrenia. PMID- 28560261 TI - Brain structure, function, and neurochemistry in schizophrenia and bipolar disorder-a systematic review of the magnetic resonance neuroimaging literature. AB - Since Emil Kraepelin's conceptualization of endogenous psychoses as dementia praecox and manic depression, the separation between primary psychotic disorders and primary affective disorders has been much debated. We conducted a systematic review of case-control studies contrasting magnetic resonance imaging studies in schizophrenia and bipolar disorder. A literature search in PubMed of studies published between January 2005 and December 2016 was conducted, and 50 structural, 29 functional, 7 magnetic resonance spectroscopy, and 8 combined imaging and genetic studies were deemed eligible for systematic review. Structural neuroimaging studies suggest white matter integrity deficits that are consistent across the illnesses, while gray matter reductions appear more widespread in schizophrenia compared to bipolar disorder. Spectroscopy studies in cortical gray matter report evidence of decreased neuronal integrity in both disorders. Functional neuroimaging studies typically report similar functional architecture of brain networks in healthy controls and patients across the psychosis spectrum, but find differential extent of alterations in task related activation and resting state connectivity between illnesses. The very limited imaging-genetic literature suggests a relationship between psychosis risk genes and brain structure, and possible gene by diagnosis interaction effects on functional imaging markers. While the existing literature suggests some shared and some distinct neural markers in schizophrenia and bipolar disorder, it will be imperative to conduct large, well designed, multi-modal neuroimaging studies in medication-naive first episode patients that will be followed longitudinally over the course of their illness in an effort to advance our understanding of disease mechanisms. PMID- 28560264 TI - Thought disorder measured as random speech structure classifies negative symptoms and schizophrenia diagnosis 6 months in advance. AB - In chronic psychotic patients, word graph analysis shows potential as complementary psychiatric assessment. This analysis relies mostly on connectedness, a structural feature of speech that is anti-correlated with negative symptoms. Here we aimed to verify whether speech disorganization during the first clinical contact, as measured by graph connectedness, can correctly classify negative symptoms and the schizophrenia diagnosis 6 months in advance. Positive and negative syndrome scale scores and memory reports were collected from 21 patients undergoing first clinical contact for recent-onset psychosis, followed for 6 months to establish diagnosis, and compared to 21 well-matched healthy subjects. Each report was represented as a word-trajectory graph. Connectedness was measured by number of edges, number of nodes in the largest connected component and number of nodes in the largest strongly connected component. Similarities to random graphs were estimated. All connectedness attributes were combined into a single Disorganization Index weighted by the correlation with the positive and negative syndrome scale negative subscale, and used for classifications. Random-like connectedness was more prevalent among schizophrenia patients (64 * 5% in Control group, p = 0.0002). Connectedness from two kinds of memory reports (dream and negative image) explained 88% of negative symptoms variance (p < 0.0001). The Disorganization Index classified low vs. high severity of negative symptoms with 100% accuracy (area under the receiver operating characteristic curve = 1), and schizophrenia diagnosis with 91.67% accuracy (area under the receiver operating characteristic curve = 0.85). The index was validated in an independent cohort of chronic psychotic patients and controls (N = 60) (85% accuracy). Thus, speech disorganization during the first clinical contact correlates tightly with negative symptoms, and is quite discriminative of the schizophrenia diagnosis. PMID- 28560263 TI - Dopamine D2 receptors and the circadian clock reciprocally mediate antipsychotic drug-induced metabolic disturbances. AB - Antipsychotic drugs are widely prescribed medications, used for numerous psychiatric illnesses. However, antipsychotic drugs cause serious metabolic side effects that can lead to substantial weight gain and increased risk for type 2 diabetes. While individual drugs differ, all antipsychotic drugs may cause these important side effects to varying degrees. Given that the single unifying property shared by these medications is blockade of dopamine D2 and D3 receptors, these receptors likely play a role in antipsychotic drug-induced metabolic side effects. Dopamine D2 and dopamine D3 receptors are expressed in brain regions critical for metabolic regulation and appetite. Surprisingly, these receptors are also expressed peripherally in insulin-secreting pancreatic beta cells. By inhibiting glucose-stimulated insulin secretion, dopamine D2 and dopamine D3 receptors are important mediators of pancreatic insulin release. Crucially, antipsychotic drugs disrupt this peripheral metabolic regulatory mechanism. At the same time, disruptions to circadian timing have been increasingly recognized as a risk factor for metabolic disturbance. Reciprocal dopamine and circadian signaling is important for the timing of appetitive/feeding behaviors and insulin release, thereby coordinating cell metabolism with caloric intake. In particular, circadian regulation of dopamine D2 receptor/dopamine D3 receptor signaling may play a critical role in metabolism. Therefore, we propose that antipsychotic drugs' blockade of dopamine D2 receptor and dopamine D3 receptors in pancreatic beta cells, hypothalamus, and striatum disrupts the cellular timing mechanisms that regulate metabolism. Ultimately, understanding the relationships between the dopamine system and circadian clocks may yield critical new biological insights into mechanisms of antipsychotic drug action, which can then be applied into clinical practice. PMID- 28560265 TI - Isoform specific differences in phospholipase C beta 1 expression in the prefrontal cortex in schizophrenia and suicide. AB - Our previous study demonstrated that phospholipase C beta 1 mRNA was down regulated in Brodmann's area 46 from subjects with schizophrenia. However, phospholipase C beta 1 protein has also been shown to be lower in Brodmann's area 8 and 9 from teenage suicide subjects, creating a potential confound in interpreting the findings in schizophrenia due to the high suicide rate associated with this disorder. To begin to reconcile and consolidate these findings, in this study, we measured mRNA and protein levels of phospholipase C beta 1 variants a and b in Brodmann's area 46 and Brodmann's area 9 from subjects with schizophrenia, many of whom were suicide completers, and determined the diagnostic specificity of observed findings. Consistent with our previous study, levels of phospholipase C beta 1 a and b mRNA, but not protein, were lower in Brodmann's area 46 from subjects with schizophrenia. In Brodmann's area 9, phospholipase C beta 1a protein levels were lower in subjects with schizophrenia, while phospholipase C beta 1b mRNA was higher and protein was lower in those that had died of suicide. Altered protein levels in Brodmann's area 9 appeared to be diagnostically specific, as we did not detect these changes in subjects with bipolar disorder, major depressive disorder or suicide completers with no diagnosis of mental illness. We further assessed the relationship between phospholipase C beta 1 and levels of muscarinic receptors (CHRMs) that signal through this protein, in both human and Chrm knockout mouse central nervous system tissue, and found no strong relationship between the two. Understanding central nervous system differences in downstream effector pathways in schizophrenia may lead to improved treatment strategies and help to identify those at risk of suicide. PMID- 28560266 TI - The effect of cognitive remediation in individuals at ultra-high risk for psychosis: a systematic review. AB - Cognitive deficits are prominent features of the ultra-high risk state for psychosis that are known to impact functioning and course of illness. Cognitive remediation appears to be the most promising treatment approach to alleviate the cognitive deficits, which may translate into functional improvements. This study systematically reviewed the evidence on the effectiveness of cognitive remediation in the ultra-high risk population. The electronic databases MEDLINE, PsycINFO, and Embase were searched using keywords related to cognitive remediation and the UHR state. Studies were included if they were peer-reviewed, written in English, and included a population meeting standardized ultra-high risk criteria. Six original research articles were identified. All the studies provided computerized, bottom-up-based cognitive remediation, predominantly targeting neurocognitive function. Four out of five studies that reported a cognitive outcome found cognitive remediation to improve cognition in the domains of verbal memory, attention, and processing speed. Two out of four studies that reported on functional outcome found cognitive remediation to improve the functional outcome in the domains of social functioning and social adjustment. Zero out of the five studies that reported such an outcome found cognitive remediation to affect the magnitude of clinical symptoms. Research on the effect of cognitive remediation in the ultra-high risk state is still scarce. The current state of evidence indicates an effect of cognitive remediation on cognition and functioning in ultra-high risk individuals. More research on cognitive remediation in ultra-high risk is needed, notably in large-scale trials assessing the effect of neurocognitive and/or social cognitive remediation on multiple outcomes. PMID- 28560268 TI - Learning stable and predictive network-based patterns of schizophrenia and its clinical symptoms. AB - : Schizophrenia is often associated with disrupted brain connectivity. However, identifying specific neuroimaging-based patterns pathognomonic for schizophrenia and related symptom severity remains a challenging open problem requiring large scale data-driven analyses emphasizing not only statistical significance but also stability across multiple datasets, contexts and cohorts. Accurate prediction on previously unseen subjects, or generalization, is also essential for any useful biomarker of schizophrenia. In order to build a predictive model based on functional network feature patterns, we studied whole-brain fMRI functional networks, both at the voxel level and lower-resolution supervoxel level. Targeting Auditory Oddball task data on the FBIRN fMRI dataset (n = 95), we considered node-degree and link-weight network features and evaluated stability and generalization accuracy of statistically significant feature sets in discriminating patients vs. CONTROLS: We also applied sparse multivariate regression (elastic net) to whole-brain functional connectivity features, for the first time, to derive stable predictive features for symptom severity. Whole brain link-weight features achieved 74% accuracy in identifying patients and were more stable than voxel-wise node-degrees. Link-weight features predicted severity of several negative and positive symptom scales, including inattentiveness and bizarre behavior. The most-significant, stable and discriminative functional connectivity changes involved increased correlations between thalamus and primary motor/primary sensory cortex, and between precuneus (BA7) and thalamus, putamen, and Brodmann areas BA9 and BA44. Precuneus, along with BA6 and primary sensory cortex, was also involved in predicting severity of several symptoms. Overall, the proposed multi-step methodology may help identify more reliable multivariate patterns allowing for accurate prediction of schizophrenia and its symptoms severity. PMID- 28560267 TI - Electroconvulsive therapy-induced brain functional connectivity predicts therapeutic efficacy in patients with schizophrenia: a multivariate pattern recognition study. AB - Previous studies suggested that electroconvulsive therapy can influence regional metabolism and dopamine signaling, thereby alleviating symptoms of schizophrenia. It remains unclear what patients may benefit more from the treatment. The present study sought to identify biomarkers that predict the electroconvulsive therapy response in individual patients. Thirty-four schizophrenia patients and 34 controls were included in this study. Patients were scanned prior to treatment and after 6 weeks of treatment with antipsychotics only (n = 16) or a combination of antipsychotics and electroconvulsive therapy (n = 13). Subject-specific intrinsic connectivity networks were computed for each subject using a group information-guided independent component analysis technique. Classifiers were built to distinguish patients from controls and quantify brain states based on intrinsic connectivity networks. A general linear model was built on the classification scores of first scan (referred to as baseline classification scores) to predict treatment response. Classifiers built on the default mode network, the temporal lobe network, the language network, the corticostriatal network, the frontal-parietal network, and the cerebellum achieved a cross validated classification accuracy of 83.82%, with specificity of 91.18% and sensitivity of 76.47%. After the electroconvulsive therapy, psychosis symptoms of the patients were relieved and classification scores of the patients were decreased. Moreover, the baseline classification scores were predictive for the treatment outcome. Schizophrenia patients exhibited functional deviations in multiple intrinsic connectivity networks which were able to distinguish patients from healthy controls at an individual level. Patients with lower classification scores prior to treatment had better treatment outcome, indicating that the baseline classification scores before treatment is a good predictor for treatment outcome. PMID- 28560270 TI - A cross-country Exchange Market Pressure (EMP) dataset. AB - The data presented in this article are related to the research article titled - "An exchange market pressure measure for cross country analysis" (Patnaik et al. [1]). In this article, we present the dataset for Exchange Market Pressure values (EMP) for 139 countries along with their conversion factors, rho (rho). Exchange Market Pressure, expressed in percentage change in exchange rate, measures the change in exchange rate that would have taken place had the central bank not intervened. The conversion factor rho can interpreted as the change in exchange rate associated with $1 billion of intervention. Estimates of conversion factor rho allow us to calculate a monthly time series of EMP for 139 countries. Additionally, the dataset contains the 68% confidence interval (high and low values) for the point estimates of rho's. Using the standard errors of estimates of rho's, we obtain one sigma intervals around mean estimates of EMP values. These values are also reported in the dataset. PMID- 28560271 TI - Data from docking simulations to develop an efficient strategy able to evaluate the interactions between RAGE and MDA-induced albumin adducts. AB - This data article contains the results of docking simulations performed in order to develop a suitable in silico strategy able to assess the stability of the putative complexes between RAGE and MDA induced adducts on human albumin as experimentally determined doi: 10.1016/j.redox.2016.12.017, (Degani et al., 2017) [1]. The docking simulations involved different approaches to give a simplified yet realistic representation of the protein adducts and their environment. With increasing complexity, simulations involved the corresponding albumin tripeptides and pentapeptides with the modified residue in the central position as well as pseudo-structures which were generated by collecting the albumin residues around the adducted residue within a sphere of 7.5 A and 5 A radius. The reliability of the tested approaches was assessed by monitoring the score differences between adducted and unmodified residues. The obtained results revealed the greater predictive power of the spherical pseudo-structures compared to the simple tri- or pentapeptidic sequences thus suggesting that RAGE recognition involves residues which are spatially close to the modified residue even though not necessarily adjacent in the primary sequence. PMID- 28560269 TI - Fractures in indigenous compared to non-indigenous populations: A systematic review of rates and aetiology. AB - BACKGROUND: Compared to non-indigenous populations, indigenous populations experience disproportionately greater morbidity, and a reduced life expectancy; however, conflicting data exist regarding whether a higher risk of fracture is experienced by either population. We systematically evaluate evidence for whether differences in fracture rates at any skeletal site exist between indigenous and non-indigenous populations of any age, and to identify potential risk factors that might explain these differences. METHODS: On 31 August 2016 we conducted a comprehensive computer-aided search of peer-reviewed literature without date limits. We searched PubMed, OVID, MEDLINE, CINAHL, EMBASE, and reference lists of relevant publications. The protocol for this systematic review is registered in PROSPERO, the International Prospective Register of systematic reviews (CRD42016043215). Using the World Health Organization reference population as standard, hip fracture incidence rates were re-standardized for comparability between countries. RESULTS: Our search yielded 3227 articles; 283 potentially eligible articles were cross-referenced against predetermined criteria, leaving 27 articles for final inclusion. Differences in hip fracture rates appeared as continent-specific, with lower rates observed for indigenous persons in all countries except for Canada and Australia where the opposite was observed. Indigenous persons consistently had higher rates of trauma-related fractures; the highest were observed in Australia where craniofacial fracture rates were 22 times greater for indigenous compared to non-indigenous women. After adjustment for socio-demographic and clinical risk factors, approximately a three-fold greater risk of osteoporotic fracture and five-fold greater risk of craniofacial fractures was observed for indigenous compared to non-indigenous persons; diabetes, substance abuse, comorbidity, lower income, locality, and fracture history were independently associated with an increased risk of fracture. CONCLUSIONS: The observed paucity of data and suggestion of continent-specific differences indicate an urgent need for further research regarding indigenous status and fracture epidemiology and aetiology. Our findings also have implications for communities, governments and healthcare professionals to enhance the prevention of trauma-related fractures in indigenous persons, and an increased focus on modifiable lifestyle behaviours to prevent osteoporotic fractures in all populations. PMID- 28560272 TI - Chorological maps for the main European woody species. AB - A novel chorological data compilation for the main European tree and shrub species is presented. This dataset was produced by combining numerous and heterogeneous data collected from 20th century atlas monographs providing complete species distribution maps, and from more recent national to regional atlases, occurrence geodatabases and scientific literature. The dataset is composed of numerous species distribution maps available in geographical information system (GIS) format, created by compiling, evaluating and synthesizing data of all collected sources. The geometry of the individual datasets describes contiguous large areas of occupancy of each species as polygons and fragmented or isolated occurrences as points. Since this geodatabase is intended to provide a synthetic continental-scale overview of the species ranges, the maps represent the species' general chorology and the presence/absence information should not be considered absolute in terms of geolocation. Errors and imprecisions arising from the interpretation and digitalization processes are likely to occur, especially in those areas where detailed information is scarce. As new information sources become available, these will be used to address current data gaps, implement corrections and updates of the chorology dataset as well as expanding it to comprise additional species. PMID- 28560273 TI - A reconstructed melanoma data set for evaluating differential treatment benefit according to biomarker subgroups. AB - The data presented in this article are related to the research article entitled "Measuring differential treatment benefit across marker specific subgroups: the choice of outcome scale" (Satagopan and Iasonos, 2015) [1]. These data were digitally reconstructed from figures published in Larkin et al. (2015) [2]. This article describes the steps to digitally reconstruct patient-level data on time to-event outcome and treatment and biomarker groups using published Kaplan-Meier survival curves. The reconstructed data set and the corresponding computer programs are made publicly available to enable further statistical methodology research. PMID- 28560274 TI - Properties of particle phases for metal-matrix-composite design. AB - Successful metallurgical design of metal-matrix-composites relies on the knowledge of the intrinsic property profiles of the metal matrix and especially the compounds employed for particles, whiskers or fibres. In this work we compiled the key properties melting point, bulk modulus, shear modulus, Young's modulus, density, hardness, Poisson's ratio and structure/space group from the widespread literature data for the most relevant compound types, i.e. borides, carbo-borides, carbides, oxides, nitrides and intermetallic phases. PMID- 28560276 TI - Hydrolysis rate constants and activation parameters for phosphate- and phosphonate-bridged phthalonitrile monomers under acid, neutral and alkali conditions. AB - Hydrolysis data for Bis(3-(3,4-dicyanophenoxy)phenyl) phenyl phosphate and Bis(3 (3,4-dicyanophenoxy)phenyl) phenylphosphonate under pH 4, 7 and 10 are presented. Conversion/time plots collected by HPLC analysis, typical chromatograms and NMR spectra of the reactions products are given. Pseudo-first order rate constants are determined for both substrates at 25, 50 and 80 degrees C. Activation parameters were calculated from Arrhenius equation. PMID- 28560275 TI - Data on genome analysis of Bacillus velezensis LS69. AB - The data presented in this article are related to the published entitled "Whole genome sequencing of Bacillus velezensis LS69, a strain with a broad inhibitory spectrum against pathogenic bacteria" (Liu et al., 2017) [1]. Genome analysis revealed B. velezensis LS69 has a good potential for biocontrol and plant growth promotion. This article provides an extended analysis of the genetic islands, core genes and amylolysin loci of B. velezensis LS69. PMID- 28560277 TI - Theoretical assessment data for the binding of sepsis causing pathogens to ApoH beads. AB - The data presented in this paper supports the research article "A rapid, highly sensitive and culture-free detection of pathogens from blood by positive enrichment" ( Vutukuru et al., 2016) [1]. We compared a list of sepsis causing pathogens to the ApoH binding data given to us by ApoH technologies. The data highlights the binding of ApoH beads to sepsis causing pathogens. PMID- 28560278 TI - Dataset on exogenous application of salicylic acid and methyljasmonate and the accumulation of caffeine in young leaf tissues and catabolically inactive endosperms. AB - Exogenous exposure of coffee plants to 50 MUM and 500 MUM salicylic acid through liquid hydroponic medium or the exposure to volatile fumes of methyljasmonate was carried out to study the role of salicylic acid and methyljasmonate on the accumulation of caffeine and other methylxanthines like 7-methylxanthine, theobromine and theophylline. Transcript levels of the first, second and third N methyltransferase involved in the core caffeine biosynthetic pathway namely, xanthosine methyltransferase (XMT), methylxanthine methyltransferase (MXMT) and di-methylxanthine methyltransferase (DXMT) was investigated by semi-quantitative RT-PCR for validating the reason behind the changes of caffeine biosynthetic potential under the influence of the two analogues of plant phytohormones. Maturing coffee fruits are known to be biologically inactive with respect to caffeine biosynthetic activity in the endosperms. To understand this, fruits were treated with different doses of salicylic acid in a time-course manner and the de repression of tissue maturation-mediated knockdown of caffeine biosynthesis by exogenously applied salicylic acid was achieved. In our companion paper [1] it was shown that the repression of NMT genes during the dry weight accumulation phase of maturing endosperm could be relaxed by the exogenous application of salicylic acid and methyljasmonate. A probable model based on the work carried out therein and based on other literature [2], [3], [4] was proposed to describe that the crosstalk between salicylic acid or methyljasmonate and the ABA/ethylene pathway and might involve transcription factors downstream to the signaling cascade. PMID- 28560279 TI - Data for the generation of RNA spatiotemporal distributions and interpretation of Chk1 and SLBP protein depletion phenotypes during Drosophila embryogenesis. AB - The data presented in this article is related to the research article entitled "Biochemical Fractionation of Time-Resolved Drosophila Embryos Reveals Similar Transcriptomic Alterations in Replication Checkpoint and Histone mRNA Processing Mutants" (Lefebvre et al., 2017) [1]. This article provides a spatiotemporal transcriptomic analysis of early embryogenesis and shows that mutations in the checkpoint factor grapes/Chk1 and the histone mRNA processing factor SLBP selectively impair zygotic gene expression. Here, lists of transcripts enriched in early syncytial embryos, late blastoderm embryos, cytoplasmic and nuclear extracts of blastoderm embryos are made public, along with transcription factor motif occurrence for genes enriched in each context. In addition, extensive lists of genes down-regulated upon Chk1 and SLBP protein depletion in embryos are released to enable further analyses. PMID- 28560280 TI - Data for iTRAQ-based quantification of the cardiac proteome of rainbow trout (Oncorhynchus mykiss) at rest and with exercise training. AB - This data article presents the first description of the rainbow trout cardiac ventricle at the level of the proteome, with more than 700 proteins identified and quantified using isobaric tags for relative and absolute quantitation (iTRAQ) and LC-MS/MS. The abundances of these proteins were compared across 4 durations of moderate exercise training (0, 4, 7, and 14 d), and a total of 107 proteins were differentially abundant during the course of the training program. The differentially abundant proteins are presented here grouped by functional classification. In the research article associated with this data [1], the temporal changes in the cardiac proteome are discussed in the context of cardiac remodelling and development of a trained heart phenotype. PMID- 28560281 TI - Microarray data and gene expression statistics for Saccharomyces cerevisiae exposed to simulated asbestos mine drainage. AB - Here we describe microarray expression data (raw and normalized), experimental metadata, and gene-level data with expression statistics from Saccharomyces cerevisiae exposed to simulated asbestos mine drainage from the Vermont Asbestos Group (VAG) Mine on Belvidere Mountain in northern Vermont, USA. For nearly 100 years (between the late 1890s and 1993), chrysotile asbestos fibers were extracted from serpentinized ultramafic rock at the VAG Mine for use in construction and manufacturing industries. Studies have shown that water courses and streambeds nearby have become contaminated with asbestos mine tailings runoff, including elevated levels of magnesium, nickel, chromium, and arsenic, elevated pH, and chrysotile asbestos-laden mine tailings, due to leaching and gradual erosion of massive piles of mine waste covering approximately 9 km2. We exposed yeast to simulated VAG Mine tailings leachate to help gain insight on how eukaryotic cells exposed to VAG Mine drainage may respond in the mine environment. Affymetrix GeneChip(r) Yeast Genome 2.0 Arrays were utilized to assess gene expression after 24-h exposure to simulated VAG Mine tailings runoff. The chemistry of mine-tailings leachate, mine-tailings leachate plus yeast extract peptone dextrose media, and control yeast extract peptone dextrose media is also reported. To our knowledge this is the first dataset to assess global gene expression patterns in a eukaryotic model system simulating asbestos mine tailings runoff exposure. Raw and normalized gene expression data are accessible through the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) Database Series GSE89875 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE89875). PMID- 28560282 TI - Clinical and biochemical data of endothelial function in Women Consuming Combined Contraceptives. AB - The data presented in this article are associated with the research article entitled "Heme-Nitrosylated Hemoglobin and Oxidative Stress in Women Consuming Combined Contraceptives. Clinical Application of the EPR Spectroscopy" (Lobysheva et al., 2017 [1]), and describe the characteristics of redox status in blood, as well as biochemical and clinical parameters of young female subjects consuming (or not) contraceptive pills (CP). Erythrocyte concentration of reduced thiols reflecting erythrocyte redox capacity was measured before and after sample deproteinization by electron paramagnetic resonance spectroscopy (EPR) using a nitroxide biradical spin probe specifically interacting with reduced thiols; additional data were obtained by a colorimetric method using Ellman's reagents in the same samples. The products of nitric oxide oxidation, nitrite and total NOx (in presence of nitrate reductase) were measured in the plasma of study subjects by a colorimetric assay based on the detection of red-violet colored azo dye after reaction of nitrite with the Griess reagent. Biochemical and clinical parameters reflective of cardiovascular risk factors (diastolic blood pressure, C reactive protein, triglycerides and homocysteine concentrations in venous blood) were compared in subgroups of consumers of CP containing ethinyl estradiol and different types of synthetic progestogens. Parameters reflective of the integrity of the vasculature, - erythrocyte concentration of heme-nitrosylated hemoglobin (5-coordinate alpha-heme-FeII-NO, HbNO) measured directly by the EPR subtraction method; index of reactive hyperemia response (FRHI) measured by digital pulse tonometry using EndoPAT; oxidative vascular stress measured as total plasma peroxide concentration were compared in subgroups of young women taking CP containing ethinyl estradiol at different concentrations and for various durations. PMID- 28560283 TI - Dataset on characterization of hemin-azide derivative and DNA oligonucleotide hemin conjugate. AB - In this article newly synthesized azide derivative of hemin and DNA-hemin conjugate are characterized. Hemin-azide was purified using HPLC and characterized using elemental analysis, IR and NMR. The DNA-hemin conjugate was obtained via click chemistry [1] and click reaction was carried out using traditional Cu-catalyzed and Cu-free approaches. The final product was successfully obtained using Cu-free cycloaddition. The identity of product was confirmed using Maldi TOF spectrometry. Obtained hemin-DNA conjugate exhibited peroxidase-like activity. PMID- 28560284 TI - Data demonstrating the anti-oxidant role of hemopexin in the heart. AB - The data presented in this article are related to the research article entitled Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress (G. Ingoglia, C. M. Sag, N. Rex, L. De Franceschi, F. Vinchi, J. Cimino, S. Petrillo, S. Wagner, K. Kreitmeier, L. Silengo, F. Altruda, L. S. Maier, E. Hirsch, A. Ghigo and E. Tolosano, 2017) [1]. Data show that heme induces reactive oxygen species (ROS) production in primary cardiomyocytes. H9c2 myoblastic cells treated with heme bound to human Hemopexin (Hx) are protected from heme accumulation and oxidative stress. Similarly, the heme-driven oxidative response is reduced in primary cardiomyocytes treated with Hx-heme compared to heme alone. Our in vivo data show that mouse models of hemolytic disorders, beta-thalassemic mice and phenylhydrazine-treated mice, have low serum Hx associated to enhanced expression of heme- and oxidative stress responsive genes in the heart. Hx-/- mice do not show signs of heart fibrosis or overt inflammation. For interpretation and discussion of these data, refer to the research article referenced above. PMID- 28560285 TI - Data on the association of CMPK1 with clinicopathological features and biological effect in human epithelial ovarian cancer. AB - Human epithelial ovarian cancer (EOC) is the most lethal gynecological disease. However, the molecular mechanisms by which transforming growth factor-beta (TGF beta) regulates ovarian tumor progression markers remain unclear. The present data show cytidine monophosphate kinase (CMPK) as an EOC biomarker and are related to the article entitled "Cytidine monophosphate kinase is inhibited by the TGF-beta signalling pathway through the upregulation of miR-130b-3p in human epithelial ovarian cancer" [1]. CMPK, as well as cystatin B [2] and beta-2 microglobulin [3], is overexpressed in human epithelial-type ovarian tumors. CMPK is an enzyme required for nucleic acid biosynthesis [4] and is regulated by the TGF-beta signaling pathway in EOC cells [1]. Furthermore, the data show the effect of CMPK-shRNA on EOC cell apoptosis and TGF-beta-induced Smad2 phosphorylation. CMPK expression in two EOC cell lines OVCAR-3 and SK-OV-3 is regulated by multiple miRNAs and some of these miRNAs may affect EOC chemoresistance [5]. PMID- 28560286 TI - Uncovering Pathogenic Mechanisms of Inflammatory Bowel Disease Using Mouse Models of Crohn's Disease-Like Ileitis: What is the Right Model? AB - Crohn's disease and ulcerative colitis, together known as inflammatory bowel disease, are debilitating chronic disorders of unknown cause and cure. Our evolving understanding of these pathologies is enhanced greatly by the use of animal models of intestinal inflammation that allow in vivo mechanistic studies, preclinical evaluation of new therapies, and investigation into the causative factors that underlie disease pathogenesis. Several animal models, most commonly generated in mice, exist for the study of colitis. The appropriateness of their use often can be determined by their mode of generation (ie, chemical induction, T-cell transfer, targeted genetic manipulation, spontaneously occurring, and so forth), the type of investigation (mechanistic studies, pathogenic experiments, preclinical evaluations, and so forth), and the type of inflammation that occurs in the model (acute vs chronic colitis, tissue injury/repair, and so forth). Although most murine models of inflammatory bowel disease develop inflammation in the colon, Crohn's disease most commonly occurs in the terminal ileum, where a very limited number of mouse models manifest disease. This review discusses appropriate experimental applications for different mouse models of colitis, and highlights the particular utility of 2 highly relevant models of Crohn's-like ileitis-the spontaneous SAMP1/YitFc inbred mouse strain and the genetically engineered TnfDeltaAU-rich element/+ mouse model of tumor necrosis factor overexpression, both of which bear strong resemblance to the human condition. Similar to patients with Crohn's disease, SAMP1/YitFc ileitis develops spontaneously, without chemical, genetic, or immunologic manipulation, making this model particularly relevant for studies aimed at identifying the primary defect underlying the occurrence of Crohn's ileitis, as well as preclinical testing of novel treatment modalities. PMID- 28560288 TI - Regulation of Gastric Carcinogenesis by Inflammatory Cytokines. AB - Chronic inflammation caused by infection with Helicobacter pylori and autoimmune gastritis increases an individual's risk of developing gastric cancer. More than 90% of gastric cancers are adenocarcinomas, which originate from epithelial cells in the chronically inflamed gastric mucosa. However, only a small subset of chronic gastritis patients develops gastric cancer, implying a role for genetic and environmental factors in cancer development. A number of DNA polymorphisms that increase gastric cancer risk have mapped to genes encoding cytokines. Many different cytokines secreted by immune cells and epithelial cells during chronic gastritis have been identified, but a better understanding of how cytokines regulate the severity of gastritis, epithelial cell changes, and neoplastic transformation is needed. This review summarizes studies in both human and mouse models, describing a number of different findings that implicate various cytokines in regulating the development of gastric cancer. PMID- 28560287 TI - Mend Your Fences: The Epithelial Barrier and its Relationship With Mucosal Immunity in Inflammatory Bowel Disease. AB - The intestinal epithelium can be easily disrupted during gut inflammation as seen in inflammatory bowel disease (IBD), such as ulcerative colitis or Crohn's disease. For a long time, research into the pathophysiology of IBD has been focused on immune cell-mediated mechanisms. Recent evidence, however, suggests that the intestinal epithelium might play a major role in the development and perpetuation of IBD. It is now clear that IBD can be triggered by disturbances in epithelial barrier integrity via dysfunctions in intestinal epithelial cell intrinsic molecular circuits that control the homeostasis, renewal, and repair of intestinal epithelial cells. The intestinal epithelium in the healthy individual represents a semi-permeable physical barrier shielding the interior of the body from invasions of pathogens on the one hand and allowing selective passage of nutrients on the other hand. However, the intestinal epithelium must be considered much more than a simple physical barrier. Instead, the epithelium is a highly dynamic tissue that responds to a plenitude of signals including the intestinal microbiota and signals from the immune system. This epithelial response to these signals regulates barrier function, the composition of the microbiota, and mucosal immune homeostasis within the lamina propria. The epithelium can thus be regarded as a translator between the microbiota and the immune system and aberrant signal transduction between the epithelium and adjacent immune cells might promote immune dysregulation in IBD. This review summarizes the important cellular and molecular barrier components of the intestinal epithelium and emphasizes the mechanisms leading to barrier dysfunction during intestinal inflammation. PMID- 28560289 TI - Initiation and Maintenance of Gastric Cancer: A Focus on CD44 Variant Isoforms and Cancer Stem Cells. AB - Gastric cancer is the third most common cause of cancer-related death. Although the incidence of gastric cancer in the United States is relatively low, it remains significantly higher in some countries, including Japan and Korea. Interactions between cancer stem cells and the tumor microenvironment can have a substantial impact on tumor characteristics and contribute to heterogeneity. The mechanisms responsible for maintaining malignant cancer stem cells within the tumor microenvironment in human gastric cancer are largely unknown. Tumor cell and genetic heterogeneity contribute to either de novo intrinsic or the therapy induced emergence of drug-resistant clones and eventual tumor recurrence. Although chemotherapy often is capable of inducing cell death in tumors, many cancer patients experience recurrence because of failure to effectively target the cancer stem cells, which are believed to be key tumor-initiating cells. Among the population of stem cells within the stomach that may be targeted during chronic Helicobacter pylori infection and altered into tumor-initiating cells are those cells marked by the cluster-of-differentiation (CD)44 cell surface receptor. CD44 variable isoforms (CD44v) have been implicated as key players in malignant transformation whereby their expression is highly restricted and specific, unlike the canonical CD44 standard isoform. Overall, CD44v, in particular CD44v9, are believed to mark the gastric cancer cells that contribute to increased resistance for chemotherapy- or radiation-induced cell death. This review focuses on the following: the alteration of the gastric stem cell during bacterial infection, and the role of CD44v in the initiation, maintenance, and growth of tumors associated with gastric cancer. PMID- 28560290 TI - Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel Syndrome. AB - BACKGROUND & AIMS: Options for the prevention of short-bowel syndrome-associated liver disease (SBS-ALDs) are limited and often ineffective. The farnesoid X receptor (FXR) is a newly emerging pharmaceutical target and FXR agonists have been shown to ameliorate cholestasis and metabolic disorders. The aim of this study was to assess the efficacy of obeticholic acid (OCA) treatment in preventing SBS-ALDs. METHODS: Piglets underwent 75% small-bowel resection (SBS) or sham surgery (sham) and were assigned to either a daily dose of OCA (2.4 mg/kg/day) or were untreated. Clinical measures included weight gain and stool studies. Histologic features were assessed. Ultraperformance liquid chromatography tandem mass spectrometry was used to determine bile acid composition in end point bile and portal serum samples. Gene expression of key FXR targets was assessed in intestinal and hepatic tissues via quantitative polymerase chain reaction. RESULTS: OCA-treated SBS piglets showed decreased stool fat and altered liver histology when compared with nontreated SBS piglets. OCA prevented SBS-associated taurine depletion, however, further analysis of bile and portal serum samples indicated that OCA did not prevent SBS-associated alterations in bile acid composition. The expression of FXR target genes involved in bile acid transport and synthesis increased within the liver of SBS piglets after OCA administration whereas, paradoxically, intestinal expression of FXR target genes were decreased by OCA administration. CONCLUSIONS: Administration of OCA in SBS reduced fat malabsorption and altered bile acid composition, but did not prevent the development of SBS-ALDs. We postulate that extensive small resection impacts the ability of the remnant intestine to respond to FXR activation. PMID- 28560292 TI - Metaplasia in the Stomach Arises From Gastric Chief Cells. AB - The development of intestinal-type gastric cancer is preceded by loss of parietal cells (oxyntic atrophy) and the induction of metaplastic cell lineages in the gastric mucosa. For example, mouse models have shown that spasmolytic polypeptide expressing metaplasia can develop following oxyntic atrophy through transdifferentiation of zymogen-secreting chief cells. Evolution of spasmolytic polypeptide-expressing metaplasia from chief cells occurs via a coordinated dismantling of their secretory apparatus and reprogramming of their transcriptome. Increasing evidence suggests that the process of chief cell reprogramming requires the influence of inflammatory cytokines and requires both zymogen granule autophagy and alterations in gene transcription. It is likely that spasmolytic polypeptide-expressing metaplasia is a physiological repair mechanism that is similar to those that occur in other tissues (eg, pancreas) for recruiting reparative progenitor cells in response to mucosal wounds. Chronic inflammation can induce a recurring pattern of persistent reprogramming/metaplasia that increases the risk for neoplasia. PMID- 28560291 TI - Gastrin and Gastric Cancer. AB - Gastric cancer is the third leading cause of cancer-related mortality worldwide. Despite progress in understanding its development, challenges with treatment remain. Gastrin, a peptide hormone, is trophic for normal gastrointestinal epithelium. Gastrin also has been shown to play an important role in the stimulation of growth of several gastrointestinal cancers including gastric cancer. We sought to review the role of gastrin and its pathway in gastric cancer and its potential as a therapeutic target in the management of gastric cancer. In the normal adult stomach, gastrin is synthesized in the G cells of the antrum; however, gastrin expression also is found in many gastric adenocarcinomas of the stomach corpus. Gastrin's actions are mediated through the G-protein-coupled receptor cholecystokinin-B (CCK-B) on parietal and enterochromaffin cells of the gastric body. Gastrin blood levels are increased in subjects with type A atrophic gastritis and in those taking high doses of daily proton pump inhibitors for acid reflux disease. In experimental models, proton pump inhibitor-induced hypergastrinemia and infection with Helicobacter pylori increase the risk of gastric cancer. Understanding the gastrin:CCK-B signaling pathway has led to therapeutic strategies to treat gastric cancer by either targeting the CCK-B receptor with small-molecule antagonists or targeting the peptide with immune based therapies. In this review, we discuss the role of gastrin in gastric adenocarcinoma, and strategies to block its effects to treat those with unresectable gastric cancer. PMID- 28560293 TI - Isthmus Stem Cells Are the Origins of Metaplasia in the Gastric Corpus. AB - The acquisition of genetic/epigenetic mutations in long-lived gastrointestinal stem cells leads to the development of cancer, as well as precancerous lesions such as metaplasia and dysplasia. In the proximal stomach corpus, this model of progression from stem cells has been supported by studies in mice and human beings, showing abundant proliferation in the isthmus and clonal expansion of mutated cells from the stem cell region. An alternative theory proposes that gastric metaplasia arises from mature differentiated chief cells. Despite reports of low levels of proliferation in chief cells in acute injury models, there is little evidence for reprogramming of chief cells into long-lived stem cells that continuously supply progeny over time. Critical flaws in the chief cell transdifferentiation theory include the definition of acute SPEM, the chief cell damaging effect of chemical reagents, and the specificity of chief cell lineage tracing. In contrast, there is now strong evidence regarding the stem cell origins of gastric metaplasia that refutes the transdifferentiation theory. Here, we briefly review the history and definition of gastric metaplasia, and outline in detail the evidence that supports the stem cell origin of metaplasia. PMID- 28560294 TI - Psoriasis vulgaris with fibrokeratoma from pityriasis amiantacea. PMID- 28560295 TI - Isoradiotopic response of lichen planus after radiotherapy of the breast. PMID- 28560296 TI - Alopecia after injection of ATX-101 for reduction of submental fat. PMID- 28560297 TI - Uterine lipoleiomyosarcoma: Complete medullary compression as presentation of a solitary metastasis. AB - *A rare case of lipoleiomyosarcoma.*Patient presented at our center with paraplegia caused by a solitary vertebral metastasis of a uterine cancer.*Lobectomy performed for a solitary lung metastasis. PMID- 28560298 TI - Successful treatment of low-grade endometrial cancer in premenopausal women with an aromatase inhibitor after failure with oral or intrauterine progesterone. AB - INTRODUCTION: Young women with endometrial intraepithelial hyperplasia or low grade endometrial carcinoma are potential candidates for conservative fertility sparing therapy utilizing progesterone rather than hysterectomy. High-dose progesterone treatment is associated with 55-80% initial response but high relapse rates. Using aromatase inhibitors in conjunction with high-dose progesterone has largely been unstudied. CASE DESCRIPTIONS: Three obese premenopausal women with endometrial cancer failed to respond to oral or intrauterine progesterone as first line therapy. Due to their desire to continue to pursue fertility sparing treatment options, an aromatase inhibitor was added to their treatment regimen. This resulted in resolution of their malignancy in each case. DISCUSSION: In obese premenopausal women, the mechanism of malignant transformation in endometrial carcinoma is considered to be an association with relatively high levels of serum estrogen from peripheral conversion of androgens to estrone in adipose tissue with a deficiency in progesterone exposure due to chronic anovulation. Using aromatase inhibitors seems reasonable as an adjunct to progesterone given the high likelihood that this population has a significant proportion of their estrogen production coming from peripheral conversion in adipose tissue. This case series is unique in that each woman initially failed to respond to progesterone but had resolution when an aromatase inhibitor was added to their treatment regimen. This would suggest that obese women with low grade malignancy or hyperplasia who have no radiographic evidence of deep myometrial invasion, ovarian or retroperitoneal metastases and who wish to retain their fertility may be treated with intrauterine progesterone and an aromatase inhibitor. PMID- 28560299 TI - The age-old problem of acne. AB - Acne vulgaris is one of the top three most commonly encountered dermatological problems worldwide in both primary and secondary care. Acne diagnosis and treatment date back to ancient Greek and Egyptian times. This article explores acne through the ages and discusses past theories on etiology and treatment with particular focus on the discovery of retinoids and their impact on women's health. PMID- 28560301 TI - Pemphigoid gestationis: Clinical and histologic features of twenty-three patients. PMID- 28560300 TI - Striae gravidarum: Risk factors, prevention, and management. AB - BACKGROUND: Striae gravidarum (SG) are atrophic linear scars that represent one of the most common connective tissue changes during pregnancy. SG can cause emotional and psychological distress for many women. Research on risk factors, prevention, and management of SG has been often inconclusive. METHODS: We conducted a literature search using textbooks, PubMed, and Medline databases to assess research performed on the risk factors, prevention, and management of SG. The search included the following key words: striae gravidarum, pregnancy stretch marks, and pregnancy stretch. We also reviewed citations within articles to identify relevant sources. RESULTS: Younger age, maternal and family history of SG, increased pre-pregnancy and pre-delivery weight, and increased birth weight were the most significant risk factors identified for SG. Although few studies have confirmed effective prevention methods, Centella asiatica extract, hyaluronic acid, and daily massages showed some promise. Treatment for general striae has greatly improved over the last few years. Topical tretinoin >= 0.05% has demonstrated up to 47% improvement of SG and non-ablative fractional lasers have consistently demonstrated 50 to 75% improvement in treated lesions of striae distensae. CONCLUSION: Overall, SG has seen a resurgence in research over the last few years with promising data being released. Results of recent studies provide dermatologists with new options for the many women who are affected by these disfiguring marks of pregnancy. PMID- 28560302 TI - Three cases of localized cutaneous nodular amyloidosis in patients with limited systemic sclerosis and a brief literature review. AB - Localized cutaneous nodular amyloidosis (LCNA) is the rarest form of localized cutaneous amyloidosis. In patients with LCNA, local plasma cells secrete immunoglobulin light chains called amyloid L via an unknown mechanism. LCNA has been associated with autoimmune connective tissue diseases such as most commonly Sjogren syndrome. A few reported cases of LCNA are associated with limited systemic sclerosis (LSSc). We report three cases of LCNA in patients with LSSc to add to the existing literature, discuss the disease association and proposed pathophysiology, and briefly review the existing information in current literature. It is important to closely follow patients with LCNA to monitor progression to systemic amyloidosis. PMID- 28560303 TI - Persistent lip enlargement: An unusual presentation of lupus erythematosus. AB - Macrocheilia is a challenging problem with a variety of underlying causes that are both local and systemic, and granulomatous causes underlie the majority of cases. In this study, we report on a 31-year old man who presented with a chronic lower lip enlargement and a nodular submental erythematous lesion. He was otherwise clinically healthy. Laboratory test results were within the normal limit except for a positive anti-double stranded DNA test result. A diagnosis of cutaneous lupus erythematosus was made on the basis of histopathology and direct immunofluorescence. The lesions resolved dramatically after treatment with hydroxychloroquine. Lupus erythematosus should be considered when examining patients who present with chronic lip swelling. PMID- 28560304 TI - Defining the mimics and clinico-histological diagnosis criteria for mycosis fungoides to minimize misdiagnosis. AB - BACKGROUND: Mycosis fungoides (MF) is a significant diagnostic challenge; it has various differential diagnosis especially at an early stage. Our aim was to describe mimics of MF clinically and histologically, and to define significant diagnostic criteria of the disease. METHODS: This was a retro-prospective cohort of 370 patients in whom the diagnosis of MF was suspected clinically. RESULTS: MF was histologically confirmed in 15.4% of cases and rejected in 84.5%. Other identified histologically diagnosis were eczema, psoriasis; nonspecific dermatitis, lichen, lupus; pseudolymphoma, parapsoriasis and toxidermia. 4 patients with palmoplantar MF were wrongly treated as eczema, and 10 patients with psoriasiform MF were initially treated as psoriasis. We also described the clinical, histological and immunohistochemistry diagnostic criteria for distinguishing MF from benign dermatosis. CONCLUSIONS: Misdiagnosis of MF was a real problem for this study, because it shared common clinical and histological characteristics with other inflammatory diseases like eczema and psoriasis. Therefore, defining significant clinico-histological diagnosis criteria of MF would be of great help and would increase the accuracy of the diagnosis. PMID- 28560305 TI - Hydrocortisone 1% cream and sertaconazole 2% cream to treat facial seborrheic dermatitis: A double-blind, randomized clinical trial. AB - BACKGROUND: Seborrheic dermatitis (SD) is a chronic dermatitis with periods of remission and relapse that requires long-term treatment. OBJECTIVE: We compared the efficacy and safety of treatment with sertaconazole with standard corticosteroid medications in adults with facial SD. METHODS: In this double blind, randomized controlled trial, 60 patients with a diagnosis of SD were enrolled. Patients were instructed to apply either sertaconazole 2% cream (30 patients) or hydrocortisone 1% cream (30 patients) twice daily to the affected area of the face. The severity of facial SD was assessed at 0, 2, and 4 weeks of treatment. Secondary efficacy measures included patient assessment of seborrhea, adverse events, and improvement percentage (IP). RESULTS: SD lesions cleared significantly (p < .05) and similarly in both treatment groups (p > .05). Both treatments resulted in significant improvement of SD lesions and the rate of adverse events was similar in both groups. The IP was higher for treatment with hydrocortisone in Week 2 and similar in both groups at the end of the study. LIMITATIONS: Limitations include the small number of patients who were recruited for this study and the lack of evaluation of time to relapse. CONCLUSION: Treatment with topical sertaconazole may be regarded as a substitute for topical corticosteroid medications due to the fewer adverse events and similar efficacy. PMID- 28560306 TI - Spironolactone for the treatment of acne in women, a retrospective study of 110 patients. AB - BACKGROUND: There is limited evidence on the safety and efficacy of spironolactone in the treatment of women with acne. Thus, for many dermatologists spironolactone remains an alternative rather than a mainstay treatment for female patients with acne. METHODS: An electronic medical records search tool was used to select data from a group of women who received spironolactone to treat acne and were evaluated with the comprehensive acne severity scale (CASS) before treatment and at all follow-up visits. Data points were collected for CASS scores at each follow-up visit, concurrent and previous treatments, and side effects. These data points were used to draw conclusions about the safety and efficacy of spironolactone in this patient population. RESULTS: There were 110 patients that met all eligibility requirements. Of these, 94 patients saw an improvement in their CASS score and 61 patients completely cleared their score to 0. There were 16 patients who did not improve and six who relapsed after initial improvement. The women saw an average improvement in their acne by 73.1% for the face, 75.9% for the chest, and 77.6% for the back. Fifty-one women experienced side effects, but only six found them bothersome enough to stop taking spironolactone. CONCLUSION: A majority of women in this study saw a dramatic improvement in their acne while treated with spironolactone. There were low rates of relapse or discontinuation of the medication. To further promote the use of spironolactone as a first-line systemic treatment for women with acne, there must be more prospective controlled trials. PMID- 28560307 TI - Lupus profundus limited to a site of trauma: Case report and review of the literature. AB - Lupus erythematosus profundus (LEP) is a rare form of chronic cutaneous lupus erythematosus. We report on a case of a 56-year-old Caucasian woman who presented with a single, persistent, painful rash on the left hip and lateral aspect of the left upper thigh, which had been present for 2.5 years. The patient had a history of previous injury to this area before the rash started. Clinical findings showed an inflamed, hyperpigmented, and indurated plaque with a linear skin invagination and no associated systemic symptoms. A skin biopsy test result confirmed the diagnosis of LEP and the clinical and laboratory examinations ruled out systemic lupus erythematosus. After 2 months of treatment with methotrexate 20 mg weekly and 1 month of prednisolone 7.5 mg daily, the skin rash improved considerably. We also present a brief review of the epidemiology, etiology, clinical features, histopathology, laboratory findings, differential diagnosis, and treatment of LEP. PMID- 28560308 TI - Resting-state network dysfunction in Alzheimer's disease: A systematic review and meta-analysis. AB - INTRODUCTION: We performed a systematic review and meta-analysis of the Alzheimer's disease (AD) literature to examine consistency of functional connectivity alterations in AD dementia and mild cognitive impairment, using resting-state functional magnetic resonance imaging. METHODS: Studies were screened using a standardized procedure. Multiresolution statistics were performed to assess the spatial consistency of findings across studies. RESULTS: Thirty-four studies were included (1363 participants, average 40 per study). Consistent alterations in connectivity were found in the default mode, salience, and limbic networks in patients with AD dementia, mild cognitive impairment, or in both groups. We also identified a strong tendency in the literature toward specific examination of the default mode network. DISCUSSION: Convergent evidence across the literature supports the use of resting-state connectivity as a biomarker of AD. The locations of consistent alterations suggest that highly connected hub regions in the brain might be an early target of AD. PMID- 28560309 TI - Single-nucleotide polymorphisms are associated with cognitive decline at Alzheimer's disease conversion within mild cognitive impairment patients. AB - INTRODUCTION: The growing public threat of Alzheimer's disease (AD) has raised the urgency to quantify the degree of cognitive decline during the conversion process of mild cognitive impairment (MCI) to AD and its underlying genetic pathway. The aim of this article was to test genetic common variants associated with accelerated cognitive decline after the conversion of MCI to AD. METHODS: In 583 subjects with MCI enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI; ADNI-1, ADNI-Go, and ADNI-2), 245 MCI participants converted to AD at follow-up. We tested the interaction effects between individual single-nucleotide polymorphisms and AD diagnosis trajectory on the longitudinal Alzheimer's Disease Assessment Scale-Cognition scores. RESULTS: Our findings reveal six genes, including BDH1, ST6GAL1, RAB20, PDS5B, ADARB2, and SPSB1, which are directly or indirectly related to MCI conversion to AD. DISCUSSION: This genome-wide association study sheds light on a genetic mechanism of longitudinal cognitive changes during the transition period from MCI to AD. PMID- 28560310 TI - Longitudinal evaluation of criteria for subjective cognitive decline and preclinical Alzheimer's disease in a memory clinic sample. AB - INTRODUCTION: Subjective cognitive decline (SCD) and biomarker-based "at-risk" concepts such as "preclinical" Alzheimer's disease (AD) have been developed to predict AD dementia before objective cognitive impairment is detectable. We longitudinally evaluated cognitive outcome when using these classifications. METHODS: Memory clinic patients (n = 235) were classified as SCD (n = 122): subtle cognitive decline (n = 36) and mild cognitive impairment (n = 77) and subsequently subclassified into SCDplus and National Institute on Aging Alzheimer's Association (NIA-AA) stages 0 to 3. Mean (standard deviation) follow up time was 48 (35) months. Proportion declining cognitively and prognostic accuracy for cognitive decline was calculated for all classifications. RESULTS: Among SCDplus patients, 43% to 48% declined cognitively. Among NIA-AA stage 1 to 3 patients, 50% to 100% declined cognitively. The highest positive likelihood ratios (+LRs) for subsequent cognitive decline (+LR 6.3), dementia (+LR 3.4), and AD dementia (+LR 6.5) were found for NIA-AA stage 2. DISCUSSION: In a memory clinic setting, NIA-AA stage 2 seems to be the most successful classification in predicting objective cognitive decline, dementia, and AD dementia. PMID- 28560312 TI - Editorial: eNeuro Offers a Unique Interactive Experience to Reviewer Training. PMID- 28560314 TI - Correction: Horikawa and Ojima. Cortical Activation Patterns Evoked by Temporally Asymmetric Sounds and Their Modulation by Learning (eNeuro March/April 2017, 4(2) e0241-16.2017 1-19 https://doi.org/10.1523/ENEURO.0241-16.2017). AB - [This corrects the article DOI: 10.1523/ENEURO.0241-16.2017.]. PMID- 28560311 TI - Acute Knockdown of Kv4.1 Regulates Repetitive Firing Rates and Clock Gene Expression in the Suprachiasmatic Nucleus and Daily Rhythms in Locomotor Behavior. AB - Rapidly activating and inactivating A-type K+ currents (IA) encoded by Kv4.2 and Kv4.3 pore-forming (alpha) subunits of the Kv4 subfamily are key regulators of neuronal excitability. Previous studies have suggested a role for Kv4.1 alpha subunits in regulating the firing properties of mouse suprachiasmatic nucleus (SCN) neurons. To test this, we utilized an RNA-interference strategy to knockdown Kv4.1, acutely and selectively, in the SCN. Current-clamp recordings revealed that the in vivo knockdown of Kv4.1 significantly (p < 0.0001) increased mean +/- SEM repetitive firing rates in SCN neurons during the day (6.4 +/- 0.5 Hz) and at night (4.3 +/- 0.6 Hz), compared with nontargeted shRNA-expressing SCN neurons (day: 3.1 +/- 0.5 Hz; night: 1.6 +/- 0.3 Hz). IA was also significantly (p < 0.05) reduced in Kv4.1-targeted shRNA-expressing SCN neurons (day: 80.3 +/- 11.8 pA/pF; night: 55.3 +/- 7.7 pA/pF), compared with nontargeted shRNA expressing (day: 121.7 +/- 10.2 pA/pF; night: 120.6 +/- 16.5 pA/pF) SCN neurons. The magnitude of the effect of Kv4.1-targeted shRNA expression on firing rates and IA was larger at night. In addition, Kv4.1-targeted shRNA expression significantly (p < 0.001) increased mean +/- SEM nighttime input resistance (Rin; 2256 +/- 166 MOmega), compared to nontargeted shRNA-expressing SCN neurons (1143 +/- 93 MOmega). Additional experiments revealed that acute knockdown of Kv4.1 significantly (p < 0.01) shortened, by ~0.5 h, the circadian period of spontaneous electrical activity, clock gene expression and locomotor activity demonstrating a physiological role for Kv4.1-encoded IA channels in regulating circadian rhythms in neuronal excitability and behavior. PMID- 28560313 TI - Urothelial Tight Junction Barrier Dysfunction Sensitizes Bladder Afferents. AB - Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic voiding disorder that presents with pain in the urinary bladder and surrounding pelvic region. A growing body of evidence suggests that an increase in the permeability of the urothelium, the epithelial barrier that lines the interior of the bladder, contributes to the symptoms of IC/BPS. To examine the consequence of increased urothelial permeability on pelvic pain and afferent excitability, we overexpressed in the urothelium claudin 2 (Cldn2), a tight junction (TJ) associated protein whose message is significantly upregulated in biopsies of IC/BPS patients. Consistent with the presence of bladder-derived pain, rats overexpressing Cldn2 showed hypersensitivity to von Frey filaments applied to the pelvic region. Overexpression of Cldn2 increased the expression of c-Fos and promoted the activation of ERK1/2 in spinal cord segments receiving bladder input, which we conceive is the result of noxious stimulation of afferent pathways. To determine whether the mechanical allodynia observed in rats with reduced urothelial barrier function results from altered afferent activity, we examined the firing of acutely isolated bladder sensory neurons. In patch-clamp recordings, about 30% of the bladder sensory neurons from rats transduced with Cldn2, but not controls transduced with GFP, displayed spontaneous activity. Furthermore, bladder sensory neurons with tetrodotoxin-sensitive (TTX-S) action potentials from rats transduced with Cldn2 showed hyperexcitability in response to suprathreshold electrical stimulation. These findings suggest that as a result of a leaky urothelium, the diffusion of urinary solutes through the urothelial barrier sensitizes bladders afferents, promoting voiding at low filling volumes and pain. PMID- 28560315 TI - Proactive Control: Neural Oscillatory Correlates of Conflict Anticipation and Response Slowing. AB - Proactive control allows us to anticipate environmental changes and adjust behavioral strategy. In the laboratory, investigators have used a number of different behavioral paradigms, including the stop-signal task (SST), to examine the neural processes of proactive control. Previous functional MRI studies of the SST have demonstrated regional responses to conflict anticipation-the likelihood of a stop signal or P(stop) as estimated by a Bayesian model-and reaction time (RT) slowing and how these responses are interrelated. Here, in an electrophysiological study, we investigated the time-frequency domain substrates of proactive control. The results showed that conflict anticipation as indexed by P(stop) was positively correlated with the power in low-theta band (3-5 Hz) in the fixation (trial onset)-locked interval, and go-RT was negatively correlated with the power in delta-theta band (2-8 Hz) in the go-locked interval. Stimulus prediction error was positively correlated with the power in the low-beta band (12-22 Hz) in the stop-locked interval. Further, the power of the P(stop) and go RT clusters was negatively correlated, providing a mechanism relating conflict anticipation to RT slowing in the SST. Source reconstruction with beamformer localized these time-frequency activities close to brain regions as revealed by functional MRI in earlier work. These are the novel results to show oscillatory electrophysiological substrates in support of trial-by-trial behavioral adjustment for proactive control. PMID- 28560316 TI - VMAT2-Mediated Neurotransmission from Midbrain Leptin Receptor Neurons in Feeding Regulation. AB - Leptin receptors (LepRs) expressed in the midbrain contribute to the action of leptin on feeding regulation. The midbrain neurons release a variety of neurotransmitters including dopamine (DA), glutamate and GABA. However, which neurotransmitter mediates midbrain leptin action on feeding remains unclear. Here, we showed that midbrain LepR neurons overlap with a subset of dopaminergic, GABAergic and glutamatergic neurons. Specific removal of vesicular monoamine transporter 2 (VMAT2) in midbrain LepR neurons (KO mice) disrupted DA accumulation in vesicles, but failed to cause a significant change in the evoked release of either glutamate or GABA to downstream neurons. While KO mice showed no differences on chow, they presented a reduced high-fat diet (HFD) intake and resisted to HFD-induced obesity. Specific activation of midbrain LepR neurons promoted VMAT2-dependent feeding on chow and HFD. When tested with an intermittent access to HFD where first 2.5-h HFD eating (binge-like) and 24-h HFD feeding were measured, KO mice exhibited more binge-like, but less 24-h HFD feeding. Interestingly, leptin inhibited 24-h HFD feeding in controls but not in KO mice. Thus, VMAT2-mediated neurotransmission from midbrain LepR neurons contributes to both binge-like eating and HFD feeding regulation. PMID- 28560317 TI - Gain Control in Predictive Smooth Pursuit Eye Movements: Evidence for an Acceleration-Based Predictive Mechanism. AB - The smooth pursuit eye movement system incorporates various control features enabling adaptation to specific tracking situations. In this work, we analyzed the interplay between two of these mechanisms: gain control and predictive pursuit. We tested human responses to high-frequency perturbations during step ramp pursuit, as well as the pursuit of a periodically moving target. For the latter task, we found a nonlinear interaction between perturbation response and carrier acceleration. Responses to perturbations where the initial perturbation acceleration was contradirectional to carrier acceleration increased with carrier velocity, in a manner similar to that observed during step-ramp pursuit. In contrast, responses to perturbations with ipsidirectional initial perturbation and carrier acceleration were large for all carrier velocities. Modeling the pursuit system suggests that gain control and short-term prediction are separable elements. The observed effect may be explained by combining the standard gain control mechanism with a derivative-based short-term predictive mechanism. The nonlinear interaction between perturbation and carrier acceleration can be reproduced by assuming a signal saturation, which is acting on the derivative of the target velocity signal. Our results therefore argue for the existence of an internal estimate of target acceleration as a basis for a simple yet efficient short-term predictive mechanism. PMID- 28560318 TI - Differential Effects of Retinoic Acid Concentrations in Regulating Blood-Brain Barrier Properties. AB - The blood-brain barrier (BBB) is a multifaceted property of the brain vasculature that protects the brain and maintains homeostasis by tightly regulating the flux of ions, molecules, and cells across the vasculature. Blood vessels in the brain are formed by endothelial cells that acquire barrier properties, such as tight and adherens junctions, soon after the brain vasculature is formed. Endothelial WNT signaling is crucial to induce these BBB properties by regulating their expression and stabilization. Recent studies have implicated retinoic acid (RA) signaling in BBB development and shown that pharmacological concentrations of RA (>=5 um) can induce BBB properties in cultured brain endothelial cells. However, a recent study demonstrated that RA inhibits endothelial WNT signaling during brain development, suggesting that RA does not promote BBB properties. We therefore investigated whether RA plays a physiological role in BBB development. We found that BBB function and junctional protein expression was unaffected in mouse mutants that have a reduced capacity to synthesize RA (Rdh10 mutants). Furthermore, embryos exposed to a RA-enriched diet did not enhance BBB protein expression. Together, our data indicate that RA is not capable of inducing, nor is it required for, BBB protein expression in vivo. Like other studies, we found that pharmacological concentrations of RA induce BBB genes in cultured murine brain endothelial cells, and this may involve activation of the LXR/RXR signaling pathway. Our data do not support a role for RA in BBB development, but confirm reports that pharmacological RA is a robust tool to induce BBB properties in culture. PMID- 28560319 TI - Cyclical nursing patterns in wild orangutans. AB - Nursing behavior is notoriously difficult to study in arboreal primates, particularly when offspring suckle inconspicuously in nests. Orangutans have the most prolonged nursing period of any mammal, with the cessation of suckling (weaning) estimated to occur at 6 to 8 years of age in the wild. Milk consumption is hypothesized to be relatively constant over this period, but direct evidence is limited. We previously demonstrated that trace element analysis of bioavailable elements from milk, such as barium, provides accurate estimates of early-life diet transitions and developmental stress when coupled with growth lines in the teeth of humans and nonhuman primates. We provide the first detailed nursing histories of wild, unprovisioned orangutans (Pongo abelii and Pongo pygmaeus) using chemical and histological analyses. Laser ablation inductively coupled plasma mass spectrometry was used to determine barium distributions across the teeth of four wild-shot individuals aged from postnatal biological rhythms. Barium levels rose during the first year of life in all individuals and began to decline shortly after, consistent with behavioral observations of intensive nursing followed by solid food supplementation. Subsequent barium levels show large sustained fluctuations on an approximately annual basis. These patterns appear to be due to cycles of varying milk consumption, continuing until death in an 8.8-year-old Sumatran individual. A female Bornean orangutan ceased suckling at 8.1 years of age. These individuals exceed the maximum weaning age reported for any nonhuman primate. Orangutan nursing may reflect cycles of infant demand that relate to fluctuating resource availability. PMID- 28560320 TI - Nighttime temperature and human sleep loss in a changing climate. AB - Human sleep is highly regulated by temperature. Might climate change-through increases in nighttime heat-disrupt sleep in the future? We conduct the inaugural investigation of the relationship between climatic anomalies, reports of insufficient sleep, and projected climate change. Using data from 765,000 U.S. survey respondents from 2002 to 2011, coupled with nighttime temperature data, we show that increases in nighttime temperatures amplify self-reported nights of insufficient sleep. We observe the largest effects during the summer and among both lower-income and elderly respondents. We combine our historical estimates with climate model projections and detail the potential sleep impacts of future climatic changes. Our study represents the largest ever investigation of the relationship between sleep and ambient temperature and provides the first evidence that climate change may disrupt human sleep. PMID- 28560322 TI - Perpetuating the myth of the return of native forests. AB - Vina et al. imply that native forests account for China's marked increase in tree cover and that tree plantations play a minimal role. All 71 tweets linked to the article reinforce the idea that China's native forests are returning, whereas a review of their methodology indicates that it is not likely accurate. Referring news articles (n = 19) were dominated by terms associated with native forests, whereas tree plantations were rarely mentioned. PMID- 28560321 TI - Directional mechanical stability of Bacteriophage phi29 motor's 3WJ-pRNA: Extraordinary robustness along portal axis. AB - The molecular motor exploited by bacteriophage phi29 to pack DNA into its capsid is regarded as one of the most powerful mechanical devices present in viral, bacterial, and eukaryotic systems alike. Acting as a linker element, a prohead RNA (pRNA) effectively joins the connector and ATPase (adenosine triphosphatase) components of the phi29 motor. During DNA packing, this pRNA needs to withstand enormous strain along the capsid's portal axis-how this remarkable stability is achieved remains to be elucidated. We investigate the mechanical properties of the phi29 motor's three-way junction (3WJ)-pRNA using a combined steered molecular dynamics and atomic force spectroscopy approach. The 3WJ exhibits strong resistance to stretching along its coaxial helices, demonstrating its super structural robustness. This resistance disappears, however, when external forces are applied to the transverse directions. From a molecular standpoint, we demonstrate that this direction-dependent stability can be attributed to two Mg clamps that cooperate and generate mechanical resistance in the pRNA's coaxial direction. Our results suggest that the asymmetric nature of the 3WJ's mechanical stability is entwined with its biological function: Enhanced rigidity along the portal axis is likely essential to withstand the strain caused by DNA condensation, and flexibility in other directions should aid in the assembly of the pRNA and its association with other motor components. PMID- 28560324 TI - CRISPR/Cas9 gene drives in genetically variable and nonrandomly mating wild populations. AB - Synthetic gene drives based on CRISPR/Cas9 have the potential to control, alter, or suppress populations of crop pests and disease vectors, but it is unclear how they will function in wild populations. Using genetic data from four populations of the flour beetle Tribolium castaneum, we show that most populations harbor genetic variants in Cas9 target sites, some of which would render them immune to drive (ITD). We show that even a rare ITD allele can reduce or eliminate the efficacy of a CRISPR/Cas9-based synthetic gene drive. This effect is equivalent to and accentuated by mild inbreeding, which is a characteristic of many disease vectoring arthropods. We conclude that designing such drives will require characterization of genetic variability and the mating system within and among targeted populations. PMID- 28560323 TI - CTCF facilitates DNA double-strand break repair by enhancing homologous recombination repair. AB - The repair of DNA double-strand breaks (DSBs) is mediated via two major pathways, nonhomologous end joining (NHEJ) and homologous recombination (HR) repair. DSB repair is vital for cell survival, genome stability, and tumor suppression. In contrast to NHEJ, HR relies on extensive homology and templated DNA synthesis to restore the sequence surrounding the break site. We report a new role for the multifunctional protein CCCTC-binding factor (CTCF) in facilitating HR-mediated DSB repair. CTCF is recruited to DSB through its zinc finger domain independently of poly(ADP-ribose) polymers, known as PARylation, catalyzed by poly(ADP-ribose) polymerase 1 (PARP-1). CTCF ensures proper DSB repair kinetics in response to gamma-irradiation, and the loss of CTCF compromises HR-mediated repair. Consistent with its role in HR, loss of CTCF results in hypersensitivity to DNA damage, inducing agents and inhibitors of PARP. Mechanistically, CTCF acts downstream of BRCA1 in the HR pathway and associates with BRCA2 in a PARylation dependent manner, enhancing BRCA2 recruitment to DSB. In contrast, CTCF does not influence the recruitment of the NHEJ protein 53BP1 or LIGIV to DSB. Together, our findings establish for the first time that CTCF is an important regulator of the HR pathway. PMID- 28560325 TI - Harnessing the hygroscopic and biofluorescent behaviors of genetically tractable microbial cells to design biohybrid wearables. AB - Cells' biomechanical responses to external stimuli have been intensively studied but rarely implemented into devices that interact with the human body. We demonstrate that the hygroscopic and biofluorescent behaviors of living cells can be engineered to design biohybrid wearables, which give multifunctional responsiveness to human sweat. By depositing genetically tractable microbes on a humidity-inert material to form a heterogeneous multilayered structure, we obtained biohybrid films that can reversibly change shape and biofluorescence intensity within a few seconds in response to environmental humidity gradients. Experimental characterization and mechanical modeling of the film were performed to guide the design of a wearable running suit and a fluorescent shoe prototype with bio-flaps that dynamically modulates ventilation in synergy with the body's need for cooling. PMID- 28560326 TI - Field-induced magnetic instability within a superconducting condensate. AB - The application of magnetic fields, chemical substitution, or hydrostatic pressure to strongly correlated electron materials can stabilize electronic phases with different organizational principles. We present evidence for a field induced quantum phase transition, in superconducting Nd0.05Ce0.95CoIn5, that separates two antiferromagnetic phases with identical magnetic symmetry. At zero field, we find a spin-density wave that is suppressed at the critical field MU0H* = 8 T. For H > H*, a spin-density phase emerges and shares many properties with the Q phase in CeCoIn5. These results suggest that the magnetic instability is not magnetically driven, and we propose that it is driven by a modification of superconducting condensate at H*. PMID- 28560328 TI - Does basic energy access generate socioeconomic benefits? A field experiment with off-grid solar power in India. AB - This article assesses the socioeconomic effects of solar microgrids. The lack of access to electricity is a major obstacle to the socioeconomic development of more than a billion people. Off-grid solar technologies hold potential as an affordable and clean solution to satisfy basic electricity needs. We conducted a randomized field experiment in India to estimate the causal effect of off-grid solar power on electricity access and broader socioeconomic development of 1281 rural households. Within a year, electrification rates in the treatment group increased by 29 to 36 percentage points. Daily hours of access to electricity increased only by 0.99 to 1.42 hours, and the confidence intervals are wide. Kerosene expenditure on the black market decreased by 47 to 49 rupees per month. Despite these strong electrification and expenditure effects, we found no systematic evidence for changes in savings, spending, business creation, time spent working or studying, or other broader indicators of socioeconomic development. PMID- 28560329 TI - Fast label-free multilayered histology-like imaging of human breast cancer by photoacoustic microscopy. AB - The goal of breast-conserving surgery is to completely remove all of the cancer. Currently, no intraoperative tools can microscopically analyze the entire lumpectomy specimen, which results in 20 to 60% of patients undergoing second surgeries to achieve clear margins. To address this critical need, we have laid the foundation for the development of a device that could allow accurate intraoperative margin assessment. We demonstrate that by taking advantage of the intrinsic optical contrast of breast tissue, photoacoustic microscopy (PAM) can achieve multilayered histology-like imaging of the tissue surface. The high correlation of the PAM images to the conventional histologic images allows rapid computations of diagnostic features such as nuclear size and packing density, potentially identifying small clusters of cancer cells. Because PAM does not require tissue processing or staining, it can be performed promptly and intraoperatively, enabling immediate directed re-excision and reducing the number of second surgeries. PMID- 28560327 TI - Antibody-mediated neutralization of soluble MIC significantly enhances CTLA4 blockade therapy. AB - Antibody therapy targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) elicited survival benefits in cancer patients; however, the overall response rate is limited. In addition, anti-CTLA4 antibody therapy induces a high rate of immune-related adverse events. The underlying factors that may influence anti CTLA4 antibody therapy are not well defined. We report the impact of a cancer derived immune modulator, the human-soluble natural killer group 2D (NKG2D) ligand sMIC (soluble major histocompatibility complex I chain-related molecule), on the therapeutic outcome of anti-CTLA4 antibody using an MIC transgenic spontaneous TRAMP (transgenic adenocarcinoma of the mouse prostate)/MIC tumor model. Unexpectedly, animals with elevated serum sMIC (sMIChi) responded poorly to anti-CTLA4 antibody therapy, with significantly shortened survival due to increased lung metastasis. These sMIChi animals also developed colitis in response to anti-CTLA4 antibody therapy. Coadministration of an sMIC-neutralizing monoclonal antibody with the anti-CTLA4 antibody alleviated treatment-induced colitis in sMIChi animals and generated a cooperative antitumor therapeutic effect by synergistically augmenting innate and adoptive antitumor immune responses. Our findings imply that a new combination therapy could improve the clinical response to anti-CTLA4 antibody therapy. Our findings also suggest that prescreening cancer patients for serum sMIC may help in selecting candidates who will elicit a better response to anti-CTLA4 antibody therapy. PMID- 28560330 TI - A two-dimensional semiconductor transistor with boosted gate control and sensing ability. AB - Transistors with exfoliated two-dimensional (2D) materials on a SiO2/Si substrate have been applied and have been proven effective in a wide range of applications, such as circuits, memory, photodetectors, gas sensors, optical modulators, valleytronics, and spintronics. However, these devices usually suffer from limited gate control because of the thick SiO2 gate dielectric and the lack of reliable transfer method. We introduce a new back-gate transistor scheme fabricated on a novel Al2O3/ITO (indium tin oxide)/SiO2/Si "stack" substrate, which was engineered with distinguishable optical identification of exfoliated 2D materials. High-quality exfoliated 2D materials could be easily obtained and recognized on this stack. Two typical 2D materials, MoS2 and ReS2, were implemented to demonstrate the enhancement of gate controllability. Both transistors show excellent electrical characteristics, including steep subthreshold swing (62 mV dec-1 for MoS2 and 83 mV dec-1 for ReS2), high mobility (61.79 cm2 V-1 s-1 for MoS2 and 7.32 cm2 V-1 s-1 for ReS2), large on/off ratio (~107), and reasonable working gate bias (below 3 V). Moreover, MoS2 and ReS2 photodetectors fabricated on the basis of the scheme have impressively leading photoresponsivities of 4000 and 760 A W-1 in the depletion area, respectively, and both have exceeded 106 A W-1 in the accumulation area, which is the best ever obtained. This opens up a suite of applications of this novel platform in 2D materials research with increasing needs of enhanced gate control. PMID- 28560331 TI - Repeated divergent selection on pigmentation genes in a rapid finch radiation. AB - Instances of recent and rapid speciation are suitable for associating phenotypes with their causal genotypes, especially if gene flow homogenizes areas of the genome that are not under divergent selection. We study a rapid radiation of nine sympatric bird species known as capuchino seedeaters, which are differentiated in sexually selected characters of male plumage and song. We sequenced the genomes of a phenotypically diverse set of species to search for differentiated genomic regions. Capuchinos show differences in a small proportion of their genomes, yet selection has acted independently on the same targets in different members of this radiation. Many divergent regions contain genes involved in the melanogenesis pathway, with the strongest signal originating from putative regulatory regions. Selection has acted on these same genomic regions in different lineages, likely shaping the evolution of cis-regulatory elements, which control how more conserved genes are expressed and thereby generate diversity in classically sexually selected traits. PMID- 28560332 TI - Dynamic and programmable self-assembly of micro-rafts at the air-water interface. AB - Dynamic self-assembled material systems constantly consume energy to maintain their spatiotemporal structures and functions. Programmable self-assembly translates information from individual parts to the collective whole. Combining dynamic and programmable self-assembly in a single platform opens up the possibilities to investigate both types of self-assembly simultaneously and to explore their synergy. This task is challenging because of the difficulty in finding suitable interactions that are both dissipative and programmable. We present a dynamic and programmable self-assembling material system consisting of spinning at the air-water interface circular magnetic micro-rafts of radius 50 MUm and with cosinusoidal edge-height profiles. The cosinusoidal edge-height profiles not only create a net dissipative capillary repulsion that is sustained by continuous torque input but also enable directional assembly of micro-rafts. We uncover the layered arrangement of micro-rafts in the patterns formed by dynamic self-assembly and offer mechanistic insights through a physical model and geometric analysis. Furthermore, we demonstrate programmable self-assembly and show that a 4-fold rotational symmetry encoded in individual micro-rafts translates into 90 degrees bending angles and square-based tiling in the assembled structures of micro-rafts. We anticipate that our dynamic and programmable material system will serve as a model system for studying nonequilibrium dynamics and statistical mechanics in the future. PMID- 28560335 TI - Global disparity in the supply of commercial weather and climate information services. AB - Information about weather and climate is vital for many areas of decision-making, particularly under conditions of increasing vulnerability and uncertainty related to climate change. We have quantified the global commercial supply of weather and climate information services. Although government data are sometimes freely available, the interpretation and analysis of those data, alongside additional data collection, are required to formulate responses to specific challenges in areas such as health, agriculture, and the built environment. Using transactional data, we analyzed annual spending by private and public organizations on commercial weather and climate information in more than 180 countries by industrial sector, region, per capita, and percentage of GDP (gross domestic product) and against the country's climate and extreme weather risk. There are major imbalances regarding access to these essential services between different countries based on region and development status. There is also no relationship between the level of climate and weather risks that a country faces and the level of per capita spending on commercial weather and climate information in that country. At the international level, action is being taken to improve access to information services. With a better understanding of the flows of commercial weather and climate information, as explored in this study, it will be possible to tackle these regional and development-related disparities and thus to increase resilience to climate and weather risks. PMID- 28560334 TI - Extraordinary linear dynamic range in laser-defined functionalized graphene photodetectors. AB - Graphene-based photodetectors have demonstrated mechanical flexibility, large operating bandwidth, and broadband spectral response. However, their linear dynamic range (LDR) is limited by graphene's intrinsic hot-carrier dynamics, which causes deviation from a linear photoresponse at low incident powers. At the same time, multiplication of hot carriers causes the photoactive region to be smeared over distances of a few micrometers, limiting the use of graphene in high resolution applications. We present a novel method for engineering photoactive junctions in FeCl3-intercalated graphene using laser irradiation. Photocurrent measured at these planar junctions shows an extraordinary linear response with an LDR value at least 4500 times larger than that of other graphene devices (44 dB) while maintaining high stability against environmental contamination without the need for encapsulation. The observed photoresponse is purely photovoltaic, demonstrating complete quenching of hot-carrier effects. These results pave the way toward the design of ultrathin photodetectors with unprecedented LDR for high definition imaging and sensing. PMID- 28560333 TI - Learning to read alters cortico-subcortical cross-talk in the visual system of illiterates. AB - Learning to read is known to result in a reorganization of the developing cerebral cortex. In this longitudinal resting-state functional magnetic resonance imaging study in illiterate adults, we show that only 6 months of literacy training can lead to neuroplastic changes in the mature brain. We observed that literacy-induced neuroplasticity is not confined to the cortex but increases the functional connectivity between the occipital lobe and subcortical areas in the midbrain and the thalamus. Individual rates of connectivity increase were significantly related to the individual decoding skill gains. These findings crucially complement current neurobiological concepts of normal and impaired literacy acquisition. PMID- 28560336 TI - Chiral plasmonics. AB - We present a comprehensive overview of chirality and its optical manifestation in plasmonic nanosystems and nanostructures. We discuss top-down fabricated structures that range from solid metallic nanostructures to groupings of metallic nanoparticles arranged in three dimensions. We also present the large variety of bottom-up synthesized structures. Using DNA, peptides, or other scaffolds, complex nanoparticle arrangements of up to hundreds of individual nanoparticles have been realized. Beyond this static picture, we also give an overview of recent demonstrations of active chiral plasmonic systems, where the chiral optical response can be controlled by an external stimulus. We discuss the prospect of using the unique properties of complex chiral plasmonic systems for enantiomeric sensing schemes. PMID- 28560337 TI - Simple technologies and diverse food strategies of the Late Pleistocene and Early Holocene at Huaca Prieta, Coastal Peru. AB - Simple pebble tools, ephemeral cultural features, and the remains of maritime and terrestrial foods are present in undisturbed Late Pleistocene and Early Holocene deposits underneath a large human-made mound at Huaca Prieta and nearby sites on the Pacific coast of northern Peru. Radiocarbon ages indicate an intermittent human presence dated between ~15,000 and 8000 calendar years ago before the mound was built. The absence of fishhooks, harpoons, and bifacial stone tools suggests that technologies of gathering, trapping, clubbing, and exchange were used primarily to procure food resources along the shoreline and in estuarine wetlands and distant mountains. The stone artifacts are minimally worked unifacial stone tools characteristic of several areas of South America. Remains of avocado, bean, and possibly cultivated squash and chile pepper are also present, suggesting human transport and consumption. Our new findings emphasize an early coastal lifeway of diverse food procurement strategies that suggest detailed observation of resource availability in multiple environments and a knowledgeable economic organization, although technologies were simple and campsites were seemingly ephemeral and discontinuous. These findings raise questions about the pace of early human movement along some areas of the Pacific coast and the level of knowledge and technology required to exploit maritime and inland resources. PMID- 28560338 TI - High seismic attenuation at a mid-ocean ridge reveals the distribution of deep melt. AB - At most mid-ocean ridges, a wide region of decompression melting must be reconciled with a narrow neovolcanic zone and the establishment of full oceanic crustal thickness close to the rift axis. Two competing paradigms have been proposed to explain melt focusing: narrow mantle upwelling due to dynamic effects related to in situ melt or wide mantle upwelling with lateral melt transport in inclined channels. Measurements of seismic attenuation provide a tool for identifying and characterizing the presence of melt and thermal heterogeneity in the upper mantle. We use a unique data set of teleseismic body waves recorded on the Cascadia Initiative's Amphibious Array to simultaneously measure seismic attenuation and velocity across an entire oceanic microplate. We observe maximal differential attenuation and the largest delays ([Formula: see text] s and deltaTS ~ 2 s) in a narrow zone <50 km from the Juan de Fuca and Gorda ridge axes, with values that are not consistent with laboratory estimates of temperature or water effects. The implied seismic quality factor (Qs <= 25) is among the lowest observed worldwide. Models harnessing experimentally derived anelastic scaling relationships require a 150-km-deep subridge region containing up to 2% in situ melt. The low viscosity and low density associated with this deep, narrow melt column provide the conditions for dynamic mantle upwelling, explaining a suite of geophysical observations at ridges, including electrical conductivity and shear velocity anomalies. PMID- 28560339 TI - Robust nanogenerators based on graft copolymers via control of dielectrics for remarkable output power enhancement. AB - A robust nanogenerator based on poly(tert-butyl acrylate) (PtBA)-grafted polyvinylidene difluoride (PVDF) copolymers via dielectric constant control through an atom-transfer radical polymerization technique, which can markedly increase the output power, is demonstrated. The copolymer is mainly composed of alpha phases with enhanced dipole moments due to the pi-bonding and polar characteristics of the ester functional groups in the PtBA, resulting in the increase of dielectric constant values by approximately twice, supported by Kelvin probe force microscopy measurements. This increase in the dielectric constant significantly increased the density of the charges that can be accumulated on the copolymer during physical contact. The nanogenerator generates output signals of 105 V and 25 MUA/cm2, a 20-fold enhancement in output power, compared to pristine PVDF-based nanogenerator after tuning the surface potential using a poling method. The markedly enhanced output performance is quite stable and reliable in harsh mechanical environments due to the high flexibility of the films. On the basis of these results, a much faster charging characteristic is demonstrated in this study. PMID- 28560340 TI - Inducing superconductivity in Weyl semimetal microstructures by selective ion sputtering. AB - By introducing a superconducting gap in Weyl or Dirac semimetals, the superconducting state inherits the nontrivial topology of their electronic structure. As a result, Weyl superconductors are expected to host exotic phenomena, such as nonzero-momentum pairing due to their chiral node structure, or zero-energy Majorana modes at the surface. These are of fundamental interest to improve our understanding of correlated topological systems, and, moreover, practical applications in phase-coherent devices and quantum applications have been proposed. Proximity-induced superconductivity promises to allow these experiments on nonsuperconducting Weyl semimetals. We show a new route to reliably fabricate superconducting microstructures from the nonsuperconducting Weyl semimetal NbAs under ion irradiation. The significant difference in the surface binding energy of Nb and As leads to a natural enrichment of Nb at the surface during ion milling, forming a superconducting surface layer (Tc ~ 3.5 K). Being formed from the target crystal itself, the ideal contact between the superconductor and the bulk may enable an effective gapping of the Weyl nodes in the bulk because of the proximity effect. Simple ion irradiation may thus serve as a powerful tool for the fabrication of topological quantum devices from monoarsenides, even on an industrial scale. PMID- 28560341 TI - Photonic-plasmonic hybrid single-molecule nanosensor measures the effect of fluorescent labels on DNA-protein dynamics. AB - Current methods to study molecular interactions require labeling the subject molecules with fluorescent reporters. However, the effect of the fluorescent reporters on molecular dynamics has not been quantified because of a lack of alternative methods. We develop a hybrid photonic-plasmonic antenna-in-a nanocavity single-molecule biosensor to study DNA-protein dynamics without using fluorescent labels. Our results indicate that the fluorescein and fluorescent protein labels decrease the interaction between a single DNA and a protein due to weakened electrostatic interaction. Although the study is performed on the DNA XPA system, the conclusion has a general implication that the traditional fluorescent labeling methods might be misestimating the molecular interactions. PMID- 28560342 TI - How birds direct impulse to minimize the energetic cost of foraging flight. AB - Birds frequently hop and fly between tree branches to forage. To determine the mechanical energy trade-offs of their bimodal locomotion, we rewarded four Pacific parrotlets with a seed for flying voluntarily between instrumented perches inside a new aerodynamic force platform. By integrating direct measurements of both leg and wing forces with kinematics in a bimodal long jump and flight model, we discovered that parrotlets direct their leg impulse to minimize the mechanical energy needed to forage over different distances and inclinations. The bimodal locomotion model further shows how even a small lift contribution from a single proto-wingbeat would have significantly lengthened the long jump of foraging arboreal dinosaurs. These avian bimodal locomotion strategies can also help robots traverse cluttered environments more effectively. PMID- 28560343 TI - Divergence of species responses to climate change. AB - Climate change can have profound impacts on biodiversity and the sustainability of many ecosystems. Various studies have investigated the impacts of climate change, but large-scale, trait-specific impacts are less understood. We analyze abundance data over time for 86 tree species/groups across the eastern United States spanning the last three decades. We show that more tree species have experienced a westward shift (73%) than a poleward shift (62%) in their abundance, a trend that is stronger for saplings than adult trees. The observed shifts are primarily due to the changes of subpopulation abundances in the leading edges and are significantly associated with changes in moisture availability and successional processes. These spatial shifts are associated with species that have similar traits (drought tolerance, wood density, and seed weight) and evolutionary histories (most angiosperms shifted westward and most gymnosperms shifted poleward). Our results indicate that changes in moisture availability have stronger near-term impacts on vegetation dynamics than changes in temperature. The divergent responses to climate change by trait- and phylogenetic-specific groups could lead to changes in composition of forest ecosystems, putting the resilience and sustainability of various forest ecosystems in question. PMID- 28560345 TI - Observation and ultrafast dynamics of a nonvalence correlation-bound state of an anion. AB - Nonvalence states of molecular anions play key roles in processes, such as electron mobility, in rare-gas liquids, radiation-induced damage to DNA, and the formation of anions in the interstellar medium. Recently, a class of nonvalence bound anion state has been predicted by theory in which correlation forces are predominantly responsible for binding the excess electron. We present a direct spectroscopic observation of this nonvalence correlation-bound state (CBS) in the para-toluquinone trimer cluster anion. Time-resolved photoelectron velocity map imaging shows that photodetachment of the CBS produces a narrow and highly anisotropic photoelectron distribution, consistent with detachment from an s-like orbital. The CBS is bound by ~50 meV and decays by vibration-mediated autodetachment with a lifetime of 700 +/- 100 fs. These states are likely to be common in large and/or polarizable anions and clusters and may act as doorway states in electron attachment processes. PMID- 28560346 TI - Nonlocally sensing the magnetic states of nanoscale antiferromagnets with an atomic spin sensor. AB - The ability to sense the magnetic state of individual magnetic nano-objects is a key capability for powerful applications ranging from readout of ultradense magnetic memory to the measurement of spins in complex structures with nanometer precision. Magnetic nano-objects require extremely sensitive sensors and detection methods. We create an atomic spin sensor consisting of three Fe atoms and show that it can detect nanoscale antiferromagnets through minute, surface mediated magnetic interaction. Coupling, even to an object with no net spin and having vanishing dipolar stray field, modifies the transition matrix element between two spin states of the Fe atom-based spin sensor that changes the sensor's spin relaxation time. The sensor can detect nanoscale antiferromagnets at up to a 3-nm distance and achieves an energy resolution of 10 MUeV, surpassing the thermal limit of conventional scanning probe spectroscopy. This scheme permits simultaneous sensing of multiple antiferromagnets with a single-spin sensor integrated onto the surface. PMID- 28560344 TI - The timetable of evolution. AB - The integration of fossils, phylogeny, and geochronology has resulted in an increasingly well-resolved timetable of evolution. Life appears to have taken root before the earliest known minimally metamorphosed sedimentary rocks were deposited, but for a billion years or more, evolution played out beneath an essentially anoxic atmosphere. Oxygen concentrations in the atmosphere and surface oceans first rose in the Great Oxygenation Event (GOE) 2.4 billion years ago, and a second increase beginning in the later Neoproterozoic Era [Neoproterozoic Oxygenation Event (NOE)] established the redox profile of modern oceans. The GOE facilitated the emergence of eukaryotes, whereas the NOE is associated with large and complex multicellular organisms. Thus, the GOE and NOE are fundamental pacemakers for evolution. On the time scale of Earth's entire 4 billion-year history, the evolutionary dynamics of the planet's biosphere appears to be fast, and the pace of evolution is largely determined by physical changes of the planet. However, in Phanerozoic ecosystems, interactions between new functions enabled by the accumulation of characters in a complex regulatory environment and changing biological components of effective environments appear to have an important influence on the timing of evolutionary innovations. On the much shorter time scale of transient environmental perturbations, such as those associated with mass extinctions, rates of genetic accommodation may have been limiting for life. PMID- 28560347 TI - Carbon dots in zeolites: A new class of thermally activated delayed fluorescence materials with ultralong lifetimes. AB - Thermally activated delayed fluorescence (TADF) materials are inspiring intensive research in optoelectronic applications. To date, most of the TADF materials are limited to metal-organic complexes and organic molecules with lifetimes of several microseconds/milliseconds that are sensitive to oxygen. We report a facial and general "dots-in-zeolites" strategy to in situ confine carbon dots (CDs) in zeolitic matrices during hydrothermal/solvothermal crystallization to generate high-efficient TADF materials with ultralong lifetimes. The resultant CDs@zeolite composites exhibit high quantum yields up to 52.14% and ultralong lifetimes up to 350 ms at ambient temperature and atmosphere. This intriguing TADF phenomenon is due to the fact that nanoconfined space of zeolites can efficiently stabilize the triplet states of CDs, thus enabling the reverse intersystem crossing process for TADF. Meanwhile, zeolite frameworks can also hinder oxygen quenching to present TADF behavior at air atmosphere. This design concept introduces a new perspective to develop materials with unique TADF performance and various novel delayed fluorescence-based applications. PMID- 28560348 TI - Molecular "surgery" on a 23-gold-atom nanoparticle. AB - Compared to molecular chemistry, nanochemistry is still far from being capable of tailoring particle structure and functionality at an atomic level. Numerous effective methodologies that can precisely tailor specific groups in organic molecules without altering the major carbon bones have been developed, but for nanoparticles, it is still extremely difficult to realize the atomic-level tailoring of specific sites in a particle without changing the structure of other parts (for example, replacing specific surface motifs and deleting one or two metal atoms). This issue severely limits nanochemists from knowing how different motifs in a nanoparticle contribute to its overall properties. We demonstrate a site-specific "surgery" on the surface motif of an atomically precise 23-gold atom [Au23(SR)16]- nanoparticle by a two-step metal-exchange method, which leads to the "resection" of two surface gold atoms and the formation of a new 21-gold atom nanoparticle, [Au21(SR)12(Ph2PCH2PPh2)2]+, without changing the other parts of the starting nanoparticle structure. This precise surgery of the nanocluster reveals the different reactivity of the surface motifs and the inner core: the least effect of surface motifs on optical absorption but a distinct effect on photoluminescence (that is, a 10-fold enhancement of luminescence after the tailoring). First-principles calculations further reveal the thermodynamically preferred reaction pathway for the formation of [Au21(SR)12(Ph2PCH2PPh2)2]+. This work constitutes a major step toward the development of atomically precise, versatile nanochemistry for the precise tailoring of the nanocluster structure to control its properties. PMID- 28560350 TI - Increasing the revenue from lignocellulosic biomass: Maximizing feedstock utilization. AB - The production of renewable chemicals and biofuels must be cost- and performance- competitive with petroleum-derived equivalents to be widely accepted by markets and society. We propose a biomass conversion strategy that maximizes the conversion of lignocellulosic biomass (up to 80% of the biomass to useful products) into high-value products that can be commercialized, providing the opportunity for successful translation to an economically viable commercial process. Our fractionation method preserves the value of all three primary components: (i) cellulose, which is converted into dissolving pulp for fibers and chemicals production; (ii) hemicellulose, which is converted into furfural (a building block chemical); and (iii) lignin, which is converted into carbon products (carbon foam, fibers, or battery anodes), together producing revenues of more than $500 per dry metric ton of biomass. Once de-risked, our technology can be extended to produce other renewable chemicals and biofuels. PMID- 28560349 TI - Argininosuccinate synthase 1 is an intrinsic Akt repressor transactivated by p53. AB - The transcription factor p53 is at the core of a built-in tumor suppression system that responds to varying degrees of stress input and is deregulated in most human cancers. Befitting its role in maintaining cellular fitness and fidelity, p53 regulates an appropriate set of target genes in response to cellular stresses. However, a comprehensive understanding of this scheme has not been accomplished. We show that argininosuccinate synthase 1 (ASS1), a citrulline aspartate ligase in de novo arginine synthesis pathway, was directly transactivated by p53 in response to genotoxic stress, resulting in the rearrangement of arginine metabolism. Furthermore, we found that x-ray irradiation promoted the systemic induction of Ass1 and concomitantly increased plasma arginine levels in p53+/+ mice but not in p53-/- mice. Notably, Ass1+/- mice exhibited hypersensitivity to whole-body irradiation owing to increased apoptosis in the small intestinal crypts. Analyses of ASS1-deficient cells generated using the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated 9) system revealed that ASS1 plays a pivotal role in limiting Akt phosphorylation. In addition, aberrant activation of Akt resulting from ASS1 loss disrupted Akt-mediated cell survival signaling activity under genotoxic stress. Building on these results, we demonstrated that p53 induced an intrinsic Akt repressor, ASS1, and the perturbation of ASS1 expression rendered cells susceptible to genotoxic stress. Our findings uncover a new function of p53 in the regulation of Akt signaling and reveal how p53, ASS1, and Akt are interrelated to each other. PMID- 28560352 TI - Endourologic Management of an Iatrogenic Ureteral Avulsion Using a Thermoexpandable Nickel-Titanium Alloy Stent (Memokath 051). AB - Background: The use of ureteroscopy in the management of urolithiasis is well established. Ureteral avulsion is a rare but challenging complication of the procedure. Postureteral injury strictures are a common result of such injuries and are typically managed with reconstructive surgery or endoscopically with polymer stent. This case represents the first effective management of ureteral avulsion and subsequent ureteral stricture using a Memokath ureteral stent. Case Presentation: A 54-year-old gentleman presented to the Department of Urology with right loin pain as a result of right renal calculi, previously treated with extracorporeal shockwave lithotripsy. The patient was investigated with ultrasonography and noncontrast CT of his urinary tract, revealing mild right sided hydroureteronephrosis and two right proximal ureteral stones, measuring 9 and 4 mm, respectively. He underwent a right semirigid ureteroscopy and laser stone fragmentation with complete stone clearance, but on withdrawal of the ureteroscope, a right ureteral injury occurred with ureteral mucosal avulsion extending from the L3/L4 vertebrae to the right vesicoureteral junction. Upon consideration of several options for management of this ureteral avulsion, the patient opted for endourologic stenting. After 10 months, the patient developed a ureteral stricture as a result of the avulsion. He was troubled with stent related symptoms and wanted to avoid reconstructive surgery and, therefore, opted for a Memokath ureteral stent. The patient recovered well with excellent renal function and drainage on subsequent mercaptoacetyl-triglycyl renogram. Conclusion: Ureteral avulsion is a rare but important complication of ureteroscopy with numerous options available for management. Discussions should be had with the patient to weigh the various options, and metallic stents should be considered in the long-term management of such injuries and their sequel. PMID- 28560353 TI - A Large Posteriorly Located Prostatic Mass Lesion Challenging the Robotic Surgeon: Prostate Leiomyoma. AB - Background: Prostatic leiomyoma is a benign and rare condition of the prostate. Robotic surgery is increasingly being applied in the surgical management of prostate cancer. Case Presentation: Herein, a mass lesion that was located in the posterior part of the prostate between seminal vesicles that was identified during robotic surgery is presented. This lesion further challenged the console surgeon during performing a robotic radical prostatectomy procedure for a 200 g large prostate with prostate cancer. Conclusion: Prostatic leiomyomas that are benign mesenchymal smooth muscle tumors might present as a posteriorly located mass lesion between seminal vesicles that could challenge the surgeon during surgery, which should be kept in mind. PMID- 28560354 TI - Citation analysis of scientific categories. AB - Databases catalogue the corpus of research literature into scientific categories and report classes of bibliometric data such as the number of citations to articles, the number of authors, journals, funding agencies, institutes, references, etc. The number of articles and citations in a category are gauges of productivity and scientific impact but a quantitative basis to compare researchers between categories is limited. Here, we compile a list of bibliometric indicators for 236 science categories and citation rates of the 500 most cited articles of each category. The number of citations per paper vary by several orders of magnitude and are highest in multidisciplinary sciences, general internal medicine, and biochemistry and lowest in literature, poetry, and dance. A regression model demonstrates that citation rates to the top articles in each category increase with the square root of the number of articles in a category and decrease proportionately with the age of the references: articles in categories that cite recent research are also cited more frequently. The citation rate correlates positively with the number of funding agencies that finance the research. The category h-index correlates with the average number of cites to the top 500 ranked articles of each category ([Formula: see text]). Furthermore, only a few journals publish the top 500 cited articles in each category: four journals publish 60% ([Formula: see text]) of these and ten publish 81% ([Formula: see text]). PMID- 28560355 TI - Lake Afrera, a structural depression in the Northern Afar Rift (Red Sea). AB - The boundary between the African and Arabian plates in the Southern Red Sea region is displaced inland in the northern Afar rift, where it is marked by the Red Sea-parallel Erta Ale, Alaita, and Tat Ali volcanic ridges. The Erta Ale is offset by about 20 and 40 km from the two en echelon ridges to the south. The offset area is highly seismic and marked by a depression filled by lake Afrera, a saline body of water fed by hydrothermal springs. Acoustic bathymetric profiles show ~80 m deep canyons parallel to the NNW shore of the lake, part of a system of extensional normal faults striking parallel to the Red Sea. This system is intersected by oblique structures, some with strike-slip earthquakes, in what might evolve into a transform boundary. Given that the lake's surface lies today about 112 m below sea level, the depressed (minus ~190 m below sea level) lake's bottom area may be considered the equivalent of the "nodal deep" in slow-slip oceanic transforms. The chemistry of the lake is compatible with the water having originated from hydrothermal liquids that had reacted with evaporites and basalts, rather than residual from evaporation of sea water. Bottom sediments include calcitic grains, halite and gypsum, as well as ostracod and diatom tests. The lake's level appears to have dropped by over 10 m during the last ~50 years, continuing a drying up trend of the last few thousand years, after a "wet" stage 9,800 and 7,800 years before present when according to Gasse (1973) Lake Afrera covered an area several times larger than at present. This "wet" stage corresponds to an early Holocene warm-humid climate that prevailed in Saharan and Sub Saharan Africa. Lake Abhe, located roughly 250 km south of Afrera, shows similar climate-driven oscillations of its level. PMID- 28560351 TI - Global increase in replication fork speed during a p57KIP2-regulated erythroid cell fate switch. AB - Cell cycle regulators are increasingly implicated in cell fate decisions, such as the acquisition or loss of pluripotency and self-renewal potential. The cell cycle mechanisms that regulate these cell fate decisions are largely unknown. We studied an S phase-dependent cell fate switch, in which murine early erythroid progenitors transition in vivo from a self-renewal state into a phase of active erythroid gene transcription and concurrent maturational cell divisions. We found that progenitors are dependent on p57KIP2-mediated slowing of replication forks for self-renewal, a novel function for cyclin-dependent kinase inhibitors. The switch to differentiation entails rapid down-regulation of p57KIP2 with a consequent global increase in replication fork speed and an abruptly shorter S phase. Our work suggests that cell cycles with specialized global DNA replication dynamics are integral to the maintenance of specific cell states and to cell fate decisions. PMID- 28560356 TI - ROTAVAC(r) does not interfere with the immune response to childhood vaccines in Indian infants: A randomized placebo controlled trial. AB - A phase III randomized double-blind placebo-controlled trial was conducted in the urban neighborhoods of Delhi to assess whether Oral Rotavirus Vaccine ROTAVAC(r) interferes with the immune response to childhood vaccines when coadministered. Infants aged 6 weeks were randomized to receive three doses of either ROTAVAC(r) or placebo along with childhood vaccines: Oral Polio Vaccine and vaccines against Diphtheria, Pertussis, Tetanus, Hepatitis B and Haemophilus influenza type b given as Pentavalent at 6, 10, 14 weeks of age. Blood specimens were collected from all infants at baseline and 4 weeks post dose 3 to assess the immune response to antigens in Oral Polio Vaccine, Pentavalent and ROTAVAC(r) vaccines. Non-inferiority of immune response to all vaccine components of the childhood vaccines when ROTAVAC(r) was administered concurrently was demonstrated. Non inferior immune responses to childhood vaccines were evaluated based on the seroprotective levels of antibodies against polio types 1, 2, and 3, Diphtheria toxoid, Tetanus toxoid, Haemophilus influenza type b anti- polyribosyl ribitol phosphate antibodies and Hepatitis B antibodies; and the Geometric Mean Concentration for Pertussis. The proportion of infants who seroconverted (>=4 fold rise) was 38.6% in the ROTAVAC(r) group and 12.2% in the placebo group. The frequency and severity of immediate adverse events, adverse events and serious adverse events were similar in both groups. None of the five reported deaths were considered to be related to the ROTAVAC(r) and no case of intussusception meeting Brighton Diagnostic Certainty Level I criteria was reported. This study demonstrated that ROTAVAC(r) can be safely administered with childhood vaccines without interfering with the immune response to the antigens contained in these vaccines. PMID- 28560357 TI - Impact of heme on specific antibody production in mice: promotive, inhibitive or null outcome is determined by its concentration. AB - Free heme is an endogenous danger signal that provokes innate immunity. Active innate immunity provides a precondition of an effective adaptive immune response. However, heme catabolites, CO, biliverdin and bilirubin trigger immunosuppression. Furthermore, free heme induces expression of heme oxygenase-1 to increase production of CO, biliverdin and bilirubin. As such, free heme can play a paradoxical role in adaptive immunity. What is the outcome of the animal immune response to an antigen in the presence of free heme? This question remains to be explored. Here, we report the immunization results of rats and mice after intraperitoneal injection of formulations containing BSA and heme. When the heme concentrations were below 1 MUM, between 1 MUM and 5 MUM and above 5 MUM, production of anti-BSA IgG and IgM was unaffected, enhanced and suppressed, respectively. The results suggest that heme can influence adaptive immunity by double concentration-thresholds. If the heme concentrations are less than the first threshold, there is no effect on adaptive immunity; if the concentrations are more than the first but less than the second threshold, there is promotion effect; and if the concentrations are more than the second threshold, there is an inhibitory effect. A hypothesis is also presented here to explain the mechanism. PMID- 28560358 TI - Hepatocyte-specific expression of constitutively active Alk5 exacerbates thioacetamide-induced liver injury in mice. AB - While Transforming growth factor-betas (Tgf-betas) have been known to play an important role in liver fibrosis through an activation of Hepatic Stellate Cells (HSC), their fibrotic role on hepatocytes in liver damage has not been addressed thoroughly. To shed more light on the hepatocyte-specific role of Tgf-beta signaling during liver fibrosis, we generated transgenic mice expressing constitutively active Tgf-beta type I receptor Alk5 under the control of albumin promoter. Uninjured mice with increased Tgf-beta/Alk5 signaling in hepatocytes (caAlk5/Alb-Cre mice) did not show characteristics related to hepatocyte death, fibrosis and inflammation. When subjected to thioacetamide (TAA) treatment, caAlk5/Alb-Cre mice exhibited more severe liver injury, when compared to control littermates. After TAA administration for 12 weeks, an increase in pathological changes was evident in caAlk5/Alb-Cre livers, with higher number of infiltrating cells in the portal and periportal area. Immunohistochemistry for F4/80, myeloperoxidase and CD3 showed that there was an increased accumulation of macrophages, neutrophils and T-lymphocytes, respectively, in caAlk5/Alb-Cre livers. Coincidently, we observed an exacerbated liver damage as seen by increases in serum aminotransferase level and number of apoptotic hepatocytes in caAlk5/Alb-Cre mice. Sirius staining of collagen demonstrated that the fibrotic response was worsened in caAlk5/Alb-Cre mice. The enhanced fibrosis in mutant livers was associated with marked production of alpha-SMA-positive myofibroblast. Hepatic expression of genes indicative of HSC activation was greater in caAlk5/Alb-Cre mice. In conclusion, our data indicated that elevation of Tgf-beta signaling via Alk5 in hepatocytes is not sufficient to induce liver pathology but plays an important role in amplifying TAA-induced liver damage. PMID- 28560359 TI - Analysis of plastic residues in maple sap and syrup collected from tubing systems sanitized with isopropyl alcohol. AB - A plastic tubing system operated under vacuum is usually used to collect sap from maple trees during spring time to produce maple syrup. This system is commonly sanitized with isopropyl alcohol (IPA) to remove microbial contamination colonizing the system during the sugar season. Questions have been raised whether IPA would contribute to the leaching of plastic residues in maple sap and syrup coming from sanitized systems. First, an extraction experiment was performed in the lab on commercial plastic tubing materials that were submitted to IPA under harsh conditions. The results of the GC-MS analysis revealed the presence of many compounds that served has target for further tests. Secondly, tests were done on early and mid-season maple sap and syrup coming from many sugarbushes using IPA or not to determine potential concentrations of plastic residues. Results obtained from sap and syrup samples showed that no quantifiable (< 1-75 MUg/L) concentration of any plastic molecules tested was determined in all samples coming from IPA treated or not treated systems. However, some samples of first sap run used as a rinse solution to be discarded before the season start and that were coming from non sanitized or IPA sanitized systems, showed quantifiable concentrations of chemical residue such as ultraviolet protector (octabenzone). These results show that IPA can be safely used to sanitize maple sap collection system in regards to the leaching of plastic residues in maple sap and syrup and reinforced the need to thoroughly rinse the tubing system at the beginning of the season for both sanitized and non sanitized systems. PMID- 28560360 TI - A wash-free SNAP-tag fluorogenic probe based on the additive effects of quencher release and environmental sensitivity. AB - A 1,8-naphthalimide-derived fluorogenic probe was reported to label SNAP-tag fusion proteins in living cells. The probe can rapidly label a SNAP-tag and exhibit a fluorescence increase of 36-fold due to the additive effects of environment sensitivity of fluorophores and inhibition of photo-induced electron transfer from O6-benzylguanine to the fluorophore. The labeling of intracellular proteins has been successfully achieved without a wash-out procedure. PMID- 28560361 TI - A fluorescence turn-on probe for human (bovine) serum albumin based on the hydrolysis of a dioxaborine group promoted by proteins. AB - A fluorescence "off-on" probe CBF, constructed by incorporating a dioxaborine unit into a microenvironment-sensitive fluorophore, was developed for serum albumin (SA). Upon binding to SA, the dioxaborine group in CBF was hydrolyzed into beta-diketonate, which triggered dramatic fluorescence enhancement (over 1000-fold) along with a remarkable blue-shift (~100 nm). The bioimaging results suggested that more SA were taken in by cancer cells. PMID- 28560362 TI - A new approach to surface activation of porous nanomaterials using non-thermal helium atmospheric pressure plasma jet treatment. AB - Non-thermal helium atmospheric pressure plasma jet treatment is applied to the surface activation of porous TiO2 nanoparticle assemblies. Treatment conditions such as the working distance of the plasma discharge, helium gas flow rate, and treatment time are optimized for effective removal of contaminants from the assembly surface. Laser desorption/ionization time-of-flight mass spectrometry (LDI-TOF MS) is applied to detect trace amounts of contaminants on assembly surfaces. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations confirm that the nanoparticle assemblies retain their original perfect spherical structures as well as their ultra-fine convex-concave nano surfaces even after the plasma jet treatment. N2 adsorption/desorption and X-ray diffraction (XRD) measurements show no significant changes in their BET specific surface areas and crystal structures, respectively. The plasma jet-treated TiO2 nanoparticle assemblies show a 3.8 fold improvement in their reaction rate constants for methylene blue degradation and a 2 fold enhancement of their photocurrents under UV irradiation when compared with untreated TiO2. PMID- 28560363 TI - Formation of (PNP)Rh complexes containing covalent rhodium-zinc bonds in studies of potential Rh-catalysed Negishi coupling. AB - While investigating rhodium-catalyzed Negishi coupling, it was observed that the (PNP)Rh fragment readily inserted into zinc-carbon bonds to form isolable molecules with covalent rhodium-zinc bonds. PMID- 28560364 TI - Copper-catalyzed acyltrifluoromethylation of alkenes: rapid access to trifluoroethyl indanones and related compounds. AB - Copper-catalyzed acyltrifluoromethylation of alkenes has been developed for the first time, affording trifluoroethyl indanones and related cyclic ketones in promising yields with excellent diastereoselectivity. The fast incorporation of CF3 and indanone into a single molecule renders it an efficient and valuable tool for the synthesis of biologically active compounds. PMID- 28560365 TI - A 365 nm UV LED-excitable antenna ligand for switchable lanthanide luminescence. AB - The time-resolved luminescence of lanthanide complexes is a highly sensitive and widely used bioassay technology for clinical diagnostics. With the time-resolved luminescence detection the naturally occurring autofluorescence of biological matrices, solid supports and plastics can be avoided. A major drawback of the current technique is that the luminescent lanthanide labels require ultraviolet (UV) excitation, typically shorter than 360 nm, which is strongly absorbed and can damage living biological systems. The lack of cost-efficient high power solid state excitation light sources for UV excitation further limits the development of low-cost and more compact measurement instruments for time-resolved luminescence and the potential use of lanthanide luminescence in different applications. Switchable lanthanide luminescence is a binary probe technology that inherently enables a high signal modulation in a separation-free detection of targets. The intrinsically luminescent lanthanide chelate is split into two nonluminescent moieties, a lanthanide ion carrier chelate and a light harvesting antenna ligand, each of which can be attached to a separate molecular probe. A luminescent lanthanide complex is formed only when the two probes bind adjacently to the target molecule. Herein we describe a new 365 nm excitable antenna ligand (AL360) for switchable lanthanide luminescence of europium(iii) (EuIII) that would enable the use of 365 nm light emitting diodes (LEDs) as an excitation light source for time-resolved fluorescence imaging and detection. With the acquired subpicomolar assay sensitivity it would be applicable for solution or surface arrays and UV LED microscopy. PMID- 28560366 TI - A cascade C-H functionalization/cyclization reaction of N-arylpyridin-2-amines with alpha,beta-unsaturated aldehydes for the synthesis of dihydroquinolinone derivatives under rhodium catalysis. AB - A novel cascade C-H functionalization/cyclization reaction of N-arylpyridin-2 amines with alpha,beta-unsaturated aldehydes has been developed under rhodium catalysis, affording dihydroquinolinone derivatives in moderate to excellent yields. A plausible mechanism of dual catalytic cycles by rhodium(iii) catalysis is also proposed. PMID- 28560367 TI - Antimicrobial nitric oxide releasing surfaces based on S-nitroso-N acetylpenicillamine impregnated polymers combined with submicron-textured surface topography. AB - A novel dual functioning antimicrobial CarboSil 20 80A polymer material that combines physical topographical surface modification and nitric oxide (NO) release is prepared and evaluated for its efficacy in reducing bacterial adhesion in vitro. The new biomaterial is created via a soft lithography two-stage replication process to induce submicron textures on its surface, followed by solvent impregnation with the NO donor, S-nitroso-N-acetylpenicillamine (SNAP), to obtain long-term (up to 38 d) NO release. The NO releasing textured polymer surface is evaluated against four bacteria commonly known to cause infections in hospital settings and the results demonstrate that the combined strategy enables a synergistic effect on reducing the bacterial adhesion of Staphylococcus epidermidis and Pseudomonas aeruginosa bacteria. PMID- 28560368 TI - Ultra-low fouling methylimidazolium modified surfaces for the detection of HER2 in breast cancer cell lysates. AB - We synthesized novel ultra-low fouling ionic liquids and demonstrated their use with surface plasmon resonance (SPR) sensing for the analysis of HER2 in breast cancer cell lysates. Whilst biomarkers are commonly detected in serum, this remains challenging for cancer diagnosis due to their low concentrations in circulation and in some cases, there is a poor correlation between serum and tissue concentrations. Therefore, a cell lysate constitutes an interesting biosample for cancer diagnosis and typing, which has been largely unexploited for chemical biosensing of cancer biomarkers. However, high fouling of surfaces in contact with the cell lysate and the absence of effective surface chemistry to prevent fouling are currently limiting biomarker analysis in cell lysates. To address this challenge, we report the synthesis of 1-(carboxyalkyl)-3-(12 mercaptododecyl)-1H-imidazolium ionic liquids with different anions (Br-, BF4-, PF6-, ClO4-, and NTf2-) and ethyl and pentyl chains to form monolayers and analyse specific proteins from cell lysates. The most efficient ionic liquid monolayer, 1-(carboxyethyl)-3-(12-mercaptododecyl)-1H-imidazolium bromide, was able to eliminate the nonspecific adsorption (surface coverage of 2 +/- 2 ng cm 2) of a concentrated cell lysate (protein concentration of ~3.5 mg mL-1), which was significantly better than carboxy-PEG (surface coverage of 14 +/- 7 ng cm-2), a benchmark monolayer commonly used to reduce nonspecific adsorption. These ionic liquid monolayers were modified with anti-HER2 and the detection of the HER2 breast cancer biomarker was carried out in crude breast cancer cell lysates, as shown with HER2-negative MCF-7 cells spiked with HER2 and with HER2 positive SK BR-3 cells. PMID- 28560369 TI - Synthesis of well-defined pentagonally prismatic silver nanoparticles: role of bromide in (100) stabilization and facet preservation. AB - We have demonstrated the effect of bromide for exclusive (100) stabilization that enabled the preparation of pentagonal prisms (AgPPNPs), a newly developed nanoscale shape. High-quality precursors and exact amount of bromide were necessary requirements for the precise length and faceting control. Bromide excess resulted in AgPPNP rounding, highlighting a delicate balance in faceting control and shape preservation. PMID- 28560370 TI - Antineoplastic drugs and their analysis: a state of the art review. AB - The number of patients suffering from cancer is constantly increasing and, consequently, the number of different chemotherapy treatments administered is increasing. Given the high reactivity and toxicity of antineoplastic drugs, analytical methods are required in all pharmaceutical fields, from drug development to their elimination in wastewater; including formulation quality control, environment and human exposure and therapeutic drug monitoring. The aim of this paper is to provide an overview of the analytical methods available for the determination of antineoplastic drugs in different matrices such as pharmaceutical formulations, biological and environmental samples. The applicability and performance of the reported methods will be critically discussed, with focus on the most commonly used antineoplastic drugs. Only conventional compounds and small molecules for targeted therapy will be considered in the present review. PMID- 28560371 TI - Precursor determined lateral size control of monolayer MoS2 nanosheets from a series of alkylammonium thiomolybdates: a reversal of trend between growth media. AB - The growth of ligand-free MoS2 nanosheets with mean lateral sizes below 5 nm at 270 degrees C is reported. Nanosheets grown from a melt of tetraalkylammonium tetrathiomolybdates, [R4N]2[MoS4] (R = n-butyl, n-hexyl or n-octyl) vary in width between mean lateral sizes of 4.35 and 2.1 nm. Inclusion of the precursors into a polymer matrix shows the opposite trend in lateral dimensions with sheet widths ranging from 3.5 to 4.8 nm. PMID- 28560377 TI - Low-temperature, high-mobility, solution-processed metal oxide semiconductors fabricated with oxygen radical assisted perchlorate aqueous precursors. AB - In this report, a simple and general chemical route for fabricating MO semiconducting films at a relatively low temperature without any fuel additives or special annealing steps was demonstrated. The precursor, which consisted of perchlorate, nitrate, and water, is easily converted into In2O3 at an annealing temperature of 250 degrees C due to oxygen radical assisted decomposition and generation of a large amount of heat. It is found that perchlorate salt can decompose and form an oxide film with high quality at a lower temperature when assisted by nitrate salt. The optimized In2O3-TFT fabricated via this precursor exhibits a saturation mobility of 14.5 cm2 V-1 s-1. Furthermore, this approach has been expanded to the fabrication of ZnO films and attained improved performance, indicating its universality. PMID- 28560378 TI - Predicting working beyond retirement in the Netherlands: an interdisciplinary approach involving occupational epidemiology and economics. AB - Objectives No study so far has combined register-based socioeconomic information with self-reported information on health, demographics, work characteristics, and the social environment. The aim of this study was to investigate whether socioeconomic, health, demographic, work characteristics and social environmental characteristics independently predict working beyond retirement. Methods Questionnaire data from the Study on Transitions in Employment, Ability and Motivation were linked to data from Statistics Netherlands. A prediction model was built consisting of the following blocks: socioeconomic, health, demographic, work characteristics and the social environment. First, univariate analyses were performed (P0<.15), followed by correlations and logistic multivariate regression analyses with backward selection per block (P0<.15). All remaining factors were combined into one final model (P0<.05). Results In the final model, only factors from the blocks health, work and social environmental characteristics remained. Better physical health, being intensively physically active for >2 days/week, higher body height, and working in healthcare predicted working beyond retirement. If respondents had a permanent contract or worked in handcraft, or had a partner that did not like them to work until the official retirement age, they were less likely to work beyond retirement. Conclusion Health, work characteristics and social environment predicted working beyond retirement, but register-based socioeconomic and demographic characteristics did not independently predict working beyond retirement. This study shows that working beyond retirement is multifactorial. PMID- 28560379 TI - VPA and MEL induce apoptosis by inhibiting the Nrf2-ARE signaling pathway in TMZ resistant U251 cells. AB - Chemoresistance is the primary obstacle to effective treatment of glioblastoma, the most lethal brain tumor. Our previous study demonstrated that Nf-E2 related factor 2 (Nrf2), a traditional cytoprotective transcription factor, was overexpressed in gliomas and promoted malignancy. The present study aimed to investigate the expression levels of Nrf2-antioxidant response element (ARE) signaling pathway genes in temozolomide (TMZ)-resistant U251 human glioblastoma cells (U251-TMZ). Additionally, the effect of valproic acid (VPA) and melatonin (MEL) on Nrf2 expression in U251-TMZ cells and their association with chemoresistance was investigated. The results of the present study indicated that the expression levels of components of the Nrf2-ARE signaling pathway were increased in U251-TMZ cells compared with U251 parent cells. Silencing of Nrf2 by transfection with small interfering RNA restored the chemosensitivity of U251-TMZ cells. The Nrf2 inhibitors VPA and MEL successfully reduced Nrf2 expression and survival in U251-TMZ cells treated with TMZ, accompanied by increased reactive oxygen species levels and apoptosis. Therefore, VPA and MEL may be potential chemotherapeutic sensitizers for the treatment of chemoresistant glioblastoma. PMID- 28560380 TI - Sorafenib induces variations of the DNA methylome in HA22T/VGH human hepatocellular carcinoma-derived cells. AB - Sorafenib is currently used to treat advanced and/or unresectable hepatocellular carcinoma (HCC), but the increase of the median survival was only 3 months. Moreover, sorafenib has severe side effects and patients develop resistance quickly. Epigenetic alterations such as DNA methylation play a decisive role in the development and progression of HCC. To our knowledge, there are no studies that analysed the global DNA methylation changes in HCC cells treated with sorafenib. Using MeDip-chip technologies, we found 1230 differentially methylated genes in HA22T/VGH cells treated with sorafenib compared to untreated cells. Gene ontology and pathway analysis allowed identifying several enriched signaling pathways involved in tumorigenesis and cancer progression. Among the genes differentially methylated we found genes related to apoptosis, angiogenesis and invasion, and genes belonging to pathways known to be deregulated in HCC such as RAF/MEK/ERK, JAK-STAT, PI3K/AKT/mTOR and NF-kappaB. Generally, we found that oncogenes tended to be hypermethylated and the tumor suppressor genes tended to be hypomethylated after sorafenib treatment. Finally, we validated MeDip-chip results for several genes found differentially methylated such as BIRC3, FOXO3, MAPK3, SMAD2 and TSC2, using both COBRA assay and direct bisulfite sequencing and we evaluated their mRNA expression. Our findings suggest that sorafenib could affect the methylation level of genes associated to cancer-related processes and pathways in HCC cells, some of which have been previously described to be directly targeted by sorafenib. PMID- 28560381 TI - Hypomethylation of the Toll-like receptor-2 gene increases the risk of essential hypertension. AB - Studies on the etiology of essential hypertension (EH) have demonstrated that chronic inflammation contributes to the onset and development of elevated blood pressure. Toll-like receptors (TLRs), important immune receptors, serve a role in chronic inflammation and are associated with EH. In the present study, 96 patients with EH, and 96 age- and sex-matched healthy controls were recruited, and eight cytosine-phosphate-guanine (CpG) dinucleotides (CpG1-8) were analyzed using bisulfite pyrosequencing technology. It was observed that the methylation levels of all of the eight CpG dinucleotides were decreased in the EH group compared with the control group; however, only CpG1 (2.83+/-1.34 vs. 3.44+/-1.75; P=0.009), CpG6 (3.58+/-3.64 vs. 8.30+/-4.13; P<0.001) and CpG8 (8.91+/-5.32 vs. 11.33+/-3.87; P<0.001) were significantly different, as demonstrated by paired t test analysis. In addition, logistic regression analysis demonstrated that CpG6 hypomethylation was a risk factor of EH (odds ratio=1.10; adjusted P=0.009), and CpG6 methylation level was observed to be negatively correlated with systolic blood pressure (r=-0.304; P<0.001) and diastolic blood pressure (r=-0.329; P<0.001). Additionally, receiver operating characteristic curve analysis demonstrated that a methylation level of 7.5% for CpG6 (area under the curve, 0.834; P<0.001) was an appropriate threshold value to predict the risk of EH. With generalized multifactor dimensionality reduction, a potential gene-gene interaction between CpG6 and CpG8 (P=0.001), and gene-environment interactions between smoking, alcohol consumption, CpG6, CpG7 and CpG8 (P=0.011), were observed. In conclusion, the results of the present study demonstrated that hypomethylation of the TLR2 promoter, particularly CpG6, was associated with the risk of EH in this population. Additionally, a gene-gene interaction between CpG6 and CpG8, and interactions between environmental factors, including smoking and alcohol consumption, and CpG6, CpG7 and CpG8, may be associated with the risk of EH. PMID- 28560382 TI - Revealing radiotherapy- and chemoradiation-induced pathway dynamics in glioblastoma by analyzing multiple differential networks. AB - The progression of glioblastoma (GBM) is driven by dynamic alterations in the activity and connectivity of gene pathways. Revealing these dynamic events is necessary in order to understand the pathological mechanisms of, and develop effective treatments for, GBM. The present study aimed to investigate dynamic alterations in pathway activity and connectivity across radiotherapy and chemoradiation conditions in GBM, and to give system-level insights into molecular mechanisms for GBM therapy. A total of two differential co-expression networks (DCNs) were constructed using Pearson correlation coefficient analysis and one sided t-tests, based on gene expression profiles and protein-protein interaction networks, one for each condition. Subsequently, shared differential modules across DCNs were detected via significance analysis for candidate modules, which were obtained according to seed selection, module search by seed expansion and refinement of searched modules. As condition-specific differential modules mediate differential biological processes, the module connectivity dynamic score (MCDS) was implemented to explore dynamic alterations among them. Based on DCNs with 287 nodes and 1,052 edges, a total of 28 seed genes and seven candidate modules were identified. Following significance analysis, five shared differential modules were identified in total. Dynamic alterations among these differential modules were identified using the MCDS, and one module with significant dynamic alterations was identified, termed the dynamic module. The present study revealed the dynamic alterations of shared differential modules, identified one dynamic module between the radiotherapy and chemoradiation conditions, and demonstrated that pathway dynamics may applied to the study of the pathogenesis and therapy of GBM. PMID- 28560384 TI - Hydrogen sulfide inhibits mitochondrial fission in neuroblastoma N2a cells through the Drp1/ERK1/2 signaling pathway. AB - Hydrogen sulfide (H2S) has been demonstrated to have various effects on mitochondrial function. The aim of the present study was to investigate the effects of H2S on mitochondrial fission and the potential underlying mechanisms of these effects. Transmission electron microscopy analysis demonstrated that sodium hydrosulfide (NaHS, a donor of H2S) inhibited mitochondrial fission in a dose- and time-dependent manner. Treating neuro-2a (N2a) mouse neuroblastoma cells with 400 uM NaHS for 16 h significantly increased the % of elongated mitochondria and reduced the number of mitochondria per cell compared with untreated cells. In addition, the viability and ATP generation of N2a cells that were treated with various concentrations of NaHS was examined. The results demonstrated that treatment with 400 and 600 uM NaHS increased cell viability and ATP generation compared with untreated cells. To further understand the effects of H2S on mitochondrial morphology, the protein and mRNA expression levels of dynamin 1 like (Dnm1l, also known as Drp1) were examined, and the results demonstrated that NaHS dose-dependently reduced Drp1 mRNA and protein levels, consistent with the mitochondrial morphology changes. To determine whether H2S affects mitochondrial morphology through Drp1 expression, Drp1 was overexpressed in N2a cells using a lentivirus encoding the Drp1 cDNA. It was observed that Drp1 overexpression reversed the effects of NaHS. Furthermore, NaHS promoted the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and the effects of NaHS on Drp1 expression were abolished by an ERK1/2 inhibitor (PD98059). The results of the present study indicate that the H2S-induced decrease in Drp1 mRNA and protein levels and mitochondrial fission may involve the ERK1/2 signaling pathway. The present study suggests that H2S may be used in the future as a potential therapeutic for diseases that may be mediated by abnormal mitochondria fragmentation, such as Alzheimer's disease. PMID- 28560383 TI - Effects of genistein supplementation on genome-wide DNA methylation and gene expression in patients with localized prostate cancer. AB - Epidemiological studies have shown that dietary compounds have significant effects on prostate carcinogenesis. Among dietary agents, genistein, the major isoflavone in soybean, is of particular interest because high consumption of soy products has been associated with a low incidence of prostate cancer, suggesting a preventive role of genistein in prostate cancer. In spite of numerous studies to understand the effects of genistein on prostate cancer, the mechanisms of action have not been fully elucidated. We investigated the differences in methylation and gene expression levels of prostate specimens from a clinical trial of genistein supplementation prior to prostatectomy using Illumina HumanMethylation450 and Illumina HumanHT-12 v4 Expression BeadChip Microarrays. The present study was a randomized, placebo-controlled, double-blind clinical trial on Norwegian patients who received 30 mg genistein or placebo capsules daily for 3-6 weeks before prostatectomy. Gene expression changes were validated by quantitative PCR (qPCR). Whole genome methylation and expression profiling identified differentially methylated sites and expressed genes between placebo and genistein groups. Differentially regulated genes were involved in developmental processes, stem cell markers, proliferation and transcriptional regulation. Enrichment analysis suggested overall reduction in MYC activity and increased PTEN activity in genistein-treated patients. These findings highlight the effects of genistein on global changes in gene expression in prostate cancer and its effects on molecular pathways involved in prostate tumorigenesis. PMID- 28560385 TI - The PI3K/Akt/mTOR pathway is involved in CVB3-induced autophagy of HeLa cells. AB - Recent studies have found that viral myocarditis (VMC) associated with coxsackievirus B3 (CVB3) causes autophagy activation after infection, but the specific mechanism is not clear. The present study demonstrated that the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)/mammalian target of rapamycin (mTOR) signaling pathway participates in CVB3-induced autophagy. We found that the light chain 3 (LC3)-II/LC3-I ratio was increased and p62 and p mTOR were altered at different times during CVB3 infection. To further assess the effects of this signaling pathway on CVB3 infection and viral replication, we selected 24 h post-inoculation (h.p.i.) as our research time point to conduct our next study. We inhibited the function of PI3K, Akt1 and mTOR. The outcome showed that inhibition of PI3K with ZSTK474 alleviated autophagy and decreased CVB3 mRNA replication and VP1 expression. Inhibition of mTOR with rapamycin promoted autophagy and viral mRNA replication but did not impact VP1 expression. Inhibition of Akt with MK2206 aggravated autophagy induced by viral infection. In our research, p62 exhibited a decrease at the beginning of infection but then increased as infection time increased. This finding may serve as a clue to elucidate the function of autophagy at different times of infection. However, the details merit further study. In conclusion, our findings suggest that the PI3K/Akt/mTOR signaling pathway participates in the process of autophagy induced by CVB3 infection. This finding may provide a new perspective of CVB3-induced autophagy. PMID- 28560386 TI - Fangchinoline suppresses growth and metastasis of melanoma cells by inhibiting the phosphorylation of FAK. AB - Melanoma is a malignant tumor with high degree of malignancy, metastasis and high mortality. The etiology of melanoma has not been fully elucidated, and there is no effective drug for the complete treatment of melanoma. In recent years, many traditional Chinese herbal medicines have played an important role in clinical treatment and experimental research on cancer. As a natural product, fangchinoline has the characteristics of enhancing immune function, low toxicity and good liver protection features, so it is considered to be a new type of anticancer drug. In the present study, we found that fangchinoline has inhibitory effects on the proliferation and metastasis of A375 and A875 cells in a concentration-dependent manner. Fangchinoline inhibited the proliferation of A375 and A875 cell activity with IC50 values of 12.41 and 16.20 uM. We also found that fangchinoline could significantly reduce the phosphorylation of Focal adhesion kinase (FAK). In summary, we demonstrated that fangchinoline inhibits the proliferation and metastasis of melanoma cells by suppressing FAK and its downstream signaling pathway. More importantly, we provide a novel mechanism that fangchinoline could be an effective candidate for the treatment of melanoma. PMID- 28560387 TI - Reciprocal antagonistic regulation of N-myc mRNA by miR-17 and the neuronal specific RNA-binding protein HuD. AB - Neuroblastoma is a childhood cancer originating from embryonic neural crest cells. Amplification of the proto-oncogene N-myc, seen in ~30% of neuroblastoma tumors, is a marker for poor prognosis. Recently discovered small regulatory RNAs, microRNAs (miRNAs), are implicated in cancers, including neuroblastoma. miRNAs downregulate the expression of genes by binding to the 3'-untranslated regions (3'-UTRs), thereby inhibiting translation or inducing degradation of cognate mRNAs. Our study sought to identify miRNAs that regulate N-myc expression and thereby malignancy in neuroblastoma. miRNAs whose expression negatively correlates with N-myc expression were identified from a miRNA microarray of 4 N myc-amplified neuroblastoma cell lines. Three of these miRNAs (miR-17, miR-20a and miR-18a) belong to the miR-17-92 cluster, previously shown to be upregulated by N-myc. qPCR validation of these miRNAs in a larger panel of cell lines revealed that levels of miR-17 were inversely proportional to N-myc mRNA amounts in the N-myc-amplified cell lines. Notably, miR-17 also downregulated N-myc protein synthesis in the N-myc-amplified cells, thereby generating a negative feedback regulatory loop between the proto-oncogene and this miRNA. Moreover, the neuronal-specific RNA-binding protein HuD (ELAVL4), which regulates the processing/stability of N-myc mRNA, competes with miR-17 for a binding site in the 3'-UTR of N-myc. Thus, N-myc levels appear to be modulated by the antagonistic interactions of both miR-17, as a negative regulator, and HuD, as a positive regulator, providing further evidence of the complex cellular control mechanisms of this oncogene in N-myc-amplified neuroblastoma cells. PMID- 28560388 TI - Inhibition of IGF-1 receptor kinase blocks the differentiation into cardiomyocyte like cells of BMSCs induced by IGF-1. AB - Bone marrow mesenchymal stem cells (BMSCs) have the potential to transdifferentiate into cardiomyocyte-like cells (CLCs) if an appropriate cardiac environment is provided. Insulin-like growth factor-1 (IGF-1) plays an important role in the cell migration, survival and differentiation of BMSCs. However, the effect of IGF-1 on the cellular differentiation remains unclear. In the present study, BMSCs were isolated from rat femurs and tibias and the cells were purified at passage 6 (P6). IGF-1 and IGF-1 receptor (IGF-1R) kinase inhibitor I-OMe AG538 were added to detect if IGF-1 could induce BMSCs to transdifferentiate into CLCs and if I-OMe AG538 could inhibit IGF-1-mediated receptor activation and downstream signaling. Immunostaining demonstrated that all P6 BMSCs express CD29 and CD44 but not CD45. BMSCs induced by 15 ng/ml IGF-1 revealed positivity for cardiac troponin-T and cardiac troponin-I. The optimal induction time was 14 days but the expression of these proteins were incompletely inhibited by 300 nmol/l I OMe AG538 and completely inhibited by 10 umol/l I-OMe AG538. Western blotting showed that the level of IGF-1R autophosphorylation and the expression of cTnT and cTnI were higher when BMSCs were induced for 14 days. I-OMe AG538 selectively inhibited IGF-1-mediated growth and signal transduction and the inhibitory effect of I-OMe AG538 were not reverted in the presence of exogenous IGF-1. In addition, when a time course analysis of the effects of I-OMe AG538 on mitogen-activated protein kinase kinase and phosphatidylinositol 3-kinase signaling were done, we observed a transient inhibitory effect on Erk1/2 and Akt phosphorylation, in keeping with the inhibitory effects on cell growth. Taken together, these data indicate that I-OMe AG538 could inhibit IGF-1-induced CLCs in BMSCs and this effect is time- and concentration-dependent. PMID- 28560389 TI - Elemene inhibits the migration and invasion of 4T1 murine breast cancer cells via heparanase. AB - Elemene (ELE), a natural plant drug extracted from Curcumae Rhizoma, has been widely used for cancer treatment in China for more than 20 years. Although it is reported to be a broad-spectrum anticancer drug, the mechanism underlying the action of ELE in the treatment of breast cancer remains to be fully elucidated. Heparanase, a mammalian endo-D-glucuronidase, is involved in degradation of the extracellular matrix (ECM), and thus promotes tumor progression and metastasis. The downregulation of heparanase can effectively reduce tumor malignant behaviors. In the present study, the inhibitory effects of ELE were evaluated in breast cancer cells using a Cell Counting kit 8 assay. The migratory and invasive capabilities of cancer cells were investigated using a wound healing assay, real time cell analysis and a Transwell assay. In addition, western blot analysis was used to assess alterations in the expression levels of key proteins. The present results confirmed the antiproliferative and antimetastatic effects of ELE, using low-molecular weight heparin (LMWH) as a positive control. In addition, ELE was demonstrated to downregulate the expression of heparanase, and decrease the phosphorylation of extracellular signal-regulated kinase and AKT. These findings suggested that ELE may be a promising agent targeting heparanase in the treatment of breast cancer. PMID- 28560390 TI - Prognostic value of PAX9 in patients with esophageal squamous cell carcinoma and its prediction value to radiation sensitivity. AB - Abnormal paired box 9 (PAX9) expression is associated with tumorigenesis, cancer development, invasion and metastasis. The present study investigated the prognostic significance of PAX9 in esophageal squamous cell carcinoma (ESCC) and its role in predicting radiation sensitivity. A total of 52.8% (121/229) ESCC tissues were positive for PAX9. The 1-, 3- and 5-year disease-free survival (DFS) rates were 72.2, 35.2 and 5.6%, respectively, and the overall survival (OS) rates were and 86.1, 44.4, and 23.1%, respectively, in PAX9-positive tumors. In PAX9 negative tumors, the one-, three- and five-year DFS rates were 76.9, 47.9 and 24.0%, and the OS rates were 90.9, 57.9 and 38.8%, respectively. Univariate analysis revealed that PAX9, differentiation, T stage, lymph node metastasis, and tumor-node-metastasis stage were associated with OS. Multivariate analysis of DFS and OS revealed that the hazard ratios for PAX9 were 0.624 (95% CI: 0.472-0.869, P=0.004) and 0.673 (95% CI: 0.491-0.922, P=0.014), respectively. Patients that received adjuvant therapy exhibited significant differences in the 5-year DFS (P<0.001) and OS (P<0.001). PAX9-positive ESCC patients who received post-surgery radiotherapy had a significantly greater 5-year DFS (P=0.011) and OS (P=0.009) than patients who received surgery only. Thus, PAX9 may be an independent prognostic factor for the surgical treatment of ESCC and a possible predictor of radiation sensitivity. PMID- 28560391 TI - Fisetin inhibits liver cancer growth in a mouse model: Relation to dopamine receptor. AB - Fisetin (3,3',4',7-tetrahydroxyflavone), a natural abundant flavonoid, is produced in different vegetables and fruits. Fisetin has been reported to relate to various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. Dopamine receptors (DRs) belonging to G protein-coupled receptor family, are known as the target of ~50% of all modern medicinal drugs. DRs consist of various proteins, functioning as transduction of intracellular signals for extracellular stimuli. We found that fisetin performed as DR2 agonist to suppress liver cancer cells proliferation, migration and invasion. Caspase-3 signaling was activated to induce apoptosis for fisetin administration. Furthermore, TGF-beta1 was also inhibited in fisetin-treated liver cancer cells, reducing epithelial-mesenchymal transition (EMT). Additionally, fisetin downregulated VEGFR1, p-ERK1/2, p38 and pJNK, ameliorating liver cancer progression. In vivo, the orthotopically implanted tumors from mice were inhibited by fisetin adminisatration accompanied by prolonged survival rate and higher levels of dopamine. Together, the results indicated a novel therapeutic strategy to suppress liver cancer progression associated with DR2 regulation, indicating that dopamine might be of importance in liver cancer progression. PMID- 28560392 TI - The blueberry component pterostilbene has potent anti-myeloma activity in bortezomib-resistant cells. AB - Multiple myeloma (MM) is an incurable hematologic malignancy because of its drug resistance. Pterostilbene (Pter) is found mainly in blueberries and grapes. The effects of Pter and its exact pharmacologic mechanisms on chemoresistant myeloma are not known. Herein, we investigated the anti-myeloma activity of Pter in bortezomib-resistant cell line H929R and explored the related mechanism of action for the first time. We found that Pter inhibited proliferation of H929R cells and promoted apoptosis of the cells through a caspase-dependent pathway, loss of mitochondrial membrane potential, and activation of Akt and p38 mitogen-activated protein kinase (MAPK) signaling pathways. DNA damage and S-phase arrest might be involved in Pter-related toxicity in H929R cells. Pter and the histone deacetylase inhibitors panobinostat or vorinostat inhibited proliferation of H929R cells in a synergistic manner. These data supported that Pter might be a promising natural compound for relapsed/refractory myeloma therapy, especially against myeloma resistant to bortezomib chemotherapy. PMID- 28560393 TI - The inhibition of NOTCH2 reduces UVB-induced damage in retinal pigment epithelium cells. AB - Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly. The pathogenesis of dry AMD remains indistinct and the mechanism of retinal pigment epithelium (RPE) cells death in dry AMD is controversial. The aim of the present study was to investigate the functions of Notch signaling in ultraviolet B (UVB)-induced damage of RPE cells. It was identified that, in RPE cells, UVB increased intracellular reactive oxygen species (ROS) and induced cell apoptosis. In addition, UVB activated Notch signaling in a dose dependent manner. Surprisingly, NOTCH2, but not NOTCH1, was demonstrated to be the major Notch receptor in RPE cells. Under normal conditions, the inhibition of NOTCH2 reduced cell growth and cell migration, but had no impact on intracellular ROS and cell apoptosis. However, in the presence of UVB, the inhibition of NOTCH2, but not NOTCH1, attenuated intracellular ROS and cell apoptosis. The function of Notch signaling involved in UVB damage of RPE cells may not only be significant to understanding the pathogenesis of AMD (especially dry AMD), but also useful for designing effective therapeutic agents for dry AMD. PMID- 28560394 TI - MicroRNA-526a targets p21-activated kinase 7 to inhibit tumorigenesis in hepatocellular carcinoma. AB - MicroRNAs belong to a series of noncoding RNAs and have diverse roles in several biological processes. The association between aberrant microRNA expression and tumorigenesis is complex and remains to be fully elucidated. The present study investigated whether microRNA (miR) -526a can suppress the progression of hepatocellular carcinoma (HCC) in vitro and in vivo. Reverse transcription quantitative polymerase chain reaction, luciferase reporter assay, invasion assay, western blotting and in vivo implantation were used to investigate the potential function of miR-526a. The present study observed that the level of miR 526a was downregulated in HCC tissues and well-established cell lines. In addition, the ectopic introduction of miR-526a into Huh7 and HepG2 cells significantly attenuated HCC tumorigenesis, including proliferation, migration and invasion. The growth of tumor xenografts was also inhibited following transfection with miR-526a. Using overlapping strategies, p21-activated kinase 7 (PAK7) was predicted to be a target for miR-526a, and this was verified experimentally. An inverse correlation was found between miR-526a and PAK7 in HCC tissues. The results of the present study revealed a novel function of miR-526a and may provide crucial insight into therapeutic interventions targeting microRNAs. PMID- 28560396 TI - Mitochondrial Ca2+ removal amplifies TRAIL cytotoxicity toward apoptosis resistant tumor cells via promotion of multiple cell death modalities. AB - Ca2+ has emerged as a new target for cancer treatment since tumor-specific traits in Ca2+ dynamics contributes to tumorigenesis, malignant phenotypes, drug resistance, and survival in different tumor types. However, Ca2+ has a dual (pro death and pro-survival) function in tumor cells depending on the experimental conditions. Therefore, it is necessary to minimize the onset of the pro-survival Ca2+ signals caused by the therapy. For this purpose, a better understanding of pro-survival Ca2+ pathways in cancer cells is critical. Here we report that Ca2+ protects malignant melanoma (MM) and osteosarcoma (OS) cells from tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) cytotoxicity. Simultaneous measurements using the site-specific Ca2+ probes showed that acute TRAIL treatment rapidly and dose-dependently increased the cytosolic Ca2+ concentration ([Ca2+]cyt) and mitochondrial Ca2+ concentration ([Ca2+]mit) Pharmacological analyses revealed that the [Ca2+]mit remodeling was under control of mitochondrial Ca2+ uniporter (MCU), mitochondrial permeability transition pore (MPTP), and a Ca2+ transport pathway sensitive to capsazepine and AMG9810. Ca2+ chelators and the MCU inhibitor ruthenium 360, an MPTP opener atractyloside, capsazepine, and AMG9810 all decreased [Ca2+]mit and sensitized these tumor cells to TRAIL cytotoxicity. The Ca2+ modulation enhanced both apoptotic and non apoptotic cell death. Although the [Ca2+]mit reduction potentiated TRAIL-induced caspase-3/7 activation and cell membrane damage within 24 h, this potentiation of cell death became pronounced at 72 h, and not blocked by caspase inhibition. Our findings suggest that in MM and OS cells mitochondrial Ca2+ removal can promote apoptosis and non-apoptotic cell death induction by TRAIL. Therefore, mitochondrial Ca2+ removal can be exploited to overcome the resistance of these cancers to TRAIL. PMID- 28560397 TI - Effects of interleukin-17 on human retinal vascular endothelial cell capillary tube formation in vitro. AB - The present study aimed to investigate the effect of and mechanism underlying interleukin (IL)-17 on human retinal vascular endothelial cell (HREC) capillary tube formation in vitro. The expression of IL-17 receptor (IL-17R) in human HRECs was quantified using reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot analyses. The roles of IL-17 in HREC migration and capillary tube formation were detected using a wound scratching assay and three-dimensional Matrigel assay, respectively, in vitro. HREC proliferation was examined using a cell counting kit-8 assay with administration of serial doses of IL-17. The effects of IL-17 on the expression of vascular endothelial growth factor (VEGF), intercellular cell adhesion molecule (ICAM)-1, IL-6 and IL-8 in HRECs were evaluated using RT-PCR and western blot analyses. The results revealed that the HRECs expressed IL-17R, and the number of intact capillary tubes formed by HRECs in the presence of IL-17 was markedly higher, compared with that in the blank control group. The wound scratching assay showed that the numbers of migrated HRECs stimulated with IL-17 at concentrations of 100 or 500 ng/ml were significantly higher, compared with the number in the control group. The RT-PCR and western blot analyses showed that IL-17 significantly promoted the expression of VEGF, ICAM-1, IL-6 and IL-8 by the HRECs. The proliferation of HRECs in the presence of IL-17 was also significantly increased. Therefore, IL-17 increased HREC capillary tube formation through promoting HREC migration, proliferation, and expression levels of VEGF, ICAM-1, IL-6 and IL-8. PMID- 28560395 TI - HSVtk/GCV system on hepatoma carcinoma cells: Construction of the plasmid pcDNA3.1-pAFP-TK and targeted killing effect. AB - Previous studies demonstrated that herpes simplex virus thymidine kinase (HSVtk) could phosphorylate non-toxic gancyclovir (GCV) efficiently to produce phosphorylated products that result in cell apoptosis, to kill tumor cells. The present study aimed to construct a plasmid vector, pcDNA3.1-pAFP-TK, carrying the suicide gene driven by the alpha-fetoprotein (AFP) promoter, to investigate the cytotoxicity of HSVtk/GCV suicide gene system on hepatoma carcinoma cells. Reverse transcription-polymerase chain reaction and western blotting results demonstrated that the HSVtk gene was effectively expressed in HepG2 hepatoma carcinoma cells transfected with pcDNA3.1-pAFP-TK plasmid, whereas HSVtk gene expression was not detected in normal HL-7702 liver cells. In addition, MTT assays indicated that cell viability of HepG2 cells with the plasmid pcDNA3.1 pAFP-TK decreased in a dose-dependent manner following treatment with GCV for 48 h. Flow cytometry also revealed that the cell apoptosis rate and mitochondrial membrane potential reduction rate in the HepG2 cells treated with HSVtk/GCV suicide gene system were significantly higher than in the control group. Apoptosis rates in the control group and the pcDNA3.1-pAFP-TK group were (1.00+/ 0.62%) and (38.70+/-6.03%), respectively. Mitochondrial membrane potential reduction rates in the control group and the pcDNA3.1-pAFP-TK group were (0.57+/ 0.11%) and (22.84+/-5.79%), respectively. Caspase-3 staining demonstrated that activated caspase-3 increased significantly in the HepG2 cells treated with HSVtk/GCV suicide gene system, whereas in the control group activated caspase-3 increase was not observed. The results of the present study, therefore, indicated that HSVtk suicide gene was obviously expressed in the HepG2 cells and that the HSVtk/GCV system was effective at killing HepG2 hepatoma carcinoma cells. PMID- 28560398 TI - Toxic proteins from Croton tiglium L. exert a proinflammatory effect by inducing release of proinflammatory cytokines and activating the p38-MAPK signaling pathway. AB - The aim of the present study was to determine the toxic targets of proteins from Croton tiglium L. and to investigate the potential mechanism of their toxicity. The toxic targets were determined by oral medication and intraperitoneal injection. The median lethal dose of oral medication in mice was calculated using Bliss software (2,752.8-3,407.5 mg/kg), and that of intraperitoneal injection was 195.8-272.69 mg/kg. The results of histopathological examination demonstrated that the kidney was primarily impaired by intraperitoneal injection, with slight degeneration of renal tubular epithelial cells. As to oral medication, the digestive tract was primarily injured, which manifested as congestion, bleeding, serious edema and other symptoms. Oral administration of the proteins caused gastrointestinal edema by increasing the intestinal permeability. Severe edema was associated with the inflammatory response, therefore the association between the toxicity of the proteins and inflammation was investigated. The proinflammatory effects of the crude proteins on the release of inflammatory mediator prostaglandin E2 (PGE2) were evaluated through intraperitoneal injection and the production of proinflammatory cytokines in RAW264.7 macrophages. Maximum PGE2 was released in the mice in vivo following intraperitoneal injection with 400 mg crude protein/kg body weight. Proinflammatory cytokines in macrophages, including tumor necrosis factor-alpha and interleukin-1beta, were produced in dose- and time-dependent manners in vitro. furthermore, the expressions of cell signaling molecules were detected by western blotting. The inflammatory response induced by crude protein in macrophages was associated with the mitogen-activated protein kinase (MAPK) signaling pathway mainly including p38-MAPK, extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase 1/2/3 and the activated p38-MAPK signaling pathway. However, extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinases 1-3 exhibited no significant response. PMID- 28560399 TI - MicroRNA expression analysis during FK506-induced osteogenic differentiation in rat bone marrow stromal cells. AB - FK506 (also known as tacrolimus) is a potent immunosuppressive agent that is widely used in the treatment of graft-rejection and autoimmune diseases. FK506 has attracted additional attention owing to its potential role in osteogenic differentiation and bone formation. MicroRNAs (miRNAs) have been demonstrated to serve important roles in the regulation of osteogenic differentiation; however, identification of specific miRNAs and their roles in regulating FK506-induced osteogenic differentiation have been poorly examined. In the present study, osteodifferentiation of rat bone marrow stromal cells (BMSCs) was induced with varying concentrations of FK506 (5-5,000 nM) for 3, 7 and 14 days. Differentially expressed miRNAs were profiled using miRNA array, verified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and subjected to gene ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Results from the present study identified a subset of miRNAs that were differentially expressed, of which five upregulated miRNAs (miR-106b 5p, miR-101b-3p, miR-193a-3p, miR-485-3p and miR-142-3p) and four downregulated miRNAs (miR-27a-3p, miR-207, miR-218a-2-3p and let-7a-5p) were confirmed by RT qPCR. GO and KEGG analysis revealed that the predicted target genes of these miRNAs are involved in multiple biological processes and signaling pathways, including cell differentiation and the mitogen-activated protein kinase (MAPK) signaling pathway. Verification of the miRNA-target genes revealed that Smad5, Jagged 1 and MAPK9 were significantly upregulated, whereas Smad7, BMP and activin membrane-bound inhibitor, and dual-specificity phosphatase 2 were significantly downregulated during FK506-induced osteodifferentiation. The present study may provide an experimental basis for further research on miRNA functions during FK506-induced osteogenic differentiation in rat BMSCs. PMID- 28560400 TI - Altered gene expression of hepatic cytochrome P450 in a rat model of intermittent hypoxia with emphysema. AB - Patients with respiratory overlap syndrome (OS), defined as concomitant chronic obstructive pulmonary disease and obstructive sleep apnea syndrome, may exhibit an increased blood concentration of ingested drugs. This poor elimination of drugs is primarily attributed to downregulated gene expression of the drug metabolizing cytochrome P450 enzymes (CYPs) in the liver. However, the underlying mechanisms of the decreased expression of CYPs in OS are poorly understood. In order to address this, a rat model of intermittent hypoxia with emphysema was evaluated in the present study, by analyzing liver gene expression using the reverse transcription-quantitative polymerase chain reaction. Intermittent hypoxia and cigarette smoke exposure caused upregulation of hepatic inflammatory cytokines, while CYPs were downregulated. This downregulation of CYPs was associated with an increase in nuclear factor (NF)-kappaB expression and a decrease in the expression of nuclear receptors pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor, which are the upstream regulatory molecules of CYPs. The results of the present study indicated that, during the development of OS, systematic inflammatory reactions may downregulate hepatic CYP gene expression via the NF-kappaB signaling pathway. PMID- 28560402 TI - Anticancer effects of phytocannabinoids used with chemotherapy in leukaemia cells can be improved by altering the sequence of their administration. AB - Phytocannabinoids possess anticancer activity when used alone, and a number have also been shown to combine favourably with each other in vitro in leukaemia cells to generate improved activity. We have investigated the effect of pairing cannabinoids and assessed their anticancer activity in cell line models. Those most effective were then used with the common anti-leukaemia drugs cytarabine and vincristine, and the effects of this combination therapy on cell death studied in vitro. Results show a number of cannabinoids could be paired together to generate an effect superior to that achieved if the components were used individually. For example, in HL60 cells, the IC50 values at 48 h for cannabidiol (CBD) and tetrahydrocannabinol (THC) when used alone were 8 and 13 uM, respectively; however, if used together, it was 4 uM. Median-effect analysis confirmed the benefit of using cannabinoids in pairs, with calculated combination indices being <1 in a number of cases. The most efficacious cannabinoid-pairs subsequently synergised further when combined with the chemotherapy agents, and were also able to sensitise leukaemia cells to their cytotoxic effects. The sequence of administration of these drugs was important though; using cannabinoids after chemotherapy resulted in greater induction of apoptosis, whilst this was the opposite when the schedule of administration was reversed. Our results suggest that when certain cannabinoids are paired together, the resulting product can be combined synergistically with common anti-leukaemia drugs allowing the dose of the cytotoxic agents to be dramatically reduced yet still remain efficacious. Nevertheless, the sequence of drug administration is crucial to the success of these triple combinations and should be considered when planning such treatments. PMID- 28560401 TI - Prostaglandin E2 promotes human CD34+ cells homing through EP2 and EP4 in vitro. AB - Recently, certain studies have demonstrated in vitro that prostaglandin E2 (PGE2) promotes human cluster of differentiation (CD)34+ cell homing. However, the sub type receptors activated by PGE2 are unknown, as the PGE2 receptor EP1-4 subtypes (EP1-4) are expressed on the membrane of human CD34+ cells. Based on the above, the present study aimed to screen the receptor subtype activity by PGE2 to promote human CD34+ cell homing. It was observed that human CD34+ cells expressed the four PGE2 sub-receptors, particularly EP2 and 4. PGE2 increased EP2 and 4 mRNA expression significantly, while EP1 and 3 mRNA exhibited no significant alteration. PGE2, EP2 agonist (EP2A), and EP4A upregulated C-X-C chemokine receptor 4 mRNA and protein expression in human CD34+ cells, and promoted stromal cell-derived factor 1alpha (SDF-1alpha) expression in bone marrow mesenchymal stem cells (BMMSCs). These phenomena were inhibited by the associated receptor antagonists. PGE2, EP2A, and EP4A facilitated human CD34+ cell migration towards SDF-1alpha and BMMSCs. The results of the present study suggested that PGE2 promoted human CD34+ cell homing through EP2 and 4 receptors in vitro. PMID- 28560403 TI - Anti-fibrotic effect of Sedum sarmentosum Bunge extract in kidneys via the hedgehog signaling pathway. AB - Sedum sarmentosum Bunge (SSBE) is a perennial plant widely distributed in Asian countries, and its extract is traditionally used for the treatment of certain inflammatory diseases. Our previous studies demonstrated that SSBE has marked renal anti-fibrotic effects. However, the underlying molecular mechanisms remain to be fully elucidated. The present study identified that SSBE exerts its inhibitory effect on the myofibroblast phenotype and renal fibrosis via the hedgehog signaling pathway in vivo and in vitro. In rats with unilateral ureteral obstruction (UUO), SSBE administration reduced kidney injury and alleviated interstitial fibrosis by decreasing the levels of transforming growth factor (TGF)-beta1 and its receptor, and inhibiting excessive accumulation of extracellular matrix (ECM) components, including type I and III collagens. In addition, SSBE suppressed the expression of proliferating cell nuclear antigen, and this anti-proliferative activity was associated with downregulation of hedgehog signaling activity in SSBE-treated UUO kidneys. In cultured renal tubular epithelial cells (RTECs), recombinant TGF-beta1 activated hedgehog signaling, and resulted in induction of the myofibroblast phenotype. SSBE treatment inhibited the activation of hedgehog signaling and partially reversed the fibrotic phenotype in TGF-beta1-treated RTECs. Similarly, aristolochic acid mediated upregulated activity of hedgehog signaling was reduced by SSBE treatment, and thereby led to the abolishment of excessive ECM accumulation. Therefore, these findings suggested that SSBE attenuates the myofibroblast phenotype and renal fibrosis via suppressing the hedgehog signaling pathway, and may facilitate the development of treatments for kidney fibrosis. PMID- 28560404 TI - Intermittent low dose irradiation enhances the effectiveness of radio- and chemo therapy for human colorectal adenocarcinoma cell line HT-29. AB - Low dose irradiation (LDIR) induces hormesis and adaptive response in organism and mammalian cell lines. Notably, LDIR generates distinct biological effects in cancer cells from normal cells, e.g., it may affect the growth of cancer cells via the activation of certain cell signaling pathway, which does not exist in normal cells. Therefore, LDIR is considered as a promising assistant method of clinical cancer therapy. In this study, we chose human colorectal adenocarcinoma cell line HT-29 as the experimental model, and investigated the differential biological effects between 250 mGy single dose LDIR and 250 mGy intermittent LDIR pretreatments in high dose irradiation (HDIR) radiotherapy and 5-fluorouracil (5 FU) based chemotherapy. Through the cell growth assays, we observed that 250 mGy intermittent LDIR pretreatment significantly increased the killing effect of both radiotherapy and chemotherapy. Western blotting results showed that intermittent LDIR pretreatment apparently activated the ATM/p53 (ataxia telangiectasia mutated, ATM) pathway in radiotherapy; it also activated ERK and p38MAPK pathways in chemotherapy. When we used chemical inhibitors to block the ATM/p53 or p38MAPK pathways, the intermittent LDIR induced cell growth inhibitions were reversed. However, blockage of ERK pathway could not affect the cell growth inhibiton in chemotherapy. Taken together, our findings evaluated the intermittent LDIR as a potential valuable method that can enhance the effectiveness of radiotherapy and chemotherapy, especially in the radio- or chemo-resistant tumor types. PMID- 28560405 TI - MARK2 inhibits the growth of HeLa cells through AMPK and reverses epithelial mesenchymal transition. AB - Microtubule affinity-regulating kinases (MARKs; MARK1, MARK2, MARK3 and MARK4) act directly downstream of LKB1, the multitasking tumor-suppressor kinase, and thereby mediate its biological effects. Current understanding of the function of MARKs is greatly restricted to regulation of cell polarity. However, whether or how MARKs contribute to cellular growth control remains largely unknown. In the present study, we utilized an inducible lentiviral expression system that allows rapid MARK expression in LKB1-deficient HeLa cells, and characterized additional functions of MARKs: overexpression of MARK2 in HeLa cells resulted in a decrease in cell growth, inhibition of colony formation and arrest in G1 cell cycle phase, with AMPK as the putative downstream effector upregulating the expression of p21 and p16. MARK2 was found to play a role in F-actin reorganization and to contribute to reversal of epithelial-mesenchymal transition (EMT) as exemplified in the case of HeLa cells that exhibited phenotypic changes, reduced cell migration and invasion. Our findings unveil the coordinated regulation of cell growth and EMT mediated by MARK2, and also provide new insights into the mechanisms underlying the anti-metastatic activity of MARK2. PMID- 28560406 TI - Silencing of ATM expression by siRNA technique contributes to glioma stem cell radiosensitivity in vitro and in vivo. AB - Evidence has shown that both high expression of the ataxia-telangiectasia mutated (ATM) gene and glioma stem cells (GSCs) are responsible for radioresistance in glioma. Thus, we hypothesized that brain tumor radiosensitivity may be enhanced via silencing of the ATM gene in GSCs. In the present study we successfully induced GSCs from two cell lines and used CD133 and nestin to identify GSCs. A lentivirus was used to deliver siRNA-ATMPuro (A group) to GSCs prior to radiation, while siRNA-HKPuro (N group) and GSCs (C group) were used as negative and blank controls, respectively. RT-qPCR and western blotting were performed to verify the efficiency of the siRNA-ATM technique. The expression of the ATM gene and ATM protein were significantly downregulated post-transfection. Cell Counting Kit-8 (CCK-8) and colony formation assays revealed that the A group demonstrated weak cell proliferation and lower survival fractions post-irradiation compared to the C/N groups. Flow cytometry was used to examine the percentage of cell apoptosis and G2 phase arrest, which were both higher in the A group than in the C/N groups. We found that the comet tail percentage evaluated by comet assay was higher in the A group than in the C/N groups. After radiation treatment, three radiosensitive genes [p53, proliferating cell nuclear antigen (PCNA), survivin] exhibited a decreasing tendency as determined by RT-qPCR. Mice underwent subcutaneous implantation, followed by radiation, and the resulting necrosis and hemorrhage were more obvious in the A group than in the N groups. In conclusion, silencing of ATM via the siRNA technique improved radiosensitivity of GSCs both in vitro and in vivo. PMID- 28560407 TI - Tensile strength suppresses the osteogenesis of periodontal ligament cells in inflammatory microenvironments. AB - The present study aimed to investigate the role of orthodontic force in osteogenesis differentiation, matrix deposition and mineralization in periodontal ligament cells (PDLCs) cells in inflammatory microenvironments. The mesenchymal origin of PDLCs was confirmed by vimentin and cytokeratin staining. PDLCs were exposed to inflammatory cytokines (5 ng/ml IL-1beta and 10 ng/ml TNF-alpha) and/or tensile strength (0.5 Hz, 12% elongation) for 12, 24 or 48 h. Cell proliferation and tensile strength-induced cytokine expression were assessed by MTT assay and ELISA, respectively. Runt-related transcription factor 2 (RUNX2) and type I collagen (COL-I) expression were analysed by reverse transcription quantitative polymerase chain reaction and western blot analysis. Additionally, alkaline phosphatase activity was measured, and the mineralization profile was evaluated by alizarin red S staining. PDLCs exposed to tensile strength in inflammatory microenvironments exhibited reduced proliferation and mineralization potential. Treatment with the inflammatory cytokines IL-1beta and TNF-alpha increased RUNX2 expression levels; however, decreased COL-I expression levels, indicating that bone formation and matrix deposition involve different mechanisms in PDL tissues. Notably, RUNX2 and COL-I expression levels were decreased in PDLCs exposed to a combination of an inflammatory environment and loading strength. The decreased osteogenic potential in an inflammatory microenvironment under tensile strength suggests that orthodontic force may amplify periodontal destruction in orthodontic patients with periodontitis. PMID- 28560408 TI - Collagen-derived N-acetylated proline-glycine-proline upregulates the expression of pro-inflammatory cytokines and extracellular matrix proteases in nucleus pulposus cells via the NF-kappaB and MAPK signaling pathways. AB - N-acetylated proline-glycine-proline (N-Ac-PGP) is a chemokine involved in inflammatory diseases and is found to accumulate in degenerative discs. N-Ac-PGP has been demonstrated to have a pro-inflammatory effect on human cartilage endplate stem cells. However, the effect of N-Ac-PGP on human intervertebral disc cells, especially nucleus pulposus (NP) cells, remains unknown. The purpose of this study was to investigate the effect of N-Ac-PGP on the expression of pro inflammatory factors and extracellular matrix (ECM) proteases in NP cells and the molecular mechanism underlying this effect. Therefore, Milliplex assays were used to detect the levels of various inflammatory cytokines in conditioned culture medium of NP cells treated with N-Ac-PGP, including interleukin-1beta (IL-1beta), IL-6, IL-17, tumor necrosis factor-alpha (TNF-alpha) and C-C motif ligand 2 (CCL2). RT-qPCR was also used to determine the expression of pro-inflammatory cytokines and ECM proteases in the NP cells treated with N-Ac-PGP. Moreover, the role of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) signaling pathways in mediating the effect of N-Ac-PGP on the phenotype of NP cells was investigated using specific signaling inhibitors. Milliplex assays showed that NP cells treated with N-Ac-PGP (10 and 100 ug/ml) secreted higher levels of IL-1beta, IL-6, IL-17, TNF-alpha and CCL2 compared with the control. RT qPCR assays showed that NP cells treated with N-Ac-PGP (100 ug/ml) had markedly upregulated expression of matrix metalloproteinase 3 (MMP3), MMP13, a disintegrin and metalloproteinase with thrombospondin motif 4 (ADAMTS4), ADAMTS5, IL-6, CCL 2, CCL-5 and C-X-C motif chemokine ligand 10 (CXCL10). Moreover, N-Ac-PGP was shown to activate the MAPK and NF-kappaB signaling pathways in NP cells. MAPK and NF-kappaB signaling inhibitors suppressed the upregulation of proteases and pro inflammatory cytokines in NP cells treated with N-Ac-PGP. In conclusion, N-Ac-PGP induces the expression of pro-inflammatory cytokines and matrix catabolic enzymes in NP cells via the NF-kappaB and MAPK signaling pathways. N-Ac-PGP is a novel therapeutic target for intervertebral disc degeneration. PMID- 28560409 TI - Construction of disease-specific transcriptional regulatory networks identifies co-activation of four gene in esophageal squamous cell carcinoma. AB - Even though various molecules may serve as biomarkers, little is known concerning the mechanisms underlying the carcinogenesis of ESCC, particularly the transcriptional regulatory network. Thus, in the present study, paired ESCC and non-cancerous (NC) tissues were assayed by Affymetrix microarray assays. Passing Attributes between Networks for Data Assimilation (PANDA) was used to construct networks between transcription factors (TFs) and their targets. AnaPANDA program was applied to compare the regulatory networks. A hypergeometric distribution model-based target profile similarity analysis was utilized to find co-activation effects using both TF-target networks and differential expression data. There were 1,116 genes upregulated and 1,301 genes downregulated in ESCC compared with NC tissues. In TF-target networks, 16,970 ESCC-specific edges and 9,307 NC specific edges were identified. Edge enrichment analysis by AnaPANDA indicated 17 transcription factors (NFE2L2, ELK4, PAX6, TLX1, ESR1, ZNF143, TP53, REL, ELF5, STAT1, TBP, NHLH1, FOXL1, SOX9, STAT3, ELK1, and HOXA5) suppressed in ESCC and 5 (SPIB, BRCA1, MZF1, MAFG and NFE2L1) activated in ESCC. For SPIB, MZF1, MAFG and NFE2L1, a strong and significant co-activation effect among them was detected in ESCC. In conclusion, the construction of transcriptional regulatory networks found SPIB, MZF1, MAFG and NFE2L1 co-activated in ESCC, which provides distinctive insight into the carcinogenesis mechanism of ESCC. PMID- 28560411 TI - CpG methylation patterns are associated with gene expression variation in osteosarcoma. AB - Osteosarcoma is a common malignant tumor in childhood and adolescence (nearly 5% of all cases of cancer in children), as well as a type of tumor with poor prognosis. However, the pathogenesis and molecular mechanisms of osteosarcoma remains to be elucidated. The aim of the current study was to determine the association between methylation and gene expression changes in osteosarcoma cell line. Microarray data were obtained from the Gene Expression Omnibus database (GSE36004). Genome-wide methylation status was determined in 19 different osteosarcoma cell lines and 6 normal controls. Differentially expressed genes (DEGs) were identified from cancer cells with genefilter package in R and differentially methylated sites were screened with CpGassoc package in R. Integrated gene expression with methylation profiles, genes differentially expressed and methylated, were obtained, and transcriptional regulatory network construction was performed. Functional annotation was performed for genes in the network using the DAVID online tool. Following integrated analysis, a total of 75 methylated sites were demonstrated to be localized at a transcription factor binding region. These sites may be bound by 83 transcription factors which will then alter the expression of 75 downstream DEGs. In the regulatory network, seizure related 6 homolog like 2 (SEZ6L2) had the highest degree of upregulation and was demonstrated to be regulated by 12 transcription factors. Furthermore, kin of IRRE like (KIRREL), centrosomal protein 72 (CEP72) and cyclin-dependent kinase 4 (CDK4) were also regulated by more than three transcription factors. Functional annotation revealed that the upregulated genes were primarily involved in the cell cycle pathway. Several differentially methylated sites were associated with upregulation of SEZ6L2, KIRREL, CEP72 and CDK4 and may have an important role in the pathogenesis of osteosarcomas through promotion of cell proliferation and metastasis. PMID- 28560410 TI - DCLK1 is correlated with MET and ERK5 expression, and associated with prognosis in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is an aggressive cancer for which more effective treatments are needed. In this study, strong to moderate staining of MET and ERK5 was detected in 67.1 and 48% of the analyzed 73 human mesothelioma tumors, and significant correlation of MET and ERK5 expression was identified (P<0.05). We evaluated the doublecortin-like kinase 1 (DCLK1) expression in human mesothelioma tumors. Our results showed that 50.7% of the immunohistochemistry analyzed human mesothelioma tumors have strong to moderate staining of DCLK1, and its expression is significantly correlated with MET or ERK5 expression (P<0.05). Also, the upregulation of DCLK1 is correlated with poor prognosis in MPM patients (P=0.0235). To investigate whether DCLK1 is downstream of MET/ERK5 signaling in human mesothelioma, the effect of DCLK1 expression was analyzed after treatments with either the MET inhibitor XL184 or the ERK5 inhibitor XMD8-92 in human mesothelioma cell lines. Our results showed that the MET inhibitor XL184 reduced the expression of phospho-ERK5 and DCLK1 expression in human mesothelioma cell lines. In addition, the ERK5 inhibitor XMD8-92 reduced the expression of phospho ERK5 and DCLK1 expression in human mesothelioma cell lines. Furthermore, XML184 and XMD8-92 treatment impaired invasion and tumor sphere formation ability of H290 mesothelioma cells. These results suggest that DCLK1 is regulated by MET/ERK5 signaling in human mesothelioma, and the MET/ERK5/DCLK1 signaling cascade could be further developed into a promising therapeutic target against mesothelioma. PMID- 28560412 TI - Farnesoid X receptor deletion improves cardiac function, structure and remodeling following myocardial infarction in mice. AB - The farnesoid X receptor (FXR) is implicated in cholesterol and bile acid homeostasis; however, its role following myocardial infarction (MI) has yet to be elucidated. The aim of the present study was to investigate the effects of FXR knockout on left ventricular (LV) remodeling following MI. Coronary arteries of wild type (WT) and FXR-/- mice were permanently occluded to cause MI, and serial echocardiographic and histological tests were conducted. At 4 weeks post-MI, FXR /- mice exhibited significantly smaller infarct sizes (34.20+/-2.58 vs. 44.20+/ 3.19%), improved ejection fraction (47.31+/-1.08 vs. 37.64+/-0.75%) and reduced LV chamber dilation compared with WT mice. LV remodeling was significant as early as 7 days post-MI in FXR-/- compared with WT mice. Histological features associated with enhanced long-term remodeling and improved functionality, such as increased angiogenesis via detection of CD31 and reduced fibrosis, were observed in the FXR-/- group. Myocyte apoptosis within the infarcted zones appeared significantly reduced by day 7 in FXR-/- mice. In conclusion, the results of the present study suggested that FXR knockout may participate in the preservation of post-MI cardiac functionality, via reducing fibrosis and chronic apoptosis, and ameliorating ventricular function. PMID- 28560413 TI - Coptidis Rhizoma induces intrinsic apoptosis through BAX and BAK activation in human melanoma. AB - Malignant melanoma has exhibited a rising incidence in recent years worldwide. Although various molecular targeted drugs are being researched and developed for melanoma patients, their efficacy appears to be unsatisfactory. Over the past few years, several reports have demonstrated that Coptidis Rhizoma water extracts (CR) or its major active chemical component, berberine, has anticancer activities in various types of cancer, including melanoma. However, their underlying mechanisms have not been well understood. In the present study, we determined that CR suppressed melanoma cell viability, which was mainly mediated through apoptosis. In addition, the expression levels of anti-apoptotic proteins, BCL2A1, MCL1 and BCL-w, were strongly suppressed by CR treatment. Furthermore, multi domain pro-apoptotic proteins BAX and BAK were activated by CR treatment and were also required for the CR-induced apoptosis. Collectively, CR or some formulations containing CR, may be effective safe treatment strategies for human melanoma. PMID- 28560414 TI - Bone marrow stromal cells promote neuromotor functional recovery, via upregulation of neurotrophic factors and synapse proteins following traumatic brain injury in rats. AB - It has previously been demonstrated that bone marrow stromal cells (BMSCs) exhibit great therapeutic potential in neuronal injuries; however, there is limited understanding of the precise underlying mechanisms that contribute to functional improvement following brain injury. The aim of the present study was to assess the effect of BMSC treatment on traumatic brain injury (TBI) in rats, and investigate if they migrate to injured areas and promote neuromotor functional recovery via upregulation of neurotrophic factors and synaptic proteins. BMSCs were cultured in vitro from female Sprague Dawley (SD) rat bone marrow and were subsequently infused into male adult SD rats via the tail vein, following induction of TBI. The results demonstrated that treatment with BMSCs significantly reduced TBI-induced neuromotor impairment and neuronal loss, as assessed by rota rod testing, western blot analysis, modified neurological severity score and immunohistochemistry. The distribution of transplanted BMSCs was tracked by monitoring the expression of sex determining region Y (SRY) in rats. The number of cells double-positive for SRY/neuronal nuclear antigen or SRY/glial fibrillary acidic protein was increased in the BMSC group, which demonstrated that BMSCs migrated to injured areas and differentiated into neurons and astrocytes, following TBI. Furthermore, administration of BMSCs increased expression of vascular endothelial growth factor and brain derived neurotrophic factor. Protein expression levels of synaptophysin were downregulated following TBI and this was reversed in part by treatment with BMSCs. These findings uncovered some underlying mechanisms of action of BMSCs, and may lead to their potential use as a future effective therapeutic agent for the treatment of TBI. PMID- 28560415 TI - Bioinformatics analyses of the differences between lung adenocarcinoma and squamous cell carcinoma using The Cancer Genome Atlas expression data. AB - The present study aimed to explore gene and microRNA (miRNA) expression differences between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified by analyzing mRNA and miRNA expression data in normal and cancerous lung tissues that were obtained from The Cancer Genome Atlas database. A total of 778 DEGs and 7 DEMs were identified. Altered gene functions and signaling pathways were investigated using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, which revealed that DEGs were significantly enriched in extracellular matrix organization, cell differentiation, negative regulation of toll signaling pathway, and several other terms and pathways. Transcription factor (TF)-miRNA-gene networks in LUAD and LUSC were predicted using the TargetScan, Miranda, and TRANSFAC databases, which revealed the regulatory links among the TFs, DEMs, and DEGs. The central TFs, i.e., the TFs in the middle of the TF-miRNA-gene network, of LUAD and LUSC were similar. Although LUAD and LUSC shared similar miRNAs in the predicted networks, miR-29b-3p was demonstrated to be upregulated only in LUAD, whereas miR-1, miR-105-5p, and miR 193b-5p were altered in LUSC. These findings may improve our understanding of the different molecular mechanisms in non-small cell lung cancers and may promote new and accurate strategies for prevention, diagnosis, and treatment. PMID- 28560416 TI - XAF1 expression levels in a non-small cell lung cancer cohort and its potential association with carcinogenesis. AB - The process of lung carcinogenesis is still not well understood and involves different levels of regulation of several genes. The search for molecular biomarkers, which can be applicable to clinical practice, has been the focus of various studies. XIAP-associated factor 1 (XAF1) was previously shown to be downregulated in many types of tumors, including squamous cell lung cancer. XAF1 is a pro-apoptotic protein and its restoration was found to sensitize cancer cells to apoptotic stimuli; however, the precise mechanism involved in the downregulation of XAF1 in tumors is unknown and promoter hypermethylation or heat shock transcription factor 1 (HSF1) may be involved. Therefore, the aim of the present study was to evaluate the expression of XAF1 in tumors and adjacent non tumor specimens from non-small cell lung cancer (NSCLC) patients, and its potential association with various factors including clinicopathological characteristics and other genes involved in NSCLC. Our results indicated that XAF1 expression was markedly altered in NSCLC tumor samples when compared to that found in normal lung tissues. Predominantly, XAF1 was downregulated in the tumors, except in never-smoker patients. In addition, XAF1 may also be important in the whole cell stress mechanism where the p53 status is crucial. PMID- 28560417 TI - Atheroprotective effects of statins in patients with unstable angina by regulating the blood-borne microRNA network. AB - Experimental studies have demonstrated several effects of statins in acute coronary syndrome (ACS) that may extend their clinical benefit beyond the lipid profile modification itself. However, the precise underlying mechanism remains to be elucidated. microRNAs (miRNAs) serve significant roles in the pathophysiology of atherosclerotic plaque progression. The present study investigated the protective role of statins in patients with unstable angina (UA) by regulating the circulating miRNA network. miRNA array results demonstrated that there were 21 differentially expressed miRNAs in non-statin-treated patients with UA (n=8) compared with non-coronary artery disease controls (n=8), and 33 differentially expressed miRNAs in statin-treated patients with UA (n=8) compared with non statin patients. TargetScan and miRanda programs were used to predict miRNAs target genes. miRNAs target genes in vascular endothelial cells and monocytes were clustered based on the CGAP SAGE library via the Database for Annotation, Visualization and Integrated Discovery (DAVID) platform, and miRNA target genes in platelets were clustered based on a UP tissue-specific library via the DAVID platform. The PANTHER database via DAVID platform was used to perform signaling pathway analysis. The miRNA-gene/pathway network was visualized by Cytoscape software. Bioinformatic analysis suggested that statin-induced miRNAs functions were primarily enriched in angiogenesis, integrin and platelet derived growth factor signaling pathways in UA patients. In endothelial cells and platelets, statin-induced miRNAs primarily targeted the integrin signaling pathway, and in monocytes primarily targeted cytoskeletal regulation by the Rho GTPase signaling pathway. These results revealed that statins may serve systematic protective roles in UA patients by influencing the circulating miRNA regulatory network. Further studies are required to verify the functions of statin-induced miRNAs in endothelial cells, platelets and monocytes. PMID- 28560418 TI - An FGF8b-mimicking peptide with potent antiangiogenic activity. AB - Fibroblast growth factor (FGF) 8b interacts with its receptors and promotes angiogenesis in hormone-dependent tumors. In the present study, we demonstrated that a short peptide, termed 8b-13, which mimics part of the FGF8b structure, significantly inhibited the proliferation and migration of human umbilical vein endothelial cells (HUVECs) triggered by FGF8b using 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT), flow cytometry and an in vitro scratch assay. In addition, the findings from western blotting and reverse transcription quantitative polymerase chain reaction revealed that 8b-13 appeared to counteract the effects of FGF8b on the expression of cyclin D1, the activation of signaling cascades, and the expression of proangiogenic factors; these actions may be involved in the mechanism underlying the inhibitory effects of 8b-13 on FGF8b induced HUVEC proliferation and migration. The present results suggested that 8b 13 may be considered a potent FGF8b antagonist with antiangiogenic activity, and may have potential as a novel therapeutic agent for the treatment of cancer characterized by abnormal FGF8b upregulation. PMID- 28560419 TI - Upregulation of miR-101 enhances the cytotoxic effect of anticancer drugs through inhibition of colon cancer cell proliferation. AB - This study investigated the effect of miR-101 on proliferation, migration, invasion, and chemotherapy sensitivity in colon cancer cell lines HT-29 and RKO. MicroRNAs are a class of small noncoding RNA molecules, which play important roles in diverse biological processes of human cancers, such as carcinogenesis, development, differentiation, and apoptosis. The expression of miR-101 in colon cancer and adjacent non-tumor tissues were examined by quantitative real-time polymerase chain reaction. The expression of miR-101 was upregulated by recombinant adenovirus Ad-miR-101. Cell proliferation was detected by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cloning methods. Cell migration and invasion potential were examined using Transwell migration and Matrigel invasion chamber assays. Drug sensitivity to 5 fluorouracil (5-FU) and cisplatin (DDP) was explored using MTT assays and l acridine orange/ethidium bromide double staining. The expression of miR-101 decreased in colon cancer tissues compared with adjacent non-tumor tissues. The upregulated expression of miR-101 suppressed cell proliferation and inhibited cell migration and invasion in HT-29 and RKO colon cancer cell lines. The overexpression of miR-101 promoted the inhibitory effect of 5-FU and DDP on HT-29 cells. The expression of miR-101 was downregulated in colon cancer. The upregulated expression of miR-101 inhibited proliferation and migration, and increased the sensitivity of colon cancer cells to chemotherapy. PMID- 28560420 TI - The restraining effect of baicalein and U0126 on human cervical cancer cell line HeLa. AB - To explore the restraining effect of baicalein and the mitogen-activation protein kinase kinase inhibitor, U0126, on human cervical cell line HeLa proliferation, apoptosis and migration. HeLa cells were treated by different concentrations of baicalein or U0126. A Cell Counting Kit (CCK)-8 assay was applied to examine cell viability. Flow cytometry was used to determine cell cycle and apoptosis. A wound healing assay was performed to detect cell migration. A terminal deoxynucleotidyl transferase dUTP nick end labeling assay was adopted to test cell apoptosis. Reverse transcription-quantitative polymerase chain reaction and western blot analysis was used to detect apoptosis gene and protein expression. CCK-8 assay demonstrated that baicalein and U0126 suppressed HeLa cell viability by dose dependence. TUNEL, Annexin V-fluorescein isothiocyanate/propidium iodide, and ratio of Bcl-2-associated X protein and B cell lymphoma 2 indicated that baicalein and U0126 induced HeLa cell apoptosis. Flow cytometry revealed that baicalein blocked the cell cycle of HeLa in G0/G1 phase. A wound healing assay demonstrated that baicalein significantly inhibited HeLa cell migration compared with control. Baicalein and U0126 markedly downregulated extracellular signal regulated kinase 1/2, matrix metalloproteinase (MMP) 2 and MMP9 levels both in mRNA and protein. In the present study, the authors demonstrated that baicalein and U0126 may be used in cervical cancer treatment by inhibiting cell migration and inducing cell apoptosis. PMID- 28560421 TI - A novel damage mechanism: Contribution of the interaction between necroptosis and ROS to high glucose-induced injury and inflammation in H9c2 cardiac cells. AB - Recently, a novel mechanism known as 'programmed necrosis' or necroptosis has been shown to be another important mechanism of cell death in the heart. In this study, we investigated the role of necroptosis in high glucose (HG)-induced injury and inflammation, as well as the underlying mechanisms. In particular, we focused on the interaction between necroptosis and reactive oxygen species (ROS) in H9c2 cardiac cells. Our results demonstrated that the exposure of H9c2 cardiac cells to 35 mM glucose (HG) markedly enhanced the expression level of receptor interacting protein 3 (RIP3), a kinase which promotes necroptosis. Importantly, co-treatment of the cells with 100 uM necrostatin-1 (a specific inhibitor of necroptosis) and HG for 24 h attenuated not only the increased expression level of RIP3, but also the HG-induced injury and inflammation, as evidenced by an increase in cell viability, a decrease in ROS generation, the attenuation of the dissipation of mitochondrial membrane potential and a decrese in the secretion levels of inflammatory cytokines, i.e., interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. Furthermore, treatment of the cells with 1 mM N-acetyl-L cysteine (a scavenger of ROS) for 60 min prior to exposure to HG significantly reduced the HG-induced increase in the RIP3 expression level, as well as the injury and inflammatory response described above. Taken together, the findings of this study clearly demonstrate a novel damage mechanism involving the positive interaction between necroptosis and ROS attributing to HG-induced injury and inflammation in H9c2 cardiac cells. PMID- 28560422 TI - Effects of maternal acrolein exposure during pregnancy on testicular testosterone production in fetal rats. AB - Acrolein has been reported to have diverse toxic effects on various organs, including the reproductive system. However, little is known regarding the effects of maternal acrolein exposure on testicular steroidogenesis in male offspring. The present study investigated the effects of acrolein on fetal testosterone production and associated genes. Pregnant Sprague-Dawley rats were intraperitoneally injected with vehicle (normal saline) or 1, 2 or 5 mg/kg acrolein from gestational day (GD) 14-20, and fetal testes were examined on GD 21. Fetal body and testicular weights were markedly reduced in pups following exposure to high doses of acrolein (5 mg/kg) in late pregnancy. Notably, in utero exposure of 5 mg/kg acrolein significantly decreased the testicular testosterone level and downregulated the expression levels of steroidogenic acute regulatory protein (StAR) and 3beta-hydroxysteroid dehydrogenase (3beta-HSD), whereas the levels of other steroidogenic enzymes, including scavenger receptor class B, cholesterol side-chain cleavage enzyme and steroid 17 alpha-hydroxylase/17,20 lyase, were unaffected. Furthermore, the 3beta-HSD immunoreactive area in the interstitial region of the fetal testes was reduced at a 5 mg/kg dose, whereas the protein expression levels of 4-hydroxynonenalwere dose-dependently increased following maternal exposure to acrolein. mRNA expression levels of insulin-like factor 3, a critical gene involved in testicular descent, were unaltered following maternal acrolein exposure. Taken together, the results of the present study suggested that maternal exposure to high doses of acrolein inhibited fetal testosterone synthesis, and abnormal expression of StAR and 3beta-HSD may be associated with impairment of the steroidogenic capacity. PMID- 28560423 TI - Prokaryotic expression, purification and characterization of human cyclooxygenase 2. AB - Cyclooxygenase-2 (COX-2) is a key enzyme which catalyzes the conversion of arachidonic acid (AA) into prostaglandins (PGs). It plays an important role in pathophysiological processes, such as tumorigenesis, angiogenesis, inflammation and tumor cell drug resistance. Therefore, COX-2 has been viewed as an important target for cancer therapy. The preparation of COX-2 protein is an important initial step for the subsequent development of COX-2 inhibitors. In this study, we report a strategy to heterologously express truncated human COX-2 (trCOX-2) in Escherichia coli (E. coli) BL21(DE3) host cells. Following denaturation, purification and renaturation, we successfully obtained enzymatically active trCOX-2 containing 257 residues of the C-terminus. Homology modeling and molecular docking analyses revealed that trCOX-2 retained the predicted 3D catalytic domain structure and AA could still bind to its hydrophobic groove. Western blot analysis and ELISA indicated that the trCOX-2 still retained its characteristic antigenicity and binding activity, while COX assays revealed that trCOX-2 maintained its enzyme activity. On the whole, in this study, we provided a novel method to isolate trCOX-2 possessing AA binding and catalytic activities. This study thus lays a foundation to facilitate further investigations of COX-2 and offers a valuable method with which to achieve the prokaryotic expression of a eukaryotic membrane protein. PMID- 28560424 TI - Secretomic profiling of cells from hollow fiber bioreactor reveals PSMA3 as a potential cholangiocarcinoma biomarker. AB - Cholangiocarcinoma (CCA), derived from the bile duct, occurs with a relatively high incidence in Northeast Thailand. Early diagnosis is still hampered by the lack of sufficient biomarkers. In recent years, biomarker discovery using secretomes has provided interesting results, including our studies on CCA secretomes, especially with three-dimensional cell cultures. Thus, cells cultured using the hollow fiber bioreactor (HFB) with 20 kDa molecular weight cut-off (MWCO) yielded higher quality and quantity of secretomes than those from conditioned media of the monolayer culture (MNC) system. In this study, we employed the HFB culture system with 5 kDa MWCO and compared conditioned media from the HFB and MNC systems using two-dimensional gel electrophoresis, followed by identifying proteins of interest by liquid chromatography and mass spectrometry (LC/MS/MS). Two out of 4 spots of NGAL or lipocalin-2 were found to show highest increase in expression of 19.93-fold and 18.79-fold in HFB compared to MNC. Interestingly, all 14 proteasome subunits including proteasome subunit alpha type-1 to type-7 and beta type-1 to type-7 showed 2.92-fold to 12.13-fold increased expression in HFB. The protein-protein interactions of upregulated proteins were predicted, and one of the main interaction clusters involved 20S proteasome subunits. Proteasome activity in the HFB conditioned media was also found to be higher than that in MNC conditioned media. Three types of proteasome subunit were also validated by immunoblotting and showed higher expression in the HFB system compared to MNC system. Proteasome subunit alpha type-3 (PSMA3) showed the highest level in plasma of cholangiocarcinoma patients compared to normal and hepatocellular carcinoma patients by immunodetection, and is of interest as a potential biomarker for cholangiocarcinoma. PMID- 28560426 TI - DcR3 promotes hepatoma cell migration by downregulating E-cadherin expression. AB - Decoy receptor 3 (DcR3), a decoy molecule belonging to the tumor necrosis factor receptor superfamily (TNFRSF), is a soluble receptor that can neutralize the biological effects of three other TNFSF members, namely, Fas ligand (FasL/TNFSF6/CD95L), LIGHT (TNFSF14) and TNF-like molecule 1A (TL1A/TNFSF15). DcR3 expression is increased in tumor cells. As such, DcR3 has been considered a potential biomarker to predict cancer invasion and progression of inflammation. However, the molecular mechanisms of DcR3 in tumor progression and metastasis remain poorly described. In the present study, DcR3 induced cytoskeleton remodeling, inhibited E-cadherin expression, and promoted cancer cell migration. Immunofluorescence and flow cytometry demonstrated that DcR3 expression was increased in hepatoma cells, whereas E-cadherin expression was significantly downregulated. Immunohistochemistry revealed that DcR3 and E-cadherin exhibited an opposite expression pattern between normal and cancerous liver tissues. Moreover, DcR3 treatment promoted IkappaBalpha degradation and p65 nuclear translocation. Therefore, the present study uncovered the mechanism underlying the function of DcR3 in cancer cell migration and provides evidence that DcR3 may be a potential target for cancer therapy. PMID- 28560425 TI - Investigating critical genes and gene interaction networks that mediate cyclophosphamide sensitivity in chronic myelogenous leukemia. AB - Drug resistance is an obstacle in the treatment of chronic myelogenous leukemia (CML), and is a common reason for treatment failure or disease progression. However, the underlying mechanisms of cyclophosphamide resistance remain poorly defined. In the present study, microarray data concerning cyclophosphamide sensitive and -resistant chronic myelogenous leukemia cell lines were analyzed. A total of 258 differentially-expressed genes (DEGs) were identified between these two groups, from which 139 DEGs were upregulated and 119 were downregulated. Several candidate genes that were associated with cyclophosphamide resistance were also identified. These DEGs were subsequently classified using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis. A total of 487 biological processes and 17 KEGG pathways were revealed to be enriched. Furthermore, an interaction network was established to identify the core genes that regulated cyclophosphamide resistance. Signal transducer and activator of transcription 5A (STAT5A), FYN proto-oncogene, Src family tyrosine kinase and spleen associated tyrosine kinase were revealed to be the hub genes in multiple enriched biological processes and signaling pathways, indicating that these were involved in mediating cyclophosphamide sensitivity in CML cells. The expression levels of 5 DEGs were also confirmed in two human CML cell lines (K 562 and KU812) by reverse transcription-quantitative polymerase chain reaction. Furthermore, selective knockdown of STAT5A and S100 calcium binding protein A4 (S100A4) recovered cyclophosphamide sensitivity in K-562 cells, suggesting their involvement in drug resistance. The present study identified several potential genes and pathways contributing to cyclophosphamide resistance, and confirmed the involvement of STAT5A and S100A4 in drug resistance. These results enable improved understanding of the mechanisms underlying drug resistance in CML cells. PMID- 28560427 TI - Araliasaponin II isolated from leaves of Acanthopanax henryi (Oliv.) Harms inhibits inflammation by modulating the expression of inflammatory markers in murine macrophages. AB - Araliasaponin II (AS II) is a bioactive compound isolated from Acanthopanax henryi (Oliv.) Harms, a plant widely used in traditional oriental medicine. The present study investigated the anti-inflammatory effects of AS II using murine macrophages. The effects of AS II on inflammatory mediator and cytokine production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells was evaluated. Nitric oxide (NO) and cytokine production were determined using the Griess reagent and an ELISA kit. The expression levels of cytokines, inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA were examined by reverse transcription-quantitative polymerase chain reaction. The expression levels of iNOS, COX-2 and toll-like receptor (TLR)-4 protein were examined by western blotting. Translocation of nuclear factor-kappaB (NF-kappaB) and TLR-4 expression were visualized by immunofluorescence staining. AS II markedly inhibited the production of NO and prostaglandin E2, and reduced iNOS and COX-2 expression at the transcriptional and translational levels. AS II downregulated the expression of interleukin-6 and tumor necrosis factor-alpha at the protein and mRNA levels. Furthermore, pre-treatment with AS II significantly suppressed the TLR-4-NF kappaB signaling pathway; this effect may be cause by AS II competing with LPS for binding to TLR-4 and subsequently inhibiting translocation of the NF kappaB/p65 protein to the nucleus. The results suggested that the anti inflammatory properties of AS II may result from inhibiting pro-inflammatory mediators by suppressing the initiation of the inflammatory response and inhibiting TLR-4-NF-kappaB signaling pathways. PMID- 28560428 TI - Metformin ameliorates hepatic steatosis and improves the induction of autophagy in HFD-induced obese mice. AB - The present study aimed to investigate the effect of metformin on the induction of autophagy in the liver and adipose tissues of a mouse model of obesity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity associated hepatic steatosis, and treated with metformin (150 mg/kg/d) by intraperitoneal injection for the final 4 weeks of HFD feeding. Body weight was recorded weekly, and the food intake of the mice was recorded daily during the treatment period. Liver and adipose tissues were harvested for histological and molecular analyses. The results revealed that metformin significantly reduced body weight without altering food intake in the HFD mice, particularly in the epididymal white adipose tissue (eWAT). Metformin treatment ameliorated HFD induced hepatic steatosis and serum levels of triglycerides, which was consistent with a marked increase in the expression levels of microtubule-associated protein 1 light chain 3 (LC3) and AMP-activated protein kinase (AMPK) in the liver following metformin treatment. However, metformin suppressed the expression of LC3 in the eWAT without altering the expression of AMPK, compared with that in the HFD mice. In conclusion, metformin reduced the body weight and hepatic steatosis of the HFD-induced obese mice, without altering food intake. The effects of metformin treatment may be attributable to the improved induction of hepatic autophagy and the inhibited induction of adipose tissue autophagy. PMID- 28560429 TI - Modified citrus pectin inhibits galectin-3 function to reduce atherosclerotic lesions in apoE-deficient mice. AB - Galectin-3 is a carbohydrate-binding lectin, which has been implicated in the modulation of atherosclerotic pathophysiology, and is highly expressed in monocytes, macrophages and endothelial cells within atherosclerotic plaques. Modified citrus pectin (MCP) is produced from citrus pectin via pH and temperature modifications, which break it into shorter, non-branched, galactose rich carbohydrate chains. MCP is able to tightly bind with galectin-3, via recognition of its carbohydrate recognition domain, and facilitates the modulation of galectin-3-induced bioactivity. The present study explored the effects of MCP on the initiation of atherosclerosis. Eight-week-old apolipoprotein E-deficient mice were treated with 1% MCP and fed an atherogenic diet for 4 weeks. The effects of MCP on atherosclerotic initiation were determined by pathological analysis and scanning electron microscope (SEM) imaging. MCP treatment reduced the size of atherosclerotic lesion areas, which was accompanied by decreased numbers of macrophages and smooth muscle cells (SMCs). Furthermore, SEM examination of the surface of the atheroma-prone vessel wall indicated that MCP treatment reduced endothelial injury. To analyze the effects of MCP on monocyte adhesion, firstly, oxidized-low density lipoprotein and various concentrations of MCP (0.025, 0.05, 0.1 and 0.25%) were incubated with the human umbilical vein endothelial cells (HUVECs) for stimulation and following this, the U937 cells were plated onto the HUVECs. The results revealed that MCP reduced the adhesion of U937 monocytes to HUVECs, indicating the adhesion-inhibiting effects of MCP. In conclusion, the present study revealed that MCP, a galectin-3 inhibitor, reduced the size of atherosclerotic lesions by inhibiting the adhesion of leucocytes to endothelial cells. Inhibition of galectin-3 function may be a therapeutic strategy for the treatment of atherosclerosis. PMID- 28560431 TI - Overexpression of miR-15b-5p promotes gastric cancer metastasis by regulating PAQR3. AB - Gastric cancer (GC) is the fifth most common cancer in the world, with 952,000 new cases diagnosed in 2012. Tumor metastasis is the major cause of cancer recurrence and death. miR-15b-5p has been reported to be dysregulated in numerous types of cancers. However, the role of miR-15b-5p in GC metastasis remains unclear. An miRNA microarray was adopted to analyze the miRNA expression profile. By employing quantitative real-time polymerase chain reaction (qRT-PCR), miR-15b 5p expression levels were detected in GC cell lines, tissues and plasma samples. In addition, the effects of miR-15b-5p on cell proliferation, migration and invasion were studied by applying gain-of-function approaches. Moreover, the target of miR-15b-5p was assessed by dual-luciferase assay, and the mechanism underlying the regulation of GC metastasis by miR-15b-5p was assessed by rescue experiments. The results revealed that miR-15b-5p was upregulated in GC cell lines, tissues and plasma samples. A high plasma level of miR-15b-5p was correlated with distant tumor metastasis. In addition, overexpression of miR-15b 5p in GC cells promoted cell proliferation, migration, invasion and epithelial mesenchymal transition (EMT). Moreover, progestin and adipoQ receptor family member 3 (PAQR3) was found to be a direct target of miR-15b-5p and re-expression of PAQR3 in miR-15b-5p-overexpressing GC cells partly attenuated the proliferation, migration and invasion. These findings revealed that miR-15b-5p promotes the metastasis of GC cells through PAQR3 and may represent a potential biomarker of GC. PMID- 28560430 TI - Fyn/heterogeneous nuclear ribonucleoprotein E1 signaling regulates pancreatic cancer metastasis by affecting the alternative splicing of integrin beta1. AB - Pancreatic cancer is characterized by a dense desmoplastic reaction in which extracellular matrix proteins accumulate and surround tumor cells. Integrins and their related signaling molecules are associated with progression of pancreatic cancer. In the present study, the association between the metastasis of pancreatic cancer and the expression of hnRNP E1 and integrin beta1 was evaluated. In vitro and in vivo experiments were designed to study the mechanism underlying the regulation of integrin beta1 splicing by the Fyn/hnRNP E1 spliceosome. Expression of hnRNP E1 and integrin beta1A were associated with metastasis of pancreatic cancer. Inhibition of Fyn activity upregulated the expression of P21-activated kinase 1 and promoted the phosphorylation and nuclear localization of hnRNP E1, leading to the construction of a spliceosome complex that affected the alterative splicing of integrin beta1. In the hnRNP E1 spliceosome complex, hnRNP A1 and serine/arginine-rich splicing factor 1 were responsible for binding to the pre-mRNA of integrin beta1. Suppression of Fyn activity and/or overexpression of hnRNP E1 decreased the metastasis of pancreatic cancer cells. In pancreatic cancer, the present study demonstrated a novel mechanism by which Fyn/hnRNP E1 signaling regulates pancreatic cancer metastasis by affecting the alternative splicing of integrin beta1. hnRNP E1 and integrin beta1A are associated with the metastasis of pancreatic cancer and may be novel molecular targets for pancreatic cancer treatment. PMID- 28560433 TI - Overexpression of GLP-1 receptors suppresses proliferation and cytokine release by airway smooth muscle cells of patients with chronic obstructive pulmonary disease via activation of ABCA1. AB - Glucagon-like peptide-1 (GLP-1) is an important insulin secretagogue that possesses anti-inflammatory effects. GLP-1 receptor (GLP-1R) agonists have been demonstrated to serve a pivotal role in the treatment of obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). However, the specific function and underlying mechanisms of GLP-1R in COPD remain uncertain. The aim of the present study was to investigate the action and underlying mechanisms of GLP-1R in airway smooth muscle (ASM) cells from COPD patients. GLP 1R expression levels were markedly decreased in ASM cells from COPD patients compared with those from healthy controls. ASM cell proliferation and migration, and the levels of the inflammatory cytokines interleukin (IL)-1beta, IL-4, tumor necrosis factor (TNF)-alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured. Transfection of pcDNA3.1-GLP-1R had inhibitory effects on ASM cell proliferation and migration, whereas GLP-1R small interfering (si)RNA reversed these effects. Furthermore, the present study demonstrated that GLP-1R overexpression markedly suppressed IL-1beta, IL-4, TNF-alpha and GM-CSF levels. GLP-1R overexpression upregulated the expression levels of adenosine triphosphate binding cassette, subfamily A, member 1 (ABCA1) in ASM cells, and the effects of GLP-1R on cell proliferation and migration, and inflammatory cytokine expression in ASM cells was abolished by siRNA-mediated silencing of ABCA1. The results of the present study suggested that GLP-1R contributes to COPD pathology, potentially via an ABCA1-mediated pathway. PMID- 28560432 TI - Otoprotective effects of ethosuximide in NOD/LtJ mice with age-related hearing loss. AB - Despite long-term efforts to elucidate the mechanisms responsible for age-related hearing loss (AHL), there is currently no available treatment strategy able to provide a cure. Apoptotic cell death, including that of hair cells and spiral ganglion neurons (SGNs) in the cochlea has been proposed to be the classic theory behind the development of AHL. As calcium signaling plays key roles in signal transduction in apoptosis, in this study, we selected ethosuximide, which is able to block T-type calcium (Ca2+ion) channels, suppressing Ca2+. We hypothesized that the apoptotic pathway may be blocked through the inhibition of T-type Ca2+ channels in cochlear cells in NOD/LtJ mice. NOD/LtJ mice were divided into 2 groups as follows: the ethosuximide-treated and untreated (control) groups. Ethosuximide was administered by intraperitoneal injection every other day from post-natal day seven (P7) until the mice were 8 weeks of age. Following treatment, auditory-evoked brainstem response (ABR) thresholds and distortion product oto-acoustic emission (DPOAE) of the mice in the 2 groups were measured at different time points. Morphometric analysis and the expression of genes involved in the T-type Ca2+-mediated apoptotic pathway were monitored. The ABR and DPOAE results revealed that the NOD/LtJ mice exhibited early-onset and rapidly progressive AHL. A histological examination revealed that hair cell degeneration coincided with the progression of hearing loss. Hair cell and SGN was were significantly lower and auditory function was significantly improved in the ethosuximide-treated group compared to the untreated group. Our data thus indicate that ethosuximide prevents the degeneration of cochlear cells by regulating the expression of genes in apoptotic pathways. Our findings suggest that activating the T-type Ca2+ channel and downstream genes may be key pathological mechanisms responsible for AHL in NOD/LtJ mice. PMID- 28560434 TI - miR-30e acts as a tumor suppressor in hepatocellular carcinoma partly via JAK1/STAT3 pathway. AB - Hepatocellular carcinoma (HCC) is the leading cause of cancer-associated mortalities. The effective diagnostic and therapeutic targets for HCC are still unclear. miR-30e was differentially expressed in the majority of HCC tissues and cell lines. The aim of this study was to investigate the functional roles of miR 30e and their modulation of cancer networks in HCC cells. We determined the expression of miR-30e by quantitative real-time polymerase chain reaction, and found downregulation of miR-30e in HepG2 and HuH7 cells. miR-30e mimics significantly inhibited the proliferation, migration, and invasion of HepG2 and HuH7 cells, and promoted cell apoptosis, but did not influence the cell cycle. Dual-luciferase reporter assays were applied to identify JAK1 as target of miR 30e. miR-30e mimics downregulated the expression levels of JAK1 and vimentin in mRNA and protein in HepG2 and HuH7 cells. Silence of JAK1 by small interfering RNAs inhibited cell proliferation, migration and invasion of HCC cells. Furthermore, we verified that, IL-6, an agonist of JAK1/STAT3 pathway partly recovered the inhibition of miR-30e mimics on cell migration. Taken together, these findings confirmed our speculation that the functional effect of miR-30e on HCC cells, in part, is dependent on the JAK1/STAT3 signaling pathway. It was suggested that miR-30e has a critical role in the suppression of HCC and presents a novel mechanism of miRNA-mediated JAK1 expression in cancer cells that might be a good prognostic marker for survival of HCC patients. PMID- 28560436 TI - Differences in molecular regulation between osteochondroma and bizarre parosteal osteochondromatous proliferation. AB - The differences in molecular mechanisms between osteochondroma and bizarre parosteal osteochondromatous proliferation (BPOP) remain to be fully elucidated. In the present study, the differentially expressed genes between BPOP and osteochondroma were obtained from the Gene Expression Omnibus online database, and the associations among these genes were analyzed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) online bioinformatics software. The results revealed several differentially expressed genes between human BPOP and osteochondroma. These differentially expressed genes were also enriched in different subgroups based on the analysis using DAVID online software, including 'transforming growth factor beta receptor signaling pathway', 'BMP signaling pathway', 'Wnt receptor signaling pathway', 'response to chemical stimulus', 'regulation of inflammatory response', 'response to stress', 'glycosaminoglycan binding', 'polysaccharide binding', 'extracellular matrix structural constituent' and 'growth factors binding'. Taken together, these findings led to the conclusion that different gene regulatory mechanisms exist between BPOP and osteochondroma. Environmental stimulation and inflammation may contribute to BPOP or osteochondroma, and differences in extracellular matrix may contribute to differences in biological characteristics between BPOP and osteochondroma. PMID- 28560435 TI - MicroRNA-146a promotes gastric cancer cell apoptosis by targeting transforming growth factor beta-activated kinase 1. AB - Accumulating evidence suggests that microRNA (miR)-146a functions as an oncogene or tumor suppressor in various cancers. However, the role of miR-146a in gastric cancer (GC) remains to be elucidated. The present study investigated the function of miR-146a in GC cells. The results of the present study revealed that miR-146a modulates GC cell apoptosis. Overexpression of miR-146a significantly increased apoptosis of SGC-7901 cells, whereas inhibition of miR-146a protected cells from apoptosis. miR-146a expression in GC cells was inversely correlated with transforming growth factor beta-activated kinase 1 (TAK1) expression, at the mRNA and protein levels. Furthermore, small interfering RNA-mediated silencing of TAK1 enhanced GC cell apoptosis, whereas overexpression of TAK1 promoted survival of GC cells. Overexpression of miR-146a or knockdown of TAK1 led to a marked increase in inhibitor of kappaBalpha (IkappaBalpha) and a decrease in B-cell lymphoma 2 (Bcl-2) expression levels in SGC-7901 cells. By contrast, silencing of miR-146a or TAK1 overexpression downregulated IkappaBalpha and upregulated Bcl-2 expression levels. Therefore, the results of the present study demonstrated a novel negative feedback mechanism to promote GC cell apoptosis involving the miR 146a/TAK1/nuclear factor-kappaB axis. PMID- 28560438 TI - Synergistic role of Cul1 and c-Myc: Prognostic and predictive biomarkers in colorectal cancer. AB - Colorectal cancer (CRC) is one of the most common malignant tumors, and its high rates of recurrence and metastasis are the important causes of treatment failure in CRC. Therefore, the development of valuable molecular markers to accurately predict the prognosis of CRC patients is vital. In the present study, we determined the expression of Cullin1 (Cul1) and c-Myc in a CRC tissue microarray containing 470 cancer and corresponding normal tissues by immunohistochemistry. We found that Cul1 and c-Myc expression was significantly upregulated in the CRC cancer tissues compared with that noted in the adjacent non-cancer tissues. High Cul1 expression in cancer tissues was associated with depth of invasion (P=0.005), lymph node metastasis (P=0.001) and TNM stage (P=0.015). High c-Myc expression in cancer tissues was significantly positively association with age (P=0.004), depth of invasion (P<0.001), lymph node metastasis (P<0.001) and TNM stage (P<0.001). Multivariate Cox regression analysis revealed that Cul1 or c-Myc expression was an independent and unfavorable prognostic factor for CRC patients [hazard ratio (HR), 0.749, 95% confidence interval (CI), 0.563-0.996, P<0.05; and HR, 0.384, 95% CI, 0.257-0.472, P<0.001, respectively]. Furthermore, Cul1 and c Myc exhibited synergistic potential for the prediction of CRC prognosis, and the patients with low expression of both Cul1 and c-Myc had a favorable survival outcome (P<0.001). PMID- 28560437 TI - The expression of DNA methyltransferases3A is specifically downregulated in chorionic villi of early embryo growth arrest cases. AB - The aim of the present study was to investigate the expression pattern of four DNA methyltransferases (DNMT1, DNMT3A, DNMT3B and DNMT3L) in placenta chorionic villi of early embryo growth arrest patients. Chorionic villous specimens were obtained from 40 pregnant patients diagnosed with early embryo growth arrest and 40 healthy women who underwent selective pregnancy termination. Reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and western blot analysis were performed to characterize the mRNA and protein expression of DNMTs in chorionic villous cells. It was identified, among the four DNMTs, DNMT3B presented the highest level of protein expression in both patient groups. Although the mRNA expressions of the four DNMTs were comparable, the DNMT3A protein was specifically downregulated in patients with early embryo growth arrest. Therefore, the current study suggests that an abnormal decrease in DNMT3A protein levels may be involved in the pathogenesis of early embryo growth arrest. PMID- 28560439 TI - Isoliquiritigenin inhibits the proliferation of human renal carcinoma Caki cells through the ROS-mediated regulation of the Jak2/STAT3 pathway. AB - Isoliquiritigenin (ISL) is a flavonoid with chalcone structure that has been noted in licorice and shallot, which are generally used in traditional Chinese medicine. ISL has demonstrated various pharmacological effects including antioxidant, anti-inflammatory and antitumor activity. However, the molecular mechanisms underlying the anticancer effects of ISL remain poorly understood. The present study revealed that ISL significantly decreased viability and induced apoptosis in human renal carcinoma Caki cells. The ISL-induced apoptosis was associated with the cleavage of caspase-9, -7 and -3, and that of PARP. Moreover, ISL increased the expression of pro-apoptotic protein Bax and diminished the expression of anti-apoptotic protein Bcl-2, and Bcl-xl, thereby increasing cytochrome c release. Treatment of cells with ISL also induced the expression of p53 through downregulation of murine double minute 2 (Mdm2). Furthermore, ISL generated reactive oxygen species (ROS), and pretreatment with ROS scavenger N acetyl cysteine (NAC) and NADPH oxidase inhibitor diphenyleneiodonium abrogated the ISL-induced apoptosis. One of the key oncogenic signaling pathways is mediated through signal transducer and activator of transcription 3 (STAT3), which promotes abnormal cell proliferation. Incubation of cells with ISL markedly diminished phosphorylation and DNA binding activity of STAT3, and reduced expression of STAT3 responsive gene products, such as cyclin D1 and D2. ISL also attenuated constitutive phosphorylation of upstream kinase, Janus-activated kinase 2 (Jak2). Pretreatment with NAC abrogated the inhibitory effect of ISL on activation of STAT3 and blocked the cleavage of caspase-9, -7 and -3, and that of PARP in Caki cells. Taken together, the present study provides the first report that ISL induces apoptosis in Caki cells via generation of ROS, which causes induction of p53 and inhibition of the STAT3 signaling pathway. PMID- 28560441 TI - CGRP attenuates hyperoxia-induced oxidative stress-related injury to alveolar epithelial type II cells via the activation of the Sonic hedgehog pathway. AB - The aim of this study was to examine the effect of calcitonin gene-related peptide (CGRP) on primary alveolar epithelial type II (AECII) cells and expression of Sonic hedgehog (SHH) signaling pathway components following exposure to hyperoxia. The AECII cells were isolated and purified from premature rats and exposed to air (21% oxygen), air + CGRP, hyperoxia (95% oxygen) or hyperoxia + CGRP. The production of intracellular reactive oxygen species (ROS) was determined using the 2',7'-dichlorofluorescin diacetate molecular probe. The levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in the culture supernatant were detected by spectrophotometry. The apoptosis of AECII cells was assayed by flow cytometry, and the mRNA and protein expression levels of Shh and Ptc1 in the AECII cells were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot analysis and immunofluorescence, respectively. The cellular pathological changes partly improved and apoptosis was markedly decreased upon treatment with CGRP under hyperoxic conditions. The levels of ROS in the hyperoxia + CGRP group were significantly lower than thoe in the hyperoxia group. In addition, the hyperoxia induced increase in MDA levels and the decrease in SOD activity in the culture supernatant of the AECII cells were attenuated by CGRP. Compared with the cells exposed to air, hyperoxia markedly inhibited the mRNA and protein expression levels of Shh and Ptc1 in the AECII cells; however, this inhibition was partly attenuated by treatment with CGRP. On the whole, our data suggest that CGRP can partly protect AECII cells from hyperoxia-induced injury, and the upregulation of CGRP may be a potential therapeutic approach with which to combat hyperoxia induced lung injury, which may be associated with the activation of the SHH signaling pathway. PMID- 28560440 TI - The protective effects of PCPA against monocrotaline-induced pulmonary arterial hypertension are mediated through the downregulation of NFAT-1 and NF-kappaB. AB - Inflammation and remodeling play a role in the pathogenesis of pulmonary arterial hypertension (PAH). Nuclear factor-kappaB (NF-kappaB) and nuclear factor of activated T cells-1 (NFAT-1) participate in inflammation and remodeling in a number of diseases. As a tryptophan hydroxylase inhibitor, 4-chloro-DL phenylalanine (PCPA) had been reported to exert anti-inflammatory and remodeling effects. Therefore, we hypothesized that PCPA may attenuate monocrotaline (MCT) induced PAH through the NFAT-1 and NF-kappaB signaling pathways. In order to confirm our hypothesis, we divided 68 Sprague-Dawley male rats into 4 groups as follows: the control, MCT, MCT + P1 and MCT + P2 groups. MCT was administered at a dose of 60 mg/kg once via intraperitoneal injection. PCPA was administered via intraperitoneal injection at a dose of 50 or 100 mg/kg once daily for 21 consecutive days. We then measured the hemodynamic index and morphological analysis was carried out on the lung tissues. Western blot analysis and immunohistochemistry were used to examine the levels of NFAT-1 and NF-kappaB p 65. The expression levels of phosphorylated inhibitor of NF-kappaB kinase (p IKK), IKK, phosphorylated extracellular signal-regulated kinase (p-ERK), ERK, intercellular adhesion molecule-1 (ICAM-1) and inter-leukin-6 (IL-6) were examined by western blot analysis. MCT was found to significantly induce PAH, with inflammation and remodeling of the lung tissues. This was associatd with an increased expression of NFAT-1, p-IKK, p-ERK and nuclear p65. PCPA significantly attenuated MCT-induced inflammation and arterial remodeling, and decreased the expression of NFAT-1, as well as that of relevant proteins of the NF-kappaB signaling pathway. The above-mentioned findings suggest that the inhibitory effects of PCPA on MCT-induced inflammation and arterial remodeling are related to the downregulation of the NFAT-1 and NF-kappaB signaling pathways in rats with PAH. PMID- 28560442 TI - New bioactive peptide reduces the toxicity of chemotherapy drugs and increases drug sensitivity. AB - Anticancer bioactive peptide (ACBP) is extracted from normal goat spleens and exhibits antitumor activity alone and in combination with low cisplatin doses to achieve antitumor efficacy similar to higher cisplatin doses via sustained medication modes. In the present study, we investigated whether elevated levels of induced or normal ACBP in MKN-45 gastric cancer (GC) cells may reduce their toxicity to oxaliplatin (L-OHP) in a dose-dependent manner. The growth inhibition rate (IR), morphological changes and gene expression were examined in MKN-45 GC cells. Compared with normal ACBP, induced ACBP alone significantly enhanced the anticancer activity of L-OHP-mediated apoptosis and reduced the amount and side effects of L-OHP (P<0.05). The inhibition of cancer cell growth at high concentrations of induced ACBP and L-OHP was significantly more effective than at low concentrations. In addition, for the first time, we examined the potential of a combination of induced ACBP and L-OHP to increase L-OHP sensitivity in human gastric carcinoma xenograft tumors. Nude mice were implanted with human gastric carcinoma MKN-45 cells and treated with an intraperitoneal injection of 0.5 ml of normal saline, 30 ug/ml ACBP, 20 ug/ml L-OHP or 30 ug/ml ACBP + 20 ug/ml L-OHP [combination of anticancer bioactive peptide and oxaliplatin (A+L)] via the tail vein twice a week. In vivo short-term intermittent use of induced ACBP alone significantly inhibited MKN-45 tumor growth. The combination of induced ACBP and L-OHP also significantly improved the quality of life of the nude mice and reduced the toxicity of L-OHP. Based on flow cytometry and gene expression analyses, A+L significantly increased the proportion of cells in the G2/M phase (P<0.05) relative to ACBP or L-OHP alone, and short-term intraperitoneal injection of ACBP increased the sensitizing effect of L-OHP. Collectively, these results suggest that high levels of induced ACBP in combination with L-OHP via a short-term intermittent medication mode could be a useful clinical therapeutic strategy for GC. PMID- 28560443 TI - Rutaecarpine alleviates renal ischemia reperfusion injury in rats by suppressing the JNK/p38 MAPK signaling pathway and interfering with the oxidative stress response. AB - In the present study, the protective effect and the potential underlying mechanism of rutaecarpine (Ru) on renal ischemia reperfusion injury (IRI) in rats were investigated. A renal ischemia reperfusion mouse model was established. Ru at 30, 60 mg/kg administered intraperitoneally prior to reperfusion led to attenuated renal injury. The results demonstrated that Ru treatment significantly reduced the content of serum creatinine, urea nitrogen and neutrophil gelatinase associated lipocalin in rats with renal IRI. In addition, Ru treatment improved the degree of renal proximal tubular necrosis, decreased the content of inflammatory cytokines in reperfused renal tissue and increased serum superoxide dismutase levels to protect the kidney. The associated underlying mechanism may involve the inhibition of p38 kinase phosphorylation and c-Jun N-terminal kinase, anti-lipid peroxidation, elimination of free radicals, and a reduction in the degree of apoptotic damage and oxidative stress injury induced by renal IRI. Therefore, Ru may be a suitable compound for the prevention and treatment of renal IRI. PMID- 28560444 TI - Schisandrin B attenuates the inflammatory response, oxidative stress and apoptosis induced by traumatic spinal cord injury via inhibition of p53 signaling in adult rats. AB - Schisandrin B is an active monomer of the Chinese magnolia vine (Schisandra chinensis) that can reduce transaminase activity in liver cells, inhibit lipid peroxidation, enhance antioxidant status, has protective effects in the liver and has antitumor effects. The present study investigated the potential protective effects of schisandrin B on the p53 signaling pathway in attenuating the inflammatory response, oxidative stress and apoptosis induced by traumatic spinal cord injury (TSCI) in adult rats. Behavioral examination, inclined plate test and spinal cord water content were used to evaluate the protective effect of schisandrin B in TSCI rats. The expression levels of superoxide dismutase (SOD), malondialdehyde (MDA), nuclear factor (NF)-kappaB subunit p65 and tumor necrosis factor (TNF)-alpha were examined using ELISA kits. Western blot analysis was performed to analyze the protein expression of caspase-3 and phosphorylated (p) p53 in TSCI rats. In the present study, schisandrin B improved behavioral examination results and the maximum angle of inclined plate test, and inhibited spinal cord water content in rats with TSCI. Notably, schisandrin B reduced the activation of traumatic injury-associated pathways, including SOD, MDA, NF-kappaB p65 and TNF-alpha, in TSCI rats. In addition, schisandrin B suppressed the TSCI induced expression of caspase-3 and p-p53 in TSCI rats. These results indicated that schisandrin B may attenuate the inflammatory response, oxidative stress and apoptosis in TSCI rats by inhibiting the p53 signaling pathway in adult rats. PMID- 28560445 TI - Genistein and menaquinone-4 treatment-induced alterations in the expression of mRNAs and their products are beneficial to osteoblastic MC3T3-E1 cell functions. AB - The aim of the present study was to determine the molecular basis of the beneficial effects of genistein and/or menaquinone-4 (MK-4) on bone quality. Initially, 1 uM genistein was applied to MC3T3-E1 cells for 24 h and the upregulated mRNAs that were detected by microarray were selected for further examination by reverse transcription-quantitative-polymerase chain reaction. Among them, alterations were observed in the level of GATA-binding protein 6 (GATA6), Notch gene homolog 2 (NOTCH2), Wnt family member 5A (WNT5A), bone gamma carboxyglutamate protein (BGLAP), chondroadherin (CHAD), dipeptidyl peptidase 4 (DPP4), ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), alkaline phosphatase (ALP) 3 and ATPase phospholipid-transporting 11A (ATP11A) in response to treatment with 0.1 uM 17-beta-estradiol, 1 uM genistein, and/or 1 uM MK-4. GATA6, NOTCH2 and WNT5A are considered to be associated with osteoclast, but not osteoblast, function; however, increases in osteoblastic mRNAs, including BGLAP and CHAD, were observed in each of the treatment groups at 48 h. Immunocytochemical analysis confirmed an increase in CHAD and DPP4 proteins following the administration of genistein + MK-4. Furthermore, genistein + MK-4 led to alterations in cell morphology to spindle or oval shapes, and increased the intensity of ALP staining. Although the level of ALP mRNA was not consistently altered in response to the treatments, a marked increase in ALP activity was observed following 96 h treatment with genistein + MK-4. Therefore, the simultaneous intake of genistein and MK-4 appears to be beneficial for the maintenance of bone quality. PMID- 28560446 TI - Prediction of marker genes associated with hypertension by bioinformatics analyses. AB - This study aimed to explore the underlying marker genes associated with hypertension by bioinformatics analyses. A gene expression profile (GSE54015) was downloaded. The differentially expressed genes (DEGs) between the normotensive female (NF) and hypertensive female (HF), and between the normotensive male (NM) and hypertensive male (HM) groups were analyzed. Gene Ontology (GO) and pathway enrichment analyses were performed, followed by protein-protein interaction (PPI) network construction. The transcription factors (TFs), and the common DEGs between the HF and HM groups were then analyzed. In total, 411 DEGs were identified between the HF and NF groups, and 418 DEGs were identified between the HM and NM groups. The upregulated DEGs in the HF and HM groups were enriched in 9 GO terms, including oxidation reduction, such as cytochrome P450, family 4, subfamily b, polypeptide 1 (Cyp4b1) and cytochrome P450, family 4, subfamily a, polypeptide 31 Cyp4a31). The downregulated DEGs were mainly enriched in GO terms related to hormone metabolic processes. In the PPI network, cytochrome P450, family 2, subfamily e, polypeptide 1 (Cyp2e1) had the highest degree in all 3 analysis methods in the HF group. Additionally, 4 TFs were indentified from the 2 groups of data, including sterol regulatory element binding transcription factor 1 (Srebf1), estrogen receptor 1 (Esr1), retinoid X receptor gamma (Rxrg) and peroxisome proliferator-activated receptor gamma (Pparg). The intersection genes were mainly enriched in GO terms related to the extracellular region. On the whole, our data indicate that the DEGs, Cyp4b1, Cyp4a31 and Loxl2, and the TFs, Esr1, Pparg and Rxrg, are associated with the progression of hypertension, and may thus serve as potential therapeutic targets in this disease. PMID- 28560447 TI - GROalpha overexpression drives cell migration and invasion in triple negative breast cancer cells. AB - Triple negative breast cancer (TNBC) is a subtype of highly aggressive breast cancer with poor prognosis. The main characteristic feature of TNBC is its lack of expression of ER, PR and HER2 receptors that are targets for treatments. Hence, it is imperative to identify novel therapeutic strategies to target TNBC. Our aim was to examine whether GROalpha is a specific marker for TNBC metastasis. For this we performed qPCR, ELISA, migration/invasion assays, western blotting, and siRNA transfections. Evaluation of baseline GROalpha expression in different breast cancer (BC) subtypes showed that it is significantly upregulated in breast tumor cells, specifically in TNBC cell line. On further evaluation in additional 17 TNBC cell lines we found that baseline GROalpha expression was significantly elevated in >50% of the cell lines validating GROalpha overexpression specifically in TNBC cells. Moreover, GROalpha-stimulation in MCF7 and SKBR3 cells and GROalpha-knockdown in MDA-MB-231 and HCC1937 cells elicited dramatic changes in migration and invasion abilities in vitro. Corresponding changes in EMT markers were also observed in phenotypically modified BC cells. Furthermore, mechanistic studies identified GROalpha regulating EMT markers and migration/invasion via MAPK pathway and specific inhibition using PD98059 resulted in the reversal of effects induced by GROalpha on BC cells. In conclusion, our study provides strong evidence to suggest that GROalpha is a critical modulator of TNBC migration/invasion and proposes GROalpha as a potential therapeutic target for treatment of TNBC metastasis. PMID- 28560448 TI - Multiple Nav1.5 isoforms are functionally expressed in the brain and present distinct expression patterns compared with cardiac Nav1.5. AB - It has previously been demonstrated that there are various voltage gated sodium channel (Nav) 1.5 splice variants expressed in brain tissue. A total of nine Nav1.5 isoforms have been identified, however, the potential presence of further Nav1.5 variants expressed in brain neurons remains to be elucidated. The present study systematically investigated the expression of various Nav1.5 splice variants and their associated electrophysiological properties in the rat brain tissue, via biochemical analyses and whole-cell patch clamp recording. The results demonstrated that adult Nav1.5 was expressed in the rat, in addition to the neonatal Nav1.5, Nav1.5a and Nav1.5f isoforms. Further studies indicated that the expression level ratio of neonatal Nav1.5 compared with adult Nav1.5 decreased from 1:1 to 1:3 with age development from postnatal (P) day 0 to 90. This differed from the ratios observed in the developing rat hearts, in which the expression level ratio decreased from 1:4 to 1:19 from P0 to 90. The immunohistochemistry results revealed that Nav1.5 immunoreactivity was predominantly observed in neuronal cell bodies and processes, whereas decreased immunoreactivity was detected in the glial components. Electrophysiological analysis of Nav1.5 in the rat brain slices revealed that an Na current was detected in the presence of 300 nM tetrodotoxin (TTX), however this was inhibited by ~1 uM TTX. The TTX-resistant Na current was activated at -40 mV and reached the maximum amplitude at 0 mV. The results of the present study demonstrated that neonatal and adult Nav1.5 were expressed in the rat brain and electrophysiological analysis further confirmed the functional expression of Nav1.5 in brain neurons. PMID- 28560449 TI - Hypoxia-induced angiopoietin-like protein 4 as a clinical biomarker and treatment target for human prostate cancer. AB - Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional protein, playing roles in glucose and lipid metabolism, inflammation, angiogenesis, and tumorigenesis. Recent research suggests that ANGPTL4 is induced by hypoxia and is a useful diagnostic or prognostic marker for various cancers. However, it remains unclear whether ANGPTL4 expression influences prostate cancer. Here we examined the biological and clinical relevance of ANGPTL4 expression in prostate cancer. Firstly we examined ANGPTL4 expression in the prostate cancer cell lines LNCaP and LNCaP/CH incubated at 1% O2 for at least 6 months. We compared cellular proliferation, migration, and ANGPTL4 secretion in a culture medium between these cell lines. In addition, we investigated the effect of various concentrations of recombinant ANGPTL4 protein (rANGPTL4) on cellular proliferation and intracellular signaling pathways. Moreover, we used ANGPTL4 knockdown by RNA interference to investigate the influence of ANGPTL4 expression on these cell lines. Finally, we investigated the correlation between ANGPTL4 expression in prostate cancer specimens and clinicopathological parameters using immunohistochemistry. Our data suggested that the expression of ANGPTL4 in hypoxic conditions was 14.4-fold higher than that in normoxic condition. ANGPTL4 secretion in the culture medium increased 7.0-fold. In addition, rANGPTL4 increased cellular proliferation 1.72-fold via Akt activation. Moreover, ANGPTL4 knockdown decreased cell growth and its secretion by 25.7 and 41.4%, respectively, compared with the control. A multivariate analysis showed that positive ANGPTL4 expression in the resected specimens was an independent prognostic indicator of biochemical recurrence (P=0.03, hazard ratio = 2.02). Our results show that ANGPTL4 is induced by hypoxia and promotes cancer progression via the activated PI3K/Akt pathway. Moreover, ANGPTL4 can be used as a prognostic marker for prostate cancer patients undergoing radical prostatectomy. PMID- 28560450 TI - Upregulation of SOCS3 in lung CD4+ T cells in a mouse model of chronic PA lung infection and suppression of Th17-mediated neutrophil recruitment in exogenous SOCS3 transfer in vitro. AB - Neutrophilic airway inflammation in chronic lung infections caused by Pseudomonas aeruginosa (PA) is associated with T helper (Th)17 responses. Suppressor of cytokine signaling 3 (SOCS3) is the major negative modulator of Th17 function through the suppression of signal transducer and activator of transcription (STAT)3 activation. The aim of the present study was to investigate the expression of SOCS3 in lung CD4+ T cells in a mouse model of chronic PA lung infection and the effect of exogenous SOCS3 on Th17-mediated neutrophil recruitment in vitro. A mouse model of chronic PA lung infection was established and the activation of STAT3 and Th17 response in lung tissues and lung CD4+ T cells was assessed. The protein and mRNA expression of SOCS3 in lung CD4+ T cells was analyzed by western blotting and reverse transcription-quantitative polymerase chain reaction. The authors constructed a recombinant lentivirus carrying the SOCS3 gene and transferred it into lung CD4+ T cells isolated from a mouse model. These transfected cells were stimulated with interleukin (IL)-23 in vitro and the protein level of p-STAT3 and retinoid-related orphan receptor (ROR)gammat was determined by western blotting. The expression of IL-17A+ cells was analyzed by flow cytometry and the level of IL-17A in cell culture supernatant was measured by ELISA. The mouse lung epithelial cell line, MLE-12, was cocultured with lung CD4+ T cells that overexpressed the SOCS3 gene and the culture supernatant was harvested and used for a chemotaxis assay. Compared with control mice, mice with chronic PA lung infection had significantly higher level of p-STAT3 and Th17 response in both lung tissues and lung CD4+ T cells. The protein and mRNA level of SOCS3 in lung CD4+ T cells increased as the chronic PA lung infection developed. Exogenous SOCS3 gene transfer in PA-infected lung CD4+ T cells decreased p-STAT3 and RORgammat expression and suppressed the level of IL 17A+ cells in vitro. MLE-12 cells cocultured with SOCS3-overexpressing lung CD4+ T cells expressed a significantly lower level of neutrophil chemoattractants chemokine (C-X-C motif) ligand (CXCL) 1 and CXCL5, and recruited significantly smaller numbers of migrating neutrophils than those cocultured with control cells. SOCS3 was upregulated in lung CD4+ T cells following the activation of STAT3/Th17 axis in a mouse model of chronic PA lung infection. Exogenous SOCS3 transfer in PA-infected lung CD4+ T cells suppresses Th17-mediated neutrophil recruitment in vitro. PMID- 28560451 TI - FoxO3a plays a key role in the protective effects of pomegranate peel extract against amikacin-induced ototoxicity. AB - The use of amikacin (AMK) in present treatment strategies results in severe ototoxicity; however, the underlying molecular mechanisms of this toxicity remain unclear. In this study, we investigated the effectiveness of orally administered pomegranate peel extract (PPE), a strong antioxidant, as a protective agent against AMK-induced ototoxicity. To this end, PPE was orally administered to adult BALB/c mice for 5 days, and the mice were then concurrently treated with AMK (500 mg/kg/day for 15 consecutive days). Auditory threshold shifts induced by AMK were significantly attenuated. The results of immunohistochemical staining and western blot analysis revealed that PPE exerted its protective effects by by downregulating the phosphorylation of Forkhead box O3a (FoxO3a), an important transcription factor which is involved in the responses to oxidative stress. The results also showed that PPE treatment inhibited mitogen-activated protein kinase phosphorylation, prevented the activation of pro-apoptotic protein caspase-3, decreased the levels of apoptosis-inducing Bax protein, and increased the levels of the anti-apoptotic mediator, Bcl-2, induced by AMK in the mouse cochlea. Taken together, our experimental findings suggest that phosphorylated FoxO3a mediates AMK-induced apoptosis in BALB/c mice cochlea. PPE effectively attenuated oxidative stress and ototoxicity by regulating FoxO3a, and may thus prove to be beneficial in protecting auditory cells from ototoxic drugs. PMID- 28560452 TI - Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A. AB - We have shown that a novel STAT3 inhibitor arctigenin (Atn) induces significant cytotoxicity in triple-negative breast cancer (TNBC) cells. This study further delineated molecular mechanisms where by Atn triggered cytotoxicity in TNBC cells. We found Atn can also inhibit metastasis in TNBC cells through cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway. CIP2A is an endogenous inhibitor of protein phosphatase 2A (PP2A), which can increase the migration and invasion of various cancer cells. PP2A is a tumor suppressor, which is functionally defective in various cancers. Atn-induced metastasis inhibition was associated with reactivation of PP2A, downregulation of CIP2A and Akt phosphorylation. Silencing CIP2A enhanced Atn-induced metastasis inhibition and apoptosis in TNBCs. Furthermore, ectopic expression of CIP2A or inhibition of PP2A in TNBC cells abolished the effects of Atn. In conclusion, we found that enhancement of PP2A activity by inhibition of CIP2A, at least in part, promotes the anti-metastasis effect induced by Atn. Our findings disclose the novel therapeutic mechanism of this targeted agent, and suggest the therapeutic potential and feasibility of developing PP2A enhancers as a novel anticancer strategy. PMID- 28560453 TI - Nrf2 mediates the protective effects of homocysteine by increasing the levels of GSH content in HepG2 cells. AB - Homocysteine (Hcy) and glutathione (GSH) are crucial reduction-oxidation mediators. The underlying mechanisms governing the effects of Hcy on GSH generation in the progression of alcoholic liver disease has so far received little attention. The present study hypothesized that the antioxidant transcriptional factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) may participate in Hcy-mediated regulation of GSH production in HepG2 human liver cancer cells. MTT assay was used to study the cytotoxicity of homocysteine, western blot analysis and immunofluorescence staining were used to determine the effect of Hcy on Nrf2 expression. Our data demonstrated that HepG2 cells exposed to exogenous levels of Hcy (0-100 uM) exhibited elevated GSH levels in a concentration-dependent manner. Furthermore, 4-hydroxynonenal (4-HNE)-induced cell injury was attenuated by Hcy; however, this protective effect was blocked by the GSH-production inhibitor buthionine sulfoximine. Hcy treatment was able to induce Nrf2 protein expression in HepG2 cells. Treatment with the Nrf2 activator tert-butylhydroquinone (0-100 uM) increased GSH expression in a concentration dependent manner; however, Nrf2-siRNA abolished the Hcy-induced increase in GSH expression and cellular protection in 4-HNE-stressed HepG2 cells. In conclusion, the antioxidant transcriptional factor Nrf2 was demonstrated to mediate the Hcy induced increase in GSH expression levels and cellular protection in HepG2 cells. PMID- 28560455 TI - MicroRNA-146a-5p enhances cisplatin-induced apoptosis in ovarian cancer cells by targeting multiple anti-apoptotic genes. AB - MicroRNAs play a crucial role in gene expression regulation in various types of cancers. Previous studies show the expression level of miR-146a-5p is downregulated in epithelial ovarian cancer. Further investigations suggest this downregulation is responsible for apoptosis resistance in ovarian cancer cells. However, the mechanism of how miR-146a-5p promotes apoptosis remains unclear. In this study, the role of miR-146a-5p in cisplatin-induced apoptosis of ovarian cancer cells was assessed by DAPI staining, MTT assays, and monitoring expression of XIAP, BCL2L2, BIRC2 and BIRC5 through a dual-luciferase assay. Our results show that miR-146a-5p can regulate three important anti-apoptotic genes including XIAP, BCL2L2 and BIRC5 via their 3'UTRs. Not only can overexpression of miR-146a 5p downregulate the expression of XIAP in SKOV3 cells, but it also lowers the IC50 values of cisplatin in OVCAR3 and SKOV3 cells and enhances the susceptibility of OVCAR3, SKOV3 and primary ovarian cancer cells to cisplatin induced apoptosis. The effect of XIAP rescuing cisplatin-induced apoptosis accelerated by miR-146a-5p further supports our conclusion. Our results suggest that the regulation of three anti-apoptotic genes by miR-146-5p enhances the therapeutic effects of cisplatin. PMID- 28560454 TI - Silencing of type Igamma phosphatidylinositol phosphate kinase suppresses ovarian cancer cell proliferation, migration and invasion. AB - Metastasis is the major cause of death in ovarian cancer patients. Given that the molecular mechanism underlying metastasis formation is critical for improving therapeutic development and clinical treatment, it must be fully understood. Recent studies have revealed that lipid kinase type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma) participates in the metastasis of breast cancer and colon cancer by regulating cell migration and invasion. However, its role in the progression of ovarian cancer is unclear. Here we showed that PIPKIgamma expression is upregulated in multiple epithelial ovarian cancer cell lines. Silencing of PIPKIgamma impaired PI3K/AKT signaling and inhibited the aggressive behaviors of epithelial ovarian cancer cells, including proliferation, migration and invasion. Moreover, we found that PIPKIgamma was required for the activation of signal transducer and activator of transcription 3 (STAT3) in epithelial ovarian cancer cells, indicating that STAT3 may also be engaged in the PIPKIgamma dependent aggressiveness of epithelial ovarian cancer cells. Our results, for the first time, identified PIPKIgamma as a novel regulator in epithelial ovarian cancer cells that promotes cell proliferation, migration and invasion by activating multiple signaling pathways. Therefore, we propose that PIPKIgamma could potentially be a therapeutic target for the early detection and treatment of epithelial ovarian cancer. Further studies employing in vivo models are necessary to test this possibility. PMID- 28560457 TI - Regulation of autophagy and EMT by the interplay between p53 and RAS during cancer progression (Review). AB - Cellular autophagy and epithelial-mesenchymal transition (EMT) are key events mostly resulted from the interplay of tumor suppressors and oncogenes during cancer progression. The master tumor suppressor p53 may control tumor cell autophagy and EMT through the transcriptional induction of multiple target genes, while the activated oncogene RAS may also play a critical role in regulating mitogenic signaling to tumor cell autophagy and EMT. Although the fundamental functions of p53 and RAS are well understood, the interactive effects of p53 and RAS on autophagy and EMT are still unclear. In this review, we highlight the recent advances in the regulation of autophagy and EMT by p53 and RAS, aiming to explore novel therapeutic targets and biomarkers in cancer treatment and prevention. PMID- 28560456 TI - Investigation of the major cytochrome P450 1A2 genetic variant in a healthy Tibetan population in China. AB - The cytochrome P450 (CYP) 1A2 gene is involved in the metabolism of several carcinogens and clinically important drugs, generating a high potential for pharmacokinetic interactions. Since no data are available for Tibetan aborigines, the present study aimed to investigate the distribution of variant CYP1A2 alleles in a population living in Tibetan region of China. Genotyping analyses of CYP1A2 were conducted in 96 unrelated, healthy volunteers of Tibetan ancestry using direct sequencing assays. A total of 14 different CYP1A2 polymorphisms, including two novel variants (1690G>A and 2896C>T) in the intron region and a novel non synonymous one (795G>C, Gln265His) were detected. CYP1A2*1A (6.77%), CYP1A2*1B (58.33%) and CYP1A2*1F (14.58%) were the most frequent defective alleles identified in the sample. The frequencies of the prevalent genotypes CYP1A2*1A/*1B, *1B/*1B, *1B/*1F were 13.54%, 16.67% and 29.17%, respectively. In addition, the novel non-synonymous variant 795G>C (Gln265His) was predicted to be benign by PolyPhen-2 and SIFT tools. The present study provides useful information on the pattern of CYP1A2 polymorphisms in Chinese Tibetan population. The current results may have potential benefits for the development of personalized medicine in the Tibetan population. PMID- 28560458 TI - EphA2 receptor activation with ephrin-A1 ligand restores cetuximab efficacy in NRAS-mutant colorectal cancer cells. AB - Patients with wild-type KRAS metastatic colorectal cancer (mCRC) that harbors NRAS activating mutations do not benefit from anti-EGFR therapies. Very little is known about oncogenic NRAS signaling driving mCRC unresponsiveness to the EGFR directed antibody cetuximab. Using a system of paired NRAS-mutant and wild-type isogenic mCRC cell lines to explore signaling pathways engaged by the common oncogenic NRAS Q61K variant upon challenge with cetuximab, we uncovered an unexpected mechanism of resistance to cetuximab involving dysregulation of the ephrin-A1/EphA2 signaling axis. Parental NRAS+/+ cells, but not NRASQ61K/+ cells, activated the ephrin receptor ephA1 in response to cetuximab treatment. Moreover, whereas cetuximab treatment significantly downregulated EPHA2 gene expression in NRAS+/+ cells, EPHA2 expression in NRASQ61K/+ cells was refractory to cetuximab. Remarkably, pharmacologically mimicked ephrin-A1 engagement to ephA2 converted NRAS-mutant into RAS wild-type mCRC cells in terms of cetuximab efficacy. Accordingly, activation of the ephA2 receptor by bioactive recombinant human ephrin-A1/Fc-fusion protein suppressed the cetuximab-unresponsive hyperactivation of MAPK and AKT and fully restored cetuximab activity in NRAS-mutant colorectal cells. Collectively, these findings reveal that the clinical benefit of cetuximab in mCRC might necessarily involve the suppression of the ligandless oncogenic signaling of the ephA2 receptor. Hence, ligand-dependent tumor suppressor signaling using therapeutic ephA2 agonists might offer new therapeutic opportunities to clinically widen the use of cetuximab in NRAS-mutated and/or ephA2-dependent mCRC tumors. PMID- 28560459 TI - sigma-1 receptor stimulation protects against pressure-induced damage through InsR-MAPK signaling in human trabecular meshwork cells. AB - The purpose of the present study was to investigate the protective effect of the sigma-1 receptor (Sig-1R) agonist (+)-pentazocin (PTZ) on pressure-induced apoptosis and death of human trabecular meshwork cells (hTMCs). The expression levels of Sig-1R and insulin receptor (InsR) were examined in hTMCs. Cells were cultured under a pressure of 0, 20, 40, 60 and 80 mmHg for 48 h, and under 80 mmHg for 44 h, after which the cells were treated with (+)-PTZ (20 uM), N-(2-(3,4 dichlorophenyl)ethyl)-N-methyl-2-(dimethylamino) ethylamine (BD-1063; 20 uM) administered 30 min prior to (+)-PTZ, or BD-1063 (20 uM) and then exposed to 80 mmHg again until the 48 h time-point. The changes of the cells were observed by optical and electron microscopy, the apoptosis and death of hTMCs were detected by ethidium bromide/acridine orange dual staining assay and the expression of Sig 1R and InsR by reverse transcription-quantitative polymerase chain reaction and western blot analysis. The phosphorylation of extracellular signal-regulated kinase (ERK), an important downstream protein of the InsR-mitogen-activated protein kinases (MAPK) signaling pathway, was also detected by western blot analysis when (+)-PTZ and BD-1063 were added to the 80 mmHg-treated cells. Sig 1Rs and InsRs were expressed in hTMCs. The apoptosis and death of hTMCs increased from 40 mmHg with 50% cell death when the pressure was at 80 mmHg and the structure of the cells noticeably changed. The expression of Sig-1R and InsR increased along with the elevation of pressure. (+)-PTZ decreased the apoptosis and death of hTMCs and increased the expression of Sig-1R and InsR, and the phosphorylation of ERK. Such effects were blocked by BD-1063. The present study suggested that Sig-1R agonist (+)-PTZ can protect hTMCs from pressure-induced apoptosis and death by activating InsR and the MAPK signal pathway. PMID- 28560460 TI - Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid cancer cell lines. AB - Cell cycle control is a promising target in cancer treatments, and some small molecule cyclin-dependent kinase (CDK) inhibitors have exhibited clinical effectiveness. However, no biomarkers predictive of efficacy have been developed. Recent studies have revealed that CDK inhibitor (CKI) proteins, such as p27 and p16, also induced cytoprotective autophagy in cancer cells. However, it is unclear whether small-molecule CKIs also induce autophagy in solid tumors, as induced autophagy promotes cancer cell survival. In this study, we revealed that a CDK4 inhibitor and a CKI with a broad range of targets (flavopiridol) induced autophagy in some, but not all, solid cancer cell lines. Autophagy induction by CDK4 inhibitor was observed in BT474, MDA-MB435S, SKBr3 (derived from breast cancer), A431 (derived from epidermoid cancer), and SW480 (derived from colorectal cancer) cell lines. No such autophagy was observed in MCF7, MDA-MB231 (derived from breast cancer), NCI-N87 (derived from gastric cancer), and KMST-6 (derived from a fibroblast). In the cell lines showing autophagy, which was induced by CDK4 inhibitor, the combination of CDK4 inhibitor and autophagy inhibition by either chloroquine (CQ) or knockdown of ATG5 or BECN1 induced apoptosis. However, it did not induce apoptosis in the cell lines in which autophagy was not induced by CDK4 inhibitor. These findings indicate that the autophagy induced by CDK4 inhibitor mimics stress-induced autophagy in some solid cancer cell lines. The combination of a small-molecule CKI involved in G1/S arrest and an autophagy inhibitor leads to a synthetic lethal interaction and could become a new antitumor strategy for solid tumors showing cytoprotective autophagy induced by small-molecule CKIs. PMID- 28560461 TI - Increased SLC7A8 expression mediates L-DOPA uptake by renal tubular epithelial cells. AB - The kidney serves a central role in the control of blood pressure through the release of vasoactive substances and the urinary excretion of Na+. Patients with essential hypertension usually exhibit persistent high blood pressure accompanied by Na+ retention. L-dihydroxyphenylalanine (L-DOPA) is an amino acid, converted by the enzyme aromatic L-amino acid decarboxylase to dopamine. The uptake of L DOPA by cells of the proximal tubular epithelium of the kidney is controlled by the L-type amino acid transporter 2 (LAT2). LAT2 belongs to the solute carrier family 7 (SLC7) of amino acid transporters and is coded by the SLC7A8 gene. SLC7A8 expression is increased in the second-order mesenteric arteries and kidneys of spontaneously hypertensive rats. The present study aimed to investigate the physiological role of the SLC7A8 gene in L-DOPA handling by kidney cells. Selective upregulation of SLC7A8 mRNA and protein levels was achieved by adenoviral transduction of NRK-52E cells, which retain several properties of proximal tubular epithelial cells. In addition, L-DOPA uptake was determined using high performance liquid chromatography; NRK-52E cells expressing SLC7A8 exhibited increased uptake of L-DOPA. The results of the present study suggested that SLC7A8 may serve a critical role in blood pressure control through regulating L-DOPA uptake in renal epithelial cells of the proximal tubule. PMID- 28560462 TI - Remote ischemic postconditioning confers neuroprotective effects via inhibition of the BID-mediated mitochondrial apoptotic pathway. AB - Ischemic postconditioning has been demonstrated to alleviate brain ischemia/reperfusion-induced neuronal apoptosis; however, the protective mechanisms underlying the improved and more convenient method of remote ischemic postconditioning (RIPostC) are only recently beginning to be elucidated. Mitochondria are important in the regulation of cell apoptosis, and the B-cell lymphoma 2 (Bcl-2) homology 3 interacting-domain death agonist (BID) promotes the insertion/oligomerization of Bcl-2-associated X protein into the mitochondrial outer membrane, leading to the release of proapoptotic proteins from the mitochondria. The present study hypothesized that RIPostC targets the BID mediated mitochondrial apoptotic pathway to exert neuroprotective effects, and the optimal time window for RIPostC application was investigated. RIPostC was conducted as follows: Three 10-min cycles of bilateral femoral artery occlusion with intervals of 10 min reperfusion after 0, 10 or 30 min of brain reperfusion. The results revealed that reperfusion induced significant activation of BID, via proteolytic cleavage and translocation to the mitochondria, as determined using western blot analysis and immunofluorescence staining. Mitochondrial release of cytochrome c was additionally detected during BID activation, all of which were inhibited by the application of RIPostC. When RIPostC was applied during reperfusion, it demonstrated a significant protective effect. Furthermore, the infarct volume, neurological function and the degree of neuronal apoptosis were improved with application of RIPostC. These results suggested that the protective mechanisms of RIPostC may be associated with inhibition of the BID-mediated mitochondrial apoptotic pathway, which may act as a potential molecular target for therapeutic intervention in the future. PMID- 28560463 TI - [Local therapy with dye formulations]. PMID- 28560464 TI - ["Indolent" pigmented skin tumor for more than 20 years]. PMID- 28560465 TI - [Lanadelumab : Future plasma-independent subcutaneous prophylaxis for bradykinin mediated angioedema?] PMID- 28560467 TI - [Suspicious papilla in a 27-year-old man]. PMID- 28560466 TI - Real-life effectiveness of spa therapy in rheumatic and musculoskeletal diseases: a retrospective study of 819 patients. AB - The objective of this study is to determine the use and efficacy of spa therapy in patients with a wide spectrum of rheumatic and musculoskeletal diseases under real-life clinical practice circumstances. In this retrospective observational study at the Medical Ecology and Hydroclimatology Department of Istanbul Faculty of Medicine, the records of all adult patients with rheumatic and musculoskeletal diseases who were prescribed a spa therapy in various health resorts in Turkey between 2002 and 2012 were analyzed. Patients sojourned to and stayed at a health resort and followed a usual 2-week course of spa therapy. The patients were examined within a week before and after the spa therapy at the department by the physicians and outcome measures were pain intensity (visual analog scale, VAS), patient's general evaluation (VAS), physician's general evaluation (VAS), Health Assessment Questionnaire (HAQ), Lequesne's Functional Index (LFI), Western Ontario and McMaster Universities Index (WOMAC), Waddell Index (WI), Neck Pain and Disability Scale (NPDS), Shoulder Disability Questionnaire (SDQ), Fibromyalgia Impact Questionnaire (FIQ), and Beck's Depression Inventory (BDI). In total, 819 patients were included in the analysis. The diagnoses were 536 osteoarthritis; 115 fibromyalgia; 50 lumbar disc herniation; 34 cervical disc herniation; 23 nonspecific low back pain; 22 ankylosing spondylitis; 16 rheumatoid arthritis; 9 rotator cuff tendinitis; and 14 other conditions/diseases including scoliosis, stenosing flexor tenosynovitis, congenital hip dislocation in adult, Behcet's disease, de Quervain tendinopathy, psoriatic arthritis, osteoporosis, fracture rehabilitation, and diffuse idiopathic skeletal hyperostosis. Statistically significant decrease in pain scores was found in all patients except hip osteoarthritis (p = 0.063) and rheumatoid arthritis (p = 0.134) subgroups; and statistically significant improvement in function in all patients except hip osteoarthritis (p = 0.068), rheumatoid arthritis (p = 0.111), and rotator cuff tendinitis (p = 0.078) subgroups. In daily clinical practice, spa therapy is prescribed and practiced mainly for osteoarthritis, then fibromyalgia, lumbar/cervical disc herniation, and nonspecific low back pain; and less for ankylosing spondylitis, rheumatoid arthritis, and rotator cuff tendinitis. The study results suggest that real-life spa therapy may be effective in a variety of rheumatic and musculoskeletal diseases by improving pain and function. PMID- 28560468 TI - [Ultra-widefield angiography for retinal vein occlusion : How large is large enough?] AB - BACKGROUND: The introduction of full fundus angiography (FAG) for retinal vein occlusion (RVO) has enriched diagnostic imaging; however, it is unclear how much of the retina has to be visualized to evaluate the risk of neovascularization. We investigated the 102 degrees Spectralis camera to assess if imaging beyond the central 102 degrees is necessary. METHODS: In this retrospective study we assessed 80 eyes of 80 patients with RVO to analyze central and peripheral ischemia using the ultra-widefield 102 degrees Spectralis camera. The standard viewer software was used to delineate ischemic areas (IA) and to measure the amount of pixels of IA in correlation to the total amount of pixels in the peripheral image. RESULTS: Among the 80 eyes with RVO there were 51 eyes with ischemic areas (central and/or peripheral), of which IA could be detected in 49 eyes by analyzing a fovea-centered FAG image. The average IA in these 51 eyes was 23.5% of the total image area and 53.7% of disc areas, respectively. DISCUSSION: A fovea-centered FAG image with a 102 degrees angle appears to be sufficient to determine the clinically relevant extent of IA. Old recommendations and imaging methods should be rethought. The 102 degrees Spectralis camera provides a clinically suitable, fast and exact method which might replace old methods to describe and document the extent of ischemia by disc areas. PMID- 28560469 TI - Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I. AB - Lysosomal storage diseases (LSDs) are rare inherited metabolic disorders characterized by a dysfunction in lysosomes, leading to waste material accumulation and severe organ damage. Enzyme replacement therapy (ERT) and haematopoietic stem cell transplant (HSCT) have been exploited as potential treatments for LSDs but pre-clinical and clinical studies have shown in some cases limited efficacy. Intravenous ERT is able to control the damage of visceral organs but cannot prevent nervous impairment. Depending on the disease type, HSCT has important limitations when performed for early variants, unless treatment occurs before disease onset. In the attempt to overcome these issues, gene therapy has been proposed as a valuable therapeutic option, either ex vivo, with target cells genetically modified in vitro, or in vivo, by inserting the genetic material with systemic or intra-parenchymal, in situ administration. In particular, the use of autologous haematopoietic stem cells (HSC) transduced with a viral vector containing a healthy copy of the mutated gene would allow supra normal production of the defective enzyme and cross correction of target cells in multiple tissues, including the central nervous system. This review will provide an overview of the most recent scientific advances in HSC-based gene therapy approaches for the treatment of LSDs with particular focus on metachromatic leukodystrophy (MLD) and mucopolysaccharidosis type I (MPS-I). PMID- 28560470 TI - Cost per response for abatacept versus adalimumab in rheumatoid arthritis by ACPA subgroups in Germany, Italy, Spain, US and Canada. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disorder leading to disability and reduced quality of life. Effective treatment with biologic DMARDs poses a significant economic burden. The Abatacept versus Adalimumab Comparison in Biologic-Naive RA Subjects with Background Methotrexate (AMPLE) trial was a head-to-head, randomized study comparing abatacept in serum anti-citrullinated protein antibody (ACPA)-positive patients, with increasing efficacy across ACPA quartile levels. The aim of this study was to evaluate the cost per response accrued using abatacept versus adalimumab in ACPA-positive and ACPA-negative patients with RA from the health care perspective in Germany, Italy, Spain, the US and Canada. A cost-consequence analysis (CCA) was designed to compare the monthly costs per responding patient/patient in remission. Efficacy, safety and resource use inputs were based on the AMPLE trial. A one-way deterministic sensitivity analysis (OWSA) was also performed to assess the impact of model inputs on the results for total incremental costs. Cost per response in ACPA positive patients favoured abatacept compared with adalimumab (ACR20, ACR90 and HAQ-DI). Subgroup analysis favoured abatacept with increasing stringency of response criteria and serum ACPA levels. Cost per remission (DAS28-CRP) favoured abatacept in ACPA-negative patients, while cost per CDAI and SDAI favoured abatacept in ACPA-positive patients. Abatacept was consistently favoured in ACPA Q4 patients across all outcomes and countries. Cost savings were greater with abatacept when more stringent response criteria were applied and also with increasing ACPA levels, which could lead to a lower overall health care budget impact with abatacept compared with adalimumab. PMID- 28560471 TI - Impact of laser fiber tip cleavage on power output for ureteroscopy and stone treatment. AB - PURPOSE: Holmium:YAG laser is the most used laser for urolithiasis. Generally, we use metallic scissors to cut the fiber tip to restore its effectiveness. Many cleaving methods have been described to avoid fiber damage and to restore its greatest power to the fiber. There is a lack of information regarding which cleaving method should be used and its effect on the fiber. In order to compare these effects, we studied different cleavage methods in terms of power output and its effects on the fiber. METHODS: New single-use 272-MUm fibers were used with a holmium:YAG laser lithotripter. Five kinds of fiber tips were compared: a new intact fiber, cleaved with ceramic scissors, cleaved with metallic scissors, first cleaved then stripped and first stripped then cleaved. The fibers were used against synthetic stones (BegoStone(r)) similar to calcium oxalate monohydrate, with fragmentation (SP, 5 Hz, 1.5 J) and dusting (LP, 15 Hz, 0.5 J) settings. We measured power output at 0, 1, 5, 10 and 15 min. RESULTS: For fragmentation parameters, there was a statistical difference between the 5 groups at 0 and 1 min of laser use (p < 0.05) and none for time period over 1 min (p = 0.077 0.658). For dusting parameters, there was a statistical difference between the 5 groups at 0 min of laser use (p < 0.05) and none for time period over 0 min (p = 0.064-1). CONCLUSION: Cleaving the fiber tip may restore its effectiveness to the fiber, but only for a limited time, although it may preserve the scopes from damage. PMID- 28560472 TI - Prevalence, clonality, and pathogenicity of Staphylococcus epidermidis isolates in newborn feces. AB - Coagulase-negative staphylococci (CoNS) are the most prevalent pathogens causing late-onset sepsis in neonates. The question is whether neonates acquire endemic hospital-adapted clones or incidentally occurring CoNS strains after birth during their hospital stay. Therefore, a prospective study was performed on the prevalence of CoNS in the stool of babies (born vaginally or by cesarean section) during their first days of life. Their clonal relatedness and potential to induce invasive disease were characterized. CoNS were analyzed from the stool samples of newborns with a load of CoNS above 103 colony-forming units (CFU)/mL. The identification of CoNS was performed phenotypically and genotypically. For typing, repetitive polymerase chain reaction (PCR), pulsed-field gel electrophoresis, and multilocus sequence typing were used. Resistance profiles, biofilm production, the presence of icaAD and of IS256 were determined as well. From a total of 207 stool samples (56 newborns), CoNS were detected in 41% of the newborns, mostly on day 3 for the first time (62.5%). Staphylococcus epidermidis was isolated in 85.7% of cases, harbored no IS256 element, and mostly expressed no biofilm. The isolates were separated into four main clusters by repetitive sequence-based PCR. 24% of the strains showed no antimicrobial resistance. 20% were resistant against four antibiotics of two different antibiotic classes. The remaining strains were resistant only against one antimicrobial substance class. Thus, it can be concluded that newborns do not acquire hospital-adapted endemic, multidrug-resistant S. epidermidis isolates during their first days of life. Yet, the results support the thesis that, during hospital stay, environmental parameters may convert sensible/noninvasive S. epidermidis strains into multidrug resistant strains with characteristics of invasiveness. PMID- 28560473 TI - Low-intensity laser therapy efficacy evaluation in FVB mice subjected to acute and chronic arthritis. AB - Rheumatoid arthritis, an autoimmune inflammation, has a high prevalence in the population, and while therapy is available, it required often injection of drugs causing discomfort to patients. This study evaluates the clinical and histological effect of low-intensity laser therapy (LILT) as an alternative treatment, in a murine model of acute and chronic inflammation. FVB mice received either a Zymosan A injection into one knee joint inducing acute inflammation, followed after 15 min or 24 h by LILT or a collagen bovine type II injection emulsified in "Freund's Complete Adjuvant" to induce chronic arthritis, followed at 4 weeks with multiple LILT sessions. LILT mediated by either 660, 808, or 905 nm and tissue response was evaluated based on clinical symptoms and histological analysis of inflammatory infiltrate and damage to the articular surfaces. LILT can be effective in elevating clinical symptoms, so Kruskal-Wallis testing indicated no significant differences between knees affected by acute arthritis and treated once with LILT and an injured knee without treatment (p > 0.05) for 660 and 808 nm with some improvements for the 905-nm LILT. Mice receiving two treatments for acute arthritis showed exacerbation of inflammation and articular resorption following therapy with a 660-nm continuous laser (p < 0.05). For chronic inflammation, differences were not noted between LILT treated and untreated injured knee joints (p > 0.05). Among the lasers, the 905 nm tends to show better results for anti-inflammatory effect in acute arthritis, and the 660 nm showed better results in chronic arthritis. In conclusion, LILT wavelength selection depends on the arthritis condition and can demonstrate anti inflammatory effects for chronic arthritis and reduced resorption area in this murine model. PMID- 28560474 TI - Vertebral fracture in postmenopausal Chinese women: a population-based study. AB - : In a random sample of postmenopausal Chinese women, the prevalence of radiographic vertebral fractures increased from 13% between ages 50 and 59 to over 50% after age 80 years. A model with seven clinical risk factors predicted the probability of vertebral fractures as well with as without BMD and better than a model with only three risk factors. More than half an hour of outdoor activity per day might correlate with lower risk of vertebral fracture in this population. INTRODUCTION: We aimed to describe the prevalence and develop a model for prediction of radiographic vertebral fractures in a large random sample of postmenopausal Chinese women. METHODS: We enrolled 1760 women from an age stratified random sample of postmenopausal women in Beijing, China. The presence of vertebral fracture was assessed by semi-quantitative grading of lateral thoracolumbar radiographs, risk factors by interview, bone mineral density (BMD) of the proximal femur and lumbar spine by dual x-ray absorptiometry (DXA), and markers of bone turnover from a fasting blood sample. Associations of these factors were analyzed in logistic models and discrimination by areas of receiver operating characteristics curves (AUC). RESULTS: The prevalence of vertebral fracture, ranged from 13.4% ages 50 to 59 years old to 58.1% at age 80 years or older. Older age, a history of non-vertebral fracture, lower femoral neck BMD T score, body mass index (BMI), height loss, housework, and less than half an hour of outdoor activity were significantly associated with increased probability of having a vertebral fracture. A model with those seven factors had a similar AUC with or without BMD and performed better than a simple model with three factors. CONCLUSION: This study is from a true random sample of postmenopausal women in urban China with high response rate. The prevalence of vertebral fractures in postmenopausal women in Beijing increases from 13% under age 60 to over 50% by age 80 years. A model with seven clinical risk factors with or without BMD is better than simple models and may guide the use of spine x-rays to identify women with vertebral fractures. More than half an hour of outdoor activity might correlate with lower risk of vertebral fracture in this population. PMID- 28560476 TI - Erratum to: X-ray Induced and Thermostimulated Luminescence of new Fluorine Containing Compounds (Potential Luminophores, Scintillators and Dosimeters). PMID- 28560475 TI - Generation of membrane potential beyond the conceptual range of Donnan theory and Goldman-Hodgkin-Katz equation. AB - Donnan theory and Goldman-Hodgkin-Katz equation (GHK eq.) state that the nonzero membrane potential is generated by the asymmetric ion distribution between two solutions separated by a semipermeable membrane and/or by the continuous ion transport across the semipermeable membrane. However, there have been a number of reports of the membrane potential generation behaviors in conflict with those theories. The authors of this paper performed the experimental and theoretical investigation of membrane potential and found that (1) Donnan theory is valid only when the macroscopic electroneutrality is sufficed and (2) Potential behavior across a certain type of membrane appears to be inexplicable on the concept of GHK eq. Consequently, the authors derived a conclusion that the existing theories have some limitations for predicting the membrane potential behavior and we need to find a theory to overcome those limitations. The authors suggest that the ion adsorption theory named Ling's adsorption theory, which attributes the membrane potential generation to the mobile ion adsorption onto the adsorption sites, could overcome those problems. PMID- 28560478 TI - Storeroom 99: a place for words to support families of ICU patients. PMID- 28560477 TI - Daclatasvir and asunaprevir in hemodialysis patients with hepatitis C virus infection: a nationwide retrospective study in Japan. AB - BACKGROUND: Hepatitis C virus (HCV) infection is common in hemodialysis patients and worsens their prognosis, while antiviral therapy options are limited. Recently, clinical trial and real-world, small-scale studies have reported excellent responses to direct-acting antivirals in patients with advanced chronic kidney diseases. However, real-world, large-scale data were lacking. This large multicenter analysis included HCV-infected hemodialysis patients receiving combination therapy with a nonstructural protein 5A (NS5A) inhibitor, daclatasvir (DCV), and a protease inhibitor, asunaprevir (ASV). METHODS: Twenty-three centers in Japan participated in this study of 123 hemodialysis patients with genotype 1 HCV infection, who received DCV/ASV combination therapy between November 2014 and March 2016. We collected and analyzed data relating to treatment outcome, baseline clinical information, laboratory measurements (during and after the treatment), and adverse events. RESULTS: Thirty-nine patients (31.7%) had advanced liver fibrosis, 12 (9.8%) had histories of hepatocellular carcinoma (HCC), and 18 (14.6%) had baseline resistance-associated variants (RAVs) of NS5A. The overall sustained virological response (SVR)12 rate was 95.9% (118/123). Notably, all patients with HCC and 94.4% (17/18) of those with NS5A RAVs achieved SVR12. Significant factors associated with non-SVR were advanced fibrosis and the interleukin-28B non-TT genotype at rs8099917. Four patients (3.3%) discontinued therapy because of adverse events including elevated serum alanine transaminase levels (n = 2), rash (n = 1), and HCC (n = 1); all of these achieved SVR12. CONCLUSIONS: This real-world, nationwide study revealed that DCV/ASV combination therapy was safe and highly effective for hemodialysis patients with genotype 1 HCV infections. This study was registered at the UMIN Clinical Trials Registry (UMIN000024227). PMID- 28560479 TI - The importance of rectal washout for the oncological outcome after Hartmann's procedure for rectal cancer: analysis of population-based data from the Swedish Colorectal Cancer Registry. AB - BACKGROUND: During rectal cancer surgery the bowel may contain viable, exfoliated cancer cells, a potential source for local recurrence (LR). The amount and viability of these cells can be reduced using intraoperative rectal washout, a procedure that reduces the LR risk after anterior resection. The aim of this study was to analyse the impact of washout on oncological outcome when performed in Hartmann's procedure (HP) for rectal cancer. METHODS: A national cohort study on data for patients registered from 1995 to 2007 in the Swedish Colorectal Cancer Registry was carried out. The final analysis included patients belonging to TNM stages I-III who had undergone R0 HP with a registered 5-year follow-up. Multivariate analysis was performed. RESULTS: A total of 1188 patients were analysed (686 washout and 502 no washout). No differences were detected between the washout group and the no washout group concerning rates of LR [7% (49/686) vs. 10% (49/502); p = 0.13], distant metastasis (DM) [17% (119/686) vs. 18% (93/502); p = 0.65], and overall recurrence (OAR) [21% (145/686) vs. 24% (120/502); p = 0.29]. For both groups, the 5-year cancer-specific survival was below 50%. In multivariate analysis, washout neither decreased the risk of LR, DM, or OAR nor increased overall or the cancer-specific 5-year survival. CONCLUSIONS: The oncological outcome did not improve when washout was performed in HP for rectal cancer. PMID- 28560480 TI - Patient quality of life and short-term surgical outcomes between robotic and laparoscopic anterior resection for adenocarcinoma of the rectum. AB - PURPOSE: To compare patient quality of life (QoL) and short-term surgical outcomes between robotic anterior resection (r-AR) and laparoscopic (l-AR) approach. METHODS: Consecutive patients having undergone either robotic or laparoscopic AR for adenocarcinoma were studied. All operations were performed by two surgeons experienced in laparoscopic and recently introduced robotic surgery. Surgical outcomes were determined by post-operative histology and short-term complications. QoL was prospectively assessed using the EORTC QLC-CR30 and QLC CR29 questionnaires. RESULTS: In total, 36 patients (18 r-AR) with a median follow-up of 12 months following surgery (9-month robotic and 20-month laparoscopic) were studied. The two groups were similarly matched for age and gender. Laparoscopic patients had a lower ASA grade (p = 0.02). There was no significant difference in surgical outcomes between groups. r-AR patients reported lower pain scales (2 +/- 6 vs. 11 +/- 13) (p = 0.04), lower levels of insomnia 0 vs. 8 +/- 15 (p = 0.04) and a lower abdominal pain scale (2 +/- 9 vs. 17 +/- 27) (p = 0.04). Male impotence scores were higher in l-AR 33 +/- 35 compared to r-AR 7 +/- 21 (p = 0.03). CONCLUSION: Despite its recent introduction to our centre, the quality of oncological resection using the robotic surgery is comparable to laparoscopy. Lower impotence and QoL scores in patients after robotic procedure may be explained on the basis of better visualisation and precise tissue handling. PMID- 28560481 TI - Fluorescence to highlight the urethra: a human cadaveric study. AB - BACKGROUND: Urethral injury is a complication feared by surgeons performing transanal TME (TaTME) or abdominoperineal excision (APE) procedures. Injury during TaTME occurs when the prostate is inadvertently mobilised or as a direct injury similar to the direct injury during the perineal dissection of APE procedures. We performed a proof of principle study to assess the feasibility of using indocyanine green (ICG) to fluoresce the urethra in human cadavers. METHODS: Indocyanine green at varying doses was mixed with Instillagel and infiltrated into the urethra of male human cadavers. The urethra was exposed through either a perineal incision or by mobilisation of the prostate during a TaTME dissection and fluorescence observed using a PINPOINT laparoscope (NOVADAQ). Brightness was assessed on the images using ImageJ (National Institute of Health). RESULTS: Eight cadavers were included in the study. Fluorescence was visualised in the urethra in all eight cadavers. Minimal dissection was required to obtain fluorescence transperineally. In one cadaver, the urethra was demonstrated under fluorescence using a simulated TaTME with additional fluorescence also being observed in the prostate. There was no correlation between brightness and dosing. CONCLUSIONS: This novel proof of principle study demonstrates a simple way in which the urethra may be easily identified preventing it from injury during surgery. PMID- 28560483 TI - Conditional loss of hepatocellular Hedgehog signaling in female mice leads to the persistence of hepatic steroidogenesis, androgenization and infertility. AB - The Hedgehog signaling pathway is known to be involved in embryogenesis, tissue remodeling, and carcinogenesis. Because of its involvement in carcinogenesis, it seems an interesting target for cancer therapy. Indeed, Sonidegib, an approved inhibitor of the Hedgehog receptor Smoothened (Smo), is highly active against diverse carcinomas, but its use is also reported to be associated with several systemic side effects. Our former work in adult mice demonstrated hepatic Hedgehog signaling to play a key role in the insulin-like growth factor axis and lipid metabolism. The current work using mice with an embryonic and hepatocyte specific Smo deletion describes an adverse impact of the hepatic Hedgehog pathway on female fertility. In female SAC-KO mice, we detected androgenization characterized by a 3.3-fold increase in testosterone at 12 weeks of age based on an impressive induction of steroidogenic gene expression in hepatocytes, but not in the classic steroidogenic organs (ovary and adrenal gland). Along with the elevated level of testosterone, the female SAC-KO mice showed infertility characterized by juvenile reproductive organs and acyclicity. The endocrine and reproductive alterations resembled polycystic ovarian syndrome and could be confirmed in a second mouse model with conditional deletion of Smo at 8 weeks of age after an extended period of 8 months. We conclude that the down-regulation of hepatic Hedgehog signaling leads to an impaired hormonal balance by the induction of steroidogenesis in the liver. These effects of Hedgehog signaling inhibition should be considered when using Hedgehog inhibitors as anti-cancer drugs. PMID- 28560482 TI - Integrated In Silico Fragment-Based Drug Design: Case Study with Allosteric Modulators on Metabotropic Glutamate Receptor 5. AB - GPCR allosteric modulators target at the allosteric binding pockets of G protein coupled receptors (GPCRs) with indirect influence on the effects of an orthosteric ligand. Such modulators exhibit significant advantages compared to the corresponding orthosteric ligands, including better chemical tractability or physicochemical properties, improved selectivity, and reduced risk of oversensitization towards their receptors. Metabotropic glutamate receptor 5 (mGlu5), a member of class C GPCRs, is a promising therapeutic target for treating many central nervous system diseases. The crystal structure of mGlu5 in the complex with the negative allosteric modulator mavoglurant was recently reported, providing a fundamental model for designing new allosteric modulators. Computational fragment-based drug discovery represents a powerful scaffold hopping and lead structure-optimization tool for drug design. In the present work, a set of integrated computational methodologies was first used, such as fragment library generation and retrosynthetic combinatorial analysis procedure (RECAP) for novel compound generation. Then, the compounds generated were assessed by benchmark dataset verification, docking studies, and QSAR model simulation. Subsequently, structurally diverse compounds, with reported or unreported scaffolds, can be observed from top 20 in silico synthesized compounds, which were predicted to be potential mGlu5 modulators. In silico compounds with reported scaffolds may fill SAR holes in known, patented series of mGlu5 modulators. And the generation of compounds without reported tests on mGluR indicates that our approach is doable for exploring and designing novel compounds. Our case study of designing allosteric modulators on mGlu5 demonstrated that the established computational fragment-based approach is a useful methodology for facilitating new compound design in the future. PMID- 28560484 TI - A New Look at Precipitants of Overt Hepatic Encephalopathy in Cirrhosis. AB - BACKGROUND AND AIMS: Overt hepatic encephalopathy (HE) is a major cause of significant morbidity and mortality in patients with liver cirrhosis. We examined the frequency and profile of the precipitating factors resulting in hospitalizations for overt HE. METHODS: We conducted both retrospective and prospective studies to identify clinical precipitants of overt HE in patients with cirrhosis. The retrospective study patients were hospitalized at a large urban safety-net hospital, and the prospective study included the patients admitted at a liver transplant center. RESULTS: There were a total of 149 patients with cirrhosis and overt HE (91 males, mean age 55.3 +/- 8.6 years) in the retrospective group and 45 patients (27 males, mean age 58.3 +/- 8.2 years) in the prospective group of the study. The average MELD score was 16 +/- 6.8 in the retrospective group and 22.7 +/- 7.2 in the prospective group. Dehydration (46-76%), acute kidney injury (32-76%), lactulose nonadherence (about 50%), constipation (about 40%), and infections (20-42%) were the most frequently identified precipitants for hospitalization in retrospective and prospective groups. Multiple precipitants were identified in 60 (40.3%) patients in the retrospective group and 34 (76%) patients in the prospective group. CONCLUSIONS: Multiple concurrent precipitating factors were identified in the majority of patients with overt HE requiring hospitalization. Dehydration due to various causes was the most common precipitant of overt HE, followed by acute kidney injury (AKI), constipation, and infections. Prevention of dehydration, AKI, and constipation by close outpatient monitoring may be an effective measure to prevent hospitalization for overt HE in patients with cirrhosis. PMID- 28560485 TI - Evaluation of end-tidal CO2 pressure at the anaerobic threshold for detecting and assessing pulmonary hypertension. AB - Cardiopulmonary exercise testing (CPET) is useful for the evaluation of patients with suspected or confirmed pulmonary hypertension (PH). End-tidal carbon dioxide pressure (PETCO2) during exercise is reduced with elevated pulmonary artery pressure. However, the utility of ventilatory parameters such as CPET for detecting PH remains unclear. We conducted a review in 155 patients who underwent right heart catheterization and CPET. Fifty-nine patients had PH [mean pulmonary arterial pressure (mPAP) >=25 mmHg]. There was an inverse correlation between PETCO2 at the anaerobic threshold (AT) and mPAP (r = -0.66; P < 0.01). Multiple regression analysis showed that PETCO2 at the AT was independently associated with an elevated mPAP (P = 0.04). The sensitivity and specificity of CPET for PH were 80 and 86%, respectively, when the cut-off value identified by receiver operating characteristic curve analysis for PETCO2 at the AT was <=34.7 mmHg. A combination of echocardiography and CPET improved the sensitivity in detecting PH without markedly reducing specificity (sensitivity 87%, specificity 85%). Evaluation of PETCO2 at the AT is useful for estimating pulmonary pressure. A combination of CPET and previous screening algorithms for PH may enhance the diagnostic ability of PH. PMID- 28560488 TI - Lived Religion as Reproductive Decision-Making Resource Among Romanian Women Who Use Abortion as Contraception. AB - This article draws upon qualitative ethnographic data collected between 2005 and 2013 in southern Romania among women who have been consistently using abortion as a contraceptive method. It particularly considers the role that lived religion might have played in some individuals' strategies to render abortion a justifiable practice. Over the last seven decades, Romanian women's experiences of abortion have often been at odds with both secular and religious regulations. This study shifts the perspective from the biopolitics and the bioethics of abortion toward women's own reproductive decision-making strategies in a context of enduring traditional patriarchy. It explores the fluid and pragmatic ways in which some Romanians use the notions of "God's will," "sin," "redemption," "afterlife," and "Godparenting" to redefine abortion as a partially disembodied reproductive event. As a reproductive decision-making resource, lived religion empowers women to navigate the lived complexities of conception and contraception. PMID- 28560486 TI - New scoring model (DARSYM score) to predict post-discharge bleeding after successful second-generation drug-eluting stent implantation. AB - We aimed to create a scoring model to predict post-discharge bleeding (PDB) after drug-eluting stent (DES) implantation in Japanese subjects. We enrolled 1912 consecutive patients undergoing DES implantation (age 70 +/- 10 years; 72% male). PDB was defined as a composite of type 5, 3, and 2 bleeding using the Bleeding Academic Research Consortium criteria. A Cox proportional hazard model assessed predictors, and we then derived a clinical model stratifying risk of PDB after DES implantation. Ninety-eight patients (6.7%) experienced PDB; gastrointestinal bleeding (GIB) was most common (n = 66, 67%), followed by intracranial bleeding (n = 24, 25%). PDB was independently associated with age >80 years [risk ratio (RR): 1.89, p < 0.001], hypertension (RR: 1.68, p = 0.03), severe renal dysfunction (RR: 1.56, p = 0.04), anemia on admission (RR: 1.75, p = 0.02), prior history of GIB (RR: 3.49, p < 0.001), NSAIDs use (RR: 2.33, p = 0.03), and introduction of triple antithrombotic therapy (RR: 2.94, p < 0.001). A clinical prediction rule for risk of bleeding events including seven baseline factors was derived. A better predictive ability for PDB was found using this new scoring system than the HAS-BLED score [c statistics, 0.85 (95% CI 0.83-0.87) and c statistics, 0.71 (95% CI 0.69-0.73), respectively; p < 0.001]. This new scoring system including patient characteristics and laboratory variables can identify patients at high risk of PDB after DES implantation. PMID- 28560487 TI - Effect of venous stenting on intracranial pressure in idiopathic intracranial hypertension. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) is characterised by an increased intracranial pressure (ICP) in the absence of any central nervous system disease or structural abnormality and by normal CSF composition. Management becomes complicated once surgical intervention is required. Venous sinus stenosis has been suggested as a possible aetiology for IIH. Venous sinus stenting has emerged as a possible interventional option. Evidence for venous sinus stenting is based on elimination of the venous pressure gradient and clinical response. There have been no studies demonstrating the immediate effect of venous stenting on ICP. METHODS: Patients with a potential or already known diagnosis of IIH were investigated according to departmental protocol. ICP monitoring was performed for 24 h. When high pressures were confirmed, CT venogram and catheter venography were performed to look for venous stenosis to demonstrate a pressure gradient. If positive, venous stenting would be performed and ICP monitoring would continue for a further 24 h after deployment of the venous stent. RESULTS: Ten patients underwent venous sinus stenting with concomitant ICP monitoring. Nine out of ten patients displayed an immediate reduction in their ICP that was maintained at 24 h. The average reduction in mean ICP and pulsatility was significant (p = 0.003). Six out of ten patients reported a symptomatic improvement within the first 2 weeks. CONCLUSIONS: Venous sinus stenting results in an immediate reduction in ICP. This physiological response to venous stenting has not previously been reported. Venous stenting could offer an alternative treatment option in correctly selected patients with IIH. PMID- 28560489 TI - The Effect of Holly Quran Voice With and Without Translation on Stress, Anxiety and Depression During Pregnancy: A Randomized Controlled Trial. AB - This study aimed to investigate the effect of Holy Quran on stress, anxiety and depression in Iranian pregnant women. A total of 168 participants were allocated randomly into three groups. Group I received broadcast of the Holy Quran with translation, group II received broadcast of the Holy Quran without translation, and group III was the control group. After intervention, scores of perceived stress, state anxiety, trait anxiety and depression in group I and group II were significantly lower compared with the control group. The Holly Quran with translation and without it, both are the effective for reducing stress, anxiety and depression during pregnancy. PMID- 28560491 TI - Answer to the Letter to the Editor of S. Huang et al. concerning "New classification for the treatment of pyogenic spondylodiscitis: validation study on a population of 250 patients with a follow-up of 2 years" by Enrico Pola et al. Eur Spine J (2017) doi:10.1007/s00586-017-5043-5. PMID- 28560490 TI - Laser capture microdissection protocol for gene expression analysis in the brain. AB - Laser capture microdissection (LCM) allows the isolation of specific cell populations from complex tissues that can be then used for gene expression studies. However, there are no reproducible protocols to study RNA in the brain and, particularly, in the substantia nigra. RNA is a very labile biomolecule that is easily degraded during manipulation. LCM studies use low amounts of material and special precautions must be taken to preserve RNA yield and integrity, which are decisive for PCR analysis. The RNA yield and/or integrity can be affected negatively by tissue manipulation, LCM process and RNA extraction. We have optimized these three critical steps using nigral tissue sections, and developed a LCM protocol to obtain high-quality RNA for gene expression analysis. The optimal LCM protocol requires the use of 20 um-thick tissue sections mounted on glass slides and processed for rapid tyrosine hydroxylase immunofluorescence. Additionally, a total microdissected tissue area of 1 mm2 and a column-based RNA extraction method were used to obtain a high RNA yield and integrity. In the rat substantia nigra, we demonstrated the expression of RNA for the angiotensin type 1 and type 2 receptors using this optimized LCM protocol. In conclusion, the LCM protocol reported here can be used to study the expression of both scarcely or abundantly expressed genes in the different brain regions of mammals under both physiological and pathological conditions. PMID- 28560492 TI - Simulation Modelling in Healthcare: An Umbrella Review of Systematic Literature Reviews. AB - BACKGROUND: Numerous studies examine simulation modelling in healthcare. These studies present a bewildering array of simulation techniques and applications, making it challenging to characterise the literature. OBJECTIVE: The aim of this paper is to provide an overview of the level of activity of simulation modelling in healthcare and the key themes. METHODS: We performed an umbrella review of systematic literature reviews of simulation modelling in healthcare. Searches were conducted of academic databases (JSTOR, Scopus, PubMed, IEEE, SAGE, ACM, Wiley Online Library, ScienceDirect) and grey literature sources, enhanced by citation searches. The articles were included if they performed a systematic review of simulation modelling techniques in healthcare. After quality assessment of all included articles, data were extracted on numbers of studies included in each review, types of applications, techniques used for simulation modelling, data sources and simulation software. RESULTS: The search strategy yielded a total of 117 potential articles. Following sifting, 37 heterogeneous reviews were included. Most reviews achieved moderate quality rating on a modified AMSTAR (A Measurement Tool used to Assess systematic Reviews) checklist. All the review articles described the types of applications used for simulation modelling; 15 reviews described techniques used for simulation modelling; three reviews described data sources used for simulation modelling; and six reviews described software used for simulation modelling. The remaining reviews either did not report or did not provide enough detail for the data to be extracted. CONCLUSION: Simulation modelling techniques have been used for a wide range of applications in healthcare, with a variety of software tools and data sources. The number of reviews published in recent years suggest an increased interest in simulation modelling in healthcare. PMID- 28560493 TI - Three-dimensional analysis of linear vestibulo-ocular reflex in humans during eccentric rotation while facing downwards. AB - When participants undergo eccentric rotation (ER), i.e., they are rotated while displaced from the axis of rotation, they undergo both rotational stimulation and linear acceleration, which induces both the angular vestibulo-ocular reflex (aVOR) and linear VOR (lVOR). During ER, the lVOR induced by tangential linear acceleration enhances the eye movement induced by aVOR. In this study, we attempted to measure aVOR and lVOR separately, while participants underwent ER while facing the ground in a dark room. We analyzed three-dimensional eye movements using a video-oculography system. The participants sat on the ER chair either directly above the center of rotation, or with their head out, head in, right ear out, or left ear out against the center of rotation. Under these conditions, the rotational axis of the eye was perpendicular to the ground for rotational stimulation (aVOR), and the axis was parallel to the ground for linear stimulation (lVOR). Thus, measured eye movements could be separated into these two components. At 0.1 and 0.3 Hz rotation, we observed aVOR but not lVOR. However, when the stimulation frequency was above 0.5 Hz, we observed both aVOR and lVOR. These data indicate that lVOR is activated when the stimulation frequency is above 0.5 Hz. We conclude that it is possible to separately analyze aVOR and lVOR, and to simultaneously assess the function of aVOR and lVOR by analyzing eye movements induced when participants undergo ER above 0.5 Hz while facing the ground. PMID- 28560494 TI - Spatial limits of visuotactile interactions in the presence and absence of tactile stimulation. AB - The presence of a light flash near to the body not only increases the ability to detect a weak touch but also increases reports of feeling a weak touch that did not occur. The somatic signal detection task (SSDT) provides a behavioural marker by which to clarify the spatial extent of such visuotactile interactions in peripersonal space. Whilst previous evidence suggests a limit to the spatial extent over which visual input can distort the perception of tactile stimulation during the rubber hand illusion, the spatial boundaries of light-induced tactile sensations are not known. In a repeated measures design, 41 participants completed the SSDT with the light positioned 1 cm (near), 17.5 cm (mid) or 40 cm (far) from the tactile stimulation. In the far condition, the light did not affect hit, or false alarm rates during the SSDT. In the near and mid conditions, the light significantly increased hit rates and led to a more liberal response criterion, that is, participants reported feeling the touch more often regardless of whether or not it actually occurred. Our results demonstrate a spatial boundary over which visual input influences veridical and non-veridical touch perception during the SSDT, and provide further behavioural evidence to show that the boundaries of the receptive fields of visuotactile neurons may be limited to reach space. PMID- 28560496 TI - Evaluation of ecotoxicological impact of new pyrrole-derived aminophosphonates using selected bioassay battery. AB - Six new dimethyl N-arylamino(2-pyrrolyl)methylphosphonates 2a-f were synthesized by the modified aza-Pudovik reaction. Their ecotoxicological impact using battery of bioassay was assessed using Microtox and Ostracodtoxit tests as well as phytotoxicity towards two plants, dicotyledonous radish (Raphanus sativus) and monocotyledonous oat (Avena sativa) following the OECD 208 Guideline. Ecotoxicological properties of compounds 2a-f in aspect of acute and chronic toxicity were evaluated using Heterocypris incongruens and Aliivibrio fisheri tests. The obtained results showed that tested aminophosphonates 2a-f have moderate-to-high phyto- and ecotoxicological impact. They are toxic for both plants but more toxic against dicotyledonous. The investigated compounds showed important ecotoxicity against Heterocypris incongruens crustaceans and Aliivibrio fisheri bacteria. It was found that the substituents of the phenyl ring plays a key role in the degree of toxicity. Results showed that investigated compounds are ecologically toxic and that any of their application should be implemented with care. PMID- 28560495 TI - Development of a novel method for the strengthening and toughening of irradiation sterilized bone allografts. AB - Reconstruction of large skeletal defects is a significant and challenging issue. Bone allografts are often used for such reconstructions. However, sterilizing bone allografts by using gamma-irradiation, damages collagen and causes the bone to become weak, brittle and less fatigue resistant. In a previous study, we successfully protected the mechanical properties of human cortical bone by conducting a pre-treatment with ribose, a natural and biocompatible agent. This study focuses on examining possible mechanisms by which ribose might protect the bone. We examined the mechanical properties, crosslinking, connectivity and free radical scavenging potentials of the ribose treatment. Human cortical bone beams were treated with varying concentration of ribose (0.06-1.2 M) and gamma irradiation before testing them in 3-point bending. The connectivity and amounts of crosslinking were determined with Hydrothermal-Isometric-Tension testing and High-Performance-Liquid-Chromatography, respectively. The free radical content was measured using Electron Paramagnetic Resonance. Ribose pre-treatment improved the mechanical properties of irradiation sterilized human bone in a pre-treatment concentration-dependent manner. The 1.2 M pre-treatment provided >100% of ultimate strength of normal controls and protected 76% of the work-to-fracture (toughness) lost in the irradiated controls. Similarly, the ribose pre-treatment improved the thermo-mechanical properties of irradiation-sterilized human bone collagen in a concentration-dependent manner. Greater free radical content and pentosidine content were modified in the ribose treated bone. This study shows that the mechanical properties of irradiation-sterilized cortical bone allografts can be protected by incubating the bone in a ribose solution prior to irradiation. PMID- 28560497 TI - Fate and transport of furrow-applied granular tefluthrin and seed-coated clothianidin insecticides: Comparison of field-scale observations and model estimates. AB - The transport of agricultural insecticides to water bodies may create risk of exposure to non-target organisms. Similarly, widespread use of furrow-applied and seed-coated insecticides may increase risk of exposure, yet accessible exposure models are not easily adapted for furrow application, and only a few examples of model validation of furrow-applied insecticides exist using actual field data. The goal of the current project was to apply an exposure model, the Pesticide in Water Calculator (PWC), to estimate the concentrations of two in-furrow insecticides applied to maize: the granular pyrethroid, tefluthrin, and the seed coated neonicotinoid, clothianidin. The concentrations of tefluthrin and clothianidin in surface runoff water, sampled from a field in central Illinois (USA), were compared to the PWC modeled pesticide concentrations in surface runoff. The tefluthrin concentrations were used to optimize the application method in the PWC, and the addition of particulate matter and guttation droplets improved the models prediction of clothianidin concentrations. Next, the tefluthrin and clothianidin concentrations were calculated for a standard farm pond using both the optimized application method and the application methods provided in PWC. Estimated concentrations in a standard farm pond varied by a factor of 100 for tefluthrin and 50 for clothianidin depending on the application method used. The addition of guttation droplets and particulate matter to the model increased the annual clothianidin concentration in a standard farm pond by a factor of 1.5, which suggested that these transport routes should also be considered when assessing neonicotinoid exposure. PMID- 28560498 TI - Gender-based normative values for pattern-reversal and flash visually evoked potentials under binocular and monocular stimulation in healthy adults. AB - PURPOSE: To determine gender-based normative values for pattern-reversal (PR) and flash (F) visually evoked potentials (VEP) under binocular and monocular stimulation in healthy adults. METHODS: Healthy adults (age >=18 years) were recruited among university employees and students. Inclusion criteria were absence of abnormalities in fundoscopy, tracking ability, stereopsis and pupillary reflexes; best-corrected visual acuity <=.00 logMAR; and refractive error (spherical equivalent) from -6.00 to +6.00. Exclusion criteria were previous intraocular surgery, systemic and/or neurological disorders. Binocular and monocular tests were performed according to International Society for Clinical Electrophysiology of Vision standards for PRVEP (reversal rate = 1.9 Hz, checkerboard stimuli 15' and 60' at 100% contrast) and FVEP (3 cd s/m2, rate = 1 Hz). VEP parameters of amplitude (uV) and peak times (ms) were measured. Inter ocular differences, inter-peak intervals (N135-N75) and binocular summation were determined. RESULTS: Fifty-four subjects (28 females; mean age = 40.4 +/- 13.7 years; median = 40.0 years) were included. Mean P100 latencies for 15' and 60' stimuli were, respectively, 94.6 +/- 4.7 ms and 96.1 +/- 4.2 for women. Mean values of P100 latency for men were 97.4 +/- 4.9 for 15' and 97.7 +/- 4.2 for 60' stimuli. Larger mean P100 for 15' checks was observed in women (12.8 +/- 5.7 uV) than men (8.6 +/- 2.5 uV) in PRVEP. Similar results were found for FVEP N2-P2 amplitudes (mean = 14.6 +/- 4.9 for women and 9.8 +/- 4.0 for men). CONCLUSIONS: Gender-based normative values for PRVEP and FVEP were determined, with women disclosing higher responses than men for smaller stimuli in the visual pathway. The use of gender-based normative values in the analysis of clinical VEP data for diagnostic and therapeutic purposes is recommendable. Additional analysis including inter-peak intervals and binocular summation ratio might improve the diagnostic power of VEP. PMID- 28560499 TI - The Impact of Substance Use on Adherence to Antiretroviral Therapy Among HIV Infected Women in the United States. AB - Research is scant regarding differential effects of specific types of recreational drugs use on antiretroviral therapy adherence among women, particularly to single-tablet regimens (STR). This is increasingly important in the context of marijuana legalization. We examined the effects of self-reported substance use on suboptimal (<95%) adherence in the Women's Interagency HIV Study, 2003-2014. Among 1799 HIV-infected women, the most prevalent substance used was marijuana. In multivariable Poisson GEE regression, substance use overall was significantly associated with suboptimal adherence (adjusted prevalence ratio, aPR = 1.20, 95% CI 1.10-1.32), adjusting for STR use, socio demographic, behavioral, and clinical factors. Among STR users, compared to no drug use, substance use overall remained detrimental to ART adherence (aPR = 1.61, 95% CI 1.24-2.09); specifically, both marijuana (aPR = 1.48, 95% CI: 1.11 1.97) and other drug use (aPR = 1.87, 95% CI 1.29-2.70) predicted suboptimal adherence. These findings highlight the need to intervene with drug-using women taking antiretroviral therapy to maintain effective adherence. PMID- 28560500 TI - Synergistic induction of apoptosis by combination treatment with mesupron and auranofin in human breast cancer cells. AB - Urokinase-type plasminogen activator (uPA) has been validated as a predictive or prognostic biomarker protein, and mesupron is considered the first-in-class anticancer agent to inhibit uPA activity in human breast cancer. In the present study, we showed that the synergism between mesupron and auranofin, a thioredoxin reductase inhibitor, for inducing of apoptosis in MCF-7 human breast cancer cells. Our results demonstrated that mesupron and auranofin significantly lead to inhibition of the cancer cells proliferation; cell cycle arrest at the G1/S phase of the cell cycle, and apoptosis as indicated by caspase 3 activation, poly(ADP ribose) polymerase cleavage, and annexin V staining. Isobologram analyses of MCF 7 cells showed a clear synergism between mesupron and auranofin. This combined treatment decreased the levels of mitochondrial anti-apoptotic factors, such as BCL-2, BCL-xL, and MCL-1 and caused nuclear translocation of apoptosis-inducing factor. Mitochondrial membrane potential (Deltapsi m ) was found to be strongly disrupted in combination-treated cells. In addition, combination treatment significantly enhanced the overproduction of reactive oxygen species, which was rescued by N-acetylcysteine treatment. The combination treatment suppressed phosphorylation of Akt, thus contributing to apoptosis. Taken together, our data suggest that the use of mesupron in combination with auranofin may be important in achieving high anticancer synergy. PMID- 28560501 TI - Relationship of bone mineral density with valvular and annular calcification in community-dwelling older people: The Cardiovascular Health Study. AB - : Associations between bone mineral density and aortic valvular, aortic annular, and mitral annular calcification were investigated in a cross-sectional analysis of a population-based cohort of 1497 older adults. Although there was no association between continuous bone mineral density and outcomes, a significant association between osteoporosis and aortic valvular calcification in men was found. INTRODUCTION: The process of cardiac calcification bears a resemblance to skeletal bone metabolism and its regulation. Experimental studies suggest that bone mineral density (BMD) and valvular calcification may be reciprocally related, but epidemiologic data are sparse. METHODS: We tested the hypothesis that BMD of the total hip and femoral neck measured by dual-energy X-ray absorptiometry (DXA) is inversely associated with prevalence of three echocardiographic measures of cardiac calcification in a cross-sectional analysis of 1497 older adults from the Cardiovascular Health Study. The adjusted association of BMD with aortic valve calcification (AVC), aortic annular calcification (AAC), and mitral annular calcification (MAC) was assessed with relative risk (RR) regression. RESULTS: Mean (SD) age was 76.2 (4.8) years; 58% were women. Cardiac calcification was highly prevalent in women and men: AVC, 59.5 and 71.0%; AAC 45.1 and 46.7%; MAC 42.8 and 39.5%, respectively. After limited and full adjustment for potential confounders, no statistically significant associations were detected between continuous BMD at either site and the three measures of calcification. Assessment of WHO BMD categories revealed a significant association between osteoporosis at the total hip and AVC in men (adjusted RR compared with normal BMD = 1.24 (1.01-1.53)). In graded sensitivity analyses, there were apparent inverse associations between femoral neck BMD and AVC with stenosis in men, and femoral neck BMD and moderate/severe MAC in women, but these were not significant. CONCLUSION: These findings support further investigation of the sex-specific relationships between low BMD and cardiac calcification, and whether processes linking the two could be targeted for therapeutic ends. PMID- 28560502 TI - Proximal carious lesions infiltration-a 3-year follow-up study of a randomized controlled clinical trial. AB - INTRODUCTION: Infiltration of carious lesion has been claimed as a promising approach for the management of non-cavitated proximal lesions (NCPL). Clinical studies have suggested that this approach may reduce NCPL progression in individuals whose caries risk was not change over the studied period. OBJECTIVE: This study aimed to assess the additional benefit of infiltration of NCPL over a 3-year period in a group of individuals who received treatment and control of carious activity. MATERIALS AND METHODS: Twenty-two caries-active subjects that possessed at least a pair of NCPL in posterior teeth were selected for this study totalizing 36 pairs of lesion. In a split-mouth design, lesions were randomly allocated to test (infiltration) or placebo treatments. At follow-up, lesions were radiographically analyzed, progression was determined by radiographic pair wise comparison and differences in number of progressing lesions between test, and placebo-treated surfaces were compared. RESULTS: Seventeen subjects (27 pairs of lesions) were followed up. Only four subjects were caries-active at the follow up. In the test group, 2/27 (7.4%) lesions and in the placebo group 5/27 (18.5%) lesions had progressed. No statistical difference was observed between the studied groups (p = 0.453). CONCLUSION: Subjects under treatment focusing on controlling caries activity presented low progression rates in both infiltrated and non-infiltrated NCPL. As only very few lesions progressed in both groups, no significant additional effect could be found. Further studies with larger sample sizes are necessary. CLINICAL RELEVANCE: Infiltration of NCPL may have limited additional effect if other treatments focused on controlling caries activity are successful. PMID- 28560503 TI - Effect of increasing fruit and vegetable intake by dietary intervention on nutritional biomarkers and attitudes to dietary change: a randomised trial. AB - PURPOSE: Low fruit and vegetable consumption is linked with an increased risk of death from vascular disease and cancer. The benefit of eating fruits and vegetables is attributed in part to antioxidants, vitamins and phytochemicals. Whether increasing intake impacts on markers of disease remains to be established. This study investigates whether increasing daily intake of fruits, vegetables and juices from low (approx. 3 portions), to high intakes (approx. 8 portions) impacts on nutritional and clinical biomarkers. Barriers to achieving the recommended fruit and vegetable intakes are also investigated. METHOD: In a randomised clinical trial, the participants [19 men and 26 women (39-58 years)] with low reported fruit, juice and vegetable intake (<3 portions/day) were randomised to consume either their usual diet or a diet supplemented with an additional 480 g of fruit and vegetables and fruit juice (300 ml) daily for 12 weeks. Nutritional biomarkers (vitamin C, carotenoids, B vitamins), antioxidant capacity and genomic stability were measured pre-intervention, at 4-, 8- and 12 weeks throughout the intervention. Samples were also taken post-intervention after a 6-week washout period. Glucose, homocysteine, lipids, blood pressure, weight and arterial stiffness were also measured. Intake of fruit, fruit juice and vegetables was reassessed 12 months after conducting the study and a questionnaire was developed to identify barriers to healthy eating. RESULTS: Intake increased significantly in the intervention group compared to controls, achieving 8.4 portions/day after 12 weeks. Plasma vitamin C (35%), folate (15%) and certain carotenoids [alpha-carotene (50%) and beta-carotene (70%) and lutein/zeaxanthin (70%)] were significantly increased (P < 0.05) in the intervention group. There were no significant changes in antioxidant capacity, DNA damage and markers of vascular health. Barriers to achieving recommended intakes of fruits and vegetables measured 12 months after the intervention period were amount, inconvenience and cost. CONCLUSION: While increasing fruit, juice and vegetable consumption increases circulating level of beneficial nutrients in healthy subjects, a 12-week intervention was not associated with effects on antioxidant status or lymphocyte DNA damage. TRIAL REGISTRATION: This trial was registered at Controlled-Trials.com; registration ISRCTN71368072. PMID- 28560504 TI - Development of Cordycepin Formulations for Preclinical and Clinical Studies. AB - There is extensive literature on in vivo studies with cordycepin, but these studies were generally conducted without validation of the various formulations, especially in terms of the solubility of cordycepin in the dosing vehicles used. Cordycepin is a promising drug candidate in multiple therapeutic areas, and there is a growing interest in studies aimed at assessing the pharmacological activity of this compound in relevant animal disease models. It is likely that many reported in vivo studies used formulations in which cordycepin was incompletely soluble. This can potentially confound the interpretation of pharmacokinetics and efficacy results. Furthermore, the presence of particles in intravenously administered suspension can cause adverse effects and should be avoided. Here, we present the results from our development of simple and readily applicable formulations of cordycepin based on quantitative solubility assessment. Homogeneous solutions of cordycepin were prepared in phosphate-buffered saline (PBS) at different pH levels, suitable as formulations for both intravenously and oral administration. For the purpose of high-dose oral administration, we also developed propylene glycol (PPG)-based vehicles in which cordycepin is completely soluble. The stability of the newly developed formulations was also assessed, as well as the feasibility of their sterilisation by filtration. Additionally, an HPLC-UV method for the determination of cordycepin in the formulations, which may also be useful for other purposes, was developed and validated. Our study could provide useful information for improvement of future preclinical and clinical studies involving cordycepin. PMID- 28560505 TI - A Cheap and Convenient Method of Liposome Preparation Using Glass Beads as a Source of Shear Force. AB - Liposomes, the biocompatible lipid bilayer vesicles, have attracted immense attention due to their distinctive features such as efficient vehicle for the delivery of a wide range of therapeutic agents, adjustable formulation properties, and high drug entrapment efficiency. In this contribution, we present a simple method for the preparation of liposomes using glass beads and compared the potential of this method with conventional methods of liposome preparation. The prepared liposomes were characterized by different analytical techniques (HPLC, DLS, TEM, differential scanning calorimetry, and in vitro drug release). Our findings revealed that the particle size of liposomes is mainly dependent on the size of the glass beads and the glass bead shearing time. An average liposome size of 67.7 +/- 25.5 nm was obtained using 2-mm glass beads after 24-h incubation at 200 rpm. The liposomes prepared under the optimized conditions exhibited a high encapsulation efficiency of 92.1 +/- 1.7% with 31.08% drug release after 360 min at 37 degrees C. In conclusion, the developed method is a simple and convenient process of liposome preparation of different sizes with desirable entrapment efficiency capacity. PMID- 28560506 TI - Biomimetic Dissolution: A Tool to Predict Amorphous Solid Dispersion Performance. AB - The presented study describes the development of a membrane permeation non-sink dissolution method that can provide analysis of complete drug speciation and emulate the in vivo performance of poorly water-soluble Biopharmaceutical Classification System class II compounds. The designed membrane permeation methodology permits evaluation of free/dissolved/unbound drug from amorphous solid dispersion formulations with the use of a two-cell apparatus, biorelevant dissolution media, and a biomimetic polymer membrane. It offers insight into oral drug dissolution, permeation, and absorption. Amorphous solid dispersions of felodipine were prepared by hot melt extrusion and spray drying techniques and evaluated for in vitro performance. Prior to ranking performance of extruded and spray-dried felodipine solid dispersions, optimization of the dissolution methodology was performed for parameters such as agitation rate, membrane type, and membrane pore size. The particle size and zeta potential were analyzed during dissolution experiments to understand drug/polymer speciation and supersaturation sustainment of felodipine solid dispersions. Bland-Altman analysis was performed to measure the agreement or equivalence between dissolution profiles acquired using polymer membranes and porcine intestines and to establish the biomimetic nature of the treated polymer membranes. The utility of the membrane permeation dissolution methodology is seen during the evaluation of felodipine solid dispersions produced by spray drying and hot melt extrusion. The membrane permeation dissolution methodology can suggest formulation performance and be employed as a screening tool for selection of candidates to move forward to pharmacokinetic studies. Furthermore, the presented model is a cost-effective technique. PMID- 28560507 TI - Comparison of CROES, S.T.O.N.E, and Guy's scoring systems for the prediction of stone-free status and complication rates following percutaneous nephrolithotomy in patients with chronic kidney disease. AB - PURPOSE: To evaluate and compare the accuracy of S.T.O.N.E, Clinical Research Office of the Endourological Society (CROES), and Guy's stone score in patients with chronic kidney disease (CKD) following percutaneous nephrolithotomy (PNL). METHODS: The charts of patients who had undergone a prone percutaneous nephrolithotomy from June 2006 to June 2016 were retrospectively analyzed. Patients accepted as stage 3 and higher according to chronic kidney disease epidemiology collaboration formula, were enrolled into the study. Calculation of the CROES, S.T.O.N.E, and Guy's scoring system (SS) was made as defined in original papers. Patients were categorized into four scores according to CROES, into nine scores according to S.T.O.N.E, and into four scores according to Guy's SS. RESULTS: A total of 303 patients fulfilled the study inclusion criteria. The mean preoperative eGFR and creatinine levels were 47 mL/min and 1.55 mg/dL, respectively. In patients who were stone free and those with residual stones, the mean CROES SS was 179 and 137 (p < 0.001), the mean S.T.O.N.E score was 8.8 and 9.9 (p < 0.001), and the mean Guy's SS was 1.8 and 2.4 (p < 0.001), respectively. Multivariate regression analysis revealed CROES SS was the only scoring system, which had a predictive value for PNL outcome in patients with CKD (p = 0.011) and any of three SS were not useful for predicting PNL complications in patients with CKD. CONCLUSION: Our study demonstrated the CROES SS was the only independent factor in the prediction of PNL outcome in CKD patients. Furthermore, three of the NSSs were not useful for predicting PNL complications in patients with CKD. PMID- 28560508 TI - Does the Use of a Checklist Help Medical Students in the Detection of Abnormalities on a Chest Radiograph? AB - The interpretation of chest radiographs is a complex task that is prone to diagnostic error, especially for medical students. The aim of this study is to investigate the extent to which medical students benefit from the use of a checklist regarding the detection of abnormalities on a chest radiograph. We developed a checklist based on literature and interviews with experienced thorax radiologists. Forty medical students in the clinical phase assessed 18 chest radiographs during a computer test, either with (n = 20) or without (n = 20) the checklist. We measured performance and asked participants for feedback using a survey. Participants that used a checklist detected more abnormalities on images with multiple abnormalities (M = 50.1%) than participants that could not use a checklist (M = 41.9%), p = 0.04. The post-experimental survey shows that on average, participants considered the checklist helpful (M = 3.25 on a five-point scale), but also time consuming (M = 3.30 on a five-point scale). In conclusion, a checklist can help medical students to detect abnormalities in chest radiographs. Moreover, students tend to appreciate the use of a checklist as a helpful tool during the interpretation of a chest radiograph. Therefore, a checklist is a potentially important tool to improve radiology education in the medical curriculum. PMID- 28560509 TI - Evaluation of Coronary Artery Disease and Coronary Anomalies with a Handheld Smartphone. AB - The purpose of this study was to determine the diagnostic accuracy of an iPhone for evaluation of the coronary arteries on coronary CT angiography (CTA) in comparison to a standard clinical workstation. Fifty coronary CTA exams were selected to include a range of normal and abnormal cases including both coronary artery disease (CAD) of varying severity and coronary artery anomalies. Two cardiac radiologists reviewed each exam on a standard clinical workstation initially and then on an iPhone 6 after a washout period. Coronary stenosis was evaluated on a 4-point scale and presence of coronary anomalies was recorded. Two additional cardiac radiologists reviewed all cases in consensus on the standard workstation and these results were used as the reference standard. When reader results were compared to the reference standard, there was no significant difference in agreement for per-vessel stenosis scores using either the iPhone or standard clinical workstation. The intraobserver intertechnology agreement on a per-vessel basis for obstructive CAD were 97.4% (299/307, kappa = 0.777) and 97.5% (317/325, kappa = 0.804) for the two readers. All cases of coronary anomalies were identified by both readers regardless of the device used. Coronary CTA examinations can be interpreted on a smartphone with diagnostic accuracy comparable to a standard workstation. 3D visualization app on the iPhone may facilitate urgent coronary CTA review when a workstation is not available. PMID- 28560510 TI - The role of neurotensin as a novel biomarker in the endoscopic screening of high risk population for developing colorectal neoplasia. AB - Colorectal cancer screening programs aim at early detection of cancer to reduce incidence rates and mortality. The objective of this study is to identify the role of neurotensin in the endoscopic screening of high-risk population for developing colorectal neoplasia. Blood samples from patients referred for urgent colonoscopy to investigate symptoms suspicious of colorectal cancer were collected. Blood neurotensin levels were measured using enzyme-linked immunosorbent assay. Colonoscopy findings were used as reference for determining the diagnostic accuracy of blood neurotensin. The study comprised 26 patients in total: 12 healthy and 14 with colon pathology (13 high-grade dysplasia adenomatous polyps, 1 adenocarcinoma). There were no statistically significant differences in the clinical and biochemical parameters between colon pathology and healthy group except neurotensin levels. Pathology in colon was associated with 3.7-fold increase in NT levels. In multivariate analysis, patients with pathology in colon have increased serum neurotensin levels compared to controls adjusted for age, gender, BMI and co-morbidities. The value of 12.93 pg/ml is associated with 87.5% sensitivity and 91.7% specificity for discriminating the colon pathology from normal colonic epithelium (p = 0.001). Neurotensin plasma values differentiate healthy people from patients suffering from colonic pathologies such as adenomatous polyps and cancer. The use of neurotensin as a potential endoscopic screening tool for identifying high-risk population for developing colorectal cancer is promising, but much has to be done before it is validated in larger scale prospective studies. PMID- 28560511 TI - Caveolin-1 is Markedly Downregulated in Patients with Early-Stage Colorectal Cancer. AB - BACKGROUND: Caveolin-1 (CAV-1), the main scaffold protein in caveolae, is frequently deregulated in human cancer. Of importance, this protein has been described to show tumor suppressor or oncogenic properties depending on the cell type and the stage of the disease. In fact, its role in colorectal cancer (CRC) remains to be fully clarified due to discrepancies in the literature. METHODS: We analyzed CAV-1 by western blot in a set of early-stage CRC patients with paired tumor tissue and normal colonic mucosa available. CAV-1 mRNA and expression levels of miR-124, 133 and 802 were quantified by real-time PCR. RESULTS: We found CAV-1 strongly downregulated in 76.2% of tumor samples and associated with the subgroup of elderly patients (p = 0.027). We observed by real-time PCR a lack of correlation between CAV-1 mRNA and protein levels in some cases with CAV-1 downregulated by western blot, and miR-124 deregulation was identified as a potential contributing alteration to decrease CAV-1 protein expression. CONCLUSION: CAV-1 is commonly downregulated in patients with primary CRC, which suggests its tumor suppressor role in early stages of this disease. Moreover, based on our findings, the previous discrepancies observed in different studies to date could be due to a complex posttranscriptional CAV-1 regulation. PMID- 28560513 TI - Immunohistochemical Detection of Sphingosine-1-Phosphate and Sphingosine Kinase-1 in Human Tissue Samples and Cell Lines. AB - Sphingosine-1-phosphate (S1P) and the enzyme primarily responsible for its production, sphingosine kinase-1 (SphK-1), are dysregulated in multiple human diseases including cancer, multiple sclerosis (MS), diabetes, neurological diseases, fibrosis, and certain pathologies associated with impaired angiogenesis such as age-related macular degeneration (AMD). Antibody-based techniques to identify and localize S1P and SphK-1 within cells and tissue specimens represent a powerful tool, not only to understand biological role of these molecules but also to validate these unique in-class targets in multiple state diseases. Consequently, the potential applications of these molecules for therapy and diagnostic purposes are currently under investigation. Here, we describe a new improved technique, Agitated Low Temperature Epitope Retrieval (ALTER) for staining procedures, to identify expression of S1P and SphK-1 in human frozen tissue samples. The challenges encountered in the process of localization in tissue samples of lipid molecules such as S1P are discussed. PMID- 28560512 TI - Biological Implant for Complex Abdominal Wall Reconstruction: A Single Institution Experience and Review of Literature. AB - AIM: To present our single institution and surgeon's complex abdominal wall reconstructions (CAWR) experience with PermacolTM mesh through a non-randomized study. PATIENTS AND METHOD: Data of 51 consecutive patients were prospectively collected between 2003 and 2015. Patients had a median of 3 comorbidities (range 0-10) and 68% were Center for Disease Control class II-IV. The mean previous repair was 1.3 (range, 0-12), and 25 (44%) had a mesh in situ. The median defect size was 625 cm2. RESULTS: Among the 56 CAWR procedures, in 16 (29%) bowel resection/anastomosis was performed. The overall post-operative complication rate was 45%, and it was wound-related except from 1 patient dead for myocardial infarction. One was lost at follow-up. Five were re-operated for recurrence with a second Permacol mesh, leading to 14 (26%) overall recurrences at a mean follow up of 44 months (range, 4-123). In 33 (59%) cases, fascial closure was achieved. The mesh placement was intraperitoneal in 89%, retro-muscular in 9% and supra fascial in 1% of cases. A multivariate analysis showed that predictor risk for recurrence was more than 3 previous repairs, wound class III-IV, whereas age, type of comorbidities, defect size and fascial closure did not influence the recurrence. Median post-operative performance status was 0 (range; 0-3). A satisfaction questionnaire was obtained in 43 patients, and 86% of them were satisfied with the outcome. CONCLUSIONS: Biological materials have the potential to reduce morbidity and improve outcome of definitive repair of CAWR. PMID- 28560514 TI - Illumina-Based Sequencing Analysis Directed Selection for Actinobacterial Probiotic Candidates for Banana Plants. AB - As potential probiotic candidates, plant vertically transmitted actinobacteria are beneficial to growth and health of host plants. New methods to isolate the actinobacterial taxa with low growth rates should be developed. Based on the actinobacterial population information, the probiotic actinobacterial taxa could be directly isolated from healthy banana shoot tips. However, actinobacterial DNAs with high GC contents could bias estimates of actinobacteria by PCR. In the study, two amplicon sequencing strategies were adopted to elucidate the endophytic actinobacterial community of banana plants. More than 92.5% bacterial OTUs were affiliated with actinobacteria by these two strategies, and total 14,289 actinobacterial OTUs with above 97% similarity were detected in banana shoot tips. Although the libraries generated by the two strategies differed in the abundance of some genera, Mycobacterium and Nocardia dominated both libraries and most actinobacterial taxa were overlapped. Higher phylogenetic resolution actinobacteriome of banana plants was successfully established. Based on the endophytic actinobacterial community information, the streptomycetes were isolated from shoot tips. Pot experiments illustrated that the strain could promote banana plantlet growth and elevate resistance to Fusarium oxysporum f. sp. cubense (FOC) under FOC infested soils. The results suggested that the selection for probiotic agents based on actinobacteriome analysis is reliable and feasible compared with present greenhouse selection. PMID- 28560515 TI - Stimulating Effects of Sucrose and Inulin on Growth, Lactate, and Bacteriocin Productions by Pediococcus pentosaceus. AB - Sucrose and inulin, when combined with glucose, behaved as stimulating agents of bacteriocin production by Pediococcus pentosaceus ATCC 43200. When such microbial strain was grown in glucose-based Man, Rogosa, and Sharpe (MRS) medium, without any additional supplement, it showed higher maximum cell concentration (2.68 +/- 1.10 g/L) and longer generation time (2.17 +/- 0.02 h), but lower specific growth rate (0.32 +/- 0.01 h-1) than in the same medium supplemented with 1.0% of both ingredients (2.53 +/- 1.10 g/L, 1.60 +/- 0.05 h and 0.43 +/- 0.02 h-1, respectively). Glucose replacement by sucrose or inulin almost completely suppressed growth, hence confirming that it is the preferred carbon source for this strain. Qualitatively, similar results were observed for lactate production, which was 59.8% higher in glucose-based medium. Enterococcus and Listeria strains were sensitive to bacteriocin, whose antimicrobial effect after 8 h increased from 120.25 +/- 0.35 to 144.00 +/- 1.41 or 171.00 +/- 1.41 AU/mL when sucrose or inulin was added to the glucose-based MRS medium. Sucrose and inulin were also able to speed up P. pentosaceus growth in the exponential phase. PMID- 28560517 TI - A contemporary analysis of clinical and demographic factors of chronic rhinosinusitis patients and their association with disease severity. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is highly prevalent, significantly decreases quality of life and leads to tremendous health care costs every year. No recent study has characterised the prevalence of potentially CRS-modifying patient characteristics and simultaneously shown their impact on CRS severity. AIMS: We sought to determine the prevalence of potential clinical and demographic CRS-modifying characteristics and their associations with CRS symptom severity in a large contemporary cohort of CRS patients. METHODS: Retrospective review of CRS patients who visited our rhinology clinics between February 2016 and February 2017 was conducted. CRS symptom severity was measured using the 22-item Sinonasal Outcomes Test (SNOT-22) questionnaire, which all patients received. Association was sought between SNOT-22 score (as dependent variable) and patients' clinical and demographic characteristics using linear regression. RESULTS: Of the 572 included patients, the mean age was 51.1 years (SD = 15.8) and the mean SNOT-22 score was 34.3 (SD = 22.6). Prevalence of granulomatous diseases, immunodeficiency and cystic fibrosis were each approximately 5%. Prevalence of aeroallergen hypersensitivity was 42.3% and prevalence of asthma was 27.8%. More severe CRS symptomatology was associated with smoking tobacco (adjusted beta = 5.47, p = 0.034) and comorbid asthma (adjusted beta = 12.02, p < 0.001), whilst less severe symptomatology was associated with older age (adjusted beta = -0.23, p = 0.002) and diagnosis of cystic fibrosis (adjusted beta = -11.87, p = 0.009). CONCLUSIONS: In a contemporary cohort of CRS patients, prevalence of disease modifying comorbidities ranged from approximately 5 to over 40%. Smoking tobacco and asthma were associated with more severe CRS symptomatology, whilst older age and diagnosis of cystic fibrosis were associated with less severe CRS symptomatology. PMID- 28560516 TI - Clinical scores for outcomes of rhythm control or arrhythmia progression in patients with atrial fibrillation: a systematic review. AB - Patients with atrial fibrillation (AF) are commonly managed with rhythm control strategy, but the natural history of this common arrhythmia leads itself to progression from paroxysmal to persistent or permanent AF, and recurrences are evident despite rhythm control treatments using cardioversion or catheter ablation. Numerous clinical factors have been associated with outcomes of rhythm control or arrhythmia progression in patients with AF. The more common factors have been used to formulate risk stratification scores, to help predict the outcomes of rhythm control treatments or AF progression. This review article provides an overview on the published clinical risk scores related to outcomes of rhythm control strategy or AF progression. PMID- 28560518 TI - miR-210 expression in PBMCs from patients with systemic lupus erythematosus and rheumatoid arthritis. AB - BACKGROUND: In hypoxic conditions, miRNA-210 plays an important role in regulating the expression of hypoxia-inducing factor-1alpha (HIF-1alpha) and the differentiation of T helper 17 (Th17) cells, and this may be involved in the development and function of the immune system. AIMS: This study was to investigate the miR-210 expression levels in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and its association with the clinical and laboratory features of both diseases. METHODS: Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to detect miR-210 expression levels in PBMCs from 35 patients with SLE, 38 patients with RA, and 35 healthy controls. RESULTS: Compared with the healthy controls, the miR-210 expression levels were significantly increased in patients with SLE (P = 0.001) and there was increased significantly expression of miR-210 in SLE with pleuritis (Z = -2.345, P = 0.019) and anti-SSB/La-positive group (Z = -2.076, P = 0.038). However, we have not found the significant correlation between the miR-210 levels and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (r s = 0.091, P = 0.602). Although, no significant difference between miR-210 levels in RA patients and those in healthy controls was found (Z = -1.226, P = 0. 220). There was a significant decreased expression of miR-210 in active RA patients than inactive RA patients (Z = -4.011, P < 0.001). CONCLUSIONS: The dysregulation of miR-210 levels in SLE and RA patients suggests that miR-210 might play an important role in the pathogenesis of these diseases. PMID- 28560519 TI - Molecular hydrogen affects body composition, metabolic profiles, and mitochondrial function in middle-aged overweight women. AB - BACKGROUND: Molecular hydrogen (H2) effectively treats obesity-related disorders in animal models, yet no studies have investigated the effectiveness and safety of H2 for improving biomarkers of obesity in humans. AIM: In this double blind, placebo-controlled, crossover pilot trial, we evaluated the effects of H2 intervention on body composition, hormonal status, and mitochondrial function in ten (n = 10) middle-aged overweight women. METHODS: Volunteers received either hydrogen-generating minerals (supplying ~6 ppm of H2 per day) or placebo by oral administration of caplets for 4 weeks. The primary end-point of treatment efficacy was the change in the body fat percentage from baseline to 4 weeks. In addition, assessment of other body composition indices, screening laboratory studies, and evaluation of side effects were performed before and at follow-up. Clinical trial registration www.clinicaltrials.gov , ID number NCT02832219. RESULTS: No significant differences were observed between treatment groups for changes in weight, body mass index, and body circumferences at 4-week follow-up (P > 0.05). H2 treatment significantly reduced body fat percentage (3.2 vs. 0.9%, P = 0.05) and arm fat index (9.7 vs. 6.0%, P = 0.01) compared to placebo administration, respectively. This was accompanied by a significant drop in serum triglycerides after H2 intervention comparing to placebo (21.3 vs. 6.5%; P = 0.04), while other blood lipids remained stable during the study (P > 0.05). Fasting serum insulin levels dropped by 5.4% after H2 administration, while placebo intervention augmented insulin response by 29.3% (P = 0.01). CONCLUSIONS: It appears that orally administered H2 as a blend of hydrogen-generating minerals might be a beneficial agent in the management of body composition and insulin resistance in obesity. PMID- 28560520 TI - What is the evidence for the performance of generic preference-based measures? A systematic overview of reviews. AB - OBJECTIVE: To assess the evidence on the validity and responsiveness of five commonly used preference-based instruments, the EQ-5D, SF-6D, HUI3, 15D and AQoL, by undertaking a review of reviews. METHODS: Four databases were investigated using a strategy refined through a highly sensitive filter for systematic reviews. References were screened and a search for grey literature was performed. Identified citations were scrutinized against pre-defined eligibility criteria and data were extracted using a customized extraction template. Evidence on known group validity, convergent validity and responsiveness was extracted and reviewed by narrative synthesis. Quality of the included reviews was assessed using a modified version of the AMSTAR checklist. RESULTS: Thirty reviews were included, sixteen of which were of excellent or good quality. The body of evidence, covering more than 180 studies, was heavily skewed towards EQ-5D, with significantly fewer studies investigating HUI3 and SF-6D, and very few the 15D and AQoL. There was also lack of head-to-head comparisons between GPBMs and the tests reported by the reviews were often weak. Where there was evidence, EQ-5D, SF-6D, HUI3, 15D and AQoL seemed generally valid and responsive instruments, although not for all conditions. Evidence was not consistently reported across reviews. CONCLUSIONS: Although generally valid, EQ-5D, SF-6D and HUI3 suffer from some problems and perform inconsistently in some populations. The lack of head-to head comparisons and the poor reporting impedes the comparative assessment of the performance of GPBMs. This highlights the need for large comparative studies designed to test instruments' performance. PMID- 28560521 TI - Primary care supply and quality of care in England. AB - We investigated the relationship between primary care supply and quality of care in England. We analysed 35 process measures of quality of care covering 13 medical conditions using English Longitudinal Study of Aging data linked to area of residence indicators. Greater GP density had a statistically significant and positive association with quality of care, and distance to GP practice had a statistically significant and negative association. The effects were concentrated in indicators of care related to cardiovascular diseases and arthritis, and on specific indicators for diabetes, incontinence and hearing problems. The results suggest that better primary care supply can improve quality of care. PMID- 28560522 TI - 2-Hydroxy-4-methoxy benzoic acid attenuates the carbon tetra chloride-induced hepatotoxicity and its lipid abnormalities in rats via anti-inflammatory and antioxidant mechanism. AB - BACKGROUND AND AIM: Liver inflammation stimulates various inflammatory cytokines and initiates injury through oxidative stress. The aim of this study was to curtaile the liver injury through natural principles such as 2-hydroxy-4-methoxy benzoic acid (HMBA). METHODS: The current study examines the hepatoprotective and lipid lowering effect of HMBA against carbon tetra chloride (CCl4)-mediated liver toxicity in male Wistar rats. RESULTS: The hepatoprotective effects of HMBA against CCl4-induced liver damage, were evident from low serum transaminases activities, reduced hepatic lipid peroxidation and collagen content, restoration of total glutathione, and recouping of the inflammatory cytokines, such as TNF alpha, IL-1beta, IL-10, and IL-6 levels. Further it was found that the treatment of HMBA, significantly lowered (P<0.01) the levels of total cholesterol, triglycerides, free fatty acids and phospholipids in serum and liver. To investigate the mechanism behind the hepatoprotective and lipid lowering effect, the activities of heme oxygenase (HO1), and myeloperoxidase (MPO) were measured and expression levels were quantified through western blot following HMBA administration. The results showed that HMBA administration significantly decreased the activity of HO1 (P<0.001), and increased the activity of MPO (P<0.001); further similar finding was observed in western analysis. The hepatoprotective, lipid lowering and shifting key defensive enzyme activities are similar to that of standard drug such as N-acetylcysteine. CONCLUSION: HMBA is competent of shielding liver from CCl4-induced hepatotoxicity, and this is associated with the lipid lowering, inflammatory cytokine restoration and induction of defensive enzyme activities. PMID- 28560523 TI - Five-Year Outcomes: Laparoscopic Greater Curvature Plication for Treatment of Morbid Obesity. AB - BACKGROUND: Laparoscopic greater curvature plication (LGCP) is a newer metabolic/bariatric surgical procedure that requires no resection, bypass, or implantable device. We report outcomes in a cohort of LGCP patients at 5-year follow-up. METHODS: Body mass index (BMI, kg/m2) evolution, excess weight loss (%EWL), excess BMI loss (%EBMIL), and total weight loss (%TWL) were recorded. Repeated measures analysis of variance (ANOVA) was used to assess BMI change over 5 years. Two-step cluster analysis was used to profile LGCP patients according to significant characteristics relative to successful 5-year weight loss. RESULTS: Of patients entering the study between 2010 and 2011 with complete weight data through 5-year follow-up (86.9%, 212/244), mean age was 45.8 +/- 10.9 years; mean baseline BMI, 41.4 +/- 5.5 (81.6% women); 58 patients (27.4%) had type 2 diabetes. Mean operative time was 69.0 min; mean hospitalization, 38 h (24-72). ANOVA indicated a significant BMI reduction out to 2 years (p < 0.001), a plateau at 3 and 4 years, and a moderate but significant BMI increase at 5 years (p < 0.01). EBMIL at 1, 2, 3, 4, and 5 years was as follows: 50.7 +/- 9.1%, 61.5 +/- 8.1%, 60.2 +/- 7.0%, 58.5 +/- 7.0%, and 56.8 +/- 6.3%. At 5 years, 79.2% (168/212) of patients were successful; 20.8% (44/212) experienced a suboptimal weight outcome; mean weight regain, 9.2%. Cluster analysis identified four distinct LGCP patient profiles. Diabetes improvement rate was 65.5%. There were 12 reoperations (4.9%): 4 emergency (1.6%) and 8 (3.3%) elective. There was no mortality. CONCLUSIONS: At 5-year follow-up, LGCP proved to be safe and effective, with 56.8% EBMIL and a low rate of complications. PMID- 28560525 TI - How Do I Do a Laparoscopic One-Anastomosis Gastric Bypass in a Patient with Situs Inversus Totalis. PMID- 28560524 TI - Pharmacokinetics in Morbid Obesity: Influence of Two Bariatric Surgery Techniques on Paracetamol and Caffeine Metabolism. AB - PURPOSE: The purpose of the study was to study the impact of the two most common bariatric surgery techniques on paracetamol pharmacokinetics (a marker of gastric emptying) and caffeine metabolism (a marker of liver function). MATERIALS AND METHODS: In the present prospective study, we studied 24 morbid obese patients before, at 4 weeks, and 6 months after having undergone sleeve gastrectomy (n = 10) or Roux-en-Y gastric bypass (n = 14). For comparative purposes, 28 healthy controls (14 normal weights and 14 overweights) were also included in the study. RESULTS: Paracetamol pharmacokinetics was altered in the obese participants leading to lower bioavailability. Bariatric surgery resulted in faster absorption and normalized pharmacokinetic parameters, prompting an increase in paracetamol bioavailability. No differences were found between surgical procedures. In the case of caffeine, the ratio paraxanthine/caffeine did not differ between morbid obese and healthy individuals. This ratio remained unmodified after surgery, indicating that the liver function (assessed by cytochrome P450 1A2 activity) was unaffected by obesity or bariatric surgery. CONCLUSIONS: Paracetamol pharmacokinetics and caffeine plasma levels are altered in severely obese patients. The two studied bariatric surgical techniques normalize paracetamol oral bioavailability without impairing the liver function (measured by cytochrome P450 1A2 activity). PMID- 28560526 TI - Resident Training in Bariatric Surgery-A National Survey in the Netherlands. AB - PURPOSE: Surgical procedures for morbid obesity, including laparoscopic Roux-en-Y gastric bypass (LRYGB), are considered standardized laparoscopic procedures. Our goal was to determine how bariatric surgery is trained in the Netherlands. MATERIALS AND METHODS: Questionnaires were sent to lead surgeons from all 19 bariatric centers in the Netherlands. At least two residents or fellows were surveyed for each center. Dutch residents are required to collect at least 20 electronic Objective Standard Assessment of Technical Skills (OSATS) observations per year, which include the level of supervision needed for specific procedures. Centers without resident accreditation were excluded. RESULTS: All 19 surgeons responded (100%). Answers from respondents who worked at teaching hospitals with residency accreditation (12/19, 63%) were analyzed. The average number of trained residents or fellows was 14 (range 3-33). Preferred procedures were LRYGB (n = 10), laparoscopic gastric sleeve (LGS) resection (n = 1), or no preference (n = 1). Three groups could be discerned for the order in which procedural steps were trained: unstructured, in order of increasing difficulty, or in order of chronology. Questionnaire response was 79% (19/24) for residents and 73% (8/11) for fellows. On average, residents started training in bariatric surgery in postgraduate year (PGY) 4 (range 0-5). The median number of bariatric procedures performed was 40 for residents (range 0-148) and 220 during fellowships (range 5 306). CONCLUSIONS: Training in bariatric surgery differs considerably among centers. A structured program incorporating background knowledge, step-wise technical skills training, and life-long learning should enhance efficient training in bariatric teaching centers without affecting quality or patient safety. PMID- 28560528 TI - Success of Percutaneous Endoscopic Gastrostomy by Single Balloon Enteroscopy in Patients Who Have Undergone Roux-en-Y Gastric Bypass. AB - Data is limited regarding the success and safety of percutaneous endoscopic gastrostomy (PEG) placements by single balloon enteroscopy (SBE) in patients with Roux-en-Y gastric bypass (RNY-GB) anatomy. We report on 23 cases of PEG placements by SBE with overall technical success of reaching the excluded stomach 70% and with PEG placement success rate of 69%. No intra-procedural adverse events occurred. This technique seems safe when feasible for PEG placement in patients with RNY-GB anatomy. PMID- 28560527 TI - Outcomes of Partnered Individuals Undergoing Bariatric Surgery Together: A Single Institution Case Series. AB - There exists marked variation in weight loss among the 200,000 annual bariatric patients, and many of these patients struggle with weight regain. Several studies have suggested that positive social support may significantly impact bariatric surgery outcomes, leading to more excess weight loss and maintenance of this weight loss through appropriate lifestyle changes. We sought to understand this by assessing clinical and behavioral outcomes among married couples whereby both spouses underwent bariatric surgery at our institution. In our case series, we found evidence that married couples meet or exceed postoperative weight loss milestones at 12, 18, and 24 months and did not show signs of weight regain as a group at 18 or 24 months. Among partners who underwent the same clinical pathway at our single institution, women tended to lose more weight than men at 12 months. Additionally, while there was significant variation in postoperative follow-up among patients, we found that partners within couples typically exhibited the same behavior with respect to postoperative visits when they had their surgeries within a year of each other. This case series suggests that partnered patients undergoing bariatric surgery can meet or exceed weight loss outcomes and may practice similar follow-up adherence. PMID- 28560529 TI - Desire for Core Tastes Decreases After Sleeve Gastrectomy: a Single-Center Longitudinal Observational Study with 6-Month Follow-up. AB - INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) modifies gastrointestinal substances that control hunger and satiation via the brain-gut axis. A potential mechanism implicated in weight loss is the shift in food preferences. Our aim was to assess changes in taste preferences and their relationship to weight loss. METHODS: This is a prospective longitudinal observational study in 100 consecutive LSG patients. Questionnaire with photographs of tastes was administered before surgery, at postoperative (PO) day 6 and PO month 6. Participants asked to rate each item in terms of desire to consume on a 5-point Likert scale. RESULTS: Preoperative demographics are as follows: 77 women/23 men, mean age 40.8 +/- 12 years, and mean BMI 42.46 +/- 6.7 kg/m2. Mean 6-month PO % total body weight loss (%TBWL): 24 +/- 6.2%. Preferences for bitter, salty, umami, fatty, sour, spicy, and sweet decreased significantly from baseline to PO day 6 (p < 0.001) and to PO month 6 (p < 0.002). Preferences of water (4.22) did not change significantly; red wine (1.8) and cigarettes (1.86) decreased significantly at PO day-6, but returned to baseline range at PO month 6. The highest changes of preferences in 6 months were observed for fatty (delta = 1.58) and sweet (delta = 0.95), (p < 0.002). Preference for salty at 6 months negatively correlated with %TBWL (p = 0.01). CONCLUSION: LSG seems to be associated with a rapid and sustained decrease in preferences for all core tastes, detectable already at PO day 6. Preferences for sweet and fatty food undergo the highest decline, whereas preferences of water, red wine, and cigarette remain unchanged. The decrease in salty preference seems to correlate with 6-month %TBWL. Further studies are needed on the long-term impact of taste changes after LSG. PMID- 28560530 TI - Reliability and Validity of the Musculoskeletal Tumor Society Scoring System for the Upper Extremity in Japanese Patients. AB - BACKGROUND: The Musculoskeletal Tumor Society (MSTS) scoring system developed in 1993 is a widely used disease-specific evaluation tool for assessment of physical function in patients with musculoskeletal tumors; however, only a few studies have confirmed its reliability and validity. QUESTIONS/PURPOSES: The aim of this study was to validate the MSTS scoring system for the upper extremity (MSTS-UE) in Japanese patients with musculoskeletal tumors for use by others in research. Does the MSTS-UE have: (1) sufficient reliability and internal consistency; (2) adequate construct validity; and (3) reasonable criterion validity in comparison to the Toronto Extremity Salvage Score (TESS) or SF-36? METHODS: Reliability was performed using test-retest analysis, and internal consistency was evaluated with Cronbach's alpha coefficient. Construct validity was evaluated using a scree plot to confirm the construct number and the Akaike information criterion network. Criterion validity was evaluated by comparing the MSTS-UE with the TESS and SF 36. RESULTS: The test-retest reliability with intraclass correlation coefficient (0.95; 95% CI, 0.91-0.97) was excellent, and internal consistency with Cronbach's alpha (0.7; 95% CI, 0.53-0.81) was acceptable. There were no ceiling and floor effects. The Akaike Information Criterion network showed that lifting ability, pain, and dexterity played central roles among the components. The MSTS-UE showed substantial correlation with the TESS scoring scale (r = 0.75; p < 0.001) and fair correlation with the SF-36 physical component summary (r = 0.37; p = 0.007). Although the MSTS-UE showed slight correlation with the SF-36 mental component summary, the emotional acceptance component of the MSTS-UE showed fair correlation (r = 0.29; p = 0.039). CONCLUSIONS: We can conclude that the MSTS is not an adequate measure of general health-related quality of life; however, this system was designed mainly to be a simple measure of function in a single extremity. To evaluate the mental state of patients with musculoskeletal tumors in the upper extremity, further study is needed. PMID- 28560531 TI - Not the Last Word: Rethinking the Resident Research Requirement. PMID- 28560534 TI - Exercise Testing and Stress Imaging in Aortic Valve Disease. AB - OPINION STATEMENT: Aortic valve disease and especially aortic stenosis (AS) is a growing cardiac pathology. Aortic valve replacement (AVR) is still the only treatment with proven benefit on survival in symptomatic patients and in patients with a left ventricular ejection fraction (LVEF) <50%. The benefit of prophylactic AVR in asymptomatic patients is still unproven. Once symptoms develop, the prognosis worsens. Exercise testing has emerged as a tool to unmask the "pseudo-asymptomatic" patients with AS (those without self-reporting symptoms), to link "exercise induced dyspnea" more confidently and more objectively to aortic valve disease and to allow for a safe "watchful waiting strategy" in "pseudo-symptomatic" patients (those with dyspnea unrelated to aortic valve disease). In cases in which exercise testing is unable to link dyspnea to aortic valve disease, exercise stress echocardiography and cardiopulmonary exercise testing may be helpful. Whatever the results of exercise testing with regard to symptom development, an increase in mean aortic valve pressure gradient >18-20 mmHg was associated with an increased risk of cardiac related events in severe AS patients (class IIb indication for AVR in the ESC guidelines). The decrease in LVEF during exercise as well as the development of exercise induced pulmonary hypertension, as revealed by exercise stress echocardiography, may be also useful in the risk stratification of these asymptomatic patients with severe AS. Data on the role of exercise echocardiography in asymptomatic severe aortic regurgitation patients is still scarce and further studies are needed. It seems that an exercise induced decrease in LVEF by 5% may be a better predictor of LV systolic dysfunction after AVR in asymptomatic patients or in patients with minimal symptoms. Exercise testing and exercise echocardiography are safe in the asymptomatic patients with aortic disease, provide useful clinical information that may help in risk assessment of these complicated patients and their use should be encouraged especially in heart valve clinics. PMID- 28560532 TI - Can A Multivariate Model for Survival Estimation in Skeletal Metastases (PATHFx) Be Externally Validated Using Japanese Patients? AB - BACKGROUND: Objective survival estimates are important when treating or studying outcomes in patients with skeletal metastases. One decision-support tool, PATHFx (www.pathfx.org) is designed to predict each patient's postsurgical survival trajectory at 1, 3, 6, and 12 months in patients undergoing stabilization for skeletal metastases. PATHFx has been externally validated in various western centers, but it is unknown whether it may be useful in Asian patient populations. QUESTIONS/PURPOSES: We asked (1) whether the PATHFx models are as predictive in Japanese patients by estimating the area under the receiver operator characteristic curve (AUC); we considered an AUC greater than 0.7 as an adequate predictive value. We also (2) performed decision curve analysis at various times to determine whether and how PATHFx should be used clinically at those times. PATIENTS AND METHODS: A Bayesian model is a statistical method to explore conditional, probabilistic relationships between variables to estimate the likelihood of an outcome using observed data. We applied the PATHFx Bayesian models to an independent dataset containing the records of patients who underwent skeletal stabilization for metastatic bone disease at one of five Japanese referral centers and had a followup longer than 12 months for survivors. Of 270 patients in the database, we excluded nine patients from analysis because their followup was less than 12 months, and finally we included 261 patients in the analysis. Data examined included age at the time of surgery, sex, indication for surgery (impending fracture or completed pathologic fracture), number of bone metastases (solitary or multiple), presence or absence of visceral or lymph node metastases, preoperative hemoglobin concentration, absolute lymphocyte count, and the primary oncologic diagnosis. We performed receiver operating characteristic curve analysis and estimated the AUC as a measure of discriminatory ability. Decision curve analysis was performed to determine if and how the models should be used in the clinical setting. RESULTS: The AUCs for the 1-, 3-, 6-, and 12 month models were 0.77 (95% CI, 0.63-0.86), 0.80 (95% CI, 0.72-0.87), 0.83 (95% CI, 0.77-0.89), and 0.80 (95% CI, 0.75-0.86), respectively. Decision analysis indicated that the models conferred a positive net benefit (above the lines assuming none or all survive at each time) although the CIs of the AUC for 1 month were wide, suggesting that this dataset could not adequately predict 1 month survival. CONCLUSIONS: Our findings show PATHFx is suitable for clinical use in Japan and may be used to guide surgical decision making or as a risk stratification method in support of clinical trials involving Japanese patients at 3, 6, and 12 months. More studies will be necessary to confirm the validity of the 1-month survival predictions of this mode. Other patient populations will need to be studied to confirm its usefulness in other non-Western and non Japanese populations. LEVEL OF EVIDENCE: Level II, prognostic study. PMID- 28560533 TI - Sociomotor action control. AB - Our actions affect the behavior of other people in predictable ways. In the present article, we describe a theoretical framework for action control in social contexts that we call sociomotor action control. This framework addresses how human agents plan and initiate movements that trigger responses from other people, and we propose that humans represent and control such actions literally in terms of the body movements they consistently evoke from observers. We review evidence for this approach and discuss commonalities and differences to related fields such as joint action, intention understanding, imitation, and interpersonal power. The sociomotor framework highlights a range of open questions pertaining to how representations of other persons' actions are linked to one's own motor activity, how specifically they contribute to action initiation, and how they affect the way we perceive the actions of others. PMID- 28560535 TI - The hidden epidemic of schistosomiasis in recent African immigrants and asylum seekers to Italy. AB - The prevalence of schistosomiasis among recent refugees from sub-Saharan Africa in Italy is unknown. This is a retrospective review of African immigrants screened at Centre for Tropical Diseases of Negrar from March 2014 to February 2016. Of the 373 immigrants tested, 34% were positive at least at one schistosomiasis test. The proportion of positive ELISA serology was 103/373 (27.6%). At microscopy, infected subjects were 65/373 (17.4%), (51% Schistosoma haematobium, 38% Schistosoma mansoni, 11% both). CCA antigen for S. mansoni was positive in 47/373 individuals (12.6%). We found a particularly high positivity rate in subjects from Mali (72.1%) and Ivory Coast (48%). This "hidden epidemic" of schistosomiasis cannot be longer neglected, considering the risk of severe complications, and the effective and inexpensive treatment available. PMID- 28560536 TI - Prostate cancer incidence as an iceberg. PMID- 28560537 TI - Association between childhood adversity and a diagnosis of personality disorder in young adulthood: a cohort study of 107,287 individuals in Stockholm County. AB - Childhood adversity (CA) may increase the risk for later developing of personality disorder (PD). However, less is known about the association between cumulative CA and PD, and the role of childhood psychopathology and school performance. The current study examined the relationship between a range of CAs and a diagnosis of PD in young adulthood, and the roles of childhood psychopathology and school performance in this relationship. All individuals born in Stockholm County 1987-1991 (n = 107,287) constituted our cohort. Seven CAs were measured between birth and age 14: familial death, parental criminality, parental substance abuse and psychiatric morbidity, parental separation and/or single-parent household, household public assistance and residential instability. Individuals were followed from their 18th birthday until they were diagnosed with PD or until end of follow-up (December 31st 2011). Adjusted estimates of risk of PD were calculated as hazard ratios (HR) with 95% confidence intervals (CI). Associations were observed between cumulative CA and PD. During the follow-up 770 individuals (0.7%) were diagnosed with PD. Individuals exposed to 3+ CAs had the highest risks of being diagnosed with PD (HR 3.0, 95% CI 2.4-3.7). Childhood psychopathology and low school grades further increased the risk of PD among individuals exposed to CA. Cumulative CA is strongly associated with a diagnosis of PD in young adulthood. Our findings indicate that special attention should be given in schools and health services to children exposed to adversities to prevent decline in school performance, and to detect vulnerable individuals that may be on negative life-course trajectories. PMID- 28560538 TI - Coenzyme Q10 and niacin mitigate streptozotocin- induced diabetic encephalopathy in a rat model. AB - Diabetic encephalopathy is an important complication of diabetes characterized by cognitive impairment, neurochemical and structural abnormalities. This study aimed to investigate the effect of coenzyme Q10 (CoQ10) and niacin as well as their combination in the treatment of encephalopathy associated with streptozotocin (STZ)- induced diabetes in rats. Glibenclamide (reference diabetic drug) and donepezil hydrochloride (acetylcholinesterase inhibitor) were also evaluated. Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg). One month after STZ injection, diabetic rats were treated with the aforementioned drugs for two weeks. The evaluation was done through measuring glucose level, total antioxidant capacity (TAC), interleukin 6 (IL6), DNA degradation as well as serotonin and noradrenaline as neurotransmitters. The present data illustrated that combining CoQ10 and niacin exhibiting the most potent effect in improving the measured parameters and ameliorating some of diabetes complications. PMID- 28560539 TI - Symptoms of central sensitization and comorbidity for juvenile fibromyalgia in childhood migraine: an observational study in a tertiary headache center. AB - BACKGROUND: Central sensitization is an important epiphenomenon of the adult migraine, clinically expressed by allodynia, pericranial tenderness and comorbidity for fibromyalgia in a relevant number of patients. This study aimed to evaluate the frequency and the clinical characteristics of allodynia, pericranial tenderness, and comorbidity for Juvenile Fibromialgia (JFM) in a cohort of migraine children selected in a tertiary headache center. METHODS: This was an observational cross-sectional study on 8-15 years old migraine patients. Allodynia was assessed by a questionnaire. Pericranial tenderness and comorbidity for JFM as well as their possible association with poor quality of life and migraine related disability, and with other clinical symptoms as anxiety, depression, sleep disorders and pain catastrophizing, were also evaluated. RESULTS: One hundred and fifty one patients were selected, including chronic migraine (n degrees 47), migraine without aura (n degrees 92) and migraine with aura (n degrees 12) sufferers. Allodynia was reported in the 96,6% and pericranial tenderness was observed in the 68.8% of patients. Pericranial tenderness was more severe in patients with more frequent migraine and shorter sleep duration. Allodynia seemed associated with anxiety, pain catastrophizing and high disability scores. Comorbidity for JFM was present in the 0.03% ofpatients. These children presented with a severe depression and a significant reduction of quality of life as compared to the other patients. CONCLUSIONS: This study outlined a relevant presence of symptoms of central sensitization among children with migraine. Severe allodynia and comorbidity for JFM seemed to cause a general decline of quality of life, which would suggest the opportunity of a routine assessment of these clinical features. PMID- 28560540 TI - Post-traumatic headache: the use of the sport concussion assessment tool (SCAT-3) as a predictor of post-concussion recovery. AB - BACKGROUND: Given that post-traumatic headache is one of the most prevalent and long-lasting post-concussion sequelae, causes significant morbidity, and might be associated with slower neurocognitive recovery, we sought to evaluate the use of concussion screening scores in a concussion clinic population to assess for post traumatic headache. METHODS: This is a retrospective cross-sectional study of 254 concussion patients from the New York University (NYU) Concussion Registry. Data on the headache characteristics, concussion mechanism, concussion screening scores were collected and analyzed. RESULTS: 72% of the patients had post traumatic headache. About half (56.3%) were women. The mean age was 35 (SD 16.2). 90 (35%) patients suffered from sport-related concussions (SRC). Daily post traumatic headache patients had higher Sport Concussion Assessment Tool (SCAT)-3 symptom severity scores than the non-daily post-traumatic headache and the headache-free patients (50.2 [SD 28.2] vs. 33.1 [SD 27.5] vs. 21.6 SD23], p < 0.001). Patients with SRC had lower headache intensity (4.47 [SD 2.5] vs. 6.24 [SD 2.28], p < 0.001) and SCAT symptom severity scores (33.9 [SD 27.4] vs. 51.4 [SD 27.7], p < 0.001) than the other patients, but there were no differences in post-traumatic headache prevalence, frequency, and Standardized Assessment of Concussion (SAC) scores. CONCLUSION: The presence and frequency of post-traumatic headache are associated with the SCAT-3 symptom severity score, which is the most important predictor for post-concussion recovery. The SCAT-3 symptom severity score might be a useful tool to help characterize patients' post-traumatic headache. PMID- 28560541 TI - Differential inhibitory response to telcagepant on alphaCGRP induced vasorelaxation and intracellular Ca2+ levels in the perfused and non-perfused isolated rat middle cerebral artery. AB - BACKGROUND: Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators identified to date. The present study elucidates the differential interaction of CGRP, its receptor and the effect of the CGRP receptor antagonist telcagepant on intracellular Ca2+ -levels and tension in rat middle cerebral arteries (MCA) by pressurized arteriography, FURA-2/wire myography and immunohistochemistry. METHODS: A pressurized arteriograph system was used to evaluate changes in MCA tension when subjected to CGRP and/or telcagepant. Intracellular calcium levels were evaluated using a FURA-2/wire myograph system. Localization of the CGRP-receptor components was verified using immunohistochemistry. RESULTS: Abluminal but not luminal alphaCGRP (10-12-10-6 M) caused concentration-dependent vasorelaxation in rat MCA. Luminal telcagepant (10 6 M) failed to inhibit this relaxation, while abluminal telcagepant inhibited the relaxation (10-6 M). Using the FURA-2 method in combination with wire myography we observed that alphaCGRP reduced intracellular calcium levels and in parallel the vascular tone. Telcagepant (10-6 M) inhibited both vasorelaxation and drop in intracellular calcium levels. Both functional components of the CGRP receptor, CLR (calcitonin receptor-like receptor) and RAMP1 (receptor activity modifying peptide 1) were found in the smooth muscle cells but not in the endothelial cells of the cerebral vasculature. CONCLUSIONS: This study thus demonstrates the relaxant effect of alphaCGRP on rat MCA. The vasorelaxation is associated with a simultaneous decrease in intracellular calcium levels. Telcagepant reduced relaxation and thwarted the reduction in intracellular calcium levels localized in the vascular smooth muscle cells. In addition, telcagepant may act as a non competitive antagonist at concentrations greater than 10-8 M. PMID- 28560542 TI - The role of attachment insecurity in the emergence of anxiety symptoms in children and adolescents with migraine: an empirical study. AB - BACKGROUND: It is widely recognised that there are associations between headache, psychiatric comorbidity and attachment insecurity in both adults and children. The aims of this study were: 1) to compare perceived attachment security and anxiety in children and adolescents with migraine without aura and a healthy control group; 2) to test whether the child's perceived security of attachment to the mother and the father mediated the association between migraine and anxiety. METHODS: One hundred children and adolescents with Migraine without Aura were compared with a control group of 100 children without headache. The Security Scale (measures perceived security of attachments) and the Self-Administered Psychiatric Scales for Children and Adolescents, a measure of anxiety symptoms, were administered to all participants. RESULTS: The clinical group had lower attachment security than the control group and higher scores on all anxiety scales. Anxiety was negatively correlated with attachment. Children's attachment to their mother mediated the increase in global anxiety in the clinical group. Insecure paternal attachment was associated with greater insecurity in maternal attachment, suggesting that there is a complex pathway from migraine to anxiety symptoms mediated by perceived insecurity of paternal attachment and hence also by perceived insecurity of maternal attachment. CONCLUSION: These results suggest that insecure parental attachment may exacerbate anxiety in children and adolescents with migraine and point to the importance of multimodal interventions, perhaps taking account of family relationships, for children and adolescents with migraine. PMID- 28560543 TI - Bone and soft tissue histology: a new approach to determine characteristics of offending instrument in sharp force injuries. AB - This paper describes a new approach to determine characteristics of the implement used to inflict trauma which involves the histological analysis of exogenous particles. Based on Locard's principle "every contact leaves a trace," we decided to assess whether histological examination of bone and soft tissue around a penetrating injury (sharp force trauma) could provide evidence of the offending implement. Case reports and experimental studies have demonstrated the potential of cut mark features in bone to identify the causative implement and potentially assist in identifying the perpetrator. Scanning electron microscopy in combination with energy-dispersive X-ray spectrometry (SEM/EDS) have previously been reported to identify exogenous particles from various implements. In medical research, histological techniques are used to study the impact of foreign particles in tissues originating from implants. However, the routine use of histology in forensic medicine focuses on understanding type and timing of injuries. Based on three forensic cases, the results presented in this paper demonstrate that histology offers a cost-efficient and reliable means to detect foreign particles related to offending implement and/or to the environment where the victim was located. The interpretation of histological results was performed in conjunction with the macroscopic autopsy findings and anthropological analysis of bone samples. PMID- 28560544 TI - Profile of osteoarthritic patients undergoing hip or knee arthroplasty, a step toward a definition of the "need for surgery". AB - AIMS: The objective of this study is to characterize, based on clinical, radiographic, health-related, quality-of-life-related, and demographic variables, the profile of a large, homogeneous, cohort of patients undergoing knee or hip arthroplasty, in a public hospital. Current regulatory guidelines for structure modifying agent are not clear regarding hard clinical endpoint. The "need for surgery" has been suggested as a potential relevant outcome, but, until now, it is poorly defined. By characterizing a large number of patients who undergo total hip or total knee replacement, this paper aims at providing a contribution to the better definition of the "need for surgery" in advanced OA of the lower limbs. METHODS: Consecutive patients who underwent primary knee arthroplasty (KA) or hip arthroplasty (HA) between December 2008 and February 2013, in an academic hospital, and who were diagnosed with hip or knee osteoarthritis (OA) (ACR criteria). Data collected at baseline included demographic and clinical data; Kellgren-Lawrence radiological grading; Western Ontario and Mc Master Universities Arthritis Index (WOMAC); EuroQol five dimensions questionnaire and EuroQol visual analog scale; and 36-item Short Form Health Survey. RESULTS: 626 subjects were included, 346 with hip OA and 280 with knee OA. Significant differences between subjects in need of an HA or of a KA were seen in terms of age (66.5 years versus 65 for hip), duration of complaints (2188 days versus 1146.5 for hip), BMI (28.68 kg/m2 versus 27.07), radiological status (severe OA were found in 79.85% in knee group and 68.73% in hip group), comorbidities (FCI higher in knee group), traumatic of surgical history (37 versus 6%), and health related quality of life and function (patients with HA had a poorer clinical status regarding WOMAC and WOMAC subscale). CONCLUSION: Significant differences were observed between patients undergoing KA or HA. These differences might be useful to better understand the "need for surgery" status in these indications. This concept may help to define responders and failures to pharmacological treatment of OA. PMID- 28560545 TI - Relationships among peak expiratory flow rate, body composition, physical function, and sarcopenia in community-dwelling older adults. AB - BACKGROUND AND AIM: Although respiratory muscle strength is known to decrease with age, the relationship between pulmonary function and sarcopenia remains to be examined. The present study aimed to determine the relationship between peak expiratory flow rate (PEFR) and skeletal muscle mass/sarcopenia in community dwelling older adults. METHODS: We utilized data from 427 older adults (age 74.4 +/- 5.3 years, men/women 157/270) who had participated in the 2015 Otassha Kenshin, a longitudinal study that excluded participants with air-flow limitations. Diagnoses of sarcopenia were based on criteria outlined in the Consensus Report of the Asian Working Group for Sarcopenia and adjusted for Japanese individuals. We compared body composition, physical function, and lung function between patients with and without sarcopenia. Receiver operating characteristic analysis (ROC) for sarcopenia was performed using PEFR, calf circumference, and body mass index. RESULTS: Sixty-five participants (men/women 12/53) were diagnosed with sarcopenia. Patients with sarcopenia were older than those without sarcopenia, and had lower height, weight, body mass index, skeletal muscle mass, appendicular skeletal mass, and skeletal muscle index. Stepwise multiple regression analysis identified whole-body skeletal mass as an independent factor for PEFR. ROC analysis of sarcopenia identified a cut-off value of 5.0 L s for PEFR, with a sensitivity of 0.62, specificity of 0.77, and area under the curve of 0.73 (95% CI 0.67-0.79; P < 0.001). DISCUSSION AND CONCLUSION: Our findings suggest that physical function is more strongly associated with respiratory muscle mass than total skeletal muscle mass and that PEFR may be a valid indicator of sarcopenia. PMID- 28560546 TI - Medial parapatellar approach leads to internal rotation of tibial component in total knee arthroplasty. AB - PURPOSE: The purpose of this study was to investigate if the type of approach [medial parapatellar approach (MPA) versus lateral parapatellar approach with tibial tubercle osteotomy (LPA)] influences rotation of femoral and/or tibial component and leg axis in total knee arthroplasty (TKA). It was the hypothesis that MPA leads to an internally rotated tibial TKA component. METHODS: This study included 200 consecutive patients in whom TKA was performed using either a parapatellar medial (n = 162, MPA) or parapatellar lateral approach with tibial tubercle osteotomy (n = 38, LPA). All patients underwent clinical follow-up, standardized radiographs and computed radiography (CT). TKA components' position and the whole leg axis were assessed on 3D reconstructed CT scans (sagittal, coronal and rotational). Mean values of TKA component position and the whole leg alignment of both groups were compared using a t test. The tibial component was graded as internally rotated (<3 degrees of external rotation (ER)), neutral rotation (equal or between 3 degrees and 6 degrees of ER) and externally rotated (>6 degrees ER). The femoral component was graded as internally rotated [>3 degrees of internal rotation (IR)], neutral rotation (equal or between -3 degrees IR and 3 degrees of ER) and externally rotated (>3 degrees ER). RESULTS: There was no significant difference in terms of whole leg axis after TKA between both groups (MPA: 0.2 degrees valgus +/- 3.4; LPA: 0.0 degrees valgus +/- 3.5). Means of tibial component rotation were 2.7 degrees ER +/- 6.1 (MPA) and 7.6 degrees ER +/- 5.4 (LPA). Patients of group LPA presented a significantly less internally rotated (LPA: 18.4%; MPA: 48.8%) and more externally rotated (LPA: 52.6%; MPA: 22.8%) tibial component (p < 0.001). No significant differences were seen for the femoral component position, tibial valgus/varus and tibial slope. CONCLUSION: The type of approach (medial versus lateral) significantly influenced tibial TKA component rotation. It appears that a MPA tends to internally rotate the tibial TKA component and a LPA tends to externally rotate the tibial TKA. The anterior cortex should not be used as landmark for tibial TKA component placement when using the lateral approach with tibial tubercle osteotomy. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 28560547 TI - Gender Differences in Resistance to Schooling: The Role of Dynamic Peer-Influence and Selection Processes. AB - Boys engage in notably higher levels of resistance to schooling than girls. While scholars argue that peer processes contribute to this gender gap, this claim has not been tested with longitudinal quantitative data. This study fills this lacuna by examining the role of dynamic peer-selection and influence processes in the gender gap in resistance to schooling (i.e., arguing with teachers, skipping class, not putting effort into school, receiving punishments at school, and coming late to class) with two-wave panel data. We expect that, compared to girls, boys are more exposed and more responsive to peers who exhibit resistant behavior. We estimate hybrid models on 5448 students from 251 school classes in Sweden (14-15 years, 49% boys), and stochastic actor-based models (SIENA) on a subsample of these data (2480 students in 98 classes; 49% boys). We find that boys are more exposed to resistant friends than girls, and that adolescents are influenced by the resistant behavior of friends. These peer processes do not contribute to a widening of the gender gap in resistance to schooling, yet they contribute somewhat to the persistence of the initial gender gap. Boys are not more responsive to the resistant behavior of friends than girls. Instead, girls are influenced more by the resistant behavior of lower status friends than boys. This explains to some extent why boys increase their resistance to schooling more over time. All in all, peer-influence and selection processes seem to play a minor role in gender differences in resistance to schooling. These findings nuance under investigated claims that have been made in the literature. PMID- 28560548 TI - Media use, sports activities, and motor fitness in childhood and adolescence. AB - BACKGROUND: Physical activity is one of the key determinants of physical, mental, and social health of children and adolescents. Therefore, the early development of health-relevant behavior patterns is of high relevance. AIM: To examine the impact of selected socioeconomic factors as well as media consumption, on sports activities and the motor skills of 10- to 14-year-old secondary school students. METHODS: Body height and body weight were measured. The motor skills were determined with the Deutschen Motorik Test (DMT 6-18; German Motor Test). Information about media use, media equipment, recreational sports activities, migration status, and the parents' profession was collected by means of a standardized questionnaire. RESULTS: A total of 391 adolescents have been tested (male 235; female 156). Body mass index (BMI) types are evenly distributed on gender. On a weekday, the pupils spend 10.3 h using media (SD +/- 9.1 h). On weekends, media use increases up to 12 h per day on average (SD +/- 9.7 h). The number of available media is independent from the age of the respondents and the social status of their families. According to bivariate correlations, heavy media use, a high BMI as well as migration status correlate negatively with both sports activities and motor skills. BMI seems to have the strongest influence on athletic performance (b = 0.41). CONCLUSION: Media use is an important determinant of juvenile sports activity and motor performance, being part of a complex juvenile leisure behavior. PMID- 28560549 TI - Cost Analysis of Prostate Artery Embolization (PAE) and Transurethral Resection of the Prostate (TURP) in the Treatment of Benign Prostatic Hyperplasia. AB - PURPOSE: Prostatic arterial embolization (PAE) has emerged as a minimally invasive alternative to TURP; however, there are limited cost comparisons reported. The purpose of this study was to compare in-hospital direct costs of elective PAE and TURP in a hospital setting. MATERIALS AND METHODS: Institutional Review Board-approved retrospective review was performed on patients undergoing PAE and TURP from January to December 2014. Inclusion criteria included male patients greater than 40 years of age who presented for ambulatory TURP or PAE with no history of prior surgical intervention for BPH. Direct costs were categorized into the following categories: nursing and operating room or interventional room staffing, operating room or interventional supply costs, anesthesia supplies, anesthesia staffing, hospital room cost, radiology, and laboratory costs. Additionally, length of stay was evaluated for both groups. RESULTS: The mean patient age for the TURP (n = 86) and PAE (n = 70) cohorts was 71.3 and 64.4 years, respectively (p < 0.0001). Intra-procedural supplies for PAE were significantly more costly than TURP ($1472.77 vs $1080.84, p < 0.0001). When including anesthesia supplies and nursing/staffing, costs were significantly more expensive for TURP than PAE ($2153.64 vs $1667.10 p < 0.0001). The average length of stay for the TURP group was longer at 1.38 versus 0.125 days for the PAE group. Total in-hospital costs for the TURP group ($5338.31, SD $3521.17) were significantly higher than for PAE ($1678.14, SD $442.0, p < 0.0001). CONCLUSIONS: When compared to TURP, PAE was associated with significantly lower direct in hospital costs and shorter hospital stay. PMID- 28560550 TI - Reply To: Safety and Efficacy of Y-90 Radioembolization After Prior Major Hepatic Resection: Dosimetric Consideration. PMID- 28560551 TI - Repetitive Blunt Trauma and Arterial Injury in the Hand. AB - INTRODUCTION/PURPOSE: Arterial injury in the hand is most often due to repetitive blunt trauma. Although not always associated with significant impairment, it may cause serious ischemic damage or considerable disability. As a cause of digital ischemia, the frequency of this disorder is widely under appreciated. This study reviews the clinical and angiographic features of this condition. MATERIALS/METHODS: An extensive literature review combined with the authors experience with arterial injury in the hand due to repetitive blunt hand trauma is summarized with emphasis on mechanisms of injury and pathologic changes to explain the angiographic findings and clinical presentations. RESULTS: Angiographic findings are related to severity of injury and underlying changes in the arterial wall. The clinical presentation varies from asymptomatic to digital necrosis and gangrene, related to severity of arterial injury, collateral circulation, and the highly variable arterial anatomy in the hand. CONCLUSION: Early recognition is important because compared to many other causes of digital ischemia in the upper extremities, traumatic arterial injury is frequently readily treatable. Angiographic findings and clinical presentation are often characteristic. The diagnosis should not be based on a clear history of repetitive hand trauma since the patient may be unaware of this occurrence. PMID- 28560552 TI - Children With and Without Dystonia Share Common Muscle Synergies While Performing Writing Tasks. AB - Childhood dystonia is a movement disorder characterized by muscle overflow and variability. This is the first study that investigates upper limb muscle synergies in childhood dystonia with the twofold aim of deepening the understanding of neuromotor dysfunctions and paving the way to possible synergy based myocontrol interfaces suitable for this neurological population. Nonnegative matrix factorization was applied to the activity of upper-limb muscles recorded during the execution of writing tasks in children with dystonia and age-matched controls. Despite children with dystonia presented compromised kinematics of the writing outcome, a strikingly similarity emerged in the number and structure of the synergy vectors extracted from children in the two groups. The analysis also revealed that the timing of activation of the synergy coefficients did not significantly differ, while the amplitude of the peaks presented a slight reduction. These results suggest that the synergy analysis has the ability of capturing the uncorrupted part of the electromyographic signal in dystonia. Such an ability supports a possible future use of muscle synergies in the design of myocontrol interfaces for children with dystonia. PMID- 28560553 TI - Quantification of Inter-Erythrocyte Forces with Ultra-High Frequency (410 MHz) Single Beam Acoustic Tweezer. AB - Efforts on quantitative measurements of the interactive forces of red blood cells (RBC) have been pursued for many years in hopes of a better understanding of hemodynamics and blood rheology. In this paper, we report an approach based on an ultra-high frequency (410 MHz) single beam acoustic tweezer (SBAT) for quantitative measurements of inter-RBC forces at a single cell level. The trapping forces produced by this ultra-high frequency (UHF) SBAT can be quantitatively estimated with a micropipette. Since the focal beam diameter of the 410 MHz ultrasonic transducer used in this SBAT was only 6.5 micrometer (MUm), which was smaller than that of a RBC (~7.5 MUm), it was made possible to directly apply the beam to a single RBC and measure inter-RBC forces against the pre-calibrated acoustic trapping forces as another example of potential cellular applications of the SBAT. The magnitude of these forces was found to be 391.0 +/- 86.4 pN. Finally, it is worth noting that unlike several other methods, this method does not require the measuring device to be in contact with the cells. PMID- 28560555 TI - Reply to the letter to the editor concerning "Endoscopic tympanoplasty: learning curve for a surgeon already trained in microscopic tympanoplasty". PMID- 28560554 TI - Continuous local analgesia is effective in postoperative pain treatment after medium and large incisional hernia repair. AB - INTRODUCTION: Incisional hernias are a frequent complication of laparotomy. Open surgery is still an option for the treatment of incisional hernias with medium and large wall defects. Major opioids are routinely used in the treatment of postoperative pain, with several side effects. Continuous local analgesia can be effective in postoperative pain management after various surgical interventions. However, very few reports exist on its application in incisional hernias. PURPOSE: We assessed the effectiveness of ropivacaine in reducing the need for systemic analgesics in postoperative pain management related to these interventions. METHODS: We conducted an open-label, prospective, randomized design study. One hundred patients with medium and large incisional hernias were treated by open surgery. Thirty patients with abdominal defects > 8 cm received continuous postoperative local analgesia with ropivacaine 5 mg/ml. Thirty four and 36 patients (abdominal defects of more, and respectively less than 8 cm) received conventional analgesia. RESULTS: Continuous local anesthesia during the first 72 h after surgery reduced the number of patients needing analgesia with pethidine (17 vs 47% and 53%, p = 0.006), as well as the cumulative doses of pethidine (p < 0.05), tramadol (p < 0.001), and metamizole (p < 0.001) needed to control postoperative pain. Catheter installation for local anesthesia did not increase surgery time (p = 0.16) or the rate of local complications. CONCLUSION: Continuous local analgesia reduces the need for systemic opioids and can be successfully used in the postoperative pain management after medium and large incisional hernias treated by open surgery. PMID- 28560556 TI - Shear Stress Induces Phenotypic Modulation of Vascular Smooth Muscle Cells via AMPK/mTOR/ULK1-Mediated Autophagy. AB - Phenotypic modulation of vascular smooth muscle cells (VSMCs) is involved in the pathophysiological processes of the intracranial aneurysms (IAs). Although shear stress has been implicated in the proliferation, migration, and phenotypic conversion of VSMCs, the molecular mechanisms underlying these events are currently unknown. In this study, we investigated whether shear stress(SS) induced VSMC phenotypic modulation was mediated by autophagy involved in adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) pathway. The results show that shear stress could inhibit the expression of key VSMC contractile genes and induce pro inflammatory/matrix-remodeling genes levels, contributing to VSMCs phenotypic switching from a contractile to a synthetic phenotype. More importantly, Shear stress also markedly increased the levels of the autophagy marker microtubule associated protein light chain 3-II (LC3II), Beclin-1, and p62 degradation. The autophagy inhibitor 3-methyladenine (3-MA) significantly blocked shear-induced phenotypic modulation of VSMCs. To further explore the molecular mechanism involved in shear-induced autophagy, we found that shear stress could activate AMPK/mTOR/ULK1 signaling pathway in VSMCs. Compound C, a pharmacological inhibitor of AMPK, significantly reduced the levels of p-AMPK and p-ULK, enhanced p-mTOR level, and finally decreased LC3II and Beclin-1 level, which suggested that activated AMPK/mTOR/ULK1 signaling was related to shear-mediated autophagy. These results indicate that shear stress promotes VSMC phenotypic modulation through the induction of autophagy involved in activating the AMPK/mTOR/ULK1 pathway. PMID- 28560558 TI - A quick glance at selected topics in this issue. AB - A quick glance at selected topics in this issue" aims to highlight selected articles and provide a quick review to the readers. PMID- 28560557 TI - Heterogeneity Among Neutrophils. AB - Neutrophils (PMNs) play a key role in innate defence mechanisms. Generally, PMNs were considered to have a homogeneous population of mature and diversified cells. It seems, however, that their pleiotropic action results from the existence of different subpopulations in this group of cells. There are data that confirm the involvement of PMNs in the direct activation of other cells in non-specific response, as well as specialised cells in specific response. For example, there have been observations of PMNs with different levels of activity in relation to lymphocytes, and a population was identified which had characteristics similar to those of cells which are capable of presenting antigens. There are also reports of PMNs which demonstrate different survival time or capacity for chemotaxis. Other studies suggest that the neutrophil response to Staphylococcus aureus is diverse (not identical among all neutrophil). There are also reports of PMNs with varying activity during inflammation, which might explain many as yet unknown pathophysiological aspects of their hyperreactivity. The functional dualism of PMNs in the course of neoplastic disorders raises a lot of controversy. This paper presents the current state of knowledge of the heterogeneity of PMNs and their potential roles in different stages of disease. PMID- 28560559 TI - Greatest opportunities for growth in nuclear cardiology. PMID- 28560560 TI - FDG PET/CT in prosthetic heart valve endocarditis: There is no need to wait. PMID- 28560561 TI - Investigation of Ion Transmission Effects on Intact Protein Quantification in a Triple Quadrupole Mass Spectrometer. AB - Recently, direct intact protein quantitation using triple quadrupole mass spectrometry (QqQ-MS) and multiple reaction monitoring (MRM) was demonstrated (J. Am. Soc. Mass Spectrom. 27, 886-896 (2016)). Even though QqQ-MS is known to provide extraordinary detection sensitivity for quantitative analysis, we found that intact proteins exhibited a less than 5% ion transmission from the first quadrupole to the third quadrupole mass analyzer in the presence of zero collision energy (ZCE). With the goal to enhance intact protein quantitation sensitivity, ion scattering effects, proton transfer effects, and mass filter resolution widths were examined for their contributions to the lost signal. Protein standards myoglobin and ubiquitin along with small molecules reserpine and vancomycin were analyzed together with various collision induced dissociation (CID) gases (N2, He, and Ar) at different gas pressures. Mass resolution settings played a significant role in reducing ion transmission signal. By narrowing the mass resolution window by 0.35 m/z on each side, roughly 75%-90% of the ion signal was lost. The multiply charged proteins experienced additional proton transfer effects, corresponding to 10-fold signal reduction. A study of increased sensitivity of the method was also conducted with various MRM summation techniques. Although the degree of enhancement was analyte-dependent, an up to 17 fold increase in sensitivity was observed for ubiquitin using a summation of multiple MRM transitions. Biological matrix, human urine, and equine plasma were spiked with proteins to demonstrate the specificity of the method. This study provides additional insight into optimizing the use and sensitivity of QqQ-MS for intact protein quantification. Graphical Abstract ?. PMID- 28560563 TI - Mobility Peak Tailing Reduction in a Differential Mobility Analyzer (DMA) Coupled with a Mass Spectrometer and Several Ionization Sources. AB - The differential mobility analyzer (DMA) is a narrow-band linear ion mobility filter operating at atmospheric pressure. It combines in series with a quadrupole mass spectrometer (Q-MS) for mobility/mass analysis, greatly reducing chemical noise in selected ion monitoring. However, the large flow rate of drift gas (~1000 L/min) required by DMAs complicates the achievement of high gas purity. Additionally, the symmetry of the drying counterflow gas at the interface of many commercial MS instruments, is degraded by the lateral motion of the drift gas at the DMA entrance slit. As a result, DMA mobility peaks often exhibit tails due to the attachment of impurity vapors, either (1) to the reagent ion within the separation cell, or (2) to the analyte of interest in the ionization region. In order to greatly increase the noise-suppression capacity of the DMA, we describe various vapor-removal schemes and measure the resulting increase in the tailing ratio, (TR = signal at the peak maximum over signal two half-widths away from this maximum). Here we develop a low-outgassing DMA circuit connected to a mass spectrometer, and test it with three ionization sources (APCI, Desolvating-nano ESI, and Desolvating low flow SESI). While prior TR values were in the range 100 1000, the three new sources achieve TR ~ 105. The SESI source has been optimized for maximum sensitivity, delivering an unprecedented gain for TNT of 190 counts/fg, equivalent to an ionization efficiency of one out of 140 neutral molecules. Graphical Abstract ?. PMID- 28560562 TI - Design of a TW-SLIM Module for Dual Polarity Confinement, Transport, and Reactions. AB - Here we describe instrumental approaches for performing dual polarity ion confinement, transport, ion mobility separations, and reactions in structures for lossless ion manipulations (SLIM). Previous means of ion confinement in SLIM, based upon rf-generated pseudopotentials and DC fields for lateral confinement, cannot trap ions of opposite polarity simultaneously. Here we explore alternative approaches to provide simultaneous lateral confinement of both ion polarities. Traveling wave ion mobility (IM) separations experienced in such SLIM cause ions of both polarities to migrate in the same directions and exhibit similar separations. The ion motion (and relative motion of the two polarities) under both surfing and IM separation conditions are discussed. In surfing conditions the two polarities are transported losslessly and non-reactively in their respective potential minima (higher absolute voltage regions confine negative polarities, and lower absolute potential regions are populated by positive polarities). In separation mode, where ions roll over an overtaking traveling wave, the two polarities can interact during the rollovers. Strategies to minimize overlap of the two ion populations to prevent reactive losses during separations are presented. A theoretical treatment of the time scales over which two populations (injected into a DC field-free region of the dual polarity SLIM device) interact is considered, and SLIM designs for allowing ion/ion interactions and other manipulations with dual polarities at 4 Torr are presented. Graphical Abstract ?. PMID- 28560565 TI - A Novel Triethylphosphonium Charge Tag on Peptides: Synthesis, Derivatization, and Fragmentation. AB - Charge tagging is a peptide derivatization process that commonly localizes a positive charge on the N-terminus. Upon low energy activation (e.g., collision induced dissociation or post-source decay) of charge tagged peptides, relatively few fragment ions are produced due to the absence of mobile protons. In contrast, high energy fragmentation, such as 157 nm photodissociation, typically leads to a series of a-type ions. Disadvantages of existing charge tags are that they can produce mobile protons or that they are undesirably large and bulky. Here, we investigate a small triethylphosphonium charge tag with two different linkages: amide (158 Da) and amidine bonds (157 Da). Activation of peptides labeled with a triethylphosphonium charge tag through an amide bond can lead to loss of the charge tag and the production of protonated peptides. This enables low intensity fragment ions from both the protonated and charge tagged peptides to be observed. Triethylphosphonium charge tagged peptides linked through an amidine bond are more stable. Post-source decay and photodissociation yield product ions that primarily contain the charge tag. Certain amidine induced fragments are also observed. The previously reported tris(trimethoxyphenyl) phosphonium acetic acid N-hydroxysuccinimidyl ester charge tag shows a similar fragment ion distribution, but the mass of the triethylphosphonium tag label is 415 Da smaller. Graphical Abstract ?. PMID- 28560564 TI - An Electrospray Ionization Mass Spectrometry Study on the "In Vacuo" Hetero Oligomers Formed by the Antimicrobial Peptides, Surfactin and Gramicidin S. AB - It was previously observed that the lipopeptide surfactants in surfactin (Srf) have an antagonistic action towards the highly potent antimicrobial cyclodecapeptide, gramicidin S (GS). This study reports on some of the molecular aspects of the antagonism as investigated through complementary electrospray ionization mass spectrometry techniques. We were able to detect stable 1:1 and 2:1 hetero-oligomers in a mixture of surfactin and gramicidin S. The noncovalent interaction between GS and Srf, with the proposed equilibrium: GS~Srf<->GS+Srf correlated to apparent K d values of 6-9 MUM in gas-phase and 1 MUM in aqueous solution. The apparent K d values decreased with a longer incubation time and indicated a slow oligomerization equilibrium. Furthermore, the low MUM K dapp values of GS~Srf<->GS+Srf fell within the biological concentration range and related to the 2- to 3-fold increase in [GS] needed for bacterial growth inhibition in the presence of Srf. Competition studies indicated that neither Na+ nor Ca2+ had a major effect on the stability of preformed heterodimers and that GS in fact out-competed Ca2+ and Na+ from Srf. Traveling wave ion mobility mass spectrometry revealed near symmetrical peaks of the heterodimers correlating to a compact dimer conformation that depend on specific interactions. Collision induced dissociation studies indicated that the peptide interaction is most probably between one Orn residue in GS and the Asp residue, but not the Glu residue in Srf. We propose that flanking hydrophobic residues in both peptides stabilize the antagonistic and inactive peptide hetero-oligomers and shield the specific polar interactions in an aqueous environment. Graphical Abstract ?. PMID- 28560566 TI - Excitation energy transfer in phycobiliproteins of the cyanobacterium Acaryochloris marina investigated by spectral hole burning. AB - The cyanobacterium Acaryochloris marina developed two types of antenna complexes, which contain chlorophyll-d (Chl d) and phycocyanobilin (PCB) as light-harvesting pigment molecules, respectively. The latter membrane-extrinsic complexes are denoted as phycobiliproteins (PBPs). Spectral hole burning was employed to study excitation energy transfer and electron-phonon coupling in PBPs. The data reveal a rich spectral substructure with a total of four low-energy electronic states whose absorption bands peak at 633, 644, 654, and at about 673 nm. The electronic states at ~633 and 644 nm can be tentatively attributed to phycocyanin (PC) and allophycocyanin (APC), respectively. The remaining low-energy electronic states including the terminal emitter at 673 nm may be associated with different isoforms of PC, APC, or the linker protein. Furthermore, the hole burning data reveal a large number of excited state vibrational frequencies, which are characteristic for the chromophore PCB. In summary, the results are in good agreement with the low-energy level structure of PBPs and electron-phonon coupling parameters reported by Gryliuk et al. (BBA 1837:1490-1499, 2014) based on difference fluorescence line-narrowing experiments. PMID- 28560568 TI - Outcome of carotid artery stenting in the hands of vascular surgeons. AB - OBJECTIVES: To analyze the procedural and clinical outcomes of carotid artery stenting (CAS) in the hands of endovascular trained vascular surgeons. METHODS: Between April 2008 to May 2013, 1197 patients were treated for extracranial internal carotid artery (ICA) stenosis. The proportion of endovascular treated patients was 5.0% (CAS n = 60 vs. carotid endarterectomy (CEA) n = 1137). All patients in the CAS group (44 males, median age 70 years) were treated by two senior vascular surgeons experienced in endovascular methods. Restenosis was the indication for CAS in 32 out of 60 patients (53.3%). Further indications were contralateral ICA occlusion (n = 14, 23.3%), radiogenic ICA stenosis (n = 5, 8.3%), high-risk candidates for CEA (n = 4, 6.6%), and the presence of contralateral recurrent paresis (n = 2, 3.3%). High-risk patients for CEA were defined as patients with history of severe cardiac disease and patients with impaired general condition. 84.4% (n = 27) of the restenosis were asymptomatic with a mean degree of stenosis of 83.7%, and 12.9% (n = 4) were symptomatic (degree of stenosis of 90%). Mean procedural and fluoroscopy time were 61 and 14 min. Study endpoints were periprocedural stroke-related mortality and morbidity, restenosis rate, and overall survival. Follow-up was performed by duplex ultrasound with a median follow-up period of 12 months (range 1-55). RESULTS: The periprocedural stroke rate of CAS within 30 days was 3.3% (one ischemic stroke, one intracranial hemorrhage); two additional patients suffered TIA (3.3%). None of the patients had a myocardial infarction perioperatively. The mortality rate was 0. CAS procedures were completed in 90.0% (n = 54) of cases. Dropout rate was 8.3% (n = 5) for morphological reasons (e.g., carotid kinking). Intraoperative complication rate was 1.7% (n = 1) including one patient who suffered intraoperative rupture of access vessels. The conversion rate with subsequent CEA procedure was 6.6% (n = 4 of 5). The restenosis rate during follow-up was 3.3% after CAS. The reintervention rate during the median follow-up period of 12 months (1-55 months) was 5.5% (n = 3/54). Two patients received a reintervention with successful balloon angioplasty; in one case, a diagnostic angiography was performed excluding the presence of a relevant restenosis. No additional stent was implanted. The survival rate was 100% at 1 year, 90.4% at 2 years, and 77.7% at 3 years. CONCLUSION: CAS, in the hands of vascular surgeons, is feasible with a moderate perioperative risk in a highly selected patient cohort. A procedure termination rate of approximately 10% shows that the complementary therapy using CAS procedure is not overused by surgeons. PMID- 28560567 TI - Gd3+-chelated lipid accelerates solid-state NMR spectroscopy of seven transmembrane proteins. AB - Solid-state NMR (SSNMR) is an attractive technique for studying large membrane proteins in membrane-mimetic environments. However, SSNMR experiments often suffer from low efficiency, due to the inherent low sensitivity and the long recycle delays needed to recover the magnetization. Here we demonstrate that the incorporation of a small amount of a Gd3+-chelated lipid, Gd3+-DMPE-DTPA, into proteoliposomes greatly shortens the spin-lattice relaxation time (1H-T 1) of lipid-reconstituted membrane proteins and accelerates the data collection. This effect has been evaluated on a 30 kDa, seven-transmembrane protein, Leptosphaeria rhodopsin. With the Gd3+-chelated lipid, we can perform 2D SSNMR experiments 3 times faster than by diamagnetic control. By combining this paramagnetic relaxation-assisted data collection with non-uniform sampling, the 3D experimental times are reduced eightfold with respect to traditional 3D experiments on diamagnetic samples. A comparison between the paramagnetic relaxation enhancement (PRE) effects of Cu2+- and Gd3+-chelated lipids indicates the much higher relaxivity of the latter. Hence, a tenfold lower concentration is needed for Gd3+-chelated lipids to achieve comparable PRE effects to Cu2+ chelated lipids. In addition, Gd3+-chelated lipids neither alter the protein structures nor induce significant line-width broadening of the protein signals. This work is expected to be beneficial for structural and dynamic studies of large membrane proteins by SSNMR. PMID- 28560569 TI - Epstein-Barr virus and thyroid cancer: the controversy remains. PMID- 28560570 TI - Effect of Lorenzo's Oil on Hepatic Gene Expression and the Serum Fatty Acid Level in abcd1-Deficient Mice. AB - Lorenzo's oil is known to decrease the saturated very long chain fatty acid (VLCFA) level in the plasma and skin fibroblasts of X-linked adrenoleukodystrophy (ALD) patients. However, the involvement of Lorenzo's oil in in vivo fatty acid metabolism has not been well elucidated. To investigate the effect of Lorenzo's oil on fatty acid metabolism, we analyzed the hepatic gene expression together with the serum fatty acid level in Lorenzo's oil-treated wild-type and abcd1 deficient mice. The change in the serum fatty acid level in Lorenzo's oil-treated abcd1-defcient mice was quite similar to that in the plasma fatty acid level in ALD patients supplemented with Lorenzo's oil. In addition, we found that the hepatic gene expression of two peroxisomal enzymes, Dbp and Scp2, and three microsomal enzymes, Elovl1, 2, and 3, were significantly stimulated by Lorenzo's oil. Our findings indicate that Lorenzo's oil activates hepatic peroxisomal fatty acid beta-oxidation at the transcriptional level. In contrast, the transcriptional stimulation of Elovl1, 2, and 3 by Lorenzo's oil does not cause changes in the serum fatty acid level. It seems likely that the inhibition of these elongation activities by Lorenzo's oil results in a decrease in saturated VLCFA. Thus, these results not only contribute to a clarification of the mechanism by which the saturated VLCFA level is reduced in the serum of ALD patients by Lorenzo's oil-treatment, but also suggest the development of a new therapeutic approach to peroxisomal beta-oxidation enzyme deficiency, especially mild phenotype of DBP deficiency. PMID- 28560571 TI - Molecular studies with Aedes (Stegomyia) aegypti (Linnaeus, 1762), mosquito transmitting the dengue virus. AB - Dengue is an infectious viral disease, which can present a wide clinical picture, ranging from oligo or asymptomatic forms, to bleeding and shock, and can progress to death. The disease problem has increased in recent years, especially in urban and suburban areas of tropical and subtropical regions. There are five dengue viruses, called serotypes (DEN-1, DEN-2, DEN-3, DEN-4, and DEN-5), which belong to the Flaviviridae family and are transmitted to humans through infected mosquito bites, with the main vector the Aedes aegypti mosquito (Linnaeus, 1762). Studies performed with Ae. aegypti, aimed at their identification and analysis of their population structure, are fundamental to improve understanding of the epidemiology of dengue, as well for the definition of strategic actions that reduce the transmission of this disease. Therefore, considering the importance of such research to the development of programs to combat dengue, the present review considers the techniques used for the molecular identification, and evaluation of the genetic variability of Ae. aegypti. PMID- 28560572 TI - Tumor suppressor p53 induces apoptosis of host lymphocytes experimentally infected by Leishmania major, by activation of Bax and caspase-3: a possible survival mechanism for the parasite. AB - Apoptosis of infected host macrophages by Leishmania spp. is mainly addressed as one of the survival mechanisms of the parasite. However, there is no eligible data about whether tumor suppressor p53 could induce the apoptosis of host lymphocytes-treated Leishmania major via the mitochondrial intrinsic pathway. In this study, the amastigotes of L. major obtained from ten cutaneous leishmaniases (CL) patients were separately isolated and cultured in N.N.N and RPMI 1640 media. L. major was definitely confirmed by targeting Cyt b gene following sequencing. Subsequently, 2-3 * 106 lymphocytes obtained from ten healthy individuals were isolated and co-cultured with 1-2 * 106 L. major promastigotes. Following 6 h of exposure time, the enzymatic activity of caspase-3 was determined by fluorometric assay in each L. major-treated lymphocytes and cell control (only lymphocyte). The mRNA expressions of Bax, Bcl-2, p53, and caspase-3 genes were assessed by quantitative real-time-PCR analysis following 6 to 9 h of exposure times. The Bcl 2 mRNA expression in L. major-treated lymphocytes was 100-fold down-regulated relative to cell control. The mRNA expressions of p53 and caspase-3 were over expressed 1.8- and 3.2-fold up-regulated relative to control lymphocytes, respectively. The Bax/Bcl-2 ratio and caspase-3 activity were higher than the control group (Pv <0.05). The current new findings indicate that the apoptotic effects of L. major-treated host lymphocytes dependent on p53 tumor suppressor via mitochondrial pathway may probably address as an auxiliary survival mechanism of L. major in CL patients. However, here is much work ahead to figure out the multiple functions played by apoptosis in the evasion of L. major. PMID- 28560573 TI - Sarcocystis dehongensis n. sp. (Apicomplexa: Sarcocystidae) from water buffalo (Bubalus bubalis) in China. AB - Water buffalo (Bubalus bubalis) is the intermediate host for at least four species of Sarcocystis: S. fusiformis, S. buffalonis, S. levinei, and S. sinensis/S. dubeyi. Here, a new species, Sarcocystis dehongensis, is reported in 51 of 756 (6.7%) water buffaloes in China. By light microscopy, the cysts of S. dehongensis were macroscopic, up to 18.5 mm long and 95 MUm in diameter; 4.9-11.9 MUm villous protrusions extended beyond the sarcocyst wall. Using transmission electron microscopy, the sarcocyst wall had lancet- or leaf-like protrusions in longitudinal section, but the cross section showed that the protrusions appeared as mushroom-like in shape with a core of tightly packed microtubules, similar to "type 24." BLAST searches revealed that S. dehongensis shared the most similarities with the 18S rDNA sequence of S. hardangeri (92.4%) and mitochondrial cox1 gene sequence of S. ovalis (81.0%), whereas no sequences in GenBank were found to be significantly similar to the ITS-1 region of S. dehongensis. A phylogenetic analysis based on 18S rDNA and mitochondrial cox1 gene sequences suggested that S. dehongensis was closely related to Sarcocystis species from cervids that employ corvids as definitive hosts. PMID- 28560574 TI - EORTC PET response criteria are more influenced by reconstruction inconsistencies than PERCIST but both benefit from the EARL harmonization program. AB - BACKGROUND: This study evaluates the consistency of PET evaluation response criteria in solid tumours (PERCIST) and European Organisation for Research and Treatment of Cancer (EORTC) classification across different reconstruction algorithms and whether aligning standardized uptake values (SUVs) to the European Association of Nuclear Medicine acquisition (EANM)/EARL standards provides more consistent response classification. MATERIALS AND METHODS: Baseline (PET1) and response assessment (PET2) scans in 61 patients with non-small cell lung cancer were acquired in protocols compliant with the EANM guidelines and were reconstructed with point-spread function (PSF) or PSF + time-of-flight (TOF) reconstruction for optimal tumour detection and with a standardized ordered subset expectation maximization (OSEM) reconstruction known to fulfil EANM harmonizing standards. Patients were recruited in three centres. Following reconstruction, EQ.PET, a proprietary software solution was applied to the PSF +/ TOF data (PSF +/- TOF.EQ) to harmonize SUVs to the EANM standards. The impact of differing reconstructions on PERCIST and EORTC classification was evaluated using standardized uptake values corrected for lean body mass (SUL). RESULTS: Using OSEMPET1/OSEMPET2 (standard scenario), responders displayed a reduction of -57.5% +/- 23.4 and -63.9% +/- 22.4 for SULmax and SULpeak, respectively, while progressing tumours had an increase of +63.4% +/- 26.5 and +60.7% +/- 19.6 for SULmax and SULpeak respectively. The use of PSF +/- TOF reconstruction impacted the classification of tumour response. For example, taking the OSEMPET1/PSF +/- TOFPET2 scenario reduced the apparent reduction in SUL in responding tumours ( 39.7% +/- 31.3 and -55.5% +/- 26.3 for SULmax and SULpeak, respectively) but increased the apparent increase in SUL in progressing tumours (+130.0% +/- 50.7 and +91.1% +/- 39.6 for SULmax and SULpeak, respectively). Consequently, variation in reconstruction methodology (PSF +/- TOFPET1/OSEMPET2 or OSEM PET1/PSF +/- TOFPET2) led, respectively, to 11/61 (18.0%) and 10/61 (16.4%) PERCIST classification discordances and to 17/61 (28.9%) and 19/61 (31.1%) EORTC classification discordances. An agreement was better for these scenarios with application of the propriety filter, with kappa values of 1.00 and 0.95 compared to 0.75 and 0.77 for PERCIST and kappa values of 0.93 and 0.95 compared to 0.61 and 0.55 for EORTC, respectively. CONCLUSION: PERCIST classification is less sensitive to reconstruction algorithm-dependent variability than EORTC classification but harmonizing SULs within the EARL program is equally effective with either. PMID- 28560576 TI - Dengue associated choroiditis: a rare entity. AB - BACKGROUND: We report a case of choroiditis during dengue fever. RESULTS: A 35 year-old female presented with blurring of vision during dengue fever. Her fundus examination revealed yellow deep choroidal lesions at right macula, multiple small, yellowish subretinal macular dots along papillomacular bundle, and hyperemic disc. There was a small retinal hemorrhage at temporal margin of disc. The left eye had similar small discrete lesion superonasal and inferotemporal to macula. CONCLUSIONS: We report a hitherto undescribed case of choroiditis in a dengue patient. PMID- 28560575 TI - Unknown biological effects of L-glucose, ALA, and PUFA. AB - Key substrates including glucose, amino acids, and fatty acids play core roles in nutrient metabolism. In this review, we describe phenomena observed when key substrates are applied to cells. We focused on three promising substrates: L glucose derivatives, 5-aminolevulinic acid, and polyunsaturated fatty acid. Since they are assumed to give a specific reaction when they are transported into cells or metabolized in cells, they are expected to be applied in a clinical setting. We provide the latest knowledge regarding their behaviors and effects on cells. PMID- 28560577 TI - Impact of inflammation on early hematopoiesis and the microenvironment. AB - Steady-state hematopoiesis is maintained by slowly dividing, self-renewing hematopoietic stem cells (HSCs) and their offspring, lineage-specified downstream progenitors in bone marrow (BM). It was previously thought that hematopoietic stresses such as infection or other inflammatory stimuli, are mostly recognized by terminally differentiated immune cells, i.e., front-line defenders at the local site of reaction, and that they produce factors that directly act on hematopoietic stem and progenitors (HSPCs) in BM and subsequently stimulate them to rebuild and sustain the hemato-lymphatic system. However, accumulating evidence now indicates that primitive HSPCs, as well as microenvironmental cells in BM are also able to sense systemically migrating hematopoietic stress signals, and respond by orchestrating on-site hematopoiesis via direct and indirect mechanisms. While inflammation has many beneficial roles in activating the immune system for defense or facilitating tissue repair, it also shows detrimental effects if sustained chronically, i.e., might lead to HSPC damage as bone marrow failure or leukemia. Thus, inflammation requires tight control of initiation and termination in time and space dependent manner. PMID- 28560578 TI - MD simulation study of the diffusion and local structure of n-alkanes in liquid and supercritical methanol at infinite dilution. AB - The diffusion coefficients of 14 n-alkanes (ranging from methane to n tetradecane) in liquid and supercritical methanol at infinite dilution (at a pressure of 10.5 MPa and at temperatures of 299 K and 515 K) were deduced via molecular dynamics simulations. Values for the radial distribution function, coordination number, and number of hydrogen bonds were then calculated to explore the local structure of each fluid. The flexibility of the n-alkane (as characterized by the computed dihedral distribution, end-to-end distance, and radius of gyration) was found to be a major influence and hydrogen bonding to be a minor influence on the local structure. Hydrogen bonding reduces the flexibility of the n-alkane, whereas increasing the temperature enhances its flexibility, with temperature having a greater effect than hydrogen bonding on flexibility. Graphical abstract The flexibility of the alkane is a major influence and the hydrogen bonding is a minor influence on the first solvation shell; the coordination numbers of long-chain n-alkanes in the first solvation shell are rather low. PMID- 28560579 TI - Multi-parametric analysis reveals enhanced G2-phase arrest of an optimized anti HER2 antibody to inhibit breast cancer. AB - OBJECTIVES: To find a "me-better" antibody by epitope-specific antibody optimization and multi-parametric analysis. RESULTS: Using epitope-specific library based on the commercial drug, Pertuzumab/2C4, we screened a novel human anti-HER2 antibody, MIL5, which has slightly higher affinity than the drug. MIL5 and 2C4 share the same epitope to bind HER2; however, MIL5 bound to HER2 His235 His245 more tightly than 2C4, which could be the main reason of its enhanced affinity. In vivo experiments also showed MIL5 had stronger anti-cancer activity than 2C4; however, the classical flow cytometry assays to detect cell apoptosis or cycling did not show convincing evidence of the advantages of MIL5. Thus we introduced the multi-parameter in-cell analysis method to evaluate the superiority of MIL5 to 2C4 in arresting cancer cells in G2-phase to inhibit cell growth and/or proliferation. CONCLUSION: Multi-parametric method confirmed stronger arrest of G2 by MIL5 to show better anti-cancer function both in vitro and in vivo than 2C4. PMID- 28560580 TI - PMicroRNA-124a regulates LPS-induced septic cardiac dysfunction by targeting STX2. AB - OBJECTIVE: To examine the role of miR-124a in LPS-induced septic cardiac insufficiency where underlying mechanism is unclear. RESULTS: Expression of miR 124a was decreased in myocardium of LPS-induced septic cardiac dysfunction model. miR-124a antagomiR or agomiR were injected via tail vein to induce miR-124a dysregulated model. miR-124a antagomiR aggravated LPS-induced cardiac dysfunction and apoptosis, while miR-124a agomiR had the opposite effect. Syntaxin-2 (STX2) was indicated as a candidate target gene by bioinformatic software. Further experiments confirmed that STX2 was downregulated in miR-124a agomiR-treated rats but upregulated in miR-124a antagomiR-treated rats, and STX2 inhibition could strongly block the miR-124a antagomiR-associated increase in cell apoptosis. Luciferase reporter activity assay indicated that STX2 was a direct target of miR 124a. Serological detection reveled that miR-124a was down-regulated in the plasma of septic cardiac dysfunction rats. CONCLUSIONS: miR-124a aggravates LPS induced cardiac dysfunction and the miR-124a/STX2 pathway might serve as the potential diagnostic and therapeutic targets for septic cardiac dysfunction. PMID- 28560581 TI - Antimicrobial and anti-biofilm properties of polypropylene meshes coated with metal-containing DLC thin films. AB - A promising strategy to reduce nosocomial infections related to prosthetic meshes is the prevention of microbial colonization. To this aim, prosthetic meshes coated with antimicrobial thin films are proposed. Commercial polypropylene meshes were coated with metal-containing diamond-like carbon (Me-DLC) thin films by the magnetron sputtering technique. Several dissimilar metals (silver, cobalt, indium, tungsten, tin, aluminum, chromium, zinc, manganese, tantalum, and titanium) were tested and compositional analyses of each Me-DLC were performed by Rutherford backscattering spectrometry. Antimicrobial activities of the films against five microbial species (Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis) were also investigated by a modified Kirby-Bauer test. Results showed that films containing silver and cobalt have inhibited the growth of all microbial species. Tungsten DLC, tin-DLC, aluminum-DLC, zinc-DLC, manganese-DLC, and tantalum-DLC inhibited the growth of some strains, while chromium- and titanium-DLC weakly inhibited the growth of only one tested strain. In-DLC film showed no antimicrobial activity. The effects of tungsten-DLC and cobalt-DLC on Pseudomonas aeruginosa biofilm formation were also assessed. Tungsten-DLC was able to significantly reduce biofilm formation. Overall, the experimental results in the present study have shown new approaches to coating polymeric biomaterials aiming antimicrobial effect. PMID- 28560582 TI - Towards standardization of 18F-FET PET imaging: do we need a consistent method of background activity assessment? AB - BACKGROUND: PET with O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) has reached increasing clinical significance for patients with brain neoplasms. For quantification of standard PET-derived parameters such as the tumor-to-background ratio, the background activity is assessed using a region of interest (ROI) or volume of interest (VOI) in unaffected brain tissue. However, there is no standardized approach regarding the assessment of the background reference. Therefore, we evaluated the intra- and inter-reader variability of commonly applied approaches for clinical 18F-FET PET reading. The background activity of 20 18F-FET PET scans was independently evaluated by 6 readers using a (i) simple 2D-ROI, (ii) spherical VOI with 3.0 cm diameter, and (iii) VOI consisting of crescent-shaped ROIs; each in the contralateral, non-affected hemisphere including white and gray matter in line with the European Association of Nuclear Medicine (EANM) and German guidelines. To assess intra-reader variability, each scan was evaluated 10 times by each reader. The coefficient of variation (CoV) was assessed for determination of intra- and inter-reader variability. In a second step, the best method was refined by instructions for a guided background activity assessment and validated by 10 further scans. RESULTS: Compared to the other approaches, the crescent-shaped VOIs revealed most stable results with the lowest intra-reader variabilities (median CoV 1.52%, spherical VOI 4.20%, 2D-ROI 3.69%; p < 0.001) and inter-reader variabilities (median CoV 2.14%, spherical VOI 4.02%, 2D-ROI 3.83%; p = 0.001). Using the guided background assessment, both intra-reader variabilities (median CoV 1.10%) and inter-reader variabilities (median CoV 1.19%) could be reduced even more. CONCLUSIONS: The commonly applied methods for background activity assessment show different variability which might hamper 18F-FET PET quantification and comparability in multicenter settings. The proposed background activity assessment using a (guided) crescent-shaped VOI allows minimization of both intra- and inter-reader variability and might facilitate comprehensive methodological standardization of amino acid PET which is of interest in the light of the anticipated EANM technical guidelines. PMID- 28560583 TI - Monitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using 111In bevacizumab. AB - BACKGROUND: The ability to image vascular endothelial growth factor (VEGF) could enable prospective, non-invasive monitoring of patients receiving anti-angiogenic therapy. This study investigates the specificity and pharmacokinetics of 111In bevacizumab binding to VEGF and its use for assessing response to anti-angiogenic therapy with rapamycin. Specificity of 111In-bevacizumab binding to VEGF was tested in vitro with unmodified radiolabelled bevacizumab in competitive inhibition assays. Uptake of 111In-bevacizumab in BALB/c nude mice bearing tumours with different amounts of VEGF expression was compared to that of isotype matched control antibody (111In-IgG1kappa) with an excess of unlabelled bevacizumab. Intratumoural VEGF was evaluated using ELISA and Western blot analysis. The effect of anti-angiogenesis therapy was tested by measuring tumour uptake of 111In-bevacizumab in comparison to 111In-IgG1kappa following administration of rapamycin to mice bearing FaDu xenografts. Uptake was measured using gamma counting of ex vivo tumours and effect on vasculature by using anti CD31 microscopy. RESULTS: Specific uptake of 111In-bevacizumab in VEGF-expressing tumours was observed. Rapamycin led to tumour growth delay associated with increased relative vessel size (8.5 to 10.3, P = 0.045) and decreased mean relative vessel density (0.27 to 0.22, P = 0.0015). Rapamycin treatment increased tumour uptake of 111In-bevacizumab (68%) but not 111In-IgGkappa and corresponded with increased intratumoural VEGF165. CONCLUSIONS: 111In-bevacizumab accumulates specifically in VEGF-expressing tumours, and changes after rapamycin therapy reflect changes in VEGF expression. Antagonism of mTOR may increase VEGF in vivo, and this new finding provides the basis to consider combination studies blocking both pathways and a way to monitor effects. PMID- 28560586 TI - Erratum to: Shodagor Family Strategies : Balancing Work and Family on the Water. PMID- 28560584 TI - RNA-based regulation in type I toxin-antitoxin systems and its implication for bacterial persistence. AB - Bacterial dormancy is a valuable survival strategy upon challenging environmental conditions. Dormant cells tolerate the consequences of high stress levels and may re-populate the environment upon return to favorable conditions. Antibiotic tolerant bacteria-termed persisters-regularly cause relapsing infections, increase the likelihood of antibiotic resistance, and, therefore, earn increasing attention. Their generation often depends on toxins from chromosomal toxin antitoxin systems. Here, we review recent insights concerning RNA-based control of toxin synthesis, and discuss possible implications for persister generation. PMID- 28560585 TI - Creation, characterization and utilization of Cryptococcus neoformans mutants sensitive to micafungin. AB - We constructed deletion mutants of Cryptococcus neoformans var neoformans (serotype D) genes encoding late ergosterol biosynthetic pathway enzymes and found that the mutations enhanced susceptibility to various drugs including micafungin, one of the echinocandins, to which wild-type Cryptococcus strains show no susceptibility. Furthermore, through isolation of a mutant resistant to micafungin from a micafungin-sensitive erg mutant and genetic analysis of it, we found that the responsible mutation occurred in the hotspot 2 of FKS1 encoding beta-1, 3-glucan synthase, indicating that micafungin inhibited the growth of the erg mutant via inhibiting Fks1 activity. Addition of ergosterol to the culture of the erg mutants recovered the resistance to micafungin, suggesting that the presence of ergosterol in membrane inhibits the accession of micafungin to its target. We found that a loss of one of genes encoding subunits of v-ATPase, VPH1, made Cryptococcus cells sensitive to micafungin. Our observation that the erg2 vph1 double mutant was more sensitive to micafungin than either single mutant suggests that these two genes act differently in becoming resistant to micafungin. The erg mutants allowed us to study the physiological significance of beta-1, 3-glucan synthesis in C. neoformans; the inhibition of beta-1, 3-glucan synthesis induced cell death and changes in cellular morphology. By observing the erg mutant cells recovering from the growth inhibition imposed by micafungin, we recognized beta-1, 3-glucan synthesis would suppress filamentous growth in C. neoformans. PMID- 28560588 TI - The Power of the Case Narrative - Can it be Brought to Bear on Duplicate Detection? PMID- 28560589 TI - A case of Wilson's disease presenting with paroxysmal dystonia. PMID- 28560587 TI - Evolutionary relationships and expression analysis of EUL domain proteins in rice (Oryza sativa). AB - BACKGROUND: Lectins, defined as 'Proteins that can recognize and bind specific carbohydrate structures', are widespread among all kingdoms of life and play an important role in various biological processes in the cell. Most plant lectins are involved in stress signaling and/or defense. The family of Euonymus-related lectins (EULs) represents a group of stress-related lectins composed of one or two EUL domains. The latter protein domain is unique in that it is ubiquitous in land plants, suggesting an important role for these proteins. RESULTS: Despite the availability of multiple completely sequenced rice genomes, little is known on the occurrence of lectins in rice. We identified 329 putative lectin genes in the genome of Oryza sativa subsp. japonica belonging to nine out of 12 plant lectin families. In this paper, an in-depth molecular characterization of the EUL family of rice was performed. In addition, analyses of the promoter sequences and investigation of the transcript levels for these EUL genes enabled retrieval of important information related to the function and stress responsiveness of these lectins. Finally, a comparative analysis between rice cultivars and several monocot and dicot species revealed a high degree of sequence conservation within the EUL domain as well as in the domain organization of these lectins. CONCLUSIONS: The presence of EULs throughout the plant kingdom and the high degree of sequence conservation in the EUL domain suggest that these proteins serve an important function in the plant cell. Analysis of the promoter region of the rice EUL genes revealed a diversity of stress responsive elements. Furthermore analysis of the expression profiles of the EUL genes confirmed that they are differentially regulated in response to several types of stress. These data suggest a potential role for the EULs in plant stress signaling and defense. PMID- 28560590 TI - High-resolution mapping reveals linkage between genes in common bean cultivar Ouro Negro conferring resistance to the rust, anthracnose, and angular leaf spot diseases. AB - KEY MESSAGE: Co-segregation analysis and high-throughput genotyping using SNP, SSR, and KASP markers demonstrated genetic linkage between Ur-14 and Co-3 4 /Phg 3 loci conferring resistance to the rust, anthracnose and angular leaf spot diseases of common bean. Rust, anthracnose, and angular leaf spot are major diseases of common bean in the Americas and Africa. The cultivar Ouro Negro has the Ur-14 gene that confers broad spectrum resistance to rust and the gene cluster Co-3 4 /Phg-3 containing two tightly linked genes conferring resistance to anthracnose and angular leaf spot, respectively. We used co-segregation analysis and high-throughput genotyping of 179 F2:3 families from the Ruda (susceptible) * Ouro Negro (resistant) cross-phenotyped separately with races of the rust and anthracnose pathogens. The results confirmed that Ur-14 and Co-3 4 /Phg-3 cluster in Ouro Negro conferred resistance to rust and anthracnose, respectively, and that Ur-14 and the Co-3 4 /Phg-3 cluster were closely linked. Genotyping the F2:3 families, first with 5398 SNPs on the Illumina BeadChip BARCBEAN6K_3 and with 15 SSR, and eight KASP markers, specifically designed for the candidate region containing Ur-14 and Co-3 4 /Phg-3, permitted the creation of a high-resolution genetic linkage map which revealed that Ur-14 was positioned at 2.2 cM from Co-3 4 /Phg-3 on the short arm of chromosome Pv04 of the common bean genome. Five flanking SSR markers were tightly linked at 0.1 and 0.2 cM from Ur-14, and two flanking KASP markers were tightly linked at 0.1 and 0.3 cM from Co-3 4 /Phg-3. Many other SSR, SNP, and KASP markers were also linked to these genes. These markers will be useful for the development of common bean cultivars combining the important Ur-14 and Co-3 4 /Phg-3 genes conferring resistance to three of the most destructive diseases of common bean. PMID- 28560591 TI - Individual- and Family-Level Determinants of Risky Sexual Behavior Among Swedish- and Foreign-Born Young Adults 18-30 Years of Age, Residing in Skane, Sweden. AB - In Sweden, various public health interventions have been performed to reduce risky sexual behaviors among young people and promote safer and positive approaches to sexuality, while attempting to bridge the gap between the less privileged or more vulnerable young people and their more privileged peers. This study aimed to compare the individual- and familial-level determinants of risky sexual behavior among foreign-born and Swedish-born young adults 18-30 years of age residing in Skane, the south of Sweden. This was a cross-sectional study that used a questionnaire to collect data from 2968 randomly selected respondents between 18 and 30 years between January and March 2013. The associations were analyzed using chi-square tests, and simple and multiple logistic regression analyses. Younger age, i.e., individual-level factor, and living with only one parent or another person while growing up, i.e., familial-level factor, increased the risk of engaging in sexual risk taking for both Swedish- and foreign-born youth. Male gender was related to a higher risk of engaging in sexual risk-taking behaviors among foreign-born youth but was not as important as influence on sexual risk taking among Swedish-born youth. Parental education level, on the other hand, was significantly associated with sexual intercourse on the "first night" and early sexual debut solely among Swedish-born youth. Condom use was not associated with any family-level factor among both Swedish-born and foreign-born youth. The design of sexual reproductive health and rights messages and interventions to target risky sexual behavior among Swedish youth should take into consideration immigration status (for example, being Swedish-born or foreign born), individual- and family-level characteristics, as well as the type of behavioral change or outcome desired. PMID- 28560592 TI - A Scale for the Assessment of Sexual Standards Among Youth: Psychometric Properties. AB - The (hetero)sexual double standard (SDS), prescribing sexual modesty for girls and sexual prowess for boys, negatively affects sexual and mental health. Nevertheless, endorsement and enactment of the SDS is still common. In this study, we respond to recent calls for modernization in the field of sexual double standard research. We describe the development of the "Scale for the Assessment of Sexual Standards among Youth" (SASSY), as well as its psychometric properties. This instrument was designed to measure contemporary sexual double standard endorsement, defined as "the degree to which an individual's attitude reflects a divergent set of expectations for boys and girls, in that boys are expected to be relatively more sexually active, assertive, and knowledgeable and girls are expected to be relatively more sexually reserved, passive, and inexperienced" among adolescents and emerging adults. In Study 1, a pool of 35 items was administered in a Dutch sample (N = 465, 54.8% female, age 16-20). A 20-item set formed a one-dimensional and internally consistent scale and was subsequently administered in a second Dutch sample. Study 2 (N = 818, 58.4% female, age 16-25) again assessed the 20-item set. After dropping one item, the 19-item SASSY proved to be one-dimensional and internally consistent, exhibiting good test-retest reliability, construct validity, and convergent validity. Finally, the instrument showed configural and metric measurement invariance across gender, age, education level, and sexual experience level, and configural, metric, and scalar measurement invariance across time. These studies confirmed the 19-item SASSY to be a reliable and valid new tool for the assessment of contemporary sexual double standard endorsement among adolescents and emerging adults. PMID- 28560593 TI - Base Excess as a Predictor of Complications in Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy. AB - BACKGROUND: Base excess is important in assessing metabolic status. Postoperative management in patients undergoing cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal malignancies can be a challenge, and we therefore sought to investigate perioperative predictors of overall morbidity in CRS/HIPEC patients at our institution. METHODS: Patients who underwent CRS/HIPEC from 2012 to 2016 were identified retrospectively from a prospectively collected institutional database. Patient demographics and perioperative variables were obtained and the comprehensive complication index (CCI) was calculated for each patient in order to assess perioperative morbidity. Stepwise linear regression analyses were performed, with CCI as the outcome variable. RESULTS: A total of 72 CRS/HIPEC patients had recorded base excesses in the first 48 h postoperatively. Mean immediate postoperative base excess was -6.0 mmol/L (interquartile range [IQR] -8 to -4.1), mean delta base excess at 48 h was +4.3 mmol/L (IQR +2.1 to +6.2), and mean CCI was 25.2 (IQR 8.7-36.7). On multivariate analysis, delta base excess was the only significant predictor of CCI, demonstrating a protective effect (p = 0.001). In patients who experienced less than the mean delta base excess of +4.3 mmol/L, lower delta base excess was an independent predictor of complications (p < 0.001). CONCLUSIONS: Delta base excess is an independent predictor of morbidity in patients undergoing CRS/HIPEC. A delta base excess of greater than +4.3 mmol/L at 48 h may be an appropriate goal for resuscitation of CRS/HIPEC patients in the immediate postoperative period. Standardized protocols to correct the base deficit in CRS/HIPEC patients during the early postoperative period can potentially help mitigate perioperative morbidity. PMID- 28560594 TI - FBXO50 Enhances the Malignant Behavior of Gastric Cancer Cells. AB - BACKGROUND: Challenges to our understanding the molecular mechanisms of the progression of gastric cancer (GC) must be overcome to facilitate the identification of novel biomarkers and therapeutic targets. In this article, we analyzed the expression of the gene encoding F-box-only 50 (FBXO50) and determined whether it contributes to the malignant phenotype of GC. METHODS: FBXO50 messenger RNA (mRNA) levels and copy numbers of the FBXO50 locus were determined in 10 GC cell lines and a nontumorigenic epithelial cell line. Polymerase chain reaction array analysis was performed to identify genes coordinately expressed with FBXO50. The effects of inhibiting FBXO50 on GC cell proliferation, adhesion, invasiveness, and migration were evaluated using a small interfering RNA targeted to FBXO50 mRNA. To evaluate the clinical significance of FBXO50 expression, we determined the levels of FBXO50 mRNA in tissues acquired from 200 patients with GC. RESULTS: The levels of FBXO50 mRNA were increased in five GC cell lines and positively correlated with those of ITGA5, ITGB1, MMP2, MSN, COL5A2, GNG11, and WNT5A. Copy number gain of the FBXO50 locus was detected in four GC cell lines. Inhibition of FBXO50 expression significantly decreased the proliferation, adhesion, migration, and invasiveness of GC cell lines. In clinical samples, high FBXO50 expression correlated with increased pT4, invasive growth, lymph node metastasis, and positive peritoneal lavage cytology. Patients with high FBXO50 expression had a significantly higher prevalence of recurrence after curative gastrectomy and were more likely to experience shorter overall survival. CONCLUSIONS: FBXO50 may represent a biomarker for GC phenotypes and as a target for therapy. PMID- 28560595 TI - Trends in Sexual Function After Breast Cancer Surgery. AB - PURPOSE: Sexual dysfunction is assumed to be common, but understudied, in breast cancer patients. Herein, we use the validated female sexual functioning index (FSFI) to evaluate changes in female sexual function after breast cancer surgery. METHODS: The FSFI assesses sexual function in six domains (desire, arousal, lubrication, orgasm, satisfaction, pain) on a 36-point scale, with scores >26.6 indicating better sexual function. We identified 226 women with unilateral breast cancer undergoing surgery at our institution from June 2010-January 2015. All completed the FSFI preoperatively and at a median of 13 months postoperatively. We quantified declines in FSFI scores and considered p-values <0.05 statistically significant. RESULTS: Overall, 119 women had breast-conserving surgery (BCS), 40 had unilateral mastectomy (UM), and 67 had UM plus contralateral prophylactic mastectomy (CPM). All women had similar baseline FSFI scores (medians: BCS, 26.3; UM, 25.2; UM+CPM, 23.7; p = 0.23). At follow-up, sexual function had declined significantly in BCS (23.5; p < 0.001) and UM (17.4; p = 0.010), but was unchanged in UM+CPM (22.8; p = 0.74) women. Interestingly, all women maintained their desire for sex (p = 0.17). BCS and UM women demonstrated significant declines in all other subscale domains (all p < 0.045). UM+CPM women demonstrated no decline in any subscale domain, yet did not exhibit superior sexual function to those having UM or BCS (medians: BCS, 23.5; UM, 17.4; UM+CPM, 22.8; p = 0.21). CONCLUSIONS: Baseline sexual dysfunction exists in women diagnosed with breast cancer. Surgery negatively impacts sexual function. Patients who choose mastectomy do not exhibit superior sexual function over those having BCS at 13 months following surgery. PMID- 28560596 TI - Standard Pathologic Features Can Be Used to Identify a Subset of Estrogen Receptor-Positive, HER2 Negative Patients Likely to Benefit from Neoadjuvant Chemotherapy. AB - BACKGROUND: The benefit of neoadjuvant chemotherapy (NAC) in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancers and in invasive lobular carcinoma (ILC) is uncertain due to the low rates of pathologic complete response (pCR). OBJECTIVE: The aim of this study was to determine if pathologic features can identify subsets likely to benefit from NAC. METHODS: Patients with stage I-III ER+, HER2- breast cancer receiving NAC were retrospectively reviewed. Endpoints were downstaging to breast-conserving surgery (BCS) and nodal pCR after NAC. Patients were grouped by progesterone receptor (PR) status and grade/differentiation (high grade or poor [HP] vs. non-HP). RESULTS: From 2007 to 2016, 402 ER+/HER2- cancers in patients receiving NAC were identified. Median age was 50 years, 98% were clinical stage II-III, and 75% were cN+. Overall pCR rate was 5%; breast pCR in 7% and nodal pCR in 15% of cN+ patients (p < 0.0001). Patients with ILC initially ineligible for BCS (n = 56) were less likely to downstage than those with invasive ductal carcinoma (IDC; n = 183, 16 vs. 48%, p <= 0.0001), with a similar trend in the axilla (p = 0.086). The rates of BCS eligibility after NAC were highest in PR-/HP patients (62%) and lowest in PR+/non-HP patients (29%) [p = 0.005]. In the axilla, nodal pCR among cN+ patients (n = 301) ranged from 0 to 35% (p < 0.0001) within these groups, and was most frequent in PR-/HP patients. CONCLUSIONS: ER+/HER2- patients most likely to benefit from NAC are those with PR and HP tumors. Patients with ILC are unlikely to downstage in the breast or axilla compared with IDC. The use of these criteria can assist in defining the initial treatment approach. PMID- 28560597 TI - Increased Grade in Neuroendocrine Tumor Metastases Negatively Impacts Survival. AB - BACKGROUND: Tumor grade is an important predictor of survival in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), as determined by Ki-67 expression and mitotic rate. NETs generally grow indolently, but some cells may acquire traits facilitating metastasis. It is unclear how frequently metastases differ in grade from their primary tumors, and whether increasing grade in metastases affects prognosis. METHODS: Ki-67 immunohistochemistry was performed on resected GEPNET specimens and cases with results for both primary tumors and concurrent metastases were identified. Grade was determined using a modified World Health Organization classification (Ki-67: G1 = 0-2%; G2 > 2-20%; G3 > 20%). RESULTS: Ki-67 was performed on both the primary tumor and metastases in 103 patients. Tumor grade was higher in metastases from 25 (24%) patients, 24 increased from G1 to G2, and 1 increased from G2 to G3; 68 (66%) patients had no change in grade (42 G1 and 26 G2), and 10 (10%) decreased from G2 to G1. No clinicopathologic factors were predictive of higher grade in metastases. The 5 year progression-free survival (PFS) was 55% for patients with stable grade versus 8% of patients with increased grade, while 5-year overall survival (OS) was 92 and 54%, respectively. The 5-year OS of patients who had stable grade with G1 and G2 primaries was 92 and 64%, respectively. CONCLUSIONS: Nearly one-third of patients had metastases with a different grade than their primary, and, when grade increased, both PFS and OS significantly decreased. Determining the grade in both the primary tumor and a metastasis is important for estimating prognosis and to help inform decisions regarding additional therapies. PMID- 28560598 TI - The Impact of Residual Disease After Preoperative Systemic Therapy on Clinical Outcomes in Patients with Inflammatory Breast Cancer. AB - BACKGROUND: Inflammatory breast cancer (IBC) is a rare and aggressive disease treated with multimodality therapy: preoperative systemic therapy (PST) followed by modified radical mastectomy (MRM), chest wall and regional nodal radiotherapy, and adjuvant biologic therapy and/or endocrine therapy when appropriate. In non IBC, the degree of pathologic response to PST has been shown to correlate with time to recurrence (TTR) and overall survival (OS). We sought to determine if pathologic response correlates with oncologic outcomes of IBC patients. METHODS: Following review of IBC patients' records (1997-2014), we identified 258 stage III IBC patients; 181 received PST followed by MRM and radiotherapy and were subsequently analyzed. Pathologic complete response (pCR) to PST, hormone receptor and human epidermal growth factor receptor 2 (HER2) status, grade, and histology were evaluated as predictors of TTR and OS by Cox model. RESULTS: Overall, 95/181 (52%) patients experienced recurrence; 93/95 (98%) were distant metastases (median TTR 3.2 years). Seventy-three patients (40%) died (median OS 6.9 years). pCR was associated with improved TTR (hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.09-0.46, p < 0.01, univariate; HR 0.17, 95% CI 0.07 0.41, p < 0.0001, multivariate) and improved OS (HR 0.26, 95% CI 0.11-0.65, p < 0.01, univariate). In patients with pCR, grade III (HR 1.91, 95% CI 1.16-3.13, p = 0.01), and triple-negative phenotype (HR 3.54, 95% CI 1.79-6.98, p = 0.0003) were associated with shorter TTR, while residual ductal carcinoma in situ was not (HR 0.85, 95% CI 0.53-1.35, p = 0.48, multivariate). CONCLUSIONS: In stage III IBC, pCR was associated with prognosis, further influenced by grade, hormone receptor, and HER2 status. Investigating mechanisms that contribute to better response to PST could help improve oncologic outcomes in IBC. PMID- 28560599 TI - Computed Tomography Image Texture: A Noninvasive Prognostic Marker of Hepatic Recurrence After Hepatectomy for Metastatic Colorectal Cancer. AB - BACKGROUND: Recurrence after resection of colorectal liver metastases (CRLMs) occurs in up to 75% of patients. Preoperative prediction of hepatic recurrence may inform therapeutic strategies at the time of initial resection. Texture analysis (TA) is an established technique that quantifies pixel intensity variations (heterogeneity) on cross-sectional imaging. We hypothesized that tumoral and parenchymal changes that are predictive of overall survival (OS) and recurrence in the future liver remnant (FLR) can be detected using TA on preoperative computed tomography (CT) images. METHODS: Patients who underwent resection for CRLM between 2003 and 2007 with appropriate preoperative CT scans were included (n = 198) in this retrospective study. Texture features extracted from the tumor and FLR, and clinicopathologic variables, were incorporated into a multivariable survival model. RESULTS: Quantitative imaging features of the FLR were an independent predictor of both OS and hepatic disease-free survival (HDFS). Tumor texture showed significant association with OS. TA of the FLR allowed patient stratification into two groups, with significantly different risks of hepatic recurrence (hazard ratio 2.09, 95% confidence interval 1.33 3.28; p = 0.001). Patients with homogeneous parenchyma had approximately twice the risk of hepatic recurrence (41 vs. 20%). CONCLUSION: TA of the tumor and FLR are independently associated with OS, and TA of the FLR is independently associated with HDFS. Patients with homogeneous parenchyma had a significantly higher risk of hepatic recurrence. Preoperative TA of the liver represents a potential biomarker to identify patients at risk of liver recurrence after resection for CRLM. PMID- 28560600 TI - Short-Course Radiotherapy Followed by Neoadjuvant Bevacizumab, Capecitabine, and Oxaliplatin and Subsequent Radical Treatment in Primary Stage IV Rectal Cancer: Long-Term Results of a Phase II Study. AB - BACKGROUND: In a Dutch phase II trial conducted between 2006 and 2010, short course radiotherapy followed by systemic therapy with capecitabine, oxaliplatin, and bevacizumab as neoadjuvant treatment and subsequent radical surgical treatment of primary tumor and metastatic sites was evaluated. In this study, we report the long-term results after a minimum follow-up of 6 years. METHODS: Patients with histologically confirmed rectal adenocarcinoma with potentially resectable or ablatable metastases in liver or lungs were eligible. Follow-up data were collected for all patients enrolled in the trial. Overall and recurrence-free survival were calculated using the Kaplan-Meier method. RESULTS: Follow-up data were available for all 50 patients. After a median follow-up time of 8.1 years (range 6.0-9.8), 16 patients (32.0%) were still alive and 14 (28%) were disease-free. The median overall survival was 3.8 years (range 0.5-9.4). From the 36 patients who received radical treatment, two (5.6%) had a local recurrence and 29 (80.6%) had a distant recurrence. CONCLUSIONS: Long-term survival can be achieved in patients with primary metastatic rectal cancer after neoadjuvant radio- and chemotherapy. Despite a high number of recurrences, 32% of patients were alive after a median follow-up time of 8.1 years. PMID- 28560601 TI - Induction Chemotherapy Followed by Resection or Irreversible Electroporation in Locally Advanced Pancreatic Cancer (IMPALA): A Prospective Cohort Study. AB - BACKGROUND: Following induction chemotherapy, both resection or irreversible electroporation (IRE) may further improve survival in patients with locally advanced pancreatic cancer (LAPC). However, prospective studies combining these strategies are currently lacking, and available studies only report on subgroups that completed treatment. This study aimed to determine the applicability and outcomes of resection and IRE in patients with nonprogressive LAPC after induction chemotherapy. METHODS: This was a prospective, single-center cohort study in consecutive patients with LAPC (September 2013 to March 2015). All patients were offered 3 months of induction chemotherapy (FOLFIRINOX or gemcitabine depending on performance status), followed by exploratory laparotomy for resection or IRE in patients with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 nonprogressive, IRE-eligible tumors. RESULTS: Of 132 patients with LAPC, 70% (n = 93) started with chemotherapy (46% [n = 61] FOLFIRINOX). After 3 months, 59 patients (64%) had nonprogressive disease, of whom 36 (27% of the entire cohort) underwent explorative laparotomy, resulting in 14 resections (11% of the entire cohort, 39% of the explored patients) and 15 IREs (11% of the entire cohort, 42% of the explored patients). After laparotomy, 44% (n = 16) of patients had Clavien-Dindo grade 3 or higher complications, and 90-day all-cause mortality was 11% (n = 4). With a median follow-up of 24 months, median overall survival after resection, IRE, and for all patients with nonprogressive disease without resection/IRE (n = 30) was 34, 16, and 15 months, respectively. The resection rate in 61 patients receiving FOLFIRINOX treatment was 20%. CONCLUSION: Induction chemotherapy followed by IRE or resection in nonprogressive LAPC led to resection or IRE in 22% of all-comers, with promising survival rates after resection but no apparent benefit of IRE, despite considerable morbidity. Registered at Netherlands Trial Register (NTR4230). PMID- 28560602 TI - Progression to T1 High Grade (T1HG) from a Lower Stage/Grade is Associated with Poorer Survival Outcomes than Initial Diagnosis with T1HG Bladder Cancer. AB - BACKGROUND: Several studies have documented a poor prognosis in those patients who were initially diagnosed with non-muscle-invasive bladder cancer (NMBIC) and progressed to muscle-invasive bladder cancer (MIBC) compared with those who initially presented with MIBC. However, studies regarding this issue have not yet been performed in patients with T1 high-grade (T1HG) tumor. We aimed to compare survival outcomes between patients diagnosed as T1HG after initial transurethral resection of the bladder tumor (TUR-BT) and patients who presented with lower stage and/or grade but progressed to T1HG at the time of tumor recurrence. METHODS: The study comprised 499 patients who had a diagnosis of T1HG after initial TUR-BT (initial T1HG group) and 62 patients who progressed to T1HG after TUR-BT at the time of tumor recurrence (progressed T1HG group). Progression was defined as recurrence to a higher grade and/or stage than the previous result, while MIBC progression was defined as progression to stage T2 or higher and/or N+, and/or M1. RESULTS: The median overall survival (OS) and cancer-specific survival (CSS) durations were 38.0 and 29.0 months, respectively. Kaplan-Meier curve analysis showed significantly decreased 5-year OS (74.4 vs. 57.4%), CSS (86.4 vs. 72.8%), and MIBC progression-free survival (82.6 vs. 62.2%) in the progressed T1HG group. Multivariate analysis revealed that progressed T1HG was a significant predictor of OS, CSS, and MIBC progression (all, p < 0.05). CONCLUSIONS: The progressed T1HG group showed poorer survival outcomes compared with the initial T1HG group. Consequently, in patients who progress to T1HG, intensive surveillance and treatment strategies should be considered. PMID- 28560603 TI - Micro-RNA-130a-3p Regulates Gemcitabine Resistance via PPARG in Cholangiocarcinoma. AB - BACKGROUND: The prognosis of cholangiocarcinoma (CCA) is so poor that its chemoresistance needs to be reduced. In this study, we focused on the microRNAs (miRNAs) associated with gemcitabine resistance of CCA and assessed the clinical significance of miRNAs and their target genes. METHODS: We performed miRNA microarray analysis for two CCA cell lines (CCLP-1 and MzChA-1) and their gemcitabine-resistant (GR) cells. An miR-130a-3p mimic was induced into CCA cells using lipofection, and we used pioglitazone as a peroxisome proliferator activated receptor-gamma (PPARgamma) agonist in vitro. The expression of miR-130a 3p was studied in 27 intrahepatic CCA samples after laser capture microdissection (LCM) and by immunohistochemistry from patients who had undergone curative resection from March 2004 to November 2012 at Osaka University Hospital. RESULTS: miR-130a-3p expression was upregulated in CCLP-1-GRs and MzChA-1-GRs significantly more than in their parental cells. Transfection of the miR-130a-3p mimic into CCA cells increased gemcitabine resistance, and we detected PPARG as a target gene of miR-130a-3p. Furthermore, pioglitazone had a synergistic effect with gemcitabine and alleviated gemcitabine resistance of CCA GR cells. Moreover, clinical examination revealed that for patients who underwent adjuvant gemcitabine therapy, those who were PPARgamma positive had significantly longer disease-free survival than those who were PPARgamma negative (n = 5 and 11, respectively; p = 0.027). CONCLUSIONS: Our data suggest that miR-130a-3p was associated with gemcitabine resistance in CCA through PPARG, and there is a possibility that pioglitazone can be used for the treatment of CCA. PMID- 28560604 TI - Anthropogenic protection alters the microbiome in intertidal mangrove wetlands in Hainan Island. AB - Intertidal mangrove wetlands are of great economic and ecological importance. The regular influence of tides has led to the microbial communities in these wetlands differing significantly from those in other habitats. In this study, we investigated the microbiomes of the two largest mangrove wetlands in Hainan Island, China, which have different levels of anthropogenic protection. Soil samples were collected from the root zone of 13 mangrove species. The microbial composition, including key functional groups, was assessed using Illumina sequencing. Bioinformatics analysis showed that there was a significant difference in the microbiomes between the protected Bamen Bay and the unprotected Dongzhai Bay. The overall microbiome was assigned into 78 phyla and Proteobacteria was the most abundant phylum at both sites. In the protected wetland, there were fewer marine-related microbial communities, such as sulfate reducing bacteria, and more terrestrial-related communities, such as Verrucomicrobia methanotrophs. We also observed distinct microbial compositions among the different mangrove species at the protected site. Our data suggest that the different microbiomes of the two mangrove wetlands are the result of a complex interaction of the different environmental variables at the two sites. PMID- 28560605 TI - Social support, stress coping strategies, resilience and posttraumatic growth in a Polish sample of HIV-infected individuals: results of a 1 year longitudinal study. AB - This study investigated the level of posttraumatic growth (PTG) and its association with the level of social support, stress coping strategies and resilience among a people living with HIV (PLWH) in a 1 year longitudinal study. We also controlled for age, HIV infection duration and the presence of posttraumatic stress symptoms (PTSS). From the 290 participants, initially eligible for the study, 110 patients were recruited for the first assessment and 73 patients participated in a follow-up assessment. Participants filled out following psychometric tools: the Posttraumatic Growth Inventory (PTGI), the Berlin Social Support Scales (BSSS), the Mini-COPE Inventory, the Resiliency Assessment Scale (SPP-25) and the PTSD-F questionnaire. Received support and resilience were positively, whereas return to religion as coping strategy was negatively related to the PTG. Clinicians and researchers need to focus on potentially positive consequences of HIV infection, i.e. PTG, and factors that might promote it among PLWH. PMID- 28560606 TI - Biological Invasion Influences the Outcome of Plant-Soil Feedback in the Invasive Plant Species from the Brazilian Semi-arid. AB - Plant-soil feedback is recognized as the mutual interaction between plants and soil microorganisms, but its role on the biological invasion of the Brazilian tropical seasonal dry forest by invasive plants still remains unclear. Here, we analyzed and compared the arbuscular mycorrhizal fungi (AMF) communities and soil characteristics from the root zone of invasive and native plants, and tested how these AMF communities affect the development of four invasive plant species (Cryptostegia madagascariensis, Parkinsonia aculeata, Prosopis juliflora, and Sesbania virgata). Our field sampling revealed that AMF diversity and frequency of the Order Diversisporales were positively correlated with the root zone of the native plants, whereas AMF dominance and frequency of the Order Glomerales were positively correlated with the root zone of invasive plants. We grew the invasive plants in soil inoculated with AMF species from the root zone of invasive (I changed) and native (I unaltered) plant species. We also performed a third treatment with sterilized soil inoculum (control). We examined the effects of these three AMF inoculums on plant dry biomass, root colonization, plant phosphorous concentration, and plant responsiveness to mycorrhizas. We found that I unaltered and I changed promoted the growth of all invasive plants and led to a higher plant dry biomass, mycorrhizal colonization, and P uptake than control, but I changed showed better results on these variables than I unaltered. For plant responsiveness to mycorrhizas and fungal inoculum effect on plant P concentration, we found positive feedback between changed-AMF community (I changed) and three of the studied invasive plants: C. madagascariensis, P. aculeata, and S. virgata. PMID- 28560607 TI - Femoral nerve and lumbar plexus injury after minimally invasive lateral retroperitoneal transpsoas approach: electrodiagnostic prognostic indicators and a roadmap to recovery. AB - Injury to the lumbosacral (LS) plexus is a well-described complication after lateral retroperitoneal transpsoas approaches to the spine. The prognosis for functional recovery after lumbosacral plexopathy or femoral/obturator neuropathy is unclear. We designed a retrospective case-control study with patients undergoing one-level lateral retroperitoneal transpsoas lumbar interbody fusion (LLIF) between January 2011 and June 2016 to correlate electrodiagnostic assessments (EDX) to physiologic concepts of nerve injury and reinnervation, and attempt to build a timeline for patient evaluation and recovery. Cases with post operative obturator or femoral neuropathy were identified. Post-operative MRI, nerve conduction studies (NCS), electromyography (EMG), and physical examinations were performed at intervals to assess clinical and electrophysiologic recovery of function. Two hundred thirty patients underwent LLIF. Six patients (2.6%) suffered severe femoral or femoral/obturator neuropathy. Five patients (2.2%) had immediate post-operative weakness. One of the six patients developed delayed weakness due to a retroperitoneal hematoma. Five out of six patients (83%) demonstrated EDX findings at 6 weeks consistent with axonotmesis. All patients improved to at least MRC 4/5 within 12 months of injury. In conclusion, neurapraxia is the most common LS plexus injury, and complete recovery is expected after 3 months. Most severe nerve injuries are a combination of neurapraxia and variable degrees of axonotmesis. EDX performed at 6 weeks and 3, 6, and 9 months provides prognostic information for recovery. In severe injuries of proximal femoral and obturator nerves, observation of proximal to distal progression of small-amplitude, short-duration (SASD) motor unit potentials may be the most significant prognostic indicator. PMID- 28560608 TI - Utility of preoperative meningioma consistency measurement with magnetic resonance elastography (MRE): a review. AB - Meningioma consistency is a critical factor that influences preoperative planning for surgical resection. Recent studies have investigated the utility of preoperative magnetic resonance elastography (MRE) in predicting meningioma consistency. However, it is unclear whether existing methods are optimal for application to clinical practice. The results and conclusions of these studies are limited by their imaging acquisition methods, such as the use of a single MRE frequency and the use of shear modulus as the final measurement variable, rather than its storage and loss modulus components. In addition, existing studies do not account for the effects of cranial anatomy, which have been shown to significantly distort the MRE signal. Given the interaction of meningiomas with these anatomic structures and the lack of supporting evidence with more accurate imaging parameters, MRE may not yet be reliable for use in clinical practice. PMID- 28560609 TI - Addition of exogenous SOD1 aggregates causes TDP-43 mislocalisation and aggregation. AB - ALS is characterised by a focal onset of motor neuron loss, followed by contiguous outward spreading of pathology throughout the nervous system, resulting in paralysis and death generally within a few years after diagnosis. The aberrant release and uptake of toxic proteins including SOD1 and TDP-43 and their subsequent propagation, accumulation and deposition in motor neurons may explain such a pattern of pathology. Previous work has suggested that the internalization of aggregates triggers stress granule formation. Given the close association of stress granules and TDP-43, we wondered whether internalisation of SOD1 aggregates stimulated TDP-43 cytosolic aggregate structures. Addition of recombinant mutant G93A SOD1 aggregates to NSC-34 cells was found to trigger a rapid shift of TDP-43 to the cytoplasm where it was still accumulated after 48 h. In addition, SOD1 aggregates also triggered cleavage of TDP-43 into fragments including a 25 kDa fragment. Collectively, this study suggests a role for protein aggregate uptake in TDP-43 pathology. PMID- 28560610 TI - Association between growth dynamics, morphological parameters, the chromosomal status of the blastocysts, and clinical outcomes in IVF PGS cycles with single embryo transfer. AB - PURPOSE: The purpose of the present study is to examine interconnection between speed of embryo development, the genetic status of the blastocysts, and clinical outcomes in IVF preimplantation genetic screening (PGS) cycles with single embryo transfer (SET). METHODS: The retrospective comparative study has been performed between January 2013 and January 2016. Seven hundred thirty-seven cycles of IVF treatment with PGS, followed by 503 SETs, were included in the study. Normally fertilized oocytes were hatched on day 3, were cultured to the blastocyst stage, and were biopsied only when at least three to seven cells were herniating from zona pellucida on the morning of day 5 (<=118 h) or day 6 (>=139 h). A total of 3705 embryos were analyzed for euploidy rates and blastocyst morphology. All embryos were vitrified after the biopsy, and selected embryos were subsequently thawed for a hormone replacement frozen embryo transfer cycle. RESULTS: The euploidy rate was significantly higher among embryos biopsied on day 5 versus day 6: 59.44 +/- 4.1 and 48.19 +/- 3.8, respectively, p < 0.05. The difference in euploidy rates between embryos biopsied on day 5 versus day 6 in matched age groups increased from 5.83 to 25.46% with advancing maternal age. Our data demonstrated no statistically significant difference in euploidy rates between good-quality embryos biopsied on day 5 in the group of patients <38 years old and embryos in PGS cycles using donor oocytes: 71.12% (336/472) and 75.68% (221/292), respectively, p = 0.174, chi 2 = 1.848. In 270 out of 503 SETs, transferred embryos were biopsied on day 5 (ongoing pregnancy rate was 64.6% in a group of patients <38 years old, and in a group of patients >=38 years old, ongoing PR was 64.2%). In 233 out of 503 cycles, transferred embryos were biopsied on day 6 (ongoing PR was 46.6% in a group of patients <38 years old, and in a group of patients >=38 years old, ongoing PR was 50.8%). In all study groups, the ongoing pregnancy rate was higher when the transferred embryo was available for biopsy on day 5. CONCLUSIONS: Good- and fair-quality embryos available for biopsy on day 5 have higher euploidy rates and have a higher chance to result in an ongoing pregnancy. Euploidy rate has significant variations within the same age group depending on the morphology of the blastocysts. PMID- 28560611 TI - Have You Talked about It: Advance Care Planning among African Americans Living with HIV in Baltimore. AB - Advance care planning (ACP) is the process of planning for when individuals are unable to make their own healthcare decisions. Research suggests ACP is understudied among HIV-positive African Americans. We explored ACP knowledge, preferences, and practices with HIV-positive African Americans from an urban HIV specialty clinic (AFFIRM study). Participants completed surveys and interviews. Descriptive analyses and Poisson regression were conducted on survey data. Qualitative interviews were coded using grounded theory/constant comparative method. Participants were mostly male (55.1%). Half rated their current pain as at least six out of ten (50.8%). Two-thirds had discussed ACP with providers or supporters (66.2%). Qualitative themes were: (1) impact of managing pain on quality of life and healthcare, (2) knowledge/preferences for ACP, and (3) sources of HIV supportive care and coping (N = 39). Correlates of having discussed ACP included: moderate pain intensity (p < 0.10), including supporters in health decisions (p < 0.001), religious attendance (p < 0.05), and knowledge of healthcare mandates (p < 0.01; N = 276). Findings highlight the need for patient education to document healthcare preferences and communication skills development to promote inclusion of caregivers in decision-making. PMID- 28560612 TI - Characterization of Stress in Low-Income, Inner-City Mothers of Children with Poorly Controlled Asthma. AB - The goal of this longitudinal analysis was to characterize factors associated with the experience of life stress in low-income, inner-city mothers of minority children with high-risk asthma.Participants (n = 276) reported on family demographics, child asthma control and healthcare utilization, social support, contemporary life difficulties (housing, finances, violence exposure) measured by the validated Crisis in Family Systems scale, and daily stress. Latent growth curve modeling examined predictors of life stress across 12 months as a function of home and community difficulties, asthma-specific factors, and social support. Mothers were primarily single (73%), unemployed (55%), and living in extreme poverty with most (73%) reporting an annual family income <$20,000 (73%). The children were young (mean age = 5.59, SD = 2.17), African-American (96%), and had poorly controlled asthma (94%) at study enrollment. Higher daily stress was associated with financial difficulties, safety concerns in the home and community, and housing problems. Access to social support was consistently related to reduced stress. The only asthma-specific factor associated with life stress was healthcare utilization, with more emergency services for asthma related to higher daily stress. Findings underscore the clinical significance of assessing diverse home and community stressors and social support in low-income, inner-city caregivers of children with poorly controlled asthma. PMID- 28560614 TI - Letter to the editor. PMID- 28560613 TI - The Relationship between Neighborhood Disorder, Social Networks, and Indoor Cigarette Smoking among Impoverished Inner-City Residents. AB - Impoverished urban neighborhoods tend to have higher rates of smoking and higher rates of exposure to secondhand smoke as compared to more affluent neighborhoods. Contextual factors of neighborhood disorder and social network and household composition may have an impact on indoor smoking behaviors. The TIDE study examined psychosocial factors associated with smoking behaviors among impoverished inner-city smokers in Baltimore, Maryland. Among a community recruited sample of 413 smokers who lived with others, most (73%) reported that they or others smoked in their residence. Cohabitation with children, elderly, and those with asthma and other respiratory condition was not associated with indoor smoking. Neighborhood disorder, the proportion of social network members who smoked with the study participant, and the proportion of household members who smoked were all independently associated with smoking indoors. The study findings suggest the importance of addressing neighborhood and social network factors when developing programs for promoting indoor smoking bans as well as cessation and prevention programs. PMID- 28560615 TI - Effect of continuous dialysis on blood ph in acidemic hypercapnic animals with severe acute kidney injury: a randomized experimental study comparing high vs. low bicarbonate affluent. AB - BACKGROUND: Controlling blood pH during acute ventilatory failure and hypercapnia in individuals suffering from severe acute kidney injury (AKI) and undergoing continuous renal replacement therapy (CRRT) is of paramount importance in critical care settings. In this situation, the optimal concentration of sodium bicarbonate in the dialysate is still an unsolved question in critical care since high concentrations may worsen carbon dioxide levels and low concentrations may not be as effective in controlling pH. METHODS: We performed a randomized, non blinded, experimental study. AKI was induced in 12 female pigs via renal hilum ligation and hypoventilation by reducing the tidal volume during mechanical ventilation with the goal of achieving a pH between 7.10-7.15. After achieving the target pH, animals were randomized to undergo isovolemic hemodialysis with one of two bicarbonate concentrations in the dialysate (40 mEq/L [group 40] vs. 20 mEq/L [group 20]). RESULTS: Hemodynamic, respiratory, and laboratory data were collected. The median pH value at CRRT initiation was 7.14 [7.12, 7.15] in group 20 and 7.13 [7.09, 7.14] in group 40 (P = ns). The median baseline PaCO2 was 74 [72, 81] mmHg in group 20 vs. 79 [63, 85] mmHg in group 40 (P = ns). After 3 h of CRRT, the pH value was 7.05 [6.95, 7.09] in group 20 and 7.12 [7.1, 7.14] in group 40 (P < 0.05), with corresponding values of PaCO2 of 85 [79, 88] mmHg vs. 81 [63, 100] mmHg (P = ns). The difference in pH after 3 h was due to a metabolic component [standard base excess -10.4 [-12.5, -9.5] mEq/L in group 20 vs. -7.6 [ 9.2, -5.1] mEq/L in group 40) (P < 0.05)]. Despite the increased infusion of bicarbonate in group 40, the blood CO2 content did not change during the experiment. The 12-h survival rate was higher in group 40 (67% vs. 0, P = 0.032). CONCLUSIONS: A higher bicarbonate concentration in the dialysate of animals undergoing hypercapnic respiratory failure was associated with improved blood pH control without increasing the PaCO2 levels. PMID- 28560617 TI - A Case Study of Negative Affixes in Sadegh Hedayat's Letters: The Effect of Bipolar Mood Disorder. AB - This research studies the morphological features found in Sadegh Hedayat's letters, who, based on linguistic and psychological studies, may have had bipolar disorder. It aims to assess the impact of various types of moods on the frequency of negative affixes through qualitative analysis of the letters' text. The letters are written in Persian, and include six negative derivational affixes. As bipolar disorder includes four episodes, all letters are analyzed on the basis of six negative affixes concerning the episodes using SPSS. The results indicate that each episode shows totally different characteristics in using negative affixes. In fact, Hedayat mostly used negative affixes in depression, confirming psychological studies, and it is revealed that he mostly used negative affixes in hypomania when he experienced an irritated mood. Moreover, the frequency of negative affixes in mixed episode shows a combination of hypomania and depression, which is in agreement with previous studies. Additionally, euthymia shows few negative affixes. PMID- 28560616 TI - 1H, 13C, and 15N backbone and sidechain resonance assignments of a monomeric variant of E. coli deoxyribose-5-phosphate aldolase. AB - Deoxyribose-5-phosphate aldolase (DERA) catalyses the reversible conversion of 2 deoxyribose-5-phosphate (dR5P) into glyceraldehyde-3-phosphate (G3P) and acetaldehyde. For industrial applications, this enzyme is used in organic synthesis for aldol reactions between acetaldehyde as a donor and a wide range of aldehydes as acceptors. Here, we present a near complete set of sequence-specific 1H, 13C and 15N resonance assignments of a 28 kDa monomeric variant of the Escherichia coli DERA. These assignments provide the basis for ongoing structural and dynamic analysis of DERA substrate specificity. PMID- 28560618 TI - Dissipation pattern and risk quotients assessment of amisulbrom in Korean melon cultivated in plastic house conditions. AB - Amisulbrom formulated as suspension concentrate was applied at the rate recommended for Korean melon to determine the dissipation pattern (at two different sites), the pre-harvest residue limit (PHRL), and risk assessments. Samples collected over 10 days were extracted using liquid-liquid extraction (LLE) and cleaned up with solid-phase extraction (SPE) Florisil cartridge. Residual concentrations were determined using liquid chromatography-ultraviolet detector (LC-UVD) and confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The standard showed good instrument response linearity with a correlation coefficient (R 2) = 0.9999, and the recovery ranged from 87.5 to 93.7%. The dissipation half-life calculated from two different sites were found to be 7.0 and 8.8 days for sites 1 and 2, respectively. A PHRL graph constructed from the data indicated that if the residue levels were less than 0.55-0.59 mg/kg 3 days before harvest or less than 0.61-0.74 mg/kg 7 days before harvest, then they would be lower than the maximum residue limits (MRLs) at harvest. Risk assessments showed that the risk quotient (RQ) was 4.39-3.47% at 0 day, declined to 1.53-1.63% at 10 days. Therefore, the current data indicate that the amisulbrom can be applied safely to Korean melon; hence, it is unlikely to induce adverse health effects in consumers. PMID- 28560620 TI - 13C NMR spectroscopy characterization of particle-size fractionated soil organic carbon in subalpine forest and grassland ecosystems. AB - BACKGROUND: Soil organic carbon (SOC) and carbon (C) functional groups in different particle-size fractions are important indicators of microbial activity and soil decomposition stages under wildfire disturbances. This research investigated a natural Tsuga forest and a nearby fire-induced grassland along a sampling transect in Central Taiwan with the aim to better understand the effect of forest wildfires on the change of SOC in different soil particle scales. Soil samples were separated into six particle sizes and SOC was characterized by solid state 13C nuclear magnetic resonance spectroscopy in each fraction. RESULTS: The SOC content was higher in forest than grassland soil in the particle-size fraction samples. The O-alkyl-C content (carbohydrate-derived structures) was higher in the grassland than the forest soils, but the alkyl-C content (recalcitrant substances) was higher in forest than grassland soils, for a higher humification degree (alkyl-C/O-alkyl-C ratio) in forest soils for all the soil particle-size fractions. CONCLUSIONS: High humification degree was found in forest soils. The similar aromaticity between forest and grassland soils might be attributed to the fire-induced aromatic-C content in the grassland that offsets the original difference between the forest and grassland. High alkyl-C content and humification degree and low C/N ratios in the fine particle-size fractions implied that undecomposed recalcitrant substances tended to accumulate in the fine fractions of soils. PMID- 28560619 TI - Cariprazine: A Review in Schizophrenia. AB - Cariprazine (VraylarTM) is a dopamine D3-preferring D2/D3 receptor partial agonist indicated for the treatment of patients with schizophrenia. This narrative review summarizes pharmacological, efficacy and tolerability data relevant to the use of cariprazine in patients with this disorder. In 6-week, phase IIb and III trials in patients with schizophrenia, cariprazine was significantly more efficacious than placebo in improving schizophrenia symptoms, including improvements in Positive and Negative Syndrome Scale (PANSS) total scores. It was associated with a significantly longer time to relapse than placebo in a long-term, phase III, relapse-prevention study. Cariprazine was also significantly more efficacious than risperidone in improving PANSS Factor Score for Negative Symptoms in a phase III trial in patients with predominantly negative symptoms of schizophrenia, a typically difficult to treat group of patients. Cariprazine was generally well tolerated in clinical trials, with most adverse events being of mild to moderate severity, and metabolic changes observed were considered generally not clinically significant. Cariprazine is a useful addition to the treatment options for schizophrenia, and may be of particular use in patients with predominantly negative symptoms. PMID- 28560622 TI - Micro-electrolysis/retinervus luffae-based simultaneous autotrophic and heterotrophic denitrification for low C/N wastewater treatment. AB - Nitrogen bioremediation in organic insufficient wastewater generally requires an extra carbon source. In this study, nitrate-contaminated wastewater was treated effectively through simultaneous autotrophic and heterotrophic denitrification based on micro-electrolysis carriers (MECs) and retinervus luffae fructus (RLF), respectively. The average nitrate and total nitrogen removal rates reached 96.3 and 94.0% in the MECs/RLF-based autotrophic and heterotrophic denitrification (MRAHD) system without ammonia and nitrite accumulation. The performance of MRAHD was better than that of MEC-based autotrophic denitrification for the wastewater treatment with low carbon nitrogen (COD/N) ratio. Real-time quantitative polymerase chain reaction (qPCR) revealed that the relative abundance of nirS type denitrifiers attached to MECs (4.9%) and RLF (5.0%) was similar. Illumina sequencing suggested that the dominant genera were Thiobacillus (7.0%) and Denitratisoma (5.7%), which attached to MECs and RLF, respectively. Sulfuritalea was discovered as the dominant genus in the middle of the reactor. The synergistic interaction between autotrophic and heterotrophic denitrifiers played a vital role in the mixotrophic substrate environment. PMID- 28560621 TI - Lymphocytes as Biomarkers of Therapeutic Response in Rheumatic Autoimmune Diseases, Is It a Realistic Goal? AB - Many therapies are available for patients with rheumatoid arthritis (RA) while biological therapies have limited effects in patients with systemic lupus erythematosus (SLE) and primary Sjogren's syndrome (pSS). In both cases, biomarkers predicting drug response would be very useful to guide clinicians in their choice. We performed a systematic review to evaluate the value of lymphocyte phenotyping as a marker of therapeutic response. Of the 1063 articles retrieved, 39 fulfilled inclusion criteria and were included in the present review (25 for RA, 10 for SLE, and 4 for pSS). Lymphocyte phenotyping was described as a biomarker of therapeutic response in many studies, but most results could not be confirmed by independent teams using multivariate analysis. The most consistent result might be the association between rituximab response and the levels of memory B cells before therapy, although some studies were controversial. Thus, lymphocyte phenotyping cannot yet be proposed as a biomarker of response in rheumatic autoimmune diseases. The lack of reproducibility between studies may be explained by technical issues influencing lymphocyte phenotyping so standardization procedures should be developed for future studies. The patients' characteristics vary between studies, and large population studies, including a wide range of patients' characteristics and biomarkers, are required to provide predictive models for clinical outcomes. The use of new flow cytometry techniques such as single-cell mass cytometry technology might also help finder reliable biomarkers in the future. PMID- 28560623 TI - Exposure assessment of honeybees through study of hive matrices: analysis of selected pesticide residues in honeybees, beebread, and beeswax from French beehives by LC-MS/MS. AB - Apiculture and pollination services are seriously threatened by bee weakening and losses phenomena. In this context, a survey was performed on samples from beehives across French areas during the 2012-2016 growing seasons, primarily taken from symptomatic colonies. A total of 488 honeybees, beebread, and wax were analyzed for the presence of pesticide residues. A total of 13 analytes including neonicotinoids and pyrethroids insecticides together with some of their metabolites and the fungicide boscalid were screened within samples. Methodologies based on efficient modified quick, easy, cheap, effective, rugged, and safe extractions followed by an LC-MS/MS quantification were implemented for each matrix. Thirty-eight percent of the 125 bee samples, 61% of the 87 wax samples, and 77% of the 276 beebread samples contained at least one of the targeted pesticides. Beebread was the most contaminated matrix with an average of two pesticide detections by positive sample and a maximum of seven compounds for a sample. Neonicotinoids and boscalid were the most often detected pesticides, whatever the matrix. The comparison of neonicotinoid detections in samples collected before and after the partial neonicotinoid ban in France displays a decrease in the frequency of detections for contamination levels lower than 1 ng/g in beebread. For higher levels and other matrices, no tendency can be drawn. PMID- 28560624 TI - Urinary metabolomic profiling in rats exposed to dietary di(2-ethylhexyl) phthalate (DEHP) using ultra-performance liquid chromatography quadrupole time-of flight tandem mass spectrometry (UPLC/Q-TOF-MS). AB - Di(2-ethylhexyl) phthalate (DEHP) is an omnipresent environmental chemical with widespread nonoccupational human exposure through multiple ways. Although considerable efforts have been invested to investigate mechanisms of DEHP toxicity, the key metabolic biomarkers of DEHP toxicity remain to be identified. The aim of this study was to assess the urinary metabonomics of dietary DEHP in rats using the technique of ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS). Fourteen female Wistar rats were divided into two groups and given increasing dietary doses of DEHP for 30 consecutive days. The urinary metabolite profile was studied using ultra performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) enabled clusters to be clearly separated. Eleven principal urinary metabolites were identified as contributing to the clusters. The clusters in the positive electrospray ionization (ESI) mode were xanthurenic acid, kynurenic acid, nonate, N6-methyladenosine, and L-isoleucyl-L-proline. The clusters in the negative ESI mode were hippuric acid, tetrahydrocortisol, citric acid, phenylpropionylglycine, cPA(18:2(9Z, 12Z)/0:0), and LysoPC(14:1(9Z)). The urinary metabonomic changes indicated that exposure to dietary DEHP can affect energy-related metabolism, liver and renal function, fatty acid metabolism, and cause DNA damage in rats. The findings of this study on the urinary metabolites and metabolic pathways of DEHP may form the basis for future studies on the mechanisms of toxicity of this commonly found environmental chemical. PMID- 28560627 TI - Testing the EKC hypothesis by considering trade openness, urbanization, and financial development: the case of Turkey. AB - This study investigates the environmental Kuznets curve (EKC) hypothesis for the case of Turkey from 1960 to 2013 by considering energy consumption, trade, urbanization, and financial development variables. Although previous literature examines various aspects of the EKC hypothesis for the case of Turkey, our model augments the basic model with several covariates to develop a better understanding of the relationship among the variables and to refrain from omitted variable bias. The results of the bounds test and the error correction model under autoregressive distributed lag mechanism suggest long-run relationships among the variables as well as proof of the EKC and the scale effect in Turkey. A conditional Granger causality test reveals that there are causal relationships among the variables. Our findings can have policy implications including the imposition of a "polluter pays" mechanism, such as the implementation of a carbon tax for pollution trading, to raise the urban population's awareness about the importance of adopting renewable energy and to support clean, environmentally friendly technology. PMID- 28560628 TI - Fate of selected drugs in the wastewater treatment plants (WWTPs) for domestic sewage. AB - The wide diffusion of Emerging Organic Micropollutants (EOMs) in the environment is receiving increasing attention due to their potential toxicological effects on living organisms. So far, the Wastewater Treatment Plants (WWTPs) have not been designed with the purpose to remove these contaminants; therefore, they can represent the major source of release into the environment both through the effluent and the wasted sludge. The fate of EOMs in the WWTPs is still not completely known; further investigations are therefore needed to assess if it is possible to exploit the existing treatment units to reduce EOM concentrations or which processes must be implemented to this purpose. Among the wide class of EOMs, the present study focused on the following drugs of abuse: amphetamine (AM), methamphetamine (MET), 11-nor-Delta9-THC-9carboxy (THC-COOH) and benzoylecgonine (BEG). Presence and removal efficiency of these drugs in the activated sludge tank of a WWTP for domestic sewage was investigated through analyses at both full-scale and laboratory scale. Determinations conducted in the full-scale WWTP highlighted that, among the searched drugs, AM was found to be the most abundant in the influent and effluent of the biological oxidation tank, while 11-nor-Delta9-THC-9carboxy was present at the lowest concentration. Some removal took place in the units prior to the oxidation tank, although the main reduction was observed to occur in the biological oxidation reactor. All the drugs showed a wide variability of the measured concentrations during the week and the day. Taking into account results from both full-scale observations and batch tests, removals in the biological reactor were found within the following ranges: 33-84% for AM, 33-97% for MET, 33-57% for BEG and 29-83% for THC-COOH. These removals were due to a combination of adsorption and biodegradation mainly, while volatilization did not play a significant role. Other processes, e.g. hydrolysis, were likely to occur. PMID- 28560625 TI - Fullerol C60(OH)24 nanoparticles and mycotoxigenic fungi: a preliminary investigation into modulation of mycotoxin production. AB - Increased use of fullerols in various fields and expected increase of their environmental spread impose the necessity for testing fullerol nanoparticles (FNP) effects on microbiota. There is little information available on the interaction of mycotoxigenic fungi and FNP, despite FNP having a great potential of modifying mycotoxin production. Namely, FNP exhibit both ROS-quenching and ROS producing properties, while oxidative stress stimulates mycotoxin synthesis in the fungi. In order to shed some light on the extent of interaction between FNP and mycotoxigenic fungi, the effects of fullerol C60(OH)24 nanoparticles (10, 100, 1000 ng/mL) on mycelial growth, aflatoxin production and oxidative stress modulation in an aflatoxigenic strain of Aspergillus flavus (NRRL 3251) during 168 h of incubation in a liquid culture medium were examined. FNP slightly reduced mycelial biomass weight, but significantly decreased aflatoxin concentration in media. Lipid peroxide content, superoxide dismutase, catalase and glutathione peroxidase activities suggest that FNP treatments hormetically reduced oxidative stress within fungal cells in turn suppressing aflatoxin production. These findings contribute to the assessment of environmental risk and application potential of fullerols. PMID- 28560626 TI - Use of halophytes in pilot-scale horizontal flow constructed wetland treating domestic wastewater. AB - Recent findings encourage the use of halophytes in constructed wetlands for domestic wastewater treatment due to their special physiological characteristics as the ability to accumulate heavy metals and salts in their tissues makes them ideal candidates for constructed wetland vegetation. In this particular study, we investigated the application of halophytic plants in a horizontal flow constructed wetland for domestic wastewater treatment purposes. The pilot plant which was situated in Crete (Greece) was planted with a polyculture of halophytes (Tamarix parviflora, Juncus acutus, Sarcocornia perrenis, and Limoniastrum monopetalum). The system's performance was monitored for a period of 11 months during which it received primary treated wastewater from the local wastewater treatment plant. Results show that halophytes developed successfully in the constructed wetland and achieved organic matter and pathogen removal efficiencies comparable to those reported for reeds in previous works (63% and 1.6 log units, respectively). In addition, boron concentration in the effluent was reduced by 40% in comparison with the influent. Salinity as expressed by electrical conductivity did not change during the treatment, indicating that the accumulation of salts in the leaves is not able to overcome electrical conductivity increasing due to evapotranspiration. The results indicate an improvement in the treatment of domestic wastewater via the use of halophyte planted CWs. PMID- 28560629 TI - Extreme learning machines: a new approach for modeling dissolved oxygen (DO) concentration with and without water quality variables as predictors. AB - In this paper, several extreme learning machine (ELM) models, including standard extreme learning machine with sigmoid activation function (S-ELM), extreme learning machine with radial basis activation function (R-ELM), online sequential extreme learning machine (OS-ELM), and optimally pruned extreme learning machine (OP-ELM), are newly applied for predicting dissolved oxygen concentration with and without water quality variables as predictors. Firstly, using data from eight United States Geological Survey (USGS) stations located in different rivers basins, USA, the S-ELM, R-ELM, OS-ELM, and OP-ELM were compared against the measured dissolved oxygen (DO) using four water quality variables, water temperature, specific conductance, turbidity, and pH, as predictors. For each station, we used data measured at an hourly time step for a period of 4 years. The dataset was divided into a training set (70%) and a validation set (30%). We selected several combinations of the water quality variables as inputs for each ELM model and six different scenarios were compared. Secondly, an attempt was made to predict DO concentration without water quality variables. To achieve this goal, we used the year numbers, 2008, 2009, etc., month numbers from (1) to (12), day numbers from (1) to (31) and hour numbers from (00:00) to (24:00) as predictors. Thirdly, the best ELM models were trained using validation dataset and tested with the training dataset. The performances of the four ELM models were evaluated using four statistical indices: the coefficient of correlation (R), the Nash-Sutcliffe efficiency (NSE), the root mean squared error (RMSE), and the mean absolute error (MAE). Results obtained from the eight stations indicated that: (i) the best results were obtained by the S-ELM, R-ELM, OS-ELM, and OP-ELM models having four water quality variables as predictors; (ii) out of eight stations, the OP-ELM performed better than the other three ELM models at seven stations while the R-ELM performed the best at one station. The OS-ELM models performed the worst and provided the lowest accuracy; (iii) for predicting DO without water quality variables, the R-ELM performed the best at seven stations followed by the S-ELM in the second place and the OP-ELM performed the worst with low accuracy; (iv) for the final application where training ELM models with validation dataset and testing with training dataset, the OP-ELM provided the best accuracy using water quality variables and the R-ELM performed the best at all eight stations without water quality variables. Fourthly, and finally, we compared the results obtained from different ELM models with those obtained using multiple linear regression (MLR) and multilayer perceptron neural network (MLPNN). Results obtained using MLPNN and MLR models reveal that: (i) using water quality variables as predictors, the MLR performed the worst and provided the lowest accuracy in all stations; (ii) MLPNN was ranked in the second place at two stations, in the third place at four stations, and finally, in the fourth place at two stations, (iii) for predicting DO without water quality variables, MLPNN is ranked in the second place at five stations, and ranked in the third, fourth, and fifth places in the remaining three stations, while MLR was ranked in the last place with very low accuracy at all stations. Overall, the results suggest that the ELM is more effective than the MLPNN and MLR for modelling DO concentration in river ecosystems. PMID- 28560630 TI - Diplopia as isolated presentation of varicella zoster central nervous system reactivation. AB - Here, we report a patient who developed diplopia secondary to a right cranial nerve III and IV palsy, as well as fever and headache. Cerebrospinal fluid analysis (CSF) showed high varicella-zoster virus (VZV)-DNA viral load (>300,000,000 copies/ml). VZV antibodies in CSF was >=1:16. Diagnosis of neurological reactivation of VZV infection was made without the presence of characteristic vesicular rash. Quantitative real-time PCR for VZV and intrathecal dosage of VZV IgM and IgG should be performed in cases suspected for viral encephalitis and also in all patients with not otherwise attributable cranial nerve lesions. PMID- 28560632 TI - Improvements in brain and behavior following eradication of hepatitis C. AB - Despite recent advances in treatment, hepatitis C remains a significant public health problem. The hepatitis C virus (HCV) is known to infiltrate the brain, yet findings from studies on associated neurocognitive and neuropathological changes are mixed. Furthermore, it remains unclear if HCV eradication improves HCV associated neurological compromise. This study examined the longitudinal relationship between neurocognitive and neurophysiologic markers among healthy HCV- controls and HCV+ adults following successful HCV eradication. We hypothesized that neurocognitive outcomes following treatment would be related to both improved cognition and white matter integrity. Participants included 57 HCV+ participants who successfully cleared the virus at the end of treatment (sustained virologic responders [SVRs]) and 22 HCV- controls. Participants underwent neuropsychological testing and, for a nested subset of participants, neuroimaging (diffusion tensor imaging) at baseline and 12 weeks following completion of HCV therapy. Contrary to expectation, group-level longitudinal analyses did not reveal significant improvement in neurocognitive performance in the SVRs compared to the control group. However, a subgroup of SVRs demonstrated a significant improvement in cognition relative to controls, which was related to improved white matter integrity. Indeed, neuroimaging data revealed beneficial effects associated with clearing the virus, particularly in the posterior corona radiata and the superior longitudinal fasciculus. Findings suggest that a subgroup of HCV+ patients experienced improvements in cognitive functioning following eradication of HCV, which appears related to positive changes in white matter integrity. Future research should examine whether any additional improvements in neurocognition and white matter integrity among SVRs occur with longer follow-up periods. PMID- 28560635 TI - Preface for the Ursula Sonnewald Honorary Issue of Neurochemical Research. PMID- 28560633 TI - Simultaneous living donor liver transplant with sleeve gastrectomy for metabolic syndrome and NASH-related ESLD-First report from India. AB - Nonalcoholic steatohepatitis (NASH) with morbid obesity and metabolic syndrome is now a common cause of end-stage liver disease (ESLD). These patients are high risk candidates for liver transplant, and require bariatric surgery to prevent recurrent disease in the new liver. Data reports bariatric surgery after transplant, which maybe difficult because of adhesions between the stomach and liver in living donor liver transplant (LDLT) recipient. We report the first case of combined LDLT with sleeve gastrectomy (SG) from India. A morbidly obese diabetic woman with NASH-related ESLD was planned for combined right lobe LDLT with open SG, in view of failed diet therapy, musculo-skeletal complaints, and restricted mobility. Postoperatively, with liver graft functioning adequately, bariatric diet restrictions resulted in maximum reduction of 25% weight, achieving a target BMI below 30 kg/m2 within 2 months, along with complete cure of diabetes and better ambulation. Thus, combination of LDLT and bariatric surgery in the same sitting is safe and effective in management of metabolic syndrome and associated NASH-related ESLD. PMID- 28560631 TI - Genetics of HIV-associated sensory neuropathy and related pain in Africans. AB - Despite the use of safer antiretroviral medications, the rate of HIV-associated sensory neuropathy (HIV-SN), the most common neurological complication of HIV, remains high. This condition is often painful and has a negative effect on quality of life. Up to 90% of those with HIV-SN experience pain for which there is no effective analgesic treatment. Genetic factors are implicated, but there is a lack of a comprehensive body of research for African populations. This knowledge gap is even more pertinent as Africans are most affected by HIV. However, recent studies performed in Southern African populations have identified genes displaying potential as genetic markers for HIV-SN and HIV-SN-associated pain in Africans. Here, we review the published studies to describe current knowledge of genetic risk factors for this disease in Africa. PMID- 28560634 TI - Modulation of IgG-FcRn interactions to overcome antibody-mediated inhibition of nerve regeneration. PMID- 28560636 TI - Monkeys and mountains in Yunnan, China. PMID- 28560637 TI - Characterization of Thiomonas delicata arsenite oxidase expressed in Escherichia coli. AB - Microbial arsenite oxidation is an essential biogeochemical process whereby more toxic arsenite is oxidized to the less toxic arsenate. Thiomonas strains represent an important arsenite oxidizer found ubiquitous in acid mine drainage. In the present study, the arsenite oxidase gene (aioBA) was cloned from Thiomonas delicata DSM 16361, expressed heterologously in E. coli and purified to homogeneity. The purified recombinant Aio consisted of two subunits with the respective molecular weights of 91 and 21 kDa according to SDS-PAGE. Aio catalysis was optimum at pH 5.5 and 50-55 degrees C. Aio exhibited stability under acidic conditions (pH 2.5-6). The V max and K m values of the enzyme were found to be 4 umol min-1 mg-1 and 14.2 uM, respectively. SDS and Triton X-100 were found to inhibit the enzyme activity. The homology model of Aio showed correlation with the acidophilic adaptation of the enzyme. This is the first characterization studies of Aio from a species belonging to the Thiomonas genus. The arsenite oxidase was found to be among the acid-tolerant Aio reported to date and has the potential to be used for biosensor and bioremediation applications in acidic environments. PMID- 28560638 TI - Induction of fungal laccase production under solid state bioprocessing of new agroindustrial waste and its application on dye decolorization. AB - Lignocellulosic wastes are generally produced in huge amounts worldwide. Peach waste of these obtained from fruit juice industry was utilized as the substrate for laccase production by Pleurotus eryngii under solid state bioprocessing (SSB). Its chemical composition was determined and this bioprocess was carried out under stationary conditions at 28 degrees C. The effects of different compounds; copper, iron, Tween 80, ammonium nitrate and manganese, and their variable concentrations on laccase production were investigated in detail. The optimum production of laccase (43,761.33 +/- 3845 U L-1) was achieved on the day of 20 by employing peach waste of 5.0 g and 70 uM Cu2+, 18 uM Fe2+, 0.025% (v/v) Tween 80, 4.0 g L-1 ammonium nitrate, 750 uM Mn2+ as the inducers. The dye decolorization also researched to determine the degrading capability of laccase produced from peach culture under the above-mentioned conditions. Within this scope of the study, methyl orange, tartrazine, reactive red 2 and reactive black dyes were treated with this enzyme. The highest decolorization was performed with methyl orange as 43 +/- 2.8% after 5 min of treatment when compared to other dyes. Up to now, this is the first report on the induction of laccase production by P. eryngii under SSB using peach waste as the substrate. PMID- 28560639 TI - Production of biodiesel from microalgae through biological carbon capture: a review. AB - Gradual increase in concentration of carbon dioxide (CO2) in the atmosphere due to the various anthropogenic interventions leading to significant alteration in the global carbon cycle has been a subject of worldwide attention and matter of potential research over the last few decades. In these alarming scenario microalgae seems to be an attractive medium for capturing the excess CO2 present in the atmosphere generated from different sources such as power plants, automobiles, volcanic eruption, decomposition of organic matters and forest fires. This captured CO2 through microalgae could be used as potential carbon source to produce lipids for the generation of biofuel for replacing petroleum derived transport fuel without affecting the supply of food and crops. This comprehensive review strives to provide a systematic account of recent developments in the field of biological carbon capture through microalgae for its utilization towards the generation of biodiesel highlighting the significance of certain key parameters such as selection of efficient strain, microalgal metabolism, cultivation systems (open and closed) and biomass production along with the national and international biodiesel specifications and properties. The potential use of photobioreactors for biodiesel production under the influence of various factors viz., light intensity, pH, time, temperature, CO2 concentration and flow rate has been discussed. The review also provides an economic overview and future outlook on biodiesel production from microalgae. PMID- 28560640 TI - MERS-CoV papain-like protease (PLpro): expression, purification, and spectroscopic/thermodynamic characterization. AB - Within a decade, MERS-CoV emerged with nearly four times higher case fatality rate than an earlier outbreak of SARS-CoV and spread out in 27 countries in short span of time. As an emerging virus, combating it requires an in-depth understanding of its molecular machinery. Therefore, conformational characterization studies of coronavirus proteins are necessary to advance our knowledge of the matter for the development of antiviral therapies. In this study, MERS-CoV papain-like protease (PLpro) was recombinantly expressed and purified. Thermal folding pathway and thermodynamic properties were characterized using dynamic multimode spectroscopy (DMS) and thermal shift assay. DMS study showed that the PLpro undergoes a single thermal transition and follows a pathway of two-state folding with T m and van't Hoff enthalpy values of 54.4 +/- 0.1 degrees C and 317.1 +/- 3.9 kJ/mol, respectively. An orthogonal technique based on intrinsic tryptophan fluorescence also showed that MERS-CoV PLpro undergoes a single thermal transition and unfolds via a pathway of two-state folding with a T m value of 51.4 degrees C. Our findings provide significant understandings of the thermodynamic and structural properties of MERS-CoV PLpro. PMID- 28560641 TI - Plant growth-promoting actinobacteria: a new strategy for enhancing sustainable production and protection of grain legumes. AB - Grain legumes are a cost-effective alternative for the animal protein in improving the diets of the poor in South-East Asia and Africa. Legumes, through symbiotic nitrogen fixation, meet a major part of their own N demand and partially benefit the following crops of the system by enriching soil. In realization of this sustainability advantage and to promote pulse production, United Nations had declared 2016 as the "International Year of pulses". Grain legumes are frequently subjected to both abiotic and biotic stresses resulting in severe yield losses. Global yields of legumes have been stagnant for the past five decades in spite of adopting various conventional and molecular breeding approaches. Furthermore, the increasing costs and negative effects of pesticides and fertilizers for crop production necessitate the use of biological options of crop production and protection. The use of plant growth-promoting (PGP) bacteria for improving soil and plant health has become one of the attractive strategies for developing sustainable agricultural systems due to their eco-friendliness, low production cost and minimizing consumption of non-renewable resources. This review emphasizes on how the PGP actinobacteria and their metabolites can be used effectively in enhancing the yield and controlling the pests and pathogens of grain legumes. PMID- 28560642 TI - Identification and characterization of microRNAs and their targets in high altitude stress-adaptive plant maca (Lepidium meyenii Walp). AB - MicroRNAs (miRNAs) are endogenous, short (~21-nucleotide), non-coding RNA molecules that play pivotal roles in plant growth, development, and stress response signaling. In this study using recently published draft genome sequence of a high-altitude plant maca (Lepidium meyenii Walp) and applying genome-wide computational-based approaches, a total of 62 potentially conserved miRNAs belonging to 28 families were identified and four (lme-miR160a, lme-miR164c, lme miR 166a, and lme-miR 319a) of them further validated by RT-PCR. Deploying psRNATarget tool a total of 99 potential miRNA target transcripts were also identified in maca. Targets include a number of transcription factors like Squamosa promoter-binding, NAC, MYB, auxin response factor, APETALA, WRKY, and F box protein. To the best of my knowledge, this is the first genome-based miRNA profiling of a high-altitude plant. PMID- 28560643 TI - In vitro seed germination and biochemical profiling of Artemisia absinthium exposed to various metallic nanoparticles. AB - In the recent years, nanotechnology has attained much attention in the every field of science. The synthesis, characterisation and applications of metallic nanoparticles (MNPs) have become an important branch of nanotechnology. In the current study, MNPs were synthesised through polyols process and applied in vitro to study their effect on medicinally important plant : Artemisia absinthium. The current study strives to check the effect of MNPs, i.e., Ag, Cu and Au on seed germination, root and shoot length, seedling vigour index (SVI) and biochemical profiling in A. absinthium. The seeds were inoculated on MS medium supplemented with various combinations of MNPs suspension. The seed germination was greatly influenced upon the application of MNPs and was recorded highest for the silver nanoparticles (AgNPs) suspensions. The best result for seed germination (98.6%) was obtained in MS medium supplemented with AgNPs as compared to control (92.9%) and other nanoparticles, i.e., copper (69.6%) and gold (56.5%), respectively, after 35 days of inoculation. Significant results were obtained for root length, shoot length and SVI in response to application of AgNPs as compared to copper nanoparticles (CuNPs) and gold nanoparticles (AuNPs). These nanoparticles (NPs) could induce stress in plants by deploying the endogenous mechanism. In response to these stresses, plants produce various defence compounds. Total phenolic content (TPC) and total flavonoid content (TFC) were significant in the MS medium supplemented with AgNPs as compared to other NPs, while DPPH radical scavenging assay (RSA) was highest in AuNPs treated plantlets. The MNPs showed higher toxicity level and enhanced secondary metabolites production, total phenolic content, total flavonoid content, antioxidant activity, superoxide dismutase (SOD) activity and total protein content. PMID- 28560644 TI - Biosorption and equilibrium isotherms study of cadmium removal by Nostoc muscorum Meg 1: morphological, physiological and biochemical alterations. AB - Rice fields of Meghalaya especially in the coal mining belt receive water contaminated by effluents from mines that are known to carry harmful heavy metal ions such as Cu, Fe, Zn, Ni, Cd, As, Pb, Cr, etc. Cd exposure was analyzed in the cyanobacterium Nostoc muscorum Meg 1 isolated from a contaminated rice field in Sohra, Meghalaya, India. Toxicity study established 0.5 ppm on day 3 to be the LD50. At LD50 chlorophyll a and total protein concentration was reduced by 50.9 and 52.5%, while nitrogenase and glutamine synthetase activities were inhibited by 40.8 and 38.4%. EDX and FTIR analyses confirmed Cd binding and participation of hydroxyl, carbonyl, carboxyl and phosphate groups in biosorption of Cd onto the cell surfaces. SEM study established morphological changes. At pH 8.0 and temperature 25 +/- 2 degrees C, the cyanobacterium removed 92% Cd within 24 h. Of this, 91% Cd was adsorbed on the cell surface while 4% was internally accumulated. The energy required for internal accumulation of Cd was partly provided in the form of ATP synthesized during active photosynthesis. The Langmuir isotherm was found best fitted with a R 2 value 0.98 when compared to Freundlich and Temkin adsorption isotherms. The maximum sorption capacity, Q max, of the organism was 71.4 mg of Cd per g of biomass. R L value of 0.29 indicated favorable interaction between cyanobacterial biomass and Cd. The adsorption intensity, n value 7.69 g/L obtained from Freundlich isotherm showed that the organism possessed high Cd sorption capacity. PMID- 28560645 TI - A comparative assessment of morphological and molecular diversity among Sechium edule (Jacq.) Sw. accessions in India. AB - Genetic variation of 36 Sechium edule accessions collected across 12 states in India was assessed using morphological traits and DAMD markers. Eighteen fruit morphological traits (both qualitative and quantitative) were evaluated to confirm the variations in the present collection. Quantitative traits showed major variations with respect to fruit weight (7.85-498.33 g/fruit), fruit length (5.8-15 cm/fruit), fruit diameter (6-28 cm/fruit) and length of the spine (0-5 cm). Qualitative traits were also diverse in fruit colour, shape, spine density, reticulation, flexibility of spine and furrow depth. The first six principle components showed 82.88% variation in the principal component analysis. The principal component analysis revealed that fruit weight, fruit width, fruit diameter, fruit shape, length of spine, spine density and furrow depth had a significant contribution to the total variation. The DNA analysis performed using DAMD primers were used for deducing the diversity at DNA level. The collection produced 102 bands out of which 97 were polymorphic and the percentage polymorphism ranged between 66.66 and 100 per primer. Discrete pattern of clustering was obtained using UPGMA method of complete linkage percent disagreement revealing high diversity among the collected accessions. Thus, the present study indicates that molecular and morphological marker map would improve our knowledge of S. edule and would facilitate efforts to breed improved S. edule cultivars. PMID- 28560646 TI - Synergistic effect of Chryseobacterium gleum sp. SUK with ACC deaminase activity in alleviation of salt stress and plant growth promotion in Triticum aestivum L. AB - Soil salinity is major abiotic stresses affecting morphological, biochemical and physiological processes of plant growth. Chryseobacterium gleum sp. SUK isolated from salt-stressed soil exhibited ACC (1-aminocyclopropane-1-carboxylate) deaminase activity with IAA (indole acetic acid), siderophore, ammonia, hydrogen cyanide production, 2% salt tolerance and fungal cell wall degrading enzyme production (cellulase, protease). The isolate also showed a poultry feather degrading activity which is the main waste material of poultry industry and opulent source of proteins, amino acids, nitrogen, phosphorous, calcium, potassium, manganese, zinc and copper. Application of feather-degraded lysate with the degrading isolate, C. gleum sp. SUK denotes triple role of bioformulation to surmount salinity stress, management of poultry waste disposal and utilization of feathers degraded products as a biostimulant for better growth of plants as well as strain SUK having multifarious plant growth promoting traits. Wheat crops exposed to salt stressor were inoculated with studied bioformulation. Results of plant analysis showed improvement in root and shoot length, fresh and dry weight, chlorophyll, proteins, amino acids, phenolics, flavonoids content and decreased level of proline. In addition, Na+ uptake was decreased and K+ uptake was increased. Therefore, application of novel bioformulation could increase the yield of crops by ameliorating growth of plants and alleviating the salinity stress. PMID- 28560647 TI - Cytomorphological and nitrogen metabolic enzyme analysis of psychrophilic and mesophilic Nostoc sp.: a comparative outlook. AB - Cyanobacterial diazotrophs play a significant role in environmental nitrogen economy despite their habitat either tropical or polar. However, the phenomenon by which it copes with temperature induced stress is poorly understood. Temperature response study of psychrophilic and mesophilic Nostoc strains explores their adaptive mechanisms. The selected psychrophilic and mesophilic strains were confirmed as Nostoc punctiforme and Nostoc calcicola respectively, by ultrastructure and 16S rDNA phylogeny. The psychrophilic strain has extensive glycolipid and polysaccharide sheath along with characteristic deposition of cyanophycin, polyhydroxybutyrate granules, and carboxysomes. This is possibly an adaptive strategy exhibited to withstand the freezing temperature and high intense of ultraviolet rays. The biomass measured in terms of dry weight, protein, and chlorophyll indicated a temperature dependant shift in both the psychrophilic and mesophilic strains and attained maximum growth in their respective temperature niches. At low temperature, psychrophilic organism exhibited nitrogenase activity, while mesophilic strains did not. The maximum glutamine synthetase activity was observed at 4 degrees C for psychrophilic and 37 degrees C for mesophilic strains. Activity at 4 degrees C in psychrophilic strains revealed their energetic mechanism even at low temperature. The nitrate and nitrite reductase of both psychrophilic and mesophilic strains showed maximum activity at 37 degrees C denoting their similar nitrogen assimilating mechanisms for combined nitrogen utilization. The activity studies of nitrogen fixation/assimilation enzymes have differential effects at varying temperatures, which provide valuable insights of physiological contribution and role of Nostoc strains in the biological nitrogen cycle. PMID- 28560648 TI - Smoking behaviour and health care costs coverage: a European cross-country comparison. AB - The empirical evidence about the effect of smoking on health care cost coverage is not consistent with the expectations based on the notion of adverse selection. This evidence is mostly based on correlational studies which cannot isolate the adverse selection effect from the moral hazard effect. Exploiting data from the Survey of Health, Aging, and Retirement in Europe, this study uses an instrumental variable strategy to identify the causal effect of daily smoking on perceived health care cost coverage of those at age 50 or above in 12 European countries. Daily smoking is instrumented by a variable indicating whether or not there is any other daily smoker in the household. A self-assessment of health care cost coverage is used as the outcome measure. Among those who live with a partner (72% of the sample), the result is not statistically significant which means we find no effect of smoking on perceived health care cost coverage. However, among those who live without a partner, the results show that daily smokers have lower self-assessed perceived health care cost coverage. This finding replicates the same counter-intuitive relationship between smoking and health insurance presented in previous studies, but in a language of causality. In addition to this, we contribute to previous studies by a cross-country comparison which brings in different institutional arrangements, and by using the self-assessed perceived health care cost coverage which is broader than health insurance coverage. PMID- 28560650 TI - Effects of Learning Strategy Training on the Writing Performance of College Students with Asperger's Syndrome. AB - Individuals with autism spectrum disorders (ASD) are increasingly entering institutions of higher education. However, many are not prepared for the academic and social demands of postsecondary environments. Although studies have evaluated academic and social interventions for children and adolescents with ASD, little research exists on the college population. The current study utilized a multiple baseline across participants design to evaluate the effectiveness of a writing learning strategy on the writing performance of three college students with ASD. Results indicated that the quality of writing performance improved following strategy instruction. In addition, participants were able to generalize strategy use to content specific writing tasks. PMID- 28560649 TI - Group B Streptococcus causes severe sepsis in term neonates: 8 years experience of a major Chinese neonatal unit. AB - BACKGROUND: In contrast to industrialized countries, the clinical characteristics of neonatal sepsis caused by Group B Streptococcus (GBS) are largely unexplored in China. METHODS: A retrospective case series study was performed at a high capacity neonatal unit in Shanghai, China from January 2008 to December 2015. Clinical characteristics of neonates with culture-proven GBS sepsis and antibiotic susceptibility of isolated strains were analyzed. RESULTS: Forty-three term neonates were included during the study period. The majority (74.4%) had early-onset sepsis with symptoms of respiratory distress. Meningitis was significantly more common in lateonset sepsis than in early-onset sepsis (81.5% vs. 18.8%, P<0.0001). Approximately one third of all patients (n=16) developed severe sepsis, defined as sepsis with organ dysfunctions, and respiratory dysfunction/failure was the most common (32.6%). The in-hospital mortality rate of GBS sepsis was 4.7%. Neonates who progressed to severe sepsis had significantly lower pH level at the onset of symptoms than those who did not (7.26+/-0.12 vs. 7.39+/-0.05, P=0.006). Treatment of severe GBS sepsis required lots of medical resources including extracorporeal membrane oxygenation. All tested GBS strains were susceptible to penicillin, but the rate of resistance to clindamycin (84.0%) and erythromycin (88.0%) was high. CONCLUSIONS: GBS as a pathogen for neonatal sepsis has been receiving little attention in China. Our data demonstrated that GBS sepsis was likely to be fulminant. Early recognition followed by antibiotics and adequate supportive therapies was critical for successful treatment. Chinese clinicians should be aware of GBS infection when treating neonatal sepsis, especially in the absence of universal maternal GBS screening. PMID- 28560651 TI - Bilateral choroidal neovascularization associated with gyrate atrophy managed with intravitreal bevacizumab. AB - PURPOSE: To report a case with gyrate atrophy (GA) complicated by bilateral choroidal neovascularization (CNV) treated with intravitreal bevacizumab. CASE PRESENTATION: A 20-year-old man presented with a complaint of sudden visual decrease in his both eyes. Best-corrected visual acuity (BCVA) was 20/400 and 20/500, with a spherical refractive error of -2.00 and -1.75 D, in the right and left eyes, respectively. Dilated fundus examination revealed multiple bilateral, sharply defined chorioretinal atrophy areas in the midperipheral and peripheral zone with the suspicion of CNV in both eyes. Spectral-domain optical coherence tomography revealed bilateral cystoid macular edema consistent with CNV development which was confirmed by fundus fluorescein angiography. Single dose of intravitreal bevacizumab injections were performed to both eyes of the patient. At the first month after the injection, the BCVA improved and OCT revealed scar formation without any intraretinal/subretinal fluid in both eyes. At the first year follow-up, the maculas remained dry on the OCT and the BCVA was preserved. No additional injections were needed. CONCLUSION: Intravitreal bevacizumab might be a treatment alternative, which provides satisfactory anatomical and functional results and leads to a better central vision in cases with GA complicated by CNV. PMID- 28560652 TI - Comparative study of visual function and ocular aberrations of two different one piece designed hydrophilic acrylic intraocular lens. AB - PURPOSE: To determine whether the aspherical IOL, Tecnis ZCB00, can improve the visual quality by measuring visual acuity, wavefront aberrations, and contrast sensitivity. METHODS: It was a retrospective case series. Patients who underwent phacoemulsification cataract surgery were divided into two groups. One group (Group TC) was implanted with one-piece aspherical acrylic IOL (Tecnis ZCB00, AMO); the other (Group SA) was implanted with one-piece spherical acrylic IOL (Sensar AAB00, AMO). Eighty-eight eyes were selected into this study, among them 43 eyes in 26 male cases and 45 eyes in 29 female cases. Thirty-six eyes in 23 cases were in Group TC, and 52 eyes in 32 cases were in Group SA. Three months postoperatively, aberrations were analyzed with i-Trace visual function analyzer (Tracy Technologies, USA). Contrast sensitivities were measured with Takaci-CGT 1000 contrast glare tester (Seiko, Japan). RESULTS: All the 88 eyes underwent phacoemulsification with intraocular lens implantation, without complications during or after surgery. Three months postoperatively, the uncorrected vision acuity in Group TC was significantly better than in Group SA (P = 0.007). At the pupil size of 5.0 mm, higher-order aberrations in Group TC were significantly higher than in Group SA (P = 0.02), especially the spherical aberration (Z 40 ) (P < 0.001); at the pupil size of 4.0 mm, Z 40 in Group SA was statistically higher than in Group TC (P < 0.001); at the pupil size of 3.0 mm, higher-order aberrations such as coma (Z 3-1,1 ) and trefoil aberration (Z 3-3,3 ) in Group SA were obviously higher than in Group TC (P = 0.01). In the low spatial frequency, the contrast sensitivity and the glare sensitivity in Group TC were significantly higher than in Group SA (P < 0.05). CONCLUSIONS: By the short-term follow-up (3 months), the aspherical acrylic IOL can reduce the higher-order aberrations (especially the spherical aberration) and increase the contrast sensitivity to improve the visual performance. PMID- 28560653 TI - Association of Single Nucleotide Polymorphisms in XRCC1 (194) and XPD (751) with Age-related cataract. AB - PURPOSE: Age-related cataract (ARC) is a multifactorial disease and different risk factors, including genetic and environmental, are responsible for the development of its various types. The aim of this study was to find out a correlation, if any, between ARC and the single nucleotide polymorphisms (SNPs) in DNA repair genes XRCC1 (X-ray repair cross-complementary-1) [Arg194Trp (rs1799782)] and XPD (xerodermapigmentosa complementation group D) [Lys751Gln (rs13,181]. METHOD: The genotype at these two SNPs was analyzed in 260 subjects (125 control and 135 patients) from Southern Punjab population (Pakistan) by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Genotype at both analyzed codons was correlated either individually or in various combinations with the studied epidemiological factors known to be associated with ARC. RESULTS: Our results indicated that both SNPs Arg194Trp in XRCC1 (P = 0.967) and Lys751Gln in XPD (P = 0.995) were not associated with ARC whether they were analyzed individually or in combined form (P > 0.05). Analysis of epidemiological factors revealed that age (P < 0.001), cast of subjects (P = 0.001), diabetes (P < 0.001), hypertension (P = 0.001), smoking habit (P = 0.01), drug abuse (P < 0.05), steroid use (P = 0.001) and body weight (P < 0.001) can influence the incidence of ARC in enrolled subjects. After applying Binary logistic regression it was found that the weight (P < 0.01), family history (P = 0.05), drug abuse (P = 0.05), smoking (P < 0.05) and steroid use (P < 0.05) has a significant association with the phenotype of the subjects. All epidemiological factors were also studied in association with various genotypic combinations of both SNPS, diabetes was the only factor that had a significant association (P < 0.001) association with ARC. Hypertension (P = 0.01), body weight (P < 0.05) and cast (P < 0.001) were found associated with ARC when epidemiological factors were individually correlated with ARC. Result of the two proportion test indicated that gender had no influence on the incidence of disease. CONCLUSION: It is concluded that studied SNPs in XRCC1 and XPD have no association with the incidence of age related cataract in the analyzed group of subjects. PMID- 28560654 TI - Newer Vaccines against Mosquito-borne Diseases. AB - Mosquitos are responsible for a number of protozoal and viral diseases. Malaria, dengue, Japanese encephalitis (JE) and chikungunya epidemics occur commonly all over the world, leading to marked mortality and morbidity in children. Zika, Yellow fever and West Nile fever are others requiring prevention. Environmental control and mosquito bite prevention are useful in decreasing the burden of disease but vaccination has been found to be most cost-effective and is the need of the hour. RTS,S/AS01 vaccine is the first malaria vaccine being licensed for use against P. falciparum malaria. Dengvaxia (CYD-TDV) against dengue was licensed first in Mexico in 2015. A Vero-cell derived, inactivated and alum adjuvanted JE vaccine based on the SA14-14-2 strain was approved in 2009 in North America, Australia and various European countries. It can be used from 2 mo of age. In India, immunization is carried out in endemic regions at 1 y of age. Another inactivated Vero-cell culture derived Kolar strain, 821564XY, JE vaccine is being used in India. Candidate vaccines against dengue, chikungunya and West Nile fever are been discussed. A continued research and development of new vaccines are required for controlling these mosquito-borne diseases. PMID- 28560657 TI - Ionic Liquids for Supercapacitor Applications. AB - Supercapacitors are electrochemical energy storage devices in which the charge is accumulated through the adsorption of ions from an electrolyte on the surface of the electrode. Because of their large ionic concentrations, ionic liquids have widely been investigated for such applications. The main properties that have to be optimized are the electrochemical window, the electrical conductivity, and the interfacial capacitances. Ionic liquids allow a significant improvement of the former, but they suffer from their high viscosity. In this review, I will discuss the advantages and the inconvenience of using ionic liquids in supercapacitors. Some innovative approaches using mixtures of ionic liquids or redox-active ions will also be critically addressed. PMID- 28560655 TI - A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen. AB - PURPOSE: Diindolylmethane (DIM), a bioactive metabolite of indole-3-carbinol found in cruciferous vegetables, has proposed cancer chemoprevention activity in the breast. There is limited evidence of clinically relevant activity of DIM or long-term safety data of its regular use. A randomized, double-blind, placebo controlled trial was conducted to determine the activity and safety of combined use of BioResponse DIM(r) (BR-DIM) with tamoxifen. METHODS: Women prescribed tamoxifen (n = 130) were randomly assigned oral BR-DIM at 150 mg twice daily or placebo, for 12 months. The primary study endpoint was change in urinary 2/16alpha-hydroxyestrone (2/16alpha-OHE1) ratio. Changes in 4-hydroxyestrone (4 OHE1), serum estrogens, sex hormone-binding globulin (SHBG), breast density, and tamoxifen metabolites were assessed. RESULTS: Ninety-eight women (51 placebo, 47 DIM) completed intervention; compliance with treatment was >91%. BR-DIM increased the 2/16alpha-OHE1 ratio (+3.2 [0.8, 8.4]) compared to placebo (-0.7 [-1.7, 0.8], P < 0.001). Serum SHBG increased with BR-DIM compared to placebo (+25 +/- 22 and +1.1 +/- 19 nmol/L, respectively). No change in breast density measured by mammography or by MRI was observed. Plasma tamoxifen metabolites (endoxifen, 4-OH tamoxifen, and N-desmethyl-tamoxifen) were reduced in women receiving BR-DIM versus placebo (P < 0.001). Minimal adverse events were reported and did not differ by treatment arm. CONCLUSION: In patients taking tamoxifen for breast cancer, daily BR-DIM promoted favorable changes in estrogen metabolism and circulating levels of SHBG. Further research is warranted to determine whether BR DIM associated decreases in tamoxifen metabolites, including effects on endoxifen levels, attenuates the clinical benefit of tamoxifen. TRIAL REGISTRATION: ClinicalTrials.gov NCT01391689. PMID- 28560659 TI - ? PMID- 28560658 TI - Safety, pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir, a novel liver-targeting, anti-hepatitis B virus drug, in healthy Chinese subjects. AB - BACKGROUND: Pradefovir is efficiently converted to adefovir [9-(2 phosphonylmethoxyethyl) adenine (PMEA)], producing high hepatic PMEA concentration but low levels in the systemic circulation and kidney. The aim of this study is to evaluate the tolerability, adverse effect (AEs), pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir. METHODS: Fifty healthy subjects were divided into five groups and randomized within each group at a ratio of 3:1:1 to receive a single ascending dose of pradefovir (10, 30, 60, 90, or 120 mg), and 10 mg adefovir dipivoxil (ADP) or placebo. Blood and urine samples were collected and analyzed. A total of 1930 polymorphic loci were analyzed in 6 blood samples collected from the 90 mg pradefovir group. RESULTS: The single oral dose of pradefovir up to 120 mg was well tolerated. A total of 29 dose-limited mild AEs were reported in 17 subjects. The peak plasma concentration (C max) and area under the curve (AUC)0-48 of serum pradefovir ranged from (21.41 +/- 12.98) to (447.33 +/- 79.34) ng/mL and (46.10 +/- 29.45) to (748.18 +/- 134.15) ng h/mL across the dose range, respectively. The C max and AUC0-48 of serum PMEA ranged from 18.10 +/- 4.96 to 312.33 +/- 114.19 ng/mL and 72.65 +/- 28.25 to 1095.48 +/- 248.47 ng h/mL. Generally, no kidney impairment was observed. Pharmacogenetic analysis identified three metabolism-related single nucleotide polymorphism (SNP) locis, P450 (cytochrome) oxidoreductase [POR (rs6965343)], arylamine N-acetyltransferases [NAT1 (rs4986993)] and CYP2F1 (rs305968)], and one distribution-related loci, orosomucoid 2 [ORM2 (rs12685968)]. CONCLUSIONS: The single oral dose of pradefovir 10-120 mg was well tolerated. SNPs may be associated with variable rates of adverse events. TRIAL REGISTRATION NUMBER: CTR20140341. PMID- 28560656 TI - Social well-being is associated with less pro-inflammatory and pro-metastatic leukocyte gene expression in women after surgery for breast cancer. AB - PURPOSE: Satisfaction with social resources, or "social well-being," relates to better adaptation and longer survival after breast cancer diagnosis. Biobehavioral mechanisms linking social well-being (SWB) to mental and physical health may involve inflammatory signaling. We tested whether reports of greater SWB were associated with lower levels of pro-inflammatory and pro-metastatic leukocyte gene expression after surgery for non-metastatic breast cancer. METHODS: Women (N = 50) diagnosed with non-metastatic (0-III) breast cancer were enrolled 2-8 weeks after surgery. SWB was assessed with the social/family well being subscale of the FACT-B. Leukocyte gene expression for specific pro inflammatory (cytokines, chemokines, and COX-2) and pro-metastatic genes (e.g., MMP9) was derived from microarray analysis. RESULTS: Multiple regression analyses controlling for age, stage of disease, days since surgery, education, and body mass index (BMI) found higher levels of SWB related to less leukocyte pro inflammatory and pro-metastatic gene expression (p < 0.05). Emotional well-being, physical well-being, and functional well-being did not relate to leukocyte gene expression (p > 0.05). Greater SWB remained significantly associated with less leukocyte pro-inflammatory and pro-metastatic gene expression after controlling for depressive symptoms. CONCLUSIONS: Results have implications for understanding mechanisms linking social resources to health-relevant biological processes in breast cancer patients undergoing primary treatment. CLINICAL TRIAL REGISTRATION NUMBER: NCT01422551. PMID- 28560660 TI - Impact of treatment on survival of patients with secondary glioblastoma. AB - Data concerning treatment of secondary glioblastoma evolving from previously treated WHO II or III grade tumors are very scarce. The aim of this study was to evaluate the impact of surgical resection and adjuvant treatment on survival in patients with secondary glioblastoma. Thirty-nine patients with secondary glioblastoma evolving from previously treated lower grade gliomas between 2004 and 2015 were included. We evaluated the extent of resection, pathological parameters, adjuvant treatment, as well as survival after malignant transformation. The primary tumor grade was WHO II in 16 (41.0%) and WHO III in 23 (59.0%) patients. Median age was 43 years (range 23-67). Median KPS was 80 (range 60-100) before surgery, and 70 (range 50-100) after surgery. Gross total resection (GTR) of contrast-enhancing disease was achieved in 19 (48.7%) patients. Adjuvant treatment was radio-chemotherapy in 23 (59.0%), radiotherapy in three (7.7%), chemotherapy in five (12.8%) and none in eight (20.5%) patients. Median survival was 11 months (range 1-35) in the entire group. Time since initial diagnosis and previous treatment did not correlate with survival after glioblastoma. Failed GTR, poor KPS after surgery, and no adjuvant treatment were prognostic factors for shorter survival in univariate analysis (p < 0.0001, p = 0.028 and p = 0.003). In selected patients, complete resection and adjuvant treatment may prolong survival in spite of multiple previous therapies. PMID- 28560662 TI - MGMT promoter methylation status: time for a frank discussion. PMID- 28560661 TI - Outcome and prognostic factors in patients with brain metastases from small-cell lung cancer treated with whole brain radiotherapy. AB - The purpose of this study was to evaluate prognostic factors associated with overall survival (OS) and neurological progression free survival (nPFS) in small cell lung cancer (SCLC) patients with brain metastases who received whole-brain radiotherapy (WBRT). From 2003 to 2015, 229 SCLC patients diagnosed with brain metastases who received WBRT were analyzed retrospectively. In this cohort 219 patients (95%) received a total photon dose of 30 Gy in 10 fractions. The prognostic factors evaluated for OS and nPFS were: age, Karnofsky Performance Status (KPS), number of brain metastases, synchronous versus metachronous disease, initial response to chemotherapy, the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) class and thoracic radiation. Median OS after WBRT was 6 months and the median nPFS after WBRT was 11 months. Patients with synchronous cerebral metastases had a significantly better median OS with 8 months compared to patients with metachronous metastases with a median survival of 3 months (p < 0.0001; HR 0.46; 95% CI 0.31-0.67). Based on RPA classification median survival after WBRT was 17 months in RPA class I, 7 months in class II and 3 months in class III (p < 0.0001). Karnofsky performance status scale (KPS < 70%) was significantly associated with OS in both univariate (HR 2.84; p < 0.001) and multivariate analyses (HR 2.56; p = 0.011). Further, metachronous brain metastases (HR 1.8; p < 0.001), initial response to first-line chemotherapy (HR 0.51, p < 0.001) and RPA class III (HR 2.74; p < 0.001) were significantly associated with OS in univariate analysis. In multivariate analysis metachronous disease (HR 1.89; p < 0.001) and initial response to chemotherapy (HR 0.61; p < 0.001) were further identified as significant prognostic factors. NPFS was negatively significantly influenced by poor KPS (HR 2.56; p = 0.011), higher number of brain metastases (HR 1.97; p = 0.02), and higher RPA class (HR 2.26; p = 0.03) in univariate analysis. In this series, the main prognostic factors associated with OS were performance status, time of appearance of intracranial disease (synchronous vs. metachronous), initial response to chemotherapy and higher RPA class. NPFS was negatively influenced by poor KPS, multiplicity of brain metastases, and higher RPA class in univariate analysis. For patients with low performance status, metachronous disease or RPA class III, WBRT should be weighed against supportive therapy with steroids alone or palliative chemotherapy. PMID- 28560663 TI - CD147 and glioma: a meta-analysis. AB - Gliomas are the most common primary brain tumors. This meta-analysis aimed to systematically evaluate the relationship between CD147 expression in tissues and the clinicopathological features of patients with glioma. We searched PubMed (1966-2016), EMBASE (1980-2016), Cochrane Library (1996-2016), Web of Science (1945-2016), China National Knowledge Infrastructure (1982-2016), and Wan Fang databases (1988-2016). Quality assessment of the literature was performed using the Newcastle-Ottawa Scale, with Revman 5.3 and Stata 14.0 for analysis. In total, 1806 glioma patients from 19 studies were included, and patients with CD147 overexpression had poorer overall survival [hazard ratio (HR) = 2.211, P < 0.0001], a higher risk of recurrence (HR = 2.20, P = 0.0025), and a lower 5-year survival rate [odds ratio (OR) 0.12; 95% CI 0.08-0.19; P < 0.00001]. We observed significant differences in CD147 expression when comparing glioma tissues versus non-cancerous brain tissues (OR 20.42; 95% CI 13.94-29.91; P < 0.00001), tumor grades III-IV versus grades I-II (OR 5.88, 95% CI 4.15-8.34; P < 0.00001), and large versus small tumors (OR 1.58, 95% CI 1.04-2.40; P = 0.03). We also observed a significant correlation with matrix metalloproteinase (MMP) 2 (OR 39.11, 95% CI 11.47-133.34; P < 0.00001) and MMP9 (OR 13.35, 95% CI 4.67-38.18; P < 0.00001). CD147 expression did not differ based on patient's age (young vs. old, P = 0.89) or gender (female vs. male, P = 0.57). CD147 expression may be a potential prognostic biomarker for poorer overall and relapse-free survival, and may affect the 5-year survival rate in glioma patients. CD147 expression is also closely correlated with poor clinical characteristics in glioma patients. PMID- 28560664 TI - External validation of the diffuse intrinsic pontine glioma survival prediction model: a collaborative report from the International DIPG Registry and the SIOPE DIPG Registry. AB - We aimed to perform external validation of the recently developed survival prediction model for diffuse intrinsic pontine glioma (DIPG), and discuss its utility. The DIPG survival prediction model was developed in a cohort of patients from the Netherlands, United Kingdom and Germany, registered in the SIOPE DIPG Registry, and includes age <3 years, longer symptom duration and receipt of chemotherapy as favorable predictors, and presence of ring-enhancement on MRI as unfavorable predictor. Model performance was evaluated by analyzing the discrimination and calibration abilities. External validation was performed using an unselected cohort from the International DIPG Registry, including patients from United States, Canada, Australia and New Zealand. Basic comparison with the results of the original study was performed using descriptive statistics, and univariate- and multivariable regression analyses in the validation cohort. External validation was assessed following a variety of analyses described previously. Baseline patient characteristics and results from the regression analyses were largely comparable. Kaplan-Meier curves of the validation cohort reproduced separated groups of standard (n = 39), intermediate (n = 125), and high-risk (n = 78) patients. This discriminative ability was confirmed by similar values for the hazard ratios across these risk groups. The calibration curve in the validation cohort showed a symmetric underestimation of the predicted survival probabilities. In this external validation study, we demonstrate that the DIPG survival prediction model has acceptable cross-cohort calibration and is able to discriminate patients with short, average, and increased survival. We discuss how this clinico-radiological model may serve a useful role in current clinical practice. PMID- 28560665 TI - Radiation-agent combinations for glioblastoma: challenges in drug development and future considerations. AB - Glioblastoma is an aggressive disease characterized by moderate initial response rates to first-line radiation-chemotherapy intervention followed by low poor response rates to second-line intervention. This article discusses novel strategic platforms for the development of radiation-investigational agent combination clinical trials for primary and recurrent glioblastoma in a NCI-NCTN settings with simultaneous analysis of challenges in the drug development process. PMID- 28560666 TI - Circulating Tumor Cells as Cancer Biomarkers in the Clinic. AB - It is believed that the development of metastatic cancer requires the presence of circulating tumor cells (CTCs) , which are found in a patient's circulation as rare abnormal cells comingled with billions of the normal red and white blood cells. The systems developed for detection of CTCs have brought progress to cancer treatment. The molecular characterization of CTCs can aid in the development of new drugs, and their presence during treatment can help clinicians determine the prognosis of the patient. Studies have been carried out in patients early in the disease course, with only primary tumors, and the role of CTCs in prognosis seems to be as important as it is in patients with metastatic disease. The published studies on CTCs have focused on their prognostic significance, their utility in real-time monitoring of therapies, the identification of therapeutic and resistance targets, and understanding the process of metastasis . The analysis of CTCs during the early stages, as a "liquid biopsy," helps to monitor patients at different points in the disease course, including minimal residual disease, providing valuable information about the very early assessment of treatment effectiveness. Finally, CTCs can be used to screen patients with family histories of cancer or with diseases that can lead to the development of cancer. With standard protocols, this easily obtained and practical tool can be used to prevent the growth and spread of cancer. In this chapter, we review some important aspects of CTCs , surveying the disease aspects where these cells have been investigated. PMID- 28560667 TI - Strategies for Isolation and Molecular Profiling of Circulating Tumor Cells. AB - Cancer is the leading cause of death by disease worldwide, and metastasis is responsible for more than 90% of the mortality of cancer patients. Metastasis occurs when tumor cells leave the primary tumor, travel through the blood stream as circulating tumor cells (CTCs), and then colonize secondary tumors at sites distant from the primary tumor. The capture, identification, and analysis of CTCs offer both scientific and clinical benefits. On the scientific side, the analysis of CTCs could help elucidate possible genetic alterations and signaling pathway aberrations during cancer progression, which could then be used to find new methods to stop cancer progression. On the clinical side, non-invasive testing of a patient's blood for CTCs can be used for patient diagnosis and prognosis, as well as subsequent monitoring of treatment efficacy in routine clinical practice. Additionally, investigation of CTCs early in the progression of cancer may reveal targets for initial cancer detection and for anti-cancer treatment. This chapter will evaluate strategies and devices used for the isolation and identification of CTCs directly from clinical samples of blood. Recent progress in the understanding of the significance of both single CTCs and circulating tumor microemboli will be discussed. Also, advancements in the use of CTC-based liquid biopsy in clinical diagnosis and the potential of CTC-based molecular characterization for use in clinical applications will be summarized. PMID- 28560668 TI - Aptamer-Based Methods for Detection of Circulating Tumor Cells and Their Potential for Personalized Diagnostics. AB - Cancer diagnostics and treatment monitoring rely on sensing and counting of rare cells such as cancer circulating tumor cells (CTCs) in blood. Many analytical techniques have been developed to reliably detect and quantify CTCs using unique physical shape and size of tumor cells and/or distinctive patterns of cell surface biomarkers. Main problems of CTC bioanalysis are in the small number of cells that are present in the circulation and heterogeneity of CTCs. In this chapter, we describe recent progress towards the selection and application of synthetic DNA or RNA aptamers to capture and detect CTCs in blood. Antibody-based approaches for cell isolation and purification are limited because of an antibody's negative effect on cell viability and purity. Aptamers transform cell isolation technology, because they bind and release cells on-demand. The unique feature of anti-CTC aptamers is that the aptamers are selected for cell surface biomarkers in their native state, and conformation without previous knowledge of their biomarkers. Once aptamers are produced, they can be used to identify CTC biomarkers using mass spectrometry. The biomarkers and corresponding aptamers can be exploited to improve cancer diagnostics and therapies . PMID- 28560669 TI - Development of a Protocol for Single-Cell Analysis of Circulating Tumor Cells in Patients with Solid Tumors. AB - Genomic characterization of circulating tumor cells (CTCs) enables the monitoring of tumor progression and of adaption occurring during treatment. CTC molecular characterization represents indeed a precious tool to implement in the clinical practice for better dealing with acquired resistance to systemic treatment and tumor evolution. Unfortunately CTCs are very rare and enrichments from blood samples and subsequent identification of these cells are technically very challenging. We describe here the main steps leading to the development of a technical protocol for visualization, enumeration and recovery of single CTCs exploiting the recently developed DEPArrayTMplatform. Our description of the technical workflow starts with evaluation of pre-analytical aspects related to blood sample collection warning about the possible effects on immunoreactivity profiles which may bias the interpretation. Subsequently, other CTC-enrichment approaches are critically discussed and compared in relation to their performances with the DEPArrayTM. Identification of CTCs represents another critical point due to their heterogeneity and due to the still-to-be clarified role of different subpopulations, typically epithelial, mesenchymal or mixed. Finally, issues related to single cell analysis are illustrated. The chapter ends with an overview of results obtained on real clinical samples which support the reliability of the protocol and its transferability to the daily clinical routine. PMID- 28560670 TI - Flow Cytometric Methods for Circulating Tumor Cell Isolation and Molecular Analysis. AB - Circulating tumor cells provide a non-invasive source of tumor material that can be valuable at all stages of disease management, including screening and early diagnosis, monitoring response to therapy, identifying therapeutic targets, and assessing development of drug resistance. Cells isolated from the blood of cancer patients can be used for phenotypic analysis, tumor genotyping, transcriptional profiling, as well as for ex vivo culture of isolated cells. There are a variety of novel technologies currently being developed for the detection and analysis of rare cells in circulation of cancer patients. Flow cytometry is a powerful cell analysis platform that is increasingly being used in this field of study due to its relatively high throughput and versatility with respect to the large number of commercially available antibodies and fluorescent probes available to translational and clinical researchers. More importantly, it offers the ability to easily recover viable cells with high purity that are suitable for downstream molecular analysis, thus making it an attractive technology for cancer research and as a diagnostic tool. PMID- 28560671 TI - Enrichment and Detection of Circulating Tumor Cells and Other Rare Cell Populations by Microfluidic Filtration. AB - The current standard methods for isolating circulating tumor cells (CTCs) from blood involve EPCAM-based immunomagnetic approaches. A major disadvantage of these strategies is that CTCs with low EPCAM expression will be missed. Isolation by size using filter membranes circumvents the reliance on this cell surface marker, and can facilitate the capture not only of EPCAM-negative CTCs but other rare cells as well. These cells that are trapped on the filter membrane can be characterized by immunocytochemistry (ICC) , enumerated and profiled to elucidate their clinical significance. In this chapter, we discuss advances in filtration systems to capture rare cells as well as downstream ICC methods to detect and identify these cells. We highlight our recent clinical study demonstrating the feasibility of using a novel method consisting of automated microfluidic filtration and sequential ICC for detection and enumeration of CTCs, as well as circulating mesenchymal cells (CMCs), circulating endothelial cells (CECs), and putative circulating stem cells (CSCs). We hypothesize that simultaneous analysis of circulating rare cells in blood of cancer patients may lead to a better understanding of disease progression and development of resistance to therapy. PMID- 28560672 TI - Detection and Enumeration of Circulating Tumor Cells with Invasive Phenotype. AB - Circulating tumor cells (CTCs) disseminate from solid primary cancers into the peripheral blood and lymphatic vessels and can lead to metastatic tumor development; thus, CTC assays are an important clinical tool for monitoring progression and evaluating prognosis in cancer. However, CTCs are limited in number and heterogeneous in their biological and physical properties, making their detection, isolation, and enumeration a major challenge. To overcome these difficulties, novel techniques have been developed to detect and enumerate CTCs with an invasive phenotype. In this chapter, we will summarize these recently developed methods and detail two novel methods for capturing and enriching CTCs on the basis of their viability and their invasive properties. PMID- 28560673 TI - Molecular Profiling and Significance of Circulating Tumor Cell Based Genetic Signatures. AB - Cancer kills by metastasizing beyond the primary site. Early detection, surgical intervention and other treatments have improved the survival rates of patients with cancer, however, once metastasis occurs, responses to conventional therapies become significantly less effective, and this remains the leading cause of death. Circulating tumor cells (CTCs) are tumor cells that have preferentially disseminated from the primary tumor mass into the hematological system, and are en route to favorable distant sites where if they survive, can develop into metastases. They may be the earliest detectable cells with metastatic ability, and are gaining increasing attention because of their prognostic value in many types of cancers including breast, prostate, colon and lung. Recent technological advances have removed barriers that previously hindered the detection and isolation of these rare cells from blood, and have exponentially improved the genetic resolution at which we can characterize signatures that define CTCs. Some of the most significant observations from such examinations are described here. Firstly, aberrations that were thought to be unique to CTCs are detected at subclonal frequencies within primary tumors with measurable heterogeneity, indicating pre-existing genetic signatures for metastasis. Secondly, these subclonal events are enriched in CTCs and metastases, pointing towards the selection of a more 'fit' component of tumor cells with survival advantages. Lastly, this component of cancer cells may also be the chemoresistant portion that escapes systemic treatment, or acquires resistance during progression of the disease. The future of cancer management may include a standardized method of measuring intratumor heterogeneity of the primary as well as matched CTCs. This will help identify and target rare aberrations within primary tumors that make them more adept to disseminate, and also to monitor the development of treatment resistant subclones as cancer progresses. PMID- 28560674 TI - Detection of Gene Rearrangements in Circulating Tumor Cells: Examples of ALK-, ROS1-, RET-Rearrangements in Non-Small-Cell Lung Cancer and ERG-Rearrangements in Prostate Cancer. AB - Circulating tumor cells (CTCs) hold promise as biomarkers to aid in patient treatment stratification and disease monitoring. Because the number of cells is a critical parameter for exploiting CTCs for predictive biomarker's detection, we developed a FISH (fluorescent in situ hybridization) method for CTCs enriched on filters (filter-adapted FISH [FA-FISH]) that was optimized for high cell recovery. To increase the feasibility and reliability of the analyses, we combined fluorescent staining and FA-FISH and developed a semi-automated microscopy method for optimal FISH signal identification in filtration-enriched CTCs . Here we present these methods and their use for the detection and characterization of ALK-, ROS1-, RET-rearrangement in CTCs from non-small-cell lung cancer and ERG-rearrangements in CTCs from prostate cancer patients. PMID- 28560675 TI - Enrichment, Isolation and Molecular Characterization of EpCAM-Negative Circulating Tumor Cells. AB - The presence of EpCAM-positive circulating tumor cells (CTCs) in the peripheral blood is associated with poor clinical outcomes in breast, colorectal and prostate cancer, as well as the prognosis of other tumor types. In addition, recent studies have suggested that the presence of CTCs undergoing epithelial-to mesenchymal transition and, as such, may exhibit reduced or no expression of epithelial proteins e.g. EpCAM, might be related to disease progression in metastatic breast cancer (MBC) patients. Analyzing the neoplastic nature of this EpCAM-low/negative (EpCAM-neg) subpopulation remains an open issue as the current standard detection methods for CTCs are not efficient at identifying this subpopulation of cells. The possible association of EpCAM-neg CTCs with EpCAM positive (EpCAM-pos) CTCs and role in the clinicopathological features and prognosis of MBC patients has still to be demonstrated. Several technologies have been developed and are currently being tested for the identification and the downstream analyses of EpCAM-pos CTCs. These technologies can be adapted and implemented into workflows to isolate and investigate EpCAM-neg cells to understand their biology and clinical relevance. This chapter will endeavour to explain the rationale behind the identification and analyses of all CTC subgroups, as well as to review the current strategies employed to enrich, isolate and characterize EpCAM-negative CTCs. Finally, the latest findings in the field will briefly be discussed with regard to their clinical relevance. PMID- 28560676 TI - Expression of Epithelial Mesenchymal Transition and Cancer Stem Cell Markers in Circulating Tumor Cells. AB - The characterization of circulating tumor cells (CTC) has the potential not only to provide important insights into molecular alterations of advanced tumor disease but also to facilitate risk prediction. Epithelial mesenchymal transition (EMT) has been discovered as important process for the development of metastases and the dissemination of tumor cells into the blood stream. In different tumor types, CTC with a mesenchymal phenotype have been reported that have presumably underwent EMT. Moreover, CTC with stem-cell like characteristics have been postulated as important drivers of tumor progression. Different platforms have been introduced to allow CTC enrichment independent of expression of epithelial antigens, as these may be downregulated in EMT- or stem-cell-like CTC. Both for CTCs with EMT- or stem-cell features different markers have been proposed. However, there is still a lack of evidence on the association of these markers with functional features and characteristics for stem cells and cells undergoing EMT. PMID- 28560677 TI - Mesenchymal-Epithelial Transition and Circulating Tumor Cells in Small Cell Lung Cancer. AB - Cancer patients die of metastatic disease but knowledge regarding individual steps of this complex process of intravasation, spread and extravasation leading to secondary lesions is incomplete. Subpopulations of tumor cells are supposed to undergo an epithelial-mesenchymal transition (EMT), to enter the bloodstream and eventually establish metastases in a reverse process termed mesenchymal epithelial transition (MET). Small cell lung cancer (SCLC) represents a unique model to study metastatic spread due to early dissemination and relapse, as well as availability of a panel of circulating cancer cell (CTC) lines recently. Additionally, chemosensitive SCLC tumor cells switch to a completely resistant phenotype during cancer recurrence. In advanced disease, SCLC patients display extremely high blood counts of CTCs in contrast to other tumors, like breast, prostate and colon cancer. Local inflammatory conditions at the primary tumor site and recruitment of macrophages seem to increase the shedding of tumor cells into the circulation in processes which may proceed independently of EMT. Since millions of cells are released by tumors into the circulation per day, analysis of a limited number of CTCs at specific time points are difficult to be related to the development of metastatic lesions which may occur approximately one year later. We have obtained a panel of SCLC CTC cell line from patients with relapsing disease, which share characteristic markers of this malignancy and a primarily epithelial phenotype with unique formation of large tumorospheres, containing quiescent and hypoxic cells. Although smoking and inflammation promote EMT, partial expression of vimentin indicates a transitional state with partial EMT in these cell lines at most. The CTC lines exhibit high expression of EpCAM , absent phosphorylation of beta-catenin and background levels of Snail. Provided that these tumor cells had ever undergone EMT, here in advanced disease MET seem to have occurred already in the peripheral circulation. Alternative explanations for the expression of mesenchymal markers of the CTC lines are the heterogeneity of SCLC cells, cooperative migration or altered gene expression in response to the inflammatory tumor microenvironment allowing for tumor spread without EMT/MET. PMID- 28560678 TI - Clinical Relevance of a Candidate Stem Cell Marker, p75 Neurotrophin Receptor (p75NTR) Expression in Circulating Tumor Cells. AB - Despite advances in its diagnosis and multimodal therapies, the prognosis of esophageal squamous cell carcinoma (ESCC) patients remains poor, because of high incidences of metastasis . Recent reports suggested that circulating tumor stem cells (CTSCs), rather than circulating tumor cells (CTCs), were more accurate diagnostic marker for metastasis, because tumor stem cells or cancer stem cells (CSCs) are more responsible for metastasis through processes such as epithelial mesenchymal transition (EMT) and tumor initiation. A neurotrophin receptor p75 (p75NTR) is expressed in a candidate CSC s in ESCC, which possess enhanced tumorigenicity along with strong expression of EMT-related genes. Our recent report using two-color flow cytometry demonstrated that CTC counts based on a combined expression of epithelial cell adhesion molecule (EpCAM) and p75NTR was significantly higher in peripheral blood samples of ESCC patients than healthy controls. In addition, EpCAM + p75NTR+, but not EpCAM + p75NTR- CTC counts, correlated with clinically diagnosed distant metastasis and pathological venous invasion in surgically resected primary ESCC tumors. Malignant cytology of the isolated EpCAM + p75NTR+ cells was microscopically confirmed as well. These results demonstrated that EpCAM + p75NTR+ CTC count was a more accurate diagnostic marker than EpCAM+ CTC count, suggesting the highly metastatic potential of CTCs with p75NTR expression.Investigation using the isolated EpCAM + p75NTR+ CTCs to assess their stem cell properties may shed light on their roles in tumor metastasis in ESCC.Further investigations based on large-scale prospective studies with long term follow up may provide us with evidences for its clinical use. PMID- 28560679 TI - Personalized Treatment Through Detection and Monitoring of Genetic Aberrations in Single Circulating Tumor Cells. AB - Circulating tumor cells (CTCs) present a viable alternative to access tumor materials other than primary biopsies in cancer. This disease is among the most widespread in the world and is difficult to target because of its complex nature, challenges in getting quality samples and dynamic temporal changes in response to treatment. Conventional methods of detection and monitoring the disease profile do not suffice to be able to target the heterogeneity that exists at the cellular level. CTCs have been identified as a possible substitute for tumor tissue samples, and can be used to complement current disease management. Challenges in CTCs molecular analysis lie in the purity of the sample, which is masked by the presence of large quantities of white blood cells (WBCs) . In this chapter, we present a microfluidic biochip platform that performs secondary purification to isolate single CTCs efficiently. Studying single CTCs will allow for sensitive detection of critical mutations and addressing intercellular variances that will be otherwise missed easily due to low mutation frequencies when evaluating bulk cell retrieval. Using the biochip, we isolated single CTCs, and conducted personalized integrated EGFR mutational analysis using conventional polymerase chain reaction (PCR) and Sanger sequencing. We also demonstrated that high quality next generation sequencing (NGS) libraries can be readily generated from these samples. In our initial study, we revealed that the dominant EGFR mutations such as L858R and T790M could be detected in Non Small Cell Lung Cancer (NSCLC) patients with low CTC counts. We envision the biochip will enable efficient isolation of rare single cells from samples. This technology coupled with downstream molecular characterization of CTCs will aid in realizing the personalized medicine for cancer patients. PMID- 28560680 TI - Glycan Markers as Potential Immunological Targets in Circulating Tumor Cells. AB - We present here an experimental approach for exploring a new class of tumor biomarkers that are overexpressed by circulating tumor cells (CTCs) and are likely targetable in immunotherapy against tumor metastasis. Using carbohydrate microarrays, anti-tumor monoclonal antibodies (mAbs) were scanned against a large panel of carbohydrate antigens to identify potential tumor glycan markers. Subsequently, flow cytometry and fiber-optic array scanning technology (FAST) were applied to determine whether the identified targets are tumor-specific cell surface markers and are, therefore, likely suitable for targeted immunotherapy. Finally, the tumor glycan-specific antibodies identified were validated using cancer patients' blood samples for their performance in CTC-detection and immunotyping analysis. In this article, identifying breast CTC-specific glycan markers and targeting mAbs serve as examples to illustrate this tumor biomarker discovery strategy. PMID- 28560681 TI - Significance of EGFR Expression in Circulating Tumor Cells. AB - This chapter focuses on a deep description of the epidermal growth factor receptor (EGFR) expression in circulating tumor cells (CTCs) and its main role in cancer progression, genetic changes related to metastasis , and resistance to treatment. The aberrant behavior of cancer cells is caused by genetic mutations and altered patterns of gene expression. These changes can be responsible for an increase in cell motility but also an ability of CTCs to survival in different microenvironments, as well as developing therapy-resistant clones. Finally, CTCs can acquire the ability to invade distant organs, where metastatic foci can develop. PMID- 28560684 TI - Simulation-based education: what's it all about? PMID- 28560685 TI - How a needs assessment study taught us a lesson about the ethics of educational research. PMID- 28560682 TI - Epithelial-to-mesenchymal transition in tumor progression. AB - The epithelial-to-mesenchymal transition (EMT) is a biological process in which a non-motile epithelial cell changes to a mesenchymal state with invasive capacities. However, the EMT program is involved in both physiological and pathological processes. Cancer-associated EMT is known to contribute to increase invasiveness and metastasis, resistance to therapies, and generation of cell populations with stem cell-like characteristics and therefore is deeply involved in tumor progression. This process is finely orchestrated by multiple signaling pathways and regulatory transcriptional networks. The hallmark of EMT is the loss of epithelial surface markers, mainly E-cadherin, and the acquisition of mesenchymal phenotype. These events can be mediated by EMT transcription factors which can cooperate with several enzymes to repress the E-cadherin expression and regulate EMT at the epigenetic and post-translational level. A growing body of evidence indicates that cancer cells can reside in various phenotypic states along the EMT spectrum, where cells can jointly retain epithelial traits with mesenchymal ones. This type of phenotypic plasticity endows cancer cells with tumor-initiating potential. The identification of the signaling pathways and modulators that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions. PMID- 28560683 TI - The impact of a multifaceted intervention including sepsis electronic alert system and sepsis response team on the outcomes of patients with sepsis and septic shock. AB - BACKGROUND: Compliance with the clinical practice guidelines of sepsis management has been low. The objective of our study was to describe the results of implementing a multifaceted intervention including an electronic alert (e-alert) with a sepsis response team (SRT) on the outcome of patients with sepsis and septic shock presenting to the emergency department. METHODS: This was a pre-post two-phased implementation study that consisted of a pre-intervention phase (January 01, 2011-September 24, 2012), intervention phase I (multifaceted intervention including e-alert, from September 25, 2012-March 03, 2013) and intervention phase II when SRT was added (March 04, 2013-October 30, 2013) in a 900-bed tertiary-care academic hospital. We recorded baseline characteristics and processes of care in adult patients presenting with sepsis or septic shock. The primary outcome measures were hospital mortality. Secondary outcomes were the need for mechanical ventilation and length of stay in the intensive unit and in the hospital. RESULTS: After implementing the multifaceted intervention including e-alert and SRT, cases were identified with less severe clinical and laboratory abnormalities and the processes of care improved. When adjusted to propensity score, the interventions were associated with reduction in hospital mortality [for intervention phase II compared to pre-intervention: adjusted odds ratio (aOR) 0.71, 95% CI 0.58-0.85, p = 0.003], reduction in the need for mechanical ventilation (aOR 0.45, 95% CI 0.37-0.55, p < 0.0001) and reduction in ICU LOS and hospital LOS for all patients as well as ICU LOS for survivors. CONCLUSIONS: Implementing a multifaceted intervention including sepsis e-alert with SRT was associated with earlier identification of sepsis, increase in compliance with sepsis resuscitation bundle and reduction in the need for mechanical ventilation and reduction in hospital mortality and LOS. PMID- 28560686 TI - Trends in drug offers among adolescents in the United States, 2002-2014. AB - BACKGROUND: Being offered illicit drugs is a critical factor leading to drug initiation and other psychosocial risk behaviors among adolescents in the United States. However, there exist few studies examining the recent trends in drug offers among adolescents, particularly across racial/ethnic subgroups. The present study examines trends and psychosocial/behavioral correlates of drug offers among adolescents of the three largest racial/ethnic groups. METHODS: We used data from the 2002-2014 National Survey on Drug Use and Health of adolescents aged 12-17, which include African-American, Hispanic, and White adolescents (n = 199,700) in the U.S. We estimated the prevalence of past-month drug offers by race/ethnicity, and conducted logistic regression analyses to test the significance of the trends and to examine the correlates of drug offers. RESULTS: Overall, the prevalence of drug offers decreased significantly from 16.3% in 2002 to 12.3% in 2014, reflecting a 24.5% reduction in the relative proportion of adolescents who were offered drugs. While the decreasing trends were observed in all subgroups (e.g., race/ethnicity), the decreases were more limited among African-American and Hispanic youth than White youth. As a result, while no differences were observed at the outset of the study, a higher proportion of African-American and Hispanic adolescents were offered drugs between 2012 and 2014. CONCLUSIONS: Findings suggest a general decline in drug offers among adolescents in the U.S., but racial/ethnic differences in prevalence were identified. This underscores the importance of further efforts to understand the racial/ethnic differences in drug offers and suggests the need for culturally sensitive drug prevention programs. PMID- 28560687 TI - HIV-1 gp120 Upregulates Brain-Derived Neurotrophic Factor (BDNF) Expression in BV2 Cells via the Wnt/beta-Catenin Signaling Pathway. AB - HIV-1 gp120 plays a critical role in the pathogenesis of HIV-associated pain, but the underlying molecular mechanisms are incompletely understood. This study aims to determine the effect and possible mechanism of HIV-1 gp120 on BDNF expression in BV2 cells (a murine-derived microglial cell line). We observed that gp120 (10 ng/ml) activated BV2 cells in cultures and upregulated proBDNF/mBDNF. Furthermore, gp120-treated BV2 also accumulated Wnt3a and beta-catenin, suggesting the activation of the Wnt/beta-catenin pathway. We demonstrated that activation of the pathway by Wnt3a upregulated BDNF expression. In contrast, inhibition of the Wnt/beta-catenin pathway by either DKK1 or IWR-1 attenuated BDNF upregulation induced by gp120 or Wnt3a. These findings collectively suggest that gp120 stimulates BDNF expression in BV2 cells via the Wnt/beta-catenin signaling pathway. PMID- 28560689 TI - Clinical characteristics of menstrually related and non-menstrual migraine. AB - Migraine attacks increase during the perimenstrual period in approximately half of female migraineurs. There are differences in the pathogenesis and clinical features of menstrually related and non-menstrual migraine attacks. The objective of this study was to compare the characteristics of migraine in patients with menstrually related and non-menstrual migraine, and to investigate the differences between premenstrual, menstrual, and late-menstrual migraine attacks. Three-hundred and thirty-two women with migraine without aura were evaluated using questionnaires and diaries to determine the characteristics of headache, preceding and accompanying symptoms, and the relation of migraine attacks and menstruation. One-hundred and sixty-three women had menstrually related migraine without aura (49.1%). Duration of disease and duration of headache were longer (p = 0.002 and p < 0.001, respectively), and nausea, vomiting, phonophobia, and aggravation of headache with physical activity were more frequent in patients with menstrually related migraine (p = 0.005, p = 0.006, p < 0.001 and p = 0.006, respectively). Premonitory symptoms and allodynia were observed more frequently in the menstrually related migraine group (p = 0.012 and p = 0.004, respectively). Perimenstrual migraine attacks occurred premenstrually (days -2 and -1) in 46 patients (25.3%), menstrually (days 1 to 3) in 90 patients (49.4%), and late menstrually (days 4 to 7) in 19 patients (10.4%). Our results showed that the duration of headache was longer and accompanying symptoms were more frequent and diverse in patients with menstrually related migraine without aura, suggesting that these findings may reflect the increase in excitability or susceptibility of the brain in these patients. PMID- 28560688 TI - ANCA-associated vasculitis with renal involvement. AB - Systemic vasculitis is a rare but severe group of diseases characterized by inflammation and necrosis of blood vessels. The size of the vessel affected varies among the different forms of vasculitis and there are three main subgroups: large, medium and small vessel vasculitis. Among small vessel vasculitis, the antineutrophil cytoplasmic antibody (ANCA)-associated forms are of particular importance. This subgroup includes: microscopic polyangiitis, granulomatosis with polyangiitis (Wegener's), eosinophilic granulomatosis with polyangiitis (Churg-Strauss) and the form limited to the kidney. ANCA are serum autoantibodies directed against proteins present in the cytoplasmic granules of neutrophils and represent the serological markers of small vessel vasculitis. Renal involvement is present in the majority of patients with ANCA-associated vasculitis (AAV) and the consequences of a missed or delayed diagnosis of renal vasculitis are potentially life threatening. Patient survival and the risk of end stage renal disease are closely associated with renal function at presentation. The gold standard for diagnosis remains renal biopsy. In 2010, a new histopathological classification based on the percent of normal glomeruli, cellular crescent or global sclerotic glomeruli was proposed. The aim of this classification was to predict the renal prognosis. Nowadays, remission can be achieved and maintained in most cases with a combination of high-dose steroid and immunosuppressive drugs. This therapy has to be continued for at least 24 months after a substantial remission has been obtained because early cessation of treatment is associated with an increased risk of relapse. For this reason, patients should be regularly monitored in order to promptly diagnose and treat a possible recurrence of AAV. This review will focus on kidney involvement in AAV with an overview of the clinical-pathological characteristics and therapeutic strategy for these conditions. PMID- 28560690 TI - Extrarenal determinants of kidney filter function. AB - The kidney is an organ involved in cross talk with many human organs. The link between the immune system and the kidney has been studied in some detail, although data precisely elucidating their interaction are sparse, in particular with regard to the function of the kidney filter apparatus. Current research suggests that an understanding of the impairment of this cross talk between the bone marrow, as a fundament of the immune system and the kidney will provide meaningful insights into the pathophysiological mechanisms of impaired kidney filter function. Circulating factors have long been implicated in the pathogenesis of idiopathic nephrotic syndrome, particularly focal segmental glomerulosclerosis (FSGS) and its recurrence. Soluble urokinase receptor (suPAR) has emerged as a circulating factor responsible for FSGS and also as an early predictive marker for the development of various renal diseases. The bone marrow has recently been revealed as a predominant source of suPAR with deleterious effects on the kidney filter. These new findings have led to bone marrow or hematopoietic stem cell transplants being considered as potential therapeutic options for preventing the post-transplantation recurrence of FSGS or even as a treatment for the original disease associated with high suPAR levels. Whereas bone marrow transplantation for patients with pre-existing chronic kidney disease is challenging, recent clinical trials have demonstrated the promising outcome of combined bone marrow and kidney transplantation in patients with kidney failure. In this review, with its brief update on suPAR, we describe the critical new role of the bone marrow in the pathogenesis of the kidney disease process and the functional connection between these two organs through the soluble mediator, suPAR. We also comment on the feasibility of bone marrow transplants for the treatment of patients with chronic renal failure arising from recurrent FSGS. PMID- 28560692 TI - Engineering kidney cells: reprogramming and directed differentiation to renal tissues. AB - Growing knowledge of how cell identity is determined at the molecular level has enabled the generation of diverse tissue types, including renal cells from pluripotent or somatic cells. Recently, several in vitro protocols involving either directed differentiation or transcription-factor-based reprogramming to kidney cells have been established. Embryonic stem cells or induced pluripotent stem cells can be guided towards a kidney fate by exposing them to combinations of growth factors or small molecules. Here, renal development is recapitulated in vitro resulting in kidney cells or organoids that show striking similarities to mammalian embryonic nephrons. In addition, culture conditions are also defined that allow the expansion of renal progenitor cells in vitro. Another route towards the generation of kidney cells is direct reprogramming. Key transcription factors are used to directly impose renal cell identity on somatic cells, thus circumventing the pluripotent stage. This complementary approach to stem-cell based differentiation has been demonstrated to generate renal tubule cells and nephron progenitors. In-vitro-generated renal cells offer new opportunities for modelling inherited and acquired renal diseases on a patient-specific genetic background. These cells represent a potential source for developing novel models for kidney diseases, drug screening and nephrotoxicity testing and might represent the first steps towards kidney cell replacement therapies. In this review, we summarize current approaches for the generation of renal cells in vitro and discuss the advantages of each approach and their potential applications. PMID- 28560691 TI - Role of TGF-beta in metastatic colon cancer: it is finally time for targeted therapy. AB - Colorectal cancer (CRC) is one of the most frequent tumor types in Western countries. Approximately 20 % of patients show metastasis at the time of diagnosis, with the liver being one of the most affected organs. Transforming growth factor-beta (TGF-beta) plays a regulatory role not only in the physiology of the normal colon but also in the development of CRC and its metastatic process. In this review, we analyze the molecular mechanisms leading to TGF-beta dysregulation in tumor and stroma cells and the modification of the microenvironment that fosters CRC metastasis. Recent genomic studies have identified a CRC subtype with a mesenchymal and aggressive phenotype having TGF beta as a hub gene of this signature. Consistent with these findings, the inhibition of TGF-beta signaling has been shown to impair experimental CRC metastasis to the liver. Based on these and other results conducted in various tumor types, the pharmaceutical industry has developed a variety of strategies to target TGF-beta. We provide up-to-date information of these therapies, which are currently in preclinical or clinical trials. PMID- 28560693 TI - Quantifying podocyte depletion: theoretical and practical considerations. AB - Podocyte depletion is a central event in the pathogenesis of many glomerular diseases. For this reason, methods to quantify podocyte depletion have become increasingly important. Here, we review currently available methods for quantifying podocyte depletion, including the analysis of glomerular cross sections, the most important and common stereological methods and newer techniques such as whole glomerular analysis in optically cleared samples. Each method has advantages and limitations. We therefore discuss theoretical and practical considerations to assist the selection of the most appropriate method for an individual study. PMID- 28560694 TI - Role of apoptosis in the development of autosomal dominant polycystic kidney disease (ADPKD). AB - Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disorder in the Western world and is characterized by cystogenesis that often leads to end-stage renal disease (ESRD). Mutations in the pkd1 gene, encoding for polycystin-1 (PC1) and its interaction partner pkd2, encoding for polycystin-2 (PC2), are the main drivers of this disease. PC1 and PC2 form a multiprotein membrane complex at cilia sites of the plasma membrane and at intracellular membranes. This complex mediates calcium influx and stimulates various signaling pathways regulating cell survival, proliferation and differentiation. The molecular consequences of pkd1 and pkd2 mutations are still a matter of debate. In particular, the ways in which the cysts are initially formed and progress throughout the disease are unknown. The mechanisms proposed to play a role include enhanced cell proliferation, increased apoptotic cell death and diminished autophagy. In this review, we summarize our current understanding about the contribution of apoptosis to cystogenesis and ADPKD. We present the animal models and the tools and methods that have been created to analyze this process. We also critically review the data that are in favor or against the involvement of apoptosis in disease generation. We argue that apoptosis is probably not the sole driver of cystogenesis but that a cooperative action of cell death, compensatory cell proliferation and perturbed autophagy gradually establish the disease. Finally, we propose novel strategies for uncovering the mode of action of PC1 and PC2 and suggest means by which their dysfunction or loss of expression lead to cystogenesis and ADPKD development. PMID- 28560695 TI - High-Tech Drugs in Creaky Formulations. AB - Recent literature reviews and registration documents covering novel Signal Transduction Inhibitors in the treatment of cancer paint a picture of inefficiency and variability, where formulation improvements could be valuable. In this article, we discuss apparent drug design flaws as we impose the current standard formulation practice. PMID- 28560696 TI - Impact of the Charge Ratio on the In Vivo Immunogenicity of Lipoplexes. AB - PURPOSE: The present study investigated the immunogenic potential of different cationic liposome formulations with a DNA plasmid encoding Pfs25, a malaria transmission-blocking vaccine candidate. METHODS: Pfs25 plasmid DNA was complexed with cationic liposomes to produce lipoplexes at different charge ratios of the cationic lipid head group to the nucleotide phosphate (N:P). The formation of lipoplexes was visualized by Cryogenic-TEM. Confocal microscopy of lipoplexes formed with GFP encoding plasmid DNA, and flow cytometry was used to determine their in vitro transfection capability. Two different lipoplex formulations using plasmid DNA encoding Pfs25 were evaluated for in vivo immunogenicity after intramuscular administration in Balb/c mice. Immune sera were analyzed by ELISA. RESULTS: The results demonstrated that the cationic liposome-mediated DNA immunization with an N:P charge ratio of 1:3 (anionic lipoplexes) is more effective than the use of naked plasmid DNA alone. No antibody response was observed when lipoplexes with a higher N:P charge ratio of 10:3 (cationic lipoplexes) were used. Trehalose was added to some lipoplex formulations as a cryoprotectant and adjuvant, but it did not yield any further improvement of immunogenicity in vivo. CONCLUSIONS: The results suggest that Pfs25 plasmid DNA delivered as lipoplexes at a charge ratio of 1:3 elicited strong immunogenicity in mice and may be improved further to match the immune responses of DNA vaccines administered by in vivo electroporation. PMID- 28560697 TI - The Cardiotoxic Mechanism of Doxorubicin (DOX) and Pegylated Liposomal DOX in Mice Bearing C-26 Colon Carcinoma: a Study Focused on microRNA Role for Toxicity Assessment of New Formulations. AB - PURPOSE: MicroRNAs (miRs) are a group of small non-coding RNAs that regulate transcriptional or post-transcriptional gene expression. The aim of the present study was to investigate the role of miR -1, -21 and -145 and their targets in cardiotoxicity-induced by DOX and pegylated liposomal DOX. METHODS: BALB/c mice subjected to subcutaneous injection of C-26 tumor cells. Eight days after tumor inoculation, animals were divided into 6 groups: control, liposome, DOX (6 and 9 mg/kg) and PL-DOX (6 and 9 mg/kg). The formulations were administered one time per week for four weeks. 24 h after the last injection, mice were sacrificed; blood and heart samples were taken. Western blot analysis was done on protein extracts to investigate the expression of cardiac caspase-3, -8, Bax, Bcl2, Programmed cell death 4 (PDCD4) and BCL2/Adenovirus E1B 19 kDa Interacting Protein 3 (BNIP3). The expression levels of miR -1, -21 and -145 were also evaluated by quantitative real-time PCR. RESULTS: Mice treated with both DOX formulations showed a marked inhibition in tumor growth. Western blot analysis indicated that the expression level of cardiac caspase-3, caspase-8, Bax and BNIP3 were up-regulated due to DOX injection (9 mg/kg). Exposure of mice with DOX resulted in a significant increase in cardiac miR-1 and miR-21 expression level. PL-DOX treatment did not change the proteins and miRs expression. CONCLUSION: The results suggest that miR -1, -21 and -145 may involve in cardiotoxicity induced by DOX. Evaluation of miRs signaling pathways might be of potential value for toxicity assessment of new formulations. Graphical Abstract The cardiotoxic mechanism of doxorubicin (DOX) and pegylated liposomal DOX (PL-DOX). PMID- 28560698 TI - A Biocompatible Synthetic Lung Fluid Based on Human Respiratory Tract Lining Fluid Composition. AB - PURPOSE: To characterise a biorelevant simulated lung fluid (SLF) based on the composition of human respiratory tract lining fluid. SLF was compared to other media which have been utilized as lung fluid simulants in terms of fluid structure, biocompatibility and performance in inhalation biopharmaceutical assays. METHODS: The structure of SLF was investigated using cryo-transmission electron microscopy, photon correlation spectroscopy and Langmuir isotherms. Biocompatibility with A549 alveolar epithelial cells was determined by MTT assay, morphometric observations and transcriptomic analysis. Biopharmaceutical applicability was evaluated by measuring the solubility and dissolution of beclomethasone dipropionate (BDP) and fluticasone propionate (FP), in SLF. RESULTS: SLF exhibited a colloidal structure, possessing vesicles similar in nature to those found in lung fluid extracts. No adverse effect on A549 cells was apparent after exposure to the SLF for 24 h, although some metabolic changes were identified consistent with the change of culture medium to a more lung-like composition. The solubility and dissolution of BDP and FP in SLF were enhanced compared to Gamble's solution. CONCLUSION: The SLF reported herein constitutes a biorelevant synthetic simulant which is suitable to study biopharmaceutical properties of inhalation medicines such as those being proposed for an inhaled biopharmaceutics classification system. PMID- 28560699 TI - Identification of Strategic Residues at the Interface of Antigen-Antibody Interactions by In Silico Mutagenesis. AB - Structural information pertaining to antigen-antibody interactions is fundamental in immunology, and benefits structure-based vaccine design. Modeling of antigen antibody immune complexes from co-crystal structures or molecular docking simulations provides an extensive profile of the epitope at the interface; however, the key amino acids involved in the interaction must be further clarified, often through the use of experimental mutagenesis and subsequent binding assays. Here, we describe an in silico mutagenesis method to identify key sites at antigen-antibody interfaces, using significant increase in pH-dependency energy among saturated point mutations. Through a comprehensive analysis of the crystal structures of three antigen-antibody immune complexes, we show that a cutoff value of 1 kcal/mol of increased interaction energy provides good congruency with the experimental non-binding mutations conducted in vitro. This in silico mutagenesis strategy, in association with energy calculations, may provide an efficient tool for antibody-antigen interface analyses, epitope optimization, and/or conformation prediction in structure-based vaccine design. PMID- 28560700 TI - An improved design of optical sensor for long-term measurement of arterial blood flow waveform. AB - We present here the improved design and development of optical sensor for non invasive measurements of arterial blood flow waveform. The sensor is based on a physical principle of reflective photoplethysmography (PPG). As the light source we used serially connected infrared diodes whereas NPN silicon phototransistors were used as light detectors. The electronic components were molded into square package and poured with silicone. Such preparation produced an elastic superficies that allowed excellent attachment of the sensor on the skin's surface. Moreover, a serial connection of infrared diodes and phototransistors completely eliminated signal artifacts caused by minor muscle contractions. The sensor recording performances were examined at the photoplethysmographic sites on three different arteries; the commune carotid, femoral and radial and, on each site the sensor demonstrated remarkable capability to make a consistent, reproducible measurements. Because of the advantageous physical and electrical properties, the new sensor is suitable for various cardiovascular diagnostics procedures, especially when long-term measurements of arterial blood flow waveform are required, for monitoring of different parameters in cardiovascular units and for research. PMID- 28560701 TI - Nano-Calorimetry based point of care biosensor for metabolic disease management. AB - Point of care (POC) diagnostics represents one of the fastest growing health care technology segments. Developments in microfabrication have led to the development of highly-sensitive nanocalorimeters ideal for directly measuring heat generated in POC biosensors. Here we present a novel nano-calorimeter-based biosensor design with differential sensing to eliminate common mode noise and capillary microfluidic channels for sample delivery to the thermoelectric sensor. The calorimeter has a resolution of 1.4 +/- 0.2 nJ/(Hz)1/2 utilizing a 27 junction bismuth/titanium thermopile, with a total Seebeck coefficient of 2160 MUV/K. Sample is wicked to the calorimeter through a capillary channel making it suitable for monitoring blood obtained through a finger prick (<1 MUL sample required). We demonstrate device performance in a model assay using catalase, achieving a threshold for hydrogen peroxide quantification of 50 MUM. The potential for our device as a POC blood test for metabolic diseases is shown through the quantification of phenylalanine (Phe) in serum, an unmet necessary service in the management of Phenylketonuria (PKU). Pegylated phenylalanine ammonia-lyase (PEG-PAL) was utilized to react with Phe, but reliable detection was limited to <5 mM due to low enzymatic activity. The POC biosensor concept can be multiplexed and adapted to a large number of metabolic diseases utilizing different immobilized enzymes. PMID- 28560702 TI - Hybrid intracerebral probe with integrated bare LED chips for optogenetic studies. AB - This article reports on the development, i.e., the design, fabrication, and validation of an implantable optical neural probes designed for in vivo experiments relying on optogenetics. The probes comprise an array of ten bare light-emitting diode (LED) chips emitting at a wavelength of 460 nm and integrated along a flexible polyimide-based substrate stiffened using a micromachined ladder-like silicon structure. The resulting mechanical stiffness of the slender, 250-MUm-wide, 65-MUm-thick, and 5- and 8-mm-long probe shank facilitates its implantation into neural tissue. The LEDs are encapsulated by a fluropolymer coating protecting the implant against the physiological conditions in the brain. The electrical interface to the external control unit is provided by 10-MUm-thick, highly flexible polyimide cables making the probes suitable for both acute and chronic in vivo experiments. Optical and electrical properties of the probes are reported, as well as their in vivo validation in acute optogenetic studies in transgenic mice. The depth-dependent optical stimulation of both excitatory and inhibitory neurons is demonstrated by altering the brain activity in the cortex and the thalamus. Local network responses elicited by 20-ms-long light pulses of different optical power (20 MUW and 1 mW), as well as local modulation of single unit neuronal activity to 1-s-long light pulses with low optical intensity (17 MUW) are presented. The ability to modulate neural activity makes these devices suitable for a broad variety of optogenetic experiments. PMID- 28560703 TI - Allogenic Blood Transfusion Is an Independent Predictor of Poorer Peri-operative Outcomes and Reduced Long-Term Survival after Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: a Review of 936 Cases. AB - INTRODUCTION: There is a paucity of data on the impact of allogenic blood transfusion (ABT) on morbidity and survival outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). METHODS: Nine hundred and thirty-five consecutive CRS/HIPEC procedures were performed between 1996 and 2016 at a high-volume institution in Sydney, Australia. Of these, 337(36%) patients required massive ABT (MABT) (>=5 units). Peri-operative complications were graded according to the Clavien-Dindo classification. The association of concomitant MABT with 21 peri-operative outcomes and overall survival (OS) was assessed using univariate and multivariate analyses. RESULTS: In-hospital mortality was 1.8%. Patients requiring MABT had more extensive disease as reflected by a higher peritoneal cancer index (>=17) (70 vs. 29%, p < 0.001) and longer operative times (>=9 h) (82 vs. 35%, p < 0.001). After accounting for confounding factors, MABT was associated with in-hospital mortality (relative risk (RR), 7.72; 95% confidence interval (CI), 1.35-10.11; p = 0.021) and grade III/IV morbidity (RR, 2.05; 95% CI, 1.42-2.95; p < 0.001). MABT was associated with an increased incidence of prolonged hospital stay (>=28 days) (RR, 1.86; 95% CI, 1.26-2.74; p = 0.002) and intensive care unit stay (>=4 days) (RR, 1.83; 95% CI, 1.24-2.70, p = 0.002). It was also associated with a significant OS in patients with colorectal cancer peritoneal carcinomatosis (RR 4.49; p < 0.001) and pseudomyxoma peritonei (RR, 4.37; p = 0.026), but not appendiceal cancer (p = 0.160). CONCLUSION: MABT is an independent predictor for poorer peri-operative outcomes including in-hospital mortality and grade III/IV morbidity. It may also compromise long-term survival, particularly in patients with colorectal cancer peritoneal carcinomatosis. PMID- 28560704 TI - Surgical Ampullectomy with Complete Resection of the Common Bile Duct: a New Procedure for Radical Resection of Non-invasive Ampulloma with Biliary Extension. AB - Extension of ampulloma into the lower common bile duct (CBD) is observed in up to 30% of cases. This biliary extension can prevent complete tumor resection thus is considered as a contraindication for endoscopic and even surgical ampullectomy. For ampullomas associated with a prolonged biliary extension, a pancreaticoduodenectomy is associated with a high morbidity and can be considered as an overtreatment for a benign neoplasm. The present study describes a new surgical approach including ampullectomy with complete resection of the intrapancreatic CBD and restoration of both biliary and pancreatic flow by two separate anastomoses. This procedure was performed in seven patients for a non invasive ampulloma with a 25- to 70-mm CBD involvement. No patients died and three developed postoperative complications. Resection was R0 in all patients but one. With a 24-month median follow-up (range = 3-84), no patients developed pancreatic insufficiency or tumor recurrence. PMID- 28560705 TI - Patient-Centered Outcome Instruments in Esophageal and Gastric Surgery. PMID- 28560706 TI - Local Hemodynamic Differences Between Commercially Available Y-Grafts and Traditional Fontan Baffles Under Simulated Exercise Conditions: Implications for Exercise Tolerance. AB - Fontan completion, resulting in a total cavopulmonary connection (TCPC), is accomplished using a lateral tunnel (LT), extracardiac conduit (ECC), or recently a bifurcated Y-graft. The local energetic differences between these graft types have not been substantially analyzed under exercise conditions. The present study evaluates the energetic performance of Y-grafts under simulated exercise conditions, compares their performance to the previous LT/ECC Fontan options, and discusses implications for exercise tolerance and hemodynamic predictability. Twenty Y-graft and 20 LT/ECC patients were analyzed. TCPC anatomies and flow waveforms were reconstructed using patient-specific cardiac magnetic resonance (CMR) images and phase-contrast CMR. Computational fluid dynamics simulations were performed to quantify indexed power loss (iPL) under both resting and simulated exercise conditions. Comparisons between graft types were investigated. iPL was significantly higher (p < 0.01) for Y-grafts at all activity levels. No significant interaction effects were observed between graft type and activity level. iPL at rest was strongly correlated (r 2 = 0.97, p < 0.001) with iPL at moderate exercise for Y-grafts, but less so for the LT/ECC cohort (r 2 = 0.66, p < 0.001). Similar results were seen for intense exercise, with a strong correlation for Y-grafts (r 2 = 0.94, p < 0.001) and a moderate correlation for LT/ECC (r 2 = 0.52, p < 0.001). Commercially available Y-grafts were found to have significantly higher iPL at all activity levels, suggesting worse exercise tolerance than the LT/ECC alternatives. Y-grafts offered impressive hemodynamic predictability which was not seen in the LT/ECC cohort. Our results encourage the further evaluation of an area-preserving Y-graft design to offer both improved energetic performance and hemodynamic predictability. Commercial Y-grafts show worse energetics, but more predictable responses than traditional Fontan connections under simulated exercise conditions. During simulated exercise conditions, commercially available Y-grafts show predictable but inferior energetic performance compared to lateral tunnel and extracardiac conduit Fontan connections, suggesting poorer exercise capacity. If Y-graft use is continued, these results encourage further evaluation of a cross sectional area-preserving Y graft design as a additional alternative for Fontan completion. PMID- 28560707 TI - Current trends in tendinopathy: consensus of the ESSKA basic science committee. Part I: biology, biomechanics, anatomy and an exercise-based approach. AB - Chronic tendinopathies represent a major problem in the clinical practice of sports orthopaedic surgeons, sports doctors and other health professionals involved in the treatment of athletes and patients that perform repetitive actions. The lack of consensus relative to the diagnostic tools and treatment modalities represents a management dilemma for these professionals. With this review, the purpose of the ESSKA Basic Science Committee is to establish guidelines for understanding, diagnosing and treating this complex pathology. PMID- 28560708 TI - Tonabersat Prevents Inflammatory Damage in the Central Nervous System by Blocking Connexin43 Hemichannels. AB - The cis benzopyran compound tonabersat (SB-220453) has previously been reported to inhibit connexin26 expression in the brain by attenuating the p38-mitogen activated protein kinase pathway. We show here that tonabersat directly inhibits connexin43 hemichannel opening. Connexin43 hemichannels have been called "pathological pores" based upon their role in secondary lesion spread, edema, inflammation, and neuronal loss following central nervous system injuries, as well as in chronic inflammatory disease. Both connexin43 hemichannels and pannexin channels released adenosine triphosphate (ATP) during ischemia in an in vitro ischemia model, but only connexin43 hemichannels contributed to ATP release during reperfusion. Tonabersat inhibited connexin43 hemichannel-mediated ATP release during both ischemia and reperfusion phases, with direct channel block confirmed using electrophysiology. Tonabersat also reduced connexin43 gap junction coupling in vitro, but only at higher concentrations, with junctional plaques internalized and degraded via the lysosomal pathway. Systemic delivery of tonabersat in a rat bright-light retinal damage model (a model for dry age related macular degeneration) resulted in significantly improved functional outcomes assessed using electroretinography. Tonabersat also prevented thinning of the retina, especially the outer nuclear layer and choroid, assessed using optical coherence tomography. We conclude that tonabersat, already given orally to over 1000 humans in clinical trials (as a potential treatment for, and prophylactic treatment of, migraine because it was thought to inhibit cortical spreading depression), is a connexin hemichannel inhibitor and may have the potential to be a novel treatment of central nervous system injury and chronic neuroinflammatory disease. PMID- 28560711 TI - Recent advances in hypertrophic scar. AB - Hypertrophic scars (HTS) are predominant diseases after burn and trauma, which cause severe physiological and psychological problems. HTS have been researched for decades, and our knowledge about the mechanisms of HTS formation process has been increasing. However, the effects of currently available prevention and treatment strategies are limited. In this review, we summarize currently known mechanisms and recent studies of HTS, including extracellular matrix, matrix metalloproteinases, fibroblasts, myofibroblasts and their contraction ability, keratinocytes, growth factors, inflammatory and immune response, and stem cell treatment, hoping for a better understanding of HTS generation, development and effective translation to treatment strategies. PMID- 28560709 TI - Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease. AB - Sporadic late-onset Alzheimer's disease (LOAD), the most common form of dementia in the elderly, causes progressive and severe loss of cognitive abilities. With greater numbers of people living to advanced ages, LOAD will increasingly burden both the healthcare system and society. There are currently no available disease modifying therapies, and the failure of several recent pathology-based strategies has highlighted the urgent need for effective therapeutic targets. With aging as the greatest risk factor for LOAD, targeting mechanisms by which aging contributes to disease could prove an effective strategy to delay progression to clinical dementia by intervention in elderly individuals in an early prodromal stage of disease. Excess neural activity in the hippocampus, a recently described phenomenon associated with age-dependent memory loss, was first identified in animal models of aging and subsequently translated to clinical conditions of aging and early-stage LOAD. Critically, elevated activity was similarly localized to specific circuits within the hippocampal formation in aged animals and humans. Here we review evidence for hippocampal hyperactivity as a significant contributor to age-dependent cognitive decline and the progressive accumulation of pathology in LOAD. We also describe studies demonstrating the efficacy of reducing hyperactivity with an initial test therapy, levetiracetam (Keppra), an atypical antiepileptic. By targeting excess neural activity, levetiracetam may improve cognition and attenuate the accumulation of pathology contributing to progression to the dementia phase of LOAD. PMID- 28560712 TI - Endogenous Probes for Drug Transporters: Balancing Vision With Reality. AB - Various endogenous probes have been identified for a number of hepatic and renal drug transporters and available clinical data indicate that they could be leveraged in phase I trials to facilitate subject phenotyping and drug-drug interaction (DDI) assessment. Despite the progress, however, it is recognized that the menu of probes needs expanding, that existing probes need further characterization and validation, and that compound files need to be built in support of probe absorption-metabolism-distribution-excretion-DDI modeling exercises. PMID- 28560713 TI - Time domain measurement of the vascular and myocardial branches of the baroreflex: A study in physically active versus sedentary individuals. AB - This study tests the spontaneous sequence method for the evaluation of the cardiac, vasomotor, and myocardial branches of the baroreflex. Systolic blood pressure (SBP), interbeat interval (IBI), stroke volume (SV), preejection period (PEP), and total peripheral resistance (TPR) were continuously recorded in 33 physically active and 25 sedentary participants at rest and during a mental arithmetic task. Sequences of spontaneous covariation between SBP and IBI (for the cardiac branch), SV and PEP (for the myocardial branch), and TPR (for the vasomotor branch) were located. The slope of the regression line between values in the sequences produced an estimate of baroreflex sensitivity (BRS), and the proportion of progressive SBP changes that elicited reflex modulations yielded an estimate of baroreflex effectiveness (BEI). The active group showed greater BRS in all three branches than the sedentary group. Cardiac and vasomotor BEI decreased during the arithmetic task in the sedentary group but not in the active one. Only cardiac BRS decreased during the arithmetic task. In conclusion, the method appears appropriate for the simultaneous assessment of the three baroreflex branches. The assessment of the vascular branch of the baroreflex may have prognostic relevance in the development of hypertension or other cardiometabolic diseases. PMID- 28560714 TI - Clinical presentation and echocardiographic diagnosis of postinfarction papillary muscle rupture: A review of 22 cases. AB - BACKGROUND: Acute myocardial infarctions (AMI) continue to be common in the United States. Mechanical complications of AMI can lead to cardiogenic shock (CS) and death. The aim of this study was to review the cases of papillary muscle ruptures in the setting of myocardial infarctions at a tertiary care center, with a focus on the clinical presentation and echocardiographic diagnosis. METHODS: This was a retrospective study from January 1, 2000 through December 31, 2014. In all, 22 patients with AMI and papillary muscle rupture (AMI-PMR) who had surgical intervention were identified. RESULTS: The average age was 70 (+/-11) with 16 (73%) males. Six patients presented with ST-elevation myocardial infarctions (STEMI) and all underwent emergent revascularization with primary percutaneous coronary intervention (PCI) prior to the diagnosis of AMI-PMR. The other 16 patients presented with a non-STEMI. In total, 17 (77%) of the 22 patients were diagnosed with an AMI-PMR within 7 days from their onset of symptoms. In all, 12 patients (55%) had anterolateral papillary muscle ruptures (ALPMR), and the other 10 had posteromedial papillary muscle ruptures (PMPMR). Ruptures were complete in 10 patients (45%). Patients presented with pulmonary edema early (<7 days) more commonly than late (>14 days). Transthoracic echocardiography was able to demonstrate severe mitral regurgitation in 86% and a definitive or suggestive diagnosis in 93%. All 22 patients survived to operative management, and the overall in-hospital mortality rate was 9%. CONCLUSION: In conclusion, ischemic papillary muscle ruptures continue to occur, but with prompt diagnosis by echocardiography and rapid surgical management, the mortality rate continues to decline. PMID- 28560715 TI - Incomplete Kawasaki disease presenting as bilateral hip synovitis. PMID- 28560710 TI - HCN Channel Targets for Novel Antidepressant Treatment. AB - Major depressive disorder (MDD) is a chronic and potentially life threatening illness that carries a staggering global burden. Characterized by depressed mood, MDD is often difficult to diagnose and treat owing to heterogeneity of syndrome and complex etiology. Contemporary antidepressant treatments are based on improved monoamine-based formulations from serendipitous discoveries made > 60 years ago. Novel antidepressant treatments are necessary, as roughly half of patients using available antidepressants do not see long-term remission of depressive symptoms. Current development of treatment options focuses on generating efficacious antidepressants, identifying depression-related neural substrates, and better understanding the pathophysiological mechanisms of depression. Recent insight into the brain's mesocorticolimbic circuitry from animal models of depression underscores the importance of ionic mechanisms in neuronal homeostasis and dysregulation, and substantial evidence highlights a potential role for ion channels in mediating depression-related excitability changes. In particular, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are essential regulators of neuronal excitability. In this review, we describe seminal research on HCN channels in the prefrontal cortex and hippocampus in stress and depression-related behaviors, and highlight substantial evidence within the ventral tegmental area supporting the development of novel therapeutics targeting HCN channels in MDD. We argue that methods targeting the activity of reward-related brain areas have significant potential as superior treatments for depression. PMID- 28560716 TI - Risk stratification and long-term risk prediction of E6 oncoprotein in a prospective screening cohort in China. AB - E6 oncoprotein is a necessary agent of HPV driven oncogenic transformation. This study is aimed at evaluating the risk stratification potency of HPV 16/18 E6 oncoprotein (E6) as a triage method for HPV positivity. Moreover, it also acts as a predictor of cervical intraepithelial neoplasia grade 3 or worse (CIN3+). The screening cohort of 1,997 women was followed for a 15 year period in approximate five-year intervals. Participants were concurrently screened by HPV DNA testing (HC2), liquid based cytology (LBC), visual inspection with acetic acid (VIA) and were referred to colposcopy and biopsy if any tests reflected positive. E6 was performed on cervical samples collected from this cohort in 2005 and 2014. The ability of E6 to predict CIN3+ risk after the five- and ten-year interval was evaluated. Among HPV positive women in 2005, E6 indicated the lowest positive rate (9.9%) compared to LBC (48.4%) and VIA (28.0%), however, a higher prevalence rate (10.3%) and 10-year cumulative incidence rate (53.0%) of CIN3+ were detected among women who were E6 positive. Meanwhile, only 4.2% and 2.9% of women with abnormal LBC and positive VIA were diagnosed as prevalent CIN3+ in 2005, 23.0% and 16.5% developed to CIN3+ after year 10, respectively. Strong associations were found between precedent and subsequent HPV persistence and E6 oncoprotein expression (ORadjusted = 40.0 and 21.2, respectively). E6 oncoprotein could serve as a low-cost, highly specific, strongly indicative point-of-care method in the triage and treatment of HPV positive women. PMID- 28560718 TI - Suzuki Cross-Coupling for Post-Complexation Derivatization of Non-Racemic Bis Cyclometalated Iridium(III) Complexes. AB - A straightforward method for post-complexation derivatizations of diastereo- and enantiomerically pure bis-cyclometalated benzoxazole and benzothiazole iridium(III) complexes is reported. Triflate- and bromine-functionalized iridium(III) complex dimers, represented as [Ir(MU-Cl)(C^N)2 ]2 , were converted to the corresponding diastereomeric complexes, represented as Ir(C^N)2 (N^O), using readily available chiral salicyloxazolines and salicylthiazolines as ancillary ligands, which are represented as N^O. The Ir(C^N)2 (N^O) complexes, formed as mixtures of diastereomers, were then resolved by flash chromatography and the diastereomerically pure complexes Ir(C^N)2 (N^O) subjected to Suzuki cross-couplings. The post-complexation cross-couplings proceed without affecting the metal-located stereocenter and hence provide post-complexation derivatized non-racemic iridium(III) complexes, which were not easily accessible with previous methods. This strategy expands the toolbox to access functionalized non racemic iridium(III) complexes for diverse applications in the life sciences, materials sciences, and catalysis. PMID- 28560719 TI - Visual system pathology in humans and animal models of blast injury. AB - Injury from blast exposure is becoming a more prevalent cause of death and disability worldwide. The devastating neurological impairments that result from blasts are significant and lifelong. Progress in the development of effective therapies to treat injury has been slowed by its heterogeneous pathology and the dearth of information regarding the cellular mechanisms involved. Within the last decade, a number of studies have documented visual dysfunction following injury. This brief review examines damage to the visual system in both humans and animal models of blast injury. The in vivo use of the retina as a surrogate to evaluate brain injury following exposure to blast is also highlighted. PMID- 28560720 TI - Home mechanical ventilation for stable COPD in GOLD 2017: What are we ventilating? PMID- 28560721 TI - Electronically Activated Organoboron Catalysts for Enantioselective Propargyl Addition to Trifluoromethyl Ketones. AB - A broadly applicable, practical, scalable, efficient and highly alpha- and enantioselective method for addition of a silyl-protected propargyl moiety to trifluoromethyl ketones has been developed. Reactions, promoted by 2.0 mol % of a catalyst that is derived in situ from a readily accessible aminophenol compound at ambient temperature, were complete after only 15 minutes at room temperature. The desired tertiary alcohols were isolated in up to 97 % yield and 98.5:1.5 enantiomeric ratio. Alkyl-, alkenyl-, alkynyl-, aryl- or heteroaryl-substituted trifluoromethyl ketones can be used. Utility is highlighted by application to a transformation that is relevant to enantioselective synthesis of BI 653048, a compound active against rheumatoid arthritis. PMID- 28560723 TI - Impact of distress related to attenuated psychotic symptoms in individuals at ultra high risk of psychosis: Findings from the Longitudinal Youth at Risk Study. AB - AIM: Recent studies have highlighted that attenuated psychotic symptoms (APS) are an important source of distress in ultra high risk (UHR) individuals and that this distress is related to transition to psychosis (TTP). This study examined distress associated with APS in UHR individuals and investigated its association with TTP. METHODS: The Comprehensive Assessment of At-Risk Mental State (CAARMS) was used to identify 173 UHR individuals, who were included as participants in the study. Distress related to APS was self-reported. Functioning was assessed on the Social and Occupational Functioning Assessment Scale. Associations between each of the 4 APS subscales in the CAARMS-non-bizarre ideas (NBI), perceptual abnormalities (PA), unusual thought content (UTC) and disorganized speech (DS) with its distress level were examined. RESULTS: Of the 173 UHR participants, 154 (89%) reported distress related to one or more APS. NBI was rated to be the most distressing out of the 4 APS by the highest number of participants (32.9%) compared to UTC (12.1%), PA (24.9%) and DS (2.9%). Mean distress scores were significantly associated with CAARMS composite scores (P < .001). However, there was no significant relationship between distress scores and functioning. Both mean distress scores (OR = 1.034, P = .029) and functioning (OR = 0.892, P = .022) were significant predictors of transition to psychosis at 1 year of follow up. CONCLUSIONS: This study provides additional evidence to link subjective distress experienced by UHR individuals to APS and to their subsequent clinical outcomes and has significant clinical implications. PMID- 28560722 TI - Effectiveness of Drugs in Routine Care: A Model for Sequential Monitoring of New Medicines Using Dronedarone as Example. AB - Although there is no doubt about the scientific value of randomized controlled clinical trials, they are usually conducted in selected populations different from those treated in clinical practice. Therefore, it is important to optimize real-time postmarketing evaluation of the effectiveness, safety, and cost of new drugs. Using electronic health records and administrative health databases from a well-defined region with universal access to healthcare, we have built a framework for real-time sequential monitoring of the effectiveness of newly marketed drugs in routine care. We chose the antiarrhythmic agent dronedarone as the study drug and flecainide as the comparator drug for illustration of the model. We demonstrate that this model produces consistent results with increasing precision over time as data accumulates in the clinical systems. We believe that use of this model at the introduction of new drugs can provide complementary evidence, especially in settings of adaptive licensing of new drugs. PMID- 28560717 TI - Organ dysfunction, injury and failure in acute heart failure: from pathophysiology to diagnosis and management. A review on behalf of the Acute Heart Failure Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). AB - Organ injury and impairment are commonly observed in patients with acute heart failure (AHF), and congestion is an essential pathophysiological mechanism of impaired organ function. Congestion is the predominant clinical profile in most patients with AHF; a smaller proportion presents with peripheral hypoperfusion or cardiogenic shock. Hypoperfusion further deteriorates organ function. The injury and dysfunction of target organs (i.e. heart, lungs, kidneys, liver, intestine, brain) in the setting of AHF are associated with increased risk for mortality. Improvement in organ function after decongestive therapies has been associated with a lower risk for post-discharge mortality. Thus, the prevention and correction of organ dysfunction represent a therapeutic target of interest in AHF and should be evaluated in clinical trials. Treatment strategies that specifically prevent, reduce or reverse organ dysfunction remain to be identified and evaluated to determine if such interventions impact mortality, morbidity and patient-centred outcomes. This paper reflects current understanding among experts of the presentation and management of organ impairment in AHF and suggests priorities for future research to advance the field. PMID- 28560725 TI - Treatment Efficacy of Multiple Family Therapy for Chinese Families of Children with Attention Deficit Hyperactivity Disorder. AB - The treatment efficacy of multiple family therapy (MFT) for Chinese families of children with attention deficit hyperactivity disorder (ADHD) has not been studied in the past. In this paper, the effect of MFT on different aspects of the lives of the parents in the experimental group (n = 61) was compared with the effect of only the psychoeducational talks on parents in the control group (n = 53). The results of a MANOVA have shown that by the time they reached the posttreatment phase, the parents who had completed the full 42 hours of the MFT program perceived their children's ADHD symptoms as being less serious and less pathological than they had originally thought compared to the parents in the control group. The effect of MFT on parent-child relationships, parenting stress, parental efficacy, hope, and perceived social support was statistically insignificant. Contributions and limitations of our study are discussed. PMID- 28560724 TI - The time course of pupil dilation evoked by visual sexual stimuli: Exploring the underlying ANS mechanisms. AB - The early processing of visual sexual stimuli shows signs of automaticity. Moreover, there is evidence for sex-specific patterns in cognitive and physiological responding to erotica. However, little is known about the time course of rapid pupillary responses to sexual stimuli and their correspondence with other measures of autonomic activity in women and men. To study pupil dilation as an implicit measure of sexual arousal at various stages of picture processing, we presented 35 heterosexual participants with pictures showing either erotic couples or single (male/female) erotic nudes, contrasted with people involved in everyday situations. Brightness-adjusted grayscale pictures were shown for a duration of 2,500 ms within the central visual field, alternating with perceptually matched patches. Left pupil diameter was recorded at 500 Hz using a video-based eye tracker. Skin conductance and heart rate were coregistered and correlated with latent components of pupil dilation (dissociated by temporal PCA). Whereas stimulus-evoked changes in pupil size indicated virtually no initial constriction, a rapid effect of appetence emerged (dilation to erotica within 500 ms). Responses at early stages of processing were remarkably consistent across both sexes. In contrast, later phases of pupil dilation, subjective ratings, and skin conductance responses showed a sex specific pattern. Moreover, evidence for an association of early-onset pupil dilation and heart rate acceleration was found, suggestive of parasympathetic inhibition, whereas the late component was mainly related to sympathetically mediated skin conductance. Taken together, our results indicate that different temporal components of pupil responses to erotic stimuli may reflect divergent underlying neural mechanisms. PMID- 28560726 TI - Payment Reform and Health Disparities: Changes in Dialysis Modality under the New Medicare Dialysis Payment System. AB - OBJECTIVE: To evaluate the effect of the Medicare dialysis payment reform on potential disparities in the selection of peritoneal dialysis (PD) for the treatment of end-stage renal disease (ESRD). DATA SOURCES: Centers for Medicare & Medicaid Services (CMS) ESRD Medical Evidence Form, Medicare claims, and other CMS data for 2008-2013. STUDY DESIGN: We examined the association of patient age, race/ethnicity, urban/rural location, pre-ESRD care, comorbidities, insurance, and other factors with the selection of PD as initial dialysis modality across prereform (2008-2009), interim (2010), and postreform (2011-2013) time periods. PRINCIPAL FINDINGS: Selection of PD increased among diverse patient subgroups following the payment reform. However, the lower PD selection observed with older age, black race, Hispanic ethnicity, less pre-ESRD care, and Medicaid insurance before the reform largely remained in the initial postreform years. CONCLUSIONS: Despite recent growth in PD, there may be ongoing disparities in access to PD that have largely not been mitigated by the payment reform. There is potential for modifying provider financial incentives to achieve policy goals related to cost and quality of care. However, even with a substantial shift in financial incentives, separate initiatives to reduce existing disparities in care may be needed. PMID- 28560727 TI - Choosing the optimal method of blood pressure measurement for limited-resource rural communities in the "Community Health Assessment Program-Philippines". AB - The Community Health Assessment Program-Philippines (CHAP-P) is an international collaboration of investigators whose aim is to adapt a previously proven Canadian community-based cardiovascular awareness and prevention intervention to the Philippines and other low-middle-income countries. Choosing a method of blood pressure measurement for the research program presents a challenge. There is increasing consensus globally that blood pressure measurement with automated devices is preferred. Recommendations from low-middle-income countries, including the Philippines, are less supportive of automated blood pressure devices. The value placed on factors including device accuracy, durability, cost, energy source, and complexity differ with local context. Our goal was to support the progress of local policy concerning blood pressure measurement while testing a comprehensive approach to community-based screening for cardiovascular risk. The authors describe the challenges in making a choice of blood pressure device and the approach to determine optimal method of measurement for our research program. PMID- 28560728 TI - Decreasing hazards of Alzheimer's disease with the use of antidepressants: mitigating the risk of depression and apolipoprotein E. AB - OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disease, manifesting in clinically observable deficits in memory, thinking, and behavior that disproportionately affects older adults. Susceptibility genes, such as apolipoprotein epsilon4, have long been associated with an increased risk of AD diagnosis. Studies have shown associations between depression and increased risk of AD development. Furthermore, findings from previous investigations suggest mixed effects in the use of psychotropic medication in older adults. The hypothesis for this study is that antidepressant use modifies the increased hazard of depression or such that a non-significant hazard will result with respect to eventual AD development. METHODS: Utilizing data from the National Alzheimer's Coordinating Center, we examined evaluations of 11,443 cognitively intact participants. Survival analysis was used to explore relationships between depression, apolipoprotein E, AD diagnosis, and antidepressant use. RESULTS: An analytical sample of 8732 participants with normal cognition was examined. Among users of antidepressant medication, the hazard, in most cases, was no longer statistically significant. One generic medication showed protective benefits for users (p < 0.001). In addition, there was a statistically significant relationship between recent depression (n = 2083; p < 0.001), lifetime depression (n = 2068; p < 0.05), and epsilon4 carrier status (n = 2470; p < 0.001) and AD development. CONCLUSIONS: The findings suggest that a mechanism related to antidepressant use may reduce the hazard of eventual AD. Furthermore, the findings reinforce the association between depression, apolipoprotein E (APOE) epsilon4, and AD diagnosis. This study contributes to the emerging literature exploring interventions aimed at decreasing the risk of AD by targeting potentially modifiable psychosocial risk factors such as depression. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28560729 TI - Determining the factors associated with blood-borne virus testing of substance misusers presenting to hospital. AB - BACKGROUND: Diagnosing blood-borne virus (BBV) infection is an essential first step in eliminating transmission and securing access to treatment amongst substance misusers. AIMS: To determine the proportion of substance misusers presenting to hospital who undergo BBV testing and the factors influencing testing. METHODS: A retrospective cross-sectional study was performed of patients presenting to two Sydney teaching hospitals with substance misuse diagnoses between January and April 2015. Proportions tested for human immunodeficiency virus, hepatitis C and hepatitis B previously and during the index hospitalisation presentation were examined. Multivariable analysis was performed to determine factors associated with testing. RESULTS: Of 239 patients, 47 (19.7%) had a documented BBV at baseline. Of those with unknown BBV status, 29 (12.8%) had undergone some attempt at testing during presentation; 3.1% had their hepatitis B immunity assessed. Factors associated with an increased likelihood of testing during presentation included documented injecting drug use (odds ratio (OR) 15.14; 95% confidence interval (CI) 4.21-54.50; P < 0.001), admission under a physician (OR 11.79; 95% CI 2.82-49.40; P = 0.001) and admission on a Friday (OR 4.46; 95% CI 1.28-15.48; P = 0.02). Patients who had had more than one previous admission in the preceding 6 months (OR 0.24; 95% CI 0.078-0.73; P = 0.01) or a length of stay of 1 day or less (OR 0.17; 95% CI 0.032-0.87; P = 0.033) were less likely to be tested. CONCLUSION: Despite the high baseline prevalence of BBV infections in the population, there were many missed opportunities for BBV testing. We found patient-, admission- and clinician-level barriers that could be addressed to enhance BBV testing uptake. PMID- 28560730 TI - Perception paradox between the doctors and patients in the industrial bureaucratic age of medicine: Defensive versus offensive medicine in anticoagulation and atrial fibrillation ablation. PMID- 28560731 TI - Vaccine discussions with parents: The experience of Australian paediatricians. AB - AIM: Health-care providers are crucial in maintaining parental confidence in vaccination. Health-care providers are the most commonly accessed resource by parents for vaccine-related information and are highly trusted. We investigated paediatricians' (i) frequency of vaccine discussions; (ii) specific vaccine related topics discussed; (iii) perceived role in childhood vaccination; (iv) challenges faced when having discussions; (v) confidence in vaccine-related knowledge and communication skills; and (vi) interest in online education and training. METHODS: We invited members of the Australian Paediatric Research Network to complete an online Research Electronic Data Capture survey in 2015 2016. RESULTS: Of 383 active Australian Paediatric Research Network members, 165 (43%) completed the online survey. A total of 61% reported 'frequently' or 'almost always' having vaccine-related discussions, with 15% 'rarely' having them. 'Lack of time' was the most commonly reported barrier to having vaccine discussions (54%). Vaccine necessity was most commonly discussed (33%), followed by vaccine safety (24%), general vaccine concerns (23%) and catch-up schedules (23%). While only 25% of paediatricians lacked confidence in their vaccine related knowledge and 11% in their communication skills, most expressed interest in online training to address vaccine knowledge (62%) and communication skills (53%). CONCLUSION: Paediatricians play a key role in maintaining public confidence in vaccination. However, opportunities to address concerns are not being maximised by Australian paediatricians. There is a need and desire for training and resources to increase vaccine knowledge and communication skills for paediatricians, to optimise the frequency and effectiveness of vaccine discussions with parents and to ensure ongoing high immunisation coverage rates in Australia. PMID- 28560732 TI - Log Odds and the Interpretation of Logit Models. AB - OBJECTIVE: We discuss how to interpret coefficients from logit models, focusing on the importance of the standard deviation (sigma) of the error term to that interpretation. STUDY DESIGN: We show how odds ratios are computed, how they depend on the standard deviation (sigma) of the error term, and their sensitivity to different model specifications. We also discuss alternatives to odds ratios. PRINCIPAL FINDINGS: There is no single odds ratio; instead, any estimated odds ratio is conditional on the data and the model specification. Odds ratios should not be compared across different studies using different samples from different populations. Nor should they be compared across models with different sets of explanatory variables. CONCLUSIONS: To communicate information regarding the effect of explanatory variables on binary {0,1} dependent variables, average marginal effects are generally preferable to odds ratios, unless the data are from a case-control study. PMID- 28560733 TI - Complete remission with romidepsin in a patient with T-cell acute lymphoblastic leukemia refractory to induction hyper-CVAD. AB - T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T LBL) are neoplasms that originate from T-cell precursors. Outcomes in adult patients with T-ALL/LBL remain unsatisfactory; early relapse following intensive induction chemotherapy is a concern, and patients with relapsed or refractory disease have a poor prognosis. Romidepsin is a potent, class 1 selective histone deacetylase inhibitor approved for the treatment of patients with peripheral T cell lymphoma who have had >=1 prior therapy and patients with cutaneous T-cell lymphoma who have had >=1 prior systemic therapy. Here, we report the case of an adult patient with T-ALL refractory to induction hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD). Treatment with romidepsin was initiated, and romidepsin in combination with hyper CVAD resulted in complete remission, with mild tumor lysis syndrome as the only detectable additional toxicity. The patient eventually underwent allogeneic stem cell transplant while in first complete remission. Prior studies have shown that romidepsin is capable of inducing durable responses with manageable toxicities in patients with mature T-cell lymphomas. This case study describes the successful use of romidepsin in combination with hyper-CVAD in an adult patient with refractory T-ALL and highlights the activity of romidepsin in the T-cell lineage. The potential of romidepsin-containing regimens in patients with T-ALL/LBL deserves further study. PMID- 28560734 TI - Substrate properties of zebrafish Rtn4b/Nogo and axon regeneration in the zebrafish optic nerve. AB - This study explored why lesioned retinal ganglion cell (RGC) axons regenerate successfully in the zebrafish optic nerve despite the presence of Rtn4b, the homologue of the rat neurite growth inhibitor RTN4-A/Nogo-A. Rat Nogo-A and zebrafish Rtn4b possess characteristic motifs (M1-4) in the Nogo-A-specific region, which contains delta20, the most inhibitory region of rat Nogo-A. To determine whether zebrafish M1-4 is inhibitory as rat M1-4 and Nogo-A delta20, proteins were recombinantly expressed and used as substrates for zebrafish single cell RGCs, mouse hippocampal neurons and goldfish, zebrafish and chick retinal explants. When offered as homogenous substrates, neurites of hippocampal neurons and of zebrafish single cell RGCs were inhibited by zebrafish M1-4, rat M1-4, and Nogo-A delta20. Neurite length increased when zebrafish single cell RGCs were treated with receptor-type-specific antagonists and, respectively, with morpholinos (MO) against S1PR2 and S1PR5a-which represent candidate zebrafish Nogo-A receptors. In a stripe assay, however, where M1-4 lanes alternate with polylysine-(Plys)-only lanes, RGC axons from goldfish, zebrafish, and chick retinal explants avoided rat M1-4 but freely crossed zebrafish M1-4 lanes suggesting that zebrafish M1-4 is growth permissive and less inhibitory than rat M1-4. Moreover, immunostainings and dot blots of optic nerve and myelin showed that expression of Rtn4b is very low in tissue and myelin at 3-5 days after lesion when axons regenerate. Thus, Rtn4b seems to represent no major obstacle for axon regeneration in vivo because it is less inhibitory for RGC axons from retina explants, and because of its low abundance. PMID- 28560735 TI - Impact of the Swedish National Stroke Campaign on stroke awareness. AB - BACKGROUND: Time delay from stroke onset to arrival in hospital is an important obstacle to widespread reperfusion therapy. To increase knowledge about stroke, and potentially decrease this delay, a 27-month national public information campaign was carried out in Sweden. AIMS: To assess the effects of a national stroke campaign in Sweden. METHODS: The variables used to measure campaign effects were knowledge of the AKUT test [a Swedish equivalent of the FAST (Face Arm-Speech-Time)] test and intent to call 112 (emergency telephone number) . Telephone interviews were carried out with 1500 randomly selected people in Sweden at eight points in time: before, three times during, immediately after, and nine, 13 and 21 months after the campaign. RESULTS: Before the campaign, 4% could recall the meaning of some or all keywords in the AKUT test, compared with 23% during and directly after the campaign, and 14% 21 months later. Corresponding figures were 15%, 51%, and 50% for those remembering the term AKUT and 65%, 76%, and 73% for intent to call 112 when observing or experiencing stroke symptoms. During the course of the campaign, improvement of stroke knowledge was similar among men and women, but the absolute level of knowledge for both items was higher for women at all time points. CONCLUSION: The nationwide campaign substantially increased knowledge about the AKUT test and intention to call 112 when experiencing or observing stroke symptoms, but knowledge declined post-intervention. Repeated public information therefore appears essential to sustain knowledge gains. PMID- 28560736 TI - Enantioseparation of ofloxacin and its four related substances with ligand exchange-micellar electrokinetic chromatography using copper(II)-L-isoleucine complex as chiral selector. AB - A ligand-exchange micellar electrokinetic capillary electrophoresis system with copper(II)-L-isoleucine complexes as the chiral selector incorporated in micelles of sodium dodecyl sulfate (SDS) was developed for the enantioseparation of ofloxacin and its four related substances (impurities A, C, E, and F). The effects of important parameters affecting separation such as buffer pH, SDS concentration, chiral selector concentration, and organic additive were investigated in detail. Under optimum experimental conditions, enantioseparation of ofloxacin, impurities A, C, E, and F enantiomers was accomplished with resolutions of 4.28, 2.83, 3.40, 3.58, and 2.46, respectively. Further, simultaneous separation of impurities A, C, E, and F enantiomers was achieved using 10 mmol/L NH4 OAc as the running buffer containing 4 mmol/L copper sulfate,20 mmol/L L-isoleucine, 20 mmol/L SDS, and 5% methanol at pH 8.5. To the best of our knowledge, the simultaneous enantioseparation of four impurities of ofloxacin has not been reported previously. PMID- 28560738 TI - Evaluation of ultrasound reporting for thyroid cancer diagnosis and surveillance. AB - BACKGROUND: Despite the importance of ultrasound imaging in thyroid disease care, ultrasound reports vary greatly in the features described. It is essential that ultrasound reports contain and present all components necessary for a clinical decision in a reader-friendly format. METHODS: One hundred ninety thyroid and neck ultrasound reports were scored using the universal ultrasound report template developed by Su et al, along with the American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid Association (AACE/AME/ETA) guidelines. All ultrasounds were performed on patients seen between August and November 2015 by a single surgeon (M.L.U), and originated from a variety of physicians and institutions. RESULTS: An average of 30.9% of Su et al's criteria was satisfactorily included in the reports. Similar results were reached when the ATA and the AACE/AME/ETA guidelines were applied as scoring templates. CONCLUSION: Our results reveal the wide variation in ultrasound reporting. The standardization of ultrasound reporting would help to improve physicians' ability to properly diagnose and manage patients with thyroid disease. PMID- 28560737 TI - Reduced regional cerebral blood flow in patients with heart failure. AB - AIMS: Heart failure (HF) patients show significant lateralized neural injury, accompanied by autonomic, mood and cognitive deficits. Both gray and white matter damage occurs and probably develops from altered cerebral blood flow (CBF), a consequence of impaired cardiac output. However, the distribution of regional CBF changes in HF patients is unknown, but is an issue in determining mechanisms of neural injury. Our aim was to compare regional CBF changes in HF with CBF in control subjects using non-invasive pseudo-continuous arterial spin labelling (ASL) procedures. METHODS AND RESULTS: We collected pseudo-continuous ASL data from 19 HF patients [mean age 55.5 +/- 9.1 years; mean body mass index 27.7 +/- 5.3 kg/m2 ; 13 male) and 29 control subjects (mean age 51.4 +/- 5.3 years; mean body mass index 25.7 +/- 3.6 kg/m2 ; 18 male), using a 3.0-Tesla magnetic resonance imaging (MRI) scanner. Whole-brain CBF maps were calculated, normalized to a common space, smoothed and compared between groups using ANCOVA (covariates; age, gender and gray matter volume). Reduced CBF appeared in multiple sites in HF patients in comparison with controls, with principally lateralized lower flow in temporal, parietal and occipital regions. Areas with decreased CBF included the bilateral prefrontal, frontal, temporal and occipital cortex, thalamus, cerebellum, corona radiate, corpus callosum, hippocampus and amygdala. CONCLUSIONS: Heart failure patients showed lower, and largely lateralized, CBF in multiple autonomic, mood and cognitive regulatory sites. The reduced CBF is likely to contribute to the lateralized brain injury, leading to the autonomic and neuropsychological deficits found in the condition. PMID- 28560739 TI - Predictive value of different prostate-specific antigen-based markers in men with baseline total prostate-specific antigen <2.0 ng/mL. AB - OBJECTIVES: To investigate the predictive value of various molecular forms of prostate-specific antigen in men with baseline prostate-specific antigen <2.0 ng/mL. METHODS: The case cohort comprised 150 men with a baseline prostate specific antigen level <2.0 ng/mL, and who developed prostate cancer within 10 years. The control cohort was 300 baseline prostate-specific antigen- and age adjusted men who did not develop prostate cancer. Serum prostate-specific antigen, free prostate-specific antigen, and [-2] proenzyme prostate-specific antigen were measured at baseline and last screening visit. The predictive impact of baseline prostate-specific antigen- and [-2] proenzyme prostate-specific antigen-related indices on developing prostate cancer was investigated. The predictive impact of those indices at last screening visit and velocities from baseline to final screening on tumor aggressiveness were also investigated. RESULTS: The baseline free to total prostate-specific antigen ratio was a significant predictor of prostate cancer development. The odds ratio was 6.08 in the lowest quintile baseline free to total prostate-specific antigen ratio subgroup. No serum indices at diagnosis were associated with tumor aggressiveness. The Prostate Health Index velocity and [-2] proenzyme prostate specific antigen/free prostate-specific antigen velocity significantly increased in patients with higher risk D'Amico risk groups and higher Gleason scores. CONCLUSIONS: Free to total prostate-specific antigen ratio in men with low baseline prostate-specific antigen levels seems to predict the risk of developing prostate cancer, and it could be useful for a more effective individualized screening system. Longitudinal changes in [-2] proenzyme prostate-specific antigen-related indices seem to correlate with tumor aggressiveness, and they could be used as prognostic tool before treatment and during active surveillance. PMID- 28560741 TI - Method development for the determination of elements in Hypericum perforatum L. (St John's wort) herb and preparations using inductively coupled plasma-optical emission spectroscopy and microwave digestion. AB - OBJECTIVES: A method was developed to analyze St John's wort (Hypericum perforatum L.) herb and preparations using inductively coupled plasma-optical emission spectroscopy (ICP-OES) to determine the quantity of 11 elements (Al, B, Ba, Ca, Cu, Fe, Mg, Mn, Ni, Sr and Zn). METHODS: This study includes the evaluation of digestion acids and calibration methods, as well as instrumental parameters such as choice of nebulizer and emission wavelength. KEY FINDINGS: Two nebulizers (Conikal and SeaSpray) performed similarly for most elements, and two optimum wavelengths were determined for each element. Five acids were evaluated for the digestion of the Polish Certified Reference Material Tea Leaves (INCT-TL 1), while three were taken forward to use for the different St John's wort formulations (i.e. herb, capsule and tablet). A simple protocol using 5 ml HNO3 was sufficient in most cases; however, variability was observed for elements often bound in silicates (e.g. Al, Fe and Zn). An external weighted calibration was also found to be preferential over unweighted, and the use of standard addition affected some concentration values up to 20%. CONCLUSIONS: Therefore, this paper presents the development and optimized method parameters to be used with ICP-OES that will allow the analysis of 11 key elements present in St John's wort herb and preparations. PMID- 28560742 TI - The relationships between lipid ratios and arterial stiffness. PMID- 28560740 TI - Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination. AB - Remyelination is in the center of new therapies for the treatment of multiple sclerosis to resolve and improve disease symptoms and protect axons from further damage. Although remyelination is considered beneficial in the long term, it is not known, whether this is also the case early in lesion formation. Additionally, the precise timing of acute axonal damage and remyelination has not been assessed so far. To shed light onto the interrelation between axons and the myelin sheath during de- and remyelination, we employed cuprizone- and focal lysolecithin induced demyelination and performed time course experiments assessing the evolution of early and late stage remyelination and axonal damage. We observed damaged axons with signs of remyelination after cuprizone diet cessation and lysolecithin injection. Similar observations were made in early multiple sclerosis lesions. To assess the correlation of remyelination and axonal damage in multiple sclerosis lesions, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the number of APP- and SMI32- positive damaged axons and the density of SMI31-positive and silver impregnated preserved axons. Early de- and remyelinating lesions did not differ with respect to axonal density and axonal damage, but we observed a lower axonal density in late stage demyelinated multiple sclerosis lesions than in remyelinated multiple sclerosis lesions. Our findings suggest that remyelination may not only be protective over a long period of time, but may play an important role in the immediate axonal recuperation after a demyelinating insult. PMID- 28560745 TI - Aspirin in heart failure: don't throw the baby (aspirin) out with the bathwater. PMID- 28560743 TI - Occurrence of BAP1 germline mutations in cutaneous melanocytic tumors with loss of BAP1-expression: A pilot study. AB - Melanocytic BAP1-associated intradermal tumors (MBAITs) can either be sporadic or associated with a cancer-predisposition syndrome. In this study we explored the clinical status of 136 patients in which at least one MBAIT was found. 49/136 (36%) of them gave their signed consent for an oncogenetic BAP1 blood test. 28/136 patients (20%) diagnosed with an MBAIT had other MBAITs and/or a personal or familial history of BAP1-related cancers that could clinically designate them as potential carriers of a BAP1 germline mutation. 17 of these 28 patients underwent oncogenetic testing. A deleterious mutation of BAP1 was confirmed in 12/17 cases. 4/17 cases were wild-type; all had a single MBAIT and a history of skin melanoma. A variant of unknown significance was found in one case with multiple MBAITs. Among the 12 mutated cases, multiple MBAITs were present in 10/12 cases and were the only clinical sign in 4/12 cases. The remaining 32/49 blood-tested cases with an isolated MBAIT were wild type for BAP1 in 25/32 cases or showed a variant of unknown significance in 7/32 cases. We recommend, following the diagnosis of a MBAIT, performing a BAP1 immunohistochemistry in all other cutaneous melanocytic tumors removed previously or simultaneously and all skin melanomas. This screening could help clinicians prioritize which patients would most benefit from oncogenetic testing. PMID- 28560744 TI - Silage preparation and fermentation quality of kudzu, sugarcane top and their mixture treated with lactic acid bacteria, molasses and cellulase. AB - We studied silage fermentation of kudzu (KZ), sugarcane top (ST) and their mixtures treated with additives to be able to effectively use available local feed resources. The silages were prepared using KZ, ST, KZ 90% + ST 10%, KZ 80% + ST 20%, KZ 70% + ST 30% and KZ 60% + ST 40%, based on fresh matter (FM). These silages were treated with 108 colony-forming units/g epiphytic lactic acid bacteria (LAB), 5% molasses and 0.02% cellulase of FM. The KZ contained higher crude protein (CP; 14.52%) content and lower levels of neutral detergent fiber (NDF; 62.15%) than those of ST (6.84% CP and 64.93% NDF) based on dry matter (DM). The KZ 60% + ST 40% silage fermented well with a higher (P < 0.05) lactic acid content and lower (P < 0.05) pH than those of the other mixed silages. Silages treated with molasses had lower (P < 0.05) ammonia-N, NDF, acid detergent fiber, and hemi-cellulose contents as well as pH, but higher (P < 0.05) DM, water soluble carbohydrate, and lactic acid contents, than those of the control, LAB and cellulase treatments. The results confirmed that KZ 60% + ST 40% was the best mixing ratio to prepare silage, and molasses improved silage fermentation and fiber degradation. PMID- 28560746 TI - Network component analysis reveals developmental trajectories of structural connectivity and specific alterations in autism spectrum disorder. AB - The structural organization of the brain can be characterized as a hierarchical ensemble of segregated modules linked by densely interconnected hub regions that facilitate distributed functional interactions. Disturbances to this network may be an important marker of abnormal development. Recently, several neurodevelopmental disorders, including autism spectrum disorder (ASD), have been framed as disorders of connectivity but the full nature and timing of these disturbances remain unclear. In this study, we use non-negative matrix factorization, a data-driven, multivariate approach, to model the structural network architecture of the brain as a set of superposed subnetworks, or network components. In an openly available dataset of 196 subjects scanned between 5 and 85 years we identify a set of robust and reliable subnetworks that develop in tandem with age and reflect both anatomically local and long-range, network hub connections. In a second experiment, we compare network components in a cohort of 51 high-functioning ASD adolescents to a group of age-matched controls. We identify a specific subnetwork representing an increase in local connection strength in the cingulate cortex in ASD (t = 3.44, P < 0.001). This work highlights possible long-term implications of alterations to the developmental trajectories of specific cortical subnetworks. Hum Brain Mapp 38:4169-4184, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28560747 TI - Can assessment of afferent thermal sensitivity shed light onto multiple sclerosis diagnosis and disease progression? AB - Podcast available at: http://www.yada yada.co.uk/wiley/ExperimentalPhysiology/audio/Ep1_july17.mp3. PMID- 28560748 TI - p16 protein expression and correlation with clinical and pathological features in osteosarcoma of the jaws: Experience of 37 cases. AB - BACKGROUND: In literature, no markers have been reported as predictive and prognostic factors in osteosarcoma of the jaw. METHODS: A retrospective analysis of p16 expression was performed in 37 patients with high-grade osteosarcoma of the jaw to investigate its potential prognostic and predictive value. RESULTS: p16 positivity was found in 56.7% of cases. The absence of p16 expression was associated with an adverse disease-free survival (P = .003). At the multivariate Cox regression, positive margins were the only independent factor. In the subgroup of 17 patients who underwent neoadjuvant chemotherapy, a significant association was noted between p16 expression and pathological response to chemotherapy (P = .015) and the negativity of p16 increased the risk of negative outcome (P = .01). CONCLUSION: Our data indicate that the wide surgical margin is the most important prognostic factor. The expression of p16 confers greater sensitivity to chemotherapy and its loss of expression is associated with a worse prognosis. PMID- 28560750 TI - Blood pressure and all-cause mortality by level of cognitive function in the elderly: Results from a population-based study in rural Greece: Methodological issues. PMID- 28560751 TI - Differential control of respiratory frequency and tidal volume during high intensity interval training. AB - NEW FINDINGS: What is the central question of this study? By manipulating recovery intensity and exercise duration during high-intensity interval training (HIIT), we tested the hypothesis that fast inputs contribute more than metabolic stimuli to respiratory frequency (fR ) regulation. What is the main finding and its importance? Respiratory frequency, but not tidal volume, responded rapidly and in proportion to changes in workload during HIIT, and was dissociated from some markers of metabolic stimuli in response to both experimental manipulations, suggesting that fast inputs contribute more than metabolic stimuli to fR regulation. Differentiating between fR and tidal volume may help to unravel the mechanisms underlying exercise hyperpnoea. Given that respiratory frequency (fR ) has been proposed as a good marker of physical effort, furthering the understanding of how fR is regulated during exercise is of great importance. We manipulated recovery intensity and exercise duration during high-intensity interval training (HIIT) to test the hypothesis that fast inputs (including central command) contribute more than metabolic stimuli to fR regulation. Seven male cyclists performed an incremental test, a 10 and a 20 min continuous time trial (TT) as preliminary tests. Subsequently, recovery intensity and exercise duration were manipulated during HIIT (30 s work and 30 s active recovery) by performing four 10 min and one 20 min trial (recovery intensities of 85, 70, 55 and 30% of the 10 min TT mean workload; and 85% of the 20 min TT mean workload). The work intensity of the HIIT sessions was self-paced by participants to achieve the best performance possible. When manipulating recovery intensity, fR , but not tidal volume (VT ), showed a fast response to the alternation of the work and recovery phases, proportional to the extent of workload variations. No association between fR and gas exchange responses was observed. When manipulating exercise duration, fR and rating of perceived exertion were dissociated from VT , carbon dioxide output and oxygen uptake responses. Overall, the rating of perceived exertion was strongly correlated with fR (r = 0.87; P < 0.001) but not with VT . These findings may reveal a differential control of fR and VT during HIIT, with fast inputs appearing to contribute more than metabolic stimuli to fR regulation. Differentiating between fR and VT may help to unravel the mechanisms underlying exercise hyperpnoea. PMID- 28560749 TI - Comparison of annual percentage change in breast cancer incidence rate between Taiwan and the United States-A smoothed Lexis diagram approach. AB - Recent studies compared the age effects and birth cohort effects on female invasive breast cancer (FIBC) incidence in Asian populations with those in the US white population. They were based on age-period-cohort model extrapolation and estimated annual percentage change (EAPC) in the age-standardized incidence rates (ASR). It is of interest to examine these results based on cohort-specific annual percentage change in rate (APCR) by age and without age-period-cohort model extrapolation. FIBC data (1991-2010) were obtained from the Taiwan Cancer Registry and the U.S. SEER 9 registries. APCR based on smoothed Lexis diagrams were constructed to study the age, period, and cohort effects on FIBC incidence. The patterns of age-specific rates by birth cohort are similar between Taiwan and the US. Given any age-at-diagnosis group, cohort-specific rates increased overtime in Taiwan but not in the US; cohort-specific APCR by age decreased with birth year in both Taiwan and the US but was always positive and large in Taiwan. Given a diagnosis year, APCR decreased as birth year increased in Taiwan but not in the US. In Taiwan, the proportion of APCR attributable to cohort effect was substantial and that due to case ascertainment was becoming smaller. Although our study shows that incidence rates of FIBC have increased rapidly in Taiwan, thereby confirming previous results, the rate of increase over time is slowing. Continued monitoring of APCR and further investigation of the cause of the APCR decrease in Taiwan are warranted. PMID- 28560752 TI - Selective embolization therapy for intrarenal artery stenosis causing renovascular hypertension: Efficacy and follow-up renal imaging. AB - We report the case of a young woman treated with selective renal embolization for renovascular hypertension caused by intrarenal artery stenosis and show follow-up imaging of the treated kidney. An 18-year-old woman had renin-dependent hypertension with intrarenal artery stenosis caused by fibromuscular dysplasia. A middle branch artery was nearly occluded, resulting in segmental renal ischemia with excessive renin secretion. Because our angioplasty attempt for revascularization failed as a result of technical difficulty, we performed selective embolization of the diseased vessel by anhydrous ethanol. The embolization promptly ameliorated hyperreninemia and resistant hypertension without deterioration of renal function. Findings from magnetic resonance imaging showed disappearance of the blood flow in the embolized area corresponding to the ischemic lesion that had been revealed by diffusion-weighted imaging. Thus, selective embolization can be effective in treating renovascular hypertension by intrarenal stenosis for which angioplasty is not feasible. Additionally, renal magnetic resonance imaging is useful for evaluating the causative ischemic lesion and embolized area. PMID- 28560753 TI - Big thrombus "sitting" in an atrial septal aneurysm. AB - A 79 year-old-man presented three episodes of upper gastrointestinal bleeding and weight loss. Endoscopy revealed bleeding and extrinsic compression at the pyloric region. Computed tomography scan showed a pancreatic tumor, peritoneal carcinomatosis, vascular infiltration, and incidentally found a partially calcified hypodense lesion of 35 mm in the left atrium, suggesting a myxoma or a thrombus. Echocardiography revealed moderate left atrium enlargement, dilated left atrial appendage with spontaneous echo contrast, moderate dilatation and dysfunction of the left ventricle, ejection fraction was 39%, and an atrial septal aneurysm in which a piriform, mass of 35*33*25 mm, was "sitting," suggesting an organized thrombus. PMID- 28560755 TI - Cephalopod embryonic shells as a tool to reconstruct reproductive strategies in extinct taxa. AB - An exhaustive study of existing data on the relationship between egg size and maximum size of embryonic shells in 42 species of extant cephalopods demonstrated that these values are approximately equal regardless of taxonomy and shell morphology. Egg size is also approximately equal to mantle length of hatchlings in 45 cephalopod species with rudimentary shells. Paired data on the size of the initial chamber versus embryonic shell in 235 species of Ammonoidea, 46 Bactritida, 13 Nautilida, 22 Orthocerida, 8 Tarphycerida, 4 Oncocerida, 1 Belemnoidea, 4 Sepiida and 1 Spirulida demonstrated that, although there is a positive relationship between these parameters in some taxa, initial chamber size cannot be used to predict egg size in extinct cephalopods; the size of the embryonic shell may be more appropriate for this task. The evolution of reproductive strategies in cephalopods in the geological past was marked by an increasing significance of small-egged taxa, as is also seen in simultaneously evolving fish taxa. PMID- 28560756 TI - Evaluation of the Efficiency of the Nursing Care Plan Applied Using NANDA, NOC, and NIC Linkages to Elderly Women with Incontinence Living in a Nursing Home: A Randomized Controlled Study. AB - PURPOSE: Evaluate the efficiency of the nursing care plan, applied with the use of NANDA-I, NOC, and NIC (NNN) linkages, for elderly women with incontinence who live in nursing homes. METHODS: A randomized controlled experimental design was applied. NNN linkages were prepared and applied for 12 weeks in an experimental group. NOC scales were evaluated again for two groups. RESULTS: A 0.5 NOC point change targeted in all elderly in the experimental group were provided between pretest-posttest scores. The experimental group had higher life quality and lower incontinence severity/symptoms than the control group. CONCLUSION: It is important that NNN linkages effective for solving the problems are used in different groups and with larger samples to create further evidence linking NNN. PMID- 28560754 TI - Oncostatin M induces RIG-I and MDA5 expression and enhances the double-stranded RNA response in fibroblasts. AB - Interleukin (IL)-6-type cytokines have no direct antiviral activity; nevertheless, they display immune-modulatory functions. Oncostatin M (OSM), a member of the IL-6 family, has recently been shown to induce a distinct number of classical interferon stimulated genes (ISG). Most of them are involved in antigen processing and presentation. However, induction of retinoic acid-inducible gene (RIG)-I-like receptors (RLR) has not been investigated. Here we report that OSM has the capability to induce the expression of the DExD/H-Box RNA helicases RIG-I and melanoma differentiation antigen 5 (MDA5) as well as of the transcription factors interferon regulatory factor (IRF)1, IRF7 and IRF9 in primary fibroblasts. Induction of the helicases depends on tyrosine as well as serine phosphorylation of STAT1. Moreover, we could show that the OSM-induced STAT1 phosphorylation is predominantly counter-regulated by a strong STAT3-dependent SOCS3 induction, as Stat3 as well as Socs3 knock-down results in an enhanced and prolonged helicase and IRF expression. Other factors involved in regulation of STAT1 or IRF1 activity, like protein tyrosine phosphatase, non-receptor type 2 (PTPN2), promyelocytic leukaemia protein (PML) or small ubiquitin-related modifier 1 (SUMO1), play a minor role in OSM-mediated induction of RLR. Remarkably, OSM and interferon-gamma (IFN-gamma) synergize to mediate transcription of RLR and pre-treatment of fibroblasts with OSM fosters the type I interferon production in response to a subsequent encounter with double-stranded RNA. Together, these findings suggest that the OSM-induced JAK/STAT1 signalling is implicated in virus protection of non-professional immune cells and may cooperate with interferons to enhance RLR expression in these cells. PMID- 28560757 TI - Lipoprotein ratios are better than conventional lipid parameters in predicting arterial stiffness in young men. AB - Although dyslipidemia is associated with cardiovascular disease, there are conflicting data about the role of serum lipids and their ratios in promoting arterial stiffness. The authors aimed to compare serum lipid profiles to predict arterial stiffness, which was assessed by brachial-ankle pulse wave velocity in young Chinese men. A total of 1015 participants aged 18 to 44 years without serious comorbidities were recruited for conventional detection. Anthropometrics, brachial-ankle pulse wave velocity, serum lipids, and other laboratory data were measured. Univariate analysis and multivariate logistic regression were performed to examine the relationship between serum lipid profiles and brachial-ankle pulse wave velocity. Participants with high brachial-ankle pulse wave velocity exhibited higher levels of total cholesterol, triglyceride (TG), low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol (HDL-C), total cholesterol/HDL-C, TG/HDL-C, low-density lipoprotein cholesterol/HDL-C, and non HDL-C/HDL-C. The subsequent multivariable logistic regression showed that TG/HDL C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and TG significantly increased the risk for arterial stiffness after adjustment for confounding factors. Results indicate that lipid ratios are superior to conventional lipid parameters for predicting arterial stiffness in young men and that the TG/HDL-C ratio has the strongest association with arterial stiffness. PMID- 28560758 TI - Stress and brain functional changes in patients with Crohn's disease: A functional magnetic resonance imaging study. AB - BACKGROUND: In Crohn's disease (CD) patients, stress is believed to influence symptoms generation. Stress may act via central nervous system pathways to affect visceral sensitivity and motility thus exacerbating gastrointestinal symptoms. The neural substrate underpinning these mechanisms needs to be investigated in CD. We conducted an explorative functional magnetic resonance imaging (fMRI) study in order to investigate potential differences in the brain stress response in CD patients compared to controls. METHODS: 17 CD patients and 17 healthy controls underwent a fMRI scan while performing a stressful task consisting in a Stroop color-word interference task designed to induce mental stress in the fMRI environment. KEY RESULTS: Compared to controls, in CD patients the stress task elicited greater blood oxygen level dependent (BOLD) signals in the midcingulate cortex (MCC). CONCLUSIONS & INFERENCES: The MCC integrate "high" emotional processes with afferent sensory information ascending from the gut. In light of these integrative functions, the stress-evoked MCC hyperactivity in CD patients might represent a plausible neural substrate for the association between stress and symptomatic disease. The MCC dysfunction might be involved in mechanisms of central disinhibition of nociceptive inputs leading to amplify the visceral sensitivity. Finally, the stress-evoked MCC hyperactivity might affect the regulation of intestinal motility resulting in exacerbation of disease symptoms and the autonomic and neuroendocrine regulation of inflammation resulting in enhanced inflammatory activity. PMID- 28560759 TI - Analysis of common barriers to rural patients utilizing hospice and palliative care services: An integrated literature review. AB - BACKGROUND AND PURPOSE: The aim of this literature review is to explore barriers and potential solutions related to hospice (HC) and palliative care (PC) services among rural residents. Although the healthcare system is continually advancing, healthcare providers may not be optimizing HC and PC referrals for the growing rural population who underutilize these services. Suggested methods to close the utilization gap between HC and PC services among rural patients appear feasible, but universal effectiveness cannot be determined. METHODS: An integrative literature review was conducted to evaluate diverse sources of literature. An electronic literature search was carried out using databases MEDLINE, CINAHL, Cochrane, PsycINFO, and Pubmed. The search was limited to English only, full text, peer reviewed, and published between 2010 and 2016. Search terms included rural, hospice, palliative, care access, and barriers. CONCLUSION: There are several barriers that interrelate to decreased utilization of PC and HC for rural populations and there are many options for overcoming them to equalize care. IMPLICATIONS FOR PRACTICE: Although advances to the general healthcare system are expediently rising, the rural patient population seems to fall short of these important life-changing services, especially in the realm of PC/HC. Beginning in primary care, this patient population can be affected and included in a positive manner. PMID- 28560760 TI - Oral antiplatelet therapy: impact for transfusion medicine. AB - Patients on antiplatelet therapy, be it aspirin only, or aspirin in combination with oral adenosine diphosphate (ADP) receptor inhibitors like clopidogrel, prasugrel and ticagrelor, or the protease-activated receptor-1 inhibitor vorapaxar, may develop bleeding or need transient reversal of platelet blockade for acute interventions. In this review, we summarize reports on patients with antiplatelet therapy receiving platelet concentrates due to bleeding, and in vitro experiments estimating the feasibility to restore platelet function by spiking blood from healthy individuals or patients on antiplatelet treatment with noninhibited platelets. So far, all clinical data were gained from patients on aspirin with or without ADP P2Y12 receptor inhibitors. Platelet inhibition due to clopidogrel, and to some extent also prasugrel may be overcome by platelet transfusion, but clinical data on massive platelet transfusion in these patients are lacking. Platelet transfusion may even be associated with worse outcomes. Ticagrelor-mediated platelet inhibition remains a challenge, as case reports show that platelet transfusion did not restore haemostasis. Prescription of the latter therefore demands a particular stringent indication. PMID- 28560761 TI - Physicians' reasons not to discontinue long-term used off-label antipsychotic drugs in people with intellectual disability. AB - BACKGROUND: People with intellectual disability (ID) frequently use antipsychotic drugs on an off-label base, often for many years. Physicians' decisions to discontinue these drugs not only depend on patient characteristics, like the presence of mental or behavioural disorders, but also on environmental factors, such as inappropriate living circumstances, and on attitudes, knowledge and beliefs of staff, clients and their representatives towards the effects of antipsychotic drug use. In this study, we therefore investigated the influence of participant and setting-related factors on decisions of physicians not to discontinue off-label prescribed antipsychotics. METHODS: The study took place in living facilities of six service providers for people with ID spread over the Netherlands and staffed with support professionals, nurses, behavioural scientist and physicians and was part of an antipsychotics discontinuation trial. ID physicians had to decide whether the off-label use of antipsychotics could be discontinued. Medical and pharmaceutical records were used to establish the prevalence of antipsychotic drug use in the study population, along with duration of use and whether the use was off-label. Reasons of physicians not to discontinue the prescription of antipsychotics in those participants who used off label antipsychotics for more than a year were collected and categorised as related to participant or setting characteristics, including lack of consent to discontinue, and staff members, participants or their legal representatives. RESULTS: Of the 3299 clients of the service providers, 977 used one or more antipsychotic drugs. The prevalence of antipsychotic drug use was 30%. Reasons for use were in 5% of cases, a chronic psychotic disorder classified according to Diagnostic System Mental Disorders, Fourth Edition, criteria, in 25%, present or past (suspected) non-schizophrenia-related psychotic symptoms and in 69%, challenging behaviours. Overall, physicians were willing to discontinue their prescriptions in 51% of cases, varying from 22% to 87% per service provider. The odds for decisions of physicians to discontinue off-label prescriptions varied from 0.19 to 13.95 per service provider. The variables 'a living situation with care and support' and 'challenging behaviour' were associated with a higher chance of discontinuation. The main reasons for decisions not to discontinue were concerns for symptoms of restlessness, the presence of an autism spectrum disorder, previously unsuccessful attempts to discontinue and objections against discontinuation of legal representatives. Reasons for physicians' decisions not to discontinue the off-label use of antipsychotics varied largely between the service providers. CONCLUSIONS: The prevalence of antipsychotic drug use for off label indications in people with ID remains high. The results of this study indicate that there is a large variation in clinical practice of physicians regarding discontinuation of long-term antipsychotic drug prescriptions, which may be partially related to environmental factors as setting culture and attitudes of staff towards off-label antipsychotic drug use in persons with ID. PMID- 28560762 TI - Low-dose Desmopressin and Tolterodine Combination Therapy for Treating Nocturia in Women with Overactive Bladder: A Double-blind, Randomized, Controlled Study. AB - OBJECTIVE: Evaluation of safety and efficacy of desmopressin/tolterodine combination therapy in women. METHODS: This double-blind, randomized, proof-of concept study enrolled 106 patients (>=18 years), with overactive bladder (OAB) and nocturia, with >=2 nocturnal voids, receiving a 3-month once-daily combination (desmopressin 25 ug, orally-disintegrating tablets [ODT]/tolterodine 4 mg [Detrol(r) LA]; n = 49) or monotherapy (tolterodine 4 mg/placebo ODT; n = 57). Primary endpoint was change from baseline in mean number of nocturnal voids. Secondary endpoints were change from baseline in nocturnal voided volume, time to first nocturnal void, and quality-of-life. Post-hoc exploratory analysis were performed for patients with and without baseline nocturnal polyuria (NP, n = 47 each). RESULTS: Overall population showed a non-significant reduction in mean number of nocturnal voids with combination versus monotherapy (full analysis set: adjusted treatment contrast [TC], -0.34; P = 0.112). Change in mean nocturnal void volume (TC, -64.16 mL; P = 0.103), mean time to first nocturnal void (TC, 18.00 min; P = 0.385) and Nocturia Impact (NI) Diary(c) scores were comparable. In post-hoc analysis, NP patients showed a benefit with combination versus monotherapy for nocturnal void volume (P = 0.034) and time to first nocturnal void (P = 0.045), and a non-significant improvement in NI Diary(c) scores. Safety profile was comparable between treatments. A single transient event of asymptomatic clinically significant hyponatremia in combination group resolved subsequently. CONCLUSION: Low-dose desmopressin could be safely combined with tolterodine for treating nocturia in women with OAB, with a significant benefit in women with NP. Further, prospective validation studies of combination therapy are warranted in mixed NP/OAB population, based on this favorable proof-of concept finding. PMID- 28560763 TI - Implementation and evaluation of a peer review process for advanced practice nurses in a university hospital setting. AB - BACKGROUND AND PURPOSE: Over the past decade, implementation of the peer review process for the development of the advanced practice nurse (APN) has been emphasized. However, little exists in the literature regarding APN peer review. The peer review process is intended to help demonstrate competency of care, enhance quality improvement measures, and foster the professional growth of the APN. METHODS: APNs serving on a professional governance council within a university teaching hospital developed a model of peer review for APNs. Nine months after the tool was implemented, an anonymous follow-up survey was conducted. A follow-up request was sent 4 weeks later to increase the number of respondents. Likert scales were used to elicit subjective data regarding the process. CONCLUSIONS: Of 81 APNs who participated in the survey, more than half (52%) felt that the process would directly improve their professional practice. IMPLICATIONS FOR PRACTICE: Survey results show that the peer review process affected APN professional practice positively. Additional research might include pathways for remediation and education of staff, evaluation of alternate methods to improve application to clinical practice, and collection of outcome data. The models presented provide a foundation for future refinement to accommodate different APN practice settings. PMID- 28560764 TI - Incidence of sleep disturbances in patients with familial Mediterranean fever and the relation of sleep quality with disease activity. AB - AIM: To evaluate the sleep quality and the relation of sleep quality with depression, anxiety, fatigue and disease activity in adult patients with familial Mediterranean fever (FMF). METHOD: One hundred and seventy-four FMF patients and 84 age-sex matched healthy individuals were included in this study. The Pittsburgh Sleep Quality Index (PSQI), Multidimensional Assessment of Fatigue (MAF) and the Hospital Anxiety and Depression Index (HADS) were used to assess sleep quality, fatigue, depression and anxiety, respectively. RESULT: FMF patients had significantly higher depression, anxiety, fatigue and PSQI scores than healthy controls. As the severity of the disease increased, scores of total PSQI and its domains increased. Patients with total PSQI score higher than 5 had statistically significantly higher erythrocyte sedimentation rates (ESR), serum C reactive protein and serum amyloid levels during attacks, more attack numbers in last 3 months and worse fatigue, depression scores. Total PSQI score was positively correlated with inflammatory markers during attacks, attack numbers in the last 3 months and fatigue score. Logistic regression models identified disease duration, ESR during attacks, fatigue, attack numbers in the last 3 months as predictors of poor sleep quality. CONCLUSION: Poor sleep quality is common in adult FMF patients. Anxiety, depression and fatigue are more frequent in FMF patients than healthy individuals. Poor sleep quality is associated with inflammatory marker levels during attacks, fatigue and attack numbers in the last 3 months. PMID- 28560765 TI - An Amazonian rainforest and its fragments as a laboratory of global change. AB - We synthesize findings from one of the world's largest and longest-running experimental investigations, the Biological Dynamics of Forest Fragments Project (BDFFP). Spanning an area of ~1000 km2 in central Amazonia, the BDFFP was initially designed to evaluate the effects of fragment area on rainforest biodiversity and ecological processes. However, over its 38-year history to date the project has far transcended its original mission, and now focuses more broadly on landscape dynamics, forest regeneration, regional- and global-change phenomena, and their potential interactions and implications for Amazonian forest conservation. The project has yielded a wealth of insights into the ecological and environmental changes in fragmented forests. For instance, many rainforest species are naturally rare and hence are either missing entirely from many fragments or so sparsely represented as to have little chance of long-term survival. Additionally, edge effects are a prominent driver of fragment dynamics, strongly affecting forest microclimate, tree mortality, carbon storage and a diversity of fauna. Even within our controlled study area, the landscape has been highly dynamic: for example, the matrix of vegetation surrounding fragments has changed markedly over time, succeeding from large cattle pastures or forest clearcuts to secondary regrowth forest. This, in turn, has influenced the dynamics of plant and animal communities and their trajectories of change over time. In general, fauna and flora have responded differently to fragmentation: the most locally extinction-prone animal species are those that have both large area requirements and low tolerance of the modified habitats surrounding fragments, whereas the most vulnerable plants are those that respond poorly to edge effects or chronic forest disturbances, and that rely on vulnerable animals for seed dispersal or pollination. Relative to intact forests, most fragments are hyperdynamic, with unstable or fluctuating populations of species in response to a variety of external vicissitudes. Rare weather events such as droughts, windstorms and floods have had strong impacts on fragments and left lasting legacies of change. Both forest fragments and the intact forests in our study area appear to be influenced by larger-scale environmental drivers operating at regional or global scales. These drivers are apparently increasing forest productivity and have led to concerted, widespread increases in forest dynamics and plant growth, shifts in tree-community composition, and increases in liana (woody vine) abundance. Such large-scale drivers are likely to interact synergistically with habitat fragmentation, exacerbating its effects for some species and ecological phenomena. Hence, the impacts of fragmentation on Amazonian biodiversity and ecosystem processes appear to be a consequence not only of local site features but also of broader changes occurring at landscape, regional and even global scales. PMID- 28560766 TI - Systolic longitudinal strain correlates with visual assessment of regional left ventricular function during dobutamine stress echocardiography and discriminates the segments with induced contractility impairment. AB - BACKGROUND: The relationship between visual and strain assessment of left ventricular (LV) function during dobutamine stress echocardiography (DSE) remains poorly investigated. We assessed systolic longitudinal strain (SLS) and strain rate (SLSR) in segments visually graded as normokinetic, hypokinetic, or akinetic at baseline (0) and peak stage (1) of DSE and compared deformation changes between segments with and without induced contractility worsening. METHODS: From 250 patients examined by DSE, 238 patients with diagnostic test were included, mean age of 62+/-9 years (105 females). Regional LV contractility was assessed visually and measured using SLS and SLSR in 4284 segments. RESULTS: The LV segments during baseline and peak stage of DSE revealed gradual decrease in absolute values of SLS (from 17.7+/-6.4% in normokinetic to 11.7+/-8.4% in akinetic segments at rest, and from 17.2+/-8.5% to 14.4+/-7.8% at peak, P<.001), as measured by automated function imaging (AFI) and SLSR (from 1.1+/-0.37 s-1 in normokinetic to 0.9+/-0.29 s-1 in akinetic at rest, and from 2.32+/-0.92 to 2.13+/-0.85 s-1 at peak). The decrease in SLS in segments with contractility worsening was higher than in segments without induced impairment (DeltaSLS 2% vs 0%, P<.0001 for all LV segments and 2% vs 1%, P=.02 in mid-LV segments). Absolute value of regional SLS <23% at peak DSE and decrease in SLS >2% from baseline showed 90% and 76% sensitivity for the detection of contractility impairment. CONCLUSION: Strain analysis quantifies segmental LV contractility not only at rest and peak DSE but may be helpful in detection of stress-induced contractility worsening. PMID- 28560767 TI - Reviewing the quality of discourse information measures in aphasia. AB - BACKGROUND: Discourse is fundamental to everyday communication, and is an increasing focus of clinical assessment, intervention and research. Aphasia can affect the information a speaker communicates in discourse. Little is known about the psychometrics of the tools for measuring information in discourse, which means it is unclear whether these measures are of sufficient quality to be used as clinical outcome measures or diagnostic tools. AIMS: To profile the measures used to describe information in aphasic discourse, and to assess the quality of these measures against standard psychometric criteria. METHODS & PROCEDURES: A scoping review method was employed. Studies were identified using a systematic search of Scopus, Medline and Embase databases. Standard psychometric criteria were used to evaluate the measures' psychometric properties. MAIN CONTRIBUTION: The current review summarizes and collates the information measures used to describe aphasic discourse, and evaluates their quality in terms of the psychometric properties of acceptability, reliability and validity. Seventy-six studies described 58 discourse information measures, with a mean of 2.28 measures used per study (SD = 1.29, range = 1-7). Measures were classified as 'functional' measures (n = 33), which focused on discourse macrostructure, and 'functional and structural' measures (n = 25), which focused on micro-linguistic and macro structural approaches to discourse. There were no reports of the acceptability of data generated by the measures (distribution of scores, missing data). Test retest reliability was reported for just 8/58 measures with 3/8 > 0.80. Intra rater reliability was reported for 9/58 measures and in all cases percentage agreement was reported rather than reliability. Per cent agreement was also frequently reported for inter-rater reliability, with only 4/76 studies reporting reliability statistics for 12/58 measures; this was generally high (>.80 for 11/12 measures). The majority of measures related clearly to the discourse production model indicating content validity. A total of 36/58 measures were used to make 41 comparisons between participants with aphasia (PWA) and neurologically healthy participants (NHP), with 31/41 comparisons showing a difference between the groups. Four comparisons were made between discourse genres, with two measures showing a difference between genres, and two measures showing no difference. CONCLUSIONS: There is currently insufficient information available to justify the use of discourse information measures as sole diagnostic or outcome measurement tools. Yet the majority of measures are rooted in relevant theory, and there is emerging evidence regarding their psychometric properties. There is significant scope for further psychometric strengthening of discourse information measurement tools. PMID- 28560768 TI - Modeling event count data in the presence of informative dropout with application to bleeding and transfusion events in myelodysplastic syndrome. AB - In many biomedical studies, it is often of interest to model event count data over the study period. For some patients, we may not follow up them for the entire study period owing to informative dropout. The dropout time can potentially provide valuable insight on the rate of the events. We propose a joint semiparametric model for event count data and informative dropout time that allows for correlation through a Gamma frailty. We develop efficient likelihood based estimation and inference procedures. The proposed nonparametric maximum likelihood estimators are shown to be consistent and asymptotically normal. Furthermore, the asymptotic covariances of the finite-dimensional parameter estimates attain the semiparametric efficiency bound. Extensive simulation studies demonstrate that the proposed methods perform well in practice. We illustrate the proposed methods through an application to a clinical trial for bleeding and transfusion events in myelodysplastic syndrome. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28560771 TI - The Lancet Commission on hypertension: Addressing the global burden of raised blood pressure on current and future generations. PMID- 28560769 TI - Patient Experience of Chronic Illness Care and Medical Home Transformation in Safety Net Clinics. AB - OBJECTIVE: To examine the relationship between medical home transformation and patient experience of chronic illness care. STUDY SETTING: Thirteen safety net clinics located in five states enrolled in the Safety Net Medical Home Initiative. STUDY DESIGN: Repeated cross-sectional surveys of randomly selected adult patients were completed at baseline (n = 303) and postintervention (n = 271). DATA COLLECTION METHODS: Questions from the Patient Assessment of Chronic Illness Care (PACIC) (100-point scale) were used to capture patient experience of chronic illness care. Generalized estimating equation methods were used to (i) estimate how differential improvement in patient-centered medical home (PCMH) capability affected differences in modified PACIC scores between baseline and postintervention, and (ii) to examine cross-sectional associations between PCMH capability and modified PACIC scores for patients at completion of the intervention. PRINCIPAL FINDINGS: In adjusted analyses, high PCMH improvement (above median) was only marginally associated with a larger increase in total modified PACIC score (adjusted beta = 7.7, 95 percent confidence interval [CI]: 1.1 to 16.5). At completion of the intervention, a 10-point higher PCMH capability score was associated with an 8.9-point higher total modified PACIC score (95 percent CI: 3.1-14.7) and higher scores in four of five subdomains (patient activation, delivery system design, contextual care, and follow up/coordination). CONCLUSIONS: We report that sustained, 5-year medical home transformation may be associated with modest improvement in patient experience of chronic illness care for vulnerable populations in safety net clinics. PMID- 28560770 TI - A Radiographic Measurement of the Anterior Epidural Space at L4-5 Disc Level. AB - To observe the morphology character of the anterior epidural space at the L4-5 disc level and to provide an anatomical basis for safely and accurately performing a percutaneous endoscopic lumbar discectomy (PELD). Fifty-five cases with L5 S1 lumbar disc herniation were included in this study, and cases with L4 5 disease were excluded. When the puncture needle reached the epidural space at the L5 S1 level, iohexol was injected at the pressure of 50 cm H2 O during the PELD, then C-Arm fluoroscopy was used to obtain standard lumbar frontal and lateral images. The widths of epidural space at the level of the L4 lower endplate, the L5 upper endplate, as well as the middle point of the L4-5 disc were measured from the lumbar lateral X-ray film. Epidural space at the L4-5 disc plane performs like a trapezium chart with a short side at the head end and a long side at the tail end in the lumbar lateral X-ray radiograph, while the average widths of epidural space were 10.2 +/- 2.5, 12.3 +/- 2.3, and 13.8 +/- 2.6 mm at the upper, middle, and lower level of the L4-5 disc. Understanding the morphological characteristics of epidural space will contribute to improving the safety of the tranforaminal percutaneous endoscopy technique. PMID- 28560772 TI - Promoting reproducibility in addiction research. PMID- 28560774 TI - Role of P-glycoprotein inhibitors in children with drug-resistant epilepsy. AB - OBJECTIVE: The role of P-glycoprotein (Pgp), one of the known multidrug transporters, has been suggested in drug-resistant epilepsy (DRE). The following study aimed to measure the serum level of Pgp as a possible indicator of tissue Pgp overexpression in patients with DRE and to assess the efficacy of verapamil (as a Pgp inhibitor agent) in these patients. MATERIAL AND METHODS: A group of 24 patients with DRE were recruited and subdivided into two groups, one receiving verapamil and the other receiving a placebo in a double-blind randomized study. Pgp serum levels were measured at enrollment and 12 months later. Twenty medically controlled epileptic patients served as a control group. RESULTS: A significant statistical increase was found in the Pgp level of patients when compared the control group. Patients on both verapamil and the placebo showed improvement in seizure frequency and severity where statistical analysis showed no significant differences. CONCLUSION: Pgp serum levels in patients with DRE were significantly elevated compared to patients with medically controlled epilepsy. The effect of verapamil as Pgp inhibitor on DRE requires further evaluation and research. PMID- 28560773 TI - Untargeted analysis to monitor metabolic changes of garlic along heat treatment by LC-QTOF MS/MS. AB - Black garlic is increasing its popularity in cuisine around the world; however, scant information exists on the composition of this processed product. In this study, polar compounds in fresh garlic and in samples taken at different times during the heat treatment process to obtain black garlic have been characterized by liquid chromatography coupled to tandem mass spectrometry in high resolution mode. Ninety-five compounds (mainly amino acids and metabolites, organosulfur compounds, and saccharides and derivatives) were tentatively identified in all the analysed samples and classified as a function of the family they belong to. Statistical analysis of the results allowed establishing that the major changes in garlic occur during the first days of treatment, and they mainly affect to the three representative families. The main pathways involved in the synthesis of the compounds affected by heat treatment, and their evolution during the process were studied. PMID- 28560775 TI - Joint Congress of The 6th Biennial Congress of the Asian-Pacific Hepato-Pancreato Biliary Association & The 29th Meeting of Japanese Society of Hepato-Biliary Pancreatic Surgery. PMID- 28560776 TI - Spontaneous language production of Italian children with cochlear implants and their mothers in two interactive contexts. AB - BACKGROUND: In recent years many studies have shown that the use of cochlear implants (CIs) improves children's skills in processing the auditory signal and, consequently, the development of both language comprehension and production. Nevertheless, many authors have also reported that the development of language skills in children with CIs is variable and influenced by individual factors (e.g., age at CI activation) and contextual aspects (e.g., maternal linguistic input). AIMS: To assess the characteristics of the spontaneous language production of Italian children with CIs, their mothers' input and the relationship between the two during shared book reading and semi-structured play. METHODS & PROCEDURES: Twenty preschool children with CIs and 40 typically developing children, 20 matched for chronological age (CATD group) and 20 matched for hearing age (HATD group), were observed during shared book reading and semi structured play with their mothers. Samples of spontaneous language were transcribed and analysed for each participant. The numbers of types, tokens, mean length of utterance (MLU) and grammatical categories were considered, and the familiarity of each mother's word was calculated. OUTCOMES & RESULTS: The children with CIs produced shorter utterances than the children in the CATD group. Their mothers produced language with lower levels of lexical variability and grammatical complexity, and higher proportions of verbs with higher familiarity than did the mothers in the other groups during shared book reading. The children's language was more strongly related to that of their mothers in the CI group than in the other groups, and it was associated with the age at CI activation. CONCLUSIONS & IMPLICATIONS: The findings suggest that the language of children with CIs is related both to their mothers' input and to age at CI activation. They might prompt suggestions for intervention programs focused on shared-book reading. PMID- 28560778 TI - Daily oral administration of low-dose methotrexate has greater antirheumatic effects in collagen-induced arthritis rats. AB - OBJECTIVES: Methotrexate (MTX) is administered once or thrice weekly to patients with rheumatoid arthritis (RA). Even though RA continually progresses, MTX is not administered daily. Therefore, we investigated whether the daily administration of a low dose of MTX inhibits the progression of arthritis in collagen-induced arthritis (CIA) rats. METHODS: Methotrexate was orally administered once weekly, thrice weekly and once daily to CIA rats, and arthritis scores were measured. KEY FINDINGS: When the same dose of MTX was administered, the exacerbation of arthritis was inhibited significantly more in the once-daily group than in the other groups. When the dose in the once-daily group was reduced to one-fourth that of the current standard dosing method, arthritis scores were markedly lower in the once-daily group than in the once and thrice-weekly groups. CONCLUSIONS: The daily administration of a low dose of MTX not only maintained normal levels that estimated adverse effects but also suppressed the progression of arthritis significantly more than the current standard dosing method. The results indicate that the reconsideration of dosing schedules based on the characteristics of MTX will lead to more effective RA therapy than that currently used in clinical practice. PMID- 28560777 TI - In child and adult migraineurs the somatosensory cortex stands out ... again: An arterial spin labeling investigation. AB - Over the past decade, human brain imaging investigations have reported altered regional cerebral blood flow (rCBF) in the interictal phase of migraine. However, there have been conflicting findings across different investigations, making the use of perfusion imaging in migraine pathophysiology more difficult to define. These inconsistencies may reflect technical constraints with traditional perfusion imaging methods such as single-photon emission computed tomography and positron emission tomography. Comparatively, pseudocontinuous arterial spin labeling (pCASL) is a recently developed magnetic resonance imaging technique that is noninvasive and offers superior spatial resolution and increased sensitivity. Using pCASL, we have previously shown increased rCBF within the primary somatosensory cortex (S1) in adult migraineurs, where blood flow was positively associated with migraine frequency. Whether these observations are present in pediatric and young adult populations remains unknown. This is an important question given the age-related variants of migraine prevalence, symptomology, and treatments. In this investigation, we used pCASL to quantitatively compare and contrast blood flow within S1 in pediatric and young adult migraineurs as compared with healthy controls. In migraine patients, we found significant resting rCBF increases within bilateral S1 as compared with healthy controls. Furthermore, within the right S1, we report a positive correlation between blood flow value with migraine attack frequency and cutaneous allodynia symptom profile. Our results reveal that pediatric and young adult migraineurs exhibit analogous rCBF changes with adult migraineurs, further supporting the possibility that these alterations within S1 are a consequence of repeated migraine attacks. Hum Brain Mapp 38:4078-4087, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28560779 TI - Efficacy and tolerability of initial high vs low doses of S-(-)-amlodipine in hypertension. AB - In an 8-week randomized trial of patients with mild or moderate hypertension, the authors investigated the efficacy and tolerability of initial high (5.0 mg/d) vs low (2.5 mg/d) doses of S-(-)-amlodipine (equivalent to 5 and 10 mg of racemic amlodipine, respectively). In the S-(-)-amlodipine 2.5-mg group (n=263), 24-hour ambulatory systolic/diastolic blood pressure (+/-standard deviation) decreased from 131.5+/-15.0/82.1+/-10.7 mm Hg at baseline to 126.0+/-13.5/78.5+/-9.5 mm Hg at 8 weeks of follow-up by a least square mean (+/-standard error) change of 6.0+/-0.6/3.8+/-0.4 mm Hg. In the S-(-)-amlodipine 5-mg group (n=260), the corresponding changes were from 133.6+/-13.7/83.1+/-9.9 mm Hg to 125.0+/ 12.0/78.2+/-8.9 mm Hg by 8.1+/-0.6/4.7+/-0.4 mm Hg, respectively. The between group differences in changes in 24-hour systolic/diastolic blood pressure were 2.1/0.9 (P=.02/.17) mm Hg. Similar trends were observed for daytime and nighttime ambulatory and clinic blood pressure. The incidence rate was similar for all adverse events. An initial high dose of S-(-)-amlodipine improved ambulatory blood pressure control with similar tolerability as an initial low dose in hypertension. PMID- 28560780 TI - Double-blind randomized phase III study comparing a mixture of natural agents versus placebo in the prevention of acute mucositis during chemoradiotherapy for head and neck cancer. AB - BACKGROUND: There is no widely accepted intervention in the prevention of acute mucositis during chemoradiotherapy for head and neck carcinoma. In the present double-blind study, we tested 4 natural agents, propolis, aloe vera, calendula, and chamomile versus placebo. METHODS: Patients undergoing concomitant chemo intensity-modulated radiotherapy (IMRT) were given natural agent or matched placebo; grade 3 mucositis on physical examination according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was the primary endpoint. Various covariates were tested at logistic regression, including the individual amount of mucosa receiving at least 9.5 Gy per week (V9.5w). RESULTS: One hundred seven patients were randomized from January 2011 to July 2014, and 104 were assessable (51%-49% were assigned to the placebo group and 53%-51% were assigned to the natural agent). Overall, 61 patients developed peak grade 3 mucositis with no difference between arms (P = .65). Conversely, V9.5w (P = .007) and primary site (P = .037) were independent predictors. CONCLUSION: The selected natural agents do not prevent mucositis, whereas the role of V9.5w is confirmed. PMID- 28560781 TI - Attending to the heart is associated with posterior alpha band increase and a reduction in sensitivity to concurrent visual stimuli. AB - Attentional mechanisms have been studied mostly in specific sensory domains, such as auditory, visuospatial, or tactile modalities. In contrast, attention to internal interoceptive visceral targets has only recently begun to be studied, despite its potential importance in emotion, empathy, and self-awareness. Here, we studied the effects of shifting attention to the heart using a cue-target detection paradigm during continuous EEG recordings. Subjects were instructed to count either a series of visual stimuli (visual condition) or their own heartbeats (heart condition). Visual checkerboard stimuli were used as attentional probes throughout the task. Consistent with previous findings, attention modulated the amplitude of the heartbeat-evoked potentials. Directing attention to the heart significantly reduced the visual P1/N1 amplitude evoked by the attentional probe. ERPs locked to the attention-directing cue revealed a novel frontal positivity around 300 ms postcue. Finally, spectral power in the alpha band over parieto-occipital regions was higher while attending to the heart when compared to the visual task-and correlated with subject's performance in the interoceptive task. These results are consistent with a shared, resource-based attentional mechanism whereby allocating attention to bodily signals can affect early responses to visual stimuli. PMID- 28560782 TI - Benefit of cardiopoietic mesenchymal stem cell therapy on left ventricular remodelling: results from the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) study. AB - AIMS: Left ventricular (LV) reverse remodelling is an important marker of improved outcomes in patients with advanced heart failure (HF). We examined the impact of the intramyocardial administration of bone-marrow-derived, lineage directed, autologous cardiopoietic mesenchymal stem cells (C3BS-CQR-1) on LV remodelling in patients with advanced HF enrolled in the CHART-1 study. METHODS AND RESULTS: Patients (n=351) with symptomatic advanced HF secondary to ischaemic heart disease, and reduced LV ejection fraction (LVEF <35%) were randomized to receive C3BS-CQR-1 or a sham procedure. In a post hoc analysis we examined the effect of C3BS-CQR-1 on LV reverse remodelling within 1 year of the procedure and the influence of C3BS-CQR-1 dosing in the 271 patients treated as randomized. Delivery of C3BS-CQR-1 was associated with a progressive decrease in both LV end diastolic volume (LVEDV) and end-systolic volume (LVESV) within 52 weeks after treatment. At 1 year, the LVEDV and LVESV of treated patients decreased by 17.0 mL and 12.8 mL greater than controls (P=0.006 and P=0.017, respectively). The effect on LVEDV was maintained after multivariable adjustment for baseline age, systolic blood pressure, LVEDV, LVEF and history of myocardial infarction. The largest reverse remodelling was evident in the patients receiving a moderate number of injections (<20). CONCLUSION: In CHART-1, intramyocardial administration of cardiopoietic stem cells led to reverse remodelling as evidenced by significant progressive decreases in LVEDV and LVESV through the 52 weeks of follow-up. Further studies are needed to explore the dose response with regard to cell number and injected volume, and reverse remodelling. PMID- 28560784 TI - Reversible and cachexia-associated feline skin fragility syndrome in three cats. AB - BACKGROUND: Feline skin fragility syndrome (FSFS) is an acquired disorder characterized by altered collagen production resulting in an extremely thin and fragile skin. FSFS is associated with diseases characterized by excessive steroidal hormones that can inhibit collagen synthesis. It is also described concomitantly with severe inflammatory, infectious or neoplastic conditions where the pathogenesis remains largely unknown. OBJECTIVES: To describe three cases of FSFS in cats that become cachectic secondary to different causes without glucocorticoid involvement. To describe the histopathological features of connective tissue for both fragile skin and the skin after healing. RESULTS: All cats developed cachexia in less than two months (body condition score ranging from 1-1.5). Concomitant diseases were diagnosed in Case 1 (aspiration pneumonia due to mega-oesophagus) and Case 2 (feline immunodeficiency virus (FIV)). In Case 3, malnutrition was suspected as a primary cause. The main histological feature of fragile skin was an atrophic dermis with pale eosinophilic, thin and irregular collagen fibres with numerous red cores observed with Masson's stain. Elastic fibres were normal. Postrecovery histopathological findings at 11 (Case 1) and six months (Case 3) after diagnosis, indicated normalization of the collagen and of the whole skin as compared with controls. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first report describing a reversible, nonsteroid-induced FSFS, associated with rapidly developing cachexia in cats. PMID- 28560783 TI - End-of-Life Care Planning in Accountable Care Organizations: Associations with Organizational Characteristics and Capabilities. AB - OBJECTIVE: To measure the extent to which accountable care organizations (ACOs) have adopted end-of-life (EOL) care planning processes and characterize those ACOs that have established processes related to EOL. DATA SOURCES: This study uses data from three waves (2012-2015) of the National Survey of ACOs. Respondents were 397 ACOs participating in Medicare, Medicaid, and commercial ACO contracts. STUDY DESIGN: This is a cross-sectional survey study using multivariate ordered logit regression models. We measured the extent to which the ACO had adopted EOL care planning processes as well as organizational characteristics, including care management, utilization management, health informatics, and shared decision-making capabilities, palliative care, and patient-centered medical home experience. PRINCIPAL FINDINGS: Twenty-one percent of ACOs had few or no EOL care planning processes, 60 percent had some processes, and 19.6 percent had advanced processes. ACOs with a hospital in their system (OR: 3.07; p = .01), and ACOs with advanced care management (OR: 1.43; p = .02), utilization management (OR: 1.58, p = .00), and shared decision-making capabilities (OR: 16.3, p = .000) were more likely to have EOL care planning processes than those with no hospital or few to no capabilities. CONCLUSIONS: There remains considerable room for today's ACOs to increase uptake of EOL care planning, possibly by leveraging existing care management, utilization management, and shared decision-making processes. PMID- 28560785 TI - Image of a left atrial mass after a cardiopulmonary bypass in a child. AB - Invagination of an appendage into the left atrium is a rare complication. It occurs spontaneously or after open-heart surgery. In our case, a postoperative transesophageal echocardiogram, after closure of a ventricular septal defect in a 5-month-old infant, revealed a large mass in the left atrium. A diagnosis of a left appendage inversion was confirmed after external examination of the heart. Herein, we provide echocardiographic images before, during, and after manual reversion of the left appendage. Misdiagnosis of this complication could have led to an additional unnecessary surgical procedure that could have impacted on the patient's morbidity. PMID- 28560786 TI - Medication compliance and clinical outcomes of fixed-dose combinations vs free combinations of an angiotensin II receptor blocker and a calcium channel blocker in hypertension treatment. AB - Using the National Health Insurance Research Database of Taiwan, the authors identified 1136 patients taking fixed-dose combination and 4544 patients taking free combinations of an angiotensin II receptor blocker and a dihydropyridine calcium channel blocker from January 2009 to December 2012. At a mean follow-up of 2.1 years, the fixed-dose combination was associated with improved medication adherence and persistence and better survival free from major adverse cardiac events and hospitalization for heart failure compared with the free combination regimens. PMID- 28560787 TI - A role for interleukin 17A in IBD-related neuroplasticity. AB - BACKGROUND: Changes to the structure and function of the innervation of the gut contribute to symptom generation in inflammatory bowel diseases (IBD). However, delineation of the mechanisms of these effects has proven difficult. Previous work on sympathetic neurons identified interleukin (IL)-17A as a novel neurotrophic cytokine. Since IL-17A is involved in IBD pathogenesis, we tested the hypothesis that IL-17A contributes to neuroanatomical remodeling during IBD. METHODS: Immunohistochemistry for tyrosine hydroxylase was used to identify sympathetic axons in mice with dextran sulphate sodium (DSS)-induced colitis and controls. Axon outgrowth from sympathetic neurons in response to incubation in cytokines or endoscopic patient biopsy supernatants was quantified. KEY RESULTS: DSS-induced colitis led to an increase in tyrosine hydroxylase immunoreactivity in the inflamed colon but not the spleen. Colonic supernatants from mice with colitis and biopsy supernatants from Crohn's disease patients increased axon outgrowth from mouse sympathetic neurons compared to supernatants from uninflamed controls. An antibody that neutralized IL-17A blocked the ability of DSS-induced colitis and Crohn's disease supernatants to induce axon extension. CONCLUSIONS AND INFERENCES: These findings identify IL-17A as a potential mediator of neuroanatomical remodeling of the gut innervation during IBD. PMID- 28560789 TI - Janet I. Sprent. PMID- 28560788 TI - Introduction to a Virtual Issue on root traits. PMID- 28560790 TI - Progressing from 'functional' to mechanistic traits. PMID- 28560791 TI - Linking plant hydraulics and beta diversity in tropical forests. PMID- 28560792 TI - Timing of return to work and women's breastfeeding practices in urban Malaysia: A qualitative study. AB - Nearly half of the working population in Malaysia are women, and with only a short period of maternity leave, they may struggle to achieve the recommended 6 months of exclusive breastfeeding. The aim of this paper was to explore the relationship between the timing of return to work and beliefs and breastfeeding practices among women in urban Malaysia. A qualitative inquiry based on a phenomenological framework and multiple methods was used: face-to-face interview, participant diary and researcher field notes. Data collection took place in Penang and the Klang Valley, Malaysia, from March to September 2011. Eligible participants were purposely identified at randomly selected recruitment sites. A thematic analysis method was used to develop the typologies and categories of the findings. A total of 40 working women with a mean age of 32 years (SD 3.4) were interviewed and 15 participated in the diary writing. Most women (75%) returned to work between 2 and 3 months. Only 10% returned to work 4 months or later postpartum, and 15% had an early return to work (defined here as less than 2 months). The women fell into three groups: Passionate women with a strong determination to breastfeed, who exclusively breastfed for 6 months; Ambivalent women, who commenced breastfeeding but were unable to sustain this after returning to work; and Equivalent women, who perceived formula feeding as equally nutritious as breast milk. Although longer maternity leave was very important for Ambivalent women to maintain breastfeeding, it was not as important for the Equivalent or Passionate women. In conclusion, returning earlier was not an absolute barrier to continuing breastfeeding. Instead, a woman's beliefs and perceptions of breastfeeding were more important than the timing of her return to work in determining her ability to maintain breastfeeding or breast milk feeding. PMID- 28560793 TI - Tregitopes and impaired antigen presentation: Drivers of the immunomodulatory effects of IVIg? AB - INTRODUCTION: Although intravenous immunoglobulin (IVIg) is commonly used in the clinic to treat various autoimmune and severe inflammatory diseases, the mode of action is not fully elucidated. This work investigates two proposed mechanisms: (1) the potential role of regulatory T-cell epitopes (Tregitopes) from the constant domain of IgG in the immunosuppressive function of IVIg; and (2) a potential impact of IVIg on the ability of antigen presenting cells (APCs) to present peptides. METHODS AND RESULTS: Investigation of the HLA class II peptide repertoire from IVIg-loaded dendritic cells (DCs) via MHC-associated peptide proteomics (MAPPs) revealed that numerous IgG-derived peptides were strongly presented along the antibody sequence. Surprisingly, Tregitopes 167 and 289 did not show efficient natural presentation although they both bound to HLA class II when directly loaded as "naked" peptides on human DCs. In addition, both Tregitopes could not reproduce the inhibitory effect of IVIg in a human in vitro T-cell proliferation assay as well as in vivo in mice. MAPPs data demonstrate that presentation of peptides from several antigens remained unchanged even when competed with high doses of IVIg, in both human and mouse. CONCLUSION: These data suggest that the effects mediated by IVIg are not caused by Tregitopes nor by impaired antigen presentation. PMID- 28560794 TI - A novel marketing mix and choice architecture framework to nudge restaurant customers toward healthy food environments to reduce obesity in the United States. AB - This review identified and adapted choice architecture frameworks to develop a novel framework that restaurant owners could use to promote healthy food environments for customers who currently overconsume products high in fat, sugar and sodium that increase their risk of obesity and diet-related non-communicable diseases. This review was conducted in three steps and presented as a narrative summary to demonstrate a proof of concept. Step 1 was a systematic review of nudge or choice architecture frameworks used to categorize strategies that cue healthy behaviours in microenvironments. We searched nine electronic databases between January 2000 and December 2016 and identified 1,244 records. Inclusion criteria led to the selection of five choice architecture frameworks, of which three were adapted and combined with marketing mix principles to highlight eight strategies (i.e. place, profile, portion, pricing, promotion, healthy default picks, prompting or priming and proximity). Step 2 involved conducting a comprehensive evidence review between January 2006 and December 2016 to identify U.S. recommendations for the restaurant sector organized by strategy. Step 3 entailed developing 12 performance metrics for the eight strategies. This framework should be tested to determine its value to assist restaurant owners to promote and socially normalize healthy food environments to reduce obesity and non-communicable diseases. PMID- 28560795 TI - Management of an asymptomatic patient with the apical variant of hypertrophic cardiomyopathy. AB - Healthcare professionals are faced with challenging decisions regarding patient evaluation and management on a daily basis. Once a diagnosis is made, additional challenges include how to proceed with the management. Here, we present an eighty two-year-old female who was incidentally diagnosed with the apical variant of hypertrophic cardiomyopathy on a transthoracic echocardiogram. She was found to have newly diagnosed atrial fibrillation, but was otherwise asymptomatic from a cardiomyopathy standpoint. No specific guidelines exist for this patient population. Therefore, how does one proceed with the management of an asymptomatic patient with the apical variant of hypertrophic cardiomyopathy? PMID- 28560797 TI - The effects of rapid eye movement sleep deprivation during late pregnancy on newborns' sleep. AB - Sleep deprivation during pregnancy is an emerging concern, as it can adversely affect the development of the offspring brain. This study was conducted to evaluate the effects of deprivation of rapid eye movement (REM) sleep during the third term of pregnancy on the sleep-wake profiles of neonates in the Wistar rat model. Sleep-wake patterns were assessed through electrophysiological measures and behavioural observations during postnatal days 1-21 on pups born to REM sleep deprived dams and control rats. Pups of REM sleep-deprived dams had active sleep that was not only markedly higher in percentage during all the days studied, but also had reduced latency during later postnatal days 15-21. Quiet sleep and wake periods were lower. These factors, along with less frequent but longer sleep-wake cycles, indicated maturational delay in the sleep-wake neural networks. The disruption of time-bound growth of sleep-wake neural networks was substantiated further by the decreased slope of survival plots in the sleep bouts. Examination of altered sleep-wake patterns during early development may provide crucial information concerning deranged neural development in the offspring. This is the first report, to our knowledge, to show that maternal sleep deprivation during pregnancy can delay and impair the development of sleep-wake profile in the offspring. PMID- 28560796 TI - Postoperative Evaluation of Reduction Loss in Proximal Humeral Fractures: A Comparison of Plain Radiographs and Computed Tomography. AB - OBJECTIVE: To compare postoperative CT images with plain radiographs for measuring prognostic factors of reduction loss of fractures of the proximal part of the humerus. METHODS: A total of 65 patients who sustained fractures of the proximal humerus treated with locking plates from June 2012 to October 2015 were retrospectively analyzed. There were 24 men and 41 women, with a mean age of 60.0 years (range, 22-76 years). According to the Neer classification system of proximal humeral fracture, there were 26 two-part, 27 three-part and 12 four-part fractures of the proximal part of the humerus, and all fractures were treated with open reduction and internal fixation (ORIF) using locked plating. All postoperative CT images and plain radiographs of the patients were obtained. Prognostic factors of the reduction loss were the change of neck shaft angle (NSA) and the change of humeral head height (HHH). The change of NSA and HHH were evaluated by the difference between postoperative initial and final follow-up measurement. Reduction loss was defined as the change >=10 degrees for NSA or >=5 mm for HHH. The NSA and HHH were measured using plain radiographs and 3-D CT images, both initially and at final follow-up. The paired t-test was used for comparison of NSA, change of NSA, HHH, and change of HHH between two image modalities. The differences between two image modalities in the assessment of reduction loss were examined using the chi2 -test (McNemar test). Intraclass correlation coefficients (ICC) were used to assess the intra-observer and inter observer reliability. RESULTS: 3-D CT images (ICC range, 0.834-0.967) were more reliable in all parameters when compared with plain radiographs (ICC range, 0.598 0.915). Significant differences were found between the two image modalities in all parameters (plain radiographs: initial NSA = 133.6 degrees +/- 3.8 degrees , final NSA = 130.0 degrees +/- 1.9 degrees , initial HHH = 17.9 +/- 0.9 mm, final HHH = 15.8 +/- 1.5 mm; 3-D CT: initial NSA = 131.4 degrees +/- 3.4 degrees , final NSA = 128.8 degrees +/- 1.7 degrees , initial HHH = 16.8 +/- 1.2 mm, final HHH = 14.5 +/- 1.1 mm; all P < 0.05). In the assessment of reduction loss, the percentage was 16.9% (11/65) for the plain radiographs and 7.7% (5/65) for the 3 D CT scans (P < 0.05). For the 5 patients with reduction loss, which were observed by two imaging modalities, the mean Constant-Murley score was 61.0 +/- 1.6. The patients with reduction loss, observed only in plain radiographs but not CT images, had good shoulder function (Constant-Murley score: 82.7 +/- 1.0). CONCLUSIONS: Our data reveal that 3-D CT images are more reliable than plain radiographs in the assessment of the prognostic factors of reduction loss of fractures of the proximal part of the humerus with treatment of locking plates; this reliable CT technique can serve as an effective guideline for the subsequent clinical management of patients. PMID- 28560798 TI - VNS and pregnancy: A multicentric experience of four cases. AB - BACKGROUND: Vagus nerve stimulation system (VNS) has been employed worldwide as adjunctive therapy in drug-resistant epileptic patients. Only nine previous pregnancies with six-positive outcomes have been reported in women with epilepsy treated with VNS since 1998. AIMS OF THE STUDY: To communicate the experience of pregnancies in women treated with VNS in our country. METHODS: Clinical data of four female patients treated with VNS during pregnancy and delivery in five gestations is described. RESULTS: Four pregnancy outcomes were positive and one ended in spontaneous abortion, probably more related to the use antiepileptic drugs than VNS itself. Two births were vaginal and the other two with cesarean section. None of the complications during delivery were attributed to VNS. No teratogenicity was documented. CONCLUSIONS: Based on our experience VNS constitutes a safe therapy for the treatment of drug-resistant epilepsy in women of childbearing potential and during pregnancy and delivery. Larger series will be useful to confirm this finding. PMID- 28560799 TI - Blood pressure management and guideline adherence in hypertensive emergencies and urgencies: A comparison between telemedically supported and conventional out-of hospital care. AB - Prehospital hypertensive emergencies and urgencies are common, but evidence is lacking. Telemedically supported hypertensive emergencies and urgencies were prospectively collected (April 2014-March 2015) and compared retrospectively with a historical control group of on-scene physician care in the emergency medical service of Aachen, Germany. Blood pressure management and guideline adherence were evaluated. Telemedical (n=159) vs conventional (n=172) cases: blood pressure reductions of 35+/-24 mm Hg vs 44+/-23 mm Hg revealed a group effect adjusted for baseline differences (P=.0006). Blood pressure management in categories: no reduction 6 vs 0 (P=.0121); reduction <=25% (recommended range) 113 vs 110 patients (P=.2356); reduction >25% to 30% 13 vs 29 (0.020); reduction >30% 12 vs 16 patients (P=.5608). The telemedical approach led to less pronounced blood pressure reductions and a tendency to improved guideline adherence. Telemedically guided antihypertensive care may be an alternative to conventional care especially for potentially underserved areas. PMID- 28560801 TI - What is it about old muscles? PMID- 28560800 TI - Emerging Targets of Diuretic Therapy. AB - Diuretics are commonly prescribed for treatment in patients with hypertension, edema, or heart failure. Studies on hypertensive and salt-losing disorders and on urea transporters have contributed to better understanding of mechanisms of renal salt and water reabsorption and their regulation. Proteins involved in the regulatory pathways are emerging targets for diuretic and aquaretic therapy. Integrative high-throughput screening, protein structure analysis, and chemical modification have identified promising agents for preclinical testing in animals. These include WNK-SPAK inhibitors, ClC-K channel antagonists, ROMK channel antagonists, and pendrin and urea transporter inhibitors. We discuss the potential advantages and side effects of these potential diuretics. PMID- 28560802 TI - The effect of preoperative oral administration of prednisolone on postoperative pain in patients with symptomatic irreversible pulpitis: a single-centre randomized controlled trial. AB - AIM: This single-centre randomized, double-blind, placebo-controlled clinical trial assessed the effect of a preoperative, single, oral dose of prednisolone on postoperative pain and postoperative analgesic intake in patients with symptomatic, irreversible pulpitis in mandibular molars. METHODOLOGY: Four hundred participants, randomly assigned to two equal groups, received either 40 mg prednisolone or placebo tablets 30 min before single-visit root canal treatment. Patients recorded their pain level 6, 12 and 24 h after treatment on a 100-mm visual analogue scale. All patients received a sham capsule to take if needed as a postoperative analgesic, and, if the pain persisted, an analgesic was prescribed. The relative risk reduction and 95% confidence intervals (CI) were estimated for binary data. Mann-Whitney U-test was used to compare postoperative pain intensity between groups. RESULTS: The relative risk reduction in pain incidence was 20.31% (95% CI: 12.03%, 27.82%) at 6 h, 23.39% (95% CI: 14.75%, 31.16%) at 12 h and 28.85% (95% CI: 18.08%, 38.20%) at 24 h. Prednisolone had significantly less post-obturation pain intensity compared to placebo at 6, 12 and 24 h (P < 0.001). The relative risk reduction in sham-capsule intake was 54% (95% CI: 38%, 66%) and of analgesic intake was 55% (95% CI: 3%, 79%). No adverse effects were recorded. CONCLUSION: Preoperative oral administration of a single dose of 40 mg prednisolone was beneficial to control short-term post-obturation pain after single-visit root canal treatment in patients with symptomatic irreversible pulpitis reducing pain incidence after 24 h by approximately 30% and postoperative analgesic intake by approximately 55%. PMID- 28560803 TI - Troubleshooting the collect concentration monitor alarm in therapeutic thrombocytapheresis. PMID- 28560805 TI - What has preoperative radio(chemo)therapy brought to localized rectal cancer patients in terms of perioperative and long-term outcomes over the past decades? A systematic review and meta-analysis based on 41,121 patients. AB - We asked what preoperative radiotherapy/chemoradiotherapy (PRT/PCRT) has brought to patients in terms of perioperative and long-term outcomes over the past decades. A systematic review and meta-analysis was conducted using PubMed, Embase and Web of Science databases. All original comparative studies published in English that were related to PRT/PCRT and surgical resection and which analyzed survival, postoperative and quality of life outcomes were included. Data synthesis and statistical analysis were carried out using Stata software. Data from 106 comparative studies based on 80 different trials enrolling 41,121 patients were included in our study. Based on our overall analyses, PRT/PCRT significantly improved patients' local recurrence-free survival (LRFS), but neither overall survival (OS) nor metastasis-free survival (MFS) showed improvement. In addition, PRT significantly increased the postoperative morbidity and mortality but PCRT did not have a significant effect. Furthermore, PRT/PCRT significantly increased the risk of postoperative wound complications but not anastomotic leakage and bowel obstruction. Our comprehensive subgroup analyses further supported the aforementioned results. Meanwhile, long-term anorectal symptoms (impaired squeeze pressures, use of pads, incontinence and urgency) and erectile dysfunction were also significantly increased in patients after PRT/PCRT. The benefits of PRT/PCRT as applied over the last several decades have not been sufficient to improve OS. Metastases of primary tumor and postoperative adverse effects were the two primary obstacles for an improved OS. In fact, the greatest advantage of PRT/PCRT is still local tumor control and a significantly improved LRFS. PMID- 28560804 TI - Wnt is necessary for mesenchymal to epithelial transition in colorectal cancer cells. AB - BACKGROUND: Metastasis underlies most colorectal cancer mortality. Cancer cells spread through the body as single cells or small clusters of cells that have an invasive, mesenchymal, nonproliferative phenotype. At the secondary site, they revert to a proliferative "tumor constructing" epithelial phenotype to rebuild a tumor. We previously developed a unique in vitro three-dimensional model, called LIM1863-Mph, which faithfully recapitulates these reversible transitions that underpin colorectal cancer metastasis. Wnt signaling plays a key role in these transitions and is initiated by the coupling of extracellular Wnt to Frizzled (FZD). Using the LIM1863-Mph model system we demonstrated that the Wnt receptor FZD7 is necessary for mesenchymal to epithelial transition (MET). Here we investigate the role of Wnt in MET. RESULTS: Wnt secretion is dependent on palmitoylation by Porcupine (PORC). A PORC inhibitor (IWP2) that prevents Wnt secretion, blocked the epithelial transition of mesenchymal LIM1863-Mph cells. Wnt gene array analysis identified several Wnts that are upregulated in epithelial compared with mesenchymal LIM1863-Mph cells, suggesting these ligands in MET. Wnt2B was the most abundant differentially expressed Wnt gene. Indeed, recombinant Wnt2B could overcome the IWP2-mediated block in epithelial transition of mesenchymal LIM1863-Mph cells. CONCLUSIONS: Wnt2B co-operates with Frizzled7 to mediate MET in colorectal cancer. Developmental Dynamics 247:521-530, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28560807 TI - Psychometric evaluation of the Cohen-Mansfield Agitation Inventory in an acute general hospital setting. AB - OBJECTIVES: The Cohen-Mansfield Agitation Inventory (CMAI; (Cohen-Mansfield and Kerin, 1986)) is a well-known tool for assessing agitated behaviours in people with dementia who reside in long-term care. No studies have evaluated the psychometric qualities and factor structure of the CMAI in acute general hospitals, a setting where people with demand may become agitated. METHOD: Longitudinal study investigating pain, agitation and behavioural problems in 230 people with dementia admitted to acute general hospitals in 2011-2012. Cohen Mansfield Agitation Inventory was completed as part of a battery of assessments including PAINAD to measure pain. RESULTS: A nine-item two-factor model of aggressive and nonaggressive behaviours proved to be the best-fitting measurement model in this sample, (chi2 = 96.3, df = 26, p<0.001; BIC [Bayesian Information Criterion] = 4593.06, CFI [Comparative Fit Index] = 0.884, TLI [Tucker Lewis Index] = 0.839, RMSEA [Root Mean Square Error of the Approximation] = 0.108). Although similar to the original factor structure, the new model resulted in the elimination of item 13 (screaming). Validity was confirmed with the shortened CMAI showing similar associations with pain as the original version of the CMAI, in particular the link between aggressive behaviours and pain. CONCLUSION: The factor structure of the CMAI was broadly consistent with the original solution although a large number of items were removed. Scales reflecting physical and verbal aggression were combined to form an Aggressive factor, and physical and verbal nonaggressive behaviours were combined to form the Nonaggressive factor. A shorter, more concise version of the CMAI was developed for use in acute general hospital settings. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28560806 TI - Factors associated with future intentions to use personal vaporisers among those with some experience of vaping. AB - INTRODUCTION AND AIMS: Personal vaporisers (PV), including e-cigarettes, may be a harm reduction strategy for tobacco control. This study aims to identify factors associated with future intentions to vape among smokers and ex-smokers in Australia and the UK. DESIGN AND METHODS: Cross-sectional data of smokers and ex smokers (n = 1199, mean age = 45.3 years, 44.8% male), collected in 2014/2015 and divided into four subgroups: smoking past vapers (SPV), smoking vapers (SV), ex smoking past vapers (ESPV) and ex-smoking vapers (ESV), from the International Tobacco Control Australia and UK surveys were analysed by using regression models. RESULTS: Higher vaping satisfaction increased vaping intentions for all groups except ESPV. Perceiving PVs as less harmful predicted intentions to vape for all groups except ESV. The importance of PVs for stopping smoking predicted lower intentions to continue vaping for SV, but higher intentions to initiate vaping for SPV. The importance of PVs for cutting down smoking was a positive predictor only for SPV. Among ex-smokers, importance for maintaining not smoking was a positive predictor for ESPV, but not for ESV. The importance of perceiving vapour being less harmful also depended on vaping status for ex-smokers. The only country interaction was that only in the UK was perceiving PVs as less harmful associated with intention among SPV. DISCUSSION AND CONCLUSION: Factors influencing intentions vary by smoking and/or vaping status, with greater differences between the ex-smoker subgroups. This is consistent with PVs being seen as a way of managing smoking, rather than something that has intrinsic value, for all except the ex-smoking vapers. [Ma BH, Yong H-H, Borland R, McNeill A, Hitchman SC. Factors associated with future intentions to use personal vaporisers among those with some experience of vaping. Drug Alcohol Rev 2017;00:000-000]. PMID- 28560808 TI - Optical Communication among Oscillatory Reactions and Photo-Excitable Systems: UV and Visible Radiation Can Synchronize Artificial Neuron Models. AB - Neuromorphic engineering promises to have a revolutionary impact in our societies. A strategy to develop artificial neurons (ANs) is to use oscillatory and excitable chemical systems. Herein, we use UV and visible radiation as both excitatory and inhibitory signals for the communication among oscillatory reactions, such as the Belousov-Zhabotinsky and the chemiluminescent Orban transformations, and photo-excitable photochromic and fluorescent species. We present the experimental results and the simulations regarding pairs of ANs communicating by either one or two optical signals, and triads of ANs arranged in both feed-forward and recurrent networks. We find that the ANs, powered chemically and/or by the energy of electromagnetic radiation, can give rise to the emergent properties of in-phase, out-of-phase, anti-phase synchronizations and phase-locking, dynamically mimicking the communication among real neurons. PMID- 28560809 TI - Editorial Comment to Assessment of sexual function in Japanese men with prostate cancer undergoing permanent brachytherapy without androgen deprivation therapy: Analysis from the Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation database. PMID- 28560810 TI - Changes of cortical activation in swallowing following high frequency repetitive transcranial magnetic stimulation in older adults. AB - BACKGROUND: This study explored whether high-frequency repetitive transcranial magnetic stimulation (rTMS) can induce positive changes in the cortical areas of older adults who do not have functional difficulties in swallowing. METHODS: Ten healthy, right-handed, elderly volunteers were subjected to 18F-labeled fluorodeoxyglucose positron emission tomography(FDG-PET) scans when at rest, swallowing before rTMS, and swallowing after rTMS. During the swallowing study, water was infused orally via a catheter at a rate of 600 mL/h. Subjects swallowed water every 20 seconds following a light flash for 30 minutes. During rest, the light source was active, but subjects were requested not to swallow. The rTMS consisted of 5 Hz applied to a pharyngeal motor hot spot in the right hemisphere for 10 minutes every weekday for 2 weeks. The intensity of the stimulation was set at 90% of the thenar motor threshold of the same hemisphere. The differences between each patient's active image and the control images (P<.05) on a voxel-by voxel basis were examined to find significant increases in metabolism using statistical parametric mapping software. KEY RESULTS: The cortical areas activated by swallowing before rTMS included the bilateral sensorimotor cortex (Brodmann's areas 3 and 4) and showed symmetry. The cortical areas activated by swallowing after rTMS were the same as the areas before rTMS. There was no statistical difference between the two swallowing activation areas. CONCLUSIONS AND INFERENCES: Older adults displayed the symmetry of cortical control of swallowing function. High frequency rTMS did not affect the activation in the swallowing sensorimotor cortices of elderly people. PMID- 28560811 TI - Comparing the Effectiveness of Dynamic Treatment Strategies Using Electronic Health Records: An Application of the Parametric g-Formula to Anemia Management Strategies. AB - OBJECTIVE: To compare the effectiveness of dynamic anemia management strategies by applying the parametric g-formula to electronic health records. DATA SOURCE/STUDY SETTING: Patients with end-stage renal disease from the US Renal Data System who had congestive heart failure or ischemic heart disease and were undergoing hemodialysis in outpatient dialysis facilities between 2006 and 2010. STUDY DESIGN: We explicitly emulated a target trial of three erythropoietin dosing strategies (aimed at achieving a low, middle, or high hematocrit) and estimated the observational analog of the per-protocol effect. RESULTS: Of 156,945 eligible patients, 41,970 died during the 18-month follow-up. Compared to the low-hematocrit strategy, the estimated risk of death was 4.6 (95% CI 4.4-4.9) percentage points higher under the high-hematocrit strategy and 1.8 (95% CI 1.7 1.9) percentage points higher under the mid-hematocrit strategy. The corresponding risk differences for a composite outcome of death and myocardial infarction were similar. CONCLUSION: An explicit emulation of a target trial using electronic health records, combined with the parametric g-formula, allowed comparison of real-world dynamic strategies that have not been compared in randomized trials. PMID- 28560814 TI - E. B. Robson, PhD (1928- 2016). Galton Professor of Human Genetics, University College London and Editor-in-Chief of the Annals of Human Genetics, died July 18th 2016. PMID- 28560813 TI - Impact of positive margins on outcomes of oropharyngeal squamous cell carcinoma according to p16 status. AB - BACKGROUND: Currently, positive surgical margins in head and neck cancer are considered to be an indicator for postoperative chemoradiotherapy (CRT) over radiotherapy (RT) alone. However, there are less data regarding the impact of margin status on human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC). METHODS: We performed a retrospective review of 55 patients with oropharyngeal SCC undergoing primary surgical treatment. The impact of margin status on disease-specific survival (DSS) was studied according to p16 status. RESULTS: Twenty-one patients had positive margins. Adjuvant treatment in these cases was CRT (n = 6), RT alone (n = 14), and none (n = 1). Among p16-negative patients, positive margins and dysplasia at margins predicted significantly worse DSS. Among patients with p16-positive disease, margin status had no impact on DSS. CONCLUSION: Patients with p16-positive oropharyngeal SCC and positive margins after excision maintain a low risk of recurrence despite most receiving RT alone as adjuvant treatment. These findings raise questions regarding the additional benefit of postoperative CRT in this group. PMID- 28560815 TI - Covariate-adjusted borrowing of historical control data in randomized clinical trials. AB - The borrowing of historical control data can be an efficient way to improve the treatment effect estimate of the current control group in a randomized clinical trial. When the historical and current control data are consistent, the borrowing of historical data can increase power and reduce Type I error rate. However, when these 2 sources of data are inconsistent, it may result in a combination of biased estimates, reduced power, and inflation of Type I error rate. In some situations, inconsistency between historical and current control data may be caused by a systematic variation in the measured baseline prognostic factors, which can be appropriately addressed through statistical modeling. In this paper, we propose a Bayesian hierarchical model that can incorporate patient-level baseline covariates to enhance the appropriateness of the exchangeability assumption between current and historical control data. The performance of the proposed method is shown through simulation studies, and its application to a clinical trial design for amyotrophic lateral sclerosis is described. The proposed method is developed for scenarios involving multiple imbalanced prognostic factors and thus has meaningful implications for clinical trials evaluating new treatments for heterogeneous diseases such as amyotrophic lateral sclerosis. PMID- 28560812 TI - Threshold position control of anticipation in humans: a possible role of corticospinal influences. AB - KEY POINTS: Sudden unloading of preloaded wrist muscles elicits motion to a new wrist position. Such motion is prevented if subjects unload muscles using the contralateral arm (self-unloading). Corticospinal influences originated from the primary motor cortex maintain tonic influences on motoneurons of wrist muscles before sudden unloading but modify these influences prior to the onset and until the end of self-unloading. Results are interpreted based on the previous finding that intentional actions are caused by central, particularly corticospinal, shifts in the spatial thresholds at which wrist motoneurons are activated, thus predetermining the attractor point at which the neuromuscular periphery achieves mechanical balance with environment forces. By maintaining or shifting the thresholds, descending systems let body segments go to the equilibrium position in the respective unloading tasks without the pre-programming of kinematics or muscle activation patterns. The study advances the understanding of how motor actions in general, and anticipation in particular, are controlled. ABSTRACT: The role of corticospinal (CS) pathways in anticipatory motor actions was evaluated using transcranial magnetic stimulation (TMS) of the primary motor cortex projecting to motoneurons (MNs) of wrist muscles. Preloaded wrist flexors were suddenly unloaded by the experimenter or by the subject using the other hand (self-unloading). After sudden unloading, the wrist joint involuntarily flexed to a new position. In contrast, during self-unloading the wrist remained almost motionless, implying that an anticipatory postural adjustment occurred. In the self-unloading task, anticipation was manifested by a decrease in descending facilitation of pre-activated flexor MNs starting ~72 ms before changes in the background EMG activity. Descending facilitation of extensor MNs began to increase ~61 ms later. Conversely, these influences remained unchanged before sudden unloading, implying the absence of anticipation. We also tested TMS responses during EMG silent periods produced by brief muscle shortening, transiently resulting in similar EMG levels before the onset and after the end of self-unloading. We found reduced descending facilitation of flexor MNs after self unloading. To explain why the wrist excursion was minimized in self-unloading due to these changes in descending influences, we relied on previous demonstrations that descending systems pre-set the threshold positions of body segments at which muscles begin to be activated, thus predetermining the equilibrium point to which the system is attracted. Based on this notion, a more consistent explanation of the kinematic, EMG and descending patterns in the two types of unloading is proposed compared to the alternative notion of direct pre-programming of kinematic and/or EMG patterns. PMID- 28560816 TI - Scan-layered reconstructions: A pilot study of a nondestructive dental histoanatomical analysis method and digital workflow to create restorations driven by natural dentin and enamel morphology. AB - OBJECTIVE: This work aims to present a pilot study of a non-destructive dental histo-anatomical analysis technique as well as to push the boundaries of the presently available restorative workflows for the fabrication of highly customized ceramic restorations. MATERIALS AND METHODS: An extracted human maxillary central incisor was subject to a micro computed tomography scan and the acquired data was transferred into a workstation, reconstructed, segmented, evaluated and later imported into a Computer-Aided Design/Computer-Aided Manufacturing software for the fabrication of a ceramic resin-bonded prosthesis. RESULTS: The obtained prosthesis presented an encouraging optical behavior and was used clinically as final restoration. CONCLUSION: The digitally layered restorative replication of natural tooth morphology presents today as a clear possibility. New clinical and laboratory-fabricated, biologically inspired digital restorative protocols are to be expected in the near future. CLINICAL SIGNIFICANCE: The digitally layered restorative replication of natural tooth morphology presents today as a clear possibility. This pilot study may represent a stimulus for future research and applications of digital imaging as well as digital restorative workflows in service of esthetic dentistry. PMID- 28560817 TI - Outcomes of pulmonary arterial hypertension therapy in Australia: is monotherapy adequate? AB - BACKGROUND: In Australia, government-subsidised treatment of pulmonary arterial hypertension (PAH) is limited to monotherapy. Recent international guidelines advocate that initial combination therapy be considered for all symptomatic PAH patients. AIM: To characterise 'real-life' outcomes in PAH patients initiated on monotherapy. METHODS: We performed a retrospective analysis of 100 consecutive PAH patients at a single centre who were commenced on monotherapy for PAH between 2004 and 2015. The composite clinical end-point of 'treatment failure' was prospectively defined as (i) >15% fall in 6-min walk distance (6MWD) on follow up, (ii) physician judgement of inadequate treatment response, (iii) adverse drug effect requiring cessation and (iv) death or transplantation. RESULTS: At initiation of therapy, mean age was 54 +/- 18 years, and underlying diagnoses included idiopathic (36%), connective tissue disease-associated (37%) and congenital heart disease-associated-PAH (25%). Baseline 6MWD was 360 +/- 140 m, and 75% were in either the New York Heart Association functional classes III or IV. Over a median follow up of 38 months (interquartile range 20-67), 62% of the subjects met the criteria for a clinical failure event. Median time to monotherapy failure was 24 months (95% confidence interval 14-34), with death or transplantation being the most common clinical failure event. Estimated 1-, 3- and 5-year survival rates from time of treatment initiation were 92, 75 and 66%. CONCLUSION: The majority of patients failed initial monotherapy therapy within 2 years of treatment initiation. Broader access to approved PAH agents is needed to enable combination therapy in line with evidence-based international guidelines. PMID- 28560818 TI - Emotion regulation deficits in regular marijuana users. AB - Effective regulation of negative affective states has been associated with mental health. Impaired regulation of negative affect represents a risk factor for dysfunctional coping mechanisms such as drug use and thus could contribute to the initiation and development of problematic substance use. This study investigated behavioral and neural indices of emotion regulation in regular marijuana users (n = 23) and demographically matched nonusing controls (n = 20) by means of an fMRI cognitive emotion regulation (reappraisal) paradigm. Relative to nonusing controls, marijuana users demonstrated increased neural activity in a bilateral frontal network comprising precentral, middle cingulate, and supplementary motor regions during reappraisal of negative affect (P < 0.05, FWE) and impaired emotion regulation success on the behavioral level (P < 0.05). Amygdala-focused analyses further revealed impaired amygdala downregulation in the context of decreased amygdala-dorsolateral prefrontal cortex functional connectivity (P < 0.05, FWE) during reappraisal in marijuana users relative to controls. Together, the present findings could reflect an unsuccessful attempt of compensatory recruitment of additional neural resources in the context of disrupted amygdala prefrontal interaction during volitional emotion regulation in marijuana users. As such, impaired volitional regulation of negative affect might represent a consequence of, or risk factor for, regular marijuana use. Hum Brain Mapp 38:4270 4279, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28560819 TI - Radiographic assessment of pulmonary fluid clearance and lung aeration in newborn calves delivered by elective Caesarean section. AB - The aim of this study was to develop a radiographic standard for the assessment of pulmonary fluid clearance and lung aeration in newborn calves. Caesarean delivered mature calves (n = 9) underwent lung assessment by thoracic radiography as well as arterial and venous blood gas analysis within the first 30 min, 1, 2, 3, 6, 12 and 24 hr after birth. The results indicated that newborn calves delivered by elective Caesarean section suffered from a physiological combined respiratory and metabolic acidosis with the dominance of respiratory acidosis, and an improvement in these conditions was recorded within 24 hr after birth. Concerning the radiographic results, clear lung fields, improvement in lung expansion, air content of the lung and absence of lung opacification occurred within 24 hr of birth. Furthermore, the ventral lung quadrant showed an improvement in radiographic opacification and lung expansion earlier than the dorsal lung regions. The findings of this study support the potential role of thoracic radiography in the assessment of pulmonary fluid clearance and lung aeration in newborn calves. PMID- 28560820 TI - Children's and parents' opinions on the sport-related food environment: a systematic review. AB - Sport is a key setting for interventions to address child obesity given its obesogenic nature. Understanding children's and parents' opinions on the sport related food environment is critical in developing effective programmes and policies to improve children's health. This systematic review synthesizes quantitative and qualitative research examining children's and parents' opinions on the sport-related food environment. During July 2016, a range of electronic databases of academic and grey literature were searched. Thirty-two publications (11 including children, 17 parents and 4 both) were included for review. The publications were assessed using the Analysis Grid for Environments Linked to Obesity framework to categorize the sport-related food environment into the physical, sociocultural, economic and political environments. The literature available investigating children's and parents' opinions of the sport-related food environment suggests that many children and parents consider the environment neither conducive to nor supportive of children's healthy food behaviours or wider health and well-being. Both groups would likely support actions to change and improve it. This systematic review found that original research specifically investigating children's and parents' perspectives on almost all aspects of the sport-related food environment is limited. Thus, there is scope for further investigation into this important part of children's food environments. PMID- 28560821 TI - Ecto-5'-nucleotidase (CD73) regulates peripheral chemoreceptor activity and cardiorespiratory responses to hypoxia. AB - KEY POINTS: Carotid body dysfunction is recognized as a cause of hypertension in a number of cardiorespiratory diseases states and has therefore been identified as a potential therapeutic target. Purinergic transmission is an important element of the carotid body chemotransduction pathway. We show that inhibition of ecto-5'-nucleotidase (CD73) in vitro reduces carotid body basal discharge and responses to hypoxia and mitochondrial inhibition. Additionally, inhibition of CD73 in vivo decreased the hypoxic ventilatory response, reduced the hypoxia induced heart rate elevation and exaggerated the blood pressure decrease in response to hypoxia. Our data show CD73 to be a novel regulator of carotid body sensory function and therefore suggest that this enzyme may offer a new target for reducing carotid body activity in selected cardiovascular diseases. ABSTRACT: Augmented sensory neuronal activity from the carotid body (CB) has emerged as a principal cause of hypertension in a number of cardiovascular related pathologies, including obstructive sleep apnoea, heart failure and diabetes. Development of new targets and pharmacological treatment strategies aiming to reduce CB sensory activity may thus improve outcomes in these key patient cohorts. The present study investigated whether ecto-5'-nucleotidase (CD73), an enzyme that generates adenosine, is functionally important in modifying CB sensory activity and cardiovascular respiratory responses to hypoxia. Inhibition of CD73 by alpha,beta-methylene ADP (AOPCP) in the whole CB preparation in vitro reduced basal discharge frequency by 76 +/- 5% and reduced sensory activity throughout graded hypoxia. AOPCP also significantly attenuated elevations in sensory activity evoked by mitochondrial inhibition. These effects were mimicked by antagonism of adenosine receptors with 8-(p-sulfophenyl) theophylline. Infusion of AOPCP in vivo significantly decreased the hypoxic ventilatory response (Delta PMID- 28560822 TI - Relationship of changes in strain rate indices estimated from velocity-encoded MR imaging to loss of muscle force following disuse atrophy. AB - PURPOSE: This study explores changes in strain rate (SR) (rate of regional deformation) parameters extracted from velocity-encoded MRI and their relationship to muscle force loss following 4-week unilateral lower limb suspension in healthy humans. METHODS: Two-dimensional SR maps were derived from three directional velocity-encoded MR phase-contrast images of the medial gastrocnemius in seven subjects. Atrophy-related and regional differences in the SR eigenvalues, angle between the SR and muscle fiber (SR-fiber angle), and strain rates in the fiber basis were statistically analyzed using analysis of variance and linear regression. RESULTS: During isometric contraction, SR in the fiber cross section (SRin-plane ) was significantly lower, and the SR-fiber angle was significantly higher postsuspension (P < 0.05). On multiple variable regression analysis, the volume of medial gastrocnemius, SRin-plane , and SR fiber angle were significantly associated with force and changes in the, and the SR eigenvalues and shear SR were significantly associated with change in force with disuse. CONCLUSIONS: Changes in SR-fiber angle, SRin-plane , and shear SR as well as their ability to predict force and force changes may reflect the role of remodeling of the extracellular matrix in disuse atrophy and its functional consequence in reducing lateral transmission of force. Magn Reson Med 79:912-922, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28560823 TI - Identification and quantification of predominant metabolites of synthetic cannabinoid MAB-CHMINACA in an authentic human urine specimen. AB - An autopsy case in which the cause of death was judged as drug poisoning by two synthetic cannabinoids, including MAB-CHMINACA, was investigated. Although unchanged MAB-CHMINACA could be detected from solid tissues, blood and stomach contents in the case, the compound could not be detected from a urine specimen. We obtained six kinds of reference standards of MAB-CHMINACA metabolites from a commercial source. The MAB-CHMINACA metabolites from the urine specimen of the abuser were extracted using a QuEChERS method including dispersive solid-phase extraction, and analyzed by liquid chromatography-tandem mass spectrometry with or without hydrolysis with beta-glucuronidase. Among the six MAB-CHMINACA metabolites tested, two predominant metabolites could be identified and quantified in the urine specimen of the deceased. After hydrolysis with beta glucuronidase, an increase of the two metabolites was not observed. The metabolites detected were a 4-monohydroxycyclohexylmethyl metabolite M1 (N-(1 amino-3,3-dimethyl-1-oxobutan-2-yl)-1-((4-hydroxycyclohexyl)methyl)-1H-indazole-3 carboxamide) and a dihydroxyl (4-hydroxycyclohexylmethyl and tert-butylhydroxyl) metabolite M11 (N-(1-amino-4-hydroxy-3,3-dimethyl-1-oxobutan-2-yl)-1-((4 hydroxycyclohexyl)methyl)-1H-indazole-3-carboxamide). Their concentrations were 2.17 +/- 0.15 and 10.2 +/- 0.3 ng/mL (n = 3, each) for M1 and M11, respectively. Although there is one previous in vitro study showing the estimation of metabolism of MAB-CHMINACA using human hepatocytes, this is the first report dealing with in vivo identification and quantification of MAB-CHMINACA metabolites in an authentic human urine specimen. PMID- 28560824 TI - Emphasis on abdominal obesity as a modifier of eplerenone effect in heart failure: hypothesis-generating signals from EMPHASIS-HF. PMID- 28560825 TI - PhredEM: a phred-score-informed genotype-calling approach for next-generation sequencing studies. AB - A fundamental challenge in analyzing next-generation sequencing (NGS) data is to determine an individual's genotype accurately, as the accuracy of the inferred genotype is essential to downstream analyses. Correctly estimating the base calling error rate is critical to accurate genotype calls. Phred scores that accompany each call can be used to decide which calls are reliable. Some genotype callers, such as GATK and SAMtools, directly calculate the base-calling error rates from phred scores or recalibrated base quality scores. Others, such as SeqEM, estimate error rates from the read data without using any quality scores. It is also a common quality control procedure to filter out reads with low phred scores. However, choosing an appropriate phred score threshold is problematic as a too high threshold may lose data, while a too low threshold may introduce errors. We propose a new likelihood-based genotype-calling approach that exploits all reads and estimates the per-base error rates by incorporating phred scores through a logistic regression model. The approach, which we call PhredEM, uses the expectation-maximization (EM) algorithm to obtain consistent estimates of genotype frequencies and logistic regression parameters. It also includes a simple, computationally efficient screening algorithm to identify loci that are estimated to be monomorphic, so that only loci estimated to be nonmonomorphic require application of the EM algorithm. Like GATK, PhredEM can be used together with a linkage-disequilibrium-based method such as Beagle, which can further improve genotype calling as a refinement step. We evaluate the performance of PhredEM using both simulated data and real sequencing data from the UK10K project and the 1000 Genomes project. The results demonstrate that PhredEM performs better than either GATK or SeqEM, and that PhredEM is an improved, robust, and widely applicable genotype-calling approach for NGS studies. The relevant software is freely available. PMID- 28560827 TI - Cytopathology of high-grade fetal adenocarcinoma of the lung: A case report and cytological analysis. PMID- 28560826 TI - Training alters the distribution of perilipin proteins in muscle following acute free fatty acid exposure. AB - KEY POINTS: The lipid droplet (LD)-associated perilipin (PLIN) proteins promote intramuscular triglyceride (IMTG) storage, although whether the abundance and association of the PLIN proteins with LDs is related to the diverse lipid storage in muscle between trained and sedentary individuals is unknown. We show that lipid infusion augments IMTG content in type I fibres of both trained and sedentary individuals. Most importantly, despite there being no change in PLIN protein content, lipid infusion did increase the number of LDs connected with PLIN proteins in trained individuals only. We conclude that trained individuals are able to redistribute the pre-existing pool of PLIN proteins to an expanded LD pool during lipid infusion and, via this adaptation, may support the storage of fatty acids in IMTG. ABSTRACT: Because the lipid droplet (LD)-associated perilipin (PLIN) proteins promote intramuscular triglyceride (IMTG) storage, we investigated the hypothesis that differential protein content of PLINs and their distribution with LDs may be linked to the diverse lipid storage in muscle between trained and sedentary individuals. Trained (n = 11) and sedentary (n = 10) subjects, matched for age, sex and body mass index, received either a 6 h lipid or glycerol infusion in the setting of a concurrent hyperinsulinaemic euglycaemic clamp. Sequential muscle biopsies (0, 2 and 6 h) were analysed using confocal immunofluorescence microscopy for fibre type-specific IMTG content and PLIN associations with LDs. In both groups, lipid infusion increased IMTG content in type I fibres (trained: +62%, sedentary: +79%; P < 0.05) but did not affect PLIN protein content. At baseline, PLIN2 (+65%), PLIN3 (+105%) and PLIN5 (+53%; all P < 0.05) protein content was higher in trained compared to sedentary individuals. In trained individuals, lipid infusion increased the number of LDs associated with PLIN2 (+27%), PLIN3 (+73%) and PLIN5 (+40%; all P < 0.05) in type I fibres. By contrast, in sedentary individuals, lipid infusion only increased the number of LDs not associated with PLIN proteins. Acute free fatty acid elevation therefore induces a redistribution of PLIN proteins to an expanded LD pool in trained individuals only and this may be part of the mechanism that enables fatty acids to be stored in IMTG. PMID- 28560828 TI - Toward Benzobis(thiadiazole)-based Diradicaloids. AB - We theoretically predicted that acetylene-bridged benzo[1,2-c;4,5 c']bis[1,2,5]thiadiazole (BBT) oligomers would show a quick increase of diradical character with the extension of chain length. To validate the hypothesis, six stable BBT-based diradicaloids were synthesized and fully characterized by X-ray crystallographic analysis and various spectroscopic measurements. Three of them showed prominent paramagnetic activity at elevated temperatures due to thermal population from the open-shell singlet ground state to triplet excited state. It was also found that substitution by electron-donating triphenylamine groups at the termini promoted the diradical character and reduced the singlet-triplet energy gap, and at the same time, resulted in intense near-infrared absorption. PMID- 28560830 TI - Intrathecal Opioid Therapy for Non-Malignant Chronic Pain: A Long-Term Perspective. AB - OBJECTIVES: Many patients with intrathecal opioid pumps do adhere to the therapy for many years but there is scarce knowledge about the long-term effects of intrathecal opioid therapy (IOT) of more than three years. We sought to assess the long-term efficacy and the presence of typical side-effects and complications of IOT. METHODS: A chart review was conducted on all patients with intrathecal opioid pumps that had been treated at our institution between 1.11.1990 and 31.12.2014. Information regarding age, gender, diagnosis, age at time of implant, duration of disease, pump type in use, revision operations, and opioid doses over time was recorded. Moreover, a questionnaire was given to the patients containing the following items: pain scores on the NRS with and without IOT, pain related disability, unwanted side-effects of opioid therapy, anxiety, and depression. RESULTS: Thirty-six patients (21 m/15 f, mean age 62.9 years, range 30.5-83.9 years, SD 11.0 years) were studied. Mean duration of intrathecal therapy at time of study was 11.8 years. Thirty-two patients had gas-driven pumps and four patients had programmable pumps. The mean actual dose in those patients receiving morphine sulfate was 4.6 mg/day (range 0.2-11.1 mg, SD 2.63 mg). Pain levels prior to pump implantation were 7.98 (NRS) (range 4-10, SD 1.62). Pain levels directly after pump implantation were 4.87 (range 2-7, SD 1.86) and at time of follow-up 4.44 (range 0-9, SD 2.03). The most common unwanted side-effects reported by the patients were fatigue, obstipation, urinary retention, and sexual dysfunction. There was no life-threatening complication or permanent neurological deficit. CONCLUSIONS: IOT seems to be effective also for long-term application. Clinically unwanted side-effects are relatively frequent but not the limiting factor for patient satisfaction. PMID- 28560829 TI - Dynamic phosphocreatine imaging with unlocalized pH assessment of the human lower leg muscle following exercise at 3T. AB - PURPOSE: To develop a high temporal resolution imaging method that measures muscle-specific phosphocreatine (PCr) resynthesis time constant (tauPCr ) and pH changes in muscles of the lower leg following exercise on a clinical 3T MRI scanner. METHODS: We developed a frequency-selective 3D non-Cartesian FLORET sequence to measure PCr with 17-mm nominal isotropic resolution (28 mm actual resolution) and 6-s temporal resolution to capture dynamic metabolic muscle activity. The sequence was designed to additionally collect inorganic phosphate spectra for pH quantification, which were localized using sensitivity profiles of individual coil elements. Nineteen healthy volunteers were scanned while performing a plantar flexion exercise on an in-house developed ergometer. Data were acquired with a dual-tuned multichannel coil array that enabled phosphorus imaging and proton localization for muscle segmentation. RESULTS: After a 90-s plantar flexion exercise at 0.66 Hz with resistance set to 40% of the maximum voluntary contraction, tauPCr was estimated at 22.9 +/- 8.8 s (mean +/- standard deviation) with statistical coefficient of determination r2 = 0.89 +/- 0.05. The corresponding pH values after exercise were in the range of 6.9-7.1 in the gastrocnemius muscle. CONCLUSION: The developed technique allows measurement of muscle-specific PCr resynthesis kinetics and pH changes following exercise, with a temporal resolution and accuracy comparable to that of single voxel 31 P-MRS sequences. Magn Reson Med 79:974-980, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28560831 TI - Stereochemical assignment of fusiccocadiene from NMR shielding constants and vibrational circular dichroism spectroscopy. AB - The absolute configuration (AC) of the common precursor of the fusicoccane family of terpenoids, fusicocca-2,10(14)-diene (FCdiene), had only been deduced by a lengthy total synthesis, or indirectly from crystal structures of fusicoccin A. However, in particular the AC determinations based on downstream products of the terpene synthase intrinsically overlook potential epimerization reactions. In this contribution, we confirm the relative stereochemistry of FCdiene by comparison of experimental and predicted 13 C-NMR chemical shifts, and finally determine the absolute configuration from an analysis of its infrared and vibrational circular dichroism spectra. PMID- 28560834 TI - Advanced statistical methodologies to address inherent study limitations. Author Response to Ayubi and Saeid. PMID- 28560832 TI - Effects of a lifestyle intervention on REM sleep-related OSA severity in obese individuals with type 2 diabetes. AB - The aim of this study was to determine if an intensive lifestyle intervention (ILI) reduces the severity of obstructive sleep apnea (OSA) in rapid-eye movement (REM) sleep, and to determine if longitudinal changes in glycaemic control are related to changes in OSA severity during REM sleep over a 4-year follow-up. This was a randomized controlled trial including 264 overweight/obese adults with type 2 diabetes (T2D) and OSA. Participants were randomized to an ILI targeted to weight loss or a diabetes support and education (DSE) control group. Measures included anthropometry, apnea-hypopnea index (AHI) during REM sleep (REM-AHI) and non-REM sleep (NREM-AHI) and glycated haemoglobin (HbA1c) at baseline and year 1, year 2 and year 4 follow-ups. Mean baseline values of REM-AHI were significantly higher than NREM-AHI in both groups. Both REM-AHI and NREM-AHI were reduced significantly more in ILI versus DSE, but these differences were attenuated slightly after adjustment for weight changes. Repeated-measure mixed-model analyses including data to year 4 demonstrated that changes in HbA1c were related significantly to changes in weight, but not to changes in REM-AHI and NREM-AHI. Compared to control, the ILI reduced REM-AHI and NREM-AHI during the 4-year follow-up. Weight, as opposed to REM-AHI and NREM-AHI, was related to changes in HbA1c. The findings imply that weight loss from a lifestyle intervention is more important than reductions in AHI for improving glycaemic control in T2D patients with OSA. PMID- 28560833 TI - Use of microwave ablation in the treatment of patients with multiple primary malignant tumors. AB - A 56-year-old man was admitted to our hospital in 2007, complaining of an irritating cough. Computed tomography examination demonstrated a mass in the right lung and enlargement of the hilar and mediastinal lymph nodes. Small cell lung cancer was confirmed by pathological examination after fibro-bronchoscope biopsy. The patient was treated with received sequential chemotherapy and radiotherapy. Preventive radiotherapy of the whole brain was performed after complete remission of the lung disease. Seven years after diagnosis, follow-up computed tomography revealed masses in both the liver and kidney. Subsequent percutaneous biopsy confirmed hepatocellular carcinoma in the liver and renal clear cell carcinoma in the kidney. The patient received microwave ablation for the treatment of both liver and renal tumors, and is doing well with no recurrence after two years of follow-up. PMID- 28560835 TI - A comparison of pulse oximetry and cerebral oxygenation in children with severe sleep apnea-hypopnea syndrome: a pilot study. AB - Near infrared spectroscopy (NIRS) has been used to assess the impact of obstructive sleep apnea-hypopnea syndrome (OSAHS) on cerebral oxygenation. However, the relationship between the variations in the cerebral tissue oxygen saturation (DeltaTOI) and pulse oximetry (DeltaSpO2 ) has not been assessed in children with OSAHS. Consecutive clinically stable children with severe OSAHS [apnea-hypopnea index (AHI) >15 events h-1 ] diagnosed during a night-time polygraphy with simultaneous recording of cerebral oxygenation with NIRS (NIRO 200NX, Hamamatsu Photonics KK) were included between September 2015 and June 2016. Maximal DeltaSpO2 (SpO2 drop from the value preceding desaturation to nadir) and concomitant variations in transcutaneous carbon dioxide (DeltaPtcCO2 ), maximal DeltaTOI and maximal variations in cerebral oxygenated (O2 Hb) and deoxygenated (HHb) haemoglobin were reported. The relationships between DeltaSpO2 , DeltaPtcCO2 and DeltaTOI, DeltaO2 Hb and DeltaHHb were investigated. The data from five children (three boys, aged 9.6 +/- 6.7 years, AHI 16-91 events h-1 ) were analysed. Strong correlations were found between DeltaSpO2 and DeltaTOI (r = 0.887, P < 0.001), but also with DeltaO2 Hb and DeltaHHb with a particular pattern in the youngest child with a dark skin pigmentation. Mean DeltaSpO2 was 20 +/- 17% and mean DeltaTOI was 8 +/- 7%. Maximal DeltaSpO2 of approximately 70% were coupled with DeltaTOI of no more than 35%. DeltaPtcCO2 correlated only weakly with the cerebral oxygenation indexes. This pilot study shows a strong relationship between pulse oximetry and cerebral oxygenation in children with OSAHS, with lower changes in TOI compared to SpO2 . Future studies should address the clinical impact of respiratory events on cerebral oxygenation and its consequences. PMID- 28560836 TI - Sensitivity analysis of magnetic field measurements for magnetic resonance electrical impedance tomography (MREIT). AB - PURPOSE: Clinical use of magnetic resonance electrical impedance tomography (MREIT) still requires significant sensitivity improvements. Here, the measurement of the current-induced magnetic field (DeltaBz,c ) is improved using systematic efficiency analyses and optimization of multi-echo spin echo (MESE) and steady-state free precession free induction decay (SSFP-FID) sequences. THEORY AND METHODS: Considering T1 , T2 , and T2* relaxation in the signal-to noise ratios (SNRs) of the MR magnitude images, the efficiency of MESE and SSFP FID MREIT experiments, and its dependence on the sequence parameters, are analytically analyzed and simulated. The theoretical results are experimentally validated in a saline-filled homogenous spherical phantom with relaxation parameters similar to brain tissue. Measurement of DeltaBz,c is also performed in a cylindrical phantom with saline and chicken meat. RESULTS: The efficiency simulations and experimental results are in good agreement. When using optimal parameters, DeltaBz,c can be reliably measured in the phantom even at injected current strengths of 1 mA or lower for both sequence types. The importance of using proper crusher gradient selection on the phase evolution in a MESE experiment is also demonstrated. CONCLUSION: The efficiencies observed with the optimized sequence parameters will likely render in-vivo human brain MREIT feasible. Magn Reson Med 79:748-760, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28560837 TI - The relationship between sleep and glucagon-like peptide 1 in patients with abnormal glucose tolerance. AB - Glucagon-like peptide 1 plays a role in glucose regulation. Sleep disturbances (obstructive sleep apnea, insufficient or poor sleep quality) have been shown to adversely affect glucose metabolism. This study aimed to explore the relationship between sleep and glucagon-like peptide 1 regulation in patients with abnormal glucose tolerance. Seventy-one adults with haemoglobin A1c levels between 5.7% and < 6.5% and no history of diabetes participated. Habitual sleep duration and efficiency were obtained from 7-day actigraphy recordings. Obstructive sleep apnea was assessed using an overnight home monitor. Glucagon-like peptide 1 levels were measured during a 75-g glucose tolerance. The area under the curve of glucagon-like peptide 1 was calculated. The mean age (SD) was 55.1 (8.3) years and median (interquartile range) haemoglobin A1c was 5.97% (5.86, 6.23). There was no relationship between sleep duration or efficiency and fasting or area under the curve glucagon-like peptide 1. Glucagon-like peptide 1 levels did not differ among those sleeping <= 5.75, > 5.75-< 6.5 or >= 6.5 h per night. Increasing apnea-hypopnea index, an indicator of obstructive sleep apnea severity, correlated with lower area under the curve glucagon-like peptide 1 (B 0.242, P = 0.045), but not with fasting glucagon-like peptide 1 (B -0.213, P = 0.079). After adjusting for sex, haemoglobin A1c and body mass index, increasing apnea-hypopnea index was negatively associated with having area under the curve glucagon-like peptide 1 in the highest quartile (odds ratio 0.581, P = 0.028, 95% CI 0.359, 0.942). This study demonstrated that increasing obstructive sleep apnea severity was associated with lower glucagon-like peptide 1 response to glucose challenge. This could possibly be an additional mechanism by which obstructive sleep apnea affects glucose metabolism. Whether raising glucagon-like peptide 1 levels in patients with abnormal glucose tolerance with more severe obstructive sleep apnea will be beneficial should be explored. PMID- 28560838 TI - Optimal climate for large trees at high elevations drives patterns of biomass in remote forests of Papua New Guinea. AB - Our ability to model global carbon fluxes depends on understanding how terrestrial carbon stocks respond to varying environmental conditions. Tropical forests contain the bulk of the biosphere's carbon. However, there is a lack of consensus as to how gradients in environmental conditions affect tropical forest carbon. Papua New Guinea (PNG) lies within one of the largest areas of contiguous tropical forest and is characterized by environmental gradients driven by altitude; yet, the region has been grossly understudied. Here, we present the first field assessment of aboveground biomass (AGB) across three main forest types of PNG using 193 plots stratified across 3,100-m elevation gradient. Unexpectedly, AGB had no direct relationship to rainfall, temperature, soil, or topography. Instead, natural disturbances explained most variation in AGB. While large trees (diameter at breast height > 50 cm) drove altitudinal patterns of AGB, resulting in a major peak in AGB (2,200-3,100 m) and some of the most carbon rich forests at these altitudes anywhere. Large trees were correlated to a set of climatic variables following a hump-shaped curve. The set of "optimal" climatic conditions found in montane cloud forests is similar to that of maritime temperate areas that harbor the largest trees in the world: high ratio of precipitation to evapotranspiration (2.8), moderate mean annual temperature (13.7 degrees C), and low intra-annual temperature range (7.5 degrees C). At extreme altitudes (2,800-3,100 m), where tree diversity elsewhere is usually low and large trees are generally rare or absent, specimens from 18 families had girths >70 cm diameter and maximum heights 20-41 m. These findings indicate that simple AGB-climate-edaphic models may not be suitable for estimating carbon storage in forests where optimal climate niches exist. Our study, conducted in a very remote area, suggests that tropical montane forests may contain greater AGB than previously thought and the importance of securing their future under a changing climate is therefore enhanced. PMID- 28560841 TI - Short-term acclimation to warmer temperatures accelerates leaf carbon exchange processes across plant types. AB - While temperature responses of photosynthesis and plant respiration are known to acclimate over time in many species, few studies have been designed to directly compare process-level differences in acclimation capacity among plant types. We assessed short-term (7 day) temperature acclimation of the maximum rate of Rubisco carboxylation (Vcmax ), the maximum rate of electron transport (Jmax ), the maximum rate of phosphoenolpyruvate carboxylase carboxylation (Vpmax ), and foliar dark respiration (Rd ) in 22 plant species that varied in lifespan (annual and perennial), photosynthetic pathway (C3 and C4 ), and climate of origin (tropical and nontropical) grown under fertilized, well-watered conditions. In general, acclimation to warmer temperatures increased the rate of each process. The relative increase in different photosynthetic processes varied by plant type, with C3 species tending to preferentially accelerate CO2 -limited photosynthetic processes and respiration and C4 species tending to preferentially accelerate light-limited photosynthetic processes under warmer conditions. Rd acclimation to warmer temperatures caused a reduction in temperature sensitivity that resulted in slower rates at high leaf temperatures. Rd acclimation was similar across plant types. These results suggest that temperature acclimation of the biochemical processes that underlie plant carbon exchange is common across different plant types, but that acclimation to warmer temperatures tends to have a relatively greater positive effect on the processes most limiting to carbon assimilation, which differ by plant type. The acclimation responses observed here suggest that warmer conditions should lead to increased rates of carbon assimilation when water and nutrients are not limiting. PMID- 28560840 TI - Long-term quality of life after definitive treatment for prostate cancer: patient reported outcomes in the second posttreatment decade. AB - Definitive treatment for prostate cancer includes radical prostatectomy (RP), external beam radiation therapy (EBRT), and brachytherapy (BT). The different side effect profiles of these options are crucial factors for patients and clinicians when deciding between treatments. This study reports long-term health related quality of life (HRQOL) for patients in their second decade after treatment for prostate cancer. We used a validated survey to assess urinary, bowel, and sexual function and HRQOL in a prospective cohort of patients diagnosed with localized prostate cancer 14-18 years previously. We report and compare the outcomes of patients who were initially treated with RP, EBRT, or BT. Of 230 eligible patients, the response rate was 92% (n = 211) and median follow up was 14.6 years. Compared to baseline, RP patients had significantly worse urinary incontinence and sexual function, EBRT patients had worse scores in all domains, and BT patients had worse urinary incontinence, urinary irritation/obstruction, and sexual function. When comparing treatment groups, RP patients underwent larger declines in urinary continence than did BT patients, and EBRT and BT patients experienced larger changes in urinary irritation/obstruction. Baseline functional status was significantly associated with long-term function for urinary obstruction and bowel function domains. This is one of the few prospective reports on quality of life for prostate cancer patients beyond 10 years, and adds information about the late consequences of treatment choices. These data may help patients make informed decisions regarding treatment choice based on symptoms they may experience in the decades ahead. PMID- 28560839 TI - Suppressor of fused controls cerebellar neuronal differentiation in a manner modulated by GLI3 repressor and Fgf15. AB - BACKGROUND: Deficiency of Suppressor of Fused (SuFu), an intracellular mediator of Hedgehog signaling, in the murine mid-hindbrain disrupts cerebellar morphogenesis and cell differentiation in a manner that is rescued by constitutive expression of GLI3 transcriptional repressor (GLI3R). Here, we determined SuFu functions in cerebellar radial precursors following the stage of mid-hindbrain specification using a Blbp-Cre transgene. RESULTS: SuFu-deficient cerebella were severely dysplastic, and characterized by laminar disorganization, and delayed differentiation of ventricular zone-derived precursors. In vitro analysis of cerebellar precursors isolated from control and mutant mice demonstrated an increased proportion of radial glial precursors vs. Tuj1-positive neurons in mutant cultures. Abnormal cell differentiation in SuFu-deficient precursors was rescued by a constitutively expressed GLI3R knock-in allele, albeit with variable penetrance. Using RNA expression analysis in control and SuFu-deficient cerebellar anlage, we identified up-regulation of Fgf15 in mutant tissue. Strikingly, exogenous hFGF19, a mFGF15 ortholog, inhibited neuronal differentiation in cultures of wild-type cerebellar precursors. Moreover, siRNA mediated knockdown of Fgf15 in SuFu-deficient cerebellar precursors rescued their delayed differentiation to neurons. CONCLUSIONS: Together, our results show that SuFu promotes cerebellar radial precursor differentiation to neurons. SuFu function is mediated in part by GLI3R and down-regulation of Fgf15 expression. Developmental Dynamics 247:156-169, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28560842 TI - Three-dimensional stereophotogrammetric analysis of 50 smiles: A study of dento facial proportions. AB - OBJECTIVES: The purpose of this study was to analyze 50 smiles using 3D stereophotogrammetry (3D-spg)-based facial reconstruction, to calculate ratios involving measurements of the distances between dental and facial landmarks and to compare these ratios with the golden ratio phi (1.618). MATERIALS AND METHODS: Fifty subjects with no obvious malocclusion participated in this study. For each subject, 4 photographs were acquired using the LifeViz MiniTM, an absolute calibration 3D-spg system. Facial and dental landmarks (based on Farkas' definitions) were fixed, and 8 distances were measured. Four ratios were then calculated and compared with the value of 1.618. RESULTS: The ratio "incisal edge of the maxillary central incisor-lower border of the chin/subnasal point-incisal edge of the maxillary central incisor" (IE-Me/SN-IE) was 1.693 +/- 0.190, the ratio "right endocanthion-left endocanthion/right exocanthion-right endocanthion" was 1.582 +/- 0.173, the ratio "incisal edge of the maxillary central incisor distal edge of the right canine/distal edge of the right canine-right labial commissure" was 1.670 +/- 0.355, and the ratio "right labial commissure-left labial commissure/distal edge of the right canine-distal edge of the left canine" was 1.602 +/- 0.136. In contrast, the vertical ratio IE-Me/SN-IE significantly differed from the golden ratio (1 sample t test, P = .009). CONCLUSION: This study revealed that the observed ratios were surprisingly close to the golden ratio. Only the vertical ratio differed from the golden ratio, whereas the horizontal ratios appear to be adequately approximated by phi. CLINICAL SIGNIFICANCE: If the distances from reference points of the face to teeth within a harmonious smile exhibited recurring esthetic proportions, knowledge of such ratios would provide an additional tool for the elaboration of esthetic treatment plans. In addition, this knowledge could provide guidance when planning tooth positions and dental proportions by encouraging consideration of the global nature of the oro-facial sphere. PMID- 28560843 TI - Superelectrophilic Behavior of an Anion Demonstrated by the Spontaneous Binding of Noble Gases to [B12 Cl11 ]. AB - It is common and chemically intuitive to assign cations electrophilic and anions nucleophilic reactivity, respectively. Herein, we demonstrate a striking violation of this concept: The anion [B12 Cl11 ]- spontaneously binds to the noble gases (Ngs) xenon and krypton at room temperature in a reaction that is typical of "superelectrophilic" dications. [B12 Cl11 Ng]- adducts, with Ng binding energies of 80 to 100 kJ mol-1 , contain B-Ng bonds with a substantial degree of covalent interaction. The electrophilic nature of the [B12 Cl11 ]- anion is confirmed spectroscopically by the observation of a blue shift of the CO stretching mode in the IR spectrum of [B12 Cl11 CO]- and theoretically by investigation of its electronic structure. The orientation of the electric field at the reactive site of [B12 Cl11 ]- results in an energy barrier for the approach of polar molecules and facilitates the formation of Ng adducts that are not detected with reactive cations such as [C6 H5 ]+ . This introduces the new chemical concept of "dipole-discriminating electrophilic anions." PMID- 28560844 TI - Evaluation of the skeletal and dental effects in orthodontic patients with maxillary lateral incisor agenesis. AB - OBJECTIVE: The purpose of this study was to evaluate the transverse dimension of the dentoalveolar and skeletal widths in both unilateral (UMLIA) and bilateral (BMLIA) maxillary lateral incisor agenesis groups. MATERIALS AND METHODS: The study sample consisted of 59 patients (34 females and 25 males) divided into three groups as UMLIA group (16 patients; 14.94 +/- 1.37 years), BMLIA group (21 patients; 14.46 +/- 1.53 years) and control group (22 patients; 15.28 +/- 1.70 years) without tooth agenesis. Transversal measurements (maxillary and mandibular intercanine, interpremolar, intermolar, intercanine alveolar, interpremolar alveolar, intermolar alveolar widths) were done on dental casts. Craniofacial skeletal measurements were done with posteroanterior cephalometric radiographs. Statistical testing was performed with the one-way variance analysis, Kruskal Wallis and post hoc tests. RESULTS: UMLIA and BMLIA groups had statistically significantly narrower skeletal apical base of the maxilla, maxillary intercanine and intercanine alveolar widths compared with the control group (P < .05). Moreover, UMLIA and BMLIA groups had statistically significantly similar dental, alveolar and skeletal features (P > .05). CONCLUSIONS: The UMLIA and BMLIA groups showed statistically significantly smaller values for maxillary intercanine, maxillary intercanine alveolar and skeletal maxillary widths compared with the control group. CLINICAL SIGNIFICANCE: This study provides information the transverse dimension of the dental, alveolar and skeletal widths with maxillary lateral incisor agenesis patients. Knowledge of transverse dimension of the dental, alveolar and skeletal widths with maxillary lateral incisor agenesis patients is important for diagnosis and treatment planning. PMID- 28560845 TI - Spinocerebellar ataxia type 10: common haplotype and disease progression rate in Peru and Brazil. AB - BACKGROUND AND PURPOSE: Spinocerebellar ataxia type 10 is a neurodegenerative disorder that is due to an expanded ATTCT repeat tract in the ATXN10 gene. Our aim was to describe clinical characteristics and intragenic haplotypes of patients with spinocerebellar ataxia type 10 from Brazil and Peru. METHODS: Expanded alleles were detected by repeat-primed polymerase chain reaction. Disease progression was measured by the Scale for the Assessment and Rating of Ataxia, and the Neurological Examination Score for Spinocerebellar Ataxias when possible. Haplotypes were constructed based on polymorphic markers within and outside the gene. RESULTS: Thirteen new families were diagnosed (three from Peru). Patients from three Brazilian families diagnosed previously were also reassessed. In total, 25 individuals (16 families) were evaluated. Mean (+/- SD) age at onset and disease duration were 34.8 +/- 10.2 and 12 +/- 8 years, respectively. Common findings were ataxia, dysarthria/dysphagia, nystagmus, pyramidal signs, ophthalmoparesis and seizures. No associations were found between clinical findings and geographical origins. Twelve patients living in remote regions were examined only once. In the remaining individuals, the Scale for the Assessment and Rating of Ataxia score, and Neurological Examination Score for Spinocerebellar Ataxias worsened by 0.444 (95% CI, -0.088 to 0.800) and 0.287 (95% CI, -0.061 to 0.635) points/year, respectively. A common haplotype, 19CGGC14, was found in 11/13 of Brazilian and in 1/3 of Peruvian families. CONCLUSIONS: The progression rate was slower than in other spinocerebellar ataxias. A consistently recurrent intragenic haplotype was found, suggesting a common ancestry for most, if not all, patients. PMID- 28560846 TI - Outcome following treatment of feline gastrointestinal mast cell tumours. AB - Prognosis of feline gastrointestinal mast cell tumours (FGIMCT), based on limited available literature, is described as guarded to poor, which may influence treatment recommendations and patient outcome. The purpose of this study is to describe the clinical findings, treatment response, and outcome of FGIMCT. Medical records of 31 cats diagnosed with and treated for FGIMCT were retrospectively reviewed. Data collected included signalment, method of diagnosis, tumour location (including metastatic sites), treatment type, cause of death and survival time. Mean age was 12.9 y. Diagnosis was made via cytology (n = 15), histopathology (n = 13) or both (n = 3). Metastatic sites included abdominal lymph node (n = 10), abdominal viscera (n = 4) and both (n = 2). Therapeutic approaches included chemotherapy alone (n = 15), surgery and chemotherapy (n = 7), glucocorticoid only (n = 6) and surgery and glucocorticoid (n = 3). Lomustine (n = 15) and chlorambucil (n = 12) were the most commonly used chemotherapy drugs. Overall median survival time was 531 d (95% confidence interval 334, 982). Gastrointestinal location, diagnosis of additional cancers, and treatment type did not significantly affect survival time. Cause of death was tumour-related or unknown (n = 12) and unrelated (n = 8) in the 20 cats dead at the time of analysis. The prognosis for cats with FGIMCT may be better than previously reported, with 26% of cats deceased from an unrelated cause. Surgical and medical treatments (including prednisolone alone) were both associated with prolonged survival times. Treatment other than prednisolone may not be necessary in some cats. Continued research into prognostic factors and most effective treatment strategies are needed. PMID- 28560847 TI - Importance of prumycin produced by Bacillus amyloliquefaciens SD-32 in biocontrol against cucumber powdery mildew disease. AB - BACKGROUND: Powdery mildew disease of cucurbits is caused mainly by Podosphaera fusca, which is one of the most important limiting factors in cucurbit production worldwide. Previously we reported that Bacillus amyloliquefaciens biocontrol strain SD-32 produces C17 bacillomycin D and [Ile 2002]surfactin, and that these metabolites play important roles in SD-32's biocontrol over cucumber gray mold disease. Our further investigation demonstrated that the culture broth and its supernatant suppressed cucumber powdery mildew disease in greenhouse experiments. However, the active principle(s) remained unknown. RESULTS: The active compound was isolated from the culture supernatant after anti-powdery mildew disease activity-guided purification and identified as prumycin. Prumycin significantly suppressed the disease, whereas bacillomycin D and [Ile 2002]surfactin did not. Prumycin did not induce the expression of plant defense genes (PR1a and VSP1), suggesting that it does not act via plant defense response. Light microscopic observations of prumycin-treated cucumber cotyledon suggested that prumycin inhibits the conidial germination of P. fusca. CONCLUSION: This study demonstrates that prumycin is a major factor in SD-32's suppression of cucumber powdery mildew disease. Our findings shed light for the first time on prumycin's role in biocontrol by Bacillus against this disease. (c) 2017 Society of Chemical Industry. PMID- 28560848 TI - Advanced Silicon Chemistry in Australia: Forming Strong Links with Asia. AB - This paper details Australian commercial and academic silicon research. Areas of interest include silicon metal, polysiloxane polymers, copolymers, cyclics, emulsions, microemulsions, silanes, silane coupling agents, sol-gel chemistry and water-treatments, porous silicon, polysiloxane degradation, silicon hydrogel contact lenses, silanolate synthesis, siloxane interfacial polymerisation, hydrosilylation, polysiloxane electrolytes for lithium ion batteries, silanes for PBX materials, octafunctionalized polyhedral oligomeric silsesquioxanes (POSS), POSS hybrids, sol-gel hydrogenation catalysts, silane modification of silica, sol gel energy storage, silicate grout stabilisation, GeoPolymer concretes, aerogel insulating foams, "Phaco-Ersatz" Accommodating Gel-Intraocular Lens technologies. Strong collaborative opportunities, in silicon, with Asia, exist with organisations such as: 1) The Asian Silicon Society and 2) The Agency for the Assessment and Application of Technology (BPPT) Indonesia. PMID- 28560850 TI - Modulation of Open-shell Characters of Amine-inserted Diphenoquinones via Structural Modification. AB - In this study, a series of triphenylamine derivatives with two 2,6 diphenylphenoxy radicals (2 a-d), which could be regarded as amine-inserted diphenoquinones have been synthesized and investigated their structures and electronic properties. The structures of 2 a-d were confirmed by single-crystal X ray analysis, showing the characteristic bond length alternation patterns for closed-shell quinoids. The solutions of 2 a-d exhibited clear ESR signals even at room temperature, indicating their thermally accessible diradical states. The NMR and ESR measurements showed that the diradical character of 2 a-d were increased in the order of 2 a<2 b<2 c<2 d, well-reproduced by theoretical calculations. The results of this work strongly suggest that the diradical character of this class of compounds could be tuned by changing the substituent on the central nitrogen atom. PMID- 28560849 TI - Transcription factors CEP-1/p53 and CEH-23 collaborate with AAK-2/AMPK to modulate longevity in Caenorhabditis elegans. AB - A decline in mitochondrial electron transport chain (ETC) function has long been implicated in aging and various diseases. Recently, moderate mitochondrial ETC dysfunction has been found to prolong lifespan in diverse organisms, suggesting a conserved and complex role of mitochondria in longevity determination. Several nuclear transcription factors have been demonstrated to mediate the lifespan extension effect associated with partial impairment of the ETC, suggesting that compensatory transcriptional response to be crucial. In this study, we showed that the transcription factors CEP-1/p53 and CEH-23 act through a similar mechanism to modulate longevity in response to defective ETC in Caenorhabditis elegans. Genomewide gene expression profiling comparison revealed a new link between these two transcription factors and AAK-2/AMP kinase (AMPK) signaling. Further functional analyses suggested that CEP-1/p53 and CEH-23 act downstream of AAK-2/AMPK signaling and CRTC-1 transcriptional coactivator to promote stress resistance and lifespan. As AAK-2, CEP-1, and CEH-23 are all highly conserved, our findings likely provide important insights for understanding the organismal adaptive response to mitochondrial dysfunction in diverse organisms and will be relevant to aging and pathologies with a mitochondrial etiology in human. PMID- 28560851 TI - Significance of flower pot cells in effusion cytology. AB - Cells with long polar hair-like processes referred to as 'flower pot cells' are a rare but beautiful morphological feature observed in effusions of diverse etiologies. This report describes these cells in effusions seen in ovarian borderline serous tumours, malignant mesothelioma and in reactive mesothelial cells with or without accompanying malignant cells. These processes were better appreciated in air-dried May-Grunwald-Giemsa stained smears. PMID- 28560852 TI - The significant effects of puberty on the genetic diathesis of binge eating in girls. AB - OBJECTIVE: Recent data show significant phenotypic and genetic associations between ovarian hormones and binge eating in adulthood. Theories of hormonal risk focus on puberty and the possibility that hormone activation induces changes in genetic effects that then lead to differential risk for binge eating in postpuberty and adulthood. Although this theory is difficult to test in humans, an indirect test is to examine whether genetic influences on binge eating increase during the pubertal period in girls. Prior work has shown pubertal increases in genetic influences on overall disordered eating symptoms, but no study to date has examined binge eating. The present study was the first to examine these increases for binge eating. METHODS: Participants included 1,568 female twins (aged 8-25 years) from the Michigan State University Twin Registry. Binge eating and pubertal development were assessed with self-report questionnaires. RESULTS: Twin moderation models showed significant linear increases in genetic effects from prepuberty (5%) to postpuberty (42%), even after controlling for the effects of age and body mass index. DISCUSSION: Results provide critical support for increased genetic influences on binge eating during puberty. Additional studies are needed to identify hormonal mechanisms and fully test contemporary models of ovarian hormone risk. PMID- 28560853 TI - Combination of chemotherapy and gefitinib as first-line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial. AB - To explore the optimal treatment strategy for patients who harbor sensitive EGFR mutations, a head-to-head study was performed to compare chemotherapy and gefitinib in combination or with either agent alone as first-line therapy, in terms of efficacy and safety. A total of 121 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations were randomly assigned to receive gefitinib combined with pemetrexed and carboplatin, pemetrexed plus carboplatin or gefitinib alone. The progression-free survival (PFS) of patients in the combination group (17.5 months, 95% CI, 15.3-19.7) was longer than that of patients in the chemotherapy group (5.7 months, 95% CI, 5.2-6.3) or gefitinib (11.9 months, 95% CI, 9.1-14.6) group. The (hazard ratios) HRs of PFS for the combination group vs. chemotherapy and gefitinib groups were 0.16 (95% CI, 0.09 0.29, p < 0.001) and 0.48 (95% CI, 0.29-0.78, p = 0.003), respectively. The overall response rate (ORR) in the combination therapy group, chemotherapy group and the gefitinib group was 82.5%, 32.5% and 65.9%, respectively. The combinational strategy resulted in longer overall survival (OS) than chemotherapy (HR = 0.46, p = 0.016) or gefitinib (HR = 0.36, p = 0.001) alone. Our finding suggested that treatment with pemetrexed plus carboplatin combined with gefitinib could provide better survival benefits for patients with lung adenocarcinoma harboring sensitive EGFR mutations. PMID- 28560854 TI - Pharmacogenetic analysis of irreversible severe cisplatin-induced nephropathy: a case report of a 27-year-old woman. AB - In this report we describe a young patient diagnosed with bulky FIGO stage IIIb squamous cell cervix carcinoma with severe and irreversible nephropathy after three weekly low-doses of cisplatin. Besides several known risk factors such as hypomagnesemia and hypoalbuminemia, the patient also proved to be homozygously polymorphic for two polymorphisms within the COMT gene (c.615 + 310C>T and c.616 367C>T). As COMT polymorphism has been associated with cisplatin-induced ototoxicity, its effect on nephrotoxicity of cisplatin should be the subject of further investigation. PMID- 28560855 TI - N-Heterocyclic Phosphenium Complex of Manganese: Synthesis and Catalytic Activity in Ammonia Borane Dehydrogenation. AB - A neutral N-heterocyclic phosphenium complex of manganese was synthesised by a metathesis approach and characterised by IR, NMR, and XRD studies. The short P-Mn distance suggests a substantial metal-ligand double bond character. Reaction with a hydride produced an anionic phosphine complex, which was also characterised by IR and NMR spectroscopy and, after anion exchange, a single-crystal XRD study. Protonation of the anion occurs at the metal to yield a neutral phosphine metal carbonyl hydride, which releases dihydrogen upon irradiation with UV light. These reactions confirm the electrophilic nature of the phosphenium ligand and suggest that the title complex might undergo reactions displaying metal-ligand cooperativity. Surprisingly, reaction with ammonia borane (AB) did not proceed under transfer hydrogenation of the Mn=P double bond but through the catalytic dehydrogenation of AB. The phosphenium complex behaves here as a class II catalyst, which dehydrogenates AB to NH2 BH2 that was trapped with cyclohexene. Computational model studies led to the identification of two possible catalytic cycles, which differ in the regioselectivity of the initial AB activation step. In one case, the activation proceeds as cooperative transfer hydrogenation of the Mn=P bond, whereas in the other case a H+ /H- pair is transferred to the phosphorus atom and a nitrogen atom of the phosphenium unit, resulting in a ligand-centred reaction in which the metal fragment acts merely as stabilising substituent. Unexpectedly, this pathway, which constitutes a new reaction mode for phosphenium complexes, seems to be better in accord with experimental findings on the course of the catalysis. PMID- 28560856 TI - Peripancreatic paraganglioma mimics pancreatic/gastrointestinal neuroendocrine tumor on fine needle aspiration: Report of two cases and review of the literature. AB - Cytologic diagnosis of extra-adrenal paraganglioma presenting as a peripancreatic mass is challenging with a high error rate due to its rarity. We report two cases of peripancreatic masses identified by radiology. Endoscopic ultrasound-guided fine needle aspiration (FNA) of the masses showed a moderately cellular tumor composed of small to medium sized neoplastic cells with round to oval nuclei, arranged singly and in loose clusters. Focal rosette-like structures were present. The cells were positive for neuroendocrine markers (synaptophysin and chromogranin). A diagnosis of a neoplasm with neuroendocrine differentiation and neuroendocrine tumor was made respectively on FNA for each case. The subsequent surgical resection of the tumors revealed peripancreatic paraganglioma. Although paraganglioma has been reported in the literature, the detailed comparison of perpancreatic paraganglioma versus pancreatic/gastrointestinal neuroendocrine tumor is still lacking. Therefore using these two cases with literature review, we wish to illustrate the differential diagnosis between these two entities based on cytomorphology and immunohistochemical study. PMID- 28560857 TI - Interpersonal sensitivity, bullying victimization and paranoid ideation among help-seeking adolescents and young adults. AB - AIM: The effects of a negative interpersonal experience, such as bullying victimization in childhood and adolescence, can be strong and long lasting. Bullying victimization is associated with paranoid ideation and suspiciousness. Few studies have focused on personality traits of victims of bullying. The aim of this study is to investigate whether a particular personality trait called interpersonal sensitivity may be related to suspiciousness in those who experienced bullying victimization. METHODS: The study sample consisted of 147 help-seeking adolescents (mean age 17 years) selected after a screening phase (Prodromal Questionnaire) and evaluated with the Structured Interview for Psychosis-risk Syndromes (SIPS). All participants were specifically asked if they had experienced either psychological bullying or physical bullying, and they completed the Interpersonal Sensitivity Measure (IPSM). RESULTS: Of the whole sample, 30 (20%) participants had experienced psychological bullying or physical bullying at least once in their life. Performing a multiple regression, bullying victimization was found to be an independent predictor of subtle paranoid ideation and suspiciousness. Interpersonal sensitivity was also found to be an independent predictor of subtle paranoid ideation; in particular, two IPSM subscales, fragile inner-self and separation anxiety, showed a significant correlation with subtle paranoid ideation. CONCLUSIONS: Our results confirmed that bullying victimization is a negative interpersonal experience associated with paranoid ideation and suspiciousness. However, being overly sensitive and having negative beliefs about the self as fragile and vulnerable to threat also lead to a tendency to attribute experiences as externally caused and, in turn, facilitate the formation and maintenance of paranoid ideation. PMID- 28560858 TI - Basal subtype is predictive for response to cetuximab treatment in patient derived xenografts of squamous cell head and neck cancer. AB - Cetuximab is the single targeted therapy approved for the treatment of head and neck cancer (HNSCC). Predictive biomarkers have not been established and patient stratification based on molecular tumor profiles has not been possible. Since EGFR pathway activation is pronounced in basal subtype, we hypothesized this activation could be a predictive signature for an EGFR directed treatment. From our patient-derived xenograft platform of HNSCC, 28 models were subjected to Affymetrix gene expression studies on HG U133+ 2.0. Based on the expression of 821 genes, the subtype of each of the 28 models was determined by integrating gene expression profiles through centroid-clustering with previously published gene expression data by Keck et al. The models were treated in groups of 5-6 animals with docetaxel, cetuximab, everolimus, cis- or carboplatin and 5 fluorouracil. Response was evaluated by comparing tumor volume at treatment initiation and after 3 weeks of treatment (RTV). Tumors distributed over the 3 signature-defined subtypes: 5 mesenchymal/inflamed phenotype (MS), 15 basal type (BA), 8 classical type (CL). Cluster analysis revealed a strong correlation between response to cetuximab and the basal subtype. RTV MS 3.32 vs. BA 0.78 (MS vs. BA, unpaired t-test, p 0.0002). Cetuximab responders were distributed as following: 1/5 in MS, 5/8 in CL and 13/15 in the BA group. Activity of classical chemotherapies did not differ between the subtypes. In conclusion basal subtype was associated with response to EGFR directed therapy in head and neck squamous cell cancer patient-derived xenografts. PMID- 28560859 TI - Electron Transfer of Cytochrome c on Surface-Enhanced Raman Scattering-Active Substrates: Material Dependence and Biocompatibility. AB - Surface-enhanced Raman spectroscopy (SERS) represents a powerful approach for studying the structure and reaction of proteins in fundamental and applied sciences. The surface properties of SERS-active materials determine important parameters such as Raman enhancement ability, biocompatibility, and electronic communication between supports and proteins. Here, electron transfer (ET) of Cyt c on noble metals and transition metals is investigated by SERS spectroscopy. The results here indicate that the ET occurs from the reduced state of Cyt c to silver substrate, depending on the laser wavelengths. Nickel and cobalt can directly transfer electrons to the oxidized state of Cyt c, which enables a reductive activity of these transition metal nanoparticles (NPs). This study demonstrates the role of transition metals as electron donors for Cyt c and has proved that the charge transfer theory for SERS is applicable for explanation of the ET between Cyt c and Ag NPs. PMID- 28560861 TI - What impact does trauma have on the at-risk mental state? A systematic literature review. AB - Identification of individuals with an at-risk mental state (ARMS) who are at a heightened risk of developing psychosis allows researchers and clinicians to identify what factors are associated with poorer outcomes and transitions to psychosis. A number of socioenvironmental factors are linked to an increase risk of developing psychosis, of which childhood trauma is widely acknowledged. The current review aims to examine what impact trauma has on the ARMS by reviewing reported relationships between trauma variables and transition to psychosis, ARMS severity, adaptive functioning and comorbid symptomology from both cross sectional and prospective design studies. A literature search was conducted for all relevant original research articles published in the English language up to December 2015 using 3 electronic databases: PsycINFO, Web of Science and PubMed. A total of 6 papers met the inclusion criteria and were included in the current review. Trauma was found to have a significant impact on the ARMS observed through reported relationships between trauma variables and transition to psychosis, ARMS severity, adaptive functioning and comorbid symptomology. Sexual trauma demonstrated the most consistent trauma variable to impact the ARMS. Individuals with an ARMS who have experienced sexual trauma are at a heightened risk of poorer outcomes and transitions to psychosis. Further prospective design studies are required to examine this observation further. PMID- 28560860 TI - The intrinsic cause of color fading in sliced cooked cured beef during chilled storage. AB - The relationship between color change and other physical and chemical characteristics of sliced cooked cured beef (SCCB) during chilled storage were investigated using principal components analysis (PCA) to determine the color fading causes. Samples were prepared and stored at 8 degrees C for up to 35 days in a vacuum package to simulate a supermarket storage environment; related indicators were measured periodically every week. The results showed that the first PC explained 59.82% of the total variation, and the second explained 22.28%. PC1 was a concentrated reflection of color changes of SCCB during storage and PC2 was an environment factor causing the change of color. The change in apparent redness is mainly caused by redox reaction of the nitroso hemochromogen (NH) (eigenvectors of a*, C and NH in PC1 were all the maximum value of 0.28); a* was correlated with NH (0.96), free sulfhydryls (0.98), carbonyl derivatives ( 0.95) formed during protein oxidation, and malondialdehyde (-0.98) and dienes ( 0.92) formed by lipid oxidation. Color fading was significantly correlated with oxidizing and reducing power, existing forms of nitrogen and with the pH of the meat matrix. Changes in the internal environment of the sample initially influenced L* and b* values, and subsequently a*. PMID- 28560863 TI - Cellulosic Biomass-Reinforced Polyvinylidene Fluoride Separators with Enhanced Dielectric Properties and Thermal Tolerance. AB - Safety issues are critical barriers to large-scale energy storage applications of lithium-ion batteries (LIBs). Using an ameliorated, thermally stable, shutdown separator is an effective method to overcome the safety issues. Herein, we demonstrate a novel, cellulosic biomass-material-blended polyvinylidene fluoride separator that was prepared using a simple nonsolvent-induced phase separation technique. This process formed a microporous composite separator with reduced crystallinity, uniform pore size distribution, superior thermal tolerance, and enhanced electrolyte wettability and dielectric and mechanical properties. In addition, the separator has a superior capacity retention and a better rate capability compared to the commercialized microporous polypropylene membrane. This fascinating membrane was fabricated via a relatively eco-friendly and cost effective method and is an alternative, promising separator for high-power LIBs. PMID- 28560866 TI - Stretchable Piezoelectric Substrate Providing Pulsatile Mechanoelectric Cues for Cardiomyogenic Differentiation of Mesenchymal Stem Cells. AB - Ex vivo induction of cardiomyogenic differentiation of mesenchymal stem cells (MSCs) before implantation would potentiate therapeutic efficacy of stem cell therapies for ischemic heart diseases because MSCs rarely undergo cardiomyogenic differentiation following implantation. In cardiac microenvironments, electric pulse and cyclic mechanical strain are sequentially produced. However, no study has applied the pulsatile mechanoelectric cues (PMEC) to stimulate cardiomyogenic differentiation of MSCs ex vivo. In this study, we developed a stretchable piezoelectric substrate (SPS) that can provide PMEC to human MSCs (hMSCs) for cardiomyogenic differentiation ex vivo. Our data showed that hMSCs subjected to PMEC by SPS underwent promoted cardiac phenotype development: cell alignment and the expression of cardiac markers (i.e., cardiac transcription factors, structural proteins, ion channel proteins, and gap junction proteins). The enhanced cardiac phenotype development was mediated by the upregulation of cardiomyogenic differentiation-related autocrine factor expression, focal adhesion kinase, and extracellular signal-regulated kinases signaling pathways. Thus, SPS providing electrical and mechanical regulation of stem cells may be utilized to potentiate hMSC therapies for myocardial infarction and provide a tool for the study of stem cell biology. PMID- 28560862 TI - Low serum bilirubin level predicts the development of chronic kidney disease in patients with type 2 diabetes mellitus. AB - BACKGROUND/AIMS: We evaluated whether serum bilirubin levels can predict the development of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus (T2DM). METHODS: This was a retrospective observational longitudinal study of patients presenting at the Pusan National University Hospital. A total of 349 patients with T2DM and preserved kidney function (estimated glomerular filtration rate >= 60 mL/min/1.73 m2) were enrolled. The main outcome was the development of CKD stage 3 or greater. The patients were divided into four groups according to the quartiles of the total serum bilirubin levels at baseline. RESULTS: The group with the lowest range of total serum bilirubin level (Q1) showed the highest cumulative incidence of CKD stage 3 or greater than that of the other lower quartiles (Q1 vs. Q4; hazard ratio [HR], 6.75; 95% confidence interval [CI], 1.54 to 29.47; p = 0.011). In multivariate analysis, the risk of developing CKD stage 3 or greater was higher in the second lowest quartile of the serum bilirubin level than that in the highest quartile of the serum bilirubin level (Q2 vs. Q4; HR, 9.36; 95% CI, 1.33 to 65.73; p = 0.024). In the normoalbuminuria subgroup (n = 236), multivariate analysis showed that the risk of developing CKD stage 3 or greater was higher in the lowest quartile of the serum bilirubin level than that in the highest quartile of the serum bilirubin level (Q1 vs. Q4; HR, 7.36; 95% CI, 1.24 to 35.82; p = 0.019). CONCLUSIONS: Serum bilirubin might be an early clinical marker for predicting the progression of CKD in patients with T2DM and preserved renal function. PMID- 28560864 TI - DNA Replication Dynamics and Cellular Responses to ATP Competitive CDC7 Kinase Inhibitors. AB - The CDC7 kinase, by phosphorylating the MCM DNA helicase, is a key switch for DNA replication initiation. ATP competitive CDC7 inhibitors are being developed as potential anticancer agents; however how human cells respond to the selective pharmacological inhibition of this kinase is controversial and not understood. Here we have characterized the mode of action of the two widely used CDC7 inhibitors, PHA-767491 and XL-413, which have become important tool compounds to explore the kinase's cellular functions. We have used a chemical genetics approach to further characterize pharmacological CDC7 inhibition and CRISPR/CAS9 technology to assess the requirement for kinase activity for cell proliferation. We show that, in human breast cells, CDC7 is essential and that CDC7 kinase activity is formally required for proliferation. However, full and sustained inhibition of the kinase, which is required to block the cell-cycle progression with ATP competitor compounds, is problematic to achieve. We establish that MCM2 phosphorylation is highly sensitive to CDC7 inhibition and, as a biomarker, it lacks in dynamic range since it is easily lost at concentrations of inhibitors that only mildly affect DNA synthesis. Furthermore, we find that the cellular effects of selective CDC7 inhibitors can be altered by the concomitant inhibition of cell-cycle and transcriptional CDKs. This work shows that DNA replication and cell proliferation can occur with reduced CDC7 activity for at least 5 days and that the bulk of DNA synthesis is not tightly coupled to MCM2 phosphorylation and provides guidance for the development of next generation CDC7 inhibitors. PMID- 28560865 TI - Understanding the Critical Role of the Ag Nanophase in Boosting the Initial Reversibility of Transition Metal Oxide Anodes for Lithium-Ion Batteries. AB - The initial reversible capacity, a critical impediment in transition metal oxide based anodes, is augmented in conversion-reaction-involved CoO anodes for lithium ion batteries, by incorporating a chemically synthesized Ag nanophase. With an increase in the added amount of Ag nanophase from 5 to 15 wt %, the initial capacity loss decreases linearly up to 31.7%. The Ag nanophase maintains its pristine metallic nature without undergoing phase transformations, even during repeated vigorous electrochemical reactions of the active CoO phase. Complementary ex situ chemical/physical analyses suggest that the Ag nanophase promotes the catalytic generation of reversible gel-like/polymeric films wherein lithium ions are stored capacitively in the low-voltage region below 0.7 V during discharging. These scientific findings would provide a heretofore unrecognized pathway to resolving a major issue associated with the critical irreversibility in conversion-type transition metal oxide anodes. PMID- 28560867 TI - Quasi-Two-Dimensional h-BN/beta-Ga2O3 Heterostructure Metal-Insulator Semiconductor Field-Effect Transistor. AB - beta-gallium oxide (beta-Ga2O3) and hexagonal boron nitride (h-BN) heterostructure-based quasi-two-dimensional metal-insulator-semiconductor field effect transistors (MISFETs) were demonstrated by integrating mechanical exfoliation of (quasi)-two-dimensional materials with a dry transfer process, wherein nanothin flakes of beta-Ga2O3 and h-BN were utilized as the channel and gate dielectric, respectively, of the MISFET. The h-BN dielectric, which has an extraordinarily flat and clean surface, provides a minimal density of charged impurities on the interface between beta-Ga2O3 and h-BN, resulting in superior device performances (maximum transconductance, on/off ratio, subthreshold swing, and threshold voltage) compared to those of the conventional back-gated configurations. Also, double-gating of the fabricated device was demonstrated by biasing both top and bottom gates, achieving the modulation of the threshold voltage. This heterostructured wide-band-gap nanodevice shows a new route toward stable and high-power nanoelectronic devices. PMID- 28560868 TI - Metabolic Design of Corynebacterium glutamicum for Production of l-Cysteine with Consideration of Sulfur-Supplemented Animal Feed. AB - l-Cysteine is a valuable sulfur-containing amino acid widely used as a nutrition supplement in industrial food production, agriculture, and animal feed. However, this amino acid is mostly produced by acid hydrolysis and extraction from human or animal hairs. In this study, we constructed recombinant Corynebacterium glutamicum strains that overexpress combinatorial genes for l-cysteine production. The aims of this work were to investigate the effect of the combined overexpression of serine acetyltransferase (CysE), O-acetylserine sulfhydrylase (CysK), and the transcriptional regulator CysR on l-cysteine production. The CysR overexpressing strain accumulated approximately 2.7-fold more intracellular sulfide than the control strain (empty pMT-tac vector). Moreover, in the resulting CysEKR recombinant strain, combinatorial overexpression of genes involved in l-cysteine production successfully enhanced its production by approximately 3.0-fold relative to that in the control strain. This study demonstrates a biotechnological model for the production of animal feed supplements such as l-cysteine using metabolically engineered C. glutamicum. PMID- 28560869 TI - Quantitation of Rotundone in Grapefruit (Citrus paradisi) Peel and Juice by Stable Isotope Dilution Assay. AB - Aroma extract dilution analyses of the aromas of peels and juices of white and pink grapefruits revealed that rotundone, responsible for peppery, spicy, and woody odors, was detected for the first time at high flavor dilution factors of 256-1024. In both juices, rotundone was detected at the highest flavor dilution factor of 1024. Rotundone in grapefruits was quantitated by a stable isotope dilution assay with a newly synthesized deuterium-labeled internal standard, rotundone-d2,3: its levels were 2180 and 1920 ng/kg in white and pink grapefruit peels and 29.6 and 49.8 ng/kg in white and pink grapefruit juices, respectively. On the basis of these results, sensory analysis was performed to assess the effects of rotundone on a white grapefruit juice aroma reconstitute. This sensory analysis revealed that rotundone does not impart a woody odor or affect any of the existing attributes, but increases various attributes, thus confirming that rotundone is indispensable for the aroma of grapefruit juice. PMID- 28560870 TI - Balanced Ambipolar Organic Field-Effect Transistors by Polymer Preaggregation. AB - Ambipolar organic field-effect transistors (OFETs) based on heterojunction active films still suffer from an imbalance in the transport of electrons and holes. This problem is related to an uncontrolled phase separation between the donor and acceptor organic semiconductors in the thin films. In this work, we have developed a concept to improve the phase separation in heterojunction transistors to enhance their ambipolar performance. This concept is based on preaggregation of the donor polymer, in this case poly(3-hexylthiophene) (P3HT), before solution mixing with the small-molecular-weight acceptor, phenyl-C61-butyric acid methyl ester (PCBM). The resulting heterojunction transistor morphology consists of self assembled P3HT fibers embedded in a PCBM matrix, ensuring balanced mobilities reaching 0.01 cm2/V s for both holes and electrons. These are the highest mobility values reported so far for ambipolar OFETs based on P3HT/PCBM blends. Preaggregation of the conjugated polymer before fabricating binary blends can be regarded as a general concept for a wider range of semiconducting systems applicable in organic electronic devices. PMID- 28560871 TI - Forecasting Chronic Diseases Using Data Fusion. AB - Data fusion, that is, extracting information through the fusion of complementary data sets, is a topic of great interest in metabolomics because analytical platforms such as liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy commonly used for chemical profiling of biofluids provide complementary information. In this study, with a goal of forecasting acute coronary syndrome (ACS), breast cancer, and colon cancer, we jointly analyzed LC-MS, NMR measurements of plasma samples, and the metadata corresponding to the lifestyle of participants. We used supervised data fusion based on multiple kernel learning and exploited the linearity of the models to identify significant metabolites/features for the separation of healthy referents and the cases developing a disease. We demonstrated that (i) fusing LC-MS, NMR, and metadata provided better separation of ACS cases and referents compared with individual data sets, (ii) NMR data performed the best in terms of forecasting breast cancer, while fusion degraded the performance, and (iii) neither the individual data sets nor their fusion performed well for colon cancer. Furthermore, we showed the strengths and limitations of the fusion models by discussing their performance in terms of capturing known biomarkers for smoking and coffee. While fusion may improve performance in terms of separating certain conditions by jointly analyzing metabolomics and metadata sets, it is not necessarily always the best approach as in the case of breast cancer. PMID- 28560872 TI - Correction to "Photoreductive Elimination of Chlorine from Antimony in an [SbPd]VII Complex". PMID- 28560873 TI - Enantioselective Synthesis of Tetrahydropyridines/Piperidines via Stepwise [4 + 2]/[2 + 2] Cyclizations. AB - A phosphine-catalyzed novel enantioselective [4 + 2]-annulation reaction between allene ketones and 1-azadienes has been developed, and tetrahydropyridines were obtained in good yields and with excellent enantioselectivities. Subsequent exposure of tetrahydropyridines to benzyne leads to a [2 + 2]-cyclization, creating optically enriched polycyclic piperidines with a quaternary stereogenic center and a cyclobutene moiety. The reported stepwise [4 + 2]/[2 + 2] cycloadditions represent a new approach to access enantiomerically enriched nitrogen-containing six-membered ring systems. PMID- 28560874 TI - Single Biosensor for Simultaneous Quantification of Glucose and pH in a Rat Brain of Diabetic Model Using Both Current and Potential Outputs. AB - Glucose and pH are two important indicators of diabetes mellitus. However, their dynamic changes at the same time in brain are still not clear, mainly due to a lack of a single biosensor capable of simultaneous quantification of two species in a live rat brain. In this work, a selective and sensitive ratiometric electrochemical biosensor was developed for simultaneously quantifying glucose and pH using both current and potential outputs in a rat brain of diabetic model. Here, glucose oxidase was first employed as a specific recognition element for both glucose and pH because the active center (FAD) could undergo a 2H+/2e- process. Moreover, an insensitive molecule toward pH and glucose was used as an inner-reference element to provide a built-in correction to improve the accuracy. The ratio between the oxidation peak current density of glucose and that of ABTS gradually increased with increasing concentration of glucose, and showed a good linearity in the range of 0.3-8.2 mM. Meanwhile, the midpotential difference between glucose oxidase and 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) positively shifted with pH decreasing, leading to accurate determination of pH in the linear range of 5.67-7.65. Thus, combined with the unique properties of carbon fiber microelectrode, including easy to insert and good biocompatibility, the developed single biosensor was successfully applied to detect pH and glucose at the same time in hippocampus, striatum, and cortex in a live rat brain of diabetic model. PMID- 28560875 TI - Cobalt(III)-Catalyzed C-H Activation: Azo Directed Selective 1,4-Addition of Ortho C-H Bond to Maleimides. AB - Highly selective azo directed 1,4-addition of an ortho C-H bond to maleimides has been developed using Co(III) catalyst. This reaction furnishes 3-arylated succinimide derivatives in good yields with excellent selectivity. This protocol exhibits a broad substrate scope and is compatible with symmetrical and unsymmetrical azobenzene derivatives, with maleimides and maleate esters. Preliminary deuterium incorporation studies have been performed to understand the mechanism of the reaction. PMID- 28560876 TI - Facile and Large-Area Preparation of Porous Ag3PO4 Photoanodes for Enhanced Photoelectrochemical Water Oxidation. AB - Photoelectrochemical (PEC) water splitting is a promising approach for renewable energy, where the development of efficient photoelectrodes, especially photoanodes for water oxidation is still challenging. In this paper, we report the novel solution-processed microcrystalline Ag3PO4 photoanodes with tunable porosity depending on the reaction time. These porous Ag3PO4 films were grown on large-area (4.5 * 4.5 cm2) silver substrates via an air-exposed and room temperature immersion reaction. Enhanced light absorption abilities were exhibited by the synthesized Ag3PO4 films with optimized porosity resulted from prolonged reaction times (>=20 h), due to which appreciable water splitting performance was demonstrated when they were utilized as photoanodes. Particularly, the highly porous 20 h Ag3PO4 photoanode presented a photocurrent density of around 4.32 mA/cm2, which is nearly three times higher than that of the nonporous 1 h Ag3PO4 photoanode (1.48 mA/cm2) at 1 V vs Ag/AgCl. Moreover, superior stability of the 20 h Ag3PO4 photoanode has also been confirmed by the 5 h successive PEC water splitting experiment. Therefore, both the scalable and facile fabrication method, and considerable photoactivity and stability of these Ag3PO4 photoanodes together suggest their great potential for efficient solar-to fuel energy conversion and other PEC applications. PMID- 28560877 TI - Formation of Germa-ketenimine on the Ge(100) Surface by Adsorption of tert-Butyl Isocyanide. AB - Reactions of the (100) surfaces of Ge and Si with organic molecules have been generally understood within the concept of "dimers" formed by the 2 * 1 surface reconstruction. In this work, the adsorption of tert-butyl isocyanide on the Ge(100)-2 * 1 surface at large exposures is investigated under ultrahigh vacuum conditions. A combination of infrared spectroscopy, X-ray photoelectron spectroscopy, and temperature-programmed desorption experiments along with dispersion-corrected density functional theory calculations is used to determine the surface products. Upon adsorption of a dense monolayer of tert-butyl isocyanide, a product whose structure resembles a germa-ketenimine (N=C=Ge) with sigma donation toward and pi back-donation from the Ge(100) surface appears. Formation of this structure involves divalent-type surface Ge atoms that arise from cleavage of the Ge(100)-2 * 1 surface dimers. Our results reveal an unprecedented class of reactions of organic molecules at the Ge(100) surface. PMID- 28560879 TI - What Is Required for Highly Oxidized Molecules To Form Clusters with Sulfuric Acid? AB - We have studied the specific requirements of a given neutral organic molecule to act as a stabilizer in sulfuric acid induced new particle formation. Based on an analysis of the reaction Gibbs free energies between simple functional groups and sulfuric acid, carboxylic acid groups are identified to show the strongest hydrogen bonding interaction with sulfuric acid. The free energy associated with the hydrogen bonding between sulfuric acid and 14 different carboxylic acids of atmospheric relevance reveal that the binding strength is very dependent on the ability of sulfuric acid to form an additional hydrogen bond via its vacant S-OH group to a gamma-carbonyl group in the organic molecule. Extending the analysis to monoterpene oxidation products and further to large dimer esters, we identify the following necessary criteria for a given organic oxidation product to efficiently stabilize sulfuric acid clustering: (1) weak or no intramolecular hydrogen bonds in the isolated monomer; (2) more than two carboxylic acid groups. As a proof of concept we show that these requirements correspond to the docking of a sulfuric acid molecule between two non-interacting carboxylic acid groups in the organic molecule. These findings suggests that, for a given organic oxidation product to participate in the initial steps in new particle formation involving sulfuric acid, very distinct molecular features are required. PMID- 28560878 TI - Serial Metabolome Changes in a Prospective Cohort of Subjects with Influenza Viral Infection and Comparison with Dengue Fever. AB - Influenza virus infection (IVI) and dengue virus infection (DVI) are major public health threats. Between IVI and DVI, clinical symptoms can be overlapping yet infection-specific, but host metabolome changes are not well-described. Untargeted metabolomics and targeted oxylipinomic analyses were performed on sera serially collected at three phases of infection from a prospective cohort study of adult subjects with either H3N2 influenza infection or dengue fever. Untargeted metabolomics identified 26 differential metabolites, and major perturbed pathways included purine metabolism, fatty acid biosynthesis and beta oxidation, tryptophan metabolism, phospholipid catabolism, and steroid hormone pathway. Alterations in eight oxylipins were associated with the early symptomatic phase of H3N2 flu infection, were mostly arachidonic acid-derived, and were enriched in the lipoxygenase pathway. There was significant overlap in metabolome profiles in both infections. However, differences specific to IVI and DVI were observed. DVI specifically attenuated metabolites including serotonin, bile acids and biliverdin. Additionally, metabolome changes were more persistent in IVI in which metabolites such as hypoxanthine, inosine, and xanthine of the purine metabolism pathway remained significantly elevated at 21-27 days after fever onset. This study revealed the dynamic metabolome changes in IVI subjects and provided biochemical insights on host physiological similarities and differences between IVI and DVI. PMID- 28560881 TI - Stable, Fluorescent Polymethylmethacrylate Particles for the Long-Term Observation of Slow Colloidal Dynamics. AB - Suspensions of solid micron-scale colloidal particles in liquid solvents are a foundational model system used to explore a wide range of phase transitions, including crystallization, gelation, spinodal decomposition, and the glass transition. One of the most commonly used systems for these investigations is the fluorescent spherical particles of polymethylmethacrylate (PMMA) suspended in a mixture of nonpolar solvents that match the density and the refractive index of the particles to minimize sedimentation and scattering. However, the particles can swell in these solvents, changing their size and density, and may leak the fluorescent dye over days to weeks; this constrains the exploration of slow and kinetically limited processes, such as near-boundary phase separation or the glass transition. In this paper, we produce PMMA colloidal particles that employ polymerizable and photostable cyanine-based fluorescent monomers spanning the range of visible wavelengths and a polymeric stabilizer prepared from polydimethylsiloxane, PDMS-graft-PMMA. Using microcalorimetry, we characterize the thermodynamics of an accelerated equilibration process for these dispersions in the buoyancy- and refractive-index-matching solvents. We use confocal differential dynamic microscopy to demonstrate that they behave as hard spheres. The suspended particles are stable for months to years, maintaining fixed particle size and density, and do not leak dye. Thus, these particles enable longer term experiments than may have been possible earlier; we demonstrate this by observing spinodal decomposition in a mixture of these particles with a depletant polymer in the microgravity environment of the International Space Station. Using fluorescence microscopy, we observe coarsening over several months and measure the growth of the characteristic length scale to be a fraction of a picometer per second; this rate is among the slowest observed in a phase separating system. Our protocols should facilitate the synthesis of a variety of particles. PMID- 28560880 TI - Quantitative Proteomics Analysis Confirmed Oxidative Metabolism Predominates in Streptomyces coelicolor versus Glycolytic Metabolism in Streptomyces lividans. AB - Recent physiological studies indicated that S. lividans metabolism was mainly glycolytic, whereas S. coelicolor metabolism was mainly oxidative. To determine whether such metabolic characteristics were correlated with consistent proteomics features, a comparative label-free, shotgun proteomics analysis of these strains was carried out. Among 2024 proteins identified, 360 showed significant differences in abundance between the strains. This study revealed that S. coelicolor catabolized glucose less actively than S. lividans, whereas the amino acids present in the medium were catabolized less actively by S. lividans than by S. coelicolor. The abundance of glycolytic proteins in S. lividans was consistent with its high glycolytic activity, whereas the abundance of proteins involved in the catabolism of amino acids in S. coelicolor provided an explanatory basis for its predominantly oxidative metabolism. In this study, conducted under conditions of low O2 availability, proteins involved in resistance to oxidative stress and those belonging to a DosR-like dormancy regulon were abundant in S. coelicolor, whereas tellurium resistance proteins were abundant in S. lividans. This indicated that the strains reacted differently to O2 limitation. Proteins belonging to the CDA, RED, and ACT pathways, usually highly expressed in S. coelicolor, were not detected under these conditions, whereas proteins of siderophores, 5-hydroxyectoine, and terpenoid biosynthetic pathways were present. PMID- 28560882 TI - Gambling disorder: Association between duration of illness, clinical, and neurocognitive variables. AB - Background and aims Gambling disorder (GD) may have its onset in a wide range of ages, from adolescents to old adults. In addition, individuals with GD tend to seek treatment at different moments in their lives. As a result of these characteristics (variable age at onset and variable age at treatment seeking), we find subjects with diverse duration of illness (DOI) in clinical practice. DOI is an important but relatively understudied factor in GD. Our objective was to investigate clinical and neurocognitive characteristics associated with different DOI. Methods This study evaluated 448 adults diagnosed with GD. All assessments were completed prior to treatments being commenced. Results Our main results were: (a) there is a negative correlation between DOI and lag between first gambling and onset of GD; (b) lifetime history of alcohol use disorder (AUD) is associated with a longer duration of GD; (c) the presence of a first-degree relative with history of AUD is associated with a more extended course of GD; and (d) there is a negative correlation between DOI and quality of life. Discussion This study suggests that some important variables are associated with different DOI. Increasing treatment-seeking behavior, providing customized psychological interventions, and effectively managing AUD may decrease the high levels of chronicity in GD. Furthermore, research on GD such as phenomenological studies and clinical trials may consider the duration of GD in their methodology. DOI might be an important variable when analyzing treatment outcome and avoiding confounders. PMID- 28560883 TI - A deletion mutation in nfxB of in vitro-induced moxifloxacin-resistant Pseudomonas aeruginosa confers multidrug resistance. AB - The modulation of efflux pump functions under fluoroquinolone (FQ) exposure is of great concern as it could result in occurrence of multidrug-resistant (MDR) bacterial strains. In this study, MDR mechanism in Pseudomonas aeruginosa induced via moxifloxacin (MOX) pressure was investigated. After serial MOX [concentration of 0.5 * the minimum inhibitory concentration (MIC)] exposure, the fully susceptible P. aeruginosa ATCC 9027 strain has increased its MIC not only toward MOX (1->128 mg/L) but also to other antibiotics. Furthermore, this MOX-exposed strain did not revert to antibiotic-sensitive phenotype when being cultured in antibiotic-free medium for 12 days. No mutation was observed for FQ-target (gyrA and parC) or most investigated efflux regulatory genes (mexT, mexR, and nalC) except nfxB in which a 100-bp deletion was found. This associated with the elevated expression of multidrug efflux pump operon (mexCD-oprJ) which could directly result in MDR phenotype. PMID- 28560885 TI - Research in health information management: An expanding field of enquiry. PMID- 28560884 TI - Dual antiplatelet therapy duration in patients following percutaneous coronary intervention or after acute coronary syndrome: one size does not fit all. PMID- 28560886 TI - Ultrasound-Guided Thrombin Injection Is a Safe and Effective Treatment for Femoral Artery Pseudoaneurysm in the Morbidly Obese. AB - INTRODUCTION: Ultrasound-guided thrombin injection (UGTI) is a well-established practice for the treatment of femoral artery pseudoaneurysm. This procedure is highly successful but dependent on appropriate pseudoaneurysm anatomy and adequate ultrasound visualization. Morbid obesity can present a significant technical challenge due to increased groin adiposity, resulting in poor visualization of critical structures needed to safely perform the procedure. We aim to evaluate the safety and efficacy of UGTI to treat femoral artery pseudoaneurysm in the morbidly obese. METHODS: This is a retrospective cohort study in which all patients who underwent UGTI at The Ohio State University Ross Heart Hospital from 2009 to 2014 were analyzed for patient characteristics and stratified by body mass index (BMI). Patients with BMI >= 35 were considered morbidly obese and were compared to patients with a BMI < 35. Outcome was failed treatment resulting in residual pseudoaneurysm. RESULTS: Our cohort consisted of 54 patients who underwent thrombin injection. There were 41 nonmorbidly obese and 13 morbidly obese patients. Mean age was 64.5 years. The cohort was 44.4% male. There were 6 failures, of which 1 underwent successful repeat injection and 5 underwent open surgical repair. There was no statistically significant difference in failure between nonmorbidly obese and morbidly obese patients (9.8% vs 15.4%, P = .45). There were no embolic/thrombotic complications. CONCLUSION: Ultrasound guided thrombin injection is a safe and effective therapy in the morbidly obese for the treatment of femoral artery pseudoaneurysm. In the hands of experienced sonographers and surgeons with adequate visualization of the pseudoaneurysm sac, UGTI should remain a standard therapy in the morbidly obese. PMID- 28560887 TI - The gut microbiome and cardiovascular risk: current perspective and gaps of knowledge. PMID- 28560888 TI - The evolution of acute burn care - retiring the split skin graft. AB - The skin graft was born in 1869 and since then, surgeons have been using split skin grafts for wound repair. Nevertheless, this asset fails the big burn patient, who deserves an elastic, mobile and robust outcome but who receives the poorest possible outcome based on donor site paucity. Negating the need for the skin graft requires an autologous composite cultured skin and a material capable of temporising the burn wound for four weeks until the composite is produced. A novel, biodegradable polyurethane chemistry has been used to create two such products. This paper describes the design, production, optimisation and evaluation of several iterations of these products. The evaluation has occurred in a variety of models, both in vitro and in vivo, employing Hunterian scientific principles, and embracing Hunter's love and appreciation of comparative anatomy. The process has culminated in significant human experience in complex wounds and extensive burn injury. Used serially, the products offer robust and elastic healing in deep burns of any size within 6 weeks of injury. PMID- 28560891 TI - Expression of Foxp3 and its prognostic significance in colorectal cancer. AB - The aim of this study was to explore the expression and clinical significance of Foxp3 in colorectal tumor cells. An immunohistochemistry assay was used to detect the expression of Foxp3 in 173 cases of colorectal cancer. The relationship between the clinicopathological factors and the prognosis of colorectal cancer was analyzed. The rate of positive Foxp3 expression in tumor cells was 89.7%. There were no significant differences between cases with and without expression of Foxp3 with regard to sex, age, primary cancer sites, and distal metastasis. The expression of Foxp3 was negatively correlated with lymph node metastasis and pathological tumor, node, metastasis (pTNM) stage in tumor cells ( P < 0.05), which reflects the depth of invasion. Foxp3 expression also had a positive correlation with the degree of differentiation ( P < 0.01). A high level of Foxp3 expression was observed more often in tumor cells compared to tumor-surrounding tissues ( P = 0.003). High expression of Foxp3 was also associated with longer overall and disease-free survival ( P ? 0.001). Foxp3 expression in colorectal cancer cells correlates with many clinicopathological characteristics; moreover, high expression of Foxp3 may be a promising potential prognostic factor for patients with colorectal cancer. PMID- 28560889 TI - Association of HIV/AIDS Clinician Warm Line Utilization with Diagnosis and Management of Antiretroviral Treatment Failure in Mozambique: A Retrospective Analysis of Program Data. AB - In accordance with global HIV/AIDS goals, Mozambique is attempting to improve management of antiretroviral treatment failure (TF). We sought to determine whether the utilization of a national HIV/AIDS clinician telephone consultation service increased recognition and reporting of TF. In a retrospective analysis of routinely collected program data from telephone consultation logs and Mozambique's national registry of second-line antiretroviral requests, we used linear mixed methods to describe the association between TF-related telephone consultations and submission of second-line requests, which required documentation of the TF diagnosis. The unit of analysis was the health facility. Available data included 1417 consultations (390 [27.5%] TF related) and 2662 second-line requests from 1011 health units (2015-2016 data). In multivariable analyses, each TF-related consultation was associated with an increase of 0.61 (95% confidence interval 0.15 to 1.06) second-line requests. In this setting, TF related telephone consultation was positively and significantly associated with diagnosis and reporting of antiretroviral TF. PMID- 28560893 TI - Physical Fitness and Frailty Syndrome in Institutionalized Older Women. AB - Associations between frailty and physical-functional fitness (PFF) indicators in frail women over 65 years of age remain largely unexplored. This study analyzed the relationship between frailty syndrome (FS) and PFF indicators and assessed how the latter might predict the former. Participants were 119 elderly women (81.96 +/- 7.89 years) recruited from four social and healthcare centers. PFF was assessed through muscle strength tests of upper and lower limbs, endurance, agility-dynamic balance, flexibility, and body composition. The following FS indicators were assessed: weight loss, exhaustion, weakness, slowness, and low physical activity level. Significant correlations were found between FS and endurance, agility-dynamic balance, upper and lower limbs muscle strength tests. Comparitive analyses also revealed that, among FS groups, the frail subgroup performed significantly poorer on all PFF measures except body composition. Additionally, a receiving operating characteristics curve analysis revealed good diagnostic accuracy for predicting FS using the agility-dynamic balance test (Area Under Curve [AUC] = .82, 95% CI [0.74, 0.90]; sensitivity and specificity were 70.4% and 84.8% for the cutoff = 16.22 seconds). Accurately, the risk of frail condition (not pre-frail) increases about 2.12% per second spent in this test. Thus, the agility-dynamic balance test is a promising tool for screening institutionalized older people for risk of FS. PMID- 28560892 TI - Self-Reported Versus Accelerometer-Assessed Daily Physical Activity in Childhood Obesity Treatment. AB - We investigated the relationship between interview-based subjective ratings of physical activity (PA) engagement and accelerometer-assessed objectively measured PA in children and adolescents with overweight or obesity. A total of 92 children and adolescents (40 males, 52 females) with BMI >= 90th percentile for sex and age, aged 5-17 years had valid GT3X + accelerometer-assessed PA and interview assessed self-reported information on PA engagement at the time of enrollment in a multidisciplinary outpatient tertiary treatment for childhood obesity. Accelerometer-derived mean overall PA and time spent in moderate to vigorous physical intensity were generated, applying cut-offs based on Vector Magnitude settings as defined by Romanzini et al. (2014), and a physical activity score (PAS) based on self-reported data. Overall, a higher self-reported PAS was correlated with higher accelerometer-assessed daily total PA levels ( r = 0.34, p < .01) and children who reported a high PAS were more physically active compared with children who reported a low PAS. There was a fair level of agreement between self-reported PAS and accelerometer-assessed PA (Kappa agreement = 0.23; 95% CI = [0.03, 0.43]; p = .01). PAS, derived from self-report, may be a useful instrument for evaluating PA at a group level among children and adolescents enrolled in multidisciplinary obesity treatment. PMID- 28560895 TI - Age Diversity in the Workplace: The Effect of Relational Age Within Supervisor Employee Dyads on Employees' Work Engagement. AB - Although having a younger supervisor or a supervisor of a similar age runs counter to the traditional older supervisor-younger subordinate norm, it is becoming increasingly common in the 21st-century workplace. The current study uses theories of relational demography and relational norms as well as Selective Optimization with Compensation theory and the job demands-resources model to understand how relational age within supervisor-employee dyads influences workers' engagement. Cross-sectional data from a multiworksite (U.S.-based) sample of 2,195 workers aged 18 to 81 years were used to estimate ordinary least squares regression models. After accounting for a variety of factors that could influence engagement levels (i.e., demographics, health status, and job or personal resources), findings indicated that employees with similar-age supervisors were less engaged than employees with older supervisors. Moreover, while employees who did not know the ages of their supervisors were just as engaged as employees with older supervisors. Implications for engaging an age diverse workforce are discussed. PMID- 28560894 TI - Growth of Verticillium longisporum in Xylem Sap of Brassica napus is Independent from Cultivar Resistance but Promoted by Plant Aging. AB - As Verticillium stem striping of oilseed rape (OSR), a vascular disease caused by Verticillium longisporum, is extending into new geographic regions and no control with fungicides exists, the demand for understanding mechanisms of quantitative resistance increases. Because V. longisporum is strictly limited to the xylem and resistance is expressed in the systemic stage post root invasion, we investigated a potential antifungal role of soluble constituents and nutritional conditions in xylem sap as determinants of cultivar resistance of OSR to V. longisporum. Assessment of biometric and molecular genetic parameters applied to describe V. longisporum resistance (net area under disease progress curve, stunting, stem thickness, plant biomass, and V. longisporum DNA content) showed consistent susceptibility of cultivar 'Falcon' in contrast to two resistant genotypes, 'SEM' and 'Aviso'. Spectrophotometric analysis revealed a consistently stronger in vitro growth of V. longisporum in xylem sap extracted from OSR compared with the water control. Further comparisons of fungal growth in xylem sap of different cultivars revealed the absence of constitutive or V. longisporum induced antifungal activity in the xylem sap of resistant versus susceptible genotypes. The similar growth of V. longisporum in xylem sap, irrespective of cultivar, infection with V. longisporum and xylem sap filtration, was correlated with about equal amounts of total soluble proteins in xylem sap from these treatments. Interestingly, compared with younger plants, xylem sap from older plants induced significantly stronger fungal growth. Growth enhancement of V. longisporum in xylem sap of aging plants was reflected by increased contents of carbohydrates, which was consistent in mock or V. longisporum-infected plants and independent from cultivar resistance. The improved nutritional conditions in the xylem of more mature plants may explain the late appearance of disease symptoms, which are observed only in late maturity stages of plants in the field. While falsifying the presence of antifungal activity in xylem sap of resistant cultivars, this study strengthens previous findings that indicated a significant role of physical cell wall bound resistance factors involved in quantitative, cultivar-related resistance of B. napus to V. longisporum. PMID- 28560896 TI - Bayesian two-part bent-cable Tobit models with skew distributions: Application to AIDS studies. AB - This paper presents a new development of a bent-cable two-part Tobit model to identify both phasic patterns and mixture of advancing (to AIDS) and non advancing patients of HIV. In identification of such phasic patterns, estimation of a transition period for the development of drug resistance to antiretroviral (ARV) drug or therapy is carried out using longitudinal data that have a gradual change from a declining phase to an increasing phase. In addition to phasic changes, there are also problems of skewness and left-censoring in the response variable because of a lower limit of detection. A relatively large percentage of data below limit of detection are recorded more than expected under an assumed skew-distribution. To properly accommodate these features, we present an extension of the random effects bent-cable Tobit model that incorporates a mixture of true undetectable observations and those values from a skew-normal distribution for a response with left-censoring, skewness and phasic patterns. The proposed methods are illustrated using real data from an AIDS clinical study. PMID- 28560897 TI - Fructosamine: A Negative Acute Phase Reactant. PMID- 28560899 TI - Shared Electronic Health Record Systems: Key Legal and Security Challenges. AB - Use of shared electronic health records opens a whole range of new possibilities for flexible and fruitful cooperation among health personnel in different health institutions, to the benefit of the patients. There are, however, unsolved legal and security challenges. The overall aim of this article is to highlight legal and security challenges that should be considered before using shared electronic cooperation platforms and health record systems to avoid legal and security "surprises" subsequent to the implementation. Practical lessons learned from the use of a web-based ulcer record system involving patients, community nurses, GPs, and hospital nurses and doctors in specialist health care are used to illustrate challenges we faced. Discussion of possible legal and security challenges is critical for successful implementation of shared electronic collaboration systems. Key challenges include (1) allocation of responsibility, (2) documentation routines, (3) and integrated or federated access control. We discuss and suggest how challenges of legal and security aspects can be handled. This discussion may be useful for both current and future users, as well as policy makers. PMID- 28560898 TI - A Systematic Review of Reviews Evaluating Technology-Enabled Diabetes Self Management Education and Support. AB - BACKGROUND: Since the introduction of mobile phones, technology has been increasingly used to enable diabetes self-management education and support. This timely systematic review summarizes how currently available technology impacts outcomes for people living with diabetes. METHODS: A systematic review of high quality review articles and meta analyses focused on utilizing technology in diabetes self-management education and support services was conducted. Articles were included if published between January 2013 and January 2017. RESULTS: Twenty five studies were included for analysis. The majority evaluated the use of mobile phones and secure messaging. Most studies described healthy eating, being active and metabolic monitoring as the predominant self-care behaviors evaluated. Eighteen of 25 reviews reported significant reduction in A1c as an outcome measure. Four key elements emerged as essential for improved A1c: (1) communication, (2) patient-generated health data, (3) education, and (4) feedback. CONCLUSION: Technology-enabled diabetes self-management solutions significantly improve A1c. The most effective interventions incorporated all the components of a technology-enabled self-management feedback loop that connected people with diabetes and their health care team using 2-way communication, analyzed patient-generated health data, tailored education, and individualized feedback. The evidence from this systematic review indicates that organizations, policy makers and payers should consider integrating these solutions in the design of diabetes self-management education and support services for population health and value-based care models. With the widespread adoption of mobile phones, digital health solutions that incorporate evidence-based, behaviorally designed interventions can improve the reach and access to diabetes self management education and ongoing support. PMID- 28560900 TI - Effect of BGM Accuracy on the Clinical Performance of CGM: An In-Silico Study. AB - BACKGROUND: Standard management of type 1 diabetes (T1D) relies on blood glucose monitoring based on a range of technologies from self-monitoring of blood glucose (BGM) to continuous glucose monitoring (CGM). Even as CGM technology matures, patients utilize BGM for calibration and dosing. The question of how the accuracy of both technologies interact is still not well understood. METHODS: We use a recently developed data-driven simulation approach to characterize the relationship between CGM and BGM accuracy especially how BGM accuracy impacts CGM performance in four different use cases with increasing levels of reliance on twice daily calibrated CGM. Simulations are used to estimate clinical outcomes and isolate CGM and BGM accuracy characteristics that drive performance. RESULTS: Our results indicate that meter (BGM) accuracy, and more specifically systematic positive or negative bias, has a significant effect on clinical performance (HbA1c and severe hypoglycemia events) in all use-cases generated for twice daily calibrated CGMs. Moreover, CGM sensor accuracy can amplify or mitigate, but not eliminate these effects. CONCLUSION: As a system, BGM and CGM and their mode of use (use-case) interact to determine clinical outcomes. Clinical outcomes (eg, HbA1c, severe hypoglycemia, time in range) can be closely approximated by linear relationships with two BGM accuracy characteristics, namely error and bias. In turn, the coefficients of this linear relationship are determined by the use-case and by CGM accuracy (MARD). PMID- 28560902 TI - Changing people's perceptions and creating a vibrant learning environment. AB - There has been a long-standing perception that care homes are a backwater for nursing careers, largely due to inequity in accessing workplace training opportunities compared with those in the NHS. PMID- 28560903 TI - 'Susan and Dena's vision, hard work and enthusiasm were unbeatable'. AB - Susan Wills and Dena Ross have reduced unplanned and avoidable admissions by supporting the carers to manage residents safely in their nursing homes. PMID- 28560901 TI - New Faces of HIV Infection: Age, Race, and Timing of Entry into HIV Care in the Southeastern United States. AB - Among younger men who have sex with men (MSM), the incidence of HIV is rising nationally. Of the 281 persons who entered into care at a large HIV clinic in the southeastern United States in 2010 to 2012, 78 (27.8%) were <25 years old at the time of diagnosis. Those in the younger group were more likely than those aged >=25 to be black (59.0% versus 37.4%), MSM (78.2% versus 55.2%), and to have a longer median time from diagnosis to entry into care (71 versus 53 days; P < .05 each). In adjusted survival analysis, persons of black race were less likely to enter care after diagnosis than those of nonblack race (hazard ratio = 0.75, P = .02). Young MSM represent an important target population for prevention and HIV testing interventions, and there is a need to shorten the time from diagnosis to linkage to care, particularly in persons aged <25 and of black race. PMID- 28560905 TI - 'If you don't like how your service is run, say so'. AB - What is your job? I am a commissioner and a nurse, which means I have roles, such as clinical audit, that other commissioners do not have. My job involves assessing the needs of the local population, looking for gaps and filling these with the appropriate services. PMID- 28560906 TI - Beloved Old Age and What to Do About It: Margery Allingham's The Relay Handed on to Julia Jones Beloved Old Age and What to Do About It: Margery Allingham's The Relay Handed on to Julia Jones 192pp L10.99 Golden Duck 9781899262298 1899262296 [Formula: see text]. AB - This book offers the perspectives of two people caring for older family members: novelist Margery Allingham in the 1950s and her biographer Julia Jones, whose mother is in her nineties and living in supported housing, today. PMID- 28560907 TI - Joint launch of frailty resource. AB - The RCN older people's forum and RCNi have launched an online resource for nurses to help patients with frailty. PMID- 28560908 TI - Valuable online resources and outstanding nursing talent. AB - Welcome to the June issue of Nursing Older People. RCNi has recently launched an online frailty resource in conjunction with the RCN older people's forum. Access to this valuable resource is included in your subscription to the journal and I encourage you to visit it. PMID- 28560909 TI - Use 'nursing intuition' in assessments, say senior care home staff. AB - Care home nurses need to ensure they are putting patients at the heart of decisions about care from their admission onwards, according to two senior nurses in the field. PMID- 28560910 TI - Deconditioning due to hospitalisation. AB - Functional decline as a result of admission to hospital has been well documented since 1944. Older people are at much higher risk of deconditioning than their younger counterparts. This research focus summarises two early studies on deconditioning and one recent study that records the incidence of iatrogenic disability during hospitalisation. PMID- 28560911 TI - Story in numbers. AB - Ageing in the 21st century. PMID- 28560912 TI - Hospital-associated deconditioning and dysfunction. AB - A paper published in 1991 in the Journal of the American Geriatrics Society describes hospitalisation as a 'devastating' event for an older person. This was conceptualised as stemming from three discrete processes: the illness itself, adverse effects of treatment and the general effects of deconditioning. PMID- 28560913 TI - Functional impact of ten days of bed rest in healthy older adults. AB - Kortebein and colleagues published a seminal paper in 2008 that reported a study involving 11 older participants older than 67 who underwent ten days of enforced bed rest. Such a study would not gain ethical consent today. PMID- 28560914 TI - Preventable iatrogenic disability in elderly patients during hospitalisation. AB - A French study involving 503 patients of 75 years and over reviewed the frequency, causes and preventability of disability induced by a hospital stay. PMID- 28560916 TI - 'I have Alzheimer's disease and I have a voice'. AB - I am a single woman of a certain age. I have Alzheimer's disease and I live alone without a carer. I manage as best I can, but I am often in terror of inevitable future deterioration. PMID- 28560917 TI - Caring for patients with Parkinson's disease in general hospital settings. AB - Parkinson's disease (PD) is a common progressive neurological condition. There are 127,000 people with the disease in the UK, that is, one in every 500 of the population. In 2014-15 there were 14,000 hospital admissions of people with PD in England. However, PD is often not the primary cause of admission. Urinary tract infections and pneumonia, for example, are frequent causes of hospital admission for people with PD. Therefore, nurses on general medical and surgical wards will often care for people with PD. This article aims to provide an update on PD and explore the nurse's role in assessment and provision of safe and effective care for patients with PD in acute hospital settings. PMID- 28560918 TI - '125 years of savings needed to live well'. AB - The unachievable cost of dementia care is revealed in a new report that also highlights the loneliness of carers. PMID- 28560919 TI - Short-term corticosteroid use may be associated with increased risk of adverse events. AB - The aim of this study was to determine the frequency of serious adverse events associated with corticosteroid use, specifically fracture, sepsis and venous thromboembolism (VTE). PMID- 28560920 TI - Care homes needed for new research into managing falls. AB - Academics conducting a L1.8 million research project are recruiting care homes to test a new falls procedure. Funded by the National Institute for Health Research, the three-year project involves trials of a new training package and guidelines designed by the University of Nottingham's Division of Rehabilitation and Ageing. The trials are taking place at residential and care homes in the East Midlands, West Yorkshire and East Anglia. PMID- 28560921 TI - Horse-riding simulation can be part of balance training for people with knee osteoarthritis. AB - This study explores whether simulated horse-riding exercises can help older people with osteoarthritis of the knee. PMID- 28560922 TI - International experts call for atrial fibrillation screening programme. AB - Screening programmes need to be introduced to detect irregular heart rates among older patients, according to an international collaboration of experts. PMID- 28560923 TI - Anti-tau vaccine is successful in clinical trial for people with Alzheimer's disease. AB - Alzheimer's disease progressively impairs cognition and daily function, and death usually occurs five to ten years after diagnosis. There are drugs available to treat the disease's symptoms, but they do not halt or slow its progression. PMID- 28560924 TI - Anguish at outliving our adult children. AB - 'Old age ain't no place for sissies', film star Bette Davis (pictured) once said, and how right she was. PMID- 28560925 TI - Integrated Care in Action: A Practical Guide for Health, Social Care and Housing Supports Miller Robin Brown Hilary and Mangan Catherine Integrated Care in Action: A Practical Guide for Health, Social Care and Housing Supports 232pp L22.99 Jessica Kingsley 9781849056465 1849056463 [Formula: see text]. AB - The blurb of this book suggests it is about leading, managing and delivering integrated care, but it could be applied to any kind of change in healthcare services. PMID- 28560926 TI - The value of life story work for staff, people with dementia and family members. AB - Dementia is a term used to describe a collection of symptoms that include problems with memory, self-care, reasoning and communication. Care interventions that focus on preserving people's dignity and identity are therefore essential. Using Driscoll's reflective model to guide critical thinking, this article reflects on the use of one intervention, namely life story work, to promote person-centred care for people with dementia. It explores the value or effect of life story work for healthcare staff, the person with dementia and family members. It also highlights best practice guidelines that are useful to consider to promote its optimal success as an intervention in dementia care, for example, instigating it early in the dementia journey and embedding it in a supportive culture. It is important to highlight to nursing students the many positive aspects of incorporating life story work into practice. PMID- 28560927 TI - GP services and care homes. AB - Essential facts Improving how GPs and care home staff work together is essential if residents are to receive more timely care, according to the Social Care Institute for Excellence (SCIE). PMID- 28560929 TI - Advances in percutaneous interventional therapies: the tricuspid valve. AB - Tricuspid regurgitation (TR) is a prevalent valve condition, with an estimated 1.6 million people in the USA living with moderate or greater severity. Functional TR, which predominantly develops due to left-sided heart disease, is the predominant condition affecting the tricuspid valve in the Western world and severe TR is associated with substantial morbidity and mortality. In part, due to a prolonged latency period with insidious symptoms, patients are often referred for surgery at advanced stages, with associated increased or prohibitive surgical risk. In addition, surgical treatment can result in high rates of recurrence. Therefore, there is an unmet need for percutaneous therapies that may provide a relatively low-risk treatment option. There are several devices with early human feasibility data available that will be reviewed in this article. PMID- 28560930 TI - Hand Rub Consumption Has Almost Doubled in 132 German Hospitals Over 9 Years. AB - Annual surveillance data (2007-2015), collected continuously in 132 German hospitals, was evaluated for development of alcohol-based hand-rub consumption (AHC) as a surrogate parameter for hand hygiene adherence. Overall, the median increase in AHC was 94%. The increases over 9 years were significant in all units and quartiles of AHC at baseline. Infect Control Hosp Epidemiol 2017;38:870-872. PMID- 28560931 TI - Psychosis and dementia: risk factor, prodrome, or cause? AB - BACKGROUND: Progression of dementia is often associated with the emergence of neuropsychiatric symptoms (NPS), though there is recent evidence that NPS may occur in prodromal dementia (PrD) and impact clinical course. Mood and anxiety symptoms are the NPS that tend to occur most frequently in PrD and thus have been most extensively studied. Comparatively, there has been little focus on psychotic symptoms in PrD. METHODS: The authors review the existing literature on psychosis in PrD, including the functional psychosis of early and late onset, with a focus on epidemiology, phenomenology, and clinical course and treatment considerations. RESULTS: Patients with psychotic disorders at baseline such as schizophrenia may be more at risk for developing dementia over time, although this is not completely clear. Psychotic symptoms are likely more common in PrD than previously understood based on factor analysis studies, although they are much more common in established dementia. Variability in findings may reflect the heterogeneous nature of PrD studies to date and the lack of inclusion of patients with late onset psychosis in most clinical studies. The presence of psychosis in patients with PrD may be associated with a worse prognosis in terms of mortality and conversion to dementia. CONCLUSIONS: Research to date suggests that psychosis in PrD may be more common than previously thought and impact clinical course negatively. Future studies incorporating patients with late onset psychotic disorders, and focusing on the impact of early recognition and treatment, are required to more fully understand the role of psychosis in PrD. PMID- 28560932 TI - Redescription and genetic characterization of Cystidicoloides vaucheri, including first description of male and current status on the phylogeny of Cystidicolidae (Nematoda: Habronematoidea). AB - Cystidicoloides vaucheri collected in the stomach of the redtail catfish Phractocephalus hemioliopterus from River Acre, State of Acre, Brazil is redescribed, including the first description of males and the first genetic characterization based upon 18S and 28S genes of the rRNA. Newly collected females were biometrically smaller than those reported in the original description, but similar morphology shared by the two samples revealed that they belong to the same species. Scanning electron micrographs showed the accurate structure of the cephalic region, described here in detail. Furthermore, the morphology of males completed the specific diagnosis, strengthening the validity of the species. The three other congeners differ from C. vaucheri mainly as follows: in C. dlouhyi the area rugosa is absent, the cephalic structures in C. fischeri are completely distinct, and in both species the spicules have membranous outgrowths, absent in C. vaucheri. Despite the dubious generic assignment of C. izecksohni, it differs from C. vaucheri in several biometrical and morphological features. Because of data availability, only sequences of the 18S were used for phylogenetic reconstructions. Results showed that the genus Ascarophis and the families Cystidicolidae and Physalopteridae are not monophyletic. Cystidicoloides vaucheri formed an independent branch clustering with representatives of Cystidicolidae, confirming its validity. The inclusion of Salmonema and Spinitectus within Cystidicolidae should be reviewed, since they formed an assemblage with species from Rhabdochonidae. In fact, current classification of some taxa belonging to Habronematoidea, Physalopteroidea and Thelazioidea need to be re-evaluated, mainly based on molecular data from different genes. PMID- 28560934 TI - Organic food consumption during pregnancy is associated with different consumer profiles, food patterns and intake: the KOALA Birth Cohort Study. AB - OBJECTIVE: To find out how the consumption of organic food during pregnancy is associated with consumer characteristics, dietary patterns and macro- and micronutrient intakes. DESIGN: Cross-sectional description of consumer characteristics, dietary patterns and macro- and micronutrient intakes associated with consumption of organic food during pregnancy. SETTING: Healthy, pregnant women recruited to a prospective cohort study at midwives' practices in the southern part of the Netherlands; to enrich the study with participants adhering to alternative lifestyles, pregnant women were recruited through various specific channels. SUBJECTS: Participants who filled in questionnaires on food frequency in gestational week 34 (n 2786). Participant groups were defined based on the share of organic products within various food types. RESULTS: Consumers of organic food more often adhere to specific lifestyle rules, such as vegetarianism or anthroposophy, than do participants who consume conventional food only (reference group). Consumption of organic food is associated with food patterns comprising more products of vegetable origin (soya/vegetarian products, vegetables, cereal products, bread, fruits, and legumes) and fewer animal products (milk and meat), sugar and potatoes than consumed in conventional diets. These differences translate into distinct intakes of macro- and micronutrients, including higher retinol, carotene, tocopherol and folate intakes, lower intakes of vitamin D and B12 and specific types of trans-fatty acids in the organic groups. These differences are seen even in groups with low consumption of organic food. CONCLUSIONS: Various consumer characteristics, specific dietary patterns and types of food intake are associated with the consumption of organic food during pregnancy. PMID- 28560933 TI - Measuring Antibiotic Appropriateness for Urinary Tract Infections in Nursing Home Residents. AB - We assessed the appropriateness of initiating antibiotics in 49 nursing home (NH) residents receiving antibiotics for urinary tract infection (UTI) using 3 published algorithms. Overall, 16 residents (32%) received prophylaxis, and among the 33 receiving treatment, the percentage of appropriate use ranged from 15% to 45%. Opportunities exist for improving UTI antibiotic prescribing in NH. Infect Control Hosp Epidemiol 2017;38:998-1001. PMID- 28560935 TI - Medical and psychosocial determinants of risk of postpartum depression: a cross sectional study. AB - OBJECTIVE: The aim of this study was to investigate the degree of risk of maternal postpartum depression during the second month of puerperium. METHOD: In total, 387 postnatal women filled out a questionnaire concerning their health and social status, as well as the following tests: the Edinburgh Postnatal Depression Scale (EPDS), the Patient Health Questionnaire-9 (PHQ-9), the Neo Five-Factor Inventory (NEO-FFI) Personality Inventory and the Berlin Social Support Scales. After 4-8 weeks, patients responded to another questionnaire with the EPDS and the PHQ-9. RESULTS: In total, 48 patients (12.40%) were found to be at risk of postpartum depression between the fourth and eighth weeks after delivery. Premenstrual syndrome [adjusted odds ratio (ORa)=2.93, confidence interval (CI) 1.30-6.63] and EPDS>12 points during the first week after the delivery (ORa=3.74, CI 1.59-9.04) increased the risk of postnatal depression. A similar role is played by a high result in neuroticism scale of the NEO-FFI (ORa=1.50, CI 1.17 1.92) and a positive family history of any psychiatric disorder (ORa=1.03, CI 1.01-1.06). CONCLUSION: A history of premenstrual syndrome and a higher risk of affective disorder soon after a childbirth are associated with greater chances of depressive symptoms in the second month postpartum. This is also the case if a patient is neurotic and has a relative with a history of any psychiatric disorder. Such women should have their mental status carefully evaluated. PMID- 28560936 TI - Self-rated health is associated with subsequent functional decline among older adults in Japan. AB - BACKGROUND: Previous studies have reported that self-rated health (SRH) predicts subsequent mortality. However, less is known about the association between SRH and functional ability. The aim of this study was to examine whether SRH predicts decline in basic activities of daily living (ADL), even after adjustment for depression, among community-dwelling older adults in Japan. METHODS: A three-year prospective cohort study was conducted among 654 residents aged 65 years and older without disability in performing basic ADL at baseline. SRH was assessed using a visual analogue scale (range; 0-100), and dichotomized into low and high groups. Information on functional ability, sociodemographic factors, depressive symptoms, and medical conditions were obtained using a self-administered questionnaire. Logistic regression analysis was used to examine the association between baseline SRH and functional decline three years later. RESULTS: One hundred and eight (16.5%) participants reported a decline in basic ADL at the three-year follow-up. Multiple logistic regression analysis showed that the low SRH group had a higher risk for functional decline compared to the high SRH group, even after controlling for potential confounding factors (odds ratio (OR) = 2.4; 95% confidence interval (CI) = 1.3-4.4). Furthermore, a 10-point difference in SRH score was associated with subsequent functional decline (OR = 1.37; 95% CI = 1.16-1.61). CONCLUSIONS: SRH was an independent predictor of functional decline. SRH could be a simple assessment tool for predicting the loss or maintenance of functional ability in community-dwelling older adults. Positive self-evaluation might be useful to maintain an active lifestyle and stay healthy. PMID- 28560937 TI - Comparison of flock characteristics, journey duration and pathology between flocks with a normal and a high percentage of broilers 'dead-on-arrival' at abattoirs. AB - This study investigated high mortality in broilers transported to slaughter in Norway by comparing data from flocks with normal and high mortality during transportation. The data sources consisted of necropsy findings in 535 broilers dead-on-arrival (DOA), production data and slaughterhouse data, along with average journey duration for the 61 associated flocks. The mean Norwegian DOA% for 2015 was 0.10. In this study, normal-mortality flocks were defined as flocks with a mean DOA% up to 0.30 and high mortality as flocks with a mean DOA% above 0.30. DOA% was calculated per flock. The most frequent pathological finding was lung congestion which was observed in 75.5% of the DOA broilers. This postmortem finding was significantly more common in broilers from high-mortality flocks (89.3%) than in DOA broilers from normal-mortality flocks (58%). The following variables had a significantly (P<0.05) higher median in the high-mortality flocks: flock size, 1st week mortality, foot pad lesion score, carcass rejection numbers and journey duration. The results indicate that high broiler mortality during transportation to the abattoir may be linked to several steps in the broiler production chain. The results suggest that preventive measures are to be considered in improvement of health and environmental factors during the production period and throughout the journey duration. PMID- 28560938 TI - DEFINING THE RELEVANT OUTCOME MEASURES IN MEDICAL DEVICE ASSESSMENTS: AN ANALYSIS OF THE DEFINITION PROCESS IN HEALTH TECHNOLOGY ASSESSMENT. AB - BACKGROUND: Defining relevant outcome measures for clinical trials on medical devices (MD) is complex, as there is a large variety of potentially relevant outcomes. The chosen outcomes vary widely across clinical trials making the assessment in evidence syntheses very challenging. The objective is to provide an overview on the current common procedures of health technology assessment (HTA) institutions in defining outcome measures in MD trials. METHODS: In 2012-14, the Web pages of 126 institutions involved in HTA were searched for methodological manuals written in English or German that describe methods for the predefinition process of outcome measures. Additionally, the institutions were contacted by email. Relevant information was extracted. All process steps were performed independently by two reviewers. RESULTS: Twenty-four manuals and ten responses from the email request were included in the analysis. Overall, 88.5 percent of the institutions describe the type of outcomes that should be considered in detail and 84.6 percent agree that the main focus should be on patient relevant outcomes. Specifically related to MD, information could be obtained in 26 percent of the included manuals and email responses. Eleven percent of the institutions report a particular consideration of MD related outcomes. CONCLUSIONS: This detailed analysis on common procedures of HTA institutions in the context of defining relevant outcome measures for the assessment of MD shows that standardized procedures for MD from the perspective of HTA institutions are not widespread. This leads to the question if a homogenous approach should be implemented in the field of HTA on MD. PMID- 28560939 TI - A NEW HEALTH TECHNOLOGY ASSESSMENT SYSTEM FOR JAPAN? SIMULATING THE POTENTIAL IMPACT ON THE PRICE OF SIMEPREVIR. AB - OBJECTIVES: Japanese authorities have announced a plan to introduce a health technology assessment (HTA) system in 2016. This study assessed the potential impact of such a policy on the price of the antivirologic drug simeprevir. METHODS: Taking the antivirologic drug simeprevir as an example, we compared the current Japanese price with hypothetical prices that might result if a U.K. (cost utility) or German (efficiency frontier) style HTA assessment was in place. RESULTS: The simeprevir unit price under the current Japanese pricing scheme is 13,122 Japanese yen (equivalent to 109.35 U.S. dollars as of April 2015). Depending on the selection of comparators and the pricing method, and assuming that HTA will be used as a basis for price setting, the estimated prices of simeprevir vary up to four times higher than under the current Japanese pricing scheme. CONCLUSIONS: Although the analysis is based on only one drug, it cannot be taken for granted that a new HTA system would reduce public healthcare expenditure in Japan. PMID- 28560940 TI - Priority of Patient Safety Associated With Robotic Surgical Instruments-Response to Landenberg et al. PMID- 28560941 TI - Thyroid cancer has a small impact on patient-partner relationships and their frequency of sexual activity. AB - : ABSTRACTObjective:This cross-sectional survey examined changes in perceived relationships and sexual activity in a sample of thyroid cancer patients and their partners, taking into account sociodemographic and disease-related variables, as well as such outcome measures as anxiety, depression, fatigue, and quality of life (QoL). METHOD: A total of 38 patients with thyroid cancer who were being treated at the department of nuclear medicine in Zurich or Lucerne over the preceding seven years, as well as their partners, completed questionnaires about the quality of their relationships (RQ), about perceptions of changes in their relationships, and about their frequency of sexual activity. They also filled out prevalidated questionnaires related to anxiety, depression, fatigue, and QoL. RESULTS: Some 17 patients (44.7%) and 16 partners (42.1 %) reported that the cancer diagnosis had changed their relationships. Of these, 10 (26.3%) patients and 9 (23.7%) partners reported positive changes only, while 7 patients (18.4%) and 7 partners (18.4%) reported mixed or negative changes. A perceived mixed/negative relationship change was associated with increased depression and lower RQ in patients and partners, as well as with increased anxiety in patients. While the frequency of sexual activity only changed in roughly half of patients and partners (16 patients [42.1%] and 20 partners [52.6%]), increased sexual activity was associated with lower physical QoL scores and a higher depression score than in counterparts who reported no change. SIGNIFICANCE OF RESULTS: Compared to other cancer sites, in our sample thyroid cancer had a relatively small impact on patient-partner relationships and levels of intimacy. We found that screening patients and their partners with a simple question-"Did the diagnosis of cancer change your relationship?"-can lead to early detection of couples who are potentially at risk for perceived negative relationship changes and can facilitate timely psychosocial referral for couple's therapy. PMID- 28560942 TI - Categorization and Analysis of Disaster Health Publications: An Inventory. AB - Disaster Medicine is a relatively new discipline. Understanding of the current status of its science is needed in order to develop a roadmap for the direction and structure of future studies that will contribute to building the science of the health aspects of disasters (HADs). The objective of this study was to examine the existing, peer-reviewed literature relevant to the HADs to determine the status of the currently available literature underlying the science of the HADs. A total of 709 consecutive, peer-reviewed articles published from 2009-2014 in two disaster-health-related medical journals, Prehospital and Disaster Medicine (PDM) and Disaster Medicine and Public Health Preparedness (DMPHP), were examined. Of these, 495 were disaster-related (PDM, 248; DMPHP, 247). Three major categories defined these disaster-related research articles: (1) Epidemiological studies comprised 50.5%; (2) Interventional, 20.3%; and (3) Syntheses, 26.9%. Interventional studies were sub-categorized into: (a) Relief Responses, 23.0%; (b) Recovery Responses, 2.0%; or (c) Risk-Reduction Interventions, 75.0%. Basically, the inventories were consistent within the two journals. Reported indicators of outcomes related to the responses were constrained to achievement indicators (numbers accomplished). Syntheses articles were sub-categorized into: (a) Literature Reviews, 17.6%; (b) Opinions, 25.2%; (c) Models, 24.4%; (d) Frameworks, 6.9%; (e) Guidelines, 13.0%; (f) Tools, 3.0%; (g) Protocols, Policies, or Criteria, 2.3%; or (h) Conference Summaries, 7.6%. Trend analyses indicated that the relative proportions of articles in each category and sub category remained relatively constant over the five years. No randomized controlled trials (RTCs), non-randomized, comparative controlled trials (CCTs), or systematic reviews were published in these journals during the period examined. Each article also was examined qualitatively for objectives, study type, content, language, and structure. There was no common structure used for any category or sub-categories. In addition, the terminology used was inconsistent and often confusing. This categorization process should be applied to other peer-reviewed journals that publish research related to HADs. As evidenced in the current study, the evidence base for HADs is far from robust and is disorganized, making the development of scientific evidence on which to base best practices difficult. A stronger evidence base is needed to develop the science associated with the HADs. This will require a common structure and terminology to facilitate comparisons. Greater depth of reporting is needed in order to render the Epidemiological studies more useful in mitigating the negative health impacts of hazard-related events. Interventional studies must be structured and include outcomes, impacts, benefits, and costs with robust indicators. The outcomes and impacts of Risk-Reduction Interventions will require the evaluation of changes in the epidemiology documented in future events or exercises. Birnbaum ML , Adibhatla S , Dudek O , Ramsel-Miller J . Categorization and analysis of disaster health publications: an inventory. Prehosp Disaster Med. 2017;32(5):473-482 . PMID- 28560943 TI - Informant questionnaire on cognitive decline in the elderly (IQCODE) for classifying cognitive dysfunction as cognitively normal, mild cognitive impairment, and dementia. AB - BACKGROUND: The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) is a reliable, validated informant-based instrument in screening for cognitive dysfunction. However, previous studies have evaluated only the ability to discriminate dichotomously, such as dementia from cognitively normal (CN) individuals or mild cognitive impairment (MCI) from CN. This study investigated the ability of the IQCODE to classify not only dichotomous but also multiple stages of cognitive dysfunction. METHODS: We examined 228 consecutive participants (76 CN, 76 with MCI, and 76 with dementia). Receiver operating characteristic (ROC) curves determined dichotomous classification parameters. Multi-category ROC surfaces were evaluated to classify three stages of cognitive dysfunction. RESULTS: Dichotomous classification using the ROC curve analyses showed that the area under the ROC curve was 0.91 for dementia from participants without dementia and 0.71 for MCI from CN. Simultaneous multi-category classification analyses showed that the volume under the ROC surface was 0.61 and the derived optimal cut-off points were 3.15 and 3.73 for CN, MCI, and dementia. The Youden index for the IQCODE was estimated as 0.51 and the derived optimal cut off points were 3.33 and 3.70. The overall classification accuracy by the VUS was 58.3% and that by the Youden index 61.8%. CONCLUSIONS: IQCODE is useful to classify the dichotomous and multi-category stages of cognitive dysfunction. PMID- 28560944 TI - Feed intake and milk production in dairy cows fed different grass and legume species: a meta-analysis. AB - The aim of this meta-analysis was to compare feed intake, milk production, milk composition and organic matter (OM) digestibility in dairy cows fed different grass and legume species. Data from the literature was collected and different data sets were made to compare families (grasses v. legumes, Data set 1), different legume species and grass family (Data set 2), and different grass and legume species (Data set 3+4). The first three data sets included diets where single species or family were fed as the sole forage, whereas the approach in the last data set differed by taking the proportion of single species in the forage part into account allowing diets consisting of both grasses and legumes to be included. The grass species included were perennial ryegrass, annual ryegrass, orchardgrass, timothy, meadow fescue, tall fescue and festulolium, and the legume species included were white clover, red clover, lucerne and birdsfoot trefoil. Overall, dry matter intake (DMI) and milk production were 1.3 and 1.6 kg/day higher, respectively, whereas milk protein and milk fat concentration were 0.5 and 1.4 g/kg lower, respectively, for legume-based diets compared with grass based diets. When comparing individual legume species with grasses, only red clover resulted in a lower milk protein concentration than grasses. Cows fed white clover and birdsfoot trefoil yielded more milk than cows fed red clover and lucerne, probably caused by a higher OM digestibility of white clover and activity of condensed tannins in birdsfoot trefoil. None of the included grass species differed in DMI, milk production, milk composition or OM digestibility, indicating that different grass species have the same value for milk production, if OM digestibility is comparable. However, the comparison of different grass species relied on few observations, indicating that knowledge regarding feed intake and milk production potential of different grass species is scarce in the literature. In conclusion, different species within family similar in OM digestibility resulted in comparable DMI and milk production, but legumes increased both DMI and milk yield compared with grasses. PMID- 28560945 TI - Detecting delirium superimposed on dementia: diagnostic accuracy of a simple combined arousal and attention testing procedure. AB - BACKGROUND: Detecting delirium superimposed on dementia (DSD) can be challenging because assessment partly relies on cognitive tests that may be abnormal in both conditions. We hypothesized that a combined arousal and attention testing procedure would accurately detect DSD. METHODS: Patients aged >=70 years were recruited from five hospitals across Europe. Delirium was diagnosed by physicians using DSM-5 criteria using information from nurses, carers, and medical records. Dementia was ascertained by the Informant Questionnaire on Cognitive Decline in the Elderly. Arousal was measured using the Observational Scale of Level of Arousal (OSLA), which assesses eye opening, eye contact, posture, movement, and communication. Attention was measured by participants signaling each time an "A" was heard when "S-A-V-E-A-H-A-A-R-T" was read out. RESULTS: The sample included 114 persons (mean age 82 years (SD 7); 54% women). Dementia alone was present in 25% (n = 28), delirium alone in 18% (n = 21), DSD in 27% (n = 31), and neither in 30% (n = 34). Arousal and attention was assessed in n = 109 (96%). Using OSLA, 83% participants were correctly identified as having delirium (sensitivity 85%, specificity 82%, AUROC 0.92). The attention task correctly classified 76% of participants with delirium (sensitivity 90%, specificity 64%, AUROC 0.80). Combining scores correctly classified 91% of participants with delirium (sensitivity 84%, specificity 92%, AUROC 0.94). Diagnostic accuracy remained high in the subgroup with dementia (93% correctly classified, sensitivity 94%, specificity 92%, AUROC 0.98). CONCLUSIONS: This combined arousal-attention assessment to detect DSD was brief yet had high diagnostic accuracy. Such an approach could have clinical utility for diagnosing DSD. PMID- 28560946 TI - Development and Application of an Antibiotic Spectrum Index for Benchmarking Antibiotic Selection Patterns Across Hospitals. AB - Standard metrics for antimicrobial use consider volume but not spectrum of antimicrobial prescribing. We developed an antibiotic spectrum index (ASI) to classify commonly used antibiotics based on activity against important pathogens. The application of this index to hospital antibiotic use reveals how this tool enhances current antimicrobial stewardship metrics. Infect Control Hosp Epidemiol 2017;38:993-997. PMID- 28560947 TI - Food security among individuals experiencing homelessness and mental illness in the At Home/Chez Soi Trial. AB - OBJECTIVE: Individuals experiencing homelessness are particularly vulnerable to food insecurity. The At Home/Chez Soi study provides a unique opportunity to first examine baseline levels of food security among homeless individuals with mental illness and second to evaluate the effect of a Housing First (HF) intervention on food security in this population. DESIGN: At Home/Chez Soi was a 2-year randomized controlled trial comparing the effectiveness of HF compared with usual care among homeless adults with mental illness, stratified by level of need for mental health services (high or moderate). Logistic regressions tested baseline associations between food security (US Food Security Survey Module), study site, sociodemographic variables, duration of homelessness, alcohol/substance use, physical health and service utilization. Negative binomial regression determined the impact of the HF intervention on achieving levels of high or marginal food security over an 18-month follow-up period (6 to 24 months). SETTING: Community settings at five Canadian sites (Moncton, Montreal, Toronto, Winnipeg and Vancouver). SUBJECTS: Homeless adults with mental illness (n 2148). RESULTS: Approximately 41 % of our sample reported high or marginal food security at baseline, but this figure varied with gender, age, mental health issues and substance use problems. High need participants who received HF were more likely to achieve marginal or high food security than those receiving usual care, but only at the Toronto and Moncton sites. CONCLUSIONS: Our large multi site study demonstrated low levels of food security among homeless experiencing mental illness. HF showed promise for improving food security among participants with high levels of need for mental health services, with notable site differences. PMID- 28560948 TI - Variation in blood serum proteins and association with somatic cell count in dairy cattle from multi-breed herds. AB - Blood serum proteins are significant indicators of animal health. Nevertheless, several factors should be considered to appropriately interpret their concentrations in blood. Therefore, the objectives of this study were (1) to assess the effect of herd productivity, breed, age and stage of lactation on serum proteins and (2) to investigate association between serum proteins and somatic cell count (SCC) in dairy cattle. Milk and blood samples were collected from 1508 cows of six different breeds (Holstein Friesian, Brown Swiss, Jersey, Simmental, Rendena and Alpine Grey) that were housed in 41 multi-breed herds. Milk samples were analyzed for composition and SCC, while blood samples were analyzed for serum proteins (i.e. total protein, albumin, globulin and albumin-to globulin ratio (A : G)). Herds were classified as low or high production, according to the cow's average daily milk energy yield adjusted for breed, days in milk (DIM) and parity. Data were analyzed using a linear mixed model that included the fixed effects of DIM, parity, SCS, breed, herd productivity and the random effect of the Herd-test date within productivity level. Cows in high producing herds (characterized also by greater use of concentrates in the diet) had greater serum albumin concentrations. Breed differences were reported for all traits, highlighting a possible genetic mechanism. The specialized breed Jersey and the two dual-purpose local breeds (Alpine Grey and Rendena) had the lowest globulin concentration and greatest A : G. Changes in serum proteins were observed through lactation. Total protein reached the highest concentration during the 4th month of lactation. Blood albumin increased with DIM following a quadratic pattern, while globulin decreased linearly. As a consequence, A : G increased linearly during lactation. Older cows had greater total protein and globulin concentrations, while albumin concentration seemed to be not particularly affected by age. A linear relationship between serum proteins and SCS was observed. High milk SCS was associated with greater total protein and globulin concentrations in blood. The rise in globulin concentration, together with a decrease in albumin concentrations, resulted in a decline in A : G as SCS of milk increased. In conclusion, such non-genetic factors must be considered to appropriately interpret serum proteins as potential animal welfare indicator and their evaluation represents an important first-step for future analysis based on the integration of metabolomics, genetic and genomic information for improving the robustness of dairy cows. PMID- 28560950 TI - MALAT1 Promotes the Proliferation and Metastasis of Osteosarcoma Cells By Activating the Rac1/JNK Pathway Via Targeting MiR-509. AB - Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA (lncRNA) that contributes to the initiation and development of many solid tumors, including osteosarcoma (OS). In this study, we showed that MALAT1 was increased in human OS tissues and cell lines. MALAT1 knockdown suppressed OS cell growth and metastasis, induced OS cell apoptosis and delayed tumor growth in an OS xenograft model. We also detected downregulation of microRNA-509 (miR-509), a suppressor of OS growth, in OS tissues and cell lines. Then, we identified that miR-509 is a direct target of MALAT1 and Ras-related C3 botulinum toxin substrate 1 (Rac1) is a direct target of miR-509. MALAT1 may promote OS cell growth through inhibition of miR-509, leading to the activation of Rac1/JNK pathway. Our results suggest a MALAT1/miR-509/Rac1 axis that mediates OS cell proliferation and tumor progression. PMID- 28560949 TI - A conceptual model: Redesigning how we provide palliative care for patients with chronic obstructive pulmonary disease. AB - : ABSTRACTBackground:Despite significant needs, patients with chronic obstructive pulmonary disease (COPD) make limited use of palliative care, in part because the current models of palliative care do not address their key concerns. OBJECTIVE: Our aim was to develop a tailored model of palliative care for patients with COPD and their family caregivers. METHOD: Based on information gathered within a program of studies (qualitative research exploring experiences, a cohort study examining service use), an expert advisory committee evaluated and integrated data, developed responses, formulated principles to inform care, and made recommendations for practice. The informing studies were conducted in two Australian states: Victoria and South Australia. RESULTS: A series of principles underpinning the model were developed, including that it must be: (1) focused on patient and caregiver; (2) equitable, enabling access to components of palliative care for a group with significant needs; (3) accessible; and (4) less resource intensive than expansion of usual palliative care service delivery. The recommended conceptual model was to have the following features: (a) entry to palliative care occurs routinely triggered by clinical transitions in care; (b) care is embedded in routine ambulatory respiratory care, ensuring that it is regarded as "usual" care by patients and clinicians alike; (c) the tasks include screening for physical and psychological symptoms, social and community support, provision of information, and discussions around goals and preferences for care; and (d) transition to usual palliative care services is facilitated as the patient nears death. SIGNIFICANCE OF RESULTS: Our proposed innovative and conceptual model for provision of palliative care requires future formal testing using rigorous mixed-methods approaches to determine if theoretical propositions translate into effectiveness, feasibility, and benefits (including economic benefits). There is reason to consider adaptation of the model for the palliative care of patients with other nonmalignant conditions. PMID- 28560951 TI - miR-3188 Regulates Cell Proliferation, Apoptosis, and Migration in Breast Cancer by Targeting TUSC5 and Regulating the p38 MAPK Signaling Pathway. AB - This study intended to investigate the effects of miR-3188 on breast cancer and to reveal the possible molecular mechanisms. miR-3188 was upregulated and TUSC5 was downregulated in breast cancer tissues and MCF-7 cells compared to normal tissue and MCF-10 cells. After MCF-7 cells were transfected with miR-3188 inhibitor, cell proliferation and migration were inhibited, whereas apoptosis was promoted. Luciferase reporter assay suggested that TUSC5 was a target gene of miR 3188. In addition, miR-3188 overexpression increased the p-p38 expression, while miR-3188 suppression decreased the p-p38 expression significantly. miR-3188 regulated breast cancer progression via the p38 MAPK signaling pathway. In conclusion, miR-3188 affects breast cancer cell proliferation, apoptosis, and migration by targeting TUSC5 and activating the p38 MAPK signaling pathway. miR 3188 may serve as a potential therapeutic agent for the treatment of breast cancer. PMID- 28560953 TI - Nelfinavir and Ritonavir Kill Bladder Cancer Cells Synergistically by Inducing Endoplasmic Reticulum Stress. AB - The human immunodeficiency virus (HIV) protease inhibitor nelfinavir acts against malignancies by inducing endoplasmic reticulum (ER) stress. The HIV protease inhibitor ritonavir, on the other hand, not only induces ER stress but also inhibits P-glycoprotein's pump activity and thereby enhances the effects of its substrate drugs. We therefore postulated that ritonavir in combination with nelfinavir would kill bladder cancer cells effectively by inducing ER stress cooperatively and also enhancing nelfinavir's effect. Nelfinavir was shown to be a P-glycoprotein substrate, and the combination of nelfinavir and ritonavir inhibited bladder cancer cell growth synergistically. It also suppressed colony formation significantly. The combination significantly increased the number of cells in the sub-G1 fraction and also the number of annexin V+ cells, confirming robust apoptosis induction. The combination induced ER stress synergistically, as evidenced by the increased expression of glucose-regulated protein 78, ER resident protein 44, and endoplasmic oxidoreductin-1-like protein. It also increased the expression of the mammalian target of rapamycin (mTOR) inhibitor AMP-activated protein kinase and caused dephosphorylation of S6 ribosomal protein, demonstrating that the combination also inhibited the mTOR pathway. We also found that the combination enhanced histone acetylation synergistically by decreasing the expression of HDACs 1, 3, and 6. PMID- 28560954 TI - Development and Validation of a GC-MS Method for the Analysis of Homogentisic Acid in Strawberry Tree (Arbutus unedo L.) Honey. AB - To confirm the botanical origin of strawberry tree (Arbutus unedo L.) honey, a liquid-liquid extraction followed by GC-MS method was developed for the quantitative determination of homogentisic acid (HGA), the main phenolic compound in this honey. Different parameters affecting extraction, such as the type and volume of extraction solvents, pH of the solution, and amount of salt, were optimized. The method showed good linearity (r2 = 0.9990) over the tested concentration range (50-500 mg/kg) and a low LOD (0.3 mg/kg). Precision expressed as RSD was <7%. The average accuracy was 95%. The optimized method was applied for determining the HGA content in strawberry tree honey samples from Croatia. The HGA content in analyzed samples (n = 7) ranged from 245.1 to 485.9 mg/kg. The proposed method provided reliable performance and can be easily implemented for the routine monitoring of HGA in strawberry tree honey in order to assure honey QC. PMID- 28560956 TI - Complementary role of cardiac computed tomography to transesophageal echocardiography in the evaluation of prosthetic valve dysfunction. PMID- 28560955 TI - Effects of astaxanthin in mice acutely infected with Trypanosoma cruzi. AB - During Trypanosoma cruzi infection, oxidative stress is considered a contributing factor for dilated cardiomyopathy development. In this study, the effects of astaxanthin (ASTX) were evaluated as an alternative drug treatment for Chagas disease in a mouse model during the acute infection phase, given its anti inflammatory, immunomodulating, and anti-oxidative properties. ASTX was tested in vitro in parasites grown axenically and in co-culture with Vero cells. In vivo tests were performed in BALB/c mice (4-6 weeks old) infected with Trypanosoma cruzi and supplemented with ASTX (10 mg/kg/day) and/or nifurtimox (NFMX; 100 mg/kg/day). Results show that ASTX has some detrimental effects on axenically cultured parasites, but not when cultured with mammalian cell monolayers. In vivo, ASTX did not have any therapeutic value against acute Trypanosoma cruzi infection, used either alone or in combination with NFMX. Infected animals treated with NFMX or ASTX/NFMX survived the experimental period (60 days), while infected animals treated only with ASTX died before day 30 post-infection. ASTX did not show any effect on the control of parasitemia; however, it was associated with an increment in focal heart lymphoplasmacytic infiltration, a reduced number of amastigote nests in cardiac tissue, and less hyperplasic spleen follicles when compared to control groups. Unexpectedly, ASTX showed a negative effect in infected animals co-treated with NFMX. An increment in parasitemia duration was observed, possibly due to ASTX blocking of free radicals, an anti-parasitic mechanism of NFMX. In conclusion, astaxanthin is not recommended during the acute phase of Chagas disease, either alone or in combination with nifurtimox. PMID- 28560957 TI - Autophagy in myocardial ischemia reperfusion injury: Friend or foe? PMID- 28560958 TI - Exosomes-ADMS: A novel therapy thought in myocardial ischemia reperfusion injury. PMID- 28560959 TI - CYP2C19*2 and CYP2C19*3 allelomorphism in Turkish population. PMID- 28560960 TI - Acute rheumatic fever and isolated myocarditis. PMID- 28560961 TI - Metabolic disorder caused by antipsychotic treatment may facilitate the development of atrial fibrillation. PMID- 28560962 TI - Statins therapy might be beneficial in the treatment of myocardial ischemia reperfusion injury. PMID- 28560963 TI - Association between statins use and erectile dysfunction. PMID- 28560964 TI - Osteocalcin: A stiff challenge for arteries. PMID- 28560965 TI - Limit the uptake of milk by young people: A method to prevent the occurrence of heart failure. PMID- 28560966 TI - Incretin-based therapy for type 2 diabetes: What have we learned from the meta analyses? PMID- 28560967 TI - Increased risk of thromboembolic events in adult congenital heart disease patients with atrial tachyarrhythmias: Bias due to the data sparsity. PMID- 28560968 TI - Telomere length: A newly marker for predicting atrial fibrillation? PMID- 28560969 TI - Dual risk stratification for dual antiplatelet therapy: SYNTAX and CHA2DS2-VASc score. PMID- 28560970 TI - Methods of assessment of the post-exercise cardiac autonomic recovery: Additional important factors to be considered. PMID- 28560971 TI - Opinions on the strategy of forced diuresis with matched controlled hydration to prevent post procedural acute kidney injury in the catheterization laboratory. PMID- 28560972 TI - Response to: Avicenna (Ibn Sina) aspect of atherosclerosis. PMID- 28560973 TI - Patient selection and high-tech equipment: A great double act in coronary computed tomography angiography. PMID- 28560974 TI - Letter to Editor: Management and research in cancer treatment-related cardiovascular toxicity: Challenges and perspective. PMID- 28560975 TI - Inhibition of IL-17 might be a novel therapeutic target in the treatment of myocardial ischemia reperfusion injury. PMID- 28560976 TI - Regarding the article of Manczuk et al. (2017; 230: 549-555) entitled "Ideal cardiovascular health is associated with self-rated health status. The Polish Norwegian Study (PONS)." PMID- 28560977 TI - Reply to the letter to editor by Gaye et al. PMID- 28560978 TI - QTc interval prolongation in Systemic Sclerosis: Correlations with clinical variables and arrhythmic risk. PMID- 28560979 TI - QTc interval prolongation in systemic sclerosis. PMID- 28560980 TI - Comment on direct bilirubin as predictor of severity and mortality in idiopathic pulmonary arterial hypertension. PMID- 28560981 TI - Reply to "Comment on direct bilirubin as predictor of severity and mortality in idiopathic pulmonary arterial hypertension". PMID- 28560982 TI - Acute type B aortic dissection risk predictors: Thoracic aorta anatomic variables. PMID- 28560983 TI - Acute type B aortic dissection risk predictors: Thoracic aorta anatomic variables. PMID- 28560984 TI - Carotid artery disease and neurocognitive impairment. PMID- 28560985 TI - Carotid artery disease and neurocognitive impairment. PMID- 28560986 TI - Interlaboratory reproducibility of LC-MS untargeted lipidomics results in patients with calcific coronary disease: Methodological issues. PMID- 28560987 TI - The promising therapeutic agents for heart diseases: Histone Methyltransferase inhibitors. PMID- 28560988 TI - Anomalous origin of the left coronary artery from the pulmonary artery: Early manifestation preventing diagnosis. PMID- 28560989 TI - Liver kinase b1: A promising therapeutic approach for 'Browning' the cardiac adipose tissues. PMID- 28560990 TI - Transforming growth factor (TGF)-beta1 signal pathway: A promising therapeutic target for attenuating cardiac fibrosis. PMID- 28560991 TI - National progress on antimicrobial resistance. PMID- 28560992 TI - Purdah and the gagging of science. PMID- 28560993 TI - Financing preparedness at a national level. PMID- 28560994 TI - A new chapter for the NCD Alliance: stronger together. PMID- 28560996 TI - Offline: B-day-time to get real. PMID- 28560995 TI - Respiratory medicine and critical care: a call for papers for ERS. PMID- 28560997 TI - Scott Gottlieb sworn in to head the FDA. PMID- 28560998 TI - Data reveal state of Venezuelan health system. PMID- 28560999 TI - New era for health in The Gambia? PMID- 28561000 TI - STREAM characterisation correction. PMID- 28561001 TI - STREAM characterisation correction - Authors' reply. PMID- 28561002 TI - Artificial trachea transplantation is not ready for patients. PMID- 28561003 TI - The MERIDIAN trial: caution is needed. PMID- 28561004 TI - Acromegaly in Lorenzo the Magnificent, father of the Renaissance. PMID- 28561005 TI - Management of patients at risk of acute kidney injury. AB - Acute kidney injury (AKI) is a multifaceted syndrome that occurs in different settings. The course of AKI can be variable, from single hit and complete recovery, to multiple hits resulting in end-stage renal disease. No interventions to improve outcomes of established AKI have yet been developed, so prevention and early diagnosis are key. Awareness campaigns and education for health-care professionals on diagnosis and management of AKI-with attention to avoidance of volume depletion, hypotension, and nephrotoxic interventions-coupled with electronic early warning systems where available can improve outcomes. Biomarker based strategies have not shown improvements in outcome. Fluid management should aim for early, rapid restoration of circulatory volume, but should be more limited after the first 24-48 h to avoid volume overload. Use of balanced crystalloid solutions versus normal saline remains controversial. Renal replacement therapy should only be started on the basis of hard criteria, but should not be delayed when criteria are met. On the basis of recent evidence, the risk of contrast-induced AKI might be overestimated for many conditions. PMID- 28561006 TI - Strategies for long-term preservation of kidney graft function. AB - Kidney transplantation has become a routine procedure in the treatment of patients with kidney failure, and requires collaboration of experts from different disciplines, such as nephrology, surgery, immunology, pathology, infectious disease medicine, cardiology, and oncology. Grafts can be obtained from deceased or living donors, with different logistical requirements and implications for long-term graft patency. 1-year graft survival rates are greater than 95% in many centres but improvement of long-term function remains a challenge. New developments in molecular immunology and computational biology have increased precision of donor and recipient matching of HLA and non-HLA compatibility. Individual omics-wide molecular diagnostics, extracorporeal therapies, and drug developments allow for precise individual decision making and treatment. Tolerance induction by mixed chimerism without toxic conditioning and with a low risk of graft versus host disease is a visionary but realistic goal. Some of these innovations are already used in modern transplant centres and will allow advancement in long-term allograft preservation. PMID- 28561007 TI - Application of Flow Cytometry to the Detection of Pathogenic Bacteria. AB - Outbreaks of infections have emphasized the necessity for rapid and economic detection methods for pathogens in samples ranging from those of clinical origin to food products during production and retail storage, and increasingly, in environmental samples. Flow cytometry (FCM) allows the rapid acquisition of multi parametric data regarding cell populations within fluidised samples. However, the application of FCM to pathogen detection depends on the availability of specific fluorescent probes such as antibodies and RNA probes capable of detecting and isolating pathogens from these diverse samples. A particular issue for FCM methodology is the ability to recover and discriminate bacteria from the sample matrix which may pose a major technical hurdle towards accurate and sensitive analysis. This review article focuses on detection of pathogens using FCM in samples originating from food, water, environmental and clinical sources and outlines the current state of the art and potential future applications. PMID- 28561008 TI - Adsorption of 3d, 4d, and 5d transition metal atoms on beta 12-Borophene. AB - We perform an ab initio study of the electronic structure and magnetic properties of 3d, 4d and 5d transition metals (TM) adsorbed on freestanding and Ag(1 1 1) supported [Formula: see text]-borophene. The stability of TM adsorption is high for all atoms and increases with the period. For the 3d TM adsorption we observed strong exchange effects. The Ag(1 1 1)-surface induced small effects on the calculated properties. Studying the magnetic interaction between TMs, VIB atoms showed direct exchange, while VIIB and Fe showed 2p(B)-mediated indirect exchange. In the ultimate case of a one-dimensional TM array, Ru and Os also show direct exchange effects. PMID- 28561009 TI - Humidity-enhanced sub-ppm sensitivity to ammonia of covalently functionalized single-wall carbon nanotube bundle layers. AB - A low-cost method for carbon nanotubes (CNTs) network production from solutions on flexible polyethylene naphthalate substrates has been adopted to prepare high quality and well characterized SWCNT bundle layers to be used as the active layer in chemiresistor gas sensors. Two types of SWCNTs have been tested: pristine SWCNTs, deposited from a surfactant solution, and covalently functionalized SWCNTs, deposited from a dimethyl-acetamide solution. The humidity effects on the sensitivity of the SWCNTs network to NH3 have been investigated. The results show that relative humidity favors the response to NH3, confirming recent theoretical predictions. The COOH-functionalized sample displays the largest response owing to both its hydrophilic nature, favoring the interaction with H2O molecules, and its largest surface area. Compared to data available in the literature, the present sensors display a remarkable sensitivity well below the ppm range, which makes them quite promising for environmental and medical applications, where NH3 concentrations (mostly of the order of tens of ppb) have to be detected. PMID- 28561010 TI - In-plane heterostructures of Sb/Bi with high carrier mobility. AB - In-plane two-dimensional (2D) heterostructures have been attracting public attention due to their distinctive properties. However, the pristine materials that can form in-plane heterostructures are reported only for graphene, hexagonal BN, transition-metal dichalcogenides. It will be of great significance to explore more suitable 2D materials for constructing such ingenious heterostructures. Here, we demonstrate two types of novel seamless in-plane heterostructures combined by pristine Sb and Bi monolayers by means of first-principle approach based on density functional theory. Our results indicate that external strain can serve as an effective strategy for bandgap engineering, and the transition from semiconductor to metal occurs when a compressive strain of -8% is applied. In addition, the designed heterostructures possess direct band gaps with high carrier mobility (~4000 cm2 V-1 s-1). And the mobility of electrons and holes have huge disparity along the direction perpendicular to the interface of Sb/Bi in-plane heterostructures. It is favorable for carriers to separate spatially. Finally, we find that the band edge positions of Sb/Bi in-plane heterostructures can meet the reduction potential of hydrogen generation in photocatalysis. Our results not only offer alternative materials to construct versatile in-plane heterostructures, but also highlight the applications of 2D in-plane heterostructures in diverse nanodevices and photocatalysis. PMID- 28561011 TI - Rapid implementation of the repair-misrepair-fixation (RMF) model facilitating online adaption of radiosensitivity parameters in ion therapy. AB - INTRODUCTION: Treatment planning for ion therapy must account for physical properties of the beam as well as differences in the relative biological effectiveness (RBE) of ions compared to photons. In this work, we present a fast RBE calculation approach, based on the decoupling of physical properties and the [Formula: see text] ratio commonly used to describe the radiosensitivity of irradiated cells or organs. MATERIAL AND METHODS: In the framework of the mechanistic repair-misrepair-fixation (RMF) model, the biological modeling can be decoupled from the physical dose. This was implemented into a research treatment planning system for carbon ion therapy. RESULTS: The presented implementation of the RMF model is very fast, allowing online changes of [Formula: see text]. For example, a change of [Formula: see text] including a complete biological modeling and a recalculation of RBE for [Formula: see text] voxel takes 4 ms on a 4 CPU, 3.2 GHz workstation. DISCUSSION AND CONCLUSION: The derived decoupling within the RMF model allows fast changes in [Formula: see text], facilitating online adaption by the user. This provides new options for radiation oncologists, facilitating online variations of the radiobiological input parameters during the treatment plan evaluation process as well as uncertainty and sensitivity analyses. PMID- 28561012 TI - Mn 3d bands and Y-O hybridization of hexagonal and orthorhombic YMnO3 thin films. AB - We report here the O K-edge x-ray absorption spectra of hexagonal and orthorhombic YMnO3 thin films, aiming at comparing the changes in the Mn 3d bands as well as the role of Y 4d-O 2p hybridization. The experimental results were analyzed using first principles (GGA) band structure calculations. The spectra present clear differences in the Mn 3d bands, which are attributed to changes in the Mn-O coordination and symmetry. A strong Y 4d-O 2p hybridization is observed in both the hexagonal and orthorhombic films, and its possible role on the occurrence of the observed ferroelectricity is discussed. PMID- 28561013 TI - Photoresponsive lipid-polymer hybrid nanoparticles for controlled doxorubicin release. AB - Currently, photoresponsive nanomaterials are particularly attractive due to their spatial and temporal controlled drug release abilities. In this work, we report a photoresponsive lipid-polymer hybrid nanoparticle for remote controlled delivery of anticancer drugs. This hybrid nanoparticle comprises three distinct functional components: (i) a poly(D,L-lactide-co-glycolide) (PLGA) core to encapsulate doxorubicin; (ii) a soybean lecithin monolayer at the interface of the core and shell to act as a molecular fence to prevent drug leakage; (iii) a photoresponsive polymeric shell with anti-biofouling properties to enhance nanoparticle stability, which could be detached from the nanoparticle to trigger the drug release via a decrease in the nanoparticle's stability under light irradiation. In vitro results revealed that this core-shell nanoparticle had excellent light-controlled drug release behavior (76% release with light irradiation versus 10% release without light irradiation). The confocal microscopy and flow cytometry results also further demonstrated the light controlled drug release behavior inside the cancer cells. Furthermore, a CCK8 assay demonstrated that light irradiation could significantly improve the efficiency of killing cancer cells. Meanwhile, whole-animal fluorescence imaging of a tumor-bearing mouse also confirmed that light irradiation could trigger drug release in vivo. Taken together, our data suggested that a hybrid nanoparticle could be a novel light controlled drug delivery system for cancer therapy. PMID- 28561014 TI - Simulating effects of brain atrophy in longitudinal PET imaging with an anthropomorphic brain phantom. AB - In longitudinal positron emission tomography (PET), the presence of volumetric changes over time can lead to an overestimation or underestimation of the true changes in the quantified PET signal due to the partial volume effect (PVE) introduced by the limited spatial resolution of existing PET cameras and reconstruction algorithms. Here, a 3D-printed anthropomorphic brain phantom with attachable striata in three sizes was designed to enable controlled volumetric changes. Using a method to eliminate the non-radioactive plastic wall, and manipulating BP levels by adding different number of events from list-mode acquisitions, we investigated the artificial volume dependence of BP due to PVE, and potential bias arising from varying BP. Comparing multiple reconstruction algorithms we found that a high-resolution ordered-subsets maximization algorithm with spatially variant point-spread function resolution modeling provided the most accurate data. For striatum, the BP changed by 0.08% for every 1% volume change, but for smaller volumes such as the posterior caudate the artificial change in BP was as high as 0.7% per 1% volume change. A simple gross correction for striatal volume is unsatisfactory, as the amplitude of the PVE on the BP differs depending on where in the striatum the change occurred. Therefore, to correctly interpret age-related longitudinal changes in the BP, we must account for volumetric changes also within a structure, rather than across the whole volume. The present 3D-printing technology, combined with the wall removal method, can be implemented to gain knowledge about the predictable bias introduced by the PVE differences in uptake regions of varying shape. PMID- 28561015 TI - Necl 4 and RNase 5 Are Important Biomarkers for Gastric and Colon Adenocarcinomas. AB - BACKGROUND There is a need to identify new prognostic factors that may be used in addition to the known risk factors in gastrointestinal adenocarcinomas. In this study, we aimed to determine the expression of Necl 4 and RNase 5 biomarkers in gastric and colon adenocarcinomas, as well as the prognostic efficacy of these biomarkers in gastric and colon adenocarcinomas. MATERIAL AND METHODS Ninety-two cases resected due to stomach and colon adenocarcinoma were included in the study. The expression of Necl 4 and RNase 5 biomarkers was evaluated by immunohistochemical staining of the stomach and colon normal mucosa and adenocarcinoma areas. RESULTS In colon adenocarcinomas, there was a significant association between Necl 4 and lymphovascular invasion, vascular invasion, and perineural invasion (p<0.05). There was a significant association between RNase 5 and histological differentiation in colon adenocarcinomas (p<0.05). There was no association between RNase 5 and Necl 4 in gastric or colon adenocarcinomas. CONCLUSIONS Necl 4 may have prognostic value in colon adenocarcinomas, but it is difficult to ascertain in gastric adenocarcinomas. PMID- 28561017 TI - Anapole nanolasers for mode-locking and ultrafast pulse generation. AB - Nanophotonics is a rapidly developing field of research with many suggestions for a design of nanoantennas, sensors and miniature metadevices. Despite many proposals for passive nanophotonic devices, the efficient coupling of light to nanoscale optical structures remains a major challenge. In this article, we propose a nanoscale laser based on a tightly confined anapole mode. By harnessing the non-radiating nature of the anapole state, we show how to engineer nanolasers based on InGaAs nanodisks as on-chip sources with unique optical properties. Leveraging on the near-field character of anapole modes, we demonstrate a spontaneously polarized nanolaser able to couple light into waveguide channels with four orders of magnitude intensity than classical nanolasers, as well as the generation of ultrafast (of 100 fs) pulses via spontaneous mode locking of several anapoles. Anapole nanolasers offer an attractive platform for monolithically integrated, silicon photonics sources for advanced and efficient nanoscale circuitry. PMID- 28561016 TI - Light-driven liquid metal nanotransformers for biomedical theranostics. AB - Room temperature liquid metals (LMs) represent a class of emerging multifunctional materials with attractive novel properties. Here, we show that photopolymerized LMs present a unique nanoscale capsule structure characterized by high water dispersibility and low toxicity. We also demonstrate that the LM nanocapsule generates heat and reactive oxygen species under biologically neutral near-infrared (NIR) laser irradiation. Concomitantly, NIR laser exposure induces a transformation in LM shape, destruction of the nanocapsules, contactless controlled release of the loaded drugs, optical manipulations of a microfluidic blood vessel model and spatiotemporal targeted marking for X-ray-enhanced imaging in biological organs and a living mouse. By exploiting the physicochemical properties of LMs, we achieve effective cancer cell elimination and control of intercellular calcium ion flux. In addition, LMs display a photoacoustic effect in living animals during NIR laser treatment, making this system a powerful tool for bioimaging. PMID- 28561019 TI - Reply to C Harling. PMID- 28561020 TI - England uses a competency-based approach to consent for health interventions. PMID- 28561018 TI - Maternal heterozygous NLRP7 variant results in recurrent reproductive failure and imprinting disturbances in the offspring. AB - It has been shown previously that homozygous and compound-heterozygous variants affecting protein function in the human NLRP genes impact reproduction and/or fetal imprinting patterns. These variants represent so-called 'maternal effect mutations', that is, although female variant carriers are healthy, they are at risk of reproductive failure, and their offspring may develop aberrant methylation and imprinting disorders. In contrast, the relevance to reproductive failure of maternal heterozygous NLRP7 variants remains unclear. The present report describes the identification of a heterozygous NLRP7 variant in a healthy 28-year-old woman with a history of recurrent reproductive failure, and the molecular findings in two of the deceased offspring. Next-generation sequencing (NGS) for NLRP variants was performed. In the tissues of two offspring (one fetus; one deceased premature neonate) methylation of imprinted loci was tested using methylation-specific assays. Both pregnancies had been characterized by the presence of elevated human chorionic gonadotropin (hCG) levels and ovarian cysts. In the mother, a heterozygous nonsense 2-bp deletion in exon 5 of the NLRP7 gene was identified (NM_001127255.1:c.2010_2011del, p.(Phe671Glnfs*18)). In the two investigated offspring, heterogeneous aberrant methylation patterns were detected at imprinted loci. The present data support the hypothesis that heterozygous NLRP7 variants contribute to reproductive wastage, and that these variants represent autosomal dominant maternal effect variants which lead to aberrant imprinting marks in the offspring. Specific screening and close prenatal monitoring of NLRP7 variant carriers is proposed. Egg donation might facilitate successful pregnancy in heterozygous NLRP7 variant carriers. PMID- 28561021 TI - CRISPR/Cas9 targeting events cause complex deletions and insertions at 17 sites in the mouse genome. AB - Although CRISPR/Cas9 genome editing has provided numerous opportunities to interrogate the functional significance of any given genomic site, there is a paucity of data on the extent of molecular scars inflicted on the mouse genome. Here we interrogate the molecular consequences of CRISPR/Cas9-mediated deletions at 17 sites in four loci of the mouse genome. We sequence targeted sites in 632 founder mice and analyse 54 established lines. While the median deletion size using single sgRNAs is 9 bp, we also obtain large deletions of up to 600 bp. Furthermore, we show unreported asymmetric deletions and large insertions of middle repetitive sequences. Simultaneous targeting of distant loci results in the removal of the intervening sequences. Reliable deletion of juxtaposed sites is only achieved through two-step targeting. Our findings also demonstrate that an extended analysis of F1 genotypes is required to obtain conclusive information on the exact molecular consequences of targeting events. PMID- 28561022 TI - IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression. AB - NOTCH1 signalling contributes to defective remyelination by impairing differentiation of oligodendrocyte progenitor cells (OPCs). Here we report that IL-17 stimulation induces NOTCH1 activation in OPCs, contributing to Th17 mediated demyelinating disease. Mechanistically, IL-17R interacts with NOTCH1 via the extracellular domain, which facilitates the cleavage of NOTHC1 intracellular domain (NICD1). IL-17-induced NOTCH1 activation results in the interaction of IL 17R adaptor Act1 with NICD1, followed by the translocation of the Act1-NICD1 complex into the nucleus. Act1-NICD1 are recruited to the promoters of several NOTCH1 target genes (including STEAP4, a metalloreductase important for inflammation and cell proliferation) that are specifically induced in the spinal cord by Th17 cells. A decoy peptide disrupting the IL-17RA-NOTCH1 interaction inhibits IL-17-induced NOTCH1 activation and attenuates Th17-mediated experimental autoimmune encephalitis (EAE). Taken together, these findings demonstrate critical crosstalk between the IL-17 and NOTCH1 pathway, regulating Th17-induced inflammatory and proliferative genes to promote demyelinating disease. PMID- 28561024 TI - Giant electron-hole transport asymmetry in ultra-short quantum transistors. AB - Making use of bipolar transport in single-wall carbon nanotube quantum transistors would permit a single device to operate as both a quantum dot and a ballistic conductor or as two quantum dots with different charging energies. Here we report ultra-clean 10 to 100 nm scale suspended nanotube transistors with a large electron-hole transport asymmetry. The devices consist of naked nanotube channels contacted with sections of tube under annealed gold. The annealed gold acts as an n-doping top gate, allowing coherent quantum transport, and can create nanometre-sharp barriers. These tunnel barriers define a single quantum dot whose charging energies to add an electron or a hole are vastly different (e-h charging energy asymmetry). We parameterize the e-h transport asymmetry by the ratio of the hole and electron charging energies etae-h. This asymmetry is maximized for short channels and small band gap tubes. In a small band gap device, we demonstrate the fabrication of a dual functionality quantum device acting as a quantum dot for holes and a much longer quantum bus for electrons. In a 14 nm long channel, etae-h reaches up to 2.6 for a device with a band gap of 270 meV. The charging energies in this device exceed 100 meV. PMID- 28561023 TI - Expression of CD226 is associated to but not required for NK cell education. AB - DNAX accessory molecule-1 (DNAM-1, also known as CD226) is an activating receptor expressed on subsets of natural killer (NK) and T cells, interacts with its ligands CD155 or CD112, and has co-varied expression with inhibitory receptors. Since inhibitory receptors control NK-cell activation and are necessary for MHC-I dependent education, we investigated whether DNAM-1 expression is also involved in NK-cell education. Here we show an MHC-I-dependent correlation between DNAM-1 expression and NK-cell education, and an association between DNAM-1 and NKG2A that occurs even in MHC class I deficient mice. DNAM-1 is expressed early during NK-cell development, precedes the expression of MHC-I-specific inhibitory receptors, and is modulated in an education-dependent fashion. Cd226-/- mice have missing self-responses and NK cells with a normal receptor repertoire. We propose a model in which NK-cell education prevents or delays downregulation of DNAM-1. This molecule endows educated NK cells with enhanced effector functions but is dispensable for education. PMID- 28561025 TI - End-Triassic mass extinction started by intrusive CAMP activity. AB - The end-Triassic extinction is one of the Phanerozoic's largest mass extinctions. This extinction is typically attributed to climate change associated with degassing of basalt flows from the central Atlantic magmatic province (CAMP). However, recent work suggests that the earliest known CAMP basalts occur above the extinction horizon and that climatic and biotic changes began before the earliest known CAMP eruptions. Here we present new high-precision U-Pb ages from CAMP mafic intrusive units, showing that magmatic activity was occurring ~100 Kyr ago before the earliest known eruptions. We correlate the early magmatic activity with the onset of changes to the climatic and biotic records. We also report ages from sills in an organic rich sedimentary basin in Brazil that intrude synchronously with the extinction suggesting that degassing of these organics contributed to the climate change which drove the extinction. Our results indicate that the intrusive record from large igneous provinces may be more important for linking to mass extinctions than the eruptive record. PMID- 28561027 TI - Formation of metallic cation-oxygen network for anomalous thermal expansion coefficients in binary phosphate glass. AB - Understanding glass structure is still challenging due to the result of disorder, although novel materials design on the basis of atomistic structure has been strongly demanded. Here we report on the atomic structures of the zinc phosphate glass determined by reverse Monte Carlo modelling based on diffraction and spectroscopic data. The zinc-rich glass exhibits the network formed by ZnOx (averaged x<4) polyhedra. Although the elastic modulus, refractive index and glass transition temperature of the zinc phosphate glass monotonically increase with the amount of ZnO, we find for the first time that the thermal expansion coefficient is very sensitive to the substitution of the phosphate chain network by a network consisting of Zn-O units in zinc-rich glass. Our results imply that the control of the structure of intermediate groups may enable new functionalities in the design of oxide glass materials. PMID- 28561028 TI - Hot excited state management for long-lived blue phosphorescent organic light emitting diodes. AB - Since their introduction over 15 years ago, the operational lifetime of blue phosphorescent organic light-emitting diodes (PHOLEDs) has remained insufficient for their practical use in displays and lighting. Their short lifetime results from annihilation between high-energy excited states, producing energetically hot states (>6.0 eV) that lead to molecular dissociation. Here we introduce a strategy to avoid dissociative reactions by including a molecular hot excited state manager within the device emission layer. Hot excited states transfer to the manager and rapidly thermalize before damage is induced on the dopant or host. As a consequence, the managed blue PHOLED attains T80=334+/-5 h (time to 80% of the 1,000 cd m-2 initial luminance) with a chromaticity coordinate of (0.16, 0.31), corresponding to 3.6+/-0.1 times improvement in a lifetime compared to conventional, unmanaged devices. To our knowledge, this significant improvement results in the longest lifetime for such a blue PHOLED. PMID- 28561026 TI - R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein. AB - The R2TP/Prefoldin-like (R2TP/PFDL) complex has emerged as a cochaperone complex involved in the assembly of a number of critical protein complexes including snoRNPs, nuclear RNA polymerases and PIKK-containing complexes. Here we report on the use of multiple target affinity purification coupled to mass spectrometry to identify two additional complexes that interact with R2TP/PFDL: the TSC1-TSC2 complex and the U5 small nuclear ribonucleoprotein (snRNP). The interaction between R2TP/PFDL and the U5 snRNP is mostly mediated by the previously uncharacterized factor ZNHIT2. A more general function for the zinc-finger HIT domain in binding RUVBL2 is exposed. Disruption of ZNHIT2 and RUVBL2 expression impacts the protein composition of the U5 snRNP suggesting a function for these proteins in promoting the assembly of the ribonucleoprotein. A possible implication of R2TP/PFDL as a major effector of stress-, energy- and nutrient sensing pathways that regulate anabolic processes through the regulation of its chaperoning activity is discussed. PMID- 28561029 TI - Bacterial RadA is a DnaB-type helicase interacting with RecA to promote bidirectional D-loop extension. AB - Homologous recombination (HR) is a central process of genome biology driven by a conserved recombinase, which catalyses the pairing of single-stranded DNA (ssDNA) with double-stranded DNA to generate a D-loop intermediate. Bacterial RadA is a conserved HR effector acting with RecA recombinase to promote ssDNA integration. The mechanism of this RadA-mediated assistance to RecA is unknown. Here, we report functional and structural analyses of RadA from the human pathogen Streptococcus pneumoniae. RadA is found to facilitate RecA-driven ssDNA recombination over long genomic distances during natural transformation. RadA is revealed as a hexameric DnaB-type helicase, which interacts with RecA to promote orientated unwinding of branched DNA molecules mimicking D-loop boundaries. These findings support a model of DNA branch migration in HR, relying on RecA-mediated loading of RadA hexamers on each strand of the recipient dsDNA in the D-loop, from which they migrate divergently to facilitate incorporation of invading ssDNA. PMID- 28561030 TI - Metabolic network analysis reveals microbial community interactions in anammox granules. AB - Microbial communities mediating anaerobic ammonium oxidation (anammox) represent one of the most energy-efficient environmental biotechnologies for nitrogen removal from wastewater. However, little is known about the functional role heterotrophic bacteria play in anammox granules. Here, we use genome-centric metagenomics to recover 17 draft genomes of anammox and heterotrophic bacteria from a laboratory-scale anammox bioreactor. We combine metabolic network reconstruction with metatranscriptomics to examine the gene expression of anammox and heterotrophic bacteria and to identify their potential interactions. We find that Chlorobi-affiliated bacteria may be highly active protein degraders, catabolizing extracellular peptides while recycling nitrate to nitrite. Other heterotrophs may also contribute to scavenging of detritus and peptides produced by anammox bacteria, and potentially use alternative electron donors, such as H2, acetate and formate. Our findings improve the understanding of metabolic activities and interactions between anammox and heterotrophic bacteria and offer the first transcriptional insights on ecosystem function in anammox granules. PMID- 28561032 TI - Pairwise frictional profile between particles determines discontinuous shear thickening transition in non-colloidal suspensions. AB - The process by which sheared suspensions go through a dramatic change in viscosity is known as discontinuous shear thickening. Although well-characterized on the macroscale, the microscopic mechanisms at play in this transition are still poorly understood. Here, by developing new experimental procedures based on quartz-tuning fork atomic force microscopy, we measure the pairwise frictional profile between approaching pairs of polyvinyl chloride and cornstarch particles in solvent. We report a clear transition from a low-friction regime, where pairs of particles support a finite normal load, while interacting purely hydrodynamically, to a high-friction regime characterized by hard repulsive contact between the particles and sliding friction. Critically, we show that the normal stress needed to enter the frictional regime at nanoscale matches the critical stress at which shear thickening occurs for macroscopic suspensions. Our experiments bridge nano and macroscales and provide long needed demonstration of the role of frictional forces in discontinuous shear thickening. PMID- 28561031 TI - Real-time visualization of clustering and intracellular transport of gold nanoparticles by correlative imaging. AB - Mechanistic understanding of the endocytosis and intracellular trafficking of nanoparticles is essential for designing smart theranostic carriers. Physico chemical properties, including size, clustering and surface chemistry of nanoparticles regulate their cellular uptake and transport. Significantly, even single nanoparticles could cluster intracellularly, yet their clustering state and subsequent trafficking are not well understood. Here, we used DNA-decorated gold (fPlas-gold) nanoparticles as a dually emissive fluorescent and plasmonic probe to examine their clustering states and intracellular transport. Evidence from correlative fluorescence and plasmonic imaging shows that endocytosis of fPlas-gold follows multiple pathways. In the early stages of endocytosis, fPlas gold nanoparticles appear mostly as single particles and they cluster during the vesicular transport and maturation. The speed of encapsulated fPlas-gold transport was critically dependent on the size of clusters but not on the types of organelle such as endosomes and lysosomes. Our results provide key strategies for engineering theranostic nanocarriers for efficient health management. PMID- 28561033 TI - Smooth 2D manifold extraction from 3D image stack. AB - Three-dimensional fluorescence microscopy followed by image processing is routinely used to study biological objects at various scales such as cells and tissue. However, maximum intensity projection, the most broadly used rendering tool, extracts a discontinuous layer of voxels, obliviously creating important artifacts and possibly misleading interpretation. Here we propose smooth manifold extraction, an algorithm that produces a continuous focused 2D extraction from a 3D volume, hence preserving local spatial relationships. We demonstrate the usefulness of our approach by applying it to various biological applications using confocal and wide-field microscopy 3D image stacks. We provide a parameter free ImageJ/Fiji plugin that allows 2D visualization and interpretation of 3D image stacks with maximum accuracy. PMID- 28561034 TI - A damaged genome's transcriptional landscape through multilayered expression profiling around in situ-mapped DNA double-strand breaks. AB - Of the many types of DNA damage, DNA double-strand breaks (DSBs) are probably the most deleterious. Mounting evidence points to an intricate relationship between DSBs and transcription. A cell system in which the impact on transcription can be investigated at precisely mapped genomic DSBs is essential to study this relationship. Here in a human cell line, we map genome-wide and at high resolution the DSBs induced by a restriction enzyme, and we characterize their impact on gene expression by four independent approaches by monitoring steady state RNA levels, rates of RNA synthesis, transcription initiation and RNA polymerase II elongation. We consistently observe transcriptional repression in proximity to DSBs. Downregulation of transcription depends on ATM kinase activity and on the distance from the DSB. Our study couples for the first time, to the best of our knowledge, high-resolution mapping of DSBs with multilayered transcriptomics to dissect the events shaping gene expression after DSB induction at multiple endogenous sites. PMID- 28561036 TI - Review of techniques and studies characterizing the release of carbon nanotubes from nanocomposites: Implications for exposure and human health risk assessment. AB - Composites made with engineered nanomaterials (nanocomposites) have a wide range of applications, from use in basic consumer goods to critical national defense technologies. Carbon nanotubes (CNTs) are a popular addition in nanocomposites because of their enhanced mechanical, thermal, and electrical properties. Concerns have been raised, though, regarding potential exposure and health risks from nanocomposites containing CNTs because of comparisons to other high aspect ratio fibers. Assessing the factors affecting CNT release from composites is therefore paramount for understanding potential exposure scenarios that may occur during product handling and manipulation. Standardized methods for detecting and quantifying released CNTs, however, have not yet been developed. We therefore evaluated experimental approaches deployed by various researchers, with an emphasis on characterizing free versus composite bound CNTs. From our analysis of published studies characterizing CNT releases from nanocomposites, we found that the qualitative and quantitative methods used across studies varied greatly, thus limiting the ability for objective comparison and evaluation of various release factors. Nonetheless, qualitative results indicated that factors such as composite type, CNT functionalization, and energy input during manipulation (i.e., grinding) may affect CNT release. Based on our findings, we offer several recommendations for future product testing and assessment of potential exposure and health risks associated with CNT nanocomposites. PMID- 28561035 TI - Inner centromere localization of the CPC maintains centromere cohesion and allows mitotic checkpoint silencing. AB - Faithful chromosome segregation during mitosis requires that the kinetochores of all sister chromatids become stably connected to microtubules derived from opposite spindle poles. How stable chromosome bi-orientation is accomplished and coordinated with anaphase onset remains incompletely understood. Here we show that stable chromosome bi-orientation requires inner centromere localization of the non-enzymatic subunits of the chromosomal passenger complex (CPC) to maintain centromeric cohesion. Precise inner centromere localization of the CPC appears less relevant for Aurora B-dependent resolution of erroneous kinetochore microtubule (KT-MT) attachments and for the stabilization of bi-oriented KT-MT attachments once sister chromatid cohesion is preserved via knock-down of WAPL. However, Aurora B inner centromere localization is essential for mitotic checkpoint silencing to allow spatial separation from its kinetochore substrate KNL1. Our data infer that the CPC is localized at the inner centromere to sustain centromere cohesion on bi-oriented chromosomes and to coordinate mitotic checkpoint silencing with chromosome bi-orientation. PMID- 28561037 TI - Milk-cereal and whole-grain dietary patterns protect against low bone mineral density among male adolescents and young adults. AB - BACKGROUND/OBJECTIVES: Evidence supporting the possible effect of dietary factors on adult bone health has emerged in recent decades. The purpose of this study was to ascertain the influence of different dietary patterns on bone mineral density (BMD) among Korean male youth. SUBJECTS/METHODS: Data were extracted from the Korean National Health and Nutrition Examination Survey (KNHANES) during 2008 2011. The subjects included 1351 male aged 10-25 years. We defined 'low BMD group' as subjects with a BMD Z-score of -2.0 or less. Dietary patterns were derived from 20 food groups via factor analysis. RESULTS: Three dietary patterns meat and vegetable, white rice and kimchi, milk-cereal and whole grain-were derived. The 'milk-cereal and whole-grain' dietary pattern score showed positive association with energy, protein, fat, calcium, phosphorus, potassium, riboflavin and vitamin C intakes. Participants in the top tertile of the milk-cereal and whole-grain pattern were less likely to have low BMD, compared with subjects in the bottom tertile (odds ratio=0.36, 95% confidence interval=0.16-0.81, P=0.018). CONCLUSIONS: Our findings suggest that the milk-cereal and whole-grain dietary pattern may have a benign influence on bone health in the Korean male youth. PMID- 28561039 TI - Sedentary behavior and compensatory mechanisms in response to different doses of exercise-a randomized controlled trial in overweight and obese adults. AB - BACKGROUND/OBJECTIVES: To examine compensatory changes in sedentary behavior (SB) and light-intensity physical activities (LIPA) in response to a 22-week exercise training program in overweight/obese adults; and to determine if different forms of exercise training and physical activity recommendations interact with these compensatory changes. SUBJECTS/METHODS: Eighty-nine overweight and obese individuals (body mass index (BMI): 25-34.9 kg/m2, 48% males), aged 18-50 years, were randomized into four intervention groups (strength, endurance, combined strength + endurance and physical activity recommendations) with a 25-30% caloric restriction of total daily energy expenditure for 22 weeks. Energy expenditure was measured by accelerometry before, during and after the program. RESULTS: LIPA increased significantly (P<0.001) after three months and at the end of intervention compared to baseline (pre: 281+/-9 min; 3 months: 303+/-9 min; post: 312+/-8 min). SB percentage decreased by 5.3 at the end of the intervention (P=0.002). No interactions were observed between groups or sexes. Significant correlations were found between SB and body weight, fat mass, android fat mass and lean body mass before and after the intervention (P<0.05). LIPA was also significantly correlated with all these body composition variables in the pre intervention, but only correlated with body weight at the end of intervention. CONCLUSIONS: There were no compensatory changes after a combined exercise and diet program; where minutes in LIPA increased and %SB decreased after the program, without differences among exercise modes. Greater physical activity levels can contribute to a better percentage and distribution of body tissues. PMID- 28561038 TI - The role of energy intake and energy misreporting in the associations between eating patterns and adiposity. AB - BACKGROUND/OBJECTIVES: Research examining associations between eating occasion (EO) frequency and adiposity is inconclusive; studies examining the impact of energy misreporting are rare. This study examined associations between eating patterns and adiposity, with adjustment for energy misreporting, in a nationally representative sample of Australian adults. SUBJECTS/METHODS: Dietary intake was assessed via two 24-h recalls collected during the 2011-12 National Nutrition and Physical Activity Survey (n=4050 adults, aged ?19 years). Frequencies of all EOs, meals and snacks were calculated. Height, weight and waist circumference (WC) were measured. Energy misreporting was assessed as the ratio of energy intake to predicted energy expenditure (EI:EE). Energy misreporters were identified by EI:EE ratios, <0.68 or >1.32. Multivariate regression models assessed associations between eating patterns and body mass index (BMI), WC, overweight/obesity (BMI ?25 kg m-2) and central overweight/obesity (WC ?94 cm in men and ?80 cm in women). RESULTS: After adjustment for covariates and EI:EE, frequency of all EOs, meals (women only) and snacks was positively associated with WC and BMI (all P<0.01). Snack, but not meal frequency, was also associated with overweight/obesity (men: OR=1.22, 95% CI 1.07-1.39; women: OR=1.26, 95% CI 1.10-1.43) and central overweight/obesity (men: OR=1.17, 95% CI 1.04-1.32; women: OR=1.21, 95% CI 1.06-1.37). Multivariate analysis that excluded energy misreporters and adjusted for EI yielded either null or inverse associations (P<0.05). CONCLUSIONS: These findings suggest that the associations between eating patterns and adiposity are complicated by the role of EI and energy misreporting. Longitudinal research that considers the impact of EI and energy misreporting is needed to better understand the relationship between eating patterns and obesity. PMID- 28561040 TI - The mystery of longevity in Cilento: a mix of a good dose of genetic predisposition and a balanced diet based on the Mediterranean model. PMID- 28561041 TI - Acquired IFNgamma resistance impairs anti-tumor immunity and gives rise to T-cell resistant melanoma lesions. AB - Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNgamma secretion by CD8+ T cells is critical for therapy efficacy having anti proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNgamma resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNgamma signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNgamma activity. JAK1/2 mutants further evolve into T-cell resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNgamma. Allelic JAK1/2 losses predisposing to IFNgamma resistance development are frequent in melanoma. Subclones harbouring inactivating mutations emerge under various immunotherapies but are also detectable in pre-treatment biopsies. Our data demonstrate that JAK1/2 deficiency protects melanoma from anti-tumour IFNgamma activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNgamma resistance should be considered in therapeutic decision making. PMID- 28561042 TI - Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data. AB - Two genes are synthetically lethal (SL) when defects in both are lethal to a cell but a single defect is non-lethal. SL partners of cancer mutations are of great interest as pharmacological targets; however, identifying them by cell line-based methods is challenging. Here we develop MiSL (Mining Synthetic Lethals), an algorithm that mines pan-cancer human primary tumour data to identify mutation specific SL partners for specific cancers. We apply MiSL to 12 different cancers and predict 145,891 SL partners for 3,120 mutations, including known mutation specific SL partners. Comparisons with functional screens show that MiSL predictions are enriched for SLs in multiple cancers. We extensively validate a SL interaction identified by MiSL between the IDH1 mutation and ACACA in leukaemia using gene targeting and patient-derived xenografts. Furthermore, we apply MiSL to pinpoint genetic biomarkers for drug sensitivity. These results demonstrate that MiSL can accelerate precision oncology by identifying mutation specific targets and biomarkers. PMID- 28561043 TI - HSPs drive dichotomous T-cell immune responses via DNA methylome remodelling in antigen presenting cells. AB - Immune responses primed by endogenous heat shock proteins, specifically gp96, can be varied, and mechanisms controlling these responses have not been defined. Immunization with low doses of gp96 primes T helper type 1 (Th1) immune responses, whereas high-dose immunization primes responses characterized by regulatory T (Treg) cells and immunosuppression. Here we show gp96 preferentially engages conventional and plasmacytoid dendritic cells (pDCs) under low and high doses, respectively, through CD91. Global DNMT-dependent epigenetic modifications lead to changes in protein expression within these antigen-presenting cells. Specifically, pDCs upregulate neuropilin-1 to enable the long term interactions of pDCs with Treg cells, thereby enhancing suppression of Th1 anti-tumour immunity. Our study defines a CD91-dependent mechanism through which gp96 controls dichotomous immune responses relevant to the therapy of cancer and autoimmunity. PMID- 28561044 TI - Engineered clearing agents for the selective depletion of antigen-specific antibodies. AB - Here we have designed a novel class of engineered antibody-based reagents ('Seldegs') that induce the selective degradation of antigen-specific antibodies. We demonstrate the rapid and specific clearance of antibodies recognizing the autoantigen, myelin oligodendrocyte glycoprotein and tumour target, HER2. Seldegs have considerable potential in multiple areas, including the treatment of antibody-mediated autoimmunity and diagnostic imaging. PMID- 28561047 TI - Force sensing in cytokinesis. PMID- 28561045 TI - Oligolysine-based coating protects DNA nanostructures from low-salt denaturation and nuclease degradation. AB - DNA nanostructures have evoked great interest as potential therapeutics and diagnostics due to ease and robustness of programming their shapes, site-specific functionalizations and responsive behaviours. However, their utility in biological fluids can be compromised through denaturation induced by physiological salt concentrations and degradation mediated by nucleases. Here we demonstrate that DNA nanostructures coated by oligolysines to 0.5:1 N:P (ratio of nitrogen in lysine to phosphorus in DNA), are stable in low salt and up to tenfold more resistant to DNase I digestion than when uncoated. Higher N:P ratios can lead to aggregation, but this can be circumvented by coating instead with an oligolysine-PEG copolymer, enabling up to a 1,000-fold protection against digestion by serum nucleases. Oligolysine-PEG-stabilized DNA nanostructures survive uptake into endosomal compartments and, in a mouse model, exhibit a modest increase in pharmacokinetic bioavailability. Thus, oligolysine-PEG is a one-step, structure-independent approach that provides low-cost and effective protection of DNA nanostructures for in vivo applications. PMID- 28561046 TI - Cancer-cell intrinsic gene expression signatures overcome intratumoural heterogeneity bias in colorectal cancer patient classification. AB - Stromal-derived intratumoural heterogeneity (ITH) has been shown to undermine molecular stratification of patients into appropriate prognostic/predictive subgroups. Here, using several clinically relevant colorectal cancer (CRC) gene expression signatures, we assessed the susceptibility of these signatures to the confounding effects of ITH using gene expression microarray data obtained from multiple tumour regions of a cohort of 24 patients, including central tumour, the tumour invasive front and lymph node metastasis. Sample clustering alongside correlative assessment revealed variation in the ability of each signature to cluster samples according to patient-of-origin rather than region-of-origin within the multi-region dataset. Signatures focused on cancer-cell intrinsic gene expression were found to produce more clinically useful, patient-centred classifiers, as exemplified by the CRC intrinsic signature (CRIS), which robustly clustered samples by patient-of-origin rather than region-of-origin. These findings highlight the potential of cancer-cell intrinsic signatures to reliably stratify CRC patients by minimising the confounding effects of stromal-derived ITH. PMID- 28561048 TI - Erratum: SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis. PMID- 28561049 TI - Championing authorship attribution. PMID- 28561051 TI - Cell forces meet cell metabolism. AB - Epithelial cells form energetically costly cell-cell adhesions in response to mechanical forces. How cells obtain their energy during this event is unclear. Activity of a key regulator of cell metabolism, the AMP-activated protein kinase (AMPK), is now shown to be mechanoresponsive, and thus can bridge adhesion mechanotransduction and energy homeostasis. PMID- 28561052 TI - Corrigendum: The tetrameric kinesin Kif25 suppresses pre-mitotic centrosome separation to establish proper spindle orientation. PMID- 28561050 TI - Multiscale force sensing in development. AB - The seminal observation that mechanical signals can elicit changes in biochemical signalling within cells, a process commonly termed mechanosensation and mechanotransduction, has revolutionized our understanding of the role of cell mechanics in various fundamental biological processes, such as cell motility, adhesion, proliferation and differentiation. In this Review, we will discuss how the interplay and feedback between mechanical and biochemical signals control tissue morphogenesis and cell fate specification in embryonic development. PMID- 28561053 TI - Mitochondria link metabolism and epigenetics in haematopoiesis. AB - Due to their varied metabolic and signalling roles, mitochondria are important in mediating cell behaviour. By altering mitochondrial function, two studies now identify metabolite-induced epigenetic changes that have profound effects on haematopoietic stem cell fate and function. PMID- 28561054 TI - Endoglin moves and shapes endothelial cells. AB - Vascular malformations result from improper blood vessel responses to molecular and mechanical signals. Two studies now show that endothelial cell migration and cell shape changes are perturbed in mutants lacking the TGFbeta/BMP co-receptor endoglin, leading to arteriovenous shunts. Endoglin coordinates endothelial cell responses to ligand-receptor signalling and flow-mediated mechanical cues. PMID- 28561055 TI - Forces in cell biology. PMID- 28561056 TI - EGFR probes matrix stiffness. PMID- 28561057 TI - Mechanical control of antigen uptake. PMID- 28561058 TI - Reducing interferon'ce in stem cells. AB - Little is known regarding how the interactions of stem cells with the immune system regulate their plasticity. A study now describes a mechanism by which normal breast and cancer stem cells utilize miR-199a to downregulate the corepressor LCOR and minimize responses to type I interferon. PMID- 28561059 TI - Reversing stratification during wound healing. AB - The involvement of proliferation and migration in epidermal healing has long been recognized, but three studies now reveal how a variety of individual cell behaviours achieve a collective epithelial response, and how diverse repair routes are taken by cells of different origins. PMID- 28561060 TI - Formin' a perinuclear actin cage in confined migration. PMID- 28561061 TI - Regulated membrane remodeling by Mic60 controls formation of mitochondrial crista junctions. AB - The mitochondrial contact site and cristae organizing system (MICOS) is crucial for the formation of crista junctions and mitochondrial inner membrane architecture. MICOS contains two core components. Mic10 shows membrane-bending activity, whereas Mic60 (mitofilin) forms contact sites between inner and outer membranes. Here we report that Mic60 deforms liposomes into thin membrane tubules and thus displays membrane-shaping activity. We identify a membrane-binding site in the soluble intermembrane space-exposed part of Mic60. This membrane-binding site is formed by a predicted amphipathic helix between the conserved coiled-coil and mitofilin domains. The mitofilin domain negatively regulates the membrane shaping activity of Mic60. Binding of Mic19 to the mitofilin domain modulates this activity. Membrane binding and shaping by the conserved Mic60-Mic19 complex is crucial for crista junction formation, mitochondrial membrane architecture and efficient respiratory activity. Mic60 thus plays a dual role by shaping inner membrane crista junctions and forming contact sites with the outer membrane. PMID- 28561062 TI - Inhibition of gelatinase B/MMP-9 does not attenuate colitis in murine models of inflammatory bowel disease. AB - One third of patients with inflammatory bowel disease (IBD) inadequately respond to anti-TNF treatment and preclinical data suggest that matrix metalloproteinase 9 (MMP-9) is a novel therapeutic target. Here we show that IBD clinical and histopathological parameters found in wild type mice challenged with three different models of colitis, acute and chronic dextran sodium sulphate (DSS), and acute 2,4,6-trinitrobenzenesulfonic acid-induced colitis are not attenuated in MMP-9 knockout mice. We find similar colonic gene expression profiles in wild type and MMP-9 knockout mice in control and acute DSS conditions with the exception of eleven genes involved in antimicrobial response during colitis. Parameters of chronic colitis are similar in wild type and MMP-9 knockout mice. Pharmacological inhibition of MMP-9 with bio-active peptides does not improve DSS colitis. We suggest that MMP-9 upregulation is a consequence rather than a cause of intestinal inflammation and we question whether MMP-9 represents a disease target in IBD. PMID- 28561064 TI - Turbulence hierarchy in a random fibre laser. AB - Turbulence is a challenging feature common to a wide range of complex phenomena. Random fibre lasers are a special class of lasers in which the feedback arises from multiple scattering in a one-dimensional disordered cavity-less medium. Here we report on statistical signatures of turbulence in the distribution of intensity fluctuations in a continuous-wave-pumped erbium-based random fibre laser, with random Bragg grating scatterers. The distribution of intensity fluctuations in an extensive data set exhibits three qualitatively distinct behaviours: a Gaussian regime below threshold, a mixture of two distributions with exponentially decaying tails near the threshold and a mixture of distributions with stretched-exponential tails above threshold. All distributions are well described by a hierarchical stochastic model that incorporates Kolmogorov's theory of turbulence, which includes energy cascade and the intermittence phenomenon. Our findings have implications for explaining the remarkably challenging turbulent behaviour in photonics, using a random fibre laser as the experimental platform. PMID- 28561065 TI - Beat frequency quartz-enhanced photoacoustic spectroscopy for fast and calibration-free continuous trace-gas monitoring. AB - Quartz-enhanced photoacoustic spectroscopy (QEPAS) is a sensitive gas detection technique which requires frequent calibration and has a long response time. Here we report beat frequency (BF) QEPAS that can be used for ultra-sensitive calibration-free trace-gas detection and fast spectral scan applications. The resonance frequency and Q-factor of the quartz tuning fork (QTF) as well as the trace-gas concentration can be obtained simultaneously by detecting the beat frequency signal generated when the transient response signal of the QTF is demodulated at its non-resonance frequency. Hence, BF-QEPAS avoids a calibration process and permits continuous monitoring of a targeted trace gas. Three semiconductor lasers were selected as the excitation source to verify the performance of the BF-QEPAS technique. The BF-QEPAS method is capable of measuring lower trace-gas concentration levels with shorter averaging times as compared to conventional PAS and QEPAS techniques and determines the electrical QTF parameters precisely. PMID- 28561063 TI - Selective analysis of cancer-cell intrinsic transcriptional traits defines novel clinically relevant subtypes of colorectal cancer. AB - Stromal content heavily impacts the transcriptional classification of colorectal cancer (CRC), with clinical and biological implications. Lineage-dependent stromal transcriptional components could therefore dominate over more subtle expression traits inherent to cancer cells. Since in patient-derived xenografts (PDXs) stromal cells of the human tumour are substituted by murine counterparts, here we deploy human-specific expression profiling of CRC PDXs to assess cancer cell intrinsic transcriptional features. Through this approach, we identify five CRC intrinsic subtypes (CRIS) endowed with distinctive molecular, functional and phenotypic peculiarities: (i) CRIS-A: mucinous, glycolytic, enriched for microsatellite instability or KRAS mutations; (ii) CRIS-B: TGF-beta pathway activity, epithelial-mesenchymal transition, poor prognosis; (iii) CRIS-C: elevated EGFR signalling, sensitivity to EGFR inhibitors; (iv) CRIS-D: WNT activation, IGF2 gene overexpression and amplification; and (v) CRIS-E: Paneth cell-like phenotype, TP53 mutations. CRIS subtypes successfully categorize independent sets of primary and metastatic CRCs, with limited overlap on existing transcriptional classes and unprecedented predictive and prognostic performances. PMID- 28561066 TI - WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy. AB - Autophagy is controlled by AMPK and mTOR, both of which associate with ULK1 and control the production of phosphatidylinositol 3-phosphate (PtdIns3P), a prerequisite for autophagosome formation. Here we report that WIPI3 and WIPI4 scaffold the signal control of autophagy upstream of PtdIns3P production and have a role in the PtdIns3P effector function of WIPI1-WIPI2 at nascent autophagosomes. In response to LKB1-mediated AMPK stimulation, WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes, controlling their size, to which WIPI3, in complex with FIP200, also contributes. Upstream, WIPI3 associates with AMPK-activated TSC complex at lysosomes, regulating mTOR. Our WIPI interactome analysis reveals the scaffold functions of WIPI proteins interconnecting autophagy signal control and autophagosome formation. Our functional kinase screen uncovers a novel regulatory link between LKB1-mediated AMPK stimulation that produces a direct signal via WIPI4, and we show that the AMPK-related kinases NUAK2 and BRSK2 regulate autophagy through WIPI4. PMID- 28561067 TI - Real-time monitoring of hydrophobic aggregation reveals a critical role of cooperativity in hydrophobic effect. AB - The hydrophobic interaction drives nonpolar solutes to aggregate in aqueous solution, and hence plays a critical role in many fundamental processes in nature. An important property intrinsic to hydrophobic interaction is its cooperative nature, which is originated from the collective motions of water hydrogen bond networks surrounding hydrophobic solutes. This property is widely believed to enhance the formation of hydrophobic core in proteins. However, cooperativity in hydrophobic interactions has not been successfully characterized by experiments. Here, we quantify cooperativity in hydrophobic interactions by real-time monitoring the aggregation of hydrophobic solute (hexaphenylsilole, HPS) in a microfluidic mixer. We show that association of a HPS molecule to its aggregate in water occurs at sub-microsecond, and the free energy change is -5.8 to -13.6 kcal mol-1. Most strikingly, we discover that cooperativity constitutes up to 40% of this free energy. Our results provide quantitative evidence for the critical role of cooperativity in hydrophobic interactions. PMID- 28561069 TI - A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis. AB - Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms with variable risk of evolution into post-PV and post-ET myelofibrosis, from now on referred to as secondary myelofibrosis (SMF). No specific tools have been defined for risk stratification in SMF. To develop a prognostic model for predicting survival, we studied 685 JAK2, CALR, and MPL annotated patients with SMF. Median survival of the whole cohort was 9.3 years (95% CI: 8-not reached-NR ). Through penalized Cox regressions we identified negative predictors of survival and according to beta risk coefficients we assigned 2 points to hemoglobin level <11 g/dl, to circulating blasts ?3%, and to CALR-unmutated genotype, 1 point to platelet count <150 * 109/l and to constitutional symptoms, and 0.15 points to any year of age. Myelofibrosis Secondary to PV and ET Prognostic Model (MYSEC-PM) allocated SMF patients into four risk categories with different survival (P<0.0001): low (median survival NR; 133 patients), intermediate-1 (9.3 years, 95% CI: 8.1-NR; 245 patients), intermediate-2 (4.4 years, 95% CI: 3.2-7.9; 126 patients), and high risk (2 years, 95% CI: 1.7-3.9; 75 patients). Finally, we found that the MYSEC-PM represents the most appropriate tool for SMF decision-making to be used in clinical and trial settings. PMID- 28561070 TI - Biotransformation of p-xylene into terephthalic acid by engineered Escherichia coli. AB - Terephthalic acid (TPA) is an important industrial chemical currently produced by energy intensive and potentially hazardous p-xylene (pX) oxidation process. Here we report the development of metabolically engineered Escherichia coli system for biological transformation of pX into TPA. The engineered E. coli strain harbours a synthetic TPA pathway optimized through manipulation of expression levels of upstream and downstream modules. The upstream pathway converts pX to p-toluic acid (pTA) and the downstream pathway transforms pTA to TPA. In a two-phase partitioning fermentation, the engineered strain converts 8.8 g pX into 13.3 g TPA, which corresponds to a conversion yield of 96.7 mol%. These results suggest that the E. coli system presented here might be a promising alternative for the large-scale biotechnological production of TPA and lays the foundations for the future development of sustainable approaches for TPA production. PMID- 28561068 TI - Gamma-Hydroxybutyrate Increases Resting-State Limbic Perfusion and Body and Emotion Awareness in Humans. AB - Gamma-hydroxybutyrate (GHB) is a GHB-/GABA-B receptor agonist inducing a broad spectrum of subjective effects including euphoria, disinhibition, and enhanced vitality. It is used as treatment for neuropsychiatric disorders including narcolepsy and alcohol withdrawal, but is also a drug of abuse. Non-medical users report enhancement of body and emotion awareness during intoxication. However, the neuronal underpinnings of such awareness alterations under GHB are unknown so far. The assessment of regional cerebral blood flow (rCBF) by pharmacological magnetic resonance imaging (phMRI) enables the elucidation of drug-induced functional brain alterations. Thus, we assessed the effects of GHB (35 mg/kg p.o.) in 17 healthy males on rCBF and subjective drug effects, using a placebo controlled, double-blind, randomized, cross-over design employing arterial spin labeling phMRI. Compared to placebo, GHB increased subjective ratings for body and emotion awareness, and for dizziness (p<0.01-0.001, Bonferroni-corrected). A whole-brain analysis showed increased rCBF in the bilateral anterior cingulate cortex (ACC) and the right anterior insula under GHB (p<0.05, cluster-corrected). ACC and insula rCBF are correlated with relaxation, and body and emotion awareness (p<0.05-0.001, uncorrected). Interaction analyses revealed that GHB induced increase of body awareness was accompanied by increased rCBF in ACC, whereas relaxation under GHB was accompanied by elevated rCBF in right anterior insula (p<0.05, uncorrected). In conclusion, enhancement of emotion and body awareness, and increased perfusion of insula and ACC bears implications both for the properties of GHB as a drug of abuse as well as for its putative personalized potential for specific therapeutic indications in affective disorders. PMID- 28561072 TI - Immunotherapy: Macrophages hijack anti-PD-1 therapy. PMID- 28561073 TI - Targeted therapies: J-ALEX hints at new first-line in NSCLC. PMID- 28561071 TI - Clinical utility of gene-expression signatures in early stage breast cancer. AB - Breast cancer is a heterogeneous disease, with different subtypes having a distinct biological, molecular, and clinical course. Assessments of standard clinical and pathological features have traditionally been used to determine the use of adjuvant systemic therapy in patients with early stage breast cancer; however, the ability to identify those who will benefit from adjuvant chemotherapy remains a challenge, leading to the overtreatment of some patients. Advances in molecular medicine have substantially improved the accuracy of gene expression profiling of breast tumours, resulting in improvements in the ability to predict a patient's risk of breast cancer recurrence and likely response to endocrine therapy and/or chemotherapy. These genomic assays, several of which are commercially available, have aided physicians in tailoring treatment decisions for patients at the individual level. Herein, we describe the available data on the clinical validity of the most widely available assays in patients with early stage breast cancer, with a focus on the development, validation, and clinical application of these assays, in addition to the anticipated outcomes of ongoing prospective trials. We also review data from comparative studies of these assays and from cost-effectiveness analyses relating to their clinical use. PMID- 28561075 TI - HIV-1 transmitted drug resistance mutations among antiretroviral therapy-Naive individuals in Surabaya, Indonesia. AB - BACKGROUND: The emergence of transmitted drug resistance (TDR) compromises the effect of antiretroviral therapy (ART), resulting in treatment failure of human immunodeficiency virus (HIV) disease. Although more than a decade has passed since ART was introduced into Indonesia, information on TDR is limited. Here, a genotypic study of TDR among ART-naive individuals was conducted in Surabaya, Indonesia. METHOD: HIV-1 seropositive participants were recruited from the communities of commercial sex workers and intravenous drug users as well as from the university teaching hospital in Surabaya. Protease (PR) and reverse transcriptase (RT) genes were sequenced in order to conduct HIV-1 subtyping and phylogenetic analysis and to detect TDR. TDR was defined as the presence of at least one surveillance drug resistance mutation on the WHO list or major drug resistance mutations in the International AIDS Society-USA panel. RESULT: Fifty two and 47 of the PR and RT genes, respectively, were successfully sequenced in the 58 samples. HIV-1 subtyping revealed that 86.3% (50/58) of the sequenced samples were classified as CRF01_AE, 8.6% as subtype B, 3.4% as B/CRF01_AE, and 1.7% as A/G/CRF01_AE. TDR of PR inhibitors was not detected in this study. In contrast, TDR of RT inhibitors was detected in 4.3% (2/47) of samples. In addition, minor drug resistance mutations were detected in 98.1% (51/52) and 12.8% (6/47) of PR and RT genes, respectively. CONCLUSION: This study clarified the predominance of the CRF01_AE strain in Surabaya, Indonesia. The prevalence of TDR was below 5%, indicating that the currently available first-line regimen is still effective in Surabaya. However, the prevalence might be underestimated since we detected only major population of HIV-1 in individuals. Therefore, continuous surveillance is required in order to detect the emergence of TDR in the early phase. PMID- 28561076 TI - Polyamides and their functionalization: recent concepts for their applications as biomaterials. AB - Synthetic polyamides (nylons) are very important polymers with applications in many fields, and recently their use in biology and medicine has become more and more important. Different recent concepts and strategies for the functionalization and applications of nylons as biomaterials are summarized in this article, with a focus on their utilization as scaffolds for tissue engineering, membranes and bioactive surfaces. PMID- 28561074 TI - Succinate and its G-protein-coupled receptor stimulates osteoclastogenesis. AB - The mechanism underlying bone impairment in patients with diabetes mellitus, a metabolic disorder characterized by chronic hyperglycaemia and dysregulation in metabolism, is unclear. Here we show the difference in the metabolomics of bone marrow stromal cells (BMSCs) derived from hyperglycaemic (type 2 diabetes mellitus, T2D) and normoglycaemic mice. One hundred and forty-two metabolites are substantially regulated in BMSCs from T2D mice, with the tricarboxylic acid (TCA) cycle being one of the primary metabolic pathways impaired by hyperglycaemia. Importantly, succinate, an intermediate metabolite in the TCA cycle, is increased by 24-fold in BMSCs from T2D mice. Succinate functions as an extracellular ligand through binding to its specific receptor on osteoclastic lineage cells and stimulates osteoclastogenesis in vitro and in vivo. Strategies targeting the receptor activation inhibit osteoclastogenesis. This study reveals a metabolite mediated mechanism of osteoclastogenesis modulation that contributes to bone dysregulation in metabolic disorders. PMID- 28561077 TI - Reactions between hydroxyl-substituted alkylperoxy radicals and Criegee intermediates: correlations of the electronic characteristics of methyl substituents and the reactivity. AB - The reactions of four hydroxyl-substituted alkylperoxy (RO2) radicals with four stabilized Criegee intermediates (SCIs) were investigated. Due to the existence of various reactive sites in both RO2 and SCI, various reaction modes were obtained. By adjusting the relative orientation of the two components of the reactants, different pathways were predicted. The addition of RO2 radical terminal oxygen atom to SCI carbonyl carbon is a favorable reaction mode. For RO2 radicals, increasing the number of methyl substituents in beta-carbon will promote the addition reaction. Carbonyl oxides with hydrogen atoms as substituents in the anti-position react faster than the corresponding carbonyl oxides with hydrogen atom substituents in the syn-position. Thus, the reaction barrier can be "tuned" by the substitution of alkyl groups. The analysis of the transition states have revealed that there were correlations between the reaction barrier heights, NPA charges and electron spin population of the terminal oxygen of RO2, as well as between the interatomic distances of O-C in transition states. As the oligomers formed by the sequential addition of SCIs to RO2 radicals are the common components of secondary organic aerosols, the investigation was able to contribute to understand the formation of SOA. PMID- 28561078 TI - Determination of growth regimes of Pd nanostructures on c-plane sapphire by the control of deposition amount at different annealing temperatures. AB - Metallic nanoparticles (NPs) with tunable physical, optical and catalytic properties have a wide range of applications including various optoelectronics, sensors and fuel cells. In this paper, we demonstrate the evolution of various physical properties, configurations, size and density of palladium (Pd) nanostructures on sapphire(Al2O3) (0001) by the systematic control of deposition amount (DA) at distinct annealing temperatures. The transformation of the deposited thin films into various Pd NPs is achieved by the dewetting of the thin film by means of surface diffusion, nucleation, Volmer-Weber growth and surface energy minimization mechanism. Depending on the evolution of size, density and configuration, five distinctive regimes of Pd nanostructures are demonstrated: (i) nucleation and evolution of small NPs between 1 and 3 nm, (ii) medium NPs with the dominating vertical growth between 5 and 20 nm, (iii) laterally expanded large NPs between 30 and 40 nm, (iv) irregular coalesced Pd NPs between 50 and 80 nm and (v) voids evolution between 100 and 200 nm. Initial film thickness and annealing temperature play major roles on the dewetting process and the resulting Pd nanostructures are notably distinguished. The fabricated Pd nanostructures influence the lattice vibration modes of sapphire(0001) such as gradual decrement in the intensity and left-shift of the peak position with increased surface coverage. In addition, the optical properties are studied by UV-VIS-NIR (300-1100 nm) reflectance spectra, which shows the reflectance, absorption and scattering over the wavelength and are closely related to the morphology evolution of Pd nanostructures. PMID- 28561079 TI - Determinants of the host-guest interactions between alpha-, beta- and gamma cyclodextrins and group IA, IIA and IIIA metal cations: a DFT/PCM study. AB - The most widely used native cyclodextrins are alpha-, beta- and gamma cyclodextrins containing six, seven or eight alpha-d-glucopyranoside units in the ring, respectively. Although the ligation properties of these host molecules have been extensively studied, a number of questions regarding their metal binding and selectivity remain unaddressed: to what extent do the size and flexibility of the host alpha-, beta- and gamma-cyclodextrins influence their metal affinity/selectivity? Which metal is the most preferred binding partner of alpha , beta- and gamma-cyclodextrins? How do the charge, size and preferred coordination number of the metal cation shape its interactions with the host cyclodextrin? Can the guest metal cation inflict structural alterations in the host molecule and, if so, how do these changes correlate with the metal's properties? In the present study, by employing density functional theory (DFT) calculations combined with polarizable continuum model (PCM) computations, we try to answer these questions by evaluating the thermodynamic parameters of the IA, IIA and IIIA group metal binding to alpha, beta- and gamma-cyclodextrins. We assess how the interaction between the two binding partners depends on (1) the size, valence state and preferred coordination number of the guest metal cations, (2) the size and flexibility of the host molecule, and (3) the dielectric properties of the environment. The series of group IA (Na+ and Rb+), IIA (Mg2+ and Sr2+) and IIIA (Al3+ and In3+) metal cations have been chosen for the task as they allow us to study the effect of various metal parameters (variable charge, ionic radius and coordination number) on the strength and form of the interactions with the host cyclodextrins. PMID- 28561080 TI - Diacetylene polymerization on a bulk insulator surface. AB - Molecular electronics has great potential to surpass known limitations in conventional silicon-based technologies. The development of molecular electronics devices requires reliable strategies for connecting functional molecules by wire like structures. To this end, diacetylene polymerization has been discussed as a very promising approach for contacting single molecules with a conductive polymer chain. A major challenge for future device fabrication is transferring this method to bulk insulator surfaces, which are mandatory to decouple the electronic structure of the functional molecules from the support surface. Here, we provide experimental evidence for diacetylene polymerization of 3,3'-(1,3-butadiyne-1,4 diyl)bisbenzoic acid precursors on the (10.4) surface of calcite, a bulk insulator with a band gap of around 6 eV. When deposited on the surface held at room temperature, ordered islands with a (1 * 3) superstructure are observed using dynamic atomic force microscopy. A distinct change is revealed upon heating the substrate to 485 K. After heating, molecular stripes with a characteristic inner structure are formed that excellently match the expected diacetylene polymer chains in appearance and repeat distance. The corresponding density functional theory computations reveal molecular-level bonding patterns of both the (1 * 3) superstructure and the formed striped structure, confirming the assignment of on-surface diacetylene polymerization. Transferring the concept of using diacetylene polymerization for creating conductive connections to bulk insulator surfaces paves the way towards application-relevant systems for future molecular electronic devices. PMID- 28561081 TI - Cobalt-porphine catalyzed CO2 electro-reduction: a novel protonation mechanism. AB - The urgent need for artificially fixing CO2 calls for catalysts of high efficiency. The transition metal functionalized porphyrin (TMP) is one of the most important types of organic catalysts for CO2 reduction. However, the catalytic mechanisms of TMP in CO2 reduction still remain controversial. Starting from the previously neglected catalyst self-protonation model, we uncover a new CO2 reduction mechanism on cobalt-porphine, which involves an indirect proton transfer step occurring at the beginning of the reduction cycle. Based on this protonation mechanism, we demonstrate the different correlations between producing rate and pH for the formation of CO and methane, in good agreement with available experimental observations. Our results reveal how pH and potential affect the CO2 reduction process, providing important clues and insights for further optimization of TMP catalysts. PMID- 28561082 TI - Heteroaggregation of oppositely charged particles in the presence of multivalent ions. AB - Time-resolved dynamic light scattering is used to measure absolute heteroaggregation rate coefficients and the corresponding stability ratios for heteroaggregation between amidine and sulfate latex particles. These measurements are complemented by the respective quantities for the homoaggregation of the two systems and electrophoresis. Based on the latter measurements, the stability ratios are calculated using Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. In monovalent salt solutions, the two types of particles investigated are oppositely charged. In the presence of multivalent ions, however, one particle type reverses its charge, while the charge of the other particle type is hardly affected. In this region, the heteroaggregation stability ratio goes through a pronounced maximum when plotted versus concentration. This region of slow aggregation is wider than the one observed in the corresponding homoaggregation process. One also finds that the onset of this region sensitively depends on the boundary conditions used to calculate the double layer force. The present results are more in line with constant potential boundary conditions. PMID- 28561083 TI - A DFT study of the adsorption of glycine in the interlayer space of montmorillonite. AB - The adsorption properties of clay minerals have been widely studied in several technological areas, due to their versatility, absorption capacity and catalytic properties. The interaction of amino acids with clay surfaces can be interesting due to their role in prebiotic scenarios. Different degrees of hydration and the adsorption of the glycine molecule and glycinium cation in the interlayer space of montmorillonite were investigated by means of calculations based on density functional theory (DFT). Our calculations show that the cation exchange of K+ by glycinium in the interlayer of hydrated K-montmorillonite is highly possible and exothermic. This supports previous experimental results by explaining the possible adsorption of glycine as a molecule and cation. Glycine is adsorbed in a zwitterionic form in the interlayer without being solvated with water. Besides, glycine and glycinium are highly exothermically adsorbed in the interlayer. The interlayer spacings under different conditions were in agreement with the experimental values. Hydrogen bonds and electrostatic interactions between molecules and surface atoms are responsible for this exothermicity. The IR spectra were calculated and compared with the experimental results showing interesting frequency shifts depending on the intermolecular interactions in the interlayer space of montmorillonite. PMID- 28561084 TI - A label-free colorimetric biosensor for sensitive detection of vascular endothelial growth factor-165. AB - Sensitive detection of a low abundant protein is essential for biomedical research and clinical diagnostics. Herein, we develop a label-free colorimetric biosensor for the sensitive detection of recombinant human vascular endothelial growth factor-165 (VEGF165). This biosensor consists of an aptamer-based hairpin probe, an assistant DNA-trigger duplex and a linear template. In the presence of VEGF165, the specific binding of VEGF165 with the aptamer-based hairpin probe results in the opening of a hairpin probe and the opened hairpin probe subsequently hybridizes with the single-stranded region of the assistant DNA trigger duplex to initiate the strand displacement amplification (SDA) to yield abundant triggers. The released triggers can further function as the primers to anneal with the hairpin probe and lead to the opening of the hairpin structure, which subsequently hybridizes with the assistant DNA-trigger duplex to initiate the next round of SDA reaction and generates more triggers. Large amounts of triggers could be generated by the synergistic operation of dual SDA reaction, and the obtained triggers can initiate a new round of SDA reaction to yield numerous G-quadruplex DNAzymes, which subsequently catalyze the conversion of ABTS2- to ABTS- by H2O2 to yield a color change with the assistance of a cofactor hemin. In contrast, in the absence of target VEGF165, the hairpin probe, the assistant DNA-trigger duplex and the linear template can stably coexist in solution, and thus no color change is observed because no trigger can initiate SDA to generate the G-quadruplex DNAzyme. This biosensor has a low detection limit of 1.70 pM and a dynamic range over 3 orders of magnitude from 24.00 pM to 11.25 nM. Moreover, the biosensor shows excellent specificity toward the target VEGF165 and the entire reaction can be carried out in an isothermal manner without the involvement of a high precision thermal cycler, making the current assay extremely cost effective. PMID- 28561085 TI - Enhanced conductivity of sodium versus lithium salts measured by impedance spectroscopy. Sodium cobaltacarboranes as electrolytes of choice. AB - The development of new types of ion conducting materials is one of the most important challenges in the field of energy. Lithium salt polymer electrolytes have been the most convenient, and thus the most widely used in the design of the new generation of batteries. However, in this work, we have observed that Na+ ions provide a higher conductivity, or at least a comparable conductivity to that of Li+ ions in the same basic material. This provides an excellent possibility to use Na+ ions in the design of a new generation of batteries, instead of lithium, to enhance conductivity and ensure wide supply. Our results indicate that the dc conductivity is larger when the anion is [Co(C2B9H11)2]-, [COSANE]-, compared to tetraphenylborate, [TPB]-. Our data also prove that the dc-conductivity behavior of Li+ and Na+ salts is opposite with the two anions. At 40 degrees C, the conductivity values change from 1.05 * 10-2 S cm-1 (Li[COSANE]) and 1.75 * 10-2 S cm-1 (Na[COSANE]) to 2.8 * 10-3 S cm-1 (Li[TPB]) and 1.5 * 10-3 S cm-1 (Na[TPB]). These findings indicate that metallacarboranes can be useful components of mixed matrix membranes (MMMs), providing excellent conductivity when the medium contains sufficient amounts of ionic components and a certain degree of humidity. PMID- 28561086 TI - Diabetic wound regeneration using heparin-mimetic peptide amphiphile gel in db/db mice. AB - There is an urgent need for more efficient treatment of chronic wounds in diabetic patients especially with a high risk of leg amputation. Biomaterials capable of presenting extracellular matrix-mimetic signals may assist in the recovery of diabetic wounds by creating a more conducive environment for blood vessel formation and modulating the immune system. In a previous study, we showed that glycosaminoglycan-mimetic peptide nanofibers are able to increase the rate of closure in STZ-induced diabetic rats by induction of angiogenesis. The present study investigates the effect of a heparin-mimetic peptide amphiphile (PA) nanofiber gel on full-thickness excisional wounds in a db/db diabetic mouse model, with emphasis on the ability of the PA nanofiber network to regulate angiogenesis and the expression of pro-inflammatory cytokines. Here, we showed that the heparin-mimetic PA gel can support tissue neovascularization, enhance the deposition of collagen and expression of alpha-smooth muscle actin (alpha SMA), and eliminate the sustained presence of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in the diabetic wound site. As the absence of neovascularization and overexpression of pro-inflammatory markers are a hallmark of diabetes and interfere with wound recovery by preventing the healing process, the heparin-mimetic PA treatment is a promising candidate for acceleration of diabetic wound healing by modulating angiogenesis and local immune response. PMID- 28561088 TI - Mapping the ionic fingerprints of molecular monolayers. AB - We have previously proposed, and experimentally resolved, an ionic charge relaxation model for redox inactive self-assembled monolayers (SAMs) on metallic electrodes in contact with a liquid electrolyte. Here we analyse, by capacitance spectroscopy, the resistance and capacitance terms presented by a range of thiolated molecular films. Molecular dynamics simulations support a SAM-specific energy barrier to solution-phase ions. Once surmounted, the entrapped ions support a film embedded ionic capacitance and non-faradaic relaxation, which can be assigned as a particular case of general electrochemical capacitance. PMID- 28561090 TI - The new age of MOFs and of their porous-related solids. PMID- 28561089 TI - Hierarchical core-shell CoMn2O4@MnO2 nanoneedle arrays for high-performance supercapacitors. AB - Hierarchical mesoporous core-shell CoMn2O4@MnO2 nanoneedle arrays on nickel foam have been manufactured via a two-step hydrothermal process. Electrochemical performances of the CoMn2O4@MnO2 nanomaterials have been tested for supercapacitors and demonstrated outstanding properties. The CoMn2O4@MnO2 electrode delivers a specific capacitance of 2126 F g-1 at a current density of 1 A g-1 in 2 M KOH aqueous solution and also shows an excellent cycling stability, which retains 94.4% of the initial capacitance after 5000 charge/discharge cycles at a current density of 4 A g-1. The result confirms the superiority of the CoMn2O4@MnO2 electrode compared with the CoMn2O4 electrode and demonstrates the potential application of the CoMn2O4@MnO2 nanoneedle array electrode for high performance energy storage device applications. PMID- 28561091 TI - Design of a highly active base catalyst through utilizing organic-solvent-treated layered silicate Hiroshima University Silicates. AB - Crystalline layered silicates are promising materials for the rational design of innovative catalysts owing to their wide variety and easily tunable surfaces. However, diffusional limitation in their interlayer spaces limits their catalytic efficiency. Herein, we have developed a novel synthesis route to a highly active layered silicate catalyst utilizing Hiroshima University Silicates (HUSs). We attempted to tune the stacking structure of the silicate layers of HUS-2 and HUS 7 ion-exchanged with hexadecyltrimethylammonium (C16TMA) using organic-solvent treatment, and found that cyclohexane treatment of HUS-7 gave an aggregate of randomly restacked silicate nanosheets without degradation of the original silicate framework. We prepared amine-modified base catalysts by grafting with aminopropyltriethoxysilane, and investigated their catalytic performances in the transesterification of triacetin with methanol. The catalyst based on HUS-7 exhibited a much higher catalytic activity than that based on HUS-2 despite their similar framework topology. Moreover, the activity of the HUS-7-based catalyst was far superior to those of other base catalysts, such as amine-modified mesoporous silica, catalyst resin, and alkylamine. Detailed characterization of the catalysts revealed that the improved accessibility of reactant molecules to the immobilized functional units, which is derived from both the randomly stacked silicate layers and the bulky interlayer molecules incorporated, is the primary reason for the high catalytic efficiency of the layered silicate catalyst. PMID- 28561092 TI - A field analysis of lampricide photodegradation in Great Lakes tributaries. AB - The lampricides 3-trifluoromethyl-4-nitrophenol (TFM) and 2',5-dichloro-4' nitrosalicylanilide (niclosamide) are added to Great Lakes tributaries to target the sea lamprey, an invasive parasitic fish. This study examines the photochemical behavior of the lampricides in Carpenter Creek, Sullivan Creek, and the Manistique River. The observed loss of TFM in Carpenter and Sullivan Creeks (i.e., 34 and 19%) was similar to the loss of bromide in parallel time of passage studies (i.e., 30 and 29%), demonstrating that TFM photodegradation was minimal in both tributaries during the lampricide application. Furthermore, the absence of inorganic and organic photoproducts in the Manistique River demonstrates that TFM and niclosamide photodegradation was minimal in this large tributary, despite its long residence time (i.e., 3.3 days). Kinetic modeling was used to identify environmental variables primarily responsible for the limited photodegradation of TFM in the field compared to estimates from laboratory data. This analysis demonstrates that the lack of TFM photodegradation was attributable to the short residence times in Carpenter and Sullivan Creeks, while depth, time of year, time of day, and cloud cover influenced photochemical fate in the Manistique River. The modeling approach was extended to assess how many of the 140 United States tributaries treated with lampricides in 2015 and 2016 were amenable to TFM photolysis. While >50% removal of TFM due to photolysis could occur in 13 long and shallow tributaries, in most systems lampricides will reach the Great Lakes untransformed. PMID- 28561093 TI - Order-disorder phase transitions in Au-Cu nanocubes: from nano-thermodynamics to synthesis. AB - Catalysts have been widely used in industries and can be optimized by tuning the composition and chemical ordering of the elements involved in the nano-alloy. Among bi-metallic alloys, the Au-Cu system is of particular interest because it exhibits ordered phases at low temperatures. Nevertheless, the temperature at which these ordered structures are formed is totally unknown at the nanoscale. Consequently, to speed up the development of these catalysts, this paper theoretically predicts the structural phase transitions between ordered and disordered phases for the Au-Cu system by using nano-thermodynamics. Following the predictions, the suggested annealing temperatures have been carefully chosen and consequently, Au-Cu ordered nanocubes have been successfully synthesized through a solventless protocol. The results are fully supported by electron microscopy observations. PMID- 28561094 TI - Unusual spin-polarized electron state in fullerene induced by carbon adatom defect. AB - First-principles calculations show that a carbon adatom defect at the Def[5, 6] site on the surface of C60 can produce a more stable spin-polarized singlet electronic state instead of a magnetic triplet state. This is clearly different from the cases of graphene and nanotubes. The mechanism results from the electron population of the adatom, which produces antiferromagnetic coupling around the C60 cage and the adatom itself. Our calculations show the same phenomenon occurs in other IPR fullerenes, such as C70 and C80. These findings extend the understanding of the magnetic origin of pure carbon structures and are valuable for research related to the spin polarization of carbon systems. PMID- 28561095 TI - Metal carbonate complexes formed through the capture of ambient O2 and CO2 by elemental metals in 1-methylimidazole: molecular Cu(CO3)(MeIm)3 and polymeric M(CO3)(MeIm)2.2H2O (M = Co, Zn). AB - When immersed in 1-methylimidazole, the metals copper, zinc, and cobalt will react with ambient dioxygen and carbon dioxide to yield the blue-green molecular complex Cu(CO3)(MeIm)3 and the pair of isostructural polymeric complexes Zn(CO3)(MeIm)2.2H2O and Co(CO3)(MeIm)2.2H2O, respectively. PMID- 28561096 TI - Enhancements in catalytic reactivity and selectivity of homobimetallic complexes containing heteroditopic ligands. AB - Rh(i) and Ir(i) homobimetallic complexes were synthesised using a heteroditopic ligand system on a xanthene scaffold containing a monodentate N-heterocyclic carbene ligand and a bidentate bis(pyrazol-1-yl)methane ligand. The complexes were tested as catalysts for the two-step dihydroalkoxylation and two-step hydroamination/hydrosilylation reactions. This is the first known report of an organometallic group 9 complex, Ir(i) bimetallic complex, 13, to selectively favour the opposite spirocyclisation product from that reported in the literature, 14cvs.14b. The Ir(i) homobimetallic complex catalyses the intramolecular hydroamination reaction of alkynamines efficiently and proved to be a highly active catalyst for promoting the subsequent hydrosilylation of the pyrrolines; completing the hydrosilylation reactions in less than 40 seconds. A chloro-bridged bimetallic species was observed in the solid state, revealing that the COD co-ligands present underwent an oxidation. PMID- 28561100 TI - Energetic pi-conjugated vinyl bridged triazoles: a thermally stable and insensitive heterocyclic cation. AB - A new family of vinyl bridge 1,1'-(ethane-5-yl)-bis(3,4-diamino-1,2,4-triazolium) salts were explored as novel structural energetic materials. These new salts were further characterized by elemental analysis, infrared and multinuclear NMR spectra. Structural confirmation of nine salts such as 4-11 and 14 was supported by single-crystal X-ray diffraction. Theoretical investigations associated with heats of formation and detonation performance were carried out by employing the Gaussian 09 program and the EXPLO5 V6.02 code, respectively. The sensitivities towards impact and friction were studied using BAM standards. According to the experimental and computational data, these salts show densities ranging from 1.61 to 1.82 g cm-3 at 298 K, good thermal stabilities (Td: 217 degrees C-322 degrees C), excellent detonation performance (P: 7809 m s-1 to 9640 m s-1, D: 24.6 GPa-33.9 GPa) and rational impact and friction sensitivities (IS: 4 J to 60 J, FS: 120 N to 360 N). PMID- 28561097 TI - DNA preservation in silk. AB - The structure of DNA is susceptible to alterations at high temperature and on changing pH, irradiation and exposure to DNase. Options to protect and preserve DNA during storage are important for applications in genetic diagnosis, identity authentication, drug development and bioresearch. In the present study, the stability of total DNA purified from human dermal fibroblast cells, as well as that of plasmid DNA, was studied in silk protein materials. The DNA/silk mixtures were stabilized on filter paper (silk/DNA + filter) or filter paper pre-coated with silk and treated with methanol (silk/DNA + PT-filter) as a route to practical utility. After air-drying and water extraction, 50-70% of the DNA and silk could be retrieved and showed a single band on electrophoretic gels. 6% silk/DNA + PT-filter samples provided improved stability in comparison with 3% silk/DNA + filter samples and DNA + filter samples for DNA preservation, with ~40% of the band intensity remaining at 37 degrees C after 40 days and ~10% after exposure to UV light for 10 hours. Quantitative analysis using the PicoGreen assay confirmed the results. The use of Tris/borate/EDTA (TBE) buffer enhanced the preservation and/or extraction of the DNA. The DNA extracted after storage maintained integrity and function based on serving as a functional template for PCR amplification of the gene for zinc finger protein 750 (ZNF750) and for transgene expression of red fluorescence protein (dsRed) in HEK293 cells. The high molecular weight and high content of a crystalline beta-sheet structure formed on the coated surfaces likely accounted for the preservation effects observed for the silk/DNA + PT-filter samples. Although similar preservation effects were also obtained for lyophilized silk/DNA samples, the rapid and simple processing available with the silk-DNA-filter membrane system makes it appealing for future applications. PMID- 28561101 TI - On the outside looking in: rethinking the molecular mechanism of 1,3-dipolar cycloadditions from the perspective of bonding evolution theory. The reaction between cyclic nitrones and ethyl acrylate. AB - In this work we report on the progress that has been made towards gaining an understanding of the molecular mechanism of 1,3-dipolar cycloadditions using the bonding evolution theory (BET). A detailed analysis of the flow of electron density along the reaction pathway of the formal 1,3-dipolar cycloaddition reaction between cyclic nitrones (pyrroline-1-oxide and 2,3,4,5 tetrahydropyridine-1-oxide) and ethyl acrylate, as a case study, allowed the nature of the molecular mechanisms to be characterized. The present study provides a deep insight into the reaction mechanism, based on the electron density rearrangements given by the structural stability domains, and their connection with the bond breaking/forming processes along the reaction pathway. The electron pushing formalism is a powerful tool to describe chemical reactivity. Here, we show how the Lewis structures can be recovered and how curly arrows describe electron density transfers in chemical reaction mechanisms based on the BET results. The reaction mechanism is described by four consecutive events taking place as the reaction progresses: (1) the population of the initial N-C double bond is transferred to the N and C atoms; (2) the population of the initial double C-C bond is transferred to the C atoms. Along the ortho pathway the next steps are: (3) the C-C bond-forming process, and (4) the O-C bond forming process. The order of (3) and (4) is inverted in the meta channel. Based on the sequence of the structural stability domains along the intrinsic reaction coordinate, a new synchronicity index is proposed, allowing us to classify and quantify the (a)synchronicity of the 1,3-DC reactions and, therefore, the nature of the reaction mechanism. PMID- 28561102 TI - Two bilayer metal-organic frameworks with rare trinuclear heterometal clusters and tunable photoluminescence. AB - Two bilayer metal-organic frameworks (MOFs) respectively containing trinuclear Pb/K and Cd/Na clusters have been solvothermally synthesized. Photoluminescence studies showed that they exhibit tunable purple-to-red-to-green and purple-to green luminescence behaviours by variation of excitation light, respectively. PMID- 28561103 TI - Correlation and squeezing for optical transistor and intensity for router applications in Pr3+:YSO. AB - We realized an optical transistor and router utilizing multi-order fluorescence and spontaneous parametric four-wave mixing. Specifically, the optical routing action was derived from the results of splitting in the intensity signal due to a dressing effect, whereas the transistor as a switch and amplifier was realized by a switching correlation and squeezing via a nonlinear phase. A substantial enhancement of the optical contrast was observed for switching applications using correlation and squeezing contrary to the intensity signal. Moreover, the controlling parameters were also configured to devise a control mechanism for the optical transistor and router. PMID- 28561105 TI - Elucidating the structure of light absorbing styrene carbocation species formed within zeolites. AB - Styrene derivatives can form carbocation species upon contact with zeolites. In this study, structures of a series of styrene derivatives with substituents in the para position, which have been obtained experimentally, were elucidated using theoretical calculations. Styrene with F, Cl, Br, methyl (Me) and methoxy (MeO) groups was studied by means of (TD)-DFT calculations. Electronic structure changes depending on the substituents, Br and MeO, showed smaller HOMO-LUMO gaps in the series. Theoretical excitation energies of two dimeric species were found to match very well with absorption bands reported experimentally. Ternary and secondary carbocation dimeric species were found to be responsible for the absorption of light in the visible region. Both structures were studied using aromaticity indexes as well as atoms-in-molecules theory to understand the changes in electron delocalization to produce non-typical light absorbing compounds. Aromatic rings with all the substituents lose aromaticity to reinforce charge transfer within the molecule, stabilizing the adjacent carbocation species. The results are attractive to interpret the electronic spectra of such compounds formed within zeolites and for a better understanding of the electronic structure as well as the reaction mechanisms of the carbocation species. PMID- 28561106 TI - Effect of water on the effective Goldschmidt tolerance factor and photoelectric conversion efficiency of organic-inorganic perovskite: insights from first principles calculations. AB - Water is often believed to be the leading killer of perovskite solar cells' efficiency. However, recent experimental results show that perovskite solar cells have higher photoelectric conversion efficiency in a suitably moist environment. In this study, the relationship between the interstitial water molecule and the theoretical maximum efficiency of the perovskite absorber layer is discussed based on density functional theory calculations. Our calculated results show that an interstitial water molecule can enlarge the effective Goldschmidt tolerance factor, which is an empirical structural parameter for the structure of the perovskite material. The primitive MAPbI3 structure is not the ideal perovskite structure with the highest photoelectric conversion efficiency. Surprisingly, appropriate interstitial water molecules are beneficial to perovskite absorbers in terms of increasing photoelectric conversion efficiency. This can be attributed to the relatively larger effective Goldschmidt tolerance factor of the perovskite structure with an interstitial water molecule, which affects the photoelectric conversion efficiency of the perovskite structure. Our calculations indicate that the perovskite absorbers with a H2O : MAPbI3 ratio of 1/4-1/2 have a relatively higher photoelectric conversion efficiency. This study helps us understand the role of the interstitial molecule in the perovskite structure deeply, which is very useful in the design and optimization of the perovskite absorbers for high-efficiency perovskite cells. PMID- 28561112 TI - Determination of zero-field splitting in Co2+ halide complexes with magnetic and far-IR measurements. AB - Three penta-coordinate Co2+ complexes with halide substitutes were synthesized. Their zero-field splitting (ZFS) parameters were determined by fitting dc magnetic data and far-infrared magneto-transmission spectra. The results gave an unusual case that complexes with heavier halide atoms bear smaller ZFS parameters. PMID- 28561113 TI - Iron-catalyzed C-H/N-H activation by triazole guidance: versatile alkyne annulation. AB - Iron-catalyzed C-H/N-H functionalizations were achieved by the aid of modular triazole amides. The alkyne annulation allowed for the expedient synthesis of valuable isoquinolone scaffolds with high levels of chemo-, site- and regio selectivities. PMID- 28561114 TI - Cool white, persistent room-temperature phosphorescence in carbon dots embedded in a silica gel matrix. AB - Herein we report the observation of room-temperature phosphorescence from carbon dots (CDs) embedded in a silica gel matrix. The precursors used in the synthesis (malonic acid and ethylene diamine) were chosen to have the surface of the CDs rich in C[double bond, length as m-dash]O and C[double bond, length as m-dash]N functionalities. The CDs in an aqueous dispersion exhibit an intense blue fluorescence and upon incorporation into silica gel demonstrate a green after glow, which is visible even to the naked eye. The phosphorescence measurements indicated that the life-time of phosphorescence emission is about 1.8 s, under 380 nm excitation, which is the highest magnitude reported for CDs in solid-state matrices. Moreover, the 1931 CIE color parameters corresponding to the phosphorescence emission are in the white gamut region of the chromaticity diagram. PMID- 28561115 TI - Horizontally aligned carbon nanotube arrays: growth mechanism, controlled synthesis, characterization, properties and applications. AB - Carbon nanotubes (CNTs) have attracted worldwide research interest in the past two decades owing to their extraordinary properties and wide applications in numerous fields. Among various types of CNTs, the horizontally aligned CNT (HACNT) arrays, which consist of CNTs grown on flat substrates and parallel with each other with large intertube distances and lengths up to centimeters, show many advantages due to their perfect structures and extraordinary mechanical, thermal and electrical properties. HACNTs show great potential as building blocks for transparent displays, nano electronics, quantum lines, field emission transistors, superstrong tethers, aeronautics and astronics materials, and even space elevators. During the past years, great progress has been achieved in HACNT research. In this review, we systematically review the growth mechanism, structure control, morphology control, characterization, manipulation, properties, and applications of HACNTs. Finally, we present a summary and outlook for the future development of HACNTs. We hope these advances will shed light on the future study of HACNTs. PMID- 28561116 TI - Multistage extraction platform for highly efficient and fully continuous purification of nanoparticles. AB - This paper presents a fully-continuous novel liquid-liquid-extraction (LLE) platform for the purification of nanoparticles. The use of multistage operation enhances the purity of the final stream without the expense of high solvent consumption. Two case studies, purification of CdSe quantum dots in organic solvent and that of gold nanoparticles in water, demonstrate that the LLE platform is versatile, non-destructive, and highly efficient. PMID- 28561118 TI - A close-packed 3D plasmonic superlattice of truncated octahedral gold nanoframes. AB - We report the surface-enhanced Raman scattering (SERS) enhancement of three dimensional (3D) close-packed plasmonic superlattices of truncated octahedral gold nanostructures. Experimentally, we resolved two different types of hot spots, one originates from the face-to-face contacts and the other is from the edge-to-edge contacts among the 3D close-packed plasmonic superlattice of gold nanostructures. The high degree of homogeneity of truncated octahedral Au@Pt nanoparticles (TOh Au@Pt NPs) and truncated octahedral Pt@Au nanoframes (TOh Pt@Au NFs) allowed them to self-assemble into remarkable 3D close-packed plasmonic superlattices. The morphological evolution and the corresponding optical behavior of TOh Pt@Au NFs were systematically monitored during each synthetic process. The measured SERS enhancement on the hot spots from the edge to-edge contacts of TOh Pt@Au NFs was five times greater than the SERS response from the analogous face-to-face contacts of TOh Au@Pt NPs under the same given experimental conditions. The hollow interior and well-defined structural morphology of TOh Pt@Au NFs will allow researchers to design highly programmable 3D plasmonic superlattices for efficient SERS enhancement. PMID- 28561120 TI - Paramagnetic ionic plastic crystals containing the octamethylferrocenium cation: counteranion dependence of phase transitions and crystal structures. AB - In recent years, ionic plastic crystals have attracted much attention. Many metallocenium salts exhibit plastic phases, but factors affecting their phase transitions are yet to be elucidated. To investigate these factors, we synthesized octamethylferrocenium salts with various counteranions [Fe(C5Me4H)2]X ([1]X; X- = B(CN)4-, C(CN)3-, N(CN)2-, FSA (= (SO2F)2N-), FeCl4-, GaCl4- and CPFSA (= CF2(SO2CF2)2N-)) and elucidated their crystal structures and phase behavior. Correlations between the crystal structures and phase sequences, and the shapes and volumes of the anions are discussed. Except for [1][CPFSA], these salts exhibit phase transitions to plastic phases at or above room temperature (TC = 298-386 K), and the plastic phases exhibit either NaCl- or anti-NiAs-type structures. X-ray crystal structure analyses of these salts at 100 K revealed that they have structures in which cations and anions are alternately arranged, with the exception of [1][CPFSA]. [1][CPFSA] exhibits a structure in which anions and cations are separately stacked to form columns. [1][N(CN)2] exhibits a polar crystal structure that undergoes a monotropic phase transition to a centrosymmetric structure. The magnetic susceptibilities of room-temperature plastic crystals [1][GaCl4] and [1][FeCl4] were investigated; the latter exhibits a small ferromagnetic interaction at low temperatures. PMID- 28561123 TI - Correction: Giant vesicles from rehydrated crude mixtures containing unexpected mixtures of amphiphiles formed under plausibly prebiotic conditions. AB - Correction for 'Giant vesicles from rehydrated crude mixtures containing unexpected mixtures of amphiphiles formed under plausibly prebiotic conditions' by Michele Fiore et al., Org. Biomol. Chem., 2017, 15, 4231-4240. PMID- 28561121 TI - Photo-clickable microRNA for in situ fluorescence labeling and imaging of microRNA in living cells. AB - A photo-clickable microRNA whose fluorescence was able to be turned on by mild light irradiation was constructed and the in situ fluorescence turn-on of the photo-clickable microRNA-122 in living cells was demonstrated by light irradiation with spatial and temporal resolution. PMID- 28561125 TI - Preparation and characterization of a calcium-phosphate-silicon coating on a Mg Zn-Ca alloy via two-step micro-arc oxidation. AB - Magnesium alloys are the most promising implant materials due to their excellent biodegradability. However, their high degradation rate limits their practical application. In this study, we produced a calcium-phosphate (Ca-P) coating and a calcium-phosphate-silicon (Ca-P-Si) coating via one-step and two-step micro-arc oxidation processes, respectively. The microstructure and chemical composition of the MAO coatings were characterized using SEM, XRD and EDS. The degradation behaviors of the MAO coatings and the substrate were investigated using electrochemical techniques and immersion tests in simulated body fluid (SBF). The results show that the silicate was successfully incorporated into the Ca-P coating in the second MAO step, and this also increased the thickness of the coating. The Ca-P-Si coatings remarkably reduced the corrosion rate of the Mg alloy and Ca-P coating during 18 days of immersion in SBF. In addition, the bone like apatite layer on the sample surface demonstrated the good biomineralization ability of the Ca-P-Si coating. Potentiodynamic polarization results showed that the MAO coating could clearly enhance the corrosion resistance of the Mg alloy. Moreover, we propose the growth mechanism of the MAO coating in the second step. PMID- 28561126 TI - Impulsive laser-induced alignment of OCS molecules at FERMI. AB - We demonstrate the experimental realization of impulsive alignment of carbonyl sulfide (OCS) molecules at the Low Density Matter Beamline (LDM) at the free electron laser FERMI. OCS molecules in a molecular beam were impulsively aligned using 200 fs pulses from a near-infrared laser. The alignment was probed through time-delayed ionization above the sulphur 2p edge, resulting in multiple ionization via Auger decay and subsequent Coulomb explosion of the molecules. The ionic fragments were collected using a time-of-flight mass spectrometer and the analysis of ion-ion covariance maps confirmed the correlation between fragments after Coulomb explosion. The analysis of the CO+ and S+ channels allowed us to extract the rotational dynamics, which is in agreement with our theoretical description as well as with previous experiments. This result opens the way for a new class of experiments at LDM within the field of coherent control of molecules with the possibilities that a precisely synchronized optical-pump XUV-probe laser setup like FERMI can offer. PMID- 28561127 TI - Integrating perfusable vascular networks with a three-dimensional tissue in a microfluidic device. AB - Creating vascular networks in tissues is crucial for tissue engineering. Although recent studies have demonstrated the formation of vessel-like structures in a tissue model, long-term culture is still challenging due to the lack of active perfusion in vascular networks. Here, we present a method to create a three dimensional cellular spheroid with a perfusable vascular network in a microfluidic device. By the definition of the cellular interaction between human lung fibroblasts (hLFs) in a spheroid and human umbilical vein endothelial cells (HUVECs) in microchannels, angiogenic sprouts were induced from microchannels toward the spheroid; the sprouts reached the vessel-like structures in a spheroid to form a continuous lumen. We demonstrated that the vascular network could administer biological substances to the interior of the spheroid. As cell density in the spheroid is similar to that of a tissue, the perfusable vasculature model opens up new possibilities for a long-term tissue culture in vitro. PMID- 28561128 TI - Molecular dynamics study of solvated aniline and ethylene glycol monomers confined in calcium silicate nanochannels: a case study of tobermorite. AB - The combination of organic and inorganic materials can result in materials with extraordinary performance. In this work, molecular dynamics was employed to investigate the structure, dynamics, interfacial behavior, and polymerization tendency of two types of monomers, aniline (AN) and ethylene glycol (EG), confined in the nanopores of calcium silicate hydrate (C-S-H) gel. The interaction mechanism between the polymer and C-S-H gel has been interpreted: the silicate chains can provide nonbridging oxygen sites to accept H-bonds from the hydroxyl in EG and -NH2 functional groups in AN monomers. Due to stronger H-bond interactions, EG monomers are more likely to penetrate deeper into the C-S-H surface and exhibit a more pronounced orientation preference and longer resident time in the interfacial region compared with AN monomers. However, neighboring AN monomers exhibit strong spatial correlation and prefer to aggregate as large clusters, while EG monomers diffuse separately in bulk solution. Dynamically, the diffusion coefficients of monomers in the vicinity of the C-S-H surface were greatly reduced compared with those in the bulk solution due to restriction by H bonds and attraction to surface calcium ions. Furthermore, with increasing monomer concentration, both monomers achieved greater surface adsorption density and penetration depth, and longer interfacial resident times. Higher concentrations also contributed to increased cluster size for AN monomers. The interaction mechanism in this organic-inorganic system provides useful guidelines for polymer selection, design, and fabrication of C-S-H/polymer nanocomposites. PMID- 28561129 TI - AlCl3 catalyzed coupling of N-benzylic sulfonamides with 2-substituted cyanoacetates through carbon-nitrogen bond cleavage. AB - A new cross-coupling reaction of N-benzylic sulfonamides with 2-substituted cyanoacetates for the synthesis of 2-substituted benzylbenzene was reported. In the presence of AlCl3, a broad range of N-benzylic sulfonamides reacted smoothly with 2-substituted cyanoacetates to afford structurally diverse benzylbenzenes in moderate to excellent yields. The conversion could be enlarged to gram-scale efficiently. The practicability of this approach was further manifested in the synthesis of a related bioactive agent with high anti-inflammatory activity. PMID- 28561131 TI - Feeding Jejunostomy: Is It a Safe Route in Pediatric Patients? Single Institution Experience. AB - INTRODUCTION: Impossibility to place a gastrostomy and failed gastroesophageal reflux surgery with unsafe swallow are the main indications to Feeding Jejunostomy (FJ) in children. The aim of this study is to quantify the incidence of complications associated with FJ. MATERIALS AND METHODS: A retrospective review of patients who had surgically inserted FJ between January 2009 and August 2013 at our institution was conducted. Data were obtained from medical records, operative notes, and radiology database, focusing on complications. RESULTS: A total of 19 patients, average age 39.6 months (3-168 months), were treated during the study period. Indications to FJ were gastroesophageal reflux disease (GERD) associated with unsafe swallow in 12, esophageal atresia in 5, and foregut dysmotility in 2. Seventeen FJ were inserted via laparotomy and 2 were laparoscopically assisted. In all cases, a serosal tunnel on the antimesenteric border was fashioned. No intraoperative complications were recorded. Tube dislodgement/blockage occurred on an average of 0.48 times per month in 18 out of 19 patients. The average radiation dose received for tube reinsertion/manipulation was 3.316 mSv/year/patient (0-10.66). Major postoperative complications occurred in 7 out of 19. After an average follow-up of 21 months, two have abandoned the use of FJ due to poor tolerance and three have fully weaned off. Two patients died due to unrelated causes. CONCLUSION: FJ, as an alternative means for enteral feeding, may require multiple readmissions and exposure to radiological procedures. The high risk of severe complications should be considered when offering this procedure. PMID- 28561130 TI - The effects of natural language processing on cross-institutional portability of influenza case detection for disease surveillance. AB - OBJECTIVES: This study evaluates the accuracy and portability of a natural language processing (NLP) tool for extracting clinical findings of influenza from clinical notes across two large healthcare systems. Effectiveness is evaluated on how well NLP supports downstream influenza case-detection for disease surveillance. METHODS: We independently developed two NLP parsers, one at Intermountain Healthcare (IH) in Utah and the other at University of Pittsburgh Medical Center (UPMC) using local clinical notes from emergency department (ED) encounters of influenza. We measured NLP parser performance for the presence and absence of 70 clinical findings indicative of influenza. We then developed Bayesian network models from NLP processed reports and tested their ability to discriminate among cases of (1) influenza, (2) non-influenza influenza-like illness (NI-ILI), and (3) 'other' diagnosis. RESULTS: On Intermountain Healthcare reports, recall and precision of the IH NLP parser were 0.71 and 0.75, respectively, and UPMC NLP parser, 0.67 and 0.79. On University of Pittsburgh Medical Center reports, recall and precision of the UPMC NLP parser were 0.73 and 0.80, respectively, and IH NLP parser, 0.53 and 0.80. Bayesian case-detection performance measured by AUROC for influenza versus non-influenza on Intermountain Healthcare cases was 0.93 (using IH NLP parser) and 0.93 (using UPMC NLP parser). Case-detection on University of Pittsburgh Medical Center cases was 0.95 (using UPMC NLP parser) and 0.83 (using IH NLP parser). For influenza versus NI-ILI on Intermountain Healthcare cases performance was 0.70 (using IH NLP parser) and 0.76 (using UPMC NLP parser). On University of Pisstburgh Medical Center cases, 0.76 (using UPMC NLP parser) and 0.65 (using IH NLP parser). CONCLUSION: In all but one instance (influenza versus NI-ILI using IH cases), local parsers were more effective at supporting case-detection although performances of non-local parsers were reasonable. PMID- 28561132 TI - Safely Decreasing Rigid Bronchoscopies for Foreign-Body Aspiration in Children: An Algorithm for the Emergency Department. AB - INTRODUCTION: Rigid bronchoscopy was traditionally performed in the management of foreign-body aspiration (FBA). More recently, since development of a less invasive method, flexible bronchoscopy has been proposed in some centers for the management of FBA. For the past few years, we have applied a decisional algorithm, privileging flexible bronchoscopy for diagnosis and, in some cases, for extraction of foreign body (FB). Our aims are first to analyze our current management of FBA and second to examine the bronchoscopic findings and complications. MATERIALS AND METHODS: Retrospective medical chart review of all patients with clinical suspicion of FBA who underwent bronchoscopy (flexible and/or rigid) from 2009 through 2014. RESULTS: An FB was found in 23 (33%) of the 70 patients included in the study (45 boys, 25 girls; median age: 21.5 months). Diagnosis of FBA was made on first intention in 22/23 (96%) and extraction was performed in 7/23 (30%) by flexible bronchoscopy. Rigid bronchoscopy was necessary for the extraction of the 16/23 (70%) remaining FBs. The rigid procedure was performed as first intention in only two (3%) patients, and one of the two was negative. Among the clinical signs of FBA, none were > 90% specific except for apnea (100%), but which was poorly sensitive (22%). Seven clinical and radiologic signs were found to be significantly different between FB+ and FB- groups: sudden choking, cyanosis, apnea, decreased breath sounds, atelectasis, mediastinal shift, and air trapping. Conversely, when none of these symptoms or signs and no clear history of sudden choking were present (in 15/70 patients), no FB was found. No life-threatening complications or death were observed. CONCLUSION: Our current management of FBA allows us to avoid almost all negative rigid bronchoscopies. In addition, we identified some symptoms and clinical and radiologic signs whose absence was highly predictive of negative bronchoscopy. We propose a novel algorithm for management of FBA that will help decrease the number of negative bronchoscopies. PMID- 28561133 TI - Primary versus Staged Closure of Exomphalos Major: Cardiac Anomalies Do Not Affect Outcome. AB - AIM: The objective of the study is to describe management of exomphalos major and investigate the effect of congenital cardiac anomalies. METHODS: A single center retrospective review (with audit approval) was performed of neonates with exomphalos major (fascial defect >= 5cm +/- liver herniation) between 2004 and 2014.Demographic and operative data were collected and outcomes compared between infants who had primary or staged closure. Data, median (range), were analyzed appropriately. RESULTS: A total of 22 patients were included, 20 with liver herniation and 1 with pentalogy of Cantrell. Gestational age was 38 (30-40) weeks, birth weight 2.7 (1.4-4.6) kg, and 13 (60%) were male. Two were managed conservatively due to severe comorbidities, 5 underwent primary closure, and 15 had application of Prolene (Ethicon Inc) mesh silo and serial reduction. Five died, including two managed conservatively, none primarily of the exomphalos. Survivors were followed up for 38 months (2-71). Cardiac anomalies were present in 20 (91%) patients: 8 had minor and 12 major anomalies. Twelve (55%) patients had other anomalies. Primary closure was associated with shorter length of stay (13 vs. 85 days, p = 0.02), but infants had similar lengths of intensive care stay, duration of parenteral feeds, and time to full feeds. Infants with cardiac anomalies had shorter times to full closure (28 vs. 62 days, p = 0.03), but other outcomes were similar. CONCLUSION: Infants whose defect can be closed primarily have a shorter length of stay, but other outcomes are similar. Infants with more significant abdominovisceral disproportion are managed with staged closure; the presence of major cardiac anomalies does not affect surgical outcome. PMID- 28561135 TI - Time and Speed of Vascular Pedicle Dissection in Deep Inferior Epigastric Artery Perforator Flap Elevation. PMID- 28561134 TI - Cavitron Ultrasonic Surgical Aspirator-Assisted Pancreatic Resection in Hyperinsulinism. PMID- 28561136 TI - The Foxgloves (Digitalis) Revisited. AB - This review provides a renewed look at the genus Digitalis. Emphasis will be put on those issues that attracted the most attention or even went through paradigmatic changes since the turn of the millennium. PubMed and Google Scholar were used ("Digitalis" and "Foxglove" were the key words) to identify research from 2000 till 2017 containing data relevant enough to be presented here. Intriguing new results emerged from studies related to the phylogeny and taxonomy of the genus as well as to the biosynthesis and potential medicinal uses of the key active compounds, the cardiac glycosides. Several Eastern and Western Foxgloves were studied with respect to their propagation in vitro. In this context, molecular biology tools were applied and phytochemical analyses were conducted. Structure elucidation and analytical methods, which have experienced less exciting progress, will not be considered here in great detail. PMID- 28561137 TI - [The Development of Social Innovations in Health Care and the Role of Science and Research]. AB - In the course of demographic, epidemiological and social changes, various challenges arise concerning the organization of health care and health promotion for the population. Innovative approaches are needed to face these challenges. The focus in the theoretical work is on the analysis of the development of social innovations and on the role of science and research to solve social problems. First of all, the notion of innovation based on technologies will be expanded by social innovations. 2 approaches to promote social innovations are discussed: the systematic discovery and development of solutions in practice as well as the co productive development in the terms of transdisciplinary research. It will be demonstrated that a cooperative and co-productive research and development process brings new requirements regarding scientific practice so that a discussion about the organisation and general conditions of transdisciplinary research and development in the health (service) research has to be strengthened. PMID- 28561138 TI - Skin Color and Maternal Near Miss: Exploring a Demographic and Health Survey in Brazil. AB - Purpose In 2013, it was estimated that 289,000 maternal deaths occurred worldwide. The maternal mortality ratio has decreased in many countries in the past decades, due to early identification and treatment of obstetric complications, despite the dissimilarities observed in diverse locations and populations. Black women, for instance, have always been more susceptible to the occurrence of maternal mortality and severe morbidity. Therefore, the objective of this study is to assess skin color as a predictive factor for maternal near miss (MNM) in a sample of Brazilian women interviewed in the Brazilian National Demographic and Health Survey (DHS) of 2006. Method A secondary analysis of the DHS database, a population-based cross-sectional nationally representative study was conducted. This database is of public domain. The risk of maternal complications according to ethnic group and the associated sociodemographic characteristics were evaluated. For the data analysis, the odds ratios and respective 95% confidence intervals were calculated. Results In the sample interviewed, 59% of women were black or brown (mixed-race). Approximately 23% of women had some complication, and 2% of these women had at least one MNM pragmatic criterion. The MNM rate was 31 per 1,000 live births, and its occurrence was not statistically different among the ethnic groups. The only factors identified that were considered to be associated with the occurrence of MNM were maternal age above 40 and women not currently attending school, but only among white women. Conclusion The 2006 DHS results did not show a higher occurrence of maternal complications, and specifically of MNM associated with black/brown skin color. PMID- 28561139 TI - [Not Available]. PMID- 28561140 TI - Assessment of Iron Status and the Effect of Red Blood Cell Transfusion in Premature Infants. PMID- 28561141 TI - Survival, Short-Term, and Long-Term Morbidities of Neonates with Birth Weight < 500 g. PMID- 28561143 TI - Assessment of Anthropometric Measurements as Predictors of Car Seat Screening Failure. PMID- 28561142 TI - Lipoprotein Heterogeneity Early in Pregnancy and Preterm Birth. PMID- 28561144 TI - Serum Endocan Level as a Predictive Marker for Hemodynamically Significant Patent Ductus Arteriosus in Very Low Birth Weight Infants. PMID- 28561145 TI - Evolutionary Triangulation to Refine Genetic Association Studies of Spontaneous Preterm Birth. PMID- 28561146 TI - Failed Vacuum and the Long-Term Neurological Impact on the Offspring. PMID- 28561147 TI - ? PMID- 28561148 TI - [Preoperative Preparation: Patient Blood Management - What is Optimal?] AB - Patient Blood Management (PBM) focusses on anemia management, the minimization of (unnecessary) iatrogenic blood loss and the exhaustion of natural tolerance to anemia with rational use of red blood cell transfusion. The focus of the current review article is now the preoperative phase with the following PBM components: management of anemia, pre-transfusion analytics and management of anticoagulants. Preoperative anemia is an independent risk factor for increased perioperative morbidity and mortality. In elective surgery, the causes of anemia should be diagnosed prior to surgery as early as possible, and if indicated, a specific treatment for treatable causes should be initiated. Preoperative pre-transfusion analytics should be performed by a step-wise approach depending on the transfusion probability (and the baseline hemoglobin) and current in-house data. Management of (oral) anticoagulants needs to consider an individual risk stratification for bleeding and thromboembolic events, should be initiated in the preoperative phase, and should specify whether the anticoagulant needs to be continued, stopped or bridged. Long-term success of the preoperative PBM program can only be guaranteed with clearly defined responsibilities in the preoperative PBM team, communication and training of all those involved in the process of care. PMID- 28561149 TI - [Preoperative Evaluation and Arrangements: The Elderly Patient]. AB - : With a constantly growing portion of elderly within our population and the advances of modern medicine, surgery on aged and very aged patients has become a daily hospital routine. Due to the physical and mental features of ageing these patients face special perioperative risks. They display a higher rate of complications, morbidity and cognitive deficits which might in the end lead to persisting need of care. Even in the healthy elderly, most organ functions are "physiologically" instable or deficient and the homeostasis of health and disease is fragile. The preoperative evaluation of the aged patient has to be extended towards risk factors and pathologic pre-conditions which derive especially from high age and are so far not determined by a mere "fit-for-anaesthesia?" EVALUATION: This includes assessment of frailty and functional status as well as the evaluation of pre-existing cognitive deficits, malnutrition and polypharmacy. Prevention of postoperative cognitive deficits and delirium is an important goal of medical therapy and requires i. a. omission of benzodiazepines, BIS-controlled anaesthesia, focus on patient's comfort and orientation and inclusion of close relatives and confidants in all processes. Considering all this, an elderly patient might require more time than usually given to be well prepared for anaesthesia, surgery and the postoperative course. The altered physiology and the special risk profile of the aged patient demand special attention and time throughout the perioperative phase. With an increasing number of elderly presenting for surgery, it is likely that more age-adapted structures and processes become implemented in our hospitals. PMID- 28561150 TI - [Preoperative Optimization of Pulmonary Diseases - an Approach]. AB - Preoperative identification of patients with an increased risk for perioperative pulmonary complications is crucial for the anesthesiological management. These complications were underestimated in the past, but are associated with an increased morbidity and mortality when occuring. Patients with preexisting pulmonary diseases are at increased risk for perioperative pulmonary complications. In the recent past more emphasis was placed on preoperative optimization of the underlying pulmonary diseases like COPD or Asthma bronchiale. The knowledge of pathophysiology and pharmacological treatment options in this special subset of patients is essential. It has been shown that preventive programs in the preoperative setting were able to reduce pulmonary complications. PMID- 28561151 TI - [Acute Pain Therapy in Appendectomy]. AB - The acute pain therapy in the setting of conventional or laparoscopic appendectomy has to be initiated by the surgeon. The success of acute pain therapy holds a direct relevance for quality of life, morbidity, chronification of pain, and economic aspects. A written consent between participating occupational groups and medical faculties based on existing guidelines is a crucial prerequisite for a well-functioning acute pain therapy. An adequately informed patient is able to actively take part in the process of his acute pain therapy. He becomes "part of the team". An efficient acute pain therapy always consists of a combination of non-medical procedures, technical operative aspects, and medical procedures. PMID- 28561152 TI - [Hypercapnic Raised Intracerebral Pressure - Ecmo Therapy Despite Major Intracerebral Haemorrhage]. AB - We report a case of a 29-year-old primigravida asian woman with severe peripartal HELLP-syndrome. During delivery she developed coma. HELLP syndrome, complicated by severe intracerebral hemorrhage was detected. During course of therapy with drainage of intraventricular intracerebral hemorrhage, the patient developed pneumonia followed by severe acute respiratory distress syndrome (ARDS) with critically raised ICP. After 31 days of stabilization by extracorporeal membrane oxygenation (ECMO) and lung protective ventilation the patient was weaned of ECMO therapy. Following a period of 107 days including the weaning of respirator therapy her neurologic status improved and she was able to follow commands, move upper and lower extremities on request, and recognize her relatives. PMID- 28561153 TI - ? PMID- 28561154 TI - Different Kinematics of Knees with Varus and Valgus Deformities. AB - Few data exist of kinematics of knees with varus and valgus deformities combined with osteoarthritis. The purpose of this study was to reveal different (1) tibiofemoral kinematics, (2) medial and lateral gaps, and (3) condylar liftoff of osteoarthritic knees with either varus or valgus deformity before and after total knee arthroplasty (TKA). For this purpose, 40 patients for TKA were included in this study, 23 knees with varus deformity and 17 knees with valgus deformity. All patients underwent computer navigation, and kinematics was assessed before making any cuts or releases and after implantation. Osteoarthritic knees with valgus deformity showed a significant difference in tibia rotation relative to the femur with flexion before and after TKA, whereas knees with varus deformity did not. Knees with a valgus deformity showed femoral external rotation in extension and femoral internal rotation in flexion, whereas knees with a varus deformity revealed femoral internal rotation in extension and femoral external rotation in flexion. In both groups, gaps increased after TKA. Condylar liftoff was not observed in the varus deformity group after TKA. In the valgus deformity group, condylar liftoff was detected after TKA at knee flexion of 50 degrees and more. This study revealed significant differences in tibiofemoral kinematics between osteoarthritic knees with a varus or valgus deformity before and after TKA. Valgus deformities showed a paradoxic movement pattern. These in vivo intraoperative results need to be confirmed using fluoroscopic or radiographic three-dimensional matching before and after TKA. PMID- 28561155 TI - Hematologic Malignancies Are Associated with Adverse Perioperative Outcomes following Total Knee Arthroplasty. AB - The treatment of hematologic malignancies has advanced over the years, resulting in an improved survival of patients. As a result, these patients may be a part of the increasing population requiring total knee arthroplasty (TKA); however, they might be at a higher risk of adverse perioperative outcomes. The purpose of this study was to determine the perioperative outcomes (complications, length of stay [LOS], and costs) of patients with hematologic malignancies following TKA. This study used the Nationwide Inpatient Sample (NIS) to identify patients who underwent TKA in the United States from 2000 to 2011. Patients diagnosed with any hematologic malignancy (N = 24,714) were then stratified by Hodgkin's disease (N = 791), Non-Hodgkin's lymphoma (N = 7,096), plasma cell dyscrasias (N = 1,621), leukemia (N = 8,005), myeloproliferative disease (N = 5,746), and/or myelodysplastic syndromes (N = 1,608) for determining the complications that occurred during admission. Propensity matching was performed for demographics, hospital characteristics, and comorbidities, which yielded 24,491 patients with any hematologic malignancy and 24,458 control patients. Additionally, propensity matching was performed for the hematologic malignancy subtypes. Multivariable regression models were used to analyze the surgical and medical complications, LOS, and costs. The annual frequency of THA in patients with any hematologic malignancy increased from 2000 to 2011 (p < 0.0001). Hematologic malignancies were associated with an increased risk of any surgery-related complication (odds ratio [OR] = 1.31, p < 0.0001) and any general medical complication (OR = 1.38, p < 0.0001). Patients with any hematologic malignancy had increased odds of complications, including acute postoperative anemia (OR = 1.29, p < 0.0001), hematoma/seroma (OR = 1.65, p < 0.02), peripheral vascular disease (OR = 2.23, p = 0.046), deep venous thrombosis (DVT) (OR = 1.95, p = 0.02), and blood transfusion (OR = 1.61, p < 0.0001). Hematologic malignancies were associated with an increased incremental LOS (0.13 d, p < 0.0001) and an increased incremental cost ($788, p < 0.0001). Thus, we conclude that following TKA, patients with hematologic malignancies are at an increased risk of perioperative complications, longer LOS, and higher costs. The risk quantification for adverse perioperative outcomes in association with an increased cost may help design different risk stratification and reimbursement methods in such patients when undergoing TKA. PMID- 28561156 TI - Revision Total Knee Arthroplasty Using a Constrained Condylar Knee Prosthesis Combined with a Posterior Stabilized Articular Surface. AB - Intraoperative assessment of valgus-varus stability is crucial for choosing articular surfaces with different levels of constraint. Legacy constrained condylar knee (CCK) prostheses are readily available to assemble and use with a CCK articular surface or a posterior stabilized (PS) articular surface in revision knee arthroplasty surgeries. We wanted to validate outcomes of revision total knee arthroplasty (TKA) using legacy CCK prostheses combined with a PS articular surface. Thirty-seven patients were enrolled and followed up for more than 2 years. Range of motion (ROM), the Knee Society score (KSS), the Knee Society functional score (KSS-F), and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) were used to evaluate outcomes. Follow-up was a mean of 86.5 months (range: 28-152 months). The mean age of the participants was 69.8 years (range: 31-86 years). The mean ROM was 110.5 degrees, the KSS was 86.2 points, the KSS-F was 68.3 points, and the WOMAC score was 22.6 points. Seven participants had implant failures: five because of delayed infections and two because of posterior dislocations. In conclusion, revision TKA using a CCK prosthesis combined with a PS articular surface might provide satisfactory mid-term outcomes. Delayed infection was the most common cause of implant failure. Dislocation might occur in middle-old or older patients despite careful intraoperative examination of valgus-varus stability, extension-flexion gap balancing, and signs of recurvatum. PMID- 28561157 TI - High Varus Angle and Lower Posterior Tibial Slope Associated with PCL Injury in Cruciate Retaining Total Knee Arthroplasty: An MRI Study. AB - The posterior tibial slope (PTS) is important for performing a tibial cut that does not injure the posterior cruciate ligament (PCL). In this study, the amount of PCL fibers sacrificed under simulated tibial cuts with varying posterior inclinations was evaluated using magnetic resonance images (MRIs) of osteoarthritic varus knees. Knee X-rays, orthoroentgenograms, and MRIs of 113 Kellgren and Lawrence grades 3 to 4 osteoarthritic knees were included. Four different simulated tibial cuts were performed at 0, 3, 5 degrees and parallel to the tibia plateau 3 mm below of the most defective part of the cartilage in the medial plateau. Correlations between the PCL avulsion amount and the PTS and varus alignment of the lower extremity were analyzed for all four simulated tibial cut levels. The maximum amount of PCL was preserved with a 0-degree tibial cut in patients with a PTS of more than 8 degrees. With increased tibial cut angles, the posterior slope resulted in an increased amount of avulsed PCL. Although the amount of avulsed PCL was proportional with the varus alignment, it was inversely proportional with the sagittal slope. The number of injured PCLs also increased as the slope of the tibial cuts increased. Patients with mild varus alignments and high PTSs are more suitable for cruciate retaining total knee arthroplasty. PMID- 28561158 TI - Does Age Influence How Patients Rate Their Experience of Care after Total Knee Arthroplasty? PMID- 28561160 TI - Video Comment on Marietta Iacucci et al. PMID- 28561159 TI - New Constituents from Gymnocarpos decander. AB - The phytochemical investigation of Gymnocarpos decander aerial parts extract afforded two new saponins, 3-O-beta-D-glucuronopyranosyl-2beta,3beta,16alpha,23 tetrahydroxyolean-12-en-28-O-beta-D-apiofuranosyl-(1 -> 3)-beta-D-xylopyranosyl (1 -> 4)-alpha-L-rhamnopyranosyl-(1 -> 2)-alpha-L-arabinopyranosyl ester (1), 3-O beta-D-glucuronopyranosyl-2beta,3beta,16alpha-trihydroxyolean-12-en-28-O-alpha-L rhamnopyranosyl-(1 -> 3)-beta-D-xylopyranosyl-(1 -> 4)-alpha-L-rhamnopyranosyl-(1 -> 2)-alpha-L-arabinopyranosyl ester (2), and three new flavonol glycosides, isorhamnetin 3-O-2''''-O-acetyl-beta-D-xylopyranosyl-(1 -> 6)-[beta-D apiofuranosyl-(1 -> 2)]-beta-D-glucopyranoside (3), isorhamnetin 3-O-2'''-O acetyl-beta-D-xylopyranosyl-(1 -> 6)-beta-D-glucopyranoside (4), and quercetin 3 O-2'''-O-acetyl-beta-D-xylopyranosyl-(1 -> 6)-beta-D-glucopyranoside (5), together with three known compounds. Their structures were determined by spectroscopic methods including 1D and 2D NMR analysis and high-resolution mass spectrometry. The new isolates were investigated for their potential cytotoxic activity on three cancer cell lines. Compounds 1 and 2 showed moderate antiproliferative activity. PMID- 28561161 TI - Video Comment on Yoshihiro Nakazato et al. PMID- 28561162 TI - Is it time to stop using percutaneous transhepatic biliary drainage? PMID- 28561163 TI - Multiple white flat lesions in the gastric corpus are not intestinal metaplasia. PMID- 28561164 TI - White flat lesions in the gastric corpus may be intestinal metaplasia. PMID- 28561167 TI - [Buried Penis: A Comprehensive Review on Aetiology, Classification and Plastic Surgical Reconstruction]. AB - The buried penis, also called hidden or concealed penis, is associated with morbid obesity or seen after massive weight loss in adults. In highly obese, bariatric patients, the penile shaft invaginates into the pre-pubic fat masses, resulting in voiding problems and urine wetting of the surrounding tissue. This leads to infection, skin maceration, lichen sclerosus and eczema. Sole circumcision without mons pubis plasty or penile fixation does not suffice to alleviate the discomfort and leads to recurrence. In post-bariatric patients, penile retraction is only partially present or absent, but abundant pre-pubic skin tissue forms an apron covering the genitals with problems in hygiene and sexual intercourse. In these cases, plastic-reconstructive interventions include mons pubis plasty with or without penile fixation. This article provides a comprehensive overview on aetiology, a novel classification of the buried penis and plastic-surgical reconstructive interventions matched to the stages of the condition. PMID- 28561168 TI - [Plastic Surgical Correction of Buried Penis]. AB - A "buried penis" causes functional problems and embarrassment. In the past, this complex condition was only seen in extremely overweight patients or as a result of severe inflammations in this region. More recently, this problem has also been observed in patients with massive weight loss following bariatric surgery. In these patients there is an abundance of extremely flaccid skin in the suprapubic region, which covers the penis and causes it to "disappear". This leads to balanitis and, in turn, further retraction of the penis. The only solution to this condition is a sophisticated surgical approach in 3 phases: At first, suprapubic tissues must be lifted. Secondly, the penis must be completely denuded and debrided and the correct penopubic/penoscrotal angles must be reconstructed. The last phase includes a strainless coverage of the remaining defect of the penis. This condition has not been widely described in the literature. The general incidence and prevalence in the postbariatric population is unknown, probably due to patients' embarrassment and lack of knowledge on the physicians' end. Nevertheless, the buried penis can be successfully exposed through careful, structured surgical treatment and an interdisciplinary approach between plastic surgeons and urologists. PMID- 28561169 TI - [Adequate Antibiotic Prophylaxis and Therapy of Periprosthetic Infections of the Breast - Review of 468 Consecutive Implant Removals]. AB - Background Periprosthetic infections are feared complications in aesthetic as well as in reconstructive breast surgery. The purpose of our study was to evaluate our institution's specific culture data and to identify most common organisms and suitable antibiotics for prophylaxis and first line treatment in implant-based breast surgery. Patients and Methods We analyzed all patients with a change or removal of breast implants in the period from 01.01.2012 to 31.12.2015 retrospectively. Based on the medical records, the surgical indications were identified and specifically analyzed for signs of infection and capsular fibrosis. In addition, we assessed all microbiological data of these interventions. Results 468 implant removals or exchanges were performed in 360 patients. Microbiological smears were gathered from 169 patients (249 implants). Bacteria were cultured from 23 implants (21 patients). In 6 additional implants (four patients) a periprosthetic infection was present, without pathogen detection. In most cases, advanced capsular fibrosis was the reason for implant exchange. In 17 smears bacterial detection was carried out despite absence of clinical signs of infection. In 17 cases coagulase-negative staphylococci were detected. In 4 Staphylococcus aureus, and once each E. coli, Morganella morganii and Proprionibacterium acnes (one double infection). All pathogens were sensitive to piperacillin/tazobactam and vancomycin. One resistancy was seen to cefuroxime and amoxicillin/clavulanic acid, and 2 to gentamicin, ciprofloxacin and clindamycin. Conclusion In the majority of cases, pathogen detection was an incidental finding, while capsular contracture caused surgical revision. Pathogens and resistance patterns found in this study differed from the majority of international publications. In our institution, Cefuroxime and amoxicillin/clavulanic acid have been proven to be a reasonable choice for prevention and treatment of periprosthetic infections. Especially in fulminant infections piperacillin/tazobactam would be our choice for initial treatment, until the specific antibiogram is available. PMID- 28561171 TI - [A Dentist's Accidental Self-Injury by Hydrofluoric Acid - Hydrofluoric Acid Burns]. PMID- 28561170 TI - [Radiation-induced angiosarcoma of the breast]. AB - Background Radiation-induced angiosarcomas of the breast are rare secondary malignancies that occur after adjuvant radiation of breast cancer. They grow in a multifocal manner and frequently develop local recurrences. Therefore, they often pose a surgical challenge. Due to their rarity it is still unclear whether a radical surgical approach leads to a beneficial outcome. The aim of this study was to determine the prognostic significance of surgical margins. Patients and methods We retrospectively assessed the outcome of 18 patients who underwent surgical treatment at our institution. The median follow-up was 4.4 years. Univariate analyses were performed to determine the prognostic significance of the assessed factors on local recurrence-free survival (LRFS) and overall survival (OS). Results The median patient age was 66.3 years. The median latency between radiation and angiosarcoma occurrence was 6.9 years. The estimated 5-year rates for LRFS and OS were 25.0% (95% confidence interval [CI]: 7.8-47.2) and 53.8% (95% CI: 26.8-74.8). R0 resection of the primary lesion was associated with a significant improvement in LRFS (p=0.017) and OS (p=0.013). Moreover, R0 resection of the last local recurrence was also associated with a more favourable OS (p=0.040). Conclusions Due to their aggressive growth pattern and pronounced tendency to local recurrence, a radical surgical approach should be sought in the treatment of radiation-induced angiosarcomas. Wherever feasible, surgical treatment should aim at R0 margins in order to improve local control and OS. PMID- 28561172 TI - [Delayed Post-burn Scar Reconstruction of the Dorsum of the Hand with a Collagen Elastin-based Dermal Substitute and Split-skin Graft]. AB - The hands are involved in more than 80% of severe (grade IIb-III) burn accidents. Even if appropriate initial surgical care is provided in a timely manner, this does not necessarily guarantee a satisfactory outcome in terms of function and aesthetics if interdisciplinary postoperative care and patient compliance are inadequate. In the following case, a grade IIb-III burn, this led to unstable scars on the back of both hands and an intrinsic-minus hand position, bilaterally. Our case study demonstrates that even a delayed reconstruction with a collagen- elastin-based dermal substitute and split-skin graft combined with appropriate interdisciplinary postoperative care may lead to an excellent result comparable with the function and aesthetics of healthy hands, albeit with a significant effort. PMID- 28561173 TI - [Comment on the Article of Dagobert Lindlau: Reread: Eduard Zeis, Handbook of Plastic Surgery, Berlin 1838]. PMID- 28561175 TI - [Multiple sclerosis fatigue, its neural correlates, and its modulation with tDCS]. AB - Multiple sclerosis (MS) is a chronic progressive and inflammatory disease of the central nervous system and causes high rates of non-traumatic disability in young adults. Fatigue is frequently reported by a major part of patients during the disease course and dramatically increases the burden of illness. Despite the high prevalence of fatigue and its enormous impact on quality of life, its pathophysiological mechanisms are still unclear. Its etiology is multifactorial and complex, and is usually classified into 'primary' fatigue resulting from the pathological brain changes versus 'secondary' fatigue following disease symptoms, sleep disturbances, mood disorders, and side effects of medication. Hypotheses concerning the pathophysiology of this symptom are based on radiological, physiological, and endocrine data. It has been suggested that fatigue refers to structural and functional changes in a variety of neuronal networks. Over the past years, non-invasive brain stimulation methods were used to modulate brain function, especially transcranial direct current stimulation (tDCS) has proven to impact neuronal connectivity; however evidence is still sparse due to the pilot character of the studies. In this review we aim at discussing the neuronal correlates of fatigue and the potential influence of tDCS in the modulation of the symptoms. PMID- 28561176 TI - [Early Diagnosis of Chorea-Acanthocytosis: Orofacial Dyskinesia, Epileptic Seizures, and HyperCKemia]. AB - Chorea-acanthocytosis is an uncommon neurodegenerative disorder. Early diagnosis is often challenging. The triad of orofacial dyskinesia, epileptic seizures, and hyperCKemia should alert neurologists of a neuroacanthocytosis syndrome. The diagnosis can be confirmed by detection of chorein deficiency or through molecular genetics (VPS13A mutation). PMID- 28561177 TI - [Risk Factors for Postoperative Delirium after Cardiac Surgery]. AB - Background Delirium is a common psychiatric disorder after cardiac surgery and predisposes patients to increased mortality and morbidity. Its prevention requires knowledge of the risk factors involved. Objective What are preoperative risk factors for postoperative delirium after cardiac surgery? Methods Prospective longitudinal study of 241 elective cardiac surgical patients with preoperative assessment of potential risk factors and delirium assessment twice daily over five postoperative days. Results 13 % of the patients experienced delirium. Reduced cognitive performance (OR: 3.80; 95 % CI: 1.66 - 8.66), higher comorbidity (OR: 1.36; 95 % CI: 1.07 - 1.7) and higher age (OR: 1.08; 95 % CI: 1.02 - 1.13) increased the risk of delirium. Conclusion Delirium after cardiac surgery is common. It occurs in particular in patients with low cognitive performance, higher comorbidity and higher age. PMID- 28561178 TI - [19th century Russian research about collective behavior]. AB - In the 19th century, collective behavior or crowd psychology was given a broad interest in psychiatric research. But until today the focus had always been on French, English or German publications neglecting the comprehensive Russian research that exists. That's why, the authors wish to elaborate 19th century Russian points of view on crowd psychology.Our research revealed that most of the Russian authors discussed imitation, suggestion, and hereditary predisposition - as did their colleagues in the West. Contrary to that, the 1881 monograph by Viktor Kandinsky could be regarded as an outstanding work because it presents an independent hypothesis on crowd psychology. Kandinsky postulated a gradual transition from normal to pathological based on neuro-anatomical und physiological presumptions. He postulated a causal chain which starts with exaltation followed by ecstasy, illusions, and at least hallucinations. He regarded exaltation to be a precondition in which a person accepts notions uncritically. Thus, in an exalted crowd one person that hallucinates may "infect" the others easily. People prone to mysticism, with a passion for mysterious things or on outstanding skills would be at a high risk of being infected. On the other hand, Kandinsky's hypothesis also implies that no one is exempt from such infection. PMID- 28561179 TI - [Lithium treatment in patients with impaired kidney function: Between Scylla and Charybdis]. AB - Introduction In quite a few patients with bipolar disorder there is no real alternative to lithium treatment despite impaired kidney function. Is it possible to continue lithium treatment despite kidney malfunction by changing dosage and/or frequency of administration? Case Report We report on a 65-year-old woman suffering from bipolar-I disorder who had been on lithium treatment for many decades. While on lithium, the glomerular filtration rate (GFR) decreased constantly. A decision had to be made whether to switch to a more tolerable o.d. administration or to taper off lithium. Conclusion With a single dose at bedtime, the serum levels remained stable; however, kidney function unfortunately did not improve. A relevant increase of GFR above the level of 60 mL/min/1,73 m2 was only achieved after a 50% dose reduction leading also to a substantial decrease of lithium serum levels. A kidney protective lithium application in patients with reduced renal function is like sailing between Scylla and Charybdis. PMID- 28561180 TI - [Cognitive Disorders in Schizophrenia]. AB - Cognitive disorders in schizophrenia can be observed in relatives and persons even before the first episode. The patterns of these disorders may be specific to the occurrence of a later episode. After the first episode, the disorders remain relatively stable and are partly correlated with negative symptoms. Furthermore, the cognitive deficits have a negative impact on the social and occupational functional level. Recent studies suggest that cognitive remediation has small to moderate effects on cognition, and thus can also improve overall patient function. PMID- 28561181 TI - [The Load of Injustice: A Longitudinal Analysis of the Impact of Subjectively Perceived Income Injustice on the Risk of Stress-Associated Diseases Based on the German Socio-Economic Panel Study]. AB - BACKGROUND: Income injustice is regarded as a psychosocial strain and associated with an increased risk of stress-related diseases. The physiological stress response is thereby considered as a central link. The aim of the study is to reveal the influence of subjectively perceived income injustice on stress associated diseases, taking into consideration the load duration. METHOD: Based on the German Socio-Economic Panel Study, data on 5,657 workers in the survey years 2005-2013 were analyzed. The dependent variable reflect the doctor's diagnosed new cases of diabetes, asthma, cardiopathy, stroke, hypertension and depression in the years 2009-2013 as an index. Key predictor is the injustice perception of one's income. In order to operationalize the duration of the injustice perception, the values of the variable for the years 2005, 2007 and 2009 were accumulated. Using logit models, stratified for gender and volume of employment, factors were identified that affect the probability of stress-related diseases. RESULTS: If income was perceived as unjust for over 5 years, the odds of stress-related diseases were strongly enhanced for women (OR 1.64; 95% CI 1.17 2.30). Women working full-time seemed to be particularly affected (OR 2.43; 95% CI 1.54-3.84). Men working full-time perceiving their income as unjust also showed an increased risk for stress diseases (OR 1.43; CI 1.03-1.98). The more often income was assessed as unjust, the higher was the probability of stress related diseases. CONCLUSIONS: Perceived income injustice seems to be a significant risk factor for stress-related diseases within a dose-response relationship with increasing duration of exposure. Findings of stress research indicate that this represents the 'allostatic load'. Gender-specific differences in stress reaction as well as in the appraisal of the stressors can be associated with gender-specific work and life conditions and therefore provide explanatory approaches for the revealed effects. PMID- 28561182 TI - [The Costs of Overweight and Obesity: a Systematic Review]. AB - AIM OF THE STUDY: The aim of this paper was to conduct a systematic review of cost-of-illness studies for overweight and adiposity in Germany. METHODS: We conducted a PubMed search to identify relevant studies. To increase comparability, all cost data were inflated to 2014 prices. For bottom-up studies, we additionally calculated relative cost-differences between normal weight and overweight, as well as adiposity. These relative differences were pooled using meta-analytical techniques and extrapolated to the German population. RESULTS: We identified 15 bottom-up studies, 6 top-down studies and 2 Markov simulations. On average, top-down studies reported direct costs of 7.9 billion Euros and indirect costs of 3.6 billion Euros. Due to between-study heterogeneity, we were not able to pool absolute costs reported in bottom-up studies. The pooled relative cost differences for studies conducted with adult persons were +22% for the difference between normal weight and overweight and +53% for the difference between normal weight and adiposity. The corresponding effect sizes were 0.07 (- 0.05; 0.19) and 0.15 (0.02; 0.28), respectively. In studies conducted with children and adolescents, relative cost-differences were considerably smaller with corresponding effect sizes being close to zero. Extrapolation of relative pooled cost-differences from bottom-up studies to the German total population yielded direct and indirect excess costs of 22.2 billion Euros for overweight and 23.0 billion Euros for adiposity. CONCLUSION: We found substantial heterogeneity of cost findings between studies for top-down and bottom-up studies as well, which points to substantial uncertainty and strongly hampers clear statements about the costs of overweight and adiposity. Our findings imply that costs are underestimated by top-down studies, whereas overestimated by our extrapolation. The true costs presumably lie between the findings of both approaches. PMID- 28561183 TI - Salivary Cortisol, Perceived Stress, and Metabolic Syndrome: A Matched Case Control Study in Female Shift Workers. AB - Although the pathogenesis of metabolic syndrome (MetS) is complex and multifactorial, there is limited information if psychological factors, such as stress exposure, are involved in the etiology of MetS. Therefore, this study investigated the associations between MetS and cortisol levels and perceived stress levels among women shift workers in Southern Brazil. A matched case control study was conducted, including 50 cases of MetS and 200 age-matched controls (+/-3 years, 4 for each case). Salivary cortisol levels were evaluated immediately after waking and one upon returning home from work. Perceived stress levels were measured by the Perceived Stress Scale with 10 items (PSS-10). Multivariate-adjusted associations between MetS and salivary cortisol levels and perceived stress levels were assessed by conditional logistic regression. Means+/ standard deviations of salivary cortisol levels were not significantly different between cases and controls either immediately after waking (5.37+/-4.10 vs. 6.03+/-5.39 nmol/l; p = 0.53) or after work (2.74+/-2.87 vs. 2.78+/-2.85 nmol/l; p = 0.93). There was no significant difference in perceived stress level between cases and controls (14.2+/-5.9 vs. 15.5+/-5.6; p = 0.15). No independent association was observed in the multivariate model between MetS and salivary cortisol level or perceived stress level after these exposures were stratified into tertiles. Overall, there was no difference between women with or without MetS in regard to the free salivary cortisol and perceived stress. Our results do not support an association between stress exposure and MetS among women shift workers. PMID- 28561184 TI - Measuring VLDL1-Triglyceride and VLDL2-Triglyceride Kinetics in Men: Effects of Dietary Control on Day-to-Day Variability. AB - The aim of this study was to assess the impact of dietary control on VLDL1- and VLDL2-TG kinetics and associated metabolic parameters. Twelve overweight/obese men were randomized to a provided 3 day isocaloric diet with fixed macronutrient composition (diet group, n=6) or to their regular unrestricted diet (non-diet group, n=6). VLDL1- and VLDL2-TG turnovers were measured twice 2-4 weeks apart, using primed-constant infusion of ex vivo labeled [1-14C]VLDL1-TG and [9,10 3H]VLDL2-TG. Isocaloric diet intervention lowered the difference in the mean of both VLDL2-TG secretion and clearance rate (p<0.01), and the coefficient of variation (CV) of VLDL2-TG clearance rate (p<0.05). The difference in mean and CV of the other kinetic estimates (VLDL1-TG secretion, clearance and oxidation rate) were lowered, but not significantly. The CV's of total triglyceride, VLDL1-TG, and VLDL2-TG concentrations were significantly lowered by diet intervention compared to regular diet; total triglyceride (31%-5%, p<0.01), VLDL1-TG (42%-9%, p<0.01), and VLDL2-TG (36%-10%, p<0.01). In conclusion, VLDL1- and VLDL2-TG kinetics show great day-to-day variability, which may be diminished by diet intervention. Therefore, standardized macronutrient intake prior to study days improves the probability of demonstrating significant outcomes of cross-sectional and intervention studies of VLDL1-TG and VLDL2-TG kinetics and metabolism. PMID- 28561186 TI - Muscle Response to Complete Peripheral Nerve Injury: Changes of Acetylcholine Receptor and Creatine Kinase Activity over Time. AB - Background This study was designed to assess the changes of acetylcholine receptor (AChR) and creatine kinase (CK) levels, which are important biochemical markers for muscle viability in cases of long-term muscle denervation. Scientists and peripheral nerve surgeons may find these data important regarding maximal range of muscle viability applicable for timing of effective peripheral nerve reconstructive surgery. Methods The study was conducted on 48 rats (96 gastrocnemius muscles), whose right legs were denervated by removing a 10-mm segment of sciatic nerve, while their left legs remained intact. Under general anesthesia, the rats were euthanized at seven points in time, on days 7, 14, 21, 30, 60, 120, and 210. In both legs, AChR was quantified by 125I-alpha bungarotoxin, whereas CK activity was measured using a spectrophotometric method. Results CK levels in the denervated limb reached a minimal level of 34% on day 30 in comparison to the intact limb and remained at this level up to 210 days after operation. AChR levels in the denervated limb reached a minimal level of 38% on day 120 in comparison to the intact limb and remained at this level up to 210 days after operation. Conclusion The present study shows that AChR and CK levels in rat denervated muscles remain constant at about third of its intact condition for a period of at least a third of rat's lifetime postinjury. PMID- 28561185 TI - High Leptin Level Attenuates Embryo Development in Overweight/Obese Infertile Women by Inhibiting Proliferation and Promotes Apoptosis in Granule Cell. AB - Obesity appears to be associated with female reproductive dysfunction and infertility. Women with obesity undergoing in vitro fertilization (IVF) had poor oocyte quality, decreased embryo development, and poor pregnancy outcome. However, the mechanism linking obesity to poor reproductive outcomes is still unclear. Obesity is frequently accompanied with elevated leptin levels. Here we aimed to evaluate the effect of high leptin level in follicular fluid (FF) on the proliferation and apoptosis in granule cells and correlate these findings with poor reproductive outcomes in infertile women with overweight or obesity who underwent IVF treatment. We investigated clinical and ongoing pregnancy rates in 189 infertile women who underwent IVF. Leptin levels were quantified in peripheral blood and FF as well. In vitro cell model was used to explore the potential effect of high leptin on the proliferation and apoptosis in granulosa cells. Results showed reduced clinical and ongoing pregnancy rates in overweight/obesity women who underwent IVF compared to control with normal BMI. On the other hand, leptin levels presented significant increase in peripheral blood and FF in overweight/obese women. Leptin level in FF was negatively correlated to good quality embryo rate. Importantly, in vitro study showed that leptin inhibited cells proliferation and promoted apoptosis by upregulation of caspase-3 and downregulation of Bcl-2 in granulosa cells in a dose dependent manner. These observations suggest that leptin may acts as a local mediator to attenuate embryo development and reduce fertility in obese patients. PMID- 28561187 TI - Letter to the Editor: Morbidity of the Free Fibula Flap Reconstruction in Head and Neck Malignancies. PMID- 28561188 TI - Reply to Letter to the Editor: Morbidity of the Free Fibula Flap Reconstruction in Head and Neck Malignancies. PMID- 28561190 TI - In-Hospital Outcomes Following Extracorporeal Membrane Oxygenation in a Retrospective Cohort of Infants. PMID- 28561189 TI - Delayed Umbilical Cord Clamping at <32 Weeks' Gestation: Implementation and Outcomes. PMID- 28561191 TI - Platelet-Rich Fibrin Conduits as an Alternative to Nerve Autografts for Peripheral Nerve Repair. PMID- 28561192 TI - Heart Rate and Oxygen Uptake Kinetics in Type 2 Diabetes Patients - A Pilot Study on the Influence of Cardiovascular Medication on Regulatory Processes. AB - The aim of this pilot study was to investigate whether there are differences in heart rate and oxygen uptake kinetics in type 2 diabetes patients, considering their cardiovascular medication. It was hypothesized that cardiovascular medication would affect heart rate and oxygen uptake kinetics and that this could be detected using a standardized exercise test. 18 subjects were tested for maximal oxygen uptake. Kinetics were measured in a single test session with standardized, randomized moderate-intensity work rate changes. Time series analysis was used to estimate kinetics. Greater maxima in cross-correlation functions indicate faster kinetics. 6 patients did not take any cardiovascular medication, 6 subjects took peripherally acting medication and 6 patients were treated with centrally acting medication. Maximum oxygen uptake was not significantly different between groups. Significant main effects were identified regarding differences in muscular oxygen uptake kinetics and heart rate kinetics. Muscular oxygen uptake kinetics were significantly faster than heart rate kinetics in the group with no cardiovascular medication (maximum in cross correlation function of muscular oxygen uptake vs. heart rate; 0.32+/-0.08 vs. 0.25+/-0.06; p=0.001) and in the group taking peripherally acting medication (0.34+/-0.05 vs. 0.28+/-0.05; p=0.009) but not in the patients taking centrally acting medication (0.28+/-0.05 vs. 0.30+/-0.07; n.s.). It can be concluded that regulatory processes for the achievement of a similar maximal oxygen uptake are different between the groups. The used standardized test provided plausible results for heart rate and oxygen uptake kinetics in a single measurement session in this patient group. PMID- 28561194 TI - Impact of the Ile105Val Polymorphism of the Glutathione S-transferase P1 (GSTP1) Gene on Obesity and Markers of Cardiometabolic Risk in Young Adult Population. AB - The aim of the study was to investigate the association between Glutathione S transferase P1 (GSTP1) gene polymorphism with obesity and markers of cardiometabolic risk. A cross-sectional study was carried out in individuals aged>=18 and <=30 years. The study included 54 normal weight, 27 overweight and 68 obese volunteers. Anthropometric measurements and biochemical parameters were evaluated, the DNA was extracted from blood samples and polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used to measure GSTP1 Ile105Val gene polymorphism of the study participants. Also, biochemical analysis and hormone assays were carried out. A positive association between GSTP1 polymorphism and obesity was observed on subjects carrying at least one G allele (AG and GG). GG genotype was found only in the obese group. The G allele carriers presented 2.4 times higher chance of obesity when compared to those with the AA genotype. These results were independent of sex and age. We suggest that despite a study in population regional (south of Brazil), the GSTP1 gene polymorphism may play a significant role in the increase of susceptibility of obesity and contribute to identify the cardiovascular risk in young adults. PMID- 28561193 TI - Success Rates in a Diabetes Specialist Nurse-Led Education Programme: Re-setting the Glucostat. AB - Analysis of National Diabetes Audit data from 2011-2012 of newly diagnosed people with type 1 diabetes mellitus (DM) found low initial success rates in much of the UK at 20% on initial training, while an unusually high success rate of 75% achieving target HbA1C<58 mmol/mol (< 7.5%) was found in Cheshire (England average=40.8%). We present a review of the approach taken by the Cheshire Diabetes team in the 12 months following diagnosis. Between 2012 and 2013, 15 consecutive newly diagnosed people with type 1 DM were followed up for 18 months. All received support and advice by community Diabetes Specialist Nurses (DSNs) and Dieticians covering Central and Eastern Cheshire, UK. Mean+/-SD age at diagnosis was 23+/-3 years. The period of contact with the DSN service varied from 7-12 weeks. Baseline HbA1C of 99 mmol/mol [11.2%] (95% CI: 86-111 mmol/mol [10.0-12.3%]) declined by ~50% to 49 mmol/mol [6.6%] (41-57 mmol/mol [5.9-7.4%]; F=16.9, p<0.001) at 6 months and did not change between 6-12 months. Of those newly diagnosed with type 1 DM, 84.6% achieved a target HbA1C<58 mmol/mol (<7.5%) and 61.5% met a target<48 mmol/mol (<6.5%). There was no significant weight change during the study. The key elements of this bio-psycho-social approach by the DSN team included providing psychological support, patient engagement, demonstrating positive regard, gaining trust, identifying health-seeking behaviour, providing key decision-making skills and developing a self-management plan. This resulted in improvements in overall glycaemic control well above the national average without untoward weight gain. The UK National Diabetes Audit (2011-2012) in newly diagnosed type 1 diabetics in Cheshire, UK, showed a success rate at 6 months post-diagnosis of 75% achieving a target HbA1C<58 mmol/mol (<7.5%) compared with the national average of 40.8%. Initially thought to be erroneous, these excellent results were confirmed. The approach taken to achieve them is herein described. PMID- 28561195 TI - Computer-aided diagnosis for colonoscopy. PMID- 28561196 TI - A novel endoloop system for closure of colonic mucosal defects through a single channel colonoscope. AB - Background and study aims Successful closure of the postoperative mucosal defect is crucial for endoscopic treatment. The purse-string suture strategy via a double-channel endoscope has been recommended as being both safe and feasible for large gastrointestinal mucosal defects. However, for colonic treatment, use of a single-channel colonoscope is more popular because of its longer length and greater flexibility. A novel pre-detached endoloop system was therefore developed for endoscopic purse-string suture closure via a single-channel endoscope. This study evaluated its feasibility and efficacy, especially for right colonic mucosal defects. Patients and methods A total of 18 patients with colonic defects post-endoscopic submucosal dissection (ESD) were treated using the single-channel endoscope method. Results All mucosal defects were successfully closed using the novel closure technique. No severe complications, such as massive intraoperative bleeding, delayed bleeding, peritonitis, or perforation, were recorded. All patients recovered well after ESD and left the hospital within 7 days. Conclusions This novel pre-detached endoloop strategy via a single-channel endoscope was safe and feasible for the closure of colonic mucosal defects using an endoscopic purse-string suture. PMID- 28561197 TI - Endoscopic hand-suturing for defect closure after gastric endoscopic submucosal dissection: a pilot study in animals and in humans. AB - Background and study aims Mucosal suturing enables reliable and optimal defect closure after endoscopic treatments. We developed and investigated the feasibility of endoscopic hand-suturing (EHS) after gastric endoscopic submucosal dissection (ESD) in porcine in vivo models and in human clinical cases. Patients and methods EHS involving continuous suturing of the mucosal layers using a through-the-scope needle-holder and absorbable barbed suture, was performed after gastric ESD in six live pigs and in eight consecutive patients. Success rates, adverse events, and suture maintenance were subsequently investigated. Results EHS was successfully completed in all six pigs and eight patients (100 %) without severe adverse events. However, at 1 week postoperatively the suture closures had not been maintained in all six porcine cases and in the first four clinical cases. In the later four clinical cases, wider and tight suturing of the mucosal edges ensured that the defects remained closed until postoperative week 4. Conclusion EHS is a feasible procedure that may facilitate secure and refined endoscopic surgeries. Mucosal closure in such cases can be maintained using firm suturing.Clinical trial number: UMIN000017125. PMID- 28561198 TI - Risk of infection following colonoscopy and sigmoidoscopy in symptomatic patients. AB - Background and study aims Previous studies describing the incidence of infection after colonoscopy and sigmoidoscopy are limited. The aim of this study was to determine the incidence of infection, and to propose a nomogram to predict the probability of infection following colonoscopy and sigmoidoscopy in symptomatic patients. Patients and methods A nationwide retrospective study was conducted by analyzing the National Health Insurance Research Database of Taiwan. The incidence of infection within 30 days after colonoscopy and sigmoidoscopy was assessed and compared with a control group matched at a ratio of 1:1 based on age, sex, and the date of examination. Results In all, 112 543 patients who underwent colonoscopy or sigmoidoscopy and 112 543 matched patients who did not undergo these procedures were included. The overall incidence of infection within 30 days after colonoscopy and sigmoidoscopy was 0.37 %, which was significantly higher than that of the control group (0.04 %; P < 0.001). Diverticulitis, peritonitis, and appendicitis were the most common infections. Patients who underwent colonoscopy or sigmoidoscopy had a 9.38-fold risk of infection (95 % confidence interval, 6.81 - 12.93; P < 0.001) compared with the control group. The predicted infection-free rates of the nomogram were closely aligned with the actual infection-free rates, with a bootstrapping concordance index of 0.763. Conclusions Colonoscopy and sigmoidoscopy are associated with an increased risk of infection, which may occur after these procedures. Our nomogram may provide clinicians with an easy tool to evaluate the risk of infection after colonoscopy and sigmoidoscopy in symptomatic patients. PMID- 28561199 TI - Efficacy of self-expandable metal stents in management of benign biliary strictures and comparison with multiple plastic stents: a meta-analysis. AB - Background and study aims There is burgeoning interest in the utilization of covered self-expandable metal stents (CSEMSs) for managing benign biliary stricture (BBS). This systematic review and meta-analysis evaluated cumulative stricture resolution and recurrence rates using CSEMSs and compared performance of CSEMSs and multiple plastic stents (MPS) in BBS management. Method Searches in several databases identified studies including >= 10 patients that utilized CSEMSs for BBS treatment. Weighted pooled rates were calculated for stricture resolution and recurrence. Pooled risk ratios (RRs) comparing CSEMSs with MPS were calculated for stricture resolution, stricture recurrence, and adverse events. Pooled difference in means was calculated to compare number of endoscopic retrograde cholangiopancreatographies (ERCPs) in each group. Results The meta analysis included 22 studies with 1298 patients. Weighted pooled rate for BBS resolution with CSEMS was 83 % (95 % confidence limits [95 %CLs] 78 %, 87 %; I2 = 72 %). On meta-regression analysis, resolution in chronic pancreatitis patients and post-orthotopic liver transplant patients were significant predictors of heterogeneity. Weighted pooled rate for stricture recurrence with CSEMSs was 16 % (11 %, 22 %). Overall rate of adverse events requiring intervention and/or hospitalization was 15 %. Four randomized controlled trials with 213 patients compared CSEMSs with MPS: the pooled RRs for stricture resolution, recurrence, and adverse events were 1.07 (0.97, 1.18), 0.88 (0.48, 1.63), and 1.16 (0.71, 1.88), respectively with no heterogeneity. Pooled difference in means for number of ERCPs was - 1.71 ( - 2.33, - 1.09) in favor of CSEMS. Conclusions CSEMSs appear to have excellent efficacy in BBS management. They are as effective as MPS but require fewer ERCPs to achieve clinical success. PMID- 28561200 TI - [Exposure of Adolescents to Leisure-Time Noise: Results of the First Follow-Up of the Ohrkan Cohort Study]. AB - Objective Analysis of changes in leisure noise exposure among adolescents during 2.5 years of follow-up. Methods The analysis is based on the Ohrkan cohort study. A total of 2 149 9th graders in the City of Regensburg (mostly aged 15-16 years) were recruited between 2009-2011. At 2.5-year follow-up, the participants were asked again about leisure noise exposure. Both at baseline (O-I) and in the follow-up (O-II), self-reported frequency of participation in noisy activities was combined with literature-based values of usual sound levels to calculate the total weekly noise exposure. This exposure was compared to the lower exposure action value (lEAV) of 80 dB(A) given by the occupational health and safety regulations. Logistic regression was used to determine the factors associated with leisure noise exposure above the lEAV. Results Exposure data from both time points were available for 1 704 adolescents (54% female). The percentage of participants who were exposed to leisure noise exceeding the lEAV increased from 75 to 92% due to more persons visiting discotheques in O-II. In both surveys, the activity reported by the highest percentage of participants and with the longest exposure duration was listening to pop music via portable listening devices (PLD) although the proportion of users decreased slightly. Not being a pupil affected PLD use at volume levels >80 dB (A) whereas older age was associated with noise exposure in discotheques. Conclusions O-II shows that adolescents are engaged in leisure activities under harmful noise levels and that noise exposure sources are changing with age. These issues should be considered in the developing of prevention programs. PMID- 28561201 TI - [First Insights into Scope of Practice and Salary of Physician Assistants, A New Healthcare Profession, in Germany]. AB - Background In 2010, the first government-approved physician assistant (PA) program was introduced at the Baden-Wuerttemberg Cooperative State University Karlsruhe (DHBW). There are not sufficient data regarding the scope of practice and salary of our graduates. Therefore, the aim of the present study was to obtain information regarding these. Methods The survey included all graduates (2 classes, n=27). A specific questionnaire was developed, including 37 questions e. g. on the current employment status, scope of practice, salary and job satisfaction regarding the PA program and career. A descriptive analysis of the data was carried out using SPSS. Results 25 graduates participated in the survey (96.1%); the average age of participants was 32.2 years (25-53 years). 88% (n=22) were employed as a PA, most of them worked in internal medicine (n=11) or surgery (n=9). Responsibilities that are often or very often assigned to the PAs are preparing final documents, taking over a coordinating role in the therapeutic team, as well as participation in taking patient medical history and conducting physical examinations. In two-thirds of respondents, the gross monthly base salary (full-time position) was about 3000 euros. 77.3% (n=17) of graduates were generally satisfied or very satisfied with their current situation. Conclusions It appears that graduates of the DHBW are well integrated into the staff structure of hospitals, as far as the scope of practice and average salary are concerned. Further studies on the integration of this new profession in Germany and on their extended scope of practice in comparison to established healthcare professions will be conducted. PMID- 28561202 TI - [Job Satisfaction of Young Professionals in Health Care]. AB - Background Job satisfaction in health care is currently important in view of workforce shortage in the health care area. The purpose of this study was to evaluate job satisfaction in young health professionals and to identify factors possibly influencing overall job satisfaction. Methods About one year after graduating from vocational training, a total of 579 graduates from various health care professions [Nursing (N), Nursing and Geriatric Nursing; Therapy (TP), Physical therapy and Logopaedics; Diagnostics (D), Diagnostic Radiography and Biomedical Science], were invited to participate in an online-survey. Job satisfaction was assessed with the 10-item Warr-Cook-Wall (WCW) job satisfaction questionnaire. Descriptive analysis of the WCW was performed, and the impact of various factors on job satisfaction was determined by stepwise linear regression analysis. Results In total, 189 graduates (N, n=121; TP, n=32; D, n=36) were included in data analysis (32.6% response rate). Overall job satisfaction in all young professionals was 4.9+/-1.6 (mean+/-SD) and was slightly higher in TP (5.4+/-1.4) compared with N (4.7+/-1.6) and D (5.0+/-1.5), respectively. Highest satisfaction was identified with "colleagues" and lowest satisfaction with "income" was identified in all professional groups. Colleagues and fellow workers showed the highest score of association regarding overall job satisfaction in regression analysis. Conclusions As a whole, our data suggest good to very good satisfaction in various WCW items of job satisfaction. "Colleagues" were shown to have a high impact on job satisfaction. To improve the attractiveness of job profiles in health care, the presented results may provide a valuable input regarding workforce shortage. PMID- 28561203 TI - Relationship Between Daily Dose, Serum Concentration, and Clinical Response to Quetiapine in Children and Adolescents with Psychotic and Mood Disorders. AB - Introduction In child and adolescent psychiatry, therapeutic drug monitoring (TDM) is strongly recommended. However, therapeutic ranges (TR) are defined only for adults. The objectives of this naturalistic study were to assess the relationships between serum quetiapine concentration, daily dose, and clinical outcomes as well as the determinants of pharmacokinetic variability. Furthermore, it was elucidated whether the recommended TR for adult patients with psychotic disorders is valid for children and adolescents. Methods TDM was performed in 180 pediatric patients treated with quetiapine. Psychopathological changes were assessed by the Clinical Global Impression - Improvement scale (CGI-I). Adverse drug reactions (ADRs) were assessed by using a short form of the Udvalg for Kliniske Undersogelser (UKU) side effect rating scale. Results A weak positive linear relationship between daily dose (mean 349.9+/-248.9 mg/day) and serum concentration of quetiapine (rs=0.496, p<0.001) was found (mean age 15.6+/-1.9 years, 45.6% male, 31.1% monotherapy), but no relationship between serum concentration and clinical outcome was found. Dose variation accounted for only 12.5% (rs2=0.125) of the variability of serum concentrations. No effects by gender, age, body weight, smoking habits, and co-medication were found. The majority of patients with psychotic (67.8%) and mood disorders (74.5%) showed a serum concentration below the suggested lower limit (100 ng/mL) of the TR for adults. Discussion There are several limitations of this study because of the naturalistic design, and our results should therefore be interpreted with caution. Notwithstanding, our data suggest that the lower limit of the TR for quetiapine is lower than the limit in adult patients. PMID- 28561204 TI - Oral Administration of (S)-Allyl-l-Cysteine and Aged Garlic Extract to Rats: Determination of Metabolites and Their Pharmacokinetics. AB - (S)-Allyl-l-cysteine is the major bioactive compound in garlic. (S)-Allyl-l cysteine is metabolized to (S)-allyl-l-cysteine sulfoxide, N-acetyl-(S)-allyl-l cysteine, and N-acetyl-(S)-allyl-l-cysteine sulfoxide after oral administration. An accurate LC-MS/MS method was developed and validated for the simultaneous quantification of (S)-allyl-l-cysteine and its metabolites in rat plasma, and the feasibility of using it in pharmacokinetic studies was tested. The analytes were quantified by multiple reaction monitoring using an atmospheric pressure ionization mass spectrometer. Because significant quantitative interference was observed between (S)-allyl-l-cysteine and N-acetyl-(S)-allyl-l-cysteine as a result of the decomposition of N-acetyl-(S)-allyl-l-cysteine at the detector source, chromatographic separation was required to discriminate (S)-allyl-l cysteine and its metabolites on a reversed-phase C18 analytical column with a gradient mobile phase consisting of 0.1% formic acid and acetonitrile. The calibration curves of (S)-allyl-l-cysteine, (S)-allyl-l-cysteine sulfoxide, N acetyl-(S)-allyl-l-cysteine, and N-acetyl-(S)-allyl-l-cysteine sulfoxide were linear over each concentration range, and the lower limits of quantification were 0.1 ug/mL [(S)-allyl-l-cysteine and N-acetyl-(S)-allyl-l-cysteine] and 0.25 ug/mL [(S)-allyl-l-cysteine sulfoxide and N-acetyl-(S)-allyl-l-cysteine sulfoxide]. Acceptable intraday and inter-day precisions and accuracies were obtained at three concentration levels. The method satisfied the regulatory requirements for matrix effects, recovery, and stability. The validated LC-MS/MS method was successfully used to determine the concentration of (S)-allyl-l-cysteine and its metabolites in rat plasma samples after the administration of (S)-allyl-l cysteine or aged garlic extract. PMID- 28561205 TI - Treatment with Mountain-Cultivated Ginseng Alleviates Trimethyltin-Induced Cognitive Impairments in Mice via IL-6-Dependent JAK2/STAT3/ERK Signaling. AB - Panax ginseng is the most widely used herbal medicine for improving cognitive functions. The pharmacological activity and underlying mechanisms of mountain cultivated ginseng, however, have yet to be clearly elucidated, in particular, against trimethyltin-induced cognitive dysfunction. We previously reported that interleukin-6 plays a protective role against trimethyltin-induced cognitive dysfunction. Because of this, we have implemented a study system that uses interleukin-6 null (-/-) and wild-type mice. Interestingly, mountain-cultivated ginseng significantly upregulated interleukin-6 expression. With this study, we sought to determine whether the interleukin-6-dependent modulation of the Janus kinase 2/signal transducer activator of transcription 3 and extracellular signal regulated kinase signaling network is also associated with the pharmacological activity of mountain-cultivated ginseng against trimethyltin-induced cognitive dysfunction. Trimethyltin treatment (2.4 mg/kg, intraperitoneal) causes the downregulation of Janus kinase 2/signal transducer activator of transcription 3, extracellular signal-regulated kinase signaling, and impairment of the cholinergic system. We found that mountain-cultivated ginseng treatment (50 mg/kg, intraperitoneal) significantly attenuated cognitive impairment normally induced by trimethyltin by upregulating p-Janus kinase 2/signal transducer activator of transcription 3, p-extracellular signal-regulated kinase signaling, and the cholinergic system. Trimethyltin-induced cognitive impairments were more pronounced in interleukin-6 (-/-) mice than wild-type mice, and they were markedly reduced by treatment with either mountain-cultivated ginseng or recombinant interleukin-6 protein (6 ng, intracerebroventricular). Additionally, treatment with either AG490 (20 mg/kg, intraperitoneal), a Janus kinase 2/signal transducer activator of transcription 3 inhibitor, or U0126 (2 ug/head, intracerebroventricular), an extracellular signal-regulated kinase inhibitor, reversed the effects of mountain-cultivated ginseng treatment. The effects of mountain-cultivated ginseng treatment were comparable to those of recombinant interleukin-6 protein in interleukin-6 (-/-) mice. Our results, therefore, suggest that mountain-cultivated ginseng acts through interleukin-6-dependent activation of Janus kinase 2/signal transducer activator of transcription 3/extracellular signal-regulated kinase signaling in order to reverse cognitive impairment caused by trimethyltin treatment. PMID- 28561206 TI - 4H Leukodystrophy: A Brain Magnetic Resonance Imaging Scoring System. AB - 4H (hypomyelination, hypodontia and hypogonadotropic hypogonadism) leukodystrophy (4H) is an autosomal recessive hypomyelinating white matter (WM) disorder with neurologic, dental, and endocrine abnormalities. The aim of this study was to develop and validate a magnetic resonance imaging (MRI) scoring system for 4H. A scoring system (0-54) was developed to quantify hypomyelination and atrophy of different brain regions. Pons diameter and bicaudate ratio were included as measures of cerebral and brainstem atrophy, and reference values were determined using controls. Five independent raters completed the scoring system in 40 brain MRI scans collected from 36 patients with genetically proven 4H. Interrater reliability (IRR) and correlations between MRI scores, age, gross motor function, gender, and mutated gene were assessed. IRR for total MRI severity was found to be excellent (intraclass correlation coefficient: 0.87; 95% confidence interval: 0.80-0.92) but varied between different items with some (e.g., myelination of the cerebellar WM) showing poor IRR. Atrophy increased with age in contrast to hypomyelination scores. MRI scores (global, hypomyelination, and atrophy scores) significantly correlated with clinical handicap (p < 0.01 for all three items) and differed between the different genotypes. Our 4H MRI scoring system reliably quantifies hypomyelination and atrophy in patients with 4H, and MRI scores reflect clinical disease severity. PMID- 28561208 TI - ? PMID- 28561209 TI - [Pregnancy Rhinitis - an Update]. AB - Pregnancy rhinitis (PR), a common condition in pregnant women, is defined as long lasting nasal congestion due to mucosal swelling and increased secretion without any signs of infection, allergy or tumor, starting at any time during pregnancy and disappearing within 2 weeks of delivery. Smoking and a sensitization to house dust mites are known risk factors. While a definitive pathophysiological concept for PR does not exist, hormonal influences are discussed. We present a stepwise therapeutic strategy for PR and an overview to the latest literature. PMID- 28561210 TI - Cardiac Etiologies of Hydrops Fetalis. AB - Cardiac etiologies of hydrops fetalis have been a topic of concern due to challenging perinatal management. The common cardiac etiologies leading to hydrops fetalis include structural cardiac anomalies, cardiac dysrhythmias, cardiac tumors, cardiomyopathy and myocarditis. The mechanisms of cardiogenic hydrops fetalis may be: 1) elevation of atrial pressure and volume overload, 2) decrease of cardiac output, and 3) development of congestive heart failure. The diagnosis of hydrops fetalis was usually made at 19-36 gestational weeks, when ultrasound is a highly effective diagnostic method. Intrauterine interventions for certain congenital heart defects, maternal transplacental or direct fetal medications and fetal pacing placement for cardiac arrhythmias, and fetal or postnatal tumor resections are important progressions of etiologic treatment for hydrops fetalis. Treatment strategies for hydrops fetalis per se are usually ultrasound-guided pericardiocentesis and feto-amniotic shunting, whereas reaccumulation may require further interventions in utero or postnatally. Hydrops fetalis often carries a poor prognosis, and mortality remains high. Current developments in the management of hydrops fetalis should encourage physicians to attempt further fetal interventions. PMID- 28561207 TI - Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease. AB - We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutieres syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context. PMID- 28561211 TI - [Increasing Consumption of Crystal Meth in Saxony and its Risks for Mother and Child - Experiences at a Level I Perinatal Center from a Pediatric Viewpoint]. AB - Over the past several years, the number of first-time users of methamphetamine considerably increased within the Free State of Saxony. This number also, and especially, includes women of child-bearing age and young mothers. A supportive intervention aimed at reducing the effects of drug abuse should begin in a timely way - during pregnancy at latest, but better before it. To develop an optimal care protocol for both the mother and her child, more knowledge regarding the personal conditions of the women as well as the specific features of later child development after prenatal methamphetamine exposure (PME) is vital. In this study, the data of 129 women and their newborns with PME who were admitted to a Level-1 perinatal center between 2007 and 2015 were analyzed. At delivery, two thirds of the women were aged 20-30 years. Only 48% attended their first preventive examination in pregnancy within the first 12 weeks. Their children subsequently presented with heterogeneous withdrawal symptoms, and pathological findings of the heart, urogenital and central nervous system. The present data aims to sensitize pediatric and obstetric health professionals to the need for timely and adequate care and support. A pathway model of detoxification treatment for mother and child - "The Dresden Crystal Path" - is presented. It combines public and voluntary youth welfare organizations, public health authorities, a public drugs advisory service as well as medical care facilities. Moreover, it describes the coordination of different medical subspecialties such as pediatrics, obstetrics/gynecology and psychiatry. PMID- 28561212 TI - [A new German Scale for Assessing Parental Stress after Preterm Birth (PSS:NICU_German/2-scales)]. AB - : Background Preterm birth is known to be a stressful and anxious situation for parents, which might have long-term impact on the psychological health of mothers and even on the development of their preterm infants. Objective The Parental Stressor Scale: Neonatal Intensive Care Unit (PSS:NICU) was developed to assess parental stress after preterm birth through three subscales [1]. The aim of the present study was to examine the psychometric properties and the dimensionality of the German version of the PSS:NICU to develop a reliable German version of the PSS:NICU. Methods For the development (exploratory factor analysis) 100 parents of preterm infants answered the questionnaire. Results The Sights and Sounds subscale was removed from the German version of the PSS:NICU due to low number of items. A PSS: NICU_German/2-scales was developed consisting of 2 subscales: Infant Behavior and Appearance (7 Items, Cronbach's alpha=0,82) and Parental Role Alteration (6 Items, Cronbach's alpha=0,87). Conclusions The PSS:NICU_German/2 scales is a reliable and economic scale for the assessment of parental stress after preterm birth. PMID- 28561213 TI - ? PMID- 28561214 TI - ? PMID- 28561215 TI - ? PMID- 28561216 TI - [Return to Work: A Psychoeducational Module - An Intervention Study]. AB - : OBJECTIV: e This study evaluated a psychoeducational intervention that aimed to facilitate return to work. METHODS: The randomized-controlled study trial was established at three psychiatric hospitals. The status of permanent employment in an age group of 18 to 60 served as main inclusion criterion. The intervention consisted of 5 sessions and covered topics such as disclosure of the diagnosis to colleagues and supervisors or legal frameworks in the return-to-work process. Participants of the control group received treatment as usual. RESULTS: The informative value of the comparisons was decreased by strong differences between the groups at baseline due to an allocation bias. However, participants of the intervention group felt more secure and prepared regarding their return to the workplace. In addition, participants developed a higher level of understanding regarding their rights within the legal frameworks when returning to work. More participants of the control group returned to work within 3 months. The decisive factor for a successful return to work was the intention of the participants to return at baseline. CONCLUSION: The psychoeducational program was well accepted among participants and appeared to be a useful addition to individual counseling by social workers. However,the program did not increase the likelihood to return to work within three months. PMID- 28561217 TI - ["The Crutch is in the corner ..." - Experience of Mental Ill People with Cross Sectoral Care in Integrated Care - A Qualitative Study]. AB - The aim of the qualitative study was the evaluation of experiences with integrated care especially with the care in network "NetzWerk psychische Gesundheit" (NWpG) from the perspective of mental ill patients. The patients were recruited from the NWpG. Focus groups were conducted in five of these networks and analyzed with qualitative content analysis. 40 mental ill patients participated on the focus groups. Overall, they were very positive about their care in such a network. Especially, aspects like need orientation, 24/7 telephone hotline, involvements of relatives as well as outreach care has been experienced as a support for their own care. The health care in NWpG seems to be important for an independent existence and presents relevant components for an autonomous life. PMID- 28561219 TI - New Thieme Research Awards: Call for Pacesetting Contributions to Drug Research. PMID- 28561218 TI - [50th Anniversary of Psychiatric Attitude Research in Germany]. AB - Objective Analysis of the development of psychiatric attitude research in Germany over the past 50 years. Methods Historical overview based on systematic reviews of population-based studies. Results In the beginning, public attitudes towards people with mental disorders and towards psychiatry were studied from a sociological perspective, later on research was guided by a social psychological or individual psychological approach. This provided important insights into processes underlying the stigma of mental illness (e. g., role of labeling, causal attributions, beliefs into a continuum between mental health and illness, prevalence estimates etc.). Substantial contributions have also been made as regards the study of time trends in public attitudes and beliefs about mental illness, the investigation of the impact of the media on public attitudes, and the evaluation of the effectiveness of anti-stigma and awareness programs. Conclusion Despite these undisputable advancements it is about time to compliment the individual by a societal perspective. This appears particularly necessary in view of current trends in Germany towards sociopolitical radicalization. PMID- 28561220 TI - Preparation and Characterization of Gold Nanoparticles in the Presence of Citrate and Soybean Seed Extract in an Acidic Conditions. AB - Through the present study, an eco-friendly method was used to synthesize the gold nanoparticles (GNPs) by using the sodium citrate and extract of the soybean seed as reducing the agents at PH 3. X-Ray diffraction (XRD) method was used to evaluate the crystal structure of as-synthesized NPs and it's revealed that this method leads to well crystallized GNPs. In order to determine the particle size and their distribution, field emission scanning microscopy (FE-SEM) and dynamic light scattering (DLS) were used. The results showed that, the average particle size distribution of synthesized GNPs in solutions containing of the soybean extract and 1% citrate at PH 3 is about 109.6 and 140.9 nm, respectively. Also, we find that the average size of GNPs is 40 and 33 nm from solutions of citrate and soybean extract, respectively. It was concluded that using the extract of soybean seeds as reducing agent can lead to GNPs with small size and narrow size distribution. PMID- 28561221 TI - Design and Synthesis of New 1,3,4-Oxadiazole - Benzothiazole and Hydrazone Derivatives as Promising Chemotherapeutic Agents. AB - Looking for new cytotoxic and antimicrobial agents with improved antitumor activity, a series of hydrazide and oxadiazole derivatives were designed and synthesized using 3-methoxyphenol as starting substance. Novel N'-(arylidene)-2 (3-methoxyphenoxy)acetohydrazide derivatives (4a-f)/1-(4-substitutedphenyl)-2-[(5 [(3-methoxyphenoxy)methyl]-1,3,4-oxadiazol-2-yl)thio]ethan-1-one derivatives (6a f)/N-(6-substitutedbenzothiazol-2-yl)-2-[(5-[(3-methoxyphenoxy)methyl]-1,3,4 oxadiazol-2-yl)thio]acetamide derivatives (7a-e) were obtained and evaluated for their in vitro antimicrobial activity against various gram-positive, gram negative bacteria and fungi. The antimicrobial activity potential of the compounds against gram-negative bacteria was found to have higher compared to the potential against gram-positive bacteria. Also, compounds were screened for their antiproliferative activity against 2 selected human tumor cell lines, A549 lung, MCF7 breast cancer cell line and mouse embryo fibroblast cell line, NIH/3T3 as healthy cell line. Among the compounds evaluated, compound 7c bearing 1,3,4 oxadiazole ring and 6-methoxy benzothiazole moiety exhibited the highest inhibitory activity against A549 and MCF-7 tumor cell lines in contrary to NIH/3T3 cell line, as desired. PMID- 28561222 TI - Cromolyn Sodium Attenuates Paraquat-Induced Lung Injury by Modulation of Proinflammatory Cytokines. AB - The current study aimed to investigate the effects of Cromolyn Sodium (CS) on proinflammatory cytokines in Paraquat (PQ)-induced lung damage in rat. Animals were randomly divided into 5 groups. Group 1 and 2 received nebulized vehicle and CS (8 mg/kg) for 3 consecutive weeks, respectively. Group 3 was treated with single oral dose of PQ (40 mg/kg). Groups 4 and 5 were PQ groups which received nebulized CS (6 and 8 mg/kg/day, respectively) from 1 week before to 2 weeks after PQ administration. Finally, the animals were scarified and the changes of hydroxyproline (HP) and histology were evaluated in lung tissue. In addition, IL 1beta, TNF-alpha and IL-8 levels were determined in serum samples. The results showed that lung HP level as well as IL-1beta, TNF-alpha and IL-8 were significantly lower in the CS treated rats as compared to PQ group. The best response, however, was observed with the 8 mg/kg of CS as confirmed by histology findings. This study suggests that CS may prevent progression of PQ-induced lung damage by decreasing of inflammatory cytokines. PMID- 28561223 TI - Antidiabetic Activity of Extract and Compounds from an Endophytic Fungus Nigrospora oryzae. AB - The fungal extract as well as the 3 biosynthetic compounds, (S)-(+)-2-cis-4-trans abscisic acid (1), , 7'-hydroxy-abscisic acid (2) and 4-des-hydroxyl altersolanol A (3) from the endophytic fungus, Nigrospora oryzae, isolated from Combretum dolichopetalum leaf were investigated for their antidiabetic potential.The antidiabetic activity was determined in alloxan-induced diabetic mice by monitoring their fasting blood sugar for 9 h.The extract and the compounds (1-3) significantly (p<0.001) reduced the fasting blood sugar of the diabetic mice.The present study has shown that the biosynthetic products of the endophytic fungus, N. oryzae, exhibited strong antidiabetic activity. It has further shown that endophytic fungi could be an alternative source of novel compounds for management of diabetes. PMID- 28561224 TI - Variant PIK3R1 Hypermorphic Mutation and Clinical Phenotypes in a Family with Short Statures, Mild Immunodeficiency and Lymphoma. AB - Background Heterozygous point mutations in the GT splice donor consensus sequence of exon 11 of the PIK3R1 gene (coding for p85alpha, p55alpha, and p50alpha regulatory subunits of PI3K) lead to exon skipping and thereby to an aberrant protein that leaves PI3K hyperactivated. Several patients with this particular variant of PI3 kinase delta syndrome (APDS) suffering from sinopulmonary infections and lymphoproliferation have been described. Methods (Whole exome) sequencing, evaluation of cellular and clinical phenotypes. Results We here report a family with a new heterozygous mutation in this gene, a 9 bp deletion (c.1418_1425+1del) that, however, leads to the same skipping of exon 11. The clinical phenotypes of their members partly overlap features of patients of other reports. Conclusions We found a new mutation in PIK3R1 and show how broad the resulting clinical spectrum can be. PMID- 28561225 TI - Feasibility, Risk Profile and Diagnostic Yield of Stereotactic Biopsy in Children and Young Adults with Brain Lesions. AB - Objective To evaluate the feasibility, safety, and diagnostic yield of stereotactic biopsy (SB) in children and adolescents with cerebral lesions. Methods We performed a systematic review of the literature and a retrospective analysis of all pediatric and adolescent patients who underwent SB for unclear brain lesions at our center. We collected patient and lesion-associated parameters, analysed the rate of procedural complications and diagnostic yield. Results Our institutional series consisted of 285 SBs in 269 children and young adults between 1989 and 2016 (median age, 9 (range 1-18) years). There was no procedure-related mortality. Permanent and transient morbidity was 0.7% and 5.8%, respectively. Lesions were located in brain lobes (26.3%) and in midline structures (73.7%). The diagnostic yield was 97.5% and histology consisted low grade gliomas (44.2%), high-grade gliomas (15.1%), non-glial tumors (22.8%), and non-neoplastic disease (15.4%). Morbidity was not associated with tumor location, age, histology or intraoperative position of the patient. In order to compare our findings with previous reports, we reviewed 25 studies with 1 109 children and young adults which had underwent SB. The diagnostic yield ranged between 83% and 100%. The reported morbidity and mortality rates range from 0-27% and 0-3.3%, respectively. Conclusions SB in this particular patient population is a safe and a high-yield diagnostic procedure and indicates therefore its importance in the light of personalized medicine with the development of individual molecular treatment strategies. PMID- 28561226 TI - Neonatal Arterial Ischemic Stroke - A Hospital Based Active Surveillance Study in Germany. AB - Background Neonatal arterial ischemic stroke (NAIS) accounts for substantial long term sequelae in children. The potential effectiveness of neuroprotective therapies needs to be evaluated in appropriate studies with sufficient power. Objective To identify annual number of NAIS cases in Germany potentially eligible for randomized interventional trials. Methods Active surveillance for NAIS in 345 pediatric hospitals with questionnaire based validation of reported cases. Results Incidence of NAIS (7.1/100000 births) was in the range of other population-based studies. To design future clinical trials with anticoagulative or regenerative therapies, it is of major importance to distinguish between cases with or without relevant perinatal pathology. Children without underlying disease or premature birth accounted for 56% of all reported NAIS cases (primary NAIS). In 69% of the primary cases clinical seizures were observed. Although 31% showed other, less pathognomonic symptoms, NAIS was diagnosed. Mean time span between onset of symptoms and diagnosis was 2.9 days. The sensitivity of the initial ultrasound performed in all cases was 69%. Conclusions NAIS is a rare but not negligible morbidity in newborns. Asymptomatic children account for 56% of NAIS in all neonates. In these, not only seizures but also other unexplained symptoms should trigger diagnostic work-up with cUS and cMRI. Negative initial ultrasound results do not exclude NAIS. PMID- 28561227 TI - [Quality Characteristics and Prevalence of Exercise Therapy During Childhood Cancer Treatment in Germany]. AB - Background Exercise and adapted physical activity during and after treatment for childhood cancer have a large potential to diminish several side and late effects of treatment. However, the prevalence of such interventions is low. The aim of this investigation is to identify interventions in the clinical setting in Germany and to examine their quality and structural characteristics. Method 54 hospitals were investigated for the existence of relevant interventions and if applicable the quality and structural characteristics of these according to DIN EN 15224:2012 and further characteristics of structural quality in written form or by telephone. Results 48 hospitals took part in the investigation and filled out the questionnaire (CR 89%). Of these, 9 (19%) offer exercise therapy during treatment and/or aftercare. The remaining 39 (81%) did not offer exercise therapy at the time of investigation. Exercise therapy represents a permanent component of adjuvant treatment in the 9 identified hospitals. The qualifications of exercise therapy staff seem appropriate as well as conditions concerning rooms and equipment. Yet, funding of exercise therapy is mainly realized through donations and 3rd party funds. Conclusion The majority of childhood cancer patients in Germany do not have access to adapted physical activity during treatment or aftercare. The body of evidence for exercise therapy in the pediatric oncology setting is growing, as well as the network between exercise scientists/therapists in this field. To date, an exercise manual for pediatric oncology in German and a comprehensive financing option of such interventions via health insurance is not available. PMID- 28561229 TI - Growth Failure Caused by Premature Epiphyseal Closure in a Child Treated with Isotretinoin for Neuroblastoma. PMID- 28561228 TI - 2017 GPOH Guidelines for Diagnosis and Treatment of Patients with Neuroblastic Tumors. AB - The clinical course of neuroblastoma is more heterogeneous than any other malignant disease. Most low-risk patients experience regression after limited or even no chemotherapy. However, more than half of high-risk patients die from disease despite intensive multimodal treatment. Precise patient characterization at diagnosis is key for risk-adapted treatment. The guidelines presented here incorporate results from national and international clinical trials to produce recommendations for diagnosing and treating neuroblastoma patients in German hospitals outside of clinical trials. PMID- 28561230 TI - Enhancement of Quercetin Oral Bioavailability by Self-Nanoemulsifying Drug Delivery System and their Quantification Through Ultra High Performance Liquid Chromatography and Mass Spectrometry in Cerebral Ischemia. AB - Background Quercetin (Qur) and its major in vivo bioactive metabolites i. e., 3' O-methyl quercetin, 4'-O-methyl quercetin and quercetin 7-O-beta-D-glucuronide, may be used to treat cerebral ischemia however the poor aqueous solubility and less intestinal absorption of Qur results low bioavailability. Purpose To improve Qur bioavailability through preparation of nanoformulation and to develop and validate a sensitive quantification method for Qur detection in brain homogenate. Methods Qur-containing self-nanoemulsifying drug delivery system (Qur-SNEDDS) was developed to form oil-in-water nanoemulsions in situ. Ultra-high performance liquid chromatography electrospray ionization-synapt mass spectrometric method (UHPLC/ESI-QTOF-MS/MS) was developed and validated for quantification whereas for optimal recovery of analyte, a liquid-liquid extraction method (LLE) was used. Results A droplet size of 94.63+/-3.17 nm and zeta potential of -17.91+/-1.02 mV for nanoemuslion, elution time for Qur and internal standard (IS) Rutin as 1.21 and 1.50 min alongwith a transition at m/z 301.04/151.03 and 609.21/299.21, were observed respectively. Similarly, linear dynamic range (1.00 ng/mL-2 000.0 ng/mL), intra and inter-assay i. e., %CV of 0.26-2.04, lower limit of detection (LOD) 0.08 ng/mL as well as lower limit of quantitation (LOQ) as 0.131 ng/mL were also observed. Conclusion The developed method have advantage over previous all methods i. e., less time consuming (<3.0), low consumption of solvents (flow rate 0.20 mL/min.) via small size column, more accuracy and specificity as well as use of acetonitrile as compared to hazardous solvents. This certainly adds advantages for green chromatography technique and supports application of current developed method for quantification and evaluation of Qur-SNEDDS. PMID- 28561231 TI - Large Intra-subject Variability in Caffeine Pharmacokinetics: Randomized Cross over Study of Single Caffeine Product. AB - Background Average bioequivalence has been criticized for not adequately addressing individual variations. Importance of subjects' blinding in bioequivalence studies has not been well studied. We explored the extent of intra subject pharmacokinetic variability and effect of drug-ingestion unawareness in subjects taking single caffeine product. Methods A single-dose randomized cross over design was used to compare pharmacokinetics of 200 mg caffeine, described as caffeine (overt) or as placebo (covert). Maximum concentration (Cmax), Cmax first time (Tmax), area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or to Tmax of overt caffeine (AUCOverttmax), and Cmax/AUCI were calculated blindly using standard non compartmental method. Percentages of individual covert/overt ratios that are outside the +/-25% range were determined. Covert-vs-overt effect on caffeine pharmacokinetics was evaluated by 90% confidence interval (CI) and 80.00-125.00% bioequivalence range. Results 32 healthy subjects (6% females, mean (SD) age 33.3 (7.2) year) participated in the study (28 analysed). Out of the 28 individual covert/overt ratios, 23% were outside the +/-25% range for AUCT, 30% for AUCI, 20% for AUCOverttmax, 30% for Cmax, and 43% for Tmax. There was no significant covert-vs-overt difference in any of the pharmacokinetic parameters studied. Further, the 90% CIs for AUCT, AUCI, Cmax, AUCOverttmax, and Cmax/AUCI were all within the 80.00-125.00% bioequivalence range with mean absolute deviation of covert/overt ratios of 3.31%, 6.29%, 1.43%, 1.87%, and 5.19%, respectively. Conclusions Large intra-subject variability in main caffeine pharmacokinetic parameters was noted when comparing an oral caffeine product to itself. Subjects' blinding may not be important in average bioequivalence studies. PMID- 28561232 TI - Effect of Different Sampling Schedules on Results of Bioavailability and Bioequivalence Studies: Evaluation by Means of Monte Carlo Simulations. AB - Bioavailability and bioequivalence study is one of the most frequently performed investigations in clinical trials. Bioequivalence testing is based on the assumption that 2 drug products will be therapeutically equivalent when they are equivalent in the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed and becomes available at the site of drug action. In recent years there has been a significant growth in published papers that use in silico studies based on mathematical simulations to analyze pharmacokinetic and pharmacodynamic properties of drugs, including bioavailability and bioequivalence aspects. The goal of this study is to evaluate the usefulness of in silico studies as a tool in the planning of bioequivalence, bioavailability and other pharmacokinetic assays, e.g., to determine an appropriate sampling schedule. Monte Carlo simulations were used to define adequate blood sampling schedules for a bioequivalence assay comparing 2 different formulations of cefadroxil oral suspensions. In silico bioequivalence studies comparing different formulation of cefadroxil oral suspensions using various sampling schedules were performed using models. An in vivo study was conducted to confirm in silico results. The results of in silico and in vivo bioequivalence studies demonstrated that schedules with fewer sampling times are as efficient as schedules with larger numbers of sampling times in the assessment of bioequivalence, but only if Tmax is included as a sampling time. It was also concluded that in silico studies are useful tools in the planning of bioequivalence, bioavailability and other pharmacokinetic in vivo assays. PMID- 28561233 TI - 2017 Eberhard F. Mammen Award Announcements: Part I-Most Popular Articles. PMID- 28561234 TI - Point-of-Care Testing in Acute Hemorrhagic and Thrombotic States. PMID- 28561235 TI - How Long Does It Take for Clopidogrel and Ticagrelor to Inhibit Platelets in Patients Undergoing Primary Percutaneous Coronary Intervention? A Detailed Pharmacodynamic Analysis: Time Course of Platelet Reactivity in STEMI (TOPS). AB - Antiplatelet therapy plays a pivotal role in patients with an ST-segment elevation myocardial infarction (STEMI) to prevent further atherothrombotic events, such as stent thrombosis. Although the risk of stent thrombosis is highest in the first hours after primary percutaneous coronary intervention (pPCI), little is known about when an adequate level of platelet inhibition is achieved following a clopidogrel or ticagrelor loading dose in STEMI patients. Patients presenting with STEMI in whom pPCI was performed and who were loaded with 600 mg clopidogrel or 180 mg ticagrelor were eligible for enrolment in this nonrandomized, open label, single-center study. Platelet reactivity was measured before PCI, 6 and 24 hours after loading dose and after 2, 7, and 14 days, using the VerifyNow P2Y12 assay as well as 20 umol/L adenosine diphosphate stimulated light transmittance aggregometry (LTA). We analyzed the time until a VerifyNow result of < 236 P2Y12 reaction units or LTA maximum platelet aggregation of < 64.5% was reached. A total of 28 patients were participated in this study. Platelet reactivity dropped below the high platelet reactivity cutoff level after 11.4 (VerifyNow) and 5.7 (LTA) hours in patients who were loaded with clopidogrel, and after 2.4 (VerifyNow) and 3.9 (LTA) hours in patients who were loaded with ticagrelor. Despite the administration of a clopidogrel or ticagrelor loading dose, it still takes multiple hours (2-11) to reach adequate platelet inhibition in STEMI patients. This might indicate the need for additional antiplatelet therapy in the first hours after loading in patients undergoing pPCI with stenting. PMID- 28561236 TI - [Quo vadis DGPRAC: associated members' goals for the future]. AB - Plastic surgery is extremely diverse and offers various fields of work. To provide optimal support for plastic surgeons in training, it is therefore paramount to know their mid- and long-term goals. To that end, we conducted a web based survey among the 462 associated members of the German Association of Plastic, Reconstructive and Aesthetic Surgeons (DGPRAC). Besides asking questions about the current status, we specifically inquired about the pursued setting and main area of work. 84 completed questionnaires were evaluated. Most respondents saw their future in a private practice setting. Reconstructive surgery and aesthetic surgery were by far the most sought-after fields, while only a few of the associated members pursued a career in hand surgery, and none of them wished to work in burn care. At the same time, they felt that aesthetic surgery was the field where training was most insufficient. Therefore, measures need to be taken to improve the training in aesthetic surgery. Also, it is paramount to increase the attractiveness of both the fields of hand surgery and burn care to assure highly qualified care in the future. PMID- 28561237 TI - QSAR Study of Artemisinin Analogues as Antimalarial Drugs by Neural Network and Replacement Method. AB - Quantitative structure-activity relationship (QSAR) models were derived for 179 analogues of artemisinin, a potent antimalarial agent. Molecular descriptors derived solely from molecular structure were used to represent molecular structure. Utilizing replacement method, a subset of 11 descriptors was selected. General regression neural network (GRNN) was used to construct the nonlinear QSAR models in all stages of study. The relative standard error percent in antimalarial activity predictions for the training set by the application of cross-validation (RMSE-CV) was 0.43, and for test set (RMSEtest) was 0.51. GRNN analysis yielded predicted activities in the excellent agreement with the experimentally obtained values (R2training = 0.967 and R2test = 0.918). The mean absolute error for the test set was computed as 0.4115. PMID- 28561238 TI - Sensitive LC-MS/MS Method for the Simultaneous Determination of Bendamustine and its Active Metabolite, gamma-Hydroxybendamustine in Small Volume Mice and Dog Plasma and its Application to a Pharmacokinetic Study in Mice and Dogs. AB - A highly sensitive, specific and rapid LC-ESI-MS/MS method has been developed and validated for the simultaneous quantification of bendamustine (BM) and gamma hydroxybendamustine (HBM) in small volume (20 uL) mice and dog plasma using phenacetin as an internal standard (IS) as per regulatory guidelines. Both the analytes and IS were extracted from mice and dog plasma using a liquid-liquid extraction method. Chromatography was achieved on Atlantis dC18 column using an isocratic mobile phase (0.2% formic acid:acetonitrile, 25:75) at a flow rate of 0.40 mL/min. The total chromatographic run time was 3.0 min and the elution of BM, HBM and IS occurred at ~1.2, 1.2 and 2.0 min, respectively. A linear response function was established 0.11-518 ng/mL for both the analytes in mice and dog plasma. The intra- and inter-day accuracy and precisions were in the range of 3.46-12.9 and 3.63-8.23%; 1.15-9.00 and 7.86-9.49% for BM and HBM, respectively in mice plasma and 2.15-6.49 and 1.73-13.1%; 4.35-13.9 and 4.33-10.5% for BM and HBM, respectively in dog plasma. This novel method has been applied to a pharmacokinetic study in mice and dogs. PMID- 28561239 TI - Determination of Fenofibric Acid in Rat Plasma and its Application to a Comparative Pharmacokinetic Study of JW322 and Fenofibrate. AB - In this study, a sensitive and reliable method for the quantitation of fenofibric acid in rat plasma was developed and validated using high performance liquid chromatography (HPLC). The plasma samples were prepared by deproteinization, and sildenafil was used as an internal standard. Chromatographic separation was achieved using a reversed-phase (C18) column. The mobile phase, 0.02 M ammonium acetate buffer:acetonitrile (35:65, v/v), was run at a flow rate of 1.0 mL/min, and the column eluent was monitored using an ultraviolet detector at 280 nm at room temperature. The retention times of sildenafil (an internal standard), and fenofibric acid were approximately 5.9 and 7.7 min, respectively. The quantitation limit of fenofibric acid in rat plasma was 0.03 MUg/mL. Pharmacokinetic parameters of fenofibric acid was evaluated after oral (at doses of 20 mg/kg) administration of JW322 and fenofibrate in rats. After oral administration (20 mg/kg) of JW322, relative bioavailability was approximately 272.8% compared to fenofibrate. PMID- 28561240 TI - Preparation and Characterization of Copolymeric Polymersomes for Protein Delivery. AB - Biodegradable copolymeric polymersomes have been used for controlled drug delivery of proteins. These polymersomes important areas to overcome formulation associated problems of the proteins. The aim of this study was to develop polymersomes using biodegradable copolymers for delivery of bovine serum albumin (BSA) as a model protein. Encapsulated BSA by mPEG-PCL polymersomes led to formation of BSA-loaded mPEG-PCL polymersomes. The polymersomes synthesized with the protein-polymer ratio of 1:4 at 15 000 rpm gave maximum loading, minimum polydispersion with maximally sustained protein release pattern, among the prepared polymersomes. Investigation on FTIR and DSC results revealed that such a high encapsulation efficiency is due to strong interaction between BSA and the copolymer.The particles size and their morphology of polymersomes were determined by DLS and AFM.The encapsulation efficiency of BSA was 91.02%. The results of AFM showed that the polymersomes had spherical shapes with size of 49 nm.The sizes of BSA-loaded polymersomes ranged from 66.06 nm to 84.97 nm. The results showed that polymersomes exhibited a triphasic release, for BSA. Overall, the results indicated that mPEG-PCL polymersomes can be considered as a promising carrier for proteins. PMID- 28561241 TI - In vitro Controlled Release from Solid Pharmaceutical Formulations of two new Adamantane Aminoethers with Antitubercular Activity (I). AB - The aim of the present investigation was to develop matrix tablet formulations for the in vitro controlled release of 2 new tuberculocidal adamantane aminoethers (compounds I and II), congeneric to the adamantane derivative SQ109, which is in final clinical trials, using carefully selected excipients, such as polyvinylpyrrolidone, sodium alginate and lactose. The tablets were prepared using the direct compression method and dissolution experiments were conducted using the US Pharmacopoeia type II apparatus (paddle method) in gastric and intestinal fluids. The results confirm that both analogues, albeit more lipophilic than SQ109, showed satisfactory in vitro release characteristics from solid pharmaceutical formulations. In conclusion, these formulations merit further assessment by conducting in the future bioavailability in vivo studies. PMID- 28561242 TI - The Importance of Facts and the Role of Academic Publishers in Today's World-A Publisher's View. PMID- 28561243 TI - Pulmonary Disease and Critical Illness in Pregnancy. PMID- 28561244 TI - General Management Principles of the Pregnant Woman. AB - Pregnancy is a dynamic process that consists of profound physiological changes mediated by hormonal, mechanical, and circulatory pathways. Understanding of changes in physiology is essential for distinguishing abnormal and normal signs and symptoms in a pregnant patient. These physiological changes also have important pharmacotherapeutic considerations for a pregnant patient. Although there are limited data to guide decisions regarding medications and diagnostic procedures in pregnancy, a careful review of risks should be balanced with review of risk of withholding a medication or procedure. Interventional pulmonary procedures can be safely performed in pregnant women while keeping in mind the maternal anatomic and physiologic changes. Furthermore, management of a maternal cardiopulmonary arrest requires important modifications in patient positioning and intravenous access to ensure adequate efficacy of chest compressions, circulation, and airway management. This review will provide an overview of maternal physiologic changes with a focus on cardiopulmonary physiology, pharmacotherapeutic considerations, diagnostic and interventional pulmonary procedures during pregnancy, and cardiopulmonary resuscitation in pregnancy. PMID- 28561246 TI - Pulmonary Hypertension in Pregnancy. AB - Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy associated with abnormal cardiopulmonary hemodynamics and a limited life expectancy due to right heart failure. Young women are preferentially affected. Women with PAH are at increased risk of complications and death during pregnancy for both the mother and the fetus. While it is not well characterized how changes in sex steroids and other hormones during pregnancy affect pulmonary hypertension, many expected systemic and heart-lung physiologic adaptations during gestation are poorly tolerated in women with PAH. Despite the approval of numerous therapies for PAH in recent years, pregnancy avoidance or early termination is still recommended in women with PAH because of poor outcomes. In this review, we will discuss physiologic and hormonal changes in pregnancy as they relate to pulmonary vascular disease and right heart function. We will review current consensus recommendations and outline the management of pregnancy in PAH when it does occur. PMID- 28561245 TI - Pulmonary Complications of Pregnancy: Venous Thromboembolism. AB - Unique considerations are needed when diagnosing and treating venous thromboembolism (VTE) in women who are pregnant or postpartum. What are the risks to the fetus, such as drug exposure or the risk of radiation with diagnostic imaging? How does the physiology of pregnancy affect imaging techniques and anticoagulation management? How should anticoagulation be managed around labor and delivery? These questions highlight some of the important considerations needed when managing a pregnant patient with suspected or confirmed VTE. This review outlines what is known about the epidemiology, pathophysiology, clinical risk factors, diagnosis, and therapeutic management of VTE in pregnancy. We also review our preferred diagnostic and treatment algorithm for a pregnant patient with suspected or confirmed VTE. PMID- 28561247 TI - Asthma during Pregnancy: Exacerbations, Management, and Health Outcomes for Mother and Infant. AB - One in 10 pregnant women worldwide has asthma and of these, 10% will have a severe exacerbation requiring oral corticosteroids (OCSs) in pregnancy. This review of recent publications in the field will describe the effects of exacerbation on maternal and neonatal health, the use of asthma medications during pregnancy, and will suggest novel management approaches for asthma in pregnancy. Pregnancy results in unpredictable changes in the disease; therefore, regular monitoring of symptoms is recommended. Uncontrolled asthma is frequently described in cohorts of pregnant women with asthma, and some recent studies show associations with adverse perinatal outcomes, as previously demonstrated with exacerbations. Guidelines for the management of asthma recommend the continued use of inhaled corticosteroids (ICSs) in pregnancy, with budesonide having a particularly good safety profile. Recent data suggest small effects of asthma and/or asthma medication use on congenital malformations; however, there is less data available on the safety of ICS/long-acting beta agonist combinations, which are increasingly used for maintenance treatment. Novel management strategies are needed to address the complex needs of pregnant women with asthma. These include medication nonadherence and the presence of numerous comorbidities which can affect asthma, such as rhinitis, cigarette smoking, obesity, and mental health issues. Inflammation-based management has been shown to be effective in reducing exacerbations in pregnancy and may also improve perinatal outcomes. The involvement of a multidisciplinary team and the assessment of comorbidities have potential to improve the health of mothers and their offspring. PMID- 28561248 TI - Pulmonary Infections in Pregnancy. AB - Pregnant women experience physiological and immunological changes that increase the risk or severity of certain pulmonary infections. These changes also affect drug disposition, which impacts treatment choices. In this article, we review the available data on (1) the physiological and immunological changes that specifically impact tuberculosis, influenza, and varicella pneumonia; (2) active and latent tuberculosis management, including drug monitoring and maternal-infant outcomes; (3) the treatment and prevention of influenza; and (4) the diagnosis and management of varicella pneumonia. Clinical trials often exclude pregnant women, but there is a consensus that treating pregnant women for tuberculosis, influenza, and varicella pneumonia improves outcomes for both the woman and her child. PMID- 28561249 TI - Interstitial Lung Disease in Women of Child-Bearing Age. AB - Interstitial lung disease (ILD) is an inflammatory and fibrotic infiltrative process of the lung that is often associated with collagen vascular disease in women. Untreated, it results in collagen deposition in the lung interstitium that can lead to a slow suffocating death. Pregnancy planning is often not discussed with women who have ILD due to concerns about potentially aggravating the disease process, or due to lack of knowledge about the safety of medications used to treat ILD. With improved understanding of the pathophysiology of both autoimmune disease and ILD, it has become clear that safe, planned pregnancies are possible in most women with ILD. In this article, our aim is to review diagnosis, treatment, and disease course of ILD in women who are planning a pregnancy or are pregnant. Better understanding of the disease process and knowledge of safe treatments will likely lead to improved pregnancy planning in women with ILD. PMID- 28561250 TI - Predictors of Maternal Mortality and Prognostic Models in Obstetric Patients. AB - The use of predictive models has been proposed as a potential tool to reduce maternal morbidity and mortality, by aiding in the timely identification of potential high-risk patients. Prognostic models in critical care have been used to characterize the severity of illness of specific diseases. Physiological changes in pregnancy may result in general critical illness prediction models overestimating mortality in obstetric patients. Models that specifically reflect the unique characteristics of obstetric patients may have better prognostic value. Recently developed tools have focused on identifying at-risk patients before they require intensive care unit (ICU) admission to target early interventions and prevent acute clinical decompensation. The aim of the newest scoring systems, specifically designed for groups of obstetric patients receiving non-ICU care, is to reduce maternal morbidity and mortality by identifying early high-risk patients and initiating prompt effective medical responses. PMID- 28561251 TI - Management of Acute Respiratory Failure in Pregnancy. AB - Respiratory failure affects up to 1 in 500 pregnancies, more commonly in the postpartum period. The causes of respiratory failure include several pregnancy specific conditions such as preeclampsia, amniotic fluid embolism, and peripartum cardiomyopathy. Pregnancy may also increase the risk or severity of other conditions, such as asthma, thromboembolism, viral pneumonitis, and gastric acid aspiration. Changes to maternal respiratory physiology and the presence of a fetus may affect the assessment and management of these patients. In addition to identifying pregnancy-specific causes, some differences exist in the management of the pregnant woman with acute respiratory failure. Endotracheal intubation in pregnancy carries a significant risk, due to upper airway edema and rapid oxygen desaturation following apnea. Few studies have addressed prolonged mechanical ventilation management in pregnancy. Optimizing oxygenation is important, but whether permissive hypercapnia is tolerated during pregnancy remains unclear. Delivery of the fetus is often considered but does not always improve maternal respiratory function and should be reserved only for cases where benefit to the fetus is anticipated. PMID- 28561252 TI - General Care of the Pregnant Patient in the Intensive Care Unit. AB - Pregnant women represent a small subset of all intensive care unit (ICU) admissions and may require intensive care for "obstetric" or "nonobstetric" reasons. Women may be admitted to the ICU at any stage of pregnancy or in the postpartum period. Pregnancy may be discovered at the time of admission to the ICU. Pregnancy impacts on ICU care in a variety of ways and requires a multidisciplinary approach to management. Pregnancy is associated with considerable physiological changes that affect most organ systems, including an expansion in blood volume, an increase in minute ventilation, and an increased risk of thrombosis. The enlarging uterus may be associated with mechanical complications due to compression and displacement of other structures. The growing fetus places considerable demands upon the mother, being reliant on maternal systems for oxygenation, nutrition and disposal of carbon dioxide, and other waste products. This "second patient" must be considered when managing the pregnant woman. Optimal management of the mother usually constitutes best treatment for the fetus. Maternal shock and physiological disturbance, medications, and ionizing radiation from diagnostic imaging may have harmful effects on the unborn child. Delivery of the fetus for either maternal or fetal indications may be necessary and should be planned for, even if considered unlikely to be required. Care of the postpartum woman has its own challenges, including managing lactation and facilitating mother/infant contact. In this article, the general care aspects of ICU treatment of the pregnant woman will be discussed, including monitoring, physiological target setting, and general supportive care. PMID- 28561253 TI - Obstetric Disorders in the ICU. AB - Pregnant and postpartum patients represent a challenge to critical care physicians, as two patients in one have to be cared for and because specific obstetric disorders, not universally covered in formal critical care training, need to be managed. Pregnancy also alters physiologic norms, so that the critical care physician may either fail to recognize a value as abnormal in pregnancy or mistakenly identify as abnormal a value within the normal range for a pregnant woman. In this article, we will review the most frequent obstetric causes of admission of pregnant/postpartum patients to the intensive care unit (hypertensive disease of pregnancy, obstetric hemorrhage, and obstetric sepsis) along with their diagnostic criteria, clinical presentation, and recommended treatment. We will also cover some specific, although less frequent, obstetric disorders, such as acute fatty liver of pregnancy, peripartum cardiomyopathy, and amniotic fluid embolism. Our primary aim is to improve quality of care for these types of patients. PMID- 28561254 TI - [Importance of Job Demands for Rehabilitation Patients - Application of an Index According to Occupations]. AB - OBJECTIVE: To investigate the importance of job demands for rehabilitation patients. METHODS: A secondary data analysis of 2,089 rehabilitation patients of the Federal German Pension Insurance was conducted. The job exposure index of Kroll was used based on occupations. RESULTS: The prevalence of high job demands was 11.2%. The index correlated significantly with reha-relevant impairments. Furthermore, there was a significant association between high job demands and an unfavorable return-to-work prognosis at discharge from rehabilitation, also independently of the presence of self-reported severe restrictions of work ability. CONCLUSION: The job exposure index reflects occupation-specific job demands of rehabilitation patients. The construction of the index based on the relevant occupation classifications enables its broad application in analyses using routinely collected health data. PMID- 28561255 TI - [Total Hip and Knee Arthroplasty - Utilization of Postoperative Rehabilitation]. AB - BACKGROUND: After total hip and knee arthroplasty, patients have different options of subsequent treatment: an early postoperative rehabilitation, with or without a period at home, or only outpatient services. The aim of this study was to identify factors predicting the utilization of an early postoperative rehabilitation. METHODS: This cross-sectoral analysis is based on claims data of AOK Baden-Wurttemberg (Statutory Health Insurance), Deutsche Rentenversicherung Bund and Deutsche Rentenversicherung Baden-Wurttemberg (German Pension Insurance). Predictors for participation in an early postoperative rehabilitation and for an interim period were determined using logistic regression analysis. RESULTS: 82.6% of 9 232 patients were going to an early postoperative rehabilitation after total hip arthroplasty. After total knee arthroplasty, 83.9% of 7 656 patients were utilizing postoperative rehabilitation. Moreover, there was less utilization of postoperative rehabilitation in young, male and foreign patients. The analysis shows that the utilization of post-acute rehabilitation was significantly predicted by sociodemographic variables (age, sex, nationality) as well as comorbidity, outpatient treatment and medication. CONCLUSION: The results provide an indication of higher severity of patients in group "postoperative rehabilitation without a period at home". Nevertheless there are some indications for under-utilization of certain patient groups. PMID- 28561256 TI - Lack of K140 immunoreactivity in junctional epidermolysis bullosa skin and keratinocytes associates with misfolded laminin epidermal growth factor-like motif 2 of the beta3 short arm. AB - Recessive mutations in the LAMA3, LAMB3 and LAMC2 genes that encode laminin-332 (LM332) (alpha3a, beta3 and gamma2 chains, respectively) cause different junctional epidermolysis bullosa (JEB) subtypes. Biallelic truncating mutations in any of these three genes usually lead to lack of protein expression resulting in the severe generalized JEB subtype, while missense or splice-site mutations in at least one allele lead to reduced expression typical of JEB generalized intermediate (JEB-gen intermed) or localized. Here, we molecularly characterized an adult patient with JEB showing negative skin staining for the anti-beta3 chain monoclonal antibody K140. This antibody recognizes an as yet unidentified epitope within the laminin beta3 short arm. The patient harbours a homozygous splice-site mutation resulting in highly aberrant transcripts with partial skipping of the LAMB3 exon that encodes the laminin epidermal growth factor-like motif 2 of the beta3 short arm (beta3-LE2). At the protein level, mutation consequences predict a misfolded beta3-LE2 motif and, indeed, we found that LM332 is correctly assembled but retained in the endoplasmic reticulum (ER) where it colocalizes with the lumenal ER chaperone protein BiP, leading to dramatically reduced secretion. Lack of K140 reactivity to mutant LM332 was confirmed by immunoprecipitation and Western blot analyses. Our findings not only identify the beta3-LE2 subdomain as the region recognized by K140, but also show that misfolding of LM332 structural motifs and subsequent protein retention in the ER is a common pathomechanism in JEB-gen intermed. In addition to its usefulness in antigen mapping diagnosis of JEB subtypes, this knowledge is relevant to the design of therapeutic strategies aimed at releasing ER-retained LM332 in JEB. PMID- 28561257 TI - Recommendations for Use of Affirmative Psychotherapy With LGBT Older Adults. AB - Affirmative therapy is a type of psychotherapy used to validate and advocate for the needs of sexual and gender minority clients. Therapists use verbal and nonverbal means to demonstrate an affirming stance toward lesbian, gay, bisexual, and transgender (LGBT) clients. Although this therapeutic approach can be used with LGBT individuals across the lifespan, the case presented in this paper highlights the benefit of using this approach with older LGBT individuals. Discussion of the unique challenges faced by older LGBT people will be followed with an illustrative case that shows ways that affirmative therapy can help individuals achieve greater self-actualization. The case formulation and conclusion will highlight specific ways that therapists can convey an affirmative stance and help clients feel welcome and accepted in the therapeutic setting. Recommendations for environmental cues, intake questions, and treatment skills will be offered at the conclusion. PMID- 28561258 TI - Adjunct steroids in the treatment of peritonsillar abscess: A systematic review. AB - OBJECTIVES: This study systematically reviews the existing literature on the efficacy of adjuvant corticosteroids in improving clinical outcomes after peritonsillar abscess (PTA) drainage. STUDY DESIGN: Systematic review. METHODS: We performed a literature search of MEDLINE, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Scopus, Embase, and ClinicalTrials.gov from inception to June 2016. Inclusion criteria included randomized controlled trials (RCTs) evaluating adjuvant corticosteroids after PTA drainage. Data were systematically collected on study design, patient demographics, and clinical characteristics. Two independent investigators reviewed all manuscripts and summarized the data. RESULTS: Three RCTs comprising 153 patients were included. The results were not pooled due to heterogeneity in the method in which outcomes were measured and reported. The trials also varied on the type of steroid (dexamethasone, methylprednisolone) administered and method of drainage (incision, aspiration). All three RCTs reported statistically significant improvement in body temperature from adjuvant steroid administration compared to placebo. Pain scores, mouth opening, time to painless oral intake, and duration of hospitalization were significantly improved in only one or two of the three RCTs between the steroid and control group. No adverse side effects from steroid administration were reported. CONCLUSIONS: Steroids as an adjunct therapy to the treatment of PTA may result in faster recovery. However, further investigation with larger RCTs and standardized outcomes are warranted. LEVEL OF EVIDENCE: 1a. Laryngoscope, 128:72-77, 2018. PMID- 28561259 TI - Cost-effectiveness of high-sensitivity faecal immunochemical test and colonoscopy screening for colorectal cancer. AB - BACKGROUND: Colorectal cancer screening can decrease morbidity and mortality. However, there are widespread differences in the implementation of programmes and choice of strategy. The primary objective of this study was to estimate lifelong costs and health outcomes of two of the currently most preferred methods of screening for colorectal cancer: colonoscopy and sensitive faecal immunochemical test (FIT). METHODS: A cost-effectiveness analysis of colorectal cancer screening in a Swedish population was performed using a decision analysis model, based on the design of the Screening of Swedish Colons (SCREESCO) study, and data from the published literature and registries. Lifelong cost and effects of colonoscopy once, colonoscopy every 10 years, FIT twice, FIT biennially and no screening were estimated using simulations. RESULTS: For 1000 individuals invited to screening, it was estimated that screening once with colonoscopy yielded 49 more quality adjusted life-years (QALYs) and a cost saving of ?64 800 compared with no screening. Similarly, screening twice with FIT gave 26 more QALYs and a cost saving of ?17 600. When the colonoscopic screening was repeated every tenth year, 7 additional QALYs were gained at a cost of ?189 400 compared with a single colonoscopy. The additional gain with biennial FIT screening was 25 QALYs at a cost of ?154 300 compared with two FITs. CONCLUSION: All screening strategies were cost-effective compared with no screening. Repeated and single screening strategies with colonoscopy were more cost-effective than FIT when lifelong effects and costs were considered. However, other factors such as patient acceptability of the test and availability of human resources also have to be taken into account. PMID- 28561260 TI - Analysis of gluconate metabolism for pyruvate production in engineered Escherichia coli based on genome-wide transcriptomes. AB - : For pyruvate-producing strains, intracellular reduced nicotinamide adenine dinucleotide (NADH) accumulation is the main reason for the glycolysis inhibition. Comparing with glucose, using sodium gluconate as carbon source brought a decrease in NADH production and an increase in pyruvate production in engineered strain YP211. In order to explore the metabolic advantages of gluconate, genome-wide transcriptome analysis was employed to compare the metabolic differences between the two carbon sources. The results showed that the transcription of the genes gntU, gntK, and gntT responsible for transport and phosphorylation of gluconate, and genes edd and eda belonging to the Entner Doudoroff (ED) pathway, was significantly enhanced. This suggested that the shortest route for the synthesis of pyruvate from gluconate was activated, and the synthesis of NADH was halved. Besides, the transcription of genes glpABCDTKF related to the glycerol metabolism was significantly enhanced, which might be because glycerol metabolism pathways were activated in the absence of glucose. These results provided valuable information for the further design of metabolic pathways in the construction of pyruvate-producing strains. SIGNIFICANCE AND IMPACT OF THE STUDY: Comparing with glucose, using sodium gluconate as carbon source brought a decrease in nicotinamide adenine dinucleotide and an increase in pyruvate production in engineered strain YP211. From the genome-wide transcriptome analysis, the Entner-Doudoroff pathway was activated strongly in gluconate metabolism, which innovatively provided a shorter and more effective pathway for pyruvate production. PMID- 28561261 TI - Analysis of chloroplast genomes and a supermatrix inform reclassification of the Rhodomelaceae (Rhodophyta). AB - With over a thousand species, the Rhodomelaceae is the most species-rich family of red algae. While its genera have been assigned to 14 tribes, the high-level classification of the family has never been evaluated with a molecular phylogeny. Here, we reassess its classification by integrating genome-scale phylogenetic analysis with observations of the morphological characters of clades. In order to resolve relationships among the main lineages of the family we constructed a phylogeny with 55 chloroplast genomes (52 newly determined). The majority of branches were resolved with full bootstrap support. We then added 266 rbcL, 125 18S rRNA gene and 143 cox1 sequences to construct a comprehensive phylogeny containing nearly half of all known species in the family (407 species in 89 genera). These analyses suggest the same subdivision into higher-level lineages, but included many branches with moderate or poor support. The circumscription for nine of the 13 previously described tribes was supported, but the Lophothalieae, Polysiphonieae, Pterosiphonieae and Herposiphonieae required revision, and five new tribes and one resurrected tribe were segregated from them. Rhizoid anatomy is highlighted as a key diagnostic character for the morphological delineation of several lineages. This work provides the most extensive phylogenetic analysis of the Rhodomelaceae to date and successfully resolves the relationships among major clades of the family. Our data show that organellar genomes obtained through high throughput sequencing produce well-resolved phylogenies of difficult groups, and their more general application in algal systematics will likely permit deciphering questions about classification at many taxonomic levels. PMID- 28561262 TI - Quantification of regional variations in glenoid trabecular bone architecture and mineralization using clinical computed tomography images. AB - The purpose of this study was to demonstrate feasibility of a clinical CT imaging and analysis technique to quantify regional variations in trabecular bone architecture and mineralization of glenoid bones. Specifically, our objective was to determine to what extent clinical CT imaging of intact upper extremities can describe variations of trabecular bone architectures at anatomic and peri-implant regions by comparing trabecular bone architectures as measured by high resolution, micro CT imaging of same excised glenoid bones. Bone volume fraction (BVF), trabecular bone thickness (TbTh), number of trabecular bone (TbN), spacing (TbS), pattern factor (TbPf), bone surface area (BSA), and skeletal connectivity (Conn.), in addition to bone mineral content (BMC) and bone mineral density (BMD), were quantified from both clinical and micro CT images using whole bone, anatomic, and peri-implant bone masks. Strong correlations of BVF, TbTh, TbSp, BMC, and BMD were found between clinical CT and micro CT imaging methods. The variations in BVF, TbTh, TbSp, TbN, BMC, and BMD at anatomical and peri-implant regions were larger than those at whole bone regions. In this study, we have demonstrated that this clinical CT imaging methodology can be used to quantify variations of a patient's glenoid bone at anatomic and peri-implant levels. Statement of Clinical Significance. An in vivo quantitative assessment of glenoid trabecular bone architecture in the anatomic and peri-implant regions may improve our understanding on the role of bone quality on glenoid component loosening following total shoulder arthroplasty. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:85-96, 2018. PMID- 28561263 TI - Providing teachers with education on epilepsy increased their willingness to handle acute seizures in children from one to 10 years of age. AB - AIM: In Germany, preschool teachers supervise children up to six years of age and are also responsible for supervising older pupils after school. This study explored the impact of a teaching session on epilepsy for teachers in charge of children from 1 to 10 years of age. METHODS: We evaluated the benefit of a teaching session offered to all preschool teachers in Leipzig, Germany, in 2014 2015, by asking them to complete the same questionnaire 12-24 months pre intervention, and 12 months postintervention. RESULTS: Both questionnaires were completed by 123 teachers. The number of teachers who felt they were prepared to handle an acute seizure rose from 36 (29%) pre-intervention to 65 (53%) post intervention (p < 0.001) and their willingness to administer a prescribed rescue medication rose from 66 (54%) to 93 (76%, p < 0.001). The session also increased the number of teachers who were prepared to take children with epilepsy on excursions under any circumstance from 38 (31%) to 52 (42%, p < 0.05). In addition, the number of teachers who would place a solid object in the child's mouth during an attack fell from 16 (13%) to seven (6%) (p < 0.05). CONCLUSION: Providing a teaching session on epilepsy increased the teachers' knowledge and willingness to act and reduced obsolete, counterproductive measures. PMID- 28561264 TI - Virulence markers associated with Trueperella pyogenes infections in livestock and companion animals. AB - : Trueperella pyogenes is an opportunistic pathogen that causes diverse pyogenic infections in livestock. The genes that encode the exotoxin pyolysin (plo) and other putative factors that promote adhesion of pathogen to host cells (fimbriae fimA, fimC, fimE, fimG, neuraminidases nanH, nanP, and collagen-binding protein cbpA) have been associated with virulence, particularly in mastitis and uterus infections of dairy cows. However, the role of these virulence markers in the pathogenicity of the agent in domestic animals infections still is incompletely understood. The genes plo, fimA, fimC, fimE, fimG, nanH, nanP, and cbpA were investigated in 71 T. pyogenes strains recovered from cattle, sheep, goats, dogs, equines, and a pig, recovered from mastitis (n = 35), and non-mastitis (n = 36) cases (abscesses, reproductive tract diseases, pneumonia, lymphadenitis, encephalitis). The most common genes harboured by the isolates were: plo (71/71 = 100.0%), fimA (70/71 = 98.6%), nanP (56/71 = 78.9%), fimE (53/71 = 74.6%), fimC (46/71 = 64.8%) and nanH (45/71 = 63.4%), whereas cbpA (6/71 = 8.4%) and fimG (4/71 = 5.6%) were uncommon. The most frequent genotypes were plo/fimA/fimE/fimC/nanH/nanP (17/71 = 23.9%), plo/fimA/fimE/nanH/nanP (13/71 = 18.3%), and plo/fimA/fimE/fimC/nanP (11/71 = 15.5%). No association was observed between the presence of genes vs clinical signs or host species. To the best of our knowledge, this is the first report on aforementioned virulence factors of pathogen detected in diseased horses and dogs. SIGNIFICANCE AND IMPACT OF THE STUDY: The role of particular virulence factors of Trueperella pyogenes that determine different pyogenic infections among domestic animals is poorly understood. Eight putative virulence genes and genotype profiles of 71 isolates were investigated among different clinical manifestations in domestic animals. The most common genes were plo (71/71 = 100.0%), fimA (70/71 = 98.6%), nanP (56/71 = 78.9%), fimE (53/71 = 74.6%), fimC (46/71 = 64.8%) and nanH (45/71 = 63.4%), whereas plo/fimA/fimE/fimC/nanH/nanP (17/71 = 23.9%), plo/fimA/fimE/nanH/nanP (13/71 = 18.3%), and plo/fimA/fimE/fimC/nanP (11/71 = 15.5%) were the most frequent genotypes. Studies involving virulence factors are critical in the investigation of molecular epidemiology, pathogenicity, and hypothetical differences in the virulence among T. pyogenes strains from different geographical areas. PMID- 28561265 TI - Mild TSH resistance: Clinical and hormonal features in childhood and adulthood. AB - OBJECTIVE: Mutations in TSH receptor (TSHR) are associated with TSH resistance, a genetic defect characterized by a heterogeneous phenotype ranging from severe hypothyroidism to subclinical hypothyroidism (SCH). We assessed the clinical and hormonal pattern of TSHR variants in a series of pediatric patients, and the long term outcome of growth, biochemical measurements of metabolism, and neuropsychological functions in TSHR mutations carriers. DESIGN: Observational, retrospective study. PATIENTS: Thirty four children (age 7 days to 11 years) and 18 adult carriers of TSHR variants. MEASUREMENTS: The TSHR gene was sequenced by PCR-amplified direct sequencing in 111 pediatric patients with slight to moderate elevation of TSH and normal FT4 levels. The study focused on the: auxological and biochemical parameters, thyroid ultrasound, bone age, bone mineral density (BMD), and intellectual outcome (IQ) were collected during the long follow-up (1-15 years). RESULTS: Seventeen different TSHR variants (eight novel) were identified in 34 of the 111 pediatric patients, with a high prevalence of familial cases (27/34). Neonatal screening for congenital hypothyroidism was positive in half of the TSHR carriers. Growth, IQ, BMD, and biochemical parameters were normal in all subjects. Twenty patients received L-T4 replacement therapy, in all cases before genetic analysis. After re-evaluation, six patients resumed L-T4 therapy: they were compound heterozygous, or single heterozygous and with associated conditions at risk of thyroid impairment (SGA). No adults presented clinical features consistent with impaired thyroid function. CONCLUSIONS: Children carriers of TSHR variants, regardless of L-T4 treatment, show regular growth and neuropsychological development, with no evident biochemical and US alterations. PMID- 28561266 TI - Sublingual immunotherapy provides long-term relief in allergic rhinitis and reduces the risk of asthma: A retrospective, real-world database analysis. AB - BACKGROUND: Allergy immunotherapy (AIT) is the only treatment for allergic rhinitis (AR) and/or allergic asthma (AA) with long-term efficacy. However, there are few real-life data on the progression of AR and/or AA in patients receiving AIT. OBJECTIVES: To assess the real-world, long-term efficacy of grass pollen sublingual immunotherapy (SLIT) tablets in AR and their impact on asthma onset and progression. METHODS: In a retrospective analysis of a German longitudinal prescription database, AR patients treated with grass pollen SLIT tablets were compared with a control group not having received AIT. Multiple regression analysis was used to compare changes over time in rescue symptomatic AR medication use after treatment cessation, asthma medication use, and the time to asthma onset in the two groups. RESULTS: After applying all selection criteria, 2851 SLIT and 71 275 control patients were selected for the study. After treatment cessation, AR medication use was 18.8 percentage points lower (after adjustment for covariates, and relative to the pretreatment period) in SLIT tablet group than in the non-AIT group (P<.001). Asthma onset was less frequent in SLIT tablet group than in non-AIT group (odds ratio: 0.696, P=.002), and time to asthma was significantly longer (hazard ratio: 0.523; P=.003). After SLIT cessation, asthma medication use fell by an additional 16.7 percentage points (relative to the pretreatment period) in the SLIT tablet group vs the non-AIT group (P=.004). CONCLUSIONS: Real-world treatment of AR patients with grass pollen SLIT tablets was associated with slower AR progression, less frequent asthma onset, and slower asthma progression. PMID- 28561267 TI - Differences in Lip Support with and without Labial Flanges in a Maxillary Edentulous Population. Part 1: Objective Analysis. AB - PURPOSE: To study the objective differences in lip support using common facial soft tissue markers, when evaluating patients wearing a maxillary denture with a labial flange in comparison to an experimental flangeless denture. MATERIALS AND METHODS: A total of 31 maxillary edentulous patients who were esthetically satisfied with their existing maxillary denture were recruited in this clinical study. The maxillary denture was then duplicated in clear acrylic resin. Two standardized full-face digital photographs (frontal and profile) were made with the duplicate denture in the mouth. The labial flange of the duplicate denture was then removed from first premolar to first premolar region, to create the experimental flangeless denture. It was returned to the oral cavity, and 2 additional full-face digital photographs were made. The differences between these images were studied using 5 facial anatomic markers (subnasale, labrale superior, stomion, nasolabial angle, lip thickness). A paired sample t-test was used to compare differences in measurements for various anatomic markers using an alpha value of 0.05. RESULTS: For profile images, there were no statistically significant differences between photographs with and without a labial flange for anatomic markers- labrale superior and stomion (p < 0.05). There was a statistically significant difference for subnasale as well as the nasolabial angle but the magnitude of the difference was too small to be clinically significant (p < 0.05). For frontal images, there was no statistically significant difference in lip thickness between photographs with and without a labial flange. Additionally, there was no association between differences in measurements and patient-related factors such as gender and prior years of edentulism. CONCLUSIONS: Removal of a labial flange in a maxillary denture resulted in minimal and clinically insignificant anatomic differences in lip support between flange and flangeless dentures, when analyzed in frontal and profile images. PMID- 28561269 TI - Combined impact of healthy lifestyle factors on lifespan: two prospective cohorts. AB - BACKGROUND: The impact of multiple healthy lifestyle factors on survival time is unclear. OBJECTIVE: The aim of this study was to examine differences in survival time associated with a healthy lifestyle versus a less healthy lifestyle. METHODS: This study consisted of 33 454 men (Cohort of Swedish Men) and 30 639 women (Swedish Mammography Cohort) aged 45-83 years and free of cancer and cardiovascular disease at baseline. The healthy lifestyle factors included the following: (i) nonsmoking; (ii) physical activity at least 150 min per week; (iii) alcohol consumption of 0-14 drinks per week; (iv) and healthy diet defined as a modified Dietary Approaches to Stop Hypertension Diet score above the median. Cox proportional hazards regression models and Laplace regression were used to estimate, respectively, hazard ratios of all-cause mortality and differences in survival time. RESULTS: During follow-up from 1998 through 2014, 8630 deaths amongst men and 6730 deaths amongst women were ascertained through linkage to the Swedish Cause of Death Register. Each of the four healthy lifestyle factors was inversely associated with all-cause mortality and increased survival time. Compared with individuals with no or one healthy lifestyle factor, the multivariable hazard ratios of all-cause mortality for individuals with all four health behaviours were 0.47 (95% 95% confidence interval [CI]: 0.44-0.51) in men and 0.39 (95% CI: 0.35-0.44) in women. This corresponded to a difference in survival time of 4.1 (95% CI: 3.6-4.6) years in men and 4.9 (95% CI: 4.3-5.6) years in women. CONCLUSION: Adopting healthy lifestyle behaviours may markedly increase lifespan. PMID- 28561268 TI - Near infrared spectroscopy for measuring changes in bone hemoglobin content after exercise in individuals with spinal cord injury. AB - Bone blood perfusion has an essential role in maintaining a healthy bone. However, current methods for measuring bone blood perfusion are expensive and highly invasive. This study presents a custom built near-infrared spectroscopy (NIRS) instrument to measure changes in bone blood perfusion. We demonstrated the efficacy of this device by monitoring oxygenated and deoxygenated hemoglobin changes in the human tibia during and after exercise in able-bodied and in individuals with spinal cord injury (SCI), a population with known impaired peripheral blood perfusion. Nine able-bodied individuals and six volunteers with SCI performed a 10 min rowing exercise (functional electrical stimulation rowing for those with SCI). With exercise, during rowing, able-bodied showed an increase in deoxygenated hemoglobin in the tibia. Post rowing, able-bodied showed an increase in total blood content, characterized by an increase in total hemoglobin content due primarily to an increase in deoxygenated hemoglobin. During rowing and post-rowing, those with SCI showed no change in total blood content in the tibia. The current study demonstrates that NIRS can non-invasively detect changes in hemoglobin concentration in the tibia. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:183-191, 2018. PMID- 28561270 TI - Barriers to generating PDX models of HPV-related head and neck cancer. AB - OBJECTIVES/HYPOTHESIS: Delineate factors impacting the creation and use of patient-derived xenografts (PDXs) of human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs). STUDY DESIGN: Laboratory-based translational study. METHODS: Fifty-one surgically resected HNSCCs, including 31 HPV + cancers, were implanted into NOD/SCID/IL-2Rgamma-/- (NSG) mice using standardized methodology. Clinical and pathologic factors were tested for association with engraftment. The gross, histologic, and molecular features of established HPV + PDXs were analyzed in comparison to their tumors of origin. RESULTS: Negative HPV status and perineural invasion (PNI) were independent, additive factors associated with increased PDX formation. Epstein-Barr virus positive (EBV+) human large B-cell lymphomas grew from 32% of HPV + HNSCC cases that failed to engraft. Successfully established HPV + PDXs retained basaloid histology and often developed cystic growth patterns typical of HPV + nodal metastases. They also maintained elevated p16INK4A levels and expression of E6/E7 viral oncogene transcripts. CONCLUSION: Reduced engraftment by HPV + tumors lacking PNI likely results in selection biases in HNSCC PDX models. Formation of EBV + lymphomas in NSG mice further reduces the generation of HPV + models and must be ruled out before long-term use of PDXs. Nevertheless, the retention of distinctive pathologic traits and viral oncogene expression by HPV + PDXs provides a viable in vivo platform for basic and translational studies as well as a resource for generating advanced in vitro models. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:2777-2783, 2017. PMID- 28561273 TI - A case of multifocal scarring alopecia. PMID- 28561272 TI - Cannabinoid CB1 /CB2 receptor agonists attenuate hyperactivity and body weight loss in a rat model of activity-based anorexia. AB - BACKGROUND AND PURPOSE: Anorexia nervosa (AN) is a serious psychiatric condition characterized by excessive body weight loss and disturbed perceptions of body shape and size, often associated with excessive physical activity. There is currently no effective drug-related therapy of this disease and this leads to high relapse rate. Clinical data suggest that a promising therapy to treat and reduce reoccurrence of AN may be based on the use of drugs that target the endocannabinoid (EC) system, which appears dysregulated in AN patients. EXPERIMENTAL APPROACH: The activity-based anorexia (ABA) rodent model mimics the severe body weight loss and increased physical activity, as well as the neuroendocrine disturbances (i.e. hypoleptinaemia and hypercortisolaemia) in AN. This study investigated whether cannabinoid agonists can effectively modify anorexic-like behaviours and neuroendocrine changes in rats subjected to a repeated ABA regime that mimics the human condition in which patients repeatedly undergo a recovery and illness cycle. KEY RESULTS: Our data show that subchronic treatment with both the natural CB1 /CB2 receptor agonist Delta9 tetrahydrocannabinol and the synthetic CB1 /CB2 receptor agonist CP-55,940 significantly reduced body weight loss and running wheel activity in ABA rats. These behavioural effects were accompanied by an increase in leptin signalling and a decrease in plasma levels of corticosterone. CONCLUSION AND IMPLICATIONS: Taken together, our results further demonstrate the involvement of the EC system in AN pathophysiology and that strategies which modulate EC signalling are useful to treat this disorder, specifically in patients where physical hyperactivity plays a central role in its progression and maintenance. PMID- 28561275 TI - Screening for biosurfactant production by 2,4,6-trinitrotoluene-transforming bacteria. AB - AIMS: To isolate and identify TNT-transforming cultures from explosive contaminated soils with the ability to produce biosurfactants. METHODS AND RESULTS: Bacteria (pure and mixed cultures) were selected based on their ability to transform TNT in minimum media with TNT as the sole nitrogen source and an additional carbon source. TNT-transforming bacteria were identified by 16S rRNA gene sequencing. TNT transformation rates were significantly lower when no additional carbon or nitrogen sources were added. Surfactant production was enabled by the presence of TNT. Fourteen cultures were able to transform the explosive (>50%); of these, five showed a high transformation capacity (>90%), and six produced surfactants. CONCLUSIONS: All explosive-transforming cultures contained Proteobacteria of the genera Achromobacter, Stenotrophomonas, Pseudomonas, Sphingobium, Raoultella, Rhizobium and Methylopila. These cultures transformed TNT when an additional carbon source was added. Remarkably, Achromobacter spanius S17 and Pseudomonas veronii S94 have high TNT transformation rates and are surfactant producers. SIGNIFICANCE AND IMPACT OF THE STUDY: TNT is a highly toxic, mutagenic and carcinogenic nitroaromatic explosive; therefore, bioremediation to eliminate or mitigate its presence in the environment is essential. TNT-transforming cultures that produce surfactants are a promising method for remediation. To the best of our knowledge, this is the first report that links surfactant production and TNT transformation by bacteria. PMID- 28561274 TI - Statistical shape modelling of hip and lumbar spine morphology and their relationship in the MRC National Survey of Health and Development. AB - The anatomical shape of bones and joints is important for their proper function but quantifying this, and detecting pathological variations, is difficult to do. Numerical descriptions would also enable correlations between joint shapes to be explored. Statistical shape modelling (SSM) is a method of image analysis employing pattern recognition statistics to describe and quantify such shapes from images; it uses principal components analysis to generate modes of variation describing each image in terms of a set of numerical scores after removing global size variation. We used SSM to quantify the shapes of the hip and the lumbar spine in dual-energy x-ray absorptiometry (DXA) images from 1511 individuals in the MRC National Survey of Health and Development at ages 60-64 years. We compared shapes of both joints in men and women and hypothesised that hip and spine shape would be strongly correlated. We also investigated associations with height, weight, body mass index (BMI) and local (hip or lumber spine) bone mineral density. In the hip, all except one of the first 10 modes differed between men and women. Men had a wider femoral neck, smaller neck-shaft angle, increased presence of osteophytes and a loss of the femoral head/neck curvature compared with women. Women presented with a flattening of the femoral head and greater acetabular coverage of the femoral head. Greater weight was associated with a shorter, wider femoral neck and larger greater and lesser trochanters. Taller height was accompanied by a flattening of the curve between superior head and neck and a larger lesser trochanter. Four of the first eight modes describing lumbar spine shape differed between men and women. Women tended to have a more lordotic spine than men with relatively smaller but caudally increasing anterior posterior (a-p) vertebral diameters. Men were more likely to have a straighter spine with larger vertebral a-p diameters relative to vertebral height than women, increasing cranially. A weak correlation was found between body weight and a-p vertebral diameter. No correlations were found between shape modes and height in men, whereas in women there was a weak positive correlation between height and evenness of spinal curvature. Linear relationships between hip and spine shapes were weak and inconsistent in both sexes, thereby offering little support for our hypothesis. In conclusion, men and women entering their seventh decade have small but statistically significant differences in the shapes of their hips and their spines. Associations with height, weight, BMI and BMD are small and correspond to subtle variations whose anatomical significance is not yet clear. Correlations between hip and spine shapes are small. PMID- 28561276 TI - Intestinal microbiota in patients with chronic hepatitis C with and without cirrhosis compared with healthy controls. AB - BACKGROUND & AIMS: The importance of the intestinal microbiota for the onset and clinical course of many diseases, including liver diseases like non-alcoholic steatohepatitis and cirrhosis, is increasingly recognized. However, the role of intestinal microbiota in chronic hepatitis C virus (HCV) infection remains unclear. METHODS: In a cross-sectional approach, the intestinal microbiota of 95 patients chronically infected with HCV (n=57 without cirrhosis [NO-CIR]; n=38 with cirrhosis [CIR]) and 50 healthy controls (HC) without documented liver diseases was analysed. RESULTS: Alpha diversity, measured by number of phylotypes (S) and Shannon diversity index (H'), decreased significantly from HC to NO-CIR to CIR. S and H' correlated negatively with liver elastography. Analysis of similarities revealed highly statistically significant differences in the microbial communities between HC, NO-CIR and CIR (R=.090; P<1.0*10-6 ). Stratifying for HCV genotypes even increased the differences. In addition, we observed distinct patterns in the relative abundance of genera being either positive or negative correlated with diseases status. CONCLUSIONS: This study shows that not only the stage of liver disease but also HCV infection is associated with a reduced alpha diversity and different microbial community patterns. These differences might be caused by direct interactions between HCV and the microbiota or indirect interactions facilitated by the immune system. PMID- 28561277 TI - A Large-Scale Study of Misophonia. AB - OBJECTIVE: We aim to elucidate misophonia, a condition in which particular sounds elicit disproportionally strong aversive reactions. METHOD: A large online study extensively surveyed personal, developmental, and clinical characteristics of over 300 misophonics. RESULTS: Most participants indicated that their symptoms started in childhood or early teenage years. Severity of misophonic responses increases over time. One third of participants reported having family members with similar symptoms. Half of our participants reported no comorbid clinical conditions, and the other half reported a variety of conditions. Only posttraumatic stress disorder (PTSD) was related to the severity of the misophonic symptoms. Remarkably, half of the participants reported experiencing euphoric, relaxing, and tingling sensations with particular sounds or sights, a relatively unfamiliar phenomenon called autonomous sensory meridian response (ASMR). CONCLUSION: It is unlikely that another "real" underlying clinical, psychiatric, or psychological disorder can explain away the misophonia. The possible relationship with PTSD and ASMR warrants further investigation. PMID- 28561278 TI - The effects of testosterone on body composition in obese men are not sustained after cessation of testosterone treatment. AB - BACKGROUND: Testosterone treatment in obese dieting men augments the diet associated loss of fat mass, but protects against loss of lean mass. We assessed whether body composition changes are maintained following withdrawal of testosterone treatment. METHODS: We conducted a prespecified double-blind randomized placebo-controlled observational follow-up study of a randomized controlled trial (RCT). Participants were men with baseline obesity (body mass index >30 kg/m2 ) and a repeated total testosterone level <12 nmol/L, previously enrolled in a 56-week testosterone treatment trial combined with a weight loss programme. Main outcome measures were mean adjusted differences (MAD) (95% confidence interval), in body composition between testosterone- and placebo treated men at the end of the observation period. RESULTS: Of the 100 randomized men, 82 completed the RCT and 64 the subsequent observational study. Median [IQR] observation time after completion of the RCT was 82 weeks [74; 90] in men previously receiving testosterone (cases) and 81 weeks [67;91] in men previously receiving placebo (controls), P=.51. At the end of the RCT, while losing similar amounts of weight, cases had, compared to controls, lost more fat mass, MAD -2.9 kg (-5.7, -0.2), P=.04, but had lost less lean mass MAD 3.4 kg (1.3, 5.5), P=.002. At the end of the observation period, the former between-group differences in fat mass, MAD -0.8 kg (-3.6, 2.0), P=1.0, in lean mass, MAD -1.3 kg (-3.0, 0.5), P=.39, and in appendicular lean mass, MAD -0.1 kg/m2 (-0.3, 0.1), P=.45, were no longer apparent. During observation, cases lost more lean mass, MAD -3.7 kg (-5.5, -1.9), P=.0005, and appendicular lean mass, MAD -0.5 kg/m2 ( 0.8, -0.3), P<.0001 compared to controls. CONCLUSIONS: The favourable effects of testosterone on body composition in men subjected to a concomitant weight loss programme were not maintained at 82 weeks after testosterone treatment cessation. PMID- 28561280 TI - Anti-FcgammaRIIB (CD32) Antibodies Differentially Modulate Murine FVIII-Specific Recall Response in vitro. AB - Fc gamma receptors (FcgammaRs) for IgG regulate adaptive immune responses by modulating activating and inhibitory signalling pathways within immune cells. Data from a haemophilia A mouse model demonstrate that genetic deletion or blockade of the inhibitory FcgammaR (CD32) suppresses the formation of antibody secreting cells (ASCs) in vitro. Mechanisms preventing the FVIII-specific recall response, however, remain unclear. Here, the potential role of CD32 inhibition was studied by differentially modulating receptor activity with selected anti CD32 monoclonal antibodies (mAbs). Splenocytes from immunized FVIII-/- mice were restimulated with FVIII in the absence or presence of different anti-CD32 mAbs over 6 days. At day 6, cytokine release was quantified from cell culture supernatant and the formation of FVIII-specific ASCs assessed. Binding of FVIII containing immune complexes (F8-ICs) to bone marrow-derived dendritic cells (BMdDCs) was also investigated. The antagonistic CD32 mAb AT128 suppressed the formation of FVIII-specific ASCs and reduced secretion of IFN-gamma and IL-10. In contrast, the agonistic mAbs AT130-2 and AT130-5, and their F(ab')2 fragments, allowed the formation of FVIII-specific ASCs, even though the full IgG of AT130-2 reduced binding of F8-ICs to CD32. Data suggest that an inhibitory signal is transmitted when F8-ICs bind to CD32 and that this signal is required during memory B cell (MBC) activation to support formation of FVIII-specific ASCs. If the inhibitory signal is lacking due to CD32 deletion or blockade with antagonistic anti-CD32 mAbs, FVIII-specific T cell stimulation and ASC formation are suppressed, whereas agonistic stimulation of CD32 restores T cell stimulation and ASC formation. PMID- 28561281 TI - Race differences in reproducibilities: The HERITAGE family study. AB - The HERITAGE (HEalth, RIsk factors, exercise Training And GEnetics) Family Study is a multicenter clinical trial conducted by five institutions in the United States and Canada. The overall objective of the study is to investigate the role of the genotype in cardiovascular, metabolic, and hormonal responses to aerobic exercise training and the contribution of regular exercise to changes in cardiovascular disease and diabetes risk factors in white and black families. Since the accuracy of the assessment of the response to training depends on how repeatable or reproducible the measurements are, it is important to assess potential racial differences in reproducibilities, which may have implications for pooling data across races. The sample studied consisted of 96 blacks and 304 whites. The black sample had 46 males with mean age 33.6 +/- 14.2 years and 40 females with mean age 33.9 +/- 12.7 years. The white sample had 152 males with mean age 35.5 +/- 14.9 years, and 152 females with mean age 34.9 +/- 14.3 years. Reproducibilities, as measured by intraclass correlations among repeated measures, were comparable between whites and blacks for variables in the anthropometry, i.e, lipid, exercise test, and blood pressure domains. Reproducibilities in both races exceeded 0.85 for most of the variables. When the within-race reproducibilities are very high, statistical significance of any observed racial difference in the reproducibilities may not be very meaningful. There was a significant racial difference in the reproducibility for Apoprotein A1 (0.73 in blacks, 0.89 in whites, P < 0.01). However, this is not a cause for concern, since only one among 37 comparisons was significant. Am. J. Hum. Biol. 9:415-424, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561279 TI - A modified colorectal screening score for prediction of advanced neoplasia: A prospective study of 5744 subjects. AB - BACKGROUND AND AIM: We validated a modified risk algorithm based on the Asia Pacific Colorectal Screening (APCS) score that included body mass index (BMI) for prediction of advanced neoplasia. METHODS: Among 5744 Chinese asymptomatic screening participants undergoing a colonoscopy in Hong Kong from 2008 to 2012, a random sample of 3829 participants acted as the derivation cohort. The odds ratios for significant risk factors identified by binary logistic regression analysis were used to build a scoring system ranging from 0 to 6, divided into "average risk" (AR): 0; "moderate risk" (MR): 1-2; and "high risk" (HR): 3-6. The other 1915 subjects formed a validation cohort, and the performance of the score was assessed. RESULTS: The prevalence of advanced neoplasia in the derivation and validation cohorts was 5.4% and 6.0%, respectively (P = 0.395). Old age, male gender, family history of colorectal cancer, smoking, and BMI were significant predictors in multivariate regression analysis. A BMI cut-off at > 23 kg/m2 had better predictive capability and lower number needed to screen than that of > 25 kg/m2 . Utilizing the score developed, 8.4%, 57.4%, and 34.2% in the validation cohort were categorized as AR, MR, and HR, respectively. The corresponding prevalence of advanced neoplasia was 3.8%, 4.3%, and 9.3%. Subjects in the HR group had 2.48-fold increased prevalence of advanced neoplasia than the AR group. The c-statistics of the modified score had better discriminatory capability than that using predictors of APCS alone (c-statistics = 0.65 vs 0.60). CONCLUSIONS: Incorporating BMI into the predictors of APCS score was found to improve risk prediction of advanced neoplasia and reduce colonoscopy resources. PMID- 28561282 TI - Growth of the Czech child population 0-18 years compared to the World Health Organization growth reference. AB - Nationwide anthropological surveys of 0-18-year-old children were carried out in the Czech Republic (former Czech regions of Czechoslovakia) five times during the last 40 years, at 10-year intervals. The measurements provide reference data for the growth of the Czech child population and at the same time ample material for comparison with other populations. A comparison of the results of such nationwide anthropometric surveys with the World Health Organization (WHO) growth reference implies that the growth trend of Czech children is comparable with the WHO reference. The greatest similarity in the shape of the WHO height curves and the results obtained in Czechoslovakia was in 1971. The results obtained in the nationwide surveys also imply that the secular trend still exerts its effect. In the case of height, this finding is consistent during the whole period of 40 years. Concerning weight in higher age categories, especially in girls, the trend slowed down or stopped. Furthermore, there is no problem of malnutrition in the Czech child population. Similarly, as in any other developed nations, the prevalence of overweight and obesity is the problem that merits attention. Am. J. Hum. Biol. 9:459-468, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561283 TI - Somatic comparisons at three ages of South Korean males and males of other Asian groups. AB - Somatic data were collected during July 1995 on 154 males, ages 6, 9, and 15 years, residing in urban Pusan, South Korea, and on 157 age peers residing in rural regions surrounding the city. Comparisons are made between urban and rural groups for measures of body size and form, skinfold thicknesses, the body mass index (BMI), and estimated arm muscle area (ARM). The data were analyzed in 2 (urban-rural) * 3 (age) analyses of variance with an alpha level of P < 0.05. Age differences were evident for all dimensions. A significant main effect for urban rural differences was found for stature, sitting height, lower limb height, upper limb length, arm girth, calf girth, shoulder width, hip width, body weight, and the sum of skinfolds. Regardless of age, urban children were larger than rural children. The interaction was nonsignificant. Except for the trunk width index, urban and rural boys did not differ on measures of body form. Similar means were obtained for the BMI and ARM in urban and rural boys. Compared with data collected four decades ago, present day 6, 9, and 15 year old males are taller and heavier at every age, indicating secular gains. Pusan males are similar in stature to age peers in Taiwan and Japan, and taller than the Chinese. Am. J. Hum. Biol. 9:493-503, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561284 TI - Relationship between physical activity, socioeconomic status, and physical fitness of 8-15-year-old youth from Mozambique. AB - A cross-sectional study of 593 students (277 boys, 316 girls) 8-15 years of age was done to evaluate the physical fitness (PF) of children and adolescents from Maputo, Mozambique, relative to socioeconomic status (SES) and physical activity (PA). PF was assessed by a battery of field tests including the sit and reach, sit-ups, hand grip strength, a 10 * 5 meters shuttle run, and two distance runs, 1,600 and 2,400 meters. PA was estimated with a questionnaire designed for this population. Students were divided into three groups according to region of residence, which was used as the criterion of SES. PA was more intense among underprivileged students due to domestic activities and walking time per day. PF significantly differed among SES groups. Poor students exhibited significantly better results on the sit and reach and endurance runs, while privileged children performed better on sit-ups and the shuttle run. There were no differences in grip strength. Comparison with North American reference data suggests that Mozambican youth have greater flexibility and cardiorespiratory endurance, but less absolute strength and power. The results suggest that SES is an important determinant of fitness in Mozambique, especially because of its influence on body size, composition, and on PA. In addition, cultural effects on the performance of the tests were indicated. Am. J. Hum. Biol. 9:449-457, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561285 TI - Proportion of adipose tissue-free body mass as skeletal muscle: Magnitude and constancy in men. AB - Although it is often assumed that skeletal muscle (SM) is a fixed proportion of adipose tissue-free body mass (ATFM), there is little data in living humans that supports this hypothesis. Limited data from elderly cadavers suggests a relatively constant proportion of ATFM as SM in men (mean +/- SD, 0.540 +/- 0.046) and women (0.489 +/- 0.049). The present study tested the hypothesis that SM is a relatively constant proportion of ATFM in healthy men. Whole body SM and ATFM were measured using multiscan computerized axial tomography. The SM/ATFM ratio in the men (n = 24) was 0.563 +/- 0.036 which was not significantly different from the value found in the elderly male cadavers. Multiple regression analysis indicated that the SM/ATFM ratio was significantly related to 1/ATFM (P = 0.036) and the body mass index (P = 0.024), and not with age. Further study is needed of other possible factors such as physical activity, gender, race, and disease state, that may effect the relationship between SM and ATFM. Am. J. Hum. Biol. 9:487-492, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561286 TI - Relationships of physical activity and somatic characteristics with physical fitness and motor skill in prepubertal girls. AB - The purpose of this study was to examine the relationships between physical activity and somatic growth with motor skill and physical fitness in prepubertal girls. The subjects were 215, 7-10-year-old girls. Somatic characteristics included 15 dimensions. Physical fitness was assessed by the EUROFIT battery of 9 tests. Motor skill development was based on quantitative and qualitative assessment of the overhand throw. Physical activity was assessed by parental seven-day physical activity recall for the child. Sum of five skinfolds was significantly negatively related with motor fitness after controlling for the effects of physical activity (r = -0.27 to -0.39). Somatic characteristics were not significantly related with fitness items and throwing stage after controlling for physical activity. Age-specific partial correlations between physical activity, fitness items, quantitative, and qualitative characteristics of the overhand throw, were not significant. After controlling for body size and subcutaneous fatness, aerobic fitness was significantly related with physical activity of moderate to high intensity. Am. J. Hum. Biol. 9:513-521, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561287 TI - Socioeconomic differences in growth of metacarpal II during adolescence in females: Interactions with sexual and skeletal maturity. AB - In order to study the role of socioeconomic status (SES) in growth of the second metacarpal (MC) during adolescence in females, 352 cross-sectional observations of 34 girls from high SES 11-17 years of age were compared with 876 cross sectional observations of age-matched low to middle SES Turkish girls. Values for MC length (L), L/outer diameter (D), total cortical thickness (C), C/L, C/D%, stature, weight, stages of secondary sexual development (SSD), and skeletal age (SA) were significantly greater in the high SES, while outer (D) and medullary diameter (M), C-area, M-area, and MC-volume were significantly smaller. The estimated total average increase in C/year was 0.21 versus 0.22 mm in low-middle and high SES girls, respectively, being twice as high before 14 years compared with at 14-17 years. The decrease in M started earlier and was steeper in the high SES. M was significantly smaller in the high SES when SSD or years before and after menarche was controlled, and also after SA of 14 years, while C was not significantly different under these conditions. M and D values for a given L were significantly greater in low-middle SES girls, while differences in C were not significant. It was concluded that reduced C for age in low-middle SES girls is a reflection of their overall slower growth relative to high SES girls, and once they catch up in growth the difference in C between groups is no longer significant. However, there still is a greater D for a given L, which is mainly due to significantly greater M for L, which was present at the beginning of the study. Am. J. Hum. Biol. 9:439-448, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561288 TI - "Month of birth effect" does not alter longitudinal growth in an experimental animal model. AB - Previous cross-sectional human and animal data collected in the southern hemisphere suggest that month of birth influences growth throughout life; individuals born between August and January (spring/summer) were larger than individuals born between February and July (fall/winter) throughout their life cycle. It has been suggested that there is some form of annual global variation which may be caused by extraterrestrial factors. The present study, utilizing an experimental animal model, investigated the "month of birth effect" in the northern hemisphere on the somatic and skeletal growth of rabbits. The study sample consisted of 135 laboratory bred and reared New Zealand white rabbits (Oryctolagus cuniculus) from 62 different litters; spring/summer rabbits (n = 75) were born between February and July; fall/winter rabbits (n = 60) were born between August and January. Serial longitudinal body mass and craniofacial radiographic growth data were collected at 10, 25, 42, 84, and 126 days of age. Results from a two-way ANOVA showed no significant (P > 0.05) differences in the month of birth main effect or in the age * month of birth interaction for either somatic or skeletal growth. Results from the present study do not support the "month of birth effect" hypothesis. It was concluded that variations in growth patterns are more likely controlled by local environmental factors such as hemispheric seasonality in photoperiod or temperature, and not by more exotic factors such as the earth's orbital trajectory around the sun or global energy fields. Am. J. Hum. Biol. 9:481-486, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561289 TI - Electrophoretic protein polymorphisms in Kaingang and Guarani Indians of Southern Brazil. AB - A total of 337 Kaingang and Guarani Indians from two localities were studied in relation to 18 protein genetic loci. In one of the localities, members of these two groups live side by side but show little genetic similarity, emphasizing the influence of cultural factors in the mating behavior of human groups. Integrating the present results with previous ones, it was verified that the genetic relationships among six Kaingang populations do not follow the pattern expected from their geographical distribution. Comparisons made with three other Ge~ speaking tribes indicate that the Kaingang did not separate well from them. Most (96%) of the variability in the six polymorphic systems considered occur at the intrapopulational level. Am. J. Hum. Biol. 9:505-512, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561290 TI - Growth of metacarpal II during female adolescence: Relationships to stature, weight, and skeletal and sexual maturity. AB - Growth of the second metacarpal (MC) was evaluated during female adolescence in 110 Turkish girls who were followed longitudinally starting from 8.5 to 11 years until a Greulich and Pyle skeletal age (SA) >=17 years was reached. Stature (St), weight (Wt), stage of secondary sexual development (SSD), length (L), and medullary (M) and outer diameters (D) of MC were measured. Total cortical thickness (C) of MC was derived as the difference between D and M. Yearly rates of growth in L, D, C, and St were calculated for each 6 months from the smoothed data. Peak length (PLV), peak D (PDV), and peak C (PCV) velocities and the ages at reaching these peaks were determined. L at fusion was 62.4 +/- 3.0 mm and correlated significantly with adult stature (AdSt). PLV was 4.09 +/- 0.60 mm/yr at a mean age of 12.28 +/- 0.90 years and it correlated best with PHV (r = 0.52), then with L at fusion and AdSt, but not with ages at PLV, PHV, PDV, fusion, and onset of SSD. PLV occurred synchronously with PDV, 0.1 years after PHV, 0.9 years after onset of the breast bud, 0.4 years after onset of axillary hair, and 1.1 years before menarche. Age at PLV correlated best with age at PHV, and in decreasing order with ages at fusion, menarche, PDV, and onset of SSD, but not with PLV, PDV, PHV, L at fusion, and AdSt. The most important single factor determining MC L was St (R = 0.77). Multifactorial analysis showed that in conjunction with St, D and C are contributory determinants of L, while SA is not. MC D was primarily determined by L. In conjunction with L, C and chronological age (CA) contributed positively and SA negatively. Velocity of C reached its peak at 13.04 +/- 1.20 years, 0.72 and 0.76 years after PLV and PDV, respectively. After 14 years, C continued to increase significantly, while growth increments in D and L were greatly reduced. This was realized by a significant reduction in M, which indicates that there is endosteal deposition of bone. Increase in C was significantly associated with increasing stages of SSD and inversely with M. Multifactorial analysis, however, showed that SSD is not an independent factor and that C is determined primarily by SA, and then inversely by M and directly by L. Once these factors are known, other factors, such as SSD, St, and Wt, lose their significance. Am. J. Hum. Biol. 9:425-438, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561291 TI - Plasticity of adolescent growth in boys. AB - The present analysis examines the plasticity of adolescent growth in 21 selected historic and recent growth studies from 6 European countries, the U.S., and Japan, during the last 150 years. Mean stature at the age of 6 years has significantly increased by approximately 6 mm per decade (P < 0.05), whereas adult stature has risen by approximately 10 mm per decade (P < 0.01). Developmental tempo has also increased. Mean age at take-off significantly dropped by approximately 2 years per century (P < 0.01), and age at peak height velocity by 1.7 years per century (P < 0.01). Yet, the secular trend affected different parts of the growth curves in a different way so that the shape of the growth curves has also changed. Whereas adolescent growth rose significantly in the last century (P < 0.01) and increasingly contributed to the improvement of adult stature, no significant modification of the prepubertal portion was evident. Though early childhood and adolescent growth appeared equally plastic, both parameters were statistically independent, indicating differences in the regulation of early and adolescent growth. Yet, the factors that regulate adolescent growth still remain to be elucidated. Am. J. Hum. Biol. 9:469-480, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561292 TI - Guideline for the diagnosis and treatment of scabies in Japan (third edition): Executive Committee of Guideline for the Diagnosis and Treatment of Scabies. AB - In the current work, we present our new guideline for the diagnosis and treatment of scabies which we, the Executive Committee convened by the Japanese Dermatological Association, developed to ensure proper diagnosis and treatment of scabies in Japan. Approval of phenothrin topical use under the National Health Insurance in August 2014 led to this action. Permethrin, a topical anti-scabietic medication belonging to the same pyrethroid group as phenothrin, is already in use worldwide. In this guideline, we introduce criteria for a proper diagnosis of scabies, treatment algorithm for common and crusted (hyperkeratotic) scabies, and prevention. The major change from our second edition is the treatment algorithm. As phenothrin is now available, the first-line therapy for common scabies is either topical phenothrin lotion or oral ivermectin. The second-line option for topical treatment is sulfur-containing ointments, crotamiton cream or benzyl benzoate lotion. gamma-Benzene hexachloride ointment is no longer provided for clinical use. In an immunosuppressed patient, the treatment option is still the same, but with close follow up. If the symptoms persist, diagnosis and treatment must be reassessed. For hyperkeratotic scabies and nail scabies, removal of thick crust, cutting of nails and occlusive dressing are additionally required. The safety and effectiveness of combined treatment with topical and oral medications are not yet confirmed. Further assessment is needed. In addition to appropriate treatment, it is essential to educate patients and health-care workers and to conduct epidemiological studies to prevent further spread of the disease through effectively utilizing available resources including manpower, finance, logistics and time. PMID- 28561293 TI - Age differences in somatotypes of Garhwali males 17-60 years of age. AB - Changes in somatotype with age were investigated in a cross-sectional sample of 400 Garhwali men from northwest India. The subjects, 17-60 years of age, were somatotyped with the Heath-Carter anthropometric protocol. The overall mean somatotype was 3.0-3.7-3.1. A one-way MANOVA indicated significant differences among the nine age groups. Pairwise comparisons using Hotelling's T2 showed significant differences between men up to 29 years and those over 30 years. Garhwali men 30+ years of age were more endomorphic and less ectomorphic than younger men. The mean somatotype for men 30+ years was 3.3-3.9-2.7 and for men <30 years was 2.8-3.3-3.9. Endomorphy and mesomorphy increased with age with a reciprocal decrease in ectomorphy up to 55 years; the trend was somewhat reversed thereafter. The somatotype categories mesomorphic ectomorph and mesomorph ectomorph included the greatest proportion of Garhwali men <30 years; maximum percentages of men 30+ years belonged to the mesomorph-endomorph, endomorphic mesomorph and mesomorphic endomorph categories. Garhwali men were more ectomorphic and less endomorphic and mesomorphic than Canadians. Am. J. Hum. Biol. 9:285-290, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561294 TI - Beta-globin gene cluster haplotypes in an admixed Venezuelan population. AB - Haplotype frequencies for the beta-globin gene cluster were determined in 96 chromosomes from a Venezuelan mixed population. Twelve haplotypes were observed, the most frequent of which were 2, 3, and 4; all others showed prevalences below 10%. When the results were compared with those of 13 other groups using a phylogenetic tree, they clustered in an intermediate position somewhat nearer to those of four sub-Saharan African populations. This is in accordance with historical and other genetic data which indicate an important contribution of people of African ancestry to this population. The high heterozygosity (80%) and the intermediate position in the tree, on the other hand, possibly reflect past intermixture of these African-derived individuals with Europeans and Amerindians. Am. J. Hum. Biol. 9:323-327, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561295 TI - Evaluation of infection and nutritional status as determinants of cellular immunosuppression. AB - While an association between severe protein-energy malnutrition and diminished cellular immunity has been documented, the impact of lesser grades of malnutrition on cellular immunosuppression is less clear. This study emphasizes that the relationship between mild-to- moderate malnutrition and cellular immune function, assessed through delayed-type hypersensitivity testing, is often obscured by the immunosuppressive effects of concurrent infection. Results from an 18-month prospective field study of nutritional status, cellular immune function and morbidity among 62 nomadic Turkana children ages 8 months to 10 years were used to quantify the immunosuppressive effects of mild-to-moderate malnutrition and infection. When controlling for infection at the time of DTH testing, children below -2 s.d. of the reference median weight- for-height or weight-for-age were at least 3 times as likely to be anergic (non-responsive) as children at the reference median. At the same time, infected children experienced a 4.9 times higher risk of being anergic compared to uninfected children. These findings suggest that mild-to-moderate malnutrition and infection are significant independent risk factors for impaired cellular immune function among Turkana children. Am. J. Hum. Biol. 9:381-390, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561296 TI - Longitudinal assessment of hormonal and physical alterations during normal puberty in boys. IV: Predictions of adult height by the Bayley-Pinneau, Roche Wainer-Thissen, and Tanner-Whitehouse methods compared. AB - To determine how accurately the Roche-Wainer-Thissen (RWT), Tanner-Whitehouse (TW2), and Bayley-Pinneau (BP) prediction models estimated adult height, serial height predictions were made for 23 healthy boys (mean initial age 10.4 +/- 1.1 years) every 8 months from 8-15 years of age. The RWT model was tested using Greulich-Pyle (RWT-GP) and Fels (RWT-Fels) bone ages. Stature was measured every 4 months until near final height was attained (growth rate <1cm . 8 mo-1). Mean age at near final height was 18.4 +/- 1.4 years. To assure that the predictions were as accurate and precise as possible, bone age assessments were made by experts in each method. To investigate the influence of maturation on the predictions, the boys were grouped by Fels bone ages: <11 yr, 11-13.99 yr, and 14 14.99 yr. Comparison of the prediction bias and of the root mean square errors (RMSE) showed that the TW2 model gave the most accurate results, followed by the RWT and BP models. The adult height was generally underpredicted by the TW2 model and overpredicted by the RWT and BP models. The RMSE was reduced for each of the models as the bone age approached maturity. The TW2 model had the smallest average RMSE in all bone age groups. In the <11 yr bone age group, the RWT-Fels, RWT-GP, and BP models produced RMSEs that were 16.4%, 18.4%, 62.1%, respectively, greater than the TW2 model. For the 11-13.99 yr group, RMSE by the RWT-Fels, RWT GP, and BP models were 7.5%, 18.0%, and 15.2%, respectively, greater than the TW2 model. In the 14-14.99 yr group the RWT-GP model had a 45.5% greater RMSE than the TW2 model, whereas the RWT-Fels model produced a RMSE only 15.2% greater than TW2. The RWT-Fels model produced a lower RMSE than the RWT-GP model for all bone age groups. Although the data are probably as accurate and precise as presently possible, biologically significant error remains, especially with overprediction of adult height in normally growing boys by the BP and RWT models. It is recommended that regardless of the prediction model implemented, caution be used when advising patients of their predicted adult height since all of the models tested had outlying predictions. Am. J. Hum. Biol. 9:371-380, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561298 TI - Tel-Aviv-Heidelberg Three Generation Offspring Study: Genetic and environmental sources of variation and covariation among plasma lipids, lipoproteins, and apoliproteins. AB - Multivariate genetic analysis, implemented in the statistical package for pedigree analysis, FISHER, was carried out on a large sample of Israeli pedigrees to evaluate heritability and genetic correlations among an array of plasma lipids: total cholesterol (TCHL), triglycerides (TRIG), HDL-C and HDL2-C, HDL3-C, LDL-C and HDL-C%, apolipoproteins A and B (APO-A1 and APO-B), lipoprotein LP(a) and fibrinogen (FIBR). Multiple regression analysis showed that although sex, age, smoking and other study environmental factors, have a significant contribution to the variation of each plasma lipid, they exert little effect on covariation in lipids. Genes, however, are important factors of the variation and covariation in lipids. Thus, variance component analysis showed that the genetic component of the study variables, adjusted on age, sex and environmental factors, ranged between 31% for logarithm-transformed TRIG and 77% for plasma concentrations of LP(a). Coefficients of multiple genetic determination of the genetic variation of each variable attributable to all of the other variables, ranged from low values (<30%) for TRIG, LP(a) and FIBR, to moderate (64%) for HDL2-C. The genetic variation of each of the remaining variables was completely explained by variation in other lipids. The results of a factor analyses of phenotypic, genetic and environmental correlation matrices were similar and clearly identified several clusters of variables. The first included APO-A1, HDL C, HDL2-C and HDL3-C, and the second-APO-B, LDL-C and THCL. Further analysis showed that it was probable the genetic component of variation of HDL3-C plasma concentration that fully depended on APO-A1, while those of LDL-C and TCHL fully depended on APO-B. The degree of correlation between TRIG, LP(a), FIBR and other variables, if any, was considerably lower. Am. J. Hum. Biol. 9:357-370, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561297 TI - Swift and sure-footed on the Savanna: A study of Hadzabe gaits and feet in Northern Tanzania. AB - Data on footprints and gait of 54 Hadzabe, 6-70 years of age expand understanding of pedal morphology of unshod people and assist the development of ideas about the evolution of hominid bipedality and upright posture. Contrary to published data on gaits and pedal morphology of unshod populations, Hadzabe (also known as Hadza) from northern Tanzania exhibit values of stride length, relative stride length, and walking speeds that exceed those of rural and small-town populations. In all observable plantar features, including foot indices, an interdigital space between the hallux and second toe, fanning of the foot anteriorly, and foot angles (in-toeing and out-toeing), Hadzabe feet are comparable with those of never-shod Machiguengas in Peru. On average, Hadzabe hallucal gaps and ball widths are narrower than those of Machiguengas and other unshod short people. Hadzabe feet are also characterized by valgus halluces versus the varus halluces of never-shod Machiguengas and certain West Africans. Although characterized by a valgus toe, Hadzabe hallucal angles, which do not exceed 20 degrees , are lower than those of Northern Hemispheric urbanites and shod rural populations of the Southern and Northern Hemispheres. Hadzabe also exhibit less medial and lateral rotation of the hip joint than Machiguengas do. The heel and the longitudinal arch impressions of the Hadzabe footprints closely resemble those of the Laetoli bipeds in the manner of weight distribution during locomotion. The striking similarity of footprint impressions, especially the heel and the longitudinal arch, between Hadzabe and Laetoli hominid footprints clearly imply that the pedal features of the Laetoli printmakers are remarkably humanoid. Am. J. Hum. Biol. 9:303-321, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561299 TI - Sex differences in pubertal growth of the heart. AB - The aim of this study was to determine sex differences in growth of the heart during puberty. Three-year increments of growth of the heart and body structures and functions related to heart size were compared between the sexes. Echocardiographically estimated left ventricular mass (LVM) represented heart size, body surface area (BSA) represented the area supplied by the left ventricle, and diastolic blood pressure (DBP) represented a segment of arterial resistance. Pubertal changes in these and several other parameters were compared in 67 healthy girls and 84 healthy boys followed longitudinally from 11.5 to 14.5 years. Increments were compared by t-tests. Left ventricular mass of boys was larger than in girls. The sex difference was not significant at 11.5 years, but increased during the three pubertal years. LVM increased 26% in girls and 53% in boys (P <.001). During the same period, BSA increased 22% in girls and 29% in boys (P <.001), while DBP increased 6% in girls and 9% in boys (P <.05). The larger increment of BSA and DBP in boys corresponds to the sex difference in the increment of the heart size. These differences account, in part, for the greater increase (P <.001) in physical working capacity in boys compared to girls. Am. J. Hum. Biol. 9:297-302, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561300 TI - Identifying saltatory growth patterns in infancy: A comparison of results based on measurement protocol. AB - The present analyses address the question of how frequently time-intensive growth measurements need to be taken in order to provide sufficient data for the statistical identification of pulsatile saltatory growth patterns during infancy. The daily serial growth measurements of three infants during 4 months are analyzed in seven subsets, which include progressively fewer data points from daily to weekly intervals. Saltatory growth pulse identification and growth pattern analyses are compared between the temporally distinctive data sets by the saltatory algorithm and continuous curvilinear models. Statistically significant pulse identification and saltatory growth pattern resolution decrease with time intervals > 2-5 days in these data sets. These results suggest that the convenience of a Monday, Wednesday, Friday protocol may not be sufficient to characterize saltatory growth in individual infants, and the dependability factor is a significant source of error that may contribute to growth pattern misperception in data collected by infrequent protocols. Am. J. Hum. Biol. 9:343 355, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561301 TI - Interrelationships of age and the body mass index with risk factors of non insulin dependent diabetes in European and migrant Asian males. AB - A comparative study of the interrelationships of age and the body mass index (BMI) with several risk factors for non-insulin-dependent diabetes mellitus (NIDDM) in adult White European (hereafter called European n = 262) and migrant Indian (n = 39) and Pakistani (n = 100) males residing in Peterborough, East Anglia, revealed significantly lower mean total cholesterol (TC), but higher mean diastolic blood pressure (DBP) in Asian men. Similar associations between age and fasting blood glucose (FBG), total cholesterol (TC), systolic (SBP), and diastolic (DBP) blood pressure were observed in Asian and European men, but TC, SBP and DBP differed between the ethnic groups. The BMI showed a significant relationship (after removal of the age effect) with SBP and DBP in all ethnic groups, but there was no significant ethnic group heterogeneity in the associations of BMI with FBG, TC, SBP and DBP. The distributions (age and BMI controlled) of TC, SBP and DBP were significantly different in Asians compared with Europeans. Am. J. Hum. Biol. 9:291-296, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561302 TI - Bone loss, traditional diet, and cold adaptation in Arctic populations. AB - North American Inuit and Inupiat ("Eskimo") populations have been described as having a lower bone mass relative to Caucasians as a consequence of their traditional high-protein "acid-ash" diet. However, this bone buffering mechanism has also been implicated as a risk factor for osteoporosis in industrialized Caucasian populations, and one recent study has found a positive association between dietary protein, and bone mass in premenopausal women. The original studies documenting the Eskimo-Caucasian difference in aging bone loss do not consider the consequences of population variation in body composition, in particular lean body mass (LBM), which correlates with bone mass. The possibility also exists that the original reference sample may be exceptional rather than normative for bone mineral density (BMD). Regression analysis was conducted on published age- and sex-specific cohort means for BMD, and bone mineral content adjusted for estimates of LBM for the original Eskimo-Caucasian comparisons, and for an additional Caucasian sample from Belgium. Significant differences were found between all groups, including Belgians, and the Wisconsin sample for BMD, supporting the notion of the latter having exceptional bone quality when measured as BMD. When adjusted for LBM, the Eskimo samples are distinct in pattern and magnitude of aging bone loss relative to Caucasians, supporting the hypothesis of real inter-population differences. However, given the current ambiguity surrounding the "protein-calcium buffering" model, an alternative explanation is offered. It is hypothesized that the accelerated bone loss among the Inuit and Inupiat reflects higher production and utilization of the thyroid hormones, T4 and T3 , as a mechanism of cold adaptation through enhanced nonshivering thermogenesis. Am. J. Hum. Biol. 9:329-341, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561303 TI - The patterns of historical population movements in Europe and some of their genetic consequences. AB - Population movements of 891 ethnic units in Europe over the past 4,200 years, and the correlations of these movements with modern genetic distances were investigated on a one-degree-square grid of the continent. There is significant spatial pattern in movements from sources, to targets, and overall. Patterns change significantly over time. Patterns of sources and targets differ significantly. Modern movements are more numerous than ancient movements. Movements on the periphery of Europe are few in number and are concentrated in direction, while Central European movements are numerous and unconcentrated in direction. Modern genetic distance is negatively correlated with the amount of population exchange between localities. Regional genetic variance is positively correlated with number of movements into, but not out of, areas. The findings are interpreted in the context of European ethnohistory and population biology. Am. J. Hum. Biol. 9:391-404, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561304 TI - Math anxiety and math performance in children: The mediating roles of working memory and math self-concept. AB - BACKGROUND: Numerous studies, most of them involving adolescents and adults, have evidenced a moderate negative relationship between math anxiety and math performance. There are, however, a limited number of studies that have addressed the mechanisms underlying this relation. AIMS: This study aimed to investigate the role of two possible mediational mechanisms between math anxiety and math performance. Specifically, we sought to test the simultaneous mediating role of working memory and math self-concept. SAMPLE: A total of 167 children aged 8-12 years participated in this study. METHODS: Children completed a set of questionnaires used to assess math and trait anxiety, math self-concept as well as measures of math fluency and math problem-solving. Teachers were asked to rate each student's math achievement. As measures of working memory, two backward span tasks were administered to the children. RESULTS: A series of multiple mediation analyses were conducted. Results indicated that both mediators (working memory and math self-concept) contributed to explaining the relationship between math anxiety and math achievement. CONCLUSIONS: Results suggest that working memory and self-concept could be worth considering when designing interventions aimed at helping students with math anxiety. Longitudinal designs could also be used to better understand the mediational mechanisms that may explain the relationship between math anxiety and math performance. PMID- 28561305 TI - Genetic fusion protein 3*STa-ovalbumin is an effective coating antigen in ELISA to titrate anti-STa antibodies. AB - Heat-stable toxin type I (STa)-ovalbumin chemical conjugates are currently used as the only coating antigen in ELISA to titrate anti-STa antibodies for ETEC vaccine candidates. STa-ovalbumin chemical conjugation requires STa toxin purification, a process that can be carried out by only a couple of laboratories and often with a low yield. Alternative ELISA coating antigens are needed for anti-STa antibody titration for ETEC vaccine development. In the present study, we genetically fused STa toxin gene (three copies) to a modified chicken ovalbumin gene for genetic fusion 3*STa-ovalbumin, and examined application of this fusion protein as an alternative coating antigen of anti-STa antibody titration ELISA. Data showed fusion protein 3*STa-ovalbumin was effectively expressed and extracted, and anti-STa antibody titration ELISA using this recombinant protein (25 ng per well) or STa-ovalbumin chemical conjugates (10 ng/well) showed the same levels of sensitivity and specificity. Furthermore, mice immunized with this fusion protein developed anti-STa antibodies; induced antibodies showed in vitro neutralization activity against STa toxin. These results indicate that recombinant fusion protein 3*STa-ovalbumin is an effective ELISA coating antigen for anti-STa antibody titration, enabling a reliable reagent supply to make standardization of STa antibody titration assay feasible and to accelerate ETEC vaccine development. PMID- 28561306 TI - Stapes prosthesis length and hearing outcomes. AB - OBJECTIVES: First, to determine if prosthesis length plays a role in optimizing successful hearing outcomes in stapedotomy surgery; and second, to determine if patient factors such as height are correlated with prosthesis length. STUDY DESIGN: Retrospective chart review. METHODS: Retrospective chart review of patients undergoing stapedotomy surgeries with adequate follow up. Length of prosthesis, pre-/postoperative audiograms, and follow-up data were obtained. RESULTS: The primary group consisted of 227 cases. The prosthesis length ranged from 3.75 mm to 4.75 mm (median 4.25 mm). The greatest improvement in postoperative air-bone gap (ABG) occurred in the 4.25 mm group, and the least in the 3.75 mm group. Patient height showed a positive, although weak, correlation with prosthesis length. No findings reached statistical significance. CONCLUSION: Accurate measurement of prosthesis length is important for successful postoperative hearing outcomes. There is a positive but not significant correlation between patient height and prosthesis length. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:722-726, 2018. PMID- 28561307 TI - Differences in Lip Support with and without Labial Flanges in a Maxillary Edentulous Population. Part 2: Blinded Subjective Analysis. AB - PURPOSE: To study the subjective differences in facial esthetics evaluations among lay people, general dentists, and prosthodontists, when evaluating images of patients wearing a maxillary denture with a labial flange in comparison to an experimental flangeless denture. MATERIALS AND METHODS: A random sample of 20 maxillary edentulous patients from the original sample of 31 patients described in part 1 of the study was selected for this study. A total of 60 judges comprising 15 general dentists, 15 prosthodontists, and 30 lay people were recruited for subjective analysis. The judges were blinded about the objectives of the study and were asked to rate the facial esthetics of each image using a 100 mm visual analog scale (VAS) instrument. Four digital images per subject (total of 80 images) were evaluated in a random order, twice by all 60 judges. A repeated measures general linear mixed modeling method using restricted maximum likelihood estimation was performed using mixed procedure in a statistical software package to study the differences in evaluations. RESULTS: The overall VAS ratings of facial esthetics for images with flangeless dentures were slightly lower compared to images with labial flanges, and this difference was statistically significant (p < 0.05). This was true for both profile and frontal images; however, the magnitude of the difference was too small (no greater than 4 mm on a 100 mm scale) to be clinically significant. There were no statistically significant differences in facial esthetics ratings irrespective of the background or gender of the judges. CONCLUSIONS: Flangeless dentures resulted in slightly lower ratings of facial esthetics compared to images with a labial flange, but the differences were clinically insignificant. This was true for all judges comprising general dentists, prosthodontists, and lay people and for both frontal and profile images. PMID- 28561308 TI - Knowledge, perception, and practice of patients about pityriasis versicolor in Kaduna, North Central Nigeria. AB - BACKGROUND: Although pityriasis versicolor (PV) is a common fungal infection of the skin affecting up to 50% of the population in the tropics, little is known about what patients know, believe, or feel about the condition. METHODS: In a cross-sectional questionnaire study of 608 consecutive patients attending the General Outpatient Department and Skin Clinic of a public hospital in Kaduna, Nigeria, self-report of PV, knowledge about its causes, treatments used by patients, and perception and feelings about the condition were assessed. RESULTS: Overall 608 patients were studied (239/594 [40.2%] males, 355/594 [59.8%] females, age 11-49 years, mean +/- SD age of 29.3 +/- 10.1). Lifetime self-report prevalence of PV was 271/606 (44.7%) (males: 117/239 [50.0%] females: 148/355 [41.7%] P = 0.09). Three hundred and twenty-seven of 608 (53.8%) patients believed PV was transmitted from another person while 204/608 (33.6%) believed the condition was caused by poor personal hygiene. One hundred and thirty of 608 (21.4%) thought PV was caused by fungi living on the skin. Virtually all respondents who had PV had used at least one preparation with more than half visiting a healthcare facility. A total of 305/608 (50.2%), 189/608 (31.1%), and 142/608 (23.4%) respondents reported feeling or likely feeling uncomfortable, embarrassed, or ashamed, respectively, about PV. Being considered a dirty person (45.6%) and being avoided by other people (28%) were common concerns of respondents. CONCLUSION: Most patients did not know what caused PV, and many were uncomfortable, embarrassed, and ashamed, and feared being considered dirty and avoided by others. PMID- 28561309 TI - A Simple Nanocellulose Coating for Self-Cleaning upon Water Action: Molecular Design of Stable Surface Hydrophilicity. AB - Coating solid surfaces with cellulose nanofibril (CNF) monolayers via physical deposition was found to keep the surfaces free of a variety of oils, ranging from viscous engine oil to polar n-butanol, upon water action. The self-cleaning function was well correlated with the unique molecular structure of the CNF, in which abundant surface carboxyl and hydroxy groups are uniformly, densely, and symmetrically arranged to form a polar corona on a crystalline nanocellulose strand. This isotropic core-corona configuration offers new and easily adoptable guidance to design self-cleaning surfaces at the molecular level. Thanks to its excellent self-cleaning behavior, the CNF coating converted conventional meshes into highly effective membranes for oil-water separation with no prior surface treatment required. PMID- 28561310 TI - Structurally Diverse Boron-Nitrogen Heterocycles from an N2 O23- Formazanate Ligand. AB - Five new compounds comprised of unprecedented boron-nitrogen heterocycles have been isolated from a single reaction of a potentially tetradentate N2 O23- formazanate ligand with BF3 ?OEt2 and NEt3 . Optimized yields for each product were obtained through variation of experimental conditions and rationalized in terms of relative Gibbs free energies of the products as determined by electronic structure calculations. Chemical reduction of two of these compounds resulted in the formation of a stable anion, radical anion, and diradical dianion. Structural and electronic properties of this new family of redox-active heterocycles were characterized using UV/vis absorption spectroscopy, cyclic voltammetry and X-ray crystallography. PMID- 28561313 TI - They also serve: Chamorro male fertility in the pre-world war ii period. AB - Male fertility, a generally overlooked aspect in studies of human reproductive patterns, is examined from the reproductive life histories of Chamorro males with essential completed fertility by 1941. Males in this "natural fertility" indigenous population of the Pacific island of Guam exhibit low levels of couple infertility which are counteracted by high levels of adult male mortality, while new unions formed after the death of female partners tend to reduce completed fertility by only about one child. Delayed age at the time of union formation is largely compensated by reduction in birthspacing intervals among offspring of older fathers. Early terminators, formerly fertile couples of reproductive age who fail for unspecified biological or behavioral reasons to continue reproducing, affect an equal or even larger impact than adult male mortality on failure to attain theoretical male fertility maxima in this population. Am. J. Hum. Biol. 10:23-35, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561314 TI - Comparative study of craniofacial morphology and bite force in Fijians and Japanese. AB - An anthropological survey was conducted in Fiji in 1994 and 1995 to study dental arch form, craniofacial morphology, and bite force of Fijians. Measurements were obtained from dental casts, cephalograms, and thin pressure-sensitive sheets (Dental Prescale(r)) for bite force analysis. Results were compared with those of Japanese. In every direction, the size of the dental arch in Fijians was larger than in Japanese. Fijians displayed longer palates, longer mandibles, and bimaxillary protrusion. There was no significant difference in upper and lower facial heights. FH to lower incisor angle in Fijians was significantly larger than in Japanese. Fijians were characterized by a small palatal plane angle, occlusal plane angle and mandibular plane angle, and were thus brachyfacial. The Japanese tended to be more dolichofacial. The distances from the Cd line to the pterygoid muscles, masseter muscles, and teeth in Fijians were significantly longer than in Japanese. Occlusal contact areas of Fijians were also greater than those of Japanese. The results indicate that the masticatory muscles and craniofacial morphologies supporting them would be better integrated in Fijians than in Japanese. Am. J. Hum. Biol. 10:63-72, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561315 TI - Blood pressure and adiposity: A comparative study of socioeconomically diverse groups of Andhra Pradesh, India. AB - The effect of adiposity on blood pressures, systolic (SBP), and diastolic (DBP), was examined in a sample of 1119 individuals (456 males, 663 females), 18-75 years, from socioeconomically diverse populations from Southern Andhra Pradesh, India. The populations were graded into four socioeconomic groups, group I seminomadic Yerukalas, group II-hard working scheduled caste Mala and the Muslims, group III-land owning agricultural castes Reddy and Balija, and group IV sedentary urban dwelling castes such as Brahmins, Vyshyas, and Marwadis. There was a trend of increase in mean blood pressures and the frequency of hypertensives (SBP >=160 and/or DBP >=95) with increasing age in all groups, and the increase was more distinct from group I to group IV. Mean values of body mass index (BMI: weight/height2 ) and body fat (SF4: sum of biceps, triceps, subscapular, and suprailiac skinfolds) also showed an increasing trend from group I to group IV. A somewhat opposite trend was evident in two indices of fat distribution, centripetal fat ratio (CFR: ratio of subscapular to the sum of subscapular and triceps skin fold thicknesses) and the relative fat pattern index (RFPI: ratio of subscapular skinfold thickness to the sum of subscapular and suprailiac skinfold thicknesses). Step-wise regression analysis indicated that while one or the other adiposity measures along with one of the age terms significantly contributed to SBP variation among males in the affluent groups III and IV, neither any adiposity measure nor age explain the variation in group I, and only body fat, not age, in group II. A qualitatively similar pattern was observed in females, except that BMI explained a significant amount of variation in SBP in group I, and only age and not any of the adiposity measures, in group IV. Besides age, BMI and fat pattern indices accounted for a significant amount of variation in DBP, while RFPI explained a significant amount of variation in group IV. The amount of variation in SBP explained by the age and adiposity measures increased from the traditional to urbanized groups in males (2.4% to 24.8%) and females (11.4% to 43.6%). A similar trend was observed in case of DBP in both males (0.2% to 15.4%) and females (7.6% to 21.8%). Analysis of covariance of the pooled sample suggested that each of five categorical variables-physical activity, smoking, income, food habit, and group membership-independently explained a significant amount of residual variation in SBP of males, while only food habit and social status did so in females. DBP variation, however, was significantly accounted for by only three of the five (excluding food habit and smoking) categorical variables in males and by none in females. The effect of categorical variables on the residual variation in SBP becomes increasingly significant from the traditional to the urbanized groups in males, while this trend is not consistent in females. Am. J. Hum. Biol. 10:5-21, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561311 TI - Growth and enzymatic activity of Leucoagaricus gongylophorus, a mutualistic fungus isolated from the leaf-cutting ant Atta mexicana, on cellulose and lignocellulosic biomass. AB - : A mutualistic fungus of the leaf-cutting ant Atta mexicana was isolated and identified as Leucoagaricus gongylophorus. This isolate had a close phylogenetic relationship with L. gongylophorus fungi cultivated by other leaf-cutting ants as determined by ITS sequencing. A subcolony started with ~500 A. mexicana workers could process 2 g day-1 of plant material and generate a 135 cm3 fungus garden in 160 days. The presence of gongylidia structures of ~35 MUm was observed on the tip of the hyphae. The fungus could grow without ants on semi-solid cultures with alpha-cellulose and microcrystalline cellulose and in solid-state cultures with grass and sugarcane bagasse, as sole sources of carbon. The maximum CO2 production rate on grass (Vmax = 17.5 mg CO2 Lg-1 day-1 ) was three times higher than on sugarcane bagasse (Vmax = 6.6 mg CO2 Lg-1 day-1 ). Recoveries of 32.9 mgglucose gbiomass-1 and 12.3 mgglucose gbiomass-1 were obtained from the fungal biomass and the fungus garden, respectively. Endoglucanase activity was detected on carboxymethylcellulose agar plates. This is the first study reporting the growth of L. gongylophorus from A. mexicana on cellulose and plant material. SIGNIFICANCE AND IMPACT OF THE STUDY: According to the best of our knowledge, this is the first report about the growth of Leucoagaricus gongylophorus, isolated from the colony of the ant Atta mexicana, on semisolid medium with cellulose and solid-state cultures with lignocellulosic materials. The maximum CO2 production rate on grass was three times higher than on sugarcane bagasse. Endoglucanase activity was detected and it was possible to recover glucose from the fungal gongylidia. The cellulolytic activity could be used to process lignocellulosic residues and obtain sugar or valuable products, but more work is needed in this direction. PMID- 28561316 TI - Normal masticatory function of girls and young women: mandibular masticatory movements. AB - Mandibular masticatory movements were evaluated in 10 young adult women and 12 young girls. All subjects had normal occlusion with minimal overjet. Masticatory movements of the incisors were recorded in three dimensions with an Optotrak(r) camera system while subjects chewed gum in a habitual manner for 20 seconds. A masticatory analysis program divided each masticatory cycle into four phases and averaged the duration, excursions, and velocities of all cycles for each subject. Duration of the total cycle was longer in women because they had longer slow opening and slow closing phases than girls. Women had a significantly larger vertical component of opening during slow opening and the power stroke than girls. Women also had a significantly larger posterior component of opening during slow opening and the power stroke than did girls. At maximum opening, women also tended to have the incisors in a more posterior position. There were no differences between the groups for the amount of maximum lateral excursion during chewing. Vertical velocity during fast opening and fast closing was slower for women, but there were no age-related differences during the slow open and slow close phases. Am. J. Human Biol. 10:53-62, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561317 TI - Response. PMID- 28561318 TI - Multilocus DNA profiling using the probe 33.6 in the Tamil Nadu population of South India. AB - Using the multilocus minisatellite probe 33.6 in combination with the HinfI restriction enzyme, the extent of genetic variation detected by DNA fingerprinting was estimated in 102 unrelated individuals of the Dravidian Hindu population of Tamil Nadu, South India. In this first study of its kind on an anthropologically defined Indian population, DNA fragments of size >2.5 kb could be reliably scored. Results indicate that the Tamilian Hindus show an average number of bands per individual somewhat smaller (15.69 for fragments of size >2.5 kb) than that in other Caucasian populations. For comparable molecular weight of fragment sizes, the Tamilian Hindus show a lower level of band sharing probabilities between unrelated individuals compared with other Caucasians. Nevertheless, the probe 33.6 offers a high level of individualization of DNA fingerprints for unrelated individuals in Tamil Nadu. Computations on expected band sharing frequencies between various biological relatives and expected DNA fingerprint identity indicate that this multilocus minisatellite probe can be efficiently used in resolving forensic identification and parentage testing cases in this South Indian population in spite of its high level of inbreeding. Am. J. Hum. Biol. 10:87-93, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561320 TI - Letter to the Editor. PMID- 28561319 TI - Permanent tooth emergence among Zambian schoolchildren: a standard for the assignment of ages. AB - There is sufficient variation in the timing of permanent tooth emergence to warrant population specific standards. Due to the lack of reliable ages in rural Zambia, a tooth emergence standard is derived from an urban sample of 543 Zambian schoolchildren. The standard allows assignment of an age to a child based on the total number of permanent teeth emerged. As a way to evaluate the ability of the standard to assign correct ages to Zambian children, a randomly chosen test (10%) sample was withheld from the formation of the standard. Accuracy of the standard in assigning ages to children in both the test and main samples was assessed in +/-0.5, +/-1.0, and +/-2.0 year intervals. Both the main and test samples were able to accurately assign correct ages within +/-0.5 year ~40% of the time and within +/-1.0 year ~65% of the time for both males and females. To further facilitate use in field settings, the standard was visually smoothed. Once again the accuracy of the standard was very similar when applied to the main and test samples. The smoothed standard was as accurate as the original standard. The smoothed standard is thus recommended for application to rural Zambian children of unknown or unreliable age. Am. J. Hum. Biol. 10:45-51, 1998. (c) 1998 Wiley Liss, Inc. PMID- 28561321 TI - Corticomedular index of the right tibia in the diagnosis of osteopenia in prehistoric skeletal remains. AB - This study examined the diagnostic accuracy of the corticomedular index obtained at the midpoint of the shaft of right tibia as an indicator of osteopenia in a prehistoric sample composed of 133 individuals. Osteopenia was assessed by a histomorphometrical measure of trabecular bone volume (TBV) in an undecalcified bone section of a small part of the proximal epiphysis to: Mild, moderate, and severe osteopenia were defined as TBV values less than 17.5%, 15%, and 12.5%, respectively. The corticomedular index (CI) was determined on X-ray films of the tibiae. Mean TBV of the sample was 17.93 +/- 4.97%, it was moderately correlated with CI (r = 0.43, p < 0.0001). CI values under 0.20 showed high specificity in the diagnosis of all degrees of osteopenia, whereas CI values under 0.275 showed relatively high sensitivity (90.4%) in the diagnosis of severe osteopenia. These methods were then prospectively applied in a further sample of 41 right tibiae also from a prehistoric sample of Gran Canaria. The results were similar to those in the larger sample. Thus, CI may be a useful tool in detecting osteopenia in earlier populations. Am. J. Hum. Biol. 10:37-44, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561322 TI - Cross-sectional survey of growth of urban and rural "cape coloured" schoolchildren: anthropometry and functional tests. AB - The patterns of physical growth (height, weight, length of body segments, circumferences, and widths) and function (grip strength, reflexes, and pulse rates) of "Cape Coloured" schoolchildren were studied. Urban and rural groups were selected with maximum contrasting socioeconomic status (SES). Data were collected between 1986 and 1988 and included 906 males and 1,068 females of high SES between 5 and 20 years in the Cape Town urban area and 834 males and 940 females of low SES between 5 and 19 years in the Little Karoo region. Means and standard deviations of 20 characteristics by age are presented separately for males and females and urban and rural groups. The heights and weights of prepubertal urban children match American reference data, but postpubertally they decline somewhat, whereas these measurements of the rural children consistently lie ~1 standard deviation below the urban group. Skinfold thicknesses of urban children match or exceed the American reference, implying that their nutritional needs are being met well. Functional indicators of rural children are much poorer than those of urban children. The results of the urban children may provide a target for the improvement in growth status of rural children. Am. J. Hum. Biol. 10:73-85, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561323 TI - A Two-Step Synthesis of 2-Spiropiperidines. AB - A general two-step synthesis of 2-spiropiperidines has been developed. delta Amino-beta-ketoesters can be reacted with cyclic ketones to generate 2 spiropiperidines in good to excellent yields. The 2-spiropiperidines formed occupy an under-explored region of 3D-chemical space and are novel scaffolds for use in drug discovery programs. These 2-spiropiperidines can be further functionalised to generate small highly sp3 -rich structures, which exhibit an excellent likeness to lead-molecules in drug discovery. PMID- 28561324 TI - Curcumin Ameliorates Kidney Function and Oxidative Stress in Experimental Chronic Kidney Disease. AB - Chronic kidney disease (CKD) is known to involve inflammation, oxidative stress and apoptosis. Here, we investigated the impact of curcumin (diferuloyl methane, a phenolic turmeric pigment), which has strong antioxidant, anti-inflammatory and anti-apoptotic activities on kidney structure and function in rats with adenine induced CKD. Rats were treated for 5 weeks with adenine to induce CKD-like renal damage and combined with three doses of curcumin. Markers of kidney function and oxidative stress were quantified in plasma, urine, renal homogenates and on kidney tissue. Curcumin was found to significantly abate adenine-induced toxic effects such as reduced creatinine clearance, elevated neutrophil gelatinase associated lipocalin levels and raised urinary N-acetyl-beta-D-glucosaminidase activities. Curcumin markedly reduced renal morphological damage and histopathological markers of inflammation, fibrosis and apoptosis. Curcumin further reduced adenine-induced hypertension, urinary albumin, the inflammatory cytokines IL-1beta, IL-6 and TNF-alpha, cystatin C and adiponectin. It restored plasma sclerostin concentrations and lowered oxidative stress in renal homogenates. In animals treated with the two higher curcumin concentrations, alone or in combination with adenine, an increased expression of the antioxidative transcription factor Nrf2 was found as well as up-regulation of the activity of its direct target glutathione reductase, and of an indirect target, the glutathione level. In conclusion, curcumin exhibits salutary effects against adenine-induced CKD in rats by reducing inflammation and oxidative stress via up regulation of the transcription factor Nrf2. PMID- 28561325 TI - Assays for Infliximab Drug Levels and Antibodies: A Matter of Scales and Categories. AB - Immunogenicity is a frequent cause of secondary non-response to tumour necrosis factor (TNF) inhibitors. Drug level measurement and detection of antidrug antibodies have been shown to be cost effective and clinically relevant, and a large number of assays are available for these purposes. It is, however, difficult to compare assays and translate results into clinical meaningful information due to different methodological approaches and a lack of assay standardization. We have analysed infliximab drug levels and antidrug antibodies in 107 patient samples using enzyme-linked immunoassays (ELISA), immunofluorometric assays (IFMA) and reporter-gene assays (RGA). The RGA gave the lowest results for drug levels, whereas the IFMA detected the highest number of antidrug antibody positive sera. Applying individualized therapeutic ranges to each assay resulted in agreement among all three assays in 74% of samples for drug levels and 98% of samples for antidrug antibodies. We found that TNF inhibitor monitoring assays measure on different scales and that the agreement between quantitative results is limited. However, interassay differences can partially be overcome by assay-individualized translations of quantities into categories, which also is necessary for a meaningful clinical application. Our data demonstrate that assays should not be used interchangeably and that direct comparison of quantitative drug levels obtained with different assays should be avoided. PMID- 28561326 TI - Symptom improvement, recurrence and infection after laparoscopic ventral rectopexy using biologic mesh. PMID- 28561327 TI - Smoking and olfactory dysfunction: A systematic literature review and meta analysis. AB - OBJECTIVES/HYPOTHESIS: A systematic review and meta-analysis of the literature was undertaken, examining the association between tobacco smoking and olfactory function in humans, utilizing PubMed and Web of Science (1970-2015) as data sources. STUDY DESIGN: Systematic literature review and meta-analysis. METHODS: This database review of studies of smoking and olfaction, with a focus on identifying high-quality studies (based on modified versions of the Newcastle Ottawa Scale), used validated olfactory tests among the generally healthy population. RESULTS: We identified 11 studies meeting inclusion criteria. Of 10 cross-sectional studies, two were excluded from meta-analysis because the cohorts they studied were included in another article in the review. In meta-analysis, current smokers had substantially higher odds of olfactory dysfunction compared to never smokers (odds ratio [OR] = 1.59, 95% confidence interval [CI] = 1.37 1.85). In contrast, former smokers were found to have no difference in risk of impaired olfaction compared to never smokers (OR = 1.05, 95% CI = 0.91-1.21). The single longitudinal study reviewed found a trend toward increased risk of olfactory decline over time in ever smokers; this trend was stronger in current as compared to former smokers. CONCLUSIONS: Current smoking, but not former smoking, is associated with significantly increased risk of olfactory dysfunction, suggesting that the effects of smoking on olfaction may be reversible. Future studies that prospectively evaluate the impact of smoking cessation on improvement in olfactory function are warranted. LEVEL OF EVIDENCE: N/A. Laryngoscope, 127:1753-1761, 2017. PMID- 28561328 TI - Inferior thyroid artery ligation increases hypocalcemia after thyroidectomy: A meta-analysis. AB - OBJECTIVE: To assess the effect of truncal ligation of the inferior thyroid artery in comparison with ligation of secondary branches as a risk factor for postoperative hypocalcemia. DATA SOURCES: A search was conducted using the Medical Subject Headings and free-text terms "thyroid*" and "truncal ligation*" in PubMed Central, PubMed, Embase, and Latin American and Caribbean Health Sciences Literature databases for trials published between January 1985 and October 2016. A Google search with the same terms, and a "snowball" approach was designed to retrieve the largest number of articles. REVIEW METHODS: Controlled trials (randomized or not) of adults who underwent total/bilateral subtotal thyroidectomy were searched, and truncal ligation versus nontruncal ligation of the inferior thyroid artery was compared. Data were acquired following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Methodological quality of randomized controlled trials was assessed in accordance with Cochrane Collaboration guidelines, and for nonrandomized controlled trials, the Newcastle-Ottawa quality assessment scale for cohort studies was used. Pooled results are presented as risk differences with a random effects model. The main outcome was postoperative temporary and definitive hypocalcemia. RESULTS: We found 11 nonrandomized controlled trials and nine randomized controlled trials with 1940 patients: 977 patients in the trunk ligation group and 963 patients in the nontruncal ligation group. The risk difference for biochemical hypocalcemia was 6% (95% confidence interval [CI]: 2% to 11%), for symptomatic hypocalcemia 6% (95% CI: 1% to 10%), and definitive hypocalcemia 0% (95% CI: -1% to 1%) in the whole group. CONCLUSIONS: Truncal ligation of the inferior thyroid artery increases the risk of temporary and symptomatic hypocalcemia but not the risk of definitive hypocalcemia. Laryngoscope, 128:534-541, 2018. PMID- 28561329 TI - Sputum basophils and asthma diagnosis: dawn of a new era? PMID- 28561331 TI - Comparative study of flex heart rate in three samples of Nepali boys. AB - Flex heart rate (HR, beats per minute) has assumed increasing importance in studies of energy expenditure and physical activity. Flex HR is defined as the mean of maximum rest and minimum exercise HR recorded during a standard test. This report examines methodological and substantive issues regarding the measurement and interpretation of population variation in flex HR values. Flex HR was determined for 80 Nepali 10-14-year-old boys living in contrasting physical and socioeconomic environments (31 village boys, 24 urban middle-class schoolboys, and 25 homeless street boys). The three populations exhibited significant differences in flex HR, with villagers averaging lower values than school or homeless boys (91, 100, and 103 bpm, respectively, P < 0.0001). They also differed in mean resting HR (P < 0.0002), but not in the percentage increase of flex over resting HR. To evaluate reliability, flex HR measurements were repeated on 14 school boys after a 3-month interval. Mean initial and repeat values were not significantly different, but discrepancies were large for individual subjects (-15 to +24 bpm). This suggests that flex HR is reliable at the population level, but not necessarily stable for individuals over time. The range of factors contributing to variation in flex HR between and within populations have implications for the use of HR monitoring to estimate levels of physical activity. (c) 1996 Wiley-Liss, Inc. PMID- 28561332 TI - Ancient DNA: Methods, progress, and perspectives. AB - The advent of the polymerase chain reaction as a standard molecular genetic technique and the demonstration that nucleic acids are routinely preserved in prehistoric material have led to a dramatic increase in molecular approaches to archaeological problems. These genetic approaches to long-standing problems in prehistory hold considerable promise to clarify issues of population origins, migrations, and settlement patterns, as well as ancestor/descendant relationships. The evolving methods for manipulating and analyzing ancient DNA (aDNA) are reviewed here, as are more recent applications of these methods to anthropologically relevant samples. In addition, new preliminary material is presented on mtDNA variation in Anasazi samples from the U.S. Southwest. The initial samples analyzed indicate similarity to contemporary populations of the Greater Southwest, as evidenced by the modest frequency of a 9bp deletion in Region V of the mtDNA molecule, and the possible absence of haplogroup D. (c) 1996 Wiley-Liss, Inc. PMID- 28561333 TI - Genetic structure of the Utah Mormons: A comparison of kinship estimates from DNA blood groups, genealogies, and ancestral arrays. AB - Kinship estimates based on shared proportions of European ancestry are constructed for 284 Utah males born in eight geographic subdivisions. These "ancestral kinship" estimates are compared with kinship coefficients based on DNA polymorphisms, blood groups, genealogies, isonymy, and migration matrices. At the subdivision level, a high correlation is observed between ancestral kinship and kinship based on isonymy. Comparing individuals, a significant correlation is obtained between ancestral kinship and genealogy derived kinship. Kinship estimates based on DNA and blood groups do not correlate significantly with ancestral kinship. This is most likely due to the effects of several generations of random mating in this population. (c) 1996 Wiley-Liss, Inc. PMID- 28561334 TI - Introduction: Individual, intra-, and inter-population variability in human DNA. PMID- 28561335 TI - DNA interpopulational variation in Siberian indigenous populations: The mountain Altai. AB - Using mtDNA and classical markers, previous studies have found that the Altai are genetically divergent from the rest of Siberia. This study uses five variable number tandem repeat (VNTR) loci to examine the relationship of the Altai to other indigenous Siberian populations. Frequencies of VNTR fragments have been obtained from the DNA of 95 individuals living in the Altai village of Mendur Sokkon. A Kolmogorov-Smirnov test shows that the Altai are significantly different from the Evenki village of Surinda at loci D11S129 and D20S15. In addition, the Altai are also statistically different from the Evenki village of Poligus at locus D11S129. The test reveals no differences between the Ket village of Sulamai and Mendur-Sokkon. The GST value obtained for Siberia is significant and is almost equal to that found for the GST of American ethnic groups. The significance of the GST values was verified through random resampling of the data. The GST value is an effect of the relative isolation of the Evenki as well as gene flow into the Kets and Altai; this is shown in a plot of rn versus mean heterozygosity. Although genetic differentiation between the Siberian groups is significant, an R matrix analysis, which uses American and Siberian ethnic groups, shows that the Siberians form a tight cluster. When the R matrix, GST , and the Kolmogorov-Smirnov results are combined, the Altai appear to be genetically different among Siberian populations, yet they are not as genetically divergent as previous studies have shown. (c) 1996 Wiley-Liss, Inc. PMID- 28561330 TI - Impaired activity of adherens junctions contributes to endothelial dilator dysfunction in ageing rat arteries. AB - KEY POINTS: Ageing-induced endothelial dysfunction contributes to organ dysfunction and progression of cardiovascular disease. VE-cadherin clustering at adherens junctions promotes protective endothelial functions, including endothelium-dependent dilatation. Ageing increased internalization and degradation of VE-cadherin, resulting in impaired activity of adherens junctions. Inhibition of VE-cadherin clustering at adherens junctions (function-blocking antibody; FBA) reduced endothelial dilatation in young arteries but did not affect the already impaired dilatation in old arteries. After junctional disruption with the FBA, dilatation was similar in young and old arteries. Src tyrosine kinase activity and tyrosine phosphorylation of VE-cadherin were increased in old arteries. Src inhibition increased VE-cadherin at adherens junctions and increased endothelial dilatation in old, but not young, arteries. Src inhibition did not increase dilatation in old arteries treated with the VE cadherin FBA. Ageing impairs the activity of adherens junctions, which contributes to endothelial dilator dysfunction. Restoring the activity of adherens junctions could be of therapeutic benefit in vascular ageing. ABSTRACT: Endothelial dilator dysfunction contributes to pathological vascular ageing. Experiments assessed whether altered activity of endothelial adherens junctions (AJs) might contribute to this dysfunction. Aortas and tail arteries were isolated from young (3-4 months) and old (22-24 months) F344 rats. VE-cadherin immunofluorescent staining at endothelial AJs and AJ width were reduced in old compared to young arteries. A 140 kDa VE-cadherin species was present on the cell surface and in TTX-insoluble fractions, consistent with junctional localization. Levels of the 140 kDa VE-cadherin were decreased, whereas levels of a TTX-soluble 115 kDa VE-cadherin species were increased in old compared to young arteries. Acetylcholine caused endothelium-dependent dilatation that was decreased in old compared to young arteries. Disruption of VE-cadherin clustering at AJs (function blocking antibody, FBA) inhibited dilatation to acetylcholine in young, but not old, arteries. After the FBA, there was no longer any difference in dilatation between old and young arteries. Src activity and tyrosine phosphorylation of VE cadherin were increased in old compared to young arteries. In old arteries, Src inhibition (saracatinib) increased: (i) 140 kDa VE-cadherin in the TTX-insoluble fraction, (ii) VE-cadherin intensity at AJs, (iii) AJ width, and (iv) acetylcholine dilatation. In old arteries treated with the FBA, saracatinib no longer increased acetylcholine dilatation. Saracatinib did not affect dilatation in young arteries. Therefore, ageing impairs AJ activity, which appears to reflect Src-induced phosphorylation, internalization and degradation of VE cadherin. Moreover, impaired AJ activity can account for the endothelial dilator dysfunction in old arteries. Restoring endothelial AJ activity may be a novel therapeutic approach to vascular ageing. PMID- 28561336 TI - Validity of the body mass index as an indicator of adiposity in an ethnically diverse population of youths. AB - The primary objective was to investigate the influences of ethnicity and pubertal stage on the ability of body mass index (BMI) to rank adiposity in a cohort of 402 Asian, African, Hispanic, and White Americans, aged 9-25 years. BMI was calculated from measured weight and height. Body composition and pubertal stage were determined by dual energy x-ray absorptiometry and self-rating, respectively. Multiple linear regression models with BMI, ethnicity, puberty, and age as explanatory variables were used to determine if ethnicity and pubertal stage modify the ability of BMI to predict percent of body weight that is fat (%BF). Spearman's correlation coefficients of BMI with %BF were also estimated. Both ethnicity and pubertal stage interacted with BMI. The correlation between BMI and %BF (r) was much higher in females (r = 0.72, P < 0.001) than in males (r = 0.15, NS). Among females, correlations did not vary much by pubertal stage, but tended to be higher in Blacks. Among males, correlations tended to be low during mid-puberty. However, a high correlation between BMI and lean body mass (LBM) was consistently observed in mid-pubertal males across all ethnic groups. Stratification by quartile of BMI showed that the correlation was >0 (P < .05) only in the highest quartile. Thus, in an ethnically diverse cohort of 9-25 year olds, the correlation between BMI and %BF is poor in the lower quartiles of BMI. In comparison, LBM correlates better with BMI than %BF in the lower quartiles of BMI. (c) 1996 Wiley-Liss, Inc. PMID- 28561337 TI - Relationship of skeletal age to limb composition during pubescence. AB - The relationships between skeletal age (SA) and limb composition (arms, legs, and all four limbs) in terms of fat mass (FM), fat-free mass (FFM), muscle mass (MM) and bone mineral content (BMC) were investigated in 55 males and 53 females aged 9-15 years. The Fels method was used to assess hand-wrist SAs which were expressed as SA/chronological age (SA/CA). The limb composition data were obtained from a Lunar dual-energy x-ray absorptiometer using 3.6z software. The means for the limb composition variables increased gradually with age except in males for whom FM decreased from 12 to 13 years, and FFM and MM increased markedly from 13 to 14 years. There were similar findings when the limb composition data were expressed as percentages of body weight. All of the regressions of SA/CA on limb composition variables had positive slopes. Each of the slopes was significant for males, but nonsignificant for females. (c) 1996 Wiley-Liss, Inc. PMID- 28561338 TI - Molecular population genetic studies of the island peoples of the South Pacific. AB - The introduction of molecular genetic techniques to survey DNA variation directly has greatly advanced the study of inter- and intra-population variability. One of the first DNA polymorphisms to be surveyed for population variation was the alpha globin copy number variants in Melanesia, and this study indicated a new role for malarial selection. Subsequently, DNA sequence polymorphism was investigated by the definition of haplotypes, which result from linkage disequilibrium among site polymorphisms. Distributions of alpha-globin haplotypes clearly demonstrate the effects of migration on population affinities in Melanesia and Polynesia. Analysis of neutral diversity in the nuclear genome has been enriched by the discovery of variable numbers of tandem repeats (VNTRs), particularly the hypervariable mini-satellites. Highly allelic VNTRs are sensitive to the effects of genetic drift caused by bottlenecks or population subdivision, and in Oceania they reflect the demography of colonization. Because VNTRs are subject to high and variable rates of mutation, they are informative within a range of recent evolutionary time scales and, together with other DNA polymorphisms, contribute to a more complete interpretation of a population's history. (c) 1996 Wiley-Liss, Inc. PMID- 28561339 TI - Intraindividual variation in the basal metabolic rate of women: Effect of the menstrual cycle. AB - The validity of using the basal metabolic rate (BMR) to calculate an individual's energy requirements is based upon the assumption that the intraindividual variation in BMR is small. Early studies (pre-1940) on BMR in women had shown that the menstrual cycle may have a profound effect, contributing to high levels of intraindividual variation. To investigate this issue further, and to explore whether BMR is indeed a biological constant in women, sequential measurements of BMR were made in women over one menstrual cycle. Two independent studies were undertaken in which the BMR of 12 weight-stable women (not taking the contraceptive pill) was measured every day (excluding weekends) for a period of 5 weeks. The six women participating in the first study were measured using a Douglas bag, while the six subjects in the second study were measured with a Deltatrac (Datex, Helsinki). Nine of the 12 subjects demonstrated a peak in BMR during the late luteal phase of the menstrual cycle, while 8 of the 12 subjects exhibited a fall in BMR after the onset of menstruation. Group analysis of the results indicated that the BMR during the early follicular phase was significantly lower than the BMR during the late luteal phase (Wilcoxon's signed rank test: P < 0.01). The level of intraindividual variation was assessed by calculating the coefficient of variation (CV) for the measurement period. The CV in six of the women exhibited a level of variation comparable to men (2-4%). However, intraindividual variation in the BMR of the other six women was considerably higher (up to 12%). In these six women, therefore, BMR may not be considered a biological constant. All available data on sequential measurements of BMR in fertile women were collated from the literature for the first time, and statistically analyzed. BMR during the early follicular phase was found to be significantly lower (P < 0.05) than during the late luteal phase. Further work on the biological constancy of BMR in women and the impact of the menstrual cycle on BMR is required. This area is of particular importance given the fact that the energy requirements of both individuals and populations are now calculated using the BMR. (c) 1996 Wiley-Liss, Inc. PMID- 28561340 TI - Heart rate monitoring of physical activity among village, school, and homeless Nepali boys. AB - Continuous HR monitoring, in conjunction with self-reports and direct observation of physical activity, was undertaken in three samples of 10-13-year-old Nepali boys living in different physical and socioeconomic environments. A total of 134 daytime HR profiles were recorded from 67 boys (76 from 31 villagers, 39 from 20 urban middle-class schoolboys, and 19 from 16 homeless street boys). Habitual levels of physical activity were compared using mean daytime HR (bpm) and the following indicators: percentage time during which boys are active (HR> flex, defined as an individual's average between resting and exercising HR), moderately active (HR> flex + 20%, also HR> 119 bpm), and vigorously active (HR> 139 bpm) over 10 hours of daylight. Mean daytime HR (102 bpm) and percentage time spent vigorously active (4%) did not differ between samples, despite obvious differences in lifestyles; thus better indicators are needed to characterize levels of physical activity. Percentage time spent active (HR> flex) was significantly higher (P < 0.0001) for villagers participating in subsistence activities, as a result of low flex HR values, indicating a higher level of physical fitness. Evaluation of moderate physical activity was sensitive to the choice of indicator, either an individual calibrated (above flex) or an absolute threshold of HR elevation. The former may be more appropriate than the latter to compare physical activity levels in populations with different lifestyles and levels of physical fitness. (c) 1996 Wiley-Liss, Inc. PMID- 28561341 TI - Y-chromosome-specific restriction fragment length polymorphisms (RFLPs): Relevance to human evolution and human variation. AB - The human Y chromosome comprises two distinct parts: the pseudoautosomal region on the tip of the short arm that pairs with the X chromosome in male meiosis and undergoes recombination, and the remainder of the chromosome, which is male specific and not involved in recombination. It is this haploid part of the Y chromosome, with its accumulation of mutations, that is of interest to human biologists because the variation within it potentially reflects the paternal line in human evolution (just as mtDNA analysis represents maternal lineages). The Y chromosome, however, appears to contain very few restriction fragment length polymorphisms (RFLPs), and furthermore, understanding of the polymorphic basis of some of these is presently imperfect. These latter problems include the possibility of multiple origins of the same allele, especially in repeat sequence polymorphisms, and failure to recognize the ancestral allele at a locus. All of these restrictions and difficulties mean that no comprehensive understanding of either Y chromosome evolution or its variability among the world's populations is yet possible. This report examines the current knowledge of Y-chromosome population genetics obtained using probes such as p12f, p49a, pYAP, and pYalphal, including their use in measuring gene flow and also in population histories and differentiation. Most studies have reported allele frequencies at a particular locus, but a fuller understanding of Y chromosome evolution and variation will require haplotype data. One interesting observation is the low diversity for some Y-chromosome polymorphisms in African populations compared to Caucasoids, a contrast to the pattern seen for other DNA polymorphisms. The role of different mate choice systems in acting to substantially reduce Y-chromosome variation is considered. (c) 1996 Wiley-Liss, Inc. PMID- 28561342 TI - An evolutionary perspective on maladaptive traits and cultural conformity. AB - The problem of maladaptive cultural traits is explored through the notion of adaptive psychological mechanisms. It is suggested that the theory of a specific conformity mechanism is plausible, supported by multidisciplinary data, and helpful in explaining the proliferation and persistence of human maladaptive behavior. (c) 1996 Wiley-Liss, Inc. PMID- 28561343 TI - Pan-Arctic sea ice-algal chl a biomass and suitable habitat are largely underestimated for multiyear ice. AB - There is mounting evidence that multiyear ice (MYI) is a unique component of the Arctic Ocean and may play a more important ecological role than previously assumed. This study improves our understanding of the potential of MYI as a suitable habitat for sea ice algae on a pan-Arctic scale. We sampled sea ice cores from MYI and first-year sea ice (FYI) within the Lincoln Sea during four consecutive spring seasons. This included four MYI hummocks with a mean chl a biomass of 2.0 mg/m2 , a value significantly higher than FYI and MYI refrozen ponds. Our results support the hypothesis that MYI hummocks can host substantial ice-algal biomass and represent a reliable ice-algal habitat due to the (quasi-) permanent low-snow surface of these features. We identified an ice-algal habitat threshold value for calculated light transmittance of 0.014%. Ice classes and coverage of suitable ice-algal habitat were determined from snow and ice surveys. These ice classes and associated coverage of suitable habitat were applied to pan Arctic CryoSat-2 snow and ice thickness data products. This habitat classification accounted for the variability of the snow and ice properties and showed an areal coverage of suitable ice-algal habitat within the MYI-covered region of 0.54 million km2 (8.5% of total ice area). This is 27 times greater than the areal coverage of 0.02 million km2 (0.3% of total ice area) determined using the conventional block-model classification, which assigns single-parameter values to each grid cell and does not account for subgrid cell variability. This emphasizes the importance of accounting for variable snow and ice conditions in all sea ice studies. Furthermore, our results indicate the loss of MYI will also mean the loss of reliable ice-algal habitat during spring when food is sparse and many organisms depend on ice-algae. PMID- 28561344 TI - Bilateral vestibulopathy with positive Tullio phenomenon. AB - : We describe the case of a 34-year-old patient presenting with the unique combination of bilateral vestibulopathy in combination with noise- and pressure induced nystagmus. Bilateral vestibular dysfunction was demonstrated by pathological results in video-based head impulse testing as well as in caloric testing. In contrast, cervical vestibular-evoked myogenic potentials were normal, demonstrating normal sacculus function. Due to the positive Tullio phenomenon, semicircular dehiscence syndrome was excluded. Recently, this symptom combination was related to the histopathological finding of vestibular atelectasis. LEVEL OF EVIDENCE: NA.Laryngoscope, 128:1223-1225, 2018. PMID- 28561346 TI - SPONTANEOUS MUTATIONS FOR LIFE-HISTORY CHARACTERS IN AN OBLIGATE PARTHENOGEN. AB - By allowing mutations to accumulate spontaneously in different lines derived from a single female of an obligately parthenogenetic Daphnia, it has become possible to estimate the rate at which new genetic variance for life-history characters arises as well as to identify the average pleiotropic effects of mutant polygenes. The estimated polygenic mutation rates are quite compatible with those available for sexual organisms. The results are therefore in conflict with the hypothesis that parthenogens compensate for the loss of recombination by elevating the mutation rate. Based on these results, it is argued that the rate of phenotypic evolution may be enhanced as much as five-fold by sexuality. However, if dominance or epistatic gene interactions are of major importance, or if the sensitivity to environmental effects is reduced or the rate of polygenic mutation enhanced under asexuality, the full advantage of sex will not be attained and may even be reversed. Regardless of these conditions, it is clear that the mutational rate of production of polygenic variation is sufficient to allow significant rates of phenotypic evolution in purely asexual organisms. PMID- 28561345 TI - Outcome after one year of upper airway stimulation for obstructive sleep apnea in a multicenter German post-market study. AB - OBJECTIVE/HYPOTHESIS: Upper airway stimulation (UAS) of the hypoglossal nerve has been implemented in the routine clinical practice for patients with moderate-to severe obstructive sleep apnea (OSA) who could not adhere to continuous positive airway pressure. This study reports objective and patient-reported outcome after 12 months of implantation. STUDY DESIGN: Multicenter prospective single-arm study. METHODS: Consecutive patients who received the UAS system (Inspire Medical Systems, Inc., Minneapolis, Minnesota, Maple Grove, MN, U.S.A.) were enrolled in three German centers. Key study exclusion criteria included body mass index > 35 kg/m2 , apnea-hypopnea index (AHI) < 15 or > 65, or complete concentric collapse at the soft palate during sedated endoscopy. Data collection at 6- and 12-month visit include home sleep test and patient-reported outcome measures. RESULTS: Among the total of 60 participants, the median AHI reduced from 28.6 to 9.5 from baseline to 12 months. Patient-reported outcome measured in Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire both improved significantly from baseline to 12 months. The average usage time was 39.1 +/- 14.9 hours per week among all participants based on recordings by the implanted device. One patient requested a removal of the device for cosmetic and other personal reasons and was completed without sequelae. CONCLUSION: This study supported that UAS is a safe and effective treatment option for patients with OSA in routine clinical practice. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:509-515, 2018. PMID- 28561347 TI - EVOLUTION OF ALTRUISM IN KIN-STRUCTURED AND RANDOM SUBDIVIDED POPULATIONS. AB - A. population structure favorable to the evolution of an altruistic trait is studied by Monte Carlo simulation. The model is based on a small-scale nonindustrial human society but seems generalizable to other highly social mammals. Three hierarchical levels are recognized: 1) the ecologically isolated local group (hamlet) which may be composed of kin and/or unrelated individuals; 2) the deme (settlement) comprising several such groups which interbreed; and 3) the set of demes (metapopulation) among which gene flow occurs. The first two levels of the model are based on D. S. Wilson's structured deme concept; the third allows for gene flow among demes in the metapopulation and for the structured diffusion of alleles across a wider area than might be included within the scope of a single deme. The simulation models genetic drift by a process of hamlet formation which may be random, or variously kin-structured. Hamlets may then become extinct based on a probability function of their gene frequencies. Individual selection within settlements is modeled deterministically, and gene flow among settlements is modeled as two-dimensional steppingstone migration of random or kin-structured groups. Results of the simulations show that, with realistic values for group sizes, moderate extinction rate, and high rates of migration (m > 27%), disadvantageous alleles (s = 10% and 25%) may increase markedly due to differential hamlet extinction over the course of 50 generations. The greater the degree of kin-structuring of founder groups, the higher the variance among hamlets and the faster the rate of increase of the allele for altruism. Nonetheless, even in some randomly founded groups, a clear increase in the altruism gene frequency occurred. It is also notable that kin-structured group selection by hamlet extinction may be effective when the initial frequency of altruism genes is very low (average of one per deme) and among a relatively small number of demes (25). Thus the process of group extinction in a hierarchically structured population allows rapid increase of an allele for altruism under plausible demographic conditions. PMID- 28561348 TI - THE PRECISION OF HISTOCOMPATIBILITY RESPONSE IN CLONAL RECOGNITION IN TROPICAL MARINE SPONGES. AB - Recently discovered histocompatibility-like phenomena in sponges (Phylum Porifera) have prompted attempts to measure the precision with which allogeneic grafts are recognized and rejected. The results of these investigations have been extremely varied, ranging from suggestions that allorecognition does not occur to suggestions that every genetically distinct individual may be unique in histocompatibility type. Interpretation of these findings is complicated by the variation in methods and species used by different workers. Here we compare various measurements of allorecognition precision for several species of tropical marine sponges. From our results we conclude that 1) tissue implant grafts are more prone to artifact than grafts between intact sponges; 2) the possibility of clonal propogation should be considered when graft acceptances are observed between sponges selected from a single population; and 3) allozyme variation in Niphates erecta shows that occasional grafts between genetically different individuals may be accepted. PMID- 28561349 TI - BUTTERFLY WING MARKINGS ARE MORE ADVANTAGEOUS DURING HANDLING THAN DURING THE INITIAL STRIKE OF AN AVIAN PREDATOR. AB - The "false head" hypothesis states that due to the posterior ventral wing markings of certain butterflies which resemble a "false head," visually hunting predators, such as birds, are deceived into attacking the hind wing area rather than the true head of the butterfly. In the laboratory, six groups of artificially marked dead cabbage butterflies, Pieris rapae, were presented to Blue Jays, Cyanocitta cristata. Of the six "false head" markings, only the eyespot significantly influenced the point of attack. All of the "false head" markings, however, led to a greater proportion of attacks to the hind wing area of the butterfly. In the course of prey handling following an initial attack, each of the six "false head" markings significantly directed predator handling strikes away from the true head of captive butterflies to the anal angle of the hind wing. In a second experiment, live P. rapae with "false head" markings were mishandled and thus escaped, significantly more frequently than controls. Therefore, "false head" markings may confer a selective advantage by increasing the probability of escape, particularly during handling. PMID- 28561350 TI - FORTHCOMING MEETING. PMID- 28561351 TI - INTRAPOPULATIONAL VARIATION IN POLLEN-MEDIATED GENE FLOW IN PLANTAGO LANCEOLATA L. AB - The extent of genetic variation in pollen-mediated gene flow distance was measured for a population of the wind-pollinated herb, Plantago lanceolata. Twenty-nine genotypes were collected from a natural population, clonally replicated, and grown to reproductive maturity in a greenhouse. Relative gene flow distances were measured for each replicate and genotype in a wind tunnel. Approximately five percent of the total variation in gene flow distance was attributable to variation among genotypes. Most of the remaining variation was attributable to differences between the early part of the growing season, when most of the flowering occurs, and the remainder of the season, when flowering is sparse. The rankings of the genotypes' gene flow distances showed significant concordance between the early-season measures and measures from later in the summer. There was no correlation between the average inflorescence height for a plant and the average gene flow distance for that plant. For analysis of pollen characteristics suspected as causal factors of variation in gene flow distance, the variation in gene flow distance was divided into two components: that due to environmental (seasonal) differences, and that due to the differences among genotypes within runs. Variation in both the buoyant properties of the pollen grains and their adhesiveness was significantly partially correlated with environmental variation in gene flow distance, while only the buoyant properties of the pollen grains were significantly partially correlated with among-genotype variation in gene flow distances. PMID- 28561352 TI - GROUP SIZE FACTORS AND GEOGRAPHIC VARIATION OF MORPHOMETRIC CORRELATION. AB - Within-locality correlations among eight morphological traits of the fundatrix and among 15 morphological traits of the alate fundatrigeniae of the aphid Pemphigus populicaulis Fitch were examined for among-locality variation. A jackknife procedure revealed highly significant differences among correlation matrices representing 34 local samples from eastern North America. Most bivariate correlations also differed significantly among samples. Although very low correlations cannot differ, for moderate or strong correlations the average magnitude of correlation is not a good predictor of the degree of interlocality difference. Nearly half of the variation among localities is in the level of "overall correlation," which is positively correlated with intralocality size variation. Despite significant differences among localities, spatial autocorrelation tests failed to reveal any significant geographic pattern in correlations. Monte Carlo experiments suggest that if geographic patterns in the correlations were of the same magnitude as those for the means of these traits, some of these patterns would have been detected. Factor analyses of the pooled within-locality correlation matrices, after oblique rotation to simple structure, reveal appendage and body-size factors for both alates and stem mothers. In general, correlations between traits with high loadings on the same factor differ among localities, whereas substantial correlations that do not vary geographically are between traits that are not well resolved by the factor analyses. It is hypothesized that the apparently random geographic differences in correlation are caused by chance differences in the mode of response to short term selection. Geographic patterns in trait means are established by selection, but, because local population sizes are finite, similar response to selection occurs by diverse physiological or developmental mechanisms in different populations, just as replicate lines in artificial selection experiments may achieve the same response by diverse mechanisms. These diverse mechanisms of response will have diverse effects on genetic variance and covariance, causing correlation patterns to vary geographically. Several forces will oppose continued divergence of these patterns. PMID- 28561353 TI - THE COSTS OF CHANGING SEX AND THE ONTOGENY OF MALES UNDER CONTEST COMPETITION FOR MATES. AB - In its simplest form, the size-advantage hypothesis predicts that individuals should change sex in order to increase their reproductive success. In terms of lifetime expectations, this must be true for the hypothesis to hold. However, as we review here, some loss of reproductive success may occur immediately after sex change. Unavoidable costs (e.g., those resulting from a restructuring of the gonad) have not been adequately distinguished from adaptive allocations of resources which diminish current reproduction in favor of large increases in future mating success. This strategy can become particularly important for species in which a few males monopolize matings. To illustrate this idea, we describe the changes in mating frequency as mature females become sexually active males in three species of protogynous wrasses. In one species, a male defends a permanent, all-purpose territory composed of up to 12 females. When he is removed, a single female changes sex and successfully completes mating sequences with all females in the territory within an average of 5.6 days. This duration roughly corresponds to the time required for functional transformation of gonads; thus, individuals in this species suffer few reproductive losses as a result of changing sex. The largest males in two other species mate with an average of 25 to 50 females per day, but only by successfully defending reproductive territories. In one of those species, individuals that changed sex mated infrequently over a two-year period after sexual transformation and, by the end of the study, were still well below the average size of males that consistently obtained territories. Sex-changed individuals in the other species had very low reproductive success for up to 45% of the maximum lifespan as a male. It is improbable that the substantial cost of changing sex in the latter two species results from gonad restructuring or from mistakes due to imprecise cues for sex change. Instead, the cost appears to represent an investment in growth rather than current reproduction as a means of rapidly attaining a size advantage when individuals face intense competition for extraordinarily successful mating territories. PMID- 28561354 TI - LOCAL POPULATION DIFFERENTIATION FOR COMPATIBILITY IN AN ANNUAL LEGUME AND ITS HOST-SPECIFIC FUNGAL PATHOGEN. AB - Severe attack by the fungal pathogen Synchytrium decipiens frequently occurs in natural populations of the annual plant Amphicarpaea bracteata (Leguminosae) in eastern North America. Field transplant experiments indicate that there is significant population differentiation in the plant-fungus association over distances of 1 km or greater: plants transplanted back into their population of origin become heavily infected, while foreign plants from populations 1 or 100 km away experience little or no infection, even though these foreign plants are subject to heavy fungal attack in their native populations. To investigate the fine structure of population differentiation, progeny of A. bracteata plants collected at six sites at 30 m intervals along a transect were inoculated with a single strain of S. decipiens in a controlled environment. Fungal lesions were initiated in all 36 plant progeny groups tested, yet there was highly significant, 5-fold variation among plants from different sites in the mean number of fungal lesions developing per plant. In addition, all fungal lesions aborted without maturing spores on all plants from one site on the transect. Fungal lesion abortion rates averaged only 9% on plants from the other five sites. Such local population differentiation in plant-pathogen compatibility may be related to A. bracteata's high degree of self-pollination. Limited long distance recombination in A. bracteata due to self-pollination and spatially restricted pollen flow may be a major factor preventing the evolution of increased plant resistance to fungal attack. PMID- 28561355 TI - THE COLONIZATION OF DROSOPHILA SUBOBSCURA IN CHILE. II. CLINES IN THE CHROMOSOMAL ARRANGEMENTS. AB - Drosophila subobscura is a Palearctic species that was first detected in the New World in Puerto Montt (Chile) in February 1978. Since that time, it has spread over a broad area and increased in population density. The South American populations exhibit a high level of chromosomal polymorphism: 20 different arrangements exist, distributed among five chromosomes. Chromosomal arrangement heterozygosity varies from 0.55 to 0.61 in the nine populations examined. Incipient clines in the frequencies of the arrangements are appearing; these clines follow the same latitudinal direction as in the Old World. Wing length significantly decreases with latitude, as it does in Europe. The colonization of South America by D. subobscura appears to be a major natural experiment with outcomes that duplicate the distributional patterns-in chromosomal polymorphism and in wing length-observed in the Old World, thereby strongly supporting the adaptive significance of these patterns. The data show a very rapid effect of natural selection promoting genetic differentiation among natural populations. PMID- 28561356 TI - GENETIC COVARIATION AMONG LIFE-HISTORY COMPONENTS: THE EFFECT OF NOVEL ENVIRONMENTS. PMID- 28561357 TI - ON THE DARWINIAN HYPOTHESIS OF THE ADAPTIVE SIGNIFICANCE OF TRISTYLY. AB - Darwin proposed that the function of the stamen-style polymorphism in heterostylous plants is to increase the probability of legitimate (compatible) pollinations among the floral morphs. Conspicuous pollen trimorphism in tristylous Pontederia cordata enables a test of the hypothesis. Comparison of the composition of pollen loads in naturally pollinated stigmas of intact and emasculated flowers were made at a population in Paugh Lake, Ontario, which was visited primarily by bumblebees. The magnitude of legitimate pollination was analyzed by ANOVA. In intact flowers, significant legitimate pollination was detected in the long-styled morph only. Following emasculation legitimate pollination was evident in the long- and short-styled morphs, with the mid-styled morph just short of displaying significant legitimate pollination. Similar results were obtained by chi-square analysis. It has been suggested that heterostyly may reduce mutual interference between maternal and paternal reproductive function. Two aspects of pollen-stigma interference were investigated in P. cordata. The potential importance of stigmatic or stylar clogging by incompatible pollen was examined by controlled field pollinations and measurements of seed set. The results indicate that prior application of large amounts of incompatible pollen has no significant effect on the seed set of open pollinated inflorescences. Comparison of legitimate pollen capture in intact and emasculated flowers provided no evidence that the presence of stamens within flowers of the floral morphs interferes with the receipt of legitimate pollen. Pollen-stigma interference remains to be demonstrated in heterostylous plants. PMID- 28561358 TI - REPRODUCTIVE ECOLOGY AND BIOGEOGRAPHY OF INDO-WEST PACIFIC ANGELFISHES (PISCES: POMACANTHIDAE). AB - Analysis of the relationships between duration of the pelagic larval stage (as indicated by otolith microstructure), adult size, and the extent of geographic distribution for Indo-West Pacific angelfishes (Pomacanthidae) indicates that neither adult size nor larval duration significantly predicts extent of distribution, either individually or jointly in a multiple regression. These results are robust for both the family as a whole and the genus best represented in our data (Centropyge). If larval duration and adult size do have an effect, it is only jointly and at the genus level. However, larval duration and adult size do correlate significantly and negatively with one another. The operational factor seems to be egg size, which correlates positively with adult size, and negatively with duration of the pelagic larval stage. Similar correlations are evident in both marine invertebrates and at least some other coral-reef fishes, suggesting they are of widespread significance. The limited ability of either reproductive parameter to predict extent of species distribution indicates, first, that even in a group as morphologically conservative as the Indo-West Pacific pomacanthids, neither a two-fold difference between species in larval duration nor a two order of magnitude difference in female fecundity markedly affects extant distributions; and secondly, that either undescribed biological factors or historical constraints are of paramount importance. Available evidence suggests that dispersal abilities of most coral reef fishes, in fact, may be limited, despite the nearly universal occurrence of a pelagic stage in development. PMID- 28561359 TI - CONFIDENCE LIMITS ON PHYLOGENIES: AN APPROACH USING THE BOOTSTRAP. AB - The recently-developed statistical method known as the "bootstrap" can be used to place confidence intervals on phylogenies. It involves resampling points from one's own data, with replacement, to create a series of bootstrap samples of the same size as the original data. Each of these is analyzed, and the variation among the resulting estimates taken to indicate the size of the error involved in making estimates from the original data. In the case of phylogenies, it is argued that the proper method of resampling is to keep all of the original species while sampling characters with replacement, under the assumption that the characters have been independently drawn by the systematist and have evolved independently. Majority-rule consensus trees can be used to construct a phylogeny showing all of the inferred monophyletic groups that occurred in a majority of the bootstrap samples. If a group shows up 95% of the time or more, the evidence for it is taken to be statistically significant. Existing computer programs can be used to analyze different bootstrap samples by using weights on the characters, the weight of a character being how many times it was drawn in bootstrap sampling. When all characters are perfectly compatible, as envisioned by Hennig, bootstrap sampling becomes unnecessary; the bootstrap method would show significant evidence for a group if it is defined by three or more characters. PMID- 28561360 TI - LIFE HISTORY STUDIES OF THE LESSER SNOW GOOSE (ANSER CAERULESCENS CAERULESCENS). VI. PLUMAGE POLYMORPHISM, ASSORTATIVE MATING AND FITNESS. AB - The investigated the hypothesis that positive assortative mating for plumage coloration observed in populations of the dichromatic Lesser Snow Goose (Anser caerulescens caerulescens) evolved and persists due to selective advantages accruing to individuals choosing mates phenotypically similar to themselves. We examined potential differences between pure (white * white, blue * blue) and mixed (white * blue, blue * white) pairs for an array of fitness components related to both fecundity and viability. While no differences were detected for most components, mixed pairs consistently enjoyed enhanced nesting success relative to their pure counterparts. In addition, pre-reproductive viability and female offspring recruitment were significantly greater for mixed pairs for some of the cohorts examined. Not only have we failed to find enhanced reproductive success associated with positive assortment, we have provided evidence that there is some advantage associated with negative assortment. In light of our findings, we suggest: 1) that positive assortment results from the use of familial color as one element in species recognition; 2) that the enhanced fitness of mixed pairs, particularly with respect to nesting success, results from complementation of parental behavior; and 3) that while negative assortment will not likely become the rule in this population, the selective advantage of mixed pairs is a potential determinant of pair type frequencies in the La Perouse Bay population. PMID- 28561361 TI - MICROGEOGRAPHIC LINEAGE ANALYSIS BY MITOCHONDRIAL GENOTYPE: VARIATION IN THE COTTON RAT (SIGMODON HISPIDUS). AB - We evaluate the use of mitochondrial DNA (mtDNA) genetic markers to describe population structure and matrilineal kinship on a microgeographic scale. An analysis of restriction site variation in 134 cotton rats (Sigmodon hispidus) collected from a 3.2 hectare field revealed significant spatial and temporal heterogeneity in frequencies of mtDNA genotypes among nest sites. Inspection of particular genotypes provided additional information about minimum numbers of female lineages (family units) per nest site, and the possible matrilineal affiliations of individuals. However, since shared genotypes are not necessarily synapomorphs having arisen within the study area, conclusions about dispersal must remain reserved. Study of the maternally-transmitted mtDNA genome offers novel perspectives on the meaning of microgeographic population structure. PMID- 28561362 TI - REPLY TO GILBERT. PMID- 28561363 TI - ADAPTIVE RADIATION AND GENETIC DIFFERENTIATION IN HAWAIIAN BIDENS. AB - The genus Bidens (Asteraceae) has undergone extensive adaptive radiation on the Hawaiian Islands. The 19 species and eight subspecies endemic to Hawaii exhibit much more morphological and ecological differentiation than the continental members of the genus. However, the Hawaiian taxa have the same chromosome number and retain the capacity to interbreed in all possible combinations. Twenty-two populations of 15 Hawaiian taxa and four populations of American taxa were compared at 21 loci controlling eight enzyme systems. Populations of Hawaiian taxa are highly polymorphic. However, little genetic differentiation has occurred among taxa in spite of the high levels of genetic variability. Genetic identities calculated for pairs of populations show that populations of the same taxon are genetically more similar than are populations belonging to different taxa, but all values are high. The level of genetic differentiation that has occurred among the species of Hawaiian Bidens is comparable to the level of genetic differences found among populations within single continental plant species. Moreover, there is no correlation between the isozyme data and morphological data. No groups of taxa are evident in the genetic data, although morphological groups exist. Genetic differentiation at isozyme loci has not occurred at the same rate as the acquisition of presumably adaptive morphological and ecological characters in Hawaiian Bidens. Adaptive radiation may be limited to a few genes controlling morphological and ecological characters. PMID- 28561364 TI - OVIPOSITION SITE SELECTION BY DROSOPHILA MELANOGASTER AND DROSOPHILA SIMULANS. AB - The effects of texture and larval residues in the medium on oviposition site selection (OSS) by Drosophila melanogaster and Drosophila simulans were studied. Drosophila melanogaster laid over 95% of its eggs in sieved medium (vs. unsieved medium); D. simulans laid all of its eggs in sieved medium. Surgical removal of antennal segments, and of fore-, mid-, or hindtarsi did not affect this result, indicating that sense organs involved in discriminating between sieved and unsieved medium are not confined to only one of the tested structures. In a "multiple choice" experiment, females were allowed to lay eggs in sieved medium of three types: unconditioned (fresh) medium, medium conditioned by D. melanogaster larvae (i.e., medium containing larval residues of D. melanogaster), and medium conditioned by D. simulans larvae. This choice experiment was performed with D. melanogaster and with D. simulans, using three densities of females (10, 20, and 40 per experimental unit). Both species laid more eggs in unconditioned medium than in either of the conditioned media, and density had no effect. D. melanogaster laid more eggs near the edges of food patches than in the center, whereas D. simulans showed no preference for edge or center. Under crowded conditions, both species survived at a higher rate in conditioned media (egg-to-adult survival) than in unconditioned medium, leading to the anomalous conclusion that females of these species seem not to maximize the survival of their offspring. This anomaly was partially resolved by the finding that medium already containing larvae gave lower survival rates than unoccupied medium. PMID- 28561366 TI - GENETIC ORIGIN OF MALE DIPLOIDY IN THE FIRE ANT, SOLENOPSIS INVICTA (HYMENOPTERA: FORMICIDAE), AND ITS EVOLUTIONARY SIGNIFICANCE. AB - Male diploidy was studied in natural populations of the fire ant, Solenopsis invicta, in order to find an explanation from population genetics for the apparently common occurrence of this phenomenon in some North American populations. The association of male diploidy with polygyne (more than one queen per colony) populations in this species led us to expect that the two phenomena are causally linked. We proposed three hypotheses, based on current knowledge of sex-determining mechanisms in the Hymenoptera, to explain the loss of genetic diversity associated with high rates of diploid male production in S. invicta: a) allelic diversity was reduced during colonization of North America by a small founder group; b) allelic diversity was reduced during subsequent subfounding of the several polygyne populations; and c) genetic structuring of polygyne populations due to local inbreeding caused reduced allelic diversity and/or increased homozygosity. An extensive survey revealed that diploid males are common in all four polygyne (P) populations studied, and that none occur in the monogyne (M) population in north-central Georgia. On the other hand, newly mated (i.e., colony-founding) queens from this same M population produced diploid males in the laboratory, and in the Georgia M and P populations, the frequencies of queens that produce diploid males were shown to be similar. We conclude that the frequent production of diploid males in S. invicta has resulted from a loss of allelic diversity during colonization of North America rather than from any special genetic attribute of P populations. We found no evidence for genetic structuring of the Georgia P population or for decreased allelic diversity relative to the Georgia M population. Thus, the exclusive occurrence of diploid males in P populations does not reflect a fundamental difference between P and M populations in the genetic determinants of male diploidy but is, rather, the result of differential mortality of diploid-male-producing colonies of the two forms. In view of these results, the common occurrence of male diploidy in the P form of S. invicta cannot be taken as evidence of a role for kin selection in the evolution of polygyny. (In this paper, "polygyny" is used to refer to a multiple queen society.) Studies of the progeny of single queens with allozyme markers demonstrated that diploid male S. invicta are produced biparentally, as in other hymenopteran species. Diploid males were found to take part in the normal summer mating flights in the Georgia P population, although the significance of this behavior is unknown. Males sampled from two P populations exhibited bimodal size distributions, with the diploid males consistently larger than haploids. Assuming a single locus sex determinant, we estimate 15 alleles at this locus for both forms of the ant in North America. PMID- 28561367 TI - A MOLECULAR APPROACH TO THE ROLE OF HISTORICITY IN EVOLUTION. I. EXPERIMENTAL DESIGN WITH ENZYME POLYMORPHISM IN DROSOPHILA MELANOGASTER. AB - I investigate the role of the past history (characterized by two inverse sequences of three environments) experienced by Drosophila melanogaster populations, on the allozyme frequencies at four loci (alpha-Gpdh, Adh, Est-6, Pgm) in a common and constant final environment. The only locus for which an effect of past history was detected is Adh. Although not unambiguous, this result is discussed in terms of interactions between this locus and other polymorphic loci. For Est-6 and Pgm, no influence of past history was seen. As for alpha Gpdh, the substantial heterogeneity between replicate populations belonging to the same historical series is probably due to a hitch-hiking effect of genes surrounding this locus. More generally, the role of historicity (i.e., the factors originating from the past history of a population and being accountable for its contemporary evolution) in creating genetic diversity between populations and among species is discussed. PMID- 28561368 TI - COMMENT ON MUTAGENESIS AND COMPETITION IN DROSOPHILA. PMID- 28561369 TI - PATTERNS OF CHARACTER DIVERGENCE AND THE EVOLUTION OF REPRODUCTIVE ECOTYPES OF DALECHAMPIA SCANDENS (EUPHORBIACEAE). AB - The variation of four floral characters (resin-gland area, gland-stigma distance, gland-anther distance, and anther-stigma distance) was analyzed across 15 populations of Dalechampia scandens occurring sympatrically, in various combinations, with five other congeners. Univariate and multivariate analysis of variance and a posteriori comparison tests indicate that there are significant statistical patterns of character divergence away from sympatric congeners for three of the floral characters. These characters, which on the basis of common garden studies appear to be under genetic control, may not vary independently; i.e., genetic control may be overlapping. The characters appear to be functionally related. Populations of Dalechampia scandens occurring sympatrically with congeners possessing relatively large resin glands, large gland-stigma distances and large anther-stigma distances (e.g., D. dioscoreifolia and D. affinis) have significantly smaller resin glands, gland-stigma distances and anther-stigma distances than do populations occurring sympatrically with congeners with relatively small resin glands, gland-stigma distances, and anther stigma distances (e.g., D. cissifolia, D. heteromorpha and D. schottii). Populations of D. scandens not sympatric with other Dalechampia species generally have intermediately sized structures. The pattern of bidirectional divergence is consistent with the evolutionary scenario that selection against interspecific pollination has resulted in local ecotypic differentiation and character displacement in populations sympatric with ecologically similar congeners. PMID- 28561371 TI - REDUCTION IN PAGE CHARGES. PMID- 28561370 TI - FORAGING DYNAMICS OF BIRD PREDATORS ON OVERWINTERING MONARCH BUTTERFLIES IN MEXICO. AB - By suspending nets within and adjacent to a 2.25 hectare overwintering colony of monarch butterflies in Mexico, we estimated that black-backed orioles and black headed grosbeaks killed 4,550 to 34,300 and an average of 15,067 butterflies per day. A conservative calculation of mortality through the 135 day overwintering season was 2.034 million butterflies, or about 9% of the colony. The birds preyed selectively upon male butterflies, possibly because of a difference in fat content, or possibly because females contain higher concentrations and larger amounts of cardenolide or other defensive chemicals. The risk to individual monarchs of being killed was much greater on the colony periphery and in thinned areas of the forest. Bird predation thus is sufficient to have played a major role in shaping the evolution of the monarch's overwintering and aggregation behavior. Substantial daily variation in predation intensity occurred, 26% of which was attributable to the birds eating more butterflies on colder days, and 30% of which was attributable to a 7.85 day predation cycle. The hypothesis is put forward that the birds feed cyclically because they build up toxic levels of cardenolides or other defensive chemicals contained in the butterflies. The cyclic predation may reduce total predation on the colony by as much as 50%. Such chemical-based group protection is interpreted as a fortuitous by-product of the evolution of unpalatability through selective processes acting on other phases of the monarch's life history. PMID- 28561372 TI - MxA is a positive regulator of type I IFN signaling in HCV infection. AB - Type I interferons (IFNs) are a family of primordial cytokines that respond to various pathogen infections including Hepatitis C virus (HCV). Type I IFNs signal through Jak/STAT pathway leading to the production of a few hundred interferon stimulated genes (ISGs). The aim of this study was to explore the role of one of these ISGs, MxA in HCV infection and type I IFN production. Plasmid encoding MxA was cloned into PcDNA3.1-3*tag vector and MxA expression was confirmed both at mRNA (RT-PCR) and protein (Western blot, WB) levels. IFNalpha and IFNbeta productions were quantified by RT-PCR from cell lysate and by ELISA kit from culture medium following MxA over-expression in Huh7.5.1 cells. The activation status of Jak/STAT signaling pathway was examined at three levels: p-STAT1 (WB), interferon sensitive response element (ISRE) activity (dual luciferase reporter gene assay), and levels of ISG expression (RT-qPCR). J6/JFH1 HCV culture system was used to study the role of MxA in HCV replication. Our findings indicated that MxA over-expression inhibited HCV replication and potentiated the IFNalpha mediated anti-HCV activity; MxA stimulated the production of IFNalpha, IFNbeta, and enhanced IFNalpha-induced activation of Jak-STAT signaling pathway. We concluded that MxA is a positive regulator of type I IFN signaling in HCV infection. PMID- 28561374 TI - Practical guide for selection of 1 H qNMR acquisition and processing parameters confirmed by automated spectra evaluation. AB - In our recent paper, a new technique for automated spectra integration and quality control of the acquired results in qNMR was developed and validated (Monakhova & Diehl, Magn. Res. Chem. 2017, doi: 10.1002/mrc.4591). The present study is focused on the influence of acquisition and postacquisition parameters on the developed automated routine in particular, and on the quantitative NMR (qNMR) results in general, which has not been undertaken previously in a systematic and automated manner. Results are presented for a number of model mixtures and authentic pharmaceutical products measured on 500- and 600-MHz NMR spectrometers. The influence of the most important acquisition (spectral width, transmitter [frequency] offset, number of scans, and time domain) and processing (size of real spectrum, deconvolution, Gaussian window multiplication, and line broadening) parameters for qNMR was automatically investigated. Moderate modification of the majority of the investigated parameters from default instrument settings within evaluated ranges does not significantly affect the trueness and precision of the qNMR. Lite Gaussian window multiplication resulted in accuracy improvement of the qNMR output and is recommended for routine measurements. In general, given that the acquisition and processing parameters were selected based on the presented guidelines, automated qNMR analysis can be employed for reproducible high-precision concentration measurements in practice. PMID- 28561373 TI - c-Jun N-Terminal Kinases (JNKs) Are Critical Mediators of Osteoblast Activity In Vivo. AB - The c-Jun N-terminal kinases (JNKs) are ancient and evolutionarily conserved regulators of proliferation, differentiation, and cell death responses. Currently, in vitro studies offer conflicting data about whether the JNK pathway augments or represses osteoblast differentiation, and the contribution of the JNK pathway to regulation of bone mass in vivo remains unclear. Here we show that Jnk1-/- mice display severe osteopenia due to impaired bone formation, whereas Jnk2-/- mice display a mild osteopenia only evident in long bones. In order to both confirm that these effects were osteoblast intrinsic and assess whether redundancy with JNK1 masks a potential contribution of JNK2, mice with a conditional deletion of both JNK1 and JNK2 floxed conditional alleles in osteoblasts (Jnk1-2osx ) were bred. These mice displayed a similar degree of osteopenia to Jnk1-/- mice due to decreased bone formation. In vitro, Jnk1-/- osteoblasts display a selective defect in the late stages of osteoblast differentiation with impaired mineralization activity. Downstream of JNK1, phosphorylation of JUN is impaired in Jnk1-/- osteoblasts. Transcriptome analysis showed that JNK1 is required for upregulation of several osteoblast-derived proangiogenic factors such as IGF2 and VEGFa. Accordingly, JNK1 deletion results in a significant reduction skeletal vasculature in mice. Taken together, this study establishes that JNK1 is a key mediator of osteoblast function in vivo and in vitro. (c) 2017 American Society for Bone and Mineral Research. PMID- 28561375 TI - Finding a Trans-Affirmative Provider: Challenges Faced by Trans and Gender Diverse Psychologists and Psychology Trainees. AB - This article explores some of the challenges faced by trans and gender diverse (TGD) individuals who not only are attempting to access trans-affirmative care, but who are also members of the very profession from which they are seeking services. The authors explore challenges related to finding supervision, accessing care for assessment services, and finding a provider for personal counseling. With each example, the authors unpack the challenges and also address the implications for training for all involved. Based on these challenges that TGD psychologists and trainees face in attempting to access care, the authors provide recommendations related to trans-affirmative training for psychologists. PMID- 28561376 TI - Digital story telling in social justice nursing education. AB - OBJECTIVES: The purpose of this study was to explore and evaluate how digital stories integrated into public health nursing education can teach social justice concepts essential for nurse leadership. DESIGN AND SAMPLE: Four digital stories were selected and incorporated into a public health nursing course. Students were asked to reflect on these stories. A retrospective qualitative analysis was completed on the student narrative reflections and analyzed for themes. A total of 108 narrative reflections of public health nursing students were included from 2015 to 2016. RESULTS: Themes were identified based on analysis and include Encountering Vulnerability, Questioning Systems and Choosing Moral Courage. CONCLUSIONS: Digital stories offer an innovative medium to convey the importance of story, advance social justice as an essential practice of nursing, and create opportunities that addresses social justice in nursing and in developing nursing leaders. PMID- 28561377 TI - Country-wide seroprevalence studies on Crimean-Congo hemorrhagic fever and hantavirus infections in general population of Bulgaria. AB - Crimean-Congo hemorrhagic fever (CCHF) and hantavirus infections are the two viral hemorrhagic fevers spread in Europe. To test actual circulation of CCHF virus (CCHFV) and hantaviruses in Bulgaria, we conducted country-wide seroepidemiological studies. Serum samples were collected prospectively from 1500 residents of all 28 districts in Bulgaria. CCHFV seroprevalence of 3.7% was revealed. Anamnesis for tick bites, contact with livestock, age over 40 years and residency in Haskovo district were found as risk factors. The highest CCHFV seroprevalence was observed in the known endemic districts in southeastern Bulgaria: Haskovo (28%) and Yambol (12%). Reactive samples were found in residents of 20 of the 28 districts in Bulgaria. In comparison with the previous studies, the data presented indicate that CCHFV increased substantially its circulation in the endemic regions and was introduced in many new areas. Hantavirus seroprevalence was based on results of the immunoblot and estimated as 3.1%. Surprisingly, contrary to all available data, Puumala virus seroprevalence rate was 2.3% versus 0.8% of Dobrava-Belgrade virus. Evidence for hantavirus IgG seropositivity was found in residents of 23 of the 28 districts in the country. The first hantavirus seroprevalence study in Bulgaria showed that Puumala virus is probably more wide-spread in the country than Dobrava-Belgrade virus. PMID- 28561378 TI - Epidemiology of bloodstream infections after myeloablative and non-myeloablative allogeneic hematopoietic stem cell transplantation: A single-center cohort study. AB - BACKGROUND: Patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) often develop bloodstream infections (BSI). We aimed to describe the etiologies and antibiotic resistance patterns of BSI after allo HSCT, and, as knowledge about the impact of conditioning regimen is limited, we looked at the incidence, timing, risk factors, and mortality of BSI separately for myeloablative (MA)- and non-myeloablative (NMA)-conditioned patients. METHODS: All 460 patients (207 MA- and 253 NMA-conditioned) who underwent their first allo-HSCT at our center from 2008 to 2013 were included in a historical cohort. BSI were registered from initiation of conditioning to day 360 after transplantation. RESULTS: BSI occurred in 34% (95% confidence interval [CI]: 28%, 41%) of MA-conditioned patients and in 17% (95% CI: 12%, 22%) of NMA-conditioned patients. Of all isolates, 68% were gram-positive bacteria (GPB), 23% gram negative bacteria (GNB), and 9% fungi. The GPB/GNB ratio declined from 2008 to 2014 (P for trend <.01). Of all GNB, 47% were multidrug resistant (MDR), but the proportion declined over the study period. In a multivariate Cox regression model, only acute graft-versus-host disease was associated with a higher hazard of first BSI (hazard ratio 2.50, 95% CI: 1.48, 4.21). Overall 30-day survival after a BSI was higher for MA-conditioned patients than for NMA-conditioned patients (89% vs 74%, P=.04). CONCLUSION: MA-conditioned patients experience BSI more often than NMA-conditioned patients in the year after allo-HSCT. While BSI are increasingly caused by GNB, the rate of MDR GNB is declining. PMID- 28561379 TI - Cytotoxic and genotoxic effects of 131 I and 60 Co in follicular thyroid cancer cell (WRO) with and without recombinant human thyroid-stimulating hormone treatment. AB - Normally, differentiated thyroid cancer (DTC) tends to be biologically indolent, highly curable and has an excellent prognosis. However, the treatment may fail when the cancer has lost radioiodine avidity. The present study was carried out in order to evaluate the cytotoxic and genotoxic effects of 131 I and 60 Co and radioiodine uptake in WRO cells, derived from DTC, harboring the BRAFV600E mutation. WRO cells showed a relatively slow cell cycle of 96.3 h with an unstable karyotype containing various double minutes. The genotoxicity assay (micronucleus test) showed a relative high radioresistance to 131 I (0.07-3.70 MBq/mL), independent of treatment with recombinant human thyroid-stimulating hormone (rhTSH). For the cytotoxicity assay, WRO cells were also relatively resistant to 60 Co (range: 0.2-8.3 Gy), but with a gradual decrease of viability as a function of time for higher doses (20 and 40 Gy, starting from the fifth to sixth day). For internal irradiation with 131 I, WRO cells showed a decline in viability at radioactive concentration higher than 1.85 MBq/mL; this was even more effective at 3.70 MBq/mL, but only when preceded by rhTSH, in coincidence with the highest level of 131 I uptake. These data show promising results, since the loss of the ability of thyroid cells to concentrate radioiodine is considered to be one of the main factors responsible for the failure of 131 I therapy in patients with DTC. The use of tumor-derived cell lines as a model for in vivo tumor requires, however, further investigations and deep evaluation of the corresponding in vivo effects. Environ. Mol. Mutagen. 58:451-461, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28561380 TI - Functional Adaptation of the Calcaneus in Historical Foot Binding. AB - The normal structure of human feet is optimized for shock dampening during walking and running. Foot binding was a historical practice in China aimed at restricting the growth of female feet for aesthetic reasons. In a bound foot the shock-dampening function normally facilitated by the foot arches is withdrawn, resulting in the foot functioning as a rigid extension of the lower leg. An interesting question inspiring this study regards the nature of adaptation of the heel bone to this nonphysiological function using the parameters of cancellous bone anisotropy and 3D fabric topology and a novel intertrabecular angle (ITA) analysis. We found that the trabecular microarchitecture of the normal heel bone, but not of the bound foot, adapts to function by increased anisotropy and preferred orientation of trabeculae. The anisotropic texture in the normal heel bone consistently follows the physiological stress trajectories. However, in the bound foot heel bone the characteristic anisotropy pattern fails to develop, reflecting the lack of a normal biomechanical input. Moreover, the basic topological blueprint of cancellous bone investigated by the ITA method is nearly invariant in both normal and bound foot. These findings suggest that the anisotropic cancellous bone texture is an acquired characteristic that reflects recurrent loading conditions; conversely, an inadequate biomechanical input precludes the formation of anisotropic texture. This opens a long-sought-after possibility to reconstruct bone function from its form. The conserved topological parameters characterize the generic 3D fabric of cancellous bone, which is to a large extent independent of its adaptation to recurrent loading and perhaps determines the mechanical competence of trabecular bone regardless of its functional adaptation. (c) 2017 American Society for Bone and Mineral Research. PMID- 28561381 TI - Estrogen-dependent efficacy of limb ischemic preconditioning in female rats. AB - Our aim was to examine the effects of ischemic preconditioning (IPC) on the local periosteal and systemic inflammatory consequences of hindlimb ischemia reperfusion (IR) in Sprague-Dawley rats with chronic estrogen deficiency (13 weeks after ovariectomy, OVX) in the presence and absence of chronic 17beta estradiol supplementation (E2, 20 ug kg-1 , 5 days/week for 5 weeks); sham operated (non-OVX) animals served as controls. As assessed by intravital fluorescence microscopy, rolling and the firm adhesion of polymorphonuclear neutrophil leukocytes (PMNs) gave similar results in the Sham + IR and OVX + IR groups in the tibial periosteal microcirculation during the 3-h reperfusion period after a 60-min tourniquet ischemia. Postischemic increases in periosteal PMN adhesion and PMN-derived adhesion molecule CD11b expressions, however, were significantly reduced by IPC (two cycles of 10'/10') in Sham animals, but not in OVX animals; neither plasma free radical levels (as measured by chemiluminescence), nor TNF-alpha release was affected by IPC. E2 supplementation in OVX animals restored the IPC-related microcirculatory integrity and PMN derived CD11b levels, and TNF-alpha and free radical levels were reduced by IPC only with E2. An enhanced estrogen receptor beta expression could also be demonstrated after E2 in the periosteum. Overall, the beneficial periosteal microcirculatory effects of limb IPC are lost in chronic estrogen deficiency, but they can be restored by E2 supplementation. This suggests that the presence of endogenous estrogen is a necessary facilitating factor of the anti-inflammatory protection provided by limb IPC in females. The IPC-independent effects of E2 on inflammatory reactions should also be taken into account in this model. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:97-105, 2018. PMID- 28561382 TI - Differences in Lip Support with and without Labial Flanges in a Maxillary Edentulous Population - Part 3: Unblinded and Discriminatory Subjective Analysis. AB - PURPOSE: To study the subjective differences in direct lip support assessments and to determine if dentists and laypeople are able to discern and correctly identify direct changes in lip support between flange and flangeless dentures. MATERIALS AND METHODS: A random sample of 20 maxillary edentulous patients described in part 2 of the study was used for analysis. A total of 60 judges comprising 15 general dentists, 15 prosthodontists, and 30 laypeople, the majority of who were distinct from part 2 of the study, were recruited. All images used in this study were cropped at the infraorbital level and converted to black and white tone, to encourage the judges to focus on lip support. The judges were un-blinded to the study objectives and told what to look for, and were asked to rate the lip support of each of the 80 images on a 100 mm visual analog scale (VAS). The judges then took a discriminatory sensory analysis test (triangle test) where they were required to correctly identify the image with a flangeless denture out of a set of 3 images. Both the VAS and triangle test ratings were conducted twice in a random order, and mean ratings were used for all analyses. RESULTS: The overall VAS ratings of lip support for images with flangeless dentures were slightly lower compared to images with labial flanges, and this difference was statistically significant (p < 0.0001). This was true for both profile and frontal images. However, the magnitude of these differences was too small (no greater than 5 mm on a 100-mm scale) to be clinically significant or meaningful. The differences in VAS ratings were not significant between the judges. For the triangle test, judges overall correctly identified the flangeless denture image in 55% of frontal image sets and 60% of profile image sets. The difference in correct identification rate between frontal and profile images was statistically significant (p < 0.0001). For frontal and profile images, prosthodontists had the highest correct identification rate (61% and 69%), followed by general dentists (53% and 68%) and by laypeople (53% and 50%). The difference in correct identification rate was statistically significant between various judges (p = 0.012). For all judges, the likelihood of correctly identifying images with flangeless dentures was significantly greater than 1/3, which was the minimum chance for correct identification (p < 0.0001). CONCLUSIONS: Removal of a labial flange in a maxillary denture resulted in slightly lower ratings of lip support compared to images with a labial flange, but the differences were clinically insignificant. When judges were forced to look for differences, flangeless dentures were detected more often in profile images. Prosthodontists detected the flangeless dentures more often than general dentists and laypeople. PMID- 28561383 TI - Differences in Lip Support with and without Labial Flanges in a Maxillary Edentulous Population. Part 4: Patient-Centered Analysis. AB - PURPOSE: To study the subjective differences in facial esthetics evaluations and the ability to distinguish facial changes due to changes in lip support, when evaluated by patients themselves. An additional objective was to study the differences between patients' self-evaluation versus evaluation of other patients. MATERIALS AND METHODS: A total of 22 maxillary edentulous patients from the original sample of 31 patients described in Part 1 of the study, returned to participate in this part of the study. The 22 patients acted as judges for all images in this study, and were therefore un-blinded to the objectives and details of the study. Patients first completed evaluation of facial esthetics on a visual analog scale (VAS). Four digital images per patient (total of 88 images) were evaluated in a random order, twice by all 22 patients. The mean scores from all judgments were used as the outcomes to be analyzed. All patients then took a discriminatory sensory analysis test (triangle test) where they were required to correctly identify the image with a flangeless denture out of a set of 3 images. Both the VAS and triangle test ratings were conducted twice in a random order, and mean ratings were used for all analyses. RESULTS: For VAS analysis, there were no statistically significant or clinically significant differences in facial esthetics ratings between flange and flangeless dentures (p < 0.05). This was true for both profile and frontal images, irrespective of self-evaluation versus evaluation of other patients, years of patient edentulism, and judge (patient) gender. For the triangle test, frontal images had a correct identification rate of 50.2% and profile images of 50.4%, and the difference was not significant. There were no significant differences in triangle test results with respect to self-evaluation versus evaluation of other patients and judge (patient) gender. For all patients, the likelihood of correctly identifying images with flangeless dentures was significantly greater than 1/3, which was the minimum chance for correct identification (p < 0.0001). CONCLUSIONS: Flangeless dentures resulted in no differences in facial esthetics ratings for frontal and profile images, when evaluated by patients. When patients were forced to look for differences, flangeless dentures were detected in half of the image sets. These findings were similar for self-evaluation versus evaluation of other patients and for both patient genders. PMID- 28561385 TI - The decanalization of weight, recumbent length, and head circumference during infancy. AB - This study has estimated the extent to which 659 infants in the Fels Longitudinal Study maintained their positions in canals on the current NCHS growth charts during 6- and 12-month intervals. These canals are the zones between adjacent major percentile lines (5th, 10th, 25th, 50th, 75th, 90th, and 95th) on the growth charts. The probabilities of increases or decreases in level by two or more canals were calculated. Additionally, the probabilities were calculated for changes in level from between the 5th and 10th percentiles or between the 90th and 95th percentiles to zones beyond the 5th or 95th percentiles, respectively (transitions from normal limits). The analyses were made from birth to 36 months for weight and from 1-36 months for length and head circumference. The probabilities of decanalization were larger for weight than for length or head circumference for the interval from birth to 6 months, but not later. The probabilities for each variable analyzed tended to be large for young age intervals and larger for changes toward the medians than for changes from the medians. The directions of decanalization for weight from birth to 6 months were related to birth weight and those for length were related to midparent stature for the intervals from 6-12 months in each sex, 1-12 months in girls, and 6-18 months in boys. Am. J. Hum. Biol. 9:689-698, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561384 TI - Bone wax extrusion through postauricular wounds: A case series. AB - Bone wax is an effective hemostatic agent that generally is considered safe. However, because it is nonabsorbable, significant complications can occur. We present the first two reported cases of delayed migration and extrusion of bone wax through postauricular wounds due to foreign body reaction and granuloma formation following mastoid surgery. We also present a literature review of complications associated with intraoperative bone wax use and discuss alternative hemostatic agents. Laryngoscope, 128:369-372, 2018. PMID- 28561386 TI - Principal components analysis of morphological measures in the Quebec family study: Familial correlations. AB - Principal components analysis was carried out on 13 morphological dimensions collected in the first phase of the Quebec Family Study (weight, height, fat mass (FM), fat-free mass (FFM), body surface area, six skinfolds, arm and calf girths). The first four principal components (PCs) account for 85.9% of the total phenotypic variance in the anthropometric dimensions. The first PC has almost equal loadings on the 13 variables, indicating its role as an overall body size and adiposity measure. This interpretation is supported by its high intraindividual correlations with other composite indices such as the BMI and sum of six skinfolds (SF6). An interesting finding compared to other studies dealing with PCs of only skinfolds is that the second component appears to contrast measures of body fat with those that are fat free or that represent overall body size, thus indexing a different dimension to the fat patterning. It explains 17% of the total phenotypic variance. The commonly observed component for the trunk extremity contrast is represented as the fourth principal component. The third component primarily indexes height, although an extremity-trunk contrast is also weakly represented. Together, the 3rd and 4th components explain ~10% of the total variance. The intraindividual correlation of PC3 with the trunk-extremity skinfold ratio (TER) is moderately negative (-0.307), whereas that of PC4 is highly positive (0.764). Analysis of familial correlations (parent-offspring and sibling) shows that the familial effect (transmissibility) ranges 0.43-0.75 for the first four PCs. The lack of significant spouse correlation for most of the PCs suggests that these familial effects may be primarily genetic. Am. J. Hum. Biol. 9:725-733, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561387 TI - Secular changes in stature, weight, fatness, overweight, and obesity in urban African American adolescents from the mid-1950's to the mid-1990's. PMID- 28561388 TI - Delayed visuomotor development in children born to adolescent mothers. AB - The objective of the present study was to determine visuomotor development of children born to adolescent mothers and to compare it with that observed in those born to adult mothers. The sample included 59 urban Mestizo children, 7-8 years of age, who were born to adolescent mothers, and 73 urban Mestizo children of the same age, who were born to adult mothers (>20 years). Visuomotor development was assessed using the Bender test. Children born to adolescent mothers had a higher number of errors in the Bender Gestalt scores compared to those obtained by children born to adult mothers. Items of perseverance and integration in the Bender-Gestalt test were the most affected in children born to adolescent mothers. Of the children born to adolescent mothers, 13.8% repeated a school grade compared to 4.3% of children born to adult mothers (P < 0.01). Differences in sociocultural circumstances between the adolescent and adult mothers may have influenced the results. Nevertheless, children born to adolescent mothers have delayed visuomotor maturation and a low performance at school. Am. J. Hum. Biol. 9:717-723, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561390 TI - The effect of maternal nutritional variables on birthweight outcomes of infants born to Sherpa women at low and high altitudes in Nepal. AB - A prospective, longitudinal study was conducted in Nepal to investigate the effects of maternal nutrition on the pregnancy outcome of Sherpa women living at low and high altitudes. It was hypothesized that variation in nutrition and energy expenditure of pregnant women would correlate with variation in infant birthweight. Anthropometric dimensions, energy consumption and expenditure, and demographic and migration information were collected on a large sample of women living in two regions of Nepal: the Khumbu region (3480-3930 m) and Kathmandu (1330 m). This paper reports findings for a subset of the sample; 17 women at low altitude and 21 women at high altitude who became pregnant and were followed during pregnancy. The results showed no significant differences for mean birthweights between the low (X = 3069 +/- 341 grams) and high (X = 3099 +/- 483 grams) altitude samples. Furthermore, larger birthweights were associated with larger weight gains during pregnancy for the high altitude sample. A stepwise regression analysis found a negative association between high energy expenditures during the second trimester and infant birthweight, but positive associations were found between third trimester calcium and second trimester protein intakes and birthweight. Prepregnancy BMI and stature were associated positively with infant birthweight, suggesting that good nutritional status prior to pregnancy may play an important role in pregnancy outcome for this population. Am. J. Hum. Biol. 9:751-763, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561389 TI - Seasonal height velocity variation in boys and girls 8-18 years. AB - This study investigated the seasonal variation in height velocity during the summer and winter months. The subjects were healthy children, 109 boys and 119 girls, 8.5-18.0 years of age who are part of an ongoing longitudinal study of bone mineral accrual. Anthropometric dimensions were taken twice a year, in the fall in conjunction with the annual bone assessment measures and 6 months later. Six-month velocities for height were calculated, which produced 982 velocities in boys and 1043 velocities in girls. Over the age range studied, summer velocities accounted for at least 67% of the total yearly growth in boys and 60% of the total yearly growth in girls. Separate two-way ANOVAs (season by age) were used to compare the summer and winter velocities over half-yearly age increments in both sexes. Season and age effects were significant (P < 0.01), but the interaction effect was not significant. The seasonal differences converged in the later years when the summer and winter velocities decreased to zero. The results demonstrate the importance of considering seasonal variation in height velocity in designing studies and in assessing and interpreting growth data. Am. J. Hum. Biol. 9:709-715, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561391 TI - Estimation of the optimum density of the Selk'nam from Tierra del Fuego: Inferences about human dynamics in extreme environments. AB - The Selk'nam, a hunter-gatherer group that inhabited Isla Grande (Tierra del Fuego), became extinct soon after coming into contact with Europeans (XIX century). The population of this tribe was estimated from mission archives and the application of a hunter-gatherer ecological model. Both approaches suggest that the widely accepted number of 3,500-4,000 individuals for this human group is an overestimation, and that 1,500 may be more accurate. This yields a population density of 0.04 persons/km2 , a very low value, but which is in accordance with the extremely harsh environment. The low population density was an essential adaptive strategy to the complex ecological equilibrium of Tierra del Fuego. Indirectly, this factor may have contributed to the rapid disappearance of this population with the breakdown of the traditional way of life. In addition, the missionary registers show that most of the aborigines died of infectious diseases, a situation exacerbated by the high population density in the missions. The reconstruction of the decline of the Selk'nam population may be used to evaluate the impact of European contact on other American hunter-gatherer groups and also to elucidate the adaptive patterns of human groups in adverse environments. Am. J. Hum. Biol. 9:699-708, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561392 TI - Worldwide genetic diversity at the HLA-DQA1 locus. AB - Genotype, gene, or phenotype frequency data, obtained by PCR analysis with sequence specific oligonucleotide probes at the HLA-DQA1 locus, in 176 population samples, each consisting of 30 or more individuals, from all around the world were analyzed. The sampled populations were assigned to the following nine groups: African, Afro-American, American Native, American Mestizo, Asian, American Caucasian, European Caucasian, Caucasian from other regions, and Pacific Islanders. Observed genotype proportions agreed with Hardy-Weinberg expectations (HWE) in 90 of the 102 populations for which genotype data are available. The 12 discordant population samples were of substantial mixed origin. For these discordant populations, 41 of the 252 (population by genotype) data points showed significant departures of the observed frequencies in comparison to their HWE predictions. The deviations, by and large (38 of the 41), were in the direction of HWE over-estimating the actual genotype frequencies. Total heterozygosity (HT ) at a worldwide level was 79%, and varied from 56% in American Natives to >80% in Caucasians. Of the total diversity, 94.4% was due to intra-population and 5.6% to inter-population variation (FST ), partitioned into 3.0% inter-population within groups and 2.6% inter-group variation. FST for the locus was high among Africans and American Natives (>9%) and low in Afro-Americans and American Caucasians (<0.5%). The range for allele specific FST was 0.2% to 5.9%, and the lowest value did not correspond to the same allele in all nine groups. A variance component analysis of allele frequencies showed no relationship of the ratio of between/within group variation with the world average frequency of the respective alleles. The first three principal components explained 36.2%, 27.5%, and 22.9% of the total allelic diversity, respectively. For Caucasian and Afro-American samples, the first two PCs formed clusters by groups. In contrast, the American Native, Asian, and Pacific Islander groups showed a greater inter-population diversity, while the corresponding principal component scores of the American Mestizo samples were between American Natives and Caucasians. In aggregate, the analyses indicate that genetic drift in contrast to natural selection, more readily explains the pattern of worldwide diversity at the HLA-DQA1 locus. Am. J. Hum. Biol. 9:735-749, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561393 TI - Decanalization of weight and stature during childhood and adolescence. AB - The probabilities that children and adolescents alter their positions to non adjacent canals (decanalization) on the current NCHS growth charts have been estimated. In this context, canals are the zones between the major percentile levels (5th, 10th, 25th, 50th, 75th, 90th, and 95th) that are shown on the charts. These probabilities were calculated for one- and 2-year intervals, beginning at each annual age from 3-16 years, using serial data for weight and stature from 329 male and 303 female participants in the Fels Longitudinal Study. The probabilities of particular types of decanalizations, categorized by the initial canal and the direction of the change in relative level (decrease/loss; increase/gain) are presented. The probabilities for 1-year intervals were very low and, therefore, they are not presented. Additionally, probabilities were calculated for transitions from the canal between the 5th and 10th percentiles to the zone below the 5th percentile and from the canal between the 90th and 95th percentiles to the zone above the 95th percentile. Both these transitions are shifts to levels that are outside the normal range, and are more common than decanalization. The probabilities of decanalization and of transitions from the normal range were generally larger for weight than for stature except for transitions from the canal between the 90th and 95th percentiles to the zone beyond the 95th percentile. The probabilities for both weight and stature tended to be larger for changes toward the medians than for changes from the medians. Decanalizations that involved increases in level were significantly related to advanced skeletal maturation at ages younger than the usual age of peak height velocity and to retarded skeletal maturation at ages older than the usual age of peak height velocity. Am. J. Hum. Biol. 10:351-359, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561394 TI - Spectral and bout detection analysis of physical activity patterns in healthy, prepubertal boys and girls. AB - Little is known about the frequency-intensity patterns of naturally occurring physical activity in children. A data set obtained previously by direct observation of physical activity in 8 girls and 7 boys (all prepubertal, ages 6 10) was analyzed with spectral analysis to detect significant frequency-intensity relationships. Pulse detection algorithms were used to characterize the number of exercise bouts, their duration and relative intensity. Spectral analysis revealed that physical activity bouts were frequent, pulsatile, and random with no significant frequencies detected during many 24-min periods of observation. An average of 83 +/- 11 bouts per hour were observed in boys and 89 +/- 12 bouts per hour in girls, and the mean duration of an exercise bout was 21 +/- 5 sec for boys and 20 +/- 4 sec for girls (NS). While high-intensity exercise bouts comprised less than 20% of the time spent in physical activity, duration of high intensity exercise bouts tended to be longer and accounted for about 40% of the energy expenditure associated with physical activity. Spontaneous physical activity in prepubertal children is characterized by frequent bouts of brief, mostly low intensity exercise, randomly interspersed with less frequent, but metabolically substantial high intensity bouts. These findings are potentially useful in assessing the impact of disease on quality of life in children, investigating the relationship between physical activity and mechanisms of growth and development, and creating new approaches for in-laboratory exercise testing in children. Am. J. Hum. Biol. 10:289-297, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561395 TI - Birth ponderal index and body mass index reference curves in a large population. AB - A file of 100,716 children born between 1984 and 1988 in 22 maternity wards was used to estimate for each week of gestational age and gender, the exponent beta which makes an index Weight/Lengthbeta independent from length. It varied with gestational age but remained near 3. Therefore, Rohrer's index (Weight/Length3 ) appears as a good approximation to assess neonatal weight as a whole, taking length into account. However, literature suggests that Quetelet's index (Weight/Length2 ) might be a better indicator of fat mass. In both cases, percentile curves take gestational age into account. Curves by gestational age between 32 and 42 weeks of amenorrhea and by gender, for Quetelet's and Rohrer's indices have been plotted. The values vary with gestational age. For example, the tenth percentile of Quetelet's index shifts from 7.8-12.3 kg/m2 in boys and from 7.9-12.2 kg/m2 in girls. Am. J. Hum. Biol. 10:327-340, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561396 TI - Physical fitness and body composition in relation to physical activity in prepubescent Senegalese children. AB - Relationships among estimated body composition, habitual physical activity, and physical fitness were considered in Senegalese children 8.5-13.5 years of age. Anthropometric dimensions (arm and calf circumferences, trunk, and extremity skinfolds, body mass index), four motor performances (dash, standing long jump, throw, grip strength), a step-test (cardiorespiratory fitness), and heart rate (HR) monitoring (physical activity) were collected in 140 children (66 boys and 74 girls). Age and sex had a major effect on indicators of body composition and physical fitness. Height stunting used as an indicator of chronic undernutrition had a remarkable effect on body composition but only a limited influence on physical fitness. Physical activity, represented by percentage of time above the flex-HR (%fHR), did not vary with sex, age, and nutritional status. However, there was a low-to-moderate correlation between %fHR and several body composition indices, grip strength, and cardiorespiratory fitness. Comparisons of children in the upper and lower quartiles of %fHR indicated that better indices of body composition in boys, and better strength and cardiorespiratory fitness in girls were positively associated with a higher level of physical activity. Am. J. Hum. Biol. 10:385-396, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561398 TI - Transcutaneous electrical muscle stimulation does not alter regional arm adiposity and muscularity. AB - The present study evaluated the effects of an electrical muscle stimulation (EMS) training protocol claimed to elicit site-specific fat reduction and muscle hypertrophy. The protocol includes 6 weeks (3 sessions/week, 10 contractions/session) of high frequency (2500 Hz) transcutaneous EMS training on upper arm muscle and fat tissue. Two groups of 10 subjects were stimulated either on the dominant biceps brachii (B) or triceps brachii (T). The non-dominant arm served as a control. Post-training measures of upper arm fat and muscle tissue evaluated with girths, skinfolds, and ultrasound measures of fat did not change following EMS training of the treatment and control arms (p > 0.05). Upper arm x ray measurements to estimate total upper arm volume, muscle plus bone volume, and fat volume also did not change significantly for groups B and T following training (p > 0.05). The results thus indicate no selective upper arm muscle hypertrophy or site-specific fat reduction with high frequency EMS training of healthy muscle. Am. J Hum. Biol. 10:317-326, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561397 TI - Frequency of color blindness among Nigerian school children in Lagos. AB - Plates 1-15 of the Ishihara tests for color blindness were administered to 5,580 boys and 5,405 girls in primary and secondary schools in Lagos. The difference between males and females in the frequency of total color blindness was not significant. The frequency of total color blindness among the children was 0.19%. However, the frequencies of red-green color blindness, which were 3.60% and 0.81% among the males and females, respectively, were significantly different. Deutans occurred at a higher frequency than protans among both male and female red-green color blind individuals, but the differences among males and also females were not significant. In addition, there was no significant difference between the sexes in the occurrence of deutans and protans. Although the frequency of red green color blindness detected among males in this study is significantly lower than that reported for Lagos in another survey, which gave a frequency similar to that for Caucasians, the frequency obtained in the present study is similar to frequencies reported for other populations of Blacks of African Ancestry. Am. J. Hum. Biol. 10:283-288, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561399 TI - Validity of published prediction equations for body composition in high altitude Bolivian Aymara as evaluated by doubly labeled water. PMID- 28561400 TI - Response. PMID- 28561401 TI - Urbanization and child growth in Nepal. AB - The growth of children (0-60 months) of rural-to-urban migrant women was studied in a population of carpet-making workers in a peri-urban community of Kathmandu, Nepal. Mean height-for-age (HAZ) and weight-for-age (WAZ) z-scores are compared for two groups of children belonging to recent urban migrant women (resident <5 years) and to long-term migrants (resident ?5 years). The process of urbanization and adaptation to the city environment was explored by examining cohort differences in health care utilization, diarrheal morbidity, breastfeeding practices, demographic, and socioeconomic characteristics. On average, both children of recent and long-term migrants have moderate-to-severe linear growth retardation after 12 months of age. There is, however, a statistically significant difference in mean HAZ and WAZ scores between children depending on maternal length of urban residence status; children of long-term migrants have better growth status compared to children of recent migrants. Nevertheless, there are no significant differences between long-term and recent migrant families in terms of socioeconomic characteristics and selected biobehavioral practices which have been associated with modernization and adaptation to an urban environment. It is concluded that the process of adaptation to an urban environment cannot be explained by standard biobehavioral indicators of modernization and requires further consideration. Am. J Hum. Biol. 10:307-315, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561402 TI - Effects of ethnicity, gender, obesity, and age on central fat distribution: Comparison of dual x-ray absorptiometry measurements in white, black, and Puerto Rican adults. AB - Population based studies relying primarily upon anthropometric surrogates of fat distribution have shown that central or upper-body adiposity is related to ethnicity, gender, age, and total body fatness. As an improvement over anthropometry, dual x-ray absorptiometry (DXA) provides more precise measurements of fat mass (FM) in the total body and trunk. DXA was performed on 510 apparently healthy White (81 females (f), 64 males (m)), Black (94 f, 79 m), and Puerto Rican (102 f, 100 m) adults aged 20-75 years in order to determine and compare the effects of race, gender, age, and total FM on trunk FM. Trunk FM was greater for Blacks and Puerto Ricans than Whites, irrespective of gender (P < 0.014). Puerto Rican males and females had a greater proportion of fat in the trunk (%TrFM) than Whites or Blacks (P < 0.001), and Whites and Blacks were similar with respect to %TrFM (P > 0.67). Females had less %TrFM than males in all three ethnic groups (all P < 0.001). Based on multiple regression analysis, ethnicity did not affect the relationship of trunk and total FM among males (P > 0.16), but the coefficient for total FM was larger for Puerto Rican compared to Black females (P = 0.043). Trunk FM increased with age in Whites and Puerto Ricans (P < 0.02), but not Blacks (P > 0.24). The effects of age did not differ by gender or ethnicity among Whites and Puerto Ricans (P > 0.10). Adjustment for total FM and age eliminated ethnic and gender differences in trunk FM (all P > 0.37). The results suggest that the high levels of central adiposity observed among Blacks and Hispanics relative to Whites reflect patterns of generalized obesity observed in the respective populations. Patterns of accumulation of truncal FM with increasing age and obesity may not be generalizable to all ethnic groups. Am. J. Hum. Biol. 10:361-369, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561403 TI - Letter to the editor. PMID- 28561404 TI - Comparison of five-site skinfold thicknesses in late pregnancy vs early postpartum. AB - To test the hypothesis that the sum (?) of five skinfold thicknesses in the immediate postpartum period is significantly less than that obtained in the last month of pregnancy in healthy American women, a standardized approach was used to measure skinfold thicknesses at five sites in 81 healthy, active women. Measures were obtained in the last month of pregnancy and again in the first month postpartum. Prior to pregnancy the subjects ranged in age from 24-39 years and weighed between 45-87 kg. The ? of five skinfold thicknesses ranged between 34 and 162 mm. During pregnancy, weight gain ranged between 6.5-24.6 kg with a mean gain of 14.5 kg. The ? of five skinfold thicknesses peaked between 8-36 weeks gestation and the peak increase ranged from -19 mm to +63 mm above preconceptual levels. In late pregnancy, the ? of five skinfold thicknesses ranged between 34.1 and 166.8 mm (mean = 91.7 mm), and postpartum, the range and mean values were similar (38.1-156.4 mm, and 91.8 mm). When values obtained in late pregnancy are compared with those obtained postpartum, the r2 value was 0.9122. There was also good correlation at each of the skinfold sites (r2 's = 0.8001-0.9239), except the abdomen (r2 = 0.6049). In conclusion, the hypothesis is incorrect; the ? of five skinfold thicknesses in the immediate postpartum period is as acceptable a measure of late pregnancy subcutaneous fat deposition and/or retention as that obtained in the last month of pregnancy in present day healthy American women. Am. J Hum. Biol. 10:299-305, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561406 TI - Apparatus for precision calibration of skinfold calipers. AB - Despite the fact that skinfold calipers are widely used to measure subcutaneous adipose tissue, the current methods of calibration are quite crude. Methods such as hanging masses from the caliper jaws until they remain open, lack validity and reliability because the caliper jaws are stationary instead of dynamic, and the opening jaws give an upscale reading of the jaw gap not a downscale reading that occurs when the calipers are being used to measure skinfolds. This report describes how to build an apparatus capable of measuring static and dynamic, upscale and downscale jaw pressures of a variety of caliper types and also provides guidelines specifically for calibration and servicing of Harpenden calipers. The key areas to maintain are the caliper springs (which should have spring coefficients ranging 1.104-1.153 N.mm-1 ), the pivot joint (which should operate smoothly), the indicator mechanism (which should require only 0.78-0.88 N for full movement), and the jaw alignment which should be square to ensure that the full effective jaw surface area of 90 mm2 is applied to the skinfold. While there are insufficient data at this time to prescribe rigid calibration criteria, assessment of approximately 100 new and used Harpenden calipers indicates that, after servicing, the important dynamic downscale jaw pressure will range 7.7-8.4 g.mm-2 at 5 mm of jaw gap and 7.3-8.0 g.mm-2 at 40 mm of jaw gap. Dynamic upscale jaw pressure should be within 1.0-1.5 g.mm-2 of the corresponding dynamic downscale jaw pressure. Am. J. Hum. Biol. 10:689-697, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561405 TI - Somatotype and indicators of metabolic fitness in youth. AB - The relationship between physique and metabolic fitness was examined in a sample of 413 boys and 343 girls 9-18 years of age from Phase I of the Quebec Family Study. Physique was assessed using the Heath-Carter anthropometric somatotype. Indicators of metabolic fitness were plasma triglyceride levels (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL C), and blood glucose levels (GLY). The sample was divided into three age groups, 9-12, 13-15, and 16-18 years of age. A partial canonical correlation analysis was used to quantify the relationship between the standardized somatotype and metabolic fitness variables (z-transformed) with age as the covariate. In both boys and girls the first canonical correlation is significant (P ? 0.001) and indicates a relationship between the physique and metabolic fitness variables. By age group, the 16-18 year old boys, and the 9-12, 13-15, 16-18 year old girls demonstrate significant canonical correlations (P ? 0.03). Overall, 8% to 19% of the variance in metabolic fitness can be explained by the Heath-Carter anthropometric somatotype. The makeup of the canonical variates is similar for all age groups. Generally, the physique domain is characterized by a positive loading for ectomorphy and negative loadings for endomorphy and mesomorphy. The metabolic fitness domain has a positive loading for HDL-C and negative loadings for TG, LDL-C, and GLY. The results suggest that in youth 9-18 years, a physique characterized by high endomorphy and mesomorphy is associated with higher levels of TG, LDL-C, and GLY, and lower levels of HDL-C. Am. J. Hum. Biol. 10:341-350, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561407 TI - The contribution of adolescent growth to shorter adult statures among girls of Chinese ancestry. AB - Researchers have hypothesized that shorter mean statures at onset of the adolescent spurt and more rapid skeletal maturation during adolescence among East Asian populations contribute significantly to their shorter mean adult statures compared to European populations. The goal of this study is to use longitudinal height growth data modeled with the Preece-Baines Model 1 (PB1) function to examine the relative importance of adolescent growth to population differences in adult stature. Biological variables for 303 Chinese females from the Da-an District in Taipei, Taiwan, are compared with those for 23 British and 69 Euro American females. Results indicate that 96% of the difference in adult statures (4.37 cm) between the British and urban Chinese may be attributed to the greater amount of time available to the British for preadolescent growth. Growth during adolescence between these two groups is not significantly different. When comparisons are made with the Euro-American sample from Berkeley, California, only about 26% of the difference in adult stature (6.96 cm) may be attributed to the later age at take-off. Much (53.2%) of the difference has already accrued by take-off among the Chinese. Small, but statistically significant differences in adolescent growth also exist. When considered within the context of other longitudinal studies of European and American females, this study gives only modest support to the hypothesis that more rapid skeletal maturation leads to reduced amounts of adolescent growth among East Asian populations. Interestingly, though, population differences do appear to exist in the relationship between the relative timing of an individual's growth spurt and spurt intensity. Am. J. Hum. Biol. 10:735-746, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561408 TI - Fat distribution in relation to sex and socioeconomic status in children 4-19 years. AB - Fat distribution was studied in an urban sample of boys and girls 4.5 to 19.5 years from the Basque province of Biscay by means of Principal Component Analysis (PCA) of five skinfolds. The PCA extracted four components, which explained 99.1% of the total variance. The first principal component revealed strong stability across age and sex, and was related to a pattern of central body fat distribution. The three other components, upper-lower trunk fat, lateral-medial trunk fat, and upper-lower extremity fat, showed poor stability due largely to the influence of age and, to a lesser degree, sex. In both sexes, individual scores of the four factors did not show multivariate differences by socioeconomic status when a MANOVA with age, age2 and age3 as covariates was done. Nevertheless, the first factor scores were significantly higher only in the poorer socioeconomic group of girls. The results are explained in the context of either different lifestyles related to socioeconomic status, a protective effect against environmental stress on urban males, or greater plasticity of trunk fat relative to extremity fat in females. Am. J. Hum. Biol. 10:799-806, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561409 TI - Malaria infection and human behavioral factors: A stochastic model analysis for direct observation data in the Solomon Islands. AB - The effect of human behavior on malaria infection was investigated in a holoendemic area in the Solomon Islands, using a newly developed mathematical model based on the results of blood examinations and 2 weeks of direct observations. The present study indicated that the place where individuals spent the evening had no significant relation to malaria infection, but that some kinds of clothes significantly reduced malaria infection. However, as the result of prediction by the Susceptible-Exposed-Infective-Recovered (SEIR) model, effective control of malaria transmission would require as much as 95% coverage by protection even in the case that the protective measure was highly effective. The results strongly suggested protection measures besides bed net distribution in addition to the necessity of health education. Am. J. Hum. Biol. 10:781-789, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561410 TI - Proceedings of the Human Biology Association 23rd Annual Meeting, March 30-April 1, 1998, Salt Lake Hilton Hotel, Salt Lake City, Utah. PMID- 28561411 TI - Enamel hypoplasias related to famine stress in living Chinese. AB - The relationship between linear enamel hypoplasia (LEH) and nutritional stress caused by a grave historical famine (1959-1961) was investigated among contemporary Chinese. Based on dental observations in a sample of 3,014 subjects from rural and urban China, and data on famine stress from a variety of historical sources, hypotheses regarding the relation between LEH and nutritional stress were tested. Famine stress raised LEH prevalence significantly in the birth cohorts having their teeth developing during famine years; therefore, a correlation between nutritional stress and formation of LEH as suggested by previous studies was indicated. Rural subjects had significantly higher LEH prevalence than urban subjects, and this was attributed to poorer nutritional and living conditions in rural areas. Males had a slightly higher LEH prevalence than females, so that female biological buffering to environmental stress appears to have outweighed possible cultural practice of daughter neglect in this difference. Am. J. Hum. Biol. 10:723-733, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561412 TI - The influence of relative age on success and dropout in male soccer players. AB - The consistent asymmetry in the birth-date distribution of senior professional soccer players has led us to investigate whether similar asymmetries emerge throughout youth categories in soccer. Birth dates were considered for professional players, national youth teams, youth players transferred to top teams, and regular youth league players. Kolmogorov Smirnov tests assessed differences between observed and expected birth-date distributions. Regression analyses examined the relationship between month of birth and number of participants at various levels of play in soccer. Results indicated that youth players born from August to October (the early part of the selection year), beginning in the 6-8 year age group, are more likely to be identified as talented and to be exposed to higher levels of coaching. Eventually, these players are more likely to be transferred to top teams, to play for national teams, and to become involved professionally. In comparison, players born late in the selection year tended to dropout as early as 12 years of age. Recommendations suggest a review of the 24-month age band and current methods for talent detection and selection. Am. J. Hum. Biol. 10:791-798, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561413 TI - Secular change in running performance of Japanese adolescents: A longitudinal developmental study. AB - A 5-year longitudinal cohort study of the running development of Japanese adolescents was conducted at a secondary school in Tokyo from 1968 to 1994. The purpose was to investigate changes in the pattern of development over time. The test items were an endurance run (1,500 m for boys and 1,000 m for girls) and a dash (50 m for both sexes). The total number of subjects was 512 boys and 516 girls in the endurance run, and 825 boys and 895 girls in the dash. These students entered the first grade of the school from 1968 to 1989 at the age of 12 years, and were followed for the next 5 years. In the analyses, a quadratic regression model was used to characterize intra-individual, age-related changes in running performance. The model fit the observed data, and the validity of the model was confirmed. Secular changes in the running development of boys were minimal over the last 30 years. Changes in girls, however, had three different patterns: 1) an overall decrease in performance with an almost unchanged estimated performance in the first grade, 2) a greater decrease in the late teenage years, and 3) a decrease in the age of maximal performance. Secular changes in physical growth (stature and body mass index) could not fully explain the secular changes in the running development of girls, suggesting that the underlying causes may be social and cultural. Am. J. Hum. Biol. 10:765-779, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561414 TI - Protein genetic studies among the Tupi-Monde Indians of the Brazilian Amazonia. AB - A sample of 417 individuals belonging to three Tupi-Monde-speaking tribes (Gaviao, Surui, Zoro) were variously studied in relation to 26 genetic protein systems. Previous investigations performed among the Surui in relation to some of these systems were confirmed. The three groups do not depart markedly from the genetic pattern already established for South American Indians and show low inter ethnic admixture. When these results are combined with those from 10 other Tupi tribes, two clear geographic groupings (southeastern and northwestern) can be discerned. Using different methods to evaluate the same genetic distance matrices, different patterns of association between the Tupi-Monde populations were obtained. The populations are probably too similar among themselves, blurring finer relationships. Am. J. Hum. Biol. 10:711-722, 1998. (c) 1998 Wiley Liss, Inc. PMID- 28561415 TI - Growth rates of children of subsaharan African ancestry born to immigrant parents and of French children in Paris. AB - This comparative survey is based on two populations of children born and raised in Paris or the Paris area: 320 French children and 129 children whose parents are both of African ancestry from the Subsaharan area. They are part of a first generation born outside of their respective countries. A longitudinal study of growth from birth to four years of age shows population differences. The length and weight at birth of full-term African babies are significantly less than of French newborns. But, African infants catch-up quickly and reach the same length as French infants during the first month of life; their weight is already significantly greater than that of French infants from 1 to 6 months. The body mass index (BMI, W/H2 ) during the breast-feeding period indicates that the infants are of well nourished status. After the first year of life, the means for the BMI of the children born to Subsaharan immigrant parents are lower than means for French children. This suggests poorer nutritional status, which may be associated with the marginal socioeconomic status of African families living in the Paris area. Am. J. Hum. Biol. 10:757-763, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561416 TI - Household headship and nutritional status: Female-headed versus male/dual-headed households. AB - Approximately one-third of all poor urban households in Latin America are headed by females. This study compares the nutritional status of women and children from female-headed (FHH) and male/dual headed (MHH/DHH) households in economically disadvantaged neighborhoods in Cali, Colombia. Data collected included socioeconomic indicators, anthropometric dimensions, dietary intake, and interviews documenting household composition. Classification of household headship was based on the acknowledged head and the primary economic provider of the household. Of the households in this study, 81 (80%) were from MHH/DHHs and 20 (20%) from FHHs. FHHs had fewer material possessions and lived in houses made of less expensive materials compared to MHH/DHHs. However, there were no significant differences in the nutritional status of women or children in FHHs vs MHH/DHHs. Most women had BMIs within the normal range (19-29 kg/m2 ). The majority of children (95%) had weight-for-height z-scores within +/-2 of the NCHS references. These results suggest that while FHHs in Cali were economically poorer, the women studied appeared to have had access to sufficient food sources for themselves and their children. Am. J. Hum. Biol. 10:699-709, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561417 TI - Second metacarpal cross-sectional geometry: Rehabilitating a circular argument. AB - Radiogrammetry of the second metacarpal has long served as a measure of normal and abnormal bone growth and aging, functional asymmetry, and fracture risk in osteoporosis. The method relies on algebraic interpretation (circular or elliptical models) of uni- or biplanar radiographic images. This paper tests the conformance of these models with actual measures of metacarpal geometric variation in a sample of 356 bones from an historic archaeological sample. Both the circular and elliptical models significantly over-estimate actual values for all variables (e.g., total area (3.05% and 9.42%, respectively) and cortical area (7.25% and 12.25%), bending rigidity about the mediolateral (13.88% and 20.92%) and anteroposterior axes (17.35% for the elliptical model). The greater degree of systematic bias found for the elliptical model is contrary to results of an earlier study (Lazenby, 1997), and suggests that sample composition can influence the method error associated with a particular approach. The import of radiogrammetric bias will depend on the degree of shape variation among samples compared (e.g., left vs right, male vs female, etc.), which in most cases cannot be predetermined. Consequently, reduced major axis equations were derived from regressing actual on estimated values for total area (TA), cortical area (CA) and two measures of bending rigidity (Ix, Iy) in order to permit adjustment for radiogrammetric error associated with these algebraic models. Application of these formulae to a hold-out sample showed no significant differences between actual and predicted values. Am. J. Hum. Biol. 10:747-756, 1998. (c) 1998 Wiley Liss, Inc. PMID- 28561418 TI - Heritability of hippocampal subfield volumes using a twin and non-twin siblings design. AB - The hippocampus is composed of distinct subfields linked to diverse functions and disorders. The subfields can be mapped using high-resolution magnetic resonance images, and their volumes can potentially be used as quantitative phenotypes for genetic investigation of hippocampal function. We estimated the heritability of hippocampus subfield volumes of 465 subjects from the Human Connectome Project (twins and non-twin siblings) using two methods. The first used a univariate model to estimate heritability with and without adjustment for total brain volume (TBV) and ipsilateral hippocampal volume to determine if heritability was uniquely attributable to subfield volume rather than confounds that attributed to global volumes. We observed the right: subiculum, cornu ammonis 2/3, and cornu ammonis 4/dentate gyrus subfields had the highest significant heritability estimates after adjusting for ipsilateral hippocampal volume. In the second analysis, we used a bivariate model to investigate the shared heritability and genetic correlation of the subfield volumes with TBV and ipsilateral hippocampal volume. Genetic correlation demonstrates shared genetic architecture between phenotypes and shared heritability is what proportion of the genetic architecture of one trait is shared by the other. Highest genetic correlations were between subfield volumes and ipsilateral hippocampal volume than with TBV. The pattern was opposite for shared heritability suggesting that subfields share greater proportion of the genetic architecture with TBV than with ipsilateral hippocampal volume. The relationship between the genetic architecture of TBV, hippocampal volume, and of individual subfields should be accounted for when using hippocampal subfield volumes as quantitative phenotypes for imaging genetics studies. Hum Brain Mapp 38:4337-4352, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28561419 TI - Endothelial cells co-cultured with renal carcinoma cells significantly reduce RECK expression under chemical hypoxia. AB - Renal cell carcinoma (RCC) is characterized by excessive angiogenesis, while chronic kidney disease (CKD) suffers from the opposite problem-failure of reparative angiogenesis. It can be due to their different responses to hypoxic environment. But the specific molecular regulators are still unclear. This study is aimed to explore the influence of human renal cell cancer cells (786-0) and human renal tubular epithelial cells (HK-2) on RECK expression, proliferation, and angiogenesis of adjacent microvascular endothelial cells (HMEC-1) under chemical hypoxia. Cobalt chloride (CoCl2 ) treatment was used to simulate the hypoxia environment in RCC and CKD. Co-culture, cell proliferation assay, and tube formation assay were used to evaluate the influence of 786-0 or HK-2 cells on proliferation and angiogenesis of adjacent HMEC-1 cells. Effects of different environments on RECK expressions in 786-0, HK2, or HMEC-1 cells were determined by Western blot. We found that both 786-0 cells and HK2 cells can upregulate RECK expression of adjacent HMEC-1 cells in normoxic conditions. However, under hypoxia, the HMEC-1 cells co-cultured with 786-0 significantly reduced RECK expression and there was no significant change in HMEC-1 cells co-cultured with HK2 cells. We also found that 786-0 significantly enhanced the proliferation and angiogenesis of adjacent HMEC-1 cells. Our results suggested that some paracrine substances produced by 786-0 cells may reduce RECK expression of adjacent HMEC-1 cells and enhance their proliferation and in vitro angiogenic capacity. PMID- 28561420 TI - Cab4b, the first human platelet antigen carried by glycoprotein IX discovered in a context of severe neonatal thrombocytopenia. AB - : Essentials Life-threatening maternofetal thrombocytopenias mostly depend on alphaIIb beta3 antigens. We performed serological, genomic and in vitro studies of two life-threatening thrombocytopenias. Identification of a c.368C>T variation leading to Pro123Leu substitution in GPIX. A rare GPIX variant reported in a genomic database define a new alloantigen. SUMMARY: Background After three miscarriages, a 39-year-old woman gave birth, with a 1-year interval, to two severely thrombocytopenic neonates (4 *109 L-1 and 33 *109 L-1 ) with intracranial hemorrhages. Transfusion of platelet concentrates corrected the thrombocytopenia. The outcome was favorable for the first child, but the second one died 10 days after cesarean delivery (31 weeks of gestation + 6 days). Methods Serologic studies were performed with mAb-specific immobilization of platelet antigens and flow cytometry techniques. Human platelet alloantigen (HPA) genotyping was performed with the BioArray HPA BeadChip and PCR-sequence-specific primer techniques. Genomic DNA was studied by direct sequencing of PCR products. The mutant glycoprotein (GP) was expressed in transiently transfected HEK293 cells. Results In MAIPA assay, the maternal serum faintly reacted with GPIbIX from paternal and child 1 platelets, but not with maternal or panel platelets. No maternofetal incompatibility was found in the 22 known HPA systems, tested except for HPA-1b in child 2. A new alloantigen carried by GPIbIX was suspected. Genomic sequencing revealed a paternal GPIX variation (NM_000174.4:c.368C>T). The father and children were heterozygous and incompatible with the mother, who was NM_000174.4:c.368C homozygous. The maternal serum reacted with the GPIX NP_000165.1:p.Leu123 form coexpressed with GPIb in transfected HEK293 cells. The NM_000174.4:c.368T allele (rs202229101) has a minor allele frequency of 0.0002, and was not detected in 120 French subjects (families with fetal and neonatal alloimmune thrombocytopenia [FNAIT]), suggesting that it is rarely implicated in alloimmunization. Conclusion The NP_000165.1:p.Leu123 allele named Cab4b is the first platelet alloantigen described on GPIX. In the absence of other known maternofetal incompatibility, the child 1 case suggests that anti-Cab4b alloantibodies can induce severe thrombocytopenias. PMID- 28561422 TI - Determinants of breastfeeding in four Canadian Ojibwa communities: A decision making model. AB - A prospective cohort study was conducted to determine the patterns of breastfeeding and factors associated with breastfeeding choice and duration among Canadian Aboriginal (Ojibwa) women from third trimester to 12 weeks postpartum. The survey included demographic, obstetric and infant feeding information, measures of "breastfeeding beliefs," "breastfeeding confidence," and "referent support." Thirty-six Treaty-status women, living in or near four Manitoba First Nations communities, were interviewed prenatally and subsequently gave birth to a live infant between December 1993 and June 1994. Demographic, obstetric and infant feeding information from 20 women who missed the prenatal interview were obtained retrospectively. The overall response rate was 98% of eligible women. Outcome measures included initiation and duration of breastfeeding. Explanatory variables included factors associated with breastfeeding initiation/duration, based on a revision of the Ajzen and Fishbein (1980) decision-making model. Breastfeeding rates were 57% (initiated), 44% (week 1), 32% (week 4), and 18% (week 12). The decision-making model demonstrated construct validity for breastfeeding choice. Multivariate modelling indicated "prenatal intent" and "breastfeeding confidence" as best predictors of breastfeeding choice. Best predictors of duration were "satisfaction with breastfeeding at 2 weeks" and "postpartum referent scores." "Satisfaction" was negatively correlated with the number of verbalized problems. Reasons for weaning included "insufficient milk" and "soreness." Community intervention programs could focus on breastfeeding beliefs, confidence and referent support, and decrease early weaning by screening for preventable problems. Am. J. Hum. Biol. 9:579-593, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561423 TI - Assessment of motor ability of 4- and 5-year-old children. AB - The aim of this investigation was to develop a test battery to measure the motor abilities of 4- and 5-year-old children. The subjects were 932 healthy kindergarten children from Tartu, Estonia: boys, 4 years, n = 205; boys, 5 years, n = 267; girls, 4 years, n = 224; girls, 5 years, n = 236. Height and body mass were measured, and the body mass index (BMI, kg/m2 ) was calculated. The following motor ability tests were used: 3-min run (cardiorespiratory endurance), standing long jump (explosive strength), 4 * 10 m shuttle-run (running speed, agility), situps for 30 sec (trunk strength), sit-and-reach (flexibility), and sand bag (150 g) throw with the dominant hand (explosive strength, coordination). The motor tests were repeated 1 week later in subgroups of 28-33 children. Most of the tests had an acceptable reliability (r > 0.75) and none had a poor reliability (r < 0.40). There were significant (P < 0.05-0.001) differences between 4- and 5-year-old boys and girls in all tests except the sit-and-reach between the 4- and 5-year-old girls. Performances of boys were generally better than those of girls of the same age. Test results were often dependent on height and body mass, but not on the BMI. When body size and age were statistically controlled with second-order partial correlations, the relationships were greatly reduced or no longer significant. Stepwise regression analysis revealed that age, height, and mass of the children accounted for only a small percentage of the variance in performances. The greatest contribution to total variance was accounted for by body size in the 3-min run in 4-year-old boys (6%). Am. J. Hum. Biol. 9:659-664, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561421 TI - Pharmacokinetics of Transdermal Etofenamate and Diclofenac in Healthy Volunteers. AB - Little is known about the course of the plasma concentration and the bioavailability of non-steroidal anti-inflammatory drugs (NSAIDs) contained in dermal patches. We compared an etofenamate prototype patch (patent EP 1833471) and a commercially available diclofenac epolamine patch regarding the bioavailability of the active ingredients relative to respective i.m. applications and regarding their plasma concentration-time course. Twenty-four healthy human volunteers were treated using a parallel group design (n = 12 per group) with a single dermal patch (removed after 12 hr) followed (after a latency of 48 hr) by eight consecutive dermal patches every 12 hr to reach steady-state conditions. The patches were generally well tolerated, but one volunteer treated with etofenamate developed an allergic contact dermatitis. After the first patch, Cmax was 0.81 +/- 0.11 (mean +/- S.E.M.) ng/mL (reached 12 hr after patch removal) for diclofenac and 31.3 +/- 3.8 ng/mL for flufenamic acid (reached at patch removal), the main metabolite of etofenamate. Etofenamate was not detectable. After repetitive dosing, trough plasma concentrations after the eighth dose were 1.72 +/- 0.32 ng/mL for diclofenac and 48.7 +/- 6.6 ng/mL for flufenamic acid. Bioavailabilities (single dose) relative to i.m. applications were 0.22 +/- 0.04% for diclofenac and 1.15 +/- 0.06% for flufenamic acid. In conclusion, the relative bioavailability (compared to the respective i.m. application) of both drugs is low. The maximal plasma concentrations after topical administration of these drugs are well below the IC50 values for COX-1 and COX-2, explaining the absence of dose-dependent toxicities. PMID- 28561424 TI - Body composition and blood pressures in school children 6-14 years of age. AB - The relationship between parameters of estimated body composition (FFM = fat free mass, FM = fat mass, %F = percentage fat) and blood pressure was examined in a sample of 1418 school-children (712 males, 706 females), 6-14 years of age from L'Aquila and its province (Abruzzo), Italy. Systolic and diastolic blood pressures increased from 6-14 years in both sexes (males: systolic pressure 93.08 +/- 14.95 to 122.29 +/- 13.27 mm Hg; diastolic pressure: 59.60 +/- 11.60 to 74.83 +/- 8.35 mm Hg; females: systolic pressure: 97.12 +/- 13.16 to 120.56 +/- 8.02 mm Hg; diastolic pressure: 61.93 +/- 10.23 to 76.67 +/- 4.85 mm Hg). FFM and FM estimated by anthropometry and bioelectrical impedance, exhibited similar growth trends (Anthropometry: in males, FFM: 20.55-47.20 kg and FM: 4.14-12.01 kg; in females, FFM: 19.95-41.90 kg and FM: 5.03-15.84 kg; Impedance: in males, FFM: 18.40-47.30 kg and FM: 6.26-11.91 kg; in females, FFM: 17.47-36.97 kg and FM: 7.61-20.77 kg). Correlations between body composition parameters and blood pressures were generally significant. In particular, there was a strong relationship between systolic blood pressure and both FM and %F, the correlations being higher when the body composition parameters were estimated by anthropometry. Am. J. Hum. Biol. 9:535-544, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561425 TI - Assessment of body composition by using a new chart method. AB - The body mass index (BMI, weight/height2 ), is commonly used as a simple and valid way of assessing body composition. However, the significance of the BMI is not clear, since body mass is composed of two main components: fat-free mass (FFM) and fat mass (FM), each with different densities. In order to graphically present body composition as a quantitative measure, a chart based on the fat-free mass index (FFMI, FFM/height2 ) and fat mass index (FMI; FM/height2 ), as reported in a previous paper (Hattori, J. Anthropol. Soc. Nippon 99:141-148, 1991), was revised by adding information on both the percentages of body fat (%fat) and the BMI. The benefit of the new chart method is its simplicity which comes from the application of two variables on a two dimensional chart. The chart containing the lines of %fat and the BMI can be of use in detecting multiple aspects of body composition since it provides four pieces of information at the same time: FMI, FFMI, BMI, and %fat. Am. J Hum. Biol. 9:573-578, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561426 TI - Fat-free mass and fat mass in active boys during adolescence. AB - Longitudinal body composition data were examined in 24 active and 10 control boys between the ages of 12.3 and 15.3 years. The main objectives were (1) to contrast the distance and velocity curves of fat-free mass (FFM) and fat mass (FM) in active and control groups using chronological and maturity bases, and (2) to compare the timing and magnitude of peak velocities in FFM and FM in relation to those of body mass. FFM was greater in active than control boys irrespective of whether data were aligned according to chronological age (CA), peak height velocity (PHV), or peak FFM velocity. When aligned on CA there was a tendency for FM to be greater in the control group. There were definitive adolescent spurts in body mass and FFM in both active and control groups. The spurt in FFM was significantly greater in active than control boys around the time of PHV (-0.5 to +0.5 yr PHV). Fat velocities declined in the active group and increased in the control group. The pooled data showed no significant differences in the ages at which peak velocities occurred in height, body mass, FFM, or FM. It was concluded that (1) the tendency for active boys to have a larger FFM and a smaller FM is influenced by increased physical activity, and (2) the ages at PFV and PFFMV occur at the same time as the age at PBMV, and that these events coincide with the age at PHV. Am. J. Hum. Biol. 9:617-627, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561427 TI - Comparative study of flex heart rate in colombian children and in pregnant, lactating, and non-pregnant, nonlactating women. AB - The heart rate (HR) value employed to separate resting and active portions of the calibration curves used to estimate energy expenditure (EE) from minute-by-minute HR recordings is called the flex-HR. The present study has characterized it, the resting HR and the average daily HR during the awake portion of the day (12-14 h) by comparing age, gender and nutritional status effects related to measured maximum oxygen consumption (V O 2 max; ml/min/kg body weight)in school-aged Colombian children (145 boys and 132 girls), 6-16 years of age. The same HR variables have been individually measured in nutritionally normal, nonpregnant, nonlactating (NPNL; n = 48), pregnant (n = 26), and lactating (n = 18) women, 19 43 years of age, on three occasions separated by 3 months. In general, the flex HR followed the differences observed in resting and average daily HRs. All three values decreased with age in children, were higher in girls than boys, and did not exhibit differences between nutritionally normal and undernourished children. All three HRs had a statistically significant negative relationship with V O 2 max in boys but not in girls. NPNL and lactating women showed no significant change in the mean values of the repeated HR measurements but exhibited maximum individual differences of flex-HR of -56 to +42 beats/min. Pregnant women had higher HRs in all 3 rounds of measurement compared to NPNL subjects. The data support the generalization that the flex-HR method of estimating EE is appropriate in groups of subjects but not in individuals, and that individual calibration of subjects close to the time of application to the making of EE measurements is an important feature of its use. Am. J. Hum. Biol. 9:647-657, 1997. (c) Wiley-Liss, Inc. PMID- 28561428 TI - Characteristics of young men with clustering risk factors for coronary heart disease: The cardiovascular risk in young finns study. AB - The majority of coronary heart disease (CHD) arises from a population with only moderately elevated risk factor levels. This study addressed the issue of whether clustering of moderately adverse levels of serum low density lipoprotein cholesterol (LDL-C), serum high density lipoprotein cholesterol (HDL-C), and diastolic blood pressure (DBP) was detectable in children and young adults. Significant clustering of these factors was observed in young men (ages 18-24 years) (Observed/Expected [O/E] ratio = 1.5, p = 0.014), whereas in young women or children no clustering greater than due to chance was found. In males, clustering tended to increase with age. Compared to young women, young men had a higher relative intake of dietary fat, and smoked and used alcohol more often. Compared to men without risk factors, the men at risk were significantly more obese, consumed more dietary fat, and smoked more often. The highest degree of clustering was seen in the highest quartile for the subscapular skinfold thickness (O/E ratio = 2.4). In conclusion, high LDL-C, low HDL-C, and high DBP cluster in young adult males. The clear sex difference observed in clustering may be one of the causes for the susceptibility of adult men to CHD. Am. J. Hum. Biol. 9:565-571, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561429 TI - Evaluation of a dermatoglyphic index to detect placental type variation in MZ twins. AB - A dermatoglyphic index, which was previously used retrospectively to assess relationships between placental type in MZ twins with other variables, was tested for verification in two new separate samples of twins of known placental type. In both a French twin sample (19 monochorionic and 24 dichorionic) and the U.S. twin sample (49 monochorionic and 22 dichorionic), dermatoglyphic index scores were higher in monochorionic than dichorionic pairs. The difference in scores attained statistical significance when the two new samples were pooled. It is concluded that although the index cannot be used retrospectively to classify an individual MZ twin pair, an association of the placental type dermatoglyphic score with another variable in a group of MZ twins without any placentation information provides support for continuing to investigate prenatal effects on the associated variable. Am. J. Hum. Biol. 9:609-615, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561430 TI - PI, GC, HP, and TF serum protein polymorphisms in Siena, Tuscany, Italy, with a review of data for Italy. AB - The genetic polymorphism of four serum proteins (PI, GC, HP, and TF) is analyzed in a sample of 200 unrelated individuals from the province of Siena, Tuscany, central Italy. Siena is traditionally divided into 17 Contrade, that act as social units. The aim of this report is to ascertain whether this peculiar organization has led to genetic differentiation among the inhabitants of each Contrada and from other populations of Italy. For this purpose, the frequencies of genetic markers found in Siena are also compared with those reported for the same serum proteins in Italy based on provincial samples from the literature. The statistical analyses (heterozygosity estimates, F-statistics, and cluster analysis) suggest that the Contrade represent only a cultural and historical institution without biological consequence and that the Italian population can be considered genetically homogeneous. Am. J. Hum. Biol. 9:629-646, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561431 TI - Combined effects of the tempo of maturation and mid-parent height on the shape of individual growth curves. AB - The concurrent effects of mid-parent height and tempo of maturation on variation of the individual growth curve were examined. Data of 183 boys from the Wroclaw Growth Study were used. The functional and biological parameters were derived from fitting Preece-Baines model 1 to individual data. All subjects were divided into three categories of mid-parent height and maturation rate, resulting in nine groups. MANOVA showed significant differences in the functional and biological parameters for three maturity and mid-parent height groups, separately. However, insignificant interactions indicated independence of the two factors. Univariate analysis revealed that the first factor (tempo of maturation) adjusts time and velocity at the beginning (T1, V1) and peak (T2, V2) of the adolescent growth spurt. This factor accounts for the shape of the curve. It places the curve along age and velocity axes. The other factor (mid-parent height) is responsible for general elevation of the growth curve on the centile distribution, placing it on the appropriate centile. This regulates height parameters, i.e., height at take off (H1), height at peak height velocity (H2), and adult height (AH). The simultaneous influence of the two factors leads to estimation of a more specific and more probable type of a curve. This kind of the estimation allows diminishing variance and prediction error. Am. J. Hum. Biol. 9:555-563, 1997. (c) 1997 Wiley Liss, Inc. PMID- 28561432 TI - Estimation of inbreeding, kinship, genetic distances, and population structure from surnames: The island of Hvar, Croatia. AB - The aim of this study was to estimate inbreeding, kinship, genetic distances, and population structure of the island of Hvar using surnames of the population from 10 villages. Total inbreeding on the island, estimated from the frequency of isonymous marriages, amounted to 0.0228. Total kinship (unreduced variance) of the entire island amounted to 0.0411, a value indicative of very isolated populations with accumulated kinship over time. The analysis of genetic relationships based on surnames among the villages did not reveal the division of the island's villages into two clusters, "eastern" and "western", as was the case in previous studies when clustering was based on biological, biocultural, and sociocultural traits. In addition, kinship and genetic distances determined from surnames revealed a poor fit to an isolation by distance model (for kinship, R2 = 14.6%, a = 0.1101, b = 0.3573; for genetic distances, R2 = 0.0%, a = 0.5686, b = 121.52), which is in contrast to the results of previous analyses based on other traits. In order to estimate how closely parameters obtained from surnames represented real interpopulational distances, matrices of kinship and genetic distances between 10 villages (determined from surnames) were correlated to corresponding distance matrices based on migrational, sociocultural, anthropometric, physiological, dermatoglyphic, and genetic traits that were previously reported in the literature on the very same samples. The kinship matrix correlated poorly with other distance matrices, while the genetic distance matrix determined from surnames was in a good correlation with distance matrices based on linguistics (r = 0.65 for basic and r = 0.63 for cultural vocabulary), metacarpal bone dimensions (r = 0.54) and genetics (determined from systems of erythrocyte antigens and isoenzymes, r = 0.45). Am. J. Hum. Biol. 9:595-607, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561433 TI - On the relationship between pregnancy weight gain and chorioamnionitis. AB - Chorioamnionitis refers to infection of the amniotic fluid by such agents as Streptococcus sp., E. coli and Ureaplasma sp. It has not only been linked to the risk of premature rupture of the membranes and preterm delivery, but also to increased morbidity and mortality among neonates born to mothers with such infections. The possible association between maternal gestational weight gain and chorioamnionitis was examined in data using a case sample of 62 and control sample of 168 Israeli women. Univariate analysis demonstrated a significant increase in the incidence of chorioamnionitis among mothers delivering before 33 weeks gestation who displayed inadequate gestational weight gain according to the IOM standards. Comparison of logistic regression analyses between mothers who developed chorioamnionitis at different stages of their pregnancies, controlling for the effects of maternal anthropometric, sociodemographic, and obstetric factors, showed that inadequate weight gain significantly increased the risk of chorioamnionitis among those delivering very prematurely. The differences in significant risk factors suggest the possibility that pre- and full-term chorioamnionitis may not have the same etiologies. Am. J. Hum. Biol. 9:545-553, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561436 TI - Silver(III)???Silver(III) Interactions that Stabilize the syn Form in a Porphyrin Dimer Upon Oxidation. AB - The interaction between two AgII porphyrins, connected covalently through a highly flexible ethane bridge, in a metalloporphyrin dimer has been investigated upon stepwise oxidation. X-ray structure determination of one and two-electron oxidized complexes has clearly revealed only metal-centered oxidation that results in short Ag-N (porphyrin) distance with large distortion in the porphyrin macrocycle. The 2e-oxidized complex exhibits significant metallophilic interaction in the form of a close AgIII ???AgIII contact that brings two porphyrin rings more cofacial with syn-conformation, which would otherwise stabilize in an anti-form. The interaction also leads to an intense emission peak at 546 nm at 77 K in the photoluminescence study. PMID- 28561435 TI - Comparing methods for fetal fraction determination and quality control of NIPT samples. AB - OBJECTIVE: To compare available analysis methods for determining fetal fraction on single read next generation sequencing data. This is important as the performance of non-invasive prenatal testing (NIPT) procedures depends on the fraction of fetal DNA. METHODS: We tested six different methods for the detection of fetal fraction in NIPT samples. The same clinically obtained data were used for all methods, allowing us to assess the effect of fetal fraction on the test result, and to investigate the use of fetal fraction for quality control. RESULTS: We show that non-NIPT methods based on body mass index (BMI) and gestational age are unreliable predictors of fetal fraction, male pregnancy specific methods based on read counts on the Y chromosome perform consistently and the fetal sex-independent new methods SeqFF and SANEFALCON are less reliable but can be used to obtain a basic indication of fetal fraction in case of a female fetus. CONCLUSION: We recommend the use of a combination of methods to prevent the issue of reports on samples with insufficient fetal DNA; SANEFALCON to check for presence of fetal DNA, SeqFF for estimating the fetal fraction for a female pregnancy and any Y-based method for estimating the fetal fraction for a male pregnancy. (c) 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd. PMID- 28561437 TI - Ratiometric Fluorescent Probes for the Detection of Reactive Oxygen Species. AB - Reactive oxygen species (ROS) are endogenously produced oxidants with various functions ranging from host defense to signaling. These transient species can cause severe damage to the body when their production is dysregulated or when environmental factors elevate their concentrations. To study their effects and prevent oxidative harm, tools capable of monitoring ROS in cells and tissue in a sensitive and selective fashion are required. In this Review, a summary of existing ratiometric probes is provided, together with a critical discussion of selected examples. PMID- 28561434 TI - Intracellular origin and ultrastructure of platelet-derived microparticles. AB - : Essentials Platelet microparticles play a major role in pathologies, including hemostasis and thrombosis. Platelet microparticles have been analyzed and classified based on their ultrastructure. The structure and intracellular origin of microparticles depend on the cell-activating stimulus. Thrombin-treated platelets fall apart and form microparticles that contain cellular organelles. SUMMARY: Background Platelet-derived microparticles comprise the major population of circulating blood microparticles that play an important role in hemostasis and thrombosis. Despite numerous studies on the (patho)physiological roles of platelet-derived microparticles, mechanisms of their formation and structural details remain largely unknown. Objectives Here we studied the formation, ultrastructure and composition of platelet-derived microparticles from isolated human platelets, either quiescent or stimulated with one of the following activators: arachidonic acid, ADP, collagen, thrombin or calcium ionophore A23187. Methods Using flow cytometry, transmission and scanning electron microscopy, we analyzed the intracellular origin, structural diversity and size distributions of the subcellular particles released from platelets. Results The structure, dimensions and intracellular origin of microparticles depend on the cell-activating stimulus. The main structural groups include a vesicle surrounded by one thin membrane or multivesicular structures. Thrombin, unlike other stimuli, induced formation of microparticles not only from the platelet plasma membrane and cytoplasm but also from intracellular structures. A fraction of these vesicular particles having an intracellular origin contained organelles, such as mitochondria, glycogen granules and vacuoles. The size of platelet derived microparticles depended on the nature of the cell-activating stimulus. Conclusion The results obtained provide a structural basis for the qualitative differences of various platelet activators, for specific physiological and pathological effects of microparticles, and for development of advanced assays. PMID- 28561438 TI - A case of caecal perforation treated by laparoscopic caecectomy - a video vignette. PMID- 28561439 TI - Relative and interacting effects of sex, race, and environment upon body cell mass in healthy adults. AB - Most epidemiologic studies in nutrition have concentrated on body fat and obesity because of associated health risks, while few studies have examined factors that influence body cell mass (BCM). The relative influences of sex, race, environment, and age upon BCM were compared by analyzing the results of bioimpedance analyses in two cohorts of 1094 healthy adults, including Africans in Zaire, plus African Americans and Caucasians in New York City. Men were taller, heavier, and had a larger BCM and fat-free mass (FFM) than women, while women had more fat than men. African American men and women had more BCM, FFM, and fat than Africans. In contrast, BCM and FFM were not different in African Americans and Caucasians, and body fat was higher only in African American than in Caucasian women. Sex influenced the effects of environment and race, since the majority of the weight differences in men were in FFM, while the majority of the weight differences in women were in fat. The effect of sex upon BCM was stronger than the effects of environment (p < 0.001) or race (p < 0.001), and the effect of environment was stronger than the effect of race (p = 0.012), so that the relative strengths were sex > environment > race. Race had a stronger effect upon FFM than upon BCM. Since race did not affect BCM significantly, it may affect other components of FFM, e.g., extracellular water or solids, such as skeletal mass. The results demonstrate that sex affects normal body composition to a greater degree than race or environment. Am. J. Hum. Biol. 10:259-268, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561440 TI - In-depth study of breastfeeding structure: New data from Mali. AB - A number of variables, including ethnic affiliation, time of day, infant and maternal ages, and infant dietary supplementation, are used to compare their effects on breastfeeding structure of two groups of rural Malian women. The agro fishing Bozo and the transhumant pastoralist Fulbe live in the Inner Niger Delta of Mali. On-demand breastfeeding is practiced by these groups. Lactation continues throughout the infant's second year of life and often into the third. Comparisons are made with data from other traditional societies to highlight differences in breastfeeding structure and its determinants. Ethnic affiliation does not have any significant effect on nursing variables, and the suckling patterns of the Fulbe and Bozo women are comparable in this study. Suckling activity does not vary according to time of day, although individual women exhibit different temporal patterns of nursing behavior. Infant age is significantly and negatively correlated to session duration. As infants get older and their diets are supplemented with food other than breastmilk, their appetites decrease and, consequently, they suckle less. However, there is much individual variation in this relationship, and it is argued that the decrease in suckling due to supplementation may be offset by an increase in suckling due to infants demanding the breast for physical affection. Maternal age, in contrast, is not correlated with any nursing variable in this study. This indicates that there is no decrease in physiological capacity to provide milk and that access to surrogate caretakers is either not correlated with maternal age, or is not a strategy employed by these women. Am. J. Hum. Biol. 10:179-190, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561441 TI - Stunting in an Andean community: Prevalence and etiology. AB - The magnitude and potential causes of linear growth retardation in a rural agricultural community of the Ecuadorian Andes are examined. Growth stunting is common in this population, as height-for-age Z-scores (HAZ) for boys and girls 1 5 years average -2.2 and -2.0, respectively. Dietary analyses suggest multiple nutrient deficiencies. The diet appears to be moderately deficient in energy, protein, calcium, and vitamin A, and more severely limiting in zinc. Additionally, analyses of the local water supply and household hygiene indicate that risk of infection is relatively high among this population. Of the 23 days for which water quality was monitored, slight Escherichia coli contamination was observed on 13 days (57%), and moderate contamination was seen once (4%). Overall, it appears that growth faltering in this population reflects the synergistic effect of mild-to-moderate malnutrition and disease. It is unlikely that malnutrition alone is sufficient to explain the degree of stunting seen in this and other Andean populations. Rather, the stress of coping with chronic disease in the presence of malnutrition may contribute to early childhood growth faltering and compromise potential catch up growth later in life. Am. J. Hum. Biol. 10:229-240, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561442 TI - Anthropometric determinants of risk factors in an African American population. AB - This study assessed the association of biological markers, including cholesterol, HDL, LDL, triglycerides, ApoA-1, and ApoB, with estimates of the body composition, including the conicity index (CI), BMI, bioelectrical impedance analysis, and the waist-to-hip ratio (WHR). One hundred-twenty-six African American adults (43-males, 83-females) from a public housing community in the District of Columbia were recruited. Females were four times more likely to be obese than were males. Among the four anthropometric indicators, the WHR was the best method to explain the variances in biological markers, including cholesterol and ApoB levels in females. The CI showed relationships with log triglyceride levels in females, while percentage body fat (%BF) explained the variances of log HDL and log ApoA-1 in males. For cholesterol, log triglycerides and ApoB, mean values were positively associated with tertiles of the WHR, whereas mean values of log HDL and log ApoA-1 were negatively associated with tertiles of %BF. The WHR and CI, indicators of relative body fat distribution, are more related to risk factors for CVD and diabetes among females than is the BMI. Am. J. Hum. Biol. 10:249-258, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561443 TI - Medical ethnobiology of the highland Maya of Chiapas, Mexico: The gastrointestinal diseases. PMID- 28561444 TI - Butterfat feeding in early infancy in african populations: New hypotheses. AB - The feeding of butterfat and animal milk to infants during their first 6 months has been documented in a number of pastoralist populations in Africa and elsewhere. In the view of the majority of nutrition scientists and physicians, this practice heightens the risk of malnutrition and infection for the infant. Where these nonbreastmilk foods are used to replace breastmilk, this view certainly is justified. In high-risk populations who use foods such as butterfat as complements to unrestricted breastfeeding, however, the relationship between early supplementation and infant growth and morbidity may be complex. Moreover, it may be mediated by the nutritional status of mothers and the nutritional adequacy of their breastmilk. In this work, the ecological context of butterfat feeding in Turkana, Kenya, is examined. It is argued that butterfat promotes positive infant energy balance prior to the critical period of the transition to active immunity, which occurs during the stressful dry season. Breastmilk alone may be inadequate to sustain growth and fat storage of young infants, since the diet and nutritional status of Turkana mothers suggest that fat content of their milk may be at the low end of the human range. In an environment where selection pressure is assumed to be high, a strategy of complementing the fat in human milk with butterfat may prolong positive energy balance of infants and enhance their resistance to infection and their survival during the critical period. Hence, it is an important component of human adaptation in Turkana. Am. J. Hum. Biol. 10:163-178, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561445 TI - Ecology of breastfeeding in the United States: An applied perspective. AB - Breastfeeding initiation and duration have followed distinct cycles in the United States. Despite recent increases, breastfeeding rates still fall short of public health goals. This paper takes an applied perspective to examine the potential role of human biologists in enhancing the promotion of breastfeeding in the United States. The conceptual model of breastfeeding held by policy makers and public health professionals is distinguished from that of human biologists. An integrated model is proposed that incorporates the sociodemographic factors of the public health model with the components of breastfeeding structure and early mother-infant interaction of the human biology model. It is suggested that human biologists can contribute to the more effective promotion of breastfeeding by promoting inclusion of a wide range of anthropological research on infant feeding, clarifying the vocabulary of infant feeding, and expanding their own research to include participation in the development and testing of breastfeeding interventions. Am. J. Hum. Biol. 10:221-228, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561446 TI - Hydration as a limiting factor in lactation. AB - A relatively untapped area of research concerning lactation and hydration exists for bioanthropologists interested in the ecology of breastfeeding. This review details current limited knowledge on the topic with recommendations about relevant research questions for human biologists. On average, lactating mothers produce >750 ml/day milk for their infants. Breastfeeding thus promotes a powerful thirst stimulus in the lactating mother, resulting in a 12-16% increase in fluid intake among Western women. Thirst during lactation may be mediated by oxytocin release, since this hormone is structurally similar to the antidiuretic hormone, vasopressin. Prolactin also may be involved. A few studies among Western women concluded that moderate dehydration does not affect milk production, but it is not known how lactating women in hot and/or dry climates respond to chronically limited water supplies. Lactating women in such environments may use both physiological and behavioral adaptations to conserve fluid requirements, such as reducing activities during breastfeeding and carrying extra fluid supplies while travelling. Given the limited state of knowledge on lactation and hydration, future field studies should incorporate research to determine the importance of adequate fluids in maintaining milk production and the health of both mothers and infants. Am. J. Hum. Biol. 10:151-161, 1998. (c) 1998 Wiley Liss, Inc. PMID- 28561447 TI - Bacterial toxins and enteral feeding of premature infants at risk for necrotizing enterocolitis. AB - Bacterial translocation and enteral feeding are factors implicated in neonatal necrotizing enterocolitis (NEC) in the preterm infant. A cohort of 60 preterm low birth-weight (LBW) infants (600-1,600 g at birth) consecutively admitted to the neonatal intensive care unit (NICU; N = 183) were prospectively followed to evaluate the role of bacterial endotoxins (lipopolysaccharides) and enteral feeding in the development of NEC. Stage I NEC was identified in 14/60 (23%) infants. In all, 15% (9/60) of infants followed, which represented roughly 5% of higher risk, LBW infants admitted to the NICU, progressed to Stage II or III NEC disease. Infants not enterally fed (nothing by mouth [NPO]) were at greatest risk of developing NEC. No infant who was breast milk fed progressed to Stage II or III NEC. The protective effect of breast milk was most evident when compared with the combined group of NPO or formula-feeding infants per person-week at risk (RR = .15, P < .04). Toxin-producing bacteria and endotoxin levels in stool filtrates predicted early and advanced stages of NEC disease. Cytokine concentrations (interleukin-6 [IL-6]) in stool appeared of limited value in reflecting mucosally limited disease in the gastrointestinal tract. Overgrowth of toxin-producing bacteria and their toxin products may adversely affect gut barrier function; monitoring endotoxin concentrations in stool filtrates may be most clinically useful in NPO and formula-fed infants identified at risk of developing NEC. Am. J. Hum. Biol. 10:211-219, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561448 TI - Ecology of breastfeeding: Approaches toward improvement of women's and children's health. AB - It is well established that breastfeeding has significant benefits for infant health and plays an important role in regulating maternal fecundity. However, many questions remain regarding the mechanisms underlying these relationships and the sources of the observed variation among individuals and populations. For example, women of seemingly comparable breastfeeding magnitude and nutritional status display substantial heterogeneity in the duration of postpartum subfecundity. This variation may be related to breastfeeding structure, which in turn is the consequence of variation in ecological conditions. In addition to theoretical questions, it is essential that efforts are directed toward addressing the issues of improving women's and children's health. Women have multiple roles and obligations, including a responsibility for their own well being as well as that of their children. Women also have a right to determine the course of action most appropriate for themselves. Under suitable conditions, breastfeeding is the best choice for the well-being of both the mother and infant; hence, provided with these conditions most women will choose to breastfeed. Working within an ecological perspective, human biologists have an opportunity to bridge the gap between theoretical and practical issues by conducting research that also contributes to the advocacy of women's and children's health. Am. J. Hum. Biol. 10:145-149, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561449 TI - Biological and behavioral factors influence group differences in prolactin levels among breastfeeding Nepali women. AB - This study of two natural fertility Nepali groups, the Tamang and Kami, identifies biological and behavioral factors associated with population differences in fertility. Previous research had established that Tamang experience longer interbirth intervals than Kami despite similarly intense nursing practices, and bear considerably higher energy expenditure due to workload. This cross-sectional study of 71 breastfeeding women includes prolactin determinations on three blood spot samples collected 5, 30, and 50 minutes following a timed nursing bout, and data on maternal age, BMI, menstrual status, previous birth interval, parity, infant age, nursing bout length, and durations of supplementation and postpartum amenorrhea. The findings show that Tamang breastfeeding mothers have higher average prolactin levels than Kami for as long as 22 months postpartum. Tamang mothers sustain average prolactin levels above those of nonpregnant, nonlactating women for nearly 2 years postpartum, whereas prolactin levels among Kami breastfeeding mothers are the same as this latter group after 1 year postpartum. Furthermore, the findings indicate that Tamang mothers have higher average prolactin levels regardless of maternal age, physical status (BMI, weight, or height), or infant age, and the rate of decline in prolactin from 5 to 50 minutes after suckling is significantly greater for Kami than Tamang. Since factors associated with prolactin levels differ by group, the findings also emphasize that populations vary not only in the strength of effects that proximate determinants have on fertility regulation, but also in the pathways by which they exert their effects (direct physiological versus indirect behavioral). Am. J. Hum. Biol. 10:191-210, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561450 TI - Body composition in Central Asia populations: Fat patterning variation in the Kazakhs of the Tien Shan mountains and the Uighurs of Semericia. AB - Eleven anthropometric variables related to fat patterning were analyzed in two populations of Central Asia, the Kazakhs of the Tien Shan mountains (2100 m) and the Uighurs of the Semericia plains. Subjects were healthy unrelated males, 122 Kazakhs and 79 Uighurs, 19-65 years. Comparisons were done with a preliminary analysis of variance and then by covariance analysis, taking into account the influence of age. The Uighurs, independently of age, show higher values than Kazakhs for all of the characteristics related to fat patterning, but principal components analysis suggests a similar somatic structure in the two samples. The presence of lower adiposity in the Kazakhs than in the Uighurs could be related to stress, probably associated with nutrition and lifestyle in a mountain environment. Am. J. Hum. Biol. 10:241-247, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561451 TI - Hyperspectral Imaging to Determine the Properties and Homogeneity of Renewable Carbon Materials. AB - Hyperspectral imaging within the near infrared (NIR) region offers a fast and reliable way for determining the properties of renewable carbon materials. The chemical information provided by a spectrum combined with the spatial information of an image allows mathematical operations that can be performed in both the spectral and spatial domains. Here, we show that hyperspectral NIR imaging can be successfully used to determine the properties of hydrothermally prepared carbon on the material and pixel levels. Materials produced from different feedstocks or prepared under different temperatures can also be distinguished, and their homogeneity can be evaluated. As hyperspectral imaging within the NIR region is non-destructive and requires very little sample preparation, it can be used for controlling the quality of renewable carbon materials destined for a wide range of different applications. PMID- 28561452 TI - Optical coherence tomography angiography of the macular microvasculature changes in retinitis pigmentosa. AB - PURPOSE: To investigate the macular microvasculature changes by optical coherence tomography angiography (OCTA) and analyse the correlation between these changes and central visual function in patients with retinitis pigmentosa (RP). METHODS: We measured the area of the foveal avascular zone (FAZ) and the foveal and parafoveal flow density (FFD and PFD, respectively) in the superficial (S) and deep (D) retinal plexus by OCTA (AngioVue) and compared these values between 73 RP patients and 36 healthy controls. We analysed the relationships between these microvasculature measurements and central visual functions such as visual acuity (VA) and the values of static perimetry tests (Humphrey Field Analyzer, the central 10-2 program) in the RP patients. RESULTS: The FFD-S, PFD-S and PFD-D were significantly decreased in the RP patients compared to the controls (all p < 0.05), whereas there was no significant difference in the FAZ-S, FAZ-D or FFD-D (all p > 0.05). A subgroup analysis showed that the RP patients with VA <20/20 had increased FAZ-S compared to the controls and RP patients with VA >=20/20 (p = 0.01 and p = 0.007, respectively). Spearman rank testing demonstrated that PFD-S and PFD-D were significantly correlated with all of the central visual parameters (all p < 0.01). The FAZ-S and FFD-S were significantly correlated with VA, and FAZ-D and FFD-D showed no significant correlation. CONCLUSION: Both the superficial and deep layers of the parafoveal microvasculature are attenuated in RP and correlated with reduced central visual function. The foveal microvasculature, especially in the deep layer, was relatively preserved until mild-to-moderately advanced stages. PMID- 28561453 TI - The impact of developing a speech and swallow rehab program: Improving patient satisfaction and multidisciplinary care. AB - OBJECTIVES/HYPOTHESIS: The objective of this study was to evaluate the impact of developing an integrated head and neck cancer speech and swallowing rehabilitation program on physician/team focus on functional outcomes. STUDY DESIGN: Prospective cross-sectional design. METHODS: Surveys regarding physician behavior and patient satisfaction with speech and swallowing were administered in an academic oncology practice prior to and 1 year following establishment of a dedicated head and neck speech and swallowing rehabilitation program. Participants included new and established head and neck cancer patients recruited consecutively. The primary outcome was physician behavior regarding speech and swallowing outcomes (as measured by discussion of function, providing suggestions regarding function, and referral to speech-language pathology services). RESULTS: A total of 199 surveys were returned at the first time point and 271 at the second. Demographic variables were comparable between the two groups. The later cohort was more likely to report team discussion and suggestions regarding speech and swallowing function than the former (P < .001, 95% confidence interval [CI]: 0.775 to -0.265; P < .001, 95% CI: -0.928 to -0.035, respectively). Although there was no significant difference between the groups in regard to satisfaction with speech (P = .07), more favorable satisfaction with swallowing was reported by the later cohort (P = .028, 95% CI: -0.531 to -0.029). CONCLUSIONS: Integration of speech and swallowing rehabilitation into head and neck cancer programs is associated with increased physician focus on functional outcomes and greater patient satisfaction in regard to swallowing function. We advocate for standard integration of such services into the multidisciplinary head and neck cancer care team. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2578-2581, 2017. PMID- 28561454 TI - Hepatitis B treatment eligibility in West Africa: Uncertainties and need for prospective cohort studies. AB - BACKGROUND & AIMS: While universal screening of hepatitis B virus (HBV) is recommended in high burden countries, little is known about the proportion of HBV infected persons in need of antiviral therapy in these settings. METHODS: Prisoners in Senegal and Togo as well as female sex workers and men who have sex with men in Cote d'Ivoire were screened for HBV infection. All HBsAg-positive participants underwent transient elastography, alanine aminotransferase (ALT) and HBV viral load (VL) quantification. Individuals with cirrhosis or those aged >30 years with an HBV replication >=20 000 IU/mL and elevated ALT were considered eligible for antiviral therapy. RESULTS: Of 1256 participants, 110 (8.8%) were HBsAg positive; their median age was 30 years [interquartile range: 25-33] and 96 (86.5%) were men. Three individuals (2.7%) had cirrhosis, while 28 (29.5%) of 94 participants with available measurements had an HBV VL >=20 000 IU/mL. Overall, 11 (10.0%) subjects were considered eligible for immediate antiviral treatment (2.1% of participants in Dakar, 7.7% in Abidjan and 21.6% in Lome, P=.001) and 59 (53.4%) for close monitoring due to the presence of significant liver fibrosis, elevated ALT or significant HBV replication. CONCLUSIONS: Among vulnerable populations in West Africa, a minority of HBV-infected individuals were eligible for immediate antiviral therapy. Prospective cohort studies are necessary to evaluate anti-HBV treatment eligibility facing the significant proportion of individuals with active chronic HBV infection. PMID- 28561455 TI - Co-assembly of Patchy Polymeric Micelles and Protein Molecules. AB - The development in the synthesis and self-assembly of patchy nanoparticles has resulted in the creation of complex hierarchical structures. Co-assembly of polymeric nanoparticles and protein molecules combines the advantages of polymeric materials and biomolecules, and will produce new functional materials. Co-assembly of positively charged patchy micelles and negatively charged bovine serum albumin (BSA) molecules is investigated. The patchy micelles, which were synthesized using block copolymer brushes as templates, leads to co-assembly with protein molecules into vesicular structures. The average size of the assembled structures can be controlled by the molar ratio of BSA to patchy micelles. The assembled structures are dissociated in the presence of trypsin. The protein polymer hybrid vesicles could find potential applications in medicine. PMID- 28561456 TI - Investigation of Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G promoter polymorphism in Indian venous thrombosis patients: A case-control study. AB - BACKGROUND: The role of PAI-1 4G/5G polymorphism in venous thrombosis has been contradictory. PAI-1 4G/4G genotype is associated with elevated levels of PAI-1 resulting in a hypofibrinolytic state and a higher thrombotic risk. OBJECTIVE: In this study, the distribution of genotypes and frequency of alleles of the 4G/5G polymorphism of PAI-1 gene in Indian patients with different types of venous thrombosis was investigated for its role in development of thrombosis. METHOD: A total of 87 portal vein thrombosis (PVT), 71 Budd-Chiari syndrome (BCS), 156 cerebral vein thrombosis (CVT), and 163 deep vein thrombosis (DVT) patients were studied alongside 251 healthy controls for the PAI-1 4G/5G polymorphism by allele specific PCR. RESULTS: Frequency of 4G/4G genotype was higher in all groups in comparison with controls. 4G/4G was associated with PVT risk (OR=2.51, 95% CI=1.29-4.96, P=.0075), BCS risk (OR=5.98, 95% CI=2.68-13.42, P<.0001), and DVT risk (OR=1.75, 95% CI=0.98-3.02, P=.0225). This is the first case-control study from India establishing PAI-1 4G/4G as a strong risk factor for abdominal thrombosis (PVT and BCS). Statistically significant association was not found between 4G/4G genotype and CVT risk. CONCLUSION: PAI-1 4G/4G is a strong risk factor for venous thrombosis in Indian patients and should be included in laboratory testing panel of thrombophilia. PMID- 28561457 TI - Early childhood determinants of age at menarche in rural guatemala. AB - The influence of early childhood determinants on age at menarche was investigated in a sample of Guatemalan women who participated as children in a nutrition intervention study conducted from 1969 to 1977. Age at menarche was retrospectively estimated in 1991 and 1992. Mean age at menarche was 13.7 (+/ 1.3) years. Data on linear growth, diarrhea and respiratory illnesses, and energy intake from supplementation as well as home sources were available between birth and 7 years of age. Socioeconomic status (SES) data were collected in 1975. Four hundred and ninety-seven women who had reached menarche by 1992 were grouped into three categories of stunting based on their height-for-age z-scores (none, >-2.0; moderate, -2.0 SD to -3.0 SD; severe, <-3.0 SD relative to National Center for Health Statistics reference data) at 3 years of age. About 78% of the sample was moderately or severely stunted at 3 years of age. The group that was severely stunted in childhood reached menarche at 14.1 +/- 1.4 years, significantly later than those who were moderately stunted (13.7 +/- 1.2 years) or not stunted (13.5 +/- 1.3 years). Using multiple linear regression methods, stunting was a significant predictor of age at menarche. Average energy intake (kcal/d) from home diet was associated with earlier menarche independent of preschool growth status. Percent time ill with diarrhea was positively associated with age at menarche. When the effects of diet, supplement, percent time ill with diarrhea and respiratory illnesses, and SES were taken into account, the independent influence of stunting on age at menarche persisted and remained significant. (c) 1996 Wiley-Liss, Inc. PMID- 28561458 TI - Ovarian function in the latter half of the reproductive lifespan. AB - The relationship of age to four aspects of ovarian function was investigated: daily progesterone levels, pulsatile progesterone secretion, follicular and luteal estradiol levels, and preovulatory estradiol levels. Daily progesterone levels decrease after age 40. Pulsatile progesterone secretion remains approximately stable with age, though older women have somewhat higher late luteal activity. Daily follicular and luteal estradiol levels decrease with advancing age, but preovulatory peak estradiol remains stable. Some of these changes undoubtedly have negative effects on fecundity, such as lower follicular estradiol and average progesterone, via effects on endometrial development and support. But other changes identified, such as stability of preovulatory estradiol levels and thereby presumptive capacity to stimulate a luteinizing hormone (LH) surge despite lower follicular and luteal levels, as well as increased pulsatile progesterone secretion around the time of implantation, appear designed to conserve and maintain function. Thus, ovarian endocrine function over the course of reproductive life represents a process of change, but not one of generalized functional decline. Rather, aging with respect to ovarian endocrine function may proceed on a track, or on multiple tracks, which are largely separable from the continual depletion of oocyte stores which occurs over the lifetime. (c) 1996 Wiley-Liss, Inc. PMID- 28561459 TI - Evolution of the human life cycle. AB - Social mammals have three basic stages of postnatal development: infant, juvenile, and adult. Some species also have a brief female post-reproductive stage. The human life cycle, however, is best described by five stages: infant, child, juvenile, adolescent, and adult. Women in both traditional and industrial societies may also have a long post-reproductive stage. Analyses of bones and teeth of early hominids who died as subadults suggest that the evolution of the new life stages of childhood and adolescence are not of ancient origin. The current human pattern evolved after the appearance of Homo erectus. It is possible that evidence for the existence of the post-reproductive stage for women will also be recoverable from the fossil record because the hormonal changes associated with menopause have profound effects on bone density and histology of tubular bones. It is hypothesized that the new life stages of the human life cycle represent feeding and reproductive specializations of the genus Homo. (c) 1996 Wiley-Liss, Inc. PMID- 28561460 TI - Assessing cardiovascular risk and stress-related blood pressure variability in young women employed in wage jobs. AB - This overview discusses how aspects of behavior and stressors inherent in the lifestyles of contemporary women affect their cardiovascular health. Three main issues are addressed. The first is the applicability of cardiovascular risk data collected on prior generations of working women in predicting the health outcomes of the current generation of women. It is argued that the earlier data may not adequately describe the health risk of the current generation because of changes in the nature of women's paid employment in recent decades, and because the compartmentalization of economic, leisure, and domestic activities may have affected how stress associated with each influences cardiovascular measures such as blood pressure. Second, the influence of the environment on lifestyle is briefly discussed in the context that differences in the results of studies examining lifestyle stressors may occur as a consequence of local physical and cultural environmental differences which influence lifestyle. Third, the effects of daily microenvironmental changes on blood pressure are discussed and it is argued that perceived socioeconomic roles may influence the cardiovascular response to the stressors inherent in each microenvironment. Because the lifestyles of women change over the lifespan, it is concluded that the impact of lifestyle on cardiovascular risk must be studied at all stages of life. (c) 1996 Wiley-Liss, Inc. PMID- 28561461 TI - Proceedings of Human Biology Association 21st Annual Meeting, April 8-10, 1996, Sheraton Imperial Hotel, Durham, North Carolina. PMID- 28561462 TI - Lifespan approach to the study of human biology: An introductory overview. PMID- 28561463 TI - Excessive gestational weight gain and chronic disease risk. AB - Excessive deposition of central body and abdominal (centripetal) fat early in life often will presage the later development of cardiovascular and metabolic diseases. Data from urban, low-income women from Camden, New Jersey, were used to examine the influence of gestational weight gain on patterns of weight change and fat deposition in 118 young women followed over two consecutive pregnancies. Adjusting for confounding factors, there was a significant (P < 0.05) dose response relationship between the amount of gestational gain (in the subsequent pregnancy) and increases in postpartum weight compared with the postpartum in the prior pregnancy: +1.5 kg with a low gain, +2.9 kg with recommended amounts of gain, and +7.9 kg with excessive gain. Excessive gain (18+ kg) was common (18%) in the sample. The incidence of "new" obesity (body mass index [BMI] >29.0 in the subsequent postpartum but not the index postpartum) increased significantly with gestational gain: 4.7% with low gain, 7.0% with recommended gains, and 25.0% with excessive gain. There were similar dose-response increases related to gestational weight gain in all skinfolds (suprailiac, subscapular, and triceps) and the sum of the skinfolds. However, in women with excessive gains, fat was increased disproportionately at upper (+52%) and lower (+48%) central body sites, compared with the periphery (+27%), and compared with increases in women with lesser gestational gains. Thus, excessive gestational weight gain, which is common among low-income women, may be a factor which promotes obesity and a centripetal fat pattern during the reproductive years, thereby increasing the risk for cardiovascular and metabolic diseases in later life. (c) 1996 Wiley-Liss, Inc. PMID- 28561464 TI - The relation of lifetime reproduction to survivorship in women and men: A prospective study. AB - The relation of lifetime reproduction to survivorship was investigated among 1,533 women and 1,230 men from Southern California who were born between 1880 and 1929. Analyses used the total group and two 25-year birthyear subcohorts (1880 1904 and 1905-1929). Follow-up for vital status was 100% and included 41,399 person-years, from baseline (1972-1974) through mid-1990. Cox proportional hazards analyses were adjusted for age, body mass index, estrogen use in women, and socioeconomic status. Alternate sets of analyses for each sex used reproduction coded dichotomously, and as a continuous variable. Parous women had significantly poorer survivorship than nulliparous women in the total group (P = 0.003) and among women born 1880-1904 (P = 0.02), but not among women born 1905 1929 (P = 0.08). Analyses using number of biological children showed significantly poorer maternal survivorship "per child ever born" among the total group of women (P = 0.04) and among women born 1880-1904 (P = 0.01), but not among women born 1905-1929 (P = 0.96). Further analyses confirmed that women's risk per child tended to increase with maternal age. Equivalent sets of analyses for men showed no relationship between reproduction and survivorship. The survivorship differences between women's birthyear subcohorts may be due to secular trends or age-specific disease patterns. Study findings tend to support the latter, and suggest that childbearing may increase or accelerate women's mortality from certain diseases which occur late in life, and that risk may increase with age. (c) 1996 Wiley-Liss, Inc. PMID- 28561465 TI - Developmental influences on adult ovarian hormonal function. AB - The hypothesis is advanced that levels of ovarian hormonal function in adult women are associated with the tempo of growth and maturation in childhood and adolescence. Empirical data are presented documenting a correlation between menarcheal age and adult ovarian hormonal function both within and between populations. It is noted that this relationship is compatible with current understanding of the mechanisms underlying pubertal maturation of ovarian hormonal function. Functionally, such a relationship could serve the purpose of modulating adult fecundity to chronic environmental conditions. Alternative hypotheses include the possibility that the relationship is not causal but rather reflects either confounded effects of some common cause or the persistence of acute environmental effects through time. Proper testing of such alternative hypotheses will require longitudinal data on migrant populations, changing environments, or secular trends within populations. The importance of establishing the relationship between development and adult ovarian hormonal function is not limited to issues of fecundity and fertility, but includes other areas of female general and reproductive health. (c) 1996 Wiley-Liss, Inc. PMID- 28561466 TI - Symptoms of menopause in relation to the timing of reproductive events and past menstrual experience. AB - The framework of the lifespan approach is used to examine the frequency of symptoms associated with menopause. Symptom frequencies are examined in relation to past menstrual symptom experience and the timing of reproductive events. Data were drawn from a cross-sectional community survey carried out in Greene County, New York. The symptoms most often reported were hot flashes, irritability, mood changes, sweating, and headaches. Frequencies of vasomotor symptoms (hot flashes, sweating) were highly correlated. Frequencies of psychological symptoms (irritability, mood change) were also highly correlated. Neither vasomotor nor psychological symptoms were associated with parity, age at menarche, or ages at first and last childbirth. Frequency of hot flashes was significantly associated with post-menopause status, later age at natural menopause, and fewer years of education. In contrast, frequency of psychological symptoms was not related to menopause status, age at natural menopause, or years of education. Menstrual abdominal cramps and leg cramping were associated with hot flash frequency at menopause, but not frequency of menopausal mood change. In contrast, menstrual bloating and mood changes were associated with menopausal irritability and mood change. Self-reported vasomotor and psychological symptoms demonstrated dissimilar relationships to lifespan events. It is difficult to determine, however, which dimension of the lifespan (biological, sociocultural, or psychological) is involved in determining differences in menopansal symptom frequencies. (c) 1996 Wiley-Liss, Inc. PMID- 28561467 TI - Growth in height and weight of South African urban infants from birth to five years: The Birth to Ten Study. AB - The Birth To Ten (BTT) birth cohort study was designed to investigate the health and growth of children living in the Soweto-Johannesburg Metropole, South Africa. During 1990-1991, 4034 singleton births, from a total birth population of 5449 that occurred between 23 April and 8 June, 1990, were enrolled into the study. Anthropometric, socioeconomic, health, nutritional, and demographic data were collected at birth and at 3, 6, 12, 24, 48, and 60 months. Socioeconomic data relating to household commodities, maternal education, and paternal occupation were combined to create socioeconomic status (SES) groups for comparative purposes. Mean birth weights were less than American norms and demonstrated significant differences between the sexes. The percentage of low birth weight children of normal gestational age (7.1%) was similar to that of developed countries. Growth in weight exceeded that of the National Center for Health Statistics (NCHS) reference during the first 6 months and then fell to -0.43 Z scores by 4 years. Height growth was consistently less than the NCHS reference and the prevalence of stunting and wasting increased to 22.4% and 6.8%, respectively, by 2 years. Catch-up occurred between 4 and 5 years resulting in a reduction in the prevalence of stunting and wasting to 5.4% and 0.8%, respectively, at 5 years. SES differences were apparent throughout the time period but only reached significance in height and weight after 4 years of age. Am. J. Hum. Biol. 10:495-504, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561468 TI - Timing of the influence of maternal nutritional status during pregnancy on fetal growth. AB - This study, which used data from a longitudinal nutrition study of mothers and infants in rural Guatemala, tested a hypothesis that the influence of maternal nutritional status on various measurements of fetal growth is trimester-specific. The relationships between various measures of newborn size and the changes of maternal anthropometry at various stages of pregnancy were analyzed by ordinary least squares multiple regression techniques. The sample included 235 mother infant pairs who had complete anthropometry for both the newborns (weight, length, and head circumference) and their mothers at 3, 6, and 9 months of pregnancy (weight, height, circumferences of mid-upper arm and thigh, skinfold thicknesses at biceps, triceps, calf, thigh, and subscapular sites). Each kilogram of maternal weight gain in the second and third trimester was associated with statistically significant increases in birth weight of 62 g (P < 0.001) and 26 g (P < 0.05), respectively. Newborn length and head circumference were significantly associated with maternal weight gain and the changes in maternal thigh skinfolds in mid-pregnancy only. The overall results suggest that maternal nutritional status in mid-pregnancy rather than in late pregnancy is a more important determinant of fetal growth in weight, length, and head circumference. Am. J. Hum. Biol. 10:529-539, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561469 TI - Renin, ANP, ACE polymorphisms, blood pressure and age in American Samoans: Preliminary data. AB - Molecular studies have identified numerous candidate genes that may influence interindividual variation in physiologically important endpoints. Among these are molecular variants of three proteins associated with blood pressure regulation, renin, atrial natriuretic peptide (ANP), and angiotensin-converting enzyme (ACE). These loci are polymorphic in all populations examined. The purpose of this study was to determine gene and genotype frequencies at these three loci in a sample of American Samoans and to examine associations of the various genotypes with blood pressure, hypertension, and age. Genotype frequencies of a BglI restriction fragment length polymorphisms (RFLP) at the renin locus were slightly out of Hardy-Weinberg expectations (P ? 0.025). Frequencies of a BglI RFLP at the ANP locus and of the insertion/deletion polymorphism at the ACE locus approximated Hardy-Weinberg expectations (P ? 0.10). These frequencies differed from those reported in "Afro-Caribbean" and "Caucasian" samples from London. Neither average blood pressures nor the frequencies of either systolic or diastolic hypertension differed significantly across genotypes at the ANP or ACE loci. However, systolic pressure was elevated among those heterozygous for the renin BglI cut site (P = 0.07). Mean age was 34.4 years among individuals heterozygous for the ANP BglI cut site, while it was 46.0 years for homozygotes without the site (P = 0.04). After dividing the sample at its median age (45 years), 31.8% of younger, but only 8.7% of older participants were ANP BglI heterozygotes (G = 9.48; P = 0.005). Am. J. Hum. Biol. 10:439-449, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561470 TI - Two decade trends in birth weight and early childhood growth in Papua New Guinea. AB - At present, little is known about patterns of early growth and development in foraging and small-scale horticultural populations. Moreover, still less is known about secular changes in growth in these populations. Data collected in 1967, 1976, and 1989 are presented for birth weight and subsequent growth to 5 years among Au forager-horticulturalists of Papua New Guinea. Despite the launching of health campaigns over the last two decades aimed at bettering the nutritional status of the Au, the data show that average birth weight has remained stable and low at just over 2600 g. Weight- and length-for-age also show no significant changes among traditional Au over the last 20 years, and remain on average, at just below the U.S. 5th percentile. Evidence for the start of a positive secular trend in birth weight and subsequent growth is seen, however, among a small group of Au children residing in households that have a source of wage income. These individuals show an increase of 150 g in birth weight, and over the subsequent 5 years of growth average 93 g heavier and 2.6 cm taller than Au children in traditional households. In addition to providing baseline data on child growth in a forager-horticulturalist society, the findings provide evidence for a secular trend newly underway, and suggest that health promotion campaigns alone without socioeconomic development may be insufficient in effecting change in growth status in rural communities. Am. J. Hum. Biol. 10:483-493, 1998. (c) 1998 Wiley Liss, Inc. PMID- 28561471 TI - Prevalence of obesity and contributing factors among Sherpa women in urban and rural Nepal. AB - Dietary and lifestyle changes have profound influences on the body mass and nutritional status of individuals living in developed countries. This report used data from a prospective longitudinal study to assess the prevalence of obesity among Sherpa women and to determine which factors were most predictive of it. The body mass index (BMI), energy consumption and expenditures, and physical activity patterns were compared for nonpregnant, premenopausal women living in urban low altitude (n = 216); urban high altitude (n = 56); and rural high altitude (n = 93) settings. Area of residence was highly predictive of the BMI. The mean body weight and BMI were significantly higher for the urban low altitude sample (53.3 kg and 23.5 kg/m2 , respectively) than for the total high altitude sample (51.4 kg and 21.8 kg/m2 , respectively). The rural, high altitude sample had the lowest mean body weight (50.1 kg), triceps skinfold (18.5 mm), and BMI (21.3 kg/m2 ). Although mean BMI was in the range associated with the overall lowest risk to health, distribution of the BMI showed that 29% of the urban low altitude sample were classified obese. The prevalence of obesity was correlated with reduced energy expenditure, not to an increase in consumed calories. Reduced energy expenditures appear to be related to shifts in occupation, access to motorized transportation, and increased affluence, which has allowed Sherpas to hire servants to do manual labor. These data suggest that Sherpa women may potentially be at risk of chronic health problems in the future because of increased adiposity. Am. J. Hum. Biol. 10:519-528, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561472 TI - Genes play an important role in bone aging. AB - Pathological changes in bones like osteoarthritis and osteoporosis are among the most frequent outcomes of age and aging. Presently, little is known about the genetic basis of peak bone mass or rate of bone loss, or on the genetics of bone formation and resorption. This paper reviews modern studies, dealing with the genetic aspects of bone formation and bone aging. The currently most popular measures of bone aging are: osteometric measurements (OSM) including measures of cortical thickness, bone mineral density (BMD), and osteographic scores (OSS) basing on descriptive criteria of bone age. These three are important clinical tools for predicting chronic degenerative disease and estimating biological age of individuals. Despite abundant data on ethnic and racial differences in these bone aging measures, modern knowledge regarding the genetics of the processes came primarily from family studies of BMD which point to strong familial and probably also genetic effects on bone mass. Regardless of the measurement technique or skeletal site selected, heritability estimates of BMD in most studies account for about 60% of the total variation in bone mass. Similarity of heritability estimates in most studies suggests that the same genetic factors operate on both weight-bearing and nonweight-bearing bones. However, genetic heritability may be overestimated in some family studies due to underestimation of common environmental effects. Segregation analysis, performed to date, reveals strong effect of potential major locus on BMD of both compact and trabecular bone, but much remains to be clarified. Genetic factors affecting BMD may be mediated through biochemical turnover of bone. Hence, segregation, linkage, and molecular biology are the staples of any genetic analysis of BMD, while the study of biochemical factors regulating bone turnover should elucidate the full picture of bone formation and aging. Am. J. Hum. Biol. 10:421-438, 1998. (c) 1998 Wiley Liss, Inc. PMID- 28561473 TI - Longitudinal change in forced expiratory volume in healthy, non-smoking men and women: The Baltimore Longitudinal Study of Aging. PMID- 28561474 TI - Age at menarche and prevalence of oligo/amenorrhea in top Polish athletes. AB - The representative sample of a population of top Polish athletes (>75% of all participants in Poland's Winter and Summer National Championships during 1992 1994) was investigated using a questionnaire. The athletic group numbered 926 women in total. The control group (n = 708) in the same age range (15-37 years) as the athletes was randomly chosen from the Warsaw population. The mean menarcheal age of all athletes was 13.6 +/- 1.3 years, and it was statistically different from the controls (12.9 +/- 1.2 years). Athletes who started training before menarche were more numerous (661) than those who started training after menarche (265). The mean menarcheal age was also different for those groups (13.9 +/- 1.3 years vs. 13.0 +/- 1.3 years). In all sports except cross-country skiing and biathlon, the menarcheal age of girls starting training before menarche was later as compared to the age of those starting training after menarche. The prevalence of oligo/amenorrhea (?9 menstrual cycles per year) was much higher for all younger and premenarche trained athletes than postmenarche trained girls. This prevalence also was much higher for athletes than for controls. Early maturers were engaged in team games, fencing, and judo, but late maturers were engaged in cross-country skiing and biathlon, track and field-long and middle distances, and marathon. It may indicate the presence of the sport's selection factor. Am. J. Hum. Biol. 10:511-517, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561475 TI - Evolution of human lifespan: Past, future, and present. AB - The only satisfactory general theory for understanding the biology of aging is that provided by evolutionary genetics. The central theoretical result of the evolutionary theory of aging is that aging is caused by a fall in the force of natural selection, beginning at the time of the onset of reproduction and continuing until the cessation of reproduction. This formal result has been tested using breeding experiments in which the force of natural selection is altered in replicated laboratory populations. As predicted by the evolutionary theory of aging, such experiments can readily postpone aging. A recent advance has been the discovery of late-life mortality plateaus in human and other populations. These can be predicted theoretically from the late-life plateau in the force of natural selection, when it remains at or near zero. It is virtually certain that human lifespan has substantially increased over its last few million years of evolution. Evolutionary theory can explain this increase in terms of decreased ecological vulnerability resulting from increased brain size. The immediate future of human evolution is unlikely to see extensive genetic increases in lifespan, given the experimental data on rates of change in lifespan with experimental populations. But, evolutionary research suggests that there are few fundamental biological barriers to the extension of human lifespan, only practical barriers. Am. J. Hum. Biol. 10:409-420, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561476 TI - Does the relationship of ambulatory blood pressure to position and location vary by age, sex, race/ethnicity, or body mass index? AB - The effects of position and location on ambulatory blood pressure, and the variability in these effects across individuals was examined. The extent to which the variability among individuals could be predicted by age, sex, race/ethnicity, and body mass was also assessed. The data include 24-hour ambulatory blood pressure recordings of 246 subjects from an ongoing worksite study. A random coefficients model yielded estimates of within-person and between-person effects. The position and location of individuals significantly affect their ambulatory blood pressure. As position changes from reclining to sitting to standing, blood pressure increases, after controlling for location. Likewise, blood pressure is typically higher at work than at home, controlling for position. The effects on blood pressure of both position and location vary considerably across persons. Interpersonal variability, measured by the standard deviation, is typically 30 75% as large as the variability in mean levels of blood pressure. There is also an interaction effect of position and location: the difference in blood pressure between standing and sitting down at work is not the same as the corresponding difference at home. Age, sex, race/ethnicity, and body mass index (BMI) predict 17% of the interpersonal variability in average systolic blood pressure while sitting at home, and 6% in diastolic blood pressure. The analysis of whether the effects of position or location vary by age, sex, race/ethnicity or BMI shows that the difference between work and home blood pressures is not significantly related to any of these four factors. However, the difference between awake and sleep diastolic blood pressures can be predicted, in part, by age and perhaps race/ethnicity. As age increases, the drop in diastolic blood pressure during sleep is attenuated. Hispanics also appear to experience a smaller drop in blood pressure during sleep. The drop in blood pressure associated with lying down (while awake) is similarly related to age and race/ethnicity. The increase in blood pressure associated with standing (vs. sitting) while at work is also attenuated in older individuals. Although significant interaction effects were demonstrated, these four major risk factors for hypertension predicted only small percentages of the interpersonal variability in the effects of position and location on blood pressure. Am. J. Hum. Biol. 10:459-470, 1998. (c) 1998 Wiley Liss, Inc. PMID- 28561478 TI - Human biology and aging: Recent advances and new directions. PMID- 28561477 TI - Brain weight of Northwest Indian children and adolescents. AB - Brain weight of 708 individuals, 329 neonates (211 males and 118 females), 142 infants (101 males, 41 females), and 237 children and adolescents (136 males and 101 females), from Chandigarh region of northwest India were measured. Brain weight was 371.9 +/- 89.5 gm in male newborns and 342.5 +/- 72.2 gm in female newborns (P > 0.05). It increased to 444.7 +/- 87.2 gm in the former and 405.0 +/ 78.5 gm in the latter at the end of the neonatal period (28 days). Brain weight increased to 845.7 +/- 163.4 gm in males and 803.0 +/- 100.1 gm in females at the end of 12 months (P > 0.05), and then to 1241.9 +/- 104.5 gm in the age group of 5-6 years in males and to 1101.3 +/- 37.5 gm in the age group of 3-4 years in females. Thereafter, there was a gradual increase in the brain weight to 1326.9 +/- 126.9 gm in male and 1206.3 +/- 86.4 gm in female adolescents in the age group of 16-17 years (P < 0.01). By the age of 6 years, about 94.5% (95.6% in males and 93.3% in females) of adult brain weight was attained. Sex differences became evident after the age of 14 years. Relationships between brain weight and age, supine body length, body weight and body surface area were also considered. Am. J. Hum. Biol. 10:505-509, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561479 TI - Menarche, menopause, and migration: Implications for breast cancer research. AB - A multigenerational delay in the rise of breast cancer incidence rates has been documented among immigrants to the United States. Prompted by this observation, this study examines three breast cancer risk factors, age at menarche, parity, and age at menopause, in relation to each other and in relation to migration status and language most often used in U.S. Hispanic populations. Mexican American (n = 1,502), Cuban American (n = 534), and Puerto Rican (n = 700) women, aged 30-74 years, were drawn from the Hispanic Health and Nutrition Examination Survey (HHANES), 1982-1984. Mean recalled age at menarche was significantly later among first generation compared to second generation immigrants in both Mexican Americans (13.3 vs 12.8 years) and Puerto Ricans (12.8 vs 11.9 years). Among Mexican Americans, more children were reported by first generation immigrants than women of the third or more generations (4.9 vs 4.0 children) and by Spanish speakers compared to women who used English more frequently (4.5 vs 3.3 children). Mean and median ages at menopause were later among second generation Mexican American women than first generation women. There was a small, significant, positive correlation between recalled ages at menarche and menopause within each of the first generation Hispanic subgroups. The unique positive correlation between ages at menarche and menopause among first generation immigrants may relate to having spent early years in the country of origin and later years in the United States. Am. J. Hum. Biol. 10:451-457, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561480 TI - Prevalence and significance of HBeAg and isolated anti-HBc in several institutions for the mentally retarded in the autonomous community of madrid. AB - Hepatitis B virus (HBV) surface antigen (HBsAg) and antibody to HBsAg (antiHBs) are excellent markers for HBV infection and its immunity. A total of 414 patients, 312 Down syndrome and 102 non-Down's syndrome, were studied, and 142 were residents of an institution (RI), whereas 272 were in nonresidential care (NRC). Of the total, 28 (6.8%) were HBsAg positive, and of these, 16 (57.1%) had a positive test for the Hepatitis Be antigen (HBeAg). Proportionately more Down syndrome chronic carriers of HBsAg acquired the persistent Hepatitis Be antigen (HBeAg) than non-Down syndrome patients 15 (65.2%) vs. 1 (20%). The presence of HBeAg was correlated with abnormal liver function and high titres of HBsAg. Testing for the IgM antibody to the hepatitis B core antigen (IgM AntiHBc) facilitated the identification of acute and chronic hepatitis infection in both RI and NRC individuals. The significance of isolated antiHBc seropositivity in Down syndrome patients remains unclear. It is not certain whether the isolated antiHBc seropositivity represents chronic "low levels" of HBV, past infection, or false-positive tests, and whether this test should be employed as a vaccine screening test. Am. J. Hum. Biol. 9:29-33 (c) 1997 Wiley-Liss, Inc. PMID- 28561481 TI - Reliability of multiple frequency bioelectrical impedance analysis: An intermachine comparison. AB - The technical reliability (i.e., interinstrument and interoperator reliability) of three SEAC-swept frequency bioimpedance monitors was assessed for both errors of measurement and associated analyses. In addition, intraoperator and intrainstrument variability was evaluated for repeat measures over a 4-hour period. The measured impedance values from a range of resistance-capacitance circuits were accurate to within 3% of theoretical values over a range of 50-800 ohms. Similarly, phase was measured over the range 1 degrees -19 degrees with a maximum deviation of 1.3 degrees from the theoretical value. The extrapolated impedance at zero frequency was equally well determined (+/-3%). However, the accuracy of the extrapolated value at infinite frequency was decreased, particularly at impedances below 50 ohms (approaching the lower limit of the measurement range of the instrument). The interinstrument/operator variation for whole body measurements were recorded on human volunteers with biases of less than +/-1% for measured impedance values and less than 3% for phase. The variation in the extrapolated values of impedance at zero and infinite frequencies included variations due to operator choice of the analysis parameters but was still less than +/-0.5%. Am. J. Hum. Biol. 9:63-72 (c) 1997 Wiley-Liss, Inc. PMID- 28561482 TI - The Raymond Pearl memorial lecture, 1996: The eternal triangle-genes, phenotype, and environment. AB - Attempts to understand the causes for phenotypical differences in the biology and behavior of human populations have tended to focus alternatively on genetic, cultural, and natural environmental variables. The relative narrowness of focus in these studies often impedes the development of research design appropriate to the hypothesis and the process of reaching reasonable conclusions. Past research on native high-altitude populations is used first to illustrate the deficiencies of research based on single variables and errors which can occur in conclusions about causal factors when potential genetic contributions are excluded. Analyses of blood pressure data from Samoan modernization studies are used to illustrate the complexity of determining causality in the development of a pathological condition. The need for better qualified cross-cultural measures is emphasized. Am. J. Hum. Biol. 9:93-101 (c) 1997 Wiley-Liss, Inc. PMID- 28561483 TI - Multicompartment model of body composition assessment in Chinese-American adults. AB - Using hydrodensitometry, dual energy x-ray absorptiometry, and deuterium dilution techniques, multiple compartment body composition assessment was performed on 29 adult Chinese-American men (n = 11) and women (n = 18). The purpose of the investigation was to determine if significant differences exist in the estimation of percentage of body fat (%BF) and fat-free mass (FFM), based on 2-, 3-, and 4 compartment models of body composition. Height, weight, and the body mass index (BMI) for the men were 170 cm, 63 kg, and 22 kg/m2 ; for the women, values were 161 cm, 59 kg, and 23 kg/m2 , respectively. Estimated values for %BF from density alone and density adjusted for TBW were not significantly different for either the men or women (20.5% vs. 18.8%) and (28.2% vs. 27.4%). However, %BF estimated from the 4-compartment model of density, TBW and BMC resulted in significantly lower values for both groups, 17.5% for men and 26.8% for women. The lack of a significant difference in %BF between density only and density adjusted for TBW indicates that TBW was within the accepted constancy value associated with hydrodensitometry. When density was adjusted for variation in both TBW and BMC, a significant decline occurred in the estimate of %BF for men, but not for women. The average TBW to FFM ratio was 0.75., 0.74, and 0.73 when using FFM values from 2-, 3-, and 4-compartment models, respectively. The average BMC to FFM ratio from two-, three-, and four-compartment estimates of FFM were 0.054, 0.053, and 0.052 for the men and 0.060, 0.059, and 0.059 for the women. The results suggest that Chinese-American men and women have similar TBW/FFM ratios, but the BMC/FFM ratio is higher in women than men. Am. J. Hum. Biol. 9:21-27 (c) 1997 Wiley-Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America. PMID- 28561484 TI - Dietary pattern and growth of 10-12-year-old Bolivian girls and boys: Relation between altitude and socioeconomic status. AB - The purpose of the study was to determine the impact of nutrition and physical activity on growth and health of 228 native Bolivian prepubertal girls and boys 10-12 years of age, from high socioeconomic status (HSES) and low socioeconomic status (LSES), living at high altitude (HA) in La Paz (~4,000 m) and at low altitude (LA) in St. Cruz (~400 m). In the 4 years of the study, dietary information and daily physical activities were obtained with the 24-hour recall method by interviewing the child and mother. All food items were converted into grams, and nutrients were calculated by using food composition tables for Latin America. Physical activities were estimated in four intensity levels and calculated in terms of energy output. The results show that nutritional intake is influenced by socioeconomic status, but not by altitude. Overall, the energy and nutrient intake of the HSES girls and boys was significantly higher (P <= 0.01) than the intake of the LSES children at both altitudes; no sex effect was evident. HSES girls and boys consumed greater amounts of nutrients, especially protein and fat; they were taller but also fatter. The physical activity of LSES children was higher than that of HSES children. The lower energy intake and the higher energy expenditure of LSES children were reflected in their smaller body size. Am. J. Hum. Biol. 9:51-62 (c) 1997 Wiley-Liss, Inc. PMID- 28561485 TI - Buoyancy of African black and European white males. AB - Twenty-six male swimmers (13 Blacks, 13 Whites) matched for age, weight, and stature were subjects in the comparison of anthropometric characteristics and horizontal and vertical buoyancies. Subjects were tested in a swimming pool in the horizontal position. The time necessary for the body to return to the vertical position defined horizontal buoyancy. Vertical buoyancy was the hydrostatic lift necessary to maintain the subject immersed to the nose. The results indicated similarities in arm span, trunk flexibility, and full inspiration and exhalation of Black and White subjects. However, there were differences in body fat distribution (P <= 0.05) and buoyancies (P <= 0.01), with Whites storing more fat and having better buoyancy than Blacks. Am. J. Hum. Biol. 9:87-92 (c) 1997 Wiley-Liss, Inc. PMID- 28561486 TI - Somatotype and cardiovascular risk factors in healthy adults. AB - Relationships between cardiovascular risk factors and Heath-Carter anthropometric somatotype components were considered in 642 healthy adults free from overt disease: 68 males and 177 females, 30-39 years, and 233 males and 224 females, 40 49 years of age. Risk factors included systolic and diastolic blood pressures (SBP, DBP), fasting glycemia (GLYC), triglycerides (TG), plasma cholesterol (CHOL), the high density lipoprotein cholesterol fraction (HDL-C), and the HDL C/CHOL ratio. Correlations between risk factors and each somatotype component were calculated after controlling for the effects of the other two somatotype components. Correlations were generally low and at best moderate, with significant correlations ranging from -0.23 to +0.23 in males and -0.20 to +0.30 in females. The relationships were stronger in the older group, 40-49 years, but the pattern of correlations was different in men and women. Endomorphy tended to be positively related to risk factors in older females, whereas ectomorphy tended to be negatively related to risk factors in older males. Comparison of somatotypes of individuals at the extremes of the distributions for each risk factor (upper and lower tertiles) were generally consistent with the direction of the correlations. For each cardiovascular risk, those with a poorer profile tended to be more endomorphic and mesomorphic and less ectomorphic than those with a better profile, who were more ectomorphic and less endomorphic and mesomorphic. The association was more apparent in males than in females and more so in those 40-49 years of age than in the younger age group. Although the correlations suggest that body type is weakly associated with common cardiovascular risk factors in healthy men and women, somatotype associations are more apparent at the extremes of the distributions of specific risk factors. Am. J. Hum. Biol. 9:11-19 (c) 1997 Wiley-Liss, Inc. PMID- 28561487 TI - Physiological and cognitive responses to cold exposure in 11-12-year-old boys. AB - This study investigated the effects of cold and exercise in the cold on the physiological and cognitive responses of 11-12-year-old boys. Children were dressed in sweat suits and exposed to cold (CD, 7 degrees C), cool (CL, 13 degrees C), and neutral (N, 22 degrees C) environments for 110 minutes, with 10 minutes of light exercise (1 watt . kg body wt-1 ) midway through the exposure. A 30-minute "recovery" in neutral conditions followed each session. Session order was randomized. Rectal temperature (Tre) decreased significantly more in CD compared to CL and N, and continued to decrease during the recovery period. Chest skin temperature (Tch) was significantly different between conditions and remained stable even in CD, despite the decrease in Tre. Tch returned to prechamber values during the recovery period. Hand temperature (Th) decreased during CL and CL, and remained significantly lower than prechamber values following the recovery. Exercise heart rate was lower in the CD and CL(115 +/- 13 and 119 +/- 20 beats . min-1 ) compared to N (130 +/- 17 beats . min-1 ). No differences were observed in oxygen consumption between sessions. No differences were also observed between sessions in cognitive performance on language and math tests. It was concluded that while the study conditions did not appear to affect cognitive capacity in boys, they proved sufficient to disturb core temperature. This disturbance was not corrected 30 minutes following cold exposure. Am. J. Hum. Biol. 9:39-49 (c) 1997 Wiley-Liss, Inc. PMID- 28561488 TI - Accuracy of anthropometric estimation of muscle cross-sectional area of the arm in males. AB - Mid-arm cross-sectional muscle area was studied in several domains to evaluate nutritional status and muscle area and hypertrophy in revalidation and strength related studies. In this study, anthropometrically determined muscle + bone area formulas were validated against Houndsfield unit-based CT-scan measures at mid humerus (stretched and relaxed), and mid-humerus -3 and -6 cm positions in 75 healthy male twins. Muscle + bone area estimates calculated by mid-arm circumference and the triceps skinfold (MBA.ANg, MBA.ANh) underestimated muscle area determined by CT imaging (MUS.CT) at all scans. The formula, including triceps and biceps skinfold (MBA.ANf), was in closer agreement with MUS.CT. It is therefore suggested that both the biceps and triceps skinfolds (or additional arm skinfolds) be used to estimate muscle area at the mid-arm position. The results emphasize the use of (nonremovable) landmarks in longitudinal studies that consider mid-arm muscle cross-sectional area, since the muscle area in three scans over a 6 cm region of the upper arm differs substantially and is in the same range as expected hypertrophic changes after short-term resistance training programs. Am. J. Hum. Biol. 9:73-86 (c) 1997 Wiley-Liss, Inc. PMID- 28561489 TI - Familial resemblance in height and weight in an endogamous Hahisya caste population of rural West Bengal. AB - Intrafamilial resemblance and heritability of height and weight in an endogamous, agricultural caste population of rural West Bengal ("Mahisya") were estimated from data for 540 individuals, 110 parent pairs and 187 sons and 133 daughters (children as well as adults) from 110 nuclear families. Multiple regression with age and sex adjustments was used. A trend of greater mother-child than father child correlation was observed, but was not significant. Sibling correlations indicated no evidence of sex linkage. Heritability for height (h2 = 0.603) was greater than that for weight (h2 = .405). Am. J. Hum. Biol. 9:7-9 (c) 1997 Wiley Liss, Inc. PMID- 28561490 TI - Organ weights in healthy and apparently healthy Danish infants. AB - The weights of brain, heart, liver, kidneys, spleen, lungs, and thymus were registered in 222 forensic autopsies of Danish infants aged 1 week to 0.99 year (137 males, 85 females), who prior to death were healthy or apparently healthy based on clinical evidence. Variability of organ weights was estimated, and the relationship between individual organ weights and age, body weight, and body length, and the sum of organ weights was evaluated in relation to age, body weight, and body length. No significant differences were found between males and females, and between the healthy and apparently healthy infants. There was a positive, significant correlation of the individual organ weights with age, body weight, and body length. It was most pronounced for the weight of the brain and least pronounced for the thymus. Am. J. Hum. Biol. 9:35-38 (c) 1997 Wiley-Liss, Inc. PMID- 28561491 TI - Frequencies of HLA-A and HLA-B alleles in a Mexico City mestizo sample. AB - The aim of the present study was to evaluate the frequency of HLA-A and HLA-B antigens in a sample of the Mexico City Mestizo population. Previous similar studies were done by other authors in nonrelated individuals, while the present investigation was performed in families (parents and offspring), and therefore, a more accurate estimate of gene and haplotype frequencies was obtained. The predominant antigens in descending order are A2, A24, and A28 at the A locus, whereas B39 and B35 are at the B locus, all with gene frequencies above 0.1. As expected, the two more frequent haplotypes were A2-B16 and A2-B35 (considering main specificities), both with frequencies of 0.056. Seven of the 18 significant delta values of the haplotypes (observed vs. expected) remained significant after correcting for the number of comparisons, indicating the presence of linkage disequilibrium between the HLA-A and HLA-B regions. However, only A1-B8 and A19 B13 were found to be in disequilibrium in another Mexico City Mestizo sample which had very similar HLA-A and HLA-B allele frequencies to those in the present survey, suggesting that the biological significance of the other associations is rather doubtful. Am. J. Hum. Biol. 9:1-5 (c) 1997 Wiley-Liss, Inc. PMID- 28561492 TI - HIERARCHICAL SELECTION THEORY AND SEX RATIOS. II. ON APPLYING THE THEORY, AND A TEST WITH FIG WASPS. AB - Predictions from the theory of sex ratios in subdivided populations are tested by studying fig wasps (Agaonidae). Observations strongly support the qualitative prediction that fig wasp sex ratios (males/total) decrease with increasing amounts of both inbreeding and competition among male relatives for access to mates (local mate competition). However, the observed sex ratio is consistently lower than predicted by previous quantitative models. Many assumptions underlying these models are unrealistic. Each unrealistic assumption is discussed as it applies to fig wasps, and where appropriate, new quantitative predictions are derived based on more realistic assumptions. New predictions are compared to the data in an a posteriori fashion and are found to be much closer to the observations than previous models from the literature, but further work will be required before a close match between theory and observation can be claimed. PMID- 28561493 TI - THE EVOLUTION OF TRACHEID DIAMETER IN EARLY VASCULAR PLANTS AND ITS IMPLICATIONS ON THE HYDRAULIC CONDUCTANCE OF THE PRIMARY XYLEM STRAND. AB - A cumulative correlation analysis of the maximum diameter of primary xylem tracheids recorded for 41 tracheophyte fossils, plotted against their ages (ranging from the Upper Silurian to the Lower Devonian), yields a Spearman rank coefficient (rsp ) of 0.696 (P < 0.01). Data for specimens taxonomically referable to zosterophyllophytes and lycopods reveal an increase in the range and maximum diameter of tracheids from the Siegenian to the Emsian. Correlation analysis of these data yields an rsp value of 0.95 (P < 0.02). The mean and maximum tracheid diameters recorded for rhyniophytes, when correlated against stratigraphic occurrence, yield rsp values of 0.81 (P < 0.05) and 0.85 (P < 0.02), respectively. A correlation analysis of the data for rhyniophytes, trimerophytes and progymnosperms yields an rsp value of 0.87 (P < 0.01). Therefore, despite a relatively small sample size of early Paleozoic plants, the available data show a surprising level of statistical robustness. The data are interpreted to indicate that during the early evolution of tracheophytes, both the range and maximum tracheid diameter of the primary xylem increased, while in some plant lineages (zosterophyllophytes) there is evidence for a plateauing of maximum tracheid diameters by the Middle Devonian. The statistical trends in the data are interpreted within the context of the evolution of the hydraulic conductance of tracheophyte primary xylem. PMID- 28561495 TI - A THEORY OF FAUNAL BUILDUP FOR COMPETITION COMMUNITIES. AB - Invasion-structured communities have more species than do coevolution-structured communities assembled using the same resource distribution. Species in invasion structured communities are tightly packed, occupying the upper portion of the resource axis; species in coevolution-structured communities are more widely spaced, and most are located in the lower portion of the resource axis. As a consequence, coevolution-structured communities tend to be more stable than comparable invasion-structured communities, but more open to invasion. Both invasion-structured and coevolution-structured communities have niche separations that are significantly different than would be expected if species were assorted at random. Two-species communities formed by the invasion-only algorithm under asymmetric competition had the majority of their niche separations in the range 0 0.5. All other communities had niche separations that were greater than expected. The most common separations were in the range 1.0-3.5. Thus, while not a common feature of many communities, nicheseparation patterns similar to those described by Hutchinson (1959) appear as an "ensemble" property of many communities. The faunal-buildup graphs formed by the coevolutionary algorithm differ from those formed by the invasion-only algorithm, showing community cycling whenever asymmetric competition is present. Through this cycling behavior the coevolutionary faunal-buildup algorithm provides both a theoretical basis for Wilson's (1959) taxon cycle and a hypothesis explaining the distribution of Anolis lizards in the Lesser Antilles. PMID- 28561496 TI - ON IRREVERSIBLE EVOLUTION. PMID- 28561497 TI - ASSOCIATIONS BETWEEN ALLOZYME FREQUENCIES AND SOIL CHARACTERISTICS IN GAILLARDIA PULCHELLA (COMPOSITAE). AB - Selection favoring different alleles in different environments frequently has been suggested as an explanation for allozyme variation within and among populations. This hypothesis predicts that allozyme frequencies will be correlated with environmental variables. Previous studies on allozyme frequency environment covariation in plants often have relied on qualitative assessments of the environment and have emphasized highly autogamous species. We have examined allozyme frequency-soil associations in Gaillardia pulchella, an obligately outcrossed annual plant, by regressing the frequencies of 15 common allozymes representing six polymorphic enzyme loci on principal components from a set of 20 quantitative soil variables. Fifty-one populations, representing four taxonomic varieties, were included in the analysis. Among the 26 populations representing the var. pulchella, allozymes Adh-2f and Pgm-1c were significantly associated with a block of highly inter-correlated soil characteristics which serve to discriminate between soils derived from calcareous vs. non-calcareous rock types. This geographically complex pattern of allozyme frequency-soil covariation is not likely to be spurious and, thus, indicates the presence of adaptively differentiated soil races, or ecotypes. However, these results are not sufficient to conclude that the allozyme frequency divergence between ecotypes was mediated by selection, either directly or through genetic hitchhiking. The pattern of allozyme frequency-soil covariation within var. pulchella was not found among the other taxonomic varieties. Patterns of genotype-environment covariation often may be recognizable only within geographically or environmentally restricted groups of populations because of the confounding influences of other environmental variables. PMID- 28561498 TI - ON ESTIMATING RELATEDNESS USING GENETIC MARKERS. PMID- 28561499 TI - MATING PREFERENCE AND ITS RELEVANCE TO ADAPTATION IN DROSOPHILA MELANOGASTER: INVERSION POLYMORPHISM AND DDT RESISTANCE. AB - The importance of adult mating success as a component of fitness influencing inversion polymorphism in two DDT-resistant populations of Drosophila melanogaster was investigated. The polymorphism involved In(3R)P and the Standard (St) gene arrangement. In population 731R the St/St females showed greater mating propensity than In/In females, while in population J2 the In/In females showed a significant positive association between mating propensity and the percentage of St/St males present. Mating preference data showed that St/St males were selectively favored over In/In males in both populations. No differences were observed between St/St and St/In karyotypes in either population. Frequency dependent mating in the form of a rare male mating disadvantage for the In/In males tested against the St/St males in 731R was observed; the St/St males in this case showed a marginally significant rare male mating advantage. Thus, mating success as well as previously measured fecundity and fertility all indicate a selective advantage of the St chromosome over the In chromosome in both populations. This fitness relationship does not predict the equilibrium condition of 70-80% St/In, 20-30% In/In, and 0-10% St/St found in the DDT environment, whereas previously collected larval viability data and estimated adult survivorship do. In at least one population (731R), the adult mating success data do predict the dynamics of the polymorphism in the absence of DDT, whereas viability does not. These results, although limited to two populations under two environments (presence or absence of DDT), suggest that the relationship between adaptation to the environment under study and various components of fitness needs to be investigated fully before assessing which fitness components are most important in determining the effects of natural selection in specific populations. PMID- 28561500 TI - REPLY TO HAFNER AND PETERSEN. PMID- 28561501 TI - ETHOLOGICAL DIVERGENCE IN ALLOPATRY AND ASYMMETRICAL ISOLATION IN THE SOUTH PACIFIC AEDES SCUTELLARIS SUBGROUP. AB - Ethological isolation among eight species of mosquitoes in the Aedes scutellaris subgroup of the south Pacific was investigated by offering females a simultaneous choice between males of their own species and males of another species. The degree of ethological isolation between these largely allopatric, island-dwelling mosquitoes was associated with time since the species had become geographically isolated by the fragmentation of the Outer Melanesian Arc 2-10 mya. The degree of ethological isolation between species pairs was observed to be significantly correlated with the degree of genetic isolation based on other published studies of allozyme variation and percentage egg hatch from interspecific hybridizations. However, ethological isolation was asymmetrical for some species pairs within the same island region. Asymmetrical isolation was especially prominent in Polynesia, where females of two older species discriminated against males of newer species, while females of the newer species failed to discriminate. PMID- 28561502 TI - alpha-LACTALBUMIN AND THE ORIGINS OF LACTATION. PMID- 28561503 TI - THE ECOLOGICAL GENETICS OF INTRODUCED POPULATIONS OF THE GIANT TOAD, BUFO MARINUS. III. GEOGRAPHICAL PATTERNS OF VARIATION. AB - The allele frequencies at ten polymorphic loci are described from 31 Bufo marinus populations in the Moreton Bay region in southeastern Queensland, Australia and the variation of these is found to be non-random in all cases. The pattern of non randomness varies among loci, being clinal in two instances. The allele frequencies at the same ten loci are also described for 12 populations sampled from throughout B. marinus' Australian range. The frequency variation on this larger geographical scale is non-random at all but two loci (Mpi and Hbdh) and also varies among loci, in this case being clinal in four instances. In both cases, the patterns of variation are most reasonably explained as having resulted from genetic drift occurring during the recent range expansion which B. marinus is known to have experienced in Australia. It seems that natural selection has played little, if any, role in generating the observed gene frequency patterns. These results emphasize the need for caution in interpreting geographical patterns of variation. They show that even when clinal patterns exist at some loci but not at others, one cannot conclude that the patterns result from natural selection, unless the demographic histories of the studied populations are known and are inconsistent with the alternative hypothesis that the patterns result from genetic drift. PMID- 28561505 TI - FAUNAL TURNOVER IN SOUTH AMERICAN FOSSIL AVIFAUNAS: THE INSUFFICIENCIES OF THE FOSSIL RECORD. PMID- 28561504 TI - HISTORICAL EVIDENCE FOR FLUCTUATION IN LEVELS OF HYBRIDIZATION. PMID- 28561506 TI - PATTERNS OF ALLOZYME RELATIONSHIPS COMPARED WITH MORPHOLOGY, HYBRIDIZATION, AND GEOLOGIC HISTORY IN ALLOPATRIC ISLAND-DWELLING MOSQUITOES. AB - Allozyme relationships were compared with morphology, interspecific hybridization, and geologic history in 14 closely-related species in the Aedes (Stegomyia) scutellaris subgroup. The phylogeny generated by the electrophoretic data was generally in agreement with morphological classifications except that one morphologically distinct species pair (A. alcasidi and A. malayensis) showed only populational differentiation and several nearly identical morphological pairs in Polynesia (e.g., A. pseudoscutellaris and A. polynesiensis) were very distant genetically. A molecular clock, based on the ratio between genetic distance and divergence time (one unit of Nei's distance = 11 million years) inferred from a dated geologic event, was used to compare zoogeography, morphology, and biochemical relationships. Genetic distances between species from the Solomon Islands and the Vanuatu-Polynesia area correspond to an early Pliocene separation of these areas. An invasion of Micronesia occurred approximately 5 million years ago. Most remaining speciation occurred during the mid-Pliocene as islands moved into their present-day positions. The close relationship between southeast Asian and Philippine species could have resulted from the recent onset of isolation in the Pleistocene. Interspecific hybridization potential was not significantly correlated with Nei's genetic distance. Many quite distantly related species readily hybridize, while some closely related pairs show only unidirectional compatibility. Slight interspecific morphological divergence and the independence of hybridization capabilities from phylogeny are not unexpected in a group in which species are allopatric and occupy similar habitats. PMID- 28561508 TI - THE SOCIETY THANKS ROBERT AND MARGARET BEER. PMID- 28561507 TI - SELECTION AMONG "SPECIES": A FORMULATION IN TERMS OF NATURAL FUNCTIONAL UNITS. AB - The unit that directly evolves under the action of higher-level natural selection "among species" must be the higher-level analogue of the population. Contrary to present formulations of "species selection," clades (or other higher taxa) do not fulfill the basic structural and dynamic criteria to be so considered. Clades are not localized, their members do not share an environment, and they cannot be said to respond to local selective regimes. Traditional species selection does not provide a causal mechanism for evolutionary change in terms of the interaction of the units of selection with a shared environment in the way that conventional organismic selection does; as used by some authors, species selection is a purely descriptive term. Communities do fulfill the criteria required by a theory of natural selection. Within communities, selection is among the populations of different species that make up the community, here termed "avatars" of those species. Avatars are the closest analogues of individual organisms in traditional selection theory. Just as populations evolve by organismic selection, communities evolve by avatar selection, and more inclusive units, the higher-level analogues of the species, evolve as their component communities do. This formulation of higher-level selection reveals a congruence with processes at the lower, organism based level and suggests the most profitable direction to be taken in attempts at formal extension of selection theory. PMID- 28561509 TI - ENVIRONMENTAL AND GENETIC DETERMINANTS OF PLANT SIZE IN VIOLA SORORIA. AB - Survivorship and fecundity in the forest herb, Viola sororia, are size-dependent. The basis of size variation among individuals of Viola sororia was investigated with a uniform environment experiment. Plants collected from natural populations were vegetatively reproduced and grown under two light regimes in a greenhouse. Analysis of quantitative variation showed: 1) significant differences between light treatments for characters related to plant shape and relative growth rate; 2) significant among-genet variation for plant size, plant shape and relative growth rate but none for physiological characters; and 3) a size threshold for cleistogamous seed production and rhizome production. Heritability estimates for the characters associated with plant size and shape ranged from 0.09 to 0.39, indicating significant genetic determination for these traits. In addition, among genet differences in relative growth rate were substantial. The results of this study suggest that the size variation found in natural populations is not solely a function of environmental heterogeneity but is significantly influenced by the genotypes composing the population. PMID- 28561510 TI - RADIAL CONDENSATION IN THE AXIS OF THE EVOLVING LIMB. PMID- 28561511 TI - SIBLING SPECIES, CALL DIFFERENCES, AND SPECIATION IN GREEN LACEWINGS (NEUROPTERA: CHRYSOPIDAE: CHRYSOPERLA). AB - Green lacewings of the morphologically homogeneous carnea-plorabunda-downesi group within the chrysopid genus Chrysoperla produce unique, species-specific, substrate-borne songs during courtship and mating; both sexes sing, and partners must reciprocally exchange their acoustical signals before copulation will occur. Two widespread, sympatric North American representatives of this complex, the sibling species pair C. plorabunda and C. downesi, hybridize readily in the laboratory but not in nature. This species pair has been presented as exemplifying sympatric speciation by disruptive selection. Here, it is shown from tape-playback and female-choice experiments that calls represent bona fide reproductive isolating mechanisms between the two species. Furthermore, call analyses of F1 , F2 , F3 , and backcross progeny of the two species confirm polygenic control of call expression, in which different alleles at each of several loci are fixed in each taxon. Sex linkage of traits is absent, but the various features of the calls are not completely independent of one another in their patterns of inheritance. These and other life-history data cast doubt on several major premises of the sympatric speciation hypothesis and suggest that call alteration might have triggered the speciation event giving rise to the siblings. A complex of cryptic "song morphs" physically and ecologically identical to C. plorabunda and C. downesi, but singing different songs, exists in the mountains of western North America, while the Alps of central Europe harbor populations of C. carnea that have undergone call differentiation in an analogous but independent manner. It is proposed that call divergence may in itself be driving the speciation process within this section of Chrysoperla, by greatly accelerating the rate at which full reproductive isolation between populations can be achieved. PMID- 28561513 TI - SUMMARY OF THE MINUTES OF THE SSE COUNCIL MEETING. PMID- 28561512 TI - AGGREGATION FORMATION AND ASSORTATIVE MATING IN TWO MELOID BEETLES. AB - Males and females of the meloid beetles Lytta magister and Tegrodera aloga form large aggregations in Sonoran Desert habitat. Males and females of L. magister fly to prominent ridgetop landmarks, where they feed on flowering shrubs, mate (probably just once in any one aggregation), and disperse, with the group forming and disbanding in a few days. Males and females of T. aloga form very large, mobile bands that march across the desert flatland feeding and mating; females probably leave after a single copulation, with the result that the group becomes increasingly male-biased in its sex ratio. The aggregations persist for a minimum of 2-3 weeks. Great variation in body size characterizes both species. Positive assortative mating occurs in L. magister but not in T. aloga, possibly because males and females of the two species incur different costs and benefits for selective mating. It is probable that body size in Lytta correlates both with female fecundity and with male spermatophore size or amount of cantharidin contributed during copulation. This should favor males that mate with large females while also favoring females that mate with large males. If large individuals pair off, this will leave smaller individuals to settle for one another, leading to positive assortative mating. The same argument may not apply to T. aloga, perhaps because its copulations are shorter and its aggregations longer-lived, and therefore any one mating does not eliminate chances to copulate again within the band. PMID- 28561514 TI - THE GENETIC BASIS OF THE ECOLOGICAL AMPLITUDE OF SPARTINA PATENS. II. VARIANCE AND CORRELATION ANALYSIS. AB - Reciprocal transplantations of Spartina patens genotypes from adjacent salt marsh, swale, and dune habitats provided evidence for genetic differentiation among subpopulations, due at least in part to contrasting selection regimes. Genet survival in the different habitats was related to the amount of genetic divergence. In the dune habitat, marsh ramets showed the lowest survival, swale ramets showed intermediate survival, and dune ramets showed the highest survival. This relationship was not reciprocal, however. The marsh habitat afforded an environment where survival was maximal for all genotypes. Thus, by comparison, the dune environment appeared to impose a more intense selection pressure, and the swale an intermediate selection pressure on Spartina patens. In each site resident genotypes tended to show greater relative fitness than aliens. This evidence for genetic divergence corroborates that previously reported on morphometric (Silander and Antonovics, 1979) and allozymic traits (Silander, 1984). High levels of phenotypic plasticity may permit greater adaptation to the spatially and temporally heterogeneous environment occupied by S. patens than would genetic variation alone. Dune and swale genets were more phenotypically plastic across traits examined than were marsh genotypes. The higher plasticity in these peripheral subpopulations may confer increased fitness among residents and compensate for observed declines in genetic variation. A slight decrease in genetic variability was evident from marsh to dune subpopulations. However, since the differences in genetic variation among subpopulations were small, and disparities did occur, it is unlikely that evolutionary divergence is retarded primarily by a lack of genetic variability in the characters considered. Evidence is presented to indicate that evolutionary divergence among subpopulations may be retarded by negative or unfavorable correlations among characters being selected simultaneously. These negative correlations may increase extinction probabilities in small peripheral populations, such as those represented by the dune or swale, and are likely to lower fitness. Based on these observations, I hypothesize that further microevolution may be retarded in peripheral dune and swale subpopulations, primarily by unfavorable genetic correlation structures among fitness components or characters under simultaneous selection. Contributing factors may include lowered genetic variance and higher levels of phenotypic plasticity. PMID- 28561515 TI - WHY DISTASTEFUL BUTTERFLIES HAVE APOSEMATIC LARVAE AND ADULTS, BUT CRYPTIC PUPAE: EVIDENCE FROM PREDATION EXPERIMENTS ON THE MONARCH AND THE EUROPEAN SWALLOWTAIL. PMID- 28561516 TI - THE EFFECTS OF MULTIPLE FACTORS ON VIABILITY SELECTION IN HYLA GRATIOSA TADPOLES. AB - Two full sib families of Hyla gratiosa larvae were compared in growth rate and survival under twelve ecological conditions in field enclosures. The twelve conditions represented the independent absence or presence of two predators (nymphal dragonflies and larval salamanders) and a range of three initial tadpole densities (8, 16, 32 larvae per enclosure). This 2 * 2 * 3 design for variance analysis was replicated five times in a natural pond. The presence of either predator reduced survival levels by 24%. There was no consistent effect of tadpole density on survival. However, at low tadpole density (8 per enclosure), the presence of salamanders did not affect tadpole survival levels; effect of the salamanders was restricted to the higher densities (16 and 32 per enclosure). The combined effect on overall survival of the two predators was additive. One sibship (denoted A) consistently displayed a higher survival level than the other (denoted B). However, the level of differential survival, measured as the survival of B relative to A, varied among predator combinations. Survival differences among treatments and sibships were related to body size differences. The changing levels of differential survival between sibships did not reflect a changing level of differential body size but, rather, an ecologically mediated change in the relationship between the level of body size variation and the subsequent level of survival variation. Ecological factors such as conspecific density variation or predator abundance do not act as isolated selective pressures but, rather, interact in their effects on mortality rates. These interactions cause the value of a trait related to a fitness component to vary with ecological condition. These results suggest that a thorough understanding of how selection really does act in natural populations requires a thorough understanding of the relevant ecological factors, a point all too often unappreciated. PMID- 28561517 TI - Malakoplakia after kidney transplantation: Case report and literature review. AB - Malakoplakia is a granulomatous disease associated with an infectious etiology, usually involving the urinary tract. It reveals itself as a recurrent urinary tract infection (r-UTI), and in some cases, it is associated with impairment of renal function. Immunosuppression is one of its main associated factors, and it has been increasingly described in patients with solid organ transplantation (SOT), mainly kidney transplantation. Macroscopically, it can form masses and sometimes it may be confused with neoplasia, which is why histological findings are fundamental for the diagnosis. Here, we present a case of bladder malakoplakia, manifested by r-UTI from Escherichia coli in a patient with renal transplantation, refractory to long-term antibiotic treatment and reduction in immunosuppression, which resolved after surgical management. We also summarize the clinical characteristics of malakoplakia and compare them with previous reports in the literature on SOT. PMID- 28561518 TI - Bioelectrical impedance changes during the menstrual cycle. AB - Numerous physiological factors that may influence estimates of body composition based on bioelectrical impedance analysis (BIA) have been recognized. The two studies to date investigating changes in bioelectrical impedance during the menstrual cycle have produced conflicting results. Male control subjects were included in this study in an attempt to discern variations in bioelectrical impedance associated with the menstrual cycle in women from those due to other physiological variables affecting both sexes. Body weight and bioelectrical impedance (tetrapolar Holtain Analyzer; 50 kHz, 800 MUA) were measured two to five times per week for one menstrual cycle (21-34 days) on 42 women (6 taking an oral contraceptive, OC), aged 19.0-34.4 years, and for 22-32 days on 28 men (18.9 24.1 years). Body weight in the non-OC women decreased significantly between menses and the late follicular phase, and increased significantly between the late follicular phase and the premenstruum (paired t test, P < 0.05). These changes were not correlated with matching bioelectrical impedance changes (linear regression, P > 0.05). Bioelectrical impedance in the non-OC women, and body weight and bioelectrical impedance in the OC women and the men, did not differ significantly over the measurement period. Likewise, estimated lean body mass (LBM) and total body water (TBW) derived from BIA remained stable. The intraobserver test-retest reliability (Smeas ) of bioelectrical impedance was 12.3 ohm (2.8% of mean bioelectrical impedance) which produced as much as a 10 12% error in estimating LBM and TBW. Measurement error was reduced to 4 ohm in a subgroup where electrode positions were marked with indelible ink. These results indicate that body composition assessments based on BIA measured at 50 kHz are not affected by the menstrual cycle. Am. J. Hum. Biol. 9:155-161, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561519 TI - Developmental, genetic, and environmental components of lung volumes at high altitude. AB - Vital capacity and residual lung volume (in terms of 1/min or ml/m2 of body surface area) of 357 subjects (205 males, 152 females) was evaluated in La Paz, Bolivia, situated at 3,750 m. The sample included: (1) 37 high altitude rural natives (all male), (2) 125 high altitude urban natives (69 male, 58 female), (3) 85 Bolivians of foreign ancestry acclimatized to high altitude since birth (40 male, 45 female), (4) 63 Bolivians of foreign ancestry acclimatized to high altitude during growth (30 male, 33 female), and (5) 47 non-Bolivians of either European or North American ancestry acclimatized to high altitude during adulthood (24 male, 23 female). Results indicate that (1) all samples studied, irrespective of origin or acclimatization status, have larger lung volumes than those predicted from sea level norms; (2) the high altitude rural natives have significantly greater lung volumes (vital capacity and residual lung volume) than the high altitude urban natives and all the non-native high altitude samples; (3) males acclimatized to high altitude since birth or during growth attain similar lung volumes as high altitude urban natives and higher residual lung volumes than subjects acclimatized to high altitude during adulthood but lower than the high altitude rural natives; (4) females acclimatized to high altitude since birth or during growth attain similar lung volumes as subjects acclimatized to high altitude during adulthood; (5) age at arrival to high altitude is inversely related to residual lung volume but not vital capacity; (6) among subjects acclimatized to high altitude during growth, approximately 20-25% of the variability in residual lung volume can be explained by developmental factors; (7) among high altitude rural and urban natives, it appears that approximately 20 25% of the variability in residual lung volume at high altitude can be explained by genetic traits associated with skin reflectance and genetic traits shared by siblings; and (8) vital capacity, but not the residual lung volume, is inversely related to occupational activity level. Together these data suggest that the attainment of vital capacity at high altitude is influenced more by environmental factors, such as occupational activity level, and body composition than developmental acclimatization. On the other hand, the attainment of an enlarged residual volume is related to both developmental acclimatization and genetic factors. Am. J. Hum. Biol. 9:191-203, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561520 TI - Facial clefting and Amerindian admixture in populations of Santiago, Chile. AB - Among congenital malformations, cleft lip with and/or without cleft palate has the highest relative frequencies and shows ethnic variation in prevalence. Both malformations are generally more common among the Asian than European populations. Many populations of Chile have genes of Amerindian and Spanish ancestry, with considerable variation in the degree of Amerindian admixture. Therefore, the association of clefting incidence with Amerindian admixture was investigated. The frequency of cleft lip and/or cleft palate in infants born in three private and two public maternity service clinics of Santiago, Chile, is reported. The private clinic patients have a higher socioeconomic status (SES) than those receiving the public services. They also differ in estimated Amerindian admixture. More than 200,900 consecutive birth records were reviewed. The rate of clefting malformations is 15.3 per 10,000 live births. Based on allele frequencies at the ABO and Rh blood group loci, the percentage of Amerindian admixture is higher in infants born in the public compared to those born in the private maternity service clinics. Amerindian admixture is positively correlated (Spearman's p = 0.9, P = 0.008) with clefting rate across these samples. Clefting is also associated with SES, with lower SES showing higher clefting rates. Mothers of clefting newborns also have higher estimated Amerindian admixture compared to those of normal newborns. The results support the view that in Chilean populations, susceptibility to clefting is related to Amerindian ancestry. Am. J. Hum. Biol. 9:225-232, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561521 TI - Distribution of subcutaneous fat and muscle thicknesses in young and middle-aged women. AB - Thicknesses of subcutaneous fat tissue at 13 sites (triceps, biceps, forearm, subscapular, abdomen, suprailiac, axilla, chest, quadriceps, suprapatellar, hamstrings, posterior calf, medial calf), and muscle tissue at nine sites (triceps, biceps, forearm, subscapular, abdomen, quadriceps, suprapatellar, hamstrings, posterior calf) were determined by using the B-mode ultrasound technique. Subjects were 36 young (18-29 years) and 44 middle-aged women (45-64 years). Body density averaged 1.047 +/- 0.007 g . ml-1 (SD) for the young, and 1.022 +/- 0.005 g . ml-1 for the middle-aged women. The middle-aged women showed significantly thicker subcutaneous fat than the young at all sites, and the relative differences between the two groups were larger on the trunk and adjacent sites. Muscle thicknesses on the trunk and quadriceps were significantly higher in the young women than in the middle-aged, but values for the upper extremities and calf were not significant between the two groups. The sum of subcutaneous fat thicknesses at 13 sites was significantly correlated with fat mass relative to the second power of stature (FM . St-2 ) in both groups, r = 0.766 (P < 0.05) for the young and r = 0.803 (P < 0.05) for the middle aged women. For subcutaneous fat thickness per unit FM . St-2 , the young women showed significantly higher values than the middle-aged on both the upper and lower extremities. The sum of muscle thicknesses at nine sites was significantly correlated with fat-free mass per unit stature2 (FFM . St-2 ) in both groups, r = 0.764 (P < 0.05) for the young and r = 0.636 (P < 0.05) for the middle-aged. The relative values of muscle thicknesses to FFM . St-2 were significantly lower on the abdomen and quadriceps in the middle-aged women than in the young. Thus compared with the young, the middle-aged women have thicker subcutaneous fat thicknesses along the whole body and thinner muscle thicknesses on the trunk and quadriceps regions. Moreover, it appears that in middle-aged women, the relative distribution of subcutaneous fat and muscle thicknesses to FM and FFM, respectively, show disproportionately higher fat stores internally than subcutaneously, and more rapid atrophy of muscle tissues at the anterior sites of the trunk and thigh than at other body sites. Am. J. Hum. Biol. 9:247-255, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561522 TI - Role of infant feeding practice, sex, and age on fatness and subcutaneous fat distribution in infancy: Longitudinal analysis of multiple skinfold measurements. AB - The aim of this study was to determine whether subcutaneous fatness and fat distribution differ on the basis of feeding practice and sex during the first 6 months of life. Longitudinal principal components analysis (PCA) was done on skinfolds measured at five sites in 45 breast-fed and 41 formula-fed infants. The first component represented fatness, the second component change in fatness, and the third component upper body/lower body fat distribution. Analysis of the components indicated that fatness and the proportion of lower body fat were greater in breast-fed than in formula-fed infants; however, when race was included as a predictor, the differences in lower body fat did not persist. The interpretation of components and the group differences were confirmed by repeated measures analysis of variance (ANOVA) on the sum of skinfolds (fatness) or simple skinfold ratios (fat distribution). Group differences for fatness and upper body/lower body fat persisted when race was included as a predictor. Longitudinal PCA of another indicator, the Rohrer index, suggested that fatness was greater in formula-fed than breast-fed infants. Collectively, these findings suggest that formula-fed infants have less subcutaneous fat than breast-fed infants; however, formula-fed infants may have either more internal fat or more lean body mass. Am. J. Hum. Biol. 9:179-190, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561523 TI - Absence of the alpha-1-antitrypsin PI*Z allele in Tunisia substantiates the particular genetic structure of African populations. AB - Alpha-1-antitrypsin (PI) phenotypes were studied in a sample of 450 Tunisians. The observed frequencies of PI alleles were identical to those in African populations, with a very low incidence of PI*S and virtual absence of PI*Z. Such figures are similar to estimates in Asians and clearly opposite to those in Europeans. Am. J. Hum. Biol. 9:223-224, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561524 TI - Lactose digestion capacity and perceived symptomatic response after dairy product consumption in Tokelau Island migrants. AB - When lactose-malabsorbing individuals use dairy products decreased lactase activity and the subsequent reduction in hydrolysis of ingested lactose can result in gastrointestinal and gaseous symptoms (lactose intolerance). This article examines lactose malabsorption, perceived gastrointestinal symptoms, and dairy product consumption in a Tokelau Island migrant population in New Zealand. Questionnaire data were collected and lactose digestion capacity was determined for 58 individuals 15-71 years of age. Additional questionnaire data were collected for 137 Tokelau migrants, 18-50 years of age. Breath hydrogen analysis indicated that 63.8% (CI = 51.4-76.2%) of Tokelau migrants were lactose malabsorbers, while 22.4% (11.7-33.1%) can absorb lactose [results are inconclusive for 13.8% (4.9-22.7%) of the population]. This was consistent with results reported for other Polynesian populations. Tokelau Island migrants reported relatively low levels of gastrointestinal distress after the consumption of daily products. Less than 50% of those with lactose malabsorption perceived gastrointestinal symptoms after a 50 g of lactose in 300 ml of water, while one third of this group reported symptoms after approximately 240 ml (one glass) or less of milk. However, without confirmation by double-blind studies, it is difficult to state the extent to which symptoms are actually due to lactose. Neither the ability to absorb lactose nor perceived gastrointestinal symptoms are associated with the frequency or quantity of dairy product consumption (P > 0.05). Patterns of dairy product consumption are just as likely due to other physiological, psychological, cultural, and social factors. Am. J. Hum. Biol. 9:233-246, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561525 TI - Carrier detection of hemophilia by immunological and coagulation assays in a selected sample of the Mexican population. PMID- 28561526 TI - Assessment of enamel hypoplasia in a high status burial site. AB - Social differentiation is a characteristic of all societies, and higher social status is often associated with better nutrition and good health. Traditional archeologically inferred social status has been linked with biological evidence such as skeletal robusticity and the incidence of disease. In this regard, linear enamel hypoplasia (LEH) is considered a good indicator of health, and individuals with a high status should, at least in theory, not suffer from severe defects. In order to test this hypothesis, the prevalence and occurrence of LEH were assessed in a skeletal sample at the Fort Center, Florida, site. Located near Lake Okeechobee, this site was occupied from about A.D. 200-800, and was considered a mortuary ceremonial center. These archeological findings suggested that individuals buried there belonged to a high class and merited special mortuary rituals. Although 1,835 teeth were found, only 679 maxillary and 393 mandibular teeth were analyzed. The upper I1 and lower C are reported to be most representative for LEH, and were thus selected for further analysis. There were 45 left incisors and 48 left canines. Results indicated that about 95% of incisors and 98% of canines were affected. The occurrence of severe hypoplastic lines was much lower (between 30% and 40%). The minimum number of defects affecting the canine surpassed three, thus showing evidence of repeated stress during childhood. Hypoplasia was first observed between the ages of 1.0 and 1.5 years for incisors and between 2.0 and 2.5 years for canines. Severe defects were first noted to occur at 2.5-3.0 years of age for incisors and 3.0-3.5 years for canines. In conclusion, the high frequency of LEH in this socially elite population seems to prove that in prehistory even privileged classes were severely subjected to stress and the social stratification alone was not sufficient to buffer them from rigorous environments. Am. J. Hum. Biol. 9:213 222, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561527 TI - Relationship of physical performance to maturation in perimenarchal girls. AB - The relationship of physical performance to maturation, characterized by the onset of menarche, was examined annually from 1989 to 1992 among 61 healthy, active perimenarchal girls from 10 to 14 years. Within each age group, differences in selected physical performance variables between and among three maturity groups, early, average, and late, were compared. Subjects categorized as having early or late maturation were those whose age at menarche was minus or plus, respectively, one standard deviation from the mean age at menarche 12.70 + 0.99 yr (range 10.29-14.65). Subjects demonstrated steady progression with age in breast and pubic hair development. Weight, estimated lean body weight and fat weights, and stature increased significantly with age and maturation. With the exceptions of flexibility, bent arm hang, standing vertical jump, and relative maximum oxygen uptake, the performance measures of running speed, functional strength, explosive strength, static strength, upper body power, and aerobic power improved significantly with age and maturation. Generally more mature subjects tended to perform significantly better than the less mature, but there are fewer significant performance differences between and among maturation groups within specific age groups. Therefore, whereas more mature 10- and 14-year-old females may, within the same age group, have only a very slight advantage in some physical performance abilities over their less mature age mates, more mature females aged 11, 12, and 13 years have a greater physical performance advantage. Am. J. Hum. Biol. 9:163-171, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561528 TI - Age at menarche and comparison of the growth and performance of pre- and post menarcheal girls in China. AB - The median menarcheal ages (MMAs) of Chinese girls in 1991 were calculated by using the status quo method and probit analysis in 64,322 schoolgirls 8-18 years of age. The sample was randomly selected from 29 provinces of China. The MMAs were 13.01 +/- 1.19 and 13.64 +/- 1.24 years for urban and rural girls, respectively. These estimates were 0.16 and 0.20 years lower than that of Chinese urban and rural girls in 1985, respectively. The associations between growth status and the timing of menarche were also analyzed by comparing of 10 indicators of somatic growth and motor ability between the pre- and post menarcheal girls. Early maturers consistently have high means of stature, weight, and vital capacity than late maturers. By contrast, the late maturers tend to have a linear physique and more potential of increasing stature and lower limbs into late adolescence. Late maturers also tend to have more potential in catching up in motor abilities, which were inferior to those of early maturers during early adolescence. Am. J. Hum. Biol. 9:205-212, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561529 TI - Somatotypes of 7- to 16-year-old boys in Saskatchewan, Canada. AB - The purpose of this study was to examine the stability of somatotypes of 63 boys in Saskatoon, Canada who were followed from 7 to 16 years of age. Somatotype photos were taken annually and rated by a criterion rater (BH-R). Comparisons were made longitudinally across all years using repeated-measures ANOVAs of the whole somatotype (S), somatotype attitudinal means (SAM), analysis of categories, separate components (endomorphy, mesomorphy, ectomorphy), and partial correlations. In the first year, the means were age = 7.1 yr, height = 121.0 cm, mass = 22.8 kg, S = 2.9-3.6-1.6, and SAM = 1.1. In the last year, the means were age = 16.7 yr, height = 172.6 cm, mass = 59.9 kg, S = 2.5-4.0-3.7, and SAM = 1.4. Mean somatotypes across years were different [F(9,558) = 67.9, P < .01], with the largest differences between 7-10 yr and 14-16 yr. These differences were largely due to significant increases in mesomorphy (F = 24.6, P < .01) and ectomorphy (F = 159.9, P < .01). Partial correlations between ages for each component, with the other two held constant, revealed poor predictions for three or more years apart (r2 < .35). Thus, both group and individual somatotypes changed between 7 and 16 years of age. The overall pattern was from endo-mesomorph through central to mesomorph-ectomorph somatotypes. The trends are similar to those observed in comparable samples from other countries. Am. J. Hum. Biol. 9:257-272, 1997. (c) 1997 Wiley-Liss, Inc. PMID- 28561530 TI - Preparation of a novel radiotracer targeting the EphB4 receptor via radiofluorination using spiro azetidinium salts as precursor. AB - The visualization of Eph receptors, which are overexpressed in various tumor entities, using selective small molecule Eph inhibitors by means of positron emission tomography is a promising approach for tumor imaging. N (Pyrimidinyl)indazolamines represent a class of compounds, which are known to have high affinity especially for the EphB4 receptor. Radiofluorination of these compounds could provide a highly specific imaging agent and was investigated using a classical nucleophilic introduction of [18 F]fluoride as well as a less common nucleophilic ring-opening reaction of azetidinium salts. In the past, radiofluorinations using azetidinium precursors were demonstrated to result in high radiochemical yields in short periods. For this purpose, an azetidinium precursor based on the N-(pyrimidinyl)indazolamine lead compound was developed, and radiofluorination was successfully accomplished. The respective [18 F]radiotracer was quickly prepared with high radiochemical purity >97% and in a radiochemical yield of 34%. PMID- 28561531 TI - Chemical Recognition of Active Oxygen Species on the Surface of Oxygen Evolution Reaction Electrocatalysts. AB - Owing to the transient nature of the intermediates formed during the oxygen evolution reaction (OER) on the surface of transition metal oxides, their nature remains largely elusive by the means of simple techniques. The use of chemical probes is proposed, which, owing to their specific affinities towards different oxygen species, unravel the role played by these species on the OER mechanism. For that, tetraalkylammonium (TAA) cations, previously known for their surfactant properties, are introduced, which interact with the active oxygen sites and modify the hydrogen bond network on the surface of OER catalysts. Combining chemical probes with isotopic and pH-dependent measurements, it is further demonstrated that the introduction of iron into amorphous Ni oxyhydroxide films used as model catalysts deeply modifies the proton exchange properties, and therefore the OER mechanism and activity. PMID- 28561532 TI - Pretreatment albumin level predicts survival in head and neck squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: Poor nutritional status in patients with head and neck squamous cell carcinoma (HNSCC) is associated with tumor progression and survival. This study examined the prognostic value of nutritional and hematological markers in patients with HNSCC who received definitive treatments. STUDY DESIGN: A prospective observational cohort study. METHODS: This study included 338 consecutive patients who underwent surgery and/or radiotherapy/chemoradiotherapy for treatment-naive HNSCC. Body weight and nutritional and hematological parameters were regularly measured before and after treatment. Univariate and multivariate analyses using Cox proportional hazards models were performed to identify factors associated with disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: Body weight, serum total protein and albumin levels, and hematological variables significantly decreased after treatment. Univariate analyses illustrated that age, tumor site, T and N classifications, overall stage, pretreatment serum albumin (<3.5 g/dL) and hemoglobin (<12 g/dL) levels, and neutrophil-lymphocyte ratio were significantly associated with DFS, CSS, and OS (all P < .05). Multivariate analyses identified age, tumor site, N classification, and pretreatment albumin levels as independent predictors of DFS, CSS, and OS (all P < .05). Patients with low serum albumin levels prior to treatment experienced approximately sixfold increases in the risks of tumor progression and cancer specific and overall mortality compared to the findings in their counterparts. CONCLUSIONS: Our results suggest that pretreatment serum albumin levels predict DFS, CSS, and OS in patients who received definitive treatment for HNSCC. These findings might help to predict treatment outcome and guide nutritional intervention in patients with HNSCC. LEVEL OF EVIDENCE: 2b. Laryngoscope, 127:E437-E442, 2017. PMID- 28561533 TI - Emergence of Bruton's tyrosine kinase-negative Hodgkin lymphoma during ibrutinib treatment of chronic lymphocytic leukaemia. AB - Chronic lymphocytic leukaemia (CLL) is a chronic B-cell lympho-proliferative disorder in which lymphomatous transformations occur in 5%-15% of patients. Histologically these cases resemble diffuse large B-cell lymphoma, or Richter's transformation, in over 80% of cases. Rare cases of transformation to Hodgkin lymphoma (HL) have been reported in the literature with an estimated prevalence of 0.4%. We report a case of a 67-year-old female with CLL treated with the novel Bruton's tyrosine kinase (Btk) inhibitor, ibrutinib, who subsequently presented with intractable fevers. Bone marrow trephine, and lymph node biopsy revealed classical HL with negative immuno-histochemistry for Btk in HL cells, on a backdrop of CLL. The patient commenced treatment with Adriamycin, Vinblastine and Dacarbazine (AVD), which resulted in an excellent response. Hodgkin transformation of CLL is rare with a single retrospective study of 4121 CLL patients reporting only 18 cases. Btk expression in HL cells is recently recognised in classical HL; however, the majority of HLs are Btk negative. Given that Btk inhibitors have recently been shown to induce genomic instability in B cells, in the context of their widespread use, such emerging cases are increasingly relevant. PMID- 28561535 TI - Lita F. Osmunden. PMID- 28561536 TI - Serial changes in blood pressure from childhood into young adulthood for females in relation to body mass index and maturational age. AB - This study determines: (1) patterns of change from childhood to young adulthood in body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP), (2) effects of elevated BMI values on changes in blood pressures (BP), (3) extent of tracking for SBP, DBP, and BMI, and (4) prediction of future risk for elevated BP from earlier values. Annual serial BP and BMI data were available for 198 white females, ages 8-22 years, enrolled in the Fels Longitudinal Study. Patterns of change in BMI were described by a random effects model with a time series model for the correlated residuals. Serial BMI measures were differentiated from age-specific means to measure relative individual BMI levels. Serial BP were analyzed using a similar model to the BMI where relative individual BMI levels were included as an explanatory variable. There was a general increasing trend for SBP, DBP, and BMI from 8-22 years, but the rates of increase declined with age. At the same chronological age, early menarche females had a significantly greater BMI mean value than late menarche females. An average increase of 1 kg/m2 in deviation from BMI population means resulted in an average increase of 1.2 mmHg in SBP and 0.6 mmHg in DBP. Having SBP and DBP levels 1 standard deviation above mean levels, relative to females at mean levels, as early as age 9 represents an odds ratio of 2 for exceeding national 75th percentile levels of SBP and DBP at age 21. Am. J. Hum. Biol. 10: 589-598, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561534 TI - Gender differences in healthy aging and Alzheimer's Dementia: A 18 F-FDG-PET study of brain and cognitive reserve. AB - Cognitive reserve (CR) and brain reserve (BR) are protective factors against age associated cognitive decline and neurodegenerative disorders. Very limited evidence exists about gender effects on brain aging and on the effect of CR on brain modulation in healthy aging and Alzheimer's Dementia (AD). We investigated gender differences in brain metabolic activity and resting-state network connectivity, as measured by 18 F-FDG-PET, in healthy aging and AD, also considering the effects of education and occupation. The clinical and imaging data were retrieved from large datasets of healthy elderly subjects (HE) (225) and AD patients (282). In HE, males showed more extended age-related reduction of brain metabolism than females in frontal medial cortex. We also found differences in brain modulation as metabolic increases induced by education and occupation, namely in posterior associative cortices in HE males and in the anterior limbic affective and executive networks in HE females. In AD patients, the correlations between education and occupation levels and brain hypometabolism showed gender differences, namely a posterior temporo-parietal association in males and a frontal and limbic association in females, indicating the involvement of different networks. Finally, the metabolic connectivity in both HE and AD aligned with these results, suggesting greater efficiency in the posterior default mode network for males, and in the anterior frontal executive network for females. The basis of these brain gender differences in both aging and AD, obtained exploring cerebral metabolism, metabolic connectivity and the effects of education and occupation, is likely at the intersection between biological and sociodemographic factors. Hum Brain Mapp 38:4212-4227, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28561537 TI - Perceptions and patterns of physical activity: A comparison of Mohawk/Cayuga and non-native adolescents. AB - This study examined the relationships between habitual physical activity and self referent thought among Native and non-Native grade 9 students in Southern Ontario. The Habitual Activity Estimation Scale (HAES) and the Children's Self perception of Adequacy in and Predilection for Physical Activity (CSAPPA) scale were administered to 74% of eligible native students (13M, 13F) and 87% of eligible non-Native students (65M, 65F). All were attending the same secondary school, adjacent to the Six Nations (Mohawk/Cayuga) reservation. Natives and non Natives differed (P < .01) with respect to physical activity levels, predilection for physical activity, and enjoyment of physical education, with Native students reporting less physical activity than the non-Native group. There were no significant differences in perceived adequacy between the two groups. Further investigations are needed to determine how far these results can be generalized to less prosperous Native bands in other parts of Canada and the U.S. Nevertheless, it appears that physical educators should develop culturally appropriate interventions to increase physical activity among Native youth, in consultation with Native leadership. Am. J. Hum. Biol. 10:629-635, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561538 TI - Nutrition, bone mass, and subsequent risk of hip fracture in white women. AB - The interrelationships between nutritional status, concurrent bone density, bone dimensions, and risk of subsequent hip fracture were investigated using data from the first National Health and Nutrition Examination Survey and its three follow up studies. A cohort of 890 White women aged 45 years or older who received nutritional and bone measurements in the baseline survey in 1971-75 were recontacted in 1982-84, 1986, and 1987. Height, weight, serum albumin, total energy intake, bone density, and bone dimensions were measured at baseline. Thirty-three incident hip fractures were identified during 12,190 person-years of follow-up. Total energy intake and serum albumin were little correlated with concurrent bone density and bone dimensions. Serum albumin, total energy intake, and weight tended to be inversely associated with risk of hip fracture. The multivariable relative risks were 0.75 (95% confidence interval [CI] = 0.57-0.98) for one standard deviation increment of serum albumin, 0.67 (95% CI = 0.42-1.07) for dietary energy intake, and 0.61 (95% CI = 0.38-0.97) for weight, respectively. Height was positively, but not significantly associated with risk of hip fracture. Nutritional effects on hip fracture were independent of concurrent bone density and bone dimensions. Higher bone density was protective of subsequent hip fracture (relative risk = 0.55, 95% CI = 0.36-0.83, for one standard deviation increment of bone density) independent of effects related to concurrent nutritional status. Thus, poor nutritional status and reduced bone density appeared to increase the risks of subsequent hip fracture independently. Am. J. Hum. Biol. 10:661-667, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561539 TI - Growth studies in Jena, Germany: Changes in body size and subcutaneous fat distribution between 1975 and 1995. AB - This report presents results of an anthropological investigation on Jena, Germany, schoolchildren from 1995. Stature and weight, body mass index (BMI), and four skinfolds (biceps, triceps, subscapular, suprailiac) are presented for children 7-14 years of age and are compared with results of investigations on schoolchildren carried out in Jena in 1975 and 1985. Between those years, in both sexes there were no significant differences in stature, weight, and consequently in the BMI. In this timespan, a trend toward a reduction of subcutaneous fat was noted. A different development was observed in the period 1985-1995. Stature as well as body weight increased, and because the increase in weight was greater than expected from the increase in stature, there also was an increase in the BMI. A large increase in overall subcutaneous fatness was also found. In 1995, the highest amount of body fat was observed in Jena children since 1975. Changes in the distribution of subcutaneous fat tissue occurred. Between 1975 and 1985, the ratio of trunk to extremity skinfolds (T/E ratio) decreased significantly in boys and girls in all ages, but increased between 1985 and 1995. In spite of this increase, children had the largest T/E ratio in 1975. Changes in the nutritional situation and other factors in living conditions, possibly related to the unification of Germany in 1989 influencing somatic development, are considered. Am. J. Hum. Biol. 10:579-587, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561540 TI - Fertility, migration, and mortality in an old order Amish community. AB - Mortality, fertility, and migration data were used to identify population structure in a group of Old Order Amish living in New York State. Two thousand and sixteen individuals were accounted for since the community was first formed in 1948 and this is nearly total ascertainment of the population. Further, ethnography compared Amish households to neighboring non-Amish households to understand differences in health beliefs, caregiving patterns, and economic strategies. Despite evidence that suggests that the Amish have health risks comparable to U.S. population and that they under-utilize health care, this study demonstrates that Amish age standardized death rates are 19% below the U.S. death rate in 1960. Natural fertility combined with low infant mortality, migrating to form new communities when population density increased, and selective but appropriate use of western biomedicine have emerged as strong cultural patterns that facilitated reproductive success and longevity among the Amish. Am. J. Hum. Biol. 10:619-628, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561541 TI - Changes in height and motor performance relative to peak height velocity: A mixed longitudinal study of Spanish boys and girls. AB - Longitudinal changes in stature and motor performance were studied in an adolescent sample of 36 boys and 53 girls. Peak height velocity (PHV) was determined in 28 boys and 38 girls using non-smoothed polynomials. The estimations of PHV and the age-at-PHV are, respectively, 11.4 +/- 2.2 cm/yr and 13.0 +/- 0.63 years (boys), and 8.7 +/- 1.6 cm/yr and 12.4 +/- 0.57 years (girls). Performances in explosive strength (standing long jump; medicine ball throw) and flexibility (trunk maximal flexion) exhibit peak development during the year following PHV in both sexes. Maximal mean growth velocities in an endurance run (six minutes) occur before PHV in girls and after PHV in boys. Peak velocities in agility (4 * 6 m shuttle run), running speed (40 m dash) and abdominal strength-resistance (sit-ups for 30 seconds) occur before PHV in both sexes. There also is an acceleration of performances in these three tests after PHV. The results indicate that performance in several motor tests shows an adolescent spurt of an intensity that is proportionally comparable to the adolescent height spurt in both sexes. The dynamics of changes in motor performance in relation to PHV appears similar in both sexes. The most striking difference occurs in the endurance run. Am. J. Hum. Biol. 10:647-660, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561542 TI - Genetic structure of southwestern Corsica (France). AB - The distribution of nine red cell enzymes (ACP, ADA, AK, DIA, ESD, GLO1, PGM1, PGD, and SOD) and seven plasma proteins (C3, GC, HP, ORM, PI, PLG, and TF) was analyzed in a sample of 274 unrelated individuals from the southwestern area of Corsica (France), specifically from Ajaccio and nearby villages. The aim of the research was to study the genetic structure of Corsica and to add further to our knowledge about microgeographic variability of polymorphisms in Corsica. The analysis, carried out by genetic distances and R-matrix through 39 alleles of 13 genetic markers, reveals a certain degree of differentiation within Corsica. The results show a genetic heterogeneity between Corsica and other European and Mediterranean populations, although the genetic differences appear to be smaller between Corsicans and Sardinians than among Corsicans and other compiled populations. Am. J. Hum. Biol. 10:567-577, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561543 TI - Secular growth changes in the stature and weight of Amerindian schoolchildren and adults in the Chilean Andes, 1972-1987. AB - A positive secular trend for stature and weight is evident in rural Aymara speaking Indians of the Parinacota Province (>3,000 m) in the northern Chilean Andes. The study is based on two cross-sectional growth surveys carried out in 1972 and 1987. In the survey of 1972, which was undertaken by other authors, a sample of 190 individuals was considered. The 1987 survey, performed by the present author, comprises a sample of 170 Indians. Both children and adults of each sex, ages 6-29 years, are included. Secular comparisons of age-grouped means indicate a secular increase in stature and weight in Aymara children, adolescents, and adults in the Parinacota Province between 1972 and 1987. The Aymara tend to be taller and heavier in 1987. The estimated secular increase for stature is 2.1 cm/decade for males and 1.8 cm/decade for females. For weight, the increase is 2.3 kg/decade for males and 1.5 kg/decade for females. In all cases, growth gains tend to be greater in males than in females. The body mass index also increases slightly. The secular changes in stature and weight are statistically significant in both sexes. From additional nutritional data on the Aymara samples compared, it is concluded that the observed secular increases might primarily reflect improved food supply over the past two decades. Am. J. Hum. Biol. 10:607-617, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561544 TI - Non-linear patterns of growth in very low birth weight infants. AB - The deviations of daily weight, weekly length and head circumference from linear growth were analyzed in 87 very low birth weight infants. The deviations exhibited a highly significant polynomial oscillation not only for weight, but also for length and head circumference. The weight amplitudes were larger for males than for females. They were also larger in infants appropriate for gestational age than in small-for-date infants. The difference with trophicity may be related to the process of adjustment of catch-up in small-for-date infants. However, the mechanisms of these oscillatory deviations could also be explained by clinical events, method of feeding, or homeostatic regulation. Further studies are required to elucidate the role of the different factors. Am. J. Hum. Biol. 10:637-646, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561545 TI - Skin reflectance of lowland Bolivian youths of European ancestry. AB - The skin reflectances of 257 Bolivian youths of European ancestry (140 males, 117 females; 9.0-19.9 yr) residing in Santa Cruz, Bolivia (average altitude of 400 m) are described. Reflectances were measured at three wavelengths (425 nm, 545 nm, and 685 nm) on two different sites, the medial surface of the inner upper arm and the forehead. Males tended to be darker than females, significantly on the inner upper arm (P < .05). Males tended to darken significantly with age on both the upper arm and the forehead (P < .05), while females tended to lighten with age on the upper arm and darken with age on the forehead. However, with the exception of reflectances at 545 nm on the inner upper arm, the age changes in females were insignificant (P > .05). The results of comparisons between two groups based on maternal and paternal surnames (two Spanish surnames, at least one non-Spanish European surnames) were consistent with expectations, or with those with two Spanish surnames tending to be significantly darker than those with one or more non-Spanish European surname (P < .05). Finally, the results of a principal components analysis of reflectances were similar to those found in a previous study of highland Bolivians of Aymara ancestry. Am. J. Hum. Biol. 10:559-565, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561546 TI - Changing concepts in skeletal physiology: Wolff's Law, the Mechanostat, and the "Utah Paradigm". AB - According to the Utah paradigm of skeletal physiology: (1) mechanical forces on skeletons generate signals in skeletal organs that control the biologic mechanisms that determine the architecture and strength of those organs, (2) these occur in ways that let the organs endure their voluntary mechanical usage for life without hurting or breaking, (3) to work properly, these mechanisms need nonmechanical factors (hormones, vitamins, calcium, genes, cytokines, etc.), (4) only mechanical factors can guide those mechanisms in time and anatomical space, (5) this arrangement determines skeletal health and disorders can cause or help to cause numerous disorders of skeletal and extraskeletal organs (the collagenous tissue in ligaments and tendons also forms a part of extraskeletal organs). Accumulated evidence now strongly supports these features of the Utah paradigm, which supplements a 1960 paradigm. It incites reassessment of some former ideas about skeletal physiology and disease. Some controversies ensue that will take time to resolve. After they are resolved, skeletal science, medicine, and surgery should be significantly better than before and different in unforeseeable respects as well. Am. J. Hum. Biol. 10:599-605, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561547 TI - Acute mountain sickness: Is there a lag period before symptoms? AB - The present study was designed to determine if symptoms of acute mountain sickness are presented within six hours after arrival at high altitude. Seventeen male subjects, 23-30 years, were studied. The subjects were professional soccer players, life-long residents at low altitudes except one player who was playing soccer in a team at 3400 m (512 mm Hg of Barometric Pressure) during an entire year in 1995. The players were transported by a commercial airline from Lima (150 m) to Cusco (3400 m). The trip lasted 1 hour. Heart rate and arterial oxygen saturation were measured at rest in Lima (150 m), at the time of arrival at Cusco, and at 4 and 6 hours after arrival at 3400 m. On day 6 at high altitude, the physical performance during a soccer game was assessed. The symptoms of acute mountain sickness (AMS) were assessed 6 hours after arrival at Cusco with a self administered questionnaire, and thereafter each 24-hours up to 5 days of exposure to high altitude. The following symptoms were assessed: headache, gastrointestinal symptoms, dizziness, fatigue, and sleep abnormalities. AMS was defined by a Lake-Louise score ?4 (self-assessment only). Thirty five percent of the soccer players developed AMS within 6 hours after arrival by air at 3400 m altitude. Arterial oxygen saturation at arrival was higher in those player who developed AMS within 6 hours after arrival (94.3 +/- 0.94% vs 90.8 +/- 2.36; P < 0.001). From arrival to 6 hours of exposure to altitude, there was a significant fall in arterial oxygen saturation in those men who developed AMS than in those who did not. Results from the stepwise multiple regression (R2 = 0.59; P < 0.04) and logistic regression (R2 = 0.48; P < 0.0019) analyses showed that the difference between arterial oxygen saturation at sea level and at arrival at Cusco was a predictor for the development of AMS within 6 hours upon arrival at altitude. This suggests that the lower the difference between arterial oxygen saturation at sea level and at arrival, the higher the probability to develop AMS within 6 hours after arrival at 3400 m. The presentation of AMS, however, does not predict low performance in physical activity at high altitude. Am. J. Hum. Biol. 10:669-677, 1998. (c) 1998 Wiley-Liss, Inc. PMID- 28561548 TI - Corrigendum : Uveal Melanoma Treatment and Prognostication. PMID- 28561549 TI - Editorial. AB - It was 27 years ago, during my Masters that I was introduced to this journal, then edited by Peter James. He was one of a succession of icons of Dental Public Health to have filled this role including Denis O'Mullane, Martin Downer and until December, my colleague and friend Mike Lennon. Many of us have looked up to those pioneers with respect and reverence. The journal has always been the place to look for UK based research in DPH, and now it is fulfilling that purpose for on a European scale as well. PMID- 28561550 TI - The oral health of people with learning disabilities - a user-friendly questionnaire survey. AB - Impetus for action: To conduct a user-friendly questionnaire survey of the oral health and service needs of adults with learning disabilities. Solution: Researchers collaborated with local self-advocacy services to develop a questionnaire adapted from one used in a regional postal survey. The questionnaire, which covered dental status, oral health and dental services use, was sent to a random sample of people from the learning disability case register. Outcome: Of 2,000 questionnaires mailed, 117 were returned undelivered and 625 were completed (response rate 31.3%). The self-reported dental status of people with learning disabilities appeared similar to that of the 2008 postal survey of the general population in Sheffield. The major difference in dental status was 11.5% of people with learning disabilities wore upper dentures and 7.2% wore lower dentures, compared to 21.2% and 12.1% of the general population in Sheffield. Challenges: Using the case register as a recruitment instrument may have excluded people with learning disabilities not registered. Time and finances only permitted one mailing. Analysis on the basis of deprivation could not be conducted. Future implications and learning points: Contrary to current practice, it is possible to include people with learning disabilities in oral health surveys. A multidisciplinary team was essential for enabling the progression and implementation of inclusive research and for people with learning disabilities and their supporters to engage meaningfully. This level of collaboration appears necessary if we are committed to ensuring that people with learning disabilities and their supporters are made visible to policy and decision-makers. PMID- 28561551 TI - Sugar before bed: a simple dietary risk factor for caries experience. AB - : Clinical care pathways have placed renewed emphasis on caries risk assessment and the ability to predict and prevent further disease. With diet considered a key factor in the development of caries, the level of caries risk posed by dietary habits, such as the frequency of intake and timing of free sugars is questioned. OBJECTIVE: To identify reliable and simple dietary risk factors for caries experience. RESEARCH DESIGN: A cross-sectional observational study of a convenience sample with data gained from clinical examinations, questionnaire and a 24 hour dietary-recall interview. PARTICIPANTS: 128 subjects aged 11-12 from comprehensive schools in Greater Manchester and Newcastle upon-Tyne, UK. OUTCOME MEASURES: free sugars consumed between meals, before bed and total % of total free sugars consumed were assessed from dietary assessments led by a dietitian. D4-6MFT was generated with a caries threshold of ICDAS stage 4 from clinical examinations. RESULTS: Analysis revealed no significant differences in caries experience when looking specifically at caries into dentine, referred to as the cavity group (split at D4-6MFT), between high and low deprivation, consumption of free sugars between meals and free sugars (%). The consumption of free sugars within the hour before bed revealed a statistically significant difference between the cavity/no cavity groups (p=0.002). Logistic regression analysis on the cavity/no cavity groups revealed an odds ratio of 2.4 (95%CI 1.3,4.4) for free sugars consumption before bedtime. CONCLUSIONS: The study suggests that the consumption of free sugars before bedtime may be an important risk factor for adolescent caries into dentine experience. PMID- 28561553 TI - Access to urgent dental care: a scoping review. AB - Objective: To summarise the literature on urgent dental care and to identify research priorities on the organisation and delivery of urgent dental services. Basic research design: Scoping review using Andersen's behavioural model of health service utilisation for a framework analysis of the data. Main outcome measures: Gaps in the literature, defined as those factors and interactions identified by Andersen's model as having a contributory role in access to health services that were not evident in the source papers. Results: Fifty-six papers met the inclusion criteria for the review. The factors most often considered were; demographic, socioeconomic, perceived and evaluated need, and health behaviours. Patient outcomes of evaluated health and quality of life following urgent dental care were the least studied variables, with the exception of patient satisfaction. No studies were identified on community values/norms of people accessing urgent dental care, on health economic evaluations or on studies of how urgent dental services mitigate use of other medical services. No studies were identified on urgent need for populations living in water fluoridated areas or on the relationship between service design and efficient or effective access as measured by patient outcomes. Conclusion: Future research on patient outcomes and the comparison of different service models for urgent dental care through measures of equity, effectiveness and efficiency of access are needed to inform future policy and organisation of these services. PMID- 28561552 TI - Measuring oral health impact among care home residents in Wales. AB - Objective: To explore inequalities in oral health impact among care home residents using OHIP-14 and ADHS criteria. Basic research design: Cross-sectional survey with structured interview and clinical examination using 2009 ADHS criteria including OHIP-14. Comparisons were made between groups of residents and with findings from the ADHS 2009. Participants: Care homes and residents were randomly selected. Those without capacity and non-English/Welsh speakers were excluded. 447 residents answered all OHIP-14 questions and had full oral examination. Main Outcome Measure: OHIP-14. Results: Reporting of OHIP problems was more common among care home residents compared with older people examined in the ADHS 2009 (50% vs 40%). There was no difference in the mean number of impacts between residents who were: dentate/edentate; denture wearing/non-denture wearing; with/without caries. Residents reporting 'problems and pain in your mouth at the moment', or 'occasional or more frequent dry mouth', more often experienced OHIP-14 impacts. Conclusion: Compared with peers living in the community, both dentate and edentate care home residents are more likely to live with one or more impacts. Two simple questions related to 'Any problems and pain in your mouth?' and 'Do you have frequent dry mouth?' may help to target care home residents more likely to experience oral health impacts. PMID- 28561554 TI - Urinary fluoride excretion in preschool children after intake of fluoridated milk and use of fluoride-containing toothpaste. AB - Objective: To assess the urinary fluoride excretion in preschool children after drinking fluoridated milk with 0.185 mg F and 0.375 mg F and to study the impact of use of fluoride toothpaste. Basic research design: Double-blind cross-over study. Participants: Nine healthy children, 2.5-4.5 years of age. Intervention: In a randomized order, participants drank 1.5 dl milk once daily for 7 days with no fluoride added (control), 0.185 mg fluoride added and 0.375 mg fluoride added. The experiment was performed twice with (Part I) and without (Part II) parental tooth brushing with 1,000 ppm fluoride toothpaste. The fluoride content in the piped drinking water was 0.5 mg F/L. Main outcome measure: Urinary fluoride excretion. Results: The 24-hour urinary fl uoride excretion/kg body weight varied from 0.014 mg F for the placebo intervention and non-fluoride toothpaste to 0.027 mg F for the 0.375 mg intervention with use of 1,000 ppm fluoride toothpaste. The difference compared with the placebo intervention was not statistically significant for any of the interventions when fluoride toothpaste was used (p?0.05) while it was statistically significantly different when non-fluoride toothpaste was used (p?0.05). Conclusions: All sources of fluoride must be considered when designing community programs. With 0.5 mg F/L in the drinking water and daily use of fluoride toothpaste, most children had a fluoride intake optimal for dental health. In this setting, additional intake of fluoride milk was within safe limits up to 0.185 mg/day while conclusions about the safety of 0.375 mg/day were uncertain. PMID- 28561555 TI - Directly observed daily mouth care provided to care home residents in one area of Kent, UK. AB - Objective: To gather accurate data on the daily mouth care provided in care homes including tooth brushing, oral health assessment, and recording of care provided. Basic research design: Direct observation and notes review. Clinical setting: Both nursing and 'regular' care homes. Participants: 365 Residents living in 16 care homes and their carers underwent observation, notes review or data collection in some form. Main outcome measures: Provision of mouth morning care. Results: Of 161 residents observed, most (93, 58%) did not have their teeth/dentures brushed. If performed, brushing was often carried out by the resident themselves (36 cases, 53%), rather than by a carer (32 cases, 44%). Carers used a toothbrush to clean inside a resident's mouth in just 7 cases (4.3% of all personal care routines observed). Smaller care homes were no more likely to brush residents teeth than larger care homes, and nursing homes were no more likely to brush teeth than other care homes. Of the 309 sets of notes available for review, 41 (13%) contained a dedicated oral health needs assessment, and 109 (35%) contained a daily oral care chart in some form. Mouth care was often recorded inaccurately (15% of cases). Conclusions: This is the first observational study in the UK to assess oral care actually provided to residents by carers in care homes. The findings reveal a substantially different picture of daily mouth care than was previously understood and suggest that many of the nation's care home residents may not be receiving adequate, or any, oral health care. PMID- 28561556 TI - Association between sense of coherence and oral health-related quality of life among toddlers. AB - Objective: To assess the relationship between sense of coherence (SOC) and oral health-related quality of life (OHRQoL) among children aged one to three years. Participants: A cross-sectional study was conducted with 276 mother-child pairs randomly selected from the city of Diamantina, Brazil. Method: Information was obtained on socio-demographic factors. The short version of Antonovsky's sense of coherence scale (SOC 13) and the Early Childhood Oral Health Impact Scale (ECOHIS) were administered. The children were examined for dental caries. Statistical analysis involved descriptive statistics, the calculation of Spearman's correlation coefficients and adjusted Poisson regression models. Results: SOC was significantly associated with the child's OHRQoL in the multivariate analysis. Children of mothers with high SOC (PR 0.96; 95%CI 0.93,0.98; p=0.045) had a lower prevalence of a negative impact on OHRQoL. Children with severe dental caries had a greater prevalence of a negative impact on OHRQoL (PR 2.53; 95%CI 1.77,3.62; p?0.001). Conclusions: Maternal SOC could be a psychosocial determinant of the OHRQoL of children aged one to three years. Severe dental caries was associated with poorer quality of life. PMID- 28561557 TI - Tobacco use in late adolescence among rural Sri Lankans. AB - Objective: To determine the prevalence of, and factors associated with, tobacco use among 16-19 year old students from rural Sri Lanka. Basic research design: A cross-sectional study where the data were collected by means of a pre-tested self administered questionnaire. Participants: 390, 16-19 year old students selected from 9 schools in Ampara education zone. Results: Nearly 22% of the sample had used tobacco during their life and the prevalence of ever smokeless tobacco use (19%) was higher than the prevalence of ever smoking (10%). The prevalence of current smoking was 16% in males and 1% in females while 23% and 3% of males and females were current smokeless tobacco users respectively. Current smoking was independently associated with gender and having a smoker at home while current smokeless tobacco use was significantly associated with gender, maternal education and paternal occupation. Conclusion: The prevalence of tobacco use was high in these rural students. PMID- 28561558 TI - Dental caries experience among Albanian pre-school children: a national survey. AB - Objective: To determine the dental caries experience and treatment needs among 5 year-olds in Albania. Research Design: This cross sectional study was conducted in 2015 by using a cluster sampling technique. The dmft was used to assess dental caries experience and caries prevalence as percentages of children with dmf?0. Caries treatment needs were assessed with dt/dmft x 100, missing teeth with mt/dmft x 100 and ft /dmft x 100 as the Care Index. Participants: 2,039 five-year olds, from 17 districts of Albania were selected . Children's residency was divided into 3 main regions (South, West, Central and North). Method: WHO 2013 diagnostic criteria were used and dental caries was recorded at cavity level d3. Results:: The mean age was 5.4 (SD 0.5) years. The caries prevalence (dmf?0) was 84.1%. The prevalence of children without cavitated lesions (d=0) was 20.1%. The mean dmft index was 4.41 (SD 3.83). The caries treatment needs were 84% (SD 26%). Conclusions: The Albanian 5-year-olds assessed in this survey had a high dental caries experience and untreated cavities in the primary dentition. The national health authorities should introduce preventive programs and improved dental care access for this age group. PMID- 28561559 TI - A model for oral health gradients in children: using structural equation modeling. AB - : Detecting the underlying socioeconomic and behavioral determinants is essential for reducing oral health disparities in children. OBJECTIVE: To test a conceptual model in children to explore the interaction amongst social, environmental, behavioral factors and oral health outcomes. METHODS: This analytic cross sectional study was performed in 2014-2015 in Shiraz, Iran. The sampling was conducted using a multistage stratified design to represent the whole 6-year-olds in Shiraz County. Participants were 830, 6-year-old first grade primary schoolchildren and their parents. Children were examined to register decayed, missing and filled teeth (dmft) and simplified oral hygiene index (OHI-S). Parents were asked for data on socio-cultural risk factors, oral health behaviors and children's oral health related quality of life (C-OHRQoL). Data on environmental risk factors were collected from several sources. The proposed model, a development of Peterson's, was tested using structural equation modeling (SEM). RESULTS: The tested model could empirically demonstrate the wide range of social and behavioral factors affecting C-OHRQoL. Socioeconomic status (SES) affected the OHRQoL of children through several pathways. Tooth brushing frequency, use of oral health services and consuming cariogenic foods were the mediators, through which SES affected dmft and subsequently C-OHRQoL. CONCLUSIONS: Using the modified Petersen's model and SEM, the paths in which different distal and proximal factors affect oral health outcomes in children could be clearly identified. It showed that addressing the underlying social, economic and behavioral determinants is essential for reducing oral health disparities among Iranian children. PMID- 28561560 TI - Using the simplified case mix tool (sCMT) to identify cost in special care dental services to support commissioning. AB - : To commission dental services for vulnerable (special care) patient groups effectively, consistently and fairly an evidence base is needed of the costs involved. The simplified Case Mixed Tool (sCMT) can assess treatment mode complexity for these patient groups. OBJECTIVE: To determine if the sCMT can be used to identify costs of service provision. CLINICAL SETTING: Patients (n=495) attending the Sussex Community NHS Trust Special Care Dental Service for care were assessed using the sCMT. MAIN MEASURES: sCMT score and costs (staffing, laboratory fees, etc.) besides patient age, whether a new patient and use of general anaesthetic/intravenous sedation. METHOD: Statistical analysis (adjusted linear regression modelling) compared sCMT score and costs then sensitivity analyses of the costings to age, being a new patient and sedation use were undertaken. Regression tables were produced to present estimates of service costs. RESULTS: Costs increased with sCMT total scale and single item values in a predictable manner in all analyses except for 'cooperation'. Costs increased with the use of IV sedation; with each rising level of the sCMT, and with complexity in every sCMT category, except cooperation. CONCLUSION: Costs increased with increase in complexity of treatment mode as measured by sCMT scores. Measures such as the sCMT can provide predictions of the resource allocations required when commissioning special care dental services. PMID- 28561561 TI - Oral health and oral health behaviours of five-year-old children in the Charedi Orthodox Jewish Community in North London, UK. AB - OBJECTIVE: To report on the oral health status and oral health behaviours of five year-old Charedi Orthodox Jewish children attending schools in London, UK. BASIC RESEARCH DESIGN: Cross-sectional survey. METHOD: Clinical examinations mirroring the 2015 National Dental Public Health Epidemiology Programme for England for five-year-olds and a parental questionnaire on oral health behaviours. PARTICIPANTS: 137 five-year-olds attending Charedi Orthodox Jewish schools in Hackney, North London. MAIN OUTCOME MEASURES: Prevalence dmft?0 (%) and severity (mean dmft) of dental caries. RESULTS: Of these children 58% had experienced dental caries (95%CI 50,67), the mean number of decayed, missing and filled teeth was 2.38 (95%CI 1.90,2.82) and 23% (95%CI 16,30) had caries affecting their incisors. Only 20% reported that their children had their teeth brushed twice a day and 16% of the children started having their teeth brushed between six months and one year of age. CONCLUSIONS: The oral health of five-year-old children in the Charedi Orthodox Jewish community is significantly worse than their counterparts across Hackney, London and England. The establishment of robust baseline data supports the local authority plan to develop targeted oral health improvement programmes tailored to address the health needs and cultural sensitivities of this community. PMID- 28561562 TI - Using National-Scale Data To Develop Nutrient-Microcystin Relationships That Guide Management Decisions. AB - Quantitative models that predict cyanotoxin concentrations in lakes and reservoirs from nutrient concentrations would facilitate management of these resources for recreation and as sources of drinking water. Development of these models from field data has been hampered by the high proportion of samples in which cyanotoxin concentrations are below detection limits and by the high variability of cyanotoxin concentrations within individual lakes. Here, we describe a national-scale hierarchical Bayesian model that addresses these issues and that predicts microcystin concentrations from summer mean total nitrogen and total phosphorus concentrations. This model accounts for 69% of the variance in mean microcystin concentrations in lakes and reservoirs of the conterminous United States. Mean microcystin concentrations were more strongly associated with differences in total nitrogen than total phosphorus. A general approach for assessing this and similar types of models for their utility for guiding management decisions is also described. PMID- 28561563 TI - Reducing Friction in the Eye: A Comparative Study of Lubrication by Surface Anchored Synthetic and Natural Ocular Mucin Analogues. AB - Biomaterials used in the ocular environment should exhibit specific tribological behavior to avoid discomfort and stress-induced epithelial damage during blinking. In this study, two macromolecules that are commonly employed as ocular biomaterials, namely, poly(vinylpyrrolidone) (PVP) and hyaluronan (HA), are compared with two known model glycoproteins, namely bovine submaxillary mucin (BSM) and alpha1-acid glycoprotein (AGP), with regard to their nonfouling efficiency, wettability, and tribological properties when freely present in the lubricant, enabling spontaneous adsorption, and when chemisorbed under low contact pressures. Chemisorbed coatings were prepared by means of photochemically triggered nitrene insertion reactions. BSM and AGP provided boundary lubrication when spontaneously adsorbed in a hydrophobic contact with a coefficient of friction (CoF) of ~0.03-0.04. PVP and HA were found to be excellent boundary lubricants when chemisorbed (CoF <= 0.01). Notably, high-molecular-weight PVP generated thick adlayers, typically around 14 nm, and was able to reduce the CoF below 0.005 when slid against a BSM-coated poly(dimethylsiloxane) pin in a tearlike fluid. PMID- 28561564 TI - Functionalized Ionic Microgel Sensor Array for Colorimetric Detection and Discrimination of Metal Ions. AB - A functional ionic microgel sensor array was developed by using 1-(2 pyridinylazo)-2-naphthaleno (PAN)- and bromothymol blue (BTB)-functionalized ionic microgels, which were designed and synthesized by quaternization reaction and anion-exchange reaction, respectively. The PAN microgels (PAN-MG) and BTB microgels (BTB-MG) were spherical in shape with a narrow size distribution and exhibited characteristic colors in aqueous solution in the presence of various trace-metal ions, which could be visually distinguished by the naked eye. Such microgels could be used for the colorimetric detection of various metal ions in aqueous solution at submicromolar levels, which were lower than the U.S. Environmental Protection Agency standard for the safety limit of metal ions in drinking water. A total of 10 species of metal ions in aqueous solution, Ba2+, Cr3+, Mn2+, Pb2+, Fe3+, Co2+, Zn2+, Ni2+, Cu2+, and Al3+, were successfully discriminated by the as-constructed microgel sensor array combined with discriminant analysis, agglomerative hierarchical clustering, and leave-one-out cross-validation analysis. PMID- 28561565 TI - Importance of Solvent Removal Rate on the Morphology and Device Performance of Organic Photovoltaics with Solvent Annealing. AB - Solvent vapor annealing has been widely used in organic photovoltaics (OPV) to tune the morphology of bulk heterojunction active layer for the improvement of device performance. Unfortunately, the effect of solvent removal rate (SRR) after solvent annealing, which is one of the key factors that impact resultant morphology, on the morphology and device performance of OPV has never been reported. In this work, the nanoscale morphology of small molecule (SM):fullerene bulk heterojunction (BHJ) solar cell from different SRRs after solvent annealing was examined by small-angle neutron scattering and grazing incidence X-ray scattering. The results clearly demonstrate that the nanoscale morphology of SM:fullerene BHJ especially fullerene phase separation and concentration of fullerene in noncrystalline SM was significantly impacted by the SRR. The enhanced fullerene phase separation was found with a decrease of SRR, while the crystallinity and molecular packing of SM remained unchanged. Correlation to device performance shows that the balance between pure fullerene phase and mixing phase of SM and fullerene is crucial for the optimization of morphology and enhancement of device performance. Moreover, the specific interfacial area between pure fullerene phase and mixing phase is crucial for the electron transport and thus device performance. More importantly, this finding would provide a more careful and precise control of morphology of SM:fullerene BHJ and offers a guideline for further improvement of device performance with solvent annealing. PMID- 28561566 TI - Strontium Titanate Based Artificial Leaf Loaded with Reduction and Oxidation Cocatalysts for Selective CO2 Reduction Using Water as an Electron Donor. AB - Thin film of SrTiO3 nanorods loaded with reduction and oxidation cocatalysts drove the selective reduction of carbon dioxide (CO2) into carbon monoxide (CO), as well as caused the production of equivalent oxygen molecules through water oxidation under UV irradiation. The described film functioned as a free-standing plate without any bias potential application, similar to a natural leaf. The film was facilely fabricated by a simple hydrothermal and annealing treatment of a titanium substrate to produce the SrTiO3 nanorod film (STO film) followed by two steps of loading the reduction and oxidation cocatalysts onto the surface of the STO. As a reduction cocatalyst, a CuxO nanocluster was chosen to achieve selective reduction of CO2 into CO, whereas a cobalt- and phosphate-based cocatalyst (CoPi) facilitated oxidation on the STO surface to promote oxygen generation. For the photocatalysis test, a wireless film was simply set into an aqueous solution bubbled with CO2 in a reactor, and CO production was observed in the headspace of the reactor under UV irradiation. Compared to the bare STO film, the dual cocatalyst-loaded STO film exhibited 2.5 times higher CO generation. H2 production was very limited in our system, and the amount of molecules generated by the reduction reaction was almost twice that of the generated oxygen molecules, proving that water molecules acted as electron donors. Our artificial leaf consists of abundant and nontoxic natural elements and represents the first achievement of stoichiometric CO2 reduction using water as an electron donor by a free-standing natural leaflike plate form. PMID- 28561567 TI - Clathrin-Independent Killing of Intracellular Mycobacteria and Biofilm Disruptions Using Synthetic Antimicrobial Polymers. AB - Current membrane targeting antimicrobials fail to target mycobacteria due to their hydrophobic membrane structure, ability to form drug-resistant biofilms, and their natural intracellular habitat within the confines of macrophages. In this work, we describe engineering of synthetic antimicrobial polymers (SAMPs) derived from biocompatible polyamides that can target drug-sensitive and drug resistant mycobacteria with high selectivity. Structure-activity relationship studies revealed that reduced hydrophobicity of cationic pendants induces enhanced and selective permeabilization of mycobacterial membranes. The least hydrophobic SAMP (TAC1) was found to be the most active with maximum specificity toward mycobacteria over E. coli, S. aureus, and mammalian cells. Membrane perturbation studies, scanning electron microscopy, and colony PCR confirmed the ability of TAC1 to induce membrane lysis and to bind to the genomic material of mycobacteria, thereby inducing mycobacterial cell death. TAC1 was most effective in perfusing and disrupting the mycobacterial biofilms and was also able to kill the intracellular mycobacteria effectively without inducing any toxicity to mammalian cells. Cellular uptake studies revealed clathrin independent uptake of TAC1, thereby allowing it to escape hydrolytic lysosomal degradation and effectively kill the intracellular bacteria. Therefore, this manuscript presents the design and selective antimycobacterial nature of polyamide polymers with charged hydrophobic pendants that have ability to disrupt the biofilms and kill intracellular mycobacteria. PMID- 28561568 TI - Tunable Semiconducting Polymer Nanoparticles with INDT-Based Conjugated Polymers for Photoacoustic Molecular Imaging. AB - Photoacoustic imaging combines both excellent spatial resolution with high contrast and specificity, without the need for patients to be exposed to ionizing radiation. This makes it ideal for the study of physiological changes occurring during tumorigenesis and cardiovascular disease. In order to fully exploit the potential of this technique, new exogenous contrast agents with strong absorbance in the near-infrared range, good stability and biocompatibility, are required. In this paper, we report the formulation and characterization of a novel series of endogenous contrast agents for photoacoustic imaging in vivo. These contrast agents are based on a recently reported series of indigoid pi-conjugated organic semiconductors, coformulated with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, to give semiconducting polymer nanoparticles of about 150 nm diameter. These nanoparticles exhibited excellent absorption in the near-infrared region, with good photoacoustic signal generation efficiencies, high photostability, and extinction coefficients of up to three times higher than those previously reported. The absorption maximum is conveniently located in the spectral region of low absorption of chromophores within human tissue. Using the most promising semiconducting polymer nanoparticle, we have demonstrated wavelength-dependent differential contrast between vasculature and the nanoparticles, which can be used to unambiguously discriminate the presence of the contrast agent in vivo. PMID- 28561569 TI - Probing the Effects of Ligand Field and Coordination Geometry on Magnetic Anisotropy of Pentacoordinate Cobalt(II) Single-Ion Magnets. AB - In this work, the effects of ligand field strength as well as the metal coordination geometry on magnetic anisotropy of pentacoordinated CoII complexes have been investigated using a combined experimental and theoretical approach. For that, a strategic design and synthesis of three pentacoordinate CoII complexes [Co(bbp)Cl2].(MeOH) (1), [Co(bbp)Br2].(MeOH) (2), and [Co(bbp)(NCS)2] (3) has been achieved by using the tridentate coordination environment of the ligand in conjunction with the accommodating terminal ligands (i.e., chloride, bromide, and thiocyanate). Detailed magnetic studies disclose the occurrence of slow magnetic relaxation behavior of CoII centers with an easy-plane magnetic anisotropy. A quantitative estimation of ZFS parameters has been successfully performed by density functional theory (DFT) calculations. Both the sign and magnitude of ZFS parameters are prophesied well by this DFT method. The theoretical results also reveal that the alpha -> beta (SOMO-SOMO) excitation contributes almost entirely to the total ZFS values for all complexes. It is worth noting that the excitation pertaining to the most positive contribution to the ZFS parameter is the dxy -> dx2-y2 excitation for complexes 1 and 2, whereas for complex 3 it is the dz2 -> dx2-y2 excitation. PMID- 28561570 TI - Correction to Multifunctional Enzymatically Generated Hydrogels for Chronic Wound Application. PMID- 28561571 TI - pH-Dependent Inversion of Hofmeister Trends in the Water Structure of the Electrical Double Layer. AB - Specific ion effects (SIEs) are known to influence the acid/base behavior of silica and the interfacial structure of water, yet evidence of the effect of pH on SIEs is lacking. Here broadband vibrational sum frequency generation (SFG) spectroscopy was used to study SIEs on the water structure at the electrical double layer (EDL) of silica as a function of pH and monovalent cation identity from pH 2-12 at 0.5 M salt concentration. SFG results indicate a direct Hofmeister series of cation adsorption at pH 8 (Li+ < Na+ < K+ < Cs+), with an inversion in this series occurring at pH > 10. In addition, an inversion in SFG intensity trends also occurred at pH < 6, which was attributed to contributions from asymmetric cation hydration and EDL overcharging. The highly pH-dependent SIEs for silica/water have implications for EDL models that often assume pH independent parameters. PMID- 28561572 TI - Access to Perfluoroalkyl-Substituted Enones and Indolin-2-ones via Multicomponent Pd-Catalyzed Carbonylative Reactions. AB - A simple method for accessing perfluoroalkyl-substituted enones is described applying a four-component palladium-catalyzed carbonylative coupling of aryl boronic acids together with terminal alkynes and perfluoroalkyl iodides in the presence of carbon monoxide. A wide range of highly functionalized enones can thus be prepared in a single operation in good yields. With 2-aminophenylalkynes, an intramolecular aminocarbonylation event overrules providing the indolin-2-one framework. Finally, adaptation of the two-chamber technology expands the method to the synthesis of the aforementioned structures with 13C-isotope labeling. PMID- 28561573 TI - Syntheses, Crystal Structures, and Nonlinear Optical Activity of Cs2Ba[AnO2(C2H5COO)3]4 (An = U, Np, Pu) and Unprecedented Octanuclear Complex Units in KR2(H2O)8[UO2(C2H5COO)3]5 (R = Sr, Ba). AB - X-ray diffraction was applied to the elucidation of crystal structures of single crystals of Cs2Ba[AnO2(C2H5COO)3]4, where An = U(I), Np(II), Pu(III), and KR2(H2O)8[UO2(C2H5COO)3]5, where R = Sr(IV), Ba (polymorphs V-a and V-b). FTIR spectra were analyzed for the uranium-containing crystals I, IV, and V-b. Isostructural cubic crystals I-III are constructed of typical mononuclear anionic complex units [AnO2(C2H5COO)3]- and charge-balancing Cs and Ba cations. Features of actinide contraction in the six U-Np-Pu isostructural series known to date are analyzed. In crystal structures of IV and V two typical complexes [UO2(C2H5COO)3] bind with a hydrated Sr or Ba cation to form the rare trinuclear neutral complex unit {R(H2O)4[UO2(C2H5COO)3]2}, where R = Sr, Ba. Two such trinuclear units and one typical mononuclear unit further bind with a K cation to form the unprecedented octanuclear neutral complex unit K[UO2(C2H5COO)3]{R(H2O)4[UO2(C2H5COO)3]2}2. As the derived polynuclear complexes of uranyl ion with carboxylate ligands in the crystal structures of IV and V are not the first but are rare examples, the equilibrium between mono and polynuclear complex units in aqueous solutions is discussed. The two polymorphic modifications V-a and V-b were studied at 100 K and at room temperature, respectively. Peculiarities of noncovalent interactions in crystal structures of the two polymorphs are revealed using Voronoi-Dirichlet tessellation. The nonlinear optical activity of noncentrosymmetric crystals I was estimated by its ability for second harmonic generation. PMID- 28561574 TI - Molecular Complexity and Retrosynthesis. AB - An atom-environment complexity measure, CA, to assess local changes in complexity during synthetic transformations is described. The complexity measure is based on applying Shannon's equation to the number and diversity of paths up to two bonds in length emanating from an atom node. The method requires no explicit accounting for bond type, stereochemistry, ring membership, symmetry, or molecular size. CA varies with expectation across a number of basic reaction examples and may identify the key disconnections to guide retrosynthesis. PMID- 28561575 TI - Employing OpenCL to Accelerate Ab Initio Calculations on Graphics Processing Units. AB - We present an extension of our graphics processing units (GPU)-accelerated quantum chemistry package to employ OpenCL compute kernels, which can be executed on a wide range of computing devices like CPUs, Intel Xeon Phi, and AMD GPUs. Here, we focus on the use of AMD GPUs and discuss differences as compared to CUDA based calculations on NVIDIA GPUs. First illustrative timings are presented for hybrid density functional theory calculations using serial as well as parallel compute environments. The results show that AMD GPUs are as fast or faster than comparable NVIDIA GPUs and provide a viable alternative for quantum chemical applications. PMID- 28561577 TI - Developments in the Reactivity of 2-Methylimidazolium Salts. AB - Unexpected and unusual reactivity of 2-methylimidazolium salts toward aryl-N sulfonylimines and aryl aldehydes is here reported. Upon reaction with aryl-N sulfonylimines, the addition product, arylethyl-2-imidazolium-1-tosylamide (3), is formed with moderate to good yields, while upon reaction with aldehydes, the initial addition product (6) observed in NMR and HPLC-MS experimental analysis is postulated by us as an intermediate to the final conversion to carboxylic acids. Studies in the presence and absence of molecular oxygen allow us to conclude that the imidazolium salts is crucial for the oxidation. A detailed mechanistic study was carried out to provide insights regarding this unexpected reactivity. PMID- 28561579 TI - Chemoselective Access to gamma-Ketoesters with Stereogenic Quaternary alpha Center or gamma-Keto Nitriles by Aerobic Reaction of alpha-Cyanoesters and Styrenes. AB - Chemoselective access to either gamma-ketoesters with a quaternary all-carbon alpha-stereogenic center or gamma-keto nitriles is described by copper-catalyzed aerobic reaction of styrenes with alpha-cyanoesters. Formal oxo-enolation or oxo cyanomethylation of styrenes is achieved via a sequence of addition of enolate (or cyanomethyl) radical to olefin and oxidation of the resulting radical adduct. This method starts from abundant and cheap feedstock under aerobic conditions, without any prefunctionalization or the production of stoichiometric metal salts waste, making it very attractive for practical use. PMID- 28561578 TI - Controllable Structures Designed with Multiple-Dielectric Responses in Hybrid Perovskite-Type Molecular Crystals. AB - In this report, two new hybrid organic-inorganic perovskite-type compounds, (IBA)CdBr3 (1; IBA = isobutylammonium cation, i-C4H9-NH3) and (IBA)2CdBr4 (2), have been successfully synthesized by reasonable modulation of the ratio of the reactants. 1 with a one-dimensional (1D) chained structure presents sequential solid-state phase transitions, and 2 with a two-dimensional (2D) layered structure undergoes triple structural phase transitions. The phase transitions are attributable to the stepwise ordering process of the organic IBA cation of the title compounds, which also exhibit temperature-dependent dielectric transitions and dielectric anisotropies. Among the different structural environments, the dynamic motions of organic cations show distinct differences, driving the variation of physical properties. PMID- 28561581 TI - Odd [n]Cumulenes (n = 3, 5, 7, 9): Synthesis, Characterization, and Reactivity. AB - In comparison to the omnipresent two- and three-dimensional allotropes of carbon, namely, graphite and diamond (as well as recent entries graphene, carbon nanotubes, and fullerenes), a detailed understanding of the one-dimensional carbon allotrope carbyne is not well established, and even the existence of carbyne has been a matter of controversy over the past decades. Composed of sp hybridized carbon, carbyne could potentially exist in two forms, either as a polyyne (alternating single and triple bonds, expected to show a semiconducting behavior) or as a cumulene (all carbon atoms are connected via double bonds, predicted to show metallic behavior). Although a number of publications are available on the hypothetical structure and properties of carbyne, specific knowledge about its physical and spectroscopic characteristics is still unclear. In order to predict the properties of carbyne, the synthesis and study of model compounds, namely, polyynes and cumulenes, has been a promising avenue. The synthesis of polyynes has been extensively explored in the last decades, culminating with the isolation of a polyyne with 22 acetylene units, which allows extrapolation to the properties of carbyne. Extended cumulenes, on the other hand, have remained much less well-known, and specific studies of properties versus molecular length are quite limited. A limiting factor to the study of [n]cumulenes has been their dramatically increased reactivity, especially in comparison to polyynes of comparable length. For example, most known [7]cumulenes can only be handled in solution, while the polyynes of equivalent length (i.e., a triyne with three acetylene units) are quite stable. [9]Cumulenes are the longest derivatives studied to date. In this Account, we describe our efforts to design and synthesize odd [n]cumulenes (i.e., n = 3, 5, 7, 9) that are sufficiently persistent under ambient conditions to allow in depth characterization of physical and spectral properties. This goal has been achieved through modification of the end-capping groups by increasing the steric bulk and thereby shielding the reactive cumulene framework to provide stable [7]- and [9]cumulenes. An alternative route to stabilization is accomplished via encapsulation of the cumulene skeleton in a macrocycle, that is, formation of cumulene rotaxanes. The new sterically encumbered cumulenic products are reasonably stable under normal laboratory conditions, although some readily undergo cycloaddition reactions to give interesting products. We have explored preliminary trends for the reactivity of long [n]cumulenes. Finally, trends in the series of [n]cumulene model compounds are now discernible, including a thorough consideration of bond length alternation (BLA) in long [n]cumulenes using X-ray crystallographic analyses, as well as electronic properties via UV vis spectroscopy and cyclic voltammetry. PMID- 28561580 TI - Free-Energy Calculations of Ionic Hydration Consistent with the Experimental Hydration Free Energy of the Proton. AB - Computational free-energy correction strategies and the choice of experimental proton hydration free energy, DeltaGs*(H+), are analyzed to investigate the apparent controversy in experimental thermodynamics of ionic hydration. Without corrections, the hydration free-energy (DeltaGhyd) calculations match experiments with DeltaGs*(H+) = -1064 kJ/mol as reference. Using the Galvani surface potential the resulting (real) DeltaGhyd are consistent with DeltaGs*(H+) = -1098 kJ/mol. When applying, in an ad hoc manner, the discrete solvent correction, DeltaGhyd matching the "consensus" DeltaGs*(H+) of -1112 kJ/mol are obtained. This analysis rationalizes reports on DeltaGhyd calculations for ions using different experimental references. For neutral amino acid side chains DeltaGhyd are independent of the water model, whereas there are large differences in DeltaGhyd due to the water model for charged species, suggesting that long-range ordering of water around ions yields an important contribution to the DeltaGhyd. These differences are reduced significantly when applying consistent corrections, but to obtain the most accurate results it is recommended to use the water model belonging to the force field. PMID- 28561582 TI - Interplay Of Stereochemistry, Conformational Rigidity, And Ease Of Synthesis For 13-Membered Cyclic Peptidomimetics Containing APC Residues. AB - As part of a program to design small molecules that bind proteins, we require cyclic peptides (or peptidomimetics) that are severely constrained such that they adopt one predominant conformation in solution. This paper describes syntheses of the 13-membered cyclic tetrapeptides 1 containing aminopyrrolidine carboxyl (APC) residues. A linear precursor was prepared and used to determine optimal conditions for cyclization of that substrate. A special linker was prepared to enable cyclization of similar linear peptidomimetics on a solid phase, and the solution-phase cyclization conditions were shown to be appropriate for this too. Stereochemical variations were then used to determine the ideal APC configuration for cyclization of the linear precursors (on a solid phase, using the conditions identified previously). Consequently, a series of compounds were prepared that are representative of compounds 1. Conformational studies of representative compounds in DMSO solution were performed primarily using (i) NOE studies, (ii) quenched molecular dynamics simulations using no constraints from experiment, and (iii) MacroModel calculations with NMR constraints. All three strategies converged to the same conclusion: the backbone of molecules based on 1 tends to adopt one preferential conformation in solution and that conformation can be predicted from the stereochemistries of the alpha-amino acids involved. PMID- 28561583 TI - Preparation of a Novel Intumescent Flame Retardant Based on Supramolecular Interactions and Its Application in Polyamide 11. AB - The flammability and melt dripping of the widely used bio-based polyamide 11 (PA 11) have attracted much attention in the last decade, and they are still a big challenge for the fire science society. In this work, a novel single macromolecular intumescent flame retardant (AM-APP) that contains an acid source and a gas source was prepared by supramolecular reactions between melamine and p aminobenzene sulfonic acid, followed by an ionic exchange with ammonium polyphosphate. The chemical structure of AM-APP was characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy, and scanning electron microscopy. AM-APP and TiO2 were then introduced into PA 11 by melt compounding to improve the fire resistance of the composite. The fire performance of PA 11 composites was evaluated by the limiting oxygen index (LOI), vertical burning (UL-94), and cone calorimetry tests. The results showed that the presence of 22% AM-APP and 3% TiO2 increased the LOI value from 22.2 to 29.2%, upgraded the UL-94 rating from no rating to V-0, completely eliminated melt dripping, and significantly decreased the peak heat release rate from 943.4 to 177.5 kW/m2. The thermal behaviors were investigated by thermogravimetric (TG) analysis and TG-FTIR. It is suggested that AM-APP produces an intumescent char structure and releases inert gases, whereas TiO2 may consolidate the char layers, leading to the improvement in the fire resistance of PA 11. PMID- 28561584 TI - In Situ Detection and Imaging of Telomerase Activity in Cancer Cell Lines via Disassembly of Plasmonic Core-Satellites Nanostructured Probe. AB - The label-free localized surface plasmon resonance (LSPR) detection technique has been identified as a powerful means for in situ investigation of biological processes and localized chemical reactions at single particle level with high spatial and temporal resolution. Herein, a core-satellites assembled nanostructure of Au50@Au13 was designed for in situ detection and intracellular imaging of telomerase activity by combining plasmonic resonance Rayleigh scattering spectroscopy with dark-field microscope (DFM). The Au50@Au13 was fabricated by using 50 nm gold nanoparticles (Au50) as core and 13 nm gold nanoparticles (Au13) as satellites, both of them were functionalized with single chain DNA and gathered proximity through the highly specific DNA hybridization with a nicked hairpin DNA (O1) containing a telomerase substrate (TS) primer as linker. In the presence of telomerase, the telomeric repeated sequence of (TTAGGG)n extended at the 3'-end of O1 would hybridized with its complementary sequences at 5'-ends. This led the telomerase extension product of O1 be folded to form a rigid hairpin structure. As a result, the Au50@Au13 was disassembled with the releasing of O1 and Au13-S from Au50-L, which dramatically decreased the plasmon coupling effect. The remarkable LSPR spectral shift was observed accompanied by a detectable color change from orange to green with the increase of telomerase activity at single particle level with a detection limit of 1.3 * 10-13 IU. The ability of Au50@Au13 for in situ imaging intracellular telomerase activity, distinguishing cancer cells from normal cells, in situ monitoring the variation of cellular telomerase activity after treated with drugs were also demonstrated. PMID- 28561585 TI - Switchable Diastereoselectivity in the Fluoride-Promoted Vinylogous Mukaiyama Michael Reaction of 2-[(Trimethylsilyl)oxy]furan Catalyzed by Crown Ethers. AB - The fluoride-promoted vinylogous Mukaiyama-Michael reaction of 2 [(trimethylsilyl)oxy]furan with diverse alpha,beta-unsaturated ketones is described. The TBAF-catalyzed VMMR afforded high anti-diastereoselectivity irrespective of the solvents used. The KF/crown ethers catalytic systems proved to be highly efficient in terms of yields and resulted in a highly diastereoselective unprecedented solvent/catalyst switchable reaction. Anti adducts were obtained as single diastereomers or with excellent diastereoselectivities when benzo-15-crown-5 in CH2Cl2 was employed. On the other hand, high syn-diastereoselectivities (from 73:27 to 96:4) were achieved by employing dicyclohexane-18-crown-6 in toluene. On the basis of DFT calculations, the catalysts/solvent-dependent switchable diastereoselectivities are proposed to be the result of loose or tight cation-dienolate ion pairs. PMID- 28561586 TI - Anti-inflammatory 12,20-Epoxypregnane and 11,12-seco-Pregnane Glycosides from the Stems of Hoya kerrii. AB - Five 12,20-epoxypregnane glycosides (1-3, 5, and 6) and two 11,12-seco-pregnane glycosides (4 and 7) with spirodilactone motifs, as well as spirodilactone cleavage products 8 and 9, were isolated from the stems of Hoya kerrii. The relative configurations of the three related skeletons were supported by ROESY experiments and X-ray crystallographic analyses. The isolates were evaluated for their anti-inflammatory activity based on the inhibition of NO production in RAW264.7 cells, and some showed IC50 values ranging from 12.6 to 96.5 MUM. The most potent compound, 9a, was also examined for its anti-inflammatory mechanism against mRNA expression and was found to down-regulate mRNA expression of iNOS and COX-2 in a dose-dependent manner. PMID- 28561587 TI - Protective Effects of Functional Chicken Liver Hydrolysates against Liver Fibrogenesis: Antioxidation, Anti-inflammation, and Antifibrosis. AB - Via an assay using an Amino Acid Analyzer, pepsin-digested chicken liver hydrolysates (CLHs) contain taurine (365.57 +/- 39.04 mg/100 g), carnosine (14.03 +/- 1.98 mg/100 g), and anserine (151.58 +/- 27.82 mg/100 g). This study aimed to evaluate whether CLHs could alleviate thioacetamide (TAA)-induced fibrosis. A dose of 100 mg TAA/kg BW significantly increased serum liver damage indices and liver cytokine contents. Cell infiltration and monocytes/macrophages in livers of TAA-treated rats were illustrated by the H&E staining and immunohistochemical analysis of cluster of differentiation 68 (CD68, ED1), respectively. A significantly increased hepatic collagen accumulation was also observed and quantified under TAA treatment. A significant up-regulation of transforming growth factor-beta (TGF-beta) and SMAD family member 4 (SMAD4) caused by TAA treatment further enhanced alpha smooth muscle actin (alphaSMA) gene and protein expressions. The liver antioxidant effects under TAA treatment were significantly amended by 200 and 600 mg CLHs/kg BW. Hence, the ameliorative effects of CLHs on liver fibrogenesis could be attributed by antioxidation and anti-inflmmation. PMID- 28561589 TI - Desymmetrization of meso-1,2-Diols by a Chiral N,N-4-Dimethylaminopyridine Derivative Containing a 1,1'-Binaphthyl Unit: Importance of the Hydroxy Groups. AB - We developed an acylative desymmetrization of meso-1,2-diols using a binaphthyl based N,N-4-dimethylaminopyridine (DMAP) derivative 1h with tert-alcohol substituents. The reaction proceeds with a wide range of acyclic meso-1,2-diols and six-membered-ring meso-1,2-diols to provide a monoacylate selectively with a high enantiomeric ratio (er). Only 0.1 mol % of the catalyst facilitated the reaction within a short reaction time (3 h) to afford enantio-enriched monoacylated products in moderate to good yield. Several control experiments revealed that the tert-alcohol units of catalyst 1h play a significant role in achieving high catalytic activity, chemoselectivity of monoacylation, and enantioselectivity. PMID- 28561590 TI - Dynamics of Microscale Liquid Propagation in Micropillar Arrays. AB - Understanding the dynamics of microscale liquid propagation in micropillar arrays can lead to significant enhancement in macroscopic propagation modeling. Such a phenomenon is fairly complicated, and a fundamental understanding is lacking. The aim here is to estimate three main parameters in liquid propagation, capillary pressure, average liquid height, and contact angle on the pillar side, through modeling and experimental validation. We show that the capillary pressure is not constant during liquid propagation, and the average capillary pressure is evaluated using its maximum and minimum values. The average liquid height influences the permeability of such a structure, which is challenging to determine as a result of the complicated three-dimensional (3D) meniscus shape. A simple physical model is provided in this paper to predict the average liquid height with less than 7% error. The contact angle on the micropillar side, which has considerable impact on the capillary pressure and the average liquid height, has been debated for a long time. We propose a model to predict this contact angle and validate it against experimental values in the literature. Our findings also indicate that the microscopic motion of the liquid front is significantly affected by the ratio of the pillar height to edge-to-edge spacing, and a correlation is provided for quantification. The proposed models are able to predict the droplet spreading dynamics and estimate spreading distance and time reasonably. PMID- 28561588 TI - Protein Domain Mimics as Modulators of Protein-Protein Interactions. AB - Protein-protein interactions (PPIs) are ubiquitous in biological systems and often misregulated in disease. As such, specific PPI modulators are desirable to unravel complex PPI pathways and expand the number of druggable targets available for therapeutic intervention. However, the large size and relative flatness of PPI interfaces make them challenging molecular targets. This Account describes our systematic approach using secondary and tertiary protein domain mimics (PDMs) to specifically modulate PPIs. Our strategy focuses on mimicry of regular secondary and tertiary structure elements from one of the PPI partners to inspire rational PDM design. We have compiled three databases (HIPPDB, SIPPDB, and DIPPDB) of secondary and tertiary structures at PPI interfaces to guide our designs and better understand the energetics of PPI secondary and tertiary structures. Our efforts have focused on three of the most common secondary and tertiary structures: alpha-helices, beta-strands, and helix dimers (e.g., coiled coils). To mimic alpha-helices, we designed the hydrogen bond surrogate (HBS) as an isosteric PDM and the oligooxopiperazine helix mimetic (OHM) as a topographical PDM. The nucleus of the HBS approach is a peptide macrocycle in which the N-terminal i, i + 4 main-chain hydrogen bond is replaced with a covalent carbon-carbon bond. In mimicking a main-chain hydrogen bond, the HBS approach stabilizes the alpha-helical conformation while leaving all helical faces available for functionalization to tune binding affinity and specificity. The OHM approach, in contrast, envisions a tetrapeptide to mimic one face of a two-turn helix. We anticipated that placement of ethylene bridges between adjacent amides constrains the tetrapeptide backbone to mimic the i, i + 4, and i + 7 side chains on one face of an alpha-helix. For beta-strands, we developed triazolamers, a topographical PDM where the peptide bonds are replaced by triazoles. The triazoles simultaneously stabilize the extended, zigzag conformation of beta-strands and transform an otherwise ideal protease substrate into a stable molecule by replacement of the peptide bonds. We turned to a salt bridge surrogate (SBS) approach as a means for stabilizing very short helix dimers. As with the HBS approach, the SBS strategy replaces a noncovalent interaction with a covalent bond. Specifically, we used a bis-triazole linkage that mimics a salt bridge interaction to drive helix association and folding. Using this approach, we were able to stabilize helix dimers that are less than half of the length required to form a coiled coil from two independent strands. In addition to demonstrating the stabilization of desired structures, we have also shown that our designed PDMs specifically modulate target PPIs in vitro and in vivo. Examples of PPIs successfully targeted include HIF1alpha/p300, p53/MDM2, Bcl-xL/Bak, Ras/Sos, and HIV gp41. The PPI databases and designed PDMs created in these studies will aid development of a versatile set of molecules to probe complex PPI functions and, potentially, PPI-based therapeutics. PMID- 28561591 TI - Development of Selective Clk1 and -4 Inhibitors for Cellular Depletion of Cancer Relevant Proteins. AB - In cancer cells, kinases of the Clk family control the supply of full-length, functional mRNAs coding for a variety of proteins essential to cell growth and survival. Thus, inhibition of Clks might become a novel anticancer strategy, leading to a selective depletion of cancer-relevant proteins after turnover. On the basis of a Weinreb amide hit compound, we designed and synthesized a diverse set of methoxybenzothiophene-2-carboxamides, of which the N-benzylated derivative showed enhanced Clk1 inhibitory activity. Introduction of a m-fluorine in the benzyl moiety eventually led to the discovery of compound 21b, a potent inhibitor of Clk1 and -4 (IC50 = 7 and 2.3 nM, respectively), exhibiting an unprecedented selectivity over Dyrk1A. 21b triggered the depletion of EGFR, HDAC1, and p70S6 kinase from the cancer cells, with potencies in line with the measured GI50 values. In contrast, the cellular effects of congener 21a, which inhibited Clk1 only weakly, were substantially lower. PMID- 28561592 TI - Pressure Dependence of the Boson Peak of Glassy Glycerol. AB - The pressure dependence of the boson peak (BP) of glycerol, including its behavior across the liquid-glass transition, has been studied using Raman scattering. A significant increase of the BP frequency was observed with pressure up to 11 GPa at room temperature. The pressure dependence of BP frequency nuBP is proportional to (1+P/P0)1/3, where P and P0 are the pressure and a constant, respectively, consistent with a soft potential model. The characteristic length of medium range order is close in size to a cyclic trimer of glycerol molecules, as predicted by the medium range order of a BP excitation using molecular dynamics simulations, and the pressure dependence of a characteristic medium range order is nearly constant. The pressure induced structural changes in glycerol can be understood in terms of the shrinkage of voids with cyclic trimers persisting to at least 11 GPa. Pressure dependence of the intermolecular O-H stretching mode indicates that the intermolecular hydrogen bond distances gradually decrease up to the glass transition pressure of ~5 GPa and become nearly constant in the glassy state, indicating the disappearance of free volume in the dense glass. PMID- 28561593 TI - Ionothermal Design of Crystalline Halogeno(cyano)cuprate Family: Structure Diversity, Solid-State Luminescence, and Photocatalytic Performance. AB - A general preparative method for multifunctional halogeno(cyano)cuprate materials in ionic liquids is developed in this work. Under ionothermal conditions, alkylimidazolium-based ionic liquids serving as solvent, charge-compensating, and structure-directing agent, as well as reactant lead to 12 members of the novel hybrid halogeno(cyano)cuprate family with a general formula of [R1R2R3IM]b+c a[CuaXb(CN)c] (R1R2R3IM = alkylimidazolium cations, X = halide anions). X-ray single-crystal diffractions show that diverse inorganic halogeno(cyano)cuprate components vary from discrete complexes (1 and 2), one-dimensional (1D) chains (3 7), two-dimensional (2D) layer (8), to three-dimensional (3D) open frameworks (9 12). 1 and 2 are of zero-dimensional discrete structures containing triangular [CuX3]2- anions. In complexes 3-7, pentagonal bipyramidal [Cu2X3] units are bridged by CN groups to give 1D [Cu2X3(CN)]2- inorganic chains, which are charge balanced by the surrounded alkylimidazolium cations. 2D inorganic [Cu5ClI2(CN)4]2 layer in complex 8 is alternately packed with [VMIM]+ organic cations. In complex 9, left- and right-handed Cu-CN helical chains connect each other to give a 3D open framework, which are further entrapped by 1D zigzag Cu-CN chains and [PMIM]+ cations. Diverse unique Cu(I) atoms and cyanide or halide bridging groups in 10, 11, and 12 are extended into 3D anionic open frameworks with 1D channels, which are occupied by alkylimidazolium cations. For all hybrid halogeno(cyano)cuprate complexes, the extensively existing C-H...X or C-H...pi hydrogen bonds help to stabilize the ultimate supramolecular packing structures. Notably, the distances between adjacent Cu(I) centers range from 2.420(2) to 2.989(2) A in all polymeric frameworks, which indicate strong Cu...Cu interactions. Thanks to the cooperation of conjugate pi electron cyanide systems with halide ions and/or Cu...Cu interactions, compounds 1-12 all demonstrate strong solid-state photoluminescence and semiconducting performance. Specially, hybrid halogeno(cyano)cuprates reported herein first exhibit excellent photocatalytic degradation of organic dye. To the best of our knowledge, fewer than 10 crystalline halogeno(cyano)cuprate compounds were obtained before this work, although different synthetic routes have been involved. Clearly, the discovery of this large hybrid material family under ionothermal conditions is important for the further development of novel functional halogeno(cyano) filled shell d10 metal crystalline materials. PMID- 28561594 TI - Reversible Shape Transformation of Ultrathin Polydopamine-Stabilized Droplet. AB - Here we report on the flattening of water droplets using an ultrathin membrane of autopolymerized polydopamine at the air/water interface. This has only been previously reported with the use of synthetic or extracted peptides, two dimensional designed synthetic peptide thin films with thicknesses of several tens of nanometers. However, in the previous study, the shape of the water droplet was changed irreversibly and the phenomenon was observed only at the air/water interface. In the present study, an ultrathin polydopamine membrane stabilized droplet induced the flattening of a water droplet at the air/liquid and liquid/liquid interfaces because a polydopamine membrane was spontaneously formed at these interfaces. Furthermore, a reversible transformation of the droplet to flat and dome shape droplets were discovered at the liquid/liquid interface. These are a completely new system because the polydopamine membrane is dynamically synthesized at the interface and the formation speed of the polydopamine membrane overcomes the flattening time scale. These results will provide new insight into physical control of the interfacial shapes of droplets. PMID- 28561595 TI - Beyond-Cassie Mode of Wetting and Local Contact Angles of Droplets on Checkboard Patterned Surfaces. AB - Droplet wetting and distortion on flat surfaces with heterogeneous wettability are studied using the 3D Shan-Chen pseudopotential multiphase lattice Boltzmann model (LBM). The contact angles are compared with the Cassie mode, which predicts an apparent contact angle for flat surfaces with different wetting properties, where the droplet size is large compared to the size of the heterogeneity. In this study, the surface studied consists in a regular checkboard pattern with two different Young's contact angles (hydrophilic and hydrophobic) and equal surface fraction. The droplet size and patch size of the checkboard are varied beyond the limit where Cassie's equation is valid. A critical ratio of patch size to droplet radius is found below which the apparent contact angle follows the Cassie mode. Above the critical value, the droplet shape changes from a spherical cap to a more distorted form, and no single contact angle can be determined. The local contact angles are found to vary along the contact line between minimum and maximum values. The droplet is found to wet preferentially the hydrophilic region, and the wetted area fraction of the hydrophilic region increases quasi linearly with the ratio between patch and droplet sizes. We propose a new equation beyond the critical ratio, defining an equivalent contact angle, where the wetted area fractions are used as weighting coefficients for the maximum and minimum local contact angles. This equivalent contact angle is found to equal Cassie's contact angle. PMID- 28561597 TI - MIS techniques in orthopedics. PMID- 28561596 TI - Higher exercise intensity delays postexercise recovery of impedance-derived cardiac sympathetic activity. AB - Systolic time intervals (STIs) provide noninvasive insights into cardiac sympathetic neural activity (cSNA). As the effect of exercise intensity on postexercise STI recovery is unclear, this study investigated the STI recovery profile after different exercise intensities. Eleven healthy males cycled for 8 min at 3 separate intensities: LOW (40%-45%), MOD (75%-80%), and HIGH (90%-95%) of heart-rate (HR) reserve. Bio-impedance cardiography was used to assess STIs - primarily pre-ejection period (PEP; inversely correlated with cSNA), as well as left ventricular ejection time (LVET) and PEP:LVET - during 10 min seated recovery immediately postexercise. Heart-rate variability (HRV), i.e., natural logarithm of root mean square of successive differences (Ln-RMSSD), was calculated as an index of cardiac parasympathetic neural activity (cPNA). Higher preceding exercise intensity elicited a slower recovery of HR and Ln-RMSSD (p < 0.001), and these measures did not return to baseline by 10 min following any intensity (p <= 0.009). Recovery of STIs was also slower following higher intensity exercise (p <= 0.002). By 30 s postexercise, higher preceding intensity resulted in a lower PEP (98 +/- 14 ms, 75 +/- 6 ms, 66 +/- 5 ms for LOW, MOD, and HIGH, respectively, p < 0.001). PEP recovered to baseline (143 +/- 11 ms) by 5 min following LOW (139 +/- 13 ms, p = 0.590) and by 10 min following MOD (145 +/- 17 ms, p = 0.602), but was still suppressed at 10 min following HIGH (123 +/- 21 ms, p = 0.012). Higher preceding exercise intensity attenuated the recovery of indices for cSNA (from STIs) and cPNA (from HRV) in a graded dose-response fashion. While exercise intensity must be considered, acute recovery may be a valuable period during which to concurrently monitor these noninvasive indices, to identify potentially abnormal cardiac autonomic responses. PMID- 28561598 TI - Minimally invasive spine surgery. A surgical manual. Second edition. PMID- 28561599 TI - Intraoperative Temperature Management. PMID- 28561600 TI - Current Pneumonia Surveillance Methodology: Similar Underestimation in Trauma and Surgical Patients in the Intensive Care Unit. AB - BACKGROUND: In 2013, the Centers for Disease Control and Prevention (CDC) developed new surveillance definitions for ventilator-associated events (VAE), leading to concerns that hospitals may be underreporting the true incidence of ventilator-associated pneumonias (VAPs). We sought to compare rates of clinically diagnosed VAP with CDC defined possible VAPs (PVAPs) in patients with a VAE in the surgical/trauma intensive care unit (STICU). HYPOTHESIS: Significant difference exists between rates of clinical VAP and PVAP in patients with at least one VAE. PATIENTS AND METHODS: All STICU patients with >=1 VAE, between 1/1/2013 and 10/31/2015 were identified. Age, length of stay (LOS), ICU and ventilator days were collected. RESULTS: There were 134 patients who had >=1 VAE. Mean age was 54.3 (+/-17.1) years. Mean LOS, median ICU, and median ventilator days were 26.3 (+/-14.1), 21.0 (17.0-33.0), and 17.0 (12.8-24.0) days, respectively. There were 68 cases of clinically diagnosed VAP, but only 37% met PVAP criteria. We compared 43 cases of clinical VAP, not meeting PVAP criteria, with the 25 PVAPs. Both groups had similar outcomes. The PVAPs were more likely to have an abnormal temperature (48.0% vs. 14.0%, p = 0.004), abnormal white blood cell count (84.0% vs. 18.6%, p < 0.001), or new antibiotic agent initiated (100% vs. 18.6%, p < 0.001) as VAE triggers. Comparison of the 93 trauma and 41 surgical patients demonstrated trauma patients were younger (51.2 vs. 61.5 y, p = 0.001), but had similar outcomes and rates of clinical VAP (48.4% and 43.9%, p = NS). Only 20.4% of trauma and 14.6% of surgical patients, however, had a PVAP reported. For patients with at least one VAE, the sensitivity and specificity for PVAP detecting VAP was 36.8% and 96.0%, respectively. CONCLUSION: The new CDC definition for PVAP grossly underestimates the clinical diagnosis of VAP and reports less than a third of the patients treated for VAP. Reporting differences were similar for trauma and surgical patients. PMID- 28561601 TI - Physical principles of ultrasonic dissection and clinical application of BERCHTOLD SONO-CUT reusable ultrasonic scissors. AB - Technical principles and physical action mechanisms of ultrasonic dissection are introduced. We list various indications for using the BERCHTOLD SONO-CUT scissors and describe early clinical experiences, e.g. in pediatric laparoscopic surgery. PMID- 28561602 TI - The endoluminal management of duodenal lesions. AB - Benign duodenal lesions such as adenomas and webs have traditionally been approached endoscopically. Unfortunately, endoscopic polypectomies are limited by the size and villous nature of the lesions as well as their locations within the lumen. Duodenal web resections may be restricted by the size of the opening leading to inadequate lumen size and recurrence. When these procedures fail, conventional open or laparoscopic surgery with its attendant morbidity is often necessary. Recent advances in camera optics and mini-Iaparoscopic instrumentation have expanded the laparoscopic options available to treat mucosal and submucosal lesions of the upper GI tract. Laparoscopic endoluminal surgery has evolved into a viable option for the treatment of many intragastric lesions. We have successfully extrapolated this concept to the treatment of proximal duodenal lesions. Successful resection of a duodenal web and a large tubulovillous adenoma are presented. Laparoendoscopic intraluminal management of benign duodenal lesions is safe, feasible, and effective. PMID- 28561603 TI - Technology and application of the reusable Olympus Ultrasonic Dissector. AB - With US scalpels a new era of laparoscopic surgery has begun. We have given instances of the striking advantages of modern ultrasonic dissectors in general, and of the SonoSurg system in particular. Key aspects are reusability, modularity and multi-functionality. Modularity allows for extension of the basic scalpel e.g. to an aspirator, reusability results in cost effectiveness. Nevertheless, ultrasonically activated devices are not limited to the well-known scalpels and aspirators. New technologies such as the SonoSurg ultrasound trocar and combination instruments are currently under development. PMID- 28561604 TI - Aggressive endoscopic mucosal resection in the upper GI tract - Hook knife EMR method. AB - We have developed a new EMR method, the 'Hook knife' method, for the en-bloc resection of larger lesions. First, we placed marks around the lesion with a coagulation tip. Next, 10% glycerol diluted epinephrine solution was injected into the submucosal layer to separate the mucosa from the muscular layer proper. Then, we cut the mucosa around the lesion with a needle knife. Finally, we cut the submucosal fibers and vessels using a hook-type knife and resected the lesions. A large en-bloc resection, >=70 mm in size, was possible with this new EMR method. Because of this, the histological examination for both the range of lateral spreading and the depth of invasion can be made more precisely. Aggressive endoscopic mucosal resection is established by this new EMR method. PMID- 28561605 TI - Technology and clinical application of ultrasonic dissection. AB - The implementation of UltraCision (The Harmonic Scalpel) can be seen as a milestone in the development of surgery. Ultrasound is now used for tissue cutting and/or simultaneous vessel sealing and transection. No electric current passes through the patient. Thus the typical complications associated with electrocautery can be avoided. This technology was primarily developed for videoscopic surgery and then successfully transferred to all branches of open surgery. The clean and blood-saving dissection technology and the ability to dissect very close to sensitive structures in oncological surgery are highly beneficial for patients. The development of new blades and multifunctional shears has further enhanced both practicability and ergonomics. UltraCision can now be used for the complete surgical spectrum, both in open and in laparoscopic surgery. PMID- 28561606 TI - Endoluminal intragastric treatment of gastric carcinoma. AB - Early gastric cancer accounts for more than 50% of resected gastric cancer cases in Japan. Because of the increased incidence of early gastric cancer, endoluminal minimally invasive intragastric treatments have been developed. The rate of lymph node metastasis is very low in early gastric cancer, especially in mucosal cancer. There are two popular strategies in Japan for the management of patients with mucosal cancer: endoscopic mucosal resection (EMR) and intragastric mucosal resection (IGMR). EMR is more popular: from 1993 to 1997, over 35,000 cases of early gastric cancer have been treated by EMR in Japan. IGMR was developed in 1993, and 256 cases of early gastric cancer, which were not appropriate for EMR because of size and location, have been treated successfully by IGMR. These data suggest that in Japan 20%-30% of patients with early gastric cancer are treated by endoluminal intragastric procedures. In this paper we review the indications for, techniques pertaining to, and outcomes of EMR and IGMR in Japan. PMID- 28561607 TI - Dissection technologies. PMID- 28561609 TI - MITAT - Current state and future perspectives. PMID- 28561608 TI - Endoluminal resection of gastric intestinal stromal tumors (GIST). AB - Endoluminal surgery, the combination of flexible endoscopy and percutaneous transgastric laparoscopy, has expanded the role of minimally invasive surgery in treating foregut diseases. This imaginative technique blends the skills of endoscopist and laparoscopist. The stomach is well-suited for this technique as it is an expandable, large volume organ readily accessible to a flexible endoscope, and the relative ease of placing endoscopically or laparoscopically guided percutaneous, transgastric ports provides access for laparoscopic instrumentation. The resection of gastric stromal tumors provides one of the few opportunities to integrate flexible endoscopy and laparoscopy. Proper training in the appropriate indications to utilize endoluminal techniques and familiarity with the multiple modifications from the original intragastric techniques described nearly a decade ago will allow surgeons to approach small, predominately endoluminal gastric stromal tumors with low malignant potential located in the cardia, along the posterior gastric wall, near the gastroesophageal junction or proximal to the pylorus. PMID- 28561610 TI - The Stretta procedure for the treatment of gastro esophageal reflux disease (GERD). AB - Gastroesophageal reflux disease (GERD) is one of the most common disorders of the gastrointestinal tract. Laparoscopic anti-reflux surgery has been shown to be safe and effective for the treatment of GERD with excellent symptom control. However, an approach to the treatment of GERD that has less morbidity than surgery and obviates the need for drugs is desirable. The endoscopic delivery of temperaturecontrolled radiofrequency energy (RF) to the gastroesophageal junction (GE), termed Stretta (Curon Medical, Sunnyvale, CA, USA), has recently been shown to be safe, well tolerated, and highly effective in patients with GERD. We review the basic principles, technique, potential mechanisms of action, and effectiveness of the Stretta procedure. PMID- 28561611 TI - Saline enhanced thermal sealing of tissue: Potential for bloodless surgery. AB - A new technology has been introduced that combines radiofrequency (RF) energy with simultaneous saline irrigation. We present a description of the technology, its fundamental effect on tissue, selected preclinical results, and early clinical outcomes in a variety of surgical disciplines. The initial product that incorporates this technology is the TissueLink Floating BallTM, a monopolar surface coagulator, available in both laparoscopic and open shaft lengths. The low flow rate of saline couples RF to tissue and provides Cooling to limit the tissue temperature to no greater than 100 degrees C. This prevents desiccation, eschar, smoke, and sticking associated with conventional dry electrosurgical devices with dry electrodes. The primary tissue effect OCcurs at tissue temperatures in the range of 60-80 degrees C and involves the shrinkage of the Type I collagen that OCcurs in the walls of blood vessels, airways, bile ducts and other biological vessels. The shrinkage of the collagen closes the lumen and seals the vessel. Data is presented on the depth of the tissue effect and the chronic healing response in porcine liver. Early clinical results in the form of case reports are presented for both general and thoracic surgical applications, particularly for highly vascularized parenchymatous organs such as liver and lung. The use of the TissueLink device for liver resections has shown the potential to dramatically reduce blood loss. Its use in thoracic surgery has demonstrated it is capable of achieving both hemostasis and aerostasis. PMID- 28561612 TI - Early clinical experience with water-jet dissection (hydro-jet) during nerve sparing radical retropubic prostatectomy. AB - Successful preservation of the neuro-vascular bundle (NVB) during anatomical nerve-sparing radical retropubic prostatectomy (NS-RRP) for patients with clinically localized prostate cancer is a great operative challenge. We employed a new dissection method using water-jet technology for the preservation of the NVB. We evaluated intraoperative parameters, complications and early functional results regarding continence and potency. The results were compared to a conventional operative technique. Bilateral NS-RRP was performed by the same urologist in 36 consecutive cases between January and December 2000. Eighteen patients underwent NS-RRP using water-jet dissection (ERBE Helix Hydro-Jet). Eighteen patients underwent a standard NS-RRP. Water-jet dissection was used exclusively for nerve-sparing. We assessed blood loss, operation time, complications and incidence of blood transfusions. Early continence and potency rates were evaluated. Nerve-sparing using the Hydro-Jet technique appeared to be easier, more subtle and faster compared with the standard surgical technique. The exact dissection of the layers allowed a selective dissection and better control of crossing vessels to the prostate. Blood loss was reduced by 36% (p=0.02), no blood transfusion was necessary and the operation time was reduced by 20% (p=0.02). There were no major complications. Continence rates 3 months after RRP were 77.7% in the water jet group and 66.6% in the standard group, and overall potency rates (any grade of erection) were 77.7% and 55.5% respectively. Water jet dissection is a feasible, safe and efficient technique to facilitate NS-RRP. There is a minimal learning curve with comparable functional results to the conventional procedure. Further improvements in the water-jet application and a longer follow-up might lead to further improvements in continence and potency rates in patients undergoing NS-RRP. PMID- 28561613 TI - Technology of water-jet dissection. AB - For about 20 years, water-jet dissection has been used as a surgical technique. Due to the development of suitable instruments, devices, and operation strategies, water-jet dissection is becoming increasingly interesting for applications, especially for dissections where the atraumatical and/or tissueselective preparation or separation of tissue structures is mandatory. Prerequisites for the effective and safe application of the water-jet dissection are, on the one side, the knowledge of the relevant physical characteristics of the tissues in question, as well as their mechanical connections, and, on the other side, the knowledge of the relevant physical effects of a water-jet. The present paper will deal with these aspects. PMID- 28561614 TI - Early endoscopic management of anastomotic leakage of esophageal atresia. AB - Anastomotic leaks (AL) of esophageal atresia (EA) close spontaneously with tube drainage and nutritional support, but this conservative management carries some risk factors. The present study describes an alternative endoscopic approach in evaluation and management. The endoscopic procedure, including esophagoscopy, catheterization of leakage point, and application of fibrin glue (FG) has been evaluated. It was applied seven times to four patients. The diagnostic criteria, the technique and the results are discussed. It has been determined that early endoscopic demonstration of AL in EA and application of FG prevent the possible complications of the conservative management, such as mediastinitis and lung collapse with pneumothorax due to ineffective chest drain, and side effects of parenteral nutrition and antibiotics. If a quickly solidified FG in a proper amount "0,5 ml) is used in an early phase with a correct positioning of the AL by radiological or endoscopic examination, a satisfactory result can be obtained. PMID- 28561615 TI - Development of a new haemostatic dissecting forceps utilizing controlled heat as an energy source. AB - We tested a prototype of a new thermal surgical system in animal experiments. This device utilizes controlled heat as an energy source and seals and divides small- to medium-size vessels. The forceps we used in the current study are shaped like dissecting forceps used in conventional open surgery, and their grippers can open bilaterally. Heating elements are built into a gripper. The temperature adjustment is controlled by monitoring the electric resistance. Since the new device utilizes no ultrasonic energy, unfavorable phenomena such as cavitations or mist production are not observed. In a preliminary experiment, 12 segments of animal arteries were sealed and cut by the prototype forceps. Five artery stumps did not burst at the maximum pressure of the manometer system (1471 mmHg). The other seven stumps showed burst pressure ranging from 525 mmHg to 1051 mmHg. It is feasible to utilize controlled heat as a new alternative energy source for haemostatic surgical dissection. The new thermal dissector we are in the process of developing showed safe and quick sealing and cutting of the vessels in the experimental settings. PMID- 28561616 TI - Design of multifunctional compliant mechanisms for minimally invasive surgery. AB - Compliant mechanisms that can perform multiple unique functions have great potential for use in minimally invasive therapy. A fully compliant mechanism may be thought of as a monolithic mechanism without hinge joints which uses elastic deformation to achieve force and motion transmission. Incorporating multifunctional compliant mechanisms into minimally invasive surgical tools has many possible advantages, including reduced instrument exchanges and additional dexterity at the surgical site. Compliant mechanisms also offer the advantage of single-piece construction and ease of manufacture over their rigid-link counterparts, eliminating the need for complex millimeter-scale assembly and cleaning in hinge areas. A multicriteria topology optimization procedure for the design of multifunctional compliant mechanisms is illustrated through the design of a combination tool that will perform forceps and scissor function. A working solid model of the combination forceps/scissors has been generated based on the optimal topology. Results of detailed finite element modeling are discussed along with implications for practical manufacture and implementation. PMID- 28561617 TI - LigaSure AtiasTM Instrument. AB - It is the objective of this article to describe the features and applications of the LigaSureTM vessel sealing system and the new laparoscopic LigaSure AtlasTM instrument with both vessel sealing and tissue dividing capabilities. This new technique works by fusing the collagen and elastine in vessel walls to create a permanent seal. The fusion mechanism results in strong burst strength characteristics as compared to standard bipolar and ultrasonic coagulating instruments. This new energy-based source continually monitors the clinical effect on the tissue and provides greater tissue sealing with minimal damage to surrounding tissue. Studies have shown that the automated LigaSureTM device is safe, efficient, and easy to use and reduces intraoperative blood loss and operative time in many surgical procedures. PMID- 28561618 TI - Endoluminal surgery. PMID- 28561619 TI - The treatment of pancreatic pseudocysts by laparoscopic drainage: endoluminal and lesser sac techniques. AB - A variety of approaches are now available to drain pancreatic pseudocysts (PP) when indicated. In addition to open surgery, endoscopic, laparoscopic, intra luminal, and percutaneous techniques are available as therapeutic options to facilitate drainage of mature symptomatic PP. The laparoscopic lesser sac technique is appealing since it * relies on a secure stapled anastomosis, * provides an adequate sized cystgastrostomy to facilitate drainage, and * utilizes minimally invasive techniques to diminish operative morbidity and expedite return to normal activities. Short-term follow-up data suggest that this approach is feasible, effective and reproducible, Long-term studies demonstrating the efficacy of laparoscopic drainage of PP using the lesser sac technique are needed to validate these early favorable outcomes. PMID- 28561621 TI - Effects of Oestradiol and the Oestrogen Antagonist lei 182,780 on the Delayed Type Hypersensitivity (DTH) Index and on Serum Levels of lgM and lgG in Ovariectomised Balb/C and MRL/Mp-Lpr/Lpr Mice, a Model of Systemic Lupus Erythematosus (SLE). AB - The effects of oestradiol and the oestrogen receptor antagonist ICI 182,780 were investigated on the DTH index, serum IgG and IgM levels and spleen weight in female BALB/c and MRLIMP-Ipr/lpr mice. At six weeks, the mice were ovariectomisecl, and one week later, over a four-week period, given biweekly s.c. doses of (i) 5MUJ l of oli ve oil, or (i i) 5 MU1 of oil containing 3.2 MUg of 17beta-oestradiol (E2), or (iii) 5 MUl of oil containing (3.2 MUl of E2 + ICI 182,780 , at a dose of 30 mg/kg), or (iv) the same dose of ICI 182,780 alone. E2 significantly raised the DTH index in BALB/c mice; this effect was prevented if ICI 182,780 was included in the injectio n . The DTH index in MRL mice was unaffected by any of the treatments. All steroid u.eatments raised serum IgG levels in BALB/c mice, but those in sera of MRL were un affected and were significantly higher than those measured in BALB/c mice . ICI 182,780 depressed TgM in BALB/c mice, while all steroidtreatments increased JgM in MRL mice. ICI 182,780 de pressed spleen weights in both strains. Oes u.ogen may influence Bcell functiontlu.ough ICI 182,780-se nsitive receptors, and ICI 182,780 may have agonist actions on the immune system. (200 words). PMID- 28561627 TI - Hearing Rehabilitation For Deafened Adults - A Psychosocial Approach. PMID- 28561630 TI - [Nurse style of central vein! Our experience in the peripherally inserted central venous catheter]. AB - What is PICC line insertion? The PICC is a soft, flexible catheter which is made of polyurethane or silicone, and is inserted via an upper or lower extremity peripheral vein into superior or inferior vena cava. The origin of PICC line dates back to the early 1950s. Since the introduction of the PICC catheter, this method of venous catheterization has gone through many changes as regards the technique of insertion or the type of catheter used. Despite the routine use of PICC line worldwide, little progress has been made in its use in Hungary. In this short review we will briefly summarise the use of PICC line, its indications, advantages, disadvantages, and on complementary devices which are necessary during the procedure. We discuss our experience in insertion of PICC line at Pecs University, where the procedure is solely done by a certified registered nurse. We hope that with continuous progression of nurse competency, this procedure will be implemented at a higher scale in Hungary. Orv Hetil. 2017; 158(22): 856-863. PMID- 28561626 TI - Sex Differences in High School Athletes' Knowledge of Sport-Related Concussion Symptoms and Reporting Behaviors. AB - CONTEXT: Recent researchers have reported that athletes' knowledge of sport related concussion (SRC) has increased but that athletes still lack knowledge of all the signs and symptoms of SRC. Understanding the signs and symptoms of SRC and the dangers of playing while symptomatic are critical to reporting behaviors in high school athletes. OBJECTIVE: To examine sex differences in knowledge of SRC symptoms and reasons for not reporting a suspected SRC to an authoritative figure in high school athletes. DESIGN: Cross-sectional study. SETTING: Survey. PATIENTS OR OTHER PARTICIPANTS: A total of 288 athletes across 7 sports (198 males [68.8%] and 90 females [31.2%]). MAIN OUTCOME MEASURE(S): A validated knowledge-of-SRC survey consisted of demographic questions, a list of 21 signs and symptoms of SRC, and reasons why athletes would not report their SRC. The independent variable was sex. Athlete knowledge of SRC symptoms was assessed by having participants identify the signs and symptoms of SRC from a list of 21 symptoms. Knowledge scores were calculated by summing the number of correct answers; scores ranged from 0 to 21, with a score closer to 21 representing greater knowledge. Reporting-behavior questions asked athletes to choose reasons why they decided not to report any possible SRC signs and symptoms to an authoritative figure. RESULTS: A sex difference in total SRC symptom knowledge was found (F286 = 4.97, P = .03, d = 0.26). Female high school athletes had more total SRC symptom knowledge (mean +/- standard deviation = 15.06 +/- 2.63; 95% confidence interval = 14.54, 15.57) than males (14.36 +/- 2.76; 95% confidence interval = 13.97, 14.74). Chi-square tests identified significant relationships between sex and 8 different reasons for not reporting an SRC. CONCLUSIONS: High school males and females had similar SRC symptom knowledge; however, female athletes were more likely to report their concussive symptoms to an authoritative figure. PMID- 28561631 TI - [Semmelweis of the 17th century or Jean Baptiste Denis and the first human transfusion (1667)]. PMID- 28561632 TI - [Traumatic asphyxia with permanent visual loss. Case report]. AB - Traumatic asphyxia is a rare condition that occurs after compressive thoracoabdominal trauma, which is characterized by subconjunctival hemorrhage, cervicofacial cyanosis, edema and petechiae. Serious life-threatening thoracic and abdominal injuries may coexist. After conservatory treatment in most cases complete recovery is achieved, but in isolated cases permanent neurological lesions may occur. We present the case of the 39-year-old male patient who suffered a compressive thoracoabdominal trauma. The physical examination showed the characteristic "ecchymotic mask". After surgical treatment of the abdominal injuries and intensive therapy the patient was discharged with permanent vision loss. The high retrograde venous pressure in the head and neck may be associated with neuronal ischemia, which can lead to irreversible optic nerve atrophy. It is therefore important to carry out an early, routine and complete ophtalmologic examination, especially in the intubated and poorly cooperative patients. Orv Hetil. 2017; 158(22): 864-868. PMID- 28561634 TI - [Social anxiety and self-esteem: Hungarian validation of the "Brief Fear of Negative Evaluation Scale - Straightforward Items"]. AB - INTRODUCTION: Although social anxiety disorder (SAD) is the third most frequent emotional disorder with 13-15% prevalence rate, it remains unrecognized very often. Social phobia is associated with low self-esteem, high self-criticism and fear of negative evaluation by others. It shows high comorbidity with depression, alcoholism, drug addiction and eating disorders. AIM: To adapt the widely used "Fear of Negative Evaluation" (FNE) social phobia questionnaire. METHOD: Anxiety and mood disorder patients (n = 255) completed the Fear of Negative Evaluation Scale (30, 12 and 8 item-versions) as well as social cognition, anxiety and self esteem questionnaires. RESULTS: All the three versions of the FNE have strong internal validity (alpha>0.83) and moderate significant correlation with low self esteem, negative social cognitions and anxiety. The short 8-item BFNE-S has the strongest disciminative value in differentiating patients with social phobia and with other emotional disorders. CONCLUSIONS: The Hungarian version of the BFNE-S is an effective tool for the quick recognition of social phobia. Orv Hetil. 2017; 158(22): 843-850. PMID- 28561635 TI - [Role of the diet in urinary stone formation and prevalence]. AB - In Hungary and in the developed countries urinary stones occur more often due to nutritional habits, obesity and sedentary lifestyle beside the endocrine and metabolic causes. In the daily urological and family doctor practice prevention should have an important role. Prevention is based not only on body weight control, physical exercise and medical treatment, but on proper diet as well. The nutritional components can change the consistence of urine, causing supersaturation, which is essential in stone formation. Specific nutritional components can either prevent stone formation (increased fluid intake, citrate, magnesium, fruits and vegetables) or either increase stone formation (decreased fluid intake, proteins, carbohydrates, oxalate, salt, increased calcium intake, ascorbic-acid etc). We summarized evidence-based practical dietary suggestions on the primary and secondary prevention of urinary stones. Orv Hetil. 2017; 158(22): 851-855. PMID- 28561636 TI - Choosing "Something Else" as a Sexual Identity: Evaluating Response Options on the National Health Interview Survey. AB - PURPOSE: Researchers struggle to find effective ways to measure sexual and gender identities to determine whether there are health differences among subsets of the LGBTQ+ population. METHOD: This study examines responses on the National Health Interview Survey (NHIS) sexual identity questions among 277 LGBTQ+ healthcare providers. RESULTS: Eighteen percent indicated that their sexual identity was "something else" on the first question, and 57% of those also selected "something else" on the second question. Half of the genderqueer/gender variant participants and 100% of transgender-identified participants selected "something else" as their sexual identity. CONCLUSION: The NHIS question does not allow all respondents in LGBTQ+ populations to be categorized, thus we are potentially missing vital health disparity information about subsets of the LGBTQ+ population. PMID- 28561637 TI - A Study To Assess the Numbers and Prevalence of Bacillus cereus and Its Toxins in Pasteurized Fluid Milk. AB - Bacillus cereus is a pathogenic adulterant of raw milk and can persist as spores and grow in pasteurized milk. The objective of this study was to determine the prevalence of B. cereus and its enterotoxins in pasteurized milk at its best before date when stored at 4, 7, and 10 degrees C. More than 5.5% of moderately temperature-abused products (stored at 7 degrees C) were found to contain >105 CFU/mL B. cereus , and about 4% of them contained enterotoxins at a level that may result in foodborne illness; in addition, more than 31% of the products contained >105 CFU/mL B. cereus and associated enterotoxins when stored at 10 degrees C. Results from a growth kinetic study demonstrated that enterotoxin production by B. cereus in pasteurized milk can occur in as short as 7 to 8 days of storage at 7 degrees C. The higher B. cereus counts were associated with products containing higher butterfat content or with those produced using the conventional high-temperature, short-time pasteurization process. Traditional indicators, aerobic colony counts and psychrotrophic counts, were found to have no correlation with level of B. cereus in milk. The characterization of 17 representative B. cereus isolates from pasteurized milk revealed five toxigenic gene patterns, with all the strains carrying genes encoding for diarrheal toxins but not for an emetic toxin, and with one strain containing all four diarrheal enterotoxin genes (nheA, entFM, hblC, and cytK). The results of this study demonstrate the risks associated even with moderately temperature-abused pasteurized milk and the necessity of a controlled cold chain throughout the shelf life of fluid milk to enhance product safety and minimize foodborne illness. PMID- 28561638 TI - Mitigation of Salmonella on Pet Food Kibbles by Using Liquid and Powdered 3 Hydroxy-3-Methylbutyric Acid. AB - In recent years, several pet food recalls have been attributed to Salmonella contamination. In addition to the negative impacts on animal health, Salmonella contaminated pet foods have been linked to infection in humans. With that in mind, the U.S. Food and Drug Administration has set forth a zero-tolerance policy for Salmonella in pet foods. Typically, pet foods are extruded or processed at high temperatures that are sufficient to reduce pathogenic bacteria. However, the possibility for postextrusion contamination still exists. One potential method to reduce the risk of postextrusion contamination of pet foods with Salmonella is through the addition of a chemical additive coating. The objective of this research was to evaluate the ability of beta-hydroxy-beta-methylbutyrate (HMB), in either free acid (HMBFA) or calcium salt (CaHMB) form, to reduce postextrusion contamination of dry extruded dog kibble with Salmonella. Three trials were conducted with HMBFA and CaHMB coated onto the kibbles at levels of 0, 0.1, 0.3, 0.5, 0.9, and 1.5% (w/w). The coated kibbles were then inoculated with Salmonella enterica subsp. enterica Enteritidis (ATCC 13076), with enumeration done on days 0, 1, 2, 7, and 14 postinoculation. Subsamples on each day were serially diluted, spread plated to xylose lysine deoxycholate agar, and incubated at 37 degrees C for 24 h. Salmonella colonies were then counted and log CFU per gram was calculated. The 1.5% HMBFA reduced counts by 4.9 +/- 0.2 log units on day 1, whereas the positive control only decreased 2.2 +/- 0.1 log units (P < 0.0001). The 1.5% CaHMB level decreased counts by 7.1 +/- 0.04 log units by day 7 compared with the control decrease of 2.1 +/- 0.1 log units (P < 0.0001). All HMBFA and CaHMB treatments resulted in the elimination of detectable Salmonella counts by day 14 (P < 0.0001 versus controls). In conclusion, HMB coating was effective at reducing Salmonella artificially inoculated to dog kibbles in a model of postextrusion contamination. PMID- 28561639 TI - Susceptibility of Salmonella Biofilm and Planktonic Bacteria to Common Disinfectant Agents Used in Poultry Processing. AB - Poultry contaminated with Salmonella enterica subsp. enterica are a major cause of zoonotic foodborne gastroenteritis. Salmonella Heidelberg is a common serotype of Salmonella that has been implicated as a foodborne pathogen associated with the consumption of improperly prepared chicken. To better understand the effectiveness of common antimicrobial disinfectants (i.e., peroxyacetic acid [PAA], acidified hypochlorite [aCH], and cetylpyridinium chloride [CPC]), environmental isolates of nontyphoidal Salmonella were exposed to these agents under temperature, concentration, and contact time conditions consistent with poultry processing. Under simulated processing conditions (i.e., chiller tank and dipping stations), the bacteriostatic and bactericidal effects of each disinfectant were assessed against biofilm and planktonic cultures of each organism in a disinfectant challenge. Log reductions, planktonic MICs, and mean biofilm eradication concentrations were computed. The biofilms of each Salmonella isolate were more resistant to the disinfectants than were their planktonic counterparts. Although PAA was bacteriostatic and bactericidal against the biofilm and planktonic Salmonella isolates tested at concentrations up to 64 times the concentrations commonly used in a chiller tank during poultry processing, aCH was ineffective against the same isolates under identical conditions. At the simulated 8-s dipping station, CPC was bacteriostatic against all seven and bactericidal against six of the seven Salmonella isolates in their biofilm forms at concentrations within the regulatory range. These results indicate that at the current contact times and concentrations, aCH and PAA are not effective against these Salmonella isolates in their biofilm state. The use of CPC should be considered as a tool for controlling Salmonella biofilms in poultry processing environments. PMID- 28561641 TI - Global Health Initiatives of the International Oncology Community. AB - Cancer has become one of the leading causes of morbidity and mortality in low- and middle-income countries (LMICs), where 60% of the world's total new cases are diagnosed. The challenge for effective control of cancer is multifaceted. It mandates integration of effective cancer prevention, encouraging early detection, and utilization of resource-adapted therapeutic and supportive interventions. In the resource-constrained setting, it becomes challenging to deliver each service optimally, and efficient allocation of resources is the best way to improve the outcome. This concept was translated into action through development of resource stratified guidelines, pioneered by the Breast Health Global Initiative (BHGI), and later adopted by most oncology societies in an attempt to help physicians deliver the best possible care in a limited-resource setting. Improving outcome entails collaboration between key stakeholders, including the pharmaceutical industry, local and national health authorities, the World Health Organization (WHO), and other nonprofit, patient-oriented organizations. Therefore, we started to observe global health initiatives-led by ASCO, the Union for International Cancer Control (UICC), and the WHO-to address these challenges at the international level. This article discusses some of these initiatives. PMID- 28561640 TI - Future Genetic/Genomic Biomarker Testing in Non-Small Cell Lung Cancer. PMID- 28561642 TI - Minimizing Minimally Invasive Surgery for Endometrial Carcinoma. PMID- 28561643 TI - Making the Case for Improving Oncology Workforce Diversity. PMID- 28561644 TI - Can Cancer Truths Be Told? Challenges for Medical Journalism. PMID- 28561645 TI - The Road to Addressing Noncommunicable Diseases and Cancer in Global Health Policy. PMID- 28561646 TI - Bench-to-Bedside Approaches for Personalized Exercise Therapy in Cancer. AB - The past 2 decades have witnessed a growing body of work investigating the feasibility and efficacy of exercise therapy on a broad array of outcomes in many different oncology scenarios. Despite this heterogeneity, the exercise therapy prescription approach and the dose tested has been largely similar. Thus, current exercise therapy prescriptions in the oncology setting adopt a one-size-fits-all approach. In this article, we provide an overview of personalization of exercise therapy in cancer using the principles of training as an overarching framework. Specifically, we first review the fundamentals of exercise prescription in chronic disease before focusing attention on application of these principles to optimize the safety and efficacy of exercise therapy on (1) cancer treatment induced cardiovascular toxicity and (2) tumor progression and metastasis. PMID- 28561648 TI - Tissue-Agnostic Drug Development. AB - The U.S. Food and Drug Administration (FDA) has approved drugs to treat patients with tumor types based on a single anatomic site, such as renal cell carcinoma or melanoma, rather than on a biomarker alone. This standard approach is based on a number of factors, including heterogeneity of drug effects in different biomarker positive tumor types. Additionally, drug development for some drugs was primarily directed toward a specific genomic abnormality in a specific tumor type (e.g., drugs for anaplastic lymphoma kinase [ALK] fusion-positive non-small cell lung cancer). In such cases, differences in biology, differences in natural histories of different cancers, differences in mutation frequencies among cancers, or differences in concomitant therapies may have necessitated diverse development considerations. As described in U.S. regulations [21 CFR 201, CFR 201.57(c)(2)], the indications and usage section of drug labeling "must state that a drug is indicated for the treatment, prevention, mitigation, cure, or diagnosis of a recognized disease or condition or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition." Such regulations, however, do not require that disease be defined solely as a specific tumor type. This manuscript will highlight scientific/biologic issues, clinical trial designs, and regulatory issues pertaining to the development of drugs agnostic of tumor type. Although the manuscript will discuss regulatory considerations as understood by the authors regarding tissue-agnostic drug development, it should not be considered formal or binding FDA guidance or policy. PMID- 28561649 TI - Mastering Resilience in Oncology: Learn to Thrive in the Face of Burnout. AB - Oncology clinician burnout has become a noteworthy issue in medical oncology directly affecting the quality of patient care, patient satisfaction, and overall organizational success. Due to the increasing demands on clinical time, productivity, and the evolving medical landscape, the oncology clinician is at significant risk for burnout. Long hours in direct care with seriously ill patients/families, limited control over daily responsibilities, and endless electronic documentation, place considerable professional and personal demands on the oncologist. As a result, the oncology clinician's wellness is adversely impacted. Physical/emotional exhaustion, cynicism, and feelings of ineffectiveness evolve as core signs of burnout. Unaddressed burnout may affect cancer clinician relationships with their patients, the quality of care delivered, and the overall physical and emotional health of the clinician. Oncology clinicians should be encouraged to build upon their strengths, thrive in the face of adversity and stress, and learn to positively adapt to the changing cancer care system. Fostering individual resilience is a key protective factor against the development of and managing burnout. Empowering clinicians at both the individual and organizational level with tailored resilience strategies is crucial to ensuring clinician wellness. Resilience interventions may include: burnout education, work-life balance, adjustment of one's relationship to work, mindful practice, and acceptance of the clinical work environment. Health care organizations must act to provide institutional solutions through the implementation of: team-based oncology care, communication skills training, and effective resiliency training programs in order to mitigate the effects of stress and prevent burnout in oncology. PMID- 28561647 TI - Social Media and Mobile Technology for Cancer Prevention and Treatment. AB - Given the number of lives affected by cancer and the great potential for optimizing well-being via lifestyle changes, patients, providers, health care systems, advocacy groups, and entrepreneurs are looking to digital solutions to enhance patient care and broaden prevention efforts. Thousands of health-oriented mobile websites and apps have been developed, with a majority focused upon lifestyle behaviors (e.g., exercise, diet, smoking). In this review, we consider the use and potential of social media and mHealth technologies for cancer prevention, cancer treatment, and survivorship. We identify key principles in research and practice, summarize prior reviews, and highlight notable case studies and patient resources. Further, with the potential for scaled delivery and broad reach, we consider application of social media and mHealth technologies in low-resource settings. With clear advantages for reach, social media and mHealth technologies offer the ability to scale and engage entire populations at low cost, develop supportive social networks, connect patients and providers, encourage adherence with cancer care, and collect vast quantities of data for advancing cancer research. Development efforts have been rapid and numerous, yet evaluation of intervention effects on behavior change and health outcomes are sorely needed, and regulation around data security issues is notably lacking. Attention to broader audiences is also needed, with targeted development for culturally diverse groups and non-English speakers. Further investment in research to build the evidence base and identify best practices will help delineate and actualize the potential of social media and mHealth technologies for cancer prevention and treatment. PMID- 28561650 TI - Higher-Level Pathway Objectives of Epigenetic Therapy: A Solution to the p53 Problem in Cancer. AB - Searches for effective yet nontoxic oncotherapies are searches for exploitable differences between cancer and normal cells. In its core of cell division, cancer resembles normal life, coordinated by the master transcription factor MYC. Outside of this core, apoptosis and differentiation programs, which dominantly antagonize MYC to terminate cell division, necessarily differ between cancer and normal cells, as apoptosis is suppressed by biallelic inactivation of the master regulator of apoptosis, p53, or its cofactor p16/CDKN2A in approximately 80% of cancers. These genetic alterations impact therapy: conventional oncotherapy applies stress upstream of p53 to upregulate it and causes apoptosis (cytotoxicity)-a toxic, futile intent when it is absent or nonfunctional. Differentiation, on the other hand, cannot be completely suppressed because it is a continuum along which all cells exist. Neoplastic evolution stalls advances along this continuum at its most proliferative points-in lineage-committed progenitors that have division times measured in hours compared with weeks for tissue stem cells. This differentiation arrest is by mutations/deletions in differentiation-driving transcription factors or their coactivators that shift balances of gene-regulating protein complexes toward corepressors that repress instead of activate hundreds of terminal differentiation genes. That is, malignant proliferation without differentiation, also referred to as cancer "stem" cell self-renewal, hinges on druggable corepressors. Inhibiting these corepressors (e.g., DNMT1) releases p53-independent terminal differentiation in cancer stem cells but preserves self-renewal of normal stem cells that express stem cell transcription factors. Thus, epigenetic-differentiation therapies exploit a fundamental distinction between cancer and normal stem cell self renewal and have a pathway of action downstream of genetic defects in cancer, affording favorable therapeutic indices needed for clinical progress. PMID- 28561651 TI - Precision Oncology: Who, How, What, When, and When Not? AB - Precision oncology, defined as molecular profiling of tumors to identify targetable alterations, is rapidly developing and has entered the mainstream of clinical practice. Genomic testing involves many stakeholders working in a coordinated fashion to deliver high-quality tissue samples to high-quality laboratories, where appropriate next-generation sequencing (NGS) molecular analysis leads to actionable results. Clinicians should be familiar with the types of genomic variants reported by the laboratory and the technology used to determine the results, including limitations of current testing methodologies and reports. Interpretation of genomic results is best undertaken with multidisciplinary input to reduce uncertainty in clinical recommendations relating to a documented variant. Non-small cell lung cancer has emerged as a prototype disease where genomic data from at least several well-documented alterations with approved targeted agents are essential for optimal treatment from diagnosis of advanced disease. Due to the development of resistance to targeted therapies, resampling and retesting of tumors, including using liquid biopsy technology after clinical progression, may be important in making treatment decisions. The value of molecular profiling depends on avoiding both underutilization for well-documented variant target-drug pairs and overutilization of variant-drug therapy without proven benefit. As techniques evolve and become more cost effective, the use of molecular testing may prove to add more specificity and improve outcomes for a larger number of patients. PMID- 28561652 TI - Evolving Treatment Paradigm in Metastatic Renal Cell Carcinoma. AB - The treatment paradigm for advanced and metastatic renal cell carcinoma (mRCC) has evolved rapidly since the arrival of targeted therapies and novel immunotherapies. mRCC was previously treated only with cytokines. However, discoveries of mutations affecting the von Hippel-Lindau tumor suppressor gene (leading to increased expression of VEGF and hypoxia inducible factor/HIF-1) and of deregulations in the phosphatidylinositol-3 kinase/AKT/mTOR pathway (resulting in tumor angiogenesis, cell proliferation, and tumor growth) have led to the development of numerous targeted therapies. The U.S. Food and Drug Administration (FDA) has thus approved a total of nine targeted therapies since 2005, including VEGF tyrosine kinase inhibitors (sunitinib, pazopanib, axitinib, sorafenib, and lenvatinib), a monoclonal antibody targeting VEGF (bevacizumab), mTOR inhibitors (temsirolimus and everolimus), and a multityrosine kinase inhibitor (cabozantinib). Furthermore, the development of immune checkpoint inhibitors has again shifted the mRCC therapeutic landscape with the FDA's approval of nivolumab. Herein, we discuss the unprecedented changes in the field of clear cell histology mRCC in both the first-line and salvage settings, and we also discuss future therapies and recommend a treatment paradigm on sequencing of these agents. PMID- 28561653 TI - Bone Sarcoma Pathology: Diagnostic Approach for Optimal Therapy. AB - The pathologic interpretation of malignant bone tumors is one of the more challenging areas in surgical pathology. This is based on the reality that primary bone sarcomas are uncommon, demonstrate significant morphologic heterogeneity, and have a broad spectrum of biology. Accordingly, it is difficult for pathologists to acquire the necessary experience to confidently and accurately diagnose bone sarcomas. The task is further complicated by the fact that it requires the integration of clinical and radiologic information into the diagnostic process. Lastly, molecular aberrations in sarcomas are being newly discovered and their identification is often critical to make specific diagnoses. The pathologist's role in guiding optimal treatment in biopsy specimens is to make an accurate diagnosis and provide the grade and molecular aberrations when appropriate. The pathology report of resected tumors must confirm this information and assess the surgical resection margins and the percentage of necrosis if the sarcoma has been treated with neoadjuvant systemic therapy. PMID- 28561654 TI - The Current Landscape of Early Drug Development for Patients With Sarcoma. AB - Until recently, advancements in the treatment of patients with adult soft tissue sarcomas have been relatively slow. This is, in part, due to their heterogeneity and rarity. A better understanding of the biology and differences among the various histologies has led to substantial growth in novel strategies. In addition to novel cytotoxic chemotherapies, agents targeting platelet-derived growth factor receptor-alpha (PDGFRalpha), mTOR, and angiogenesis are areas of active investigation. Additionally, with the success of checkpoint inhibitors in other malignancies and early encouraging results of checkpoint inhibitors in some sarcoma subtypes, this approach is being widely investigated in various sarcomas. As we increasingly recognize and treat each sarcoma histology as a separate disease, it is important to spread awareness of the exciting clinical trials available to our patients with these rare malignancies. PMID- 28561655 TI - Fertility, Cardiac, and Orthopedic Challenges in Survivors of Adult and Childhood Sarcoma. AB - The combination of cisplatin, doxorubicin, and methotrexate was established as the standard backbone of contemporary osteosarcoma therapy in 1986. Since then, however, further improving the survival of patients with osteosarcoma has been challenging-30% to 40% of patients with osteosarcoma still die of this disease. In addition, these patients often experience loss of fertility at a young age, short- and long-term treatment-related cardiotoxicity, and adverse orthopedic effects from surgical resection of the tumor or endoprosthetic reconstructions. Cancer treatment often markedly increases the risk of infertility later in life, causing many patients substantial distress and regret. Sperm banking and oocyte cryopreservation are standard of care and should be available to all at-risk patients. Newer techniques, such as autologous gonadal tissue transplant for prepubertal children, are being developed, and newer systemic agents have infertility risk profiles that remain undefined and warrant further study. Cost and access remain barriers to these options. The late effects of anthracycline induced cardiotoxicity are also increasingly a problem for these patients. These effects are often progressive and can be disabling. Adding dexrazoxane to doxorubicin therapy significantly reduces the risk for most adverse cardiac outcomes without compromising the efficacy of induction chemotherapy. Limb salvage surgery remains the standard of care for treatment in the majority of patients with extremity sarcomas. Modular metal prostheses and allograft reconstructions comprised the majority of surgical procedures for limb salvage surgery. The most common mechanism of failure of these implants is infection and mechanical failure of the implant. PMID- 28561656 TI - Whence High-Grade Serous Ovarian Cancer. AB - Our understanding of epithelial ovarian cancer has blossomed, and we now recognize that it is a collection of varied histologic and molecularly different malignancies, many of which may not derive from a true ovarian anatomic precursor. High-grade serous ovarian cancer (HGSOC) is a unique type of epithelial cancer. It is characterized by nearly universal mutation in and dysfunction of p53, genomic instability rather than driver mutations, advanced stage at onset, and probable fallopian tube epithelium origin, with a serous tubal in situ carcinoma precursor. Germline deleterious mutations in BRCA1 and BRCA2, as well as other less prevalent genes involved in DNA repair, such as PALB2 and RAD51c, are associated with its carcinogenesis and may predict susceptibility to classes of treatment agents, including DNA-damaging agents and DNA repair inhibitors. Loss of function of these genes is associated with homologous recombination dysfunction (HRD). It is now recognized that there may be HGSOC with wild-type BRCA1 and BRCA2 with an identifiable HRD phenotype. Such HRD tumors also may be more susceptible to certain classes of treatments and may be phenotypically detectable with a composite molecular biomarker that has been shown to be predictive for response to PARP inhibitors. Use of this new knowledge of the anatomic and molecular background of HGSOC has led to the rational design of novel combinations of treatment classes to create an HRD-like cellular environment and thus drive treatment benefits. PMID- 28561658 TI - More Medicine, Fewer Clicks: How Informatics Can Actually Help Your Practice. AB - In the information age, we expect data systems to make us more effective and efficient-not to make our lives more difficult! In this article, we discuss how we are using data systems, such as electronic health records (EHRs), to improve care delivery. We illustrate how US Oncology is beginning to use real-world evidence to facilitate trial accrual by automatic identification of eligible patients and how big data and predictive analytics will transform the field of oncology. Some information systems are already being used at the point of care and are already empowering clinicians to improve the care of their patients in real time. Telehealth platforms are being used to bridge gaps that currently exist in expertise, geography, and technical capability. Optimizing virtual collaboration, such as through virtual tumor boards, is empowering communities that are geographically disparate to coordinate care. Informatics methods can provide solutions to the challenging problems of how to manage the vast amounts of data confronting the practicing oncologist, including information about treatment regimens, side effects, and the influence of genomics on the practice of oncology. We also discuss some of the challenges of clinical documentation in the modern era, and review emerging efforts to engage patients as digital donors of their EHR data. PMID- 28561657 TI - Clinical Pathways and the Patient Perspective in the Pursuit of Value-Based Oncology Care. AB - The art of practicing oncology has evolved substantially in the past 5 years. As more and more diagnostic tests, biomarker-directed therapies, and immunotherapies make their way to the oncology marketplace, oncologists will find it increasingly difficult to keep up with the many therapeutic options. Additionally, the cost of cancer care seems to be increasing. Clinical pathways are a systematic way to organize and display detailed, evidence-based treatment options and assist the practitioner with best practice. When selecting which treatment regimens to include on a clinical pathway, considerations must include the efficacy and safety, as well as costs, of the therapy. Pathway treatment regimens must be continually assessed and modified to ensure that the most up-to-date, high quality options are incorporated. Value-based models, such as the ASCO Value Framework, can assist providers in presenting economic evaluations of clinical pathway treatment options to patients, thus allowing the patient to decide the overall value of each treatment regimen. Although oncologists and pathway developers can decide which treatment regimens to include on a clinical pathway based on the efficacy of the treatment, assessment of the value of that treatment regimen ultimately lies with the patient. Patient definitions of value will be an important component to enhancing current value-based oncology care models and incorporating new, high-quality, value-based therapeutics into oncology clinical pathways. PMID- 28561659 TI - How Should We Intervene on the Financial Toxicity of Cancer Care? One Shot, Four Perspectives. AB - The median price of a month of chemotherapy has increased by an order of magnitude during the past 20 years, far exceeding inflation over the same period. Along with rising prices, increases in cost sharing have forced patients to directly shoulder a greater portion of those costs, resulting in undue financial burden and, in some cases, cost-related nonadherence to treatment. What can we do to intervene on treatment-related financial toxicity of patients? No one party can single-handedly solve the problem, and the solution must be multifaceted and creative. A productive discussion of the problem must avoid casting blame and, instead, must look inward for concrete starting points toward improvement in the affordability and value of cancer care. With these points in mind, the authors representatives from the pharmaceutical industry, insurance providers, oncologists, and patient advocacy-have each been asked to respond with a practical answer to the provocative hypothetical question, "If you could propose one thing, and one thing only, in terms of an action or change by the constituency you represent in this discussion, what would that be?" PMID- 28561660 TI - The Oncology Care Model: Perspectives From the Centers for Medicare & Medicaid Services and Participating Oncology Practices in Academia and the Community. AB - Cancer care delivery in the United States is often fragmented and inefficient, imposing substantial burdens on patients. Costs of cancer care are rising more rapidly than other specialties, with substantial regional differences in quality and cost. The Centers for Medicare & Medicaid Services (CMS) Innovation Center (CMMIS) recently launched the Oncology Care Model (OCM), which uses payment incentives and practice redesign requirements toward the goal of improving quality while controlling costs. As of March 2017, 190 practices were participating, with approximately 3,200 oncologists providing care for approximately 150,000 unique beneficiaries per year (approximately 20% of the Medicare Fee-for-Service population receiving chemotherapy for cancer). This article provides an overview of the program from the CMS perspective, as well as perspectives from two practices implementing OCM: an academic health system (Yale Cancer Center) and a community practice (Hematology Oncology Associates of Central New York). Requirements of OCM, as well as implementation successes, challenges, financial implications, impact on quality, and future visions, are provided from each perspective. PMID- 28561661 TI - Operable Melanoma: Screening, Prognostication, and Adjuvant and Neoadjuvant Therapy. AB - The importance of reducing the numbers of patients with late-stage melanoma, identifying which patients are most likely to progress, and treating these patients at the earliest possible stage cannot be overemphasized. Improved screening of patients prior to diagnosis has the advantage of identifying early stage disease that is for the most part treatable by surgical methods. The process of melanoma screening is rapidly evolving through population-based programs, mobile health technologies, and advanced imaging tools. For patients with newly diagnosed melanoma, accurately estimating disease prognosis has important implications for management and follow-up. Prognostic factors are individual host- or tumor-related factors or molecules that correlate with genetic predisposition and clinical course. These include clinical covariates and host and tumor proteomic/genomic markers that allow the prognostic subclassification of patients. Adjuvant therapy for high-risk surgically resected melanoma targets residual micrometastatic disease with the goal of reducing the risk of relapse and mortality. In the United States, three regimens have achieved regulatory approval for adjuvant therapy, including high-dose interferon alpha, pegylated interferon alpha, and ipilimumab at 10 mg/kg. Phase III trials have reported benefits in relapse-free survival (all regimens) and overall survival (high-dose interferon alpha and ipilimumab). The management of locally/regionally advanced melanoma may benefit from neoadjuvant therapy, which is the subject of several ongoing studies. Recent studies have shown promising clinical activity and yielded important biomarker findings and mechanistic insights. PMID- 28561662 TI - Systemic Therapy Options for Patients With Unresectable Melanoma. AB - There has been a therapeutic revolution in the treatment of metastatic melanoma over the past decade. Patients presenting with inoperable disease have several therapeutic options, which can include both targeted and immune therapy. Immune checkpoint inhibitors have demonstrated an improvement in overall survival and led to some durable responses. However, toxicity, especially in combination regimens, can be severe. Adverse events should be anticipated, diagnosed as early as possible, monitored, and managed. Combination BRAF and MEK inhibition has also been shown to improve overall survival in patients with V600E-mutated melanoma. Responses to therapy are often rapid, and treatment is not associated with immune related adverse events. Current trials are under way to determine which option is optimal as frontline therapy for patients with V600E melanoma. In patients with progressive disease despite standard therapies, clinical trials are recommended. There are several promising agents in development. PMID- 28561664 TI - Data Commons to Support Pediatric Cancer Research. AB - The falling costs and increasing fidelity of high-throughput biomedical research data have led to a renaissance in cancer surveillance and treatment. Yet, the amount, velocity, and complexity of these data have overcome the capacity of the increasing number of researchers collecting and analyzing this information. By centralizing the data, processing power, and tools, there is a valuable opportunity to share resources and thus increase the efficiency, power, and impact of research. Herein, we describe current data commons and how they operate in the oncology landscape, including an overview of the International Neuroblastoma Risk Group data commons as a paradigm case. We outline the practical steps and considerations in building data commons. Finally, we discuss the unique opportunities and benefits of creating a data commons within the context of pediatric cancer research, highlighting the particular advantages for clinical oncology and suggested next steps. PMID- 28561665 TI - New Classification for Central Nervous System Tumors: Implications for Diagnosis and Therapy. AB - The 2016 World Health Organization Classification of Tumors of the Central Nervous System (WHO 2016) represents a noteworthy divergence from prior classification schemas. This new classification introduced the concept of "integrated diagnoses" based on a marriage of both phenotypic (microscopic) and genotypic parameters, with the intended goals of improving diagnostic accuracy and patient management. The result is a major restructuring in many of the brain tumor categories, with the codification of multiple new tumor entities and subgroups. It is therefore imperative that pathologists, clinicians, and neuro oncology researchers alike rapidly become familiar with this new classification schema. Many of the diagnostic updates set forth in the WHO 2016 have impacted brain tumor types that commonly arise in the pediatric age group, particularly within the diffuse glioma, ependymoma, and embryonal tumor categories. This review gives a brief overview of (1) the WHO 2016 as it relates to pediatric central nervous system (CNS) tumors, with an emphasis on molecular diagnostic tools used in the clinical arena, (2) ongoing and developing approaches to the molecular and genomic classification of pediatric CNS tumors, and (3) the impact of this new classification schema on clinical trials in pediatric neuro-oncology. PMID- 28561666 TI - Integration of Genomics Into Treatment: Are We There Yet? AB - Using advances in genetic analysis to segment and direct treatment of multiple myeloma (MM) represents a way of maintaining therapeutic progress. Recent genetic analyses have opened the possibility of enhancing risk stratification approaches and of using different risk and biologic strata as part of clinical trials. The Myeloma Genome Project is a collaborative project that has compiled the largest set of cases with sequencing and have outcome data that are available for stratification purposes. Mutation-targeted treatment of the Ras pathway has been shown to be active in MM, but is compromised by the presence of the subclonal genetic variation typical of myeloma. Going forward, risk and biologically stratified therapy for MM looks to be a promising way of maintaining therapeutic progress, as does precision immunotherapy directed by the cellular context of the bone marrow. PMID- 28561663 TI - Beyond Alkylating Agents for Gliomas: Quo Vadimus? AB - Recent advances in therapies have yielded notable success in terms of improved survival in several cancers. However, such treatments have failed to improve outcome in patients with gliomas for whom surgery followed by radiation therapy and chemotherapy with alkylating agents remain the standard of care. Genetic and epigenetic studies have helped identify several alterations specific to gliomas. Attempts to target these altered pathways have been unsuccessful due to various factors, including tumor heterogeneity, adaptive resistance of tumor cells, and limitations of access across the blood-brain barrier. Novel therapies that circumvent such limitations have been the focus of intense study and include approaches such as immunotherapy, targeting of signaling hubs and metabolic pathways, and use of biologic agents. Immunotherapeutic approaches including tumor-targeted vaccines, immune checkpoint blockade, antibody-drug conjugates, and chimeric antigen receptor-expressing cell therapies are in various stages of clinical trials. Similarly, identification of key metabolic pathways or converging hubs of signaling pathways that are tumor specific have yielded novel targets for therapy of gliomas. In addition, the failure of conventional therapies against gliomas has led to a growing interest among patients in the use of alternative therapies, which in turn has necessitated developing evidence based approaches to the application of such therapies in clinical studies. The development of these novel approaches bears potential for providing breakthroughs in treatment of more meaningful and improved outcomes for patients with gliomas. PMID- 28561667 TI - Myeloma in Elderly Patients: When Less Is More and More Is More. AB - Multiple myeloma is a plasma cell malignancy that occurs among older adults and accounts for 15% of all hematologic malignancies in the United States. Thirty five percent of patients are diagnosed at age 75 or older. Novel therapeutics and routine use of autologous stem cell transplantation (ASCT) have led to substantial improvements in patient survival, although improvements have been more impressive among patients younger than age 65. Finding the balance between under- and overtreating elderly patients is one of the biggest challenges specific to them as a subgroup of patients with MM. Decision making about which therapies and their dose intensity and duration should be influenced by a patient's functional status, personal preferences, disease characteristics, and ability to tolerate therapy. ASCT should be considered for all patients younger than age 80, assuming that they are not frail. The attainment of a stringent complete response and minimal residual disease negativity is associated with improved progression-free and overall survival. Again, consideration of quality of life for these patients is paramount. Although there is a growing list of tools to sort through these issues, a fully integrated approach has not yet been finely tuned, leaving additional work to be done for the treatment of elderly patients with MM. PMID- 28561668 TI - Established and Novel Prognostic Biomarkers in Multiple Myeloma. AB - Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by notable interpatient heterogeneity. There have been important advances in therapy and overall survival, but some patients with high-risk features still have poor survival rates. Therefore, accurate identification of this subset of patients has been integral to improvement of patient outcome. During the last few years, cytogenetics, gene expression profiling, MRI and PET/CT, as well as serum free light chain assays have been used as accurate biomarkers to better characterize the diverse course and outcome of the disease. With the recent advances of massive parallel sequencing techniques, the development of new models that better stratify high-risk groups are beginning to be developed. The use of multiparameter flow cytometry and next-generation sequencing have paved the way for assessment of minimal residual disease and better prognostication of post therapeutic outcomes. Circulating tumor cells and circulating tumor DNA are promising potential biomarkers that demonstrate the spatial and temporal heterogeneity of MM. Finally, more prognostic markers are being developed that are specific to immunotherapeutic agents. In this review, we discuss these traditional and novel biomarkers that have been developed for MM and also those that can predict disease progression from precursor stages. Together, these biomarkers will help improve our understanding of the intrapatient and interpatient variabilities and help develop precision medicine for patients with high-risk MM. PMID- 28561669 TI - Role of Chemotherapy and Targeted Therapy in Early-Stage Non-Small Cell Lung Cancer. AB - On the basis of several randomized trials and meta-analyses, adjuvant chemotherapy is the accepted standard of care for certain patients with early stage non-small cell lung cancer (NSCLC). Patients with stage II, IIIA, or large (>= 4 cm) IB tumors are candidates for adjuvant chemotherapy. The survival improvement with adjuvant chemotherapy is approximately 5% at 5 years, though certain trials have suggested that it can be 8% to 10%. Neoadjuvant chemotherapy also has shown a survival advantage, though the volume of data with this approach is far less than that of adjuvant chemotherapy. The combination of cisplatin and vinorelbine is the most well-studied regimen, but current consensus is to use four cycles of any of the platinum-based chemotherapy regimens commonly used as front-line therapy for patients with advanced-stage NSCLC. Trials to define biomarkers that can predict benefit from adjuvant chemotherapy have not been successful, but results of other such trials are still awaited. On the basis of the benefit observed with targeted agents in patients with advanced-stage disease and driver genetic alterations in their tumors, ongoing trials are evaluating the utility of these targeted agents as adjuvant therapy. Similarly, clinical benefit observed with checkpoint inhibitors has prompted assessment of these drugs in patients with early-stage NSCLC. It is very likely, in the future, that factors other than the anatomy of the tumor will be used to select patients with early stage NSCLC for systemic therapy and that the choice of systemic therapy will extend beyond platinum-based chemotherapy. PMID- 28561670 TI - The Road of Mentorship. AB - Mentorship can be the cornerstone of professional development and career satisfaction. There is literature to support that mentorship not only improves job satisfaction, but also improves productivity, facilitates personal growth, and can rekindle our passion while lessening the risk of compassion fatigue. Mentorship is a developmental relationship that changes as the relationship evolves. There are two broad categories of mentorship: traditional and transformational. There are four subtypes within each of those areas: formal, informal, spot, or peer. Mentorship is critical to the professional development of junior colleagues. Good mentorship is guiding and steering younger partners and other colleagues toward paths of success. As a mentor, one should be looking for opportunities for formal professional development and engagement of mentees. Self-motivation is the hallmark of the successful mentee. The mentee should be able to set his or her own goals, strive to actively seek feedback, ask questions, and keep an accurate record of progress. Although the onus is on the mentee to reach out, mentorship has bidirectional value directly related to the efforts of both parties. There are many benefits to mentorship, such as the promotion of learning, personal development, improved job satisfaction, and improved job performance. Barriers exist, including the rapidly changing landscape of oncology, time constraints, lack of self-awareness, and generational differences. Through a career, mentoring needs will change, as will mentors. PMID- 28561671 TI - Pathology Issues in Thoracic Oncology: Histologic Characterization and Tissue/Plasma Genotyping May Resolve Diagnostic Dilemmas. AB - Lung cancer is a heterogeneous diagnosis that encompasses a spectrum of histologic and molecular subgroups. A paradigm shift favoring selection of treatment based on histologic and molecular makeup has positively affected prognosis for patients with metastatic lung cancer, with select patients experiencing durable responses to treatment. However, prognosis remains poor for the majority of patients. Furthermore, oncologists are increasingly faced with challenging dilemmas related to histopathologic and molecular characterization of tumors, both at diagnosis and during treatment. In this review, we focus on three particular challenges: (1) management of mixed histology tumors, a particularly aggressive group of lung cancers, (2) distinguishing multiple primary lung tumors from intrapulmonary metastases, and (3) incorporation of liquid biopsies into the diagnostic algorithm and subsequent follow-up of patients with advanced lung cancer. This review will summarize the existing literature and highlight the potential for molecular genotyping to help refine approaches to each of these challenges. PMID- 28561672 TI - Pancreatic Adenocarcinoma: Improving Prevention and Survivorship. AB - Pancreatic cancer is a growing problem in oncology, given slowly rising incidence and continued suboptimal outcomes. A concerted effort to reverse this tide will require prevention, early diagnosis, and improved systemic therapy for curable disease. We focus on these aspects in detail in this study. Hereditary pancreatic cancer is an underappreciated area. With the growing use of genomics (both somatic and germline) in cancer care, there is increasing recognition of hereditary pancreatic cancer cases: around 10% of all pancreatic cancer may be related to familial syndromes, such as familial atypical multiple mole and melanoma (FAMMM) syndrome, hereditary breast and ovarian cancer, Lynch syndrome, and Peutz-Jeghers syndrome. Screening and surveillance guidelines by various expert groups are discussed. Management of resectable pancreatic cancer is evolving; the use of multiagent systemic therapies, in the adjuvant and neoadjuvant settings, is discussed. Current and emerging data, along with ongoing clinical trials addressing important questions in this area, are described. Surveillance recommendations based on latest ASCO guidelines are also discussed. Finally, the multimodality management of borderline resectable pancreatic cancer is discussed. The various clinicoanatomic definitions of this entity, followed by consensus definitions, are described. Then, we focus on current opinions and practices around neoadjuvant therapy, discussing chemotherapy and radiation aspects, and the role of surgical resection. PMID- 28561673 TI - Best Practices and Practical Nuances in the Treatment of Gastric Cancer in High Risk Global Areas. AB - Gastric cancer is an aggressive disease that is very frequent in Latin America. The reasons for this increased incidence is not clear. Associated with the lack of minimum health care opportunities, lack of accurate statistics and reporting data beyond epidemiologic data, and raw nonreliable data, there is little known of the actual clinical course and treatment of these patients. Understanding epidemiologic data may allow us to encourage the adequate use and distribution of the meager resources that exist. PMID- 28561674 TI - Gastric Cancer in Southern Europe: High-Risk Disease. AB - Gastric cancer is an aggressive disease. Several risk factors are involved in gastric cancer pathogenesis, likely Helicobacter pylori (H. pylori) infection, genetic factors in hereditary syndromes, lifestyle, and diet. However, well implemented screening strategies are lacking in most countries, including those in Southern Europe. Nevertheless, gastric cancer outcomes are better in some Southern European countries than in others, likely because of the incidence and distribution of different histologic types. Robotic surgery has been gaining favor as a treatment of early-stage disease, and the need for perioperative chemotherapy or adjuvant chemoradiotherapy (CRT) for locally advanced disease has been debated. In the metastatic setting, trastuzumab in combination with chemotherapy has helped to extend survival compared with chemotherapy alone for HER2-positive disease. This article will describe how gastric cancer is assessed and treated in Southern Europe in an attempt to correlate these approaches from a global perspective. PMID- 28561675 TI - Gastric Cancer in Asia: Unique Features and Management. AB - Gastric cancer (GC) poses a burden to patients across the globe as the third leading cause of cancer deaths worldwide. Incidence of GC is particularly high in Asian countries, which is attributed to the prevalence of Helicobacter pylori (H. pylori) infection and has prompted the establishment of unique treatment strategies. D2 gastrectomy, which was established in the 1950s in Japan, has served as a gold standard for locally advanced GC for over half a century. Since the beginning of the 21st century, endoscopic resection (ER) techniques and minimally invasive laparoscopic surgery have greatly changed the treatment of patients with early GC. S-1, which showed a striking survival benefit in a large randomized trial in Japan, has been used as adjuvant therapy for the last decade. Likewise, S-1-based chemotherapy regimens are currently the standard of care for the treatment of unresectable/metastatic GC in Asia. Along with the development of standardized therapy, novel techniques and new drugs have been rapidly brought into clinical practice. State-of-the-art sentinel node (SN) navigation surgery enables clinicians to perform truly minimally invasive surgery for early GC, and appropriate chemotherapy regimens are now determined by a tumor's molecular expression. New classifications based on gene signatures are proposed and may replace conventional clinical classifications. Such highly individualized treatment has the potential to alter our clinical practice in GC in the near future. The best practice in each geographic region should be shared and integrated, resulting in the best practice without borders. PMID- 28561676 TI - The Promise of Immunotherapy in the Treatment of Hepatocellular Carcinoma. AB - Advanced hepatocellular carcinoma (HCC) has presented a therapeutic challenge. Despite its heterogeneity, which is partially related to its various etiologies, it frequently arises in a background of chronic inflammation, which makes it a potentially excellent candidate for immunotherapeutic approaches. There is evidence of antitumor immunity in HCC as manifested by the cell infiltrate and its association with prognosis, the presence of tumor-associated antigens, and the reports of immune-mediated spontaneous regressions. However, both the liver itself and the tumor environment possess a diverse armamentarium of mechanisms that suppress antitumor immunity. Here, we describe the rationale for immunotherapy in HCC and discuss the emerging clinical data from various immunotherapeutic approaches including checkpoint inhibition, cell therapy, oncolytic viral therapy, and various combinatorial approaches. We also highlight the potential for various modalities to be adapted across different stages of the disease. PMID- 28561677 TI - Immunotherapy for Esophageal and Gastric Cancer. AB - PD-L1 upregulation occurs in approximately 40% of gastroesophageal cancers. However, unlike other solid tumors, there is minimal PD-L1 expressed on the cancer cells; rather, expression occurs predominantly on infiltrating myeloid cells. Preliminary clinical data involving single-agent PD-1/PD-L1 inhibitors in metastatic gastroesophageal cancer have reported response rates of 22%-27% for patients with PD-L1+ tumors and 10%-17% for unselected patients. The phase III ONO-4538-12 (ATTRACTION 2) trial has demonstrated an improved overall survival for nivolumab compared with placebo for patients with heavily pretreated gastric cancer. In the future, we will need better biomarkers to select those most likely to respond and/or identify patients who may need combination immunotherapeutics or alternate strategies. A number of subsets of gastric cancer with different immune signatures, most notably tumors positive for Epstein-Barr virus and microsatellite instability, have been identified, with approximately 50% and 94% PD-L1+ staining seen on tumor cells and immune cells in the EBV subtype and approximately 33% and 45% PD-L1+ staining seen on tumor cells and immune cells in MSI high tumors. Both subtypes demonstrate PD-L1+ immune cells with tumor infiltrating patterns, unlike the more commonly seen PD-L1+ immune cells at the invasive margin. PD-L2 expression has been reported in 52% of esophageal adenocarcinomas but little is known about the expression of other immune checkpoints. Additional factors that suggest gastroesophageal cancers may respond to checkpoint inhibition include the high somatic mutation burden and the link with chronic inflammation. Here we provide a comprehensive review of the checkpoint inhibitor data published to date in advanced esophagogastric cancers and rationalize how the immune microenvironment in these diverse tumors can explain response or resistance to immunotherapeutics. PMID- 28561678 TI - Deploying Immunotherapy in Pancreatic Cancer: Defining Mechanisms of Response and Resistance. AB - The immune reaction to pancreatic ductal adenocarcinoma (PDAC) is a strong prognostic determinant of clinical outcomes and may be a promising therapeutic target. We use multiplex immunohistochemistry to illustrate distinct patterns of T-cell and myeloid cell infiltration seen in PDAC that have therapeutic implications and discuss the current state of immunotherapy in this disease. Based on collective findings from clinical and preclinical studies, two conceptual models have emerged for applying immunotherapy in PDAC that involve (1) restoring elements of T-cell immunosurveillance and (2) redirecting myeloid cells to condition tumors with increased sensitivity to cytotoxic therapies. Overall, the success of immunotherapy in PDAC will most likely rely on strategic combinations of therapies that are informed by well-designed correlative analyses that consider the spatial heterogeneity of immune responses detected in malignant tissues. PMID- 28561679 TI - Biomarker Testing for Personalized Therapy in Lung Cancer in Low- and Middle Income Countries. AB - There have been many important advances in personalized therapy for patients with lung cancer, particularly for those with advanced disease. Molecular testing is crucial for implementation of personalized therapy. Although the United States and many Western countries have come far in the implementation of personalized therapy for lung cancer, there are substantial challenges for low- and middle income countries (LMICs). Globally, the LMICs display great heterogeneity in the pattern of implementation of molecular testing and targeted therapy. The current review presents an attempt to identify the challenges and obstacles for the implementation of molecular testing and the use of targeted therapies in these areas. Lack of infrastructure, lack of technical expertise, economic factors, and lack of access to new drugs are among the substantial barriers. PMID- 28561681 TI - Cancer Care and Control as a Human Right: Recognizing Global Oncology as an Academic Field. AB - The global burden of cancer incidence and mortality is on the rise. There are major differences in cancer fatality rates due to profound disparities in the burden and resource allocation for cancer care and control in developed compared with developing countries. The right to cancer care and control should be a human right accessible to all patients with cancer, regardless of geographic or economic region, to avoid unnecessary deaths and suffering from cancer. National cancer planning should include an integrated approach that incorporates a continuum of education, prevention, cancer diagnostics, treatment, survivorship, and palliative care. Global oncology as an academic field should offer the knowledge and skills needed to efficiently assess situations and work on solutions, in close partnership. We need medical oncologists, surgical oncologists, pediatric oncologists, gynecologic oncologists, radiologists, and pathologists trained to think about well-tailored resource-stratified solutions to cancer care in the developing world. Moreover, the multidisciplinary fundamental team approach needed to treat most neoplastic diseases requires coordinated investment in several areas. Current innovative approaches have relied on partnerships between academic institutions in developed countries and local governments and ministries of health in developing countries to provide the expertise needed to implement effective cancer control programs. Global oncology is a viable and necessary field that needs to be emphasized because of its critical role in proposing not only solutions in developing countries, but also solutions that can be applied to similar challenges of access to cancer care and control faced by underserved populations in developed countries. PMID- 28561680 TI - Thinking Differently in Global Health in Oncology Using a Diagonal Approach: Harnessing Similarities, Improving Education, and Empowering an Alternative Oncology Workforce. AB - Cancer is a leading global cause of death, and diverse and minority populations suffer worse outcomes compared with white people from Western societies. Within the United States, African Americans and other blacks, Hispanics, Asians, and American Indians have lower cancer survival rates than whites. In the rest of the world, those from low- and middle-income countries have the greatest disparities, but even those from non-Western high-income countries such as Oman and the United Arab Emirates are diagnosed with cancer at later stages and suffer increased mortality. Although considerable differences exist among these populations, similarities and synergies are also apparent. Challenges can be very similar in reaching these populations effectively for cancer control to improve outcomes, and innovative strategies are needed to effectively make change. In this review, the authors discuss new approaches to the prevention and early detection of cancer as well as the implementation of programs in global oncology and put in evidence cultural similarities and challenges of different populations, highlighting strategies to improve cancer survival and quality care around the world through innovations in training and education, empowerment of an alternative workforce, and a diagonal approach to cancer care using case studies drawn from the authors' work and experience. PMID- 28561682 TI - Advances in the Treatment of Advanced Extracutaneous Melanomas and Nonmelanoma Skin Cancers. AB - Cutaneous malignancies make up the greatest proportion of all human cancers and include melanomas as well as nonmelanoma skin cancers (NMSCs) such as basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), as well as less common Merkel cell carcinoma (MCC), cutaneous lymphomas, cutaneous adnexal tumors, Kaposi sarcomas, and other sarcomas. Each of these NMSCs differ significantly in biology, clinical behavior, and optimal treatment recommendations from each other and from cutaneous melanoma. Similarly, less common extracutaneous melanomas, such as mucosal (MMs) and uveal (UMs), are unique biologic and clinical entities that require distinct diagnostic and management considerations. In this review, we summarize recent advances in biology and treatment of extracutaneous melanomas and NMSCs, including MMs, UMs, cSCC, BCC, and MCC. PMID- 28561683 TI - Breast Cancer in the Central Nervous System: Multidisciplinary Considerations and Management. AB - Breast cancer is the second most common primary tumor associated with central nervous system (CNS) metastases. Patients with metastatic HER2-positive or triple negative (estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, HER2-negative) breast cancer are at the highest risk of developing parenchymal brain metastases. Leptomeningeal disease is less frequent but is distributed across breast cancer subtypes, including lobular breast cancer. Initial treatment strategies can include surgery, radiation, intravenous or intrathecal chemotherapy, and/or targeted approaches. In this article, we review the epidemiology of breast cancer brain metastases, differences in clinical behavior and natural history by tumor subtype, and important considerations in the multidisciplinary treatment of these patients. We will highlight new findings that impact current standards of care, clinical controversies, and notable investigational approaches in clinical testing. PMID- 28561684 TI - Optimizing Breast Cancer Adjuvant Radiation and Integration of Breast and Reconstructive Surgery. AB - Postmastectomy radiotherapy (PMRT) reduces the risk of locoregional and distant recurrence and improves overall survival in women with lymph node-positive breast cancer. Because of stage migration and improvements in systemic therapy and other aspects of breast cancer care, the absolute benefit of PMRT and regional nodal irradiation may be small in some favorable subsets of patients with very low nodal burden, and newer consensus guidelines do not mandate PMRT in all node positive cases. The use and need for PMRT may considerably complicate breast reconstruction after mastectomy and therefore mandates multidisciplinary input that takes into account patient choice given potential risk of acute and long term toxicities, benefits, life expectancy, the biology of the tumor, plans for systemic therapy, and actual tumor burden. Management of axillary lymph node metastases is changing with selective use of axillary lymph node dissection for advanced disease, sentinel lymph node biopsy alone for clinically and pathologic node-negative cases receiving mastectomy, and targeted axillary dissection alone among patients with eradication of initial biopsy-proven nodal metastases with neoadjuvant systemic therapy use. In general, when the need for PMRT is anticipated, autologous reconstruction should be delayed. This comprehensive article reviews the current indications and implications regarding integration of breast cancer surgery and timing of reconstruction with optimum radiation delivery to achieve the best possible patient outcomes. PMID- 28561685 TI - Lifestyle Interventions to Improve Cardiorespiratory Fitness and Reduce Breast Cancer Recurrence. AB - As patients are living longer after a cancer diagnosis, survivorship is becoming increasingly important in cancer care. The sequelae of multimodality therapies include weight gain and decreased cardiorespiratory fitness, which increase cardiovascular risk. Evidence suggests that physical activity reduces the risk of breast cancer recurrence and death. Avoidance of weight gain after therapy also improves outcomes after a diagnosis of breast cancer. Prospective randomized trials must be performed to determine the benefits of specific physical activity and dietary habits for survivors of breast cancer. This review outlines the important physiologic changes that occur with antineoplastic therapy and the important role of exercise and diet. PMID- 28561687 TI - New Insight Into the Biology, Risk Stratification, and Targeted Treatment of Myelodysplastic Syndromes. AB - In myelodysplastic syndromes (MDS), somatic mutations occur in five major categories: RNA splicing, DNA methylation, activated cell signaling, myeloid transcription factors, and chromatin modifiers. Although many MDS cases harbor more than one somatic mutation, in general, there is mutual exclusivity of mutated genes within a class. In addition to the prognostic significance of individual somatic mutations, more somatic mutations in MDS have been associated with poor prognosis. Prognostic assessment remains a critical component of the personalization of care for patient with MDS because treatment is highly risk adapted. Multiple methods for risk stratification are available with the revised International Prognostic Scoring System (IPSS-R), currently considered the gold standard. Increasing access to myeloid gene panels and greater evidence for the diagnostic and predictive value of somatic mutations will soon make sequencing part of the standard evaluation of patients with MDS. In the absence of formal guidelines for their prognostic use, well-validated mutations can still refine estimates of risk made with the IPSS-R. Not only are somatic gene mutations advantageous in understanding the biology of MDS and prognosis, they also offer potential as biomarkers and targets for the treatment of patients with MDS. Examples include deletion 5q, spliceosome complex gene mutations, and TP53 mutations. PMID- 28561688 TI - Novel Therapeutics in Acute Myeloid Leukemia. AB - In this review, we focus on three key areas in acute myeloid leukemia (AML) developmental therapeutics: FLT3 inhibitors, IDH inhibitors, and drugs that may be particularly beneficial in secondary AML. PMID- 28561686 TI - Advances in the Treatment of Pediatric Bone Sarcomas. AB - Bone tumors make up a significant portion of noncentral nervous system solid tumor diagnoses in pediatric oncology patients. Ewing sarcoma and osteosarcoma, both with distinct clinical and pathologic features, are the two most commonly encountered bone cancers in pediatrics. Although mutations in the germline have classically been more associated with osteosarcoma, there is recent evidence germline alterations in patients with Ewing sarcoma also play a significant role in pathogenesis. Treatment advances in this patient population have lagged behind that of other pediatric malignancies, particularly targeted interventions directed at the biologic underpinnings of disease. Recent advances in biologic and genomic understanding of these two cancers has expanded the potential for therapeutic advancement and prevention. In Ewing sarcoma, directed focus on inhibition of EWSR1-FLI1 and its effectors has produced promising results. In osteosarcoma, instead of a concentrated focus on one particular change, largely due to tumor heterogeneity, a more diversified approach has been adopted including investigations of growth factors inhibitors, signaling pathway inhibitors, and immune modulation. Continuing recently made treatment advances relies on clinical trial design and enrollment. Clinical trials should include incorporation of biological findings; specifically, for Ewing sarcoma, assessment of alternative fusions and, for osteosarcoma, stratification utilizing biomarkers. Expanded cancer genomics knowledge, particularly with solid tumors, as it relates to heritability and incorporation of family history has led to early identification of patients with cancer predisposition. In these patients through application of cost-effective evidence-based screening techniques the ultimate goal of cancer prevention is becoming a realization. PMID- 28561689 TI - Improving Cancer Care Through the Patient Experience: How to Use Patient-Reported Outcomes in Clinical Practice. AB - Poorly controlled symptoms are common and debilitating during cancer treatment and can affect functional status and quality of life, health care resource utilization, treatment adherence, and cancer survivorship. Historically, the patient experience, including symptoms during treatment, has not been tracked or documented in the patient health record. Measurement of patient-reported outcomes (PROs), including symptoms, is an essential component to cancer care focused on the illness impact to the patient and family. PROs can be useful at the individual level for monitoring and promoting symptom care both in the clinic and remotely and at the population level for aggregating population data for use in research and quality improvement initiatives. Implementation of PROs in cancer clinical care requires a carefully thought out process to overcome challenges related to integrating PROs into existing electronic health records and clinical work flow. Issues with implementing PRO collection may include making decisions about measurement tools, modes of delivery, frequency of measurement, and interpretation that are guided by a clarification of the purpose for collecting PROs. We focus on three aspects of PRO use: (1) improving care for individual patients, (2) analyzing aggregated data to improve care and outcomes overall, and (3) considerations in implementing PRO collection. PMID- 28561690 TI - Understanding the New WHO Classification of Lymphoid Malignancies: Why It's Important and How It Will Affect Practice. AB - Improved delineation of lymphoid malignancy biology has prompted refinement of the 2008 World Health Organization (WHO) classification of hematopoietic and lymphoid tumors with a new framework introduced in 2016. This knowledge has provided valuable insights regarding management. Early clonal proliferations have been set apart given their limited potential for malignant dissemination. Increasing knowledge of molecular drivers of aggressive lymphomas has allowed subclassification and opportunity for clinical investigations to personalize therapy. New insights into T-cell pathophysiology has allowed grouping based on shared molecular and cellular features. This article will summarize the key changes in terms of diagnosis and histopathologic definitions, the impact of these changes on clinical management, and the challenges of future research in this field. PMID- 28561691 TI - Improving Quality and Value of Cancer Care for Older Adults. AB - The concepts of quality and value have become ubiquitous in discussions about health care, including cancer care. Despite their prominence, these concepts remain difficult to encapsulate, with multiple definitions and frameworks emerging over the past few decades. Defining quality and value for the care of older adults with cancer can be particularly challenging. Older adults are heterogeneous and often excluded from clinical trials, severely limiting generalizable data for this population. Moreover, many frameworks for quality and value focus on traditional outcomes of survival and toxicity and neglect goals that may be more meaningful for older adults, such as quality of life and functional independence. A history of quality and value standards and an evaluation of some currently available standards and frameworks elucidate the potential gaps in application to older adults with cancer. However, narrowing the focus to processes of care presents several opportunities for improving the care of older adults with cancer now, even while further work is ongoing to evaluate outcomes and efficiency. New models of care, including the patient-centered medical home, as well as new associated bundled payment models, would be advantageous for older adults with cancer, facilitating collaboration, communication, and patient-centeredness and minimizing the fragmentation that impairs the current provision of cancer care. Advances in information technology support the foundation for these models of care; these technologies facilitate communication, increase available data, support shared decision making, and increase access to multidisciplinary specialty care. Further work will be needed to define and to continue to tailor processes of care to achieve relevant outcomes for older patients with cancer to fulfill the promise of quality and value of care for this vulnerable and growing population. PMID- 28561692 TI - Health Disparities and the Global Landscape of Lymphoma Care Today. AB - Lymphoma encompass a wide variety of distinct disease entities, including, but not limited to, subtypes of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). In the last 3 decades, therapeutic advancements have resulted in substantial improvements in lymphoma outcome. In most high-income regions, HL is a largely curable disease and for patients with two frequent subtypes of NHL, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), survival has dramatically improved with the incorporation of rituximab as a standard treatment approach. Despite these advances, outcomes vary between and across populations. This review will provide updated information about health disparities in lymphoma in the United States and across the globe. PMID- 28561693 TI - Age and Sex in Non-Hodgkin Lymphoma Therapy: It's Not All Created Equal, or Is It? AB - Age is the most prominent factor for survival in all patients diagnosed with lymphoma, and male sex implies an increased and independent risk for a worse progression-free survival (PFS) and overall survival (OS) in most lymphomas, possibly with the exception of mantle cell lymphoma (MCL). The worse outcome for elderly patients is only partially explained by decreased tolerance to treatment regimens associated with the increasing number and severity of comorbidities. Little is known about specific differences in lymphoma biology with respect to age and sex, and this is changing only slowly despite the recent rise in interest about these issues. To better understand the differences and their underlying mechanisms, questions of age- and sex-specific outcomes, their correlation with pharmacokinetic data, and planned and received doses, must be addressed and reported in prospective clinical trials. Such studies must be accompanied by translational research that investigates biologic differences of lymphomas between old and young and male and female patients by addressing the microenvironment, cytogenetics including next-generation sequencing and systems biology of lymphomas, and correlation of these findings with treatment results. This knowledge will enable us to adjust lymphoma treatment to the necessities of more personalized medicine. PMID- 28561694 TI - Current Approaches to Mantle Cell Lymphoma: Diagnosis, Prognosis, and Therapies. AB - Mantle cell lymphoma (MCL) is a unique lymphoma subtype, both biologically and clinically. Virtually all cases are characterized by a common genetic lesion, t(11;14), resulting in overexpression of cyclin D1. The clinical course is moderately aggressive, and the disease is considered incurable. Considerable biologic and clinical heterogeneity exists, with some patients experiencing a rapidly progressive course, while others have disease that is readily managed. New tools exist for risk stratification and may allow for a more personalized approach in the future. Landmark studies have been completed in recent years and outcomes appear to be improving. Randomized clinical trials have clarified the role of high-dose cytarabine (Ara-C) for younger patients and have demonstrated a role for maintenance rituximab therapy. Multiple areas of uncertainty remain, however, and are the focus of ongoing research. This review focuses on (1) strategies to differentiate between aggressive and less aggressive cases, (2) understanding who should receive hematopoietic stem cell transplantation, and (3) the role for maintenance therapy in MCL. PMID- 28561695 TI - Biomarkers for Checkpoint Inhibition. AB - The identification of predictive biomarkers for the benefit of cancer immunotherapy is the holy grail of the burgeoning immunotherapy field. Recent work has shown that there are a core of concepts that establish the presence of an immune cell-infiltrate, an inflammatory signature of the tumor microenvironment, and the availability of target antigens defined by mutated neoantigens, as critical for the success of the checkpoint blockade. Genetic analyses have shown that resistance to PD-1 blockade, either innate or adaptive, may be due to existing or de novo mutations in signaling pathways critical for T cell function in a modest proportion of cases. Major hurdles in the field that remain to be overcome are the difficulty of obtaining tumor biopsies for biomarker assessment, the heterogeneity of biomarker expression within tumors and within different tumors from the same patient, and the inducibility of some biomarkers by disease-related processes. Although assessment of peripheral blood or serum biomarkers would be ideal, few data suggest that they would reliably predict outcome with checkpoint blockade. Ultimately, some amalgamated biomarker that includes tumor and host factors will be required to predict which patients are likely to benefit from, or be resistant to, the effects of checkpoint inhibition. PMID- 28561696 TI - Using the New ASCO Clinical Practice Guideline for Palliative Care Concurrent With Oncology Care Using the TEAM Approach. AB - Palliative care alongside usual oncology care is now recommended by ASCO as the standard of care for any patient with advanced cancer on the basis of multiple randomized trials that show better results with concurrent care than with usual oncology care. Some benefits include better quality of life, better symptom management, reduced anxiety and depression, less caregiver distress, more accordance of care with the wishes of the patient, and less aggressive end-of life care. Several studies show a survival advantage of several months, and many show considerable cost savings: better care at an affordable cost. However, there are not enough palliative care specialists available, so oncologists must practice exemplary primary palliative care. Protocols used in the clinical trials, similar to those designed for new chemotherapy agents, help oncologists use the TEAM approach of extra time, typically an hour a month spent with the palliative care team; education, especially about prognostic awareness and realistic options, which include formal setting of goals of care and discussion of advance directives; formal assessments for symptoms and for spiritual and psychosocial health; and management by an interdisciplinary team. These are all potentially accomplished by an oncology practice to replicate the services provided by concurrent palliative care. PMID- 28561697 TI - Screening and Treating Prostate Cancer in the Older Patient: Decision Making Across the Clinical Spectrum. AB - Treatment of the growing geriatric patient population is increasingly being recognized as a necessary priority of the oncology community. As the most common cancer among men in developed countries, prostate cancer afflicts a sizable portion of elderly men. Caring for this population requires knowledge of aspects of disease presentation, screening strategies, treatment approaches, and survivorship care considerations unique to the geriatric population. In this article, we review characteristics of prostate cancer screening and treatment decision making for localized disease in elderly men, including a discussion of the biology of disease in the elderly population. We also review best practices for providing treatment for localized and recurrent disease in an elderly population, including engaging in a basic geriatric assessment to determine fitness for treatment, eliciting information about patient preferences and support systems, and balancing treatment decisions in the context of these factors using the resources of a multidisciplinary care team. We then consider complications of prostate cancer survivorship related to systemic treatment in the elderly population of men with this disease. Finally, we emphasize the importance of engaging patients in treatment decision making across the spectrum of disease to personalize treatment plans and provide optimal care. PMID- 28561699 TI - Personalizing Therapy for Metastatic Prostate Cancer: The Role of Solid and Liquid Tumor Biopsies. AB - Although biopsies of metastatic prostate cancer are rarely undertaken in the clinical setting, there is increasing interest in developing personalized approaches to therapy by taking into account the genetic and phenotypic changes in an individual tumor. Indeed, analysis of metastatic prostate tumors can predict sensitivity to agents that inhibit DNA repair and resistance to novel hormonal agents, such as abiraterone and enzalutamide, and identify phenotypic changes, such as neuroendocrine differentiation, that have important clinical implications. Although obtaining metastatic tumor tissue is necessary for this genomic and molecular profiling, knowing when to biopsy, selecting the appropriate metastatic lesion, and interpreting the results are major challenges facing clinicians today. In this article, we discuss the rationale for obtaining metastatic tumor tissue, review the bioinformatic approach to analyzing these specimens, discuss the timing and approach to solid and liquid tumor biopsies, review the challenges associated with obtaining and acting on clinically relevant results, and discuss opportunities for the future. PMID- 28561698 TI - Diagnosis and Treatment of Prostate Cancer: What Americans Can Learn From International Oncologists. AB - The three main sections in this article illustrate a number of facets of European health care. The first section looks at the influence of NICE on treatment of metastatic castration-resistant prostate cancer. The second section explores the impact of molecular imaging on diagnosis and treatment, in particular the development and clinical implementation of 68Ga PET imaging in prostate cancer. The final section of the session looks at the STAMPEDE trial and how running a trial on this scale has impacted care of prostate cancer in the United Kingdom and also at the uptake of docetaxel chemotherapy in hormone-sensitive advanced disease. PMID- 28561700 TI - Value-Based Medicine and Integration of Tumor Biology. AB - Clinical oncology is in the midst of a genomic revolution, as molecular insights redefine our understanding of cancer biology. Greater awareness of the distinct aberrations that drive carcinogenesis is also contributing to a growing armamentarium of genomically targeted therapies. Although much work remains to better understand how to combine and sequence these therapies, improved outcomes for patients are becoming manifest. As we welcome this genomic revolution in cancer care, oncologists also must grapple with a number of practical problems. Costs of cancer care continue to grow, with targeted therapies responsible for an increasing proportion of spending. Rising costs are bringing the concept of value into sharper focus and challenging the oncology community with implementation of value-based cancer care. This article explores the ways that the genomic revolution is transforming cancer care, describes various frameworks for considering the value of genomically targeted therapies, and outlines key challenges for delivering on the promise of personalized cancer care. It highlights practical solutions for the implementation of value-based care, including investment in biomarker development and clinical trials to improve the efficacy of targeted therapy, the use of evidence-based clinical pathways, team based care, computerized clinical decision support, and value-based payment approaches. PMID- 28561701 TI - For Our Patients, for Ourselves: The Value of Personal Reflection in Oncology. AB - Caring for patients with cancer is a great privilege as well as an emotionally and intellectually challenging task. Stress and burnout are prevalent among oncology clinicians, with serious repercussions for the care of patients. Professional societies must provide guidance for trainees and practicing physicians to mitigate the negative consequences of stress on their personal lives and medical practice. Reflection, reading, and writing about personal experiences provide outlets for fortifying personal reserves and promoting resilience to allow us to recognize the joy and meaning of our work and to forge connections with our peers. Herein, we present some of our own reflections on how and why one might take time to write, and about the power of the written word in oncology and medicine. PMID- 28561702 TI - Perspectives on the Use of Clinical Pathways in Oncology Care. AB - Pathways and guidelines are valuable tools to provide evidence-based care in oncology. Pathways may be more restrictive than guidelines because they attempt (where possible) to reduce cost, add efficiency, and remove unwarranted variability. Pathways offer an opportunity to measure, report, and improve quality of care; they can drive to evidence-based targeted therapy where appropriate; they can enhance efficiency through standardization; and, finally, they can be a vehicle to enhance participation in clinical trials. Pathway implementation requires understanding and commitment on the part of the physician and leadership as they may initially disrupt workflow, but ultimately have the ability to enhance patient care. ASCO criteria have been published for the development and implementation of high-quality oncology pathway programs. Future challenges for pathways include incorporation of molecular testing and appropriate targeted care in a real-time precision oncology approach. PMID- 28561703 TI - Hematologic Malignancies: Plasma Cell Disorders. AB - Multiple myeloma (MM) is a plasma cell malignancy characterized by the growth of tumor cells in the bone marrow. Properties of the tumor microenvironment provide both potential tumor-promoting and tumor-restricting properties. Targeting underlying immune triggers for evolution of tumors as well as direct attack of malignant plasma cells is an emerging focus of therapy for MM. The monoclonal antibodies daratumumab and elotuzumab, which target the plasma cell surface proteins CD38 and SLAMF7/CS1, respectively, particularly when used in combination with immunomodulatory agents and proteasome inhibitors, have resulted in high response rates and improved survival for patients with relapsed and refractory MM. A number of other monoclonal antibodies are in various stages of clinical development, including those targeting MM cell surface antigens, the bone marrow microenvironment, and immune effector T cells such as antiprogrammed cell death protein 1 antibodies. Bispecific preparations seek to simultaneously target MM cells and activate endogenous T cells to enhance efficacy. Cellular immunotherapy seeks to overcome the limitations of the endogenous antimyeloma immune response through adoptive transfer of immune effector cells with MM specificity. Allogeneic donor lymphocyte infusion can be effective but can cause graft-versus host disease. The most promising approach appears to be genetically modified cellular therapy, in which T cells are given novel antigen specificity through expression of transgenic T-cell receptors (TCRs) or chimeric antigen receptors (CARs). CAR T cells against several different targets are under investigation in MM. Infusion of CD19-targeted CAR T cells following salvage autologous stem cell transplantation (SCT) was safe and extended remission duration in a subset of patients with relapsed/refractory MM. CAR T cells targeting B-cell maturation antigen (BCMA) appear most promising, with dramatic remissions seen in patients with highly refractory disease in three ongoing trials. Responses are associated with degree of CAR T-cell expansion/persistence and often toxicity, including cytokine release syndrome (CRS) and neurotoxicity. Ongoing and future studies are exploring correlates of response, ways to mitigate toxicity, and "universal" CAR T cells. PMID- 28561704 TI - New Developments and Challenges in Rare Genitourinary Tumors: Non-Urothelial Bladder Cancers and Squamous Cell Cancers of the Penis. AB - The diagnosis and treatment of rare genitourinary tumors is inherently challenging. The Rare Diseases Act of 2002 initially defined a rare disorder as one that affects fewer than 200,000 Americans. The lack of widely available clinical guidelines, limited research funding, and inaccessible clinical trials often lead to difficulty with treatment decisions to guide practitioners in rendering effective care for patients with rare genitourinary cancers. This article will discuss basic tenets of diagnosis and treatment as well as recent developments and clinical trials in rare non-urothelial bladder cancers and penile squamous cell cancers. PMID- 28561705 TI - Metabolic Alterations in Cancer and Their Potential as Therapeutic Targets. AB - Otto Warburg's discovery in the 1920s that tumor cells took up more glucose and produced more lactate than normal cells provided the first clues that cancer cells reprogrammed their metabolism. For many years, however, it was unclear as to whether these metabolic alterations were a consequence of tumor growth or an adaptation that provided a survival advantage to these cells. In more recent years, interest in the metabolic differences in cancer cells has surged, as tumor proliferation and survival have been shown to be dependent upon these metabolic changes. In this educational review, we discuss some of the mechanisms that tumor cells use for reprogramming their metabolism to provide the energy and nutrients that they need for quick or sustained proliferation and discuss the potential for therapeutic targeting of these pathways to improve patient outcomes. PMID- 28561706 TI - Practice-Changing Abstracts From the 2016 Society for Neuro-Oncology Annual Scientific Meeting. AB - The most relevant practice-changing presentations at the 2016 Society for Neuro Oncology (SNO) Annual Scientific Meeting revolved around the topic of the new 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors. The most notable change in this new classification is the introduction of molecular markers into the morphologic classification of diffuse gliomas (isocitrate dehydrogenase [IDH] mutation, 1p19q codeletion, and H3K27M mutation), ependymomas (RELA fusion), medulloblastomas (WNT- and sonic hedgehog activated), and other embryonal tumors (C19MC amplification), thus allowing for more precise diagnosis of these entities compared with the use of morphologic features alone. Among the clinical trials presented, only one phase III trial evaluating a device therapy for treatment of newly diagnosed glioblastoma (EF14; tumor-treating fields) met prespecified statistical criteria for success, showing a modest benefit in progression-free survival and overall survival in patients without progression after radiation and concurrent temozolomide. Other topics of interest included the spatial and temporal heterogeneity of primary brain tumors and the prevalence of burnout among neuro-oncologists. PMID- 28561707 TI - American Society for Radiation Oncology 2016 Annual Meeting: Central Nervous System Abstracts. AB - The American Society for Radiation Oncology's (ASTRO) 2016 scientific program presented a number of excellent abstracts focusing on brain and spine tumors. Selected abstracts will be reviewed in this article. PMID- 28561708 TI - Systemic Therapy for Non-Clear Cell Renal Cell Carcinoma. AB - Treatment options for metastatic clear cell renal cell carcinoma (ccRCC) have evolved markedly over the past decade, with multiple targeted therapies approved for the disease. In contrast, little improvement has been made in the management of metastatic non-clear cell RCC (nccRCC). Non-clear cell disease is an umbrella term that encompasses multiple biologically distinct entities, including but not limited to papillary, chromophobe, and sarcomatoid RCC. To date, prospective studies have largely explored treatments for ccRCC (e.g., VEGF- and mTOR-directed therapies) in trials that aggregate non-clear cell histologies. However, the studies do not acknowledge the varying biology of each non-clear cell subtype. Emerging studies in nccRCC should examine individual histologies and apply biologically relevant therapies. An example of this is SWOG 1500, a randomized phase II study that will compare a VEGF-inhibitor to one of three MET-directed therapies in patients with metastatic papillary RCC. Until the biologic diversity of nccRCC is appreciated, outcomes are likely to remain dismal. PMID- 28561709 TI - Practice Model for Advanced Practice Providers in Oncology. AB - According to ASCO, the number of practicing oncologists has remained stable despite growth demands, leading to an overall shortage in many areas of the country. Nurse practitioners and physician assistants are advanced practice providers (APPs) who can assist in the provision of support and care to patients with cancer, but the role of the APP in the oncology setting has not been well defined. There exists a variety of different practice patterns for APPs who work in oncology, and the lack of role definition and absence of an established practice model are considered leading causes of APP attrition. According to the American Academy of Nurse Practitioners, it has been well demonstrated that, when nurse practitioners are allowed to work to the full scope of their education and preparation, there are notable cost reductions and quality improvements in patient care. The focus of APP education and training is on health promotion, disease prevention, and primary care medical management, but most APPs have limited exposure to management of cancer in patients. With this in mind, Aurora Cancer Care developed a practice model for APPs who work in oncology. The goal of the model is to enhance the quality of care delivered to patients and provide a stimulating work environment that fosters excellent collaborative relationships with oncologist colleagues, supports professional growth, and allows APPs to practice to the full extent of their licensure. PMID- 28561710 TI - Standard and Genomic Tools for Decision Support in Breast Cancer Treatment. AB - Over the past few decades, comprehensive characterization of the cancer genome has elucidated pathways that drive cancer and mechanisms of resistance to therapy and provided important insights for development of new therapies. These advances have resulted in the development of prognostic and predictive tools for use in clinical settings, which can assist clinicians and patients in making informed decisions about the benefits of established therapies. In early-stage breast cancer, multiparameter genomic assays are now available for decision making about the duration of adjuvant endocrine therapy and the use of adjuvant chemotherapy. Similarly, in metastatic disease, there are multiple commercially available next generation sequencing options for identifying genetic alterations in tumors that may be targeted with a drug. Although these tools hold great promise for providing precision medicine, it can be difficult for the treating physician to evaluate their clinical utility and appropriately select tools for individual clinical situations. This review summarizes the currently available genomic tools in breast cancer, the data underlying their clinical validity and utility, and how they can be used in conjunction with standard clinicopathologic data for making adjuvant and metastatic treatment decisions. PMID- 28561711 TI - Optimal Management of Early and Advanced HER2 Breast Cancer. AB - Approximately 15%-20% of breast cancer is HER2 positive, and patients with this subtype of disease historically had worse outcomes than patients with HER2 negative disease. However, the introduction of HER2-directed therapies has dramatically altered outcomes for these patients, especially for persons with early disease. However, despite these achievements, metastatic disease is still not curable. This review summarizes the current treatment approach for patients in the preoperative and adjuvant setting, including data regarding selecting the optimal chemotherapy partner as well as determining the duration and type of anti HER-directed therapy. This article also reviews how to approach patients with advanced HER2-positive disease and discusses promising new therapies that are in development. PMID- 28561712 TI - Novel Targeted Agents and Immunotherapy in Breast Cancer. AB - The treatment of breast cancer is generally determined according to breast cancer subtype: hormone receptor-positive (luminal), triple-negative (basal-like), and HER2-overexpressing breast cancer. Recent years have seen the development of exciting novel and potent therapeutics based on molecular pathways, immune modulation, and antibody conjugates. In this article, we cover new and emerging therapeutic areas and ongoing clinical trials that may result in further improvements in breast cancer outcomes. PMID- 28561713 TI - Collaborating With Advanced Practice Providers: Impact and Opportunity. AB - Although significant progress has been made in cancer care, access to coordinated, high-quality care across the cancer care continuum remains a challenge for many patients. With significant workforce shortages in oncology anticipated, physician assistants (PAs) and nurse practitioners (NPs)-known collectively as advanced practice providers (APPs)-are considered to be a part of the solution to bridging the gap between the supply of and demand for oncology services. APPs are integral to the provision of team-based care in oncology, and optimizing the roles of all members of the patient's care team is vital to ensuring the teams are cost-effective and that each team member is performing at the functional level intended. Studies have shown significant patient, physician, and APP satisfaction with collaborative care models, and APPs are well positioned to enhance value for patients in the oncology setting. Understanding the full scope of APP impact can be challenging as it extends well beyond direct patient care. As rapid progress in cancer care continues, innovative approaches to care delivery will be necessary to ensure patients' access. Effective oncologist-APP partnerships will be key to providing optimal, value-centered care to patients. PMID- 28561714 TI - Personalizing Adjuvant Therapy for Stage II/III Colorectal Cancer. AB - This review focuses on three areas of interest with respect to the treatment of stage II and III colon and rectal cancer, including (1) tailoring adjuvant therapy for the geriatric population, (2) the controversy as to the optimal adjuvant therapy strategy for patients with locoregional rectal cancer and for patients with colorectal resectable metastatic disease, and (3) discussion of the microenvironment, molecular profiling, and the future of adjuvant therapy. It has become evident that age is the strongest predictive factor for receipt of adjuvant chemotherapy, duration of treatment, and risk of treatment-related toxicity. Although incorporating adjuvant chemotherapy for patients who have received neoadjuvant chemoradiation and surgery would appear to be a reasonable strategy to improve survivorship as an extrapolation from stage III colon cancer adjuvant trials, attempts at defining the optimal rectal cancer population that would benefit from adjuvant therapy remain elusive. Similarly, the role of adjuvant chemotherapy for patients after resection of metastatic colorectal cancer has not been clearly defined because of very limited data to provide guidance. An understanding of the biologic hallmarks and drivers of metastatic spread as well as the micrometastatic environment is expected to translate into therapeutic strategies tailored to select patients. The identification of actionable targets in mesenchymal tumors is of major interest. PMID- 28561715 TI - Endometrial Cancer: Is This a New Disease? AB - The incidence of endometrial cancer is increasing, and the age of onset is younger than in prior years. Although endometrial cancer still occurs more commonly in older women, for whom the mortality rate is increasing, it also is being diagnosed in younger and younger women. The underlying cause of the increase in incidence is the epidemic of obesity and the resulting hyperinsulinemia. Conservative treatment may be indicated for younger women who wish to retain their fertility. Lifestyle modifications such as diet and exercise can modulate the risk of developing endometrial cancer as well as prevent recurrence and other comorbidities associated with obesity. PMID- 28561716 TI - Breast Cancer After Childhood, Adolescent, and Young Adult Cancer: It's Not Just About Chest Radiation. AB - Women who have been treated for a childhood, adolescent, or young adult cancer are at an increased risk for developing breast cancer at a young age, and breast cancer accounts for the most common subsequent malignant neoplasm among female childhood and adolescent cancer survivors. Risk of breast cancer in these survivors appears to be a multifaceted relationship between constitutional factors, exposures to radiation therapy (RT) and chemotherapy, and genetic predisposition. Given the significant morbidities and mortality associated with a breast cancer diagnosis, it is imperative that health care providers understand the risks, biology and genetics, recommended surveillance guidelines for early detection, and potential prevention strategies for women who have survived pediatric and young adult cancer. PMID- 28561717 TI - Addressing the Survivorship Care Needs of Patients Receiving Extended Cancer Treatment. AB - Cancer survivorship care and research has typically focused on the health care needs of people with cancer following the acute phase of treatment. Work in this area, however, has faced challenges in identifying when treatment is complete for many forms of cancer. Acknowledging this challenge, the scope of survivorship research is often expanded to include patients also receiving maintenance or prophylactic therapy. Inherent in this expanded definition is the recognition that for many individuals, cancer is a chronic disease requiring extended treatment over many years. Three distinct patient populations can be identified for which extended treatment poses important survivorship care needs that, to date, have not been adequately addressed. The first group includes patients receiving extended endocrine therapy, such as women with breast cancer receiving tamoxifen and/or aromatase inhibitors as well as men with prostate cancer receiving androgen deprivation therapy. The second group includes patients receiving extended targeted therapy to control disease, as exemplified by patients with chronic myelogenous leukemia receiving treatment with tyrosine kinase inhibitors. A key issue in both of these patient groups is the need to identify and address factors that contribute to difficulties in maintaining high levels of adherence to the prescribed therapy over extended periods of time. The third group includes patients receiving novel therapies for advanced or metastatic cancer that can extend life for prolonged periods. A key issue for this group is the need to understand and address their unique supportive care needs. PMID- 28561718 TI - Systemic Therapy for Metastatic Colorectal Cancer: From Current Standards to Future Molecular Targeted Approaches. AB - Over the past 20 years, substantial advances have been made in the treatment of patients with metastatic colorectal cancer (mCRC). In particular, there is now a wide range of options for the front-line treatment of mCRC. Sophisticated molecular technologies have been developed to identify novel prognostic and predictive biomarkers for CRC. DNA sequencing technology has made remarkable advances in recent years, primarily as a result of the development of next generation sequencing and whole exome sequencing, which are powerful new tools for the discovery of predictive molecular biomarkers to facilitate the delivery of personalized medicine. In addition to tumor tissue, recent efforts have focused on analyzing circulating tumor DNA in peripheral blood. Herein, we review the evolution of standard chemotherapy and targeted therapy strategies for the treatment of mCRC in the front-line setting, the molecular technologies that are presently being used to facilitate our ability to practice individualized medicine, and the practical aspects of applying molecular biomarkers to everyday clinical practice. PMID- 28561720 TI - mHealth: Mobile Technologies to Virtually Bring the Patient Into an Oncology Practice. AB - Accompanied by the change in the traditional medical landscape, advances in wireless technology have led to the development of telehealth or mobile health (mHealth), which offers an unparalleled opportunity for health care providers to continually deliver high-quality care. This revolutionary shift makes the patient the consumer of health care and empowers patients to be the driving force of management of their own health through mobile devices and wearable technology. This article presents an overview of technology as it pertains to clinical practice considerations. Telemedicine is changing the way clinical care is delivered without regard for proximity to the patient, whereas nonclinical telehealth applications affect distance education for consumers or clinicians, meetings, research, continuing medical education, and health care management. Technology has the potential to reduce administrative burdens and improve both efficiency and quality of care delivery in the clinic. Finally, the potential for telehealth approaches as cost-effective ways to improve adherence to treatment is explored. As telehealth advances, health care providers must understand the fundamental framework for applying telehealth strategies to incorporate into successful clinical practice. PMID- 28561719 TI - Chronic Myeloid Leukemia: What Every Practitioner Needs to Know in 2017. AB - The prognosis of chronic phase chronic myeloid leukemia (CML) has improved so that life expectancy for patients responding to tyrosine kinase inhibitors (TKIs) is now equivalent to age-matched controls. Attention should be paid to comorbidities that impact survival. The success of TKI therapy can be easily and reliably assessed at well-accepted time points using quantitative polymerase chain reaction (PCR) standardized to the international scale. Patient-reported outcome (PRO) tools are readily available for use in the clinic and provide complementary information on the tolerance of TKIs. Effectively managing adverse events of TKIs can improve compliance and quality of life. Discontinuation of TKIs is the next frontier in CML. In select patients with sustained deep molecular remission, a discontinuation of TKI is associated with a durable treatment-free remission in approximately 50%. Patient engagement in their discontinuation can be achieved through a provider multi-team coaching, is complementary to the available guidelines, and may provide an additional safety net so that these discontinuations remain safe when applied in general practices. PMID- 28561721 TI - Managing Resistance to EFGR- and ALK-Targeted Therapies. AB - Targeted therapies have transformed the management of non-small cell lung cancer (NSCLC) and placed an increased emphasis on stratifying patients on the basis of genetic alterations in oncogenic drivers. To date, the best characterized molecular targets in NSCLC are the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Despite steady advances in targeted therapies within these molecular subsets, however, acquired resistance to therapy is near universal. Recent preclinical models and translational efforts have provided critical insights into the molecular mechanisms of resistance to EGFR and ALK inhibitors. In this review, we present a framework for understanding resistance to targeted therapies. We also provide overviews of the molecular mechanisms of resistance and strategies to overcome resistance among EGFR-mutant and ALK rearranged lung cancers. To date, these strategies have centered on the development of novel next-generation inhibitors, rationale combinations, and use of local ablative therapies, such as radiotherapy. PMID- 28561723 TI - Wedge Resection Versus Anatomic Resection: Extent of Surgical Resection for Stage I and II Lung Cancer. AB - Currently, surgery for lung cancer with curative intent consists of resection (removal) of the proper extent of lung parenchyma that bears the cancer lesion along with locoregional lymph nodes to assess possible cancer metastasis. Lobectomy, at least, is preferred with regard to the extent of parenchymal resection. The history of lung cancer surgery, which started around 1933 as pneumonectomy (resection of the entire lung on either side), can be characterized as an attempt to minimize the extent of parenchymal resection. In the early 1960s, pneumonectomy was replaced by lobectomy, which has long been respected as the standard surgical mode. However, the transition from lobectomy to a lesser resection, such as segmentectomy or wedge resection, was not recommended because of the results of a randomized trial performed by the North American Lung Cancer Study Group in the 1980s. As of now, the extent of parenchymal resection remains lobectomy, and lesser resection is indicated only for patients who have a compromised pulmonary reserve. Very recently, because of the advent of CT screening programs and improvements in imaging technology, fainter and smaller lung cancers are being discovered. For these smaller and earlier lung cancers, there is some uncertainty about whether lobectomy still should be indicated, as it is for larger tumors with a diameter of 3 cm or more. Therefore, several randomized trials are ongoing to compare lobectomy with lesser resections; endpoints are overall survival and postoperative pulmonary function. Until the results of these trials are available, lung cancer should still be removed by lobectomy rather than by limited resection, such as segmentectomy or wedge resection. PMID- 28561722 TI - Therapeutic Bone-Modifying Agents in the Nonmetastatic Breast Cancer Setting: The Controversy and a Value Assessment. AB - Clinical trials and meta-analyses investigating bisphosphonates as an adjuvant breast cancer therapy have shown a consistent trend, with postmenopausal women and women receiving ovarian suppression with gonadotropin-releasing hormone therapy gaining improved breast cancer outcomes with the use of adjuvant bisphosphonate therapy. The interpretation of these data is controversial, because the primary endpoints of the majority of adjuvant bisphosphonate studies have been negative. Pros and cons as well as the value of adjuvant bisphosphonate therapy are discussed here. PMID- 28561724 TI - Strategies to Maximize Patient Participation in Clinical Trials. AB - Despite considerable interest and success in oncology drug development, the minority of patients with cancer diagnoses enroll in clinical trials. Multiple obstacles account for this low enrollment rate. An improvement in patient participation in clinical trials could increase patient access to novel and potentially promising agents, provide faster trial results, and, with implementation of rational eligibility criteria, allow for a better understanding of the drug's safety and efficacy in a heterogeneous population. We present barriers and potential solutions to maximize patient participation, including a review of the ASCO and Friends of Cancer Research (FoCR) Modernizing Eligibility Criteria Project, U.S. Food and Drug Administration (FDA) regulatory considerations, an industry perspective, and a patient perspective. PMID- 28561725 TI - Challenges in Opening and Enrolling Patients in Clinical Trials. AB - Clinical trials are key elements of the processes that account for many of the recent advances in cancer care, including decreased mortality rates and increased survivorship; better supportive care; and improved understanding of cancer risk, prevention, and screening. This research also has led to the validation of numerous exciting new types of cancer treatments, such as molecularly targeted therapies and immunotherapies. Clinical trials, however, are becoming more and more challenging to conduct. Research programs must comply with legal and regulatory requirements that can be inefficient and costly to implement and often are variably interpreted by institutions and sponsors and sponsors' representatives, including contract research organizations. Some of these requirements are essential to protect the safety of trial participants, to promote the scientific integrity of research, or to ensure that trial conduct is efficient and adequately resourced. Such requirements are important to preserve. However, some requirements do not fulfill any of these goals and, in fact, hinder research and slow patient access to safe and effective treatments. This article discusses some of the identified issues that are slowing the process of cancer clinical trials, such as conservatively interpreted guidelines by pharmaceutical companies and contract research organizations; overprotective language for contracts; and patient protections by health systems and universities. The article also discusses possible solutions to these problems that are slowing down the cancer therapies that patients need. PMID- 28561726 TI - Caring for the Older Population With Advanced Lung Cancer. AB - The management of advanced lung cancer is changing rapidly, with new drug approvals occurring almost monthly. The average age of a newly diagnosed patient with advanced lung cancer remains around age 70. Caring for the older adult with advanced cancer differs from the care of younger adults. Chronologic age often does not accurately reflect the physiologic and functional status of older adults. Selecting treatment based on age alone results in undertreatment and overtreatment of many older adults. Addressing issues such as multiple chronic conditions, polypharmacy, geriatric syndromes, and heterogeneity in functional status among an expanding menu of treatment options for advanced disease is increasingly difficult, particularly among older adults historically underrepresented in clinical trials. In this article, we highlight key issues in caring for the older adult with advanced non-small cell lung cancer and the continued need for data supporting current and emerging treatment options. Key issues include the unique challenges of managing advanced lung cancer and a summary of the current treatment evidence as they apply to the elderly lung cancer population including supportive care strategies, risk stratification, and patient-reported outcomes. PMID- 28561727 TI - Social Media for Networking, Professional Development, and Patient Engagement. AB - Social media has become an established method of communication, and many physicians are finding these interactive tools and platforms to be useful for both personal and professional use. Risks of social media, or barriers to its use, include perceived lack of time, privacy concerns, and the risk of damage to one's reputation by unprofessional behavior. Of the social media platforms, Twitter has become favored by physicians and other health care professionals. Although one of the most obvious uses of social media is for rapid dissemination and receipt of information, oncologists are finding that social media is important for networking through blogs, Facebook, and Twitter. These platforms also have potential for providing opportunities for professional development, such as finding collaborators through networking, participation in Twitter journal clubs, and participating in online case-based tumor boards. Social media can also be used for patient engagement, such as through participation in tweet chats. There is emerging data that patient engagement through these platforms may lead to improvement in some health-related outcomes; however, data are sparse for oncology-specific outcomes. Efforts are underway to determine how to assess how social media engagement impacts health outcomes in oncology patients. PMID- 28561729 TI - European/U.S. Comparison and Contrasts in Ovarian Cancer Screening and Prevention in a High-Risk Population. AB - The history of screening and prevention of ovarian cancer among high-risk women in the United States and Europe is one of mutual inspiration, with researchers learning from each others' findings and insights and collaborating with investigators from both sides of the Atlantic ocean. Examples of simultaneous and joint development of knowledge and scientific points of view include the paradigm shift from ovarian to fallopian tube high-grade serous cancer and the cessation of simultaneous adoption of ovarian cancer screening by clinicians in both the United States and Europe. Examples of joint efforts with fruitful results include international collaboration in large population-based, genome-wide association studies and in epidemiologic database studies. Research in the field of hereditary ovarian cancer is a great example of mutual inspiration and joint efforts for the purpose of improving knowledge and health care for women with hereditary ovarian cancer. PMID- 28561730 TI - Pharmacokinetic/Pharmacodynamic Modeling for Drug Development in Oncology. AB - High drug attrition rates remain a critical issue in oncology drug development. A series of steps during drug development must be addressed to better understand the pharmacokinetic (PK) and pharmacodynamic (PD) properties of novel agents and, thus, increase their probability of success. As available data continues to expand in both volume and complexity, comprehensive integration of PK and PD information into a robust mathematical model represents a very useful tool throughout all stages of drug development. During the discovery phase, PK/PD models can be used to identify and select the best drug candidates, which helps characterize the mechanism of action and disease behavior of a given drug, to predict clinical response in humans, and to facilitate a better understanding about the potential clinical relevance of preclinical efficacy data. During early drug development, PK/PD modeling can optimize the design of clinical trials, guide the dose and regimen that should be tested further, help evaluate proof of mechanism in humans, anticipate the effect in certain subpopulations, and better predict drug-drug interactions; all of these effects could lead to a more efficient drug development process. Because of certain peculiarities of immunotherapies, such as PK and PD characteristics, PK/PD modeling could be particularly relevant and thus have an important impact on decision making during the development of these agents. PMID- 28561728 TI - Adoptive T-Cell Therapy for Solid Tumors. AB - Chimeric antigen receptor (CAR) T-cell therapy is an innovative form of immunotherapy wherein autologous T cells are genetically modified to express chimeric receptors encoding an antigen-specific single-chain variable fragment and various costimulatory molecules. Upon administration, these modified T cells traffic to, and recognize, cancer cells in an HLA-independent manner. CAR T-cell therapy has shown remarkable success in the treatment of CD-19-expressing B-cell acute lymphocytic leukemia. However, clinical gains to the same magnitude have not been reported in solid tumors. Several known obstacles to CAR T-cell therapy for solid tumors include target antigen identification, effective trafficking to the tumor, robust activation, proliferation, and in vivo cytotoxicity. Beyond these T-cell intrinsic properties, a complex and dynamic immunosuppressive tumor microenvironment in solid tumors hinders T-cell efficacy. Notable advancements in CAR design to include multiple costimulatory molecules, ligands, and soluble cytokines have shown promise in preclinical models, and some of these are currently in early-phase clinical trials. In this review, we discuss selected solid tumor malignancies and relevant preclinical data and highlight clinical trial results that are available. Furthermore, we outline some obstacles to CAR T cell therapy for each tumor and propose strategies to overcome some of these limitations. PMID- 28561731 TI - Pain and Opioids in Cancer Care: Benefits, Risks, and Alternatives. AB - Pain remains common in the setting of malignancy, occurring as a consequence of cancer and its treatment. Several high-quality studies confirm that more than 50% of all patients with cancer experience moderate to severe pain. The prevalence of pain in cancer survivors is estimated to be 40%, while close to two-thirds of those with advanced disease live with pain. Progress has occurred in the management of cancer pain, yet undertreatment persists. Additionally, new challenges are threatening these advances. These challenges are numerous and include educational deficits, time restraints, and limited access to all types of care. New challenges to access are occurring as a result of interventions designed to combat the prescription drug abuse epidemic, with fewer clinicians willing to prescribe opioids, pharmacies reluctant to stock the medications, and payers placing strict limits on reimbursement. A related challenge is our evolving understanding of the risks of long-term adverse effects associated with opioids. And reflective of the opioid abuse epidemic affecting the general population, the potential for misuse or abuse exists in those with cancer. Guidelines have been developed to support oncologists when prescribing the long term use of opioids for cancer survivors. The challenges surrounding the use of opioids, and the need for safe and effective alternative analgesics, are leading to intense interest in the potential benefits of cannabis for cancer-related pain. Oncologists are faced with questions regarding the types of cannabis available, differences between routes of administration, data concerning safety and efficacy, and legal and regulatory dynamics. PMID- 28561732 TI - Ferric citrate controls serum phosphorus in dialysis patients: retrospective data?. AB - Ferric citrate is an approved phosphate binder for use in patients with chronic kidney disease on dialysis. Clinical trials demonstrated that ferric citrate controlled serum phosphorus levels and increased iron stores. The aim of this retrospective chart review was to evaluate real-world bone mineral and anemia parameter data from patients treated with ferric citrate. 92 adult dialysis patients taking ferric citrate (average starting dose of 6 tablets/day) for at least 6 months were included. Bone mineral, anemia, and iron biomarker levels were extracted from patient medical records before and during the first 6 months of ferric citrate treatment; 21 (23%) patients were phosphate binder naive, and 71 (77%) patients had been on other phosphate binders. Before starting ferric citrate, 22% of patients had serum phosphorus <= 5.5 mg/dL, increasing to 65% of patients at 6 months of treatment (month 6). Mean (standard error of the mean (SEM)) baseline serum phosphorus was 6.55 +/- 0.17 mg/dL decreasing to 5.40 +/- 0.17 mg/dL at month 6. Mean (SEM) baseline hemoglobin, ferritin, and transferrin saturation were 10.6 +/- 0.2 g/dL, 734 +/- 65 ng/mL, and 27.1 +/- 1.6%, respectively, and 11.1 +/- 0.2 g/dL, 947 +/- 66 ng/mL, and 37 +/- 1.9%, respectively, at month 6. The serum phosphorus and anemia biomarker levels observed in this retrospective chart review were similar to those seen in clinical trials.?. PMID- 28561734 TI - Poring over furrows. AB - Cryo-electron microscopy reveals the structure of a chloride channel that is closely related to a protein that transports lipids. PMID- 28561733 TI - Structural basis for anion conduction in the calcium-activated chloride channel TMEM16A. AB - The calcium-activated chloride channel TMEM16A is a member of a conserved protein family that comprises ion channels and lipid scramblases. Although the structure of the scramblase nhTMEM16 has defined the architecture of the family, it was unknown how a channel has adapted to cope with its distinct functional properties. Here we have addressed this question by the structure determination of mouse TMEM16A by cryo-electron microscopy and a complementary functional characterization. The protein shows a similar organization to nhTMEM16, except for changes at the site of catalysis. There, the conformation of transmembrane helices constituting a membrane-spanning furrow that provides a path for lipids in scramblases has changed to form an enclosed aqueous pore that is largely shielded from the membrane. Our study thus reveals the structural basis of anion conduction in a TMEM16 channel and it defines the foundation for the diverse functional behavior in the TMEM16 family. PMID- 28561735 TI - Learning shapes the aversion and reward responses of lateral habenula neurons. AB - The lateral habenula (LHb) is believed to encode negative motivational values. It remains unknown how LHb neurons respond to various stressors and how learning shapes their responses. Here, we used fiber-photometry and electrophysiology to track LHb neuronal activity in freely-behaving mice. Bitterness, pain, and social attack by aggressors intensively excite LHb neurons. Aversive Pavlovian conditioning induced activation by the aversion-predicting cue in a few trials. The experience of social defeat also conditioned excitatory responses to previously neutral social stimuli. In contrast, fiber photometry and single-unit recordings revealed that sucrose reward inhibited LHb neurons and often produced excitatory rebound. It required prolonged conditioning and high reward probability to induce inhibition by reward-predicting cues. Therefore, LHb neurons can bidirectionally process a diverse array of aversive and reward signals. Importantly, their responses are dynamically shaped by learning, suggesting that the LHb participates in experience-dependent selection of behavioral responses to stressors and rewards. PMID- 28561736 TI - A cell cycle-independent, conditional gene inactivation strategy for differentially tagging wild-type and mutant cells. AB - Here, we describe a novel method based on intronic MiMIC insertions described in Nagarkar-Jaiswal et al. (2015) to perform conditional gene inactivation in Drosophila. Mosaic analysis in Drosophila cannot be easily performed in post mitotic cells. We therefore, therefore, developed Flip-Flop, a flippase-dependent in vivo cassette-inversion method that marks wild-type cells with the endogenous EGFP-tagged protein, whereas mutant cells are marked with mCherry upon inversion. We document the ease and usefulness of this strategy in differential tagging of wild-type and mutant cells in mosaics. We use this approach to phenotypically characterize the loss of SNF4Agamma, encoding the gamma subunit of the AMP Kinase complex. The Flip-Flop method is efficient and reliable, and permits conditional gene inactivation based on both spatial and temporal cues, in a cell cycle-, and developmental stage-independent fashion, creating a platform for systematic screens of gene function in developing and adult flies with unprecedented detail. PMID- 28561739 TI - Inactivation of proteolytic enzymes by Eubothrium rugosum (Cestoda) from the gut of burbot Lota lota. AB - Parasitic organisms inhabiting the alimentary canal should permanently resist the destructive action of host digestive enzymes. The intestinal parasites were shown to produce specific protease inhibitors protecting them from proteolysis. However, little is known about this adaptive mechanism in cestodes so far, especially for the tapeworms dwelling inside the fish intestines. Here, we explored the ability to inactivate proteolytic enzymes in the fish tapeworm Eubothrium rugosum (Batsch, 1786) (Bothriocephalidea) parasitising the intestine of wild burbot, Lota lota (Linnaeus). The assays were conducted with different concentrations of commercial trypsin and homogenate of intestinal mucosa both being the sources of proteinases. The incubation of live E. rugosum in trypsin solutions of two different concentrations caused a significant decrease in the enzyme activity. The extent of activity reduction was dependent on trypsin concentration. At the same time, the inhibitory effect of the worm incubation medium turned out to be statistically insignificant. These findings suggest partial adsorption of the enzyme to the tegument surface, with its further inactivation. In contrast to the incubation medium, the worm extract suppressed over 80% of trypsin activity and nearly half of the proteolytic activity in the mucosa homogenate. Notably, the inhibitory activity of the tapeworms hardly depended on their size characteristics. Finally, the research has demonstrated secretion of proteinase inhibitor in E. rugosum, which appears to be essential for its survival in enzymatically hostile environment. PMID- 28561737 TI - Synergistic interactions with PI3K inhibition that induce apoptosis. AB - Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a PIK3CA mutant human breast cancer cell. We identified 5 genes (PIM2, ZAK, TACC1, ZFR, ZNF565) whose suppression induced cell death upon PI3K inhibition. We showed that small molecule inhibitors of the PIM2 and ZAK kinases synergize with PI3K inhibition. In addition, using a microscale implementable device to deliver either siRNAs or small molecule inhibitors in vivo, we showed that suppressing these 5 genes with PI3K inhibition induced tumor regression. These observations identify targets whose inhibition synergizes with PI3K inhibitors and nominate potential combination therapies involving PI3K inhibition. PMID- 28561740 TI - A new genus of proteocephalid tapeworm (Cestoda) from the marbled swamp eel Synbranchus marmoratus Bloch (Synbranchiformes: Synbranchidae) in the River Parana basin, Argentina. AB - Synbranchiella gen. n. is proposed to accommodate Synbranchiella mabelae sp. n. (Proteocephalidae: Monticelliinae) from the intestine of the marbled swamp eel Synbranchus marmoratus Bloch, in the River Colastine, a tributary of the middle River Parana in Argentina. The new genus is placed in the Monticelliinae because of the cortical position of the genital organs. It differs from all known monticelliine genera by the following combination of characters: (i) scolex robust, with a conical apex, without metascolex; (ii) biloculate suckers with a conspicuous septum separating unequally-sized loculi and a robust non-adherent area, lacking free posterior margin; (iii) vitelline follicles in two narrow lateral bands, extended throughout the nearly entire proglottid length; (iv) vagina always anterior to the cirrus-sac, with an inconspicuous vaginal sphincter; (v) a genital pore pre-equatorial. Scanning electron microscopy revealed three types of microtriches on the tegument surface: acicular and capiliform filitriches and gladiate spinitriches. A phylogenetic analysis of the large subunit nuclear ribosomal RNA gene (lsrDNA, D1-D3 domains) confirms that S. mabelae represents an independent lineage within a large clade comprised mainly from Neotropical taxa parasitising catfishes. This is the second proteocephalidean cestode described from a Neotropical synbranchiform fish host. PMID- 28561738 TI - Oxidative stress induces stem cell proliferation via TRPA1/RyR-mediated Ca2+ signaling in the Drosophila midgut. AB - Precise regulation of stem cell activity is crucial for tissue homeostasis and necessary to prevent overproliferation. In the Drosophila adult gut, high levels of reactive oxygen species (ROS) has been detected with different types of tissue damage, and oxidative stress has been shown to be both necessary and sufficient to trigger intestinal stem cell (ISC) proliferation. However, the connection between oxidative stress and mitogenic signals remains obscure. In a screen for genes required for ISC proliferation in response to oxidative stress, we identified two regulators of cytosolic Ca2+ levels, transient receptor potential A1 (TRPA1) and ryanodine receptor (RyR). Characterization of TRPA1 and RyR demonstrates that Ca2+ signaling is required for oxidative stress-induced activation of the Ras/MAPK pathway, which in turns drives ISC proliferation. Our findings provide a link between redox regulation and Ca2+ signaling and reveal a novel mechanism by which ISCs detect stress signals. PMID- 28561741 TI - An acid-free water-born quaternized chitosan/montmorillonite loaded into an innovative ultra-fine bead-free water-born nanocomposite nanofibrous scaffold; in vitro and in vivo approaches. AB - An acid-free water-born chitosan derivative/montmorillonite has been successfully synthesized. A natural-based biopolymer, N-(2-hydroxy) propyl-3-trimethyl ammonium chitosan chloride, was synthesized, and its structure confirmed by Fourier transform infrared microscopy and conductometric titration. It was applied to the cationic ion-exchange reaction of montmorillonite. Then, the synthesized materials were used to produce water-born composite scaffolds for tissue engineering applications and formed an ultra-fine bead-free multicomponent nanofibrous scaffold. The scaffold was subjected to in vitro and in vivo investigations. The effects of both acidic and neutral reaction media on the efficiency of the cationic ion-exchange reaction of montmorillonite were investigated. A mechanism has been suggested for the more efficient cationic ion exchange reaction achieved in the absence of the acid. In in vitro studies, the modified montmorillonite showed synergistic biocompatibility and cell growth with enhanced bioactivity compared to unmodified clay and even chitosan and the chitosan derivative. Scanning electron microscopy showed ultra-fine bead-free nanocomposite nanofibers. Improved biocompatibility, cell attachment, and cell growth were observed for the nanofibrous scaffolds compared to the individual components. In vivo experiments showed complete restoration of a critical-sized full-thickness wound without infection in 21 d. The technique provides a guideline to achieve chitosan nanofibrous morphology for multifunctional biomedical applications. PMID- 28561742 TI - A general strategy toward graphitized carbon coating on iron oxides as advanced anodes for lithium-ion batteries. AB - Integration of carbon materials with benign iron oxides is blazing a trail in constructing high-performance anodes for lithium-ion batteries (LIBs). In this paper, a unique general, simple, and controllable strategy is developed toward in situ uniform coating of iron oxide nanostructures with graphitized carbon (GrC) layers. The basic synthetic procedure only involves a simple dip-coating process for the loading of Ni-containing seeds and a subsequent Ni-catalyzed chemical vapor deposition (CVD) process for the growth of GrC layers. More importantly, the CVD treatment is conducted at a quite low temperature (450 degrees C) and with extremely facile liquid carbon sources consisting of ethylene glycol (EG) and ethanol (EA). The GrC content of the resulting hybrids can be controllably regulated by altering the amount of carbon sources. The electrochemical results reveal remarkable performance enhancements of iron oxide@GrC hybrids compared with pristine iron oxides in terms of high specific capacity, excellent rate and cycling performance. This can be attributed to the network-like GrC coating, which can improve not only the electronic conductivity but also the structural integrity of iron oxides. Moreover, the lithium storage performance of samples with different GrC contents is measured, manifesting that optimized electrochemical property can be achieved with appropriate carbon content. Additionally, the superiority of GrC coating is demonstrated by the advanced performance of iron oxide@GrC compared with its corresponding counterpart, i.e., iron oxides with amorphous carbon (AmC) coating. All these results indicate the as-proposed protocol of GrC coating may pave the way for iron oxides to be promising anodes for LIBs. PMID- 28561743 TI - Mantle Cell Lymphoma with MYC Rearrangement: A Report of 17 Patients: Erratum. PMID- 28561744 TI - Synthesis and Thrombin, Factor Xa and U46619 Inhibitory Effects of Non-Amidino and Amidino N2-Thiophenecarbonyl- and N2-Tosylanthranilamides. AB - Thrombin (factor IIa) and factor Xa (FXa) are key enzymes at the junction of the intrinsic and extrinsic coagulation pathways and are the most attractive pharmacological targets for the development of novel anticoagulants. Twenty non amidino N2-thiophencarbonyl- and N2-tosyl anthranilamides 1-20 and six amidino N2 thiophencarbonyl- and N2-tosylanthranilamides 21-26 were synthesized to evaluate their activated partial thromboplastin time (aPTT) and prothrombin time (PT) using human plasma at a concentration of 30 ug/mL in vitro. As a result, compounds 5, 9, and 21-23 were selected to study the further antithrombotic activity. The anticoagulant properties of 5, 9, and 21-23 significantly exhibited a concentration-dependent prolongation of in vitro PT and aPTT, in vivo bleeding time, and ex vivo clotting time. These compounds concentration-dependently inhibited the activities of thrombin and FXa and inhibited the generation of thrombin and FXa in human endothelial cells. In addition, data showed that 5, 9, and 21-23 significantly inhibited thrombin catalyzed fibrin polymerization and mouse platelet aggregation and inhibited platelet aggregation induced by U46619 in vitro and ex vivo. Among the derivatives evaluated, N-(3'-amidinophenyl)-2 ((thiophen-2''-yl)carbonylamino)benzamide (21) was the most active compound. PMID- 28561746 TI - A Low-Cost System Based on Image Analysis for Monitoring the Crystal Growth Process. AB - Many techniques are used to monitor one or more of the phenomena involved in the crystallization process. One of the challenges in crystal growth monitoring is finding techniques that allow direct interpretation of the data. The present study used a low-cost system, composed of a commercial webcam and a simple white LED (Light Emitting Diode) illuminator, to follow the calcium carbonate crystal growth process. The experiments were followed with focused beam reflectance measurement (FBRM), a common technique for obtaining information about the formation and growth of crystals. The images obtained in real time were treated with the red, blue, and green (RGB) system. The results showed a qualitative response of the system to crystal formation and growth processes, as there was an observed decrease in the signal as the growth process occurred. Control of the crystal growth was managed by increasing the viscosity of the test solution with the addition of monoethylene glycol (MEG) at 30% and 70% in a mass to mass relationship, providing different profiles of the RGB average curves. The decrease in the average RGB value became slower as the concentration of MEG was increased; this reflected a lag in the growth process that was proven by the FBRM. PMID- 28561745 TI - HiSeeker: Detecting High-Order SNP Interactions Based on Pairwise SNP Combinations. AB - Detecting single nucleotide polymorphisms' (SNPs) interaction is one of the most popular approaches for explaining the missing heritability of common complex diseases in genome-wide association studies. Many methods have been proposed for SNP interaction detection, but most of them only focus on pairwise interactions and ignore high-order ones, which may also contribute to complex traits. Existing methods for high-order interaction detection can hardly handle genome-wide data and suffer from low detection power, due to the exponential growth of search space. In this paper, we proposed a flexible two-stage approach (called HiSeeker) to detect high-order interactions. In the screening stage, HiSeeker employs the chi-squared test and logistic regression model to efficiently obtain candidate pairwise combinations, which have intermediate or significant associations with the phenotype for interaction detection. In the search stage, two different strategies (exhaustive search and ant colony optimization-based search) are utilized to detect high-order interactions from candidate combinations. The experimental results on simulated datasets demonstrate that HiSeeker can more efficiently and effectively detect high-order interactions than related representative algorithms. On two real case-control datasets, HiSeeker also detects several significant high-order interactions, whose individual SNPs and pairwise interactions have no strong main effects or pairwise interaction effects, and these high-order interactions can hardly be identified by related algorithms. PMID- 28561747 TI - In-Process Atomic-Force Microscopy (AFM) Based Inspection. AB - A new in-process atomic-force microscopy (AFM) based inspection is presented for nanolithography to compensate for any deviation such as instantaneous degradation of the lithography probe tip. Traditional method used the AFM probes for lithography work and retract to inspect the obtained feature but this practice degrades the probe tip shape and hence, affects the measurement quality. This paper suggests a second dedicated lithography probe that is positioned back-to back to the AFM probe under two synchronized controllers to correct any deviation in the process compared to specifications. This method shows that the quality improvement of the nanomachining, in progress probe tip wear, and better understanding of nanomachining. The system is hosted in a recently developed nanomanipulator for educational and research purposes. PMID- 28561748 TI - A Point Temperature Sensor Based on Upconversion Emission in Er3+/Yb3+ Codoped Tellurite-Zinc-Niobium Glass. AB - Er3+/Yb3+ codoped tellurite-zinc-niobium (TZNb) glass was prepared by the melt quenching method and used for the construction of a point all-fiber temperature sensor. The glass thermal stability and network structural properties were studied by differential thermal analysis and Raman spectrum, respectively. High glass transition temperature is beneficial to widen the working temperature range. The dependence of fluorescence intensity ratio (FIR) of green upconversion emissions on the surrounding temperature from 276 to 363 K was experimentally investigated and the maximum temperature sensitivity is 95 * 10-4 K-1 at 363 K. Strong green upconversion emission, broad temperature measurement range and high sensitivity indicate this point temperature sensor is a promising optical device for application on optical temperature sensing. PMID- 28561749 TI - The Missing Piece in Biosynthesis of Amphidinols: First Evidence of Glycolate as a Starter Unit in New Polyketides from Amphidinium carterae. AB - Two new members of the amphidinol family, amphidinol A (1) and its 7-sulfate derivative amphidinol B (2), were isolated from a strain of Amphidinium carterae of Lake Fusaro, near Naples (Italy), and chemically identified by spectroscopic and spectrometric methods. Amphidinol A showed antifungal activity against Candida albicans (MIC = 19 ug/mL). Biosynthetic experiments with stable isotope labelled acetate allowed defining the elongation process in 1. For the first time the use of glycolate as a starter unit in the polyketide biosynthesis of amphidinol metabolites was unambiguously demonstrated. PMID- 28561750 TI - Enhanced Flexibility and Reusability through State Machine-Based Architectures for Multisensor Intelligent Robotics. AB - This paper presents a state machine-based architecture, which enhances the flexibility and reusability of industrial robots, more concretely dual-arm multisensor robots. The proposed architecture, in addition to allowing absolute control of the execution, eases the programming of new applications by increasing the reusability of the developed modules. Through an easy-to-use graphical user interface, operators are able to create, modify, reuse and maintain industrial processes, increasing the flexibility of the cell. Moreover, the proposed approach is applied in a real use case in order to demonstrate its capabilities and feasibility in industrial environments. A comparative analysis is presented for evaluating the presented approach versus traditional robot programming techniques. PMID- 28561751 TI - The Role of Somatic L1 Retrotransposition in Human Cancers. AB - The human LINE-1 (or L1) element is a non-LTR retrotransposon that is mobilized through an RNA intermediate by an L1-encoded reverse transcriptase and other L1 encoded proteins. L1 elements remain actively mobile today and continue to mutagenize human genomes. Importantly, when new insertions disrupt gene function, they can cause diseases. Historically, L1s were thought to be active in the germline but silenced in adult somatic tissues. However, recent studies now show that L1 is active in at least some somatic tissues, including epithelial cancers. In this review, we provide an overview of these recent developments, and examine evidence that somatic L1 retrotransposition can initiate and drive tumorigenesis in humans. Recent studies have: (i) cataloged somatic L1 activity in many epithelial tumor types; (ii) identified specific full-length L1 source elements that give rise to somatic L1 insertions; and (iii) determined that L1 promoter hypomethylation likely plays an early role in the derepression of L1s in somatic tissues. A central challenge moving forward is to determine the extent to which L1 driver mutations can promote tumor initiation, evolution, and metastasis in humans. PMID- 28561752 TI - Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-kappaB) Activation and NF-kappaB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy. AB - A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant 7 (AR-V7), nuclear factor-kappa B (NF-kappaB) was activated and could result in up-regulated interleukin (IL)-6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-kappaB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7 induced NF-kappaB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-kappaB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-kappaB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-kappaB activation via the previously-reported MT1 receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-kappaB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion. PMID- 28561753 TI - The Complete Structure of the Core Oligosaccharide from Edwardsiella tarda EIB 202 Lipopolysaccharide. AB - The chemical structure and genomics of the lipopolysaccharide (LPS) core oligosaccharide of pathogenic Edwardsiella tarda strain EIB 202 were studied for the first time. The complete gene assignment for all LPS core biosynthesis gene functions was acquired. The complete structure of core oligosaccharide was investigated by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, electrospray ionization mass spectrometry MSn, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The following structure of the undecasaccharide was established: The heterogeneous appearance of the core oligosaccharide structure was due to the partial lack of beta-d-Galp and the replacement of alpha-d-GlcpNAcGly by alpha-d-GlcpNGly. The glycine location was identified by mass spectrometry. PMID- 28561755 TI - Rapid Screening and Identification of Diterpenoids in Tinospora sinensis Based on High-Performance Liquid Chromatography Coupled with Linear Ion Trap-Orbitrap Mass Spectrometry. AB - Diterpenoids are considered the major active compounds in Tinospora sinensis in virtue of their special structures and activities. Herein, an analytical method was developed for rapid screening and identification of diterpenoids in T. sinensis using high-performmance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry (HPLC-LTQ-Orbitrap) in negative ion mode. Two diterpenoid reference standards were first analyzed to obtain their characteristic ESI-MS/MS fragmentation patterns. Then, based on the extracted ion chromatogram (EIC) data-mining method and characteristic fragmentation pathways analysis, diterpenoids in T. sinensis were rapidly screened and identified. After that, an important parameter, Clog P, was adopted to discriminate between the isomers of diterpenoids. As a result, 63 diterpenoids were characterized from the extract of T. sinensis, including 10 diterpenoids and 53 diterpenoid glycosides. Among them, 15 compounds were tentatively identified as new compounds. Finally, target isolation of one diterpenoid glycoside named tinosineside A was performed based on the obtained results, which further confirmed the deduced fragmentation patterns and identified diterpenoid profile in T. sinensis. The results demonstrated that the established method could be a rapid, effective analytical tool for screening and characterization of diterpenoids in the complex systems of natural medicines. PMID- 28561754 TI - Plant Lectins and Lectin Receptor-Like Kinases: How Do They Sense the Outside? AB - Lectins are fundamental to plant life and have important roles in cell-to-cell communication; development and defence strategies. At the cell surface; lectins are present both as soluble proteins (LecPs) and as chimeric proteins: lectins are then the extracellular domains of receptor-like kinases (LecRLKs) and receptor-like proteins (LecRLPs). In this review; we first describe the domain architectures of proteins harbouring G-type; L-type; LysM and malectin carbohydrate-binding domains. We then focus on the functions of LecPs; LecRLKs and LecRLPs referring to the biological processes they are involved in and to the ligands they recognize. Together; LecPs; LecRLKs and LecRLPs constitute versatile recognition systems at the cell surface contributing to the detection of symbionts and pathogens; and/or involved in monitoring of the cell wall structure and cell growth. PMID- 28561756 TI - Local Actions of Melatonin in Somatic Cells of the Testis. AB - The pineal hormone melatonin regulates testicular function through the hypothalamic-adenohypophyseal axis. In addition, direct actions of melatonin in somatic cells of the testis have been described. Melatonin acts as a local modulator of the endocrine activity in Leydig cells. In Sertoli cells, melatonin influences cellular growth, proliferation, energy metabolism and the oxidation state, and consequently may regulate spermatogenesis. These data pinpoint melatonin as a key player in the regulation of testicular physiology (i.e., steroidogenesis, spermatogenesis) mostly in seasonal breeders. In patients with idiopathic infertility, melatonin exerts anti-proliferative and anti-inflammatory effects on testicular macrophages, and provides protective effects against oxidative stress in testicular mast cells. Consequently, melatonin is also involved in the modulation of inflammatory and oxidant/anti-oxidant states in testicular pathology. Overall, the literature data indicate that melatonin has important effects on testicular function and male reproduction. PMID- 28561757 TI - Implications of Extracellular Matrix Production by Adipose Tissue-Derived Stem Cells for Development of Wound Healing Therapies. AB - The synthesis and deposition of extracellular matrix (ECM) plays an important role in the healing of acute and chronic wounds. Consequently, the use of ECM as treatment for chronic wounds has been of special interest-both in terms of inducing ECM production by resident cells and applying ex vivo produced ECM. For these purposes, using adipose tissue-derived stem cells (ASCs) could be of use. ASCs are recognized to promote wound healing of otherwise chronic wounds, possibly through the reduction of inflammation, induction of angiogenesis, and promotion of fibroblast and keratinocyte growth. However, little is known regarding the importance of ASC-produced ECM for wound healing. In this review, we describe the importance of ECM for wound healing, and how ECM production by ASCs may be exploited in developing new therapies for the treatment of chronic wounds. PMID- 28561758 TI - Lactobacillus reuteri I5007 Modulates Intestinal Host Defense Peptide Expression in the Model of IPEC-J2 Cells and Neonatal Piglets. AB - Modulation of the synthesis of endogenous host defense peptides (HDPs) by probiotics represents a novel antimicrobial approach for disease control and prevention, particularly against antibiotic-resistant infections in human and animals. However, the extent of HDP modulation by probiotics is species dependent and strain specific. In the present study, The porcine small intestinal epithelial cell line (IPEC-J2) cells and neonatal piglets were used as in-vitro and in-vivo models to test whether Lactobacillus reuteri I5007 could modulate intestinal HDP expression. Gene expressions of HDPs, toll-like receptors, and fatty acid receptors were determined, as well as colonic short chain fatty acid concentrations and microbiota. Exposure to 108 colony forming units (CFU)/mL of L. reuteri I5007 for 6 h significantly increased the expression of porcine beta Defensin2 (PBD2), pBD3, pBD114, pBD129, and protegrins (PG) 1-5 in IPEC-J2 cells. Similarly, L. reuteri I5007 administration significantly increased the expression of jejunal pBD2 as well as colonic pBD2, pBD3, pBD114, and pBD129 in neonatal piglets (p < 0.05). This was probably associated with the increase in colonic butyric acid concentration and up-regulating expression of Peroxisome Proliferator-Activated Receptor-gamma (PPAR-gamma) and G Protein-Coupled Receptor 41 (GPR41) (p < 0.05), but not with stimulation of Pattern-Recognition Receptors. Additionally, supplementation with L. reuteri I5007 in the piglets did not affect the colonic microbiota structure. Our findings suggested that L. reuteri I5007 could modulate intestinal HDP expression and improve the gut health of neonatal piglets, probably through the increase in colonic butyric acid concentration and the up-regulation of the downstream molecules of butyric acid, PPAR-gamma and GPR41, but not through modifying gut microbiota structure. PMID- 28561759 TI - Heteromer Nanostars by Spontaneous Self-Assembly. AB - Heteromer star-shaped nanoparticles have the potential to carry out therapeutic agents, improve intracellular uptake, and safely release drugs after prolonged periods of residence at the diseased site. A one-step seed mediation process was employed using polylactide-co-glycolic acid (PLGA), polyvinyl alcohol (PVA), silver nitrate, and tetrakis(hydroxymethyl)phosphonium chloride (THPC). Mixing these reagents followed by UV irradiation successfully produced heteromer nanostars containing a number of arm chains attached to a single core with a high yield. The release of THPC from heteromer nanostars was tested for its potential use for breast cancer treatment. The nanostars present a unique geometrical design exhibiting a significant intracellular uptake by breast cancer cells but low cytotoxicity that potentiates its efficacy as drug carriers. PMID- 28561760 TI - The Development of Non-Enzymatic Glucose Biosensors Based on Electrochemically Prepared Polypyrrole-Chitosan-Titanium Dioxide Nanocomposite Films. AB - The performance of a modified electrode of nanocomposite films consisting of polypyrrole-chitosan-titanium dioxide (Ppy-CS-TiO2) has been explored for the developing a non-enzymatic glucose biosensors. The synergy effect of TiO2 nanoparticles (NPs) and conducting polymer on the current responses of the electrode resulted in greater sensitivity. The incorporation of TiO2 NPs in the nanocomposite films was confirmed by X-ray photoelectron spectroscopy (XPS) spectra. FE-SEM and HR-TEM provided more evidence for the presence of TiO2 in the Ppy-CS structure. Glucose biosensing properties were determined by amperommetry and cyclic voltammetry (CV). The interfacial properties of nanocomposite electrodes were studied by electrochemical impedance spectroscopy (EIS). The developed biosensors showed good sensitivity over a linear range of 1-14 mM with a detection limit of 614 MUM for glucose. The modified electrode with Ppy-CS nanocomposite also exhibited good selectivity and long-term stability with no interference effect. The Ppy-CS-TiO2 nanocomposites films presented high electron transfer kinetics. This work shows the role of nanomaterials in electrochemical biosensors and describes the process of their homogeneous distribution in composite films by a one-step electrochemical process, where all components are taken in a single solution in the electrochemical cell. PMID- 28561763 TI - The Impact of Diet Protein and Carbohydrate on Select Life-History Traits of The Black Soldier Fly Hermetia illucens (L.) (Diptera: Stratiomyidae). AB - This study examined the impact of diet protein and carbohydrate percentages as well as moisture on the immature development, survivorship, and resulting adult longevity and egg production of the black soldier fly, Hermetiaillucens (L.) (Diptera: Stratiomyidae). Moisture impacted development and corresponding life history traits more than protein:carbohydrate content; larvae were unable to develop on diets at 40% moisture. Larvae fed diets at 70% moisture developed faster, grew larger, and required less food than those reared on diets at 55% moisture. Larvae reared on the balanced diet (21% protein:21% carbohydrate) at 70% moisture developed the fastest on the least amount of food and had the greatest survivorship to the prepupal stage. Adult emergence and longevity were similar across treatments, indicating immature life-history traits were impacted the most. The control (Gainesville house fly) diet was superior to the artificial diets for all parameters tested. These differences could indicate that other constituents (e.g., associated microbes) serve a role in black soldier fly development. These data are valuable for industrialization of this insect as a "green" technology for recycling organic waste, which can be highly variable, to produce protein for use as feed in the livestock, poultry, and aquaculture industries, as well as for bioenergy production. PMID- 28561762 TI - Consumption of Dairy Yogurt Containing Lactobacillus paracasei ssp. paracasei, Bifidobacterium animalis ssp. lactis and Heat-Treated Lactobacillus plantarum Improves Immune Function Including Natural Killer Cell Activity. AB - The aim of this study was to investigate the impact of consuming dairy yogurt containing Lactobacillus paracasei ssp. paracasei (L. paracasei), Bifidobacterium animalis ssp. lactis (B. lactis) and heat-treated Lactobacillus plantarum (L. plantarum) on immune function. A randomized, open-label, placebo-controlled study was conducted on 200 nondiabetic subjects. Over a twelve-week period, the test group consumed dairy yogurt containing probiotics each day, whereas the placebo group consumed milk. Natural killer (NK) cell activity, interleukin (IL)-12 and immunoglobulin (Ig) G1 levels were significantly increased in the test group at twelve weeks compared to baseline. Additionally, the test group had significantly greater increases in serum NK cell activity and interferon (IFN)-gamma and IgG1 than placebo group. Daily consumption of dairy yogurt containing L. paracasei, B. lactis and heat-treated L. plantarum could be an effective option to improve immune function by enhancing NK cell function and IFN-gamma concentration (ClinicalTrials.gov: NCT03051425). PMID- 28561761 TI - A Review of Issues Related to Data Acquisition and Analysis in EEG/MEG Studies. AB - Electroencephalography (EEG) and magnetoencephalography (MEG) are non-invasive electrophysiological methods, which record electric potentials and magnetic fields due to electric currents in synchronously-active neurons. With MEG being more sensitive to neural activity from tangential currents and EEG being able to detect both radial and tangential sources, the two methods are complementary. Over the years, neurophysiological studies have changed considerably: high density recordings are becoming de rigueur; there is interest in both spontaneous and evoked activity; and sophisticated artifact detection and removal methods are available. Improved head models for source estimation have also increased the precision of the current estimates, particularly for EEG and combined EEG/MEG. Because of their complementarity, more investigators are beginning to perform simultaneous EEG/MEG studies to gain more complete information about neural activity. Given the increase in methodological complexity in EEG/MEG, it is important to gather data that are of high quality and that are as artifact free as possible. Here, we discuss some issues in data acquisition and analysis of EEG and MEG data. Practical considerations for different types of EEG and MEG studies are also discussed. PMID- 28561765 TI - Improving the Power Conversion Efficiency of Carbon Quantum Dot-Sensitized Solar Cells by Growing the Dots on a TiO2 Photoanode In Situ. AB - Dye-sensitized solar cells (DSSCs) are highly promising since they can potentially solve global energy issues. The development of new photosensitizers is the key to fully realizing perspectives proposed to DSSCs. Being cheap and nontoxic, carbon quantum dots (CQDs) have emerged as attractive candidates for this purpose. However, current methodologies to build up CQD-sensitized solar cells (CQDSCs) result in an imperfect apparatus with extremely low power conversion efficiencies (PCEs). Herein, we present a simple strategy of growing carbon quantum dots (CQDs) onto TiO2 surfaces in situ. The CQDs/TiO2 hybridized photoanode was then used to construct solar cell with an improved PCE of 0.87%, which is higher than all of the reported CQDSCs adopting the simple post adsorption method. This result indicates that an in situ growing strategy has great advantages in terms of optimizing the performance of CQDSCs. In addition, we have also found that the mechanisms dominating the performance of CQDSCs are different from those behind the solar cells using inorganic semiconductor quantum dots (ISQDs) as the photosensitizers, which re-confirms the conclusion that the characteristics of CQDs differ from those of ISQDs. PMID- 28561764 TI - Five New Limonoids from Peels of Satsuma Orange (Citrus reticulata). AB - Five new: 21,23-dihydro-21-hydroxy-23-oxonomilin (1), 21,23-dihydro-23-methoxy-21 oxonomilin (2), 21,23-dihydro-21-hydroxy-23-oxonomilinic acid methyl ester (3), 21,23-dihydro-23-methoxy-21-oxolimonin (4), and 21,23-dihydro-21-oxolimonin (5), and seven known limonoids were isolated from peels of satsuma orange (Citrus reticulata). The isolated compounds were evaluated for their inhibitory effects on macrophage activation by an inhibitory assay of nitric oxide (NO) production. Among them, compound (2) exhibited NO inhibitory activity without cytotoxicity. PMID- 28561766 TI - Genotypic Variation in Wheat Flour Lysophospholipids. AB - Lysophospholipids (LPLs) are the most abundant polar lipids in wheat endosperm and naturally complex with amylose, affecting starch physicochemical properties. We analyzed LPLs in wheat flour from 58 cultivars which differ by grain hardness using liquid chromatography mass spectrometry (LCMS). There were significant differences in LPL content between cultivars, demonstrating that genotype rather than environment contributes most to the total variance in wheat endosperm LPLs. Polar lipids such as LPLs may play a role in grain hardness through their interaction with puroindoline proteins, however, no strong correlation between kernel hardness and LPLs was detected. This may reflect the location of LPLs within the starch granule as opposed to the puroindoline proteins outside starch granules. LPLs may have an indirect relationship with kernel hardness as they could share the same origin as polar lipids that interact with puroindoline on the starch granule surface. PMID- 28561767 TI - Health, Well-Being and Energy Poverty in Europe: A Comparative Study of 32 European Countries. AB - Despite growing pan-European interest in and awareness of the wide-ranging health and well-being impacts of energy poverty-which is characterised by an inability to secure adequate levels of energy services in the home-the knowledge base is largely British-centric and dominated by single-country studies. In response, this paper investigates the relationship between energy poverty, health and well being across 32 European countries, using 2012 data from the European Quality of Life Survey. We find an uneven concentration of energy poverty, poor health, and poor well-being across Europe, with Eastern and Central Europe worst affected. At the intersection of energy poverty and health, there is a higher incidence of poor health (both physical and mental) amongst the energy poor populations of most countries, compared to non-energy poor households. Interestingly, we find the largest disparities in health and well-being levels between energy poor and non-energy poor households occur within relatively equal societies, such as Sweden and Slovenia. As well as the unique challenges brought about by rapidly changing energy landscapes in these countries, we also suggest the relative deprivation theory and processes of social comparison hold some value in explaining these findings. PMID- 28561769 TI - Water Consumption in European Children: Associations with Intake of Fruit Juices, Soft Drinks and Related Parenting Practices. AB - Background: High intake of fruit juices and soft drinks contributes to excessive weight gain and obesity in children. Furthermore, parenting practices play an important role in the development of children's dietary habits. The way parents play this role in the development of their children's choices of beverages is still unclear. Objectives: To study the associations: (1) of both fruit juices and soft drinks consumption with water consumption of children and (2) The associations between parenting practices towards fruit juices and soft drinks and water consumption of children. Design: Cross-sectional data from 6 to 8 year old children from seven European communities (n = 1187) were collected. Associations among fruit juices, soft drinks, the respective parenting practices and the child's water consumption were assessed by parental questionnaires. Results: The consumption of water was inversely associated with that of soft drinks but not with the consumption of fruit juices. The child's water intake was favorably influenced when stricter parenting practices towards soft drinks were adopted (e.g., less parental allowance, low home availability and high parental self efficacy in managing intake). There was less influence observed of parenting practices towards fruit juices. Fruit juices were consumed more often than soft drinks. Conclusions: Low consumption of soft drinks-and not of fruit juices-was associated with high water consumption in children in the current study. Moreover, parenting practices towards both fruit juices and soft drinks were associated with the water intake of the children, irrespective of their socio economic status. PMID- 28561768 TI - Ontogeny of Sex-Related Differences in Foetal Developmental Features, Lipid Availability and Fatty Acid Composition. AB - Sex-related differences in lipid availability and fatty acid composition during swine foetal development were investigated. Plasma cholesterol and triglyceride concentrations in the mother were strongly related to the adequacy or inadequacy of foetal development and concomitant activation of protective growth in some organs (brain, heart, liver and spleen). Cholesterol and triglyceride availability was similar in male and female offspring, but female foetuses showed evidence of higher placental transfer of essential fatty acids and synthesis of non-essential fatty acids in muscle and liver. These sex-related differences affected primarily the neutral lipid fraction (triglycerides), which may lead to sex-related postnatal differences in energy partitioning. These results illustrate the strong influence of the maternal lipid profile on foetal development and homeorhesis, and they confirm and extend previous reports that female offspring show better adaptive responses to maternal malnutrition than male offspring. These findings may help guide dietary interventions to ensure adequate fatty acid availability for postnatal development. PMID- 28561770 TI - Identification of Differentially Expressed Micrornas Associate with Glucose Metabolism in Different Organs of Blunt Snout Bream (Megalobrama amblycephala). AB - Blunt snout bream (Megalobrama amblycephala) is a widely favored herbivorous fish species and is a frequentlyused fish model for studying the metabolism physiology. This study aimed to provide a comprehensive illustration of the mechanisms of a high-starch diet (HSD) induced lipid metabolic disorder by identifying microRNAs (miRNAs) controlled pathways in glucose and lipid metabolism in fish using high-throughput sequencing technologies. Small RNA libraries derived from intestines, livers, and brains of HSD and normal-starch diet (NSD) treated M. amblycephala were sequenced and 79, 124 and 77 differentially expressed miRNAs (DEMs) in intestines, livers, and brains of HSD treated fish were identified, respectively. Bioinformatics analyses showed that these DEMs targeted hundreds of predicted genes were enriched into metabolic pathways and biosynthetic processes, including peroxisome proliferator-activated receptor (PPAR), glycolysis/gluconeogenesis, and insulin signaling pathway. These analyses confirmed that miRNAs play crucial roles in glucose and lipid metabolism related to high wheat starch treatment. These results provide information on further investigation of a DEM-related mechanism dysregulated by a high carbohydrate diet. PMID- 28561771 TI - Characterization and Genome Analysis of a Nicotine and Nicotinic Acid-Degrading Strain Pseudomonas putida JQ581 Isolated from Marine. AB - The presence of nicotine and nicotinic acid (NA) in the marine environment has caused great harm to human health and the natural environment. Therefore, there is an urgent need to use efficient and economical methods to remove such pollutants from the environment. In this study, a nicotine and NA-degrading bacterium-strain JQ581-was isolated from sediment from the East China Sea and identified as a member of Pseudomonas putida based on morphology, physio biochemical characteristics, and 16S rDNA gene analysis. The relationship between growth and nicotine/NA degradation suggested that strain JQ581 was a good candidate for applications in the bioaugmentation treatment of nicotine/NA contamination. The degradation intermediates of nicotine are pseudooxynicotine (PN) and 3-succinoyl-pyridine (SP) based on UV, high performance liquid chromatography, and liquid chromatography-mass spectrometry analyses. However, 6 hydroxy-3-succinoyl-pyridine (HSP) was not detected. NA degradation intermediates were identified as 6-hydroxynicotinic acid (6HNA). The whole genome of strain JQ581 was sequenced and analyzed. Genome sequence analysis revealed that strain JQ581 contained the gene clusters for nicotine and NA degradation. This is the first report where a marine-derived Pseudomonas strain had the ability to degrade nicotine and NA simultaneously. PMID- 28561772 TI - Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin. AB - Searching of new enantiomerically pure chiral derivatives of xanthones (CDXs) with potential pharmacological properties, particularly those with anti inflammatory activity, has remained an area of interest of our group. Herein, we describe in silico studies and in vitro inhibitory assays of cyclooxygenases (COX 1 and COX-2) for different enantiomeric pairs of CDXs. The evaluation of the inhibitory activities was performed by using the COX Inhibitor Screening Assay Kit. Docking simulations between the small molecules (CDXs; known ligands and decoys) and the enzyme targets were undertaken with AutoDock Vina embedded in PyRx-Virtual Screening Tool software. All the CDXs evaluated exhibited COX-1 and COX-2 inhibition potential as predicted. Considering that the (S)-(-)-enantiomer of the nonsteroidal anti-inflammatory drug ketoprofen preferentially binds to albumin, resulting in lower free plasma concentration than (R)-(+)-enantiomer, protein binding affinity for CDXs was also evaluated by spectrofluorimetry as well as in in silico. For some CDXs enantioselectivity was observed. PMID- 28561775 TI - Stability Study of Sunscreens with Free and Encapsulated UV Filters Contained in Plastic Packaging. AB - Sunscreens play a fundamental role in skin cancer prevention and in protection against photo-aging. UV filters are often photo-unstable, especially in relation to their vehicles and, being lipophilic substances, they are able to interact with plastic packaging. Finally, UV filter stability can be significantly affected by the routine use of the product at high temperatures. This work aims to study the stability of sunscreen formulations in polyethylene packaging. Butyl methoxydibenzoylmethane and octocrylene, both in a free form and as encapsulated filters were chosen as UV filters. Stability evaluations were performed both in the packaging and on the formulations. Moreover, a further two non-destructive techniques, near-infrared (NIR) spectroscopy and a multiple light scattering technique, were also used to evaluate the stability of the formulation. Results demonstrated clearly that all of the pack underwent significant changes in its elastic/plastic behavior and in external color after solar irradiation. From the evaluation of the extractable profile of untreated and treated packaging material an absorption of 2-phenoxyethanol and octocrylene were shown. In conclusion, the results highlighted clearly that a reduction of the UV filter in the formulation packed in high-density polyethylene/low-density polyethylene (HDPE/LDPE) material can occur over time, reducing the protective effect of the product when applied to the skin. PMID- 28561774 TI - Salt Sensitive Tet-Off-Like Systems to Knockdown Primordial Germ Cell Genes for Repressible Transgenic Sterilization in Channel Catfish, Ictalurus punctatus. AB - Repressible knockdown approaches were investigated for transgenic sterilization in channel catfish, Ictalurus punctatus. Two primordial germ cell (PGC) marker genes, nanos and dead end, were targeted for knockdown, and an off-target gene, vasa, was monitored. Two potentially salt sensitive repressible promoters, zebrafish adenylosuccinate synthase 2 (ADSS) and zebrafish racemase (Rm), were each coupled with four knockdown strategies: ds-sh RNA targeting the 5' end (N1) or 3' end (N2) of channel catfish nanos, full-length cDNA sequence of channel catfish nanos for overexpression (cDNA) and ds-sh RNA targeting channel catfish dead end (DND). Each construct had an untreated group and treated group with sodium chloride as the repressor compound. Spawning rates of full-sibling P1 fish exposed or not exposed to the constructs as treated and untreated embryos were 93% and 59%, respectively, indicating potential sterilization of fish and repression of the constructs. Although the mRNA expression data of PGC marker genes were inconsistent in P1 fish, most F1 individuals were able to downregulate the target genes in untreated groups and repress the knockdown process in treated groups. The results indicate that repressible transgenic sterilization is feasible for reproductive control of fish, but more data from F2 or F3 are needed for evaluation. PMID- 28561773 TI - Can Co-Activation of Nrf2 and Neurotrophic Signaling Pathway Slow Alzheimer's Disease? AB - Alzheimer's disease (AD) is a multifaceted disease that is hard to treat by single-modal treatment. AD starts with amyloid peptides, mitochondrial dysfunction, and oxidative stress and later is accompanied with chronic endoplasmic reticulum (ER) stress and autophagy dysfunction, resulting in more complicated pathogenesis. Currently, few treatments can modify the complicated pathogenic progress of AD. Compared to the treatment with exogenous antioxidants, the activation of global antioxidant defense system via Nrf2 looks more promising in attenuating oxidative stress in AD brains. Accompanying the activation of the Nrf2-mediated antioxidant defense system that reduce the AD-causative factor, oxidative stress, it is also necessary to activate the neurotrophic signaling pathway that replaces damaged organelles and molecules with new ones. Thus, the dual actions to activate both the Nrf2 antioxidant system and neurotrophic signaling pathway are expected to provide a better strategy to modify AD pathogenesis. Here, we review the current understanding of AD pathogenesis and neuronal defense systems and discuss a possible way to co-activate the Nrf2 antioxidant system and neurotrophic signaling pathway with the hope of helping to find a better strategy to slow AD. PMID- 28561777 TI - Effect of Selected Mercapto Flavor Compounds on Acrylamide Elimination in a Model System. AB - The effect of four mercapto flavor compounds (1,2-ethanedithiol, 1-butanethiol, 2 methyl-3-furanthiol, and 2-furanmethanethiol) on acrylamide elimination were investigated in model systems. The obtained results showed that mercaptans assayed were effective in elimination arylamide in a model system. Their reactivities for decreasing acrylamide content depended on mercaptan's molecular structure and acrylamide disappearance decreased in the following order: 1,2 ethanedithiol > 2-methyl-3-furanthiol > 1-butanethiol > 2-furanmethanethiol. Mercaptans were added to acrylamide to produce the corresponding 3-(alkylthio) propionamides. This reaction was irreversible and only trace amounts of acrylamide were formed by thermal heating of 3-(alkylthio) propanamide. Although a large amount disappeared, only part of the acrylamide conversed into 3 (alkylthio) propionamides. All of these results constitute a fundamental proof of the complexity of the reactions involved in the removal of free acrylamide in foods. This implies mercapto flavor/aroma may directly or indirectly reduce the level of acrylamide in food processing. This study could be regarded as a pioneer contribution on acrylamide elimination in a model system by the addition of mercapto flavor compounds. PMID- 28561779 TI - Transcriptomics, NF-kappaB Pathway, and Their Potential Spaceflight-Related Health Consequences. AB - In space, living organisms are exposed to multiple stress factors including microgravity and space radiation. For humans, these harmful environmental factors have been known to cause negative health impacts such as bone loss and immune dysfunction. Understanding the mechanisms by which spaceflight impacts human health at the molecular level is critical not only for accurately assessing the risks associated with spaceflight, but also for developing effective countermeasures. Over the years, a number of studies have been conducted under real or simulated space conditions. RNA and protein levels in cellular and animal models have been targeted in order to identify pathways affected by spaceflight. Of the many pathways responsive to the space environment, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) network appears to commonly be affected across many different cell types under the true or simulated spaceflight conditions. NF-kappaB is of particular interest, as it is associated with many of the spaceflight-related health consequences. This review intends to summarize the transcriptomics studies that identified NF-kappaB as a responsive pathway to ground-based simulated microgravity or the true spaceflight condition. These studies were carried out using either human cell or animal models. In addition, the review summarizes the studies that focused specifically on NF kappaB pathway in specific cell types or organ tissues as related to the known spaceflight-related health risks including immune dysfunction, bone loss, muscle atrophy, central nerve system (CNS) dysfunction, and risks associated with space radiation. Whether the NF-kappaB pathway is activated or inhibited in space is dependent on the cell type, but the potential health impact appeared to be always negative. It is argued that more studies on NF-kappaB should be conducted to fully understand this particular pathway for the benefit of crew health in space. PMID- 28561780 TI - Synthesis and Evaluation of Novel 2-Pyrrolidone-Fused (2-Oxoindolin-3 ylidene)methylpyrrole Derivatives as Potential Multi-Target Tyrosine Kinase Receptor Inhibitors. AB - Signaling pathways of VEGFs and PDGFs are crucial in tumor angiogenesis, which is essential in solid tumor progression and metastasis. This study reports our strategy for designing and synthesizing a series of novel 2-pyrrolidone-fused (2 oxoindolin-3-ylidene)methylpyrrole derivatives as potential multi-target tyrosine kinase receptor inhibitors. The target compounds were obtained by condensation of 5-substituted oxindoles with N-substituted 2-pyrrolidone aldehyde 7 in satisfactory yields. Of these, 11 and 12 had the highest potency and, compared to sunitinib, showed: (1) significant increase in anti-proliferation of various cancer cells with a favorable selective index (SI); (2) higher inhibitory potency against both VEGFR-2 and PDGFRbeta. The molecular modeling results showed that, in terms of VEGFR-2 binding, the synthesized products had a similar binding mode to sunitinib but with tighter interaction. PMID- 28561776 TI - Qualitative Versus Quantitative Mammographic Breast Density Assessment: Applications for the US and Abroad. AB - Mammographic breast density (MBD) has been proven to be an important risk factor for breast cancer and an important determinant of mammographic screening performance. The measurement of density has changed dramatically since its inception. Initial qualitative measurement methods have been found to have limited consistency between readers, and in regards to breast cancer risk. Following the introduction of full-field digital mammography, more sophisticated measurement methodology is now possible. Automated computer-based density measurements can provide consistent, reproducible, and objective results. In this review paper, we describe various methods currently available to assess MBD, and provide a discussion on the clinical utility of such methods for breast cancer screening. PMID- 28561781 TI - Comparison of the Peripheral Reactive Hyperemia Index with Myocardial Perfusion Reserve by 82Rb PET/CT in HIV-Infected Patients. AB - After the introduction of antiretroviral therapy (ART) the life expectancy of patients infected with human immunodeficiency virus (HIV) is now approaching that of the general population and the importance of non-AIDS co-morbidities is increasing. Specifically, the risk of coronary artery disease (CAD) seems to be higher in HIV-infected patients and an accurate risk prediction of CAD is of high importance for optimal long term treatment. In this study, we assessed the correlation of the endoPAT, which is an office-based CVD screening tool with the myocardial perfusion reserve by 82-rubidium PET/CT. We measured the reactive hyperemia index, which is a measure of the endothelial responsiveness, by the use of an endoPAT device (Itamar Medical, Caesarea, Israel) in 48 ART treated HIV infected patients with high CD 4 cell counts and viral suppression (HIV-RNA < 20 copies/mL), who had previously undergone measurement of the myocardial perfusion reserve by 82-rubidium PET/CT for study purposes. We found an inverse correlation between the reactive hyperemia index and the myocardial perfusion reserve which most likely indicates different vascular physiology. This study did not find evidence to suggest the immediate implementation of the reactive hyperemia index as a screening tool for early coronary artery disease in well-treated HIV infected patients pending further validation in larger prospective studies. PMID- 28561782 TI - Some Physical Properties of Protein Moiety of Alkali-Extracted Tea Polysaccharide Conjugates Were Shielded by Its Polysaccharide. AB - Polysaccharide conjugates were alkali-extracted from green tea (TPC-A). Although it contained 11.80% covalently binding proteins, TPC-A could not bind to the Coomassie Brilliant Blue dyes G250 and R250. TPC-A had no expected characteristic absorption peak of protein in the UV-vis spectrum scanning in the range of 200 700 nm. The UV-vis wavelength of 280 nm was not suitable to detect the presence of the protein portion of TPC-A. The zeta potential of TPC-A merely presented the negative charge properties of polysaccharides instead of the acid-base property of its protein section across the entire pH range. Furthermore, TPC-A was more stable when the pH of solution exceeded 4.0. In addition, no precipitation or haze was generated in the TPC-A/(-)-epigallocatechin gallate (EGCG) mixtures during 12 h storage. TPC-A has emulsifying activity, which indicated that its protein moiety formed hydrophobic groups. Thus, it was proposed that some physical properties of TPC-A protein were shielded by its olysaccharide, since the protein moiety was wrapped by its polysaccharide chains. PMID- 28561783 TI - Electromagnetic Field Assessment as a Smart City Service: The SmartSantander Use Case. AB - Despite the increasing presence of wireless communications in everyday life, there exist some voices raising concerns about their adverse effects. One particularly relevant example is the potential impact of the electromagnetic field they induce on the population's health. Traditionally, very specialized methods and devices (dosimetry) have been used to assess the strength of the E field, with the main objective of checking whether it respects the corresponding regulations. In this paper, we propose a complete novel approach, which exploits the functionality leveraged by a smart city platform. We deploy a number of measuring probes, integrated as sensing devices, to carry out a characterization embracing large areas, as well as long periods of time. This unique platform has been active for more than one year, generating a vast amount of information. We process such information, and the obtained results validate the whole methodology. In addition, we discuss the variation of the E-field caused by cellular networks, considering additional information, such as usage statistics. Finally, we establish the exposure that can be attributed to the base stations within the scenario under analysis. PMID- 28561778 TI - EZH2 in Cancer Progression and Potential Application in Cancer Therapy: A Friend or Foe? AB - Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, catalyzes tri methylation of histone H3 at Lys 27 (H3K27me3) to regulate gene expression through epigenetic machinery. EZH2 functions as a double-facet molecule in regulation of gene expression via repression or activation mechanisms, depending on the different cellular contexts. EZH2 interacts with both histone and non histone proteins to modulate diverse physiological functions including cancer progression and malignancy. In this review article, we focused on the updated information regarding microRNAs (miRNAs) and long non coding RNAs (lncRNAs) in regulation of EZH2, the oncogenic and tumor suppressive roles of EZH2 in cancer progression and malignancy, as well as current pre-clinical and clinical trials of EZH2 inhibitors. PMID- 28561784 TI - Metallic Glass/PVDF Magnetoelectric Laminates for Resonant Sensors and Actuators: A Review. AB - Among magnetoelectric (ME) heterostructures, ME laminates of the type Metglas like/PVDF (magnetostrictive+piezoelectric constituents) have shown the highest induced ME voltages, usually detected at the magnetoelastic resonance of the magnetostrictive constituent. This ME coupling happens because of the high cross correlation coupling between magnetostrictive and piezoelectric material, and is usually associated with a promising application scenario for sensors or actuators. In this work we detail the basis of the operation of such devices, as well as some arising questions (as size effects) concerning their best performance. Also, some examples of their use as very sensitive magnetic fields sensors or innovative energy harvesting devices will be reviewed. At the end, the challenges, future perspectives and technical difficulties that will determine the success of ME composites for sensor applications are discussed. PMID- 28561786 TI - Distributed Piezoelectric Sensor System for Damage Identification in Structures Subjected to Temperature Changes. AB - Structural health monitoring (SHM) is a very important area in a wide spectrum of fields and engineering applications. With an SHM system, it is possible to reduce the number of non-necessary inspection tasks, the associated risk and the maintenance cost in a wide range of structures during their lifetime. One of the problems in the detection and classification of damage are the constant changes in the operational and environmental conditions. Small changes of these conditions can be considered by the SHM system as damage even though the structure is healthy. Several applications for monitoring of structures have been developed and reported in the literature, and some of them include temperature compensation techniques. In real applications, however, digital processing technologies have proven their value by: (i) offering a very interesting way to acquire information from the structures under test; (ii) applying methodologies to provide a robust analysis; and (iii) performing a damage identification with a practical useful accuracy. This work shows the implementation of an SHM system based on the use of piezoelectric (PZT) sensors for inspecting a structure subjected to temperature changes. The methodology includes the use of multivariate analysis, sensor data fusion and machine learning approaches. The methodology is tested and evaluated with aluminum and composite structures that are subjected to temperature variations. Results show that damage can be detected and classified in all of the cases in spite of the temperature changes. PMID- 28561785 TI - Bioactive Natural Product and Superacid Chemistry for Lead Compound Identification: A Case Study of Selective hCA III and L-Type Ca2+ Current Inhibitors for Hypotensive Agent Discovery. AB - Dodoneine (Ddn) is one of the active compounds identified from Agelanthusdodoneifolius, which is a medicinal plant used in African pharmacopeia and traditional medicine for the treatment of hypertension. In the context of a scientific program aiming at discovering new hypotensive agents through the original combination of natural product discovery and superacid chemistry diversification, and after evidencing dodoneine's vasorelaxant effect on rat aorta, superacid modifications allowed us to generate original analogues which showed selective human carbonic anhydrase III (hCA III) and L-type Ca2+ current inhibition. These derivatives can now be considered as new lead compounds for vasorelaxant therapeutics targeting these two proteins. PMID- 28561787 TI - Production of Recombinant Antimicrobial Polymeric Protein Beta Casein-E 50-52 and Its Antimicrobial Synergistic Effects Assessment with Thymol. AB - Accelerating emergence of antimicrobial resistance among food pathogens and consumers' increasing demands for preservative-free foods are two contemporary challenging aspects within the food industry. Antimicrobial packaging and the use of natural preservatives are promising solutions. In the present study, we used beta-casein-one of the primary self-assembly proteins in milk with a high polymeric film production capability-as a fusion partner for the recombinant expression of E 50-52 antimicrobial peptide in Escherichia coli. The pET21a-BCN-E 50-52 construct was transformed to E. coli BL21 (DE3), and protein expression was induced under optimized conditions. Purified protein obtained from nickel affinity chromatography was refolded under optimized dialysis circumstances and concentrated to 1600 ug/mL fusion protein by ultrafiltration. Antimicrobial activities of recombinant BCN-E 50-52 performed against Escherichia coli, Salmonella typhimurium, Listeria monocytogenes, Staphylococcus aureus, Aspergillus flavus, and Candida albicans. Subsequently, the synergistic effects of BCN-E 50-52 and thymol were assayed. Results of checkerboard tests showed strong synergistic activity between two compounds. Time-kill and growth kinetic studies indicated a sharp reduction of cell viability during the first period of exposure, and SEM (scanning electron microscope) results validated the severe destructive effects of BCN E 50-52 and thymol in combination on bacterial cells. PMID- 28561788 TI - Comprehensive Characterization for Ginsenosides Biosynthesis in Ginseng Root by Integration Analysis of Chemical and Transcriptome. AB - Herbgenomics provides a global platform to explore the genetics and biology of herbs on the genome level. Panax ginseng C.A. Meyer is an important medicinal plant with numerous pharmaceutical effects. Previous reports mainly discussed the transcriptome of ginseng at the organ level. However, based on mass spectrometry imaging analyses, the ginsenosides varied among different tissues. In this work, ginseng root was separated into three tissues-periderm, cortex and stele-each for five duplicates. The chemical analysis and transcriptome analysis were conducted simultaneously. Gene-encoding enzymes involved in ginsenosides biosynthesis and modification were studied based on gene and molecule data. Eight widely-used ginsenosides were distributed unevenly in ginseng roots. A total of 182,881 unigenes were assembled with an N50 contig size of 1374 bp. About 21,000 of these unigenes were positively correlated with the content of ginsenosides. Additionally, we identified 192 transcripts encoding enzymes involved in two triterpenoid biosynthesis pathways and 290 transcripts encoding UDP glycosyltransferases (UGTs). Of these UGTs, 195 UGTs (67.2%) were more highly expressed in the periderm, and that seven UGTs and one UGT were specifically expressed in the periderm and stele, respectively. This genetic resource will help to improve the interpretation on complex mechanisms of ginsenosides biosynthesis, accumulation, and transportation. PMID- 28561789 TI - Careful with That Axe, Gene, Genome Perturbation after a PEG-Mediated Protoplast Transformation in Fusarium verticillioides. AB - Fusarium verticillioides causes ear rot disease in maize and its contamination with fumonisins, mycotoxins harmful for humans and livestock. Lipids, and their oxidized forms, may drive the fate of this disease. In a previous study, we have explored the role of oxylipins in this interaction by deleting by standard transformation procedures a linoleate diol synthase-coding gene, lds1, in F. verticillioides. A profound phenotypic diversity in the mutants generated has prompted us to investigate more deeply the whole genome of two lds1-deleted strains. Bioinformatics analyses pinpoint significant differences in the genome sequences emerged between the wild type and the lds1-mutants further than those trivially attributable to the deletion of the lds1 locus, such as single nucleotide polymorphisms, small deletion/insertion polymorphisms and structural variations. Results suggest that the effect of a (theoretically) punctual transformation event might have enhanced the natural mechanisms of genomic variability and that transformation practices, commonly used in the reverse genetics of fungi, may potentially be responsible for unexpected, stochastic and henceforth off-target rearrangements throughout the genome. PMID- 28561790 TI - Himatanthus drasticus Leaves: Chemical Characterization and Evaluation of Their Antimicrobial, Antibiofilm, Antiproliferative Activities. AB - Plant-derived products have played a fundamental role in the development of new therapeutic agents. This study aimed to analyze antimicrobial, antibiofilm, cytotoxicity and antiproliferative potentials of the extract and fractions from leaves of Himatanthusdrasticus, a plant from the Apocynaceae family. After harvesting, H. drasticus leaves were macerated and a hydroalcoholic extract (HDHE) and fractions were prepared. Antimicrobial tests, such as agar-diffusion, Minimum Inhibitory Concentration (MIC) and Minimal Bactericidal Concentration (MBC) were carried out against several bacterial species. Staphylococcus aureus, Pseudomonas aeruginosa, Listeria monocytogenes and Klebsiella pneumoniae were inhibited by at least one extract or fraction in the agar-diffusion assay (inhibition halos from 12 mm to 30 mm). However, the lowest MIC value was found for HDHE against K. pneumoniae. In addition, HDHE and its fractions were able to inhibit biofilm formation at sub-inhibitory concentrations (780 ug/mL and 1.56 ug/mL). As the best activities were found for HDHE, we selected it for further assays. HDHE was able to increase ciprofloxacin (CIP) activity against K. pneumoniae, displaying synergistic (initial concentration CIP + HDHE: 2 ug/mL + 600 ug/mL and 2.5 ug/mL + 500 ug/mL) and additive effects (CIP + HDHE: 3 ug/mL + 400 ug/mL). This action seems to be associated with the alteration in bacterial membrane permeability induced by HDHE (as seen by propidium iodide labeling). This extract was non-toxic for red blood cell or human peripheral blood mononuclear cells (PBMCs). Additionally, it inhibited the lipopolysaccharide induced proliferation of PBMCs. The following compounds were detected in HDHE using HPLC-ESI-MS analysis: plumieride, plumericin or isoplumericin, rutin, quercetin and derivatives, and chlorogenic acid. Based on these results we suggest that compounds from H. drasticus have antimicrobial and antibiofilm activities against K. pneumoniae and display low cytotoxicity and anti proliferative action in PBMC stimulated with lipopolysaccharide. PMID- 28561791 TI - Epigenetic Control of Human Endogenous Retrovirus Expression: Focus on Regulation of Long-Terminal Repeats (LTRs). AB - Transposable elements, including endogenous retroviruses (ERVs), comprise almost 45% of the human genome. This could represent a significant pathogenic burden but it is becoming more evident that many of these elements have a positive contribution to make to normal human physiology. In particular, the contributions of human ERVs (HERVs) to gene regulation and the expression of noncoding RNAs has been revealed with the help of new and emerging genomic technologies. HERVs have the common provirus structure of coding open reading frames (ORFs) flanked by two long-terminal repeats (LTRs). However, over the course of evolution and as a consequence of host defence mechanisms, most of the sequences contain INDELs, mutations or have been reduced to single LTRs by recombination. These INDELs and mutations reduce HERV activity. However, there is a trade-off for the host cells in that HERVs can provide beneficial sources of genetic variation but with this benefit comes the risk of pathogenic activity and spread within the genome. For example, the LTRs are of critical importance as they contain promoter sequences and can regulate not only HERV expression but that of human genes. This is true even when the LTRs are located in intergenic regions or are in antisense orientation to the rest of the gene. Uncontrolled, this promoter activity could disrupt normal gene expression or transcript processing (e.g., splicing). Thus, control of HERVs and particularly their LTRs is essential for the cell to manage these elements and this control is achieved at multiple levels, including epigenetic regulations that permit HERV expression in the germline but silence it in most somatic tissues. We will discuss some of the common epigenetic mechanisms and how they affect HERV expression, providing detailed discussions of HERVs in stem cell, placenta and cancer biology. PMID- 28561792 TI - Short-Term Associations between Air Pollution Concentrations and Respiratory Health-Comparing Primary Health Care Visits, Hospital Admissions, and Emergency Department Visits in a Multi-Municipality Study. AB - Acute effects of air pollution on respiratory health have traditionally been investigated with data on inpatient admissions, emergency room visits, and mortality. In this study, we aim to describe the total acute effects of air pollution on health care use for respiratory symptoms (ICD10-J00-J99). This will be done by investigating primary health care (PHC) visits, inpatient admissions, and emergency room visits together in five municipalities in southern Sweden, using a case-crossover design. Between 2005 and 2010, there were 81,019 visits to primary health care, 38,217 emergency room visits, and 25,271 inpatient admissions for respiratory symptoms in the study area. There was a 1.85% increase (95% CI: 0.52 to 3.20) in the number of primary health care visits associated with a 10 ug/m3 increase in nitrogen dioxide (NO2) levels in Malmo, but not in the other municipalities. Air pollution levels were generally not associated with emergency room visits or inpatient admissions, with one exception (in Helsingborg there was a 2.52% increase in emergency room visits for respiratory symptoms associated with a 10 ug/m3 increase in PM10). In conclusion, the results give weak support for short-term effects of air pollution on health care use associated with respiratory health symptoms in the study area. PMID- 28561793 TI - Role of Free Radicals and Biotransformation in Trichloronitrobenzene-Induced Nephrotoxicity In Vitro. AB - This study determined the comparative nephrotoxic potential of four trichloronitrobenzenes (TCNBs) (2,3,4-; 2,4,5-; 2,4,6-; and 3,4,5-TCNB) and explored the effects of antioxidants and biotransformation inhibitors on TCNB induced cytotoxicity in isolated renal cortical cells (IRCC) from male Fischer 344 rats. IRCC were incubated with a TCNB up to 1.0 mM for 15-120 min. Pretreatment with an antioxidant or cytochrome P450 (CYP), flavin monooxygenase (FMO), or peroxidase inhibitor was used in some experiments. Among the four TCNBs, the order of decreasing nephrotoxic potential was approximately 3,4,5- > 2,4,6- > 2,3,4- > 2,4,5-TCNB. The four TCNBs exhibited a similar profile of attenuation of cytotoxicity in response to antioxidant pretreatments. 2,3,4- and 3,4,5-TCNB cytotoxicity was attenuated by most of the biotransformation inhibitors tested, 2,4,5-TCNB cytotoxicity was only inhibited by isoniazid (CYP 2E1 inhibitor), and 2,4,6-TCNB-induced cytotoxicity was inhibited by one CYP inhibitor, one FMO inhibitor, and one peroxidase inhibitor. All of the CYP specific inhibitors tested offered some attenuation of 3,4,5-TCNB cytotoxicity. These results indicate that 3,4,5-TCNB is the most potent nephrotoxicant, free radicals play a role in the TCNB cytotoxicity, and the role of biotransformation in TCNB nephrotoxicity in vitro is variable and dependent on the position of the chloro groups. PMID- 28561794 TI - Antibiotic Resistance and Virulence Phenotypes of Recent Bacterial Strains Isolated from Urinary Tract Infections in Elderly Patients with Prostatic Disease. AB - Acute bacterial prostatitis is one of the frequent complications of urinary tract infection (UTI). From the approximately 10% of men having prostatitis, 7% experience a bacterial prostatitis. The purpose of this study was to investigate the prevalence of uropathogens associated with UTIs in older patients with benign prostatic hyperplasia and to assess their susceptibility to commonly prescribed antibiotics as well as the relationships between microbial virulence and resistance features. Uropathogenic Escherichia coli was found to be the most frequent bacterial strain isolated from patients with benign prostatic hyperplasia, followed by Enterococcus spp., Enterobacter spp., Klebsiella spp., Proteus spp., Pseudomonas aeruginosa, and Serratia marcescens. Increased resistance rates to tetracyclines, quinolones, and sulfonamides were registered. Besides their resistance profiles, the uropathogenic isolates produced various virulence factors with possible implications in the pathogenesis process. The great majority of the uropathogenic isolates revealed a high capacity to adhere to HEp-2 cell monolayer in vitro, mostly exhibiting a localized adherence pattern. Differences in the repertoire of soluble virulence factors that can affect bacterial growth and persistence within the urinary tract were detected. The Gram-negative strains produced pore-forming toxins-such as hemolysins, lecithinases, and lipases-proteases, siderophore-like molecules resulted from the esculin hydrolysis and amylases, while Enterococcus sp. strains were positive only for caseinase and esculin hydrolase. Our study demonstrates that necessity of investigating the etiology and local resistance patterns of uropathogenic organisms, which is crucial for determining appropriate empirical antibiotic treatment in elderly patients with UTI, while establishing correlations between resistance and virulence profiles could provide valuable input about the clinical evolution and recurrence rates of UTI. PMID- 28561795 TI - Evaluation of Low-Cost Mitigation Measures Implemented to Improve Air Quality in Nursery and Primary Schools. AB - Indoor air pollution mitigation measures are highly important due to the associated health impacts, especially on children, a risk group that spends significant time indoors. Thus, the main goal of the work here reported was the evaluation of mitigation measures implemented in nursery and primary schools to improve air quality. Continuous measurements of CO2, CO, NO2, O3, CH2O, total volatile organic compounds (VOC), PM1, PM2.5, PM10, Total Suspended Particles (TSP) and radon, as well as temperature and relative humidity were performed in two campaigns, before and after the implementation of low-cost mitigation measures. Evaluation of those mitigation measures was performed through the comparison of the concentrations measured in both campaigns. Exceedances to the values set by the national legislation and World Health Organization (WHO) were found for PM2.5, PM10, CO2 and CH2O during both indoor air quality campaigns. Temperature and relative humidity values were also above the ranges recommended by American Society of Heating, Refrigerating, and Air-Conditioning Engineers (ASHRAE). In general, pollutant concentrations measured after the implementation of low-cost mitigation measures were significantly lower, mainly for CO2. However, mitigation measures were not always sufficient to decrease the pollutants' concentrations till values considered safe to protect human health. PMID- 28561796 TI - Synthesis, Characterization and Protonation Behavior of Quinoxaline-Fused Porphycenes. AB - 9,10-Quinoxaline-fused porphycenes 1a-H2 and 1b-H2 were synthesized by intramolecular McMurry coupling. As a result of the annulation of the quinoxaline moiety on the porphycene skeleton, 1a-H2 and 1b-H2 display absorption and fluorescence in the near infra-red (NIR) region. Additionally, the quinoxaline moieties of 1a-H2 and 1b-H2 act as electron-withdrawing groups, introducing lower reduction potentials than for pristine porphycene. The protonation occurred at the nitrogen atoms in the cavity of freebase porphycenes and at the quinoxaline moieties for their nickel complexes to give diprotonic species. PMID- 28561797 TI - TRAV7-2*02 Expressing CD8+ T Cells Are Responsible for Palladium Allergy. AB - While metallic biomaterials have led to an improvement in the quality of life, metal allergies, especially to palladium (Pd), has caused a recent increase in allergic patients. Metal allergy is known to be a T cell-mediated delayed-type hypersensitivity (DTH); however, the pathogenic T cell subsets and the specific T cell receptor (TCR) have not been identified. Therefore, we attempted to identify the pathogenic T cells responsible for Pd allergy. We found that activating CD8+ T cells significantly increased and that the TRAV (TCRalpha variable) 7-2*02 chain skewed in Pd allergic mice. Furthermore, adoptive transfer experiments revealed that in vitro-cultured Pd-stimulated antigen presenting cells (APCs) function as memory APCs with recipient mice developing Pd allergy and that the frequency of TRAV7-2*02 increases the same as conventional Pd allergic mice. In contrast, neither proliferation of CD8+ T cells nor increasing of TRAV7-2*02 was observed in major histocompatibility complex I (MHC I)-deficient Pd-APCs transferred to mice. Taken together, we revealed that TRAV7-2*02-expressing CD8+ T cells are the pathogenic T cells for the development of Pd allergy. We also identified the CDR3 consensus motif of pathogenic TCRs as CAAXSGSWQLIF in TRAV7 2*02/TRAJ (TCRalpha junction)22*01 positive cells. These results suggest that the specific TCRs represent novel targets for the development of diagnostics and treatments for metal allergy. PMID- 28561799 TI - Extending Participatory Sensing to Personal Exposure Using Microscopic Land Use Regression Models. AB - Personal exposure is sensitive to the personal features and behavior of the individual, and including interpersonal variability will improve the health and quality of life evaluations. Participatory sensing assesses the spatial and temporal variability of environmental indicators and is used to quantify this interpersonal variability. Transferring the participatory sensing information to a specific study population is a basic requirement for epidemiological studies in the near future. We propose a methodology to reduce the void between participatory sensing and health research. Instantaneous microscopic land-use regression modeling (uLUR) is an innovative approach. Data science techniques extract the activity-specific and route-sensitive spatiotemporal variability from the data. A data workflow to prepare and apply uLUR models to any mobile population is presented. The uLUR technique and data workflow are illustrated with models for exposure to traffic related Black Carbon. The example uLURs are available for three micro-environments; bicycle, in-vehicle, and indoor. Instantaneous noise assessments supply instantaneous traffic information to the uLURs. The activity specific models are combined into an instantaneous personal exposure model for Black Carbon. An independent external validation reached a correlation of 0.65. The uLURs can be applied to simulated behavioral patterns of individuals in epidemiological cohorts for advanced health and policy research. PMID- 28561798 TI - NF-kappaB in Hematological Malignancies. AB - NF-kappaB (Nuclear Factor Kappa-light-chain-enhancer of activated B cells) transcription factors are critical regulators of immunity, stress response, apoptosis, and differentiation. Molecular defects promoting the constitutive activation of canonical and non-canonical NF-kappaB signaling pathways contribute to many diseases, including cancer, diabetes, chronic inflammation, and autoimmunity. In the present review, we focus our attention on the mechanisms of NF-kappaB deregulation in hematological malignancies. Key positive regulators of NF-kappaB signaling can act as oncogenes that are often prone to chromosomal translocation, amplifications, or activating mutations. Negative regulators of NF kappaB have tumor suppressor functions, and are frequently inactivated either by genomic deletions or point mutations. NF-kappaB activation in tumoral cells is also driven by the microenvironment or chronic signaling that does not rely on genetic alterations. PMID- 28561800 TI - Alternative Access to Functionalized 2,8-Ethanonoradamantane Derivatives. AB - 7a-(Methoxycarbonyl)-N-methyl-1,3a,5,6,7,7a-hexahydro-4H-1,4,6 (epiethane[1,1,2]triyl)indene-4,9-dicarboximide has been prepared through a modification of a previous synthetic sequence, in which the benzyloxymethyl hydroxyl protecting group has been replaced by methoxymethyl, to avoid the apparent formation of a benzyl ester derivative as a side product. The overall yield of the new synthetic sequence is comparable to the previous one. Two advantages of the new procedure are: (a) no benzyl ester was formed and (b) a stereoisomeric mixture of syn- and anti-alcohols at the beginning of the synthetic sequence could be separated and the rest of the synthesis could be carried out with the main syn-stereoisomer instead of the corresponding stereoisomeric mixture as it was the case in the previous process. Additionally, several functional 2,8-ethanonoradamantane derivatives have been prepared. PMID- 28561801 TI - Is Erythrocyte Protoporphyrin a Better Single Screening Test for Iron Deficiency Compared to Hemoglobin or Mean Cell Volume in Children and Women? AB - Hemoglobin (Hb), mean cell volume (MCV), and erythrocyte protoporphyrin (EP) are commonly used to screen for iron deficiency (ID), but systematic evaluation of the sensitivity and specificity of these tests is limited. The objective of this study is to determine the sensitivity and specificity of Hb, MCV, and EP measurements in screening for ID in preschool children, non-pregnant women 15-49 years of age, and pregnant women. Data from the National Health and Nutrition Examination Surveys (NHANES) (NHANES 2003-2006: n = 861, children three to five years of age; n = 3112, non-pregnant women 15 to 49 years of age. NHANES 1999 2006: n = 1150, pregnant women) were examined for this purpose. Children or women with blood lead >=10 ug/dL or C-reactive protein (CRP) >5.0 mg/L were excluded. ID was defined as total body iron stores <0 mg/kg body weight, calculated from the ratio of soluble transferrin receptor (sTfR) to serum ferritin (SF). The receiver operating characteristic (ROC) curve was used to characterize the sensitivity and specificity of Hb, MCV, and EP measurements in screening for ID. In detecting ID in children three to five years of age, EP (Area under the Curve (AUC) 0.80) was superior to Hb (AUC 0.62) (p < 0.01) but not statistically different from MCV (AUC 0.73). In women, EP and Hb were comparable (non-pregnant AUC 0.86 and 0.84, respectively; pregnant 0.77 and 0.74, respectively), and both were better than MCV (non-pregnant AUC 0.80; pregnant 0.70) (p < 0.01). We concluded that the sensitivity and specificity of EP in screening for ID were consistently superior to or at least as effective as those of Hb and MCV in each population examined. For children three to five years of age, EP screening for ID was significantly better than Hb and similar to MCV. For both non-pregnant and pregnant women, the performance of EP and Hb were comparable; both were significantly superior to MCV. PMID- 28561802 TI - Nanofluid Types, Their Synthesis, Properties and Incorporation in Direct Solar Thermal Collectors: A Review. AB - The global demand for energy is increasing and the detrimental consequences of rising greenhouse gas emissions, global warming and environmental degradation present major challenges. Solar energy offers a clean and viable renewable energy source with the potential to alleviate the detrimental consequences normally associated with fossil fuel-based energy generation. However, there are two inherent problems associated with conventional solar thermal energy conversion systems. The first involves low thermal conductivity values of heat transfer fluids, and the second involves the poor optical properties of many absorbers and their coating. Hence, there is an imperative need to improve both thermal and optical properties of current solar conversion systems. Direct solar thermal absorption collectors incorporating a nanofluid offers the opportunity to achieve significant improvements in both optical and thermal performance. Since nanofluids offer much greater heat absorbing and heat transfer properties compared to traditional working fluids. The review summarizes current research in this innovative field. It discusses direct solar absorber collectors and methods for improving their performance. This is followed by a discussion of the various types of nanofluids available and the synthesis techniques used to manufacture them. In closing, a brief discussion of nanofluid property modelling is also presented. PMID- 28561804 TI - Corrigendum: Green tea consumption is associated with reduced incident CHD and improved CHD-related biomarkers in the Dongfeng-Tongji cohort. AB - This corrects the article DOI: 10.1038/srep24353. PMID- 28561805 TI - Corrigendum: A new gender-specific model for skin autofluorescence risk stratification. AB - This corrects the article DOI: 10.1038/srep10198. PMID- 28561803 TI - Utilization of Multi-Immunization and Multiple Selection Strategies for Isolation of Hapten-Specific Antibodies from Recombinant Antibody Phage Display Libraries. AB - Phage display technology provides a powerful tool for the development of novel recombinant antibodies. In this work, we optimized and streamlined the recombinant antibody discovery process for haptens as an example. A multi immunization approach was used in order to avoid the need for construction of multiple antibody libraries. Selection methods were developed to utilize the full potential of the recombinant antibody library by applying four different elution conditions simultaneously. High-throughput immunoassays were used to analyse the binding properties of the individual antibody clones. Different carrier proteins were used in the immunization, selection, and screening phases to avoid enrichment of the antibodies for the carrier protein epitopes. Novel recombinant antibodies against mycophenolic acid and ochratoxin A, with affinities up to 39 nM and 34 nM, respectively, were isolated from a multi-immunized fragment antigen binding (Fab) library. PMID- 28561806 TI - Genetic-based interactions among tree neighbors: identification of the most influential neighbors, and estimation of correlations among direct and indirect genetic effects for leaf disease and growth in Eucalyptus globulus. AB - An individual's genes may influence the phenotype of neighboring conspecifics. Such indirect genetic effects (IGEs) are important as they can affect the apparent total heritable variance in a population, and thus the response to selection. We studied these effects in a large, pedigreed population of Eucalyptus globulus using variance component analyses of Mycosphearella leaf disease, diameter growth at age 2 years, and post-infection diameter growth at ages 4 and 8 years. In a novel approach, we initially modeled IGEs using a factor analytic (FA) structure to identify the most influential neighbor positions, with the FA loadings being position-specific regressions on the IGEs. This involved sequentially comparing FA models for the variance-covariance matrices of the direct and indirect effects of each neighbor. We then modeled IGEs as a distance based, combined effect of the most influential neighbors. This often increased the magnitude and significance of indirect genetic variance estimates relative to using all neighbors. The extension of a univariate IGEs model to bivariate analyses also provided insights into the genetic architecture of this population, revealing that: (1) IGEs arising from increased probability of neighbor infection were not associated with reduced growth of neighbors, despite adverse fitness effects being evident at the direct genetic level; and (2) the strong, genetic based competitive interactions for growth, established early in stand development, were highly positively correlated over time. Our results highlight the complexities of genetic-based interactions at the multi-trait level due to (co)variances associated with IGEs, and the marked discrepancy occurring between direct and total heritable variances. PMID- 28561808 TI - Prostate cancer: Lineage predicts ADT response. PMID- 28561809 TI - Kidney cancer: Bap1 and Pbrm1 determine tumour grade. PMID- 28561807 TI - Personalized peptide vaccines and their relation to other therapies in urological cancer. AB - Immunotherapy is an important therapeutic modality for urological cancers and several immunological agents for their treatment, such as sipuleucel-T and immune checkpoint inhibitors, have been approved by the FDA. Personalized peptide vaccines (PPVs) are an immunotherapy that uses multiple cancer peptides that are selected to complement pre-existing host immunity. Vaccination with an appropriate, individualized selection of peptides, chosen from a list of candidates, induces stronger and more rapid antitumour immunity in comparison with inoculation of conventional peptide vaccines. Phase I and phase II trials have shown that PPVs are safe and effective in urological cancers. Randomized trials in patients with castration-resistant prostate cancer showed that PPVs can significantly improve progression-free survival and overall survival. However, further studies are needed to evaluate the utility of PPVs in other urological cancers, to identify those patients who will derive the greatest benefit from this approach and to optimize the protocols for combination therapies involving PPVs. PMID- 28561810 TI - Infection: Intravesical gentamicin ameliorates recurrent UTI. PMID- 28561812 TI - Pain: Chondroitin sulfate is superior to hyaluronic acid. PMID- 28561811 TI - Prostate cancer: AZGP1 expression predicts favourable outcomes. PMID- 28561813 TI - Therapeutic approaches for spinal muscular atrophy (SMA). AB - Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder characterized by progressive muscle wasting and loss of muscle function due to severe motor neuron dysfunction, secondary to mutations in the survival motor neuron 1 (SMN1) gene. A second neighboring centromeric gene, SMN2, is intact in all patients but contains a C-to-T variation in exon 7 that affects a splice enhancer and determines exclusion of exon 7 in the majority of its transcript, leading to an unstable protein that cannot substitute for mutant SMN1. Following successful studies on disease models and intensive studies on SMN functions in the past decade, SMN upregulation targeting SMN2, has been suggested as a possible therapeutic approach. Recently, we have witnessed an historical turning point with the first disease-modifying treatment receiving Food and Drug Administration approval and now being available to patients also outside the clinical trial. This innovative treatment is an antisense oligonucleotide, which, administered intrathecally, is able to increase exon 7 inclusion in the majority of the SMN2 mRNA and increase the production of fully functional SMN protein. Alternative advanced therapies, such as viral vector mediated gene therapy and orally available small molecules, are also showing promising results in early clinical trial phases. PMID- 28561814 TI - The SMA Trust: the role of a disease-focused research charity in developing treatments for SMA. AB - SMA is a rare hereditary neuromuscular disease that causes weakness and muscle wasting as a result of the loss of spinal motor neurons. In its most severe form, SMA is the commonest genetic cause of death in infants, and children with less severe forms of SMA face the prospect of lifelong disability from progressive muscle wasting, loss of mobility and limb weakness. The initial discovery of the defective gene has been followed by major advances in our understanding of the genetic, cellular and molecular basis of SMA, providing the foundation for a range of approaches to treatment, including gene therapy, antisense oligonucleotide treatments and more traditional drug-based approaches to slow or halt disease progression. The approval by the US Food and Drug Administration (FDA) of Spinraza (nusinersen), the first targeted treatment for spinal muscular atrophy (SMA), is a historic moment. Disease-focused research charities, such as The SMA Trust (UK), continue to have a crucial role in promoting the development of additional treatments for SMA, both by funding translational research and by promoting links between researchers, people living with SMA and other stakeholders, including pharmaceutical companies and healthcare providers. PMID- 28561816 TI - Validity and reliability of three-dimensional scanning compared to conventional anthropometry for children and adolescents: methodological mistake. PMID- 28561817 TI - Epigallocatechin-3-gallate attenuates cerebral cortex damage and promotes brain regeneration in acrylamide-treated rats. AB - Acrylamide (ACR) is a neurotoxic industrial chemical intermediate, which is also present in food and water. We investigated the neuroprotective effects of epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, on ACR-treated rat brain. Rats were pre-treated with EGCG for 4 d and then administered ACR and EGCG for 14 d. EGCG increased acetylcholinesterase (AChE) activity and the rate of Nissl-positive cells in ACR-treated rats. Senescence associated beta-galactosidase (SA-beta-gal) staining indicated that EGCG attenuated ACR-induced senescence. Tumour necrosis factor alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) protein expression indicated that EGCG inhibited ACR-induced inflammation. In addition, immunohistochemical analysis of nestin and brain-derived neurotrophic factor (BDNF) revealed that EGCG promoted brain regeneration in ACR-treated rats. Altogether, our results suggest that EGCG can attenuate ACR-induced brain damage and promote regeneration in the cerebral cortex of rats. Therefore, we hypothesized that EGCG may alleviate ACR-related nerve injury. PMID- 28561818 TI - Anisotropic thermal expansion of SnSe from first-principles calculations based on Gruneisen's theory. AB - Based on Gruneisen's theory, the elastic properties and thermal expansion of bulk SnSe with the Pnma phase are investigated by using first-principles calculations. Our numerical results indicate that the linear thermal expansion coefficient along the a direction is smaller than the one along the b direction, while the one along the c direction shows a significant negative value, even at high temperature. The numerical results are in good accordance with experimental results. In addition, generalized and macroscopic Gruneisen parameters are also presented. It is also found that SnSe possesses negative Possion's ratio. The contributions of different phonon modes to NTE along the c direction are investigated, and it is found that the two modes which make the most important contributions to NTE are transverse vibrations perpendicular to the c direction. Finally, we analyze the relation of elastic constants to negative thermal expansion, and demonstrate that negative thermal expansion can also occur even with all positive macroscopic Gruneisen parameters. PMID- 28561815 TI - Effects of therapeutic hypothermia on white matter injury from murine neonatal hypoxia-ischemia. AB - BackgroundTherapeutic hypothermia (TH) is the standard of care for neonates with hypoxic-ischemic encephalopathy, but it is not fully protective in the clinical setting. Hypoxia-ischemia (HI) may cause white matter injury (WMI), leading to neurological and cognitive dysfunction.MethodsP9 mice were subjected to HI as previously described. Pups underwent 3.5 h of systemic hypothermia or normothermia. Cresyl violet and Perl's iron staining for histopathological scoring of brain sections was completed blindly on all brains. Immunocytochemical (ICC) staining for myelin basic protein (MBP), microglia (Iba1), and astrocytes (glia fibrillary acidic protein (GFAP)) was performed on adjacent sections. Volumetric measurements of MBP coverage were used for quantitative analysis of white matter.ResultsTH provided neuroprotection by injury scoring for the entire group (n=44; P<0.0002). ICC analysis of a subset of brains showed that the lateral caudate was protected from WMI (P<0.05). Analysis revealed decreased GFAP and Iba1 staining in hippocampal regions, mostly CA2/CA3. GFAP and Iba1 directly correlated with injury scores of normothermic brains.ConclusionTH reduced injury, and qualitative data suggest that hippocampus and lateral caudate are protected from HI. Mildly injured brains may better show the benefits of TH. Overall, these data indicate regional differences in WMI susceptibility and inflammation in a P9 murine HI model. PMID- 28561819 TI - SO2 and SO3 reactions with [(C5Me5)2Sm-O-Sm(C5Me5)2]: a DFT investigation and comparison with CO2 reactivity. AB - Recently, it was shown that samarocene oxide [Cp*2Sm-O-SmCp*2] with Cp* = C5Me5 could react with organic and inorganic anhydrides. The reactions of [Cp*2Sm-O SmCp*2] with SO2 and SO3 are reported using DFT calculations and compared with the reactivity of CO2. These reactions exhibit similar features yielding [Cp*2-Sm (MU-eta1:eta2-OSO2)-SmCp*2] similar to [Cp*2-Sm-(MU-eta1:eta2-OCO2)-SmCp*2] and [Cp*2-Sm-(MU-eta2:eta2-O2SO2)-SmCp*2] complexes. PMID- 28561820 TI - Mechanistic insight into the thermal activation of Togni's trifluoromethylation reagents. AB - Herein we investigate the propensity of hypervalent iodine based electrophilic trifluoromethylating agents to undergo thermally induced fragmentation of the F3C I-O motif. For the first time we are able to observe a dissociative electron transfer mechanism using mass spectroscopy techniques to generate and trap CF3 radicals. Consistent with this mechanism, alkyl radical elimination from these reagents is in full support of an intermediate cyclic iodanyl radical and a reagent-specific temperature of maximum radical production was found to correlate with reported solution phase reactivity. PMID- 28561822 TI - Synthesis, characterization and oxygen atom transfer reactivity of a pair of Mo(iv)O- and Mo(vi)O2-enedithiolate complexes - a look at both ends of the catalytic transformation. AB - Two new molybdenum complexes (Bu4N)2[MoIVO(ntdt)2] (1) and (Ph4P)2[MoVIO2(ntdt)2] (2) (ntdt = 2-naphthyl-1,4-dithiolate) were synthesized using asymmetric dithiolene precursors and were characterized as structural models for the active site of arsenite oxidase, a molybdopterin bearing enzyme. The ligand was obtained readily by a two-step synthesis starting from 2-bromo-2'-acetonapthone. Complexes 1 and 2 were obtained by reaction of the resulting 4-naphthyl-1,3-dithiol-2-one with metal precursors trans-[MoO2(CN)4]4- and cis-[MoO2(NCS)4]2- respectively. Notably and to the best of our knowledge, this work constitutes the first utilization of the latter in dithiolene chemistry. 1 and 2 were characterized by NMR and IR spectroscopy, by cyclic voltammetry, mass spectrometry, elemental analysis and in case of 1 by single-crystal X-ray diffraction. The molecular structure of compound 1 exhibits the less common cis isomeric form (i.e. the naphthyl groups of the 2-naphthyl-1,4-dithiolate ligands are located on the same side of the MoS4 square base). Structural, spectroscopic and electrochemical data are discussed in context. The catalytic oxo-transfer properties of 1 and 2 were investigated by oxo-transfer reactions from DMSO to PPh3 with varied catalyst : PPh3 ratios. Interestingly, the oxygen atom transfer reaction from DMSO to PPh3 starting from compound 2 was found to be more efficient under the given conditions than when the reduced catalyst 1 was employed as initial species. The two catalytic systems are discussed and compared in terms of their reactivity. PMID- 28561821 TI - Environmental trends of metals and PCDD/Fs around a cement plant after alternative fuel implementation: human health risk assessment. AB - This study aimed at evaluating the potential impact of a cement plant after 4 years of the employment of alternative fuel. In June 2015, concentrations of PCDD/Fs and metals were determined in soils, vegetation and air in order to measure potential changes with respect to previous surveys before (July 2011) and after (June 2013) the employment of alternative fuel. Risks to human health were also assessed. In soils, metal levels were similar to those observed in June 2013 (p > 0.05). In comparison with July 2011, the increment was only statistically significant for As and Cd (p < 0.05). A notable increase in levels of PCDD/Fs was noted when current levels in soils (1.14 ng WHO-TEQ per kg) were compared with those observed in July 2011 (0.37 ng WHO-TEQ per kg) (p > 0.05) and June 2013 (0.41 ng WHO-TEQ per kg) (p < 0.05). This increase was mainly caused by the increase in PCDD/F levels at one sampling site, which showed the heterogeneity of PCDD/F levels in soils, possibly as a result of different point emissions over the years. On the other hand, temporal trends in levels of metals and PCDD/Fs in vegetation showed a clear decrease, which indicated that the particle fraction of these pollutants would potentially be removed from leaf surfaces by wash-off. In air, levels were similar to those found in previous surveys. The results of PCA showed that the change in fuel had not affected the environmental profiles of metals and PCDD/Fs around the cement plant. The exposure of the population living in the surroundings of the plant was measured and it was shown that diet was the major contributor for both metals and PCDD/Fs, with percentages of over 97%, the only exceptions being As and Pb, for which dietary intake accounted for 43% and 71% of the total exposure, respectively. Environmental non-cancer and cancer risks were within the limits considered as acceptable by international standards. PMID- 28561823 TI - A glycosylation strategy to develop a low toxic naphthalimide fluorescent probe for the detection of Fe3+ in aqueous medium. AB - A glycosylation strategy based on click chemistry was employed to develop a naphthalimide-based Fe3+ fluorescent probe with low cytotoxicity and good water solubility. The selectivity and sensitivity to Fe3+ of three synthesized naphthalimide-based fluorescent probes follows a Nap-PZ < Nap-OH < Nap-Glc trend, because Nap-PZ was modified with a good water-soluble group. The cytotoxicity follows a Nap-PZ > Nap-OH > Nap-Glc trend, because the exposed toxic group of Nap PZ was shielded by a good biocompatible group. The detection limit toward Fe3+ ion follows a Nap-PZ (7.40 * 10-6 M) > Nap-OH (2.73 * 10-7 M) > Nap-Glc (4.27 * 10-8 M) trend. Moreover, Nap-Glc could be used to detect Fe3+ in living cells. The fluorescent "off-on" response of Nap-Glc towards Fe3+ could be recognized by the naked eye, and the "off-on" fluorescent mechanism also was demonstrated by theoretical calculations. Therefore, Nap-Glc is a novel glucosyl naphthalimide fluorescent probe for environmental or biological detection of Fe3+ with low cytotoxicity and good water-solubility. PMID- 28561824 TI - Tetrel, pnictogen and chalcogen bonds identified in the gas phase before they had names: a systematic look at non-covalent interactions. AB - The terms tetrel bond, pnictogen bond and chalcogen bond were coined recently to describe non-covalent interactions involving group 14, 15 and 16 atoms, respectively, acting as the electrophilic site that seeks a nucleophilic region of another molecule, for example a non-bonding electron pair or pi-electron pair of a Lewis base. Many complexes containing these non-covalent bonds were identified and characterised in isolation in the gas phase by rotational and vibrational spectroscopy long before they were given these names. In this article, the geometries so determined for selected examples of complexes of each type are rationalised in terms of the molecular electrostatic surface potentials of the component molecules. Examples of chalcogen-bonded complexes considered are based mainly on sulfur dioxide, with the region near the sulfur atom as the electrophilic site that interacts with n-electron and pi-electron pairs for a range of simple Lewis base molecules. For tetrel bonds, the examples discussed involve the carbon atom of carbon dioxide as the electrophilic centre, while for pnictogen bonds the central nitrogen of the closely related molecule nitrous oxide is chosen. Geometrical similarities within each series allow simple definitions of each type of non-covalent bond that are conformal with that recently advanced for the halogen bond, a related non-covalent interaction. PMID- 28561825 TI - Indocyanine green-loaded gold nanostars for sensitive SERS imaging and subcellular monitoring of photothermal therapy. AB - We have demonstrated that a typical nanothermometer was incorporated in a bovine serum albumin stabilized gold nanostar-indocyanine green (denoted as GNS-ICG-BSA) nanoprobe to realize surface-enhanced Raman scattering (SERS) imaging-based real time sensitive monitoring of intracellular temperature in photothermal therapy (PTT), which significantly improved the spatial resolution compared to infrared thermal imaging. Herein, an exogenous thermosensitive molecule, ICG, acting as a tri-functional agent, was selected as the Raman reporter instead of direct cellular biochemical changes. The triggering of the obtained probe was unaffected by the cellular microenvironment, so it can act as a monitor of PTT in various cell types. High-resolution mass spectrometry (HRMS) was used to investigate the thermosensitive mechanism of ICG. The actively targeted GNS-ICG-BSA nanotags were used to induce SERS mapping-guided in vitro PTT of U87 glioma cells. Meanwhile, small temperature variations within a cell during PTT can be precisely monitored through the SERS fingerprint information, with a spatial resolution at the subcellular level and a sensitivity of 0.37 degrees C. Thus, the integrated GNS ICG-BSA nanotags can be treated as a theranostic probe, a SERS imaging probe and an intracellular thermometer. Moreover, the good biocompatibility and the low cytotoxicity of GNS-ICG-BSA nanotags, together with their superior photothermal ablation effect on U87 glioma cells have been confirmed. This suggested that the implanted nanothermometry approach would be promising for a better understanding of the biological processes at subcellular level and provide new insights into the fabrication of a multifunctional nanoplatform. Furthermore, this study revealed that the SERS-based monitoring technique can offer great potential for theranostics as an emerging strategy. PMID- 28561828 TI - Leveraging a temperature-tunable, scale-like microstructure to produce multimodal, supersensitive sensors. AB - The microstructure of a flexible film plays an important role in its sensing capability. Here, we fabricate a temperature-dependent wrinkled single-walled carbon nanotube (SWCNT)/polydimethyl-siloxane (PDMS) film (WSPF) and a wrinkle dependent scale-like SWCNT/PDMS film (SSPF) successfully, and address the formation and evolution mechanisms of each film. The low elastic modulus and high coefficient of thermal expansion of the PDMS layer combined with the excellent piezoresistive behavior of the SWCNT film motivated us to investigate how the scale-like microstructure of the SSPF could be used to design multimodal-sensing devices with outstanding capabilities. The results show that SSPFs present supersensitive performance in mechanical loading (an effective sensitivity of up to 740.7 kPa-1) and in temperature (a tunable thermal index of up to 29.9 * 103 K). These exceptional properties were demonstrated in practical applications in a programmable flexile pressure sensor, thermal/light monitor or switch, etc., and were further explained through the macroscopic and microscopic piezoresistive behaviors of scale-like SWCNT coatings. PMID- 28561826 TI - Microfluidic-based high-throughput optical trapping of nanoparticles. AB - Optical tweezers have emerged as a powerful tool for multiparametric analysis of individual nanoparticles with single-molecule sensitivity. However, its inherent low-throughput characteristic remains a major obstacle to its applications within and beyond the laboratory. This limitation is further exacerbated when working with low concentration nanoparticle samples. Here, we present a microfluidic based optical tweezers system that can 'actively' deliver nanoparticles to a designated microfluidic region for optical trapping and analysis. The active microfluidic delivery of nanoparticles results in significantly improved throughput and efficiency for optical trapping of nanoparticles. We observed a more than tenfold increase in optical trapping throughput for nanoparticles as compared to conventional systems at the same nanoparticle concentration. To demonstrate the utility of this microfluidic-based optical tweezers system, we further used back-focal plane interferometry coupled with a trapping laser for the precise quantitation of nanoparticle size without prior knowledge of the refractive index of nanoparticles. The development of this microfluidic-based active optical tweezers system thus opens the door to high-throughput multiparametric analysis of nanoparticles using precision optical traps in the future. PMID- 28561829 TI - Core-shell CoFe2O4@Co-Fe-Bi nanoarray: a surface-amorphization water oxidation catalyst operating at near-neutral pH. AB - The exploration of high-performance and earth-abundant water oxidation catalysts operating under mild conditions is highly attractive and challenging. In this communication, core-shell CoFe2O4@Co-Fe-Bi nanoarray on carbon cloth (CoFe2O4@Co Fe-Bi/CC) was successfully fabricated by in situ surface amorphization of CoFe2O4 nanoarray on CC (CoFe2O4/CC). As a 3D water oxidation electrode, CoFe2O4@Co-Fe Bi/CC shows outstanding activity with an overpotential of 460 mV to drive a geometrical catalytic current density of 10 mA cm-2 in 0.1 M potassium borate (pH 9.2). Notably, it also demonstrates superior long-term durability for at least 20 h with 96% Faradic efficiency. Density functional theory calculations indicate that the conversion from OOH* to O2 is the rate-limiting step and the high water oxidation activity of CoFe2O4@Co-Fe-Bi/CC is associated with the lower free energy of 1.84 eV on a Co-Fe-Bi shell. PMID- 28561831 TI - A dynamic cell entry pathway of respiratory syncytial virus revealed by tracking the quantum dot-labeled single virus. AB - Studying the cell entry pathway at the single-particle level can provide detailed and quantitative information for the dynamic events involved in virus entry. Indeed, the viral entry dynamics cannot be monitored by static staining methods used in cell biology, and thus virus dynamic tracking could be useful in the development of effective antiviral strategies. Therefore, the aim of this work was to use a quantum dot-based single-particle tracking approach to monitor the cell entry behavior of the respiratory syncytial virus (RSV) in living cells. The time-lapse fluorescence imaging and trajectory analysis of the quantum dot labeled RSV showed that RSV entry into HEp-2 cells consisted of a typical endocytosis trafficking process. Three critical events during RSV entry were observed according to entry dynamic and fluorescence colocalization analysis. Firstly, RSV was attached to lipid rafts of the cell membrane, and then it was efficiently delivered into the perinuclear region within 2 h post-infection, mostly moving and residing into the lysosome compartment. Moreover, the relatively slow velocity of RSV transport across the cytoplasm and the formation of the actin tail indicated actin-based RSV motility, which was also confirmed by the effects of cytoskeletal inhibitors. Taken together, these findings provided new insights into the RSV entry mechanism and virus-cell interactions in RSV infection that could be beneficial in the development of antiviral drugs and vaccines. PMID- 28561832 TI - Live-cell monochromatic dual-label sub-diffraction microscopy by mt-pcSOFI. AB - We expand photochromic super-resolution optical fluctuation imaging (pcSOFI) to monochromatic dual-channel sub-diffraction microscopy. Multi-tau (mt-)pcSOFI unmixes spectrally identical reversibly switchable fluorescent proteins (RSFPs) based on their blinking kinetics. We show that mt-pcSOFI can be used to simultaneously image two structures in living cells with existing RSFPs and the newly developed ffDronpa-F. PMID- 28561833 TI - Molecular dynamic heterogeneity in relation to free volume and relaxation dynamics in organic glass-formers: oligomeric cis-1,4-poly(isoprene). AB - Herein, a combined study of the molecular rotation dynamics and free volume in cis-1,4-poly(isoprene) using two external probing techniques via ESR and PALS together with relaxation dynamics of the host medium via BDS is presented. The spectral evolution of the spin probe TEMPO from simulations over a wide range from 100 K up to 300 K exhibits three different regions of its correlation time consisting of a slow regime at low temperatures followed by the molecular dynamic heterogeneity zone from T = T = 155 K = 0.82 * T up to Tc ? 236 K = 1.26 * T and ending with a fast regime at high temperatures with the further characteristic ESR temperatures, T = 186 K ? T and T = 260 K. These are in close coincidence with four characteristic PALS temperatures: T = 160 K, T = 190 K, T = 227 K, and T = 263 K. Finally, using BDS, we revealed that the high-frequency features of the structural relaxation of 1,4-PIP 0.8k were related to the observed effects in the ESR and PALS response of the liquid state. PMID- 28561834 TI - Organoindium-modified monodisperse ellipsoid-/platelet-like periodic mesoporous silicas. AB - In this study, an indium(iii) silylamide complex was respectively grafted onto monodisperse ellipsoid-like (E) and platelet-like (P) large-pore hexagonal periodic mesoporous silicas (PMSs) SBA-15 to afford hybrid materials In[N(SiMe3)2]3@SBA-15E and In[N(SiMe3)2]3@SBA-15P with well-defined surface species ([triple bond, length as m-dash]SiO)2In[N(SiMe3)2], [triple bond, length as m-dash]SiOIn[N(SiMe3)2]2, and [triple bond, length as m-dash]SiOSiMe3. Surface ligand exchange between silylamido and alkoxyl group led to the conversion of surface species ([triple bond, length as m-dash]SiO)2In[N(SiMe3)2] and [triple bond, length as m-dash]SiOIn[N(SiMe3)2]2 into ([triple bond, length as m dash]SiO)2In(OR) and [triple bond, length as m-dash]SiOIn(OR)2 (R = Me, Et, iPr) with donor ligands thf or NH3, respectively, revealing that silylamido coordinated to the indium centre could be completely exchanged with alkoxyl groups (-OMe, OEt or OiPr). Solid-state 1H, 13C and 29Si nuclear magnetic resonance spectra and elemental analyses confirmed that surface species [triple bond, length as m-dash]SiOIn[N(SiMe3)2]2 are dominant in comparison with bipodal ([triple bond, length as m-dash]SiO)2In[N(SiMe3)2] and [triple bond, length as m dash]SiOSiMe3. The diffuse reflectance infrared Fourier-transform spectroscopy of In-modified hybrid materials directly evidenced the alteration of surface species before and after grafting of In[N(SiMe3)2]3 and surface ligand exchange. In addition, the change of pore parameters (pore diameter, specific surface area and pore volume) monitored by nitrogen physisorption also indirectly corroborated the immobilization of the indium complex and the occurrence of ligand exchanges between -[N(SiMe3)2]2 and -OR (R = Me, Et, iPr) on the surface of SBA-15. Note that the calcination of In-modified hybrid materials at 540 degrees C led to the formation of crystalline In2O3 nanoparticles with different sizes which were respectively located in the internal pore and on the external surface of SBA-15 due to the pore confinement effect, migration effect and shape effect of the parent support, but the long-range ordered mesopore arrays were still preserved and the crystalline structures of In2O3 were verified by powder X-ray diffraction and transmission electron microscopy. PMID- 28561835 TI - vhfRNAi: a web-platform for analysis of host genes involved in viral infections discovered by genome wide RNAi screens. AB - Knockdown of host genes using high-throughput genome-wide RNA interference screens has identified numerous host factors that affect viral infections, which would be helpful in understanding host-virus interactions. We have developed a vhfRNAi web resource based on genome-wide RNAi experiments for viruses. It contains experimental details of 12 249 entries (host factors + restriction factors) for 18 viruses. Simultaneously, this resource encompasses analysis of overlapping genes, genome wide association studies, gene ontology (GO), pathogen interacting proteins, interaction networks and pathway enrichment. Using overlap analysis, it was found that Influenza A virus shared overlapping host genes with the majority of viruses including Hepatitis C virus and Dengue virus 2. In the genome wide association studies analysis, 429 diseases/traits were mapped, of which obesity-related traits were the most common. GO analysis revealed that the major categories belonged to metabolic processes, molecule transport, signal transduction, proteolysis, etc. In the pathogen interacting protein analysis, protein interaction data from different resources can be explored for further understanding of host-virus biology. By pathway enrichment analysis, a total of 8955 genes were mapped on 303 pathways with most of the hits coming from metabolic pathways. We have found 491 genes that are not essential for the host but essential for the virus and can be targeted to inhibit the virus. These may be explored as potential candidates for drug targets. The resource is freely accessible at and will be useful in understanding host-virus biology as well as identification of targets for the development of antiviral therapeutics. PMID- 28561838 TI - Vibrational optical activity as probe for intermolecular interactions. AB - A main focus of physical chemistry and related disciplines targets a detailed and fundamental characterization of intermolecular interactions. Interests are manifold and range from gaining experimental evidence for a particular interaction to the theoretical dissection of its exact quantum mechanical origin. In this perspective article, we discuss some recent developments in the field of vibrational circular dichroism (VCD) spectroscopy, which aim for its application for the characterization of intermolecular interactions of chiral molecules. Following a brief qualitative discussion of theoretical aspects of VCD spectroscopy, we show how the introduction of chirality into suitable model systems can give unprecedented insights into molecular complexes in the solution phase. In particular, we focus on solute-solvent interactions as well as the formation of the active conformation between catalyst and reactant, and also discuss the phenomenon of induced VCD signatures of achiral interaction partners. PMID- 28561839 TI - Sessile droplets for chemical and biological assays. AB - Sessile droplets are non-movable droplets spanning volumes in the nL-to-MUL range. The sessile-droplet-based platform provides a paradigm shift from the conventional, flow-based lab-on-a-chip philosophy, yet offering similar benefits: low reagent/sample consumption, high throughput, automation, and most importantly flexibility and versatility. Moreover, the platform relies less heavily on sophisticated fabrication techniques, often sufficient with a hydrophobic substrate, and no pump is required for operation. In addition, exploiting the physical phenomena that naturally arise when a droplet evaporates, such as the coffee-ring effect or Marangoni flow, can lead to fascinating applications. In this review, we introduce the physics of droplets, and then focus on the different types of chemical and biological assays that have been implemented in sessile droplets, including analyte concentration, particle separation and sorting, cell-based assays, and nucleic acid amplification. Finally, we provide our perspectives on this unique micro-scale platform. PMID- 28561840 TI - Silicon doped boron clusters: how to make stable ribbons? AB - A doping of small boron clusters with silicon atoms leads to the formation of stable boron nanoribbon structures. We present an analysis on the geometric and electronic structure, using MOs and electron localization function (ELF) maps, of boron ribbons represented by the dianions B10Si22- and B12Si22-. The effect of Si dopants and the origin of the underlying electron count [pi2(n+1)sigma2n] are analyzed. Interaction between both systems of delocalized pi and sigma electrons creating alternant B-B bonds along the perimeter of a ribbon induces its high thermodynamic stability. The enhanced stability is related to the self-locked phenomenon. PMID- 28561841 TI - Correction: Oleuropein down-regulated IL-1beta-induced inflammation and oxidative stress in human synovial fibroblast cell line SW982. AB - Correction for 'Oleuropein down-regulated IL-1beta-induced inflammation and oxidative stress in human synovial fibroblast cell line SW982' by Maria Luisa Castejon, et al., Food Funct., 2017, DOI: 10.1039/c7fo00210f. PMID- 28561842 TI - 13-cis-Retinoic acid on coinage metals: hierarchical self-assembly and spin generation. AB - Hierarchical self-assembly of 13-cis-retinoic acid on Au(111) and Ag(111) was investigated using low-temperature scanning tunnelling microscopy. On both surfaces, molecules form dimers by hydrogen bonds and the dimers arrange into ordered two-dimensional arrays through van der Waals forces. Three packing modes are observed on Au(111) and only one on Ag(111). We tentatively attribute the different patterns on the two surfaces to a stronger molecule-substrate interaction on Ag(111) and site-dependent molecular adsorption on different atomic lattices. In addition, 13-cis-ReA on Au(111) can be made to carry a localized spin. PMID- 28561843 TI - Graphene nanoflakes functionalized with cobalt/cobalt oxides formation during cobalt organic framework carbonization. AB - In this contribution, we present the synthesis and carbonization mechanism of metal-organic frameworks (MOFs) based on cobalt and terephthalic acid, with detailed attention to the carbonization mechanism of cobalt-based organic frameworks. The evolution of the unique morphology of carbonized cobalt organic frameworks induced by temperature allows the synthesis of a hybrid of multi layered carbon structures with metal and metal oxide nanoparticles placed between them. The formation of various phases and diameter distributions of cobalt nanoparticles resulted in the partial degradation of carbon structure and exfoliation. Presented data describe the connection between cobalt particle oxidation and carboreduction with the phenomenon of metal particle agglomeration. The presented study allows us to select carbonization conditions in order to obtain the desired cobalt crystalline structure on the graphene flakes from cobalt-based MOFs. PMID- 28561844 TI - Substrate coating by conductive polymers through spontaneous oxidation and polymerization. AB - A variety of substrates and substances were coated with conductive polymers at low temperature under ambient pressure. The substrate coating with heteroaromatic polymers proceeded through spontaneous oxidation and polymerization of the monomers, such as pyrrole (Py) and thiophene (Tp) derivatives. The monomer liquid, the solid nitrate oxidant, and the substrate were put in a closed vessel. The vapor of the activated monomer was spontaneously generated on the surface of the solid nitrate oxidant through the diffusion of the monomer vapor. The monomer and its activated species were adsorbed and polymerized on the surface of any substrate in the reaction vessel. The thickness was controlled by the reaction time. The substituents of the monomers had an influence on the coating rate. The morphology of the coated polymers was changed by the substrates with different wettabilities. The thin coating of the heteroaromatic polymer was applied to the preparation of an electrode for charge storage based on the redox reaction. The thin coating on the current collector showed an enhanced high-rate charge discharge performance. The present synthetic approach can be applied to the coating of polymer materials on a variety of substrates from the monomer vapor under mild conditions. PMID- 28561845 TI - Dynamic properties of the growth hormone releasing hormone receptor (GHRHR) and molecular determinants of GHRH binding. AB - The growth hormone-releasing hormone receptor (GHRHR) is a member of the class B GPCR subfamily. GHRH, a 44-residue neuropeptide produced in the hypothalamus, regulates the secretion of growth hormone through its binding to GHRHR. It has recently been associated with several types of cancer such as prostate, breast, pancreatic and ovarian cancer. Family B GPCR peptides bind in a two-step model, where first the C-terminal region of the peptide interacts with the extracellular domain (ECD) of the receptor and subsequently, the N-terminal interacts with the seven transmembrane domain (TMD), resulting in activation. Structural information on family B GPCRs is limited; therefore, the use of computational methods may assist their efficient targeting towards new therapeutics. Here, we have utilized several computational tools, such as homology modelling, docking, large-scale molecular dynamics and principal component analysis (PCA), in order to: (a) gain information on the dynamic properties of the receptor domains and (b) propose a structural model for the interactions between GHRH and the ECD and TMD regions of GHRHR respectively. We conclude that PCA analysis can be used for studying such relative movements in family B GPCRs and provide a structural model, which may assist in the design of highly anticipated non-peptide antagonists against GHRHR. PMID- 28561846 TI - Interface passivation and electron transport improvement of polymer solar cells through embedding a polyfluorene layer. AB - In this contribution, a series of conducting polyfluorenes (PF) are introduced to improve interface adhesion and boost charge extraction of the TiO2 electron transport layer of inverted polymer solar cells (PSCs). After employing poly (9,9 dihexylfluorenyl-2,7-diyl) (PDF), poly[(9,9-dioctylfluorenyl-2,7-diyl)-alt-co (1,4-benzo-{2,1',3}-thiadiazole)] (PDFBT), and poly[(4-(5-(7-methyl-9,9-dioctyl 9H-fluoren-2-yl) thiophen-2-yl)-7-(5-methylthiophen-2 yl)benzo[c][1,2,5]thiadiazole)] (PFTBT) as capping layers, interfacial coherence improvement and energy loss decrease are both achieved, facilitating charge transfer from the active layer to the TiO2 layer. The optimized contact, enhanced electrical conductivity, and reduced internal resistance contribute to increased short-circuit current density and fill factor, leading to an enhanced power conversion efficiency (PCE) from 5.72% up to 7.97%. The employment of the PF capping TiO2 buffer layer provides a promising approach to develop high efficiency PSCs. PMID- 28561848 TI - Details make the difference: a family of tetranuclear CuIIMnIII complexes with cube-like and double open cube-like cores. AB - The "direct synthesis" approach, namely one-pot reaction of metal powders and ammonium salt with a methanol solution of a polydentate Schiff base (H2L) formed in situ from salicylaldehyde and ethanolamine, has been successfully used for the preparation of the new heterometallic compounds [Cu3Mn(L)4(CH3OH)3]I3 (1), [Cu3Mn(L)4(CH3OH)3(H2O)]NCS.H2O (2), [Cu3Mn(L)4(CH3OH)(H2O)2.55]Br.0.45H2O (3) and [Cu3Mn(L)4(H2O)3.4]BF4.0.6H2O (4). Crystallographic analysis revealed that 1 4 are based on the tetranuclear core {CuMnIII(MU3-O)4} where the metal centres are joined by the oxygen bridges of Schiff base ligands forming a cube-like arrangement. The novel heterometallic compound [Cu3Mn(L)4(CH3OH)3]2[Mn(NCS)4].2CH3OH (5) has been obtained by the "building block" approach using the reaction of [Cu(HL)2] with manganese acetate and NH4NCS in methanol. The crystal structure of 5 revealed the {CuMnIII(MU-O)2(MU3-O)2} metal core which can be viewed as a double open cube. In spite of a similar {Cu3MnO4} atom set in the cores of 1-5, the complexes show rather different molecular structures and significantly differ by the number and combinations of coordinated CH3OH/H2O solvent molecules. Variable-temperature (2-300 K) magnetic susceptibility along with variable-field magnetization measurements of 1-5 showed a decrease of the effective magnetic moment value at low temperature, indicative of the antiferromagnetic coupling of medium size (-55 to -22 cm-1). For these systems resembling a compressed prism the coupling constant in walls J4 correlates with the averaged bonding angles in walls alpha: J4vs. alpha develops approximately according to a straight line. PMID- 28561853 TI - Nickel-cobalt-layered double hydroxide nanosheet arrays on Ni foam as a bifunctional electrocatalyst for overall water splitting. AB - Bifunctional electrocatalysts, which are active both for the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER), can increase the efficiency of overall water splitting, which is considered an attractive technology for hydrogen production. In this study, we report NiCo-LDH ultrathin nanosheets grown on nickel foam as a bifunctional electrocatalyst for overall water splitting. When used as OER and HER electrodes, NiCo-LDH/NF demonstrated excellent water splitting performance, achieving a current density of 10 mA cm-2 at 1.66 V. Thus, the synthesis of hierarchical 3D porous structure composed of 2D ultrathin nanosheets in NiCo-LDH/NF demonstrated the significance of structural features for achieving a high electrocatalytic activity in overall water splitting. PMID- 28561851 TI - Reactivity of U-associated osteopontin with lactoferrin: a one-to-many complex. AB - Uranium is the heaviest natural element, mainly found in aqueous medium as the hexavalent uranyl ion (UO22+). Bones are the main organs in which uranium accumulates, depending on as yet unknown molecular and cellular mechanisms. Recently, it has been revealed that osteopontin (OPN), a protein involved in bio mineralization processes, and its main naturally occurring cleaved form (fOPN), have nanomolar affinities for UO22+. The binding of UO22+ is due to both the phosphorylation sites and acidic residues of these proteins and is accompanied by a slight gain in secondary structure. OPN is an Intrinsically Disordered Protein (IDP), a family of proteins which play a crucial role in several interaction networks, where phosphorylations are thought to be key elements. OPN has been shown to bind lactoferrin (LF) and the two proteins have antagonist functions in the modulation of the bio-mineralization process. However, to date, there has been no evidence that UO22+ and LF compete in their binding to OPN or not. Based on a series of convergent experimental data, this study first addressed in detail the LF/fOPN interaction and proposed a LF:fOPN 4/1 maximal stoichiometry. Moreover the phosphorylations were demonstrated to be necessary for the stability of such complexes. The interaction of preformed UO22+/fOPN complexes with LF was also investigated and the occurrence of several entities involving the three partners was demonstrated. These complexes did not reveal any significant conformational changes compared to those obtained in the absence of UO22+. The results have shown not only that LF and UO22+ do not compete, but also that these complexes are likely to be more stable than LF/fOPN complexes, as indicated by their melting temperature (Tm) values. The potential impact of those uranyl stabilized ternary complexes on some biological pathways now remains to be assessed. Nonetheless, this work has contributed to shedding light on the formation of stable ternary complexes involving a large structured protein, an IDP and an exogenous metal. PMID- 28561854 TI - Electrocatalytic proton reduction by a model for [NiFeSe] hydrogenases. AB - Two new heterodinuclear nickel-iron complexes [Ni(pbSmSe)FeCpCO]PF6 and [Ni(xbSmSe)FeCpCO]PF6 were synthesized as mimics of the [NiFeSe] hydrogenase active site (HCp = cyclopentadiene; H2pbSmSe = 1,9-diselenol-3,7-dithia-2,2,8,8 tetramethylnonane; H2xbSmSe = 1,2,-bis(2-thiabutyl-3,3-dimethyl-4 selenol)benzene). The compounds were characterized by single crystal X-ray diffraction and cyclic voltammetry. X-ray structure determinations showed that in both NiFe complexes the nickel(ii) center is in a square-planar S2Se2 environment; the two selenolate donors are bridging to the iron(ii) center that is further coordinated to an eta5-cyclopentadienyl group and a carbon monoxide ligand. Electrochemical studies showed that the complex [Ni(pbSmSe)FeCpCO]PF6 is an electrocatalyst for the production of H2 in DMF in the presence of acetic acid at -2.1 V vs. Fc+/Fc; a foot-of-the-wave (FOWA) analysis of the catalytic currents yielded an estimation of kobs of 24 s-1. PMID- 28561855 TI - The mechanism of ammonium bisulfate formation and decomposition over V/WTi catalysts for NH3-selective catalytic reduction at various temperatures. AB - In this study, the mechanism of ammonium bisulfate (ABS) formation and decomposition over V/WTi for the NH3-selective catalytic reduction (SCR) at various temperatures was deeply investigated. Bridged bidentate, chelating bidentate, and tridentate sulfates bound to TiO2 were formed as dominant intermediates at 200, 250, and 300 degrees C, respectively. These sulfates reacted with affinitive ammonium species to form ammonium (bi)sulfate species and also covered the active sites and embedded the VOSO4 intermediates, which resulted in an inferior intrinsic NH3-SCR conversion rate at 200 degrees C and 250 degrees C. At 300 degrees C, trace amounts of ABS on TiO2 presented no influence on the NH3-SCR performance. The electrons deviating towards sulfates through the bond between ABS and metal oxides (WO3 and TiO2) weakened the stability of ABS and lowered its decomposition temperature, whereas the vanadia species played the opposite role due to the sulfur species existing in an electron saturation state with the formation of the VOSO4 intermediate. The presence of NO + O2 could break the bonds inside ABS and it could react with the ammonium species originating from ABS, which pulls NH3 out of the ABS formation equilibrium and accelerates its decomposition and competitively inhibits its formation. Correspondingly, the faster NH3-SCR conversion rate and higher N2 selectivity improve the ABS poisoning resistance of the V/WTi catalyst at low temperatures. PMID- 28561856 TI - La(iii) biodistribution profiles from intravenous and oral dosing of two lanthanum complexes, La(dpp)3 and La(XT), and evaluation as treatments for bone resorption disorders. AB - Trivalent lanthanum (La3+) has the potential to treat bone resorption disorders (such as osteoporosis) by eliciting a bone-building response in the cells which control skeletal remodelling. Because La3+ suffers from extremely poor intestinal absorption, specifically designed chelators are required in order that a biologically active form of lanthanum can be administered orally. Two such chelators, 1,2-dimethyl-3-hydroxy-4-pyridinone (Hdpp) and bis {[bis(carboxymethyl)amino]methy}phosphinic acid (H5XT), have previously been the subjects of extensive physical, in vitro, and in vivo testing as the tris- and mono-lanthanum(iii) complexes La(dpp)3 and La(XT), respectively. In this manuscript, we expand upon those studies to include 4-week intravenous (IV) and oral La3+ biodistribution profiles, which show that the metal ion initially accumulates in the liver followed by preferential redistribution and retention by bone. Of the two compounds, La(XT) demonstrates the more favourable in vivo characteristics, therefore dose-dependent oral biodistribution studies were carried out with this complex. These show drug saturation above a dose of 100 mg kg-1 day-1, so liver histology was performed in order to assess any potential toxicity. Finally, we improve upon the physical characterization of La(dpp)3 to include a single crystal X-ray structure, which exhibits an 8-coorindate La3+ centre with two bound water molecules, and a disordered exoclathrate-type hydrogen bonded network. PMID- 28561858 TI - Palladium-catalyzed geometrically selective hydrogenation of (Z)-trifluoromethyl alkenyl triflate: an efficient approach to (Z) or (E)-3,3,3-trifluoropropenyl derivatives. AB - A Pd-catalyzed hydrogenation of (Z)-trifluoromethyl alkenyl triflate providing either (Z)- or (E)-3,3,3-trifluoropropenyl derivatives with excellent divergent geometric control in good yield is described. Catalyzed by Pd(OAc)2/PPh3, the reduction of (Z)-trifluoromethyl alkenyl triflates with HSiEt3 gave (E)-3,3,3 trifluoropropenyl derivatives, and while using HCOOH/Et3N as the reducing agent, the (Z)-isomers were obtained through an elimination/hydrogenation tandem pathway. Both transformations showed excellent geometrical selectivity. PMID- 28561849 TI - Symbiosis-inspired approaches to antibiotic discovery. AB - Covering: 2010 up to 2017Life on Earth is characterized by a remarkable abundance of symbiotic and highly refined relationships among life forms. Defined as any kind of close, long-term association between two organisms, symbioses can be mutualistic, commensalistic or parasitic. Historically speaking, selective pressures have shaped symbioses in which one organism (typically a bacterium or fungus) generates bioactive small molecules that impact the host (and possibly other symbionts); the symbiosis is driven fundamentally by the genetic machineries available to the small molecule producer. The human microbiome is now integral to the most recent chapter in animal-microbe symbiosis studies and plant microbe symbioses have significantly advanced our understanding of natural products biosynthesis; this also is the case for studies of fungal-microbe symbioses. However, much less is known about microbe-microbe systems involving interspecies interactions. Microbe-derived small molecules (i.e. antibiotics and quorum sensing molecules, etc.) have been shown to regulate transcription in microbes within the same environmental niche, suggesting interspecies interactions whereas, intraspecies interactions, such as those that exploit autoinducing small molecules, also modulate gene expression based on environmental cues. We, and others, contend that symbioses provide almost unlimited opportunities for the discovery of new bioactive compounds whose activities and applications have been evolutionarily optimized. Particularly intriguing is the possibility that environmental effectors can guide laboratory expression of secondary metabolites from "orphan", or silent, biosynthetic gene clusters (BGCs). Notably, many of the studies summarized here result from advances in "omics" technologies and highlight how symbioses have given rise to new anti-bacterial and antifungal natural products now being discovered. PMID- 28561861 TI - Publication Integrity, Accessibility, and Women Authors. AB - An implicit assumption of considerable importance is that manuscripts published in professional journals should reflect integrity on the part of authors, peer reviewers, and publishers. Unfortunately, some evidence continues to emerge that calls into question a view that all responsible parties are willing to play by the rules. PMID- 28561862 TI - A Volunteer Basketball Clinic for Children with Disabilities: Professional Development Impact on Student-Athletes and Physical Therapy Students. AB - The purpose of this study was to assess the change in perceptions of student athletes, physical therapy students, and parents of children who helped to facilitate an athletic skills camp for children with disabilities. Participants experienced 3 hours of basketball activity yearly. Data were collected for 3 consecutive years from a total of 51 parents, 15 student-athletes, and 22 physical therapy students. Pre- and post-survey data were evaluated by two independent researchers. Common themes were developed for all participant groups and cross-group comparisons were evaluated. Findings indicated a synergistic benefit for student-athletes and physical therapy students derived from their impact and children with disabilities. Perceptual changes in students included a decrease in fear in working with disabled children, an appreciation for the value of having fun, and increased growth in civic identity and desire to volunteer. PMID- 28561859 TI - Human calprotectin affects the redox speciation of iron. AB - We report that the metal-sequestering human host-defense protein calprotectin (CP, S100A8/S100A9 oligomer) affects the redox speciation of iron (Fe) in bacterial growth media and buffered aqueous solution. Under aerobic conditions and in the absence of an exogenous reducing agent, CP-Ser (S100A8(C42S)/S100A9(C3S) oligomer) depletes Fe from three different bacterial growth media preparations over a 48 h timeframe (T = 30 degrees C). The presence of the reducing agent beta-mercaptoethanol accelerates this process and allows CP Ser to deplete Fe over a ~1 h timeframe. Fe-depletion assays performed with metal binding-site variants of CP-Ser show that the hexahistidine (His6) site, which coordinates Fe(ii) with high affinity, is required for Fe depletion. An analysis of Fe redox speciation in buffer containing Fe(iii) citrate performed under aerobic conditions demonstrates that CP-Ser causes a time-dependent increase in the [Fe(ii)]/[Fe(iii)] ratio. Taken together, these results indicate that the hexahistidine site of CP stabilizes Fe(ii) and thereby shifts the redox equilibrium of Fe to the reduced ferrous state under aerobic conditions. We also report that the presence of bacterial metabolites affects the Fe-depleting activity of CP-Ser. Supplementation of bacterial growth media with an Fe(iii) scavenging siderophore (enterobactin, staphyloferrin B, or desferrioxamine B) attenuates the Fe-depleting activity of CP-Ser. This result indicates that formation of Fe(iii)-siderophore complexes blocks CP-mediated reduction of Fe(iii) and hence the ability of CP to coordinate Fe(ii). In contrast, the presence of pyocyanin (PYO), a redox-cycling phenazine produced by Pseudomonas aeruginosa that reduces Fe(iii) to Fe(ii), accelerates Fe depletion by CP-Ser under aerobic conditions. These findings indicate that the presence of microbial metabolites that contribute to metal homeostasis at the host/pathogen interface can affect the metal-sequestering function of CP. PMID- 28561864 TI - Longitudinal Tracking of Workplace Outcomes for Undergraduate Allied Health Students Undertaking Placements in Rural Australia. AB - : Creating positive experiences in rural practice at the undergraduate level can influence allied health students' attitudes to working rurally. This study aimed to evaluate allied health students' experiences of their short-term, medium-term, or long-term rural placement and to follow their career outcomes. METHODS: The study used a mixed-methods design that utilised qualitative and quantitative data. Students from six allied health degree programs undertaking placements in Tamworth and Taree were invited to participate. Participation comprised of a series of surveys and an individual in-depth semi-structured interview. RESULTS: 198 students completed 257 end-of-placement surveys as of June 2014, with 72.7% reporting an intention to work rurally after placement. Fifty-five percent (n=51) of the 92 students who had never lived in a rural area had a more favourable attitude towards working rurally following placement. After 1 year, 50% of graduates were working in a rural or remote location, compared to 23.7% of all graduates from these disciplines. CONCLUSIONS: Preliminary findings indicated a positive perception of the rural placement experience and impact on intention to work rurally or in a rural location, particularly from those who had not previously spent time in a rural area. Future directions are to investigate longer-term workforce outcomes and the impact on the rural health workforce. PMID- 28561863 TI - Academic Achievement, Perceived Stress, Admission Data, and Sociodemographic Background Among Therapy Students in Israel. AB - BACKGROUND: Academic achievement (AA) is of great importance in the academic world. The aims of this study were to: 1) identify contributors to AA of physical therapy (PT) students; 2) evaluate students' perceived stress (PS); and 3) identify contributors to PS. METHODS: A cross-sectional study involving three undergraduate PT classes in a single academic year was performed 1 week prior to final examinations. Current grade point average (GPA) and admission data were collected from administrative records. Additional data, collected using an online questionnaire, included the Perceived Stress Scale 10 (PSS), Scale for Assessing Academic Stress (SAAS), and selected sociodemographic variables. Regression analysis identified contributors to AA and to PS. RESULTS: Records of 153 students and questionnaires of 118 students were included in the study. Combined grades from psychometric tests and matriculation exams at admission, low PS, absence due to military reserve service during the academic year, and participation in the second and third years of the PT program accounted for a modest variance (31.1% ) in students' GPA. CONCLUSIONS: The low contribution of admission criteria to GPA suggests that there is no justification for raising the level of the present criteria. PMID- 28561865 TI - Assessing Health Professional Students' Cultural Competence Using a Global Perspective. AB - BACKGROUND: The United States has become a diverse society, and healthcare professionals must view culture from a global perspective. The purpose of this study was to determine cultural competence levels of entering and exiting health science students within and across differing professional programs using the Global Worldview Cultural Competence Survey (GWCCS). PARTICIPANTS: 196 students participated in the study: 146 were entering students and 59 were exiting students. From the 146 entering students, 138 surveys were usable in the data analysis, and 58 of the 59 exiting were usable. PROCEDURE: Two separate cohorts of health professional students completed the GWCCS. Cohort 1 completed the GWCCS during the first 2 weeks of their academic program, and Cohort 2 completed the GWCCS in their final-year post-clinical experience. RESULTS: A significant difference in GWCCS total score was observed between entering and exiting students in health sciences, with the exiting students being more culturally competent. CONCLUSION: Although this study did not utilize a longitudinal study design, the findings demonstrate that the exiting cohort of health science students was more culturally competent than the entering cohort of health science students as determined by the GWCCS. However, neither cohort of students reached the level of proficiency. PMID- 28561866 TI - Institutional Readiness for Interprofessional Education Among Nutrition and Dietetics and Athletic Training Education Programs. AB - Organizations recommend interprofessional education (IPE) as a means of promoting collaborative patient-centered care. In turn, various external accreditors in the health professions have integrated IPE competencies into their standards. However, little is known about how athletic training (AT) and nutrition and dietetics (ND) have incorporated IPE into their educational programs. This study examined institutional factors that affect the level of IPE participation within ND and AT programs in the United States. The Interprofessional Education Assessment and Planning Instrument for Academic Institutions was distributed electronically to directors of accredited programs in ND and AT. In addition to gathering demographic information, survey questions addressed the institutions' level of involvement and commitment to IPE. Differences emerged between ND and AT programs for several items in the instrument. Factors that affected the differences included program level and academic unit in which the program resides. Results also suggest that ND and AT programs have similar levels of IPE participation, but there are great opportunities for growth. Institutional factors such resource commitment, academic unit type, and level of program may affect implementation and contribute to the development and success of IPE initiatives. PMID- 28561867 TI - Effectiveness of EvenupTM Shoe-Lift Use Among Individuals Prescribed a Walking Boot. AB - BACKGROUND: Walking boots are prescribed after foot and ankle injuries, allowing immediate ambulation for patients. However, temporary limb-length inequality (LLI) may result, causing dysfunction and pain, including low back pain. The EvenupTM shoe-lift was designed to eliminate joint pathology, pain, and gait deviations resulting from walking-boot-induced LLI, yet no clinical trials have been reported on its effectiveness. METHODS: Thirty-four subjects undergoing unilateral lower-extremity orthopedic medical and rehabilitative care were recruited for this study. Seventeen subjects were assigned to an intervention group using a walking boot on the foot of their involved side and the EvenupTM on the other foot, while the control group used a walking boot only on the involved side. Outcome measures included the lower extremity functional scale (LEFS), modified Oswestry low back pain disability questionnaire (OSW), numeric pain rating scale, ankle range of motion (ROM) and strength. RESULTS: All subjects, regardless of the intervention, demonstrated improved function, decreased pain, increased ROM, and increased strength. Additionally, a clinically relevant difference was found between the intervention and control groups for the OSW and LEFS. CONCLUSION: LEFS and OSW results suggest EvenupTM use added value in the form of improved patient function. PMID- 28561868 TI - Improving Critical Thinking Using a Web-Based Tutorial Environment. AB - With a broad range of subject matter, students often struggle recognizing relationships between content in different subject areas. A scenario-based learning environment (SaBLE) has been developed to enhancing clinical reasoning and critical thinking among undergraduate students in a medical laboratory science program and help them integrate their new knowledge. SaBLE incorporates aspects of both cognitive theory and instructional design, including reduction of extraneous cognitive load, goal-based learning, feedback timing, and game theory. SaBLE is a website application that runs in most browsers and devices, and is used to develop randomly selected scenarios that challenge user thinking in almost any scenario-based instruction. User progress is recorded to allow comprehensive data analysis of changes in user performance. Participation is incentivized using a point system and digital badges or awards. SaBLE was deployed in one course with a total exposure for the treatment group of approximately 9 weeks. When assessing performance of SaBLE participants, and controlling for grade point average as a possible confounding variable, there was a statistically significant correlation between the number of SaBLE levels completed and performance on selected critical-thinking exam questions addressing unrelated content. PMID- 28561869 TI - Caregivers Are Heroes: An Innovative Educational Strategy Designed to Promote Compassion/Caring in Health Professional Students. AB - BACKGROUND: Compassionate care is recognized as an intrinsic element of patient centered care. Although the evidence seems to indicate that compassionate care can be developed in health professions students, few methodologies reported have been interprofessional in nature. This paper describes Caregivers Are Heroes, an interprofessional educational strategy designed to imbue compassion/caring. METHODS: The sample population consisted of 51 caregivers and 170 students enrolled in three graduate programs during the 2014 summer semester. Students conducted caregiver interviews (CGI) in interprofessional groups of 3 to 4 students. Pre- and post-CGI surveys were designed to measure change in student attitudes and perceptions from the CGI experience. Questions were taken from the Attitude Towards Helping Others (AHO) scale and the Zarit Burden Interview Screen (ZBIS). RESULTS: Analysis indicated a significant change in responses for one of the four AHO statements and significant correlation between caregiver ZBIS score and student post-CGI ZBIS score. CONCLUSION: Quantitative outcomes support the use of this strategy to promote changes in student attitudes that might lead to caring and compassion when interacting with caregivers and the recipients of their care. The variability of caregiver ZBIS scores is consistent with the literature on caregiver burden and emphasizes the need for students to appreciate the individuality of the caregiver experience. PMID- 28561870 TI - Physical Therapist Students' Perceptions from Performing Strength and Conditioning Training: Academic, Professional, and Clinical Benefits. AB - BACKGROUND: The purpose of this qualitative study was to assess the perceptions of Doctor of Physical Therapy (DPT) students in performing collegiate athletes' strength and conditioning training. METHODS: Four DPT students with the Certified Strength and Conditioning Specialist (CSCS) credential voluntarily provided collegiate athletes strength and conditioning training. Students were interviewed to obtain their perceptions of how the experience impacted performance in DPT school and perceptions of anticipated future benefits. RESULTS: Seven themes emerged from interviews: improved communication skills, movement analysis experience, improved time management/organization, increased understanding of exercises, attention to psychosocial aspects, interprofessional experience, and improved performance in coursework. CONCLUSION: DPT students with the CSCS credential perceived benefits from performing strength and conditioning training outside the standard DPT curriculum. PMID- 28561871 TI - Promoting Role Clarity for Health Professional Students Participating in an Interprofessional Behavior Change Counseling Workshop. AB - Interprofessional role clarity is linked to improving team collaboration and clinical care, yet there are barriers to implementing interprofessional curricula targeted to learner achievement of this competency. A behavior change counseling skills workshop for first-year advanced practice nursing (APN) (n=153) and third year pharmacy (PharmD) (n=127) students was modified to include learning experiences for enhancing interprofessional role clarity. Students rated the importance of each profession's contributions in nine patient care activities before and after the workshop. APN and PharmD students increased their ratings of the merit of each profession in counseling patients in several care activities. Findings suggest that providing interprofessional students an opportunity to learn core skills together can also foster an understanding of each other's professional roles and responsibilities. PMID- 28561872 TI - Prevalence and Predictors of Anxiety in Doctor of Physical Therapy Students. AB - Anxiety is a condition with multiple physical manifestations and sequelae, including negatively impacting learning. The prevalence of anxiety and the factors that predict it in health professions students are unknown. The current study assessed the prevalence of anxiety in DPT students and examined the predictors of anxiety. The findings showed high student anxiety levels that were analogous to military recruits. Female gender and low GPA were predictors of anxiety in the sample. Further research is necessary to determine other factors that contribute to anxiety so that interventions to reduce anxiety in health professions students can be initiated. PMID- 28561873 TI - The Reciprocity Team: Development of an Interprofessional Research Collaboration. AB - The purpose of this article is to articulate and provide detail about an interprofessional research collaboration at a public university in a rural area of western United States. This interprofessional research collaboration was organized to explore infant and maternal reciprocity. As a part of the organization and process portion of the collaborative effort, the authors identify the unique attributes of their collaboration. Additionally, barriers to collaborative research are presented, with opportunities and recommendations made to support existing and future interprofessional collaborative efforts for basic science scholars, clinicians, and educators in health-related professions. PMID- 28561874 TI - A Review of 52 Pedigrees with Epidermolysis Bullosa Simplex Identifying Ten Novel Mutations in KRT5 and KRT14 in Australia. AB - Epidermolysis bullosa simplex (EBS) is a rare heritable skin fragility disorder, most commonly caused by dominant mutations in KRT5 and KRT14. EBS shows clinical heterogeneity with localised, intermediate and generalised severe forms, which tend to correlate with the location and nature of the disease causing mutations. We therefore aimed to identify the KRT5 and KRT14 mutations in patients diagnosed with EBS in Australia, and explore in depth the genotype to the phenotype correlations in patients with novel variants. Australian patients who were diagnosed with EBS after referral to the Australian National Diagnostic Laboratory for EB were offered mutation screening in the KRT5 and KRT14 genes. From this, 32 different mutations in KRT5 and KRT14 were identified within 39 of 52 pedigrees. Ten of these mutations from 9 different pedigrees were novel, a further fatal case caused by KRT5 E477K is reported and in addition the third reported case of digenic inheritance in EBS was also observed. PMID- 28561875 TI - Prurigo Pigmentosa in a 21-year-old Caucasian Man: A Clinicopathological Correlation. AB - is missing (Short communication). PMID- 28561876 TI - Methotrexate-associated Sexual Dysfunction: Two Case Reports. AB - is missing (Short communication). PMID- 28561877 TI - Subcutaneous Nodule on the Right Palm of a Young Boy: A Quiz. AB - is missing (Quiz). PMID- 28561878 TI - Epidemiology-based assessment of tumor marker overordering in breast cancer: an algorithm to examine different disease conditions. AB - Laboratory tests are frequently overused and have elevated inappropriateness rates. We previously developed a model to investigate the rate of utilization of tumor markers (TMs) in outpatients as an indirect indicator of inappropriateness. The model was based on the comparison between the number of actually ordered and expected tests, with the latter estimated on the basis of both epidemiological data and recommendations of available clinical practice guidelines.In this paper we propose an algorithm to distinguish prevalent cases without evidence of disease from those with metastatic spread, on the basis of both epidemiological and clinical information. The algorithm allows for a more precise prediction of the expected TM requests per year, to be compared with the actual number of requested TMs in order to assess possibly inappropriate overordering rates. Moreover, the implementation of the algorithm renders the epidemiologically based model more flexible to develop accurate indicators for appropriateness in the use of TMs in different stages of disease and for different clinical questions. A practical application with CA15.3 requests in breast cancer is presented. PMID- 28561879 TI - Des-gamma-carboxy prothrombin in hepatocellular cancer patients waiting for liver transplant: a systematic review and meta-analysis. AB - BACKGROUND: The use of des-gamma-carboxy prothrombin (DCP) as a predictor of the risk of recurrence of hepatocellular cancer (HCC) after liver transplant (LT) has recently gained interest, especially in view of the recent extension of the eligibility criteria of these patients for LT. The aim of the present study is to look into this important matter based on a systematic review and meta-analysis. METHODS: A systematic literature review about the role of DCP in the specific setting of LT for HCC has been conducted. RESULTS: Three selected studies, which showed a high rate of homogeneity (I2 = 0.0%), confirmed that the tumor marker DCP is a useful predictive factor, indicating a 5-fold increased risk for HCC recurrence after LT (p<0.001). CONCLUSIONS: The meta-analysis enabled us to underline the importance of DCP in the refinement of the eligibility criteria of HCC patients for LT. This information, based on Japanese studies performed in the setting of living-donor LT only, needs further validation in the Western world both in the setting of post-mortem and living-donor LT. PMID- 28561880 TI - Meta-analysis of prognostic role of Ki-67 labeling index in gastric carcinoma. AB - BACKGROUND: This meta-analysis aimed to elucidate the prognostic role of the Ki 67 labeling index (LI) in gastric cancer (GC). METHODS: The current study included 3,615 GC patients in 20 eligible studies, and evaluated the prognostic role of Ki-67 LI in GC. Subgroup analysis was conducted based on depth of invasion and cutoff value for high Ki-67 LI. RESULTS: A high Ki-67 LI correlated significantly with worse survival (hazard ratio [HR] = 1.214, 95% confidence interval [CI], 1.004-1.468). However, there was no significant correlation between high Ki-67 LI and worse survival in advanced GC (HR = 1.252, 95% CI, 0.801-1.956). The subgroup with cutoff value <=25% showed a significant correlation with worse survival, but this was not seen in the subgroup with cutoff >25% (HR = 1.433, 95% CI, 1.094-1.876 vs. HR = 1.005, 95% CI, 0.801 1.262). In addition, in the 10% =70) for the SCHFI. Lower knowledge, income, and educational level, shorter duration of disease, fewer people living at home, older age, and being unemployed were significant predictors of low self-care scores. Characteristics of the cultural, social, and healthcare environment in Jordan may help explain some results. Nurses may play a role in improving knowledge and self-care among patients with heart failure in Jordan. Studies of the effect of educational programs on knowledge and self-care among patients with heart failure are recommended. PMID- 28561897 TI - Temperature and Preeclampsia: Is the Association Valid? PMID- 28561896 TI - Creating a placental inflammatory composite index that has a high prognostic relevance to child morbidity. AB - AIM: Selecting pathologic measures of placental inflammation that affect pregnancy and childhood health is largely empirical. We aimed to systematically select several core inflammation-related placental measures to construct a novel placental inflammatory evaluation criterion with a high prognostic relevance to child morbidity. METHODS: We used data from the US Collaborative Perinatal Project (1959-1976), a longitudinal birth cohort study that recruited women during pregnancy and followed the children until 7 years of age. Bootstrap resampling, least absolute shrinkage and selection operator, and receiver operator curve were used to select placental pathologic measures that were closely related to child morbidity to form a placental inflammatory composite index. RESULTS: Twenty-six candidate placental inflammation-related measures were ranked based on their close association with adverse neonatal outcomes. The top five placental measures were: (i) neutrophilic infiltration in umbilical artery; (ii) placental weight-birthweight ratio; (iii) necrosis in decidua capsularis; (iv) bacterial colony in epithelium of amnion; and (v) opacity of membranes and fetal surface. Several composite indexes were constructed. A five-measure composite index that had the highest prognostic relevance was chosen. Compared with subjects without any of the five abnormal measures, those with any lesion ranging from 1 to 5 had a 1.2- to 4.6-fold risk of adverse child outcomes, respectively. CONCLUSION: Our composite index is simple, evidence-based, and has predictive value for child morbidity. It may be used as a novel placental inflammatory evaluation criterion. PMID- 28561893 TI - Extrinsic regulation of hematopoietic stem cells in development, homeostasis and diseases. AB - Lifelong generation of blood and immune cells depends on hematopoietic stem cells (HSCs). Their function is precisely regulated by complex molecular networks that integrate and respond to ever changing physiological demands of the body. Over the past several years, significant advances have been made in understanding the extrinsic regulation of HSCs during development and in homeostasis. Propelled by technical advances in the field, the cellular and molecular components of the microenvironment that support HSCs in vivo are emerging. In addition, the interaction of HSCs with their niches is appreciated as a critical contributor to the pathogenesis of a number of hematologic disorders. Here, we review these advances in detail and highlight the extrinsic regulation of HSCs in the context of development, homeostasis, and diseases. WIREs Dev Biol 2017, 6:e279. doi: 10.1002/wdev.279 For further resources related to this article, please visit the WIREs website. PMID- 28561899 TI - A Big Data Analysis Approach for Rail Failure Risk Assessment. AB - Railway infrastructure monitoring is a vital task to ensure rail transportation safety. A rail failure could result in not only a considerable impact on train delays and maintenance costs, but also on safety of passengers. In this article, the aim is to assess the risk of a rail failure by analyzing a type of rail surface defect called squats that are detected automatically among the huge number of records from video cameras. We propose an image processing approach for automatic detection of squats, especially severe types that are prone to rail breaks. We measure the visual length of the squats and use them to model the failure risk. For the assessment of the rail failure risk, we estimate the probability of rail failure based on the growth of squats. Moreover, we perform severity and crack growth analyses to consider the impact of rail traffic loads on defects in three different growth scenarios. The failure risk estimations are provided for several samples of squats with different crack growth lengths on a busy rail track of the Dutch railway network. The results illustrate the practicality and efficiency of the proposed approach. PMID- 28561898 TI - Validation of a Point-of-Care Quantitative Equine IgG Turbidimetric Immunoassay and Comparison of IgG Concentrations Measured with Radial Immunodiffusion and a Point-of-Care IgG ELISA. AB - BACKGROUND: Point-of-care (POC) diagnostic tests with good sensitivity and specificity are needed for diagnosing failure of transfer of passive immunity (FTPI) in foals. Turbidimetric immunoassays (TIA) have these characteristics and provide quantitative results. A commercially available TIA-based POC test (POC TIA) has not been validated in horses. OBJECTIVE: To validate a POC-TIA and compare results of POC-TIA, a POC-ELISA, and radial immunodiffusion (RID). ANIMALS: Heparinized blood samples (n = 127) from 48 hospitalized foals (<12 hour to 48 days). METHODS: Prospective validation study. IgG concentrations were measured using RID (gold standard), POC-TIA, and POC-ELISA. Agreement between assays was assessed using Bland-Altman analysis. Sensitivity and specificity were calculated using ROC curves. Inter- and intra-assay coefficients of variation (CVs) and linearity were evaluated for POC-TIA. RESULTS: The mean bias (95% limits of agreement) between RID and POC-TIA was -4 (-185 to 176), 27 (-201 to 255), and 308 (-377 to 993) mg/dL for samples with IgG concentrations of <400, 400-800, and >800 mg/dL, respectively. Sensitivity and specificity at optimal cutoff were 94 and 100% for the POC-TIA and 94 and 100% for the POC-ELISA to detect IgG <400 mg/dL, and 85 and 87% (POC-TIA) and 69 and 79% (POC-ELISA) to detect IgG <=800 mg/dL. Intra- and interassay CVs for POC-TIA ranged between 1.6 3.8 and 11.9-18.8%, respectively. Linearity of the dilution series was preserved (R2 > 0.96). CONCLUSIONS AND CLINICAL IMPORTANCE: The POC-TIA provided unambiguous results and had sufficient sensitivity, specificity, accuracy, and precision to be used as an alternative to other POC tests to assess FTPI in foals. PMID- 28561901 TI - Psychosocial factors and traumatic dental injuries among adolescents. AB - OBJECTIVES: To examine the association of traumatic dental injuries (TDI) and psychosocial factors in adolescents and to identify psychological profiles associated with TDI. METHODS: A cross-sectional study was conducted involving 531 students aged 13-16 years. Data were collected through oral examination and a structured interview with the adolescents, in conjunction with a questionnaire answered by their mothers. Associations between TDI and independent variables were analysed using a model-based approach, while an exploratory data analysis was applied to identify homogenous clusters of adolescents in relation to their sense of coherence (SoC), perception of parental support and their mothers' SoC. These clusters were examined further for associations with TDI and psychosocial variables. RESULTS: The prevalence of TDI was 15.8%. Adolescents with high TDI prevalence were males, nonfirstborns, or those frequently engaging in physical activity. In addition, both their own SoC and that of their mother were low and they reported low parental support. They were also prone to complaining about the behaviour of their peer group. The hierarchical cluster analysis (HCA) demonstrated three homogenous clusters. The cluster with the highest scores for all psychological variables included adolescents with low TDI prevalence, low paternal punishment, spacious home environment, high Family Affluence Scale (FAS) score, good school grades, few complaints about schoolmates and higher maternal education. CONCLUSIONS: Psychosocial factors appear to influence an adolescent's risk of TDI. High parental support, high own and maternal SoC and a higher socioeconomic status (SES) are typical of adolescents with low TDI experience. PMID- 28561900 TI - Muscle changes in patients with diabetes and chronic exertional compartment syndrome before and after treatment with fasciotomy. AB - INTRODUCTION: Muscle changes in patients with diabetes and lower leg pain due to chronic exertional compartment syndrome (CECS) were investigated before and after fasciotomy. METHODS: The tibialis anterior muscle was analyzed with histochemical and morphological techniques in 7 patients with diabetes and CECS before fasciotomy and in 5 of them 1 year after fasciotomy. Nondiabetic patients with CECS and healthy participants served as references. RESULTS: Before treatment, walking distance until occurrence of pain was limited (<0.2 km). Intramuscular pressure was significantly higher than in reference participants. Muscle analysis showed changes pathognomonic for neuropathy and myopathy and a restricted capillary network, with significantly more severe changes in the muscles of patients with diabetes than in the muscles of nondiabetic patients. Treatment with fasciotomy improved clinical signs, increased walking ability, and reduced muscle abnormalities, but muscle capillarization remained low. DISCUSSION: Patients with diabetes and CECS have distinct pathological changes in affected muscles. Pressure-relieving fasciotomy triggers a regenerative response in the muscle tissue but not in the capillary bed. Muscle Nerve 57: 229-239, 2018. PMID- 28561902 TI - Safety and Pharmacokinetics of Bendamustine Rapid-Infusion Formulation. AB - Bendamustine hydrochloride (BDM) is approved in the United States to treat chronic lymphocytic leukemia and relapsed indolent B-cell non-Hodgkin lymphoma. The first formulation marketed in the United States (original BDM) was a lyophilized product requiring reconstitution prior to dilution to the final admixture. A liquid formulation of BDM was subsequently introduced that did not require reconstitution before dilution. Both formulations are administered as a 500 mL admixture with a recommended infusion time of 30 or 60 minutes for chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma, respectively. A newer liquid BDM formulation (rapid BDM) is a ready-to-dilute solution not requiring reconstitution that dilutes into an admixture of only 50 mL and can be safely administered in a shorter infusion time (10 minutes). Rapid BDM admixture also has longer stability at room temperature than both lyophilized and liquid BDM formulations (6 vs 2 to 3 hours). This phase 1, open-label, randomized, crossover (3-period, partially replicated) study, conducted in "end-of-life" cancer patients at 10 oncology centers in the United States, demonstrates that rapid BDM is bioequivalent to original BDM as determined by area under the curve. Expected differences in maximum plasma concentration and time to maximum plasma concentration were observed between study treatments, given the substantially shorter infusion time of rapid BDM. No clinically relevant differences in other evaluated pharmacokinetic parameters were found. Rapid BDM infusions were safe and tolerable for cancer patients in this study. The overall safety profiles of the 2 BDM formulations were comparable, with no new safety signals identified and no differences in infusion-related adverse events. PMID- 28561905 TI - Calibrated brightfield-based imaging for measuring intracellular protein concentration. AB - Intracellular protein concentration is an essential cell characteristic, which manifests itself through the refractive index. The latter can be measured from two or more mutually defocused brightfield images analyzed using the TIE (transport-of-intensity equation). In practice, however, TIE does not always achieve quantitatively accurate results on biological cells. Therefore, we have developed a calibration procedure that involves successive imaging of cells in solutions containing different amounts of added protein. This allows one to directly relate the output of TIE (T) to intracellular protein concentration C (g/L). The resultant relationship has a simple form: C ~ 1.0(T/V), where V is the cell volume (MUm3 ) and 1.0 is an empirical coefficient. We used calibrated TIE imaging to characterize the regulatory volume increase (RVI) in adherent HeLa cells placed in a hyperosmotic solution. We found that while no RVI occurs over the first 30-60 min, the protein concentration fully recovers after 20 h. Because interpretation of such long experiments may depend on whether protein concentration varies significantly throughout the cell cycle, we measured this parameter in three cell lines: HeLa, MDCK and DU145. Our data indicate that protein concentration remains relatively stable in these cells. (c) 2017 International Society for Advancement of Cytometry. PMID- 28561904 TI - Neonatal abstinence syndrome: Neurobehavior at 6 weeks of age in infants with or without pharmacological treatment for withdrawal. AB - Use and abuse of prescription opioids and concomitant increase in Neonatal Abstinence Syndrome (NAS), a condition that may lead to protracted pharmacological treatment in more than 60% of infants, has tripled since 2000. This study assessed neurobehavioral development using the NICU Network Neurobehavioral Scale in 6-week old infants with prenatal methadone exposure who did (NAS+; n = 23) or did not (NAS-; n = 16) require pharmacological treatment for NAS severity determined by Finnegan Scale. An unexposed, demographically similar group of infants matched for age served as comparison (COMP; n = 21). NAS+, but not NAS- group, had significantly lower scores on the regulation (p < .01) and quality of movement (p < .01) summary scales than the COMP group. The NAS+ and NAS- groups had higher scores on the stress-abstinence scale than the COMP group (p < .05). NAS diagnosis (NAS +) was associated with poorer regulation and quality of movement at 6 weeks of age compared to infants without prenatal methadone exposure from the same demographic. PMID- 28561903 TI - Arcuate nucleus neuropeptide coexpression and connections to gonadotrophin releasing hormone neurones in the female rhesus macaque. AB - The underlying hypothalamic neurocircuitry by which metabolism and feeding regulates reproductive function has been well-studied in the rodent; however, recent data have demonstrated significant neuroanatomical differences in the human brain. The present study had three objectives, centred on arcuate nucleus neuropeptides regulating feeding and reproduction: (i) to characterise coexpression patterns in the female nonhuman primate; (ii) to establish whether these neuronal populations make potential contacts with gonadotophin-releasing hormone (GnRH) neurones; and (iii) to determine whether these contacts differ between the low and high GnRH-releasing states of pre-puberty and adulthood, respectively. Female nonhuman primates have several coexpression patterns of hypothalamic neuropeptides that differ from those reported in rodents. Cocaine- and amphetamine-regulated transcript (CART) is not coexpressed with pro opiomelanocortin but instead with neuropeptide Y (NPY). CART is also expressed in a subpopulation of kisspeptin cells in the nonhuman primate, similar to observations in humans but diverging from findings in rodents. Very few GnRH expressing neurones received close appositions from double-labelled kisspeptin/CART fibres; however, both single-labelled kisspeptin and CART fibres were in frequent apposition with GnRH neurones, with no differences between prepubertal and adult animals. NPY/agouti-related peptide (AgRP) coexpressing fibres contacted significantly more GnRH neurones in prepubertal animals than adults, consistent with increased NPY and AgRP mRNA observed in prepubertal animals. The findings of the present study detail significant differences in arcuate nucleus neuropeptide coexpression in the monkey compared to the rodent and are consistent with the hypothesis that arcuate nucleus NPY/AgRP neurones play an inhibitory role in controlling GnRH neuronal regulation in the prepubertal primate. PMID- 28561906 TI - Outcomes and patterns of failure for sinonasal undifferentiated carcinoma (SNUC): The Mayo Clinic Experience. AB - BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) is a rare aggressive disease arising in the nasal cavity and paranasal sinuses with poor prognosis and unclear optimal management. METHODS: Forty patients were analyzed. Nasal cavity was the most common primary site. Most patients presented with T4 disease, received trimodality therapy, and were treated with intensity-modulated radiotherapy (IMRT). RESULTS: Median follow-up was 6.9 years. Sixteen patients (40%) experienced recurrent disease, 5 local (12.5%), 1 regional (2.5%), and 10 distant (25%). The 5-year overall survival (OS), recurrence-free survival (RFS), and locoreginal control (LRC) were 44%, 39%, and 71%, respectively. Patients treated with trimodality therapy had better outcomes compared to single modality therapy. Improved OS was noted with IMRT and with doses >=60 Gy. The most common cause of death was distant metastasis. CONCLUSION: SNUC is an aggressive malignancy with a high tendency to metastasize. Better outcomes were obtained with a trimodality approach. Modern radiotherapy (RT) techniques and doses >= 60 Gy were associated with improved OS. PMID- 28561907 TI - Clinical significance of epithelial-to-mesenchymal transition in laryngeal carcinoma: Its role in the different subsites. AB - BACKGROUND: During epithelial-to-mesenchymal transition, cancer cells lose adhesion capacity gaining migratory properties. The role of the process on prognosis has been evaluated in 50 cases of laryngeal carcinoma. METHODS: E cadherin, N-cadherin, beta-catenin, alpha-catenin, gamma-catenin, caveolin-1, and vimentin immunohistochemical expression were evaluated using a double score based on staining intensity and cellular localization. RESULTS: Cytoplasmic E-cadherin and alpha/gamma catenin staining were associated with a decrease in survival, cytoplasmic beta-catenin was associated with advanced stage, and N-cadherin and vimentin expression were associated with poor differentiation and tumor relapse. On the basis of cancer cells, epithelial or mesenchymal morphological and immunophenotypic similarity we identified 4 main subgroups correlated with a transition to a more undifferentiated phenotype, which have a different pattern of relapse and survival. CONCLUSION: The negative prognostic role of epithelial to-mesenchymal transition has been confirmed and a predictive role in glottic tumors has been suggested, leading us to propose epithelial-to-mesenchymal transition as an additional adverse feature in laryngeal carcinoma. PMID- 28561908 TI - Successful treatment of uterine artery pseudoaneurysm with laparoscopic temporary clamping of bilateral uterine arteries, followed by hysteroscopic surgery. AB - Surgical strategies for the treatment of uterine artery pseudoaneurysm (UAP) include transarterial embolization and ultrasound-guided low-dose thrombin injection. Such strategies, however, have limitations and include the risk of ischemic damage to the uterus. We report a case of UAP treated with a new hysteroscopic and laparoscopic technique. A 29-year-old G1P0 woman with spontaneous abortion was transferred to the present institution because of hemorrhagic shock. We diagnosed ruptured UAP on transvaginal ultrasound with color Doppler. Emergency laparoscopic temporary clamping of the bilateral uterine arteries was done to reduce the bleeding, and transcervical resection to stop the hemorrhaging and to collect the pseudoaneurysm tissue. After surgery, blood flow to the myometrium was monitored on ultrasound. By postoperative day 48, normal menstruation had restarted, and no intrauterine adhesions were observed. On pathology of the UAP, a dilated spiral artery without its characteristic elastic fibers was identified. This surgical approach may help preserve fertility and allow for pathological diagnosis of UAP. PMID- 28561909 TI - Electrodiagnostic tests are unlikely to change management in those with a known cause of typical distal symmetric polyneuropathy. PMID- 28561910 TI - Assessment of porosity index of the femoral neck and tibia by 3D ultra-short echo time MRI. AB - PURPOSE: To measure the porosity index (PI) by ultrashort echo-time magnetic resonance imaging (UTE MRI) of the femoral neck and tibia; assess its correlations with age, gender, and body mass index (BMI); and analyze the PI correlations between both sites to assess whether tibial PI can reflect changes of femoral neck PI. MATERIALS AND METHODS: In all, 68 healthy men and women (mean age, 45.7 +/- 15.9 years) underwent 3D UTE MRI (3.0T) of the hip and mid-shaft tibia. PI of the inferior femoral neck cortex and the whole cortex of the tibia were analyzed. Associations between parameters and differences of PIs between men and women, pre- and postmenopausal women were tested. RESULTS: Femoral neck PI was negatively correlated with age (r = -0.385, P = 0.043) and curvilinearly correlated with BMI (R2 = 0.225, P = 0.041) in men. Tibial PI was correlated with BMI (r = -0.477, P = 0.002) in women and age (r = 0.469, P = 0.043) in postmenopausal women, although P = 0.097 (r = 0.403) after adjustment for BMI. Femoral PI was significantly higher in men than in women (P < 0.001). No significant difference in femoral and tibial PI was observed between pre- and postmenopausal women. The femoral neck and tibial PIs were not significantly correlated in any group. CONCLUSION: PIs had some correlations with age, gender, and BMI. Since femoral neck PI was not correlated with tibial PI, the tibia cannot substitute the femoral neck for estimating bone quality. Direct assessment of the femoral neck cortex is needed. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2018;47:820-828. PMID- 28561911 TI - Biofilm formation and virulence factor analysis of Staphylococcus aureus isolates collected from ovine mastitis. AB - AIMS: To perform a phenotypic and genotypic characterization of 258 Staphylococcus aureus isolates from clinical ovine mastitis and used for the preparation of inactivated autogenous vaccines. METHODS AND RESULTS: The potential for biofilm production was determined by phenotypic test of Congo Red Agar (CRA) and by PCR for the detection of icaA/D genes. Isolates were also screened by PCR for the presence of enterotoxins (sea, seb, sec, sed and see), toxic shock syndrome toxin (tsst), leukotoxins (lukD-E, lukM and lukPV83), haemolysins (hly-beta and hly-gamma), autolysin (atlA) genes and encoding microbial surface components recognizing adhesive matrix molecules (MSCRAMMs: clfA, clfB, fnbA, fnbB, bbp, cna, eno, fib, epbs, sdrC, sdrD and SdrE). None of the 258 isolates showed biofilm-forming ability on CRA and harboured icaA/D genes. The most frequent pyrogenic toxin superantigen genes amplified were sec plus tsst-1, which were found strictly in combination with 71.3% of the Staph. aureus isolates tested. None of the isolates harboured the genes encoding sea and see. Of the 258 isolates tested, 159 (61.6%) possessed all lukD-E/lukM/lukPV83 genes, 123 (47.7%) harboured both hly-beta/hly-gamma genes, whereas almost all (97.3%) were PCR positive for atlA gene. With respect to adhesion determinants, 179 (69.4%) isolates presented simultaneously four genes (fnbA, fib, clfA and clfB) for fibronectin- and fibrinogen-binding proteins. CONCLUSIONS: In this search, several putative virulence determinants have been identified in ovine Staph. aureus isolates collected in Sardinia. SIGNIFICANCE AND IMPACT OF THE STUDY: Some of the putative virulence determinants could be considered as components of a vaccine because of their role in ovine mastitis pathogenesis. PMID- 28561912 TI - Crystallization Kinetics and Morphology Control of Formamidinium-Cesium Mixed Cation Lead Mixed-Halide Perovskite via Tunability of the Colloidal Precursor Solution. AB - The meteoric rise of the field of perovskite solar cells has been fueled by the ease with which a wide range of high-quality materials can be fabricated via simple solution processing methods. However, to date, little effort has been devoted to understanding the precursor solutions, and the role of additives such as hydrohalic acids upon film crystallization and final optoelectronic quality. Here, a direct link between the colloids concentration present in the [HC(NH2 )2 ]0.83 Cs0.17 Pb(Br0.2 I0.8 )3 precursor solution and the nucleation and growth stages of the thin film formation is established. Using dynamic light scattering analysis, the dissolution of colloids over a time span triggered by the addition of hydrohalic acids is monitored. These colloids appear to provide nucleation sites for the perovskite crystallization, which critically impacts morphology, crystal quality, and optoelectronic properties. Via 2D X-ray diffraction, highly ordered and textured crystals for films prepared from solutions with lower colloidal concentrations are observed. This increase in material quality allows for a reduction in microstrain along with a twofold increase in charge-carrier mobilities leading to values exceeding 20 cm2 V-1 s-1 . Using a solution with an optimized colloidal concentration, devices that reach current-voltage measured power conversion efficiency of 18.8% and stabilized efficiency of 17.9% are fabricated. PMID- 28561913 TI - Dissection of Kinase Isoforms through Orthogonal and Chemical Inducible Signaling Cascades. AB - Interference from endogenous signaling enzymes represents a major hurdle for building orthogonal signaling cascades inside cells, particularly among closely related isoforms within an enzyme family. Here, we employed a genetically encoded chemical decaging strategy to build orthogonally activated kinase isoforms, with the endogenous counterparts temporally disabled by an extracellularly delivered bacterial effector. This approach eliminated any potential interference from other kinase isoforms as well as endogenous kinases, which allowed the specific, gain-of-function report of mitogen-activated protein kinase kinase 1 (MEK1) activity as opposed to MEK2 with high temporal resolution. Our study dissected the distinct enzymatic activity, feedback regulation and signal outputs between these closely related kinase isoforms. PMID- 28561914 TI - Opioid Use Disorder in Pregnancy. AB - Opioid use disorder (OUD) in pregnancy has increased significantly in the past 10 years. Women with OUD may often be undertreated or untreated because of limited accessibility to treatment, particularly in rural areas. Because detoxification is not recommended during pregnancy due to the potential for adverse outcomes in the fetus and a high risk of relapse for the woman, more primary care providers need to be well versed in opioid-assisted therapy. In addition, recent changes in Food and Drug Administration regulations now allow nurse practitioners and physician assistants with specialized training to provide buprenorphine treatment for pregnant women with OUD in primary care settings. The purpose of this article is to provide information and guidance for clinicians working with and treating this population. PMID- 28561915 TI - Migraines in Women: Current Evidence for Management of Episodic and Chronic Migraines. AB - Migraine headache is a disabling brain disorder that affects millions of women in the United States. Many migraine sufferers are undertreated. Both inadequate treatment and overuse of abortive migraine medication can contribute to progression from episodic to chronic migraine disorders. A significant number of migraine headaches or severity of episodic migraine headaches warrants treatment with prophylactic medications for prevention. This clinical update reviews the pathophysiology and diagnosis of migraine headaches in women, discusses the efficacy of abortive and chronic pharmacologic treatment, and examines strategies to prevent progression from episodic migraine to chronic migraine. A discussion of treatment during pregnancy and lactation is included. PMID- 28561916 TI - Thermal Disproportionation of Oxo-Functionalized Graphene. AB - Graphene production by wet chemistry is an ongoing scientific challenge. Controlled oxidation of graphite introduces oxo functional groups; this material can be processed and converted back to graphene by reductive defunctionalization. Although thermal processing yields conductive carbon, a ruptured and undefined carbon lattice is produced as a consequence of CO2 formation. This thermal process is not understood, but it is believed that graphene is not accessible. Here, we thermally process oxo-functionalized graphene (oxo-G) with a low (4-6 %) and high degree of functionalization (50-60 %) and find on the basis of Raman spectroscopy and transmission electron microscopy performed at atomic resolution (HRTEM) that thermal processing leads predominantly to an intact carbon framework with a density of lattice defects as low as 0.8 %. We attribute this finding to reorganization effects of oxo groups. This finding holds out the prospect of thermal graphene formation from oxo-G derivatives. PMID- 28561917 TI - Impact of Providing Compassion on Job Performance and Mental Health: The Moderating Effect of Interpersonal Relationship Quality. AB - PURPOSE: To examine the relationships of providing compassion at work with job performance and mental health, as well as to identify the role of interpersonal relationship quality in moderating these relationships. DESIGN AND METHODS: This study adopted a two-stage survey completed by 235 registered nurses employed by hospitals in Taiwan. All hypotheses were tested using hierarchical regression analyses. FINDINGS: The results show that providing compassion is an effective predictor of job performance and mental health, whereas interpersonal relationship quality can moderate the relationships of providing compassion with job performance and mental health. CONCLUSIONS: When nurses are frequently willing to listen, understand, and help their suffering colleagues, the enhancement engendered by providing compassion can improve the provider's job performance and mental health. Creating high-quality relationships in the workplace can strengthen the positive benefits of providing compassion. CLINICAL RELEVANCE: Motivating employees to spontaneously exhibit compassion is crucial to an organization. Hospitals can establish value systems, belief systems, and cultural systems that support a compassionate response to suffering. In addition, nurses can internalize altruistic belief systems into their own personal value systems through a long process of socialization in the workplace. PMID- 28561919 TI - Current trends and future perspectives of dental pulp capping materials: A systematic review. AB - To systematically review the literature to analyze the current trends and future perspectives of dental pulp capping materials through an analysis of scientific and technological data. This study is reported in accordance with the PRISMA Statement. Nine databases were screened: PubMed (MedLine), Lilacs, IBECS, BBO, Web of Science, Scopus, SciELO, Google Scholar, and The Cochrane Library. Additionally, the following patent applications were searched online in Questel Orbit (Paris, France), USPTO, EPO, JPO, INPI, and Patentscope databases. A total of 716 papers and 83 patents were included. Calcium hydroxide was the main type of material studied, especially for direct pulp capping, followed by MTA. Patents related to adhesives or resins increased from 1998 e 2008, while in the last years, a major increase was observed in bioactive materials (containing bioactive proteins), materials derived from MTA (calcium silicate, calcium phosphate and calcium aluminate-based cements) and MTA. It was possible to obtain a scientific and technological overview of pulp capping materials. MTA has shown favorable results in vital pulp therapy that seem to surpass the disadvantages of calcium hydroxide. Recent advances in bioactive materials and those derived from MTA have shown promising results that could improve biomaterials used in vital pulp treatments. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1358-1368, 2018. PMID- 28561918 TI - Dose Finding of Lenvatinib in Subjects With Advanced Hepatocellular Carcinoma Based on Population Pharmacokinetic and Exposure-Response Analyses. AB - Hepatocellular carcinoma (HCC) accounts for up to 90% of primary liver cancer occurrences worldwide. Lenvatinib, a multikinase inhibitor, was approved in radioiodine-refractory differentiated thyroid cancer. In this phase 2 study (study 202), we aimed to identify the lenvatinib optimal dose for subjects with advanced HCC Child-Pugh class A. Pooled data from phase 1 studies in healthy adults and in subjects with mixed tumor types, and from study 202 in subjects with HCC, were analyzed using a population pharmacokinetic approach. The relationship between treatment-emergent adverse events leading to withdrawal or dose reduction during cycle 1 and lenvatinib exposure was explored by logistic regression analysis. A receiver operating characteristics analysis was used to investigate the best cutoff values of lenvatinib exposure and body weight to identify a high-risk group for early dose modification. The final pharmacokinetic model included body-weight effects on apparent clearance and volume. The relationship between the lenvatinib area under the plasma concentration-time curve (AUC) at steady state and body weight demonstrated an increase in AUC as body weight decreased in subjects with HCC. An exposure-response relationship was observed, with higher lenvatinib AUC and lower body weight resulting in earlier drug withdrawal or dose reduction. The best cutoff values for body weight and lenvatinib AUC were 57.8 kg and 2430 ng.h/mL, respectively, to predict the group at high risk for early drug withdrawal or dose reduction. We therefore recommend 12-mg and 8-mg starting doses for subjects >=60 kg and <60 kg, respectively, in subjects with HCC Child-Pugh class A. PMID- 28561920 TI - Two-dimensional and shear wave elastography ultrasound: A reliable method to analyse spastic muscles? AB - INTRODUCTION: Few data exist on the feasibility and reliability of measuring muscular atrophy in 2 dimensions (2D) by ultrasonography (US) and elasticity with shear wave elastography (SWE) in spastic muscles. METHODS: Fourteen patients with chronic stroke took part in 2 intersession reliability experiments performed with 1-week intervals between sessions. Pennation angle (PA), muscle thickness (MT), and shear elastic modulus (u) were measured in spastic gastrocnemius medialis (GM) muscles at rest and at maximal passive stretching in paretic and nonparetic legs. RESULTS: On the paretic side, the coefficient of variation (CV) in GM was 6.30% for MT and 6.40% for PA at rest and was 7.53% and 8.26% for MT and PA, respectively, at maximal passive stretching. The reliability of the u measurement was good only for GM at rest on the paretic side (CV = 9.86%). DISCUSSION: 2D US associated with SWE shows promise for assessing structural changes in muscles. With some methodological adaptations, this approach could help guide spasticity treatment. Muscle Nerve 57: 222-228, 2018. PMID- 28561921 TI - Specific Enhancement of Catalytic Activity by a Dicopper Core: Selective Hydroxylation of Benzene to Phenol with Hydrogen Peroxide. AB - A dicopper(II) complex, stabilized by the bis(tpa) ligand 1,2-bis[2-[bis(2 pyridylmethyl)aminomethyl]-6-pyridyl]ethane (6-hpa), [Cu2 (MU-OH)(6-hpa)]3+ , was synthesized and structurally characterized. This complex catalyzed selective hydroxylation of benzene to phenol using H2 O2 , thus attaining large turnover numbers (TONs) and high H2 O2 efficiency. The TON after 40 hours for the phenol production exceeded 12000 in MeCN at 50 degrees C under N2 , the highest value reported for benzene hydroxylation with H2 O2 catalyzed by homogeneous complexes. At 22 % benzene conversion, phenol (95.2 %) and p-benzoquinone (4.8 %) were produced. The mechanism of H2 O2 activation and benzene hydroxylation is proposed. PMID- 28561922 TI - Master in oral biology program: A path to addressing the need for future dental educators. AB - In dental education, the anatomical sciences, which include gross anatomy, histology, embryology, and neuroanatomy, encompass an important component of the basic science curriculum. At Creighton University School of Dentistry, strength in anatomic science education has been coupled with a solid applicant pool to develop a novel Master of Science in Oral Biology, Anatomic Sciences track degree program. The program provides a heavy emphasis on developing teaching skills in predoctoral students as well as exposure to research processes to encourage the cohort to pursuing a career in academic dentistry. The individuals considered for this program are applicants for admission to the School of Dentistry that have not been accepted into the entering dental class for that year. The students undertake a two year curriculum, studying anatomic sciences with a special emphasis on teaching. The students also must complete a research project that requires a thesis. The students in the program are guaranteed acceptance to dental school upon successful completion of the program. After six years, the first ten students have received their Master of Science degrees and continued in dental school. The program is favorably viewed by the faculty and participating students. It is also considered successful by metrics. Nine of the ten graduates have said they would like to participate in academic dentistry in some capacity during their careers. Anat Sci Educ 10: 607-612. (c) 2017 American Association of Anatomists. PMID- 28561924 TI - Nausea and vomiting: Therapeutic orphans of pediatric oncology. PMID- 28561925 TI - Evolution of sensory neuropathy after initiation of antiretroviral therapy. AB - INTRODUCTION: We studied the evolution of sensory neuropathy after antiretroviral therapy (ART) in human immunodeficiency virus-infected South Africans. METHODS: Enrolment commenced before ART with 6-monthly follow-ups for 24 months. Symptomatic distal sensory polyneuropathy (SDSP) was defined as one symptom and sign. Symptom/sign scores were compared between visits. RESULTS: We enrolled 184 participants. Pre-ART, 16% had SDSP. After 18 months of ART, pain prevalence decreased in those with pre-ART SDSP (odds ratio [OR], 0.09; 95% confidence interval [95%CI], 0.03-0.29). Symptoms improved in 50% ever experiencing pain (mean improvement = 4.5 on 11-point scale). Participants SDSP-free pre-ART developed SDSP at a rate of 18 per 100 person-years. After 24 months (n = 102), 18% had SDSP. Stavudine (60% of cohort) did not predict incident SDSP, but associated with increased prevalence of reduced/absent reflexes at 18 months (OR, 2.24; 95% CI, 1.08-4.65). DISCUSSION: Painful symptoms improved during ART. Evolving sensory neuropathy was due to increasing small and large fiber dysfunction. Muscle Nerve 57: 371-379, 2018. PMID- 28561923 TI - Quantification and characterization of grouped type I myofibers in human aging. AB - INTRODUCTION: Myofiber type grouping is a histological hallmark of age-related motor unit remodeling. Despite the accepted concept that denervation reinnervation events lead to myofiber type grouping, the completeness of those conversions remains unknown. METHODS: Type I myofiber grouping was assessed in vastus lateralis biopsies from Young (26 +/- 4 years; n = 27) and Older (66 +/- 4 years; n = 91) adults. Grouped and ungrouped type I myofibers were evaluated for phenotypic differences. RESULTS: Higher type I grouping in Older versus Young was driven by more myofibers per group (i.e., larger group size) (P < 0.05). In Older only, grouped type I myofibers displayed larger cross-sectional area, more myonuclei, lower capillary supply, and more sarco(endo)plasmic reticulum calcium ATPase I (SERCA I) expression (P < 0.05) than ungrouped type I myofibers. DISCUSSION: Grouped type I myofibers retain type II characteristics suggesting that conversion during denervation-reinnervation events is either progressive or incomplete. Muscle Nerve 57: E52-E59, 2018. PMID- 28561926 TI - Quantitative sonographic assessment of myotonia. AB - INTRODUCTION: This study explores ultrasound imaging for qualitative and quantitative assessment of myotonia. METHODS: Sixteen patients with myotonia and 16 controls underwent sonographic evaluation of the thenar eminence muscles to assess the relaxation time after muscle percussion. RESULTS: The mean time for complete muscle relaxation in patients with myotonia was longer than that of controls. A cutoff of > 0.9 s for myotonia detection had a sensitivity of 88% and a specificity of 100%. The interrater reliability was moderate for qualitative assessment but was high for quantitative assessment. The relaxation time did not correlate with the number of trinucleotide repeats in patients with myotonic dystrophy. DISCUSSION: Sonographic evaluation for the presence of myotonia is feasible, sensitive, and specific but does not correlate with disease severity in myotonic dystrophy. Muscle Nerve 57: 146-149, 2018. PMID- 28561928 TI - Chemoselective Modification of Vinyl DNA by Triazolinediones. AB - A new method for the post-synthetic modification of nucleic acids was developed that involves mixing a phenyl triazolinedione (PTAD) derivative with DNA containing a vinyl nucleobase. The resulting reactions proceeded through step wise mechanisms, giving either a formal [4+2] cycloaddition product, or, depending on the context of nucleobase, PTAD addition along with solvent trapping to give a secondary alcohol in water. Catalyst-free addition between PTAD and the terminal alkene of 5-vinyl-2'-deoxyuridine (VdU) was exceptionally fast, with a second-order rate constant of 2*103 m-1 s-1 . PTAD derivatives selectively reacted with VdU-containing oligonucleotides in a conformation-selective manner, with higher yields observed for G-quadruplex versus duplex DNA. These results demonstrate a new strategy for copper-free bioconjugation of DNA that can potentially be used to probe nucleic acid conformations in cells. PMID- 28561927 TI - Mononeuritis multiplex associated with minocycline in an adolescent. PMID- 28561929 TI - Adverse events of group psychotherapy in the in-patient setting - results of a naturalistic trial. AB - OBJECTIVE: Adverse events of psychotherapy have often been neglected in research. In this study, potential adverse events of group psychotherapies in a psychiatric hospital were systematically assessed, explored for predictors and linked to treatment outcome. METHOD: A naturalistic trial was conducted in 180 in-patients attending different group psychotherapies. Adverse events were assessed using three different measures: (i) weekly reporting of unwanted treatment reactions, (ii) mood changes in response to every single group session and (iii) premature group termination. RESULTS: Different measures of adverse events were weakly associated. Deterioration of mood state and/or unwanted treatment reactions were experienced by 60-65% of all patients. Reports of unwanted treatment reactions decreased over time and were negatively associated with symptom improvement. However, mood state deterioration was constant and unrelated to treatment outcome. The rate of premature group termination was 34%. Significant predictors of adverse events included patient characteristics as well as disadvantageous group conditions. CONCLUSIONS: For the majority of patients, group psychotherapy in the in-patient setting is associated with adverse events. Changes over time and a strong correlation with general symptom severity must be considered in the assessment and interpretation of adverse events. Predictors should be considered as potential risk factors in future research. PMID- 28561930 TI - Ultrahigh and Selective SO2 Uptake in Inorganic Anion-Pillared Hybrid Porous Materials. AB - The efficient capture of SO2 is of great significance in gas-purification processes including flue-gas desulfurization and natural-gas purification, but the design of porous materials with high adsorption capacity and selectivity of SO2 remains very challenging. Herein, the selective recognition and dense packing of SO2 clusters through multiple synergistic host-guest and guest-guest interactions by controlling the pore chemistry and size in inorganic anion (SiF62 , SIFSIX) pillared metal-organic frameworks is reported. The binding sites of anions and aromatic rings in SIFSIX materials grasp every atom of SO2 firmly via Sdelta+ ...Fdelta- electrostatic interactions and Odelta- ...Hdelta+ dipole dipole interactions, while the guest-guest interactions between SO2 molecules further promote gas trapping within the pore space, which is elucidated by first principles density functional theory calculations and powder X-ray diffraction experiments. These interactions afford new benchmarks for the highly efficient removal of SO2 from other gases, even if at a very low SO2 concentration. Exceptionally high SO2 capacity of 11.01 mmol g-1 is achieved at atmosphere pressure by SIFSIX-1-Cu, and unprecedented low-pressure SO2 capacity is obtained in SIFSIX-2-Cu-i (4.16 mmol g-1 SO2 at 0.01 bar and 2.31 mmol g-1 at 0.002 bar). More importantly, record SO2 /CO2 selectivity (86-89) and excellent SO2 /N2 selectivity (1285-3145) are also achieved. Experimental breakthrough curves further demonstrate the excellent performance of these hybrid porous materials in removing low-concentration SO2 . PMID- 28561931 TI - Germanium-Assisted Direct Growth of Graphene on Arbitrary Dielectric Substrates for Heating Devices. AB - Direct growth of graphene on dielectric substrates is a prerequisite to the development of graphene-based electronic and optoelectronic devices. However, the current graphene synthesis methods on dielectric substrates always involve a metal contamination problem, and the direct production of graphene patterns still remains unattainable and challenging. Herein, a semiconducting, germanium (Ge) assisted, chemical vapor deposition approach is proposed to produce monolayer graphene directly on arbitrary dielectric substrates. By the prepatterning of a catalytic Ge layer, the graphene with desired pattern can be achieved conveniently and readily. Due to the catalysis of Ge, monolayer graphene is able to form on Ge-covered dielectric substrates including SiO2 /Si, quartz glass, and sapphire substrates. Optimization of the process parameters leads to complete sublimation of the catalytic Ge layer during or immediately after formation of the monolayer graphene, enabling direct deposition of large-area and continuous graphene on dielectric substrates. The large-area, highly conductive graphene synthesized on a transparent dielectric substrate using the proposed approach has exhibited a wide range of applications, including in both defogger and thermochromic displays, as already successfully demonstrated here. PMID- 28561932 TI - Lenalidomide-responsive anti-myelin-associated glycoprotein neuropathy. PMID- 28561933 TI - Cx36, Cx43 and Cx45 in mouse and rat cerebellar cortex: species-specific expression, compensation in Cx36 null mice and co-localization in neurons vs. glia. AB - Electrical synapses formed by connexin36 (Cx36)-containing gap junctions between interneurons in the cerebellar cortex have been well characterized, including those formed between basket cells and between Golgi cells, and there is gene reporter-based evidence for the expression of connexin45 (Cx45) in the cerebellar molecular layer. Here, we used immunofluorescence approaches to further investigate expression patterns of Cx36 and Cx45 in this layer and to examine localization relationships of these connexins with each other and with glial connexin43 (Cx43). In mice, strain differences were found, such that punctate labelling for Cx36 was differentially distributed in the molecular layer of C57BL/6 vs. CD1 mice. In mice with EGFP reporter representing Cx36 expression, Cx36-puncta were localized to processes of stellate cells and other cerebellar interneurons. Punctate labelling of Cx45 was faint in the molecular layer of wild type mice and was increased in intensity in mice with Cx36 gene ablation. The vast majority of Cx36-puncta co-localized with Cx45-puncta, which in turn was associated with the scaffolding protein zonula occludens-1. In rats, Cx45-puncta were also co-localized with Cx36-puncta and additionally occurred along Bergmann glial processes adjacent to Cx43-puncta. The results indicate strain and species differences in Cx36 as well as Cx45 expression, possible compensatory processes after loss of Cx36 expression and localization of Cx45 to both neuronal and Bergmann glial gap junctions. Further, expression of both Cx43 and Cx45 in Bergmann glia of rat may contribute to the complex properties of junctional coupling between these cells and perhaps to their reported coupling with Purkinje cells. PMID- 28561934 TI - Risk of impaired cognition after prenatal exposure to psychotropic drugs. AB - OBJECTIVE: Prenatal exposure to psychotropic drugs may affect the trajectories of brain development. In a register study, we investigated whether such exposure is associated with long-term impaired cognitive abilities. METHOD: Individuals born in Denmark in 1995-2008 were included. As proxies for cognitive impairment, requiring special needs education, attending special needs school, diagnoses of neurological/mental disorder, missed final examinations, and low school grade average were used. We accounted for maternal confounders. RESULTS: We identified 868 159 individuals of whom 13 983 (1.6%) were prenatally exposed. The adjusted odds ratio (OR) was 0.97[0.92-1.02] for requiring special needs education, 1.28[1.14-1.43] for attending special needs school, 1.32[1.20-1.46] for a neurological/mental disorder diagnosis, 1.37[1.22-1.54] for missing the final examinations, and 1.13[0.82-1.55] for obtaining a low school grade average. Exposure to psycholeptics (primarily antipsychotics and sedatives) was correlated with significantly increased risk for four outcomes. The highest was the risk of missing the primary school examinations (OR: 1.51[1.29-1.76]). The overall highest risk concerned the presence of a neurological/mental disorder after prenatal exposure to psychoanaleptics (primarily antidepressants) (OR: 1.86[1.24 2.78). CONCLUSION: Prenatal exposure to psychotropic drugs affects proxy outcomes of cognitive disabilities at school age. Exposure to psycholeptics carries the largest risk. The role of psychoanaleptics is currently unclear. PMID- 28561935 TI - Clinicopathological characteristics of KIT and protein kinase C-delta expression in adenoid cystic carcinoma: comparison with chromophobe renal cell carcinoma and gastrointestinal stromal tumour. AB - AIMS: KIT overexpression is frequently observed in adenoid cystic carcinomas (AdCCs), chromophobe renal cell carcinomas (ChRCCs), and gastrointestinal stromal tumours (GISTs). Persistent KIT activation has been reported to be mediated by protein kinase C (PKC)-delta in a subset of colon cancers with wild-type KIT overexpression, and by PKC-theta in GISTs with mutant KIT overexpression. To elucidate the clinical implications of PKC-delta and PKC-theta expression in KIT expressing tumours, we investigated the expression of KIT, PKC-delta and PKC theta in AdCCs and ChRCCs in comparison with GISTs. METHODS AND RESULTS: KIT expression, PKC-delta expression and PKC-theta expression were analysed in whole sections from 41 AdCCs, 40 ChRCCs and 56 GISTs by immunohistochemistry. Membranous expression of KIT was found in 34 AdCCs and all ChRCCs, whereas cytoplasmic expression of KIT was found in 46 GISTs. In AdCCs, PKC-delta expression was associated with histological grade (P = 0.049), lymphovascular invasion (P = 0.004), perineural invasion (P = 0.002), and KIT positivity (P = 0.002). PKC-delta positivity was associated with shorter relapse-free survival (RFS) (P = 0.017) and a tendency for there to be shorter overall survival (OS) (P = 0.090) in patients with AdCCs. No clinicopathological associations were observed between PKC-delta and KIT expression in ChRCCs. In GISTs, PKC-theta expression was associated with higher mitotic count (P = 0.011) and high grade according to the modified National Institutes of Health criteria (P < 0.001). PKC theta positivity was associated with shorter RFS (P = 0.016) and a tendency for there to be shorter OS (P = 0.051) in patients with GISTs. CONCLUSIONS: PKC-delta expression is associated with KIT expression and the prognosis of patients with AdCCs, suggesting that PKC-delta may be a potential therapeutic target for AdCCs. PMID- 28561936 TI - Catalysis of Extracellular Deamination by a FAD-Linked Oxidoreductase after Prodrug Maturation in the Biosynthesis of Saframycin A. AB - The biosynthesis of antibiotics in bacteria is usually believed to be an intracellular process, at the end of which the matured compounds are exported outside the cells. The biosynthesis of saframycin A (SFM-A), an antitumor antibiotic, requires a cryptic fatty acyl chain to guide the construction of a pentacyclic tetrahydroisoquinoline scaffold; however, the follow-up deacylation and deamination steps remain unknown. Herein we demonstrate that SfmE, a membrane bound peptidase, hydrolyzes the fatty acyl chain to release the amino group; and SfmCy2, a secreted oxidoreductase covalently associated with FAD, subsequently performs an oxidative deamination extracellularly. These results not only fill in the missing steps of SFM-A biosynthesis, but also reveal that a FAD-binding oxidoreductase catalyzes an unexpected deamination reaction through an unconventional extracellular pathway in Streptmyces bacteria. PMID- 28561937 TI - Hyperconjugation Is the Source of Helicity in Perfluorinated n-Alkanes. AB - Hyperconjugative, steric, and electrostatic effects were evaluated as possible sources of the helicity in linear perfluorinated alkanes through analysis of natural bond orbitals and classical electrostatics. Contrary to previous rationalizations, which indicate dominating steric or electrostatic effects, this analysis indicates that hyperconjugative stabilization through sigmaCC ->sigma*CF interactions are the underlying driving force for the origin of the observed helicity in perfluoroalkanes. PMID- 28561938 TI - Prenatal diagnosis of four-vessel umbilical cord with supernumerary vein varix: A case report and literature review. AB - Four-vessel umbilical cord with two arteries and two veins, and fetal intra abdominal umbilical vein varix are rare fetal vascular pathologies, associated with congenital anomalies and an adverse perinatal outcome, respectively. We report a case of a healthy male neonate born at a gestational age of 38 weeks, five days, after prenatal sonographic diagnosis of a four-vessel umbilical cord with a supernumerary vein varix. To the best of our knowledge, this is the first case with this combination. PMID- 28561939 TI - A Rapid Total Synthesis of Ciprofloxacin Hydrochloride in Continuous Flow. AB - Within a total residence time of 9 min, the sodium salt of ciprofloxacin was prepared from simple building blocks via a linear sequence of six chemical reactions in five flow reactors. Sequential offline acidifications and filtrations afforded ciprofloxacin and ciprofloxacin hydrochloride. The overall yield of the eight-step sequence was 60 %. No separation of intermediates was required throughout the synthesis when a single acylation reaction was applied to remove the main byproduct, dimethylamine. PMID- 28561940 TI - Reproductive biology of Ferocactus recurvus (Mill.) Borg subsp. recurvus (Cactaceae) in the Tehuacan-Cuicatlan Valley, Mexico. AB - Mexico has one of the highest diversities of barrel cacti species worldwide; however, all are threatened and require conservation policies. Information on their reproductive biology is crucial, but few studies are available. Ferocactus recurvus subsp. recurvus is a barrel cactus endemic to the Tehuacan-Cuicatlan Valley. Our research aimed to characterise its floral and pollination biology. We hypothesised bee pollination, as suggested by its floral morphology and behaviour, and self-incompatibility, like most barrel cacti studied. Three study sites were selected in the semiarid Zapotitlan Valley, Mexico. We examined 190 flowers from 180 plants to determine: morphometry and behaviour of flowers, flower visitors and probable pollinators, and breeding system. Flowers showed diurnal anthesis, lasting 2-5 days, the stigma being receptive on day 2 or 3 after the start of anthesis. Flowers produced scarce/no nectar and main visitors were bees (Apidae), followed by flies (Muscidae), ants (Formicidae), thrips (Thripidae) and hummingbirds (Throchilidae); however, only native bees and occasionally wasps contacted the stigma and anthers. Pollination experiments revealed that this species is self-incompatible and xenogamous. In natural conditions, fruit set was 60% and cross-pollination fruit set was 100%. Percentage seed germination resulting from cross-pollination was higher than in the control treatment. Our results provide ecological information for conservation programmes to ensure a high probability of breeding and seed production in natural populations of F. recurvus. PMID- 28561941 TI - Intramolecularly Protein-Crosslinked DNA Gels: New Biohybrid Nanomaterials with Controllable Size and Catalytic Activity. AB - DNA micro- and nanogels-small-sized hydrogels made of a crosslinked DNA backbone constitute new promising materials, but their functions have mainly been limited to those brought by DNA. Here a new way is described to prepare sub-micrometer sized DNA gels of controllable crosslinking density that are able to embed novel functions, such as an enzymatic activity. It consists of using proteins, instead of traditional base-pairing assembly or covalent approaches, to form crosslinks inside individual DNA molecules, resulting in structures referred to as intramolecularly protein-crosslinked DNA gels (IPDGs). It is first shown that the addition of streptavidin to biotinylated T4DNA results in the successful formation of thermally stable IPDGs with a controllable crosslinking density, forming structures ranging from elongated to raspberry-shaped and pearl-necklace like morphologies. Using reversible DNA condensation strategies, this paper shows that the gels can be reversibly actuated at a low crosslinking density, or further stabilized when they are highly crosslinked. Finally, by using streptavidin-protein conjugates, IPDGs with various enzymes are successfully functionalized. It is demonstrated that the enzymes keep their catalytic activity upon their incorporation into the gels, opening perspectives ranging from biotechnologies (e.g., enzyme manipulation) to nanomedicine (e.g., vectorization). PMID- 28561942 TI - Total Synthesis of Dictyodendrins by the Gold-Catalyzed Cascade Cyclization of Conjugated Diynes with Pyrroles. AB - In total and formal syntheses of dictyodendrins B, C, E, and F, the key step involved the direct construction of the pyrrolo[2,3-c]carbazole core by the gold catalyzed annulation of a conjugated diyne with a pyrrole to form three bonds and two aromatic rings. The subsequent introduction of substituents at the C1 (Suzuki Miyaura coupling), C2 (addition to an aldehyde), N3 (alkylation), and C5 positions (Ullman coupling) provided divergent access to dictyodendrins. PMID- 28561943 TI - Association between insomnia and atrial fibrillation in a Chinese population: A cross-sectional study. AB - BACKGROUND: Insomnia is the most prevalent sleep disorder; however, little research has explored the link between insomnia and atrial fibrillation (AF). HYPOTHESIS: Insomnia is associated with increased risk of AF in a Chinese population. METHODS: A total of 8371 Chinese participants (4314 males; mean age, 42.4 +/- 13.1 years) were enrolled in this cross-sectional study to investigate the association between insomnia and AF. AF was assessed in a standard supine resting position with a 10-s 12-lead electrocardiograph (ECG) or by self-reported history. Insomnia was assessed using the Athens Insomnia Scale (AIS), and a score of >=6 was regarded as having insomnia. The association between insomnia and AF was determined by logistic regression analysis. RESULTS: Among the 8371 subjects, 1074 (12.8%) had different degrees of insomnia, and AF was observed in 50 subjects (0.60%). After adjusting for potential confounders, individuals with insomnia had moderately increased likelihood of suffering from AF compared with those without insomnia (odds ratio [OR]: 1.92, 95% confidence interval [CI]: 1.00 3.70, P = 0.05). After stratifying data by age, a significant positive association was found in those age <40 years (OR: 6.52, 95% CI: 1.64-25.83, P = 0.01), and a similar trend existed in males after stratifying by sex, although this relationship was not statistically significant (OR: 2.11, 95% CI: 0.92-4.83, P = 0.08). CONCLUSIONS: Individuals with insomnia may have a higher risk of AF in the particular Chinese population assessed in this study. Age (<40 years) is a significant factor in the association between insomnia and AF. PMID- 28561944 TI - A global bibliometric analysis of otolaryngology: Head and neck surgery literature. AB - OBJECTIVE: Bibliometrics uses analysis of content and citations of journal articles to quantify trends in published data. We aim to use bibliometric analysis to identify the global contribution by country to the ENT surgical literature over a 5-year period. DATA SOURCE: The top 20 countries for number of articles published in surgery and the 11 English-language otolaryngology surgical journals with the highest impact factors (IF) were included. Numbers of scientific articles per year (2009-2013) per country for each journal were identified through PubMed. As a marker of quality, a mean IF for each country was calculated, using number of articles and journal IF. These data were compared against population, GDP and dollars spent on research. RESULTS: In total, 10 574 articles were included. The USA was the largest contributor, with 4462 articles published over 5 years. The second largest was the UK (1215 articles). Spain's mean IF was 2.136, followed by Taiwan (2.110). The Netherlands (19.7) and the UK (18.9) had the highest number of publications per million population. When considering overall research spending per country, Greece had the most cost effective publication output. The least cost-effective country was Japan. India, Greece and Japan had the greatest increase in publication quality. CONCLUSIONS: Bibliometric analysis can be used to identify not only major centres of English language ENT surgical research, such as the USA and UK but centres that are producing high-quality data, such as Spain, and cost-effective research, such as the UK. It can also highlight areas of increasing success in ENT research. PMID- 28561945 TI - Beta Blocker Administration During Emergency Department Evaluation for Acute Coronary Syndrome Is Associated With Lower Posttraumatic Stress Symptoms 1-Month Later. AB - We examined whether beta blocker administration in the emergency department (ED) during evaluation for suspected acute coronary syndrome (ACS) was associated with posttraumatic stress disorder (PTSD) symptoms 1-month later. Participants (N = 350) were enrolled in the Reactions to Acute Care and Hospitalization (REACH) study, an ongoing observational cohort study of ED predictors of medical and psychological outcomes after evaluation for suspected ACS. Beta blockade during evaluation in the ED was extracted from medical records, and PTSD symptoms in response to the experience of suspected ACS were assessed 1-month later via telephone. Beta blockade in the ED was associated with lower PTSD symptoms 1 month later, b = -2.80, beta = -.09, p = .045, after adjustment for demographics, preexisting psychological and medical covariates, and participants' distress during ED evaluation. Despite small effects, findings suggest that beta blockade during ED evaluation for suspected ACS-a time period relevant to fear consolidation of the memory of this potentially life-threatening event-may have protective effects for later psychological health. PMID- 28561946 TI - New Paradigm for Translational Modeling to Predict Long-term Tuberculosis Treatment Response. AB - Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect. A mouse-to-human translational pharmacokinetics (PKs) - pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions. The model included Mycobacterium tuberculosis growth function in mice, adaptive immune response effect on bacterial growth, relationships among moxifloxacin, rifapentine, and rifampin concentrations accelerating bacterial death, clinical PK data, species-specific protein binding, drug-drug interactions, and patient-specific pathology. Simulations of recent trials testing 4-month regimens predicted 65% (95% confidence interval [CI], 55-74) relapse-free patients vs. 80% observed in the REMox-TB trial, and 79% (95% CI, 72 87) vs. 82% observed in the Rifaquin trial. Simulation of 6-month regimens predicted 97% (95% CI, 93-99) vs. 92% and 95% observed in 2RHZE/4RH control arms, and 100% predicted and observed in the 35 mg/kg rifampin arm of PanACEA MAMS. These results suggest that the model can inform regimen optimization and predict outcomes of ongoing trials. PMID- 28561947 TI - Modeling the Transmission of Measles and Rubella to Support Global Management Policy Analyses and Eradication Investment Cases. AB - Policy makers responsible for managing measles and rubella immunization programs currently use a wide range of different vaccines formulations and immunization schedules. With endemic measles and rubella transmission interrupted in the region of the Americas, all five other regions of the World Health Organization (WHO) targeting the elimination of measles transmission by 2020, and increasing adoption of rubella vaccine globally, integrated dynamic disease, risk, decision, and economic models can help national, regional, and global health leaders manage measles and rubella population immunity. Despite hundreds of publications describing models for measles or rubella and decades of use of vaccines that contain both antigens (e.g., measles, mumps, and rubella vaccine or MMR), no transmission models for measles and rubella exist to support global policy analyses. We describe the development of a dynamic disease model for measles and rubella transmission, which we apply to 180 WHO member states and three other areas (Puerto Rico, Hong Kong, and Macao) representing >99.5% of the global population in 2013. The model accounts for seasonality, age-heterogeneous mixing, and the potential existence of preferentially mixing undervaccinated subpopulations, which create heterogeneity in immunization coverage that impacts transmission. Using our transmission model with the best available information about routine, supplemental, and outbreak response immunization, we characterize the complex transmission dynamics for measles and rubella historically to compare the results with available incidence and serological data. We show the results from several countries that represent diverse epidemiological situations to demonstrate the performance of the model. The model suggests relatively high measles and rubella control costs of approximately $3 billion annually for vaccination based on 2013 estimates, but still leads to approximately 17 million disability-adjusted life years lost with associated costs for treatment, home care, and productivity loss costs of approximately $4, $3, and $47 billion annually, respectively. Combined with vaccination and other financial cost estimates, our estimates imply that the eradication of measles and rubella could save at least $10 billion per year, even without considering the benefits of preventing lost productivity and potential savings from reductions in vaccination. The model should provide a useful tool for exploring the health and economic outcomes of prospective opportunities to manage measles and rubella. Improving the quality of data available to support decision making and modeling should represent a priority as countries work toward measles and rubella goals. PMID- 28561948 TI - Identification of fucosylated Fetuin-A as a potential biomarker for cholangiocarcinoma. AB - PURPOSE: Cholangiocarcinoma (CCA) is a malignancy of the bile ducts. The purpose of this discovery study was to identify effective serum markers for surveillance of cholangiocarcinoma. EXPERIMENTAL DESIGN: Using a glycomic method, patients with CCA were determined to have increased levels of alpha-1,3 and alpha-1,6 linked fucosylated glycan. Proteomic analysis of the serum fucosylated proteome identified proteins such as alpha-2-macroglobulin, kininogen, hemopexin, fetuin A, alpha-1 anti-trypsin, and ceruloplasmin as being hyperfucosylated in HCC. The levels of these glycoproteins in 109 patients with CCA, primary sclerosing cholangitis (PSC), and control patients were compared to the performance of CA-19 9, the current "gold standard" assay for cholangiocarcinoma. RESULTS: Fucosylated Fetuin-A (fc-Fetuin-A) had the best ability to differentiate CCA from PSC, with an AUROC of 0.812 or 0.8665 at differentiating CCA from those with PSC or other liver disease. CA-19-9 had poor ability to differentiate PSC from cholangiocarcinoma (AUROC of 0.625). CONCLUSION AND CLINICAL RELEVANCE: Using glycomic and proteomic methods we identified a set of proteins that contain altered glycan in the sera of those with CCA. One of these proteins, fucosylated Fetuin-A may have value in the surveillance of people at risk for the development of cholangiocarcinoma. PMID- 28561949 TI - Gastrointestinal tract carcinoma in pediatric and adolescent age: The Italian TREP project experience. AB - BACKGROUND: Gastrointestinal (GI) carcinomas are very rare in the pediatric and adolescent age range. We report the clinical features, treatment, and outcome of a series of children and adolescents with GI carcinoma prospectively registered in the Italian Tumori Rari in Eta Pediatrica (TREP) project. METHODS: The TREP project developed diagnostic and therapeutic guidelines based on recommendations currently in use for adults. Clinical data were centrally registered and reviewed. RESULTS: Fifteen patients were registered over the years 2000-2016. Most of the tumors were colorectal carcinomas (12 cases). All but one patient had advanced-stage disease (American Joint Committee on Cancer stages III-IV), and the majority of patients had aggressive histological subtypes, i.e. poorly differentiated (G3) (five patients), mucinous (four patients), and signet ring (two patients) adenocarcinomas. Surgery was performed in 13 of 15 patients, and was radical in nine of 13 patients. Only one patient received postoperative radiotherapy. All patients received chemotherapy, with the addition of bevacizumab in two cases. Nine patients were still alive at the time of the present report, but two of them had only just completed their treatment program and one patient is still on treatment. Six patients died due to disease progression. CONCLUSIONS: This prospective report on pediatric GI tract carcinomas confirms the rarity and biological aggressiveness of these diseases in pediatric and adolescent age. Further prospective studies are needed to explore the distinct biology of tumor in this age group in order to find new therapeutic targeted agents. PMID- 28561950 TI - Poly(N-(4-aminobutyl)-acrylamide) as mimetic polylysine for improving survival and differentiation of cerebellar granule neurons. AB - Poly(N-(4-aminobutyl)-acrylamide) (P4Am) and poly-d-lysine (PDL) possess the same butylamine side chain. The main difference is the peptide structure, which is in the main chain of PDL but in the side chain of P4Am. PDL has been extensively used in the preparation of neuronal cultures. We assumed neurons are sensitive enough to distinguish such structure difference so these two cationic polymers were compared at serial coating concentrations for culturing cerebellar granule neurons from 7-day-old Wistar rats in this study. Cellular viability and morphology assay showed no obvious difference for neurons cultured at high coating concentrations (>0.31 ug/mL) of these two polymers. In contrast, the difference in the peptide structure between P4Am and PDL could be distinguished by neurons at low coating concentrations (< 0.16 ug/mL). P4Am at low coating concentration could keep aggregates with three or four thick processes to support a more complete neural network with higher cellular viability than PDL. This suggests the interaction between neurons and the specific peptide structure of P4Am at low coating concentration was able to improve survival and differentiation of cultured cerebellar granule neurons. Although neural cells exhibited different morphologies and activities on high and low P4Am coating concentrations, immunofluorescence imaging confirmed most of cultured cells were functionally mature neurons, stained by neurofilament, synapsin I, and GAP43. The information should be useful for designing new biomaterials for regeneration of damaged circuits following disease or trauma. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1194-1201, 2018. PMID- 28561951 TI - Safety and efficacy of DOACs vs acenocoumarol in patients undergoing catheter ablation of atrial fibrillation. AB - BACKGROUND: Thromboembolic complications can be life-threatening during atrial fibrillation (AF) catheter ablation. The aim of our study was to evaluate the safety and efficacy of continuous treatment using direct oral anticoagulants (DOACs) as an alternative to uninterrupted acenocoumarol for periprocedural anticoagulation. HYPOTHESIS: Continuous treatment with DOACs has similar safety and efficacy compared to acenocoumarol. METHODS: We enrolled 474 patients (mean age, 58 years; 68.4% male) undergoing AF catheter ablation between June 2013 and December 2016. All patients were equally assigned to take acenocoumarol (group 1, 136 patients) or DOACs (group 2, 338 patients) for >=2 months before the procedure. We compared thromboembolic and bleeding complications between the 2 groups. RESULTS: Our analysis showed no significant difference in major and minor complications between the 2 patient groups. Specifically, 3 of 136 patients (2.2%) using uninterrupted acenocoumarol had a major complication (1 patient [0.7%] had transient ischemic attack resolved 8 hours later, 1 [0.7%] had pericardial tamponade, and 1 [0.7%] had a subcapsular renal hematoma) and 2 patients (1.4%) had minor complications (1 [0.7%] pseudoaneurysm and 1 [0.7%] groin hematoma). In group 2, 1 of 338 patients (0.3%) had a major complication (transient ischemic attack). In the same group, 7 patients (2.1%) had a minor complication (1 patient [0.3%] presented with pseudoaneurysm, 4 [1.2%] with pericardial effusion <1 cm, 1 [0.3%] femoral arteriovenous fistula between the femoral artery and femoral vein, and 1 [0.7%] groin hematoma). CONCLUSIONS: DOACs and acenocoumarol have similar safety and effectiveness regarding thromboembolic complications prevention without increasing bleeding complications. PMID- 28561952 TI - The impact of stereoscopic imagery and motion on anatomical structure recognition and visual attention performance. AB - Gross anatomy is located in a three-dimensional space. Visualizing aspects of structures in gross anatomy education should aim to provide information that best resembles their original spatial proportions. Stereoscopic three-dimensional imagery might offer possibilities to implement this aim, though some research has revealed potential impairments that may result from observing stereoscopic visualizations, such as discomfort. However, possible impairments of working memory such as decreased visual attention performance due to applying this technology in gross anatomy education have not yet been investigated. Similarly, in gross anatomy education the impact of stereoscopic imagery on learners' recognition of anatomical-spatial relationships and the impact of different presentation formats have only been investigated in a small number of studies. In this study, the performance of 171 teacher trainees working on the anatomy of hearing was examined, either with non-stereoscopic or stereoscopic imagery. Static and dynamic picture presentations were applied. Overall, benefits for stereoscopic imagery on estimating anatomical-spatial relations were found. The performance on a visual attention test indicates that the impact of stereoscopic visualizations on the human cognitive system varies more from person to person compared to non-stereoscopic visualizations. In addition, combinations of temporarily moving pictures and stereoscopic imagery lead to decreased visual attention performance compared to combinations of moving pictures and non stereoscopic imagery. Anat Sci Educ 11: 15-24. (c) 2017 American Association of Anatomists. PMID- 28561953 TI - Binary Synergistic Sensitivity Strengthening of Bioinspired Hierarchical Architectures based on Fragmentized Reduced Graphene Oxide Sponge and Silver Nanoparticles for Strain Sensors and Beyond. AB - Recently, stretchable electronics have been highly desirable in the Internet of Things and electronic skins. Herein, an innovative and cost-efficient strategy is demonstrated to fabricate highly sensitive, stretchable, and conductive strain sensing platforms inspired by the geometries of a spiders slit organ and a lobsters shell. The electrically conductive composites are fabricated via embedding the 3D percolation networks of fragmentized graphene sponges (FGS) in poly(styrene-block-butadiene-block-styrene) (SBS) matrix, followed by an iterative process of silver precursor absorption and reduction. The slit- and scale-like structures and hybrid conductive blocks of FGS and Ag nanoparticles (NPs) provide the obtained FGS-Ag-NP-embedded composites with superior electrical conductivity of 1521 S cm-1 , high break elongation of 680%, a wide sensing range of up to 120% strain, high sensitivity of ~107 at a strain of 120%, fast response time of ~20 ms, as well as excellent reliability and stability of 2000 cycles. This huge stretchability and sensitivity is attributed to the combination of high stretchability of SBS and the binary synergistic effects of designed FGS architectures and Ag NPs. Moreover, the FGS/SBS/Ag composites can be employed as wearable sensors to detect the modes of finger motions successfully, and patterned conductive interconnects for flexible arrays of light-emitting diodes. PMID- 28561954 TI - Evidence for the presence of a bacterial endosymbiont in the pecan scab pathogen Venturia effusa (basyonym: Fusicladium effusum). AB - AIMS: To determine whether Venturia effusa, the causative fungal agent of pecan scab, harbours a bacterial symbiont. METHODS AND RESULTS: Venturia effusa isolates were maintained on potato dextrose agar amended with antibiotics (chloramphenicol (100 MUg ml-1 ) and tetracycline 100 (MUg ml-1 )). Genomic DNA extracted from mycelia was used to target eubacterial 16S rDNA. A 1.4-kbp PCR amplified product using 16S rDNA degenerate primers was cloned, sequenced and found to have 99% identities with Actinobacteria representatives. Attempts to culture the detected bacteria apart from the fungus following agitation and fungal cell lysis were unsuccessful using standard bacteriological media under either aerobic or anaerobic conditions. Fungal structures were visualized using scanning electron microscopy and putative bacterial formations associated with the fungal mycelia were observed. Fluorescence in situ hybridization using 16S rDNA oligonucleotides illuminated spores and portions of the hyphae. CONCLUSIONS: This is the first report to provide both molecular microbiological and microscopic evidence in support of the hypothesis that V. effusa harbours endosymbiotic bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Findings from this research contribute fundamental information regarding the biology of the fungus that may ultimately lead to identifying a target of the pathogen for use in management and/or avoidance strategies. PMID- 28561956 TI - Outcomes for olfactory neuroblastoma treated with induction chemotherapy. AB - BACKGROUND: Oncologic outcomes for induction chemotherapy and its role in patients with advanced olfactory neuroblastoma (ONB) remain unclear. METHODS: A retrospective review of 15 consecutive patients with extensive local invasion and/or nodal disease treated with induction chemotherapy with curative intent followed by definitive local therapy. RESULTS: The majority of patients were treated with cisplatin and etoposide. The response to chemotherapy was 68% (10/15). Response was 78% (7/9) in the high Hyams high-grade group and 50% (3/6) in the Hyams low-grade group. Seven patients had complete response (CR) and 3 patients were able to avoid orbital exenteration. The 5-year disease-free survival (DFS) and overall survival (OS) were 71% and 78%, respectively, with a trend toward improved survival in patients with CR. CONCLUSION: ONB is a chemosensitive tumor and induction chemotherapy is an acceptable strategy for aggressive and locoregional advanced disease. Hyams grade may predict chemosensitivity and CR may be associated with improved survival. PMID- 28561955 TI - Biexponential T2 relaxation estimation of human knee cartilage in vivo at 3T. AB - PURPOSE: To evaluate biexponential T2 relaxation mapping of human knee cartilage in vivo in clinically feasible scan times. MATERIALS AND METHODS: T2 -weighted magnetic resonance (MR) images were acquired from eight healthy volunteers using a standard 3T clinical scanner. A 3D Turbo-Flash sequence was modified to enable T2 -weighted imaging with different echo times. Series of T2 -weighted images were fitted using mono- and biexponential models with two- and four-parametric nonlinear approaches, respectively. RESULTS: Biexponential relaxation of T2 was detected in the knee cartilage in five regions of interest in all eight healthy volunteers. Short/long relaxation components of T2 were estimated to be 8.27 +/- 0.68 / 45.35 +/- 3.79 msec with corresponding fractions of 41.3 +/- 1.1% / 58.6 +/- 4.6%, respectively. The monoexponential relaxation of T2 was measured to be 26.9 +/- 2.27 msec. The experiments showed good repeatability with coefficient of variation root mean square (CVrms ) < 18% in all regions. The only difference in gender was observed in medial tibial cartilage, where the biexponential T2 in female volunteers was significantly higher compared to male volunteers (P = 0.014). Significant differences were observed in T2 relaxation between different regions on interest. CONCLUSION: Biexponential relaxation of T2 was observed in the human knee cartilage in vivo. The short and long components are thought to be related to the tightly bound and loosely bound macromolecular water compartments. These preliminary results of biexponential T2 analysis could potentially be used to increase the specificity for detection of early osteoarthritis by measuring different water compartments and their fractions. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:809-819. PMID- 28561957 TI - A retrospective study of anti-inflammatory use in dogs with pulmonary blastomycosis: 139 cases (2002-2012). AB - OBJECTIVE: To determine the effect of anti-inflammatory medications on 30-day survival of dogs treated for pulmonary blastomycosis. DESIGN: Retrospective study. SETTING: University teaching hospital. ANIMALS: One hundred thirty nine client-owned dogs with confirmed pulmonary blastomycosis. MEASUREMENTS AND MAIN RESULTS: The medical records of dogs diagnosed with pulmonary blastomycosis between May 2002 and October 2012 were identified. Of 139 dogs, 85 (61%) survived to 30 days, 38 (27%) were euthanized due to progressive clinical disease, 13 (10%) died secondary to respiratory or cardiac arrest, and 3 (2%) did not survive to 30 days but had an unknown cause of death. Cases were classified based on the anti-inflammatory therapy that was used: nonsteroidal anti-inflammatory drugs (NSAID), corticosteroids, both, or none. Controlling for the effects of itraconazole dose, sex, age, and pretreatment with anti-inflammatory medication, the odds for survival to 30 days was not statistically different between dogs who received no anti-inflammatory medication and the dogs who received NSAIDs (P = 0.86), corticosteroids (P = 0.65), or both (P = 0.27). The need for supplemental oxygen was associated with decreased survival (P < 0.0001). CONCLUSIONS: In this population of dogs with pulmonary blastomycosis, the use of anti-inflammatory medications during therapy did not impact 30-day survival; however, the need for oxygen supplementation was associated with significantly lower survival. PMID- 28561958 TI - Identification of Free Radical Scavengers from Brazilian Green Propolis Using Off Line HPLC-DPPH Assay and LC-MS. AB - Brazilian green propolis is known as an appreciable natural antioxidant with abundant polyphenolic compounds. For quality control, a fingerprint-efficacy study of Brazilian green propolis was carried out in this work. Chemical fingerprints of Brazilian green propolis from 22 different sources were determined by HPLC and investigated by similarity analysis. The fingerprint efficacy relationships between chemical fingerprint and DPPH radical-scavenging activity were established. The results showed that 14 characteristic common peaks were identified, and 9 compounds were discovered with free radical-scavenging activities. Caffeoylquinic acids and artepillin C might be the major effective components for quality control of Brazilian green propolis due to their specificity and strong antioxidant activity. This study provides new markers for the quality assessment of Brazilian green propolis and its derived products. PMID- 28561959 TI - Review of Efficacy of Complementary and Alternative Medicine Treatments for Menopausal Symptoms. AB - Complementary and alternative medicine (CAM) treatments have been used for thousands of years around the world. There has been increased interest in utilizing CAM for menopausal symptoms since the release of results of the Women's Health Initiative elucidated long-term adverse effects associated with hormone therapy. Women looking for more natural or safer means to treat hot flushes, night sweats, and other menopausal symptoms often turn to CAM such as yoga, phytoestrogens, or black cohosh. Yet there have been few well-conducted studies looking at the efficacy of these treatments. This review examines randomized clinical trials, systematic reviews, and meta-analyses evaluating the effectiveness of commonly used CAM for the treatment of menopausal symptoms. PMID- 28561961 TI - A MOLECULAR PHYLOGENY OF THE FELIDAE: IMMUNOLOGICAL DISTANCE. AB - The phylogenetic distances between 34 of the 37 extant species of Felidae were estimated using albumin immunological distances (AID). Albumins from ten cat species were used to prepare antisera in rabbits. A consensus phylogeny was constructed from a matrix of reciprocal AID measurements using four distinct phylogenetic algorithms. A series of one-way measurements using the ten index antisera and those 24 species for which albumins were available (but antisera were not), permitted addition of these "species' limbs" to the previously derived phylogenetic trees. The major conclusions of the derived topology were: 1) the earliest branch of the feline radiation occurred approximately 12 million years B.P. and led to the small South American cats (ocelot, margay, Geoffroy's cat, etc.); 2) the second branching occurred 8-10 million years B.P. and included the close relatives of the domestic cat (wildcats, jungle cat, sand cat, and black footed cat) plus Pallas's cat; 3) the third lineage which began to radiate 4-6 million years B.P. was the pantherine lineage, which included several early branches (cheetah, serval, clouded leopard, golden cats, and puma) and a very recent (2 million years B.P.) split between the lynxes and the modern great cats (Panthera). The topology of the Felidae derived from albumin immunological distance is highly consistent with the karyological disposition of these species, as well as with the fossil record of this family. Because of the recent divergence of this group, the presented data set and the derived topology contain certain unresolved phylogenetic relationships which are so indicated. PMID- 28561962 TI - EVOLUTION IN THE SEASONAL THETA MODELS. PMID- 28561960 TI - Acute respiratory distress syndrome and septic shock in a cat with disseminated toxoplasmosis. AB - OBJECTIVE: To describe acute respiratory distress syndrome (ARDS) and septic shock in a cat with disseminated toxoplasmosis. CASE SUMMARY: A 2-year-old neutered male domestic shorthair cat was presented for acute respiratory distress. At the time of presentation it had been receiving cyclosporine for treatment of eosinophilic dermatitis. Thoracic radiographs revealed severe mixed nodular interstitial and alveolar patterns. An endotracheal wash was performed, which confirmed a diagnosis of pulmonary toxoplasmosis. Despite initial treatment with oxygen supplementation and intravenous clindamycin, the cat developed refractory hypoxemia and hypotension requiring mechanical ventilation and vasopressor support within 24 hours of hospital admission. Cardiac arrest occurred 56 hours after admission. Necropsy was performed and histopathology revealed protozoal organisms disseminated throughout the heart, lungs, liver, and brain. NEW OR UNIQUE INFORMATION PROVIDED: The clinical and necropsy findings presented here are consistent with ARDS secondary to disseminated toxoplasmosis in a cat. This is the first detailed report of ARDS in a cat. Toxoplasma titer testing and antimicrobial prophylaxis should be considered in cats prior to immunosuppressive treatment with cyclosporine. PMID- 28561963 TI - FACTORS DETERMINING A CLUTCH SIZE REDUCTION IN CALIFORNIA GULLS (LARUS CALIFORNICUS): A MULTI-HYPOTHESIS APPROACH. AB - In the thirty-five years since David Lack first highlighted the importance of clutch size, a large number of hypotheses have been proposed relating clutch size variation to various environmental and demographic factors. Despite a great deal of both empirical and theoretical work on clutch size, there has been very little effort to test many of the competing hypotheses in explaining a clutch size difference between two populations of the same species. I have taken the latter approach in an effort to explain a clutch size reduction in the California Gull (Larus californicus) population at Mono Lake, California. I compared the breeding biologies of the gulls at Mono Lake and at Great Salt Lake, Utah, collecting data for three breeding seasons at Mono Lake and one breeding season at Great Salt Lake. These data included measurements of the conditions of 60 adults, growth and mortality measurements for approximately 900 chicks, 4450 nest-hours of parental care observations, and the results of egg-removal experiments on 40 females. I tested seven hypotheses to explain the clutch size reduction: age structure, egg predation, bet-hedging, effort reallocation, most productive brood size, parental mortality, and pre-egg food limitation. Each of these hypotheses is described in detail in the introduction. The pre-egg food limitation hypothesis is best able to explain the clutch size reduction at Mono Lake, although the egg-removal experiments show that the resource limitation is relative and not absolute. Clutch size variation at each site need not be viewed as the result of fine scaled evolutionary adjustment, although the general clutch size decision machinery is presumably molded by selection. Future research must focus on the details of this clutch size decision machinery and its application to the concept of reproductive effort. PMID- 28561964 TI - GENOTYPE-ENVIRONMENT INTERACTION AND THE EVOLUTION OF PHENOTYPIC PLASTICITY. AB - Studies of spatial variation in the environment have primarily focused on how genetic variation can be maintained. Many one-locus genetic models have addressed this issue, but, for several reasons, these models are not directly applicable to quantitative (polygenic) traits. One reason is that for continuously varying characters, the evolution of the mean phenotype expressed in different environments (the norm of reaction) is also of interest. Our quantitative genetic models describe the evolution of phenotypic response to the environment, also known as phenotypic plasticity (Gause, 1947), and illustrate how the norm of reaction (Schmalhausen, 1949) can be shaped by selection. These models utilize the statistical relationship which exists between genotype-environment interaction and genetic correlation to describe evolution of the mean phenotype under soft and hard selection in coarse-grained environments. Just as genetic correlations among characters within a single environment can constrain the response to simultaneous selection, so can a genetic correlation between states of a character which are expressed in two environments. Unless the genetic correlation across environments is +/- 1, polygenic variation is exhausted, or there is a cost to plasticity, panmictic populations under a bivariate fitness function will eventually attain the optimum mean phenotype for a given character in each environment. However, very high positive or negative correlations can substantially slow the rate of evolution and may produce temporary maladaptation in one environment before the optimum joint phenotype is finally attained. Evolutionary trajectories under hard and soft selection can differ: in hard selection, the environments with the highest initial mean fitness contribute most individuals to the mating pool. In both hard and soft selection, evolution toward the optimum in a rare environment is much slower than it is in a common one. A subdivided population model reveals that migration restriction can facilitate local adaptation. However, unless there is no migration or one of the special cases discussed for panmictic populations holds, no geographical variation in the norm of reaction will be maintained at equilibrium. Implications of these results for the interpretation of spatial patterns of phenotypic variation in natural populations are discussed. PMID- 28561965 TI - QUANTUM CHANGES IN GASTROPOD SHELL MORPHOLOGY NEED NOT REFLECT SPECIATION. PMID- 28561966 TI - LIFE HISTORY VARIATION IN PRIMATES. AB - Extensive variation in life-history patterns is documented across primate species. Variables included are gestation length, neonatal weight, litter size, age at weaning, age at sexual maturity, age at first breeding, longevity, and length of the estrous cycle. Species within genera and genera within subfamilies tend to be very similar on most measures, and about 85% of the variation remains when the subfamily is used as the level for statistical analysis. Variation in most life-history measures is highly correlated with variation in body size, and differences in body size are associated with differences in behavior and ecology. Allometric relationships between life-history variables and adult body weight are described; subfamily deviations from best-fit lines do not reveal strong correlations with behavior or ecology. However, for their body size, some subfamilies show consistently fast development across life-history stages while others are characteristically slow. One exception to the tendency for relative values to be positively correlated is brain growth: those primates with relatively large brains at birth have relatively less postnatal brain growth. Humans are a notable exception, with large brains at birth and high postnatal brain growth. PMID- 28561967 TI - STATISTICAL ANALYSIS OF HETEROZYGOSITY DATA: INDEPENDENT SAMPLE COMPARISONS. AB - The distribution of mean heterozygosities under an infinite allele model with constant mutation rate was examined through simulation studies. It was found that, although the variance of the distribution decreases with increasing numbers of loci examined as expected, the shape of the distribution may remain skewed or bimodal. The distribution becomes symmetrical for increasing mean heterozygosity levels and numbers of loci. As a result, parametric statistical tests may not be valid for making comparisons among populations or species. Independent sample t tests were examined in detail to determine the frequency of rejection of the null hypothesis when pairs of samples are drawn from populations with the same mean heterozygosity. Differing numbers of loci and levels of mean heterozygosity were examined. For mean heterozygosity levels above 7.5%, t-tests provide the proper rejection rate, with as few as five loci. When mean heterozygosity is as low as 2.5%, the t-test is conservative even when 40 loci are examined in each population. Independent sample t-tests were then examined for their power to detect true differences between populations as the degree of difference and number of loci vary. Although large differences can be found with high certainty, differences on the order of 5% heterozygosity may require that large numbers of loci (>40) be examined in order to be 80% or more certain of detecting them. In addition, it is emphasized that, for small numbers of loci (<25), the statistical detection of differences of interesting magnitude requires that relatively rare sampling events occur and that much larger differences be observed among the samples than exist for the population means. Two reasons exist for the lack of sensitivity of the test procedures. First, when mean heterozygosity levels are low, the non-normality of the sample means is perhaps most important. Second, even when mean heterozygosity levels are high or when sample sizes are large enough so sample means are approximately normally distributed, the intrinsically high interlocus variance of heterozygosity estimates makes the tests insensitive to the presence of heterozygosity differences that might be biologically meaningful. Finally, the implications of the results of this study are discussed with regard to observed low levels of correlation between heterozygosity and other explanatory variables. PMID- 28561969 TI - EVOLUTION BACK ISSUES. PMID- 28561968 TI - EXPERIMENTAL STUDIES OF THE EVOLUTIONARY SIGNIFICANCE OF SEXUAL REPRODUCTION II. A TEST OF THE DENSITY-DEPENDENT SELECTION HYPOTHESIS. AB - This study tests the hypothesis that one evolutionary advantage of sexual reproduction is that it produces genetically variable progeny with a density dependent advantage mediated by resource partitioning or pest pressure. Our experimental approach involved planting separate plots of sexually-derived and asexually-derived tillers of the grass Anthoxanthum odoratum in density gradients at the two natural sites from which the source material was taken. The sexual progeny displayed a significant fitness advantage compared to the asexual progeny. But, in contrast to the expectations of the density-dependent selection hypothesis, the advantage of the sexually produced progeny is most marked at lower densities. Thus, the results of this experiment and our previous report (Antonovics and Ellstrand, 1984) seem to best support the frequency-dependent selection hypothesis for the advantage of sexual reproduction. PMID- 28561970 TI - AERODYNAMICS, THERMOREGULATION, AND THE EVOLUTION OF INSECT WINGS: DIFFERENTIAL SCALING AND EVOLUTIONARY CHANGE. AB - We examine several aerodynamic and thermoregulatory hypotheses about possible adaptive factors in the evolution of wings from small winglets in insects. Using physical models of Paleozoic insects in a wind tunnel, we explore the potential effects of wings for increasing gliding distance, increasing dispersal distance during parachuting, improving attitude control or stability, and elevating body temperatures during thermoregulation. The effects of body size and shape, wing length, number, and venation, and meteorological conditions are considered. Hypotheses consistent with both fixed and moveable wing articulations are examined. Short wings have no significant effects on any of the aerodynamic characteristics, relative to wingless models, while large wings do have significant effects. In contrast, short wings have large thermoregulatory effects relative to wingless models, but further increases in wing length do not significantly affect thermoregulatory performance. At any body size, there is a wing length below which there are significant thermoregulatory effects of increasing wing length, and above which there are significant aerodynamic effects of increasing wing length. The relative wing length at which this transition occurs decreases with increasing body size. These results suggest that there could be no effective selection for increasing wing length in wingless or short winged insects in relation to increased aerodynamic capacity. Our results are consistent with the hypothesis that insect wings initially served a thermoregulatory function and were used for aerodynamic functions only at larger wing lengths and/or body sizes. Thus, we propose that thermoregulation was the primary adaptive factor in the early evolution of wings that preadapted them for the subsequent evolution of flight. Our results illustrate an evolutionary mechanism in which a purely isometric change in body size may produce a qualitative change in the function of a given structure. We propose a hypothesis in which the transition from thermoregulatory to aerodynamic function for wings involved only isometric changes in body size and argue that changes in body form were not a prerequisite for this major evolutionary change in function. PMID- 28561971 TI - HUTCHINSONIAN RATIOS AND LOG-NORMAL DISTRIBUTIONS. PMID- 28561972 TI - THE INFLUENCE OF ENVIRONMENTAL VARIATION ON GROUP AND INDIVIDUAL SELECTION IN A CRESS. AB - An experimental study of group and individual selection for leaf area under different patterns of environmental variation is presented. This study, which uses the cress Arabidopsis thaliana, demonstrates that group selection can occur in plants. The response to group selection was always in the expected direction, but surprisingly, the response to individual selection was not. Furthermore the interaction between group and individual selection was significant. Individual selection interfered with the response to group selection whether the two forces were acting in concert or were opposed. The effects of the environmental variation treatments were detected mainly as three-way interactions with group and individual selection. Group selection was more effective in environments that interfered with individual selection, as well as in environments that did not interfere with group selection. These results suggest that the ability of a character to respond to group selection, individual selection, or both will depend on a great many factors and that the relative importance of the different levels of selection can only be determined empirically. PMID- 28561973 TI - FACTORS DETERMINING THE ACCURACY OF CLADOGRAM ESTIMATION: EVALUATION USING COMPUTER SIMULATION. AB - We developed a simulation model of phylogenesis with which we generated a large number of phylogenies and associated data matrices. We examined the characteristics of these and evaluated the success of three taxonomic methods (Wagner parsimony, character compatibility, and UPGMA clustering) as estimators of phylogeny, paying particular attention to the consequences of changes in certain evolutionary assumptions: relative rate of evolution in three different evolutionary contexts (phyletic, parent lineage, and daughter lineage); relative rate of evolution in different directions (novel forward, convergent forward, or reverse); variation of evolutionary rates; and topology of the phylogenetic tree. Except for variation of evolutionary rates, all the evolutionary parameters that we controlled had significant effects on accuracy of phylogenetic reconstructions. Unexpectedly, the topology of the phylogeny was the most important single factor affecting accuracy; some phylogenies are more readily estimated than others for simply historical reasons. We conclude that none of the three estimation methods is very accurate, that the differences in accuracy among them are rather small, and that historical effects (the branching pattern of a phylogeny) may outweigh biological effects in determining the accuracy with which a phylogeny can be reconstructed. PMID- 28561974 TI - DISRUPTIVE SELECTION ON HABITAT PREFERENCE AND THE EVOLUTION OF REPRODUCTIVE ISOLATION: AN EXPLORATORY EXPERIMENT. AB - A. pair of replicate experiments was carried out to examine the role of habitat specialization in the process of sympatric speciation. The rationale of the experimental design was that disruptive selection for habitat preference can facilitate the process of sympatric speciation by reducing an antagonistic interaction between the processes of recombination and selection. Replicate populations of Drosophila melanogaster were subjected to disruptive selection for habitat preference and simultaneous selection for positive assortative mating, for a period of 46 generations. The experimental protocol simulated the introduction of a frugivorous fly population into a new environment that contained a mosaic of eight equally abundant habitats. Only two habitats were suitable to the flies, and these required opposite patterns of geotaxis, phototaxis, chemotaxis, and developmental time to be successfully located. At the beginning of each generation, flies were placed as pupae into the middle of a maze containing eight discrete habitats. To produce disruptive selection on habitat preference, only those flies that chose one or the other of two selected habitats were permitted to contribute gametes to the next generation. Flies from each of the selected habitats were cultured separately to simulate independent carrying capacities within each habitat. Because flies rarely mated until they assorted themselves into the available habitats, genes affecting habitat preference pleiotropically produced assortative mating between flies with similar habitat preference. A genetic marker was used to continuously monitor the level of potential gene flow between the flies derived from the two selected habitats. During the course of the experiment, there was a gradual increase in the philopatry of the flies, indicating the development of habitat specialization. The evolution of habitat specialization resulted in substantial reproductive isolation between the subpopulations utilizing each habitat resource. PMID- 28561975 TI - POSITIONS AVAILABLE. PMID- 28561976 TI - SONG DIALECTS AND GENE FLOW IN THE WHITE-CROWNED SPARROW, ZONOTRICHIA LEUCOPHRYS NUTTALLI. PMID- 28561977 TI - RELATIVE PERFORMANCE OF SELFED AND OUTCROSSED PROGENY IN IMPATIENS CAPENSIS. AB - This study compares survival and growth of progeny derived from chasmogamous (CH) and cleistogamous (CL) flowers in Impatiens capensis, a forest annual. When progeny were grown in the field, CH seeds had significantly higher survival rates over winter (64% versus 56%), and the survival advantage of outcrossed progeny was not attributable to seed weight differences. No differences in seedling growth were detected. Greenhouse comparisons revealed no difference in seed survival but a 30% growth advantage to CH seedlings. We found no changes in developmental homeostasis of three leaf shape characters between inbred and outbred progeny, nor was there any difference in variability within CH and CL families. The outcrossing advantage observed in these experiments could not have been caused by avoidance of sib competition. Theory predicts that self-pollinated progenies may be more variable than outcrossed progenies if rare, recessive alleles are important contributors to genetic variances. Electrophoretic markers indicate that progeny derived from CH flowers are predominantly outcrossed (at least 54-97%). PMID- 28561978 TI - PARAMETER EVOLUTION IN THE theta-MODEL. PMID- 28561979 TI - PHYLOGENETICS OF THE LISIANTHIUS SKINNERI (GENTIANACEAE) SPECIES COMPLEX IN PANAMA UTILIZING DNA RESTRICTION FRAGMENT ANALYSIS. AB - The well-delimited and evolutionary interesting tropical shrub group, the Lisianthius skinneri (Gentianaceae) species complex, was analyzed for variation in nuclear ribosomal DNA and chloroplast DNA by restriction endonuclease fragment analysis. A most parsimonious tree using variations in both DNAs was constructed for seven populations in the group by including an appropriate outgroup. This phylogeny is significantly more compatible with the DNA data than most, but not all, less parsimonious phylogenies. At least two distinct lineages have independently evolved geographically restricted, cloud forest species from the putative ancestral, widespread, and lower elevation L. skinneri. Lisianthius skinneri itself is shown to be paraphyletic with populations derived separately from the two distinct lineages. Except for a switch in the placement of two populations, this DNA-based phylogeny is congruent with an isozyme-based Wagner network depicting relationships in the species complex. Relative rates of divergence, in terms of nuclear ribosomal DNA, chloroplast DNA, isozymes, and morphology, differ markedly within and between lineages. The non-transcribed spacer region of ribosomal DNA is shown to evolve in a manner that is not in accord with a molecular clock hypothesis. Small population sizes, restricted and isolated nature of populations, and probable founder events are suggested as instrumental in causing this lack of concerted divergence within and between lineages of the L. skinneri species complex. PMID- 28561980 TI - MALE EFFECTS ON FECUNDITY IN DROSOPHILA MELANOGASTER. AB - Effects of male Drosophila melanogaster on female fecundity and productivity were examined, considering both females held in containers with males and females exposed to male effects not involving contact. Females were more fecund when male effects were present, and the largest increase was recorded when vials were previously conditioned by males. This effect was probably due to the growth of transmitted microorganisms, which were observed on the laying surface, as further experiments with vials conditioned by virgin females showed a similar increase in fecundity. A male-specific effect was isolated by conditioning bottles containing only agar with males and virgin females. The observation of a male factor that stimulates oviposition without mating is novel and suggests complicated fertility interactions between the sexes. PMID- 28561982 TI - GENETIC VARIATION IN A COURTSHIP-RELATED MALE CHARACTER IN DROSOPHILA SILVESTRIS FROM A SINGLE HAWAIIAN LOCALITY. AB - The large Drosophila species of Hawaii display sexual dimorphism and elaborate species-specific courtship patterns. Male characters related to courtship attract particular attention since they frequently constitute the most conspicuous taxonomic differences between Hawaiian species. The present study concerns intraspecific genetic variation in a courtship-related male character. D. silvestris, endemic to the geologically new volcanoes of Hawaii island, displays a brush of large dorsal cilia on the tibia of the foreleg of the male fly. This is used to stimulate the female during courtship. Genetic variation between local populations has previously been shown to exist for both sexual behavior and cilia number. The present paper reports the results of a study of cilia number variation in males collected at a single site over the period 1976-1980. Male progeny of females captured in nature were also studied. The mean number of cilia in the natural population was stable except for 1979 when it rose significantly, falling back again in 1980. The data indicate the existence of ample genetic variance for this character, existing as a balanced polymorphism in the natural population. The character appears to be under stabilizing selection. It is hypothesized that sexual selection is a contributing factor. PMID- 28561983 TI - SELECTION ON BILL CHARACTERS IN A POPULATION OF DARWIN'S FINCHES: GEOSPIZA CONIROSTRIS ON ISLA GENOVESA, GALAPAGOS. AB - Lande and Arnold's (1983) technique for measuring selection on correlated quantitative traits was used to identify the targets of selection and to reveal the direction of selection on three bill dimensions, during different stages of the life cycle in a population of Darwin's finches, Geospiza conirostris, on Isla Genovesa, Galapagos. There was a tendency towards disruptive selection during dry conditions, arising from differential survival. In terms of longevity and breeding success of females, the direction of selection was to increase bill length. For males competing for territories, selection acted to increase bill depth and bill length. The effects of male-male interactions were separated from those of female choice. Male-male interactions selected for deep and long bills, whereas females chose their mates on the basis of a male's territory position and plumage coloration. The results reveal three factors constraining changes in bill dimensions: a tendency for the mean of a dimension to shift in one direction is counteracted by selection in the opposite direction on 1) another, positively correlated, bill dimension, 2) the same dimension in the other sex, and 3) the same dimension at another stage of the life cycle. If these factors are overcome by strong directional selection at one stage of the life cycle and relaxation at another, there can be an evolutionary response because the bill dimensions in this population are known to be heritable. The results complement those found in studies of G. fortis on another island and strengthen the view that these populations of Darwin's finches are frequently subjected to natural selection. PMID- 28561984 TI - SIZE-DISASSORTATIVE MATING IN THE CHRYSOMELID BEETLE CHRYSOLINA AURICHALCEA (COLEOPTERA: CHRYSOMELIDAE). PMID- 28561985 TI - GENETIC VARIATION, DIFFERENTIATION, AND EVOLUTION IN A SPECIES COMPLEX OF TROPICAL SHRUBS BASED ON ISOZYMIC DATA. AB - An isozyme investigation of the Lisianthius skinneri (Gentianaceae) species complex in central Panama assayed levels of genetic variation within and among isolated populations and was used to reconstruct phylogenetic relationships within the complex. The widespread and low elevation L. skinneri and one derived cloud forest endemic species, L. habuensis, are depauperate in genetic variation. Three other endemic cloud forest species exhibiting larger population sizes and apparently more outcrossed breeding systems have higher levels of heterozygosity but retain low levels of allelic diversity. More than 90% of the genetic variation in the species complex is confined to among-population differentiation rather than witnin-population variation. Isozyme-based relationships within the species complex using both genetic divergence values (Fitch and Margoliash algorithm) and shared allelic states (Nelson and Van Horn algorithm) are identical. This network is not entirely congruent with a previous DNA-based network. Geographical isolation, small population size, low allelic diversity, and high levels of among-population differentiation suggest that repeated instances of founder events and genetic drift have been important in the evolution of this tropical shrub complex. PMID- 28561987 TI - Oral misoprostol alone versus oral misoprostol and Foley's catheter for induction of labor: A randomized controlled trial. AB - AIM: The aim of this study was to evaluate the efficacy of oral misoprostol and Foley's catheter versus oral misoprostol alone for induction of labor. METHODS: This open-label randomized controlled trial included 335 women requiring induction of labor. A total of 166 women were randomly allocated to induction with oral misoprostol alone and 169 women were assigned for induction with Foley's balloon catheter and oral misoprostol using a computer-generated allocation sequence. The primary outcome was rate of failure to achieve vaginal delivery within 24 h of induction. RESULTS: The proportion of women failing to achieve vaginal delivery within 24 h in the combination group was lower (11.8% vs 28.7%, P = 0.001). When the two groups were stratified according to parity, the difference remained statistically significant only for parous women. The median induction-to-delivery interval (13.0 h vs 19 h, P = 0.000) and the median number of doses of misoprostol used (2 vs 3, P = 0.000) were lower in the combination group. The number of women who delivered vaginally in the combination group was significantly higher (91% vs 79%, P = 0.001). More neonates born to women in the misoprostol group had Apgar scores < 7 and were admitted to the neonatal intensive care unit (P = 0.016 and P = 0.007, respectively). CONCLUSION: The rate of failure to achieve vaginal delivery within 24 h was lower with Foley's balloon and oral misoprostol as compared to oral misoprostol alone. PMID- 28561986 TI - Rationale, design, and baseline characteristics of the CLARIFY registry of outpatients with stable coronary artery disease. AB - BACKGROUND: Despite major advances in prevention and treatment, coronary artery disease (CAD) remains the leading cause of death worldwide. Whereas many sources of data are available on the epidemiology of acute coronary syndromes, fewer datasets reflect the contemporary management and outcomes of stable CAD patients. HYPOTHESIS: A worldwide contemporary registry would improve our knowledge about stable CAD. The main objectives are to describe the demographics, clinical profile, contemporary management and outcomes of outpatients with stable CAD; to identify gaps between evidence and treatment; and to investigate long-term prognostic determinants. METHODS: CLARIFY (ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) is an ongoing international observational longitudinal registry. Stable CAD patients from 45 countries in Europe, Asia, America, Middle East, Australia and Africa were enrolled between November 2009 and June 2010. The inclusion criteria were previous myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischemia or prior revascularization procedure. The main exclusion criteria were serious non-cardiovascular disease, conditions interfering with life expectancy or severe other cardiovascular disease (including advanced heart failure). Follow-up visits were planned annually for up to 5 years, interspersed with 6-month telephone calls. RESULTS: Of the 32,703 patients enrolled, most (77.6%) were male, age (mean +/- SD) was 64.2 +/- 10.5 years, and 71.0% were receiving treatment for hypertension; mean +/- SD resting heart rate was 68.2 +/- 10.6 bpm. Patients were enrolled based on a history of myocardial infarction >3 months earlier (57.7%), having at least one stenosis >50% on coronary angiography (61.1%), proven symptomatic myocardial ischemia on non-invasive testing (23.1%), or history of percutaneous coronary intervention or coronary artery bypass graft (69.8%). Baseline characteristics were similar across the four subgroups identified by the four inclusion criteria. CONCLUSION: CLARIFY will provide a useful resource for understanding the current epidemiology of stable CAD. PMID- 28561989 TI - Light-Driven, Caterpillar-Inspired Miniature Inching Robot. AB - Liquid crystal elastomers are among the best candidates for artificial muscles, and the materials of choice when constructing microscale robotic systems. Recently, significant efforts are dedicated to designing stimuli-responsive actuators that can reproduce the shape-change of soft bodies of animals by means of proper external energy source. However, transferring material deformation efficiently into autonomous robotic locomotion remains a challenge. This paper reports on a miniature inching robot fabricated from a monolithic liquid crystal elastomer film, which upon visible-light excitation is capable of mimicking caterpillar locomotion on different substrates like a blazed grating and a paper surface. The motion is driven by spatially uniform visible light with relatively low intensity, rendering the robot "human-friendly," i.e., operational also on human skin. The design paves the way toward light-driven, soft, mobile microdevices capable of operating in various environments, including the close proximity of humans. PMID- 28561988 TI - Electron Hopping Across Hemin-Doped Serum Albumin Mats on Centimeter-Length Scales. AB - Exploring long-range electron transport across protein assemblies is a central interest in both the fundamental research of biological processes and the emerging field of bioelectronics. This work examines the use of serum-albumin based freestanding mats as macroscopic electron mediators in bioelectronic devices. In particular, this study focuses on how doping the protein mat with hemin improves charge-transport. It is demonstrated that doping can increase conductivity 40-fold via electron hopping between adjacent hemin molecules, resulting in the highest measured conductance for a protein-based material yet reported, and transport over centimeter length scales. The use of distance dependent AC impedance and DC current-voltage measurements allows the contribution from electron hopping between adjacent hemin molecules to be isolated. Because the hemin-doped serum albumin mats have both biocompatibility and fabrication simplicity, they should be applicable to a range of bioelectronic devices of varying sizes, configurations, and applications. PMID- 28561990 TI - Prenatal diagnosis of Duchenne and Becker muscular dystrophies: Underestimated problem of the secondary prevention of monogenetic disorders. AB - AIM: The aim of this study was to analyze the influence of effective preconceptional testing for carrier status in women at risk for Duchenne and Becker muscular dystrophies (D/BMD) on the prenatal diagnosis. METHODS: A retrospective analysis of 201 prenatal tests was performed in 169 Polish women at risk, in regard to time of testing for carrier status (prior to conception or during pregnancy) and carrier status of tested women, including confirmed D/BMD carriers (n = 78; 46.2%), D/BMD non-carriers - tested for germline mosaicism risk (n = 23; 13.6%), and women at risk with uncertain carrier status (n = 68; 40.2%). RESULTS: Only 52.7% of women were tested for D/BMD carrier status prior to conception and in these women prenatal diagnosis was carried out more frequently in the first trimester of pregnancy (64.7% vs 47.8%; P = 0.035). The results of prenatal testing in male fetuses in pregnancies of confirmed D/BMD carriers and D/BMD non-carriers - tested for germline mosaicism risk were conclusive in all cases, whereas in women with uncertain carrier status, only 60.0% of results were conclusive. Eighty-five of 103 female fetuses (82.5%) were tested prenatally and in 31.8% of them fetal carrier status was confirmed. CONCLUSION: Carrier status testing in women prior to conception has a positive impact on the frequency of first-trimester prenatal diagnosis and known D/BMD carrier status on the effectiveness of prenatal diagnosis. Due to the low percentage of women tested effectively prior to conception, carrier status testing in the families at risk should be propagated (including possibility of prenatal diagnosis of female fetuses). PMID- 28561991 TI - Development of a novel bioactive glass suitable for osteosarcoma-related bone grafts. AB - In this study, zinc borate-based glasses with increasing gallium content (0, 2.5, 5, 10, and 15 wt % Ga) were synthesized and their effect on the viability and proliferation of preosteoblasts and osteosarcoma cancer cells were investigated. Methyl thiazolyl tetrazolium (MTT) cell viability assays using glass degradation extracts revealed that the extracts from glasses with lower Ga contents could enhance the viability of preosteoblasts, while extracts from the glass composition with 15 wt % Ga caused statistically significant reduction of their viability. MTT cell viability assays using the extracts and osteosarcoma cells showed that only extracts from the glass composition with 5 wt % Ga (G3) did not cause a statistically significant increase in the viability of cancer cells for all degradation periods (1 day, 7 days, and 28 days). G3 was selected as the most suitable composition for the osteosarcoma-related graft operations as it could improve the viability of preosteoblasts without increasing the viability of cancer cells. The viability of preosteoblasts and osteosarcoma cells in contact with the glass powders were also investigated using MTT assays. The results showed that the G3 powders could enhance the viability of preosteoblasts while decreasing the viability of osteosarcoma cells. Finally, live/dead assays revealed that suppression of proliferation appeared to be the mechanism causing the observed reductions in the viability of osteosarcoma cells exposed to G3 powders. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1186-1193, 2018. PMID- 28561992 TI - Reply. PMID- 28561993 TI - Removable partial denture alloys processed by laser-sintering technique. AB - Removable partial dentures (RPDs) are traditionally made using a casting technique. New additive manufacturing processes based on laser sintering has been developed for quick fabrication of RPDs metal frameworks at low cost. The objective of this study was to characterize the mechanical, physical, and biocompatibility properties of RPD cobalt-chromium (Co-Cr) alloys produced by two laser-sintering systems and compare them to those prepared using traditional casting methods. The laser-sintered Co-Cr alloys were processed by the selective laser-sintering method (SLS) and the direct metal laser-sintering (DMLS) method using the Phenix system (L-1) and EOS system (L-2), respectively. L-1 and L-2 techniques were 8 and 3.5 times more precise than the casting (CC) technique (p < 0.05). Co-Cr alloys processed by L-1 and L-2 showed higher (p < 0.05) hardness (14-19%), yield strength (10-13%), and fatigue resistance (71-72%) compared to CC alloys. This was probably due to their smaller grain size and higher microstructural homogeneity. All Co-Cr alloys exhibited low porosity (2.1-3.3%); however, pore distribution was more homogenous in L-1 and L-2 alloys when compared to CC alloys. Both laser-sintered and cast alloys were biocompatible. In conclusion, laser-sintered alloys are more precise and present better mechanical and fatigue properties than cast alloys for RPDs. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1174-1185, 2018. PMID- 28561994 TI - Pathogen-inducible Ta-Lr34res expression in heterologous barley confers disease resistance without negative pleiotropic effects. AB - Plant diseases are a serious threat to crop production. The informed use of naturally occurring disease resistance in plant breeding can greatly contribute to sustainably reduce yield losses caused by plant pathogens. The Ta-Lr34res gene encodes an ABC transporter protein and confers partial, durable, and broad spectrum resistance against several fungal pathogens in wheat. Transgenic barley lines expressing Ta-Lr34res showed enhanced resistance against powdery mildew and leaf rust of barley. While Ta-Lr34res is only active at adult stage in wheat, Ta Lr34res was found to be highly expressed already at the seedling stage in transgenic barley resulting in severe negative effects on growth. Here, we expressed Ta-Lr34res under the control of the pathogen-inducible Hv-Ger4c promoter in barley. Sixteen independent barley transformants showed strong resistance against leaf rust and powdery mildew. Infection assays and growth parameter measurements were performed under standard glasshouse and near-field conditions using a convertible glasshouse. Two Hv-Ger4c::Ta-Lr34res transgenic events were analysed in detail. Plants of one transformation event had similar grain production compared to wild-type under glasshouse and near-field conditions. Our results showed that negative effects caused by constitutive high expression of Ta-Lr34res driven by the endogenous wheat promoter in barley can be eliminated by inducible expression without compromising disease resistance. These data demonstrate that Ta-Lr34res is agronomically useful in barley. We conclude that the generation of a large number of transformants in different barley cultivars followed by early field testing will allow identifying barley lines suitable for breeding. PMID- 28561995 TI - Mean platelet volume may not show the presence and severity of hyperemesis gravidarum: Reply. PMID- 28561996 TI - 2D MoS2 Neuromorphic Devices for Brain-Like Computational Systems. AB - Hardware implementation of artificial synapses/neurons with 2D solid-state devices is of great significance for nanoscale brain-like computational systems. Here, 2D MoS2 synaptic/neuronal transistors are fabricated by using poly(vinyl alcohol) as the laterally coupled, proton-conducting electrolytes. Fundamental synaptic functions, such as an excitatory postsynaptic current, paired-pulse facilitation, and a dynamic filter for information transmission of biological synapse, are successfully emulated. Most importantly, with multiple input gates and one modulatory gate, spiking-dependent logic operation/modulation, multiplicative neural coding, and neuronal gain modulation are also experimentally demonstrated. The results indicate that the intriguing 2D MoS2 transistors are also very promising for the next-generation of nanoscale neuromorphic device applications. PMID- 28561997 TI - Defining moments for conscious time and content. AB - The spatiotemporal scales of natural phenomena define the observational granularity needed for scientific characterization. In cognitive neurosciences, neural oscillations delineate temporal scales that may naturally provide the computational resolution for information processing in the brain. Do neural oscillations define moments for the perception of time? PMID- 28561998 TI - Deposition of mannose-binding lectin and ficolins and activation of the lectin pathway of complement on the surface of polyurethane tubing used for cardiopulmonary bypass. AB - The artificial surface used for cardiopulmonary bypass (CPB) is a crucial factor activating the complement system and thus contributing to the generation of a systemic inflammatory response. The activation of classical and alternative pathways on this artificial surface is well known. In contrast, lectin pathway (LP) activation has not been fully investigated, although noted during CPB in several studies. Moreover, we have recently proved the contribution of the LP to the generation of the systemic inflammatory response syndrome after pediatric cardiac surgery. The aim of this study was to assess LP-mediated complement activation on the surface of polyurethane CPB circuit tubing (noncoated Chalice (r) ), used for CPB procedures in children with congenital heart disease. We found deposition of mannose-binding lectin, ficolin-1, -2, and -3 on the surface of unused tubing and on tubing used for CPB from a small minority of patients. Furthermore, we observed deposition of complement C4 activation products on tubing used for CPB and previously unused tubing after incubation with normal serum. The latter finding indicates LP activation in vitro on the polyurethane surface. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1202-1208, 2018. PMID- 28561999 TI - Allyl-Palladium-Catalyzed Ketone Dehydrogenation Enables Telescoping with Enone alpha,beta-Vicinal Difunctionalization. AB - The telescoping of allyl-palladium catalyzed ketone dehydrogenation with organocuprate conjugate addition chemistry allows for the introduction of aryl, heteroaryl, vinyl, acyl, methyl, and other functionalized alkyl groups chemoselectively to a wide variety of unactivated ketone compounds via their enone counterparts. The compatibility of the dehydrogenation conditions additionally allows for efficient trapping of the intermediate enolate with various electrophiles. The utility of this approach is demonstrated by comparison to several previously reported multistep sequences. PMID- 28562000 TI - Atomistic Approach toward Selective Photocatalytic Oxidation of a Mustard-Gas Simulant: A Case Study with Heavy-Chalcogen-Containing PCN-57 Analogues. AB - Here we describe the synthesis of two Zr-based benzothiadiazole- and benzoselenadiazole-containing metal-organic frameworks (MOFs) for the selective photocatalytic oxidation of the mustard gas simulant, 2-chloroethyl ethyl sulfide (CEES). The photophysical properties of the linkers and MOFs are characterized by steady-state absorption and emission, time-resolved emission, and ultrafast transient absorption spectroscopy. The benzoselenadiazole-containing MOF shows superior catalytic activity compared to that containing benzothiadiazole with a half-life of 3.5 min for CEES oxidation to nontoxic 2-chloroethyl ethyl sulfoxide (CEESO). Transient absorption spectroscopy performed on the benzoselenadiazole linker reveals the presence of a triplet excited state, which decays with a lifetime of 9.4 MUs, resulting in the generation of singlet oxygen for photocatalysis. This study demonstrates the effect of heavy chalcogen substitution within a porous framework for the modulation of photocatalytic activity. PMID- 28562001 TI - Antiscaling Magnetic Slippery Surfaces. AB - Scale formation is a common problem in a wide range of industries such as oil and gas, water desalination, and food processing. Conventional solutions for this problem including mechanical removal and chemical dissolution are inefficient, costly, and sometimes environmentally hazardous. Surface modification approaches have shown promises to address this challenge. However, these approaches suffer from intrinsic existence of solid-liquid interfaces leading to high rate of scale nucleation and high adhesion strength of the formed scale. Here, we report a new surface called magnetic slippery surface in two forms of Newtonian fluid (MAGSS) and gel structure (Gel-MAGSS). These surfaces provide a liquid-liquid interface to elevate the energy barrier for scale nucleation and minimize the adhesion strength of the formed scale on the surface. Performance of these new surfaces in both static and dynamic (under fluid flow) configurations is examined. These surfaces show superior antiscaling properties with an order of magnitude lower scale accretion compared to the solid surfaces and offer longevity and stability under high shear flow conditions. We envision that these surfaces open a new path to address the scale problem in the relevant technologies. PMID- 28562002 TI - Dual Imprinted Polymer Thin Films via Pattern Directed Self-Organization. AB - Synthetic topographically patterned films and coatings are typically contoured on one side, yet many of nature's surfaces have distinct textures on different surfaces of the same object. Common examples are the top and bottom sides of the butterfly wing or lotus leaf, onion shells, and the inside versus outside of the stem of a flower. Inspired by nature, we create dual (top and bottom) channel patterned polymer films. To this end, we first develop a novel fabrication method to create ceramic line channel relief structures by converting the oligomeric residue of stamped poly(dimethylsiloxane) (PDMS) nanopatterns on silicon substrates to glass (SiOx, silica) by ultraviolet-ozone (UVO) exposure. These silica patterned substrates are flow coated with polystyrene (PS) films and confined within an identically patterned top confining soft PDMS elastomer film. Annealing of the sandwich structures drives the PS to rapidly mold fill the top PDMS pattern in conjunction with a dewetting tendency of the PS on the silica pattern. Varying the film thickness h, from less than to greater than the pattern height, and varying the relative angle between the top-down and bottom-up patterned confinement surfaces create interesting uniform and nonuniform digitized defects in PS channel patterns, as also a defect-free channel regime. Our dual patterned polymer channels provide a novel fabrication route to topographically imprinted Moire patterns (whose applications range from security encrypting holograms to sensitive strain gauges), and their basic laser light diffractions properties are illustrated and compared to graphical simulations and 2D-FFT of real-space AFM channel patterns. While traditional "geometrical" and "fringe" Moire patterns function by superposition of two misaligned optical patterned transmittance gratings, our topographic pattern gratings are quite distinct and may allow for more unique holographic optical characteristics with further development. PMID- 28562003 TI - Effect of Alkylation on the Cellular Uptake of Polyethylene Glycol-Coated Gold Nanoparticles. AB - Alkyl groups (CnH2n+1) are prevalent in engineered bionanomaterials used for many intracellular applications, yet how alkyl groups dictate the interactions between nanoparticles and mammalian cells remains incomprehensively investigated. In this work, we report the effect of alkylation on the cellular uptake of densely polyethylene glycol-coated nanoparticles, which are characterized by their limited entry into mammalian cells. Specifically, we prepare densely PEGylated gold nanoparticles that bear alkyl chains of varying carbon chain lengths (n) and loading densities (termed "alkyl-PEG-AuNPs"), followed by investigating their uptake by Kera-308 keratinocytes. Strikingly, provided a modest alkyl mass percentage of 0.2% (2 orders of magnitude lower than that of conventional lipid based NPs) in their PEG shells, dodecyl-PEG-AuNPs (n = 12) and octadecyl-PEG AuNPs (n = 18) can enter Kera-308 cells 30-fold more than methoxy-PEG-AuNPs (no alkyl groups) and hexyl-PEG-AuNPs (n = 6) after 24 h of incubation. Such strong dependence on n is valid for all serum concentrations considered (even under serum-free conditions), although enhanced serum levels can trigger the agglomeration of alkyl-PEG-AuNPs (without permanent aggregation of the AuNP cores) and can attenuate their cellular uptake. Additionally, alkyl-PEG-AuNPs can rapidly enter Kera-308 cells via the filipodia-mediated pathway, engaging the tips of membrane protrusions and accumulating within interdigital folds. Most alkyl-PEG-AuNPs adopt the "endo-lysosomal" route of trafficking, but ~15% of them accumulate in the cytosol. Regardless of intracellular location, alkyl-PEG-AuNPs predominantly appear as individual entities after 24 h of incubation. Our work offers insights into the incorporation of alkyl groups for designing bionanomaterials for cellular uptake and cytosolic accumulation with intracellular stability. PMID- 28562004 TI - pKa-Dependent Facilitated Transport of CO2 across Hyperthin Polyelectrolyte Multilayers. AB - Hyperthin (ca. 20-30 nm thick) polyelectrolyte multilayers have been fabricated that are capable of facilitated transport of CO2. These membranes were fabricated from polycations bearing pendant groups of varying basicity plus poly(sodium 4 styrenesulfonate) as a polycounterion. A strong dependency of such transport on the basicity of the pendant groups (i.e., fixed carrier sites) has been found, where pKa values in the range of ca. 5-7 appear optimal. PMID- 28562005 TI - Hydrazide-Derivatized Microgels Bond to Wet, Oxidized Cellulose Giving Adhesion Without Drying or Curing. AB - Hydrazide-derivatized poly(N-isopropylacrylamide-co-acrylic acid) microgels gave strong adhesion to wet, TEMPO oxidized, regenerated cellulose membranes without a drying or heating step. Adhesion was attributed to hydrazone covalent bond formation with aldehyde groups present on the cellulose surfaces. This is one of only three chemistries we have found that gives significant never-dried adhesion between wet cellulose surfaces. By contrast, for cellulose joints that have been dried and heated before wet testing, the hydrazide-hydrazone chemistry offers no advantages over standard paper industry wet strength resins. The design rules for the hydrazide-microgel adhesives include: cationic microgels are superior to anionic gels; the lower the microgel cross-link density, the higher the adhesion; longer PEG-based hydrazide tethers offer no advantage over shorter attachments; and, adhesion is independent of microgel diameter. Many of these rules were in agreement with predictions of a simple adhesion model where the microgels were assumed to be ideal springs. We propose that the unexpected, high cohesion between neighboring microgels in multilayer films was a result of bond formation between hydrazide groups and residual NHS-carboxyl esters from the preparation of the hydrazide microgels. PMID- 28562006 TI - Activation of Natural Products Biosynthetic Pathways via a Protein Modification Level Regulation. AB - Natural products are critical for drug discovery and development; however their discovery is challenged by the wide inactivation or silence of microbial biosynthetic pathways. Currently strategies targeting this problem are mainly concentrated on chromosome dissembling, transcription, and translation-stage regulations as well as chemical stimulation. In this study, we developed a novel approach to awake cryptic/silenced microbial biosynthetic pathways through augmentation of the conserved protein modification step-phosphopantetheinylation of carrier proteins. Overexpression of phosphopantetheinyl transferase (Pptase) genes into 33 Actinomycetes achieved a significantly high activation ratio at which 23 (70%) strains produced new metabolites. Genetic and biochemical studies on the mode-of-action revealed that exogenous PPtases triggered the activation of carrier proteins and subsequent production of metabolites. With this approach we successfully identified five oviedomycin and halichomycin-like compounds from two strains. This study provides a novel approach to efficiently activate cryptic/silenced biosynthetic pathways which will be useful for natural products discovery. PMID- 28562007 TI - Visible Thermochromism in Vanadium Pentoxide Coatings. AB - Although di-vanadium pentoxide (V2O5) has been a candidate of extensive research for over half a century, its intrinsic thermochromism has not been reported so far. Films of V2O5 grown on silicon, glass, and metal substrates by metal organic chemical vapor deposition in this study exhibit a thermally induced perceptible color change from bright yellow to deep orange. Temperature-dependent UV-vis spectroscopy and X-ray diffraction allow the correlation between the reversible continuous red shift of the absorption and the anisotropic thermal expansion along the (001) direction, that is, perpendicular to the sheets constituting the layered structure. Furthermore, the possibility of tuning the thermochromic behavior was demonstrated via a chemical doping with chromium. PMID- 28562009 TI - Biphenylene and Phagraphene as Lithium Ion Battery Anode Materials. AB - We present results of density functional theory calculations on the lithium (Li) ion storage capacity of biphenylene (BP) membrane and phagraphene (PhG) which are two-dimensional defected-graphene-like membranes. Both membranes show a larger capacity than graphene, Li2C6 and Li1.5C6 compared to LiC6. We find that Li is very mobile on these materials and does not interact as strongly with the membranes. In the case of BP we also investigated the possible volume expansion on Li insertion. We find a 11% expansion, which is very similar to the one found in graphite. Our findings show that both membranes are suitable materials for lithium ion battery anodes. PMID- 28562008 TI - Inhibition of Abeta Amyloid Growth and Toxicity by Silybins: The Crucial Role of Stereochemistry. AB - The self-assembling of the amyloid beta (Abeta) peptide into neurotoxic aggregates is considered a central event in the pathogenesis of Alzheimer's disease (AD). Based on the "amyloid hypothesis", many efforts have been devoted to designing molecules able to halt disease progression by inhibiting Abeta self assembly. Here, we combine biophysical (ThT assays, TEM and AFM imaging), biochemical (WB and ESI-MS), and computational (all-atom molecular dynamics) techniques to investigate the capacity of four optically pure components of the natural product silymarin (silybin A, silybin B, 2,3-dehydrosilybin A, 2,3 dehydrosilybin B) to inhibit Abeta aggregation. Despite TEM analysis demonstrated that all the four investigated flavonoids prevent the formation of mature fibrils, ThT assays, WB and AFM investigations showed that only silybin B was able to halt the growth of small-sized protofibrils thus promoting the formation of large, amorphous aggregates. Molecular dynamics (MD) simulations indicated that silybin B interacts mainly with the C-terminal hydrophobic segment 35MVGGVV40 of Abeta40. Consequently to silybin B binding, the peptide conformation remains predominantly unstructured along all the simulations. By contrast, silybin A interacts preferentially with the segments 17LVFF20 and 27NKGAII32 of Abeta40 which shows a high tendency to form bend, turn, and beta sheet conformation in and around these two domains. Both 2,3-dehydrosilybin enantiomers bind preferentially the segment 17LVFF20 but lead to the formation of different small-sized, ThT-positive Abeta aggregates. Finally, in vivo studies in a transgenic Caenorhabditis elegans strain expressing human Abeta indicated that silybin B is the most effective of the four compounds in counteracting Abeta proteotoxicity. This study underscores the pivotal role of stereochemistry in determining the neuroprotective potential of silybins and points to silybin B as a promising lead compound for further development in anti-AD therapeutics. PMID- 28562010 TI - In-Situ Phase Transition Control in the Supercooled State for Robust Active Glass Fiber. AB - The construction of a dopant-activated photonic composite is of great technological importance for various applications, including smart lighting, optical amplification, laser, and optical detection. The bonding arrangement around the introduced dopants largely determines the properties, yet it remains a daunting challenge to manipulate the local state of the matrix (i.e., phase) inside the transparent composite in a controllable manner. Here we demonstrate that the relaxation of the supercooled state enables in-situ phase transition control in glass. Benefiting from the unique local atom arrangement manner, the strategy offers the possibility for simultaneously tuning the chemical environment of the incorporated dopant and engineering the dopant-host interaction. This allows us to effectively activate the dopant with high efficiency (calculated as ~100%) and profoundly enhance the dopant-host energy exchange interaction. Our results highlight that the in-situ phase transition control in glass may provide new opportunities for fabrication of unusual photonic materials with intense broadband emission at ~1100 nm and development of the robust optical detection unit with high compactness and broadband photon harvesting capability (from X-ray to ultraviolet light). PMID- 28562011 TI - Effect of Lithium Borate Additives on Cathode Film Formation in LiNi0.5Mn1.5O4/Li Cells. AB - A direct comparison of the cathode-electrolyte interface (CEI) generated on high voltage LiNi0.5Mn1.5O4 cathodes with three different lithium borate electrolyte additives, lithium bis(oxalato)borate (LiBOB), lithium 4-pyridyl trimethyl borate (LPTB), and lithium catechol dimethyl borate (LiCDMB), has been conducted. The lithium borate electrolyte additives have been previously reported to improve the capacity retention and efficiency of graphite/LiNi0.5Mn1.5O4 cells due to the formation of passivating CEI. Linear sweep voltammetry (LSV) suggests that incorporation of the lithium borates into 1.2 M LiPF6 in EC/EMC (3/7) electrolyte results in borate oxidation on the cathode surface at high potential. The reaction of the borates on the cathode surface leads to an increase in impedance as determined by electrochemical impedance spectroscopy (EIS), consistent with the formation of a cathode surface film. Ex-situ surface analysis of the electrode via a combination of SEM, TEM, IR-ATR, XPS, and high energy XPS (HAXPES) suggests that oxidation of all borate additives results in deposition of a passivation layer on the surface of LiNi0.5Mn1.5O4 which inhibits transition metal ion dissolution from the cathode. The passivation layer thickness increases as a function of additive structure LiCDMB > LPTB > LiBOB. The results suggest that the CEI thickness can be controlled by the structure and reactivity of the electrolyte additive. PMID- 28562012 TI - Dicyanobenzothiadiazole Derivatives Possessing Switchable Dielectric Permittivities. AB - Benzothiadiazoles are important electron acceptors and are frequently employed as electron-deficient components of donor-acceptor polymers. We report the effect of nitrile functionalities on the reactivity, steric hindrance, optoelectronic properties, and dielectric permittivity in dicyanobenzothioadiazole (DCNBT). Dielectric spectroscopy in the bulk and in solution assisted by DFT-calculations revealed that these molecules can be engineered to engender maximum values of the dipole moment and of dielectric permittivity due to the strong electron withdrawing effect of the nitrile groups. The self-assembly in the bulk was investigated by X-ray scattering performed on single crystals, fibers (2D-WAXS), and thin films (GiWAXS). Combining these results, we found a switching of dielectric permittivity of the 4,7-alkylthienyl-substituted dicyanobenzothiadiazole at the transition from the liquid crystalline to the isotropic phase with values capable of competing with the best known rodlike liquid crystals. PMID- 28562013 TI - Dodecahedral W@WC Composite as Efficient Catalyst for Hydrogen Evolution and Nitrobenzene Reduction Reactions. AB - Core-shell composites with strong phase-phase contact could provide an incentive for catalytic activity. A simple, yet efficient, H2O-mediated method has been developed to synthesize a mesoscopic core-shell W@WC architecture with a dodecahedral microstructure, via a one-pot reaction. The H2O plays an important role in the resistance of carbon diffusion, resulting in the formation of the W core and W-terminated WC shell. Density functional theory (DFT) calculations reveal that adding W as core reduced the oxygen adsorption energy and provided the W-terminated WC surface. The W@WC exhibits significant electrocatalytic activities toward hydrogen evolution and nitrobenzene electroreduction reactions, which are comparable to those found for commercial Pt/C, and substantially higher than those found for meso- and nano-WC materials. The experimental results were explained by DFT calculations based on the energy profiles in the hydrogen evolution reactions over WC, W@WC, and Pt model surfaces. The W@WC also shows a high thermal stability and thus may serve as a promising more economical alternative to Pt catalysts in these important energy conversion and environmental protection applications. The current approach can also be extended or adapted to various metals and carbides, allowing for the design and fabrication of a wide range of catalytic and other multifunctional composites. PMID- 28562014 TI - Ten Good Reasons for the Use of the Tellurium-Centered Anderson-Evans Polyoxotungstate in Protein Crystallography. AB - Protein crystallography represents at present the most productive and most widely used method to obtain structural information on target proteins and protein ligand complexes within the atomic resolution range. The knowledge obtained in this way is essential for understanding the biology, chemistry, and biochemistry of proteins and their functions but also for the development of compounds of high pharmacological and medicinal interest. Here, we address the very central problem in protein crystallography: the unpredictability of the crystallization process. Obtaining protein crystals that diffract to high resolutions represents the essential step to perform any structural study by X-ray crystallography; however, this method still depends basically on trial and error making it a very time- and resource-consuming process. The use of additives is an established process to enable or improve the crystallization of proteins in order to obtain high quality crystals. Therefore, a more universal additive addressing a wider range of proteins is desirable as it would represent a huge advance in protein crystallography and at the same time drastically impact multiple research fields. This in turn could add an overall benefit for the entire society as it profits from the faster development of novel or improved drugs and from a deeper understanding of biological, biochemical, and pharmacological phenomena. With this aim in view, we have tested several compounds belonging to the emerging class of polyoxometalates (POMs) for their suitability as crystallization additives and revealed that the tellurium-centered Anderson-Evans polyoxotungstate [TeW6O24]6- (TEW) was the most suitable POM-archetype. After its first successful application as a crystallization additive, we repeatedly reported on TEW's positive effects on the crystallization behavior of proteins with a particular focus on the protein-TEW interactions. As electrostatic interactions are the main force for TEW binding to proteins, TEW with its highly negative charge addresses in principle all proteins possessing positively charged patches. Furthermore, due to its high structural and chemical diversity, TEW exhibits major advantages over some commonly used crystallization additives. Therefore, we summarized all features of TEW, which are beneficial for protein crystallization, and present ten good reasons to promote the use of TEW in protein crystallography as a powerful additive. Our results demonstrate that TEW is a compound that is, in many respects, predestined as a crystallization additive. We assume that many crystallographers and especially researchers, who are not experts in this field but willing to crystallize their structurally unknown target protein, could benefit from the use of TEW as it is able to promote both the crystallization process itself and the subsequent structure elucidation by providing valuable anomalous signals, which are helpful for the phasing step. PMID- 28562015 TI - Temporal Dynamics of Bacterial and Fungal Colonization on Plastic Debris in the North Sea. AB - Despite growing evidence that biofilm formation on plastic debris in the marine environment may be essential for its biodegradation, the underlying processes have yet to be fully understood. Thus, far, bacterial biofilm formation had only been studied after short-term exposure or on floating plastic, yet a prominent share of plastic litter accumulates on the seafloor. In this study, we explored the taxonomic composition of bacterial and fungal communities on polyethylene plastic sheets and dolly ropes during long-term exposure on the seafloor, both at a harbor and an offshore location in the Belgian part of the North Sea. We reconstructed the sequence of events during biofilm formation on plastic in the harbor environment and identified a core bacteriome and subsets of bacterial indicator species for early, intermediate, and late stages of biofilm formation. Additionally, by implementing ITS2 metabarcoding on plastic debris, we identified and characterized for the first time fungal genera on plastic debris. Surprisingly, none of the plastics exposed to offshore conditions displayed the typical signature of a late stage biofilm, suggesting that biofilm formation is severely hampered in the natural environment where most plastic debris accumulates. PMID- 28562016 TI - Brown Carbon Production in Ammonium- or Amine-Containing Aerosol Particles by Reactive Uptake of Methylglyoxal and Photolytic Cloud Cycling. AB - The effects of methylglyoxal uptake on the physical and optical properties of aerosol containing amines or ammonium sulfate were determined before and after cloud processing in a temperature- and RH-controlled chamber. The formation of brown carbon was observed upon methylglyoxal addition, detected as an increase in water-soluble organic carbon mass absorption coefficients below 370 nm and as a drop in single-scattering albedo at 450 nm. The imaginary refractive index component k450 reached a maximum value of 0.03 +/- 0.009 with aqueous glycine aerosol particles. Browning of solid particles occurred at rates limited by chamber mixing (<1 min), and in liquid particles occurred more gradually, but in all cases occurred much more rapidly than in bulk aqueous studies. Further browning in AS and methylammonium sulfate seeds was triggered by cloud events with chamber lights on, suggesting photosensitized brown carbon formation. Despite these changes in optical aerosol characteristics, increases in dried aerosol mass were rarely observed (<1 MUg/m3 in all cases), consistent with previous experiments on methylglyoxal. Under dry, particle-free conditions, methylglyoxal reacted (presumably on chamber walls) with methylamine with a rate constant k = (9 +/- 2) * 10-17 cm3 molecule-1 s-1 at 294 K and activation energy Ea = 64 +/- 37 kJ/mol. PMID- 28562017 TI - Toxic Aromatics Induced Responsive Facets for a Pore Surface Functionalized Luminescent Coordination Polymer. AB - A luminescent coordination polymer was synthesized based on a linker prefunctionalization-based design principle coupled with an appropriate template selection protocol adopted during crystallization. Luminescent linker derived photoluminescence emission signature together with the reversibly dynamic host polymer exhibited a unique response toward environmentally toxic aromatics in the solid state, arguably crucial for the designed development of toxin-responsive solid materials. PMID- 28562018 TI - Supply and Demand for Improved Sanitation: Results from Randomized Pricing Experiments in Rural Tanzania. AB - Improving access to sanitation is a global public health priority. Sufficient consumer demand is required for sanitation coverage to expand through private provision. To measure consumer demand for hygienic latrine platform products in rural Tanzania, we conducted a randomized, voucher-based real-money sales trial with 1638 households with unimproved latrines. We also evaluated multiple supply chain options to determine the costs of supplying latrine platform products to rural households. For concrete latrine SanPlats, 60% of households were willing to pay US$0.48 and 10% of households were willing to pay US$4.05, yet the average cost of supplying the SanPlat to households was US$7.51. Similarly, for plastic sanitary platforms, willingness-to-pay (WTP) dropped from almost 60% at a price of US$1.43 to 5% at a price of US$12.29, compared to an average supply cost of US$23.28. WTP was not significantly different between villages that had participated in the National Sanitation Campaign and those that had not. Randomized informational interventions, including hygiene data-sharing and peer based exposure to latrine platform products, had minimal effects on WTP. In conclusion, current household demand for latrine platform products is too low to achieve national goals for improved sanitation coverage through fully commercial distribution. PMID- 28562019 TI - Mass Spectrometric Characterization of Circulating Covalent Protein Adducts Derived from Epoxide Metabolites of Carbamazepine in Patients. AB - Carbamazepine (CBZ) is an effective antiepileptic drug that has been associated with hypersensitivity reactions. The pathogenesis of those reactions is incompletely understood but is postulated to involve a complex interplay between the drug's metabolism, genetic variation in human leukocyte antigens, and adverse activation of the immune system. Multiple T-cell activation mechanisms have been hypothesized including activation by drug-peptide conjugates derived from proteins haptenated by reactive metabolites. However, definitive evidence of the drug-protein adducts in patients has been lacking. In this study, mass spectrometry was used to characterize protein modifications by microsomally generated metabolites of CBZ and in patients taking CBZ therapy. CBZ 10,11 epoxide (CBZE), a major electrophilic plasma metabolite of CBZ, formed adducts with glutathione-S-transferase pi (GSTP; Cys47) and human serum albumin (HSA; His146 and His338, but not Cys34) in vitro via notably divergent side-chain selectivity. Both proteins were adducted at the same residues by undefined monoxygenated metabolites ([O]CBZ) when they were incubated with human liver microsomes, NADPH and CBZ. There was also evidence for formation of a CBZ adduct at His146 and His338 of HSA derived via dehydration from an intermediate arene oxide adduct. Glutathione trapping of reactive metabolites confirmed microsomal production of CBZE and indicated simultaneous production of arene oxides. In 15 patients prescribed CBZ therapy, [O]CBZ-modified HSA (His146) was detected in all subjects. The relative amount of adduct was moderately positively correlated with plasma concentrations of CBZ (r2 = 0.44, p = 0.002) and CBZE (r2 = 0.35, p = 0.006). Our results have provided the first chemical evidence for microsomal production of [O]CBZ species that are able to escape the microsomal domain to react covalently with soluble proteins. This study has also demonstrated the presence of circulating [O]CBZ-modified HSA in patients without hypersensitivity reactions who were receiving standard CBZ therapy. The implications of those circulating adducts for susceptibility to CBZ hypersensitivity merit further immunological investigation in hypersensitive patients. PMID- 28562020 TI - Evaluation and Modeling of Vapor-Liquid Equilibrium and CO2 Absorption Enthalpies of Aqueous Designer Diamines for Post Combustion Capture Processes. AB - Novel absorbents with improved characteristics are required to reduce the existing cost and environmental barriers to deployment of large scale CO2 capture. Recently, bespoke absorbent molecules have been specifically designed for CO2 capture applications, and their fundamental properties and suitability for CO2 capture processes evaluated. From the study, two unique diamine molecules, 4-(2-hydroxyethylamino)piperidine (A4) and 1-(2-hydroxyethyl)-4 aminopiperidine (C4), were selected for further evaluation including thermodynamic characterization. The solubilities of CO2 in two diamine solutions with a mass fraction of 15% and 30% were measured at different temperatures (313.15-393.15 K) and CO2 partial pressures (up to 400 kPa) by thermostatic vapor liquid equilibrium (VLE) stirred cell. The absorption enthalpies of reactions between diamines and CO2 were evaluated at different temperatures (313.15 and 333.15 K) using a CPA201 reaction calorimeter. The amine protonation constants and associated protonation enthalpies were determined by potentiometric titration. The interaction of CO2 with the diamine solutions was summarized and a simple mathematical model established that could make a preliminary but good prediction of the VLE and thermodynamic properties. Based on the analyses in this work, the two designer diamines A4 and C4 showed superior performance compared to amines typically used for CO2 capture and further research will be completed at larger scale. PMID- 28562021 TI - Shotgun Proteomics Analysis Discards Alkali Labile Phosphate as a Reliable Method To Assess Vitellogenin Levels in Mytilus galloprovincialis. AB - Vitellogenin, the egg yolk precursor, is a well-known biomarker of endocrine disruption in oviparous vertebrates. In invertebrates, such as bivalves, it has been used in the last 10 years for the same purpose, despite the limited knowledge of invertebrate endocrinology. In bivalves, vitellogenin levels are usually estimated using an indirect technique, alkali labile phosphate (ALP), that assumes that vitellogenin is the most abundant phosphorylated protein in the analyzed tissue. In this study, we applied shotgun proteomics for the identification and quantification of vitellogenin in marine mussel gonads and compared the results with those obtained with the ALP method. The proteomic analysis revealed that vitellogenin is only detected in female gonads with expression levels that are rather variable among female mussels at different stages of gonad development. ALP analysis, on the contrary, detected similar amounts of phosphorylated proteins regardless of sex or gonad development stage. These results show evidence that the ALP method is not providing reliable information about Vtg levels, at least in marine mussel gonads. ALP is not a good proxy to assess Vtg levels in marine mussels, and careful verification of the adequacy of the procedure should be done before ALP is further assumed as a proxy of Vtg in other bivalve mollusks. PMID- 28562022 TI - Engineering a Native Inducible Expression System in Shewanella oneidensis to Control Extracellular Electron Transfer. AB - Shewanella oneidensis MR-1 is a model organism for understanding extracellular electron transport, in which cells transfer intracellular electrons to an extracellular terminal electron acceptor such as insoluble minerals or poised electrodes. Biotechnological applications exploiting the respiratory capabilities of Shewanella species have led to their proposed use in wastewater treatment, bioremediation, and remote sensors. Transcriptional regulation tools can be used to rationally engineer S. oneidensis, optimizing performance in biotechnological applications, introducing new capabilities, or investigating physiology. Engineered gene expression in S. oneidensis has primarily involved the use of foreign regulatory systems from Escherichia coli. Here we characterize a native S. oneidensis pathway that can be used to induce gene expression with trimethylamine N-oxide, then engineer strains in which extracellular electron transfer is controlled by this compound. The ability to induce this pathway was assessed by measuring iron reduction over time and by analyzing anodic current produced by cells grown in bioreactors. PMID- 28562023 TI - Mechanistic Insight from Calorimetric Measurements of the Assembly of the Binuclear Metal Active Site of Glycerophosphodiesterase (GpdQ) from Enterobacter aerogenes. AB - Glycerophosphodiesterase (GpdQ) from Enterobacter aerogenes is a binuclear metallohydrolase with a high affinity for metal ions at its alpha site but a lower affinity at its beta site in the absence of a substrate. Isothermal titration calorimetry (ITC) has been used to quantify the Co(II) and Mn(II) binding affinities and thermodynamics of the two sites in wild-type GpdQ and two mutants, both in the absence and in the presence of phosphate. Metal ions bind to the six-coordinate alpha site in an entropically driven process with loss of a proton, while binding at the beta site is not detected by ITC. Phosphate enhances the metal affinity of the alpha site by increasing the binding entropy and the metal affinity of the beta site by enthalpic (Co) or entropic (Mn) contributions, but no additional loss of protons. Mutations of first- and second-coordination sphere residues at the beta site increase the metal affinity of both sites by enhancing the binding enthalpy. In particular, loss of the hydrogen bond from second-sphere Ser127 to the metal-coordinating Asn80 has a significant effect on the metal binding thermodynamics that result in a resting binuclear active site with high catalytic activity. While structural and spectroscopic data with excess metal ions have indicated a bridging hydroxide in the binuclear GpdQ site, analysis of ITC data here reveals the loss of a single proton in the assembly of this site, indicating that the metal-bound hydroxide nucleophile is formed in the resting inactive mononuclear form, which becomes catalytically competent upon binding the second metal ion. PMID- 28562024 TI - An Amino-Coordinated Metal-Organic Framework for Selective Gas Adsorption. AB - A novel 3D porous metal organic framework, JUC-141, constructed by 5 aminoisophthalic acid and Cu(NO3)2, has been synthesized successfully. The carboxyl groups in the ligand coordinate to Cu2+ to form the classic Cu2(COO)4 paddle wheel SBU, and the assembly of the SBUs with the isophthalic acid moieties leads to a kagome lattice. Interestingly, the amino groups in the ligand also take part in the coordination and link to the dipole of the paddle wheel as pillars, thus forming a 3D porous framework with eea topology. The sizes of the channels are 5.2 A in the direction of [111] and 10.9 A in the direction of [001]. Gas sorption tests show that the CO2 adsorption capacities of JUC-141 are 79.94 and 51.39 cm3 g-1 at 273 and 298 K under 1 atm pressure, respectively. However, the N2 adsorption capacities of JUC-141 are 13.90 and 6.76 cm3 g-1 at 273 and 298 K under 1 atm pressure, respectively. IAST calculations indicate that the selectivity values of CO2/N2 are 21.62 at 273 K and 27.60 at 298 K under 101 kPa, respectively. Good selective adsorption of CO2 over N2 makes JUC-141 possible for CO2 storage and separation. PMID- 28562025 TI - Monitoring and Control of an Adsorption System Using Electrical Properties of the Adsorbent for Organic Compound Abatement. AB - Adsorption systems typically need gas and temperature sensors to monitor their adsorption/regeneration cycles to separate gases from gas streams. Activated carbon fiber cloth (ACFC)-electrothermal swing adsorption (ESA) is an adsorption system that has the potential to be controlled with the electrical properties of the adsorbent and is studied here to monitor and control the adsorption/regeneration cycles without the use of gas and temperature sensors and to predict breakthrough before it occurs. The ACFC's electrical resistance was characterized on the basis of the amount of adsorbed organic gas/vapor and the adsorbent temperature. These relationships were then used to develop control logic to monitor and control ESA cycles on the basis of measured resistance and applied power values. Continuous sets of adsorption and regeneration cycles were performed sequentially entirely on the basis of remote electrical measurements and achieved >=95% capture efficiency at inlet concentrations of 2000 and 4000 ppmv for isobutane, acetone, and toluene in dry and elevated relative humidity gas streams, demonstrating a novel cyclic ESA system that does not require gas or temperature sensors. This contribution is important because it reduces the cost and simplifies the system, predicts breakthrough before its occurrence, and reduces emissions to the atmosphere. PMID- 28562026 TI - Centralized Drinking Water Treatment Operations Shape Bacterial and Fungal Community Structure. AB - Drinking water microbial communities impact opportunistic pathogen colonization and corrosion of water distribution systems, and centralized drinking water treatment represents a potential control for microbial community structure in finished drinking water. In this article, we examine bacterial and fungal abundance and diversity, as well as the microbial community taxonomic structure following each unit operation in a conventional surface water treatment plant. Treatment operations drove the microbial composition more strongly than sampling time. Both bacterial and fungal abundance and diversity decreased following sedimentation and filtration; however, only bacterial abundance and diversity was significantly impacted by free chlorine disinfection. Similarly, each treatment step was found to shift bacterial and fungal community beta-diversity, with the exception of disinfection on the fungal community structure. We observed the enrichment of bacterial and fungal taxa commonly found in drinking water distribution systems through the treatment process, for example, Sphingomonas following filtration and Leptospirillium and Penicillium following disinfection. Study results suggest that centralized drinking water treatment processes shape the final drinking water microbial community via selection of community members and that the bacterial community is primarily driven by disinfection while the eukaryotic community is primarily controlled by physical treatment processes. PMID- 28562028 TI - Thermal Reduction of NOx with Recycled Plastics. AB - This study develops technology for mitigation of NOx formed in thermal processes using recycled plastics such as polyethylene (PE). Experiments involve sample characterization, and thermogravimetric decomposition of PE under controlled atmospheres, with NOx concentration relevant to industrial applications. TGA Fourier transform infrared (FTIR) spectroscopy and NOx chemiluminescence serve to obtain the removal efficiency of NOx by fragments of pyrolyzing PE. Typical NOx removal efficiency amounts to 80%. We apply the isoconversional method to derive the kinetic parameters, and observe an increasing dependency of activation energy on the reaction progress. The activation energies of the process span 135 kJ/mol to 226 kJ/mol, and 188 kJ/mol to 268 kJ/mol, for neat and recycled PE, respectively, and the so-called compensation effect accounts for the natural logarithmic pre-exponential ln (A/min-1) factors of ca. 19-35 and 28-41, in the same order, depending on the PE conversion in the experimental interval of between 5 and 95%. The observed delay in thermal events of recycled PE reflects different types of PE in the plastic, as measurements of intrinsic viscosity indicate that, the recycled PE comprises longer linear chains. The present evaluation of isoconversional activation energies affords accurate kinetic modeling of both isothermal and nonisothermal decomposition of PE in NOx-doped atmosphere. Subsequent investigations will focus on the effect of mass transfer and the presence of oxygen, as reburning of NOx in large-scale combustors take place at higher temperatures than those included in the current study. PMID- 28562029 TI - P- and N-Coordination of the Ambidentate Ligand HN[P(i-Pr)2]2 with Group 13 Trihalides. AB - Five different coordination motifs were observed upon reaction of the simple group 13 Lewis acids MCl3 (M = In, Ga, Al, B) or BF3.Et2O with the ambidentate bis(diisopropylphosphino)amine ligand HN[P(i-Pr)2]2. In a 1:1 reaction mixture, the softer Lewis acids InCl3, GaCl3 and BCl3 coordinate to one of the two P atoms of the ligand. In contrast, AlCl3 and BF3 prefer coordination to the harder N atom. In all cases, the acidic N-H proton is shifted to P upon complexation with a metal. By altering the reaction stoichiometry, 2:1 metal-ligand complexes could be isolated for three of the combinations. BCl3 gives a bis-adduct via the two P atoms. GaCl3 produces a salt consisting of a [GaCl4]- anion and a P,P-chelated [LGaCl2]+ cation. Most unexpectedly, the reaction with InCl3 in methanol resulted in solvent deprotonation by the ligand to give two symmetric [(i-Pr2PH)2N]+ cations in which all the basic P sites are coordinated to H rather than the group 13 Lewis acid. These cations are balanced by the unique complex dianion [(MeO)6In4Cl8.2MeOH]2-. All complexes were characterized with a combination of multinuclear NMR spectroscopy and single-crystal X-ray diffraction. PMID- 28562027 TI - Intein Zymogens: Conditional Assembly and Splicing of Split Inteins via Targeted Proteolysis. AB - Naturally split inteins have found widespread use in chemical biology due to their ability to drive the ligation of separately expressed polypeptides through a process termed protein trans-splicing (PTS). In this study, we harness PTS by rendering association of split intein fragments conditional upon the presence of a user-defined protease. We show that these intein "zymogens" can be used to create protein sensors and actuators that respond to the presence of various stimuli, including bacterial pathogens, viral infections, and light. We also show that this design strategy is compatible with several orthogonal split intein pairs, thereby opening the way to the creation of multiplexed sensor systems. PMID- 28562030 TI - Switching Protein Localization by Site-Directed RNA Editing under Control of Light. AB - Site directed RNA editing is an engineered tool for the posttranscriptional manipulation of RNA and proteins. Here, we demonstrate the inclusion of additional N- and C-terminal protein domains in an RNA editing-dependent manner to switch between protein isoforms in mammalian cell culture. By inclusion of localization signals, a switch of the subcellular protein localization was achieved. This included the shift from the cytoplasm to the outer-membrane, which typically is inaccessible at the protein-level. Furthermore, the strategy allows to implement photocaging to achieve spatiotemporal control of isoform switching. The strategy does not require substantial genetic engineering, and might well complement current optogenetic and optochemical approaches. PMID- 28562032 TI - Copper-Catalyzed Arylation of Benzylic C-H bonds with Alkylarenes as the Limiting Reagents. AB - A novel copper-catalyzed arylation of benzylic C-H bonds with nucleophilic arylboronic acids has been developed that provides an efficient way to synthesize various 1,1-diarylalkanes with a broad substrate scope and excellent functional group compatibility. The reactions occur at room temperature using alkylarenes as the limiting reagents, which allows access to the arylation of the more valuable and complex bioactive compounds. PMID- 28562031 TI - Europium-Labeled Synthetic C3a Protein as a Novel Fluorescent Probe for Human Complement C3a Receptor. AB - Measuring ligand affinity for a G protein-coupled receptor is often a crucial step in drug discovery. It has been traditionally determined by binding putative new ligands in competition with native ligand labeled with a radioisotope of finite lifetime. Competing instead with a lanthanide-based fluorescent ligand is more attractive due to greater longevity, stability, and safety. Here, we have chemically synthesized the 77 residue human C3a protein and conjugated its N terminus to europium diethylenetriaminepentaacetate to produce a novel fluorescent protein (Eu-DTPA-hC3a). Time-resolved fluorescence analysis has demonstrated that Eu-DTPA-hC3a binds selectively to its cognate G protein-coupled receptor C3aR with full agonist activity and similar potency and selectivity as native C3a in inducing calcium mobilization and phosphorylation of extracellular signal-regulated kinases in HEK293 cells that stably expressed C3aR. Time resolved fluorescence analysis for saturation and competitive binding gave a dissociation constant (Kd) of 8.7 +/- 1.4 nM for Eu-DTPA-hC3a and binding affinities for hC3a (pKi of 8.6 +/- 0.2 and Ki of 2.5 nM) and C3aR ligands TR16 (pKi of 6.8 +/- 0.1 and Ki of 138 nM), BR103 (pKi of 6.7 +/- 0.1 and Ki of 185 nM), BR111 (pKi of 6.3 +/- 0.2 and Ki of 544 nM) and SB290157 (pKi of 6.3 +/- 0.1 and Ki of 517 nM) via displacement of Eu-DTPA-hC3a from hC3aR. The macromolecular conjugate Eu-DTPA-hC3a is a novel nonradioactive probe suitable for studying ligand-C3aR interactions with potential value in accelerating drug development for human C3aR in physiology and disease. PMID- 28562034 TI - Correction to "Palladium-Catalyzed Enantioselective C-H Activation of Aliphatic Amines Using Chiral Anionic BINOL-Phosphoric Acid Ligands". PMID- 28562033 TI - Toward a Droplet-Based Single-Cell Radiometric Assay. AB - Radiotracers are widely used to track molecular processes, both in vitro and in vivo, with high sensitivity and specificity. However, most radionuclide detection methods have spatial resolution inadequate for single-cell analysis. A few existing methods can extract single-cell information from radioactive decays, but the stochastic nature of the process precludes high-throughput measurement (and sorting) of single cells. In this work, we introduce a new concept for translating radioactive decays occurring stochastically within radiolabeled single-cells into an integrated, long-lasting fluorescence signal. Single cells are encapsulated in radiofluorogenic droplets containing molecular probes sensitive to byproducts of ionizing radiation (primarily reactive oxygen species, or ROS). Different probes were examined in bulk solutions, and dihydrorhodamine 123 (DHRh 123) was selected as the lead candidate due to its sensitivity and reproducibility. Fluorescence intensity of DHRh 123 in bulk increased at a rate of 54% per Gy of X-ray radiation and 15% per MBq/ml of 2-deoxy-2-[18F]-fluoro-d glucose ([18F]FDG). Fluorescence imaging of microfluidic droplets showed the same linear response, but droplets were less sensitive overall than the bulk ROS sensor (detection limit of 3 Gy per droplet). Finally, droplets encapsulating radiolabeled cancer cells allowed, for the first time, the detection of [18F]FDG radiotracer uptake in single cells through fluorescence activation. With further improvements, we expect this technology to enable quantitative measurement and selective sorting of single cells based on the uptake of radiolabeled small molecules. PMID- 28562035 TI - Ligand Binding Constants to Lithium Hexamethyldisilazide Determined by Diffusion Ordered NMR Spectroscopy. AB - We report the direct measurement of ligand-binding constants of organolithium complexes using a 1H NMR/diffusion-ordered NMR spectroscopy (DOSY) titration technique. Lithium hexamethyldisilazide complexes with ethereal and ester donor ligands (THF, diethyl ether, MTBE, THP, tert-butyl acetate) are characterized using 1H NMR and X-ray crystallography. Their aggregation and solvation states are confirmed using diffusion coefficient-formula weight correlation analysis, and the 1H NMR/DOSY titration technique is applied to obtain their binding constants. Our work suggests that steric hindrance of ethereal ligands plays an important role in the aggregation, solvation, and reactivity of these complexes. It is noteworthy that diffusion methodology is utilized to obtain binding constants. PMID- 28562036 TI - Mechanism for the Excited-State Multiple Proton Transfer Process of Dihydroxyanthraquinone Chromophores. AB - The single and dual cooperated proton transfer dynamic process in the excited state of 1,5-dihydroxyanthraquinone (1,5-DHAQ) was theoretically investigated, taking solvent effects (ethanol) into account. The absorption and fluorescence spectra were simulated, and dual fluorescence exhibited, which is consistent with previous experiments. Analysis of the calculated IR and Raman vibration spectra reveals that the intramolecular hydrogen bonding interactions (O20-H21...O24 and O22-H23...O25) are strengthened following the excited proton transfer process. Finally, by constructing the potential energy surfaces of the ground state, first excited singlet state, and triplet state, the mechanism of the intramolecular proton transfer of 1,5-DHAQ can be revealed. PMID- 28562038 TI - Use of Fe-Impregnated Biochar To Efficiently Sorb Chlorpyrifos, Reduce Uptake by Allium fistulosum L., and Enhance Microbial Community Diversity. AB - Fe-impregnated biochar was assessed as a method to remove the pesticide pollutant chlorpyrifos, utilizing biochar/FeOx composite synthesized via chemical coprecipitation of Fe3+/Fe2+ onto Cyperus alternifolius biochar. Fe-impregnated biochar exhibited a higher sorption capacity than pristine biochar, resulting in more efficient removal of chlorpyrifos from water. Soil was dosed with pristine or Fe-impregnated biochar at 0.1 or 1.0% w/w, to evaluate chlorpyrifos uptake in Allium fistulosum L. (Welsh onion). The results showed that the average concentration of chlorpyrifos and its degradation product, 3,5,6-trichloro-2 pyridinol (TCP), decreased in A. fistulosum L. with increased levels of pristine biochar and Fe-biochar. Fe-biochar was found to be more effective in reducing the uptake of chlorpyrifos by improving the sorption ability and increasing plant root iron plaque. Bioavailability of chlorpyrifos is reduced with both biochar and Fe-biochar soil dosing; however, the greatest persistence of chlorpyrifos residues was observed with 1.0% pristine biochar. Microbial community analysis showed Fe-biochar to have a positive impact on the efficiency of chlorpyrifos degradation in soils, possibly by altering microbial communities. PMID- 28562037 TI - Computational Discovery and Experimental Validation of Inhibitors of the Human Intestinal Transporter OATP2B1. AB - Human organic anion transporters (OATPs) are vital for the uptake and efflux of drugs and endogenous compounds. Current identification of inhibitors of these transporters is based on experimental screening. Virtual screening remains a challenge due to a lack of experimental three-dimensional protein structures. Here, we describe a workflow to identify inhibitors of the OATP2B1 transporter in the DrugBank library of over 5,000 drugs and druglike molecules. OATP member 2B1 transporter is highly expressed in the intestine, where it participates in oral absorption of drugs. Predictions from a Random forest classifier, prioritized by docking against multiple comparative protein structure models of OATP2B1, indicated that 33 of the 5,000 compounds were putative inhibitors of OATP2B1. Ten predicted inhibitors that are prescription drugs were tested experimentally in cells overexpressing the OATP2B1 transporter. Three of these ten were validated as potent inhibitors of estrone-3-sulfate uptake (defined as more than 50% inhibition at 20 MUM) and tested in multiple concentrations to determine exact IC50. The IC50 values of bicalutamide, ticagrelor, and meloxicam suggest that they might inhibit intestinal OATP2B1 at clinically relevant concentrations and therefore modulate the absorption of other concomitantly administered drugs. PMID- 28562039 TI - Temporal Labeling of Nascent RNA Using Photoclick Chemistry in Live Cells. AB - We report the first cellular application of a photoclick SPAAC reagent to label azide-functionalized RNA. 350 nm irradiation of a cyclopropenone caged oxo dibenzocyclooctyne (photo-ODIBO) biotin yields formation of the SPAAC reactive species, which rapidly forms adducts with RNA containing 2'-azidoadenosine (2'N3 A). Photo-ODIBO was found to be highly stable in the presence of thiols, conferring greater stability relative to ODIBO. Light activated photo-ODIBO enabled tagging of cellular RNA, in addition to fluorescent imaging as well as enrichment of RNA in cell subpopulations via selective irradiation. PMID- 28562040 TI - Synthesis of Bisdesmosidic Oleanolic Acid Saponins via a Glycosylation Deprotection Sequence under Continuous Microfluidic/Batch Conditions. AB - We report the first synthesis of a series of bisdesmosidic oleanolic acid saponins using microflow reactor Comet X-01 via a continuous flow glycosylation batch deprotection sequence. The main results of this study can be summarized as follows: (1) The microfluidic glycosylation of oleanolic acid at C-28 was achieved in quantitative yield and was applied to the synthesis of six C-28 monoglycosidic saponins. (2) The microfluidic glycosylation of oleanolic acid at C-3 was achieved in good yield without orthoester byproduct formation and was applied to the synthesis of three bisdesmosidic saponins. (3) The continuous synthesis of saponins via a microfluidic glycosylation-batch deprotection sequence was achieved in four steps involving two purifications. Thus, the continuous microfluidic glycosylation-deprotection process is expected to be suitable for the preparation of a library of bisdesmosidic oleanolic acid saponins for in vivo pharmacological studies. PMID- 28562041 TI - Preparation and Characterization of Controlled-Release Avermectin/Castor Oil Based Polyurethane Nanoemulsions. AB - Avermectin (AVM) is a low-toxic and high-active biopesticide, but it can be easily degraded by UV light. In this paper, biodegradable castor oil-based polyurethanes (CO-PU) are synthesized and used as carriers to fabricate a new kind of AVM/CO-PU nanoemulsion through an emulsion solvent evaporation method, and the chemical structure, colloidal property, AVM loading capacity, controlled release behavior, foliar adhesion, and photostability of the AVM/CO-PU drug delivery systems are investigated. Results show that AVM is physically encapsulated in the CO-PU carrier nanospheres, the diameter of the AVM/CO-PU nanoparticles is <50 nm, and the AVM/CO-PU films are flat and smooth without any AVM aggregate. The drug loading capacity is up to 42.3 wt % with a high encapsulation efficiency of >85%. The release profiles indicate that the release rate is relatively high at the early stage and then slows, which can be adjusted by loaded AVM content, temperature, and pH of the release medium. The foliar pesticide retention of the AVM/CO-PU nanoemulsions is improved, and the photolysis rate of AVM in the AVM/CO-PU nanoparticles is significantly slower than that of the free AVM. A release mechanism of the AVM/CO-PU nanoemulsions is proposed, which is controlled by both diffusion and matrix erosion. PMID- 28562042 TI - Solvent Effects on Optical Rotation: On the Balance between Hydrogen Bonding and Shifts in Dihedral Angles. AB - Optical rotations of several conformers of four fluorinated molecules containing the 1-naphthalene or 4-(benzyloxy)phenyl group at the stereocenter have been calculated both in the gas phase and in an aqueous environment. For the compounds containing the 4-(benzyloxy)phenyl group, solvent effects on the optical rotations have also been investigated in chloroform as solvent. Optical rotations have been obtained by time-dependent density functional theory (TDDFT) with the CAM-B3LYP functional and the aug-cc-pVDZ basis set at lambda = 589 nm. Implicit and explicit solvent effects were investigated through the polarizable continuum model (PCM) and a microsolvation approach in conjunction with PCM, respectively. In the latter model, solvent molecules are considered as an explicit solvent and their positions are obtained by geometry optimizations for different conformers of the chiral molecule. For molecules containing the 1-naphthalene group, this model gives the same optical rotation signs for all conformers as compared to both gas phase and PCM results and reduces absolute deviations between calculations and experiment. Also, the microsolvation model reproduces the sign of the experimental optical rotations for the molecules containing the 4 (benzyloxy)phenyl group using both water and chloroform as solvent. In a microsolvation model, however, the water and chloroform solvent molecules have similar hydrogen bonds but different effects on the conformation and thereby on the optical rotation since one dihedral angle, having a large effect on the optical rotation, is strongly sensitive to hydrogen bonding to water but not to chloroform. Our investigations demonstrate that a microsolvation approach in conjunction with PCM predicts optical rotations in reasonable agreements with experiments for both sign and magnitude. PMID- 28562043 TI - Far-Zone Resonant Energy Transfer in X-ray Photoemission as a Structure Determination Tool. AB - Near-zone Forster resonant energy transfer is the main effect responsible for excitation energy flow in the optical region and is frequently used to obtain structural information. In the hard X-ray region, the Forster law is inadequate because the wavelength is generally shorter than the distance between donors and acceptors; hence, far-zone resonant energy transfer (FZRET) becomes dominant. We demonstrate the characteristics of X-ray FZRET and its fundamental differences with the ordinary near-zone resonant energy-transfer process in the optical region by recording and analyzing two qualitatively different systems: high density CuO polycrystalline powder and SF6 diluted gas. We suggest a method to estimate geometrical structure using X-ray FZRET employing as a ruler the distance-dependent shift of the acceptor core ionization potential induced by the Coulomb field of the core-ionized donor. PMID- 28562044 TI - Revealing the Chemistry and Morphology of Buried Donor/Acceptor Interfaces in Organic Photovoltaics. AB - With power conversion efficiencies (PCEs) of <13% and plagued by stability issues, organic photovoltaics (OPVs) still lack wide adoption, despite significant recent advances. Currently, the most progress in OPV device performance is achieved by "trial-and-error" preparation procedures that lead to complex and largely unknown-despite tremendous analytical efforts-morphologies. Here, we demonstrate a proof-of-principle, chemical imaging methodology that combines experimental high spatial sensitivity and chemical selectivity with theoretical modeling, capable of analyzing the three-dimensional composition and morphology of virtually any device. Allowing the precise measurement of composition and direct visualization of film morphology with depth, our approach reveals the intricate buried donor/acceptor (D/A) interface of a model polymer/fullerene system, poly(3-hexylthiphene-2,5-diyl)/[6,6]-phenyl-C61-butyric acid methyl ester (P3HT/PCBM). In particular, our technique is able to identify and quantify the D/A interface length, that is, the extent of molecular mixing at the D/A interface, a parameter crucial for device performance, yet never measured. Extracting this parameter allows demonstrating that, contrary to the general understanding, when starting with a fully mixed D/A phase in our model system, thermal annealing, which is known to substantially (however limited) increase the device performance by phase segregation, does not create but small amounts of pure phases, leaving the device mostly mixed, which limits the performance improvement. PMID- 28562045 TI - Dimerization and Structural Stability of Amyloid Precursor Proteins Affected by the Membrane Microenvironments. AB - The lipid raft microenvironment is implicated in the generation of the pathological amyloid-beta (Abeta) species in amyloid precursor protein (APP) that is associated with neurodegenerative diseases. Evidence shows that APP forms a transmembrane homodimer with changeable structures as a function of the membrane compositions. However, the molecular responsibility of the dimerization and structural alteration for the amyloidogenic process in segregated membranes remains largely unclear. Here, we performed multiple coarse grained (CG) simulations to explore the behavioral preference of the transmembrane domain of APP (called C99) that is affected by the lipid raft microenvironment. The results showed that C99 was anchored at the boundary of the lipid raft relying on the conserved hydrophobic motif of V710xxA713xxxV717xxxV721. Moreover, the dimerization of C99 was greatly destabilized by the lipid raft, which led to a susceptible switching packing conformation. The molecular driving forces were derived from the combined regulation of the saturated lipids and cholesterols rather than from the simple binding competition of cholesterol in the C99 dimerization. The molecular details of the differential dimerization in the raft forming and bulk fluid bilayer environments were compared, and the structural information was helpful for further understanding the enzymolysis responsiveness of APP. PMID- 28562046 TI - Gunnilactams A-C, Macrocyclic Tetralactams from the Mycelial Culture of the Entomogenous Fungus Paecilomyces gunnii. AB - Three novel macrocyclic tetralactams, gunnilactam A (1), gunnilactam B (2), and gunnilactam C (3), were isolated from the submerged fermentation broth of Paecilomyces gunnii, an entomogenous fungus identified as the anamorph of Cordyceps gunnii. Their structures were determined using NMR data, HREIMS, and single-crystal X-ray crystallography. Gunnilactam A exhibited selective cytotoxic activity against human prostate cancer C42B cells with an IC50 value of 5.4 MUM. PMID- 28562047 TI - Surface Plasmon Coupling and Control Using Spherical Cap Structures. AB - Propagating surface plasmons (PSPs) launched from a protruded silver spherical cap structure are investigated using photoemission electron microscopy (PEEM) and finite difference time domain (FDTD) calculations. Our combined experimental and theoretical findings reveal that PSP coupling efficiency is comparable to conventional etched-in plasmonic coupling structures. Additionally, plasmon propagation direction can be varied by linear rotation of the driving laser polarization. A simple geometric model is proposed in which the plasmon direction selectivity is proportional to the projection of the linear laser polarization on the surface normal. A application for the spherical cap coupler as a gate device is proposed. Overall, our results indicate that protruded cap structures hold great promise as elements in emerging surface plasmon applications. PMID- 28562048 TI - Lychee (Litchi chinensis Sonn.) Pulp Phenolic Extract Confers a Protective Activity against Alcoholic Liver Disease in Mice by Alleviating Mitochondrial Dysfunction. AB - Mitochondria play an important role in the initiation and development of alcoholic liver disease (ALD). Our previous studies found lychee pulp phenolic extract (LPPE) exerted protective effect against ALD partly by inhibiting fatty acid beta-oxidation, and phenolic-rich lychee pulp extract improved restraint stress-induced liver injury by inhibiting mitochondrial dysfunction. The aim of this study was to investigate whether LPPE exerted protective effect against ALD via modulating mitochondrial function. The mice were treated with an ethanol containing liquid diet alone or in combination with LPPE for 8 weeks. LPPE supplementation significantly alleviated hepatic steatosis, suppressed serum aspartate aminotransferase activity, and decreased triglyceride levels in serum and liver. On the basis of lipid peroxidation and antioxidant enzyme analyses, LPPE supplementation inhibited serum and hepatic oxidative stress. Moreover, LPPE supplementation significantly suppressed mitochondrial 8-hydroxy-2' deoxyguanosine level, and increased mitochondrial membrane potential, mitochondrial DNA content, activities of mitochondrial complexes I and IV, and hepatic ATP level. Furthermore, LPPE supplementation significantly inhibited cytoplasmic cytochrome c level and caspase-3 activity, repressed Bax expression and Bax/Bcl-2 ratio, and increased Bcl-2 expression in liver. In summary, LPPE exerts beneficial effects against alcoholic liver injury by alleviating mitochondrial dysfunction. PMID- 28562049 TI - Protective Effect of Camellia Oil (Camellia oleifera Abel.) against Ethanol Induced Acute Oxidative Injury of the Gastric Mucosa in Mice. AB - Camellia oil, a common edible oil in Taiwan and China, has health effects for the gastrointestinal tract in folk medicine, and it contains abundant unsaturated fatty acids and phytochemicals. However, the preventive effect of camellia oil on ethanol-induced gastric ulcers remains unclear. This study was aimed to evaluate the preventive effect of camellia oil on ethanol-induced gastric injury in vitro and in vivo as well as its mechanisms of action. In an in vitro study, our results showed that pretreatment of RGM-1 cells with camellia oil enhanced the migration ability as well as increased heat shock protein expression and reduced apoptotic protein expression. In animal experiments, mice pretreated with camellia oil effectively showed improved ethanol-induced acute injury of the gastric muscosa and oxidative damage through the enhancement of antioxidant enzyme activities and heat shock protein and PGE2 production, as well as the suppression of lipid peroxidation, apoptosis-related proteins, pro-inflammatory cytokines, and NO production. Histological injury score and hemorrhage score in ethanol-induced gastric mucosal damage dramatically elevated from the control group (0.00 +/- 0.0) to 3.40 +/- 0.7 and 2.60 +/- 0.5, respectively. However, treatments with camellia oil or olive oil (2 mL/kg bw) and lansoprazole (30 mg/kg bw) showed significant decreases in elevation of injury score and hemorrhage score (p < 0.05). Therefore, camellia oil has the potential to ameliorate ethanol induced acute gastric mucosal injury through the inhibition of inflammation and oxidative stress. PMID- 28562050 TI - A Michael Addition-Asymmetric Transfer Hydrogenation One-Pot Enantioselective Tandem Process for Syntheses of Chiral gamma-Secondary Amino Alcohols. AB - An aza-Michael addition-asymmetric transfer hydrogenation tandem process for preparation of chiral gamma-secondary amino alcohols has been developed. This one pot tandem process involves an aza-Michael addition of aryl-substituted enones and amines to form aryl-substituted gamma-secondary amino ketones, followed by a Ru-catalyzed asymmetric transfer hydrogenation to form aryl-substituted gamma secondary amino alcohols. An advantageous feature of this tandem reaction is that it provides various gamma-secondary amino alcohols in high yields with high enantioselectivities. PMID- 28562051 TI - Homogeneously Mixed Monolayers: Emergence of Compositionally Conflicted Interfaces. AB - The ability to manipulate interfaces at the nanoscale via a variety of thin-film technologies offers a plethora of avenues for advancing surface applications. These include surfaces with remarkable antibiofouling properties as well as those with tunable physical and electronic properties. Molecular self-assembly is one notably attractive method used to decorate and modify surfaces. Of particular interest to surface scientists has been the thiolate-gold system, which serves as a reliable method for generating model thin-film monolayers that transform the interfacial properties of gold surfaces. Despite widespread interest, efforts to tune the interfacial properties using mixed adsorbate systems have frequently led to phase-separated domains of molecules on the surface with random sizes and shapes depending on the structure and chemical composition of the adsorbates. This feature article highlights newly emerging methods for generating mixed thin film interfaces, not only to enhance the aforementioned properties of organic thin films, but also to give rise to interfacial compositions never before observed in nature. An example would be the development of monolayers formed from bidentate adsorbates and other unique headgroup architectures that provide the surface bonding stability necessary to allow the assembly of interfaces that expose mixtures of chains that are fundamentally different in character (i.e., either phase-incompatible or structurally dissimilar), producing compositionally "conflicted" interfaces. By also exploring the prior efforts to produce such homogeneously blended interfaces, this feature article seeks to convey the relationships between the methods of film formation and the overall properties of the resulting interfaces. PMID- 28562052 TI - Critical Role of Methylammonium Librational Motion in Methylammonium Lead Iodide (CH3NH3PbI3) Perovskite Photochemistry. AB - Raman and photoluminescence (PL) spectroscopy are used to investigate dynamic structure-function relationships in methylammonium lead iodide (MAPbI3) perovskite. The intensity of the 150 cm-1 methylammonium (MA) librational Raman mode is found to be correlated with PL intensities in microstructures of MAPbI3. Because of the strong hydrogen bond between hydrogens in MA and iodine in the PbI6 perovskite octahedra, the Raman activity of MA is very sensitive to structural distortions of the inorganic framework. The structural distortions directly influence PL intensities, which in turn have been correlated with microstructure quality. Our measurements, supported with first-principles calculations, indicate how excited-state MA librational displacements mechanistically control PL efficiency and lifetime in MAPbI3-material parameters that are likely important for efficient photovoltaic devices. PMID- 28562053 TI - Numerical Simulation of Coalescence-Induced Jumping of Multidroplets on Superhydrophobic Surfaces: Initial Droplet Arrangement Effect. AB - The coalescence-induced droplet jumping on superhydrophobic surfaces (SHSs) has attracted considerable attention over the past several years. Most of the studies on droplet jumping mainly focus on two-droplet coalescence events whereas the coalescence of three or more droplets is actually more frequent and still remains poorly understood. In this work, a 3D lattice Boltzmann simulation is carried out to investigate the effect of initial droplet arrangements on the coalescence induced jumping of three equally sized droplets. Depending on the initial position of droplets on the surface, the droplet coalescence behaviors can be generally classified into two types: one is that all droplets coalesce together instantaneously (concentrated configuration), and the other is that the initial coalesced droplet sweeps up the third droplet in its moving path (spaced configuration). The critical Ohnesorge number, Oh, for the transition of inertial capillary-dominated coalescence to inertially limited-viscous coalescence is found to be 0.10 for droplet coalescence on SHSs with a contact angle of 160 degrees . The jumping droplet velocity for concentrated multidroplet coalescence at Oh ? 0.10 still follows the inertial-capillary scaling with an increased prefactor, which indicates a viable jumping droplet velocity enhancement scheme. However, the droplet jumping velocity is drastically reduced for the spaced configuration compared to that for the aforementioned concentrated configuration. Because Oh exceeds 0.10, the effects of initial droplet arrangements on multidroplet jumping become weaker as viscosity plays a key role in the merging process. This work will provide effective guidelines for the design of functional SHSs with enhanced droplet jumping for a wide range of industrial applications. PMID- 28562054 TI - Highly Selective Synthesis of Dihydrobenzo[d]isoxazoles and Dihydrobenzo[d]oxazoles from Oximes and Arynes via in Situ Generation of Nitrones. AB - An efficient method for the synthesis of dihydrobenzo[d]isoxazoles and dihydrobenzo[d]oxazoles bearing a quaternary carbon center has been developed. The reaction involves generation of a ketonitrone intermediate in situ from a ketoxime and an aryne. A novel thermal rearrangement of the dihydrobenzo[d]isoxazole products to the corresponding dihydrobenzo[d]oxazoles has been observed. These transformations tolerate a variety of functional groups and offer a rapid and efficient way to diverse dihydrobenzo[d]isoxazoles and dihydrobenzo[d]oxazoles under mild transition-metal-free conditions. PMID- 28562055 TI - Formal Total Synthesis of Actinoranone and Asymmetric Synthesis of Labda-7,13-(E) dien-15-ol. AB - The syntheses of the polyketide and terpenoid fragments of actinoranone are reported in a concise fashion, relying on catalytic methods. Minimization on the use of protecting groups and redox reactions allowed the synthesis of the carbon backbone of actinoranone in 20 steps (11 steps for LLS). The asymmetric synthesis of labda-7,13-(E)-dien-15-ol is also disclosed. PMID- 28562056 TI - One-Dimensional van der Waals Material Tellurium: Raman Spectroscopy under Strain and Magneto-Transport. AB - Experimental demonstrations of one-dimensional (1D) van der Waals material tellurium (Te) have been presented by Raman spectroscopy under strain and magneto transport. Raman spectroscopy measurements have been performed under strains along different principle axes. Pronounced strain response along the c-axis is observed due to the strong intrachain covalent bonds, while no strain response is obtained along the a-axis due to the weak interchain van der Waals interaction. Magneto-transport results further verify its anisotropic property, which results in dramatically distinct magneto-resistance behaviors in terms of three different magnetic field directions. Specifically, phase coherence length extracted from weak antilocalization effect, Lphi ~ T-0.5, claims its two-dimensional (2D) transport characteristics when an applied magnetic field is perpendicular to the thin film. In contrast, Lphi ~ T-0.33 is obtained from universal conductance fluctuations once the magnetic field is along the c-axis of Te, which indicates its nature of 1D transport along the helical atomic chains. Our studies, which are obtained on high quality single crystal Te thin film, appear to serve as strong evidence of its 1D van der Waals structure from experimental perspectives. It is the aim of this paper to address this special concept that differs from the previous well-studied 1D nanowires or 2D van der Waals materials. PMID- 28562057 TI - Chemoselective and Diastereoconvergent Cu(II)-Catalyzed Aerobic Endoperoxidation of Polycarbonyls. AB - The diastereoconvergent synthesis of spirocyclic endoperoxides using a Meldrum's acid scaffold has been accomplished by employing readily available feedstock chemicals. Site selective C-H oxidation of the bis(beta-dicarbonyl) substrates was performed using elemental oxygen as the stoichiometric oxidant and a commercial Cu(II) catalyst. Sequential hydrogenolysis and ionic reduction of these endoperoxides provided fully substituted tetrahydrofurans in high yields and diastereoselectivity. PMID- 28562058 TI - Digestive Ripening: A Fine Chemical Machining Process on the Nanoscale. AB - A comprehensive overview of the process of digestive ripening that is known to convert polydisperse nanocrystals to monodisperse ones is presented. Apart from highlighting the role of organic molecules (ligands) in achieving size control, the roles of other parameters such as the nanocrystal-ligand binding strength and the temperature at which the reaction is carried out in accomplishing size control are also delineated. The generality of the procedure is illustrated by providing examples of how it is used to prepare monodisperse nanocrystals of different metals, alloy systems, and ultrasmall nanocrystals and also to narrow the size distribution in complex binary and ternary nanocrystal systems. Finally, the current status as far as the theoretical understanding of how size control is being achieved by digestive ripening is laid out, emphasizing at the same time the necessity to undertake more systematic studies to completely realize the full potential of this practically very useful procedure. PMID- 28562059 TI - Thiadiazole-fused Quinoxalineimide as an Electron-deficient Building Block for N type Organic Semiconductors. AB - A strong electron-accepting planar pi-conjugated framework, thiadiazole-fused quinoxalineimide (TQI), was designed and synthesized. Three TQI-based small molecules exhibit deep lowest-unoccupied molecular orbital (LUMO) levels, which require air stable n-channel conduction (~-4.0 eV). Among these molecules, Hex TQI-Br exhibits air-stable n-channel charge transport with a moderate mobility of 0.044 cm2 V-1 s-1. PMID- 28562060 TI - Sphagnum Moss as an Indicator of Contemporary Rates of Atmospheric Dust Deposition in the Athabasca Bituminous Sands Region. AB - Sphagnum moss was collected from ombrotrophic (rain-fed) peat bogs to quantify dust emissions from the open-pit mining and upgrading of Athabasca bituminous sands (ABS). A total of 30 bogs were sampled in the ABS region, and 5 were sampled in central Alberta. Ash was separated into the acid-insoluble ash (AIA) and acid-soluble ash (ASA) fractions using HCl. The AIA concentrations increase toward industry from 0.4 +/- 0.5% to 4.7 +/- 2.0% over a distance of 30 km; the control site at the Utikuma Region Study Area (URSA) yielded 0.29 +/- 0.07% (n = 30). Mass accumulations rates showed similar spatial variation. The morphology and mineralogy of the AIA particles were studied using scanning electron microscopy and energy-dispersive X-ray analysis and the particle size distributions using optical methods. Particle size was more variable in moss closer to industry. Major ions in the ASA fraction showed elevated accumulation rates of Ca, K, Fe, Mg, P, and S, with P being up to 5 times greater in samples nearest industry compared to those in distal locations. Given that P has been regarded as the growth-limiting nutrient in bogs, fertilization of nutrient-poor ecosystems, such as these from fugitive emissions of dusts from open-pit mining, may have long-term ecological ramifications. PMID- 28562062 TI - Quantum Dynamics with Short-Time Trajectories and Minimal Adaptive Basis Sets. AB - Methods for solving the time-dependent Schrodinger equation via basis set expansion of the wave function can generally be categorized as having either static (time-independent) or dynamic (time-dependent) basis functions. We have recently introduced an alternative simulation approach which represents a middle road between these two extremes, employing dynamic (classical-like) trajectories to create a static basis set of Gaussian wavepackets in regions of phase-space relevant to future propagation of the wave function [J. Chem. Theory Comput., 11, 8 (2015)]. Here, we propose and test a modification of our methodology which aims to reduce the size of basis sets generated in our original scheme. In particular, we employ short-time classical trajectories to continuously generate new basis functions for short-time quantum propagation of the wave function; to avoid the continued growth of the basis set describing the time-dependent wave function, we employ Matching Pursuit to periodically minimize the number of basis functions required to accurately describe the wave function. Overall, this approach generates a basis set which is adapted to evolution of the wave function while also being as small as possible. In applications to challenging benchmark problems, namely a 4-dimensional model of photoexcited pyrazine and three different double-well tunnelling problems, we find that our new scheme enables accurate wave function propagation with basis sets which are around an order-of magnitude smaller than our original trajectory-guided basis set methodology, highlighting the benefits of adaptive strategies for wave function propagation. PMID- 28562061 TI - Methane and Benzene in Drinking-Water Wells Overlying the Eagle Ford, Fayetteville, and Haynesville Shale Hydrocarbon Production Areas. AB - Water wells (n = 116) overlying the Eagle Ford, Fayetteville, and Haynesville Shale hydrocarbon production areas were sampled for chemical, isotopic, and groundwater-age tracers to investigate the occurrence and sources of selected hydrocarbons in groundwater. Methane isotopes and hydrocarbon gas compositions indicate most of the methane in the wells was biogenic and produced by the CO2 reduction pathway, not from thermogenic shale gas. Two samples contained methane from the fermentation pathway that could be associated with hydrocarbon degradation based on their co-occurrence with hydrocarbons such as ethylbenzene and butane. Benzene was detected at low concentrations (<0.15 MUg/L), but relatively high frequencies (2.4-13.3% of samples), in the study areas. Eight of nine samples containing benzene had groundwater ages >2500 years, indicating the benzene was from subsurface sources such as natural hydrocarbon migration or leaking hydrocarbon wells. One sample contained benzene that could be from a surface release associated with hydrocarbon production activities based on its age (10 +/- 2.4 years) and proximity to hydrocarbon wells. Groundwater travel times inferred from the age-data indicate decades or longer may be needed to fully assess the effects of potential subsurface and surface releases of hydrocarbons on the wells. PMID- 28562063 TI - Asymmetric Hydrogenation of Tetrasubstituted Cyclic Enones to Chiral Cycloalkanols with Three Contiguous Stereocenters. AB - A highly efficient iridium-catalyzed asymmetric hydrogenation of tetrasubstituted cyclic enones has been developed for the enantioselective synthesis of chiral cycloalkanols with three contiguous stereocenters. The C?O and C?C bonds of the enone substrates were hydrogenated sequentially in one pot with excellent enantioselectivity (92 to >99% ee) and diastereoselectivity (dr 95:5 to >99:1). The reaction provided a practical approach to all of the stereoisomers of the antiulcer drug rosaprostol. PMID- 28562064 TI - Technostress: measuring a new threat to well-being in later life. AB - OBJECTIVES: Technostress is stress induced by Information and Communication Technology (ICT) use. Research on the topic has focused primarily on the workforce and tended to overlook senior citizens. This study presents the development of a new scale, which was designed to measure technostress specifically among older adults. METHOD: The scale explores five constructs: overload, invasion, complexity, privacy and inclusion. The initial 20-item measure was tested in a pilot study and then included in an online survey of 537 Internet users aged 60 years and over. RESULTS: Based on the statistical analysis, the scale was reduced to 14 items. The constructs had good internal homogeneity, significant inter-construct correlations and high loadings on a single latent factor. The scores were well distributed along the range. Concurrent validity was assessed using the Satisfaction with Life Scale. A significant negative association was found between the two scales - a correlation that remained significant even after controlling for background variables. CONCLUSION: The new scale is useful for measuring technostress in older people, and technostress ought to be considered a particular threat to well-being in later life. Future research should explore its antecedents and consequences and identify interventions useful in alleviating its harmful effect on older ICT users. PMID- 28562066 TI - A minireview of effects of maternal diet during pregnancy on postnatal vegetable consumption: Implications for future research (a new hypothesis) and recommendations. AB - The flavor of the maternal diet is transferred to the amniotic fluid and in this way the amniotic fluid becomes a transmitter of flavor-related information, developing babies can perceive in uterus. We aimed to review the available evidence regarding the impact of prenatal exposure to flavor on postnatal vegetable-related eating behavior. Studies of our focus have been the ones that have ad hoc examined the association of prenatal experience with vegetable related flavors with vegetable consumption in children. We have identified that some studies have found this association, against others. Particularly, the first group of studies found an increased vegetable intake at weaning and late childhood associated with prenatal flavor exposure. The second set, instead, did not find this association of variables at early childhood. We propose here that the vegetable type used in these last studies might explain this disparity of results, and suggest the following hypothesis to be tested in the future: prenatal exposure to nonbitter vegetables leads to an increased vegetable consumption at early childhood in comparison to prenatal exposure to bitter vegetables, postnatal exposure to vegetables and no exposure. The experimental design of this hypothesis as well as subsequent recommendations for future research and maternal diet are also here suggested. PMID- 28562068 TI - Extroversion, social support and life satisfaction in old age: a mediation model. AB - OBJECTIVES: The aim of this study was twofold: on the one hand to analyze whether extroversion predicts social support in older people, and on the other hand to determine if different types of social support mediate the effect that extroversion has on older people's life satisfaction. METHOD: The sample comprised 406 community-dwelling older adults (M = 74.88, SD = 6.75) from urban areas of Granada, southern Spain. RESULTS: Extroversion was positively correlated with emotional (r = .23) and with affectionate support (r = .30). Extroversion and all types of social support also positively correlated with life satisfaction. The multiple mediation analysis revealed that when age, gender, marital status and loneliness were controlled, extroversion predicted emotional (B = .008, p < .01) and affectionate support (B = .015, p < .01) and emotional and affectionate support mediated the association between extroversion and life satisfaction (total effect: B = .034, SE = .0024, p < .001, r2 = .295). Results from this study highlight the fact supportive social relations are crucial for older people's life satisfaction. Also emotional and affectionate support constitutes important explanatory mechanisms of the indirect effect of extroversion on life satisfaction. CONCLUSION: Personality traits should be considered when interventions aimed at promoting life satisfaction in old age and successful aging are designed. PMID- 28562067 TI - Hypertension in HIV-Infected Adults Compared with Similar but Uninfected Adults in China: Body Mass Index-Dependent Effects of Nadir CD4 Count. AB - Hypertension is a growing problem in the HIV population. The relationship between low nadir CD4 count and hypertension in the HIV-infected population has been reported. However, the effect of nadir CD4 on hypertension due to a different body mass index (BMI) is yet to be fully elucidated. In this cross-sectional study, 345 HIV-infected participants aged >=40 years were recruited. They were frequency matched and compared with age, sex, and education with HIV-uninfected adults (n = 345). Hypertension prevalence was lower in HIV-infected than in HIV uninfected participants (23.8% vs. 31.9%; p = .011), but this association was not significant after adjusting for potential confounders. Among HIV-infected individuals, older age, overweight, with a family history of cardiovascular diseases, and nadir CD4 count <50 cells/MUl were independently associated with hypertension. Stratifying individuals with BMI category revealed that nadir CD4 count-regardless if it was operationalized as a dichotomous variable (<50 cells/MUl) or continuous variable-was found to be associated with hypertension among individuals who were underweight and obese, but not among those who were normal weight and overweight. Among HIV-uninfected individuals, older age and having a waist circumference above cutoff were significantly associated with hypertension. This is one of the first studies to demonstrate that the association of nadir CD4 and hypertension is observed in underweight and obese HIV-infected patients. While these results suggest that the relationship between nadir CD4 count and hypertension might be mediated by body weight, future longitudinal studies will be needed to validate the findings, including its causal pathways. PMID- 28562065 TI - Role of Platelet-Derived Transforming Growth Factor-beta1 and Reactive Oxygen Species in Radiation-Induced Organ Fibrosis. AB - SIGNIFICANCE: This review evaluates the role of platelet-derived transforming growth factor (TGF)-beta1 in oxidative stress-linked pathologic fibrosis, with an emphasis on the heart and kidney, by using ionizing radiation as a clinically relevant stimulus. Current radiation-induced organ fibrosis interventions focus on pan-neutralization of TGF-beta or the use of anti-oxidants and anti proliferative agents, with limited clinical efficacy. Recent Advances: Pathologic fibrosis represents excessive accumulation of collagen and other extracellular matrix (ECM) components after dysregulation of a balance between ECM synthesis and degradation. Targets based on endogenous carbon monoxide (CO) pathways and the use of redox modulators such as N-acetylcysteine present promising alternatives to current therapeutic regimens. CRITICAL ISSUES: Ionizing radiation leads to direct DNA damage and generation of reactive oxygen species (ROS), with TGF-beta1 activation via ROS, thrombin generation, platelet activation, and pro inflammatory signaling promoting myofibroblast accumulation and ECM production. Feed-forward loops, as TGF-beta1 promotes ROS, amplify these profibrotic signals, and persistent low-grade inflammation insures their perpetuation. We highlight differential roles for platelet- versus monocyte-derived TGF-beta1, establishing links between canonical and noncanonical TGF-beta1 signaling pathways in relationship to macrophage polarization and autophagy, and define points where pharmacologic agents can intervene. FUTURE DIRECTIONS: Additional studies are needed to understand mechanisms underlying the anti-fibrotic effects of current and proposed therapeutics, based on limiting platelet TGF-beta1 activity, promotion of macrophage polarization, and facilitation of collagen autophagy. Models incorporating endogenous CO and selective TGF-beta1 pathways that impact the initiation and progression of pathologic fibrosis, including nuclear factor erythroid 2-related factor (Nrf2) and redox, are of particular interest. Antioxid. Redox Signal. 27, 977-988. PMID- 28562069 TI - "We Need to Deploy Them Very Thoughtfully and Carefully": Perceptions of Analytical Treatment Interruptions in HIV Cure Research in the United States-A Qualitative Inquiry. AB - Strategies to control HIV in the absence of antiretroviral therapy are needed to cure HIV. However, such strategies will require analytical treatment interruptions (ATIs) to determine their efficacy. We investigated how U.S. stakeholders involved in HIV cure research perceive ATIs. We conducted 36 in depth interviews with three groups of stakeholders: 12 people living with HIV, 11 clinician-researchers, and 13 policy-makers/bioethicists. Qualitative data revealed several themes. First, there was little consensus on when ATIs would be ethically warranted. Second, the most frequent perceived hypothetical motivators for participating in research on ATIs were advancing science and contributing to society. Third, risks related to viral rebound were the most prevalent concerns related to ATIs. Stakeholders suggested ways to minimize the risks of ATIs in HIV cure research. Increased cooperation between scientists and local communities may be useful for minimizing risk. Further ethics research is necessary. PMID- 28562071 TI - Systematic health screening of refugees after resettlement in recipient countries: a scoping review. AB - CONTEXT: Health screening of refugees after settlement in a recipient country is an important tool to find and treat diseases. Currently, there are no available reviews on refugee health screening after resettlement. METHODS: A systematic literature search was conducted using the online Medical Literature Analysis and Retrieval System ('MEDLINE') database. Data extraction and synthesis were performed according to the PRISMA statement. RESULTS: The search retrieved 342 articles. Relevance screening was conducted on all abstracts/titles. The final 53 studies included only original scientific articles on health screening of refugees conducted after settlement in another country. The 53 studies were all from North America, Australia/New Zealand and Europe. Because of differences in country policies, the screenings were conducted differently in the various locations. The studies demonstrated great variation in who was targeted for screening and how screening was conducted. The disease most frequently screened for was tuberculosis; this was done in approximately half of the studies. Few studies included screening for mental health and non-infectious diseases like diabetes and hypertension. CONCLUSION: Health screening of refugees after resettlement is conducted according to varying local policies and there are vast differences in which health conditions are covered in the screening and whom the screening is available to. PMID- 28562072 TI - Synthesis and carbonic anhydrase inhibitory properties of new spiroindoline substituted sulphonamide compounds. AB - New spiroindoline-substituted sulphonamide compounds were synthesised and their inhibitory effects on the activity of purified human carbonic anhydrase I and II were evaluated. Human carbonic anhydrase isoenzymes (hCA-I and hCA-II) were purified from erythrocyte cells by affinity chromatography. The inhibitory effects of the 14 synthesised sulphonamides (6a-n) on esterase activities of these isoenzymes were studied in vitro. In relation to these activities, the inhibition equilibrium constants (Ki) were determined. The results showed that all the synthesised compounds inhibited the carbonic anhydrase (CA) isoenzyme activity. Among them, 6b was found to be the most active (Ki: 0.042 MUM) for hCA I and 6a (Ki: 0.151 MUM) for hCA II. PMID- 28562073 TI - Comparing multiple correspondence and principal component analyses with biomechanical signals. Example with turning the steering wheel. AB - The purpose of this article is to compare Principal Component Analysis (PCA) and a much less used method, i.e. MCA (Multiple Correspondence Analysis) with data being first changed into membership values to fuzzy space windows. For such a comparison, data from an experimental study about turning the steering wheel is used. In a didactic perspective, this article only considers one multidimensional signal with 5 components: 3 linked to the steering wheel angle and hand positions and 2 to hand effort variables. A discussion weighs out the pros and the cons of both methods with criteria such as the possibility to show complex relational phenomena, the analysis/computing time or the information loss inherent to the averaging stage (in the perspective to analyze several hundreds of large multidimensional signals). PMID- 28562075 TI - C9orf72 mutations do not influence the tau signature of amyotrophic lateral sclerosis with cognitive impairment (ALSci). AB - OBJECTIVE: C9orf72 mutations are associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and ALS-FTD. In addition to ALS-FTD, ALS patients may develop a spectrum of neuropsychological and neuropsychiatric deficits including ALS with cognitive impairment (ALSci). Here we examine the extent to which C9orf72 mutations are associated with ALSci and whether this alters the tau molecular signature. METHODS: We identified 16 ALSci cases within a post-mortem archive of 94 fully genotyped ALS cases, eight of which harboured a C9orf72 mutation, in addition to three cognitively-intact ALS cases with a C9orf72 mutation. Tau was fractionated into soluble and insoluble fractions, with or without dephosphorylation, and immunoblots for tau phospho-isoforms performed. RESULTS: Regardless of cognitive state or the presence of C9orf72 mutation, all ALS cases demonstrated six tau isoforms in both soluble and insoluble tau isolates. This pattern was unaffected by dephosphorylation. pThr175tau isoforms, a molecular signature of ALSci, were present regardless of C9orf72 genetic status. The pathognomic paired helical triplet in the insoluble tau fraction of Alzheimer's disease was not observed, regardless of cognitive or C9orf72 status. CONCLUSIONS: These findings suggest that the presence of a C9orf72 mutation does not influence the tau signature of ALS or ALSci. PMID- 28562074 TI - Phytochemical screening, total phenolic content and phytotoxic activity of corn (Zea mays) extracts against some indicator species. AB - Allelopathic effects of corn (Zea mays) extracts was studied, against seed germination and seedling growth of Phalaris minor, Helianthus annuus, Triticumaestivum, Sorghum halepense, Z. mays. Bioassay results showed that aqueous extracts of corn root and shoot, markedly affected seed germination, and other parameters compared with related controls. Preliminary phytochemical screening revealed the presence of various phytochemicals such as tannins, phlobatannins, flavonoids, terpenoids and alkaloids in both roots and shoot aqueous extracts. However, saponins were only present in the shoot aqueous extract, while in shoot ethanol extracts, only terpenoids and alkaloids were detected. Additionally, total polyphenolic (TPC) content in aqueous extracts of corn root and shoot, plus ethanol extracts of corn shoot were determined using an Ultraviolet-visible spectroscopy. Results revealed TPC content of the corn shoot aqueous extract showed the highest yield, compared to other extracts. These findings suggest that phytochemicals present in Z. mays extracts may contribute to allelopathy effect. PMID- 28562076 TI - The influence of narrow-leafed lupin seed fermentation on their chemical composition and ileal digestibility and microbiota in growing pigs. AB - The aims of this study were to provide a controlled fermentation process of blue lupin seeds (Lupinus angustifolius, cv. Neptun), monitor the changes in seed composition and determine the influence of the fermentation on the apparent ileal digestibility (AID) of crude protein (CP) and amino acids in growing pigs, compared with raw lupin seeds. The fermentation with bacteria and yeast was conducted for 24 h at 25oC under aerobic conditions. Seed fermentation increased the contents of CP, fibre, fat and ash and most of the analysed amino acids but reduced the levels of the nitrogen-free extractives. Furthermore, fermentation decreased the contents of raffinose family oligosaccharides and phytic acids but increased the alkaloid content. The AID was estimated on three barrows (mean initial body weight 25 kg), surgically fitted with a T-cannula in the distal ileum. The pigs received three diets, each for 6 d, within three experimental periods (3 * 3 Latin Square design). The diets contained soybean meal (Group SBM), raw lupin seeds (Group RL) or fermented lupin seeds (Group FL) as solely protein sources. Fermentation had a positive impact on the AID of CP and methionine, cysteine, isoleucine, leucine, phenylalanine and valine (p < 0.05). Feeding raw or fermented lupin seeds did not affect the microbial status of the ileal digesta. Moreover, ammonia content in the caecal digesta did not differ between Groups RL and FL, although it was significantly higher than in Group SBM. It can be concluded that the fermentation process modified the chemical composition of nutrients in seeds, which can influence the digestibility and utilisation of the fermentation product in animal diets compared to raw seeds. PMID- 28562077 TI - Medical student perceptions of clinical neurosurgery teaching in an undergraduate medical school curriculum. AB - AIM: The aim of this study was to evaluate undergraduate medical student perceptions as to the value of different types of neurosurgical teaching to their general neuroscience education, delivered in the penultimate year of a U.K medical school. METHODS: We surveyed penultimate-year medical students at St George's Hospital Medical School, University of London (SGUL), who were undertaking their clinical neuroscience attachment from August 2014 to July 2015. A questionnaire comprising closed Likert scale questions and an open question inviting participants to comment freely was used to assess student perception about the value of Neurosurgical sessions within their overall neuroscience education. RESULTS: Of the 316 students in the year we surveyed 247 (78.2%), of whom 201 responded (response rate 81.4%). On average, 82.8% of students either agreed or strongly agreed that neurosurgical teaching sessions made a valuable contribution to their learning. In particular, lectures by neurosurgeons, clinical teaching on the Glasgow Coma Scale in neuro-ITU, bedside teaching and neurosurgical clinics were considered the most beneficial. The majority of students felt the sessions improved their understanding of neurological examination, signs, and 'red-flags'. The sessions were also beneficial for learning neuro-imaging and understanding of neurosurgical emergencies. Over two thirds felt that theatre sessions were beneficial, significantly more so amongst students invited to 'scrub-in'. CONCLUSIONS: Students rated neurosurgical sessions highly and valued the contribution they made not only to their learning of neurosurgical conditions and emergencies, but also to their learning of general neurology and clinical neurosciences overall. Student perceived learning from theatre sessions was significantly correlated with whether or not the student had been invited to 'scrub-in'. Expert neurosurgical teaching can make a valuable, and arguably essential contribution to the undergraduate medical curriculum. PMID- 28562070 TI - The Role of MicroRNAs in Environmental Risk Factors, Noise-Induced Hearing Loss, and Mental Stress. AB - SIGNIFICANCE: MicroRNAs (miRNAs) are important regulators of gene expression and define part of the epigenetic signature. Their influence on every realm of biomedicine is established and progressively increasing. The impact of environment on human health is enormous. Among environmental risk factors impinging on quality of life are those of chemical nature (toxic chemicals, heavy metals, pollutants, and pesticides) as well as those related to everyday life such as exposure to noise or mental and psychosocial stress. Recent Advances: This review elaborates on the relationship between miRNAs and these environmental risk factors. CRITICAL ISSUES: The most relevant facts underlying the role of miRNAs in the response to these environmental stressors, including redox regulatory changes and oxidative stress, are highlighted and discussed. In the cases wherein miRNA mutations are relevant for this response, the pertinent literature is also reviewed. FUTURE DIRECTIONS: We conclude that, even though in some cases important advances have been made regarding close correlations between specific miRNAs and biological responses to environmental risk factors, a need for prospective large-cohort studies is likely necessary to establish causative roles. Antioxid. Redox Signal. 28, 773-796. PMID- 28562078 TI - Alpha-glucosidase inhibitory activity of ethanol extract, fractions and purified compounds from the wood of Albizia myriophylla. AB - Albizia myriophylla Benth. is a medicinal herb which is used as a traditional remedy for various ailments including diabetes in Thailand. In our continued investigation of the biological activity of A. myriophylla, the ethanol extract, fractions and the isolated compounds from the wood of this plant were evaluated for in vitro alpha-glucosidase inhibition using spectrophotometric method. The plant ethanol extract and its different fractions possessed alpha-glucosidase inhibitory activity in a concentration-dependent manner. Dichloromethane fraction of the wood ethanol extract exhibited the highest percent inhibition against alpha-glucosidase (69.30%) among all fractions. Subsequent alpha-glucosidase inhibition assay proved that indenoic acid (1), 8-methoxy-7, 3',4' trihydroxyflavone (2) and 3,4,7,3'-tetrahydroxyflavan (3) were partially rational for antidiabetic effect of this plant species. Among these compounds, 3 (IC50 98.59 MUg/mL) exhibited potent inhibition of alpha-glucosidase, compared with a positive control acarbose (IC50 125 MUg/mL). The inhibitory effect towards alpha glucosidase of compounds 1-3 was reported herein for the first time. PMID- 28562079 TI - Improved visual acuity after microsurgical clipping of a symptomatic anterior cerebral artery aneurysm: case report. AB - BACKGROUND: Symptomatic aneurysms of the anterior cerebral artery causing visual impairments are rare and preponderantly lacking in the literature. It is further under discussion, whether operative clipping or endovascular coiling might be superior in order to achieve visual recovery. We therefore present a case of a patient with progressive visual loss caused by an aneurysm of the right A1-A2 segment compressing the ipsilateral optic nerve. METHODS: A 57-year-old woman was admitted to our neurosurgical department with visual impairment of the right eye. On admission, visual acuity was 0.05 dpt. and visual field testings showed severe medial and lateral quadrant-anopia. MRI scans and angiography (DSA) demonstrated an aneurysm of the A1-A2 segment compressing the right optic nerve. During surgery, the aneurysm was clipped, the space-occupying dome removed and the nerve relieved from any adhesions. Instantaneously after surgery, visual acuity significantly improved from 0.05 to 0.9 dpt. CONCLUSIONS: Anterior cerebral artery aneurysms may present with acute visual impairments and surgical clipping significantly improves impaired visual acuity. PMID- 28562080 TI - Neuroimaging patterns along the ALS-FTD spectrum: a multiparametric imaging study. AB - Frontotemporal dementia is associated with considerable clinical, genetic and pathological heterogeneity. The objective of this study is to characterise the imaging signatures of the main FTD phenotypes along the ALS-FTD spectrum. A total of 100 participants underwent comprehensive multimodal neuroimaging, genetic testing and neuropsychological evaluation. Seven patients with behavioural variant FTD (bvFTD), 11 patients with non-fluent-variant primary progressive aphasia (nfvPPA), two patients with sematic-variant primary progressive aphasia(svPPA), 10 patients with amyotrophic lateral sclerosis and FTD carrying the C9orf72 hexanucleotide repeat (C9 + ALS-FTD), 10 patients with ALS-FTD without hexanucleotide repeats (C9-ALS-FTD), 20 ALS patients without behavioural or cognitive deficits (ALSnci) and 40 healthy controls (HC) were included in a prospective quantitative neuroimaging study. Phenotype-specific spatial patterns of pathology were identified along the ALS-FTD spectrum, highlighting a strikingly focal distribution of disease burden as opposed to global atrophy. Significant motor cortex and corticospinal tract degeneration was identified in both bvFTD and nfvPPA patients. C9-ALS-FTD patients exhibited widespread extramotor pathology and significant precentral gyrus atrophy compared to ALSnci patients. ROI analyses confirmed focal grey matter alterations in Broca's and Wernicke's area in language variant FTD cohorts. Our findings confirm that the clinical manifestations of FTD are underpinned by phenotype-specific patterns of white and grey matter degeneration. PMID- 28562083 TI - Cardiac light-chain deposition disease relapsing in the transplanted heart. PMID- 28562081 TI - A new sesquiterpene lactone glucoside and other constituents from Inula salsoloides with insecticidal activities on striped flea beetle (Phyllotreta striolata Fabricius). AB - A new sesquiterpene, eupatolide 13-O-beta-d-glucopyranoside (eupatolide-II, 1), lactone glucoside, along with 15 known compounds, were isolated from the whole plant of Inula salsoloides (Asteraceae). Dichloromethane extract and compounds 1 11 were used to investigate insecticidal activities against vegetable important pest, striped flea beetle (Phyllotreta striolata Fabricius). None of the samples show any toxicity under concentration of 500 times, while compound 1 and the extract had toxic effect when the concentration increased to 250 times. But the corrected mortality of compound 1 and the extract were only 44.83 and 13.80%, respectively. Compound 11 (inulasalene) showed repellency effect in the no-choice test, and the repellency rate was 70%. Compounds 1 and 3 (inulasalsolide) showed the antifeeding rates of 65.22 and 47.06%, respectively. Compound 10 (11beta,13 dihydrogeneupatolide) showed strong attractive effects on the adults, while the difference of injured area between the treatment and control was also not significant. PMID- 28562085 TI - Role of STRO-1 sorting of porcine dental germ stem cells in dental stem cell mediated bone tissue engineering. AB - Stem cells of dental origin emerged as a new source for the regeneration of tissues with advantages mainly including non-invasive collection procedures and lack of ethical contraversies with their harvest or use. In this study, porcine TGSCs (pTGSCs) were isolated from mandibular third molar tooth germs of 6-month old domestic pigs. This is the first study that reports the isolation and characterization of TGSCs from porcine third molars and their differentiation depending on STRO-1 expression. PTGSCs were sorted according to their STRO-1 expression as STRO-1(+) and STRO-1(-). Sorted and unsorted heterogenous cells (US) were characterized by their osteogenic, chondrogenic and adipogenic differentiation capabilities. STRO-1(+) cells exhibited a higher proliferation rate owing to their clonogenic properties. All three groups of cells were found differentiated into osteogenic lineage as shown by ALP activity, calcium deposition assay, detection of osteogenic mRNAs and, proteins and mineralization staining. According to differentiation analysis, STRO-1(+) cells did not show a better performance for osteogenesis compared to STRO-1(-) and US cells. This might indicate that STRO-1(+) cells might require a heterogeneous population of cells including STRO-1(-) in their niche to perform their proposed role in osteogenesis. PMID- 28562086 TI - Exploring the structural requirements in multiple chemical scaffolds for the selective inhibition of Plasmodium falciparum calcium-dependent protein kinase-1 (PfCDPK-1) by 3D-pharmacophore modelling, and docking studies. AB - Current research on antimalarial protein kinases has provided an opportunity to design kinase-based antimalarial drugs. We have developed a common feature-based pharmacophore model from a set of multiple chemical scaffolds including derivatives of 3,6-imidazopyridazines, pyrazolo[2,3-d]pyrimidines and imidazo[1,5 a]pyrazines, in order to incorporate the maximum structural diversity information in the model for the Plasmodium falciparum calcium-dependent protein kinase-1 (PfCDPK-1) target. The best pharmacophore model (Hypo-1) with the essential features of two hydrogen bond donors (HBD), one hydrophobic aromatic (HYAr) and one ring aromatic (RA) showed the classification accuracies of 86.27%, 78.43% and 100.00% in labelling the training and test set (test set-1 and test set-2) compounds into more active and less active classes. In order to identify the crucial interaction between multiple scaffold ligands and the target protein, we first developed the homology model using a template structure of P. bergheii (PbCDPK1; PDB ID: 3Q5I), and thereafter performed the docking studies. The residues such as Lys85, Phe147, Tyr148, Leu198, Val211, and Asp212 were found to be the most important interacting residues for possessing PfCDPK-1 inhibitory activity. PMID- 28562087 TI - Corrigendum. PMID- 28562088 TI - Spectroscopic characterisation of two polyketide metabolites from Cylindrocarpon sp. from driftwood. AB - Two new polyketides, (5R,7R,9R)-7,9-dihydroxy-5-decanolide and (4E,6R,9R)- 6,9 dihydroxydec-4-enoic acid (2), were isolated from rice cultures of Cylindrocarpon sp. SY-39 discovered during screening of driftwood at a Shonai coast area in Yamagata, Japan. The structures of 1 and 2 were determined using a variety of spectroscopic methods. Compound 2 exhibited moderate antimicrobial activity against Staphylococcus aureus NBRC 13276 and Aspergillus clavatus F 318a at a concentration of 50 MUg per disk. PMID- 28562089 TI - Paving the Way to Change for Youth at the Gap between Child and Adolescent and Adult Mental Health Services. AB - By 2020 mental illness will be one of the 5 most common illnesses causing morbidity, mortality and disability among youth. At least 20% of Canadian youth have a psychiatric disorder the impact of which can dramatically alter their life trajectory. Focus on the factors contributing to this problem is crucial. Lack of coordination between child and adolescent mental health systems (CAMHS) and adult mental health systems (AMHS) and consequent disruption of care during this vulnerable time of transition is one such factor. Reasons for and the impact of this divide are multilayered, many of which are embedded in outdated, poorly informed approaches to care for this population in transition. This paper considers the etiology behind these reasons as potential foci for change. The paper also briefly outlines recent initiatives ongoing in Canada and internationally that reflect appreciation of these factors in the attempt to minimize the gap in service provision for youth in transition. The need to continue with research and program development endeavours for youth with mental illness whereby access to services and readiness for transition is no longer determined by age is strongly supported. PMID- 28562091 TI - Cyberbullying in Children and Youth: Implications for Health and Clinical Practice. AB - We review the recent literature on cyberbullying and its effects on victimised youth, identifying key points. We conclude that cyberbullying, while following many of the underlying dynamics of more traditional forms of bullying, features some unique qualities that can both magnify the damage caused and make it more difficult to detect. These features include the pervasive, never-ending nature of cyberbullying and the ability to quickly reach large audiences. The potential for anonymity and the related distance afforded by screens and devices compared to in person interaction allow the cruelty of cyberbullying to go unchecked. Despite the perceived anonymity of cyberbullying, cyberbullying can be perpetrated by friends, who often have intimate knowledge about the victimised youth that can be devastating when made public. Given the difficulty schools face in preventing or even detecting cyberbullying, health care providers are an important ally, due to their knowledge of the youth, the sense of trust they bring to youth, and their independence from the school setting. We conclude by calling for routine screening of bullying by health care providers who deal with paediatric populations. PMID- 28562092 TI - The Role of Health Care Providers in Cyberbullying. PMID- 28562093 TI - Child Abuse Experiences and Perceived Need for Care and Mental Health Service Use among Members of the Canadian Armed Forces. AB - OBJECTIVE: Child abuse is associated with poor mental health outcomes in adulthood. However, little is known about how a history of child abuse may be related to perceived need for care (PNC) and mental health service use (MHSU) among Canadian military personnel. The objectives of this study were to determine 1) the relationship between child abuse history and PNC and 2) the relationship between child abuse history and MHSU in the Canadian military. METHOD: Data were drawn from the 2013 Canadian Forces Mental Health Survey ( n = 6692 Regular Force personnel between the ages of 18 and 60 years). Logistic regression was used to examine the relationships between individual child abuse types and PNC and MHSU while adjusting for sociodemographic variables, the presence of mental disorders, deployment-related variables, and other types of child abuse. Population attributable fractions (PAFs) were calculated to estimate the proportion of PNC and MHSU that may be attributable to child abuse. RESULTS: Each individual child abuse type was associated with increased odds of PNC and MHSU after adjusting for all covariates (adjusted odds ratio ranging from 1.26 to 1.80). PAFs showed that if any child abuse did not occur, PNC and MHSU among Regular Force personnel may be reduced by approximately 14.3% and 11.3%, respectively. CONCLUSIONS: This study highlights that preenlistment factors, such as a history of child abuse, have an independent association with PNC and MHSU and hence need to be considered when assessing the mental health service needs of the Canadian Regular Force personnel. PMID- 28562094 TI - Cyberbullying Prevention and Intervention Efforts: Current Knowledge and Future Directions. AB - Bullying is a serious public health concern that is associated with significant negative mental, social, and physical outcomes. Technological advances have increased adolescents' use of social media, and online communication platforms have exposed adolescents to another mode of bullying- cyberbullying. Prevention and intervention materials, from websites and tip sheets to classroom curriculum, have been developed to help youth, parents, and teachers address cyberbullying. While youth and parents are willing to disclose their experiences with bullying to their health care providers, these disclosures need to be taken seriously and handled in a caring manner. Health care providers need to include questions about bullying on intake forms to encourage these disclosures. The aim of this article is to examine the current status of cyberbullying prevention and intervention. Research support for several school-based intervention programs is summarised. Recommendations for future research are provided. PMID- 28562095 TI - The advancement of multidimensional QSAR for novel drug discovery - where are we headed? AB - INTRODUCTION: The Multidimensional quantitative structure-activity relationship (multidimensional-QSAR) method is one of the most popular computational methods employed to predict interesting biochemical properties of existing or hypothetical molecules. With continuous progress, the QSAR method has made remarkable success in various fields, such as medicinal chemistry, material science and predictive toxicology. Areas covered: In this review, the authors cover the basic elements of multidimensional -QSAR including model construction, validation and application. It includes and emphasizes the very recent developments of multidimensional -QSAR such as: HQSAR, G-QSAR, MIA-QSAR, multi target QSAR. The advantages and disadvantages of each method are also discussed and typical examples of their application are detailed. Expert opinion: Although there are defects in multidimensional-QSAR modeling, it is still of enormous help to chemists, biologists and other researchers in various fields. In the authors' opinion, the latest more precise and feasible QSAR models should be further developed by integrating new descriptors, algorithms and other relevant computational techniques. Apart from being applied in traditional fields (e.g. lead optimization and predictive risk assessment), QSAR should be used more widely as a routine method in other emerging research fields including the modeling of nanoparticles(NPs), mixture toxicity and peptides. PMID- 28562096 TI - Emerging growth factor receptor antagonists for the treatment of advanced melanoma. AB - INTRODUCTION: Therapy for metastatic melanoma has undergone a rapid transformation over the past 5-10 years. Advances in immunotherapy with checkpoint inhibitors, including both anti-CTLA-4 and anti-PD-1/PD-L1, have led to durable responses in up to 50% of patients. As our understanding of the processes driving the transformation of melanocytes has improved, progress in targeted therapies has also continued. Areas covered: Angiogenesis and the tumor's dependence on an expanded vascular supply has been a target for novel therapies since the 1970's, as this tissue is derived from endothelial cells that are genetically stable in adults. A phase II trial studying combined therapy with bevacizumab (an inhibitor of angiogenesis) and ipilimumab found promising results. Other agents such as sorafenib have not been as successful, failing to extend progression free or overall survival in clinical trials. In this paper other targeted growth factor inhibitors will also be discussed. Expert opinion: Ultimately, melanoma may not be vulnerable solely to chemotherapy or targeted therapy, but may be efficaciously treated with immunotherapy due to its high mutational rate resulting in the expression of numerous neo-antigens. Therapies with combinations of agents including growth factor receptor and either other targeted therapies or immunotherapy may be a promising complimentary approach. PMID- 28562098 TI - Dapagliflozin and renal function. Re: Diabetes and kidney disease: the role of sodium-glucose cotransporter-2 (SGLT-2) and SGLT-2 inhibitors in modifying disease outcomes. Mende CW. Curr Med Res Opin 2017;33:541-551. PMID- 28562097 TI - A simple point of care test can indicate the need for periodontal therapy to reduce the risk for adverse pregnancy outcomes in mothers attending antenatal clinics. AB - INTRODUCTION: Although the association between periodontal disease (PD) and adverse pregnancy outcomes has gained recognition amongst antenatal healthcare workers, not much has changed in practice to address it. This prospective study tested the hypothesis that BANA (N-benzoyl-DL-arginine-2-naphthylamide), a diagnostic test for PD, may inform obstetricians and other antenatal healthcare practitioners, of the risk of adverse pregnancy outcomes in mothers attending antenatal clinics. METHODS: At first visit, the presence of suspected periodontopathogens was assessed by BANA testing of dental plaque from 443 mothers attending antenatal clinics in KwaZulu-Natal, South Africa and an association later sought with pregnancy outcomes. The accuracy of BANA to predict adverse pregnancy outcomes was evaluated by the calculation of likelihood ratios. The study complied with the Declaration of Helsinki. RESULTS: Significant differences were found between pregnancy outcomes of BANA-negative and BANA positive mothers (p < 0.0001). BANA showed sensitivity and negative predictive values of 87% and 91%; 75% and 78%; 87% and 94% in detecting low birth weight, preterm delivery, and preterm low birth weight delivery respectively. CONCLUSION: This study confirms that BANA may indicate the need for periodontal therapy to reduce the risk of adverse pregnancy outcomes and could form part of the routine antenatal examination. PMID- 28562099 TI - The effectiveness of transdermal testosterone gel 1% (androgel) for poor responders undergoing in vitro fertilization. AB - The study was conducted on 110 poor responders undergoing in vitro fertilization (IVF) from October 2015 to July 2016 at the IVF Center of Millitary Medical University, Vietnam. Its aim is to investigate the effectiveness of transdermal androgel before using controlled ovarian stimulation on patients undergoing IVF. A prospective, descriptive study was conducted to compare between the group of patients who used testosterone gel and the group of those who did not in terms of the following indicators: the number of oocytes retrieved, MII oocytes, fertilization rate, number of embryos, pregnancy rate, and embryo implantation rate. The number of oocytes retrieved, number of embryos, pregnancy rate, and embryo implantation rate of the group of patients using transdermal androgel before Controlled Ovarian Stimulation (COS) were found higher than those of the control group, with statistical significance. The use of androgel before stimulating ovarian can improve the responsiveness of poor responders when undergoing IVF. PMID- 28562100 TI - Developments with experimental and investigational drugs for axial spondyloarthritis. AB - INTRODUCTION: Axial spondyloarthritis (AxS pA) is a chronic inflammatory disease for which, until recently, there were no valid therapeutic alternatives to TNF alpha blocking agents. This unmet clinical need led to explore several therapeutic targets, from proinflammatory cytokines to intracellular signaling systems. The recent approval of Secukinumab, an anti-IL-17A monoclonal antibody, marked a new step in the evolution of AxSpA treatment. Areas covered: the authors review and discuss all the biological or synthetic agents that are currently developed or that have been tested in AxSpA. News from relevant press releases by manufacturers on past, current and future developments are also reported. Several agents that target IL-17 are currently between phase 2 and 3 of clinical development. Ustekinumab, a monoclonal antibody that blocks IL-23 and IL-12 is also in phase 3 after encouraging results from a pilot study. Expert opinion: The advent of agents that target the IL-23/IL-17 axis promises to reshape the therapeutic landscape for AxSpA in the next few years. Open questions in the research agenda for these agents involve their positioning in the therapeutic strategy, their efficacy on the spectrum of skeletal and extraskeletal manifestations of AxSpA, their effect on new bone formation and their long-term tolerance. PMID- 28562101 TI - Methionine metabolism and multiple sclerosis. AB - CONTEXT: Methylation reactions are particularly important in the brain and their inhibition can lead to a number of serious pathologies. Multiple sclerosis is one of the most common neurological disorders caused by interaction of genetic and environmental factors, but little is known about its cause or factors that contribute to the disorder. Although multiple sclerosis is primarily regarded as demyelinating disorder, there are no many articles focusing on methionine determination. OBJECTIVE: The aim of this work was to investigate whether serum methionine and its related compounds like homocysteine, cysteine, glutathione and asymmetric dimethylarginine were changed in multiple sclerosis patients. MATERIALS AND METHODS: Sulphur-containing compounds were determined by using high performance liquid chromatography with electrochemical detection in a single run for providing more complex view on methionine metabolism and asymmetric dimetylarginine was measured by a commercial enzyme-linked immunosorbent assay kit. RESULTS: Methionine and glutathione were decreased, but homocysteine, asymmetric dimethylarginine and cysteine were unchanged in patients with multiple sclerosis compared with controls. CONCLUSIONS: Methionine and glutathione seem to be potential biomarkers for prognosis of the disease. PMID- 28562102 TI - Blastocyst transfer is not associated with increased unfavorable obstetric and perinatal outcomes compared with cleavage-stage embryo transfer. AB - BACKGROUND: Recent studies demonstrated controversial results of whether there are risks in fetal outcomes after blastocyst-stage embryos transfer (BT) compared with cleavage-stage embryos transfer (CT). AIMS: To compare the implantation rates (IR), clinical pregnancy rates (cPR), birth rates (BR), gestational weeks, preterm birth rates, birth weights and low birth weight rates between CT and BT groups. METHODS: A retrospective study of 1627 embryos transfer cycles was performed from May 2014 to April 2015. The cycles were divided into two groups according to transfer stage: CT on Day 3 (n = 798) and BT on Day 5 (n = 829). For the CT group, it must have surplus embryos and only surplus embryos developed to available blastocysts, the cleavage-stage embryos could be included. The clinical outcomes of two groups were analyzed. RESULTS: The IR in CT group was lower than BT group (48.98% vs. 60.68%; p < 0.01). There were no significant differences in the clinical pregnancy rate and birth rate between BT and CT groups. For singletons and twin deliveries, there were no significant differences in gestational weeks, preterm birth rates, birth weights and low birth weight rates between two groups. CONCLUSION: Blastocysts had higher implantation potential than cleavage-stage embryos. Extended embryo culture was not related to increased adverse obstetric and perinatal outcome. PMID- 28562103 TI - The paradigm shift to end tuberculosis. Are we ready to assume the changes? AB - INTRODUCTION: Tuberculosis (TB) is the number one infectious disease killer and exemplifies the most neglected of them. Drug-susceptible TB presents with high mortality especially in atypical forms, disproportionally affecting immunosuppressed and vulnerable populations. The drug-resistant TB (DR-TB) epidemic, a world crisis, is sustained and increased through person-to-person transmission in households and the community. TB diagnostics and treatment in recent years are highly evolving fields. New rapid molecular tests are changing the perspectives in diagnosis and resistance screening. Also, new drugs and shorter regimens for DR-TB are appearing. For the first time in recent history, a large number of randomized control trials are incoming. Areas covered: This article reviews most TB advances including new diagnostic tests, drugs, and regimens and outlines upcoming drug trials while disclosing the potential gaps the in development of patient-centered systems and current organizational challenges leading to a delay in the uptake of these innovations. Expert commentary: Innovations are occurring, but not many are implemented on a wide scale in developing countries. TB health systems and staff are not getting updated in parallel. More efforts and funds are needed not only to implement current novelties but also to research for future solutions to eliminate TB. PMID- 28562105 TI - Prasugrel hydrochloride for the treatment of sickle cell disease. AB - INTRODUCTION: Therapeutic options for sickle cell disease (SCD) are limited and, currently, only one drug (hydroxyurea) has FDA approval for the treatment of adult SCD. While this genetic disease is caused by hemoglobin polymerization, subsequent downstream events trigger platelet activation, vaso-occlusion and the disease's complex pathophysiology. Areas covered: The oral thienopyridine, prasugrel hydrochloride, irreversibly inhibits the P2Y12 receptors, inhibiting ADP-dependent platelet activation. We discuss recent clinical trials evaluating the pharmokinetics of prasugrel and its potential for use in SCD. Expert opinion: Prasugrel administration in SCD appears to be well tolerated and safe. However, although this drug modestly inhibits platelet activity in these patients, administration of prasugrel to a large group of children and adolescents for up to 24 months failed to convincingly reduce vaso-occlusive complications. Speculatively, prasugrel may be of occasional use for off-license purposes in patients unable or unwilling to take hydroxyurea (particularly in 12-17-year olds). Although there is currently no prospect of prasugrel being licensed for use in SCD, the success of on-going trials of other antiplatelet agents in SCD might lead to further trials of prasugrel in SCD. PMID- 28562104 TI - Liver cirrhosis stages and the incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving antiviral therapy. AB - OBJECTIVES: Long-term antiviral therapy decreases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB), however, it cannot eliminate the risk. We investigated the incidence of HCC at different stages of liver cirrhosis (LC) and identified clinical predictors for HCC development during antiviral therapy. METHODS: The data from 356 treatment-naive patients aged 40 to 69 years without a history of HCC who had received entecavir for >=6 months were collected retrospectively. The incidence of HCC was evaluated in patients with CHB only, with LC without varices (stage 1), with varices (stage 2), and with ascites (stage 3). RESULTS: The median follow-up period was 3.6 years. In total, 45 patients (12.6%) developed HCC. The annual incidence rates of HCC in patients with CHB only or LC in stages 1, 2, and 3 were 0.4%, 2.6%, 9.8%, and 6.7%, respectively. In multivariate analyzes, LC at stage 2 (hazard ratio [HR] 17.16, 95% confidence interval [C.I.] 3.93-75.01, p < .001), alcohol consumption (HR 3.84, 95% C.I. 1.99-7.39, p < .001), and older age (HR 1.06, 95% C.I. 1.01-1.11, p = .010) were significantly associated with HCC development. The risk decreased in those who stopped drinking after 2 years of abstinence (p = .0314). CONCLUSIONS: LC with significant portal hypertension (varices or ascites), alcohol consumption, and older age at the time of starting antiviral therapy are independent predictors for future HCC development. PMID- 28562106 TI - Enteral nutrition in pediatric intestinal failure: does initial feeding impact on intestinal adaptation? AB - INTRODUCTION: Primary IF can be due to impaired gut length or impaired gut function; short bowel syndrome (SBS) is the leading cause of IF. In IF patients complete enteral starvation should be avoided whenever possible and enteral/oral nutrition (EN/ON) should be employed at the maximum tolerated amount in each phase of the clinical evolution of IF. Intraluminal nutrients have stimulatory effects on epithelial cells and on trophism that enhance intestinal adaptation. Areas covered: Evidence for nutritional interventions in pediatric IF is limited and of poor quality. Clinical practice in SBS feeding are more 'experience-based' rather than 'evidence-based' and this dearth of clinical evidence is partly due to the rarity of this condition. This review updates knowledge concerning the impact of the initial diet with EN/ON in neonatal onset SBS in the process of bowel adaption. Expert commentary: Human milk resulted the preferred starting diet and it is generally combined with amino-acids (AAs) in Northern America and with hydrolyzed proteins (HFs) in Europe; polymeric diet is rarely employed. HFs were not more effective than AAs in promoting intestinal adaptation. PMID- 28562107 TI - Neurovegetative disorders of perimenopausal women treated with docosahexaenoic acid (DHA, 625 mg). AB - The study evaluated the effect of DHA 625 mg in women who experience menopausal symptoms, on sexuality and quality of life (QoL), and on the auditory brainstem response (ABR). Forty-two perimenopausal women were enrolled. The Kupperman Index (KI) was used to evaluate menopause symptoms. The Short Form-36 (SF-36), Female Sexual Function Index (FSFI), and the Female Sexual Distress Scale (FSDS) were used to assess QoL, sexual function, and sexual distress, respectively. Auditory evoked potentials to measure the ABR. The study had one follow-up at 6 months. The women reported an improvement in the KI total score (p < .001). Moreover, women reported QoL improvements in all the psychological categories (p < .001), but not in physical categories (p = NS). FSFI and FSDS total scores increased (p < .01) and the FSDS score decreased (p < .01), mainly due to arousal (p < .03) and lubrication (p < .05) sexual aspects. The ABR wave latencies were lower than the baseline values (p < .05). DHA could be effective in modulating some perimenopausal symptoms in women and, consequently could contribute to improve their QoL and sexual life. Finally, DHA seems to have a direct activity on the neuronal conduction time into the audiological system. PMID- 28562108 TI - Characteristics of children and adolescents first prescribed proton pump inhibitors or histamine-2-receptor antagonists: an observational cohort study. AB - OBJECTIVE: To describe the characteristics of pediatric patients prescribed proton pump inhibitors (PPIs) vs those of pediatric patients prescribed histamine 2-receptor antagonists (H2RAs). METHODS: Observational studies were conducted using The Health Improvement Network (THIN) and the PHARMO Database Network. Patients aged 0-18 years who were first prescribed a PPI or H2RA between October 1, 2009 and September 30, 2012 (THIN) or between September 1, 2008 and August 31, 2011 (PHARMO) were included. Patient characteristics were identified and compared between the PPI and H2RA cohorts using odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age and sex. RESULTS: The mean age (years) was higher in the PPI than in the H2RA cohorts (THIN 12.3 [n = 8204] vs 5.4 [n = 7937], PHARMO 11.0 [n = 15 362] vs 7.1 [n = 6168]). Previous respiratory disease was more common in the PPI than in the H2RA cohort in THIN (OR = 1.19, 95% CI = 1.08-1.30), as were asthma and respiratory medication use in PHARMO (OR = 1.27, 95% CI = 1.12-1.45 and OR = 1.23, 95% CI = 1.10-1.38, respectively) and oral corticosteroid use in both databases (OR = 1.45, 95% CI = 1.10-1.92 [THIN]; OR = 2.80, 95% CI = 2.11-3.71 [PHARMO]). Non-steroidal anti-inflammatory drugs, antibiotics, and oral contraceptives were also more common in PPI than in H2RA cohorts in both databases. CONCLUSIONS: Pediatric patients receiving PPIs and those receiving H2RAs may represent different patient populations. PPIs may be more commonly prescribed than H2RAs among patients with respiratory diseases. PMID- 28562109 TI - Genetic and epigenetic markers in colorectal cancer screening: recent advances. AB - INTRODUCTION: Colorectal cancer (CRC) is a heterogenous disease which develops from benign intraepithelial lesions known as adenomas to malignant carcinomas. Acquired alterations in Wnt signaling, TGFbeta, MAPK pathway genes and clonal propagation of altered cells are responsible for this transformation. Detection of adenomas or early stage cancer in asymptomatic patients and better prognostic and predictive markers is important for improving the clinical management of CRC. Area covered: In this review, the authors have evaluated the potential of genetic and epigenetic alterations as markers for early detection, prognosis and therapeutic predictive potential in the context of CRC. We have discussed molecular heterogeneity present in CRC and its correlation to prognosis and response to therapy. Expert commentary: Molecular marker based CRC screening methods still fail to gain trust of clinicians. Invasive screening methods, molecular heterogeneity, chemoresistance and low quality test samples are some key challenges which need to be addressed in the present context. New sequencing technologies and integrated omics data analysis of individual or population cohort results in GWAS. MPE studies following a GWAS could be future line of research to establish accurate correlations between CRC and its risk factors. This strategy would identify most reliable biomarkers for CRC screening and management. PMID- 28562110 TI - Epidemiology and causes of death in a Swedish cohort of patients with autoimmune hepatitis. AB - BACKGROUND: Epidemiological studies of autoimmune hepatitis (AIH) show varying figures on prevalence and incidence, and data on the long-term prognosis are scarce. Objective To investigate the epidemiology, long-term prognosis and causes of death in a Swedish AIH cohort. MATERIAL AND METHODS: Data collected from 634 AIH patients were matched to the Cause of Death Registry, and survival analyses were made. Prevalence and incidence were calculated for university hospitals with full coverage of cases and compared to the County of Vasterbotten in Northern Sweden. RESULTS: AIH point prevalence was 17.3/100,000 inhabitants in 2009, and the yearly incidence 1990-2009 was 1.2/100,000 inhabitants and year. The time between diagnosis and end of follow-up, liver transplantation or death was in median 11.3 years (range 0-51.5 years). Men were diagnosed earlier (p < .001) and died younger than women (p = .002). No gender differences were found concerning transplant-free, overall survival and liver-related death. Cirrhosis at diagnosis was linked to an inferior survival (p < .001). Liver-related death was the most common cause of death (32.7%). The relative survival started to diverge from the general population 4 years after diagnosis but a distinct decline was not observed until after more than 10 years. CONCLUSIONS: Long-term survival was reduced in patients with AIH. No gender difference regarding prognosis was seen but men died younger, probably as a result of earlier onset of disease. Cirrhosis at diagnosis was a risk factor for poor prognosis and the overall risk of liver related death was increased. PMID- 28562111 TI - Repeated annual influenza vaccination and vaccine effectiveness: review of evidence. AB - INTRODUCTION: Studies in the 1970s and 1980s signaled concern that repeated influenza vaccination could affect vaccine protection. The antigenic distance hypothesis provided a theoretical framework to explain variability in repeat vaccination effects based on antigenic similarity between successive vaccine components and the epidemic strain. Areas covered: A meta-analysis of vaccine effectiveness studies from 2010-11 through 2014-15 shows substantial heterogeneity in repeat vaccination effects within and between seasons and subtypes. When negative effects were observed, they were most pronounced for H3N2, especially in 2014-15 when vaccine components were unchanged and antigenically distinct from the epidemic strain. Studies of repeated vaccination across multiple seasons suggest that vaccine effectiveness may be influenced by more than one prior season. In immunogenicity studies, repeated vaccination blunts the hemagglutinin antibody response, particularly for H3N2. Expert commentary: Substantial heterogeneity in repeated vaccination effects is not surprising given the variation in study populations and seasons, and the variable effects of antigenic distance and immunological landscape in different age groups and populations. Caution is required in the interpretation of pooled results across multiple seasons, since this can mask important variation in repeat vaccination effects between seasons. Multi-season clinical studies are needed to understand repeat vaccination effects and guide recommendations. PMID- 28562112 TI - Major depressive disorder: insight into candidate cerebrospinal fluid protein biomarkers from proteomics studies. AB - INTRODUCTION: Major Depressive Disorder (MDD) is the leading cause of global disability, and an increasing body of literature suggests different cerebrospinal fluid (CSF) proteins as biomarkers of MDD. The aim of this review is to summarize the suggested CSF biomarkers and to analyze the MDD proteomics studies of CSF and brain tissues for promising biomarker candidates. Areas covered: The review includes the human studies found by a PubMed search using the following terms: 'depression cerebrospinal fluid biomarker', 'major depression biomarker CSF', 'depression CSF biomarker', 'proteomics depression', 'proteomics biomarkers in depression', 'proteomics CSF biomarker in depression', and 'major depressive disorder CSF'. The literature analysis highlights promising biomarker candidates and demonstrates conflicting results on others. It reveals 42 differentially regulated proteins in MDD that were identified in more than one proteomics study. It discusses the diagnostic potential of the biomarker candidates and their association with the suggested pathologies. Expert commentary: One ultimate goal of finding biomarkers for MDD is to improve the diagnostic accuracy to achieve better treatment outcomes; due to the heterogeneous nature of MDD, using bio signatures could be a good strategy to differentiate MDD from other neuropsychiatric disorders. Notably, further validation studies of the suggested biomarkers are still needed. PMID- 28562113 TI - Anaphylaxis: epidemiology, aetiology and relevance for the clinic. AB - INTRODUCTION: Anaphylaxis is responsible for considerable morbidity and may in some cases prove fatal. Areas covered: This review summarises the findings from recent studies on the epidemiology and aetiology of anaphylaxis and draws on the insights from this work and recent international guidelines to consider the implications for clinical care. Acute management of anaphylaxis is centred on early recognition, treatment with adrenaline (epinephrine) and other essential life-support measures. The importance of longer-term care of patients with a history of or at risk of anaphylaxis are also considered with a view to minimising the risk of further reactions. Tailored individual anaphylaxis management plans should be a routine component of this longer-term care with provision of adrenaline auto-injectors to those at risk of further episodes of anaphylaxis. More generally, there is a need to ensure that there are standard protocols in place to ensure that risks of triggering anaphylaxis are minimised and appropriate acute and long-term care are provided if reactions occur. Expert commentary: It is important to be aware that anaphylaxis may occur in patients of any age, sex or ethnicity. Early recognition and prompt treatment with adrenaline are potentially life-saving. Careful assessment of risk and appropriate long-term management are key to improving long-term outcomes in those at risk of repeat episodes of anaphylaxis. PMID- 28562114 TI - Macroscopic findings, incidence and characteristics of microscopic colitis in a large cohort of patients from the United Kingdom. AB - OBJECTIVE: Microscopic colitis (MC) is classically associated with normal or near normal endoscopic appearances. However, non-specific macroscopic findings have been described, the importance of biopsy location for confirming a diagnosis of MC is unclear, and reported incidence data from the United Kingdom are limited. This study was designed to assess macroscopic features, incidence, demographics, and location and positivity of biopsy samples in MC. MATERIALS AND METHODS: Retrospective, cross-sectional study of individuals with newly diagnosed MC. RESULTS: From 2010 to 2015, 540 cases of MC were reported. Macroscopic findings occurred in 16.5% (n = 89) cases, with trends towards increased frequency of ulceration or linear scarring in collagenous colitis (CC). The mean incidence of MC was 11.3 per 100,000 population/year, including 291 (53.9%) with CC (incidence 6.1 per 100,000/year), 203 (37.6%) with lymphocytic colitis (incidence 4.2 per 100,000/year) and 46 (8.5%) with MC, not otherwise specified. Most individuals were female (70.2%). Common features in patients with MC included symptom duration <6 months, weight loss, abdominal pain and use of proton pump inhibitors, statins, or non-steroidal anti-inflammatory drugs. In individuals with right- and left-sided biopsies taken, 98.2% had diagnostic features in both. However, rectal biopsies were only positive in 88.7%. CONCLUSIONS: One in six patients with MC demonstrated distinct macroscopic findings at colonoscopy. Our data confirm a female preponderance in MC, a relatively short symptom duration and use of certain drugs as common features. Both right- and left-sided biopsies were frequently positive, suggesting flexible sigmoidoscopy and biopsy could confirm a diagnosis in certain individuals. PMID- 28562115 TI - A register-based study: adverse events in colonoscopies performed in Sweden 2001 2013. AB - OBJECTIVES: The rates for colonoscopy-associated adverse events vary considerably worldwide. In Sweden, the figures are known to a limited extent. We assessed the frequency of severe colonoscopy-related adverse events and the impacts of different risk factors, including the use of general anaesthesia. MATERIAL AND METHODS: This is a retrospective population-based cohort study of the colonoscopies performed during the years 2001-2013 on adults identified in the Swedish health registers. The rates for bleeding, perforation, splenic injury and 30-day mortality were calculated. Covariates for risks were assessed in a multivariate Poisson regression model. RESULTS: There were 593,315 colonoscopies performed on the 426,560 individuals included in the study. The rates for colonoscopy-related bleeding and perforation were 0.17% and 0.11%, respectively. When polypectomy was performed, the rates were 0.53% for bleeding and 0.25% for perforation. There were 31 splenic injuries (1:20,000 colonoscopies) reported. The crude 30-day death rate for colonoscopy was 0.68%. Of those diagnosed with bleeding or perforation, 5.6% and 6.1% were dead within 30 days, respectively. The multivariate RR for perforation when general anaesthesia was employed was 2.65 (p < .001; 95%CI 1.71-4.12). CONCLUSIONS: The perforation rate seemed to be relatively high in an international perspective. General anaesthesia was associated with a significantly higher risk for perforation. Splenic injuries were more frequent than expected. PMID- 28562116 TI - Pharmacovigilance in Russia: current state of affairs, challenges, and prospects. AB - This review outlines current issues of the pharmacovigilance (PV) system in the Russian Federation, namely the present state of regulatory aspects, regulatory requirements in both Russia and the Eurasian Economic Union, and review of causes of under-reporting of adverse drug reactions. Specific attention will be focused on how the system is designed to monitor drug safety functions, reporting and accountability of pharmaceutical products, their manufacturers and medical staff, the role played by regional centers for drug-safety monitoring, and insufficient understanding of the part taken by patients in the system of PV. The prospects of the Russian PV system and its harmonization with global practice will also be discussed. PMID- 28562117 TI - Omega-3 versus isoflavones in the control of vasomotor symptoms in postmenopausal women. AB - Determine the efficacy and tolerability of omega-3 fatty acids versus soybean isoflavones in reducing the vasomotor symptoms (VMSs) frequency in postmenopausal women. A randomized, prospective, two-arm study was performed in healthy postmenopausal women aged 45-65. The two arms were: two capsules/day of omega-3 (425 mg of omega-3/capsule) administered orally (n = 38) and two tablets/day of soybean isoflavones (54.4 mg of isoflavones/tablet) (n = 30), over 16 weeks. The mean baseline frequency of moderate and severe VMSs per week in the omega-3 group was 24.56 and 23.90, respectively, and 19.65 and 19.51 in the isoflavone group. After 4 months, the reduction in moderate and severe hot flashes with omega-3 was significant (p < .001), whereas in the case of isoflavones, there was a significant difference in severe (p = .02) hot flashes after 4 months, but not in moderate hot flashes (p = .077). Omega-3 did not demonstrate significant efficacy differences versus isoflavones over time. The use of omega-3 has a beneficial effect on hot flash reduction after 4 months of treatment. This is comparable to the benefits found with soybean isoflavones after 3-4 weeks and after 4 months in severe hot flash women, but higher than those found with soybean isoflavones in moderate symptom women. PMID- 28562119 TI - Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal malignancy: preliminary results of a multi-disciplinary teamwork model in Asia. AB - BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is an emerging surgical procedure for peritoneal carcinomatosis (PC). CRS/HIPEC is a complicated treatment that requires multi-disciplinary teamwork (MDT), which may be lacking when establishing a CRS/HIPEC programme. Herein, we report our preliminary treatment outcomes with the early implementation of an MDT model for CRS/HIPEC. METHODS: From April 2015 to December 2016, 45 patients with a diagnosis of PC who received CRS/HIPEC were reviewed retrospectively in a single institution in Taiwan. RESULTS: Among the 45 patients, CRS was mainly performed by laparotomy (n = 42), and only three patients with limited PC underwent laparoscopic CRS. The first 13 patients received treatment before the MDT had been established (group 1), and the other 32 patients were treated after the MDT had been established (group 2). The highest peri-HIPEC body temperature in group 2 was significantly lower than that in group 1 (36.8 degrees C vs. 37.5 degrees C, p < 0.001). Overall, eight patients experienced major complications. The trend of a lower major complication rate was observed after the MDT model had been implemented (30.7% in group 1 vs. 12.4% in group 2, p = 0.202). Pre CRS/HIPEC abdominal pain significantly increased the risk of post-operative major complications (p = 0.017). CONCLUSIONS: Our experience suggests that the early implementation of an MDT model when establishing a CRS/HIPEC programme at a single institution may result in a higher complete cytoreduction rate and lower major complication rate, and also shorten the learning curve of this complicated procedure. PMID- 28562120 TI - Mediterranean diet adherence in the Mediterranean healthy eating, aging and lifestyle (MEAL) study cohort. AB - A decline in adherence to the Mediterranean dietary pattern has been observed over the last years. The aim of this study was to assess the level of adherence to the Mediterranean diet and possible determinants in the Mediterranean healthy Eating, Aging and Lifestyle (MEAL) study cohort. Demographic and dietary data of 1937 individuals were collected in 2014-2015 from the general population of Catania, Sicily (Italy). Food frequency questionnaires and the MEDI-LITE score were used to assess adherence to the Mediterranean diet. The score well characterised consumption of major food groups, micro- and macro-nutrients. The cohort had a general good adherence, but only a minority was highly adherent. High adherence was directly associated with education, non-smoking and physical activity and inversely with high occupational status. In conclusions, Mediterranean diet is still followed in Sicily; however, nutrition education campaigns should promote healthy traditional dietary patterns in certain groups of individuals. PMID- 28562118 TI - MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics. AB - INTRODUCTION: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with chemokine-like functions that increasingly is being studied in different aspects of cardiovascular disease. MIF was first identified as a proinflammatory and pro-survival mediator within the immune system, and a second structurally related MIF family member, D-dopachrome tautomerase (a.k.a. MIF-2), was reported recently. Both MIF family members are released by myocardium and modulate the manifestations of cardiovascular disease, specifically in myocardial ischemia. Areas covered: A scientific overview is provided for the involvement of MIF family cytokines in the inflammatory pathogenesis of atherosclerosis, myocardial infarction, and ischemia-reperfusion injury. We summarize findings of experimental, human genetic and clinical studies, and suggest therapeutic opportunities for modulating the activity of MIF family proteins that potentially may be applied in a MIF allele specific manner. Expert opinion: Knowledge of MIF, MIF-2 and their receptor pathways are under active investigation in different types of cardiovascular diseases, and novel therapeutic opportunities are being identified. Clinical translation may be accelerated by accruing experience with MIF-directed therapies currently in human testing in cancer and autoimmunity. PMID- 28562121 TI - Overweight adolescents and asthma: Revealing motivations and challenges with adolescent-provider communication. AB - OBJECTIVE: Among teens with asthma, challenges of disease management may be greater in those with a body mass index (BMI) >85th percentile compared to youth within the parameters for normal weight-for-age. This mixed-methods study assessed teens' awareness of the link between weight and asthma management, and perspectives on how medical providers might open a discussion about managing weight. METHOD: Teens aged 13-18, having BMI >85 percentile and chronic asthma, identified using health system databases and a staff email message board, were invited to complete a semi-structured, in-depth phone interview. Interviews were audio taped, transcribed, and qualitatively analyzed, using the Framework Method. Responses were summarized and themes identified. Descriptive summaries were generated for a 16-item survey of weight conversation starters. RESULTS: Of 35 teens interviewed, 24 (69%) were girls, 11 (31%) boys, 20 (63%) African-American. All teens reported having "the weight conversation" with their doctors, and preferred that parents be present. Half knew from their doctor about the link between being overweight and asthma, others knew from personal experience. Nearly all expressed the importance of providers initiating a weight management conversation. Most preferred conversation starters that recognized challenges and included parents' participation in weight management; least liked referred to "carrying around too much weight." CONCLUSIONS: Most teens responded favorably to initiating weight loss if it impacted asthma management, valued their provider addressing weight and family participation in weight management efforts. Adolescents' views enhance program development fostering more effective communication targeting weight improvement within the overall asthma management plan. PMID- 28562122 TI - A first trimester prediction model for gestational diabetes utilizing aneuploidy and pre-eclampsia screening markers. AB - OBJECTIVE: We examined whether first trimester aneuploidy and pre-eclampsia screening markers predict gestational diabetes mellitus (GDM) in a large multi ethnic cohort and the influence of local population characteristics on markers. METHODS: Clinical and first trimester markers (mean arterial pressure (MAP), uterine artery pulsatility index (UtA PI), pregnancy associated plasma protein A (PAPP-A), free-beta human chorionic gonadotropin (free-hCGbeta)) were measured in a case-control study of 980 women (248 with GDM, 732 controls) at 11 to 13 + 6 weeks' gestation. Clinical parameters, MAP-, UtA PI-, PAPP-A-, and free-hCGbeta multiples-of-the-median (MoM) were compared between GDM and controls; stratified by ethnicity, parity, and GDM diagnosis <24 versus >=24 weeks' gestation. GDM model screening performance was evaluated using AUROC. RESULTS: PAPP-A- and UtA PI-MoM were significantly lower in GDM versus controls (median ((IQR) PAPP-A-MoM 0.81 (0.58-1.20) versus 1.00 (0.70-1.46); UtA PI-MoM 1.01 (0.82-1.21) versus 1.05 (0.84-1.29); p < .05). Previous GDM, family history of diabetes, south/east Asian ethnicity, parity, BMI, MAP, UtA PI, and PAPP-A were significant predictors in multivariate analysis (p < .05). The AUC for a model based on clinical parameters was 0.88 (95%CI 0.85-0.92), increasing to 0.90 (95%CI 0.87-0.92) with first trimester markers combined. The combined model best predicted GDM <24 weeks' gestation (AUC 0.96 (95%CI 0.94-0.98)). CONCLUSIONS: Addition of aneuploidy and pre-eclampsia markers is cost-effective and enhances early GDM detection, accurately identifying early GDM, a high-risk cohort requiring early detection, and intervention. Ethnicity and parity modified marker association with GDM, suggesting differences in pathophysiology and vascular risk. PMID- 28562123 TI - The role of total body fat mass and trunk fat mass, combined with other endocrine factors, in menstrual recovery and psychopathology of adolescents with Anorexia Nervosa. AB - OBJECTIVE: To determine the threshold of total body and trunk fat mass required for menstrual recovery and to assess the impact of body composition in psychopathology of adolescents with Anorexia Nervosa (AN). METHODS: Prospective study of 60 adolescents presented with secondary amenorrhea and diagnosed with AN. Anthropometrics, body composition by dual-energy X-ray absorptiometry, hormonal studies and responses to mental health screens (EAT-26), were obtained at the beginning and at complete weight restoration, in all adolescents, independently of menstrual recovery (Group A) or not (Group B). RESULTS: At weight restoration, Group A total body fat mass, trunk fat mass, and trunk/extremities fat ratio were significantly higher (p < .001) than Group B. Menstruation was expected in 20% of total body fat mass and 20% of trunk fat mass (% of total trunk tissue). At time of menstrual recovery, total body fat mass (%) and trunk fat mass (%) were significantly negatively correlated with EAT-26 (r = 0.363, p = .032) and (r = -0.416, p = .013), respectively, while an increase of 0.40% of trunk fat mass (%) lowers EAT-26 by one unit. DISCUSSION: Trunk fat mass distribution can positively influence psychopathology of adolescents with AN. PMID- 28562124 TI - Serum stromal-derived-factor-1 (CXCL12) and its alpha chemokine receptor (CXCR4) as biomarkers in neonatal sepsis. AB - BACKGROUND: Neonatal sepsis remains one of the leading causes of morbidity and mortality both among term and preterm infants. Advances in neonatal care improved survival and reduced complications in preterm infants. Chemokines are chemotactic cytokines that give directional guidance for leukocyte migration during inflammatory process. The chemokine CXCL12 and its receptor CXCR4 are now known to play an important role in inflammatory states. However, its value as a biomarker in neonatal sepsis is unclear. OBJECTIVES: To assess the value of measuring the serum levels of alpha-chemokine receptor type 4 (CXCR-4) and stromal-derived-factor-1 (CXCL12) in diagnosis of late onset neonatal sepsis. SUBJECT AND METHODS: Serum levels of CXCL12 and CXCR4 were determined in 38 full term neonates, 23 cases of late onset sepsis (13 males and 10 female), and 15 healthy neonates as control (six males and nine females) by ELISA technique and flow-cytometry. RESULTS: Serum levels of CXCR4 and CXCL12 were significantly higher in neonates with late onset sepsis compared with the non-septic ones. The sensitivity, the specificity, and the overall accuracy of CXCL12 were 100%. The sensitivity of CXCR4 was 87%; the specificity was 80% and the overall accuracy was 84%. CONCLUSIONS: Serum CXCR4 and CXCL12 levels increase significantly in septic neonates and they are valuable marker in diagnosis of neonatal sepsis. Serum concentrations of both chemokines represent promising novel biomarkers for neonatal sepsis. PMID- 28562125 TI - A discrete choice experiment to determine UK patient preference for attributes of disease modifying treatments in Multiple Sclerosis. AB - AIMS: The recent licensing of Disease Modifying Treatments (DMTs) for Multiple Sclerosis (MS) has increased available treatment options. The aim of this study was to explore MS patients' preference for the different attributes of DMTs in the UK. MATERIALS AND METHODS: Attributes (treatment characteristics) for inclusion in the discrete choice experiment (DCE) were determined through published literature and interviews with 12 people with MS. Seven attributes were selected. Participants were presented with three hypothetical treatment options sampled from included attributes and asked for their most/least preferred options. The influence of patient characteristics and demographics on patient preference was also investigated. RESULTS: The DCE was completed by 350 people with MS (81% female, mean age = 39). Results showed that method of taking medication was the strongest determinant of preference (27%; relative importance out of 100%), followed by relapse free rate (21%) and symptom progression (14%). Risk of fatigue (8%) and type of monitoring (6%) were the weakest determinants of preference. Once-daily oral treatment was preferred over all other methods of administration. Participant characteristics did not influence data on strength of preference. LIMITATIONS: This study assumed adequate participant understanding of the discrete choice experiment task, and recruitment targeted those with access to the internet. CONCLUSIONS: These results, derived from people with MS in the UK, should be used to inform individual discussions with patients about DMT choices. PMID- 28562126 TI - A systematic literature review of methods of incorporating mortality in cost effectiveness analyses of lipid-lowering therapies. AB - AIMS: Cost effectiveness analysis (CEA) is a useful tool for estimating the value of an intervention in relation to alternatives. In cardiovascular disease (CVD), CEA is especially important, given the high economic and clinical burden. One key driver of value is CVD mortality prevention. However, data used to inform CEA parameters can be limited, given the difficulty in demonstrating statistically significant mortality benefit in randomized clinical trials (RCTs), due in part to the frequency of fatal events and limited trial durations. This systematic review identifies and summarizes whether published CVD-related CEAs have incorporated mortality benefits, and the methodology among those that did. MATERIALS AND METHODS: A systematic literature review was conducted of CEAs of lipid-lowering therapies published between 2000-2017. Health technology assessments (HTA) and full-length manuscripts were included, and sources of mortality data and methods of applying mortality benefits were extracted. Results were summarized as proportions of articles to articulate common practices in CEAs of CVD. RESULTS: This review identified 100 studies for inclusion, comprising 93 full-length manuscripts and seven HTA reviews. Among these, 99% assumed a mortality benefit in the model. However, 87 of these studies that incorporated mortality differences did so despite the trials used to inform model parameters not demonstrating statistically significant differences in mortality. None of the 12 studies that used statistically significant findings from an individual RCT were based on active control studies. In a sub-group analysis considering the 60 CEAs that incorporated a direct mortality benefit, 48 (80%) did not have RCT evidence for statistically significant benefit in CVD mortality. LIMITATIONS AND CONCLUSIONS: The finding that few CEA models included mortality inputs from individual RCTs of lipid-lowering therapy may be surprising, as one might expect that treatment efficacy should be based on robust clinical evidence. However, regulatory requirements in CVD-related RCTs often lead to insufficient sample sizes and observation periods for detecting a difference in CVD mortality, which results in the use of intermediate outcomes, composite end-points, or meta analysis to extrapolate long-term mortality benefit in a lifetime CEA. PMID- 28562127 TI - Effect of pre-treatment on in vitro gastric digestion of quinoa protein (Chenopodium quinoa Willd.) obtained by wet and dry fractionation. AB - Quinoa protein was isolated from quinoa seeds using wet fractionation that resulted in a protein isolate (QPI) with a high protein purity of 87.1% (w/dw) and a protein yield of around 54%, and a dry fractionation method delivered a quinoa protein concentrate (QPC) with a purity of 27.8% (w/dw) and yield of around 47%. The dry fractionation process only involves milling and sieving and keeps the protein in its natural, native state. The aim was to study the in vitro gastric digestibility of both protein. Attention was paid to thermal pre treatment of QPI and QPC. QPC showed significantly higher (p < .05) digestibility than QPI samples. The results were interpreted with a simple double exponential model. The fraction of easily digested protein in QPC is higher than for QPI. The better digestibility of the QPC was explained by the prevention of the formation of large aggregates during pre-heating of the protein. PMID- 28562128 TI - Recent status of pregnant women with mental disorders at a Japanese perinatal center. AB - INTRODUCTION: Recently, we have been providing comprehensive treatment for pregnant women with mental disorders involving specialists from multiple fields in cooperation with local administrative agencies. In this study, we examined the outcomes of treatment for women with perinatal mental disorders in our institute to evaluate the effect of our recent approach to improve perinatal mental health. METHODS: We retrospectively compared the outcomes between pregnant women with mental disorders who delivered from April 2015 to March 2017 with those from April 2009 to March 2011. We examined the following: presence or absence of necessity of medication, self-interruption of medication, deterioration/relapse of mental disorders, and administrative support. RESULTS: There was no significant difference in the rate of pregnant women with mental disorders between the two periods (3.2 versus 3.2%, respectively, p = .94). The rates of patients requiring medication and those with self-interruption of medication did not reach significance (p = .90 and .19, respectively) between the two periods; however, the rate of patients with deterioration/relapse of mental disorders decreased significantly during pregnancy and postpartum (20.3 versus 10.7 and 7.3 versus 1.7%, p = .04 and .03, respectively). On the other hand, the patients receiving administrative supports increased significantly over the total study period (p < .01). CONCLUSIONS: It was suggested that our recent active management of pregnant women with mental disorders might have contributed to prevent the deterioration/relapse of mental disorders during pregnancy and postpartum. PMID- 28562129 TI - Fetal response to intramuscular epinephrine for anaphylaxis during maternal penicillin desensitization for secondary syphilis. AB - Penicillin desensitization is indicated in pregnant patients with severe allergies to penicillin with syphilis. The immediate effects of intramuscular epinephrine on the fetus during desensitization remain unreported. We describe a pregnant patient with secondary syphilis and penicillin allergy who developed anaphylaxis during penicillin desensitization. Anaphylaxis resolved after administration of intramuscular epinephrine. Throughout the procedure, continuous electronic fetal monitoring showed a stable fetus without a decrease in variability, tachycardia, decelerations, or signs of fetal distress. This case showed that intramuscular epinephrine is effective in treatment of anaphylaxis in a pregnant patient with little to no immediate effects on the fetus. PMID- 28562130 TI - Effects of ospemifene on vaginal epithelium of post-menopausal women. AB - Ospemifene is a selective estrogen receptor modulator used for the treatment of vulvo-vaginal atrophy (VVA) in post-menopausal women. No direct evidence of its effects on histological features of the human vagina has been reported. To evaluate the effects of ospemifene on histological parameters, glycogen content, proliferation, and estrogen receptor alpha expression (ERalpha) of vaginal epithelium in post-menopausal women. Thirty-two post-menopausal women undergoing surgical procedures were enrolled. Sixteen subjects taking ospemifene at the time of inclusion (OSP) were compared to 16 subjects not taking any hormone (CTL). Vaginal biopsies were taken from the proximal and distal vaginal wall during surgery to evaluate histology, Ki-67 and ERalpha expression. OSP group showed thicker vaginal epithelium (349 +/- 64 vs. 245 +/- 53 MUm, p < .001), higher proliferation index (212 +/- 47 vs. 127 +/- 28 Ki-67+ cells/mm, p < .001), higher epithelial (27.3 +/- 3.1 vs. 20.6 +/- 2.9 score, p < .001) and stromal (26.6 +/- 4.9 vs. 20.6 +/- 2.6 score, p < .001) ERalpha expression when compared to the CTL group. In postmenopausal women affected by VVA, 1 month intake of ospemifene is associated with an increased maturation, and ERalpha expression of the vaginal mucosa. These changes may partially explain the improvement of symptoms of vaginal atrophy reported with this drug. PMID- 28562131 TI - Cost reduction from resolution/improvement of carcinoid syndrome symptoms following treatment with above-standard dose of octreotide LAR. AB - AIMS: To calculate the cost reduction associated with diarrhea/flushing symptom resolution/improvement following treatment with above-standard dose octreotide LAR from the commercial payor's perspective. MATERIALS AND METHODS: Diarrhea and flushing are two major carcinoid syndrome symptoms of neuroendocrine tumor (NET). Previously, a study of NET patients from three US tertiary oncology centers (NET 3-Center Study) demonstrated that dose escalation of octreotide LAR to above standard dose resolved/improved diarrhea/flushing in 79% of the patients within 1 year. Time course of diarrhea/flushing symptom data were collected from the NET 3 Center Study. Daily healthcare costs were calculated from a commercial claims database analysis. For the patient cohort experiencing any diarrhea/flushing symptom resolution/improvement, their observation period was divided into days of symptom resolution/improvement or no improvement, which were then multiplied by the respective daily healthcare cost and summed over 1 year to yield the blended mean annual cost per patient. For patients who experienced no diarrhea/flushing symptom improvement, mean annual daily healthcare cost of diarrhea/flushing over a 1-year period was calculated. RESULTS: The economic model found that 108 NET patients who experienced diarrhea/flushing symptom resolution/improvement within 1 year had statistically significantly lower mean annual healthcare cost/patient than patients with no symptom improvement, by $14,766 (p = .03). For the sub-set of 85 patients experiencing resolution/improvement of diarrhea, their cost reduction was more pronounced, at $18,740 (p = .01), statistically significantly lower than those with no improvement; outpatient costs accounted for 56% of the cost reduction (p = .02); inpatient costs, emergency department costs, and pharmacy costs accounted for the remaining 44%. LIMITATIONS: The economic model relied on two different sources of data, with some heterogeneity in the prior treatment and disease status of patients. CONCLUSIONS: Symptom resolution/improvement of diarrhea/flushing after treatment with an above standard dose of octreotide-LAR in NET was associated with a statistically significant healthcare cost decrease compared to a scenario of no symptom improvement. PMID- 28562132 TI - Burden of illness associated with sinusoidal obstruction syndrome/veno-occlusive disease in patients with hematopoietic stem cell transplantation. AB - AIMS: Sinusoidal obstruction syndrome (SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT) associated with significant morbidity and mortality. Healthcare utilization, costs, and mortality were assessed in HSCT patients diagnosed with SOS, with and without multi-organ dysfunction (MOD). MATERIALS AND METHODS: This retrospective observational study identified real-world patients undergoing HSCT between January 1, 2009 and May 31, 2014 using the Premier Healthcare Database. In absence of a formal ICD-9-CM diagnostic code, SOS patients were identified using a pre-specified definition adapted from Baltimore and Seattle criteria and clinical practice. Severe SOS (SOS/MOD) and non-severe SOS (SOS/no-MOD) were classified according to clinical evidence for MOD in the database. RESULTS: Of the 5,418 patients with a discharge diagnosis of HSCT, 291 had SOS, with 134 categorized as SOS/MOD and 157 as SOS/no MOD. The remaining 5,127 patients had HSCT without SOS. Overall SOS incidence was 5.4%, with 46% having evidence of MOD. Distribution of age, gender, and race were similar between the SOS cohorts and non-SOS patients. After controlling for hospital profile and admission characteristics, demographics, and clinical characteristics, the adjusted mean LOS was 31.0 days in SOS/MOD compared to 23.9 days in the non-SOS cohort (medians = 26.9 days vs 20.8 days, p < .001). The adjusted mean cost of SOS/MOD patients was $140,653, which was $41,702 higher than the non-SOS cohort (medians = $105,749 vs $74,395, p < .001). An almost 6 fold increased odds of inpatient mortality was associated with SOS/MOD compared to the non-SOS cohort (odds ratio = 5.88; 95% CI = 3.45-10.33). LIMITATIONS: Limitations of retrospective observational studies apply, since the study was not randomized. Definition for SOS was based on ICD-9 diagnosis codes from a hospital administrative database and reliant on completeness and accuracy of coding. CONCLUSIONS: Analysis of real-world data shows that SOS/MOD is associated with significant increases in healthcare utilization, costs, and inpatient mortality. PMID- 28562134 TI - Contribution of nucleophosmin overexpression to multidrug resistance in breast carcinoma. AB - Multidrug resistance (MDR) is a serious obstacle in breast cancer patients which limits chemotherapeutic drugs application. Our previous study confirmed that overexpression of nucleophosmin (NPM) was closely related to MDR in methotrexate resistant breast cancer cells (MCF-7/MTX), and NPM could be a potential therapeutic target for chemoresistance. In this work, we aim to investigate NPM mediated resistance mechanism in breast carcinoma. The NPM level was strongly positive in breast carcinoma tissues compared with adjacent normal samples, which was associated with lymph node metastasis. We found abnormal expression of NPM activated PI3K/Akt pathway and affected downstream apoptosis factors. Then, NPM level was attenuated by RNA interfering technology, the sensitivity of MCF-7/MTX cells to methotrexate was obviously increased, factor level of mitochondria apoptosis pathway was significantly augmented, and Akt phosphorylation was inhibited. Furthermore, examination of Akt and NPM level demonstrated that Akt inhibitor MK-2206 sensitised resistant cells to methotrexate and induced MCF 7/MTX cell apoptosis by PI3K/Akt pathway and mitochondria apoptosis pathway. These suggested NPM-induced resistance and anti-apoptosis were required for Akt activity. NPM has a crucial function in MDR of breast cancer through influencing Akt activity and resistant cell apoptosis, and it could be expected to become a therapeutic target for chemoresistance in breast cancer. PMID- 28562133 TI - Dietary nitrate does not modify blood pressure and cardiac output at rest and during exercise in older adults: a randomised cross-over study. AB - Dietary nitrate (NO3-) supplementation has been associated with improved vascular and metabolic health. We conducted a double-blind, cross-over, placebo-controlled RCT to investigate the effects of 7-d consumption of beetroot juice compared with placebo on (1) blood pressure (BP) measured in resting conditions and during exercise, (2) cardiac and peripheral vascular function and (3) biomarkers of inflammation, oxidative stress and endothelial integrity. Twenty non-smoking healthy participants aged 60-75 years and BMI 20.0-29.9 kg/m2 were recruited. Measurement was conducted before and after each 7-d intervention period. Consumption of NO3- had no effect on resting systolic and diastolic BP. NO3- consumption did not improve indexes of central and peripheral cardiac function responses during cardiopulmonary exercise testing. Dietary NO3- supplementation did not modify biomarkers of inflammation, oxidative stress and endothelial integrity. This study does not support the short-term benefits of dietary NO3- supplementation on physiological and biochemical markers of vascular health in older healthy adults. PMID- 28562135 TI - A qualitative study of medical educators' perspectives on remediation: Adopting a holistic approach to struggling residents. AB - INTRODUCTION: During residency, some trainees require the identification and remediation of deficiencies to achieve the knowledge, skills and attitudes necessary for independent practice. Given the limited published frameworks for remediation, we characterize remediation from the perspective of educators and propose a holistic framework to guide the approach to remediation. METHODS: We conducted semistructured focus groups to: explore methods for identifying struggling residents; categorize common domains of struggle; describe personal factors that contribute to difficulties; define remediation interventions and understand what constitutes successful completion. Data were analyzed through conventional content analysis. RESULTS: Nineteen physicians across multiple specialties and institutions participated in seven focus groups. Thirteen categories emerged around remediation. Some themes addressed practical components of remediation, while others reflected barriers to the process and the impact of remediation on the resident and program. The themes were used to inform development of a novel holistic framework for remediation. CONCLUSIONS: The approach to remediation requires comprehensive identification of individual factors impacting performance. The intervention should not only include a tailored learning plan but also address confounders that impact likelihood of remediation success. Our holistic framework intends to guide educators creating remediation plans to ensure all domains are addressed. PMID- 28562136 TI - G6PD deficiency and fungal infections in patients with acute myeloid leukemia: less enzyme more fungus. PMID- 28562137 TI - Correction to: Mbatha et al., High-risk human papillomavirus types in HIV infected and HIV-uninfected young women in KwaZulu-Natal, South Africa: implications for vaccination. PMID- 28562138 TI - Unilesional locally recurrent lymphomatoid papulosis with variable histological presentation. PMID- 28562139 TI - Population genetic structure and genetic diversity of Chinese pomfret at the coast of the East China Sea and the South China Sea. AB - The Chinese pomfret Pampus chinensis is one of the most economic and ecological important marine fish species in China. In the present study, the population genetic structure and genetic diversity of P. chinensis were evaluated from a total sample size of 180 individuals representing six populations from the East China Sea and the South China Sea using mitochondrial cytochrome c oxidase subunit I (COI) gene. A total of 24 variable sites (including 3 singleton sites and 21 parsimony information sites) were observed, and 18 haplotypes were defined. The haplotype diversity (Hd) of the populations ranged from 0.559 to 0.775, and the nucleotide diversity (pi) ranged from 0.330 to 1.090%. Analysis of molecular variance (AMOVA) reveals that the main variation (66.02%) was among individuals within populations. The average pairwise differences and phiST values indicated significant genetic differentiation between Dongxing population and the other populations. The results of the present study are helpful for the sustainable management and utilization of this species. PMID- 28562140 TI - The effects of global budget on cost control and readmission in rural China: a difference-in-difference analysis. AB - BACKGROUND: Global budget (GB) is considered one of the most important payment methods available. Since a new round of healthcare system reforms in 2009, the Chinese government has been paying attention to this prospective payment. However, it is unclear whether GB has influenced cost control and how it works in rural China. METHODS: YC county was chosen as the intervention group, with 33,175 inpatients before and 36,883 inpatients after the reform (2012 and 2014, respectively). ZJ county acted as the control group, with 23,668 and 29,555 inpatients, respectively. The inpatients' information was collected from a local insurance agency. The difference-in-difference method (controlling for age, gender, living status, severity of the disease, whether the patient had surgery, the level of medical institutions, and the secular trends of the two groups) was applied to estimate the effects on total spending (TS), reimbursement expense (RE), out-of-pocket payment (OOP), readmission rate, and seven kinds of medical service items. RESULTS: At per practice level, the GB was associated with a Y263.35 (p < .001) and Y447.46 (p < .001) decrease in growth of TS and RE, respectively, while OOP increased by Y188.06 (p < .001). At per capital level, the decrease in growth of TS and RE was Y64.39 (p = .301) and Y467.45 (p < .001), respectively, whereas the increase of OOP was more significant at Y408.19 (p < .001). Savings were concentrated in unclassified items (Y197.68, p < .001), drug prescription (Y69.03, p < .001), surgery (Y40.18, p < .001), cure (Y4.95, p = .565), and diagnosis (Y3.61, p = .064). Meanwhile, the readmission rate increased by 11.4% (p < .001). CONCLUSIONS: The GB has a prominent impact on curbing the growth of insurance fund expenditures, as well as drug and medical consumable costs. However, the patients' out-of-pocket payment has risen. Doctors decomposed hospitalization to deal with supervision, which was harmful to patients. Any medical insurance payment reform should be undertaken prudently, and its likely outcomes should be weighed comprehensively. PMID- 28562141 TI - Hybrid nanoparticles for the topical delivery of norfloxacin for the effective treatment of bacterial infection produced after burn. AB - The present study was designed to investigate the solubility and penetrability of norfloxacin after the topical application of developed lipid-polymer hybrid nanoparticle (LPN) formulation. The core shell of the LPNs formulation was composed of poly (lactic-co-glycolic acid) that is highly lipophilic in nature, thus control the release of drug. The developed formulations were characterised for size, shape (transmission electron microscopy [TEM], scanning electron microscopy [SEM], and atomic force microscopy), entrapment efficiency, Fourier transform infra-red (FTIR) spectroscopy, differential scanning calorimetry (DSC) and thermo gravimetric analysis (TGA). Moreover, in vitro skin permeation studies were performed to determine release profile of the drug. Norfloxacin loaded nanoparticles retained there antimicrobial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa. Stability study was suggested that the suitable storage condition should be at 4 +/- 2 degrees C/60 +/- 5% RH for the LPNs. Therefore, these nanoparticles showed a safe and effective long-lasting approach for long treatment of bacterial infections due to burn. PMID- 28562143 TI - Authors' reply. PMID- 28562142 TI - How do Swedish day center attendees with psychiatric disabilities view their worker role? A structural equation modeling study. AB - AIM: To investigate how day center attendees with psychiatric disabilities perceived their worker role and the importance of current work situation and personal factors in that respect. METHODS: Two-hundred attendees completed the Worker Role Self-assessment and questionnaires addressing possible predictors of the worker role: current employment situation, satisfaction with that situation, and a personal factor (encompassing self-esteem, self-mastery and engagement). Structural equation modeling was used. RESULTS: A model indicated two worker role factors; belief in a future worker role (WR1) and current capacities and routines (WR2). WR1 was positively influenced by having a job, younger age and the personal factor. Satisfaction with current work situation (usually unemployment) was negatively associated with WR1. The personal factor was single predictor of WR2. The attendees rated WR2 more positively than WR1. CONCLUSIONS: The personal factor was crucial for both WR1 and WR2. Work-related factors were only important for WR1. The more negative rating of belief in a future worker role may be interpreted as mistrust in the services. The attendees' positive ratings of capacities indicate, however, that they had a rehabilitation potential to develop. Enhancing self-esteem, mastery and engagement may be an avenue for staff in efforts to support the attendee's worker role. PMID- 28562144 TI - The behavioral deficits and cognitive impairment are correlated with decreased IGF-II and ERK in depressed mice induced by chronic unpredictable stress. AB - AIM: To investigate the behavioral deficits, cognitive impairment and possible mechanisms induced by chronic unpredictable stress (CUS) in mice of different ages. METHODS: The behaviors and cognition were tested using the open field test, tail suspension test and the Morris water maze. The changes in the insulin-like growth factor II (IGF-II) and the extracellular signal-regulated kinase (ERK) and phosphorylation (p-ERK) in the hippocampus (HP) and prefrontal cortex (PFC) were evaluated by immunohistochemistry. RESULTS: The 15-month-old mice revealed a significant decline in spontaneous behavior and the learning-memory function and showed a decrease in IGF-II and p-ERK expression levels in HP and PFC. Four weeks of CUS exposure induced significant anxiety- and depression-like behavior and learning-memory function impairment in 3- to 15-month-old mice, and reduced IGF II and p-ERK expression levels in HP and PFC, compared with control group mice, respectively. CONCLUSIONS: The behavioral deficits and cognitive impairment induced by CUS and aging in mice could be associated with the down-regulated expression of IGF-II and p-ERK in HP and PFC. This role seems to be dependent on the intracellular ERK pathway. PMID- 28562145 TI - Exploring educational interventions to facilitate health professional students' professionally safe online presence. AB - OBJECTIVE: To establish the most effective approach and type of educational intervention for health professional students, to enable them to maintain a professionally safe online presence. METHOD: This was a qualitative, multinational, multi-institutional, multiprofessional study. Practical considerations (availability of participants) led us to use a combination of focus groups and individual interviews, strengthening our findings by triangulating our method of data collection. The study gathered data from 57 nursing, medical and paramedical students across four sites in three countries (Aotearoa/New Zealand, Australia and Wales). A content analysis was conducted to clarify how and why students used Facebook and what strategies they thought might be useful to ensure professional usage. A series of emergent codes were examined and a thematic analysis undertaken from which key themes were crystallized. RESULTS: The results illuminated the ways in which students use social networking sites (SNS). The three key themes to emerge from the data analysis were negotiating identities, distancing and risks. Students expressed the wish to have material about professional safety on SNS taught to them by authoritative figures to explain "the rules" as well as by peers to assist with practicalities. Our interactive research method demonstrated the transformative capacity of the students working in groups. CONCLUSIONS: Our study supports the need for an educational intervention to assist health professional students to navigate SNS safely and in a manner appropriate to their future roles as health professionals. Because health professional students develop their professional identity throughout their training, we suggest that the most appropriate intervention incorporate small group interactive sessions from those in authority, and from peers, combined with group work that facilitates and enhances the students' development of a professional identity. PMID- 28562146 TI - Time trends in pediatric fracture incidence in Sweden during the period 1950 2006. AB - Background and purpose - Pediatric fracture incidence may not be stable. We describe recent pediatric fracture epidemiology and etiology and compare this to earlier data. Patients and methods - The city of Malmo (population 271,271 in 2005) in Sweden is served by 1 hospital. Using the hospital diagnosis registry, medical charts, and the radiographic archive, we identified fractures in individuals <16 years that had occurred during 2005 and 2006. We also retrieved previously collected fracture data from between 1950 and 1994, from the hospital's pediatric fracture database. We used official population data to estimate period-specific fracture incidence (the number of fractures per 105 person-years) and also age- and sex-adjusted incidence. Differences are reported as rate ratios (RRs) with 95% confidence intervals. Results - The pediatric fracture incidence during the period 2005-2006 was 1,832 per 105 person-years (2,359 in boys and 1,276 in girls), with an age-adjusted boy-to-girl ratio of 1.8 (1.6-2.1). Compared to the period 1993-1994, age-adjusted rates were unchanged (RR =0.9, 95% CI: 0.8-1.03) in 2005-2006, with lower rates in girls (RR =0.8, 95% CI: 0.7-0.99) but not in boys (RR =1.0, 95% CI: 0.9-1.1). We also found that the previously reported decrease in unadjusted incidence in Malmo from 1976-1979 to 1993-1994 was based on changes in demography, as the age-adjusted incidences were similar in the 2 periods (RR =1.0, 95% CI: 0.9-1.1). Interpretation - In Malmo, pediatric fracture incidence decreased from 1993-1994 to 2005-2006 in girls but not in boys. Changes in demography, and also other factors, influence the recent time trends. PMID- 28562147 TI - Clinical and radiological findings for early diagnosis of Herlyn-Werner Wunderlich syndrome in pediatric age: experience of a single center. AB - OBJECTIVE: The authors present their experience in the management of pediatric patients with Herlyn-Werner-Wunderlich syndrome (HWWS) considering clinical classification and anatomical characteristics of the malformation. METHODS: All the data of the patient presented at our Pediatric Surgery Unit from February 2010 to August 2015 were collected. According to the type of malformations, patients were divided in 3 groups: A (completely obstructed hemivagina), B (incompletely obstructed hemivagina), and C (communication between the duplicated cervices). RESULTS: Six patients were treated in the study period. The mean age was 9 years (2 months-15 years). According to the characteristics of the HWWS, we had 5 patients in group A, 1 in group B, and none in group C. One-stage surgical treatment was performed in all cases of complete obstruction, but in one case a second look was necessary for a better resection of the septum. At a mean follow up of 18 months all patients were symptoms free. CONCLUSIONS: Prognosis of this malformation is good in case of early diagnosis and treatment. We suggest that when a renal agenesia is diagnosed, the patient needs an ultrasonographic follow up of the contralateral kidney but also of the genital tract to find each minimal abnormalities, furthermore, a MRI scanning before the onset of menstruation can be necessary. PMID- 28562148 TI - Cross-sectional association of exercise, strengthening activities, and cardiorespiratory fitness on generalized anxiety, panic and depressive symptoms. AB - OBJECTIVE: Limited research has evaluated the individual and combined associations of physical activity (PA), cardiorespiratory fitness (CRF) and muscle strengthening activities (MSA) on generalized anxiety, panic and depressive symptoms. We evaluated this topic in a representative sample of young (20-39 years) adults, with considerations by sex. METHODS: Data from the 1999 2004 National Health and Nutrition Examination Survey (N = 2088) were used. Generalized anxiety, panic and depressive symptoms were assessed via self-report as well as using the Generalized Anxiety Disorder, Panic Disorder, and Depressive Disorders modules of the automated version of the World Health Organization Composite International Diagnostic Interview (CIDI-Auto 2.1). PA and MSA were assessed via validated self-report questionnaires and CRF was determined via a submaximal treadmill-based test. An index variable was created summing the number (range = 0-3) of these parameters for each participant. For example, those meeting PA guidelines, MSA guidelines and having moderate-to-high CRF were classified as having an index score of 3. RESULTS: MSA was not independently associated with generalized anxiety, panic and depressive symptoms, but those with higher levels of PA and CRF had a reduced odds of these symptoms (ranging from 40 to 46% reduced odds). Compared to those with an index score of 0, those with an index score of 1, 2, and 3, respectively, had a 39%, 54% and 71% reduced odds of having generalized anxiety, panic and depressive symptoms. Results were consistent across both sexes. CONCLUSION: PA and CRF, but not MSA, were independently associated with generalized anxiety, panic and depressive symptoms. There was evidence of an additive association between PA, CRF, and MSA on these symptoms. PMID- 28562150 TI - Preoperative psychosocial risk factors for poor outcomes at 1 and 5 years after total knee replacement. AB - Background and purpose - Psychosocial factors are important risk factors for poor outcomes in the first year after total knee replacement (TKR), however their impact on long-term outcomes is unclear. We aimed to identify preoperative psychosocial risk factors for poor outcomes at 1 year and 5 years after TKR. Patients and methods - 266 patients were recruited prior to TKR surgery. Knee pain and function were assessed preoperatively and at 1 and 5 years postoperative using the WOMAC Pain score, WOMAC Function score and American Knee Society Score (AKSS) Knee score. Preoperative depression, anxiety, catastrophizing, pain self efficacy and social support were assessed. Statistical analyses involved multiple linear regression and mixed effect linear regression. Results - Higher anxiety was a risk factor for worse pain at 1 year postoperative. No psychosocial factors were associated with any outcomes at 5 years postoperative. Analysis of change over time found that patients with higher pain self-efficacy had lower preoperative pain and experienced less improvement in pain up to 1 year postoperative. Higher pain self-efficacy was associated with less improvement in the AKSS up to 1 year postoperative but more improvement between 1 and 5 years postoperative. Interpretation - Preoperative anxiety was found to influence pain at 1 year after TKR. However, none of the psychosocial variables were risk factors for a poor outcome at 5 years post-operative, suggesting that the negative effects of anxiety on outcome do not persist in the longer-term. PMID- 28562149 TI - In Vivo Laser Confocal Microscopy Using the HRT-Rostock Cornea Module: Diversity and Diagnostic Implications in Patients with Uveitis. AB - PURPOSE: Keratic precipitates (KP) are a common feature of uveitis. We prospectively examined KP with the Heidelberg Retinal Tomograph II confocal laser scanning microscope and Rostock Corneal Module (HRT-RCM) to explore their diagnostic implications. METHODS: Prospective, observational, multicenter study. HRT-RCM images were classified by two masked observers. RESULTS: 120 scans on 120 eyes from 110 subjects were included. The majority (N = 93) had non-infectious uveitis. Sixty eyes had active disease at scanning. Eight KP morphologies were defined. Agreement between the two masked graders was high (Kappa value across all categories = 0.81). Cluster and nodular KP were associated with active infectious uveitis (p < 0.01): patients with cluster KP (odds ratio [OR] = 3.03, 95% confidence interval [CI]: 1.43, 6.45) and nodular KP (OR = 3.89, 95% CI: 1.42, 10.65) were more likely to have infectious uveitis than those without. CONCLUSIONS: Laser confocal microscopy of KP may have a role in determining between infectious and non-infectious uveitis. PMID- 28562152 TI - End-of-life chemotherapy use at a Finnish university hospital: a retrospective cohort study. AB - BACKGROUND: Recent trends in the end-of-life (EOL) cancer care have suggested that the levels of treatment are becoming more aggressive. The aim of this single center study was to evaluate the time from the last intravenous (IV) chemotherapy treatment to death and identify factors correlating with treatment closer to death. MATERIAL AND METHODS: The study included all patients diagnosed with cancer at Turku University Central Hospital between the years 2005 and 2013 (N = 38,982) who received IV chemotherapy during the last year of life (N = 3285). The cohort of patients and their respective clinical information were identified from electronic medical records. Statistical analysis was performed to assess and compare the treatment strategies, taking into account the patient's age, the year they were treated, and the type of cancer they were diagnosed with. RESULTS: A total of 11,250 cancer patients died during the observation time and one-third (N = 3285, 29.2%) of them had received IV chemotherapy during the last year of life. The time from the last IV chemotherapy regimen to death remained consistent across the follow-up time. During the last month of life, every third patient under the age of 50 years and only one-tenth of patients over the age of 80 years received IV chemotherapy. Hematological malignancies and lymphomas were treated closer to death when compared to other diagnostic groups. CONCLUSIONS: During the period of 9 years, the pattern of EOL IV chemotherapy treatment remained stable. Every third patient died at tertiary care. Only 7.2% of patients who received IV chemotherapy during the last year of life were treated 14 days before death, which is in line with international recommendations. However, significant variation in EOL treatment strategies between different diagnosis and age groups were identified. PMID- 28562151 TI - Low-dose splenic irradiation prior to hematopoietic cell transplantation in hypersplenic patients with myelofibrosis. PMID- 28562154 TI - Modelizing home safety as experienced by people with mental illness. AB - RATIONALE: As more individuals with mental disorders now live in the community and as the custodial care housing model has shifted to supported housing, home safety has become a rising issue, however, not well documented. OBJECTIVES: To describe the phenomenon of home safety for people with a mental disorder as well as its contributing factors. METHODS: A descriptive qualitative design was used. Individual interviews were conducted with persons with a mental disorder (n = 8), while focus groups were conducted with relatives, health and social service providers and community stakeholders (n = 21). The data were analyzed with the grounded theory analysis as described by Paille (1994). RESULTS: Findings suggest that home safety implies risk and protective factors, which are associated with (1) the person's characteristics; (2) the quality of the home environment; (3) the nature of the activities in which the individual engages. These dimensions are interrelated so that home incidents arise from a dynamic interaction between risk and protective factors. CONCLUSIONS: Home incidents therefore occur when the interaction between these dimensions is altered. Considering this situation, Occupational Therapists are well positioned to play a leading role and act as key contributors in the area of home safety in people with mental disorders. PMID- 28562153 TI - Increased frequencies of circulating and tumor-resident Vdelta1+ T cells in patients with diffuse large B-cell lymphoma. AB - Gamma-delta (gammadelta) T cells contribute to the innate immune response against cancer. In samples of 20 patients upon DLBCL diagnosis, we found that Vdelta1+ T cells were the major gammadelta T cell subset in tumors and PBMCs of patients, while Vdelta2 T cells were preponderant in PBMCs of healthy subjects. Interestingly, the germinal center (GC) subtype was associated with an increase in Vdelta1+ T cells in tumors, whereas the non-GC subtype was associated with a lower frequency of gammadelta T cells. While circulating Vdelta1+ T cells of patients or HSs mostly exhibited a naive phenotype, the majority of tumor Vdelta1+ T cells showed a central memory phenotype. Resident or circulating gammadelta T cells from patients were not functionally impaired since they produced high levels of IFN-gamma. Collectively, our findings are in favor of gammadelta T cell activation in tumors and open new perspectives for their modulation in DLBCL immunotherapy. PMID- 28562155 TI - Challenges of implementing fibromyalgia treatment guidelines in current clinical practice. AB - The current diagnostic and treatment pathway for patients with fibromyalgia (FM) is lengthy, complex, and characterized by multiple physician visits with an average 2-year wait until diagnosis. It is clear that effective identification and appropriate treatment of FM remain a challenge in current clinical practice. Ideally, FM management involves a multidisciplinary approach with the preferable patient pathway originating in primary care but supported by a range of health care providers, including referral to specialist care when necessary. After the publication of individual clinical studies, high-quality reviews, and meta analyses, recently published FM treatment guidelines have transitioned from an expert consensus to an evidence-based approach. Evidence-based guidelines provide a framework for ensuring early diagnosis and timely adoption of appropriate treatment. However, for successful outcomes, FM treatments must adopt a more holistic approach, which addresses more than just pain. Impact on the associated symptoms of fatigue and cognitive problems, sleep and mood disturbances, and lowered functional status are also important in judging the success of FM therapy. Recently published guidelines recommend the adoption of a symptom-based approach to guide pharmacologic treatment. Emerging treatment options for FM may be best differentiated on the basis of their effect on comorbid symptoms that are often associated with pain (e.g. sleep disturbance, mood, fatigue). The current review discusses the most recently published Canadian guidelines and the implications of the recent European League Against Rheumatism (EULAR) recommendations, with a focus on the challenges of implementing these guidelines in current clinical practice. PMID- 28562156 TI - Neuritin attenuates early brain injury in rats after experimental subarachnoid hemorrhage. AB - OBJECTIVES: Early brain injury (EBI) is central to the pathological progress of subarachnoid hemorrhage (SAH). In this study, we determined if neuritin protects the brain against EBI in rats and discussed the role of apoptosis pathway mediated by endoplasmic reticulum stress in this neuroprotective route. METHODS: A total of 96 male Sprague Dawley rats were divided into control, sham, SAH and SAH + neuritin groups. The rat SAH model was induced by injection 0.3 mL of nonheparinized arterial blood into the prechiasmatic cistern. Mortality assay, neurological scores, brain water content measurement, Evans blue dye assay, TUNEL stain assay and Western blot analysis were performed. RESULTS: Neuritin significantly improved the neurological scores, brain water content, blood-brain barrier (BBB) and apoptosis compared with the control and sham groups within 24 h after SAH. TUNEL staining assay results demonstrated that apoptosis was ameliorated, MMP-9 expression was reduced, whereas GRP78, CHOP, caspase-12 and ASK1 levels were markedly preserved after neuritin application. CONCLUSIONS: Our study demonstrated that neuritin plays a neuroprotective role on EBI after SAH by attenuating BBB disruption, brain edema and apoptosis. PMID- 28562157 TI - Validity of a Chinese version of the Mini Asthma Quality of Life Questionnaire (MiniAQLQ) and a comparison of completion by patients and relatives. AB - OBJECTIVE: To test the psychometric properties of the Chinese version of the Mini Asthma Quality of Life Questionnaire (MiniAQLQ) and to investigate the differences between the MiniAQLQ completed by patients (p-MiniAQLQ) and by their relatives (r-MiniAQLQ). METHODS: One hundred and two asthmatic patients and 45 relatives were recruited. The reliability was evaluated using Cronbach's alpha and intraclass correlation coefficient (ICC). The validity of the MiniAQLQ was assessed by comparing it with the Sydney Asthma Quality of Life Questionnaire (AQLQ-S) and lung function measurements. The mean quality of life scores were compared by gender and smoking history, and the p-MiniAQLQ scores were then compared with the r-MiniAQLQ scores. RESULTS: The MiniAQLQ showed high internal consistency (Cronbach's alpha = 0.901) and a high two-week reproducibility (ICC = 0.863). The cross-sectional correlations between the MiniAQLQ and the AQLQ-S were strong. Correlations between the MiniAQLQ and lung function (predicted FEV1% and PEF) ranged from poor to weak at the total or domain levels. The MiniAQLQ scores were not significantly associated with gender or smoking history. There was poor agreement between the p-MiniAQLQ and r-MiniAQLQ scores at the total or domain levels. CONCLUSIONS: The Chinese version of the MiniAQLQ showed good reliability and validity. It is reliable for evaluating the impact of asthma on patients' quality of life. Relatives of the patients did not have a comprehensive grasp of the patients' conditions. Physicians should be cautious when patients' relatives come to the hospital to seek a modified treatment when the patients are not present. PMID- 28562158 TI - Sulfate-Binding Protein (Sbp) from Xanthomonas citri: Structure and Functional Insights. AB - The uptake and transport of sulfate in bacteria is mediated by an ATP-binding cassette transporter (ABC transporter) encoded by sbpcysUWA genes, whose importance has been widely demonstrated due to their relevance in cysteine synthesis and bacterial growth. In Xanthomonas citri, the causative agent of canker disease, the expression of components from this ABC transporter and others related to uptake of organic sulfur sources has been shown during in vitro growth cultures. In this work, based on gene reporter and proteomics analyses, we showed the activation of the promoter that controls the sbpcysUWA operon in vitro and in vivo and the expression of sulfate-binding protein (Sbp), a periplasmic-binding protein, indicating that this protein plays an important function during growth and that the transport system is active during Citrus sinensis infection. To characterize Sbp, we solved its three-dimensional structure bound to sulfate at 1.14 A resolution and performed biochemical and functional characterization. The results revealed that Sbp interacts with sulfate without structural changes, but the interaction induces a significant increasing of protein thermal stability. Altogether, the results presented in this study show the evidence of the functionality of the ABC transporter for sulfate in X. citri and its relevance during infection. PMID- 28562159 TI - Automatic Associations Between One's Partner and One's Affect as the Proximal Mechanism of Change in Relationship Satisfaction: Evidence From Evaluative Conditioning. AB - The current study examined whether directly altering affective associations involving a relationship partner through evaluative conditioning can lead to changes in relationship satisfaction. Married couples ( N = 144) were asked to view a brief stream of images once every 3 days for 6 weeks. Embedded in this stream were pictures of the partner, which, according to random assignment of couples to experimental group, were paired with either positive or neutral stimuli. Couples also completed measures of automatic partner attitudes and explicit marital satisfaction at baseline and once every 2 weeks for 8 weeks. Spouses who viewed their partners paired with positive stimuli demonstrated more positive automatic partner attitudes than did control spouses, and these attitudes predicted increased self-reported marital satisfaction over time. These results provide novel evidence for a mechanism of change in relationship satisfaction, represent a step toward documenting how strong attitudes can evolve through passive exposure to information, and suggest novel avenues for relationship interventions. PMID- 28562160 TI - Work Experiences of Patients Receiving Palliative Care at a Comprehensive Cancer Center: Exploratory Analysis. AB - BACKGROUND: Employment-related issues have been largely overlooked in cancer patients needing palliative care. These issues may become more relevant as cancer evolves into more of a chronic illness and palliative care is provided independent of stage or prognosis. OBJECTIVE: To characterize the employment situations of working-age palliative care patients. DESIGN: Cross-sectional survey setting/subjects: Consecutive sample of 112 patients followed in palliative care outpatient clinics at a comprehensive cancer center. MEASUREMENTS: Thirty-seven-item self-report questionnaire covering demographics, clinical status, and work experiences since diagnosis. RESULTS: The commonest cancer diagnoses were breast, colorectal, gynecological, and lung. Eighty-one percent had active disease. Seventy-four percent were on treatment. Eighty percent recalled being employed at the time of diagnosis, with 65% working full time. At the time of the survey, 44% were employed and 26% were working full time. Most participants said work was important, made them feel normal, and helped them feel they were "beating the cancer". Factors associated with being employed included male gender, self-employed, and taking less than three months off work. Respondents with pain and/or other symptoms were significantly less likely to be working. On multivariate analysis, only pain (odds ratio [OR] 8.16, p < 0.001) and other physical symptoms (OR 5.90, p = 0.012) predicted work status; gender (OR 2.07), self-employed (OR 3.07), and current chemotherapy (OR 1.81) were included in the model, but were not statistically significant in this small sample. CONCLUSION: Work may be an important issue for some palliative care patients. Additional research is needed to facilitate ongoing employment for those who wish or need to continue working. PMID- 28562162 TI - High percentage of oral lichen planus and lichenoid lesion in oral squamous cell carcinomas. AB - OBJECTIVE: Oral lichen planus (OLP) and lichenoid lesions (OLL) are regarded as precursor lesions of oral squamous cell carcinoma (OSCC) with potential for malignant transformation. This potential is not clear due to difficulties in diagnosis of OLP and OLL. Our aim was therefore to evaluate previously identified OLP and OLL as precursor lesions in OSCC and to identify cancer related etiological factors such as smoking and alcohol consumption. MATERIAL AND METHODS: We retrospectively reviewed all cases (total 323, comprising 164 females and 159 males) with OSCC treated at the Department of Oral and Maxillofacial Diseases and Surgery, Helsinki University Hospital during 2015. Confirmed by histopathological biopsy, 58 (17.9%) had OLP and 13 had OLL (4.0%) as precursor lesion. RESULTS: Patients with OLP were slightly older than those without it. OLP was more common in females than in males (p < .0001). TN class 1 tumors were more prevalent among patients with OLP or OLL (p = .006) and cancer relapses less common (p = .005). Smoking was less frequent in patients with OLP and OLL (p < .0001). Also alcohol abuse was less frequent among these patients (p < .001). CONCLUSION: Our findings confirm the importance of active follow-up of all patients with OLP and OLL even in patients who do not fit a traditional high-risk category for OSCC. PMID- 28562161 TI - PP2A-B56gamma is required for an efficient spindle assembly checkpoint. AB - The Spindle Assembly Checkpoint (SAC) is part of a complex feedback system designed to ensure that cells do not proceed through mitosis unless all chromosomal kinetochores have attached to spindle microtubules. The formation of the kinetochore complex and the implementation of the SAC are regulated by multiple kinases and phosphatases. BubR1 is a phosphoprotein that is part of the Cdc20 containing mitotic checkpoint complex that inhibits the APC/C so that Cyclin B1 and Securin are not degraded, thus preventing cells going into anaphase. In this study, we found that PP2A in association with its B56gamma regulatory subunit, are needed for the stability of BubR1 during nocodazole induced cell cycle arrest. In primary cells that lack B56gamma, BubR1 is prematurely degraded and the cells proceed through mitosis. The reduced SAC efficiency results in cells with abnormal chromosomal segregation, a hallmark of transformed cells. Previous studies on PP2A's role in the SAC and kinetochore formation were done using siRNAs to all 5 of the B56 family members. In our study we show that inactivation of only the PP2A-B56gamma subunit can affect the efficiency of the SAC. We also provide data that show the intracellular locations of the B56 subunits varies between family members, which is consistent with the hypothesis that they are not completely functionally redundant. PMID- 28562163 TI - Everyday life in breast cancer survivors experiencing challenges: A qualitative study. AB - BACKGROUND: Early diagnosis and treatment of breast cancer results in an increasing number of survivors, some of whom face new challenges in their transition to daily life. AIM: Based on these experiences, the aim of this study was to describe the everyday life in breast cancer survivors experiencing challenges. MATERIAL AND METHOD: Eleven women recruited from a follow-up study of breast cancer patients participated in qualitative interviews about their everyday occupations seven years after ending treatment. The inductive analysis revealed ten categories that were organized into five subthemes under the two main themes 'bodily and mental loneliness' and 'new center of gravity in everyday life'. RESULTS: Findings showed how relevant information and guidance; active support to the client and their relatives; and a balance between occupations at home and at work were important matters to handle their everyday life challenges. CONCLUSION AND SIGNIFICANCE: By assisting these women in finding new patterns of meaningful occupations that positively affect their everyday life, the study suggests some central elements to be included in future follow-up practice for breast cancer survivors. Approaching this goal, occupational therapists should contribute to more involvement assisting cancer survivors and their partners in finding new patterns of meaningful occupations that positively affect their everyday life. PMID- 28562164 TI - Exploring the feasibility and usability of the experience sampling method to examine the daily lives of patients with acquired brain injury. AB - The experience sampling method (ESM) is a structured diary method with high ecological validity, in that it accurately captures the everyday context of individuals through repeated measurements in naturalistic environments. Our main objective was to investigate the feasibility of using ESM in individuals with acquired brain injury (ABI). A second goal was to explore the usability of ESM data on a clinical level, by illustrating the interactions between person, environment, and affect. The PsyMate device provided ABI patients (N = 17) with ten signals (beeps) per day during six consecutive days. Each beep was followed by a digital questionnaire assessing mood, location, activities, social context, and physical well-being. Results demonstrated high feasibility with a 71% response rate and a 99% completion rate of the questionnaires. There were no dropouts and the method was experienced as user-friendly. Time-lagged multilevel analysis showed that higher levels of physical activity and fatigue predicted higher levels of negative affect at the same point in time, but not at later time points. This study illustrates the potential of ESM to identify complex person environment dynamics after ABI, while generating understandable and easy to use graphical feedback. PMID- 28562165 TI - HER-2/Epstein-Barr virus crosstalk in human gastric carcinogenesis: A novel concept of oncogene/oncovirus interaction. AB - Gastric cancer is the fourth most common cancer and the second leading cause of cancer deaths worldwide. Additionally, it is well-known that metastatic cancer disease is a major cause of morbidity and mortality in cancer patients. Several investigations reported that HER-2 (ErbB-2 receptor) and Epstein-Barr virus (EBV) are important etiological factors in human gastric cancer, where either oncogene/oncovirus alone can derive a major event of cancer progression and metastasis via epithelial-mesenchymal transition (EMT). Herein, we discuss, for the first time, the possibility of HER-2/EBV-oncoproteins interaction in human gastric cancer initiation and/or progression. PMID- 28562166 TI - Cancer, Financial Burden, and Medicare Beneficiaries. PMID- 28562167 TI - Previously Identified Common Post-Injury Adverse Events in Traumatic Spinal Cord Injury-Validation of Existing Literature and Relation to Selected Potentially Modifiable Comorbidities: A Prospective Canadian Cohort Study. AB - Adverse events (AEs) are common during care in patients with traumatic spinal cord injury (tSCI). Increased risk of AEs is linked to patient factors including pre-existing comorbidities. Our aim was to examine the relationships between patient factors and common post-injury AEs, and identify potentially modifiable comorbidities. Adults with tSCI admitted to a Level I acute specialized spine center between 2006 and 2014 who were enrolled in the Rick Hansen SCI Registry (RHSCIR) and had AE data collected using the Spine Adverse Events Severity system were included. Patient demographic, neurological injury, and comorbidities data were obtained from RHSCIR. Potentially modifiable comorbidities were grouped into health-related conditions, substance use/withdrawal, and psychiatric conditions. Negative binomial regression and multiple logistic regression were used to model the impact of patient factors on the number of AEs experienced and the occurrence of the five previously identified common AEs, respectively. Of the 444 patients included in the study, 24.8% reported a health-related condition, 15.3% had a substance use/withdrawal condition, 8% reported having a psychiatric condition; and 79.3% experienced one or more AEs. Older age (p = 0.004) and more severe injuries (p < 0.001) were nonmodifiable independent variables significantly associated with increased AEs. The AEs experienced by patients were urinary tract infections (42.8%), pneumonia (39.2%), neuropathic pain (31.5%), delirium (18.2%), and pressure ulcers (11.0%). Risk of delirium increased in those with substance use/withdrawal; and pneumonia risk increased with psychiatric comorbidities. Opportunity exists to develop clinical algorithms that include these types of risk factors to reduce the incidence and impact of AEs. PMID- 28562168 TI - The efficacy and safety of tacrolimus monotherapy in adult-onset nephrotic syndrome caused by idiopathic membranous nephropathy. AB - INTRODUCTION: The purpose of the study is to evaluate the efficiency and safety of tacrolimus (TAC) monotherapy in the treatment of nephrotic idiopathic membranous nephropathy (IMN) compared with the protocol of cyclophosphamide (CTX) combined with corticosteroids. METHODS: In total, 58 patients with nephrotic syndrome and biopsy-proven IMN were included in this study. 30 patients received TAC monotherapy with an initial dose of 0.05-0.1 mg/kg/day. 28 patients received transvenous CTX at a dose of 0.5-0.75 g/m2 once in every month initially for 6 months and once in every 2 or 3 months for the later period, and the regimen was combined with corticosteroids (prednisone 1 mg/kg/d). All patients were observed for the treatment effects, recurrence and side effects. RESULTS: Twelve months after the initial treatment, a total of 24 (80%) patients in the TAC group and 23 (82.1%) patients in the CTX group achieved remission (either partial or complete remission). The survival curve of the probability of remission and complete remission were similar between the two groups (p > .05). Proteinuria (based on 24 h urinary protein excretion) was significantly decreased, and serum albumin was significantly increased after immunosuppressive treatment in both the groups. Estimated glomerular filtration rate (eGFR) was comparable between before and after treatment. The main adverse effects in TAC treatment were glucose intolerance, diabetes and abnormal aminotransferase. CONCLUSIONS: TAC monotherapy is an alternative therapeutic regimen for patients with nephrotic IMN. Its short term efficiency and patient tolerance are both acceptable. PMID- 28562170 TI - Pigment epithelial-derived factor in human fetal membranes. AB - OBJECTIVE: Our main objective was to document, pigment epithelial-derived factor (PEDF), a secreted serine protease inhibitor with anti-angiogenic, anti inflammatory, and anti-oxidant properties, expression in human fetal membranes from preterm prelabor rupture of the membranes (pPROM) and in in vitro cultures stimulated with cigarette smoke extract (CSE) or lipopolysaccharides (LPS), two major risk factors for pPROM (behavioral and bacterial, respectively). METHOD: We documented PEDF mRNA expression in clinical samples of fetal membranes from patients with pPROM using quantitative RT-PCR. Also, mRNA and protein levels were documented in fetal membranes (from normal term cesarean sections [not in labor]) in an organ explant system stimulated with CSE or lipopolysaccharide (LPS). Immunohistochemistry (IHC) was used to localize PEDF in fetal membranes. RESULTS: We report no changes in PEDF mRNA expression in pPROM compared to term births (p = .59) or after treatment with CSE or LPS. However, by adding sulforaphane the PEDF mRNA expression increased significantly p < .000032. PEDF was localized to both amnion and chorion layers, but no difference was seen in staining intensities after CSE or LPS treatment compared to control. CONCLUSIONS: PEDF, a product of fetal membrane cells, is unaltered in pPROM or after exposure to risk factors of pPROM. The antioxidant stimulating substance sulforaphane contribute to an increase in PEDF mRNA in fetal membranes. PMID- 28562169 TI - PLK4 phosphorylation of CP110 is required for efficient centriole assembly. AB - Centrioles are assembled during S phase and segregated into 2 daughter cells at the end of mitosis. The initiation of centriole assembly is regulated by polo like kinase 4 (PLK4), the major serine/threonine kinase in centrioles. Despite its importance in centriole duplication, only a few substrates have been identified, and the detailed mechanism of PLK4 has not been fully elucidated. CP110 is a coiled-coil protein that plays roles in centriolar length control and ciliogenesis in mammals. Here, we revealed that PLK4 specifically phosphorylates CP110 at the S98 position. The phospho-resistant CP110 mutant inhibited centriole assembly, whereas the phospho-mimetic CP110 mutant induced centriole assembly, even in PLK4-limited conditions. This finding implies that PLK4 phosphorylation of CP110 is an essential step for centriole assembly. The phospho-mimetic form of CP110 augmented the centrosomal SAS6 level. Based on these results, we propose that the phosphorylated CP110 may be involved in the stabilization of cartwheel SAS6 during centriole assembly. PMID- 28562172 TI - Applying fMRI complexity analyses to the single subject: a case study for proposed neurodiagnostics. AB - Nonlinear dynamic tools have been statistically validated at the group level to identify subtle differences in system wide regulation of brain meso-circuits, often increasing clinical sensitivity over conventional analyses alone. We explored the feasibility of extracting information at the single-subject level, illustrating two pairs of healthy individuals with psychological differences in stress reactivity. We applied statistical and nonlinear dynamic tools to capture key characteristics of the prefrontal-limbic loop. We compared single subject results with statistical results for the larger group. We concluded that complexity analyses may identify important differences at the single-subject level, supporting their potential towards neurodiagnostic applications. PMID- 28562171 TI - Modular Uniportal Video-Assisted Thoracoscopic Lobectomy and Lymphadenectomy: A Novel Pattern of Endoscopic Lung Cancer Resection. AB - BACKGROUND: Since the development of the uniportal video-assisted thoracoscopic surgery (VATS) technique, the use of uniportal VATS has become increasingly popular for the surgical resection of non-small cell lung cancer (NSCLC). The objective of this study is to introduce a novel modularly designed surgical pattern for uniportal VATS for lung cancer resection and to investigate the safety, feasibility, and efficacy of this novel method. MATERIALS AND METHODS: The clinical data of NSCLC patients who underwent a curative uniportal VATS lobectomy between March 2015 and April 2016, including via the modular pattern (MP) and the conventional pattern (CP), were retrospectively collected and analyzed. Perioperative and postoperative parameters, including the operation duration, estimated intraoperative blood loss, rate of conversion to thoracotomy, lymph node dissection number, and postoperative complications, were compared between the two groups. RESULTS: A total of 321 patients were identified, among whom 221 underwent MP uniportal VATS lobectomy and 100 were treated via CP uniportal VATS lobectomy. Patients in the MP group experienced a shorter operation duration (135.58 +/- 47.16 minutes versus 148.86 +/- 42.53 minutes, P = .017) and less estimated intraoperative blood loss (75.20 +/- 37.99 mL versus 89.50 +/- 41.11 mL, P = .003) than patients in the CP group. No significant difference was observed in the intraoperative conversion rate (2.7% versus 5.0%, P = .477), total number of lymph nodes dissected (24.67 +/- 7.73 versus 25.34 +/- 7.62, P = .471), postoperative drainage duration (4.86 +/- 1.96 days versus 4.78 +/- 2.10 days, P = .755), length of stay (9.60 +/- 2.93 days versus 9.97 +/- 2.80 days, P = .286), or incidence of postoperative complications between the two groups. No postoperative deaths occurred. CONCLUSIONS: MP uniportal VATS lobectomy combined with mediastinal lymphadenectomy appears to be a safe and feasible technique for the treatment of NSCLC. The use of this technique can reduce the operation duration and intraoperative blood loss. PMID- 28562173 TI - A novel working memory task for preschoolers: sensitivity to age differences from 3-5 years. AB - Working memory (WM) plays an important role in children's learning and is linked to later academic and occupational success. Understanding the early development of WM can provide critical clues regarding the underlying structure of executive functions and how they change over the life span. The main objectives of the present study were to (1) investigate age differences in the development of three components of WM (retrieval, substitution, transformation) on a novel preschool WM measure and (2) explore whether findings are consistent with the hierarchical model of WM development by examining perseverative and non-perseverative WM errors. Perseverative errors were hypothesized to be more strongly associated with problems substituting and transforming a representation held in mind, whereas non-perseverative errors were hypothesized to be associated with problems maintaining a representation in mind. Participants were 64 children ranging in age from 3.0 to 5.6 years. The results provide evidence for the sensitivity of the WM task to age differences from 3 to 5 years and support for the hierarchical model of WM development. PMID- 28562174 TI - Connecting Online With NASN. PMID- 28562175 TI - Nursing Informatics: Ethical Considerations for Adopting Electronic Records. AB - School districts are commonly adopting electronic storage systems, including electronic health records. Included in this adoption is a move toward cloud-based record storage systems to handle the increasing volumes of data. Deciding which system to adopt is especially difficult in times of tightening school district budgets. While there are several options to consider, including the outright purchase of a proprietary system or choosing one of a relatively new group of free programs, lead nurses must work to ensure that student information is protected and that any chosen system complies with privacy laws. This article provides a case study and presents legal and ethical considerations related to maintaining the privacy of health records in the school setting. PMID- 28562176 TI - Moving in the Wrong Direction - Health Care under the AHCA. PMID- 28562177 TI - Human-leukocyte antigen class II genes in early-onset obsessive-compulsive disorder. AB - OBJECTIVE: The exact aetiology of obsessive-compulsive disorder (OCD) is unknown, although there is evidence to suggest a gene-environment interaction model. Several lines of evidence support a possible role of the immune system in this model. METHODS: The present study explores the allele variability in HLA genes of class II (HLA-DRB1, HLA-DQB1) in a sample of 144 early-onset OCD compared with reference samples of general population in the same geographical area. RESULTS: None of the 39 alleles identified (allele frequency >1%) showed significant differences between OCD and reference populations. Pooling the different alleles that comprised HLA-DR4 (including DRB1*04:01, DRB1*04:04 and DRB1*04:05 alleles) we observed a significantly higher frequency (X21 = 5.53, P = 0.018; OR = 1.64, 95% CI 1.08-2.48) of these alleles in the early-onset OCD sample (10.8%) than in the reference population (6.8%). CONCLUSIONS: Taking into account the role of HLA class II genes in the central nervous system, the results presented here support a role of the immune system in the pathophysiological model of OCD. PMID- 28562178 TI - Corrigendum. PMID- 28562181 TI - Working memory predicts presence of auditory verbal hallucinations in schizophrenia and bipolar disorder with psychosis. AB - OBJECTIVE: The recent dramatic increase in research investigating auditory verbal hallucinations (AVHs) has broadened the former narrow focus on schizophrenia to incorporate additional populations that experience these symptoms. However, an understanding of potential shared mechanisms remains elusive. Based on theories suggesting a failure of top-down cognitive control, we aimed to compare the relationship between AVHs and cognition in two categorical diagnoses of psychosis, schizophrenia and psychotic bipolar disorder. METHOD: A total of 124 adults aged 21-60 participated, of whom 76 had present-state psychosis (schizophrenia, n = 53; bipolar disorder with psychosis, n = 23), and 48 were non clinical controls. Diagnosis and hallucination presence was determined using the Structured Clinical Diagnostic Interview for DSM-IV TR. AVHs severity was assessed using the Positive and Negative Syndrome Scale. Participants also completed the MATRICS cognitive battery. RESULTS: The bipolar disorder with psychosis group performed better than the schizophrenia group for cognitive domains of Processing speed, Attention, Working memory (WM), and Visual memory. Hierarchical binary logistic regression found that WM significantly predicted presence of AVHs in both psychotic groups, but diagnosis did not significantly increase the predictive value of the model. A hierarchical multiple linear regression found that schizophrenia diagnosis was the only significant predictor of hallucination severity. CONCLUSIONS: The findings of this study-the first, to our knowledge, to compare the relationship between AVHs and MATRICS domains across schizophrenia and bipolar disorder with psychosis-support theories that deficits in WM underly the genesis of AVHs. WM potentially represents a shared mechanism of AVHs across diagnoses, supporting dimensional classifications of these psychotic disorders. However, non-cognitive factors predictive of hallucination severity may be specific to schizophrenia. PMID- 28562180 TI - The multi-omics promise in context: from sequence to microbial isolate. AB - The numbers and diversity of microbes in ecosystems within and around us is unmatched, yet most of these microorganisms remain recalcitrant to in vitro cultivation. Various high-throughput molecular techniques, collectively termed multi-omics, provide insights into the genomic structure and metabolic potential as well as activity of complex microbial communities. Nonetheless, pure or defined cultures are needed to (1) decipher microbial physiology and thus test multi-omics-based ecological hypotheses, (2) curate and improve database annotations and (3) realize novel applications in biotechnology. Cultivation thus provides context. In turn, we here argue that multi-omics information awaits integration into the development of novel cultivation strategies. This can build the foundation for a new era of omics information-guided microbial cultivation technology and reduce the inherent trial-and-error search space. This review discusses how information that can be extracted from multi-omics data can be applied for the cultivation of hitherto uncultured microorganisms. Furthermore, we summarize groundbreaking studies that successfully translated information derived from multi-omics into specific media formulations, screening techniques and selective enrichments in order to obtain novel targeted microbial isolates. By integrating these examples, we conclude with a proposed workflow to facilitate future omics-aided cultivation strategies that are inspired by the microbial complexity of the environment. PMID- 28562182 TI - Effect of dual-attention task on attack and defensive actions in fencing. AB - The objectives of this study were to investigate the effect that the presence of two stimuli that require two different responses (dual-attention) has both, on offensive reaction-response time to a light stimulus, and on defensive response time when the stimulus is a real fencing attack. Twenty-five elite fencers and a fencing master were included in the study. The equipment included four force plates adapted to a scaffold that served as a fencing piste. Two force plates were placed, at the start position, under the fencer's feet and another two plates were placed under the master's feet. The results demonstrate that choice reaction time to visual stimuli increases in dual-task conditions with respect to simple reaction time, whereas the mean horizontal force tends to decrease in dual task. However, when the stimulus was an opponent's movement, dual-task conditions did not have any effect on the time required to initiate a defensive action. The changes in reaction time when real movements were used as stimuli challenge the validity of the reaction time to visual stimuli paradigm as a predictor of performance in fencing. Also, the results obtained demonstrate that perceptual and attentional processes play a major role in fencer performance in real competition. PMID- 28562184 TI - In Silico Probe-Based Detection of Citrus Viruses in NGS Data. AB - The conservation of plant biosecurity relies on the rapid identification of pathogenic organisms, including viruses. With next-generation sequencing (NGS), it is possible to identify multiple viruses within a metagenomic sample. In this study, we explored the use of electronic probes (e-probes) for the simultaneous detection of 11 recognized citrus viruses. E-probes were designed and screened against raw sequencing data to minimize the bioinformatic processing time required. The e-probes were able to accurately detect their cognate viruses in simulated datasets, without any false negatives or positives. The efficiency of the e-probe-based approach was validated with NGS datasets generated from different RNA preparations: double-stranded RNA (dsRNA) from 'Mexican' lime infected with different Citrus tristeza virus (CTV) genotypes, dsRNA from field samples, and small RNA and total RNA from grapefruit infected with the CTV T3 genotype. A set of probes was made available that is able to accurately detect CTV in sequence data regardless of the input dataset or the genotype that plants are infected with. PMID- 28562183 TI - * Extracellular Matrices for Bone Regeneration: A Literature Review. AB - The gold standard material for bone regeneration is still autologous bone, a mesenchymal tissue that consists mainly of extracellular matrix (ECM) (90% v/v) and little cellular content (10% v/v). However, the fact that decellularized allogenic bone grafts often present a clinical performance comparable to autologous bone grafts demonstrates the crucial role of ECM in bone regeneration. For long, the mechanism by which bone allografts function was not clear, but recent research has unveiled many unique characteristics of ECM that seem to play a key role in tissue regeneration. This is further confirmed by the fact that synthetic biomaterials with composition and properties resembling bone ECM present excellent bone regeneration properties. In this context, ECM molecules such as glycosaminoglycans (GAGs) and self-assembly peptides (SAPs) can improve the performance of bone regeneration biomaterials. Moreover, decellularized ECM derived either from native tissues such as bone, cartilage, skin, and tooth germs or from cells such as osteoblasts, chondrocytes, and stem cells has shown promising results in bone regeneration applications. Understanding the role of ECM in bone regeneration is crucial for the development of the next generation of biomaterials for bone tissue engineering. In this sense, this review addresses the state-of-the-art on this subject matter. PMID- 28562185 TI - * Hypoxia Biomimicry to Enhance Monetite Bone Defect Repair. AB - Tissue hypoxia is a critical driving force for angiogenic and osteogenic responses in bone regeneration and is, at least partly, under the control of the Hypoxia Inducible Factor-1alpha (HIF-1alpha) pathway. Recently, the widely used iron chelator deferoxamine (DFO) has been found to elevate HIF-1alpha levels independent of oxygen concentrations, thereby, creating an otherwise normal environment that mimics the hypoxic state. This has the potential to augment the biological properties of inorganic scaffolds without the need of recombinant growth factors. This pilot study investigates the effect of local delivery of DFO on bone formation and osseointegration of an anatomically matched bone graft substitute, in the treatment of segmental bone defects. Three-dimensional printing was used to create monetite grafts, which were implanted into 10 mm midshaft ulnar defects in eight rabbits. Starting postoperative day 4, one graft site in each animal was injected with 600 MUL (200 MUM) of DFO every 48 h for six doses. Saline was injected in the contralateral limb as a control. At 8 weeks, micro-CT and histology were used to determine new bone growth, vascularity, and assess osseointegration. Six animals completed the protocol. Bone metric analysis using micro-CT showed a significantly greater amount of new bone formed (19.5% vs. 13.65% p = 0.042) and an increase in bone-implant contact area (63.1 mm2 vs. 33.2 mm2 p = 0.03) in the DFO group compared with control. Vascular channel volume was significantly greater in the DFO group (20.9% vs. 16.2% p = 0.004). Histology showed increased bone formation within the osteotomy gap, more bone integrated with the graft surface as well as more matured soft tissue callus in the DFO group. This study demonstrates a significant increase in new bone formation after delivery of DFO in a rabbit long bone defect bridged by a 3D printed bioresorbable bone graft substitute. Given the safety, ease of handling, and low expense of this medication, the results of this study support further investigation into the use of iron chelators in creating a biomimetic environment for bone healing in segmental bone loss. PMID- 28562187 TI - A rare 'incidentaloma' found on low-dose CT screening for lung cancer: 'scanner beware'. AB - Screening for lung cancer with low-dose computed tomography (LDCT) has been shown to reduce mortality and has been recommended by the U.S. Preventive Services Task Force for adults 55 to 80 years of age with a 30 pack-year smoking history who are either current smokers or those that quit within 15 years. However, the overwhelming majority of abnormalities detected are not from malignancy. We report a case of pulmonary Langerhans' cell histiocytosis, here-to-fore thought of as extremely uncommon, and make readers aware that this may be increasingly found as LDCT is more widely adopted. PMID- 28562186 TI - The appropriateness of training exposures for match-play preparation in adolescent schoolboy and academy rugby union players. AB - The aim of this study was to compare the physical and movement demands between training and match-play in schoolboy and academy adolescent rugby union (RU) players. Sixty-one adolescent male RU players (mean +/- SD; age 17.0 +/- 0.7 years) were recruited from four teams representing school and regional academy standards. Players were categorised into four groups based on playing standard and position: schoolboy forwards (n = 15), schoolboy backs (n = 15), academy forwards (n = 16) and academy backs (n = 15). Global positioning system and accelerometry measures were obtained from training and match-play to assess within-group differences between conditions. Maximum data were analysed from 79 match files across 8 matches (1.3 +/- 0.5 matches per participant) and 152 training files across 15 training sessions (2.5 +/- 0.5 training sessions per participant). Schoolboy forwards were underprepared for low-intensity activities experienced during match-play, with schoolboy backs underprepared for all movement demands. Academy forwards were exposed to similar physical demands in training to matches, with academy backs similar to or exceeding values for all measured variables. Schoolboy players were underprepared for many key, position specific aspects of match-play, which could place them at greater risk of injury and hinder performance, unlike academy players who were better prepared. PMID- 28562188 TI - Nitrogen and phosphorus removed from a subsurface flow multi-stage filtration system purifying agricultural runoff. AB - : Agricultural nonpoint source pollution has been increasingly serious in China since the 1990s. The main causes were excessive inputs of nitrogen fertilizer and pesticides. A multi-stage filtration system was built to test the purification efficiencies and removal characteristics of nitrogen and phosphorus when treating agricultural runoff. Simulated runoff pollution was prepared by using river water as source water based on the monitoring of local agricultural runoff. Experimental study had been performed from September to November 2013, adopting 12 h for flooding and 12 h for drying. The results showed that the system was made adaptive to variation of inflow quality and quantity, and had good removal for dissolved total nitrogen, total nitrogen, dissolved total phosphorus (DTP), and total phosphorus, and the average removal rate was 27%, 36%, 32%, and 48%, respectively. Except nitrate ([Formula: see text]), other forms of nitrogen and phosphorus all decreased with the increase of stages. Nitrogen was removed mainly in particle form the first stage, and mostly removed in dissolved form the second and third stage. Phosphorus was removed mainly in particulate during the first two stages, but the removal of particulate phosphorus and DTP were almost the same in the last stage. An approximate logarithmic relationship between removal loading and influent loading to nitrogen and phosphorus was noted in the experimental system, and the correlation coefficient was 0.78-0.94. ABBREVIATIONS: [Formula: see text]: ammonium; [Formula: see text]: nitrite; [Formula: see text]: nitrate; DTN: dissolved total nitrogen; TN: total nitrogen; DTP: dissolved total phosphorus; TP: total phosphorus; PN: particulate nitrogen; PP: particulate phosphorus. PMID- 28562189 TI - Surfactant-enhanced bioremediation of DDTs and PAHs in contaminated farmland soil. AB - Field-scale bioremediation of dichlorodiphenyl trichloroethanes (DDTs) and polycyclic aromatic hydrocarbons (PAHs) contaminated farmland soil from the Shenyang North New Area of China was studied using the bacteria Arthrobacter globiformis. The additive effects of different concentrations of biosurfactant rhamnolipids (RLs) and anionic-nonionic mixed surfactant (SDBS-Tween 80) were evaluated. DDT and PAH removal rates by A. globiformis after 150 days of remediation were 52.1% and 21.9%, respectively. At the optimum RL concentration of 5 mg kg-1, DDTs and PAHs had removal rates of 64.3% and 35.6%, respectively, at 150 days. This was 60.7% and 29.3% higher than the control; 36.9% and 19.8% higher than soil with RL-5 alone; and 12.2% and 13.8% higher than the A. globiformis treatment alone. RL-5 can enhance soil enzyme activity and A. globiformis reproduction during the DDT and PAH biodegradation processes. This study illustrates a highly efficient, low-cost in situ soil bioremediation technology that could have practical utility. PMID- 28562190 TI - Catechin-loaded Eudragit microparticles for the management of diabetes: formulation, characterization and in vivo evaluation of antidiabetic efficacy. AB - Catechin (CT) is natural molecule proved for antidiabetic activity. Clinical application of CT is highly restricted because of its low bioavailability and ineffectiveness in in vivo conditions. Therefore, the main objective of the present investigation was to formulate CT-loaded Eudragit RS 100 microparticles and evaluated for its potential against diabetes. CT microparticles showing highest entrapment efficiency of 92.3 +/- 6.5% and higher percentage yield of 63.46 +/- 4.3% was selected as optimised formulation. CT microparticles treated rats showed significantly lower blood glucose, cholesterol, LDL, free fatty acid and triglyceride concentrations in comparison to pristine CT-treated rats. The glucose and lipid profiles of microparticle formulation were akin to normal rats. Moreover, CT microparticles did not produce obesity even after 60 days which is a comment side effect of antidiabetic drugs. These results indicate that the CT microparticles can be applied as potential and safe carrier for the treatment of diabetes. PMID- 28562192 TI - The stability of drinking water treatment residue with ozone treatment. AB - The best management of drinking water treatment residue (DWTR) in environmental remediation should be based on comprehensively understanding the effectiveness and risk of DWTR. In this study, the variation in physicochemical properties, metal lability, and adsorption capability of DWTR under oxidizing condition were investigated. The oxidizing condition was set up using ozone treatment, and the laboratory incubation test were performed within 50 d in association with thermogravimetry, Fourier Transform Infrared Spectrometry, specific surface area and porosity analyzer, fractionation, and P adsorption test. The results showed that ozone treatment had limited effect on the properties of organic matter, the lability of Al, Cu, and Fe, the P adsorption capability, and the distributions of the adsorbed P in DWTR, but the treatment increased N2 sorption/desorption, specific surface area, total pore volume of DWTR and led to the transformation of Mn from acid-soluble to reducible fractions. These findings demonstrated that DWTR generally kept stable under oxidizing environment; even oxidizing environment may induce a tendency of increasing the adsorption capability and decreasing the environmental risk of DWTR. Accordingly, the effectiveness and safety of DWTR can be maintained under natural aerobic environment, and DWTR is a reliable adsorbent that could be recycled in environmental remediation. PMID- 28562191 TI - Explaining mental health inequalities in Northern Sweden: a decomposition analysis. AB - BACKGROUND: There has been a substantial increase of income inequalities in Sweden over the last 20 years, which also could be reflected in health inequalities, including mental health inequalities. Despite the growing body of literature focusing on health inequalities in Sweden, income-related inequalities in mental health have received little attention. Particularly scarce are research from Northern Sweden and examinations of the social determinants of health inequalities. OBJECTIVES: The present study seeks to provide evidence regarding inequalities in mental health in Northern Sweden. The specific aims were to (1) quantify the income-related inequality in mental health in Northern Sweden, and (2) determine the contribution of social determinants to the inequality. METHODS: The study population comprised 25,646 participants of the 2014 Health on Equal Terms survey in the four northernmost counties of Sweden, aged 16 to 84 years old. Income-related inequalities in mental health were quantified by the concentration index and further decomposed by applying Wagstaff-type decomposition analysis. RESULTS: The overall concentration index of mental health in Northern Sweden was -0.15 (95% CI: -0.17 to -0.13), indicating income inequalities in mental health disfavoring the less affluent population. The decomposition analysis results revealed that socio-economic conditions, including employment status (31%), income (22.6%), and cash margin (14%), made the largest contribution to the pro-rich inequalities in mental health. The second-largest contribution came from demographic factors, mainly age (11.3%) and gender (6%). Psychosocial factors were of smaller importance, with perceived discrimination (8%) and emotional support (3.4%) making moderate contributions to the health inequalities. CONCLUSIONS: The present study demonstrates substantial income related mental health inequalities in Northern Sweden, and provides insights into their underpinnings. These findings suggest that addressing the root causes is essential for promoting mental health equity in this region. PMID- 28562193 TI - Mentoring relationships between senior physicians and junior doctors and/or medical students: A thematic review. AB - INTRODUCTION: Mentoring relationships are pivotal to the outcome of the mentoring process. This thematic review seeks to study the key aspects of mentoring relationships between senior physicians and junior doctors and/or medical students to inform efforts to improve mentoring programs. METHODS: Literature search was performed on publications across PubMed, ERIC, Cochrane Database of Systematic Reviews, OVID and ScienceDirect databases between 1 January 2000 and 31 December 2015 by three independent reviewers. The BEME guide and STORIES statement were used to develop a narrative from the articles selected. RESULTS: Thematic analysis of 49 articles reveals five semantic themes of initiation process, developmental process, evaluation process, sustaining mentoring relationship, and obstacles to effective mentoring. The evolving and relational dependent nature of mentoring pivots upon the compatibility of mentors and mentees and the quality of their interactions, which in turn depend on mentoring environments and awareness of mentor-, mentee-, organizational-related factors and changes in context and goals. CONCLUSIONS: Embrace of a consistent mentoring approach to ensure effective oversight of the mentoring process must be balanced with sufficient flexibility to ensure a mentee-centered approach. Efforts must be made to optimize the key aspects of mentoring relationships in order to ensure successful mentoring processes and outcomes. PMID- 28562196 TI - Antitumor and Anti-Hepatitis C Viral Response After Administration of the Anti Programmed Death 1 Antibody Pembrolizumab. PMID- 28562195 TI - mHealth App for Risk Assessment of Pigmented and Nonpigmented Skin Lesions-A Study on Sensitivity and Specificity in Detecting Malignancy. AB - BACKGROUND: With the advent of smartphone devices, an increasing number of mHealth applications that target melanoma identification have been developed, but none addresses the general context of melanoma and nonmelanoma skin cancer identification. INTRODUCTION: In this study a smartphone application using fractal and classical image analysis for the risk assessment of skin lesions is systematically evaluated to determine its sensitivity and specificity in the diagnosis of melanoma and nonmelanoma skin cancer along with actinic keratosis and Bowen's disease. MATERIALS AND METHODS: In the Department of Dermatology, Catharina Hospital Eindhoven, The Netherlands, 341 melanocytic and nonmelanocytic lesions were imaged using SkinVision app; 239 underwent histopathological examination, while the rest of 102 lesions were clinically diagnosed as clearly benign and not removed. The algorithm has been calibrated using the images of the first 233 lesions. The calibrated version of the algorithm was used in a subset of 108 lesions, and the obtained results were compared with the medical findings. RESULTS: On the 108 cases used for evaluation the algorithm scored 80% sensitivity and 78% specificity in detecting (pre)malignant conditions. DISCUSSION: Although less accurate than the dermatologist's clinical eye, the app may offer support to other professionals who are less familiar with differentiating between benign and malignant lesions. CONCLUSION: An mHealth application for the risk assessment of skin lesions was evaluated. It adds value to diagnosis tools of its type by taking into consideration pigmented and nonpigmented lesions all together and detecting signs of malignancy with high sensitivity. PMID- 28562194 TI - The cart before the horse: When cognitive neuroscience precedes cognitive neuropsychology. AB - Cognitive neuropsychology (CN) has had an immense impact on the understanding of the normal cognitive processes underlying reading, spelling, spoken language comprehension and production, spatial attention, memory, visual perception, and orchestration of actions, through detailed analysis of behavioural performance by neurologically impaired individuals. However, there are other domains of cognition and communication that have rarely been investigated with this approach. Many cognitive neuropsychologists have extended their work in language, perception, or attention by turning to functional neuroimaging or lesion-symptom mapping to identify the neural mechanisms underlying the cognitive mechanisms they have identified. Another approach to extending one's research in CN is to apply the methodology to other cognitive functions. We briefly review the domains evaluated using methods of CN to develop cognitive architectures and computational models and the domains that have used functional neuroimaging and other brain mapping approaches in healthy controls to identify the neural substrates involved in cognitive tasks over the past 20 years. We argue that in some domains, neuroimaging studies have preceded the careful analysis of the cognitive processes underlying tasks that are studied, with the consequence that results are difficult to interpret. We use this analysis as the basis for discussing opportunities for expanding the field. PMID- 28562197 TI - Improving End-of-Life Care: Palliative Care Embedded in an Oncology Clinic Specializing in Targeted and Immune-Based Therapies. AB - PURPOSE: Patients with advanced cancer benefit from early involvement of palliative care. The ideal method of palliative care integration remains to be determined, as does its effectiveness for patients treated with targeted and immune-based therapies. MATERIALS AND METHODS: We studied the impact of an embedded palliative care team that saw patients in an academic oncology clinic specializing in targeted and immune-based therapies. Patients seen on a specific day accessed the embedded model, on the basis of automatic criteria; patients seen other days could be referred to a separate palliative care clinic (usual care). We abstracted data from the medical records of 114 patients who died during the 3 years after this model's implementation. RESULTS: Compared with usual care (n = 88), patients with access to the embedded model (n = 26) encountered palliative care as outpatients more often ( P = .003) and earlier (mean, 231 v 109 days before death; P < .001). Hospice enrollment rates were similar ( P = .303), but duration was doubled (mean, 57 v 25 days; P = .006), and enrollment > 7 days before death-a core Quality Oncology Practice Initiative metric-was higher in the embedded model (odds ratio, 5.60; P = .034). Place of death ( P = .505) and end-of-life chemotherapy (odds ratio, 0.361; P = .204) did not differ between the two arms. CONCLUSION: A model of embedded and automatically triggered palliative care among patients treated exclusively with targeted and immune-based therapies was associated with significant improvements in use and timing of palliative care and hospice, compared with usual practice. PMID- 28562198 TI - Challenges for providing health care in traumatized populations: barriers for PTSD treatments and the need for new developments. AB - There is a growing recognition about the effects of traumatic experiences on mental health worldwide. With ongoing conflicts, natural disasters, interpersonal violence, and other traumatic events it is estimated that approximately 70% of the global population have been exposed to at least one lifetime traumatic experience. Research shows a substantial proportion of survivors, especially in low- and middle-income countries, would have a posttraumatic stress disorder (PTSD). During recent decades effective evidence-based treatments for PTSD have been developed. However, there are significant barriers to mental health services and trauma-informed treatments are not easily available for trauma survivors. From the perspective of social psychotraumatology several core barriers to trauma treatments were identified, including the lack of acknowledgment, and avoidance of disclosure. The need for cultural sensitivity in PTSD treatments, the potential of alternative ways of treatment delivery, and the involvement of non professional volunteers are proposed as directions for future developments in the field. PMID- 28562201 TI - Electrochemotherapy and calcium electroporation inducing a systemic immune response with local and distant remission of tumors in a patient with malignant melanoma - a case report. PMID- 28562200 TI - Underutilization of proton therapy in the treatment of pediatric central nervous system tumors: an analysis of the National Cancer Database. PMID- 28562202 TI - A case of isolated small cell carcinoma of the brain. PMID- 28562199 TI - Delivery of Community-Based Palliative Care: Findings from a Time and Motion Study. AB - BACKGROUND: Use of palliative care has increased substantially as the population ages and as evidence for its benefits grows. However, there is limited information regarding which care activities are necessary for delivering high quality, interdisciplinary, community-based palliative care. OBJECTIVES: This study aims to identify and measure the discrete clinical and administrative activities completed by a multidisciplinary team in a hospice provider-led model for providing community-based palliative care. STUDY DESIGN: A time and motion study was conducted at three care settings within a large hospice and palliative care network and a process map was drawn to describe the personnel and activities recorded. METHODS: Researchers recorded activities performed by clinical and administrative staff. Activities were categorized into those related to patient care, administrative duties, care coordination, and other. A process map of palliative care delivery was created and descriptive statistics were used to calculate the proportion of time spent on discrete activities and within each activity category. RESULTS: Over 50 hours of activities were recorded during which the clinicians interacted with 25 patients and engaged in 20 distinct tasks. Physicians spent 94% of their time on tasks related to patient care and 1% on administrative tasks. Nurse practitioners and registered nurses spent 82% and 53% of their time on patient-related tasks and 2% and 37% on administrative tasks, respectively. CONCLUSION: The delivery of palliative care is interdisciplinary and involves numerous discrete tasks and activities. Understanding the components of a community-based palliative care model is the first step to designing incentives to encourage its spread. PMID- 28562203 TI - Is Hepatic Triglyceride Content Associated with Aortic Pulse Wave Velocity and Carotid Intima-Media Thickness? The Netherlands Epidemiology of Obesity Study. AB - Purpose To test the hypothesis that hepatic triglyceride content is associated with subclinical vascular impairment and is not confounded by various cardiometabolic risk factors. Materials and Methods This study was approved by the institutional review board, and all participants gave written informed consent. In this cross-sectional analysis of baseline measurements of the Netherlands Epidemiology of Obesity study, a population-based cohort study, 1899 participants (52% men; mean age, 55 years +/- 6 [standard deviation]) underwent magnetic resonance (MR) spectroscopy and MR imaging to assess hepatic triglyceride content, aortic pulse wave velocity (PWV), and visceral fat. Carotid intima-media thickness (IMT) was acquired and measured by trained research nurses according to standard procedures. Multivariate regression analyses were used to study associations of hepatic triglyceride content with total and regional aortic PWV and carotid IMT while adjusting for several possible confounding factors, including the metabolic syndrome. Results Total aortic PWV (mean difference, 0.5 m/sec; 95% confidence interval [CI]: 0.3, 0.7) and carotid IMT (mean difference, 37 MUm; 95% CI: 25, 49) were higher in participants with hepatic steatosis. After adjusting for various covariates, a 10-fold increase in hepatic triglyceride content was associated with an increased mean aortic PWV of 0.19 m/sec (95% CI: 0.03, 0.36) in total and an increased mean aortic PWV of 0.42 m/sec (95% CI: 0.03, 0.81) in the abdominal segment. A 10-fold increase in hepatic triglyceride content was also associated with an increased mean carotid IMT of 15 MUm (95% CI: 0, 29) but not after additional adjustments for visceral and total body fat. Conclusion In this relatively large population-based cohort study, hepatic triglyceride content was associated with aortic pulse wave velocity and carotid IMT. These associations were only partly explained by the metabolic syndrome and visceral adiposity, suggesting a possible specific contribution of hepatic steatosis to subclinical vascular impairment. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28562204 TI - Contrast-enhanced MR Imaging versus Contrast-enhanced US: A Comparison in Glioblastoma Surgery by Using Intraoperative Fusion Imaging. AB - Purpose To compare contrast material enhancement of glioblastoma multiforme (GBM) with intraoperative contrast-enhanced ultrasonography (US) versus that with preoperative gadolinium-enhanced T1-weighted magnetic resonance (MR) imaging by using real-time fusion imaging. Materials and Methods Ten patients with GBM were retrospectively identified by using routinely collected, anonymized data. Navigated contrast-enhanced US was performed after intravenous administration of contrast material before tumor resection. All patients underwent tumor excision with navigated intraoperative US guidance with use of fusion imaging between real time intraoperative US and preoperative MR imaging. With use of fusion imaging, glioblastoma contrast enhancement at contrast-enhanced US (regarding location, morphologic features, margins, dimensions, and pattern) was compared with that at gadolinium-enhanced T1-weighted MR imaging. Results Fusion imaging for virtual navigation enabled matching of real-time contrast-enhanced US scans to corresponding coplanar preoperative gadolinium-enhanced T1-weighted MR images in all cases, with a positional discrepancy of less than 2 mm. Contrast enhancement of gadolinium-enhanced T1-weighted MR imaging and contrast-enhanced US was superimposable in all cases with regard to location, margins, dimensions, and morphologic features. The qualitative analysis of contrast enhancement pattern demonstrated a similar distribution in contrast-enhanced US and gadolinium enhanced T1-weighted MR imaging in nine patients: Seven lesions showed peripheral inhomogeneous ring enhancement, and two lesions showed a prevalent nodular pattern. In one patient, the contrast enhancement pattern differed between the two modalities: Contrast-enhanced US showed enhancement of the entire bulk of the tumor, whereas gadolinium-enhanced T1-weighted MR imaging demonstrated peripheral contrast enhancement. Conclusion Glioblastoma contrast enhancement with contrast enhanced US is superimposable on that provided with preoperative gadolinium enhanced T1-weighted MR imaging regarding location, margins, morphologic features, and dimensions, with a similar enhancement pattern in most cases. Thus, contrast-enhanced US is of potential use in the surgical management of GBM. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28562205 TI - Diameter of the Pulmonary Artery in Relation to the Ascending Aorta: Association with Cardiovascular Outcome. AB - Purpose To investigate whether the pulmonary artery (PA)-to-ascending aorta (Ao) ratio is associated with outcome in unselected patients referred for cardiac magnetic resonance (MR) imaging. Materials and Methods This study prospectively enrolled 650 consecutive patients (47.2% women; mean age, 56.1 years +/- 17.7 [standard deviation]). Diameters of PA and Ao were measured in axial black blood images. On the basis of previous results, a PA-to-Ao ratio of 1.0 or greater was chosen as the cutoff for further analysis. Univariable and multivariable Cox regression models were used to investigate the primary end point, which was defined as a composite of cardiovascular hospitalization and death. Results A PA to-Ao ratio of 1.0 or greater was present in 131 (20.2%) patients. Patients with a PA-to-Ao ratio of 1.0 or greater were predominantly women (P = .010); more frequently presented with atrial fibrillation (P < .001), diabetes (P < .001), and impaired renal function (P < .001); and had higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (P < .001), larger left (P = .023) and right ventricles (RV; P = .002), and worse RV function (P < .001). Patients were followed for 17.8 months +/- 12.9, during which 110 patients (16.9%) reached the primary end point. By Kaplan-Meier analysis, event-free survival was significantly worse in patients with a PA-to-Ao ratio of 1.0 or greater (log-rank test, P < .001). A PA-to-Ao ratio of 1.0 or greater was independently associated with outcome by multivariable Cox regression analysis, in addition to age, NT proBNP serum levels, and RV size. Conclusion A PA-to-Ao ratio of 1.0 or greater identified patients at risk, most likely because of elevated PA pressures. On the basis of these results, the PA-to-Ao ratio should routinely be reported at cardiac MR imaging. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28562208 TI - Prefrontal Cortex in Control: Broadening the Scope to Identify Mechanisms. AB - Sometime in the past two decades, neuroimaging and behavioral research converged on pFC as an important locus of cognitive control and decision-making, and that seems to be the last thing anyone has agreed on since. Every year sees an increase in the number of roles and functions attributed to distinct subregions within pFC, roles that may explain behavior and neural activity in one context but might fail to generalize across the many behaviors in which each region is implicated. Emblematic of this ongoing proliferation of functions is dorsal ACC (dACC). Novel tasks that activate dACC are followed by novel interpretations of dACC function, and each new interpretation adds to the number of functionally specific processes contained within the region. This state of affairs, a recurrent and persistent behavior followed by an illusory and transient relief, can be likened to behavioral pathology. In Journal of Cognitive Neuroscience, 29:10 we collect contributed articles that seek to move the conversation beyond specific functions of subregions of pFC, focusing instead on general roles that support pFC involvement in a wide variety of behaviors and across a variety of experimental paradigms. PMID- 28562207 TI - Social and Nonsocial Relational Reasoning in Adolescence and Adulthood. AB - Reasoning during social interactions requires the individual manipulation of mental representations of one's own traits and those of other people as well as their joint consideration (relational integration). Research using nonsocial paradigms has linked relational integration to activity in the rostrolateral PFC. Here, we investigated whether social reasoning is supported by the same general system or whether it additionally relies on regions of the social brain network, such as the medial PFC. We further assessed the development of social reasoning. In the social task, participants evaluated themselves or a friend, or compared themselves with their friend, on a series of traits. In the nonsocial task, participants evaluated their hometown or another town or compared the two. In a behavioral study involving 325 participants (11-39 years old), we found that integrating relations, compared with performing single relational judgments, improves during adolescence, both for social and nonsocial information. Thirty nine female participants (10-31 years old) took part in a neuroimaging study using a similar task. Activation of the relational integration network, including the rostrolateral PFC, was observed in the comparison condition of both the social and nonsocial tasks, whereas the medial PFC showed greater activation when participants processed social as opposed to nonsocial information across conditions. Developmentally, the right anterior insula showed greater activity in adolescents compared with adults during the comparison of nonsocial versus social information. This study shows parallel recruitment of the social brain and the relational reasoning network during the relational integration of social information in adolescence and adulthood. PMID- 28562206 TI - Lipopolysaccharide induces the differentiation of hepatic progenitor cells into myofibroblasts via activation of the Hedgehog signaling pathway. AB - Normally, hepatic progenitor cells (HPCs) are activated and differentiate into hepatocytes or bile ductular cells to repair liver damage during liver injury. However, it remains controversial whether the abnormal differentiation of HPCs occurs under abnormal conditions. Lipopolysaccharide (LPS), a component of the microenvironment, promotes liver fibrosis. In the present study, HPCs promoted liver fibrosis in rats following carbon tetrachloride (CCl4) treatment. Meanwhile, the LPS level in the portal vein was elevated and played a primary role in the fate of HPCs. In vitro, LPS inhibited the hepatobiliary differentiation of HPCs. Concurrently, HPCs co-cultured with LPS for 2 weeks showed a tendency to differentiate into myofibroblasts (MFs). Thus, we conclude that LPS promotes the aberrant differentiation of HPCs into MFs as a third type of descendant. This study provides insight into a novel differentiation fate of HPCs in their microenvironment, and could thus lead to the development of HPCs for treatment methods in liver fibrosis. PMID- 28562209 TI - The Phenomenal Contents and Neural Correlates of Spontaneous Thoughts across Wakefulness, NREM Sleep, and REM Sleep. AB - Thoughts occur during wake as well as during dreaming sleep. Using experience sampling combined with high-density EEG, we investigated the phenomenal qualities and neural correlates of spontaneously occurring thoughts across wakefulness, non rapid eye movement (NREM) sleep, and REM sleep. Across all states, thoughts were associated with activation of a region of the midcingulate cortex. Thoughts during wakefulness additionally involved a medial prefrontal region, which was associated with metacognitive thoughts during wake. Phenomenologically, waking thoughts had more metacognitive content than thoughts during both NREM and REM sleep, whereas thoughts during REM sleep had a more social content. Together, these results point to a core neural substrate for thoughts, regardless of behavioral state, within the midcingulate cortex, and suggest that medial prefrontal regions may contribute to metacognitive content in waking thoughts. PMID- 28562210 TI - Lateral Sinus Dural Arteriovenous Fistulas: Sinovenous Outflow Restriction Outweighs Cortical Venous Reflux as a Parameter Associated with Hemorrhage. AB - Purpose To investigate whether sinovenous outflow restriction (SOR) is more strongly associated with hemorrhage than cortical venous reflux (CVR) in patients with lateral sinus dural arteriovenous fistulas (DAVFs). Materials and Methods An institutional review board approved this retrospective study and waiver of informed consent was obtained. From 1995 to 2016, 163 cases of lateral sinus DAVFs were included and divided into hemorrhagic and nonhemorrhagic groups based on initial presentation. Their angiograms and magnetic resonance images were evaluated, with two evaluators independently grading CVR and SOR. The SOR was scored as the combined conduit score (CCS), ranging from zero (total occlusion) to 8 (fully patent). The CVR and CCS of the hemorrhagic and nonhemorrhagic groups were compared. Logistic regression models were established for both the CVR and CCS to compare their performances in discriminating DAVF hemorrhage. Results Sinovenous outflow was significantly more restrictive (lower median CCS) in the hemorrhagic group than in the nonhemorrhagic group (1 vs 6.5; P < .001). A CCS of less than or equal to 2 best discriminated between the groups with a sensitivity of 90.0% and a specificity of 88.1%. The CCS model had a higher discriminative performance than did the CVR model (area under the curve, 0.933 vs 0.843; P = .018). Conclusion The CCS grading system semiquantifies SOR. SOR may represent a stronger risk factor associated with hemorrhage in patients with lateral sinus DAVFs than does CVR, and thus may offer guidance in therapeutic decision making. (c) RSNA, 2017. PMID- 28562212 TI - Rank Selection in Nonnegative Matrix Factorization using Minimum Description Length. AB - Nonnegative matrix factorization (NMF) is primarily a linear dimensionality reduction technique that factorizes a nonnegative data matrix into two smaller nonnegative matrices: one that represents the basis of the new subspace and the second that holds the coefficients of all the data points in that new space. In principle, the nonnegativity constraint forces the representation to be sparse and parts based. Instead of extracting holistic features from the data, real parts are extracted that should be significantly easier to interpret and analyze. The size of the new subspace selects how many features will be extracted from the data. An effective choice should minimize the noise while extracting the key features. We propose a mechanism for selecting the subspace size by using a minimum description length technique. We demonstrate that our technique provides plausible estimates for real data as well as accurately predicting the known size of synthetic data. We provide an implementation of our code in a Matlab format. PMID- 28562211 TI - Hepatocellular Carcinoma: Nomograms Based on the Albumin-Bilirubin Grade to Assess the Outcomes of Radiofrequency Ablation. AB - Purpose To construct a nomogram with the albumin-bilirubin (ALBI) grade to assess the long-term outcomes of patients with early-stage hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA). Materials and Methods This retrospective study was approved by the institutional review board, and informed consent was waived. We studied 622 treatment-naive patients with HCC according to the Milan criteria who subsequently underwent RFA from 2002 to 2013. Baseline characteristics were collected to identify the risk factors for determination of poor overall survival after RFA. The multivariate Cox proportional hazards model based on significant prognostic factors of overall survival was used to construct the nomogram. Results After a median follow-up time of 35.7 months, 190 patients had died. The cumulative 5- and 10-year overall survival rates were 63.1% and 48.7%, respectively. Stratified according to ALBI grade, the cumulative 5- and 10 year survival rates were 80.0% and 67.9% for patients with grade 1, respectively, and 48.6% and 35.1% for those with grades 2-3, respectively (P < .001). Multivariate analysis results showed that patient age older than 65 years, a prothrombin time international normalized ratio greater than 1.1, alpha fetoprotein level greater than 20 ng/mL, multiple tumors, and ALBI grade 2 or 3 were associated with overall mortality. A nomogram was developed on the basis of these five variables. Internal validation with 200 bootstrapped sample sets had a good concordance index of 0.770 (95% confidence interval: 0.633, 0.876). Conclusion This simple nomogram based on the ALBI grade offers personalized long term survival data for patients with early-stage HCC who undergo RFA. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28562213 TI - Multivariate Time Series Decomposition into Oscillation Components. AB - Many time series are considered to be a superposition of several oscillation components. We have proposed a method for decomposing univariate time series into oscillation components and estimating their phases (Matsuda & Komaki, 2017 ). In this study, we extend that method to multivariate time series. We assume that several oscillators underlie the given multivariate time series and that each variable corresponds to a superposition of the projections of the oscillators. Thus, the oscillators superpose on each variable with amplitude and phase modulation. Based on this idea, we develop gaussian linear state-space models and use them to decompose the given multivariate time series. The model parameters are estimated from data using the empirical Bayes method, and the number of oscillators is determined using the Akaike information criterion. Therefore, the proposed method extracts underlying oscillators in a data-driven manner and enables investigation of phase dynamics in a given multivariate time series. Numerical results show the effectiveness of the proposed method. From monthly mean north-south sunspot number data, the proposed method reveals an interesting phase relationship. PMID- 28562214 TI - GP-Select: Accelerating EM Using Adaptive Subspace Preselection. AB - We propose a nonparametric procedure to achieve fast inference in generative graphical models when the number of latent states is very large. The approach is based on iterative latent variable preselection, where we alternate between learning a selection function to reveal the relevant latent variables and using this to obtain a compact approximation of the posterior distribution for EM. This can make inference possible where the number of possible latent states is, for example, exponential in the number of latent variables, whereas an exact approach would be computationally infeasible. We learn the selection function entirely from the observed data and current expectation-maximization state via gaussian process regression. This is in contrast to earlier approaches, where selection functions were manually designed for each problem setting. We show that our approach performs as well as these bespoke selection functions on a wide variety of inference problems. In particular, for the challenging case of a hierarchical model for object localization with occlusion, we achieve results that match a customized state-of-the-art selection method at a far lower computational cost. PMID- 28562215 TI - Predicting the Existence and Stability of Phase-Locked Mode in Neural Networks Using Generalized Phase-Resetting Curve. AB - We used the phase-resetting method to study a biologically relevant three-neuron network in which one neuron receives multiple inputs per cycle. For this purpose, we first generalized the concept of phase resetting to accommodate multiple inputs per cycle. We explicitly showed how analytical conditions for the existence and the stability of phase-locked modes are derived. In particular, we solved newly derived recursive maps using as an example a biologically relevant driving-driven neural network with a dynamic feedback loop. We applied the generalized phase-resetting definition to predict the relative-phase and the stability of a phase-locked mode in open loop setup. We also compared the predicted phase-locked mode against numerical simulations of the fully connected network. PMID- 28562216 TI - Support Vector Algorithms for Optimizing the Partial Area under the ROC Curve. AB - The area under the ROC curve (AUC) is a widely used performance measure in machine learning. Increasingly, however, in several applications, ranging from ranking to biometric screening to medicine, performance is measured not in terms of the full area under the ROC curve but in terms of the partial area under the ROC curve between two false-positive rates. In this letter, we develop support vector algorithms for directly optimizing the partial AUC between any two false positive rates. Our methods are based on minimizing a suitable proxy or surrogate objective for the partial AUC error. In the case of the full AUC, one can readily construct and optimize convex surrogates by expressing the performance measure as a summation of pairwise terms. The partial AUC, on the other hand, does not admit such a simple decomposable structure, making it more challenging to design and optimize (tight) convex surrogates for this measure. Our approach builds on the structural SVM framework of Joachims ( 2005 ) to design convex surrogates for partial AUC and solves the resulting optimization problem using a cutting plane solver. Unlike the full AUC, where the combinatorial optimization needed in each iteration of the cutting plane solver can be decomposed and solved efficiently, the corresponding problem for the partial AUC is harder to decompose. One of our main contributions is a polynomial time algorithm for solving the combinatorial optimization problem associated with partial AUC. We also develop an approach for optimizing a tighter nonconvex hinge loss-based surrogate for the partial AUC using difference-of-convex programming. Our experiments on a variety of real world and benchmark tasks confirm the efficacy of the proposed methods. PMID- 28562217 TI - Deep Restricted Kernel Machines Using Conjugate Feature Duality. AB - The aim of this letter is to propose a theory of deep restricted kernel machines offering new foundations for deep learning with kernel machines. From the viewpoint of deep learning, it is partially related to restricted Boltzmann machines, which are characterized by visible and hidden units in a bipartite graph without hidden-to-hidden connections and deep learning extensions as deep belief networks and deep Boltzmann machines. From the viewpoint of kernel machines, it includes least squares support vector machines for classification and regression, kernel principal component analysis (PCA), matrix singular value decomposition, and Parzen-type models. A key element is to first characterize these kernel machines in terms of so-called conjugate feature duality, yielding a representation with visible and hidden units. It is shown how this is related to the energy form in restricted Boltzmann machines, with continuous variables in a nonprobabilistic setting. In this new framework of so-called restricted kernel machine (RKM) representations, the dual variables correspond to hidden features. Deep RKM are obtained by coupling the RKMs. The method is illustrated for deep RKM, consisting of three levels with a least squares support vector machine regression level and two kernel PCA levels. In its primal form also deep feedforward neural networks can be trained within this framework. PMID- 28562218 TI - A Weight-Adaptive Laplacian Embedding for Graph-Based Clustering. AB - Graph-based clustering methods perform clustering on a fixed input data graph. Thus such clustering results are sensitive to the particular graph construction. If this initial construction is of low quality, the resulting clustering may also be of low quality. We address this drawback by allowing the data graph itself to be adaptively adjusted in the clustering procedure. In particular, our proposed weight adaptive Laplacian (WAL) method learns a new data similarity matrix that can adaptively adjust the initial graph according to the similarity weight in the input data graph. We develop three versions of these methods based on the L2 norm, fuzzy entropy regularizer, and another exponential-based weight strategy, that yield three new graph-based clustering objectives. We derive optimization algorithms to solve these objectives. Experimental results on synthetic data sets and real-world benchmark data sets exhibit the effectiveness of these new graph based clustering methods. PMID- 28562219 TI - Determination of the Lowest-Energy States for the Model Distribution of Trained Restricted Boltzmann Machines Using a 1000 Qubit D-Wave 2X Quantum Computer. AB - The possibility of using a quantum computer D-Wave 2X with more than 1000 qubits to determine the global minimum of the energy landscape of trained restricted Boltzmann machines is investigated. In order to overcome the problem of limited interconnectivity in the D-Wave architecture, the proposed RBM embedding combines multiple qubits to represent a particular RBM unit. The results for the lowest energy (the ground state) and some of the higher-energy states found by the D Wave 2X were compared with those of the classical simulated annealing (SA) algorithm. In many cases, the D-Wave machine successfully found the same RBM lowest-energy state as that found by SA. In some examples, the D-Wave machine returned a state corresponding to one of the higher-energy local minima found by SA. The inherently nonperfect embedding of the RBM into the Chimera lattice explored in this work (i.e., multiple qubits combined into a single RBM unit were found not to be guaranteed to be all aligned) and the existence of small, persistent biases in the D-Wave hardware may cause a discrepancy between the D Wave and the SA results. In some of the investigated cases, introduction of a small bias field into the energy function or optimization of the chain-strength parameter in the D-Wave embedding successfully addressed difficulties of the particular RBM embedding. With further development of the D-Wave hardware, the approach will be suitable for much larger numbers of RBM units. PMID- 28562220 TI - Extraction of Synaptic Input Properties in Vivo. AB - Knowledge of synaptic input is crucial for understanding synaptic integration and ultimately neural function. However, in vivo, the rates at which synaptic inputs arrive are high, so that it is typically impossible to detect single events. We show here that it is nevertheless possible to extract the properties of the events and, in particular, to extract the event rate, the synaptic time constants, and the properties of the event size distribution from in vivo voltage clamp recordings. Applied to cerebellar interneurons, our method reveals that the synaptic input rate increases from 600 Hz during rest to 1000 Hz during locomotion, while the amplitude and shape of the synaptic events are unaffected by this state change. This method thus complements existing methods to measure neural function in vivo. PMID- 28562221 TI - LQG Online Learning. AB - Optimal control theory and machine learning techniques are combined to formulate and solve in closed form an optimal control formulation of online learning from supervised examples with regularization of the updates. The connections with the classical linear quadratic gaussian (LQG) optimal control problem, of which the proposed learning paradigm is a nontrivial variation as it involves random matrices, are investigated. The obtained optimal solutions are compared with the Kalman filter estimate of the parameter vector to be learned. It is shown that the proposed algorithm is less sensitive to outliers with respect to the Kalman estimate (thanks to the presence of the regularization term), thus providing smoother estimates with respect to time. The basic formulation of the proposed online learning framework refers to a discrete-time setting with a finite learning horizon and a linear model. Various extensions are investigated, including the infinite learning horizon and, via the so-called kernel trick, the case of nonlinear models. PMID- 28562222 TI - Multiview Feature Analysis via Structured Sparsity and Shared Subspace Discovery. AB - Since combining features from heterogeneous data sources can significantly boost classification performance in many applications, it has attracted much research attention over the past few years. Most of the existing multiview feature analysis approaches separately learn features in each view, ignoring knowledge shared by multiple views. Different views of features may have some intrinsic correlations that might be beneficial to feature learning. Therefore, it is assumed that multiviews share subspaces from which common knowledge can be discovered. In this letter, we propose a new multiview feature learning algorithm, aiming to exploit common features shared by different views. To achieve this goal, we propose a feature learning algorithm in a batch mode, by which the correlations among different views are taken into account. Multiple transformation matrices for different views are simultaneously learned in a joint framework. In this way, our algorithm can exploit potential correlations among views as supplementary information that further improves the performance result. Since the proposed objective function is nonsmooth and difficult to solve directly, we propose an iterative algorithm for effective optimization. Extensive experiments have been conducted on a number of real-world data sets. Experimental results demonstrate superior performance in terms of classification against all the compared approaches. Also, the convergence guarantee has been validated in the experiment. PMID- 28562223 TI - Effect of Phase Response Curve Shape and Synaptic Driving Force on Synchronization of Coupled Neuronal Oscillators. AB - The role of the phase response curve (PRC) shape on the synchrony of synaptically coupled oscillating neurons is examined. If the PRC is independent of the phase, because of the synaptic form of the coupling, synchrony is found to be stable for both excitatory and inhibitory coupling at all rates, whereas the antisynchrony becomes stable at low rates. A faster synaptic rise helps extend the stability of antisynchrony to higher rates. If the PRC is not constant but has a profile like that of a leaky integrate-and-fire model, then, in contrast to the earlier reports that did not include the voltage effects, mutual excitation could lead to stable synchrony provided the synaptic reversal potential is below the voltage level the neuron would have reached in the absence of the interaction and threshold reset. This level is controlled by the applied current and the leakage parameters. Such synchrony is contingent on significant phase response (that would result, for example, by a sharp PRC jump) occurring during the synaptic rising phase. The rising phase, however, does not contribute significantly if it occurs before the voltage spike reaches its peak. Then a stable near-synchronous state can still exist between type 1 PRC neurons if the PRC shows a left skewness in its shape. These results are examined comprehensively using perfect integrate and-fire, leaky integrate-and-fire, and skewed PRC shapes under the assumption of the weakly coupled oscillator theory applied to synaptically coupled neuron models. PMID- 28562225 TI - The First Hundred Days for Health Care. PMID- 28562224 TI - Analytical Derivation of Nonlinear Spectral Effects and 1/f Scaling Artifact in Signal Processing of Real-World Data. AB - In estimating the frequency spectrum of real-world time series data, we must violate the assumption of infinite-length, orthogonal components in the Fourier basis. While it is widely known that care must be taken with discretely sampled data to avoid aliasing of high frequencies, less attention is given to the influence of low frequencies with period below the sampling time window. Here, we derive an analytic expression for the side-lobe attenuation of signal components in the frequency domain representation. This expression allows us to detail the influence of individual frequency components throughout the spectrum. The first consequence is that the presence of low-frequency components introduces a 1/f[Formula: see text] component across the power spectrum, with a scaling exponent of [Formula: see text]. This scaling artifact could be composed of diffuse low-frequency components, which can render it difficult to detect a priori. Further, treatment of the signal with standard digital signal processing techniques cannot easily remove this scaling component. While several theoretical models have been introduced to explain the ubiquitous 1/f[Formula: see text] scaling component in neuroscientific data, we conjecture here that some experimental observations could be the result of such data analysis procedures. PMID- 28562226 TI - Inhibition of Pathological Phenotype of Hypertrophic Scar Fibroblasts Via Coculture with Adipose-Derived Stem Cells. AB - Hypertrophic scar (HS) is a dermal fibroproliferative disease characterized by fibroblast over-proliferation, overproduction, and deposition of the extracellular matrix. Growing evidence demonstrated that adipose-derived stem cells (ASCs) secrete a plethora of trophic and antifibrotic factors, which suppress inflammation and ameliorate fibrosis of different tissues. However, few studies investigate their effect on repressing HS activity. This study evaluated the suppressing effect of ASCs on HS fibroblast bioactivity and the possible mechanism via a coculture model. HS-derived fibroblasts (HSFs) and ASCs were isolated from individual patients. HSFs or HSFs treated with transforming growth factor-beta1 (TGF-beta1) were cocultured with ASCs and the change of HSF cellular behaviors, such as cell proliferation, migration, contractility, and gene/protein expression of scar-related molecules, were evaluated by cell counting assay, cell cycle analysis, scratch wound assay, fibroblast-populated collagen lattice (FPCL) contractility assay, real-time quantitative polymerase chain reaction, ELISA, and western blotting assay. After 5 days of ASC coculture treatment, the expression levels of collagen I (Col 1), collagen III (Col 3), fibronectin (FN), TGF-beta1, interleukin-6 (IL-6), interleukin-8 (IL-8), connective tissue growth factor (CTGF), and alpha-smooth muscle actin (alpha-SMA) in HSFs decreased significantly while the expression levels of decorin (DCN) and MMP-1/TIMP-1 (matrix metalloproteinase/tissue inhibitor of MMP) ratio increased significantly. Besides, after 5 days of exogenous TGF-beta1 stimulation, the expression levels of Col 1, FN, TGF-beta1, IL-6, CTGF, and alpha-SMA in HSFs increased significantly. Impressively, all these increased gene expression levels were reversed by 5 days of ASCs coculture treatment. Additionally, the proliferation, migration, and contractility of HSFs were all significantly reduced by ASC coculture treatment. Furthermore, the protein levels of TGF-beta1 and intracellular signal pathway-related molecules, such as p-smad2, p-smad3, p Stat3, and p-ERK, were downregulated significantly in HSFs after 5 days of ASCs coculture treatment. This study demonstrated that coculture of HSFs with ASCs not only inhibited proliferation, migration, and contractility of HSFs but also decreased the expression levels of HSF-related or TGF-beta1-induced molecules. Additionally, the antifibrotic effect on HSFs was likely mediated by the inhibition of multiple intracellular signaling. The results of this study suggest the therapeutic potential of ASCs for HS treatment, which is worth of further investigation. PMID- 28562227 TI - A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord. AB - Spinal root injuries result in newly formed glial scar formation, which prevents regeneration of sensory axons causing permanent sensory loss. Previous studies showed that delivery of trophic factors or implantation of human neural progenitor cells supports sensory axon regeneration and partly restores sensory functions. In this study, we elucidate mechanisms underlying stem cell-mediated ingrowth of sensory axons after dorsal root avulsion (DRA). We show that human spinal cord neural stem/progenitor cells (hscNSPC), and also, mesoporous silica particles loaded with growth factor mimetics (MesoMIM), supported sensory axon regeneration. However, when hscNSPC and MesoMIM were combined, sensory axon regeneration failed. Morphological and tracing analysis showed that sensory axons grow through the newly established glial scar along "bridges" formed by migrating stem cells. Coimplantation of MesoMIM prevented stem cell migration, "bridges" were not formed, and sensory axons failed to enter the spinal cord. MesoMIM applied alone supported sensory axons ingrowth, but without affecting glial scar formation. In vitro, the presence of MesoMIM significantly impaired migration of hscNSPC without affecting their level of differentiation. Our data show that (1) the ability of stem cells to migrate into the spinal cord and organize cellular "bridges" in the newly formed interface is crucial for successful sensory axon regeneration, (2) trophic factor mimetics delivered by mesoporous silica may be a convenient alternative way to induce sensory axon regeneration, and (3) a combinatorial approach of individually beneficial components is not necessarily additive, but can be counterproductive for axonal growth. PMID- 28562228 TI - Preparation of cross-linked magnetic chitosan particles from steel slag and shrimp shells for removal of heavy metals. AB - In this study, a new method for preparation of cross-linked magnetic chitosan particles (MCPs) from steel slag and shrimp shells using green tea extract as crosslinking reagent has been presented. The MCPs obtained were characterized by means of X-ray diffraction analysis, Fourier-transform infrared spectroscopy, scanning electron microscopy and magnetic properties, and then were used to investigate the adsorption properties of Cu(II) and Ni(II) ions in aqueous solutions. The influence of experimental conditions such as contact time, pH value, adsorbent dose and initial metal concentration, and the possibility of regeneration were studied systematically. The Cu(II) and Ni(II) adsorption isotherms, kinetics and thermodynamics have been measured and discussed. The results show that the synthesized MCPs have high adsorption capacity for both metal ions (126.58 mg/g for Cu(II) and 66.23 mg/g for Ni(II)), and have excellent regeneration stability with efficiency of greater than 83% after five cycles of the adsorption-regeneration process. The adsorption process of Ni(II) and Cu(II) on MCPs was feasible, spontaneous and exothermic, and better described by the Langmuir model and pseudo-second-order kinetic equation. The MCPs can be applied as a low cost and highly efficient adsorbent for removal of heavy metals from wastewater due to its high adsorption capacity, easy recovery and good reusability. PMID- 28562229 TI - Effect of chromium (VI) on the multiple nitrogen removal pathways and microbial community of aerobic granular sludge. AB - The frequent appearance of Cr(VI) significantly impacts the microbial metabolism in wastewater. In this study, long-term effects of Cr(VI) on microbial community, nitrogen removal pathways and mechanism of aerobic granular sludge (AGS) were investigated. AGS had strong resistance ability to 1.0 mg/L Cr(VI). 3.0 mg/L Cr(VI) increased the heterotrophic-specific ammonia uptake rate (HSAUR) and heterotrophic-specific nitrate uptake rate (HSNUR) transiently, whereas 5.0 mg/L Cr(VI) sharply decreased the specific ammonia uptake rate (SAUR), specific nitrate uptake rate (SNUR) and simultaneous nitrification denitrification rate (SNDR). It was found that Cr (VI) has a greater inhibitory effect on autotrophic nitrification (ASAUR), and the maximal inhibition rate (IR) was 139.19%. Besides, the inhibition of Cr (VI) on nitrogen removal process belongs to non-competitive inhibition. Cr(VI) had a weaker negative impact on heterotrophic bacteria compared with that on autotrophic bacteria. Denaturing gradient gel electrophoresis analyses suggest that Acidovorax sp., flavobacterium sp., uncultured soil bacterium, uncultured nitrosospira sp., uncultured prokaryote, uncultured beta-proteobacterium and uncultured pseudomonas sp. were the dominant species. The inhibition of Cr(VI) on nitrite-oxidizing bacteria was the strongest, followed by ammonia-oxidizing bacteria and denitrifying bacteria. Linear correlations between bacterial count and biomass-specific uptake rate were observed when the Cr(VI) concentration exceeded 3 mg/L. This study revealed the effect of Cr(VI) on nitrification is more serious than that on denitrification. Autotrophic and heterotrophic nitrification, heterotrophic denitrification and simultaneous nitrification denitrification played a significant role on nitrogen removal under Cr(VI) stress. PMID- 28562230 TI - Biodegradation of phenol and benzene by endophytic bacterial strains isolated from refinery wastewater-fed Cannabis sativa. AB - The presence of benzene and phenol in the environment can lead to serious health effects in humans and warrant development of efficient cleanup strategies. The aim of the present work was to assess the potential of indigenous endophytic bacterial strains to degrade benzene and phenol. Seven strains were successfully isolated from Cannabis sativa plants irrigated with oil refinery wastewater. Molecular characterization was performed by 16S rRNA gene sequencing. Phenol was biodegraded almost completely with Achromobacter sp. (AIEB-7), Pseudomonas sp. (AIEB-4), and Alcaligenes sp. (AIEB-6) at 250, 500, and 750 mg L-1; however, the degradation was only 81%, 72%, and 69%, respectively, when exposed to 1000 mg L 1. Bacillus sp. (AIEB-1), Enterobacter sp. (AIEB-3), and Acinetobacter sp. (AIEB 2) degraded benzene significantly at 250, 500, and 750 mg L-1. However, these strains showed 80%, 72%, and 68% benzene removal at 1000 mg L-1 exposure, respectively. Rates of degradation could be modeled with first-order kinetics with rate constant values of 1.86 * 10-2 for Pseudomonas sp. (AIEB-4) and 1.80 * 10-2 h-1 for Bacillus sp. (AIEB-1) and half-lives of 1.5 and 1.6 days, respectively. These results establish a foundation for further testing of the phytoremediation of hydrocarbon-contaminated soils in the presence of these endophytic bacteria. PMID- 28562231 TI - Expanding health coverage in India: role of microfinance-based self-help groups. AB - To fulfil its commitment to universal health coverage, it will be necessary for the Indian government to expand access to appropriate and affordable health services. Through the mechanism of microfinance-based self-help groups (SHGs), poor women and their families are provided not only with access to finance to improve their livelihoods but also, in many cases, with a range of basic health services. Governments and non-governmental organisations in India have implemented large-scale programmes for the promotion of SHGs. With 93 million people organised nationally, the SHGs provide an established population base that can potentially be used to extend health coverage. However, the potential for working with SHGs to improve people's access to health services has not been an active part of the national policy discourse.. PMID- 28562233 TI - Relationship of phosphodiesterase 4D (PDE4D) gene polymorphisms with risk of ischemic stroke: a hospital based case-control study. AB - BACKGROUND: Stroke remains a leading cause of death and disability worldwide. Ischemic stroke (IS) accounts for around 80-85% of total stroke and is a complex polygenic multi-factorial disorder which is affected by a complex combination of vascular, environmental, and genetic factors. OBJECTIVE: The study was conducted with an aim to examine the relationship of single nucleotide polymorphisms (SNPs) of PDE4D (T83C, C87T, and C45T) gene with increasing risk of IS in patients in North Indian population. METHODS: In this hospital-based case-control study, 250 IS subjects and 250 age-and sex-matched control subjects were enrolled from the Neurosciences Centre, A.I.I.M.S., New Delhi, India. Deoxyribonucleic acids (DNAs) were extracted using the conventional Phenol-Chloroform isolation method. Different genotypes were determined by Polymerase chain reaction- Restriction fragment length polymorphism method. Odds ratio (OR) and 95% Confidence Interval (CI) of relationship of polymorphisms with risk of IS were calculated by conditional multivariable regression analysis. RESULTS: High blood pressure, low socioeconomic status, dyslipidemia, diabetes, and family history of stroke were observed to be statistically significant risk factors for IS. Multivariable adjusted analysis demonstrated a statistically significant relationship between SNP 83 of PDE4D gene polymorphism and increasing odds of IS under the dominant model of inheritance (OR, 1.59; 95% CI, 1.02 to 2.50; p value = 0.04) after adjustment of potential confounding variables. Stratified analysis on the basis of TOAST classification demonstrated a statistically significant association for increasing 2.73 times odds for developing large vessel disease stroke as compared to controls (OR, 2.73; 95% CI, 1.16 to 0.02; p value = 0.02). We did not find any significant association of SNPs (C87T and C45T) of the PDE4D gene with the risk of IS. CONCLUSION: SNP 83 of PDE4D gene may increase the risk for developing IS whereas SNP 87 and SNP45 of PDE4D may not be associated with the risk of IS in the North Indian population. Prospective cohort studies are required to corroborate these findings. PMID- 28562232 TI - Optical Method to Quantify Mechanical Contraction and Calcium Transients of Human Pluripotent Stem Cell-Derived Cardiomyocytes. AB - Differentiation of human pluripotent stem cells into cardiomyocytes (hPS-CMs) holds promise for myocardial regeneration therapies, drug discovery, and models of cardiac disease. Potential cardiotoxicities may affect hPS-CM mechanical contraction independent of calcium signaling. Herein, a method using an image capture system is described to measure hPS-CM contractility and intracellular calcium concurrently, with high spatial and temporal resolution. The image capture system rapidly alternates between brightfield and epifluorescent illumination of contracting cells. Mechanical contraction is quantified by a speckle tracking algorithm applied to brightfield image pairs, whereas calcium transients are measured by a fluorescent calcium reporter. This technique captured changes in contractile strain, calcium transients, and beat frequency of hPS-CMs over 21 days in culture, as well as acute responses to isoproterenol and Cytochalasin D. The technique described above can be applied without the need to alter the culture platform, allowing for determination of hPS-CM behavior over weeks in culture for drug discovery and myocardial regeneration applications. PMID- 28562234 TI - Ethics teaching in a medical education environment: preferences for diversity of learning and assessment methods. AB - BACKGROUND: Ethics and professionalism are an integral part of medical school curricula; however, medical students' views on these topics have not been assessed in many countries. OBJECTIVE: The study aimed to examine medical students' perceptions toward ethics and professionalism teaching, and its learning and assessment methods. DESIGN: A self-administered questionnaire eliciting views on professionalism and ethics education was distributed to a total of 128 final-year medical students. RESULTS: A total of 108 students completed the survey, with an 84% response rate. Medical students reported frequently encountering ethical conflicts during training but stated only a moderate level of ethics training at medical school (mean = 5.14 +/- 1.8). They noted that their education had helped somewhat to deal with ethical conflicts (mean = 5.39 +/- 2.0). Students strongly affirmed the importance of ethics education (mean = 7.63 +/- 1.03) and endorsed the value of positive role models (mean = 7.45 +/- 1.5) as the preferred learning method. The cohort voiced interest in direct faculty supervision as an approach to assessment of knowledge and skills (mean = 7.62 +/- 1.26). Female students perceived greater need for more ethics education compared to males (p = < 0.05). Students who claimed that they had experienced some unprofessional treatment had a more limited view of the importance of ethics as a subject (P = 0.001). CONCLUSION: Medical students viewed ethics education positively and preferred clinically attuned methods for learning. PMID- 28562235 TI - Attitudes and factors contributing to attrition in Canadian surgical specialty residency programs. AB - BACKGROUND: We recently studied attrition in Canadian general surgical programs; however, there are no data on whether residents enrolled in other surgical residencies harbour the same intents as their general surgical peers. We sought to determine how many residents in surgical disciplines in Canada consider leaving their programs and why. METHODS: An anonymous survey was administered to all residents in 9 surgical disciplines in Canada. Significance of association was determined using the Pearson chi2 test. The Canadian Post-MD Education Registry (CAPER) website was used to calculate the response rate. RESULTS: We received 523 responses (27.6% response rate). Of these respondents, 140 (26.8%) were either "somewhat" or "seriously" considering leaving their program. Residents wanting to pursue additional fellowship training and those aspiring to an academic career were significantly less likely to be considering changing specialties (p = 0.003 and p = 0.005, respectively). Poor work-life balance and fear of unemployment/underemployment were the top reasons why residents would change specialty (55.5% and 40.8%, respectively), although the reasons cited were not significantly different between those considering changing and those who were not (p = 0.64). Residents who were considering changing programs were significantly less likely to enjoy their work and more likely to cite having already invested too much time to change as a reason for continuing (p < 0.001). CONCLUSION: More than one-quarter of residents in surgical training programs in Canada harbour desires to abandon their surgical careers, primarily because of unsatisfactory work-life balance and limited employment prospects. Efforts to educate prospective residents about the reality of the surgical lifestyle and to optimize employment prospects may improve completion rates. PMID- 28562236 TI - Left ventricular assist device exchange: the Toronto General Hospital experience. AB - BACKGROUND: As support times for left ventricular assist devices (LVADs) become longer, several complications requiring device exchange may occur. To our knowledge, this is the first Canadian report regarding implantable LVAD exchange. METHODS: We retrospectively reviewed the cases of consecutive, unique patients implanted with an LVAD between June 2006 and October 2015 at Toronto General Hospital. RESULTS: In total, 122 patients were impanted with an LVAD during the study period. Eight patients required LVAD exchange, and 1 patient had 2 replacements (9 of 122, 7.3%). There were 7 HeartMate II (HMII), 1 HVAD and 1 DuraHeart pumps exchanged. Two of these exchanges occurred early at the time of initial implant, whereas 7 occurred late (range 8-623 d). Six exchanges were made owing to pump thrombosis. Of the 3 exchanges made for other causes, 1 HMII exchange was owing to a driveline fracture, 1 DuraHeart patient had early inflow obstruction requiring exchange to HMII at the initial implant, and the third had a suspected inflow obstruction with no evidence of thrombosis at the time of the procedure. The mean support time before exchange was 225 days, and time from exchange to transplant, death or ongoing support was 245 days. Three patients were successfully bridged to transplant, and at the time of data collection 2 were supported awaiting transplant. Three patients died after a mean duration of 394.3 days (range 78-673 d) of support postreplacement. Four cases were successfully performed using a subcostal approach. CONCLUSION: Pump thrombosis is the most common cause for LVAD exchange, which can be performed with acceptable morbidity and mortality. The subcostal approach may be the preferred procedure for an HMII exchange when indicated. PMID- 28562237 TI - Robotic-assisted thoracoscopic surgery for lung resection: the first Canadian series. AB - BACKGROUND: Robotic surgery was introduced as a platform for minimally invasive lung resection in Canada in October 2011. We present the first Canadian series of robotic pulmonary resection for lung cancer. METHODS: Prospective databases at 2 institutions were queried for patients who underwent robotic resection for lung cancer between October 2011 and June 2015. To examine the effect of learning curves on patient and process outcomes, data were organized into 3 temporal tertiles, stratified by surgeon. RESULTS: A total of 167 consecutive patients were included in the study. Median age was 66 (range 27-88) years, and 46.1% (n = 77) of patients were men. The majority of patients (n = 141, 84%) underwent robotic lobectomy. Median duration of surgery was 270 (interquartile range [IQR] 233-326) minutes, and median length of stay (LOS) was 4 (IQR 3-6) days. Twelve patients (7%) were converted to thoracotomy. Total duration of surgery and console time decreased significantly (p < 0.001) across tertiles, with a steady decline until case 20, followed by a plateau effect. Across tertiles, there was no significant difference in LOS, number of lymph node stations removed, or perioperative complications. CONCLUSION: The results of this case series are comparable to those reported in the literature. A prospective study to examine the outcomes and cost of robotic pulmonary resection compared with video-assisted thoracoscopic surgery should be done in the context of the Canadian health care system. We have presented the first consecutive case series of robotic lobectomy in Canada. Outcomes compare favourably to other series in the literature. PMID- 28562238 TI - The Orthopedic Trauma Symposium: improving care of orthopedic injuries in Haiti. AB - BACKGROUND: Although single-trip volunteer medical teams can provide much-needed acute trauma care following natural disasters, their ability to leave a legacy of improved care in the region is often limited. One way to improve treatment of traumatic injuries is through conference-based teaching, such as the Orthopedic Trauma Symposium (OTS), which took place in Haiti in 2014. However, there is little research evaluating the effectiveness of such teaching tools. We evaluated the OTS and the potential benefits of future iterations of the course. METHODS: A survey consisting of 5-point Likert scale questions as well as qualitative open feedback assessed respondents' opinions regarding the value, content and delivery of the OTS. Respondents were classified dichotomously in terms of their role in the OTS (instructor v. participant) to measure any meaningful difference in feedback. RESULTS: In total, 84% of all participants agreed that course content was clearly communicated, and 98% agreed that instructors were knowledgeable in the topics covered. Moreover, 87% of all participants responded that they would apply the training in their medical practices going forward. CONCLUSION: Haitian physicians, residents and medical students responded favourably to the OTS. Open ended questions offered concise, attainable improvements for future iterations of the course. Organizations committed to improving medical care in low- and middle income countries should take note of these findings while continuing to develop the OTS and similar initiatives globally. PMID- 28562239 TI - Vascular Access in Pediatric Patients in the Emergency Department: Types of Access, Indications, and Complications. AB - Vascular access is a potentially life-saving procedure that is a mainstay of emergency medicine practice. There are a number of challenges associated with obtaining and maintaining vascular access, and the choice of the route of access and equipment used will depend on patient- and provider-specific factors. In this issue, the indications and complications of peripheral intravenous access, intraosseous access, and central venous access are reviewed. Timely and effective assessment and management of difficult-access patients, pain control techniques that can assist vascular access, and contraindications to each type of vascular access are also discussed. PMID- 28562240 TI - Dental Emergencies: Management Strategies That Improve Outcomes. AB - Acute dental emergencies are a common chief complaint presenting to emergency departments, and they are increasing substantially in frequency. The diagnosis and management of dental emergencies is a core competency of the emergency clinician, and proper therapeutic strategies can significantly improve cosmetic and functional outcomes for patients. This issue provides a systematic review of the literature on common acute traumatic and atraumatic dental emergencies with a focus on the historical and physical examination findings that must be understood to identify life-threatening infections, relieve pain, salvage natural teeth, and communicate with specialists in the further management of patients after emergency treatment. PMID- 28562244 TI - Executive Summary: Research Gaps at the Intersection of Pediatric Neurodevelopment, Nutrition, and Inflammation in Low-Resource Settings. PMID- 28562242 TI - IFT trains in different stages of assembly queue at the ciliary base for consecutive release into the cilium. AB - Intraflagellar transport (IFT) trains, multimegadalton assemblies of IFT proteins and motors, traffic proteins in cilia. To study how trains assemble, we employed fluorescence protein-tagged IFT proteins in Chlamydomonas reinhardtii. IFT-A and motor proteins are recruited from the cell body to the basal body pool, assembled into trains, move through the cilium, and disperse back into the cell body. In contrast to this 'open' system, IFT-B proteins from retrograde trains reenter the pool and a portion is reused directly in anterograde trains indicating a 'semi open' system. Similar IFT systems were also observed in Tetrahymena thermophila and IMCD3 cells. FRAP analysis indicated that IFT proteins and motors of a given train are sequentially recruited to the basal bodies. IFT dynein and tubulin cargoes are loaded briefly before the trains depart. We conclude that the pool contains IFT trains in multiple stages of assembly queuing for successive release into the cilium upon completion. PMID- 28562245 TI - Neurodevelopment, Nutrition, and Inflammation: The Evolving Global Child Health Landscape. AB - The last decade has witnessed major reductions in child mortality and a focus on saving lives with key interventions targeting major causes of child deaths, such as neonatal deaths and those due to childhood diarrhea and pneumonia. With the transition to Sustainable Development Goals, the global health community is expanding child health initiatives to address not only the ongoing need for reduced mortality, but also to decrease morbidity and adverse exposures toward improving health and developmental outcomes. The relationship between adverse environmental exposures frequently associated with factors operating in the prepregnancy period and during fetal development is well established. Also well appreciated are the developmental impacts (both short- and long-term) associated with postnatal factors, such as immunostimulation and environmental enteropathy, and the additional risks posed by the confluence of factors related to malnutrition, poor living conditions, and the high burden of infections. This article provides our current thinking on the pathogenesis and risk factors for adverse developmental outcomes among young children, setting the scene for potential interventions that can ameliorate these adversities among families and children at risk. PMID- 28562241 TI - Cooperation between a hierarchical set of recruitment sites targets the X chromosome for dosage compensation. AB - In many organisms, it remains unclear how X chromosomes are specified for dosage compensation, since DNA sequence motifs shown to be important for dosage compensation complex (DCC) recruitment are themselves not X-specific. Here, we addressed this problem in C. elegans. We found that the DCC recruiter, SDC-2, is required to maintain open chromatin at a small number of primary DCC recruitment sites, whose sequence and genomic context are X-specific. Along the X, primary recruitment sites are interspersed with secondary sites, whose function is X dependent. A secondary site can ectopically recruit the DCC when additional recruitment sites are inserted either in tandem or at a distance (>30 kb). Deletion of a recruitment site on the X results in reduced DCC binding across several megabases surrounded by topologically associating domain (TAD) boundaries. Our work elucidates that hierarchy and long-distance cooperativity between gene-regulatory elements target a single chromosome for regulation. PMID- 28562246 TI - Assessment of Neurodevelopment, Nutrition, and Inflammation From Fetal Life to Adolescence in Low-Resource Settings. AB - Efforts to improve child neurodevelopment are critical to health, equity, and sustainable development, particularly in low-resource settings in the United States and globally. The colliding epidemics of food insecurity, infectious diseases, and noncommunicable diseases interact and impact neurodevelopment. Understanding the complex relationships between nutrition, inflammation, and neurodevelopment can inform clinical and public health interventions to improve outcomes. This article reviews key definitions, tools, and considerations for the assessment of nutrition, inflammation, and child neurodevelopment. The effectiveness of existing assessment tools to reflect status and biology, particularly in relation to each other, and to predict long-term changes in health is examined. The aim of this review is to present the extant evidence, identify critical research gaps, and suggest a research agenda for future longitudinal and intervention studies to address the assessment of nutrition, inflammation, and child neurodevelopment, particularly in low-resource settings. Despite research gaps, there is a strong relationship between nutrition, inflammation, environmental factors, and child neurodevelopment, which emphasizes the need to evaluate targeted, early interventions to improve long-term health and well-being. PMID- 28562247 TI - Neurodevelopment: The Impact of Nutrition and Inflammation During Preconception and Pregnancy in Low-Resource Settings. AB - The rapid pace of fetal development by far exceeds any other stage of the life span, and thus, environmental influences can profoundly alter the developmental course. Stress during the prenatal period, including malnutrition and inflammation, impact maternal and fetal neurodevelopment with long-term consequences for physical and mental health of both the mother and her child. One primary consequence of maternal malnutrition, inflammation, and other sources of prenatal stress is a poor birth outcome, such as prematurity or growth restriction. These phenotypes are often used as indications of prenatal adversity. In fact, the original evidence supporting the fetal programming hypothesis came from studies documenting an association between birth phenotype and the development of subsequent physical and mental health problems. Fetal growth restriction in both term and preterm infants is associated with neonatal morbidities and a wide variety of behavioral and psychological diagnoses in childhood and adolescence, including attention-deficit/hyperactivity disorder, anxiety, depression, internalizing and thought problems, poor social skills, and autism spectrum disorder. Improving maternal-child health requires interventions that begin before pregnancy and continue throughout gestation and into the postpartum period. Such interventions might include supporting pregnancy intention, maternal nutrition, health/medical care, mental health, and providing social support. This article discusses the impact of maternal nutrition and inflammation during preconception and pregnancy among women living in low resource settings, with an emphasis on key knowledge gaps that need to be addressed to guide program and policy decisions at local, regional and global levels. PMID- 28562248 TI - Neurodevelopment: The Impact of Nutrition and Inflammation During Infancy in Low Resource Settings. AB - Infancy and early childhood (ie, birth through age 24 months) represent a period of life with both exquisite opportunity and vulnerability for neurodevelopment. This is due to rapid brain development, both anatomic and functional, as well as to high nutrient requirements during a time of dependence on human milk and complementary foods. Complex interactions exist among nutrition, social, and physical environments and exposures. The newborn brain also reflects maternal exposures that occurred as the product of many interacting forces during gestation. Connections between nutrient use and acute and chronic inflammation are increasingly recognized, but the evidence base linking both nutrition and inflammation to neurodevelopment is relatively modest and quite limited for this young age group specifically. This article provides an overview of key interactions of nutritional requirements relevant to brain development and function; nutritional vulnerabilities related to maternal nutritional status and function; and the impact of environmental exposures and inflammation on nutrient homeostasis and neurodevelopment during this critical developmental window. PMID- 28562250 TI - Neurodevelopment: The Impact of Nutrition and Inflammation During Adolescence in Low-Resource Settings. AB - Approximately 1 out of 5 children worldwide suffers from childhood malnutrition or stunting and associated health conditions, including an increased susceptibility to infections and inflammation. Due to improved early interventions, most children even in low-resource settings now survive early childhood malnutrition, yet exhibit continuing evidence of neurodevelopmental deficits, including poor school achievement and behavioral problems. These conditions are compounded in children who continue to be undernourished throughout the adolescent years. At present, these sequelae of malnutrition and infection are of major concern in the adolescent population, given that young people between the ages of 10 and 24 years represent nearly one-quarter of the world's population. Therefore, there is an urgent need to focus on the well-being of this age group and, in particular, on behavioral, cognitive, and brain disorders of adolescents who experienced malnutrition, infection, and inflammation prenatally, in early childhood, and during adolescence itself. Because one-third of all women globally become pregnant during their adolescent years, brain and behavioral disorders during this period can have an intergenerational impact, affecting the health and well-being of the next generation. This article summarizes the current state of knowledge and evidence gaps regarding childhood and adolescent malnutrition and inflammation and their impact on adolescent neurodevelopment, the limited evidence regarding nutrition and psychosocial interventions, and the role of resilience and protective factors in this age group. This overview should help to inform the development of new strategies to improve the neurodevelopmental outcomes of high risk adolescent populations. PMID- 28562251 TI - Reducing Information's Speed Improves Verbal Cognition and Behavior in Autism: A 2-Cases Report. AB - According to the temporal theory of autism spectrum disorders (ASDs), audiovisual changes in environment, particularly those linked to facial and verbal language, are often too fast to be faced, perceived, and/or interpreted online by many children with ASD, which could help explain their facial, verbal, and/or socioemotional interaction impairments. Our goal here was to test for the first time the impact of slowed-down audiovisual information on verbal cognition and behavior in 2 boys with ASD and verbal delay. Using 15 experimental sessions during 4 months, both boys were presented with various stimuli (eg, pictures, words, sentences, cartoons) and were then asked questions or given instructions regarding stimuli. The audiovisual stimuli and instructions/questions were presented on a computer's screen and were always displayed twice: at real-time speed (RTS) and at slowed-down speed (SDS) using the software Logiral. We scored the boys' verbal cognition performance (ie, ability to understand questions/instructions and answer them verbally/nonverbally) and their behavioral reactions (ie, attention, verbal/nonverbal communication, social reciprocity), and analyzed the effects of speed and order of the stimuli presentation on these factors. According to the results, both participants exhibited significant improvements in verbal cognition performance with SDS presentation compared with RTS presentation, and they scored better with RTS presentation when having SDS presentation before rather than after RTS presentation. Behavioral reactions were also improved in SDS conditions compared with RTS conditions. This initial evidence of a positive impact of slowed-down audiovisual information on verbal cognition should be tested in a large cohort of children with ASD and associated speech/language impairments. PMID- 28562249 TI - Neurodevelopment: The Impact of Nutrition and Inflammation During Early to Middle Childhood in Low-Resource Settings. AB - The early to middle childhood years are a critical period for child neurodevelopment. Nutritional deficiencies, infection, and inflammation are major contributors to impaired child neurodevelopment in these years, particularly in low-resource settings. This review identifies global research priorities relating to nutrition, infection, and inflammation in early to middle childhood neurodevelopment. The research priority areas identified include: (1) assessment of how nutrition, infection, or inflammation in the preconception, prenatal, and infancy periods (or interventions in these periods) affect function in early to middle childhood; (2) assessment of whether effects of nutritional interventions vary by poverty or inflammation; (3) determination of the feasibility of preschool- and school-based integrated nutritional interventions; (4) improved assessment of the epidemiology of infection- and inflammation-related neurodevelopmental impairment (NDI); (5) identification of mechanisms through which infection causes NDI; (6) identification of noninfectious causes of inflammation-related NDI and interventions for causes already identified (eg, environmental factors); and (7) studies on the effects of interactions between nutritional, infectious, and inflammatory factors on neurodevelopment in early to middle childhood. Areas of emerging importance that require additional study include the effects of maternal Zika virus infection, childhood environmental enteropathy, and alterations in the child's microbiome on neurodevelopment in early to middle childhood. Research in these key areas will be critical to the development of interventions to optimize the neurodevelopmental potential of children worldwide in the early to middle childhood years. PMID- 28562252 TI - Time From Emergency Department Evaluation to Operation and Appendiceal Perforation. AB - BACKGROUND AND OBJECTIVES: In patients with appendicitis, the risk of perforation increases with time from onset of symptoms. We sought to determine if time from emergency department (ED) physician evaluation until operative intervention is independently associated with appendiceal perforation (AP) in children. METHODS: We conducted a planned secondary analysis of children aged 3 to 18 years with appendicitis enrolled in a prospective, multicenter, cross-sectional study of patients with abdominal pain (<96 hours). Time of initial physical examination and time of operation were recorded. The presence of AP was determined using operative reports. We analyzed whether duration of time from initial ED physician evaluation to operation impacted the odds of AP using multivariable logistic regression, adjusting for traditionally suggested risk factors that increase the risk of perforation. We also modeled the odds of perforation in a subpopulation of patients without perforation on computed tomography. RESULTS: Of 955 children with appendicitis, 25.9% (n = 247) had AP. The median time from ED physician evaluation to operation was 7.2 hours (interquartile range: 4.8-8.5). Adjusting for variables associated with perforation, duration of time (<= 24 hours) between initial ED evaluation and operation did not significantly increase the odds of AP (odds ratio = 1.0, 95% confidence interval, 0.96-1.05), even among children without perforation on initial computed tomography (odds ratio = 0.95, 95% confidence interval, 0.89-1.02). CONCLUSIONS: Although duration of abdominal pain is associated with AP, short time delays from ED evaluation to operation did not independently increase the odds of perforation. PMID- 28562253 TI - Life-Threatening Pneumopathy and U urealyticum in a STAT3-Deficient Hyper-IgE Syndrome Patient. AB - A deficiency in signal transducer and activator of transcription 3 (STAT3) is responsible for autosomal dominant hyperimmunoglobulin E syndrome, an immunodeficiency syndrome causing Staphylococcus aureus, Streptococcus pneumonia, Haemophilus influenzae, and, rarely, Pseudomonas aeruginosa and Aspergillus sp infections. Currently, intracellular pathogens are not targeted in the management of severe infections. The pathophysiologic mechanism of hyperimmunoglobulin E syndrome immunodeficiency has recently been linked to a disorder in the T helper 17 pathway and disruption of the interleukin -23/interleukin-17 axis. We report an unusual case of severe pleuropneumopathy by Ureaplasma urealyticum in a teenage girl with STAT3-deficient hyperimmunoglobulin E syndrome (STAT3 HIES). A previous case of severe lung infection by Mycoplasma pneumoniae has already been described in a STAT3-deficient patient, but U urealyticum has never been reported in patients with STAT3 HIES. After a review of the literature, it seems that the specific immunodeficiency pathway of STAT3 HIES exposes STAT3 HIES patients to Ureaplasma lung infections because the pathophysiology of STAT3 HIES and Ureaplasma is based on STAT3 and T helper 17 cells. PMID- 28562254 TI - Intractable Hypoglycemia in the Setting of Autoimmune Overlap Syndrome. AB - Evaluation of hypoglycemia in a patient with known diabetes mellitus, although usually straightforward, can at times be challenging. We present the case of an 8 year-old Latina girl initially diagnosed with type 1 diabetes mellitus in the setting of multiple autoimmune disorders, including dermatomyositis and lupus nephritis. She subsequently developed signs of insulin resistance and severe hypoglycemia, which was found to be due to insulin-receptor autoantibodies. This condition, known as type B insulin resistance, is a rare, heterogeneous metabolic disease that may feature hypoglycemia in the setting of extreme insulin resistance and hyperinsulinemia and, in this case, masqueraded as type 1 diabetes mellitus. The presence of hypoglycemia in the setting of multiple autoimmune disorders should prompt consideration of autoimmune-mediated hypoglycemia. In addition to immunologic modifying therapies, advances in diabetes care in the form of continuous glucose monitoring have provided an additional tool to manage recurrent hypoglycemia. PMID- 28562255 TI - Behavioral Problems and Socioemotional Competence at 18 to 22 Months of Extremely Premature Children. AB - BACKGROUND: Behavior and socioemotional development are crucial aspects of child development . METHODS: A total of 2505 children born at <27 weeks' gestation was evaluated at 18 to 22 months' corrected age between January 1, 2008 and December 12, 2012 (86% follow-up). The Brief Infant and Toddler Social and Emotional Assessment was used to evaluate behavioral and socioemotional problems. Cognition and language were evaluated by using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Logistic regression analysis was used to evaluate for perinatal and demographic factors associated with behavioral problems (>=75th percentile) and delayed socioemotional competence (<=15th percentile). Structural equation modeling with bootstrapping was used to identify possible associated risk factors and Bayley-III scores as mediators. RESULTS: Thirty-five percent (873) of children had behavioral problems, and 26% (637) displayed deficits in socioemotional competence. Male sex, public insurance, mothers with less than a high school education, and lower maternal age were associated with behavioral problems. Deficits in competence were associated with lower birth weight, public insurance, mothers with less than a high school education, and abnormal neuromotor exam. Bayley-III language and cognitive scores were significant mediators of the relationships between risk factors and both behavioral and competence scores (P < .05). CONCLUSIONS: Extremely premature children are at risk for behavioral problems and deficits in socioemotional competence. Sociodemographic factors were associated with both socioemotional competence and behavioral problems. Deficits in socioemotional competence were also associated with neuromotor abnormalities and cognitive and language function. PMID- 28562256 TI - Sporadic Insulinoma Presenting as Early Morning Night Terrors. AB - A 16-year-old boy with a recent diagnosis of night terrors was evaluated for recurrent early morning hypoglycemia after an early morning seizure. Evaluation in clinic with critical laboratories identified hyperinsulinemic hypoglycemia. Additional investigation revealed a sporadic insulinoma as the etiology of his hypoglycemia and all symptoms were resolved after pancreaticoduodenectomy. The importance of obtaining critical laboratory samples is highlighted and appropriate radiologic, medical, and pathologic testing is discussed. We additionally review the medical and surgical management of hyperinsulinemic hypoglycemia. A discussion of multiple endocrine neoplasia type 1 associated insulinomas is included as well. This case highlights the importance of considering hypoglycemia in the evaluation of night terrors and new-onset seizures. PMID- 28562257 TI - Smoke-Free Legislation in Spain and Prematurity. AB - BACKGROUND AND OBJECTIVE: Spain implemented a partial smoking ban in 2006 followed by a comprehensive ban in 2011. The objective was to examine the association between these smoke-free policies and different perinatal complications. METHODS: Cross-sectional study including all live births between 2000 and 2013. Selected adverse birth outcomes were: preterm births (<37 gestational weeks), small for gestational age (SGA; <10th weight percentile according to Spanish reference tables), and low birth weight (<2500 g). We estimated immediate and gradual rate changes after smoking bans by using overdispersed Poisson models with different linear trends for 2000 to 2005 (preban), 2006 to 2010 (partial ban), and 2011 to 2013 (comprehensive ban). Models were adjusted for maternal sociodemographics, health care during the delivery, and smoking prevalence during pregnancy. RESULTS: The comprehensive ban was associated with preterm birth rate reductions of 4.5% (95% confidence interval [CI]: 2.9%-6.1%) and 4.1% (95% CI: 2.5%-5.6%) immediately and 1 year after implementation, respectively. The low birth weight rate also dropped immediately (2.3%; 95% CI: 0.7%-3.8%) and 1 year after the comprehensive ban implementation (3.5%; 95% CI: 2.1%-5.0%). There was an immediate reduction in the SGA rate at the onset of the partial ban (4.9%; 95% CI: 3.5%-6.2%), which was sustained 1 year postimplementation. Although not associated with the comprehensive ban at the onset, the SGA rate declined by 1.7% (95% CI: 0.3%-3.1%) 1 year postimplementation. CONCLUSIONS: The implementation of the Spanish smoke free policies was associated with a risk reduction for preterm births and low birth weight infants, especially with the introduction of the more restrictive ban. PMID- 28562258 TI - The Impact of Pediatric-Specific Vancomycin Dosing Guidelines: A Quality Improvement Initiative. AB - BACKGROUND AND OBJECTIVES: There are limited data guiding vancomycin dosing practices in the pediatric population to target the goal troughs recommended by national vancomycin guidelines. In this study, we sought to improve adherence to guideline trough targets through a quality improvement intervention. METHODS: A retrospective analysis was first conducted to assess baseline performance. A multidisciplinary team then developed and implemented a standardized dosing algorithm recommending 15 mg/kg per dose for mild and moderate infections (goal trough: 10-15 ug/mL) and 20 mg/kg per dose for severe infections (goal trough: 15 20 ug/mL), both delivered every 6 hours (maximum single dose: 750 mg). The impact of the intervention was evaluated prospectively using standard statistics and quality improvement methodology. The outcome measures included the percentage of patients with an initial therapeutic trough and the time to therapeutic trough. RESULTS: A total of 116 patients (49 preintervention, 67 postintervention) were included. Postintervention, there was a significant increase in the percentage of patients with an initial therapeutic trough (6.1% to 20.9%, P = .03) and in the percentage of patients with initial troughs between 10 and 20 ug/mL (8.2% to 40.3%, P < .001). The time to therapeutic trough decreased from 2.78 to 1.56 days (P = .001), with the process control chart showing improved control postintervention. Vancomycin-related toxicity was unchanged by the intervention (6.1% versus 4.5%; P = .70). CONCLUSIONS: Using quality improvement methodology with standardized higher initial vancomycin doses, we demonstrated improved adherence to national trough guidelines without noted safety detriment. PMID- 28562260 TI - Ten-Year Trends in Bullying and Related Attitudes Among 4th- to 12th-Graders. AB - BACKGROUND AND OBJECTIVES: Bullying is a significant public health concern, and it has received considerable attention from the media and policymakers over the past decade, which has led some to believe that it is increasing. However, there are limited surveillance data on bullying to inform our understanding of such trends over the course of multiple years. The current study examined the prevalence of bullying and related behaviors between 2005 and 2014 and explored whether any such changes varied across schools or as a function of school-level covariates. METHODS: Youth self-reports of 13 indicators of bullying and related behaviors were collected from 246 306 students in 109 Maryland schools across 10 years. The data were weighted to reflect the school populations and were analyzed by using longitudinal hierarchical linear modeling to examine changes over time. RESULTS: The covariate-adjusted models indicated a significant improvement over bullying and related concerns in 10 out of 13 indicators (including a decrease in bullying and victimization) for in-person forms (ie, physical, verbal, relational) and cyberbullying. Results also showed an increase in the perceptions that adults do enough to stop bullying and students' feelings of safety and belonging at school. CONCLUSIONS: Prevalence of bullying and related behaviors generally decreased over this 10-year period with the most recent years showing the greatest improvements in school climate and reductions in bullying. Additional research is needed to identify factors that contributed to this declining trend. PMID- 28562259 TI - Racial and Ethnic Differences in ADHD Treatment Quality Among Medicaid-Enrolled Youth. AB - OBJECTIVES: We estimated racial/ethnic differences in attention deficit/hyperactivity disorder (ADHD) care quality and treatment continuity among Medicaid-enrolled children. METHODS: Using Medicaid data from 9 states (2008 to 2011), we identified 172 322 youth (age 6 to 12) initiating ADHD medication. Outcome measures included: (1) adequate follow-up care in the (a) initiation and (b) continuation and maintenance (C&M) treatment phases; (2) combined treatment with medication and psychotherapy (versus medication alone); (3) medication discontinuation; and (4) treatment disengagement (ie, discontinued medication and received no psychotherapy). Logistic regressions controlled for confounding measures. RESULTS: Among those initiating medication, three-fifths received adequate follow-up care in the initiation and C&M phases, and under two-fifths received combined treatment. Compared with whites, African American youth were less likely to receive adequate follow-up in either phase (P < .05), whereas Hispanic youth were more likely to receive adequate follow-up in the C&M phase (P < .001). African American and Hispanic youth were more likely than whites to receive combined treatment (P < .05). Over three-fifths discontinued medication, and over four-tenths disengaged from treatment. Compared with whites, African American and Hispanic children were 22.4% and 16.7% points more likely to discontinue medication, and 13.1% and 9.4% points more likely to disengage from treatment, respectively (P < .001). CONCLUSIONS: Care quality for Medicaid enrolled youth initiating ADHD medication is poor, and racial/ethnic differences in these measures are mixed. The most important disparities occur in the higher rates of medication discontinuation among minorities, which translate into higher rates of treatment disengagement because most youth discontinuing medication receive no psychotherapy. PMID- 28562261 TI - Early Puberty, Friendship Group Characteristics, and Dating Abuse in US Girls. AB - OBJECTIVES: The current study aimed to investigate the relationship between advanced pubertal development and adolescent dating abuse (ADA) and to test if this relationship is moderated by friendship group characteristics in a nationally representative sample of US girls. METHODS: Data were drawn from wave 1 and 2 (1995-1996) of the National Longitudinal Study of Adolescent to Adult Health. The sample included 3870 girls aged 13 to 17 years, all of whom were in romantic and/or nonromantic sexual relationships. Relative pubertal development was measured as perceived physical development as compared with peers of the same age and race and age at menarche at wave 1. Participants reported at wave 2 whether they had experienced any verbal or physical abuse in their relationships. Friendship group characteristics included the percentage of boy friends, older friends, and friends' risk behavior level. RESULTS: Negative binomial regression analyses revealed an interaction between advanced pubertal development and percentage of boy friends on ADA victimization, adjusted for age, race, parents' marital status, household income, number of relationships, self-esteem, self control, and antisocial behavior history. Advanced pubertal development was associated with more ADA victimization when girls' friendship groups comprised a higher percentage of boys. CONCLUSIONS: Findings highlight the importance of pubertal timing and friendship group characteristics to ADA victimization. Early pubertal development is a risk marker for ADA victimization, particularly when a higher percentage of girls' friends are boys. Pediatricians and adolescent health specialists should be sensitive to the elevated risk for ADA victimization in early-maturing girls. PMID- 28562262 TI - Safety Profile of Cough and Cold Medication Use in Pediatrics. AB - BACKGROUND AND OBJECTIVES: The safety of cough and cold medication (CCM) use in children has been questioned. We describe the safety profile of CCMs in children <12 years of age from a multisystem surveillance program. METHODS: Cases with adverse events (AEs) after ingestion of at least 1 index CCM ingredient (brompheniramine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, phenylephrine, and pseudoephedrine) in children <12 years of age were collected from 5 data sources. An expert panel determined relatedness, dose, intent, and risk factors. Case characteristics and AEs are described. RESULTS: Of the 4202 cases reviewed, 3251 (77.4%) were determined to be at least potentially related to a CCM, with accidental unsupervised ingestions (67.1%) and medication errors (13.0%) the most common exposure types. Liquid (67.3%), pediatric (75.5%), and single-ingredient (77.5%) formulations were most commonly involved. AEs occurring in >20% of all cases included tachycardia, somnolence, hallucinations, ataxia, mydriasis, and agitation. Twenty cases (0.6%) resulted in death; most were in children <2 years of age (70.0%) and none involved a therapeutic dose. The overall reported AE rate was 0.573 cases per 1 million units (ie, tablets, gelatin capsules, or liquid equivalent) sold (95% confidence interval, 0.553-0.593) or 1 case per 1.75 million units. CONCLUSIONS: The rate of AEs associated with CCMs in children was low. Fatalities occurred even less frequently. No fatality involved a therapeutic dose. Accidental unsupervised ingestions were the most common exposure types and single ingredient, pediatric liquid formulations were the most commonly reported products. These characteristics present an opportunity for targeted prevention efforts. PMID- 28562263 TI - Birth Weight and Intelligence in Young Adulthood and Midlife. AB - OBJECTIVES: We examined the associations between birth weight and intelligence at 3 different adult ages. METHODS: The Copenhagen Perinatal Cohort is comprised of children born in Copenhagen from 1959 to 1961. Information on birth weight and >=1 tests of intelligence was available for 4696 members of the cohort. Intelligence was assessed at a mean age of 19 years with the Borge Priens Prove test, at age 28 years with the Wechsler Adult Intelligence Scale, and at age 50 years with the Intelligenz-Struktur-Test 2000 R. RESULTS: Birth weight was significantly associated with intelligence at all 3 follow-up assessments, with intelligence scores increasing across 4 birth weight categories and declining for the highest birth weight category. The adjusted differences between those in the <2.5kg birth weight group and those in the 3.5 to 4.00kg group were >5 IQ points at all 3 follow-up assessments, corresponding to one-third of a SD. The association was stable from young adulthood into midlife,and not weaker at age 50 years. Adjustment for potential confounding factors, including infant socioeconomic status and gestational age, did not dilute the associations, and associations with intelligence were evident across the normal birth weight range and so were not accounted for by low birth weight only. CONCLUSIONS: The association between birth weight and intelligence is stable from young adulthood into midlife. These long-term cognitive consequences may imply that even small shifts in the distribution of birth size, in normal-sized infants as well, may have a large impact at the population level. PMID- 28562264 TI - Adult Consequences of Self-Limited Delayed Puberty. AB - Delayed puberty is a common condition defined as the lack of sexual maturation by an age >=2 SD above the population mean. In the absence of an identified underlying cause, the condition is usually self-limited. Although self-limited delayed puberty is largely believed to be a benign developmental variant with no long-term consequences, several studies have suggested that delayed puberty may in fact have both harmful and protective effects on various adult health outcomes. In particular, height and bone mineral density have been shown to be compromised in some studies of adults with a history of delayed puberty. Delayed puberty may also negatively affect adult psychosocial functioning and educational achievement, and individuals with a history of delayed puberty carry a higher risk for metabolic and cardiovascular disorders. In contrast, a history of delayed puberty appears to be protective for breast and endometrial cancer in women and for testicular cancer in men. Most studies on adult outcomes of self limited delayed puberty have been in small series with significant variability in outcome measures and study criteria. In this article, we review potential medical and psychosocial issues for adults with a history of self-limited delayed puberty, discuss potential mechanisms underlying these issues, and identify gaps in knowledge and directions for future research. PMID- 28562265 TI - Trends in Food and Beverage Consumption Among Infants and Toddlers: 2005-2012. AB - BACKGROUND: Nutritional guidance for infants and toddlers is lacking, and the diets of American children in the first 2 years of life are not well characterized. METHODS: Cross-sectional data from the NHANES were used to describe the diets of 0- to 23-month-olds in the United States. Participants with complete dietary data were eligible for the analysis (N = 2359). Linear regression models were constructed to identify changes from 2005 to 2008 and from 2009 to 2012 in food and beverage consumption, both overall and within sociodemographic groups. RESULTS: We observed several trends toward meeting early feeding recommendations, such as a decline in the prevalence of complementary feeding among 0- to 5-month-olds. However, the prevalence of vegetable consumption was consistently lower than desired (~25% of 6- to 11-month-olds and 20% of 12- to 23-month-olds had no reported vegetable consumption on dietary recall days in the 2009-2012 set). Subgroup analyses revealed that some trends were limited to certain populations (eg, a decline in juice consumption was observed among 6- to 11-month-old non-Hispanic whites and non-Hispanic blacks but not among Mexican Americans), and additional trends emerged within groups (eg, the prevalence of breast milk consumption declined among 0- to 5-month-old Mexican Americans). CONCLUSIONS: Although there have been some improvements in the diets of 0- to 23-month-olds in recent years, there are areas in which this population continues to fall short of current recommendations. This underscores the need for additional policy guidance for providers and education for parents and caretakers on helping infants and toddlers achieve healthy diets. PMID- 28562267 TI - An Initiative to Improve the Quality of Care of Infants With Neonatal Abstinence Syndrome. AB - BACKGROUND AND OBJECTIVES: The incidence of neonatal abstinence syndrome (NAS), a constellation of neurologic, gastrointestinal, and musculoskeletal disturbances associated with opioid withdrawal, has increased dramatically and is associated with long hospital stays. At our institution, the average length of stay (ALOS) for infants exposed to methadone in utero was 22.4 days before the start of our project. We aimed to reduce ALOS for infants with NAS by 50%. METHODS: In 2010, a multidisciplinary team began several plan-do-study-act cycles at Yale New Haven Children's Hospital. Key interventions included standardization of nonpharmacologic care coupled with an empowering message to parents, development of a novel approach to assessment, administration of morphine on an as-needed basis, and transfer of infants directly to the inpatient unit, bypassing the NICU. The outcome measures included ALOS, morphine use, and hospital costs using statistical process control charts. RESULTS: There were 287 infants in our project, including 55 from the baseline period (January 2008 to February 2010) and 44 from the postimplementation period (May 2015 to June 2016). ALOS decreased from 22.4 to 5.9 days. Proportions of methadone-exposed infants treated with morphine decreased from 98% to 14%; costs decreased from $44 824 to $10 289. No infants were readmitted for treatment of NAS and no adverse events were reported. CONCLUSIONS: Interventions focused on nonpharmacologic therapies and a simplified approach to assessment for infants exposed to methadone in utero led to both substantial and sustained decreases in ALOS, the proportion of infants treated with morphine, and hospital costs with no adverse events. PMID- 28562268 TI - Peer Victimization, Depressive Symptoms, and Substance Use: A Longitudinal Analysis. AB - BACKGROUND: Peer victimization is common among youth and associated with substance use. Yet, few studies have examined these associations longitudinally or the psychological processes whereby peer victimization leads to substance use. The current study examined whether peer victimization in early adolescence is associated with alcohol, marijuana, and tobacco use in mid- to late adolescence, as well as the role of depressive symptoms in these associations. METHODS: Longitudinal data were collected between 2004 and 2011 from 4297 youth in Birmingham, Alabama; Houston, Texas; and Los Angeles County, California. Data were analyzed by using structural equation modeling. RESULTS: The hypothesized model fit the data well (Root Mean Square Error of Approximation [RMSEA] = 0.02; Comparative Fit Index [CFI] = 0.95). More frequent experiences of peer victimization in the fifth grade were associated with greater depressive symptoms in the seventh grade (B[SE] = 0.03[0.01]; P < .001), which, in turn, were associated with a greater likelihood of alcohol use (B[SE] = 0.03[0.01]; P = .003), marijuana use (B[SE] = 0.05[0.01]; P < .001), and tobacco use (B[SE] = 0.05[0.01]; P < .001) in the tenth grade. Moreover, fifth-grade peer victimization was indirectly associated with tenth-grade substance use via the mediator of seventh-grade depressive symptoms, including alcohol use (B[SE] = 0.01[0.01]; P = .006), marijuana use (B[SE] = 0.01[0.01]; P < .001), and tobacco use (B[SE] = 0.02[0.01]; P < .001). CONCLUSIONS: Youth who experienced more frequent peer victimization in the fifth grade were more likely to use substances in the tenth grade, showing that experiences of peer victimization in early adolescence may have a lasting impact by affecting substance use behaviors during mid- to late adolescence. Interventions are needed to reduce peer victimization among youth and to support youth who have experienced victimization. PMID- 28562266 TI - Receptivity to Tobacco Advertising and Susceptibility to Tobacco Products. AB - BACKGROUND AND OBJECTIVES: Non-cigarette tobacco marketing is less regulated and may promote cigarette smoking among adolescents. We quantified receptivity to advertising for multiple tobacco products and hypothesized associations with susceptibility to cigarette smoking. METHODS: Wave 1 of the nationally representative PATH (Population Assessment of Tobacco and Health) study interviewed 10 751 adolescents who had never used tobacco. A stratified random selection of 5 advertisements for each of cigarettes, e-cigarettes, smokeless products, and cigars were shown from 959 recent tobacco advertisements. Aided recall was classified as low receptivity, and image-liking or favorite ad as higher receptivity. The main dependent variable was susceptibility to cigarette smoking. RESULTS: Among US youth, 41% of 12 to 13 year olds and half of older adolescents were receptive to at least 1 tobacco advertisement. Across each age group, receptivity to advertising was highest for e-cigarettes (28%-33%) followed by cigarettes (22%-25%), smokeless tobacco (15%-21%), and cigars (8%-13%). E cigarette ads shown on television had the highest recall. Among cigarette susceptible adolescents, receptivity to e-cigarette advertising (39.7%; 95% confidence interval [CI]: 37.9%-41.6%) was higher than for cigarette advertising (31.7%; 95% CI: 29.9%-33.6%). Receptivity to advertising for each tobacco product was associated with increased susceptibility to cigarette smoking, with no significant difference across products (similar odds for both cigarette and e cigarette advertising; adjusted odds ratio = 1.22; 95% CI: 1.09-1.37). CONCLUSIONS: A large proportion of US adolescent never tobacco users are receptive to tobacco advertising, with television advertising for e-cigarettes having the highest recall. Receptivity to advertising for each non-cigarette tobacco product was associated with susceptibility to smoke cigarettes. PMID- 28562269 TI - Ethical Conduct of Research in Children: Pediatricians and Their IRB (Part 2 of 2). AB - In part 1 of this series, we discussed the historical, ethical, and legal background that provides justification for the current system of protection of subjects of human experimentation. We also discussed briefly the implementation of those principles in institutional review board (IRB) operations. In part 2, we focus on legislation dealing with pediatric research, the rules and ethics of assent, and then turn our attention to minimal-risk studies. To that end, we discuss the minimal-risk threshold and the process of balancing benefit and risk in IRB decisions for pediatric studies. We define the notion of consent waiver as well as the procedures for expedited review, management of adverse events, and amendments to approved protocol. Finally, we mention some miscellaneous issues, including central and commercial IRB, reliance agreements, biobanks, and sample shipping regulations. PMID- 28562270 TI - When Should Trainees Call for Help With Invasive Procedures? PMID- 28562271 TI - Pandemic Influenza Preparedness Among Child Care Center Directors in 2008 and 2016. AB - BACKGROUND: Children in child care centers represent an important population to consider in attempts to mitigate the spread of an influenza pandemic. This national survey, conducted in 2008 and 2016, assessed directors' reports of their child care centers' pandemic influenza preparation before and after the 2009 H1N1 novel influenza pandemic. METHODS: This was a telephone-based survey of child care center directors randomly selected from a national database of licensed US child care centers who were queried about their preparedness for pandemic influenza. We grouped conceptually related items in 6 domains into indexes: general infection control, communication, seasonal influenza control, use of health consultants, quality of child care, and perceived barriers. These indexes, along with other center and director characteristics, were used to predict pandemic influenza preparedness. RESULTS: Among 1500 and 518 child care center directors surveyed in 2008 and 2016, respectively, preparation for pandemic influenza was low and did not improve. Only 7% of directors had taken concrete actions to prepare their centers. Having served as a center director during the 2009 influenza pandemic did not influence preparedness. After adjusting for covariates, child care health consultation and years of director's experience were positively associated with pandemic influenza preparation, whereas experiencing perceived barriers such as lack of knowing what to do in the event of pandemic influenza, was negatively associated with pandemic influenza preparedness. CONCLUSIONS: Pandemic influenza preparedness of child care center's directors needs to improve. Child care health consultants are likely to be important collaborators in addressing this problem. PMID- 28562272 TI - Racial and Ethnic Trends in Sudden Unexpected Infant Deaths: United States, 1995 2013. AB - BACKGROUND AND OBJECTIVES: Immediately after the 1994 Back-to-Sleep campaign, sudden unexpected infant death (SUID) rates decreased dramatically, but they have remained relatively stable (93.4 per 100 000 live births) since 2000. In this study, we examined trends in SUID rates and disparities by race/ethnicity since the Back-to-Sleep campaign. METHODS: We used 1995-2013 US period-linked birth infant death data to evaluate SUID rates per 100 000 live births by non-Hispanic white (NHW), non-Hispanic black (NHB), Hispanic, American Indian/Alaska Native, and Asian/Pacific Islander racial/ethnic groupings. To examine racial/ethnic disparities, we calculated rate ratios with NHWs as the referent group. Unadjusted linear regression was used to evaluate trends (P < .05) in rates and rate ratios. The distribution and rates of SUID by demographic and birth characteristics were compared for 1995-1997 and 2011-2013, and chi2 tests were used to evaluate significance. RESULTS: From 1995 to 2013, SUID rates were consistently highest for American Indian/Alaska Natives, followed by NHBs. The rate for NHBs decreased significantly, whereas the rate for NHWs also declined, but not significantly. As a result, the disparity between NHWs and NHBs narrowed slightly. The SUID rates for Hispanics and Asian/Pacific Islanders were lower than the rates for NHWs and showed a significant decrease, resulting in an increase in their advantage over NHWs. CONCLUSIONS: Each racial/ethnic group showed a unique trend in SUID rates since the Back-to-Sleep campaign. When implementing risk-reduction strategies, it is important to consider these trends in targeting populations for prevention and developing culturally appropriate approaches for racial/ethnic communities. PMID- 28562273 TI - Supporting Global Health at the Pediatric Department Level: Why and How. PMID- 28562274 TI - Ethical Controversy About Hysterectomy for a Minor. AB - One of the most complicated ethical issues that arises in children's hospitals today is the issue of whether it is ever permissible to perform a procedure for a minor that will result in permanent sterilization. In most cases, the answer is no. The availability of good, safe, long-acting contraception allows surgical options to be postponed when the primary goal of such surgical options is to prevent pregnancy. But what if a minor has congenital urogenital anomalies or other medical conditions for which the best treatment is a hysterectomy? In those cases, the primary goal of therapy is not to prevent pregnancy. Instead, sterility is an unfortunate side effect of a medically indicated treatment. Should that side effect preclude the provision of a therapy that is otherwise medically appropriate? We present a case that raises these issues, and asked experts in law, bioethics, community advocacy, and gynecology to respond. They discuss whether the best option is to proceed with the surgery or to cautiously delay making a decision to give the teenager more time to carefully consider all of the options. PMID- 28562275 TI - Frequent Binge Drinking Among US Adolescents, 1991 to 2015. AB - BACKGROUND AND OBJECTIVES: Scientific understanding of the forces involved in the decades-long decline of adolescent alcohol use in the United States is limited. This study examines specific changes in US adolescent frequent binge drinking (FBD) by age (variation due to maturation), period (variation across time that does not covary across age), and cohort (variation common to adolescents born around the same time). METHODS: We analyzed nationally representative, multicohort data from 8th, 10th, and 12th grade students sampled between 1991 and 2015 from Monitoring the Future (n = 1 065 022) to estimate age, period, and cohort effects on adolescents' FBD (defined as >=2 occasions of >=5 drinks in a row during the past 2 weeks). Age-Period-Cohort analyses were stratified by sex, race/ethnicity, and socioeconomic status (SES). Trends in the associations between demographics and FBD across historical time were examined. RESULTS: Decreases in FBD during adolescence were attributable to period and cohort effects independent of age variations. Birth cohorts between 1985 and 1990 showed the greatest decline in FBD. The Age-Period-Cohort results were consistent across sex, race/ethnicity, and SES, with the exception of slower declines seen among African American adolescents compared with white adolescents since 2007. We also found convergence in FBD by sex and divergence by SES. CONCLUSIONS: Recent declines in adolescent FBD have been driven by period and cohort effects. Attention is warranted for the slower declines in FBD seen among African American adolescents since 2007, a narrowing difference by sex, and a growing gap by SES. PMID- 28562276 TI - Childhood Social Disadvantage and Pubertal Timing: A National Birth Cohort From Australia. AB - BACKGROUND AND OBJECTIVES: Early pubertal timing is linked with a range of adverse health outcomes later. Given recent trends of earlier pubertal maturation, there is growing interest in the factors influencing pubertal timing. Socioeconomic disadvantage has been previously linked with reproductive strategies later in life. In this study, we aim to determine the association between cumulative social disadvantages in early life and early puberty in a population-based birth cohort. METHODS: Data are from the B (baby) cohort of The Longitudinal Study of Australian Children. Children (n = 5107) were aged 0 to 1 years when recruited in 2004 and 10 to 11 years (n = 3764) at Wave 6 in 2015. Household socioeconomic position (SEP) and neighborhood socioeconomic disadvantage were collected at all 6 waves. Trajectories of disadvantage were identified through latent class models. Early puberty at Wave 6 was assessed from parental reports using an adaptation of the Pubertal Development Scale. RESULTS: Cumulative exposure to extremely unfavorable household SEP in boys independently predicted a fourfold increase (odds ratio = 4.22, 95% confidence interval 2.27 7.86) in the rate of early puberty. In girls, the increase was twofold (odds ratio = 1.96, 95% confidence interval 1.08-3.56). We found no effect from neighborhood disadvantage once family SEP was taken into account. CONCLUSIONS: Cumulative exposure to household socioeconomic disadvantage in early life predicts earlier pubertal timing in both boys and girls. This may represent 1 mechanism underpinning associations between early life disadvantage and poor health in later life. PMID- 28562277 TI - Reducing Hospitalization Rates for Children With Anaphylaxis. AB - BACKGROUND AND OBJECTIVES: Most children with anaphylaxis in the emergency department (ED) are hospitalized. Opportunities exist to safely reduce the hospitalization rate for children with anaphylaxis by decreasing unnecessary hospitalizations. A quality improvement (QI) intervention was conducted to improve care and reduce hospitalization rates for children with anaphylaxis. METHODS: We used the Model for Improvement and began with development and implementation in 2011 of a locally developed evidence-based guideline based on national recommendations for the management of anaphylaxis. Guideline adoption and adherence were supported by interval reminders and feedback to providers. Patients from 2008 to 2014 diagnosed with anaphylaxis were identified, and statistical process control methods were used to evaluate change in hospitalization rates over time. The balancing measure was any return visit to the ED within 72 hours. To control for secular trends, hospitalization rates for anaphylaxis at 34 US children's hospitals over the same time period were analyzed. RESULTS: Over the study period, there were 1169 visits for children with anaphylaxis, of which 731 (62%) occurred after the QI implementation. The proportion of children hospitalized decreased from 54% to 36%, with no increase in the 72-hour ED revisit rate. The hospitalization rate across 34 other US pediatric hospitals remained static at 52% over the study period. CONCLUSIONS: We safely reduced unnecessary hospitalizations for children with anaphylaxis and sustained the change over 3 years by using a QI initiative that included evidence based guideline development and implementation, reinforced by provider reminders and structured feedback. PMID- 28562279 TI - Effectiveness of Evidence-Based Asthma Interventions. AB - BACKGROUND AND OBJECTIVES: Researchers often struggle with the gap between efficacy and effectiveness in clinical research. To bridge this gap, the Community Healthcare for Asthma Management and Prevention of Symptoms (CHAMPS) study adapted an efficacious, randomized controlled trial that resulted in evidence-based asthma interventions in community health centers. METHODS: Children (aged 5-12 years; N = 590) with moderate to severe asthma were enrolled from 3 intervention and 3 geographically/capacity-matched control sites in high risk, low-income communities located in Arizona, Michigan, and Puerto Rico. The asthma intervention was tailored to the participant's allergen sensitivity and exposure, and it comprised 4 visits over the course of 1 year. Study visits were documented and monitored prospectively via electronic data capture. Asthma symptoms and health care utilization were evaluated at baseline, and at 6 and 12 months. RESULTS: A total of 314 intervention children and 276 control children were enrolled in the study. Allergen sensitivity testing (96%) and home environmental assessments (89%) were performed on the majority of intervention children. Overall study activity completion (eg, intervention visits, clinical assessments) was 70%. Overall and individual site participant symptom days in the previous 4 weeks were significantly reduced compared with control findings (control, change of -2.28; intervention, change of -3.27; difference, -0.99; P < .001), and this result was consistent with changes found in the rigorous evidence based interventions. CONCLUSIONS: Evidence-based interventions can be successfully adapted into primary care settings that serve impoverished, high risk populations, reducing the morbidity of asthma in these high-need populations. PMID- 28562278 TI - Maternal Use of Opioids During Pregnancy and Congenital Malformations: A Systematic Review. AB - CONTEXT: Opioid use and abuse have increased dramatically in recent years, particularly among women. OBJECTIVES: We conducted a systematic review to evaluate the association between prenatal opioid use and congenital malformations. DATA SOURCES: We searched Medline and Embase for studies published from 1946 to 2016 and reviewed reference lists to identify additional relevant studies. STUDY SELECTION: We included studies that were full-text journal articles and reported the results of original epidemiologic research on prenatal opioid exposure and congenital malformations. We assessed study eligibility in multiple phases using a standardized, duplicate review process. DATA EXTRACTION: Data on study characteristics, opioid exposure, timing of exposure during pregnancy, congenital malformations (collectively or as individual subtypes), length of follow-up, and main findings were extracted from eligible studies. RESULTS: Of the 68 studies that met our inclusion criteria, 46 had an unexposed comparison group; of those, 30 performed statistical tests to measure associations between maternal opioid use during pregnancy and congenital malformations. Seventeen of these (10 of 12 case-control and 7 of 18 cohort studies) documented statistically significant positive associations. Among the case-control studies, associations with oral clefts and ventricular septal defects/atrial septal defects were the most frequently reported specific malformations. Among the cohort studies, clubfoot was the most frequently reported specific malformation. LIMITATIONS: Variabilities in study design, poor study quality, and weaknesses with outcome and exposure measurement. CONCLUSIONS: Uncertainty remains regarding the teratogenicity of opioids; a careful assessment of risks and benefits is warranted when considering opioid treatment for women of reproductive age. PMID- 28562280 TI - The Benefits of New Guidelines to Prevent Peanut Allergy. PMID- 28562281 TI - Herbal Medicines for Gastrointestinal Disorders in Children and Adolescents: A Systematic Review. AB - CONTEXT: Gastrointestinal disorders are common childhood complaints. Particular types of complementary and alternative medicine, such as herbal medicine, are commonly used among children. Research information on efficacy, safety, or dosage forms is still lacking. OBJECTIVES: To systematically summarize effectiveness and safety of different herbal treatment options for gastrointestinal disorders in children. DATA SOURCES: Medline/PubMed, Scopus, and the Cochrane Library were searched through July 15, 2016. STUDY SELECTION: Randomized controlled trials comparing herbal therapy with no treatment, placebo, or any pharmaceutical medication in children and adolescents (aged 0-18 years) with gastrointestinal disorders were eligible. DATA EXTRACTION: Two authors extracted data on study design, patients, interventions, control interventions, results, adverse events, and risk of bias. RESULTS: Fourteen trials with 1927 participants suffering from different acute and functional gastrointestinal disorders were included in this review. Promising evidence for effectiveness was found for Potentilla erecta, carob bean juice, and an herbal compound preparation including Matricaria chamomilla in treating diarrhea. Moreover, evidence was found for peppermint oil in decreasing duration, frequency, and severity of pain in children suffering from undifferentiated functional abdominal pain. Furthermore, evidence for effectiveness was found for different fennel preparations (eg, oil, tea, herbal compound) in treating children with infantile colic. No serious adverse events were reported. LIMITATIONS: Few studies on specific indications, single herbs, or herbal preparations could be identified. CONCLUSIONS: Because of the limited number of studies, results have to be interpreted carefully. To underpin evidence outlined in this review, more rigorous clinical trials are needed. PMID- 28562282 TI - Aspirin Dose and Prevention of Coronary Abnormalities in Kawasaki Disease. AB - BACKGROUND: Acetylsalicylic acid (ASA) is part of the recommended treatment of Kawasaki disease (KD). Controversies remain regarding the optimal dose of ASA to be used. We aimed to evaluate the noninferiority of ASA at an antiplatelet dose in acute KD in preventing coronary artery (CA) abnormalities. METHODS: This is a multicenter, retrospective, nonrandomized cohort study including children 0 to 10 years of age with acute KD between 2004 and 2015 from 5 institutions, of which 2 routinely use low-dose ASA (3-5 mg/kg per day) and 3 use high-dose ASA (80 mg/kg per day). Outcomes were CA abnormalities defined as a CA diameter with a z score >=2.5. We assessed the risk difference of CA abnormalities according to ASA dose. All subjects received ASA and intravenous immunoglobulin within 10 days of fever onset. RESULTS: There were 1213 subjects included, 848 in the high-dose and 365 in the low-dose ASA group. There was no difference in the risk of CA abnormalities in the low-dose compared with the high-dose ASA group (22.2% vs 20.5%). The risk difference adjusted for potential confounders was 0.3% (95% confidence interval [CI]: -4.5% to 5.0%). The adjusted risk difference for CA abnormalities persisting at the 6-week follow-up was -1.9% (95% CI: -5.3% to 1.5%). The 95% CI of the risk difference of CA abnormalities adjusted for confounders was within the prespecified 5% margin considered to be noninferior. CONCLUSIONS: In conjunction with intravenous immunoglobulin, low-dose ASA in acute KD is not inferior to high-dose ASA for reducing the risk of CA abnormalities. PMID- 28562283 TI - Effectiveness of Tympanostomy Tubes for Otitis Media: A Meta-analysis. AB - CONTEXT: Tympanostomy tube placement is the most common ambulatory surgery performed on children in the United States. OBJECTIVES: The goal of this study was to synthesize evidence for the effectiveness of tympanostomy tubes in children with chronic otitis media with effusion and recurrent acute otitis media. DATA SOURCES: Searches were conducted in Medline, the Cochrane Central Trials Registry and Cochrane Database of Systematic Reviews, Embase, and the Cumulative Index to Nursing and Allied Health Literature. STUDY SELECTION: Abstracts and full-text articles were independently screened by 2 investigators. DATA EXTRACTION: A total of 147 articles were included. When feasible, random effects network meta-analyses were performed. RESULTS: Children with chronic otitis media with effusion treated with tympanostomy tubes compared with watchful waiting had a net decrease in mean hearing threshold of 9.1 dB (95% credible interval: -14.0 to -3.4) at 1 to 3 months and 0.0 (95% credible interval: -4.0 to 3.4) by 12 to 24 months. Children with recurrent acute otitis media may have fewer episodes after placement of tympanostomy tubes. Associated adverse events are poorly defined and reported. LIMITATIONS: Sparse evidence is available, applicable only to otherwise healthy children. CONCLUSIONS: Tympanostomy tubes improve hearing at 1 to 3 months compared with watchful waiting, with no evidence of benefit by 12 to 24 months. Children with recurrent acute otitis media may have fewer episodes after tympanostomy tube placement, but the evidence base is severely limited. The benefits of tympanostomy tubes must be weighed against a variety of associated adverse events. PMID- 28562285 TI - Navigating Decisional Discord: The Pediatrician's Role When Child and Parents Disagree. AB - From the time when children enter the preteen years onward, pediatric medical decision-making can entail a complex interaction between child, parents, and pediatrician. When the child and parents disagree regarding medical decisions, the pediatrician has the challenging task of guiding the family to a final decision. Unresolved discord can affect family cohesiveness, patient adherence, and patient self-management. In this article, we outline 3 models for the pediatrician's role in the setting of decisional discord: deference, advocative, and arbitrative. In the deference model, the pediatrician prioritizes parental decision-making authority. In the advocative model, the pediatrician advocates for the child's preference in decision-making so long as the child's decision is medically reasonable. In the arbitrative model, the pediatrician works to resolve the conflict in a balanced fashion. Although each model has advantages and disadvantages, the arbitrative model should serve as the initial model in nearly all settings. The arbitrative model is likely to reach the most beneficial decision in a manner that maintains family cohesiveness by respecting the authority of parents and the developing autonomy of children. We also highlight, however, occasions when the deference or advocative models may be more appropriate. Physicians should keep all 3 models available in their professional toolkit and develop the wisdom to deploy the right model for each particular clinical situation. PMID- 28562284 TI - Epidemiology of Methicillin-Resistant Staphylococcus aureus Bacteremia in Children. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with high rates of treatment failure in adults. The epidemiology, clinical outcomes, and risk factors for treatment failure associated with MRSA bacteremia in children are poorly understood. METHODS: Multicenter, retrospective cohort study of children <=18 years hospitalized with MRSA bacteremia across 3 tertiary care children's hospitals from 2007 to 2014. Treatment failure was defined as persistent bacteremia >3 days, recurrence of bacteremia within 30 days, or attributable 30-day mortality. Potential risk factors for treatment failure, including the site of infection, vancomycin trough concentration, critical illness, and need for source control, were collected via manual chart review and evaluated using multivariable logistic regression. RESULTS: Of 232 episodes of MRSA bacteremia, 72 (31%) experienced treatment failure and 23% developed complications, whereas 5 (2%) died within 30 days. Multivariable analysis of 174 children treated with vancomycin with steady-state vancomycin concentrations obtained found that catheter-related infections (odds ratio [OR], 0.36; 95% confidence interval [CI]: 0.13-0.94) and endovascular infections (OR, 4.35; 95% CI: 1.07-17.7) were associated with lower and higher odds of treatment failure, respectively, whereas a first vancomycin serum trough concentration <10 MUg/mL was not associated with treatment failure (OR, 1.34; 95% CI, 0.49-3.66). Each additional day of bacteremia was associated with a 50% (95% CI: 26%-79%) increased odds of bacteremia-related complications. CONCLUSIONS: Hospitalized children with MRSA bacteremia frequently suffered treatment failure and complications, but mortality was low. The odds of bacteremia-related complications increased with each additional day of bacteremia, emphasizing the importance of achieving rapid sterilization. PMID- 28562287 TI - Interventions Targeting Sensory Challenges in Autism Spectrum Disorder: A Systematic Review. AB - CONTEXT: Sensory challenges are common among children with autism spectrum disorder (ASD). OBJECTIVE: To evaluate the effectiveness and safety of interventions targeting sensory challenges in ASD. DATA SOURCES: Databases, including Medline and PsycINFO. STUDY SELECTION: Two investigators independently screened studies against predetermined criteria. DATA EXTRACTION: One investigator extracted data with review by a second. Investigators independently assessed risk of bias and strength of evidence (SOE), or confidence in the estimate of effects. RESULTS: Twenty-four studies, including 20 randomized controlled trials (RCTs), were included. Only 3 studies had low risk of bias. Populations, interventions, and outcomes varied. Limited, short-term studies reported potential positive effects of several approaches in discrete skill domains. Specifically, sensory integration-based approaches improved sensory and motor skills-related measures (low SOE). Environmental enrichment improved nonverbal cognitive skills (low SOE). Studies of auditory integration-based approaches did not improve language (low SOE). Massage improved symptom severity and sensory challenges in studies with likely overlapping participants (low SOE). Music therapy studies evaluated different protocols and outcomes, precluding synthesis (insufficient SOE). Some positive effects were reported for other approaches, but findings were inconsistent (insufficient SOE). LIMITATIONS: Studies were small and short-term, and few fully categorized populations. CONCLUSIONS: Some interventions may yield modest short-term (<6 months) improvements in sensory- and ASD symptom severity-related outcomes; the evidence base is small, and the durability of the effects is unclear. Although some therapies may hold promise, substantial needs exist for continuing improvements in methodologic rigor. PMID- 28562286 TI - Nutritional and Dietary Interventions for Autism Spectrum Disorder: A Systematic Review. AB - CONTEXT: Children with autism spectrum disorder (ASD) frequently use special diets or receive nutritional supplements to treat ASD symptoms. OBJECTIVES: Our objective was to evaluate the effectiveness and safety of dietary interventions or nutritional supplements in ASD. DATA SOURCES: Databases, including Medline and PsycINFO. STUDY SELECTION: Two investigators independently screened studies against predetermined criteria. DATA EXTRACTION: One investigator extracted data with review by a second investigator. Investigators independently assessed the risk of bias and strength of evidence (SOE) (ie, confidence in the estimate of effects). RESULTS: Nineteen randomized controlled trials (RCTs), 4 with a low risk of bias, evaluated supplements or variations of the gluten/casein-free diet and other dietary approaches. Populations, interventions, and outcomes varied. Omega-3 supplementation did not affect challenging behaviors and was associated with minimal harms (low SOE). Two RCTs of different digestive enzymes reported mixed effects on symptom severity (insufficient SOE). Studies of other supplements (methyl B12, levocarnitine) reported some improvements in symptom severity (insufficient SOE). Studies evaluating gluten/casein-free diets reported some parent-rated improvements in communication and challenging behaviors; however, data were inadequate to make conclusions about the body of evidence (insufficient SOE). Studies of gluten- or casein-containing challenge foods reported no effects on behavior or gastrointestinal symptoms with challenge foods (insufficient SOE); 1 RCT reported no effects of camel's milk on ASD severity (insufficient SOE). Harms were disparate. LIMITATIONS: Studies were small and short-term, and there were few fully categorized populations or concomitant interventions. CONCLUSIONS: There is little evidence to support the use of nutritional supplements or dietary therapies for children with ASD. PMID- 28562288 TI - Tackling Bullying: Grounds for Encouragement and Sustained Focus. PMID- 28562289 TI - Prevention and Treatment of Tympanostomy Tube Otorrhea: A Meta-analysis. AB - CONTEXT: Children with tympanostomy tubes often develop ear discharge. OBJECTIVE: Synthesize evidence about the need for water precautions (ear plugs or swimming avoidance) and effectiveness of topical versus oral antibiotic treatment of otorrhea in children with tympanostomy tubes. DATA SOURCES: Searches in Medline, the Cochrane Central Trials Registry and Cochrane Database of Systematic Reviews, Excerpta Medica Database, and the Cumulative Index to Nursing and Allied Health Literature. STUDY SELECTION: Abstracts and full-text articles independently screened by 2 investigators. DATA EXTRACTION: 25 articles were included. RESULTS: One randomized controlled trial (RCT) in children assigned to use ear plugs versus no precautions reported an odds ratio (OR) of 0.68 (95% confidence interval, 0.37-1.25) for >1 episode of otorrhea. Another RCT reported an OR of 0.71 (95% confidence interval, 0.29-1.76) for nonswimmers versus swimmers. Network meta-analyses suggest that, relative to oral antibiotics, topical antibiotic-glucocorticoid drops were more effective: OR 5.3 (95% credible interval, 1.2-27). The OR for antibiotic-only drops was 3.3 (95% credible interval, 0.74-16). Overall, the topical antibiotic-glucocorticoid and antibiotic only preparations have the highest probabilities, 0.77 and 0.22 respectively, of being the most effective therapies. LIMITATIONS: Sparse randomized evidence (2 RCTs) and high risk of bias for nonrandomized comparative studies evaluating water precautions. Otorrhea treatments include non-US Food and Drug Administration approved, off-label, and potentially ototoxic antibiotics. CONCLUSIONS: No compelling evidence of a need for water precautions exists. Cure rates are higher for topical drops than oral antibiotics. PMID- 28562290 TI - Lessons From the 2013 Boston Marathon: Incorporating Residents Into Institutional Emergency Plans. PMID- 28562291 TI - Questions Remain Regarding the Effectiveness of Many Commonly Used Autism Treatments. PMID- 28562292 TI - The Road to Tolerance and Understanding. PMID- 28562294 TI - Lessons Learned From Australia: Social Disadvantage and Pubertal Timing. PMID- 28562293 TI - More Evidence Linking Smoke-Free Legislation and Lower Risk of Prematurity and Low Birth Weight. PMID- 28562295 TI - Noncigarette Tobacco Advertising May Be Hazardous to a Teen's Health. PMID- 28562296 TI - Race, Ethnicity, and SIDS. PMID- 28562297 TI - Adolescent Frequent Heavy Drinking From 1991-2015. PMID- 28562298 TI - Shared Decision-Making and Children With Disabilities: Pathways to Consensus. AB - Shared decision-making (SDM) promotes family and clinician collaboration, with ultimate goals of improved health and satisfaction. This clinical report provides a basis for a systematic approach to the implementation of SDM by clinicians for children with disabilities. Often in the discussion of treatment plans, there are gaps between the child's/family's values, priorities, and understanding of perceived "best choices" and those of the clinician. When conducted well, SDM affords an appropriate balance incorporating voices of all stakeholders, ultimately supporting both the child/family and clinician. With increasing knowledge of and functional use of SDM skills, the clinician will become an effective partner in the decision-making process with families, providing family centered care. The outcome of the process will support the beneficence of the physician, the authority of the family, and the autonomy and well-being of the child. PMID- 28562299 TI - Delayed Umbilical Cord Clamping After Birth. PMID- 28562300 TI - Fruit Juice in Infants, Children, and Adolescents: Current Recommendations. AB - Historically, fruit juice was recommended by pediatricians as a source of vitamin C and as an extra source of water for healthy infants and young children as their diets expanded to include solid foods with higher renal solute load. It was also sometimes recommended for children with constipation. Fruit juice is marketed as a healthy, natural source of vitamins and, in some instances, calcium. Because juice tastes good, children readily accept it. Although juice consumption has some benefits, it also has potential detrimental effects. High sugar content in juice contributes to increased calorie consumption and the risk of dental caries. In addition, the lack of protein and fiber in juice can predispose to inappropriate weight gain (too much or too little). Pediatricians need to be knowledgeable about juice to inform parents and patients on its appropriate uses. PMID- 28562301 TI - Pain Assessment and Treatment in Children With Significant Impairment of the Central Nervous System. AB - Pain is a frequent and significant problem for children with impairment of the central nervous system, with the highest frequency and severity occurring in children with the greatest impairment. Despite the significance of the problem, this population remains vulnerable to underrecognition and undertreatment of pain. Barriers to treatment may include uncertainty in identifying pain along with limited experience and fear with the use of medications for pain treatment. Behavioral pain-assessment tools are reviewed in this clinical report, along with other strategies for monitoring pain after an intervention. Sources of pain in this population include acute-onset pain attributable to tissue injury or inflammation resulting in nociceptive pain, with pain then expected to resolve after treatment directed at the source. Other sources can result in chronic intermittent pain that, for many, occurs on a weekly to daily basis, commonly attributed to gastroesophageal reflux, spasticity, and hip subluxation. Most challenging are pain sources attributable to the impaired central nervous system, requiring empirical medication trials directed at causes that cannot be identified by diagnostic tests, such as central neuropathic pain. Interventions reviewed include integrative therapies and medications, such as gabapentinoids, tricyclic antidepressants, alpha-agonists, and opioids. This clinical report aims to address, with evidence-based guidance, the inherent challenges with the goal to improve comfort throughout life in this vulnerable group of children. PMID- 28562302 TI - Trends in Patent Ductus Arteriosus Diagnosis and Management for Very Low Birth Weight Infants. AB - OBJECTIVE: To examine yearly trends of patent ductus arteriosus (PDA) diagnosis and treatment in very low birth weight infants. METHODS: In this retrospective cohort study of very low birth weight infants (<1500 g) between 2008 and 2014 across 134 California hospitals, we evaluated PDA diagnosis and treatment by year of birth. Infants were either inborn or transferred in within 2 days after delivery and had no congenital abnormalities. Intervention levels for treatment administered to achieve ductal closure were categorized as none, pharmacologic (indomethacin or ibuprofen), both pharmacologic intervention and surgical ligation, or ligation only. Multivariable logistic regression was used to assess risk factors for PDA diagnosis and treatment. RESULTS: PDA was diagnosed in 42.8% (12 002/28 025) of infants, with a decrease in incidence from 49.2% of 4205 infants born in 2008 to 38.5% of 4001 infants born in 2014. Pharmacologic and/or surgical treatment was given to 30.5% of patients. Between 2008 and 2014, the annual rate of infants who received pharmacologic intervention (30.5% vs 15.7%) or both pharmacologic intervention and surgical ligation (6.9% vs 2.9%) decreased whereas infants who were not treated (60.5% vs 78.3%) or received primary ligation (2.2% vs 3.0%) increased. CONCLUSIONS: There is an increasing trend toward not treating patients diagnosed with PDA compared with more intensive treatments: pharmacologic intervention or both pharmacologic intervention and surgical ligation. Possible directions for future study include the impact of these trends on hospital-based and long-term outcomes. PMID- 28562305 TI - Innovative Health Care Financing Strategies for Children and Youth With Special Health Care Needs. PMID- 28562303 TI - Maternal and Perinatal Exposures Are Associated With Risk for Pediatric-Onset Multiple Sclerosis. AB - OBJECTIVE: To determine if prenatal, pregnancy, or postpartum-related environmental factors are associated with multiple sclerosis (MS) risk in children. METHODS: This is a case-control study of children with MS or clinically isolated syndrome and healthy controls enrolled at 16 clinics participating in the US Network of Pediatric MS Centers. Parents completed a comprehensive environmental questionnaire, including the capture of pregnancy and perinatal factors. Case status was confirmed by a panel of 3 pediatric MS specialists. Multivariable logistic regression analyses were used to determine association of these environmental factors with case status, adjusting for age, sex, race, ethnicity, US birth region, and socioeconomic status. RESULTS: Questionnaire responses were available for 265 eligible cases (median age 15.7 years, 62% girls) and 412 healthy controls (median age 14.6, 54% girls). In the primary multivariable analysis, maternal illness during pregnancy was associated with 2.3 fold increase in odds to have MS (95% confidence interval [CI] 1.20-4.21, P = .01) and cesarean delivery with 60% reduction (95% CI 0.20-0.82, P = .01). In a model adjusted for these variables, maternal age and BMI, tobacco smoke exposure, and breastfeeding were not associated with odds to have MS. In the secondary analyses, after adjustment for age, sex, race, ethnicity, and socioeconomic status, having a father who worked in a gardening-related occupation (odds ratio [OR] 2.18, 95% CI 1.14-4.16, P = .02) or any use in household of pesticide related products (OR 1.73, 95% CI 1.06-2.81, P = .03) were both associated with increased odds to have pediatric MS. CONCLUSION: Cesarean delivery and maternal health during pregnancy may influence risk for pediatric-onset MS. We report a new possible association of pesticide-related environmental exposures with pediatric MS that warrants further investigation and replication. PMID- 28562306 TI - Statement of the Problem: Health Reform, Value-Based Purchasing, Alternative Payment Strategies, and Children and Youth With Special Health Care Needs. AB - There is increasing interest in maximizing health care purchasing value by emphasizing strategies that promote cost-effectiveness while achieving optimal health outcomes. These value-based purchasing (VBP) strategies have largely focused on adult health, and little is known about the impact of VBP program development and implementation on children, especially children and youth with special health care needs (CYSHCN). With the increasing emphasis on VBP, policymakers must critically analyze the potential impact of VBP for CYSCHN, because this group of children, by definition, uses more health care services than other children and inevitably incurs higher per person costs. We provide a history and definition of VBP and insurance design, noting its origin in employer sponsored health insurance, and discuss various financing and payment strategies that may be pursued under a VBP framework. The relevance of these approaches for CYSHCN is discussed, and recommendations for next steps are provided. There is considerable work to be done if VBP strategies are to be applied to CYSHCN. Issues include the low prevalence of specific special health care need conditions, how to factor in a life course perspective, in which investments in children's health pay off over a long period of time, the marginal savings that may or may not accrue, the increased risk of family financial hardship, and the potential to exacerbate existing inequities across race, class, ethnicity, functional status, and other social determinants of health. PMID- 28562308 TI - Partners for Kids Care Coordination: Lessons From the Field. AB - OBJECTIVE: The goal of this trial was to present a case study of care coordination for children and youth with special health care needs from an exclusively pediatric accountable care organization, and compare precare and postcare data on their use of inpatient and emergency department services. METHODS: This pre-post comparison of the health care utilization included a subset of 733 children enrolled in Partners for Kids care coordination funded through a delegation arrangement with several Medicaid managed care plans. We compared inpatient admissions, hospital bed days, 30-day hospital readmissions, and emergency department visits during the 6 months before their enrollment in the coordination program versus the 6 months after enrollment. RESULTS: Approximately 16 000 referrals to the Partners for Kids care coordination program were made for an estimated 12 000 children. A total of 3072 unique individual children were enrolled; the most common condition classification was mental, behavioral, and neurodevelopmental disorders (25% of enrolled children). Due to rapid turnover/churn in Medicaid managed care eligibility, the subset of children with continuous enrollment was limited to 733 children. Among this subset, the counts of inpatient admissions, bed days, and 30-day readmissions between the pre enrollment and post-enrollment period decreased (P < .05). CONCLUSIONS: These results suggest that it is possible for an accountable care organization to reduce inpatient and emergency department utilization. Going forward, the most important tasks of the care coordination team are to overcome obstacles to referral and participation and to develop methods to achieve better measures of patient-reported outcomes. PMID- 28562307 TI - The Eye of the Beholder: A Discussion of Value and Quality From the Perspective of Families of Children and Youth With Special Health Care Needs. AB - There is broad agreement that increasing the cost-effectiveness and quality of health care services, thereby achieving greater value, is imperative given this country's current spiraling costs and poor health outcomes. However, how individuals or stakeholder groups define value may differ significantly. Discussion of value in the context of health care, in particular value-based purchasing and value-based insurance design, must acknowledge that there is no universal consensus definition as to what constitutes value. To date, the consumer perspective has been underrepresented in discussions of value-based strategies such as pay for performance, capitated and bundled payments, and high deductible health plans, which have been driven primarily by payers and providers. This article will discuss 3 elements of value from the perspective of families of children and youth with special health care needs: the role of families in the delivery of care, consumer perspectives on what constitutes quality for children and youth with special health care needs, and health care and health care financing literacy, decision-making, and costs. The undervalued contributions made by family members in the delivery and oversight of pediatric care and the importance of partnering with them to achieve the goals of the Triple Aim are stressed. The article closes with a discussion of recommendations for a future policy and research agenda related to advancing the integration of the consumer perspective into value-based purchasing and value-based insurance design. PMID- 28562309 TI - Value-Based Insurance Design Pharmacy Benefits for Children and Youth With Special Health Care Needs: Principles and Opportunities. AB - Value-based insurance design (VBID) represents an innovative approach to health insurance coverage. In the context of pharmacy benefits, the goal of VBID is to minimize access barriers to the most effective and appropriate treatments for specific medical conditions. Both private and public insurance programs have explored VBID pharmacy projects primarily for medical conditions affecting adults. To date, evidence for VBID pharmacy programs for children and youth with special health care needs (CYSHCN) appears lacking. There appears to be potential for VBID concepts to be applied to pharmacy coverage benefiting CYSHCN. An overview of VBID pharmacy principles and guiding principles are presented. Opportunities for the creation of pharmacy programs with a value-based orientation and challenges to the redesign of pharmacy benefits are identified. VBID pharmacy coverage principles may be helpful to improve medication use and important clinical outcomes while lowering barriers to medication use for the population of CYSHCN. Pilot projects of VBID pharmacy benefits for children and youth should be explored. However, many questions remain. PMID- 28562310 TI - Mental Health Services Utilization and Expenditures Among Children Enrolled in Employer-Sponsored Health Plans. AB - BACKGROUND AND OBJECTIVES: Mental illness in children increases the risk of developing mental health disorders in adulthood, and reduces physical and emotional well-being across the life course. The Mental Health Parity and Addiction Equity Act (MHPAEA, 2008) aimed to improve access to mental health treatment by requiring employer-sponsored health plans to include insurance coverage for behavioral health services. METHODS: Investigators used IBM Watson/Truven Analytics MarketScan claims data (2007-2013) to examine: (1) the distribution of mental illness; (2) trends in utilization and out-of-pocket expenditures; and (3) the overall effect of the MHPAEA on mental health services utilization and out-of-pocket expenditures among privately-insured children aged 3 to 17 with mental health disorders. Multivariate Poisson regression and linear regression modeling techniques were used. RESULTS: Mental health services use for outpatient behavioral health therapy (BHT) was higher in the years after the implementation of the MHPAEA (2010-2013). Specifically, before the MHPAEA implementation, the annual total visits for BHT provided by mental health physicians were 17.1% lower and 2.5% lower for BHT by mental health professionals, compared to years when MHPAEA was in effect. Children covered by consumer-driven and high-deductible plans had significantly higher out-of-pocket expenditures for BHT compared to those enrolled PPOs. CONCLUSIONS: Our findings demonstrate increased mental health services use and higher out-of-pocket costs per outpatient visit after implementation of the MHPAEA. As consumer-driven and high-deductible health plans continue to grow, enrollees need to be cognizant of the impact of health insurance benefit designs on health services offered in these plans. PMID- 28562311 TI - Refining Our Understanding of Value-Based Insurance Design and High Cost Sharing on Children. AB - BACKGROUND: There is significant concern about the financial burdens of new insurance plan designs on families, particularly families with children and youth with special health care needs (CYSHCN). With value-based insurance design (VBID) plans growing in popularity, this study examined the implications of selected VBID cost-sharing features on children. METHODS: We studied children's health care spending patterns in 2 data sets that include high deductible and narrow network plans among others. Medical Expenditure Panel Survey data from 2007 to 2013 on 22 392 children were used to study out-of-pocket (OOP) costs according to CYSHCN, family income, and spending. MarketScan large employer insurance claims data from 2007 to 2014 (N = 4 263 452) were used to test for differences in mean total payments and OOP costs across various health plans. RESULTS: Across the data sets, we found that existing health plans place significant financial burdens on families, particularly lower income households and families with CYSHCN; individuals among the top 10% of OOP spending averaged more than $2000 per child. Although high deductible and consumer-driven plans impose substantial OOP costs on children, they do not significantly reduce spending, whereas health maintenance organizations that use network restrictions and tighter management do. CONCLUSIONS: Our results do not support the conclusion that high cost-sharing features that are common in VBID plans will significantly reduce health care spending on children. PMID- 28562312 TI - A Pediatrician's Perspective: Value-Based Care, Consumerism, and the Practice of Pediatrics: A Glimpse of the Future. PMID- 28562314 TI - Repurposing ARBs as treatments for breast cancer. PMID- 28562313 TI - Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency. AB - We sought to identify the impacts of Friedreich's ataxia (FRDA) on cardiomyocytes. FRDA is an autosomal recessive degenerative condition with neuronal and non-neuronal manifestations, the latter including progressive cardiomyopathy of the left ventricle, the leading cause of death in FRDA. Little is known about the cellular pathogenesis of FRDA in cardiomyocytes. Induced pluripotent stem cells (iPSCs) were derived from three FRDA individuals with characterized GAA repeats. The cells were differentiated into cardiomyocytes to assess phenotypes. FRDA iPSC- cardiomyocytes retained low levels of FRATAXIN (FXN) mRNA and protein. Electrophysiology revealed an increased variation of FRDA cardiomyocyte beating rates which was prevented by addition of nifedipine, suggestive of a calcium handling deficiency. Finally, calcium imaging was performed and we identified small amplitude, diastolic and systolic calcium transients confirming a deficiency in calcium handling. We defined a robust FRDA cardiac-specific electrophysiological profile in patient-derived iPSCs which could be used for high throughput compound screening. This cell-specific signature will contribute to the identification and screening of novel treatments for this life-threatening disease. PMID- 28562316 TI - Novel therapeutic target against Alzheimer. PMID- 28562317 TI - Role of seizure in neonatal stroke. PMID- 28562318 TI - Intermittent hypoxia produces Alzheimer disease? PMID- 28562315 TI - Aged induced pluripotent stem cell (iPSCs) as a new cellular model for studying premature aging. AB - Nuclear integrity and mechanical stability of the nuclear envelope (NE) are conferred by the nuclear lamina, a meshwork of intermediate filaments composed of A- and B-type lamins, supporting the inner nuclear membrane and playing a pivotal role in chromatin organization and epigenetic regulation. During cell senescence, nuclear alterations also involving NE architecture are widely described. In the present study, we utilized induced pluripotent stem cells (iPSCs) upon prolonged in vitro culture as a model to study aging and investigated the organization and expression pattern of NE major constituents. Confocal and four-dimensional imaging combined with molecular analyses, showed that aged iPSCs are characterized by nuclear dysmorphisms, nucleoskeletal components (lamin A/C prelamin isoforms, lamin B1, emerin, and nesprin-2) imbalance, leading to impaired nucleo-cytoplasmic MKL1 shuttling, actin polymerization defects, mitochondrial dysfunctions, SIRT7 downregulation and NF-kBp65 hyperactivation. The observed age-related NE features of iPSCs closely resemble those reported for premature aging syndromes (e.g., Hutchinson-Gilford progeria syndrome) and for somatic cell senescence. These findings validate the use of aged iPSCs as a suitable cellular model to study senescence and for investigating therapeutic strategies aimed to treat premature aging. PMID- 28562319 TI - Amyloid-beta breaks brain's neuroprotection. PMID- 28562320 TI - ASICs may affect GABAergic synapses. PMID- 28562321 TI - Intellectual maturity and longevity: late-blooming composers and writers live longer than child prodigies. AB - Life history theory links human physical and sexual development to longevity. However, there have been no studies on the association of intellectual development with longevity. This observational study investigates the relationship between the onset of intellectual maturity and lifespan through the life histories of composers and creative writers, whose intellectual development can be gauged through their compositions and writings. In these groups we model the relationship between the age at first creative work, and age at death using multilevel regression, adjusting for sex, date of birth, and nationality. Historical biographical records on 1110 musical composers and 1182 creative writers, born in the period 1400 AD through 1915 AD, were obtained from the Oxford Companion to Music and the Oxford Companion to English Literature. Composers and creative writers lived, respectively 0.16 (p = 0.02) and 0.18 (p < 0.01) years longer for each later year of age at first work. When completion of the first creative work is interpreted as a proxy for the onset of intellectual maturity in composers and creative writers, our findings indicate that a later onset of intellectual maturity is associated with higher longevity. PMID- 28562328 TI - Stereochemical preference toward oncotarget: Design, synthesis and in vitro anticancer evaluation of diastereomeric beta-lactams. AB - PURPOSE: In the battle against cancer discovery of new and novel chemotherapeutic agent demands extreme obligation. Development of anticancer compounds with higher potency and reduced side-effects is timely and challenging. EXPERIMENTAL DESIGN: A small series of fourteen diastereomeric beta-lactams (seven pairs) were synthesized through multi-step process exploring [2+2] ketene-imine cycloaddition as the key step. Comparative stereochemical preferences were studied through computational docking and validated by in vitro evaluation. beta-tubulin was considered as possible molecular target and in vitro anticancer evaluation was conducted against SiHa, B16F10, K562 and Chang cell lines. Caspase-3 activation assay and hematoxylin/eosin staining of the cells were also accomplished. RESULTS: Better docking scores of the cis- over the trans-beta-lactams indicated favorable beta-lactam-beta-tubulin interactions in cis-geometry. In vitro (IC50) evaluation confirmed better anticancer activity of the cis-diastereoisomers. Apoptosis-induced cell death was supported by caspase-3 activation study. A cis beta-lactam [(+/-)-Cis-3-amino-1-phenyl-4-(p-tolyl) azetidin-2-one, 6C] was found to be more active (in vitro) than the marketed natural drug colchicine against SiHa and B16F10 (six times higher potency) cell lines. Reduced toxicity (compared to colchicine) in Chang cells confirmed better site-selectivity (accordingly less side-effects) of 6C than colchicine. Aside from 6C, most of the reported molecules demonstrated good to strong in vitro anticancer activity against SiHa and B16F10 cancer cell lines. CONCLUSIONS: Stereochemical preferences of the cis beta-lactams over their trans-counterparts, toward the molecular target beta tubulin, was confirmed by docking studies and in vitro anticancer evaluation. Apoptosis was identified as the cause of cell death. The lead 6C exhibited higher potency and selectivity than the marketed drug colchicine both in silico as well as in vitro. PMID- 28562327 TI - The protein kinase MBK-1 contributes to lifespan extension in daf-2 mutant and germline-deficient Caenorhabditis elegans. AB - In Caenorhabditis elegans, reduction of insulin/IGF-1 like signaling and loss of germline stem cells both increase lifespan by activating the conserved transcription factor DAF-16 (FOXO). While the mechanisms that regulate DAF-16 nuclear localization in response to insulin/IGF-1 like signaling are well characterized, the molecular pathways that act in parallel to regulate DAF-16 transcriptional activity, and the pathways that couple DAF-16 activity to germline status, are not fully understood at present. Here, we report that inactivation of MBK-1, the C. elegans ortholog of the human FOXO1-kinase DYRK1A substantially shortens the prolonged lifespan of daf-2 and glp-1 mutant animals while decreasing wild-type lifespan to a lesser extent. On the other hand, lifespan-reduction by mutation of the MBK-1-related kinase HPK-1 was not preferential for long-lived mutants. Interestingly, mbk-1 loss still allowed for DAF-16 nuclear accumulation but reduced expression of certain DAF-16 target genes in germline-less, but not in daf-2 mutant animals. These findings indicate that mbk-1 and daf-16 functionally interact in the germline- but not in the daf-2 pathway. Together, our data suggest mbk-1 as a novel regulator of C. elegans longevity upon both, germline ablation and DAF-2 inhibition, and provide evidence for mbk-1 regulating DAF-16 activity in germline-deficient animals. PMID- 28562329 TI - Identification of polymorphisms in 12q24.1, ACAD10, and BRAP as novel genetic determinants of blood pressure in Japanese by exome-wide association studies. AB - We performed exome-wide association studies to identify genetic variants that influence systolic or diastolic blood pressure or confer susceptibility to hypertension in Japanese. The exome-wide association studies were performed with the use of Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays and with 14,678 subjects, including 8215 individuals with hypertension and 6463 controls. The relation of genotypes of 41,843 single nucleotide polymorphisms to systolic or diastolic blood pressure was examined by linear regression analysis. After Bonferroni's correction, 44 and eight polymorphisms were significantly (P < 1.19 * 10-6) associated with systolic or diastolic blood pressure, respectively, with six polymorphisms (rs12229654, rs671, rs11066015, rs2074356, rs3782886, rs11066280) being associated with both systolic and diastolic blood pressure. Examination of the relation of allele frequencies to hypertension with Fisher's exact test revealed that 100 of the 41,843 single nucleotide polymorphisms were significantly (P < 1.19 * 10-6) associated with hypertension. Subsequent multivariable logistic regression analysis with adjustment for age and sex showed that five polymorphisms (rs150854849, rs202069030, rs139012426, rs12229654, rs76974938) were significantly (P < 1.25 * 10-4) associated with hypertension. The polymorphism rs12229654 was thus associated with both systolic and diastolic blood pressure and with hypertension. Six polymorphisms (rs12229654 at 12q24.1, rs671 of ALDH2, rs11066015 of ACAD10, rs2074356 and rs11066280 of HECTD4, and rs3782886 of BRAP) were found to be associated with both systolic and diastolic blood pressure, with those at 12q24.1 or in ACAD10 or BRAP being novel determinants of blood pressure in Japanese. PMID- 28562330 TI - The correlation between pulmonary fibrosis and methylation of peripheral Smad3 in cases of pigeon breeder's lung in a Chinese Uygur population. AB - Smad3 is a key protein in the transforming growth factor-beta (TGF-beta)/Smad signaling pathway, which is involved in fibrosis in many organs. We investigated the relationship between Smad3 gene methylation and pulmonary fibrosis in pigeon breeder's lung (PBL). Twenty Uygur PBL patients with pulmonary fibrosis in Kashi between October 2015 and March 2016 were enrolled. Twenty PBL-free pigeon breeders and 20 healthy non-pigeon breeders enrolled during the same period constituted the negative and normal control groups, respectively. Participants' data and peripheral blood samples were collected, and three Smad3 CpG loci were examined. Distributions of CpG_2 and CpG_4 methylation rates did not differ across groups, whereas distributions of CpG_3 methylation rates were significantly different among the three groups. The CpG_3 methylation rate was significantly lower in the patient group than in the negative control group. Smad3 mRNA expression was significantly higher in the patient group than in the negative control group but did not differ between the two control groups. TGF betalevels were significantly higher in the patient group than in either control group (both P<0.01). Smad3 gene methylation and Smad3 mRNA expression were negatively correlated, with a correlation coefficient of -0.84. The number of pigeons bred during the preceding three months was positively correlated with Smad3 mRNA expression, with a correlation coefficient of 0.77. Smad3 gene hypomethylation might promote pulmonary fibrosis in Uygur PBL patients via increased Smad3 mRNA expression. Smad3 methylation, Smad3 mRNA expression and TGF beta level were correlated with the number of pigeons bred by patients. PMID- 28562332 TI - IRF5 is associated with adverse postoperative prognosis of patients with non metastatic clear cell renal cell carcinoma. AB - BACKGROUND: IRF5 is one member of IRFs family, and is critical for host immunity and cell response. In the present study, we sought to search the clinical and prognostic value of IFR5 in patients with non-metastatic ccRCC. RESULTS: IRF5 proved to be an adverse independent prognostic factor for overall survival (p < 0.001) and recurrence free survival (p = 0.002). The newly built nomograms could give better prediction for overall survival and recurrence free survival in ccRCC patients. MATERIALS AND METHODS: We included 264 individuals who were diagnosed with non-metastatic clear cell renal cell carcinoma in the present study. Immunohistochemistry staining was performed on tissue microarrays to evaluate the IRF5 expression. chi2 test, Fisher's exact test, t test, Kaplan-Meier method and Cox proportional hazard model were applied to evaluate the prognostic value of IRF5. Two nomograms were constructed to predict clinical outcomes for ccRCC patients after surgery. CONCLUSIONS: IRF5 was an adverse independent prognostic factor for both overall survival and recurrence free survival in patients with non-metastatic ccRCC. PMID- 28562331 TI - Dual degradation signals destruct GLI1: AMPK inhibits GLI1 through beta-TrCP mediated proteasome degradation. AB - Overexpression of the GLI1 gene has frequently been found in various cancer types, particularly in brain tumors, in which aberrant GLI1 induction promotes cancer cell growth. Therefore, identifying the molecular players controlling GLI1 expression is of clinical importance. Previously, we reported that AMPK directly phosphorylated and destabilized GLI1, resulting in the suppression of the Hedgehog signaling pathway. The current study not only demonstrates that AMPK inhibits GLI1 nuclear localization, but further reveals that beta-TrCP plays an essential role in AMPK-induced GLI1 degradation. We found that activation of AMPK promotes the interaction between beta-TrCP and GLI1, and induces beta-TrCP mediated GLI1-ubiquitination and degradation. Inhibiting AMPK activity results in the dissociation of the beta-TrCP and GLI1 interaction, and diminishes beta-TrCP mediated-GLI1 ubiquitination and degradation. On GLI1, substitution of AMPK phosphorylation sites to aspartic acid (GLI13E) results in stronger binding affinity of GLI1 with beta-TrCP, accompanied by enhanced GLI1 ubiquitination and later degradation. In contrast, the GLI1 alanine mutant (GLI13A) shows weaker binding with beta-TrCP, which is accompanied by reduced beta-TrCP-mediated ubiquitination and degradation. Together, these results demonstrate that AMPK regulates GLI1 interaction with beta-TrCP by phosphorylating GLI1 and thus both post-translational modifications by AMPK and beta-TrCP ultimately impact GLI1 degradation. PMID- 28562333 TI - Efficacy and safety comparison of chemotherapies for advanced gastric cancer: A network meta-analysis. AB - OBJECTIVE: Chemotherapy is one of the commonly used therapies for advanced gastric cancer. In this study, we performed a network meta-analysis on the efficacy and safety of common treatments to give evidences of their relative benefits. RESULTS: 32 trials with 8550 patients and 20 regimens were included in this study. According to the results of primary outcomes, 5-FU plus OXA, 5-FU plus DOC, CAP plus CIS, CAP plus OXA, S-1 plus OXA and S-1 plus PAC performed well in improving OS and ORR. As for the adverse events, S-1 had a safer effect than other treatments, conversely, 5-FU plus CIS ranked the last. However, there was no regimen with outstanding performances in both efficacy and safety. MATERIALS AND METHODS: Studies were searched from database and screened with criteria. The Bayesian framework based network meta-analysis was performed with software R and STATA. Overall survival (OS) and overall response rate (ORR) were considered as primary outcomes while adverse events as secondary outcomes. The outcomes were represented by hazard ratios or odd ratios with 95% corresponding credible intervals, respectively. CONCLUSIONS: The network meta-analysis suggested that 5-FU plus OXA and 5-FU plus DOC were recommended when efficacy was stressed. S-1 was safest but poorly effective. A regimen, as an excellent combination of efficacy and safety, is still waiting to be discovered. PMID- 28562334 TI - Gene co-expression network reveals shared modules predictive of stage and grade in serous ovarian cancers. AB - Serous ovarian cancer (SOC) is the most lethal gynecological cancer. Clinical studies have revealed an association between tumor stage and grade and clinical prognosis. Identification of meaningful clusters of co-expressed genes or representative biomarkers related to stage or grade may help to reveal mechanisms of tumorigenesis and cancer development, and aid in predicting SOC patient prognosis. We therefore performed a weighted gene co-expression network analysis (WGCNA) and calculated module-trait correlations based on three public microarray datasets (GSE26193, GSE9891, and TCGA), which included 788 samples and 10402 genes. We detected four modules related to one or more clinical features significantly shared across all modeling datasets, and identified one stage associated module and one grade-associated module. Our analysis showed that MMP2, COL3A1, COL1A2, FBN1, COL5A1, COL5A2, and AEBP1 are top hub genes related to stage, while CDK1, BUB1, BUB1B, BIRC5, AURKB, CENPA, and CDC20 are top hub genes related to grade. Gene and pathway enrichment analyses of the regulatory networks involving hub genes suggest that extracellular matrix interactions and mitotic signaling pathways are crucial determinants of tumor stage and grade. The relationships between gene expression modules and tumor stage or grade were validated in five independent datasets. These results could potentially be developed into a more objective scoring system to improve prediction of SOC outcomes. PMID- 28562335 TI - Urinary exosomes reveal protein signatures in hypertensive patients with albuminuria. AB - Albuminuria is an indicator of cardiovascular risk and renal damage in hypertensive individuals. Chronic renin-angiotensin system (RAS) suppression facilitates blood pressure control and prevents development of new-onset albuminuria. A significant number of patients, however, develop albuminuria despite chronic RAS blockade, and the physiopathological mechanisms are underexplored. Urinary exosomes reflect pathological changes taking place in the kidney. The objective of this work was to examine exosomal protein alterations in hypertensive patients with albuminuria in the presence of chronic RAS suppression, to find novel clues underlying its development. Patients were followed-up for three years and were classified as: a) patients with persistent normoalbuminuria; b) patients developing de novo albuminuria; and c) patients with maintained albuminuria. Exosomal protein alterations between groups were identified by isobaric tag quantitation (iTRAQ). Confirmation was approached by target analysis (SRM). In total, 487 proteins were identified with high confidence. Specifically, 48 proteins showed an altered pattern in response to hypertension and/or albuminuria. Out of them, 21 proteins interact together in three main functional clusters: glycosaminoglycan degradation, coagulation and complement system, and oxidative stress. The identified proteins constitute potential targets for drug development and may help to define therapeutic strategies to evade albuminuria progression in hypertensive patients chronically treated. PMID- 28562336 TI - Synergistic targeting of malignant pleural mesothelioma cells by MDM2 inhibitors and TRAIL agonists. AB - Malignant Pleural Mesothelioma (MPM) is a chemoresistant tumor characterized by low rate of p53 mutation and upregulation of Murine Double Minute 2 (MDM2), suggesting that it may be effectively targeted using MDM2 inhibitors. In the present study, we investigated the anticancer activity of the MDM2 inhibitors Nutlin 3a (in vitro) and RG7112 (in vivo), as single agents or in combination with rhTRAIL.In vitro studies were performed using MPM cell lines derived from epithelioid (ZL55, M14K), biphasic (MSTO211H) and sarcomatoid (ZL34) MPMs. In vivo studies were conducted on a sarcomatoid MPM mouse model.In all the cell lines tested (with the exception of ZL55, which carries a biallelic loss-of function mutation of p53), Nutlin 3a enhanced p21, MDM2 and DR5 expression, and decreased survivin expression. These changes were associated to cell cycle arrest but not to a significant induction of apoptosis. A synergistic pro-apoptotic effect was obtained through the association of rhTRAIL in all the cell lines harboring functional p53. This synergistic interaction of MDM2 inhibitor and TRAIL agonist was confirmed using a mouse preclinical model. Our results suggest that the combined targeting of MDM2 and TRAIL might provide a novel therapeutic option for treatment of MPM patients, particularly in the case of sarcomatoid MPM with MDM2 overexpression and functional inactivation of wild-type p53. PMID- 28562337 TI - IL13RA2 targeted alpha particle therapy against glioblastomas. AB - Glioblastoma (GBM) is the most aggressive primary malignant brain cancer that invariably results in a dismal prognosis. Chemotherapy and radiotherapy have not been completely effective as standard treatment options for patients due to recurrent disease. We and others have therefore developed molecular strategies to specifically target interleukin 13 receptor alpha 2 (IL13RA2), a GBM restricted receptor expressed abundantly on over 75% of GBM patients. In this work, we evaluated the potential of Pep-1L, a novel IL13RA2 targeted peptide, as a platform to deliver targeted lethal therapies to GBM. To demonstrate GBM specificity, we radiolabeled Pep-1L with Copper-64 and performed in vitro cell binding studies, which demonstrated specific binding that was blocked by unlabeled Pep-1L. Furthermore, we demonstrated real-time GBM localization of [64Cu]Pep-1L to orthotopic GBMs using small animal PET imaging. Based on these targeting data, we performed an initial in vivo safety and therapeutic study using Pep-1L conjugated to Actinium-225, an alpha particle emitter that has been shown to potently and irreversibly kill targeted cells. We infused [225Ac]Pep-1L into orthotopic GBMs using convection-enhanced delivery and found no significant adverse events at injected doses. Furthermore, our initial data also demonstrated significantly greater overall, median and mean survival in treated mice when compared to those in control groups (p < 0.05). GBM tissue extracted from mice treated with [225Ac]Pep-1L showed double stranded DNA breaks, lower Ki67 expression and greater propidium iodide internalization, indicating anti-GBM therapeutic effects of [225Ac]Pep-1L. Based on our results, Pep-1L warrants further investigation as a potential targeted platform to deliver anti-cancer agents. PMID- 28562338 TI - An herbal formula attenuates collagen-induced arthritis via inhibition of JAK2 STAT3 signaling and regulation of Th17 cells in mice. AB - Wenjinghuoluo prescription, a traditional Chinese medicine compound treatment of rheumatoid arthritis characterized by wind-cold-dampness arthralgia, contains five herbs, namely, C. cassia Presl., Cinnamomum cassia Presl., Paeonia lactiflora Pall., Saposhnikovia divaricate (Turcz.) Schischk., and Clematis chinensis Osbeck. We have reported that WJHL could inhibit the production of inflammatory mediators in immune cells. This study explored the effect and mechanism of WJHL on collagen-induced arthritis mice. WJHL could significantly improve clinical arthritic conditions; inhibit bone erosion and osteophyte formation in joints; decrease expression of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, and IL-17); reduce protein expression levels of JAK2, p-JAK2, STAT3, p-STAT3 and gene expression levels of JAK2, STAT3, IL-17A, RORgammat mRNA; elevate osteoprotegerin and Foxp3 mRNA levels and lower Th17 cell proportions in splenocytes. Results suggest that WJHL, specifically regulating the JAK2/STAT3 pathway and Th17 cells, may be a promising herbal medicine candidate for the treatment of RA. PMID- 28562339 TI - FAM3A mediates PPARgamma's protection in liver ischemia-reperfusion injury by activating Akt survival pathway and repressing inflammation and oxidative stress. AB - FAM3A is a novel mitochondrial protein, and its biological function remains largely unknown. This study determined the role and mechanism of FAM3A in liver ischemia-reperfusion injury (IRI). In mouse liver after IRI, FAM3A expression was increased. FAM3A-deficient mice exhibited exaggerated liver damage with increased serum levels of AST, ALT, MPO, MDA and oxidative stress when compared with WT mice after liver IRI. FAM3A-deficient mouse livers had a decrease in ATP content, Akt activity and anti-apoptotic protein expression with an increase in apoptotic protein expression, inflammation and oxidative stress when compared WT mouse livers after IRI. Rosiglitazone pretreatment protected against liver IRI in wild type mice but not in FAM3A-deficient mice. In cultured hepatocytes, FAM3A overexpression protected against, whereas FAM3A deficiency exaggerated oxidative stress-induced cell death. FAM3A upregulation or FAM3A overexpression inhibited hypoxia/reoxygenation-induced activation of apoptotic gene and hepatocyte death in P2 receptor-dependent manner. FAM3A deficiency blunted rosiglitazone's beneficial effects on Akt activation and cell survival in cultured hepatocytes. Collectively, FAM3A protects against liver IRI by activating Akt survival pathways, repressing inflammation and attenuating oxidative stress. Moreover, the protective effects of PPARgamma agonist(s) on liver IRI are dependent on FAM3A ATP-Akt pathway. PMID- 28562340 TI - Cell type-dependent HIF1 alpha-mediated effects of hypoxia on proliferation, migration and metastatic potential of human tumor cells. AB - Tumor hypoxia promotes neoangiogenesis and contributes to the radio- and chemotherapy resistant and aggressive phenotype of cancer cells. However, the migratory response of tumor cells and the role of small GTPases regulating the organization of cytoskeleton under hypoxic conditions have yet to be established. Accordingly, we measured the proliferation, migration, RhoA activation, the mRNA and protein levels of hypoxia inducible factor-1alpha (HIF-1alpha) and three small G-proteins, Rac1, cdc42 and RhoA in a panel of five human tumor cell lines under normoxic and hypoxic conditions. Importantly, HT168-M1 human melanoma cells with high baseline migration capacity showed increased HIF-1alpha and small GTPases expression, RhoA activation and migration under hypoxia. These activities were blocked by anti- HIF-1alpha shRNA. Moreover, the in vivo metastatic potential was promoted by hypoxia mimicking CoCl2 treatment and reduced upon inhibition of HIF-1alpha in a spleen to liver colonization experiment. In contrast, HT29 human colon cancer cells with low migration capacity showed limited response to in vitro hypoxia. The expression of the small G-proteins decreased both at mRNA and protein levels and the RhoA activation was reduced. Nevertheless, the number of lung or liver metastatic colonies disseminating from orthotopic HT29 grafts did not change upon CoCl2 or chetomin treatment. Our data demonstrates that the hypoxic environment induces cell-type dependent changes in the levels and activation of small GTPases and results in varying migratory and metastasis promoting responses in different human tumor cell lines. PMID- 28562344 TI - Accumulation of prohibitin is a common cellular response to different stressing stimuli and protects melanoma cells from ER stress and chemotherapy-induced cell death. AB - Melanoma is responsible for most deaths among skin cancers and conventional and palliative care chemotherapy are limited due to the development of chemoresistance. We used proteomic analysis to identify cellular responses that lead to chemoresistance of human melanoma cell lines to cisplatin. A systems approach to the proteomic data indicated the participation of specific cellular processes such as oxidative phosphorylation, mitochondrial organization and homeostasis, as well as the unfolded protein response (UPR) to be required for the survival of cells treated with cisplatin. Prohibitin (PHB) was among the proteins consistently accumulated, interacting with the functional clusters associated with resistance to cisplatin. We showed PHB accumulated at different levels in melanoma cell lines under stressing stimuli, such as (i) treatment with temozolomide (TMZ), dacarbazine (DTIC) and cisplatin; (ii) serum deprivation; (iii) tunicamycin, an UPR inducer. Prohibitin accumulated in the mitochondria of melanoma cells after cisplatin and tunicamycin treatment and its de novo accumulation led to chemoresistance melanoma cell lines. In contrast, PHB knock down sensitized melanoma cells to cisplatin and tunicamycin treatment. We conclude that PHB participates in the survival of cells exposed to different stress stimuli, and can therefore serve as a target for the sensitization of melanoma cells to chemotherapy. PMID- 28562345 TI - Three hematological indexes that may serve as prognostic indicators in patients with primary, high-grade, appendicular osteosarcoma. AB - BACKGROUND: Although alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) are considered effective prognostic factors of osteosarcoma, useful prognostic biomarkers for patients with osteosarcoma are still lacking. METHODS: A retrospective study of 106 patients with primary, high-grade, appendicular osteosarcoma obtained between 2006 and 2011 was performed to assess the prognostic value of serum ALP, LDH and fibrinogen (FBG) levels, as well as their decrease rates in osteosarcoma. The Kaplan-Meier method was employed to analyze overall survival. The Cox proportional hazard model was used to determine the significance of these prognostic biomarkers on survival distribution. RESULTS: Patients with pre-ct (before neoadjuvant chemotherapy) LDH>210U/L, post-ct (after neoadjuvant chemotherapy, but before surgery) LDH>215U/L, post-ct FBG>2.8g/L, FBG DR (Decrease Rate)<=10% tended to have a poorer prognosis. CONCLUSIONS: High pre ct and post-ct peripheral serum LDH level, high serum post-ct FBG level and low decrease rate of serum FBG were related to poor survival in patients with osteosarcoma. Fibrinogen was found to be a new valuable predictor of 5-year survival in patients with osteosarcoma for the first time. PMID- 28562346 TI - Methionine restriction on oxidative stress and immune response in dss-induced colitis mice. AB - A strong correlation exists between inflammatory bowel disease (IBD) and oxidative stress involving alterations of several key signaling pathways. It is known that methionine promotes reactive oxygen species (ROS) production; we therefore hypothesize that a methionine restriction diet would reduce ROS production, inflammatory responses, and the course of IBD. We generated a murine colitis model by dextran sodium sulfate (DSS) treatment and tested the effects of the methionine restriction diet. Forty-eight mice were randomly divided into four groups of equal size, which included a control (CON) group, an MR (methionine restriction diet) group, a DSS treated group and an MR-DSS treated group. Mice in the first two groups had unrestricted access to water for one week. Mice in the two DSS-treated groups had unrestricted access to 5% DSS solution supplied in the drinking water for the same period. Mice in the CON and DSS groups were given a basal diet, whereas mice in the MR-DSS and MR groups were fed a 0.14% MR diet. We found that DSS reduced daily weight gain, suppressed antioxidant enzyme expression, increased histopathology scores and activated NF-kappaB and nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) signaling. We also showed that the MR diet upregulated catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities, decreased myeloperoxidase (MPO), TNF-alpha and IL-1beta, and reversed activation of the NF-kappaB signaling pathway in MR-DSS mice. Taken together, our results imply that the MR diet may be considered as an adjuvant in IBD therapeutics. PMID- 28562347 TI - Epistatic SNP interaction of ERCC6 with ERCC8 and their joint protein expression contribute to gastric cancer/atrophic gastritis risk. AB - Excision repair cross-complementing group 6 and 8 (ERCC6 and ERCC8) are two indispensable genes for the initiation of transcription-coupled nucleotide excision repair pathway. This study aimed to evaluate the interactions between single nucleotide polymorphisms of ERCC6 (rs1917799) and ERCC8 (rs158572 and rs158916) in gastric cancer and its precancerous diseases. Besides, protein level analysis were performed to compare ERCC6 and ERCC8 expression in different stages of gastric diseases, and to correlate SNPs jointly with gene expression. Sequenom MassARRAY platform method was used to detect polymorphisms of ERCC6 and ERCC8 in 1916 subjects. In situ ERCC6 and ERCC8 protein expression were detected by immunohistochemistry in 109 chronic superficial gastritis, 109 chronic atrophic gastritis and 109 gastric cancer cases. Our results demonstrated pairwise epistatic interactions between ERCC6 and ERCC8 SNPs that ERCC6 rs1917799-ERCC8 rs158572 combination was associated with decreased risk of chronic atrophic gastritis and increased risk of gastric cancer. ERCC6 rs1917799 also showed a significant interaction with ERCC8 rs158916 to reduce gastric cancer risk. The expressions of ERCC6, ERCC8 and ERCC6-ERCC8 combination have similarities that higher positivity was observed in chronic superficial gastritis compared with chronic atrophic gastritis and gastric cancer. As for the effects of ERCC6 and ERCC8 SNPs on the protein expression, single SNP had no correlation with corresponding gene expression, whereas the ERCC6 rs1917799-ERCC8 rs158572 pair had significant influence on ERCC6 and ERCC6-ERCC8 expression. In conclusion, ERCC6 rs1917799, ERCC8 rs158572 and rs158916 demonstrated pairwise epistatic interactions to associate with chronic atrophic gastritis and gastric cancer risk. The ERCC6 rs1917799-ERCC8 rs158572 pair significantly influence ERCC6 and ERCC6-ERCC8 expression. PMID- 28562348 TI - Actual over 10-year survival after liver resection for patients with intrahepatic cholangiocarcinoma. AB - Partial hepatectomy is a potentially curative therapy for intrahepatic cholangiocarcinoma (ICC). Unfortunately, the overall surgical prognosis remains dismal and the actual 10-year survival has not been reported. This study aimed to document 10-year actual survival rates, identify the prognostic factors associated with 10-year survival rate, and analyze the characteristics of patients who survived >= 10 years. Among 251 patients who underwent curative liver resection for ICC between 2003 and 2006 at the Eastern Hepatobiliary Surgery Hospital, 21 patients (8.4%) survived >= 10 years. The 5-, 7-, and 10 year overall survival rates were 32.3%, 22.3% and 8.4%, respectively. The 10-year cumulative incidence of ICC-related death and recurrence were 80.9% and 85.7%, respectively. Multivariate analysis based on competing risk survival analysis identified that tumor > 5 cm was independently associated with ICC-related death and recurrence (hazard ratios: 1.369 and 1.445, respectively), in addition to carcinoembryonic antigen (CEA) >10 U/mL, carbohydrate antigen 19-9 (CA19-9) >39 U/mL, multiple nodules, vascular invasion, nodal metastasis and local extrahepatic invasion. Patients who survived >= 10 years had a longer time to first recurrence, lower levels of CEA, CA19-9 and alkaline phosphatase, less perioperative blood loss, solitary tumor, smaller tumor size, and absence of nodal metastasis or local extrahepatic invasion. In conclusion, a 10-year survival after liver resection for ICC is possible and can be expected in approximately 8.4% of patients. PMID- 28562349 TI - MicroRNA-155, induced by FOXP3 through transcriptional repression of BRCA1, is associated with tumor initiation in human breast cancer. AB - MicroRNA (miR)-155 is upregulated in breast cancer cells and in sera of patients with breast cancer, but its clinical relevance remains uncertain. The objective of the present effort was to address the transcriptional regulation of miR-155. A bioinformatics analysis of public datasets validated upregulation of miR-155 in tumor cells of patients with breast cancer, particularly those who were at early stages and had triple-negative cancers. The expression profiling and clinical relevance of miR-155 in tumor cells and blood cells were characterized by TaqMan miR assays and, in plasma and exosomes, by nest-quantitative PCR analysis. There was a positive correlation between expression of FOXP3 and miR-155 in breast cancer cell lines and primary breast cancers. In breast cancer cells, FOXP3 induced miR-155 through transcriptional repression of BRCA1. Furthermore, in an Alabama cohort, blood and plasma samples were collected from 259 participants, including patients with breast cancer or benign breast tumors, members of breast cancer families, and matched healthy female controls. For patients with early stage or localized breast cancer, there were high levels of miR-155 in both plasma and blood cells. In cultured breast cancer cells, expression of miR-155 was induced by FOXP3 but was not significantly changed in culture medium or exosomes, suggesting that circulating miR-155 originated from blood cells. These findings reveal a transcriptional axis of FOXP3-BRCA1-miR-155 in breast cancer cells and show that plasma miR-155 may serve as a non-invasive biomarker for detection of early stage breast cancer. PMID- 28562350 TI - U94 of human herpesvirus 6 down-modulates Src, promotes a partial mesenchymal-to epithelial transition and inhibits tumor cell growth, invasion and metastasis. AB - U94, the latency gene of human herpesvirus 6, was found to inhibit migration, invasion and proliferation of vascular endothelial cells (ECs). Because of its potent anti-migratory activity on ECs, we tested the capability of U94 to interfere with the individual steps of the metastatic cascade. We examined the U94 biological activity on the human breast cancer cell line MDA-MB 231, as a model of highly aggressive cancer cell. Here we show that the expression of U94 delivered by an HSV-1-based amplicon promoted down-modulation of Src and downstream molecules linked to cell motility and proliferation. Indeed, U94 expression strongly inhibited cell migration, invasiveness and clonogenicity. We investigated the effects of U94 in a three-dimensional rotary cell-culture system and observed the ability of U94 to modify tumor cell morphology by inducing a partial mesenchymal-to-epithelial transition. In fact, despite U94 did not induce any expression of the epithelial marker E-cadherin, it down-modulated different mesenchymal markers as beta-catenin, Vimentin, TWIST, Snail1, and MMP2. In vivo data on the tumorigenicity of MDA-MB 231 displayed the capability of U94 to control tumor growth, invasiveness and metastasis, as well as tumor-driven angiogenesis. The antitumor U94 activity was also confirmed on the human cervical cancer cell line HeLa. The ability of U94 to inhibit cell growth, invasion and metastasis opens the way to a promising field of research aimed to develop new therapeutic approaches for treating tumor and cancer metastasis. PMID- 28562351 TI - The bidirectional association between oral cancer and esophageal cancer: A population-based study in Taiwan over a 28-year period. AB - Previous studies have revealed that patients with oral or esophageal cancer are at higher risk for subsequently developing a second primary malignancy. However, it remains to be determined what association exists between oral cancer and esophageal cancer particularly in Asian countries where squamous cell carcinoma is the predominant type of esophageal cancer. A population-based study was carried out in Taiwan, where the incidence rates of both oral and esophageal squamous cell carcinomas are high, to test the hypothesis that oral cancer or esophageal cancer predisposes an individual to developing the other form of cancer. Our results showed that patients with primary oral cancer (n=45,859) had ten times the risk of second esophageal cancer compared to the general population. Within the same cohort, the reciprocal risk of oral cancer as a second primary in primary esophageal cancer patients (n=16,658) was also increased seven-fold. The bidirectional relationship suggests common risk factors between these two cancers. The present study is not only the first population based study in Asia to validate the reciprocal relationship between oral and esophageal squamous cell carcinomas, but also will aid in the appropriate selection of high-risk patients for a future follow-up surveillance program. PMID- 28562352 TI - Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras dependent manner. AB - Currently several combination treatments of mTor- and Ras-pathway inhibitors are being tested in cancer therapy. While multiple feedback loops render these central signaling pathways robust, they complicate drug targeting.Here, we describe a novel H-ras specific feedback, which leads to an inadvertent rapalog induced activation of tumorigenicity in Ras transformed cells. We find that rapalogs specifically increase nanoscale clustering (nanoclustering) of oncogenic H-ras but not K-ras on the plasma membrane. This increases H-ras signaling output, promotes mammosphere numbers in a H-ras-dependent manner and tumor growth in ovo. Surprisingly, also other FKBP12 binders, but not mTor-inhibitors, robustly decrease FKBP12 levels after prolonged (>2 days) exposure. This leads to an upregulation of the nanocluster scaffold galectin-1 (Gal-1), which is responsible for the rapamycin-induced increase in H-ras nanoclustering and signaling output. We provide evidence that Gal-1 promotes stemness features in tumorigenic cells. Therefore, it may be necessary to block inadvertent induction of stemness traits in H-ras transformed cells by specific Gal-1 inhibitors that abrogate its effect on H-ras nanocluster. On a more general level, our findings may add an important mechanistic explanation to the pleiotropic physiological effects that are observed with rapalogs. PMID- 28562354 TI - Circulating pre-treatment Epstein-Barr virus DNA as prognostic factor in locally advanced nasopharyngeal cancer in a non-endemic area. AB - The prognostic value of pre-treatment Epstein-Barr Virus (EBV) DNA viral load for non-endemic, locally-advanced, EBV-related nasopharyngeal cancer (NPC) patients is yet to be defined. All patients with EBV encoded RNA (EBER)-positive NPC treated at our Institution from 2005 to 2014 with chemotherapy (CT) concurrent with radiation (RT) +/- induction chemotherapy (ICT) were retrospectively reviewed. Pre-treatment baseline plasma EBV DNA (b-EBV DNA) viral load was detected and quantified by PCR. Median b-EBV DNA value was correlated to potential influencing factors by univariate analysis. Significant variables were then extrapolated and included in a multivariate linear regression model. The same variables, including b-EBV DNA, were correlated with Disease Free Survival (DFS) and Overall Survival (OS) by univariate and multivariate analysis.A total of 130 locally-advanced EBER positive NPC patients were evaluated. Overall, b-EBV DNA was detected in 103 patients (79.2%). Median viral load was 554 copies/mL (range 50-151075), and was positively correlated with T stage (p=0.002), N3a-b vs N0-1-2 stage (p=0.048), type of treatment (ICT followed by CTRT, p=0.006) and locoregional and/or distant disease recurrence (p=0.034). In the overall population, DFS and OS were significantly longer in patients with pre-treatment negative EBV DNA than in positive subjects at the multivariate analysis.Negative b-EBV DNA can be considered as prognostic biomarker of longer DFS and OS in NPC in non-endemic areas. This finding needs confirmation in larger prospective series, with standardized and inter-laboratory harmonized method of plasma EBV DNA quantification. PMID- 28562366 TI - Preparation and characterization of ferroelectric Hf0.5Zr0.5O2 thin films grown by reactive sputtering. AB - HfO2-ZrO2 solid-solution films were prepared by radio frequency sputtering, and the subsequent annealing process was optimized to render enhanced ferroelectric behavior. The target power, working pressure and O2 partial pressure ratios were varied, along with the annealing gas, time and temperature. Then, the film's structural and electrical properties were carefully scrutinized. Oxygen-deficient conditions were necessary during the sputter deposition to suppress grain growth, while annealing by O2 gas was critical to avoid defects and leakage problems. It is expected that the grain size difference under various deposition conditions combined with the degree of TiN top and bottom electrode oxidation by O2 gas will result in different ferroelectric behaviors. As a result, Hf0.5Zr0.5O2 prepared by radio frequency sputtering showed optimized ferroelectricity at 0% of O2 reactive gas, with a doubled remnant polarization value of ~20 MUC cm-2 at a thickness of 11 nm. Film growth conditions with a high growth rate (4-5 nm min-1) were favorable for achieving the ferroelectric phase film, which feasibly suppressed both the grain growth and accompanying monoclinic phase formation. PMID- 28562357 TI - Association between three VEGF polymorphisms and renal cell carcinoma susceptibility: a meta-analysis. AB - Several studies have reported an association between vascular endothelial growth factor (VEGF) gene polymorphisms rs2010963, rs3025039 and rs699947 and renal cell carcinoma (RCC). However, the results remain inconclusive and controversial. We therefore conducted a meta-analysis to evaluate this association. Electronic databases were searched for relevant case-control studies up to November 2016. RevMan 5.2 software and STATA version 12.0 were used for statistical analysis in our meta-analysis. Heterogeneity was assessed using the I2 value. Nine eligible studies were retrieved for detailed evaluation. The pooled estimates indicated that the GG genotype of VEGF rs2010963 polymorphism significantly decreased RCC risk [GG vs. GC+CC; GG vs. GC]. There was also a significant association between VEGF rs3025039 polymorphism and RCC susceptibility [CC+CT vs. TT; CC vs. TT]. Furthermore, a significant association between VEGF rs699947 polymorphism and RCC susceptibility was detected [A vs. C; AA+AC vs. CC; AA vs. AC+CC; AA vs. CC; AA vs. AC; AC vs. CC]. Subgroup analysis revealed that these associations held true especially for Asians. Our meta-analysis suggested that there may be a relationship between the VEGF rs2010963, rs3025039 and rs699947 polymorphisms and RCC susceptibility. PMID- 28562367 TI - Three-electron spin qubits. AB - The goal of this article is to review the progress of three-electron spin qubits from their inception to the state of the art. We direct the main focus towards the exchange-only qubit (Bacon et al 2000 Phys. Rev. Lett. 85 1758-61, DiVincenzo et al 2000 Nature 408 339) and its derived versions, e.g. the resonant exchange (RX) qubit, but we also discuss other qubit implementations using three electron spins. For each three-spin qubit we describe the qubit model, the envisioned physical realization, the implementations of single-qubit operations, as well as the read-out and initialization schemes. Two-qubit gates and decoherence properties are discussed for the RX qubit and the exchange-only qubit, thereby completing the list of requirements for quantum computation for a viable candidate qubit implementation. We start by describing the full system of three electrons in a triple quantum dot, then discuss the charge-stability diagram, restricting ourselves to the relevant subsystem, introduce the qubit states, and discuss important transitions to other charge states (Russ et al 2016 Phys. Rev. B 94 165411). Introducing the various qubit implementations, we begin with the exchange-only qubit (DiVincenzo et al 2000 Nature 408 339, Laird et al 2010 Phys. Rev. B 82 075403), followed by the RX qubit (Medford et al 2013 Phys. Rev. Lett. 111 050501, Taylor et al 2013 Phys. Rev. Lett. 111 050502), the spin-charge qubit (Kyriakidis and Burkard 2007 Phys. Rev. B 75 115324), and the hybrid qubit (Shi et al 2012 Phys. Rev. Lett. 108 140503, Koh et al 2012 Phys. Rev. Lett. 109 250503, Cao et al 2016 Phys. Rev. Lett. 116 086801, Thorgrimsson et al 2016 arXiv:1611.04945). The main focus will be on the exchange-only qubit and its modification, the RX qubit, whose single-qubit operations are realized by driving the qubit at its resonant frequency in the microwave range similar to electron spin resonance. Two different types of two-qubit operations are presented for the exchange-only qubits which can be divided into short-ranged and long-ranged interactions. Both of these interaction types are expected to be necessary in a large-scale quantum computer. The short-ranged interactions use the exchange coupling by placing qubits next to each other and applying exchange-pulses (DiVincenzo et al 2000 Nature 408 339, Fong and Wandzura 2011 Quantum Inf. Comput. 11 1003, Setiawan et al 2014 Phys. Rev. B 89 085314, Zeuch et al 2014 Phys. Rev. B 90 045306, Doherty and Wardrop 2013 Phys. Rev. Lett. 111 050503, Shim and Tahan 2016 Phys. Rev. B 93 121410), while the long-ranged interactions use the photons of a superconducting microwave cavity as a mediator in order to couple two qubits over long distances (Russ and Burkard 2015 Phys. Rev. B 92 205412, Srinivasa et al 2016 Phys. Rev. B 94 205421). The nature of the three electron qubit states each having the same total spin and total spin in z direction (same Zeeman energy) provides a natural protection against several sources of noise (DiVincenzo et al 2000 Nature 408 339, Taylor et al 2013 Phys. Rev. Lett. 111 050502, Kempe et al 2001 Phys. Rev. A 63 042307, Russ and Burkard 2015 Phys. Rev. B 91 235411). The price to pay for this advantage is an increase in gate complexity. We also take into account the decoherence of the qubit through the influence of magnetic noise (Ladd 2012 Phys. Rev. B 86 125408, Mehl and DiVincenzo 2013 Phys. Rev. B 87 195309, Hung et al 2014 Phys. Rev. B 90 045308), in particular dephasing due to the presence of nuclear spins, as well as dephasing due to charge noise (Medford et al 2013 Phys. Rev. Lett. 111 050501, Taylor et al 2013 Phys. Rev. Lett. 111 050502, Shim and Tahan 2016 Phys. Rev. B 93 121410, Russ and Burkard 2015 Phys. Rev. B 91 235411, Fei et al 2015 Phys. Rev. B 91 205434), fluctuations of the energy levels on each dot due to noisy gate voltages or the environment. Several techniques are discussed which partly decouple the qubit from magnetic noise (Setiawan et al 2014 Phys. Rev. B 89 085314, West and Fong 2012 New J. Phys. 14 083002, Rohling and Burkard 2016 Phys. Rev. B 93 205434) while for charge noise it is shown that it is favorable to operate the qubit on the so-called '(double) sweet spots' (Taylor et al 2013 Phys. Rev. Lett. 111 050502, Shim and Tahan 2016 Phys. Rev. B 93 121410, Russ and Burkard 2015 Phys. Rev. B 91 235411, Fei et al 2015 Phys. Rev. B 91 205434, Malinowski et al 2017 arXiv: 1704.01298), which are least susceptible to noise, thus providing a longer lifetime of the qubit. PMID- 28562353 TI - IL-17RC is critically required to maintain baseline A20 production to repress JNK isoform-dependent tumor-specific proliferation. AB - The IL-17/IL-17R axis has controversial roles in cancer, which may be explained by tumor-specific results. Here, we describe a novel molecular mechanism underlying IL-17RC-controlled tumor-specific proliferation. Triggered by IL-17RC knockdown (KD), B16 melanoma and 4T1 carcinoma cells inversely altered homeostatic tumor proliferation and tumor growth in vitro and in vivo. In contrast to the existing dogma that IL-17RC-dependent signaling activates the JNK pathway, IL-17RC KD in both tumor cell lines caused aberrant expression and activation of different JNK isoforms along with markedly diminished levels of the ubiquitin-editing enzyme A20. We demonstrated that differential up-regulation of JNK1 and JNK2 in the two tumor cell lines was responsible for the reciprocal regulation of c-Jun activity and tumor-specific proliferation. Furthermore, we showed that A20 reconstitution of IL-17RCKD clones with expression of full-length A20, but not a truncation-mutant, reversed aberrant JNK1/JNK2 activities and tumor-specific proliferation. Collectively, our study reveals a critical role of IL-17RC in maintaining baseline A20 production and a novel role of the IL-17RC A20 axis in controlling JNK isoform-dependent tumor-specific homeostatic proliferation. PMID- 28562368 TI - Heart sounds analysis using probability assessment. AB - OBJECTIVE: This paper describes a method for automated discrimination of heart sounds recordings according to the Physionet Challenge 2016. The goal was to decide if the recording refers to normal or abnormal heart sounds or if it is not possible to decide (i.e. 'unsure' recordings). APPROACH: Heart sounds S1 and S2 are detected using amplitude envelopes in the band 15-90 Hz. The averaged shape of the S1/S2 pair is computed from amplitude envelopes in five different bands (15-90 Hz; 55-150 Hz; 100-250 Hz; 200-450 Hz; 400-800 Hz). A total of 53 features are extracted from the data. The largest group of features is extracted from the statistical properties of the averaged shapes; other features are extracted from the symmetry of averaged shapes, and the last group of features is independent of S1 and S2 detection. Generated features are processed using logical rules and probability assessment, a prototype of a new machine-learning method. MAIN RESULTS: The method was trained using 3155 records and tested on 1277 hidden records. It resulted in a training score of 0.903 (sensitivity 0.869, specificity 0.937) and a testing score of 0.841 (sensitivity 0.770, specificity 0.913). The revised method led to a test score of 0.853 in the follow-up phase of the challenge. SIGNIFICANCE: The presented solution achieved 7th place out of 48 competing entries in the Physionet Challenge 2016 (official phase). In addition, the PROBAfind software for probability assessment was introduced. PMID- 28562369 TI - Combining sparse coding and time-domain features for heart sound classification. AB - OBJECTIVE: This paper builds upon work submitted as part of the 2016 PhysioNet/CinC Challenge, which used sparse coding as a feature extraction tool on audio PCG data for heart sound classification. APPROACH: In sparse coding, preprocessed data is decomposed into a dictionary matrix and a sparse coefficient matrix. The dictionary matrix represents statistically important features of the audio segments. The sparse coefficient matrix is a mapping that represents which features are used by each segment. Working in the sparse domain, we train support vector machines (SVMs) for each audio segment (S1, systole, S2, diastole) and the full cardiac cycle. We train a sixth SVM to combine the results from the preliminary SVMs into a single binary label for the entire PCG recording. In addition to classifying heart sounds using sparse coding, this paper presents two novel modifications. The first uses a matrix norm in the dictionary update step of sparse coding to encourage the dictionary to learn discriminating features from the abnormal heart recordings. The second combines the sparse coding features with time-domain features in the final SVM stage. MAIN RESULTS: The original algorithm submitted to the challenge achieved a cross-validated mean accuracy (MAcc) score of 0.8652 (Se = 0.8669 and Sp = 0.8634). After incorporating the modifications new to this paper, we report an improved cross validated MAcc of 0.8926 (Se = 0.9007 and Sp = 0.8845). SIGNIFICANCE: Our results show that sparse coding is an effective way to define spectral features of the cardiac cycle and its sub-cycles for the purpose of classification. In addition, we demonstrate that sparse coding can be combined with additional feature extraction methods to improve classification accuracy. PMID- 28562370 TI - Enhanced plasmon coupling of partly embedded gold nanospheres with surrounding silicon. AB - Gold nanospheres (AuNSs) were partly embedded into silicon through metal-assisted chemical etching, producing multiple-dimensional coupling of the plasmon resonances with the induced image charges in the surrounding medium. Rich plasmonic features of such coupling system were revealed by single particle dark field scattering spectra, characterizing by two splitted multipolar resonances at short wavelength region and a mixed dipolar resonance extending to infrared region. Numerical electrodynamic calculations indicated that the multipolar modes arise from the in-plane and out-of-plane quadrupolar resonances, which are excited by the horizontal and verticle electric field components, respectively, of the incident light owing to the enhanced coupling interaction. As the embedding depth increases, the degree of symmetry breaking in such nanoparticles/substrate system changes, resulting in significantly modified optical response, which supplies a new way to modulate the optical properties of plasmonic nanoparticles. PMID- 28562371 TI - The role of the multiparametric MRI in the diagnosis of prostate cancer in biopsy naive men. AB - PURPOSE OF REVIEW: To review the role of prebiopsy multiparametric MRI in biopsy naive men for the detection of clinically significant prostate cancer. RECENT FINDINGS: Recent level 1 evidence shows that multiparametric MRI has high sensitivity and negative predictive value for the detection of clinically significant prostate cancer in biopsy-naive men. Concurrent developments include important work in the standardization of MRI reporting. The low specificity and positive predictive value of MRI means that biopsy is still necessary following MRI. MRI-targeted prostate biopsy has emerged as an alternative diagnostic test to transrectal ultrasound guided prostate biopsy, though its exact role in biopsy naive men and the optimal technique remain to be defined. SUMMARY: There is the potential for MRI to be used as a triage test to allow a proportion of men to avoid biopsy and remain on prostate-specific antigen surveillance. MRI-suspicious areas can be sampled more intensively using MRI-targeted biopsy that can be carried out in a variety of ways. Future work should focus on the cost effectiveness of introducing a prebiopsy MRI pathway in biopsy-naive men and addressing the training needs for such a change. VIDEO ABSTRACT: http://links.lww.com/COU/A11. PMID- 28562372 TI - Masseteric to buccal branch nerve transfer. AB - PURPOSE OF REVIEW: To review recent literature pertaining to the use of masseteric-facial nerve neurorrhaphy (MFNN) for facial reanimation in patients with facial paralysis. RECENT FINDINGS: First, MFNN effectively restores some midface tone and function, including the ability to smile. Second, use of the masseteric nerve minimizes synkinesis, dysarthria, and dysphagia that frequently occur after hypoglossal-facial nerve neurorrhaphy. Third, concurrent cable grafting to the zygomatic branch from an intact proximal facial nerve remnant - when available - can restore dynamic eye closure. SUMMARY: Masseteric nerve transfer is an alternative to hypoglossal nerve transfer that improves midface appearance and function for properly selected patients with facial paralysis. PMID- 28562373 TI - Point-of-care Ultrasound Detection of Intraoperative Venous Air Embolism. PMID- 28562374 TI - Images in Anesthesiology: Air Embolism during Cardiac Catheterization and the Role for Anesthesia Use of Bedside Ultrasound. PMID- 28562375 TI - Exercise medicine for advanced prostate cancer. AB - PURPOSE OF REVIEW: Exercise is a provocative medicine, known for its preventive, complimentary and rehabilitative role in the management of cancer. Impressively, exercise is also emerging as a synergistic and targeted medicine to enhance symptom control, modulate tumour biology and delay disease progression, with the potential to increase overall survival. Given the complex clinical presentation of advanced prostate cancer patients and their omnipresent comorbidities, this review describes the current and potential role of exercise medicine in advanced prostate cancer. RECENT FINDINGS: Exercise has been shown to be safe, feasible and effective for advanced prostate cancer patients, inclusive of patients with bone metastases; a previously excluded population due to patient and clinician fear of adverse events. Preclinical data provide insight into the ability of exercise to modulate cancer-specific outcomes, may synergistically increase the potency of chemotherapy and radiotherapy and may endogenously and/or mechanically suppress tumour formation, growth and invasion in visceral and skeletal tissue. Epidemiological studies have also shown an association between physical activity and increased survival. SUMMARY: Exercise oncology is rapidly evolving, with impressive possibilities that may directly improve patient outcomes in advanced prostate cancer. Research must focus on translating preclinical trials into human clinical trials and investigate the direct effect of exercise on overall survival. PMID- 28562376 TI - Ventilation/perfusion single-photon emission computed tomography: a service evaluation. AB - OBJECTIVES: To identify the positive rate and negative predictive value (NPV) of our ventilation/perfusion (V/Q) single-photon emission computed tomography (SPECT) service as respective markers of overcalling (false positives) and undercalling (false negatives). We also identified the indeterminate rate as an indicator of the technical quality of the scans and reporter confidence. PATIENTS AND METHODS: V/Q SPECT studies carried out over 5 years were classified into positive, negative and indeterminate results. Patients who had died or had pulmonary emboli on imaging within 3 months of a negative V/Q SPECT were identified as false negatives, from which the NPV was calculated. The total number of positive and indeterminate studies as a proportion of all studies was calculated as the positive and indeterminate rates. RESULTS: The positive rate, NPV and indeterminate rates in nonpregnant patients were 24, 98.7-100 and 3.6%, respectively. The positive rate, NPV and indeterminate rates in pregnant patients were 6.8, 100 and 2.3%, respectively. CONCLUSION: The positive rate and NPV for nonpregnant patients were similar to the published literature. This suggests that we provide a safe service. The indeterminate rate was slightly higher than the stated guidelines. The study shows that the positive rate and NPV are achievable indicators of potential overcalling and undercalling in a V/Q SPECT service.This is also one of the first studies to report a positive rate in pregnant patients undergoing V/Q SPECT that other institutions can use as a standard when evaluating their services. PMID- 28562377 TI - The value of 18F-DOPA PET/CT in patients with medullary thyroid carcinoma and increased calcitonin values. AB - AIM: The aim of this prospective observational study was to examine the benefit of a fluorine-18-L-dihydroxyphenylalanine (F-DOPA) PET/computed tomography (CT) scan in patients with medullary thyroid carcinoma (MTC) in terms of increased calcitonin levels. PATIENTS AND METHODS: Twenty-eight MTC patients after initial total thyreoidectomy with increasing follow-up calcitonin levels suggestive for active disease after negative conventional imaging findings (neck ultrasound or thorax, abdomen, pelvis multislice computed tomography as standard imaging) were scanned using F-DOPA PET/CT from November 2012 to April 2016. The mean calcitonin level was 108.5 (range: 6.7-290) pmol/l and the mean carcinoembryonic antigen level was 15.7 (range: 1.1-221.9) MUg/l. The mean follow-up period was 19.7 months. RESULTS: F-DOPA PET/CT was positive in 16 out of 28 (57%) patients, mostly because of metabolically active neck and mediastinal lymph nodes metastases. Previously unknown bone metastases were found in six patients. A positive scan was reported in four patients (25% of positive scans) with a very low calcitonin value of less than 49.9 pmol/l. PET/CT findings led to a change of management and therapy in 16 out of 28 patients, with surgical procedure performed in eight patients, radiotherapy in five patients, and chemotherapy in two patients. CONCLUSION: F-DOPA PET/CT is a clinically useful modality in MTC whenever the calcitonin level is increased. There is a clear trend toward more positive scans with the higher calcitonin values, but patients with moderately elevated calcitonin values should also be taken into consideration for molecular imaging with F-DOPA PET/CT as the tumor burden in these patients is probably low, enabling further therapy to be individualized and consequently more efficient. PMID- 28562378 TI - Lack of association between COMT Val158Met and ZDHHC8 rs175174 polymorphisms and susceptibility to schizophrenia in a Brazilian population. PMID- 28562379 TI - Dexrazoxane added to doxorubicin-based adjuvant chemotherapy of breast cancer: a retrospective cohort study with a comparative analysis of toxicity and survival. AB - Dexrazoxane is indicated as a cardioprotective agent for patients receiving doxorubicin who are at increased risk for cardiotoxicity. Concerns have been raised on the use of dexrazoxane, particularly in adjuvant therapy, because of the risk of interference with the antitumor effect of doxorubicin. Two meta analyses in metastatic breast cancer have rejected this hypothesis, but have shown an apparent increase in the severity of myelosuppression when dexrazoxane is used. Here, we analyzed retrospectively a cohort of our institute database to assess whether the addition of dexrazoxane causes more bone marrow suppression in breast cancer patients receiving doxorubicin-based adjuvant therapy. The secondary objectives were assessment of the incidence of febrile neutropenia, dose-schedule modifications, recorded cardiac events or cardiac test abnormalities, and overall survival. Eight hundred and twenty-two female patients who received adjuvant (or neoadjuvant) doxorubicin and cyclophosphamide for breast cancer between 2001 and 2013 were included. One hundred and four of these patients also received dexrazoxane concurrently with the adjuvant treatment. Hospital records and, when accessible, community clinic records were reviewed. The median follow-up duration was 7 years for patients receiving dexrazoxane and 7.5 years for patients not receiving dexrazoxane. 85.6% of patients were alive at data lock. Compared with the nondexrazoxane group, patients who received dexrazoxane were older (median age at diagnosis 59 vs. 52 years) and more likely to receive dose-dense AC therapy (73 vs. 59%) and adjuvant trastuzumab treatment (29 vs. 15%). Compared with the nondexrazoxane group, dexrazoxane treatment was associated with a higher rate of hematological side effects: leukopenia (48 vs. 39%), neutropenia (45 vs. 31%, P=0.003), anemia (86 vs. 73%, P=0.005), and thrombocytopenia (37 vs. 22%, P=0.001). There were more febrile neutropenia hospitalizations (20 vs. 10%, P=0.001) and dose reductions (22 vs. 8%, P<0.001) in the dexrazoxane group, but no significant difference in the incidence of treatment delays or cancellations. The incidence of cardiac events was the same in both treatment groups with and without dexrazoxane. There was a nonsignificantly lower mortality rate in the dexrazoxane group (9.6%) compared with the nondexrazoxane group (15.0%) at data lock. Adding dexrazoxane to doxorubicin in adjuvant therapy patients leads to higher rates of bone marrow suppression in all blood components, as well as more febrile neutropenia events, and dose reductions. No differences in events defined as cardiac toxicities were detected. Dexrazoxane had no detrimental effect on survival, despite the higher hematological toxicity, the older median age, and the higher prevalence of HER2 positive disease in the dexrazoxane group. PMID- 28562380 TI - Pharmacokinetics of venetoclax in patients with 17p deletion chronic lymphocytic leukemia. AB - Venetoclax is a first-in-class orally available, B-cell lymphoma (BCL)-2 inhibitor indicated for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) harboring the 17p deletion. We used a novel approach for evaluating venetoclax pharmacokinetics using only sparse sampling in 155 patients enrolled in a phase 2, multicenter, open-label study in CLL patients with the 17p deletion. Patients received venetoclax doses within 30 min after the completion of breakfast or the first meal of the day, with no specific recommendations for the fat content in the meal. Blood samples for venetoclax assay were collected during the ramp-up period and on day 1 of weeks 8, 12, 16, 24, and every 12 weeks thereafter. The mean postdose (8 h) plasma venetoclax concentrations increased with increasing weekly venetoclax dose during the ramp up period to reach 1.89 ug/ml on week 5 day 1 at the 400 mg dose. The mean predose concentration at the 400 mg dose ranged between 0.69 and 0.99 ug/ml across visits between weeks 8 and 120. Repeated-measures analysis detected no statistical significance (P>=0.05) for the mean predose concentrations at any of the times tested from weeks 8 to 24. The study shows that the pharmacokinetic profile of venetoclax in CLL patients with the 17p deletion is comparable to the overall CLL as well as non-Hodgkin's lymphoma patient populations. Furthermore, no specific recommendation in terms of fat content in the meal is needed for the intake of venetoclax in patients with CLL. PMID- 28562381 TI - Respiratory involvement in neuromuscular disorders. AB - PURPOSE OF REVIEW: In numerous neuromuscular disorders (NMDs), respiratory muscle weakness is present, and acute or chronic respiratory failure may evolve. Very often, respiratory involvement substantially adds to the burden of disease, impairs quality of life, or reduces life expectancy. This article summarizes new aspects of both diagnosis and management of respiratory muscle weakness in patients with NMDs. RECENT FINDINGS: Drugs like deflazacort, ataluren, eteplirsen, and nusinersen are now approved treatments for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy, and others are on their way in NMDs. Although observing how innovative drugs will change the natural history of these diseases, including respiratory function over time, adequate symptomatic treatment remains meaningful and is strongly recommended. Physicians should systematically take respiratory involvement into account to improve patients' quality of life and prognosis. SUMMARY: First, it is outlined in which subtypes of NMD respiratory muscle dysfunction is particularly relevant. Second, new developments regarding diagnostic procedures, including respiratory muscle strength testing, spirometry, and sleep studies, are covered. Third, this article gives an overview on current concepts of ventilatory support and management of secretions in patients with NMD. PMID- 28562382 TI - Impact of mean platelet aggregation degree on long-term clinical outcomes among patients undergoing a complex percutaneous coronary intervention. AB - OBJECTIVE: The aim of this study was to evaluate the association between the mean platelet aggregation degree and long-term clinical outcomes in patients receiving a complex percutaneous coronary intervention (CPCI). PATIENTS AND METHODS: We screened 2141 patients after a percutaneous coronary intervention (PCI) treated with aspirin and clopidogrel. CPCI was defined as a procedure targeted to at least one of the following: left main disease, bifurcation lesion, ostial lesion, chronic total occlusion, and small-vessel stenting. ADP-induced platelet aggregation was serially measured by light transmission aggregometry at least three times after PCI and the mean value was calculated. The population was categorized on the basis of the mean ADP degree and the presence of CPCI. The primary endpoint measured was a major adverse cardiovascular and cerebral event (MACCE). RESULTS: A total of 1245 patients enrolled in the study were divided into four groups: group A (CPCI and ADP>=40%), group B (CPCI and ADP<40%), group C (non-CPCI and ADP>=40%), and group D (non-CPCI and ADP<40%). The median follow up was 29.9 months. The Cox multivariate analysis suggested that group A was an independent risk factor for MACCE (hazard ratio: 2.70, 95% confidence interval: 1.25-5.81; P<0.001). Compared with group A, the remaining groups (groups B, C, and D) had a lower rate of MACCE. When group C was set as the reference, groups B and D had similar risks for primary endpoints. CONCLUSION: Patients undergoing CPCI with a high mean ADP degree are at a high risk for MACCE. Serial platelet function testing is therefore important in patients receiving CPCI. PMID- 28562383 TI - Treatment options for stent restenosis: insights from intracoronary imaging, clinical trials, and registries. AB - Although drug-eluting stents (DES) have markedly reduced the incidence of stent restenosis (SR), the increased number and complexity of percutaneous coronary interventions performed worldwide explain the sustained prevalence of SR. Intracoronary imaging techniques remain essential tools to unravel the underlying mechanical causes potentially leading to SR. Current clinical trial data suggest that DES are the most effective therapy for the management of both bare-metal stents SR and DES-SR. In this setting, however, drug-eluting balloons represent a valid therapeutic alternative with the attractive advantage of not requiring the implantation of an additional metallic layer. In this review, we will discuss trial data on the historical evolution and the evidence supporting currently available therapeutic modalities for patients with bare-metal stents SR or DES SR. PMID- 28562384 TI - Personalized hemodynamic management. AB - PURPOSE OF REVIEW: To describe personalized hemodynamic management of critically ill patients in the operating room and the ICU. RECENT FINDINGS: Several recent clinical studies have investigated different strategies for optimizing blood pressure (BP) and flow in the operating room and in the ICU. In the past, (early) goal-directed hemodynamic treatment strategies often used predefined fixed population-based 'normal' values as hemodynamic targets. Most hemodynamic variables, however, have large interindividual variability and are dependent on several biometric factors. Personalized BP management aims to set specific BP targets for a given patient taking into account blood flow autoregulation and any history of chronic hypertension. To optimize cardiac output and oxygen delivery, individualized hemodynamic management based on functional assessment of fluid responsiveness is used. Innovative noninvasive technologies now enable preoperative assessment of a patient's personal normal hemodynamic values, which can then be targeted in the perioperative phase. In critically ill patients admitted to the ICU, adaptive multiparametric hemodynamic monitoring can help to personalize hemodynamic management. SUMMARY: Personalized hemodynamic management targets personal normal values of hemodynamic variables, which are adjusted to biometric data and adapted to the clinical situation (i.e., adequate values). This approach optimizes cardiovascular dynamics based on the patient's personal hemodynamic profile. PMID- 28562387 TI - Lipid resuscitation in acute poisoning: after a decade of publications, what have we really learned? AB - PURPOSE OF REVIEW: The decision to provide intravenous lipid emulsion (ILE) therapy as a treatment modality for the reversal of various drug toxicity was discovered in the last decade. Numerous publications, in both humans and animals attest to its clinical use, but current supporting evidence is inconsistent. RECENT FINDINGS: A recent systematic review reported evidence for benefit of ILE in bupivacaine toxicity. Human randomized trials, large observational studies as well as animal models of orogastric poisoning failed to report a clear benefit of ILE for nonlocal anesthetics poisoning. SUMMARY: ILE can be used to resuscitate local anesthetics especially bupivacaine. The impact of ILE on oral overdoses is controversial and clear evidence on benefit is lacking. A thorough risk benefit assessment with consideration of alternative options is warranted to minimize the risk of adverse effects. Evidence supports using bolus doses of ILE, while infusion rates are still debatable. PMID- 28562385 TI - Mitochondrial DNA in Sepsis. AB - PURPOSE OF REVIEW: Our understanding of critical illness is transforming as we develop a better understanding of the impact pathogen-associated molecular patterns and damage-associated molecular patterns (DAMPs) have on the pathogenesis of disease. Of the known DAMPs, there is a growing interest in mitochondrial DNA (mtDNA) as a DAMP capable of propagating the inflammatory response seen in sepsis and other conditions. In this review, we describe the varying mechanisms by which mtDNA is translocated from mitochondria into cytosol and the extracellular space where it can illicit an inflammatory response. In addition, we present some of the most recent clinical studies to examine mtDNA in critical illness. RECENT FINDINGS: Basic science research provides convincing data that mtDNA can influence the immune system through toll-like receptor 9 and inflammasomes. Clinical trials provide evidence that mtDNA is elevated in critically ill patients and is associated with mortality. SUMMARY: Although mtDNA is a DAMP shown to be elevated in numerous conditions, the clinical ramifications of this finding remain elusive. Further work is needed to determine if mtDNA can be utilized as a biomarker of disease severity or mortality. PMID- 28562386 TI - Neurotoxicity of anesthetic drugs: an update. AB - PURPOSE OF REVIEW: This article reviews the most recently published evidence that investigated anesthesia-induced neurotoxicity in both animals and humans, especially as it pertains to the perinatal period. RECENT FINDINGS: Several recent studies have focused on better understanding the complex mechanisms that underlie intravenous and volatile anesthesia-induced neurotoxicity in animals. Adjuvant agents that target these pathways have been investigated for their effectiveness in attenuating the neuroapoptosis and neurocognitive deficits that result from anesthesia exposure, including dexmedetomidine, rutin, vitamin C, tumor necrosis factor alpha, lithium, apocynin, carreic acid phenethyl ester. Five clinical studies, including one randomized control trial, provided inconsistent evidence on anesthesia-induced neurotoxicity in humans. SUMMARY: Despite a growing body of preclinical studies that have demonstrated anesthesia induced neurotoxic effects in the developing and aging brain, their effects on the human brain remains to be determined. The performance of large-scale human studies is limited by several important factors, and noninvasive biomarkers and neuroimaging modalities should be employed to define the injury phenotypes that reflect anesthesia-induced neurotoxicity. Ultimately, the use of these modalities may provide new insights into whether the concerns of anesthetics are justified in humans. PMID- 28562388 TI - Procedural sedation in the ICU and emergency department. AB - PURPOSE OF REVIEW: Procedures are increasingly being performed in the acute care setting, outside of the operating rooms (OR). This article aims to review the current literature on out-of-OR procedural sedation with a focus on the ICU and emergency department, highlighting the following topics: multidisciplinary team approach, choice of pharmacologic agent, sedation scales, current safety guidelines, anticipating complications, appropriate monitoring and necessary resources. RECENT FINDINGS: Subjective assessment of sedation using sedation scales is controversial. Addition of ketamine and dexmedetomidine to propofol for sedation improves patient and proceduralist satisfaction. The short-acting benzodiazepine remimazolam shows promise in initial phase 2 trials. Use of capnography for monitoring during sedation is being challenged by new literature from the emergency department setting. Hypoxia is the most common adverse event with procedural sedation, and the risk of pulmonary aspiration is low. SUMMARY: Multimodal/synergistic sedation under a multidisciplinary team provides the best patient satisfaction. Collection and analysis of physiological data and outcomes of patients undergoing procedural sedation is necessary to maintain compliance with regulatory bodies. There is a paucity of comprehensive guidelines for conducting research in procedural sedation; therefore, it is being currently addressed by the Sedation Consortium. PMID- 28562389 TI - Clinical course over five decades of a woman carrying 16p13.3 microduplication. PMID- 28562390 TI - Myhre syndrome with novel findings: bilateral congenital cortical cataract, bilateral papilledema, accessory nipple, and adenoid hypertrophy. PMID- 28562391 TI - Pierpont syndrome: report of a new patient. AB - Pierpont syndrome (OMIM #602342) is a rare disorder characterized by developmental delay, characteristic facial gestalt, hearing loss, and abnormal fat distribution in the distal limbs. A specific mutation in TBL1XR1 [c.1337A>G; p.(Tyr446Cys)] has been described recently in six unrelated patients with Pierpont syndrome. We report on a male child with developmental delay, distinctive facial dysmorphic features, dystrophy, and abnormal fat distribution in the feet, in whom we identified the identical TBL1XR1 mutation. This patient also had additional clinical features including microphthalmia, pendular nystagmus, cryptorchidism, dermal sinus, and peripheral joint laxity, which had not been reported previously in association with Pierpont syndrome. This patient corroborates the assumption that Pierpont syndrome is exclusively caused by the specific TBL1XR1 missense mutation p.(Tyr446Cys) and the additional features broaden the phenotypic spectrum of this rare disorder. PMID- 28562392 TI - Atypical osteogenesis imperfecta caused by a 17q21.33 deletion involving COL1A1. PMID- 28562393 TI - Association between lower air pressure and the onset of ischemic colitis: a case control study. AB - OBJECTIVE: Ischemic colitis (IC) often affects the elderly. Proarteriosclerotic factors, such as hypertension and smoking, and cardiovascular disease are considered major contributors to IC. Although a possible link between certain cerebrocardiovascular disorders and meteorological phenomena has been reported, the relationship between IC onset and weather changes remains uninvestigated. This study examined whether specific meteorological factors were associated with the occurrence of IC. PATIENTS AND METHODS: We retrospectively enrolled 303 patients who had been diagnosed with IC between January 2003 and June 2010 at Suwa Red Cross Hospital in Nagano Prefecture, Japan. The meteorological data of the days on which IC patients visited the hospital (IC+ days) were compared with those of the days on which IC patients did not (IC- days). RESULTS: Univariate analysis indicated that IC+ days had significantly lower air pressure (P<0.001), depressed air pressure from the previous day (P<0.001), and fewer daylight hours (P<0.001), as well as higher air temperature (P=0.017), air humidity (P=0.004), wind velocity (P<0.001), and rainfall (P=0.012) compared with IC- days. Multivariate logistic regression analysis of the meteorological data showed that air pressure (odds ratio: 0.935, P<0.001) and change in air pressure from the previous day (odds ratio: 0.934, P<0.001) were related to onset of IC. CONCLUSION: Lower air pressure and decrease in air pressure from the previous day are possible novel factors associated with the development of IC. PMID- 28562394 TI - Diagnostic accuracy of contrast-enhanced ultrasound for the differential diagnosis of hepatocellular carcinoma: ESCULAP versus CEUS-LI-RADS. AB - OBJECTIVE: A comparison is made of two contrast-enhanced ultrasound (CEUS) algorithms for the diagnosis of hepatocellular carcinoma (HCC) in high-risk patients: Erlanger Synopsis of Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at Risk (ESCULAP) and American College of Radiology Contrast-Enhanced Ultrasound-Liver Imaging Reporting and Data System (ACR-CEUS-LI RADSv.2016). PATIENTS AND METHODS: Focal liver lesions in 100 high-risk patients were assessed using both CEUS algorithms (ESCULAP and CEUS-LI-RADSv.2016) for a direct comparison. Lesions were categorized according to size and contrast enhancement in the arterial, portal venous and late phases.For the definite diagnosis of HCC, categories ESCULAP-4, ESCULAP-Tr and ESCULAP-V and CEUS-LI-RADS LR-5, LR-Tr and LR-5-V were compared. In addition, CEUS-LI-RADS-category LR-M (definitely/probably malignant, but not specific for HCC) and ESCULAP-category C [intrahepatic cholangiocellular carcinoma (ICC)] were compared.Histology, CE computed tomography and CE-MRI served as reference standards. RESULTS: The reference standard among 100 lesions included 87 HCCs, six ICCs and seven non-HCC non-ICC-lesions. For the diagnosis of HCC, the diagnostic accuracy of CEUS was significantly higher with ESCULAP versus CEUS-LI-RADS (94.3%/72.4%; p<0.01). Sensitivity, specificity and positive predictive value (PPV) and negative predictive value for ESCULAP/CEUS-LI-RADS were 94.3%/72.4%; 61.5%/69.2%; 94.3%/94%; and 61.5%/27.3%, respectively.The diagnostic accuracy for ICC (LR M/ESCULAP-C) was identical with both algorithms (50%), with higher PPV for ESCULAP-C versus LR-M (75 vs. 50%). CONCLUSION: CEUS-based algorithms contribute toward standardized assessment and reporting of HCC-suspect lesions in high-risk patients. ESCULAP shows significantly higher diagnostic accuracy, sensitivity and negative predictive value with no loss of specificity compared with CEUS-LI-RADS. Both algorithms have an excellent PPV. Arterial hyperenhancement is the key feature for the diagnosis of HCC with CEUS. Washout should not be a necessary prerequisite for the diagnosis of definite HCC. CEUS-LI-RADS in its current version is inferior to ESCULAP for the noninvasive diagnosis of HCC. There are two ways to improve CEUS-LI-RADS: firstly, combination of the categories LR-4 and LR-5 for the diagnosis of definite HCC, and secondly, use of subtotal infiltration of a liver lobe as an additional feature. PMID- 28562395 TI - Differential significance of early surgical complications for acute and long-term recurrence-free survival following surgical resection of hepatocellular carcinoma: do comorbidities play a role? AB - BACKGROUND: Postoperative complications of Clavien-Dindo grade 3 or more are of prognostic significance in patients who undergo liver resection for hepatocellular carcinoma (HCC). However, perioperative mortality and patient comorbidities represent relevant factors that interfere with postoperative long term survival. To clarify this, a retrospective single-center study was carried out. PATIENTS AND METHODS: Patient data were prospectively collected in a continuously updated liver resection database. Overall, 184 consecutive patients who underwent liver resection for HCC with a curative intent between March 2003 and December 2013 were selected for the study. The patients were assigned to two groups according to the presence or absence of postoperative complications. Pre existing comorbidities, perioperative mortality, surgical outcome, and long-term survival data were analyzed. RESULTS: Postoperative complications requiring revision surgery were identified in 17.4% of the patients. The in-house mortality rate was 4.8%. Compared with patients without complications, patients with complications were older and had significantly more pre-existing comorbidities, more advanced tumors, more intrahepatic metastasis, longer operation times, greater blood loss, and more extensive resections. The overall 5-year survival rates were 40.1 and 52.5% in patients with or without postoperative complications, respectively. The corresponding 5-year recurrence-free survival rates were 46.3 and 46.7% (perioperative mortality excluded). Multivariate analysis showed that elevation of the Charlson Comorbidity Index was associated independently with decreased overall and recurrence-free survival. CONCLUSION: In patients with HCC, posthepatectomy complications are confirmed to have predictive value. However, closer analysis and exclusion of perioperative mortality effects show an independent impact of pre-existing comorbidities on long-term overall und recurrence-free survival. PMID- 28562398 TI - Celebrate Home Health Aides. PMID- 28562397 TI - Simulation Research in Gastrointestinal and Urologic Care-Challenges and Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Biomedical Imaging and Bioengineering Workshop. AB - : A workshop on "Simulation Research in Gastrointestinal and Urologic Care: Challenges and Opportunities" was held at the National Institutes of Health in June 2016. The purpose of the workshop was to examine the extent to which simulation approaches have been used by skilled proceduralists (not trainees) caring for patients with gastrointestinal and urologic diseases. The current status of research findings in the use and effectiveness of simulation applications was reviewed, and numerous knowledge gaps and research needs were identified by the faculty and the attendees. The paradigm of "deliberate practice," rather than mere repetition, and the value of coaching by experts was stressed by those who have adopted simulation in music and sports. Models that are most useful for the adoption of simulation by expert clinicians have yet to be fully validated. Initial studies on the impact of simulation on safety and error reduction have demonstrated its value in the training domain, but the role of simulation as a strategy for increased procedural safety remains uncertain in the world of the expert practitioner. Although the basic requirements for experienced physicians to acquire new skills have been explored, the widespread availability of such resources is an unrealized goal, and there is a need for well-designed outcome studies to establish the role of simulation in improving the quality of health care. PMID- 28562401 TI - Using a Standardized Patient to Improve Collaboration and Problem Solving Skills With CPAP Usage in the Home. AB - A review of literature revealed a lack of research pertaining to nurses' or student nurses' knowledge of continuous positive airway pressure (CPAP) and the ability to troubleshoot CPAP malfunction. This study sought to answer the following questions: What are associate degree nursing (ADN) students' knowledge, interdisciplinary communication, and problem-solving skills regarding patients' home use of CPAP? Is there a change after participation in a simulation with a patient on CPAP in home setting? Twenty-one ADN students enrolled in small Midwest college participated. A preexperimental design of one group pretest posttest was used. Each student completed a demographic questionnaire, Mayo High Performance Teamwork Scale, Interprofessional collaborative simulation experience survey, and a CPAP knowledge base survey before and upon completion of the simulation. There were no changes in students' comfort, baseline knowledge, and basic understanding regarding CPAP. However, after the simulation, students described more detailed problem-solving skills, which included using respiratory therapists, durable medical equipment providers, and community resources. On the Mayo High Performance Teamwork Scale, all 16 items demonstrated improved scores (baseline mean = 21.65 and postsimulation mean = 25.6). PMID- 28562400 TI - Prevalence of and Factors Related to Prescription Opioids, Benzodiazepines, and Hypnotics Among Medicare Home Health Recipients. AB - High rates of controlled prescription drugs are associated with cognitive impairment, falls, and misuse and dependence. Little is known about the prevalence of these medications among older adults receiving home healthcare. The purpose of this study was to determine the frequency of, and the factors related to, opioid analgesics, benzodiazepines (BNZ), and nonbenzodiazepine (NBNZH) hypnotics among a large sample of older adults entering home healthcare services. The data came from administrative records of 133 Certified Home healthcare Agencies located across 32 states. Patients (age >= 65) receiving Medicare home healthcare services and who received a start-of-care Medicare OASIS assessment between January 1, 2013, and December 31, 2014, were included in the study (n = 87,780). Rates of controlled medication use were compared across patient-level sociodemographic, clinical, functional, and environmental variables. The prevalence of controlled medication was high, with 58% prescribed at least one class of controlled drug, 44% were prescribed an opioid, 19% were prescribed a BNZ, and almost 7% were prescribed a NBZDH. Factors independently associated with higher levels of controlled medication usage include younger-old age, white race, postsurgical status, injuries, referral from inpatient settings, and rural location. Home healthcare clinicians are well positioned to review and reconcile medication, oversee referrals and follow-up care, and provide ongoing assessment of risk regarding the use of opioids, BNZ, and hypnotics among home healthcare patients. PMID- 28562402 TI - Artificial Nutrition and Hydration in People With Late-Stage Dementia. AB - The progressive nature of dementia marks this disease as a terminal illness in the advanced stage, and palliative care rather than curative treatment is indicated. The use of feeding tubes to deliver artificial nutrition and hydration at end of life is often part of the plan of care for people with dementia. Current evidence, however, suggests that tube feeding in advanced dementia is not beneficial and the burdens of the procedure and the feedings themselves outweigh any benefits. Evidence also reveals that healthcare providers may lack evidence based knowledge about artificial nutrition and hydration to adequately inform families and surrogate decision makers. This article examines the evidence regarding use of artificial nutrition and hydration for patients with end-stage dementia and offers implications for home care clinicians. PMID- 28562403 TI - Prevention of 30-Day Readmission After Coronary Artery Bypass Surgery. AB - Although many studies have focused on risk factors for 30-day readmission after coronary artery bypass graft (CABG) surgery, there is very little known about the prevention of modifiable risk factors associated with readmission. The research questions that guided this focused literature review were (1) What are the modifiable risk factors of 30-day readmission after CABG surgery identified in recent literature? and (2) What are the clinical programs and strategies available in preventing 30-day readmission after CABG surgery? A focused literature review from 1997 to 2014 yielded 17 published reports. Findings of this review revealed a significant gap between addressing modifiable patient specific risk factors and the current clinical program initiatives, which are focused on care processes. Clinical programs and strategies for 30-day readmission after CABG surgery are evolving. Many programs and studies have included discharge planning and education as interventions to prevent 30-day readmissions; however, there is inconsistency in the literature on the impact of early discharge on readmission. Future studies need to focus on targeting the clinical modifiable risk factors and discharge planning and education, which may help to prevent 30-day readmissions. PMID- 28562404 TI - Bundle Payment Program Initiative: Roles of a Nurse Navigator and Home Health Professionals. AB - With the passage of the Affordable Care Act, The Centers for Medicare and Medicaid (CMS) introduced a new value-based payment model, the Bundle Payment Care Initiative. The CMS Innovation (Innovation Center) authorized hospitals to participate in a pilot to test innovative payment and service delivery models that have a potential to reduce Medicare expenditures while maintaining or improving the quality of care for beneficiaries. A hospital-based home care agency, Abington Jefferson Health Home Care Department, led the initiative for the development and implementation of the Bundled Payment Program. This was a creative and innovative method to improve care along the continuum while testing a value-based care model. PMID- 28562405 TI - Reviewing the 2017 American Diabetes Association Standards of Medical Care. PMID- 28562406 TI - Caregiver Education and Support. PMID- 28562407 TI - Unexpected Painful Breath. PMID- 28562408 TI - A Day in the Life of a Home Health and Hospice Aide. PMID- 28562409 TI - Writing for Publication. PMID- 28562410 TI - Documentation Dilemmas. PMID- 28562411 TI - In Celebration of Home Healthcare Aides. PMID- 28562413 TI - Renal Adiposity Confounds Quantitative Assessment of Markers of Renal Diffusion With MRI: A Proposed Correction Method. AB - OBJECTIVES: Recent studies have indicated that excessive fat may confound assessment of diffusion in organs with high fat content, such as the liver and breast. However, the extent of this effect in the kidney, which is not considered a major fat deposition site, remains unclear. This study tested the hypothesis that renal fat may impact diffusion-weighted imaging (DWI) parameters, and proposes a 3-compartment model (TCM) to circumvent this effect. METHODS: Using computer simulations, we investigated the effect of fat on assessment of apparent diffusion coefficient (ADC), intravoxel incoherent motion (IVIM), and TCM-derived pure-diffusivity. We also investigated the influence of magnetic resonance repetition (TR) and echo time (TE) on DWI parameters as a result of variation in the relative contribution of the fat signal. Apparent diffusion coefficient, IVIM and TCM DWI parameters were calculated in domestic pigs fed a high-cholesterol (obese group) or normal diet (lean group), and correlated to renal histology. Intravoxel incoherent motion-derived pure-diffusivity was also compared among 15 essential hypertension patients classified by body mass index (BMI) (high vs normal). Finally, pure-diffusivity was calculated and compared in 8 patients with atherosclerotic renal artery stenosis (ARAS) and 5 healthy subjects using IVIM and TCM. RESULTS: Simulations showed that unaccounted fat results in the underestimation of IVIM-derived pure diffusivity. The underestimation increases as the fat fraction increases, with higher pace at lower fat contents. The underestimation was larger for shorter TR and longer TE values due to the enhancement of the relative contribution of the fat signal. Moreover, TCM, which incorporates highly diffusion-weighted images (b > 2500 s/mm), could correct for fat-dependent underestimation. Animal studies in the lean and obese groups confirmed lower ADC and IVIM pure-diffusivity in obese versus lean pigs with otherwise healthy kidneys, whereas pure-diffusivity calculated using TCM were not different between the 2 groups. Similarly, essential hypertension patients with high BMI had lower ADC (1.9 vs 2.1 * 10 mm/s) and pure-diffusivity (1.7 vs 1.9 * 10 mm/s) than those with normal BMI. Pure-diffusivity calculated using IVIM was not different between the ARAS and healthy subjects, but TCM revealed significantly lower diffusivity in ARAS. CONCLUSIONS: Excessive renal fat may cause underestimation of renal ADC and IVIM-derived pure-diffusivity, which may hinder detection of renal pathology. Models accounting for fat contribution may help reduce the variability of diffusivity calculated using DWI. PMID- 28562414 TI - Spatial Distribution of Iron Within the Normal Human Liver Using Dual-Source Dual Energy CT Imaging. AB - OBJECTIVES: Explore the potential of dual-source dual-energy (DSDE) computed tomography (CT) to retrospectively analyze the uniformity of iron distribution and establish iron concentration ranges and distribution patterns found in healthy livers. MATERIALS AND METHODS: Ten mixtures consisting of an iron nitrate solution and deionized water were prepared in test tubes and scanned using a DSDE 128-slice CT system. Iron images were derived from a 3-material decomposition algorithm (optimized for the quantification of iron). A conversion factor (mg Fe/mL per Hounsfield unit) was calculated from this phantom study as the quotient of known tube concentrations and their corresponding CT values. Retrospective analysis was performed of patients who had undergone DSDE imaging for renal stones. Thirty-seven patients with normal liver function were randomly selected (mean age, 52.5 years). The examinations were processed for iron concentration. Multiple regions of interest were analyzed, and iron concentration (mg Fe/mL) and distribution was reported. RESULTS: The mean conversion factor obtained from the phantom study was 0.15 mg Fe/mL per Hounsfield unit. Whole-liver mean iron concentrations yielded a range of 0.0 to 2.91 mg Fe/mL, with 94.6% (35/37) of the patients exhibiting mean concentrations below 1.0 mg Fe/mL. The most important finding was that iron concentration was not uniform and patients exhibited regionally high concentrations (36/37). These regions of higher concentration were observed to be dominant in the middle-to-upper part of the liver (75%), medially (72.2%), and anteriorly (83.3%). CONCLUSIONS: Dual-source dual-energy CT can be used to assess the uniformity of iron distribution in healthy subjects. Applying similar techniques to unhealthy livers, future research may focus on the impact of hepatic iron content and distribution for noninvasive assessment in diseased subjects. PMID- 28562416 TI - Cryptococcal disease in the solid organ transplant setting: review of clinical aspects with a discussion of asymptomatic cryptococcal antigenemia. AB - PURPOSE OF REVIEW: Cryptococcal infections are an important cause of morbidity and mortality in solid organ transplant patients. Here, we review the microbiology, epidemiology, clinical course, treatment, and outcomes of Cryptococcus in solid organ transplant recipients. RECENT FINDINGS: We identify the unique findings in solid organ transplant patients when compared to other immunocompromised patients such as those with HIV. We also describe our experience and outcomes with regard to solid organ transplant patients who do not have positive fungal cultures, but cryptococcal antigen positivity and concern for cryptococcal disease. SUMMARY: Our review will highlight the importance of these new diagnostic techniques in those with Cryptococcus and solid organ transplant, which will be the subject of new research. PMID- 28562417 TI - Strongyloides stercoralis in solid organ transplantation: early diagnosis gets the worm. AB - PURPOSE OF REVIEW: Strongyloidiasis is a parasitic infection affecting millions of people worldwide. Complications of infection are strongly associated with alcoholism, immunosuppression, and organ transplantation. Delayed diagnosis results in hyperinfection syndrome and disseminated strongyloidiasis leading to mortality rates approaching 80%. Early detection, and prevention of infection and transmission are key to diminish this illness. RECENT FINDINGS: In this review, we cover the basic concepts in immunity, immunosuppression, and disorder necessary for understanding the infectious syndromes associated with Strongyloides stercoralis infection. Focused discussion on donor-derived transmission and recipient risk in solid organ transplantation is presented. Current methodology for diagnosis, screening algorithms, and treatment are also reviewed. SUMMARY: Strongyloidiasis complicated by hyperinfection and dissemination remains associated with a poor outcome. The poor outcome pleads for a high level of suspicion and aggressive treatment in at-risk patients. As the population of transplant patients continues to increase, the risk of infection also increases, compelling us to address this highly fatal infectious complication in solid organ transplantation (SOT). Here we review the pathology, immunology, diagnosis, and treatment of strongyloides infection in the immunosuppressed SOT population. PMID- 28562418 TI - Autologous islet transplantation: challenges and lessons. AB - PURPOSE OF REVIEW: Human islet isolation and autotransplantation [autologous islet transplant (AUTX)] is performed to prevent or ameliorate brittle diabetes after total pancreatectomy performed for benign disease. The success or failure of the transplant can be associated with a profound impact on the individual's quality of life and even survival. AUTX offers unique insights into the effects of pancreas quality, islet number, isolation technique and alternate site engraftment on transplant efficacy. Herein, we review islet isolation with a focus on potential pathways to further optimize the endocrine outcome of AUTX, and compare and contrast differences in islet processing for AUTX and allotransplantation (allogeneic islet transplant). RECENT FINDINGS: New knowledge of human islet biology and issues surrounding the engraftment process offer opportunities for innovative approaches toward optimizing islet cell transplantation. SUMMARY: Improving the rate and durability of insulin independence in the often-times marginal dose model of AUTX may provide new insight toward improving the efficiency and durability of single donor islet (allogeneic islet transplant). PMID- 28562419 TI - Endocrine disorders and hormonal therapy for adolescent acne. AB - PURPOSE OF REVIEW: Acne vulgaris is a global disease with increasing prevalence in adolescents. It has a profound impact on their quality of life, especially when endocrine disorders are also involved. Recent concerns regarding antibiotic stewardship, failures with antibiotic usage, and the development of antibiotic resistant Propionibacterium acnes have led clinicians to consider other therapeutic options for acne treatment. The present review explores hormonal therapies for the treatment of acne vulgaris. RECENT FINDINGS: There are now four different combined oral contraceptive pills that are FDA approved for the treatment of acne since its first introduction in 1960. Recent literature has provided more information on the efficacy of different generations of combined oral contraceptive pills, their side-effects, and cancer risks. Furthermore, spironolactone has been gaining wider use among dermatologists in adolescents with endocrine dysfunction. New diagnostic guidelines and treatment recommendations have also been suggested. SUMMARY: Hormonal therapies are effective and well tolerated options for the treatment of acne vulgaris in adolescents with and without endocrine disorders. They can be used as monotherapy or in conjunction with benzoyl peroxide, topical retinoic acid, or antibiotics. PMID- 28562420 TI - Statement on gender-affirmative approach to care from the pediatric endocrine society special interest group on transgender health. AB - PURPOSE OF REVIEW: The purpose of this Position Statement is to emphasize the importance of an affirmative approach to the health care of transgender individuals, as well as to improve the understanding of the rights of transgender youth. RECENT FINDINGS: Transgender youth have optimal outcomes when affirmed in their gender identity, through support by their families and their environment, as well as appropriate mental health and medical care. SUMMARY: The Pediatric Endocrine Society Special Interest Group on Transgender Health joins other academic societies involved in the care of children and adolescents in supporting policies that promote a safe and accepting environment for gender nonconforming/transgender youth, as well as adequate mental health and medical care. This document provides a summary of relevant definitions, information and current literature on which the medical management and affirmative approach to care of transgender youth are based. PMID- 28562421 TI - Ventricular fibrillation and long-QT syndrome due to panhypopituitarism. PMID- 28562422 TI - Serum calcification propensity is associated with renal tissue oxygenation and resistive index in patients with arterial hypertension or chronic kidney disease. AB - BACKGROUND: Arterial calcifications increase arterial stiffness and are associated with a faster decline of kidney function in patients with arterial hypertension (AH) and/or chronic kidney disease (CKD). Yet the underlying mechanisms linking arterial calcifications, vascular stiffness and renal function decline are incompletely understood. A novel in-vitro blood test evaluates the propensity of patient's serum to prevent the formation of calcifications by measuring the maturation time of calciprotein particles (CPP) [transformation time of amorphous calcium phosphate-containing primary CPP to crystalline hydroxyapatite-containing secondary CPP (T50)]. We hypothesized that a high arterial stiffness and a high propensity to calcify may be associated with high renal vascular resistance and low renal tissue oxygenation. METHODS: T50 was measured in patients with AH and a preserved renal function, in CKD patients and in healthy controls, a lower T50 indicating a higher risk of calcification. Pulse wave velocity (PWV) was assessed as a measure of arterial stiffness, and renal resistive index was measured by renal Doppler ultrasound. Renal tissue oxygenation was measured by blood oxygenation level-dependent MRI using the mean R2 values of the cortex, the medulla and layers of renal parenchyma. A high R2 value corresponds to a low tissue oxygenation. RESULTS: Mean T50 was 246 +/- 129 min in 58 CKD patients, 275 +/- 111 min in 48 AH patients and 324 +/- 96 min in 39 healthy controls (Panova = 0.008). In multivariable adjusted linear regression analysis, serum T50 correlated negatively with circulating calcium and phosphate levels, mean cortical and medullary R2, PWV, renal resistive index and being hypertensive. PWV was positively associated with R2 levels of outer and inner layers of renal parenchyma. CONCLUSION: The current study shows that hypertensive patients with preserved renal function as well as CKD patients have a higher risk of calcification than controls. High arterial stiffness and calcification propensity are linked to low renal tissue oxygenation and perfusion in hypertensive and CKD patients. These results provide new insights on the relationships among arterial stiffness, renal tissue oxygenation and the risk of developing CKD. PMID- 28562424 TI - Biology of Bone Formation, Fracture Healing, and Distraction Osteogenesis. AB - Distraction osteogenesis is a bone-regenerative process in which an osteotomy is followed by distraction of the surrounding vascularized bone segments, with formation of new bone within the distraction gap. Distraction osteogenesis is efficacious for reconstructing critical sized bony defects in the appendicular and craniofacial skeleton. To provide opportunity to expand applications of distraction osteogenesis, it is important to have a thorough understanding of the underlying molecular biology and physiology of bone development and fracture healing. To accomplish these objectives a review of the literature was performed using search terms "endochondral ossification, intramembranous ossification, craniofacial skeleton, appendicular skeleton, fracture healing, bone development, and distraction osteogenesis." Bones of the craniofacial and appendicular skeleton have distinct mechanisms of embryonic development. The former develops from growth centers of mesenchymal precursors through intramembranous ossification. The latter forms though endochondral ossification in growth plates. However, both endochondral and intramembranous bone share similar master regulatory transcription factors and downstream growth factors. Fracture healing mirrors the pathway by which these bones developed embryonically. In contrast, bone formed by distraction osteogenesis does so by intramembranous ossification, regardless of whether it occurs within the appendicular or craniofacial skeleton. Understanding molecular pathway differences between bone formation by these mechanisms may allow for optimization and expansion of skeletal reconstruction by distraction osteogenesis. PMID- 28562423 TI - A Report of Information Technology and Health Deficiencies in U.S. Nursing Homes. AB - OBJECTIVE: The aim of the study was to investigate the impact of nursing home (NH) information technology (IT) sophistication on publically reported health safety deficiency scores documented during standard inspections. METHODS: The sample included 807 NHs from every U.S. state. A total of 2187 health inspections were documented in these facilities. A national IT sophistication survey describing IT capabilities, extent of IT use, and degree of IT integration in resident care, clinical support, and administrative activities in U.S. NHs was used. The relationship between NH health deficiencies and IT sophistication survey scores was examined, using weighted regression. RESULTS: Controlling for registered nurse hours per resident day, deficiency scores decreased as total IT sophistication increased. Controlling for total IT sophistication score, deficiency scores decreased as registered nurse hours per resident day increased. Ownership status significantly influenced health deficiency scores. CONCLUSIONS: These results highlight the necessity to understand benefits of implementing NH IT and demonstrating its impact on patient safety. PMID- 28562425 TI - Rotational and Collic Vestibular-Evoked Myogenic Potential Testing in Normal Developing Children and Children With Combined Attention Deficit/Hyperactivity Disorder. AB - OBJECTIVES: Vestibular dysfunction in childhood can have a major effect on a child's developmental process. Balance function has been reported to be poorer in children with attention deficit and hyperactivity disorder (ADHD) than in their typically developing peers. Due to contradictory available evidence and the paucity of research on vestibular function specifically in children with combined ADHD (cADHD), we designed this aged-matched study to assess vestibular function in children with cADHD. DESIGN: We enrolled 30 typically developing children (15 boys and 15 girls; mean age, 9 years 6 months; range, 7 to 12 years) and 33 children (19 boys and 14 girls; mean age, 9 years 0 months; range, 7 to 12 years) with cADHD diagnosed by our research psychiatrist. Typically developing controls were used to obtain normative data on vestibular testing and to examine the impact of age on the vestibular response parameters, and these results were compared with those of the cADHD group. All children underwent the sinusoidal harmonic acceleration subtype of the rotary chair test (0.01, 0.02, 0.08, 0.16, and 0.32 Hz) and the cervical vestibular-evoked myogenic potential (cVEMP) test. RESULTS: At all five frequencies in the sinusoidal harmonic acceleration test, there was no significant correlation between age and any of the following rotary chair response parameters in typically developing children: vestibulo-ocular reflex (VOR) gain, phase, asymmetry, and fixation index. Furthermore, there was no significant correlation between age and any of the following cVEMP parameters for the right and left ears of control group: p1 and n1 latency, amplitude, threshold, and amplitude ratio. Significantly higher VOR gains were observed for children with cADHD at frequencies of 0.01 (p = 0.001), 0.08 (p < 0.001), 0.16 (p = 0.001), and 0.32 (p = 0.003) Hz, when compared with the control group. Furthermore, fixation abilities were significantly lower in the cADHD group than in the control group at 0.16 (p < 0.001) and 0.32 (p < 0.001) Hz. cVEMP parameters showed no significant differences between the two groups. CONCLUSIONS: Our results showed higher VOR gains and poorer fixation abilities in children with cADHD compared with typically developing children. Cerebellar dysfunction in patients with ADHD has been well documented in the literature, and our findings of cVEMP and rotary chair tests for these children showed impaired vestibular function in these children, based on increased VOR gain values and decreased fixation capabilities. Because VOR gain is mediated through the inferior olive and controlled by the cerebellum, our results suggest that central inhibition of vestibular function may be deficient in children with cADHD, resulting in higher VOR gains. Also, there is general agreement that failure of fixation suppression indicates a central lesion. The lesion can originate from the parietal-occipital cortex, the pons, or the cerebellum. However, failure of fixation suppression is most prominent in lesions involving the midline cerebellum that could be counted for children with cADHD. We believe that this contribution is theoretically and practically relevant as high VOR gains and decreased suppression capabilities may result in symptoms of reading and writing difficulties, learning disabilities, vertigo, and motion sickness in these children. Therefore, assessment of vestibular function in children with cADHD at a young age must be considered when developing rehabilitation protocols for these children. PMID- 28562427 TI - Effects of Saccular Function on Recovery of Subjective Dizziness After Vestibular Rehabilitation. AB - OBJECTIVE: We attempted to investigate whether the integrity of saccular function influences the severity of subjective dizziness after vestibular rehabilitation in vestibular neuritis. STUDY DESIGN: Retrospective analysis. SETTING: Tertiary referral center. PATIENTS: Forty-six patients with acute unilateral vestibular neuritis were included. INTERVENTIONS: Diagnostic, therapeutic, and rehabilitative. MAIN OUTCOME MEASURES: All the patients completed vestibular rehabilitation therapy until their computerized dynamic posturography and rotary chair test results were significantly improved. The rehabilitation patients were classified into the normal to mild subjective dizziness and moderate to severe subjective dizziness groups according to the dizziness handicap inventory score (cutoff of 40). Differences between the two groups were analyzed. RESULTS: After rehabilitation, 32.6% of the patients still complained of moderate to severe dizziness. Age, sex distribution, the presence of comorbidities, caloric weakness, pre- and postrehabilitation gain values in rotary chair test, postrehabilitation composite scores in posturography, and the duration of rehabilitation were not significantly different between the two groups. However, initial dizziness handicap inventory (DHI) score and composite score in dynamic posturography were worse and the proportion of patients with absent cervical vestibular-evoked myogenic potential in the moderate to severe group was much higher (93.3% vs. 35.5%, p < 0.001). After multiple regression analysis of those factors, initial DHI score and absent cervical vestibular-evoked myogenic potential response were identified as being associated with higher postrehabilitation DHI score. CONCLUSION: Saccular dysfunction in acute vestibular neuritis can contribute to persistent subjective dizziness, even after the objective parameters of vestibular function tests have been improved by vestibular rehabilitation. PMID- 28562426 TI - Age-Related Differences in the Processing of Temporal Envelope and Spectral Cues in a Speech Segment. AB - OBJECTIVES: As people age, they experience reduced temporal processing abilities. This results in poorer ability to understand speech, particularly for degraded input signals. Cochlear implants (CIs) convey speech information via the temporal envelopes of a spectrally degraded input signal. Because there is an increasing number of older CI users, there is a need to understand how temporal processing changes with age. Therefore, the goal of this study was to quantify age-related reduction in temporal processing abilities when attempting to discriminate words based on temporal envelope information from spectrally degraded signals. DESIGN: Younger normal-hearing (YNH) and older normal-hearing (ONH) participants were presented a continuum of speech tokens that varied in silence duration between phonemes (0 to 60 ms in 10-ms steps), and were asked to identify whether the stimulus was perceived more as the word "dish" or "ditch." Stimuli were vocoded using tonal carriers. The number of channels (1, 2, 4, 8, 16, and unprocessed) and temporal envelope low-pass filter cutoff frequency (50 and 400 Hz) were systematically varied. RESULTS: For the unprocessed conditions, the YNH participants perceived the word ditch for smaller silence durations than the ONH participants, indicating that aging affects temporal processing abilities. There was no difference in performance between the unprocessed and 16-channel, 400-Hz vocoded stimuli. Decreasing the number of spectral channels caused decreased ability to distinguish dish and ditch. Decreasing the envelope cutoff frequency also caused decreased ability to distinguish dish and ditch. The overall pattern of results revealed that reductions in spectral and temporal information had a relatively larger effect on the ONH participants compared with the YNH participants. CONCLUSIONS: Aging reduces the ability to utilize brief temporal cues in speech segments. Reducing spectral information-as occurs in a channel vocoder and in CI speech processing strategies-forces participants to use temporal envelope information; however, older participants are less capable of utilizing this information. These results suggest that providing as much spectral and temporal speech information as possible would benefit older CI users relatively more than younger CI users. In addition, the present findings help set expectations of clinical outcomes for speech understanding performance by adult CI users as a function of age. PMID- 28562428 TI - Single nucleotide variant in Nucleoporin 107 may be predictive of sensitivity to chemotherapy in patients with ovarian cancer. AB - BACKGROUND: Alterations in nuclear pore complex (NPC) genes have been previously associated with response to chemotherapy. Using agnostic exome sequencing, we envisioned that new alleles in NPC genes, predictive of sensitivity to platinum treatment, could be discovered. METHODS: Twenty-two platinum-sensitive and six platinum-resistant ovarian cancer patients were tested. Platinum sensitivity was defined as disease-free survival greater than 6 months. Next-generation sequencing of exomes was used to compare platinum-sensitive and platinum resistant patients. Single nucleotide variants (SNVs) associated with platinum sensitivity in NPC genes (n=30 genes) were identified. RESULTS: SNVs in three NPC genes were associated with response to platinum on univariate analysis. SNV rs79419059 (10T>C) in Nucleoporin 107 (Nup107) was associated with platinum resistance (P=0.0061), whereas rs2302811 (3662-4A>G) in Nucleoporin 188 (Nup188) and rs77246077 (3420-67T>A) in Nucleoporin 214 (Nup214) were associated with platinum sensitivity (P=0.0483 and 0.0091, respectively). Controlling for other confounders, multivariate age-adjusted Cox proportional hazard analysis showed rs79419059 to be significantly associated with platinum resistance (odds ratio: 4.519, 95% confidence interval: 1.317-15.501, P=0.0457). CONCLUSION: We identified a variant in the 3'-UTR region Nup107 unique to sensitivity to platinum in ovarian cancer. With validation of this variant, it is possible that a new marker predictive of patient response may be identified. PMID- 28562429 TI - Disenfranchised Grief in the PICU: Crying for Attention. AB - THEME: The death of any child is distressing to parents, family, friends, and healthcare staff alike. However, the close family circle is accorded the right to grieve by society, as the nature of the relationship with the child is acknowledged and socially validated. The relationship between the child and the staff caring for the child is not acknowledged to the same extent, and this may cause difficulties for staff who grieve following the death of the child. This experience is repeated many times when working in the PICU. CASE STUDIES: This article describes two cases that illustrate the unrecognized nature of disenfranchised grief for pediatric healthcare staff. DISCUSSION: Addressing the cumulative effects of bereavement on the staff in the PICU through formal and informal systems of support may reduce emotional exhaustion, improve staff retention, and enhance the care of children and families. PMID- 28562430 TI - Transplantation of bone-marrow-derived mesenchymal stem cells into a murine model of immune thrombocytopenia. AB - : Several reports have demonstrated T regulatory cells may play an important role in the pathophysiology of immune thrombocytopenia (ITP). As the immunomodulator, bone-marrow-derived mesenchymal stem cells (MSCs) (BM-MSCs) regulate T regulatory cells and show therapeutic effects on autoimmune diseases. However, it is not clear how BM-MSCs affect ITP. In this study, we explored the specific effects of BM-MSCs on ITP in mice. Using a murine model of ITP, mice were randomly divided into three groups: normal control group, ITP control group and ITP and BM-MSCs group. Platelet (PLT) levels were monitored by an automatic blood cell counter, and T regulatory cells were analyzed by flow cytometry. Compared with the untreated ITP mice, the PLT level of the ITP mice was significantly increased after BM-MSCs treatment. In the BM-MSCs group, T regulatory cells were significantly decreased. These findings demonstrate that bone-marrow-derived MSCs are effective in improving PLT levels and reducing the T regulatory cells mediating proinflammatory response in ITP mice. PMID- 28562431 TI - Lacrimal Apparatus Defect Repair: Use of the Monocanalicular Silicone Stent. PMID- 28562432 TI - A Two-Phase Pilot Study to Evaluate the Safety and Tolerability of an In Situ Polymerizing Collagen. AB - BACKGROUND: Demand for collagen-based fillers has declined primarily because of limited long-term clinical benefit and the introduction of hyaluronic acid compositions. In situ polymerizing collagen is a noncrosslinked solution of porcine collagen containing a collagenase shield that undergoes fibrillogenesis on injected into tissues forming a natural matrix. OBJECTIVE: Conduct a prospective, single-center, dual-phase open-label study in 8 subjects to evaluate the safety, tolerability, and efficacy of the porcine collagen composition. METHODS: In Phase I, potential hypersensitivity of the collagen composition was evaluated after skin testing in the back (men) or forearms of subjects (women). In Phase II, subjects showing no signs of hypersensitivity received collagen injections into the nasolabial area followed by evaluation at 1, 4, 8, and 12 weeks using the Global Aesthetic Improvement Scale. RESULTS: None of the subjects had signs of hypersensitivity and all continued in Phase II. The treating physician(s) reported no post-treatment adverse events. Improvement of the nasolabial fold was observed by the physicians and confirmed by assessment of high-resolution photographs and Global Aesthetic Improvement Scale scores over the 12-week treatment were maintained. CONCLUSION: In this pilot clinical study in situ polymerizing collagen was shown to be safe and effective throughout the 3 month study period. PMID- 28562433 TI - Platelet-Rich Plasma in Combination With 5% Minoxidil Topical Solution and 1 mg Oral Finasteride for the Treatment of Androgenetic Alopecia: A Randomized Placebo Controlled, Double-Blind, Half-Head Study. PMID- 28562434 TI - Treatment of Actinic Keratoses: A Randomized Split-Site Approach Comparison of Sequential 5-Fluorouracil and 5-Aminolevulinic Acid Photodynamic Therapy to 5 Aminolevulinic Acid Photodynamic Monotherapy. AB - BACKGROUND: Actinic keratoses (AKs) are skin lesions resulting from sun exposure and carry a risk of developing into squamous cell carcinoma. Current therapies for AK eradication include topical 5-fluorouracil (5-FU) and photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA). However, sequential therapy with 5-FU-ALA-PDT may offer improved outcome compared to ALA-PDT alone. OBJECTIVE: The purpose of this study is to compare the long-term efficacy of AK clearance by sequential therapy with 5-FU-ALA-PDT versus ALA-PDT alone. MATERIALS AND METHODS: This is a single center, randomized split-site approach study on equivalent anatomical and clinical sites. Seventeen patients were enrolled with one half of the site randomized to receive sequential 5-FU-ALA-PDT and the other side with ALA-PDT monotherapy. Total AKs were counted at baseline, 6 and 12 months. RESULTS: Median percentage reduction in AK number at 6 months for 5-FU-ALA-PDT versus ALA-PDT was 100% for 5-FU-ALA-PDT (N = 21) and 66.7% for ALA-PDT (N = 21), p = .001. Median percentage reduction in AK number at 12 months for 5-FU-ALA-PDT versus ALA-PDT was 100% for 5-FU-ALA-PDT (N = 22) and 82.6% for ALA-PDT (N = 22), p = .0002. CONCLUSION: Sequential therapy with 5-FU-ALA-PDT is more effective at AK clearance at 6 and 12 months compared to ALA-PDT monotherapy. PMID- 28562435 TI - Calcium Hydroxylapatite Dermal Filler for Treatment of Dorsal Hand Volume Loss: Results From a 12-Month, Multicenter, Randomized, Blinded Trial. AB - BACKGROUND: Calcium hydroxylapatite (CaHA) microspheres suspended in a carrier gel is an opaque dermal filler that has been used to provide immediate volume correction in the dorsal hands. OBJECTIVE: To assess the safety and effectiveness of CaHA for the correction of volume loss in the hands up to 12 months. MATERIALS AND METHODS: This multicenter, controlled, single-blind study (NCT01832090) included 114 subjects randomized 3:1 to CaHA treatment and untreated control groups. Effectiveness was assessed by blinded investigators using the validated Merz Hand Grading Scale (MHGS). Subject-reported improvement was assessed using the Global Aesthetic Improvement Scale. Effects of treatment on hand function were also assessed. RESULTS: A total of 75% of subjects achieved >=1-point improvement on the MHGS (p < .0001) at 3 months (primary end point); this response was generally maintained through 12 months. Proportions of subjects reporting improvement ranged from 98% (3 months) to 86% (12 months). There were no clinically significant differences between control and CaHA-treated subjects in any hand function measure. Adverse events were generally expected, minor, short-lived, injection-related, and similar to those observed in previous CaHA clinical studies. CONCLUSION: Treatment with CaHA results in significant improvement in the appearance of the dorsal hand and is well tolerated. PMID- 28562436 TI - Double-Blind, Placebo-Controlled Pilot Study on the Use of Platelet-Rich Plasma in Women With Female Androgenetic Alopecia. PMID- 28562437 TI - Use of Skin Biopsies Among Dermatologists. AB - BACKGROUND: Skin biopsies are essential to establish a diagnosis in many skin diseases. Utilization has been increasing rapidly and represents a significant health care cost. There are no benchmarks or baselines to guide the practice of skin biopsies. OBJECTIVE: To create a reference data set of biopsy behavior among dermatologists. METHODS: Five hundred eighty-eight dermatologists belonging to the American Dermatological Association (ADA) were surveyed. Two hundred eighty seven responded with 128 of those providing biopsy data. RESULTS: The mean percentage of biopsies that were malignant was 44.5%. This varied by subspecialty with a mean of 41.7%, 57.4%, and 4.1% of biopsies performed by general dermatologists, Mohs micrographic surgeons, and pediatric dermatologists, respectively. By category or diagnosis, the biopsies were 22.7% basal cell carcinoma, 12.0% SCC, 10.2% benign neoplasms, 10.0% nevi, 8.0% actinic keratosis, 7.6% seborrheic keratosis, 7.5% inflammatory disorders, 6.1% SCC in situ, 5.3% dysplastic nevus, 5.1% benign skin, 1.5% melanoma in situ, 1.4% melanoma, 0.9% lentigines, 0.8% other malignancies, 0.6% infectious, 0.2% not otherwise specified, and 0.1% atypical lesions. There was a statistically significant difference in biopsy results between different dermatological subspecialties. CONCLUSION: These results should help elucidate dermatologic practice patterns and thus create opportunities to improve dermatologic care and reduce health care costs. PMID- 28562439 TI - Impact of Smoke Evacuation on Patient Experience During Mohs Surgery. AB - BACKGROUND: There have been several investigations into possible health risks of surgical smoke exposure, and it has previously been associated with harboring pathogens and carcinogens. Patients in the authors' practice have expressed that the odor from the smoke created by electrosurgical equipment is unpleasant. OBJECTIVE: The authors sought to determine if smoke evacuation decreases patient perception of smoke created by electrosurgery during Mohs surgery and if it subsequently improves patient satisfaction with their surgical experience by minimizing the associated odor. MATERIALS AND METHODS: Thirty patients were enrolled in this comparative trial. Smoke evacuation was used during closure but not during Mohs stages. Patients were queried regarding their experience and preferences during and at the end of the procedure. RESULTS: 100% of patients reported the perception of a burning odor during removal of Mohs stages, compared with 40% reporting the perception of a burning odor during closure. During the Mohs stages, 66.6% of patients reported the odor as unpleasant compared with 16.6% of patients during closure. There were no statistically significant differences in patient perceptions when stratified by age, sex, or surgical site. CONCLUSION: The authors believe that using a wall suction smoke evacuation system is simple and can result in a more pleasant experience for patients undergoing Mohs surgery. PMID- 28562438 TI - Retrospective Evaluation of Topical Bimatoprost and Iris Pigmentation Change. AB - BACKGROUND: Topical bimatoprost is a topical prostaglandin analog originally used to treat glaucoma and more recently used to cosmetically induce hypertrichosis of the eyelashes. Iris pigmentation change has been noted in the treatment of glaucoma but has not been assessed with the cosmetic periorbital application of bimatoprost. OBJECTIVE: To evaluate for iris pigmentation change with the long term cosmetic use of topical bimatoprost. MATERIALS AND METHODS: A retrospective chart review in a cosmetic dermatology practice of women (N = 50) who consistently purchased topical bimatoprost over an average of 4.59 years was compared with that of age-matched non-bimatoprost patients (N = 50). A blinded evaluator assessed each patient for iris pigmentary change. RESULTS: No iris pigmentation change was noted with the cutaneous application of bimatoprost. CONCLUSION: The cutaneous application of bimatoprost appears to be safe with minimal risk for iris pigmentation change. PMID- 28562440 TI - Vitamin D in human reproduction. AB - PURPOSE OF REVIEW: Vitamin D deficiency has been associated with a wide range of human disease states and the global epidemic, particularly in reproductive aged women, has led to a focus on this complex hormones role in human reproduction. Indeed vitamin D receptors are found throughout the reproductive tract in the ovary, endometrium, and the placenta. It has roles both in calcium-dependent and independent pathways. However, agreement upon the most appropriate way to assess vitamin D status and ultimately its activity at various sites has proven challenging. RECENT FINDINGS: Investigators have studied vitamin D's role in assisted reproduction and found successful outcomes are correlated with vitamin D replete status. However, subsequent studies have found mixed results when parsing its role in folliculogenesis and oogenesis versus its impact on embryonic implantation in the endometrium. Correlation was shown in a donor oocyte model which suggests endometrial involvement; however, in a euploid blastocyst transfer model with attention to embryo and endometrial synchrony this was not seen. It may be that the major impact is proximal to blastocyst formation at the site of folliculogenesis as has been shown in a primate model. Taken together, these studies suggest that vitamin D's role may be more sophisticated when it comes to reproductive success. Further, it has become clear that the nonstandard method of determining vitamin D status in the clinical and research settings requires clarification to ensure more comparable data in future studies. SUMMARY: Vitamin D has clear roles in human health and disease, and its impact on human reproduction seems promising but requires clarification. With new techniques for assessing its status in patients and its impact at end organs as well as evolving theories regarding its potential to influence folliculogenesis, endometrial receptivity, and ovarian aging, we will soon gain additional clarity and hope to be able to impact reproductive success in a positive way. PMID- 28562441 TI - Simulation Research in Gastrointestinal and Urologic Care-Challenges and Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Biomedical Imaging and Bioengineering Workshop. AB - A workshop on ''Simulation Research in Gastrointestinal and Urologic Care: Challenges and Opportunities'' was held at the National Institutes of Health in June 2016. The purpose of the workshop was to examine the extent to which simulation approaches have been used by skilled proceduralists (not trainees) caring for patients with gastrointestinal and urologic diseases. The current status of research findings in the use and effectiveness of simulation applications was reviewed, and numerous knowledge gaps and research needs were identified by the faculty and the attendees. The paradigm of ''deliberate practice,'' rather than mere repetition, and the value of coaching by experts was stressed by those who have adopted simulation in music and sports. Models that are most useful for the adoption of simulation by expert clinicians have yet to be fully validated. Initial studies on the impact of simulation on safety and error reduction have demonstrated its value in the training domain, but the role of simulation as a strategy for increased procedural safety remains uncertain in the world of the expert practitioner. Although the basic requirements for experienced physicians to acquire new skills have been explored, the widespread availability of such resources is an unrealized goal, and there is a need for well-designed outcome studies to establish the role of simulation in improving the quality of health care. PMID- 28562442 TI - Pulse wave reflection in children: amplification through the lifecourse. PMID- 28562443 TI - Birth cohort or measurement protocol differences? PMID- 28562444 TI - Poor blood pressure control: what can we do? PMID- 28562445 TI - Reply: physics cannot be disputed. PMID- 28562446 TI - Renal resistive index for resistant hypertension. PMID- 28562447 TI - Reply. PMID- 28562448 TI - The rising incidence of nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the United States and will soon be the leading indication for liver transplantation. NAFLD can lead to cirrhosis of the liver and is usually asymptomatic. Prompt referral to a hepatologist may halt the morbidity and mortality associated with NAFLD. PMID- 28562449 TI - Genetic counseling for hereditary cancer: A primer for NPs. AB - Many patients have concerns regarding their family's cancer history and may be appropriate for referral to genetic counseling. This article examines indications for referral for genetic counseling for hereditary cancer, the process of genetic counseling and testing, and ways for NPs to collaborate with genetics providers. PMID- 28562450 TI - Considerations for Residency Programs Regarding Accepting Undocumented Students Who Are DACA Recipients. AB - The Deferred Action for Childhood Arrivals (DACA) initiative provides for the temporary deferral of enforcement of immigration laws for certain undocumented individuals brought to the United States before age 16. More than 50 medical schools now consider applicants who are DACA recipients, and medical school graduates with DACA are eligible to continue their training in graduate medical education. In this article, the authors summarize current policy and provide data on DACA recipients in medical school. They then review the implications for considering DACA recipients in graduate medical education, including employment guidelines, employer responsibilities, training at Veterans Affairs facilities, research funding, and professional licensure. They conclude by discussing the future of the DACA program and best practices for supporting students who are DACA recipients.First, there are no employment restrictions for DACA recipients with valid work authorization documents as long as their employers use Form I-9 Employment Eligibility Verification. Second, unlike H-1B or J-1 visa holders, DACA recipients do not generate additional immigration-related costs for their residency programs. Next, provisions in the Civil Rights Act prohibit employers from discriminating against applicants based on national origin or, in some cases, citizenship status. Furthermore, trainees with DACA are eligible to rotate through Veterans Affairs facilities. Finally, some states, like California and New York, have adopted policies and regulations allowing trainees with DACA who meet all professional requirements to receive a medical license. Given this state of affairs, DACA recipients should have equal standing to their peers when being evaluated for residency positions. PMID- 28562452 TI - Mixed Messages or Miscommunication? Investigating the Relationship Between Assessors' Workplace-Based Assessment Scores and Written Comments. AB - PURPOSE: The shift toward broader, programmatic assessment has revolutionized the approaches that many take in assessing medical competence. To understand the association between quantitative and qualitative evaluations, the authors explored the relationships that exist among assessors' checklist scores, task ratings, global ratings, and written comments. METHOD: The authors collected and analyzed, using regression analyses, data from the McMaster Modular Assessment Program. The data were from emergency medicine residents in their first or second year of postgraduate training from 2012 through 2014. Additionally, using content analysis, the authors analyzed narrative comments corresponding to the "done" and "done, but needs attention" checklist score options. RESULTS: The regression analyses revealed that the task ratings, provided by faculty assessors, are associated with the use of the "done, but needs attention" checklist score option. Analyses also identified that the "done, but needs attention" option is associated with a narrative comment that is balanced, providing both strengths and areas for improvement. Analysis of qualitative comments revealed differences in the type of comments provided to higher- and lower-performing residents. CONCLUSIONS: This study highlights some of the relationships that exist among checklist scores, rating scales, and written comments. The findings highlight that task ratings are associated with checklist options while global ratings are not. Furthermore, analysis of written comments supports the notion of a "hidden code" used to communicate assessors' evaluation of medical competence, especially when communicating areas for improvement or concern. This study has implications for how individuals should interpret information obtained from qualitative assessments. PMID- 28562451 TI - Values Guide Us in Times of Uncertainty: DACA and Graduate Medical Education. AB - With a new administration and Congress, there is uncertainty surrounding the future of the Deferred Action for Childhood Arrivals (DACA) program. In light of this uncertainty, medical schools have tried to better understand how they can support trainees with DACA. In their article in this issue, Nakae and colleagues describe the issues often encountered by medical students with DACA as they prepare for residency and by the program directors who receive their applications. They offer recommendations for best practices to support these trainees. The authors of this Invited Commentary expand on these important considerations, based on their experiences at a national level. They argue that the core values in academic medicine should drive decision making, the student voice is critical, teamwork is essential, and wellness deserves attention. Academic medicine is part of a larger movement with partners across the health professions and higher education focused on advancing the values of access and opportunity for all. The authors of this Invited Commentary argue that remaining steadfast and committed to the core values in medicine will allow the academic medicine community to successfully navigate these uncertain times. PMID- 28562453 TI - Continuing Professional Development for Faculty: An Elephant in the House of Academic Medicine or the Key to Future Success? AB - The scope of change required by academic medical centers (AMCs) to maintain their viability and achieve their tripartite mission in the future is large; such reform is affected by numerous global, national, and local forces. Most AMCs focus their transformational efforts on organizational infrastructure (e.g., undertaking payment reform, developing new organizational structures, investing in information technology) and educational programs (with subsequent changes in undergraduate and graduate medical education curricula). Although useful, these efforts have failed to produce the kind of change required for AMCs to succeed in the future.The authors of this Invited Commentary describe a key element missing from most of these reform efforts-the preparation of faculty for new models of health care and educational practice. To address this issue, they call for the effective, system-aligned presence of continuing professional development (CPD) programs. CPD combines continuing medical education, with its focus on content knowledge, and faculty development, with its focus on evidence-based learning methodologies, across the institution to produce a more robust, system- and outcomes-oriented program to facilitate both individual and organizational learning. If sufficiently supported, CPD programs can provide a platform for the human changes necessary to ensure the smooth transition of AMCs to new models of education, clinical research, and ultimately patient care. PMID- 28562454 TI - Exploring the Relationships Between USMLE Performance and Disciplinary Action in Practice: A Validity Study of Score Inferences From a Licensure Examination. AB - PURPOSE: Physicians must pass the United States Medical Licensing Examination (USMLE) to obtain an unrestricted license to practice allopathic medicine in the United States. Little is known, however, about how well USMLE performance relates to physician behavior in practice, particularly conduct inconsistent with safe, effective patient care. The authors examined the extent to which USMLE scores relate to the odds of receiving a disciplinary action from a U.S. state medical board. METHOD: Controlling for multiple factors, the authors used non-nested multilevel logistic regression analyses to estimate the relationships between scores and receiving an action. The sample included 164,725 physicians who graduated from U.S. MD-granting medical schools between 1994 and 2006. RESULTS: Physicians had a mean Step 1 score of 214 (standard deviation [SD] = 21) and a mean Step 2 Clinical Knowledge (CK) score of 213 (SD = 23). Of the physicians, 2,205 (1.3%) received at least one action. Physicians with higher Step 2 CK scores had lower odds of receiving an action. A 1-SD increase in Step 2 CK scores corresponded to a decrease in the chance of disciplinary action by roughly 25% (odds ratio = 0.75; 95% CI = 0.70-0.80). After accounting for Step 2 CK scores, Step 1 scores were unrelated to the odds of receiving an action. CONCLUSIONS: USMLE Step 2 CK scores provide useful information about the odds a physician will receive an official sanction for problematic practice behavior. These results provide validity evidence supporting current interpretation and use of Step 2 CK scores. PMID- 28562455 TI - SimZones: An Organizational Innovation for Simulation Programs and Centers. AB - The complexity and volume of simulation-based learning programs have increased dramatically over the last decade, presenting several major challenges for those who lead and manage simulation programs and centers. The authors present five major issues affecting the organization of simulation programs: (1) supporting both single- and double-loop learning experiences; (2) managing the training of simulation teaching faculty; (3) optimizing the participant mix, including individuals, professional groups, teams, and other role-players, to ensure learning; (4) balancing in situ, node-based, and center-based simulation delivery; and (5) organizing simulation research and measuring value. They then introduce the SimZones innovation, a system of organization for simulation-based learning, and explain how it can alleviate the problems associated with these five issues.Simulations are divided into four zones (Zones 0-3). Zone 0 simulations include autofeedback exercises typically practiced by solitary learners, often using virtual simulation technology. Zone 1 simulations include hands-on instruction of foundational clinical skills. Zone 2 simulations include acute situational instruction, such as clinical mock codes. Zone 3 simulations involve authentic, native teams of participants and facilitate team and system development.The authors also discuss the translation of debriefing methods from Zone 3 simulations to real patient care settings (Zone 4), and they illustrate how the SimZones approach can enable the development of longitudinal learning systems in both teaching and nonteaching hospitals. The SimZones approach was initially developed in the context of the Boston Children's Hospital Simulator Program, which the authors use to illustrate this innovation in action. PMID- 28562456 TI - The Problem and Goals Are Global, the Solutions Are Local: Revisiting Quality Measurements and the Role of the Private Sector in Global Health Professions Education. AB - The shortage of a competent health workforce is a global challenge. However, its manifestations and proposed solutions are very much context related (i.e., local). In addition to the shortage of health professionals, the quality of health professions education programs, institutions, and graduates, and how to measure quality, are also problematic. Commonly used metrics like the Credit Hours System and the European Credit Transfer and Accumulation System have limitations (e.g., being more focused on quantity than quality).In this Invited Commentary, the author discusses the need to revisit quality measurements in health professions education and the issue of whether the private sector has a role to play in narrowing the ever-increasing gap between the demand for health care professionals and the health care workforce shortage. PMID- 28562457 TI - The Educational Climate Inventory: Measuring Students' Perceptions of the Preclerkship and Clerkship Settings. AB - PURPOSE: To develop an instrument to assess educational climate, a critical aspect of the medical school learning environment that previous tools have not explored in depth. METHOD: Fifty items were written, capturing aspects of Dweck's performance-learning distinction, to distinguish students' perceptions of the educational climate as learning/mastery oriented (where the goal is growth and development) versus performance oriented (where the goal is appearance of competence). These items were included in a 2014 survey of first-, second-, and third-year students at six diverse medical schools. Students rated their preclerkship or clerkship experiences and provided demographic and other data. The final Educational Climate Inventory (ECI) was determined via exploratory and confirmatory factor analysis. Relationships between scale scores and other variables were calculated. RESULTS: Responses were received from 1,441/2,590 students (56%). The 20-item ECI resulted, with three factors: centrality of learning and mutual respect; competitiveness and stress; and passive learning and memorization. Clerkship students' ratings of their learning climate were more performance oriented than preclerkship students' ratings (P < .001). Among preclerkship students, ECI scores were more performance oriented in schools with grading versus pass-fail systems (P < .04). Students who viewed their climate as more performance oriented were less satisfied with their medical school (P < .001) and choice of medicine as a career (P < .001). CONCLUSIONS: The ECI allows educators to assess students' perceptions of the learning climate. It has potential as an evaluation instrument to determine the efficacy of attempts to move health professions education toward learning and mastery. PMID- 28562458 TI - Improved Learning Outcomes After Flipping a Therapeutics Module: Results of a Controlled Trial. AB - PURPOSE: To evaluate the impact on learning outcomes of flipping a pain management module in a doctor of pharmacy curriculum. METHOD: In a required first professional-year pharmacology and therapeutics course at the University of Maryland School of Pharmacy, the pain therapeutics content of the pain management module was flipped. This redesign transformed the module from a largely lecture based, instructor-centered model to a learner-centered model that included a variety of preclass activities and in-class active learning exercises. In spring 2015, the module was taught using the traditional model; in spring 2016, it was taught using the flipped model. The same end-of-module objective structured clinical exam (OSCE) and multiple-choice exam were administered in 2015 to the traditional cohort (TC; n = 156) and in 2016 to the flipped cohort (FC; n = 162). Cohort performance was compared. RESULTS: Learning outcomes improved significantly in the FC: The mean OSCE score improved by 12.33/100 points (P < .0001; 95% CI 10.28-14.38; effect size 1.33), and performance on the multiple choice exam's therapeutics content improved by 5.07 percentage points (P < .0001; 95% CI 2.56-7.59; effect size 0.45). Student performance on exam items assessing higher cognitive levels significantly improved under the flipped model. Grade distribution on both exams shifted, with significantly more FC students earning an A or B and significantly fewer earning a D or F compared with TC students. CONCLUSIONS: Student performance on knowledge- and skill-based assessments improved significantly after flipping the therapeutics content of a pain management module. PMID- 28562459 TI - Desipramine rescues emotional memory deficit induced by low doses of reserpine. AB - Emotional memory deficit is a well-known complication in early Parkinson's disease. However, its molecular mechanism is still not well known. To address this issue, we examined the cue-related fear-conditioning task and long-term potentiation (LTP) of the thalamus to the lateral amygdala in rats treated with low doses of reserpine (Res). We found that low-dose Res treatment impaired emotional memory and LTP. We also found that exogenous upregulation of norepinephrine (NE) ameliorated the impairment of LTP by facilitating beta adrenergic receptors. Finally, acute treatment with NE or desipramine rescued the impaired emotional memory induced by a low-dose of Res. These results imply a pivotal role for NE in synaptic plasticity and associative fear memory in rats treated with low doses of Res and suggest that desipramine is a potential candidate for treating Parkinson's disease-related emotional memory deficit. PMID- 28562460 TI - Team Communication Influence on Procedure Performance: Findings From Interprofessional Simulations with Nursing and Medical Students. AB - Interprofessional team performance is believed to be dependent on the development of effective team communication skills. Yet, little evidence exists in undergraduate nursing programs on whether team communication skills affect team performance. A secondary analysis of a larger study on interprofessional student teams in simulations was conducted to determine if there is a relationship between team communication and team procedure performance. The results showed a positive, significant correlation between interprofessional team communication ratings and procedure accuracy in the simulation. Interprofessional team training in communication skills for nursing and medical students improves the procedure accuracy in a simulated setting. PMID- 28562461 TI - Student Perceptions of Stressors and the Value of Coaching in a Baccalaureate Nursing Articulation Program. AB - Regionally Increasing Baccalaureate Nurses (RIBN) is a unique articulation program in North Carolina. The fourth year of RIBN is challenging; students are enrolled as full-time university students while starting part-time employment as new graduate nurses. The aim of this descriptive pilot study was to explore the anticipated and actual stressors related to the fourth year experience and evaluate the impact of monthly coaching sessions. Key stressors identified were academic workload, professional awareness/role transition/workforce adjustment, time management, and obligations to support individuals. The monthly coaching sessions were beneficial in providing a means of debriefing and reframing life events. PMID- 28562462 TI - The Challenge of Patient Notification and the Work of Follow-Up Generated by a 2 Step Testing Protocol for Group A Streptococcal Pharyngitis in the Pediatric Emergency Department. AB - OBJECTIVE: Current guidelines recommend confirmatory testing for negative rapid antigen detection tests (RADTs) for group A streptococcal pharyngitis in children. We sought to describe the work of follow-up generated by this process and frequency of our inability to notify patients of positive results. METHODS: We retrospectively reviewed laboratory and outreach nurse records of patients who had group A streptococcal pharyngitis testing performed in an academic pediatric emergency department during 2014. For patients with a negative RADT and subsequent positive backup direct nucleic acid probe test, we recorded whether the patient was successfully notified of the positive result, the number of contact attempts, and the time to antibiotic prescription. RESULTS: There were 6504 patients who had an RADT performed, of which 5474 (84.2%) were negative with a confirmatory test performed. There were 234 patients with positive confirmatory testing and not prescribed antibiotics at the time of the initial visit. Of these, 90.1% were ultimately contacted and prescribed appropriate antibiotics, whereas 7.3% were lost to follow-up and 2.6% had potentially unnecessary repeat visits. Of those contacted, 43.1% were reached only after multiple telephone calls or a letter. The median time from the negative RADT to the submission of an electronic prescription was 19.6 hours (interquartile range, 7.5-24.9 hours; range, 6-144 hours). CONCLUSIONS: Although confirmatory testing after a negative RADT in children is currently the standard of care, this practice requires a substantial amount of work. Furthermore, a significant fraction of patients are lost to follow-up or have unnecessary repeat visits. PMID- 28562463 TI - An Ethical Justification for Termination of Resuscitation Protocols for Pediatric Patients. AB - OBJECTIVE: The aim of this article was to compare specific characteristics and outcomes among adult and pediatric out-of-hospital cardiac arrest (OHCA) patients to show that the existing literature warrants the design and implementation of pediatric studies that would specifically evaluate termination of resuscitation protocols. We also address the emotional and practical concerns associated with ceasing resuscitation efforts on scene when treating pediatric patients. METHODS: Relevant prospective and retrospective studies were used to compare characteristics and outcomes between adult and pediatric OHCA patients. Characteristics analyzed were nonwitnessed arrests, absence of shockable rhythm, no return of spontaneous circulation, and survival to hospital discharge. RESULTS: Cases of unwitnessed arrests by emergency medical services providers are substantially the same in pediatric patients (41.0%-96.3%) compared with their adult counterparts (47.4%-97.7%). The adult studies revealed 57.6% to 92.2% of patients without an initial shockable rhythm. The pediatric studies showed a range of 64.0% to 98.0%. The range of adult patients without return of spontaneous circulation was 54.8% to 95.4%, and the range in pediatric patients was 68.2% to 95.6%. Survival rates among the adult studies ranged from 0.8% to 9.3% (mean, 5.0%; median, 5.2%), and in the pediatric studies they were 2.0% to 26.2% (mean, 9.2%; median, 7.7%). CONCLUSIONS: The data compared demonstrate that characteristics and outcomes are virtually identical between adult and pediatric OHCA patients. We also found the 3 chief barriers hindering further research to be invalid impediments to moving forward. This review warrants designing pediatric studies that would specifically correlate termination of resuscitation protocols with patient survival and include predictive values. PMID- 28562464 TI - Arrhythmic Side of Ondansetron Alongside Antiemetic Effect. PMID- 28562465 TI - Occult Head Injury in Children Less Than 2 Years With Suspected Child Abuse in the Emergency Department. AB - OBJECTIVE: This study aims to determine the frequency of clinically significant findings requiring emergent neurosurgical intervention on computed tomography (CT) in neurologically intact children admitted to the hospital with suspected abuse. METHODS: This was a retrospective review of neurologically stable children (0-24 months) in whom both skeletal survey and CT head were performed for child abuse evaluation from 2000 to 2011. RESULTS: A total of 132 patients met inclusion criteria (mean age, 7.6 mo; 55% male, 52% Caucasian, and 34% African American). Computed tomography scans demonstrated occult head injury in 5%; none required neurosurgical intervention or had any neurological deterioration. Average length of stay was 4 days, with average time to CT scan being 12.8 hours from triage, and average time to magnetic resonance imaging (MRI) scan of 70.5 hours. Five MRIs were performed, and 4 had identical results on CT scan. CONCLUSIONS: No clinically significant brain injury (requiring intervention) was seen in this cohort. These findings support delaying imaging in neurologically intact children to obtain MRI after hospital admission, thus, limiting radiation exposure. PMID- 28562466 TI - Evidence-Based Medicine Curriculum Improves Pediatric Emergency Fellows' Scores on In-Training Examinations. AB - OBJECTIVES: The aim of this study was to determine if implementation of our evidence-based medicine (EBM) curriculum had an effect on pediatric emergency medicine fellows' scores on the relevant section of the in-training examination (ITE). METHODS: We obtained deidentified subscores for 22 fellows over 6 academic years for the Core Knowledge in Scholarly Activities (SA) and, as a balance measure, Emergencies Treated Medically sections. We divided the subscores into the following 3 instruction periods: "baseline" for academic years before our current EBM curriculum, "transition" for academic years with use of a research method curriculum with some overlapping EBM content, and "EBM" for academic years with our current EBM curriculum. We analyzed data using the Kruskal-Wallis test, the Mann-Whitney U test, and multivariate mixed-effects linear models. RESULTS: The SA subscore median was higher during the EBM period in comparison with the baseline and transition periods. In contrast, the Emergencies Treated Medically subscore median was similar across instruction periods. Multivariate modeling demonstrated that our EBM curriculum had the following independent effects on the fellows' SA subscore: (1) in comparison with the transition period, the fellows' SA subscore was 21 percentage points higher (P = 0.005); and (2) in comparison to the baseline period, the fellows' SA subscore was 28 percentage points higher during the EBM curriculum instruction period (P < 0.001). CONCLUSIONS: Our EBM curriculum was associated with significantly higher scores on the SA section of the ITE. Pediatric emergency medicine educators could consider using fellows' scores on this section of the ITE to assess the effect of their EBM curricula. PMID- 28562467 TI - Assistive Techniques for Proximal Anastomosis in Minimally Invasive Coronary Artery Bypass Grafting. AB - We introduce assistive techniques for proximal anastomosis in off-pump minimally invasive coronary artery bypass grafting (MICS CABG) to overcome difficult access to the ascending aorta in MICS CABG. An 8-cm left thoracotomy is made in the fifth intercostal space. ThoraTrak retractor (Medtronic Inc, Minneapolis, MN USA) is used to open the thoracotomy and is pulled to the cephalad and rightward direction toward to the ascending aorta. The pericardium is opened from the ascending aorta to the left ventricular apex and to the inferior vena cava. Two retraction sutures on the pericardial edge are used to laterally displace the heart. After dissecting between the ascending aorta and main pulmonary artery, the Octopus tissue stabilizer (Medtronic Inc, Minneapolis, MN USA), of which the suction tip is bent 60 degrees, is used to retract the pulmonary artery caudally. A flexible side-biting clamp (Vitalitec Inc.) is placed on the ascending aorta, and proximal anastomoses are handsewn on the ascending aorta. A total of 31 proximal anastomoses were completed with this technique between November 2013 and June 2015. All proximal anastomosis was completed without any difficulty. In MICS CABG, the technical challenges in proximal anastomosis due to difficult access to the aorta can be overcome safely by using this technique. PMID- 28562469 TI - Gynecological Cancer as a Second Malignancy in Patients With Breast Cancer. AB - PURPOSE: The aim of this study was to determine the incidence and risk factors for gynecological cancer as second malignancy (SM) after treatment of breast cancer (BC). METHODS AND MATERIALS: Between January 1985 and December 2007, a total of 2756 patients with BC were analyzed for gynecological cancers as an SM. Analysis was carried out for patient-, disease-, and treatment-related characteristics. The Cox proportional hazards regression model was used to estimate the relative risk of gynecologic malignancies. RESULTS: The median age at BC diagnosis was 49 years and median follow-up of 14 years. In total, 25 cases of gynecological cancer were noted with an incidence of 0.9%. We observed 9 ovarian and endometrium (0.3%) as well as 7 uterine cervix (0.25%) cancers. Family history of BC was the most significant risk factor for SM (relative risk, 7.4; 95% confidence interval, 3.03-18.28; P<0.001). Women with a family history of BC had a higher incidence of endometrial (12%) and ovarian (16%) cancer compared with those who have no family history (0.1%, P = 0.003). Statistically significant higher incidence of endometrial cancer was seen in patients undergoing hormonal therapy (0.4%) as compared with those who are not undergoing hormonal therapy (0.1%, P = 0.001). Most of the endometrial (88.9%) and cervical (71%) cancers were detected at an early stage but ovarian cancers (66.6%) in advanced stage. Chemotherapy and radiotherapy did not increase the risk of gynecological SM. CONCLUSIONS: Women with BC are at risk of developing a second primary gynecological malignancy particularly of endometrium and ovary. Family history of BC was a high risk factor for gynecologic SM. These patients should be followed up for its early detection. PMID- 28562470 TI - A Comparison of Dye Versus Fluorescence Methods for Sentinel Lymph Node Mapping in Endometrial Cancer. AB - OBJECTIVE: Sentinel nodes (SNs) have been observed in several reports from Japan and overseas in cases with endometrial cancer; however, no consensus has been reached regarding the types of tracers or the method of their injection. A combination of the radioisotope (RI) and dye method is considered to be desirable. We assessed SN mapping using either dye or near-infrared fluorescence imaging to clarify a suitable method in cases of endometrial cancer. METHODS: Patients were enrolled from 92 patients diagnosed with endometrial cancer and having no extrauterine metastasis by the preoperative imaging between 2009 and 2014 at our institution. To identify the SNs, we performed 3 methods using either dye or fluorescence solutions in conjunction with a RI method. In the dye method, we injected indocyanine green in the uterine subserosa, visually identifying SNs as stained green. In the fluorescence method, a dilute indocyanine green solution (0.5 mg, fluorescence A or 0.25 mg, fluorescence B, each per 10 mL of solvent) was injected and the SN identified by the HyperEye Medical System. RESULTS: The SN detection rates were 100%, 100%, and 96% using dye and fluorescence A or B solution, respectively. Pelvic SNs were detected by the 3 methods in 98%, 100%, and 96% of cases and para-aortic SNs in 65%, 88%, and 74%, respectively. Fluorescence A solution was somewhat better than dye in detecting para-aortic SNs, although not significantly so (P = 0.07). The sensitivity and negative predictive values for detecting SNs with metastases with the dye method were 92% and 98% compared with 100% and 100%, respectively, for both fluorescence solutions. CONCLUSIONS: Although both dye and fluorescence methods performed well, no method perfectly identified para-aortic SNs. The concomitant use of the RI method is required to detect para-aortic SNs. PMID- 28562471 TI - Trends in Survival of Patients With Uterine Serous Carcinoma From 1988 to 2011: A Population-Based Study. AB - OBJECTIVE: Our study used the Surveillance, Epidemiology, and End Result database to determine if the changes in treatment paradigm observed over the last 2 decades have improved outcomes in patients with uterine serous carcinoma (USC). METHODS: Women with USC were identified using the Surveillance, Epidemiology, and End Result database from 1988 to 2011 (n = 8230) and grouped into 3 cohorts (1988 1997, 1998-2004, and 2005-2011). Disease-specific survival and overall survival were estimated. Kaplan-Meier survival curves and Cox regression models were used. RESULTS: Disease-specific survival (59 vs 94 months vs not reached; P < 0.001) and overall survival (31 vs 37 vs 45 months; P < 0.001) improved over time. In univariable analyses, only those with stage I-III and those who reside in the Western or Central regions were noted to have improvement over time. In multivariable analyses when adjusting for age, race, marital status, stage, geographic location, cancer-related surgery, extent of lymphadenectomy, and adjuvant radiation, patients who received the diagnosis during 2005 to 2011 were 22% less likely to die of uterine cancer (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.70-0.87; P < 0.001) and 17% less likely to die of any cause (HR, 0.83; 95% CI, 0.76-0.90; P < 0.0001) compared with patients who received a diagnosis during 1988-1997. Similarly, patients who received a diagnosis during 1998-2004 were 15% less likely to die of uterine cancer (HR, 0.85; 95% CI, 0.77 0.94; P = 0.0015) and 10% less likely to die of any cause (HR, 0.90; 95% CI, 0.83 0.97; P = 0.0048) compared with patients who received a diagnosis during 1988 1997. CONCLUSIONS: Changes in treatment trends for USC over the last 2 decades have resulted in an improvement in outcome especially those with stage I-III disease. PMID- 28562472 TI - Gonadotropin-Releasing Hormone Agonist Combined With a Levonorgestrel-Releasing Intrauterine System or Letrozole for Fertility-Preserving Treatment of Endometrial Carcinoma and Complex Atypical Hyperplasia in Young Women. AB - OBJECTIVES: The aim of this study was to evaluate the efficacy and safety with gonadotropin-releasing hormone agonist (GnRHa) combined with a levonorgestrel releasing intrauterine system or an aromatase inhibitor (letrozole) in young women with well-differentiated early endometrial carcinoma (EC) and complex atypical hyperplasia (CAH). METHODS: We performed a retrospective analysis including the clinical characteristics of 29 patients younger than 45 years with early well-differentiated endometrioid adenocarcinoma of the uterus (EC) or CAH who were treated at the Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, from January 2012 to April 2016. Eighteen patients were treated with the combination of intramuscular injections of GnRHa every 4 weeks with the levonorgestrel intrauterine hormonal system (Mirena(r) Bayer Health Care Pharmaceutical Inc, Wayne, NY) was inserted. Eleven patients were treated with the combination of intramuscular injections of GnRHa every 4 weeks with oral letrozole 2.5 mg daily. The patients underwent follow-up with endometrial sampling by hysteroscopy and curettage for endometrial response every 3 months. RESULTS: After a median follow-up of 18.7 months (range, 5.6-54.9 months), 15 women (88.2%) in the EC group and 12 women (100%) in the CAH group had complete response (CR) after GnRHa combination treatment. Among the women who achieved CR, 1 woman (8.3%) with CAH and 1 woman (5.9%) with EC had recurrence after CR, and they finally underwent a hysterectomy. Time to CR was similar in the 2 groups (4.5 +/- 1.9 months in the CAH group vs 5.0 +/- 2.9 months in the EC group). Ten women (34.5%) had CR after the first 3 months, 8 women (27.6%) had CR after 6 months, and 9 women (31.0%) had CR after 9 months. CONCLUSIONS: Both GnRHa with the levonorgestrel-releasing intrauterine system and GnRHa with letrozole are alternative treatments for women with CAH and EC who desire fertility preservation. A larger multicenter trial of the fertility-preserving treatment is warranted. PMID- 28562473 TI - Trends in Utilization and Cost of Cervical Spine Surgery Using the National Inpatient Sample Database, 2001 to 2013. AB - STUDY DESIGN: A retrospective review. OBJECTIVE: The aim of this study was to determine national rates of cervical spine surgery and to examine factors that underlie cost variation. SUMMARY OF BACKGROUND DATA: There has been an increase in the rate and cost of spinal surgery over the past decades, but there is little understanding of the drivers of cost variation at the national level. METHODS: We analyzed 419,830 patients who underwent cervical spine surgery (anterior cervical fusion, posterior cervical fusion, posterior cervical decompression, combined anterior/posterior cervical fusion) for degenerative conditions in the 2001 to 2013 NIS database. We determined the rates of surgery by time and geographic region, and then created univariate and multivariate models to evaluate the effect of these factors on total hospital costs: patient age, gender, race, insurance, income, county of residence, elective versus nonelective case, length of stay, risk of mortality, severity of illness, hospital bed size, wage index, hospital type, and geographic region. RESULTS: The most common type of cervical spine surgery was anterior fusion (80.6% of all surgeries). The national rates of all cervical spine surgery decreased slightly from 2001 to 2013 (75.34 to 72.20 per 100,000 adults), while the mean inflation-adjusted cost increased 64%, from $11,799 to $19,379, during this time period. Multivariate analyses showed that older age, male gender, black/other race, private insurance, greater risk of mortality/severity of illness, and longer length of stay were associated with higher costs. The wage index was positively correlated with cost, and hospitals in the western U.S. were 27% more expensive than those in the Northeast. CONCLUSION: The rate of cervical spine surgery decreased slightly, while the mean case cost increased at a rate double that of inflation from 2001 to 2013. Even after controlling for patient and hospital factors including wage index, there was significant geographic variation in the cost for cervical spine surgery. LEVEL OF EVIDENCE: 3. PMID- 28562474 TI - Responsiveness of the functioning and disability parts of the International Classification of Functioning, Disability, and Health core sets in postacute stroke patients. AB - To study the responsiveness of the International Classification of Functioning, Disability, and Health (ICF) core set with respect to human functioning and disability in stroke patients. Postacute stroke patients who were admitted to the convalescent rehabilitation wards were included in this observational cohort study. The comprehensive ICF core set for neurological conditions for postacute care and the ICF rehabilitation set were evaluated at admission and discharge using five-grade qualifiers. Extension indexes were calculated for entire two ICF core sets. Responsiveness was measured as change in the extension indexes in the ICF core sets. The correlation between changes in ICF core sets and improvement in the Functional Independence Measure (FIM) was analyzed using Spearman's correlation coefficient. The study included 108 poststroke patients (49 women, mean age 70.8 years, mean FIM score improvement: 23.0). The mean percentage of categories that showed changes with at least one qualifier level was 19.5% in the comprehensive ICF core set for neurological conditions for postacute care and 35.9% in the ICF rehabilitation set. Effect sizes in each ICF core set were moderate to large (0.79-0.80). Improvement in the two ICF core sets correlated significantly with changes in the FIM score. Our results indicate that functioning and disability parts of these two ICF core sets can detect changes in functioning and disability in patients who receive an inpatient rehabilitation program for postacute stroke. PMID- 28562475 TI - Duration of Untreated Cardiac Arrest and Clinical Relevance of Animal Experiments: The Relationship Between the "No-Flow" Duration and the Severity of Post-Cardiac Arrest Syndrome in a Porcine Model. AB - INTRODUCTION: The study investigated the effect of untreated cardiac arrest (CA), that is, "no-flow" time, on postresuscitation myocardial and neurological injury, and survival in a pig model to identify an optimal duration that adequately reflects the most frequent clinical scenario. METHODS: An established model of myocardial infarction followed by CA and cardiopulmonary resuscitation was used. Twenty-two pigs were subjected to three no-flow durations: short (8-10 min), intermediate (12-13 min), and long (14-15 min). Left ventricular ejection fraction (LVEF) was assessed together with thermodilution cardiac output (CO) and high sensitivity cardiac troponin T (hs-cTnT). Neurological impairment was evaluated by neurological scores, serum neuron specific enolase (NSE), and histopathology. RESULTS: More than 60% of animals survived when the duration of CA was <=13 min, compared to only 20% for a duration >=14 min. Neuronal degeneration and neurological scores showed a trend toward a worse recovery for longer no-flow durations. No animals achieved a good neurological recovery for a no-flow >=14 min, in comparison to a 56% for a duration <=13 min (P = 0.043). Serum NSE levels significantly correlated with the no-flow duration (r = 0.892). Longer durations of CA were characterized by lower LVEF and CO compared to shorter durations (P < 0.05). The longer was the no-flow time, the higher was the number of defibrillations delivered (P = 0.043). The defibrillations delivered significantly correlated with LVEF and plasma hs-cTnT. CONCLUSIONS: Longer no flow durations caused greater postresuscitation myocardial and neurological dysfunction and reduced survival. An untreated CA of 12-13 min may be an optimal choice for a clinically relevant model. PMID- 28562476 TI - FN14 Blockade on Pulmonary Microvascular Endothelial Cells Improves the Outcome of Sepsis-Induced Acute Lung Injury. AB - Pulmonary microvascular leakage is one of the characteristics of blood-air barrier dysfunction in septic acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Fibroblast growth factor-inducible 14 (Fn14) exerts diverse functions under certain circumstances. However, the role of Fn14 on the integrity of pulmonary microvascular endothelial cells (PMVECs) during sepsis remains unknown. Septic ALI was induced via cecal ligation and puncture (CLP). Fn14 expression on PMVECs was measured 24 h after surgery. The effects of Fn14 blockade on septic ALI were investigated in vivo and in vitro. Compared with the Sham group, Fn14 expressed in septic PMVECs was increased significantly 24 h after surgery. The protein level in bronchoalveolar lavage fluid, the lung wet to dry ratio, and neutrophil/macrophage infiltration in lungs were reduced in septic mice after Fn14 blockade. Similarly, ICAM-1 and MCP-1 levels were attenuated after Fn14 blockade or knockdown in lungs or human pulmonary microvascular endothelial cells (HPMECs). Furthermore, Fn14 silencing reduced Caspase-3 levels and upregulated the transendothelial electrical resistance level in TNF-like weak inducer of apoptosis-treated HPMECs. In addition, the degree of lung fibrosis was ameliorated and the survival of CLP mice was improved significantly after Fn14 blockade. In conclusion, Fn14 on PMVECs plays an important role in the progress of septic ALI. Fn14 blockade may prove to be an innovative lung-protective strategy for the treatment of septic ALI. PMID- 28562477 TI - Sepsis-Induced Channelopathy in Skeletal Muscles is Associated with Expression of Non-Selective Channels. AB - Skeletal muscles (~50% of the body weight) are affected during acute and late sepsis and represent one sepsis associate organ dysfunction. Cell membrane changes have been proposed to result from a channelopathy of yet unknown cause associated with mitochondrial dysfunction and muscle atrophy. We hypothesize that the channelopathy might be explained at least in part by the expression of non selective channels. Here, this possibility was studied in a characterized mice model of late sepsis with evident skeletal muscle atrophy induced by cecal ligation and puncture (CLP). At day seven after CLP, skeletal myofibers were found to present de novo expression (immunofluorescence) of connexins 39, 43, and 45 and P2X7 receptor whereas pannexin1 did not show significant changes. These changes were associated with increased sarcolemma permeability (~4 fold higher dye uptake assay), ~25% elevated in intracellular free-Ca concentration (FURA-2), activation of protein degradation via ubiquitin proteasome pathway (Murf and Atrogin 1 reactivity), moderate reduction in oxygen consumption not explained by changes in levels of relevant respiratory proteins, ~3 fold decreased mitochondrial membrane potential (MitoTracker Red CMXRos) and ~4 fold increased mitochondrial superoxide production (MitoSox). Since connexin hemichannels and P2X7 receptors are permeable to ions and small molecules, it is likely that they are main protagonists in the channelopathy by reducing the electrochemical gradient across the cell membrane resulting in detrimental metabolic changes and muscular atrophy. PMID- 28562478 TI - Neuroprotection with the P53-Inhibitor Pifithrin-MU after Cardiac Arrest in a Rodent Model. AB - BACKGROUND: The small molecule pifithrin-MU reversibility inhibits the mitochondrial pathway of apoptosis. The neuronal effects of pifithrin-MU applied after cardiac arrest are unknown. We hypothesized that pifithrin-MU reduces neuronal damage in the most vulnerable brain region, the hippocampus, after cardiac arrest. METHODS: In two randomized controlled series we administered pifithrin-MU or control in 109 rats resuscitated after 8 or 10 min of cardiac arrest. Neuronal damage was blindly assessed with histology (Fluoro Jade B: FJB, cresyl violet: CV) in the most vulnerable brain region (CA1 segment of hippocampus) and with a series of neurobehavioral tests (Open Field Task, Tape Removal Test, Morris Water Maze test). Mixed ANOVA was used to combine both series, simple comparisons were done with t tests or Mann-Whitney U test. RESULTS: Pifithrin-MU reduced the number of degenerating, FJB-positive neurons by 25% (mixed ANOVA p group = 0.014). This was more prominent after 8 min cardiac arrest (8 min arrest pifithrin-MU 94 +/- 47 vs control 128 +/- 37; n = 11 each; 10 min arrest pifithrin-MU 78 +/- 44, n = 15 vs control 101 +/- 31, n = 18; p group* arrest length interaction = 0.622). The reduction of ischemic CV-positive neurons in pifithrin-MU animals was not significant (ANOVA p group = 0.063). No significant group differences were found in neurobehavioral testing. CONCLUSION: Temporarily inhibition of apoptosis with pifithrin-MU after cardiac arrest decreases the number of injured neurons in the CA1 segment of hippocampus in a cardiac arrest rat model, without clinical correlate. Further studies should elucidate the role of this neuroprotective agent in different settings and with longer cardiac arrest. PMID- 28562479 TI - Sepsis Upregulates CD14 Expression in a MyD88-Dependent and Trif-Independent Pathway. AB - An overwhelming immune response, particularly from macrophages, plays a critical role in survival and organ damage in sepsis patients. Toll-like receptors (TLRs) are important receptors to recognize the conserved motifs expressed by invading bacteria. The TLRs except TLR3 signal via a MyD88-dependent pathway. TLR3 uses a TRIF-dependent pathway, while TLR4 uses both MyD88 and TRIF-dependent pathways. Previous studies indicated that CD14 was necessary for TLRs-dependent production of pro-inflammatory cytokines. Blocking CD14 protected against the deleterious systemic inflammatory response associated with sepsis. The aim of this study was to determine the signaling pathway of TLR activation-induced CD14 expression in models of polymicrobial sepsis and in peritoneal macrophages. We found that CD14 expression was upregulated in the lung, liver, and kidney of septic mice induced by cecal ligation puncture. In cultured peritoneal macrophages, specific agonists for all TLRs, except for TLR3, increased CD14 expression. Lipopolysaccharide induced upregulation of CD14 was abolished in peritoneal macrophages from MyD88 KO mice but increased in TRIF inhibitor, resveratrol pretreated wild-type macrophages. Moreover, MyD88 KO, but not TRIF KO mice, showed a decreased CD14 expression in the tissue of septic mice, which was associated with a strongly attenuated inflammatory response and increased survival rate. These data suggest that a MyD88-dependent and TRIF-independent pathway of TLR is activated in upregulating CD14 expression under septic conditions. This study deciphers a critical cross-talk between TLRs and CD14. PMID- 28562480 TI - Indinavir Plus Methylprednisolone Ameliorates Experimental Acute Lung Injury In Vitro and In Vivo. AB - BACKGROUND: An abnormal HMGB1 activation plays a key role in the pathogenesis of ALI. METHODS: In this study, the effects of Indinavir plus methylprednisolone on the LPS-mediated activation in human pulmonary microvascular endothelial cells (HPMECs), on the injury of AT I in vitro, and on rats with LPS-induced two-hit model with or without methylprednisolone were investigated. RESULTS: Indinavir treatment resulted in a reduction of HMGB1, its receptor TLR-4, and HMGB1's downstream p-NF-kappaB, attenuating a decrease of VE-cadherin in LPS-stimulated HPMECs. Apoptosis of AT I was attenuated with an increase of RAGE and aquaporin 5. Compared to methylprednisolone alone, methylprednisolone plus Indinavir attenuated the decrease of GRalpha and IkappaB-alpha in cytoplasm and avoid GRalpha deficiency in LPS-stimulated HPMECs for 96 h, attenuated the increase of p-NF-kappaB in nucleus. Indinavir ameliorated histopathological changes of two hit ALI model of rats with reductions in microvascular permeability, lower HMGB1, TLR4, p-NF-kappaB, and MPO expression, whereas higher RAGE, aquaporin 5, and VE cadherin in LPS-instilled lungs. Compared to methylprednisolone alone, methylprednisolone plus Indinavir attenuated the decrease of GRalpha and IkappaB alpha in cytoplasm, decreased p-NF-kappaB in nucleus of lung tissue of two-hit ALI rats, and enhanced the anti-inflammatory effect of methylprednisolone for avoiding GRalpha deficiency. CONCLUSION: It demonstrated that Indinavir prevented experimental ALI model of rats by modulating the HMGB1/TLR-4 pathway to resolve systemic inflammation response in a greater degree with methylprednisolone, reduced the use time and dose of methylprednisolone, and avoided GRalpha deficiency in ALI and ARDS. PMID- 28562481 TI - Extracorporeal Life Support Increases Survival After Prolonged Ventricular Fibrillation Cardiac Arrest in the Rat. AB - BACKGROUND: Extracorporeal life support (ECLS) for cardiopulmonary resuscitation (CPR) may increase end organ perfusion and thus survival when conventional CPR fails. The aim was to investigate, if after ventricular fibrillation cardiac arrest in rodents ECLS improves outcome compared with conventional CPR. METHODS: In 24 adult male Sprague-Dawley rats (460-510 g) resuscitation was started after 10 min of no-flow with ECLS (consisting of an open reservoir, roller pump, and membrane oxygenator, connected to cannulas in the jugular vein and femoral artery, n = 8) or CPR (mechanical chest compressions plus ventilations, n = 8) and compared with a sham group (n = 8). After return of spontaneous circulation (ROSC), all rats were maintained at 33 degrees C for 12 h. Survival to 14 days, neurologic deficit scores and overall performance categories were assessed. RESULTS: ECLS leads to sustained ROSC in 8 of 8 (100%) and neurological intact survival to 14 days in 7 of 8 rats (88%), compared with 5 of 8 (63%) and 1 of 8 CPR rats. The median survival time was 14 days (IQR: 14-14) in the ECLS and 1 day (IQR: 0 to 5) for the CPR group (P = 0.004). CONCLUSION: In a rat model of prolonged ventricular fibrillation cardiac arrest, ECLS with mild hypothermia produces 100% resuscitability and 88% long-term survival, significantly better than conventional CPR. PMID- 28562484 TI - Sex differences in the association between gray matter volume and verbal creativity. AB - The explanation for why significant sex differences are found in creativity has become an increasingly important topic. The current study applied a cognitive neuroscience perspective and voxel-based morphometry to investigate the sex differences for the association between verbal creativity and gray matter volume (GMV) in a large sample of healthy adults from the Chinese Mainland (163 men and 193 women). Furthermore, we sought to determine which brain regions are responsible for these differences. Our behavioral results showed a significant sex difference. Specifically, women scored higher than men on originality. The voxel-based morphometry results indicated that the relationship between originality and GMV differed between men and women in the left temporo-occipital junction. Higher originality scores in women were associated with more GMV. In contrast, higher originality scores in men were related to less GMV. These findings suggest the left temporo-occipital junction GMV plays a unique role in the sex differences in verbal creativity because women usually surpass men in semantic processing, which is the major function of the left temporal region. PMID- 28562483 TI - Investigation of the expression of apoptosis-inducing factor-mediated apoptosis in Hirschsprung's disease. AB - One of the widely accepted hypotheses of Hirschsprung's disease (HD) is that the absence of ganglion cells in the distal part of the intestine is caused by the death of enteric neural crest-derived cells following migration. Although a caspase-dependent pathway has not yet been detected in the HD bowel, it is unclear whether a caspase-independent pathway contributes toward aganglionosis. In the current study, we observed highly condensed marginal heterochromatin in nuclei only in the transitional segment using electron microscopy and a high proportion of TUNEL-positive cells were observed in the transitional segment. Activation of caspase was not observed in any segments of the HD bowel upon characterization of the apoptotic pathway. Rather, real-time PCR results showed that apoptosis-inducing factor (AIF) and calpain-1 mRNAs were highly expressed in the transitional segment, whereas autophagy protein 5 (Atg5) was highly expressed in the narrow segment. Western blot results were consistent with mRNA levels, with increased AIF, calpain-1, and Atg5 expressions in the transitional segment compared with the dilated segment. Furthermore, correlation analysis indicated an inverse correlation between calpain-1 and Atg5 mRNA levels in both the narrow segment and the transitional segment. These results indicated that apoptosis occurs in the HD bowel. The detection of related genes indicates that the AIF mediated apoptotic pathway may be responsible for the absence of ganglion cells in HD and calpain-1 may act as the regulatory switch between autophagy and apoptosis. PMID- 28562485 TI - Antihyperalgesic effect by herpes vector-mediated knockdown of NaV1.7 sodium channels after skin incision. AB - Postincisional hyperalgesia and allodynia play an important role in perioperative medicine. NaV1.7 sodium channel has proven to be a key player in several pain states, including acute, inflammatory, and neuropathic pain. This study investigated the effects of silencing NaV1.7 through Herpes-based gene therapy with an antisense transcript on pain states after incision of the skin in rodents. Seventy-six Balb/C mice were subdivided into six groups and were treated with no virus, control virus, or NaV1.7 antisense vector before lateral hindpaw skin incision or sham procedure. All mice were tested for mechanical allodynia, cold allodynia, and thermal hyperalgesia. For time series analysis, a two-way analysis of variance with post-hoc Bonferroni testing was used. After incision mice developed significant hypersensitivity to mechanical, cold, and heat stimuli. The NaV1.7 antisense vector blocked the hypersensitivity to mechanical, cold, and heat stimuli that was normally observed 24 and 48 h after incision. We demonstrated that a gene therapy-based NaV1.7 knockdown affects postincisional hyperalgesia and allodynia. The data provide evidence that the incision model leads to periwound hypersensitivity after incision and that application of the NaV1.7 antisense virus prevents this sensitization. This then, in turn, provides presumptive support to the hypothesis that overexpression of the NaV1.7 channel is an important mechanism underlying hyperalgesia and allodynia following skin incision. PMID- 28562486 TI - Diagnostics and laboratory role in outbreaks. AB - PURPOSE OF REVIEW: The review describes the investigative benefits of traditional and novel molecular epidemiology techniques, while acknowledging the limitations faced by clinical laboratories seeking to implement these methods. RECENT FINDINGS: Pulse-field gel electrophoresis and other traditional techniques remain powerful tools in outbreak investigations and continue to be used by multiple groups. Newer techniques such as matrix-assisted laser desorption/ionization-time of flight mass-spectrometry and whole genome sequencing show great promise. However, there is a lack of standardization regarding definitions for genetic relatedness, nor are there established criteria for accuracy and reproducibility. There are also challenges regarding availability of trained bioinformatics staff, and concerns regarding reimbursement. SUMMARY: There are many tools available for molecular epidemiologic investigation. Epidemiologists and clinical laboratorians should work together to determine which testing methods are best for each institution. PMID- 28562487 TI - The extracellular matrix in IBD: a dynamic mediator of inflammation. AB - PURPOSE OF REVIEW: The extracellular matrix (ECM) is a frequently overlooked component of the pathogenesis of inflammatory bowel disease (IBD). However, the functional and clinically significant interactions between immune as well as nonimmune cells with the ECM have important implications for disease pathogenesis. In this review, we discuss how the ECM participates in process associated with IBD that involves diverse cell types of the intestine. RECENT FINDINGS: Remodeling of the ECM is a consistent feature of IBD, and studies have implicated key ECM molecules in IBD pathogenesis. While the majority of prior studies have focused on ECM degradation by proteases, more recent studies have uncovered additional degrading enzymes, identified fragments of ECM components as potential biomarkers, and revealed that ECM synthesis is increased in IBD. These new studies support the notion that the ECM, rather than acting as a passive element, is an active participant in promoting inflammation. SUMMARY: New studies have offered exciting clues about the function of the ECM during IBD pathogenesis. The balance of ECM synthesis and turnover is altered in IBD, and the molecules involved exhibit discreet biological functions that regulate inflammation on the basis of specific cell type and matrix molecule. PMID- 28562488 TI - Does obesity increase the risk of hot flashes among midlife women?: a population based study. AB - OBJECTIVE: To evaluate the association between vasomotor symptoms and obesity in climacteric women. METHODS: We conducted a cross-sectional population-based study of 749 women aged 45 to 60 years. The dependent variable was intensity of menopausal symptoms evaluated by the menopause rating scale questionnaire. Independent variables were sociodemographic and clinical characteristics, and obesity evaluated by body mass index. RESULTS: There was no significant difference in the majority of clinical and sociodemographic characteristics between the body mass index groups. Obese women had less physical activity (P = 0.019) and a higher prevalence of hypertension (P < 0.001), diabetes (P = 0.002), urinary incontinence (P < 0.001), and urge incontinence (P = 0.0006). The total mean menopause rating scale score was 9.7. Scores for hot flashes increased progressively and were higher for participants with body mass index greater than 30 kg/m (P = 0.027). Joint and muscle pain scores also increased with increased body mass index (P < 0.001). Regarding urogenital symptoms, there was a significant difference in urinary problems only, which were more intense in obese women (body mass index >30 kg/m) (P < 0.0001). There was no significant difference in any psychological symptoms on the menopause rating scale. Factors associated with hot flash scores were higher body mass index, presence of urinary urgency, and vaginal dryness. CONCLUSIONS: We found that menopausal symptoms, including vasomotor, joint, and urinary symptoms, were related to obesity. Hot flashes were associated with higher body mass index, urinary urgency, and vaginal dryness. Understanding this relationship may contribute to the development of healthcare strategies aimed at minimizing the impact of obesity on several health issues of climacteric women. PMID- 28562489 TI - A theory of eu-estrogenemia: a unifying concept. AB - OBJECTIVE: The aim of the study was to propose a unifying theory for the role of estrogen in postmenopausal women through examples in basic science, randomized controlled trials, observational studies, and clinical practice. METHODS: Review and evaluation of the literature relating to estrogen. DISCUSSION: The role of hormone therapy and ubiquitous estrogen receptors after reproductive senescence gains insight from basic science models. Observational studies and individualized patient care in clinical practice may show outcomes that are not reproduced in randomized clinical trials. The understanding gained from the timing hypothesis for atherosclerosis, the critical window theory in neurosciences, randomized controlled trials, and numerous genomic and nongenomic actions of estrogen discovered in basic science provides new explanations to clinical challenges that practitioners face. Consequences of a hypo-estrogenemic duration in women's lives are poorly understood. The Study of Women Across the Nation suggests its magnitude is greater than was previously acknowledged. We propose that the healthy user bias was the result of surgical treatment (hysterectomy with oophorectomy) for many gynecological maladies followed by pharmacological and physiological doses of estrogen to optimize patient quality of life. The past decade of research has begun to demonstrate the role of estrogen in homeostasis. CONCLUSIONS: The theory of eu-estrogenemia provides a robust framework to unify the timing hypothesis, critical window theory, randomized controlled trials, the basic science of estrogen receptors, and clinical observations of patients over the past five decades. PMID- 28562491 TI - New findings of oxidative stress biomarkers in nutritional research. AB - PURPOSE OF REVIEW: The aim of this article is to present a brief overview of recently published articles assessing oxidative stress markers in nutritional studies. RECENT FINDINGS: Intervention and observational studies were carried out in both, healthy subjects and patients and describe the association of foodstuffs as well as isolated nutrients with biomarkers of oxidative stress. The results from human intervention studies on healthy participants and patients are controversial. Long-term interventions (>8 weeks) seem to be more effective than short-term or single-dose interventions. Results are difficult to compare because not only the methods used, also the assessed biomarkers and outcomes were very diverse. In addition, studies vary in the compounds and doses used, duration, participants and so on. Different biomarkers (damaged molecules together with antioxidants from different compartments) should be assessed to evaluate the true 'redox-status' of an individual and the impact of a nutritional intervention. SUMMARY: Both observational and interventional studies performed in healthy participants and patients show possible beneficial effects of nutrients and foodstuffs by improving oxidative stress markers and antioxidant enzyme activities. Biomarkers should be standardized to allow better comparison of results of antioxidant intervention studies. PMID- 28562490 TI - Assessing nutritional status in cancer: role of the Patient-Generated Subjective Global Assessment. AB - PURPOSE OF REVIEW: The Scored Patient-Generated Subjective Global Assessment (PG SGA) is used internationally as the reference method for proactive risk assessment (screening), assessment, monitoring and triaging for interventions in patients with cancer. This review aims to explain the rationale behind and data supporting the PG-SGA, and to provide an overview of recent developments in the utilization of the PG-SGA and the PG-SGA Short Form. RECENT FINDINGS: The PG-SGA was designed in the context of a paradigm known as 'anabolic competence'. Uniquely, the PG-SGA evaluates the patient's status as a dynamic rather than static process. The PG-SGA has received new attention, particularly as a screening instrument for nutritional risk or deficit, identifying treatable impediments and guiding patients and professionals in triaging for interdisciplinary interventions. The international use of the PG-SGA indicates a critical need for high-quality and linguistically validated translations of the PG-SGA. SUMMARY: As a 4-in-1 instrument, the PG-SGA can streamline clinic work flow and improve the quality of interaction between the clinician and the patient. The availability of multiple high-quality language versions of the PG SGA enables the inclusion of the PG-SGA in international multicenter studies, facilitating meta-analysis and benchmarking across countries. PMID- 28562493 TI - In This Issue: Contributions to CEHP Research and Practice. PMID- 28562492 TI - Congenital pseudarthrosis of the tibia in children: should we defer surgery until 3 years old? AB - Currently, the timing of surgery for congenital pseudarthrosis of the tibia (CPT) remains controversial. The aim of this study was to investigate the results of treatment of pseudarthrosis of the tibia in children younger than 3 years of age. A retrospective study was carried out to explore the relationship between postoperative complications and the age of surgery in children with CPT. The analysis was carried out on 42 patients with Crawford type IV CPT treated with a combined surgical technique between 2008 and 2012. Patients were divided into two groups according to their age: group A (<3 years) and group B (>3 years). The incidence rates of refracture, ankle valgus, tibial valgus, and limb-length discrepancy of the two groups were evaluated. Primary bone union was achieved in 28 out of 29 (97%) patients in group A and 12 out of 13 (92%) patients in group B (P>0.05). In group A, six (21%) patients developed a refracture; 14 (48%) patients had ankle valgus with a mean degree of 11 degrees (range: 5 degrees -25 degrees ); 11 (38%) patients had tibial valgus with a mean tibial valgus deformity of 8.6 degrees (range: 5 degrees -20 degrees ); and 12 (41%) patients had limb-length discrepancy with a mean limb length of 2.9 cm (range: 0.5-4 cm). In group B, five (38%) patients developed refracture; seven (54%) patients had ankle valgus with a mean degree of 14 degrees (range: 5 degrees -30 degrees ); seven (54%) patients had tibial valgus with a mean tibial valgus deformity of 10.7 degrees (range: 5 degrees -20 degrees ); and 10 (77%) patients had limb length discrepancy with a mean limb length of 2.8 cm (range: 1.5-3 cm). Groups A and B were significantly different in limb-length discrepancy (P=0.033). This study suggests that there is no need to defer surgery for pseudarthrosis of the tibia until the child is older than 3 years of age. PMID- 28562494 TI - Factors Affecting the Development and Sustainability of Communities of Practice Among Primary Care Physicians in Hong Kong. AB - INTRODUCTION: Primary care physicians (PCPs) maintain high standards of medical care by partaking in continuous learning. The learning model of communities of practice (COPs) is increasingly being used in the field of health care. This study explores the establishment and maintenance of COPs among PCPs in Hong Kong. METHODS: Sequential, semi-structured individual interview and focus group interview were conducted to explore the purposes for partaking in continuous learning, as well as barriers and facilitators for attendance among private nonspecialist PCPs in Hong Kong. Data were drawn from the discourses related to COPs. Thematic analysis with constant comparison was performed until data saturation was reached. RESULTS: PCPs voluntarily established COPs to solve clinical problems from the existing networks. Clinical interest, practice orientation, and recruitment of new members through endorsement by the existing members fostered group coherence. Conversation and interaction among members generated the "best" practice with knowledge that was applicable in specific clinical scenarios in primary care setting. COPs rejected commercial sponsorship to minimize corporate influences on learning. Updating medical knowledge, solving clinical problems, maintaining openness, engendering a sense of trust and ownership among members, and fulfilling psychosocial needs were integral to sustainability. Seeking secretariat support to aid in the logistics of meetings, enhancing external learning resources, and facilitation skills training of facilitators from professional bodies may further incentivize members to maintain COPs. DISCUSSION: Autonomy of group learning activities, recruiting specialists and allied health professionals, training facilitators, and undertaking discussion in multimedia may achieve the sustainability of COPs. PMID- 28562495 TI - Development of a Self-Rated Mixed Methods Skills Assessment: The National Institutes of Health Mixed Methods Research Training Program for the Health Sciences. AB - INTRODUCTION: Demand for training in mixed methods is high, with little research on faculty development or assessment in mixed methods. We describe the development of a self-rated mixed methods skills assessment and provide validity evidence. The instrument taps six research domains: "Research question," "Design/approach," "Sampling," "Data collection," "Analysis," and "Dissemination." Respondents are asked to rate their ability to define or explain concepts of mixed methods under each domain, their ability to apply the concepts to problems, and the extent to which they need to improve. METHODS: We administered the questionnaire to 145 faculty and students using an internet survey. We analyzed descriptive statistics and performance characteristics of the questionnaire using the Cronbach alpha to assess reliability and an analysis of variance that compared a mixed methods experience index with assessment scores to assess criterion relatedness. RESULTS: Internal consistency reliability was high for the total set of items (0.95) and adequate (>=0.71) for all but one subscale. Consistent with establishing criterion validity, respondents who had more professional experiences with mixed methods (eg, published a mixed methods article) rated themselves as more skilled, which was statistically significant across the research domains. DISCUSSION: This self-rated mixed methods assessment instrument may be a useful tool to assess skills in mixed methods for training programs. It can be applied widely at the graduate and faculty level. For the learner, assessment may lead to enhanced motivation to learn and training focused on self-identified needs. For faculty, the assessment may improve curriculum and course content planning. PMID- 28562496 TI - Can Source Triangulation Be Used to Overcome Limitations of Self-Assessments? Assessing Educational Needs and Professional Competence of Pharmacists Practicing in Qatar. AB - INTRODUCTION: Continuing professional development activities should be designed to meet the identified personal goals of the learner. This article aims to explore the self-perceived competency levels and the professional educational needs of pharmacists in Qatar and to compare these with observations of pharmacy students undergoing experiential training in pharmacies (students) and pharmacy academics, directors, and managers (managers). METHODS: Three questionnaires were developed and administered to practicing pharmacists, undergraduate pharmacy students who have performed structured experiential training rotations in multiple pharmacy outlets in Qatar and pharmacy managers. The questionnaires used items extracted from the National Association of Pharmacy Regulatory Authorities (NAPRA) Professional competencies for Canadian pharmacists at entry to practice and measured self- and observed pharmacists' competency and satisfaction with competency level. RESULTS: Training and educational needs were similar between the pharmacists and observers, although there was trend for pharmacists to choose more fact-intensive topics compared with observers whose preferences were toward practice areas. There was no association between the competency level of pharmacists as perceived by observers and as self-assessed by pharmacists (P <= .05). Pharmacists' self-assessed competency level was consistently higher than that reported by students (P <= .05). DISCUSSION: The results suggest that the use of traditional triangulation might not be sufficient to articulate the professional needs and competencies of practicing pharmacists as part of a strategy to build continuing professional development programs. Pharmacists might have a limited ability to accurately self-assess, and observer assessments might be significantly different from self-assessments which present a dilemma on which assessment to consider closer to reality. The processes currently used to evaluate competence may need to be enhanced through the use of well-designed rubrics or other strategies to empower and to better inform respondents and subsequently improve their ability to self-assess their competencies. PMID- 28562497 TI - Incorporating Lifelong Learning From Residency to Practice: A Qualitative Study Exploring Psychiatry Learners' Needs and Motivations. AB - INTRODUCTION: There has been an increased focus on lifelong learning (LLL) as a core competency to develop master learners in medical education across the learner continuum. The purpose of this study was to explore the perceptions of psychiatry residents and faculty about LLL implementation, motivation, and training needs. METHODS: This qualitative study was conducted in a large, urban, multisite psychiatry training program as part of a larger mixed methods study of LLL in psychiatry education. Using a purposive sampling approach, psychiatry residents were recruited to participate in focus groups; early career psychiatrists and psychiatry educators were recruited to participate in semistructured interviews. Content analysis of interviews and focus groups was done using the iterative, inductive method of constant comparative analysis. RESULTS: Of the 34 individuals participating in the study, 23 were residents, six were psychiatry educators, and five were early career psychiatrists. Three predominant themes were identified in participants' transcripts related to (1) the need for LLL training in residency training; (2) the implementation of LLL in residency training and practice; and (3) the spectrum of motivation for LLL from residency training into practice. DISCUSSION: This study identified the lack of preparation for LLL in residency training and the impact of this gap for psychiatrists transitioning into practice. All participants described the importance of integrating LLL training within clinical rotations and the importance of grounding LLL within the clinical workplace early in residency training to support the delivery of effective, high-quality patient care. PMID- 28562499 TI - Building Sustainable Professional Development Programs: Applying Strategies From Implementation Science to Translate Evidence Into Practice. AB - INTRODUCTION: Multisite and national professional development (PD) programs for educators are challenging to establish. Use of implementation science (IS) frameworks designed to convert evidence-based intervention methods into effective health care practice may help PD developers translate proven educational methods and models into successful, well-run programs. Implementation of the national Educational Scholars Program (ESP) is used to illustrate the value of the IS model. METHODS: Four adaptable elements of IS are described: (1) replication of an evidence-based model, (2) systematic stages of implementation, (3) management of implementation using three implementation drivers, and (4) demonstration of program success through measures of fidelity to proven models and sustainability. RESULTS: Implementation of the ESP was grounded on five established principles and methods for successful PD. The process was conducted in four IS stages over 10 years: Exploration, Installation, Initial Implementation, and Full Implementation. To ensure effective and efficient processes, attention to IS implementation drivers helped to manage organizational relationships, build competence in faculty and scholars, and address leadership challenges. We describe the ESP's fidelity to evidence-based structures and methods, and offer three examples of sustainability efforts that enabled achievement of targeted program outcomes, including academic productivity, strong networking, and career advancement of scholars. DISCUSSION: Application of IS frameworks to program implementation may help other PD programs to translate evidence-based methods into interventions with enhanced impact. A PD program can follow systematic developmental stages and be operationalized by practical implementation drivers, thereby creating successful and sustainable interventions that promote the academic vitality of health professions educators. PMID- 28562498 TI - Development and Feasibility of an Academic Detailing Intervention to Improve Prescription Drug Monitoring Program Use Among Physicians. AB - INTRODUCTION: South Carolina (SC) ranks 10th in opioid prescriptions per capita 33% higher than the national average. SC is also home to a large military and veteran population, and prescription opioid use for chronic pain is alarmingly common among veterans, especially those returning from Afghanistan and Iraq. This article describes the background and development of an academic detailing (AD) educational intervention to improve use of a Prescription Drug Monitoring Program among SC physicians who serve military members and veterans. The aim of this intervention was to improve safe opioid prescribing practices and prevent prescription opioid misuse among this high-risk population. METHODS: A multidisciplinary study team of physicians, pharmacists, psychologists, epidemiologists, and representatives from the SC's Prescription Monitoring Program used the Medical Research Council complex interventions framework to guide the development of the educational intervention. The theoretical and modeling phases of the AD intervention development are described and preliminary evidence of feasibility and acceptability is provided. RESULTS: Ninety-three physicians consented to the study from 2 practice sites. Eighty-seven AD visits were completed, and 59 one-month follow-up surveys were received. Participants rated the AD intervention high in helpfulness of information, intention to use information, and overall satisfaction with the intervention. The component of the intervention felt to be most helpful was the AD visit itself. Characteristics of the participants and the intervention, as well as anticipated barriers to behavior change are detailed. DISCUSSION: Preliminary results support the feasibility of AD delivery to veteran and community patient settings, the feasibility of facilitating Prescription Drug Monitoring Program registration during an AD visit, and that AD visits were generally found satisfying to participants and helpful in improving knowledge and confidence about safe opioid prescribing practices. The component of the intervention felt to be most helpful to the participants was the actual AD visit, and most participants rated their intentions high to use the information and tools from the visit. Intervention key messages, preliminary outcome measures, and successes and challenges in developing and delivering this intervention are discussed to advance best practices in developing educational interventions in this important area of public health. PMID- 28562500 TI - Evaluation of the Diabetes, Multidisciplinary, Experiential (DIAMANTE) Program for Retail Pharmacists: A Mixed-Method Study. AB - INTRODUCTION: The Diabetes, Multidisciplinary, Experiential (DIAMANTE) program was established to enhance collaboration between retail pharmacists and the diabetes care team in the health institutions through interprofessional education. This article describes the program and reports on an evaluation of its impact on attitudes, knowledge, and confidence of the participants in managing diabetic patients. METHODS: This study utilized a mixed-method design with focus group (FG), exit assessment, and survey. Ten participants were approached to complete the 2-week DIAMANTE program with hands-on training from a multidisciplinary diabetes team. In addition to an exit assessment and a pre-post online survey to assess attitudes of participants toward diabetes care, diabetes knowledge, and confidence in managing diabetic patients, FG was used to obtain the qualitative feedback of pharmacists. Feedback of the preceptors related to the program and pharmacist performance was also sought through an online survey. Survey data and FGs were analyzed using Wilcoxon signed-rank test and thematic analysis, respectively. RESULTS: All participants completed the program successfully. The FGs revealed four themes: program design, participants' view on preceptors, participants' perceptions of program benefits, and program's outlook. Participants perceived the program content as comprehensive and relevant. With experiential learning, the pharmacists reported improved counseling skills and increased understanding of the roles of different healthcare members. Their knowledge and confidence in managing diabetic patients was improved (P = .008). All participants passed the exit assessment. In general, the preceptors were satisfied with the program design, assessment content, and participant performance. DISCUSSION: The overall view of DIAMANTE appeared positive. The program also improved knowledge and confidence of the participants in managing diabetic patients. PMID- 28562501 TI - Collaborative Clinical Reasoning-A Systematic Review of Empirical Studies. AB - INTRODUCTION: Health care delivery involves multiple health professions, and increasingly, diagnostic and therapeutic decisions are made through interprofessional teamwork. We define collaborative clinical reasoning (CCR) as the process in which two or more health care team members negotiate diagnostic, therapeutic, or prognostic issues of an individual patient resulting in an illness or treatment plan (and to reduce uncertainty). In a systematic review, we aimed to answer the following research question: Which empirically observable factors are considered crucial influences on performance in CCR in current empirical research? METHODS: A systematic literature review was conducted. We included empirical studies taking place in a hospital setting, with a clear focus on CCR and published between January 1990 and September 2014. The studies were only included when at least one physician was part of the team. Nine articles were included in the review. RESULTS: The factors crucially influencing the CCR performance (ie, diagnosis or treatment plan of patients) are (1) the initial distribution of information over team members, (2) clinical experience of physicians within a team, (3) information exchange within a team, and (4) individual retrieval of information from the team or information representation. DISCUSSION: Despite the sparse empirical evidence on CCR, four factors influencing performance were extracted from the literature. Overall, there is little evidence though how each of these factors actually influences CCR performance. Thus, we need more empirical studies to better understand and foster CCR performance. PMID- 28562502 TI - Prescribers' Knowledge and Skills for Interpreting Research Results: A Systematic Review. AB - INTRODUCTION: Appropriate medication prescribing may be influenced by a prescriber's ability to understand and interpret medical research. The objective of this review was to synthesize the research related to prescribers' critical appraisal knowledge and skills-defined as the understanding of statistical methods, biases in studies, and relevance and validity of evidence. METHODS: We searched PubMed and other databases from January 1990 through September 2015. Two reviewers independently screened and selected studies of any design conducted in the United States, the United Kingdom, or Canada that involved prescribers and that objectively measured critical appraisal knowledge, skills, understanding, attitudes, or prescribing behaviors. Data were narratively synthesized. RESULTS: We screened 1204 abstracts, 72 full-text articles, and included 29 studies. Study populations included physicians. Physicians' extant knowledge and skills were in the low to middle of the possible score ranges and demonstrated modest increases in response to interventions. Physicians with formal education in epidemiology, biostatistics, and research demonstrated higher levels of knowledge and skills. In hypothetical scenarios presenting equivalent effect sizes, the use of relative effect measures was associated with greater perceptions of medication effectiveness and intent to prescribe, compared with the use of absolute effect measures. The evidence was limited by convenience samples and study designs that limit internal validity. DISCUSSION: Critical appraisal knowledge and skills are limited among physicians. The effect measure used can influence perceptions of treatment effectiveness and intent to prescribe. How critical appraisal knowledge and skills fit among the myriad of influences on prescribing behavior is not known. PMID- 28562503 TI - Rebooting Kirkpatrick: Integrating Information System Theory Into the Evaluation of Web-based Continuing Professional Development Interventions for Interprofessional Education. AB - INTRODUCTION: Information system research has stressed the importance of theory in understanding how user perceptions can motivate the use and adoption of technology such as web-based continuing professional development programs for interprofessional education (WCPD-IPE). A systematic review was conducted to provide an information system perspective on the current state of WCPD-IPE program evaluation and how current evaluations capture essential theoretical constructs in promoting technology adoption. METHODS: Six databases were searched to identify studies evaluating WCPD-IPE. Three investigators determined eligibility of the articles. Evaluation items extracted from the studies were assessed using the Kirkpatrick-Barr framework and mapped to the Benefits Evaluation Framework. RESULTS: Thirty-seven eligible studies yielded 362 evaluation items for analysis. Most items (n = 252) were assessed as Kirkpatrick Barr level 1 (reaction) and were mainly focused on the quality (information, service, and quality) and satisfaction dimensions of the Benefits Evaluation. System quality was the least evaluated quality dimension, accounting for 26 items across 13 studies. WCPD-IPE use was reported in 17 studies and its antecedent factors were evaluated in varying degrees of comprehensiveness. DISCUSSION: Although user reactions were commonly evaluated, greater focus on user perceptions of system quality (ie, functionality and performance), usefulness, and usability of the web-based platform is required. Surprisingly, WCPD-IPE use was reported in less than half of the studies. This is problematic as use is a prerequisite to realizing any individual, organizational, or societal benefit of WCPD-IPE. This review proposes an integrated framework which accounts for these factors and provides a theoretically grounded guide for future evaluations. PMID- 28562504 TI - Health Professions Education Graduate Programs Are a Pathway to Strengthening Continuing Professional Development. AB - The need to strengthen the preparation of individuals leading and providing continuing professional development (CPD) programs has grown dramatically within the current health care context. CPD is an integral part of the continuum of health professions education and cuts across the multiple disciplines and professions delivering health care. Each health care profession needs not only to keep up to date on new information within their specific discipline but also continue to develop and expand skills in areas that link interdisciplinary areas, such as quality of care delivery and communication skills, across various professions. In this article, we examine the changing context in which CPD is provided and explain how graduate programs in health professions education can be used as a strategy to strengthen the preparation of individuals for CPD practice and advance the delivery of CPD through evidence-based and innovative strategies. PMID- 28562507 TI - Dealing with large-scale supply lines when introducing new regimens. AB - PURPOSE OF REVIEW: As programs plan the introduction of a new antiretroviral as part of a regimen for HIV treatment, supply chain considerations need to be taken into account. The key to success is balancing the introduction of a new regimen with the phasing out of an old regimen in a manner that does not result in either a shortage or an excess supply of either product while ensuring that patients continue receiving their medications. This necessitates that country programs, donors, and procurement entities possess an appreciation of the global antiretroviral market and understand the dynamics that the manufacturing of new antiretrovirals will have on the transition. RECENT FINDINGS: Supply, demand, and financial considerations affect the capacity of the supply chain to facilitate a successful antiretroviral transition. Although this commentary draws on United States Agency for International Development experiences under the President's Emergency Plan for AIDS Relief from earlier antiretroviral treatment shifts, the approaches are applicable to other institutions and to future transitions. Three approaches were employed: ensuring the engagement of all key stakeholders in transition planning and execution, including clinicians, advocacy groups, supply chain professionals, ministry, and donors; conducting and updating regularly the national quantification and supply plans for all regimens; and introducing antiretroviral products into programs from regional warehouses based on firm orders. SUMMARY: Extensive planning and accounting for supply chain factors is essential to ensuring a smooth transition to a new regimen and to enable the global antiretroviral market to respond adequately. PMID- 28562509 TI - Clinic Attendance of Youth With Sickle Cell Disease on Hydroxyurea Treatment. AB - OBJECTIVE: The objective of this study is to describe rates of clinic attendance of youth with sickle cell disease prescribed hydroxyurea and examine potential demographic and medical factors related to consistent clinic attendance. METHODS: Participants included 148 youth diagnosed with sickle cell disease and prescribed hydroxyurea during a single calendar year. Clinic attendance and potential demographic and medical factors related to attendance were extracted via systematic retrospective medical chart review. RESULTS: Youth attended 90.3% of scheduled appointments and 85.1% of youth attended at least 80% of scheduled clinic appointments during the study window. Adjusting for other factors, multivariate analysis revealed families with fewer children in the household, families with private insurance, youth experiencing fever, and youth not experiencing pain during the calendar year were more likely to consistently attend clinic visits. CONCLUSIONS: Adherence to clinic appointments is critical to optimizing health outcomes for youth with sickle cell disease and integral for adequate monitoring of youth prescribed hydroxyurea, in particular. Findings may aid providers in appropriately identifying possible barriers to clinic attendance to develop attendance promotion interventions. PMID- 28562508 TI - Biallelic PMS2 Mutation and Heterozygous DICER1 Mutation Presenting as Constitutional Mismatch Repair Deficiency With Corpus Callosum Agenesis: Case Report and Review of Literature. AB - Constitutional mismatch repair deficiency syndrome is a cancer predisposition syndrome caused by autosomal recessive biallelic (homozygous) germline mutations in the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). The clinical spectrum includes neoplastic and non-neoplastic manifestations. We present the case of a 7 year-old boy who presented with T-lymphoblastic lymphoma and glioblastoma, together with non-neoplastic manifestations including corpus callosum agenesis, arachnoid cyst, developmental venous anomaly, and hydrocephalus. Gene mutation analysis revealed pathogenic biallelic mutations of PMS2 and heterozygous DICER1 variant predicted to be pathogenic. This report is the first to allude to a possible interaction of the mismatch repair system with DICER1 to cause corpus callosum agenesis. PMID- 28562510 TI - Pancytopenia and Hypothyroidism in a Patient With Leukemic Infiltration of the Thyroid as the First Presentation of Acute Lymphoblastic Leukemia. AB - We report the case of a 16-year-old female patient with hypothyroidism, goiter, and pancytopenia. Biopsy of the thyroid showed leukemic infiltration. After confirmation of the diagnosis of B-lymphoblastic leukemia, treatment was started. Histologic follow-up at day 33 and 79 showed no residual signs of leukemic infiltration. Hypothyroidism persisted despite successful antileukemic treatment. Leukemic infiltration of the thyroid should be considered as a differential diagnosis in patients with hypothyroidism, goiter, and pancytopenia. We suggest that follow-up of thyroid function and histology should be incorporated in the follow-up of rare patients with acute lymphoblastic leukemia with thyroid infiltration. PMID- 28562511 TI - Kawasaki Disease Complicated With Macrophage Activation Syndrome: A Systematic Review. AB - Macrophage activation syndrome (MAS), also known as secondary hemophagocytic lymphohistiocytosis, is a rare and potentially fatal complication of Kawasaki disease (KD). We report 2 cases, performed a literature search, and analyze the characteristics of MAS associated with KD. A total of 69 patients were evaluated, 34 reported the date of the diagnosis of MAS and KD, 6% had a diagnosis of MAS before KD, 21% had a simultaneous presentation, and 73% had the diagnosis of MAS after KD. Different treatment approaches were observed with corticosteroids administered in 87%, cyclosporine in 49%, etoposide (VP-16) in 39%, and monoclonal anti-TNF in 6% of cases. Coronary abnormalities were especially high in this group of patients (46%) and 9 patients died (13%). The persistence of fever with splenomegaly, hyperferritinemia, thrombocytopenia, and elevated aspartate aminotransferase (AST) should prompt the consideration of MAS complicating KD. PMID- 28562512 TI - An Unusual Cause of Fever and Rash in a Child With Severe Aplastic Anemia. AB - A 4-year-old girl with severe aplastic anemia and 2 previous failed T-depleted haploidentical peripheral blood stem cell transplants developed persistent neutropenic fever and multiple erythematous maculopapular rashes 2 days after her third T-replete haploidentical bone marrow transplant. Skin biopsy confirmed the diagnosis of Trichosporon asahii infection. She was on caspofungin prophylaxis which is not effective against Trichosporon. A high index of suspicion, prompt investigation, and appropriate treatment with voriconazole for 4 months was instrumental in controlling the infection and she remains well presently 9 months posttransplant with full donor chimerism and free from infection. PMID- 28562513 TI - Peripherally Inserted Central Catheters in Pediatric Oncology Patients: A 15-Year Population-based Review From Maritimes, Canada. AB - The present population-based study evaluates the management and complications of peripherally inserted central catheters (PICC) in all pediatric oncology patients diagnosed in Maritimes, Canada from 2000 to 2014. A total of 107 PICCs were placed in 87 (10.1%) pediatric oncology patients. A high percentage (33% and 44%, respectively) of the first and second PICC lines was associated with complications. Thrombosis, occlusion, and infection were the most frequent complications. Age above 10 years and left body side of insertion were significantly associated with PICC complications. Given the frequent use of PICCs and the high incidence (>33%) of complications, there is a need to mitigate PICC line complications. PMID- 28562514 TI - ACTN1-related Macrothrombocytopenia: A Novel Entity in the Progressing Field of Pediatric Thrombocytopenia. AB - : The most common cause of thrombocytopenia in children is immune thrombocytopenia. Nevertheless, some atypical cases should evoke the hypothesis of genetic thrombocytopenia. Indeed, in the past years, 30 new genes had been described in the field of inherited thrombocytopenia. We report a series of 11 cases of a newly diagnosed entity: ACTN1-related macrothrombocytopenia. Mutations in the gene ACTN1 cause mild macrothrombocytopenia characterized by elevated mean platelet volume and elevated immature platelet fraction, and low bleeding tendency. Its transmission is autosomal dominant. Molecular diagnosis is made by sequencing the ACTN1 gene. Its potential role in hematological malignancy predisposition remains unclear and should be clarified. CONCLUSION: We identified 11 patients with ACTN1-related macrothrombocytopenia diagnosed through pediatric probands. The aim was to underline the specificities of this entity, especially in children, and bring it to the knowledge of pediatricians. PMID- 28562515 TI - Secondary Hemophagocytic Lymphohistocytosis in a Child With Brucellosis. AB - Hemophagocytic lymphohistocytosis (HLH) is a potentially fatal hyperinflammatory syndrome that is characterized by proliferation of histiocytes and hemophagocytosis in different organs. The diagnostic criteria include fever, hepatosplenomegaly, bicytopenia, high serum ferritin level, decreased natural killer cell activity, elevated soluble CD25 level, high serum fasting triglyceride level or low fibrinogen level, and hemophagocytosis in the bone marrow, spleen, or lymph nodes. HLH can be classified as primary and secondary. Secondary HLH can be related to infections. Here we report a case of Brucella related HLH, which has been rarely reported in the literature. PMID- 28562516 TI - The Collagen Gel Droplet-embedded Culture Drug Sensitivity Test in Relapsed Hepatoblastoma. AB - There are few treatment options for patients with unresectable or refractory hepatoblastoma which has failed to respond to the standard treatment. The rarity of the disease and lack of experimental materials have hampered the development of new treatments. In this study, the collagen gel droplet-embedded culture drug sensitivity test was used to evaluate the effectiveness of the multikinase inhibitors sorafenib and sunitinib, and other drugs, in relapsed hepatoblastoma tumor tissues. Tumor samples from 6 patients with relapsed hepatoblastoma were tested for drug sensitivity by the collagen gel droplet-embedded culture drug sensitivity test; evaluable results were obtained from 5 of them. All samples were judged to be sensitive to sorafenib with a 50% growth inhibitory concentration (IC50) of 0.5 to 3.1 MUg/mL. Sunitinib did not achieve IC50 in 2 of 3 samples within the tested concentration range based on clinically observed serum concentrations. In the drug combination assay using a hepatoblastoma cell line, sorafenib showed synergistic effects with SN-38, an active metabolite of irinotecan. Our results provide the basic science background warranting future clinical trials of a combination of sorafenib and irinotecan for relapsed or refractory hepatoblastoma. PMID- 28562517 TI - Intravenous Iron Sucrose for Children With Iron Deficiency Anemia. AB - Iron deficiency anemia (IDA) is the most common nutritional deficiency in children. Most children with IDA are treated with oral iron preparations. However, intravenous (IV) iron is an alternative for children with severe IDA who have difficulty in adhering to or absorbing oral iron. We sought to describe the safety and effectiveness of IV iron sucrose for treatment of IDA in children. Pharmacy records of children who received IV iron sucrose at a children's hospital between 2004 and 2014 were reviewed. Laboratory markers of anemia and iron studies were obtained and preinfusion and postinfusion values were compared. Records were also reviewed for adverse reactions. A total of 142 patients received IV iron sucrose over 10 years. The mean age was 11 years, 9 months. One patient of 142 developed cough and wheezing during the infusion. No other adverse events were found. IV iron sucrose resulted in a statistically significant and clinically meaningful increase in hemoglobin, mean corpuscular volume, serum iron, ferritin, and % iron saturation, with a corresponding decrease in total iron binding capacity. The use of IV iron sucrose in pediatric patients with IDA is safe and leads to a moderate increase in hemoglobin and substantial improvement in iron studies. PMID- 28562518 TI - Iron Overload in Survivors of Childhood Cancer. AB - BACKGROUND: Patients transfused with packed red blood cells (PRBC), including childhood cancer survivors (CCS), experience complications. We describe iron overload (ferritin>500 ng/mL) prevalence and identify risk factors in CCS. OBSERVATIONS: Of 116 participants, 3 (2.6%) had elevated ferritin. All were teenagers at cancer diagnosis and received >8000 mL PRBC. Total PRBC volume correlated best with elevated ferritin (r=0.74; P<0.0001). PRBC (8000 mL) had the best positive and negative predictive value (75% and 100%, respectively) for iron overload. CONCLUSIONS: CCS may have iron overload. Overall prevalence is low. At risk include teenagers at diagnosis and those receiving higher total PRBC volumes. PMID- 28562519 TI - Epigenetic Combination Therapy for Children With Secondary Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) and Concurrent Solid Tumor Relapse. AB - Secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) is a rare but devastating complication of solid tumor treatment involving high-dose topoisomerase II inhibitor and alkylator chemotherapy. For relapsed or elderly MDS and AML patients ineligible for hematopoietic stem cell transplantation, epigenetic therapies, including DNA methyltransferase inhibitors and histone deacetylase inhibitors, have been utilized as palliative therapy, offering a well tolerated approach to disease stabilization, prolonged survival, and quality of life. Literature on the use of epigenetic therapies for both primary and relapsed disease is scarce in the pediatric population. Here, we report 2 pediatric patients with secondary AML and MDS, respectively, due to prior therapy for metastatic solid tumors. Both patients were ineligible for hematopoietic stem cell transplantation due to concurrent solid tumor relapse, but were treated with the epigenetic combination therapy, decitabine and vorinostat, and achieved stabilization of marrow disease, outpatient palliation, and family-reported reasonable quality of life. PMID- 28562521 TI - How Secure Is the Diagnosis of Ulcerative Colitis in Children, Even After Colectomy? AB - OBJECTIVES: We reviewed all children who have undergone a colectomy for ulcerative colitis (UC) in our tertiary referral centre in a 12-year period to assess the rate of reclassification as Crohn disease (CD). In contrast to CD, a colectomy is considered to be definitive treatment for patients with UC. Distinguishing between the 2 can be challenging when disease is manifest only within the colon-even histological examination of a colectomy specimen may be inconclusive. Historically, the recognised "rediagnosis" rate (post-colectomy) was reported at approximately 3% to 7%. A recent study suggested that a higher rate of 13% should be expected in children. This has implications in terms of pre operative counselling and surgical decision making. METHODS: A retrospective case note review of all patients who underwent a colectomy for UC between 2003 and 2014 in a single paediatric tertiary referral centre was performed. RESULTS: Of the 570 children diagnosed with inflammatory bowel disease in this period, 190 were diagnosed as UC. Of these 190 cases, 29 underwent a colectomy. None of these was re-classified following histological examination of the colectomy sample. Seven out of the 29 patients (24%) were subsequently diagnosed with CD (median follow-up 7.6 years). This is significantly higher than previously reported rates (P = 0.003). CONCLUSIONS: Our data suggest that later manifestation of CD is more common than previously thought (24%). Therefore, a diagnosis of UC in children should be regarded as provisional and a potential later diagnosis of CD taken into account when considering colectomy and J-pouch formation. PMID- 28562520 TI - Langerhans' Cell Histiocytosis Mimicking a Pott Puffy Tumor. AB - Langherans' cell histiocytosis (LCH) is a rare disease mostly affecting children in the first decade of life. As clinical presentation is extremely heterogenous, a prompt diagnosis may be challenging, sometimes leading to a diagnostic delay, especially when the disease involves a single site. Herein, we report a case of a child with an unusual presentation of (LCH) mimicking a Pott puffy tumor with extracranial and epidural abscesses, surgically treated. Through this unique case we summarize possible manifestations of LCH with bone involvement and we underline the importance of considering possible complications due to bone erosions such as infection, to avoid a misdiagnosis. PMID- 28562522 TI - A Child With Ichthyosis and Liver Failure. PMID- 28562523 TI - Risk of Eating Disorders in Patients With Celiac Disease. AB - OBJECTIVES: Several cases of eating disorders (EDs) have been reported in patients with celiac disease (CD), suggesting that ED could be a comorbidity associated with CD. Few epidemiological studies have, however, assessed this potential association. We aimed to evaluate the risk of EDs in individuals diagnosed with CD in comparison to healthy controls. METHODS: A total of 98 cases and 98 controls matched for sex, age, and body mass index between 10 and 23 years old were studied. A questionnaire was completed on medical history and sociodemographic as well as anthropometric characteristics. Various ED screening self-reported tests were administered. RESULTS: A total of 61.2% of the study population were girls with a mean age of 15.3 +/- 3.7 years old. Patients with CD scored nonsignificantly higher on all the ED screening tests than control participants. No differences were observed between study groups in terms of the frequency of individuals who exceeded the clinical cutoff identifying those at risk of ED. Patients with CD above 13 years old were associated with a 2.15-point increase in the Eating Attitude Test score compared with controls [beta coefficient = 2.15 SE 1.04; P = 0.04] after adjusting for various confounders. CONCLUSIONS: Although being a patient with CD was associated with a significantly higher Eating Attitude Test score in individuals older than 13 years old, no clear differences were observed between individuals with CD and controls in terms of risk of ED when other screening tests were used. More studies with larger samples and prospective designs are warranted to confirm these findings. PMID- 28562524 TI - The Work-Rate of Elite Hurling Match-Play. AB - Collins, DK, McRobert, A, Morton, JP, O'Sullivan, D, and Doran, DA. The work-rate of elite hurling match-play. J Strength Cond Res 32(3): 805-811, 2018-This study describes the global work-rate of elite hurling match-play and the influence which positional difference has on work-rate is considered. The movement of ninety-four players was recorded using global positioning system, sampling at 4 Hz in a total of 12 games. Data were classified according to the positional line on the field and period of the match. The total and high-speed distance of match play was 7,617 +/- 1,219 m (95% confidence interval [CI], 7,367-7,866) and 1,134 +/- 358 m (95% CI, 1,060-1,206), respectively. The maximum speed attained was 29.8 +/- 2.3 km.h with a mean speed of 6.1 +/- 1 km.h. The second {271 +/- 107 m (p = 0.001; effect size [ES] = 0.25)}, third (278 +/- 118 m [p = 0.001; ES = 0.21]), and fourth quarter (255 +/- 108 m [p = 0.001; ES = 0.31]) high-speed running distance differed significantly from that of the first quarter (330 +/- 120 m). There was a significant difference in total (p = 0.001; ES = 0.01-0.85), high-speed running (p = 0.001; ES = 0.21-0.76), and sprint (p = 0.013; ES = 0.01 0.39) distance across the positions, with midfielders undertaking the highest volume of work, followed by the half-forward and half-back lines and finally the full-forward and full-back lines. A decrease in high-speed running distance seems to occur through out the game and in particular at the latter stages of each half. Distinct positional work profiles are evident. The present finding provide a context on which training which replicates the work-rate of match-play may be formulated, thus helping to improve the physical preparation of elite players. PMID- 28562525 TI - Ophthalmoplegia associated with lung adenocarcinoma in a patient with the Lambert Eaton myasthenic syndrome: A case report. AB - RATIONALE: The Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular disease; its unique symptoms of LEMS include dry mouth with a metallic taste, constipation, and erectile dysfunction. As it is quite rare, isolated ocular muscle impairment associated with LEMS east to ignore. PATIENT CONCERNS: A 65 year-old man presented with alternating ptosis and diplopia. Isolated ocular muscle impairment had lasted for 6 years, and the patient was initially diagnosed with ocular myasthenia gravis (MG). Treatment with azathioprine only slightly improved symptoms over the first 2 months; long-term treatment was not effective. DIAGNOSES: Dynamic observation of chest computed tomography images revealed a slowly progressing nodule in the lower lobe of the left lung. The subsequent pathologic examination following mass resection confirmed a diagnosis of lung adenocarcinoma. INTERVENTIONS: The patient was ultimately diagnosed with the Lambert-Eaton myasthenic syndrome associated with pulmonary adenocarcinoma. OUTCOMES: Resection of the lung tumor relieved all symptoms. LESSONS: Other causes of ocular MG symptoms should be considered when standard MG therapy is ineffective, especially the Lambert-Eaton myasthenic syndrome. PMID- 28562527 TI - Successful treatment of infliximab in a patient with scleroderma: a case report. AB - RATIONALE: Systemic Scleroderma (SSc) is a rare connective tissue disease clinically characterized by cutaneous sclerosis and variable systemic involvement. No drug is currently available to effectively reverse the fibrotic process in SSc. Previous reports have suggested that the tumor necrosis factor (TNF) antagonists could be useful for the treatment of fibrotic disorders. However, TNFalpha has long been considered as an antifibrotic cytokine. Whether TNF antagonist is effective for SSc patients needs to be tested. PATIENT CONCERNS DIAGNOSIS: Here we report a case with a 2-year history of SSc who was effectively treated with infliximab in our clinic. INTERVENTIONS: The patient manifested skin thickening, chest tightness and arthralgia. Before admitted to our clinic, he was treated with methylprednisolone, prostacyclin, D-penicillamine and calcium antagonists but without significant improvement of his signs and symptoms. In our clinic, the patient was treated with infliximab. OUTCOMES: His signs and symptoms were continued improving during the course of treatment. His skin biopsy showed significant reduction in fibroplasia finally. LESSONS: TNF antagonist is an effective treatment for SSc. PMID- 28562526 TI - Efficacy of antidepressive medication for depression in Parkinson disease: a network meta-analysis. AB - BACKGROUND: Parkinson disease (PD) was considered as the 2nd most prevalent neurodegenerative disorder after Alzheimer disease, while depression is a prevailing nonmotor symptom of PD. Typically used antidepression medication includes tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRI), monoamine oxidase inhibitors (MAOI), and dopamine agonists (DA). Our study aimed at evaluating the efficacy of antidepressive medications for depression of PD. METHODS: Web of Science, PubMed, Embase, and the Cochrane library were searched for related articles. Traditional meta-analysis and network meta-analysis (NMA) were performed with outcomes including depression score, UPDRS-II, UPDRS-III, and adverse effects. Surface under the cumulative ranking curve (SUCRA) was also performed to illustrate the rank probabilities of different medications on various outcomes. The consistency of direct and indirect evidence was also assessed by node-splitting method. RESULTS: Results of traditional pairwise meta analysis were performed. Concerning depression score, significant improvement was observed in AD, MAOI, SSRI, and SNRI compared with placebo. NMA was performed and more information could be obtained. DA was illustrated to be effective over placebo concerning UPDRS-III, MAOI, and SNRI. DA demonstrated a better prognosis in UPDRS-II scores compared with placebo and MAOI. However, DA and SSRI demonstrated a significant increase in adverse effects compared with placebo. The SUCRA value was calculated to evaluate the ranking probabilities of all medications on investigated outcomes, and the consistency between direct and indirect evidences was assessed by node-splitting method. CONCLUSION: SSRI had a satisfying efficacy for the depression of PD patients and could improve activities of daily living and motor function of patient but the adverse effects are unneglectable. SNRI are the safest medication with high efficacy for depression as well while other outcomes are relatively poor. PMID- 28562528 TI - MicroRNA profiling in the dentate gyrus in epileptic rats: The role of miR-187 3p. AB - This study aimed to explore the role of aberrant miRNA expression in epilepsy and to identify more potential genes associated with epileptogenesis.The miRNA expression profile of GSE49850, which included 20 samples from the rat epileptic dentate gyrus at 7, 14, 30, and 90 days after electrical stimulation and 20 additional samples from sham time-matched controls, was downloaded from the Gene Expression Omnibus database. The significantly differentially expressed miRNAs were identified in stimulated samples at each time point compared to time-matched controls, respectively. The target genes of consistently differentially expressed miRNAs were screened from miRDB and microRNA.org databases, followed by Gene Ontology (GO) and pathway enrichment analysis and regulatory network construction. The overlapping target genes for consistently differentially expressed miRNAs were also identified from these 2 databases. Furthermore, the potential binding sites of miRNAs and their target genes were analyzed.Rno-miR 187-3p was consistently downregulated in stimulated groups compared with time matched controls. The predicted target genes of rno-miR-187-3p were enriched in different GO terms and pathways. In addition, 7 overlapping target genes of rno miR-187-3p were identified, including NFS1, PAQR4, CAND1, DCLK1, PRKAR2A, AKAP3, and KCNK10. These 7 overlapping target genes were determined to have a different number of matched binding sites with rno-miR-187-3p.Our study suggests that miR 187-3p may play an important role in epilepsy development and progression via regulating numerous target genes, such as NFS1, CAND1, DCLK1, AKAP3, and KCNK10. Determining the underlying mechanism of the role of miR-187-3p in epilepsy may make it a potential therapeutic option. PMID- 28562529 TI - Body mass index and risk of diabetic retinopathy: A meta-analysis and systematic review. AB - Diabetic retinopathy (DR) is a frequent cause of acquired blindness worldwide. Various studies have reported the effects of body mass index (BMI) on the risk of DR, but the results remain controversial. Therefore, a meta-analysis was performed to evaluate the relationship between BMI and the risk of DR.A systematic search was performed using the Cochrane Library, PubMed, and Embase databases to obtain articles published through December 2016. Articles regarding the association between BMI and the risk of DR were retrieved. The adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were included and then pooled with a random effects model.A total of 27 articles were included in this meta-analysis. When BMI was analyzed as a categorical variable, neither being overweight (OR = 0.89, 95% CI 0.75-1.07; P = .21; I = 65%) nor obesity (OR = 0.97, 95% CI 0.73-1.30; P = .86) were associated with an increased risk of DR when compared with normal weight. When BMI was analyzed as a continuous variable, a higher BMI was not associated with an increased risk of DR (OR = 0.99, 95% CI 0.97-1.01; P = .25; I2 = 79%). The pooled results did not significantly change after the sensitivity analysis.Based on the current publications, neither being overweight nor obesity is associated with an increased risk of DR. Further studies should confirm these findings. PMID- 28562530 TI - Adjuvant endocrine therapy alone in patients with node-positive, luminal A type breast cancer. AB - Luminal A breast cancer has a much better prognosis than other subtypes, with a low risk of local or regional recurrence. However, there is controversy around under- versus overtreatment with regard to adjuvant treatment of node-positive, luminal A breast cancer. The purpose of this study was to identify whether adjuvant systemic chemotherapy has any benefit in node-positive, luminal A breast cancer and to evaluate feasibility of endocrine therapy without chemotherapy in this group.This was a retrospective study of 11,025 patients who were surgically treated for invasive breast cancer at Samsung Medical Center between January 2004 and December 2013. Luminal A subtype was defined as ER+, HER2-, and Ki-67 < 14%. We compared AC based (AC: doxorubicin or epirubicin, plus cyclophosphamide) adjuvant chemotherapy versus endocrine therapy without chemotherapy in patients with node-positive, luminal A breast cancer.We performed 1: n matching, with a maximum n of 8 on endocrine therapy group (n = 50) to chemotherapy group (n = 642). The median age of the patients in each group at the time of surgery was 58.3 +/- 9.5 years in the chemotherapy group and 58.7 +/- 11.7 in the endocrine therapy only group. The median follow-up time was 51.9 months (range, 1-125 months). In multivariable analysis, omission of adjuvant chemotherapy in luminal A cancer had no influence on OS and DFS. Axillary lymph node metastasis and progesterone receptor (PR) status were significantly different between the endocrine therapy alone group and the chemotherapy group in terms of OS. Nuclear grade, PR status, and adjuvant radiotherapy were significantly different between the endocrine therapy alone group and the chemotherapy group with regard to DFS. In survival analysis, there were no differences in OS (P = .137) and DFS (P = .225) between the 2 groups.Adjuvant chemotherapy could provide little benefit to postmenopausal patients with luminal A, node-positive breast cancer, and endocrine therapy alone may help reduce morbidity. Future studies with a large number of patients and longer follow-up time are necessary to determine whether chemotherapy might be avoided in this patient population. PMID- 28562531 TI - Widely differing screening and treatment practice for osteoporosis in patients with inflammatory bowel diseases in the Swiss IBD cohort study. AB - Low bone mineral density (BMD) and osteoporosis remain frequent problems in patients with inflammatory bowel diseases (IBDs). Several guidelines with nonidentical recommendations exist and there is no general agreement regarding the optimal approach for osteoporosis screening in IBD patients. Clinical practice of osteoporosis screening and treatment remains insufficiently investigated.In the year 2014, a chart review of 877 patients included in the Swiss IBD Cohort study was performed to assess details of osteoporosis diagnostics and treatment. BMD measurements, osteoporosis treatment, and IBD medication were recorded.Our chart review revealed 253 dual-energy x-ray absorptiometry (DXA) scans in 877 IBD patients; osteoporosis was prevalent in 20% of tested patients. We identified widely differing osteoporosis screening rates among centers (11%-62%). A multivariate logistic regression analysis identified predictive factors for screening including steroid usage, long disease duration, and perianal disease; even after correction for all risk factors, the study center remained a strong independent predictor (odds ratio 2.3-21 compared to the center with the lowest screening rate). Treatment rates for patients with osteoporosis were suboptimal (55% for calcium, 65% for vitamin D) at the time of chart review. Similarly, a significant fraction of patients with current steroid medication were not treated with vitamin D or calcium (treatment rates 53% for calcium, 58% for vitamin D). For only 29% of patients with osteoporosis bisphosphonate treatment was started. Treatment rates also differed among centers, generally following screening rates. In patients with longitudinal DXA scans, calcium and vitamin D usage was significantly associated with improvement of BMD over time.Our analysis identified inconsistent usage of osteoporosis screening and underuse of osteoporosis treatment in IBD patients. Increasing awareness of osteoporosis as a significant clinical problem in IBD patients might improve patient care. PMID- 28562532 TI - Evaluation of a combined posterior lateral and anteromedial approach in the treatment of terrible triad of the elbow: A retrospective study. AB - BACKGROUND: This retrospective study aims to investigate the efficacy and safety of a combined posterior lateral and anteromedial approach in the treatment of terrible triad of the elbow (TTE). METHODS: TTE patients who received a combination of posterior lateral and anteromedial approach or other conservative treatments were included in the present study. The postoperative functions of the elbow and the severity of traumatic arthritis were assessed using the Mayo Elbow Performance Score (MEPS) and visual analog scale (VAS). Extension-flexion of elbow joint and rotation of forearm were also measured. RESULTS: A combined posterior lateral and anteromedial approach or other conservative treatments showed significant improvements in the activity of the elbow, MEPS, VAS, the excellent rate, and x-ray results. The postoperative healing time and complication rate of patients who received a combined posterior lateral and anteromedial approach significantly decreased compared to those who received other conservative treatments. CONCLUSIONS: Patients with TTE who received a combined posterior lateral and anteromedial treatment had an increased fracture healing rate, showed improved recovery of elbow functions and had fewer complications. PMID- 28562534 TI - Serial renography for evaluation of the impact of capecitabine therapy on renal function: A case report. AB - RATIONALE: Cancer can cause renal dysfunction and disease either directly or indirectly, through adverse effects of therapies, including chemotherapy and radiation. The assessment of renal function in cancer patients is necessary in clinical practice. PATIENT CONCERNS: A 31-year-old woman had proctoscopy performed in our hospital for a principal complaint of bloody stool for 6 months and worsening 1 month prior to presentation. DIAGNOSES: Following proctoscopy, she was diagnosed with a signet-ring cell carcinoma of the rectum. Hartman surgery was performed. Metastasis of the carcinoma to regional lymph nodes around the rectum was verified by postoperative pathology. INTERVENTIONS: The patient was treated with capecitabine, and renal function was monitored over the course of treatment by renography before, during, and after chemotherapy. OUTCOMES: We found that capecitabine caused a reversible decline of renal function. However, the value of blood urea nitrogen (BUN) and serum creatinine (Cr) remained within the normal range during chemotherapy. The patient's chemotherapy regimen was altered after her oncologists concluded that she was developing nephrotoxicity from capecitabine. She was treated with tegafur, gimeracil and oteracil potassium capsules. This patient was followed over the next 6 months, and no abnormal renal function re-occurred. LESSONS: Our experience with capecitabine shows that dosing adjustments can be warranted for chemotherapy in cancer patients, requiring monitoring of renal function. Renography may provide an early warning to protect the renal function of tumor patients when they receive chemotherapy. PMID- 28562533 TI - miRNAs as biomarkers for diagnosis of heart failure: A systematic review and meta analysis. AB - BACKGROUND: With the rapid development of molecular biology, the kind of mircoRNA (miRNA) has been introduced into emerging role both in cardiac development and pathological procedure. Thus, we conduct this meta-analysis to find out the role of circulating miRNA as a biomarker in detecting heart failure. METHODS: We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and World Health Organization clinical trials registry center to identify relevant studies up to August 2016. We performed meta-analysis in a fixed/random-effect model using Meta-disc 1.4. We used STATA 14.0 to estimate the publication bias and meta-regression. Besides, we took use of SPSS 17.0 to evaluate variance between several groups. Information on true positive, false positive, false negative, and true negative, as well as the quality of research was extracted. RESULTS: We use results from 10 articles to analyze the pooled accuracy. The overall performance of total mixed miRNAs (TmiRs) detection was: pooled sensitivity, 0.74 (95% confidence interval [CI], 0.72 to 0.75); pooled specificity, 0.69 (95%CI, 0.67 to 0.71); and area under the summary receiver operating characteristic curves value (SROC), 0.7991. The miRNA-423-5p (miR-423 5p) detection was: pooled sensitivity, 0.81 (95%CI, 0.76 to 0.85); pooled specificity, 0.67 (95%CI, 0.61 to 0.73); and SROC, 0.8600. However, taken the same patients population, we extracted the data of BNP for detecting heart failure and performed meta-analysis with acceptable SROC as 0.9291. Among the variance analysis, the diagnostic performance of miR-423-5p claimed significant advantages of other pooled results. However, the combination of miRNAs and BNP could increase the accuracy of detecting of heart failure. Unfortunately, there was no dramatic advantage of miR-423-5p compared to BNP protocol. CONCLUSION: Despite interstudy variability, the performance test of miRNA for detecting heart failure revealed that miR-423-5p demonstrated the potential to be a biomarker. However, other miRNAs were not able to provide enough evidence on promising diagnostic value for heart failure based on the current data. Moreover, the combination of miRNAs and BNP could work as a better method to detection. Unfortunately, BNP was still the most convinced biomarker for such disease. PMID- 28562535 TI - The structural changes of upper airway and newly developed sleep breathing disorders after surgical treatment in class III malocclusion subjects. AB - Bimaxillary surgery is the traditional treatment of choice for correcting class III malocclusion which is reported to cause an alteration of oropharyngeal structures and upper airway narrowing that might be a predisposing factor for obstructive sleep apnea (OSA). This study aimed to analyze sleep parameters in class III malocclusion subjects and ascertain the prevalence of snoring or OSA following bimaxillary surgery.A total of 22 patients with Le Fort I osteotomy and mandibular setback for class III malocclusion were prospectively enrolled. All patients received endoscopic examination, cephalometry, 3-dimensional computed tomography (3D-CT), and sleep study twice at 1 month before and 3 months after surgery.The patient population consisted of 5 males and 17 females with a mean body mass index of 22.5 kg/m and mean age of 22.1 years. No patients complained of sleep-related symptoms, and the results of sleep study showed normal values before surgery. Three patients (13%) were newly diagnosed with mild or moderate OSA and 6 patients (27%) showed increased loudness of snoring (over 40 dB) after bimaxillary surgery. According to cephalometric analysis and 3D-CT results, the retropalatal and retroglossal areas were significantly narrowed in class III malocclusion patients, showing snoring and sleep apnea after surgery. In addition, the total volume of the upper airway was considerably reduced following surgery in the same patients.Postoperative narrowing of the upper airway and a reduction of total upper airway volume can be induced, and causes snoring and OSA in class III malocclusion subjects following bimaxillary surgery. PMID- 28562537 TI - Recombinant human granulocyte macrophage colony stimulating factor in deep second degree burn wound healing. AB - BACKGROUND: The aim of this study was to explore the effects of recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) on deep second-degree burn wound healing. METHODS: In this study, 95 patients with a total of 190 burn wounds were treated with either rhGM-CSF or placebo, separated into 2 groups by treatment type. Wound healing rate, wound healing time, histopathological condition, and scar scale were all compared between the 2 groups. RESULTS: The healing rates in the rhGM-CSF group were remarkably higher than those in the placebo group (P < .01). The wound healing time in the rhGM-CSF group (18.8 +/- 7.6 days) was significantly shorter than that in the placebo group (25.5 +/- 4.6 days, P < .01). On the 14th day and 28th day, the average optical density of vascular endothelial factor (VEGF) in the rhGM-CSF group was larger than that in the placebo group. Meanwhile, the average optical density of fibroblast growth factor (FGF) in the rhGM-CSF group was also larger than that in the placebo group. Furthermore, the Vancouver scar scale scores of pigmentation, pliability, height, and vascularity were notable lower in the rhGM-CSF group than those in the placebo group (P < .01). CONCLUSION: The results suggest that rhGM-CSF can significantly accelerate deep second-degree burn wound healing. PMID- 28562536 TI - Acute hyperammonemic encephalopathy after fluoropyrimidine-based chemotherapy: A case series and review of the literature. AB - Acute hyperammonemic encephalopathy induced by fluoropyrimidines (FPs) is a rare complication. Its pathophysiology remains unclear, especially given the currently used regimens, including intermediate-doses of 5-fluorouracil (5-FU) or oral FP agents. We aimed to characterize the clinical manifestations in cancer patients who developed hyperammonemic encephalopathy after receiving FP-based chemotherapy.We retrospectively reviewed 1786 patients with gastrointestinal or primary-unknown cancer who received FP-based regimens between 2007 and 2012. Eleven patients (0.6%) developed acute hyperammonemic encephalopathy. The incidence according to the administered anticancer drugs were as follows: 5-FU (8 of 1176, 0.7%), S-1 (1 of 679, 0.1%), capecitabine (2 of 225, 0.9%), and tegafur uracil (UFT) (0 of 39, 0%). Ten patients (90.9%) had at least 1 aggravating factor, including infection, dehydration, constipation, renal dysfunction, and muscle loss. All the 10 patients met the definition of sarcopenia. Median time to the onset of hyperammonemic encephalopathy in the cycle was 3 days (range: 2-21). Three patients (27.3%) developed encephalopathy during the first cycle of the regimen and the remaining 8 patients during the second or more cycles. Seven patients (63.6%) had received at least 1 other FP-containing regimen before without episodes of encephalopathy.All patients recovered soon after immediate discontinuation of chemotherapy and supportive therapies, such as hydration, infusion of branched-chain amino acids, and oral lactulose intake, with a median time to recovery of 2 days (range: <1-7). Four patients (36.4%) received FP-based regimens after improvement of symptoms; 3 patients were successfully managed with dose reduction, and 1 patient, who had developed encephalopathy due to S-1 monotherapy, received modified FOLFOX-6 therapy without encephalopathy later.FP associated acute hyperammonemic encephalopathy is extremely rare, but a possible event at any time and even during the administration of oral FP agents. Particular attention is warranted when giving FP-based therapy for patients with aggravating factors, such as sarcopenia. This complication can be properly managed with early detection. PMID- 28562538 TI - Quick outpatient diagnosis in small district or general tertiary hospitals: A comparative observational study. AB - While quick diagnosis units (QDUs) have expanded as an innovative cost-effective alternative to admission for workup, studies investigating how QDUs compare are lacking. This study aimed to comparatively describe the diagnostic performance of the QDU of an urban district hospital and the QDU of its reference general hospital.This was an observational descriptive study of 336 consecutive outpatients aged >=18 years referred to the QDU of a urban district hospital in Barcelona (QDU1) during 2009 to 2016 for evaluation of suspected severe conditions whose physical performance allowed them to travel from home to hospital and back for visits and examinations. For comparison purposes, 530 randomly selected outpatients aged >=18 years referred to the QDU of the reference tertiary hospital (QDU2), also in Barcelona, were included. Clinical and QDU variables were analyzed and compared.Mean age and sex were similar (61.97 (19.93) years and 55% of females in QDU1 vs 60.0 (18.81) years and 52% of females in QDU2; P values = .14 and .10, respectively). Primary care was the main referral source in QDU1 (69%) and the emergency department in QDU2 (59%). Predominant referral reasons in QDU1 and 2 were unintentional weight loss (UWL) (21 and 16%), anemia (14 and 21%), adenopathies and/or palpable masses (10 and 11%), and gastrointestinal symptoms (10 and 19%). Time-to-diagnosis was longer in QDU1 than 2 (12 [1-28] vs 8 [4-14] days; P < .001). Malignancy was more common in QDU2 than 1 (19 vs 13%; P = .001). Patients from both groups with malignancy, aged >=65 years and requiring >2 visits to be diagnosed were in general more likely to be males, to have UWL and adenopathies and/or palpable masses but less likely anemia, to undergo more examinations except endoscopy, and to be referred onward to specialist outpatient clinics.Despite some differences, results showed that, for diagnostic purposes, the overall performance and effectiveness of QDUs of urban district and reference general hospitals in evaluating patients with potentially serious conditions were similar. This study, the first to compare the performance of 2 hospital-based QDUs, adds evidence to the opportunity of producing standardized guidelines to optimize QDUs infrastructure, functioning, and efficiency. PMID- 28562539 TI - False positive 18FDG PET-CT results due to exogenous lipoid pneumonia secondary to oily drug inhalation: A case report. AB - RATIONALE: Exogenous lipoid pneumonia is a rare condition due to abnormal presence of oily substances in the lungs. It is a rarely known cause for false positive FDG PET-CT results and can sometimes lead to invasive investigations. Searching and finding the source of the oily substance is one of the keys to the diagnosis. Inhalation of oily drugs during snorting has rarely been described. PATIENT CONCERNS: A patient with well controlled HIV infection was referred for an FDG PET-CT to assess extension of Kaposi's disease, recently removed from his right foot. The patient had no particular symptoms. DIAGNOSES: Abnormal uptake of FDG was found in a suspicious lung nodule. An experienced radiologist thought the nodule was due to lipoid pneumonia. INTERVENTIONS: Bronchoalveolar lavage fluid did not contain lipid-laden macrophages but bronchoscopy showed violet lesions resembling Kaposi's disease lesions. Lobectomy was performed after a multidisciplinary discussion. OUTCOMES: Anatomopathological analysis revealed the nodule was due to lipoid pneumonia. The patient's quality of life did not diminish after the operation and he is still in good health. The source of the oily substance causing lipoid pneumonia was found after the surgery: the patient used to snort oily drugs. LESSONS: The presence of a suspicious lung nodule possibly due to lipoid pneumonia in a patient with known Kaposi's disease was difficult to untangle and lead to invasive surgery. It is possible that if a source of exogenous lipoid pneumonia had been found beforehand, surgery could have been prevented. PMID- 28562540 TI - Excess intraoperative fluid volume administration is associated with pancreatic fistula after pancreaticoduodenectomy: A retrospective multicenter study. AB - Recent studies on perioperative fluid administration in patients undergoing pancreaticoduodenectomy (PD) have suggested that increased fluid loads are associated with worse perioperative outcomes. The purpose of this study was to investigate the relationship between intraoperative fluid (IOF) administration and postoperative pancreatic fistula (POPF), and to determine additional risk factors affecting pancreatic fistula in patients undergoing PD.From 2005 to 2014, a total of 182 patients with various periampullary diseases after PD were reviewed retrospectively at Dongguk University Ilsan Hospital, Chung-Ang University Hospital, and Dongnam Institute of Radiological and Medical Sciences. Patients were assigned to high or low IOF groups based on more or less fluid administration for supplementation of estimated blood loss and maintenance volume (12.5 mL/kg/h) than planned, respectively. The associations between IOF administration, pancreatic fistula development, and perioperative outcomes were evaluated.A total of 98 patients were assigned to the high-IOF group, and 84 to the low-IOF group. Risk factors for pancreatic fistula after univariate analysis were assignment to the high-IOF group, higher preoperative serum hemoglobin level, ampullary or bile duct cancer, pylorus preserving PD, small pancreatic duct, duct-to-mucosa pancreatojejunostomy, use of a stent, and mesh application to pancreatojejunal anastomosis. Among these, assignment to the high-IOF group (hazard ratio [HR] = 5.501, 95% CI 1.624-18.632, P = .006) and a small (<4 mm) pancreatic duct (HR = 4.129, 95% CI 1.569-14.658, P = .035) were identified as independent risk factors for the development of pancreatic fistula after multivariate analysis. However, long-term survival rate did not differ according to IOF group or duct size.Excessive IOF volume administration is associated with an increased incidence of pancreatic fistula after pancreaticoduodenectomy. PMID- 28562541 TI - Preoperative flap-site injection with ropivacaine and epinephrine in BABA robotic and endoscopic thyroidectomy safely reduces postoperative pain: A CONSORT compliant double-blinded randomized controlled study (PAIN-BREKOR trial). AB - BACKGROUND: Clinical trials on bilateral axillo-breast approach (BABA) thyroidectomy show that levobupivacaine and ropivacaine significantly reduce postoperative pain, but they focused on BABA robotic thyroidectomy only and did not identify specific sites of significant pain relief. Our objective was to assess the pain reduction at various sites and safety of ropivacaine-epinephrine flap injection in BABA thyroidectomy. METHODS: This prospective double-blinded randomized controlled trial was conducted in compliance with the revised CONSORT statement (ClinicalTrials.gov registration no. NCT02112370). Patients were randomized into the ropivacaine-epinephrine arm or control (normal saline) arm. RESULTS: From January 2014 to May 2016, 148 patients participated. The primary endpoint was site-specific pain, as measured by numeric rating scale 12 hours after surgery. The ropivacaine-epinephrine group exhibited significantly less swallowing difficulty (P = .008), anterior neck pain (P = .016), and right (P = .019) and left (P = .035) chest pain. Secondary endpoints were systolic (P = .402), diastolic (P = .827) blood pressure, and pulse rate (P = .397) after injection before incision and during surgery. The vital signs of the groups just after injection did not differ. During surgery, the ropivacaine-epinephrine patients had higher pulse rates (99 +/- 13.3 vs 88 +/- 16.1, P < .001) but within normal range. There were no adverse events such as postoperative nausea and vomiting. There was no significant difference in pain scores in either patient group between patients who underwent robotic or endoscopic interventions. CONCLUSION: BABA flap-site injection with ropivacaine and epinephrine mix before incision effectively and safely reduced postoperative pain. Future studies should focus on tailoring ropivacaine and epinephrine dosage for individuals. PMID- 28562543 TI - Clinical features and prognostic factors of adult secondary hemophagocytic syndrome: Analysis of 47 cases. AB - This study aimed to investigate the relationship between clinical features and prognosis of adult secondary hemophagocytic syndrome (HPS).A retrospective analysis was conducted on the pathogenesis, clinical manifestations, laboratory examinations, treatment options, and prognosis of 47 patients with adult secondary HPS diagnosed from January 2013 to December 2015.The average age at disease onset was (46.26 +/- 18.98) years with a male:female ratio of 1:1.14. Thirteen patients died, with the highest mortality rate in patients with HPS underlying blood system malignancy (33.33%, 2/6). The mortality rate in patients with HPS underlying autoimmune disorders was the lowest (18.75%, 3/16). The Kaplan-Meier analysis indicated that signs of hemorrhage, pulmonary and nervous system involvement, serous effusion, and decrease in the blood platelet count were associated with death. The Cox regression analysis revealed that signs of hemorrhage, pulmonary involvement, serous effusion, and nervous system involvement were independent risk factors of patient death.Adult secondary HPS has multiple etiologies and diversified clinical features. The risk of death increases in patients with signs of hemorrhage, serous effusion, pulmonary involvement, and nervous system involvement. PMID- 28562542 TI - Association between interleukin-8 levels and chronic periodontal disease: A PRISMA-compliant systematic review and meta-analysis. AB - BACKGROUND: Current publications present contradictory findings regarding interleukin-8 (IL-8) levels in patients with chronic periodontitis (CP). This systematic review compile evidences of the IL8 mRNA and protein levels in gingival tissue, saliva, and gingival crevicular fluid (GCF) investigated in patients with CP. Moreover, 2 meta-analyses were made focusing on the IL-8 levels in GCF and saliva of patients with or without CP. METHODS: Electronic searches of the PubMed, Web of Science, and Scopus databases were conducted for publications up to February 2016 that investigated the levels of IL-8 detected in individuals with CP compared with health individuals. A total of 31 publications were included in the systematic review. For meta-analyses, the strength of association was calculated by pooled odds ratios with 95% confidence intervals using RevMan 5.1 software. Heterogeneity was examined using Higgins I-squared, tau-squared, and chi tests. RESULTS: In biopsies of gingival tissue of CP patients, all studies found higher IL8 mRNA levels, and the majority of studies showed higher IL-8 protein levels in this tissue of individuals with moderate to severe CP. Four studies investigating the IL-8 levels in saliva showed inconclusive results. In spite of some studies seemed to indicate higher levels of IL-8 in GCF of CP patients, the meta-analysis results showed significantly lower IL-8 levels (pg/MUL) in GCF of CP patients in comparison with periodontally healthy subjects. CONCLUSIONS: We concluded that IL8 gene expression and IL-8 protein levels were higher in gingival tissues of CP patients when compared to periodontally health individuals. Meta-analysis of studies that measured IL-8 (pg/uL) in GCF found lower levels in CP patients. There are conflicting evidences regarding IL-8 levels in saliva. PMID- 28562544 TI - Endoscopic management of massive mercury ingestion: A case report. AB - RATIONALE: Ingestion of a massive amount of metallic mercury was thought to be harmless until the last century. After that, in a number of cases, mercury ingestion has been associated with appendicitis, impaired liver function, memory deficits, aspiration leading to pneumonitis and acute renal failure. Treatment includes gastric lavage, giving laxatives and chelating agents, but rapid removal of metallic mercury with gastroscopy has not been used. PATIENT CONCERNS: An 18 year-old man was admitted to our emergency department after drinking 1000 g of metallic mercury as a suicide attempt. DIAGNOSIS: Except from mild umbilical tenderness, he had no other symptoms. Radiography showed a metallic density in the area of the stomach. INTERVENTION: Gastroscopy was performed to remove the mercury. One large pool and several small droplets of mercury were removed from the stomach. OUTCOMES: Blood and urine mercury levels of the patient remained low during hospitalization. No symptoms of mercury intoxication developed during the follow-up period. LESSONS: Massive mercury ingestion may cause several symptoms, which can be prevented with prompt treatment. We used endoscopy to remove the mercury, which shortened the exposure time and minimized the risk of aspiration. This is the first case where endoscopy was used for the management of mercury ingestion. PMID- 28562545 TI - Sumatriptan-induced angle-closure glaucoma: A case report. AB - RATIONALE: Drug-induced bilateral angle-closure glaucoma is a rare event and should be treated correctly and promptly to prevent visual loss. PATIENT CONCERNS: We report a rare case of sumatriptan-induced bilateral angle-closure glaucoma in a young woman with migraine, and explore the possible mechanism. DIAGNOSES: We describe the clinical outcome of a patient with sumatriptan-induced bilateral angle-closure glaucoma. The patient presented with bilateral acute elevation of intraocular pressure (IOP) and myopic shift. INTERVENTIONS: The clinical symptoms and signs resolved rapidly after treatment with a topical cycloplegic agent, topical steroid, and aqueous suppressant. OUTCOMES: Based on the suspicious of malignant glaucoma, we prescribed topical phenylephrine, whose application immediately lowered the IOP. All symptoms resolved after treatment with a long-acting cycloplegic agent, topical steroid, and aqueous suppressant for 3 days. LESSONS: We presume that the mechanism underlying sumatriptan-induced bilateral angle-closure glaucoma may be correlated to the malignant glaucoma. Timely diagnosis and appropriate treatment are essential for resolving this ophthalmic emergency. PMID- 28562546 TI - Clinical outcome of laminoplasty for cervical ossification of the posterior longitudinal ligament with K-line (-) in the neck neutral position but K-line (+) in the neck extension position: A retrospective observational study. AB - Patients with cervical ossification of the posterior longitudinal ligament (OPLL) who are K-line (-) are thought to have poor clinical outcomes after laminoplasty. The aim of this study is to compare the clinical results of patients with OPLL who were K-line (-) in the neck neutral position but K-line (+) in the neck extension position (NEP group) with patients with OPLL who were K-line (+) in the neck neutral position (NNP group).Retrospectively, 42 patients who underwent cervical laminoplasty for OPLL by our surgical group during 2012 and 2013 were reviewed and were followed for at least 2 years. The patients were divided into 2 groups according to K-line status. Standing plain radiographs of the cervical spine were obtained pre- and postoperatively. Cervical spine alignment parameters included the C2-7 Cobb angle and range of motion (ROM) measured on lateral radiographs. Clinical evaluation included pre- and postoperative JOA, NDI, and VAS scores.Ten patients were classified in the NEP group, and 32 patients were classified in the NNP group. Preoperatively, the OPLL involved segments were 4.10 +/- 1.66 in the NEP group and 2.53 +/- 1.16 in the NNP group (P = .005). The canal-occupying ratios were 58.40 +/- 11.11% in the NEP group and 29.08 +/- 11.38% in the NNP group (P < .001). The mean Cobb angle of both the groups had not changed significantly at the last follow-up. The mean cervical ROM of both the groups had decreased at the last follow-up. The mean JOA score of the NEP group improved significantly from 9.70 +/- 2.16 to 12.50 +/- 2.27 (P = .014). The mean JOA score of the NNP group improved significantly from 11.91 +/- 1.69 to 14.93 +/- 1.58 (P < .001). The mean JOA recovery rate was 32.71 +/- 40.45% in the NEP group and 59.00 +/- 33.80% in the NNP group (P = .036). The NDI scores of both groups were significantly decreased, and the VAS scores of both groups had not changed significantly at the last follow-up.Laminoplasty is a relatively effective and safe procedure for patients with K-line (-) in the neck neutral position but K-line (+) in the neck extension position. Instead of anterior surgery, we recommend laminoplasty for those patients with OPLL extending to 3 or more segments. PMID- 28562547 TI - Hepatic perivascular epithelioid cell tumor treated by transarterial embolization plus radiofrequency ablation: A case report and literature review. AB - BACKGROUND: Perivascular epithelioid cell tumors (PEComas) are extremely rare mesenchymal entities with potentially malignant properties; the liver cases are not encountered frequently. Owing to themalignant potential, these tumors are treated by surgical methods to ensure total resection. In the present report, a case of liver PEComa treated by embolization combined with radiofrequency ablation (RFA) has been described. CASE SUMMARY: A 40-year-old female was admitted for the detection of a liver mass during an annual physical examination. The patient did not have any liver disease background, enhanced computed tomography (CT), and magnetic resonance revealed a huge mass in the right lobe. Pathology gave the diagnosis of PEComa, for disagreement of open surgery, a combination of transarterial embolization (TAE) and RFA were applied for treatment and the outcomes were acceptable, the patient was under follow-up to observe the long-term effect. CONCLUSION: Interventional procedures such as TAE and RFA are feasible and effective for such lesions and may serve as an alternate when resection is not indicated. Prospective studies are warranted to verify the long-term outcomes. PMID- 28562548 TI - Pedicle screw versus hybrid posterior instrumentation for dystrophic neurofibromatosis scoliosis. AB - Surgical management of severe rigid dystrophic neurofibromatosis (NF) scoliosis is technically demanding and produces varying results. In the current study, we reviewed 9 patients who were treated with combined anterior and posterior fusion using different types of instrumentation (i.e., pedicle screw, hybrid, and all hook constructs) at our institute.Between September 2001 and July 2010 at our institute, 9 patients received anterior release/fusion and posterior fusion with different types of instrumentation, including a pedicle screw construct (n = 5), a hybrid construct (n = 3), and an all-hook construct (n = 1). We compared the pedicle screw group with the hybrid group to analyze differences in preoperative curve angle, immediate postoperative curve reduction, and latest follow-up curve angle.The mean follow-up period was 9.5 +/- 2.9 years. The average age at surgery was 10.3 +/- 3.9 years. The average preoperative scoliosis curve was 61.3 +/- 13.8 degrees , and the average preoperative kyphosis curve was 39.8 +/- 19.7 degrees . The average postoperative scoliosis and kyphosis curves were 29.7 +/- 10.7 degrees and 21.0 +/- 13.5 degrees , respectively. The most recent follow-up scoliosis and kyphosis curves were 43.4 +/- 17.3 degrees and 29.4 +/- 18.9 degrees , respectively. There was no significant difference in the correction angle (either coronal or sagittal), and there was no significant difference in the loss of sagittal correction between the pedicle screw construct group and the hybrid construct group. However, the patients who received pedicle screw constructs had significantly less loss of coronal correction (P < .05). Two patients with posterior instrumentation, one with an all-hook construct and the other with a hybrid construct, required surgical revision because of progression of deformity.It is difficult to intraoperatively correct dystrophic deformity and to maintain this correction after surgery. Combined anterior release/fusion and posterior fusion using either a pedicle screw construct or a hybrid construct provide similar curve corrections both sagittally and coronally. After long-term follow-up, sagittal correction was maintained with both constructs. However, patients treated with posterior instrumentation using pedicle screw constructs had significantly less loss of coronal correction. PMID- 28562549 TI - Identification of groups with poor cost-effectiveness of peginterferon plus ribavirin for naive hepatitis C patients with a real-world cohort and database. AB - BACKGROUND: For decades, peginterferon and ribavirin (PegIFN/RBV) have been the standard-of-care for chronic hepatitis C virus (CHC) infection. However, the actual cost-effectiveness of this therapy remains unclear. We purposed to explore the real-world cost effectiveness for subgroups of treatment-naive CHC patients with PegIFN/RBV therapy in a large real-world cohort using a whole population database. METHODS: A total of 1809 treatment-naive chronic hepatitis C virus (HCV) patients (829 HCV genotype 1 [G1] and 980 HCV G2) treated with PegIFN/RBV therapies were linked to the National Health Insurance Research Database, covering the entire population of Taiwan from 1998 to 2013 to collect the total medical-care expenses of outpatient (antiviral agents, nonantiviral agents, laboratory, and consultation costs) and inpatient (medication, logistic, laboratory, and intervention costs) visits. The costs per treatment and the cost per sustained virological response (SVR) achieved were calculated. RESULTS: The average medical-care cost was USD $4823 (+/-$2984) per treatment and $6105 (+/ $3778) per SVR achieved. With SVR rates of 68.6% and 87.8%, the cost/SVR was significantly higher in G1 than those in G2 patients, respectively ($8285 vs $4663, P < .001). Treatment-naive G1 patients of old ages, those with advanced fibrosis, high viral loads, or interleukin-28B unfavorable genotypes, or those without a rapid virological response (RVR: undetectable HCV RNA at week 4), or those with complete early virological response (cEVR: undetectable HCV RNA at week 12). Treatment-naive G2 patients with high viral loads or without RVR or cEVR incurred significantly higher costs per SVR than their counterparts. The cost/SVR was extremely high among patients without RVR and in patients without cEVR. CONCLUSION: We investigated the real-world cost effectiveness data for different subgroups of treatment-naive HCV patients with PegIFN/RBV therapies, which could provide useful, informative evidence for making decisions regarding future therapeutic strategies comprising costly direct-acting antivirals. PMID- 28562550 TI - Tricyclic antidepressants for preventing migraine in adults. AB - BACKGROUND: Migraine, ranked as the 7th-highest specific cause of disability worldwide, has caused an enormous burden on the economy and society. Tricyclic antidepressant (TCA) is one of the most commonly drugs for migraine prevention. However, evidence about the efficacy and tolerability of TCAs in the prophylaxis of migraine in adults is somewhat confusing. METHODS: A computerized literature search of the PubMed, Embase, Cochrane, and Web of Science databases from inception to July 2016 was conducted. We reviewed all randomized controlled trials that assigned adults with a clinical diagnosis of migraine to TCAs or other treatments (placebo or other antidepressants). Reduction in migraine frequency or index and response rates to treatment were defined as the efficacy outcomes. Rates of dropout due to adverse effects were defined as the tolerability outcomes. RESULTS: In total 12 trials consisting of 1006 participants were identified: 9 trials compared TCAs with placebo, and the other 3 compared amitriptyline with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). A significant advantage of TCAs compared with placebo in the prevention of migraine in adults was observed (standardized mean difference [SMD] = -.75; 95% confidence interval [CI] = -1.05 to -.46; P < .00001). Participants receiving TCAs were more likely to experience an >=50% reduction in their headache burden than those receiving placebo (risk ratio [RR] =1.40; 95% CI = 0.89-2.20; P = .14). In addition, the efficacy between amitriptyline and SSRIs or SNRIs did not differ for migraine prevention in adults (SMD = -.01; 95% CI = -0.31 to 0.28; P = .94) based on the available limited trials. However, TCAs were less well tolerated than placebo (RR = 1.73; 95% CI = 1.00-2.99; P = .05) and SSRI or SNRI (RR = 2.85; 95% CI = 0.97-8.41; P = .06) on account of adverse events. CONCLUSIONS: This research reveals that TCAs were more effective than placebo, but no more than SSRI or SNRI in ameliorating the headache burden in adults with migraine. However, TCAs appeared to be less tolerated than placebo and SSRIs or SNRIs for some side effects. PMID- 28562551 TI - Final diagnoses and probability of new reason-for-encounter at an urban clinic in Japan: A 4-year observational study. AB - Past clinical data are not currently used to calculate pretest probabilities, as they have not been put into a database in clinical settings. This observational study was designed to determine the initial reasons for utilizing home visits or visits to an outpatient urban clinic in Japan.All family medical clinic outpatients and patients visited by the clinic (total = 11,688) over 1460 days were enrolled.We used a Bayes theorem-based clinical decision support system to analyze codes for initial reason-for-encounter (examination and final diagnosis: pretest probability) and final diagnosis of patients with fever (conditional pretest probability).Total number of reasons-for-encounter: 96,653 (an average of 1.2 reasons per visit). Final diagnosis: 62,273 cases (an average of 0.75 cases per visit). The most common reasons for initial examination were immunizations, physical examinations, and upper respiratory conditions. Regarding the final diagnosis, the combination of physical examinations and acute upper respiratory infections comprised 73.4% of cases. In cases where fever developed, the bulk of the final diagnoses were infectious diseases such as influenza, strep throat, and gastroenteritis of presumed infectious origin. For the elderly, fever often occurred with other health issues such as pneumonia, dementia, constipation, and sleep disturbances, though the cause of the fever remained undetermined in 40% of the cases.The pretest probability changed significantly based on the reason or the combination of reasons for which patients requested a medical examination. Using accumulated data from past diagnoses to modify subsequent subjective diagnoses, individual diagnoses can be improved. PMID- 28562552 TI - Plasma rich in growth factors for the treatment of rapidly progressing refractory corneal melting due to erlotinib in nonsmall cell lung cancer. AB - RATIONALE: Erlotinib, an antineoplastic agent, is indicated for the treatment of patients with advanced nonsmall cell lung cancer. Most common adverse events are manageable, although more severe ones require dose reduction or discontinuation of erlotinib treatment. PATIENT CONCERNS: We present a case of severe corneal ulcer treated with autologous plasma rich in growth factors. DIAGNOSES: A 76-year old woman with stage IVB (cT2a N0 M1c) lung cancer under erlotinib treatment presented with rapidly progressing corneal ulcer. Evolution was torpid and refractory to conventional treatment. INTERVENTIONS: Surgical options were dismissed because of the poor performance status of the patient. Despite temporary discontinuation of erlotinib treatment, the corneal ulcer continued to worsen with peripheral corneal neovascularization, stromal thinning, corneal edema, and profuse inflammation of the ocular surface. OUTCOMES: Treatment with autologous plasma rich in growth factors prevented an imminent corneal perforation and improved the corneal ulcer for over a year of follow-up. LESSONS: Considering the poor results of conventional treatment, both medical and surgical, management of the inflammation of the ocular surface together with the stimulation of the healing processes through regenerative therapy such as PRGF, can be an option worth considering in these cases. PMID- 28562553 TI - Efficiency and safety of tranexamic acid in reducing blood loss in total shoulder arthroplasty: A systematic review and meta-analysis. AB - OBJECTIVE: This meta-analysis aimed to evaluate the efficiency and safety of tranexamic acid for reducing blood loss and transfusion requirements in patients undergoing total shoulder arthroplasty. METHODS: A systematic search was performed in Embase (1980-2017.04, embase.com), Medline (1966-2017.04, medline.com), PubMed (1966-2017.04, pubmed.com), ScienceDirect (1985-2017.04, sciencedirect.com), and Web of Science (1950-2017.04, webofknowledge.com). Study which assessed the efficiency and safety of tranexamic acid in total shoulder arthroplasty was selected. Meta-analysis was performed using Stata 11.0 software. RESULTS: In all, 484 patients from 2 randomized controlled trials (RCTs) and 2 non-RCTs were subjected to meta-analysis. The present meta-analysis demonstrated that there was less total blood loss (mean difference [MD] -172.16, 95% confidence interval [CI] -35.46 to -308.87, P = .01, d = 0.33) and transfusion rate (odds ratio 0.34, 95% CI 0.13 to 0.91, P = .03, d = 0.29) in tranexamic acid groups compared with the control groups. There were no significant differences in duration of surgery (MD 0.02, 95% CI -0.12 to 0.22, P = .89, d = 0.19), length of stay (MD -0.06, 95% CI -0.26 to 0.14, P = .56, d = 0.20), or incidence of adverse effects such as deep venous thrombosis (odds ratio 1.15, 95% CI 0.33 to 4.00, P = .83, d = 0.53). CONCLUSION: Clinical application of tranexamic acid seemed to result in significant reductions in total blood loss, hemoglobin decline and transfusion requirements following total shoulder arthroplasty. Moreover, no increased risk of the thrombotic events was identified. Due to the limited quality of the evidence currently available, higher quality RCTs are required. PMID- 28562554 TI - Effectiveness of entecavir or telbivudine therapy in patients with chronic hepatitis B virus infection pre-treated with interferon compared with de novo therapy with entecavir and telbivudine. AB - Little is known about the optimal treatment following the initial failure of interferon therapy and the potential different efficacy with de novo therapy with entecavir (ETV) or telbivudine (LDT) and following the interferon therapy failure.ETV or LDT therapy following the interferon therapy failure was compared with that of de novo therapy with ETV or LDT in patients with chronic hepatitis B virus (HBV) infection. Treatment parameters included virological response, hepatitis B e antigen (HBeAg) seroconversion, and alanine aminotransferase (ALT) normalization.Of 180 patients studied, 56 received de novo telbivudine monotherapy (LDT group); 45 received entecavir monotherapy (ETV group); 40 received LDT following interferon (interferon-telbivudine [IFN-LDT] group); and 39 received ETV following interferon (interferon-entecavir [IFN-ETV] group). At week 52, virological response occurred in significantly more patients in the IFN ETV group than the ETV group (87.2% vs 57.8%, P = .003). At week 104, HBeAg seroconversion occurred in significantly more patients in the IFN-ETV group than the ETV group (44.4% vs 22.2%, P = .03). At week 52, virological response was achieved by significantly more patients in the IFN-LDT group than the LDT group (85.0% vs 64.3%, P = .02).This study showed that switch to rescue therapy with ETV or LDT therapy after failure of interferon therapy resulted in more rapid virologic response than with de novo treatment with either ETV or LDT; rescue therapy with ETV resulted in a greater HBeAg seroconversion rate. PMID- 28562555 TI - Impact of type 2 diabetes mellitus on the long-term mortality in patients who were treated by coronary artery bypass surgery: A systematic review and meta analysis. AB - BACKGROUND: Recent scientific reports have mainly focused on the comparison between coronary artery bypass surgery (CABG) and percutaneous coronary intervention. However, the impact of type 2 diabetes mellitus (T2DM) on mortality in patients who were treated by CABG was often ignored. Therefore, we aimed to compare the long-term mortality following CABG in patients with and without T2DM. METHODS: Studies comparing the long-term adverse outcomes following CABG in patients with and without T2DM were searched from electronic databases. Total number of deaths (primary outcome) and events of myocardial infarction (MI), major adverse cerebrovascular and cardiovascular events (MACCEs), stroke, and repeated revascularization (secondary outcomes) were carefully extracted. An analysis was carried out whereby odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the RevMan 5.3 software. RESULTS: Eleven studies with a total number of 12,965 patients were included. Current results showed that mortality was significantly higher in patients with T2DM with OR: 1.54, 95% CI: 1.37 to 1.72, P < .00001; OR: 1.53, 95% CI: 1.36 to 1.72, P < .00001; and OR: 1.53, 95% CI: 1.26 to 1.87, P < .0001 at 1 to 15, 5 to 15, and 7 to 15 years, respectively. However, MI, repeated revascularization, MACCEs, and stroke were not significantly different with OR: 1.15, 95% CI: 0.81 to 1.64, P = .44; OR: 1.09, 95% CI: 0.88 to 1.36, P = .43; OR: 1.11, 95% CI: 0.83 to 1.48, P = .48; and OR: 1.69, 95% CI: 0.93 to 3.07, P = .08, respectively. CONCLUSION: Following CABG, a significantly higher rate of mortality was continually observed in patients with T2DM compared to patients without T2DM showing that the former apparently has a high impact on the long-term mortality. However, even if T2DM is an independent risk factor for mortality, it should not be ignored that CABG remains the best revascularization strategy in these patients. PMID- 28562556 TI - Low utility of blood culture in pediatric community-acquired pneumonia: An observational study on 2705 patients admitted to the emergency department. AB - To investigate the utility of blood cultures performed on previously healthy children and adolescents with community-acquired pneumonia (CAP) at a tertiary care hospital emergency department (ED).We reviewed 3235 patients with CAP aged 6 months to 18 years who underwent blood cultures at the ED from 2009 through 2016. CAP was defined according to the International Classification of Diseases, 10th Revision codes for pneumonia and the requirement of antibiotic treatment plus any of the following: radiologically confirmed, hospitalized, or moderate to severe disease. Blood cultures were retrospectively justified by the Infectious Diseases Society of America guidelines. We measured the yield (true positive results of blood culture) and impact (blood culture-directed change in the antibiotic regimen).Of 2705 previously healthy patients with CAP, 833 (30.8%; 95% confidence interval [CI]: 29.1-32.6) underwent blood cultures justified by the current guidelines. We found 12 patients (0.4%; 95% CI: 0.2-0.8) having positive results of blood culture, 7 of whom underwent justified blood cultures. Of these 7 patients, 3 (0.11%; 95% CI: 0.02-0.3) had the yield, Streptococcus pneumoniae. No impact was made in these 3 patients with S pneumoniae.We confirmed a low utility of blood cultures in previously healthy children and adolescents with CAP who were admitted to the ED. This finding suggests the need to refine the current guidelines for obtaining blood cultures in the ED for pediatric CAP. PMID- 28562557 TI - Correlation between respiratory function and spine and thorax deformity in children with mild scoliosis. AB - Idiopathic scoliosis (IS) is the most common 3-dimensional deformation abnormality of the spine with direct effects on the thoracic cage and can potentially affect respiratory function.The purpose of the present study was to recognize whether the 3-dimensional displacement of the spine and trunk as a consequence of IS directly influences and diminishes respiratory function in children with mild IS.The study involved 68 children aged 10 to 12 years with mild thoracic or thoracolumbar IS who were the outpatients of the local Center for Corrective Gymnastics. The study consisted of 2 interrelated parts: the body posture examination using a Moire topography and the spirometric examination including measurements of basic ventilatory parameters (vital capacity [VC], forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1], and FEV1/FVC).For the majority of subjects, the results of VC were within the normal range and did not confirm the existence of features characteristic for ventilatory functional restriction. The VC does not depend on the curvature angle value or the degree of rotation of vertebral bodies. It was observed that VC in children with mild IS of 20 to 30 degree depended on thoracic kyphosis, that is, length, depth, and the thoracic kyphosis length/depth indicator.The results of performed study showed that in children with mild IS the lung volumes are reduced not only by an increased angle of the lateral curvature but also by the degree of loss of normal thoracic kyphosis. The regular respiratory function testing and back-shape analysis are advisable in children with thoracic and thoracolumbar mild IS. PMID- 28562558 TI - Clinicopathological parameters associated with histological background and recurrence after surgical intervention of vocal cord leukoplakia. AB - Histological examination of biopsy shows usefulness in the diagnosis of vocal cord leukoplakia; however, in considerable amount of cases, the examination cannot provide definitive diagnosis of malignancy from benign conditions such as hyperplasia and dysplasia. The present work therefore was aimed to identify clinicopathological factors and molecular markers predictive of recurrence and malignant transformation of vocal cord leukoplakia.Clinical data of 555 cases of vocal cord leukoplakia enrolled from July 1999 to June 2014 were analyzed. The cohort consisted of keratosis (n = 137), hyperplasia (n = 139), dysplasia (n = 177), and primary (n = 10) and invasive (n = 46) carcinoma. Correlations between patients' backgrounds, clinicopathological factors, molecular markers (p53, p16, Ki67, cytokeratin, and proliferating cell nuclear antigen), and histology backgrounds were examined using by Pearson Chi-squared or Fisher exact test. Reflux symptom index (RSI) and reflux finding score (RFS) before and after treatment were compared using Wilcoxon signed-rank test. Risk factors for disease recurrence were identified using Cox proportional hazards models of multivariate analysis. Time to recurrence was analyzed using log-rank test of Kaplan-Meier method.In the present cohort, alcohol drinking was found associated with GRBAS grade (P = .0258) and the site (P = .0298) of leukoplakia. For the different disease types, chief complaint (P = .0179), GRBAS grade (P = .0101), mucosal wave (P < .0001), and molecular markers p53 (P < .0001) and Ki67 (P < .0001) were identified as correlates. RSI and RFS were significantly lowered by surgical intervention. A single side of leukoplakia was predictive of a lower risk of recurrence (odds ratio, 0.378; 95% confidence interval, 0.197-0.723; P = .0033). Absence of mucosal wave was associated with a shorter time-to-recurrence (P = .0357).The present work identified clinicopathological factors and molecular markers associated with the different histology of vocal cord leukoplakia, and also the prognostic factor for the low risk of recurrence after surgery. PMID- 28562559 TI - Differences between healthy adults and patients with type 2 diabetes mellitus in reactivity of toe microcirculation by ultrasound combined with a warm bath test. AB - The aim of this study was to explore the feasibility and clinical value of ultrasound combined with a warm bath test in assessing the differences in reactivity of toe microcirculation between healthy adults and patients with type 2 diabetes mellitus (T2DM).A total of 56 T2DM patients were recruited as case group, whereas 50 healthy volunteers were enrolled as control group.Fasting blood glucose, glycated hemoglobin, total cholesterol, triglyceride, low-density lipoprotein cholesterol in T2DM group were significantly higher than in control group. Under stationary condition, peak systolic velocity (PSV), end-diastolic velocity (EDV), and mean velocity (MV) were lower, but pulsatility index (PI) and resistance index (RI) were higher in patients with T2DM than in controls both in dorsalis pedis artery (DPA) and plantar digital artery (PDA). On response to the warm test, PSV, EDV, and MV increased and PI and RI decreased both in DPA and PDA in these 2 groups. Moreover, the change rate in PSV, EDV, MV, PI, and RI of PDA was significantly lower in T2DM group than in control group.Color Doppler combined with a warm bath test may be used as a new method in evaluating the differences in reactivity of distal limb microvascular between healthy adults and patients with T2DM. PMID- 28562560 TI - Triglyceride glucose-body mass index is effective in identifying nonalcoholic fatty liver disease in nonobese subjects. AB - Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition that is highly correlated with obesity; however, it is not uncommon among nonobese individuals. Triglyceride (TG) and glucose index combined with body mass index (TyG-BMI) has been proposed as a favorable marker of insulin resistance. We sought to investigate the effectiveness of TyG-BMI in identifying NAFLD in nonobese subjects.We conducted a cross-sectional study in a nonobese (BMI <25.0 kg/m) Chinese population (N = 6809) of adults who underwent health examinations, including abdominal ultrasonography.The prevalence of ultrasonography-detected NAFLD was 23.9% in nonobese subjects. After adjusting for potential confounders, every 1-standard deviation increase in TyG-BMI had an odds ratio (OR) of 3.4 [95% confidence interval (95% CI), 3.0-3.9] for NAFLD. Compared with the lowest quartile of TyG-BMI, multivariable-adjusted ORs were 2.4 (1.6-3.6), 6.4 (4.2 9.7), and 15.3 (9.8-23.9) for those in the second, third, and fourth quartile, respectively. According to the receiver operating characteristic curve analysis, TyG-BMI was effective in diagnosing patients with NAFLD with an area under the curve of 0.835 (95% CI, 0.824-0.845). In comparison, TyG-BMI was superior to its components, including TyG, BMI, TG, and fasting plasma glucose, for identifying nonobese subjects at risk for NAFLD.In this study, the prevalence of NAFLD was over one-fifth in the nonobese population. TyG-BMI was an effective marker to detect NAFLD in nonobese subjects. PMID- 28562561 TI - Comparison of mid-term efficacy of spastic flatfoot in ambulant children with cerebral palsy by 2 different methods. AB - To compare the treatment efficacy of spastic flatfoot surgery by 2 different surgical methods: nonfusion subtalar arthroereisis using subtalar joint stabilizer (SJS) and Dennyson-Fulford subtalar arthrodesis (D-FSA).A total of 26 cases of ambulant children with cerebral palsy diagnosed as spastic flatfoot were surgically treated from January 2011 to December 2014. Preoperative and postoperative American Orthopedic Foot and Ankle Society-Ankle and Hindfoot (AOFAS-AH) scores, anteroposterior-talocalcaneal angles (ATAs), and lateral talar first metatarsal angles (Meary angles) of the affected foot were recorded.Among 12 children in the SJS group, the AOFAS-AH scores were median preoperative score of 61 (58-64) versus median postoperative score of 83 (75-92), with significant difference (P < .05). Of the 20 feet treated, only 1 foot developed occasional pain. Postoperative ATA was decreased from preoperative 35 degrees (20 degrees 50 degrees ) to 19 degrees (12 degrees -25 degrees ); lateral X-ray films showed that the Meary angle was decreased from preoperative 20 degrees (15 degrees -40 degrees ) to postoperative 0 degrees (0 degrees -3 degrees ). The differences in both findings were statistically significant (P < .05). Fourteen children (22 treated feet) formed the D-FSA group; all demonstrated fusion of the talocalcaneal joint; AOFAS-AH scores were median preoperative score of 61 (58-64) versus median postoperative score of 83 (75-92), with significant difference (P < .05). Only 1 foot had occasional pain. Postoperative ATA was decreased from preoperative 35 degrees (20 degrees -45 degrees ) to 16 degrees (12 degrees -25 degrees ); lateral X-ray films showed that the Meary angle was decreased from preoperative 19 degrees (10 degrees -40 degrees ) to postoperative 2 degrees (0 degrees -5 degrees ); the differences in both findings were statistically significant (P < .05).Both nonfusion subtalar arthroereisis using SJS and D-FSA were effective for the surgical treatment of spastic flatfoot, with similar clinical outcomes. PMID- 28562562 TI - The photoplethysmographic amplitude to pulse pressure ratio can track sudden changes in vascular compliance and resistance during liver graft reperfusion: A beat-to-beat analysis. AB - During liver transplantation, the thermodilution cardiac output (CO) technique cannot respond to sudden hemodynamic changes associated with postreperfusion syndrome. Photoplethysmography (PPG) can reflect changes in intravascular volume and thus can be used to assess vasomotor tone and arterial stiffness on the pressure-volume relation. We investigated whether a beat-to-beat analysis of the arterial pressure-PPG relationship can estimate dynamic changes in vascular characteristics immediately after liver graft reperfusion.In 10 recipients, arterial blood pressure and PPG waveforms recorded simultaneously were analyzed from the beginning of fall to nadir in systolic blood pressure immediately after reperfusion. On a beat-to-beat basis, we compared the ratio of the amplitude of PPG to arterial pulse pressure (PPGamp/PP, as relative vascular compliance) to total peripheral resistance (TPR) and Windkessel compliance (Cwk) obtained from the Modelflow CO algorithm.Following graft reperfusion, PPGamp/PP and Cwk increased (median 41.5%; P = .005 and 42.0%; P < .001, respectively), whereas TPR decreased (median -46.4%; P < .001). Beat-to-beat PPGamp/PP was negatively correlated with TPR (median r = -0.80 [95% CI -0.85 to -0.76] on linear regression and r = 0.84 [95% CI 0.73-0.92] on curvilinear regression), and was positively correlated with Cwk (median r = 0.86 [95% CI 0.81-0.91] on linear regression and r = 0.88 [95% CI 0.75-0.96] on curvilinear regression).Our results suggest that relative compliance, obtained from beat-to-beat analysis of PPG and arterial pressure waveforms, can track abrupt changes in vascular characteristics associated with postreperfusion syndrome. This simple index would contribute to differential diagnoses of sudden hypotension. PMID- 28562563 TI - Surgery of the primary tumor improves survival in women with stage IV breast cancer in Southwest China: A retrospective analysis. AB - The International Consensus Guidelines for advanced breast cancer (ABC) considers that the surgery of the primary tumor for stage IV breast cancer patients does not usually improve the survival. However, studies have showed that resection of the primary tumor may benefit these patients. The correlation between surgery and survival remains unclear.The impact of surgery and other clinical factors on overall survival (OS) of stage IV patients is investigated in West China Hospital. Female patients diagnosed with stage IV breast cancer between 1999 and 2014 were included (N = 223). Univariate and multivariate analysis assessed the association between surgery and OS.One hundred seventy-seven (79.4%) underwent surgery for the primary tumor, and 46 (20.6%) had no surgery. No significant differences were observed in age at diagnosis, T-stage, N-stage, histological grade, molecular subtype, hormone receptor (HR), and number of metastatic sites between 2 groups. Patients in the surgery group had dramatically longer OS (45.6 vs 21.3 months, log-rank P < .001). In univariate analysis, survival was associated with surgical treatment, residence, tumor size, lymph node, HR status, hormonal therapy, and radiotherapy. In multivariate analysis, surgery was an independent prognostic factor for OS [hazard ratio (HR), 0.569; 95% confidence interval (CI) 0.329-0.984, P = .044]. Additional independent prognostic factors were hormonal therapy (HR, 0.490; 95% CI 0.300-0.800) and radiotherapy (HR, 0.490; 95% CI 0.293-0.819). In addition, a favorable impact of surgery was observed by subgroup analysis.Our study showed that surgery of the primary breast tumor has a positive impact on OS in with stage IV breast cancer patients. PMID- 28562564 TI - Daily sedentary time and its association with risk for colorectal cancer in adults: A dose-response meta-analysis of prospective cohort studies. AB - Sedentary behavior is emerging as an independent risk factor for health. However, previous studies have indicated that sedentary behaviors are associated with the colorectal cancer risk, but presented controversial results.Studies in PubMed and EMBASE were searched update to February 2017 to identify and quantify the potential dose-response association between daily sedentary time and colorectal cancer.Twenty-eight eligible studies involving a total of 47,84,339 participants with 46,071 incident cases were included in this meta-analysis. Our results showed statistically significant association between prolong television viewing time and colorectal cancer (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.09-1.24, P < .001). Additionally, we obtained the best fit at an inflection point of 2 hours per day in piecewise regression analysis, the summary relative risk (RR) of colorectal cancer for an increase of 2 hours per day television viewing was 1.07 (95% CI 1.05-1.10, P < .001). Furthermore, prolong occupational sitting time was correlated with a significantly higher risk of colorectal cancer (OR 1.15, 95% CI 1.08-1.22, P < .001), increasing 2 hours per day of occupational sitting time per day was associated with a 4% incremental in the risk of colorectal cancer (RR 1.04, 95% CI 1.01-1.08). Additionally, prolong total sitting time was associated with a significantly higher risk of colorectal cancer (OR 1.06, 95% CI 1.03-1.09, P < .001). Increasing 2 hours of total sitting time per day was associated with a 2% incremental in the risk of colorectal cancer (RR 1.02, 95% CI 1.01-1.06). Subgroup meta-analyses in study design, study quality, number of participants, and number of cases showed consistent with the primary findings.Prolonged television viewing, occupational sitting time, and total sitting time are associated with increased risks of colorectal cancer. PMID- 28562565 TI - Perivascular epithelial cell tumor (PEComa) of the pancreas: A case report and review of literature. AB - RATIONALE: Perivascular epithelial cell tumors (PEComas) of the pancreas are rare mesenchymal tumors and, to our knowledge, only 20 cases have been reported to date. PATIENT CONCERNS: We report a 43-year-old female who presented with upper abdominal pain for 1 year. She underwent an exploratory laparotomy at a local hospital, which failed to resect the tumor. Five months later, she came to the Chinese National Cancer Center for surgery. Preoperative imaging revealed an 11.5 cm-sized mass located in the head of the pancreas. At the microscopic level, the tumor was composed of epithelioid and spindle cells possessing clear to focally granular eosinophilic cytoplasm, which grew in a nested and alveolar pattern around blood vessels. The tumor cells showed immunoreactivity for human melanoma black 45 (HMB-45), but did not express epithelial or endocrine markers. DIAGNOSES: Pancreatic PEComa. INTERVENTIONS: Pancreaticoduodenectomy, partial hepatectomy, and vascular replacement were performed. After the surgery, the patient received 4 cycles of chemotherapy. OUTCOMES: The patient is free of recurrence and metastasis 1.5 years after surgical resection. LESSONS: PEComa should be recognized as a preoperative differential diagnosis of pancreatic tumors. For treatment, removal of the tumor should be attempted, and in the case of tumors with malignant tendencies, the addition of chemotherapy should be considered. PMID- 28562566 TI - Prognostic role of the lymphocyte-to-monocyte ratio in colorectal cancer: An up to-date meta-analysis. AB - BACKGROUND: Although previous meta-analyses have proved that lymphocyte-to monocyte ratio (LMR) is a prognostic factor in solid cancers, its prognostic role in colorectal cancer (CRC) remains controversial. We, therefore, conducted this up-to-date meta-analysis to evaluate the prognostic role of the LMR in CRC. METHODS: A systematic search was performed in PubMed and Embase for relevant studies in November 2016. Article assessing the prognostic role of LMR in CRC was enrolled in this meta-analysis. Data and characteristics of each study were extracted. A meta-analysis was performed to generate pooled hazard ratio (HR) and 95% confidence intervals (95% CIs) for overall survival (OS) and disease-free survival. Begg funnel plot was used to evaluate publication bias. RESULTS: Eleven studies published between 2014 and 2016 with a total of 9045 patients were enrolled in this meta-analysis. Our findings indicated that a low LMR predicted a worse OS (HR 1.57, 95% CI 1.30-1.90, P < .001) and disease-free survival. (HR 1.25, 95% CI 1.13-1.39, P < .001) for patients with CRC. Subgroup analyses according to stage (I-III and IV) and LMR cut-off value (<3.00 and >=3.00) showed a significant prognostic value of LMR on OS. Begg funnel plot showed that publication bias existed in this meta-analysis. CONCLUSIONS: This up-to-date meta analysis shows that a low LMR is associated with poor survival in patients with CRC, although the publication bias is existed. Large-sample multicenter prospective cohort is needed to assess the role of the LMR in CRC patients. PMID- 28562568 TI - Rapid Improvement of thyroid storm-related hemodynamic collapse by aggressive anti-thyroid therapy including steroid pulse: A case report. AB - RATIONALE: Heart failure is relatively common in patients with hyperthyroidism, but thyrotoxic cardiomyopathy with poor left ventricular (LV) systolic function is very rare. PATIENT CONCERNS: We experienced a representative case of a patient who presented with severe LV dysfunction related to thyroid storm and needed extracorporeal membrane oxygenation (ECMO) temporally. DIAGNOSIS: Thyrotoxic cardiomyopathy. INTERVENTIONS AND OUTCOMES: Aggressive antithyroid therapy, including steroid pulse to hyperthyroidism, leads to the dramatic improvement of cardiac function and she was successfully weaned from ECMO. LESSONS: The most outstanding feature of the current case was the rapid decrease of cardiac injury and improvement of cardiac function by strengthening antithyroid therapy, including steroid pulse, without thyroid hormone level normalization. In thyroid storm, various systemic inflammatory reactions have different time courses and among them, the cardiac phenotype emerges in most striking and critical ways. PMID- 28562567 TI - Successful treatment of refractory cancer pain with morphine and ropivacaine: A case report. AB - RATIONALE: Pain is one of the most common and distressing symptoms experienced by cancer patients. Cancer pain is a complex phenomenon with physical, psychological, social, and cognitive domains. Although opioids remain a cornerstone of cancer pain management, they are not effective in all patients. This case highlights the successful treatment of an opioid-refractory severe cancer pain crisis with ropivacaine infusion and subsequent rapid tapering of opioid dose. PATIENT CONCERNS: This report illustrates the use of ropivacaine for cancer pain. A 62-year-old man with metastatic lung cancer was admitted to the hospital with uncontrolled chest-back and abdominal pain. DIAGNOSES: The patient was diagnosed as refractory cancer pain. INTERVENTIONS: Successful treatment with morphine and ropivacaine was performed to obtain longer opioid refractory severe cancer pain. OUTCOMES: At 1, 3, and 6 months postoperative review, 70-75% relief of pain was achieved with overall activity was improved. The analgesic effect was stable during the 6-month follow-up period. No complications were reported during the follow-up period. LESSONS: Our report demonstrates that ropivacaine is successful treatment for cancer pain in this case. It will supply us a novel navigation in cancer pain treatments. Meanwhile, this finding still needs additional study for confirmation. PMID- 28562569 TI - Traumatic open depressed cranial fracture causing occlusion of posterior superior sagittal sinus: Case report. AB - RATIONALE: The superior sagittal sinus (SSS) is the major dural sinuses that receive a considerable amount of venous drainage. Interruption of its posterior third has been suggested to cause intracranial hypertension and lead to potentially fatal consequences. PATIENT CONCERNS: We presented a 22-year-old man with a severe headache and scalp bleeding after a head chop wound. Physical examination identified a 20-cm straight laceration in his parietooccipital scalp. Computed tomography (CT) demonstrated a depressed cranial fracture (DCF) in the left parietooccipital bone, a fracture line across the midline to the right side, and penetrations of bone fragments into the brain parenchyma. DIAGNOSES: Traumatic open DCF in left parietooccipital bone. INTERVENTIONS: An emergent left parietooccipital craniotomy, followed by cranioplasty to restore the depressed bone flap, was delivered to the patient. Postoperative CT confirmed successful elevation of the DCF and removal of intracerebral bone fragments. However, postoperative CT angiography (CTA) demonstrated an absence of venous flow distal to the fracture, suggesting occlusion of the posterior third of SSS. MRV revealed a persistent absence of venous flow in the posterior third of SSS with dilated cortical venous drainage. Anticoagulation treatment was initiated 3 days after surgery, and follow-up CTA and digital subtraction angiography showed gradually improved patency in the anterior and middle two-thirds of SSS. OUTCOMES: Despite occlusion of the posterior third of SSS, patient's symptoms resolved after the operation and he was discharged without complications. LESSONS: The favorable clinical outcome after complete occlusion of the posterior third of the SSS has rarely been reported and it might be explained by our timely surgical intervention and development of compensatory cerebral collateral circulation. PMID- 28562570 TI - Adjacent segmental degeneration following Wallis interspinous stabilization implantation: Biomechanical explanations and the value of magnetic resonance imaging. AB - Adjacent segmental degeneration (ASD) is a major issue after pedicular fixation. This study examined the degeneration of the adjacent levels due to the insertion of the Wallis interspinous stabilization system compared with discectomy, using magnetic resonance imaging (MRI).Thirty-eight patients diagnosed with lumbar degeneration disorders at L4-L5 were reviewed: 19 patients underwent discectomy and Wallis system implantation (group A), and 19 patients underwent discectomy (group B). The Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) were assessed preoperatively and postoperatively. ASD was evaluated by MRI.There was no difference in the preoperative ODI scores between the 2 groups (non-normal distribution, median, 50 (40, 50) vs 50 (50, 50), P = .331), but the postoperative ODI scores were different (non-normal distribution, median, 0 (0, 32) vs 20 (20, 30), P < .005). Similar results were observed for VAS. In group A, ASD occurred in 4 patients (21.1%) in the disc and 8 (42.1%) in the facet joint at L3/4, and in 4 (21.1%) in the disc and 5 (26.3%) in the facet joint at L5/S1. In Group B, ASD occurred in 3 patients (15.8%) in the disc at L3/4, and in 4 (21.1%) in the disc at L5/S1. In general, there was no difference between the 2 groups (P > .05), except at L3/4 (P = .015).ASD of the facet joint in the cranial segment occurred after Wallis system implantation, suggesting that the Wallis system cannot prevent ASD of the facet joint, but could have some other benefits for the discs. PMID- 28562571 TI - Hemodynamic instability after pulmonary veins isolation in a patient with dual chamber pacemaker: The phantom injury of the ventricular lead. AB - INTRODUCTION: The standard treatment of sinus node dysfunction (SND) is the pacemaker implantation, and the ideal methodology for the management of atrial fibrillation (AF) is rhythm control, but this is sometimes very hard to accomplish. For such actions, complete isolation of all pulmonary veins (PVI) is currently widely accepted as the best endpoint. CASE PRESENTATION: In this case, we report a female patient, 81 years old, with controlled hypertension, without coronary artery disease, bearer of bilateral knee replacement, and dual chamber pacemaker implanted 1.5 years ago owing to sinus node disease, presenting the following symptoms: presyncope episodes associated with sustained irregular palpitation tachycardia. The evaluation of the pacemaker-recorded episodes of atrial fibrillation, the echocardiogram-presented normal systolic function and measurements, as well as the resting myocardial scintigraphy and with drug use did not demonstrate ischemia and/or fibrosis. The patient was in use of valsartan 320 mg daily, amlodipine 10 mg daily, sotalol hydrochloride 120 mg 2 times daily, and dabigatran 110 mg 2 times daily. At the end of the PVI, the patient presented hemodynamic instability, with a decrease in heart rate to 30 bpm and invasive arterial blood pressure to 60/30 mmHg. The pericardial puncture was quickly carried out with the possibility of cardiac tamponade as the first hypothesis, but no pericardial effusion was found. Next, we detected acute capture loss from the ventricular pacemaker lead, unvarying with high voltage and pulse width, even with stable impedance, sense and keeping the same position visualized by fluoroscopy. And there was soon afterwards induction of sustained ventricular tachycardia degenerating to spontaneous ventricular fibrillation. Electrical cardioversion-defibrillation was performed with 200J, and the sinus rhythm was reestablished, but there was a dead short, and the pacemaker generator was burned and disabled. CONCLUSIONS: So, we can speculate that application of atrial radiofrequency for PVI diffused through the tissues, affecting in some way the tip of the ventricular electrode, causing a microlesion in this structure and making it impossible to capture the right ventricle by the pacemaker. As we cannot see it, we can call it of phantom injury of the ventricular lead. PMID- 28562572 TI - The association of six single nucleotide polymorphisms and their haplotypes in CDH13 with T2DM in a Han Chinese population. AB - T-cadherin (CDH13) is an adiponectin receptor. Genome-wide association studies have identified the CDH13 gene as one of the most important candidate genes in influencing plasma adiponectin levels. Several studies recently reported single nucleotide polymorphisms (SNPs) in CDH13 gene were associated with T2DM. The purpose of this study was to investigate the association between T2DM and 6 SNPs (rs11646213, rs12596316, rs3865188, rs12444338, rs12051272, and rs7195409) in the CDH13 gene in a Han Chinese population. A total of 674 subjects with T2DM and 588 subjects without T2DM were genotyped using the TaqMan method. Our data showed that there was an association between the SNP-rs12596316 genotype and T2DM (P < .05). Moreover, an overdominant model of inheritance showed that being an rs12596316AG heterozygote increased the risk of T2DM (P = .0041, odds ratio = 1.39; 95% confidence interval 1.11-1.73) in comparison with rs12596316AA-GG. The other 5 SNPs did not show associations with T2DM, either in the allele levels or in different inheritance models. The haplotype analysis showed that there were no associations between any haplotypes and T2DM. Our results revealed that genetic variations in the CDH13 gene were associated with T2DM susceptibility in a Han Chinese population. These results highlight the need to study the functional effects of these CDH13 gene variants in relation to the risk of developing T2DM. PMID- 28562573 TI - Predictors of secondary amputation in patients with grade IIIC lower limb injuries: A retrospective analysis of 35 patients. AB - The aim of this study was to identify risk factors for failure of limb salvage surgery in grade IIIC lower extremity injuries.A single-institution, retrospective review was performed of all patients with grade IIIC lower limb injuries presenting from January 2009 to April 2014. We gathered the data on each patient who underwent limb salvage and analyzed the final outcome for these patients (limb salvage vs secondary amputation).Grade IIIC lower limb injuries were identified in 41 patients. Primary amputation was performed in 6 patients (15%) as the initial procedure. Thirty-five patients (85%) underwent vascular reconstruction and other surgical procedures to salvage the limb. Limb salvage was successful in 23 patients (66%); 12 patients (34%) ultimately underwent secondary amputation. The median time from injury to secondary amputation was 22.5 days (range 4-380 days). The mean Mangled Extremity Severity Score (MESS) was 7.2 +/- 1.5 (range 5-10). The MESS was significantly higher in the secondary amputation group compared with the limb salvage group. Additionally, statistical testing revealed that the limb ischemia time, complex fractures, rate of fasciotomy, and number of vascular reconstruction were significantly higher in the secondary amputation group. Muscle necrosis and extensive soft tissue defect were the main reasons for secondary amputation.The findings indicate that MESS of 7 or greater, complex fractures, limb ischemia time equal to or greater than 6 hours, and osteofascial compartment syndrome were associated with an increased risk of delayed amputation. The MESS is highly prognostic but not perfect; decision-making in patients with an MESS of 7 or greater should be re-evaluated for clinical use. PMID- 28562574 TI - Incidence and risk factors of deep venous thrombosis following arthroscopic posterior cruciate ligament reconstruction. AB - The objective of this study was to identify the incidence and associated risk factors for deep venous thrombosis (DVT) after arthroscopic posterior cruciate ligament (PCL) reconstruction.This study included 128 patients who underwent arthroscopic PCL reconstruction. Venography was performed on the operated leg 3 days postoperatively. The patients were divided into 2 groups based on whether they had DVT. A correlation analysis was performed to determine the factors associated with DVT.Of all the 128 patients, 28 patients (21.9%) developed DVT, with 4 (3.1%) in a proximal location. Significant differences were found in the mean age, time of application of tourniquet, mean VAS scores, mean D-dimer level, mean cholesterol level, and various surgical procedures in patients with DVT compared with those without DVT. DVT is difficult to diagnose solely based on clinical symptoms.The incidence of DVT was 21.9% in patients who underwent arthroscopic PCL reconstruction. The rate of asymptomatic clots in the calf region was rather high after PCL reconstruction, and the rate of proximal clots was 4%. Older age, longer durations of tourniquet application, higher VAS scores and D-dimer levels, and complex surgical procedures were all substantial risk factors for DVT after PCL reconstruction. The treatment of DVT with batroxobin and anticoagulants was effective and safe. PMID- 28562575 TI - Predictability and stability of laser-assisted subepithelial keratectomy with mitomycin C for the correction of high myopia. AB - The purpose of this study was to evaluate the predictability and stability of laser-assisted subepithelial keratectomy (LASEK) with mitomycin C (MMC) in correction of high myopia (<=-6.0 diopters [D]) as compared to low-to-moderate myopia (>-6.0 D).This is a retrospective, comparative, cohort study which included 43 eyes of 43 consecutive patients who underwent LASEK with MMC in a private hospital in Hong Kong by a single surgeon. Twenty-five eyes had high myopia (mean spherical equivalent [SE] = -8.53 +/- 1.82 D) and 18 eyes had low-to moderate myopia (mean SE = -3.99 +/- 1.37 D) before surgery.In terms of refractive predictability, mean SE was significantly better in eyes with preoperative low-to-moderate myopia than high myopia at 6 months (0.04 +/- 0.23 vs 0.31 +/- 0.52 D, P = .035). In terms of refractive stability, between 1 and 3 months, both groups had mean absolute change of SE of around 0.25 D. Between 3 and 6 months, preoperative low-to-moderate myopia group had significantly less absolute change of SE compared to high myopia group (0.07 vs 0.23 D, P = .003). More eyes with preoperative high myopia changed SE by more than 0.25 D than those with low-to-moderate myopia between 3 and 6 months (32.0% vs 5.6%, P = .057).In conclusion, LASEK with MMC is more unpredictable and unstable in correction of high myopia than low-to-moderate myopia. The refractive outcome of most low-to moderate myopia correction stabilizes at 3 months. Stability is not achieved until after 6 months in high myopia correction. PMID- 28562577 TI - Bowel management program for pediatric postoperative fecal incontinence in China: A surgeon's experience. AB - The purpose of this article is to report the status of the efficacy of and long term adherence to the Bowel Management Program (BMP) for fecal incontinence (FI) postoperation in China.Children over 3 years of age with FI postoperation referred to our medical center were included in the study. Evaluations were performed before and 2 years after their clinic visit. The cost of bowel care, improvement in incontinence, health-related quality of life, and family functioning with the BMP were analyzed.A total of 48 children with FI were included in our study, of whom 38 were boys. The median treatment fee was 660.1 dollars. The complications included abdominal pain (4 patients, 8%), occasional vomiting (2 patients, 4%), and hypoglycemia (1 patient, 2%). The incontinence status and health-related quality of life improved significantly after the BMP. Despite the good outcome of the BMP, half of the patients discontinued the program.The BMP is an effective approach to manage FI and improve the patients' quality of life. Poor long-term adherence is currently the main challenge affecting the BMP application in China. PMID- 28562576 TI - Prevalence trends in the characteristics of patients with allergic asthma in Beijing, 1994 to 2014. AB - This study aimed to determine the clinical profiles and prevalence trends during 1994 to 2014 among patients with allergic asthma (AA), which is a clinical phenotype of asthma.We retrospectively analyzed the characteristics of 319 patients who were diagnosed with AA between March 1, 1994 and February 28, 2014 at 3 Beijing centers.The patients included 155 males and 164 females, and the mean age was 50.86 +/- 15.27 years (range 13-86 years). The proportions of asthma attacks in summer and autumn were 60.7% (1994-1999), 61.8% (1999-2004), 56.4% (2004-2009), and 33.1% (2009-2014). The most frequently used medication at home was theophylline (27.9%), which was followed by inhaled corticosteroids (20.38%), inhaled corticosteroids/long-acting beta-2-agonists (10.66%), and leukotriene receptor antagonists (9.4%). The elderly group had the highest rates of summer and autumn attacks, multiple hospitalizations, reduced pulmonary function, smoking history, and positive allergen tests. The middle-aged group had the lowest rates of summer and autumn attacks, and multiple hospitalizations. The youngest group had the lowest rates of reduced pulmonary function, smoking history, and positive allergen tests. The top 5 allergens were dust (9.1%), mites (8.8%), seafood (8.2%), pollen (6.3%), and animal fur (6%). Women were significantly more likely to have a positive allergen test (93 women vs 68 men).The present study revealed the characteristics of Chinese patients with AA, and allergen-specific differences in sex and age during 1994 to 2014. The use of therapeutic drugs at home remains insufficient. PMID- 28562578 TI - A comparative study of Danhong injection and Salvia miltiorrhiza injection in the treatment of cerebral infarction: A systematic review and meta-analysis. AB - BACKGROUND: To evaluate systematically the clinical effectiveness and safety of Danhong injection (DI) and Salvia miltiorrhiza injection (SMI) in the treatment of cerebral infarction. METHODS: A literature search was conducted for retrieving randomized controlled trials (RCTs) on cerebral infarction treated by Danhong injection and SMI in the Cochrane Library, PubMed, Embase, China Biology Medicine disc, China National Knowledge Infrastructure Database, China Science and Technology Journal Database, Wanfang Database up to January 22, 2017. Two reviewers extracted information and independently assessed the quality of included RCTs by the Cochrane Risk of Bias Assessment Tool; then data were analyzed with Review Manager 5.3 software. RESULTS: Twelve RCTs involving 1044 patients were included. The result of DI group was about 27% superior to SMI group in the clinical total effective rate (relative risk 1.27, 95% confidence interval 1.19-1.35, P < .00001). In addition, DI could prefect neurologic impairment (standardized mean difference -1.22, 95% confidence interval -1.90 to 0.54, P = .0004), and adjust hemorheological parameters. Three RCTs occurred 4 cases of adverse drug reactions/adverse drug events, but there were no serious adverse drug reactions/adverse drug events. CONCLUSION: Comparing with SMI combined with western medicine, DI combined with conventional therapy is more effective in improving the clinical total effective rate and neurologic impairment, but more evidence-based medicine research needed to support our study further. PMID- 28562579 TI - MicroRNAs in the prognosis of triple-negative breast cancer: A systematic review and meta-analysis. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors characterized by their aggressive nature and poor associated survival. MicroRNAs (miRs) have been found to play an important role in the occurrence and development of human cancers, but their role in the prognosis of TNBC patients remains unclear. We performed a meta-analysis to explore the prognostic value of miRs in TNBC. METHODS: We systematically searched the PubMed, Embase, and Web of Science databases to identify eligible studies. A meta-analysis was performed to estimate the pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) for the associations between levels of miR expression (predictive factors) and overall survival (OS) and disease-free survival (DFS) (outcomes) in patients with TNBC. RESULTS: After performing the literature search and review, 21 relevant studies including 2510 subjects were identified. Six miRs (miR-155, miR-21, miR-27a/b, miR-374a/b, miR-210, and miR-454) were assessed in the meta analysis. Decreased expression of miR-155 was associated with reduced OS (adjusted HR = 0.58, 95% CI: 0.34-0.99; crude HR = 0.67, 95% CI: 0.58-0.79). High miR-21 expression was also predictive of reduced OS (crude HR = 2.50, 95% CI: 1.56-4.01). We found that elevated levels of miR-27a/b, miR-210, and miR-454 expression were associated with shorter OS, while the levels of miR-454 and miR 374a/b expression were associated with DFS. CONCLUSIONS: Specific miRs could serve as potential prognostic biomarkers in TNBC. Due to the limited research available, the clinical application of these findings has yet to be verified. PMID- 28562580 TI - Increased serum brain-derived neurotrophic factor in male schizophrenic patients with metabolic syndrome. AB - Increased prevalence of metabolic syndrome was found in patients with schizophrenia. Brain-derived neurotrophic factor (BDNF) was involved in energy metabolism and the pathophysiology of schizophrenia, but differently in males and females. We aimed to investigate the serum BDNF levels in patients with schizophrenia with and without metabolic syndrome.Patients with schizophrenia were recruited. Their demographic data were collected. Metabolic profiles and serum BDNF levels were measured. Clinical symptoms were evaluated with Positive and Negative Syndrome Scale. Metabolic syndrome was determined with the criteria provided by Ministry of Health and Welfare of Taiwan. Framingham Risk Score (FRS) for estimate of 10-year risk for coronary heart disease was provided by National Institutes of Health.Of the 81 participants, 40.7% had metabolic syndrome. Those with metabolic syndrome had higher FRS. Using analysis of covariance adjusted for age and body mass index, male patients with schizophrenia with metabolic syndrome had higher serum BDNF levels than those without (4.6 +/- 4.7 vs 3.3 +/- 3.8 ng/mL, P = .022). No statistical difference was found between female patients with and without metabolic syndrome.Significant differences of serum BDNF levels were found between male patients with schizophrenia with and without metabolic syndrome, but not in females. This finding suggested the gender difference behind the mechanism of BDNF in metabolic syndrome in schizophrenia. PMID- 28562581 TI - Prevalence and Risk Factors of Chronic Constipation Among Women Aged 50 Years and Older in Shanghai, China. AB - BACKGROUND Chronic constipation (CC) is a major public health problem worldwide, especially in elderly women. This study aimed to investigate the prevalence and risk factors of CC among women aged 50 years and older in Shanghai, China. MATERIAL AND METHODS A cross-sectional survey was conducted on 1950 women aged 50 years and older, randomly sampled in Yangpu District of Shanghai from April to October 2015. Information on demographic characteristics, lifestyle habits, medical history, and defecation situation was collected through in-person interviews. CC was defined according to Rome III criteria. The data were analyzed by chi-square test and multiple logistic regression analysis. RESULTS The response rate to the survey was 80.4%. Of the 1568 participants, 77 were diagnosed with CC, with a prevalence of 4.9%. Moreover, the prevalence increased with advancing age. Multiple logistic analyses showed that body mass index (BMI) >=25.0 kg/m2, non-manual occupation, premenopausal period, no delivery history, poor sleep quality, meat-based diet, and less physical exercise were significant risk factors for CC in the population of women aged 50 years and older. CONCLUSIONS CC was a common health problem among women aged 50 years and older in Shanghai, and the prevalence was positively associated with BMI >=25.0 kg/m2, non manual occupation, premenopausal period, no delivery history, poor sleep quality, meat-based diet, and less physical exercise. Further studies are needed to identify the risk factors and potential interventions for CC. PMID- 28562583 TI - Neurodegenerative disease: RNA repeats put a freeze on cells. PMID- 28562582 TI - The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3beta inhibition. AB - Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival, surface BCR expression is conserved in most mature B cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signalling is required for tumour cell survival. Consequently, the BCR signalling machinery has become an established target in the therapy of B cell malignancies. Here we study the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compare them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR negative (BCR-) tumour cells rapidly disappear in the presence of their BCR expressing (BCR+) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR+ tumour cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase 3 beta (GSK3beta) activity to support MYC-controlled gene expression. BCR- tumour cells exhibit increased GSK3beta activity and are rescued from their competitive growth disadvantage by GSK3beta inhibition. BCR- lymphoma variants that restore competitive fitness normalize GSK3beta activity after constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR targeted therapies may profit from combinations with drugs targeting BCR- tumour cells. PMID- 28562586 TI - Molecular biology: Local metabolites linked to memory. PMID- 28562584 TI - Structure of the Cpf1 endonuclease R-loop complex after target DNA cleavage. AB - Cpf1 is an RNA-guided endonuclease that is emerging as a powerful genome-editing tool. Here we provide insight into its DNA-targeting mechanism by determining the structure of Francisella novicida Cpf1 with the triple-stranded R-loop generated after DNA cleavage. The structure reveals the machinery involved in DNA unwinding to form a CRISPR RNA (crRNA)-DNA hybrid and a displaced DNA strand. The protospacer adjacent motif (PAM) is recognized by the PAM-interacting domain. The loop-lysine helix-loop motif in this domain contains three conserved lysine residues that are inserted in a dentate manner into the double-stranded DNA. Unzipping of the double-stranded DNA occurs in a cleft arranged by acidic and hydrophobic residues facilitating the crRNA-DNA hybrid formation. The PAM single stranded DNA is funnelled towards the nuclease site through a mixed hydrophobic and basic cavity. In this catalytic conformation, the PAM-interacting domain and the helix-loop-helix motif in the REC1 domain adopt a 'rail' shape and 'flap-on' conformations, respectively, channelling the PAM strand into the cavity. A steric barrier between the RuvC-II and REC1 domains forms the 'septum', separating the displaced PAM strand and the crRNA-DNA hybrid, avoiding DNA re-annealing. Mutations in key residues reveal a mechanism linking the PAM and DNA nuclease sites. Analysis of the Cpf1 structures proposes a singular working model of RNA guided DNA cleavage, suggesting new avenues for redesign of Cpf1. PMID- 28562585 TI - Crystal structure of the GLP-1 receptor bound to a peptide agonist. AB - Glucagon-like peptide 1 (GLP-1) regulates glucose homeostasis through the control of insulin release from the pancreas. GLP-1 peptide agonists are efficacious drugs for the treatment of diabetes. To gain insight into the molecular mechanism of action of GLP-1 peptides, here we report the crystal structure of the full length GLP-1 receptor bound to a truncated peptide agonist. The peptide agonist retains an alpha-helical conformation as it sits deep within the receptor-binding pocket. The arrangement of the transmembrane helices reveals hallmarks of an active conformation similar to that observed in class A receptors. Guided by this structural information, we design peptide agonists with potent in vivo activity in a mouse model of diabetes. PMID- 28562587 TI - Evolution: Differences can hold populations together. PMID- 28562588 TI - A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis. AB - Diarrhoeal disease is responsible for 8.6% of global child mortality. Recent epidemiological studies found the protozoan parasite Cryptosporidium to be a leading cause of paediatric diarrhoea, with particularly grave impact on infants and immunocompromised individuals. There is neither a vaccine nor an effective treatment. Here we establish a drug discovery process built on scalable phenotypic assays and mouse models that take advantage of transgenic parasites. Screening a library of compounds with anti-parasitic activity, we identify pyrazolopyridines as inhibitors of Cryptosporidium parvum and Cryptosporidium hominis. Oral treatment with the pyrazolopyridine KDU731 results in a potent reduction in intestinal infection of immunocompromised mice. Treatment also leads to rapid resolution of diarrhoea and dehydration in neonatal calves, a clinical model of cryptosporidiosis that closely resembles human infection. Our results suggest that the Cryptosporidium lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) is a target for pyrazolopyridines and that KDU731 warrants further preclinical evaluation as a drug candidate for the treatment of cryptosporidiosis. PMID- 28562589 TI - RNA phase transitions in repeat expansion disorders. AB - Expansions of short nucleotide repeats produce several neurological and neuromuscular disorders including Huntington disease, muscular dystrophy, and amyotrophic lateral sclerosis. A common pathological feature of these diseases is the accumulation of the repeat-containing transcripts into aberrant foci in the nucleus. RNA foci, as well as the disease symptoms, only manifest above a critical number of nucleotide repeats, but the molecular mechanism governing foci formation above this characteristic threshold remains unresolved. Here we show that repeat expansions create templates for multivalent base-pairing, which causes purified RNA to undergo a sol-gel transition in vitro at a similar critical repeat number as observed in the diseases. In human cells, RNA foci form by phase separation of the repeat-containing RNA and can be dissolved by agents that disrupt RNA gelation in vitro. Analogous to protein aggregation disorders, our results suggest that the sequence-specific gelation of RNAs could be a contributing factor to neurological disease. PMID- 28562590 TI - Genetic wiring maps of single-cell protein states reveal an off-switch for GPCR signalling. AB - As key executers of biological functions, the activity and abundance of proteins are subjected to extensive regulation. Deciphering the genetic architecture underlying this regulation is critical for understanding cellular signalling events and responses to environmental cues. Using random mutagenesis in haploid human cells, we apply a sensitive approach to directly couple genomic mutations to protein measurements in individual cells. Here we use this to examine a suite of cellular processes, such as transcriptional induction, regulation of protein abundance and splicing, signalling cascades (mitogen-activated protein kinase (MAPK), G-protein-coupled receptor (GPCR), protein kinase B (AKT), interferon, and Wingless and Int-related protein (WNT) pathways) and epigenetic modifications (histone crotonylation and methylation). This scalable, sequencing-based procedure elucidates the genetic landscapes that control protein states, identifying genes that cause very narrow phenotypic effects and genes that lead to broad phenotypic consequences. The resulting genetic wiring map identifies the E3-ligase substrate adaptor KCTD5 (ref. 1) as a negative regulator of the AKT pathway, a key signalling cascade frequently deregulated in cancer. KCTD5 deficient cells show elevated levels of phospho-AKT at S473 that could not be attributed to effects on canonical pathway components. To reveal the genetic requirements for this phenotype, we iteratively analysed the regulatory network linked to AKT activity in the knockout background. This genetic modifier screen exposes suppressors of the KCTD5 phenotype and mechanistically demonstrates that KCTD5 acts as an off-switch for GPCR signalling by triggering proteolysis of Gbetagamma heterodimers dissociated from the Galpha subunit. Although biological networks have previously been constructed on the basis of gene expression, protein-protein associations, or genetic interaction profiles, we foresee that the approach described here will enable the generation of a comprehensive genetic wiring map for human cells on the basis of quantitative protein states. PMID- 28562591 TI - Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. AB - Metabolic production of acetyl coenzyme A (acetyl-CoA) is linked to histone acetylation and gene regulation, but the precise mechanisms of this process are largely unknown. Here we show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) directly regulates histone acetylation in neurons and spatial memory in mammals. In a neuronal cell culture model, ACSS2 increases in the nuclei of differentiating neurons and localizes to upregulated neuronal genes near sites of elevated histone acetylation. A decrease in ACSS2 lowers nuclear acetyl-CoA levels, histone acetylation, and responsive expression of the cohort of neuronal genes. In adult mice, attenuation of hippocampal ACSS2 expression impairs long term spatial memory, a cognitive process that relies on histone acetylation. A decrease in ACSS2 in the hippocampus also leads to defective upregulation of memory-related neuronal genes that are pre-bound by ACSS2. These results reveal a connection between cellular metabolism, gene regulation, and neural plasticity and establish a link between acetyl-CoA generation 'on-site' at chromatin for histone acetylation and the transcription of key neuronal genes. PMID- 28562593 TI - Frequency dependence limits divergent evolution by favouring rare immigrants over residents. AB - Two distinct forms of natural selection promote adaptive biological diversity. Divergent selection occurs when different environments favour different phenotypes, leading to increased differences between populations. Negative frequency-dependent selection occurs when rare variants within a population are favoured over common ones, increasing diversity within populations. These two diversifying forces promote genetic variation at different spatial scales, and may act in opposition, but their relative effects remain unclear because they are rarely measured concurrently. Here we show that negative frequency-dependent selection within populations can favor rare immigrants over locally adapted residents. We reciprocally transplanted lake and stream ecotypes of threespine stickleback into lake and stream habitats, while manipulating the relative abundance of residents versus immigrants. We found negative frequency-dependence: survival was highest for the locally rare ecotype, rather than natives. Also, individuals with locally rare major histocompatibility complex (MHC) class IIb genotypes were infected by fewer parasites. This negative frequency-dependent selection will tend to favour rare immigrants over common residents, amplifying the effect of migration and undermining the efficacy of divergent natural selection to drive population differences. The only signal of divergent selection was a tendency for foreign fish to have higher parasite loads than residents, after controlling for MHC genotype rarity. Frequency-dependent ecological interactions have long been thought to promote speciation. Our results suggest a more nuanced view in which negative frequency dependence alters the fate of migrants to promote or constrain evolutionary divergence between populations. PMID- 28562592 TI - Dynamic corticostriatal activity biases social bonding in monogamous female prairie voles. AB - Adult pair bonding involves dramatic changes in the perception and valuation of another individual. One key change is that partners come to reliably activate the brain's reward system, although the precise neural mechanisms by which partners become rewarding during sociosexual interactions leading to a bond remain unclear. Here we show, using a prairie vole (Microtus ochrogaster) model of social bonding, how a functional circuit from the medial prefrontal cortex to nucleus accumbens is dynamically modulated to enhance females' affiliative behaviour towards a partner. Individual variation in the strength of this functional connectivity, particularly after the first mating encounter, predicts how quickly animals begin affiliative huddling with their partner. Rhythmically activating this circuit in a social context without mating biases later preference towards a partner, indicating that this circuit's activity is not just correlated with how quickly animals become affiliative but causally accelerates it. These results provide the first dynamic view of corticostriatal activity during bond formation, revealing how social interactions can recruit brain reward systems to drive changes in affiliative behaviour. PMID- 28562594 TI - Guided self-organization and cortical plate formation in human brain organoids. AB - Three-dimensional cell culture models have either relied on the self-organizing properties of mammalian cells or used bioengineered constructs to arrange cells in an organ-like configuration. While self-organizing organoids excel at recapitulating early developmental events, bioengineered constructs reproducibly generate desired tissue architectures. Here, we combine these two approaches to reproducibly generate human forebrain tissue while maintaining its self organizing capacity. We use poly(lactide-co-glycolide) copolymer (PLGA) fiber microfilaments as a floating scaffold to generate elongated embryoid bodies. Microfilament-engineered cerebral organoids (enCORs) display enhanced neuroectoderm formation and improved cortical development. Furthermore, reconstitution of the basement membrane leads to characteristic cortical tissue architecture, including formation of a polarized cortical plate and radial units. Thus, enCORs model the distinctive radial organization of the cerebral cortex and allow for the study of neuronal migration. Our data demonstrate that combining 3D cell culture with bioengineering can increase reproducibility and improve tissue architecture. PMID- 28562596 TI - Perspectives of older people about contingency planning for falls in the community: A qualitative meta-synthesis. AB - OBJECTIVE: Despite consistent evidence for the positive impact of contingency planning for falls in older people, implementation of plans often fail. This is likely due to lack of recognition and knowledge about perspectives of older people about contingency planning. The objective of this research was to explore the perspectives of older people living in the community about use of contingency planning for getting help quickly after a fall. METHOD: A systematic literature search seeking qualitative research was conducted in April 2014, with no limit placed on date of publication. Medline, EMBASE, Ageline, CINAHL, HealthSource- Nursing/Academic Edition, AMED and Psych INFO databases were searched. Three main concepts were explored and linked using Boolean operators; older people, falls and contingency planning. The search was updated until February 2016 with no new articles found. After removal of duplicates, 562 articles were assessed against inclusion and exclusion criteria resulting in six studies for the meta-synthesis. These studies were critically appraised using the McMaster critical appraisal tool. Bespoke data extraction sheets were developed and a meta-synthesis approach was adopted to extract and synthesise findings. FINDINGS: Three themes of 'a mix of attitudes', 'careful deliberations' and 'a source of anxiety' were established. Perspectives of older people were on a continuum between regarding contingency plans as necessary and not necessary. Levels of engagement with the contingency planning process seemed associated with acceptance of their risk of falling and their familiarity with available contingency planning strategies. CONCLUSION: Avoiding a long lie on the floor following a fall is imperative for older people in the community but there is a lack of knowledge about contingency planning for falls. This meta-synthesis provides new insights into this area of health service delivery and highlights that implementation of plans needs to be directed by the older people rather than the health professionals. PMID- 28562595 TI - Pre-transplant immune factors may be associated with BK polyomavirus reactivation in kidney transplant recipients. AB - BK polyomavirus (BKPyV) reactivation in kidney transplant recipients can lead to allograft damage and loss. The elements of the adaptive immune system that are permissive of reactivation and responsible for viral control remain incompletely described. We performed a prospective study evaluating BKPyV-specific T-cell response, humoral response and overall T-cell phenotype beginning pre-transplant through one year post-transplant in 28 patients at two centers. We performed an exploratory analysis of risk factors for the development of viremia and viruria as well as compared the immune response to BKPyV in these groups and those who remained BK negative. 6 patients developed viruria and 3 developed viremia. BKPyV specific CD8+ T-cells increased post-transplant in viremic and viruric but not BK negative patients. BKPyV-specific CD4+ T-cells increased in viremic, but not viruric or BK negative patients. Anti-BKPyV IgG antibodies increased in viruric and viremic patients but remained unchanged in BK negative patients. Viremic patients had a greater proportion of CD8+ effector cells pre-transplant and at 12 months post-transplant. Viremic patients had fewer CD4+ effector memory cells at 3 months post-transplant. Exploratory analysis demonstrated lower CD4 and higher total CD8 proportions, higher anti-BKPyV antibody titers and the cause of renal failure were associated BKPyV reactivation. In conclusion, low CD4, high CD8 and increased effector CD8 cells were found pre-transplant in patients who became viremic, a phenotype associated with immune senescence. This pre-transplant T cell senescence phenotype could potentially be used to identify patients at increased risk of BKPyV reactivation. PMID- 28562597 TI - Experience with speech sounds is not necessary for cue trading by budgerigars (Melopsittacus undulatus). AB - The influence of experience with human speech sounds on speech perception in budgerigars, vocal mimics whose speech exposure can be tightly controlled in a laboratory setting, was measured. Budgerigars were divided into groups that differed in auditory exposure and then tested on a cue-trading identification paradigm with synthetic speech. Phonetic cue trading is a perceptual phenomenon observed when changes on one cue dimension are offset by changes in another cue dimension while still maintaining the same phonetic percept. The current study examined whether budgerigars would trade the cues of voice onset time (VOT) and the first formant onset frequency when identifying syllable initial stop consonants and if this would be influenced by exposure to speech sounds. There were a total of four different exposure groups: No speech exposure (completely isolated), Passive speech exposure (regular exposure to human speech), and two Speech-trained groups. After the exposure period, all budgerigars were tested for phonetic cue trading using operant conditioning procedures. Birds were trained to peck keys in response to different synthetic speech sounds that began with "d" or "t" and varied in VOT and frequency of the first formant at voicing onset. Once training performance criteria were met, budgerigars were presented with the entire intermediate series, including ambiguous sounds. Responses on these trials were used to determine which speech cues were used, if a trading relation between VOT and the onset frequency of the first formant was present, and whether speech exposure had an influence on perception. Cue trading was found in all birds and these results were largely similar to those of a group of humans. Results indicated that prior speech experience was not a requirement for cue trading by budgerigars. The results are consistent with theories that explain phonetic cue trading in terms of a rich auditory encoding of the speech signal. PMID- 28562598 TI - Inhibition of insect olfactory behavior by an airborne antagonist of the insect odorant receptor co-receptor subunit. AB - Response to volatile environmental chemosensory cues is essential for insect survival. The odorant receptor (OR) family is an important class of receptors that detects volatile molecules; guiding insects towards food, mates, and oviposition sites. ORs are odorant-gated ion channels, consisting of a variable odorant specificity subunit and a conserved odorant receptor co-receptor (Orco) subunit, in an unknown stoichiometry. The Orco subunit possesses an allosteric site to which modulators can bind and noncompetitively inhibit odorant activation of ORs. In this study, we characterized several halogen-substituted versions of a phenylthiophenecarboxamide Orco antagonist structure. Orco antagonist activity was assessed on ORs from Drosophila melanogaster flies and Culex quinquefasciatus mosquitoes, expressed in Xenopus laevis oocytes and assayed by two-electrode voltage clamp electrophysiology. One compound, OX1w, was also shown to inhibit odorant activation of a panel of Anopheles gambiae mosquito ORs activated by diverse odorants. Next, we asked whether Orco antagonist OX1w could affect insect olfactory behavior. A Drosophila melanogaster larval chemotaxis assay was utilized to address this question. Larvae were robustly attracted to highly diluted ethyl acetate in a closed experimental chamber. Attraction to ethyl acetate was Orco dependent and also required the odorant specificity subunit Or42b. The addition of the airborne Orco antagonist OX1w to the experimental chamber abolished larval chemotaxis towards ethyl acetate. The Orco antagonist was not a general inhibitor of sensory behavior, as behavioral repulsion from a light source was unaffected. This is the first demonstration that an airborne Orco antagonist can alter olfactory behavior in an insect. These results suggest a new approach to insect control and emphasize the need to develop more potent Orco antagonists. PMID- 28562600 TI - Effects of flood irrigation on the risk of selected zoonotic pathogens in an arid and semi-arid area in the eastern Kenya. AB - To investigate the effects of irrigation on land cover changes and the risk of selected zoonotic pathogens, we carried out a study in irrigated, pastoral and riverine areas in the eastern Kenya. Activities implemented included secondary data analyses to determine land use and land cover (LULC) changes as well as human, livestock and wildlife population trends; entomological surveys to characterize mosquitoes population densities and species distribution by habitat and season; and serological surveys in people to determine the risk of Rift Valley fever virus (RVFV), West Nile fever virus (WNV), dengue fever virus (DFV), Leptospira spp. and Brucella spp. Results demonstrate a drastic decline in vegetation cover over ~25 years particularly in the irrigated areas where cropland increased by about 1,400% and non-farm land (under closed trees, open to closed herbaceous vegetation, bushlands and open trees) reduced by 30-100%. The irrigated areas had high densities of Aedes mcintoshi, Culex spp. and Mansonia spp. (important vectors for multiple arboviruses) during the wet and dry season while pastoral areas had high densities of Ae. tricholabis specifically in the wet season. The seroprevalences of RVFV, WNV and DFV were higher in the irrigated compared to the pastoral areas while those for Leptospira spp and Brucella spp. were higher in the pastoral compared to the irrigated areas. It is likely that people in the pastoral areas get exposed to Leptospira spp by using water fetched from reservoirs that are shared with livestock and wildlife, and to Brucella spp. by consuming raw or partially cooked animal-source foods such as milk and meat. This study suggests that irrigation increases the risk of mosquito-borne infections while at the same time providing a protective effect against zoonotic pathogens that thrive in areas with high livestock population densities. PMID- 28562599 TI - Arabidopsis RAD51, RAD51C and XRCC3 proteins form a complex and facilitate RAD51 localization on chromosomes for meiotic recombination. AB - Meiotic recombination is required for proper homologous chromosome segregation in plants and other eukaryotes. The eukaryotic RAD51 gene family has seven ancient paralogs with important roles in mitotic and meiotic recombination. Mutations in mammalian RAD51 homologs RAD51C and XRCC3 lead to embryonic lethality. In the model plant Arabidopsis thaliana, RAD51C and XRCC3 homologs are not essential for vegetative development but are each required for somatic and meiotic recombination, but the mechanism of RAD51C and XRCC3 in meiotic recombination is unclear. The non-lethal Arabidopsis rad51c and xrcc3 null mutants provide an opportunity to study their meiotic functions. Here, we show that AtRAD51C and AtXRCC3 are components of the RAD51-dependent meiotic recombination pathway and required for normal AtRAD51 localization on meiotic chromosomes. In addition, AtRAD51C interacts with both AtRAD51 and AtXRCC3 in vitro and in vivo, suggesting that these proteins form a complex (es). Comparison of AtRAD51 foci in meiocytes from atrad51, atrad51c, and atxrcc3 single, double and triple heterozygous mutants further supports an interaction between AtRAD51C and AtXRCC3 that enhances AtRAD51 localization. Moreover, atrad51c-/+ atxrcc3-/+ double and atrad51-/+ atrad51c-/+ atxrcc3-/+ triple heterozygous mutants have defects in meiotic recombination, suggesting the role of the AtRAD51C-AtXRCC3 complex in meiotic recombination is in part AtRAD51-dependent. Together, our results support a model in which direct interactions between the RAD51C-XRCC3 complex and RAD51 facilitate RAD51 localization on meiotic chromosomes and RAD51-dependent meiotic recombination. Finally, we hypothesize that maintenance of RAD51 function facilitated by the RAD51C-XRCC3 complex could be highly conserved in eukaryotes. PMID- 28562602 TI - Drivers of abundance and spatial distribution of reef-associated sharks in an isolated atoll reef system. AB - We investigated drivers of reef shark demography across a large and isolated marine protected area, the British Indian Ocean Territory Marine Reserve, using stereo baited remote underwater video systems. We modelled shark abundance against biotic and abiotic variables at 35 sites across the reserve and found that the biomass of low trophic order fish (specifically planktivores) had the greatest effect on shark abundance, although models also included habitat variables (depth, coral cover and site type). There was significant variation in the composition of the shark assemblage at different atolls within the reserve. In particular, the deepest habitat sampled (a seamount at 70-80m visited for the first time in this study) recorded large numbers of scalloped hammerhead sharks (Sphyrna lewini) not observed elsewhere. Size structure of the most abundant and common species, grey reef sharks (Carcharhinus amblyrhynchos), varied with location. Individuals at an isolated bank were 30% smaller than those at the main atolls, with size structure significantly biased towards the size range for young of year (YOY). The 18 individuals judged to be YOY represented the offspring of between four and six females, so, whilst inconclusive, these data suggest the possible use of a common pupping site by grey reef sharks. The importance of low trophic order fish biomass (i.e. potential prey) in predicting spatial variation in shark abundance is consistent with other studies both in marine and terrestrial systems which suggest that prey availability may be a more important predictor of predator distribution than habitat suitability. This result supports the need for ecosystem level rather than species-specific conservation measures to support shark recovery. The observed spatial partitioning amongst sites for species and life-stages also implies the need to include a diversity of habitats and reef types within a protected area for adequate protection of reef-associated shark assemblages. PMID- 28562604 TI - An appetite for understanding appetite. PMID- 28562603 TI - Evaluation of three molecular markers for identification of European primary parasitoids of cereal aphids and their hyperparasitoids. AB - Aphids are major pests of cereal crops and a suite of hymenopteran primary parasitoids play an important role in regulating their populations. However, hyperparasitoids may disrupt the biocontrol services provided by primary parasitoids. As such, understanding cereal aphid-primary parasitoid hyperparasitoid interactions is vital for a reliable parasitoid-based control of cereal aphids. For this, the ability to identify the different primary and hyperparasitoid species is necessary. Unfortunately, this is often difficult due to a lack of morphologically diagnostic features. DNA sequence-based species identification of parasitoids can overcome these hurdles. However, comprehensive DNA sequence information is lacking for many of these groups, particularly for hyperparasitoids. Here we evaluate three genes [cytochrome c oxidase subunit I (COI), 16S ribosomal RNA (16S) and 18S ribosomal RNA (18S)] for their suitability to identify 24 species of primary parasitoids and 16 species of hyperparasitoids associated with European cereal aphids. To identify aphelinid primary parasitoid species and hyperparasitoids, we found 16S to be more suitable compared to COI sequences. In contrast, the Aphidiinae are best identified using COI due to better species-level resolution and a more comprehensive DNA sequence database compared to 16S. The 18S gene was better suited for group-specific identification of parasitoids, but did not provide resolution at the species level. Our results provide a DNA sequence database for cereal aphid primary parasitoids and their associated hyperparasitoids in Central Europe, which will allow further improvement of our understanding of cereal aphid-primary parasitoid hyperparasitoid interactions in relation to aphid biological control. PMID- 28562601 TI - Multifunctional glial support by Semper cells in the Drosophila retina. AB - Glial cells play structural and functional roles central to the formation, activity and integrity of neurons throughout the nervous system. In the retina of vertebrates, the high energetic demand of photoreceptors is sustained in part by Muller glia, an intrinsic, atypical radial glia with features common to many glial subtypes. Accessory and support glial cells also exist in invertebrates, but which cells play this function in the insect retina is largely undefined. Using cell-restricted transcriptome analysis, here we show that the ommatidial cone cells (aka Semper cells) in the Drosophila compound eye are enriched for glial regulators and effectors, including signature characteristics of the vertebrate visual system. In addition, cone cell-targeted gene knockdowns demonstrate that such glia-associated factors are required to support the structural and functional integrity of neighboring photoreceptors. Specifically, we show that distinct support functions (neuronal activity, structural integrity and sustained neurotransmission) can be genetically separated in cone cells by down-regulating transcription factors associated with vertebrate gliogenesis (pros/Prox1, Pax2/5/8, and Oli/Olig1,2, respectively). Further, we find that specific factors critical for glial function in other species are also critical in cone cells to support Drosophila photoreceptor activity. These include ion transport proteins (Na/K+-ATPase, Eaat1, and Kir4.1-related channels) and metabolic homeostatic factors (dLDH and Glut1). These data define genetically distinct glial signatures in cone/Semper cells that regulate their structural, functional and homeostatic interactions with photoreceptor neurons in the compound eye of Drosophila. In addition to providing a new high-throughput model to study neuron-glia interactions, the fly eye will further help elucidate glial conserved "support networks" between invertebrates and vertebrates. PMID- 28562606 TI - The first specimen of Camarasaurus (Dinosauria: Sauropoda) from Montana: The northernmost occurrence of the genus. AB - A partial skeleton from the Little Snowy Mountains of central Montana is the first referable specimen of the Morrison Formation macronarian sauropod Camarasaurus. This specimen also represents the northernmost occurrence of a sauropod in the Morrison. Histological study indicates that, although the specimen is relatively small statured, it is skeletally mature; this further emphasizes that size is not a undeviating proxy to maturity in dinosaurs, and that morphologies associated with an individual's age and stature may be more nebulous in sauropods. PMID- 28562605 TI - The Agassiz's desert tortoise genome provides a resource for the conservation of a threatened species. AB - Agassiz's desert tortoise (Gopherus agassizii) is a long-lived species native to the Mojave Desert and is listed as threatened under the US Endangered Species Act. To aid conservation efforts for preserving the genetic diversity of this species, we generated a whole genome reference sequence with an annotation based on deep transcriptome sequences of adult skeletal muscle, lung, brain, and blood. The draft genome assembly for G. agassizii has a scaffold N50 length of 252 kbp and a total length of 2.4 Gbp. Genome annotation reveals 20,172 protein-coding genes in the G. agassizii assembly, and that gene structure is more similar to chicken than other turtles. We provide a series of comparative analyses demonstrating (1) that turtles are among the slowest-evolving genome-enabled reptiles, (2) amino acid changes in genes controlling desert tortoise traits such as shell development, longevity and osmoregulation, and (3) fixed variants across the Gopherus species complex in genes related to desert adaptations, including circadian rhythm and innate immune response. This G. agassizii genome reference and annotation is the first such resource for any tortoise, and will serve as a foundation for future analysis of the genetic basis of adaptations to the desert environment, allow for investigation into genomic factors affecting tortoise health, disease and longevity, and serve as a valuable resource for additional studies in this species complex. PMID- 28562608 TI - Correction: Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006621.]. PMID- 28562607 TI - Migratory bats respond to artificial green light with positive phototaxis. AB - Artificial light at night is spreading worldwide at unprecedented rates, exposing strictly nocturnal animals such as bats to a novel anthropogenic stressor. Previous studies about the effect of artificial light on bats focused almost exclusively on non-migratory species, yet migratory animals such as birds are known to be largely affected by light pollution. Thus, we conducted a field experiment to evaluate if bat migration is affected by artificial light at night. In late summer, we presented artificial green light of 520 nm wavelength to bats that were migrating south along the shoreline of the Baltic Sea. Using a light on off treatment, we observed that the activity of Pipistrellus nathusii and P. pygmaeus, the two most abundant migratory species at our site, increased by more than 50% in the light-on compared to the light-off treatment. We observed an increased number of feeding buzzes during the light-on compared to the light-off treatment for P. nathusii. However, feeding activity was low in general and did not increase disproportionately during the light-on treatment in relation to the overall echolocation call activity of bats. Further, P. nathusii were attracted towards the green light at a distance of about 23 m, which is way beyond the echolocation detection range for insects of Nathusius' bats. We therefore infer that migratory bats were not attracted to artificial green light because of high insect densities, but instead by positive phototaxis. We conclude that artificial light at night may potentially impact bat migration in a yet unrecognized way. PMID- 28562609 TI - Diagnostic value of repeated ice tests in the evaluation of ptosis in myasthenia gravis. AB - Twenty-six patients with ptosis related to Myasthenia gravis (MG) and 38 controls with ptosis other than MG were included. All patients were tested with the ice test 2 times on separate days in the afternoon. The margin reflex distance (MRD) was measured before and immediately after 2-minute application of ice on the eyelids. The ice test was judged positive if there was an improvement of at least 2.0 mm of MRD after the ice test. Among the patients with negative test results, 'equivocal' was defined by improvement of MRD from at least 1.0 mm to less than 2.0 mm after the ice test. Repeated ice test results showed an agreement of 61.5% in MG, and 97.4% in nonmyasthenic ptosis. Repeated ice tests increased the sensitivity by 34.6% compared to a single test. Among the patients with repeatedly negative test results, 63.6% of those who showed equivocal results at least once turned out to be MG. Of those with repeated non-equivocal negative results, nobody turned out to be MG. There was no significant difference of the ice test results between ocular MG and generalized MG (p = 0.562). PMID- 28562610 TI - Beyond causes of death: The social determinants of mortality among children aged 1-59 months in Nigeria from 2009 to 2013. AB - BACKGROUND: Millions of children worldwide suffer and die from conditions for which effective interventions exist. While there is ample evidence regarding these diseases, there is a dearth of information on the social factors associated with child mortality. METHODS: The 2014 Verbal and Social Autopsy Study was conducted based on a nationally representative sample of 3,254 deaths that occurred in children under the age of five and were reported on the birth history component of the 2013 Nigerian Demographic and Health Survey. We conducted a descriptive analysis of the preventive and curative care sought and obtained for the 2,057 children aged 1-59 months who died in Nigeria and performed regional (North vs. South) comparisons. RESULTS: A total of 1,616 children died in the northern region, while 441 children died in the South. The majority (72.5%) of deceased children in the northern region were born to mothers who had no education, married at a young age, and lived in the poorest two quintiles of households. When caregivers first noticed that their child was ill, a median of 2 days passed before they sought or attempted to seek healthcare for their children. The proportion of children who reached and departed from their first formal healthcare provider alive was greater in the North (30.6%) than in the South (17.9%) (p<0.001). A total of 548 children were moderately or severely sick at discharge from the first healthcare provider, yet only 3.9%-18.1% were referred to a second healthcare provider. Cost, lack of transportation, and distance from healthcare facilities were the most commonly reported barriers to formal care-seeking behavior. CONCLUSIONS: Maternal, household, and healthcare system factors contributed to child mortality in Nigeria. Information regarding modifiable social factors may be useful in planning intervention programs to promote child survival in Nigeria and other low-income countries in sub-Saharan Africa. PMID- 28562611 TI - Direct estimates of cause-specific mortality fractions and rates of under-five deaths in the northern and southern regions of Nigeria by verbal autopsy interview. AB - Nigeria's under-five mortality rate is the eighth highest in the world. Identifying the causes of under-five deaths is crucial to achieving Sustainable Development Goal 3 by 2030 and improving child survival. National and international bodies collaborated in this study to provide the first ever direct estimates of the causes of under-five mortality in Nigeria. Verbal autopsy interviews were conducted of a representative sample of 986 neonatal and 2,268 1 59 month old deaths from 2008 to 2013 identified by the 2013 Nigeria Demographic and Health Survey. Cause of death was assigned by physician coding and computerized expert algorithms arranged in a hierarchy. National and regional estimates of age distributions, mortality rates and cause proportions, and zonal- and age-specific mortality fractions and rates for leading causes of death were evaluated. More under-fives and 1-59 month olds in the South, respectively, died as neonates (N = 24.1%, S = 32.5%, p<0.001) and at younger ages (p<0.001) than in the North. The leading causes of neonatal and 1-59 month mortality, respectively, were sepsis, birth injury/asphyxia and neonatal pneumonia, and malaria, diarrhea and pneumonia. The preterm delivery (N = 1.2%, S = 3.7%, p = 0.042), pneumonia (N = 15.0%, S = 21.6%, p = 0.004) and malaria (N = 34.7%, S = 42.2%, p = 0.009) fractions were higher in the South, with pneumonia and malaria focused in the South East and South South; while the diarrhea fraction was elevated in the North (N = 24.8%, S = 13.2%, p<0.001). However, the diarrhea, pneumonia and malaria mortality rates were all higher in the North, respectively, by 222.9% (Z = -10.9, p = 0.000), 27.6% (Z = -2.3, p = 0.020) and 50.6% (Z = -5.7, p = 0.000), with the greatest excesses in older children. The findings support that there is an epidemiological transition ongoing in southern Nigeria, suggest the way forward to a similar transition in the North, and can help guide maternal, neonatal and child health programming and their regional and zonal foci within the country. PMID- 28562613 TI - Weather, day length and physical activity in older adults: Cross-sectional results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk Cohort. AB - BACKGROUND: A wide range of environmental factors have been related to active ageing, but few studies have explored the impact of weather and day length on physical activity in older adults. We investigate the cross-sectional association between weather conditions, day length and activity in older adults using a population-based cohort in England, the European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk study. METHODS: Physical activity was measured objectively over 7 days using an accelerometer and this was used to calculate daily total physical activity (counts per minute), daily minutes of sedentary behaviour and light, moderate and vigorous physical activity (LMVPA). Day length and two types of weather conditions, precipitation and temperature, were obtained from a local weather station. The association between these variables and physical activity was examined by multilevel first-order autoregressive modelling. RESULTS: After adjusting for individual factors, short day length and poor weather conditions, including high precipitation and low temperatures, were associated with up to 10% lower average physical activity (p<0.01) and 8 minutes less time spent in LMVPA but 15 minutes more sedentary time, compared to the best conditions. CONCLUSION: Day length and weather conditions appear to be an important factor related to active ageing. Future work should focus on developing potential interventions to reduce their impact on physical activity behaviours in older adults. PMID- 28562612 TI - Decreased emergence of HIV-1 drug resistance mutations in a cohort of Ugandan women initiating option B+ for PMTCT. AB - BACKGROUND: Since 2012, WHO guidelines for the prevention of mother-to-child transmission (PMTCT) of HIV-1 in resource-limited settings recommend the initiation of lifelong antiretroviral combination therapy (cART) for all pregnant HIV-1 positive women independent of CD4 count and WHO clinical stage (Option B+). However, long-term outcomes regarding development of drug resistance are lacking until now. Therefore, we analysed the emergence of drug resistance mutations (DRMs) in women initiating Option B+ in Fort Portal, Uganda, at 12 and 18 months postpartum (ppm). METHODS AND FINDINGS: 124 HIV-1 positive pregnant women were enrolled within antenatal care services in Fort Portal, Uganda. Blood samples were collected at the first visit prior starting Option B+ and postpartum at week six, month six, 12 and 18. Viral load was determined by real-time RT-PCR. An RT PCR covering resistance associated positions in the protease and reverse transcriptase HIV-1 genomic region was performed. PCR-positive samples at 12/18 ppm and respective baseline samples were analysed by next generation sequencing regarding HIV-1 drug resistant variants including low-frequency variants. Furthermore, vertical transmission of HIV-1 was analysed. 49/124 (39.5%) women were included into the DRM analysis. Virological failure, defined as >1000 copies HIV-1 RNA/ml, was observed in three and seven women at 12 and 18 ppm, respectively. Sequences were obtained for three and six of these. In total, DRMs were detected in 3/49 (6.1%) women. Two women displayed dual-class resistance against all recommended first-line regimen drugs. Of 49 mother-infant-pairs no infant was HIV-1 positive at 12 or 18 ppm. CONCLUSION: Our findings suggest that the WHO-recommended Option B+ for PMTCT is effective in a cohort of Ugandan HIV-1 positive pregnant women with regard to the low selection rate of DRMs and vertical transmission. Therefore, these results are encouraging for other countries considering the implementation of lifelong cART for all pregnant HIV-1 positive women. PMID- 28562614 TI - Properties of genes essential for mouse development. AB - Essential genes are those that are critical for life. In the specific case of the mouse, they are the set of genes whose deletion means that a mouse is unable to survive after birth. As such, they are the key minimal set of genes needed for all the steps of development to produce an organism capable of life ex utero. We explored a wide range of sequence and functional features to characterise essential (lethal) and non-essential (viable) genes in mice. Experimental data curated manually identified 1301 essential genes and 3451 viable genes. Very many sequence features show highly significant differences between essential and viable mouse genes. Essential genes generally encode complex proteins, with multiple domains and many introns. These genes tend to be: long, highly expressed, old and evolutionarily conserved. These genes tend to encode ligases, transferases, phosphorylated proteins, intracellular proteins, nuclear proteins, and hubs in protein-protein interaction networks. They are involved with regulating protein-protein interactions, gene expression and metabolic processes, cell morphogenesis, cell division, cell proliferation, DNA replication, cell differentiation, DNA repair and transcription, cell differentiation and embryonic development. Viable genes tend to encode: membrane proteins or secreted proteins, and are associated with functions such as cellular communication, apoptosis, behaviour and immune response, as well as housekeeping and tissue specific functions. Viable genes are linked to transport, ion channels, signal transduction, calcium binding and lipid binding, consistent with their location in membranes and involvement with cell-cell communication. From the analysis of the composite features of essential and viable genes, we conclude that essential genes tend to be required for intracellular functions, and viable genes tend to be involved with extracellular functions and cell-cell communication. Knowledge of the features that are over-represented in essential genes allows for a deeper understanding of the functions and processes implemented during mammalian development. PMID- 28562615 TI - Screening test for neutralizing antibodies against yellow fever virus, based on a flavivirus pseudotype. AB - Given the possibility of yellow fever virus reintroduction in epidemiologically receptive geographic areas, the risk of vaccine supply disruption is a serious issue. New strategies to reduce the doses of injected vaccines should be evaluated very carefully in terms of immunogenicity. The plaque reduction test for the determination of neutralizing antibodies (PRNT) is particularly time consuming and requires the use of a confinement laboratory. We have developed a new test based on the use of a non-infectious pseudovirus (WN/YF17D). The presence of a reporter gene allows sensitive determination of neutralizing antibodies by flow cytometry. This WN/YF17D test was as sensitive as PRNT for the follow-up of yellow fever vaccinees. Both tests lacked specificity with sera from patients hospitalized for acute Dengue virus infection. Conversely, both assays were strictly negative in adults never exposed to flavivirus infection or vaccination, and in patients sampled some time after acute Dengue infection. This WN/YF17D test will be particularly useful for large epidemiological studies and for screening for neutralizing antibodies against yellow fever virus. PMID- 28562616 TI - Demystifying the Capitella capitata complex (Annelida, Capitellidae) diversity by morphological and molecular data along the Brazilian coast. AB - The sibling species of Capitella capitata are globally known for their tolerance to disturbed habitats and the C. capitata complex is often used as an ecological indicator. A recent re-description proposed that C. capitata, originally described in Greenland is restricted to the Artic and Subarctic regions. Given their ecological relevance, we conducted a morphological and molecular analyses based on mtDNA sequences to investigate the diversity and distribution of the C. capitata complex along the Brazilian coast. Our morphological and molecular data were congruent and revealed the existence of four new species distinct from C. capitata, collected from the type locality. This study is the first characterization of the biodiversity and distribution of Capitella species made along the Brazilian coast and yielded a set of morphological characters corroborated by the mtDNA sequences for species identification. Our results increase the biodiversity of the genus along the Brazilian coast by describing four new species (Capitella aracaensis sp. n., Capitella biota sp. n., Capitella neoaciculata sp. n. and Capitella nonatoi sp. n.). One species was collected from only one sampling site, while the others are distributed along the coast. PMID- 28562617 TI - Taxonomy based analysis of force exchanges during object grasping and manipulation. AB - The flexibility of the human hand in object manipulation is essential for daily life activities, but remains relatively little explored with quantitative methods. On the one hand, recent taxonomies describe qualitatively the classes of hand postures for object grasping and manipulation. On the other hand, the quantitative analysis of hand function has been generally restricted to precision grip (with thumb and index opposition) during lifting tasks. The aim of the present study is to fill the gap between these two kinds of descriptions, by investigating quantitatively the forces exerted by the hand on an instrumented object in a set of representative manipulation tasks. The object was a parallelepiped object able to measure the force exerted on the six faces and its acceleration. The grasping force was estimated from the lateral force and the unloading force from the bottom force. The protocol included eleven tasks with complementary constraints inspired by recent taxonomies: four tasks corresponding to lifting and holding the object with different grasp configurations, and seven to manipulating the object (rotation around each of its axis and translation). The grasping and unloading forces and object rotations were measured during the five phases of the actions: unloading, lifting, holding or manipulation, preparation to deposit, and deposit. The results confirm the tight regulation between grasping and unloading forces during lifting, and extend this to the deposit phase. In addition, they provide a precise description of the regulation of force exchanges during various manipulation tasks spanning representative actions of daily life. The timing of manipulation showed both sequential and overlapping organization of the different sub-actions, and micro-errors could be detected. This phenomenological study confirms the feasibility of using an instrumented object to investigate complex manipulative behavior in humans. This protocol will be used in the future to investigate upper-limb dexterity in patients with sensory-motor impairments. PMID- 28562618 TI - Hebbian learning of hand-centred representations in a hierarchical neural network model of the primate visual system. AB - A subset of neurons in the posterior parietal and premotor areas of the primate brain respond to the locations of visual targets in a hand-centred frame of reference. Such hand-centred visual representations are thought to play an important role in visually-guided reaching to target locations in space. In this paper we show how a biologically plausible, Hebbian learning mechanism may account for the development of localized hand-centred representations in a hierarchical neural network model of the primate visual system, VisNet. The hand centered neurons developed in the model use an invariance learning mechanism known as continuous transformation (CT) learning. In contrast to previous theoretical proposals for the development of hand-centered visual representations, CT learning does not need a memory trace of recent neuronal activity to be incorporated in the synaptic learning rule. Instead, CT learning relies solely on a Hebbian learning rule, which is able to exploit the spatial overlap that naturally occurs between successive images of a hand-object configuration as it is shifted across different retinal locations due to saccades. Our simulations show how individual neurons in the network model can learn to respond selectively to target objects in particular locations with respect to the hand, irrespective of where the hand-object configuration occurs on the retina. The response properties of these hand-centred neurons further generalise to localised receptive fields in the hand-centred space when tested on novel hand-object configurations that have not been explored during training. Indeed, even when the network is trained with target objects presented across a near continuum of locations around the hand during training, the model continues to develop hand-centred neurons with localised receptive fields in hand-centred space. With the help of principal component analysis, we provide the first theoretical framework that explains the behavior of Hebbian learning in VisNet. PMID- 28562619 TI - Story time turbocharger? Child engagement during shared reading and cerebellar activation and connectivity in preschool-age children listening to stories. AB - Expanding behavioral and neurobiological evidence affirms benefits of shared (especially parent-child) reading on cognitive development during early childhood. However, the majority of this evidence involves factors under caregiver control, the influence of those intrinsic to the child, such as interest or engagement in reading, largely indirect or unclear. The cerebellum is increasingly recognized as playing a "smoothing" role in higher-level cognitive processing and learning, via feedback loops with language, limbic and association cortices. We utilized functional MRI to explore the relationship between child engagement during a mother-child reading observation and neural activation and connectivity during a story listening task, in a sample of 4-year old girls. Children exhibiting greater interest and engagement in the narrative showed increased activation in right-sided cerebellar association areas during the task, and greater functional connectivity between this activation cluster and language and executive function areas. Our findings suggest a potential cerebellar "boost" mechanism responsive to child engagement level that may contribute to emergent literacy development during early childhood, and synergy between caregiver and child factors during story sharing. PMID- 28562620 TI - Reprimo tissue-specific expression pattern is conserved between zebrafish and human. AB - Reprimo (RPRM), a member of the RPRM gene family, is a tumor-suppressor gene involved in the regulation of the p53-mediated cell cycle arrest at G2/M. RPRM has been associated with malignant tumor progression and proposed as a potential biomarker for early cancer detection. However, the expression and role of RPRM, as well as its family, are poorly understood and their physiology is as yet unstudied. In this scenario, a model system like the zebrafish could serve to dissect the role of the RPRM family members in vivo. Phylogenetic analysis reveals that RPRM and RPRML have been differentially retained by most species throughout vertebrate evolution, yet RPRM3 has been retained only in a small group of distantly related species, including zebrafish. Herein, we characterized the spatiotemporal expression of RPRM (present in zebrafish as an infraclass duplication rprma/rprmb), RPRML and RPRM3 in the zebrafish. By whole-mount in situ hybridization (WISH) and fluorescent in situ hybridization (FISH), we demonstrate that rprm (rprma/rprmb) and rprml show a similar spatiotemporal expression profile during zebrafish development. At early developmental stages rprmb is expressed in somites. After one day post-fertilization, rprm (rprma/rprmb) and rprml are expressed in the notochord, brain, blood vessels and digestive tube. On the other hand, rprm3 shows the most unique expression profile, being expressed only in the central nervous system (CNS). We assessed the expression patterns of RPRM gene transcripts in adult zebrafish and human RPRM protein product in tissue samples by RT-qPCR and immunohistochemistry (IHC) staining, respectively. Strikingly, tissue-specific expression patterns of the RPRM transcripts and protein are conserved between zebrafish and humans. We propose the zebrafish as a powerful tool to elucidate the both physiological and pathological roles of the RPRM gene family. PMID- 28562621 TI - Adherence to secondary prophylaxis for rheumatic heart disease is underestimated by register data. AB - OBJECTIVE: In high-burden Australian states and territories, registers of patients with acute rheumatic fever and rheumatic heart disease are maintained for patient management, monitoring of system performance and research. Data validation was undertaken for the Australian Northern Territory Rheumatic Heart Disease Register to determine quality and impact of data cleaning on reporting against key performance indicators: overall adherence, and proportion of patients receiving >=80% of scheduled penicillin doses for secondary prophylaxis. METHODS: Register data were compared with data from health centres. Inconsistencies were identified and corrected; adherence was calculated before and after cleaning. RESULTS: 2780 penicillin doses were validated; 426 inconsistencies were identified, including 102 incorrect dose dates. After cleaning, mean adherence increased (63.5% to 67.3%, p<0.001) and proportion of patients receiving >=80% of doses increased (34.2% to 42.1%, p = 0.06). CONCLUSIONS: The Northern Territory Rheumatic Heart Disease Register underestimates adherence, although the key performance indicator of >=80% adherence was not significantly affected. Program performance is better than hitherto appreciated. However some errors could affect patient management, as well as accuracy of longitudinal or inter-jurisdictional comparisons. Adequate resources are needed for maintenance of data quality in acute rheumatic fever/rheumatic heart disease registers to ensure provision of evidence-based care and accurate assessment of program impact. PMID- 28562622 TI - SUV-quantification of physiological lung tissue in an integrated PET/MR-system: Impact of lung density and bone tissue. AB - PURPOSE: The aim of the study was to investigate the influence of lung density changes as well as bone proximity on the attenuation correction of lung standardized uptake values (SUVs). METHODS AND MATERIALS: 15 patients with mostly oncologic diseases were examined in 18F-FDG-PET/CT and subsequently in a fully integrated PET/MR scanner. From each PET dataset acquired in PET/MR, four different PET reconstructions were computed using different attenuation maps (MU maps): i) CT-based MU-map (gold standard); ii) CT-based MU-map in which the linear attenuation coefficients (LAC) of the lung tissue was replaced by the lung LAC from the MR-based segmentation method; iii) based on reconstruction ii), the LAC of bone structures was additionally replaced with the LAC from the MR-based segmentation method; iv) the vendor-provided MR-based MU-map (segmentation-based method). Those steps were performed using MATLAB. CT Hounsfield units (HU) and SUVmean was acquired in different levels and regions of the lung. Relative differences between the differently corrected PETs were computed. RESULTS: Compared to the gold standard, reconstruction ii), iii) and iv) led to a relative underestimation of SUV in the posterior regions of -9.0%, -13.4% and -14.0%, respectively. Anterior and middle regions were less affected with an overestimation of about 6-8% in reconstructions ii)-iv). CONCLUSION: It could be shown that both, differences in lung density and the vicinity of bone tissue in the MU-map may have an influence on SUV, mostly affecting the posterior lung regions. PMID- 28562623 TI - Relationship between nugent score and vaginal epithelial exfoliation. AB - OBJECTIVE: Clue cells characteristic of bacterial vaginosis (BV) are thought to arise due to exfoliation of the vaginal epithelium; however, there is little published data connecting total numbers of epithelial cells to markers of BV. The purpose of this study was to enumerate exfoliated epithelial cells (independent of clue cells) and examine the relationship to Nugent score. STUDY DESIGN: We conducted a cross-sectional sub-study of the Contraceptive CHOICE Project cohort. Vaginal swabs were used to create vaginal smears for Gram staining and these smears were later scored using the Nugent method, and then two blinded observers used microscopy to enumerate exfoliated epithelial cells. The degree of epithelial cell exfoliation was compared between women diagnosed as BV-negative (Nugent score 0-3), BV-intermediate (Nugent score 4-6), and BV-positive (Nugent score 7-10). BV specimens (Nugent 7-10) were randomly matched to specimens in the two other groups (Nugent low and Nugent-intermediate), in order to avoid comparing groups of women with potentially confounding baseline demographics. RESULTS: Exfoliated epithelial cell counts were higher in the vaginal smears from BV-positive women compared with BV-negative women. Higher levels of epithelial exfoliation were also evident in BV-intermediate women compared to those with low Nugent scores. After adjustment for clustering introduced by matching, the incidence ratio of increased epithelial cell counts was 2.09 (95% CI 1.50-2.90) for the BV-intermediate women and 1.71 (95% CI 1.23-2.38) for the BV positive women. CONCLUSION: A vaginal epithelial exfoliation phenotype was measured in both Nugent-defined BV-positive and BV-intermediate women. Bacterial vaginosis and intermediate status (Nugent score >3) was associated with significantly more vaginal epithelial exfoliation compared to women with Lactobacillus-dominated microbiotas (Nugent 0-3). PMID- 28562624 TI - Application of a single-flicker online SSVEP BCI for spatial navigation. AB - A promising approach for brain-computer interfaces (BCIs) employs the steady state visual evoked potential (SSVEP) for extracting control information. Main advantages of these SSVEP BCIs are a simple and low-cost setup, little effort to adjust the system parameters to the user and comparatively high information transfer rates (ITR). However, traditional frequency-coded SSVEP BCIs require the user to gaze directly at the selected flicker stimulus, which is liable to cause fatigue or even photic epileptic seizures. The spatially coded SSVEP BCI we present in this article addresses this issue. It uses a single flicker stimulus that appears always in the extrafoveal field of view, yet it allows the user to control four control channels. We demonstrate the embedding of this novel SSVEP stimulation paradigm in the user interface of an online BCI for navigating a 2 dimensional computer game. Offline analysis of the training data reveals an average classification accuracy of 96.9+/-1.64%, corresponding to an information transfer rate of 30.1+/-1.8 bits/min. In online mode, the average classification accuracy reached 87.9+/-11.4%, which resulted in an ITR of 23.8+/-6.75 bits/min. We did not observe a strong relation between a subject's offline and online performance. Analysis of the online performance over time shows that users can reliably control the new BCI paradigm with stable performance over at least 30 minutes of continuous operation. PMID- 28562625 TI - Estimating blue whale skin isotopic incorporation rates and baleen growth rates: Implications for assessing diet and movement patterns in mysticetes. AB - Stable isotope analysis in mysticete skin and baleen plates has been repeatedly used to assess diet and movement patterns. Accurate interpretation of isotope data depends on understanding isotopic incorporation rates for metabolically active tissues and growth rates for metabolically inert tissues. The aim of this research was to estimate isotopic incorporation rates in blue whale skin and baleen growth rates by using natural gradients in baseline isotope values between oceanic regions. Nitrogen (delta15N) and carbon (delta13C) isotope values of blue whale skin and potential prey were analyzed from three foraging zones (Gulf of California, California Current System, and Costa Rica Dome) in the northeast Pacific from 1996-2015. We also measured delta15N and delta13C values along the lengths of baleen plates collected from six blue whales stranded in the 1980s and 2000s. Skin was separated into three strata: basale, externum, and sloughed skin. A mean (+/-SD) skin isotopic incorporation rate of 163+/-91 days was estimated by fitting a generalized additive model of the seasonal trend in delta15N values of skin strata collected in the Gulf of California and the California Current System. A mean (+/-SD) baleen growth rate of 15.5+/-2.2 cm y-1 was estimated by using seasonal oscillations in delta15N values from three whales. These oscillations also showed that individual whales have a high fidelity to distinct foraging zones in the northeast Pacific across years. The absence of oscillations in delta15N values of baleen sub-samples from three male whales suggests these individuals remained within a specific zone for several years prior to death. delta13C values of both whale tissues (skin and baleen) and potential prey were not distinct among foraging zones. Our results highlight the importance of considering tissue isotopic incorporation and growth rates when studying migratory mysticetes and provide new insights into the individual movement strategies of blue whales. PMID- 28562626 TI - Evaluation of awareness & utilisation of clinical practise guideline for management of adult Dengue infection among Malaysia doctors. AB - Clinical Practice Guideline (CPG) provides evidence-based guidance for the management of Dengue Infection in adult patients. A cross sectional study was conducted to evaluate awareness and utilization of CPG among doctors in public or private hospitals and clinics in Malaysia. Doctors practicing only at hospital Medical and Emergency Departments were included, while private specialist clinics were excluded in this study. A multistage proportionate random sampling according to region (Central, Northern, Southern, Eastern, Sabah and Sarawak) was performed to select study participants. The overall response rate was 74% (84% for public hospitals, 82% for private hospitals, 70% for public clinics, and 64% for private clinics). The CPG Awareness and Utilization Feedback Form were used to determine the percentage in the study. The total numbers of respondent were 634 with response rate of 74%. The mean lengths of service of the respondent were 13.98 (11.55).A higher percentages of doctors from public facilities (99%) were aware of the CPG compared to those in private facilities (84%). The percentage of doctors utilising the CPG were also higher (98%) in public facilities compared to private facilities (86%). The percentage of Medical Officer in private facilities that utilizing the CPG were 84% compares to Medical Officer in public facilities 98%. The high percentage of doctors using the CPG in both public (97%) and private (94%) hospitals were also observed. However, only 69% of doctors in private clinics utilised the CPG compared to doctors in public clinics (98%). Doctors in both public and private facilities were aware of the dengue CPG. However, most doctors in private clinic were less likely to utilise the CPG. Therefore, there is a need to increase the level of CPG utilisation especially in private clinics. PMID- 28562627 TI - Unconditional government cash transfers in support of orphaned and vulnerable adolescents in western Kenya: Is there an association with psychological wellbeing? AB - BACKGROUND: Orphaned and vulnerable adolescents (OVA) in sub-Saharan Africa are at greater risk for adverse psychological outcomes compared with their non-OVA counterparts. Social interventions that provide cash transfers (CTs) have been shown to improve health outcomes among young people, but little is known about their impact on the psychological wellbeing of OVA. OBJECTIVE: Among OVA in western Kenya, we assessed the association between living in a household that received monthly unconditional government CTs and psychological wellbeing. METHODS: We examined the likelihood of depression, anxiety, post-traumatic stress symptoms (PTSS) and positive future outlook among 655 OVA aged between 10 and 18 years who lived in 300 randomly selected households in western Kenya that either received or did not receive unconditional monthly CTs. RESULTS: The mean age was 14.0 (SD 2.4) years and 329 (50.2%) of the participants were female while 190 (29.0%) were double orphans whose biological parents were both deceased. After adjusting for socio-demographic, caregiver, and household characteristics and accounting for potential effects of participant clustering by sub-location of residence, OVA living in CT households were more likely to have a positive future outlook (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.08, 1.99), less likely to be anxious (OR 0.57, 95% CI 0.42, 0.78), and less likely to have symptoms of post-traumatic stress (OR 0.50, 95% CI 0.29, 0.89). We did not find statistically significant differences in odds of depression by CT group. CONCLUSION: OVA in CT households reported better psychological wellbeing compared to those in households not receiving CTs. CT interventions may be effective for improving psychological wellbeing among vulnerable adolescents in socioeconomically deprived households. PMID- 28562628 TI - Introduced bullfrogs are associated with increased Batrachochytrium dendrobatidis prevalence and reduced occurrence of Korean treefrogs. AB - Bullfrogs, Lithobates catesbeianus, have been described as major vectors of the amphibian chytrid fungus, Batrachochytrium dendrobatidis (Bd). Bd is widespread throughout the range of amphibians yet varies considerably within and among populations in prevalence and host impact. In our study, the presence of L. catesbeianus is correlated with a 2.5 increase in Bd prevalence in treefrogs, and the endangered Dryophytes suweonensis displays a significantly higher Bd prevalence than the more abundant D. japonicus for the 37 sites surveyed. In addition, the occurrence of L. catesbeianus was significantly correlated with a decrease in presence of D. suweonensis at sites. We could not determine if it is the presence of bullfrogs as competitors or predators that is limiting the distribution of D. suweonensis or whether this is caused by bullfrogs acting as a reservoir for Bd. However, L. catesbeianus can now be added to the list of factors responsible for the decline of D. suweonensis populations. PMID- 28562629 TI - A retrospective observational study of glucocorticoid-induced diabetes mellitus with IgA nephropathy treated with tonsillectomy plus methylprednisolone pulse therapy. AB - AIMS: To evaluate the incidence of GC-DM among patients with immunoglobulin A nephropathy (IgAN) and to confirm the risk factors for the development of GC-DM. METHODS: The medical records of patients with IgAN newly treated with the protocol of tonsillectomy combined with steroid pulse therapy were reviewed. The primary outcome was the development of GC-DM within the hospitalization period and during one year of follow-up. RESULTS: During hospitalization, 19 of the 95 patients developed GC-DM (20.0%), and the patients with GC-DM were significantly older and had a higher rate of family history of diabetes and higher HbA1c levels. The prevalence of hypertension was higher and the eGFR was numerically lower in patients with GC-DM than in those without. Older age (>=45 years) and a family history of diabetes emerged as independent risk factors for the development of GC-DM (odds ratio [OR], 6.3 and 95% confidence interval [CI], 1.6 27.6; OR, 4.4 and 95% CI, 1.2-16.6, respectively). No patients were newly diagnosed with GC-DM during 1-year observation period at out-patient clinic. CONCLUSIONS: Among the patients with IgAN, 20% developed GC-DM during the hospitalization period, confirming the family history of diabetes is clinically necessary before starting GC therapy. PMID- 28562630 TI - The influence of N-terminal acetylation on micelle-induced conformational changes and aggregation of alpha-Synuclein. AB - The biological function of alpha-Synuclein has been related to binding to lipids and membranes but these interactions can also mediate alpha-Synuclein aggregation, which is associated to Parkinson's disease and other neuropathologies. In brain tissue alpha-Synuclein is constitutively N-acetylated, a modification that plays an important role in its conformational propensity, lipid and membrane binding, and aggregation propensity. We studied the interactions of the lipid-mimetic SDS with N-acetylated and non-acetylated alpha Synuclein, as well as their early-onset Parkinson's disease variants A30P, E46K and A53T. At low SDS/protein ratios alpha-Synuclein forms oligomeric complexes with SDS micelles with relatively low alpha-helical structure. These micellar oligomers can efficiently nucleate aggregation of monomeric alpha-Synuclein, with successive formation of oligomers, protofibrils, curly fibrils and mature amyloid fibrils. N-acetylation reduces considerably the rate of aggregation of WT alpha Synuclein. However, in presence of any of the early-onset Parkinson's disease mutations the protective effect of N-acetylation against micelle-induced aggregation becomes impaired. At higher SDS/protein ratios, N-acetylation favors another conformational transition, in which a second type of alpha-helix-rich, non-aggregating oligomers become stabilized. Once again, the Parkinson's disease mutations disconnect the influence of N-acetylation in promoting this transition. These results suggest a cooperative link between the N-terminus and the region of the mutations that may be important for alpha-Synuclein function. PMID- 28562631 TI - Synergistic antibiofilm efficacy of a gallotannin 1,2,6-tri-O-galloyl-beta-D glucopyranose from Terminalia chebula fruit in combination with gentamicin and trimethoprim against multidrug resistant uropathogenic Escherichia coli biofilms. AB - In recent years the emergence of multiple drug resistance microbes has become a global public health problem. The aim of the present investigation was to evaluate possible antibiofilm efficacy of a gallotannin 1,2,6-tri-O-galloyl-beta D-glucopyranose from Terminalia chebula fruits alone and in combination with gentamicin and trimethoprim against preformed biofilms of multidrug-resistant (MDR) uropathogenic E. coli isolates using microbroth dilution, checkerboard titration and kill kinetics methods. Test gallotannin showed > 50% antibiofilm efficacy after 24 h when administered alone whereas gentamicin and trimethoprim failed to do so. But in combination, test gallotannin/gentamicin and test gallotannin/trimethoprim showed 71.24+/-6.75% and 93.4+/-8.46% antibiofilm activity respectively. On the basis of FICI values, test gallotannin/gentamicin showed synergistic interactions against 71.42% and test gallotannin/trimethoprim against 85.71% biofilm forming test bacterial isolates. Kill-kinetics study confirmed their synergistic interactions. Thus, gentamicin and trimethoprim in combination with test gallotannin may have potential for treatment of urinary tract infections caused by biofilm forming MDR uropathogenic E. coli. PMID- 28562632 TI - DrugSig: A resource for computational drug repositioning utilizing gene expression signatures. AB - Computational drug repositioning has been proved as an effective approach to develop new drug uses. However, currently existing strategies strongly rely on drug response gene signatures which scattered in separated or individual experimental data, and resulted in low efficient outputs. So, a fully drug response gene signatures database will be very helpful to these methods. We collected drug response microarray data and annotated related drug and targets information from public databases and scientific literature. By selecting top 500 up-regulated and down-regulated genes as drug signatures, we manually established the DrugSig database. Currently DrugSig contains more than 1300 drugs, 7000 microarray and 800 targets. Moreover, we developed the signature based and target based functions to aid drug repositioning. The constructed database can serve as a resource to quicken computational drug repositioning. Database URL: http://biotechlab.fudan.edu.cn/database/drugsig/. PMID- 28562633 TI - Bioinformatics identification and transcript profile analysis of the mitogen activated protein kinase gene family in the diploid woodland strawberry Fragaria vesca. AB - Mitogen-activated protein kinases (MAPKs) play essential roles in mediating biotic and abiotic stress responses in plants. However, the MAPK gene family in strawberry has not been systematically characterized. Here, we performed a genome wide survey and identified 12 MAPK genes in the Fragaria vesca genome. Protein domain analysis indicated that all FvMAPKs have typical protein kinase domains. Sequence alignments and phylogenetic analysis classified the FvMAPK genes into four different groups. Conserved motif and exon-intron organization supported the evolutionary relationships inferred from the phylogenetic analysis. Analysis of the stress-related cis-regulatory element in the promoters and subcellular localization predictions of FvMAPKs were also performed. Gene transcript profile analysis showed that the majority of the FvMAPK genes were ubiquitously transcribed in strawberry leaves after Podosphaera aphanis inoculation and after treatment with cold, heat, drought, salt and the exogenous hormones abscisic acid, ethephon, methyl jasmonate, and salicylic acid. RT-qPCR showed that six selected FvMAPK genes comprehensively responded to various stimuli. Additionally, interaction networks revealed that the crucial signaling transduction controlled by FvMAPKs may be involved in the biotic and abiotic stress responses. Our results may provide useful information for future research on the function of the MAPK gene family and the genetic improvement of strawberry resistance to environmental stresses. PMID- 28562634 TI - The significance of elevated plasma expression of microRNA 106b~25 clusters in gastric cancer. AB - OBJECTIVE: Concentrating on oncogenic role and increased plasma expression of microRNA(miR) 106b~25 clusters (involving miR 106b, miR 93 and miR 25), we evaluated significance of the over-expression of plasma miR 106b~25 in GC. METHODS: Based on 65 pairs matched GC patients and health controls, we explored clinical significance of miR 106b~25 for GC and compared their diagnostic performance with conventional tumor biomarkers including CA724, CA242, CA199 and CEA. RESULTS: Both miR 106b~25 cluster and conventional tumor biomarkers were significantly elevated in GC (All P<0.05). In ROC curves, miR 106b had the highest AUC (0.898) in diagnosing GC with optimal sensitivity of 86.2% and specificity of 92.3% at the cut-off value of 1.385. MiR 25 had moderate diagnostic efficacy (AUC = 0.817) with sensitivity of 87.6% and specificity of 76.9% at the threshold of 1.015. The AUC of miR 93 (0.756) was the lowest. The AUC, sensitivity, accuracy and Youden index of miR 106b were higher than all of four conventional biomarkers, while its specificity is higher than CA242 and CA724. The AUC of miR 25 was also higher than CA724, CA242 and CA199, while AUC of miR 93 was only higher than CA199 and CA724. Compared the diagnostic efficacy via ROC curves, miR 106b was significantly higher diagnostic efficacy than CA724, CA242 and CA199, the diagnostic efficacies of miR 93 and miR 25 were significantly higher than CA199(all P<0.05). CONCLUSIONS: Plasma miR 106b~25 cluster, especially miR 106b, were significantly increased in GC patients and may be hopeful diagnostic biomarkers. PMID- 28562635 TI - Physicians' beliefs about placebo and nocebo effects in antidepressants - an online survey among German practitioners. AB - BACKGROUND: While substantial placebo and nocebo effects have been documented in antidepressant clinical trials, physicians' awareness of the nonspecific effects in routine antidepressant treatment remains unclear. The study investigated physicians' beliefs and explanatory models regarding the desired effects and undesired side effects of antidepressants, with specific emphasis on nonspecific effects accounted for by placebo and nocebo mechanisms. METHODS: An online survey was conducted among 87 physicians (40.2% psychiatrists, 25.3% neurologists, 24.1% general practitioners, 12.6% internists, 21.8% other). The survey assessed the physician's beliefs in antidepressant effectiveness, as well as 6 explanatory models regarding antidepressant effectiveness and 8 explanatory models for the occurrence of side effects. RESULTS: Most physicians (89.7%) believed in the effectiveness of antidepressants while acknowledging a considerable role of the placebo effect by attributing around 40% of the total effects to nonspecific factors. For both antidepressant effectiveness and the occurrence of side effects, pharmacological effects were rated as most important (93.1% and 80.5% agreement), but physicians also attributed a substantial role to the patients' expectations (63.2% and 58.6%) and experiences (60.9% and 56.3%). Concerning the physician's own role in promoting nonspecific effects in antidepressant effectiveness, highest endorsements were found for the quality of the physician patient-relationship (58.6%) and own expectations (41.4%). When asked about side effects, fewer participants agreed that informing the patient about known side effects (25.2%) or the physicians' expectations themselves (17.2%) could induce side effects. CONCLUSION: Physicians, when prescribing antidepressants, are generally open towards nonspecific treatment mechanisms. However, they consider their own influence as less important than the patient's side, especially when it comes to the explanation of unwanted side effects. Awareness of the possible beneficial as well as malicious role of nonspecific mechanisms should be fostered as the first step towards optimizing antidepressant treatment by promoting placebo while avoiding nocebo effects. PMID- 28562636 TI - A systematic review of the asymmetric inheritance of cellular organelles in eukaryotes: A critique of basic science validity and imprecision. AB - We performed a systematic review to identify all original publications describing the asymmetric inheritance of cellular organelles in normal animal eukaryotic cells and to critique the validity and imprecision of the evidence. Searches were performed in Embase, MEDLINE and Pubmed up to November 2015. Screening of titles, abstracts and full papers was performed by two independent reviewers. Data extraction and validity were performed by one reviewer and checked by a second reviewer. Study quality was assessed using the SYRCLE risk of bias tool, for animal studies and by developing validity tools for the experimental model, organelle markers and imprecision. A narrative data synthesis was performed. We identified 31 studies (34 publications) of the asymmetric inheritance of organelles after mitotic or meiotic division. Studies for the asymmetric inheritance of centrosomes (n = 9); endosomes (n = 6), P granules (n = 4), the midbody (n = 3), mitochondria (n = 3), proteosomes (n = 2), spectrosomes (n = 2), cilia (n = 2) and endoplasmic reticulum (n = 2) were identified. Asymmetry was defined and quantified by variable methods. Assessment of the statistical reliability of the results indicated only two studies (7%) were judged to have low concern, the majority of studies (77%) were 'unclear' and five (16%) were judged to have 'high concerns'; the main reasons were low technical repeats (<10). Assessment of model validity indicated that the majority of studies (61%) were judged to be valid, ten studies (32%) were unclear and two studies (7%) were judged to have 'high concerns'; both described 'stem cells' without providing experimental evidence to confirm this (pluripotency and self-renewal). Assessment of marker validity indicated that no studies had low concern, most studies were unclear (96.5%), indicating there were insufficient details to judge if the markers were appropriate. One study had high concern for marker validity due to the contradictory results of two markers for the same organelle. For most studies the validity and imprecision of results could not be confirmed. In particular, data were limited due to a lack of reporting of interassay variability, sample size calculations, controls and functional validation of organelle markers. An evaluation of 16 systematic reviews containing cell assays found that only 50% reported adherence to PRISMA or ARRIVE reporting guidelines and 38% reported a formal risk of bias assessment. 44% of the reviews did not consider how relevant or valid the models were to the research question. 75% reviews did not consider how valid the markers were. 69% of reviews did not consider the impact of the statistical reliability of the results. Future systematic reviews in basic or preclinical research should ensure the rigorous reporting of the statistical reliability of the results in addition to the validity of the methods. Increased awareness of the importance of reporting guidelines and validation tools is needed for the scientific community. PMID- 28562637 TI - Identification of diagnostic peptide regions that distinguish Zika virus from related mosquito-borne Flaviviruses. AB - Zika virus (ZIKV) is a member of the Flavivirus genus of positive-sense single stranded RNA viruses, which includes Dengue, West Nile, Yellow Fever, and other mosquito-borne arboviruses. Infection by ZIKV can be difficult to distinguish from infection by other mosquito-borne Flaviviruses due to high sequence similarity, serum antibody cross-reactivity, and virus co-circulation in endemic areas. Indeed, existing serological methods are not able to consistently differentiate ZIKV from other Flaviviruses, which makes it extremely difficult to accurately calculate the incidence rate of Zika-associated Guillain-Barre in adults, microcephaly in newborns, or asymptomatic infections within a geographical area. In order to identify Zika-specific peptide regions that could be used as serology reagents, we have applied comparative genomics and protein structure analyses to identify amino acid residues that distinguish each of 10 Flavivirus species and subtypes from each other by calculating the specificity, sensitivity, and surface exposure of each residue in relevant target proteins. For ZIKV we identified 104 and 116 15-mer peptides in the E glycoprotein and NS1 non-structural protein, respectively, that contain multiple diagnostic sites and are located in surface-exposed regions in the tertiary protein structure. These sensitive, specific, and surface-exposed peptide regions should serve as useful reagents for seroprevalence studies to better distinguish between prior infections with any of these mosquito-borne Flaviviruses. The development of better detection methods and diagnostic tools will enable clinicians and public health workers to more accurately estimate the true incidence rate of asymptomatic infections, neurological syndromes, and birth defects associated with ZIKV infection. PMID- 28562638 TI - Every antibiotic, every day: Maximizing the impact of prospective audit and feedback on total antibiotic use. AB - BACKGROUND: The success of antimicrobial stewardship is dependent on how often it is completed and which antimicrobials are targeted. We evaluated the impact of an antimicrobial stewardship program (ASP) in three non-ICU settings where all systemic antibiotics, regardless of spectrum, were targeted on the first weekday after initiation. METHODS: Prospective audit and feedback (PAAF) was initiated on the surgical, respiratory, and medical wards of a community hospital on July 1, 2010, October 1, 2010, and April 1, 2012, respectively. We evaluated rates of total antibiotic use, measured in days on therapy (DOTs), among all patients admitted to the wards before and after PAAF initiation using an interrupted time series analysis. Changes in antibiotic costs, rates of C. difficile infection (CDI), mortality, readmission, and length of stay were evaluated using univariate analyses. RESULTS: Time series modelling demonstrated that total antibiotic use decreased (+/- standard error) by 100 +/- 51 DOTs/1,000 patient-days on the surgical wards (p = 0.049), 100 +/- 46 DOTs/1,000 patient-days on the respiratory ward (p = 0.029), and 91 +/- 33 DOTs/1,000 patient-days on the medical wards (p = 0.006) immediately following PAAF initiation. Reductions in antibiotic use were sustained up to 50 months after intervention initiation, and were accompanied by decreases in antibiotic costs. There were no significant changes to patient outcomes on the surgical and respiratory wards following intervention initiation. On the medical wards, however, readmission increased from 4.6 to 5.6 per 1,000 patient-days (p = 0.043), while mortality decreased from 7.4 to 5.0 per 1,000 patient-days (p = 0.001). CDI rates showed a non-significant declining trend after PAAF initiation. CONCLUSIONS: ASPs can lead to cost-effective, sustained reductions in total antibiotic use when interventions are conducted early in the course of therapy and target all antibiotics. Shifting to such a model may help strengthen the effectiveness of ASPs in non-ICU settings. PMID- 28562639 TI - Fast smooth second-order sliding mode control for systems with additive colored noises. AB - In this paper, a fast smooth second-order sliding mode control is presented for a class of stochastic systems with enumerable Ornstein-Uhlenbeck colored noises. The finite-time mean-square practical stability and finite-time mean-square practical reachability are first introduced. Instead of treating the noise as bounded disturbance, the stochastic control techniques are incorporated into the design of the controller. The finite-time convergence of the prescribed sliding variable dynamics system is proved by using stochastic Lyapunov-like techniques. Then the proposed sliding mode controller is applied to a second-order nonlinear stochastic system. Simulation results are presented comparing with smooth second order sliding mode control to validate the analysis. PMID- 28562640 TI - Anchoring plant metallothioneins to the inner face of the plasma membrane of Saccharomyces cerevisiae cells leads to heavy metal accumulation. AB - In this study we engineered yeast cells armed for heavy metal accumulation by targeting plant metallothioneins to the inner face of the yeast plasma membrane. Metallothioneins (MTs) are cysteine-rich proteins involved in the buffering of excess metal ions, especially Cu(I), Zn(II) or Cd(II). The cDNAs of seven Arabidopsis thaliana MTs (AtMT1a, AtMT1c, AtMT2a, AtMT2b, AtMT3, AtMT4a and AtMT4b) and four Noccaea caerulescens MTs (NcMT1, NcMT2a, NcMT2b and NcMT3) were each translationally fused to the C-terminus of a myristoylation green fluorescent protein variant (myrGFP) and expressed in Saccharomyces cerevisiae cells. The myrGFP cassette introduced a yeast myristoylation sequence which allowed directional targeting to the cytosolic face of the plasma membrane along with direct monitoring of the intracellular localization of the recombinant protein by fluorescence microscopy. The yeast strains expressing plant MTs were investigated against an array of heavy metals in order to identify strains which exhibit the (hyper)accumulation phenotype without developing toxicity symptoms. Among the transgenic strains which could accumulate Cu(II), Zn(II) or Cd(II), but also non-canonical metal ions, such as Co(II), Mn(II) or Ni(II), myrGFP-NcMT3 qualified as the best candidate for bioremediation applications, thanks to the robust growth accompanied by significant accumulative capacity. PMID- 28562641 TI - PGCA: An algorithm to link protein groups created from MS/MS data. AB - The quantitation of proteins using shotgun proteomics has gained popularity in the last decades, simplifying sample handling procedures, removing extensive protein separation steps and achieving a relatively high throughput readout. The process starts with the digestion of the protein mixture into peptides, which are then separated by liquid chromatography and sequenced by tandem mass spectrometry (MS/MS). At the end of the workflow, recovering the identity of the proteins originally present in the sample is often a difficult and ambiguous process, because more than one protein identifier may match a set of peptides identified from the MS/MS spectra. To address this identification problem, many MS/MS data processing software tools combine all plausible protein identifiers matching a common set of peptides into a protein group. However, this solution introduces new challenges in studies with multiple experimental runs, which can be characterized by three main factors: i) protein groups' identifiers are local, i.e., they vary run to run, ii) the composition of each group may change across runs, and iii) the supporting evidence of proteins within each group may also change across runs. Since in general there is no conclusive evidence about the absence of proteins in the groups, protein groups need to be linked across different runs in subsequent statistical analyses. We propose an algorithm, called Protein Group Code Algorithm (PGCA), to link groups from multiple experimental runs by forming global protein groups from connected local groups. The algorithm is computationally inexpensive and enables the connection and analysis of lists of protein groups across runs needed in biomarkers studies. We illustrate the identification problem and the stability of the PGCA mapping using 65 iTRAQ experimental runs. Further, we use two biomarker studies to show how PGCA enables the discovery of relevant candidate protein group markers with similar but non-identical compositions in different runs. PMID- 28562642 TI - Enhancement of multitasking performance and neural oscillations by transcranial alternating current stimulation. AB - Multitasking is associated with the generation of stimulus-locked theta (4-7 Hz) oscillations arising from prefrontal cortex (PFC). Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation technique that influences endogenous brain oscillations. Here, we investigate whether applying alternating current stimulation within the theta frequency band would affect multitasking performance, and explore tACS effects on neurophysiological measures. Brief runs of bilateral PFC theta-tACS were applied while participants were engaged in a multitasking paradigm accompanied by electroencephalography (EEG) data collection. Unlike an active control group, a tACS stimulation group showed enhancement of multitasking performance after a 90-minute session (F1,35 = 6.63, p = 0.01, etap2 = 0.16; effect size = 0.96), coupled with significant modulation of posterior beta (13-30 Hz) activities (F1,32 = 7.66, p = 0.009, etap2 = 0.19; effect size = 0.96). Across participant regression analyses indicated that those participants with greater increases in frontal theta, alpha and beta oscillations exhibited greater multitasking performance improvements. These results indicate frontal theta-tACS generates benefits on multitasking performance accompanied by widespread neuronal oscillatory changes, and suggests that future tACS studies with extended treatments are worth exploring as promising tools for cognitive enhancement. PMID- 28562643 TI - Alcohol-dysregulated microRNAs in hepatitis B virus-related hepatocellular carcinoma. AB - Alcohol consumption and chronic hepatitis B virus (HBV) infection are two well established risk factors for Hepatocellular carcinoma (HCC); however, there remains a limited understanding of the molecular pathway behind the pathogenesis and progression behind HCC, and how alcohol promotes carcinogenesis in the context of HBV+ HCC. Using next-generation sequencing data from 130 HCC patients and 50 normal liver tissues, we identified a panel of microRNAs that are significantly dysregulated by alcohol consumption in HBV+ patients. In particular, two microRNAs, miR-944 and miR-223-3p, showed remarkable correlation with clinical indication and genomic alterations. We confirmed the dysregulation of these two microRNAs in liver cell lines treated by alcohol and acetaldehyde, and showed that manipulation of miR-223-3p and miR-944 expression induces significant changes in cellular proliferation, sensitivity to doxorubicin, and the expression of both direct-binding and downstream mRNA targets. Together, the results of this study suggest that alcohol consumption in HBV+ HCCs regulates microRNAs that likely play previously uncharacterized roles in the alcohol associated carcinogenesis of HCC, and future studies of these microRNAs may be valuable for furthering the understanding and treatment of alcohol and HBV associated HCC. PMID- 28562644 TI - A quantitative indicator diagram for lytic polysaccharide monooxygenases reveals the role of aromatic surface residues in HjLPMO9A regioselectivity. AB - Lytic polysaccharide monooxygenases (LPMOs) have changed our understanding of lignocellulosic degradation dramatically over the last years. These metalloproteins catalyze oxidative cleavage of recalcitrant polysaccharides and can act on the C1 and/or C4 position of glycosidic bonds. Structural data have led to several hypotheses, but we are still a long way from reaching complete understanding of the factors that determine their divergent regioselectivity. Site-directed mutagenesis enables the investigation of structure-function relationship in enzymes and will be of major importance in unraveling this intriguing matter. In this context, it is crucial to have an enzyme assay or screening approach with a direct correlation with the desired functionality. LPMOs render this search extra challenging due to their insoluble substrates, complex pattern of reaction products and lack of synthetic standards of most oxidized products. Here, we describe a regioselectivity indicator diagram based on the time-course of only 2 HPAEC-PAD signals. The diagram was successfully used to confirm the hypothesis that aromatic surface residues influence the C1/C4 oxidation ratio in Hypocrea jecorina LPMO9A. Consequently, the diagram should become a valuable tool in the search towards better understanding and engineering of regioselectivity in LPMOs. PMID- 28562645 TI - Characterization of single cell derived cultures of periosteal progenitor cells to ensure the cell quality for clinical application. AB - For clinical applications of cells and tissue engineering products it is of importance to characterize the quality of the used cells in detail. Progenitor cells from the periosteum are already routinely applied in the clinics for the regeneration of the maxillary bone. Periosteal cells have, in addition to their potential to differentiate into bone, the ability to develop into cartilage and fat. However, the question arises whether all cells isolated from periosteal biopsies are able to differentiate into all three tissue types, or whether there are subpopulations. For an efficient and approved application in bone or cartilage regeneration the clarification of this question is of interest. Therefore, 83 different clonal cultures of freshly isolated human periosteal cells derived from mastoid periosteum biopsies of 4 donors were generated and growth rates calculated. Differentiation capacities of 51 clonal cultures towards the osteogenic, the chondrogenic, and the adipogenic lineage were investigated. Histological and immunochemical stainings showed that 100% of the clonal cultures differentiated towards the osteogenic lineage, while 94.1% demonstrated chondrogenesis, and 52.9% could be stimulated to adipogenesis. For osteogenesis real-time polymerase chain reaction (PCR) of BGLAP and RUNX2 and for adipogenesis of FABP4 and PPARG confirmed the results. Overall, 49% of the cells exhibited a tripotent potential, 45.1% showed a bipotent potential (without adipogenic differentiation), 3.9% bipotent (without chondrogenic differentiation), and 2% possessed a unipotent osteogenic potential. In FACS analyses, no differences in the marker profile of undifferentiated clonal cultures with bi- and tripotent differentiation capacity were found. Genome-wide microarray analysis revealed 52 differentially expressed genes for clonal subpopulations with or without chondrogenic differentiation capacity, among them DCN, NEDD9, TGFBR3, and TSLP. For clinical applications of periosteal cells in bone regeneration all cells were inducible. For a chondrogenic application a fraction of 6% of the mixed population could not be induced. PMID- 28562646 TI - Longitudinal changes in personal wellbeing in a cohort of people who inject drugs. AB - AIMS: To determine whether the self-reported personal wellbeing of a cohort of people who inject drugs (PWID) changes over time, and to identify longitudinal correlates of change. METHODS: We used Personal Wellbeing Index (PWI) scores reported between April 2008 and February 2015 by 757 PWID (66% male) enrolled in the Melbourne Injecting Drug Use Cohort Study (2,862 interviews; up to seven follow-up waves). A mixed-effects model was used to identify correlations between changes in temporal variables and changes in individual PWI scores while controlling for demographic variables. RESULTS: The cohort's mean PWI score did not significantly differ over time (between 54.4/100 and 56.7/100 across the first four interview waves), and was 25-28% lower than general Australian population scores (76.0/100). However, there were large variations in individuals' PWI scores between interviews. Increased psychological distress, moving into unstable accommodation, reporting intentional overdose in the past 12 months and being the victim of assault in the past six months were associated with declines in PWI scores. CONCLUSIONS: Participants experienced substantially lower levels of personal wellbeing than the general Australian population, influenced by experiences of psychological distress, assault, overdose and harms related to low socioeconomic status. The results of this study suggest a need to ensure referral to appropriate housing and health support services for PWID. PMID- 28562647 TI - Impact of adipose tissue or umbilical cord derived mesenchymal stem cells on the immunogenicity of human cord blood derived endothelial progenitor cells. AB - The application of autologous endothelial progenitor cell (EPC) transplantation is a promising approach in therapeutic cardiovascular diseases and ischemic diseases. In this study, we compared the immunogenicity of EPCs, adipose tissue (AD)-derived mesenchymal stem cells (MSCs) and umbilical cord (UC)-derived MSCs by flow cytometry and the mixed lymphocyte reaction. The impact of AD-MSCs and UC MSCs on the immunogenicity of EPCs was analyzed by the mixed lymphocyte reaction and cytokine secretion in vitro and was further tested by allogenic peripheral blood mononuclear cell (PBMC) induced immuno-rejection on a cell/matrigel graft in an SCID mouse model. EPCs and AD-MSCs express higher levels of MHC class I than UC-MSCs. All three kinds of cells are negative for MHC class II. UC-MSCs also express lower levels of IFN-gamma receptor mRNA when compared with EPCs and AD-MSCs. EPCs can stimulate higher rates of proliferation of lymphocytes than AD MSCs and UC-MSCs. Furthermore, AD-MSCs and UC-MSCs can modulate immune response and inhibit lymphocyte proliferation induced by EPCs, mainly through inhibition of the proliferation of CD8+ T cells. Compared with UC-MSCs, AD-MSCs can significantly improve vessel formation and maintain the integrity of neovascular structure in an EPC+MSC/matrigel graft in SCID mice, especially under allo-PBMC induced immuno-rejection. In conclusion, our study shows that AD-MSC is a powerful candidate to minimize immunological rejection and improve vessel formation in EPC transplantation treatment. PMID- 28562648 TI - Surviving anoxia in marine sediments: The metabolic response of ubiquitous benthic foraminifera (Ammonia tepida). AB - High input of organic carbon and/or slowly renewing bottom waters frequently create periods with low dissolved oxygen concentrations on continental shelves and in coastal areas; such events can have strong impacts on benthic ecosystems. Among the meiofauna living in these environments, benthic foraminifera are often the most tolerant to low oxygen levels. Indeed, some species are able to survive complete anoxia for weeks to months. One known mechanism for this, observed in several species, is denitrification. For other species, a state of highly reduced metabolism, essentially a state of dormancy, has been proposed but never demonstrated. Here, we combined a 4 weeks feeding experiment, using 13C-enriched diatom biofilm, with correlated TEM and NanoSIMS imaging, plus bulk analysis of concentration and stable carbon isotopic composition of total organic matter and individual fatty acids, to study metabolic differences in the intertidal species Ammonia tepida exposed to oxic and anoxic conditions. Strongly contrasting cellular-level dynamics of ingestion and transfer of the ingested biofilm components were observed between the two conditions. Under oxic conditions, within a few days, intact diatoms were ingested, degraded, and their components assimilated, in part for biosynthesis of different cellular components: 13C labeled lipid droplets formed after a few days and were subsequently lost (partially) through respiration. In contrast, in anoxia, fewer diatoms were initially ingested and these were not assimilated or metabolized further, but remained visible within the foraminiferal cytoplasm even after 4 weeks. Under oxic conditions, compound specific 13C analyses showed substantial de novo synthesis by the foraminifera of specific polyunsaturated fatty acids (PUFAs), such as 20:4(n-6). Very limited PUFA synthesis was observed under anoxia. Together, our results show that anoxia induced a greatly reduced rate of heterotrophic metabolism in Ammonia tepida on a time scale of less than 24 hours, these observations are consistent with a state of dormancy. PMID- 28562649 TI - Floral organ MADS-box genes in Cercidiphyllum japonicum (Cercidiphyllaceae): Implications for systematic evolution and bracts definition. AB - The dioecious relic Cercidiphyllum japonicum is one of two species of the sole genus Cercidiphyllum, with a tight inflorescence lacking an apparent perianth structure. In addition, its systematic place has been much debated and, so far researches have mainly focused on its morphology and chloroplast genes. In our investigation, we identified 10 floral organ identity genes, including four A class, three B-class, two C-class and one D-class. Phylogenetic analyses showed that all ten genes are grouped with Saxifragales plants, which confirmed the phylogenetic place of C. japonicum. Expression patterns of those genes were examined by quantitative reverse transcriptase PCR, with some variations that did not completely coincide with the ABCDE model, suggesting some subfunctionalization. As well, our research supported the idea that thebract actually is perianth according to our morphological and molecular analyses in Cercidiphyllum japonicum. PMID- 28562651 TI - Correction: Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice. AB - [This corrects the article DOI: 10.1371/journal.pone.0174544.]. PMID- 28562650 TI - Wearing lower-body compression garment with medium pressure impaired exercise induced performance decrement during prolonged running. AB - OBJECTIVE: To investigate the effect of wearing a lower body compression garment (CG) exerting different pressure levels during prolonged running on exercise induced muscle damage and the inflammatory response. METHODS: Eight male participants completed three exercise trials in a random order. The exercise consisted of 120 min of uphill running at 60% of VO2max. The exercise trials included 1) wearing a lower-body CG with 30 mmHg pressure [HIGH]; 2) wearing a lower-body CG with 15 mmHg pressure [MED]; and 3) wearing a lower-body garment with < 5 mmHg pressure [CON]. Heart rate (HR), and rate of perceived exertion for respiration and legs were monitored continuously during exercise. Time-course change in jump height was evaluated before and immediately after exercise. Blood samples were collected to determine blood glucose, lactate, serum creatine kinase, myoglobin, free fatty acids, glycerol, cortisol, and plasma interleukin-6 (IL-6) concentrations before exercise, 60 min of the 120 min exercise period, immediately after exercise, and 60 min after exercise. RESULTS: Jump height was significantly higher immediately after the exercise in the MED trial compared with that in the HIGH trial (P = 0.04). Mean HR during the 120 min exercise was significantly lower in the MED trial (162 +/- 4 bpm) than that in the CON trial (170 +/- 4 bpm, P = 0.01). Plasma IL-6 concentrations increased significantly with exercise in all trials, but the area under the curve during exercise was significantly lower in the MED trial (397 +/- 58 pg/ml.120 min) compared with that in the CON trial (670 +/- 86 pg/ml.120 min, P = 0.04). CONCLUSION: Wearing a lower body CG exerting medium pressure (approximately 15 mmHg) significantly attenuated decrease in jump performance than that with wearing a lower body CG exerting high pressure (approximately 30 mmHg). Furthermore, exercise-induced increases in HR and the inflammatory response were significantly smaller with CG exerted 15mmHg than that with garment exerted < 5 mmHg. PMID- 28562652 TI - Correction: Passive hypothermia (>=35 - <36 degrees C) during transport of newborns with hypoxic-ischaemic encephalopathy. AB - [This corrects the article DOI: 10.1371/journal.pone.0170100.]. PMID- 28562653 TI - Correction: Constitutive Association of Tie1 and Tie2 with Endothelial Integrins is Functionally Modulated by Angiopoietin-1 and Fibronectin. AB - [This corrects the article DOI: 10.1371/journal.pone.0163732.]. PMID- 28562654 TI - Correction: The Gastroprotective Effect of Vitex pubescens Leaf Extract against Ethanol-Provoked Gastric Mucosal Damage in Sprague-Dawley Rats. AB - [This corrects the article DOI: 10.1371/journal.pone.0157431.]. PMID- 28562655 TI - Assessment of the proliferation status of glioblastoma cell and tumour tissue after nanoplatinum treatment. AB - Glioblastoma is one of the most frequent primary brain tumours of the central nervous system, with a poor survival time. With inefficient chemotherapy, it is urgent to develop new strategies for tumour therapy. The present approach is based on the inhibition of cell proliferation using platinum nanoparticles (NP Pt). The aim of the study was to evaluate and compare the antiproliferative properties of NP-Pt and cisplatin against U87 and U118 glioma cell lines and U87 tumour tissue. NP-Pt and cisplatin were incubated with U87 and U118 glioma cells or administered directly into glioma tumour tissue. Cell morphology, the level of DNA synthesis, the migration of cells, protein expression levels of proliferating cell nuclear antigen (PCNA) and the level of DNA oxidation in glioma tumours were investigated. The results showed that NP-Pt treatment of U87 and U118 glioma cells decreased the level of DNA synthesis and the migration of cancer cells but also downregulated the level of PCNA protein expression in tumour tissue. Furthermore, NP-Pt caused oxidative DNA damage in tumour tissue to a higher degree than cisplatin. Consequently, NP-Pt can be considered as an effective inhibitor of glioblastoma tumour cell proliferation. However, the mechanism of action and potential side effects need to be elucidated further. PMID- 28562656 TI - Sympatric, temporally isolated populations of the pine white butterfly Neophasia menapia, are morphologically and genetically differentiated. AB - Temporal isolation remains an understudied, and potentially under-appreciated, mechanism of reproductive isolation. Phenological differences have been discovered in populations of the pine white butterfly (Neophasia menapia), a typically univoltine species found throughout western North America. At two locations in the Coast Range of California there are two periods of adult emergence per year, one in early summer (July) and one in late summer/autumn (September/October). Differences in flight time are accompanied by differences in wing shape and pigmentation. Here we use a combination of population genomics and morphological analyses to assess the extent to which temporal isolation is able to limit gene flow between sympatric early and late flights. Not only did we detect both genetic and morphological differences between early and late flights at the two sites, we also found that the patterns of differentiation between the two flights were different at each location, suggesting an independent origin for the two sympatric flights. Additionally, we found no evidence that these sympatric flights originated via colonization from any of the other sampled localities. We discuss several potential hypotheses about the origin of these temporally isolated sympatric flights. PMID- 28562657 TI - Correction: Oral Administration of Linoleic Acid Induces New Vessel Formation and Improves Skin Wound Healing in Diabetic Rats. AB - [This corrects the article DOI: 10.1371/journal.pone.0165115.]. PMID- 28562658 TI - New insight into the mechanism of mitochondrial cytochrome c function. AB - We investigate functional role of the P76GTKMIFA83 fragment of the primary structure of cytochrome c. Based on the data obtained by the analysis of informational structure (ANIS), we propose a model of functioning of cytochrome c. According to this model, conformational rearrangements of the P76GTKMIFA83 loop fragment have a significant effect on conformational mobility of the heme. It is suggested that the conformational mobility of cytochrome c heme is responsible for its optimal orientation with respect to electron donor and acceptor within ubiquinol-cytochrome c oxidoreductase (complex III) and cytochrome c oxidase (complex IV), respectively, thus, ensuring electron transfer from complex III to complex IV. To validate the model, we design several mutant variants of horse cytochrome c with multiple substitutions of amino acid residues in the P76GTKMIFA83 sequence that reduce its ability to undergo conformational rearrangements. With this, we study the succinate-cytochrome c reductase and cytochrome c oxidase activities of rat liver mitoplasts in the presence of mutant variants of cytochrome c. The electron transport activity of the mutant variants decreases to different extent. Resonance Raman spectroscopy (RRS) and surface enhanced Raman spectroscopy (SERS) data demonstrate, that all mutant cytochromes possess heme with the higher degree of ruffling deformation, than that of the wild-type (WT) cytochrome c. The increase in the ruffled deformation of the heme of oxidized cytochromes correlated with the decrease in the electron transport rate of ubiquinol-cytochrome c reductase (complex III). Besides, all mutant cytochromes have lower mobility of the pyrrol rings and methine bridges, than WT cytochrome c. We show that a decrease in electron transport activity in the mutant variants correlates with conformational changes and reduced mobility of heme porphyrin. This points to a significant role of the P76GTKMIFA83 fragment in the electron transport function of cytochrome c. PMID- 28562660 TI - A droplet digital PCR (ddPCR) assay to detect Helicoverpa armigera (Lepidoptera: Noctuidae) in bulk trap samples. AB - Moths in the genus Helicoverpa are some of the most important agricultural pests in the world. Two species, H. armigera (Hubner) and H. zea (Boddie), cause the majority of damage to crops and millions of dollars are spent annually on control of these pests. The recent introduction of H. armigera into the New World has prompted extensive survey efforts for this species in the United States. Surveys are conducted using bucket traps baited with H. armigera pheromone, and, because the same pheromone compounds attract both species, these traps often capture large numbers of the native H. zea. Adult H. armigera and H. zea are very similar and can only be separated morphologically by minor differences in the genitalia. Thus, a time consuming genitalic dissection by a trained specialist is necessary to reliably identify either species, and every specimen must be dissected. Several molecular methods are available for differentiating and identifying H. armigera and H. zea, including two recently developed rapid protocols using real time PCR. However, none of the published methods are capable of screening specimens in large batches. Here we detail a droplet digital PCR (ddPCR) assay that is capable of detecting a single H. armigera in a background of up to 999 H. zea. The assay has been tested using bulk extractions of 1,000 legs from actual trap samples and is effective even when using poor quality samples. This study provides an efficient, rapid, reproducible, and scalable method for processing H. armigera survey trap samples in the U.S. and demonstrates the potential for applying ddPCR technology to screen and diagnose invasive species. PMID- 28562659 TI - Naive helper T cells with high CD5 expression have increased calcium signaling. AB - The adaptive immune response is orchestrated by T helper cells and their function is dependent upon interactions between the T cell receptor (TCR), peptide MHC (pMHC) and co-receptors. TCR-pMHC interactions initiate calcium signaling cascades which determine T cell activation, survival, proliferation and differentiation. CD5 is a co-receptor that plays an important role in regulating T cell signaling and fate during thymocyte education. CD5 surface expression on mature single positive thymocytes correlates with the TCR signal strength for positive selecting self-ligands. CD5 also plays a role in T cell function after thymic development is complete. Peripheral T cells with higher CD5 expression respond better to foreign antigen than those with lower CD5 expression and CD5 high T cells are enriched in memory populations. In our study, we examined the role of CD5 expression and calcium signaling in the primary response of T cells using two Listeria monocytogenes specific T helper cells (LLO118 and LLO56). These T cells recognize the same immunodominant epitope (LLO190-205) of L. monocytogenes and have divergent primary and secondary responses and different levels of CD5 expression. We found that each T cell has unique calcium mobilization in response to in vitro stimulation with LLO190-205 and that CD5 expression levels in these cells changed over time following stimulation. LLO56 naive T helper cells, which expresses higher levels of CD5, have higher calcium mobilization than naive LLO118 T cells. Three days after in vitro stimulation, LLO118 T cells had more robust calcium mobilization than LLO56 and there were no differences in calcium mobilization 8 days after in vitro stimulation. To further evaluate the role of CD5, we measured calcium signaling in CD5 knockout LLO118 and LLO56 T cells at these three time points and found that CD5 plays a significant role in promoting the calcium signaling of naive CD5-high LLO56 T cells. PMID- 28562661 TI - Effects of patient load and travel distance on HIV transmission in rural China: Implications for treatment as prevention. AB - BACKGROUND: Sustained viral suppression through ART reduces sexual HIV transmission risk, but may require routine access to reliable and effective medical care which may be difficult to obtain in resource constrained areas. We investigated the roles of patient load and travel distance to HIV care clinic on transmission risk in HIV serodiscordant couples in Henan Province, China. METHODS: Cox proportional hazard models were used to compare HIV transmission events across couples living near, medium, or farther distances from their assigned HIV care clinics, as well as those attending clinics where clinicians bore high versus low patient loads. RESULTS: Most (84.4%) of the 3695 serodiscordant couples lived within 10 kilometers of their assigned HIV clinic, and most (73.5%) attended clinics with patient-to-provider ratios of at least 100:1. In adjusted Cox models, attending clinics where clinicians bore average patient loads of 100 or more elevated HIV transmission risk (aHR, 1.50, 95% CI, 1.00-4.84), an effect amplified in village tier clinics (aHR = 1.55; 95% CI, 1.23 6.78). Travel distance was associated with HIV transmission only after stratification; traveling medium distances to village clinics (5-10km) increased transmission risk (aHR = 1.83, 95% CI, 1.04-3.21) whereas traveling longer distances to township or county level clinics lowered transmission risk (aHR = 0.10, 95% CI, 0.01-0.75). CONCLUSION: Higher patient loads at HIV clinics was associated with risk of HIV transmission in our population, particularly at village level clinics. Farther travel distance had divergent effects based on clinic tier, suggesting unique mechanisms operating across levels of resource availability. The resource intensity of long-term HIV treatment may place significant strains on small rural clinics, for which investments in additional support staff or time-saving tools such as point-of-care laboratory testing may bring about impactful change in treatment outcomes. PMID- 28562662 TI - Active microrheology determines scale-dependent material properties of Chaetopterus mucus. AB - We characterize the lengthscale-dependent rheological properties of mucus from the ubiquitous Chaetopterus marine worm. We use optically trapped probes (2-10 MUm) to induce microscopic strains and measure the stress response as a function of oscillation amplitude. Our results show that viscoelastic properties are highly dependent on strain scale (l), indicating three distinct lengthscale dependent regimes at l1 <=4 MUm, l2~4-10 MUm, and l3>=10 MUm. While mucus response is similar to water for l1, suggesting that probes rarely contact the mucus mesh, the response for l2 is distinctly more viscous and independent of probe size, indicative of continuum mechanics. Only for l3 does the response match the macroscopic elasticity, likely due to additional stiffer constraints that strongly resist probe displacement. Our results suggest that, rather than a single lengthscale governing crossover from viscous to elastic, mucus responds as a hierarchical network with a loose biopolymer mesh coupled to a larger scaffold responsible for macroscopic gel-like mechanics. PMID- 28562663 TI - Cellular interactions between L-arginine and asymmetric dimethylarginine: Transport and metabolism. AB - This study was aimed to examine the effect of L-arginine (ARG) exposure on the disposition of asymmetric dimethylarginine (ADMA) in human endothelial cells. Although the role of ADMA as an inhibitor of endothelial nitric oxide synthase (eNOS) is well-recognized, cellular interactions between ARG and ADMA are not well-characterized. EA.hy926 human vascular endothelial cells were exposed to 15N4-ARG, and the concentrations of 15N4-ARG and ADMA in the cell lysate and incubation medium were determined by a liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) assay. Nitric oxide (NO) production was estimated by utilizing cumulative nitrite concentration via a fluorometric assay. Cells incubated with 15N4-ARG exhibited enhanced nitrite production as well as 15N4-ARG cellular uptake. These changes were accompanied by a decrease in cellular ADMA level and increase in extracellular ADMA level, indicating an efflux of endogenous ADMA from the cell. The time courses of ADMA efflux as well as nitrite accumulation in parallel with 15N4-ARG uptake were characterized. Following preincubation with 15N4-ARG and D7-ADMA, the efflux of cellular 15N4-ARG and D7 ADMA was significantly stimulated by high concentrations of ARG or ADMA in the incubation medium, demonstrating trans-stimulated cellular transport of these two amino acids. D7-ADMA metabolism was inhibited in the presence of added ARG. These results demonstrated that in addition to an interaction at the level of eNOS, ARG and ADMA may mutually influence their cellular availability via transport and metabolic interactions. PMID- 28562665 TI - Correction: A Conserved Nuclear Cyclophilin Is Required for Both RNA Polymerase II Elongation and Co-transcriptional Splicing in Caenorhabditis elegans. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006227.]. PMID- 28562664 TI - Towards the automated localisation of targets in rapid image-sifting by collaborative brain-computer interfaces. AB - The N2pc is a lateralised Event-Related Potential (ERP) that signals a shift of attention towards the location of a potential object of interest. We propose a single-trial target-localisation collaborative Brain-Computer Interface (cBCI) that exploits this ERP to automatically approximate the horizontal position of targets in aerial images. Images were presented by means of the rapid serial visual presentation technique at rates of 5, 6 and 10 Hz. We created three different cBCIs and tested a participant selection method in which groups are formed according to the similarity of participants' performance. The N2pc that is elicited in our experiments contains information about the position of the target along the horizontal axis. Moreover, combining information from multiple participants provides absolute median improvements in the area under the receiver operating characteristic curve of up to 21% (for groups of size 3) with respect to single-user BCIs. These improvements are bigger when groups are formed by participants with similar individual performance, and much of this effect can be explained using simple theoretical models. Our results suggest that BCIs for automated triaging can be improved by integrating two classification systems: one devoted to target detection and another to detect the attentional shifts associated with lateral targets. PMID- 28562668 TI - Correction: Introducing the Outbreak Threshold in Epidemiology. AB - [This corrects the article DOI: 10.1371/journal.ppat.1003277.]. PMID- 28562667 TI - Therapeutic silence of pleiotrophin by targeted delivery of siRNA and its effect on the inhibition of tumor growth and metastasis. AB - Pleiotrophin (PTN) is a secreted cytokine that is expressed in various cancer cell lines and human tumor such as colon cancer, lung cancer, gastric cancer and melanoma. It plays significant roles in angiogenesis, metastasis, differentiation and cell growth. The expression of PTN in the adult is limited to the hippocampus in an activity-dependent manner, making it a very attractive target for cancer therapy. RNA interference (RNAi) offers great potential as a new powerful therapeutic strategy based on its highly specific and efficient silencing of a target gene. However, efficient delivery of small interfering RNA (siRNA) in vivo remains a significant hurdle for its successful therapeutic application. In this study, we first identified, on a cell-based experiment, applying a 1:1 mixture of two PTN specific siRNA engenders a higher silencing efficiency on both mRNA and protein level than using any of them discretely at the same dose. As a consequence, slower melanoma cells growth was also observed for using two specific siRNA combinatorially. To establish a robust way for siRNA delivery in vivo and further investigate how silence of PTN affects tumor growth, we tested three different methods to deliver siRNA in vivo: first non-targeted in-vivo delivery of siRNA via jetPEI; second lung targeted delivery of siRNA via microbubble coated jetPEI; third tumor cell targeted delivery of siRNA via transferrin-polyethylenimine (Tf-PEI). As a result, we found that all three in vivo siRNAs delivery methods led to an evident inhibition of melanoma growth in non-immune deficiency C57BL/6 mice without a measureable change of ALT and AST activities. Both targeted delivery methods showed more significant curative effect than jetPEI. The lung targeted delivery by microbubble coated jetPEI revealed a comparable therapeutic effect with Tf-PEI, indicating its potential application for target delivery of siRNA in vivo. PMID- 28562666 TI - Quantitative analysis of the CD4+ T cell response to therapeutic antibodies in healthy donors using a novel T cell:PBMC assay. AB - Many biopharmaceuticals (BPs) are known to be immunogenic in the clinic, which can result in modified pharmacokinetics, reduced efficacy, allergic reactions and anaphylaxis. During recent years, several technologies to predict immunogenicity have been introduced, but the predictive value is still considered low. Thus, there is an unmet medical need for optimization of such technologies. The generation of T cell dependent high affinity anti-drug antibodies plays a key role in clinical immunogenicity. This study aimed at developing and evaluating a novel in vitro T cell:PBMC assay for prediction of the immunogenicity potential of BPs. To this end, we assessed the ability of infliximab (anti-TNF-alpha), rituximab (anti-CD20), adalimumab (anti-TNF-alpha) and natalizumab (anti-alpha4 integrin), all showing immunogenicity in the clinic, to induce a CD4+ T cells response. Keyhole limpet hemocyanin (KLH) and cytomegalovirus pp65 protein (CMV) were included as neo-antigen and recall antigen positive controls, respectively. By analyzing 26 healthy donors having HLA-DRB1 alleles matching the European population, we calculated the frequency of responding donors, the magnitude of the response, and the frequency of BP-specific T cells, as measured by 3[H] thymidine incorporation and ELISpot IL-2 secretion. KLH and CMV demonstrated a strong T cell response in all the donors analyzed. The frequency of responding donors to the BPs was 4% for infliximab, 8% for adalimumab, 19% for rituximab and 27% for natalizumab, which is compared to and discussed with their respective observed clinical immunogenicity. This study further complements predictive immunogenicity testing by quantifying the in vitro CD4+ T cell responses to different BPs. Even though the data generated using this modified method does not directly translate to the clinical situation, a high sensitivity and immunogenic potential of most BPs is demonstrated. PMID- 28562669 TI - Design and preliminary analysis of a vaginal inserter for speculum-free cervical cancer screening. AB - OBJECTIVE: Cervical cancer screening usually requires use of a speculum to provide a clear view of the cervix. The speculum is one potential barrier to screening due to fear of pain, discomfort and embarrassment. The aim of this paper is to present and demonstrate the feasibility of a tampon-sized inserter and the POCkeT Colposcope, a miniature pen sized-colposcope, for comfortable, speculum-free and potentially self-colposcopy. STUDY DESIGN: We explored different designs using 3D computer-aided design (CAD) software and performed mechanical testing simulations on each. Designs were rapid prototyped and tested using a custom vaginal phantom across a range of vaginal pressures and uterine tilts to select an optimal design. Two final designs were tested with fifteen volunteers to assess cervix visualization, comfort and usability compared to the speculum and the optimal design, the curved-tip inserter, was selected for testing in volunteers. RESULTS: We present a vaginal inserter as an alternative to the standard speculum for use with the POCkeT Colposcope. The device has a slim tubular body with a funnel-like curved tip measuring approximately 2.5 cm in diameter. The inserter has a channel through which a 2 megapixel (MP) mini camera with LED illumination fits to enable image capture. Mechanical finite element testing simulations with an applied pressure of 15 cm H2O indicated a high factor of safety (90.9) for the inserter. Testing of the device with a custom vaginal phantom, across a range of supine vaginal pressures and uterine tilts (retroverted, anteverted and sideverted), demonstrated image capture with a visual area comparable to the speculum for a normal/axial positioned uteri and significantly better than the speculum for anteverted and sideverted uteri (p<0.00001). Volunteer studies with self-insertion and physician-assisted cervix image capture showed adequate cervix visualization for 83% of patients. In addition, questionnaire responses from volunteers indicated a 92.3% overall preference for the inserter over the speculum and all indicated that the inserter was more comfortable than the speculum. The inserter provides a platform for self cervical cancer screening and also enables acetic acid/Lugol's iodine application and insertion of swabs for Pap smear sample collection. CONCLUSION: This study demonstrates the feasibility of an inserter and miniature-imaging device for comfortable cervical image capture of women with potential for synergistic HPV and Pap smear sample collection. PMID- 28562671 TI - Integrative genomic analyses for identification and prioritization of long non coding RNAs associated with autism. AB - Genetic studies have identified many risk loci for autism spectrum disorder (ASD) although causal factors in the majority of cases are still unknown. Currently, known ASD risk genes are all protein-coding genes; however, the vast majority of transcripts in humans are non-coding RNAs (ncRNAs) which do not encode proteins. Recently, long non-coding RNAs (lncRNAs) were shown to be highly expressed in the human brain and crucial for normal brain development. We have constructed a computational pipeline for the integration of various genomic datasets to identify lncRNAs associated with ASD. This pipeline utilizes differential gene expression patterns in affected tissues in conjunction with gene co-expression networks in tissue-matched non-affected samples. We analyzed RNA-seq data from the cortical brain tissues from ASD cases and controls to identify lncRNAs differentially expressed in ASD. We derived a gene co-expression network from an independent human brain developmental transcriptome and detected a convergence of the differentially expressed lncRNAs and known ASD risk genes into specific co expression modules. Co-expression network analysis facilitates the discovery of associations between previously uncharacterized lncRNAs with known ASD risk genes, affected molecular pathways and at-risk developmental time points. In addition, we show that some of these lncRNAs have a high degree of overlap with major CNVs detected in ASD genetic studies. By utilizing this integrative approach comprised of differential expression analysis in affected tissues and connectivity metrics from a developmental co-expression network, we have prioritized a set of candidate ASD-associated lncRNAs. The identification of lncRNAs as novel ASD susceptibility genes could help explain the genetic pathogenesis of ASD. PMID- 28562670 TI - Increased threshold of short-latency motor evoked potentials in transgenic mice expressing Channelrhodopsin-2. AB - Transgenic mice that express channelrhodopsin-2 or its variants provide a powerful tool for optogenetic study of the nervous system. Previous studies have established that introducing such exogenous genes usually does not alter anatomical, electrophysiological, and behavioral properties of neurons in these mice. However, in a line of Thy1-ChR2-YFP transgenic mice (line 9, Jackson lab), we found that short-latency motor evoked potentials (MEPs) induced by transcranial magnetic stimulation had a longer latency and much lower amplitude than that of wild type mice. MEPs evoked by transcranial electrical stimulation also had a much higher threshold in ChR2 mice, although similar amplitudes could be evoked in both wild and ChR2 mice at maximal stimulation. In contrast, long latency MEPs evoked by electrically stimulating the motor cortex were similar in amplitude and latency between wild type and ChR2 mice. Whole-cell patch clamp recordings from layer V pyramidal neurons of the motor cortex in ChR2 mice revealed no significant differences in intrinsic membrane properties and action potential firing in response to current injection. These data suggest that corticospinal tract is not accountable for the observed abnormality. Motor behavioral assessments including BMS score, rotarod, and grid-walking test showed no significant differences between the two groups. Because short-latency MEPs are known to involve brainstem reticulospinal tract, while long-latency MEPs mainly involve primary motor cortex and dorsal corticospinal tract, we conclude that this line of ChR2 transgenic mice has normal function of motor cortex and dorsal corticospinal tract, but reduced excitability and responsiveness of reticulospinal tracts. This abnormality needs to be taken into account when using these mice for related optogenetic study. PMID- 28562672 TI - Rapid detection and strain typing of Chlamydia trachomatis using a highly multiplexed microfluidic PCR assay. AB - Nucleic acid amplification tests (NAATs) are recommended by the CDC for detection of Chlamydia trachomatis (Ct) urogenital infections. Current commercial NAATs require technical expertise and sophisticated laboratory infrastructure, are time consuming and expensive, and do not differentiate the lymphogranuloma venereum (LGV) strains that require a longer duration of treatment than non-LGV strains. The multiplexed microfluidic PCR-based assay presented in this work simultaneously interrogates 13 loci to detect Ct and identify LGV and non-LGV strain-types. Based on amplified fragment length polymorphisms, the assay differentiates LGV, ocular, urogenital, and proctocolitis clades, and also serovars L1, L2, and L3 within the LGV group. The assay was evaluated in a blinded fashion using 95 clinical swabs, with 76 previously reported as urogenital Ct-positive samples and typed by ompA genotyping and/or Multi-Locus Sequence Typing. Results of the 13-plex assay showed that 51 samples fell within urogenital clade 2 or 4, 24 samples showed both clade 2 and 4 signatures, indicating possible mixed infection, gene rearrangement, or inter-clade recombination, and one sample was a noninvasive trachoma biovar (either a clade 3 or 4). The remaining 19 blinded samples were correctly identified as LGV clade 1 (3), ocular clade 3 (4), or as negatives (12). To date, no NAAT assay can provide a point-of-care applicable turnaround time for Ct detection while identifying clinically significant Ct strain types to inform appropriate treatment. Coupled with rapid DNA processing of clinical swabs (approximately 60 minutes from swab in to result-out), the assay has significant potential as a rapid POC diagnostic for Ct infections. PMID- 28562673 TI - Analysis of ParB-centromere interactions by multiplex SPR imaging reveals specific patterns for binding ParB in six centromeres of Burkholderiales chromosomes and plasmids. AB - Bacterial centromeres-also called parS, are cis-acting DNA sequences which, together with the proteins ParA and ParB, are involved in the segregation of chromosomes and plasmids. The specific binding of ParB to parS nucleates the assembly of a large ParB/DNA complex from which ParA-the motor protein, segregates the sister replicons. Closely related families of partition systems, called Bsr, were identified on the chromosomes and large plasmids of the multi chromosomal bacterium Burkholderia cenocepacia and other species from the order Burkholeriales. The centromeres of the Bsr partition families are 16 bp palindromes, displaying similar base compositions, notably a central CG dinucleotide. Despite centromeres bind the cognate ParB with a narrow specificity, weak ParB-parS non cognate interactions were nevertheless detected between few Bsr partition systems of replicons not belonging to the same genome. These observations suggested that Bsr partition systems could have a common ancestry but that evolution mostly erased the possibilities of cross-reactions between them, in particular to prevent replicon incompatibility. To detect novel similarities between Bsr partition systems, we have analyzed the binding of six Bsr parS sequences and a wide collection of modified derivatives, to their cognate ParB. The study was carried out by Surface Plasmon Resonance imaging (SPRi) mulitplex analysis enabling a systematic survey of each nucleotide position within the centromere. We found that in each parS some positions could be changed while maintaining binding to ParB. Each centromere displays its own pattern of changes, but some positions are shared more or less widely. In addition from these changes we could speculate evolutionary links between these centromeres. PMID- 28562675 TI - Addressing tuberculosis control in fragile states: Urban DOTS experience in Kabul, Afghanistan, 2009-2015. AB - Tuberculosis (TB) is a major public health problem in Afghanistan, but experience in implementing effective strategies to prevent and control TB in urban areas and conflict zones is limited. This study shares programmatic experience in implementing DOTS in the large city of Kabul. We analyzed data from the 2009-2015 reports of the National TB Program (NTP) for Kabul City and calculated treatment outcomes and progress in case notification using rates, ratios, and confidence interval. Urban DOTS was implemented by the NTP in partnership with United States Agency for International Development (USAID)-funded TB projects, the World Health Organization (WHO), and the private sector. Between 2009 and 2015, the number of DOTS-providing centers in Kabul increased from 22 to 85. In total, 24,619 TB patients were enrolled in TB treatment during this period. The case notification rate for all forms of TB increased from 59 per 100,000 population to 125 per 100,000. The case notification rate per 100,000 population for sputum-smear positive TB increased from 25 to 33. The treatment success rate for all forms of TB increased from 31% to 67% and from 47% to 77% for sputum-smear-positive TB cases. The treatment success rate for private health facilities increased from 52% in 2010 to 80% in 2015. In 2013, contact screening was introduced, and the TB yield was 723 per 100,000-more than two times higher than the estimated national prevalence of 340 per 100,000. Contact screening contributed to identifying 2,509 child contacts of people with TB, and 76% of those children received isoniazid preventive therapy. The comprehensive urban DOTS program significantly improved service accessibility, TB case finding, and treatment outcomes in Kabul. Public- and private-sector involvement also improved treatment outcomes; however, the treatment success rate remains higher in private health facilities. While the treatment success rate increased significantly, it remains lower than the national average, and more efforts are needed to improve treatment outcomes in Kabul. We recommend that the urban DOTS approach be replicated in other countries and cities in Afghanistan with settings similar to Kabul. PMID- 28562674 TI - How does functionality proceed in ACL reconstructed subjects? Proceeding of functional performance from pre- to six months post-ACL reconstruction. AB - This is the first study examining functionality of subjects with anterior cruciate ligament (ACL) tears and a subsequent reconstruction comprehensively by multiple test sessions from pre- to six months post-reconstruction. The purpose was to evaluate if a generally applied rehabilitation program restores functionality to levels of healthy controls. Subjects with unilateral tears of the ACL were compared to matched healthy controls throughout the rehabilitation. 20 recreational athletes were tested: T1 (preoperative), 6 weeks after tear; T2, 6 weeks, T3, 3 months, T4, 6 months post-reconstruction. At all test sessions, subjects self-evaluated their activity level with the Tegner activity score and their knee state with the Knee Injury and Osteoarthritis Outcome Score. Passive range of motion during knee flexion and extension and leg circumference were measured as functional clinical tests. Bilateral countermovement jumps, one-leg jumps for distance and isometric force tests in knee flexion and extension with 90 degrees and 110 degrees knee angle were conducted as functional performance tests. For determination of functionality, leg symmetry indices (LSIs) were calculated by dividing values of the injured by the uninjured leg. In the ACL group most LSIs decreased from T1 to T2, and increased from T2 and T3 to T4. LSIs of ACL subjects remained lower than LSIs of healthy controls at 6 months post reconstruction in nearly all parameters. Self-evaluation of ACL subjects showed, additionally, that activity level was lower than the pre-injury level at 6 months post-reconstruction. Low LSIs and low self-evaluation indicate that knee joint functionality is not completely restored at 6 months post-reconstruction. The study shows that multiple comprehensive testing throughout the rehabilitation gives detailed images of the functional state. Therefore, the functional state of ACL reconstructed individuals should be evaluated comprehensively and continuously throughout the rehabilitation to detect persisting deficiencies detailed and adapt rehabilitation programs individually depending on the functionality. PMID- 28562676 TI - Nasal colonization and bacterial contamination of mobile phones carried by medical staff in the operating room. AB - BACKGROUND: Mobile phones (MPs) have been an essential part of the lives of healthcare professionals and have improved communication, collaboration, and sharing of information. Nonetheless, the widespread use of MPs in hospitals has raised concerns of nosocomial infections, especially in areas requiring the highest hygienic standards such as operating rooms (ORs). This study evaluated the incidence of bacterial contamination of the MPs carried by medical staff working in the OR and determined its association with bacterial colonization of this personnel. METHODS: This is an observational cohort study. Medical staffs working in the OR were asked to take bacterial cultures from their MPs, anterior nares, and dominant hands. To identify the relation between MP contamination and bacterial colonization of the medical staff, genotyping of Staphylococcus aureus (SA) was done via Staphylococcus protein A gene (spa) typing and pulsed-field gel electrophoresis (PFGE). RESULTS: A total of 216 swab samples taken from 72 medical-staff members were analyzed. The culture-positive rate was 98.1% (212/216). In 59 (27.3%) samples, the bacteria were possible clinical pathogens. The anterior nares were the most common site of colonization by clinical pathogens (58.3%, 42/72), followed by MPs (13.9%, 10/72) and the dominant hand (9.7%, 7/72). SA was the most commonly isolated clinical pathogen and was found in 43 (19.9%) samples. In 66 (94.3%) of the 70 staff members for whom bacteria were detected on their MPs, the same bacteria were detected in nares or hand. Among 31 medical staff who were carriers of SA in the anterior nares or dominant hand, 8 (25.8%) were found to have SA on their MPs, and genotyping confirmed the same SA strain in 7 (87.5%) of them. CONCLUSION: A high rate of bacterial nasal colonization and MPs contamination were found among the OR medical staff. An MP may be a reservoir for pathogen contamination in the OR. PMID- 28562677 TI - Correction: Helios expression and Foxp3 TSDR methylation of IFNy+ and IFNy- Treg from kidney transplant recipients with good long-term graft function. AB - [This corrects the article DOI: 10.1371/journal.pone.0173773.]. PMID- 28562678 TI - Comparison of three nudge interventions (priming, default option, and perceived variety) to promote vegetable consumption in a self-service buffet setting. AB - BACKGROUND: Dietary choices in out-of-home eating are key for individual as well as for public health. These dietary choices are caused by a wide array of determinants, one of which is automatic decision-making. Nudging is attracting considerable interest due to its understanding and application of heuristic biases among consumers. The aim of this study is to test and compare three nudges in promoting vegetable consumption among test persons in a food lab-based experiment. METHODS: The initial sample consisted of 88 participants recruited in Copenhagen, Denmark. Each study participant was randomly assigned to one of the three experiments: priming, default and perceived variety. The priming arm of the experiment consisted of creating a leafy environment with green plants and an odour of herbs. In the default arm of the experiment, the salad was pre-portioned into a bowl containing 200g of vegetables. The third experiment divided the pre mixed salad into each of its components, to increase the visual variety of vegetables, yet not providing an actual increase in items. Each individual was partaking twice thus serving as her/his own control, randomly assigned to start with control or experimental setting. RESULTS: The default experiment successfully increased the energy intake from vegetables among the study participants (124 kcal vs. 90 kcal in control, p<0.01). Both the priming condition and perceived variety reduced the total energy intake among the study participants (169 kcal, p<0.01 and 124 kcal, p<0.01, respectively), mainly through a decrease in the meat-based meal component. CONCLUSIONS: Considerable progress has been made with regard to understanding the use of nudging in promoting a healthier meal composition, including increasing vegetable intake. This study suggests that the nature of a nudge-based intervention can have different effects, whether it is increasing intake of healthy components, or limiting intake of unhealthy meal components. This work has demonstrated that consumer behaviour can be influenced without restricting or providing incentives for behaviour change. The present findings have promising application to the foodservice sector. PMID- 28562679 TI - Change in clinical outcomes during the transition of adjuvant chemotherapy for stage III colorectal cancer. AB - BACKGROUND: There are robust data supporting the contribution of oxaliplatin (L OHP) regarding clinical outcomes for colorectal cancer (CRC) in an adjuvant setting in European and US trials; however, there is no Japanese clinical evidence although L-OHP has been approved since 2009. We examined the transition of adjuvant chemotherapy for stage III colorectal cancer in our institute. METHODS: A total of 642 patients with histopathologically confirmed stage III CRC underwent curative surgery from 2005 to 2010. We examined disease free survival (DFS), overall survival (OS) and prognostic factors for stage III CRC patients who underwent adjuvant chemotherapy. RESULTS: A total of 509 patients received adjuvant chemotherapy. 3-year DFS and 5-year OS rates were 74.5% and 87.5%, respectively. The frequency of inclusion of L-OHP as adjuvant chemotherapy was increased after 2008. A total of 189 patients received adjuvant chemotherapy from 2005 to 2007 increasing to 320 patients from 2008 to 2010; the 5-year OS rates were 82.4% and 91.5%, respectively, and the 3-year DFS rates were 69.2% and 76.6%, respectively (OS, P = 0.007; DFS, P = 0.023). In univariate analysis, adjuvant chemotherapy including L-OHP was no significant deference compared to FU monotherapy. (OS: HR 0.88, 95%CI 0.4-1.91, p = 0.75, DFS: HR 0.78, 95%CI 0.21 2.3, p = 0.29). In multivariate analysis, the OS was predicted by means of N stage (HR = 2; 95%CI, 1.1-3.8; P = 0.02) and pathology (HR = 0.28; 95%CI, 0.13 0.59; P = 0.0008). The DFS was predicted by means of N stage (HR = 2.67; 95%CI, 1.82-3.9; P < 0.05), T stage (HR = 1.61; 95%CI, 1.1-2.3; P = 0.01) pathology (HR = 0.47; 95%CI, 0.29-0.75; P < 0.05) and venous invasion (HR = 2.06; 95%CI, 1.12 3.77; P = 0.01). CONCLUSIONS: Clinical outcomes of stage III CRC patients receiving adjuvant chemotherapy improved. The frequency of L-OHP usage was increasing annually, however it was no influence for clinical outcomes in this study. It will be necessary to reevaluate additional effect of L-OHP with more patients. PMID- 28562681 TI - An optimization design proposal of automated guided vehicles for mixed type transportation in hospital environments. AB - AIM: The aim of this paper is to present an optimization proposal in the automated guided vehicles design used in hospital logistics, as well as to analyze the impact of its implementation in a real environment. METHOD: This proposal is based on the design of those elements that would allow the vehicles to deliver an extra cart by the towing method. So, the proposal intention is to improve the productivity and the performance of the current vehicles by using a transportation method of combined carts. RESULTS: The study has been developed following concurrent engineering premises from three different viewpoints. First, the sequence of operations has been described, and second, a proposal of design of the equipment has been undertaken. Finally, the impact of the proposal has been analyzed according to real data from the Hospital Universitario Rio Hortega in Valladolid (Spain). In this particular case, by the implementation of the analyzed proposal in the hospital a reduction of over 35% of the current time of use can be achieved. This result may allow adding new tasks to the vehicles, and according to this, both a new kind of vehicle and a specific module can be developed in order to get a better performance. PMID- 28562680 TI - Genome-wide association study provides strong evidence of genes affecting the reproductive performance of Nellore beef cows. AB - Reproductive traits are economically important for beef cattle production; however, these traits are still a bottleneck in indicine cattle since these animals typically reach puberty at older ages when compared to taurine breeds. In addition, reproductive traits are complex phenotypes, i.e., they are controlled by both the environment and many small-effect genes involved in different pathways. In this study, we conducted genome-wide association study (GWAS) and functional analyses to identify important genes and pathways associated with heifer rebreeding (HR) and with the number of calvings at 53 months of age (NC53) in Nellore cows. A total of 142,878 and 244,311 phenotypes for HR and NC53, respectively, and 2,925 animals genotyped with the Illumina Bovine HD panel (Illumina(r), San Diego, CA, USA) were used in GWAS applying the weighted single step GBLUP (WssGBLUP) method. Several genes associated with reproductive events were detected in the 20 most important 1Mb windows for both traits. Significant pathways for HR and NC53 were associated with lipid metabolism and immune processes, respectively. MHC class II genes, detected on chromosome 23 (window 25 26Mb) for NC53, were significantly associated with pregnancy success of Nellore cows. These genes have been proved previously to be associated with reproductive traits such as mate choice in other breeds and species. Our results suggest that genes associated with the reproductive traits HR and NC53 may be involved in embryo development in mammalian species. Furthermore, some genes associated with mate choice may affect pregnancy success in Nellore cattle. PMID- 28562682 TI - An elevated serum alkaline phosphatase level in hepatic metastases of grade 1 and 2 gastrointestinal neuroendocrine tumors is unusual and of prognostic value. AB - BACKGROUND: In our clinical practice we have observed that despite a high hepatic metastatic tumor burden, serum alkaline phosphatase (AP) levels are frequently normal in cases of metastatic neuroendocrine tumor (NET). PATIENTS AND METHODS: We retrospectively reviewed the records of patients with grade 1 and 2 NETs with liver metastases but without bone metastases seen at our institution in 2013. In total, 49 patients were included (22 female), with a median age of 60 years (range: 28 to 84 years). The primary tumors were located in the duodenum/pancreas (n = 29), small bowel (n = 17) or colon/rectum (n = 3); 10 cases were grade 1 and 39 grade 2. Hepatic involvement was bulky, with more than 10 lesions in 23 patients and a tumor burden above 10% of the liver volume in 26 patients. RESULTS: Serum AP levels were elevated (>= upper limit of normal (ULN)) in 16 patients. In multiparametric analysis, elevated serum AP levels were not associated with the primary site, grade, or number or volume of metastases. In multiparametric analysis, progression-free survival was only correlated with grade (p = 0.010) and AP level (p = 0.017). CONCLUSIONS: Serum AP levels are frequently normal in liver metastases from NET, even in the event of a major tumor burden, and the serum AP level can be of prognostic value. PMID- 28562683 TI - Quantitating morphological changes in biological samples during scanning electron microscopy sample preparation with correlative super-resolution microscopy. AB - Sample preparation is critical to biological electron microscopy (EM), and there have been continuous efforts on optimizing the procedures to best preserve structures of interest in the sample. However, a quantitative characterization of the morphological changes associated with each step in EM sample preparation is currently lacking. Using correlative EM and superresolution microscopy (SRM), we have examined the effects of different drying methods as well as osmium tetroxide (OsO4) post-fixation on cell morphology during scanning electron microscopy (SEM) sample preparation. Here, SRM images of the sample acquired under hydrated conditions were used as a baseline for evaluating morphological changes as the sample went through SEM sample processing. We found that both chemical drying and critical point drying lead to a mild cellular boundary retraction of ~60 nm. Post fixation by OsO4 causes at least 40 nm additional boundary retraction. We also found that coating coverslips with adhesion molecules such as fibronectin prior to cell plating helps reduce cell distortion from OsO4 post-fixation. These quantitative measurements offer useful information for identifying causes of cell distortions in SEM sample preparation and improving current procedures. PMID- 28562684 TI - Bottles to trees: Plastic beverage bottles as an alternative nursery growing container for reforestation in developing countries. AB - Reforestation is needed globally to help restore degraded sites, combat desertification, protect watersheds, and provide forest products. This involves planting forest tree seedlings grown in local nurseries, but technologies to produce quality seedlings are lacking in developing countries. Modern nursery containers used to propagate seedlings have internal-surface barriers (ribs or ridges) or side-slits to prevent root spiraling. These are cost prohibitive or unavailable in developing countries and so polybags (plastic bags) are more commonly used, despite their tendency to produce seedlings with deformed root systems that have less potential to establish on field sites. Discarded plastic bottles, which are readily available worldwide, may be a feasible alternative for seedling propagation. We conducted two experiments to assess the potential of repurposed plastic beverage bottles to grow quality trees: 1) Container Comparison-to evaluate Arizona walnut (Juglans major [Toor.] Heller) and Afghan pine (Pinus eldarica Medw.) seedling root and shoot development in two plastic bottle types compared to modern nursery containers and polybags, and 2) Bottle Modification-to examine the effects of root spiraling prevention techniques (side slits, internal-ridges, and control) and container opacity (green, black, and clear) on Afghan pine seedling morphological attributes. Nursery growth and first year seedling field performance were evaluated for both experiments. In experiment one, seedlings of both species had fewer spiraled roots in bottle containers compared to polybags. Arizona walnut had more fibrous root systems in polybags, while Afghan pine root system fibrosity was greatest in bottle containers. First-year field performance of both species was not affected by container type. In experiment two, less spiraled roots occurred in containers with air-slits and interior-ridges compared to the control. The effects of container opacity on seedling morphology were inconsistent. Root spiral prevention and opacity had no influence on Afghan pine one-year survival, field height and diameter, with the exception of opacity for height growth, whereby seedlings grown in green containers were taller than those grown in black containers, but seedlings grown in clear containers were similar to both. Our results provide the first evidence that plastic bottle containers may provide an effective alternative for production of high quality seedlings, which may benefit agroforestry, reforestation, restoration, and conservation programs in developing countries. PMID- 28562685 TI - Gender difference in relationship between serum ferritin and 25-hydroxyvitamin D in Korean adults. AB - BACKGROUND: The present study was conducted to assess the gender difference in the relationship between serum ferritin and 25-hydroxyvitamin D [25(OH)D] in Korean adults. METHODS: A total of 5,147 adults (2,162 men, 1,563 premenopausal women, and 1,422 postmenopausal women) aged >= 20 years from the Korean National Health and Nutrition Examination Survey (KNHANES) data (2012) were analyzed. A covariance test adjusted for covariates was performed for serum ferritin levels in relation to vitamin D status (vitamin D deficiency, 25(OH)D < 10.0 ng/mL; vitamin D insufficiency, 25(OH)D >= 10.0, < 20.0 ng/mL; vitamin D sufficiency, 25(OH)D >= 20.0 ng/mL). RESULTS: The key study results were as follows: First, in men, in terms of serum ferritin levels by serum 25(OH)D level after adjusting for age, smoking, alcohol drinking, regular exercise, SBP, DBP, WM. TC, TGs, HDL-C, FPG, Hb, Hct, MCV, and Fe, serum ferritin levels were inversely increased with the increasing of serum 25(OH)D level (P = 0.012). Second, in premenopausal women, after adjusting for related variables, serum ferritin levels were increased with the increasing of serum 25(OH)D level (P = 0.003). Third, in postmenopausal women, after adjusting for related variables, serum ferritin levels were not significantly increased with the increasing of serum 25(OH)D level (P = 0.456). CONCLUSION: Serum 25(OH)D level was inversely associated with the serum ferritin levels in men, but was positively associated with the serum ferritin levels in premenopausal women, and was not associated with the serum ferritin levels in postmenopausal women. PMID- 28562686 TI - Consolation in the aftermath of robberies resembles post-aggression consolation in chimpanzees. AB - Post-aggression consolation is assumed to occur in humans as well as in chimpanzees. While consolation following peer aggression has been observed in children, systematic evidence of consolation in human adults is rare. We used surveillance camera footage of the immediate aftermath of nonfatal robberies to observe the behaviors and characteristics of victims and bystanders. Consistent with empathy explanations, we found that consolation was linked to social closeness rather than physical closeness. While females were more likely to console than males, males and females were equally likely to be consoled. Furthermore, we show that high levels of threat during the robbery increased the likelihood of receiving consolation afterwards. These patterns resemble post aggression consolation in chimpanzees and suggest that emotions of empathic concern are involved in consolation across humans and chimpanzees. PMID- 28562687 TI - The four-transmembrane protein MAL2 and tumor protein D52 (TPD52) are highly expressed in colorectal cancer and correlated with poor prognosis. AB - The four-transmembrane protein MAL2 and tumor protein D52 (TPD52) have been shown to be involved in tumorigenesis of various cancers. However, their roles in colorectal cancer (CRC) remain unclear. In this study, we explored the expressions of MAL2 and TPD52 in tumor specimens resected from 123 CRC patients and the prognostic values of the two proteins in CRC. Immunohistochemical analyses showed that MAL2 (P<0.001) and TPD52 (P<0.001) were significantly highly expressed in primary carcinoma tissues compared with adjacent non-cancerous mucosa tissues. And TPD52 exhibited frequent overexpression in liver metastasis tissues relative to primary carcinoma tissues (P = 0.042), while MAL2 in lymphnode and liver metastasis tissues showed no significant elevation. Real-time quantitative PCR (RT-qPCR) showed the identical results. Correlation analyses by Pearson's chi-square test demonstrated that MAL2 in tumors was positively correlated with tumor status (pathological assessment of regional lymph nodes (pN, P = 0.024)), and clinic stage (P = 0.017). Additionally, the expression of TPD52 was detected under the same condition and was shown to be positively correlated withtumor status (pathological assessment of the primary tumor (pT, P = 0.035), distant metastasis (pM, P = 0.001)) and CRC clinicopathology(P = 0.024). Kaplan-Meier survival curves indicated that positive MAL2 (P<0.001) and TPD52 (P<0.001) expressions were associated with poor overall survival (OS) in CRC patients. Multivariate analysis showed that MAL2 and TPD52 expression was an independent prognostic factor for reduced OS of CRC patients. Moreover, overexpression of TPD52 in CRC SW480 cells showed an increased cell migration (P = 0.023) and invasion (P = 0.012) through inducing occurrence of epithelial mesenchymal transition (EMT) and activating focal adhesion kinase (FAK)-mediated integrin signalling and PI3K/Akt signalling.Whereas TPD52-depleted cells showed the reverse effect. These data suggested that MAL2 and TPD52 might be potential biomarkers for clinical prognosis and might be a promising therapeutic target for CRC. PMID- 28562688 TI - Smooth muscle cell-specific Notch1 haploinsufficiency restricts the progression of abdominal aortic aneurysm by modulating CTGF expression. AB - AIMS: Infiltration of macrophages and apoptosis of vascular smooth muscle cells (VSMCs) promote the development of abdominal aortic aneurysm (AAA). Previously, we demonstrated that global Notch1 deficiency prevents the formation of AAA in a mouse model. Herein, we sought to explore the cell-specific roles of Notch1 in AAA development. METHODS AND RESULTS: Cell-specific Notch1 haploinsufficient mice, generated on Apoe-/- background using Cre-lox technology, were infused with angiotensin II (1000 ng/min/kg) for 28 days. Notch1 haploinsufficiency in myeloid cells (n = 9) prevented the formation of AAA attributed to decreased inflammation. Haploinsufficiency of Notch1 in SMCs (n = 14) per se did not prevent AAA formation, but histoarchitectural traits of AAA including elastin degradation and aortic remodeling, were minimal in SMC-Notch1+/-;Apoe-/- mice compared to Apoe-/- mice (n = 33). Increased immunostaining of the contractile SMC-phenotype markers and concomitant decreased expression of synthetic SMC phenotype markers were observed in the aortae of SMC-Notch1+/-;Apoe-/- mice. Expression of connective tissue growth factor (CTGF), a matrix-associated protein that modulates the synthetic VSMC phenotype, increased in the abdominal aorta of Apoe-/- mice and in the adventitial region of the abdominal aorta in human AAA. Notch1 haploinsufficiency decreased the expression of Ctgf in the aorta and in vitro cell culture system. In vitro studies on SMCs using the Notch1 intracellular domain (NICD) plasmid, dominant negative mastermind-like (dnMAML), or specific siRNA suggest that Notch1, not Notch3, directly modulates the expression of CTGF. CONCLUSIONS: Our data suggest that lack of Notch1 in SMCs limits dilation of the abdominal aorta by maintaining contractile SMC-phenotype and preventing matrix-remodeling. PMID- 28562689 TI - Comparison of single-marker and multi-marker tests in rare variant association studies of quantitative traits. AB - In genetic association studies of rare variants, low statistical power and potential violations of established estimator properties are among the main challenges of association tests. Multi-marker tests (MMTs) have been proposed to target these challenges, but any comparison with single-marker tests (SMTs) has to consider that their aim is to identify causal genomic regions instead of variants. Valid power comparisons have been performed for the analysis of binary traits indicating that MMTs have higher power, but there is a lack of conclusive studies for quantitative traits. The aim of our study was therefore to fairly compare SMTs and MMTs in their empirical power to identify the same causal loci associated with a quantitative trait. The results of extensive simulation studies indicate that previous results for binary traits cannot be generalized. First, we show that for the analysis of quantitative traits, conventional estimation methods and test statistics of single-marker approaches have valid properties yielding association tests with valid type I error, even when investigating singletons or doubletons. Furthermore, SMTs lead to more powerful association tests for identifying causal genes than MMTs when the effect sizes of causal variants are large, and less powerful tests when causal variants have small effect sizes. For moderate effect sizes, whether SMTs or MMTs have higher power depends on the sample size and percentage of causal SNVs. For a more complete picture, we also compare the power in studies of quantitative and binary traits, and the power to identify causal genes with the power to identify causal rare variants. In a genetic association analysis of systolic blood pressure in the Genetic Analysis Workshop 19 data, SMTs yielded smaller p-values compared to MMTs for most of the investigated blood pressure genes, and were least influenced by the definition of gene regions. PMID- 28562690 TI - Initial computed tomography imaging details during first-line systemic therapy is of significant prognostic value in patients with naive, unresectable metastatic renal cell carcinoma. AB - PURPOSE: We aimed to determine the prognostic significance of computed tomography imaging parameters of unresectable primary renal tumor lesions, obtained at baseline and at first follow-up, on overall survival in naive, unresectable metastatic renal cell carcinoma patients during first-line systemic therapy. MATERIALS AND METHODS: Clinicopathological parameters of 56 patients treated between 2007 and 2015, including imaging parameters (such as the longest tumor diameter, necrotic area diameter, and attenuation in primary renal tumor lesions on baseline vs. follow-up computed tomography), were retrospectively reviewed to derive predictive factors of overall survival. The best overall response was measured according to the RECIST v1.1. RESULTS: The median treatment period was 206.3 days and the median follow-up was 14.6 months. Forty-four (78.6%) patients progressed after a median 4.6 months of progression-free survival, and 6 (10.7%) patients survived with a median overall survival of 12.5 months. Multivariate analysis showed that the baseline tumor diameter (hazard ratio [HR] 0.903) and mean attenuation (HR 0.936), change of tumor diameter (HR 0.714) and necrosis diameter (HR 0.861), change in the percentage of tumor diameter (HR 1.483) and of necrosis diameter (HR 1.028) between baseline and follow-up computed tomography images; treatment duration (HR 0.986) and baseline serum hemoglobin (HR 1.790) and albumin level (HR 0.060) were significant factors for overall survival (p<0.05). CONCLUSION: The study showed that baseline and first follow-up computed tomography findings of primary renal lesions during first-line systemic therapy are useful and significant predictors of OS in patients with naive unresectable mRCC. PMID- 28562691 TI - Chronic treatment with paeonol improves endothelial function in mice through inhibition of endoplasmic reticulum stress-mediated oxidative stress. AB - Endoplasmic reticulum (ER) stress leads to endothelial dysfunction which is commonly associated in the pathogenesis of several cardiovascular diseases. We explored the vascular protective effects of chronic treatment with paeonol (2' hydroxy-4'-methoxyacetophenone), the major compound from the root bark of Paeonia suffruticosa on ER stress-induced endothelial dysfunction in mice. Male C57BL/6J mice were injected intraperitoneally with ER stress inducer, tunicamycin (1 mg/kg/week) for 2 weeks to induce ER stress. The animals were co-administered with or without paeonol (20 mg/kg/oral gavage), reactive oxygen species (ROS) scavenger, tempol (20 mg/kg/day) or ER stress inhibitor, tauroursodeoxycholic acid (TUDCA, 150 mg/kg/day) respectively. Blood pressure and body weight were monitored weekly and at the end of treatment, the aorta was isolated for isometric force measurement. Protein associated with ER stress (GRP78, ATF6 and p eIF2alpha) and oxidative stress (NOX2 and nitrotyrosine) were evaluated using Western blotting. Nitric oxide (NO) bioavailability were determined using total nitrate/nitrite assay and western blotting (phosphorylation of eNOS protein). ROS production was assessed by en face dihydroethidium staining and lucigenin enhanced chemiluminescence assay, respectively. Our results revealed that mice treated with tunicamycin showed an increased blood pressure, reduction in body weight and impairment of endothelium-dependent relaxations (EDRs) of aorta, which were ameliorated by co-treatment with either paeonol, TUDCA and tempol. Furthermore, paeonol reduced the ROS level in the mouse aorta and improved NO bioavailability in tunicamycin treated mice. These beneficial effects of paeonol observed were comparable to those produced by TUDCA and tempol, suggesting that the actions of paeonol may involve inhibition of ER stress-mediated oxidative stress pathway. Taken together, the present results suggest that chronic treatment with paeonol preserved endothelial function and normalized blood pressure in mice induced by tunicamycin in vivo through the inhibition of ER stress-associated ROS. PMID- 28562692 TI - Mannose-binding lectin-deficient genotypes as a risk factor of pneumococcal meningitis in infants. AB - OBJECTIVES: The objective of this study was to evaluate to evaluate the role of mannose-binding-lectin deficient genotypes in pneumococcal meningitis (PM) in children. METHODS: We performed a 16-year retrospective study (January 2001 to March 2016) including patients <= 18 years with PM. Variables including attack rate of pneumococcal serotype (high or low invasive capacity) and MBL2 genotypes associated with low serum MBL levels were recorded. RESULTS: Forty-eight patients were included in the study. Median age was 18.5 months and 17/48 episodes (35.4%) occurred in children <= 12 months old. Serotypes with high-invasive disease potential were identified in 15/48 episodes (31.2%). MBL2 deficient genotypes accounted for 18.8% (9/48). Children <= 12 months old had a 7-fold risk (95% CI: 1.6-29.9; p < 0.01) of having a MBL2 deficient genotype in comparison to those > 12 months old. A sub-analysis of patients by age group revealed significant proportions of carriers of MBL2 deficient genotypes among those <= 12 months old with PM caused by opportunistic serotypes (54.5%), admitted to the PICU (Pediatric Intensive Care Unit) (46.7%) and of White ethnicity (35.7%). These proportions were significantly higher than in older children (all p<0.05). CONCLUSIONS: Our results suggest that differences in MBL2 genotype in children <=12 months old affects susceptibility to PM, and it may have an important role in the episodes caused by non-high invasive disease potential serotypes. PMID- 28562693 TI - From medical imaging data to 3D printed anatomical models. AB - Anatomical models are important training and teaching tools in the clinical environment and are routinely used in medical imaging research. Advances in segmentation algorithms and increased availability of three-dimensional (3D) printers have made it possible to create cost-efficient patient-specific models without expert knowledge. We introduce a general workflow that can be used to convert volumetric medical imaging data (as generated by Computer Tomography (CT)) to 3D printed physical models. This process is broken up into three steps: image segmentation, mesh refinement and 3D printing. To lower the barrier to entry and provide the best options when aiming to 3D print an anatomical model from medical images, we provide an overview of relevant free and open-source image segmentation tools as well as 3D printing technologies. We demonstrate the utility of this streamlined workflow by creating models of ribs, liver, and lung using a Fused Deposition Modelling 3D printer. PMID- 28562694 TI - Correction: CD40 Activation Rescues Antiviral CD8+ T Cells from PD-1-Mediated Exhaustion. AB - [This corrects the article DOI: 10.1371/journal.ppat.1003490.]. PMID- 28562697 TI - Classificatory volatility and (in)consistency of racial inequality. AB - Monitoring racial inequalities, whether socioeconomic or health-related, assumes stability in racial classification. Otherwise, the dynamics of these inequalities could result from racial reclassification rather than from processes related to socioeconomic and health inequalities per se. The study proposes a typology of uncertainty in racial classification (contextual - temporal, geographic, procedural - and sampling) and draws on the literature and nationally representative secondary data to discuss the magnitude of racial variability in Brazil according to these five dimensions. The results show that at least two of these uncertainties - geographic and procedural - are substantial, but have little influence on the racial gap in income. We address the impacts of these results on the existence and extent of racial inequalities in health and conclude that the structure of inequalities between whites and blacks is consistent, although skin color classification is volatile. PMID- 28562695 TI - Label-free pathology by spectrally sliced femtosecond stimulated Raman scattering (SRS) microscopy. AB - Optical "virtual biopsy" is an attractive way to improve disease diagnosis and surgical guidance. Many optical microscopy techniques have been developed to provide diagnostic information without the need for tissue sectioning or staining. Among these techniques, label-free chemical imaging is the most desirable. Recently, it has been shown that narrowband, picosecond stimulated Raman scattering (SRS) can achieve comparable morphological contrast to hematoxylin and eosin staining (H&E staining), the 'gold standard' of pathology. However, to translate the technique from the bench to the bedside, optimal laser sources and parameters have yet to be identified. Here we describe an improvement to the narrowband SRS microscopy techniques for label-free tissue imaging. Through spectral slicing of broadband, femtosecond pulses, we are able to maintain the same protein/lipid contrast as narrowband SRS while achieving a higher signal-to-noise ratio (SNR). Our method draws upon the benefits of femtosecond pulses (e.g. higher peak power) while preserving those of picosecond pulses (e.g. adequate spectral resolution). We demonstrate this achievement through protein/lipid signal and contrast quantification of mouse brain tissue as a function of bandwidth, and comparison with numerical simulations. Further method validation is provided through imaging of additional mouse tissues: liver, kidney, and skin. PMID- 28562696 TI - PTH[1-34] improves the effects of core decompression in early-stage steroid associated osteonecrosis model by enhancing bone repair and revascularization. AB - Steroid-associated osteonecrosis (SAON) might induce bone collapse and subsequently lead to joint arthroplasty. Core decompression (CD) is regarded as an effective therapy for early-stage SAON, but the prognosis is unsatisfactory due to incomplete bone repair. Parathyroid hormone[1-34] (PTH[1-34]) has demonstrated positive efficacy in promoting bone formation. We therefore evaluated the effects of PTH on improving the effects of CD in Early-Stage SAON. Distal femoral CD was performed two weeks after osteonecrosis induction or vehicle injection, with ten of the ON-induced rabbits being subjected to six-week PTH[1-34] treatment and the others, including ON-induced and non-induced rabbits, being treated with vehicle. MRI confirmed that intermittent PTH administration improved SAON after CD therapy. Micro-CT showed increased bone formation within the tunnel. Bone repair was enhanced with decreased empty osteocyte lacunae and necrosis foci area, resulting in enhanced peak load and stiffness of the tunnel. Additionally, PTH enlarged the mean diameter of vessels in the marrow and increased the number of vessels within the tunnels, as well as elevated the expression of BMP-2, RUNX2, IGF-1, bFGF and VEGF, together with serum OCN and VEGF levels. Therefore, PTH[1-34] enhances the efficacy of CD on osteogenesis and neovascularization, thus promoting bone and blood vessels repair in the SAON model. PMID- 28562698 TI - Measurement and modeling of race and health in Brazil: continuing the discussion. AB - Recent reviews have discussed the conceptualization of race in health studies in Brazil. This review further documents and discusses specific measurement and modeling issues with regard to race and how this can impact result interpretation. Three scientific databases were used to search the literature on race and three health outcomes. The search yielded 38 empirical studies on birth outcomes, self-rated health, and weight. Results suggest that, while there are racial patterns in the overall literature, conceptual and methodological challenges can be addressed to clarify the ways in which racial group membership is linked to health. PMID- 28562699 TI - Sociodemographic characteristics of indigenous population according to the 2000 and 2010 Brazilian demographic censuses: a comparative approach. AB - The sociodemographic profiles of different segments of the Brazilian population have been the object of multiple inter-census comparisons. This study compared the age distribution, number of household residents, formal schooling, and income of indigenous persons according to the population censuses of 2000 and 2010. There was an important decrease in the number of residents per occupied household, and slight aging of the indigenous population, except in the urban North. Meanwhile, there was a proportional increase in individuals with per capita household income up to one minimum wage, along with a reduction in the income bracket of more than two minimum wages in the country's five major geographic regions, in both urban and rural areas. Although schooling also increased, the increments differed according to geographic region and urban versus rural area; the urban Southeast showed larger gains in schooling, while the rural North and Central displayed smaller increases. The study emphasizes the need for more in-depth research focusing on specificities and backing the evaluation and implementation of public policies for the indigenous population. PMID- 28562700 TI - Adaptation and validation of the Diabetes Management Self-Efficacy Scale to Brazilian Portuguese. AB - Objective:: to perform the cultural adaptation and validation of the Diabetes Management Self-efficacy Scale for Patients with Type 2 Diabetes Mellitus with a Brazilian population sample. Method:: cross-sectional methodological study in which the adaptation and validation process included the stages recommended in the literature. Construct validity and reliability were assessed with 200 adults with type 2 diabetes mellitus. Results:: the items indicated by the panel of judges and by the target population were adjusted in the cultural adaptation to improve clarity and understanding. The instrument's four factors remained in the confirmatory factor analysis with factor loadings of items greater than 0.30, except for factor 4; convergent validity, verified by the multitrait-multimethod analysis, presented inter-item correlations from 0.37 to 0.92, while for discriminant validity, 100% of the items presented greater correlation in their own factors. Cronbach's coefficient alpha for the total scale was 0.78, ranging from 0.57 to 0.86 among factors. Conclusion:: semantic, cultural, conceptual and idiomatic equivalences were achieved and the instrument's Brazilian version also presented psychometric properties that showed evidence of reliability and validity. Thus, it can be applied both in clinical practice and research. Self efficacy is useful for planning and assessing educational interventions, as well as predicting behavior modification in self-care. PMID- 28562701 TI - Role of Primary Health Care in child hospitalization due to pneumonia: a case control study. AB - Objective:: to evaluate the association of primary health care and other potential factors in relation to hospitalization due to pneumonia, among children aged under five years. Method:: epidemiological study with a case-control, hospital-based design, which included 345 cases and 345 controls, matched according to gender, age and hospital. Data were collected using a pre-coded questionnaire and the Primary Care Assessment Tool, analyzed by means of multivariate logistic regression, following the assumptions of a hierarchical approach. Results:: the protective factors were: family income >US$216.12 (OR=0.68), weight gain during pregnancy >=10 kg (OR=0.68), quality of Primary Health Care (OR for scores >3.41=0.57; OR for scores >3.17 and <=3.41=0.50), gastro-esophageal reflux (OR=0.55), overweight (OR=0.37) and birth interval >=48 months (OR=0.28). The risk factors included: parity (2 childbirths: OR=4.60; >=3 childbirths: OR=3.25), out-of-date vaccination (OR=2.81), undernutrition (OR=2.53), history of wheezing (>=3 episodes OR=2.37; 1 episode: OR=2.13), attendance at daycare center (OR=1.67), and use of medicines over the past month (OR=1.67). Conclusion:: primary health care and its child health care practices, such as nutritional monitoring, immunization, care to prevalent illnesses, prenatal care and family planning need to be prioritized to avoid child hospitalization due to pneumonia. PMID- 28562702 TI - A new contribution to the classification of stressors affecting nursing professionals. AB - Objective:: to identify and classify the most important occupational stressors affecting nursing professionals in the medical units within a hospital. Method:: quantitative-qualitative, descriptive and prospective study performed with Delphi technique in the medical units of a general university hospital, with a sample of 30 nursing professionals. Results:: the stressors were work overload, frequent interruptions in the accomplishment of their tasks, night working, simultaneity of performing different tasks, not having enough time to give emotional support to the patient or lack of time for some patients who need it, among others. Conclusion:: the most consensual stressors were ranked as work overload, frequent interruptions in the accomplishment of their tasks, night working and, finally, simultaneity of performing different tasks. These results can be used as a tool in the clinical management of hospital units, aiming to improve the quality of life of nursing professionals, organizational models and, in addition, continuous improvement in clinical treatment. PMID- 28562703 TI - ? PMID- 28562704 TI - ? PMID- 28562705 TI - ? PMID- 28562706 TI - ? PMID- 28562707 TI - Period prevalence and anthropometric predictors of premature rupture of membranes in Mexican women, 2009-2012. PMID- 28562708 TI - ? PMID- 28562709 TI - ? PMID- 28562710 TI - ? PMID- 28562711 TI - ? PMID- 28562712 TI - ? PMID- 28562714 TI - [Changes in prices of taxed sugar-sweetened beverages and nonessential energy dense food in rural and semi-rural areas in Mexico]. AB - Objective:: To estimate changes in prices associated with the implementation of the tax to sugar sweetened beverages (SSB) and to nonessential energy dense food in 2014. Materials and methods:: Price data were collected in rural and semi rural areas in December 2013, and April and December 2014. Fixed effects models were used to estimate changes in prices of beverages and nonessential energy dense food, stratified by region, retailer and package size. Results:: The SSB tax did not pass completely through prices: prices increased on average 0.73 pesos per liter. For nonessential energy dense food, the tax passed completely or was overshifted for cookies, cereal bars and cereal boxes. Conclusion:: The potential effect of the taxes on consumption could be attenuated in rural areas as the pass through prices was incomplete. PMID- 28562716 TI - [Effective coverage of treatment of hypertension in Mexican adults by states]. AB - Objective:: To estimate the effective coverage (EC) of treatment of hypertension (HT) in Mexican adults in 2012 and compared with those reported in 2006. Materials and methods:: The National Health and Nutrition Survey 2012 was analyzed. The EC has three dimensions: health need as prevalence of HT, utilization of health services when the need is real and quality as recovering health after the treatment. The EC of treatment of HT was estimated using instrumental variables. Results:: In 2012, the EC national of treatment of HT was 28.3% (95%CI 26.5-30.1), ranging from Michoacan with 19.3% (15.3-23.4) to State of Mexico with 39.7% in (25.3-54.0). From 2006 to 2012 the national EC increased 22.5%. Conclusion:: The EC treatment of hypertension is low and heterogeneous. The use of synthetic indicators should be a daily exercise of measurement, because report summarizes the performance of state health systems. PMID- 28562715 TI - Evaluation of HIV, STI and CD4 results among voluntary attendees at the HIV/AIDS program of Mexico City. AB - Objective:: To describe results of HIV, sexually transmitted diseases (STI) and CD4 counts at the HIV-specialized Condesa Clinic (CC) in Mexico City. Materials and methods:: Individuals who requested voluntary counseling and testing at CC were studied. We identified antibodies against HIV, syphilis, hepatitis C, and hepatitis B HBsAg. CD4 cell counts and viral load of HIV positive individuals were also obtained. Late HIV infection diagnosis was established if CD4 counts were lower than 200 cells/MUL. Results:: Global seroprevalence of HIV, syphilis, HBsAg, and anti HCV markers was of 20.1, 6, 1 and 1, respectively. Men displayed higher seroprevalence of infection markers than women. Among men, HIV infection was related to age and with all STI markers. Late HIV diagnosis was 31.8%. The risk of late HIV diagnosis was higher among women and it increased as age increased. Conclusions:: Differences between genders regarding HIV and STIs prevalence as well as risk factors for HIV infection and late HIV diagnosis were observed. PMID- 28562713 TI - Smokefree implementation in Colombia: Monitoring, outside funding, and business support. AB - Objective:: To analyze successful national smokefree policy implementation in Colombia, a middle income country. Materials and methods:: Key informants at the national and local levels were interviewed and news sources and government ministry resolutions were reviewed. Results:: Colombia's Ministry of Health coordinated local implementation practices, which were strongest in larger cities with supportive leadership. Nongovernmental organizations provided technical assistance and highlighted noncompliance. Organizations outside Colombia funded some of these efforts. The bar owners' association provided concerted education campaigns. Tobacco interests did not openly challenge implementation. Conclusions:: Health organization monitoring, external funding, and hospitality industry support contributed to effective implementation, and could be cultivated in other low and middle income countries. PMID- 28562717 TI - [Quality and compliance with Clinical Practice Guidelines of Chronic Noncommunicable Diseases in primary care]. AB - Objective:: To assess the quality and compliance of clinical practice guidelines (CPG) applicable to chronic non-communicable diseases (CNCD) in primary healthcare (CS), and views of staff on the barriers, facilitators and their use. Materials and methods:: 18 valued CPG with AGREEII, 3 are selected to develop indicators and assess compliance using lot quality acceptance sample (LQAS, standard 75 / 95% threshold 40 / 75% respectively, alpha:0. 05, beta:0. 10) on 5 CS. 70 professionals surveyed about knowledge and use of CPG. Results:: Average quality of the CPG was 57.2%; low rating in domains: "Applicability" (<25%), "Stakeholder involvement" (43.5%) and "Rigour of development" (55.0%). Compliance in CS ranges from 39 to 53.4%. Professionals show uneven knowledge of CPG; 44 to 45% (according to CPG), they declare that they are not used, they identify as main barriers the lack of training, and their difficult accessibility and management. Conclusions:: The quality and implementation of evaluated CPG is deficient constituting an opportunity of improvement in health services. PMID- 28562718 TI - [Economic and health impact of prenatal care in pregnant women with public health insurance in Colombia during 2014]. AB - Objective:: To estimate health care costs of live births and the impact of prenatal care visit (PCV) in women from poor households. Materials and methods:: A randomized sample of 9 244 pregnant women (out of total= 25 000). Mean differences and proportions were calculated to compare results in both groups of women. The costs were estimated in American Dollars (USD) 2014, from the payer's perspective. Results:: 75% of women live in urban areas. The mean age was 23 years old (CI95% 23.5-23.8). The average cost with PCV was USD 609.1 (CI95%: 581 632.7) and without PCV was USD 857.8 (CI95%: 774.7-923.8) and 87% of women attended at least one PCV. The health care costs increased in 32% (CI95% 27.1-41) in women who did not attended PCV. Conclusion:: The PCV is an efficient and effective intervention for managing the risk of maternal health. PMID- 28562719 TI - [Validation of a scale to assess the labour quality of life in public hospitals from Tlaxcala]. AB - Objective:: To validate a scale for assessing the labour quality of life in public hospitals (LQL-PH) from Tlaxcala, Mexico. Materials and methods:: The instrument was validated among 669 health workers from six hospitals from the Ministry of Health of Tlaxcala, Mexico. Content validity was by inquiry to experts, construct validity by factor analysis, criterion validity by comparing with other scales, and reliability with Cronbach's Alpha. Results:: The factor analysis uncovered four dimensions: "individual welfare", "conditions and labour environment", "organization", and "well-being accomplished by the work"; reliability was 0.921. Workers who perceibed better LQL-PH were: under 50 years old, with temporary contract, with less seniority in job, with work schedule at daytime of weekends, and those with academic degree. Conclusions:: LQL-PH showed to be an instrument phsycometrically valid and reliable. It's recommendable to prove this scale in other public and private health institutions, as well as its relationship with key health care indicators of labour performance and management. PMID- 28562720 TI - [An epidemiological but invisibilized marker: indebtedness within an Afromexican town in Oaxaca]. AB - Objective:: To explore indebtedness dynamics in an Afromexican town by an inclusive epidemiological approach. Materials and methods:: Qualitative study through 75 questionnaires, 20 interviews to depth and six focal groups in a support process to the Municipal Health Commission in Santiago Tapextla, Oaxaca. Results:: Catastrophic expenses due to insufficient medical care were the principal causal item. Indebtedness processes with patrimonial loss are dominant, generating dependence spirals of difficult resolution that impact the familiar dynamics and the pathology evolution. Conclusions:: In spite of its inexistence within sanitary official programs, indebtedness dynamics constitute an epidemiological marker by the uncovering of structural inattention conditions that reflect the imposed, naturalized and pathogenic hierarchization proper of coloniality. To analyze this process at local and global levels is a complex but essential public health task. PMID- 28562721 TI - [Salud Colectiva awarded DOAJ Seal]. PMID- 28562722 TI - [Social health insurance in China: principal reforms and inequalities]. AB - This article analyzes the social health insurance system in China, its reforms and the principal social inequalities uncovered. Based in the work of a number of authors of reference, it is possible to observe that rural and urban reforms follow the same pattern: large systems that were gradually reduced and then again expanded relatively quickly. Improvements notwithstanding, some of China's historical problems persist, especially the rural-urban gap and regional disparities. The lack of integration of workers that migrate from the country to the city is reproduced in the current Chinese public health system, constituting one of the primary challenges to be faced at present. PMID- 28562723 TI - [Commercial sexual exploitation of children: Meanings and practices of people who work and reside in downtown Medellin (Colombia), 2015]. AB - The commercial sexual exploitation of children is a public health problem and a serious violation of the rights of children and adolescents. The response to this problem has been affected by the meanings and practices of the actors involved. In order to contribute to a better understanding of the problem, a qualitative social study using a grounded theory approach was carried out between 2014 and 2015. The aim was to understand the meanings and practices regarding this issue of people who spend time in an area of the city center with a high presence of commercial sexual exploitation of children and adolescents. The techniques used were participant observation and semi-structured interviews. We found that the predominate conceptions lead to practices that aggravate and perpetuate rights violations. Although practices of protection towards victims were identified, these were limited to critical aspects of the context. Actions to eradicate commercial sexual exploitation should work with the community and the meanings within the community regarding sexual exploitation so as to potentiate the victim protection practices carried out and reduce barriers to such practices. PMID- 28562724 TI - [Mesothelioma mortality in Argentina, 1980-2013]. AB - Mesothelioma mortality and its socio-demographic and temporal patterns in Argentina from 1980 to 2013 were estimated using data from death certificates obtained from the Vital Statistics System of Argentina's National Ministry of Health. There were 3,259 mesothelioma deaths corresponding to an age-adjusted mortality of 3.1/1,000,000 in 1980 and 5.7/1,000,000 in 2013, an average increase of 84.1% in 34 years. This raising trend became clearer after 1997. Males had higher mortality estimates compared with women in every year of the series; these findings suggest past exposure to asbestos. It is plausible that the asbestos exposure was mostly occupational, which is more common among men. Actions related to reinforcing the asbestos ban already in place and strengthening health surveillance directed at workplaces, previously exposed workers, and the population in general are recommended. PMID- 28562725 TI - [The individual and the State as agents responsible for the production of healthy societies: a thematic analysis from the perspective of health professionals in Catalonia (Spain)]. AB - This article aims to analyze the meanings upon which health promotion intervention practices are based, and the consequences of these meanings in the identification of responsibilities in health. The passage of Catalonia's Public Health Law 18/2009 facilitated the development of the Demonstrative Project of the Public Health Agency, in the framework of which fieldwork for the Plan for Health Education and Promotion in Children and Adolescents in La Garrotxa (region of Catalonia) was carried out. In this way, 20 interviews with key informants were conducted. Through a thematic analysis, it was found that the State and the individual are identified as the primary agents responsible for the production of healthy societies. It was also evidenced that, in the articulation between the discourses referring to free and rational decision-making and those referring to the social, political and economic environment, different approaches towards responsibility are construed, with effects related to the potentiation (or lack thereof) of the State as a guarantor of the population's health in opposition to blaming of the individual. PMID- 28562726 TI - [Contraception and maternity: Findings of a quali-quantitative study with 18- and 19-year-olds in four provinces of Argentina]. AB - The article analyzes the factors that facilitate or hinder access and effective use of contraception by 18- and 19-year-olds living in the cities of Resistencia (province of Chaco), Posadas (province of Misiones) and Santiago del Estero (province of Santiago del Estero) as well as the health regions V and VII of the province of Buenos Aires. Data comes from a survey applied to a purposeful sample of 480 adolescent females (including respondents without children, with one child, and with more than one child) and 21 semi-structured interviews with a population of the same profile. In response to the survey, 74.2% reported using contraception "always" and 12.2% "most of the time." The pill and condoms were the most widely used methods (41.7% and 37.0% respectively). Only 13.2% used a mid- to long-term method (intrauterine device or injectable contraceptive). The main reasons reported by those who "never" use a method (13.6%) were: wanting to become pregnant (27.6%) and partner refusal (27.6%). The interviews revealed difficulties in the use of contraception methods and deficits in contraception counseling. PMID- 28562727 TI - [Capabilities and challenges in monitoring the availability of and access to health services in Argentina]. AB - Monitoring the utilization, quality and performance of health services through indicators is a growing necessity of decision makers. Given the importance of indicators related to availability of, quality of and access to health services by the population, the objective of this article is to research the capacity of information sources produced officially in Argentina since 2000 to generate such indicators, and to identify the extent that such sources comply with the requirements of frequency, disaggregation and publication. The research results show that the information officially available in the country does not allow for the calculation of all indicators, or allows for their construction at only some moments in time, evidencing the need to incorporate new sources or adapt existing ones. PMID- 28562728 TI - [Distribution of dental caries and its association with variables of social protection in children 12 years of age in the county of Avellaneda, Province of Buenos Aires]. AB - Different international organizations have indicated the need to analyze the conditions of each population in order to identify groups and individuals at risk as an operational strategy in pursuit of greater equity, efficacy and efficiency in the health system. The aim of this study was to identify differentials in the dental caries profiles of children attending public schools in the county of Avellaneda (Province of Buenos Aires, Argentina) and their association with variables of social protection. In 2014, an observational, analytical and cross sectional study was performed with a sample of 656 students 12 years of age from 40 public schools in the 8 county districts (out of a total universe of 3580 individuals distributed in 70 schools). The dental status of 12-year-old schoolchildren living in the localities evaluated showed an unequal distribution; sub-groups with high caries prevalence, morbidity and severity were identified, requiring the targeting of health interventions. An association between untreated disease and lack of social protection was observed. PMID- 28562729 TI - [Geographical distribution of fluoride in the public water supply in the province of Tucuman, Argentina]. AB - This work studied the geographical distribution of fluoride content in the public water supply in the province of Tucuman, Argentina. A total of 1,210 samples were collected in 190 localities of the 17 departments of the province during the 2008 2012 period. The analytical determination was performed using the SPADNS method and QGis 2.16 was used for processing the information. The fluoride content requirements in the studied localities were determined according to the Argentine Food Code. The results showed that 94% of population studied consumed water with fluoride concentrations below the recommended limits, 5% were exposed to fluoride concentrations above the required maximum limit and 1% consumed water at optimal fluoride concentrations. The maps showed a heterogeneous geographical distribution of fluorides, in which areas with deficit, excess and recommended values of fluorides can be differentiated; in some departments an inverse relationship between the density of the hydrological network and fluoride concentration can be observed. In the capital of the province, the average value found was 0.32 mg/l, presenting a homogeneous geographical distribution. The information obtained is indispensable for the proper management of fluoride, so as to improve public health through policy. PMID- 28562730 TI - [Socio-epidemiological and cultural aspects of cutaneous leishmaniasis: conceptions, attitudes and practices in the populations of Tierralta and Valencia (Cordoba, Colombia)]. AB - This article focuses on the conceptions, attitudes and practices of the inhabitants from four villages (veredas) in Tierralta and Valencia (Cordoba, Colombia), who have suffered from or are aware of the existence of cutaneous leishmaniasis. A mixed methodology was implemented based in a qualitative design using interviews and focus groups (n=45) and an epidemiological design which included applying the Montenegro test (n=251), uncovering suspected cases of cutaneous leishmaniasis in humans, (n=5) and applying epidemiological surveys (n=409). Among the results, a lack of knowledge regarding the vector was found; although respondents could identify the Lutzomyia (known as "alu"), they did not correlate it with cutaneous leishmaniasis. In addition, traditional home treatments were more frequently used, increasing the underrecording of cases. With respect to healthcare personnel, flaws in diagnosis and treatment were found, which reinforces adherence to home treatments. This scenario calls for a reflection upon the challenges of the health care system in relation to the interventions of health personnel in communities situated in endemic areas. PMID- 28562731 TI - [Helminthology according to the philosophy of science of Imre Lakatos]. AB - Lakatos's philosophy of science has been used for different branches of biology, however this has not been true for helminthology. Therefore, this article examines the possibility of using his methodology of scientific research programmes (SRP) for reconstructing the history of the discipline of helminthology. It is upheld that the first SRP in biology was inaugurated by Aristotle, and its protective belt included a small group of auxiliary hypotheses referring to helminths. This programme continued up until the 17th century, when two rival programmes in helminthology arose: the internalist and the externalist. After the second half of the 19th century the internalist SRP was abandoned, while the externalist considerably broadened its protective belt during the 20th century. The internalist programme was abandoned due to the crucial experiments of Kuchenmeister, which permitted the consolidation of the externalist SRP. PMID- 28562732 TI - [Salt in the diet: opinions, guides and evidence]. PMID- 28562733 TI - Randomized clinical study on the analgesic effect of local infiltration versus spinal block for hemorrhoidectomy. AB - BACKGROUND AND OBJECTIVES:: Postoperative analgesia and early recovery are important for hospital discharge. The primary objective of this study was to compare the analgesic effectiveness of perianal infiltration and subarachnoid anesthesia for hemorrhoidectomy. The secondary objective was to compare time to discharge, adverse effects and complications. DESIGN AND SETTING:: Randomized, prospective and comparative study at Dr. Mario Gatti Hospital. METHODS:: Forty patients aged 18-60, in American Society of Anesthesiologists physical status category 1 or 2, were included. The local group (LG) received local infiltration (0.75% ropivacaine) under general anesthesia; the spinal group (SG) received subarachnoid block (2 ml of 0.5% bupivacaine). Analgesic supplementation consisted of fentanyl for LG and lidocaine for SG. Postoperative pain intensity, sphincter relaxation, lower-limb strength, time to discharge, analgesic dose over one week and adverse effects were assessed. RESULTS:: Eleven LG patients (52.4%) required supplementation, but no SG patients. Pain intensity was higher for LG up to 120 min, but there were no differences at 150 or 180 min. There were no differences in the need for paracetamol or tramadol. Times to first analgesic supplementation and hospital discharge were longer for SG. The adverse effects were nausea, dizziness and urinary retention. CONCLUSIONS:: Pain intensity was higher in LG than in SG over the first 2 h, but without differences after 150 and 180 min. Time to first supplementation was shorter in LG. There were no differences in doses of paracetamol and tramadol, or in adverse effects. REGISTRATION:: ClinicalTrials.gov NCT02839538. PMID- 28562734 TI - Simultaneous meningioma and brain metastasis from renal cell carcinoma - a rare presentation. Case report. AB - CONTEXT:: Brain metastases are the most common tumors of the central nervous system. Because of their high frequency, they may be associated with rare situations. Among these are tumor-to-tumor metastasis and an even a rarer situation called simultaneous brain tumors, which are more related to primary tumors of the reproductive and endocrine systems. CASE REPORT:: A 56-year-old male patient with a history of renal cell carcinoma (which had previously been resected) presented with a ventricular lesion (suggestive of metastatic origin) and simultaneous olfactory groove lesion (probably a meningioma). First, only the ventricular lesion was dealt with, but after a year, the meningothelial lesion increased and an occipital lesion appeared. Therefore, both of these were resected in a single operation. All the procedures were performed by the same neurosurgeon. The patient evolved without neurological deficits during the postoperative period. After these two interventions, the patient remained well and was referred for adjuvant treatment. CONCLUSIONS:: This study provides the first description of an association between these two tumors. Brain metastases may be associated with several lesions, and rare presentations such as simultaneity with meningioma should alert neurosurgeons to provide the best oncological treatment. PMID- 28562735 TI - Dieulafoy's disease of the bronchial tree: a case report. AB - CONTEXT:: Dieulafoy's disease of the bronchial tree is a very rare condition. Few cases have been reported in the literature. It can be asymptomatic or manifest with massive hemoptysis. This disease should be considered among heavy smokers when recurrent massive hemoptysis is present amid otherwise normal findings. The treatment can be arterial embolization or surgical intervention. CASE REPORT:: A 16-year-old girl was admitted to the emergency department due to hemoptysis with an unknown lesion in the bronchi. She had suffered massive hemoptysis and respiratory failure one week before admission. Fiberoptic bronchoscopy revealed a lesion in the bronchus of the right lower lobe, which was suspected to be a Dieulafoy lesion. Segmentectomy of the right lower lobe and excision of the lesion was carried out. The outcome for this patient was excellent. CONCLUSION:: Dieulafoy's disease is a rare vascular anomaly and it is extremely rare in the bronchial tree. In bronchial Dieulafoy's disease, selective embolization has been suggested as a method for cessation of bleeding. Nevertheless, standard anatomical lung resection is a safe and curative alternative. PMID- 28562737 TI - Nonalcoholic fatty liver disease and bariatric surgery: a comprehensive review. AB - CONTEXT AND OBJECTIVE:: Nonalcoholic fatty liver disease (NAFLD) has been increasingly diagnosed worldwide and is now recognized as a source of public health concern. It comprises a wide spectrum of histological features that range from simple steatosis to severe forms of fibrosis, steatohepatitis and even cirrhosis. The impact of bariatric surgery on the course of NAFLD in individuals with obesity has been extensively studied. DESIGN AND SETTING:: Narrative review; public university hospital. METHODS:: A comprehensive review was conducted based on an online search on the electronic databases MEDLINE and LILACS using the MeSH terms "fatty liver" and "bariatric surgery". RESULTS:: The exact mechanisms that lead to improvement in NAFLD following bariatric surgery are not completely understood. Since Roux-en-Y gastric bypass (RYGB) is the bariatric surgical procedure most performed worldwide, it is also the one from which the effects on NAFLD have been most studied, although there is also consistent evidence regarding the effects from gastric banding, sleeve gastrectomy and biliopancreatic diversions. CONCLUSION:: According to the currently available evidence, bariatric surgery leads to significant improvement in NAFLD. Further research, especially by means of randomized controlled trials enrolling larger cohorts of individuals, is needed to determine the optimal procedure for this group of subjects. PMID- 28562736 TI - Bariatric surgery as a treatment for pseudotumor cerebri: case study and narrative review of the literature. AB - CONTEXT: Pseudotumor cerebri occurs when there is an increase in intracranial pressure without an underlying cause, usually leading to loss of vision. It is most commonly observed in obese women of child-bearing age. CASE REPORT: A 46 year-old woman presented at our service with idiopathic intracranial hypertension that had been diagnosed two years earlier, which had led to chronic refractory headache and an estimated 30% loss of visual acuity, associated with bilateral papilledema. She presented partial improvement of the headache with acetazolamide, but the visual loss persisted. Her intracranial pressure was 34 cmH2O. She presented a body mass index of 39.5 kg/m2, also associated with high blood pressure. Computed tomography of the cranium with endovenous contrast did not show any abnormalities. She underwent Roux-en-Y gastric bypass with uneventful postoperative evolution. One month following surgery, she presented a 24% excess weight loss. An ophthalmological examination revealed absence of visual loss and remission of the papilledema. There were no new episodes of headache following the surgery. There was also complete resolution of high blood pressure. The intracranial pressure decreased to 24 cmH2O, six months after the surgery. CONCLUSION: Although the condition is usually associated with obesity, there are few reports of bariatric surgery among individuals with pseudotumor cerebri. In cases studied previously, there was high prevalence of resolution or improvement of the disease following bariatric surgery. There is no consensus regarding which technique is preferable. Thus, further research is necessary in order to establish a specific algorithm. PMID- 28562738 TI - Metastatic adenocarcinoma involving the right ventricle and pulmonary artery leading to right heart failure: case report. AB - CONTEXT: Obstruction of the right ventricular outflow tract due to metastatic disease is rare. Clinical recognition of cardiac metastatic tumors is rare and continues to present a diagnostic and therapeutic challenge. CASE REPORT: We present the case of a patient who had severe respiratory insufficiency and whose clinical examinations revealed a giant tumor mass extending from the right ventricle to the pulmonary artery. We discuss the diagnostic and therapeutic options. CONCLUSION: In patients presenting with acute right heart failure, right ventricular masses should be kept in mind. Transthoracic echocardiography appears to be the most easily available, noninvasive, cost-effective and useful technique in making the differential diagnosis. PMID- 28562739 TI - Breaking bad news: doctors' skills in communicating with patients. AB - CONTEXT AND OBJECTIVE:: Breaking bad news is one of doctors' duties and it requires them to have some skills, given that this situation is difficult and distressful for patients and their families. Moreover, it is also an uncomfortable condition for doctors. The aim of this study was to evaluate doctors' capacity to break bad news, ascertain which specialties are best prepared for doing this and assess the importance of including this topic within undergraduate courses. DESIGN AND SETTING:: Observational cross-sectional quantitative study conducted at a university hospital in Belo Horizonte (MG), Brazil. METHODS:: This study used a questionnaire based on the SPIKES protocol, which was answered by 121 doctors at this university hospital. This questionnaire investigated their attitudes, posture, behavior and fears relating to breaking bad news. RESULTS:: The majority of the doctors did not have problems regarding the concept of bad news. Nevertheless, their abilities diverged depending on the stage of the protocol and on their specialty and length of time since graduation. Generally, doctors who had graduated more than ten years before this survey felt more comfortable and confident, and thus transmitted the bad news in a better conducted manner. CONCLUSION:: Much needs to be improved regarding this technique. Therefore, inclusion of this topic in undergraduate courses is necessary and proposals should be put forward and verified. PMID- 28562740 TI - Intensive care unit team perception of palliative care: the discourse of the collective subject. AB - OBJECTIVE: To learn the perception of health professionals in an intensive care unit towards palliative care. METHOD: This was a descriptive and qualitative study based on the converging care approach conducted at an intensive care unit in the South of Brazil. Semi-structured interviews were used to investigate the understanding of the professionals about palliative care in this unit. The data were organized and analyzed using the discourse of the collective subject method with the help of Qualiquantisoft(r) software. RESULTS: Participants included 37 professionals (12 nurses, 11nursing technicians, 5 physical therapists and 9 doctors). The key ideas extracted from the interviews were: care in the end stage of life that avoids futile measures; comfort care; lack of standardized care and lack of team training. CONCLUSION: The professionals perceived palliative care as appropriate in the last stages of life, with no need for futile treatment or as comfort measures. However, they are aware of the lack of standardization and lack of capacity building in this area, which leads them to conceive palliative care as terminal care, and measures are recommended to break with this stigma. OBJETIVO: Conhecer a percepcao dos profissionais de saude de uma Unidade de Terapia Intensiva acerca do cuidado paliativo. METODO: Pesquisa descritiva, qualitativa do tipo Convergente Assistencial realizada em uma Unidade de Terapia Intensiva da regiao sul do Brasil. Utilizou-se de entrevista semiestruturada que investigou o entendimento e a compreensao sobre cuidado paliativo nesta unidade. Os dados foram organizados e analisados pela tecnica do discurso do sujeito coletivo com auxilio do software Qualiquantisoft(r). RESULTADOS: Participaram do estudo 37 profissionais (12 enfermeiros, 11 tecnicos de enfermagem, cinco fisioterapeutas e nove medicos). As ideias centrais extraidas dos relatos: cuidado na fase terminal da vida sem medidas futeis; cuidados de conforto; falta uniformizar a assistencia e falta capacitacao para a equipe. CONCLUSAO: Os profissionais percebem o cuidado paliativo apropriado na fase terminal da vida, sem necessidade de medidas futeis de tratamento e promotoras de conforto. No entanto, estao conscientes da falta de uniformizacao e da sua capacitacao nesta materia, o que os leva a conceber o paliativismo como cuidado de terminalidade, pelo que se recomendam medidas para romper com este estigma. PMID- 28562741 TI - Self-efficacy scale for the establishment of good relationships with families in neonatal and pediatric hospital settings. AB - OBJECTIVE: The purpose of this study was to develop and test the psychometric properties of the Self-efficacy Scale for the Establishment of Good Relationships with Families in Neonatal and Pediatric Hospital Settings. METHOD: Methodological study grounded on self-efficacy theory was conducted in three phases: conceptual and operational definition (review of the literature and interviews with the target population), content validity (opinion of five experts e three clinical nurses), and exploratory factor analysis and internal consistency reliability (cross-sectional survey with a valid sample of 194 nurses). RESULTS: A ten-point Likert scale with 40-item was designed and one item was excluded after review by experts. Three factors emerged from the exploratory factor analysis. The Cronbach's alpha for all items was 0.983 with item-total correlations in the range 0.657 to 0.847. Cronbach's alpha value if item deleted were less than or equal to 0.983. CONCLUSION: The final version of the scale demonstrated psychometric adequacy. It is a useful tool to be administered in the clinical, educational and research nursing fields to measure nurses' self-efficacy beliefs concerning the establishment of good relationships with families. OBJETIVO: El proposito de este estudio fue desarrollar y probar las propiedades psicometricas de la Escala de Autoeficacia para el Establecimiento de Buenas Relaciones con las Familias en Ambientes Neonatales y Pediatricos. METODO: Estudio metodologico fundamentado en la teoria de la auto-eficacia se realizo en tres fases: conceptual y definicion operacional (revision de la literatura y entrevistas con la poblacion objetivo), la validez de contenido (opinion de cinco expertos y tres enfermeras clinicas), y el factor de analisis exploratorio e fiabilidad interna de consistencia (estudio transversal con una muestra valida de 194 enfermeras). RESULTADOS: La escala de Likert de diez puntos con 40 items fue disenada y un elemento fue excluido despues de la revision por expertos. Hay tres factores que emergieron del analisis factorial exploratorio. El alfa de Cronbach para todas las partidas fue 0,983, con correlaciones item-total en el rango de 0,657 a 0.847. El Valor alfa de Cronbach excluyendo el item quedo inferior o igual a 0.983. CONCLUSION: La version final de la escala demostro psicometria adecuada. Se trata de una herramienta util para ser administrada en los campos clinicos, educativos y de enfermeria de investigacion para medir las creencias de autoeficacia de enfermeros sobre el establecimiento de buenas relaciones con las familias. PMID- 28562742 TI - Factors associated with the incidence of pressure ulcer during hospital stay. AB - OBJECTIVE: Estimating the incidence rate of pressure ulcers and verifying factors associated with this occurrence in a cohort of hospitalized patients. METHOD: This is a cohort study in which the considered outcome was the time until pressure ulcer occurrence. Estimated effect of the variables on the cumulative incidence ratio of the outcome was performed using the Cox proportional hazards model. Variable selection occurred via the Logrank hypothesis test. RESULTS: The sample consisted of 442 adults, with 25 incidents of pressure ulcers. Patients with high scores on the Braden scale presented a higher risk of pressure ulcer incidence when compared to those classified into the low score category. CONCLUSION: These results reinforce the importance of using the Braden Scale to assist in identifying patients more likely to develop pressure ulcers. OBJETIVO: Estimar a taxa de incidencia de ulcera por pressao e verificar fatores associados a essa ocorrencia em uma coorte de pacientes hospitalizados. METODO: Trata-se de estudo de coorte no qual o desfecho foi a ocorrencia da ulcera por pressao. A estimativa do efeito das variaveis para a proporcao de incidencia acumulada do desfecho foi realizada utilizando o modelo de riscos proporcionais de Cox. A selecao das variaveis ocorreu por meio do teste de hipoteses Logrank. RESULTADOS: A amostra foi composta de 442 adultos, com 25 casos incidentes de ulcera por pressao. Pacientes com altos escores na escala de Braden apresentaram maior risco de incidencia de ulcera por pressao quando comparados com aqueles classificados na categoria de baixo escore. CONCLUSAO: Os resultados reforcam a importancia do uso da Escala de Braden para auxiliar na identificacao dos pacientes com maior probabilidade de desenvolver ulcera por pressao. PMID- 28562743 TI - Reproductive aspects and knowledge of family planning among women with Acquired Immunodeficiency Syndrome. AB - OBJECTIVE: To analyze the reproductive aspects and knowledge of family planning among women with Acquired Immunodeficiency Syndrome (AIDS). METHOD: Cross sectional and descriptive study carried out from January to December, 2015, in the outpatient care of infectious disease unit in a hospital located in Fortaleza, Ceara. Data were collected through a form applied by interview in a private setting. RESULTS: 102 women participated in the study. Most were aware that they were serologically positive with human immunodeficiency virus (HIV) during prenatal care (96.1%) and did not intend to have more children (63.7%). Women who were less than 39 years of age, had a higher educational level, and a shorter time of antiretroviral therapy had better chances of having children (p<=0.05). Having a steady partner increased the chance of desiring to have children, while tubal ligation was higher among women that did not receive counseling on family planning. Knowledge of family planning was limited because of lack of assistance provided by health professionals. OBJETIVO: Analisar aspectos reprodutivos e conhecimento sobre planejamento familiar de mulheres com sindrome da imunodeficiencia adquirida (Aids). METODO: Estudo transversal, descritivo, realizado de janeiro a dezembro de 2015, no ambulatorio de infectologia de um hospital em Fortaleza, Ceara. Os dados foram coletados por meio de formulario, aplicado por entrevista em ambiente privativo. RESULTADOS: Participaram do estudo 102 mulheres. A maioria delas teve conhecimento da sorologia positiva para virus da imunodeficiencia humana (HIV) durante o pre natal (96,1%), e estas nao pretendiam mais ter filhos (63,7%). Mulheres com idade menor que 39 anos, maior escolaridade e menor tempo de terapia antirretroviral tiveram maiores chances de ter filhos (p<=0,05). Mulheres com idade menor que 39 anos e maior escolaridade tiveram maiores chances de ter informacoes corretas sobre ter filhos na vigencia do HIV (p<=0,05). Ter parceiro fixo aumentou a chance de desejar ter filhos, enquanto a laqueadura tubaria foi maior em mulheres que nao receberam orientacoes sobre planejamento familiar. CONCLUSAO: A maioria das mulheres com Aids nao pretendem mais ter filhos. O conhecimento sobre o planejamento familiar foi limitado por falta de orientacoes pelos profissionais de saude. OBJETIVO: Analizar aspectos reproductivos y el conocimiento acerca de planificacion familiar de las mujeres con sindrome de inmunodeficiencia adquirida (SIDA). METODO: Estudio transversal, descriptivo realizado de enero a diciembre de 2015, en la sala de enfermedades infecciosas de un hospital de Fortaleza, Ceara. Los datos fueron recolectados a traves de una entrevista semiestructurada de forma de cuestionario en un ambito privado. RESULTADOS: El estudio incluyo a 102 mujeres. La mayoria de ellos tenian conocimiento de ser seropositivas para el virus de la inmunodeficiencia humana (VIH) durante la atencion prenatal (96,1%), y que no tenia intencion de tener mas hijos (63,7%). Mujeres menores de 39 anos, con educacion superior y terapia antirretroviral mas corta eran mas propensas a tener hijos (p=0,05). Mujeres con edades de menos de 39 anos y mas educacion tenian mas probabilidades de tener la informacion correcta acerca de tener hijos en presencia del VIH (p=0,05). Tener pareja estable aumento la posibilidad de desear tener hijos, mientras que la ligadura de trompas fue mayor en las mujeres que no han recibido orientacion sobre la planificacion familiar. CONCLUSION: La mayoria de las mujeres con SIDA no tienen intencion de tener hijos. El conocimiento acerca de la planificacion familiar se vio limitada por la falta de orientacion por los profesionales de la salud. PMID- 28562744 TI - Common mental disorders and associated factors: a study of women from a rural area. AB - OBJECTIVE: Identifying the prevalence of Common Mental Disorders and analyzing the influence of sociodemographic, economic, behavioral and reproductive health variables on Common Mental Disorders in women of childbearing age living in the rural area of Uberaba-MG, Brazil. METHOD: An observational and cross-sectional study. Socio-demographic, economic, behavioral and reproductive health instruments were used, along with the Self-Reporting Questionnaire (SRQ-20) to identify common mental disorders. Multiple logistic regression was used for multivariate data analysis. RESULTS: 280 women participated in the study. The prevalence of Common Mental Disorders was 35.7%. In the logistic regression analysis, the variables of living with a partner and education level were associated with Common Mental Disorders, even after adjusting for the other variables. CONCLUSION: Our findings evidenced an association of social and behavioral factors with Common Mental Disorders among rural women. Identification and individualized care in primary health care are essential for the quality of life of these women. OBJETIVO: Identificar a prevalencia do transtorno mental comum e analisar a influencia de variaveis sociodemograficas, economicas, comportamentais e de saude reprodutiva sobre o transtorno mental comum em mulheres em idade fertil, residentes na zona rural do municipio de Uberaba-MG, Brasil. METODO: Estudo observacional e transversal. Foram utilizados instrumentos de caracterizacao sociodemografica, economica, comportamental e de saude reprodutiva, e o Self-Reporting Questionnaire (SRQ-20) para identificar os transtornos mentais comuns. Na analise multivariada dos dados, foi utilizada a regressao logistica multipla. RESULTADOS: Participaram do estudo 280 mulheres. A prevalencia do transtorno mental comum foi de 35,7%. Na analise de regressao logistica, as variaveis convivencia com o companheiro e escolaridade, associaram se ao transtorno mental comum, mesmo apos o ajuste para as demais variaveis. CONCLUSAO: Os achados evidenciaram a associacao de fatores sociais e comportamentais com o transtorno mental comum, entre mulheres rurais. A identificacao e a assistencia individualizada na atencao primaria de saude sao essenciais para a qualidade de vida destas mulheres. OBJETIVO: Identificar la prevalencia de trastornos mentales comunes y analizar la influencia de las variables socio-demograficas, economicas, de comportamiento y de salud reproductiva en el trastorno mental comun en las mujeres en edad fertil, que viven en el municipio rural de Uberaba, Minas Gerais, Brasil. METODO: Estudio observacional y transversal. Se usaron instrumentos sociodemograficos, economicos, de comportamiento y salud reproductiva, y el Self-Reporting Questionnaire (SRQ-20) para identificar los trastornos mentales comunes. En el analisis multifactorial de los datos, se utilizo la regresion logistica multiple. RESULTADOS: El estudio incluyo a 280 mujeres. La prevalencia de los trastornos mentales comunes fue de 35,7%. En el analisis de regresion logistica, las variables convivencia con su pareja y la escolarizacion se asociaron con trastorno mental comun, incluso despues de ajustar por otras variables. CONCLUSION: Los resultados muestran la relacion entre los factores sociales y de comportamiento con el trastorno mental comun entre las mujeres rurales. La identificacion y la atencion individual en la atencion primaria de salud son esenciales para la calidad de vida de las mujeres. PMID- 28562745 TI - The nursing department's view towards moroccan patients. AB - OBJECTIVE: To determine the Melilla Hospital Nursing Department's attitude towards Moroccan patients. METHOD: Descriptive ex post facto study. A questionnaire has been handed over to staff, on the Immigration Attitude Scale for Nursing. RESULTS: In general, nurses exhibit negative attitudes towards Moroccan patients, such as: the increase in crime is caused by the arrival of immigrants, those who commit offenses must be expelled from Spain, they take advantage of the Spanish health system and too many resources are devoted to immigration. The worst-rated immigrants are the Moroccans, considering that they do not pay much attention to their personal hygiene and do not adapt to their host countries. CONCLUSION: It is necessary to work with the nursing staff to change these attitudes. Future degree students must be trained in cultural skills and the care of immigrants will improve with a greater commitment towards cultural differences. OBJETIVO: Conocer la actitud de enfermeria del Hospital de Melilla hacia los pacientes marroquies. METODO: Estudio ex post facto descriptivo. Se ha pasado un cuestionario de Escala de Actitud ante la Inmigracion para Enfermeria. RESULTADOS: En general las enfermeras presentan actitudes negativas ante los pacientes marroquies, como: el aumento de la delincuencia es provocado por la llegada de inmigrantes, los que delinquen deben ser expulsados de Espana, se aprovechan del sistema sanitario y se dedican demasiados recursos para la inmigracion. Los inmigrantes peores valorados son los marroquies, considerando que son pocos cuidadosos con su higiene personal y no se adaptan a los paises de acogida. CONCLUSION: Es necesario trabajar con el personal de enfermeria para que cambien estas actitudes. Las futuras promociones de Grado deben estar formadas en competencias culturales y mejoraran los cuidados a los inmigrantes como un mayor compromiso con la diferencia cultural. PMID- 28562746 TI - Perioperative fasting time among cancer patients submitted to gastrointestinal surgeries. AB - OBJECTIVE: To identify the length of perioperative fasting among patients submitted to gastrointestinal cancer surgeries. METHOD: Retrospective cohort study, developed by consulting the medical records of 128 patients submitted to gastrointestinal cancer surgeries. RESULTS: The mean of total length of fasting was 107.6 hours. The total length of fasting was significantly associated with the number of symptoms presented before (p=0.000) and after the surgery (p=0.007), the length of hospital stay (p=0.000), blood transfusion (p=0.013), nasogastric tube (p=0.001) and nasojejunal tube (p=0,003), postoperative admission at ICU (p=0.002), postoperative death (p=0.000) and length of preoperative fasting (p=0.000). CONCLUSION: The length of fasting is associated with complications that affect the quality of the patients' postoperative recovery and nurses' work. The nursing team should be alert to this aspect and being responsible for overseeing the patients' interest, should not permit the unnecessary extension of fasting. OBJETIVO: Identificar la duracion del ayuno perioperatorio entre los pacientes sometidos a cirugias de cancer gastrointestinal. METODO: Estudio de cohorte retrospectivo, por consulta de los registros medicos de 128 pacientes sometidos a cirugias de cancer gastrointestinal. RESULTADOS: La media de la duracion total del ayuno fue de 107,6 horas. La duracion total del ayuno se asocio significativamente con el numero de sintomas presentados antes (p=0,000) y despues de la cirugia (p=0,007), la duracion de la estancia hospitalaria (p=0,000), transfusion de sangre (p=0,013),tubo nasogastrico (P=0,003), ingreso postoperatorio en la UCI (p=0,002), muerte postoperatoria (p=0,000) y duracion del ayuno preoperatorio (p=0,000). CONCLUSION: La duracion del ayuno se asocia con complicaciones que afectan la calidad de la recuperacion postoperatoria de los pacientes y el trabajo de enfermeria. El equipo de enfermeria debe estar alerta en relacion a este aspecto y ser responsable de supervisar el interes de los pacientes, no permitiendo la extension innecesaria del ayuno. PMID- 28562747 TI - Pain assessment and management in patients undergoing endovascular procedures in the catheterization laboratory. AB - OBJECTIVE: To describe how pain is assessed (characteristic, location, and intensity) and managed in clinical practice in patients undergoing endovascular procedures in the catheterization laboratory setting. METHOD: Cross-sectional study with retrospective data collection. RESULTS: Overall, 345 patients were included; 116 (34%) experienced post-procedural pain; in 107 (92%), pain characteristics were not recorded; the location of pain was reported in 100% of patients, and its intensity in 111 (96%); management was largely pharmacologic; of the patients who received some type of management (n=71), 42 (59%) underwent reassessment of pain. CONCLUSION: The location and intensity of pain are well reported in clinical practice. Pharmacologic pain management is still prevalent. Additional efforts are needed to ensure recording of the characteristics of pain and its reassessment after interventions. OBJETIVO: Describir como se evalua el dolor (caracteristicas, localizacion e intensidad) y su manejo en la practica clinica en pacientes sometidos a procedimientos endovasculares en el laboratorio de cateterizacion. METODO: Estudio transversal con recoleccion retrospectiva de datos. RESULTADOS: En total, se incluyeron 345 pacientes; 116 (34%) experimentaron dolor post-procedimiento; en 107 (92%), no se registraron las caracteristicas del dolor; la localizacion del dolor se informo en el 100% de los pacientes, y su intensidad en 111 (96%); el manejo fue en gran medida farmacologico; de los pacientes que recibieron algun tipo de tratamiento (n=71), 42 (59%) fueron sometidos a reevaluacion del dolor. CONCLUSION: La ubicacion y la intensidad del dolor se informan bien en la practica clinica. El manejo farmacologico del dolor sigue siendo frecuente. Se necesitan esfuerzos adicionales para asegurar el registro de las caracteristicas del dolor y su reevaluacion despues de las intervenciones. PMID- 28562748 TI - Implications of SNPs on toll-like receptor genes in malaria: what do we know? PMID- 28562749 TI - A meta-analysis of TLR4 and TLR9 SNPs implicated in severe malaria. AB - Toll-like receptors (TLRs) are critical mediators of the inflammatory response to malarial infection, and gene polymorphisms affecting TLR function may be partially responsible for inter-individual variation in disease manifestation. However, there are inconsistencies in the associations of common genetic variants of TLR4 (D299G) and TLR9 (T-1237C and T-1486C) with malaria outcome. A comprehensive search was conducted to identify relevant and independent Plasmodium falciparum-infected case-control studies, and meta-analysis including six studies for each SNP was performed to obtain more precise estimates of the pooled effects of these variants. The results showed significant associations of the -1486C allele with the risk of severe malaria in allele contrast (T vs. C, p = 0.004, OR = 1.26) and homozygous (TT vs. CC, p = 0.03, OR = 1.51) genetic models. There was no association between the D299G or T-1237C variants and uncomplicated or severe malaria using any of the genetic models tested. However, in stratified analysis, -1237C was associated with the risk of severe malaria in Indian adults (TT vs. TC, p = 0.06, OR = 2.13; TT vs. TC+CC, p <0.00001, OR = 2.65), suggesting that our results must be considered preliminary. The robustness of -1486C as a risk factor warrants investigation into its functionality in malaria pathogenesis. Further, the lack of an association with the T-1237C variant was weak, and future studies examining more detailed individual data from different ethnic groups are essential for confirmation of its genetic contribution to malaria. PMID- 28562750 TI - Circulating microRNA as a marker for predicting liver disease progression in patients with chronic hepatitis B. AB - INTRODUCTION: Hepatitis B virus (HBV) constitutes an important risk factor for cirrhosis and hepatocellular carcinoma (HCC). The link between circulating microRNAs and HBV has been previously reported, although not as a marker of liver disease progression in chronic hepatitis B (CHB). The aim of this study was to characterize miRNA expression profiles between CHB with and without cirrhosis or HCC. METHODS: : A total of 12 subjects were recruited in this study. We employed an Affymetrix Gene Chip miRNA 3.0 Array to provide universal miRNA coverage. We compared microRNA expression profiles between CHB with and without cirrhosis/HCC to discover possible prognostic markers associated with the progression of CHB. RESULTS: : Our results indicated 8 differently expressed microRNAs, of which miRNA-935, miRNA-342, miRNA-339, miRNA-4508, miRNA-3615, and miRNA-3200 were up regulated, whereas miRNA-182 and miRNA-4485 were down-regulated in patients with CHB who progressed to cirrhosis/HCC as compared to those without progression. CONCLUSIONS: : We demonstrated the differential expression of miRNA-935, miRNA 342, miRNA-339, miRNA-4508, miRNA-3615, miRNA-3200, miRNA-182, and miRNA-4485 between patients with HBV without cirrhosis/HCC and those who had progressed to these more severe conditions. These miRNAs may serve as novel and non-invasive prognostic markers for early detection of CHB-infected patients who are at risk of progression to cirrhosis and/or HCC. PMID- 28562751 TI - Carbapenem-resistant Acinetobacter baumannii contamination in an intensive care unit. AB - INTRODUCTION:: Acinetobacter baumannii is a major pathogen causing infections in intensive care units (ICUs). In this study, we aimed to evaluate the presence of A. baumannii in an ICU environment and gloves from ICU workers and to characterize the antimicrobial resistance of the isolates in comparison with those isolated from ICU patients at the same hospital. METHODS:: ICU samples were collected from March to November 2010. Isolates biochemically characterized as Acinetobacter calcoaceticus-Acinetobacter baumannii complex were evaluated by PCR targeting the 16S rDNA and bla OXA-51 genes. Antimicrobial susceptibility was determined using the disk diffusion method, and carbapenem-resistant isolates were also evaluated for the minimum inhibitory concentration of imipenem using broth microdilution. The presence of the bla OXA-23 gene was evaluated in isolates with reduced susceptibility to carbapenems. RESULTS:: A. baumannii was detected in 9.5% (84) of the 886 samples collected from the ICU environment, including from furniture, medical devices, and gloves, with bed rails being the most contaminated location (23.8%; 20/84). Multidrug-resistant (MDR) A. baumannii was found in 98.8% (83/84) of non-clinical and 97.8% (45/46) of clinical isolates. Reduced susceptibility to carbapenems was detected in 83.3% (70/84) of non-clinical and 80.4% (37/46) of clinical isolates. All isolates resistant to carbapenems harbored bla OXA-23. CONCLUSIONS:: We found a strong similarity between the antimicrobial susceptibility profiles of non-clinical and clinical A. baumannii isolates. Such data highlight the ICU environment as a potential origin for the persistence of MDR A. baumannii, and hence the ICU may be a source of hospital-acquired infections caused by this microorganism. PMID- 28562752 TI - Phenotypic methods for screening carbapenem-resistant Enterobacteriaceae and assessment of their antimicrobial susceptibility profile. AB - INTRODUCTION: : In this study, we used phenotypic methods to screen carbapenem resistant Enterobacteriaceae (CREs) and evaluated their antimicrobial sensitivity profile. METHODS:: One hundred and seventy-eight CREs were isolated at a university hospital in south Brazil in a one-year period. Samples were assessed using disk diffusion tests with inhibitors of beta-lactamases such as phenylboronic acid (AFB), cloxacillin (CLOXA), and ethylenediaminetetraacetic acid (EDTA). Strains with differences in zone diameters >= 5mm for disks supplemented or not were considered producers of carbapenemases. RESULTS: : Klebsiella pneumoniae was the most prevalent CRE, which appeared in 80.3% cases (n = 143). Among clinical materials, the rectal swab was responsible for 43.4% of the isolations (n = 62), followed by urine (18.9%; n = 27). Among the CREs identified in this study, the growth of 56.7% (n = 101) isolates, which were putative producers of Klebsiella pneumoniae carbapenemase (KPC), were inhibited by AFB, whereas 7.3% (n = 13) isolates were inhibited by both AFB and CLOXA and were considered as putative producers of plasmid-mediated AmpC; approximately 3.4% (n = 6) were inhibited by EDTA, which possibly produced metallo-beta lactamase. Lastly, 32.6% (n = 58) cases showed negative results for AFB, CLOXA, and EDTA sensitivity, and represented another class of beta-lactamases and/or mechanism of resistance. CONCLUSIONS:: Phenotypic screening of CREs is important for clinical laboratories that monitor outbreaks of resistant microbes. Phenotypic tests that use carbapenemase inhibitors and enhancers such as AFB, CLOXA, and EDTA are necessary since they are good screening methods for the detection of carbapenemases. PMID- 28562753 TI - Group B Streptococcus detection in pregnant women via culture and PCR methods. AB - INTRODUCTION:: Group B Streptococcus (GBS), a source of neonatal infection, colonizes the gastrointestinal and genitourinary tracts of pregnant women. Routine screening for maternal GBS in late pregnancy and consequent intrapartum antibiotic prophylaxis have reduced the incidence of early-onset GBS neonatal infection. The aim of this study was to evaluate the performance of PCR, compared to culture (gold standard), in GBS colonization screening of pregnant women, and to establish the prevalence of GBS colonization among this population. METHODS:: Vaginal introitus and perianal samples were collected from 204 pregnant women, between the 35th and 37th weeks of pregnancy, at the Obstetrics and Gynecology Unit of the University of Caxias do Sul General Hospital between June 2008 and September 2009. All samples were cultured after enrichment in a selective medium and then assayed by culture and PCR methods. RESULTS:: The culture and PCR methods yielded detection rates of vaginal/perianal GBS colonization of 22.5% and 26%, respectively (sensitivity 100%; specificity 95.6%; positive and negative predictive values 86.8% and 100%, respectively). A higher prevalence of GBS colonization was detected in the combined vaginal and perianal samples by both culture and PCR assay analyses. CONCLUSIONS:: PCR is a faster and more efficient method for GBS screening, allowing for optimal identification of women who should receive intrapartum antibiotic prophylaxis to prevent newborn infection. PMID- 28562754 TI - Evaluation of antioxidant therapy in experimental Chagas disease. AB - INTRODUCTION:: Stimulation of inflammatory mediators such as cytokines and chemokines may cause oxidative stress in Chagas disease. In this study, we evaluated the merit of vitamins C and E as antioxidant therapy to minimize the oxidative stress-induced damage in an experimental model of Chagas disease. METHODS:: Ninety-six Swiss mice were infected with Trypanosoma cruzi QM2 and treated with vitamins C, E, or both (C/E) for 60 and 120 days, and their effects compared to placebo administration were evaluated in the acute and chronic disease phases. RESULTS: : There was no difference in parasitemia among treatment groups. However, histological analysis showed more severe inflammation in the skeletal muscle in the vitamin supplementation groups at both the acute and chronic phases. Biochemical analyses during the acute phase showed increased ferric-reducing ability of plasma (FRAP) and glutathione (GSH) levels in the vitamin C and C/E groups. In the chronic phase, a decrease in GSH levels was observed in the vitamin E group and a decrease in thiobarbituric acid reactive substances (TBARS) was observed in the vitamin C/E group. Moreover, there was a decrease in TBARS in the cardiac tissues of the vitamin C and C/E groups compared to that of the placebo group, although this level was greater in the vitamin E group than in the vitamin C group. CONCLUSIONS: : The antioxidant action of vitamins C and E reduced oxidative stress in both the acute and chronic phases of Chagas disease, with a marked effect from joint administration, indicating their inherent synergism. PMID- 28562755 TI - Evaluating respiratory musculature, quality of life, anxiety, and depression among patients with indeterminate chronic Chagas disease and symptoms of pulmonary hypertension. AB - INTRODUCTION:: Chagas disease (CD) is progressive and incapacitating, especially when cardiopulmonary function is affected. For example, respiratory muscle weakness can cause dyspnea upon exertion and fatigue, which may be exacerbated when it is associated with pulmonary hypertension (PH). The present study aimed to evaluate respiratory musculature, quality of life, anxiety, and depression among patients with indeterminate chronic CD and symptoms of PH. METHODS:: All individuals completed a clinical evaluation, spirometry, a 6-min walking test, respiratory musculature testing using maximum inspiratory pressure (PImax) and maximum expiratory pressure (PEmax), the Hospital Anxiety and Depression Scale, and the SF-36 questionnaire. RESULTS:: We evaluated 107 patients who were assigned to a control group with only CD (G1, 8 patients), a group with CD and possible PH (G2, 93 patients), and a group with CD and echocardiography evidence of PH (G3, 6 patients). The three groups had similar values for PImax and PEmax. Compared to the G1 and G2 groups, the G3 group covered significantly less distance during the 6-min walking test and had a significantly shorter predicted distance (p < 0.05 vs. the G1 group). All three groups had similar values for their spirometry results, Hospital Anxiety and Depression Scale scores, and SF-36 questionnaire results. CONCLUSIONS:: Patients with indeterminate chronic CD and symptoms of PH did not experience significant impairment in the studied variables, with the exception of the 6-min walking test, which suggests a low exercise tolerance. PMID- 28562756 TI - Concordance between IFNgamma gene +874 A/T polymorphism and interferon-gamma expression in a TB-endemic indigenous setting. AB - INTRODUCTION: : Interferon-gamma (IFN-gamma) plays a crucial role in resistance to mycobacterial diseases; accordingly, variants of the gene encoding this cytokine may be associated with elevated risk of contracting pulmonary tuberculosis (TB). METHODS:: Blood samples were collected from 135 Warao indigenous individuals with newly diagnosed sputum culture-positive TB. Of these, 24 were diagnosed with active tuberculosis (ATB). The study comprised 111 participants, who were grouped as follows: 1) 14 tuberculin skin test (TST) positive Warao indigenous individuals and 4 that were QuantiFERON-TB?Gold In-Tube (QFT-IT) test-positive, collectively comprising the latent TB infection group (LTBI), n = 18), and 2) healthy controls who were QFT-IT- and TST-negative, comprising the control group (CTRL, n = 93). Detection of the IFN gamma gene (IFNG) +874A/T polymorphism was performed via PCR and quantification of IFNG expression via qPCR. RESULTS: : Relative to indigenous and white Americans, ATB and CTRL groups had a higher frequency of the IFNG SNP (+874A): 23 (95.8%) and 108 (97.3%), respectively. Indigenous Warao individuals homozygous for the IFNG (+874) A allele exhibited 3.59-fold increased risk of developing TB (95% confidence interval, 2.60-4.96, p =0.0001). A decreased frequency of the AT genotype was observed in individuals with pulmonary TB (4.16%) and controls (0.90%). The frequency of the TT genotype was decreased among controls (1.80%); none of the patients with TB were found to have this genotype. The differences in IFNG expression between the groups, under unstimulated and stimulated conditions, were not statistically significant. CONCLUSIONS:: Preliminary results demonstrate concordance between IFNG +874 A/A genotype and low expression of IFNG. PMID- 28562757 TI - Analysis of clinical data and T helper 1/T helper 2 responses in patients with different clinical forms of leprosy. AB - INTRODUCTION: : Currently, there are no laboratory tests or sensitive and specific molecular markers for the early diagnosis of leprosy. The aim of this study was to analyze the clinical characteristics of patients with leprosy and investigate their immunological profile, comparing this with the type of lesion and the presence or absence of a Bacillus Calmette-Guerin (BCG) vaccination scar. METHODS:: Statistical analyzes were performed by employing comparative tests (Pearson's chi-square) to evaluate the variables in different clinical forms, considering significance at the 5% level. RESULTS: : The study identified a predominance of lepromatous leprosy (26.9%) in patients aged between 34-53 years. Caucasians predominantly had borderline tuberculoid (BT) clinical forms (42%); a predominance of males with borderline lepromatous (19%) and lepromatous leprosy (26.9%) forms was observed; and the presence of BCG vaccination scars (27.5%) and lower limb nerves were more affected (38%) predominantly in the BT clinical form. Significant differences were identified, which included hypochromic lesions predominantly in the BT clinical form (24%); diffuse-type lesions predominantly in the tuberculoid (TT) clinical form (28%); ill-defined lesion border dominance in lepromatous leprosy (LL) clinical forms (30%); an irregular lesion limit predominantly in LL clinical forms (32%); and a predominant Th1 immune response in the BT clinical form (41.7%). CONCLUSIONS: : The evaluation of the immunological profile in leprosy patients may contribute to the more detailed diagnosis and possibly better characterization of the prognosis for these individuals. PMID- 28562758 TI - Presence of Mycobacterium leprae genotype 4 in environmental waters in Northeast Brazil. AB - INTRODUCTION:: This study quantified Mycobacterium leprae bacilli in environmental water samples from five municipalities in the State of Ceara by quantitative polymerase chain reaction (qPCR) and compared the identified genotypes with those obtained from leprosy patient biopsies. METHODS:: We collected five replicas from each of the 30 selected reservoirs and skin lesion biopsies from 25 new leprosy cases treated at a reference center in Fortaleza, Ceara from 2010 to 2013. The 16S rRNA gene region of M. leprae was amplified by qPCR and a standard curve was created with the pIDTBlue 16SrRNAMlep plasmid. The Juazeiro do Norte water samples and the biopsies were genotyped (single nucleotide polymorphism [SNP] 1 to 4) and the SNP 4 genotypes were subtyped. RESULTS:: Of the 149 water samples analyzed, 54.4% were positive for the M. leprae DNA. The M. leprae bacilli copy number ranged from 1.42 * 10 -1 to 1.44 * 10 + 2 . Most biopsies showed SNP type 4 (64%), while all samples from Juazeiro do Norte were SNP type 4, with subtype 4-N appearing at the highest frequency. CONCLUSIONS:: We suggest that environmental waters containing M. leprae bacilli play an important role in disease transmission, justifying PGL-1 seropositivity in individuals living in areas where there is no reported case, and in leprosy cases individuals who report no previous contact with other case. Therefore, further investigation is needed to clarify disease transmission in this region and to explore the role of the environment. We also suggest that in this area surveillance for leprosy cases should be intensified. PMID- 28562759 TI - Assessment of the sensory and physical limitations imposed by leprosy in a Brazilian Amazon Population. AB - INTRODUCTION: Leprosy often results in sensory and physical limitations. This study aimed to evaluate these limitations using a quantitative approach in leprosy patients in Belem (Para, Brazil). METHODS: This epidemiological, cross sectional study measured the sensory impairment of smell and taste through the use of a questionnaire and evaluated activity limitations of daily life imposed by leprosy through the Screening of Activity Limitation and Safety Awareness (SALSA) Scale. Data were collected from 84 patients and associations between the degree of disability and clinical and epidemiological characteristics were assessed. RESULTS: The majority of patients were men (64.3%), married (52.4%), age 31-40 years old (26.2%), had primary education (50%), and were independent laborers (36.9%). The multibacillary operational classification (81%), borderline clinical form (57.1%), and 0 degrees of physical disability (41.7%) were predominant. SALSA scores ranged from 17 to 59 points, and being without limitations was predominant (53.6%). The risk awareness score ranged from 0 to 8, with a score of 0 (no awareness of risk) being the most common (56%). Evaluation of smell and taste sensory sensitivities revealed that 70.2% did not experience these sensory changes. Patients with leprosy reactions were 7 times more likely to develop activity limitations, and those who had physical disabilities were approximately four times more likely to develop a clinical picture of activity limitations. CONCLUSIONS: Most patients showed no sensory changes, but patients with leprosy reactions were significantly more likely to develop activity limitations. Finally, further studies should be performed, assessing a higher number of patients to confirm the present results. PMID- 28562760 TI - ? AB - INTRODUCTION: : Bottlenecks still exist during human immunodeficiency virus care that may delay the achievement of better outcomes. METHODS: : We established a monitoring system to trace patients throughout the human immunodeficiency virus/acquired immunodeficiency syndrome care process in Juiz de Fora, Brazil, to identify potential bottlenecks. RESULTS: : Among 250 patients, 17.6% abandoned follow-up. Our monitoring system tracked 86.4% of patients through the medication logistics control system and 2.3% through the mortality information system. Two percent of patients were not located by our monitoring system. CONCLUSIONS: : A pathway care process contributes to a better understanding of the barriers to the treatment cascade. PMID- 28562761 TI - Ascogregarina taiwanensis infection in Aedes aegypti and Aedes albopictus in Santa Catarina, South Brazil. AB - INTRODUCTION: This study registers Ascogregarina spp. infection in field populations of Aedes aegypti and Aedes albopictus in a subtropical region of Brazil. METHODS: Mosquito larvae collected in tires placed in four municipalities of Santa Catarina were identified morphologically and assessed for Ascogregarina sp. infection using morphological and molecular methods. RESULTS: Both mosquito species harbored Ascogregarina taiwanensis, whose genomic DNA was confirmed in both the Aedes species by PCR. DNA sequences were deposited in GenBank. Conclusion: Both Ae. albopictus e Ae. aegypti harbor Ascogregarina sp. PMID- 28562762 TI - A duplex endpoint PCR assay for rapid detection and differentiation of Leptospira strains. AB - INTRODUCTION:: This study aimed to develop a duplex endpoint PCR assay for rapid detection and differentiation of Leptospira strains. METHODS:: Primers were designed to target the rrs (LG1/LG2) and ligB (LP1/LP2) genes to confirm the presence of the Leptospira genus and the pathogenic species, respectively. RESULTS:: The assay showed 100% specificity against 17 Leptospira strains with a limit of detection of 23.1pg/ul of leptospiral DNA and sensitivity of 103 leptospires/ml in both spiked urine and water. CONCLUSIONS:: Our duplex endpoint PCR assay is suitable for rapid early detection of Leptospira with high sensitivity and specificity. PMID- 28562763 TI - Prevalence and antimicrobial susceptibility of non-fermenting Gram-negative bacilli isolated from clinical samples at a tertiary care hospital. AB - INTRODUCTION:: We compared the prevalence and antimicrobial susceptibility of non fermenting gram-negative bacilli (NFGNB) isolated from clinical samples at a Brazilian tertiary care hospital in 2008 and 2013. METHODS:: Collected data included patient's name, age, sex, inpatient unit, laboratory record number, type of biological material, culture test result, and antimicrobial susceptibility of isolated strains. RESULTS:: Out of 19,112 culture tests analyzed, 926 (4.8%) were positive for NFGNB. Among these, 45.2% were metallo-beta-lactamase (MBL) producing strains. CONCLUSION: : Between 2008 and 2013, the number of MBL producing NFGNB isolates increased by 21.5%, which was accompanied by a consequent reduction in susceptibility to antimicrobials. PMID- 28562764 TI - Serosurvey of anti- Leptospira sp. and anti- Toxoplasma gondii antibodies in capybaras and collared and white-lipped peccaries. AB - INTRODUCTION:: Brazilian native species are reemerging as increasingly free ranging populations. METHODS:: Sera from 31 capybaras (Hydrochoerus hydrochaeris) and 28 peccaries (Pecari tajacu and Tayassu pecari) were tested for anti Leptospira and anti-Toxoplasma gondii antibodies using microscopic seroagglutination test. RESULTS:: Nineteen percent of free-ranging and 10.0% of captive capybaras, along with 31.8% of collared peccaries, were seropositive for T. gondii. None was seropositive for Leptospira sp. CONCLUSIONS:: The present findings indicated low risk of disease, particularly among capybaras and white lipped peccaries; however, active surveillance programs are important for monitoring wildlife health and public health once they are in public parks around cities. PMID- 28562765 TI - Leprosy in Southern Brazil: a twenty-year epidemiological profile. AB - INTRODUCTION:: This study evaluated leprosy rates in Rio Grande do Sul, an area with a historically low prevalence. However, recent studies are lacking. METHODS:: Data extracted from a National Database were analyzed for clinical features and compared to 1980s data. Tendency was assessed via stationarity analysis. RESULTS:: Between 1990 and 2011, 4,770 cases were reported (0.21/10,000 inhabitants; 95% CI = 0.19-0.24). Detection was slightly higher among males, 1.9% cases were among children and most multibacillary (74.7%) at diagnosis. CONCLUSIONS:: Leprosy is controlled in RS, but most cases are multibacillary. Early identification is important to avoid disabilities due to late diagnosis. PMID- 28562766 TI - Wuchereria bancrofti infection in Haitian immigrants and the risk of re-emergence of lymphatic filariasis in the Brazilian Amazon. AB - INTRODUCTION:: Lymphatic filariasis (LF) is a public health problem in Haiti. Thus, the emigration of Haitians to Brazil is worrisome because of the risk for LF re-emergence. METHODS:: Blood samples of Haitian immigrants, aged >=18 years, who emigrated to Manaus (Brazilian Amazon), were examined using thick blood smears, membrane blood filtration, and immunochromatography. RESULTS: : Of the 244 immigrants evaluated, 1 (0.4%) tested positive for W. bancrofti; 11.5% reported as having received LF treatment in Haiti. CONCLUSIONS: : The re emergence of LF in Manaus is unlikely, due to its low prevalence and low density of microfilaremia among the assessed Haitian immigrants. PMID- 28562767 TI - Infrared thermography to diagnose and manage venomous animal bites and stings. AB - INTRODUCTION: Infrared imaging (IR) is a noninvasive technique that quantifies body surface temperature, producing a digital color image. IR has been used to study diseases in which skin temperature can reflect the presence of inflammation. METHODS: This was an observational pilot study of eight patients envenomed by snakes, spiders, and scorpions. All patients were examined using a thermal camera. RESULTS: In all cases, we obtained infrared images that corroborated clinical findings indicating localized effects of venom, specifically inflammation. CONCLUSIONS: IR has potential for use as a research, diagnostic, and monitoring tool for localized effects of animal venoms. PMID- 28562768 TI - Chikungunya virus infection with severe neurologic manifestations: report of four fatal cases. AB - Here, we present four patients with confirmed Chikungunya virus infection showing atypical neurologic manifestations and death. This case series includes patients ranging in age from five to 92 years, with or without comorbidities. This report is important, as very few cases in the literature reporting death due to atypical Chikungunya virus infection are available. PMID- 28562769 TI - Intralesional treatment with meglumine antimoniate in three patients with New World cutaneous leishmaniasis and large periarticular lesions with comorbidities. AB - Although New World cutaneous leishmaniasis is not itself a life-threatening disease, its treatment with systemic antimonials can cause toxicity that can be dangerous to some patients. Intralesional meglumine antimoniate provides a viable, less toxic alternative. Herein, we describe an alternative treatment with subcutaneous intralesional injections of meglumine antimoniate into large periarticular lesions of three patients with cutaneous leishmaniasis and comorbidities. This treatment was safe, successful, and well tolerated. This case series suggests that intralesional meglumine antimoniate is an effective therapy for cutaneous leishmaniasis, even with periarticular lesions. This hypothesis should be tested in controlled clinical trials. PMID- 28562770 TI - Paracoccidioidomycosis with sarcoid-like lesions:a diagnostic challenge. AB - Clinical presentation of paracoccidioidomycosis (PCM) can be diverse. Morphology and quantity of skin lesions depends on interactions between host immunity and fungus virulence. Diagnosis can be a challenge considering that this fungus has low virulence and some individuals have immunity to microorganism, which results in well-marked granulomas without visible microorganisms. We report herein a clinical presentation of sarcoid-like PCM, initially diagnosed as tuberculoid leprosy. This rare type of PCM is often mistaken for other types of chronic granulomatous diseases. Diagnosis was confirmed after 4 years when a special stain analysis helped in the identification of the specific etiologic agent. PMID- 28562771 TI - Facial botryomycosis-like pyoderma in an HIV-infected patient: remission after initiation of darunavir and raltegravir. AB - Botryomycosis is an uncommon, chronic, suppurative, bacterial infection that primarily affects the skin and subcutaneous tissues. It has long been associated with defects of cellular immunity. We report a 28-year-old woman who presented with a chronic, ulcerated lesion with draining sinuses in the right malar region. Predisposing factors were HIV infection with poor immunological control, alcoholism, and a previous trauma to the right cheek. Several courses of antimicrobial therapy provided only partial and temporary remission. Complete clinical remission was only achieved 5 years later when a novel antiretroviral regimen composed of darunavir and raltegravir was initiated. PMID- 28562772 TI - Spleen damage in a dog naturally infected by Leishmania infantum. PMID- 28562773 TI - ? PMID- 28562774 TI - Physiological, cellular and molecular aspects of the desiccation tolerance in Anadenanthera colubrina seeds during germination. AB - During germination, orthodox seeds become gradually intolerant to desiccation, and for this reason, they are a good model for recalcitrance studies. In the present work, physiological, biochemical, and ultrastructural aspects of the desiccation tolerance were characterized during the germination process of Anadenanthera colubrina seeds. The seeds were imbibed during zero (control), 2, 8, 12 (no germinated seeds), and 18 hours (germinated seeds with 1 mm protruded radicle); then they were dried for 72 hours, rehydrated and evaluated for survivorship. Along the imbibition, cytometric and ultrastructural analysis were performed, besides the extraction of the heat-stable proteins. Posteriorly to imbibition and drying, the evaluation of ultrastructural damages was performed. Desiccation tolerance was fully lost after root protrusion. There was no increase in 4C DNA content after the loss of desiccation tolerance. Ultrastructural characteristics of cells from 1mm roots resembled those found in the recalcitrant seeds, in both hydrated and dehydrated states. The loss of desiccation tolerance coincided with the reduction of heat-stable proteins. PMID- 28562776 TI - Parasitism by Monogenoidea in Piaractus mesopotamicus (Characiformes, Characidae) cultivated in Parana River (Brazil). AB - This study investigated the occurrence, prevalence, mean abundance and mean intensity of monogenoidean parasites in Piaractus mesopotamicus farmed in cages in the reservoir of the Itaipu Hydroelectric Power Station, Parana River, Brazil. The parasite distribution pattern and the correlation of prevalence and abundance with the total length of hosts were also investigated. Four monogenoidean species were collected: Anacanthorus penilabiatus, A. toledoensis, Mymarothecium ianwhitingtoni and M. viatorum. All the parasites collected in P. mesopotamicus showed the typical aggregated distribution pattern, and the abundance and the prevalence did not shown any correlation with the total length of hosts. PMID- 28562775 TI - Acetylcholine produces contractions mediated by the cyclooxygenase pathway in arterial vessels in the Chilean frog (Calyptocephalella gayi). AB - Previous studies performed in marine fish (I. conceptionis and G. laevifrons) showed that indomethacin blocked arterial contraction mediated by acetylcholine (ACh). The objective of this study was to determine if contraction induced by acetylcholine is mediated by the cyclooxygenase pathway in several arterial vessels in the Chilean frog Calyptocephalella gayi. Arteries from the pulmonary (PA), dorsal (DA), mesenteric (MA) and iliac (IA) regions were dissected from 6 adult specimens, and isometric tension studies were done using dose response curves (DRC) for ACh (10-13 to 10-3 M) in presence of a muscarinic antagonist (Atropine 10-5 M) and an unspecific inhibitor of cyclooxygenases (Indomethacin, 10-5M). All the studied arteries exhibited vasoconstriction mediated by ACh. This vasoconstriction was abolished in the presence of atropine in DA, MA and IA and attenuated in PA. Indomethacin abolished the vasoconstriction in MA and attenuated the response in PA, DA and IA. Similar to marine fish, C. gayi have an ACh-mediated vasoconstrictor pattern regulated by muscarinic receptors that activate a cyclooxygenase contraction pathway. These results suggest that the maintenance in vasoconstrictor mechanisms mediated by ACh->COX ->vasoconstriction is conserved from fish to frogs. PMID- 28562777 TI - Proteic and phenolics compounds contents in Bacupari callus cultured with glutamine and nitrogen sources. AB - In this study was evaluated the influence of glutamine supplementation on the endogenous content of amino acids, proteins, total phenolics, flavonoids and proanthocyanidins in Bacupari callus. The explants were inoculated in MS medium, MS with half concentration of the nitrogen salts (MS1/2) and nitrogen-free MS, supplemented with glutamine (5, 10, 30 and 60mM) named as Gln5, Gln10, Gln30 and Gln60. Amino acids and proteins were analyzed after 20, 80 and 140 days and the secondary metabolites on the 140th day. There was no difference in the amino acids on the 20th day. On the 80th day the treatments MS and MS1/2 presented the lowest levels. On the 140th day MS and MS1/2 presented the lowest amino acid concentration and Gln10 the highest. Concerning proteins, there was difference only on the 140th day, being the highest concentrations observed in Gln5, and the lowest in MS1/2 treatment. Total phenolics content was higher in the treatment Gln60 and lowest in MS. Treatments Gln5, Gln10, Gln30 and MS1/2 were statistically equal. For flavonoids, the highest values occurred in the treatments Gln30, Gln60 and MS1/2 and the lowest in Gln5, Gln10 and MS. Similarly, for the proanthocyanidins the highest concentrations were observed in treatment Gln60 and the lowest in Gln5 and MS. In conclusion, the treatment with 60mM of glutamine favors the protein accumulation and production of secondary metabolites in Bacupari callus. PMID- 28562779 TI - Record of Leptoglossus cinctus (Hemiptera: Coreidae) associated with the native tree Byrsonima sericea (Malpighiaceae) and the cashew tree Anacardium occidentale (Anacardiaceae). PMID- 28562778 TI - The beetle Costalimaita ferruginea (Coleoptera: Chysomelidae) in Eucalyptus plantations in transition area of Amazon and Cerrado Biomes. AB - Costalimaita ferruginea (Coleoptera: Chrysomelidae) attacks Eucalyptus plants causing severe damage through netting of the leaves. Recently, this Coleoptera has been reported attacking Myrtaceae in Mato Grosso State and, studies about the occurrence of this beetle in commercial plantations of eucalypts has been the subject of researchers through monitoring programmes in the forest protection area. With the beginning of the rainy season, adults were observed causing damage in eucalypt plantations in four cities that are part of the transition region of Amazon and Cerrado Biomes. The spots where these insects were observed are located in Feliz Natal, Lucas do Rio Verde, Sorriso and Vera. The purpose of this study was to report the new occurrences and to characterize the attack period of the beetle C. ferruginea in Eucalyptus plantations in Middle-North region of Mato Grosso State, region of Biomes Transition. PMID- 28562780 TI - First record of leucism for Atractus reticulatus (Serpentes: Dipsadidae). PMID- 28562781 TI - Potential distribution and conservation of the Colobosauroides carvalhoi Soares and Caramaschi, 1998: a rare and endemic lizard of Northeast Brazil. AB - Ecological niche modeling has contributed to the investigation of the geographical distribution and conservation of rare or little recorded species. Therefore, we studied the known and potential distributions of Colobosauroides carvalhoi Soares and Caramaschi 1998 and discuss the implications for its conservation. Data were obtained by manual collections made in quarterly samplings in three different regions, considering the regions with occurrence records and surrounding areas. The known distribution was determined by occurrence records and literature data, and potential distribution was estimated with an ecological niche model by the MaxEnt algorithm. Twenty-five specimens were collected exclusively in forest formations of Caatinga and Caatinga-Cerrado. Our data corroborated the relative rarity of C. carvalhoi and reflected the biogeographical history of the group, where it is restricted to forest formations with milder environmental conditions. The occurrence records indicated new records of C. carvalhoi, but the known distribution value is compatible with a restricted distribution. The ecological niche model estimated few areas with environmental suitability for the species and corroborated the restricted and relict distribution patterns. Finally, the known and potential distribution values were compatible with criteria for threatened species. These results suggest a worrisome scenario for C. carvalhoi conservation. However, the limited data about the species population do not allow the proper definition of its conservation status. Therefore, we suggest using potential distribution values with alternative criteria for redefining the conservation status of C. carvalhoi and the development of new studies that support a better assessment of its conservation aspects. PMID- 28562783 TI - Occurrence of Allorhogas sp. (Hymenoptera: Braconidae: Doryctinae) associated with galls on seeds of Inga vera (Fabaceae) in Brazil. PMID- 28562782 TI - First record of Solmundella bitentaculata (Cnidaria: Aeginidae) in Para State Shelf, Brazil. PMID- 28562784 TI - Karyosystematic and karyotype evolution of Panstrongylus lutzi (Neiva & Pinto, 1923) (Hemiptera, Triatominae). PMID- 28562785 TI - Cytogenetic analysis in different populations of Rhodnius prolixus and R. nasutus from different countries of South America. PMID- 28562786 TI - Structure dynamics of a fish community over ten years of formation in the reservoir of the hydroelectric power plant in upper Uruguay River. AB - The objective of this study was to evaluate the structure of the fish assemblage in the ten years following the closing of the lake of the Ita Hydroelectric Power Plant. Seasonal collections were conducted from 2001 to 2010. During this period, 44,834 fish were captured, totaling 3,818.01 kg, among 8 orders, 24 families and 84 species. In general, profound changes were not observed in the fish assemblage in the ten years after the formation of the Ita lake. Few species changed in dominance over time, while many were rare in the environment. The ichthyofauna in the reservoir was dominated by small and medium size opportunist species that conduct short or no migratory movements. Among the most abundant, six species were responsible for more than 50% of the numeric representation: Steindachnerina brevipinna, Astyanax fasciatus, Apareiodon affinis, Hypostomus isbrueckeri, Iheringichthys labrosus and Loricariichthys anus. The increase in the representation of the later species stood out. The biomass was dominated by Steindachneridion scriptum, Prochilodus lineatus, I. laborsus, Schizodon nasutus, Hoplias malabaricus, Acestrorhynchus pantaneiro, Hoplias lacerdae, H. isbrueckeri and L. anus. Despite the presence of large migrators in the region of the reservoir, their vulnerability was revealed by the low numeric abundance and accidental capture. The k-dominance curve of numerical abundance and biomass indicates a moderately disturbed community, in which the representation of small species was also important to the amounts of biomass. PMID- 28562787 TI - Effect of land use in seasonal abundance of Eared Dove (Zenaida auriculata) in Southwestern Brazil. AB - Changes at the landscape scale associated with expansion in agricultural land use and changes in agricultural practices are common causes of alteration in patterns of abundance and composition of avian communities. Eared Dove (Zenaida auriculata - Des Murs, 1847) is among the most common species in the Neotropics, considered both as game and pest in some countries. Here we characterized the regional and seasonal patterns of Eared Doves abundance in Southwestern Brazil and examined the relationship between landscape features and these abundance patterns. We counted Eared Doves using the point count system along routes in summer and winter and recorded land use at two scales. We used linear regressions to model the effect of landscape matrix and land use at local scale with Doves abundance in two seasons. At the landscape scale, in winter, the abundance was greater in routes crossing landscapes dominated by plantations. In summer, it was lower in routes with large tracts of forests and mixed farming. While in winter, at the local scale, the Doves abundance was greater in routes with higher frequency of maize plantations, in summer higher abundances were observed in routes with higher frequency of sugar cane and soybean plantations. Agricultural settings, which include both sustained production of food in the form of grains as well as and large stretches of habitat suitable for reproduction, favor large population of Eared Doves. PMID- 28562788 TI - Economic valuation of the ecosystem services provided by a protected area in the Brazilian Cerrado: application of the contingent valuation method. AB - Considering that the economic valuation of ecosystem services is a useful approach to support the conservation of natural areas, we aimed to estimate the monetary value of the benefits provided by a protected area in southeast Brazil, the Serra do Cipo National Park. We calculated the visitor's willingness to pay to conserve the ecosystems of the protected area using the contingent valuation method. Located in a region under intense anthropogenic pressure, the Serra do Cipo National Park is mostly composed of rupestrian grassland ecosystems, in addition to other Cerrado physiognomies. We conducted a survey consisting of 514 interviews with visitors of the region and found that the mean willingness to pay was R$ 7.16 year-1, which corresponds to a total of approximately R$ 716,000.00 year-1. We detected that per capita income, the household size, the level of interest in environmental issues and the place of origin influenced the likelihood that individuals are willing to contribute to the conservation of the park, as well as the value of the stated willingness to pay. This study conveys the importance of conserving rupestrian grassland and other Cerrado physiognomies to decision makers and society. PMID- 28562789 TI - Nursing in cardiology: state of the art and frontiers of knowledge. PMID- 28562790 TI - Validation of an instrument regarding nursing intervention in patients in vasoactive therapy. AB - Objective: to validate the content of a Standard Operational Procedure, regarding nursing interventions in emergency patients treated with vasoactive drugs. Method: methodological study, carried out from December 2015 to January 2016. Content validity was determined by 16 experts (13 nurses, 2 pharmacists and one biomedical scientist), who judged it through a four-point Likert scale. The items were evaluated in terms of: feasibility, objectivity, simplicity, clearness, pertinence and accuracy. The Content Validity Index was applied, accepting the value >= 0.90. Results: two rounds of evaluation were required to achieve the minimum index. The items were reviewed regarding writing, dilution, indication and replacement interval. The instrument was validated with 33 items and with total Content Validity Index of 0.99. Conclusion: the instrument was considered appropriate, fractionally and globally, for nursing care for the patient treated with vasoactive drugs in emergency, in a safe and reliable way. PMID- 28562791 TI - Terms of the specialized nursing language for the care of ostomates. AB - Objectives:: to identify terms of the specialized nursing language for the care of ostomates from the literature of the area, and to map the identified terms with terms of the International Classification for Nursing Practice (ICNP(r)). Method:: descriptive study of quantitative approach guided by the guidelines for the elaboration of terminology subsets of the ICNP(r). The terms were collected in 49 scientific articles, extracted using a computational tool, selected according to the relevance for the theme, and normalized and mapped with the ICNP(r). Results:: 20,668 terms were extracted. The standardization process resulted in 425 relevant terms (151 were constant in ICNP(r) and 274 were not contained in ICNP(r)), of which 154 were similar, 19 were more comprehensive, 50 were more restricted, and 51 were not in concordance. Conclusion:: the use of standardized language can minimize the ambiguities and redundancies identified in the mapping. The existence of terms not in concordance with the ICNP(r) reinforces the need for constant updating of this classification. Objetivos:: identificar termos da linguagem especializada de enfermagem para o cuidado a pessoa ostomizada, a partir da literatura da area; e mapear os termos identificados com termos da Classificacao Internacional para a Pratica de Enfermagem (CIPE(r)). M: etodo: pesquisa descritiva, de abordagem quantitativa, orientada pelas diretrizes para a elaboracao de subconjuntos terminologicos da CIPE(r). Os termos foram coletados em 49 artigos cientificos, extraidos com uso de ferramenta computacional, selecionados de acordo com a pertinencia ao tema, normalizados e mapeados com a CIPE(r). Resultados:: foram extraidos 20.668 termos. A normalizacao resultou em 425 termos pertinentes, sendo: 151 termos constantes e 274 nao constantes na CIPE(r); dos quais 154 similares, 19 mais abrangentes, 50 mais restritos e 51 sem concordancia. Conclusao:: o uso de linguagem padronizada pode minimizar ambiguidades e redundancias identificadas no mapeamento. A existencia de termos sem concordancia com a CIPE(r) reforca a necessidade de atualizacao constante dessa classificacao. PMID- 28562792 TI - Nursing appointment and cardiometabolic control of diabetics: a randomized clinical trial. AB - Objective: to verify the effect of nursing appointment on cardiometabolic profile of people with Diabetes Mellitus type 2. Method: randomized controlled trial, developed with 134 individuals chosen for two groups: intervention and control. The intervention consisted of three nursing appointments alternated bimonthly, with two phone calls, over five months. The control group received usual care offered by the Health Unit. Data were collected through semi-structured interviews before and after the intervention, in addition to conducting laboratory tests. Results: after the intervention, a significant difference was shown in the amount of glycated hemoglobin (p = 0.006) and in the systolic blood pressure (p = 0.031), which were higher in the control group. Conclusion: besides being low-cost and easy to develop on the monitoring routine of people with diabetes, the intervention performed influenced positively the biochemical profile. Objetivo: verificar o efeito da consulta de enfermagem sobre o perfil cardiometabolico de pessoas com Diabetes Mellitus tipo 2. Metodo: ensaio clinico controlado e randomizado, desenvolvido com 134 individuos sorteados para dois grupos: intervencao e controle. A intervencao consistiu em tres consultas de enfermagem bimensais alternadas, com duas ligacoes telefonicas, ao longo de cinco meses. O grupo-controle recebeu os cuidados habituais oferecidos pela Unidade de Saude. Os dados foram coletados mediante entrevistas semiestruturadas antes e apos a intervencao, alem da realizacao de exames laboratoriais. Resultados: apos a intervencao, foi evidenciada diferenca significativa no valor da hemoglobina glicada (p=0,006) e da pressao arterial sistolica (p=0,031), que se mostraram mais elevadas no grupo-controle. Conclusao: a intervencao realizada, alem de ser de baixo custo e de facil desenvolvimento na rotina de acompanhamento da pessoa com diabetes, influenciou positivamente a melhora do perfil bioquimico. PMID- 28562794 TI - Cost of nursing most frequent procedures performed on severely burned patients. AB - Objective: to identify the mean direct cost (MDC) of the most frequent procedures performed by nursing professionals on severely burned patients in an Intensive Care Unit. Method: exploratory-descriptive quantitative single-case study. The MDC was calculated by multiplying time (timed) spent by nursing professionals in the performance of the procedures by the unit cost of direct labor, and adding the costs of material and medicine/solutions. Results: a MDC of US$ 0.65 (SD=0.36) was obtained for "vital signs monitoring"; US$ 10.00 (SD=24.23) for "intravenous drug administration"; US$ 5.90 (SD=2.75) for "measurement of diuresis"; US$ 0.93 (SD=0.42) for "capillary blood glucose monitoring"; and US$ 99.75 (SD=129.55) for "bandaging". Conclusion: the knowledge developed can support managerial decision-making, contribute to the efficiency distribution of the resources involved and, when possible, provide cost-containment or cost minimization strategies without impairing the quality of nursing care. PMID- 28562793 TI - Nursing Activities Score and Acute Kidney Injury. AB - Objective:: to evaluate the nursing workload in intensive care patients with acute kidney injury (AKI). Method:: A quantitative study, conducted in an intensive care unit, from April to August of 2015. The Nursing Activities Score (NAS) and Kidney Disease Improving Global Outcomes (KDIGO) were used to measure nursing workload and to classify the stage of AKI, respectively. Results:: A total of 190 patients were included. Patients who developed AKI (44.2%) had higher NAS when compared to those without AKI (43.7% vs 40.7%), p <0.001. Patients with stage 1, 2 and 3 AKI showed higher NAS than those without AKI. A relationship was identified between stage 2 and 3 with those without AKI (p = 0.002 and p <0.001). Conclusion:: The NAS was associated with the presence of AKI, the score increased with the progression of the stages, and it was associated with AKI, stage 2 and 3. Objetivo:: avaliar a carga de trabalho de enfermagem em pacientes de terapia intensiva com lesao renal aguda (LRA). Metodo:: estudo quantitativo, em Unidade de Terapia Intensiva, no periodo de abril a agosto de 2015. O Nursing Activities Score (NAS) e o Kidney Disease Improving Global Outcomes (KDIGO) foram utilizados para medir a carga de trabalho de enfermagem e classificar o estagio da LRA, respectivamente. Resultados:: foram incluidos 190 pacientes. Os pacientes que desenvolveram LRA (44,2%) possuiam NAS superiores quando comparados aos sem LRA (43,7% vs 40,7%), p<0,001. Os pacientes com LRA nos estagios 1, 2 e 3 de LRA demonstraram NAS superiores aos sem LRA, houve relacao entre os estagios 2 e 3 com os sem LRA, p=0,002 e p<0,001. Conclusao:: o NAS apresentou associacao com a existencia de LRA, visto que seu valor aumenta com a progressao dos estagios, tendo associacao com os estagios 2 e 3 de LRA. PMID- 28562795 TI - Low completion rate of hepatitis B vaccination in female sex workers. AB - Objective:: to assess predictive factors for noncompletion of the hepatitis B vaccination schedule in female sex workers in the city of Teresina, Northeastern Brazil. Method:: 402 women were interviewed and, for those who did not wish to visit specialized sites, or did not know their hepatitis B vaccination status, the vaccine was offered at their workplaces. Bi- and multivariate analyses were performed to identify potential predictors for noncompletion of the vaccination schedule. Results:: of the 284 women eligible for vaccination, 258 (90.8%) received the second dose, 157/258 (60.8%) and 68/258 (26.3%) received the second and third doses, respectively. Working at clubs and consuming illicit drugs were predictors for noncompletion of the vaccination schedule. Conclusion:: the high acceptability of the vaccine's first dose, associated with low completion rates of the vaccination schedule in sex workers, shows the need for more persuasive strategies that go beyond offering the vaccine at their workplaces. Objetivo:: avaliar fatores preditores de nao completude do esquema vacinal contra hepatite B em mulheres que se prostituem em Teresina, Nordeste do Brasil. Metodo:: Um total de 402 mulheres foi entrevistado e, para as que se negaram a irem a lugares especializados, ou desconheciam sua situacao vacinal contra hepatite B, a vacina foi oferecida no local do trabalho. Analises bi e multivariadas foram realizadas para identificar potenciais preditores de nao completude do esquema vacinal. Resultados:: Das 284 mulheres elegiveis para vacinacao, 258 (90,8%) receberam a primeira dose, 157/258 (60,8%) e 68/258 (26,3%) receberam a segunda e terceira doses. Trabalhar em boates e consumir drogas ilicitas foram preditores de nao completude do esquema vacinal (p<0,05). Conclusao:: A elevada aceitabilidade da primeira dose da vacina, associada a baixa completude do esquema vacinal em profissionais do sexo, evidencia a necessidade de estrategia mais persuasiva que va alem da oferta da vacina no local de trabalho. PMID- 28562796 TI - Care path of person with stroke: from onset to rehabilitation. AB - Objective:: to describe the care path of the person with stroke goes through and to identify the important events in this path. Method:: qualitative descriptive exploratory research, using the semi-structured interview technique based on Meleis's Middle-Range Theory. The sample was composed of 13 people who became dependent after a stroke and were admitted to two hospital units in the region of Vale do Ave, Portugal. Data were collected between January and October 2013. Content analysis was used to analyze the data. Results:: The data revealed that the person's care path goes from recognition of the symptoms to preparation for hospital discharge. Adapting to the new situation of dependence brings the need for new competencies. Final considerations:: The research aims to contribute to the improvement of nursing care regarding care for people with stroke including onset, recovery and rehabilitation, and home care. Objetivo:: Descrever o percurso da pessoa com Acidente Vascular Encefalico e identificar os acontecimentos significativos neste percurso. Metodo:: Abordagem qualitativa e natureza exploratoria- descritiva, valeu-se da tecnica de entrevista semiestruturada baseada na Teoria de Medio Alcance de Meleis. Participaram 13 pessoas que se tornaram dependentes devido a Acidente Vascular Encefalico e recorreram a duas Unidades da regiao do Vale do Ave, Portugal. A colheita de dados deu-se durante Janeiro a Outubro de 2013. Para analise dos dados foi utilizada a analise de conteudo. Resultados:: Os dados revelaram que o trajeto da pessoa vai desde o reconhecimento dos sintomas ate a preparacao da alta hospitalar. A dependencia traz a necessidade de adquirir competencias para se adaptar a nova situacao. Consideracoes finais:: Espera-se contribuir para a melhoria dos cuidados de enfermagem no atendimento das pessoas acometidas com Acidente Vascular Encefalico, desde o acometimento, recuperacao e reabilitacao, ate aos cuidados domiciliares. PMID- 28562797 TI - Integrality of care: challenges for the nurse practice. AB - Objective: to understand the role of the nurse in the collegiate management model of a teaching hospital, in the integrality of care perspective. Method: a single case study with multiple units of analysis, with the theoretical proposition "integrality of care is a result of the care offered to the user by multiple professionals, including the nurse". Data were obtained in a functional unit of a teaching hospital through interviews with 13 nurses in a non-participant observation and document analysis. Results: from the analytical categories emerged subcategories that allowed understanding that the nurse promotes integrality of care through nursing management, team work and integration of services. Final considerations: the theoretical proposition was confirmed and it was verified that the nursing management focus on attending to health care needs and is a strategy to provide integrality of care. PMID- 28562798 TI - Violence against children and adolescents: the perspective of Primary Health Care. AB - Objective: To analyze the care provided by Basic Health Units (BHU) to families involved in domestic intrafamily violence against children and adolescents. Method: Qualitative research, based on the Paradigm of Complexity. Data collection was performed with 41 professionals through focus groups and semi structured interviews. Results: The following categories emerged from data analysis: 'Everything comes here', which reflects the legitimate place of BHUs for the population and the actions taken to build care for families; and 'We only do what is really necessary', which brings the look to violence still based on the positivist and biomedical paradigm. Final considerations: The model of understanding and construction of work processes in the BHU is structured in the aforementioned paradigm. Nurses have the possibility to become agents of change, both in professionals' training and in the care thought and provided to communities. PMID- 28562799 TI - Promoting oral care in the preschool child: effects of a playful learning intervention. AB - Objective: To compare the number of appropriate behaviors for tooth brushing before and after a playful learning intervention with preschool children. Method: A quasi-experimental, quantitative, before and after study design was conducted in an early childhood educational institution, with children between three and five years of age. The intervention consisted of three meetings with educational activities about tooth brushing, whose outcome was evaluated by means of observation of ten behaviors suitable for tooth brushing. Results: Forty-four children participated in the study. The mean of adequate behaviors was 4.4 before the intervention, and 8.5 after the intervention. A significant increase in the adoption of appropriate behaviors for tooth brushing (p <0.01) was identified. Conclusion: Nurses can enhance oral health promotion actions with preschoolers in preschool institution using playful learning interventions. PMID- 28562800 TI - Guide of attributes of the nurse's political competence: a methodological study. AB - Objective: To build and validate a guide of attributes of the nurse's political competence. Method: Methodological research. This study comprised the construction of the instrument through literature review; experts validation of pre-established attributes for composing the guide; and clinical validation in the nurses work environment/reality. The data collection took place in the months from August to October 2014, and the analysis was based on the content analysis of Bardin and use of Epi info 3.5. All ethical precepts have been complied with. Results: From 29 attributes found in the literature, 25 have been validated by experts. Clinical/practical validation involved the participation of 43 nurses, who observed that the attributes are not articulated with the professional practices developed by them. Conclusion: The attributes of the nurse's political competence were identified with support of literature. It is concluded that the professionals still have limited and fragmented perception of political competence, expressing difficulty/limitation. PMID- 28562801 TI - Cancellation of elective surgeries in a Brazilian public hospital: reasons and estimated reduction. AB - Objective: To characterize cancellations of elective surgeries according to clinical and non-clinical reasons, as well as to verify seasonal influence and determine the estimated reduction of the index. Method: Quantitative, descriptive and retrospective study with secondary data extracted from the Public Hospital of the State of Sao Paulo database. Results: Out of the 8,443 (100%) elective surgeries scheduled, 7,870 (93.21%) were performed and 573 (6.79%) were canceled. Out of these 573 (100%) people, 48.33% were canceled for clinical reasons and 46.40% were for non-clinical reasons. Among the non-clinical reasons for surgery cancellations, those related to medical reasons stood out: at the request of the surgeon/change of approach (17.93%), followed by non-hospitalized patient (8.96%). There was no indication of seasonality regarding the reasons for cancellation in the assessed period. Conclusion: Although the rate of elective surgeries cancellations is lower than that of other hospitals with similar characteristics, it is still possible to reduce it from 6.79% to 1.36%, considering that 80% of the reasons for cancellation are avoidable. PMID- 28562802 TI - Contributions of Public Health to nursing practice. AB - Objective:: Analyze the perceptions of undergraduate nursing students about the contributions of public health to nursing practice in the Unified Health System. Method:: Qualitative Descriptive Study. Data collection was carried out through semi-directed interviews with 15 students. The language material was analyzed according to content and thematic analysis. Results:: Thematic categories were established, namely: "Perceptions about Public Health" and "Contribution of Public Health to nursing practice in the Unified Health System". Final considerations:: Perceptions about Public Health are diversified, but converge to the recognition of this field as the basis for training nurses qualified to work in the SUS with technical competence, autonomy and focusing on the integrality in health care. Objetivo:: Analisar as percepcoes de alunos do curso de bacharelado em Enfermagem acerca das contribuicoes da Saude Coletiva para o trabalho de enfermeiros no Sistema Unico de Saude. Metodo:: Estudo descritivo, com abordagem qualitativa. A coleta de dados foi realizada mediante a tecnica da entrevista semidirigida com 15 alunos. O material de linguagem foi analisado segundo a tecnica de analise de conteudo tematico-categorial. Resultados:: Foram produzidas as categorias tematicas "Percepcoes acerca da Saude Coletiva" e "Contribuicao da Saude Coletiva ao trabalho do enfermeiro no Sistema Unico de Saude". Consideracoes finais:: As percepcoes sobre a Saude Coletiva sao plurais, mas convergem para o reconhecimento desse campo como base de sustentacao da formacao de enfermeiros habilitados a trabalhar no SUS com competencia tecnica, autonomia e com foco na integralidade do cuidado em saude. PMID- 28562803 TI - The experience of rural families in the face of cancer. AB - Objective: To understand the meanings of cancer within the experience of rural families and how such meanings influence family dynamics. Method: Qualitative study guided by Symbolic Interactionism as a theoretical framework and Grounded Theory as a methodological framework. Six rural families (18 participants) undergoing the experience of having a relative with cancer participated in the interview. Results: Constant comparative analysis of data allowed the elaboration of an explanatory substantive theory, defined by the main category Caregiving to support the family world, which represents the family's symbolic actions and strategies to reconcile care for the patient and care for family life. Final considerations: Throughout the experience, rural families seek to preserve the interconnected symbolic elements that provide support for the family world: family unit, land, work and care. PMID- 28562804 TI - Validation of the adherence questionnaire for Brazilian chronic kidney disease patients under hemodialysis. AB - Objective: To validate the evaluation questionnaire on adherence of chronic kidney disease (CKD) patients under hemodialysis. Method: We verified the following psychometric properties of the instrument: reliability (stability and internal consistency) and validity (face, content, and construct). Results: The intraclass correlation coefficient reached a value of 0.98 for the adherence questions and 0.91 for the perception questions. Regarding the kappa of the 14 questions examined, 12 had a value > 0.8, whereas the Cronbach's alpha had a value of 0.57. Experts ensured the face and content validity of the instrument, giving it an overall content validity index of 0.96. Construct validity, analyzed by Mann-Whitney test, was achieved as all domains showed a significant association with p<0.01. Conclusion: We verified, by the presented results, that the instrument has been validated for use in Brazil. PMID- 28562805 TI - High prevalence of enteroparasites in children from Ribeirao Preto, Sao Paulo, Brazil. AB - Objective:: To determine the prevalence of intestinal parasites and possible associated factors. Method:: Cross-sectional epidemiological study of 962 children (3-12-years) from an area within the scope of a basic health unit in Ribeirao Preto, Sao Paulo, Brazil. Data were collected by home interviews and three-sample stool analysis and evaluated with the chi-square and Fisher's exact tests (p<0.05). Results:: The prevalence of intestinal parasites was significantly high (57.5%). Giardia lamblia was the most prevalent (50.8%), followed by Ascaris lumbricoides (17.8%), Entamoeba histolytica, Hymenolepis nana, Entamoeba coli and Enterobius vermiculares (5.6-7.3%) and other parasites of lower prevalence, such as Schistosoma japonicum (1%) and Schistosoma mansoni (0.5%). No statistically significant associations were detected between prevalence and the risk factors analyzed. Conclusion:: Since the area presents good conditions of environmental sanitation, health education programs should be implemented that emphasize hygiene procedures for the hands and for food and water to be consumed by the population. PMID- 28562806 TI - Virtual learning object and environment: a concept analysis. AB - Objective: To analyze the concept of virtual learning object and environment according to Rodgers' evolutionary perspective. Method: Descriptive study with a mixed approach, based on the stages proposed by Rodgers in his concept analysis method. Data collection occurred in August 2015 with the search of dissertations and theses in the Bank of Theses of the Coordination for the Improvement of Higher Education Personnel. Quantitative data were analyzed based on simple descriptive statistics and the concepts through lexicographic analysis with support of the IRAMUTEQ software. Results: The sample was made up of 161 studies. The concept of "virtual learning environment" was presented in 99 (61.5%) studies, whereas the concept of "virtual learning object" was presented in only 15 (9.3%) studies. Conclusion: A virtual learning environment includes several and different types of virtual learning objects in a common pedagogical context. PMID- 28562807 TI - Power relations in the family health team: focus on nursing. AB - Objective: to analyze the power relations that permeate the work of the family health team, and to discuss perspectives of emancipation of these subjects, focusing on nursing and community health agents. Method: a qualitative study with a family health team from a municipality in the countryside of the state of Sao Paulo. Data were collected through systematic observation and interview with workers. A thematic content analysis was performed. Results: three categories were identified: the work of the family health team and power relations; power relations between the nurse and the healthcare team; and the relations among the nursing team and between community agents and the nurse. The team produces relations of power moved by hierarchical knowledge that move in the search for the reordering of powers. Final considerations: it is necessary to review the contradictions present in the performance scenario of the family health teams, with a view toward making power relations more flexible. PMID- 28562808 TI - Validation of the self-assessment of communication skills and professionalism for nurses. AB - Objectives:: to translate, adapt cross-culturally and validate into Brazilian Portuguese the following instrument: "Self-assessment of communication skills and professionalism in residents" for the nursing professional, and to determine if personal characteristics and performance of the nurse interfere in the self assessment about professionalism and interpersonal communication. Method:: quantitative study. Results:: the sample consisted of 110 nurses with mean age of 32 years old (+/- 7.3), most of them were women (n = 80; 72.7%). The internal consistency of the scale "Autoavaliacao sobre profissionalismo e comunicacao interpessoal entre enfermeiro e paciente" presented moderate and satisfactory reliability (alpha=0,712). Factorial analysis identified four factors: Interpersonal Skills, Exchange of Information, Honesty in the Relationship and Professionalism. Conclusion:: the instrument is valid and reliable in Portuguese and for Brazilian culture. Interpersonal Skills changed with gender and marital status. Ability to exchange information was influenced by gender and working sector. Self-assessment of professionalism changed with marital status. Objetivos:: traduzir, adaptar culturalmente e validar para o portugues o instrumento Self-assessment of communication skills and professionalism in residents para o profissional enfermeiro e avaliar se caracteristicas pessoais e de atuacao do enfermeiro interferem na autoavaliacao sobre o profissionalismo e comunicacao interpessoal. Metodo:: estudo metodologico quantitativo. Resultados:: A amostra foi de 110 enfermeiros com media de idade de 32 anos (+/-7,3) e a maioria mulheres (n=80; 72,7%). A consistencia interna da escala "Autoavaliacao sobre profissionalismo e comunicacao interpessoal entre enfermeiro e paciente" apresentou confiabilidade moderada e satisfatoria (alpha=0,712). A analise fatorial identificou quatro fatores: Habilidade Interpessoal, Troca de Informacao, Sinceridade na Relacao e Profissionalismo. Conclusao:: o instrumento e valido e confiavel na lingua portuguesa e para a cultura brasileira. A habilidade interpessoal modificou-se com sexo e estado civil. A troca de informacoes foi influenciada pelo sexo e setor de atuacao. A autoavaliacao do profissionalismo modificou-se com estado civil. PMID- 28562809 TI - Use of technologies in intravenous therapy: contributions to a safer practice. AB - Objectives: To identify what are the difficulties of the nursing staff in the management of technologies during intravenous therapy (IVT) and discuss the difficulties identified under the perspective of patient's safety. Method: Descriptive study of qualitative approach with data collected by semi-structured interview and analyzed by the Alceste software. Results: The greatest difficulty of cognitive and technical emphasis was the lack of training; and regarding administrative emphasis, the greatest difficulty was the lack of material and human resources. Infusion pumps and their proper use were highlighted as the technological resource that most contributed to patient safety. Final considerations: The lack of training is presented as the greatest difficulty of nursing professionals and permeates safety issues of both patient and professional when using the hard technologies in IVT. Training is essential to the development of techniques, considered nursing tools. PMID- 28562810 TI - Teaching-learning evaluation on the ICNP(r) using virtual learning environment. AB - Objective: Evaluating the teaching-learning process of undergraduates and nursing professionals on the International Classification for Nursing Practice (ICNP(r)) through a course on Moodle Platform. Method: Mixed research conducted with 51 nursing students and nurses. Many technological and educational resources were used. To collect data, two semi-structured questionnaires were applied and focus groups were carried out. Statistical and thematic analysis of the data was performed. Results: There was a correlation between the Wiki variable, the Animation Video (p = 0.002) and the Arch Method (p = 0.04), as well as a correlation between the Forum, the Virtual Book (P < 0.001) and time (p = 0.009). Three topics emerged: innovation in the application of technological resources, distance education in the professional education and permanent education and the teaching-learning process on the ICNP(r) in a collaborative way. Conclusion: Teaching-learning strategies and technological resources used were pointed out as innovative and helped students have a better performance. PMID- 28562811 TI - Use of the Diffusion of Innovation Model in venous ulcers by specialized professionals. AB - Objective:: To analyze the influence of the evidence and of the opinion of peers on the decisions of specialists regarding the agreement with recommendations for prevention and treatment of venous ulcer. Methods:: This is a quasi-experimental study with two interventions: provision of studies with the evidence of the recommendations and provision of the opinion of peers, with sample of 73 specialized doctors and nurses. Delphi technique was used in the search for agreement, with three rounds. Results:: The participants evaluated 82 recommendations organized into eight domains: evaluation of patient and wound; documentation of clinical findings; care with the wound and surrounding skin; indication of dressing; use of antibiotics; improvement of venous return and prevention of recurrence; referrals of patients; and professional training. The interventions resulted in statistically significant changes in four domains. Conclusion:: The interventions were able to change the opinion of participants, leading them to agreement regarding the recommendations, regardless of the level of evidence. Objetivo:: Analisar a influencia das evidencias e da opiniao dos pares sobre as decisoes dos especialistas quanto a concordancia com recomendacoes para prevencao e tratamento de ulcera venosa. Metodo:: Estudo quase-experimental com duas intervencoes: fornecimento de estudos com as evidencias das recomendacoes e opiniao dos pares, com amostra de 73 especialistas medicos e enfermeiros. Utilizou-se a tecnica Delphi na busca de concordancia, com 3 rodadas. Resultados:: Os participantes avaliaram 82 recomendacoes organizadas em 8 dominios: avaliacao do paciente e de sua lesao; documentacao dos achados clinicos; cuidado com a lesao e pele ao redor; indicacao da cobertura; uso de antibiotico; melhoria do retorno venoso e prevencao de recidiva; encaminhamentos dos pacientes; e capacitacao profissional. As intervencoes resultaram em mudancas estatisticamente signifi cativas em 4 dominios. Conclusao:: As intervencoes foram capazes de modificar a posicao dos participantes, levando-os para a posicao de concordancia a respeito das recomendacoes, independentemente do nivel de evidencia. PMID- 28562812 TI - Insulin therapy waste produced in the households of people with diabetes monitored in Primary Care. AB - Objective: To analyze the insulin therapy waste disposal produced in the households of people with diabetes mellitus (DM). Method: Cross-sectional study with 105 Primary Care patients. Socio-demographic and clinical variables and insulin therapy practice were analyzed through the absolute and relative frequencies, Fisher's exact test and prevalence ratio (PR). Results: The association between types of insulin (60.0%), administered with a disposable syringe attached to a needle (80.9%), and a high percentage of reuse and disposal in normal household waste (57.1%) stood out. The professionals who most frequently provided guidance to people with diabetes were the nurses. Patients who had received instructions about disposal were 21 times more likely to dispose of waste properly than those who had not (PR 21.5; P < 0.0001). Age, gender, skin color, education, marital status, occupational status and type of DM did not interfere in the disposal (P > 0.05). Conclusion: People with diabetes served in Primary Health Care require guidance and material resources to carry out the appropriate disposal of insulin therapy waste. PMID- 28562813 TI - Opioid analgesic administration in patients with suspected drug use. AB - Objective:: To identify the prevalence of patients suspected of drug use according to the nursing professionals' judgement, and compare the behavior of these professionals in opioid administration when there is or there is no suspicion that patient is a drug user. Method:: A cross-sectional study with 507 patients and 199 nursing professionals responsible for administering drugs to these patients. The Chi-Square test, Fisher's Exact and a significance level of 5% were used for the analyzes. Results:: The prevalence of suspected patients was 6.7%. The prevalence ratio of administration of opioid analgesics 'if necessary' is twice higher among patients suspected of drug use compared to patients not suspected of drug use (p = 0.037). Conclusion:: The prevalence of patients suspected of drug use was similar to that of studies performed in emergency departments. Patients suspected of drug use receive more opioids than patients not suspected of drug use. Objetivo:: Identificar a prevalencia de pacientes com suspeita de uso de drogas conforme opiniao de profissionais de enfermagem e comparar a conduta desses profissionais na administracao de opioides quando ha ou nao suspeita de que o paciente seja usuario de drogas. Metodo:: Estudo transversal com 507 pacientes e 199 profissionais de enfermagem responsaveis pela administracao de medicamentos a esses pacientes. Para as analises foram utilizados os testes de Qui-Quadrado, Exato de Fisher e um nivel de significancia de 5%. Resultados:: A prevalencia de pacientes suspeitos foi 6,7%. A razao de prevalencia de administracao de analgesicos opioides "se necessario" e duas vezes maior entre os pacientes suspeitos em relacao aos nao suspeitos (p=0,037). Conclusao:: A prevalencia de suspeitos foi semelhante a de estudos realizados em departamentos de emergencia. Os suspeitos de serem usuarios de drogas recebem mais opioides do que os nao suspeitos. PMID- 28562814 TI - Comprehension of the education handout and health literacy of pacemaker users. AB - Objective: To verify the comprehension of the education handout and the level of Functional Health Literacy of individuals with cardiac pacemaker (PM) and whether there is correlation between the comprehension and Functional Health Literacy (FHL). Method: Cross-sectional study with 63 individuals with PM who answered to comprehension tests of the handout, literacy assessment (SAHLPA-50) and cognition (MMSE). Measurements of dispersion, Pearson correlation and multiple linear regression were calculated. Results: Most women, study time <= 9 years, 66.21 (average age) presented no cognitive changes. An adequate literacy level was evidenced in 50.8% individuals with PM and satisfactory comprehension of the handout. No correlation was identified between FHL, handout comprehension, age, years of study and cognition. Conclusion: The handout comprehension assessed by individuals with appropriate FHL indicated that it can be a printed material suitable for use, aiming to improve care process and knowledge of individuals with PM. PMID- 28562815 TI - Health Conditions and Memory Performance: a study with older adult women. AB - Objective: to verify the correlation between health condition and memory performance of older adult women in the community. Method: Analytical cross sectional study developed with 28 older adult women living in Cuiaba-MT. They answered the Mini-Mental State Examination (MMSE), and a shortened Geriatric Depression Scale (GDS-15) to screen for dementia and depression symptoms. Memory skills were assessed through Rey Auditory Verbal Learning Test (RAVLT). Results: The mean age was 66.36 years and 75% of the participants had educational level higher than 7 years. The MMSE mean score was 28.45. The correlations found were: educational level and immediate memory (r = 0.49; p = 0.008); delayed recall and immediate memory (r = 0.71; p < 0.001); memory recognition and immediate memory (r = 0.43; p = 0.021) and recognition memory with delayed recall (r = 0.47; p = 0.012). Conclusion: High scores in the MMSE and a satisfactory health perception among the participants were evident. There was no correlation between memory performance and health perception. PMID- 28562816 TI - Influence of hormonal contraceptives and the occurrence of stroke: integrative review. AB - Objective:: To identify scientific evidence regarding the influence of hormonal contraceptive use and the occurrence of stroke. Method:: Integrative review of the literature, through database search using the descriptors "contraceptive agents", "contraceptive devices", "contraceptives, Oral" and "Stroke". Original studies in Portuguese, Spanish and English, published in full and available online were included. Studies that did not answer our guiding questions and duplicated studies were excluded. Results:: Women using combined oral contraceptives have higher risk of stroke, even with a lower hormonal dosage and different types of progestogen, regardless of the duration of use. The use of contraceptives associated with smoking, hypertension, migraine, hypercholesterolemia, obesity and sedentary lifestyle increases the chance of stroke. Contraceptive patch and vaginal ring are associated to increased risk. Conclusion:: Use of combined hormonal contraceptives, except for the injectable and the transdermal ones, increases the chance of occurrence of the event. Progestogen-only contraceptives were considered safe. Objetivo:: Identificar evidencias cientificas acerca da influencia do uso de anticoncepcionais hormonais na ocorrencia do acidente vascular cerebral (AVC). Metodo:: Revisao integrativa da literatura, com pesquisa em bases de dados, utilizando os descritores "contraceptive agents", "contraceptive devices", "contraceptives, Oral" e "stroke". Foram incluidos artigos originais nos idiomas portugues, espanhol e ingles, publicados na integra e disponiveis eletronicamente. Foram excluidos artigos que nao respondiam as questoes norteadoras e repetidos. Resultados:: Usuarias de anticoncepcional oral combinado apresentam risco maior de AVC, mesmo com dosagem hormonal menor e diferentes tipos de progestageno, independente do tempo de uso. A presenca associada de tabagismo, hipertensao arterial, enxaqueca, hipercolesterolemia, obesidade e sedentarismo aumenta a chance desse desfecho. Adesivo anticoncepcional e anel vaginal sao relacionados ao aumento desse risco. Conclusao:: A exposicao aos anticoncepcionais hormonais combinados aumenta a chance de ocorrencia do evento, exceto o injetavel e o transdermico. Os exclusivos de progestageno foram considerados seguros. PMID- 28562817 TI - Continuing education in health from the perspective of Augustine of Hippo. AB - Objective:: To reflect about continuing education from the perspective of Augustine of Hippo and his theories based on the construction of knowledge and the learning process. Method:: This is a theoretical reflection study whose aim is to propose dimensions of analysis, emphasizing the history and challenges of continuing education. Such dimensions analyze the production of knowledge in Augustinian pedagogy, its historical aspects and its close relationship with lifelong education in health professions. Results:: The results show the difficulty of continuing education to reach adequate importance in health services, and that of academia in appropriating the thoughts of renowned philosophers such as Augustine. This is a result of ignorance about the convergence of these principles and their relevance. Final considerations:: Continuing education and Augustinian pedagogy walk hand in hand in terms of care, meeting the needs that originate from practice and that are reflected in it, challenging isolated knowledge and putting different areas of knowledge to work together. Objetivo:: Refletir sobre a educacao permanente na perspectiva de Agostinho de Hipona e suas teorias pautadas na construcao do conhecimento e no processo de aprendizagem. Metodo:: Trata-se de uma reflexao teorica cujo intuito e propor dimensoes de analise, enfatizando a historia e os desafios da educacao permanente. Tais dimensoes analisam a producao do conhecimento na pedagogia agostiniana, seus aspectos historicos e sua relacao proxima com a educacao permanente em saude. Resultados:: Revela a dificuldade da educacao permanente em ter sua dimensao alcancada noservico de saude, tal qual a da academia de apropriar-se do pensamento de filosofos renomados como Agostinho, fruto do desconhecimento da convergencia desses pressupostos e de sua relevancia. Consideracoes Finais:: Considera-se que a educacao permanente e a pedagogia agostiniana caminham juntas no cuidar, atendendo as necessidades advindas da pratica e nela refletida, confrontando os saberes isolados e com eles operando em conjunto. PMID- 28562818 TI - Clinical reasoning in nursing: teaching strategies and assessment tools. AB - Objective:: To present the concept and development of teaching strategies and the assessment tools regarding clinical reasoning for accurate practice. Method:: This is a theoretical reflection based on scientific studies. Results:: Comprehension of the essential concepts of the thought process and its articulation with the different teaching strategies and the assessment tools which has allowed presenting ways to improve the process of diagnostic or therapeutic clinical reasoning. Conclusion:: The use of new strategies and assessment tools should be encouraged in order to contribute to the development of skills that lead to safe and effective decision making. Objetivo:: Apresentar o conceito de raciocinio clinico, seu desenvolvimento, as estrategias para seu ensino e os instrumentos de avaliacao para uma pratica acurada. Metodo:: Trata-se de uma reflexao teorica fundamentada em estudos cientificos. Resultados:: A compreensao dos conceitos essenciais do processo de pensamento e sua articulacao com as diferentes estrategias de ensino e com os instrumentos de avaliacao permitiram exemplificar meios de aprimorar o processo de raciocinio clinico diagnostico ou terapeutico. Conclusao:: A utilizacao de novas estrategias e instrumentos de avaliacao deve ser estimulado para contribuir com o desenvolvimento das habilidades que culminam na tomada de decisao segura e eficaz. PMID- 28562820 TI - Entropy Generation Minimization Analysis of Active Magnetic Regenerators. AB - A performance assessment of active magnetocaloric regenerators using entropy generation minimization is presented. The model consists of the Brinkman Forchheimer equation to describe the fluid flow and coupled energy equations for the fluid and solid phases. Entropy generation contributions due to axial heat conduction, fluid friction and interstitial heat transfer are considered. Based on the velocity and temperature profiles, local rates of entropy generation per unit volume were integrated to give the cycle-average entropy generation in the regenerator, which is the objective function of the optimization procedure. The solid matrix is a bed of gadolinium spherical particles and the working fluid is water. Performance evaluation criteria of fixed cross-section (face) area (FA) and variable geometry (VG) are incorporated into the optimization procedure to identify the most appropriate parameters and operating conditions under fixed constraints of specified temperature span and cooling capacity. PMID- 28562821 TI - A potent larvicidal agent against Aedes aegypti mosquito from cardanol. AB - Cardanol is a constituent of Cashew Nut Shell Liquid that presents larvicidal activity against Aedes aegypti. The isolation of cardanol is somewhat troublesome, however, in this work we describe an efficient and inexpensive method to obtain it as a pure material. The compound was used as starting material to make chemical transformation leading to saturated cardanol, epoxides and, halohydrins. These derivatives were tested for toxicity against Aedes aegypti larvae. The results showed that iodohydrins are very promising compounds for making commercial products to combat the vector mosquito larvae presenting a LC50 of 0.0023 ppm after 72 h of exposure. PMID- 28562822 TI - Commemorative Volume of the Centenary of the Brazilian Academy of Sciences. PMID- 28562823 TI - Transcolonic Perirectal NOTES Access (PNA): A feasibility study with survival in swine model. AB - Transrectal access still has some unsolved issues such as spatial orientation, infection, access and site closure. This study presents a simple technique to perform transcolonic access with survival in a swine model series. A new technique for NOTES perirectal access to perform retroperitoneoscopy, peritoneoscopy, liver and lymphnode biopsies was performed in 6 pigs, using Totally NOTES technique. The specimens were extracted transanally. The flexible endoscope was inserted through a posterior transmural incision and the retrorectal space. Cultures of bacteria were documented for the retroperitoneal space and intra abdominal cavity after 14 days. Rectal site was closed using non absorbable sutures. There was no bowel cleansing, nor preoperative fasting. The procedures were performed in 6 pigs through transcolonic natural orifice access using available endoscopic flexible instruments. All animals survived 14 days without complications, and cultures were negative. Histopathologic examination of the rectal closure site showed adequate healing of suture line and no micro abscesses. The results of feasibility and safety of experimental Transcolonic NOTES potentially brings new frontiers and future wider applications for minimally invasive surgery. The treatment of colorectal, abdominal and retroperitoneal diseases through a flexible Perirectal NOTES Access (PNA) is a promising new approach. PMID- 28562824 TI - Insect Galls of the Parque Nacional do Itatiaia (Southeast Region, Brazil). AB - The Parque Nacional do Itatiaia (PNI) (Brazilian Southeast Region) was surveyed monthly for insect galls from February/2014 to December/ 2015. A total of 432 gall morphotypes were found. This number places the PNI as the richest Atlantic forest area in number of gall morphotypes. The galls were found on 47 plant families. Among them, Asteraceae were pointed out as the superhost. The gall richness in the lower part of the PNI is higher than that of the plateau. The insect galls were found in 154 native, 56 endemic and only one exotic plant species. Concerning the conservational status, the host plants include two vulnerable species with three morphotypes together. Several new botanical records were reported. Leaves were the most galled plant organ, followed by stems. Globoid, green, glabrous and one-chambered galls were the most frequent. Cecidomyiidae were the most common gallers. Parasitoids, successors and inquilines composed the associated fauna. PMID- 28562825 TI - Shallow aquifer response to climate change scenarios in a small catchment in the Guarani Aquifer outcrop zone. AB - Water availability restrictions are already a reality in several countries. This issue is likely to worsen due to climate change, predicted for the upcoming decades. This study aims to estimate the impacts of climate change on groundwater system in the Guarani Aquifer outcrop zone. Global Climate Models (GCM) outputs were used as inputs to a water balance model, which produced recharge estimates for the groundwater model. Recharge was estimated across different land use types considering a control period from 2004 to 2014, and a future period from 2081 to 2099. Major changes in monthly rainfall means are expected to take place in dry seasons. Most of the analysed scenarios predict increase of more than 2 oC in monthly mean temperatures. Comparing the control and future runs, our results showed a mean recharge change among scenarios that ranged from ~-80 to ~+60%, depending on the land use type. As a result of such decrease in recharge rates, the response given by the groundwater model indicates a lowering of the water table under most scenarios. PMID- 28562826 TI - Looking for attitudes related to amphibian species decline: how are peer-reviewed publications of education activities compared to ecological research? AB - Biodiversity decline has been the focus of discussions in the last decade, especially on the amphibian species decline. After a scientometric analysis using international databases, we found that the number of peer-reviewed articles considering education practices related to the theme increased along with the number of ecological researches. However, the increase in ecological researches is much higher than the increase in publications of education practices. Studies suggest that conservation attitudes are important and that education practices are an important tool for improving human perceptions on this subject. In this sense, increase the publication of projects and programs results related to local education practices in international journals could help the dissemination of efficient methods for conservation, as well as facilitating access to information internationally, since species decline, especially for amphibians, is a global concern. Then, we suggest that educational practices, at least when related to conservation, should follow a more standardized protocol, and be published in international journals, as the efficiency of such practices should be evaluated and methods once published could help other nations to improve their ecological literacy. PMID- 28562827 TI - Partitioning of the diffuse attenuation coefficient for photosynthetically available irradiance in a deep dendritic tropical lake. AB - We studied the effects of particulate and dissolved optically active components on the attenuation of photosynthetic active radiation (PAR) in a tropical lake. The temporal and spatial distribution of tripton, Chl-a and aCDOM(440) and their relative contribution to the diffuse PAR attenuation coefficient (Kd) was investigated at 21 sites (dry and wet seasons and two intermediate periods) and at monthly interval at 1 pelagic site. Higher values of Kd were observed during the mixing period, characterized by a higher concentration of tripton and Chl-a compared to the stratified rainy season. In the spatial sampling PAR attenuation was dominated by tripton absorption/scattering (average relative contribution of 79%), followed by Chl-a (average 11.6%). In the monthly sampling tripton and Chl a accounted for most of the Kd with relative contributions of 47.8% and 35.6%, respectively. Multiple linear regression analysis showed that Chl-a and tripton in combination explained 97% of the monthly variation in Kd (p<0.001), but Chl-a had more influence (higher regression coefficient). Thus, although most of light attenuation was due to tripton, seasonal variations in phytoplankton abundance were responsible for most of the temporal fluctuations in Kd. PMID- 28562828 TI - Inhibitory effects on the production of inflammatory mediators and reactive oxygen species by Mori folium in lipopolysaccharide-stimulated macrophages and zebrafish. AB - Mori folium, the leaf of Morus alba L. (Moraceae), has been traditionally used for various medicinal purposes from ancient times to the present. In this study, we examined the effects of water extract of Mori folium (WEMF) on the production of inflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), and reactive oxygen species (ROS) in lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages. Our data indicated that WEMF significantly suppressed the secretion of NO and PGE2 in RAW 264.7 macrophages without any significant cytotoxicity. The protective effects were accompanied by a marked reduction in their regulatory gene expression at the transcription level. WEMF attenuated LPS induced intracellular ROS production in RAW 264.7 macrophages. It inhibited the nuclear translocation of the nuclear factor-kappa B p65 subunit and the activation of mitogen-activated protein kinases in LPS-treated RAW 264.7 macrophages. Furthermore, WEMF reduced LPS-induced NO production and ROS accumulation in zebrafish. Although more efforts are needed to fully understand the critical role of WEMF in the inhibition of inflammation, the findings of the present study may provide insights into the approaches for Mori folium as a potential therapeutic agent for inflammatory and antioxidant disorders. PMID- 28562829 TI - Differences between NMRI and DBA/2J mice in the development of somites and susceptibility to methylnitrosourea-induced skeleton anomalies. AB - The development of DBA/2J mouse strain embryos is nearly 12 h - or 6 somite pairs - delayed as compared to the outbred NMRI mouse embryos of the same age on gestation days (GD) 8-12. To evaluate inter-strain differences in susceptibility to teratogens, dams were treated with methylnitrosourea (MNU, 5 mg/kg body weight i.p.) on defined gestation days (NMRI: GD 9, 91/2 or 10; DBA/2J: GD 10 or 101/2). Skeletal anomalies produced by MNU on both mouse strains varied with the GD of treatment. The pattern of anomalies produced by MNU on a given GD markedly differed between the two mouse strains, yet they were similar -with a few exceptions- when exposures at equivalent embryonic stages are compared. Findings from this study indicated that strain-dependent differences in the developmental stage of mouse embryos of the same gestational age occur, a possibility that has been often neglected when inter-strain differences in susceptibility to developmental toxicants are interpreted. PMID- 28562830 TI - Systemic Arterial Hypertension in Patients Exposed to Cesium-137 in Goiania-GO: Prevalence Study. AB - Background:: Systemic Arterial Hypertension (SAH) in the Brazilian population, in populations not exposed to Cesio-137, presents a prevalence of 28% nationwide. However, in the group of radioactivity victims, these values are unknown. Objective:: To analyze the prevalence of hypertension in patients exposed to Cesium-137 in Goiania, enrolled in the Sistema de Monitoramento dos Radioacidentados (SISRAD) (Radioactivtity Victims Monitoring System) of the Centro de Assistencia aos Radioacidentados (C.A.R.A) (Assistence Center for Radioactivity Victims). Methods:: This is a descriptive, observational cross sectional epidemiological study carried out in Goiania-Goias, from August 2013 to October 2014, with a group of patients enrolled in the Sistema de Monitoramento dos Radioacidentados (SISRAD) of the Centro de Assistencia a Radioacidentados (C.A.R.A.). A total of 102 radioactive patients were divided into two groups: group 1 with 40 and group 2 with 62 participants. A field survey was conducted with a closed and semi-structured questionnaire in which the following contexts were addressed: sociodemographic profile, life habits and personal background. A database was created using the Google Forms application from the Google Web technologies company. The duly collected and stored data were imported and analyzed in the statistical software SPSS, version 21. Results:: The prevalence of SAH reached a total of 25% (12 individuals) of the 48 interviewees, 50% of women (24) and 50% of men (24), of which 22.9% (11) of the radioactivity victims revealed to be smokers. Conclusion:: The prevalence of SAH in the radioactivity victims population is similar to that of the population in general. Fundamentos:: A Hipertensao Arterial Sistemica (HAS) na populacao brasileira, em populacoes nao expostas ao Cesio-137, apresenta prevalencia de 28% em ambito nacional. Porem, no grupo de radioacidentados, esses valores sao desconhecidos. Objetivo:: Analisar a prevalencia da HAS em pacientes expostos ao Cesio-137 ocorrido em Goiania, cadastrados no Sistema de Monitoramento dos Radioacidentados (SISRAD) do Centro de Assistencia aos Radioacidentados (C.A.R.A). Metodos:: Estudo epidemiologico do tipo descritivo, observacional de carater transversal realizado em Goiania-Goias, no periodo de agosto de 2013 a outubro de 2014, com grupo de pacientes cadastrados no Sistema de Monitoramento dos Radioacidentados (SISRAD) do Centro de Assistencia aos Radioacidentados (C.A.R.A). Participaram da pesquisa 48 radioacidentados de um total de 102 que foram subdivididos em dois grupos: grupo 1 com 40 e o grupo 2 com 62 participantes. Realizou-se uma pesquisa de campo com questionario fechado e semi-estruturado em que foram abordados os seguintes contextos: perfil sociodemografico, habitos de vida e antecedentes pessoais. Criou-se um banco de dados utilizando-se o aplicativo Google Forms, da empresa de tecnologias na Web Google. Os dados devidamente coletados e armazenados foram importados e analisados no software estatistico SPSS, versao 21. Resultados:: Dos 48 entrevistados a prevalencia de HAS atingiu um total 25% deles (12 individuos), sendo 50% de mulheres (24) e 50% de homens (24), dentre estes, 22,9% (11) dos radioacidentados revelaram ser tabagistas. Conclusao:: A prevalencia de HAS na populacao de radioacidentados se manifesta de forma semelhante ao da populacao em geral. PMID- 28562831 TI - Three-Dimensional Volumetric Assessment of Diastolic Function by Cardiac Magnetic Resonance Imaging: The Multi-Ethnic Study of Atherosclerosis (MESA). AB - Background:: Cardiac Magnetic Resonance is in need of a simple and robust method for diastolic function assessment that can be done with routine protocol sequences. Objective:: To develop and validate a three-dimensional (3D) model based volumetric assessment of diastolic function using cardiac magnetic resonance (CMR) imaging and compare the results obtained with the model with those obtained by echocardiography. Methods:: The study participants provided written informed consent and were included if having undergone both echocardiography and cine steady-state free precession (SSFP) CMR on the same day. Guide points at the septal and lateral mitral annulus were used to define the early longitudinal relaxation rate (E'), while a time-volume curve from the 3D model was used to assess diastolic filling parameters. We determined the correlation between 3D CMR and echocardiography and the accuracy of CMR in classifying the diastolic function grade. Results:: The study included 102 subjects. The E/A ratio by CMR was positively associated with the E/A ratio by echocardiography (r = 0.71, p < 0.0001). The early diastolic relaxation velocity by tissue Doppler and longitudinal relaxation rate for the lateral mitral annulus displacement were positively associated (p = 0.007), as were the ratio between Doppler E/e' and CMR E/E' (p = 0.01). CMR-determined normalized peak E (NE) and deceleration time (DT) were able to predict diastolic dysfunction (areas under the curve [AUCs] = 0.70 and 0.72, respectively). In addition, the lateral E/E' ratio showed good utility in identifying diastolic dysfunction (AUC = 0.80). Overall, echocardiography and CMR interobserver and intraobserver agreements were excellent (intraclass correlation coefficient range 0.72 - 0.97). Conclusion:: 3D modeling of standard cine CMR images was able to identify study subjects with reduced diastolic function and showed good reproducibility, suggesting a potential for a routine diastolic function assessment by CMR. Fundamento:: A ressonancia magnetica cardiaca necessita de um metodo simples e robusto para a avaliacao da funcao diastolica que pode ser feito com sequencias protocolares de rotina. Objetivo:: Desenvolver e validar a avaliacao volumetrica da funcao diastolica atraves de um modelo tridimensional (3D) com utilizacao de imagens de ressonancia magnetica cardiaca (RMC) e comparar os resultados obtidos com este modelo com os obtidos por ecocardiografia. Metodos:: Os participantes do estudo assinaram um termo de consentimento e foram incluidos se tivessem sido submetidos no mesmo dia tanto a ecocardiografia quanto a cine RMC com precessao livre no estado estacionario (steady-state free precession, SSFP). Pontos-guia foram utilizados no anel mitral septal e lateral para definir a velocidade de estiramento no inicio da diastole (E'), enquanto curvas de volume-tempo do modelo 3D foram utilizadas para avaliar os parametros de enchimento diastolico. Foram determinadas a correlacao entre a RMC 3D e a ecocardiografia, alem da acuracia da RMC em classificar o grau de funcao diastolica. Resultados:: Ao todo, 102 sujeitos foram incluidos no estudo. A razao E/A pela RMC esteve positivamente associada com a razao E/A obtida pela ecocardiografia (r = 0,71, p < 0,0001). Estiveram positivamente associadas a velocidade de relaxamento diastolico inicial ao Doppler tecidual e a velocidade de relaxamento longitudinal de deslocamento do anel mitral lateral (p = 0,007), bem como a razao entre E/e' por Doppler e E/E' pela RMC (p = 0,01). A velocidade normalizada de pico de enchimento (EM) determinada pela RMC e o tempo de desaceleracao (TD) foram capazes de predizer a disfuncao diastolica (areas sob a curva [AUCs] = 0,70 e 0,72, respectivamente). Alem disso, a razao E/E' lateral mostrou boa utilidade para a identificacao da disfuncao diastolica (AUC = 0,80). No geral, a ecocardiografia e a RMC apresentaram excelente concordancia interobservador e intraobservador (coeficiente de correlacao intraclasse 0,72 - 0,97). Conclusao:: Uma modelagem 3D de imagens padroes de cine RMC foi capaz de identificar os individuos do estudo com funcao diastolica reduzida e mostrou uma boa reprodutibilidade, sugerindo ter potencial na avaliacao rotineira da funcao diastolica por RMC. PMID- 28562832 TI - Thromboembolism and bleeding risk scores and predictors of cardiac death in a population with atrial fibrillation. AB - Background: Atrial fibrillation (AF) is a common arrhythmia, with risk of systemic embolism and death. It presents rheumatic etiology in up to 32% of developing countries, whose anticoagulation and evolution data are scarce. Objectives: to determine the predictors of cardiac death considering the clinical profile, thromboembolism and bleeding scores of patients with AF of a single center, with high prevalence of rheumatic heart disease. Methods: 302 patients with AF were studied, mean age 58.1 years; 161 women; 96 pts with rheumatic etiology. Patients underwent clinical and laboratory evaluation, measurement of risk scores and the mean follow-up of 12.8 months. Results: 174 were using warfarin. The averages of the HAS-BLED and ATRIA scores were 1.4 and 1.2, respectively. Percent time in therapeutic range of international normalized ratio was 45.8%. Thirty patients (9.9%) had cardiac death and 41 had some type of bleeding due to warfarin. By univariate analysis, there was statistical significance between cardiac death and permanent AF, blood pressure, systolic dysfunction, R2CHADS2, CCS, EHRA and HAS-BLED. There was no association with valvular AF. By multivariate analysis, systemic arterial and pulmonary artery pressures, classification CCS and systolic dysfunction showed statistical significance. Conclusions: There was no association between cardiac death and valvular AF. Independent predictors of cardiac death were low measures of blood pressure, higher score CCS classification and the presence of systolic ventricular dysfunction. PMID- 28562834 TI - Hypertriglyceridemic Waist Phenotype and Changes in the Fasting Glycemia and Blood Pressure in Children and Adolescents Over One-Year Follow-Up Period. AB - Background:: The hypertriglyceridemic waist (HTW) phenotype is defined as the simultaneous presence of increased waist circumference (WC) and serum triglycerides (TG) levels and it has been associated with cardiometabolic risk in children and adolescents. Objective:: The objective was to evaluate the influence of HTW phenotype in the fasting glycemia and blood pressure in children and adolescents over one-year follow-up period. Methods:: It is a cohort study involving 492 children and adolescents from 7 to 15 years old, both genders, who were submitted to anthropometric, biochemical and clinical evaluation at the baseline, and also after 6 and 12 months of follow-up. Generalized Estimating Equation (GEE) models were calculated to evaluate the longitudinal influence of the HTW phenotype in the glycemia and blood pressure over one-year. Results:: It was observed a prevalence of 10.6% (n = 52) of HTW phenotype in the students. The GEE models identified that students with HTW phenotype had an increase of 3.87 mg/dl in the fasting glycemia mean (CI: 1.68-6.05) and of 3.67mmHg in the systolic blood pressure (SBP) mean (CI: 1.55-6.08) over one-year follow-up, after adjusting for confounding variables. Conclusions:: The results of this study suggest that HTW phenotype is a risk factor for longitudinal changes in glycemia and SBP in children and adolescents over one-year follow-up period. Fundamento:: O fenotipo de cintura hipertrigliceridemica (CHT) e definido como a presenca simultanea de circunferencia de cintura (CC) e niveis sericos de triglicerides (TG) aumentados e tem sido associado com risco cardiometabolico em criancas e adolescentes. Objetivo:: Avaliar a influencia do fenotipo CHT na glicemia de jejum e na pressao arterial em criancas e adolescentes em um periodo de acompanhamento de um ano. Metodos:: Trata-se de um estudo de coorte envolvendo 492 criancas e adolescentes de 7 a 15 anos de ambos os sexos, que foram submetidos a avaliacao antropometrica, bioquimica e clinica no inicio e tambem apos 6 e 12 meses de seguimento. Os modelos de Equacao de Estimulacao Generalizada (GEE) foram calculados para avaliar a influencia longitudinal do fenotipo CHT na glicemia e na pressao arterial ao longo de um ano. Resultados:: Foi observada uma prevalencia de 10,6% (n = 52) do fenotipo CHT nos estudantes. Os modelos GEE identificaram que os estudantes com fenotipo CHT apresentaram aumento de 3,87 mg/dl na media de glicemia em jejum (IC: 1,68-6,05) e de 3,67 mmHg na pressao arterial sistolica media (PAS) (IC: 1,55-6,08) depois de um ano de acompanhamento, apos ajuste para variaveis de confusao. Conclusoes:: Os resultados deste estudo sugerem que o fenotipo CHT e um fator de risco para alteracoes longitudinais da glicemia e da PAS em criancas e adolescentes em um periodo de um ano de seguimento. PMID- 28562835 TI - Academic Achievement of American Indian and Alaska Native Students: Does Social Emotional Competence Reduce the Impact of Poverty. AB - Social-emotional competence may be a protective factor for academic achievement among American Indian and Alaska Native (AI/AN) students. This study used Fisher's r to Z transformations to test for group differences in the magnitude of relationships between social-emotional competence and achievement. Hierarchical linear modeling was used to determine the variance in academic achievement explained by student race, poverty, and social-emotional competence, and the schoolwide percentage of students by race. Data are from 335 students across 6 schools. This study suggests that promoting social-emotional competence among AI/AN students could be a strategy for reducing disparities in academic achievement and the consequences of these disparities. PMID- 28562836 TI - Healing the Spirit: Exploring Sexualized Trauma and Recovery among Indigenous Men in Toronto. AB - Colonial policies in Canada have led to social disruption and intergenerational trauma across Indigenous nations, contributing to high rates of sexualized violence within many communities. While mental health and social science discourse has identified the harmful impacts of violence against Indigenous women in Canada, there continues to be a lack of focus on the unique mental health needs of Indigenous men in this regard. This article reviews the results of a nationally funded research study which looked at the mental health and healing needs of Indigenous men in Toronto who have experienced sexualized trauma. This study followed Indigenous protocols for research and was conducted in partnership with Anishnawbe Health Toronto, a culture-based community health center. The methodology utilized a narrative inquiry and interviewed six community men about their recovery journeys and ten community healers and counselors about recovery through a gendered lens. The results explore the discourses that contribute to the social construction of masculinity(ies) and the impacts of these social norms on help-seeking behaviors. These results inform culturally appropriate and gender relevant mental health service provision for Indigenous male clients recovering from sexualized trauma. PMID- 28562833 TI - The Effect of Physical Resistance Training on Baroreflex Sensitivity of Hypertensive Rats. AB - Background:: Baroreceptors act as regulators of blood pressure (BP); however, its sensitivity is impaired in hypertensive patients. Among the recommendations for BP reduction, exercise training has become an important adjuvant therapy in this population. However, there are many doubts about the effects of resistance exercise training in this population. Objective:: To evaluate the effect of resistance exercise training on BP and baroreceptor sensitivity in spontaneously hypertensive rats (SHR). Method:: Rats SHR (n = 16) and Wistar (n = 16) at 8 weeks of age, at the beginning of the experiment, were randomly divided into 4 groups: sedentary control (CS, n = 8); trained control (CT, n = 8); sedentary SHR (HS, n = 8) and trained SHR (HT, n = 8). Resistance exercise training was performed in a stairmaster-type equipment (1.1 * 0.18 m, 2 cm between the steps, 80 degrees incline) with weights attached to their tails, (5 days/week, 8 weeks). Baroreceptor reflex control of heart rate (HR) was tested by loading/unloading of baroreceptors with phenylephrine and sodium nitroprusside. Results:: Resistance exercise training increased the soleus muscle mass in SHR when compared to HS (HS 0.027 +/- 0.002 g/mm and HT 0.056 +/- 0.003 g/mm). Resistance exercise training did not alter BP. On the other hand, in relation to baroreflex sensitivity, bradycardic response was improved in the TH group when compared to HS (HS -1.3 +/- 0.1 bpm/mmHg and HT -2.6 +/- 0.2 bpm/mmHg) although tachycardia response was not altered by resistance exercise (CS -3.3 +/- 0.2 bpm/mmHg, CT -3.3 +/- 0.1 bpm/mmHg, HS -1.47 +/- 0.06 bpm/mmHg and HT -1.6 +/- 0.1 bpm/mmHg). Conclusion:: Resistance exercise training was able to promote improvements on baroreflex sensitivity of SHR rats, through the improvement of bradycardic response, despite not having reduced BP. Fundamento:: Os barorreceptores atuam como reguladores da pressao arterial (PA); no entanto, sua sensibilidade encontra-se prejudicada em pacientes hipertensos. Dentre as recomendacoes para a reducao da PA, o treinamento fisico tem se tornado um importante adjunto na terapia dessa populacao. Porem, ainda ha diversos questionamentos sobre os efeitos de treinamento fisico resistido nessa populacao. Objetivo:: Avaliar o efeito do treinamento fisico resistido na PA e na sensibilidade de barorreceptores em ratos espontaneamente hipertensos (SHR). Metodo:: Ratos SHR (n = 16) e Wistar (n = 16) com 08 semanas de idade foram aleatoriamente divididos em 4 grupos: controle sedentario (CS, n = 8); controle treinado (CT, n = 8); SHR sedentario (HS, n = 8) e SHR treinado (HT, n = 8). O treinamento fisico foi realizado em aparato com degraus (1,1 * 0,18 m, 2 cm entre os degraus, 80 degrees inclinacao) com peso fixado na cauda, (5 vezes por semana durante 8 semanas). O controle barorreflexo da frequencia cardiaca (FC) foi testado com estimulos de fenilefrina e nitroprussiato de sodio. Resultados:: O treinamento resistido foi capaz de aumentar a massa muscular do soleo em ratos SHR (HS 0,027 +/- 0,002 g/mm e HT 0,056 +/- 0,003 g/mm). Nao houve alteracao da PA com o treinamento. Por outro lado, houve melhora na resposta bradicardica da sensibilidade barorreflexa no grupo HT (HS -1,3 +/- 0,1 bpm/mmHg e HT -2,6 +/- 0,2 bpm/mmHg), no entanto, a resposta taquicardica nao foi alterada pelo exercicio resistido (CS -3,3 +/- 0,2 bpm/mmHg, CT -3,3 +/- 0,1 bpm/mmHg, HS -1,47 +/- 0,06 e HT -1,6 +/- 0,1). Conclusao:: O exercicio fisico resistido foi capaz de otimizar a sensibilidade barorreflexa dos ratos SHR por meio da melhora a resposta bradicardica, apesar de nao alterar a PA. PMID- 28562837 TI - Residential Substance Abuse Treatment for Urban American Indians and Alaska Natives, Part I: Services and Staff. AB - Although residential substance abuse treatment is utilized extensively by urban American Indians and Alaska Natives (AI/ANs), there are few detailed descriptions of this care. This study delineated services provided by and interviewed staff working at residential programs designed for chemically dependent urban AI/ANs. Study agencies were compared to national data from residential programs serving general population clients. Study agencies delivered arrays of services substantially broader than those provided by general population programs. As well as culturally specific programs tailored for AI/ANs plus so-called "mainstream" substance abuse treatments, study facilities provided numerous ancillary services, such as care for clients' children. PMID- 28562838 TI - Residential Substance Abuse Treatment for Urban American Indians and Alaska Natives, Part II: Costs. AB - The present study examined costs of two residential substance abuse treatment programs designed for urban American Indians and Alaska Natives (AI/ANs). Costs for one agency were well within national norms, while costs at the other program were less than expected from nationwide data. Economies of scale accounted for much of the difference between observed and expected costs. Culturally specific residential substance abuse treatment services can be provided to urban AI/ANs within budgets typically found at mainstream programs. PMID- 28562839 TI - Changes in Physical Activity Barriers among American Indian Elders: A Pilot Study. AB - The objective of the present study was to assess whether selfreported physical activity barriers could be reduced among American Indian elders who participated in a 6-week randomized physical activity trial that compared the use of a pedometer only to that of pedometers with step-count goal setting. Elders (N = 32) were compared on the Barriers to Being Physically Active Quiz after participating in a pilot physical activity trial. Elders were classified into high- and low-barrier groups at baseline and compared on self-reported physical activity, health-related quality of life, pedometer step counts, and 6-minute walk performance. At the conclusion of the 6-week trial, only the lack of willpower subscale significantly decreased. The low-barrier group reported significantly higher physical activity engagement and improved mental health quality of life than the high-barrier group. The groups did not differ on daily step counts or 6-minute walk performance. Additional research is needed with a larger sample to understand relevant activity barriers in this population and assess whether they can be modified through participation in structured physical activity and exercise programs. PMID- 28562840 TI - Mental health service and provider preference among American Indians with type 2 diabetes. AB - In this study, we investigated mental health service and provider preferences of American Indian adults with type 2 diabetes from two tribes in the northern Midwest. Preferences were determined and compared by participant characteristics. After controlling for other factors, living on reservation lands was associated with increased odds of Native provider preference, and decreased odds of biomedical service preference. Anxiety also was associated with decreased odds of biomedical service preference. Spiritual activity engagement and past health care discrimination were associated with increased odds of traditional service preference. We discuss implications for the types of mental health services offered and characteristics of providers who are recruited for tribal communities. PMID- 28562841 TI - Native VOICES: Adapting a video-based sexual health intervention for American Indian teens and young adults using the ADAPT-ITT model. AB - American Indian and Alaska Native (AI/AN) youth experience disproportionate rates of sexually transmitted infections (STIs). Despite their need for culturally appropriate sexual health interventions, few evidence-based programs have been designed for or rigorously evaluated with AI/AN youth. The primary goal of this study was to adapt a video-based HIV/STI intervention for AI/AN teens and young adults (15-24 years old) living in urban and reservation settings. To capture the heterogeneous experience of AI/AN youth, as well as the viewpoints of adult stakeholders, formative research activities were carried out in collaboration with three geographically dispersed communities in the Pacific Northwest using focus groups and key informant interviews, following the ADAPT-ITT model. Based on participants' feedback, the team produced a culturally tailored intervention toolkit containing a Users Guide, the Native VOICES video, condom and dental dam demonstration videos, and a selection of condoms and dental dams. Forthcoming analyses are evaluating the effectiveness of the Native VOICES intervention with AI/AN youth living across the U.S. PMID- 28562842 TI - Participatory visual methods for American Indian communities and mental health conversations. AB - Visual methods serve a unique purpose in that they help generate data that uncover experiences, knowledge, and contextual factors that lead to a greater shared understanding about a topic. We describe the process and results of one American Indian community-based organization's success using visual methods to prompt community conversations about mental health and substance abuse. We uncovered community members' mental health perspectives and experiences through visual vignettes. Our hope is that other communities and funding agencies see the value and promise of visual methods as a valid approach that promotes shared dialogue, decision making, and conversations for future generations. PMID- 28562843 TI - The prostitution and trafficking of American Indian/Alaska Native women in Minnesota. AB - We examined social and physical violence experienced by American Indian/Alaska Native (AI/AN) women in prostitution and their impacts on the mental and physical health of 105 women (81% Anishinaabe, mean age = 35 years) recruited through service agencies in three Minnesota cities. In childhood, abuse, foster care, arrests, and prostitution were typical. Homelessness, rape, assault, racism, and pimping were common. The women's most prevalent physical symptoms included muscle pain, impaired memory or concentration, and headaches. Symptoms of post-traumatic stress disorder and dissociation were common, with more severe psychological symptoms associated with worse health. Most of the women wanted to leave prostitution and they most often identified counseling and peer support as necessary to accomplish this. Most saw colonization and prostitution of AI/AN women as connected. PMID- 28562845 TI - EVOLUTION AND HYBRIDIZATION IN THE UTETHEISA ORNATRIX COMPLEX (LEPIDOPTERA:ARCTIIDAE). I. INTER- AND INTRAPOPULATION VARIATION AND ITS RELATION TO HYBRIDIZATION. PMID- 28562844 TI - Development and piloting of a brief intervention for suicidal American Indian adolescents. AB - American Indian (AI) adolescents have the highest suicide death and attempt rates of any U.S. group, yet few interventions have been developed or evaluated for this population. This paper presents the first adaptation of a brief evidence based intervention for AI adolescents from one reservation who made a suicide attempt. We describe our community-driven approach to intervention development and a small pilot study (n = 13). Preliminary findings indicate reductions in adolescents' negative thinking, depression, and suicidal ideation, and an increase in psychological service utilization. Key innovations include delivery by AI paraprofessionals and potential to strengthen the continuum of care between emergency department and outpatient settings. PMID- 28562846 TI - THERIAN AND QUASI-MAMMALS. PMID- 28562847 TI - COMPETITIVE INTERACTIONS AND THE EVOLUTION OF ECOLOGICAL NICHES AS ILLUSTRATED BY THE AUSTRALIAN HONEYEATER GENUS MELITHREPTUS (MELIPHAGIDAE). PMID- 28562848 TI - THE FREQUENCY OF INTERBREEDING BETWEEN TWO SIBLING SPECIES OF DACUS (DIPTERA) IN WILD POPULATIONS. PMID- 28562850 TI - ON THE EVOLUTIONARY SIGNIFICANCE OF E. COLI, YEAST, AND RABBIT LIVER sRNA METHYLATION. PMID- 28562849 TI - MIMETIC VERSUS DISRUPTIVE COLORATION IN INTERGRADING POPULATIONS OF LIMENITIS ARTHEMIS AND ASTYANAX BUTTERFLIES. PMID- 28562851 TI - ISLAND PATTERNS IN THE SOLOMON ISLANDS BIRD FAUNA. PMID- 28562852 TI - POSTMATING ISOLATION IN THE HYLA EWINGI COMPLEX (ANURA : HYLIDAE). PMID- 28562853 TI - SIZE-FECUNDITY RELATIONSHIPS AND THEIR EVOLUTIONARY IMPLICATIONS IN FIVE DESMOGNATHINE SALAMANDERS. PMID- 28562854 TI - PARTIAL REPRODUCTIVE ISOLATION IN THE GENUS PARTULA (GASTROPODA) ON MOOREA. PMID- 28562856 TI - SUPERNUMERARY CHROMOSOMES IN HAPLOPAPPUS VALIDUS (RYDB.) CORY. PMID- 28562855 TI - COMPONENTS OF VARIANCE OF ODONTOMETRIC TRAITS IN A WILD-DERIVED POPULATION OF PEROMYSCUS LEUCOPUS. PMID- 28562857 TI - AN EXPERIMENTAL EVALUATION OF PREMATING ISOLATION IN THE HYLA EWINGI COMPLEX (ANURA : HYLIDAE). PMID- 28562858 TI - THE POPULATION BIOLOGY OF THE BUTTERFLY, EUPHYDRYAS EDITHA. VIII. OVIPOSITION AND ITS RELATION TO PATTERNS OF OVIPOSITION IN OTHER BUTTERFLIES. PMID- 28562859 TI - INTRASPECIFIC COMBAT AND THE EVOLUTION OF THE CAPRINI. PMID- 28562860 TI - THE EVOLUTIONARY SIGNIFICANCE OF THE SPECIATION OF EUPHRASIA IN EUROPE. PMID- 28562861 TI - GENOTYPE FREQUENCY AND MATING SUCCESS IN THE WILLISTONI SPECIES GROUP OF DROSOPHILA. PMID- 28562862 TI - ADAPTIVE SIGNIFICANCE OF MYCOPHAGY IN STORED-PRODUCT ARTHROPODA. PMID- 28562864 TI - HYPOTHETICAL MECHANISM OF SPECIATION. PMID- 28562865 TI - CHANGES IN GENETIC CONSTITUTION OF A POPULATION OF SPHAEROMA RUGICAUDA (CRUSTACEA: ISOPODA). PMID- 28562866 TI - CHROMOSOME EVOLUTION IN THE POCKET MOUSE, PEROGNATHUS GOLDMANI OSGOOD. PMID- 28562867 TI - CONSTANCY OF THE PENTAMEROUS COROLLA PHENOTYPE IN NATURAL POPULATIONS OF LINANTHUS. PMID- 28562868 TI - THE RELATIONSHIP OF EVOLUTIONARY THEORY TO PHENETIC TAXONOMY. PMID- 28562869 TI - COLOR-PHASE IN GIBBONS. PMID- 28562870 TI - SELECTION FOR REPRODUCTIVE ISOLATION BETWEEN TWO POPULATIONS OF MAIZE, ZEA MAYS L. PMID- 28562871 TI - THE DEPENDENCE OF BEE-MEDIATED POLLEN AND GENE DISPERSAL UPON PLANT DENSITY. PMID- 28562872 TI - ORIGIN AND EVOLUTION OF FUNCTION OF THE MESONYCHID CONDYLARTH FEEDING MECHANISM. PMID- 28562873 TI - GLOGER'S RULE AND PIGMENTATION OF COLLEMBOLA. PMID- 28562874 TI - EXPERIMENTAL STUDIES ON HYBRIDIZATION AND SEXUAL ISOLATION BETWEEN SOME APHYTIS SPECIES (HYMENOPTERA: APHELINIDAE). III. THE SIGNIFICANCE OF REPRODUCTIVE ISOLATION BETWEEN INTERSPECIFIC HYBRIDS AND PARENTAL SPECIES. PMID- 28562875 TI - NEW EVIDENCE ON THE ORIGIN OF THE HEXAPLOID OATS. PMID- 28562876 TI - SELECTIVE MATING AND EYE PIGMENTATION: AN ANALYSIS OF THE VISUAL COMPONENT IN THE COURTSHIP BEHAVIOR OF DROSOPHILA MELANOGASTER. PMID- 28562877 TI - EXTINCTION-ORIGINATION EQUILIBRIA IN LATE CENOZOIC LAND MAMMALS OF NORTH AMERICA. PMID- 28562878 TI - GEOGRAPHICAL VARIATION AND EVOLUTION IN PSEUDOSINELLA VIOLENT A (FOLSOM). PMID- 28562879 TI - RELATIVE FITNESS OF INTROGRESSED AND PARENTAL POPULATIONS OF DROSOPHILA MOJAVENSIS AND D. ARIZONENSIS. PMID- 28562880 TI - A CYTOLOGICAL STUDY ON SOME RECENTLY COLLECTED STRAINS OF DROSOPHILA PAULISTORUM. PMID- 28562882 TI - MEASUREMENT OF SELECTION USING DISTANCE STATISTICS IN THE PREHISTORIC ORANG-UTAN PONGO PYGMAEUS PALAEOSUMATRENSIS. PMID- 28562883 TI - AN ANALYSIS OF NATURAL SELECTION IN LABORATORY POPULATIONS OF DACUS (TEPHRITIDAE: DIPTERA). PMID- 28562884 TI - EVOLUTION OF WING REDUCTION IN CRANE FLIES (DIPTERA : TIPULIDAE). PMID- 28562885 TI - LEVELS OF INTEGRATION IN MAMMALIAN DENTITIONS: AN ANALYSIS OF CORRELATIONS IN NESOPHONTES MICRUS (INSECTIVORA) AND ORYZOMYS COUESI (RODENTIA). PMID- 28562886 TI - MICROTUS POPULATION BIOLOGY. II. GENETIC CHANGES AT THE TRANSFERRIN LOCUS IN FLUCTUATING POPULATIONS OF TWO VOLE SPECIES. PMID- 28562887 TI - AN ATTEMPT TO VERIFY MIMETIC ADVANTAGE IN A NEOTROPICAL ENVIRONMENT. PMID- 28562888 TI - SUBSPECIES AND SYMPATRY IN DARWIN'S FINCHES. PMID- 28562889 TI - HERITABILITY OF SOME LINEAR BODY MEASUREMENTS AND THEIR RATIOS IN THE LEOPARD FROG RANA PIPIENS. PMID- 28562890 TI - BERGMANN'S RULE AND CLIMATIC ADAPTATION IN WOODRATS (NEOTOMA). PMID- 28562891 TI - SYMPATRIC HOST RACE FORMATION AND SPECIATION IN FRUGIVOROUS FLIES OF THE GENUS RHAGOLETIS (DIPTERA, TEPHRITIDAE). PMID- 28562892 TI - THE RELATION BETWEEN MODE OF REPRODUCTION AND EXTENT OF SPECIATION IN WOODY GENERA OF THE CALIFORNIA CHAPARRAL. PMID- 28562893 TI - THE EARLY EVOLUTION OF THE PERISSODACTYLA. PMID- 28562894 TI - MATING PROPENSITY, CHROMOSOMAL POLYMORPHISM, AND DEPENDENT CONDITIONS IN DROSOPHILA PERSIMILIS II. FACTORS BETWEEN LARVAE AND BETWEEN ADULTS. PMID- 28562895 TI - "ISOLATING MECHANISMS" IN THE BLUE-WINGED WARBLER-GOLDEN-WINGED WARBLER COMPLEX. PMID- 28562896 TI - COMPARATIVE STUDIES OF ARRANGEMENTS WITHIN AND BETWEEN POPULATIONS OF DROSOPHILA PSEUDOOBSCURA. PMID- 28562899 TI - HYBRIDIZATION AND ITS TAXONOMIC IMPLICATIONS IN THE SCAEVOLA GAUDICHAUDIANA COMPLEX OF THE HAWAIIAN ISLANDS. PMID- 28562900 TI - SELECTION FOR AND AGAINST ETHOLOGICAL ISOLATION BETWEEN DROSOPHILA PSEUDOOBSCURA AND DROSOPHILA PERSIMILIS. PMID- 28562897 TI - SELF-INCOMPATIBILITY ALLELES IN THE POPULATION OF OENOTHERA ORGANENSIS. PMID- 28562901 TI - THE EVOLUTIONARY SIGNIFICANCE OF MOUNTAIN SHEEP HORNS. PMID- 28562902 TI - THE BIOTA OF LONG-DISTANCE DISPERSAL. IV. GENETIC SYSTEMS IN THE FLORAS OF OCEANIC ISLANDS. PMID- 28562903 TI - THE PERIODICAL CICADA PROBLEM. II. EVOLUTION. PMID- 28562904 TI - CYTOGENETICS OF RUBUS. V. NATURAL HYBRIDIZATION BETWEEN R. PROCERUS P. J. MUELL. AND R. LACINIATUS WILLD. PMID- 28562906 TI - CLIMATOLOGICAL DISTRIBUTION OF A GRASSHOPPER SUPERNUMERARY CHROMOSOME. PMID- 28562905 TI - THE ORIGIN AND SIGNIFICANCE OF INTRASPECIFIC POLYPLOIDY: EXPERIMENTAL EVIDENCE FROM SOLANUM CHACOENSE. PMID- 28562907 TI - ESTIMATION OF CONSERVATISM OF CHARACTERS BY CONSTANCY WITHIN BIOLOGICAL POPULATIONS. PMID- 28562908 TI - BODY SIZES OF POIKILOTHERM VERTEBRATES AT DIFFERENT LATITUDES. PMID- 28562909 TI - IMMUNOLOGY AND RATES OF ENZYME EVOLUTION IN THE AMPHIBIA IN RELATION TO THE ORIGINS OF CERTAIN TAXA. PMID- 28562910 TI - PREMATING ISOLATING MECHANISMS IN SYMPATRIC AND ALLOPATRIC HYLA REGILLA AND HYLA CALIFORNIAE. PMID- 28562912 TI - THE POPULATION BIOLOGY OF THE BUTTERFLY, EUPHYDRYAS EDITHA. IV. SPERM PRECEDENCE A PRELIMINARY REPORT. PMID- 28562911 TI - THE MIMETIC SIGNIFICANCE OF ERYTHROLAMPRUS AESCULAPII OCELLATUS PETERS FROM TOBAGO. PMID- 28562913 TI - MONTHLY FREQUENCY CHANGES OF DROSOPHILA PSEUDOOBSCURA THIRD CHROMOSOME GENE ARRANGEMENTS IN A CALIFORNIA LOCALITY. PMID- 28562914 TI - BIRDS AS AGENTS OF LONG-DISTANCE DISPERSAL FOR DISJUNCT PLANT GROUPS OF THE TEMPERATE WESTERN HEMISPHERE. PMID- 28562915 TI - THE EFFECTS OF SELECTION BY CLIMATE ON THE LAND-SNAIL CEPAEA NEMORALIS (L.). PMID- 28562916 TI - LONG-TERM CHANGES IN CHROMOSOMALLY POLYMORPHIC LABORATORY STOCKS OF DROSOPHILA PAVANI. PMID- 28562917 TI - THE ADAPTIVE ECOLOGY OF THE SPECIES GROUPS OF THE GENUS LEPTODACTYLUS (AMPHIBIA, LEPTODACTYLIDAE). PMID- 28562918 TI - A NOTE ON STABILITY AND CONVERGENCE OF GENETIC SYSTEMS. PMID- 28562919 TI - CHROMOSOMAL EVOLUTION IN TROPICAL HARDWOODS. PMID- 28562920 TI - ALTERNATIVE ROUTES TO EVOLUTIONARY SUCCESS AS EXHIBITED BY AFRICAN CICHLID FISHES OF THE GENUS TILAPIA AND THE SPECIES FLOCKS OF THE GREAT LAKES. PMID- 28562921 TI - MICROEVOLUTION WITHIN THREE SPECIES OF HAWAIIAN DROSOPHILA. PMID- 28562922 TI - ECOTYPIC VARIATION IN THE NON-BREEDING SEASON IN MIGRATORY POPULATIONS: A STUDY OF TARSAL LENGTH IN SOME FRINGILLIDAE. PMID- 28562923 TI - ON THE USE OF CONSTANCY IN ESTIMATING CONSERVATISM OF CHARACTERS. PMID- 28562924 TI - CHROMOSOME TRANSLOCATIONS IN GAYOPHYTUM (ONAGRACEAE). PMID- 28562925 TI - TRANSITIONAL POPULATIONS OF DROSOPHILA PAULISTORUM. PMID- 28562926 TI - DIFFERENTIAL VARIATION OF MALES AND FEMALES IN POLISTES EXCLAMANS. PMID- 28562927 TI - DEFICIENCIES OF THE SYNTHETIC THEORY OF EVOLUTION. PMID- 28562928 TI - THE EFFECT OF COROLLA COLOR AND OUTLINE ON INTERSPECIFIC POLLEN FLOW IN PHLOX. PMID- 28562929 TI - PROTEIN POLYMORPHISM AND GENIC HETEROZYGOSITY IN TWO EUROPEAN SUBSPECIES OF THE HOUSE MOUSE. PMID- 28562931 TI - PHENETIC SIMILARITY AND PHYLOGENETIC RELATIONSHIPS AMONG STRAINS OF ORYZA PERENNIS, ESTIMATED BY METHODS OF NUMERICAL TAXONOMY. PMID- 28562930 TI - THE PRINCIPLE OF METACHROMISM: A CRITIQUE. PMID- 28562932 TI - UNORTHODOXIES IN REPTILIAN PHYLOGENY. PMID- 28562933 TI - SQUASH AND GOURD BEES (PEPONAPIS, XENOGLOSSA) AND THE ORIGIN OF THE CULTIVATED CUCURBITA. PMID- 28562934 TI - A BIOMETRIC ANALYSIS OF POPULATIONS OF POA ANNUA L. PMID- 28562935 TI - DYNAMICS OF CLONAL MICROSPECIES IN CHOLLA CACTUS. PMID- 28562936 TI - A REAPPRAISAL OF MATING CALL DIFFERENTIATION IN HYLA CADAVERINA (= HYLA CALIFORNIAE) AND HYLA REGILLA. PMID- 28562937 TI - THE RELATIONSHIP BETWEEN MATING SPEED AND WING LENGTH IN DROSOPHILA SUBOBSCURA. PMID- 28562938 TI - EVOLUTION IN THE HOUSE SPARROW. II. ADAPTIVE DIFFERENTIATION IN NORTH AMERICAN POPULATIONS. PMID- 28562939 TI - GEOGRAPHY OF THE SIBLING SPECIES RELATED TO DROSOPHILA WILLISTONI, AND OF THE SEMISPECIES OF THE DROSOPHILA PAULISTORUM COMPLEX. PMID- 28562940 TI - ON REVERSIONS TO FORMER ANCESTRAL CONDITIONS IN MEGADRILE OLIGOCHAETES. PMID- 28562941 TI - SOUND PRODUCTION DURING COURTSHIP IN SIX SPECIES OF SUNFISH (CENTRARCHIDAE). PMID- 28562943 TI - COADAPTATION OF THE PAYNE INVERSION WITH A PREVIOUSLY UNRELATED GENETIC BACKGROUND IN DROSOPHILA MELANOGASTER. PMID- 28562942 TI - GEOGRAPHIC AND REPRODUCTIVE ISOLATION IN ATLANTIC AND PACIFIC POPULATIONS OF PANAMANIAN BATHYGOBIUS. PMID- 28562944 TI - FERTILITY AND FITNESS OF XO MALES IN DROSOPHILA I. QUALITATIVE STUDY. PMID- 28562945 TI - WHITTAKER'S FIVE KINGDOMS OF ORGANISMS: MINOR REVISIONS SUGGESTED BY CONSIDERATIONS OF THE ORIGIN OF MITOSIS. PMID- 28562946 TI - A STATISTICAL ANALYSIS OF GEOGRAPHIC VARIATION IN THE PUPAE OF THREE SPECIES OF CULICOIDES (DIPTERA: CERATOPOGONIDAE). PMID- 28562947 TI - THE ECOLOGICAL RELATIONSHIP OF THE SALAMANDER AMBYSTOMA LATERALE TO ITS ALL FEMALE, GYNOGENETIC ASSOCIATE. PMID- 28562948 TI - HYBRIDIZATION BETWEEN ANOPHELES CRUCIANS AND ANOPHELES BRADLEYI. PMID- 28562949 TI - POLLINATOR FLIGHT DIRECTIONALITY AND ITS EFFECT ON POLLEN FLOW. PMID- 28562950 TI - ORGANOPHYLETIC TRENDS IN SEVERAL MICROMORPHOLOGICAL FLORAL TRAITS IN THE HEXAPLOID CULTIVATED OATS (AVENA). PMID- 28562951 TI - MULTIPLE CHARACTER ANALYSIS AND CHROMOSOME STUDIES IN THE TRIPSACUM LANCEOLATUM COMPLEX. PMID- 28562952 TI - THE ALLOPATRIC MODEL AND PHYLOGENY IN PALEOZOIC INVERTEBRATES. PMID- 28562953 TI - ESTIMATION OF RELATIVE VIABILITY AND FECUNDITY OF COLOR POLYMORPHISMS IN ANURANS. PMID- 28562954 TI - EVOLUTIONARY STATUS OF THE ROCKY MOUNTAIN POPULATION OF WOOD FROGS. PMID- 28562955 TI - WIND POLLINATION IN THE ANGIOSPERMS: EVOLUTIONARY AND ENVIRONMENTAL CONSIDERATIONS. PMID- 28562957 TI - EVOLUTION OF DENTAL GROWTH AND ADAPTATION IN MAMMALIAN CARNIVORES. PMID- 28562956 TI - THE SENSORY BASIS OF MATE SELECTION IN DROSOPHILA. PMID- 28562958 TI - BIOCHEMICAL SYSTEMATICS AND PHYLOGENETIC INTERPRETATIONS IN THE GENUS AQUILEGIA. PMID- 28562959 TI - MATING SELECTION IN THE CALIFORNIA OAK MOTH (LEPIDOPTERA, DIOPTIDAE). PMID- 28562960 TI - QUANTITATIVE STUDIES ON MATING SYSTEMS. III. METHODS FOR THE ESTIMATION OF MALE GAMETOPHYTIC SELECTIVE VALUES AND DIFFERENTIAL OUTCROSSING RATES. PMID- 28562961 TI - THE VERTEBRATE NOSE, REMARKS ON ITS STRUCTURAL AND FUNCTIONAL ADAPTATION AND EVOLUTION. PMID- 28562962 TI - FECUNDITY IN PRIMITIVE PLETHODONTID SALAMANDERS. PMID- 28562963 TI - VARIANCE OF GENE FREQUENCIES. PMID- 28562964 TI - SEED-EATERS VERSUS SEED SIZE, NUMBER, TOXICITY AND DISPERSAL. PMID- 28562965 TI - SMALL ISLANDS AND THE EQUILIBRIUM THEORY OF INSULAR BIOGEOGRAPHY. PMID- 28562966 TI - ON THE ADAPTIVE VALUE OF SEXUAL DIMORPHISM: II. UNISEXUALITY. PMID- 28562967 TI - MUTANT GENES AND THE EMIGRATION BEHAVIOR OF PHAENICIA SERICATA (DIPTERA, CALLIPHORIDAE). PMID- 28562968 TI - THE MULTIPLE ORIGINS OF THE PLACENTAL CARNIVORES. PMID- 28562969 TI - THE EVOLUTION, FUNCTIONING AND BREAKDOWN OF HETEROMORPHIC INCOMPATIBILITY SYSTEMS. I. THE PLUMBAGINACEAE. PMID- 28562970 TI - COEVOLUTION OF MUTUALISM BETWEEN ANTS AND ACACIAS IN CENTRAL AMERICA. PMID- 28562971 TI - THE ADAPTIVE RADIATION OF THE PHENACODONTID CONDYLARTHS AND THE ORIGIN OF THE PERISSODACTYLA. PMID- 28562972 TI - THE ORIGIN OF DIOECISM FROM HETEROSTYLY IN NYMPHOIDES (MENYANTHACEAE). PMID- 28562973 TI - THE ADAPTIVE SIGNIFICANCE OF GASTROPOD TORSION. PMID- 28562974 TI - FEEDING SPECIALIZATIONS AND THE CLASSIFICATION OF TERRESTRIAL SALAMANDERS. PMID- 28562975 TI - FUNCTIONAL MORPHOLOGY AND EVOLUTION OF THE CERATOPSIAN DINOSAURS. PMID- 28562976 TI - POPULATION VARIABILITY OF CERCOCARPUS IN THE WHITE MOUNTAINS OF CALIFORNIA AS RELATED TO HABITAT. PMID- 28562977 TI - ZOOGEOGRAPHY AND EVOLUTION. PMID- 28562978 TI - NEARLY ROOTED INCISORS IN AN ABNORMAL RAT, AND CONTROL OF TOOTH GROWTH. PMID- 28562980 TI - THE RELATIONSHIPS OF THE TREE SHREWS: THE EVIDENCE OF THE NERVOUS SYSTEM. PMID- 28562979 TI - VARIATION IN BLOOD GROUP FREQUENCIES IN POPULATIONS OF SONG SPARROWS OF THE SAN FRANCISCO BAY REGION. PMID- 28562981 TI - GENETICS OF NATURAL POPULATIONS. XXXVIII. CONTINUITY AND CHANGE IN POPULATIONS OF DROSOPHILA PSEUDOOBSCURA IN WESTERN UNITED STATES. PMID- 28562982 TI - HYBRIDIZATION AS A SOURCE OF VARIATION FOR ADAPTATION TO NEW ENVIRONMENTS. PMID- 28562983 TI - THE EVOLUTION OF THREE DIPLOID SPECIES OF OENOTHERA SUBGENUS ANOGRA (ONAGRACEAE). PMID- 28562984 TI - THE INTERIOR SEMISPECIES OF DROSOPHILA PAULISTORUM. PMID- 28562985 TI - POTENTIAL EXTINCTION THROUGH COMPETITION BETWEEN TWO SPECIES OF TERRESTRIAL SALAMANDERS. PMID- 28562986 TI - SELF-FERTILITY IN MARITIME AND ZINC MINE POPULATIONS OF ARMERIA MARITIMA (MILL.) WILLD. PMID- 28562987 TI - FURTHER GENETIC STUDIES OF THE SOUTH AMHERST POPULATION OF DROSOPHILA MELANOGASTER. PMID- 28562988 TI - POLYMORPHISM AND EGG-SIZE IN THE SHEEP NEMATODE, HAEMONCHUS CONTORTUS. PMID- 28562989 TI - ANALYSIS OF A GENERAL POPULATION GENETIC MODEL OF MEIOTIC DRIVE. PMID- 28562990 TI - THE EVOLUTIONARY DYNAMICS OF THE DESERT WOODRAT, NEOTOMA LEPIDA. PMID- 28562991 TI - QUANTITATIVE VARIATION AND CHROMOSOMAL ARRANGEMENTS IN A POPULATION OF DROSOPHILA PERSIMILIS FROM THE REDWOODS. PMID- 28562992 TI - DEVELOPMENTAL INSTABILITY IN SPECIES AND HYBRIDS OF LIATRIS. PMID- 28562993 TI - COMPETITION BETWEEN DROSOPHILA MELANOGASTER AND D. SIMULANS ON MEDIA SUPPLEMENTED WITH SACCHAROMYCES AND SCHIZOSACCHAROMYCES. PMID- 28562994 TI - METACHROMISM LIKE IT IS. PMID- 28562995 TI - A MODEL FOR THE EVOLUTION OF PINNIPED POLYGYNY. PMID- 28562996 TI - POPULATION FITNESS OF GEOGRAPHIC STRAINS OF DROSOPHILA SERRATA AS MEASURED BY INTERSPECIFIC COMPETITION. PMID- 28562998 TI - STUDIES ON NATURAL POPULATIONS OF DROSOPHILA XI. FITNESS COMPONENTS AND COMPETITION BETWEEN DROSOPHILA FUNEBRIS AND D. VIRILIS. PMID- 28562997 TI - THE POPULATION BIOLOGY OF ANNUAL GRASSLAND HEMIPARASITES. II. REPRODUCTIVE PATTERNS IN ORTHOCARPUS. PMID- 28562999 TI - PARALLEL EVOLUTION IN THE ADAPTIVE ECOLOGY OF LEPTODACTYLID FROGS OF SOUTH AMERICA AND AUSTRALIA. PMID- 28563000 TI - METABOLIC AND MORPHOLOGICAL ADAPTATION TO HETEROGENOUS ENVIRONMENTS BY THE PACIFIC TREE TOAD, HYLA REGULA. PMID- 28563001 TI - CHANGES OF CYTOPLASMIC FACTORS DURING THE EVOLUTION OF THE CULTIVATED POTATO. PMID- 28563002 TI - PHENOTYPIG DIMORPHISM AND POPULATIONAL FITNESS IN PHLOX. PMID- 28563003 TI - CYNODONT POSTCRANIAL ANATOMY AND THE "PROTOTHERIAN" LEVEL OF MAMMALIAN ORGANIZATION. PMID- 28563004 TI - TAXONOMIC DIVERSITY OF ISLAND BIOTAS. PMID- 28563005 TI - A BIOMETRICAL STUDY ON THE SEMISPECIES OF THE DROSOPHILA PAULISTORUM COMPLEX. PMID- 28563006 TI - EVOLUTIONARY STRATEGIES IN LIZARD REPRODUCTION. PMID- 28563007 TI - THE INTERACTION BETWEEN THE PAYNE INVERSION AND GENETIC BACKGROUND IN THE TUMOROUS-HEAD STRAIN OF DROSOPHILA MELANOGASTER. PMID- 28563008 TI - GENETICS OF LUPINUS. II. THE SELECTIVE DISADVANTAGE OF THE PINK FLOWER COLOR MUTANT IN LUPINUS NANUS. PMID- 28563009 TI - A MULTIVARIATE MORPHOMETRIC ANALYSIS OF DIVERGENCE IN SKULL MORPHOLOGY AMONG GEOGRAPHICALLY CONTIGUOUS AND ISOLATED GROUPS OF WHITE-TAILED DEER (ODOCOILEUS VIRGINIANUS) IN MICHIGAN. PMID- 28563010 TI - PLANKTON EVOLUTION. PMID- 28563011 TI - ADDITIONAL EVIDENCE ON SEXUAL ISOLATION WITHIN DROSOPHILA BIRCHII. PMID- 28563012 TI - THE B-CHROMOSOME SYSTEM OF MYRMELEOTETTIX MACULATUS (THUNB). IV. THE DYNAMICS. PMID- 28563013 TI - ON THE MAINTENANCE OF A SHELL PATTERN AND BEHAVIOR POLYMORPHISM IN ACMAEA DIGITALIS, A LIMPET. PMID- 28563014 TI - MEASUREMENTS BY DNA HYBRIDIZATION IN VITRO OF THE GENETIC BASIS OF PARASITIC REDUCTION. PMID- 28563015 TI - NATURAL CROSSING BETWEEN APIS MELLIFERA ADANSONII AND APIS MELLIFERA LIGUSTICA. PMID- 28563016 TI - COMMENTS ON INTROGRESSION AND REPRODUCTIVE ISOLATING MECHANISMS IN THE BLUE WINGED WARBLER-GOLDEN-WINGED WARBLER COMPLEX. PMID- 28563017 TI - A COMPUTER SIMULATION STUDY OF THE EFFECTS OF TWO BEHAVIORAL TRAITS ON THE GENETIC STRUCTURE OF SEMI-ISOLATED POPULATIONS. PMID- 28563018 TI - RODENT DNA: COMPARISONS BETWEEN SPECIES. PMID- 28563020 TI - REPRODUCTIVE STRATEGIES IN PITHECELLOBIUM AND ENTEROLOBIUM-FURTHER INFORMATION. PMID- 28563019 TI - THE GENETIC BASIS OF CROSSING BARRIERS BETWEEN ORYZA PERENNIS SUBSP. BARTHII AND ITS RELATED TAXA. PMID- 28563021 TI - HABITAT SELECTION AND COMPETITION AMONG SIBLING SPECIES OF SATYRID BUTTERFLIES. PMID- 28563022 TI - A REPLY TO DR. FARRIS' COMMENT ON EVOLUTION IN THE DROSOPHILA OBSCURA SPECIES GROUP. PMID- 28563023 TI - STRATEGIES FOR EGG PRODUCTION. PMID- 28563024 TI - THE REPRODUCTIVE BEHAVIOUR AND THE NATURE OF SEXUAL SELECTION IN SCATOPHAGA STERCORARIA L. (DIPTERA: SCATOPHAGIDAE). IX. SPATIAL DISTRIBUTION OF FERTILIZATION RATES AND EVOLUTION OF MALE SEARCH STRATEGY WITHIN THE REPRODUCTIVE AREA. PMID- 28563025 TI - GENETIC AND REPRODUCTIVE DIFFERENTIATION OF THE SUBSPECIES, DROSOPHILA EQUINOXIALIS CARIBBENSIS. PMID- 28563026 TI - A COMMENT ON EVOLUTION IN THE DROSOPHILA OBSCURA SPECIES GROUP. PMID- 28563027 TI - EPISTATIC GENE INTERACTION, CROSSING OVER, AND LINKED AND UNLINKED INVERSIONS IN DROSOPHILA SUBOBSCURA. PMID- 28563028 TI - GENETIC VARIATION, SELECTION AND SPECIATION IN THOMOMYS TALPOIDES POCKET GOPHERS. PMID- 28563029 TI - ON TOOTH SUCCESSION IN DIADEMODON. PMID- 28563030 TI - RIGID AND FLEXIBLE CHROMOSOMAL POLYMORPHISMS IN NEIGHBORING POPULATIONS OF DROSOPHILA PSEUDOOBSCURA. PMID- 28563032 TI - ANALYTICAL ZOOGEOGRAPHY OF NORTH AMERICAN MAMMALS. PMID- 28563031 TI - SEXUAL DIMORPHISM IN SKATES (RAJIDAE) AND ITS POSSIBLE ROLE IN DIFFERENTIAL NICHE UTILIZATION. PMID- 28563033 TI - BIOCHEMICAL GENETICS OF SUNFISH. I. GEOGRAPHIC VARIATION AND SUBSPECIFIC INTERGRADATION IN THE BLUEGILL, LEPOMIS MACROCHIRUS. PMID- 28563034 TI - A NOTE ON THE SPEED OF GENE FREQUENCY CHANGES IN REVERSE DIRECTIONS IN A FINITE POPULATION. PMID- 28563035 TI - BREEDING SYSTEMS OF TREE SPECIES OF A LOWLAND TROPICAL COMMUNITY. PMID- 28563036 TI - ON THE MALE REPRODUCTIVE BEHAVIOR AND SUSTAINED POLYMORPHISM OF THE RT LOCUS IN LABORATORY POPULATIONS OF EPHESTIA KUHNIELLA. PMID- 28563037 TI - GENETIC DIVERGENCE AND MORPHOLOGICAL CONVERGENCE IN THE PRAIRIE DOGS, CYNOMYS GUNNISONI AND CYNOMYS LEUCURUS I. MORPHOLOGICAL AND ECOLOGICAL ANALYSES. PMID- 28563038 TI - THE EVOLUTION OF SOCIAL BEHAVIOR IN PRIMITIVELY SOCIAL BEES: A MULTIVARIATE ANALYSIS. PMID- 28563039 TI - THE ADAPTIVE SIGNIFICANCE OF ALARM CALLS GIVEN BY SHOREBIRDS ON THEIR WINTER FEEDING GROUNDS. PMID- 28563040 TI - CONSEQUENCES OF LONG-TERM ARTIFICIAL SELECTION, INBREEDING, AND ISOLATION IN PHLOX: I. THE EVOLUTION OF CROSS-INCOMPATIBILITY. PMID- 28563041 TI - ISOZYME VARIATION IN NATURAL POPULATIONS OF DROSOPHILA BUZZATII. PMID- 28563042 TI - CRUISING SPEED DURING MIGRATION OF THE STRIPED MULLET (MUGIL CEPHALUS L.): AN EVOLUTIONARY RESPONSE TO PREDATION? PMID- 28563043 TI - DEVONIAN AMPHIBIANS: DID THEY EXCRETE CARBON DIOXIDE VIA SKIN, GILLS, OR LUNGS? PMID- 28563044 TI - NATURAL SELECTION AND RANDOM GENETIC DRIFT IN PHENOTYPIC EVOLUTION. PMID- 28563045 TI - PARTIALLY SUCCESSFUL ATTEMPT TO ENHANCE REPRODUCTIVE ISOLATION BETWEEN SEMISPECIES OF DROSOPHILA PAULISTORUM. PMID- 28563046 TI - MORTALITY AND ADAPTIVE MECHANISMS OF ORYZA PERENNIS STRAINS. PMID- 28563047 TI - SEXUAL SELECTION AND RESOURCE-ACCRUING ABILITIES IN ANOLIS GARMANI. PMID- 28563048 TI - STRAINS OF NEUROSPORA COLLECTED FROM NATURE. PMID- 28563049 TI - GENETIC DIVERGENCE AND MORPHOLOGICAL CONVERGENCE IN THE PRAIRIE DOGS. CYNOMYS GUNNISONI AND CYNOMYS LEUCURUS II. GENETIC ANALYSES. PMID- 28563050 TI - ENVIRONMENTAL AND GENETICAL CORRELATES OF DISRUPTIVE COLORATION IN THE WATER SNAKE, NATRIX S. SIPEDON. PMID- 28563051 TI - FERTILE GLUMES IN PRIMITIVE CULTIVATED WHEATS. PMID- 28563052 TI - SELECTION AND STABILITY IN THE COMPLEX POLYMORPHISM OF MORABA SCURRA. PMID- 28563053 TI - EVOLUTION IN MIXED POPULATIONS OF TRIBOLIUM. PMID- 28563054 TI - THE REPRODUCTIVE BIOLOGY OF RHUS INTEGRIFOLIA AND RHUS OVATA (ANACARDIACEAE). PMID- 28563055 TI - NUMBERS OF BIRD SPECIES ON THE CALIFORNIA ISLANDS. PMID- 28563056 TI - RANDOM VS. NON-RANDOM MATING IN THE SULFUR BUTTERFLIES, COLIAS EURYTHEME AND COLIAS PHILODICE (LEPIDOPTERA: PIERIDAE). PMID- 28563057 TI - SOME FUNCTIONAL ASPECTS OF MOLAR EVOLUTION. PMID- 28563059 TI - COURTSHIP INTERACTION IN THE SEMISPECIES OF DROSOPHILA PAULISTORUM. PMID- 28563058 TI - RAPID POPULATION DIFFERENTIATION IN A MOSAIC ENVIRONMENT. II. MORPHOLOGICAL VARIATION IN ANTHOXANTHUM ODORATUM. PMID- 28563060 TI - EVOLUTIONARY IMPLICATIONS OF ZAHNREIHEN. PMID- 28563061 TI - THE EVOLUTION OF THE USE OF TOOLS BY FEEDING ANIMALS. PMID- 28563062 TI - POLLINATION BIOLOGY OF NEMOPHILA MENZIESII (HYDROPHYLLACEAE) WITH COMMENTS ON THE EVOLUTION OF OLIGOLECTIC BEES. PMID- 28563063 TI - MAINTENANTE OF CHROMOSOMAL POLYMORPHISM IN A POPULATION OF DROSOPHILA PSEUDOOBSCURA: VIABILITY UNDER CROWDED AND UNCROWDED CONDITIONS. PMID- 28563064 TI - DNA CONTENT IN RELATION TO PHYLOGENY OF SELECTED BOREAL FOREST PLANTS. PMID- 28563065 TI - COMPETITION BETWEEN METAL TOLERANT AND NORMAL PLANT POPULATIONS ON NORMAL SOIL. PMID- 28563066 TI - EFFECTS OF POPULATION DENSITY ON THE FREQUENCY-DEPENDENT SELECTION IN THE ESTERASE-6 LOCUS OF DROSOPHILA MELANOGASTER. PMID- 28563067 TI - INTRASPECIFIC VARIATION IN NUCLEAR VOLUME IN FOUR CONIFERS. PMID- 28563068 TI - EMBRYONIC TEMPERATURE ADAPTATIONS AND GENETIC COMPATIBILITY IN TWO ALLOPATRIC POPULATIONS OF THE SPADEFOOT TOAD, SCAPHIOPUS HAMMONDI. PMID- 28563070 TI - THE EVOLUTION OF SPINY LOBSTERS (PALINURIDAE): A STUDY OF EVOLUTION IN THE MARINE ENVIRONMENT. PMID- 28563069 TI - MATING PROPENSITY, CHROMOSOMAL POLYMORPHISM, AND DEPENDENT CONDITIONS IN DROSPHILA PERSIMILIS. PMID- 28563071 TI - EVIDENCE FOR AUTOPOLYPLOIDY IN EPILOBIUM ANGUSTIFOLIUM (ONAGRACEAE). PMID- 28563072 TI - LATENT NEOMORPHS AND THE EVOLUTION OF DOMINANCE. PMID- 28563073 TI - GEOGRAPHIC VARIATION AND CLIMATIC ADAPTATION IN A FIELD CRICKET (ORTHOPTERA: GRYLLIDAE). PMID- 28563074 TI - INTERSPECIFIC COMPETITION, EGG CANNIBALISM AND THE LENGTH OF LARVAL INSTARS IN TRIBOLIUM. PMID- 28563075 TI - SELECTION AND INVERSION POLYMORPHISM IN EXPERIMENTAL POPULATIONS OF DROSOPHILA PSEUDOOBSCURA INITIATED WITH THE CHROMOSOMAL CONSTITUTIONS OF NATURAL POPULATIONS. PMID- 28563076 TI - THE ORIGIN OF SORGHUM BICOLOR. II. DISTRIBUTION AND DOMESTICATION. PMID- 28563077 TI - MORPHOLOGICAL VARIATION IN SOLANUM X EDINENSE, A HYBRID OF THE COMMON POTATO. PMID- 28563078 TI - THE MEASUREMENT OF ISOLATION ON ARCHIPELAGOS, AND ITS RELATION TO INSULAR FAUNAL SIZE AND ENDEMISM. PMID- 28563079 TI - SUPPORT FOR BAKER'S LAW-AS A RULE. PMID- 28563080 TI - RANDOM SAMPLING AND THE RATE OF GENE REPLACEMENT. PMID- 28563081 TI - COMPARISONS OF PRIMATE CATALASE TRYPTIC PEPTIDES AND IMPLICATIONS FOR THE STUDY OF MOLECULAR EVOLUTION. PMID- 28563082 TI - BEHAVIOR OF MALE SUNFISHES (GENUS LEPOMIS) TOWARDS FEMALES OF THREE SPECIES. PMID- 28563083 TI - FORAMEN PSEUDOVALE AND QUASI-MAMMALS. PMID- 28563084 TI - WHY DOES THE GENOTYPE NOT CONGEAL? PMID- 28563085 TI - THE EFFECT OF REPRODUCTIVE PERFORMANCE ON THE DOMESTICATION OF THE PRAIRIE DEERMOUSE, PEROMYSCUS MANICULATUS BAIRDII. PMID- 28563087 TI - NATURAL SELECTION FOR REPRODUCTIVE ISOLATION IN PHLOX. PMID- 28563088 TI - EARLY REPTILIAN EVOLUTION RE-VIEWED. PMID- 28563089 TI - COEVOLUTION OF PLANTS AND HERBIVORES: PASSION FLOWER BUTTERFLIES. PMID- 28563090 TI - EFFECTS OF LARVAL BIOTIC RESIDUES ON VIABILITY IN FOUR SPECIES OF DROSOPHILA. PMID- 28563091 TI - BIOLOGICAL CONSIDERATIONS OF THE MARSUPIAL-PLACENTAL DICHOTOMY. PMID- 28563092 TI - SIMULTANEOUS SELECTIVE PREDATION ON TWO FEATURES OF A MIXED SIBLING SPECIES POPULATION. PMID- 28563093 TI - ISLAND BIOGEOGRAPHY OF ANTS. PMID- 28563094 TI - THE SOCIAL SIGNIFICANCE OF AVIAN WINTER PLUMAGE VARIABILITY. PMID- 28563096 TI - BULLETIN. PMID- 28563097 TI - CHARACTER DISPLACEMENT IN THE RADIOLARIAN GENUS, EUCYRTIDIUM. PMID- 28563098 TI - ECOLOGICAL COMPETITION AND THE ADVANTAGE OF THE RARE TYPE IN DROSOPHILA MELANOGASTER. PMID- 28563100 TI - THE BIOGEOGRAPHY OF LABORATORY ISLANDS. PMID- 28563099 TI - THE GENETIC COMPOSITION OF PHILAENUS SPUMARIUS POPULATIONS IN ISLAND HABITATS VARIABLY AFFECTED BY VOLES. PMID- 28563101 TI - LATE CENOZOIC EVOLUTION OF TROPICAL LOWLAND VEGETATION IN VERACRUZ, MEXICO. PMID- 28563102 TI - CHROMOSOME EVOLUTION AND ANEUPLOID REDUCTION IN CALYCADENIA PAUCIFLORA (ASTERACEAE). PMID- 28563103 TI - REVERSED SEX-LIMITED MIMICRY IN A BEETLE. PMID- 28563104 TI - A CYTOGENETIC STUDY OF THE WHITE-THROATED SPARROW, ZONOTRICHIA ALBICOLLIS (GMELIN). PMID- 28563105 TI - SATURNIID MOTHS AS MIMICS: AN ALTERNATIVE INTERPRETATION OF ATTEMPTS TO DEMONSTRATE MIMETIC ADVANTAGE IN NATURE. PMID- 28563106 TI - IS THERE A CONSTANT FITNESS VALUE FOR A GIVEN GENOTYPE? NO! PMID- 28563107 TI - EVOLUTION OF FOOD-PLANT PREFERENCE IN THE BUTTERFLY EUPHYDRYAS EDITHA. PMID- 28563108 TI - THE REPRODUCTIVE SYSTEM OF JEPSONIA HETERANDRA. PMID- 28563109 TI - THE EFFECTS OF CROWDING ON CHROMOSOMAL POLYMORPHISM OF DROSOPHILA PAVANI. PMID- 28563110 TI - THE OPERATION OF SELECTION IN SITUATIONS OF INTERSPECIFIC COMPETITION. PMID- 28563111 TI - THE DYNAMICS OF PLANT DOMESTICATION: CULTIVATION EXPERIMENTS WITH ORYZA PERENNIS AND ITS HYBRID WITH O. SATIVA. PMID- 28563112 TI - A NEW APPROACH TO MEASURING GENETIC SIMILARITY. PMID- 28563113 TI - PHENOLOGICAL RELATIONSHIPS OF SOME ACULEATE HYMENOPTERA, THEIR DIPTERAN MIMICS, AND INSECTIVOROUS BIRDS. PMID- 28563115 TI - LEVELS OF GENETIC COMPATIBILITY OF RANA AREOLATA WITH SOUTHWESTERN MEMBERS OF THE RANA PIPIENS COMPLEX (ANURA: RANIDAE). PMID- 28563114 TI - FURTHER STUDIES OF THE ETIOLOGY OF HYBRID MALE STERILITY IN DROSOPHILA PAULISTORUM. PMID- 28563116 TI - CYTOGENETIC STUDIES IN CLARKIA, SECTION PRIMIGENIA. V. INTERSPECIFIC HYBRIDIZATION BETWEEN C. AMOENA HUNTIANA AND C. LASSENENSIS. PMID- 28563117 TI - TRACHEAL DEAD SPACE IN THE RESPIRATION OF BIRDS. PMID- 28563118 TI - THE EFFECTS OF PREDATION ON ARTIFICIAL MIMETIC POLYMORPHISMS WITH PERFECT AND IMPERFECT MIMICS AT VARYING FREQUENCIES. PMID- 28563119 TI - INDUSTRIAL MELANISM IN THE TWO-SPOT LADYBIRD AND SMOKE ABATEMENT. PMID- 28563120 TI - THE EVOLUTION OF REPRODUCTIVE ISOLATION IN CLARKIA, SECTION MYXOCARPA. PMID- 28563121 TI - ADAPTIVE ZONES AND THE ORDERS OF MAMMALS. PMID- 28563122 TI - THE YAHOOS RIDE AGAIN. PMID- 28563123 TI - GENE FREQUENCIES IN A MARINE ECTOPROCT: A CLINE IN NATURAL POPULATIONS RELATED TO SEA TEMPERATURE. PMID- 28563124 TI - EVOLUTION IN CONSTANT AND FLUCTUATING ENVIRONMENTS: THERMAL TOLERANCES OF DESERT PUPFISH (CYPRINODON). PMID- 28563125 TI - EVOLUTIONARY RELATIONSHIPS IN THE OUTCROSSING DIPLOID ANNUAL SPECIES OF STEPHANOMERIA (COMPOSITAE). PMID- 28563126 TI - ERRATA. PMID- 28563127 TI - THE COMPONENTS OF SEXUAL SELECTION. PMID- 28563128 TI - ASEXUAL REPRODUCTION AND ENVIRONMENTAL PREDICTABILITY IN CESTODES (CYCLOPHYLLIDEA: TAENIIDAE). PMID- 28563129 TI - EVOLUTION-SCIENCE VERSUS CREATION-SCIENCE. PMID- 28563130 TI - ALDEHYDE OXIDASE DISTRIBUTION IN PICTURE-WINGED HAWAIIAN DROSOPHILA: EVOLUTIONARY TRENDS. PMID- 28563131 TI - HAWKMOTHS AND THE GEOGRAPHIC PATTERNS OF FLORAL VARIATION IN AQUILEGIA CAERULEA. PMID- 28563132 TI - INBREEDING IN AN ISLAND POPULATION OF THE GREAT TIT. PMID- 28563133 TI - MATE CHOICE IN THE WOOD FROG, RANA SYLVATICA. PMID- 28563134 TI - A GEOGRAPHIC PERSPECTIVE ON THE ECOLOGY OF COMPOUND LEAVES. PMID- 28563135 TI - DIVERGENCE IN ALLOPATRY: MOLECULAR AND MORPHOLOGICAL DIFFERENTIATION BETWEEN SEA URCHINS SEPARATED BY THE ISTHMUS OF PANAMA. PMID- 28563136 TI - FLORAL SEX RATIOS AND LIFE HISTORY IN ARALIA NUDICAULIS (ARALIACEAE). PMID- 28563137 TI - ESTIMATING THE DEGREE OF POLYANDRY IN NATURAL POPULATIONS. PMID- 28563138 TI - STRAINING AT GNATS AND SWALLOWING RATIOS: CHARACTER DISPLACEMENT. PMID- 28563139 TI - EFFECTS OF SOCIAL ORGANIZATION AND ENVIRONMENTAL DIVERSITY ON DETERMINING THE GENETIC STRUCTURE OF A POPULATION OF THE WILD RABBIT, ORYCTOLAGUS CUNICULUS. PMID- 28563140 TI - COURTSHIP BEHAVIOR AND EVOLUTIONARY STATUS OF THE HAWAIIAN DROSOPHILA PRIMAEVA HARDY AND KANESHIRO. PMID- 28563141 TI - EVOLUTION OF HOST PLANT UTILIZATION IN LABORATORY POPULATIONS OF THE SOUTHERN COWPEA WEEVIL, CALLOSOBRUCHUS MACULATUS FABRICIUS (COLEOPTERA: BRUCHIDAE). PMID- 28563143 TI - COMMUNITY-WIDE CHARACTER DISPLACEMENT REEXAMINED. PMID- 28563142 TI - ALGEBRA OF INCLUSIVE FITNESS. PMID- 28563144 TI - PATTERNS OF SIZE VARIATION IN BEES AND EVOLUTION OF COMMUNICATION SYSTEMS. PMID- 28563145 TI - ADAPTIVE SIGNIFICANCE OF DELAYED ATTAINMENT OF PLUMAGE IN MALE AMERICAN REDSTARTS: TESTS OF TWO HYPOTHESES. PMID- 28563146 TI - MORPHOLOGICAL VARIATION IN THE HORSESHOE CRAB LIMULUS POLYPHEMUS. PMID- 28563147 TI - PARENTAL CARE AND MODE OF FERTILIZATION IN ECTOTHERMIC VERTEBRATES. PMID- 28563148 TI - PLEIOTROPY AND PARAPATRIC SPECIATION. PMID- 28563149 TI - THE BREEDING SYSTEM OF GILIA ACHILLEIFOLIA: VARIATION IN FLORAL CHARACTERISTICS AND OUTCROSSING RATE. PMID- 28563150 TI - RAPID DIVERGENCE OF PLANT POPULATIONS IN RESPONSE TO RECENT CHANGES IN SOIL CONDITIONS. PMID- 28563151 TI - GENETIC DIVERSITY AND POPULATION STRUCTURE IN PITCH PINE (PINUS RIGIDA MILL.). PMID- 28563152 TI - MATE RECOGNITION AND MECHANICAL ISOLATION IN ENALLAGMA DAMSELFLIES (ODONATA: COENAGRIONIDAE). PMID- 28563153 TI - SEX DETERMINING TEMPERATURES IN TURTLES: A GEOGRAPHIC COMPARISON. PMID- 28563154 TI - ON THE ROLE OF CHROMOSOMAL INVERSIONS IN SPECIATION. PMID- 28563155 TI - BREEDING SYNCHRONY IN THE LESSER SNOW GOOSE (ANSER CAERULESCENS CAERULESCENS): I. GENETIC AND ENVIRONMENTAL COMPONENTS OF HATCH DATE VARIABILITY AND THEIR EFFECTS ON HATCH SYNCHRONY. PMID- 28563156 TI - HERITABILITY OF BLUE TIT TARSUS LENGTH FROM NORMAL AND CROSS-FOSTERED BROODS. PMID- 28563157 TI - SELECTION FOR HOST MODIFICATION BY INSECT PARASITOIDS. PMID- 28563158 TI - ALLOZYME VARIATION IN COREOPSIS NUECENSOIDES AND C. NUECENSIS (COMPOSITAE), A PROGENITOR-DERIVATIVE SPECIES PAIR. PMID- 28563159 TI - ECOLOGICAL AND BEHAVIORAL BASIS FOR REPRODUCTIVE ISOLATION IN THE SYMPATRIC ENCHENOPA BINOTATA COMPLEX (HOMOPTERA. MEMBRACIDAE). PMID- 28563160 TI - MICROHABITAT DIFFERENCES AMONG GENETICALLY SIMILAR SPECIES OF PARTULA. PMID- 28563161 TI - PINNIPED THERMOREGULATION: COMMENTS ON THE "EFFECTS OF COLD ON THE EVOLUTION OF PINNIPED BREEDING SYSTEMS". PMID- 28563163 TI - Society for the Study of Evolution and American Society of Naturalists 1982 Meetings. PMID- 28563162 TI - IS HOST CASTRATION AN EVOLUTIONARY STRATEGY OF BOT FLIES? PMID- 28563164 TI - SEXUAL DIMORPHISM IN ARALIA NUDICAULIS L. (ARALIACEAE). PMID- 28563165 TI - SPECIATION RATES AND MORPHOLOGICAL DIVERGENCE IN FISHES: TESTS OF GRADUAL VERSUS RECTANGULAR MODES OF EVOLUTIONARY CHANGE. PMID- 28563166 TI - EXPERIMENTAL CHANGES IN RESOURCE STRUCTURE AND MALE DENSITY: SIZE-RELATED DIFFERENCES IN MATING SUCCESS AMONG MALE SCATOPHAGA STERCORARIA. PMID- 28563167 TI - ORIGIN OF INVERSIONS AND WALLACE'S RULE OF TRIADS. PMID- 28563168 TI - SEXUAL SELECTION IN A BRENTID WEEVIL. PMID- 28563169 TI - GROUP SELECTION VERSUS INDIVIDUAL SELECTION: AN EXPERIMENTAL ANALYSIS. PMID- 28563170 TI - GENETIC VARIATION AND THE BREEDING SYSTEM OF GILIA ACHILLEIFOLIA. PMID- 28563171 TI - RAPID ORIGIN OF SEXUAL ISOLATION AND CHARACTER DIVERGENCE IN A CLINE. PMID- 28563172 TI - RATE OF ENVIRONMENTAL CHANGE AND ADAPTATION IN THE COPEPOD EURYTEMORA AFFINIS. PMID- 28563173 TI - EXTREME LEVELS OF GENETIC VARIABILITY IN TWO RED SEA CERITHIUM SPECIES (GASTROPODA: CERITHIDAE). PMID- 28563174 TI - HERITABILITY OF SEX RATIO IN TURTLES WITH ENVIRONMENTAL SEX DETERMINATION. PMID- 28563175 TI - ON THE QUANTIFICATION OF PROMISCUITY (OR "PROMYSCUS" MANICULATUS ?). PMID- 28563176 TI - GENETIC STRUCTURE OF POPULATIONS OF THE BROWN SNAIL (HELIX ASPERSA). I. MICROGEOGRAPHIC VARIATION. PMID- 28563177 TI - ADAPTIVE DIFFERENTIATION WITH LITTLE GENIC CHANGE BETWEEN TWO NATIVE CALIFORNIA MINNOWS. PMID- 28563178 TI - SEMISPECIES OF DROSOPHILA ATHABASCA DISTINGUISHABLE BY MALE COURTSHIP SOUNDS. PMID- 28563179 TI - COMPETITION BETWEEN METAL TOLERANT AND NORMAL PLANT POPULATIONS; A FIELD EXPERIMENT ON NORMAL SOIL. PMID- 28563180 TI - CHIASMA FREQUENCY AND ADAPTABILITY IN LOCUSTS. PMID- 28563181 TI - THE EVOLUTION OF SUBDIOECY IN MORPHOLOGICALLY GYNODIOECIOUS SPECIES OF FUCHSIA SECT. ENCLIANDRA (ONAGRACEAE). PMID- 28563182 TI - GEOGRAPHIC VARIATION IN NORTH AMERICAN COLONIES OF CEPAEA NEMORALIS. PMID- 28563183 TI - SELECTION FOR MATING ACTIVITY IN TWO CHROMOSOMAL ARRANGEMENTS OF DROSOPHILA PSEUDOOBSCURA. PMID- 28563184 TI - ALLOZYMES OF GALAPAGOS TOMATOES: POLYMORPHISM, GEOGRAPHIC DISTRIBUTION, AND AFFINITIES. PMID- 28563185 TI - MORE ON COMPLEX LIFE CYCLES. PMID- 28563186 TI - THE NOVEL FLAVONOID CHEMISTRY AND PHYLOGENETIC ORIGIN OF PHLOX FLORIDANA. PMID- 28563187 TI - HIGH FREQUENCY OF ONE ELEMENT OF SEGREGATION DISTORTER IN NATURAL POPULATIONS OF DROSOPHILA MELANOGASTER. PMID- 28563188 TI - CORRELATIONS BETWEEN QUANTITATIVE CHARACTERS AND ENZYME GENOTYPES IN AVENA BARBATA. PMID- 28563189 TI - ON THE EVOLUTION OF COMPLEX LIFE CYCLES. PMID- 28563190 TI - EVOLUTIONARY AND ECOLOGICAL RELATIONSHIPS BETWEEN AQUILEGIA FORMOSA AND A. PUBESCENS (RANUNCULACEAE), TWO PERENNIAL PLANTS. PMID- 28563191 TI - SEXUAL DRIVE OF NORMAL AND SR FLIES OF DROSOPHILA NEBULOSA. PMID- 28563192 TI - GENETIC VARIATION AND SPECIATION IN NEW WORLD CICHLIDS. PMID- 28563193 TI - CONTROLS OF NUMBER OF BIRD SPECIES ON MONTANE ISLANDS IN THE GREAT BASIN. PMID- 28563194 TI - HARD AND SOFT SELECTION REVISITED. PMID- 28563196 TI - PHENOTYPIC VARIATION AND THE OUTCOME OF INTERSPECIFIC COMPETITION IN HYLID TADPOLES. PMID- 28563195 TI - VARIATION IN THE BREEDING SYSTEM OF ELYMUS CANADENSIS. PMID- 28563197 TI - LATITUDINAL GRADIENTS IN THE SPECIES DIVERSITY OF NORTH AMERICAN MAMMALS. PMID- 28563199 TI - SELECTIVE MORTALITY AND REPRODUCTION IN A NATURAL POPULATION OF BUFO BOREAS. PMID- 28563198 TI - PATTERNS OF ALLOZYMIC SIMILARITY IN ECOLOGICALLY CENTRAL AND MARGINAL POPULATIONS OF HORDEUM JUBATUM IN UTAH. PMID- 28563200 TI - SALE OF BACK ISSUES OF EVOLUTION. PMID- 28563201 TI - DIVERGENCE IN THE ENCHENOPA BINOTATA SAY COMPLEX (HOMOPTERA: MEMBRACIDAE) EFFECTED BY HOST PLANT ADAPTATION. PMID- 28563202 TI - THE INVERSION POLYMORPHISM OF KEYACRIS SCURRA AND THE ADAPTIVE TOPOGRAPHY. PMID- 28563203 TI - THE DISTRIBUTION OF AN ESTERASE POLYMORPHISM IN MACROGYNES AND MICROGYNES OF MYRMICA RUBRA LATREILLE. PMID- 28563204 TI - PAEDOMORPHOSIS IN RELATION TO RATES OF MORPHOLOGICAL AND MOLECULAR EVOLUTION IN THE SALAMANDER ANEIDES FLAVIPUNCTATUS (AMPHIBIA, PLETHODONTIDAE). PMID- 28563205 TI - FLORAL MIMICRY BY EPIDENDRUM IBAGUENSE (ORCHIDACEAE) IN PANAMA. PMID- 28563206 TI - MALADAPTATION IN A MARGINAL POPULATION OF THE MOSQUITO FISH, GAMBUSIA AFFINIS. PMID- 28563207 TI - SEXUAL SELECTION AND THE EVOLUTION OF PAIR-BONDING IN SOLDIER BEETLES. PMID- 28563209 TI - Joint Meeting of The Society for the Study of Evolution and American Society of Naturalists Tucson, Arizona June 29-July 2, 1980. PMID- 28563208 TI - THE POPULATION BIOLOGY OF THE WHITE-LIPPED LAND SNAIL, TRIODOPSIS ALBOLABRIS: GENETIC VARIABILITY. PMID- 28563210 TI - THE DISTRIBUTIONS OF GENDER IN FOUR ANGIOSPERM SPECIES ILLUSTRATING TWO EVOLUTIONARY PATHWAYS TO DIOECY. PMID- 28563211 TI - THE IMPLICATIONS OF OVUM SIZE VARIABILITY FOR OFFSPRING FITNESS AND CLUTCH SIZE WITHIN SEVERAL POPULATIONS OF SALAMANDERS (AMBYSTOMA). PMID- 28563212 TI - EVOLUTION AND SPECIATION OF HOST PLANT SPECIFIC YEASTS. PMID- 28563213 TI - SEXUAL SELECTION AND DIMORPHISM IN TWO DEMES OF A SYMBIOTIC, PAIR-BONDING SNAPPING SHRIMP. PMID- 28563214 TI - NATURAL SELECTION ON COLOR PATTERNS IN POECILIA RETICULATA. PMID- 28563215 TI - AN EXAMINATION OF THE TROPHIC RESOURCE STABILITY THEORY USING OYSTER SPECIES OF THE FAMILY OSTREIDAE. PMID- 28563216 TI - ENZYME VARIATION IN SEMI-ISOLATED POPULATIONS OF THE MOUNTAIN FLY CHAMAEMYIA HERBARUM. PMID- 28563217 TI - INHIBITION OF CANNIBALISM IN CICHLA OCELLARIS AND HYPOTHESIS OF PREDATOR MIMICRY AMONG SOUTH AMERICAN FISHES. PMID- 28563218 TI - LIFE-HISTORY VARIATION IN POA ANNUA. PMID- 28563219 TI - PHOSPHOGLUCOSE ISOMERASE POLYMORPHISM AND NATURAL SELECTION IN THE SAND CRAB, EMERITA TALPOIDA. PMID- 28563220 TI - EXTINCTION, REPOPULATION, AND POPULATION SIZE IN NATURAL POPULATIONS OF AMBUSHBUGS. PMID- 28563221 TI - THE EVOLUTIONARY EFFECTS OF METALLIFEROUS AND OTHER ANOMALOUS SOILS IN SOUTH CENTRAL AFRICA. PMID- 28563222 TI - ADAPTIVE FEATURES OF MAMMALIAN REPRODUCTION. PMID- 28563223 TI - AN EXAMPLE OF SPORANGIAL INDEHISCENCE IN THE FILICOPSIDA. PMID- 28563224 TI - GENERAL CONCEPTS ON THE EVOLUTIONARY BIOLOGY OF PARASITES. PMID- 28563225 TI - EVOLUTION AT THE alpha-GPDH LOCUS IN DROSOPHILIDAE. PMID- 28563226 TI - STATISTICAL TESTS FOR NATURAL SELECTION ON QUANTITATIVE CHARACTERS. PMID- 28563227 TI - THE EVOLUTION OF AUTOGAMY IN SPECIES OF THE MUSTARD GENUS LEAVENWORTHIA. PMID- 28563228 TI - GENETIC AND ENVIRONMENTAL CORRELATIONS OF MORPHOMETRIC TRAITS IN RANDOMBRED HOUSE MICE. PMID- 28563229 TI - A SUGGESTION CONCERNING THE CRETACEOUS RISE TO DOMINANCE OF THE ANGIOSPERMS. PMID- 28563230 TI - THE LANSING EFFECT REVISITED. II.-CUMULATIVE AND SPONTANEOUSLY REVERSIBLE PARENTAL AGE EFFECTS ON FECUNDITY IN DROSOPHILA MELANOGASTER. PMID- 28563231 TI - ON THE SUPPOSED SPECTRUM BETWEEN BATESIAN AND MULLERIAN MIMICRY. PMID- 28563232 TI - WHAT IS FREQUENCY-DEPENDENT SELECTION? PMID- 28563233 TI - TRANSLOCATION HETEROZYGOSITY, GENETIC HETEROZYGOSITY, AND INBREEDING IN CLARKIA SPECIOSA. PMID- 28563234 TI - BOTTLENECK EFFECTS ON AVERAGE HETEROZYGOSITY AND GENETIC DISTANCE WITH THE STEPWISE MUTATION MODEL. PMID- 28563235 TI - DINOSAUR HAVERSIAN BONE AND ENDOTHERMY. PMID- 28563236 TI - THE EXISTENCE OF MULLERIAN MIMICRY. PMID- 28563237 TI - GENIC DIVERSITY IN CAVE-DWELLING CRICKETS (CEUTHOPHILUS GRACILIPES). PMID- 28563238 TI - GENETICS OF LUPINUS. X. GENETIC VARIABILITY, HETEROZYGOSITY AND OUTCROSSING IN COLONIAL POPULATIONS OF LUPINUS SUCCULENTUS. PMID- 28563239 TI - DETECTION OF THE EFFECTS OF SELECTION ON PROTEIN POLYMORPHISMS IN NATURAL POPULATIONS BY MEANS OF A DISTANCE ANALYSIS. PMID- 28563240 TI - STABILIZING SELECTION FOR SIZE AS RELATED TO MATING FITNESS IN TETRAOPES. PMID- 28563241 TI - OUTCROSSING IN NATURAL POPULATIONS. V. ANALYSIS OF OUTCROSSING, INBREEDING, AND SELECTION IN CLARKIA EXILIS AND CLARKIA TEMBLORIENSIS. PMID- 28563242 TI - ECOLOGY AND EVOLUTION OF THE PITCHER-PLANT MOSQUITO. 2. THE SUBSTRUCTURE OF FITNESS. PMID- 28563243 TI - CYTOGENETICS AND AFFINITIES OF VERNONIA (COMPOSITAE) FROM THE MEXICAN HIGHLANDS AND EASTERN NORTH AMERICA. PMID- 28563245 TI - CLIMATIC SELECTION IN CEPAEA HORTENSIS AT THE NORTHERN LIMIT OF ITS RANGE IN ICELAND. PMID- 28563244 TI - EVOLUTION OF THE MIGRATION RESPONSE: EMIGRATION BY TRIBOLIUM AND THE INFLUENCE OF AGE. PMID- 28563246 TI - WHY MALE-HAPLOID AND SEX-LINKED GENETIC SYSTEMS SEEM TO HAVE UNUSUALLY SEX LIMITED MUTATIONAL GENETIC LOADS. PMID- 28563247 TI - HETEROSIS OVERDOMINANCE AND FREQUENCY-DEPENDENT SELECTION IN DROSOPHILA MELANOGASTER AT THE SEPIA LOCUS. PMID- 28563248 TI - BREEDING SYSTEM POLYMORPHISM IN A HETEROSTYLOUS SPECIES. PMID- 28563249 TI - COMPONENTS OF FITNESS IN THE UNISEXUAL FISH POECILIOPSIS MONACHA-OCCIDENTALIS. PMID- 28563250 TI - POPULATION GENETICS AND EVOLUTIONARY BIOLOGY OF THE CAVE BEETLE PTOMAPHAGUS HIRTUS. PMID- 28563251 TI - SEXUAL SELECTION IN NOTHOBRANCHIUS GUENTHERI (PISCES: CYPRINODONTIDAE). PMID- 28563252 TI - ISOLATION BETWEEN AQUILEGIA FORMOSA AND A. PUBESCENS: A REPLY AND RECONSIDERATION. PMID- 28563253 TI - MAINTENANCE OF MALES AND FEMALES IN HERMAPHRODITE POPULATIONS AND THE EVOLUTION OF DIOECY. PMID- 28563254 TI - MULTIVARIATE ALLOMETRY AND AUSTRALOPITHECINE VARIATION. PMID- 28563255 TI - GENIC DIVERGENCE AND LOCAL POPULATION DIFFERENTIATION BY RANDOM DRIFT IN THE POCKET GOPHER GENUS GEOMYS. PMID- 28563257 TI - MULTIVARIATE ANALYSIS OF THE INTROGRESSIVE REPLACEMENT OF CLARKIA NITENS BY CLARKIA SPECIOSA POLYANTHA (ONAGRACEAE). PMID- 28563256 TI - SIZE AND ENVIRONMENTAL PREDICTABILITY FOR SALAMANDERS. PMID- 28563258 TI - ECOLOGY AND EVOLUTION OF THE PITCHER-PLANT MOSQUITO. 3. RESOURCE TRACKING BY A NATURAL POPULATION. PMID- 28563260 TI - CHROMOSOMAL VARIATION IN THE PLAINS WOODRAT: GEOGRAPHICAL DISTRIBUTION OF THREE CHROMOSOMAL MORPHS. PMID- 28563259 TI - CONSEQUENCES OF LONG-TERM ARTIFICIAL SELECTION, INBREEDING AND ISOLATION IN PHLOX. II. THE ORGANIZATION OF ALLOZYMIC VARIABILITY. PMID- 28563261 TI - SELECTION AT TWO LEVELS IN HYBRID POPULATIONS OF MUSCA DOMESTICA. PMID- 28563262 TI - INTRA-POPULATION DIFFERENTIATION IN ANNUAL PLANTS I. VERONICA PEREGRINA L. RAISED UNDER NON-COMPETITIVE CONDITIONS. PMID- 28563263 TI - ON THE REALITY OF ZAHNREIHEN AND THE NATURE OF REALITY IN MORPHOLOGICAL STUDIES. PMID- 28563264 TI - UNCORRELATED RANDOM ENVIRONMENTS AND THEIR EFFECTS ON GENE FREQUENCY. PMID- 28563265 TI - A MODEL TO EXPLAIN MOLT-BREEDING OVERLAP AND CLUTCH SIZE IN SOME TROPICAL BIRDS. PMID- 28563266 TI - EVOLUTIONARY RESPONSES OF PLANTS TO SEED-EATERS: PINE SQUIRREL PREDATION ON LODGEPOLE PINE. PMID- 28563267 TI - NATURALLY OCCURRING VARIATION IN LARVAL COLOR OF COLIAS BUTTERFLIES: ISOLATION FROM TWO COLORADO POPULATIONS. PMID- 28563269 TI - THE EVOLUTION OF CLUTCH SIZE AND REPRODUCTIVE RATES IN PARASITIC CUCKOOS. PMID- 28563268 TI - FREQUENCY-DEPENDENT MATE SELECTION IN MORMONIELLA VITRIPENNIS. PMID- 28563270 TI - GENETIC ANALYSIS OF NORTH AMERICAN POPULATIONS OF THE PINK SALMON, ONCORHYNCHUS GORBUSCHA, POSSIBLE EVIDENCE FOR THE NEUTRAL MUTATION-RANDOM DRIFT HYPOTHESIS. PMID- 28563271 TI - THE ORIGIN AND FUNCTION OF "BIZARRE" STRUCTURES: ANTLER SIZE AND SKULL SIZE IN THE "IRISH ELK," MEGALOCEROS GIGANTEUS. PMID- 28563272 TI - THE EVOLUTION OF AIR-BREATHING IN PALEOZOIC GNATHOSTOME FISHES. PMID- 28563273 TI - COADAPTATION AND RECESSIVE LETHAL CONTENT IN DDT RESISTANT POPULATIONS OF DROSOPHILA MELANOGASTER. PMID- 28563274 TI - GENETIC DIVERGENCE OF DEATH VALLEY PUPFISH SPECIES: BIOCHEMICAL VERSUS MORPHOLOGICAL EVIDENCE. PMID- 28563276 TI - GENETIC CONFIRMATION OF THE ORIGIN OF CLARKIA LINGULATA. PMID- 28563275 TI - EVOLUTION OF A TRIHYBRID UNISEXUAL FISH (POECILIOPSIS, POECILIIDAE). PMID- 28563277 TI - MUTATION IN SITU AND THE ORIGIN OF LOCALIZED POLYMORPHISM IN AVENA BARBATA. PMID- 28563278 TI - AUTOCORRELATED RANDOM ENVIRONMENTS AND THEIR EFFECTS ON GENE FREQUENCY. PMID- 28563279 TI - INTERSPECIFIC HYBRIDIZATION, HETEROZYGOSITY AND GENE EXCHANGE IN PHLOX. PMID- 28563280 TI - DNA-DNA HYBRIDIZATION STUDIES OF BIRDS. PMID- 28563281 TI - GROUP SELECTION, SEX, AND FOSSILS. PMID- 28563282 TI - REPLY TO COMMENTS ON "CHROMOSOMAL EVOLUTION IN PEROMYSCUS". PMID- 28563283 TI - GENETIC VARIATION IN HAWAIIAN DROSOPHILA I. CHROMOSOME AND ALLOZYME POLYMORPHISM IN D. SETOSIMENTUM AND D. OCHROBASIS FROM THE ISLAND OF HAWAII. PMID- 28563284 TI - THE ROLE OF PREDATION IN THE EVOLUTION OF SOCIAL BEHAVIOR OF NATURAL POPULATIONS OF THE GUPPY, POECILIA RETICULATA (PISCES: POECILIIDAE). PMID- 28563286 TI - LEPTOTHORAX DULOTICUS AND THE BEGINNINGS OF SLAVERY IN ANTS. PMID- 28563285 TI - FECUNDITY IN DISTYLOUS AND SELF-INCOMPATIBLE HOMOSTYLOUS PLANTS OF MITCHELLA REPENS (RUBIACEAE). PMID- 28563287 TI - GENETICS OF NATURAL POPULATIONS XLII. THREE DECADES OF GENETIC CHANGE IN DROSOPHILA PSEUDOOBSCURA. PMID- 28563288 TI - GREGARIOUS NESTING OF THE MASON BEE HOPLITIS ANTHOCOPOIDES AND THE EVOLUTION OF PARASITISM AND SOCIALITY AMONG MEGACHILID BEES. PMID- 28563289 TI - PHYLOGENETIC EVOLUTION IN COLUMBIDAE AS REVEALED BY INTERRELATIONSHIPS OF GENETIC SYSTEMS OF ANTIGENIC CHARACTERS. PMID- 28563290 TI - TOOTH REPLACEMENT: EFFICIENCY, PATTERNS AND EVOLUTION. PMID- 28563292 TI - NATURAL SELECTION ON MORPHOLOGICAL PHENOTYPES OF THE LIZARD UTA STANSBURIANA. PMID- 28563291 TI - THE BOTTLENECK EFFECT AND GENETIC VARIABILITY IN POPULATIONS. PMID- 28563293 TI - MONOMORPHIC MIMICRY IN NEARCTIC LIMENITIS BUTTERFLIES: EXPERIMENTAL HYBRIDIZATION OF THE L. ARTHEMIS-ASTYANAX COMPLEX WITH L. ARCHIPPUS. PMID- 28563294 TI - EVOLUTIONARY GENETICS OF INSULAR ADRIATIC LIZARDS. PMID- 28563295 TI - DIOECISM IN TROPICAL FOREST TREES. PMID- 28563296 TI - AN ELECTROPHORETIC STUDY OF EVOLUTION IN CAPSICUM (SOLANACEAE). PMID- 28563298 TI - VARIATION IN DEVELOPMENT PATTERNS OF LARVAL ANURANS IN TEMPORARY PONDS. I. PERSISTENT VARIATION WITHIN A HYLA GRATIOSA POPULATION. PMID- 28563297 TI - A CASE OF STRESS RELATED HETEROZYGOTE SUPERIORITY IN NATURE. PMID- 28563299 TI - A NATURAL EXPERIMENT IN LIFE-HISTORY EVOLUTION: FIELD DATA ON THE INTRODUCTION OF MOSQUITOFISH (GAMBUSIA AFFINIS) TO HAWAII. PMID- 28563300 TI - CLONAL DIVERSITY AND POPULATION STRUCTURE IN A REEF-BUILDING CORAL, ACROPORA CERVICORNIS: SELF-RECOGNITION ANALYSIS AND DEMOGRAPHIC INTERPRETATION. PMID- 28563301 TI - DISTRIBUTION OF SEXUAL AND APOMICTIC POPULATIONS OF ANTENNARIA PARLINII. PMID- 28563302 TI - GAMETIC SELECTION AND HEMOGLOBIN POLYMORPHISMS IN PEROMYSCUS MANICULATUS: A REJOINDER. PMID- 28563303 TI - A POPULATION GENETICAL STUDY OF THE AFRICAN MOSQUITO ANOPHELES MARSHALLII (THEOBALD). PMID- 28563304 TI - HYBRID ORIGIN OF POLYPLOIDY IN FRESHWATER SNAILS OF THE GENUS BULINUS (MOLLUSCA: PLANORBIDAE). PMID- 28563305 TI - Society Meetings. PMID- 28563306 TI - BREEDING SYSTEM AND HABITAT EFFECTS ON FITNESS COMPONENTS IN THREE NEOTROPICAL COSTUS (ZINGIBERACEAE). PMID- 28563307 TI - THE ACCUMULATION OF GENETIC VARIATION IN A PARTHENOGENETIC SNAIL. PMID- 28563308 TI - SELECTION COMPONENTS AFFECTING HEMOGLOBINS IN PEROMYSCUS MANICULATUS: A RE EVALUATION. PMID- 28563309 TI - TEMPORAL STABILITY OF LACTATE DEHYDROGENASE-A CLINES OF THE HIGH COCKSCOMB, ANOPLARCHUS PURPURESCENS. PMID- 28563310 TI - INTERSPECIFIC HYBRIDIZATION AND GENETIC DIVERGENCE IN MILKWEED BUGS (ONCOPELTUS: HEMIPTERA: LYGAEIDAE). PMID- 28563311 TI - A COST OF REPRODUCTION IN A TERRESTRIAL ISOPOD. PMID- 28563312 TI - GENETIC AND ENVIRONMENTAL DETERMINANTS OF WING POLYMORPHISM IN THE WATERSTRIDER LIMNOPORUS CANALICULATUS. PMID- 28563313 TI - ROLE OF CONSTITUTIVE HETEROCHROMATIN IN EVOLUTIONARY DIVERGENCE: RESULTS OF CHROMOSOME BANDING AND CONDENSATION INHIBITION STUDIES IN MUS MUSCULUS, MUS BOODUGA AND MUS DUNNI. PMID- 28563314 TI - INTRASPECIFIC GENETIC VARIATION AND HAPLODIPLOIDY, EUSOCIALITY, AND POLYGYNY IN THE HYMENOPTERA. PMID- 28563315 TI - QUANTITATIVE GENETIC RESPONSE TO ENVIRONMENTAL HETEROGENEITY IN TRIBOLIUM CONFUSUM. PMID- 28563316 TI - MULTILOCUS CLINES. PMID- 28563317 TI - AN IMMIGRATION-HYBRIDIZATION EPISODE IN PHLOX. PMID- 28563319 TI - THE GENETIC BASIS OF DIFFERENCES IN LIFE-HISTORY TRAITS AMONG SIX POPULATIONS OF MOSQUITOFISH (GAMBUSIA AFFINIS) THAT SHARED ANCESTORS IN 1905. PMID- 28563320 TI - In Memory. PMID- 28563318 TI - REPRODUCTIVE ISOLATION IN SONORAN DESERT DROSOPHILA. PMID- 28563321 TI - ALLOZYMIC AND MORPHOLOGICAL VARIATION IN POPULATION SAMPLES OF RUFOUS-COLLARED SPARROW, ZONOTRICHIA CAPENSIS, IN RELATION TO VOCAL DIALECTS. PMID- 28563322 TI - ETHOLOGICAL ISOLATION AND PHYLOGENY IN THE PLANITIBIA SUBGROUP OF HAWAIIAN DROSOPHILA. PMID- 28563323 TI - THE NATURE OF NICHE EXPANSION IN WEST INDIAN ANOLIS LIZARDS I: ECOLOGICAL CONSEQUENCES OF REDUCED COMPETITION. PMID- 28563324 TI - PARENTAL INVESTMENT AND OFFSPRING FITNESS IN THE TERRESTRIAL ISOPOD ARMADILLIDIUM VULGARE (LATR.) (CRUSTACEA: ONISCOIDEA). PMID- 28563325 TI - MATING-CALL STRUCTURE IN A HYBRID POPULATION OF THE Geocrinia laevis COMPLEX (ANURA:LEPTODACTYLIDAE) OVER A SEVEN-YEAR PERIOD. PMID- 28563326 TI - SYMPATRY OF PERIODICAL CICADA BROODS AND THE HYPOTHETICAL FOUR-YEAR ACCELERATION. PMID- 28563328 TI - PRESENCE OF THE HEREDITARY RHABDOVIRUS SIGMA AND POLYMORPHISM FOR A GENE FOR RESISTANCE TO THIS VIRUS IN NATURAL POPULATIONS OF DROSOPHILA MELANOGASTER. PMID- 28563327 TI - A POSSIBLE CASE OF MIMICRY IN LARGER MAMMALS. PMID- 28563329 TI - HYBRIDIZATION AND SPECIATION IN FOSSORIAL MOLE RATS. PMID- 28563330 TI - THE ECOLOGICAL CONTEXT OF FEMALE PATTERN POLYMORPHISM IN THE LIZARD ANOLIS SAGREI. PMID- 28563331 TI - THE EVOLUTIONARY STRATEGY OF THE EQUIDAE AND THE ORIGINS OF RUMEN AND CECAL DIGESTION. PMID- 28563332 TI - REPRODUCTIVE CHARACTER DISPLACEMENT IN THREESPINE STICKLEBACKS. PMID- 28563333 TI - CORRELATIONS BETWEEN SOME MEASURES OF GENETIC DISTANCE. PMID- 28563334 TI - FUNCTIONAL ASPECTS OF THE EVOLUTION OF FROG TONGUES. PMID- 28563335 TI - GENETIC AND BIOCHEMICAL CONSEQUENCES OF POLYPLOIDY IN TRAGOPOGON. PMID- 28563336 TI - RATES OF EVOLUTION IN CONIFERS (PINACEAE). PMID- 28563337 TI - GENETIC DIFFERENTIATION WITHIN THE ANDEAN SEMISPECIES OF DROSOPHILA PAULISTORUM. PMID- 28563338 TI - PATTERNS OF MATING IN NATURAL POPULATIONS OF XIPHOPHORUS (PISCES: POECILIIDAE). I: X. MACULATUS FROM BELIZE AND MEXICO. PMID- 28563339 TI - SOCIAL FACILITATION OF MALE SEXUAL BEHAVIOR, INTRASEXUAL COMPETITION, AND SEXUAL SELECTION IN THE GUPPY, POECILIA RETICULATA (PISCES: POECILIIDAE). PMID- 28563340 TI - ERRATUM. PMID- 28563343 TI - THE NATURE OF NICHE EXPANSION IN WEST INDIAN ANOLIS LIZARDS II: EVOLUTIONARY COMPONENTS. PMID- 28563342 TI - COLOR VARIATION AND BISEXUAL MUELLERIAN MIMICRY IN AN APOSEMATIC INSECT. PMID- 28563345 TI - EVOLUTION OF THE MERYCOIDODONT MASTICATORY APPARATUS (MAMMALIA, ARTIODACTYLA). PMID- 28563346 TI - FERTILITY AND FITNESS OF XO MALES IN DROSOPHILA. II. QUANTITATIVE ANALYSIS. PMID- 28563347 TI - WHY ARE BIRD-VISITED FLOWERS PREDOMINANTLY RED? PMID- 28563348 TI - FACTORS RESPONSIBLE FOR A CHANGE IN INTERSPECIFIC COMPETITIVE ABILITY IN DROSOPHILA. PMID- 28563350 TI - EVOLUTION OF MASTICATION IN THE ELEPHANTIDAE. PMID- 28563349 TI - A REVIEW OF SOME CURRENT CONCEPTS OF THE FUNCTIONAL EVOLUTION OF THE EAR IN TERRESTRIAL VERTEBRATES. PMID- 28563351 TI - CHROMOSOMAL POLYMORPHISM IN DROSOPHILA PSEUDOOBSCURA USED FOR DIAGNOSIS OF GEOGRAPHIC ORIGIN. PMID- 28563352 TI - FLAVERIA CAMPESTRIS (ASTERACEAE): A CASE OF POLYHAPLOIDY OR RELIC ANCESTRAL DIPLOIDY? PMID- 28563353 TI - ON THE BIOLOGICAL IMPROBABILITY OF ZAHNREIHEN AS EMBRYOLOGICAL UNITS. PMID- 28563354 TI - GENETIC VARIABILITY IN THE DEEP SEA: RELATION TO ENVIRONMENTAL VARIABILITY. PMID- 28563355 TI - PHYLETIC DIVERGENCE DATES OF HOMINOID PRIMATES. PMID- 28563356 TI - THE EFFECTS OF GENETIC BACKGROUND ON THE ECOLOGY OF SELECTION IN TRIBOLIUM POPULATIONS. PMID- 28563357 TI - CLIMATIC ADAPTATION AND PHOTOPERIODIC RESPONSE IN THE BAND-LEGGED GROUND CRICKET. PMID- 28563359 TI - GENETIC SIMILARITIES AND EVOLUTIONARY RELATIONSHIPS AMONG THE SEMISPECIES OF DROSOPHILA PAULISTORUM. PMID- 28563358 TI - GENETIC VARIABILITY AND SIMILARITY IN THE ANOLIS LIZARDS OF BIMINI. PMID- 28563360 TI - COMPETITION FOR POLLINATOR SERVICE: A STIMULUS FOR THE EVOLUTION OF AUTOGAMY. PMID- 28563361 TI - PATTERNS OF GEOGRAPHIC VARIATION IN KARYOTYPE IN THE POCKET GOPHER, THOMOMYS BOTTAE (EYDOUX AND GERVAIS). PMID- 28563362 TI - ERRATUM. PMID- 28563363 TI - MECHANICS AND THE EVOLUTION OF THE SYNAPSID JAW. PMID- 28563364 TI - THE ESTABLISHMENT OF CHROMOSOMAL VARIANTS. PMID- 28563365 TI - HETEROZYGOSITY AND GENETIC DISTANCE IN SIBLING SPECIES OF MEAT ANTS (IRIDOMYRMEX PURPUREUS GROUP). PMID- 28563366 TI - Society for the Study of Evolution and American Society of Naturalists. PMID- 28563367 TI - PARENTAL EFFORT AND THE EVOLUTION OF NEST-GUARDING TACTICS IN THE THREESPINE STICKLEBACK, GASTEROSTEUS ACULEATUS L. PMID- 28563368 TI - SEXUALLY DIMORPHIC RESPONSE TO HOST HABITAT TOXICITY IN DROSOPHILA PARASITIC WASPS. PMID- 28563369 TI - GENETIC VARIABILITY AND DIVERGENCE IN CAVE POPULATIONS OF TROGLOPHILUS CAVICOLA AND T. ANDREINII (ORTHOPTERA, RHAPHIDOPHORIDAE). PMID- 28563370 TI - EVOLUTION OF VOMERONASAL ORGANS IN VERTEBRATES. PMID- 28563371 TI - MULTIPLE MATING AND THE "SEX-RATIO" TRAIT IN DROSOPHILA PSEUDOOBSCURA. PMID- 28563372 TI - HIERARCHICAL PATTERNS OF CHROMOSOME VARIATION IN DROSOPHILA SUBOBSCURA. PMID- 28563373 TI - GENETIC STRUCTURE OF TWO SPECIES OF WATERSTRIDERS (GERRIDAE: HEMIPTERA) WITH DIFFERING DEGREES OF WINGLESSNESS. PMID- 28563374 TI - TAILSPOTS OF XIPHOPHORUS AND THE EVOLUTION OF CONSPICUOUS POLYMORPHISM. PMID- 28563375 TI - ORIGIN AND EVOLUTION OF ETHOLOGICAL ISOLATION IN SUBTERRANEAN MOLE RATS. PMID- 28563376 TI - POLLINATOR CHOICE AND STABILIZING SELECTION FOR FLOWER COLOR IN DELPHINIUM NELSONII. PMID- 28563377 TI - GENETIC INTERACTIONS BETWEEN HYBRIDIZING CYTOTYPES OF THE TENT-MAKING BAT (URODERMA BILOBATUM). PMID- 28563378 TI - GENETIC DIFFERENTIATION ALONG HOST PLANT LINES IN THE SYMPATRIC ENCHENOPA BINOTATA SAY COMPLEX (HOMOPTERA: MEMBRACIDAE). PMID- 28563379 TI - AN ANALYSIS OF A MORPH RATIO CLINE IN THE BANANAQUIT (COEREBA FLAVEOLA) ON GRENADA, WEST INDIES. PMID- 28563380 TI - GENE FLOW IN HOUSE MICE: INTRODUCTION OF A NEW ALLELE INTO FREE-LIVING POPULATIONS. PMID- 28563381 TI - UNPALATABILITY AS A DEFENSE STRATEGY OF WESTERN CHECKERSPOT BUTTERFLIES (EUPHYDRYAS SCUDDER, NYMPHALIDAE). PMID- 28563382 TI - CHROMOSOME FLOW BETWEEN CHROMOSOMALLY CHARACTERIZED TAXA OF A VOLANT MAMMAL, URODERMA BILOBATUM (CHIROPTERA: PHYLLOSTOMATIDAE). PMID- 28563383 TI - SEX RATIO OF RUMEX HASTATULUS: THE EFFECT OF ENVIRONMENTAL FACTORS AND CERTATION. PMID- 28563384 TI - EVOLUTIONARY TREES FROM GENE FREQUENCIES AND QUANTITATIVE CHARACTERS: FINDING MAXIMUM LIKELIHOOD ESTIMATES. PMID- 28563385 TI - GENETIC COMPONENTS OF SIZE AND SHAPE. II. MULTIVARIATE COVARIANCE PATTERNS IN THE RAT AND MOUSE SKULL. PMID- 28563386 TI - EFFECT OF SIZE UPON MATING PERFORMANCE WITHIN GEOGRAPHIC STRAINS OF THE HOUSEFLY, MUSCA DOMESTICA L. PMID- 28563387 TI - SEX RATIO COMPENSATION IN ANT POPULATIONS. PMID- 28563389 TI - STUDIES ON THE POPULATION BIOLOGY OF THE GENUS VIOLA. II. THE EFFECT OF PLANT SIZE ON FITNESS IN VIOLA SORORIA. PMID- 28563390 TI - EVOLUTION OF HISTOCOMPATIBILITY DIVERSITY IN AN ASEXUAL VERTEBRATE, POECILIOPSIS 2 MONACHA-LUCIDA (PISCES: POECILIIDAE). PMID- 28563391 TI - SANTA ROSALIA RECONSIDERED: SIZE RATIOS AND COMPETITION. PMID- 28563393 TI - "SCIENTIFIC CREATIONISM" BILL IN LOUISIANA BEGAT A FEUD AND A LAWSUIT. PMID- 28563392 TI - GENES AFFECTING COURTSHIP SONG AND MATING PREFERENCE IN DROSOPHILA MELANOGASTER, DROSOPHILA SIMULANS AND THEIR HYBRIDS. PMID- 28563394 TI - Society for the Study of Evolution and American Society of Naturalists 1982 Meetings. PMID- 28563395 TI - REPRODUCTIVE ISOLATION IN RELATION TO ALLOZYMIC AND CHROMOSOMAL DIFFERENTIATION IN THE GRASSHOPPER CALEDIA CAPTIVA. PMID- 28563396 TI - BASIS FOR A SKEWED SEX RATIO IN DIAPAUSE-DESTINED FLESH FLIES. PMID- 28563397 TI - EXPERIMENTAL ECOLOGICAL GENETICS IN PLANTAGO. V. COMPONENTS OF SEED YIELD IN THE RIBWORT PLANTAIN PLANTAGO LANCEOLATA L. PMID- 28563398 TI - PRE-PARTUM REPRODUCTIVE CHARACTERISTICS OF EUTHERIAN MAMMALS. PMID- 28563399 TI - TEMPORAL VARIATION OF GENDER IN ARALIA HISPIDA VENT. (ARALIACEAE). PMID- 28563400 TI - GENETIC VARIABILITY IN REPRODUCTION RATES IN MARINE PHYTOPLANKTON POPULATIONS. PMID- 28563401 TI - USING FREQUENCY DISTRIBUTIONS TO DETECT SELECTION: INVERSION POLYMORPHISMS IN DROSOPHILA PSEUDOOBSCURA. PMID- 28563402 TI - THE GENETIC BASIS OF MICRODIFFERENTIATION IN NATURAL AND EXPERIMENTAL POPULATIONS OF BORRICHIA FRUTESCENS IN RELATION TO SALINITY. PMID- 28563403 TI - DOES HIGH FECUNDITY REDUCE SURVIVAL IN SONG SPARROWS? PMID- 28563404 TI - SEX RATIO AND PARENTAL INVESTMENT IN AN ANT POPULATION. PMID- 28563405 TI - POPULATION GENETICS OF TIGRIOPUS CALIFORNICUS. II. DIFFERENTIATION AMONG NEIGHBORING POPULATIONS. PMID- 28563406 TI - A TEST OF THE CHITTY HYPOTHESIS: INHERITANCE OF LIFE-HISTORY TRAITS IN MEADOW VOLES MICROTUS PENNSYLVANICUS. AB - The Chitty hypothesis proposes that the demographic changes occurring in microtine cycles are mediated by natural selection operating on the genetic composition of the population. Implicit in this hypothesis is the assumption that a suite of life-history traits is simultaneously undergoing selection and that these traits are strongly heritable. We tested this in two ways: first, by determining whether the year-to-year differences in phenotypes in fluctuating meadow vole populations in the field are maintained in samples of young animals raised in the laboratory, and second, whether the variation seen in the field has a heritable basis as determined by half-sib analysis. Parents were obtained in the springs of successive years from a fluctuating meadow vole population. These animals were bred in small field enclosures, and their progeny were raised in the laboratory. Animals raised in the laboratory differed significantly from those in the natural field population. In the field, young from the year when population size was increasing grew more rapidly than those from the peak year; in the laboratory, the opposite occurred. The ages at sexual maturity showed similar differences. Heritability analysis was performed on body weight, growth rate, and age and weight at sexual maturity. Virtually all these traits showed significant dam effects, but small or nonexistant sire effects. Thus, most of the variation was nongenetic in origin; maternal and other environmental effects were of overriding importance. We conclude that the heritabilities of these traits in nature are usually lower than necessary for natural selection to operate in the time frames characteristic of microtine cycles. PMID- 28563407 TI - PHYLOGENETIC STUDIES OF COADAPTATION: PREFERRED TEMPERATURES VERSUS OPTIMAL PERFORMANCE TEMPERATURES OF LIZARDS. AB - The view that behavior and physiological performance are tightly coadapted is a central principle of physiological ecology. Here, we test this principle using a comparative study of evolutionary patterns in thermal preferences and the thermal dependence of sprinting in some Australian skinks (Lygosominae). Thermal preferences (Tp ) differ strikingly among genera (range 24 degrees to 35 degrees C), but critical thermal maxima (CTMax) (range 38 degrees to 45 degrees C) and optimal temperatures for sprinting (To , 32 degrees to 35 degrees C) vary less. Diurnal genera have relatively high Tp , To , and CTMax. In contrast, nocturnal genera have low Tp but have moderate to high To and CTMax. Both nonphylogenetic and phylogenetic (minimum-evolution) approaches suggest that coadaptation is tight only for genera with high Tp . Phylogenetic analyses suggest that low Tp and, thus, partial coadaptation are evolutionarily derived, indicating that low thermal preferences can evolve, even if this results in reduced performance. In one instance, thermal preferences and the thermal dependence of sprinting may have evolved in opposite directions, a phenomenon we call "antagonistic coadaptation." We speculate on factors driving partial coadaptation and antagonistic coadaptation in these skinks. PMID- 28563408 TI - GENETIC CONSEQUENCES OF OUTCROSSING IN THE CLEISTOGAMOUS ANNUAL, IMPATIENS CAPENSIS. I. POPULATION-GENETIC STRUCTURE. AB - We examined the genetic structure of 11 populations of Impatiens capensis, a cleistogamous annual herb, using starch gel electrophoresis. We sampled both cleistogamous (CL) and chasmogamous (CH) progeny (if present) from maternal parents in each population to infer maternal genotypes and to estimate the extent and pattern of inbreeding within and among populations. Only eight of 31 loci were polymorphic, with one to six (mean = 3.1) loci varying within each population. Mean heterozygosity per individual is quite low (mean = 3.9%) and comparable to highly self-fertilized species. Gene flow is low, and genetic distances do not parallel geographical distances, suggesting a population structure similar to Wright's Island model with drift among the populations. Fixation indexes within populations (f or FIS ) span the largest range yet reported for a plant species (0.26 to 0.94, mean = 0.57). Further inbreeding results from population substructuring (theta^ or FST=0.46), resulting in a total average inbreeding coefficient (F or FIT ) of 0.77. Despite these high overall levels of inbreeding, chasmogamy significantly reduces fixation, which may account for the observed greater fitness of CH progeny. PMID- 28563409 TI - EFFECT OF CANNIBALISM ON ALTERNATIVE LIFE HISTORIES IN CHARR. PMID- 28563410 TI - FIFTY YEARS OF INTERSPECIFIC HYBRIDIZATION: GENETICS AND MORPHOMETRICS OF A CONTROLLED EXPERIMENT ON THE LAND SNAIL CERION IN THE FLORIDA KEYS. AB - An unusually well documented case of secondary hybridization and introgression involving two morphologically dissimilar species of land snails is described. In 1915, 55 Bahamian Cerion casablancae were established on Bahia Honda Key, Florida. The introduced snails thrived, bred true to form, and the colony grew until about 1928 when it began to hybridize with C. incanum, the unrelated Florida species. In 1977, morphological hybrids occupied an area of about 3.5 ha. Spatial and temporal aspects of the interaction were characterized morphologically (18 shell characters were studied in source populations, founders, and hybrids sampled in 1933 and 1977) and genetically (variation at 17 allozyme loci in relevant populations sampled in 1977). In addition, special circumstances permitted us to discern the genetics of the founders: C. incanum is isogenic locally, C. casablancae is variable (Po = 0.29-0.35), and the two species are well-differentiated (Nei's D = 0.27). Hybrid intermediacy of form and continued enhanced variation appeared in characters from three covariance sets, while some unique hybrid morphologies resulted from characters in a fourth set. Comparison of 1933 with 1977 samples showed that the hybrids are gradually approaching C. incanum in phenotype. Regardless of phenotype, the snails on Bahia Honda Key were panmictic and outbreeding. There was no evidence for strong selection against hybrids, and by 1977 introduced alleles had spread over 5 ha. However, no pure C. casablancae remain; low (m = 0.026/generation) but persistent gene flow has brought about a 30% diminution of the introduced genome. These observations are useful in interpreting Cerion's remarkable variability as colonization following hurricane dispersal has undoubtedly played a role in the group's complex evolution. More generally, the results are relevant to the problem of interpreting hybrid zones of unknown origin, and the differences in the generally concordant patterns of morphological and genetic introgression reveal constraints on the way components of different coadapted genomes interact. PMID- 28563411 TI - THE HERITABLE BASIS OF VARIATION IN LARVAL DEVELOPMENTAL PATTERNS WITHIN POPULATIONS OF THE WOOD FROG (RANA SYLVATICA). AB - This study compares the heritable basis of variation in larval developmental patterns of mountain and lowland populations of the wood frog, Rana sylvatica. Additive genetic variances, heritabilities, and genetic correlations for larval developmental time and size at metamorphosis are estimated from half-sib and full sib crosses. Considerable additive-genetic variances and high heritabilities are revealed for developmental time in both the mountain and the lowland population. There was a high level of additive-genetic variance and high heritability for body size at metamorphosis in the mountain population, but these were very low in the lowland population. The genetic correlations between developmental rate and larval body size are negative for the mountain population and near zero for the lowland population. It is argued that the differences in genetic structure between these two populations reflect differences in the selective regimes of their respective environments. PMID- 28563412 TI - REPEATABILITY OF LOCOMOTOR PERFORMANCE IN NATURAL POPULATIONS OF THE LIZARD SCELOPORUS MERRIAMI. PMID- 28563413 TI - RANDOM-FRAGMENT HYBRIDIZATION ANALYSIS OF EVOLUTION IN THE GENUS NEUROSPORA: THE STATUS OF FOUR-SPORED STRAINS. AB - A random-fragment hybridization method employing nuclear DNA has been developed to explore phylogenetic relationships in the genus Neurospora. Four cloned fragments and repetitive rDNA sequences were examined for restriction-fragment polymorphisms among 14 strains representing four species. The findings demonstrate that variation among randomly selected nuclear fragments can be employed to group related taxa with a higher degree of resolution than has been obtained with other DNA hybridization methods, isozyme electrophoresis, or restriction analysis of repetitive DNA. Based on our analysis of cloned fragments, we conclude that four-spored, secondarily-homothallic strains collected worldwide represent a monophyletic group. Trees constructed on the basis of restriction-fragment cataloging and coarse-structure restriction-site maps are for the most part consistent with the present mating-based species concept. We are encouraged that this method will provide an additional important experimental tool for evolutionary studies. PMID- 28563414 TI - COMMUNITY COEVOLUTION: A COMMENT. PMID- 28563415 TI - AGGRESSION, DENSITY, AND SEXUAL DIMORPHISM IN CHERNETID PSEUDOSCORPIONS (ARACHNIDA: PSEUDOSCORPIONIDA). AB - The determinants of sexual dimorphism in a family of false scorpions (Pseudoscorpionida: Chernetidae) were investigated experimentally and with a literature analysis of comparative morphometric and habitat data. Species vary in the extent to which males and females differ in size of the pedipalps, and, in particular, in size of the pedipalpal chelae. A statistical analysis of dimorphism patterns within the Chernetidae suggests that dimorphism is a highly variable condition, relatively unconstrained by phylogenetic influences. The evolution of species with enlarged male pedipalps appears to be associated with a change from nonpairing to pairing sperm-transfer behavior and with aggressive mate acquisition by males. Experiments with Dinocheirus arizonensis demonstrate a strong correlation between male combat ability and chela size. Manipulations also suggest that superior combat ability of large males results in increased mating success only under high-density conditions. The greater success in spermatophore transfer among large males can be attributed to increased opportunity at high density for large males to interrupt matings and aggressively displace smaller males. Comparative analysis showed a positive correlation between density and enlarged male chela size across chernetid species. PMID- 28563416 TI - GEOGRAPHIC POPULATION STRUCTURE AND SPECIES DIFFERENCES IN MITOCHONDRIAL DNA OF MOUTHBROODING MARINE CATFISHES (ARIIDAE) AND DEMERSAL SPAWNING TOADFISHES (BATRACHOIDIDAE). AB - Restriction-fragment length polymorphisms in mitochondrial DNA (mtDNA) were used to evaluate population-genetic structure and matriarchal phylogeny in four species of marine fishes that lack a pelagic larval stage: the catfishes Arius felis and Bagre marinus, and the toadfishes Opsanus tau and O. beta. Thirteen informative restriction enzymes were used to assay mtDNAs from 134 specimens collected from Massachusetts to Louisiana. Considerable genotypic diversity was observed in each species. However, major mtDNA phylogenetic assemblages in catfish and toadfish (as identified in Wagner networks and UPGMA phenograms) exhibited contrasting patterns of geographic distribution: in catfish, distinct mtDNA clades were widespread, while such clades in toadfish tended to be geographically localized. By both the criteria of species' ranges and the geographic pattern of intraspecific mtDNA phylogeny, populations of marine catfish in the western Atlantic have had greater historical interconnectedness than have toadfish. Results are also compared to previously published mtDNA data in freshwater and other marine fishes. Although mtDNA differentiation among conspecific populations of continuously distributed marine fishes is usually lower than that among discontinuously distributed freshwater species inhabiting separate drainages, it is apparent that historical biogeographic factors can importantly influence genetic structure in marine as well as freshwater species. PMID- 28563417 TI - TRANSMISSION RATES AND THE EVOLUTION OF PATHOGENICITY. PMID- 28563418 TI - ALTRUISM IN MENDELIAN POPULATIONS DERIVED FROM SIBLING GROUPS: THE HAYSTACK MODEL REVISITED. AB - A group-selection model is presented in which each group is initiated by a single fertilized female and persists for several generations before dispersal. Maynard Smith (1964) concluded that altruism could not plausibly evolve under these circumstances. I show that his conclusion is an artifact of a simplifying assumption that amounts to a worst-case scenario for group selection. When the standard donor-recipient equations for altruistic behavior are used in Maynard Smith's model, Mendelian populations derived from sibling groups are often more favorable for the evolution of altruism than are the sibling groups themselves. In general, long-term and large-scale aspects of population structure may at times be important in the evolution of altruistic and other group-advantageous behaviors. PMID- 28563419 TI - THE EFFECT OF INVESTMENT IN ATTRACTIVE STRUCTURES ON ALLOCATION TO MALE AND FEMALE FUNCTIONS IN PLANTS. AB - Expressions for male and female fitnesses of partially self-fertilizing cosexual plants are derived, assuming that allocation to pollinator attraction at the time of flowering may decrease resources available for male and female primary structures. The total female fertility is assumed to be controlled by factors at two stages, flowering-time and fruiting-time, with resources for fruit maturation being limited so that maximum seed production may be limited by the availability of these resources. The fitness formulas are used to calculate ESS (evolutionarily stable strategy) allocations at flowering time to primary male and female sex functions and to attractive structures. These are compared with some data that are available for dry weights of different flower parts. The fitnesses of unisexual mutant forms are calculated, assuming that they are introduced into a population consisting mostly of the initial cosexual form and that they obey the same gain curves as that form. When compared with the fitness of the ESS cosexual form, this enables one to ask whether unisexual forms will be favored. We show that the spread of females is unlikely, unless there is high inbreeding depression and a rather high selfing rate, and that in some circumstances a linear relation between number of fertilized ovules and number of seeds matured can be less favorable for the invasion of females than is a highly concave relation. With a nearly linear relation between numbers of fertilized ovules and mature seeds, invasion by females is more likely when investment in attraction is low than when it is high. These effects are discussed in relation to the distribution of dioecy. The spread of male mutants is never likely in these models. PMID- 28563420 TI - COMPARATIVE BIOCHEMICAL GENETICS OF THREE FIRE ANT SPECIES IN NORTH AMERICA, WITH SPECIAL REFERENCE TO THE TWO SOCIAL FORMS OF SOLENOPSIS INVICTA (HYMENOPTERA: FORMICIDAE). AB - An electrophoretic study of the genetics of three fire ant species in North America was undertaken with the primary objective of further clarifying the genetic relationship between two social forms of Solenopsis invicta. Such social forms are common in many groups of ants and may, in some cases, represent significant intermediate stages in the speciation process. The monogyne and polygyne forms of S. invicta, while differing in a number of important biological traits, are genetically indistinguishable, in contrast to the substantial genetic differentiation observed between S. invicta and a second, closely related, introduced species, S. richteri. The native fire ant, S. geminata, is genetically the most distinct of the three species studied, in accord with its taxonomic placement in a different species complex. Hypotheses concerning the derivation of the polygyne form of S. invicta from the monogyne form which invoke their long term reproductive isolation in South America and separate introductions to North America appear unfounded. Although S. invicta and S. richteri are known to hybridize in North America, our study provided no evidence of gene introgression between S. invicta and the native species, S. geminata, in areas where our samples were collected. Analyses of population structure in S. invicta failed to reveal significant differentiation of populations or local inbreeding. Levels of genetic diversity in the three species studied, although not significantly different, were in the order predicted from knowledge of the population biology and recent history of the taxa, with S. richteri exhibiting the least diversity, S. geminata the greatest, and S. invicta having an intermediate level. PMID- 28563421 TI - THE FREQUENCY OF LETHAL ALLELES IN FOREST TREE POPULATIONS. PMID- 28563422 TI - THE DISPERSAL BARRIER IN THE TROPICAL PACIFIC: IMPLICATIONS FOR MOLLUSCAN SPECIATION AND EXTINCTION. AB - Stretches of deep ocean constitute barriers to the dispersal of many shallow water marine species in the tropical Pacific. The purpose of this study was to assess the selectivity of these barriers with respect to the habitat characteristics, adult size, and predation-related shell architecture of gastropods, and to explore the implications of this selectivity for macroevolutionary patterns of extinction and speciation. The dispersal barrier between continental islands (represented in my collections by species from eastern Indonesia, the southern Philippines, and the north coast of New Guinea) and the nearby oceanic Palau Islands was studied by evaluating the percentage of each architectural and habitat category that is present on the continental islands but missing in Palau. The barrier is significantly more effective against sand-dwelling species than against rock-dwellers, and among rock-dwellers it is most effective against aperturally unarmored taxa. Barriers between Palau and Guam, Guam and the Hawaiian Islands, and the Line Islands and the tropical Eastern Pacific are generally unselective with respect to substratum type and architecture. The fact that narrow-apertured species are less affected by the barrier between the continental islands and Palau than are other rock-dwelling gastropods is consistent with the interpretation that this group has been unusually resistant to extinction and highly susceptible to founder speciation when oceanic circulation is altered. These patterns of susceptibility and geographical distribution may explain why armored gastropods have increased in numbers relative to unarmored ones in the tropical Pacific during the Cenozoic. PMID- 28563423 TI - MALE MATING DISCRIMINATION IN DROSOPHILA MELANOGASTER, D. SIMULANS AND THEIR HYBRIDS. PMID- 28563424 TI - EVOLUTIONARY GENETICS OF A GYNOGENETIC FISH, POECILIA FORMOSA, THE AMAZON MOLLY. PMID- 28563425 TI - VARIATION IN PHOTOPERIODIC RESPONSE WITHIN AND AMONG SPECIES OF MILKWEED BUGS (ONCOPELTUS). PMID- 28563426 TI - SEXUAL DIMORPHISM, SEXUAL SELECTION, AND ADAPTATION IN POLYGENIC CHARACTERS. PMID- 28563427 TI - GENETIC RELATIONSHIPS OF THE COLOR MORPHS OF THE SERRANID FISH HYPOPLECTRUS UNICOLOR. PMID- 28563428 TI - HOST ABUNDANCE, JUVENILE SURVIVAL, AND OVIPOSITION PREFERENCE IN BATTUS PHILENOR. PMID- 28563429 TI - CLUTCH SIZE, BREEDING SUCCESS, AND PARENTAL SURVIVAL IN THE TREE SWALLOW (IRIDOPROCNE BICOLOR). PMID- 28563430 TI - THE ZOOGEOGRAPHY OF SPECIALIZED CAVE ANIMALS: A BIOCLIMATIC MODEL. PMID- 28563431 TI - THE APPORTIONMENT OF GENETIC VARIATION WITHIN AND AMONG POPULATIONS OF DESMODIUM NUDIFLORUM. PMID- 28563432 TI - EVOLUTION OF AN ENZYME SYSTEM: ASCORBIC ACID BIOSYNTHESIS IN MONOTREMES AND MARSUPIALS. PMID- 28563433 TI - INTERSPECIFIC COMPETITION, ISLAND BIOGEOGRAPHY AND NULL HYPOTHESES. PMID- 28563434 TI - REPRODUCTIVE STRATEGIES IN THE SURFPERCHES. I. MULTIPLE INSEMINATION IN NATURAL POPULATIONS OF THE SHINER PERCH, CYMATOGASTER AGGREGATA. PMID- 28563435 TI - BRAIN STRUCTURE IN CHIROPTERA: SOME MULTIVARIATE TRENDS. PMID- 28563436 TI - POPULATION GENETICS OF DROSOPHILA AMYLASE III. INTERSPECIFIC VARIATION. PMID- 28563437 TI - SEX RATIO IN THE SAILFIN MOLLY, POECILIA LATIPINNA. PMID- 28563438 TI - ALBUMIN EVOLUTION IN MARSUPIAL FROGS (HYLIDAE: GASTROTHECA). PMID- 28563439 TI - A COMMENT ON "MATE RECOGNITION SYSTEMS". PMID- 28563440 TI - TROPHIC DIFFERENTIATION IN ILYODON, A GENUS OF STREAM-DWELLING GOODEID FISHES: SPECIATION VERSUS ECOLOGICAL POLYMORPHISM. PMID- 28563442 TI - Joint Meeting of The Society for the Study of Evolution and American Society of Naturalists Tucson, Arizona June 29-July 2, 1980. PMID- 28563441 TI - VARIATION IN BODY SIZE AND FLIGHT PERFORMANCE IN MILKWEED BUGS (ONCOPELTUS). PMID- 28563443 TI - COADAPTATION AND TAXONOMIC DIFFERENTIATION OF SPERM AND SPERMATHECAE IN FEATHERWING BEETLES. PMID- 28563444 TI - VARIATION IN HIGHLY AND LOWLY HERITABLE MORPHOLOGICAL TRAITS AMONG SOCIAL GROUPS OF RHESUS MACAQUES (MACACA MULATTA) ON CAYO SANTIAGO. PMID- 28563445 TI - SONG DIALECTS AS BARRIERS TO DISPERSAL: A RE-EVALUATION. PMID- 28563446 TI - MULTIGENIC RESPONSE TO ETHANOL IN DROSOPHILA MELANOGASTER. PMID- 28563447 TI - SKEPTICISM TOWARDS SANTA ROSALIA, OR WHY ARE THERE SO FEW KINDS OF ANIMALS? PMID- 28563449 TI - MORPHOLOGICAL SHIFTS OF SOME ISOLATED POPULATIONS OF EUTAMIAS (RODENTIA: SCIURIDAE) IN DIFFERENT CONGENERIC ASSEMBLAGES. PMID- 28563448 TI - INFLUENCE OF ENVIRONMENT ON THE FLORAL SEX RATIO OF MONOECIOUS PLANTS. PMID- 28563450 TI - THE SOCIETY FOR THE STUDY OF EVOLUTION. PMID- 28563451 TI - GEOGRAPHICAL VARIATION IN THE REPRODUCTIVE CYCLE AND PHOTOPERIODIC DIAPAUSE OF DROSOPHILA PHALERATA AND D. TRANSVERSA (DROSOPHILIDAE:DIPTERA). PMID- 28563452 TI - Society for the Study of Evolution and American Society of Naturalists 1981 Meetings. PMID- 28563453 TI - ADAPTIVE CHANGES IN ANTIPREDATOR BEHAVIOR OF A GRASSHOPPER DURING DEVELOPMENT. PMID- 28563454 TI - FEMALE DRY WEIGHT AND FEMALE CHOICE IN CHAULIOGNATHUS PENNSYLVANICUS. PMID- 28563455 TI - A COMPARISON OF DROSOPHILA HABITATS ACCORDING TO THE PHYSIOLOGICAL ATTRIBUTES OF THE ASSOCIATED YEAST COMMUNITIES. PMID- 28563457 TI - Important Notice. PMID- 28563456 TI - EVOLUTIONARY HISTORY OF DROSOPHILA BUZZATII. I. NATURAL CHROMOSOMAL POLYMORPHISM IN COLONIZED POPULATIONS OF THE OLD WORLD. PMID- 28563458 TI - SEROTINY, GEOGRAPHY, AND FIRE IN THE PINE BARRENS OF NEW JERSEY. PMID- 28563459 TI - GAMETIC DISEQUILIBRIUM BETWEEN ESTERASE LOCI IN POPULATIONS OF CEPAEA NEMORALIS IN WESTERN NEW YORK. PMID- 28563460 TI - STUDIES OF ESTERASE 6 IN DROSOPHILA MELANOGASTER. V. PROGENY PRODUCTION AND SPERM USE IN FEMALES INSEMINATED BY MALES HAVING ACTIVE OR NULL ALLELES. PMID- 28563461 TI - SPECIES NUMBER, GENERATION LENGTH, AND THE MOLECULAR CLOCK. PMID- 28563462 TI - LATERAL PLATE POLYMORPHISM AND ONTOGENY OF THE COMPLETE PLATE MORPH OF THREESPINE STICKLEBACKS (GASTEROSTEUS ACULEATUS). PMID- 28563463 TI - CONVERGENCE AND PARALLELISM IN FOOT MORPHOLOGY IN THE NEOTROPICAL SALAMANDER GENUS BOLITOGLOSSA. I. FUNCTION. PMID- 28563464 TI - RESPONSE TO "SONG DIALECTS AS BARRIERS TO DISPERSAL: A RE-EVALUATION". PMID- 28563465 TI - SELECTION COMPONENTS OF FOUR ALLOZYMES IN NATURAL POPULATIONS OF PEROMYSCUS MANICULATUS. PMID- 28563466 TI - EVOLUTION SOCIETY NEWS. PMID- 28563467 TI - FECUNDITY IN POPULATIONS OF OXALIS ALPINA IN SOUTHEASTERN ARIZONA. PMID- 28563468 TI - In Memory. PMID- 28563469 TI - ALLOZYME LINKAGE DISEQUILIBRIA AMONG CHROMOSOME COMPLEXES IN THE PERMANENT TRANSLOCATION HETEROZYGOTE OENOTHERA BIENNIS. PMID- 28563470 TI - EVOLUTION OF SEX RATIOS IN THE ISOPOD, VENEZILLO EVERGLADENSIS. PMID- 28563471 TI - THE EVOLUTION OF INFLORESCENCE SIZE IN ASCLEPIAS (ASCLEPIADACEAE). PMID- 28563472 TI - GENETIC ANALYSIS OF THE MORPHOLOGICAL DIFFERENCES BETWEEN TWO INTERFERTILE SPECIES OF HAWAIIAN DROSOPHILA. PMID- 28563473 TI - ADAPTIVE FLEXIBILITY OF "MARGINAL" VERSUS "CENTRAL" POPULATIONS OF DROSOPHILA WILLISTONI. PMID- 28563474 TI - EVOLUTION OF DORMANCY AND ITS PHOTOPERIODIC CONTROL IN PITCHER-PLANT MOSQUITOES. PMID- 28563475 TI - SELECTION INTENSITY IN NORTH AMERICAN HOUSE SPARROWS (PASSER DOMESTICUS). PMID- 28563476 TI - EVOLUTIONARY DIVERGENCE BETWEEN TWO POPULATIONS OF DROSOPHILA PSEUDOOBSCURA. PMID- 28563477 TI - COMMUNAL CARE AND KIDNAPPING OF YOUNG BY PARENTAL CICHLIDS. PMID- 28563478 TI - BERGMANN'S RULE AND VARIATION IN STRUCTURES RELATED TO FEEDING IN THE GRAY SQUIRREL. PMID- 28563479 TI - ERRATA. PMID- 28563480 TI - FREQUENCY-DEPENDENT CHOICE, MINORITY ADVANTAGES, AND FREQUENCY-DEPENDENT NATURAL SELECTION. PMID- 28563481 TI - DO INTERTIDAL SNAILS SPAWN IN THE RIGHT PLACES? PMID- 28563482 TI - INBREEDING EFFECTS UPON ANIMALS DERIVED FROM A WILD POPULATION OF MUS MUSCULUS. PMID- 28563483 TI - VARIABILITY AND EVOLUTIONARY RATES OF CHARACTERS. PMID- 28563484 TI - MORPHOMETRIC ADAPTATION OF THE HOUSEFLY, MUSCA DOMESTICA L., IN THE UNITED STATES. PMID- 28563485 TI - CANARY ISLAND BLUE TITS AND ENGLISH COAL TITS: CONVERGENT EVOLUTION? PMID- 28563486 TI - THE ORGANIZATION OF GENETIC VARIABILITY IN PHLOX DRUMMONDII. PMID- 28563487 TI - MAINTENANCE OF POLYMORPHISM IN AN ISLAND POPULATION OF THE CALIFORNIA VOLE, MICROTUS CALIFORNICUS. PMID- 28563488 TI - ANALYSIS OF HEAD SHAPE DIFFERENCES BETWEEN TWO INTERFERTILE SPECIES OF HAWAIIAN DROSOPHILA. PMID- 28563489 TI - WHY 300 SPECIES OF HAWAIIAN DROSOPHILA? THE SEXUAL SELECTION HYPOTHESIS. PMID- 28563490 TI - COEVOLUTION OF PIERID BUTTERFLIES AND THEIR CRUCIFEROUS FOODPLANTS. II. THE DISTRIBUTION OF EGGS ON POTENTIAL FOODPLANTS. PMID- 28563491 TI - HIGH LEVELS OF GENETIC VARIABILITY IN THREE MALE-HAPLOID SPECIES (HYMENOPTERA: ARGIDAE, TENTHREDINIDAE). PMID- 28563492 TI - A MODEL FOR THE EVOLUTION OF ASYMMETRICAL MALE HYBRID STERILITY AND ITS IMPLICATIONS FOR SPECIATION. AB - Chromosomal analysis of several cases of asymmetrical male hybrid sterility in Drosophila has implicated the X- or the Y-chromosome and one or more autosomes. Here, I develop a model for the evolution of this phenomenon. An autosomal locus is assumed to affect viability and to interact with a Y-linked or an X-linked locus to determine male fertility. In a new environment, selection for viability favors a new allele at the autosomal locus, but incompatibility of this new allele with the sex-chromosome-linked gene generates male sterility. The incompatibility can be resolved if a new allele at the sex-linked locus invades the population. This results in nonreciprocal male hybrid sterility, the direction of the nonreciprocity being determined by the dominance or recessiveness of the new autosomal gene in its effect on fertility. It is shown that stable polymorphism for the autosomal locus is possible and that, if the equilibrium frequency of the new allele is above a critical value, the population will be constantly at the verge of speciation, "waiting" for the sex-linked mutation to occur. The appearance of this mutation causes a runaway process leading to rapid fixation of the new autosomal and sex-linked alleles. If the equilibrium frequency of the new autosomal allele is less than the critical value, deterministic speciation is impossible, but random drift may increase the frequency above the critical value and predispose the population to the invasion of the new sex-linked allele. Thus, both deterministic and stochastic modes of speciation are possible. Because deterministic speciation requires large selection coefficients, which impose a severe genetic load on the population, and because stochastic speciation requires repeated population bottlenecks, it is concluded that relative to the number of successful speciation events there will be many more events of deme extinction. PMID- 28563493 TI - SOME MODELS FOR DEVELOPMENT, GROWTH, AND MORPHOMETRIC CORRELATION. AB - Genetic and phenotypic correlations between morphometric traits can be a direct consequence of shared developmental history and common systems of growth regulation. Correlation between traits, therefore, need not imply direct functional or adaptive constraints on those traits. Useful models of the developmental origins of correlations will consider mechanisms that can reduce initially high correlation of traits that arise from a single developmental precursor. Several models presented here predict such correlations for different modes of fission of a precursor. Timing of developmental events may also affect correlations and respond to selection on adult traits. The models may apply to development of the tetrapod limb bud, including variance and covariance induced by known developmental mutants. PMID- 28563494 TI - CONSTRAINTS ON CHEMICAL COEVOLUTION: WILD PARSNIPS AND THE PARSNIP WEBWORM. AB - The parsnip webworm (Depressaria pastinacella) and the wild parsnip (Pastinaca sativa) together represent a potentially "coevolved" system in that throughout their ranges the plant has relatively few other herbivores and the insect has virtually no other hosts. Individual wild parsnip plants within a central Illinois population vary in their content and composition of furanocoumarins, secondary compounds with insecticidal properties. Half-sib and parent-offspring regression estimates of the heritability of furanocoumarins demonstrate that this variation is genetically based. Wild parsnip plants also vary in their resistance to damage by the parsnip webworm, which feeds on flowers and developing seeds. In an experimental garden, seed production in the primary umbel ranged from 0 to 1,664 seeds among individuals, and mean seed production of half-sib families ranged from 3.7 seeds to 446.0 seeds. Approximately 75% of the variation in resistance among half-sib families to D. pastinacella was attributable to four furanocoumarin characteristics-resistance is positively related to the proportion of bergapten and the amount of sphondin in seeds, and negatively related to the amount of bergapten and the proportion of sphondin in leaves. Each of the four resistance factors had significant heritability. Thus, resistance in wild parsnip to the parsnip webworm is to a large extent chemically based and genetically controlled. Genetic correlations among fitness and resistance characters, however, tend to limit coevolutionary responses between herbivore and plant. In greenhouse plants protected from herbivory, several of the resistance factors have negative genetic correlations with potential seed production. Ostensibly, highly resistant plants in the absence of herbivory would be at a competitive disadvantage in the field. The selective impact of the herbivore is also limited in this population by a negative genetic correlation among resistance factors. Selection to increase one resistance factor (e.g., the proportion of bergapten in the seed) would at the same time decrease the amount of a second resistance factor (e.g., the amount of sphondin in the seed). The wild parsnip and the parsnip webworm, then, appear to have reached an evolutionary "stalemate" in the coevolutionary arms race. PMID- 28563495 TI - MEASURING THE COST OF REPRODUCTION: A COMMENT ON PAPERS BY BELL. PMID- 28563496 TI - CLINAL VARIATION ASSOCIATED WITH EDAPHIC ECOTONES IN HYBRID POPULATIONS OF GAILLARDIA PULCHELLA. AB - The variety pulchella of the outcrossing annual plant species Gaillardia pulchella consists of two edaphic races in central Texas which are divergent for one morphological and four electrophoretic characters. Reduced pollen stainability in F1 hybrids suggests the races are also divergent in chromosome structure. The recent proliferation of this species on roadsides and in pastures has led to hybridization between these races. An analysis of character variation in three hybrid populations revealed significant clinal variation associated with edaphic ecotones, and the width of these clines was found to vary among characters in a consistent pattern. It is argued that this pattern is the result of different characters experiencing different effective selection regimes, with narrower clines reflecting greater differentials in effective selection. Several mechanisms are discussed by which selection may impede the transgression of alleles across the ecotones in these populations. The results of this study are compared to the results of parallel studies on the autogamous annual species Avena barbata in California, and it is suggested that the difference between these two species in the width of clines separating edaphic ecotypes may be accounted for by their different breeding systems. PMID- 28563497 TI - THE GENETICS OF ASYMMETRICAL MALE STERILITY IN DROSOPHILA MOJAVENSIS AND DROSOPHILA ARIZONENSIS HYBRIDS: INTERACTIONS BETWEEN THE Y-CHROMOSOME AND AUTOSOMES. AB - Crosses between Drosophila mojavensis and D. arizonensis produce fertile females, but the males from the cross ? D. mojavensis * ? D. arizonensis are sterile. The chromosomal basis of sperm immotility was studied in these hybrids. Interspecific crossing-over was avoided by crossing hybrid males to pure-species females, and chromosomal identification in backcross progeny was possible by means of electrophoretic markers. The main findings are as follows. The Y-chromosome and two autosomes are involved in the determination of sperm motility. The other autosomes, with the exception of the sixth which was not tested, appear to have no effect. The effect of the D. arizonensis X-chromosome was not examined, but it is established that the D. mojavensis X-chromosome has no effect on sperm motility in males carrying the D. arizonensis Y-chromosome and any combination of autosomes. The Y-chromosome and the two autosomes interact with each other in a simple and predictable way, so that certain combinations of these chromosomes always produce motile sperm and others immotile sperm. Thus, asymmetrical male hybrid sterility may have a simple genetic basis. In contrast to ethological isolation, the genetic basis for this postmating isolating mechanism does not appear to vary among conspecific populations, an observation which suggests that postmating isolation antedates ethological isolation in these species. PMID- 28563498 TI - CONTINUING STUDIES ON THE SOUTH AMHERST DROSOPHILA MELANOGASTER NATURAL POPULATION DURING THE 1970'S AND 1980'S. AB - Continuing investigations on the South Amherst Drosophila melanogaster natural population following the significant decline and recovery of lethal (le) and semilethal (sle) frequencies in the late 1960's (Ives, 1970) show that the population has been remarkably stable although it contains MR (male recombination) and/or P DNA elements (Kidwell et al., 1977a; Green, 1980). A 13 year study affirms that the lethals present are nonrandomly distributed along the second chromosome and deficient on the right; they differ significantly in distribution from spontaneous (Ives, 1973) and delta-induced lethals (Minamori and Ito, 1971). Between 1970 and 1977, a total of 4,083 second chromosomes from the Markert subpopulation were analyzed; 28.9% of the chromosomes were lethal and 7.25% were semilethal in homozygous condition. Frequencies are similar for early summer and late fall collections although the rate of allelism among lethals is significantly higher in early summer than in late fall. For the large fall (1970 1979) Porch site population, 2,519 second chromosomes were analyzed; 29.5% were lethal and 8.0% were sublethal as homozygotes; the rate of allelism among lethals was 1.50%. At Hockanum, 1977-1983, lethal and semilethal frequencies were lower; the rate of allelism among lethals was 1.43%. The chromosome map distribution of lethals does not change between summer and late fall at Markert. The overall distributions of lethals at the Markert and Hockanum sites are similar. In tests for male recombination (MR) activity in the population over a 6-year period, a total of 0.47% recombinants were observed; these were uniformly distributed along the second chromosome. Comparisons are made with other long studied D. melanogaster populations. PMID- 28563499 TI - COEVOLUTION AND AVIAN BROOD PARASITISM: COWBIRD EGGS SHOW EVOLUTIONARY RESPONSE TO HOST DISCRIMINATION. AB - The Rufous Hornero (Furnarius rufus) is an important host of the brood parasitic Shiny Cowbird (Molothrus bonariensis) in Uruguay, but not in nearby Buenos Aires Province, Argentina. Eggs of the Shiny Cowbird are extremely variable in size, and horneros eject cowbird eggs with widths less than about 88% of the widths of their own eggs. Uruguayan cowbird eggs are, on average, 12% larger than those from Buenos Aires, a geographic pattern in egg size that corresponds to the pattern of successful host use. Uruguayan cowbird eggs are also wider per unit volume than eggs from Buenos Aires. Allometric analyses of egg width and volume indicate that this shape change is apparently an evolutionary response to selection exerted by the hornero. Such a response is absent in Buenos Aires because interactions between the cowbird and the hornero are probably of recent origin there. PMID- 28563500 TI - EFFECT OF NONRANDOM LEAF ORIENTATION ON REPRODUCTION IN LACTUCA SERRIOLA L. AB - The cauline leaves of an annual, Lactuca serriola L., are naturally oriented vertically with the lamina perpendicular to the east and west. Previous physiological data indicated that this nonrandom leaf orientation should reduce water loss without substantially reducing photosynthesis and could thus influence plant growth and reproduction (Werk and Ehleringer, 1984, 1985). The effect of leaf orientation on flower and seed production was tested experimentally using potted L. serriola grown outdoors. Leaves of half the plants were forced to remain approximately horizontal while the other plants were allowed to orient naturally. The plants with horizontal leaves lost water more rapidly than the plants with naturally oriented leaves. Above-ground weight, below-ground weight, seed weight, and the number of seeds per flower were not significantly affected by leaf orientation. Flower production was a linear function of plant size for both treatments with plants with natural leaf orientation having a significantly greater slope. These results indicate that the nonrandom leaf orientation observed in L. serriola is a morphological character which can enhance reproduction. PMID- 28563501 TI - VARIATION IN THE MATING SYSTEM OF EICHHORNIA PANICULATA (SPRENG.) SOLMS. (PONTEDERIACEAE). AB - A multilocus procedure was used to estimate outcrossing rates from allozyme data in nine populations of Eichhornia paniculata from NE Brazil and Jamaica. The populations were chosen to represent stages in a proposed model of the evolutionary breakdown of tristyly to semi-homostyly; they differed in morph structure (trimorphic, dimorphic, or monomorphic) and floral traits likely to influence the mating system. The interpopulation range in outcrossing rate, t, was 0.96-0.29. Two additional populations from Jamaica, composed exclusively of self-pollinating, semi-homostylous, mid-styled plants, were invariant at 21 isozyme loci, precluding estimates of outcrossing frequency. Trimorphic populations from Brazil had uniformly high outcrossing rates of 0.96-0.88. Values for the floral morphs within populations were not significantly different. A controlled pollination experiment, comparing the competitive ability of self and cross pollen using the Got-3 marker locus, provided evidence that the maintenance of high outcrossing rates in trimorphic populations results from the prepotency of cross pollen and/or the selective abortion of selfed zygotes. Morph-dependent variation in t was detected within a dimorphic population with the L morph outcrossing with a frequency of 0.76 in comparison with 0.36 in the M morph. The difference in the mating system of floral morphs results from modifications in position of short-level stamens in flowers of the M morph resulting in automatic self-pollination. The occurrence of E. paniculata populations composed exclusively of self-pollinating, mid-styled variants is thought to be associated with the spread of genes modifying stamen position. The high level of self fertilization demonstrated in the M morph would allow automatic selection of these genes, augmented by fertility assurance in the absence of specialized pollinators. PMID- 28563502 TI - GENETIC ANALYSIS OF A HYBRID ZONE BETWEEN THE FIRE-BELLIED TOADS, BOMBINA BOMBINA AND B. VARIEGATA, NEAR CRACOW IN SOUTHERN POLAND. AB - The fire-bellied toads Bombina bombina and B. variegata differ extensively in biochemistry, morphology, and behavior. We use a survey of five diagnostic enzyme loci across the hybrid zone near Cracow in Southern Poland to estimate the dispersal rate, selection pressures, and numbers of loci which maintain this zone. The enzyme clines coincide closely with each other and with morphological and mitochondrial DNA clines. Although the zone lies on a broad transition between environments suitable for bombina and variegata, the close concordance of diverse characters, together with increased aberrations and mortality in hybrids, suggest that the zone is maintained largely by selection against hybrids. There are strong "linkage disequilibria" between each pair of (unlinked) enzyme loci (R = 0.129 [2-unit support limits: 0.119-0.139]). These are probably caused by gene flow into the zone, and they give an estimate of dispersal (sigma = 890 [790-940] m gen-1/2 ). The clines are sharply stepped, with most of the change occurring within 6.15 (5.45-6.45) km, but with long tails of introgression on either side. This implies that the effective selection pressure on each enzyme marker (due largely to disequilibrium with other loci) is s* = 0.17 (0.159-0.181) at the center but that the selection acting directly on the enzyme loci is weak or zero (se < 0.0038). The stepped pattern implies a barrier to gene flow of 220 (48-415) km. This would substantially delay neutral introgression but would have little effect on advantageous alleles; the two taxa need not evolve independently. Strong selection is needed to maintain such a barrier: hybrid populations must have their mean fitness reduced by a factor of 0.65 (0.60-0.77). This selection must be spread over a large number of loci to account for the concordant patterns and the observed cline widths (N = 300 [80-2,000]). PMID- 28563503 TI - EVOLUTION OF RIBOSOMAL DNA: FIFTY MILLION YEARS OF RECORDED HISTORY IN THE FROG GENUS RANA. AB - Evolution of nuclear ribosomal DNA (rDNA) arrays of frogs of the genus Rana was examined among 32 species that last shared a common ancestor approximately 50 million years ago. Extensive variation in restriction sites exists within the transcribed and nontranscribed rDNA spacer regions among the species, whereas rDNA coding regions exhibit comparatively little interspecific variation in restriction sites. The most parsimonious phylogenetic hypothesis for the evolution of the group was constructed based on variation in restriction sites and internal spacer lengths among the 32 species of Rana and one species of Pyxicephalus (examined for outgroup comparison). This analysis suggests that R. sylvatica of North America is more closely related to the R. temporaria group of Eurasia than to other North American Rana. The hypothesized phylogeny also supports the monophyly of the R. boylii group, the R. catesbeiana group, the R. palmipes group, the R. tarahumarae group, and the R. pipiens complex. Furthermore, the restriction site data provide information about the evolution within and among these species groups. This demonstrates that restriction site mapping of rDNA arrays provides a useful molecular technique for the examination of historical evolutionary questions across considerable periods of time. PMID- 28563504 TI - HARDY-WEINBERG AND FERTILITY SELECTION. PMID- 28563505 TI - SEX-RATIO MANIPULATION IN COLOR-BANDED POPULATIONS OF ZEBRA FINCHES. AB - Significant correlations were found between attractiveness of leg-band color (determined by preference tests [Burley et al., 1982]) and sex ratio of offspring in two long-term breeding experiments involving zebra finches. In both experiments, birds with attractive band colors produced more same-sex offspring, while birds with unattractive band colors produced more opposite-sex offspring. The results of these experiments are consistent with those of a previous experiment (Burley, 1981). To explain the earlier results, I hypothesized that parents adjust their allocation to sons and daughters to produce offspring they "expect" to be most attractive. The purpose of such sex-ratio manipulation is to enhance fitness by the production of offspring with superior mate-getting opportunities. Two alternative hypotheses are presented here. One is that sex ratios change with parental age and/or experience. Evidence does not support this hypothesis. There were no temporal trends in sex ratio independent of band color. A second possibility is that sex ratios reflect differential parental ability to rear sons and daughters. This hypothesis cannot be conclusively tested on the basis of present evidence, but available evidence does not support it. Within color classes, weights of sons and daughters did not differ. Evidence indicates that parents effect secondary sex-ratio manipulation through the selective rejection of young, usually within six days of hatching. There is no evidence of manipulation prior to egg-laying. The costs associated with brood reduction probably set limits on the extent to which secondary manipulation can be profitably employed. PMID- 28563506 TI - DYNAMICS OF POLLEN TUBE GROWTH IN THE WILD RADISH, RAPHANUS RAPHANISTRUM (BRASSICACEAE). I. ORDER OF FERTILIZATION. AB - Gametophytic competition and selection have important effects on patterns of mating in plant populations. However, the relative importance of prezygotic mechanisms is often unclear due to a paucity of observations on pollen tube growth in vivo. In this study, we present observations on pollen tube behavior in the gynoecium of wild radish. Significant variation in the order of fertilization of the linearly arranged ovules occurred within the radish ovary. This variation is evidence that prezygotic mechanisms of gamete selection operate to sort pollen tubes nonrandomly to different ovule positions in the ovary. We propose that the variation in fertilization patterns can be attributed to variance in pollen tube growth rates in the central septum of the radish gynoecium. The path of pollen tube growth and gynoecial structure deserve greater attention in future studies of gamete competition. PMID- 28563507 TI - VARIATION IN MALE REPRODUCTIVE INVESTMENT AND MALE REPRODUCTIVE SUCCESS IN WHITE SPRUCE. AB - An experimental population composed of ramets of white spruce clones was studied to determine the influence of different levels of clonal male reproductive investment on clonal male reproductive success, where the male reproductive success of different clones in the population was defined as the proportion of the seed crop sired by each clone. We present a multilocus estimation procedure which provides unbiased estimates of the proportion of seed sired by each parental genotypic class from pollen gamete frequency data, whenever gametic segregation frequencies are known. Significant linear and quadratic components were found for the relationship between the number of male cones produced and the estimated proportion of the seed crop sired. A clone that produced an exceptionally large number of male cones, however, did not have the greatest male reproductive success. In general, the results support an assumption made in theoretical models of selection on mating system modifiers regarding the relationship between male investment and male reproductive success. They also support the hypothesis that male reproductive success in wind-pollinated species continues to increase substantially with increasing male reproductive investment. PMID- 28563508 TI - CHLOROPLAST DNA EVOLUTION AND PHYLOGENETIC RELATIONSHIPS IN CLARKIA SECT. PERIPETASMA (ONAGRACEAE). AB - Restriction-site analysis of chloroplast DNA in Clarkia sect. Peripetasma (Onagraceae) was done to test previously proposed phylogenetic models. One hundred nineteen restriction-site mutations were identified among the nine species using 29 restriction enzymes, and these were used to construct rooted most parsimonious trees (Wagner and Dollo). A chloroplast DNA evolutionary clock could not be statistically rejected. Branch points of this tree were statistically tested by Felsenstein's bootstrap method. This tree 1) provided an unambiguous and detailed genealogical history for the section, 2) verified a previous partial phylogenetic model for the section based on gene duplications and differential silencing, 3) provided details of the phylogenetic model not inferred or expected based on morphology and reproductive isolation, and 4) indicated that morphology evolves at markedly different rates within and between lineages in the section. PMID- 28563509 TI - REINFORCEMENT FOR ETHOLOGICAL ISOLATION IN THE SOUTHEAST ASIAN AEDES ALBOPICTUS SUBGROUP (DIPTERA: CULICIDAE). PMID- 28563510 TI - QUANTUM AND CONTINUOUS EVOLUTION OF DNA BASE COMPOSITION IN THE YEAST GENUS PICHIA. AB - This paper investigates the noncontinuous nature and evolution of the base composition of nuclear DNA (expressed as mol% guanine + cytosine) in species of the yeast genus Pichia (sensu Kurtzman, 1984b). The pattern of change in the G + C contents in species of this genus, which range from about 27 to 52 mol%, was evaluated. When specifically those species of Pichia were analyzed that have evolved in necroses of cactus species and associated Drosophila, a periodic change in the G + C contents of approximately 3.0-3.2 mol% was detected by a "bootstrapping" method, Fourier analysis, and a nonlinear trigonometric model. Pichia species occurring in exudates of broad-leaved deciduous trees or associated Drosophila and substrates such as soil and water ("other") showed a periodicity of 2.5-2.6 mol%, whereas species associated with conifers and associated bark beetles showed no significant periodicity. Periodicity in the most recent association (cactus and resident Drosophila) as compared to the lack of periodicity in the oldest association (conifer-beetle) may indicate mixed evolutionary processes. Low mol% G + C values appear more frequently in the relatively recent cactus and Drosophila-associated yeast species. In addition, low mol% G + C species do not display the ancestral bud-meiosis mode of sexual reproduction which occurs frequently in medium to high mol% G + C yeasts. It was found that the mol% G + C content of the Drosophila- and cactus-associated Pichia species is positively correlated with the number of compounds fermented or respired by these yeast species. Possible reasons for the periodic changes in mol% G + C content accompanying speciation include aneuploidy, allopolyploidy, the presence of nuclear plasmids, and regular differences in moderately repetitive portions of DNA. Since significant DNA complementarity is virtually limited to species within a relatively narrow G + C group, this suggests that there are at least two processes which alter the G + C content between species, one saltational and one continuous. PMID- 28563511 TI - DENSITY-DEPENDENT NATURAL SELECTION IN DROSOPHILA: EVOLUTION OF PUPATION HEIGHT. PMID- 28563512 TI - INCOMPLETE BEHAVIORAL ISOLATION BETWEEN TWO DISTANTLY RELATED DROSOPHILA SPECIES. AB - Two sympatric, distantly related Drosophila species, D. affinis and D. melanogaster, interact sexually in the laboratory and in the field. When mature males from one species are tested with females or sexually attractive males from the other species, the mature males perform courtship that, in most cases, is indistinguishable from the courtship that attractive conspecific flies elicit. Moreover, some of the D. affinis females that elicit courtship from D. melanogaster males copulate with them. PMID- 28563513 TI - MIGRATION AND GENETIC DRIFT IN HUMAN POPULATIONS. AB - In humans and many other species, mortality is concentrated early in the life cycle, and is low during the ages of dispersal and reproduction. Yet precisely the opposite is assumed by classical population-genetics models of migration and genetic drift. We introduce a model in which population regulation occurs before migration. In contrast to the conventional model, our model implies that geographic variation in the allele frequencies of newborns should exceed that of adults. Thus, it is important to distinguish genetic variation of adults from that of newborns in species with human-like life cycles. Classical models deal with the variance of group allele frequencies about the allele frequency of a hypothetical "continent" or "foundation stock." Empirical studies, however, can only measure "reduced" variance, i.e., variance about the current population mean. Our model deals with reduced variance, and should therefore be more relevant to field studies. We show that reduced variance converges faster, which implies that populations are more likely to be at equilibrium with respect to reduced than unreduced variance. To summarize the effect of migration on genetic population structure, we introduce a new parameter, the effective migration rate. Unlike most population structure statistics, it does not confound the effects of mobility and population size, and it should therefore be useful for comparisons between populations. Finally, we show that the difference between geographic variation of newborn and adult allele frequencies contains information about both effective population size and effective migration rate. PMID- 28563514 TI - ADAPTIVE RESPONSES OF PREDATORS TO PREY AND PREY TO PREDATORS: THE FAILURE OF THE ARMS-RACE ANALOGY. AB - This paper analyzes a number of relatively general models of predator-prey adaptation and coadaptation. The motivation behind this work is, in part, to evaluate the "race analogy" that has been applied in analyzing predator-prey coevolution. The models are based on the assumption that increased investment in predation-related adaptations must be paid for by decreased adaptation to some other factor. Increased investment in predation-related adaptations by the prey lowers the predator's functional response, and increased investment by the predator increases the functional response. The models are used to determine how each species should respond to an increase in the predation-related investment of the other species. Several broad classes of population-dynamics models and several alternatives for the cost of predation-related adaptation are investigated. The results do not support the general applicability of the race analogy. In the type of model analyzed in greatest detail here, predator and prey adaptations combine multiplicatively in determining the predator's capture-rate constant. In such models, prey usually increase investment in predator avoidance or escape when predators increase their investment in capture. However, predators often do not change or decrease their investment in response to an increase in the prey's investment. The direction of the predator's response depends on the particular parameter that pays the cost of increased predation investment, the shape of the cost-benefit functions, and the assumptions about the population dynamics of the predator-prey system. Similar models are used to determine whether increased investment by one species should increase the rate of incorporation of mutations that improve the predation-related adaptations of the other species. The arms-race analogy also fails for this case. The results cast doubt on the usefulness of Dawkins and Krebs (1979) "life-dinner" principle. PMID- 28563515 TI - REPLY TO REZNICK ET AL. PMID- 28563517 TI - THE BREEDING SYSTEM AND VARIATION IN POPULATIONS OF POA ANNUA L. PMID- 28563518 TI - ACTIVE DISPERSAL AND PASSIVE TRANSPORT IN DROSOPHILA. PMID- 28563519 TI - RESPIRATION IN METAZOAN EVOLUTION. PMID- 28563520 TI - INTERGENOMIC MAPPING OF MAIZE, TEOSINTE AND TRIPSACUM. PMID- 28563521 TI - FREQUENCY-DEPENDENT SELECTION AT THE PAYNE INVERSION IN DROSOPHILA MELANOGASTER. PMID- 28563522 TI - TOWARD A PREDICTIVE CAVE BIOGEOGRAPHY: THE GREENBRIER VALLEY AS A CASE STUDY. PMID- 28563524 TI - CYTOPLASMIC STERILITIES THAT SEPARATE THE GROUP TUBEROSUM CULTIVATED POTATO FROM ITS PUTATIVE TETRAPLOID ANCESTOR. PMID- 28563523 TI - GENIC DIFFERENTIATION ASSOCIATED WITH THE EARLY STAGES OF SPECIATON IN THE MULLERI SUBGROUP OF DROSOPHILA. PMID- 28563525 TI - SEXUAL VIGOR AND SEXUAL SELECTION IN DROSOPHILA MELANOGASTER. PMID- 28563526 TI - CHIASMA FREQUENCY EVIDENCE ON THE EVOLUTION OF AUTOGAMY IN LIMNANTHES FLOCCOSA (LIMNANTHACEAE). PMID- 28563527 TI - GENETIC VARIATION IN SIDE-BLOTCHED LIZARDS ON ISLANDS IN THE GULF OF CALIFORNIA. PMID- 28563528 TI - GENETIC VARIATION IN LYCOPODIUM LUCIDULUM: A PHYLOGENETIC RELIC. PMID- 28563529 TI - ADAPTIVE SIGNIFICANCE OF PIGMENT POLYMORPHISMS IN COLIAS BUTTERFLIES. III. PROGRESS IN THE STUDY OF THE "ALBA" VARIANT. PMID- 28563530 TI - BREEDING SYSTEMS IN CORTADERIA (GRAMINEAE). PMID- 28563531 TI - DEMOGRAPHY AND GENETICS IN COLONIZING POPULATIONS OF BLUE GROUSE (DENDRAGAPUS OBSCURUS). PMID- 28563532 TI - THE ABSENCE OF t ALLELES IN FERAL POPULATIONS OF HOUSE MICE. PMID- 28563533 TI - STRUCTURAL RELATIONSHIPS BETWEEN SPINES AND LATERAL PLATES IN THREESPINE STICKLEBACK (GASTEROSTEUS ACULEATUS). PMID- 28563534 TI - THE ROLE OF BODY SIZE IN THE ASSEMBLY OF WEST INDIAN BIRD COMMUNITIES. PMID- 28563535 TI - SEXUAL SELECTION IN THE LOVEBUG, PLECIA NEARCTICA: THE ROLE OF MALE CHOICE. PMID- 28563536 TI - WHY ARE JUVENILES SMALLER THAN THEIR PARENTS? PMID- 28563537 TI - QUANTITATIVE GENETICS OF DEVELOPMENT: GENETIC CORRELATIONS AMONG AGE-SPECIFIC TRAIT VALUES AND THE EVOLUTION OF ONTOGENY. PMID- 28563538 TI - CONTINENTAL PATTERNS OF MORPHOLOGICAL VARIATION IN A SOUTH AMERICAN SPARROW. PMID- 28563540 TI - THE INFLUENCE OF PALEOZOIC OVULE AND CUPULE MORPHOLOGIES ON WIND POLLINATION. PMID- 28563539 TI - LARVAL ADAPTATIONS AND PATTERNS OF BRACHIOPOD DIVERSITY IN SPACE AND TIME. PMID- 28563542 TI - THE HERITABILITY OF EXTERNAL MORPHOLOGY IN DARWIN'S GROUND FINCHES (GEOSPIZA) ON ISLA DAPHNE MAJOR, GALAPAGOS. PMID- 28563541 TI - COSTS OF THERMOREGULATION IN ADULT PINNIPEDS. PMID- 28563543 TI - GENETIC DIFFERENTIATION WITHIN SUBDIVIDED POPULATIONS OF FORMICA ANTS. PMID- 28563544 TI - MORPHOLOGICAL VARIATION IN THE NEOTROPICAL SALAMANDER GENUS BOLITOGLOSSA. PMID- 28563545 TI - DNA/DNA HYBRIDIZATION STUDIES OF MUROID RODENTS: SYMMETRY AND RATES OF MOLECULAR EVOLUTION. PMID- 28563547 TI - A PITFALL IN USING PAINTED INSECTS IN STUDIES OF PROTECTIVE COLORATION. PMID- 28563546 TI - POLLEN-PISTIL RELATIONSHIPS IN THE POLEMONIACEAE. PMID- 28563548 TI - A COMPARISON OF THEORETICAL AND ELECTROPHORETIC ASSESSMENTS OF GENETIC STRUCTURE IN POPULATIONS OF THE HOUSE SPARROW (PASSER DOMESTICUS). PMID- 28563549 TI - GENETIC VARIATION FOR HOST PREFERENCE WITHIN AND AMONG POPULATIONS OF DROSOPHILA TRIPUNCTATA. PMID- 28563550 TI - BREEDING SYSTEM, GENETIC VARIABILITY, AND RESPONSE TO SELECTION IN PLECTRITIS (VALERIANACEAE). PMID- 28563551 TI - HOMAGE TO SANTA ANITA: THERMAL SENSITIVITY OF SPRINT SPEED IN AGAMID LIZARDS. PMID- 28563552 TI - THE EVOLUTION OF APOSEMATIC COLORATION IN DISTASTEFUL PREY: AN INDIVIDUAL SELECTION MODEL. PMID- 28563553 TI - POPULATION STRUCTURE AND EVOLUTION IN SUBTERRANEAN MOLE RATS. PMID- 28563554 TI - DIFFERENTIAL SURVIVORSHIP OF EVOLVING CHROMOSOMAL SPECIES OF MOLE RATS, SPALAX: AN UNPLANNED LABORATORY EXPERIMENT. PMID- 28563555 TI - Society Meetings. PMID- 28563556 TI - A CRITICAL ASSESSMENT OF PUNCTUATED EQUILIBRIA I. DURATION OF TAXA. PMID- 28563557 TI - APHID GENOTYPES, PLANT PHENOTYPES, AND GENETIC DIVERSITY: A DEMOGRAPHIC ANALYSIS OF EXPERIMENTAL DATA. PMID- 28563559 TI - REPLY TO BAWA. PMID- 28563558 TI - STATIC AND GROWTH ALLOMETRY OF MORPHOMETRIC TRAITS IN RANDOMBRED HOUSE MICE. PMID- 28563560 TI - DENSITY DEPENDENT SEXUAL SELECTION AND POSITIVE PHENOTYPIC ASSORTATIVE MATING IN NATURAL POPULATIONS OF THE SOLDIER BEETLE, CHAULIOGNATHUS PENNSYLVANICUS. PMID- 28563562 TI - THE CHALLENGES TO DARWINISM SINCE THE LAST CENTENNIAL AND THE IMPACT OF MOLECULAR STUDIES. PMID- 28563563 TI - NICHE BREADTH AND ABUNDANCE AS DETERMINANTS OF GENETIC VARIATION IN POPULATIONS OF MYCOPHAGOUS DROSOPHILID FLIES (DIPTERA:DROSOPHILIDAE). PMID- 28563564 TI - PHENOTYPIC EVOLUTION IN A CRETACEOUS FORAMINIFER. PMID- 28563565 TI - BREEDING SYSTEMS AND DISPERSAL-RELATED MATERNAL REPRODUCTIVE EFFORT OF SOUTHERN SPANISH BIRD-DISPERSED PLANTS. PMID- 28563566 TI - SEED DISPERSAL AND THE EVOLUTION OF DIOECISM IN FLOWERING PLANTS-A RESPONSE TO HERRERA. PMID- 28563568 TI - MEMO FROM THE EDUCATION COMMITTEE. PMID- 28563567 TI - THE DISTRIBUTION OF GEOSPIZA DIFFICILIS IN RELATION TO G. FULIGINOSA IN THE GALAPAGOS ISLANDS: TESTS OF THREE HYPOTHESES. PMID- 28563569 TI - SPECIATION AND MACROEVOLUTION. PMID- 28563570 TI - SEX AND VARIABILITY IN THE COMMON BROWN BUTTERFLY HETERONYMPHA MEROPE MEROPE (LEPIDOPTERA: SATYRINAE). PMID- 28563571 TI - BIOCHEMICAL POPULATION GENETICS AND SPECIATION. PMID- 28563572 TI - ESTIMATES OF FITNESS IN ERODWM POPULATIONS WITH INTRA- AND INTERSPECIFIC COMPETITION. PMID- 28563573 TI - SIMILARITY OF AMINO ACIDS IN NECTAR AND LARVAL SALIVA: THE NUTRITIONAL BASIS FOR TROPHALLAXIS IN SOCIAL WASPS. PMID- 28563574 TI - PERSPECTIVES IN EVOLUTIONARY THEORY. PMID- 28563575 TI - THE IMPACT OF PREDATION ON LIFE HISTORY EVOLUTION IN TRINIDADIAN GUPPIES: GENETIC BASIS OF OBSERVED LIFE HISTORY PATTERNS. PMID- 28563576 TI - GENETIC EVIDENCE FOR THE HYBRID ORIGIN OF THE DIPLOID PLANT STEPHANOMERIA DIEGENSIS. PMID- 28563577 TI - IS A NEGATIVE REGRESSION OF DeltaP ON P EVIDENCE OF A STABLE POLYMORPHISM? PMID- 28563578 TI - A MOLECULAR PHYLOGENETIC PERSPECTIVE ON THE ORIGINS OF MORPHOLOGICAL NOVELTIES IN THE SALAMANDERS OF THE TRIBE PLETHODONTINI (AMPHIBIA, PLETHODONTIDAE). PMID- 28563579 TI - BEHAVIORAL VARIATION IN NATURAL POPULATIONS. II. THE INHERITANCE OF A FEEDING RESPONSE IN CROSSES BETWEEN GEOGRAPHIC RACES OF THE GARTER SNAKE, THAMNOPHIS ELEGANS. PMID- 28563580 TI - QUANTITATIVE PREDICTIONS OF DELAYED MATURITY. PMID- 28563581 TI - POPULATION BIOLOGY OF CHAMAELIRIUM LUTEUM, A DIOECIOUS LILY. II. MECHANISMS GOVERNING SEX RATIOS. PMID- 28563582 TI - BEHAVIORAL VARIATION IN NATURAL POPULATIONS. I. PHENOTYPIC, GENETIC AND ENVIRONMENTAL CORRELATIONS BETWEEN CHEMORECEPTIVE RESPONSES TO PREY IN THE GARTER SNAKE, THAMNOPHIS ELEGANS. PMID- 28563583 TI - THE COST OF DOMINANCE AND ADVANTAGE OF SUBORDINATION IN A BADGE SIGNALING SYSTEM. PMID- 28563584 TI - ADAPTIVE RADIATION IN THE HAWAIIAN SILVERSWORD ALLIANCE (COMPOSITAE-MADIINAE). I. CYTOGENETICS OF SPONTANEOUS HYBRIDS. PMID- 28563585 TI - FIXATION PROBABILITIES AND FIXATION TIMES IN A SUBDIVIDED POPULATION. PMID- 28563586 TI - RELATIONSHIP BETWEEN REPRODUCTIVE SECURITY AND INTERSEXUAL SELECTION IN A JUMPING SPIDER PHIDIPPUS JOHNSONI (ARANEAE: SALTICIDAE). PMID- 28563587 TI - PATTERNS OF EVOLUTION AMONG THE ARTIODACTYLA AND PERISSODACTYLA (MAMMALIA). PMID- 28563588 TI - BUTTERFLYWEED RE-REVISITED: SPATIAL AND TEMPORAL PATTERNS OF LEAF SHAPE VARIATION IN ASCLEPIAS TUBEROSA. PMID- 28563589 TI - EVOLUTION OF COMPETITIVE ABILITY IN ESCHERICHIA COLI. PMID- 28563590 TI - MUTATION MODIFICATION IN A RANDOM ENVIRONMENT. PMID- 28563591 TI - SEX RATIO VARIATIONS IN XYLOPHILOUS ACULEATE HYMENOPTERA. PMID- 28563592 TI - CONTROL OF LARVAL GROWTH VARIATION IN A POPULATION OF PSEUDACRIS TRISERIATA (ANURA: HYLIDAE). PMID- 28563593 TI - RIVERINE BARRIERS TO GENE FLOW AND THE DIFFERENTIATION OF FENCE LIZARD POPULATIONS. PMID- 28563594 TI - Society for the Study of Evolution and American Society of Naturalists 1981 Meetings. PMID- 28563595 TI - COEVOLUTION OF HAPLO-DIPLOIDY AND SEX DETERMINATION IN THE HYMENOPTERA. PMID- 28563596 TI - ESTIMATION OF GENE FLOW AND GENETIC NEIGHBORHOOD SIZE BY INDIRECT METHODS IN A SELFING ANNUAL, TRITICUM DICOCCOIDES. AB - Rates of gene flow and neighborhood area were investigated in the selfing annual, Triticum dicoccoides. The collection of seed material was made using a spatial hierarchical sampling design in which four collection sites were 5-7 m apart, four were 15-17 m apart, and four were 100-120 m apart. Between 25 and 30 plants were scored from each site (mean sample size = 28.7). Two procedures for indirect estimation of gene flow were used on gene-frequency data from 13 polymorphic loci. The estimates of Nm using Wright's (1943a, 1943b) estimation procedure were 1.265, 0.212, and 0.357, for the closest, intermediate, and most distant distance classes, respectively. The estimates of Nm using Slatkin's (1985) private-allele procedure were 4.675 (subsample ranges: 1.544-4.675), 0.110 (subsample ranges: 0.069-0.153), and 0.670 (subsample ranges: 0.129-0.256). The results indicate a general agreement between the two procedures. Both indicate a sharp decrease in gene flow beyond the first distance class (5-7 m). The large gene-flow values and the large variation within the 5-7-m distance class are taken as evidence that a genetic neighborhood for this species may cover an area defined by a 5-m radius. The results also indicate that gene flow between populations separated by only 10 or more meters may be quite limited. PMID- 28563597 TI - DEVELOPMENTAL CORRELATES OF GENOME SIZE IN PLETHODONTID SALAMANDERS AND THEIR IMPLICATIONS FOR GENOME EVOLUTION. AB - We present an analysis of the evolutionary relationship between genome size (C value, mass of DNA per haploid nucleus) and developmental rate using observations of limb regeneration in salamanders of the family Plethodontidae. Rates of growth and differentiation of regenerating limbs are reported for 27 plethodontid species whose C-values range from 14 to 76 picograms. A phylogenetic analysis employing Felsenstein's method of independent contrasts indicates that rate of differentiation is inversely proportional to genome size, although we have not identified any statistically significant association between genome size and the growth rate of regenerating tissue. Our results are consistent with an interpretation that genome size may place a limit on the maximum rate of regeneration attainable in plethodontid salamanders. The implications of our findings for the "junk DNA," "nucleotypic DNA," "selfish DNA," and "skeletal DNA" hypotheses of genome evolution are discussed. PMID- 28563598 TI - LIFE-HISTORY EVOLUTION IN GUPPIES (POECILIA RETICULATA): 1. PHENOTYPIC AND GENETIC CHANGES IN AN INTRODUCTION EXPERIMENT. AB - Previous investigations (Reznick and Endler, 1982; Reznick, 1982a, 1982b) demonstrated that genetic differences in guppy life histories were associated with differences in predation. Guppies from localities with the pike cichlid Crenicichla alta and associated predators matured earlier, had greater reproductive efforts, and produced more and smaller offspring than did guppies from localities with only Rivulus harti as a potential predator. Crenicichla preys primarily on large, sexually mature size-classes of guppies, while Rivulus preys primarily on small, immature size-classes. These patterns of predation are hypothesized to alter mean age-specific survival. Theoretical treatments of such differences in survival predict the observed trends in age at maturity and reproductive effort. We are using introduction experiments to evaluate the role of predators in selecting for these life-history patterns. The experiment whose results are presented here was conducted in a tributary to the El Cedro River (Trinidad), where a waterfall was the upstream limit to the distribution of all fish except Rivulus. Guppies collected from the Crenicichla locality immediately below the waterfall (the downstream control) were introduced over the waterfall in 1981. This introduction released the guppies from Crenicichla predation, exposed them instead to Rivulus predation only, and also introduced them to a different environment, since the introduction site has greater canopy cover than the site of origin. Changes in guppy life-history patterns can be attributed to predation and/or the environment. Evidence from fish collected and preserved in the field demonstrated that, by mid-1983, guppies from the introduction site above the waterfall matured at larger sizes and produced fewer, larger offspring. There were no consistent differences in reproductive allotment (weight of offspring/total weight). With the exception of reproductive allotment, these patterns are identical to previous comparisons between Rivulus and Crenicichla localities. A laboratory genetics experiment demonstrated that males from the introduction site matured at a later age and at a larger size than did males from the control site downstream, as predicted from the "age-specific predation" hypothesis. No differences between localities were observed for female age and size at maturity or for reproductive effort. The trends for fecundity and offspring size were the reverse of those observed in the field. Because only the males changed in the predicted fashion, it is not possible either to reject or to accept the hypothesis of age-specific predation at this time. We discuss the possible causes for these patterns and the high degree of plasticity in the life history, as evidenced by the differences in fecundity and offspring size between the field and laboratory results. PMID- 28563599 TI - PATTERN OF PHENOTYPIC VIABILITY AND FECUNDITY SELECTION IN A NATURAL POPULATION OF IMPATIENS PALLIDA. AB - Estimates of viability and fecundity selection of 13 phenotypic characters for 1,536 individuals of Impatiens pallida growing in 24 locations within a single natural population were compared. Directional viability selection of cotyledon area, day of initial leaf production, number of leaves, and stem length was detected throughout this population. Directional fecundity selection of cotyledon area, day of initial flower production, number of leaves present on day of initial flower production, stem length on day of initial flower production, number of leaves, and stem length was also detected. Phenotypic selection of these characters was strong in some cases, and the strength of selection was significantly heterogeneous among locations. For several of the characters, directional phenotypic selection within the population was significantly positive in some locations and significantly negative in others separated by only a few meters. Fecundity selection was stronger than viability selection for some characters, implying that fecundity selection was at least as important as viability selection within this population. Soil moisture levels and light intensities played a larger role than soil nutrient levels in determining the patterns of both viability and fecundity selection, and differences in directional viability selection were more strongly related to environmental variation than were differences in fecundity selection. The pattern of phenotypic selection could not be reliably inferred from the patterns of mortality and reproduction alone. PMID- 28563600 TI - TESTING SYMMORPHOSIS: DOES STRUCTURE MATCH FUNCTIONAL REQUIREMENTS? PMID- 28563601 TI - DIFFERENCES IN INBREEDING COEFFICIENTS DO NOT EXPLAIN THE ASSOCIATION BETWEEN HETEROZYGOSITY AT ALLOZYME LOCI AND DEVELOPMENTAL STABILITY IN RAINBOW TROUT. PMID- 28563602 TI - MOLECULAR EVOLUTIONARY DIVERGENCE AMONG NORTH AMERICAN CAVE CRICKETS. II. DNA-DNA HYBRIDIZATION. AB - Single-copy DNA divergence among 23 populations of cave crickets belonging to two genera (Euhadenoecus and Hadenoecus) has been determined by DNA-DNA hybridization employing the TEACL method. These same populations have been studied for allozyme variation (Caccone and Sbordoni, 1987). In addition, a European relative (Dolichopoda laetitiae) has been included as an outgroup for rooting the phylogeny. One of the most remarkable findings is the large degree of DNA divergence among these species and populations. A DeltaTm of up to 5 degrees C has been found between populations of the same species; even further divergence is indicated by a lowered normalized percentage of reassociation. A phylogeny was constructed and tested for synchrony of rates, i.e., a molecular clock. Statistically, we could not reject the clock hypothesis. Attempts to calibrate the clock led to the conclusion that these insects are among the fastest evolving (with respect to single-copy DNA) groups yet studied-at least as fast as Drosophila and sea urchins-where a DeltaTm of 1 degrees C indicates 0.5 to 1.5 MY since the last common ancestor. In general, the phylogeny derived from the DNA data agrees with that derived from isozymes. Nei's D and DeltaTm are correlated; in this group a D of 0.1 corresponds to a DeltaTm of about 1.5 degrees C. This indicates that, relative to total single-copy DNA, the protein-coding regions of the genome are slowly evolving. PMID- 28563603 TI - PHENOTYPIC PLASTICITY AND HETEROCHRONY IN CICHLASOMA MANAGUENSE (PISCES, CICHLIDAE) AND THEIR IMPLICATIONS FOR SPECIATION IN CICHLID FISHES. AB - Cichlid fishes in African rift lakes have undergone rapid speciation, resulting in "species flocks" with more than 300 endemic species in some of the lakes. Most researchers assume that there is little phenotypic variation in cichlid fishes. I report here extensive phenotypic plasticity in a Neotropical cichlid species. I examined the influence of diet on trophic morphology during ontogeny in Cichlasoma managuense. Two groups of full siblings were fed two different diets for eight months after the onset of feeding; thereafter both groups were fed a common diet. Phenotypes that differed significantly at 8.5 months converged almost completely at 16.5 months. If feeding on two different diets is continued after 8.5 months, the phenotypes remain distinct. Differences in diet and possibly in feeding mode are believed to have caused these phenotypic changes. Phenotypic plasticity is described in terms of a qualitative model of heterochrony in which phenotypic change in morphology is explained as retardation of the normal developmental rate. If phenotypic expression of morphology is equally plastic in African cichlid species as it may be in the American cichlids, as exemplified by C. managuense, then taxonomic, ecological, and evolutionary analyses of "species flocks" may be in need of revision. However, Old World cichlids may be less phenotypically plastic than New World cichlids, and this may contribute to the observed differences in speciation rate and degree of endemism. PMID- 28563604 TI - GENETIC LOAD AND THE MATING SYSTEM IN HOMOSPOROUS FERNS. AB - The mutational genetic load was calculated assuming mutation-selection-inbreeding equilibrium and applied to homosporous ferns. Diploid species with past inbreeding should have a low genetic load while outcrossers should have a high genetic load. These predictions are consistent with the bimodal pattern of genetic load found in 18 diploid homosporous fern species. The prediction that tetraploids should have a low genetic load is also consistent with estimates of genetic load in several species. PMID- 28563605 TI - NATURAL SELECTION AND SEXUAL SELECTION ON BODY SIZE IN RED-WINGED BLACKBIRDS. PMID- 28563606 TI - A COMPARATIVE STUDY OF DIVERSIFICATION EVENTS: THE EARLY PALEOZOIC VERSUS THE MESOZOIC. AB - We compare two major long-term diversifications of marine animal families that began during periods of low diversity but produced strikingly different numbers of phyla, classes, and orders. The first is the early-Paleozoic diversification (late Vendian-Ordovician; 182 MY duration) and the other the Mesozoic phase of the post-Paleozoic diversification (183 MY duration). The earlier diversification was associated with a great burst of morphological invention producing many phyla, classes, and orders and displaying high per taxon rates of family origination. The later diversification lacked novel morphologies recognized as phyla and classes, produced fewer orders, and displayed lower per taxon rates of family appearances. The chief difference between the diversifications appears to be that the earlier one proceeded from relatively narrow portions of adaptive space, whereas the latter proceeded from species widely scattered among adaptive zones and representing a variety of body plans. This difference is believed to explain the major differences in the products of these great radiations. Our data support those models that hold that evolutionary opportunity is a major factor in the outcome of evolutionary processes. PMID- 28563607 TI - MOLECULAR EVOLUTIONARY DIVERGENCE AMONG NORTH AMERICAN CAVE CRICKETS. I. ALLOZYME VARIATION. AB - Forty-nine populations of nine species of North American cave crickets (genera Euhadenoecus and Hadenoecus) have been studied for genetic variation at 41 loci by electrophoresis. Wright's FST , Slatkin's Nm* gene-flow estimator, and Nei's genetic distances (D) have been used to compare closely related species that have different ecological requirements (cave vs. forest species), distribution patterns, and/or different degrees of geographic isolation among populations. Cave and epigean (noncave) species differ greatly in their levels of genetic differentiation. Cave species have lower rates of gene exchange (low Nm, high D, and FST ) than epigean species. Within cave species the degree of genetic differentiation among populations is correlated with the limestone structure of the area where the species occur. Species or groups of populations inhabiting areas where the limestone is continuous and highly fissured (e.g., H. subterraneus populations in the Mammoth Cave region) are genetically less differentiated than are populations occurring in regions where the limestone distribution is more fragmented, such as the Appalachian Ridge where E. fragilis occurs; this effect is more extreme in Central Tennessee where genetically differentiated E. insolitus populations occur only a few kilometers apart. This suggests that epigean dispersal through forest habitat in cave-dwelling species is negligable. For forest species, the data indicate relatively recent radiation with ongoing gene exchange among populations. For cave species, the distribution of protein polymorphisms is apparently more a function of historical patterns of gene exchange rather than current gene exchange. Phylogenetic relationships were studied using cluster analyses (UPGMA and Wagner algorithms) of Nei's and Edwards' genetic distances and multivariate analysis (correspondence analysis) of the raw allele frequencies. Different algorithms result in branching patterns that are similar but not entirely concordant with one another or with the phylogeny based on morphology. PMID- 28563608 TI - HABITAT DURATION, LENGTH OF LARVAL PERIOD, AND THE EVOLUTION OF A COMPLEX LIFE CYCLE OF A SALAMANDER, AMBYSTOMA TEXANUM. AB - In many organisms, genotypic selection may be a less effective means of adapting to unpredictable environments than is selection for phenotypic plasticity. To determine whether genotypic selection is important in the evolution of complex life cycles of amphibians that breed in seasonally ephemeral habitats, we examined whether mortality risk from habitat drying in natural populations of small-mouthed salamanders (Ambystoma texanum) corresponded to length of larval period when larvae from the same populations were grown in a common laboratory environment. Comparisons were made at two levels of organization within the species: 1) among geographic races that are under strongly divergent selection regimes associated with the use of pond and stream habitats and 2) among populations within races that use the same types of breeding habitats. Morphological evidence indicates that stream-breeding A. texanum evolved from pond-breeding populations that recently colonized streams. Larvae in streams incur heavy mortality from stream drying, so the upper bound on length of larval period is currently set by the seasonal duration of breeding sites. We hypothesized that selection would reduce length of larval period of pond-breeders that colonize streams if their larval periods are inherently longer than those of stream-breeders. The results of laboratory experiments support this hypothesis. When grown individually in a common environment, larvae from stream populations had significantly shorter larval periods than larvae from pond populations. Within races, however, length of larval period did not correlate significantly with seasonal duration of breeding sites. When males of both races were crossed to a single pond female, offspring of stream males had significantly shorter larval periods than offspring of pond males. Collectively, these data suggest that differences in complex life cycles among pond and stream-breeders are due to genotypic selection related to mortality from habitat drying. Stream larvae in the common-environment experiment were significantly smaller at metamorphosis than pond larvae. Yet, the evolution of metamorphic size cannot be explained readily by direct selection: there are no intuitively obvious advantages of being relatively small at metamorphosis in streams. A positive phenotypic correlation was observed between size at metamorphosis and length of larval period in most laboratory populations. A positive additive genetic correlation between these traits was demonstrated recently in another amphibian. Thus, we suspect that metamorphic size of stream-breeders evolved indirectly as a consequence of selection to shorten length of larval period. PMID- 28563609 TI - DEMOGRAPHY AND SEX RATIO IN SOCIAL SPIDERS. AB - Spiders that live in large cooperative societies are scattered among several taxonomic groups. All quasisocial species appear to have female-biased sex ratios, while congeneric species with less advanced forms of sociality have 1:1 sex ratios. I present two sex-ratio models that examine the interaction between the genetic structure of populations and two aspects of colony demography-the changes as the colony grows larger in fecundity per female and in colony survivorship. In the first model, I assume that all members of the population produce the same sex ratio under all conditions (monomorphic strategy), while in the second model I assume that the sex ratio can be adjusted according to stage in the colony growth cycle (conditional strategy). The results of these models are consistent with the typically observed effects of within-sex competition among relatives; the sex ratio is biased toward the sex with less intense competition. In addition to these effects, a number of interesting interactions are revealed among relatedness, demography, and constraints of the sex determining mechanism (monomorphic vs. conditional strategies). For example, when survivorship or fecundity increases as the colony grows larger, the predicted sex ratio becomes more female-biased. These demographic factors of changing viability and fecundity with changing colony size interact synergistically with relatedness, and the effect of this interaction on the sex ratio depends on the constraints of the sex-determining mechanism. There are two related roles for the models presented here. First, these models provide some general predictions about how complex variables of demography and population structure interact in shaping the evolution of social spider sex ratios. Second, the development of the models illustrates a theoretical method that provides a simple description of complex interactions between demography and population structure, as well as an example of the synergistic interaction between relatedness and cooperation in the context of a particular life history. PMID- 28563610 TI - OPPORTUNITY FOR SELECTION: AN APPROPRIATE MEASURE FOR EVALUATING VARIATION IN THE POTENTIAL FOR SELECTION? PMID- 28563611 TI - LIKELIHOOD ANALYSIS OF MITOCHONDRIAL RESTRICTION-CLEAVAGE PATTERNS FOR THE HUMAN CHIMPANZEE-GORILLA TRICHOTOMY. AB - In spite of considerable work by many evolutionary biologists, it has not been possible to separate convincingly the human (H) - chimpanzee (C) - gorilla (G) trichotomy into a pair of sequential dichotomies. There are three possible phylogenetic groupings [(HC)G, (HG)C, and (CG)H], and each has its proponents. The evidence remains ambiguous, and instead of choosing among the available phylogenies, it might be better to provide a statement of their relative probabilities. We develop a likelihood analysis of mtDNA restriction-pattern data that can be used to make such probability statements and illustrate it with data on humans, chimpanzees, gorillas, orangutans, and gibbons. The results of our analyses suggest that the best fitting model is that of the (CG)H grouping, but with a very short time span between the first and second splits. For either the (HC)G or (HG)C hypothesis, a true trichotomy is the best model (no elapsed time between the two splits). Chi-square tests indicate no compelling resolution among the three models, however, and all three retain nontrivial posterior probabilities. We also compare each model with an alternative allowing for rate heterogeneity among lineages, but there is no convincing evidence for such heterogeneity. Our results suggest that, while it may eventually be possible to resolve the trichotomy into a pair of unambiguously ordered (but very close) dichotomies, it is possible that the ancestors of all three taxa (H, C, and G) were still conspecific subsequent to the second split, perhaps no more different than the "major races" of extant Homo sapiens. PMID- 28563612 TI - INTER- AND INTRASPECIFIC VARIATION OF MOSSES IN TOLERANCE TO COPPER AND ZINC. AB - Bryophytes are often viewed as slowly evolving with little genetic variation within and among populations. A study of heavy-metal tolerance was initiated to test the capacity of bryophytes to undergo genetic differentiation in response to natural selection. Tolerance of Funaria hygrometrica to copper and zinc was greater in populations that originated on soil with high concentrations of these metals. Protonemal growth was more inhibited by the metals than was germination, and copper was more toxic than zinc. Zinc and copper tolerances were correlated, but so were the zinc and copper concentrations of native substrates. The pattern of population differentiation for heavy-metal tolerance in this species is much like that of flowering plants. Five populations of Physcomitrium pyriforme, which does not occur on metal-contaminated soil, were all highly tolerant of zinc but extremely intolerant of copper. This species seems to have an inherent tolerance to the former. Significant variation in tolerance to copper and zinc occurred among populations, but tolerance did not correlate with metal contents in native substrates. This pattern differs from that of flowering plants. Normal populations of species that colonize contaminated sites tended to be more tolerant than populations of species that do not colonize such sites. The extensive population differentiation in Funaria hygrometrica augments the evidence from electrophoretic data that there is genetic variation among populations of mosses and liverworts. PMID- 28563613 TI - THE EVOLUTION OF BONE. AB - Vertebrates are practically unique among the Metazoa in their possession of a skeleton made from calcium phosphate rather than calcium carbonate. Interpretation of the origin of a phosphatic skeleton in early vertebrates has previously centered primarily on systemic requirements for phosphate and/or calcium storage or excretion. These interpretations afford no anatomical or physiological advantage(s) that would not have been equally valuable to many invertebrates. We suggest the calcium phosphate skeleton is distinctly advantageous to vertebrates because of their relatively unusual and ancient pattern of activity metabolism: intense bursts of activity supported primarily by rapid intramuscular formation of lactic acid. Bursts of intense activity by vertebrates are followed by often protracted periods of marked systemic acidosis. This postactive acidosis apparently generates slight skeletal dissolution, associated with simultaneous vascular hypercalcemia. A variety of apparently unrelated histological features of the skeleton in a number of vertebrates may minimize this postactive hypercalcemia. We present new data that suggest that postactive skeletal dissolution would be significantly exacerbated if bone were composed of calcium carbonate rather than calcium phosphate. The former is far less stable both in vivo and in vitro than is calcium hydroxyapatite, under both resting and postactive physiological conditions. PMID- 28563615 TI - PARTHENOGENESIS IN THE TROPICAL GEKKONID LIZARD, NACTUS ARNOUXII (SAURIA: GEKKONIDAE). AB - As currently diagnosed, Nactus arnouxii includes unisexual and bisexual populations. The geographic distribution of each type was estimated by sex-ratio analysis of samples from southwestern Pacific islands. Males were absent from southern Vanuatu (excluding Aneityum), New Caledonia, and all islands to the east that have been sampled. Both types of populations appear to be present on Aneityum. Chromosome and protein analyses showed that the bisexual populations are highly polytypic and probably consist of more than one biological species. The unisexual N. arnouxii were diploid, highly heterozygous, and showed no genetic segregation. The absence of segregation suggests clonal reproduction, substantiating parthenogenesis. The high heterozygosity of the unisexuals indicates their origin through hybridization. One parent was genetically similar to the extant bisexual population from northern Vanuatu. The other parent has not been identified, but its genetic characteristics are predicted by phylogenetic analysis. PMID- 28563614 TI - CLONAL DIVERSITY IN HIGH-ARCTIC POPULATIONS OF DAPHNIA PULEX, A POLYPLOID APOMICTIC COMPLEX. AB - Based largely on analogy with latitudinal trends in species diversity, it has been proposed that levels of genotypic (clonal) diversity in parthenogenetic populations from high latitudes should be lower than those in populations from the temperate zone or the tropics. Prior studies have shown that low-arctic populations of obligately asexual Daphnia pulex are less clonally diverse than temperate-zone populations. To test for the existence of a latitudinal trend, an allozymic survey of obligately parthenogenetic populations of D. pulex was conducted at a site in the Canadian high-arctic. The study revealed the presence of 75 clones in 179 tundra ponds that were surveyed. On average, 4.5 clones coexisted in single ponds with a range of 1-14 clones. These diversity values are as great (or greater) than those observed in more southerly populations and conflict with the notion of reduced levels of genetic variation in arctic populations. Mechanisms that may influence genetic (clonal) diversity in apomictic complexes are discussed. PMID- 28563616 TI - SEASONAL VARIATION IN SEXUAL SELECTION IN THE MOTTLED SCULPIN. AB - Seasonal variation in sexual and natural selection in male mottled sculpins (Cottus bairdi) can be evaluated by calculating selection differentials, which measure the magnitude of phenotypic change resulting from selection, and by calculating indices of the opportunity for selection, which indicate the potential for phenotypic selection in a given interval. Selection differentials are high at the beginning of the breeding season and decline throughout the breeding season. The magnitude and direction of selection differentials depend on when spawning occurs and are independent of the size or age of the females that spawn. Annual selection differentials due to differences in mating success (female choice) are nearly constant between years. Annual selection differentials associated with hatching success are variable. Opportunities for selection (I = fitness variance/[mean fitness]2 ) show clear seasonal patterns. They are highest at the beginning and at the end of the spawning season. However, this variation is dependent on the mean used to calculate I, and hence variation in I values does not indicate a significant change in the variance of male fitness. PMID- 28563617 TI - REGRESSION ANALYSIS OF NATURAL SELECTION: STATISTICAL INFERENCE AND BIOLOGICAL INTERPRETATION. AB - Recent theoretical work in quantitative genetics has fueled interest in measuring natural selection in the wild. We discuss statistical and biological issues that may arise in applications of Lande and Arnold's (1983) multiple-regression approach to measuring selection. We review assumptions involved in estimation and hypothesis testing in regression problems, and we note difficulties that frequently arise as a result of violation of these assumptions. In particular, multicollinearity (extreme intercorrelation of characters) and extrinsic, unmeasured factors affecting fitness may seriously complicate inference regarding selection. Further, violation of the assumption that residuals are normally distributed vitiates tests of significance. For this situation, we suggest applications of recently developed jackknife tests of significance. While fitness regression permits direct assessment of selection in a form suitable for predicting selection response, we suggest that the aim of inferring causal relationships about the effects of phenotypic characters on fitness is greatly facilitated by manipulative experiments. Finally, we discuss alternative definitions of stabilizing and disruptive selection. PMID- 28563618 TI - FREQUENCY-DEPENDENT VARIATION FOR OUTCROSSING RATE AMONG FLOWER-COLOR MORPHS OF IPOMOEA PURPUREA. AB - In a series of previous studies, it has been shown that populations of the common morning glory Ipomoea purpurea are typically polymorphic for flower-color genes that bias pollinator service and, hence, the rate of outcrossing. In this study, we show that the rate of outcrossing for the white flower-color morph depends on its frequency in experimental populations of the morning glory. White flowers are visited less often by the primary pollinator, bumblebees, and have lower outcrossing rates than colored flowers when they are in the minority. In contrast, blue or pink flower morphs are not undervisited and do not have lowered outcrossing rates when they are rare. In plant populations where genes that increase selling are selectively favored due to their transmission bias, undervisitation of rare morphs may act to stabilize genetic variation for outcrossing rates. PMID- 28563619 TI - SELECTION FOR SEXUAL ISOLATION BETWEEN GEOGRAPHIC FORMS OF DROSOPHILA MOJAVENSIS. II. EFFECTS OF SELECTION OF MATING PREFERENCE AND PROPENSITY. PMID- 28563620 TI - DISTRIBUTION, COEXISTENCE, AND COMPETITION OF WHIRLIGIG BEETLES. PMID- 28563621 TI - THE POPULATION BIOLOGY OF THE BUTTERFLY EUPHYDRY AS EDITH A. III. SELECTION AND THE PHENETICS OF THE JASPER RIDGE COLONY. PMID- 28563622 TI - MASTEROMETRY AND EVOLUTION, AGAIN. PMID- 28563623 TI - STUDIES ON THE GENOME CONSTITUTION OF TRITICUM TIMOPHEEVI ZHUK. II. THE T. TIMOPHEEVI COMPLEX AND ITS ORIGIN. PMID- 28563624 TI - NOTICE OF RESIGNATION OF THE EDITOR. PMID- 28563625 TI - CORRELATION AND THE STRUCTURE OF INTROGRESSIVE POPULATIONS. PMID- 28563626 TI - A CASE OF GENE HOMOLOGY IN CLARKIA. PMID- 28563627 TI - THE PERIODICAL CICADA PROBLEM. I. POPULATION ECOLOGY. PMID- 28563628 TI - THE EVOLUTION OF THE GENUS MONARDA (LABIATAE). PMID- 28563629 TI - THE TEMPORAL COMPONENT OF DIVERSITY AMONG SPECIES OF BIRDS. PMID- 28563630 TI - A GENERAL THEORY OF CLUTCH SIZE. PMID- 28563631 TI - LIFE HISTORY STUDIES OF THE LESSER SNOW GOOSE (ANSER CAERULESCENS CAERULESCENS). IV. THE SELECTIVE VALUE OF PLUMAGE POLYMORPHISM: NET VIABILITY, THE TIMING OF MATURATION, AND BREEDING PROPENSITY. AB - Cooch (1961, 1963) suggested that changes in the genotypic composition of snow goose colonies comprising the Hudson Bay-Foxe Basin population could be attributed to selection favoring the blue phenotype. In the preceding paper (Cooke et al., 1985), we examined potential differences in net fecundity between the two phenotypes at La Perouse Bay in northern Manitoba. No substantial differences in any component of fecundity were detected. In the present paper, we examined potential differences in pre-reproductive and adult viability, age of maturation, and breeding propensity. Again, no differences associated with the plumage polymorphism were detected in any of these life history characteristics. Thus, despite a thorough analysis of the complete life cycle, we were unable to uncover any evidence supporting a selection hypothesis for the persistence and dynamics of this conspicuous polymorphism. An alternate hypothesis based primarily on gene flow and assortative mating appears more plausible. PMID- 28563633 TI - DEMOGRAPHIC GENETICS OF THE GRASS DANTHONIA SPICATA: SUCCESS OF PROGENY FROM CHASMOGAMOUS AND CLEISTOGAMOUS FLOWERS. PMID- 28563632 TI - GENOMIC COADAPTATION AND DEVELOPMENTAL STABILITY WITHIN INTROGRESSED POPULATIONS OF ENNEACANTHUS GLORIOSUS AND E. OBESUS (PISCES, CENTRARCHIDAE). AB - Using fluctuating bilateral asymmetry as a measure of developmental stability, we tested the hypothesis that genomic coadaptation mediates developmental stability in natural populations. Hybrid populations were more asymmetrical than populations of the parental species, and ranks of overall developmental instability were positively correlated with ranks of mean heterozygosity in these populations. The failure to find increased asymmetry in previous studies of natural hybrid populations (Jackson, 1973a, 1973b; Felley, 1980) suggests that such populations may have re-evolved coadapted genomes. Increased asymmetry in hybrid Enneacanthus populations may reflect the youthfulness of these populations. PMID- 28563635 TI - EVIDENCE FOR SELECTION AGAINST HYBRIDS IN THE FAMILY CYPRINIDAE (GENUS NOTROPIS). AB - Notropis cornutus and N. chrysocephalus are two cyprinid fishes which hybridize extensively in the midwest. In this paper, statistical analysis was used to determine if the deficiency of Notropis cornutus * N. chrysocephalus hybrids can be attributed partly to selection against hybrids. Principal component analysis was used to construct a folded hybrid index (FHI) using morphological and electrophoretic characters which distinguish N. cornutus, N. chrysocephalus, and their hybrids. A Wilcoxon signed-rank test comparing mean FHI between successive age classes within cohorts and regression analysis of FHI on age supported the conclusion that hybrids are less fit than parentals in nature; however, this analysis did not include a test of selection at zygotic and larval life history stages or partial infertility of hybrids. Selection eliminated hybrids at a rate of 9.2% per year. Considering the intensity of selection and the age of hybridization, it is surprising that premating reproductive isolating mechanisms have not been perfected by selection against gametic wastage as predicted by classical speciation theory. It appears that the reinforcement of premating isolating mechanisms is an extremely slow process, if it occurs at all, despite apparently intense selection against hybrids. PMID- 28563634 TI - A DEVELOPMENTAL ANALYSIS OF AN EVOLUTIONARY TREND: DIGITAL REDUCTION IN AMPHIBIANS. AB - In this study, we integrate information from phylogeny, comparative ontogeny, and experimental embryology in an attempt to elucidate the mechanisms controlling evolutionary trends towards digital reduction and loss observed in amphibians. Frogs and salamanders that have lost phalanges and even whole toes have done so in a very ordered manner, i.e., certain skeletal elements are lost prior to others. This pattern of morphological diversity is described and trends elucidated. It is concluded that the process is characterized by striking intraordinal convergences coupled with substantial differences between the trends observed in frogs as compared to urodeles. We argue that this pattern is essentially a reflection of the differences in the ontogenies of the two orders. Similarly, the convergences within urodeles and within anurans can be explained as the result of regulation of developmental parameters in a resilient developmental program. We further explore this hypothesis by experimentally perturbing the number of cells in the embryonic limb primordium to show that reduction in the number of mesenchymal cells secondarily affects the developmental process of pattern formation causing a rearrangement of the skeletal morphology of the foot. The same experimental manipulation has different effects in frogs as compared to salamanders. However, in both cases, the experimentally generated morphologies tend to parallel the phenotypes and trends observed in nature. Our conclusion is that most of the patterns of diversity in the digital morphology of amphibians can be explained as a reflection of developmental properties. In general, we present a methodology that attempts to empirically address the issue of identifying developmental constraint in morphological evolution. PMID- 28563637 TI - RECORDING MARVELS: THE LIFE AND WORK OF GEORGE GAYLORD SIMPSON. PMID- 28563636 TI - CHROMOSOME EVOLUTION IN TRIBOLIUM FLOUR BEETLES: EVIDENCE FROM LINKAGE OF THE HEXOKINASE-1 AND MALIC ENZYME LOCI IN T. CASTANEUM AND T. CONFUSUM. PMID- 28563638 TI - BIRD PREDATION AS A SELECTIVE AGENT IN A BUTTERFLY POPULATION. AB - In a population of the checkerspot butterfly, Euphydryas chalcedona, the detached wings of 309 individuals that had been attacked and eaten by birds were collected during a single flight season. During this time period a representative sample of 296 live butterflies in this population was photographed. Comparison of sex ratio and coloration of those butterflies that had been attacked with those that had not showed, first, that birds attacked slightly more females than males; and second, that among males, which are extremely variable in the amount of red on the forewing, birds attacked the less red individuals. PMID- 28563639 TI - DIFFICULTIES WITH THE INTERPRETATION OF PATTERNS OF GENETIC VARIATION IN THE EUSOCIAL HYMENOPTERA. PMID- 28563640 TI - POLYMORPHIC POSTTRANSLATIONAL MODIFICATION OF ALKALINE PHOSPHATASE IN ESCHERICHIA COLI. AB - Natural isolates of Escherichia coli have been examined by polyacrylamide gel electrophoresis for variant isozyme patterns of alkaline phosphatase. The polypeptide chains of this enzyme normally exist in two forms-an unmodified polypeptide product of the phoA gene and a posttranslationally modified version of the same polypeptide that has had its N-terminal arginine removed through the action of the iap gene product. These two forms of the polypeptide aggregate as dimers and thus normally form three electrophoretically distinguishable alkaline phosphatase isozymes. Among 104 strains screened, three had variant isozyme patterns. Two of these were deficient in the posttranslationally modified polypeptide, and cotransduction with cysI indicates that they carry mutant iap genes. The third variant is deficient in the unmodified form of the polypeptide. These results provide an unambiguous case of polymorphic posttranslational modification in E. coli. PMID- 28563641 TI - STABILITY OF THE NORTHERN FLICKER HYBRID ZONE IN HISTORICAL TIMES: IMPLICATIONS FOR ADAPTIVE SPECIATION THEORY. AB - The hybrid zone between the Red- and Yellow-shafted Flickers has been stable on the United States Great Plains in historical times. This conclusion is based on multivariate comparisons of historical and contemporary collections from 18 locales. Adaptive speciation theory predicts that the hybrid zone should either become broader or narrower as a result of introgressive hybridization or reinforcement of premating isolating mechanisms. Neither of these predictions was borne out. Despite 10,000-13,000 years of hybridization, mating between subspecies remains indiscriminate. The data are also inconsistent with a dynamicequilibrium hypothesis wherein narrow hybrid zones are maintained by hybrid unfitness. According to this hypothesis, the hybrid zone would probably "flow" unless it was trapped by a population density trough. The hybrid zone does not appear to be associated with such a feature. The data are consistent with a bounded hybrid superiority theory of a hybrid zone, but this is more a question of survival in a process of elimination than a resounding corroboration. PMID- 28563642 TI - INTERSPECIFIC HYBRIDIZATION BETWEEN CYCLIC PARTHENOGENS. PMID- 28563643 TI - RARE ALLELES AS INDICATORS OF GENE FLOW. AB - A. method for estimating the average level of gene flow in a subdivided population, as measured by the average number of migrants exchanged between local populations, Nm, is presented. The results from a computer simulation model show that the logarithm of Nm is approximately linearly related to the logarithm of the average frequency of private alleles, p(1), in a sample of alleles from the population. It is shown that this result is relatively insensitive to changes in parameters of the model other than Nm and the number of individuals sampled per population. The dependence of the value of p(1) on the numbers of individuals sampled provides a rough way to correct for differences in sample size. This method was applied to data from 16 species, showing that estimated values of Nm range from much greater than 1 to less than 0.1. These results confirm the qualitative analysis of Slatkin (1981). This method was also applied to subsamples from a population to show how to measure the extent of isolation of local populations. PMID- 28563644 TI - A RE-EXAMINATION OF GENETIC VARIABILITY IN DIALICTUS ZEPHYRUS (HYMENOPTERA: HALICTIDAE). PMID- 28563645 TI - PATTERNS OF VARIATION IN AQUATIC AMBYSTOMATID SALAMANDERS: KINEMATICS OF THE FEEDING MECHANISM. AB - Patterns of variation in the feeding mechanism of three species of ambystomatid salamanders (Ambystoma dumerilii, A. mexicanum, and A. ordinarium) were studied to provide insight into the nature of variation in kinematic parameters of the jaw mechanism associated with prey capture. A nested analysis of variance design provided an assessment of the amount of variation in six kinematic variables (measured from 200 frames/sec films of feeding behavior) both among species and among individuals within species. For all six variables, a highly significant proportion of the variance was explained at the intraspecific level. Among species, the most robust discriminators were variables associated with movement of the hyoid. The variables reflecting gape and lifting of the head provided no significant discrimination among species and had large error variances. The hyoid apparatus is the most phylogenetically conservative component of the feeding mechanism in lower vertebrates and was the most stereotyped component of feeding behavior within the salamander species studied here. PMID- 28563646 TI - EUSOCIALITY AND GENETIC VARIABILITY: A RE-EVALUATION. PMID- 28563647 TI - EXTENSIVE CHROMOSOMAL DIVERGENCE WITHIN A SINGLE RIVER BASIN IN THE GOODEID FISH, ILYODON FURCIDENS. AB - Extensive variation in the number of metacentric chromosomes exists among populations of the viviparous goodeid fish, Ilyodon furcidens, in the Rio Coahuayana basin of south central Mexico (states of Colima and Jalisco). The variation can be divided, somewhat arbitrarily, into four "cytotypes" with 0-2, 0 4, 6 and 10-16 metacentrics. Of these, the first, shared with the closely adjacent Rio Armeria and similar to other species of Ilyodon, is probably ancestral. The wholly non-Robertsonian nature of the variation and its extent appear to be unprecedented among teleosts, but its uniqueness is difficult to evaulate because fish chromosome data in general may be biased toward both monomorphism and Robertsonian variation. Variation is evident with all cytotypes but has been well characterized for only a single population of the 0-4M cytotype. That population, unlike most of the others, consists of two interbreeding morphs which differ in mouth width. The variation is heterogeneously distributed between the morphs; the significance of this observation is not yet clear. The distribution of the cytotypes is approximately clinal with respect to the number of metacentric chromosomes. Although the cline may be a direct response to some gradient in selection intensity, the possibility that it is the result of secondary contact of previously isolated populations, fostered by tributary transfer, is real. Allozyme comparisons reveal minimal genic divergence among the cytotypes. There are no fixed allelic differences, and the average unbiased genetic distance between the two extreme cytotypes is 0.042. Gene diversity analysis indicates that an average of less than 3% of the total variation (HT = 0.072) is partitioned among cytotypes; about 24% is partitioned among populations within cytotypes. Genic and chromosomal divergence in Ilyodon are clearly uncoupled. Laboratory F1 , backcross, and F2 intercytotype hybrids are fully viable, and are indistinguishable in fertility from our stocks derived from single populations. F3 intercytotype hybrids are also fully viable but have not yet been tested for fertility. This suggests that, during the course of chromosomal evolution, single rearrangement heterozygotes were not appreciably negatively heterotic, even though the rearrangements are probably pericentric inversions. The combined data suggest that the chromosome rearrangements, even in multiple form, do not function as significant isolating mechanisms. Chromosomal evolution in Ilyodon, though quite marked, has apparently not fostered speciation. PMID- 28563648 TI - ON THE EVOLUTION OF HANDLING TIME. PMID- 28563649 TI - THE EVOLUTION OF SELF-FERTILIZATION AND INBREEDING DEPRESSION IN PLANTS. II. EMPIRICAL OBSERVATIONS. AB - A bimodal distribution of outcrossing rates was observed for natural plant populations, with more primarily selfing and primarily outcrossing species, and fewer species with intermediate outcrossing rate than expected by chance. We suggest that this distribution results from selection for the maintenance of outcrossing in historically large, outcrossing populations with substantial inbreeding depression, and from selection for selfing when increased inbreeding, due to pollinator failure or population bottlenecks, reduces the level of inbreeding depression. Few species or populations are fixed at complete selfing or complete outcrossing. A low level of selfing in primarily outcrossing species is unlikely to be selectively advantageous, but will not reduce inbreeding depression to the level where selfing is selectively favored, particularly if accompanied by reproductive compensation. Similarly, occasional outcrossing in primarily selfing species is unlikely to regularly provide sufficient heterosis to maintain selection for outcrossing through individual selection. Genetic, morphological and ecological constraints may limit the potential for outcrossing rates in selfers to be reduced below some minimum level. PMID- 28563650 TI - LIFE HISTORY STUDIES OF THE LESSER SNOW GOOSE (ANSER CAERULESCENS CAERULESCENS). III. THE SELECTIVE VALUE OF PLUMAGE POLYMORPHISM: NET FECUNDITY. AB - Between 1969 and 1977 the frequency of the blue phenotype of the dimorphic Lesser Snow Goose (Anser caerulescens caerulescens) showed a steady increase at the La Perouse Bay colony near Churchill, Manitoba. Cooch (1961, 1963) suggested the global increase resulted from selection pressures favoring blue individuals. The selection hypothesis was evaluated by examining phenotypic differences in net fecundity. We partitioned the reproductive cycle into a series of stages, each defined by a particular index of fecundity. Despite large samples we were unable to detect any significant differences between the two maternal phenotypes in those indices that could conceivably influence population dynamics. We cannot, however, dismiss selection as the mechanism of population change, nor as a contributor to the maintenance of the polymorphism without assessing potential phenotypic differences in viability, age of maturation, and breeding propensity. These attributes are examined in the following paper (Rockwell et al., 1985). PMID- 28563651 TI - A STOCHASTIC SIMULATION STUDY ON SPECIATION BY SEXUAL SELECTION. AB - A two-locus multi-allele sexual isolation model incorporating mutation and genetic drift which was first proposed by Nei et al. (1983) is studied here. One locus controls the male mating character, and the other controls female receptivity. All females are assumed to have equal mating success. Therefore, the frequencies of female receptivity alleles are changed by mutation, drift, and hitchhiking with male character alleles. Without hitchhiking, development of sexual isolation between allopatric populations proceeds faster in smaller populations, as expected. The hitchhiking effect, by triggering the mutual reinforcement of mating behavior of both sexes (or the runaway process, Fisher [1958]), speeds up the evolution of sexual isolation significantly. For populations with 2Nv <= 0.2 (N = population size, nu = mutation rate), the rates of divergence all approach the maximum possible rate. Sympatric sexual isolation develops quite frequently if two favorable conditions are met: 1) There is no selection on female phenotype (except in some limited cases), and 2) The population size is large enough to carry several female receptivity alleles. Because of stochastic factors, these alleles may lead to the formation of two discrete groups of females, each group receptive to males of different mating characters. The formation of sympatric sexually-isolated groups is also aided significantly, at the incipient stage, by the runaway process. PMID- 28563652 TI - GENE DIVERSITY IN HYMENOPTERA. PMID- 28563653 TI - TEMPORAL ALLOZYME FREQUENCY CHANGES IN DENSITY FLUCTUATING POPULATIONS OF WILLOW GROUSE (LAGOPUS LAGOPUS L.). AB - The population density of willow grouse (Lagopus lagopus L.) in northern Scandinavia changes in synchrony with the cyclic density variations in populations of microtine rodents. To assess the genetic changes accompanying the variations in population number, allozyme variation was studied at 23 loci in 640 willow grouse, representing four mainland and one island locality sampled during high and low population density. The average heterozygosity (H = 8.3%) and proportion of polymorphic loci (P = 26%) is not lower in willow grouse than in avian species with a more stable demography; the recurrent population density changes do not appear to affect drastically the long term effective population size, presumably because of extensive migration. Significant allele frequency differences were found both between populations and between different density phases. The genetic distance (D; Nei, 1972) was, in about 50% of the cases, larger between two consecutive time periods than between two localities in a certain year. Spatial and temporal allele frequency variation each represented around 3% of the gene diversity. The temporal heterogeneity may be caused by nonrandom sampling of family groups, rather than drift of allele frequencies between generations due to small effective population size, as has been suggested for microtine species. PMID- 28563654 TI - LARGE MAMMALS ARE GENETICALLY LESS VARIABLE? PMID- 28563655 TI - THE EVOLUTION OF SELF-FERTILIZATION AND INBREEDING DEPRESSION IN PLANTS. I. GENETIC MODELS. AB - The amounts of inbreeding depression upon selfing and of heterosis upon outcrossing determine the strength of selection on the selfing rate in a population when this evolves polygenically by small steps. Genetic models are constructed which allow inbreeding depression to change with the mean selfing rate in a population by incorporating both mutation to recessive and partially dominant lethal and sublethal alleles at many loci and mutation in quantitative characters under stabilizing selection. The models help to explain observations of high inbreeding depression (> 50%) upon selfing in primarily outcrossing populations, as well as considerable heterosis upon outcrossing in primarily selfing populations. Predominant selfing and predominant outcrossing are found to be alternative stable states of the mating system in most plant populations. Which of these stable states a species approaches depends on the history of its population structure and the magnitude of effect of genes influencing the selfing rate. PMID- 28563656 TI - SPERM MIXING IN THE COCKROACH DIPLOPTERA PUNCTATA. AB - Females of the viviparous cockroach Diploptera punctata store sperm from their first mating, and do not remate until after giving birth to their first batch of young. The irradiated male technique was used to determine the outcome of sperm competition in the second batch of eggs of females mated sequentially to normal and irradiated males. It is estimated that the second male to mate with a female fertilizes approximately two thirds of the eggs in a female's second batch of eggs. Direct evidence for sperm mixing was obtained. Undeveloped eggs (fertilized by irradiated sperm) and developing embryos (fertilized by normal sperm) were found interspersed throughout oothecae that were extruded from females, demonstrating that normal and irradiated sperm were released from the spermathecae at oviposition and that they competed for fertilizations. PMID- 28563657 TI - TWO KINDS OF GENETIC VARIABILITY AND THE PROBLEM OF SPECIATION. PMID- 28563659 TI - DINOSAUR PHYSIOLOGY: A CRITIQUE. PMID- 28563658 TI - THE SUBSTITUTIONAL LOAD AND MUTATIONAL LOAD IN A FINITE POPULATION. PMID- 28563661 TI - THE PHENETICS AND ECOLOGY OF A NARROW HYBRID ZONE. PMID- 28563660 TI - MAINTENANCE OF CHROMOSOMAL POLYMORPHISM IN A POPULATION OF DROSOPHILA PSEUDOOBSCURA. II. FECUNDITY, LONGEVITY, VIABILITY AND COMPETITIVE FITNESS. PMID- 28563662 TI - A NON-GENETIC "POLYMORPHISM" IN ANARTIA FATIMA (LEPIDOPTERA: NYMPHALIDAE). PMID- 28563663 TI - DINOSAURS AS REPTILES. PMID- 28563664 TI - AN EXPLANATION FOR COPE'S RULE. PMID- 28563665 TI - CHANGING REPRODUCTIVE RATES AND POPULATION CYCLES IN LEMMINGS AND VOLES. PMID- 28563666 TI - SIGNIFICANCE OF SYMPATRY TO BEHAVIOR AND EVOLUTION OF GREAT PLAINS MEADOWLARKS. PMID- 28563667 TI - POLYPLOIDY IN FUNGI. PMID- 28563668 TI - OCCURRENCE OF SUCCESSFUL MULTIPLE INSEMINATION OF FEMALES IN NATURAL POPULATIONS OF DEER MICE (PEROMYSCUS MANICULATUS). PMID- 28563669 TI - THE EVOLUTION OF SOME MORPHOLOGICAL CHARACTERS OF THE UPPER CHEEK TEETH OF THE FOSSIL HORSES. PMID- 28563670 TI - ASSORTATIVE POLLINATION FOR STATURE IN LYTHRUM SALICARIA. PMID- 28563671 TI - EVOLUTION OF THE PREDATOR ISOCLINE. PMID- 28563672 TI - POPULATION GENETICS OF MARINE PELECYPODS. II. GENETIC DIFFERENCES IN MICROHABITATS OF MODIOLUS DEMISSUS. PMID- 28563673 TI - BODY SIZE AND NUMBERS OF PLANTS AND ANIMALS. PMID- 28563674 TI - EVOLUTION OF LITTER-SIZE IN THE PIKA, OCHOTONA PRINCEPS (RICHARDSON). PMID- 28563675 TI - MAJOR ECOLOGICAL AND GEOGRAPHIC PATTERNS IN THE EVOLUTION OF COLUBROID SNAKES. PMID- 28563676 TI - ON THE NATURE OF THE POLYMORPHISM AND MATE SELECTION PHENOMENA IN ANARTIA FATIMA (LEPIDOPTERA: NYMPHALIDAE). PMID- 28563678 TI - EFFECTS OF HUMMINGBIRD MIGRATION ON PLANT SPECIATION IN THE CALIFORNIA FLORA. PMID- 28563677 TI - Forearm skin aging: characterization by instrumental measurements. AB - BACKGROUND: The intrinsic ageing and photoaged skin present biomechanical and morphological differences, which are reflected in the appearance of roughness, superficial and deep wrinkles, atrophy, reduced elasticity, hypo- and hyperpigmentation and actinic keratosis. OBJECTIVE: To evaluate and compare the characteristics of the flexor (with a predominance of intrinsic ageing) and extensor (chronically exposed to sunlight and other environmental factors, with a predominance of photoageing) skin surfaces of the forearms. METHODS: Interventional, prospective, diagnostic study, including 23 females, aged over 60 years. The extensor and flexor faces of forearms were compared in relation to clinical parameters and non-invasive instrumental measurements, such as skin surface, elasticity, hydration as well as dermal thickness and echogenicity. RESULTS: Regarding the water content of the stratum corneum, the flexor face presented an average value higher than the extensor face. The average of measures obtained through images of high-frequency ultrasound demonstrated greater echogenicity of flexor face compared to the extensor face. The measurements of the skin surface showed significant differences between the faces. The roughness and scaliness were lower in the flexor face. Regarding the depth of wrinkles, there was no significant difference between the faces. The average of the measurements was slightly higher in the flexor face, which demonstrated that wrinkles are present in the intrinsic ageing and photoageing. The presence of elastosis and the reduction in elasticity in the clinical aspect of the photoaged face of forearms were according to the results of the non-invasive measurements. CONCLUSION: Meaningful differences in the biophysical characteristics of the extensor and flexor faces of the forearms were detected. Because the non-invasive instrumental measurements correlated with clinical findings, they may represent useful tools to assess efficacy and safety of skin ageing treatments in clinical research. PMID- 28563679 TI - PHENETICS OF NATURAL POPULATIONS I. PHENETIC RELATIONSHIPS OF INSULAR POPULATIONS OF THE SIDE-BLOTCHED LIZARD. PMID- 28563680 TI - COMPARATIVE REPRODUCTIVE BIOLOGY OF MONTANE AND PIEDMONT CHORUS FROGS. PMID- 28563681 TI - THE EFFECT OF RELATIVE FREQUENCY OF SPECIES IN COMPETITION: A REAPPRAISAL. PMID- 28563682 TI - COMPARATIVE EVOLUTION IN MIMULUS GUTTATUS OF THE BONNEVILLE BASIN. PMID- 28563683 TI - ADAPTATIONS OF RESPIRATORY SYSTEMS OF SPIDERS. PMID- 28563684 TI - DISTYLY, SELF-INCOMPATIBILITY, AND EVOLUTION IN MELOCHIA. PMID- 28563685 TI - SYNCHRONIZATION OF SEXUAL REPRODUCTION OF TREES WITHIN THE DRY SEASON IN CENTRAL AMERICA. PMID- 28563686 TI - THE PROBABILITY OF FIXATION OF A MUTANT: THE TWO-LOCUS CASE. PMID- 28563687 TI - HERPETOGEOGRAPHY OF PUERTO RICO. IV. PALEOGEOGRAPHY, FAUNAL SIMILARITY AND ENDEMISM. PMID- 28563688 TI - PHYLOGENETIC ANALYSIS: MODELS AND ESTIMATION PROCEDURES. PMID- 28563689 TI - FURTHER EVIDENCE ON SEXUAL ISOLATION WITHIN DROSOPHILA ATHABASCA. PMID- 28563690 TI - THE FITNESS OF SINGLE-SPECIES POPULATIONS OF DROSOPHILA. PMID- 28563691 TI - SURVIVAL PROCESS OF LINKED MUTANT GENES. PMID- 28563692 TI - THE SELECTIVE VALUE OF EYE AND PIGMENT LOSS IN MEXICAN CAVE FISH. PMID- 28563693 TI - STUDIES OF NATURAL POPULATIONS OF MUS. II. POLYMORPHISM AT THE T LOCUS. PMID- 28563694 TI - THE EVOLUTION OF COMPLEX LIFE CYCLE PHENOMENA: AN ECOLOGICAL PERSPECTIVE. PMID- 28563695 TI - SYSTEMATIC SIGNIFICANCE OF LUPINE ALKALOIDS WITH PARTICULAR REFERENCE TO BAPTISIA (LEGUMINOSAE). PMID- 28563696 TI - THE LOSS OF THE OPHIDIAN MIDDLE EAR. PMID- 28563697 TI - CYTOGENETIC EVIDENCE FOR LONG CONTINUED STABILITY IN THE GENUS PLANTAGO. PMID- 28563698 TI - Iron-Catalyzed Cyclotrimerization of Terminal Alkynes by Dual Catalyst Activation in the Absence of Reductants. AB - Catalyzing C-C bond-forming reactions with earth-abundant metals under mild conditions is at the heart of sustainable synthesis. The cyclotrimerization of alkynes is a valuable atom-efficient reaction in organic synthesis that is enabled by several metal catalysts, including iron. This study reports an effective iron-catalyzed cyclotrimerization for the regioselective synthesis of 1,2,4-substituted arenes (1 mol % catalyst, toluene, 20 degrees C, 5 min). A dual activation mechanism (substrate deprotonation, reductive elimination) renders the simple FeII precatalyst highly active in the absence of any reductant. PMID- 28563700 TI - BIOLOGICAL VARIABILITY IN THE PARTHENOGENETIC GRASSHOPPER WARRAMABA VIRGO (KEY) AND ITS SEXUAL RELATIVES. 1. THE EASTERN AUSTRALIAN POPULATIONS. PMID- 28563699 TI - Stability and crystal structures of His88 mutant human transthyretins. AB - Destabilization of human transthyretin (TTR) has been implicated in its misfolding and aggregation. A previous study on the neutron crystal structure of TTR suggested that a large hydrogen bond network around H88 which includes water molecules is significantly involved in the stability of wild-type TTR (WT-TTR). Here, we demonstrate that the H88R mutant associated with amyloid cardiomyopathy is substantially destabilized compared with WT-TTR. In order to clarify the role of H88 and the hydrogen bond network in the stability of TTR, we determined the thermodynamic stability and the crystal structure of H88 mutants (H88A, H88F, H88Y, and H88S). Our results suggest that in some cases TTR is destabilized due to alterations in bound water molecules as well as structural changes in TTR itself. PMID- 28563701 TI - NATURAL SELECTION FOR A FRUIT DIMORPHISM IN PLECTRITIS CONGESTA (VALERIANACEAE). PMID- 28563703 TI - MUTUAL FACILITATION BETWEEN LARVAE OF THE SIBLING SPECIES DROSOPHILA MELANOGASTER AND D. SIMULANS. PMID- 28563704 TI - GENETICS OF DACUS OLEAE. VIII. SELECTION FOR THE AMOUNT OF ACETYLCHOLINESTERASE AFTER ORGANOPHOSPHATE TREATMENT. PMID- 28563705 TI - A DARWINIAN INTERPRETATION OF HINDLIMB VARIABILITY IN FROG POPULATIONS. PMID- 28563706 TI - EVOLUTION OF INSECT LIFE HISTORIES AND HOST PLANT CHEMISTRY: HISPINE BEETLES ON HELICONIA. PMID- 28563707 TI - SEX RATIO IN THE TROPICAL TREE TRIPLARIS AMERICANA (POLYGONACEAE). PMID- 28563708 TI - CHARACTER DISPLACEMENT FOR SEXUAL ISOLATION BETWEEN DROSOPHILA MOJAVENSIS AND DROSOPHILA ARIZONENSIS. PMID- 28563709 TI - BIOLOGICAL ASPECTS OF THE MARSUPIAL-PLACENTAL DICHOTOMY: A REPLY TO LILLEGRAVEN. PMID- 28563710 TI - ON THE STRUCTURE OF FITNESS ESTIMATES UNDER POST-OBSERVATIONAL SELECTION. PMID- 28563711 TI - POPULATION GENETICS IN THE AMERICAN TROPICS. X. GENETIC LOAD DIFFERENCES IN DROSOPHILA WILLISTONI FROM COLOMBIA. PMID- 28563712 TI - A REAPPRAISAL OF THE AQUATIC SPECIALIZATIONS OF THE GALAPAGOS MARINE IGUANA (AMBLYRHYNCHUS CRISTATUS). PMID- 28563713 TI - EVOLUTIONARY ASPECTS OF MATING CALL VARIATION IN A DIPLOID-TETRAPLOID SPECIES COMPLEX OF TREEFROGS (ANURA). PMID- 28563714 TI - GENETIC DIVERSITY IN COLONIZING PARTHENOGENETIC COCKROACHES. PMID- 28563715 TI - CHIMPANZEE PREDATION AS A POSSIBLE FACTOR IN THE EVOLUTION OF RED COLOBUS MONKEY SOCIAL ORGANIZATION. PMID- 28563716 TI - VARIATION AND HETEROZYGOSITY IN SEXUALLY VS. CLONALLY REPRODUCING POPULATIONS OF POECILIOPSIS. PMID- 28563717 TI - SELECTION FOR AMYLASE ALLOZYMES IN DROSOPHILA MELANOGASTER. PMID- 28563718 TI - LIFESPAN AND FECUNDITY PATTERNS IN ROTIFERS: THE COST OF REPRODUCTION. PMID- 28563719 TI - GENETIC VARIATION IN THOMOMYS BOTTAE POCKET GOPHERS: MACROGEOGRAPHIC PATTERNS. PMID- 28563720 TI - OLFACTORY CUES AS A FACTOR IN FREQUENCY-DEPENDENT MATE SELECTION IN MORMONIELLA VITRIPENNIS. PMID- 28563721 TI - THE SOCIAL SIGNIFICANCE OF AVIAN WINTER PLUMAGE VARIABILITY: A COMMENT. PMID- 28563722 TI - REPRODUCTIVE SUCCESS AND THE EVOLUTION OF BREEDING TERRITORIES IN PUPFISH (CYPRINODON). PMID- 28563724 TI - GENETIC VARIATION ASSOCIATED WITH GROWTH RATE IN THE AMERICAN OYSTER (CRASSOSTREA VIRGIN ICA). PMID- 28563723 TI - TEMPORAL DIOECISM: AN ALTERNATIVE TO DIOECISM? PMID- 28563725 TI - WHY ARE THERE INBREEDING EFFECTS IN HAPLO-DIPLOID SYSTEMS? PMID- 28563726 TI - POPULATION SUBDIVISION AND GENETIC DIVERGENCE IN THE RED-BELLIED NEWT, TARICHA RIVULARIS. PMID- 28563727 TI - A MULTIVARIATE ANALYSIS OF BEHAVIORAL DIVERGENCE AMONG CLOSELY RELATED SPECIES OF ENDEMIC HAWAIIAN DROSOPHILA. PMID- 28563728 TI - COURTSHIP PATTERNS AND EVOLUTION OF THE DROSOPHILA ADIASTOLA AND PLANITIBIA SPECIES SUBGROUPS. PMID- 28563729 TI - EVOLUTIONARY TRANSITION FROM AMMONITE SUBPRIONOCYCLUS TO REESIDITES-PUNCTUATED OR GRADUAL? PMID- 28563730 TI - SEXUAL SELECTION IN TOADS: THE ROLES OF FEMALE CHOICE AND MALE BODY SIZE. PMID- 28563731 TI - BIOLOGICAL VARIABILITY IN THE PARTHENOGENETIC GRASSHOPPER WARRAMABA VIRGO (KEY) AND ITS SEXUAL RELATIVES. II. THE WESTERN AUSTRALIAN TAXA. PMID- 28563732 TI - SELECTIVE PREDATION OF THREESPINE STICKLEBACKS (GASTEROSTEUS ACULEATUS) BY GARTER SNAKES. PMID- 28563733 TI - ON THE MAINTENANCE OF STABILITY IN HINDWING DIVERSITY AMONG MOTHS OF THE GENUS CATOCALA (LEPIDOPTERA: NOCTUIDAE). PMID- 28563734 TI - GENETIC VARIATION IN ANNUAL PHLOX: SELF-COMPATIBLE VERSUS SELF-INCOMPATIBLE SPECIES. PMID- 28563735 TI - PHENOTYPES AND GENOTYPES IN CLADOCERAN POPULATIONS. PMID- 28563736 TI - THE EVOLUTIONARY SIGNIFICANCE OF DELAYED EMERGENCE FROM THE NEST BY HATCHLING TURTLES. PMID- 28563737 TI - MATING PATTERN AND MATING SUCCESS OF DROSOPHILA PSEUDOOBSCURA KARYOTYPES IN LARGE EXPERIMENTAL POPULATIONS. PMID- 28563738 TI - CHROMOSOMAL HOMOLOGY AND DIVERGENCE BETWEEN SIBLING SPECIES OF DEER MICE: PEROMYSCUS MANICULATUS AND P. MELANOTIS (RODENTIA, CRICETIDAE). PMID- 28563739 TI - THE ORIGIN OF TRIPSACOID MAIZE (ZEA MAYS L.). PMID- 28563740 TI - GENETIC EVIDENCE FOR NATURALLY OCCURRING HYBRIDS BETWEEN MYTILUS EDULIS AND MYTILUS GALLOPROVINCIALIS. PMID- 28563741 TI - VERTEBRATE AIR BREATHING AROSE IN FRESH WATERS AND NOT IN THE OCEANS. PMID- 28563742 TI - CORRELATIONS OF QUANTITATIVE PARAMETERS OF FECUNDITY IN AMPHIBIANS. PMID- 28563743 TI - DEMOGRAPHIC AND GENETIC RESPONSES OF TWO STRAINS OF TRIBOLIUM CASTANEUM TO A NOVEL ENVIRONMENT. PMID- 28563744 TI - REPRODUCTIVE ADAPTATIONS AMONG VIVIPAROUS FISHES (CYPRINODONTIFORMES: POECILIIDAE). PMID- 28563745 TI - DENSITY DEPENDENT FORAGING ON LIATRIS PYCNOSTACHYA. PMID- 28563747 TI - DIFFERENTIATION OF A MULTIGENE FAMILY BETWEEN POPULATIONS. AB - Differentiation of a multigene family between populations is investigated under the forces of intrachromosomal unbiased gene conversion, neutral mutation, recombination, and random drift. The infinite-site model without recombination within the gene is employed, and the average numbers of the different sites between pairs of genes at the same locus and at different loci from two populations that divided some time ago are calculated as functions of time. Since differentiation is a relative concept in which differences between populations are expressed in comparison with those within a population and since there is most likely a reduction in population size after the division of populations, the time-dependent behavior of the corresponding quantities within a population is also investigated using approximate and numerical methods. It is found that intrachromosomal unbiased gene conversion promotes differentiation at the same locus but promotes or retards that between different loci, depending on the parameters in a recently divided population. PMID- 28563748 TI - THE AERODYNAMICS OF POLLEN CAPTURE IN TWO SYMPATRIC EPHEDRA SPECIES. AB - Wind-tunnel analyses of the behavior of airborne pollen around ovules of two Ephedra species (E. trifurca and E. nevadensis) indicate that at certain airflow speeds (0.5 m/sec and 1.0 m/sec) each species is capable of biasing pollination in favor of conspecific pollen. A computer procedure was designed to evaluate the physical basis for this aerodynamic discrimination. This procedure indicates that differences in size and density confer significantly different inertial properties to the two pollen species. Operating within the specific aerodynamic environments generated around ovules from each species, these differences are sufficient to account for the biases observed in the probability of pollination. Within natural populations, there exists significant variation in pollen size (and possibly in density). Accordingly, it is possible that, under certain ambient wind conditions, ovules from each species can select subsets of the entire airborne population of Ephedra pollen. PMID- 28563746 TI - Efficient Homodifunctional Bimolecular Ring-Closure Method for Cyclic Polymers by Combining RAFT and Self-Accelerating Click Reaction. AB - An efficient metal-free homodifunctional bimolecular ring-closure method is developed for the formation of cyclic polymers by combining reversible addition fragmentation chain transfer (RAFT) polymerization and self-accelerating click reaction. In this approach, alpha,omega-homodifunctional linear polymers with azide terminals are prepared by RAFT polymerization and postmodification of polymer chain end groups. By virtue of sym-dibenzo-1,5-cyclooctadiene-3,7-diyne (DBA) as small linkers, well-defined cyclic polymers are then prepared using the self-accelerating double strain-promoted azide-alkyne click (DSPAAC) reaction to ring-close the azide end-functionalized homodifunctional linear polymer precursors. Due to the self-accelerating property of DSPAAC ring-closing reaction, this novel method eliminates the requirement of equimolar amounts of telechelic polymers and small linkers in traditional bimolecular ring-closure methods. It facilitates this method to efficiently and conveniently produce varied pure cyclic polymers by employing an excess molar amount of DBA small linkers. PMID- 28563749 TI - MALE SPERMATOPHORE INVESTMENT INCREASES FEMALE FECUNDITY IN A GRASSHOPPER. PMID- 28563750 TI - EQUILIBRIUM ANALYSIS OF SEXUAL SELECTION IN DROSOPHILA MELANOGASTER. AB - Several models for sexual selection, both by male-male competition and female choice, predict that a character which covaries with mating success should be near an equilibrium where the intensity of sexual selection opposes viability selection. This prediction was used to design experiments for estimating the intensity of sexual and viability selection on wing length in a recently captured population of Drosophila melanogaster. Observations of matings by males color marked for wing length indicated that the standardized sexual selection differential on wing length was 0.24 under a wide range of effective sex ratios. After estimating the heritability of wing length to be 0.62, the expected standardized response due to sexual selection was calculated as 0.15 (SE = 0.15). The response due to viability selection was then estimated by comparing wing lengths of progeny of flies that had been randomly mated, thereby preventing sexual selection, with progeny of flies that had been allowed to acquire mates in a mass-mating chamber. The results support an equilibrium model in that the standardized response due to viability selection (-0.31, SE = 0.08) was opposite in sign and similar in magnitude to the estimated response due to sexual selection. Observations of females orienting in front of males which differed in wing length indicated that the mating advantage accruing to long-winged males was not due to female choice. Instead, male-male competition in which the larger of two randomly chosen males succeeded in mating, explains the observed sexual selection. An experimental analysis of genotype-environment interaction revealed that larval density had a nonlinear effect on mean wing length within sibships. If a population is displaced from equilibrium, therefore, the evolutionary trajectory of mean wing length will depend both on the intensity of selection and the environment in which that selection is operating. PMID- 28563751 TI - MORPHOLOGICAL VARIABILITY IN GENETICALLY DEFINED CATEGORIES OF ANURAN HYBRIDS. AB - Hybridization phenomena in anurans have traditionally been studied through morphological comparisons, under the assumption that various hybrids (e.g., F1 's, backcrosses) are predictably intermediate to parental species. We critically evaluate this assumption by examining morphology in genetically categorized hybrids between the treefrogs Hyla cinerea and H. gratiosa. A total of 202 frogs from a hybridizing population in Alabama were assayed for allozyme and mitochondrial DNA genotype and for a large suite of osteological characters. Discriminant analyses demonstrated distinct morphological separation between the genetically "pure" parental species. Morphometric analyses of genetically identified hybrids showed: 1) an extreme range of phenotypic expression within F1 and backcross classes, and 2) no apparent directional parental bias on the F1 phenotype. Had morphology alone been used as a guide, over 40 percent of the individuals with known hybrid ancestry would have been misclassified as "pure" parental species, and about 25 percent of the backcross individuals would not have been distinguished from F1 's. These results exemplify the utility of joint comparisons of morphology and genotypic constitution in studies of natural hybridization, and they emphasize the limitations inherent in describing hybrid classes solely by morphological criteria. PMID- 28563752 TI - EVOLUTIONARY INFERENCES FROM RESTRICTION MAPS OF MITOCHONDRIAL DNA FROM NINE TAXA OF XENOPUS FROGS. AB - Restriction endonuclease cleavage maps were prepared by the double digestion method for mitochondrial DNAs (mtDNAs) purified from Xenopus borealis, X. clivii, X. fraseri, X. muelleri, X. ruwenzoriensis, X. vestitus, X. laevis victorianus, X. l. laevis, and a variant of X. laevis designated X. laevis "davis." An average of 21 cleavage sites per genome were mapped with 11 restriction endonucleases. Among the four invariant sites found are three conserved not only among the Xenopus mtDNAs tested but also among nearly all vertebrate mtDNAs examined to date. Two of these are Sac II sites in the 12S and 16S ribosomal RNA genes, and one is a Hpa I site in the gene for asparagine transfer RNA. These three sites permit the alignment and comparison of mtDNAs from different vertebrate classes. Although most of the differences observed among the Xenopus maps are attributable to point mutations causing gain or loss of restriction sites, the maps also differ by three large length mutations in or near the displacement loop. Phylogenetic analysis of 30 informative sites suggests that those members of the laevis species-group that have 36 chromosomes per somatic cell can be divided into three subgroups: 1) X. borealis, X. clivii, and perhaps X. fraseri (the "borealis" subgroup), 2) X. muelleri, and 3) the subspecies of X, laevis. The mtDNA of the hexaploid (2n = 108) species, X. ruwenzoriensis, is most similar to that of taxa in the latter two subgroups, which contrasts with the morphological similarity of this species to X. fraseri. X. ruwenzoriensis may be an allopolyploid with a mother (the contributor of the cytoplasmic mtDNA genome) on the X. laevis or X. muelleri lineage and a father on the X. fraseri lineage. We present a model showing how mtDNA and nuclear genomes can yield contrasting phytogenies for species-groups that have undergone several rounds of interspecific hybridization. Comparison of mitochondrial and nuclear sequence divergences suggests that Xenopus mtDNA, like that of mammals and birds, evolves faster than nuclear DNA. Genetic distances among mtDNAs of Xenopus species are very large, generally approaching or exceeding one substitution per nucleotide. PMID- 28563753 TI - INTERSPECIFIC COMPETITIVE INTERACTIONS AND THE MAINTENANCE OF GENOTYPIC VARIATION WITHIN TWO PERENNIAL GRASSES. AB - Theoretical models predict that natural selection acting through competitive interactions should lead to increased divergence in resource use and to more equal competitive abilities among different genotypes. The consequent overcompensatory interactions and similar competitive abilities will favor maintenance of genotypic diversity. In field experiments we found that naturally co-occurring genotypes of two perennial grasses, Danthonia spicata and Anthoxanthum odoratum, differed in interspecific competitive performance. The competitive performance of a given genotype often depended on the genotypic identity of the competing species, especially in Danthonia spicata. Both overcompensatory and undercompensatory interactions were found, but neither was prevalent for both species. These data indicate that interactions between species are complex and have an important genetic component. The results from this experiment are compatible with a competitive explanation for the maintenance of genetic variation, but the persistence of weakly competitive genotypes cannot be explained. PMID- 28563754 TI - SEX-RATIO SELECTION WITH MIGRATION: DOES FISHER'S RESULT HOLD? PMID- 28563755 TI - MATE CHOICE BASED UPON NATURALLY OCCURRING COLOR-PATTERN VARIATION IN A GUPPY POPULATION. AB - This study tested the effect of differences in the extent of orange pigment in the color pattern of male guppies on the sexual responsiveness of females. Fish used in this study were descendants of a single natural population from the Paria River of Trinidad. Males from this population have unusually large, brilliant orange spots. I used three experimental approaches to test for discrimination by females among males based on the relative area of orange in color patterns: 1) the time to mating when a male was presented to a virgin female; 2) the frequency of sexual responses of females to passing, nondisplaying males; and 3) the proportion of a male's courtship displays that elicited a female sexual response. In all three experiments, females appeared to discriminate against males with less-than-average amounts of orange in their color patterns. In at least one experiment, however, the increase in female responsiveness with increasing amounts of orange leveled off and possibly decreased at high levels of orangeness. This suggests that there may be no advantage of increased amounts of orange above a certain level. These results suggest that female choice is a mechanism for the evolution of color patterns in guppies and may have contributed to the distinctive color pattern of the Paria population. PMID- 28563756 TI - A QUANTITATIVE-GENETIC ANALYSIS OF LARVAL LIFE-HISTORY TRAITS IN HYLA CRUCIFER. AB - We used a half-sib design to examine the genetic components of phenotypic variance in several life-history traits in Hyla crucifer. Egg viability, hatchling size, larval growth rate, length of larval period, and size at metamorphosis play critical roles in determining survivorship and are subject to persistent selection. Egg viability varied among families considerably, with most embryo mortality occurring between gastrulation and neurulation. Hatchling size was the only trait in which maternal effects were influential. Dominance genetic variance played the predominant role in determining phenotypic variance in hatchling size, growth rate, and length of larval period, accounting for, respectively, 70, 63, and 47% of the total variance. Size at metamorphosis displayed little dominance genetic variance and, unlike the other traits, displayed a high heritability. All additive genetic correlations between traits were positive. The directions of environmental correlations were the same as the directions of changes that have been induced in previous experimental work. The correlations due to dominance effects described a principal axis that independent ecological studies indicate to be directly correlated with fitness. These results agree with theoretical expectations for traits under consistent directional selection. PMID- 28563757 TI - INFLUENCE OF FAMILIARITY ON FREQUENCY OF INBREEDING IN WILD HORSES. PMID- 28563758 TI - ON THE EFFECT OF FOUNDER EVENTS ON EPISTATIC GENETIC VARIANCE. AB - Mayr (1963) proposed that small isolated propagules from a large panmictic population would occasionally undergo a genetic revolution due to loss of genetic variability. More recently Templeton (1980a) has suggested that founder events may be much more important in systems that have strong epistasis. Because of the work of these and other authors it becomes an interesting theoretical problem to study the distribution of epistatic variance in a population following a founder event. In the model presented here measures of coancestry (Cockerham, 1967, 1984; Cockerham and Weir, 1973; Weir and Cockerham, 1973, 1977; Tachida and Cockerham, unpubl.) are used to examine the effect of founder events on additive-by-additive epistasis. Using this approach, the coancestries, or intraclass correlations, within individuals and within demes, together with the genetic variance components in the ancestral population are used to obtain the variance within and among demes following a founder event. Examples are analyzed for single founder events of 1-25 individuals and multiple founder events of two individuals. Following a single founder event, the contribution of the additive variance to the variance within demes relative to the additive variance in the ancestral population is always less than one. However, the contribution of epistatic variance to the variance within demes relative to the epistatic variance in the ancestral population is always greater than one. Thus, while a founder event decreases the contribution of additive variance to the variance within demes, it increases the contribution of epistatic variance to the variance within demes. The contribution of epistatic variance to the variance among demes following a single founder event is not qualitatively different from the contribution of additive variance to the variance among demes. These results indicate that epistatic variance is less likely than additive variance to cause a genetic revolution following a single founder event. When populations undergo multiple founder events the situation changes considerably. Epistatic variance may contribute as much as four times its original value to the variance among demes, while additive variance can contribute maximally twice its original value to the variance among demes. Thus, epistasis, which is relatively unimportant following a single founder event, may have major evolutionary implications if drift is allowed to continue for several generations. PMID- 28563759 TI - A MULTIFACTORIAL BEHAVIORAL STUDY OF COEXISTING DROSOPHILID SPECIES IN NATURE. AB - A multifactorial experiment was performed to differentiate among sympatric drosophilid species by their responses to several variable factors when selecting an oviposition site in nature. D. busckii, D. affinis, and S. pallida were significantly more photonegative when ovipositing 150 cm above the ground than when ovipositing 30 cm above the ground. D. busckii showed the greatest effect of height on photoresponse. D. affinis was the most photonegative at either height. There was no evidence for photobehavioral differentiation of the four species studied between two collecting sites within the habitat. Similarly, there was no difference in oviposition-site preference between flies laying eggs in the morning and the afternoon. Three of the four sympatric species can be distinguished from the others by their unique behavioral profiles, which are probably responsible for maintaining niche separation. PMID- 28563760 TI - POPULATION GENETICS OF INTRAGAMETOPHYTIC SELFING. AB - Intragametophytic selfing is a mode of reproduction occurring in homosporous ferns where two gametes from the same haploid gametophyte form a completely homozygous sporophyte. The inbreeding equilibrium is derived for a population with partial intragametophytic selfing, selfing, and outcrossing. Procedures for directly estimating the extent of intragametophytic selfing and selfing using parent-offspring data are given. The conditions for a stable polymorphism from a heterozygous-advantage fitness model are more restrictive for partial intragametophytic selfing than for selfing. The rate of decay of gametic disequilibrium is slower for partial intragametophytic selfing than for selfing. Based on these findings, one would predict that plants with intragametophytic selfing would have less polymorphism for loci with a heterozygous advantage and more gametic disequilibrium between neutral loci than is expected for populations with an equivalent amount of selfing. Data from several studies are consistent with these predictions. PMID- 28563761 TI - ANALYSIS OF FLUCTUATING ASYMMETRY IN CHEETAHS. PMID- 28563762 TI - SELECTION FOR SEXUAL ISOLATION BETWEEN GEOGRAPHIC FORMS OF DROSOPHILA MOJAVENSIS. I. INTERACTIONS BETWEEN THE SELECTED FORMS. AB - Drosophila mojavensis comprises three geographic forms occurring in the United States, the Baja California peninsula, and mainland Mexico. Peninsular and mainland forms were selected for increased sexual isolation from each other, while controls were maintained with maximum outbreeding. Response to selection was highly asymmetrical in that isolation was very high between selected peninsular males and mainland females, but nonexistent between selected mainland males and peninsular females. The heightened isolation is primarily due to some change in the peninsular males. PMID- 28563764 TI - VIABILITIES OF AMYLASE GENOTYPES IN DROSOPHILA PSEUDOOBSCURA ON STARCH AND MALTOSE FOOD. AB - In order to study the relationship between selection on an enzyme and the environment, viability was measured for genotypes at the alpha-amylase (Amy) locus of D. pseudoobscura on food containing either starch as the primary source of carbohydrates or, as a control, maltose, the breakdown product of starch by amylase. These conditions were chosen to reveal possible differences among these genotypes in their abilities to survive on starch food. Counted numbers of larvae were cultured on food with low or high levels of starch, or with maltose, at both 20 degrees C and 25 degrees C. Only under the most stressful environmental conditions, on food with a low starch concentration at 25 degrees C, did the genotypes differ significantly in viability. Four population cages maintained on food with either maltose or starch as carbohydrate sources were set up to assay differences in overall fitness among the Amy genotypes. No selective differences were observed over 10 generations, and we infer that components of fitness other than viability also differed little among the Amy genotypes on the two types of food. Thus our efforts to manipulate the environmental levels of starch, the substrate of amylase, led to measurable selective differences only under very stressful conditions. PMID- 28563763 TI - COEVOLUTION AS AN EVOLUTIONARY GAME. AB - Coevolution is modeled as a continuous game where the fitness-maximizing strategy of an individual is assumed to be a function of the strategy of other individuals who are also under selection to maximize fitness. An evolutionary stable strategy (ESS) is sought such that no rare alternative strategies can invade the community. The approach can be used to model coevolution because the ESS may be composed of a coalition of more than one strategy. This work, by modeling frequency-dependent selection, extends the approach of Roughgarden (1976) which only considered density-dependent selection. In particular, we show that the coevolutionary model of Rummel and Roughgarden (1985) does contain frequency dependent selection, and thus, their application of Roughgarden's criterion for evolutionary stability to a model for which it is not applicable leads to the erroneous conclusion that the ecological and evolutionary processes are in conflict. The utility of the game theoretic approach is illustrated by two examples. The first considers an ESS composed of a single strategy, the second an ESS composed of a coalition of two strategies. Evolution occurs on a frequency dependent adaptive landscape. For this reason, the approach is appropriate for modeling competitive speciation (Rosenzweig, 1978). Also, the game theoretic approach is designed to combine the interplay between the background environment (including the biotic components) and the evolutionary potential of the populations or organisms. The actual application of this theory will require knowledge of both. PMID- 28563765 TI - EFFECTS OF POPULATION STRUCTURE AND CONE PRODUCTION ON OUTCROSSING RATES IN ENGELMANN SPRUCE AND SUBALPINE FIR. AB - Variation in the mating systems of Engelmann spruce and subalpine fir was examined in two adjacent subpopulations in the Colorado Front Range. Multilocus outcrossing rates were estimated from analysis of allozyme variation in embryo and megagametophyte tissue. The overall multilocus outcrossing rate of 0.93 for spruce was significantly higher than the outcrossing rate of 0.89 for fir. Outcrossing rates varied from 0.73 to 0.97 for spruce and from 0.65 to 0.94 for fir when trees of each species were grouped according to age, size, spatial distribution, maternal heterozygosity, cone production, and year of sampling. In both spruce and fir, trees with higher levels of male-cone production and/or more clumped spatial distribution had lower outcrossing rates. Temporal variation in outcrossing rates within subpopulations, examined only in spruce, was less than variation between subpopulations. Male-cone production was significantly correlated with tree size, and regression analyses revealed that the highest outcrossing rates are expected on trees that are medium to large in size, rather than the largest trees in the forest. The results show that, while there is some temporal variation, patterns of male cone production and spatial distribution of individuals are the most important factors influencing outcrossing levels in these wind-pollinated forest trees. PMID- 28563766 TI - FLUCTUATING ASYMMETRY IN THE CHEETAH: METHODOLOGICAL AND INTERPRETIVE CONCERNS. PMID- 28563767 TI - LIFETIME REPRODUCTIVE SUCCESS, SELECTION, AND THE OPPORTUNITY FOR SELECTION IN THE WHITE-TAILED SKIMMER PLATHEMIS LYDIA (ODONATA: LIBELLULIDAE). AB - We present estimates of lifetime reproductive success in Plathemis lydia, a territorial dragonfly. We partition the opportunity for selection into multiplicative episodes using the techniques of Arnold and Wade (1984a, 1984b) and measure selection on several morphological and behavioral characters. For both sexes, variance in survivorship was the largest contribution to variance in lifetime reproductive success. Covariance effects are also strong for both sexes, suggesting considerable non-independence of episodes. Opportunity for selection calculated on a daily basis did not approximate analogous values determined from lifetime reproductive success. Phenotypic characters for which we investigated selection included body mass, hind wing length, first date of reproduction, and (for males) an index of territorial aggressiveness. We failed to find any significant direct targets of selection in either males or females. However, the combined effects of direct and indirect selection on early reproduction were significant for males, acting primarily through increased survivorship and increased time per day spent at the pond. Similarly, females present earlier in the season had shorter interclutch intervals. Partitioning of selection acting on male hind wing length and on aggressiveness reveals relationships between selective episodes, possibly indicative of phenotypic trade-offs between natural and sexual selection through male-male competition for females. Division of selection into episodes is a useful technique for identifying the source of selection. However, ordering effects can bias results, except when episodes occur in strictly chronological sequence. We present a method for circumventing this difficulty. PMID- 28563768 TI - RATES OF EVOLUTIONARY CHANGE IN CHROMOSOME NUMBERS IN SNAILS AND VERTEBRATES. AB - Mollusks and most non-mammalian vertebrates have been characterized as evolving an order of magnitude more slowly in morphology and karyotype compared with most groups of placental mammals. New calculations of the previously used measures of chromosomal rates of evolution for different groups of gastropods, using a larger and taxonomically broader sample, indicate that these rates had been previously underestimated, although they are still lower than those of the most rapidly evolving placental groups. When genera of approximately the same geological age are compared, little difference (less than an order of magnitude) in fossil-based measures of average rate of karyotypic evolution are found among placental mammals, frogs, lizards, and snails. Variation in rates within major groups obtained from the limited available data does not allow clear generalizations on among-group differences in chromosomal rates of evolution. PMID- 28563769 TI - EVOLUTION OF THE NUMBER OF SEXES. AB - In sexually reproducing isogamous organisms, gametes (or diploid cells in ciliates) are classified into two or more groups called sexes, and mating occurs only between cells of different sexes. We have studied the evolutionary stability of the number of sexes maintained in a population by examining population-genetic models. For models in which the diploid genome determines the sex of conjugal cells, a one-locus system with three alleles of pecking-order dominance is assumed. Unlike traditional bisexual models, the genetic dynamics then depend on a rule, called mating kinetics, which determines the proportion of matings between each pair of sexes for given proportions of cells of the three sexes. The evolutionary consequences greatly depend on the mating kinetics assumed. Of the four mating kinetics examined, two give a large advantage to rare sexes whose cells quickly find heterosexual partners, which implies an evolutionary increase in the number of sexes. In contrast, the other two mating kinetics, in which gametes wait for suitable mates without being eliminated from the gamete pool during this waiting period, produce neutrally stable dynamics with curves or a surface of equilibria. Then random drift or differential fitness among sexes would result in the loss of sex alleles until only two remain in the population. This suggests a turnover of sexes; a new sex invades and replaces resident sexes after temporary coexistence. Similar results are obtained in models with haploid sex-determination and with autogamy. These two processes, however, may help to maintain many sexes indirectly by preventing the accumulation of recessive lethal mutations on sex chromosomes. The relationship of these models to models of self sterility factors in plants and sex factors in honeybees is discussed. To summarize, the number of sexes should increase when conjugal cells must find mates during a limited period of time, otherwise a two-sex system should evolve. We conclude that there may be more isogamous species with three or more sexes than are currently known. PMID- 28563770 TI - INSENSITIVITY OF BRAIN GROWTH TO SELECTION OF FOUR-WEEK BODY MASS IN JAPANESE QUAIL. PMID- 28563771 TI - THE GENETIC CONSEQUENCES OF CONTRASTING BREEDING SYSTEMS IN PLECTRITIS (VALERIANACEAE). PMID- 28563772 TI - THE GENUS: A MACROEVOLUTIONARY PROBLEM. PMID- 28563773 TI - TEMPORAL SHIFTS IN GENE FLOW AND SEED SET: EVIDENCE FROM AN EXPERIMENTAL POPULATION OF CUCUMIS SATIVUS. PMID- 28563774 TI - SPERM DEPENDENCE OF FEMALE RECEPTIVITY TO REMATING IN DROSOPHILA MELANOGASTER. PMID- 28563775 TI - A QUANTITATIVE GENETIC ANALYSIS OF BRAIN AND BODY SIZE ASSOCIATIONS, THEIR ORIGIN AND ONTOGENY: DATA FROM MICE. PMID- 28563776 TI - MATING-TEMPERATURE RANGE IN DROSOPHILA. PMID- 28563778 TI - EVOLUTION IN A PAEDOMORPHIC LINEAGE. II. ALLOMETRY AND FORM IN THE MEXICAN AMBYSTOMATID SALAMANDERS. PMID- 28563779 TI - ON THE EVOLUTION OF EMBRYO ABORTION IN THE HERBACEOUS PERENNIAL CRYPTANTHA FLAVA. PMID- 28563780 TI - THE EFFECT OF EXPERIMENTAL DESIGN ON FEMALE RECEPTIVITY TO REMATING AND ITS IMPACT ON REPRODUCTIVE SUCCESS IN DROSOPHILA MELANOGASTER. PMID- 28563781 TI - FAUNAL TURNOVER AND DEVELOPMENT OF FOSSIL AVIFAUNAS IN SOUTH AMERICA. PMID- 28563782 TI - A QUANTITATIVE GENETIC MODEL FOR THE ORIGIN OF MATING PREFERENCES. PMID- 28563783 TI - EVOLUTION IN A PAEDOMORPHIC LINEAGE. I. AN ELECTROPHORETIC ANALYSIS OF THE MEXICAN AMBYSTOMATID SALAMANDERS. PMID- 28563785 TI - DISRUPTIVE SELECTION ON HABITAT PREFERENCE AND THE EVOLUTION OF REPRODUCTIVE ISOLATION: A SIMULATION STUDY. PMID- 28563786 TI - PATTERN BENEATH THE CHAOS: THE EFFECT OF RECRUITMENT ON GENETIC PATCHINESS IN AN INTERTIDAL LIMPET. PMID- 28563787 TI - DISPERSAL RATES OF SPECIES OF THE DROSOPHILA OBSCURA GROUP: IMPLICATIONS FOR POPULATION STRUCTURE. PMID- 28563788 TI - REACTION NORMS OF DEVELOPMENT RATE AMONG DIPLOID CLONES OF THE PARTHENOGENETIC COCKROACH PYCNOSCELUS SURINAMENSIS. PMID- 28563789 TI - GYNODIOECY IN PLANTAGO LANCEOLATA L. IV. FITNESS COMPONENTS OF SEX TYPES IN DIFFERENT LIFE CYCLE STAGES. PMID- 28563790 TI - SPECIATION IN THE GENUS CRINIA (ANURA: MYOBATRACHIDAE) IN SOUTHERN AUSTRALIA: A PHYLOGENETIC ANALYSIS OF ALLOZYME DATA SUPPORTING ENDEMIC SPECIATION IN SOUTHWESTERN AUSTRALIA. PMID- 28563791 TI - ESTIMATING F-STATISTICS FOR THE ANALYSIS OF POPULATION STRUCTURE. PMID- 28563792 TI - THE DISTRIBUTION OF POSTMATING REPRODUCTIVE ISOLATING GENES IN POPULATIONS OF THE YELLOW MONKEY FLOWER, MIMULUS GUTTATUS. AB - Postmating reproductive isolating barriers are generally believed to arise as the chance by-product of genetic differentiation. The classical view is that these barriers normally involve differentiation at many loci, and therefore require long periods of allopatric isolation. The formal genetics of, and the distribution of genes responsible for, such barriers are known in very few cases. This paper examines the distribution of the genes responsible for two different postmating barriers in 18 populations of the yellow monkey flower, Mimulus guttatus. The genetic relatedness of the populations was measured by a morphometrical analysis. Widespread polymorphism was found for three of the four components of the two genetic systems responsible for the two barriers, with at least 13 populations possessing genes for one or both of the barriers. In one system (the C7/U8 system; Christie and Macnair, 1984), the distribution of the two component genes was correlated with the morphometrical similarity and geographical location of the populations. This pattern could be produced by a historical association or by an adaptive response. In the other system (the Cerig/C10 system; Macnair and Christie, 1983), the genes were more widely dispersed, and there was no obvious morphometrical or geographical association. Populations possessing the complementary factors causing partial reproductive isolation are not always widely separated geographically. These results indicate that the spread of postmating reproductive isolating genes through drift, selection, or hitchhiking could readily cause reproductive isolation to evolve in this species.>. PMID- 28563793 TI - PHOSPHOGLUCOMUTASE GENE DUPLICATIONS IN CLARKIA (ONAGRACEAE) AND THEIR PHYLOGENETIC IMPLICATIONS. PMID- 28563794 TI - CHROMOSOMAL VARIATION IN PEROMYSCUS MANICULATUS POPULATIONS ALONG AN ELEVATIONAL GRADIENT. PMID- 28563795 TI - GEOGRAPHIC VARIATION OF SEXUAL DIMORPHISM IN SIZE OF SAVANNAH SPARROWS (PASSERCULUS SANDWICHENSIS): A TEST OF HYPOTHESES. AB - The Savannah Sparrow (Passerculus sandwichensis) is a widespread and common North American bird that shows both geographic variation and sexual dimorphism in size. I used information from 24 measurements on 1,791 individuals from 51 populations to test two hypotheses (sexual-selection and niche-partitioning) about the evolution of sexual dimorphism. Throughout their range male Savannah Sparrows are larger, on average, than females. This doubtless reflects Darwinian sexual selection, for territorial fights usually involve males, many of whom fail to obtain mates. In some parts of their range, Savannah Sparrows are commonly polygynous, whereas in others they are characteristically monogamous. Among species of American sparrows (subfamily Emberizinae) sexual size dimorphism is generally greater in polygynous species than in monogamous ones. However, I did not find a similar trend among populations of Savannah Sparrows. The amount of dimorphism in all populations of Savannah Sparrows is equivalent in magnitude to that of other species of sparrows that are commonly or regularly polygynous, and it is greater than that of other sparrow species that are characteristically monogamous. The amount of sexual dimorphism, either in overall size or in bill size, does not correlate with species diversity and does not differ between island and mainland populations. These results do not support the niche-variation hypothesis. Size dimorphism is relatively great in populations of Savannah Sparrows that are resident in southwestern salt marshes, and these birds are the only sparrow-like birds that generally breed in these marshes. Dimorphism is, in general, relatively great in marsh-dwelling species in the family Emberizidae. These species are commonly, but not always, polygynous; the mating systems of the salt-marsh Savannah Sparrows are not known. There are no significant differences in the extent of dimorphism among populations of salt-marsh sparrows, and there are few among the non-salt-marsh ones, probably reflecting conservatism in the evolution of size dimorphism. PMID- 28563796 TI - POPULATION STRUCTURE AND ESTIMATES OF GENE FLOW IN THE HOMOSPOROUS FERN POLYSTICHUM MUNITUM. AB - Levels and distribution of genetic variation were investigated in the homosporous fern, Polystichum munitum. Homosporous ferns differ from higher vascular plants in that they possess potentially bisexual gametophytes which can produce a completely homozygous sporophyte in a single generation. Because of this, it has long been maintained that ferns possess an inbreeding mating system, resulting in low levels of genetic variation and high levels of homozygosity within populations. The four populations sampled maintain high levels of genetic variation (P = 0.542; H = 0.111; A = 2.23), comparable to that maintained by populations of outcrossing seed plants. The mean fixation index, F, for the four populations was 0.052, indicating no significant deviations from Hardy-Weinberg genotypic expectations. Polystichum munitum distributes most of its genetic variation within rather than among populations. Population-genetic structure was assessed by subdividing each of two large populations into 10 * 10-m subpopulations. Comparisons of genetic variation within and among subpopulations indicated little genetic substructure within either of the artificially subdivided populations. Estimates of interpopulational gene flow (Nm) are extremely high, comparable to those reported for gymnosperms. Statistical estimates of intragametophytic selling are very low, ranging from 0 to 3%. This study suggests that Polystichum munitum is an outcrossing species. Evidence from this and other investigations indicates that fern species do not typically self fertilize and that mating systems in ferns vary as they do among species of seed plants. PMID- 28563797 TI - ISOLATING MECHANISMS IN SEABIRDS. AB - In most species of birds, differences in plumage coloration or song structure act as isolating mechanisms. In seabirds, plumages are generally drab, and vocal repertoires are limited so that other phenotypic attributes must act as isolating mechanisms. One classic study of gulls suggests that the contrast between eye color and head color acts as a reproductive isolating mechanism, but this idea has been largely refuted by widespread evidence of hybridization in gulls in the last 20 years. An examination of more than 100 species of seabirds that breed sympatrically with congeners reveals that species with bills and feet similar in color hybridize in all areas where they breed sympatrically. Species that have bills or feet of different colors either do not hybridize or they produce rare hybrids that are unable to obtain mates as adults. This suggests that bill and foot coloration act as the primary isolating mechanisms in all surface-nesting seabirds and some burrow nesters. It may be a general pattern in birds that foot color acts to supplement bill color in reproductive isolation and mate choice. PMID- 28563798 TI - SUBSPECIES OF THE CANADA GOOSE (BRANTA CANADENSIS) HAVE DISTINCT MITOCHONDRIAL DNA'S. PMID- 28563799 TI - EVOLUTION AND COADAPTATION OF THERMOREGULATORY BEHAVIOR AND WING PIGMENTATION PATTERN IN PIERID BUTTERFLIES. AB - This paper addresses the question of how the relationship between morphological structure and functional performance differs in related groups of organisms. I describe the relationship between a suite of phenotypic characters (behavioral posture and the pattern of wing pigmentation) and one function of these characters (thermoregulatory performance) for two groups of butterflies in the family Pieridae, focusing on how behavior and wing pattern interact to affect specific aspects of thermoregulation. Using both natural and experimentally created variation in wing-melanization patterns, I develop and test a series of predictions about the relations among thermoregulatory posture, melanization pattern, body temperature, and flight activity. Results show that increased melanization in different wing regions has positive, negative, or neutral effects in increasing body temperature of Pieris butterflies. The angle of the wings used during basking alters the relative importance of different modes of heat transfer and thereby determines the contribution of different dorsal wing regions to thermoregulation. Experimentally increased dorsal melanization can either increase or decrease the onset of flight activity and can directly alter thermoregulatory posture. For Pieris, dorsal melanization affects basking and flight, while ventral melanization primarily affects overheating. These results are used to generate a functional map relating melanization pattern to thermoregulatory performance in Pieris. Reflectance-basking posture, white background color, and melanization pattern represent coadapted characters in Pieris that interact to determine thermoregulatory performance. The differences in thermoregulatory posture and background color between pierid butterflies in the subfamilies Pierinae and Coliadinae have led to a reorganization and partial reversal of the thermoregulatory effects of melanization pattern. I suggest that this change in the physical mechanism of thermoregulatory adaption in pierids has qualitatively altered the nature of selection on wing-melanization pattern. PMID- 28563800 TI - DIFFERENTIATION AND INTEGRATION OF THE GENOME IN POPULATIONS OF THE MARINE COPEPOD TIGRIOPUS CALIFORNICUS. AB - Geographically separated populations of the intertidal copepod Tigriopus californicus are sharply differentiated at several enzyme-encoding gene loci. Two studies were performed to investigate the extent to which the gene pools of local populations are organized into harmoniously interacting (or "coadapted") gene complexes. In the first, the effects of interpopulation hybridization on development time were assessed. Results showed that while F1 hybrids did not differ from parental lines, mean F2 developmental times were as much as 50% longer. The second study used two unlinked enzyme polymorphisms as genetic markers to determine the genotypic specificity of F2 hybrid breakdown. For two sets of parental populations, the relative viabilities of the different two-locus genotypes were determined from segregation ratios among the F2 progeny. Sharp deviations from Mendelian ratios were observed; in the extreme, a block of genes marked by the MeF allozyme from the LJ (La Jolla) population was found to be nearly lethal when homozygous in the F2 of LJ * AB (Los Angeles) crosses. This same block of genes had a tenfold higher viability in crosses between LJ and SC (Santa Cruz). In the AB * LJ crosses, the two marker loci had independent (multiplicative) effects on viability. In the SC * LJ crosses, deviations from the multiplicative model were observed; the data indicate that parental homozygous genotypes have higher viability than predicted by independence, while nonparental homozygotes have lower than predicted viability. These results suggest that substantial integration of the genome has occurred within natural T. californicus populations. PMID- 28563801 TI - REALIZED GENE FLOW VIA POLLEN IN ARTIFICIAL POPULATIONS OF MUSK THISTLE, CARDUUS NUTANS L. AB - Realized gene flow via pollen was measured in four adjacent, artificial populations of musk thistle, Carduus nutans L. by observing the distribution of electrophoretic markers at two allozyme loci. Realized gene movement declined exponentially with distance. Dispersal distances of the marker alleles averaged 5.0 m. Estimates of effective neighborhood sizes based on the movement of these genetic markers ranged from 126 to 378 individuals. When measures of seed movement were included, estimates of effective population sizes range from 1,281 to 3,844 individuals. It is, therefore, unlikely that chance effects play a major role in shaping the genetic structure of well-established musk thistle populations. PMID- 28563802 TI - DELAYED MATURATION, NEOTENY, AND SOCIAL SYSTEM DIFFERENCES IN TWO MANAKINS OF THE GENUS CHIROXIPHIA. AB - Long-tailed manakins (Chiroxiphia linearis) and swallow-tailed manakins (C. caudata) are closely related, sexually dichromatic, lek-breeding species in which male mating success is highly skewed. Males of both species delay plumage maturation. Before reaching the definitive state, they wear a sequence of feather coats less conspicuous than that of the adult. Nondefinitive plumages probably enhance male survival in the two species; in C. caudata they may also enhance breeding success of young males, who may be fully reproductively mature their first year. In C. linearis testicular development is retarded along with that of plumage, although males may be physiologically capable of breeding prior to the acquisition of the definitive plumage. This difference probably reflects differences in the social systems of the two species. Five hypotheses have been proposed to explain the evolution of delayed plumage maturation. The sexual selection, cryptic-breeder, and winter-adaptation hypotheses suggest that it functions primarily to enhance survival of young males. The juvenile- and female mimicry hypotheses emphasize enhancement of immediate mating success. Support is provided for all but the female-mimicry hypothesis; it is argued that data are more consistent with juvenile mimicry and a neotenic origin of nondefinitive plumages. PMID- 28563803 TI - ALTERNATIVE MODELS OF CHARACTER DISPLACEMENT AND NICHE SHIFT. I. ADAPTIVE SHIFTS IN RESOURCE USE WHEN THERE IS COMPETITION FOR NUTRITIONALLY NONSUBSTITUTABLE RESOURCES. AB - This paper analyzes the influence of the nutritional status of resources on the adaptive response to interspecific competition in a consumer of those resources. The two cases compared are that in which the resources are nutritionally perfectly substitutable (in the sense of Leon and Tumpson [1975]) and that in which the resources are nonsubstitutable. Each nonsubstitutable resource must be consumed at a certain rate for population growth to occur. Evolutionarily stable strategies of resource utilization are found using models of competition for two resources. If competition occurs solely via the consumer species's effects on resource density, the adaptive response in a consumer's resource-acquisition traits is: a) divergence away from its competitor's resource-acquisition traits if resources are perfectly substitutable and b) convergence towards the competitor's resource-acquisition traits if resources are nonsubstitutable. Exceptions to both of these generalizations may occur if competitor population density affects a consumer species's per capita growth rate independently of effects on resource density. Plants and herbivores often use nonsubstitutable resources. The lack of studies of adaptive responses to competition in these organisms may be responsible for the lack of documented examples of competitive convergence. PMID- 28563804 TI - THE FUNCTION OF CALL ALTERNATION IN ANURAN AMPHIBIANS: A TEST OF THREE HYPOTHESES. AB - Males of many species of anurans alternate calls with those of their neighbors in a chorus. This pattern of calling reduces signal interference and may: 1) facilitate intermale spacing because males can better gauge the intensity of neighbors' calls if these calls do not overlap with their own; 2) help preserve species-specific temporal information in calls required to attract females; and/or 3) make it easier for females to localize males in the chorus. I tested these hypotheses with three species that exhibit call alternation, Hyla crucifer, H. versicolor, and H. microcephala. Males of all three species gave more aggressive calls to high-intensity synthetic stimuli that alternated with their calls than to those that overlapped their calls. These results support the first hypothesis. Results of four-speaker female choice experiments using alternating and overlapping calls indicate that preservation of signal integrity also is important in H. versicolor and H. microcephala, species that have fine-scale temporal information in their calls. However, the third hypothesis was not supported; females failed to discriminate among alternating and overlapping calls if the problem of signal disruption was eliminated or irrelevant. PMID- 28563805 TI - SEX ALLOCATION AND OUTCROSSING RATE: A TEST OF THEORETICAL PREDICTIONS USING BROMEGRASSES (BROMUS). AB - Predictions of sex-allocation theory were tested by comparisons among hermaphroditic bromegrass (Bromus) species that differed in outcrossing rate. Relative maternal and paternal investment were calculated using both the ratio of pollen to seed production, and absolute allocations in units of energy, nitrogen, phosphorus, potassium, magnesium, and calcium. Outcrossing rate had a large effect on sex allocation; species having greater outcrossing rates had relatively more paternal reproductive effort. Bromus inermis was obligately outcrossing, and nearly half of its reproductive effort was devoted to pollen production. Three partially outcrossed species, B. kalmii, B. ciliatus, and B. latiglumis, invested between 5% and 11% of reproductive effort in pollen production. Paternal investment was less than 2% in the selling species B. tectorum. Estimates of sex allocation were relatively unaffected by the resource currency used in calculation. The differences among species in sex allocation were mostly due to differences in anther size and seed set.>. PMID- 28563806 TI - DISSECTING CORRELATED CHARACTERS: ADAPTIVE ASPECTS OF PHENOTYPIC COVARIATION IN MELANIZATION PATTERN OF PIERIS BUTTERFLIES. AB - In this study we address the question of how much of the covariation among phenotypic characters observed in natural populations is adaptive. We examine covariation among a set of phenotypic characters that describe the wing melanization pattern of Pieris butterflies. Previous functional analyses of thermoregulatory performance allow us to predict a priori whether and how different wing melanic characters should be correlated. We quantify and analyze the variation in the wing-melanization pattern within species for a series of Pieris populations from relatively cool environments in North America and compare these results with the predictions based on our adaptive hypothesis. We consider adaptive covariation both for biogeographic variation among populations and for seasonal polyphenism (phenotypic plasticity) within populations. Our hypothesis correctly predicts many of the qualitative features of covariation in melanization among major regions of the wings, at the level of biogeographic variation among populations, for both males and females of Pieris occidentalis. When within-population variation is considered, agreement with the adaptive predictions varies considerably in different populations for both P. occidentalis and P. napi males and females. Agreement for P. napi, particularly the females, is generally poorer than for P. occidentalis. In both species, there is a consistent difference in melanization pattern between alpine and arctic sites; this difference is discussed in relation to the differences in the radiative environment between these two types of "cold" habitats. Our results suggest that some important aspects of phenotypic correlation among wing melanic characters in Pieris are adaptive. We emphasize the important distinction between covariation and co-occurrence of characters, and we discuss these results in relation to the extensive biogeographic variation and phenotypic plasticity (seasonal polyphenism) in Pieris wing-melanization patterns. PMID- 28563807 TI - EFFECTS OF AVIAN SEED DISPERSAL ON THE GENETIC STRUCTURE OF WHITEBARK PINE POPULATIONS. AB - We used allozyme analysis to examine family structure, the spatial patterning of related individuals, in two populations of whitebark pine (Pinus albicaulis), a subalpine conifer that commonly displays a multistem form. The individual stems within clumps are genetically distinct individuals, having arisen from separate seeds. Individuals within a clump are genetically more similar than individuals in different clumps, but individuals in neighboring clumps do not appear to be more similar than individuals in distant clumps. This family structure appears to be a direct result of the seed-caching behavior of Clark's nutcrackers (Nucifraga columbiana), the primary dispersal agent for whitebark pine seeds. PMID- 28563808 TI - RANDOM MATING IN THE NORTHERN FLICKER HYBRID ZONE: IMPLICATIONS FOR THE EVOLUTION OF BRIGHT AND CONTRASTING PLUMAGE PATTERNS IN BIRDS. AB - The Red-shafted and Yellow-shafted Flickers hybridize in a narrow zone on the western Great Plains of North America. The two subspecies are markedly different in six plumage traits. Plumage phenotypes were scored for the male and female of 125 mated pairs from the hybrid zone. Correlation analyses revealed no tendency towards pairing of similar phenotypes. A binomial test was performed to determine whether flickers that have parental phenotypes and are presumably immigrants rather than hybrids tend to choose mates similar to themselves. This test again indicated random mating in the hybrid zone. These data complement earlier reports in providing an additional test of alternative hybrid zone theories. Random mating along with evidence of high reproductive success in hybrids suggests that reinforcement of premating reproductive isolation is not occurring and that speciation will not result from the dynamics of the hybrid zone. At least some of the plumage traits seem to be important in the integrated courtship and territorial behaviors of flickers. Since these plumage differences have no significance in mate choice, it is inferred that they evolved in an intrasexual selection context rather than in intersexual or species-recognition contexts. Selection gradients appear to be important in restricting hybridization to a narrow zone. The gradients could result from ecological selection or from sexual selection. PMID- 28563809 TI - SAFETY FACTORS OF TROPICAL VERSUS TEMPERATE LIMPET SHELLS: MULTIPLE SELECTION PRESSURES ON A SINGLE STRUCTURE. AB - A comparison of the safety factors of tropical and temperate limpet shells in the eastern Pacific yielded two results of significance. A safety factor was defined as shell strength/maximum tenacity, where maximum tenacity (force required to detach foot) determines the maximum prying force that a crab or bird predator can exert on the shell. 1) On average, shell strength and foot tenacity for the tropical limpets were twice those for the temperate limpets. In contrast, the average safety factors for the two groups were approximately equal. This comparatively narrow range of safety factors was due to a highly significant association of greater shell strengths with greater foot tenacities. The implication of this result is that selection has acted to closely link the mechanical performances of these two rather independent structures, the shell and the foot. 2) The presence of an additional class of predators which feed on the tropical limpets was reflected in the safety factors of their shells. Whereas the shells of both tropical and temperate limpets are exposed to predator-induced prying forces, the shells of the tropical group are also exposed to lateral crushing forces generated by fish predators. This additional selection pressure was associated with several deviations from a regression of safety factor versus variability in shell strength which had been calculated previously for the temperate limpets. As predicted, the magnitudes of these deviations were correlated with the degree of exposure to this additional selection pressure. Hence, the presence of more than one selection pressure appears to have influenced the precision with which the shells of these species have become adapted to a single selection pressure. The use of safety factor analysis provides a very useful methodology for identifying additional selection pressures or adaptive constraints on biological structures. PMID- 28563810 TI - A TEST OF THE SIB-COMPETITION HYPOTHESIS FOR OUTCROSSING ADVANTAGE IN IMPATIENS CAPENSIS. AB - One of the potential selective mechanisms invoked in discussions of breeding system evolution is that competition within sibships increases the fitness of outcrossed progeny relative to selfed progeny. We tested this sib-competition hypothesis using cleistogamous (CL) and chasmogamous (CH) seeds of Impatiens capensis in a large greenhouse experiment. The experimental design was a double replacement series which also allowed us to test for inbreeding depression and overall resource partitioning among sibships. We found no evidence for strong inbreeding depression in the study population; although plants from CH seeds had a slight advantage over plants from CL seeds in total flower and pod production, CL plants had slightly higher growth. We also could not detect significant resource partitioning among sibships nor any evidence to support the sib competition hypothesis for outcrossing advantage. CH sibships were not significantly more variable than CL sibships in any of the phenotypic traits measured. These results suggest that sibling competition may have little importance in the evolution of Impatiens breeding systems. PMID- 28563811 TI - ADAPTATION AND RULES OF FORM: CHIRALITY AND SHAPE IN PARTULA SUTURALIS. PMID- 28563812 TI - POLLINATION IN FLORAL SCENT MORPHS OF POLEMONIUM VISCOSUM: A MECHANISM FOR DISRUPTIVE SELECTION ON FLOWER SIZE. AB - Plants of Polemonium viscosum have flowers that are either sweet or skunky in scent. The two morphs are preferentially pollinated by insects of strongly contrasting body size: bumblebee queens specialize on sweet flowers, flies on skunky ones. In this study 13 characters were examined in plant specimens from five populations to identify major components of intraspecific variation in flower and inflorescence morphology and test their correlation with floral scent. Factor analysis identified four major axes of morphological variation. The first explained 22% of the variance among specimens and correlated strongly with four flower size characters: sepal length, corolla tube length, corolla lobe width, and corolla lobe length. Floral scent morphs differed significantly in the multivariate representation of flower size defined by these characters. Sweet flowers had wider corolla lobes, longer corolla tubes, and longer sepals than skunky ones. Corolla lobe width accounted for the greatest amount of intermorph divergence. Divergence in flower size between morphs was maintained in mixed populations at four locations in alpine Colorado, with corollas of sweet flowers significantly broader or more flared than those of skunky flowers. Patterns of pollen receipt suggest that this difference is adaptive. In the sweet morph, pollination intensity and purity increased significantly with corolla flare. Conversely, in the skunky morph, corolla flare had little influence on pollination intensity and had a strong negative effect on purity. These findings suggest that selection for effective pollination should favor intraspecific divergence in flower size in Polemonium viscosum. PMID- 28563813 TI - FORAGER BEHAVIOR, POLLEN DISPERSAL, AND INBREEDING IN TWO SPECIES OF HUMMINGBIRD POLLINATED PLANTS. PMID- 28563814 TI - RAPID GENETIC DIFFERENTIATION AND FOUNDER EFFECT IN COLONIZING POPULATIONS OF COMMON MYNAS (ACRIDOTHERES TRISTIS). AB - Populations of common mynas introduced to Australia, New Zealand, Fiji, Hawaii, and South Africa from India during the last century were compared genetically with the extant native population using isozyme electrophoresis of 39 presumptive loci. Average heterozygosity, mean number of alleles/locus, and the percentage of polymorphic loci are lower in the introduced populations, and the 18% loss of alleles involves only alleles that are rare in the native population. The native population is only weakly subdivided genetically (FST = 0.032) whereas the introduced populations are much more differentiated (FST = 0.123), and the mean genetic distance among them is significantly greater than among native samples. The reduction in mean number of alleles/locus and average heterozygosity is greatest in the South African population, consistent with a very small effective size in the founder population. In the introduced populations, random drift is implicated by the different subsets of polymorphic loci they possess, by their greater variance in allele frequencies, and by shifts either side of the native means. It is concluded that in the evolutionarily short period of 100-120 years, bottlenecks and random drift have promoted genetic shifts equal to those between different subspecies of birds. PMID- 28563815 TI - IS THE EXTREMELY LOW HETEROZYGOSITY LEVEL IN YPONOMEUTA RORELLUS CAUSED BY BOTTLENECKS? AB - Among the common and widespread species of the small ermine moths (Yponomeuta) the almost complete absence of genetic variability from a sample of 75 protein loci is a striking feature of Y. rorellus. Congeners exhibit normal to high H levels. At least for soluble proteins, this variation estimate is a real one, not resulting from an inability of the zymogram technique to detect variation nor from a biased sample of loci. The most likely explanation for the dearth of variation observed is a bottleneck at the species' origin. Moreover, ongoing population-size fluctations in the historical past of Y. rorellus may have prevented the recovery of equilibrium H levels as a consequence of genetic drift in small populations. PMID- 28563817 TI - MITOCHONDRIAL INHERITANCE PATTERNS ACROSS A COTTONWOOD HYBRID ZONE: CYTONUCLEAR DISEQUILIBRIA AND HYBRID ZONE DYNAMICS. AB - In this study we examine the cytoplasmic inheritance patterns of an interspecific hybridizing population of Fremont and narrowleaf cottonwoods, using mitochondrial DNA. Three mitochondrial probes showing polymorphisms were used to distinguish between trees of known nuclear inheritance. Every tree screened had only one cytoplasmic genotype, either Fremont or narrowleaf. Thus, these results demonstrate that mitochondria are uniparentally inherited in these trees. Previous studies of the nuclear inheritance of this interspecific hybridizing population of cottonwood trees indicated an asymmetry in the frequency of parental genes. Using mitochondrial markers we tested one hypothesis potentially responsible for this asymmetric distribution (i.e., trees of mixed genotypes will be sterile or will not survive if their cytoplasm is derived from one or the other parent). Our results, however, show that both Fremont and narrowleaf mitochondrial markers are found in trees with mixed nuclear genotypes. Thus, nuclear-cytoplasmic incompatibilities do not appear to account for the asymmetric distribution of nuclear genotypes within the hybrid swarm. An alternative explanation for the observed asymmetric distribution of nuclear genotypes is advanced. Although nuclear-cytoplasmic incompatibilities do not appear to explain the asymmetric distribution of nuclear alleles within the hybrid zone, nonrandom associations between nuclear and cytoplasmic genotypes do exist. For example, all F1 hybrids had Fremont mitochondrial genotypes. Furthermore, backcrosses between F1 hybrid and narrowleaf trees have a higher than expected proportion of heterozygous loci and a higher than expected proportion of Fremont mitochondria. We propose that seeds, seedlings, or trees with high proportions of heterozygous loci are at a disadvantage unless they also have the Fremont mitochondrial genotype. While it is generally difficult to infer dynamic processes from static patterns, studies such as ours enable one to gain new insights to the dynamics of plant hybrid zones. A hybridization pattern of decreasingly complex backcrosses as one proceeds from higher to lower elevation within the hybrid swarm, a residue of Fremont cytoplasmic DNA within the pure narrowleaf population, and the unidirectional nature of these crosses suggest that the narrowleaf population may be spreading down the canyon and the Fremont population receding. The eventual fate of the hybrid zone, in relation to these processes, is discussed. PMID- 28563818 TI - GENETICS OF PRECALLING PERIOD IN THE ORIENTAL ARMYWORM, MYTHIMNA SEPARATA (WALKER) (LEPIDOPTERA: NOCTUIDAE), AND IMPLICATIONS FOR MIGRATION. AB - Migration in insects usually occurs prereproductively so the precalling period, between emergence and the first release of pheromone, determines the number of nights over which females of migrants such as Mythimna separata can express their migratory potential. Precalling periods (PCP's) ranged from 3 to 21 nights in F1 females from insects collected in the field in eastern China. As technical problems precluded the use of a sib-analysis design, the genetic basis of this variation was investigated by analysis of the correlation between daughters' and mother's PCP's and by selection in isofemale lines followed by reciprocal crosses. The results of these analyses indicated that PCP is strongly influenced by genes located on the X chromosome, inherited from the male parent in Lepidoptera. Genetic regulation of migratory potential, of which PCP is a crucial component, can be expected to evolve in tropical species such as Mythimna separata, whose larval habitats are associated with unpredictable tropical rainfall. This species has no preimaginal diapause but makes regular seasonal incursions every spring and early summer to high temperate latitudes at which it cannot overwinter. Where migrants are carried by winds, as occurs in these migrations, the predominantly poleward winds at this time of year must create a genetic cline across latitude, in which migratory potential of the summer populations founded by the migrants increases with increasing latitude. We suggest that X-linkage of genes influencing PCP may reduce the genetic load associated with this polymorphism by reducing the frequencies of inappropriate PCP genotypes in these summer populations. Thus, in autumn when winds are predominantly northerly, fewer individuals at any latitude will lack the capability to make the return journey southward. Some support for this model is provided by the observed distributions of PCP's of F1 females from moths collected in the field in central and northern eastern China. If X-linkage of genes influencing PCP contributes to the stability of these migratory cycles, it can be expected in other species with similar migratory strategies. PMID- 28563819 TI - THE EVOLUTION OF COSTLY MATE PREFERENCES I. FISHER AND BIASED MUTATION. AB - Fisher's runaway process is the standard explanation of the evolution of exaggerated female preferences. But mathematical formulations of Fisher's process (haploid and additive diploid) show it cannot cause stable exaggeration if female preference carries a cost. At equilibrium female fitness must be maximized. Our analysis shows that evolutionary stable exaggeration of female preference can be achieved if mutation pressure on the male character is biased, that is, mutation has a directional effect. At this equilibrium female fitness is not maximized. We discuss the reasons and evidence for believing that mutation pressure is typically biased. Our analysis highlights the previously unacknowledged importance of biased mutation for sexual selection. PMID- 28563820 TI - SEXUAL ISOLATION AMONG POPULATIONS OF DROSOPHILA MOJAVENSIS. PMID- 28563821 TI - EVOLUTION OF GENERALISTS AND SPECIALISTS IN SPATIALLY HETEROGENEOUS ENVIRONMENTS. AB - Quantitative genetic models are used to investigate the evolution of generalists and specialists in a coarse-grained environment with two habitat types when there are costs attached to being a generalist. The outcomes for soft and hard selection models are qualitatively different. Under soft selection (e.g., for juvenile or male-reproductive traits) the population evolves towards the single peak in the adaptive landscape. At equilibrium, the population mean phenotype is a compromise between the reaction that would be optimal in both habitats and the reaction with the lowest cost. Furthermore, the equilibrium is closer to the optimal phenotype in the most frequent habitat, or the habitat in which selection on the focal trait is stronger. A specialist genotype always has a lower fitness than a generalist, even when the costs are high. In contrast, under hard selection (e.g., for adult or female-reproductive traits) the adaptive landscape can have one, two, or three peaks; a peak represents a population specialized to one habitat, equally adapted to both habitats, or an intermediate. One peak is always found when the reaction with the lowest cost is not much different from the optimal reaction, and this situation is similar to the soft selection case. However, multiple peaks are present when the costs become higher, and the course of evolution is then determined by initial conditions, and the region of attraction of each peak. This implies that the evolution of specialization and phenotypic plasticity may not only depend on selection regimes within habitats, but also on contingent, historical events (migration, mutation). Furthermore, the evolutionary dynamics in changing environments can be widely different for populations under hard and soft selection. Approaches to measure costs in natural and experimental populations are discussed. PMID- 28563822 TI - NATURAL SELECTION ON FLORAL TRAITS IN TWO SPECIES OF LOBELIA WITH DIFFERENT POLLINATORS. AB - Using both multivariate and univariate regression techniques, I measured selection acting through female reproductive success in two hermaphroditic species with precise pollen placement but different pollinators: hummingbird pollinated Lobelia cardinalis and bumblebee-pollinated L. siphilitica. Six traits were analyzed in two populations of L. cardinalis and one population of L. siphilitica: flower number, mean number of flowers open per day, inflorescence height, number of days in flower, median-flower date and nectar-stigma distance. In another study it was found that female reproductive success in one population of L. cardinalis was much less pollen limited than in the other two populations, and it was therefore expected that selection of female reproductive traits in this population would be weaker. In the univariate analyses correlations caused nearly all traits to have significant directional selection coefficients. However, in the multivariate analyses no traits in L. siphilitica experienced directional or quadratic selection. Selection acted differently in the two L. cardinalis populations. The less pollen-limited population experienced positive directional selection on flower number and median-flower date, while in the other L. cardinalis population there was positive directional selection on flower number and nectar-stigma distance and both positive directional and positive quadratic selection on height. The functional significance of floral traits in these two species and the probable effect of increased sample sizes are discussed. PMID- 28563823 TI - MITOCHONDRIAL GENOTYPES HAVE NO DETECTABLE EFFECTS ON MERISTIC TRAITS IN CUTTHROAT TROUT HYBRID SWARMS. AB - Efforts to detect effects of cytoplasmic genes are confounded by the problem of partitioning nuclear and cytoplasmic effects. In this study we test for effects of mtDNA haplotype on development in hybrid populations of cutthroat trout (Oncorhynchus clarki) with randomly associated nuclear and mtDNA genotypes. We have previously described several intraspecific hybrid swarms formed by interbreeding of westslope cutthroat trout (O. c. lewisi) and Yellowstone cutthroat trout (O. c. bouvieri). Genetic distance between these subspecies is high (Nei's D = 0.30; mtDNA P = 0.02), and diagnostic alleles at multiple nuclear loci and two distinct mtDNA haplotypes are present in the hybrids. Historical associations between alleles at nuclear loci and between cytotypes and nuclear alleles have largely decayed. We test for differences in meristic characters between fish with alternate mtDNA haplotypes. Counts and fluctuating bilateral asymmetry for these characters have been previously shown to be sensitive indicators of genetic differences that affect development. No differences were found between mtDNA types in meristic counts or fluctuating asymmetry. Therefore, the alternate mtDNA haplotypes had no detectable effect on development as measured by meristic counts in these hybrid populations. However, diagnostic alleles at one nuclear allozyme locus (CK-CI) were associated with several fin ray counts. PMID- 28563824 TI - OIL FLOWERS AND OIL BEES: FURTHER EVIDENCE FOR POLLINATOR ADAPTATION. AB - We examined foreleg length and body size variation in two species of oil collecting bees (Rediviva; Melittidae) in southern Africa. Oil-collecting bees harvest oil from host flowers by rubbing their forelegs against oil-secreting trichomes. Significant differences in foreleg length occur among populations of both species. Rediviva "pallidula" populations vary significantly in mean foreleg length (11.34 +/- 0.42 mm to 12.67 +/- 0.36 mm), but not in body length (10.59 +/ 0.74 to 10.80 +/- 0.64), and foreleg length and body size are not significantly correlated. Instead, foreleg variation appears to be a function of host plant spur length. Ninety-two percent of the variance in foreleg length of R. "pallidula" is explained by mean Diascia spur length. Rediviva rufocincta populations vary significantly in mean foreleg length (10.12 +/- 0.70 mm to 12.34 +/- 0.68 mm) and in body length (9.03 +/- 0.26 mm to 10.56 +/- 0.24 mm). Foreleg length scales allometrically with body size in this species as 90.5% of the variance in foreleg length can be explained as a function of body length. Body size appears to be constrained by the morphology of the oil-secreting host plant. Both bees collect floral oil with specially modified setae on the tarsi of their forelegs. The length of the disti- + mediotarsus (refered to here as "tarsus") in relation to the entire foreleg is shorter in R. rufocincta and does not increase as rapidly with increasing foreleg length as for R. "pallidula." These differences in variation can be attributed to differences in position of oil within the flowers of the respective host plants. Rediviva "pallidula" collects oil from Diascia species that have the oil deeply situated in narrow floral spurs of varying length, while R. rufocincta collects oil from the broadly saccate flowers of Bowkeria verticillata and B. citrina. PMID- 28563825 TI - THE POTENTIAL FOR GENETIC EXCHANGE BY TRANSFORMATION WITHIN A NATURAL POPULATION OF BACILLUS SUBTILIS. AB - We have investigated the potential for genetic exchange by transformation within a Mojave Desert population of Bacillus subtilis. Almost all strains surveyed were competent for transformation, and the strains varied over almost three orders of magnitude in their levels of competence. This high degree of variation suggests that natural selection toward an optimal level of competence is, at most, very weak in this population. Six of 24 competent strains showed sexual isolation from laboratory strain 168 (i.e., heterogamic transformation was reduced). Direct crosses between selected pairs of Mojave strains indicated sexual isolation within the Mojave population. Levels of sexual isolation observed within this population of B. subtilis were much less than those previously observed for transformation between named Bacillus species. Sexual isolation between 168 and Mojave strains, and among Mojave strains, was due to differences in restriction modification systems and to DNA sequence divergence. PMID- 28563826 TI - LIFE-HISTORY DIFFERENCES IN ADJACENT WATER STRIDER POPULATIONS: PHENOTYPIC PLASTICITY OR HERITABLE RESPONSES TO STREAM TEMPERATURE? PMID- 28563827 TI - MOLECULAR AND GEOLOGIC EVIDENCE OF SHARED HISTORY BETWEEN HERMIT CRABS AND THE SYMBIOTIC GENUS HYDRACTINIA. AB - The paleobiogeographic histories of three North Atlantic hermit crab lineages were compared with a single-copy DNA-DNA hybridization phylogeny of their symbiotic hydroid genus Hydractinia to test hypotheses of shared history between these host and symbiont lineages. A survey of the geologic literature suggests that two vicariance events in the Quaternary are responsible for existing range disjunctions of the host hermit crab lineages. The Hydractinia phylogeny revealed two distinct clades, one with a primarily northern and the other with a primarily southern distribution. In two of three cases, hydroids associated with closely related hermits on both sides of the range disjunction appear as sister taxa in the phylogeny. A linear scaling between a measure of hydroid sequence divergence and independent geologic estimates of the timing of the vicariant events believed to have established the hermit crab range disjunctions is consistent with the claim of temporal coincidence of cladogenic and vicariance events. These findings provide evidence for shared history of symbiotic associations in two of the three cases. PMID- 28563828 TI - COMPONENTS OF PHENOTYPIC SELECTION: POLLEN EXPORT AND FLOWER COROLLA WIDTH IN IPOMOPSIS AGGREGATA. AB - In the hummingbird-pollinated herb Ipomopsis aggregata, selection through male function during pollination favors wide corolla tubes. We explored the mechanisms behind this selection, using phenotypic selection analysis to compare effects of corolla width on two components of male pollination success, pollinator visit rate and pollen exported per visit. During single visits by captive hummingbirds, flowers with wider corollas exported more pollen, and more dye used as a pollen analogue, to stigmas of recipient flowers. Corolla width was less strongly related to visit rate in the field, and had no direct effect on visit rate after nectar production and corolla length were controlled for. Moreover, the phenotypic selection differential was 80% higher for the effect on pollen exported per visit, suggesting that this is the more important mechanism of selection. PMID- 28563829 TI - DEVELOPMENT, FUNCTION, AND THE QUANTITATIVE GENETICS OF WING MELANIN PATTERN IN PIERIS BUTTERFLIES. AB - Do genetic correlations among phenotypic characters reflect developmental organization or functional coadaptation of the characters? We test these hypotheses for the wing melanin pattern of Pieris occidentalis butterflies, by comparing estimated genetic correlations among wing melanin characters with a priori predictions of the developmental organization and the functional (thermoregulatory) organization of melanin pattern. There were significant broad sense heritabilities and significant genetic correlations for most melanin characters. Matrix correlation tests revealed significant agreement between the observed genetic correlations and both developmental and functional predictions in most cases; this occurred even when the overlap between developmental and functional predictions was eliminated. These results suggest that both developmental organization and functional coadaptation among melanin characters influence the genetic correlation structure of melanin pattern in this species. These results have two important implications for the evolution of melanin pattern in P. occidentalis and other butterflies: 1) most phenotypic variation in pattern may reflect variation among, rather than within, sets of developmentally homologous wing melanin characters; and 2) in a changing selective environment, genetic correlations may retard the disruption of functionally coupled melanin characters, thus affecting the evolutionary response to selection. PMID- 28563830 TI - GENETIC DIFFERENTIATION OF POLISH POPULATIONS OF SOREX ARANEUS L. III. INTERCHROMOSOMAL RECOMBINATION IN A HYBRID ZONE. AB - Two parapatric chromosomal races of the common shrew (Sorex araneus) in Poland differ in their complement of metacentric arm combinations: hk, io, gr, nm (race IV), and hi, ko, gm, np (race II). In hybrids, these eight race-diagnostic metacentrics form two randomly segregating complexes. The first complex (C1 ) occurs in the form of a ring configuration ok/kh/hi/io, or a chain o/ok/kh/hi/i (when there is Robertsonian polymorphism of the element io). The second complex (C2 ) always takes the form of a six-element chain configuration r/rg/gm/mn/np/p. The C2 complex may be shortened to five or even four elements, when acrocentrics g, m and n are present. In the contact zone we found shrews of pure races (race II or IV), as well as hybrids with C1 or C2 complexes, and recombinants hi, ko, gr, nm. Complex heterozygotes are likely to suffer reduced fertility due to malsegregation at meiosis. However, the C1 hybrids with ring configurations occur with a high frequency throughout the contact zone. This suggest that their fitness is only slightly lowered relative to pure race individuals, in contrast to the hybrids with C1 or C2 chain configurations, which presumably have a more heavily reduced fertility. On the other hand, at the center of the zone there is a high proportion of recombinants, which, being chromosomal homozygotes, should display normal meiotic segregation. Furthermore, the high frequencies of recombinants within the contact zone should facilitate gene flow between the races. The occurrence of recombinants plays a similar role as the appearance of the maximum frequencies of acrocentric homozygotes described in several contact zones of S. araneus. PMID- 28563831 TI - TESTING FOR DEVELOPMENTAL CONSTRAINTS: CARPAL FUSIONS IN URODELES. PMID- 28563832 TI - ON EVOLUTION UNDER SEXUAL AND VIABILITY SELECTION: A TWO-LOCUS DIPLOID MODEL. AB - A two-locus diploid model of sexual selection is presented in which the two loci govern, respectively, a trait limited in expression in one sex (generally male) and the mating preferences of the other sex (generally female). The viability of a male depends on its genotype at the trait locus. In contrast, all females are equally viable and all individuals are equally fertile with respect to the two loci. Near fixation at both loci, evolution at the mating locus is neutral and hence a new mating preference allele will increase only through random genetic drift or through a correlated response to the increase of a new advantageous trait allele. If, however, a polymorphism is already maintained at the trait locus through overdominance in fitness then the increase of a rare preference allele depends only on the recombination rate between the loci and not on the new preference scheme. PMID- 28563833 TI - STRUCTURE OF AN ASYMMETRIC HYBRID ZONE BETWEEN TWO WATER STRIDER SPECIES (HEMIPTERA: GERRIDAE: LIMNOPORUS). AB - The water stricter species Limnoporus dissortis and L. notabilis hybridize across a broad zone in western Canada. Body length and alleles at four allozyme loci show a steep cline along the east slope of the Rocky Mountains in western Alberta, while in central British Columbia the parental phenotypes coexist without merging fully. One sex-linked locus shows little introgression, while there is apparently considerable gene flow at three autosomal loci. Although the hybrid zone has characteristics of a broad tension zone, the spatial distribution of introgression suggests that habitat patchiness and differential habitat associations of the two species also contribute to the pattern of hybridization. Asymmetry in interspecific mating success and incompatibilities of sex chromosomes with each other or with cytoplasmic factors appear to account for the occurrence of L. dissortis genotypes within the range of L. notabilis, and the lack of L. notabilis genotypes within the range of L. dissortis. The genetic structure of this hybrid zone supports the importance of sex-linked traits in maintaining the integrity of species, while its spatial structure suggests that extrinsic habitat features can combine with intrinsic genetic incompatibilities to produce complex hybrid interactions. PMID- 28563834 TI - SEX-SPECIFIC REPRODUCTIVE CONSEQUENCES OF BODY SIZE IN THE SOLITARY ECTOPARASITOID, DIGLYPHUS BEGINI. PMID- 28563835 TI - THE EVOLUTION OF COSTLY MATE PREFERENCES II. THE "HANDICAP" PRINCIPLE. AB - We use a general additive quantitative genetic model to study the evolution of costly female mate choice by the "handicap" principle. Two necessary conditions must be satisfied for costly preference to evolve. The conditions are (i) biased mutation pressure on viability and (ii) a direct relationship between the degree of expression of the male mating character and viability. These two conditions explain the success and failure of previous models of the "handicap" principle. Our model also applies to other sources of fitness variation like migration and host-parasite coevolution, which cause effects equivalent to biased mutation. PMID- 28563836 TI - POECILIA MEXICANA IS THE RECENT FEMALE PARENT OF THE UNISEXUAL FISH P. FORMOSA. PMID- 28563838 TI - VARIATION IN PREFERENCE AND SPECIFICITY IN MONOPHAGOUS AND OLIGOPHAGOUS SWALLOWTAIL BUTTERFLIES. AB - Although variation in oviposition preference and specificity for host plants has been demonstrated within populations of a variety of oligophagous insect species, it is unknown whether genetic variation in host choice is lost within populations of monophagous species. Analysis of a locally monophagous butterfly species, Papilio oregonius, and a locally oligophagous species, P. zelicaon, showed significant variation in oviposition preference within populations of both species. Females of both species chose primarily their native hosts. Nonetheless, the percentages of eggs laid by individual females among the plant species and the number of plant species on which individual females laid eggs differed significantly among isofemale strains within populations. Moreover, some females within all isofemale strains of both species laid a few eggs on Foeniculum vulgare, an umbelliferous species that does not occur in the native habitats of these populations but is a host for Papilio species in other geographic areas. The results suggest that local monophagy and oligophagy in these species reflect the relative ranking among potential plant species. Both populations harbor variation in oviposition choice that could allow for host shifts if these populations invaded new habitats. PMID- 28563837 TI - ASSOCIATIONS BETWEEN MITOCHONDRIAL AND NUCLEAR GENOTYPES IN CUTTHROAT TROUT HYBRID SWARMS. AB - We examined mtDNA and nuclear allozyme genotypes in hybrid populations formed from interbreeding of westslope cutthroat trout (Oncorhynchus clarki lewisi) and Yellowstone cutthroat trout (O. c. bouvieri). These subspecies show substantial genetic divergence (Nei's D = 0.30; mtDNA P = 0.02). Diagnostic alleles at multiple nuclear loci and two distinct mtDNA haplotypes segregate in the hybrids. Nuclear and mtDNA genotypes are largely randomly associated, although there is slight disequilibrium in both nuclear and cytonuclear measures in some samples. Consistent positive gametic disequilibria for three pairs of nuclear loci confirm one previously reported linkage, and indicate two more. Allele frequencies provide no evidence for selection on individual chromosome segments. However, westslope mtDNA haplotype frequencies exceed westslope nuclear allele frequencies in all samples. This may be explained by differences in the frequency of occurrence of reciprocal F1 matings, by viability, fertility, or sex ratio differences in the progeny of reciprocal matings, or by weak selection on mtDNA haplotypes. PMID- 28563839 TI - ONTOGENETIC VARIATION IN PATTERNS OF PHENOTYPIC INTEGRATION IN THE LABORATORY RAT. AB - I used confirmatory factor analysis to evaluate the ability of causal developmental models to predict observed phenotypic integration in limb and skull measures at five stages of postnatal ontogeny in the laboratory rat. To analyze the dynamics of phenotypic integration, I fit successive age-classes simultaneously to a common model. Growth was the principal developmental explanation of observed phenotypic covariation in the limb and skull. No complex morphogenetic model more adequately reconstructed observed covariance structure. Models that could not be interpreted in embryological terms, coupled with a growth component, provide the best models for observed phenotypic integration. During postnatal growth, some aspects of integration vary in both the skull and limb. The covariance between factors and the proportion of variance unique to each character differ between some sequential age-classes. The factor-pattern is invariant in the limb; however, repatterning in the skull occurs in the interval between eye-opening and weaning. The temporal variation in the structure of covariation suggests that functional interactions among characters may create observed patterns of phenotypic integration. The developmental constraints responsible for evolutionary modification of phenotypes might be equally dynamic and responsive to embryonic functional interactions. PMID- 28563840 TI - SEX-INVESTMENT RATIOS AND RELATEDNESS IN THE MONOGYNOUS ANT LASIUS NIGER (L.). AB - The genetic variation at two marker loci in three populations of the monogynous ant Lasius niger was used to analyze the importance of relatedness structure to sex-investment ratios in sexuals produced by colonies living in different resource conditions. From a resource-rich monoculture to a population in a resource-limited environment, dry weight investment in queens decreased from female-biased (0.76) to equality with male investment (Boomsma et al., 1982). The investment ratios in sexuals expected from the estimated relatedness ratios, resulting from kin-selection theory (Trivers and Hare, 1976), were in good agreement with the observed ratios in all populations. This indicated that the workers can capitalize on the asymmetry in relatedness, opposing the queen's interest, despite the contrast in environmental conditions in the different populations. This asymmetry, however, almost disappeared in the marginal population, due to a high frequency of double mating and worker production of males, resulting in a much reduced queen-worker conflict. We suggest that different levels of polyandry might be favored at different points of the resource gradient, with the sex ratio secondarily depending on these polyandry levels. As there was no population subdivision or spatial structure within the populations, group-selection and local-mate-competition models cannot account for the observed female-biased ratios, whereas they were rather accurately predicted by kin-selection theory. PMID- 28563841 TI - RESPONSES TO SELECTION AMONG LIFE-HISTORY TRAITS IN A NONMIGRATORY POPULATION OF MILKWEED BUGS (ONCOPELTUS FASCIATUS). AB - Genetic parameters were assessed in the nonmigratory Puerto Rico population of the milkweed bug, Oncopeltus fasciatus, and compared with parameters estimated in a migratory population from Iowa (Palmer and Dingle, 1986). Offspring-parent regression analysis provided initial estimates of heritabilities and phenotypic and genetic correlations among wing length, head-capsule width, female age at first reproduction, fecundity for the first and second five days of reproduction by females, and clutch size for the first and second five days of reproduction by females. Replicated bidirectional selection for wing length was then imposed, with a direct response to selection revealing substantial additive genetic variance for this trait, as was also the case with the Iowa population. Assays for correlated response to selection yielded two further similarities to Iowa: a positive response in head-capsule width and no consistent response in age at first reproduction. In contrast to the results with Iowa bugs, neither regression analysis nor selection revealed statistically significant genetic correlations between fecundity measures and those of other traits. In both populations the potential exists for body-size characters to evolve together independently of age at first reproduction; but in the nonmigratory Puerto Rico bugs, fecundity does not contribute to a life-history syndrome involving genetic correlations among these traits. PMID- 28563842 TI - GEOGRAPHIC VARIATION AND HETEROCHRONY IN TWO SPECIES OF COWRIES (GENUS CYPRAEA). AB - Geographic variation in the marine, Indo-Pacific cowry, Cypraea caputserpentis, involves clinal variations that parallel the ontogenetic development of adult shell characteristics. Cypraea caputdraconis, a closely related species endemic to Easter Island and Sala y Gomez, is morphologically similar to juvenile C. caputserpentis. Using multivariate measures of size and shape, I examine these patterns as a possible outcome of heterochrony, or changes in the timing of developmental events in ontogeny. Whorl-expansion rates of juvenile shells are significantly higher in C. caputdraconis when compared to C. caputserpentis and are negatively correlated with surface seawater temperatures among populations of C caputserpentis. High expansion rates, often associated with slow growth, result in a delay in the onset of lateral callus development and subsequent paedomorphosis. Ontogenetic trajectories calculated from growth series of adult and preadult shells indicate that paedomorphosis results from the combined effects of neoteny and post-displacement. Paedomorphosis among cowries may result from the advantages of larger body size relative to shell size under reduced predation intensities and associated increases in fecundity. PMID- 28563843 TI - CONSTRAINTS ON REPRODUCTIVE INVESTMENT: A COMPARISON BETWEEN AQUATIC AND TERRESTRIAL SNAKES. AB - Life-history theory predicts that "costs" of reproduction may be important evolutionary determinants of reproductive investment; previous studies on reptiles indicate that decrements to maternal mobility may be among the most important components of such costs. Biomechanical models suggest that reproductive investment in aquatic snakes may be constrained by the important locomotory role of the posterior part of the body during swimming: carrying eggs or offspring in this region would more seriously impair locomotory efficiency in swimming than in terrestrial lateral undulation. If this constraint is important, aquatic snakes would be expected to have lower clutch masses relative to body mass than terrestrial species and to carry the clutch in a more anterior position (commencing at the same proportion of maternal body length anteriorly, but not extending as far posteriorly). Comparisons between aquatic and terrestrial snakes of several families confirm these predictions. Phylogenetic analysis suggests that this pattern of reduced reproductive investment has evolved independently in each of the four ophidian lineages that contain marine species (acrochordids, homalopsine colubrids, laticaudid sea snakes, and hydrophiid sea snakes). Although it thus seems likely that these patterns represent adaptations to aquatic versus terrestrial life, the nature of the selective forces involved remains speculative. The hypothesis based on locomotory impairment of gravid females has better empirical support than any alternative hypothesis, as it successfully predicts modifications in the position of the clutch within the female's body, as well as overall reduced reproductive investment. PMID- 28563844 TI - CLONAL-DIVERSITY PATTERNS AND BREEDING-SYSTEM VARIATION IN DAPHNIA PULEX, AN ASEXUAL-SEXUAL COMPLEX. AB - Some individuals of the cladoceran crustacean, Daphnia pulex, reproduce by cyclic parthenogenesis, while others are obligate parthenogens. Cyclic parthenogenesis is the primitive breeding system; the transition to obligate parthenogenesis has been linked to sex-limited meiosis-suppression. Detailed study of patterns of breeding-system distribution and clonal diversity is justified because D. pulex is the first species in which the loss of sex has been related to this mechanism. The present study investigated the genotypic characteristics of 10 D. pulex populations from each of 22 sites in the Great Lakes watershed. This analysis revealed that populations reproducing by cyclic parthenogenesis were uncommon and restricted to southern sites. Most populations reproduced by obligate parthenogenesis, with the electrophoretic survey revealing an average of three clones per pond and 145 unique clones over the watershed. A combinatorial analysis was used to examine the relationships between clone discovery in the asexual populations and both sample size and genetic-sampling intensity. This analysis showed that the few clones found in individual ponds were readily discriminated, while diversity on a regional scale was underestimated. These methods provide a quantitative basis for assessing the level of clonal diversity in asexual populations and in asexually transmitted segments of the genome. PMID- 28563845 TI - EVALUATING A HYPOTHESIS ABOUT HETEROCHRONY: LARVAL LIFE-HISTORY TRAITS AND JUVENILE HIND-LIMB MORPHOLOGY IN HYLA CRUCIFER. AB - This paper reports the results of an investigation into whether selection on genetically based differences in the timing or rate of development (heterochrony) can give rise to nonadaptive morphological differences among individual frogs. We used a quantitative-genetics approach to examine the relationships among the life history characters time to metamorphosis and larval-growth rate and a functionally significant morphological features, relative hind-limb length, in the spring peeper, Hyla crucifer. Time to metamorphosis and growth rate had low heritabilities in our population. Morphological traits had moderate heritabilities. There were positive genetic correlations between the life-history traits and the components of relative hind-limb length but no significant correlations with the shape variable itself. We used field observations of pond drying time and experimental results of selection on growth rate to simulate the correlated responses of hind-limb shape to four reasonable selection regimes on the life-history traits. We found little evidence to suggest that relative hind limb length would display much of a correlated response to such selection. The differences in relative hind-limb length seen among closely related species or among populations of a single species that appear to be unrelated to performance differences are not obviously explicable as neutral correlated responses to selection on larval traits. PMID- 28563846 TI - A MATHEMATICAL MODEL FOR ALTRUISM IN HAYSTACKS. PMID- 28563847 TI - QUANTITATIVE GENETICS, DEVELOPMENT, AND PHYSIOLOGICAL ADAPTATION IN HOST STRAINS OF FALL ARMYWORM. AB - Two genetically differentiated host strains of fall armyworm were reared on their own and each other's host plants, rice and corn, to determine whether they were physiologically adapted to their natural hosts and whether they exhibited genetically based differences in development. Larval host had a greater impact on development in the rice strain than in the corn strain, indicating that physiology could have facilitated specialization in one strain but not the other. Consequently, behavioral mechanisms are also likely to be important in the maintenance of host specificity. Comparisons between strains indicated significant differences in one trait, the rate at which larvae gained weight. Because this character had consistently high heritabilities, genetic differentiation in development is indicated. An analysis of genotype-by environment interactions within each strain detected significant interactions for three of five traits, suggesting that genotypic performance on one host was not indicative of performance on the other. Each strain thus exhibited genetic variation that would facilitate host-associated divergence and adaptation if coupled with a mechanism that reduced gene flow between hosts. Finally, significant genetic correlations between several characters were detected when strains were reared on their natural hosts but not when they were reared on nonnatural hosts. Apparently, feeding on novel hosts caused developmental uncoupling of characters. Release from genetic constraints could provide a mechanism for physiological adjustments to newly occupied habitats. PMID- 28563848 TI - GENETIC COMPONENT OF MORPHOLOGICAL DIFFERENTIATION IN COAL TITS UNDER COMPETITIVE RELEASE. PMID- 28563849 TI - THE ROLE OF PHYLLOTACTIC PATTERN AS A "DEVELOPMENTAL CONSTRAINT" ON THE INTERCEPTION OF LIGHT BY LEAF SURFACES. AB - Computer simulations of model plants are used to assess the influence of leaf shape, size, and pattern of arrangement (= phyllotaxy) on the direct solar radiation intercepted by leaf surfaces. Changes in phyllotaxy significantly influence light interception (and, by inference, net assimilation rate) for rosette growth habits. However, changes in leaf shape and orientation and in stem length can compensate for the negative effects of leaf overlap produced by phyllotactic patterns. Phyllotaxy is viewed as a developmental limiting factor in photobiology that may necessitate compensatory changes in other morphological features not directly controlled by patterns of leaf initiation. This distinguishes it from functioning as a "developmental constraint" sensu stricto and may provide a paradigm for other features in plant evolution. PMID- 28563850 TI - EVOLUTION OF ATLANTIC AND PACIFIC COD: LOSS OF GENETIC VARIATION AND GENE EXPRESSION IN PACIFIC COD. AB - An allozyme investigation of 41 protein-coding loci in two morphologically similar fishes, Atlantic and Pacific cod, indicates that Pacific cod experienced a severe population bottleneck that led to the loss of gene diversity and gene expression. Pacific cod possesses a significantly lesser amount of gene diversity (H = 0.032) than Atlantic cod (H = 0.125) and lacks gene expression for Me-3. Allele-frequency distributions differ between species as predicted by neutral theory: Atlantic cod has a U-shaped distribution, which is expected for populations in drift-mutation equilibrium, whereas Pacific cod has a J-shaped distribution with an excess of low-frequency alleles. This excess may be explained by the appearance of new alleles through mutation which have not yet reached intermediate frequencies through drift. The population bottleneck in Pacific cod was most likely associated with founder populations that dispersed into the Pacific Ocean after the Bering Strait opened. Under the molecular-clock hypothesis a Nei genetic distance of 0.415 (based on 41 loci) suggests that Pacific cod dispersed into the Pacific Ocean soon after the Bering Strait opened in the mid-Pliocene, 3.0 to 3.5 million years ago. PMID- 28563851 TI - QUANTITATIVE GENETICS OF MORPHOLOGICAL DIFFERENTIATION IN PEROMYSCUS. II. ANALYSIS OF SELECTION AND DRIFT. AB - The hypothesis that the morphological divergence of local populations of Peromyscus is due to random genetic drift was evaluated by testing the proportionality of the among-locality covariance matrix, L, and the additive genetic covariance matrix, G. Overall, significant proportionality of L and G was not observed, indicating the evolutionary divergence of local populations does not result from random genetic drift. The forces of selection needed to differentiate three taxa of Peromyscus were reconstructed to examine the divergence of species and subspecies. The selection gradients obtained illustrate the inadequacy of univariate analyses of selection by finding that some characters evolve in the direction opposite to the force of selection acting directly on them. A retrospective selection index was constructed using the estimated selection gradients, and truncation selection on this index was used to estimate the minimum selective mortality per generation required to produce the observed change. On any of the time scales used, the proportion of the population that would need to be culled was quite low, the greatest being of the same order of magnitude as the selective intensities observed in extant natural populations. Thus, entirely plausible intensities of directional natural selection can produce species-level differences in a period of time too short to be resolved in the fossil record. PMID- 28563853 TI - SEXUAL SELECTION IN A NATURAL POPULATION OF DROSOPHILA MELANOGASTER. PMID- 28563852 TI - SPATIAL AND TEMPORAL VARIATION IN GROUP RELATEDNESS: EVIDENCE FROM THE IMPORTED WILLOW LEAF BEETLE. AB - The distribution of genetic variance within and among socially interacting groups, often quantified as the average relatedness or r, is an important determinant of the evolution of social behaviors. Models of social evolution often treat this average as a constant characteristic of a species. In this paper, we present data documenting the degree of temporal and spatial variation in the average relatedness of larval groups of imported willow leaf beetles, a species whose immatures display several primitive social behaviors. Collections of groups were made over three generations at three localities in Virginia and three localities in Illinois. Average relatedness was estimated from the distribution of electrophoretically determined genotypic frequencies within and among groups for each collection. Average relatedness ranged from 0.20 at one locality in Illinois to 0.65 at one locality in Virginia. Individual cases of pairwise differences between samples indicated that there were both temporal and locality effects. Further, statistical analysis showed the set of relatedness values to be heterogeneous with significant locality effects. Geographic genetic variance was also partitioned among trees sampled within localities in Illinois, among localities within each state, and between states. Notably, significant gene frequency variation among groups of beetles occupying closely spaced trees was detected at several localities. PMID- 28563854 TI - SEWALL WRIGHT AND POPULATION STRUCTURE IN RELATION TO EVOLUTION. PMID- 28563855 TI - GENE FLOW IN GROUND BEETLES (COLEOPTERA: CARABIDAE) OF DIFFERING HABITAT PREFERENCE AND FLIGHT-WING DEVELOPMENT. AB - Estimates of gene flow vary 100-fold among five carabid species, ranging from the winged lowland subtropical Agonum elongatulum to the flightless montane temperate Platynus angustatus. Results based on Wright's (1943) FST method, and Slatkin's (1981) graphical and (1985a) private-allele methods are concordant. Genetic heterogeneity, measured by Wright's FST , is not correlated with degree of flight wing development; one fully winged species exhibits heterogeneity of the same order as a vestigially winged species. Genetic heterogeneity is positively correlated with the average elevation of collection sites for these species. Lower levels of gene flow associated with greater genetic subdivision may occur in upland areas because of habitat fragmentation (due to topographic diversity) and habitat persistence (leading to a lower extinction rate for populations). In at least one species, the distribution of stable infraspecific polymorphisms indicates that the high estimate of present-day gene flow is likely to be due to historical gene flow and not to present-day conditions. PMID- 28563856 TI - GENETIC AND MATERNAL INFLUENCES ON BRAIN AND BODY SIZE IN RANDOMBRED HOUSE MICE. AB - Genetic and environmental (chiefly maternal) variance and covariance components were estimated for brain and body size in randombred house mice of three different ages (one, three, and five months). Heritabilities estimated from regressions of offspring on their five-month-old male parents were fairly low over all three ages, averaging about 0.2 for brain size and about 0.3 for body size. Heritability estimates from female parents were higher, however, presumably because of the influence of maternal-environmental components of variance. The total maternal impact was estimated from full-sib analyses and, for the more reliable three- and five-month ages, averaged 23% for brain size and 20% for body size. Phenotypic, genetic, and environmental correlations and regressions of brain and body size also were calculated by parent-offspring and sib-correlation techniques, the phenotypic correlations generally decreasing from about 0.4 at one month to 0.2 at three and five months. Genetic correlations of brain and body size estimated from covariances of offspring on male parents were negative whereas those from female parents were positive in sign, and this as well as positive maternal correlations was taken as evidence of the influence of maternal sources of covariance for these traits. It was concluded that, in addition to direct genetic effects, indirect genetic sources of variance and covariance mediated through the prenatal maternal environment are quite important in the determination of brain size and its association with body size. PMID- 28563857 TI - DISPERSAL AND POPULATION-GENETIC STRUCTURE OF THE COOPERATIVE SPIDER, AGELENA CONSOCIATA, IN WEST AFRICAN RAINFOREST. AB - Dispersal experiments and gel electrophoresis of allozyme polymorphisms were used to investigate the selective mode underlying cooperative behavior in the rainforest spider, Agelena consociata. Previous work has indicated that individual selection alone does not explain the cooperative and even altruistic behavior noted for this African species, which exists in groups of up to hundreds of adults. We found no evidence for active dispersal by reproductives or any age class of this spider. Nest fragmentation by falling tree limbs and storms is indicated as the cause of new nest formation within local areas, while passive dispersal by vertebrate carriers that either have some association with the nests (bats) or move through them is indicated as the probable mode of longer-distance dispersal. The population-genetic structure observed for A. consociata supports the data obtained on dispersal. Wright's FST statistic and G tests for genetic heterogeneity indicate that the populations are subdivided into genetically heterogeneous colonies. Comparisons utilizing Nei's genetic distance show colonies separated by as few as 30 m to be as genetically distinct as are colonies separated by many kilometers. There is also a marked scarcity of heterozygotes, and individuals within nests and associated colonies are genetically related about as much as are full siblings. The results of these analyses indicate that kin selection or some type of family-group selection may have been important in the evolution of cooperative behavior in the species. PMID- 28563858 TI - HERITABLE VARIATION IN FITNESS AS A PREREQUISITE FOR ADAPTIVE FEMALE CHOICE: THE EFFECT OF MUTATION-SELECTION BALANCE. PMID- 28563859 TI - SPATIAL GENETIC STRUCTURE IN A POPULATION OF PSYCHOTRIA NERVOSA. I. DISTRIBUTION OF GENOTYPES. PMID- 28563860 TI - FIELD MEASUREMENTS OF NATURAL AND SEXUAL SELECTION IN THE FUNGUS BEETLE, BOLITOTHERUS CORNUTUS. AB - Selection on three phenotypic traits was estimated in a natural population of a fungus beetle, Bolitotherus cornutus. Lifetime fitness of a group of males in this population was estimated, and partitioned into five components: lifespan, attendance at the mating area, number of females courted, number of copulations attempted, and number of females inseminated. Three phenotypic characters were measured-elytral length, horn length, and weight; there were strong positive correlations among the three characters. Selection was estimated by regressing each component of fitness on the phenotypic traits. Of the three traits, only horn length was under significant direct selection. This selection was for longer horns and was due mainly to differences in lifespan and access to females. The positive selection on horn length combined with the positive correlations between horn length and the other two characters resulted in positive total selection on all three characters. PMID- 28563861 TI - PHYSIOLOGICAL STRESS AND COLOR POLYMORPHISM IN THE INTERTIDAL SNAIL NUCELLA LAPILLUS. AB - The intertidal snail Nucella lapillus exhibits considerable variation in shell color both within and between populations differentially exposed to wave action. Populations from high-wave-energy shores tended to be highly polymorphic and were dominated by pigmented morphs (especially brown), while those at more sheltered locations exhibited less polymorphism and were predominantly white. Field and laboratory experiments were conducted to determine the role of physiological stress and selective predation in maintaining the observed distribution of color morphs. The results demonstrated that 1) physiological stress from high temperature and desiccation during periods of tidal emersion was greater on protected shores, 2) under similar natural conditions, brown morphs heated up faster, attained higher temperatures, desiccated more rapidly, and suffered greater mortality than did white morphs, and 3) when pairs of brown and white morphs were tethered intertidally there was virtually no mortality of either morph on the exposed shore or in shaded microhabitats on the protected shore, but brown morphs suffered much greater mortality in sunny microhabitats on the protected shore. These findings demonstrate that the interpopulation variation in shell color of N. lapillus is in part a response to a selective gradient in physiological stress. Selection for crypsis by visually hunting predators did not appear to play a prominent role; however, only adults were considered, and the predation experiments were conducted in the fall before shorebirds that prey on whelks had arrived from their summer feeding grounds. Further experimentation to quantify the effects of visual predators such as birds and fish, particularly on juvenile snails, is necessary to assess adequately the importance of predation. PMID- 28563862 TI - THE EFFECTS OF THE MATING SYSTEM ON PROGENY PERFORMANCE IN HYLA CRUCIFER (ANURA: HYLIDAE). AB - We performed a controlled mating experiment to determine whether genetic variation in larval traits in Hyla crucifer was predictable on the basis of mating status or body size of male parent. Larval growth rate was predictably related to body size of the sire. Males from the upper half of the body-size distribution sired offspring with 6% higher growth rates than those of offspring sired by males from the lower half of the body-size distribution. Offspring sired by males that obtained mates in nature had 3% higher growth rates than their half siblings sired by males that did not mate in nature. Genetic variation for larval period duration and size at metamorphosis was detected; however, neither mating status nor body size of sire could be used to predict values of these traits in the progeny. Although all three larval traits can affect fitness, there was no evidence that the offspring of some sires would always outperform the offspring of others in all three traits. The predictable association between adult male size and larval growth rate means that the H. crucifer mating system would have a directional effect on larval growth rate if male body size influences the outcome of male-male competition or female choice. PMID- 28563863 TI - MULTIPLE GENETIC MECHANISMS FOR THE EVOLUTION OF SENESCENCE IN DROSOPHILA MELANOGASTER. AB - We present the results of selection experiments designed to distinguish between antagonistic pleiotropy and mutation accumulation, two mechanisms for the evolution of senescence. Reverse selection for early-life fitness was applied to laboratory populations of Drosophila melanogaster that had been previously selected for late-life fitness. These populations also exhibited reduced early age female fecundity and increased resistance to the stresses of starvation, desiccation, and ethanol, when compared to control populations. Reverse selection was carried out at both uncontrolled, higher larval rearing density and at controlled, lower larval density. In the uncontrolled-density selection lines, early-age female fecundity increased to control-population levels in response to the reintroduction of selection for early-age fitness. Concomitantly, resistance to starvation declined in agreement with previous observations of a negative genetic correlation between these two characters and in accordance with the antagonistic-pleiotropy mechanism. However, resistance to stresses of desiccation and ethanol did not decline in the uncontrolled-density lines during 22 generations of reverse selection for early-life fitness. The latter results provide evidence that mutation accumulation has also played a role in the evolution of senescence in this set of Drosophila populations. No significant response in early-age fecundity or starvation resistance was observed in the controlled-density reverse-selection lines, supporting previous observations that selection on Drosophila life-history characters is critically sensitive to larval rearing density. PMID- 28563864 TI - A NEGATIVE MATERNAL EFFECT IN SPRINGT AILS. PMID- 28563865 TI - MALE MATING PREFERENCES AND ASSORTATIVE MATING IN THE SOLDIER BEETLE. AB - Mating preferences for a color characteristic were examined in three northern Georgia populations of the soldier beetle, Chauliognathus pennsylvanicus De Geer, by comparing observed and expected frequencies of matings to the same phenotype. The three populations are apparently in a zone of secondary contact between disparate color morphs. In the most northern population sampled, preferences were strong and were associated with positive assortative mating with respect to the color characteristic. In the southern population, neither assortative mating nor mating preference was strong, while in the middle population, preferences were expressed in the absence of assortative mating. Mating preferences cannot be attributed to host-plant choice, microhabitat choice, or simple conditioning on the phenotype of the last mate. However, they may represent part of a specific mate-recognition system which has been maintained in part of the zone of overlap but which has eroded in other areas. PMID- 28563866 TI - DIPLOID-TRIPLOID MOSAICS AMONG UNISEXUAL HYBRIDS OF THE MINNOWS PHOXINUS EOS AND PHOXINUS NEOGAEUS. AB - Diploid-triploid mosaics are rarely found in vertebrates, and until now they were known to be common in only two vertebrate species complexes. Here we report that diploid-triploid mosaics are widespread among unisexual hybrids of the minnows Phoxinus eos and Phoxinus neogaeus, a complex already known to contain diploid and triploid forms. Using chromosome counts and flow cytometry, we show that the mosaics occur throughout the known range of the unisexuals and are abundant in many of these natural populations. The mosaics are highly heterogeneous, showing individual variation in the ratio of diploid to triploid cells, and as a group they appear to form a continuum between the pure diploid and triploid forms. Tissue-graft analysis shows that the third genome present in the triploid cells of a mosaic is expressed, because grafts made from the mosaics show an incidence of rejection intermediate between that of the diploid (clonal) and triploid (nonclonal) biotypes. PMID- 28563867 TI - ADAPTIVE PLASTICITY IN DEVELOPMENT OF SCAPHIOPUS COUCHII TADPOLES IN DESERT PONDS. AB - Couch's spadefoot toads (Scaphiopus couchii) breed in ephemeral desert ponds that are highly variable in duration. Rapid development is expected to be advantageous in short-duration ponds, but slower development, allowing more time for growth, may be advantageous in ponds of longer duration. Previous experiments have revealed both genetic variation in development time and phenotypic plasticity in response to pond drying. In this paper, I examine the norms of reaction of five sibships of tadpoles to see whether there is genetic variation in the effect of pond duration, i.e., in phenotypic plasticity. Several important results emerged. 1) Differences among sibships in development time that were seen in the lab were also seen in the field. 2) There was no evidence for genetic variation in plasticity of development; all sibships exhibited faster development and decreased larval period in ponds of short duration. Plasticity in development appears to be adaptive, as size at metamorphosis was correlated with duration of larval period. The slowest developing sibship, however, suffered higher mortality compared to other sibships in short duration ponds. 3) Sibships did not differ in growth or size at metamorphosis in short-duration ponds, but the slowest developing sibship metamorphosed at the largest size in long duration ponds, resulting in a significant genotype x environment interaction for size at metamorphosis. Thus, although only one of the five sibships responded differently, there appears to be genetic variation for plasticity in growth, and a genetically determined trade-off between fitness in short-duration ponds (via rapid development) and fitness in long duration ponds (via large size at metamorphosis). This may explain the existence of both phenotypic plasticity and genetic variation in development. A single genotype, although capable of adaptive plasticity, is not sufficiently flexible to have equally high fitness in both long- and short-duration ponds. PMID- 28563868 TI - EFFECT OF AN EXPERIMENTAL BOTTLENECK ON MORPHOLOGICAL INTEGRATION IN THE HOUSEFLY. AB - Three measures of multivariate integration were derived from both additive genetic covariance and correlation matrices estimated from parent-offspring covariances to investigate the effect of bottlenecks of different sizes on genetic integration of morphological traits in the housefly, Musca domestica L. Bottleneck lines were initiated with one, four, or 16 pairs of flies sampled from a natural outbred (control) population. Bottlenecks of intermediate size significantly increased the average genetic correlation among traits, resulting in nearly isomorphic variation among all traits in these lines. Single-pair bottlenecks significantly disrupted the trait interrelationships, and the suites of traits identified by principal components of the additive genetic correlation and covariance matrices for the control population were no longer evident in these bottleneck lines. The alteration of the genetic relationships among traits as a result of a bottleneck suggests that nonadditive components of genetic variation affecting these traits were present in the control line. We discuss the implications of nonadditive gene action, particularly epistasis, for speciation via bottlenecks. PMID- 28563869 TI - MAJOR-GENE MODELS OF SEXUAL SELECTION UNDER CYCLICAL NATURAL SELECTION. PMID- 28563870 TI - SYMPATRIC SPECIATION IN SNAILS; A LARGELY NEGLECTED MODEL. PMID- 28563871 TI - EVOLUTIONARY REDUCTION OF COMPLEX LIFE CYCLES: LOSS OF HOST-ALTERNATION IN PEMPHIGUS (HOMOPTERA: APHIDIDAE). AB - In a Utah canyon, the aphid, Pemphigus betae, exhibits two life cycles: a cycle involving host-alternation between cottonwood trees and roots of herbaceous plants and a secondarily reduced cycle, in which the cottonwood generations are eliminated so that wingless forms live year round on roots. Relative frequencies of the two life-cycle types vary along a 30-km stretch of the canyon, with the reduced cycle predominating at upper sites. Factors underlying this life-cycle variation were examined with common-garden and transfer experiments. Results showed 1) a facultative increase in production of alternating forms in response to crowding in root colonies, 2) a genetic component to both within- and between site variation in tendency to produce alternating morphs, and 3) site-specific environmental effects on level of investment in the reduced versus alternating life cycles. Thus, the variation in frequency of life-cycle reduction in this aphid is dependent on a complex of interdependent factors. These include adaptive phenotypic plasticity, microgeographically variable cues affecting mechanisms of morph determination, and genetically based variation in tendency to show reduction versus alternation. Genetic variation between sites corresponds to microgeographic variation in success of life-cycle phases. Where cottonwood hosts are absent (lower elevations) or where the cottonwood phase has low survival (upper elevations), clones tend to produce fewer migrating morphs, as compared to clones from middle elevations, where the cottonwood phase is relatively favorable. Such independence between conditions in alternate phases is a general feature of complex life cycles and can generate strong site-specific selection for permanent life-cycle reduction. Such life-cycle shifts have sometimes been followed by extensive radiations in aphids and other groups. PMID- 28563872 TI - GENETIC VARIATION FOR LARVAL ANURAN (SCAPHIOPUS COUCHII) DEVELOPMENT TIME IN AN UNCERTAIN ENVIRONMENT. AB - Couch's spadefoot toads (Scaphiopus couchii) breed in ponds of uncertain duration. In natural ponds, larvae exhibit considerable variation in growth, size at metamorphosis, and development time. Phenotypic differences in development time may dramatically affect survivorship in these ponds. A quantitative-genetic analysis of larval traits was undertaken to determine the potential evolutionary relevance of phenotypic variation observed in the field. Additive genetic variance was detected for development time, but not for any other trait. Some variation in early growth was attributed to maternal effects; maternal effects, however, were not apparent for size at metamorphosis or development time. Nonadditive genetic effects were not statistically significant for any trait, but the nonsignificance of these effects must be interpreted cautiously, as the sample of females was relatively small and the mating design used is not very effective for detecting interactions. Genetic variation in development time in this population is most likely maintained by variability in the direction of selection as a consequence of variation in pond duration. PMID- 28563873 TI - ALPHA-CHAIN HEMOGLOBIN POLYMORPHISMS ARE CORRELATED WITH ALTITUDE IN THE DEER MOUSE, PEROMYSCUS MANICULATUS. AB - In deer mouse (Peromyscus maniculatus) populations in the western United States, alpha-globin haplotype frequency, beta-globin haplotype frequency, and base-line blood oxygen affinity (measured after acclimation to low altitude) show strong correlations with native altitude. The correlations improve when an average regional altitude is substituted for the local altitude at collection sites. This substitution roughly compensates for the effects of gene exchange between populations in areas of highly variable topography. When subspecific effects are removed with covariate analyses a significant (P < 0.05) relationship remains only for alpha-globin haplotype frequency and altitude. Thus, alpha-globin haplotype frequency, beta-globin haplotype frequency, and base-line blood oxygen affinity may be explained by either subspecific or altitudinal effects, but subspecific effects explain a larger proportion of the variance. Part of the subspecific effect may be attributable to an underlying relationship of subspecies with altitude. The analyses for the alpha-globins in conjunction with other data on the effects of alpha-globins on blood oxygen affinity and whole animal physiological performance are consistent with the hypothesis that the frequency of the alpha-globins evolved in response to selection resulting from the stress of high-altitude hypoxia. PMID- 28563874 TI - REPRODUCTIVE ISOLATION AND DISTINCT POPULATION STRUCTURES IN TWO TYPES OF THE FRESHWATER SHRIMP PALAEMON PAUCIDENS. AB - Twenty local populations of the Japanese freshwater shrimp Palaemon paucidens were electrophoretically and morphologically surveyed. Based on the diagnostic distributions of some alleles at Gpi, Mpi, Mdh-1, and Mdh-2, these populations were largely classified into two types (A and B). The A type occurred in lakes, ponds, and rivers, while the B type was observed only in rivers. Average Nei's genetic distance (D) between the two types fell into the subspecies range (D =0.1186). The coefficient of gene differentiation, GST , varied considerably between the two types. In 12 populations of the A type, with a GST value of 0.281, nine pond and lake populations showed a higher GST (0.246) than the three river populations (0.151). On the other hand, GST was 0.036 for the eight local populations of the B type. The lower rostrum tooth number had a mode of two in type A and three in type B. Type-A populations largely varied in the upper rostrum tooth number and egg size but type B did not. Under laboratory conditions, mating frequently occurred within each type, but not between types. Furthermore, no embryonic development was observed in the few cases of intertype mating. These results indicate that the A and B types had experienced cladogenic separation with pre- or postmating isolation, whereafter the A type, under geographic isolation, underwent genetic and phenotypic differentiation, while the B type, under extensive gene flow, did not undergo differentiation. PMID- 28563875 TI - SEXUAL DIMORPHISM IN BODY SIZE: A MODEL AND A TEST. PMID- 28563876 TI - HERITABILITY AND SELECTION ON CLUTCH SIZE IN DARWIN'S MEDIUM GROUND FINCHES (GEOSPIZA FORTIS). AB - I studied the causes of variation and selection on clutch size in a population of Darwin's Medium Ground Finches (Geospiza fortis) on Isla Daphne Major, using data collected over a nine-year period (1976-1984). Quantitative-genetic analyses were carried out using the first clutch laid by a female in a given year. I used both unadjusted clutch-size values and values adjusted for between-year differences in mean clutch size for repeatability and regression analyses. Repeatability of clutch size was small (<=8%) and nonsignificant in all cases. Sib-sib analyses and parent-offspring regressions gave no evidence of a significant additive genetic component to clutch-size variation. Slopes of mother-daughter regressions were actually negative, suggesting possible maternal effects of mother's clutch size on daughter's clutch size. There was a small positive relationship between female age and clutch size but no effect of male or female body size or of large scale differences in habitat quality on clutch size. Selection on clutch size was generally directional and positive: in almost all years in which successful breeding occurred, large clutches tended to fledge more chicks and produce more young surviving to the following year, possibly because there was no trade-off between clutch size and the weights of individual chicks at fledging. Thus, sustained directional selection for large clutch size may have reduced additive genetic variation in clutch size to low levels in this population. The size of a female's clutch may be primarily determined by unidentified proximate environmental factors which vary from year to year, rather than by any long-term optimization of clutch size with respect to adult survival. PMID- 28563878 TI - THE LIMITS OF AMINO ACID SEQUENCE DATA IN ANGIOSPERM PHYLOGENETIC RECONSTRUCTION. AB - Amino acid sequence data are available for ribulose biphosphate carboxylase, plastocyanin, cytochrome c, and ferredoxin for a number of angiosperm families. Cladistic analysis of the data, including evaluation of all equally or almost equally parsimonious cladograms, shows that much homoplasy (parallelisms and reversals) is present and that few or no well supported monophyletic groups of families can be demonstrated. In one analysis of nine angiosperm families and 40 variable amino acid positions from three proteins, the most parsimonious cladograms were 151 steps long and contained 63 parallelisms and reversals (consistency index = 0.583). In another analysis of six families and 53 variable amino acid positions from four proteins, the most parsimonious cladogram was 161 steps long and contained 50 parallelisms and reversals (consistency index = 0.689). Single changes in both data matrices could yield most parsimonious cladograms with quite different topologies and without common monophyletic groups. Presently, amino acid sequence data are not comprehensive enough for phylogenetic reconstruction among angiosperms. More informative positions are needed, either from sequencing longer parts of the proteins or from sequencing more proteins from the same taxa. PMID- 28563877 TI - HEMOGLOBIN POLYMORPHISMS IN DEER MICE (PEROMYSCUS MANICULATUS): PHYSIOLOGY OF BETA-GLOBIN VARIANTS AND ALPHA-GLOBIN RECOMBINANTS. AB - Wild populations of deer mice (Peromyscus maniculatus) contain hemoglobin polymorphisms at both alpha-globin (Hba, Hbc) and beta-globin (Hbd) loci. Population gene frequencies of beta-globin variants (d0 and d1 haplotypes) are not correlated with altitude, whereas a1 c1 alpha-globin haplotypes are fixed in low-altitude populations, and a0 c0 haplotypes reach near fixation at high altitudes. We examined the effects of alpha- and beta-globin variants on blood oxygen affinity and on aerobic performance, measured as maximum oxygen consumption (VO2max). Exercise and cold exposure were used to elicit VO2max. Experiments were performed at low (340 m) and high (3,800 m) altitude to include the range of oxygen partial pressures encountered by wild deer mice. Beta-globin variants had little effect on blood oxygen affinity or VO2max. Oxygen dissociation curves from a0 c0 and a1 c1 homozygotes and heterozygotes had similar shapes, but the P50 of a0 c0 homozygotes was significantly lower than that of other genotypes. Mice carrying a1 c1 /a1 c1 genotypes had the highest VO2max at low altitude, but mice with a0 c0 /a0 c0 genotypes had the highest VO2max at high altitude. Mice carrying rare recombinant alpha-globin haplotypes (a0 c1 ) had lower VO2max than nonrecombinant genotypes as a whole but in most cases were not significantly different from nonrecombinant heterozygotes (a0 c0 /a1 c1 ). We conclude that genetic adaptation to different altitudes was important in the evolution of deer mouse alpha-globin polymorphisms and in the maintenance of linkage disequilibrium in the alpha-globin loci but was not a significant factor in the evolution of beta-globin polymorphisms. PMID- 28563879 TI - EXAMINING SELECTION ON THE MULTIVARIATE PHENOTYPE: PLANT RESISTANCE TO HERBIVORES. AB - Cost-benefit theory posits that stabilizing selection, produced by a trade-off between associated costs and benefits, often maintains phenotypic traits at intermediate equilibrium values. Measurement of selection on one type of trait, resistance to herbivory, should provide evidence to test this prediction. However, most plants host more than one species of herbivore, and resistance to various herbivores may be phenotypically correlated. Consequently, selection must be measured on a multivariate phenotype, which may produce a very complex selection gradient. Canonical analysis of the matrix of quadratic coefficients of the phenotypic selection gradient is presented as a method to simplify the interpretation of the estimated multidimensional adaptive surface. Because this analytical method finds the canonical axes of second-order effects on the selection surface, it shows where nonlinear, and possibly stabilizing, selection is strongest. The resulting index traits may generate hypotheses regarding underlying resistance traits to which more than one type of herbivore responds. PMID- 28563880 TI - VARIATION IN OVIPOSITION PREFERENCE OF HELIOTHIS VIRESCENS IN RELATION TO MACROEVOLUTIONARY PATTERNS OF HELIOTHINE HOST RANGE. AB - When cotton, geranium, petunia, tobacco, tomato, and velvetleaf were presented simultaneously to strains of the Heliothine moth, Heliothis virescens (F.), from Arizona (AZ), Mississippi (MS), and North Carolina (NC), oviposition choices were similar, while a strain from the Virgin Islands (VI) was significantly different from both the AZ and MS strains. In the MS-VI six-host test, the VI strain laid a higher proportion of its eggs on tomato and a lower proportion of its eggs on petunia than did the MS strain. Since petunia and tomato are in the same plant family (Solanaceae), differences between the strains in host preference do not appear to involve traits common to all members of a plant family. In the AZ-VI six-host test, the AZ strain laid a higher percentage of its eggs on tobacco and lower percentages on geranium and velvetleaf (Malvaceae) than did the VI strain. The percentages of eggs laid on cotton (Malvaceae) by the two strains were not significantly different. When moths were placed in cages with only tobacco and geranium, the AZ strain again laid a higher percentage of its eggs on tobacco than did the VI strain. However, when host choice was restricted to tobacco and cotton or velvetleaf and cotton, no significant difference between strains was found. Reciprocal hybrids of the AZ and VI strains were intermediate to the parental stocks in their preference for tobacco over geranium, indicating that a genetic mechanism was responsible for oviposition preference. The relevance of these findings to seemingly rapid fluxes in host range among members of the Heliothinae is discussed. PMID- 28563881 TI - POPULATION STRUCTURE AND KINSHIP IN POLISTES (HYMENOPTERA, VESPIDAE): AN ANALYSIS USING RIBOSOMAL DNA AND PROTEIN ELECTROPHORESIS. AB - Six variable protein loci and one variable ribosomal DNA restriction site were used for an analysis of population structure in five species of Polistes from Texas. A sample-reuse algorithm was developed that estimated FST , FIS , and o (the coefficient of kinship) from probabilities of identity. Of the four species analyzed in detail only one, Polistes exclamans, had statistically significant values of FST . These values may reflect natural constraints on successful nesting for migrants of this species. Three of the four species had significant values of FIS and three of the four species had significant values of o. In many cases o also differed from the expected value under haplodiploidy and random mating. Values of o did not differ from expectations under haplodiploidy and local inbreeding. These results emphasize that theories of social behavior and evolution based on coefficients of kinship should include some explicit consideration of population structure. PMID- 28563882 TI - SPATIAL PATTERNS OF DIFFERENTIATION FOR GENE FLOW IN PLANTAGO LANCEOLATA. PMID- 28563883 TI - ALLOPATRIC ORIGIN OF SYMPATRIC POPULATIONS OF LAKE WHITEFISH (COREGONUS CLUPEAFORMIS) AS REVEALED BY MITOCHONDRIAL-DNA RESTRICTION ANALYSIS. AB - In the paper, restriction-fragment length polymorphisms in mitochondrial DNA (mtDNA) were studied to test the hypothesis that sympatric populations of lake whitefish in the Allegash basin have recently diverged through sympatric speciation. Thirteen restriction enzymes were used to analyze mtDNA of 156 specimens representing 13 populations from eastern Canada and northern Maine where normal and dwarf phenotypes of whitefish exist in sympatry and allopatry. Two monophyletic assemblages of populations that exhibit different geographic distributions were identified. One showed an eastern distribution that expands from Cape Breton to the Allegash basin and the other exhibits a more western distribution. The Allegash basin was the only area of overlap. The western assemblage exhibited the normal size phenotype in all cases, whereas the eastern assemblage exhibited the normal size phenotype in allopatric conditions and the dwarf size phenotype in sympatry. The existence of sympatric pairs in the Allegash basin result from the secondary contact of two monophyletic groups of whitefish that evolved allopatrically in separate refugia during the last glaciation events. The weak mtDNA difference of sympatric pairs suggests that speciation of lake whitefish in eastern North America was accompanied by only minor alterations of the ancestral gene pool. PMID- 28563884 TI - MITOCHONDRIAL DNA POLYMORPHISM AND CYTOPLASMIC INCOMPATIBILITY IN NATURAL POPULATIONS OF DROSOPHILA SIMULANS. PMID- 28563885 TI - DYNAMICS OF SEXUAL SELECTION IN DIPLOID POPULATIONS. AB - We describe results for a diploid, two-locus model for the evolution of a female mating preference directed at an attractive male trait that is subject to viability and/or fertility selection. Using computer simulation, we studied a large, random sample of parameter values, assuming additivity of alleles at the preference locus and partial dominance at the trait locus. Simulation results were classifiable into nine types of parameter sets, each differing in equilibria, evolutionary trajectories, and rates of evolution. For many parameters, evolutionary trajectories converged on curves within the allelic frequency plane and subsequently evolved along the curves toward fixation. Neutrally stable curves of equilibria did not occur in Fisherian models that assume only viability and sexual selection unless there is complete dominance at the trait locus. The Fisherian models also exhibited oscillation of allelic frequencies and unique polymorphic equilibria. "Sexy son" models in which attractive males had reduced fertility were much less likely to lead to increase in traits and preferences than were the Fisherian models. However, if less fertile males had increased viability, trait polymorphisms and fixation of rare "sexy" alleles occurred. In general, the behavior of the diploid model was much more complex than that of analogous haploid or polygenic models. PMID- 28563886 TI - FOOD QUALITY, HETEROZYGOSITY, AND FITNESS CORRELATES IN PEROMYSCUS POLIONOTUS. AB - Oldfield mice (Peromyscus polionotus) that are more heterozygous utilize food and maintain body weight under varying degrees of dietary stress better than their less heterozygous counterparts. Mice were collected in southern Florida and fed diets of three qualities. During each dietary treatment, body weight, amount of food eaten, amount of food absorbed, and feeding efficiency were determined. Body weights for all mice decreased during the experiment. More heterozygous mice maintained their weight better during periods of dietary stress than those that were less heterozygous. Mice with different levels of genetic variability had essentially the same mean feeding efficiency with high quality diets. Mice with high heterozygosities maintained the same efficiency with low quality diets, but those with lower heterozygosities had decreased feeding efficiencies. A slight increase in available energy for mice of different heterozygosities can dramatically change fitness correlated characters, such as growth rates, body weights, energy stores, and reproductive rates. PMID- 28563887 TI - INFERENCES ABOUT INBREEDING DEPRESSION BASED ON CHANGES OF THE INBREEDING COEFFICIENT. AB - In a mixed-mating population, the fitness of selfed individuals, relative to outcrossed individuals, can be estimated from observed changes of the inbreeding coefficient F. In general, three measurements of F, or two measurements of F and one of the selfing rate, spanning two generations are needed. If however, adult F is assumed constant among generations, the adult F and selfing rate of one generation are sufficient to estimate relative fitness. Estimates of the relative fitness of selfed individuals for 14 Mimulus populations, assuming equilibrium of adult F, averaged 0.38, which is significantly lower than the 0.50 threshold needed to favor selfing genotypes. However, estimates for some populations showed large variance and over the 14 populations, relative fitness did not correlate with selfing rate. Violations of the equilibrium assumption causes a positive bias of the estimate and a spurious negative correlation of estimates with selfing rate. Estimates of relative fitness based on two generations of F do not suffer these problems. The need for large sample sizes, multiallelic loci, and moderate levels of natural selfing limits the usefulness of using changes of F to infer inbreeding depression. PMID- 28563888 TI - POLLEN LOADS AND PROGENY VIGOR IN CUCURBITA PEPO: THE NEXT GENERATION. AB - Previous research on the Black Beauty bush cv. of zucchini has documented a strong positive relationship between the size of the pollen load and the vigor (performance) of the progeny. Here we report the results of three studies designed to test the hypothesis that the previously observed differences in progeny vigor are heritable. Two studies examined the transmission of the pollen load effect to subsequent generations through the ovules (female role). The third study determined if there is genetic variation for pollen performance and if the pollen load effect could be transmitted to a subsequent generation through the pollen (male role). In each of these studies the vigor of the progeny from the subsequent generation was evaluated in the greenhouse and/or the field. The results of these studies reveal (1) that the ability to sire seeds does respond to selection imposed by high pollen loads, (2) that only 23 of the 35 total traits that we measured in the three studies of transmission to subsequent generations changed in the direction predicted by the pollen competition hypothesis, (3) that only 5 of the 35 traits were significantly affected by the size of the pollen load that produced the previous generation (but all 5 were in the direction predicted by the pollen competition hypothesis), and (4) that only one study produced an overall significant difference (MANOVA) attributable to the size of the pollen load that produced the previous generation (but it too was in the direction predicted by the pollen competition hypothesis). From these experiments we conclude that pollen competition appears to play a real but minor role in the production of differences in vigor between progeny arising from low versus high pollen loads. In Black Beauty bush cv. of zucchini, maternal effects, pollen-pistil interactions, or nonrandom patterns of seed abortion must play important roles as well. PMID- 28563889 TI - COMPARISON OF RELATEDNESS ESTIMATORS. PMID- 28563890 TI - MULTIPLE EQUILIBRIA AND MAINTENANCE OF ADDITIVE GENETIC VARIANCE IN A MODEL OF PLEIOTROPY. AB - We describe a multilocus model that incorporates pleiotropic stabilizing selection on a large number of characters. We find many different stable equilibria with different levels of polymorphism and additive genetic variability. The results lend support to Wright's concept of a complex adaptive surface with many peaks of different heights. The model assumes that alleles contribute additively to the characters. We analyze the multilocus model by first considering a two-locus model. The two-locus model depends critically on having loci of different effect and on having the optimum phenotype not be that of a completely heterozygous individual. The effects of different loci need to differ only by less than a factor of two. For the multilocus, multicharacter model, we assume that completely heterozygous individuals do not have the optimum phenotype. By restricting attention to a two-allele model, we also assume that there are no alleles that can affect all characters in all possible combinations of directions. PMID- 28563891 TI - ELECTROPHORETIC CONFIRMATION OF INTERSPECIFIC HYBRIDIZATION IN AESCULUS (HIPPOCASTANACEAE) AND THE GENETIC STRUCTURE OF A BROAD HYBRID ZONE. AB - Within a broad (>200 km wide) hybrid zone involving three parapatric species of Aesculus, we observed coincident clines in allele frequency for 6 of 14 electrophoretic loci. The cooccurrence of alleles characteristic of A. pavia, A. sylvatica, and A. flava was used to estimate genetic admixtures in 48 populations involving various hybrids between these taxa in the southeastern United States. High levels of allelic polymorphism (up to 40% greater than the parental taxa) were observed in hybrid populations and also in some populations bordering the hybrid zone. A detailed analysis of a portion of the hybrid zone involving A. pavia and A. sylvatica revealed a highly asymmetrical pattern of gene flow, predominantly from Coastal Plain populations of A. pavia into Piedmont populations of A. sylvatica. Computer simulations were used to generate expected genotypic arrays for parental, F1 ; and backcross individuals, which were compared with natural populations using a character index scoring system. In these comparisons, hybrid individuals could be distinguished from either parent, but F1 and backcross progeny could not be distinguished from each other. Most hybrid populations were found to include hybrids and one of the parental taxa, but never both parents. Three populations appeared to be predominantly hybrids with no identifiable parental individuals. Hybrids occurred commonly at least 150 km beyond the range of A. pavia, but usually not more than 25 km beyond the range of A. sylvatica. Introgression, suggested by genetically hybrid individuals and significant gene admixtures of two or more species in populations lacking morphological evidence of hybridization, may extend the hybrid zone further in both directions. The absence of one or both parental species from hybrid populations implies a selective disadvantage to parentals in the hybrid zone and/or that hybridization has occurred through long-distance gene flow via pollen, primarily from A. pavia into A. sylvatica. Long-distance pollen movement in plants may generate hybrid zones of qualitatively different structure than those observed in animals, where gene flow involves dispersal of individuals. PMID- 28563892 TI - SELECTION ON LOCOMOTOR PERFORMANCE CAPACITY IN A NATURAL POPULATION OF GARTER SNAKES. AB - Selection on locomotor performance was determined for a series of marked and recaptured individuals from a population of garter snakes (Thamnophis sirtalis fitchi) in Northern California. We measured snake length and mass, burst speed, endurance on a treadmill, and the distance crawled around a stationary circular track. Size-corrected values (residuals) of mass and locomotor performance were generated from the scaling equations of S-V length (SVL). Randomization tests and regressions were used to determine the probability that a trait was a significant predictor of survivorship, and a nonparametric, cubic spline estimate of the fitness function was used to facilitate detection of the patterns of selection. From 275 ("cohort") snakes measured and tested within 8 days of birth in 1985, 79 were recaptured in the spring-summer of 1986 and subsequent years. Birth SVL was the only significant (randomization P = 0.022) predictor of neonatal survival from 1985 to 1986 with directional selection favoring larger individuals. In addition to the lab-born cohort, 382 field-born snakes from all ages in the population were captured, tested, and released during spring-summer 1986. Similar to the 1985 cohort, the survivorship of 37 of 86 neonates from 1986 to 1987 showed no significant relationship with any residual value using any statistical test. Survivorship from 1986 to 1987 for 127 of 250 yearlings (including 32 lab born cohort snakes) analyzed with the randomization test showed that greater values of both speed (P = 0.007) and distance residual (P = 0.008) significantly favored survival, whereas intermediate values of mass residual (P = 0.006) were significantly more likely to survive. Univariate regressions predicting the survival of yearlings from 1986 to 1987 gave similar results to the randomization test, but in a multiple regression with yearling burst speed residual, distance capacity residual, and a quadratic term of mass residual, distance capacity residual was the least important predictor variable. For the survivorship of 37 of the 113 older snakes, greater burst speed residual significantly favored survival (randomization P = 0.001). PMID- 28563893 TI - WHY MOTHERS DO NOT RESIST INFANTICIDE: A COST-BENEFIT GENETIC MODEL. AB - Infanticide has recently been observed in several primate species while female counterstrategies are seemingly rare. The question of why mothers do not increase their resistance to infanticide is investigated using a haploid two-locus model. A hypothesis that mothers can recover lost offspring by gaining more grandchildren is rejected in most cases, and it is shown that costs and benefits for both males and females have the strongest influence on the evolution of infanticide and obedience to it. An estimation of parameters for a natural population of hanuman langurs suggests that infanticide is more advantageous than noninfanticide and the costs of resistance, compared to obedience, is higher than its benefits. Data from other studies on primate infanticide are discussed in the light of results of the model. PMID- 28563894 TI - THE EVOLUTION OF REPRODUCTIVE ISOLATION AS A CORRELATED CHARACTER UNDER SYMPATRIC CONDITIONS: EXPERIMENTAL EVIDENCE. AB - A set of experiments is described that tests the general hypothesis that sympatric speciation is genetically feasible whenever reproductive isolation evolves indirectly as a correlated character. We specifically test the hypothesis that disruptive selection on habitat preference can lead to sympatric speciation when individuals mate locally within their selected habitat. Drosophila melanogaster was used as a model system. A 35-generation experiment using a complex habitat maze led to complete reproductive isolation between subpopulations using different spatiotemporal habitats. The reproductive isolation that developed over the course of the experiment was a result of offspring returning to mate in the habitat type selected by their parents, i.e., a gradual breakdown in migration between habitats. PMID- 28563895 TI - DISPERSAL, GENE FLOW, AND ALLELIC DIVERSITY BETWEEN LOCAL POPULATIONS OF THOMOMYS BOTTAE POCKET GOPHERS IN THE COASTAL RANGES OF CALIFORNIA. AB - We studied Thomomys bottae pocket gophers from 1979 to 1982 to determine if the amount of gene flow between local populations was sufficient to reduce allele frequency differences between them. Dispersal was quantified using three different trap techniques, and genetic changes in the population were monitored using protein variants. Additional allele frequency data were available for 1976 and 1977. We observed dispersal to be common in pre-reproductive juvenile females throughout the breeding season of their birth. Males on the other hand tended to disperse only from the end of the breeding season. Although dispersal was common, 63% of adults appeared to be recruited within 40 m of where they were born. Gene flow occurred into both established populations and into vacant habitat, but it was too low to reduce the differences in gene frequencies between the fields over seven years. We conclude that allelic diversity in T. bottae populations is a balance between random drift due to small effective population size and gene flow. PMID- 28563896 TI - THE EVOLUTION OF FORM AND FUNCTION: MORPHOLOGY AND LOCOMOTOR PERFORMANCE IN WEST INDIAN ANOLIS LIZARDS. AB - I tested biomechanical predictions that morphological proportions (snout-vent length, forelimb length, hindlimb length, tail length, and mass) and maximal sprinting and jumping ability have evolved concordantly among 15 species of Anolis lizards from Jamaica and Puerto Rico. Based on a phylogenetic hypothesis for these species, the ancestor reconstruction and contrast approaches were used to test hypotheses that variables coevolved. Evolutionary change in all morphological and performance variables scales positively with evolution of body size (represented by snout-vent length); size evolution accounts for greater than 50% of the variance in sprinting and jumping evolution. With the effect of the evolution of body size removed, increases in hindlimb length are associated with increases in sprinting and jumping capability. When further variables are removed, evolution in forelimb and tail length exhibits a negative relationship with evolution of both performance measures. The success of the biomechanical predictions indicates that the assumption that evolution in other variables (e.g., muscle mass and composition) did not affect performance evolution is probably correct; evolution of the morphological variables accounts for approximately 80% of the evolutionary change in performance ability. In this case, however, such assumptions are clade-specific; extrapolation to taxa outside the clade is thus unwarranted. The results have implications concerning ecomorphological evolution. The observed relationship between forelimb and tail length and ecology probably is a spurious result of the correlation between these variables and hindlimb length. Further, because the evolution of jumping and sprinting ability are closely linked, the ability to adapt to certain microhabitats may be limited. PMID- 28563897 TI - HABITAT CHOICE BY ALLELIC VARIANTS IN XIPHOPHORUS VARIATUS (PISCES; POECILIIDAE) AND IMPLICATIONS FOR MAINTENANCE OF GENETIC POLYMORPHISM. AB - Stream pools in northeastern Mexico exhibit gradients in dissolved oxygen (DO) concentration: low DO at the upstream ends and higher DO at the downstream ends. These pools contain populations of the variable platyfish, Xiphophorus variatus, which are polymorphic at an autosomal locus that affects tailspot pigmentation. Previous work showed that adult males of the cut-crescent morph have a lower metabolic rate than wild type males (Borowsky, 1984). Field collections were made to determine whether the morphs are distributed at random in the pools. As predicted, among adult males, all morphs were found in equal proportions at the upstream and downstream ends of the pools, except cut-crescents, which were distributed preferentially toward the upstream ends. In contrast, the opposite distributional pattern was found among adult females. Habitat choice may contribute to the stability of the tailspot polymorphism, especially so because preferences differing between the sexes can lead to disassortative mating. PMID- 28563898 TI - THE EVOLUTIONARY GENETIC STATUS OF ICELANDIC EELS. AB - The Iceland population of Anguilla eels contains an elevated frequency of fish with vertebral numbers lower than those typical of European localities. Several distinct hypotheses have been advanced to account for these morphologically atypical fish: for example, they could represent (1) genetically "pure" American expatriates, (2) genetically "pure" European types with ontogenetic abnormalities, or (3) hybrids between American and European forms. Here we critically test these and other possibilities by examining the joint distributions of allozyme markers, mitochondrial DNA markers, and vertebral numbers in Icelandic eels. The particular patterns of association among the genetic and morphological traits demonstrate that the Iceland population includes, in low frequency, the products of hybridization between American and European eels. Approximately 2-4% of the gene pool in the Iceland eel population is derived from American eel ancestry. This hybrid zone is highly unusual in the biological world, because the mating events in catadromous eels presumably take place thousands of kilometers from where the hybrids are observed as maturing juveniles. The molecular data, in conjunction with the geographic distributions, strongly suggest that the differences in migrational behavior and morphology between American and European eels include an important additive genetic component. Evolutionary hypotheses are advanced to account for the original separation of North Atlantic eels into American and European populations, and for the presence of hybrids in Iceland. PMID- 28563899 TI - RELATIVE FITNESS OF SELFED AND OUTCROSSED PROGENY IN A SELF-COMPATIBLE, PROTANDROUS SPECIES, SABATIA ANGULARIS L. (GENTIANACEAE): A COMPARISON IN THREE ENVIRONMENTS. AB - The consequences of selfing were examined for a population of self-compatible, protandrous, Sabatia angularis L. (Gentianaceae). Field-collected plants were hand-pollinated in the greenhouse to produce selfed progeny and outcrossed progeny from parents separated by a maximum of 5 m (near-outcross) and 85 m (far outcross) in the field. Self, near-outcross, and far-outcross half sib progeny were grown in the greenhouse, a garden plot, and their native habitat. Progeny were compared by multiplicative fitness functions based on seed production per hand-pollination, seed germination, rosette formation, survival to reproduction, and reproduction in each environment. Variation in reproduction among progeny groups was influenced by the environment in which they were grown. Significant inbreeding depression was detected between the self and far-outcross progeny in each environment. Only the natural environment demonstrated a greater than 50% reduction in relative fitness of self compared to near-outcross progeny. This is of biological relevance since near-outcross hand-pollinations occurred within the range of pollen and seed dispersal suggesting that inbreeding depression in S. angularis is strong enough to maintain outcrossing in the study population. In the field, the far-outcross progeny outperformed the near-outcross progeny suggesting local population substructure. The magnitude of the inbreeding depression expressed among the self progeny was the greatest in the field, intermediate in the garden plot, and the least in the greenhouse. PMID- 28563900 TI - EXPERIMENTAL EVIDENCE FOR MITOCHONDRIAL DNA INTROGRESSION BETWEEN DROSOPHILA SPECIES. AB - Differential introgression of mitochondrial genomes has been used to explain the occurrence in some species of individuals bearing mtDNA from a related species. This situation has been observed for Drosophila mauritiana (endemic to Mauritius) where a high proportion of individuals (88%) carries an mtDNA also found in D. simulans populations from Madagascar and Reunion. Using these two species, experiments were carried out to test for differential mtDNA introgression. A single virgin female from one species (initial frequency 0.03) was introduced into a population of the other. D. simulans mtDNA can, within three generations, almost entirely displace (frequency up to 0.80) D. mauritiana mtDNA. Hybrid male sterility probably curtails to a large degree parallel introgression of nuclear genes. The progress of cytoplasmic introgression is dependent on the degree of inbreeding of the recipient D. mauritiana strains. In reciprocal experiments, introgression was much less likely: few D. mauritiana migrant females are inseminated and their mtDNA frequency always remains very low. The results of these experiments support the hypothesis that a selective advantage of hybrids (probably at the nuclear level) has promoted mtDNA transfer from D. simulans Madagascar or Reunion populations into D. mauritiana through introgressive hybridization. PMID- 28563901 TI - The Discussion Section Tells Us Where We Are. PMID- 28563902 TI - Of lemurs and louse flies: The biogeochemical and biotic effects of forest disturbance on Propithecus edwardsi and its obligate ectoparasite Allobosca crassipes in Ranomafana National Park, southeastern Madagascar. AB - From alleles to ecosystems and landscapes, anthropogenic activity continues to affect the environment, with particularly adverse effects on biodiversity hotspots such as Madagascar. Selective logging has been proposed as a "win-win" conservation strategy, yet its effects on different components of biodiversity are still not fully understood. Here we examine biotic factors (i.e., dietary differences) that may be driving differences in biogeochemical stocks between disturbed and undisturbed forests. We present the stable nitrogen (delta15 N) and carbon (delta13 C) isotope composition of hair from the lemur Propithecus edwardsi and of whole bodies of its obligate ectoparasite, the louse-fly Allobosca crassipes, from sites in Ranomafana National Park (RNP) that are comparable except for the history of logging and subsequent forest regeneration. P. edwardsi and A. crassipes from the disturbed (i.e., heavily selectively logged) site are lower in 15 N and 13 C relative to P. edwardsi and A. crassipes from sites that were minimally selectively logged or not commercially logged at all. There is a ~30/00 decrease in 15 N between disturbed and undisturbed sites that corresponds to a difference of nearly a full trophic level. Flowers from Bakerella clavata, a staple food source for P. edwardsi in disturbed habitats and a fallback food for P. edwardsi in primary forests, were also analyzed isotopically. B. clavata is delta15 N-depleted in both disturbed and undisturbed sites. Data from longitudinal behavioral surveys of P. edwardsi in RNP and other forests in eastern Madagascar point to significant differences in consumption patterns of B. clavata, with P. edwardsi in disturbed forests consuming almost twice as much of this plant. Depletion of 15 N in animal tissues is a complex issue, but likely the result of the interaction of physiological and ecological factors. Anthropogenic disturbance in RNP from selective logging has had both biotic and biogeochemical effects that are observable trophically. PMID- 28563904 TI - HYBRIDIZATION BETWEEN SPECIES OF THE RANA PIPIENS COMPLEX IN CENTRAL TEXAS. PMID- 28563903 TI - High-Contrast Fluorescence Detection of Metastatic Breast Cancer Including Bone and Liver Micrometastases via Size-Controlled pH-Activatable Water-Soluble Probes. AB - Breast cancer metastasis is the major cause of cancer death in women worldwide. Early detection would save many lives, but current fluorescence imaging probes are limited in their detection ability, particularly of bone and liver micrometastases. Herein, probes that are capable of imaging tiny (<1 mm) micrometastases in the liver, lung, pancreas, kidneys, and bone, that have disseminated from the primary site, are reported. The influence of the poly(ethylene glycol) (PEG) chain length on the performance of water-soluble, pH responsive, near-infrared 4,4'-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) probes is systematically investigated to demonstrate that PEG tuning can provide control over micrometastasis tracking with high tumor-to-background contrast (up to 12/1). Optimized probes can effectively visualize tumor boundaries and successfully detect micrometastases with diameters <1 mm. The bone-metastasis targeting ability of these probes is further enhanced by covalent functionalization with bisphosphonate. This improved detection of both bone and liver micrometastases (<2 mm) with excellent tumor-to-normal contrast (5.2/1). A versatile method is thus introduced to directly synthesize modular water-soluble probes with broad potential utility. Through a single intravenous injection, these materials can image micrometastases in multiple organs with spatiotemporal resolution. They thus hold promise for metastasis diagnosis, image-guided surgery, and theranostic PEGylated drug therapies. PMID- 28563905 TI - GENETIC VARIABILITY AND FOUNDER EFFECT IN THE PITCHER PLANT SARRACENIA PURPUREA L. PMID- 28563907 TI - Evolution Meetings-Corrected Dates. PMID- 28563906 TI - SELECTION ON AMYLASE ALLOZYMES IN DROSOPHILA MELANOGASTER: SELECTION EXPERIMENTS USING SEVERAL INDEPENDENTLY DERIVED PAIRS OF CHROMOSOMES. PMID- 28563908 TI - GENETIC DIFFERENTIATION WITHIN THE MELANOGASTER SPECIES GROUP OF THE GENUS DROSOPHILA (SOPHOPHORA). PMID- 28563909 TI - AN EVOLUTIONARY EXAMINATION OF THE FLORAL DISPLAY of CATALPA SPECIOSA (BIGNONIACEAE). PMID- 28563911 TI - THE GENETIC BASIS OF THE ECOLOGICAL AMPLITUDE OF SPARTINA PATENS. I. MORPHOMETRIC AND PHYSIOLOGICAL TRAITS. PMID- 28563913 TI - COMPARATIVE ALBUMIN AND BIOCHEMICAL EVOLUTION IN PLETHODONTID SALAMANDERS. PMID- 28563912 TI - GENE DUPLICATION AND PHYLOGENY IN CLARKIA. PMID- 28563914 TI - 17-YEAR CICADAS EMERGING AFTER 18 YEARS: A NEW BROOD? PMID- 28563915 TI - Society Election Results. PMID- 28563916 TI - HYBRIDIZATION IN MILKWEED BUGS OF THE GENUS ONCOPELTUS (HEMIPTERA: LYGAEIDAE). PMID- 28563917 TI - NEIGHBORHOOD SIZE IN VIOLA. PMID- 28563918 TI - SPECIATION IN NORTH AMERICAN FIELD CRICKETS: EVIDENCE FROM ELECTROPHORETIC COMPARISONS. PMID- 28563919 TI - PHENOTYPIC CONSEQUENCES OF PARTHENOGENESIS IN CNEMIDOPHORUS LIZARDS. I. VARIABILITY IN PARTHENOGENETIC AND SEXUAL POPULATIONS. PMID- 28563920 TI - PHYLOGENETIC RELATIONSHIPS BETWEEN MAN AND THE APES: ELECTROPHORETIC EVIDENCE. PMID- 28563921 TI - POPULATION DYNAMICS OF INDIGO BUNTINGS AND THE EVOLUTION OF AVIAN POLYGYNY. PMID- 28563922 TI - NATURAL HYBRIDIZATION AND GENETIC DIVERGENCE BETWEEN THE TOADS BUFO BOREAS AND BUFO PUNCTATUS. PMID- 28563923 TI - ON THE SELECTIVE ADVANTAGE OF FRATRICIDE IN RAPTORS. PMID- 28563924 TI - EVOLUTION OF COMPETITIVE ABILITY IN MIXTURES OF DROSOPHILA MELANOGASTER: POPULATIONS WITH AN INITIAL ASYMMETRY. PMID- 28563925 TI - SALE OF BACK ISSUES OF EVOLUTION. PMID- 28563926 TI - PHENOTYPIC CONSEQUENCES OF PARTHENOGENESIS IN CNEMIDOPHORUS LIZARDS. II. SIMILARITY OF C. TESSELATUS TO ITS SEXUAL PARENTAL SPECIES. PMID- 28563927 TI - FISH PREDATION AND THE EVOLUTION OF GASTROPOD SHELL SCULPTURE: EXPERIMENTAL AND GEOGRAPHIC EVIDENCE. PMID- 28563928 TI - GENIC CHANGES ASSOCIATED WITH THE ESTABLISHMENT OF SYMPATRY IN ORIOLES OF THE GENUS ICTERUS. PMID- 28563930 TI - PROTEIN POLYMORPHISM IN THE NARROW ENDEMIC OENOTHERA ORGANENSIS. PMID- 28563929 TI - ECOLOGICAL GENERALISM IN DROSOPHILA FALLENI: GENETIC EVIDENCE. PMID- 28563931 TI - BREEDING SYSTEMS AND THE EVOLUTION OF DIOECY IN NEW ZEALAND APIOID UMBELLIFERAE. PMID- 28563932 TI - THE POPULATION STRUCTURE OF AN ASEXUAL VERTEBRATE, POECILIOPSIS 2 MONACHA-LUCIDA (PISCES: POECILIIDAE). PMID- 28563933 TI - SHELL ARCHITECTURE AND CAUSES OF DEATH OF MICRONESIAN REEF SNAILS. PMID- 28563934 TI - COUNTERGRADIENT SELECTION IN THE GREEN FROG, RANA CLAMITANS. PMID- 28563935 TI - RATES OF MOLECULAR AND CHROMOSOMAL EVOLUTION IN SALAMANDERS. PMID- 28563936 TI - INFLUENCE OF MICROHABITAT HETEROGENEITY ON GENE FREQUENCY DISTRIBUTION AND GAMETIC PHASE DISEQUILIBRIUM IN AVENA BARBATA. PMID- 28563937 TI - SEXUAL SELECTION AND BODY SIZE IN MALE RED-WINGED BLACKBIRDS. PMID- 28563938 TI - MUTUAL FACILITATION BETWEEN LARVAE OF DROSOPHILA MELANOGASTER CULTURED ON STEROL MUTANT YEAST. PMID- 28563939 TI - SEX DIFFERENCES AND FLOWERING PHENOLOGY IN THE COMMON FIG, FICUS CARICA L. PMID- 28563940 TI - ARE PARTHENOGENETIC AND RELATED BISEXUAL INSECTS EQUAL IN FERTILITY? PMID- 28563941 TI - EVOLUTIONARY GENETICS OF DIPLOID-TETRAPLOID SPECIES OF TREEFROGS OF THE GENUS HYLA. PMID- 28563942 TI - REPRODUCTIVE ISOLATION IN SYMPATRIC SPECIES OF DAYFLYING MOTHS (HEMILEUCA: SATURNIIDAE). PMID- 28563943 TI - POLYMORPHISM FOR BREEDING COLORS IN GASTEROSTEUS ACULEATUS. I. THEIR GENETICS AND GEOGRAPHIC DISTRIBUTION. PMID- 28563944 TI - EVOLUTION OF HANDLING TIME: THE FUNCTIONAL RESPONSE OF A PREDATOR TO THE DENSITY OF SYMPATRIC AND ALLOPATRIC STRAINS OF PREY. PMID- 28563945 TI - ON PREMATING ISOLATION BETWEEN TWO CLOSELY RELATED SPECIES OF HAWAIIAN DROSOPHILA. PMID- 28563946 TI - EVOLUTIONARY CHANGES IN EGG-EATING BEHAVIOR OF FLOUR BEETLES IN MIXED-SPECIES POPULATIONS. PMID- 28563947 TI - THE MORPHOLOGY OF A "HYBRID ZONE" IN CERION: VARIATION, CLINES, AND AN ONTOGENETIC RELATIONSHIP BETWEEN TWO "SPECIES" IN CUBA. PMID- 28563948 TI - FREQUENCY-DEPENDENT MATING IN A MODIFIED ALLOZYME LOCUS OF DROSOPHILA PSEUDOOBSCURA. PMID- 28563949 TI - THE PRIMARY CHARACTERISTICS OF TRIBOLIUM POPULATIONS GROUP SELECTED FOR INCREASED AND DECREASED POPULATION SIZE. PMID- 28563950 TI - GENETIC VARIATION IN HAWAIIAN DROSOPHILA VI. SEASONALLY-DEPENDENT GENE CHANGES IN DROSOPHILA MIMICA. PMID- 28563951 TI - GENETIC DRIFT IN SMALL POPULATIONS OF TRIBOLIUM. PMID- 28563952 TI - ENVIRONMENTAL AND GENETIC CONTROL OF GENDER IN THE DIMORPHIC SHRUB HEBE SUBALPINA. PMID- 28563953 TI - SENESCENCE IN NATURAL POPULATIONS OF MAMMALS: A COMPARATIVE STUDY. AB - Here, I use published mortality data from 56 natural populations of mammals to examine evidence for senescence, an increase in the probability of mortality with age. Data on extent of senescence and life history characteristics are compared across taxa in an attempt to test theories for the evolution of senescence in natural populations. In accord with theoretical expectation, senescence is highest in short-lived species with short generation times. In contrast to theoretical expectation, however, senescent increases in mortality rate do not begin until well after age at maturity in most cases. I also present evidence in support of the hypothesis that senescence will be lower in large-brained taxa. PMID- 28563954 TI - MULTIVARIATE ANALYSIS OF SELECTION IN EXPERIMENTAL POPULATIONS DERIVED FROM HYBRIDIZATION OF TWO ECOTYPES OF THE ANNUAL PLANT DIODIA TERES W. (RUBIACEAE). AB - Morphologically variable F2 genotypes derived from hybridization of coastal and inland ecotypes of the annual plant Diodia teres were used to identify selection on morphological traits in the natural habitat of each ecotype. These ecotypes occur in very different habitats, and have evolved pronounced morphological differentiation. Selection analysis can suggest whether present patterns of selection can explain morphological differences between ecotypes. F2 genotypes were characterized morphologically, clonally replicated, and transplanted into the habitat of each ecotype. Selection was measured on six morphological traits. Directional and stabilizing selection occurred on many traits; direction and strength of selection varied sharply at different stages of growth, as revealed by a path-analysis approach that divided selection into a set of independent components. Directional selection favored traits of the native population at the coastal habitat, but less so at the inland habitat. Selection was of sufficient strength to create the observed morphological differences between ecotypes in 25 100 generations, given constant selection and sufficient genetic variation. In effects on fitness, most traits were neither independent nor consistently interactive with other traits. Rather, many traits entered into strong but evanescent interactions affecting particular components of fitness. Observed interactions did not support the hypothesis that the morphology of each ecotype was functionally integrated to a high degree. PMID- 28563955 TI - GENOTYPE-ENVIRONMENT INTERACTION FOR JUVENILE GROWTH IN THE HARD CLAM MERCENARIA MERCENARIA (L.). AB - Offspring from half-sib and full-sib families of the hard clam, Mercenaria mercenaria were reared in five locations along the Atlantic Coast to test for the presence of genotype-environment interaction for juvenile growth rate. Location effects upon growth rate variation were prevalent; of the genetic effects, the additive genetic by location variance was predominant with the nonadditive genetic by location component contributing to a lesser degree to the interaction variance. The additive and nonadditive variation over all environments was negligible. Genotype-environment interaction was found to be at least partially due to a change in the amount of genetic variation expressed at each location; with significant additive variation detected at Charleston and Georgetown, SC sites and significant nonadditive variation at Millsboro, DE. Genetic covariance/correlation analysis indicated that reversals in relative family performance across locations were prevalent, implying the possibility of habitat specialization among genotypes. In addition, graphical analysis produced no evidence of a ubiquitously superior genotype. These analyses suggest that genotype-environment interaction should act to constrain the evolution of juvenile growth rate in Mercenaria, preserve any heritable variation associated with this trait and may lead to the development of phenotypic plasticity for growth. PMID- 28563956 TI - CORRELATIONS BETWEEN HETEROZYGOSITY AND PHENOTYPIC VARIABILITY IN COTTUS (TELEOSTEI: COTTIDAE): CHARACTER COMPONENTS. PMID- 28563957 TI - SPERM COMPETITION SELECTS FOR NUPTIAL FEEDING IN A BUSHCRICKET. PMID- 28563958 TI - A MORPHOLOGIC AND GENETIC STUDY OF THE ISLAND FOX, UROCYON LITTORALIS. AB - The Island Fox, Urocyon littoralis, is a dwarf form found on six of the Channel Islands located 30-98 km off the coast of southern California. The island populations differ in two variables that affect genetic variation: effective population size and duration of isolation. We estimate that the effective population size of foxes on the islands varies from approximately 150 to 1,000 individuals. Archeological and geological evidence suggests that foxes likely arrived on the three northern islands minimally 10,400-16,000 years ago and dispersed to the three southern islands 2,200-4,300 years ago. We use morphometrics, allozyme electrophoresis, mitochondrial DNA (mtDNA) restriction site analysis, and analysis of hypervariable minisatellite DNA to measure variability within and distances among island fox populations. The amount of within-population variation is lowest for the smallest island populations and highest for the mainland population. However, the larger populations are sometimes less variable, with respect to some genetic measures, than expected. No distinct trends of variability with founding time are observed. Genetic distances among the island populations, as estimated by the four techniques, are not well correlated. The apparent lack of correspondence among techniques may reflect the effects of mutation rate and colonization history on the values of each genetic measure. PMID- 28563959 TI - CALLING SONG DISPLACEMENT IN A ZONE OF OVERLAP AND HYBRIDIZATION. AB - The ground crickets Allonemobius fasciatus and A. socius meet in a mosaic zone of overlap and hybridization stretching from the East Coast to at least Illinois. To test whether male calling song differences were enhanced in sympatry, we analyzed the songs of crickets from inside and outside the zone of overlap along two transects. No evidence of calling song displacement was found in A. socius males from populations within the zone of overlap. On the other hand, A. fasciatus displayed calling song displacement in three populations. Our results are consistent with the hypothesis that the selective pressure exerted by the challenge from a related species is frequency dependent. While not a conclusive demonstration, the observed shifts in calling song are strongly suggestive of reproductive character displacement. PMID- 28563960 TI - THE RESPONSES OF DROSOPHILA MELANOGASTER TO ARTIFICIAL SELECTION ON BODY WEIGHT AND ITS PHENOTYPIC PLASTICITY IN TWO LARVAL FOOD ENVIRONMENTS. AB - To investigate the potential response to natural selection of reaction norms for age and size at maturity, fresh body weight at eclosion was mass selected under rich and poor larval food conditions in Drosophila melanogaster. The sensitivity of dry weight at eclosion to the difference between rich and poor larval food was selected using differences in sensitivities among families. For both experiments, the correlated response to selection of age at eclosion was examined. The flies were derived from wild populations and had been mass cultured in the lab for more than six months before the experiments started. These flies responded to selection on body weight upwards and downwards on both rich and poor larval food. Selection on increased or decreased sensitivity of body weight was also successful in at least one direction. Sensitivity was reduced by selection upwards in a poor environment and downwards in a rich environment. PMID- 28563961 TI - DEVELOPMENTAL MUTANTS OF VOLVOX: DOES MUTATION RECREATE THE PATTERNS OF PHYLOGENETIC DIVERSITY? AB - The nature of the variation which is created by mutation can show how the direction of evolution is constrained by internal biases arising from development and pre-existing design. We have attempted to quantify these biases by measuring eight life history characters in developmental mutants of Volvox carteri. Most of the mutants in our sample were inferior to the wild type, but deviated by less than tenfold from the wild-type mean. Characters differed in mutability, suggesting different levels of canalisation. Most correlations between life history characters among strains were positive, but there was a significant negative correlation between the size and the number of reproductive cells, suggesting an upper limit to the total quantity of germ produced by individuals. The most extreme phenotypes in our sample were very vigorous, showing that not all mutations of large effect are unconditionally deleterious. We investigated the effect of developmental constraints on the course of evolution by comparing the variance and covariance patterns among mutant strains with those among species in the family Volvocaceae. A close correspondence between patterns at these two levels would suggest that pre-existing design has a strong influence on evolution, while little or no correspondence shows the action of selection. The variance generated by mutation was equal to that generated by speciation in the family Volvocaceae, the genus Volvox, or the section Merillosphaera, depending on the character considered. We found that mutation changes the volume of somatic tissue independently of the quantity of germ tissue, so that the interspecific correlation between soma and germ can be attributed to selection. The negative correlation between size and number of germ cells among mutants of V. carteri is also seen among the larger members of the family (Volvox spp.), but not among the smaller members, suggesting a powerful design constraint that may be responsible for the absence of larger forms in the entire group. PMID- 28563962 TI - PHYLOGENY AND COADAPTATION OF THERMAL PHYSIOLOGY IN LIZARDS: A REANALYSIS. PMID- 28563963 TI - THE GENETIC CONSEQUENCES OF WORKER ANT POLLINATION IN A SELF-COMPATIBLE, CLONAL ORCHID. AB - The self-compatible orchid Microtis parviflora is pollinated by the flightless worker caste of the ant Iridomyrmex gracilis. The orchid is clonal and forms small patches, usually less than 1 m2 , of disconnected individual ramets. Ant pollinators visited and revisited a limited proportion of available inflorescences, and 40% of all flower visits occurred within plants promoting self-pollination. Pollen labels indicated that self-pollination accounted for 51% of the pollen transfers, although pollen carryover extended beyond 16 flowers on 2 or 3 inflorescences. The distribution of ant movements between plants was leptokurtic with a mean of 12.4 +/- 14.9 cm and a maximum of 89 cm, but a high proportion of movements were within clones accentuating the level of self pollination. However, some pollen transfers between inflorescences of unlike genotypes contributed to a low incidence (max = 8%) of outcrossing. In 12 patches examined by electrophoresis, the density varied from 11 to 61 inflorescences per m2 and a maximum of only 4 genotypes were detected. Electrophoretic analysis revealed populations were highly inbred: only 23% (N = 17) of the loci were polymorphic and the mean gene diversity h, was 2.7%. Heterozygotes were observed in only one population given a mean fixation index F, of 0.982. These results reflect the combined effects of restricted ant foraging and clonality. Nevertheless, while ant foraging was restricted, some outcrossing occurred and in the absence of clonality it is likely that ant foraging would have yielded a mixed mating system similar to those reported for a wide array of insect pollinators. Given the ability of ants to generate pollen flow, the reasons for the rarity of ant pollination appear to lie elsewhere. PMID- 28563964 TI - RAPID EVOLUTION OF GASTRULATION MECHANISMS IN A SEA URCHIN WITH LECITHOTROPHIC LARVAE. AB - This study documents evolutionary modifications in mechanisms of gastrulation in Heliocidaris erythrogramma, an echinoid with lecithotrophic larvae. Radially symmetrical cell rearrangements and changes in cell shape drive elongation of the archenteron in the ancestral mode of echinoid gastrulation. Cell marking experiments indicate that in H. erythrogramma, however, prolonged movement of cells over the ventral lip of the blastopore accompanies extension of the archenteron. Evolutionary modifications to archenteron extension in H. erythrogramma thus include utilization of a different type of cellular movement as well as the imposition of dorsoventral asymmetry in cellular movements. The conservation of gastrulation mechanisms among phylogenetically divergent echinoids with planktotrophic development suggests that the plesiomorphic condition has persisted at least 250 million years and perhaps much longer. Yet H. erythrogramma diverged from an ancestor with planktotrophic development only about 10 mya, indicating that morphogenetic mechanisms of early development can undergo substantial evolutionary changes, even after long periods of stasis. PMID- 28563966 TI - ECOLOGICAL VERSUS EVOLUTIONARY HYPOTHESES: DEMOGRAPHIC STASIS AND THE MURRAY NOLAN CLUTCH SIZE EQUATION. PMID- 28563965 TI - POPULATION BIOLOGY OF THE TRANS-ARCTIC EXCHANGE: MtDNA SEQUENCE SIMILARITY BETWEEN PACIFIC AND ATLANTIC SEA URCHINS. AB - MtDNAs from 2 protein coding regions comprising 576 base pairs were sequenced from 17 individual sea urchins of the species Strongylocentrotus pallidus collected from the north Pacific and north Atlantic oceans. Twelve of 17 individual sequences were identical. Two of these were further sequenced in a third, 441 base pair region, and were also found to be identical. We show how to interpret these results using a simplified Markov model of mtDNA evolution at silent sites. The model was calibrated using 3 urchin species with a published fossil record, and shows that identical S. pallidus mtDNAs in different oceans shared a common ancestor at most 90,000-150,000 years ago (95% confidence interval of upper limit of divergence). The Markov model, used to examine patterns of genetic distance within and between species, shows unexpected variation in the rate of base substitution. The rate of change of G's at fourfold sites is nearly 20 times greater than the rate of change of C's. At twofold sites, this range is less extreme, although purines consistently have a higher rate of change than pyrimidines. Striking genetic similarity and recent genetic exchange between oceans for these urchins is in marked contrast to most other trans-Arctic marine populations, which usually show morphological and genetic differentiation at the species or subspecies level. Recent fossil evidence shows that the north Atlantic and northeastern Pacific have been the scene of radical faunal changes during the Pliocene and Pleistocene. The genetic results presented here extend this conclusion to intraspecific patterns of genetic variability, and direct attention to the northwest Pacific where higher productivity and less environmental change may have left a heritage of greater marine genetic diversity. PMID- 28563967 TI - COMPARING POLLEN DISPERSAL AND GENE FLOW IN A NATURAL POPULATION. PMID- 28563968 TI - SEXUAL SELECTION IN THE MONOGAMOUS BARN SWALLOW (HIRUNDO RUSTICA). I. DETERMINANTS OF TAIL ORNAMENT SIZE. AB - The proportion of phenotypic variance in the length of the sexually selected tail of the monogamous barn swallow Hirundo rustica that is attributable to genetic variance was studied in the field in Denmark during a seven-year period. Tail length was on average 20% greater in males than in females. Tail length correlated with wing length, but not with other morphological traits. Tail length increased with the first molt, but remained constant during subsequent years. Changes in tail length between years, owing to molt were significantly affected by sex and by degree of infection with an haematophagous mite (Ornithonyssus bursa). There were significant differences in sexual size dimorphism between years, apparently as a result of environmental conditions in the African winter quarters during molt. Tail length was a highly repeatable morphological trait, and standardization of tail length for age effects only marginally increased repeatability. Heritability of tail length as estimated from regression of values for sons on those of their fathers was 0.59. This suggests that secondary sexual traits affected by strong directional selection still may show a statistically significant heritability. PMID- 28563969 TI - SSE ANNUAL MEETING. PMID- 28563970 TI - CONSTANCY OF POPULATION PARAMETERS FOR LIFE-HISTORY AND FLORAL TRAITS IN RAPHANUS SATIVUS L. II. EFFECTS OF PLANTING DENSITY ON PHENOTYPE AND HERITABILITY ESTIMATES. AB - To determine the effect of growing conditions on population parameters in wild radish, (Raphanus sativus L.: Brassicaceae), we replicated maternal and paternal half-sib families of seed across three planting densities in an experimental garden. A nested breeding design performed in the greenhouse produced 1,800 F1 seeds sown in the garden. We recorded survivorship, measured phenotypic correlations among and estimated narrow-sense and broad-sense heritabilities (h2 ) of: days to germination, days to flowering, petal area, ovule number/flower, pollen production/flower, and modal pollen grain volume. Survivorship declined with increasing density, but the relative abundances of surviving families did not differ significantly among densities. Seeds in high-density plots germinated significantly faster than seeds sown in medium- or low-density plots, but they flowered significantly later. Plants in high-density plots had fewer ovules per flower than those in the other treatments. Petal area and pollen characters did not differ significantly among densities. Densities differed with respect to the number and sign of significant phenotypic correlations. Analyses of variance were conducted to detect additive genetic variance (Va ) of each trait in each density. At low density, there were significant paternal effects on flowering time and modal pollen grain volume; in medium-density plots, germination time, flowering time and ovule number exhibited significant paternal effects; in high density plots, only pollen grain volume differed among paternal sibships. The ability to detect maternal effects on progeny phenotype also depended on density. Narrow-sense h2 estimates differed markedly among density treatments for germination time, flowering time, ovule number and pollen grain volume. Maternal, paternal and error variance components were estimated for each trait and density to examine the sources of variation in narrow-sense h2 across densities. Variance components did not change consistently across densities; each trait behaved differently. To provide qualitative estimates of genetic correlations between characters, correlation coefficients were estimated using paternal family means; these correlations also differed among densities. These results demonstrate that: a) planting density influences the magnitude of maternal and paternal effects on progeny phenotype, and of h2 estimates, b) traits differ with respect to the density in which heritability is greatest, c) density affects the variance components that comprise heritability, but each trait behaves differently, and d) the response to selection on any target trait should result in different correlated responses of other traits, depending on density. PMID- 28563971 TI - INTEGRATING PHYLOGENY AND EXPERIMENTAL ETHOLOGY: FROM PATTERN TO PROCEs. AB - Phylogenetic systematics offers ethologists a method for uncovering macroevolutionary patterns of behavioral diversity, which can be used to generate predictions for experimental investigation of microevolutionary processes. I used phylogenetic methods to disentangle the contributions of various selection pressures in the evolution of sexually dimorphic nuptial coloration in gasterosteid fishes in general, and Gasterosteus aculeatus in particular. Based upon the phylogenetic relationships between breeding colors and breeding behaviors in the gasterosteids, three predictions relevant to a discussion of nuptial coloration in G. aculeatus were proposed. The origin and elaboration of nuptial coloration was (1) weakly associated with male/male interactions (intrasexual selection), (2) moderately associated with parental care (natural selection) and (3) strongly associated with male/female interactions (intersexual selection). I tested the hypothesized macroevolutionary relationships between male breeding color and behavior in two sets of experiments studying changes in male nuptial coloration across the breeding cycle and female choice based on intensity of male color. The results of these experiments at the microevolutionary level of analysis corroborated the macroevolutionary predictions and confirmed the original intuition of previous researchers: male body color intensity is an important component of female mate choice in G. aculeatus. This study demonstrates that a phylogenetic hypothesis can generate predictions that are experimentally testable and falsifiable. PMID- 28563972 TI - RAPID BEHAVIORAL CHANGES IN MEDAKA (ORYZIAS LATIPES) CAUSED BY SELECTION FOR COMPETITIVE AND NONCOMPETITIVE GROWTH. AB - Behavior is a major component of growth rate variation in fish, but the genetic relationship between behavior and growth is largely unknown. In particular, it is not known how behavior responds to natural or artificial selection on growth. It has been argued that artificial selection for fast growth in competitive environments might lead to higher levels of overall aggression, and therefore there would be no net gain in assimilation efficiency or growth. The contrary has also been argued. It is not immediately obvious, therefore, whether fish that avoid interacting with conspecifics should grow faster, or whether more aggressive, dominant individuals should grow faster. In the present study, we artificially selected fish on the basis of growth in two environments that differed in the intensity of social interactions. In the high interaction environment (HI), food was provided to excess inside a floating cork ring, which limited access to the food and allowed fish to attempt to monopolize the food supply. In the low interaction environment (LI), an equivalent amount of food was spread over the container's surface. In each social environment, fish were selected within family for fast and for slow growth rate during two generations (G1 and G2 ). The response was measured in the third generation (G3 ) on the directly selected trait (growth) and on a correlated trait (agonistic behavior). The magnitude of the direct response to selection on growth in medaka was directly related to population density, i.e., selection was most effective at high densities. Agonistic behavior was inversely related to growth when individuals were raised and selected in an environment where enforced social interaction took place, so long as food was not limited in quantity. PMID- 28563973 TI - Phototherapy for neonatal hyperbilirubinemia. AB - Approximately 60 years ago in England, phototherapy for neonatal hyperbilirubinemia was used in clinical practice. It was introduced in Japan approximately 50 years ago. At that time, the mechanism underlying the serum bilirubin concentration decrease by phototherapy was still unknown. The mechanism was identified by chemists, biochemists, and pediatricians. Clarification started with the report that unconjugated bilirubin was excreted into bile after photoirradiation in Gunn rats. After confirmation of the molecular structure of bilirubin on X-ray analysis, the mechanism for bile excretion of unconjugated bilirubin was verified based on geometric configurational photoisomers in the Gunn rat. Finally, the reaction and excretion of structural bilirubin photoisomers was proved to be the main mechanism for the decrease in serum bilirubin during phototherapy for neonatal hyperbilirubinemia, which differs from the mechanism in the Gunn rat. The most effective and safest light source and the optimal method to evaluate phototherapy, however, remain unknown. Moreover, as for bronze baby syndrome, which is a well-known adverse reaction to phototherapy, the etiology is unclear. Hence, we review phototherapy for hyperbilirubinemia including a fundamental understanding of the bilirubin photochemical reactions, and discuss the subclinical carcinogenic risk of phototherapy and the increased mortality rate of extremely low-birthweight infants due to aggressive phototherapy, which is becoming an increasing problem. PMID- 28563975 TI - MODES OF SPECIATION AND INFERENCES BASED ON GENETIC DISTANCES. PMID- 28563976 TI - CHROMOSOMAL AND MORPHOLOGICAL CORRELATES IN TWO NEW WORLD SPARROWS (EMBERIZIDAE). PMID- 28563974 TI - Performance of a new real-time continuous glucose monitoring system: A multicenter pilot study. AB - AIMS/INTRODUCTION: The present study aimed to investigate the performance of a new real-time continuous glucose monitoring system. MATERIALS AND METHODS: Interstitial glucose levels were monitored for 7 days in 63 patients with type 1 or type 2 diabetes using the Medtrum A6 TouchCare(r) CGM System. Venous blood was collected on a randomized day of the wear period. Plasma glucose levels were measured as reference values. RESULTS: Among 1,678 paired sensor-reference values, 90.5% (95% confidence interval 89.1-91.9%) were within +/-20%/20 mg/dL of the reference values, with a mean absolute relative difference of 9.1 +/- 8.7% (95% CI: 8.9-9.2%). The percentages of paired sensor-reference values falling within zone A and B of the Clarke error grid analysis (EGA) and the type 1 diabetes consensus EGA were 99.1 and 99.8%. Continuous EGA showed that the percentages of accurate readings, benign errors, and erroneous readings were 89.9, 6.3 and 3.8%, respectively. Surveillance EGA showed that 90.6, 9.2, and 0.2% of sensor-reference values with no, slight and lower moderate risk, respectively. The mean absolute relative difference was 16.6, and 96.0% of the sensor values fell within zones A and B of the consensus EGA for hypoglycemia. More than 85% of sensor values were within +/-20%/20 mg/dL of reference values, the mean absolute relative difference was <11, and >99.5% of the sensor values fell in zones A and B of the consensus EGA. CONCLUSIONS: The Medtrum real-time continuous glucose monitoring system was numerically and clinically accurate over a large glucose range across 7 days of wear. PMID- 28563977 TI - SEXUAL DIMORPHISM IN THE STRAWBERRY FRAGARIA CHILOENSIS. PMID- 28563978 TI - POPULATION GENETICS OF CHIRONOMUS STIGMATERUS SAY (DIPTERA: CHIRONOMIDAE): II. PROTEIN VARIABILITY IN POPULATIONS OF THE SOUTHWESTERN UNITED STATES. PMID- 28563979 TI - GROUP SELECTION: THE PHENOTYPIC AND GENOTYPIC DIFFERENTIATION OF SMALL POPULATIONS. PMID- 28563980 TI - SYSTEMATICS AND HYBRIDIZATION IN THE FOUR LIVING SPECIES OF HORSESHOE CRABS. PMID- 28563981 TI - MORPHOMETRIC DIFFERENTIATION IN NEW ZEALAND POPULATIONS OF THE HOUSE SPARROW (PASSER DOMESTICUS). PMID- 28563982 TI - ENVIRONMENTAL DETERMINANTS OF OUTCROSSING IN IMPATIENS CAPENSIS (BALSAMINACEAE). PMID- 28563983 TI - THE EFFECT OF X-CHROMOSOME INHERITANCE ON MATE-SELECTION BEHAVIOR IN THE SULFUR BUTTERFLIES, COLIAS EURYTHEME AND C. PHILODICE. PMID- 28563984 TI - GENE FLOW, EFFECTIVE POPULATION SIZES, AND GENETIC VARIANCE COMPONENTS IN BIRDS. PMID- 28563985 TI - GROUP SELECTION: THE GENETIC AND DEMOGRAPHIC BASIS FOR THE PHENOTYPIC DIFFERENTIATION OF SMALL POPULATIONS OF TRIBOLIUM CASTANEUM. PMID- 28563986 TI - THE EVOLUTIONARY SIGNIFICANCE OF BUMBLE BEE COLOR PATTERNS: A MIMETIC INTERPRETATION. PMID- 28563987 TI - REPRODUCTIVE ISOLATION IN ASCLEPIAS: LOCK AND KEY HYPOTHESIS RECONSIDERED. PMID- 28563988 TI - SOME CHARACTERISTICS OF HYBRIDS DERIVED FROM THE SULFUR BUTTERFLIES, COLIAS EURYTHEME AND C. PHILODICE: PHENOTYPIC EFFECTS OF THE X-CHROMOSOME. PMID- 28563989 TI - HETEROZYGOSITY OF A NEUTRAL LOCUS LINKED TO A SELF-INCOMPATIBILITY LOCUS OR A BALANCED LETHAL. PMID- 28563990 TI - DENSITY-DEPENDENT AND DENSITY-INDEPENDENT CAUSES OF EXTINCTION OF A SALAMANDER POPULATION. PMID- 28563991 TI - A MULTIFACTORIAL GENETIC INVESTIGATION OF SPECIATION THEORY USING DROSOPHILA MELANOGASTER. PMID- 28563992 TI - MAINTENANCE OF THE THREE SEX CHROMOSOME POLYMORPHISM IN THE PLATYFISH, XIPHOPHORUS MACULATUS. PMID- 28563993 TI - COMPONENTS OF FITNESS AND FREQUENCY-DEPENDENT OVERDOMINANCE IN HERMAPHRODITE PLANTS. PMID- 28563994 TI - GENETIC DIVERGENCE AMONG FISHES OF THE EASTERN PACIFIC AND THE CARIBBEAN: SUPPORT FOR THE MOLECULAR CLOCK. PMID- 28563995 TI - Can we improve the efficacy of modern cataract surgery by using different tip designs? A comparison of balanced and tapered tip in femtosecond laser-assisted cataract surgery and manual phacoemulsification. AB - IMPORTANCE: Different tip designs in modern cataract surgery have not been studied between the reported systems. BACKGROUND: Aim of this study is to assess the efficacy of two tip designs, Intrepid(r) balanced tip (BT) and Kelman tapered tip (TT), in femtosecond laser assisted cataract surgery (FLACS) and the microcoaxial torsional phacoemulsification. DESIGN: Prospective randomized unmasked cohort outcome study (hospital setting). PARTICIPANTS: Threehundert forty-three eyes of 343 patientes underwent cataract surgery. METHODS: Data of n = 196 FLACS and n = 147 manual phacoemulsification were analysed. Intrepid(r) balanced tip and Kelman tapered tip, Alcon, USA, were tested in FLACS (LenSx Alcon, USA) und manual phaco (Alcon Centurion System, USA). Four study cohorts were formed; FLACS BT (n = 90, 70.2 years), FLACS TT (n = 106, 68.1years), Manual BT (n = 70, 71.3 years), Manual TT (n = 77, 71.8 years). The nuclei were graded in Lens Opacities Classification System (LOCS) II,III and IV. MAIN OUTCOME MEASURES: Cumulative dissipated energy (CDE%s), balanced salt solution volume (BSSml), total longitudinal energy (%s) and torsional amplitude (%s). RESULTS: Lower CDE values were seen in FLACS compared to manual phacoemulsification (CDE %s median FLACS BT 3.28, FLACS TT 4.07, Manual BT 5.57, Manual TT 6.27). There was a significant difference between CDE FLACS BT and FLACS TT (p = 0.038), and between FLACS BT and Manual TT (p = 0.001). CONCLUSIONS AND RELEVANCE: The right choice of tip designs in advanced phacoemulsification systems is a key factor in increasing efficacy in cataract surgery. The balanced tip showed a considerable energy-saving advantage in FLACS and manual phacoemulsification compared to the tapered tip. PMID- 28563996 TI - VARIATION IN THE CODING OF SPECIES IDENTITY IN THE ADVERTISEMENT CALLS OF LITORIA VERREAUXI (ANURA: HYLIDAE). AB - Variation within and among males was documented in two properties of the advertisement call of Litoria verreauxi; comparisons were also made between populations of L. verreauxi that were allopatric and sympatric with L. ewingi. Pulse rate, a property of known importance in mate recognition, was stereotyped. However, a character upon which the full expression of pulse rate depends, the depth of amplitude modulation (AM) or pulsing, was significantly lower and more variable in populations of L. verreauxi that coexisted with L. ewingi than in allopatric populations of L. verreauxi. Furthermore, there were significant changes in the depth of AM in the calls of sympatric males recorded from one night to another within the breeding season. The within-male variation (between recordings) in this character within sympatric populations was so great that statistically significant differences between males could not be detected. Thus, even if gravid females in sympatry choose a male on the basis of the degree to which his calls are pulsed, the evolutionary response to such selection would probably be very limited. The change that appears to be occurring in the temporal code for species identity vis-a-vis L. ewingi in sympatry (a change from a quantitative difference [pulse rate] to a qualitative one [pulsed versus unpulsed calls]) is probably a passive consequence of the shift to higher pulse rates. PMID- 28563997 TI - HOW SIMILAR ARE GENETIC CORRELATION STRUCTURES? DATA FROM MICE AND RATS. AB - An integral assumption of many models of morphometric evolution is the equality of the genetic variance-covariance structure across evolutionary time. To examine this assumption, the quantitative-genetic aspects of morphometric form are examined for eight pelvic traits in laboratory rats (Rattus norvegicus) and random-bred ICR mice (Mus musculus). In both species, all traits are significantly heritable, and there are significant phenotypic and genetic correlations among traits, although environmental correlations among the eight traits are low. The size relations among the pelvic variables are isometric. Three matrix-permutation tests are used to examine similarity of phenotypic, genetic, and environmental covariance and correlation matrices within and between species. Independent patterns of morphometric covariation and correlation arise from genetic and environmental effects within each species and from environmental effects between species. The patterns of phenotypic and genetic covariation and correlation are similar within each species, and the phenotypic and genetic correlations are also similar between these species. However, genetic covariance matrices show no significant statistical association between species. It is suggested that the assumption of equality of genetic variance-covariance structures across divergent taxa should be approached with caution. PMID- 28563998 TI - PATTERNS AND PROCESSES OF DIVERSIFICATION: SPECIATION AND HISTORICAL CONGRUENCE IN SOME NEOTROPICAL BIRDS. AB - This paper documents congruence in geographical patterns of speciation for four clades of birds having taxa endemic to the same areas within the Neotropics. Two genera, Pionopsitta parrots and Selenidera toucans, corroborate a well known biogeographic disjunction in which taxa endemic to southern Central America and the Choco region of northwestern South America are the sister-group to a radiation within the Amazon basin. These two genera, along with two lineages within the toucan genus Pteroglossus, also document a pattern of historical interrelationships for four well known areas of endemism within Amazonia: Guyanan + (Belem-Para + (Inambari + Napo)). These generalized historical patterns are interpreted to have arisen via fragmentation (vicariance) of a widespread ancestral biota. A review of the paleogeographic evidence suggests that these vicariance events could have originated as a result of several different mechanisms operating at various times during the Cenozoic. The inference that diversification of the Neotropical biota is primarily the result of the most recent of these possible vicariance events, namely isolation within Quaternary forest refugia, is unwarranted, given present data. These patterns of historical congruence are also interpreted as direct evidence against the hypothesis that diversification of the forest biota was a consequence of parapatric differentiation along recently established ecological gradients. PMID- 28563999 TI - MIXED MATING SYSTEMS IN HAWAIIAN BIDENS (ASTERACEAE). AB - Floral features related to the breeding system were studied for 11 species of Hawaiian Bidens. Protandry and male sterility promote outcrossing, while self compatibility and geitonogamy contribute to inbreeding. The combination of these floral mechanisms results in a mixed mating system in all species studied. Outcrossing rates of 15 populations of these species ranged from 0.43 to 0.88, averaging 0.65. Apparent selling rates of females ranged from 0 to 0.25 in seven gynodioecious populations surveyed, suggesting that there is variation in the level of biparental inbreeding among populations. The presence of females increased the level of outcrossing by an average of 9% in gynodioecious populations. This study indicates that the efficiency of gynodioecy as an outcrossing mechanism largely depends on the current outcrossing rate of hermaphrodites, the frequency of females, and the extent of genetic substructuring in populations. On average, autogamy contributed 4%, geitonogamy contributed 24%, and consanguineous mating contributed 15% to the realized selfing rate (43%) in the hermaphrodites of these species. PMID- 28564000 TI - ESTIMATING VARIANCE COMPONENTS: REPLY TO GROETERS. PMID- 28564001 TI - THE DIVERGENCE OF NEUTRAL QUANTITATIVE CHARACTERS AMONG PARTIALLY ISOLATED POPULATIONS. AB - The neutral model of phenotypic evolution has yielded several simple predictions about the long-term rates of between-population divergence of polygenic traits and about the equilibrium level of within-population variance when mutation and random genetic drift are the sole evolutionary forces. These conclusions must be modified if populations are only partially isolated. A quantitative model is presented for the development of within- and between-population variance for neutral quantitative characters in pairs of populations with arbitrary effective sizes and migration rates. Both the variance in the base population and subsequent variance generated by mutation are considered, and several dynamical and equilibrium properties are shown to be adequately described by simple approximations. The resultant formulations provide some insight into the sensitivity of measures of morphological distance to gene flow, the necessity of isolation for the accumulation of variation between incipient species, and the consequences of gene flow into captive populations of endangered species. PMID- 28564002 TI - ACCURACY OF PHYLOGENETIC-ESTIMATION METHODS UNDER UNEQUAL EVOLUTIONARY RATES. AB - A comparative study of the accuracy of three different approaches to phylogenetic estimation was made on simulated data with differing rates of change in different lineages. The three approaches were maximum likelihood, maximum parsimony, and phenetic clustering. The data were generated by simulating genetic drift with different population sizes over a simple four-species tree topology. Although the accuracy of all three approaches was found to be dependent on the number of loci (characters), maximum likelihood was found to perform considerably and consistently better than maximum parsimony or phenetic clustering. PMID- 28564003 TI - FLORAL DISPLAY IN PHYLA INCISA: CONSEQUENCES FOR MALE AND FEMALE REPRODUCTIVE SUCCESS. AB - The inflorescences of Phyla incisa consist of flowers in two phases: younger, nectar-containing flowers that have yellow corolla throats and older, nectar lacking flowers that have dark purple corolla throats. Observations of pollinator visitation patterns to both natural and manipulated inflorescences were made to determine the role of each flower phase in pollinator attraction. The effect of older-phase flowers on male and female reproductive success was determined by comparing stigmatic pollen loads and estimates of pollen removal from inflorescences having different numbers of these flowers. The pollinators of Phyla selected larger inflorescences more often than expected based upon the size distribution of inflorescences available to them. Both younger- and older-phase flowers contributed to the attraction of pollinators, but the latter were less effective in this function. The presence of older-phase flowers significantly increased the visitation rate to inflorescences and the amount of pollen removed but had little effect on pollen deposition on stigmas. The lack of correspondence between pollen deposition and pollinator-visitation rate was not due to stigma saturation, since stigma loads varied greatly. The data indicate that the deposition of pollen on stigmas in this species is a relatively stochastic process, whereas pollen removal from inflorescences occurs at a much more regular rate. Old-phase flower retention appears to contribute to reproductive success through increased pollen donation when pollinator activity is high and may also increase the probability of seed set when pollinators are rare. PMID- 28564004 TI - RELATIONSHIP BETWEEN OBSERVED COMPONENTS OF VARIANCE AND CAUSAL COMPONENTS OF VARIANCE IN A SPLIT-FAMILY, HALF-SIB, FULL-SIB ANALYSIS. PMID- 28564005 TI - EXPERIMENTAL STUDIES OF PLEIOTROPY AND EPISTASIS IN ESCHERICHIA COLI. I. VARIATION IN COMPETITIVE FITNESS AMONG MUTANTS RESISTANT TO VIRUS T4. AB - Mutants selected for novel phenotypes frequently exhibit maladaptive pleiotropic effects. One may reasonably ask whether these effects are properties of the novel phenotypes per se, or whether these effects depend upon the particular genotypes conferring the novel phenotypes. To address this issue, I examined an array of independent mutants, derived from Escherichia coli B, that were all completely resistant to the virus T4. Each resistant mutant had maladaptive pleiotropic effects, but there was highly significant variation in competitive fitness among mutants. The degree of reduction in competitive fitness was strongly associated with cross-resistance to virus T7 and with the inferred position of the mutated gene in a complex metabolic pathway. This variation in competitive fitness permits refinement of the resistant phenotype by selection among resistant genotypes. This mechanism complements refinement of the resistant phenotype by selection for epistatic modifiers of maladaptive pleiotropic effects. PMID- 28564006 TI - EPISTASIS AND THE EFFECT OF FOUNDER EVENTS ON THE ADDITIVE GENETIC VARIANCE. AB - Models of founder events have focused on the reduction in the genetic variation following a founder event. However, recent work (Bryant et al., 1986; Goodnight, 1987) suggests that when there is epistatic genetic variance in a population, the total genetic variance within demes may actually increase following a founder event. Since the additive genetic variance is a statistical property of a population and can change with the level of inbreeding, some of the epistatic genetic variance may be converted to additive genetic variance during a founder event. The model presented here demonstrates that some of the additive-by additive epistatic genetic variance is converted to additive genetic variance following a founder event. Furthermore, the amount of epistasis converted to additive genetic variance is a function of the recombination rate and the propagule size. For a single founder event of two individuals, as much as 75% of the epistatic variance in the ancestral population may become additive genetic variance following the founder event. For founder events involving two individuals with free recombination, the relative contribution of epistasis to the additive genetic variance following a founder event is equal to its proportion of the total genetic variance prior to the founder event. Traits closely related to fitness are expected to have relatively little additive genetic variance but may have substantial nonadditive genetic variance. Founder events may be important in the evolution of fitness traits, not because they lead to a reduction in the genetic variance, but rather because they lead to an increase in the additive genetic variance. PMID- 28564007 TI - EVALUATION OF THE RESTRICTED MAXIMUM-LIKELIHOOD METHOD FOR ESTIMATING PHYLOGENETIC TREES USING SIMULATED ALLELE-FREQUENCY DATA. AB - Comparisons are made of the accuracy of the restricted maximum-likelihood, Wagner parsimony, and UPGMA (unweighted pair-group method using arithmetic averages) clustering methods to estimate phylogenetic trees. Data matrices were generated by constructing simulated stochastic evolution in a multidimensional gene frequency space using a simple genetic-drift model (Brownian-motion, random-walk) with constant rates of divergence in all lineages. Ten differentphylogenetic tree topologies of 20 operational taxonomic units (OTU's), representing a range of tree shapes, were used. Felsenstein's restricted maximum-likelihood method, Wagner parsimony, and UPGMA clustering were used to construct trees from the resulting data matrices. The computations for the restricted maximum-likelihood method were performed on a Cray-1 supercomputer since the required calculations (especially when optimized for the vector hardware) are performed substantially faster than on more conventional computing systems. The overall level of accuracy of tree reconstruction depends on the topology of the true phylogenetic tree. The UPGMA clustering method, especially when genetic-distance coefficients are used, gives the most accurate estimates of the true phylogeny (for our model with constant evolutionary rates). For large numbers of loci, all methods give similar results, but trends in the results imply that the restricted maximum-likelihood method would produce the most accurate trees if sample sizes were large enough. PMID- 28564008 TI - HISTORICAL FACTORS AND ANISOPLETHIC POPULATION STRUCTURE IN TRISTYLOUS PONTEDERIA CORDATA: A REASSESSMENT. AB - Theoretical models of floral-morph frequencies in tristylous species predict a single equilibrium with all three morphs represented in equal proportions (isoplethy). North American populations of Pontederia cordata exhibit considerable heterogeneity of morph frequencies between populations, with the short-styled morph often in excess of isoplethic expectations and the long-styled morph commonly underrepresented. In a previous study, it was proposed that anisoplethic population structure in P. cordata is the result of differential male fertility, owing to genetic differences in pollen production among the morphs. In this study, the influence of historical factors on morph frequencies prior to equilibrium was investigated using a deterministic computer model. Nonequilibrium frequencies are strongly influenced by the genotypes of founding individuals, and, because tristyly is under the control of two diallelic loci, phenotypic equilibrium is approached asymptotically. The model indicates that in nonequilibrium populations the short-styled morph will be in excess and the long styled morph will be underrepresented. This suggests that historical factors play an important role in determining population structure in P. cordata. Several features of the population ecology of the species lend support to this interpretation. Historical factors should be taken into account when interpreting data from population surveys of morph frequencies in tristylous species and of other genetic polymorphisms not under single-locus control. PMID- 28564009 TI - ON THE CAUSES OF MONOPHAGY IN DROSOPHILA QUINARIA. PMID- 28564010 TI - COURTSHIP FEEDING AND THE FITNESS OF FEMALE KATYDIDS (ORTHOPTERA: TETTIGONIIDAE). AB - Katydid males (Requena verticalis) produce spermatophores with a large sperm-free spermatophylax, which is eaten by the female after mating. In this study, I asked 1) how do spermatophylax nutrients affect the fitness of the mated female and her progeny? 2) does this male-produced food substitute for other food in the diet of the female, or is it a source of specialized nutrients? and 3) does an increase in the size of the spermatophylax eaten influence female reproduction in the same way as the additional spermatophylaxes that would be obtained from multiple mating? An experimental increase either in dietary protein or the number of spermatophylaxes eaten increased the number of eggs produced. However, spermatophylax size had no effect on egg number. An increase in either the size or number of spermatophylaxes eaten resulted in an increase in egg size. There was no influence of protein in the general diet on egg size. This suggests that males provide nutrition not available from other sources. Although there were no direct effects of number of spermatophylaxes eaten by females on the overwintering survival of their progeny, offspring from females producing larger eggs had a relatively higher probability of surviving winter. The amount of spermatophylax eaten had no influence on the mean adult size of progeny but significantly increased the mean date at which sons matured to adulthood. There was no influence of dietary protein on these variables. Since maturation date is positively correlated with adult size in both sexes, it is suggested that the influence of courtship feeding on maturation date may result in an increase in adult size and thus the fitness of sons. A significant correlation between the size of the female and the mean size of her sons (but not daughters) suggests that there is also a heritable component to body size. PMID- 28564011 TI - EXPERIMENTAL STUDIES OF PLEIOTROPY AND EPISTASIS IN ESCHERICHIA COLI. II. COMPENSATION FOR MALADAPTIVE EFFECTS ASSOCIATED WITH RESISTANCE TO VIRUS T4. AB - Mutations in Escherichia coli that confer resistance to virus T4 also have maladaptive effects that reduce competitive fitness. After resistant populations had evolved for 400 generations in the absence of T4, their fitness approached that of sensitive populations allowed to evolve under identical conditions. However, the resistant populations had not reverted to sensitivity. Instead, this convergence in fitness resulted from genetic changes that compensated for maladaptive pleiotropic effects of the resistance mutations. An allele selected in an evolving resistant population reduced the competitive disadvantage associated with resistance by almost half. Interestingly, this allele was also beneficial in sensitive populations, although its fitness advantage was only about one-fifth as great as it was in the resistant population. These results run counter to a commonly held view that trade-offs between components of fitness should become more pronounced as populations approach their "selective equilibria." If a trade-off derives from some limiting energetic or material currency, then it is likely to become more pronounced as a population becomes more finely adapted. If a trade-off derives from the disruption of genetic integration, then it is likely to be diminished with further adaptation. PMID- 28564012 TI - QUEEN NUMBER IN COLONIES OF SOCIAL HYMENOPTERA AS A KIN-SELECTED ADAPTATION. AB - Using a series of kin-selection models, I examine factors that favor multiple egg laying queens (polygyny) in eusocial Hymenoptera colonies. One result is that there is a theoretical conflict of interest between the founding queens and their daughter workers over how many and which individuals should be the extra reproductives. Both castes should prefer their full sisters. Therefore, primary polygyny (multiple related foundresses) may favor queens while secondary polygyny (related queens added to mature colonies) may favor workers. Polygyny, itself, was found to be favored by high colony survivorship and low probability of queens contributing eggs to successive broods. Polygyne colonies, however, did not need to produce more offspring per brood to be selectively favored; they could be half as productive per brood as monogyne ones and still have higher lifetime fitness under some conditions. For reproductive data from eight ant species with both monogyne and polygyne colonies, the model generates results that are consistent with a kin-selection explanation of polygyny in all of them. It is proposed that queen number is an ecologically flexible trait that is influenced by a broad set of factors but is not necessarily linked to specific habitat types. Furthermore, neither polygyny nor monogyny may be reliably considered as the primitive or ancestral Hymenopteran social system. The optimal queen number within a species may evolutionarily increase or decrease, depending on the direction of environmental change. PMID- 28564013 TI - INBREEDING AND VARIANCE EFFECTIVE POPULATION NUMBERS. AB - In this paper, a correction and extension of earlier work, we derive expressions for the inbreeding effective number, NeI , and the variance effective number, NeV , with various models. Diploidy, random mating, and discrete generations are assumed and formulas for NeI are given for six situations: isogamous monoecious populations with self-fertilization permitted or excluded; monoecious populations, male and female gametes distinguished, with self-fertilization permitted or excluded; and separate sexes with or without male and female progeny distinguished. NeV is given for monoecious and separate-sexed populations. Most higher animals have separate sexes, and male and female progeny are distinguished. Letting the subscript t represent the generation in which the inbreeding effect is manifest, the inbreeding effective number is [Formula: see text] in which sigmasm,sf is the covariance of the number of male (m) and female (f) progeny of a parent of sex s (s = m or f), MUsm and MUsf are the mean numbers of sons and daughters of a parent of sex s, and Ns,t-2 is the number in the grandparental generation. For the variance effective number [Formula: see text] in which [Formula: see text] and sigmasm2 and sigmasf2 are the variances in the number of sons and daughters of a parent of sex s. Observations are made at the same age in each generation. PMID- 28564014 TI - DETERMINISTIC THEORY OF HETEROPLASMY. PMID- 28564015 TI - HYBRIDIZATION IN WESTERN ATLANTIC STONE CRABS (GENUS MENIPPE): EVOLUTIONARY HISTORY AND ECOLOGICAL CONTEXT INFLUENCE SPECIES INTERACTIONS. AB - Two distinct taxa of marine crabs (Menippe mercenaria and M. adina, sensu Williams and Felder [1986]) interbreed extensively in two disjunct areas of the coastal southeastern United States. We used variation in coloration and allele frequencies at three diagnostic loci to examine in detail the structure of the two zones of variation. A narrow hybrid zone in northwest Florida is situated at the junction of the present ranges of the two parental forms, in an area of strong ecological change and hydrological convergence. Despite extensive hybridization in this area, there is a significant deficiency of heterozygotes for the Alp-2 locus, nonrandom associations of alleles for two diagnostic loci, and an absence of certain combinations of phenotypes and genotypes. Along the Atlantic coast (east central Florida into South Carolina), a broad zone of increased variability exists within the range of M. mercenaria. Allele frequencies throughout this zone are similar to those of M. mercenaria but reflect apparent introgression from M. adina. In contrast, color patterns are quite variable, but only in the center of this zone. There is little evidence of a heterozygote deficiency, and the preferred habitat of M. mercenaria is not present. The Atlantic zone of variability is apparently expanding, with alleles at enzyme loci introgressing more rapidly than color characteristics. Despite these differences, certain features are common to both zones. These include 1) asymmetry in terms of the direction of introgression, 2) differential introgression of alleles, and 3) an almost complete absence of M. adina phenotypes that carry high proportions of M. mercenaria alleles. Differences between the two zones illustrate the influence that environmental setting, time of contact in relation to time of divergence, and location of the zone relative to the parental species ranges can have on hybridization events. However, observed similarities between the zones suggest that certain patterns of introgression and recombination may be independent of environmental setting. Thus, we suggest that factors inherent to the organism (intrinsic factors) and factors inherent to the environment (extrinsic factors) both act to structure and maintain the two hybrid zones. PMID- 28564016 TI - THE QUANTITATIVE GENETICS OF SEXUAL DIMORPHISM IN SILENE LATIFOLIA (CARYOPHYLLACEAE). I. GENETIC VARIATION. AB - It is widely recognized that there are basic conflicts between the resource needs of a plant for paternal versus maternal functions. In dioecious species, these divergent demands, and the selection pressures they impose, can lead to the evolution of sexual dimorphism. The present study was conducted to assess the potential for the evolution of sexual dimorphism in Silene latifolia by evaluating the genetic variation and genetic correlation between characters and between the sexes for a range of growth and reproductive characters. Sexual dimorphism is largely restricted to reproductive characters, particularly flower number and flower size. A canonical correlation analysis revealed considerable intercorrelation between growth characters, such as germination date, height, and leaf size, and reproductive characters; plants that grow fast early on also flower earlier, and plants that produce big leaves also produce big flowers. There was genetic variation for several sexually dimorphic characters; much of the focus in this analysis was on flower size, particularly calyx diameter. Finally, genetic correlations within and between the sexes were found that limit the rate of evolutionary divergence between the sexes. The genetic results suggest that S. latifolia has been subject to divergent selection on the two sexes for a long period of time, bringing about a gradual fixation of sex-limited gene effects, so that the remaining genetic effects are expressed in both sexes. Genetic correlations between the sexes that arise from this residual variation impose limits on further evolutionary change. PMID- 28564017 TI - CHLOROPLAST DNA INTROGRESSION IN SOUTHERN CALIFORNIA SUNFLOWERS. PMID- 28564018 TI - ARE PARALLEL MORPHOLOGIES OF CAVE ORGANISMS THE RESULT OF SIMILAR SELECTION PRESSURES? AB - The amphipod Gammarus minus is present in both caves and springs, with cave populations showing elaborated (size and antennae) and reduced (eye) characters relative to spring populations. Earlier studies have shown that cave populations resulted from independent invasions of hydrologically isolated subterranean drainages and that there is genetic variation for both elaborated and reduced characters. In this study we tested the hypothesis that a similar pattern of selection on isolated cave populations is responsible for the parallel evolution of cave morphologies. We used variation in mating success and fecundity to test for the presence of directional selection on eye, antennal, and body size characters in a set of cave and spring populations during a series of seasonal cross-sectional samplings. We found significant directional selection for smaller eyes in caves and larger eyes in springs, which supports the hypothesis that selection is responsible for reduced eye size in cave populations. We also found selection for larger body and antennal size in cave populations, which is consistent with the hypothesis that parallel patterns of selection in caves are responsible for the elaboration of body and antennal size. However, we found selection for larger body and antennal size in spring populations that is not consistent with the observed divergence of spring and cave populations. We suggest that unmeasured components of viability selection could be more important in springs than in caves and may act against the selection for larger size found in spring populations. PMID- 28564019 TI - QUANTITATIVE GENETIC MODELS FOR DEVELOPMENT, EPIGENETIC SELECTION, AND PHENOTYPIC EVOLUTION. AB - Herein we describe a general multivariate quantitative genetic model that incorporates two potentially important developmental phenomena, maternal effects and epigenetic effects. Maternal and epigenetic effects are defined as partial regression coefficients and phenotypic variances are derived in terms of age specific genetic and environmental variances. As a starting point, the traditional quantitative genetic model of additive gene effects and random environmental effects is cast in a developmental time framework. From this framework, we first extend a maternal effects model to include multiple developmental ages for the occurrence of maternal effects. An example of maternal effects occurring at multiple developmental ages is prenatal and postnatal maternal effects in mammals. Subsequently, a model of intrinsic and epigenetic effects in the absence of maternal effects is described. It is shown that genetic correlations can arise through epigenetic effects, and in the absence of other developmental effects, epigenetic effects are in general confounded with age specific intrinsic genetic effects. Finally, the two effects are incorporated into the basic quantitative genetic model. For this more biologically realistic model combining maternal and epigenetic effects, it is shown that the phenotypic regressions of offspring on mother and offspring on father can be used in some cases to estimate simultaneously maternal effects and epigenetic effects. PMID- 28564020 TI - QUANTITATIVE GENETICS AND THE EVOLUTION OF REACTION NORMS. AB - We extend methods of quantitative genetics to studies of the evolution of reaction norms defined over continuous environments. Our models consider both spatial variation (hard and soft selection) and temporal variation (within a generation and between generations). These different forms of environmental variation can produce different evolutionary trajectories even when they favor the same optimal reaction norm. When genetic constraints limit the types of evolutionary changes available to a reaction norm, different forms of environmental variation can also produce different evolutionary equilibria. The methods and models presented here provide a framework in which empiricists may determine whether a reaction norm is optimal and, if it is not, to evaluate hypotheses for why it is not. PMID- 28564021 TI - ON THE SPREAD OF NEW GENE COMBINATIONS IN THE THIRD PHASE OF WRIGHT'S SHIFTING BALANCE. PMID- 28564022 TI - THE ECOLOGY AND GENETICS OF FITNESS IN CHLAMYDOMONAS. V. THE RELATIONSHIP BETWEEN GENETIC CORRELATION AND ENVIRONMENTAL VARIANCE. PMID- 28564023 TI - ENVIRONMENTAL AND GENETIC CONSTRAINTS ON ADAPTIVE POPULATION DIFFERENTIATION IN ANTHOXANTHUM ODORATUM. AB - Maximum-likelihood estimates of environmental and broad sense genetic (co)variance components were obtained for the growth and reproductive output of clones of the grass Anthoxanthum odoratum. The clones were transplanted between a mesic and a xeric field site and across-environment genetic correlations were used to estimate the strength of genotype-environment interaction. Significant across-environment clonal covariance matrices were found for several traits, including lifetime reproductive output in one population. None of the matrices differed significantly between populations. Significant within-site clonal variation was found, but there was no significant across-environment clonal covariation. Most broad sense heritability estimates of character states within sites were small (median = 0.12), suggesting that only a slow response to selection is possible. All significant within-site clonal correlations between growth and reproductive output were positive, although the pattern of negative clonal correlations suggests that there may be a cost to first year reproduction, which might constrain future selection response. PMID- 28564024 TI - EFFECTS OF POPULATION BOTTLENECKS ON GENETIC DIVERSITY AS MEASURED BY ALLOZYME ELECTROPHORESIS. AB - Low levels of allozyme heterozygosity in populations are often attributed to previous population bottlenecks; however, few experiments have examined the relationship between heterozygosity and bottlenecks under natural conditions. The composition and number of founders of 55 experimental populations of the eastern mosquitofish (Gambusia holbrooki), maintained under simulated field conditions, were manipulated to examine the effects of bottlenecks on three components of allozyme diversity. Correlations between observed and expected values of allozyme heterozygosity, proportions of polymorphic loci, and numbers of alleles per locus were 0.423, 0.602, and 0.772, respectively. The numbers of polymorphic loci and of alleles per locus were more sensitive indicators of differences in genetic diversity between the pre-bottleneck and post-bottleneck populations than was multiple-locus heterozygosity. In many populations, single- and multiple-locus heterozygosity actually increased as a result of the founder event. The weak relationship between a population's heterozygosity and the number and composition of its founders resulted from an increase in the variance of heterozygosity due to drift of allele frequencies. There was little evidence that selection influenced the loss of allozyme variation. When it is not possible to estimate heterozygosity at a large number of polymorphic loci, allozyme surveys attempting to detect founder events and other types of bottlenecks should focus on levels of locus polymorphism and allelic diversity rather than on heterozygosity. PMID- 28564025 TI - NEUTRAL THEORY OF QUANTITATIVE GENETIC VARIANCE IN AN ISLAND MODEL WITH LOCAL EXTINCTION AND COLONIZATION. AB - Additive genetic variance maintained by mutation in a selectively neutral quantitative character is analyzed for an ideal population distributed on n islands, each with local effective size N, that exchange migrants at a small rate, m. In a stable population structure, the expected genetic variance maintained within islands is identical to that in a panmictic population of the same total size, regardless of the migration rate (m > 0). This result contrasts with Wright's classical conclusion, based on inbreeding coefficients, that at least one immigrant per island every other generation (Nm > 1/2) is necessary for the genetic variance within local populations to approach that under panmixia. The expected genetic variance maintained among islands is inversely proportional to m and increases with the number of islands, but is independent of N. Local extinction and colonization diminish the genetic variance maintained within islands by reducing the effective size of island populations through the founder effect, although the expected genetic variance within islands is nearly as large as that in a panmictic population of the same total effective size. If the founders of new colonies originate from more than one island, rates of local extinction and colonization larger than about twice the migration rate will substantially reduce the genetic variance maintained among islands. These results indicate the importance of mutation and migration in maintaining quantitative genetic variance within small local populations. PMID- 28564026 TI - THE MIXED-MODEL ANALYSIS OF VARIANCE APPLIED TO QUANTITATIVE GENETICS: BIOLOGICAL MEANING OF THE PARAMETERS. AB - The mixed-model factorial analysis of variance has been used in many recent studies in evolutionary quantitative genetics. Two competing formulations of the mixed-model ANOVA are commonly used, the "Scheffe" model and the "SAS" model; these models differ in both their assumptions and in the way in which variance components due to the main effect of random factors are defined. The biological meanings of the two variance component definitions have often been unappreciated, however. A full understanding of these meanings leads to the conclusion that the mixed-model ANOVA could have been used to much greater effect by many recent authors. The variance component due to the random main effect under the two-way SAS model is the covariance in true means associated with a level of the random factor (e.g., families) across levels of the fixed factor (e.g., environments). Therefore the SAS model has a natural application for estimating the genetic correlation between a character expressed in different environments and testing whether it differs from zero. The variance component due to the random main effect under the two-way Scheffe model is the variance in marginal means (i.e., means over levels of the fixed factor) among levels of the random factor. Therefore the Scheffe model has a natural application for estimating genetic variances and heritabilities in populations using a defined mixture of environments. Procedures and assumptions necessary for these applications of the models are discussed. While exact significance tests under the SAS model require balanced data and the assumptions that family effects are normally distributed with equal variances in the different environments, the model can be useful even when these conditions are not met (e.g., for providing an unbiased estimate of the across-environment genetic covariance). Contrary to statements in a recent paper, exact significance tests regarding the variance in marginal means as well as unbiased estimates can be readily obtained from unbalanced designs with no restrictive assumptions about the distributions or variance-covariance structure of family effects. PMID- 28564027 TI - POLYGENIC MUTATION IN DROSOPHILA MELANOGASTER: ESTIMATES FROM DIVERGENCE AMONG INBRED STRAINS. AB - A highly inbred line of Drosophila melanogaster was subdivided into 25 replicate sublines, which were independently maintained for 100 generations with 10 pairs of unselected flies per generation. The polygenic mutation rate (VM ) for two quantitative traits, abdominal and sternopleural bristle number, was estimated from divergence among sublines at 10 generation intervals from generations 30 100, and from response of each line to divergent selection after more than 65 generations of mutation accumulation. Estimates of VM averaged over males and females both from divergence among lines and from response to selection within lines were 3.3 * 10-3 VE for abdominal bristles and 1.5 * 10-3 VE for sternopleural bristles, where VE is the environmental variance. The actual rate of production of mutations affecting these traits may be considerably higher if the traits are under stabilizing selection, and if mutations affecting bristle number have deleterious effects on fitness. There was a substantial component of variance for sex * mutant effect interaction and the sublines evolved highly significant mutational variation in sex dimorphism of abdominal bristle number. Pleiotropic effects on sex dimorphism may be a general property of mutations at loci determining bristle number. PMID- 28564028 TI - BEHAVIORAL DEFENSES AGAINST AVIAN BROOD PARASITISM IN SYMPATRIC AND ALLOPATRIC HOST POPULATIONS. AB - The brown-headed cowbird (Molothrus ater) is a widespread, obligate brood parasite of North American passerine birds. In southern Manitoba, where hosts are sympatric with cowbirds, American robins (Turdus migratorius) ejected parasitic eggs from all experimentally parasitized clutches (N = 25) and no eggs were accepted for more than four days. In contrast, robins in northern Manitoba, an area where cowbirds do not breed, accepted parasitic eggs in 33% of nests (N = 18) for at least five days. Acceptance of experimental cowbird eggs by a second host, the yellow warbler (Dendroica petechia), was similar in allopatric (100% of 20 nests) and sympatric (88.6% of 35 nests) populations, but models of a female cowbird elicited greater nest defense by warblers in the area of sympatry. Neither host rejected eggs of conspecifics, thus, rejection of cowbird eggs was not an epiphenomenon of conspecific brood parasitism. These results support the hypothesis that recognition of cowbirds and their eggs evolved as adaptations to counter cowbird parasitism and not some other selection pressure. The expression of anti-parasite defenses by some individuals within allopatric populations further suggests these traits may be controlled genetically but persist in such areas either through the continued introgression of rejecter genes from sympatric populations or because of the low cost of rejection behavior when parasitism is absent or rare. PMID- 28564029 TI - UNUSUAL POPULATION GENETICS OF A PARASITIC NEMATODE: mtDNA VARIATION WITHIN AND AMONG POPULATIONS. AB - Very little is known about the distribution of genetic variance within and among populations of parasitic helminths. In this study we used mitochondrial DNA (mtDNA) restriction fragment analysis to describe the population genetic structure of Ostertagia ostertagi, a nematode parasite of cattle, in the United States. Estimates of within-population mtDNA diversity are 5 to 10 times greater than typical estimates reported for species in other taxa. Although populations are genetically differentiated for a key life-history trait, greater than 98% of the total genetic diversity is partitioned within populations, and the geographic distribution of individual mtDNA haplotypes suggests high gene flow among populations. PMID- 28564030 TI - RESPONSE TO WAPLES'S COMMENT ON HETEROZYGOSITY AND LIFE-HISTORY VARIATION IN BONY FISHES. PMID- 28564031 TI - A GENERAL MODEL FOR KIN SELECTION. AB - Inclusive fitness theory is central to our understanding of the evolution of social behavior. By showing the importance of genetic transmission through nondescendent relatives, it helps to explain the evolution of reproductively altruistic behaviors, such as those observed in the social insects. Inclusive fitness thinking is quantified by Hamilton's rule, but Hamilton's rule has often been criticized for being inexact or insufficiently general. Here I show how adopting a genic perspective yields a very general version that remains pleasingly simple and transparent. PMID- 28564032 TI - A WIDESPREAD B CHROMOSOME POLYMORPHISM MAINTAINED WITHOUT APPARENT DRIVE. AB - The transmission rates of the three main types of B chromosome present in the grasshopper Eyprepocnemis plorans were studied by two different methods: (i) cytological observation of their meiotic behavior in males and females and (ii) karyological analysis of the embryo offspring obtained either from gravid females collected in the field or from controlled crosses. We conclude that Bs are inherited in a random manner with no tendency toward accumulation or loss from either sex. The possible factors that might be responsible for the maintenance of this widespread polymorphism are discussed. PMID- 28564033 TI - MULLER'S RATCHET AND THE ADVANTAGE OF SEX IN THE RNA VIRUS ?6. AB - Population genetic models have shown that if genetic drift is strong and the rate of deleterious mutations is high, Muller's ratchet provides an advantage to sex. A previous study tested for the possibility that Muller's ratchet could work in RNA viruses, which are known to have very high mutation rates. Muller's ratchet was found to operate when lineages of the RNA bacteriophage phi6 were subjected to intensified genetic drift. The study did not determine, however, whether sex is advantageous to these viruses. We have examined whether sex can reverse the effects of Muller's ratchet by crossing nine phi6 lineages that were subjected to the ratchet in Chao's study. To determine whether there was a net advantage to sex, we analyzed the effect of crossing three lineages to all other lineages. Crossing increased significantly the fitness of two lineages, but it did not significantly affect the fitness of the third lineage. We argue that the minimal advantage of sex to these nine lineages is small, but positive. These results provide a possible scenario for the evolution of sex in an RNA phage like phi6. PMID- 28564034 TI - GENETIC POPULATION STRUCTURE AND LEVELS OF GENE FLOW IN THE STREAM DWELLING WATERSTRIDER, AQUARIUS (=GERRIS) REMIGIS (HEMIPTERA: GERRIDAE). AB - Gene flow, in combination with selection and drift, determines levels of differentiation among local populations. In this study we estimate gene flow in a stream dwelling, flightless waterstrider, Aquarius remigis. Twenty-eight Aquarius remigis populations from Quebec, Ontario, New Brunswick, Iowa, North Carolina, and California were genetically characterized at 15 loci using starch gel electrophoresis. Sampling over two years was designed for a hierarchical analysis of population structure incorporating variation among sites within streams, streams within watersheds, watersheds within regions, and regions within North America. Hierarchical F statistics indicated that only sites within streams maintained enough gene flow to prevent differentiation through drift (Nm = 27.5). Above the level of sites within streams gene flow is highly restricted (Nm <= 0.5) and no correlation is found between genetic and geographic distances. This agrees well with direct estimates of gene flow based on mark and recapture data, yielding an Ne of approximately 170 individuals. Previous assignment of subspecific status to Californian A. remigis is not supported by genetic distances between those populations and other populations in North America. Previous suggestion of specific status for south-eastern A. remigis is supported by genetic distances between North Carolina populations and other populations in North America, and a high proportion of region specific alleles in the North Carolina populations. However, because of the high degree of morphological and genetic variability throughout the range of this species, the assignment of specific or subspecific status to parts of the range may be premature. PMID- 28564035 TI - MODELS OF CHARACTER DISPLACEMENT AND THE THEORETICAL ROBUSTNESS OF TAXON CYCLES. AB - The appropriateness of the techniques used in modeling character displacement has been the focus of vigorous debate. In this paper, the three competing methods (the coevolutionarily stable community (CSC), the evolutionarily stable strategy (ESS), and quantitative genetic recursion (QGR)) are compared in models using a common ecological setting. Specific predictions of the CSC model have been used to understand features of character displacement among Cnemidophorous lizards on islands off Mexico, Anolis lizards in the Lesser Antilles and Galapagos finches. Nonetheless, the validity of the approach has been repeatedly questioned. Conceptually the three formalisms vary in the degree to which within species variability is allowed in the models. The predictions of the CSC are found not to be robust to even small violation of its fundamental assumption of absolute species monomorphy. We show by simulation and analytical observations that the CSC is not valid under frequency dependent selection, and that the ESS is the limiting case of QGR as intraspecific phenotypic variation goes to zero. Thus the ESS and the QGR models agree closely when the between-phenotype component (BPC) of the niche width is small. However, as the BPC increases, quantitative discrepancies between ESS and QGR predictions increase, although model behavior remains qualitatively similar. A fourth approach, termed "Quantitative Genetic Optimization" (QGO) analysis, is suggested, combining advantages of both the ESS and QGR. Although all approaches support the possibility of taxon cycles, the cycle patterns predicted are qualitatively different and strongly model dependent. PMID- 28564036 TI - COMPETITION-DEPENDENT ABSCISSION OF SELF-POLLINATED FLOWERS OF PHORMIUM TENAX (AGAVACEAE): A SECOND ACTION OF SELF-INCOMPATIBILITY AT THE WHOLE FLOWER LEVEL? AB - The relative success of fruit from paired self- and cross-pollinations was examined in Phormium tenax when the contrasted pollinations were separated by different distances on the same and different inflorescences. We determined whether the retention of selfed fruits differed from that of crossed fruits and whether it depended on the level of competition with crossed fruit, the number of seeds per fruit, and/or the presence of earlier developing fruit. We found that the success of selfed fruits is determined by the degree of competition with crossed fruits and may be an expression of self-incompatibility. Competition dependence of the abscission of selfed flowers has not been documented previously. It is parallel to cryptic self-incompatibility in which individual self-pollen grains are not as successful as cross-pollen when competing on the same pistil. The competition-dependent abscission of self-pollinations considered here, however, operates at the level of whole flowers. The phenomenon of competition-dependent abscission of selfed flowers in P. tenax also has implications for the measurement and interpretation of self-incompatibility in other species. Self-incompatibility is a quantitative phenomenon. The facultative success of selfing shows that the effective strength of self-incompatibility can be highly susceptible to the conditions of competition under which it is measured. The competition-dependent abscission of selfed flowers allows a high level of outcrossing to be achieved while it assures seed set when pollinations are scarce. Several other causes of intermediate selfing frequencies can also be explained by this "best-of-both-worlds" hypothesis. PMID- 28564037 TI - SPATIAL GENETIC STRUCTURE IN TWO TAMARACK [LARIX LARICINA (DU ROI) K. KOCH] POPULATIONS WITH DIFFERING ESTABLISHMENT HISTORIES. PMID- 28564038 TI - INDIVIDUAL VARIATION IN SPERM COMPETITION SUCCESS OF YELLOW DUNG FLIES, SCATOPHAGA STERCORARIA. AB - Intraspecific variation in the proportion of offspring sired by the second male to mate with a female (P2 ) is an aspect of sperm competition that has received little attention. We examined variation in the sperm competition success of individual male dung flies, Scatophaga stercoraria. In unmanipulated matings, copula duration was dependent on male size with smaller males copulating for longer. A principal component analysis was used to generate uncorrelated scores based on a male's size and copula duration. Using these scores demonstrated that P2 values were dependent both on the relative size and copula durations of competing males. When copula duration was held constant, the success of an individual male increased as his body size, relative to the first male, increased. We interrupted copulations of "large" and "small" second males and fitted the resultant P2 values to a linear model of sperm competition with unequal ejaculates. The data fit well to a model of sperm displacement in which sperm mix quickly on introduction to the sperm stores. Furthermore, they show that "large" males have a greater rate of sperm displacement than "small" males. The levels of prey availability during testis maturation may influence a male's success in sperm competition although his immediate mating history does not. We show why an understanding of variation in sperm competition success is important for understanding the mechanisms and evolutionary significance of sperm competition. PMID- 28564039 TI - A SEX DIFFERENCE IN THE PROPENSITY TO ENTER DIRECT/DIAPAUSE DEVELOPMENT: A RESULT OF SELECTION FOR PROTANDRY. AB - In monandrous mating systems with discrete nonoverlapping generations males should maximize the expected number of matings by starting to emerge before females. This is known as protandry. Moreover, Evolutionarily Stable Strategies (ESS) models show that the male emergence curve should be abruptly truncated before female emergence has ceased. In temperate areas where many insects have partial second generations, we accordingly predict that males should enter diapause development at an earlier date than should females, as a result of late emerging males being penalized in terms of fewer mating opportunities. The decision to diapause or to develop directly is usually mediated by response to environmental stimuli of which day length is the most important. Hence we predict that the mechanism by which males enter diapause at an earlier date than females will be that of the male reaction norm for diapause development being shifted towards longer day lengths when compared to that of females. As a result of the greater tendency of males to enter diapause development, partial second generations that develop directly should be female biased. As a corollary, first generations should be male biased because some males of the first generation are from the previous year. The prediction that males should enter diapause development earlier in the season, i.e., at longer day lengths, as compared to females was corroborated by rearing Pieris napi under a variety of critical day length regimes producing mixed broods of directly developing and diapausing individuals, and by outdoor rearings of cohorts of larvae of P. napi and P. rapae initiated throughout the season. The prediction that partial second generations should be female biased was corroborated by laboratory rearings at constant temperature of P. napi (Pieridae), Polygonia c-album (Nymphalidae), and Pararge aegeria (Satyridae) under critical day length conditions, producing female-biased sex ratio under direct, and male-biased sex ratio under diapause development. PMID- 28564040 TI - MAINTENANCE OF POLYGENIC VARIATION IN SPATIALLY STRUCTURED POPULATIONS: ROLES FOR LOCAL MATING AND GENETIC REDUNDANCY. AB - Although heritable genetic variation is critical to the evolutionary process, we know little about how it is maintained. Obviously, mutation-selection balance must play a role, but there is considerable doubt over whether it can account for heritabilities as high as 0.5, which are commonly found in natural populations. Most models of mutation-selection balance assume panmictic populations. In this paper we use Monte Carlo simulations to examine the effect of isolation by distance on the variation maintained by mutation in a polygenic trait subject to optimizing selection. We show that isolation by distance can substantially increase the total variation maintained in continuous populations over a wide range of dispersal patterns, but only if more than one genotype produces the optimal phenotype (genetic redundancy). Isolation by distance alone has only a slight effect on the variation maintained in the total population for neutral alleles. The combined effect of isolation by distance and genetic redundancy, however, allows the maintenance of substantial variation despite strong stabilizing selection. The mechanism is straightforward. Isolation by distance allows mutation and drift to operate independently in different parts of the population. Because of their independent evolutionary histories, different parts of the population independently draw from the available set of redundant genotypes. Because the genotypes are redundant, selection does not discriminate among them, and they will persist until eliminated by drift. The population as a whole maintains many distinct genotypes. We show that this process allows mutation to maintain high levels of variation, even under strong stabilizing selection, and that over a moderate range of dispersal patterns the amount of variation maintained in the entire population is independent of both the strength of selection and the variance of the dispersal distance. Furthermore, we show that individual heterozygosity is increased in locally mating populations when selection is strong. Finally, our simulations provide a rough picture of how selection and the dispersal pattern influence the spatial distribution of genetic and phenotypic variation. PMID- 28564041 TI - GRAPHICAL ANALYSIS OF MATING SYSTEM EVOLUTION IN PLANTS. PMID- 28564042 TI - REVISING A CLASSIC BUTTERFLY MIMICRY SCENARIO: DEMONSTRATION OF MULLERIAN MIMICRY BETWEEN FLORIDA VICEROYS (LIMENITIS ARCHIPPUS FLORIDENSIS) AND QUEENS (DANAUS GILIPPUS BERENICE). AB - Batesian and Mullerian mimicry relationships differ greatly in terms of selective pressures affecting the participants; hence, accurately characterizing a mimetic interaction is a crucial prerequisite to understanding the selective milieux of model, mimic, and predator. Florida viceroy butterflies (Limenitis archippus floridensis) are conventionally characterized as palatable Batesian mimics of distasteful Florida queens (Danaus gilippus berenice). However, recent experiments indicate that both butterflies are moderately distasteful, suggesting they may be Mullerian comimics. To directly test whether the butterflies exemplify Mullerian mimicry, I performed two reciprocal experiments using red winged blackbird predators. In Experiment 1, each of eight birds was exposed to a series of eight queens as "models," then offered four choice trials involving a viceroy (the putative "mimic") versus a novel alternative butterfly. If mimicry was effective, viceroys should be attacked less than alternatives. I also compared the birds' reactions to solo viceroy "mimics" offered before and after queen models, hypothesizing that attack rate on the viceroy would decrease after birds had been exposed to queen models. In Experiment 2, 12 birds were tested with viceroys as models and queens as putative mimics. The experiments revealed that (1) viceroys and queens offered as models were both moderately unpalatable (only 16% entirely eaten), (2) some birds apparently developed conditioned aversions to viceroy or queen models after only eight exposures, (3) in the subsequent choice trials, viceroy and queen "mimics" were attacked significantly less than alternatives, and (4) solo postmodel mimics were attacked significantly less than solo premodel mimics. Therefore, under these experimental conditions, sampled Florida viceroys and queens are comimics and exemplify Mullerian, not Batesian, mimicry. This compels a reassessment of selective forces affecting the butterflies and their predators, and sets the stage for a broader empirical investigation of the ecological and evolutionary dynamics of mimicry. PMID- 28564043 TI - GEOGRAPHIC VARIATION IN MATERNAL-AGE EFFECTS ON DIAPAUSE IN A CRICKET. PMID- 28564044 TI - THE GENETIC STRUCTURE OF HOST PLANT ADAPTATION IN A SPATIAL PATCHWORK: DEMOGRAPHIC VARIABILITY AMONG RECIPROCALLY TRANSPLANTED PEA APHID CLONES. AB - Populations of insect herbivores that feed on several host plant species may experience different selective forces on each host. When the hosts cooccur in a local area, herbivore populations can provide useful models for the study of evolutionary mechanisms in patchy environments. A first step in such a study involves determination of the genetic structure of host adaptation in the region: how is genetic variation for host use structured within and between subpopulations of herbivores on each host? The structure of genetic variation for host use reveals patterns of local adaptation, probable selective consequences of migration between hosts, and the potential for further evolution. To estimate the population structure of host adaptation in a patchwork, 7-11 pea aphid clones were collected at the beginning of the summer from each of two alfalfa and two red clover fields within a very localized area (about 15-20 km2 ). Using a reciprocal transplant in the field, replicates of these 35 clones were allowed to develop individually on each of the two crops. A complete life table was made for each replicate. Individual fitness was calculated from the life tables as the expected rate of population increase; longevity, age at first reproduction, and total fecundity were also measured for each clonal replicate. Currently, experimental estimates of genetic variation in complete life tables are virtually nonexistent for natural populations, even for single environments (Charlesworth, 1987); field studies are even less common. Because clones from each of two source crops were tested reciprocally on both hosts, variation in relative genotypic fitness on alfalfa and clover could be partitioned among clones within source crops, between fields of the same crop, and between source crops (alfalfa or red clover), providing a view of population structure. Significant clonal variation in relative performance on alfalfa and red clover was found: clones tended to have higher fitness on the crop from which they had been collected (the "home" crop) than they did on the "away" crop, suggesting local adaptation in response to patchy patterns of selection. Clonal variability within collections from the two crops suggests the potential for changes in the genetic constitution of these aphid populations within established fields as a result of clonal selection during the summer season. Significantly negative genetic correlations across crops were found for fitness and its major components. The possibility that these negative cross-environment correlations could act as evolutionary constraints on adaptation to the patchwork is considered. PMID- 28564045 TI - THE INTERACTION PHENOTYPE IN THE DROSOPHILA WILLISTONI-SPIROPLASMA SYMBIOSIS. AB - Both the population and coevolutionary dynamics of hereditary male-lethal endosymbionts, found in a wide range of insect species, depend on host fitness and endosymbiont transmission rates. This paper reports on fitness effects and transmission rates in three lines of Drosophila willistoni infected with either male-lethal spiroplasmas or a spontaneous nonmale-lethal mutant. Overall fitness measures were reduced or unaffected by the infection; however, some infected females produced more offspring in early broods. Maternal transmission rates were high, but imperfect, and varied with a female's age, host line, and spiroplasma type. No evidence for paternal or horizontal transmission was found. If an altered temporal pattern of reproduction is not a factor in countering the loss of spiroplasma hosts through imperfect maternal transmission, persistence of this endoparasitism remains unexplained. Tolerance of the infection and ability to transmit bacteria varied with both host and spiroplasma line. Analysis of the interaction between the spontaneous nonmale-lethal mutant and its host suggests this symbiosis has undergone coevolution under laboratory culture. PMID- 28564046 TI - THE INFLUENCE OF THE MATING SYSTEM ON SEED SIZE VARIATION IN CRINUM ERUBESCENS (AMARYLLIDACEAE). AB - We present evidence that extreme seed size variation in fruits of Crinum erubescens (range: 0.1 to 66.5 g per seed) occurs when mating pairs are inbred, either from selfing or biparental inbreeding. Several relatively uniform seeds of intermediate size are produced when pollen from several pollen donors is applied simultaneously to a flower. Selfed fruits and some fruits pollinated with a single pollen donor produce both large and small seeds, although selfed fruits produce fewer seeds than outcrossed fruit. These results are contrary to the hypothesis that variation in seed size is attributable to either pollen competition or differential allocation of maternal resource to seeds of different genotypes. PMID- 28564047 TI - THE ECOLOGY AND GENETICS OF FITNESS IN CHLAMYDOMONAS. IV. THE PROPERTIES OF MIXTURES OF GENOTYPES OF THE SAME SPECIES. AB - The properties of mixtures of genotypes of Chlamydomonas reinhardtii were investigated by growing them in monoculture and in all possible pairwise combinations in chemically defined axenic medium. Two sets of genotypes produced by crossing wild-type isolates were cultured in each of two physical environments. Mixtures were consistently more productive and less variable over environments than were their constituent monocultures. The average performance of a genotype in mixture was tightly correlated with its performance in monoculture. Reisolation of spores from mixtures at the end of growth showed that the mixtures became dominated by the component with the greater performance in monoculture, so that the properties of mixtures were attributable to replacement rather than to complementation. These results differ from those of similar trials using a range of different species of Chlamydomonas, where genetic interactions were found to be important. They are discussed in relation to theories of diversity and diversification, and related to the agronomic use of crop mixtures. PMID- 28564048 TI - A CHLOROPLAST DNA INVERSION MARKS AN EVOLUTIONARY SPLIT IN THE GENUS OENOTHERA. PMID- 28564049 TI - RESTRICTED GENE FLOW IN A MOVING HYBRID ZONE OF THE NEWTS TRITURUS CRISTATUS AND T. MARMORATUS IN WESTERN FRANCE. AB - Two hybridizing species of newts, Triturus cristatus and T. marmoratus, with overlapping distributions show a parapatric distribution when surveyed in detail. The factors that govern the distribution of cristatus vs. marmoratus in the departement (province) of Mayenne in western France are identified as forestation and relief. The parapatric hybrid zone running through Mayenne is narrow but widens to approximately 20 km in an area with mixed habitat. In this area most breeding sites are shared and F1 hybrids form about 4% of the total population. Analysis of survey data collected about 30 years previously also shows an essentially parapatric distribution. Comparison of past and present distribution maps reveals that cristatus has superseded marmoratus over large areas in the south of Mayenne. An area where marmoratus replaced cristatus also exists, but it is more limited in size. Gene flow between cristatus and marmoratus is analyzed using 10 diagnostic genetic markers [9 protein loci and mitochondrial (mt) DNA]. In syntopic populations nuclear gene flow is bidirectional with a mean frequency of introgressed alleles (f) of 0.3%. In allotopic populations of cristatus and marmoratus gene flow is present in areas of species replacement (f = 0.3%), while gene flow appears to be absent in those areas that have been continuously occupied by a single species. At the biogeographic level, the presence or absence of introgression is paralleled by the persistence or absence, respectively, of pockets of cristatus-marmoratus syntopy. All F1 hybrids possess the cristatus type mtDNA. This may be due to asymmetric interspecific mate choice and would explain the observed absence of introgression of the maternally inherited mtDNA genome in areas where cristatus replaced marmoratus. The cristatus-marmoratus hybrid zone bears characteristics of both the clinal (parapatric) hybrid zone model and the mosaic hybrid zone model. Such a mixed model-for which we propose the term "reticulate hybrid zone"-can be appreciated only if studied over a two dimensional geographic area and also through time. PMID- 28564050 TI - PHENOTYPE FIXATION AND GENOTYPIC DIVERSITY IN THE COMPLEX LIFE CYCLE OF THE APHID PEMPHIGUS BETAE. AB - The aphid Pemphigus betae typically shows a complex life cycle, with annual alternation between cottonwood trees, where it forms leaf galls, and herbaceous plants, where it lives on roots. Distinct phenotypes are associated with each phase. In a population in Utah, aphid clones vary in their tendencies to undergo the cottonwood phase of the life cycle, with certain clones rarely producing the winged migrants that initiate the cottonwood phase. To examine the extent of genotypic variability in life cycle traits and to determine the consequences of phase deletion for fitness in the remaining phase of the life cycle, I compared performances of sets of clones that differed in their tendencies to delete the cottonwood phase. Performances of 35 aphid clones were compared on root hosts in the laboratory, by quantifying size (a correlate of fecundity), developmental time, and mortality for clonal sublines. Clones that tend to delete the cottonwood phase and remain on roots developed faster, showed lower mortality, and were larger as compared to clones that tend to undergo an annual migration to cottonwood. These laboratory comparisons of individual clones agree with earlier findings from field experiments. Performance also varied significantly among clones within sets, with the set of clones not previously subjected to selection on root hosts showing higher variance than clones isolated following selection in the root-inhabiting phase. These data suggest that selection in the cottonwood phase opposes selection in the root phase. Thus, even in cases of polyphenism, in which divergent developmental pathways confer some independence of phenotypic expression in alternative phases, antagonistic pleiotropy limits adaptation within a phase. These findings on the correlates of intrapopulational variation in frequency of phase expression provide some of the best evidence for character release following reduction of a complex life cycle, and they support the hypothesis that the advantages of polyphenism may be limited by negative genetic correlations among fitness traits of alternative phenotypes. PMID- 28564051 TI - SELECTION OF BENEVOLENCE IN A HOST-PARASITE SYSTEM. AB - A paradigm for the evolution of cooperation between parasites and their hosts argues that the mode of parasite transmission is critical to the long-term maintenance of cooperation. Cooperation is not expected to be maintained whenever the chief mode of transmission is horizontal: a parasite's progeny infect hosts unrelated to their parent's host. Cooperation is expected to be maintained if the chief mode of transmission is vertical: a parasite's progeny infect only the parent's host or descendants of that host. This paradigm was tested using bacteria and filamentous bacteriophage (f1). When cells harboring different variants of these phage were cultured so that no infectious spread was allowed, ensuring that all parasite transmission was vertical, selection favored the variants that were most benevolent to the host-those that least harmed host growth rate. By changing the culture conditions so that horizontal spread of the phage was allowed, the selective advantage of the benevolent forms was lost. These experiments thus support the theoretical arguments that mode of transmission is a major determinant in the evolution of cooperation between a parasite and its host. PMID- 28564052 TI - PHYLOGEOGRAPHIC STRUCTURE IN MITOCHONDRIAL DNA OF THE LAKE WHITEFISH (COREGONUS CLUPEAFORMIS) AND ITS RELATION TO PLEISTOCENE GLACIATIONS. AB - Restriction-fragment length polymorphisms were employed to evaluate the phylogenetic relationships, the genetic diversity and the geographic structure in mitochondrial DNA (mtDNA) lineages of the lake whitefish, Coregonus clupeaformis. Thirteen restriction enzymes that produced 148 restriction fragments were used to assay mtDNAs of 525 specimens collected among 41 populations. The sampling covered the entire range of the species, from Alaska to Labrador. Four distinct phylogeographic assemblages were identified. The Beringian assemblage, confined to Yukon and Alaska, was phylogenetically distinct from other assemblages and exhibited the highest level of nucleotide diversity. The Acadian assemblage was confined to southeastern North America and composed of a unique mtDNA clade. The Atlantic assemblage was confined to southern Quebec and the northeastern United States and was also observed among anadromous populations of northern Hudson Bay. This group was highly polymorphic and responsible for most of the mtDNA diversity observed outside Beringia. The Mississippian assemblage occupied most of the actual range of lake whitefish, from the Mackenzie delta to Labrador. Ninety-two percent of all whitefish of this proposed origin belonged to a single mtDNA haplotype. Overall, the diversity, the geographic structure and the times of divergence of mtDNA phylogenetic assemblages correlate with the Pleistocene glaciations classically assumed to have dramatically altered the genetic diversity of northern fishes in recent evolutionary times. Our results emphasize the dominant role of these catastrophic events in shaping the population genetic structure of lake whitefish. PMID- 28564053 TI - THE EXTENT OF INTROGRESSION OUTSIDE THE CONTACT ZONE BETWEEN NOTROPIS CORNUTUS AND NOTROPIS CHRYSOCEPHALUS (TELEOSTEI: CYPRINIDAE). AB - The cyprinid fishes, Notropis cornutus and N. chrysocephalus, hybridize in a long, narrow zone in the midwestern United States. To quantify the extent of introgression of genetic markers outside of this zone, samples were collected along transects starting near the region of contact (as defined by morphological characters), followed by samples progressively more distant. Diagnostic allozymic and mitochondrial DNA (mtDNA) restriction site markers were used to estimate the extent of introgression outside of the zone, while polymorphic allozyme and mtDNA markers were used to evaluate the potential for gene flow among populations within transects. Analysis of populations from the northern transect provided evidence for differentiation of populations for some of the markers; however, on average, enough gene flow has occurred to overcome substantial differentiation. Introgressed mtDNA and allozyme haplotypes were rare and found only in the population closest to the contact zone. The rarity of introgressed alleles in the more northern populations is consistent with the recent origin of these populations after the Wisconsin glaciation (less than 12,000 years bp) and/or selection maintaining the northern boundary of the contact zone. Analysis of populations from the southern transect revealed evidence for population subdivision but no evidence for introgression at the diagnostic allozyme loci; however, nearly all individuals from this transect possessed introgressed mtDNA haplotypes, with samples furthest from the contact zone exhibiting the highest frequencies of introgression. Patterns of variation for one of the polymorphic allozyme markers (Est-A) and introgressed mtDNAs were highly correlated, suggesting that allozymic heterogeneity at this locus is also the result of introgression. The most likely explanation for these data is that these introgressed haplotypes are indicators of a more southern position of the contact zone during the Pleistocene, with the contact zone shifting northward with the recession of the glacial front. Such movement implicates selection in the maintenance of distributional limits of these species, and hence, the width and position of the contact zone. PMID- 28564054 TI - A TEST OF THE SEQUENTIAL ASSESSMENT GAME: FIGHTING IN THE BOWL AND DOILY SPIDER FRONTINELLA PYRAMITELA. AB - Male bowl and doily spiders (Frontinella pyramitela: Linyphiidae) engage in dangerous fights over access to females. Relatively smaller individuals are more at risk of fatal injury than their larger opponents. Males assess relative fighting ability during contests: smaller individuals tend to give up quickly. Fights occur between a male with information about the value of the contested female (number of fertilizable eggs) and an intruding male with less information. In this paper, a sequential assessment game (a game theory model of fighting behavior) is adapted to male combat in the bowl and doily spider to attempt a quantitative test. The model makes predictions about fight duration, probability of winning, and the occurrence of fatalities as a function of resource value and size asymmetry. Comparison with empirical data from staged contests yields a generally good quantitative agreement with the predictions. A few deviations are also noted. PMID- 28564055 TI - HERITABLE VARIATION IN RESOURCE UTILIZATION AND RESPONSE IN A WINERY POPULATION OF DROSOPHILA MELANOGASTER. AB - It has been found that Drosophila melanogaster lines from the "Chateau Tahbilk" winery cellar had higher larval ethanol resistance than lines originating from outside the cellar. Because the adaptive significance of this trait is unclear, we have reexamined genetic microdifferentiation at Tahbilk with other resources and different tests for ethanol adaptation. Cellar stocks tended to be more resistant to starvation after exposure to wine seepage than stocks originating from orchard traps outside the cellar. Lines from a grape residue pile were also more resistant to starvation after seepage exposure than orchard stocks even though these collection sites were a few meters apart. Cellar and orchard stocks did not differ in ethanol resistance as measured by larval viability tests on low sucrose medium. However, stocks from the grape residue pile showed an increase in adult longevity over ethanol vapor compared to those from the cellar or orchard stocks. These differences were not due to maternal effects. In laboratory tests of behavioral responses, cellar stocks were relatively more attracted to seepage than orchard stocks in one year but not in the other two years. The findings suggest some adaptive differentiation related to resource heterogeneity at Tahbilk. PMID- 28564056 TI - EVOLUTION OF PLUMAGE COLOR IN MALE PIED FLYCATCHERS (FICEDULA HYPOLEUCA): EVIDENCE FOR FEMALE MIMICRY. AB - We present the first evidence for sexual deception by female mimicry in birds. Using live, caged birds we show that territorial male pied flycatchers behave aggressively toward bright-colored males but display sexually toward female-like male intruders. We also show that the males that are fooled are those that lack recent sexual experience. All male pied flycatchers are dull-colored in winter. It is possible that young males are more constrained during the spring molt than older males since the former are more dull-colored in spring. According to the molt-constraints hypothesis a subadult plumage would be maladaptive in the breeding season. Analysis of male settling pattern at breeding sites in spring suggests that brownish males are allowed to settle closer to already-established males than dark-colored males. This result suggests an adaptive value of having a subadult plumage color, in particular for young males arriving late from spring migration. However, we also show that mimicry incurs a cost, that of increased aggression from females, which may explain why female-like males have reduced mating success. PMID- 28564057 TI - DISPERSAL AND GENETIC STRUCTURE IN KANGAROO RATS. AB - We used spatial autocorrelation of allele frequencies to examine local structure in a population of bannertailed kangaroo rats for which Wright's isolation-by distance model seems applicable, and for which we can estimate neighborhood size based on 10 years of data on demography and dispersal. The uniform dispersion and strong philopatric tendencies of this species provide a test case for the idea that restricted dispersal can lead to local genetic structure in small mammals. Whether we considered such complications as nonnormal dispersal distances, variation in lifetime reproductive success, fluctuating population density, and adult as well as juvenile dispersal, our estimate of effective population size was fewer than 15 animals. Nevertheless, data from four polymorphic allozyme loci analyzed over a range of separations between 50 m (approximately one home range diameter) and 1,000 m detected no evidence for spatial clustering of alleles. One resolution of this apparent paradox is that "gamete dispersal," caused by the movements of males away from their residences during the breeding season, may be a significant (and unmeasured) component of gene dispersal. Our analyses also demonstrate that a decline in population density may actually increase neighborhood size. A more general implication is that even extremely philopatric mammals have effective population sizes large enough to prevent the development of local genetic structure. PMID- 28564058 TI - ON THE LOW HERITABILITY OF LIFE-HISTORY TRAITS. AB - Life-history traits such as longevity and fecundity often show low heritability. This is usually interpreted in terms of Fisher's fundamental theorem to mean that populations are near evolutionary equilibrium and genetic variance in total fitness is low. We develop the causal relationship between metric traits and life history traits to show that a life-history trait is expected to have a low heritability whether or not the population is at equilibrium. This is because it is subject to all the environmental variation in the metric traits that affect it plus additional environmental variation. There is no simple prediction regarding levels of additive genetic variance in life-history traits, which may be high at equilibrium. Several other patterns in the inheritance of life-history traits are readily predicted from the causal model. These include the strength of genetic correlations between life-history traits, levels of nonadditive genetic variance, and the inevitability of genotype-environment interaction. PMID- 28564059 TI - GENETIC DIFFERENTIATION AND HETEROZYGOSITY IN PINYON PINE ASSOCIATED WITH RESISTANCE TO HERBIVORY AND ENVIRONMENTAL STRESS. AB - Arizona's Sunset Crater began erupting in 1064 AD and for the next 200 years buried over 2,000 km2 in ash, cinders, and lava. Soil analyses indicate that pinyon pines (Pinus edulis) currently colonizing the cinder fields are faced with a highly stressful environment. Many of these pinyons suffer chronic, intense insect herbivory that reduces plant growth and eliminates female cone production. In contrast, herbivory among pinyons growing in neighboring sandy-loam soils is minimal. Furthermore, numerous trees within the heavily infested cinder field population suffer relatively low herbivory and maintain normal growth and reproduction. We used four polymorphic enzymes to examine the relationship between herbivore attack, environmental stress and genotypes of the adjacent cinder field, and sandy-loam soil pinyon populations. Our results demonstrate that 1) resistant trees display significant genetic differences and are more heterozygous for two enzymes associated with herbivory than susceptible trees; and 2) the cinder-soil pinyons exhibit significant genetic differences and are more heterozygous for an enzyme associated with environmental stress than the neighboring sandy-loam soil pinyons. We conclude that heterozygosity of specific or closely linked loci may facilitate pinyon resistance to herbivory and environmental stress, and that strong selection across narrow geographic boundaries resulted in rapid genetic differentiation of pinyon populations. PMID- 28564060 TI - UTERINE EFFECTS, EPIGENETICS, AND POSTNATAL SKELETAL DEVELOPMENT IN THE MOUSE. AB - Reciprocal embryo transfer experiments show that skeletal dimensions in adult mice are significantly influenced by the genotype of the female providing the uterine environment in which they were raised. Embryo transfers among C3HeB/FeJ, SWR/J, and the C3SWF, hybrid strain (C3H females x SWR males) permit separation of uterine maternal genotype effects from effects arising from the progeny's own genotype. Many different aspects of adult skeletal form are significantly influenced by uterine genotype and, in some instances, the pattern of these effects correlates with events during skeletal embryology. Analyses involving the highly heterozygous C3SWF1 strain demonstrate the existence of significant dominance in maternal genes affecting skeletal development in the progeny. Further, there is a large skeletal effect due to progeny heterosis. Uterine Utter size can be manipulated as a nonheritable component of variability in embryo transfer experiments, and it has a large and systemic effect on skeletal growth and morphogenesis that persists in adult mice. Heritable uterine maternal effects are epigenetic interactions during development that can be incorporated into models of evolutionary change to provide a more complete picture of the causal agents producing morphological change. PMID- 28564061 TI - THE EFFECT OF INBREEDING ON SEED SURVIVORSHIP IN PHLOX. PMID- 28564062 TI - INTROGRESSION OF COYOTE MITOCHONDRIAL DNA INTO SYMPATRIC NORTH AMERICAN GRAY WOLF POPULATIONS. AB - Mitochondrial DNA (mtDNA) genotypes of gray wolves and coyotes from localities throughout North America were determined using restriction fragment length polymorphisms. Of the 13 genotypes found among the wolves, 7 are clearly of coyote origin, indicating that genetic transfer of coyote mtDNA into wolf populations has occurred through hybridization. The transfer of mtDNA appears unidirectional from coyotes into wolves because no coyotes sampled have a wolf derived mtDNA genotype. Wolves possessing coyote-derived genotypes are confined to a contiguous geographic region in Minnesota, Ontario, and Quebec, and the frequency of coyote-type mtDNA in these wolf populations is high (>50%). The ecological history of the hybrid zone suggests that hybridization is taking place in regions where coyotes have only recently become abundant following conversion of forests to farmlands. Dispersing male wolves unable to find conspecific mates may be pairing with female coyotes in deforested areas bordering wolf territories. Our results demonstrate that closely related species of mobile terrestrial vertebrates have the potential for extensive genetic exchange when ecological conditions change suddenly. PMID- 28564063 TI - SEX RATIO IN A NEW SPECIES OF NASONIA WITH FULLY-WINGED MALES. PMID- 28564064 TI - MORPHOMETRIC VARIABILITY IN CONTINENTAL AND ATLANTIC ISLAND POPULATIONS OF CHAFFINCHES (FRINGILLA COELEBS). AB - The magnitudes of phenotypic variances in peripherally isolated populations of common chaffinches (Fringilla coelebs) in the Azores, Madeira, and Canaries relative to their continental source populations in Iberia and Morocco have played a pivotal role in the formulation of competing hypotheses of phenotypic evolution in these isolates. Because Van Valen's niche variation hypothesis and Grant's model of island evolution were based on museum skins prone to measurement error and temporal variation, we re-examined the patterns of phenotypic variability using more precise skeletal measurements from freshly collected specimens. Levene's tests showed that univariate character variances were homogeneous in all island and continental populations, although there was a consistent trend for the magnitude of the variances to be lower for all characters in all Canary island populations. Multivariate Levene's tests, however, revealed significantly reduced total variances in the Hierro and Madeira populations compared to some Azores and continental populations. The Azores and continental populations did not differ in variability, and lower variances in the Canaries were not related to the presence or absence of the congeneric blue chaffinch (F. teydea), contrary to the predictions of Van Valen's niche variation hypothesis. Population variability was not inversely related to differentiation or isolation within the Azores or Canaries archipelagoes, opposite to the association reported by Grant. Our results also differ from both previous studies which reported much larger differences in population variabilities, and this likely reflects the use of heterogeneous samples of museum specimens, less precise external characters, and the use of tests sensitive to sample size. Differentiation among populations has been markedly greater in the Canary islands, implicating founder events and possibly historically stronger directional selection as determinants of this enhanced divergence relative to the Azores. These variance-reducing processes are unlikely to explain current lower levels of phenotypic variability because there has been sufficient time since colonization for replenishment of variability in polygenic characters. Average heterozygosities at putatively neutral allozyme loci are 1.6 times higher in the Azores compared to the Canaries, and support the view that effective population sizes are smaller in the latter archipelago. We argue that reduced variances in the Canary island populations represent lower equilibrium levels maintained by drift and mutation in populations with smaller long-term effective sizes, consistent with Lynch and Hill's neutral model of phenotypic evolution. Although episodes of selection in the past may have been interspersed with long periods of effective neutralism and drift, adaptationist hypotheses invoking a primary role for variance-reducing selection appear to be unwarranted. PMID- 28564065 TI - TESTING INFERENCES ABOUT MICRO-EVOLUTIONARY PROCESSES BY MEANS OF SPATIAL AUTOCORRELATION ANALYSIS. AB - We generated numerous simulated gene-frequency surfaces subjected to 200 generations of isolation by distance with, in some cases, added migration or selection. From these surfaces we assembled six data sets comprising from 12 to 15 independent allele-frequency surfaces, to simulate biologically plausible population samples. The purpose of the study was to investigate whether spatial autocorrelation analysis will correctly infer the microevolutionary processes involved in each data set. The correspondence between the simulated processes and the inferences made concerning them is close for five of the six data sets. Errors in inference occurred when the effect of migration was weak, due to low gene frequency differential or low migration strength; when selection was weak and against a background with a complex pattern; and when a random process isolation by distance-was the only one acting. Spatial correlograms proved more sensitive to detecting trends than inspection of gene-frequency surfaces by the human eye. Joint interpretation of the correlograms and their clusters proved most reliable in leading to the correct inference. The inspection and clustering of surfaces were useful for determining directional components. Because this method relies on common patterns across loci, as many gene frequencies as feasible should be used. We recommend spatial autocorrelation analysis for the detection of microevolutionary processes in natural populations. PMID- 28564066 TI - SELECTION ON COPULATION DURATION IN DROSOPHILA MELANOGASTER: PREDICTABILITY OF DIRECT RESPONSE VERSUS UNPREDICTABILITY OF CORRELATED RESPONSE. AB - Estimates of heritabilities and genetic correlations for seven reproductive attributes had previously been obtained from parent-offspring regression (Gromko, 1987, 1989). Copulation duration was shown to have a heritability of 0.23 and to be genetically correlated with courtship vigor (rA = -0.41) and with fertility (rA = 0.27). These observations form the basis for the prediction of direct and correlated responses to selection for increased and decreased copulation duration, which are reported here. The direct response corresponded closely to prediction, but the correlated responses did not provide consistent qualitative fit. A hypothesis is proposed to explain this difference in predictability of direct and correlated response to selection. The major postulate is that the different polygenes involved in the direct response to selection for copulation duration have different pleiotropic effects. PMID- 28564067 TI - HOST-PATHOGEN INTERACTIONS IN NATURAL POPULATIONS OF LINUM MARGINALE AND MELAMPSORA LINI: I. PATTERNS OF RESISTANCE AND RACIAL VARIATION IN A LARGE HOST POPULATION. AB - Populations of wild flax, Linum marginale and its associated rust fungus Melampsora lini growing at Kiandra, New South Wales, Australia, were sampled during the 1986-1987 growing season. Thirteen different races of M. lini were detected in a sample of 96 isolates. The distribution of isolates was uneven: race A comprised 73% of the samples; race N, 8%; and race H, 5%; while the remaining races were represented by only one or two samples. The dominance of race A increased over the course of the growing season, comprising 67% of the early season samples and increasing to 78% for those collected late in the season. The overall diversity of the pathogen population decreased late in the growing season, but this trend was not statistically significant. The average virulence of individual isolates of the pathogen population increased during the growing season. This trend was most pronounced among the minor races, where the mean number of differential hosts infected increased from 4.58 for early season samples to 5.12 and 5.08 for mid and late season samples, respectively. In contrast to the virulence pattern in the pathogen, the L. marginale population displayed a more even distribution of resistance. In a sample of 67 plants 10 resistance phenotypes were detected from their pattern of resistance/susceptibility to seven pathogen isolates. No phenotype had a frequency that exceeded 30%. Resistance phenotypes were randomly distributed on both a population level and on a fine scale. PMID- 28564068 TI - EVOLUTIONARY RESPONSE OF PREDATORS TO DANGEROUS PREY-REDUCTION OF TOXICITY OF NEWTS AND RESISTANCE OF GARTER SNAKES IN ISLAND POPULATIONS. PMID- 28564069 TI - MALE DIMORPHISMS IN BEETLES AND EARWIGS AND THE QUESTION OF DEVELOPMENTAL CONSTRAINTS. AB - Analysis of 17 species from six families indicates that male dimorphisms in weapon design may be common, at least in homed beetles. This flexibility in developmental programs constitutes evidence against the idea that the forms of these animals' weapons are the result of developmental constraints. PMID- 28564070 TI - THE COMPARISON OF QUANTITATIVE GENETIC PARAMETERS BETWEEN POPULATIONS. AB - A statistical method for comparing matrices of genetic variation and covariation between groups (e.g., species, populations, a single population grown in distinct environments) is proposed. This maximum-likelihood method provides a test of the overall null hypothesis that two covariance component matrices are identical. Moreover, when the overall null hypothesis is rejected, the method provides a framework for isolating the particular components that differ significantly between the groups. Simulation studies reveal that discouragingly large experiments are necessary to obtain acceptable power for comparing genetic covariance component matrices. For example, even in cases of a single trait measured on 900 individuals in a nested design of 100 sires and three dams per sire in each population, the power was only about 0.5 when additive genetic variance differed by a factor of 2.5. Nevertheless, this flexible method makes valid comparison of covariance component matrices possible. PMID- 28564071 TI - EVOLUTION OF BIPARENTAL CARE IN THE HERMAPHRODITIC POLYCHAETE WORM OPHRYOTROCHA DIADEMA. AB - Ophryotrocha diadema is a simultaneously hermaphroditic polychaete worm with a brief adolescent protandrous phase. In the mating system of this worm, pairs are formed preferentially between simultaneous hermaphrodites. Both partners of a pair regularly alternate sex roles, reciprocate egg exchange, and care for developing embryos. It was experimentally shown that neglected eggs have a 31% probability of dying, but eggs cared for by both parents, by a single parent, or even by an unrelated individual have a 95% probability of developing. In pairs experimentally prevented from caring for eggs, intruders succeeded in substituting one of the partners significantly more frequently than in pairs allowed to care for eggs. Thus, the main adaptive value of biparental care would be to guarantee a partner for egg reciprocation. Protandrous males are inefficient brooders, and biparental care becomes fully established only when individuals are able to reciprocate egg exchange, i.e., they have reached the simultaneously hermaphroditic stage. PMID- 28564072 TI - GENETIC VARIATION IN A FUNGAL PATHOGEN: RESPONSE TO HOST DEFENSIVE CHEMICALS. AB - In response to infection by shoot infecting pathogens, Scots pine releases cortical resin into affected tissues. The resin contains a mixture of monoterpene compounds (alpha-pinene, beta-pinene, 3-carene, beta-myrcene, limonene and beta phellandrene) that retard the growth of a range of pathogens. The proportion of each monoterpene in the resin shows substantial variation among trees within a population. Thus pathogens on different trees encounter quite different monoterpene environments. To investigate the evolutionary response of pathogens to the chemically heterogeneous environment provided by Scots pine, isolates of the ascomycete canker pathogen Crumenulopsis sororia were collected from trees within a range of natural Scots pine populations. Growth rates of these isolates were measured in the presence and absence of five host monoterpenes. Substantial heritable variation for growth rate in the presence and absence of monoterpenes, and for monoterpene tolerance was recorded, suggesting the potential for the evolution of chemically specialized pathogen subpopulations on different trees within a wood. However, genetic correlations between growth rates in different monoterpene environments and between tolerance of different monoterpenes were either positive or non-significant, and there was no evidence of "tradeoffs" in performance under different monoterpene regimes. The results suggest that, on its own, the presence of monoterpene variability within Scots pine will not lead to disruptive selection on the C. sororia population. The relationship between defensive chemical diversity and pest resistance is discussed in the light of these results. PMID- 28564073 TI - REPTILIAN PHYSIOLOGY AND THE FLIGHT CAPACITY OF ARCHAEOPTERYX. AB - Current scenarios frequently interpret the Late Jurassic bird Archaeopteryx as having had an avian-type physiology and as having been capable of flapping flight, but only from "the trees downward." It putatively lacked capacity for takeoff and powered flight from the ground upward. Data from extant reptiles indicate that if Archaeopteryx were physiologically reptilian, it would have been capable of ground upward takeoff from a standstill, as well as "trees downward" powered flight. This conclusion is based largely on a previously unrecognized attribute of locomotory (skeletal) muscle in a variety of extant reptiles: During "burst-level" activity, major locomotory muscles of a number of active terrestrial taxa generate at least twice the power (watts kg-1 muscle tissue) as those of birds and mammals. Reptilian physiological status also helps resolve the apparently uneven development of various flight support structures in Archaeopteryx (e.g., well-developed flight features but relatively unspecialized pectoral girdle, supracoracoideus muscles, etc.). Endothermy and capacity for longer-distance powered flight probably evolved only in Early Cretaceous birds, which were the first birds to have a keeled sternum, strap-like coracoid, and hypocleidium-bearing furcula. PMID- 28564074 TI - SPERM-MEDIATED GENE FLOW AND THE GENETIC STRUCTURE OF A POPULATION OF THE COLONIAL ASCIDIAN BOTRYLLUS SCHLOSSERI. AB - The genetic structure of populations of sessile and sedentary organisms is often characterized by microgeographic differentiation in gene frequencies and deviations from panmixia. In many terrestrial botanical systems, restricted gene flow via seed and pollen dispersal may have an important role in promoting such genetic patterns. Until recently, however, limited dispersal of the sexual propagules of benthic invertebrates has not been considered to play a comparable role in aquatic systems. Based on paternity analyses in the field using rare allozyme markers, it appears that concentrations of sibling sperm of the sessile, colonial ascidian Botryllus schlosseri decline rapidly within 50 cm of a source colony. In combination with spatially restricted dispersal of brooded larvae, limited dispersal of sperm should enhance the potential for genetic diversification and inbreeding. However, analysis of allelic and genotypic frequencies at three independent, polymorphic allozyme loci using F-statistics provides little evidence for microgeographic variation in gene frequencies. This lack of differentiation can be explained in terms of the absolute number (rather than concentration) of gametes and larvae dispersing from a point source, which depending on diffusion and geometric assumptions-may actually increase with distance. In contrast to the absence of differentiation, levels of inbreeding are high, even within the confines of 25 times 25-cm quadrats. The absence of genetic diversification and presence of inbreeding caution against inferring levels and causes of gene flow from indirect analysis of genetic structure and, conversely, making predictions about genetic and breeding structure based solely on direct analysis of gene flow. PMID- 28564075 TI - NATAL DISPERSAL AND POPULATION STRUCTURE IN A MIGRATORY SONGBIRD, THE INDIGO BUNTING. AB - Male and female indigo buntings (Passerina cyanea) were equally likely to return and breed in their natal areas. The distances and number of territories between natal and breeding sites were similar between the sexes. The breeding site was not limited by prior occupation of sites by breeding adults closer to the natal territory. Dispersal distances were independent of whether parents or siblings of either sex returned in the same year. Variation in distance within the natal area appeared to be independent of local population density, social competition, active kin recognition, and avoidance of incest, but was affected by date of birth. The local distribution of dispersal distances approximated a neutral model with a decreasing probability of settling with distance from the natal site. A population inbreeding coefficient DeltaF of 0.01 was estimated from known genealogies and matings. The proportion of nestlings recaptured in a later year on their natal area was 1.65% of 1,212 nestlings at the George Reserve and 8.78% of 1,332 nestlings at Niles. Locally born birds comprised 1.6% and 13.0% of the breeding population in areas of 10 and 4 km2 . Evidently most buntings settle and breed more than 2 km from their natal site. The results are inconsistent with predictions of social and avoidance-of-inbreeding hypotheses that are based on the local natal demographic environment. The results are consistent with a model of neutral dispersal within a genetically open population. PMID- 28564076 TI - MICROGEOGRAPHIC GENETIC STRUCTURE OF MORPHOLOGICAL AND LIFE HISTORY TRAITS IN A NATURAL POPULATION OF IMPATIENS CAPENSIS. AB - To investigate the microgeographic spatial structure of genetic variation for quantitative traits in a natural population of Impatiens capensis, we performed a common-garden greenhouse experiment. Seedlings were collected at 10-m intervals from a 40 times 40-m permanent grid in a natural population and grown to maturity in a greenhouse. From these parents, 3 self-fertilized seed families per grid point were then grown in a randomized design in the greenhouse and scored for a variety of morphological and life-history traits. Virtually all of the traits displayed significant variation among families, and many were significantly heterogeneous among grid points, indicating microgeographic genetic differentiation on a fine spatial scale. Overall morphological divergence, measured as Mahalanobis distances between grid points, increased with geographical distance. In general, spatial autocorrelation coefficients of grid point character means were positive at 11-20 m and negative beyond 40 m, although power for significance testing was low. The first factor in a principal component analysis of grid point means was positively loaded on height-related traits and negatively loaded on total reproduction at 50 days, accounting for 31% of the variation. This factor displayed significant positive spatial autocorrelation at 11-20 m and negative autocorrelation at >40 m. The remaining factors showed no detectable spatial structuring among grid points. These differences in spatial pattern among characters suggest that forces other than drift may have influenced the genetic structure of the population. There was no evidence for density dependent selection; seedling density was not significantly correlated with the grid point mean of any trait. PMID- 28564077 TI - COUNTERVAILING SELECTION IN DIFFERENT FITNESS COMPONENTS IN FEMALE RED DEER. AB - In individually monitored red deer (Cervus elaphus) living in the North Block of the Isle of Rhum, Scotland, juvenile survival is related to the genotype at the enzyme loci Mpi and Idh-2 (each with two alleles, f and s). To establish whether other fitness components also are related to genetic differences, we examined whether age at first breeding, fecundity, and adult survival of females were related to genotype at the same loci. Fertility in females shot outside the study area was also analyzed in relation to Mpi and Idh-2 genotype. The analyses controlled for phenotypic and environmental factors affecting female reproductive performance. At Mpi, f-carrying females in the study area bred earlier than ss individuals and tended to be more fecund. However, no association was found between Mpi genotype and adult survival. In culled females, Mpi f-carriers were more likely to be pregnant than ss females. At Idh-2, homozygous females in the study area started breeding earlier than heterozygous females. Idh-2 fs and ss females were more fecund than ff females though this relationship was complicated by an interaction with spring temperature in the year of birth. When the population was at high density, adult survival of Idh-2 ss females was better than survival of ff females, which was, in turn, better than survival of fs females. No association was found between Idh-2 genotype and fertility in culled females. Overall, the associations found in female reproductive measures favor those genotypes that survive particularly badly over the first two years of life. This result supports the idea that countervailing selection in different fitness components (antagonistic pleiotropy) is a common and powerful force maintaining polymorphism in natural populations. It may also explain how fitness components can have large heritabilities while overall fitness may have a low heritability. PMID- 28564078 TI - VARIATION IN MITOCHONDRIAL DNA OF AEDES SPECIES (DIPTERA: CULICIDAE). AB - Relationships among seven species of the Aedes scutellaris subgroup and four of the Aedes albopictus subgroup were determined using restriction fragment analysis of mtDNA. Considerable polymorphism was found among species, with an average proportion of 0.338 restriction fragments being shared among them. Fitch Margoliash, Wagner parsimony and UPGMA analyses revealed that the phylogeny based on mtDNA was only partially congruent with that based on allozymes and morphology. All three analyses, however, suggested that three species pairs, A. flavopictus-A. pseudalbopictus, A. pseudoscutellaris-A. riversi, and A. albopictus-A. polynesiensis were monophyletic with regard to their mtDNA. The results indicated that although the species in the A. scutellaris and the A. albopictus subgroups do not exhibit significant morphological divergence, their mtDNA has diverged extensively. PMID- 28564079 TI - RANDOM OFFSPRING MORTALITY AND VARIATION IN PARENTAL FITNESS. PMID- 28564080 TI - EVOLUTIONARILY STABLE MORPHOLOGIES IN PEA POPULATIONS. AB - We investigated the hypothesis that plant form can dramatically affect plant competitive ability, and that forms with dense canopies can invade populations of plants with more open canopies regardless of initial relative frequencies. Under controlled field conditions, we examined the effects of plant form on growth rate, size variation, mortality, and reproduction in high-density monocultures and mixtures of two morphologically distinct varieties of peas. These two varieties differ genetically at only the afila locus. In high-density monocultures and mixtures, peas with finely dissected, minute leaflets (af/af) grew more slowly and produced fewer seeds than Af/-individuals with large leaflets that cast more shade on neighbors. After as few as four generations, mixtures begun with 10% Af/- peas would be expected to evolve to Af/- monocultures. We conclude that an increase in morphological complexity (e.g., virtually leafless to leafy) can have dramatic ecological and evolutionary impacts on plant population dynamics. PMID- 28564081 TI - QUANTITATIVE GENETICS OF FITNESS TRAITS IN A WILD POPULATION OF PHLOX. AB - To determine if the evolution of fitness traits in the annual plant, Phlox drummondii, is constrained by lack of genetic variation, we calculated the heritability and genetic correlation of 16 traits in a field population. Full- and half-sib families of seeds were generated in the greenhouse and planted back into the study population. Of 855 seeds that germinated, 609 survived to produce fruit. For each plant we measured several aspects of plant size and three components of female fecundity: total number of fruits produced, number of seeds per fruit, and mass of individual seeds. Heritability of traits ranged from 0.00 to 0.15. Several traits showed significant levels of additive genetic variance, but we found no evidence of additive genetic variance in components of female fecundity and no evidence of negative genetic correlation between fitness traits. These results suggest that evolution in this population would be constrained by lack of heritable variation in fitness traits. PMID- 28564082 TI - CHAOBORUS PREDATION AND LIFE-HISTORY EVOLUTION IN DAPHNIA PULEX: TEMPORAL PATTERN OF POPULATION DIVERSITY, FITNESS, AND MEAN LIFE HISTORY. AB - The effect of predation by the aquatic dipteran larva Chaoborus americanus on genetic diversity and life-history evolution in the cladoceran Daphnia pulex was investigated in large replicate laboratory populations. Instantaneous daily loss rates of clonal diversity and genetic variance for fitness indicate that 93-99% of initial genetic diversity can be removed from populations during the 8-12 generations of clonal reproduction that occur each year in natural populations. In the absence of predation, the principal evolved changes in mean population life history were smaller immature body size and increased and earlier fecundity. In the presence of size-selective Chaoborus predation, populations evolved toward larger body size and increased and earlier reproduction. The difference between these two trajectories is an estimate of the direct additive effect of Chaoborus predation. This effect was manifested as evolution toward larger body size with a trend toward earlier and increased reproduction. PMID- 28564083 TI - PHYLOGENETIC RELATIONSHIPS OF NORTH AMERICAN URSIDS BASED ON ANALYSIS OF MITOCHONDRIAL DNA. PMID- 28564084 TI - ISLAND AREA AND BODY SIZE OF INSULAR MAMMALS: EVIDENCE FROM THE TRI-COLORED SQUIRREL (CALLOSCIURUS PREVOSTI) OF SOUTHEAST ASIA. PMID- 28564085 TI - GENETIC DIFFERENTIATION BETWEEN SPECIES OF THE GENUS SPEYERIA (LEPIDOPTERA: NYMPHALIDAE). PMID- 28564086 TI - SELECTION FOR TRYPTOPHAN AUXOTROPHS OF ESCHERICHIA COLI IN GLUCOSE-LIMITED CHEMOSTATS AS A TEST OF THE ENERGY CONSERVATION HYPOTHESIS OF EVOLUTION. PMID- 28564087 TI - THE EVOLUTION OF GYNODIOECY AND SUBDIOECY. PMID- 28564089 TI - EVOLUTIONARY MECHANISMS OF LIMB LOSS IN TETRAPODS. PMID- 28564088 TI - SELECTION AT ELECTROPHORETIC LOCI FOR REPRODUCTIVE PARAMETERS IN ISLAND AND MAINLAND VOLES. PMID- 28564090 TI - GENIC VARIABILITY IN THE LONGNOSE DACE, RHINICHTHYS CATARACTAE. PMID- 28564091 TI - A NOTE ON GILLESPIE'S MODEL OF ENZYME VARIATION IN NATURAL POPULATIONS. PMID- 28564092 TI - GENETIC POLYMORPHISM AND PHYLOGENY OF DROSOPHILA SUBOBSCURA. PMID- 28564093 TI - GENETIC VARIATION IN ISOLATED POPULATIONS OF THE AUSTRALIAN BUSH-RAT, RATTUS FUSCIPES. PMID- 28564094 TI - EVOLUTION OF WILD SHEEP IN IRAN. PMID- 28564095 TI - GENETIC DIFFERENTIATION IN SALAMANDERS OF THE DESMOGNATHUS OCHROPHAEUS COMPLEX (PLETHODONTIDAE). PMID- 28564096 TI - DIRECTIONAL REDUCTION OF LACTATE DEHYDROGENASE ISOZYMES IN TELEOSTS. PMID- 28564097 TI - THE COMPETITIVE RELATIONSHIP OF THREE WOODLAND SEDGES AND ITS BEARING ON THE EVOLUTION OF ANT-DISPERSAL OF CAREX PEDUNCULATA. PMID- 28564098 TI - POLLINATOR CONSTANCY AS A PRE-POLLINATION ISOLATING MECHANISM BETWEEN SYMPATRIC SPECIES OF CERCIDIUM. PMID- 28564099 TI - ON THE EVOLUTION OF LITTER SIZE IN PEROMYSCUS LEUCOPUS. PMID- 28564100 TI - Correction. PMID- 28564101 TI - THERMAL RELATIONS AND NATURAL SELECTION BY CLIMATE. PMID- 28564102 TI - Photoactivation of Anticancer Ru Complexes in Deep Tissue: How Deep Can We Go? AB - Activation of anticancer therapeutics such as ruthenium (Ru) complexes is currently a topic of intense investigation. The success of phototherapy relies on photoactivation of therapeutics after the light passes through skin and tissue. In this paper, the photoactivation of anticancer Ru complexes with 671-nm red light through tissue of different thicknesses was studied. Four photoactivatable Ru complexes with different absorption wavelengths were synthesized. Two of them (Ru3 and Ru4) were responsive to wavelengths in the "therapeutic window" (650-900 nm) and could be activated using 671-nm red light after passing through tissue up to 16-mm-thick. The other two (Ru1 and Ru2) could not be activated using red light. Additionally, activated Ru4 caused inhibition of cancer cells. These results suggest that photoactivatable Ru complexes are promising for applications in deep-tissue phototherapy. PMID- 28564103 TI - QUANTITATIVE GENETICS OF SURVIVAL AND GROWTH IN IMPATIENS CAPENSIS. AB - When variation in life-history characters is caused by many genes of small effect, then quantitative-genetic parameters may quantify constraints on rate and direction of microevolutionary change. I estimated heritabilities and genetic correlations for 16 life-history and morphological characters in two populations of Impatiens capensis, a partially self-pollinating herbaceous annual. The Madison population had little or no additive genetic variance for any of these characters, while the Milwaukee population had significant narrowsense heritabilities and genetic correlations for several traits, including adult size, which is highly correlated with fitness. All genetic correlations among fitness components were positive, hence there is no evidence for antagonistic pleiotropy among these traits. Dissimilarity of heritabilities in the two populations supports theoretical predictions that long-term changes in genetic variance covariance patterns may occur when population sizes are small and selection is strong, as may occur in many plant species. PMID- 28564104 TI - DO FLIES ADAPT? PMID- 28564105 TI - A ZONE OF OVERLAP AND HYBRIDIZATION BETWEEN TWO GROUND CRICKET SPECIES. AB - In this paper I describe a zone of overlap and hybridization between the ground crickets, Allonemobius fasciatus and A. socius (Orthoptera: Gryllidae). The former occurs in the northeastern United States, the latter is found in the southeastern United States. They meet in a contact zone of variable width that extends from the East Coast to at least Ohio. In the Allegheny Mountains, where appropriate habitats for a species adapted to a northern climate and a species adapted to a southern climate are patchily distributed and widely intermingled, the zone is broad-at least 200 km. Along the coastal plain of New Jersey, where appropriate habitats are not as widely intermingled, the zone is comparatively narrow (5-100 km). Levels of hybridization were assessed by analyzing electrophoretic data, using population genetic models and a character index approach. Both methods of data analysis agreed-where the zone is broader, levels of hybridization appear reduced. PMID- 28564106 TI - GENETIC AND ENVIRONMENTAL BASIS OF VARIABLE SEX RATIOS IN LABORATORY STRAINS OF POECILIOPSIS LUCIDA. AB - Skewed sex ratios are common among several species of Poeciliopsis, a viviparous fish from northwestern Mexico. Since previous, unrelated studies from this laboratory (Angus and Schultz, 1983) suggested that deviation from a 1:1 sex ratio might be influenced by temperature, two inbred strains of P. lucida were tested for temperature-dependent sex determination by comparing sex ratios of offspring from pregnant females held at different water temperatures. Different sex ratios were produced by the two strains at the same temperature: one strain produced almost all-male offspring at 30 degrees C and female-biased sex ratios at 24 degrees C, while the other strain produced a 1:1 sex ratio at both temperatures. At intermediate temperatures, the labile strain produced sequentially fewer males with decreasing temperatures. The other strain produced a consistent sex ratio regardless of temperature. Poeciliopsis lucida apparently has a genetic polymorphism for temperature-influenced sex determination. An hypothesis is offered for the evolutionary origin of environmental sex determination. PMID- 28564107 TI - MORPHOLOGICAL VARIABILITY AND ASYMMETRY IN THE CHEETAH (ACINONYX JUBATUS), A GENETICALLY UNIFORM SPECIES. AB - The African cheetah (Acinonyx jubatus) is an unusual species because of its extremely low amount of biochemical genetic variation. A comparative analysis of morphological variation of 16 cranial characters from four species of Felidae (ocelot, Leopardus pardalus; margay, L. wiedii; leopard, Panthera pardus; and cheetah) was undertaken to evaluate the consequence of biochemical monomorphism on morphological variation. The species were selected because the cheetah has been shown previously to possess extremely low amounts of biochemical genetic variation as opposed to the other three species which retain comparatively high levels of allozyme heterozygosity. The cheetah sample showed dramatically greater fluctuating asymmetry but was not outstanding in morphological variability. Elevated levels of fluctuating asymmetry have been interpreted as a reflection of developmental instability, which is a common consequence of inbreeding. The inverse correlation of genetic variation and developmental stability (homeostasis) observed here fulfills prior expectations and further emphasizes the genetic invariability of the cheetah species. PMID- 28564109 TI - GEOGRAPHIC VARIATION IN HOUSE FLY SIZE: ADAPTATION OR LARVAL CROWDING? PMID- 28564108 TI - COMPARATIVE PATTERNS OF GROWTH AND DEVELOPMENT IN CRICETINE RODENTS AND THE EVOLUTION OF ONTOGENY. AB - The quantitative description of growth curves for morphometric traits provides a basis for assessing the ontogenetic patterns underlying differences in morphological structure, as demonstrated with comparisons among neotomine peromyscine rodents. Morphometric differences among contemporary rodent species are shown to result from relatively simple changes in relative growth rates and timing. Quantitative ontogenetic studies add a dynamic component to the assessment of morphological similarity, thus providing a more robust procedure for detecting homoplasy than static comparison of adult morphology. Applying the principles of phylogenetic systematics to studies of developmental timing among closely related taxa may be a useful and informative complement to studies based on molecular similarity or static comparison of adult morphology. Interspecific and intraspecific differences in allometric scaling of anatomical structures may reflect differences in growth patterns among the taxa compared; caution is warranted in inferring patterns of genetic correlation from data on phenotypic scaling. PMID- 28564110 TI - FURTHER GENETIC ANALYSES OF A HYBRID ZONE BETWEEN LEOPARD FROGS (RANA PIPIENS COMPLEX) IN CENTRAL TEXAS. AB - Additional animals were collected from a previously described hybrid zone between two species of leopard frogs. The material now includes 1,054 specimens collected over a five-year period. The new and the original data were reanalyzed using two multilocus techniques: an analysis of linkage disequilibrium (Hill, 1975); and an analysis of the variance of the distribution of individual heterozygosities (Brown et al., 1980). An analysis of cline shape (Barton and Hewitt, 1983) also was performed. The zone appears to be stable in position. There are major year-to year changes in allele frequencies, but these do not show concordant patterns between localities. This is probably the result of local stochastic factors. The shapes and position of clines at five loci are similar. Multilocus analysis shows the greatest disequilibrium values in the center of the zone. The ratio of observed to expected variance of individual heterozygosity is also largest in the central localities. Analysis of a single cohort during a three-month period that included both the larval and post-metamorphic stages shows a strong shift in genotypes. The froglet population had more animals with parental genotypes and fewer hybrid combinations. This probably is a result of differential mortality due to developmental incompatibilities when hybrids begin to metamorphose. We compare the usefulness of the two multilocus analytical techniques and make recommendations about collecting procedures for future studies of hybrid zones. PMID- 28564111 TI - SEX RATIO, PARENTAL INVESTMENT, AND INTERPARENT VARIABILITY IN NESTING SUCCESS IN A SOLITARY BEE. AB - Observations of uniquely marked females of the solitary, twig-nesting bee, Osmia bruneri, were conducted under greenhouse conditions to test several predictions of sex-ratio and parental-investment theory. In support of Fisher's (1958) theory, we found that the observed sex-ratio of progeny in this dimorphic species did not differ from that expected on the basis of average male and female weights. Investment patterns also exhibited a seasonal component: female parents produced more female than male offspring early in the nesting season but reversed this pattern later. Interfemale variability was large for all nesting parameters examined. Neither female-parent size nor the rate at which females completed cells was significantly related to several estimates of parent fitness. Parent offspring heritability for size was also low. We found no evidence to support the hypothesis that progeny sex-ratios are influenced by maternal condition. Variance in progeny sex-ratios was large, but the population sex-ratio probably departs frequently from the equilibrium value. The results marginally support Kolman's (1960) prediction of large variance in progeny sex-ratios in large panmictic populations. We conclude that variability among females in investment patterns and variability in size among progenies are probably maintained by such factors as resource heterogeneity and the shape of the adult survivorship curve. PMID- 28564112 TI - EVIDENCE FOR PREDATION AS A FACTOR IN DETERMINING SHELL COLOR FREQUENCIES IN A MANGROVE SNAIL LITTORINA SP. (PROSOBRANCHIA: LITTORINIDAE). AB - It was hypothesized that in Littorina populations living on Avicennia marina in Moreton Bay, Queensland, yellow shelled individuals are at a selective advantage over other shell colors and that this advantage is due to differential selection by predators. Yellow shelled individuals were more likely to be recaptured than others, indicating a higher survival rate of yellows. When predation was restricted on ten mangrove trees, the apparent advantage of yellow shells was removed. After 18 months, the relative frequency of yellow shelled individuals was significantly lower on experimental trees than on control trees. A combination of selection for crypsis and for the less common morph is suggested as the mechanism maintaining the high levels of variation in this species. PMID- 28564113 TI - CONSTRAINTS FOR THE EVOLUTION OF FUNCTIONALLY COUPLED CHARACTERS: A NONLINEAR ANALYSIS OF A PHENOTYPIC MODEL. AB - On the basis of a phenotypic model of R. Lande a nonlinear analysis is performed to investigate the evolutionary dynamics of functionally coupled quantitative traits. The underlying fitness topography has multiple peaks with a ridge and two hills adjacent to a saddle. Evolution of a complex of functionally constrained characters corresponds precisely to moving uphill along a ridge. For modelling the topology of the ridge, I follow ideas of Rechenberg and Wagner and use a so called corridor model. The analysis reveals certain population-genetic constraints for the evolutionary emergence of a selectively favored complex of functionally constrained characters. Due to the population-genetic structure, as reflected in the pattern of variation and covariation, a population will often not be allowed to become adapted to existing physiological requirements, such as functional coupling of characters. Instead, within the present model where extinction cannot occur, it will evolve in some other direction toward an optimum that may be physiologically rather remote. In particular, there exists an optimal pattern of genetic and phenotypic variances and covariances in the following sense: on the one hand an increasing deviation from this pattern imposes increasing restrictions on the set of initial conditions enabling a population to move uphill along the ridge; on the other hand, an increasing deviation leads to a decreasing rate of adaptation along the ridge. Finally, some consequences of these constraints for possible interpretations of certain empirical results are discussed. PMID- 28564114 TI - HETEROZYGOSITY AND DEVELOPMENTAL RATE IN A STRAIN OF RAINBOW TROUT (SALMO GAIRDNERI). AB - Rainbow trout (Salmo gairdneri) with greater heterozygosity at enzyme loci also have greater developmental stability, as measured by bilateral symmetry of five meristic traits. Fish with increased amounts of liver phosphoglucomutase activity have greater developmental stability and develop faster than fish with normal activity. These observations suggest that the differences in developmental stability between homozygotes and heterozygotes may be the result of differences in developmental rate. Faster developmental rates are expected to decrease the probability of accidents during critical periods of development, resulting in a more stable or uniform phenotype. As indicated by differences in hatching time, heterozygotes tend to develop more rapidly than homozygotes. This association is not strongly expressed within families at any locus except Pgm1-t. However, heterozygotes for Mdh3,4 and Hex hatched significantly sooner than homozygotes in a population sample. These results suggest that differences in developmental rate between homozygotes and heterozygotes may account for the positive association between developmental stability and heterozygosity in rainbow trout. PMID- 28564115 TI - SEX-RATIO DETERMINATION WITHIN COLONIES OF ANTS. PMID- 28564116 TI - NATURAL SELECTION OF ALLOZYME POLYMORPHISMS: A MICROSITE TEST REVEALING ECOLOGICAL GENETIC DIFFERENTIATION IN WILD BARLEY. AB - Allozymic variation in proteins encoded by 25 loci was analyzed electrophoretically in 1982 and 1983 in 356 individual plants from a dense population of wild barley, Hordeum spontaneum, the progenitor of cultivated barley. The test involved six microniches organized in a mosaic pattern in the open Tabor oak forest at Neve Ya'ar, Israel. The microniches were i) sun-soil, ii) sun-rock, iii) shade-soil, iv) shade-rock, and the contact zones: v) soil periphery of the sun-rock microniche, and vi) soil periphery of the shade-rock microniche. Discriminant analysis indicated significant multilocus allozymic differentiation between the microniches. Our results suggest that allozyme polymorphisms in wild barley are at least partly adaptive and differentiate predominately by microniche ecological selection, rather than by stochastic processes and/or neutrality of allozymic variants. PMID- 28564117 TI - THE INHERITANCE OF COURTSHIP BEHAVIOR AND ITS ROLE AS A REPRODUCTIVE ISOLATING MECHANISM IN TWO SPECIES OF SCHIZOCOSA WOLF SPIDERS (ARANEAE; LYCOSIDAE). AB - The courtship behaviors of two morphologically similar spider species, Schizocosa ocreata and S. rovneri, are distinctive and prevent interbreeding. We used "forced" copulation between these species to investigate the mode of inheritance of the courtship behavior and to determine whether postmating isolating mechanisms exist. F1 hybrids proved to be behaviorally sterile, but they were capable of producing viable offspring when forced to interbreed. Analysis of the courtship behaviors of F1 , F2 , and backcross progeny showed that the inheritance of some aspects of these behaviors is consistent with models involving single autosomal loci. The inheritance of secondary sexual characteristics in the males is also investigated. The genes for courtship behavior and secondary sexual characteristics do not assort independently. The origin of the premating isolating mechanisms may be explained by either an initial habitat separation between the two groups, or by a founding event with each group subsequently diverging in slightly different habitats. It is suggested that the differences in the microhabitats may have a profound effect on what type of signal (visual or vibratory) would be effective. PMID- 28564118 TI - THE BIOGEOGRAPHIC EVIDENCE SUPPORTING THE PLEISTOCENE FOREST REFUGE HYPOTHESIS. AB - The prevailing explanation for the observed distributional patterns and areas of endemism of tropical forest organisms is the Pleistocene refuge hypothesis, which proposes that wide-ranging ancestral taxa were isolated into forest refuges during certain glacial periods, and that this isolation provided them with the opportunity to speciate. John Endler has recently argued that two predictions of the refuge hypothesis-that contact zones between vicars should be between refuges and that contact zones of rapidly reproducing butterflies should be wider than those of more slowly reproducing birds-are not borne out by the evidence. Endler therefore rejects the refuge hypothesis. We show that the data available are far too imprecise to permit any conclusions regarding contact zone widths and that, according to our reanalysis of the African bird data used by Endler, all the contact zones between vicars do indeed occur between refuges, exactly where they are expected. Additional strong support for the refuge hypothesis comes from the existence of many taxa endemic to the particular forest areas which have been postulated as refuges and from fragmented taxa which are still allopatric, never having come into secondary contact. PMID- 28564119 TI - PROXIMATE AND ULTIMATE CONTROLS ON LIFE-HISTORY VARIATION: THE EVOLUTION OF LITTER SIZE IN WHITE-FOOTED MICE (PEROMYSCUS LEUCOPUS). AB - Recruitment of litter-mates of nest-box-inhabiting white-footed mice was monitored to study the evolution of litter size. The frequency distribution of litter sizes was nonsymmetrical, and the most frequent litter size was less than the optimum. This was not the result of differential parental survival, which was independent of litter size produced. Recruitment remained constant or increased slightly to a peak in litters of five young, and then dropped precipitously for larger litters. The single optimum litter size of five did not appear to have any physiological correlates. Instead, the equally low probability of successful recruitment of any young from any given litter may have given rise to a bet hedging strategy of frequent iterated reproductions. A theoretical analysis of optimal parental investment in offspring was initiated under the assumption that optimal brood size represents a maximization of differences between age-specific costs and benefits of reproduction, both of which should be measured in constant currency of inclusive fitness. In the past, benefit has been measured by current fecundity, and cost by residual reproductive value. However, reproductive value is an appropriate estimate of inclusive fitness only for organisms in which parental investment has little effect on the subsequent survival of offspring to reproductive age. Reproductive value weighted by offspring survival and devalued by the degree of genetic relatedness defines a new currency, replacement value, which is more appropriate for evaluating the costs and benefits of parent offspring conflict over parental investment in current as opposed to future young. Total parent-offspring conflict intensifies with increases in current brood size. For species with severe reproductive constraints, such as post-partum estrus in white-footed mice, such conflict may force parents to curtail investment in current offspring at or near parturition of subsequent litters, even if that means reducing the survival of current young. PMID- 28564120 TI - OPTIMALITY AND CONSTRAINT IN A SELF-FERTILIZED ALGA. PMID- 28564121 TI - BIOTYPING CONFIRMS A NEARLY CLONAL POPULATION STRUCTURE IN ESCHERICHIA COLI. AB - A. reference collection of 72 natural isolates of Escherichia coli (the ECOR collection) has been examined with respect to eight metabolic capabilities (biotype characters) plus motility and resistance or sensitivity to five common antibiotics. Data from biotype characters were analyzed by means of unweighted pair-group cluster analysis, and the genetic variation among the strains defines three major clusters of strains with substantial variation within each cluster but greater genetic similarity of strains within a cluster than between clusters. These clusters define an infraspecific population structure in E. coli, which reflects the predominantly clonal mode of reproduction in this organism. The clusters identified by the biotype characters are in good agreement with those resulting from an analysis of 11 enzyme polymorphisms (allozymes) among the strains, and these are in good agreement with the infraspecific structure detected by factor analysis of allozyme data. The clusters of strains also differ in several genetic characteristics that are independent of those used in making the classification. PMID- 28564122 TI - PATTERNS OF FRUIT-SET: WHAT CONTROLS FRUIT-FLOWER RATIOS IN PLANTS? AB - Fruit-set values for 447 species of plants were examined for variations due to compatibility, breeding system, life form, latitude, type of fruit, and type of pollination. The results indicate significant differences between self-compatible and self-incompatible species in terms of 1) average fruit-set and 2) the effect of the independent variables. Breeding system, life form, and latitude were found to be the only significant independent variables for self-incompatible species, while fruit type and latitude were found to be significant for self-compatible plants. Although latitude was a significant variable for self-compatible and self incompatible species, it was correlated with other variables and may actually have no direct effect on fruit-flower ratios in plants. Hypotheses explaining the effect of the significant independent variables on fruit-flower ratios were then examined and, when possible, predictions were tested. The results indicate that the selective-abortion and bet-hedging hypotheses may be important factors contributing to the low fruit-set in self-incompatible plants, while the male function hypothesis may explain the lower fruit-flower ratios in hermaphrodites. PMID- 28564123 TI - SYNAPTIC ADAPTATION IN DEER MICE: A CELLULAR MECHANISM FOR KARYOTYPIC ORTHOSELECTION. PMID- 28564124 TI - LINKAGE DISEQUILIBRIUM AND A CONTACT ZONE IN PLETHODON CINEREUS ON THE DEL-MAR-VA PENINSULA. AB - A contact zone between two electrophoretically differentiated forms of Plethodon cinereus extends across the Del-Mar-Va Peninsula. Based on the presumed nature of regional climates during the late Pleistocene, it is suggested that the climate was inhospitable for P. cinereus on the Del-Mar-Va Peninsula at the Wisconsin maximum. It is postulated that, after the Laurentide ice sheet receded about 14,000 years BP, the peninsula was invaded by populations of P. cinereus from the north and south. When the two forms of P. cinereus met, a secondary zone of contact was produced. This contact zone is now apparent in an area in which six electrophoretic loci have concordant clinal changes in allele frequency. The lack of evidence for heterozygote deficiencies, the broad width of the contact zone, and the overall symmetry of introgression suggest that fusion of the populations is occurring freely. Two esterase loci are in linkage disequilibrium in four of eight populations to the north of the contact zone. As all populations of P. cinereus studied to date have disequilibrium coefficients of similar sign, selection is likely important in the maintenance of this linkage disequilibrium. Within the contact zone, the incidence of the linkage disequilibrium increases, but exchange of genes between the two introgressing populations may account for the higher incidence of linkage disequilibrium. PMID- 28564125 TI - REPRODUCTIVE COST, AGE-SPECIFIC SURVIVAL AND A COMPARISON OF THE REPRODUCTIVE STRATEGY IN TWO EUROPEAN TITS (GENUS PARUS). AB - Theoretical analyses of optimal reproductive rates usually assume a trade-off between offspring production and parental survival. This study verified a survival cost for willow tit males; nonbreeding males survived better than males attending a brood. Theory also predicts a smaller clutch size in birds that are less successful in transforming reproductive investments into mature offspring. As predicted, we found that crested tits, suffering a higher nest predation rate, laid smaller clutches than willow tits. The generally lower survival rate of willow tit adults may largely be attributed to their higher reproductive commitment (larger willow tit clutch size), because no significant interspecific survival difference remained between nonbreeding males. Finally, in willow tits we found a positive correlation between average clutch size and juvenile survival rate (density-dependent) the ensuing year, suggesting that willow tits may adjust clutch size in response to changing survival prospects for their young by using the breeding density as a cue. PMID- 28564126 TI - Prehabilitation for kidney transplant candidates: Is it time? AB - Many patients become frail with diminished cardiorespiratory fitness while awaiting kidney transplantation. Frailty and poor fitness powerfully predict mortality, transplant graft survival, and healthcare utilization after kidney transplantation. Efforts to intervene with post-transplant physical therapy have been met with limited success, in large part due to high study dropout. We reviewed the literature on chronic kidney disease and exercise to propose a clinical framework for physical therapy interventions to improve fitness, scheduled for before the transplant. This framework may lead to better patient retention and compliance, and thus demonstrate better efficacy in mitigating the effects of frailty and poor fitness after kidney transplantation. PMID- 28564127 TI - Impact of terlipressin infusion during and after live donor liver transplantation on incidence of acute kidney injury and neutrophil gelatinase-associated lipocalin serum levels: A randomized controlled trial. AB - BACKGROUND AND AIM: Acute kidney injury (AKI) with liver transplantation (LT) is not uncommon. Impact of terlipressin infusion on AKI, hemodynamics, and plasma concentration of neutrophil gelatinase-associated lipocalin (NGAL) was studied. METHODS: Patients (n=50) were randomized (NCT02059460, USA) into two equal groups: terlipressin vs Controls. Terlipressin (1-4 MUg/kg/h) was administrated for 5 days. Intraoperative transesophageal Doppler for hemodynamic management. Renal functions, peak portal vein blood flow velocity (PPV), and hepatic artery resistive index (HARI) were recorded. Plasma NGAL (pNGAL) was measured baseline, 2 and 24 hours postreperfusion. RESULTS: Hepatitis C virus (HCV) was the main etiology. Age, sex, model of end-stage liver disease (MELD), and renal functions were comparable. Postoperative AKI incidence and NGAL concentrations were comparable (P>.05) between terlipressin and controls groups (44% vs 48% and 112.5+/-9 vs 93.1+/-8 ng/mL), respectively, but intraoperative NGAL in both groups increased significantly 2 hours postreperfusion (P<.05). The three NGAL readings were comparable (P>.05) between AKI (n=23) and non-AKI developers (n=27). Mean arterial blood pressure (MAP) was maintained in both groups with less systemic vascular resistance (SVR) fluctuations with terlipressin. Median norepinephrine consumption was lower in terlipressin vs controls (8 vs 12 mg; P=.04). The PPV and HARI were not affected by terlipressin at any stage (P>.05). CONCLUSION: Postliver transplant AKI was not prevented by terlipressin use nor predicted by NGAL levels. PMID- 28564128 TI - THE EVOLUTIONARY ECOLOGY OF AN ANTIPREDATOR REACTION NORM: DAPHNIA PULEX AND CHAOBORUS AMERICANUS. AB - Ponds containing the parthenogenetic zooplankter Daphnia pulex with and without chaoborid predators were sampled over the course of a season. A significant (P < 0.05) Spearman rank correlation was found between predator density and the expression of an antipredator defense (neckteeth) by the Daphnia. The reaction norms (percent induction of a single genotype versus predator density) of clones isolated from predator-free and predator-rich habitats were determined in a laboratory setting. There was a statistically significant different response among the six clones tested (P < 0.05). Clones isolated from chaoborid ponds showed significantly greater sensitivity to the presence of predator than clones from predator-free ponds (P < 0.05). In the laboratory, food levels under which prey were cultured affected induction of the antipredator response. Highest induction was found at the lowest food level used. PMID- 28564129 TI - GENETIC VARIANCE FOR RATE OF POPULATION INCREASE IN NATURAL POPULATIONS OF FLOUR BEETLES, TRIBOLIUM SPP. AB - The genetic and ecological effects of population subdividsion were investigated for two wild strains of Tribolium castaneum and two wild strains of T. confusum and compared with the effects of population subdivision on the synthetic laboratory strain of T. castaneum (c-SM), used extensively in earlier experiments. For the c-SM strain, it has been shown repeatedly, for a variety of different population structures (different combinations of effective numbers, Ne , and migration rates, m), that large heritable differences in population growth rate arise among demes during 10 to 15 generations of population subdivision. Because this laboratory strain was synthesized by mass mating several "inbred" strains in 1973 (80 to 100 generations ago), it is possible that it has genetic variation for fitness (measured as the heritable variance among demes in the rate of population increase) unusually large compared to natural populations of flour beetles. In this paper, I report that natural populations of flour beetle exhibit as much or more phenotypic and genetic variation in the effects of population structure on fitness than the laboratory strain, c-SM. The observation of substantial heritable variation for fitness in natural populations is unexpected under additive theory and may be indicative of nonadditive genetic variance. PMID- 28564130 TI - WHY ARE CLUTCH SIZES MORE VARIABLE IN SOME SPECIES THAN IN OTHERS? AB - Animal species differ in the variability of their clutch sizes, as well as in mean clutch sizes. This phenomenon is particularly obvious in lizards, where virtually invariant clutch sizes have evolved independently in at least 23 lineages in seven families. Reduced variance in clutch size may arise either as an adaptation (because females with less variable clutch sizes have higher fitness) or as an indirect by-product of selection on other life-history characteristics. Comparative data on Australian scincid lizards indicate that variance in clutch sizes is lowest among species with low mean clutch sizes, small body sizes and a low variance in body sizes of adult females. Phylogenetic analysis shows that evolutionary decreases in the variance of clutch size have accompanied decreases in mean clutch sizes and decreases in the variance of adult female body sizes. Tropical lizards may also exhibit lower variance in clutch size. Most of these characteristics are correlated in occurrence, and may be allometrically tied to small body size. Hence, low variance in clutch size may be a consequence of allometric effects on a correlated suite of life-history characteristics. Exceptions to the general patterns noted above-especially, lizard species with invariant clutch sizes but large body sizes-may be due to loss of genetic variance for clutch sizes in lineages that have passed through a "bottleneck" of small body sizes and hence, low variance in clutch sizes. PMID- 28564131 TI - COMPARATIVE POPULATION GENETIC STRUCTURE OF A PARASITE (FASCIOLOIDES MAGNA) AND ITS DEFINITIVE HOST. AB - The population genetic structure of the American liver fluke, Fascioloides magna, and its definitive host the white-tailed deer, Odocoileus virginianus, was examined in South Carolina. Flukes were significantly more common in deer from river-swamp habitat than upland areas and prevalence increased with host age. The distribution of flukes among deer occurred as a negative binomial with the mean dispersion parameter, k, equal to 0.17 and the range from 0.10 to 1.11 within local areas. Significant spatial genetic differentiation was observed for flukes and deer. Patterns of genetic distance in flukes were not concordant with those of the definitive host nor were they related to geographic distance between sample locations. Spatial genetic differentiation among flukes reflected the tendency for individual hosts to harbor multiple individuals from a limited number of parasite clones. The large population size of the parasite and movements of the definitive host tend to counteract factors that lead to spatial differentiation. PMID- 28564132 TI - THE EVOLUTION OF DISPERSAL IN A MODEL OF MIXED SELFING AND RANDOM MATING. PMID- 28564133 TI - WHOLE- AND PART-FLOWER SELF-POLLINATION IN GLYCINE CLANDESTINA AND G. ARGYREA AND THE EVOLUTION OF AUTOGAMY. AB - The overall rate of self-fertilization can be viewed as the sum of two distinct processes: 1) self-pollination of all ovules in a flower (whole-flower self pollination); and 2) self-pollination of some of the ovules in a flower, occurring together with outcrossing of the remaining ovules (part-flower self pollination). In some situations these processes may be equated with different modes of self-pollination. A model of the mating system in which the progeny of separate fruits serve as the unit of observation is presented. The model partitions the overall rate of self-pollination into components attributable to whole- and part-flower selfing. When the mating system is estimated using information on marker genotypes from chasmogamous fruits in two species of Glycine together with the whole- and part-flower selfing model, the results indicate that the chasmogamous flowers in a subalpine population of G. clandestina underwent a significant level of whole-flower selfing, whereas in another, lower elevation population of G. clandestina and in a subtropical population of G. argyrea, they did not. This difference is thought to be related to the contrast in the variability of environmental conditions for insect mediated pollination between the habitats sampled. In particular, the large component of whole-flower selfing observed in the subalpine population of G. clandestina may be due to self-pollination that is induced during periods unfavorable to insect-mediated pollination. It can be demonstrated that such induced selfing will be selected whenever environmental conditions are such that pollinator activity limits seed set, and moreover that induced selfing can result in the selection of overall levels of self-pollination that are intermediate between 0 and 1. Monte Carlo simulation is employed to show that ignoring the correlation of self-fertilization events that result from whole- and part-flower selfing may lead to biased estimates of mating system parameters. PMID- 28564134 TI - NATURAL SELECTION ON HYDROID COLONY MORPHOLOGY BY INTRASPECIFIC COMPETITION. AB - Previous work on colonial hydroids in the genus Hydractinia has demonstrated that colony morphology is highly variable and determines intraspecific competitive ability. Competitive encounters are known to be common in nature, suggesting that intraspecific competition may be a major selective force acting on morphological variation. A replicated common garden experiment demonstrated a genetic basis to morphological variation and two data sets provided correlative support for the hypothesis of selection by intraspecific competition. First, morphologies inferior in competitive ability were less abundant in two adult, postcompetition, samples than in juvenile, precompetition, samples from the same populations. Second, among eight populations, the relative frequency of different morphologies was correlated with the frequency of intraspecific competition observed in each population. The direction of selection by competition on the morphological variation present in this species conflicts with recent predictions based on surveys across diverse taxa, suggesting limitations to the inference of competition as a past selective agent on the basis of present day correlations among species. PMID- 28564135 TI - HOST-PATHOGEN INTERACTIONS IN NATURAL POPULATIONS OF LINUM MARGINALE AND MELAMPSORA LINI: II. LOCAL AND REGIONAL VARIATION IN PATTERNS OF RESISTANCE AND RACIAL STRUCTURE. AB - Spatial variation in the resistance structure of Linum marginale (wild flax) populations to the rust fungus Melampsora lini, and in the racial structure of this pathogen, was investigated by sampling 10 populations distributed throughout the Kosciusko National Park, New South Wales, Australia. Considerable differences were found among populations in the structure of both host and pathogen. Host populations were divided into three broad categories: (1) populations susceptible to all testing races; (2) populations containing a strictly limited number of resistant phenotypes; and (3) populations with a considerable diversity of resistant phenotypes. The pathogen populations also showed a range of diversity. The major differences between these populations were determined by the occurrence and frequency of four common races of pathogen (races A, E, K, and N). These differences were apparent both at a regional spatial scale (over the 100 km separation of the most distant populations) and at a local scale where major differences were detected between two populations only 300 m apart. The distribution of the four common races of M. lini was consistent with the hypothesis that a fitness cost was associated with unnecessary virulence. In general, however, differences in the structure of pathogen populations from genetically very similar host populations implied that, in addition to host resistance genes, other evolutionary forces are also important in determining the genetic structure of individual pathogen populations. PMID- 28564136 TI - HALDANE'S RULE: A DEFENSE OF THE MEIOTIC DRIVE THEORY. PMID- 28564137 TI - LIGULA LENGTH AND COURTSHIP IN OCTOPUS DIGUETI: A POTENTIAL MECHANISM OF MATE CHOICE. PMID- 28564138 TI - PLASTICITY OF JAW AND SKULL MORPHOLOGY IN THE NEOTROPICAL CICHLIDS GEOPHAGUS BRASILIENSIS AND G. STEINDACHNERI. AB - I examined plasticity of jaw and skull morphology induced by feeding different diets in two species of the neotropical cichlid genus Geophagus. The two species possess different modes of development, which affect the size at which young begin feeding. I hypothesized that the difference in size at first feeding could lead to a difference in the amount of change inducible in the two species. The young of the substrate-spawning species, G. brasiliensis, which begin feeding at a smaller size, were predicted to be more plastic than those of the mouthbrooding species, G. steindachneri. The two diets used to induce differences were brine shrimp nauplii and chironomid larvae. Numerous measures of the jaw and skull differed significantly between groups fed the two diets but the amount of plasticity induced was small and would not present a problem for taxonomists. Contrary to my prediction, both the magnitude and pattern of plasticity induced in the two species was similar. Thus, mode of parental care and the size at which young begin feeding do not affect the degree of plasticity. Fish fed brine shrimp nauplii were longer in oral jaw region, but were shorter and shallower in the area behind the oral jaws. An additional group of G. brasiliensis was fed flake food to compare the results of this study to other studies. The differences in measures between fish fed brine shrimp diets and flake food diets were greater than those between fish fed brine shrimp and chironomid larvae. A possible role of plasticity for enhancing rather than retarding morphological evolution is discussed. PMID- 28564139 TI - A NEW MEASURE OF GENETIC IDENTITY BETWEEN POPULATIONS OF SEXUAL AND ASEXUAL SPECIES. AB - We define a new genetic identity measure that is especially well suited for asexual polyploid species as it circumvents errors in the estimation of gene frequencies. It also can be applied to sexuals allowing the study of phylogenetic relationships in species complexes consisting of sexuals and asexuals of different ploidy levels. The measure groups genotypes into classes dependent on homozygosity vs heterozygosity and the number of ancestral allele types vs the number of presumed new mutations. Its value is related to evolutionary time since divergence. The application of the method is illustrated by using electrophoretic data on the species group Solenobia triquetrella (Lepidoptera: Psychidae). A high similarity of estimated relationships among the proposed as well as other genetic identity measures is shown in the case of diploid sexual and asexual races of this species group. The phylogenetic relationships within the group are reanalyzed and monophyletic vs polyphyletic origin of parthenogenesis in this species complex is discussed. The genetic identity values found by the proposed procedure are explained by a polyphyletic origin of parthenogenesis, though a monophyletic origin of parthenogenesis in a broader sense cannot be excluded. The explanation of the phylogenetic relationships is based on the assumption of hybridization between related species and the extinction of one ancestral species. Furthermore, the genetic diversity is compared among sexual and parthenogenetic races of the species. PMID- 28564140 TI - THE EFFECT OF A PARTIAL BARRIER ON THE MOVEMENT OF A HYBRID ZONE. AB - Computer simulations of clines (Brues, 1972; Endler, 1977) as well as theoretical arguments (Nagylaki, 1975), have shown that steps in gene frequencies will be pulled to partial barriers (areas of reduced gene flow) if they form within approximately a cline width of the partial barrier. The behavior of a hybrid zone between two chromosomal taxa ("Moreton" and "Torresian") of the acridine grasshopper Caledia captiva in southeast Queensland has been analyzed and found to comform qualitatively with a model of altered gene flow patterns. Clines in four enzyme systems were analyzed for 1983 and 1986 along a transect across the hybrid zone. The clines have shifted towards an area of regenerating forest, while homozygote frequencies have increased at this point. This forest barrier has broken the continuity of the spatial distribution of C. captiva, forming population islands in part of the hybrid zone, and thus reducing the amount of gene flow. The distance between the barrier and the original cline is approximately of the order of a cline width, so that they would be expected to interact. Historical information suggests that the secondary contact between the "Moreton" and "Torresian" taxa occurred very recently (1844-1940), due to the intensive land-clearing activities during the European settlement. PMID- 28564141 TI - HALDANE'S RULE REVISITED. PMID- 28564142 TI - THE EFFECT OF HOST PLANT PATCH SIZE VARIATION ON THE POPULATION STRUCTURE OF A SPECIALIST HERBIVORE INSECT, TETRAOPES TETRAOPHTHALMUS. AB - The patchy local distribution of the common milkweed, Asclepias syriaca, organizes populations of a beetle that feeds on it, Tetraopes tetraophthalmus, into numerous local demes. Genetic and ecological characteristics of demes of adult milkweed beetles occupying two naturally occurring size classes of patches, defined as large and small, were studied in order to describe the effect of patch size variation on local population structure. Allele frequency variance in two of three protein polymorphisms was significantly greater in collections of beetles from an array of 13 small patches when compared to collections from an array of 11 large populations. A multivariate measure of variance using information from all 3 genetic markers confirmed that the small patches displayed greater overall genetic differentiation. This was further quantified by computing an Fst value, combined across loci, of 0.018 for the small patches and 0.004 for the large patches. No significant difference between patch size classes in mean allele frequency was detected. Mark and recapture studies of the adults found in five small and four large patches showed the residence times of adults in small patches to be less than half of those found in large patches. This was interpreted as resulting from higher emigration rates from small patches. It is proposed that greater genetic differentiation is found among demes from smaller patches because smaller patches support smaller population sizes and further because smaller patches act as net exporters of migrants while larger patches act as net migrant importers. PMID- 28564143 TI - PEMPHIGUS REVISITED: CHANGES IN GEOGRAPHIC VARIATION BUT CONSTANCY IN VARIABILITY AND COVARIATION. AB - Samples of the gall-forming aphids Pemphigus populicaulis and P. populitransversus (both elongate and globular morphs) were re-collected at sites in eastern North America after 13 to 16 years. Twenty-three morphometric characters of the galls, stem mothers, and alate fundatrigeniae were analyzed by univariate and multivariate methods. Varying proportions of the variance of each character are attributable to the four levels of variation-locality, year, year by locality interaction, and among galls (within one year and locality). The year by locality interaction level generally has the greatest variation and is highly significant. Year and locality effects tend to be lower and not significant. The variance components do not exhibit trends with time. Geographic variation patterns of single variables or factor scores in the original and revisited populations show significant spatial structure overall but lack clear-cut spatial patterns, especially clines. Observable patterns of variation match results of the spatial analyses: most characters lack clear trends; patterns in the revisited data do not resemble patterns for the same variables in the original data. Variability profiles for characters change little over the time span and are comparable among and within localities. Covariation among characters over localities is largely maintained during the time interval despite the changes in patterns. Fluctuating interclonal competition among aphids on secondary hosts is believed to cause the marked heterogeneity in space and time among the aphids in the galls. PMID- 28564144 TI - IS HALDANE'S RULE SIGNIFICANT? PMID- 28564145 TI - GENETIC CONSEQUENCES OF RARITY IN ASTER FURCATUS (ASTERACEAE), A THREATENED, SELF INCOMPATIBLE PLANT. AB - Aster furcatus is a rare, self-incompatible plant with fewer than 50 known populations throughout its range. We verified self-incompatibility in A. furcatus by conducting experimental self- and cross-pollinations and by examining seed set in a small population comprised of a single clonal genet. We examined variation at 22 electrophoretic loci in 23 populations of A. furcatus from across its range in Wisconsin, Illinois, Indiana, and Missouri. Except for two rare alleles found in single individuals in three populations, all loci but one of those examined were fixed for single alleles. The only variable locus (triosephosphate isomerase, TPI-1) tended to exhibit genotype frequencies in Hardy-Weinberg equilibrium or with a slight excess of heterozygotes. Although overall gene diversity was extremely low, TPI genotype frequencies were indicative of an outcrossing plant. We examined the subpopulation genetic structure among clonal plants within one Wisconsin population in greater detail. F statistics indicated that much of the genetic variation at the polymorphic TPI locus was due to differentiation among populations. We discuss the implications of self incompatibility and low levels of genetic variation for the evolution and conservation of Aster furcatus and other rare plants with similar breeding systems. PMID- 28564146 TI - MITOCHONDRIAL-DNA ANALYSES AND THE ORIGIN AND RELATIVE AGE OF PARTHENOGENETIC LIZARDS (GENUS CNEMIDOPHORUS). II. C. NEOMEXICANUS AND THE C. TESSELATUS COMPLEX. AB - Restriction-endonuclease analyses of mitochondrial DNAs from all six color pattern classes (A-F) of the parthenogenetic lizard Cnemidophorus tesselatus yield estimates of nucleotide divergence that are extremely low (pi = 0.06%). In digests of 75 C. tesselatus mtDNAs with 20 different restriction enzymes, only four cleavage-site differences were noted, three of which were found only in pattern class F. The near-identity of these mitochondrial DNAs with those from C. tigris marmoratus shows unequivocally that C. t. marmoratus was the species to which the maternal parent(s) of all C. tesselatus belonged. Mitochondrial-DNA analyses of another unisexual species, C. neomexicanus, led to the same conclusion. Mitochondrial DNAs from 96 individuals of these three species were extensively analyzed for cleavage-site differences; only 13 were found. The low interspecific sequence diversity found within C. neomexicanus and the C. tesselatus complex suggests a recent origin for both. Based on diversity data for mitochondrial DNA and allozymes, we estimate that a minimum of two hybridizations were required to produce all diploid C. tesselatus (C-F), followed by at least two more to generate the triploids (A and B). These data and those presented in the two accompanying papers indicate that events leading to parthenogenesis in Cnemidophorus are rare and strengthen the hypothesis that interspecific hybridization is a necessary, causal event in its establishment. PMID- 28564147 TI - FITNESS CONSEQUENCES OF OUTCROSSING IN IMPATIENS CAPENSIS: TESTS OF THE FREQUENCY DEPENDENT AND SIB-COMPETITION MODELS. AB - Using field and greenhouse experiments, we tested two hypotheses that could account for the maintenance of outcrossing in Impatiens capensis. Seedlings derived from cleistogamous (CL) and chasmogamous (CH) flowers were grown under competitive conditions while flanked by neighbors that were either related or unrelated. In both experiments, CH progeny sometimes expressed more phenotypic variability than CL progeny. In the greenhouse experiment, CH progeny attained the same weight as CL progeny, and the relatedness of neighboring plants did not affect the growth of either type. In the field experiment, CL and CH progeny performed similarly when grown with related competitors. However, CH progeny were somewhat larger when planted with nonsibs, while CL progeny were somewhat smaller under those conditions. Thus, there is no evidence that either frequency dependent selection or the avoidance of competition among siblings favors the maintenance of outcrossing in this species. We also modeled the relative variability of selfed and outcrossed progeny under several reproductive systems. When females mate with one male (progeny are full sibs), selfed progeny are often more variable than outcrossed progeny. When females engage in both selfing and outcrossing, variation among progeny is frequently maximized at an intermediate selfing rate. The sib-competition mechanism, under a range of genetic models, is not apt to promote outcrossing, since selfed progeny are commonly more variable than outcrossed progeny. PMID- 28564148 TI - THE ORIGIN AND EVOLUTION OF PARTHENOGENESIS IN HETERONOTIA BINOEI (GEKKONIDAE): EXTENSIVE GENOTYPIC DIVERSITY AMONG PARTHENOGENS. AB - Variation at 18 allozyme loci was assayed among representatives of the geographically widespread, triploid parthenogenetic form of Heteronotia binoei. A minimum of 52 different genotypes were observed among 143 individuals. Virtually all localities sampled had multiple genotypes among the unisexuals. This represents unusually high genotypic diversity for a unisexual vertebrate. Heterozygosity in the triploids was higher than in diploid bisexual populations of H. binoei. Comparison with the alleles present in the diploid bisexuals confirms that the parthenogens are hybrids and indicates that most of the genotypic diversity stems from repetitive hybrid origins. However, the presence of some alleles unique to the parthenogens suggests that mutation adds to their genetic diversity. The genetic structure of this geographically widespread parthenogen suggests the hypothesis that the persistence and spread of the unisexual lineages is facilitated by genotypic diversity. PMID- 28564149 TI - PROXIMITY-DEPENDENT CROSS-COMPATIBILITY IN PHLOX. PMID- 28564150 TI - REPRODUCTIVE ISOLATION BY HOST SPECIFICITY IN A PAIR OF PHYTOPHAGOUS LADYBIRD BEETLES. AB - Crossing experiments and food-choice tests show that two sympatric species of phytophagous ladybird beetles, Epilachna niponica and E. yasutomii, are reproductively isolated by host-plant specificity. Adult beetles selected their natural hosts when given choices, though some accepted the host of the other species when no choice was offered. In each species, survival of larvae to the second instar was significantly higher on their own host plant. No evidence for sexual isolation, gametic isolation, hybrid inviability, or reduced hybrid fertility was detected. Reproductive isolation by host specificity is an important prerequisite for certain models of sympatric speciation. Although the present example supports the plausibility of such models, an allopatric origin of host-plant specificity cannot be discounted. PMID- 28564151 TI - DNA DIVERGENCE AMONG HOMINOIDS. AB - We have determined the degree of single-copy DNA divergence among the extant members of the Hominoidea employing the technique of DNA-DNA hybridization. The species studied include humans, two species of chimpanzees, gorillas, two subspecies of orangutans, and two species of gibbons; as an outgroup we have used a member of the Old World monkeys (Cercopithecidae), the baboon. Our methods are different from those previously used and allow us to control for two factors other than base-pair mismatch that can affect the thermal stability of DNA duplexes: the base composition and duplex length. In addition, we have studied more than one individual for most species and thus are able to assess the effect of intraspecific variation on phylogenetic conclusions. The results indicate that the closest extant relatives of humans are the chimpanzees. Gorillas are the next closest, followed by orangutans and gibbons. This result is strongly supported statistically, as there is virtually no overlap in measurements between different taxa. Our conclusions are in agreement with a growing amount of molecular evidence supporting this pattern of relatedness. The data behave as a reasonably good molecular clock, and we do not see an indication of slowdown in molecular evolution in the clade containing humans and African apes, contrary to what has been documented for protein-coding regions. Because of the clocklike nature of the results, we have estimated that the divergence of humans and chimpanzees occurred about 6-8 million years ago. Results from orangutans indicate that the Borneo and Sumatra populations are genetically distinct, about as different as the named species of chimpanzees. PMID- 28564152 TI - EXPERIMENTAL STUDIES OF THE EVOLUTIONARY SIGNIFICANCE OF SEXUAL REPRODUCTION. VI. A GREENHOUSE TEST OF THE SIB-COMPETITION HYPOTHESES. AB - This study tests the hypothesis that competition among groups of sexual and asexual siblings generates an advantage for sexual females. Individual tillers of Anthoxanthum odoratum were planted singly, among other siblings from the same family, and among groups of sexual and asexual siblings from different families in pots in an unheated greenhouse. Unlike previous field experiments, there was little difference between the performance of sexual and clonal tillers after two years, despite strong treatment effects and high mortality. The results demonstrate that sib competition does not generate an advantage for sexual reproduction in biotically simple environments. PMID- 28564153 TI - MITOCHONDRIAL-DNA DIVERSITY AND THE ORIGIN OF THE MENIDIA CLARKHUBBSI COMPLEX OF UNISEXUAL FISHES (ATHERINIDAE). AB - Restriction-endonuclease analysis of mitochondrial DNA (mtDNA) of the unisexual M. clarkhubbsi complex and close sexual relatives indicated that the unisexual complex arose through multiple, nonreciprocal hybridizations involving females of M. peninsulae. High-resolution analyses using restriction endonucleases that cleave at 4-bp sites revealed mtDNA sequence diversity that was low among unisexuals but high among individuals of M. peninsulae. The identification of M. peninsulae as a parent of the unisexuals conflicts with some details of previous allozyme comparisons. One possibility is that the unisexuals were derived from hybridization involving M. beryllina and a recently extinct form of M. peninsulae. In contrast to the unisexuals, contemporary hybrids of M. peninsulae and M. beryllina are formed by reciprocal matings. The origins of extant unisexual lineages from nonreciprocal hybridizations, together with their low mtDNA diversity relative to the maternal ancestor, implies strong constraints on origins of unisexuality via hybridization. Data on reproduction by contemporary F1 hybrids reveal one form of genetic/developmental constraint: M. peninsulae and M. beryllina may now have diverged beyond the point where the hybrid origin of new unisexual lineages is possible. PMID- 28564154 TI - A TEST FOR PROXIMITY-DEPENDENT OUTCROSSING IN THE ALPINE SKYPILOT, POLEMONIUM VISCOSUM. PMID- 28564155 TI - ELECTROPHORETIC VARIATION IN THE PARTHENOGENETIC GRASSHOPPER WARRAMABA VIRGO AND ITS SEXUAL RELATIVES. AB - Allozyme variation was examined within and between parthenogenetic clones of Warramabo virgo and the sexual ancestors, undescribed species P196 and P169. Both sexual species can be separated into northern and southern races using six loci, and the separate hybrid origin for the two major groups of parthenogenetic clones (the Standard Phylad and the Boulder-Zanthus Phylad) is substantiated by the racial variation in the sexual ancestors. Heterozygosity values in the parthenogenetic species are 6-9 times higher than those in the sexual species, and there is evidence for the accumulation of new variation subsequent to the hybrid origin of both phylads. The new variation is the result of either new mutations, recombination, or both. Three loci in the Standard Phylad clones reveal "orphan" alleles not found in the sexual ancestors; these alleles probably arose subsequent to hybridization but prior to the dispersal of the parthenogenetic clones. These data, in combination with those from other genetic studies, suggest that new variation may arise as a consequence of hybridization. Collectively, the allozyme, chromosome, molecular, and morphological data suggest that the Standard Phylad clones are of a more ancient but restricted origin, with clonal variation being the result of multiple hybridizations between individuals of P196 and P169. PMID- 28564156 TI - SEXUAL DIMORPHISM IN PASSERCULUS SANDWICHENSIS AS IT IS. PMID- 28564157 TI - EXPERIMENTAL STUDIES OF THE EVOLUTIONARY SIGNIFICANCE OF SEXUAL REPRODUCTION. V. A FIELD TEST OF THE SIB-COMPETITION LOTTERY HYPOTHESIS. AB - Sexually and asexually derived tillers of Anthoxanthum odoratum were planted directly in the field to test the hypothesis that competition among groups of sexual and asexual siblings favors the maintenance of sexual reproduction in populations. The results showed a substantial fitness advantage for sexual tillers. However, in contrast with the models, the advantage of sex did not increase with increasing numbers of colonists in the patch, there were multiple survivors among colonists, and an advantage was observed even for singly planted tillers. When a truncation-selection scheme was imposed ex post facto on the data, the relative performance of sexual tillers was similar to that predicted by the Bulmer (1980) model, suggesting that sib-competition models fail due to the violation of the assumption of truncation selection. The advantage of sex was not correlated with the presence of other species, total percentage cover, or species diversity, although sites where sex was favored were physically clustered. PMID- 28564158 TI - MITOCHONDRIAL-DNA ANALYSES AND THE ORIGIN AND RELATIVE AGE OF PARTHENOGENETIC LIZARDS (GENUS CNEMIDOPHORUS). IV. NINE SEXLINEATUS-GROUP UNISEXUALS. AB - Mitochondrial DNAs (mtDNAs) from nine morphologically distinct unisexual species and five bisexual species of lizards, all from the sexlineatus species-group of Cnemidophorus, were compared using restriction endonucleases. The unisexual lizards have mtDNAs that are identical at all or nearly all of the 128 sites cleaved. Although differing little in sequence, some mtDNAs differed in size due to the presence of tandem sequence duplications. Phylogenetic analysis of cleavage maps indicates that the mtDNAs of the unisexuals are most similar to that of the bisexual species C. inornatus. Considerable mtDNA diversity exists among C. inornatus populations, and one geographically restricted subspecies, C. i. arizonae, was identified as the most probable maternal ancestor of all nine unisexuals. All but one of these are triploid, and all have at least one C. inornatus gene complement. This, together with the homogeneity of their mtDNAs, suggests that all stem from one or a small number of allodiploid females (presumably parthenogenetic) that originated in a restricted geographic area in the recent past. These data, when combined with those from allozyme studies, preclude the possibility that most of the triploid unisexuals could have arisen via fertilization of an unreduced diploid ovum from one species by a haploid sperm from a different species. PMID- 28564159 TI - OPTIMAL OUTCROSSING IN IPOMOPSIS AGGREGAT A: SEED SET AND OFFSPRING FITNEs. AB - Restricted gene flow and localized selection should establish a correlation between physical proximity and genetic similarity in many plant populations. Given this situation, fitness may decline in crosses between nearby plants (inbreeding depression), and in crosses between more widely separated plants ("outbreeding depression") mostly as a result of disruption of local adaptation. It follows that seed set and offspring fitness may be greatest in crosses over an intermediate "optimal outcrossing distance." This prediction was supported for Ipomopsis aggregata, a long-lived herbaceous plant pollinated by hummingbirds. In six replicate pollination experiments, mean seed set per flower was higher with an outcrossing distance of 1-10 m than with selfing or outcrossing over 100 m. A similar pattern appeared in the performance of offspring from experimental crosses grown under natural conditions and censused for a seven-year period. Offspring from 10-m crosses had higher survival, greater chance of flowering, and earlier flowering than those from 1-m or 100-m crosses. As a result, 1-m and 100 m offspring achieved only 47% and 68%, respectively, of the lifetime fitness of 10-m offspring. Offspring fitness also declined with planting distance from the seed parent over a range of 1-30 m, so that adaptation to the maternal environment is a plausible mechanism for outbreeding depression. Censuses in a representative I. aggregata population indicated that the herbaceous vegetation changes over a range of 2-150 m, suggesting that there is spatial variation in selection regimes on a scale commensurate with the observed effects of outbreeding depression and planting distance. We discuss the possibility that differences in seed set might in part reflect maternal mate discrimination and emphasize the desirability of measuring offspring fitness under natural conditions in assessing outcrossing effects. PMID- 28564160 TI - POLYPHYLETIC ORIGINS OF ASEXUALITY IN DAPHNIA PULEX. II. MITOCHONDRIAL-DNA VARIATION. AB - Allozyme studies of the cladoceran Daphnia pulex have shown that most populations reproduce by obligate parthenogenesis, although some cyclically parthenogenetic populations remain throughout the southern portion of its range. Clonal diversity within the obligate parthenogens is extremely high and has been attributed to the polyphyletic origin of asexuality. Specifically, it has been proposed that the clonal diversity in the obligate parthenogens was generated via the spread of a sex-limited meiosis suppressor through populations of a cyclically parthenogenetic ancestor. In this study, analysis of polymorphism of restriction endonuclease sites in the mitochondrial genome, in conjunction with allozyme analysis, was used to determine whether obligate parthenogenesis has a monophyletic or polyphyletic origin in D. pulex. An allozyme survey of 77 populations from Ontario and Michigan was first conducted to determine breeding systems and levels of clonal diversity (Hebert et al., 1989). Mitochondrial-DNA variation was then surveyed in one isolate of each clone from each population reproducing by obligate parthenogenesis and in 2-4 isolates from each population reproducing by cyclic parthenogenesis. Seventeen restriction enzymes were used in this analysis. Thirty-five mitochondrial genotypes were found among the 36 obligate clones (as identified by allozyme analysis), while 17 mitochondrial genotypes were identified among 40 cyclic isolates from 14 populations. Five mitochondrial genotypes were found in both groups. Parsimony and phenetic clustering methods were used to construct trees showing the genetic relationship among mitochondrial genotypes. The results clearly show that obligate parthenogenesis had a polyphyletic origin in this species. The close relationship between cyclic and obligate parthenogens in the Great Lakes region suggests that many obligate clones have recently been derived from cyclic populations and that the generation of clones is still occurring in this area. Patterns of clonal diversity based on the joint consideration of allozyme and mitochondrial-DNA data are discussed. PMID- 28564161 TI - SPARROW SEXUAL SIZE DIMORPHISM AND TESTIS SIZE: A COMMENT. PMID- 28564162 TI - MITOCHONDRIAL-DNA ANALYSES AND THE ORIGIN AND RELATIVE AGE OF PARTHENOGENETIC LIZARDS (GENUS CNEMIDOPHORUS). III. C. VELOX AND C. EXSANGUIS. AB - Mitochondrial DNAs (mtDNAs) of two unisexual, parthenogenetically reproducing species of whiptail lizards (Cnemidophorus velox and C. exsanguis) and their bisexual relatives were compared by restriction-enzyme analysis to assess levels of mtDNA variation and to establish the maternal ancestry of the unisexuals. No cleavage-site differences were found to be diagnostic between C. velox and C. exsanguis mtDNAs, suggesting an ancestry rooted in the same maternal lineage. The mtDNA of the unisexuals is relatively homogeneous, indicating that these lineages are of recent origin. Phylogenetic analysis revealed that the maternal ancestor of both C. velox and C. exsanguis was most probably C. burti stictogrammus, C. costatus barrancorum, or an unidentified taxon closely related to them. In addition, the mtDNA analyses demonstrate conclusively that the triploid species C. velox could not have been formed by the fertilization of an unreduced (diploid) C. inornatus egg, further strengthening the hypothesis that parthenogenesis in Cnemidophorus results from hybridization. PMID- 28564163 TI - HIGH LEVELS OF GENETIC VARIABILITY IN THE HAPLOID MOSS PLAGIOMNIUM CILIARE. AB - Horizontal starch-gel electrophoresis was used to measure variability at 14 enzyme loci from 13 natural populations of the dioecious moss Plagiomnium ciliare. Overall levels of genetic polymorphism were unexpectedly high for a haploid organism. Using a 1% frequency criterion, 71% of the loci surveyed were polymorphic for the species as a whole. The number of alleles per polymorphic locus for the species as a whole was 2.82 +/- 0.34 (mean +/- standard error), and mean gene diversity per locus was 0.078 +/- 0.035. While total gene diversity (HT = 0.178) was similar to that observed for highly outcrossed diploid plants such as pines, the variance within (HS = 0.098 +/- 0.027) and among (DST = 0.080 +/- 0.033) populations was more evenly distributed than that reported for populations of conifers. Genetic distances between populations ranged from 0.0002 to 0.2064, with mosses from the Piedmont region of the southeastern United States showing less differentiation among populations than did mosses from the Appalachian Mountains. Gene diversity was much reduced in populations from disturbed, secondary forests in the Piedmont (0.058 +/- 0.018) relative to those from minimally disturbed, primary forests in the mountains (0.146 +/- 0.048). Intensive sampling within populations revealed heterogeneity even within small (5 * 5 cm) clumps. The discovery of high levels of genetic variability in a plant with a dominant haploid life cycle challenges the traditional view of bryophytes as a genetically depauperate group. Multipleniche selection is proposed as a possible explanation for this anomaly, but the data are also consistent with the view that allozyme polymorphisms are selectively neutral. PMID- 28564164 TI - POLYPHYLETIC ORIGINS OF ASEXUALITY IN DAPHNIA PULEX. I. BREEDING-SYSTEM VARIATION AND LEVELS OF CLONAL DIVERSITY. AB - There is growing evidence that transitions from sexual to asexual reproduction are often provoked by internal genetic factors rather than extrinsic selection pressures. In the cladoceran crustacean Daphnia pulex, the shift to asexuality has been linked to sex-limited meiosis suppression. Most populations of this species reproduce by obligate parthenogenesis, but cyclically parthenogenetic populations persist in the southern portion of its range. The meiosis-suppressor model predicts that asexuality in D. pulex has polyphyletic origins and that the coexistence of cyclically parthenogenetic lines with male-producing obligately asexual clones should be unstable. For the present study, we examined the genotypic structure of D. pulex populations from a region in which there is an abrupt microgeographical shift in breeding system. Populations in Michigan largely reproduce by cyclic parthenogenesis, while those in Ontario are obligately asexual. Allozyme studies on 77 populations from this area revealed 50 obligately asexual clones, divisible into two groups: one derived from a single parent species and the other derived via interspecific hybridization. Although nearly 50% of the clones retained male production, there was, as predicted, no evidence of coexistence between cyclically parthenogenetic populations and male producing obligately asexual clones. The survey did, however, reveal a low incidence of cyclically parthenogenetic populations in Ontario. The high genotypic diversity of these populations suggests that they are not only resistant to meiosis suppression, but able to rework genetic variation gained from asexual clones into a sexual breeding system. PMID- 28564165 TI - RIBOSOMAL-DNA VARIATION AND DISTRIBUTION IN RUDBECKIA MISSOURIENSIS. PMID- 28564166 TI - FITNESS CONSEQUENCES OF VARIATION IN EGG SIZE AND FOOD ABUNDANCE IN BROOK TROUT SALVELINUS FONTINALIS. AB - Relationships between egg size and juvenile survival in brook trout, Salvelinus fontinalis, were determined experimentally at two levels of food abundance and then incorporated into a model that related maternal fitness to egg size and food supply. Egg volume was positively correlated with juvenile size at hatching and size at yolk sac resorption but had no significant effect on embryonic survival or development time. Juvenile survival was linearly related to egg size throughout the first 50 days of exogenous feeding at high and low food levels. The effects of egg size and food abundance on juvenile survival were not additive. Decreased food abundance significantly increased mortality among the smallest eggs but had a negligible effect on the largest eggs. Model simulations indicate that maternal fitness is a curvilinear function of egg size and that food supply influences both the height and the shape of the function. The fitness functions provide empirical support for the hypothesis that selection favors an increase in offspring size with reductions in resource abundance. PMID- 28564167 TI - MITOCHONDRIAL DNA VARIATION IN MONARCH BUTTERFLIES. PMID- 28564168 TI - METHODS FOR THE ANALYSIS OF COMPARATIVE DATA IN EVOLUTIONARY BIOLOGY. AB - Inferences regarding phylogenetic patterns and constraints on the evolution of characters often can be derived only from comparisons of extant species. If the phylogeny of these species is known, then the mean phenotypes of taxa can be partitioned into heritable phylogenetic effects and nonheritable residual components. Methods are presented for the estimation of phylogenywide means of characters, the variance-covariance structure of the components of taxon-specific means, and the mean phenotypes of ancestral taxa. These methods, which are largely an extension of maximum-likelihood techniques used in quantitative genetics, make an efficient use of the data, are unbiased by phylogenetically uninformative contributions to mean phenotypes, and take into account fully the nonindependence of data resulting from evolutionary relationships. Statistical tests are introduced for evaluating the significance of phylogenetic heritability and of correlations between traits, and expressions are given for the standard errors of ancestral mean phenotype estimates. It is argued that the covariance structure of phylogenetic effects provides a description of a macroevolutionary pattern, whereas that for the residual effects, when corrected for sampling error, is more closely related to a microevolutionary pattern. PMID- 28564169 TI - EFFECTS OF NONRANDOM SEED ABORTION ON PROGENY PERFORMANCE IN PHASEOLUS COCCINEUS L. AB - In this study, we sought to determine if Phaseolus coccineus normally aborts potentially viable seeds, and whether seed abortion is nonrandom with respect to progeny vigor. The ovaries of Phaseolus coccineus typically have six linearly arranged ovules. The three ovule positions at the stylar end are more likely to mature seeds than the three ovules at the basal end of the ovary. When we destroyed the developing ovules at the stylar end of the fruit after fertilization but before seed abortion, there was a significant increase in the probability that the ovules in the three basal positions would produce a mature seed. The probability of seed maturation in control fruits (no ovules destroyed) ranged from 38.3 to 42.7% over the three field seasons, whereas in the experimental fruits it ranged from 64.3 to 79.7% (similar to that of ovules at the stylar end in control fruits). We did not find any significant change in the probability of seed production in the three ovule positions in the stylar end of the ovary (the positions with high probability of seed maturation) when the basal ovules were experimentally destroyed. These results indicate that potentially viable seeds are regularly aborted in P. coccineus, with seed abortion more frequent in the basal ovule positions than at the stylar positions. In two greenhouse studies and one field study, we compared the vigor of progeny produced in the control fruits with the vigor of progeny produced in fruits where three ovules (either stylar or basal end) were destroyed. We found that the performance of the progeny from the three positions at the stylar end of the control fruits did not differ from the performance of the progeny from experimental fruits in which the three basal ovule positions were destroyed. In contrast, the progeny from the basal positions of the control fruits outperformed the progeny from the experimental fruits when the seeds were produced in the three basal ovules (stylar ovules destroyed). Our findings indicate that when the experimental treatment increased the probability of seed maturation, there was a significant decrease in the average vigor of the progeny in the remaining (basal) ovule positions. PMID- 28564170 TI - TOPOGRAPHIC DIVERSITY, ZONE WIDTH, AND THE STRENGTH OF REPRODUCTIVE ISOLATION IN A ZONE OF OVERLAP AND HYBRIDIZATION. AB - Two closely related species of ground crickets, Allonemobius fasciatus and A. socius, overlap and hybridize in a contact zone in the eastern United States. In earlier work, Howard (1986) described geographic variation in the width of the zone and in the strength of reproductive isolation between the two ground crickets. The zone was wider in the hills and mountains of southeastern Ohio and West Virginia than along the eastern coastal plain, and reproductive isolation appeared to be stronger where the zone was wider. Howard attributed the greater width in the mountains to the wide intermingling and patchy distribution of habitats appropriate for a species adapted to a northern climate and for a species adapted to a southern climate. He also pointed out that the mosaicism and the increased breadth of the zone in the mountains enhanced the probability of occurrence of reinforcement. We tested three predictions that emerged from Howard's hypothesized links among topographic diversity, zone width, and the strength of reproductive isolation. The first two predictions were fulfilled. The northern cricket, A. fasciatus, occurred in the high mountains south of its previously known distributional limit; and the zone narrowed considerably in Illinois, an area of low topographic diversity. These results provide further evidence for the importance of the environment in determining the structure of the zone. The third prediction was falsified. Contrary to the prediction, the strength of reproductive isolation between the two species was as strong in Illinois as in the Appalachian Mountains. This result suggests that if reinforcement has occurred in the zone, the width of the zone has not been a major factor in the process. PMID- 28564171 TI - GENE FLOW AND MITOCHONDRIAL DNA VARIATION IN THE KILLIFISH, FUNDULUS HETEROCLITUS. AB - Two subspecies of killifish, Fundulus heteroclitus, inhabit the Atlantic coast of the United States. The contact zones between them are typified by morphological, physiological, nuclear gene, and mitochondrial DNA clines. Considerable debate exists about the importance of restricted gene flow and natural selection in maintaining these clines. To evaluate the relative importance of these two evolutionary forces we employed analysis of mtDNA as an independent measure of gene flow. Solutions of equilibrium diffusion equations suggested that killifish dispersal must be less than 2 km to maintain previously observed allozyme frequency clines in the absence of strong selection. To determine whether populations separated by distances greater than 2 km accumulate significant genetic differences we examined a total of N = 480 individuals from five killifish populations spanning a continuous shoreline distance of 8.4 km. Distribution of the 25 detected haplotypes indicated that most of the variation was within rather than between sampling locations. No evidence of geographic structure was detected, nor were there any significant genetic differences between killifish populations. With these data, gene flow was evaluated by estimating effective migration rate (Ne m) between the populations. Ne m was estimated from Gst (Ne m = 49.4), from Fst (Ne m = 24.1), by the private alleles approach (Ne m = 18.5) and via four phylogenetic analyses (Ne m ranged from 11.4 to 16.9). Regardless of the analysis, Ne m was greater than one; the threshold level at which gene flow is strong enough to prevent differentiation due to genetic drift. This suggests that while the characteristics that distinguish Fundulus subspecies may have arisen in isolation, the current clinal distributions exhibited along the Atlantic coast are most likely maintained by selection. PMID- 28564172 TI - HETEROZYGOSITY AND LIFE-HISTORY VARIATION IN BONY FISHES: AN ALTERNATIVE VIEW. PMID- 28564173 TI - NULL MODELS FOR THE NUMBER OF EVOLUTIONARY STEPS IN A CHARACTER ON A PHYLOGENETIC TREE. AB - Random trees and random characters can be used in null models for testing phylogenetic hypothesis. We consider three interpretations of random trees: first, that trees are selected from the set of all possible trees with equal probability; second, that trees are formed by random speciation or coalescence (equivalent); and third, that trees are formed by a series of random partitions of the taxa. We consider two interpretations of random characters: first, that the number of taxa with each state is held constant, but the states are randomly reshuffled among the taxa; and second, that the probability each taxon is assigned a particular state is constant from one taxon to the next. Under null models representing various combinations of randomizations of trees and characters, exact recursion equations are given to calculate the probability distribution of the number of character state changes required by a phylogenetic tree. Possible applications of these probability distributions are discussed. They can be used, for example, to test for a panmictic population structure within a species or to test phylogenetic inertia in a character's evolution. Whether and how a null model incorporates tree randomness makes little difference to the probability distribution in many but not all circumstances. The null model's sense of character randomness appears more critical. The difficult issue of choosing a null model is discussed. PMID- 28564174 TI - HERITABLE VARIATION IN ETHANOL TOLERANCE AND ITS ASSOCIATION WITH BIOCHEMICAL TRAITS IN DROSOPHILA MELANOGASTER. AB - To help elucidate mechanisms of larval ethanol tolerance seven isochromosomal lines of Drosophila melanogaster with different second chromosomes were fed a growth-limiting concentration of ethanol (4.5% v/v) and examined for associations between growth traits and biochemical characteristics that had previously been implicated in the determination of tolerance variation. Repeated measures of survival and development time over four generations verified the inherited nature of these traits. Significant variation among the lines were evident for flux from ethanol into lipid, for activity levels of alcohol dehydrogenase and glycerol-3 phosphate oxidase (GPO), and for levels of long chain and unsaturated fatty acids. A high degree of positive association occurred among the variables. A partial correlation analysis controlling for performance of the lines on ethanol free medium revealed a strong association between the degree of long chain fatty acid content and line survival when ethanol was fed. The correlation between GPO activity and survival in an ethanol environment appeared to depend on the association of GPO activity with long chain fatty acid content. The positive correlations of flux from ethanol into lipid with many of the other variables suggested that the ADH pathway influenced the level of ethanol tolerance. These associations are all consistent with the hypothesis that the lipid content of body tissues, especially the levels of long chain and unsaturated fatty acids in cell membranes, may have an important influence on both spatial and interspecific variation in the ethanol tolerance of larvae. PMID- 28564175 TI - MULTILEVEL ANALYSIS OF MORPHOMETRIC DATA FROM NATURAL PLANT POPULATIONS: INSIGHTS INTO ONTOGENETIC, GENETIC, AND SELECTIVE CORRELATIONS IN DALECHAMPIA SCANDENS. AB - I examined patterns of covariation of three morphometric blossom characters [gland area (GA), gland-stigma distance (GSD), and bract length (BL)] within genets, among genets, and among populations of the tropical vine, Dalechampia scandens (Euphorbiaceae). Covariance between BL and GA was evenly distributed among the three levels. This observation, coupled with developmental information, indicates that the two characters change size similarly during development, that there is probably genetic covariance between them (apparently caused by pleiotropy), and that the genetic covariance may have constrained (at least proximally) the course of population differentiation with respect to these characters. Most covariance between GSD and GA occurred at the among-population level. This observation, coupled with developmental information, indicates that there is negligible ontogenetic covariance and that within populations there is probably little or no genetic covariance between the two characters. Among population covariance has probably been caused by natural selection operating in a correlated fashion on characters that functionally interact in pollination. PMID- 28564176 TI - SELF-FERTILIZATION VERSUS CROSS-FERTILIZATION IN THE HERMAPHRODITIC FRESHWATER SNAIL BULINUS GLOBOSUS. AB - Self-fertilization depression of fitness in the freshwater hermaphroditic snail Bulinus globosus, an intermediate host of the parasitic trematode Schistosoma, has been studied in a strain originating from Niger. B. globosus is an outcrosser that can self-fertilize when isolated before any copulation has occurred. The self-fertilization depression has been estimated during two successive generations. In the first generation, selfing was compared to outcrossing. Within each mating system group, selfing and outcrossing were compared again in the second generation. A striking difference was shown in favor of cross fertilization for the number of eggs laid, the survival at birth of young snails and the number of snails reaching sexual maturity. The overall self-fertilization depression is 0.920 after two generations of selfing. We discuss the relative role of selfing and outcrossing in the evolution of freshwater snail populations. PMID- 28564177 TI - THE GENETIC STRUCTURE OF SPOROPHYTIC AND GAMETOPHYTIC POPULATIONS OF THE MOSS, FUNARIA HYGROMETRICA HEDW. AB - Patterns of phenotypic and genotypic variability in two populations of the moss, Funaria hygrometrica, were investigated using measurements of gametophytic and sporophytic morphology, sporophytic reproductive output, spore germination, gametophytic growth rates and tolerances of copper, cadmium, and low nutrient conditions, and electrophoretically detectable enzyme variation. The two populations differed in all traits measured, but complete monomorphism within populations at 14 enzyme loci suggested that each represented a single clone. Variability in gametophytic growth rates and responses to different experimental media, however, occurred among haploid sib families (families of meiotic progeny derived from the same sporophyte) and among sibs within families within both populations, suggesting high levels of genetic variability. Low mean reproductive output and a high level of variability among sporophytes in a mine site population probably reflected heavy metal toxicity. Based on this study, in combination with previous work on F. hygrometrica (Shaw, 19906), somatic mutation and/or nongenetic effects appear to contribute significantly to phenotypic variability in natural populations. PMID- 28564178 TI - FLUCTUATING ODONTOMETRIC ASYMMETRY, MORPHOLOGICAL VARIABILITY, AND GENETIC MONOMORPHISM IN THE CHEETAH ACINONYX JUBATUS. AB - The magnitudes of dimensional variability and fluctuating asymmetry in dental dimensions are reported for a sample of South African cheetah Acinonyx jubatus. To test the hypothesis that elevated levels of variability and asymmetry are associated with the increased developmental instability reported for this species, our results were contrasted to those for two other felids: Felis lybica and F. caracal. These findings suggest that dental dimensions in cheetahs are not significantly more variable or asymmetric. Hence, it is concluded that the cheetah may not be as developmentally unstable as was previously supposed. PMID- 28564179 TI - SEX-RATIO SELECTION WITH GENERAL MIGRATION SCHEMES: FISHER'S RESULT DOES HOLD. PMID- 28564180 TI - MEASURING SELECTION ON A POPULATION OF DAMSELFLIES WITH A MANIPULATED PHENOTYPE. AB - The estimation of the relationship between phenotype and fitness in natural populations is constrained by the distribution of phenotypes available for selection to act on. Because selection is blind to the underlying genotype, a more variable phenotypic distribution created by using environmental effects can be used to enhance the power of a selection study. I measured selection on a population of adult damselflies (Enallagma boreale) whose phenotype had been modified by raising the larvae under various levels of food availability and density. Selection on body size (combination of skeletal and mass at emergence) and date of emergence was estimated in two consecutive episodes. The first episode was survival from emergence to sexual maturity and the second was reproductive success after attaining sexual maturity. Female survival to sexual maturity was lower, and therefore opportunity for selection greater, than males in both years. Opportunity for selection due to reproductive success was greater for males. The total opportunity for selection was greater for males one year and for females the other. Survival to sexual maturity was related to mass gain between emergence and sexual maturity. Females gained more mass and survived less well than males in both years but there was no linear relationship between size at emergence and survival for females in either year. However, females in the tails of the phenotype distribution were less likely to survive than those near the mean. In contrast, small males consistently gained more mass than large males and survived less well in one year. There was significant selection on timing of emergence in both years, but the direction of selection changed due to differences in weather; early emerging females were more successful one year and late emerging males and females the other. The number of clutches laid by females was independent of body size. Because the resources used to produce eggs are acquired after emergence and this was independent of size at emergence, female fitness did not increase with size. Small males may have had lower survival to sexual maturity but they had higher mating success than large males. Resources acquired prior to sexual maturity are essential for reproductive success and may in some species alter their success in inter- and intrasexual competition. Therefore, ignoring the mortality associated with resource acquisition will give an incomplete and potentially misleading picture of selection on the phenotype. PMID- 28564181 TI - ECOTYPIC DIVERGENCE IN ALPINE POLEMONIUM VISCOSUM: GENETIC STRUCTURE, QUANTITATIVE VARIATION, AND LOCAL ADAPTATION. AB - Polemonium viscosum has a continuous distribution from 3,500 m in the krummholz to 4,025 m on the summit ridges of Pennsylvania Mountain, Colorado. Seeds produced by plants at opposite ends of this cline, 1.5 km apart, differed significantly at allozyme loci in two consecutive breeding seasons. Mean multilocus Fst values for both years (0.015 and 0.069) were significantly different from zero, indicating restricted gene exchange between subpopulations. Average allele frequencies at two individual loci also differed significantly between families comprising krummholz and summit subpopulations. Progeny of plants growing on the summit had higher leaf production rates, more densely packed leaflets, and lower resistance to aphids than progeny of plants growing in the krummholz site, when tested under greenhouse conditions. These differences probably reflect the restricted opportunities for growth and severe exposure at high elevations, and the increased risk from herbivores near timberline. The two subpopulations did not differ in leaf length (stature), leaf width, or pubescence. Reciprocal transplanting of seedlings between krummholz and summit sites confirmed that the differences were adaptive, since progeny from each subpopulation performed significantly better in their parent's habitat. Coordinated studies of genetic structure, quantitative variation, and local adaptation across the elevational range of P. viscosum provide a comprehensive view of ecotypic divergence in this widespread alpine plant. PMID- 28564182 TI - Correction. PMID- 28564183 TI - SIX INDEPENDENT LOSSES OF THE CHLOROPLAST DNA rpl2 INTRON IN DICOTYLEDONS: MOLECULAR AND PHYLOGENETIC IMPLICATIONS. AB - Previous studies have shown that in several angiosperms and the liverwort Marchantia the chloroplast gene rpl2, encoding ribosomal protein L2, is interrupted by an intron, but that in spinach (Spinacia oleracea, Caryophyllales) this intron has been lost. We have determined the distribution of the rpl2 intron for 390 species representing 116 angiosperm families. Filter hybridizations reveal that the intron is absent from the chloroplast genomes of all examined families of the Caryophyllales, suggesting that the intron was lost in the common ancestor of the order. Sequencing of the rpl2 gene in five genera of the Caryophyllales and in Rumex (Polygonales) not only confirms the filter hybridization results, but also shows that for all taxa lacking the intron, the rpl2 gene has undergone a precise deletion of the intron. In all cases, it is the original rpl2 gene that has sustained loss of its intron. This implies that in chloroplast DNA, integration of exogenous genes (e.g., a reverse transcript of a spliced mRNA) occurs mainly by homologous, replacement recombination, rather than by illegitimate recombination elsewhere in the genome. Filter hybridizations also reveal that the rpl2 intron was lost independently in the common ancestors of at least five other lineages of dicotyledons: Saxifragaceae (s.s.), Convolvulaceae (including Cuscuta), Menyanthaceae, two genera of Geraniaceae, and one genus of Droseraceae. The molecular and phylogenetic implications of these independent intron losses are discussed. PMID- 28564184 TI - NATURAL SELECTION ON BODY SIZE AND LAYING DATE IN THE TREE SWALLOW. AB - I measured natural selection on body size and laying date in a population of tree swallows (Tachycineta bicolor) from 1986 to 1988. There was little evidence of selection on body size associated with overwinter survival. Disruptive selection on tarsus length, associated with female reproductive success, was detected in one of three years. Both repeatability and mother-daughter regression suggested that laying date was heritable. I found weak evidence of selection on laying date, associated with both overwinter survival and reproduction in females. The ecological implications of both tarsus length and laying date variation in this population could not be identified. Consequently, although I was able to identify the targets of natural selection, the ecological link between trait variation and selection remains unknown. PMID- 28564185 TI - COMPARISON OF VARIANCE COMPONENTS BETWEEN TWO POPULATIONS OF HOLCUS LANATUS: A REANALYSIS. PMID- 28564186 TI - THE COVARIANCE STRUCTURE OF LIFE-HISTORY CHARACTERS IN DAPHNIA PULEX. AB - The genetic covariance structure for life-history characters in two populations of cyclically parthenogenetic Daphnia pulex indicates considerable positive correlation among important fitness components, apparently at odds with the expectation if antagonistic pleiotropy is the dominant cause of the maintanence of genetic variation. Although there is no genetic correlation between offspring size and offspring number, present growth and present reproduction are both strongly positively correlated genetically with future reproduction, and early maturity is genetically correlated with larger clutch size. Although the ubiquity of antagonistic pleiotropy has been recently questioned, there are peculiarities of cyclical parthenogenesis that could lead to positive life-history covariance even when negative covariance would be expected in a similar sexual species. These include the influence of nonadditive gene action on evolution in clonally reproducing organisms, and the periodic release of hidden genetic variance within populations of cyclical parthenogens. Examination of matrix similarity, using the bootstrap for distribution-free hypothesis testing, reveals no evidence to suggest that the genetic covariance matrices differ between the populations. However, there is considerable evidence that the phenotypic and environmental covariance matrices differ between populations. These results indicate approximate stability of the genetic covariance matrix within species, an important assumption of many phenotypic evolution models, but should caution against the use of phenotypic in place of genetic covariance matrices. PMID- 28564188 TI - COMPARATIVE ANALYSIS OF SEX-INVESTMENT RATIOS IN SLAVE-MAKING ANTS. PMID- 28564187 TI - NONADAPTIVE EVOLUTION OF DISEASE RESISTANCE IN AN ANNUAL LEGUME. AB - Local populations of the plant Amphicarpaea bracteata often contain genetically divergent lineages that differ strongly in disease resistance toward the specialist pathogen Synchytrium decipiens. In one population, lineages with disease resistance were observed to significantly decrease in frequency over a two-year period, despite the continued presence of pathogens. Extensive self pollination in A. bracteata restricts the opportunity for recombination of alleles affecting separate traits, resulting in strong correlations between disease resistance and other ecologically important characters, including plant morphology, phenology, and patterns of reproductive allocation. Natural selection on these correlated characters may thus cause nonadaptive changes in disease resistance. These results imply that A. bracteata's mating system is a basic constraint interfering with its adaptation to pathogen attack. PMID- 28564189 TI - HYBRIDIZATION AND CRYPTIC SPECIES IN DICAMPTODON (CAUDATA: DICAMPTODONTIDAE). AB - The salamander genus Dicamptodon consists of at least four genetically divergent groups of populations with 10-19 fixed allelic differences (out of 31 loci scored) between populations in alternative groups. One of these groups corresponds to D. copei; the other three until now usually have been considered to belong to the single morphologically homogeneous species D. ensatus. Two instances of geographic contact between genetic units occur in the genus, one between D. copei and "D. ensatus" in northern Oregon and the other between two highly divergent types of "D. ensatus" in coastal northern Calfornia. In the former case no hybridization occurs, while in the latter a narrow hybrid zone has been observed. There appears to be selection against hybrids within this hybrid zone, and introgression beyond the zone is apparently nonexistent. The population groups therefore appear to be genetically independent units, and Dicamptodon is best considered to consist of four species: D. copei, D. ensatus, D. tenebrosus, and D. aterrimus. PMID- 28564190 TI - GENETIC CONSEQUENCES OF OUTCROSSING IN THE CLEISTOGAMOUS ANNUAL, IMPATIENS CAPENSIS. II. OUTCROSSING RATES AND GENOTYPIC CORRELATIONS. AB - The genetic consequences of a plant's mating system depend on both the degree of outcrossing and the genetic relationship between mates. We examined the electrophoretic genotypes of seeds derived from cleistogamous (CL) and chasmogamous (CH) flowers in six populations of the facultatively cleistogamous annual, Impatiens capensis. Multilocus estimates of the outcrossing rates for the strongly protandrous CH flowers ranged from 0.29 to 0.71 and were higher than estimates based on single-locus data. Such results suggest that the CH flowers experience variable levels of both geitonogamous self-fertilization and biparental inbreeding. A new and generally applicable technique based on the relative level of inbreeding within progeny groups provided direct estimates of the correlation between the genotypic values of outcrossed mates. These correlations varied widely among populations and contributed up to half of the inbreeding observed among the CH progeny. Such biparental inbreeding biases estimates of the outcrossing rate based on the mixed-mating model downward and influences mating-system evolution by decreasing the "cost of meiosis." PMID- 28564191 TI - THE ASSOCIATION BETWEEN THE POLYMORPHISMS AT THE Adh AND alphaGpdh LOCI AND THE In(2L)t INVERSION IN DROSOPHILA MELANOGASTER IN RELATION TO TEMPERATURE. AB - Substantial allele-frequency changes were observed at the Adh and alphaGpdh loci in a seminatural population of Drosophila melanogaster kept in a tropical greenhouse during 1972-1985. Further analysis of the changes at the Adh and alphaGpdh loci showed that linkage disequilibrium between these loci occurred for a prolonged period due to the presence of In(2L)t, a long inversion on the left arm of the second chromosome. We observed increases in the frequencies of In(2L)t and of short inversions on the left arm of the second chromosome in subpopulations kept at 29.5 degrees C or 33 degrees C. These inversion-frequency increases were accompanied by an increase in Adhs and a decrease in alphaGpdhs frequency. In populations kept at 20 degrees C and 25 degrees C, inversion frequencies decreased, while alphaGpdhs allele frequencies decreased at 25 degrees C and increased at 20 degrees C. At 33 degrees C, egg-to-adult survival of individuals possessing In(2L)t, either in the homokaryotypic or the heterokaryotypic state, was higher than that of the other karyotypes of identical allozyme constitution (i.e., Adhs alphaGpdhF ). Thus it seems that In(2L)t has a selective advantage at high temperature. We argue that the observed changes in allele frequencies at the Adh and alphaGpdh loci are, in part, due to genic selection and are not merely the result of selection acting on the chromosome rearrangements and hitchhiking of the allozymes. The results are discussed with respect to the latitudinal clines found for In(2L)t, Adh, and alphaGpdh. PMID- 28564192 TI - PHENOTYPIC CORRELATES OF GENOME SIZE VARIATION IN AEDES ALBOPICTUS. PMID- 28564193 TI - RAPID, GEOGRAPHICALLY EXTENSIVE GENETIC INTROGRESSION AFTER SECONDARY CONTACT BETWEEN TWO PUPFISH SPECIES (CYPRINODON, CYPRINODONTIDAE). AB - Apparently between 1980 and 1984, Cyprinodon variegatus was introduced into an area of the Pecos River in Texas, where it hybridized with an endemic species, C. pecosensis. Protein electrophoresis indicated that, by 1985, panmictic admixtures of these two pupfishes occupied approximately 430 river-kilometers of the Pecos River, roughly one-half of the historic range of the endemic species. The average frequency of introduced alleles at four diagnostic loci ranged from 0.18 to 0.84 at the 15 sites sampled from the Pecos River in Texas. Clinal patterns in allele frequencies suggest that C. variegatus was introduced into a mid-reach of the river and that this was followed by both upstream and downstream dispersal of the introduced alleles. All pairwise combinations of loci showed significant linkage disequilibrium. The level of disequilibrium indicates chromosomal linkage for one gene-pair, Gpi-A and Est-1. The change in pupfish allele frequencies in the Pecos River represents an extreme example of rapid natural selection in a seminatural situation. PMID- 28564194 TI - CORRELATED MATINGS IN THE PARTIAL SELFER MIMULUS GUTTATUS. AB - In partially selfing populations, siblings may be correlated for both selling and paternity. A model of the mating system based upon sampling pairs of progeny from a maternal parent is described. The model separates the correlation of selfing from the correlation of outcrossed paternal alleles and is an approach to paternity analysis suited for larger populations with fewer marker loci. Its parameters determine the components of genetic covariance between sibs and provide information about the average number of fathers in a maternal sibship. Electrophoretic markers were used to obtain estimates of correlated matings for two Mimulus guttatus populations. In both populations, about 50% selfing was observed. For two sibs randomly selected from the same capsule, the correlations of selfing between these sibs were 17% and 12% in the two populations, and the correlations of paternity (the proportion of full-sibs among outcrossed sib pairs) were 37% and 44%. Sibs from different capsules were not correlated for selfing, and the paternity correlation dropped to near 20% in both populations. However, estimates of correlated matings have high variance, lack statistical independence, and can be difficult to obtain. The use of marker loci with many alleles can alleviate these problems. PMID- 28564195 TI - A TEST OF THE ROLE OF EPISTASIS IN DIVERGENCE UNDER UNIFORM SELECTION. AB - Five populations of Drosophila melanogaster have previously been shown to be replicably different in their responses to artificial selection for knockdown resistance to ethanol fumes (Cohan and Hoffmann, 1986). The present study tests whether this divergence could be attributed to the epistatic mechanism assumed by Wright's shifting-balance model of evolution, in which alleles favored in the genetic background of one population are not favored in that of another. If this were the mechanism of divergence, crosses between selected lines from different populations would be expected to yield an epistatic loss of the selected phenotype. However, all such crosses showed a good fit to an additive model with dominance. Divergence by an epistatic mechanism may also be associated with epistatic variance within populations, but no evidence for such epistasis was found. The populations therefore appear to have responded in different ways to selection not because of epistasis but because knockdown-resistance alleles that were common in some populations were absent (or at least less common) in others. PMID- 28564196 TI - FLORAL HERBIVORY IN PASTINACA SATIVA: DO COMPENSATORY RESPONSES OFFSET REDUCTIONS IN FITNESS? PMID- 28564197 TI - ONTOGENETIC VARIATION IN PATTERNS OF DEVELOPMENTAL AND FUNCTIONAL INTEGRATION IN SKULLS OF SIGMODON FULVIVENTER. AB - Patterns of variation and covariation within populations can influence how characters respond to natural selection and random genetic drift and so constrain the ability of natural selection to modify the phenotype. We examined several potential developmental and functional explanations of character covariation throughout ontogeny using known-age samples of the cotton rat (Sigmodon fulviventer) to identify the causes of covariation and to assess the variability of patterns of covariation throughout postnatal growth. Competing developmental and functional models were fit to samples of orofacial and neurocranial measures by confirmatory factor analysis and evaluated for their ability to reconstruct observed variance-covariance matrices. Samples of successive ages were simultaneously fit to a common model to test the hypothesis that the patterns of developmental and functional integration were invariant between ages. Orofacial characters derived from the same branchial-arch primordium covary early in ontogeny. Subsequently, there is a repatterning of integration that may reflect a transition from developmental to functional sources of integration. Neurocranial characters exhibit even more variation in patterns of covariation: initially, characters appear to comprise a single integrated unit; before puberty, they appear to respond to localized bone growth; after puberty, they form separate calvarial and basicranial components. This ontogenetic variation in patterns of covariation suggests that developmental constraints are transient and flexible and that the consequences of selection may depend upon the age at which it acts. PMID- 28564198 TI - AN EXPERIMENTAL FIELD STUDY OF ANTHER-SMUT DISEASE OF SILENE ALBA CAUSED BY USTILAGO VIOLACEA: GENOTYPIC VARIATION AND DISEASE INCIDENCE. AB - Twenty cloned genotypes of Silene alba differed greatly (0-100%) in the percentage of flowering plants that became diseased by the anther-smut fungus Ustilago violacea following natural spore dispersal in a two-year field experiment. Male genotypes with the highest percentage of disease had high rates of flower production; this trait may increase the probability of spore deposition on flowers, a common site of infection. Because of this relationship, male genotypes with the highest percentage of disease also produced the most healthy flowers in the two-year period. Flowering early in the season was also a predictor of high disease levels for male genotypes in the first year. Variation among female genotypes in disease levels was not correlated with either flower production or phenology, suggesting that the sexes differ in their interaction with the pathogen. Plants of both sexes that remained nonreproductive the first year but flowered the second year could become diseased due to infection of vegetative tissue. Disease levels of the genotypes following natural spore dispersal were not correlated with disease levels of the genotypes following inoculation of vegetative tissue. This discrepancy points out that the methodology used to investigate genetic variation in disease resistance may affect the results obtained. PMID- 28564199 TI - FLOW-CYTOMETRIC ANALYSES OF NUCLEAR DNA CONTENT IN FOUR FAMILIES OF NEOTROPICAL BATS. AB - Flow-cytometric analyses of 29 species of microchiropteran bats representing four families and 20 genera revealed that bats possess only 79% (5.43 pg) of the DNA content of a "typical" mammal (e.g., Mus musculus strain C57BL; 7 pg). Chiroptera, the second largest order of mammals, is thus an exception to the prevailing view that mammals possess a minimum nuclear DNA content of 7 pg. Limitations on cell size resulting from a high metabolic rate may have constrained evolution of DNA content and could explain why the extensive heterochromatic additions that are common in some groups of mammals are absent in bats. Chromosomes of bats have been well studied; detailed chromosomal banding data are available for nearly all the species used in this investigation. However, no significant correlations were found between DNA content and karyotypic characteristics such as 2n, fundamental number, and rate or pattern of chromosomal evolution. PMID- 28564200 TI - MEASURING POLLINATOR-MEDIATED SELECTION ON MORPHOMETRIC FLORAL TRAITS: BUMBLEBEES AND THE ALPINE SKY PILOT, POLEMONIUM VISCOSUM. AB - Sweet-flowered plants of Polemonium viscosum in Colorado are visited by a fly dominated pollinator fauna at timberline (krummholz), but almost exclusively by bumblebees in higher-elevation tundra habitats. Significant increases in flower size and height are associated with increasing elevation along this habitat gradient. This paper presents the results of an experiment designed to test whether bumblebees exert sufficient selection on morphometric floral phenotypes to account for the clinal shifts seen in natural populations. Two populations of sweet-flowered plants of krummholz origin were established: one randomly pollinated, the other solely bumblebee-pollinated. I tested the effects of two independent axes of floral variation, obtained by principal-components analysis, on mean seed set per flower of plants in each population. PC1, with strong correlations to corolla diameter, corolla length, and stem height, explained a significant amount of variance in seed set for bumblebee-pollinated plants but had no bearing on that of randomly pollinated plants. PC2, with strong correlation to flower number, did not influence seed set in either population. Bumblebee behavior was correlated with variation in PC1 scores of the selected population, yielding positive directional selection on morphometric floral traits associated with PC1. Selection coefficients for PC1, corolla length, corolla diameter, and inflorescence height were estimated, respectively, as 0.11, 0.09, 0.07, and 0.06 (P < 0.025 in all cases). These results support the hypothesis that pollinator-mediated selection can bring about changes in floral form, and can explain shifts in floral morphology of P. viscosum along natural habitat gradients. PMID- 28564201 TI - MOLECULAR HETEROCHRONIES AND HETEROTOPIES IN EARLY ECHINOID DEVELOPMENT. AB - By comparing the spatial and temporal distribution of three proteins during early development in seven echinoid species, we demonstrate that both heterochronies and heterotopies in gene-product expression have accompanied the radiation of post-Paleozoic echinoids. All three proteins examined showed significant alterations in time of expression, site of expression, or both. These molecular heterochronies and heterotopies indicate that early development is not necessarily as evolutionarily conservative as morphology of embryos alone would suggest. Evolutionary alterations in early development may be more common than is generally assumed. PMID- 28564202 TI - COURTSHIP BEHAVIOR AND CONTROL OF REPRODUCTIVE ISOLATION IN DROSOPHILA MOJAVENSIS. PMID- 28564203 TI - EXPERIMENTAL EVIDENCE FOR GENETIC VARIATION IN COMPATIBILITY BETWEEN THE FUNGUS ATKINSONELLA HYPOXYLON AND ITS THREE HOST GRASSES. AB - Variation in compatibility has been documented within and among several natural plant populations infected by fungal pathogens. In this study, seeds and isolates of the fungus Atkinsonella hypoxylon (Ascomycetes, Clavicipitaceae) were collected from three populations of the grass Danthonia spicata, two populations of D. compressa, and four populations of Stipa leucotricha. Each fungal strain was reciprocally inoculated into seedlings grown in aseptic culture from its original host population, into seedlings from other conspecific host populations, and into seedlings from the other two host species. There were three distinct patterns of compatibility, as evidenced by the ability of the fungus to grow on the seedling and to colonize new tillers. Fungal strains from one host genus were incompatible with seedlings from the other host genus. Strains from the two Danthonia species were broadly compatible among Danthonia populations and had very high rates of infection, while strains from Stipa also were broadly compatible among Stipa populations but had relatively low rates of infection. Literature surveys indicate that, in contrast to pathogenic microorganisms, mutualistic microorganisms typically exhibit broad patterns of compatibility among hosts, which lack resistance to infection. The effect of A. hypoxylon on host fitness is most detrimental in Stipa, where the fewest seedlings became infected, and most beneficial in Danthonia, where most seedlings became infected. PMID- 28564204 TI - BEHAVIORAL OBSERVATIONS OF SEXUAL ISOLATION AMONG ALLOPATRIC POPULATIONS OF THE MOUNTAIN DUSKY SALAMANDER, DESMOGNATHUS OCHROPHAEUS. AB - The behavioral basis of sexual isolation was investigated in 11 crosses staged between individuals from nine allopatric populations of the Appalachian mountain dusky salamander, Desmognathus ochrophaeus. Scan-sampled observations of within population (homotypic) and between-population (heterotypic) heterosexual encounters yielded the following results. 1) Fewer heterotypic encounters than homotypic encounters resulted in insemination of females. Indices of the strength of sexual isolation based on insemination data ranged from 0.26 (lowest) to 0.82 (highest), indicating that mechanisms that confer sexual isolation may evolve during allopatric differentiation. 2) Heterotypic encounters that progressed as far as the stage of courtship during which the male stimulates the female to mate did so at the same time as homotypic encounters, although the number of the former reaching this stage was lower. 3) The time interval from courtship initiation to insemination was longer in heterotypic encounters than homotypic encounters. In some crosses, males did not attempt to initiate heterotypic encounters, indicating that this sex is responsible for sexual isolation in these instances. We use our results to formulate specific hypotheses concerning the behavioral basis of sexual isolation in these salamanders, and some possible experimental approaches are suggested. PMID- 28564205 TI - FLORAL COLOR CHANGE IN LUPINUS ARGENTEUS (FABACEAE): WHY SHOULD PLANTS ADVERTISE THE LOCATION OF UNREWARDING FLOWERS TO POLLINATORS? AB - I examined the adaptive significance of two floral traits in the perennial herb, Lupinus argenteus: 1) the retention of corollas on "spent" flowers, i.e., flowers containing inviable pollen, unreceptive stigmas, and negligible pollinator rewards and 2) a change in corolla color of retained "spent" flowers, which is restricted to a spot on the banner petal. At anthesis, this spot is yellow, and approximately four days later, it changes to purple. After the change, purple flowers remain on plants an additional 5-7 days before corolla abscission occurs; purple flowers were avoided by pollinators, presumably because they contained less pollen (rewards) than yellow ones. I experimentally tested the hypothesis that purple flowers contribute to the floral display of the plant by removing varying numbers of spent flowers and assessing the effect on pollination visitation. Pollinators preferentially approached and foraged on plants with greater numbers of flowers per inflorescence; they did not discriminate between yellow (rewarding) and purple (nonrewarding) flowers at interplant distances greater than 0.4 meters but would preferentially forage on plants with more total flowers, even if these individuals contained fewer rewarding flowers. Thus, spent flowers increased the overall attractiveness of plants to pollinators. In theory, color change may benefit plants in two ways. First, by directing pollinators to rewarding flowers, the change may increase pollinator foraging efficiency, with the result that pollinators visit more flowers before leaving plants (pollinator tenure mechanism). Second, by directing pollinators to receptive flowers, the color change may prevent incoming pollen from being wasted on unreceptive stigmas and may prevent collection of inviable pollen (pollination-efficiency mechanism). I tested the pollinator-tenure mechanism experimentally by removing pollen from yellow flowers, thereby reducing the reliability of the color-reward signal. Pollinators visited fewer total flowers on experimental plants than on controls, resulting in reduced seed production in one year. PMID- 28564206 TI - POPULATION DIFFERENTIATION AND RACIAL ADMIXTURE IN THE AFRICANIZED HONEYBEE (APIS MELLIFERA L.). AB - To study the degree of interpopulational differentiation and racial admixture in Africanized honeybees, we collected worker bees from three regions of Brazil (the northeast, the state of Sao Paulo, and Porto Alegre) and from Uruguay and determined their genotypes for 10 enzyme loci. We also performed a morphometric analysis on forewing measurements of worker bees from the northeast and Porto Alegre regions of Brazil and from Paysandu, Uruguay. Comparative analysis of interpopulational heterogeneity snowed that there are significant differences, especially at the Mdh locus, among the populations from different regions. An increase in the frequency of the MdhB allele was observed from north to south, with predominance in the Uruguayan populations. A small component of interpopulational variability was detected in the populations studied. Racial admixture was calculated from information obtained for Mdh in Africa and Europe. The percentages of racial admixture differed slightly but significantly among Brazilian regions. The morphometric study based on canonical variables exhibited a similar pattern. The greater proportions of Apis mellifera adansonii alleles in the admixture may be explained by selection during the initial stage of migration of Africanized bees and by preferential mating between individuals of the same race. Differences in the proportions of A. m. adansonii alleles between regions indicate incipient populational differentiation of Africanized bees. We suggest that greater gene flow from the European races in the south of Brazil could be one of the causes of this phenomenon. PMID- 28564207 TI - POLYPLOIDY IN PROSERIATA (PLATYHELMINTHES) AND ITS PHYLOGENETICAL IMPLICATIONS. PMID- 28564209 TI - A COEVOLUTIONARY ISOMORPHISM APPLIED TO LABORATORY STUDIES OF COMPETITION. AB - Some empirical consequences of an isomorphism between the Lotka-Volterra competitive model and a coevolutionary competitive model are developed. In both the Lotka-Volterra and coevolutionary models, four competitive outcomes are possible: 1) species one wins, 2) species two wins, 3) indeterminate outcome, and 4) stable coexistence. These two models are isomorphic in the sense that the inequalities associated with a particular competitive outcome of the Lotka Volterra model correspond in a one-to-one manner with similar inequalities associated with the same competitive outcome of the coevolutionary model. The inequalities of the Lotka-Volterra model involve the competition coefficients themselves, while the inequalities of the coevolutionary model involve the genetic variances and covariances of the competition coefficients. The isomorphism suggests some alternative interpretations of the results of classical laboratory studies of competition. The Lotka-Volterra (or ecological) hypotheses postulate that the competition coefficients are constant and that genetic considerations play no role in determining the competitive outcome. By contrast, the evolutionary hypotheses derived from the coevolutionary model postulate that the competition coefficients are variables and that the genetic variances and covariances of the competition coefficients determine the competitive outcome. The isomorphism is applied to competitive exclusion and coexistence, and to competitive indeterminacy in Tribolium. In particular, the evolutionary hypotheses isomorphic to the two classical explanations of competitive indeterminacy, the demographic stochasticity and genetic founder effect hypotheses, are constructed. The theory developed here and in a previous paper (Pease, 1984) provides one perspective on the relation among the Lotka-Volterra competition theory, quantitative genetics, competitive exclusion, the reversal of competitive dominance, coexistence, competitive indeterminacy in Tribolium, and experiments investigating the relation between genetic variability and the rate of evolution of fitness. PMID- 28564208 TI - Commissioning and quality assurance for VMAT delivery systems: An efficient time resolved system using real-time EPID imaging. AB - PURPOSE: An ideal commissioning and quality assurance (QA) program for Volumetric Modulated Arc Therapy (VMAT) delivery systems should assess the performance of each individual dynamic component as a function of gantry angle. Procedures within such a program should also be time-efficient, independent of the delivery system and be sensitive to all types of errors. The purpose of this work is to develop a system for automated time-resolved commissioning and QA of VMAT control systems which meets these criteria. METHODS: The procedures developed within this work rely solely on images obtained, using an electronic portal imaging device (EPID) without the presence of a phantom. During the delivery of specially designed VMAT test plans, EPID frames were acquired at 9.5 Hz, using a frame grabber. The set of test plans was developed to individually assess the performance of the dose delivery and multileaf collimator (MLC) control systems under varying levels of delivery complexities. An in-house software tool was developed to automatically extract features from the EPID images and evaluate the following characteristics as a function of gantry angle: dose delivery accuracy, dose rate constancy, beam profile constancy, gantry speed constancy, dynamic MLC positioning accuracy, MLC speed and acceleration constancy, and synchronization between gantry angle, MLC positioning and dose rate. Machine log files were also acquired during each delivery and subsequently compared to information extracted from EPID image frames. RESULTS: The largest difference between measured and planned dose at any gantry angle was 0.8% which correlated with rapid changes in dose rate and gantry speed. For all other test plans, the dose delivered was within 0.25% of the planned dose for all gantry angles. Profile constancy was not found to vary with gantry angle for tests where gantry speed and dose rate were constant, however, for tests with varying dose rate and gantry speed, segments with lower dose rate and higher gantry speed exhibited less profile stability. MLC positional accuracy was not observed to be dependent on the degree of interdigitation. MLC speed was measured for each individual leaf and slower leaf speeds were shown to be compensated for by lower dose rates. The test procedures were found to be sensitive to 1 mm systematic MLC errors, 1 mm random MLC errors, 0.4 mm MLC gap errors and synchronization errors between the MLC, dose rate and gantry angle controls systems of 1 degrees . In general, parameters measured by both EPID and log files agreed with the plan, however, a greater average departure from the plan was evidenced by the EPID measurements. CONCLUSION: QA test plans and analysis methods have been developed to assess the performance of each dynamic component of VMAT deliveries individually and as a function of gantry angle. This methodology relies solely on time-resolved EPID imaging without the presence of a phantom and has been shown to be sensitive to a range of delivery errors. The procedures developed in this work are both comprehensive and time-efficient and can be used for streamlined commissioning and QA of VMAT delivery systems. PMID- 28564210 TI - GENETIC AND ENVIRONMENTAL DETERMINANTS OF FOOD PREFERENCE IN DROSOPHILA TRIPUNCTATA. AB - Mark-release-recapture field experiments involving two isofemale strains of Drosophila tripunctata revealed that strain identity strongly and consistently affected the preferences of both males and females for mushrooms versus tomatoes. Females, but not males, showed an augmented preference for the type of food on which they had been kept prior to release. The behavior of F2 flies from reciprocal crosses between the two strains demonstrated that genetic variation for food preference is autosomal and largely additive. Because mating often occurs in the vicinity of food in the wild, positive assortative mating with respect to genes for food preference may lead to greater phenotypic variance in preference, which could increase the variety of food resources used by a population. PMID- 28564211 TI - GENETIC DIFFERENTIATION IN THE DROSOPHILA ATHABASCA COMPLEX. PMID- 28564212 TI - LATITUDINAL CLINE IN DROSOPHILA MELANOGASTER FOR KNOCKDOWN RESISTANCE TO ETHANOL FUMES AND FOR RATES OF RESPONSE TO SELECTION FOR FURTHER RESISTANCE. AB - We have introduced a device for selecting Drosophila for increased resistance to very high concentrations of ethanol fumes. This device has enabled us to: 1) select quickly and easily over a thousand flies at a time, and 2) score the knockdown time of every fly in the distribution, while causing very little injury to the flies. A sample of nine west coast populations of Drosophila melanogaster showed a significant trend toward higher knockdown resistance in more northern populations. A population's level of knockdown resistance was virtually uncorrelated with its alcohol dehydrogenase (Adh) allele frequencies. Five of the above nine populations were then subjected to selection for further knockdown resistance. Each population was divided randomly into four groups of 256 flies: two lines to be selected, and two lines to remain unselected as control lines. In every generation each selected line was measured for knockdown resistance, and the last quartile of flies to be knocked down was saved to continue the selection cycle. Population sizes of the selected and unselected lines were all maintained at 256. Realized heritability, based on the responses to selection of the first four generations, was calculated for each selected line. The five populations were significantly heterogeneous for heritability estimates; the average heritability of the five populations pooled was 0.143 +/- 0.019. Over the course of twelve generations, the ten selected lines increased their knockdown times by an average factor of 2.40. Before selection, the five populations were heterogeneous for knockdown resistance, and resistance was greatest among the most northern populations. The amount of change of knockdown resistance over the course of selection was also correlated with latitude: the most southern population increased its knockdown time by a factor of 2.23, and the most northern population increased it by a factor of 2.55. After ten generations of selection, the cline of knockdown resistance was about 4.5 times as steep as that before selection. Small phenotypic differences among populations before selection were thus exaggerated by the action of selection. The differences among populations in their rates of response to selection were attributed to genetic differences that existed before selection. The pattern of change of Adh frequencies over the course of selection was very inconsistent, both among and within populations. From this inconsistency of change of Adh alleles with selection, and the lack of correlation between Adh frequencies and knockdown resistance before selection, we concluded that Adh frequency changes could not have had much effect on the responses of the selected lines. PMID- 28564213 TI - THE EVOLUTIONARY SIGNIFICANCE OF BACTERIA ASSOCIATED WITH RHAGOLETIS. AB - All Rhagoletis reportedly establish associations with one or more bacterial species, but the bases for these interactions and their implications for host race formation and speciation are poorly understood. Here we present the results of four studies designed to increase our understanding of these relationships. In the first study, we identify the bacteria associated with seven Rhagoletis taxa by surveying the inhabitants of the esophageal bulb, an organ whose major function appears to be the housing of microorganisms. The results suggest that no bacterium has entered into an obligate symbiotic relationship with any of the Rhagoletis taxa surveyed, although one bacterium, Klebsiella oxytoca, is a very common associate of six of the seven. In the second study we use horizontal starch gel electrophoresis to determine the genetic similarity of K. oxytoca clones isolated from different Rhagoletis populations. This analysis provides a rare look into the genetic structure of natural populations of an enteric bacterium and permits the construction of a dendrogram for the clones-a dendrogram which indicates that there is no clear-cut pattern to the distribution of K. oxytoca genotypes among Rhagoletis. Taken together, the above studies provide indirect evidence that the bacteria associated with Rhagoletis are not important determinants of host plant specificity. The third and fourth studies assess two possible functions associated bacteria may perform for Rhagoletis: pectic substances degradation and nitrogen fixation. Our results do not lend support to either function. PMID- 28564214 TI - FEMALE-BIASED SEX RATIOS: INDIVIDUAL OR GROUP SELECTION? AB - The evolution of biased sex ratios in a randomly structured population stems from individual selection acting through local parental control (LPC) of the sex ratio and hence of the mating success of the sons and/or daughters. As a general rule, the sex ratio is biased away from the sex whose fitness is most affected by changes in the local sex ratio. This is the sex whose fitness is subject to the most effective parental control. The bias acts to increase the fitness of the rarer, controlled sex and to increase parental productivity. In the specific case of the evolution of the female-biased Hamiltonian ratios, LPC can affect the mating success of sons but has no effect on the success of daughters. It is argued here and elsewhere (Nunney, unpubl.) that group selection can only promote the spread of a genotype through the maintenance of a positive association of individuals of that genotype. The importance of positive association is well established in the special case of kin selection. Given such a definition, group selection plays no part in the evolution of the Hamiltonian sex ratios, although it is possible to conceive of circumstances under which group selection could favor an even more extreme sex ratio bias. In general, such circumstances involve kin selection. It is argued that the examination of differences in group productivity is not a useful way of looking at the process of natural selection, since (i) by dividing up almost any evolving population into random groups, some groups (those with the highest frequency of the fittest individuals) will be more productive than others; and (ii) in the specific case of the evolution of the Hamiltonian ratios, it is possible to develop models either with or without a group structure and get the same result. Hamilton (1967) originally suggested that a female-biased sex ratio arose in his model because of the advantage of reducing local mate competition (specifically, reducing competition between brothers for mates). This possibility was eliminated by developing a model in which competition between the brothers was prevented regardless of the sex ratio. It was found that the optimum sex-ratio strategy was unaffected. On the other hand, the idea of local parental control has, in each case examined, been able to account for the predicted optimum strategy. PMID- 28564215 TI - AN EMPIRICAL DEMONSTRATION OF THE LABILITY OF HETEROZYGOSITY ESTIMATES. PMID- 28564216 TI - PROXIMATE MECHANISMS OF SEXUAL SELECTION IN WOOD FROGS. AB - Observations and several types of field experiments on the mating behavior of wood frogs have revealed the proximate mechanisms for a size-related reproductive advantage in both males and females. For females, larger individuals produce larger clutches; for males, larger individuals can better remain clasped to females when contested by rival males and can better depose males clasped to other females. No results obtained support of the existence of mate choice in either males or females. Males were estimated to be 4.74 times as variable as females in the number of zygotes produced per individual per season; however, much of the variation in male RS resulted from a male-biased sex ratio at the breeding site rather than from sexual selection. After taking sex ratio effects into consideration, males were estimated to be only 1.63 times as variable as females. Patterns of variation in RS in males and females are associated with numerous sex-specific differences in life history and morphology. Life history differences include differential growth rates, ages at sexual maturity, and rates of mortality. Interpretation of how the body size dimorphism (females larger than males) in this species relates to sexual selection is consistent with information on how similar variations in body size influence RS for each sex, and how males and females differ in the functional relationship between body size and RS. Average RS increases more with body size in females than in males. Although body size directly influences RS for females, the possibility exists that, for males, other anatomical features correlated with body size more directly affect RS. Preliminary evidence suggests that sexual selection influences male arm length and that the male body size : RS relationship results as an incidental correlation. PMID- 28564217 TI - THE COMPARATIVE DEMOGRAPHY OF RECIPROCALLY SOWN POPULATIONS OF PHLOX DRUMMONDII HOOK. I. SURVIVORSHIPS, FECUNDITIES, AND FINITE RATES OF INCREASE. AB - Comparative demography of reciprocally sown populations for all stages of the life cycle of the winter annual, Phlox drummondii, was recorded for two seasons in natural sites. The sites investigated covered the natural range of the species and were separated by linear distances ranging from 10 to over 500 kilometers. Interpopulational variation was observed in all stages of the life cycle. Prereproductive survivorship ranged from 0 to 92 percent. Fecundity per plant ranged from 0 to 81 seeds. Finite rates of increase ranged from 0 to 34.1 yr-1 . The experimental populations with low values were growing in sites that received little rainfall or had experienced an insect or fungal infestation. The populations with high growth rates occurred in the northern sites which received greater rainfall. The relative fitness of individuals from the alien populations was compared to the local populations for all stages of the life cycle. The alien relative fitness for survivorship averaged 0.72. The average relative fitness of aliens for fecundity was 0.71 and that for finite rate of increase was 0.57. The life history parameters found in Phlox populations differ from one part of the range to another so that aliens have lower relative fitnesses than individuals indigenous to the site. PMID- 28564218 TI - THE ORIGIN AND DISTRIBUTION OF CLONAL DIVERSITY IN ALSOPHILA POMETARIA (LEPIDOPTERA: GEOMETRIDAE). AB - A survey of spatial and temporal variation in the frequency of electrophoretically defined genotypes in the geometrid moth Alsophila pometaria revealed a high diversity of uncommon or rare asexual genotypes and clinal distributions of two of the more common clones. There was substantial year-to year variation in genotype frequencies in seven of eleven sites. Progeny tests have revealed that sexual reproduction is uncommon in two populations and that new asexual genotypes arise from the sexual population. The recurrent origin of asexual genotypes is likely to account for the high genetic and ecological diversity of the asexual contingent of this species' populations, in contrast to the lower genetic diversity in some obligately asexual species in which such recruitment does not occur. PMID- 28564219 TI - QUANTITATIVE VARIATION OF PROGENY FROM CHASMOGAMOUS AND CLEISTOGAMOUS FLOWERS IN THE GRASS DANTHONIA SPICATA. AB - Progeny from chasmogamous (CH) and cleistogamous (CL) flowers of the grass Danthonia spicata were raised in their native habitat and in the greenhouse in order to determine how genetic variation was distributed among families and between CH and CL progeny within families. Twelve quantitative characters were measured on clones from individuals known to have arisen from either CH or CL flowers on a particular plant. Significant genetic variation existed for all characters measured. Most genetic variation was between families and two morphologically similar groups of families were identified. Relatively little genetic variation was found within families (approximately 5% of the total phenotypic variance). In field-raised plants, variance component analysis suggested that CL progeny were genetically more similar to each other than were CH progeny from the same plant. Levene's test of the average deviation of CH and CL progenies from their group means was nonsignificant but suggested there was a trend (0.05 < P < 0.10) for CH progeny to be more variable than CL progeny in the field but less variable in the greenhouse. The amount and distribution of genetic variation in the study population indicates that selective differentials would be larger among families than within families. PMID- 28564220 TI - SELF-RECOGNITION IN SPONGES AND CORALS? PMID- 28564221 TI - BARRIERS TO GENE EXCHANGE BETWEEN CLOSELY RELATED CRICKET SPECIES. II. LIFE CYCLE VARIATION AND TEMPORAL ISOLATION. AB - The closely related field crickets Gryllus firmus and Gryllus pennsylvanicus are known to hybridize in a zone of contact that extends over more than 800 km from the Blue Ridge in Virginia to southern Connecticut. Here I present evidence that the extent of temporal reproductive isolation of the two cricket species varies along the length of the zone. Adults of G. firmus and G. pennsylvanicus occur synchronously in Connecticut but G. firmus matures significantly later than G. pennsylvanicus along the Blue Ridge in Virginia. Variation in the extent of temporal isolation is a consequence of intrinsic differences in the egg-to-adult development time of G. firmus from the two localities. In laboratory rearing experiments, there is little variation in development time among crickets from G. pennsylvanicus populations ranging from Vermont to Virginia. However, G. firmus from Virginia takes significantly longer to mature than G. firmus from Connecticut. Comparisons between species from neighboring localities show that lowland Virginia G. firmus take much longer to develop and are larger as adults than montane Virginia G. pennsylvanicus. In Connecticut, crickets of the two species differ very little in development time and body size. Patterns of variation in development time and body size are compared with similar data for frogs along one of the same environmental gradients and for field crickets along similar gradients elsewhere. Although G. firmus and G. pennsylvanicus are temporally isolated in Virginia, adults of the two species do occur together. Examination of Esterase genotypes of field-inseminated females and their progeny from a mixed population on the Blue Ridge suggests that pre-mating barriers other than temporal isolation are not effective in preventing gene exchange. PMID- 28564222 TI - INTRASPECIFIC LIFE HISTORY VARIATION IN A POND SNAIL: THE ROLES OF POPULATION DIVERGENCE AND PHENOTYPIC PLASTICITY. AB - Two approaches were used to determine the degree of divergence in life histories among populations of the pond snail, Lymnaea elodes. Juvenile snails were reciprocally transferred between ponds differing in permanence and productivity, and the resulting variation in life history traits was recorded. In a second experiment, parents and their offspring from both a vernal and a permanent pond population were reared in the same pond. Proximal factors had by far the greatest effects on life history traits in the transfer experiment, with snails reared in a more productive pond showing earlier reproduction at a larger size, higher fecundity, and longer life cycle length. Snails from the more uncertain pond in terms of drying date did reproduce at an earlier age and smaller size and grew less in each pond. However, these population differences, for the most part, disappeared when snails were reared for two generations in the same environment. Much of the intraspecific variation in life histories seen in this species must therefore be considered the result of phenotypic plasticity. I argue that the plasticity in life histories itself may be adaptive to this inhabitant of unpredictable, vernal ponds. PMID- 28564223 TI - INHERITANCE OF MERISTIC VARIATION AND THE EVOLUTION OF DEVELOPMENTAL STABILITY IN RAINBOW TROUT. AB - We found relatively high heritabilities in the narrow sense for seven of eight meristic characters in a population of rainbow trout using regression of mean progeny values on mid-parent values. In sharp contrast, there is no statistically significant additive genetic variance controlling developmental stability, as measured by fluctuating asymmetry (h2 = 0.02). However, there is a significant correlation between the average heterozygosity of each family at isozyme loci and the average number of asymmetric traits per individual. We have previously reported a strong correlation between heterozygosity at protein loci and decreased fluctuating asymmetry in this and other salmonid populations. Thus, there is little or no additive, but substantial dominance, genetic variation affecting fluctuating asymmetry. This suggests that there has been directional selection for increased developmental stability. PMID- 28564224 TI - EXCLUSION OF THE ROLE OF SECONDARY CONTACT IN AN ALLELE FREQUENCY CLINE IN THE MUSSEL MYTILUS EDULIS. AB - We examined the hypothesis that secondary contact generates an allele-frequency cline at the aminopeptidase-I locus (Lap) in the marine mussel, Mytilus edulis. It has been proposed that variation at the Lap locus is neutral and that the cline results from secondary contact between differentiated oceanic and estuarine populations (Levinton, 1980). We tested this hypothesis by comparing the genotypic distributions in samples from the cline to distributions that incorporate mixing effects. We employed a statistical model that determines the degree of contact using a maximum likelihood estimator and then incorporates the mixing estimates into an expected distribution of genotypes. Wahlund effects resulting from possible admixture are thereby incorporated into the expected distribution. Failure of the model to reconcile the observed with the expected distribution of genotypes indicates that the observed population structure does not result from admixture. The null hypothesis of mixing was unable to explain about 33% of the samples. Combined tests demonstrated the general departure from the mixing model to be highly significant. The distribution of heterozygote discrepancies across the cline was inconsistent with the expectations of a mixing model. Therefore we reject explanations for the structure of the Lap cline that involve secondary contact. Selection directed at the Lap locus appears necessary to explain the genotypic structure of clinal populations. PMID- 28564225 TI - TERTIARY SPECIATION MODELS IN AUSTRALIAN ANURANS: MOLECULAR DATA CHALLENGE PLEISTOCENE SCENARIO. AB - Similarities between frogs in the faunas of southwestern and southeastern Australia have long been viewed as indicators of close genetic relationships and recent (Pleistocene) divergences. We studied albumin evolution in 16 east-west species pairs of frogs representing six genera to assess the validity of these conclusions. Analysis of albumin evolution in western species of Heleioporus and some species of Litoria suggested recent speciation in these genera, with the closest sister groups occurring in the western and not among the eastern fauna. All divergences measured between eastern and western cognate species point to a Tertiary separation extending from the late Miocene to the early Oligocene. Micro complement fixation studies provide an independent estimation of both genetic relationships between species pairs and the time of divergence of each species pair, allowing the testing of models of speciation and vicariance biogeography in a way not possible with earlier methodologies. PMID- 28564226 TI - BIOCHEMICAL GENETICS OF MOSQUITOFISH. IV. CHANGES OF ALLELE FREQUENCIES THROUGH TIME AND SPACE. AB - Gene frequency data from samples of Gambusia affinis populations at 76 localities across the Savannah River drainage were used to investigate temporal and spatial patterns in population genetic structure. Localities in the Par Pond system on the Savannah River Plant were sampled in 1971, 1977, and 1979. Allelic frequencies in these populations were generally stable through time, although significant temporal changes were observed among samples from Pond C, an impoundment receiving thermal effluent. Significant spatial heterogeneity in allele frequencies was observed on both microgeographic and regional scales. Populations within the Par Pond system were spatially subdivided at four of the five loci surveyed (mean FST = 0.051). Subdivision was even more pronounced when samples from across the Savannah River drainage were compared (mean FST = 0.196). A hierarchial analysis of gene diversity (GST ) demonstrated that most of the genic diversity across the drainage exists as within-subdivision diversity. Even when populations from such contrasting habitats as rivers, creeks, ponds, and reservoirs are compared, an average of only 13% of the total gene diversity was attributed to between-group diversity. Greatest between-group gene diversity was observed when reservoirs were compared with one another. This general pattern of low between-habitat diversity suggests that differential selection pressures are not playing a major role in producing the observed levels of subdivision. In the Par Pond system, neither single locus nor multilocus genetic distances were significantly associated with geographic distance or with its reciprocal. For samples from over the Savannah River drainage, significant correlations between genetic and geographic distance were observed only for the Gpi-2 and Pgm-2 loci. Thus, there was a general lack of concordance between genetic and geographic distances. Spatial autocorrelation demonstrated patterns consistent with Wright's isolation by distance model. Significant positive correlations in allelic frequencies among neighboring populations were observed for five of six alleles; allelic frequencies in more distantly separated populations were typically not correlated. PMID- 28564227 TI - CHROMOSOMAL EVOLUTION IN RHOGEESSA (CHIROPTERA: VESPERTILIONIDAE): POSSIBLE SPECIATION BY CENTRIC FUSIONS. AB - Within the Rhogeessa tumida-parvula complex, there are seven cytotypes involving diploid numbers of 30, 32, 34, 42, 44, and 52. Based on G-band analysis, the 30, 32, 34, and 44 forms differ from each other by centric fusions (13 different fusions were identified). Two 2n = 32 samples (one from Belize and one from Nicaragua) having essentially identical standard karyotypes differed from each other by eight fusion events. Cytotypes are allozymically distinct; however, other studies indicate that the cytotypes are morphologically very similar if not indistinguishable (LaVal, 1973; Baker, 1984). G-band chromosomal data are best interpreted as indicating that, within this complex, several species exist which should be maintained by a post-mating isolating mechanism resulting from meiotic problems in F1 individuals. Mus musculus (Capanna et al., 1977; Capanna, 1982; White, 1978) and the Rhogeessa tumida-parvula complex are unusual among mammalian species thus far studied in their pattern of chromosomal variation and presumptive mode of speciation. Strong evidence exists suggesting that in both groups populations differing by multiple centric fusions are biological species. It appears that the population and reproductive biology of Mus and Rhogeessa are quite different and any model that attempts to explain the mode of speciation in these two diverse taxa, must be compatible with their different biological characteristics. PMID- 28564228 TI - A STATISTICAL STUDY OF MATE CHOICE: SEXUAL SELECTION IN A PLETHODONTID SALAMANDER (DESMOGNATHUS OCHROPHAEUS). AB - Our experiment revealed the existence of significant variation in mating success in a salamander species in which males do not provide courtship feeding, nest sites, or parental care. Differences in mating success were based on natural variation among adult males and females, rather than on traits of an artificially selected set of potential mates. Courtship encounters deliberately involved only one male and one female, thus eliminating the potentially confounding effects of male-male competition and variations in mate encounter rate. Even after eliminating these effects and random error, some females were more likely than others to elicit spermatophore deposition by a male, and some males were more likely than others to inseminate a female. Such variation among individuals represents an opportunity for sexual selection to act on phenotypic characters that affect mating success. We advocate the use of a factorial experimental design to analyze sexual selection. This approach permits the statistical evaluation of separate male and female effects, interaction between these effects, and random effects. Designs which combine the evaluations of mating success and courtship behaviors could estimate the force of sexual selection on behavior. PMID- 28564229 TI - ON THE EVOLUTION OF PSEUDOGAMY. AB - A. density- and frequency-dependent model for the evolution and maintenance of pseudogamous females is developed and analyzed. Ecological as well as evolutionary aspects of pseudogamy are discussed. Criteria are described for the stable coexistence of sexual females and pseudogamous females under natural conditions. The conditions for invasion of a normal bisexual population by pseudogamous females are less stringent than the conditions for stable coexistence. Hence, we expect that some populations will be characterized by unstable sex ratios over time (with the resulting local extinction due to lack of males) while other populations will be characterized by stable sex ratios over time. If high population sex ratios (i.e., many females to few males) are to be stable, the net population growth rate must be large, and there can be no successful male preference for sexual females. PMID- 28564230 TI - POLLEN AND GENE DISPERSAL: THE INFLUENCES OF COMPETITION FOR POLLINATION. AB - Pollinators that forage indiscriminately can transfer pollen from one species to another, reducing the amount that reaches conspecific flowers. I present evidence that the presence of another plant species visited by the same pollinators can also reduce pollen dispersal distances and outcrossing. This has the potential to influence gene flow and reproductive success. Pollen carryover and movement patterns were measured for the shared insect pollinators of Stellaria pubera and Claytonia virginica in North Carolina. Bee flies deposited similar amounts of Stellaria pollen on a series of pistillate Claytonia flowers as on a series of pistillate Stellaria flowers. In arrays of potted plants, flies and solitary bees visited most flowers on a plant before leaving and then flew to a nearby plant chosen independently of species; 95% of moves were to one of 12 nearest neighbors. These measures of pollen carryover and movement patterns were used in a set of computer simulations to predict pollen dispersal distances. The simulations suggested that C. virginica substantially reduces outcrossing and pollen flow in S. pubera. These predictions were tested by tracking dye movement from anthers in populations of potted plants. Addition of C. virginica reduced the mean squared distance moved by dye to receptive S. pubera flowers by 23% and reduced the amount of dye moved by 51%. The estimated pollen component of gene flow was also much lower in a natural population of 5. pubera mixed with C. virginica than in the synthetic single-species populations. PMID- 28564231 TI - MICROGEOGRAPHIC VARIATION IN MITOCHONDRIAL DNA OF MEADOW VOLES (MICROTUS PENNSYLVANICUS) IN RELATION TO POPULATION DENSITY. AB - We examined mitochondrial-DNA (mtDNA) sequence heterogeneity on four adjacent trapping grids in an island population of meadow voles (Microtus pennsylvanicus) at two different population densities. Four restriction endonucleases revealed 20 different mtDNA composite phenotypes in samples totaling 198 meadow voles. There were significant heterogeneities in the distribution of four common mtDNA composite phenotypes among the four trapping grids, suggesting that there is population subdivision on a fine scale. Genetic distances between grids, mtDNA diversity within grids, and GST also varied during the study period. We found a decrease in genetic distance and an increase in diversity when the population density was high and vice versa when the population density was low. When population density was high, the coefficient of gene differentiation was smaller than the same coefficient observed when the population density was low. These changes in population subdivision and diversity are consistent with theoretical expectations of population structure in which effective female population size and dispersal are the critical variables. The data also support the hypothesis of maintenance of mtDNA diversity by population subdivision, rapid population growth rate, and dispersal. PMID- 28564232 TI - ENIGMATIC REPTILIAN SEX RATIOS. PMID- 28564233 TI - SEX RATIO, SEED PRODUCTION, BIOMASS ALLOCATION, AND THE COST OF MALE FUNCTION IN CUCURBITA FOETIDISSIMA HBK (CUCURBITACEAE). AB - In the gynodioecious plant Cucurbita foetidissima (Cucurbitaceae), females were common in all eight populations examined and made up 32% of adult plants. Females produced 1.5 (SE = 0.2) times as many seeds as did hermaphrodites. The observed difference in seed production alone is not great enough to explain the maintenance of females, especially at their current frequency. Females and hermaphrodites did not differ in number of nodes per stem, stems per plant, internode length, or size of leaves. Females produced more female biomass (fresh or dry weight) than hermaphrodites, but total investment in sexual biomass did not differ. Thus, the biomass of male flowers produced by hermaphrodites was about equal to the extra female biomass produced by females. The results support the existence of a trade-off between male and female reproduction. PMID- 28564234 TI - GENETIC POPULATION STRUCTURE OF DROSOPHILA TRIPUNCTATA: PATTERNS OF VARIATION AND COVARIATION OF TRAITS AFFECTING RESOURCE USE. AB - Drosophila tripunctata is an ecological generalist, using both fruits and mushrooms as breeding sites. Isofemale strains of this species were established from seven populations over a wide part of its range and assayed for electrophoretic variability, oviposition-site preference, and larval performance on several types of substrates. Significant variation among strains within populations was found for oviposition-site preference, larval development time on tomatoes versus mushrooms, and tolerance (as measured by development time) of the mushroom toxin alpha-amanitin. Even populations at the periphery of the range, which electrophoretic data suggest have been through bottlenecks, harbored levels of variation for oviposition-site preference approximately equal to that found in central populations. All correlations between preference and various measures of larval performance were close to zero. Thus, there is no evidence for sympatric divergence of host races or for coadapted complexes of genes related to host specificity. Strains with higher-than-average amanitin tolerance tended to develop more rapidly on tomatoes than on nontoxic mushrooms, whereas the less tolerant strains had slower development on tomatoes. This suggests that there may be genetically based correlations and trade-offs in larval performance on different breeding sites. No geographic differentiation among populations was found for either oviposition-site preference or any measure of larval performance. There is also very little electrophoretic variation among populations. Thus, the species as a whole, rather than local populations, appears to be the unit of evolution with respect to resource use in D. tripunctata. PMID- 28564235 TI - BODY SIZE, SPERM COMPETITION, AND DETERMINANTS OF REPRODUCTIVE SUCCESS IN MALE SAVANNA BABOONS. AB - One component of sexual selection is sperm competition. It has been reasoned that the intensity of sperm competition may be reflected in the relative testicular sizes of animals. Among males residing in multimale breeding systems, testicular size is relatively larger than among males residing in unimale mating systems. Information on whether differences in testicular size within a species can account for differences in male reproductive success is unavailable for natural populations of primates. A population of six troops of savanna baboons in Kenya was surveyed for morphometric analysis, and one of these troops was the subject of extensive behavioral observations afterwards. Testicular weights could not be obtained, but measurements of linear dimensions were transformed into volumetric estimates. Male weight accounted for 30% of the variance in testicular volume. Neither body size nor testicular volume was associated with differences in male reproductive activity. The outcome of fights over access to females could not be related to male body size, and ejaculatory patterns of males were independent of testicle size. Both sperm competition and aggressive competition intensified during the four-day optimum conception period, but fights over access to consort females were infrequent. Among savanna baboons, the probability of an ejaculation resulting in a conception is fairly low, which may account for the infrequency of injurious fights. Although testicle size influences sperm production, it does not influence either the timing of mating or the fertilizing capacity of spermatozoa, and both of these factors probably account for a substantial fraction of the variance in male baboon paternity. Sperm competition is an adjunct to agonistic competition as a mechanism affecting male baboon reproductive success. It is concluded that male reproductive success in baboons is affected more by social factors than by morphological traits associated with size. PMID- 28564236 TI - EVOLUTION OF THE BREEDING SEX RATIO UNDER PARTIAL SEX CHANGE. PMID- 28564237 TI - INBREEDING DEPRESSION IN PARTIALLY SELF-FERTILIZING PHLOX. AB - Inbreeding depression was measured in terms of the relative survivorship of self versus cross seed in 14 Phlox drummondii cultivars and 10 populations of P. cuspidata. The cultivars are predominantly outcrossing; P. cuspidata is predominantly self-fertilizing. The relative survivorship of self versus cross seed averages 0.84 in the cultivars and 0.99 in P. cuspidata. In wild P. drummondii, the average is 0.83. The mean number of lethal equivalents per zygote averages 0.69 in the cultivars and 0.05 in P. cuspidata, versus 0.79 in the wild P. drummondii. There is a significant negative correlation between the amount of automatic self-seed produced by a cultivar and the number of lethal equivalents it carries (r = -0.60). Phlox cuspidata has a lower level of cross-seed abortion than P. drummondii, which probably is not due to a difference in the incidence of lethal genes in their populations. PMID- 28564238 TI - ENVIRONMENTAL SENSITIVITY OF SEXUAL AND APOMICTIC ANTENNARIA: DO APOMICTS HAVE GENERAL-PURPOSE GENOTYPES? AB - The fact that apomictic taxa typically occupy a wider range of environments than their sexual relatives has generated the hypothesis that apomicts are more likely to possess "general-purpose genotypes," i.e., genotypes whose performance is relatively insensitive to changes in environmental conditions. This hypothesis was tested by cloning sexual and apomictic females of Antennaria parvifolia (Asteraceae) and growing each genotype in six growth-chamber environments varying in temperature and moisture levels. A joint regression analysis revealed that the survival of apomictic genotypes was significantly less sensitive to environmental conditions than that of sexual genotypes but demonstrated no differences with regard to flowering or biomass. However, the coefficient of variation in biomass across the six environments was significantly lower for apomicts than for sexuals, and the geometric mean of survival over the six environments was significantly higher for apomicts. Apomicts significantly exceeded sexuals in mean survival, mean flower-head production, and mean biomass. These results support the hypothesis that apomictic genotypes are more "general-purpose" than sexuals, and increase the difficulty of explaining the persistence of sexual reproduction in A. parvifolia. PMID- 28564239 TI - DENSITY-DEPENDENT SEXUAL SELECTION IN THE FUNGUS BEETLE, BOLITOTHERUS CORNUTUS. AB - The hypothesis that population density can affect sexual selection on male horn size was tested in a three-year study of a fungus beetle, Bolitotherus cornutus. Males of this species have horns that vary greatly in length. These horns are used in fights over females; longer-horned males win the majority of fights, regardless of population density. However, density does affect the relationship between horn length and access to females. In six populations of naturally and experimentally varying densities, longer-horned males gained a greater advantage in access to females in low-density populations than at high density. This increase in access to females causes an increase in the number of females inseminated by longer-horned males; thus, sexual selection for longer horns is stronger at lower densities. PMID- 28564240 TI - MOLECULAR EVIDENCE FOR A MISSING WILD RELATIVE OF MAIZE AND THE INTROGRESSION OF ITS CHLOROPLAST GENOME INTO ZEA PERENNIS. PMID- 28564242 TI - COMMENT ON A RATE TEST. PMID- 28564241 TI - THE DISSOLUTION OF A COMPLEX GENETIC POLYMORPHISM: THE EVOLUTION OF SELF FERTILIZATION IN TRISTYLOUS EICHHORNIA PANICULATA (PONTEDERIACEAE). AB - Eichhornia paniculata (Pontederiaceae) displays a wide range of outcrossing levels as a result of the dissolution of the tristylous genetic polymorphism and the evolution of semihomostyly. Population surveys, comparison of fitness components of the style morphs, and computer simulations were used to investigate the breakdown of tristyly and the selective mechanisms responsible for the evolution of self-fertilization. Of 110 populations surveyed in northeast Brazil and Jamaica, 53% were trimorphic, 25% were dimorphic, and 22% were monomorphic for style morph. The short (S) morph was underrepresented in trimorphic populations and absent from nontrimorphic populations. The mid (M) morph predominated in dimorphic populations and was the only morph in monomorphic populations. Stamen modifications promoting selfing, associated with semihomostyle evolution, were largely confined to the M morph. They were rare in trimorphic populations, common in dimorphic populations, and often fixed in monomorphic populations. Stochastic simulations and comparisons of fruit set in natural populations indicate that founder events, population bottlenecks, and lowered fertility of the S morph due to an absence of long-tongued pollinators can each account for loss of the S morph from trimorphic populations. A reduced level of disassortative mating can accentuate the rate at which the S morph is lost by both random and deterministic processes. Nontrimorphic populations occur at the geographical margins of the region surveyed and tend to be smaller and less dense than trimorphic populations. These observations and the higher fruit set of the M morph relative to the L morph in dimorphic populations suggest that reproductive assurance, favoring selfing variants of the M morph under conditions of low pollinator service, has been of primary importance in the origin of most monomorphic populations. Where pollinator service is reliable, however, automatic selection of selfing genes, aided by mating asymmetries between the morphs, can cause the M morph to spread to fixation in dimorphic populations. PMID- 28564243 TI - VARIATION IN POLLEN FLOW WITHIN AND AMONG POPULATIONS OF IPOMOPSIS AGGREGATA. AB - Pollen dispersal is a major component of gene flow in plant populations. It can influence microevolution within and among populations as well as the evolution of floral characters that affect dispersal. Most previous studies have relied on point estimates to characterize dispersal distances, even though there is likely to be substantial intrapopulational and interpopulational variation. We measured variation in pollen dispersal for the hummingbird-pollinated herb Ipomopsis aggregata (Polemoniaceae), using powdered fluorescent dyes to estimate pollen movement. Analysis of 5-6 natural populations in each of three years indicated that mean and mean squared distances of pollen dispersal, measured over the reproductive lifespan of individual plants, varied more than threefold among populations and years. Dispersal distances also shifted over the season within a given population. Unlike the variation among populations, these seasonal changes were associated in part with changes in flower density. The mean distance of pollen dispersal from an individual plant was unrelated to the date of first flowering, but did reflect two floral characters. Plants with higher variance in stamen length across flowers delivered pollen farther on average, as predicted by computer simulations of pollen carryover. Plants with lower mean stamen lengths also delivered pollen farther. Such effects of plant characters on pollen dispersal are a critical prerequisite for dispersal to evolve in response to its effects on fitness. PMID- 28564244 TI - HYPOTHESES FOR THE PRODUCTION OF EXCESS ZYGOTES: MODELS OF BET-HEDGING AND SELECTIVE ABORTION. AB - Two hypotheses can explain the overproduction of zygotes. Bet-hedging assumes that optimal brood size varies unpredictably among breeding attempts. Excess zygotes are produced so that the number of independent offspring can be flexibly adjusted downward to the optimum number for that attempt. Selective abortion suggests that parents overproduce zygotes, identify those with the highest fitness expectations, then kill or abandon those with lower fitness in order to concentrate investment in those with the best prospects. Both hypotheses for the overproduction of zygotes work in principle, alone or together, and can lead to impressive levels of zygote overproduction. For both hypotheses, high levels of zygote overproduction are only attained when the unit cost of an aborted embryo is low relative to the cost of an independent offspring. Under bet-hedging, it is also important that the variability of environmental conditions important for breeding success be high. The two hypotheses together make clear when a parent could increase its fitness by killing or abandoning its offspring. PMID- 28564245 TI - PHENOTYPIC PLASTICITY IN LIFE-HISTORY TRAITS OF FEMALE THALASSOMA BIFASCIATUM (PISCES: LABRIDAE). 1. MANIPULATIONS OF SOCIAL STRUCTURE IN TESTS FOR ADAPTIVE SHIFTS OF LIFE-HISTORY ALLOCATIONS. AB - Optimal-life-history theory is based on the relative benefit of immediate versus future reproduction. We apply this theory to the life-history tactics of female Thalassoma bifasciatum, a sex-changing coral-reef fish. Local social structure varies in this species and influences a female's chances of achieving high future reproductive success as a territorial terminal-phase male. We predicted that female life-history allocations would be flexible and responsive to variation in future reproductive prospects. We altered population size structure on four reefs, removing large fish and adding small fish. These alterations enhanced the residual reproductive value of the remaining larger female residents. The predicted response to the manipulation was a reduction in reproductive activity and an increase in growth. Our results do not support this hypothesis. Possible interpretations are that: 1) the theory, or our application of the theory, is flawed; 2) female Thalassoma are unresponsive to changes in future reproductive prospects; or 3) the design of our study was ineffectual at detecting a response. We report here an approach to the study of adaptive life-history strategies that deserves implementation in other systems. PMID- 28564246 TI - TESTING MACROEVOLUTIONARY HYPOTHESES WITH CLADISTIC ANALYSIS: EVIDENCE AGAINST RECTANGULAR EVOLUTION. AB - The properties of cladistic data sets from small monophyletic groups (6-12 species) are investigated using computer simulations of macroevolution. Two evolutionary models are simulated: gradualism and the punctuated-equilibrium hypothesis. Under the conditions of our simulations these two models of evolution make consistently different predictions about the distribution of autapomorphies among species. When strict stasis is enforced, the punctuated-equilibrium hypothesis predicts that the most expected number of autapomorphies per species will be zero, no matter how many characters are used in the analysis. As the number of characters used in the analysis increases, the distribution of the number of autapomorphies per species becomes bimodal. Under gradualism, the distribution of autapomorphies remains unimodal under all conditions, but the number of species without autapomorphies can fall to zero. A survey of real cladograms of extant monophyletic groups from a wide range of taxa indicates that the predictions of the punctuated-equilibrium hypothesis about autapomorphies do not hold. This constitutes strong evidence against the punctuated-equilibrium hypothesis. PMID- 28564247 TI - SEXUAL SELECTION BY THE HANDICAP MECHANISM. AB - The handicap mechanism of sexual selection by female choice has been strongly criticized because it does not cause sexual selection to reinforce viability selection and it cannot account for the origin of mating preferences. However, several models indicate that the handicap mechanism can have important effects when operating in conjunction with Fisher's mechanism in polygynous populations. These models have been criticized because they require that fitness remains heritable indefinitely. I develop a simple haploid model of the handicap mechanism based on nonheritable variation in paternal investment, thus eliminating the problem of heritable fitness. This model produces the same evolutonary dynamics as both simple and quantitative genetic models of the handicap mechanism based on heritable fitness. If the parameters are such that Fisherian runaway selection does not occur in the null model (i.e., the polymorphic equilibria, which lie along the "Fisher line," are stable), then the handicap mechanism turns the Fisher line into an evolutionary trajectory upon which all other trajectories converge. This occurs because Fisher's mechanism generates no net selection on female preference when the population is on the Fisher line, so that any additional source of selection (direct or indirect) on female choice causes the population to evolve deterministically along the Fisher line. This change in the evolutionary dynamics has the important consequence of eliminating the potential for rapid population divergence for mating systems via genetic drift along the Fisher line. PMID- 28564248 TI - THE ADDITIVE PARTITIONING OF SELECTION GRADIENTS. PMID- 28564249 TI - EMBRYO GROWTH AND SEED SIZE IN RAPHANUS SATIVUS: MATERNAL AND PATERNAL EFFECTS IN VIVO AND IN VITRO. AB - Theories on the evolution of the angiosperm seed disagree as to the effects of different plant tissues on embryo growth. To examine the relative contributions of maternal and paternal genes on embryo growth, we conducted controlled crosses in the greenhouse with wild radish plants (Raphanus sativus), looked for maternal, paternal, and interaction effects on embryo development, and compared the performance of embryos within fruits and in embryo culture. Maternal plant identity affected fruit set, seeds per fruit, embryo developmental stage, and mean seed weight. In embryo culture, maternal effects were found for cotyledon size and embryo weight. Paternal effects were fewer or smaller in magnitude than maternal effects. The identity of the pollen donor affected embryo developmental stage and mean seed weight. In culture, paternal effects were detected for cotyledon size and embryo weight. Our results demonstrate that both maternal and paternal elements affect embryo growth. The fact that maternal effects are greater than paternal effects on embryo development in culture may result from cytoplasmic elements or maternal nuclear genes. Embryo performance in vivo compared to that in vitro varied among maternal plants. The interaction between an embryo and its endosperm and maternal tissues may be either positive or negative, depending upon the maternal plant and the embryo's developmental stage. PMID- 28564251 TI - ADAPTATION TO SEASONALITY IN A CRICKET: PATTERNS OF PHENOTYPIC AND GENOTYPIC VARIATION IN BODY SIZE AND DIAPAUSE EXPRESSION ALONG A CLINE IN SEASON LENGTH. AB - This paper investigates patterns of phenotypic variation in the striped ground cricket (Allonemobious fasciatus) along a cline in season length and tests the hypothesis that variation in body size and diapause propensity is the result of diversifying selection due to different local conditions. We examined 83 populations and found that A. fasciatus produced a single generation per year (univoltine) north of 37 degrees N latitude and was bivoltine south of 35 degrees 30'N. Body size generally increased with increasing season length, with a sudden drop in the region corresponding to the transition from univoltine to bivoltine life cycles, reflecting the division of total season length in two within bivoltine populations. We reared ten populations in our laboratory and found that much of the interpopulation variance in body size observed in the field could be attributed to genetic differences. Diapause expression also varied significantly among populations and was strongly correlated with season length. The heritability of body size did not differ between populations, but full-sib estimates greatly exceeded parent-offspring estimates (h po2=0.15+/-0.05; h fs2=0.45+/-0.04) suggesting that there are important nonadditive genetic effects. The heritability of diapause expression, determined from analysis of full sibs, varied significantly between populations (0.33 +/- 0.10 to 1.31 +/- 0.21) with an average of 0.74 +/- 0.16. Body size and diapause expression were genetically correlated in transition-zone populations, but not in univoltine or bivoltine populations. Our findings support the suggestion that clinal variation in body size and diapause expression in the striped ground cricket reflect adaptation to season length. PMID- 28564250 TI - A COMPARISON OF THREE INDIRECT METHODS FOR ESTIMATING AVERAGE LEVELS OF GENE FLOW. AB - Three methods for estimating the average level of gene flow in natural population are discussed and compared. The three methods are FST , rare alleles, and maximum likelihood. All three methods yield estimates of the combination of parameters (the number of migrants [Nm] in a demic model or the neighborhood size [4piDsigma2 ] in a continuum model) that determines the relative importance of gene flow and genetic drift. We review the theory underlying these methods and derive new analytic results for the expectation of FST in stepping-stone and continuum models when small sets of samples are taken. We also compare the effectiveness of the different methods using a variety of simulated data. We found that the FST and rare-alleles methods yield comparable estimates under a wide variety of conditions when the population being sampled is demographically stable. They are roughly equally sensitive to selection and to variation in population structure, and they approach their equilibrium values at approximately the same rate. We found that two different maximum-likelihood methods tend to yield biased estimates when relatively small numbers of locations are sampled but more accurate estimates when larger numbers are sampled. Our conclusion is that, although FST and rare-alleles methods are expected to be equally effective in analyzing ideal data, practical problems in estimating the frequencies of rare alleles in electrophoretic studies suggest that FST is likely to be more useful under realistic conditions. PMID- 28564252 TI - THE CONSEQUENCES OF BEING DIFFERENT: SINISTRAL COILING IN CERION. AB - The overwhelming predominance of dextral coiling in gastropods is an outstanding and puzzling phenomenon. A few sinistral specimens (left coiling individuals) have been found in many dextral species. Only six sinistral shells have ever been found in Cerion; we base this analysis on the five available shells. We ask whether reversed symmetry is a simple either-or switch without further consequences for shell form, or whether sinistrality engenders associated effects, making left-coiling shells unlike their dextral deme-mates in other ways. All five sinistral shells differ in features of size and coiling late in growth, leading to relatively small apertures and a slight twist in the axis of coiling. We detect and measure this effect as follows: in multivariate morphospace, sinistrals occupy peripheral positions among their dextral deme mates; in univariate analysis, sinistrals are consistently different for a set of characters involving covariance patterns never before seen in a decade of studies on ontogenetic and age-standardized variation in dextrals; a bootstrap procedure does not recover similar patterns in randomly constituted samples of dextrals matching the true sinistral distribution; direct x-ray measures of the coiling axis detect its slight twist in sinistrals. We discuss the implications of these unsuspected associations for the issues of developmental constraint upon the evolution of morphology. PMID- 28564253 TI - ON THE RATE OF ADAPTIVE EVOLUTION. PMID- 28564254 TI - REPRODUCTIVE CHARACTER DISPLACEMENT IN PHLOX. AB - Plants of the red- and pink-flowered P. drummondii were introduced into a natural population of P. cuspidata. Their seeds were progeny-tested, and the percentage hybrid seed determined for each variant. Thirty-eight percent of the seed from the pink variant were hybrid compared to 13% of the red. The difference in hybrid production is best explained by corolla color. The self- and cross-compatibility of nine sympatric and nine allopatric populations were studied in the greenhouse. On the average, sympatric populations are more self-compatible than allopatric populations. Pollen germination is 13.7% vs. 7.3%, the difference being statistically significant. The self-compatibility differential was accompanied by a self seedset differential. On the average, sympatric populations are more cross compatible with P. cuspidata than are allopatric populations. The germination of P. cuspidata pollen on sympatric P. drummondii stigmas was 13.3% vs. 9.8% on allopatric stigmas. However, the difference is not statistically significant. The presence of P. cuspidata has promoted reproductive character divergence in P. drummondii. The shift in corolla color and the increase in self-compatibility reduce the potential for gametic wastage and interspecific hybridization. PMID- 28564255 TI - ON THE EVOLUTION OF PARTHENOGENESIS. II. INBREEDING AND THE COST OF MEIOSIS. AB - Quantitative models of genetic change were analyzed to study the effect of inbreeding on the conditions for the evolution of parthenogenesis. Although inbreeding has been proposed as a key factor that may resolve the apparent paradox between the success of biparental reproduction and the genetic advantages of uniparental reproduction, the results indicate that inbreeding does not greatly change the cost of meiosis in diploids and actually increases it in haplodiploids. Inbreeding increases parent-offspring relatedness and the reproductive value of females. These direct effects act antagonistically on the cost of meiosis: higher relatedness between parents and biparentally-derived offspring promotes biparental reproduction, and high reproductive value of females promotes thelytoky. In diploids the two effects cancel one another, while in haplodiploids the latter predominates. A survey by Hamilton (1967) showed that a high proportion of haplodiploid species that undergo close inbreeding have thelytokous relatives, an association that is consistent with the result obtained here that, apart from its effect on the sex ratio, inbreeding directly promotes parthenogenesis in haplodiploids. PMID- 28564256 TI - DEVELOPMENTAL INSTABILITY AND HIGH MERISTIC COUNTS IN INTERSPECIFIC HYBRIDS OF SALMONID FISHES. AB - Interspecific hybrids have been proposed to have reduced developmental stability in comparison to their parental species because the parental genomes have not undergone selection for the maintenance of developmental stability when they occur together. We present data from four interspecific hybrids of salmonid fishes that support this view. Natural hybrids of bull trout (Salvelinus confluentus) with brook trout (Salvelinus fontinalis) and laboratory hybrids of rainbow trout (Salmo gairdneri) with Yellowstone (Salmo clarki bouvieri), westslope (S. c. lewisi), and coastal (S. c. clarki) cutthroat trout all have higher levels of fluctuating asymmetry than either of their parental species raised in the same environment. Thus, the hybrids have reduced developmental stability. The hybrids do not have meristic counts intermediate to the counts of the parental species. The hybrids usually have counts as high as the species with the higher count for those characters that differ between the parental species and often have higher counts for those characters that do not differ between the parental species. We suggest that the tendency for interspecific hybrids to have high meristic counts may be related to differences between the species in the length and timing of the developmental periods during which the counts of the characters are determined. PMID- 28564257 TI - TITANOTHERE ALLOMETRY, HETEROCHRONY, AND BIOMECHANICS: REVISING AN EVOLUTIONARY CLASSIC. AB - A reanalysis of Osborn's titanothere data indicates that extrapolative growth of a constant allometric relationship alone ("hypermorphosis") does not account for the trend toward body and horn size increase. Empirically, we also observe possible positive changes in the y-intercept ("predisplacement" or early onset of development), and possibly, changes in the slope ("acceleration/neoteny" or changes in growth rate) between the Oligocene and Eocene groups. Theoretically, these may be responses to more massive body shapes, perforce accompanying size increase, which increase the amount of force to which the horns were subjected. PMID- 28564258 TI - FOUNDER-FLUSH SPECIATION: AN UPDATE OF EXPERIMENTAL RESULTS WITH DROSOPHILA. PMID- 28564259 TI - GEOGRAPHICAL PATTERNS AND POPULATION STRUCTURE IN PERIODICAL CICADAS BASED ON SPATIAL ANALYSIS OF ALLOZYME FREQUENCIES. AB - There are twelve major broods, or year classes, of 17-year periodical cicadas and three major broods of 13-year cicadas. Previous allozyme studies of three 13-year broods and two 17-year broods suggested that broods are distinct evolutionary units, exhibiting homogeneity within broods and heterogeneity among broods. Results from numerical phylogenetic analysis of allozyme data from these broods supported Lloyd and Dybas's (1966a, 1966b) evolutionary hypothesis and were consistent with biogeographical patterns. In the present paper, we use spatial statistics to extend the analysis of biogeographical patterns for periodical cicadas by examining geographic variation in allozyme frequencies within and among ten broods for the three most variable loci. The results from our analysis show that each gene frequency surface exhibits marked spatial autocorrelation. Three major geographic areas of similarity are indicated by the data: the eastern seaboard, the Mississippi Valley, and the eastern edge of the Great Plains. When localities are adjusted for regional membership, the autocorrelation disappears. In biological terms, broods are homogeneous breeding units. Geographically distinct localities within the same brood show little differentiation. Differentiation among populations within broods and among broods within regions exists but is less pronounced than the differentiation among geographic regions. For the particular enzymes examined, allozyme frequency differences appear to reflect the phylogenetic history of the broods rather than their environmental surroundings. PMID- 28564260 TI - UNIFYING GENETIC MODELS FOR THE EVOLUTION OF FEMALE CHOICE. AB - A best-of-N rule of female mating preferences can give rise to lines of unstable equilibria in a two-locus haploid model of sexual selection. Under the best-of-N rule, which corresponds to choice at a lek, male fitnesses can exhibit a form of positive frequency-dependence that is not seen under fixed-relative-preference rules (Kirkpatrick, 1982). This positive frequency-dependence can be strongly destabilizing. Lande's (1981) criterion for the stability of the equilibria in quantitative-genetic models of sexual selection applies exactly and in general to the related family of simple population-genetic models. This offers some insight into the workings of these models and greatly simplifies their analysis. PMID- 28564261 TI - THE PHYSIOLOGICAL BASIS OF NATURAL SELECTION AT THE LAP LOCUS. AB - An extensive research program was undertaken to evaluate the contribution of genetic variation at the Lap locus to variation in physiological traits under natural conditions. Rates of carbon and nitrogen metabolism were monitored in a population of the mussel Mytilus edulis near the center of the Lap allele frequency cline on the north shore of Long Island. The goal of this research was to establish whether the previously described genotype-dependent differences in physiological phenotype are meaningful in ecologically relevant circumstances. It was predicted from laboratory studies that, in nature, genotype-dependent differences will exist for rates of nitrogen excretion and that other aspects of the animal's physiology, particularly rates of carbon metabolism, will be unaffected by Lap genotype. Rates of amino acid and ammonia excretion were significantly dependent upon Lap genotype; individuals with the Lap94 allele exhibited greater rates of nitrogen loss. These differences among genotypes were most evident in the fall, between September and December. The genotype-dependent component of rates of nitrogen loss were also largest relative to the total rate of excretion during the fall period. As predicted, other aspects of the nitrogen metabolism (acquisition) and rates of carbon metabolism were independent of Lap genotype. There was a striking congruity among a variety of observations that all indicate that phenotypic differences in nitrogen metabolism are the basis of natural selection at the Lap locus in Long Island Sound. Rates of growth were minimal during the fall months (Hilbish, 1985) and mussels are known to lose weight in a genotype-specific manner during this period (Koehn et al., 1980). Rates of elemental gain and loss were summed to produce carbon and nitrogen budgets; these data show the fall to be a period of extended deficit in carbon and nitrogen balance. Genotype-dependent losses of ammonia and amino acids were greatest during the fall months. Finally, selection against the Lap94 allele occurs predominantly in the fall (Hilbish, 1985). The data indicate that the depletion of nitrogen resources provides the basis for selection against Lap94 genotypes during the fall months. PMID- 28564262 TI - GENETIC DIVERGENCE AND GEOGRAPHIC SPECIATION IN LAYIA (COMPOSITAE). AB - Electrophoretic variability was examined in six species of Layia (Compositae), native to California, which have previously been studied by Clausen, Keck, and Hiesey, and are regarded as a classic example of geographic speciation in plants. The study was carried out to test the hypothesis that the extent of divergence in structural genes coding enzymes is concordant with divergence in morphological characteristics, ecological traits, and reproductive isolation. Eleven enzymes specified by 17 loci were analyzed. The genetic identity values were consistent with those expected on the model that the species diverged gradually as they adapted to geographically separate habitats. Thus, the values between the three species complexes proposed by Clausen, Keck, and Hiesey (L. chrysanthemoides/L. fremontii; L. jonesii/L. leucopappa/L. munzii; L. platyglossa) were substantially lower than the values between species within the complexes. The results provide an important contrast to the very high genetic identities between species which originated rapidly from their progenitors. The electrophoretic results also provided evidence that the cytosolic isozyme of phosphoglucomutase and the cytosolic NADP-dependent isocitrate dehydrogenase in the six species are coded by duplicate genes. PMID- 28564263 TI - THE USE OF PHYLOGENY IN BEHAVIOR AND ECOLOGY. PMID- 28564264 TI - LOCALIZED ADAPTATION OF CLONES OF THE SEA ANEMONE ACTINIA TENEBROSA. AB - Adult Actinia tenebrosa were reciprocally transplanted within and between colonies separated by 2 or 4 km. These experiments revealed powerful genetic and environmental effects on adult size and asexual fecundity and demonstrate that clones may be highly locally adapted. Local adults displayed significantly greater asexual fecundity than do adults transplanted from other colonies, although all groups showed similar survivorships. This provides the first demonstration of fine scale adaptation, in either terrestrial or marine environments, for a clonal species with large, panmictic sexually breeding populations. These findings, together with the results of earlier studies of this species, strongly support the assumptions and predictions of the Strawberry-Coral Model (Williams, 1975). PMID- 28564265 TI - PARASITE PRESSURE AND THE EVOLUTION OF AMANITIN TOLERANCE IN DROSOPHILA. AB - Approximately one-half of the members of the Drosophila quinaria species-group are mycophagous. The mushroom-breeding species D. falleni, D. recens, and D. phalerata are far more tolerant of the mushroom toxin alpha-amanitin than are D. guinaria, D. palustris, and D. subpalustris, which breed in decaying water plants. The non-mycophagous species, however, are physiologically capable of larval development in mushrooms, showing that high levels of amanitin tolerance are not necessary for mycophagy. A primary selective advantage of amanitin tolerance among the mycophagous species is that it allows them to breed in mushrooms that are toxic to nematodes that infest Drosophila in other fungi and render them infertile. Parasitism, then, may be an important factor governing evolutionary patterns of resource utilization in these species. PMID- 28564266 TI - GENE FLOW IN CAVE ARTHROPODS: A QUALITATIVE AND QUANTITATIVE APPROACH. AB - Slatkin's method (1981) for analyzing gene flow levels is applied to eleven species of cave arthropods. This provides insights into the strength of gene flow as a force affecting the evolution of cave organisms, while serving as a test of Slatkin's method. The results show that patterns of gene flow are consistent with the dispersal abilities and the ecological requirements of each species. Troglobites in general have lower gene flow values than troglophiles or trogloxenes. However, the geology of the area, its vegetation profile, and the geographic distance among the populations considered are also important in determining the gene flow levels. Gene flow patterns in three cave species, Ptomaphagus hirtus, Neaphaenops tellkampfii tellkampfii and Hadenoecus subterraneus, are compared in detail. These species inhabit the same highly interconnected karst area in south-central Kentucky but differ in their ecological requirements. The results suggest that gene flow levels are more dependent upon the intrinsic characteristics of each species than upon the availability of routes for dispersal. Overall estimates of gene flow were coupled with a more detailed population-structure analysis in four terrestrial cave arthropods: Speonomus delarouzeei, Hadenoecus cumberlandicus, Hadenoecus subterraneus and Euhadenoecus puteanus. The results stress the need for this type of analysis for subdivided species, in which estimates of the average gene flow can produce misleading results. Moreover, they show how these types of measures are more relevant in describing historical patterns of gene exchange than in indicating current levels of gene flow. PMID- 28564267 TI - THE QUANTITATIVE ASSESSMENT OF PHYLOGENETIC CONSTRAINTS IN COMPARATIVE ANALYSES: SEXUAL DIMORPHISM IN BODY WEIGHT AMONG PRIMATES. AB - We have presented a formal model for the quantitative analysis of phylogenetic and specific effects on the distribution of trait values among species. Total trait values are divided into phylogenetic values, inherited from an ancestral species, and specific values, the result of independent evolution. This allows a quantitative assessment of the strength of the phylogenetic inertia, or burden, displayed by a character in a lineage, so that questions concerning the relative importance of phylogenetic constraints in evolution can be answered. The separation of phylogenetic from specific effects proposed here also allows phylogenetic factors to be explicitly included in cross-species comparative analyses of adaptation. This solves a long-standing problem in evolutionary comparative studies. Only species' specific values can provide information concerning the independent evolution of characters in a set of related species. Therefore, only correlations among specific values for traits may be used as evidence for adaptation in cross-species comparative analyses. The phylogenetic autocorrelation model was applied to a comparative analysis of the determinants of sexual dimorphism in weight among 44 primate species. In addition to sexual dimorphism in weight, mating system, habitat, diet, and size (weight itself) were included in the analysis. All of the traits, except diet, were substantially influenced by phylogenetic inertia. The comparative analysis of the determinants of sexual dimorphism in weight indicates that 50% of the variation among primate species is due to phylogeny. Size, or scaling, could account for a total of 36% of the variance, making it almost as important as phylogeny in determining the level of dimorphism displayed by a species. Habitat, mating system, and diet follow, accounting for minor amounts of variation. Thus, in attempting to explain why a particular modern primate species is very dimorphic compared to other primates, we would say first because its ancestor was more dimorphic than average, second because it is a relatively large species, and third because it is terrestrial, polygynous, and folivorous. PMID- 28564268 TI - STATISTICS OF SEXUAL ISOLATION. PMID- 28564269 TI - THE INFLUENCE OF FLOWER COLOR ON OUTCROSSING RATE AND MALE REPRODUCTIVE SUCCESS IN IPOMOEA PURPUREA. AB - Experimental populations of the annual plant, Ipomoea purpurea, composed of individuals belonging to two flower color morphs were studied to determine the effect of flower color on outcrossing rate and reproductive success as a male parent. Analyses of parent and offspring genotypes show that the pigmented and white morphs outcross at similar rates, but that the white morph is favored as a pollen donor. The result suggests that the dynamics of selection occurring at the locus coding for white versus pigmented flowers are more complex than previously believed. Factors such as frequency-dependent outcrossing rates and epistatic effects of the white allele may be operating. The results also suggest that pollinator observations are unreliable indicators of the actual mating system. PMID- 28564270 TI - COMPETITION AND THE EVOLUTION OF AGGRESSIVE BEHAVIOR IN TWO SPECIES OF TERRESTRIAL SALAMANDERS. AB - The effects of competition on the evolution of interspecific interference mechanisms were studied by comparing the aggressive behavior of two terrestrial salamander species from two localities that differ in the intensity of interspecific competition. Plethodon jordani and P. glutinosus are closely related, ecologically similar species that are sympatric at intermediate elevations in the southern Appalachian Mountains. Previous removal and transplant experiments showed that interspecific competition is more intense in the northeastern Great Smoky Mountains, where the species are narrowly sympatric, than in the nearby Balsam Mountains, where sympatry is broader. In laboratory encounters, P. glutinosus from the Great Smoky Mountains were more aggressive to heterospecific and conspecific intruders than were P. glutinosus from the Balsam Mountains. For P. jordani, however, the variation in interspecific and intraspecific aggressive behavior among individuals within populations was as great as the variation between populations. Alpha-selection (i.e., improved competitive ability by the acquisition of interspecific interference mechanisms) has occurred in populations of P. glutinosus under conditions of intense interspecific competition. The evolution of aggressive behavior appears to have been influenced by the intensity of intraspecific competition as well. PMID- 28564271 TI - EVOLUTIONARY DIVERGENCE AND CHARACTER DISPLACEMENT IN TWO PHENOTYPICALLY VARIABLE, COMPETING SPECIES. AB - Theoretical studies of character displacement lead to the view that evolutionary divergence depends primarily on incomplete utilization of available resources. Those models which incorporate constraints preventing complete utilization of resources, even in the absence of competitors, all predict character displacement. Those models which allow greater flexibility of resource use within a species predict correspondingly less divergence. Indeed, Matessi and Jayakar (1980, 1981) based their conditions for occurrence of character displacement on underutilization of resources. I extend a model used by Slatkin (1980, 1983) and Taper and Case (1985) which allows each species to fully utilize its resources in the absence of competitors. I concentrate on the biologically reasonable case in which the species, though similar, differ in their ecological characteristics. As a result of this greater biological realism, I arrive at a different conclusion regarding the conditions which lead to character displacement. The presence of a variety of biological differences between species-including as a subset those which result from resource underutilization-leads to divergence with respect to a quantitatively inherited character, due to interspecific competitive interactions. The resulting displacement can be large and depends little on the parameters chosen. The only exception, involving a character with very low heritability, occurs when the non-interactive phenotypic differences are much greater than those associated with studies of character displacement in natural populations. Thus, under conditions comparable to those encountered in the field, involving similar yet not identical species, evolutionary divergence is a consequence of interspecific competition. PMID- 28564272 TI - BERGMANN'S RULE, SEASONALITY, AND GEOGRAPHIC VARIATION IN BODY SIZE OF HOUSE SPARROWS. AB - Body size of House Sparrows is positively correlated with seasonality (annual temperature range) in both North America and Europe. Previously used climatic variables gave inconsistent or contrasting results for the two continental samples. The physiological advantage of large size in seasonal environments appears to be increased fasting ability, but this may be offset somewhat, particularly for females, by other factors, e.g., competitive interactions that influence rates of energy intake or ability to initiate breeding in the spring. It is proposed that minimization of maintenance energy costs on a per individual basis, and thus small size, is advantageous in equable (and predictable) environments. PMID- 28564273 TI - Kidney transplantation from donors with rhabdomyolysis and acute renal failure. AB - Rhabdomyolysis in deceased donors usually causes acute renal failure (ARF), which may be considered a contraindication for kidney transplantation. From January 2012 to December 2016, 30 kidneys from 15 deceased donors with severe rhabdomyolysis and ARF were accepted for transplantation at our center. The peak serum creatinine (SCr) kinase, myoglobin, and SCr of the these donors were 15 569+/-8597 U/L, 37 092+/-42 100 MUg/L, and 422+/-167 MUmol/L, respectively. Two donors received continuous renal replacement therapy due to anuria. Six kidneys exhibited a discolored appearance (from brown to glossy black) due to myoglobin casts. The kidney transplant results from the donors with rhabdomyolysis donors were compared with those of 90 renal grafts from standard criteria donors (SCD). The estimated glomerular filtration rate at 2 years was similar between kidney transplants from donors with rhabdomyolysis and SCD (70.3+/-14.6 mL/min/1.73 m2 vs 72.3+/-15.1 mL/min/1.73 m2 ). We conclude that excellent graft function can be achieved from kidneys donors with ARF caused by rhabdomyolysis. PMID- 28564274 TI - MITOCHONDRIAL GENE GENEALOGY AND GENE FLOW AMONG ISLAND AND MAINLAND POPULATIONS OF A SEDENTARY SONGBIRD, THE GREY-CROWNED BABBLER (POMATOSTOMUS TEMPORALIS). AB - Distinguishing between ongoing gene flow and purely historical association of populations can be difficult without data on times of population separation and effective population sizes. To help discriminate between these two scenarios, I examined mitochondrial DNA sequence diversity in three geographically close populations of the grey-crowned babbler (Pomatostomus temporalis) separated by water barriers of known age in the Northern Territory, Australia, using the polymerase chain reaction (PCR), direct sequencing, and genealogical methods of inference. PCR primers were designed to obtain sequences from region I, a highly variable segment of the control region. Sequence diversity in all populations was consistent with neutrality. In the population on Melville Island, a Pleistocene land-bridge island, sequence variability is as high as on the mainland and consists of two mitochondrial lineages differing by 2%. Phylogenetic analyses of the sequence variation observed among 44 individuals suggest that the number of times lineages in one population trace back to ancestors of a different population (between-population coalescent events) was too high to be compatible with a model of population divergence solely by drift since rising of the water barriers, implying instead recent or ongoing gene flow across water barriers. Similar estimates of Fst , the fraction of genetic diversity apportioned among populations, were obtained when calculated using the divergence times of alleles and when estimated from Nm values derived from trees and ranging from 0.29-0.55. Both the phylogenies and patterns of allelic divergence suggest that the population on Melville Island exchanges migrants with both continental populations, although statistical tests indicated that some alternative phylogenies implying restricted gene flow among the populations could not be discounted. PMID- 28564275 TI - THE GENETICS OF CENTRAL AND MARGINAL POPULATIONS OF DROSOPHILA SERRATA. I. GENETIC VARIATION FOR STRESS RESISTANCE AND SPECIES BORDERS. AB - A selection experiment was used to determine if levels of genetic variance in an ecologically important trait, desiccation resistance, were different in central and marginal populations. Four populations of Drosophila serrata were sampled from central and marginal areas of its distribution, along a 3000-km stretch of Australia's east coast. Rainfall patterns along this stretch of coastline change from a tropical cycle in the north to a temperate cycle in the south. Replicate lines from the four populations underwent selection for desiccation resistance for 14 generations. Realized heritabilities calculated after 10 and 14 generations of selection indicated that the four populations differed significantly in the level of genetic variation for desiccation resistance available to selection. Populations from the more southern marginal areas had lower realized heritabilities than more northern central populations. However, a corresponding increase in mean desiccation resistance toward the margin was not found. A mechanism by which D. serrata seemed to have responded to selection was a reduction in the extent that metabolic rate was increased when flies were exposed to low humidity. This response indicates genetic variation for the control of metabolic rate. In contrast, increased desiccation resistance was not associated with lipid or glycogen levels. Increased resistance to desiccation was accompanied by increased starvation resistance, but radiation resistance was not affected. Selection did not affect the degree that replicate lines or populations had diverged. PMID- 28564276 TI - PHENOTYPIC PLASTICITY IN POLYGONUM PERSICARIA. II. NORMS OF REACTION TO SOIL MOISTURE AND THE MAINTENANCE OF GENETIC DIVERSITY. AB - Adaptive phenotypic plasticity is the predicted evolutionary response to fine grained fluctuation in major environmental factors, such as soil moisture in plant habitats. This study examines genotypes from two natural populations of Polygonum persicaria, one from a relatively homogeneous, moderately moist site, and one from a site in which severe drought and root flooding occur within single growth seasons. Norms of reaction (phenotypic response curves) were determined for a random sample of eight and ten cloned genotypes, respectively, from each of the populations over a controlled moisture gradient ranging from drought to flooding. PMID- 28564277 TI - SEARCHING FOR EVOLUTIONARY PATTERNS IN THE SHAPE OF A PHYLOGENETIC TREE. AB - If all species in a clade are equally likely to speciate or become extinct, then highly symmetric and highly asymmetric phylogenetic trees are unlikely to result. Variation between species in speciation and extinction rates can cause excessive asymmetry. We developed six non-parametric statistical tests that test for nonrandom patterns of branching in any bifurcating tree. The tests are demonstrated by applying them to two published phylogenies for genera of beetles. Comparison of the power of the six statistics under a simple model of biased speciation suggests which of them may be most useful for detecting nonrandom tree shapes. PMID- 28564278 TI - POLLEN APERTURE POLYMORPHISM AND GAMETOPHYTE PERFORMANCE IN VIOLA DIVERSIFOLIA. AB - Pollen aperture polymorphism is studied in Viola diversifolia, where all plants produce three- and four-apertured pollen grains. We tested whether there are genetic differences among plants for the proportions of the different pollen morphs, and whether the morphs differ in gametophytic performance. Results show that the more apertures a pollen grain has, the more quickly it germinates but that few-apertured pollen grains have faster growing pollen tubes and longer life expectancies. The proportions of the different pollen morphs, together with pollen tube growth rates, may be inherited traits based on differences among maternal families. These results suggest that the different pollen morphs are favored in different pollination ecology situations. The production of several pollen morphs by the same individual could therefore be evolutionarily advantageous. PMID- 28564279 TI - GENOTYPIC VARIATION AND CLONAL STRUCTURE IN CORAL POPULATIONS WITH DIFFERENT DISTURBANCE HISTORIES. AB - Genotypic diversity in six populations of the endemic Hawaiian reef coral, Porites compressa, was directly related to habitat-disturbance history. The highest diversity (lowest amount of clonal proliferation) was found in populations that had been intensely or recently disturbed. In these populations, space was not limited and mean colony size was small (< 500 cm2 ), suggesting early stages of recolonization. In an undisturbed, protected habitat, lower genotypic diversity was a result of a significant degree of clonal replication of established genotypes. Unoccupied substratum was rare in this habitat, and average colony size was large (> 2500 cm2 ). Populations in intermediately disturbed habitats showed intermediate levels of diversity and clonal structure as a result of the combined contributions of sexual and asexual reproduction. Individual clones were distributed over small areas (< 4 m2 ) or distances (< 1 m) in young populations, and more broadly (> 256 m2 ) and over longer distances (> 90 m) in the older, undisturbed population. Interpretations of life-history parameters and estimates of total genetic variability in species that have the potential to reproduce asexually are dependent upon an assessment of the overall clonal structure of populations. The power of genotypic assays to reliably detect clonal versus unique colonies, as well as the spatial scales over which clonal populations are sampled, are critical to such assessments. PMID- 28564280 TI - MORPHOLOGICAL EVOLUTION OF THE DROSOPHILA VIRILIS SPECIES GROUP AS ASSESSED BY RATE TESTS FOR NATURAL SELECTION ON QUANTITATIVE CHARACTERS. AB - Two rate tests for assessing natural selection on quantitative traits are discussed for their usefulness in macroevolutionary and adaptational studies. The underlying assumptions and parameter estimation for the constant-heritability (CH) and mutation-drift-equilibrium (MDE) models, which are the bases for these tests, are discussed. The purpose of these rate tests is to determine whether morphological change has occurred either too fast to be explained by neutral drift, which suggests directional selection, or too slow, which suggests stabilizing selection. Previous formulations of these rate tests have ignored the phylogenetic component. Several models of evolution are considered to help account for phylogeny in the context of rate tests. The MDE rate test for stabilizing selection was performed on nine morphological characters among several species of the Drosophila virilis species group. These tests can be interpreted to suggest that stabilizing selection has probably been a major factor in producing the observed similarity among the Drosophila species examined. PMID- 28564281 TI - PHENOTYPIC PLASTICITY IN POLYGONUM PERSICARIA. I. DIVERSITY AND UNIFORMITY IN GENOTYPIC NORMS OF REACTION TO LIGHT. AB - Several aspects of genotype-environment interaction may act to modulate natural selection in populations that encounter variable environments. In this study the norms of reaction (phenotypic responses) of 20 cloned genotypes from two natural populations of the annual plant Polygonum persicaria were determined over a broad range of controlled light environments (8%-100% full sun). These data reveal both the extent of functionally adaptive phenotypic plasticity expressed by individual genotypes, and the patterns of diversity among genotypes for characters relevant to fitness, in response to an environmental factor that is both highly variable within populations and critical to growth and reproduction. PMID- 28564282 TI - BADGE SIZE, PHENOTYPIC QUALITY, AND REPRODUCTIVE SUCCESS IN THE HOUSE SPARROW: A STUDY ON HONEST ADVERTISEMENT. AB - Honest signaling theory suggests that advertising traits must be costly to their bearer; thus, only individuals of high phenotypic quality can exhibit maximal expression of these traits. Males of the sexually dichromatic house sparrow, Passer domesticus, have a black throat patch that functions as a badge of status. I investigated whether badge size honestly shows phenotypic quality. Badge size increases with age and decreases with advancing fledging date in yearling males; thus, badge size was larger in older individuals even though age differences were small. Badge size also increased with physical condition independent of age. These results indicate that badge size functions as an honest signal, possibly because there are costs involved in its production. I also found that males with enlarged badges acquired more nest sites than either control males or males with reduced badges. However, males with enlarged badges possessing a nest site raised fewer fledglings per year than did males with reduced badges, suggesting that cheating has no selective benefit. Further studies that accurately measure the energy expenditure allocated to badge production and that quantify additional fitness components are needed to clarify how reliable badges are maintained. PMID- 28564283 TI - COST OF REPRODUCTION IN POLEMONIUM VISCOSUM: PHENOTYPIC AND GENETIC APPROACHES. AB - I measured the effect of early reproduction on subsequent growth and survival in the alpine perennial wildflower, Polemonium viscosum. Measurements were made over 4 yr on 34 maternal sibships under natural conditions. A significant phenotypic cost of early reproduction characterized the study population. Plants that flowered after only one year's growth had twice as many leaves and 25% more shoots than nonflowering individuals of equal age. However, early flowering decreased leaf number by 18% in the subsequent year and survivorship by 20% after two years relative to changes in leaf number and survival of nonflowering plants. For such trade-offs to shape the further evolution of reproductive schedules, flowering probability and those age-specific components of plant size that represent the energetic currency for reproductive costs must be heritable. Although families showed significant heterogeneity in the probability of early flowering, most (62%) entirely failed to flower. Moreover, phenotypic variation in vegetative size components at ages 1 and 2 had little genetic basis. Only at ages 3 and 4, after vegetative and demographic costs of early reproduction had been incurred, did vegetative size components (leaf length and number, and shoot number) vary significantly among families. Results of this study provide little evidence of a genetically based trade-off between early reproduction and subsequent survival in P. viscosum. PMID- 28564284 TI - SPERMATOPHORE SIZE IN BUSHCRICKETS: COMPARATIVE EVIDENCE FOR NUPTIAL GIFTS AS A SPERM PROTECTION DEVICE. AB - During courtship and copulation, males of many insect species provide the female with a nuptial gift of a prey item or synthesized material. These gifts may be explained as a form of paternal investment by increasing female reproductive output, or in terms of mating effort by increasing male fertilization success. These explanations, while not mutually exclusive, are controversial. While experimental studies examine the maintenance of nuptial gifts in single species, comparative studies are required to indicate more general evolutionary trends. Male bushcrickets provide females with a nuptial gift, a spermatophylax, which is transferred to females at mating along with the sperm-containing ampulla. Analysis of comparative data of 28 species of bushcrickets (Orthoptera: Tettigoniidae), reveals that male spermatophore size (spermatophylax and ampulla weight) is positively correlated with female refractory period, which, in turn, correlates with male fertilization success. Moreover, gift size (the spermatophylax) covaries with ejaculate size (the ampulla), which is consistent with the hypothesis that it serves as a sperm protection device. In contrast, there is no significant correlation between any measure of female fecundity and male spermatophylax size. This indicates that the variation in spermatophore size among bushcrickets is better explained by a mating-effort function than a paternal investment function. PMID- 28564285 TI - FEMALE REPRODUCTIVE EFFORT DEPENDS ON THE DEGREE OF ORNAMENTATION OF THEIR MATES. AB - Sexual selection theory assumes that secondary sexual characters do not influence female reproductive effort. Female animals may invest relatively more in reproduction if they acquire mates of high phenotypic quality, because offspring sired by preferred males may be relatively more viable than offspring sired by less preferred males. Here we report for the first time in a field study that females of the monogamous barn swallow Hirundo rustica adjust their reproductive effort to the attractiveness of their mates. Experimental manipulation of male tail length, which is a trait currently subject to a directional female mating preference, affected the reproductive effort by females in single broods as well as their decision on the seasonal number of clutches. These results, and those of previous experiments, demonstrate that female barn swallows assess the quality of their mates throughout the reproductive season and adjust their reproductive decisions accordingly. This result has important implications for the theory of sexual selection and for the possibility of testing current models of female mate preferences, because the viability of offspring will be confounded by differential reproductive effort. PMID- 28564287 TI - PHYLOGEOGRAPHIC PATTERNS IN COASTAL NORTH AMERICAN TIGER BEETLES (CICINDELA DORSALIS SAY) INFERRED FROM MITOCHONDRIAL DNA SEQUENCES. AB - Genetic variation was assessed in the tiger beetle, Cicindela dorsalis, by sequencing of three regions of the mtDNA genome. Populations of four morphologically distinguishable subspecies were sampled from 28 representative locations covering almost the entire geographic range of the species in coastal North America. In 78 individuals analyzed for 656 base pairs from four different genes, 17 different haplotypes could be distinguished. A cladistic analysis grouped the haplotype sequences into two main lineages, one from the Atlantic Ocean and one from the Gulf of Mexico. Haplotypes within the two clades were very similar to each other. Most of the characters that distinguished these closely related haplotypes were homoplastic. The geographic distribution of haplotypes did not coincide with the distribution of morphological subspecies, but no evidence for hybridization between two subspecies could be inferred from this observation. The implications of these findings for the evolution of gene sequences at and below the species level are discussed. PMID- 28564288 TI - GENETIC VARIABILITY AND POPULATION DIFFERENTIATION INFERRED FROM DNA FINGERPRINTING IN SILVEREYES (AVES: ZOSTEROPIDAE). AB - This study evaluated DNA fingerprinting as a tool for estimating population genetic diversity and differentiation by comparing minisatellite variation in island and mainland populations of silvereyes (Aves: Zosterops lateralis). Three populations with different recent histories were compared: (1) Heron Island and neighboring islands, colonized 3000 to 4000 yr ago; (2) Lady Elliot Island, colonized within the past two decades; and (3) an adjacent mainland population, which presumably has existed for thousands of years. The degree of genetic variability within the three populations reflected both their size and the time since their colonization. Minisatellite diversity was highest in the mainland population, intermediate in the Capricorn Island group (which was shown to represent a single admixture), and lowest in the Lady Elliot Island population, possibly because of a recent population bottleneck during colonization. Mean band sharing between any two populations was less than the mean within either of those populations, and four fingerprint bands common to island birds were rare or absent in the fingerprints of mainland birds. In the absence of significant gene flow between the mainland and the islands, the populations have apparently become distinct at minisatellite loci, as evidenced by differences in both allelic diversity and in the frequencies of specific fragments. Within the Heron Island population, cohort analyses demonstrated the temporal stability of the fingerprint profile over 6 yr. This study demonstrates that length polymorphisms at minisatellite loci may be stable enough over time to retain information about recent historical and demographic effects on the relative genetic variability and differentiation of small, closely related populations. PMID- 28564289 TI - EXPERIMENTAL MOLECULAR EVOLUTION OF BACTERIOPHAGE T7. AB - We present an analysis of molecular evolution in a laboratory-generated phylogeny of the bacteriophage T7, a virus of 40 kilo-base pairs of double-stranded DNA. The known biology of T7 is used in concert with observed changes in restriction sites and in DNA sequences to produce a model of restriction-site convergence and divergence in the experimental lineages. During laboratory propagation in the presence of a mutagen, the phage lineages changed an estimated 0.5%-1.5% in base pairs; most change appears to have been G -> A or C -> T, presumably because of the mutagen employed. Some classes of restriction-site losses can be explained adequately as simple outcomes of random processes, given the mutation rate and the bias in mutation spectrum. However, some other classes of sites appear to have undergone accelerated rates of loss, as though the losses were selectively favored. Overall, the wealth of knowledge available for T7 biology contributes only modestly to these explanations of restriction-site evolution, but rates of restriction-site gains remain poorly explained, perhaps requiring an even deeper understanding of T7 genetics than was employed here. Having measured these properties of molecular evolution, we programmed computer simulations with the parameter estimates and pseudo-replicated the empirical study, thereby providing a data base for statistical evaluation of phylogeny reconstruction methods. By these criteria, replicates of the experimental phylogeny would be correctly reconstructed over 97% of the time for the three methods tested, but the methods differed significantly both in their ability to recover the correct topology and in their ability to predict branch lengths. More generally, the study illustrates how analyses of experimental evolution in bacteriophage can be exploited to reveal relationships between the basics of molecular evolution and abstract models of evolutionary processes. PMID- 28564290 TI - THE ONTOGENY OF POSTCRANIAL INTEGRATION IN THE COMMON TERN, STERNA HIRUNDO. AB - Empirical and theoretical work supports the concept that developmentally or functionally related characters tend to covary and hence evolve together. However, the dynamics of the developmental processes that establish within population covariance structures are not well understood. This paper focuses on a description of the relative growth of 16 postcranial skeletal elements during embryonic and posthatching development in the common tern, Sterna hirundo, and on a comparative analysis of ontogenetic and adult patterns of variation. Multivariate methods are used to assess the relative contributions of general growth and size-independent "shape" transformations during three major development phases. The observed patterns of integration generally correspond to functional units that tend to show greater relative growth during development immediately preceding when a unit will first be functionally required. Such age dependent functional adaptations provide an opportunity for selection to act directly on ontogenies with consequences that will be age dependent. Size and shape contributions to adult covariances, which tend to be generated during different phases of development, appear to reflect ontogenetic integration patterns characteristic of periods when global constraints, such as overall size, are most relaxed, but more localized constraints, most likely linked to age dependent functional requirements, are relatively intense. PMID- 28564291 TI - THE GENETICS OF CENTRAL AND MARGINAL POPULATIONS OF DROSOPHILA SERRATA. II. HYBRID BREAKDOWN IN FITNESS COMPONENTS AS A CORRELATED RESPONSE TO SELECTION FOR DESICCATION RESISTANCE. AB - Multiple-peak epistasis is one of the four premises that underlie Wright's shifting-balance theory of evolution. A selection experiment was conducted in an attempt to push different geographic populations to different fitness peaks as a correlated response to selection for an additively controlled character (desiccation resistance). Four populations of Drosophila serrata, sampled from central and marginal areas of its distribution along a 3000-km stretch of Australia's east coast, underwent selection for desiccation resistance for 14 generations. After selection had ceased, control lines from each of the populations were crossed to determine the amount of hybrid breakdown that existed before selection and selected lines were crossed to determine the amount of hybrid breakdown after selection. Hybrid breakdown was measured in three fitness traits: developmental time, viability, and fecundity. When the individual crosses were examined, virtually no evidence was found for hybrid breakdown between these populations. However, the level of hybrid breakdown in development time in the control lines increased as the distance between the populations in the field increased. This relationship was lost in the selected lines. Therefore, selection for desiccation resistance influenced the level of hybrid breakdown in a fitness trait, although selection may need to be maintained for longer than 14 generations if a new relationship between hybrid breakdown and distance is to be formed. PMID- 28564292 TI - PHENOTYPIC PLASTICITY IN POLYGONUM PERSICARIA. III. THE EVOLUTION OF ECOLOGICAL BREADTH FOR NUTRIENT ENVIRONMENT. AB - Norms of reaction for a number of growth and reproductive characters were determined for 15 randomly sampled Polygonum persicaria genotypes, from two natural populations originating in sites with very different nutrient availabilities. Under severely limiting nutrient conditions, these genotypes shared not only plastic responses such as increased root-to-shoot ratio, but a surprising constancy in such functionally essential characters as leaf area ratio, leaf nitrogen concentration, and propagule nitrogen content. Because functional homeostasis depends on flexibility in underlying characters, similar homeostatic results can be achieved through different combinations of underlying plastic and fixed responses in genetically different entities. For example, plants in each population maintained a relatively constant propagule nitrogen content under extreme low-nitrogen conditions by varying either the size or the tissue nitrogen concentration of propagules. These genotypes also tolerated excessive nutrient levels toxic to many plants, evidently by storing excess nutrients in shoots. Although development was altered under such circumstances, reproductive fitness was maintained. PMID- 28564293 TI - THE EFFECT OF BIASED INCLUSION OF TAXA ON THE CORRELATION BETWEEN DISCRETE CHARACTERS IN PHYLOGENETIC TREES. AB - In a published paper, a method for testing the correlation between two discrete characters was presented and applied to test whether in butterfly larvae origins of gregariousness are concentrated to lineages with aposematic coloration. The relationship was found to be nonsignificant. However, the butterfly data on which the test was applied had been compiled in another study to investigate evolutionary sequences and was biased, because there was an overrepresentation of aposematic, as compared to cryptic, branches in the sample. In the paper presented here, aposematic and cryptic clades of the original phylogeny were resolved to the same degree, and the resulting set of branches may be regarded as unbiased with respect to the hypothesis being tested. A method for testing the contingency of states in two characters was then applied to the new data set, resulting in a highly significant relationship between origins of gregariousness and aposematic coloration. I argue that when using statistical methods on phylogenetic data, it is crucial to resolve various parts of the phylogeny to the same comparable systematic unit in order not to get a distorted sample of taxa/branches. PMID- 28564295 TI - THE GENETICS AND COST OF CHEMICAL DEFENSE IN THE TWO-SPOT LADYBIRD (ADALIA BIPUNCTATA L.). AB - Ladybirds (Coccinellidae) defend themselves against attack by vertebrate predators by exuding a fluid from the femero-tibial joints. This fluid carries a noxious or toxic alkaloid. The amount of fluid produced during a single attack can be very high (up to 20% of fresh body weight), and the weight of the self synthesized alkaloid can amount to several percent of the weight of the fluid. A study was carried out on these two defense characters and two other fitness characters (body weight and growth rate) to demonstrate a cost to defense in the form of genetic trade-offs between characters. The two sexes were analyzed separately, and a jackknife procedure was used to attach errors to the estimates of Va and cova . All four characters were associated with high levels of Va , but the cova values were mixed, some being negative and others positive. Principal component analysis indicated the operation of factors constraining the cova values in males, and further possible reasons for the appearance of so many positive values are explored. A matrix analysis showed that the genetic variance/covariance matrices of the two sexes were significantly different from each other. Breeding values derived from sons plotted on breeding values from daughters had correlation coefficients significantly less than +1. This finding indicated that a substantial amount of sex-dependent gene expression was occurring. PMID- 28564294 TI - THE EFFECTS OF POPULATION SIZE AND PLANT DENSITY ON OUTCROSSING RATES IN LOCALLY ENDANGERED SALVIA PRATENSIS. AB - Multilocus outcrossing rates were estimated in natural and experimental populations of Salvia pratensis, an entomophilous, gynodioecious, protandrous perennial. Male steriles were used to check the estimation procedure of outcrossing rates in hermaphrodites. Estimates of outcrossing rates in hermaphroditic plants ranged from 38.2% to 81.8% in natural populations and from 71.5% to 95.5% in experimental populations. No correlations were found between outcrossing rates and population size. However, outcrossing in hermaphrodites was promoted by high plant densities and low frequencies of male steriles. It is argued that effective management to preserve genetic variation in populations of S. pratensis should provide for the maintenance of high plant densities. PMID- 28564296 TI - MOLECULAR TESTS OF THE HYPOTHESIZED HYBRID ORIGIN OF TWO DIPLOID HELIANTHUS SPECIES (ASTERACEAE). AB - Enzyme electrophoresis and restriction-fragment analysis of chloroplast DNA (cpDNA) and nuclear ribosomal DNA (rDNA) were used to test the hypothesis that both Helianthus neglectus and H. paradoxus are stabilized hybrid derivatives of H. annuus and H. petiolaris. The four species are annuals, diploid outcrossers, and have the same chromosome number. Helianthus annuus and H. petiolaris had the same allele in highest frequency for 16 of the 18 isozyme loci examined and had different majority alleles for only 6-Pgd3 and Pgi2. The two species had divergent rDNAs that could be distinguished by seven diagnostic restriction site mutations and three length mutations, and their cpDNAs could be differentiated by three diagnostic restriction site mutations. The alleles observed in H. neglectus were not a combination of those observed in H. annuus and H. petiolaris. Although H. neglectus had only one unique allele, it possessed none of the three alleles specific to H. annuus. In contrast, it had four of the seven alleles specific to H. petiolaris. Furthermore, H. neglectus had the same rDNA type as H. petiolaris and had the same cpDNA as that found in two populations of H. petiolaris ssp. fallax. These data allowed us to speculate that H. neglectus may be a recent derivative of H. petiolaris ssp. fallax, rather than a stabilized hybrid derivative as originally proposed. In contrast, H. paradoxus combined the alleles of H. annuus and H. petiolaris and had no unique alleles. At Adh2, H. paradoxus was monomorphic for an allele found only in H. petiolaris ssp. fallax, whereas at 6-Pgd3 and Pgi2, it was monomorphic for high frequency H. annuus alleles. Furthermore, H. paradoxus combined the rDNA repeat types of both proposed parents and had the chloroplast genome of H. annuus. These data provide compelling evidence that H. paradoxus, in contrast to H. neglectus, was derived via hybridization. PMID- 28564297 TI - PREDICTING HOST RANGE EVOLUTION: COLONIZATION OF CORONILLA VARIA BY COLIAS PHILODICE (LEPIDOPTERA: PIERIDAE). AB - Extensive sympatry is currently arising between the common sulfur butterfly, Colias philodice Latreille (Lepidoptera: Pieridae) and a potential leguminous host plant, Coronilla varia (L.). In laboratory trials, larval surviviorship and growth were higher on the primary host, Medicago sativa (L.), than on the nonhost C. varia. However, because females reared from C. varia were on average more fecund than females reared from M. sativa, fitness on C. varia (approximately as survivorship times fecundity) was commensurate with fitness on M. sativa. Thus, it is predicted that selection would favor oviposition on C. varia, if such behavior were to arise. In addition, significant among-family variation exists for several measures of larval performance on both C. varia and M. sativa, indicating that C. philodice can potentially respond to selection for increased performance on each species. Moreover, larval performance was significantly positively correlated across these species, suggesting that selection for increased performance on each species will facilitate, not constrain, evolution of increased performance on the other. It is concluded that behavioral rather than physiological barriers currently account for the absence of C. philodice from C. varia and that, if such barriers are overcome, C. philodice will expand its host plant range to include C. varia. PMID- 28564298 TI - PHYLOGENESIS OF INSECT/PLANT INTERACTIONS: HAVE PHYLLOBROTICA LEAF BEETLES (CHRYSOMELIDAE) AND THE LAMIALES DIVERSIFIED IN PARALLEL? AB - The relative importance of conservative versus locally adapted traits for species interactions is an increasingly common theme in evolutionary ecology. Obligate interactions such as those between parasites and hosts often exhibit such strong phylogenetic conservatism that current associations may reflect diversification in parallel. Parallel phylogenesis, documented for animal parasites, has been doubted for insect/plant interactions, but phylogenetic studies of highly specific insect/plant associations are very few. A comparison of phylogeny estimates for the strictly monophagous Phyllobrotica leaf beetles and their lamialean hostplants shows nearly complete concordance, strongly supporting the hypothesis of parallel diversification. The cladogram concordance is significant or nearly so (consensus index values equalling or exceeding the critical value) under randomization distributions based on Adams (though not Nelson) consensus trees. The one clear exception shows unusual natural history, suggesting an isolated host transfer. Insect distributions and plant fossil ages are consistent with a mid-Tertiary age for both clades, further disfavoring the alternative hypothesis of entirely subsequent evolution. The dependence of both larval and adult beetles on the hostplants, larval endophagy, and possible dependence of beetles on toxic host compounds for defense against predators are suggested to underlie the evolutionary persistence of this interaction. Current host use in these beetles appears to reflect primarily the phylogeny of the interaction, strengthening the thesis that history can play a major role in structuring insect/plant relationships. PMID- 28564299 TI - THE EVOLUTION OF TETRAPOD FEEDING BEHAVIOR: KINEMATIC HOMOLOGIES IN PREY TRANSPORT. AB - One of the major features of the aquatic-to-terrestrial transition in vertebrate evolution was the change in the mechanism used to transport prey from the jaws to the throat. Primarily, vertebrates use hydraulic transport, but the transition to terrestrial life was accompanied by modifications of the hyobranchial apparatus that permit tongue-based transport. Despite an extensive data base on amniote feeding systems and mechanisms of intraoral prey transport, few data are available on the mechanism of prey transport in anamniote tetrapods. Transport cycles of four Ambystoma tigrinum (Amphibia) feeding on worms and crickets were filmed at 150 flames per second to produce quantitative profiles of the intraoral transport cycles for the two prey types. During the transport cycle the head and body remain stationary relative to the background: transport in Ambystoma tigrinum thus does not involve inertial movements of the head or body. Prey type had little effect on the kinematics of prey transport. The process of prey transport may be divided into four phases: preparatory, fast opening, closing, and recovery. The preparatory phase itself is divided into two parts: an extended segment that may include slight slow opening and a static phase prior to mouth opening where no change in gape occurs. The kinematic profile of transport in terrestrial salamanders is extremely similar to that used by fishes during hydraulic (aquatic) prey transport. We hypothesize that the distinct recovery and preparatory phases in the transport cycle of anamniote tetrapods are together homologous to the slow opening phases of the amniote cycle, and that during the evolution of terrestrial prey processing systems the primitive extended preparatory phase has become greatly compressed and incorporated into the amniote gape cycle. PMID- 28564300 TI - HYBRIDS AND PHYLOGENETIC SYSTEMATICS I. PATTERNS OF CHARACTER EXPRESSION IN HYBRIDS AND THEIR IMPLICATIONS FOR CLADISTIC ANALYSIS. AB - Interspecific hybridization is considered common among plants, but the methods of cladistic systematics produce only divergently branching phylogenetic hypotheses and thus cannot give the correct phylogeny if an analysis includes hybrids. Empirical studies of the impact of known hybrids on phylogenetic analysis are lacking, and are necessary to begin to understand the problems that we face if hybrids are often included in cladistic analysis. Examination of the implications of hybrids for cladistics must begin with patterns of character expression in hybrids. This study includes 17 hybrids and their nine parental taxa that are Central American species of Aphelandra (Acanthaceae), analyzed using a set of 50 morphological characters. The hybrids are overwhelmingly intermediate as quantitatively scored for phylogenetic analysis. They express maternal and paternal, and primitive and derived characters in equal frequencies, showing no evidence of predominant inheritance of derived character states as has been assumed by most cladists who have considered hybrids theoretically. Because of their known genetic constitution, hybrids were useful in homology assessment and ordering character states. The parental character set was generally robust, but some changes were made to reflect the special evidence offered by the hybrids. These hybrids suggest that the inclusion of hybrids in phylogenetic analysis will not lead to unresolved cladograms with rampant homoplasy, as has been predicted by other authors. Instead, the patterns of character inheritance in these hybrids lead to the prediction that a hybrid will be placed by phylogenetic analysis as a basal lineage to the clade that includes its most derived parent, with relatively little effect on homoplasy. These predictions will be evaluated by incorporation of the hybrids in phylogenetic analyses, to be reported in a subsequent paper. PMID- 28564301 TI - PATERNITY ANALYSIS IN A NATURAL POPULATION OF ASCLEPIAS EXALTATA: MULTIPLE PATERNITY, FUNCTIONAL GENDER, AND THE "POLLEN-DONATION HYPOTHESIS". AB - Recently, some evolutionary biologists have argued that selection on the male component of fitness shapes the evolution of reproductive characters in angiosperms. Floral features, such as inflorescence size, that lead to increased insect visitation without a concomitant increase in seed production are viewed as adaptations to enhance the probability of fathering seeds on other plants. In tests of this "pollen donation hypothesis," male reproductive success has usually been measured indirectly by flower production, pollinator visitation, or pollen removal. We tested the pollen donation hypothesis directly by quantifying the number of seeds sired by individual genotypes in a natural population of poke milkweed, Asclepias exaltata, in southwestern Virginia. Multiple paternity was low within fruits, a fact which allowed us to use genotypes of progeny arrays to identify a unique pollen parent for 85% of the fruits produced in the population. Seeds sired (male success) and seeds produced (female success) were significantly correlated with flower number per plant (for male success, r = 0.32, P > 0.05; for female success, r = 0.66, P > 0.001). While the number of pollinaria removed, the usual estimator of male success in milkweeds, was highly correlated with numbers of seeds sired (r = 0.47; P > 0.001), it was even more highly correlated with numbers of seeds produced (r = 0.71, P > 0.001). Analysis of functional gender indicated that plants with many flowers did not behave primarily as males. In fact, individuals with the highest total reproductive success contributed equally as males and females. Furthermore, estimates of gender based on numbers of flowers produced or pollinaria removed overestimated the number of functional males in the population. In pollen-limited species, such as many milkweeds, proportional increases in both male and female reproductive success indicate the potential for selection to shape the evolution of large floral displays through both male and female functions. PMID- 28564302 TI - PAEDOMORPHOSIS IN AMBYSTOMA TALPOIDEUM: MAINTENANCE OF POPULATION VARIATION AND ALTERNATIVE LIFE-HISTORY PATHWAYS. AB - A "common garden" experiment using artifical ponds was performed to test if differences in frequency of paedomorphosis and metamorphosis among six natural populations of the salamander Ambystoma talpoideum resulted from the drying regime of the aquatic habitat acting as an agent of selection. Our experiment supports the hypothesis of genetic differentiation in the propensity to metamorphose among the populations, but gave mixed evidence that pond-drying regime is the selective force directing evolution of this trait. Some populations appear to have evolved phenotypic plasticity whereas others may have a genetic polymorphism in their propensity to metamorphose as ponds dry. PMID- 28564303 TI - GENETIC VARIATION AND TERRITORIALITY IN WILLOW PTARMIGAN (LAGOPUS LAGOPUS LAGOPUS). AB - We examined eight polymorphic esterase loci in 526 juvenile and adult willow ptarmigan (Lagopus lagopus lagopus) collected during autumn and spring over five years. The genetic structure of territorial birds during spring differed from birds on the study area in autumn. This can not be explained by selective winter mortality since juvenile birds in the autumn had the same genetic structure as the adults who had lived through at least one winter. In the spring, birds with intermediate heterozygosity had the largest territories and were more frequently mated than expected from random mating among autumn birds. The results suggest selective access to territories by genotype and stabilizing selection, especially among males, since natural selection is assumed to favor large territories and reproduction. Our data also suggest that the spring population consisted of both territorial and non-territorial birds. The genetic relationship between birds of established pairs in spring was lower than that between randomly drawn birds on the study area in the autumn. This together with the finding that parents with an intermediate level of genetic relationship produced the largest broods, suggest that optimal rather than maximal outbreeding is the most successful breeding strategy in this species. PMID- 28564304 TI - EXPERIMENTAL STUDIES OF COMMUNITY EVOLUTION II: THE ECOLOGICAL BASIS OF THE RESPONSE TO COMMUNITY SELECTION. AB - Community selection, defined as the differential proliferation and/or extinction of communities, can bring about a response that may be qualitatively different from the response to selection acting at lower levels. This is because community selection can result in genetic changes in all of the species within the community by acting on the interaction among species. In the experiment presented here, a series of one generation assays were performed on the coevolved communities of two species of flour beetles, Tribolium castaneum and T. confusum, discussed by Goodnight (1990). Two community assays and one single-species assay were performed. Taken together, these provide insights into the genetic basis of the response to community selection. The first community assay involved measuring the selected traits on the original coevolved communities that had been subjected to community selection. This assay indicated that all of the selection treatments resulted in a significant response to selection in the original coevolved communities. The single-species assay involved separating the coevolved communities into their constituent single-species populations and again measuring the selected traits on these populations. None of the single-species populations exhibited a significant response to selection; thus the responses to community selection observed in the first community assay are expressed only in a community context. The second community assay again involved separating the coevolved communities into their constituent single-species populations; however, in this assay a competitor of the opposite species that had never been exposed to community selection was added to each population to form a "reconstructed" community. The results of this assay were that for two traits, emigration rate in T. castaneum and emigration rate in T. confusum, the genetic identity of the competing species did not affect the response to selection. This indicates that the competing species was acting like a nonevolving part of the environment. For the other two traits measured, population size in T. castaneum and population size in T. confusum, the results were very different. For these traits there was no detectable response to selection in the reconstructed communities. This indicates that for these traits the response to selection cannot be attributed to a genetic change in either species independently of the other species in the community. Rather it resides in the interaction between the two species. PMID- 28564305 TI - POPULATION STRUCTURE AND COMPETITION AMONG KIN IN THE CHORUS FROG (PSEUDACRIS TRISERIATA). AB - In natural populations on Isle Royale, tadpoles of the chorus frog live in small pools on the shore of Lake Superior. Hatchling densities are high and sufficient to cause competitive impact on survivorship, growth, and development. The temporal and spatial pattern of egg laying indicates that tadpoles in many of the pools belong to single sibships. I calculated average coefficients of relationship among tadpoles under the assumption that eggs laid together are the products of the same breeding pair; the coefficients indicate that relationship among competing larvae averages approximately 0.35, and varies widely among larval subpopulations, from less than 0.1 to about 0.5. Two growth experiments were carried out in pens to test whether growth trajectories and larval characteristics at metamorphosis are influenced by relationship among competing tadpoles. In both experiments, initial density was crossed with average relationship; relationship was controlled by varying the number of sibships per pen from one to four. The same sibships were used in both experiments, but one experiment had lower initial densities and less water volume per pen than the other. In both experiments, density reduced growth, developmental rate, size at metamorphosis, survivorship to the onset of metamorphosis, and the proportion of survivors which actually attained metamorphosis by the end of the experiment. Kin effects occurred only in the experiment carried out in small pens at high initial densities: in this experiment, pure sib populations grew faster, and a higher proportion attained metamorphosis. However, there were no kin effects on larval period or body size at metamorphosis. The chorus frog appears to have a population structure conducive to kin-group selection. Furthermore, high variance in the average coefficient of relationship among pools should favor kin recognition and kin-specific interference behavior. The growth experiments suggest that the tadpoles respond to the genetic relationship of competitors, with significant effects on the distribution of fitness at metamorphosis among members of the group. PMID- 28564306 TI - ACCURACY OF ESTIMATED PHYLOGENIES: EFFECTS OF TREE TOPOLOGY AND EVOLUTIONARY MODEL. AB - A simulation study was carried out to investigate the relative importance of tree topology (both balance and stemminess), evolutionary rates (constant, varying among characters, and varying among lineages), and evolutionary models in determining the accuracy with which phylogenetic trees can be estimated. The three evolutionary context models were phyletic (characters can change at each simulated time step), speciational (changes are possible only at the time of speciation into two daughter lineages), and punctuational (changes occur at the time of speciation but only in one of the daughter lineages). UPGMA clustering and maximum parsimony ("Wagner trees") methods for estimating phylogenies were compared. All trees were based on eight recent OTUs. The three evolutionary context models were found to have the largest influence on accuracy of estimates by both methods. The next most important effect was that of the stemminess * context interaction. Maximum parsimony and UPGMA performed worst under the punctuational models. Under the phyletic model, trees with high stemminess values could be estimated more accurately and balanced trees were slightly easier to estimate than unbalanced ones. Overall, maximum parsimony yielded more accurate trees than UPGMA-but that was expected for these simulations since many more characters than OTUs were used. Our results suggest that the great majority of estimated phylogenetic trees are likely to be quite inaccurate; they underscore the inappropriateness of characterizing current phylogenetic methods as being for reconstruction rather than for estimation. PMID- 28564307 TI - FREQUENCY-DEPENDENT FITNESS CONSEQUENCES OF INTRASPECIFIC NEST PARASITISM IN SNOW GEESE. AB - The reproductive efficiency, defined as the number of breeding recruits produced per egg laid; of intraspecific nest parasites; of hosts in parasitized nests; and of unparasitized nesting females, was measured for 14 years for lesser snow geese Anser caerulescens caerulescens nesting near Churchill, Manitoba, Canada. Relative efficiencies were 0.71-0.88, 0.91, and 1.0 for eggs of parasites, hosts, and unparasitized birds, respectively. Differences in the hatching probabilities of the three classes of eggs produced the efficiency differences. Parasitic success was limited by the parasites' failure to place more eggs than expected by chance into nests at the appropriate time relative to host incubation. Host nesting success was lower when more than one parasitic egg was added to the clutch. No differences in gosling survival and breeding recruitment probabilities were detected among any categories of goslings. Thus, hatching parasitic young are at no disadvantage relative to parental young, and there is no support for the hypothesis that increased success of host young at later stages of reproduction might offset negative effects at the egg stage. The hatching efficiency of parasitic eggs declined more rapidly than that of parental eggs as the parasitism rate increased. Efficiencies were similar when 3-4% of the eggs laid per year were parasitic, but relative parasitic efficiency was significantly lower when the parasitism rate was 8-9% or more. Using ancillary information and assumptions about the fecundity, viability, and behavioral flexibility of parasitic and parental females, we conclude that intraspecific nest parasitism could compete with nesting as a reproductive strategy in this population. The conditional use of parasitism by a large component of the population in certain years, however, combined with negative-frequency dependent success, limits the potential spread of a purely parasitic strategy in this population. PMID- 28564308 TI - LOCAL VARIATION IN THE GENETIC BASIS OF PAEDOMORPHOSIS IN THE SALAMANDER AMBYSTOMA TALPOIDEUM. AB - The hypothesis that local isolated populations differed in the genetic basis for life-history traits was tested in the salamander Ambystoma talpoideum. Genetic basis was defined as the specific genetic architecture (additive and nonadditive) that contributes, along with maternal and environmental factors, to the phenotype. All crosses within and between three populations were made to produce nine F1 populations. Nine within-population crosses produced the F2 generation. This design does not permit an estimation of the exact nature of the genetic basis (e.g., additive, nonadditive) for any trait within populations. However, hybrid dissimilarity in the F2 generation was taken as evidence of a different genetic basis for a trait in each population. The genetic basis of life-history pathway (metamorphosis vs. paedomorphosis) and per capita fecundity differed between two populations. The genetic basis of life-history pathway, per capita fecundity, survival, and growth rate was similar between the remaining sets of populations. This study and related ones (Semlitsch and Wilbur, 1989; Semlitsch et al., 1990) suggest that a heterochronic shift that causes rapid morphological evolution between metamorphosis and paedomorphosis (a macroevolutionary pattern) can evolve independently and does not require a macromutation or other nonmicroevolutionary mechanisms. PMID- 28564309 TI - EXPERIMENTAL STUDIES OF COMMUNITY EVOLUTION I: THE RESPONSE TO SELECTION AT THE COMMUNITY LEVEL. AB - Coevolution generally refers to the process of two or more organisms adapting to each other as a result of individual selection. Another possibility, however, is that coevolution may result from selection acting directly at the community level. Certain types of multispecies associations, such as lichens, which are a symbiotic association between an alga and a fungus, are examples of simple two species communities that may be units of selection. The study presented here uses two species communities of Tribolium castaneum and T. confusum in an investigation of selection acting at the community level. Selection at the community level is performed on one trait measured in one species and correlated responses in other traits measured both within species and among species are monitored. I demonstrate that community selection, defined as the differential survival and or reproduction of communities, can result in significant changes in the phenotype of a community. The observed changes in the phenotype of a community as a result of community selection included changes in the trait under selection (direct effects of selection), as well as changes in traits that are not under selection (correlated responses to selection). Furthermore, two types of correlated responses to selection were observed. The first, within-species correlated responses to selection, are changes in a trait measured in one species as a result of community selection acting on another trait measured in the same species. The second, between-species correlated responses to selection, are changes in a trait measured in one species as a result of community selection acting on a trait measured in another species. Between species correlated responses to selection are of particular interest because they cannot be mediated by pathways of gene action that are internal to an individual, rather they can be mediated only through ecological pathways. In other words, between-species correlated responses to selection suggest that genetically based interactions among individuals are contributing to the response to community selection. These among species ecological pathways of gene action cannot contribute to a response to selection at a lower level; thus community selection may be able to bring about a response to selection that is qualitatively different from the response selection that would occur as a result of selection acting at a lower level. PMID- 28564310 TI - DIPLOID MALES IN A PRIMITIVELY EUSOCIAL BEE, LASIOGLOSSUM (DIALICTUS) ZEPHYRUM (HYMENOPTERA: HALICTIDAE). AB - Hymenoptera are characterized by a haplo-diploid mechanism of sex determination. Females are diploid and males are haploid. However, in many species diploid males may occur if individuals are homozygous at a sex determining locus. Diploid males were found in three out of four populations (nest aggregations) of the primitively eusocial, halictine bee Lasioglossum zephyrum for which samples of males were examined electrophoretically. The frequency of diploid males was greater in a small, geographically isolated population (the "Robinson" nest aggregation) than in a large population that had nearby neighboring populations (the "Salmon Creek A" nest aggregation). In addition, the proportion of polymorphic loci was lower in the Robinson nest aggregation suggesting that a bottleneck event or loss of alleles due to small population size occurred in the Robinson population that involved a loss in the number of alleles at the sex determining locus. PMID- 28564311 TI - EVOLUTIONARY IMPLICATIONS OF DNA DIVERGENCE IN THE DROSOPHILA OBSCURA GROUP. AB - Using DNA-DNA hybridization, we have determined the degree of single-copy DNA (scDNA) divergence among eight species of the Drosophila obscura group. These include Old World and New World species as well as members of two subgroups. Contrary to classical systematics, members of the affinis subgroup are more closely related to American members of the obscura subgroup than are Old World species. The Old World species are not a monophyletic group. The degree of scDNA divergence among species is not necessarily correlated with morphology, chromosomal divergence, or ability to form hybrids. A unique pattern of hybrid formation was found: species separated by a DeltaTm of 6.5 degrees C can form hybrids whereas species separated by a DeltaTm of 2.5 degrees C cannot. As with other groups of Drosophila, the obscura group has discrete parts of the genome evolving at very different rates. The slow evolving fraction of the nuclear genome is evolving at about the same rate as mitochondrial DNA. The additional scDNA divergence accompanying the step from partial reproductive isolation (between North American pseudoobscura and the isolated Bogota population) to full isolation is very small. The resolution of the technique was challenged by five closely related taxa with a maximum DeltaTm of 2.5 degrees C separating them; the taxa were unambiguously resolved and the "correct" phylogeny recovered. Finally, there is some indication that scDNA in the obscura group may be evolving considerably slower than in the melanogaster subgroup. PMID- 28564312 TI - DIFFERENTIAL SEED PRODUCTION IN MIMULUS GUTTATUS IN RESPONSE TO INCREASING CONCENTRATIONS OF COPPER IN THE PISTIL BY POLLEN FROM COPPER TOLERANT AND SENSITIVE SOURCES. AB - Selection can occur in the pistil, during a series of stages that include both pre-zygotic (pollen germination, pollen tube growth, and fertilization) and post zygotic events. This study explores the extent to which selection, at this level, could be due to the environmental conditions under which the maternal parent is growing. Five plants of Mimulus guttatus, tolerant to copper, were vegetatively cloned and each clone was grown in control and in solutions to which copper was added. The maternal plants received pollen from plants either tolerant or sensitive to copper. Seeds and ovules were counted to estimate the number of seeds/capsule, the seed/ovule ratio, the percent fertilization, and the proportion of zygotes aborting for each clone, treatment and pollen source combination. There were large differences among the pollen recipients for each of the measurements. However, there was a consistent pattern to seed production depending on the pollen source and copper treatment. The seed/ovule ratio was unaffected if pollen came from tolerant sources but was reduced by an average of 24% for both copper supplemented treatments if pollen came from copper sensitive sources. Thus, the data indicated that selection due to environmental factors could occur within the pistil. Differences in percent fertilization were not statistically significant, but the seed/zygote ratio showed a pattern that was similar to seed production suggesting that abortion of immature seeds was responsible for most of the difference in seed production. PMID- 28564313 TI - MORPHOLOGICAL EVOLUTION IN MUROID RODENTS I. CONSERVATIVE PATTERNS OF CRANIOMETRIC COVARIANCE AND THEIR ONTOGENETIC BASIS IN THE NEOTROPICAL GENUS ZYGODONTOMYS. AB - Analyses of craniodental measurement data from 15 wild-collected population samples of the Neotropical muroid rodent genus Zygodontomys reveal consistent patterns of relative variability and correlation that suggest a common latent structure. Eigenanalysis of each sample covariance matrix of logarithms yields a first principal component that accounts for a large fraction of the total variance. Variances of subsequent sample principal components are much smaller, and the results of bootstrap resampling together with asymptotic statistics suggest that characteristic roots of the covariance matrix after the first are seldom distinct. The coefficients of normalized first principal components are strikingly similar from sample to sample: inner products of these vectors reveal an average between-sample correlation of 0.989, and the mean angle of divergence is only about eight degrees. Since first principal component coefficients identify the same contrasts among variables as comparisons of relative variability and correlation, we conclude that a single factor accounts for most of the common latent determination of these sample dispersions. Analyses of variance based on toothwear (a coarse index of age) and sex in the wild-collected samples, and on known age and sex in a captive-bred population, reveal that specimen scores on sample first principal components are age- and sex-dependent; residual sample dispersion, however, is essentially unaffected by age, sex, or age * sex interaction. The sample first principal component therefore reflects the covariance among measured dimensions induced by general growth, and its coefficients are interpretable as exponents of postnatal growth allometry. Path analytic models that incorporate prior knowledge of the equivalent allometric effects of general growth within these samples can be used to decompose the between-sample variance by factors corresponding to other ontogenetic mechanisms of form change. The genetic or environmental determinants of differences in sample mean phenotypes induced by such mechanisms, however, can be demonstrated only by experiment. PMID- 28564315 TI - Tenth Meeting of the Willi Hennig Society. PMID- 28564314 TI - HOMOSPORY AND THE COST OF ASEXUAL REPRODUCTION. PMID- 28564316 TI - NATURAL HYBRIDIZATION BETWEEN IRIS FULVA AND IRIS HEXAGONA: PATTERN OF RIBOSOMAL DNA VARIATION. AB - Genetic variation associated with the natural hybridization of Iris fulva and I. hexagona was investigated to test for the occurrence of introgression. These species have been viewed as a classic example of the process of introgressive hybridization (Anderson, 1949). However, more recent studies have concluded that there has not been an exchange of genetic material between I. fulva and I. hexagona (Randolph et al., 1967). Our analysis has involved the examination of both allopatric and parapatric populations of I. fulva and I. hexagona with reference to diagnostic ribosomal DNA markers. The pattern of variation in the parapatric population indicates the presence of the repeated backcrossing necessary to the process of introgressive hybridization. Indeed, in the region of parapatry, we suggest that localized introgression of ribosomal sequences has occurred into both I. fulva and I. hexagona. Significantly, we have also detected the presence of the diagnostic ribosomal markers from each species in allopatric populations of the alternate species. Our findings suggest that not only is introgressive hybridization presently occurring in parapatry between I. fulva and I. hexagona, but that past hybridization between these species has resulted in introgression into areas of allopatry. PMID- 28564317 TI - GENETIC DIFFERENTIATION AMONG HOST-ASSOCIATED POPULATIONS OF THE GALLMAKER EUROSTA SOLIDAGINIS (DIPTERA: TEPHRITIDAE). AB - Eurosta solidaginis, a gallmaking tephritid (Diptera), infests at least two species of Solidago in the eastern United States. We used horizontal starch gel electrophoresis of enzymes to examine whether populations on the two principal host plant species, Solidago altissima and S. gigantea, have diverged genetically. At the d-beta-hydroxybutyrate dehydrogenase (HBDH) locus, the predominant allele in all nine populations from S. altissima (HBDH1.00 ) was absent or uncommon in all but 1 of the 12 populations from S. gigantea. At the phosphoglucomutase locus (PGM), the most common allele in all populations was PGM1.00 , but the frequency of this allele was, with one exception, higher in populations from S. gigantea than in populations from S. altissima. Genetic heterozygosity was usually greater in populations from S. altissima (H = 0.028) than in populations from S. gigantea (H = 0.009). A phylogenetic tree derived from a genetic distance matrix clustered gallmaker populations from the same host plant together. PMID- 28564318 TI - COMPONENTS OF FLOWERING TIME VARIATION IN A DESERT ANNUAL. AB - How much of the variation seen in life histories is consistent with adaptive hypotheses, and how much requires other kinds of explanation? Differences in flowering time between Sonoran (earlier flowering) and Chihuahuan Desert (later flowering) populations of the desert annual Eriogonum abertianum Torr. (Polygonaceae) are significant, repeatable between greenhouse experiments, and persist into a second greenhouse generation. These apparent genetic differences are consistent with a hypothesis of local adaptation: field demographic studies (Fox, 1989b) show that many fewer Sonoran than Chihuahuan Desert plants survive to the summer rainy season, suggesting selection for earlier flowering in the Sonoran Desert. Within natural populations there is considerable phenological complexity: time of first flowering varies by up to six months, and individuals may have zero, one, or several reproductive episodes. Greenhouse sib analyses revealed only marginal among-family genetic variation for flowering size. The resemblance between parents and offspring for size and time of flowering varied with growth conditions, suggesting that this marginal variation among families may be at least partly due to factors other than additive genetic variance. On the other hand, moisture limitation significantly delayed the onset of flowering in two independent experiments. Variation in moisture availability in both time and space is characteristic of desert environments. The phenological complexity in natural populations may thus be generated by random variation in moisture availability, possibly in conjunction with variation in germination date and plant size. The results call into question the claim that drought generally induces flowering in desert annuals. PMID- 28564319 TI - HETEROCHRONIC VARIATION IN THE DEVELOPMENTAL TIMING OF CRANIAL OSSIFICATIONS IN POECILIID FISHES (CYPRINODONTIFORMES). AB - The quantitative description of ossification sequences and other developmental events with respect to body size provides a basis for assessing the ontogenetic patterns underlying differences in morphological structure. To the extent that such sequences are evolutionarily conservative, they may also provide a basis for phylogenetic inference. Ossification profiles were examined in five species of poeciliid fishes of the genera Poecilia, Xiphophorus, and Poeciliopsis, selected to represent three lineages of varying evolutionary distinctiveness. Although ossification sequences are highly correlated among species, numerous small timing differences and reversals are evident, differences that are accentuated more among than within genera. The timing profiles by themselves, when used to construct hypothetical phylogenetic trees, contain sufficient historical information to recover evolutionary relationships consistent with conventional systematic criteria based primarily on adult osteology and external morphology. Character-state changes mapped onto the resulting trees can be interpreted directly as heterochronic accelerations and retardations of ossification. PMID- 28564320 TI - POLLINATOR ADAPTATION TO OIL-SECRETING FLOWERS-REDIVIVA AND DIASCIA. PMID- 28564321 TI - INBREEDING DEPRESSION, GENETIC LOAD, AND THE EVOLUTION OF OUTCROSSING RATES IN A MULTILOCUS SYSTEM WITH NO LINKAGE. AB - We studied deterministic models of multilocus systems subject to mutation selection balance with all loci unlinked, and with multiplicative interactions of the loci affecting fitness, in partially self-fertilizing populations. The aim was to examine the fitnesses of the zygotes produced by outcrossing and by selling, and the magnitude of inbreeding depression, in populations with different levels of inbreeding. The fates of modifiers of the outcrossing rate were also examined. With biologically plausible parameter values, inbreeding depression can be very large in moderately selfing populations, particularly when the mutant alleles are fairly recessive and selection is weak. A modifier allele reducing the selfing rate can be favored under these circumstances. In more inbred populations, inbreeding depression is lower, and selection favors alleles that increase the selfing rate. When inbreeding depression is caused by mutant alleles with strong selective disadvantage, modifiers causing large increases in selfing can often be favored even when the inbreeding depression exceeds one half, though in these circumstances modifiers increasing selfing by smaller amounts are usually eliminated. Weaker selection appears to be more favorable to the maintenance of outcrossing. PMID- 28564322 TI - THE EVOLUTION OF CLUTCH SIZE. II. A TEST OF THE MURRAY-NOLAN EQUATION. AB - We test the Murray-Nolan equation for calculating clutch sizes of birds with demographic data from a long-term study of the Florida Scrub Jay (Aphelocoma c. coerulescens). The predicted value, 3.43, is very close to the observed clutch size, 3.33. This result provides further support for the equation's being an adequate description of the relationship among the factors affecting the clutch size of birds. PMID- 28564323 TI - APOSEMATISM EVOLVES BY INDIVIDUAL SELECTION: EVIDENCE FROM MARINE GASTROPODS WITH PELAGIC LARVAE. PMID- 28564324 TI - SAFETY FACTORS IN VERTICAL STEMS: EVIDENCE FROM EQUISETUM HYEMALE. AB - Predictions from a mechanical model for hollow vertical stems are tested against morphometric and mechanical studies of the vertical stems of Equisetum hyemale. The model predicts 1) that the wall thickness of hollow internodes must be at least 15% of the external radius of shoots, 2) that the elastic modulus of stems is quantitatively related to the ratio of apoplast (cell walls) to symplast (cytoplasm) areas in transverse sections through stems, and that (3) hollow stems are designed to sustain an additional and significant proportion of their own weight. The "safety factors" predicted for a hollow vertical stem are used to examine two adaptationist explanations for hollow stems: 1) "economy in design," which argues that natural selection will favor a reduction in the metabolic cost in constructing an organ, and 2) "mechanical design," which argues that stems are designed to maximize their mechanical stability during vertical growth. Evidence from E. hyemale indicates that 1) there is a developmental limit to the maximum allotment of biomass invested in the construction of stems, 2) as stem height increases, morphometric adjustments in internodal wall thickness occur which converge on predicted safety limits, and 3) the elastic modulus of stems changes as a function of the ratio of apoplast to symplast areas seen in transverse sections through shoots. Biomechanical and developmental evidence and the allometry of E. hyemale stems are consistent with the view that stems are designed for safety and are inconsistent with some predictions based on the economy in design. PMID- 28564325 TI - HOW MUCH HERITABLE VARIATION CAN BE MAINTAINED IN FINITE POPULATIONS BY MUTATION SELECTION BALANCE? AB - The joint effects of stabilizing selection, mutation, recombination, and random drift on the genetic variability of a polygenic character in a finite population are investigated. A simulation study is performed to test the validity of various analytical predictions on the equilibrium genetic variance. A new formula for the expected equilibrium variance is derived that approximates the observed equilibrium variance very closely for all parameter combinations we have tested. The computer model simulates the continuum-of-alleles model of Crow and Kimura. However, it is completely stochastic in the sense that it models evolution as a Markov process and does not use any deterministic evolution equations. The theoretical results are compared with heritability estimates from laboratory and natural populations. Heritabilities ranging from 20% to 50%, as observed even in lab populations under a constant environment, can only be explained by a mutation selection balance if the phenotypic character is neutral or the number of genes contributing to the trait is sufficiently high, typically several hundred, or if there are a few highly variable loci that influence quantitative traits. PMID- 28564326 TI - FEMALE CHOICE AND SEXUAL SELECTION OF MALE WING MELANIN PATTERN IN PIERIS OCCIDENTALIS (LEPIDOPTERA). AB - Using field experiments, I examined the role of 13 melanin-pattern elements in mate choice by female Pieris occidentalis butterflies. Males that mated successfully differed significantly from unsuccessful males in the extent of marginal forewing melanization but not on the basis of the entire forewing pattern. Deletion of the marginal forewing melanin characters significantly reduced the mating success of manipulated males relative to controls under field conditions. Female choice in P. occidentalis may act to maximize divergence of male color pattern from that of its close relative Pieris protodice. Sexual selection for increased melanization of the marginal dorsal forewing is generated by the strong preference of females for males with such wings and may be constrained by correlations between forewing melanin characters that have different functional roles. PMID- 28564328 TI - HERITABILITY OF BODY SIZE IN CROSS-FOSTERED TREE SWALLOW BROODS. PMID- 28564327 TI - INBREEDING INCREASES GENETIC VARIANCE FOR VIABILITY IN DROSOPHILA MELANOGASTER. PMID- 28564329 TI - ON THE ORIGIN OF INCIPIENT REPRODUCTIVE ISOLATION: THE CASE OF DROSOPHILA ALBOMICANS AND D. NASUTA. AB - The nasuta subgroup of Drosophila consists of 12 known species classified within the immigrans group. D. nasuta and D. albomicans are two sibling species widely distributed throughout the Indo-Pacific tropics, which, although morphologically indistinguishable, have different meta-phase-chromosome configurations: chromosomes X and 3 are attached in D. albomicans, so that about 60% of its genes are sex-linked. Our experiments show that, at least in the laboratory, there is no sexual, mechanical, or gametic isolation between the two species. There is, however, hybrid "breakdown" expressed in three ways: 1) reduction in the number of F2 hybrids produced per culture; 2) reduction in the fertility of F2 (males) and F3 (males and females) hybrid progenies; and 3) abnormal sex ratios in the progenies of crosses between strains of certain localities. In experimental populations, the karyotypes of both species are still present in substantial frequencies after 20 generations, although the frequencies of the two karyotypes vary depending on the geographic origin of the strains. Our results support the hypothesis that, in allopatry, the evolution of postzygotic isolation precedes that of prezygotic isolation. The mtDNA is polymorphic in both D. nasuta and D. albomicans and fairly similar between them. Assuming typical rates of mtDNA evolution, the two species would have diverged from each other about 500,000 years ago, whereas the African and Indian populations of D. nasuta (considered to be different subspecies by some authors) might have diverged some 350,000 years ago. PMID- 28564330 TI - A COMPARATIVE ANALYSIS OF MORPHOLOGICAL VARIATION PATTERNS IN THE PAPIONINS. AB - Comparative studies of intraspecific variation patterns are important in attempts to reconstruct the differential selection pressures experienced by related species and in assessing the resultant observed interspecific variation. Reconstruction of past selection depends on an assumption of relatively stable patterns of genetic variance and covariance through time and across related species. Models by Lande (1979) and Turelli (1988a, 1988b) lead to contrasting expectations of stability versus lability of variation patterns, respectively, at least for closely related species. I report on a comparative study of phenotypic variance and correlation patterns in seven species of papionins, including macaques, baboons, and mangabeys, in order to determine the stability of variation patterns in this group. The three-dimensional coordinates of 12 bony landmarks on the face were used in a finite-element scaling analysis in order to measure local size variation at each landmark. Variances and correlations for these local size metrics were calculated using pooled sex-specific values. Variation patterns were compared across species using vector and matrix correlations in combination with various randomization-based significance tests. Patterns of variation and correlation were generally quite similar across the seven species, although some differences were also apparent. The overall magnitude of correlation is also similar among species, as only a few interspecific comparisons showed significant differences. Thus, it is concluded that patterns of variation and correlation in facial morphology have tended to remain stable in this group of primates. This result should allow for reconstruction of past differential selection pressures in the clade. The pattern of similarity among correlation structures for these species showed no association with their phylogenetic relationships. PMID- 28564331 TI - IS LIFETIME DATA ALWAYS NECESSARY FOR EVALUATING THE "INTENSITY" OF SELECTION? PMID- 28564332 TI - ADAPTATION BY A PARASITIC TREMATODE TO LOCAL POPULATIONS OF ITS SNAIL HOST. AB - In each of two reciprocal cross-infection experiments, a digenetic trematode (Microphallus sp.) was found to be significantly more infective to snails (Potamopyrgus antipodarum) from its local host populations. This gives strong evidence for local adaptation by the parasite and indicates that there is a genetic basis to the host-parasite interaction. It is suggested that the parasite should be able to track common snail genotypes within populations and, therefore, that it could be at least partially responsible for the persistence of sexual subpopulations of the snail in those populations that have both obligately sexual and obligately parthenogenetic females. PMID- 28564333 TI - PHYLOGENIES OF PLANT FAMILIES: A DEMONSTRATION OF PHYLOGENETIC RANDOMNESS IN DNA SEQUENCE DATA DERIVED FROM PROTEINS. PMID- 28564334 TI - GENETIC EXCHANGE BETWEEN BACILLUS SUBTILIS AND BACILLUS LICHENIFORMIS: VARIABLE HYBRID STABILITY AND THE NATURE OF BACTERIAL SPECIES. AB - Experiments employing both broth and soil cultures demonstrated the capacity for bidirectional genetic exchange between the eubacterial species Bacillus subtilis and Bacillus licheniformis. The process was studied using standard laboratory strains and wild isolates of these species. The genetic exchange in soil occurs spontaneously. The interspecific recombination involved markers for antibiotic resistance and for the use of specific carbon sources (API characters). Hybrids frequently had unstable phenotypes, i.e., lacked a consistent expression of foreign genes over repeated transfer and growth. This instability often involved a "correction" back toward the phenotype of one or the other of the parental species for many differentiating characters; the final phenotype was always that of the more probable or actually known recipient species. This "correction" process is reminiscent of phenomena associated with the instability of artificial fusion protoplasts or noncomplementing diploids of B. subtilis, as well as the merodiploids formed by intergeneric crosses with enteric bacteria. The hybrids observed here must also be diploid, in some manner, because they sequentially express traits of both parental species at rates well above the frequency of mutation. Among the unstable changes in hybrids of the wild strains there was a 3:1 bias in favor of "correction." The dynamics of the hybridization process in soil are described. It appears that the hybrids are formed most rapidly following outgrowth from spores and during the early growth of parental vegetative cell populations. Later on, the hybrids are much less frequent in the soil cultures, suggesting that they are competitively inferior to the parental species. It is argued that the capacity for recombination found between B. subtilis and B. licheniformis could locally erase their distinctness, even though they possess only about 15% DNA sequence homology. Yet they remain distinct in the wild. The methods and results of these experiments prepare the way for detailed studies of the nature of species and species boundaries throughout the genus Bacillus. PMID- 28564335 TI - THE DISTRIBUTION OF LIFE-HISTORY VARIATION IN THE DAPHNIA PULEX COMPLEX. AB - In the midwestern United States the Daphnia pulex complex consists of a mosaic of sexual and asexual populations, providing a useful model system for studying the evolutionary forces underlying the maintenance of sex. One asexual and two sexual populations were surveyed for genetic variation for isozymes, mitochondrial DNA, and life-history characters. While the sexual populations exhibited substantial levels of genetic variance for fitness characters, no variation was detected in the asexual population at any level. However, a parallel survey among asexual clones derived from other ponds revealed large amounts of quantitative variation among clones, even among those with the same molecular profile. As a group, the asexuals are more variable for life histories than are the sexual populations. The molecular data indicate a relatively recent origin for the extant asexual D. pulex. The polyphyletic origin of these clones, combined with their microevolutionary potential, provides an explanation for their broad geographic distribution. The distribution of sex in the complex cannot be explained with the standard models that assume an invariant asexual population in reproductive isolation from the parental species. Although the frequency of asexuality may be driven by the spread of a sex-limited meiosis suppressor through sexual populations, the complete displacement of sexuality may be prevented by ecological distinctions between the two classes of individuals. On average, the asexuals are larger but produce smaller clutches than the sexuals. PMID- 28564336 TI - HUTCHINSONIAN RATIOS AND STATISTICAL POWER. PMID- 28564337 TI - VARIATION IN RIBOSOMAL DNA AMONG BIOLOGICAL SPECIES OF ARMILLARIA, A GENUS OF ROOT-INFECTING FUNGI. AB - Armillaria is a genus of root-infecting fungi composed of several biological species in North America and Europe. To examine relatedness among biological species, ribosomal DNA (rDNA) from one isolate was cloned and rDNAs from 30 isolates were mapped for eight restriction enzymes. The positions of the large (26S) and small (18S) rRNA cistrons were found by Northern hybridizations of total cellular RNA with rDNA subclones and by alignment of maps with conserved restriction sites present in rRNA genes of other fungi. Nine restriction-site and two length polymorphisms were observed. Eight North American (Roman numerals) and five European (species epithets) biological species could be placed in six classes with respect to rDNA maps (rDNA class 1: I and A. ostoyae; class 2: II; class 3: A. borealis; class 4: V, IX, and X; class 5: III, VII, A. lutea, and A. cepistipes; and class 6: VI and A. mellea). Most, but not all, polymorphisms were in intergenic regions. PMID- 28564338 TI - PATTERNS OF VARIATION IN LEVELS OF HOMOPLASY. AB - Patterns of variation in levels of homoplasy were explored through statistical analyses of standardized consistency indexes. Data were obtained from 60 recent cladistic analyses of a wide variety of organisms based on several different kinds of characters. Consistency index is highly correlated with the number of taxa included in an analysis, with homoplasy increasing as the number of taxa increases. This observation is compatible with a simple model of character evolution in which 1) the probability of character-state change increases with the total number of branches in a tree and 2) the number of possible states of a character is limited. Consistency index does not show a significant relationship to the number of characters utilized in an analysis or to the taxonomic rank of the terminal taxa. When the relationship between consistency index and number of taxa is taken into account, there is no significant difference between plant and animal data sets in the amount of homoplasy. Likewise, the level of homoplasy in morphological and molecular data sets does not appear to differ significantly, although there are still too few molecular studies to be confident of this result. Future comparisons of consistency indexes, including studies along the lines established here, must take into account the influence of the number of taxa on homoplasy. PMID- 28564339 TI - THE EVOLUTION OF CLUTCH SIZE. I. AN EQUATION FOR PREDICTING CLUTCH SIZE. AB - We derive an equation for calculating the clutch sizes of birds and other long lived animals from Murray's (1979) theory on the evolution of clutch size. For the Prairie Warbler (Dendroica discolor) in Indiana, this equation predicts an average clutch size of 3.49, less than half an egg smaller than the recorded average clutch size of 3.89. We attribute the discrepancy to sampling error and suggest that the equation satisfactorily identifies the important factors affecting the evolution of clutch size. The success of the equation in predicting clutch size of the Prairie Warbler provides additional support for Murray's theory on the evolution of clutch size. PMID- 28564340 TI - RELATIONSHIPS BETWEEN GENETIC VARIABILITY AND LIFE-HISTORY FEATURES OF BONY FISHES. AB - Correlations between genetic variation and life-history variables were obtained for 80 species of bony fishes as a means of testing the hypothesis that genetic variation is directly related to 1) opportunity for balancing selection, as indicated by fecundity, and 2) environmental variation, as indicated by capacity for population increase. Genetic data were taken from the literature, and data on longevity, age at maturity, egg size, body size, and lifetime fecundity were taken from the literature where available and were otherwise estimated from other variables. Average heterozygosity does not increase significantly with increasing fecundity. However, heterozygosity is significantly associated with short generation times, quick maturation, small maximum size, and small eggs. Thus, heterozygosity appears to increase on a demographic continuum toward maximum values in species that are most strongly selected for maximizing the intrinsic rate of increase. Such species are associated with less stable environments. Thus, the results indicate a predominate role for environmental variation in controlling genetic variation of bony fishes. PMID- 28564341 TI - A FIELD TEST OF DIFFERENTIAL HOST-PLANT USAGE BETWEEN TWO SIBLING SPECIES OF RHAGOLETIS POMONELLA FRUIT FLIES (DIPTERA: TEPHRITIDAE) AND ITS CONSEQUENCES FOR SYMPATRIC MODELS OF SPECIATION. PMID- 28564342 TI - DISTRIBUTION AND EVOLUTION OF A GLUCOSEPHOSPHATE ISOMERASE DUPLICATION IN THE LEGUMINOSAE. AB - In the common bean, Phaseolus vulgaris, two loci encode cytosolic glucosephosphate isomerase (GPI) subunits, whereas in the garden pea, Pisum sativum, only one locus is expressed. As a working model, we proposed that this change in isozyme number was produced by a gene-duplication event in the lineage leading to Phaseolus after divergence from that leading to Pisum. This model was tested by analyzing the GPI phenotypes in 119 legume genera, representing all three subfamilies and 23 of the 30 tribes of the Papilionoideae. The duplication was detected in 13 of the 20 papilionoid tribes surveyed, including several members of the putatively primitive tribe Sophoreae. Thus, the duplication appears to be an ancient event, a finding incompatible with the initial hypothesis. Instead, gene silencing is postulated to account for the absence of the duplicated phenotype in many tribes, including such advanced groups as Vicieae, Trifolieae, and Cicereae. Furthermore, silencing has occurred numerous times at lower taxonomic levels, including the subtribe Phaseolinae (Phaseoleae), a monophyletic group in which ten genera were found to have duplicated phenotypes and only one (Strophostyles) appeared to have an unduplicated phenotype. Analysis of GPI phenotypes also revealed numerous cases of partial silencing of duplicate loci as well as nearly equal expression of both loci in many, taxonomically widely scattered species. If our revised hypothesis is correct, this latter result implies that most of the subtribes had formed before significant divergence between the GPI isozymes occurred and, thus, that the radiation of the Papilionoideae was rapid relative to the rate of gene silencing. PMID- 28564343 TI - THE MAINTENANCE OF POLYGENIC VARIATION IN FINITE POPULATIONS. AB - Models of the maintenance of genetic variance in a polygenic trait have usually assumed that population size is infinite and that selection is weak. Consequently, they will overestimate the amount of variation maintained in finite populations. I derive approximations for the equilibrium genetic variance, V^G in finite populations under weak stabilizing selection for triallelic loci and for an infinite "rare alleles" model. These are compared to results for neutral characters, to the "Gaussian allelic" model, and to Wright's approximation for a biallelic locus under arbitrary selection pressures. For a variety of parameter values, the three-allele, Gaussian, and Wrightian approximations all converge on the neutral model when population size is small. As expected, far less equilibrium genetic variance can be maintained if effective population size, N, is on the order of a few hundred than if N is infinite. All of the models predict that comparisons among populations with N less than about 104 should show substantial differences in V^G. While it is easier to maintain absolute V^G when alleles interact to yield dominance or overdominance for fitness, less additivity also makes V^G more susceptible to differences in N. I argue that experimental data do not seem to reflect the predicted degree of relationship between N and V^G. This calls into question the ability of mutation-selection balance or simple balancing selection to explain observed V^G. The dependence of V^G on N could be used to test the adequacy of mutation-selection balance models. PMID- 28564344 TI - MALE ALTERNATIVE REPRODUCTIVE STRATEGIES IN A MARINE ISOPOD CRUSTACEAN (PARACERCEIS SCULPTA): THE USE OF GENETIC MARKERS TO MEASURE DIFFERENCES IN FERTILIZATION SUCCESS AMONG alpha-, beta-, AND gamma-MALES. AB - Three discrete male morphs coexist in Paracerceis sculpta, a marine isopod crustacean inhabiting the northern Gulf of California. Ornamented alpha-males establish themselves in the spongocoels of intertidal sponges, where females congregate to breed. Smaller beta-males, resembling sexually mature females, enter spongocoels by deception, while tiny gamma-males invade spongocoels by stealth. Isopods breed year-round, and the operational sex ratio fluctuates widely over short durations. When females are abundant, receptive females accumulate in spongocoels, and these spongocoels are preferentially invaded by beta- and gamma-males. To test the hypothesis that the density of receptive females affects relative fertilization success among male morphs, individual beta and gamma-males, heterozygous for a dominant cuticular pigmentation allele, were placed in artificial spongocoels with an unmarked alpha-male and densities of one, two, and three unmarked, receptive females. The fertilization success of each male was determined by counting the number of marked and unmarked progeny each female produced. Alpha-males guard females effectively and sire nearly all young when one female is in a spongocoel. The success of beta- and gamma-males increases, however, and may even exceed the success of alpha-males when two or three females are present. The regular occurrence of more than one receptive female in the harems of alpha-males may contribute to the persistence of beta- and gamma-males in this species. PMID- 28564345 TI - RESPONSES TO SELECTION ON FLIGHT BEHAVIOR IN A MIGRATORY POPULATION OF MILKWEED BUG (ONCOPELTUS FASCIATUS). PMID- 28564346 TI - CROSS ABILITY OF MIMULUS GUTTATUS IN RELATION TO COMPONENTS OF GENE FIXATION. AB - The joint effects of parental gene fixation and consanguinity of mates upon the fitness of matings was examined in Mimulus guttatus. Plants from four populations were crossed at five levels of genetic relatedness, and five viability characters were scored in progeny. Parental gene fixation at 12 polymorphic allozyme loci was partitioned into local, subpopulation, and population components. A model is proposed wherein parental gene fixation influences distance-dependent crossing success. At a fixed locus, inbreeding is favored if natural selection caused allele fixation, or is disfavored if gene fixation was random. The distance between mates required to eliminate gene fixation depends upon patch size of fixation. When selective fixation and patch size differ among loci, an optimal crossing distance is possible. In M. guttatus, progeny viability generally decreased with greater relatedness between mates, but this decrease was often heterogeneous among populations. The highest pollen viability and the lowest seed set were found at an intermediate relatedness between mates. To determine whether parental gene fixation influences these crossing patterns, a type of mutational load analysis was performed. Progeny fitness was regressed on parent F and fitness estimated at F = 1. This was done for each component of F, for a) crosses that maintain gene fixation and b) crosses that eliminate gene fixation. A multiplicative, composite measure of fitness indicates that, in M. guttatus, genes fixed during local or population differentiation favor outbreeding, while genes fixed during subpopulation differentiation favor inbreeding. This predicts that random mating within subpopulations confers highest progeny fitness, exclusive of between-population matings. However, predictions did not fit the observed patterns of crossing success very well, perhaps because gene fixation was relatively low or was not adequately measured at loci influencing fitness. PMID- 28564347 TI - RELATEDNESS AND POPULATION STRUCTURE OF THE PRIMITIVELY EUSOCIAL BEE LASIOGLOSSUM ZEPHYRUM (HYMENOPTERA: HALICTIDAE) IN KANSAS. AB - Lasioglossum zephyrum is a primitively eusocial bee, which nests in small colonies of up to 20 individuals. The nests occur in patchily distributed aggregations of from a few to over 1,000 nests along periodically disturbed stream and river banks in eastern North America. We used five polymorphic allozyme loci to test for geographic structure and estimate relatedness in eight patches of nests from five aggregations in Douglas Co., Kansas. Autocorrelation analysis of gene frequencies, plus a multilocus G test, revealed a low but significant tendency for differentiation among nests within patches, among patches within aggregations, and among aggregations. Small numbers of nests restricted estimation of relatedness to three patches, of which only one had a sample size large enough to yield confidence limits narrow enough to be informative. The limits from this patch of 20 nests are 0.64 < 0.8245 < 1.01. While these limits are consistent with the true value being 0.75 (that expected under male-haploidy if each nest results from the reproduction of a single, once mated female), the occurrence of some nests with three or more genotypes shows that nest makeup is more complex than this, so that a lower value, say 0.7, is more plausible. This value is sufficiently high to indicate that kin selection is probably important in these populations. PMID- 28564348 TI - THE GENETIC BASIS OF EVOLUTION OF THE MALE COURTSHIP SOUNDS IN THE DROSOPHILA VIRILIS GROUP. AB - When courting, males of the Drosophila virilis group vibrate their wings and emit species-specific courtship sounds consisting of trains of polycyclic sound pulses. To analyze the genetic basis of evolutionary changes in the sounds we made an F1 diallel set of reciprocal crosses between the members of the virilis phylad of the group (two stocks of D. virilis and one of D. americana americana, D. a. texana, D. novamexicana, and D. lummei). We also crossed the D. virilis stocks with the members of the montana phylad of the same group (D. kanekoi, D. littoralis, D. borealis, D. flavomontana, D. lacicola, and D. montana) and made a backcross (D. virilis x D. littoralis) x D. virilis using a D. virilis marker stock (b; sv t tb gp; cd; pe). The sounds of the hybrids were analyzed using the following parameters: the length of a pulse train (PTL), the number of pulses in a train (PN), the interpulse interval (IPI), the length of a pulse (PL), the number of cycles in a pulse (CN), and the length of a cycle (CL). In the virilis phylad, the differences between species appeared to be determined mainly by autosomal genes in each sound trait. The heritabilities (narrow-/broad-sense) obtained from the diallel tables were the following: PTL 0.662/0.817, PN 0.651/0.841, IPI 0.193/0.546, PL 0.408/0.552, CN 0.425/0.719, and CL 0.361/0.764. The direction of dominance is for longer PTL, higher PN and CN, and shorter IPI and CL. PL shows ambidirectional dominance. In the sounds of the virilis phylad species, PTL and PL seem to be phenotypically the most important parameters, since their components (PN and IPI for PTL, CN and CL for PL) are negatively correlated. In crosses between D. virilis and D. littoralis or D. flavomontana reciprocal hybrids differed from each other in PTL, IPI, PL, and CN indicating X chromosomal or cytoplasmic inheritance. In the backcrosses between D. virilis and D. littoralis the role of the X chromosome was ascertained to be decisive. We conclude that an X-chromosomal major change allowing variation in IPI has occurred during the separation of the two D. virilis group phylads, the long IPI allowing variation also in PL (and CN). The evolution of the sounds in the virilis phylad has probably gone towards longer and denser pulse trains, while in the montana phylad the sounds have evolved in different directions. PMID- 28564349 TI - THE EFFECTS OF BODY MASS, PHYLOGENY, HABITAT, AND TROPHIC LEVEL ON MAMMALIAN AGE AT FIRST REPRODUCTION. AB - I examined age at first reproduction of 547 mammalian species to determine the influence of diet and habitat on the evolution of life-history traits. Body mass correlated positively with age at first reproduction, explaining 56% of the variance. Habitat and trophic groups deviated significantly from the allometric curve in a pattern generally consistent with predictions from r/K selection theory and its modifications. However, mammalian orders also deviated significantly from the allometric curve, and different habitat and diet groups contained different ratios of mammalian orders. When the effects of orders were removed, residual deviations did not differ among ecological groups. Adjusting for ecological differences did not eliminate the differences between orders. These results suggest that body mass (or some correlated factor) and phylogeny strongly constrain age at first reproduction. Ecological factors appear to have little effect on the evolution of age at first reproduction. Apparent differences in weight-specific ages at first reproduction within habitats and trophic groups may be the result of ecological selection of order composition in the present, rather than ecologically driven evolution of life history in the past. PMID- 28564350 TI - COVARIATION OF SELFING RATES WITH PARENTAL GENE FIXATION INDICES WITHIN POPULATIONS OF MIMULUS GUTTATUS. AB - Wright's gene fixation index F and two single-locus effective selfing rates-the selfing rate at loci with fixed alleles, and the selfing rate at loci without fixed alleles-were estimated in five populations of Mimulus guttatus. These two effective selfing rates describe the inbreeding observed at a single locus when both uniparental and biparental inbreeding are practiced. Estimates were made using progeny arrays assayed for six allozyme loci and two morphological loci exhibiting dominance. The average of the two selfing rates computed for subpopulations (ca. 10 m diameter) ranged from 24% to 59%, with a mean of 37%. When computed for populations (ca. 1 km diameter), average selfing rates were about 10% higher. In four populations, the selfing rate at loci with fixed alleles was higher than the selfing rate at loci without fixed alleles. Thus, the covariance of selfing with parental gene fixation was positive. In one of the populations, estimates for individual plants sampled along a transect gave positive correlations for selfing rates and for gene-fixation indices between adjacent plants. A highly positive correlation between selfing rate and gene fixation of individual plants was also observed. In another population, the covariance of selfing with gene fixation was higher for a locus causing leaf spots than for allozyme loci. This covariance is partially caused by 1) variation in homozygosity among neighborhoods and 2) biparental inbreeding within neighborhoods. The consequences of this covariance are discussed. PMID- 28564351 TI - INCORPORATION OF A EUROPEAN WEED INTO THE DIET OF A NORTH AMERICAN HERBIVORE. AB - Populations of the butterfly Euphydryas editha living within a 30 times 100-km region on the eastern slope of the Sierra Nevada range were compared for oviposition preference and ability of larvae to grow and survive on two host plants, Collinsia parviflora and Plantago lanceolata. Since its introduction approximately 100 years ago, P. lanceolata has been incorporated in the diet of E. editha in one of the study populations. The populations differed in oviposition preference; only the population that uses P. lanceolata contains some individuals that prefer P. lanceolata. Larvae from two populations, one using both P. lanceolata and C. parviflora, the other using only C. parviflora, were not found to differ in relative abilities to grow or survive on P. lanceolata. The potential for E. editha to use P. lanceolata appears in populations that have had no prior exposure to this plant, while oviposition preference for this plant has evolved in the population in which the plant now grows. PMID- 28564352 TI - MAXIMUM-LIKELIHOOD APPROACHES APPLIED TO QUANTITATIVE GENETICS OF NATURAL POPULATIONS. AB - Growing interest in adaptive evolution in natural populations has spurred efforts to infer genetic components of variance and covariance of quantitative characters. Here, I review difficulties inherent in the usual least-squares methods of estimation. A useful alternative approach is that of maximum likelihood (ML). Its particular advantage over least squares is that estimation and testing procedures are well defined, regardless of the design of the data. A modified version of ML, REML, eliminates the bias of ML estimates of variance components. Expressions for the expected bias and variance of estimates obtained from balanced, fully hierarchical designs are presented for ML and REML. Analyses of data simulated from balanced, hierarchical designs reveal differences in the properties of ML, REML, and F-ratio tests of significance. A second simulation study compares properties of REML estimates obtained from a balanced, fully hierarchical design (within-generation analysis) with those from a sampling design including phenotypic data on parents and multiple progeny. It also illustrates the effects of imposing nonnegativity constraints on the estimates. Finally, it reveals that predictions of the behavior of significance tests based on asymptotic theory are not accurate when sample size is small and that constraining the estimates seriously affects properties of the tests. Because of their great flexibility, likelihood methods can serve as a useful tool for estimation of quantitative-genetic parameters in natural populations. Difficulties involved in hypothesis testing remain to be solved. PMID- 28564353 TI - PLOIDY AND DEVELOPMENTAL RATE IN A SALAMANDER HYBRID COMPLEX (GENUS AMBYSTOMA). PMID- 28564354 TI - A TEST OF THE SPONTANEOUS HETEROSIS HYPOTHESIS FOR UNISEXUAL VERTEBRATES. AB - The coupling between clonal modes of reproduction and hybridization in unisexual vertebrates has led to the hypothesis that heterosis accounts for their ecological success (the "spontaneous heterosis" hypothesis). High levels of genic heterozygosity characteristic of unisexual-hybrid vertebrates are believed to result in enhanced growth, survivorship, and fertility relative to their sexual ancestors. To test this hypothesis, we synthesized 33 new unisexual-hybrid strains of fishes in the genus Poeciliopsis (Atheriniformes: Poeciliidae). On average, the synthetic unisexuals had lower survivorship and a higher incidence of birth defects than either of the sexual ancestors or two natural strains of unisexuals. However, a subset of these synthetic unisexuals exhibited characteristics within the range of the sexual ancestors and natural unisexual strains. These results support the alternative hypothesis that the ecological success of natural unisexuals results from selection of the most fit clones from a broad spectrum of genotypes that arose via multiple hybrid events. We propose that the coupling between unisexuality and hybridization in the vertebrates exists because hybridization is a dysgenic process that can disrupt normal gametogenesis and thus lead to clonal reproduction. PMID- 28564355 TI - MITOCHONDRIAL DNA AND PROTEIN DIFFERENTIATION BETWEEN HYBRIDIZING CYTOTYPES OF THE WHITE-FOOTED MOUSE, PEROMYSCUS LEUCOPUS. AB - Restriction-enzyme analysis of mitochondrial DNA and protein electrophoresis were used to document patterns of gene flow across a hybrid zone between chromosomal races of Peromyscus leucopus. Chromosomal markers (three inversions) are such that individuals can be classified as potential F1 's, backcrosses, or parental types. Allozymic characterization of the hybrid zone is congruent with the chromosomal data (Stangl, 1986) and indicates an assymetrical distribution of markers, with the northeastern markers being distributed at a higher frequency into southwestern populations. Restriction patterns of mtDNA suggest that the two cytotypes may have had different evolutionary histories, and the distribution of haplotypes is concordant with other genetic markers used to identify the hybrid zone. Concordant changes in chromosomes, allozymes, and mtDNA suggest that the most viable hypothesis for the origin of the zone is secondary contact. A unique aspect of this study is that the same individuals were used for protein electrophoresis, mtDNA analysis, and chromosomal analysis. Thus, patterns of genetic variation can be interpreted free of any historical bias associated with samples collected at different times. PMID- 28564356 TI - WHY HERMAPHRODITIC PLANTS PRODUCE MANY MORE FLOWERS THAN FRUITS: EXPERIMENTAL TESTS WITH AGAVE MCKELVEYANA. AB - Five hypotheses explaining the low fruit-to-flower ratios in self-incompatible hermaphroditic plants are tested for Agave mckelveyana. Results from pruning, bagging, and hand-pollination experiments indicate that "excess" flowers (i.e., flowers that fail to produce mature fruits) do not contribute to female fitness (i.e., fruit or seed production). These flowers are aborted regardless of their pollination history. Additional data on nectar production imply that these flowers act as pollen donors and contribute to male fitness. PMID- 28564357 TI - ASEXUAL REPRODUCTION IN CESTODES (CYCLOPHYLLIDEA: TAENIIDAE): ECOLOGICAL AND PHYLOGENETIC INFLUENCES. AB - Asexual reproduction, a rare trait among cestodes in general, occurs in the "larval" (metacestode) stage of species of the family Taeniidae. The distribution of this trait among taeniid species is not consistent with an ecological hypothesis of current environmental predictability. We therefore chose a subset of the family and studied their phylogenetic relationships by Wagner parsimony analysis as a test of historical influences on asexual reproduction. We produced a consensus tree based on four 50-step trees with consistency indices of 0.38. Given these hypothetical relationships, we found that asexual reproduction either arose or was lost multiple times. Moreover, this consensus tree is incongruent with both definitive and intermediate host phylogenies, and asexual reproduction does not correlate with host transfers inferred from these phylogenies. Developmental and phylogenetic constraints on asexual reproduction therefore appear to have been minimal. Given current information, neither historical constraint nor explanations invoking adaptation based on environmental predictability can account for life-history variation in these cestodes. PMID- 28564358 TI - QUANTITATIVE GENETICS OF HETEROCHRONY. AB - A model of quantitative-genetic variation in developmental processes is introduced and analyzed. The model is of a bifurcating sequence of events in which traits develop from the same tissue until a transition occurs, after which they develop partially independently. Genetic and environmental variation in both the rates of tissue growth and in the timing of transitions is considered. The model shows how genetic variation in developmental parameters governs variation and covariation in phenotypic traits and how selection on the phenotype alters the distributions of developmental parameters. Particular attention is paid to the conditions under which selection will lead to changes in the average times of developmental events. PMID- 28564359 TI - EGG VOLUME AND ENERGETIC CONTENT ARE NOT CORRELATED AMONG SIBLING OFFSPRING OF STARFISH: IMPLICATIONS FOR LIFE-HISTORY THEORY. PMID- 28564360 TI - GRADUAL CHANGE IN HUMAN TOOTH SIZE IN THE LATE PLEISTOCENE AND POST-PLEISTOCENE. AB - Starting with the onset of the last glaciation approximately 100,000 years ago and continuing to the end of the Late Pleistocene approximately 10,000 years ago, human tooth size began to reduce at a rate of 1% every 2,000 years. Both the mesial-distal and the buccal-lingual dimensions of mandibular and maxillary teeth were undergoing the same rate of reduction. From the beginning of the Post Pleistocene until the present, the overall rate of dental reduction doubled, becoming approximately 1% per thousand years. Buccal-lingual dimensions are now reducing twice as fast as mesial-distal dimensions, and maxillary teeth are reducing at an even more rapid rate than mandibular teeth. Late Pleistocene rates are comparable in Europe and the Middle East. The Post-Pleistocene rates are also the same for Europe, the Middle East, China, Japan, and Southeast Asia. It is suggested that the cookery at the beginning of the Late Pleistocene allowed the earlier changes to occur. The use of pottery within the last 10,000 years further reduced the amount of selection that had previously maintained usable tooth substance. Reduction then occurred as a consequence of the Probable Mutation Effect (Brace, 1963; McKee, 1984). PMID- 28564361 TI - ANALYSIS OF MITOCHONDRIAL DNA POLYMORPHISMS AMONG CHANNEL ISLAND DEER MICE. AB - Mitochondrial DNA (mtDNA) from 131 deer mice, Peromyscus maniculatus, collected on the eight California Channel Islands and from seven southern California mainland locations, was isolated and analyzed for restriction endonuclease fragment polymorphisms. A total of 26 mtDNA genotypes were distinguishable among the deer mice sampled. All of the island samples had mtDNA restriction-fragment patterns not found among the mainland samples. Distributions of specific restriction-fragment patterns provide evidence for at least four separate colonization events to the Channel Islands. The estimated percentage of sequence divergence between all mtDNA's in this study was less than 1%, suggesting that colonization of the islands occurred fairly recently, probably within the last 500,000 years. Levels of mtDNA heterogeneity were much lower within island populations than within mainland populations. PMID- 28564362 TI - EVOLUTIONARY RELATIONSHIPS AMONG COLONIES OF COLUMBIAN GROUND SQUIRRELS AS SHOWN BY MITOCHONDRIAL DNA. AB - Mitochondrial DNA (mtDNA) from 71 Columbian ground squirrels (Spermophilus columbianus) collected in 12 locations in western Canada were assayed for restriction-site variation with 10 endonucleases. Five of these endonucleases revealed variant patterns, and the composite genotypes were used to develop a linear transformation series among the mtDNA genotypes. Two of the four clones had a wide distribution, while the remaining two clones were geographically restricted. The mtDNA of Columbian ground squirrels was also compared to two other species of Sciuridae: Richardson's ground squirrels (S. richardsonii) and Arctic ground squirrels (S. parryii). Calculation of divergences from fragment length and restriction-site data indicated that Arctic ground squirrels and Richardson's ground squirrels were more closely related to each other than either was to Columbian ground squirrels. The transformation series among clones within the Columbian ground squirrels was rooted using Richardson's and Arctic ground squirrels as out-groups. From these data, we conclude that the colonization by female founders of Columbian ground squirrel populations occurred after deglaciation along the eastern ranges of the Rocky Mountains, while colonies on the western ranges may have been present before extensive deglaciation occurred, having existed in refugia in northwestern Alberta. PMID- 28564363 TI - THE FITNESS CONSEQUENCES OF MULTIPLE-LOCUS HETEROZYGOSITY: THE RELATIONSHIP BETWEEN HETEROZYGOSITY AND GROWTH RATE IN PITCH PINE (PINUS RIGIDA MILL.). AB - Positive correlations between measures of "fitness" and the number of electrophoretic loci for which an individual is heterozygous have been observed in many species. Two major hypotheses have been proposed to explain this phenomenon: inbreeding depression and overdominance. Until recently, there has been no way to distinguish between these hypotheses. The overdominance model devised by Smouse (1986) is used here in a reanalysis of Ledig et al.'s (1983) study of heterozygosity and growth rate in eight populations of pitch pine and is contrasted with an inbreeding-depression analysis. Ledig et al. (1983) regressed mean growth rate per heterozygosity class on the number of heterozygous loci, a method of analysis which, although it points to general trends in the data, does not differentiate between hypotheses. The correlations they obtained in four populations were significant only because regressing on the means eliminates most of the sum of squares for error and does not weight the unequally sized heterozygosity classes. Reanalysis of Ledig et al.'s data using individuals, not means, showed no significant correlations between heterozygosity and fitness. A major assumption of Smouse's overdominance model is that genetic polymorphism is in part a reflection of selection for heterozygotes at genetic equlibrium. The homozygote for the most frequent allele at a locus should be more fit than a homozygote for a less frequent allele, with the heterozygote superior to both homozygotes. Smouse's model predicts a negative, linear relationship between fitness and "adaptive distance," a variable that for a heterozygote is zero and for homozygotes is equal to the inverse of the frequency of the corresponding allele. The adaptive-distance model accounted for between 15% and 50% of the variation in growth rate within eight P. rigida population samples by accounting for genotypic differences at eight polymorphic loci. This is over twice as much of the variation in growth rate accounted for by Ledig et al.'s (1983) analysis using individuals. Significant correlations were found between adaptive distance and growth rate in four of the eight populations, but in only two of the populations were more of the partial coefficients negative than positive, as would be predicted by the overdominance hypothesis. The remaining two populations in which correlations were significant did not lend themselves to such clear-cut interpretation, as the majority of the partial coefficients were positive. Positive partial coefficients indicate that the growth rate of the heterozygote is inferior to that of at least one of the homozygotes. The adaptive-distance analysis provides evidence that specific genotypes do play a role in determining growth rate in pitch pine. The correlation between growth rate and adaptive distance increased significantly with the age of the population, possibly reflecting competition subsequent to crown closure. PMID- 28564364 TI - THE ACCUMULATION OF SEXUALLY ANTAGONISTIC GENES AS A SELECTIVE AGENT PROMOTING THE EVOLUTION OF REDUCED RECOMBINATION BETWEEN PRIMITIVE SEX CHROMOSOMES. PMID- 28564365 TI - THE STABILITY OF THE SYMBIOSIS BETWEEN DIOECIOUS FIGS AND THEIR POLLINATORS: A STUDY OF FICUS CARICA L. AND BLASTOPHAGA PSENES L. AB - Each Ficus species depends on a specific mutualistic wasp for pollination. The wasp breeds on the fig, each larva destroying a female flower. It is, however, not known why the wasps have not evolved the ability to use all female flowers. In "dioecious" figs, the wasp can only breed in the female flowers of the "male" trees, so that pollination of a female tree is always lethal. The wasps should therefore be selected to avoid female trees. Field data is presented showing that the fruiting phenology of the dioecious fig Ficus carica is such that this selection does not occur: syconia are not receptive at the same time on "male" and female trees. Most wasps are forced to emerge from the syconia of "male" trees at a time when they will not be able to reproduce, whether they avoid female trees or not. This aspect of the life cycle of the wasp, although noticed, has been obscured in most previous studies. It is shown that the fruiting phenology of Ficus carica, which stabilizes the symbiosis, is the result of short term selective pressures on the male function of the trees. Such selective pressures suggest a possible pathway from monoecy to dioecy in Ficus under seasonal climates. PMID- 28564366 TI - EVOLUTIONARY STEPS AND TRANSPOSABLE ELEMENTS IN DROSOPHILA MELANOGASTER: THE MISSING RP TYPE OBTAINED BY GENETIC TRANSFORMATION. AB - The I-R and P-M hybrid dysgenesis systems in Drosophila melanogaster have been interpreted as due to recent invasions of the genome by the I and P mobile genetic elements. Temporal and geographical surveys have never shown individuals harboring P sequences but devoid of active I elements. We describe here the successful genetic transformation by autonomous P elements of embryos initially devoid of active I elements and any P sequences. The results demonstrate that P elements may invade the genome of Drosophila melanogaster in the absence of active I elements. Using gel blotting, in situ hybridization techniques, and genetic experiments, we have monitored the behavior of newly introduced P elements in several transformed lines over 30 generations. The switch of cytotype from M to P occurred very slowly and the number of P copies simultaneously increased to about 25. These RP lines possess the properties required to induce P M hybrid dysgenesis but totally retain the R cellular state. Consequently, this new mobile element combination presents a strong reciprocal post-zygotic isolation with IM strains due to both P-M and I-R hybrid dysgenesis systems. This genomic incompatibility could be considered as a first step toward speciation in Drosophila populations. PMID- 28564367 TI - Organometallic-Mediated Alternating Radical Copolymerization of tert-Butyl-2 Trifluoromethacrylate with Vinyl Acetate and Synthesis of Block Copolymers Thereof. AB - Organometallic-mediated radical polymerization (OMRP) has given access to well defined poly(vinyl acetate-alt-tert-butyl-2-trifluoromethacrylate)-b-poly(vinyl acetate) and poly(VAc-alt-MAF-TBE) copolymers composed of two electronically distinct monomers: vinyl acetate (VAc, donor, D) and tert-butyl-2 trifluoromethacrylate (MAF-TBE, acceptor, A), with low dispersity (<=1.24) and molar masses up to 57 000 g mol-1 . These copolymers have a precise 1:1 alternating structure over a wide range of comonomer feed compositions. The reactivity ratios are determined as rVAc = 0.01 +/- 0.01 and rMAF-TBE = 0 at 40 degrees C. Remarkably, from a feed containing >50% molar VAc content, poly(VAc alt-MAF-TBE)-b-PVAc block copolymers are produced via a one-pot synthesis. Such diblock copolymers exhibit two glass transition temperatures attributed to the alternating and homopolymer sequences. The OMRP of this fluorine-containing alternating monomer system may provide access to a wide range of new polymer materials. PMID- 28564368 TI - THE SENSORY BASIS OF SEXUAL SELECTION FOR COMPLEX CALLS IN THE TUNGARA FROG, PHYSALAEMUS PUSTULOSUS (SEXUAL SELECTION FOR SENSORY EXPLOITATION). AB - Male tungara frogs (Physalaemus pustulosus) vocalize to attract females, and enhance the attractiveness of their simple, whine-only call by adding chucks to produce complex calls. Complex calls contain more total energy and are of longer duration. By virtue of the greater frequency range of the chuck, complex calls also simultaneously stimulate both the amphibian papilla and the basilar papilla of the frog's inner ear. Female phonotaxis experiments using synthetic stimuli demonstrate that an increase in the call's acoustic energy is not sufficient to account for the enhanced attractiveness of the complex call. However, the stimulation of either or both of the female's sound-sensitive inner-ear organs is sufficient to elicit her preference. We suggest that the female's sensory system generates selection that equally favors at least three evolutionary alternatives for enhancing call attractiveness and that historical constraints imposed by the male's morphology determined which of the alternatives was more likely to evolve. These data are consistent with our hypothesis of sensory exploitation, which states that selection favors those traits that elicit greater stimulation from the female's sensory system and which emphasizes the nonadaptive nature of female preference. PMID- 28564369 TI - ON THE EVOLUTION OF HUMAN BROOD SIZE. PMID- 28564370 TI - THE EVOLUTION OF TRANSPOSABLE ELEMENTS: CONDITIONS FOR ESTABLISHMENT IN BACTERIAL POPULATIONS. AB - Previous theoretical studies have shown that bacterial transposons can become established in populations by infectious transfer, even if they reduce the fitness of their host cells. Conditions for the persistence of "parasitic" transposons are, however, restrictive: i) transposition must be replicative, rather than conservative; ii) the rate of transposition must be greater than the loss in host fitness caused by the transposon; and iii) cells must exchange plasmids at rates greater than the fitness cost of the transposon. I sought to test the validity of the model underlying this theory by performing experiments with laboratory populations of the bacterium Escherichia coli, the conjugative plasmid R100, and the transposons Tn3 and Tn5. A plasmid-borne transposon was introduced at low frequency into a population of bacteria carrying the same plasmid without the transposon in a habitat where the transposon offered no benefit to its host. The fate of the invading transposon was followed by tracking the various bacterial populations appearing in the cultures. Using independent estimates of the parameters of the model, predicted population changes were generated with numerical solutions of the model, and these were compared to experimental results. Plasmids transferred into new hosts as predicted by the model, and the resulting transconjugant populations either maintained a steady low density or rose slowly in abundance. Transposition appeared to play no role in population changes. Abundance of all cell types fit theoretical predictions of a system with no transposition, despite evidence that transposition was taking place. This is exactly what the model predicted. It thus appears unlikely that deleterious or neutral transposons have much impact on the genetics of bacterial populations. This is consistent with the hypothesis that most bacterial transposons are not parasitic DNA, but rather invade and persist in populations by providing a fitness advantage to cells carrying them. PMID- 28564371 TI - THE COIL POLYMORPHISM IN PARTULA SUTURALIS DOES NOT FAVOR SYMPATRIC SPECIATION. PMID- 28564372 TI - MITOCHONDRIAL DNA DIVERSITY IN THE SEA URCHINS STRONGYLOCENTROTUS PURPURATUS AND S. DROEBACHIENSIS. AB - Restriction-fragment analysis was used to measure mitochondrial DNA (mtDNA) variability in 79 individuals of two species of temperate sea urchins. For the purple urchin Strongylocentrotus purpuratus, individuals were collected 1,500 km apart in 1985 and again from the same localities in 1988 (about one urchin generation). Twenty mtDNA genotypes belonging to four clades were found among 38 individuals. All four clades were found in both localities and in both years. Genetic structure was further tested by calculating the degree of interdeme genetic variation (GST ) and comparing this value to the GST 's from randomly shuffled data. No geographic structure was found. For S. droebachiensis, only six mtDNA genotypes were found among 41 individuals collected from the Pacific and Atlantic oceans. More than 80% of the individuals belonged to two genotypes. The genotype that dominated collections in the Pacific also occurred in the Atlantic; however, a common Atlantic genotype was never found in the Pacific. These two genotypes were identical at 64 of 65 restriction sites, and were only 0.2% divergent from each other. GST analysis confirmed that there were significant genetic differences between Atlantic and Pacific populations. The small divergence between genotypes suggests recent, but not continuous, migration. These marine species show smaller genotypic differences than terrestrial species over similar spatial and temporal scales. Both recruitment of adults from planktonic larval pools and the spread of sibling larvae over large distances from parents probably act as buffers to genetic differences in species with planktonic life-history phases. PMID- 28564373 TI - FITNESS CONSEQUENCES OF MULTIPLE PATERNITY IN WILD RADISH, RAPHANUS SATIVUS. AB - In natural populations, wild radish plants typically mate with 6-8 pollen donors, and seeds of individual fruits are usually sired by 1-4 fathers. Since radish fruits are indehiscent and gravity-dispersed, progeny are most likely to compete with a mixture of full and half siblings. The fitness consequences of single and multiple paternity were investigated in a greenhouse experiment. Seeds of every possible cross in a 5 times 5 reciprocal diallel mating design were assigned to one of three competition regimes (four full siblings, four maternal half siblings, or four unrelated individuals per pot) or were grown as singletons. After 14 weeks, the aboveground biomass of all plants was harvested and oven dried. The dry weight of singletons was more than three times that of progeny grown in competition, indicating that intraspecific competition had occurred. Full- and half-sib progenies did not differ in mean dry weight. Thus, there was no evidence that multiple paternity enhances this aspect of maternal fitness. However, the competition regime dramatically affected the coefficient of variation in dry weight of progeny within a pot. Weight hierarchies were much more pronounced in pots of half sibs and unrelated neighbors than in pots of full sibs. Also variance in dry weight attributable to sire was greatest in the half sib and "unrelated neighbors" competition regimes. These results suggest that weight hierarchies reinforce genetic differences among the offspring. PMID- 28564374 TI - PARAMYXOVIRUS PHYLOGENY: TISSUE TROPISM EVOLVES SLOWER THAN HOST SPECIFICITY. PMID- 28564375 TI - OLFACTORY-BULB SIZE AND NOCTURNALITY IN BIRDS. AB - Recent evidence shows that, despite earlier beliefs, many birds have a functional sense of smell. There is also considerable variation in olfactory-bulb size among bird species, yet the evolutionary significance of this variation has remained elusive. We argue that birds living under low-light conditions, where vision is less efficient, should have evolved or maintained an increased olfactory ability and, hence, larger olfactory bulbs. Using a family-level comparative analysis to control at least partially for taxonomic artifacts, we show that none of a series of ecological variables (diet, nest type, development, nest dispersion, and migratory behavior) accounts for variation in olfactory-bulb size once the effects of body size and brain size (measured by cerebral-hemisphere length) have been controlled. Activity timing, however, accounts for significant variation even after the removal of these other variables. We discovered 13 independent cases in which nocturnal or crepuscular lineages have evolved a diurnal habit, or vice versa, and compared relative olfactory-bulb sizes between each branch pair. In all but one case, nocturnal or crepuscular birds have larger olfactory bulbs than their diurnal counterparts. We therefore demonstrate a widespread relationship between ecology and the evolutionary development of a part of the brain. PMID- 28564376 TI - THE ASSOCIATION BETWEEN HETEROZYGOSITY AND GROWTH OF DEER FETUSES IS NOT EXPLAINED BY EFFECTS OF THE LOCI EXAMINED. PMID- 28564377 TI - EVOLUTIONARY SIGNIFICANCE OF THE LOSS OF THE CHLOROPLAST-DNA INVERTED REPEAT IN THE LEGUMINOSAE SUBFAMILY PAPILIONOIDEAE. AB - The distribution of a rare chloroplast-DNA structural mutation, the loss of a large inverted repeat, has been determined for 95 species representing 77 genera and 25 of the 31 tribes in the legume subfamily Papilionoideae. This mutation, which is regarded as a derived feature of singular origin within the subfamily, marks a group comprising six temperate tribes, the Galegeae, Hedysareae, Carmichaelieae, Vicieae, Cicereae, and Trifolieae, an assemblage traditionally considered to be monophyletic. This mutation also occurs in the chloroplast genome of Wisteria, a member of the tropical tribe Millettieae whose other members so far surveyed lack the mutation. These new DNA data, together with traditional evidence, support the hypothesis that Wisteria is an unspecialized member of a lineage that gave rise to the temperate tribes marked by the chloroplast-DNA mutation; the probable paraphylesis of Millettieae is revealed. Two other tribes, Loteae and Coronilleae (traditionally regarded as a derived element of the aforesaid temperate tribes) do not possess this chloroplast-DNA structural mutation and, therefore, presumably represent a distinct temperate lineage. This hypothesis is supported by additional evidence from pollen, inflorescence, and root-nodule morphology that suggests that the Loteae and Coronilleae share a more recent ancestry with tropical tribes such as Phaseoleae and Millettieae than with other temperate tribes. PMID- 28564378 TI - THE DEVELOPMENT AND APPLICATION OF A REFINED METHOD FOR ESTIMATING GENE FLOW FROM ANGIOSPERM PATERNITY ANALYSIS. AB - While gene flow is an important factor determining the genetic structure of populations, there are few studies that quantify it empirically. Paternity exclusion analysis has recently been employed to assess the number of seeds fathered by individuals from outside of a study population (gene flow by pollen), but appropriate estimation procedures have been limited to special cases. In this report, we illustrate a general Monte Carlo method that provides an approximate maximum-likelihood estimate of gene flow by pollen from paternity-exclusion analysis. We also show that the method can be used to estimate the number of foreign gametes received by individuals in the study population. Using these methods, we estimated that 7% and 6.3% of the seeds assayed from two wild radish populations were fathered by foreign pollen (95% confidence intervals = 5.0-9.0% and 5.4-7.2%, respectively). Each population was isolated from other radish populations by at least 150 m. Estimates of the number of foreign gametes received by individuals in a population were not correlated with selected reproductive or genetic characters, which included total flower production, total fruit production, seeds per fruit, flower color, floral phenology, and number of heterozygous marker loci. PMID- 28564379 TI - GEOGRAPHICAL AND GENETIC STRUCTURE OF LIFE-HISTORY VARIATION IN MILKWEED BUGS (HEMIPTERA: LYGAEIDAE: ONCOPELTUS). AB - Life-history variation was investigated using crosses within and among the laboratory-bred descendants of six geographic samples of the large milkweed bug, Oncopeltus fasciatus. These samples spanned the species' range, from permanent (year-round) populations on tropical islands to seasonal middle-latitude populations found in temperate North America. The seasonal populations must be refounded each year by colonists from more southern populations. Marked differences in life-history traits (particularly in age at first reproduction, clutch size, and rate of egg production) were observed among the six population samples, with tropical-island and west-coast populations being the most distinct. In the eastern and central United States, there was a marked north-south difference in life history. Crossing experiments demonstrated a genetic basis for these differences. F1 and F2 hybrids from crosses between continental populations tended to have intermediate phenotypes. The similarity of the seasonal middle latitude populations' life histories and the consistency of the distribution of life-history characteristics among populations (across years) may indicate that the north-south difference in life history is due to selection on these traits during the annual northward movement or that migrants represent a distinct genetic form of this species. PMID- 28564380 TI - REPRODUCTIVE BEHAVIOR OF FEMALE BUNTINGS: ISOLATING MECHANISMS IN A HYBRIDIZING PAIR OF SPECIES. AB - The plumage characteristics of male Indigo and Lazuli Buntings are distinct, but the two species can learn each other's songs. Populations comprising Indigo, Lazuli and hybrid individuals occur in the Great Plains of North America, and assortative mating has been inferred from morphometric data. We devised a laboratory assay for determining female preferences for visual and vocal characteristics of conspecific and heterospecific males and for mixtures of these characteristics, such as might be encountered in an overlap population. Females of both species gave more copulation-solicitation displays when exposed to conspecific plumage and vocalizations than when exposed to heterospecific plumage and vocalizations. Females gave intermediate and similar responses to the combinations of conspecific plumage with heterospecific vocalizations and heterospecific plumage with conspecific vocalizations. Thus, in the absence of other potentially important variables, female reproductive behavior is consistent with the hypothesis of assortative mating, based upon both vocal and visual traits of the males and caused by female choice in this semispecies pair. PMID- 28564381 TI - ETHANOL IN DROSOPHILA CULTURES AS A SELECTIVE FACTOR. PMID- 28564382 TI - A CHLOROPLAST-DNA PHYLOGENY OF THE WILD PERENNIAL RELATIVES OF SOYBEAN (GLYCINE SUBGENUS GLYCINE): CONGRUENCE WITH MORPHOLOGICAL AND CROSSING GROUPS. AB - Hypotheses of evolutionary relationships among the Australian wild perennial relatives of soybean (Glycine subgenus Glycine) are based largely on patterns of meiotic pairing in intra- and interspecific experimental hybrids. This evidence has indicated a number of genome groupings within the subgenus but has not resolved most phylogenetic relationships. Restriction-endonuclease site variation of chloroplast DNA (cpDNA) within the perennial subgenus is reported here, representing a sampling of approximately 3% of the approximately 150-kilobase plastome. Seven hundred twenty-one unique restriction sites were compared within Glycine using 29 restriction endonucleases; 157 sites varied within the genus. Distance and parsimony methods using these data yielded congruent results, recognizing the existence of three major groups within subgenus Glycine: the species-rich and geographically diverse A clade consisting of G. canescens and related taxa; the B clade, which includes the stoloniferous species; and the C group, containing two species with distinctive curved pods. These results are in general agreement with hypotheses based on genome analysis; inconsistencies involve the inclusion of genetically divergent taxa such as G. falcata in well supported plastome clades comprised of otherwise interfertile species. Such findings are not unexpected if crossing barriers are considered to be unique features of such anomalous species, paralleling their often numerous morphological and cpDNA autapomorphies. Consideration of cpDNA divergence within the three major clades of subgenus Glycine indicates that the rate of plastome evolution is uncoupled from rates of morphological or ecological diversification. PMID- 28564383 TI - PHASE THREE OF WRIGHT'S SHIFTING-BALANCE THEORY. AB - We examine the third phase of Wright's shifting-balance theory of evolution, the exportation by migration of favorable gene combinations from a fitter subgroup to the rest of the population. The equations are deterministic and are studied numerically. Most of the models studied involve 2-9 loci in which all intermediates between two extreme genotypes are equally unfit. If the favored combination consists of dominant alleles, it is usually fixed even if the migration rate is two orders of magnitude less than the selection coefficient, and if the combination is recessive, one order. Although Wright thought of migration as being essentially one-way, two-way migration does not significantly alter the results. We conclude that, whatever weaknesses the Wright theory may have, they are not in phase III. PMID- 28564384 TI - THE EVOLUTION OF MATERNAL INVESTMENT IN LIZARDS: AN EXPERIMENTAL AND COMPARATIVE ANALYSIS OF EGG SIZE AND ITS EFFECTS ON OFFSPRING PERFORMANCE. AB - I used comparative and experimental analysis of egg size in a Sceloporus lizard to examine a fundamental tenet of life-history theory: the presumed trade-offs among offspring number, offspring size, and performance traits related to offspring size that are likely to influence fitness. I analyzed latitudinal and elevational patterns of egg life-history characteristics among populations and experimentally manipulated egg size and hatchling size by removing yolk from the eggs to examine the causal bases of population differences in offspring traits. Mean clutch size among populations increased to the north (seven vs. 12 eggs/clutch, California vs. Washington), whereas egg size decreased (0.65 g vs. 0.40 g). The elevational patterns in southern California paralleled the latitudinal trends. Several offspring life-history traits that are correlated with egg size also varied geographically; these traits included incubation time, hatchling size, growth rate, and hatchling sprint performance. Hatchling viability of experimentally reduced eggs was remarkably high (~70%), even when up to 50% of the yolk was removed. The experimentally reduced eggs and hatchlings demonstrated the degree to which size influences each of the offspring life history traits considered. Northern eggs hatched sooner, in part because of their small size. Though growth rate is allometrically related to size within each population (i.e., smaller hatchlings grow faster on a mass-specific basis), population differences in growth rate, as measured in the laboratory, are likely to reflect genetic differentiation in the underlying physiology of growth. Moreover, smaller juveniles, because of experimental reduction, had slower sprint speeds than larger juveniles. The slower sprint speed of hatchlings from Washington compared to hatchlings from California is thus largely due to the fact that eggs are smaller in the Washington population. These results provide a basis for interpreting the evolutionary divergence of the suite of traits involved in the evolution of maternal investment per offspring in lizards. For example, evolutionary divergence in some offspring traits functionally related to size (e.g., sprint speed) may be constrained, relative to traits that are determined by other aspects of development or physiology (e.g., growth). I also discuss issues relating to the evolution of maternal investment that could be tested in laboratory and natural populations using experimentally reduced offspring. PMID- 28564385 TI - THE EVOLUTION OF SEXUAL DIMORPHISM BY SEXUAL SELECTION: THE SEPARATE EFFECTS OF INTRASEXUAL SELECTION AND INTERSEXUAL SELECTION. AB - Libellula luctuosa, a pond dragonfly found in eastern North America, is apparently sexually dimorphic. Previous studies of the mating behavior in this species suggested that both male-male competition and female mate choice are important influences. Males compete for territories, where they attract females and where mating occurs. Female behavior influences both the copulation success and the fertilization success of males. Because of temporal and spatial separation of these episodes of sexual selection, multivariate and nonparametric statistical techniques could be used to investigate the influence of components of sexual selection on various sexually dimorphic traits. Sexual dimorphism in L. luctuosa was first quantified; then the direct effects and the form of selection were estimated. Sexually dimorphic wing size, body size, wing coloration, and body coloration are distributed either continuously or discontinuously between the sexes in L. luctuosa. These traits have apparently diverged between the sexes as a result of directional sexual selection. Body size is further influenced by stabilizing selection. Intrasexual selection (success in gaining access to a territory) and intersexual selection (success in copulation and fertilization) can influence the same or different sexually dimorphic characters. Body size is influenced by directional selection during the intrasexual phase of sexual selection and is also influenced by stabilizing selection during intersexual selection. The size of the brown wing patch is influenced by directional selection, primarily during the intersexual phase of sexual selection. There is directional selection on the white wing patch during both phases. Thus, the different proximate mechanisms of sexual selection may jointly or separately affect the evolution of sexually dimorphic characters. Further empirical and theoretical investigations into the differences in the effects of intrasexual selection and intersexual selection are needed to clarify the circumstances leading to separate consequences of these two mechanisms of sexual selection. PMID- 28564386 TI - INTRACLONAL VARIATION IN MORPHOLOGY, GROWTH RATE, AND COPPER TOLERANCE IN THE MOSS, FUNARIA HYGROMETRICA. PMID- 28564387 TI - GENE GENEALOGIES WITHIN THE ORGANISMAL PEDIGREES OF RANDOM-MATING POPULATIONS. AB - Using computer simulations, we generated and analyzed genetic distances among selectively neutral haplotypes transmitted through gene genealogies with random mating organismal pedigrees. Constraints and possible biases on haplotype distances due to correlated ancestry were evaluated by comparing observed distributions of distances to those predicted from an inbreeding theory that assumes independence among haplotype pairs. Results suggest that: 1) mean time to common ancestry of neutral haplotypes can be a reasonably good predictor of evolutionary effective population size; 2) the nonindependence of haplotype paths of descent within a given gene genealogy typically produces significant departures from the theoretical probability distributions of haplotype distances; 3) frequency distributions of distances between haplotypes drawn from "replicate" organismal pedigrees or from multiple unlinked loci within an organismal pedigree exhibit very close agreement with the theory for independent haplotypes. These results are relevant to interpretations of current molecular data on genetic distances among nonrecombining haplotypes at either nuclear or cytoplasmic loci. PMID- 28564388 TI - THE STRUCTURE OF INDIVIDUAL VARIATION IN MIOCENE GLOBOROTALIA. AB - Analysis of probability distributions of individual organisms provides a common language to describe synchronic and diachronic diversity. When based on an appropriate quantitative description of morphology, this language can be used to explore the temporal component of diversity embedded in the fossil record. Miocene Globorotalia (planktonic foraminifera) from Deep Sea Drilling Project site 593 are described using two-point registration of landmarks in two views (spiral and apertural) and medial-axis analysis of the shape of the final chamber. The equiangular spiral parameters Theta (the angle of increment), r (the expansion rate), and t (the rate of translation down the spiral axis) appear as principal components of the landmark data. Chamber shape variation is described by three principal components of medial-axis curvature. Partial-least-squares analysis demonstrates that the first components of within-morphospace variation also explain the patterns of correlation between the landmark and chamber-shape morphospaces. In the landmark morphospaces, the distribution of sampled individuals is continuous and roughly elliptical with few stratigraphic changes. In the chamber-shape morphospace, the distribution is continuous but shows complex features beyond the elliptical; the occupied morphospace changes stratigraphically, but neither strict cladogenesis nor strict anagenesis explains the derivation of new morphologies. Exemplars of named morphospecies are scattered across these spaces with continuous variation among all forms. These names cannot be assumed to represent discrete entities. PMID- 28564389 TI - ENHANCEMENT OF INBREEDING DEPRESSION BY DOMINANCE AND SUPPRESSION IN IMPATIENS CAPENSIS. AB - We investigated the effect of intraspecific competition on the magnitude of inbreeding depression in Impatiens capensis by planting seeds from chasmogamous (CH) and cleistogamous (CL) flowers in three experimental greenhouse treatments: in individual pots, in flats in dense pure stands according to seed type, and in flats with the two seed types intermixed in a checkerboard array. The size distributions of plants grown in flats were significantly more hierarchical than those of plants grown individually, indicating that larger plants competitively suppressed smaller plants in the high-density treatments. The magnitude of inbreeding depression at high density depended upon the planting arrangement of CL and CH seeds. CH advantage was greatest when CH and CL seedlings were grown in competition with one another, suggesting that fitness differences between outcrossed and inbred individuals were intensified by dominance and suppression. For plants grown individually, the effects of maternal parent, seed weight, and emergence date on seedling size disappeared with plant age, whereas at high density these effects remained at the final harvest. Thus, plant density may influence patterns of natural selection both on mating system and on juvenile traits in natural Impatiens populations. PMID- 28564391 TI - THE DYNAMICS OF TWO HYBRID ZONES IN APPALACHIAN SALAMANDERS OF THE GENUS PLETHODON. AB - Two zones of intergradation between populations of Plethodon have been studied for 18 and 20 years, respectively. The data consist of systematic scores of colors, made at least twice annually. Near Heintooga Overlook in the Balsam Mountains (Great Smoky Mountains National Park), the salamanders' cheeks are gray. Proceeding north toward the Smokies, there is increasing frequency and intensity of red color at two, four, and six miles. There has been no change in the scores at any location. The width of the zone and our failure to detect any change can be explained by assuming neutrality of the character and random diffusion during the probable time since contact between the two intergrading forms, which most likely took place after the Hypsithermal Interval, 8,000-5,000 BP. At Coweeta Hydrologic Laboratory in the Nantahala Mountains, Plethodon jordani and P. glutinosus hybridize at intermediate elevations. The lateral white spots of glutinosus decrease and the red on the legs of jordani increases with elevation from 685 m to 1,052 m. At the higher elevation, the proportion of animals scored as "pure" jordani declined significantly from 1974 to 1990, an indication that the hybrid zone is spreading upward. The rate of spread is too great to be explained by random diffusion, so selection for glutinosus characters is the best explanation. The rate of spread of the hybrid zone indicates that hybridization began 60-65 years ago, at the end of the time of intense timbering. Such human disturbances have caused hybridization in other organisms. PMID- 28564392 TI - MATRIARCHAL POPULATION GENETIC STRUCTURE IN AN AVIAN SPECIES WITH FEMALE NATAL PHILOPATRY. AB - We employ mitochondrial (mt) DNA markers to examine the matrilineal component of population genetic structure in the snow goose Chen caerulescens. From banding returns, it is known that females typically nest at their natal or prior nest site, whereas males pair with females on mixed wintering grounds and mediate considerable nuclear gene flow between geographically separate breeding colonies. Despite site philopatry documented for females, mtDNA markers show no clear distinctions between nesting populations across the species' range from Wrangel Island, USSR to Baffin Island in the eastern Canadian Arctic. Two major mtDNA clades (as well as rare haplotypes) are distributed widely and provide one of the few available examples of a phylogeographic pattern in which phylogenetic discontinuity in a gene tree exists without obvious geographic localization within a species' range. The major mtDNA clades may have differentiated in Pleistocene refugia, and colonized current nesting sites through recent range expansion via pulsed or continual low-level dispersal by females. The contrast between results of banding returns and mtDNA distributions in the snow goose raises general issues regarding population structure: direct contemporary observations on dispersal and gene flow can in some cases convey a misleading impression of phylogeographic population structure, because they fail to access the evolutionary component of population connectedness; conversely, geographic distributions of genetic markers can provide a misleading impression of contemporary dispersal and gene flow because they retain a record of evolutionary events and past demographic parameters that may differ from those of the present. An understanding of population structure requires integration of both evolutionary (genetic) and contemporary (direct observational) perspectives. PMID- 28564390 TI - Development of an epitope panel for consistent identification of antigen-specific T-cells in humans. AB - We aimed to establish a panel of MHC-peptide multimers suitable as a positive control in the detection of HLA A*0201 restricted antigen specific T cells (ASTC) by flow cytometry. MHC Dextramers were loaded with HLA A*0201 binding peptides from viral antigens and melanoma targets identified from a literature search and in silico prediction. Peripheral blood mononuclear cells (PBMC) from healthy donors were analysed with the MHC Dextramers using flow cytometry. The best performing epitopes were tested on PBMC from patients undergoing testing for Mycobacterium tuberculosis infection to assess the coverage of this epitope panel. Of 21 candidate epitopes, ASTC could be detected against 12 (57.1%) in at least one of 18 healthy blood donors. Reactivity to two or more epitopes was seen in 17 of the 18 donors (94.4%). We selected the six best-performing epitopes and demonstrated a positive response in 42 (97.7%) of 43 patient samples (healthy, latent and active M. tuberculosis infection). The selected panel of six antigenic epitopes sufficed as a positive control in the detection of ASTC in HLA A*0201. Performance was robust in different stages of latent and active M. tuberculosis infection, indicating reliability also during infection. PMID- 28564393 TI - RELATIVE RESISTANCE OF GOLDENROD TO APHID ATTACK: CHANGES THROUGH THE GROWING SEASON. PMID- 28564394 TI - THE FUNCTIONAL BASIS OF NATURAL SELECTION FOR VERTEBRAL TRAITS OF LARVAE IN THE STICKLEBACK GASTEROSTEUS ACULEATUS. AB - Previous studies have demonstrated selective predation for vertebral traits of larvae in the stickleback Gasterosteus aculeatus. I tested the hypothesis that this selection results from a direct functional advantage to particular vertebral phenotypes by direct measurement of the burst swimming performance of larvae. Within a narrow window of lengths, burst speed did depend on vertebral phenotype. As in the previous predation experiments, performance was related more directly to the ratio of abdominal to caudal vertebrae (VR) than to the total number of vertebrae (VN), and the optimal VR decreased as larval length increased. Changes with length in the vertebral phenotype frequencies of wild larvae provided evidence of selection for VR and for VN in the wild. Larvae with particular VR increased in frequency in the wild at just those lengths when their relative performance was superior in the laboratory. The observed pattern of length dependent selection for vertebral number provides an explanation for the widespread trends in vertebral number that occur among populations of related fishes. PMID- 28564395 TI - ABRUPT CLINE FOR SEX CHROMOSOMES IN A HYBRID ZONE BETWEEN TWO SPECIES OF MICE. AB - We compared the patterns of movement of sex chromosomal and autosomal loci along a 160 km transect across a zone of hybridization between M. domesticus and M. musculus in southern Germany and western Austria using seven genetic markers. These included one Y-specific DNA sequence (YB10), two X-specific loci (DXWas68 and DXWas31), and four autosomal isozyme loci (Es-10, Es-1, Mpi-1, and Np-1). Random effects logistic regression analysis enabled us to examine the relationship between M. domesticus allele frequency and geographic distance from the western edge of the hybrid zone and allowed statistical evaluation of differences in cline midpoint and width among loci. More limited movement was observed for all three sex chromosomal markers across the zone compared with three of the four autosomal markers. If differential movement reflects fitness differences of specific alleles (or alleles at closely linked loci) on a hybrid background, then alleles that move to a limited extent across a hybrid zone may contribute to hybrid breakdown between two species. The limited flow of both X- and Y-specific alleles suggest that sex chromosomes have played an important role in Mus speciation. PMID- 28564396 TI - REINFORCEMENT AND REPRODUCTIVE CHARACTER DISPLACEMENT IN GASTROPHRYNE CAROLINENSIS AND G. OLIVACEA (ANURA: MICROHYLIDAE): A REEXAMINATION. AB - Tape-recorded advertisement calls of Gastrophryne carolinensis and G. olivacea, obtained in Texas and southern Louisiana, were analyzed by means of an analogue audiospectrograph. Samples were grouped into four areas: allopatric and sympatric for G. carolinensis, and combined adjacent allopatric/shallow sympatric, and sympatric for G. olivacea. Three attributes of the advertisement call (call duration, pulse rate, and dominant frequency) were investigated, with water temperature at the calling site as the independent variable. Values for dominant frequency do not overlap between species, across the full range of recording temperatures, and those of sympatric G. carolinensis are displaced away from those of both groups of G. olivacea (which are very similar)-thus indicating a pattern of geographic variation consistent with reproductive character displacement. There is considerable overlap in the values for duration and for pulse rate of each species when considered alone, but there is only slight overlap of the scatters of points for the pairs of values. For both species, no consistent patterns of correlation were detected between the three attributes of the call and the snout-vent length of the emitter, thus reducing the likelihood that the divergence in calls is due to pleiotropic effects of body size. PMID- 28564397 TI - POLLEN DISPERSAL DYNAMICS IN AN ALPINE WILDFLOWER, POLEMONIUM VISCOSUM. AB - The alpine wildflower, Polemonium viscosum, depends on insect visitors for effective pollination. Here, I examine experimentally the effects of pollinator visitation on pollen removal, pollen dispersal success, paternity, and gene flow. Bumble bee pollinators visited donor individuals homozygous for marker alleles at an isozyme (GOT-2) encoding locus and then were presented with arrays of recipient plants lacking the marker alleles. Four aspects of male fitness were estimated for each donor: the number of pollen grains dispersed to flowers of the first recipient visited, the number of offspring sired on that recipient, the proportion of offspring sired in the full array, and the proportion of mates in the array bearing seeds of the donor. Pollen removal was strongly influenced by the number of bee visits to donor flowers. The amount of pollen removed in turn significantly affected the number of pollen grains reaching flowers of the first recipient. However, because seed production decelerates with stigma pollen load, the relationship between pollen export and paternal success at this proximate scale showed diminishing returns. The probability of reaching mates within the array also increased with pollen export. These findings show that floral characters enhancing pollinator visitation rate in P. viscosum have positive effects on paternity and gene flow. PMID- 28564398 TI - EVIDENCE FOR RAPID SPECIATION FOLLOWING A FOUNDER EVENT IN THE LABORATORY. PMID- 28564399 TI - GENETIC VARIATION IN CACTOPHILIC DROSOPHILA FOR OVIPOSITION ON NATURAL YEAST SUBSTRATES. AB - Theory predicts that environmental heterogeneity in space or in time can maintain genetic polymorphism. Stable polymorphisms are expected to be more readily maintained if there are genotype specific habitat preferences. Genotype specific preferences for oviposition sites in Drosophila could be a major factor promoting habitat selection, and thus the maintenance of genetic variation. This hypothesis is being tested using the cactophilic species, D. buzzatii and D. aldrichi, where available evidence indicates a potential for such habitat selection, the habitats (oviposition sites) being yeast species found in the natural environment of these flies (cactus rots). Genetic variation for oviposition preferences was tested using isofemale lines-for D. buzzatii, a total of 60 lines from seven localities widely distributed through the species range in Australia, and for D. aldrichi, 21 lines from three of these localities. Females were given a choice of five yeast species as oviposition sites. Genetic variation for oviposition preferences on these natural substrates was demonstrated. There was significant variation among isofemale lines within populations in their patterns of preferences for oviposition on the five yeast species. However, analyses of preferences for each yeast species separately showed that the genetic variation for preferences relates to only three of the five species. Heritabilities of individual female preferences for these three species were low, ranging up to 9%. Little geographic differentiation was apparent among populations, most likely due to similar selection regimes within each population. Within populations, this kind of habitat selection could act to maintain polymorphisms, both at loci determining the habitat preferences and at other loci in linkage disequilibrium with them. PMID- 28564400 TI - INJURIES ON STICKLEBACK FROM ATTACKS BY A TOOTHED PREDATOR (ONCORHYNCHUS) AND IMPLICATIONS FOR THE EVOLUTION OF LATERAL PLATES. PMID- 28564401 TI - HETEROCHRONIC DEVELOPMENTAL PLASTICITY IN LARVAL SEA URCHINS AND ITS IMPLICATIONS FOR EVOLUTION OF NONFEEDING LARVAE. AB - Preexisting developmental plasticity in feeding larvae may contribute to the evolutionary transition from development with a feeding larva to nonfeeding larval development. Differences in timing of development of larval and juvenile structures (heterochronic shifts) and differences in the size of the larval body (shifts in allocation) were produced in sea urchin larvae exposed to different amounts of food in the laboratory and in the field. The changes in larval form in response to food appear to be adaptive, with increased allocation of growth to the larval apparatus for catching food when food is scarce and earlier allocation to juvenile structures when food is abundant. This phenotypic plasticity among full siblings is similar in direction to the heterochronic evolutionary changes in species that have greater nutrient reserves within the ova and do not depend on particulate planktonic food. This similarity suggests that developmental plasticity that is adaptive for feeding larvae also contributes to correlated and adaptive evolutionary changes in the transition to nonfeeding larval development. If endogenous food supplies have the same effect on morphogenesis as exogenous food supplies, then changes in genes that act during oogenesis to affect nutrient stores may be sufficient to produce correlated adaptive changes in larval development. PMID- 28564402 TI - A MODEL OF A HYBRID ZONE BETWEEN TWO CHROMOSOMAL RACES OF THE COMMON SHREW (SOREX ARANEUS). AB - The common shrew (Sorex araneus) is subdivided into several karyotypic races in Britain. Two of these races meet near Oxford o form the "Oxford-Hermitage" hybrid zone. We present a model which describes this system a; a "tension zone," i.e., a set of clines maintained by a balance between dispersal and selection against chromosomal heterozygotes. The Oxford and Hermitage races differ by Robertsonian fusions with monobrachial homology (kq, no versus ko), and so Fl hybrids between them would have low fertility. However, the acrocentric karyotype is found at high frequency within the hybrid zone, so that complex Robertsonian heterozygotes (kg no/q ko n) are replaced by more fertile combinations, such as (kg no/k q n o). This suggests that the hybrid zone has been modified so as to increase hybrid fitness. Mathematical analysis and simulation show that, if selection against complex heterozygotes is sufficiently strong relative to selection against simple heterozygotes, acrocentrics increase, and displace the clines for kg and no from the cline for ko. Superimposed on this separation is a tendency for the hybrid zone to move in favor of the Oxford (kg no) race. We compare the model with estimates of linkage disequilibrium and cline shape made from field data. PMID- 28564403 TI - MOLECULAR GENETICS OF ADAPTATION IN AN EXPERIMENTAL MODEL OF COOPERATION. AB - The evolution of cooperation was studied in an empirical system utilizing a parasitic bacteriophage (f1) and a bacterial host. Infected cells were propagated by serial passage so that a phage could increase its representation among infected hosts only by enhancing the rate of growth of its host. Loss of infectivity was therefore without selective penalty, and phage benevolence could potentially evolve through a variety of genetic changes. The infected hosts evolved to grow faster over the course of the study, but the genetic bases of this phenotypic change were more difficult to anticipate. Two fundamentally different types of genetic changes in the phage were revealed. One involved the loss of some phage genes, resulting in a noninfectious plasmid that continued to replicate via the parental phage replicon. The second change involved integration of the phage genome into host DNA by a process that, at low frequency, could be reversed to produce infectious phage particles. Integration is a previously unknown property of wild-type f1, and in the system studied, may have resulted from the use of a phage bearing an insert containing nonfunctional DNA. The evolution of this novel function apparently depended only on the presence of a small region in the phage genome that provided some homology to the host DNA, with the host providing all necessary functions. Although f1 is one of the simplest phages known, these observations suggest that host-parasite interactions of the filamentous phages are more complicated than previously thought. More generally, the f1 system offers a useful model for many problems concerning the genetic basis of adaptation. PMID- 28564404 TI - THE EFFECT OF FLOWER PRODUCTION ON MALE REPRODUCTIVE SUCCESS IN WILD RADISH POPULATIONS. AB - Flower production is the major determinant of pollen yield and an important component in pollinator attraction. Consequently differences among plants in flower production are expected to have a substantial impact on their relative success at fathering seed. We examined this prediction using one natural and three structured populations of wild radish. We found that a plant's relative success at fathering seed on another plant in the population (male fertility) increased with flower production. Nonetheless, the increase in fertility exhibited a diminishing marginal gain, with the relationship varying among populations. The relationship between the estimates of total number of seeds sired and flower production varied substantially among the populations examined, ranging from a weakly linear to strongly negative quadratic. Not surprisingly, the spatial structure of the population with respect to seed yield had a powerful effect on the total number of seeds sired because male fertility decreased exponentially with intermate distance. This exponential relationship occurred in all populations examined. Other covariates important to male fertility were flower color, time, the specific identity of the male parent, and male by female interaction. The identity of the male parent consistently accounted for a large portion of the variation in male fertility, indicating that other unmeasured features of the plant influenced its success. PMID- 28564405 TI - ATTRACTIVE STRUCTURES AND THE STABILITY OF HERMAPHRODITIC SEX EXPRESSION IN FLOWERING PLANTS. AB - Plant attributes serving both male and female sex functions are thought to favor hermaphroditic breeding systems over systems where sex expression is separated between individuals. Morphological features used by plants to attract biotic pollinators can be considered in this light, because such "attractive" structures are prerequisite for both pollen donation and receipt. A model involving allocation of a limiting resource between attractive structures benefiting both sex functions, structures benefiting male function only, and structures benefiting female function only, is constructed and analyzed using the evolutionary stable strategy (ESS) approach. Contrary to expectation, conditions resulting in large allocation to attractive structures tend to destabilize hermaphroditism, although the effect is slight. Substantial asymmetry in the benefits accruing to male and female fertility for a given investment in pollinator attraction produces more pronounced effects, reducing the parameter space in which hermaphroditism is expected. Results of this model are used to assess the importance of "accelerating gain" curves previously suggested for the evolution of dioecy in flowering plants. Accelerating gains associated with fruit production and dispersal represent female function only, and can be sufficient to initiate evolution toward dioecy. Accelerating gains associated with pollinator attraction may contribute to the evolution of separate sexes only if male function benefits from increased investment in attractive structures at a disproportionate rate compared to female function. Even in this instance, though, hermaphroditism may be evolutionarily stable. PMID- 28564406 TI - A RAPID, SEXUALLY SELECTED SHIFT IN MEAN BODY SIZE IN A POPULATION OF SNAKES. PMID- 28564407 TI - MEASURING SELECTION AND CONSTRAINT IN THE EVOLUTION OF GROWTH. AB - We present a quantitative genetic model for the evolution of growth trajectories that makes no assumptions about the shapes of growth trajectories that are possible. Evolution of a population's mean growth trajectory is governed by the selection gradient function and the additive genetic covariance function. The selection gradient function is determined by the impact of changes in size on the birth and death rates at different ages, and can be estimated for natural populations. The additive genetic covariance function can also be estimated empirically, as we demonstrate with four vertebrate populations. Using the genetic data from mice, a computer simulation shows that evolution of a growth trajectory can be constrained by the absence of genetic variation for certain changes in the trajectory's shape. These constraints can be visualized with an analysis of the covariance function. Results from four vertebrate populations show that while each has substantial genetic variation for some evolutionary changes in its growth trajectory, most types of changes have little or no variation available. This suggests that constraints may often play an important role in the evolution of growth. PMID- 28564408 TI - THE INFLUENCE OF DISPERSAL PATTERNS AND MATING SYSTEM ON GENETIC DIFFERENTIATION WITHIN AND BETWEEN POPULATIONS OF THE RED HOWLER MONKEY (ALOUATTA SENICULUS). AB - The relationship between social structure and partitioning of genetic variance was examined in two red howler monkey populations (W and G) in Venezuela, one of which (G) was undergoing rapid growth through colonization by new troops. Rates and patterns of gene flow had been determined through radiotelemetry and direct observation data on solitary migrants, and 10 years of troop censusing. Standard electrophoresis techniques were used to examine 29 loci in blood samples taken from 137 of the study animals. Analysis of genetic variance demonstrated: (1) a significantly high level of genetic variation among troops within populations (FST = 0.225 for W and 0.142 for G), and (2) a significant excess of heterozygosity within troops relative to expected (FIS = -0.136 for W and -0.064 for G), despite relatively high levels of observed and inferred inbreeding in W. Differences between the populations in FST values conformed to those predicted based on differences in colonization rate. Comparison of partitioning of genetic variance among different genealogical subsets of troops demonstrated that the pattern of genetic differentiation observed among troops within populations was promoted by an essentially single-male harem breeding structure, a very low rate of random exchange of breeding males among troops, and a high degree of relatedness among troop females. Between-troop genetic differentiation (FST ) was thereby increased relative to that expected from other types of social organization, while the correlation between uniting gametes within troops (FIS ) was decreased. Genetic differentiation between populations (2%) corresponded to that predicted from migration rates. Such a mosaic of genetic variation, combined with differences in reproductive success observed among troops and a high troop failure rate, create conditions in which interdemic selection could result in more rapid spread of advantageous gene combinations than would be expected in a panmictic population, particularly in a colonizing situation in which the founder population is small. PMID- 28564409 TI - NUCLEAR RIBOSOMAL DNA VARIATION AMONG RAMETS AND GENETS OF WHITE CLOVER. PMID- 28564410 TI - GLOBAL POPULATION STRUCTURE AND NATURAL HISTORY OF THE GREEN TURTLE (CHELONIA MYDAS) IN TERMS OF MATRIARCHAL PHYLOGENY. AB - To address aspects of the evolution and natural history of green turtles, we assayed mitochondrial (mt) DNA genotypes from 226 specimens representing 15 major rookeries around the world. Phylogenetic analyses of these data revealed (1) a comparatively low level of mtDNA variability and a slow mtDNA evolutionary rate (relative to estimates for many other vertebrates); (2) a fundamental phylogenetic split distinguishing all green turtles in the Atlantic-Mediterranean from those in the Indian-Pacific Oceans; (3) no evidence for matrilineal distinctiveness of a commonly recognized taxonomic form in the East Pacific (the black turtle C.m. agassizi or C. agassizi); (4) in opposition to published hypotheses, a recent origin for the Ascension Island rookery, and its close genetic relationship to a geographically proximate rookery in Brazil; and (5) a geographic population substructure within each ocean basin (typically involving fixed or nearly fixed genotypic differences between nesting populations) that suggests a strong propensity for natal homing by females. Overall, the global matriarchal phylogeny of Chelonia mydas appears to have been shaped by both geography (ocean basin separations) and behavior (natal homing on regional or rookery-specific scales). The shallow evolutionary population structure within ocean basins likely results from demographic turnover (extinction and colonization) of rookeries over time frames that are short by evolutionary standards but long by ecological standards. PMID- 28564411 TI - STOCHASTIC LOSS OF STYLE MORPHS FROM POPULATIONS OF TRISTYLOUS LYTHRUM SALICARIA AND DECODON VERTICILLATUS (LYTHRACEAE). AB - Despite the theoretical importance of stochastic processes in evolution there have been few empirical studies of the interaction between genetic drift and selection on the maintenance of polymorphisms in plant populations. We used computer models to investigate the interaction between drift and frequency dependent selection in affecting style morph frequencies in populations of tristylous species. Drift produces a distinct pattern of morph frequency variation involving: 1) the loss of the S morph and, to a lesser extent, the M morph; 2) no consistent bias in frequencies within populations; 3) a restricted pattern of variation involving a deficiency of one morph and equal excesses of the other two. Morph frequencies were surveyed in 137 populations of Lythrum salicaria from both its native range in Europe (N = 35) and recent adventive range in Ontario (N = 102), and 133 populations of Decodon verticillatus from four regions in eastern North America with different glacial histories to assess these theoretical predictions. There was a negative relationship between morph loss and population size in both species; the relationship was weaker in D. verticillatus than in L. salicaria. Morph loss was more frequent in the adventive than native range of L. salicaria, and in populations of D. verticillatus from glaciated northern regions compared with the unglaciated southern portion of its range. Simulations incorporating variation in life history, regeneration strategy and mating patterns revealed that the degree of morph loss was strongly influenced by year to year survival, clonal propagation, self-fertilization and departures from disassortative mating. Comparing the pattern of morph frequency variation between species supported these predictions. Morph loss was lower in self-incompatible L. salicaria (0% in Europe; 23% in Ontario), which reproduces through seed compared to self-compatible, clonal D. verticillatus (52%). A stochastic model provides the most parsimonious explanation for observed patterns of morph frequency variation in both species. PMID- 28564412 TI - RELATIVE SUCCESS OF SELF AND OUTCROSS POLLEN COMPARING MIXED- AND SINGLE-DONOR POLLINATIONS IN AQUILEGIA CAERULEA. AB - Flowers frequently receive both self (S) and outcross (OC) pollen, but S pollen often sires proportionally fewer seeds. Failure of S pollen can reflect evolved mechanisms that promote outcrossing and/or inbreeding depression expressed during seed development. The relative importance of these two processes was investigated in Aquilegia caerulea, a self-compatible perennial herb. In the field I performed single-donor (S or OC) and mixed-donor (S plus OC) pollinations to compare the relative success of both pollen types at various stages from pollen germination to seed maturity. Single-donor S pollinations produced significantly fewer and lighter seeds (x decrease = 12% and 3%, respectively) than OC pollinations. Abortion rates differed by an average of 38% whereas fertilization rates differed by only 5%, indicating that most differences in seed number arose postzygotically. This suggests that inbreeding depression was responsible for most failure of S pollen. One prezygotic effect measured was that 10% fewer S than OC pollen tubes reached ovaries after 42 hr, suggesting S pollen might fertilize proportionately fewer ovules after mixed pollination. Using allozyme markers, I found mixed-donor pollinations produced significantly more and heavier outcrossed than selfed seeds. However, the proportion of selfed seed, fertilized ovules, and aborted seeds for mixed-donor fruits were each predictable from pollen performance in single-donor fruits, suggesting that differential paternity is best explained by inbreeding depression during seed development. Even given these similarities between mixed- and single-donor fruits in the relative performance of S and OC pollen, both individual seed weight and seed set were significantly higher in multiply-sired fruits. PMID- 28564413 TI - SPATIAL VARIATION IN SELECTIVE REGIMES: SEXUAL SELECTION IN THE WATER STRIDER, GERRIS ODONTOGASTER. AB - Studies of phenotypic selection in natural populations are often concerned with simply detecting selection. In adopting a more mechanistic approach, this study compares the sexual selection regimes in natural populations of the water strider Gerris odontogaster with a priori predictions of selection, based on a number of previous field and laboratory studies of the behavioral mechanisms of selection. In this species, a general reluctance of females to mate allows for intersexual selection for ability to subdue reluctant females in males. Female reluctance to mate has been shown to decrease with increasing population density, suggesting that sexual selection should be weaker in high density populations. Three different populations with large differences in population density were studied. A number of traits including parasite load, body mass, body size and male abdominal process length were found to experience significant sexual selection. The investigated populations differed considerably with regard to the total strength of selection on the measured traits and the form of selection on single traits. In general, males in the population with the highest density experienced the weakest selection for grasping ability. This pattern is ascribed to density related alterations of female mating behavior. Selection for male grasping ability, as reflected by selection on male abdominal process length, is reduced in high-density populations where reluctant females are more easily subdued. Further, the studied populations differed significantly in mean phenotype and phenotypic variance for male abdominal process length. It is suggested that interpopulational differences in selective regimes may generate local adaptations with respect to male abdominal process length, and that gene flow may contribute to the maintenance of the high genetic variation in this trait. It is further suggested that more empirical effort should be made in quantifying and understanding spatial and temporal variation in selection in natural populations, since this may provide information on the prevalence of local adaptations in metric traits and on the mechanisms of selection. PMID- 28564414 TI - THE MICRO AND MACRO IN BODY SIZE EVOLUTION. AB - The diversity of body sizes of organisms has traditionally been explained in terms of microevolutionary processes: natural selection owing to differential fitness of individual organisms, or to macroevolutionary processes: species selection owing to the differential proliferation of phylogenetic lineages. Data for terrestrial mammals and birds indicate that even on a logarithmic scale frequency distributions of body mass among species are significantly skewed towards larger sizes. We used simulation models to evaluate the extent to which macro- and microevolutionary processes are sufficient to explain these distributions. Simulations of a purely cladogenetic process with no bias in extinction or speciation rates for different body sizes did not produce skewed log body mass distributions. Simulations that included size-biased extinction rates, especially those that incorporated anagenetic size change within species between speciation and extinction events, regularly produced skewed distributions. We conclude that although cladogenetic processes probably play a significant role in body size evolution, there must also be a significant anagenetic component. The regular variation in the form of mammalian body size distributions among different-sized islands and continents suggests that environmental conditions, operating through both macro- and microevolutionary processes, determine to a large extent the diversification of body sizes within faunas. Macroevolution is not decoupled from microevolution. PMID- 28564415 TI - A HIERARCHICAL ANALYSIS OF GENETIC DIFFERENTIATION IN A MONTANE LEAF BEETLE CHRYSOMELA AENEICOLLIS (COLEOPTERA: CHRYSOMELIDAE). AB - Herbivorous insects that use the same host plants as larvae and adults can have a subdivided population structure that corresponds to the distribution of their hosts. Having a subdivided population structure favors local adaptation of subpopulations to small-scale environmental differences and it may promote their genetic divergence. In this paper, I present the results of a hierarchical study of population structure in a montane willow leaf beetle, Chrysomela aeneicollis (Coleoptera: Chrysomelidae). This species spends its entire life associated with the larval host (Salix spp.), which occurs in patches along high-elevation streams and in montane bogs. I analyzed the genetic differentiation of C. aeneicollis populations along three drainages in the Sierra Nevada mountains of California at five enzyme loci: ak-1, idh-2, mpi-1, pgi-1, and pgm-1, using recent modifications of Wright's F-statistics. My results demonstrated significant differentiation (FST = 0.043) among drainages that are less than 40 kilometers apart. One locus, pgi-1, showed much greater differentiation than the other four (FST = 0.412), suggesting that it is under natural selection. C. aeneicollis populations were also subdivided within drainages, with significant differentiation 1) among patches of willows (spanning less than three kilometers) and 2) in some cases, among trees within a willow patch. My results demonstrate that this species has the capacity to adapt to local environmental variation at small spatial scales. PMID- 28564416 TI - AN EVOLUTIONARY THEORY OF CONFLICT RESOLUTION BETWEEN RELATIVES: ALTRUISM, MANIPULATION, COMPROMISE. PMID- 28564417 TI - SELECTIVE PREDATION FOR VERTEBRAL PHENOTYPE IN GASTEROSTEUS ACULEATUS: REVERSAL IN THE DIRECTION OF SELECTION AT DIFFERENT LARVAL SIZES. AB - Variation in the number of vertebrae is widespread in fishes, and is partly genetic in origin. The adaptive significance of this variation was tested by exposing larvae of the threespine stickleback (Gasterosteus aculeatus) to predation by sunfish (Lepomis gibbosus). Two vertebral characters were considered: the total number (VN) and the ratio of abdominal to caudal vertebrae (VR). Predation was selective for both characters, but selection was more directly related to VR than to VN. The direction of selection depended on larval length: as length increased, optimal VR decreased. Total selection for VR was a combination of direct selection and an indirect effect of selection acting on a correlated trait, the ratio of precaudal to caudal length. Direct and indirect selection were in opposing directions at a given larval length. Variation in vertebral number may be maintained in populations partly because the strength of selection is reduced by opposing directions between direct and indirect selection, and between total selection at different larval lengths. PMID- 28564418 TI - ONTOGENY OF INTEGRATED SKULL GROWTH IN THE COTTON RAT SIGMODON FULVIVENTER. AB - Because development is epigenetic, diverse aspects of morphology are integrated during ontogeny. Using the method of thin-plate splines, and the decomposition of these splines by their principal warps, we examine the ontogeny of integrated features of skull growth of the cotton rat, Sigmodon fulviventer as observed in landmark locations in the ventral view. Postnatal growth of the skull in Sigmodon is not adequately described by the familiar contrast between relatively rapid facial elongation and slow, precocial growth of the cranial base. No developmental units corresponding to "facial skull" and "cranial base" emerge from analysis of geometric shape change. Rather, skull growth is both more integrated and more complex, exhibiting both skull-wide integration and locally individualized regions. Like skull shape, integration has an ontogeny; different regions of the skull can be partitioned into developmentally individualized parts in different ways at different ages. The effective count of individualized parts decreases substantially before weaning occurs, suggesting that the integration required by the functionally demanding activity of chewing gradually develops before the functional transition occurs. Our description of skull growth and integration does not depend upon arbitrary a priori choices about what to measure; rather, we base our decomposition of the whole into parts upon results of the data analysis. Our approach complicates the study of heterochrony, but, because it expresses the spatiotemporal organization of ontogeny, it enables the study of heterotopy. PMID- 28564419 TI - PARTHENOGENESIS IN A FRESHWATER SNAIL: REPRODUCTIVE ASSURANCE VERSUS PARASITIC RELEASE. AB - Two alternative (but not mutually exclusive) hypotheses were contrasted for their abilities to explain the distribution of parthenogenesis in the freshwater snail Potamopyrgus antipodarum: the reproductive assurance hypothesis, which predicts that parthenogenesis will be favored in sparse populations where mates are difficult to find, and the Red Queen hypothesis, which predicts that parthenogenesis will be favored in populations that have a low risk of parasitism. The results were inconsistent with the prediction of the reproductive assurance hypothesis; male frequency was not significantly or positively correlated with snail density. Thus, there was no support for any of the hypotheses for the maintenance of sex that rely on selection for reproductive assurance to explain the distribution of parthenogenesis (e.g., recombinational repair). The results, however, were consistent with the Red Queen hypothesis; male frequency was positively and significantly correlated with the frequency of individuals infected by trematodes. This correlation suggests that parthenogenetic females have replaced sexual females in populations where parasites are rare, and that sexual females have persisted in populations where parasites are common. PMID- 28564420 TI - HOST RACE RADIATION IN THE SOAPBERRY BUG: NATURAL HISTORY WITH THE HISTORY. AB - Evolution by natural selection is remarkably well documented in the diversification of soapberry bug populations on their native and recently introduced host plants. In this century, populations of this native seed-eating insect have colonized three plant species introduced to North America. Each new host differs in fruit size from the native hosts, providing an unplanned experiment in natural selection of the insect's beak length. In each of three host shifts, beak length has increased or decreased in the direction predicted from fruit size. Furthermore, museum specimens show historical changes consistent with the host shift scenario inferred from beak length values in contemporary populations. The extent to which beak length evolution has been accompanied by evolution in other body size characters differs between the races, suggesting that the evolution has proceeded differently in each case. In all cases, significant evolution has occurred in as little as 20-50 years (40-150 generations), creating a species-level mosaic of response to simultaneous directional, diversifying, and normalizing selection. PMID- 28564421 TI - DISPERSAL IN THE WOOD FROG (RANA SYLVATICA): IMPLICATIONS FOR GENETIC POPULATION STRUCTURE. AB - Recapture of marked juvenile and adult wood frogs in five Appalachian Mountain ponds showed adults to be 100% faithful to the ponds in which they first bred, but approximately 18% of the juveniles dispersed to breed in ponds other than the one of origin. Effective population sizes were generally smaller than the population censuses and genetic neighborhoods had an average radius of 1,126 meters. Values of standardized genetic variance based on effective population size and mating success were relatively small. Genetic population structure estimated from the dispersal data suggested that ponds within about a 1,000 meter radius should show little genetic differentiation; ponds separated by a distance greater than 1,000 meters should experience little gene flow and show higher genetic differentiation. Wood frogs in these ponds do not show a meta-population structure as suggested for newts. PMID- 28564422 TI - COMMENTS ON THE CAUSES OF NATURAL SELECTION. PMID- 28564423 TI - TARGETS OF SEXUAL SELECTION: SONG AND PLUMAGE OF WOOD WARBLERS. AB - Extant hypotheses predict that, in the face of sexual selection, avian song and plumage may evolve in a concerted fashion, in an antagonistic fashion, or in ways unrelated to each other. To test these ideas regarding which traits sexual selection targets, and the consequences for other traits, we analyzed patterns of song complexity and plumage dimorphism in 56 species of wood warblers (Parulinae). Overall, males of more dimorphic species sang shorter songs more often, but did not have more complex songs. However, when monomorphic species were excluded from the analysis, we found that the total time spent singing and repertoire size increased with plumage dimorphism. Monomorphic species are predominantly ground-nesters and the greater risk of nest predation for these species may constrain males from becoming more visually conspicuous. Thus, sexual selection may have been restricted to targeting song in these species. Even though song may have been the only target of sexual selection in ground-nesting species, overall, song in those species is not more complex than in species that nest above the ground. We propose that traits targeted by sexual selection evolve in concert, except when constrained by some ecological factor. PMID- 28564424 TI - PHYLOGENETIC ANALYSIS OF CHLOROPLAST DNA RESTRICTION SITE DATA AT HIGHER TAXONOMIC LEVELS: AN EXAMPLE FROM THE ASTERACEAE. AB - Chloroplast DNA variation was examined among 57 genera of Asteraceae representing 15 currently recognized tribes. Complete cleavage maps were constructed for 11 six-base pair restriction enzymes, and a total of 927 cleavage site differences was detected, 328 of which are phylogenetically informative. The data were used to construct phylogenetic trees using both Wagner and Dollo parsimony and the resulting monophyletic groups were evaluated statistically using the bootstrap method. The level of homoplasy in the restriction site data is 54-56% (excluding autapomorphies), most of which is due to parallel site losses. The most parsimonious trees generated by both parsimony methods have nearly identical topologies at lower taxonomic levels, but differ in subfamilial circumscriptions and tribal groupings. Dollo parsimony provides support for the monophyly of two subfamilies, the Lactucoideae (excluding the Barnadesiinae) and Asteroideae, but Wagner parsimony supports the monophyly of the Asteroideae only. This incongruence is due to different assumptions of the two parsimony methods about relative rates of parallel site gains and losses. After eliminating the six most rapidly changing restriction sites or performing successive approximation, Wagner parsimony produces trees with the same subfamilial groupings as the Dollo trees. We conclude that the Dollo tree with two monophyletic subfamilies is the best estimate of phylogenetic relationships in the Asteraceae because this method more accurately reflects the evolution of restriction sites. We also demonstrate that in spite of high levels of homoplasy in chloroplast DNA restriction site data at these higher taxonomic levels, it is possible to make statistically supported estimates of phylogenetic relationships. PMID- 28564425 TI - HALDANE'S RULE AND SEX BIASSED GENE FLOW BETWEEN TWO HYBRIDIZING FLYCATCHER SPECIES (FICEDULA ALBICOLLIS AND F. HYPOLEUCA, AVES: MUSCICAPIDAE). AB - The collared flycatcher (Ficedula albicollis) and the pied flycatcher (F. hypoleuca) hybridize where their geographic ranges overlap. Restriction fragment comparison of 5% of the mitochondrial genome showed a sequence divergence of 10% between these flycatcher species. This degree of sequence divergence between a closely related pair of bird species is unusually high and contrasts with the low level of divergence between F. albicollis and F. hypoleuca in nuclear genes (Nei's D = 0.0006) revealed by enzyme electrophoresis. The low nuclear differentiation is explained by sex biassed gene flow and introgression in nuclear genes (via fertile male hybrids), while the high mitochondrial DNA sequence divergence is preserved by sterility of female hybrids, which prevents mitochondrial introgression. This pattern is in accordance with Haldane's rule and is supported by field data on hybrid fertility. The high mtDNA differentiation could be explained by transfer of mitochondrial DNA from a third species during a past period of hybridization. PMID- 28564426 TI - THE EVOLUTIONARY SIGNIFICANCE OF HYBRIDIZATION IN EUCALYPTUS. PMID- 28564427 TI - POPULATION STRUCTURE AND HOST USE IN HYBRIDIZING SUBSPECIES OF PAPILIO GLAUCUS (LEPIDOPTERA: PAPILIONIDAE). AB - Two parapatric subspecies of the eastern tiger swallowtail butterfly, Papilio glaucus glaucus and P. g. canadensis, differ greatly in larval survival and growth on host plants in the Magnoliaceae, Salicaceae, and Betulaceae. In the first part of this study, butterflies were collected from 17 sites along a transect from Georgia to Quebec and used for allozyme electrophoresis. Two X- (or Z-)linked enzyme loci (Ldh and Pgd) showed allele frequency differences that delineated a hybrid zone between the subspecies in northern Pennsylvania and south-central New York. No significant linkage disequilibrium could be detected among allozyme loci within the hybrid zone samples. Genetic differentiation at Ldh and Pgd coincides with subspecies differences in diapause control and female mimicry, which are also sex-linked. Larval offspring of butterflies from 13 of the sites were then tested in the laboratory for survival and growth on Liriodendron tulipifera (Magnoliaceae), Populus deltoides (Salicaceae) and Betula lutea (Betulaceae). Steep clines in survival rates matched the position of the hybrid zone. Hybrid zone larvae showed intermediate survival rates and significant heterogeneity among families on all three plants, indicating presence of substantial genetic variation. The results suggest that differential host use by P. g. glaucus and P. g. canadensis is maintained primarily by independent clines in selection intensity for ability to use allopatric sets of host plants, coupled with restricted gene flow across the hybrid zone. PMID- 28564428 TI - FUNCTIONAL COMPLEXES AND ADDITIVITY IN PERFORMANCE: A TEST CASE WITH "FLYING" FROGS. PMID- 28564429 TI - EXAMINING HYPOTHESES GENERATED BY FIELD MEASURES OF SEXUAL SELECTION ON MALE LIZARDS, UTA PALMERI. AB - I examined sexual selection in the iguanid lizard Uta palmeri by measuring phenotypic selection in a cohort of males. Relative fitness was estimated by copulation rate from one breeding season, and I analyzed selection on five morphological traits (snout-vent length, mass, jaw length, head width, and head depth) and on male territory quality. Only territory quality and head depth were identified as direct targets of selection in a linear selection gradient analysis. Head depth was suggested to also be subject to quadratic selection. All traits exhibited significant directional selection differentials, suggesting indirect selection also was present because of the correlation of these traits with direct targets of selection. I used these results to generate hypotheses about the mechanisms of selection. For traits not identified as direct targets of selection (snout-vent length, mass, head width, jaw length), I could accept the null hypothesis of no female preference for the analyzed male traits; if these morphological traits were preferred by females in mate choice, they would have been identified as direct targets of selection. Exploring possible functional relationships within the cohort, I found that all five morphological traits contributed to explaining variation in territorial status. And in staged aggressive interactions between males that were similar in snout-vent length and mass, winning was associated only with greater head depth and not with head width or jaw length. Several possible interpretations of these results are presented. This study suggests that differential mating success arising from variation in territory quality gives rise to indirect selection on morphology. The possible mechanisms giving rise to the proposed direct selection on head depth require further study. PMID- 28564430 TI - RETROTRANSPOSON MYS IS CONCENTRATED ON THE SEX CHROMOSOMES: IMPLICATIONS FOR COPY NUMBER CONTAINMENT. AB - Chromosomal distribution of the mys retrotransposon was examined by in situ hybridization with a biotinylated probe. Thirty-six mice from four species of the Peromyscus leucopus/maniculatus complex were examined. Mys hybridized to every chromosome in all individuals examined. However, the pattern of hybridization was nonrandom. Mys elements were excluded from C-banding regions of the autosomes, and hybridized preferentially to G-bands. The most prominent feature of these hybridizations was the preferential accumulation of mys on the X and Y chromosomes of all four species examined. Accumulation of mys on the X is incompatible with the hypothesis that selection acting on deleterious mutations is the major mechanism regulating the copy number of this element. Rather, this supports the Langley model for containment of transposable element copy number by unequal exchange during meiosis. PMID- 28564431 TI - GENOTYPE-ENVIRONMENT INTERACTION FOR CLIMATE AND COMPETITION IN A NATURAL POPULATION OF FLOUR BEETLES, TRIBOLIUM CASTANEUM. AB - The norm of reaction, the set of average phenotypes produced by a genotype in different environments, can be affected by spatial variation in natural selection especially when there exists genotype-environment interaction. In subdivided populations, the greater the genotype-environment interaction variance and the lower the migration rate, the more independent are the possible evolutionary trajectories for local adaptation. I examined genotype-environment interaction in the rate of population increase for lineages randomly derived from a wild population of Tribolium castaneum across a series of ecologically important environments. The lineages were derived from an outbred, wild-caught population by 14 generations of random genetic drift, during which the effective size of each lineage was approximately 22 breeding adults. The environments studied were the classic temperate-wet and cold-dry climates of Park (1954) in factorial combination with two genetic strains of a congeneric competitor, T. confusum. Much among-lineage genetic variation for rate of population increase was found for each of these ecologically important environments of climate and competition. Genotype-environment interaction accounted for 40.5% of the total among-lineage variance in rate of population increase signifying that the performance of a lineage in one environment is not necessarily a good predictor of its performance in another. Changing the genetic identity of the competitor changed the rate of increase of some lineages as much or more than changing the climatic conditions of temperature and humidity. This is the first empirical study to characterize the genotype-environment interaction variance associated with genetic variation in a competing congeneric species. This competitor-specific genetic variation in competitive ability may play an important role in coevolution in subdivided populations. PMID- 28564432 TI - ALLOZYME DIVERGENCE WITHIN THE BOVIDAE. AB - We describe a phylogeny of the Bovidae based on 40 allozyme loci in 27 species, representing 10 of the 14 bovid tribes described by Vrba (1985). Giraffe represented a related family (Giraffidae). A phenogram was derived using the unweighted pair-group method with arithmetic means (UPGMA), based on Nei's genetic distances (ND) between species. A tree was also derived using the neighbor-joining technique, also based on ND. To provide a cladistic interpretation, the data were analyzed by a maximum parsimony method (phylogenetic analysis using parsimony, PAUP). We found marked divergence within the Bovidae, consistent with the appearance of the family in the early Miocene. Unexpectedly, the most divergent species was the impala, which occupied a basal position in all trees. Species in the tribe Alcelaphini were the most derived taxa in all trees. These patterns conflict strongly with the previous taxonomic alliance, based on immuno-distance and anatomical evidence, of the impala as a sister group of the Alcelaphini. All trees agreed that tribes described by Vrba (1985) are monophyletic, except the Neotragini, which was polyphyletic, with suni occupying a long branch by itself. The dikdik and klipspringer were consistently placed as sister taxa to species in the Antilopini. Three tribes (Aepycerotini, Tragelaphini and Cephalophini), whose fossils have not been found outside Africa, were basal in all trees, suggesting that bovids originated in Africa. Nodes connecting the remaining tribes were closely clustered, a pattern that agrees with fossil evidence of rapid divergence within the Bovidae in the mid-Miocene (about 15 mybp). The allozyme data suggested a second phase of rapid divergence within tribes during the Plio-Pleistocene, a pattern that also agrees with fossil evidence. Rates of bovid divergence have therefore been far from constant. However, the clustering of nodes imparts considerable uncertainty to the branching order leading to the derived tribes, and to a lesser extent, species within tribes. The classical division of the Bovidae into the Boodontia and Aegeodontia does not agree with the phylogenetic grouping of tribes presented in this analysis. However, the maximum parsimony tree derived using 'local' branch swapping clustered all grazing species into a derived, monophyletic group, suggesting that grazing may have evolved only once in bovid evolution. PMID- 28564433 TI - PHYLOGENY AND THE EVOLUTION OF HOST PLANT ASSOCIATIONS IN THE LEAF BEETLE GENUS OPHRAELLA (COLEOPTERA, CHRYSOMELIDAE). AB - Species of Ophraella, a North American genus of leaf beetles (Chrysomelidae), feed variously on eight genera in four tribes of Asteraceae. A phylogenetic analysis, based on morphological features and allozymes, was undertaken to deduce the history of host affiliation within the genus. The two data sets are combined to arrive at a provisional phylogeny of the species, onto which host associations are parsimoniously mapped. Among and within the 12 species studied, at least two shifts are postulated to have occurred among congeneric plant species, five between genera in the same tribe, and four between different tribes of Asteraceae. The phylogeny of Ophraella appears not to be congruent with that of its hosts. This and other evidence indicates that many host shifts in Ophraella postdate the divergence of the host plants, a conclusion that may apply commonly to phytophagous insects. A phenetic analysis of the plants' secondary compounds provides modest support for the hypothesis that host shifts are facilitated by commonalities in plant chemistry. A possible trend in host shifts is evident, from chemically simpler to chemically more forbidding plants. The chemical barriers to host shifts in Ophraella appear to require adaptation in both behavior and in physiological attributes. There is no evidence that the host associations of these insects or the divergence in secondary chemistry of their hosts can be attributed to coevolution. PMID- 28564434 TI - THE CAUSES OF NATURAL SELECTION. AB - We discuss the necessary and sufficient conditions for identifying the cause of natural selection on a phenotypic trait. We reexamine the observational methods recently proposed for measuring selection in natural populations and illustrate why the multivariate analysis of selection is insufficient for identifying the causal agents of selection. We discuss how the observational approach of multivariate selection analysis can be complemented by experimental manipulations of the phenotypic distribution and the environment to identify not only how selection is operating on the phenotypic distribution but also why it operates in the observed manner. A significant point of departure of our work from recent discussions is in regard to the role of the environment in the study of natural selection. Instead of viewing the environment as a source of unwanted variation that obscures the relationship between phenotype and fitness, we view fitness as arising from the interaction of the phenotype with the environment. The biotic and abiotic environment is the context that gives rise to the relationship between phenotype and fitness (selection). The analysis of the causes of selection is in essence a problem in ecology. The experimental study of the association between selection gradients and environmental characteristics is necessary to identify the agents of natural selection. We recommend research methods for identifying the agency of selection that depend upon a reciprocity between the observational approach of multivariate selection analysis and the manipulative approach of field experiments in evolutionary ecology. PMID- 28564435 TI - EVOLUTION OF OBLIGATE SIBLICIDE IN BOOBIES. 2: FOOD LIMITATION AND PARENT OFFSPRING CONFLICT. AB - Proximate limitation on parental food delivery has long been invoked to explain the evolution of single-chick broods of pelagic seabirds such as masked boobies (Sula dactylatra). A second possible proximate limit on brood size is siblicide driven by genetic parent-offspring conflict (POC) over brood size, if siblicidal offspring can reduce brood size to one even if the parents' optimal brood size is greater than one. I tested these two hypotheses by experimentally suppressing obligate siblicide in masked booby broods and comparing breeding parameters of these broods with unmanipulated single-chick control broods. Per capita mortality rate of experimental nestlings was higher than that of controls, but this deficit was more than made up by larger brood size. Parents of experimental broods brought more food to offspring, had higher fledging success, and apparently incurred no additional major short-term cost of reproduction, relative to parents of control broods, thus refuting the food limitation hypothesis. Estimates of inclusive fitness of chicks in experimental broods were higher than were those of control nestlings, a result inconsistent with the POC hypothesis that the siblicidal offspring's optimal brood size is one while the parents' optimum is greater than one. This discrepency between natural brood size and apparent brood size optima might be resolved in several ways: experimental artifacts may give misleading estimates of optimal brood size; experimental and control offspring may have different reproductive values at the time of fledging; nestling masked boobies may face a special frequency-dependent case of POC in which the high risk of sharing a nest with a siblicidal sibling makes invasion of other behavioral genotypes difficult even when offspring and parent inclusive fitnesses are higher from a nonsiblicidal brood of two than from a brood of one. PMID- 28564436 TI - RESISTANCE OF GENETIC CORRELATION STRUCTURE TO DIRECTIONAL SELECTION IN DROSOPHILA MELANOGASTER. AB - The genetic covariance and correlation matrices for five morphological traits were estimated from four populations of fruit flies, Drosophila melanogaster, to measure the extent of change in genetic covariances as a result of directional selection. Two of the populations were derived from lines that had undergone selection for large or small thorax length over the preceding 23 generations. A third population was constituted using flies from control lines that were maintained with equivalent population sizes as the selected lines. The fourth population contained flies from the original cage population from which the selected and control lines had been started. Tests of the homogeneity of covariance matrices using maximum likelihood techniques revealed significant changes in covariance structure among the selected lines. Prediction of base population trait means from selected line means under the assumption of constant genetic covariances indicated that genetic covariances for the small population differed more from the base population than did the covariances for the large population. The predicted small population means diverged farther from the expected means because the additive genetic variance associated with several traits increased in value and most of the genetic covariances associated with one trait changed in sign. These results illustrate that genetic covariances may remain nearly constant in some situations while changing markedly in others. Possible developmental reasons for the genetic changes are discussed. PMID- 28564437 TI - SYSTEMATICS AND POPULATION GENETICS OF FIRE ANTS (SOLENOPSIS SAEVISSIMA COMPLEX) FROM ARGENTINA. AB - Specimens of seven fire ant species collected from their native ranges in Argentina were studied by protein electrophoresis and morphological analysis. Concordance between the genetic and morphological character sets is strong (96% agreement on identifications), suggesting that recognition of reproductively isolated populations and partitioning of intra- and interspecific variation can in most cases be achieved using appropriate characters of either type in this taxonomically difficult group. Genetic differentiation between native (Argentina) and introduced (USA) conspecific populations of two species, Solenopsis invicta and S. richteri, is rather typical of the differentiation existing between conspecific populations found within either country. Furthermore, there appears to have been little reduction of variability (heterozygosity) at enzyme loci following colonization by either species of the United States, although some rare alleles have been lost in the introduced populations. Hybridization is rare between S. invicta and S. richteri where their native ranges overlap in central Argentina, in contrast to the extensive hybridization of these species in the United States, suggesting that prezygotic barriers to gene flow have been compromised in introduced populations. Phylogenetic analysis of the seven species indicates that S. invicta and S. richteri are relatively distantly related within the S. saevissima complex. Given that hybrids between these species in the United States suffer little apparent loss of fitness, genomic incompatibilities generally may be insufficient to create effective postzygotic barriers to interspecific gene flow in this group of ants. PMID- 28564438 TI - INBREEDING EFFECTS IN CLARKIA TEMBLORIENSIS (ONAGRACEAE) POPULATIONS WITH DIFFERENT NATURAL OUTCROSSING RATES. AB - Inbreeding depression is commonly observed in natural populations. The deleterious effects of forced inbreeding are often thought to be less pronounced in populations with self-pollinating mating systems than in primarily outcrossing populations. We tested this hypothesis by comparing the performance of plants produced by artificial self- and cross-pollination from three populations whose outcrossing rate estimates were 0.03, 0.26, and 0.58. Outcrossing rates and inbreeding coefficients were estimated using isozyme polymorphisms as genetic markers. Analysis of F statistics suggests that biparental inbreeding as well as self-fertilization contribute to the level of homozygosity in the seed crop. Biparental inbreeding will reduce the heterozygosity of progeny produced by outcrossing, relative to random outcrossing expectations, and hence will reduce the effects of outcrossing versus self-fertilization. Heterotic selection may increase the average heterozygosity during the life history. Selfed and outcrossed seeds from all three populations were equally likely to germinate and survive to reproduce. However, inbreeding depression was observed in fecundity traits of plants surviving to reproduction in all three populations. Even in the population whose natural self-fertilization rate was 97%, plants grown from seed produced by self-pollination produced fewer fruits and less total seed weight than plants grown from outcrossed seed. There was no detectable inbreeding depression in estimated lifetime fitness. Inbreeding effects for all reproductive yield characters were most severe in the accession from the most outcrossing population and least severe in the accession from the most self-fertilizing population. PMID- 28564439 TI - THE INTERACTION OF BEHAVIORAL AND MORPHOLOGICAL CHANGE IN THE EVOLUTION OF A NOVEL LOCOMOTOR TYPE: "FLYING" FROGS. AB - "Flying" frogs have evolved independently several times among anurans. In all cases flyers are distinguished from their nonflying arboreal relatives by a unique set of morphological features and behavioral postures. Using both live animal field tests and wind tunnel models, this study examines the importance of this characteristic morphology and limb position on five aerial performance variables: horizontal traveling distance, minimum glide speed, maximum time aloft, maneuverability, and stability. Comparison of relative performance between a model frog with a generalized nonflying morphology and limb position and a model frog with flying morphology and limb position reveals that the morphological and positional features associated with "flying" actually decrease horizontal traveling distance but improve maneuverability. This finding suggests that maneuverability rather than horizontal travel may be the key performance parameter in the evolution of "flying" frogs. More generally, this study illustrates that (1) derived morphological and postural features do not necessarily change a suite of performance variables in the same way, and (2) the performance consequences of postural shifts are a function of morphology. These findings indicate that the potential complexity of morphological and behavioral interactions in the evolution of new adaptive types is much greater than previously considered. PMID- 28564440 TI - ALTERED MATING BEHAVIOR IN A CARSONIAN POPULATION OF DROSOPHILA SECHELLIA. AB - Mating behavior was studied in two laboratory populations of Drosophila sechellia and their reciprocal hybrids. The ancestral population was reared on a special medium, optimal for this species, while the derived population was reared on a standard Drosophila food, and underwent a bottleneck while adapting to this new medium, in a manner similar to the "founder-flush" process of Carson (1971). A significant tendency towards mating asymmetry was found, with ancestral females mating significantly less frequently with derived males than derived females with ancestral males. Analysis of hybrids suggested an important role for the male's X chromosome or for a maternal effect. No significant differences were found among parental types for their main female cuticular hydrocarbons, the proportion of courtship spent in various behavioral elements, body weight, or wing length. Significant differences were found in the structure of courtship, male locomotor activity, male cuticular hydrocarbon levels, and male courtship song inter-pulse interval (i.p.i.). None of these differences showed an X-linked effect in the reciprocal hybrids. Hypotheses put forward to explain interspecific mating asymmetries are discussed in the light of these results. PMID- 28564441 TI - ONTOGENETIC STUDIES OF FLORETS IN POA (GRAMINEAE): ALLOMETRY AND HETEROCHRONY. AB - Species distinctions in grasses are based on differences in sizes of parts, particularly floral parts, and on differences in distribution of hairs; both sets of characters are apparently subject to repeated parallel evolution. Developmental studies of florets in the genus Poa reveal that there are only two developmental trajectories for lemma length relative to anther length (a measure of time to maturity): either lemma growth is continuous with anther growth, or the lemma reaches its adult size well before the anthers do. The tuft of long, cobweb-like hairs on the callus of many species forms early in lemma development, as might be expected for a character that marks a large group of species. The five possible patterns of hair distribution on the lemma itself represent stages of a single developmental pathway; differences between species presumably reflect differences in timing of onset or truncation of the developmental program (heterochrony). PMID- 28564442 TI - TWO NEUTRALITY TESTS OF Y-LINKED RDNA VARIATION IN DROSOPHILA MELANOGASTER. AB - The evolutionary significance of Y-chromosomal ribosomal DNA sequence variation was tested by two different means. A single sample of males and females was collected from a peach orchard in central Pennsylvania. Wild-caught males and sons of wild-caught, wild-inseminated females were crossed to virgin females having an X-linked rDNA deficiency. Genomic DNA from male progeny of these crosses was extracted and digested with the single restriction endonuclease, DraI. Southern blots of these digestions, when probed with the complete rDNA probe, revealed 10 distinct patterns of restriction fragments. A chisquare test for the homogeneity of the frequency distributions of the sample of wild males and sons of wild females failed to reject a neutral null hypothesis. The allele frequency configuration was tested with the Ewens-Watterson test, and the departure from the infinite alleles neutral model was not significant. Simulations were performed to test the sensitivity of the tests to misclassification and to quantify the power of the two tests. PMID- 28564443 TI - THE EFFECT OF DISTANCE FROM THE PARENTAL SITE ON OFFSPRING PERFORMANCE AND INBREEDING DEPRESSION IN IMPATIENS CAPENSIS: A TEST OF THE LOCAL ADAPTATION HYPOTHESIS. AB - If microgeographic variation in selection within a natural plant population has resulted in local adaptation, then offspring fitness should decline with distance from the parental site. If outcrossed progeny are less well-adapted to the parental environment than inbred progeny, but perform better in environments different from that of the parent, then the fitness of inbred progeny relative to outcrossed progeny should decrease with dispersal distance from the parent. To test these predictions, we collected seedlings at 10-m intervals from a 40 times 40-m permanent grid in a natural population of Impatiens capensis, grew them in a greenhouse, and crossed them to produce outcrossed chasmogamous seeds. Seedlings from outcrossed chasmogamous and self-fertilized cleistogamous seeds were planted back into the source population in the original site of their maternal parents and in arcs 3 and 12 m from the parental location and censused weekly for survival and reproduction. The fitness of inbred offspring declined significantly and the magnitude of observed inbreeding depression increased with distance from the parental site, supporting the local adaptation hypothesis. PMID- 28564444 TI - THE EVOLUTIONARY SIGNIFICANCE OF HYBRIDIZATION IN EUCALYPTUS. PMID- 28564445 TI - SYMMETRY, LOCOMOTION, AND THE EVOLUTION OF AN ANTERIOR END: A LESSON FROM SEA URCHINS. AB - Bilaterally symmetrical, "regular" sea urchins in the Family Echinometridae (Class Echinoidea; Phylum Echinodermata) were found to lack a locomotor anterior. Heterocentrotus mammillatus and Echinometra mathaei were observed while locomoting. Members of both ellipsoidal species were found to proceed with their short or long axis foremost with statistically equivalent frequencies. This finding demonstrates that the evolution of bilateral symmetry is not always accompanied by the evolution of a locomotor "anterior" end. The elliptical echinometrid sea urchins provide a particularly appropriate study group for investigating the relationship between the evolution of body form and locomotor behavior. Although the radially symmetrical regular sea urchins, from which the echinometrids sprang, lack a locomotor anterior, all "irregular" echinoids, which are also derived from a regular ancestor but are bilaterally symmetrical, possess an "obligate" locomotor anterior. The symmetry and behavior exhibited by the elliptical echinometrid sea urchins therefore demonstrates that the first irregular echinoids (which exhibit bilateral symmetry by definition) need not have possessed a locomotor anterior as they do today. PMID- 28564446 TI - EVOLUTION AND DEVELOPMENT OF BODY SIZE AND CELL SIZE IN DROSOPHILA MELANOGASTER IN RESPONSE TO TEMPERATURE. AB - We examined the evolutionary and developmental responses of body size to temperature in Drosophila melanogaster, using replicated lines of flies that had been allowed to evolve for 5 yr at 25 degrees C or at 16.5 degrees C. Development and evolution at the lower temperature both resulted in higher thorax length and wing area. The evolutionary effect of temperature on wing area was entirely a consequence of an increase in cell area. The developmental response was mainly attributable to an increase in cell area, with a small effect on cell number in males. Given its similarity to the evolutionary response, the increase in body size and cell size resulting from development at low temperature may be a case of adaptive phenotypic plasticity. The pattern of plasticity did not evolve in response to temperature for any of the traits. The selective advantage of the evolutionary and developmental responses to temperature is obscure and remains a major challenge for future work. PMID- 28564447 TI - THE EFFECTS OF KINSHIP ON GROWTH AND DEVELOPMENT IN TADPOLES OF RANA CASCADAE. PMID- 28564448 TI - EVIDENCE FOR RESTRICTED GENE FLOW IN THE VIVIPAROUS CORAL SERIATOPORA HYSTRIX ON AUSTRALIA'S GREAT BARRIER REEF. AB - Viviparous, branching corals such as Seriatopora hystrix are expected to generate most recruits through asexual reproduction (fission or fragmentation) but are expected to use sexual reproduction to produce widely dispersed colonists. In this study, allozyme electrophoresis was used to test for variation in the relative contributions of sexual and asexual reproduction to recruitment and to assess the apparent scale of larval dispersal (gene flow) in the central Great Barrier Reef. Fifty-seven collections (within <= 25 m2 ) of fragments from sets of approximately 40 colonies were made (where possible) within each of five habitats on each of 12 reefs. These reefs, within the central region of the Great Barrier Reef, were separated by up to 90 km and included one inner-shelf continental island and groups of seven midshelf reefs and four outer-shelf reefs. Most collections contained a high level of multilocus genotypic diversity and hence showed little evidence of recruitment through fragmentation, although the majority of collections displayed large and consistent deficits of heterozygotes. Allele frequencies varied greatly among collections (FST = 0.43), and this variation was sufficient to explain two-thirds of observed deficiencies of heterozygotes via a Wahlund effect. A hierarchical assessment of FST values revealed that 45% of allelic variation occurred among reefs (FST = 0.20), and only 16% of variation within reefs was explained by variation among five major habitat types (FST = 0.05). A relatively small component of the total variation among samples was attributable to across-shelf variation among the groups of middle- and outer-shelf reefs (FST = 0.03); however, the outer-shelf reefs form a single UPGMA cluster separate from all but 4 of the other 43 collections. These data imply that widespread dispersal does occur but that the direction or magnitude of gene flow may be influenced by the along-shelf movement of major ocean currents and weather-dependent currents on or near reefs. Each reef, therefore, forms a partially isolated and highly subdivided population. PMID- 28564449 TI - GENE GENEALOGY AND DIFFERENTIATION AMONG ARBOREAL SPINY RATS (RODENTIA: ECHIMYIDAE) OF THE AMAZON BASIN: A TEST OF THE RIVERINE BARRIER HYPOTHESIS. AB - Sequence variation in the mitochondrial cytochrome b gene was examined in the arboreal spiny rat, Mesomys hispidus, collected at 15 sites along the Rio Jurua in western Amazonia, Brazil, to determine the importance of riverine barriers in the diversification of this taxon. Twenty individual haplotypes were uncovered, most of which were unique to single localities but some of which were shared among adjacent sites either along or across the river. Genealogical analyses suggest that gene flow is limited and, in combination with the unique distribution of most haplotypes, suggest that populations of this species are strongly substructured along the river. Thus, most sharing of haplotypes between adjacent localities is probably caused by historical association rather than to ongoing gene flow. Two haplotype clades were uncovered, but these correspond to headwaters versus mouth areas, not to opposite sides of the river, as would be expected by the Riverine Barrier Hypothesis. Moreover, haplotype sharing across the river was greater at its mouth than in the headwaters, a pattern opposite that expected if the river were a substantive barrier. Broader scale phylogeographic patterns of this species show that both clades have relationships to areas well outside the Rio Jurua basin. This suggests that the basin represents a relatively recent point of invasion between two more broadly distributed and differentiated geographic units of the species. PMID- 28564450 TI - ADAPTIVE DISTANCE AND THE GENETIC BASIS OF HETEROSIS. PMID- 28564451 TI - HISTORICAL BIOGEOGRAPHY OF THE BANANAQUIT (COEREBA FLAVEOLA) IN THE CARIBBEAN REGION: A MITOCHONDRIAL DNA ASSESSMENT. AB - We analyzed mitochondrial DNA (mtDNA) restriction-site variation in bananaquit (Coereba flaveola; Aves, Coerebinae) populations sampled on 12 Caribbean islands and at 5 continental localities in Central America and northern South America. Multiple fixed restriction-site differences genetically defined several regional bananaquit populations. An mtDNA clade representing all Jamaican bananaquits was the most divergent; the estimated average sequence divergence (dxy ) between Jamaican and all other mtDNA haplotypes surveyed was 0.027. Three groups of populations, representing Central America, northern South America, and the eastern Antilles (Puerto Rico to Grenada) were nearly equally differentiated among themselves (average dxy = 0.014), and may represent a single, recent range expansion. Within the eastern Antilles, three geographically restricted haplotype groups were identified: Puerto Rico, north-central Lesser Antilles (U.S. Virgin Islands to St. Lucia), and Grenada-St. Vincent. The evolutionary relationships of these groups were not clear. Genetic homogeneity of the island populations from the U.S. Virgin Islands to St. Lucia suggested a recent spread of a specific north-central Lesser Antillean haplotype through most of those islands. Haplotype variation across this region indicated that this spread may have occurred in two waves, first through the southernmost islands of St. Lucia, Martinique, and Dominica, and more recently from Guadeloupe to the north. The geographic distribution of mtDNA haplotypes, and of bananaquit populations, suggests periods of invasiveness followed by relative geographic quiescence. Although most genetic studies of bird populations have revealed homogeneity over large geographic areas, our findings provide a remarkable counterexample of strong geographic structuring of mtDNA variation over relatively small distances. Furthermore, although the mtDNA data were consistent with several subspecific distinctions, it was clear that named subspecies do not define equally differentiated evolutionary entities. PMID- 28564452 TI - COMPARATIVE EVOLUTIONARY ANALYSIS OF METABOLISM IN NINE DROSOPHILA SPECIES. AB - To attain balanced and efficient metabolism, the genes encoding enzymes involved in intermediary metabolism must be coordinately regulated. Gross misregulation of these genes can result in deleterious metabolic imbalances, as seen in transgenic laboratory organisms with altered gene dosage. By quantifying the expression of enzymes in nine related species of Drosophila, we hoped to see patterns of coordinated changes that could be related to evolutionary constraints on regulation. The storage pools of triacylglycerols and glycogen were measured, and the activities of 12 enzymes in intermediary metabolism were also quantified. When these phenotypes were placed on the phylogeny of the Drosophila species, quantitative cladistic hypotheses could be tested. The method of independent phylogenetic contrasts provides a formal statistical test of the null hypothesis that phenotypic changes of pairs of characters on a phylogenetic tree are independent. For example, G6PD and 6PGD exhibited a wide range of activity variation among species, and interspecific comparisons suggested significant coregulation. Significant coordinated changes among clades of the Drosophila phylogeny were also seen for 6PGD-malic enzyme, glycogen synthase-fatty acid synthase, G6PD-GPDH, and 6PGD-glycogen synthase, which in most cases exhibited positive intraspecific genetic correlation. This was to be contrasted with the relation between fatty-acid synthesis and fat storage, which exhibits a strong positive correlation within D. melanogaster but no significant interspecific correlation. Limitations of inferring evolutionary constraints by contrasting intraspecific phenotypic variation to interspecific divergence are briefly discussed. PMID- 28564453 TI - MULTIPLE COLONIZATIONS OF ASPLENIUM ADIANTUM-NIGRUM ONTO THE HAWAIIAN ARCHIPELAGO. AB - The extreme isolation and mid-Pacific origin of the Hawaiian archipelago has ensured that all indigenous organisms have arrived via long-distance dispersal or have evolved from successfully colonizing species. Although this isolation has also produced high rates of species endemism in angiosperms (89% or more), that rate in pteridophytes is considerably less (76%). The ratio of native species to the estimated number of original successful colonizing species in angiosperms (3.4) is more than double that for pteridophytes (1.6). One possible explanation for the lower speciation rate in pteridophytes is that populations of these species are more likely to experience interpopulational gene flow because of the great vagility of their wind-dispersed spores. We conducted isozymic surveys of populations from the island of Hawaii of the indigenous allotetraploid species Asplenium adiantum-nigrum, putatively derived from two strictly European diploid taxa. Our data support multiple hybrid origins for the populations surveyed, with a minimum of 3, and possibly as many as 17, discrete hybridization events having produced the genetic diversity observed. Since the parental taxa are not found in Hawaii, each hybrid lineage must have arrived in the archipelago independently of the others. Similar long-distance, repeated dispersal events may be occurring between insular and noninsular populations of other native pteridophytes in Hawaii and in other insular regions of the world, thus contributing to the relatively low rates of speciation and insular endemism in this ancient group of plants. PMID- 28564454 TI - INBREEDING DEPRESSION IN PARTIALLY SELF-FERTILIZING DECODON VERTICILLATUS (LYTHRACEAE): POPULATION-GENETIC AND EXPERIMENTAL ANALYSES. AB - Inbreeding depression is a major selective force favoring outcrossing in flowering plants. Some self-fertilization, however, should weaken the harmful effects of inbreeding by exposing genetic load to selection. This study examines the maintenance of inbreeding depression in partially self-fertilizing populations of the long-lived, herbaceous wetland plant, Decodon verticillatus (L.) Ell. (Lythraceae). Estimates from ten populations indicate that 30% of offspring are produced through self-fertilization. Population-genetic estimates of inbreeding depression (delta = 1 - relative mean fitness of selfed progeny) based on changes in the inbreeding coefficient for the same ten populations were uniformly high, ranging from 0.49 to 1.79 and averaging 1.11 +/- 0.29 SE. Although confidence intervals of individual population estimates were large, estimates were significantly greater than 0 in six populations and greater than 0.5 in four. Inbreeding depression was also estimated by comparing growth, survival, and flowering of experimentally selfed and outcrossed offspring from two of these populations in a 1-yr glasshouse experiment involving three density regimes; after which offspring were transplanted into garden arrays and two field sites and monitored for two consecutive growing seasons. Overall delta^ for survival averaged 0.27 +/- 0.01 in the glasshouse, 0.33 +/- 0.04 in the garden, and 0.46 +/- 0.04 in the field. The glasshouse experiment also revealed strong inbreeding depression for growth variables, especially above-soil dry weight (delta^ = 0.42 +/- 0.03). The fitness consequences of inbreeding depression for these growth variables approximately doubles if survival to maturity is determined by severe truncation selection. Despite substantial selfing, inbreeding depression appears to be a major selective force favoring the maintenance of outcrossing in D. verticillatus. PMID- 28564455 TI - THE EVOLUTION OF PLUMAGE BRIGHTNESS IN BIRDS IS RELATED TO EXTRAPAIR PATERNITY. AB - A positive association between plumage brightness of male birds and the degree of polygyny may be the result of sexual selection. Although most birds have a socially monogamous mating system, recent paternity analyses show that many offspring are fathered by nonmates. Extrapair paternity arises from extrapair copulations which are frequently initiated by females. Not all females will be able to mate with a male of the preferred phenotype, because of the mating decisions of earlier paired females; extrapair copulations may be a means for females to adjust their precopulation mate choice. We use two comparative analyses (standardized linear contrasts and pairwise comparisons between closely related taxa) to test the idea that male plumage brightness is related to extrapair paternity. Brightness of male plumage and sexual dimorphism in brightness were positively associated with high levels of extrapair paternity, even when potentially confounding variables were controlled statistically. This association between male brightness and extrapair paternity was considerably stronger than the association between male brightness and the degree of polygyny. Cuckoldry thus forms an important component of sexual selection in birds. PMID- 28564456 TI - EVOLUTION OF THE PYGMY-FOREST EDAPHIC SUBSPECIES OF PINUS CONTORT A ACROSS AN ECOLOGICAL STAIRCASE. AB - Patterns of allozyme variation within and between two of the subspecies of Pinus contorta were examined for the evolutionary relationship between them. In coastal northern California, these subspecies are parapatric. Pinus contorta ssp. contorta occurs on grassy coastal bluffs on the lowest and youngest of a sequence of five marine terraces; P. contorta ssp. bolanderi is endemic to a pygmy forest ecosystem that occurs on the increasingly older and harsher soils of the third, fourth, and fifth terraces. The soils of the upper three terraces are characterized by extreme podzolization, low pH, low nutrient availability, summer drought (with periodic fires), and winter surface flooding above the hardpan. Dune and cliff soils support a tall redwood and Douglas-fir forest between the terraces. Analyses of seeds collected from 11 pygmy-forest and 6 coastal populations showed ssp. bolanderi to have significantly less allozyme variation than spp. contorta. The two subspecies did not show the phylogenetic dichotomy in allozyme allelic constitutions expected for subspecific classification. Within ssp. bolanderi, the pattern of genetic distances correlated better with edaphic differences among sites than with geographic distance. It appears that ssp. bolanderi is a recently evolved derivative of ssp. contorta, and that the low degree of allozyme differentiation among the bolanderi populations may be due to colonization of the sites by small numbers of individuals, or to hitchhiking of allozyme loci linked to loci undergoing strong selection imposed by the severe edaphic conditions typical of bolanderi sites. PMID- 28564457 TI - LONG-TERM LABORATORY EVOLUTION OF A GENETIC LIFE-HISTORY TRADE-OFF IN DROSOPHILA MELANOGASTER. 2. STABILITY OF GENETIC CORRELATIONS. AB - Experiments in laboratory populations of Drosophila melanogaster have shown a negative genetic correlation between early-life fecundity on the one hand and starvation resistance and longevity on the other. Selection for late-life reproductive success resulted in long-lived populations that had increased starvation resistance but diminished early-life fecundity relative to short-lived controls. This pattern of differentiation proved, however, to be unstable. When assayed in a standard high-fecundity environment, the relative early fecundity of the long- and short-lived stocks reversed over a decade. That is, the long-lived populations came to have greater relative early-life fecundity, late-life fecundity, longevity and starvation resistance. Nevertheless, when these populations were assayed in other assay environments, the original trade-off was still present. We investigated the genetic structure of the short- and long-lived populations, to ask whether the inconstancy of the trade-off, as inferred from among population comparisons, is reflected in the pattern of genetic correlations within populations. For this purpose, lines from each of the short- and long lived populations that had been selected for starvation resistance were compared with unselected controls. The direct and correlated responses of these starvation selected populations suggest that (1) the original genetic trade-off was still present in the ancestral short- and long-lived populations, even when it was no longer apparent from their comparison; (2) the trade-off was present in both assay environments; and (3) selectable genotype * environment variation exists for early fecundity. We suggest that a failure of the pattern of differentiation among populations to reflect the pattern of genetic correlations, if common in natural populations, will prevent the reliable inference of genetic trade-offs from comparisons of most natural populations. PMID- 28564458 TI - POSTDISPERSAL SIBLING COMPETITION AND THE EVOLUTION OF SINGLE-SEEDEDNESS IN CRYPTANTHA FLAVA. PMID- 28564459 TI - WHEN MORPHOLOGY MISLEADS: INTERPOPULATION UNIFORMITY IN SEXUAL SELECTION MASKS GENETIC DIVERGENCE IN HARLEQUIN BEETLE-RIDING PSEUDOSCORPION POPULATIONS. AB - Differences in secondary sexual characteristics of males often provide the most conspicuous means of distinguishing between closely related species. Does this therefore imply that the absence of differentiation in exaggerated male traits between allopatric populations provides evidence of a single, genetically cohesive species? We addressed this question with a comprehensive investigation of two populations (French Guiana and Panama) of the harlequin beetle-riding pseudoscorpion, Cordylochernes scorpioides. This highly sexually dimorphic pseudoscorpion is currently described as a single species, ranging throughout the Neotropics. Our morphometric analyses detected minimal differentiation between the two populations in all nine external morphological characters measured, including sexually dimorphic traits in males. Only in traits of the spermatophore was there any appreciable level of differentiation. Behavior differentiation and prezygotic reproductive isolation were also limited: 78.3% of males successfully transferred sperm to "foreign" females, and in 63.9% of these cases, females' eggs were successfully fertilized. By contrast, extensive divergence existed in two of nine electrophoretic loci, including an essentially fixed-allele difference at the Ldh locus. Most significantly, postzygotic reproductive isolation was complete, with heteropopulation zygotes invariably aborting early in development. These results strongly suggest that the two populations are, in fact, sibling species, a conclusion supported by our recently published findings on their marked divergence in minisatellite DNA. How can such interpopulation homogeneity in male sexually dimorphic traits exist in the face of strong genetic divergence? We propose that sexual selection, oscillating between favoring small and then large males, maintains such high levels of male variability within each population that it has obscured a speciation event in which genetic divergence and postzygotic incompatibility have clearly outpaced the evolution of prezygotic reproductive isolation. PMID- 28564460 TI - ENCAPSULATION OF EGGS BY MARINE GASTROPODS: EFFECT OF VARIATION IN CAPSULE FORM ON THE VULNERABILITY OF EMBRYOS TO PREDATION. AB - Representatives of many plant and animal taxa enclose their embryos within some form of protective structure. Inter- and intraspecific differences in the morphology of these egg coverings may have profound effects on the development and survival of encapsulated embryos, yet in many taxa little is known about the causes or potential consequences of this variation. Comparisons of capsule morphology among populations of the rocky shore gastropod, Nucella emarginata, revealed significant variation in the thickness of capsule walls, the only barrier separating developing embryos from the external environment. Laboratory experiments demonstrated that thicker-walled capsules were more resistant to predation by a co-occurring isopod, Gnorimosphaeroma oregonense, than were thinner-walled capsules. Control experiments confirmed that these differences in vulnerability were not caused by differences in the palatability of the capsule wall or attractiveness of the capsule contents. The actual mechanism by which thick-walled capsules differentially protect developing embryos remains unclear, although decreased vulnerability of thick-walled capsules to these isopods may simply result from increased handling time by predators. Subtle differences in capsule morphology thus appear to have substantial effects on the survival of encapsulated embryos. Hence, predators may have played an important role in selecting for the production of thick-walled capsules among populations of N. emarginata. PMID- 28564461 TI - TRANSPOSON ABUNDANCE IN SEXUAL AND ASEXUAL POPULATIONS OF CHLAMYDOMONAS REINHARDTII. PMID- 28564462 TI - EVIDENCE FOR LONG-DISTANCE POLLEN DISPERSAL IN MILKWEEDS (ASCLEPIAS EXALTATA). AB - We investigated pollen-mediated gene flow and interspecific matings in natural populations of poke milkweed, Asclepias exaltata. Genetic data from 16 polymorphic isozymes allowed unambiguous identification of the diploid paternal genotype for 225 singly sired fruits collected from six populations in Shenandoah National Park, Virginia. Paternity analysis of progeny arrays revealed that 29% 50% (39.2%, mean) of the seeds produced in these populations were sired by plants located outside each target population. Variation among populations appears to be related to isolation distance (Kendall's tau = -0.69, N = 6, P > 0.1), although the negative correlation was statistically significant only when the results from a previous study of A. exaltata were also included in the analysis (Kendall's tau = -0.78, N = 7, P < 0.05). The coupling of standard paternity exclusion analysis on individual seeds (12 seeds/fruit) with estimation of cryptic gene flow from Monte Carlo simulations accounted for only 65% of the gene flow detected using the progeny-array analysis. These results suggest that standard paternity exclusion, incorporating cryptic gene flow, will inherently underestimate actual gene flow rates when the number of paternal parents is smaller than the number of seeds per fruit (i.e., matings are correlated). Indirect estimates of the number of migrants per generation (Nm ~ 2.3) obtained from Nei's genetic diversity statistic (GST ) are much smaller than realized gene flow measured in 1990 (Nm = 9.4, progeny-array method). In addition, interspecific hybridization with common milkweed, Asclepias syriaca, via long-distance pollen dispersal was detected in two fruits (0.8%). Thus, pollen-mediated gene flow and infrequent interspecific matings provide mechanisms to lower genetic differentiation among populations to maintain novel, low-frequency alleles within populations of A. exaltata. PMID- 28564463 TI - EVOLUTIONARY ADAPTATION TO TEMPERATURE. III. ADAPTATION OF ESCHERICHIA COLI TO A TEMPORALLY VARYING ENVIRONMENT. AB - Six lines of the bacterium Escherichia coli were propagated for 2,000 generations in a temporally varying environment. The imposed environmental regime consisted of alternating days at 32 degrees C and 42 degrees C, with rapid transitions between them. These derived lines are competitively superior to their ancestor in this variable temperature regime. We also measured changes in the fitness of these lines, relative to their common ancestor, in both the constant (32 degrees C and 42 degrees C) and transition (from 32 degrees C to 42 degrees C and from 42 degrees C to 32 degrees C) components of this temporally varying environment, to determine whether the bacteria had adapted to the particular constant temperatures or the transitions between them, or both. The experimentally evolved lines had significantly improved fitness in each of the constant environmental components (32 degrees C and 42 degrees C). However, the experimental lines had not improved in making the sudden temperature transitions that were a potentially important aspect of the temporally variable environment. In fact, fitness in making at least one of the transitions (between 32 degrees C and 42 degrees C) unexpectedly decreased. This reduced adaptation to the abrupt transitions between these temperatures is probably a pleiotropic effect of mutations that were responsible for the increased fitness at the component temperatures. Among the six experimental lines, significant heterogeneity occurred in their adaptation to the constant and transition components of the variable environment. PMID- 28564464 TI - HETEROZYGOSITY, AGGRESSION, AND POPULATION FLUCTUATIONS IN MEADOW VOLES (MICROTUS PENNSYLVANICUS). AB - We tested whether variation in heterozygosity could produce cyclic changes in population size in meadow voles (Microtus pennsylvanicus). For this to occur, three conditions must be met: (1) populations are more outbred (heterozygotic) at high than low population density, (2) heterozygotic voles are more aggressive than relatively inbred individuals, and (3) heterozygotic voles have lower reproductive fitness, though being superior at defending resources. We found no evidence that heterozygosity varied with population size or that reproductive success varied with heterozygosity. However, the former test was indirect and relatively weak. We directly measured aggression and heterozygosity of individual voles. Aggression was significantly related to heterozygosity: higher heterozygosity correlated with more aggression in males and less aggression in females. The proportion of variance in aggression that could be explained by heterozygosity was small. These results suggest that changes in population size of meadow voles could not be driven by systematic changes in heterozygosity with population size. PMID- 28564465 TI - THE QUANTITATIVE GENETICS OF SEXUAL DIMORPHISM IN SILENE LATIFOLIA (CARYOPHYLLACEAE). II. RESPONSE TO SEX-SPECIFIC SELECTION. AB - A well-established theoretical relationship exists between genetic correlations between the sexes and the dynamics of response to sex-specific selection. The present study investigates the response to sex-specific selection for two sexually dimorphic traits that have been documented to be genetically variable, calyx diameter and flower number, in Silene latifolia. Following the establishment of a base generation with a known genetic background, selection lines were established and two generations of sex-specific selection were imposed. Calyx diameter responded directly to sex-specific selection, and the positive genetic correlation between the sexes was reflected in correlated responses in the sex that was not the basis for selection within a particular line. Flower number showed a more erratic response to sex-specific selection in that selection in some lines was initially in the wrong direction, that is, selection for a decrease in flower number resulted in an increase. These erratic responses were attributable to genotype-environment interaction as reflected in significant heteroscedasticity in variance among families. Correlated responses to selection in the sex that was not the immediate basis for selection indicated the possible existence of a negative genetic correlation between the sexes for this trait. These results test for the first time the impact of genetic correlations between the sexes on the evolutionary dynamics of sexually dimorphic traits in a plant species. PMID- 28564466 TI - INVERSE RELATIONSHIP BETWEEN FUNCTIONAL MATURITY AND EXPONENTIAL GROWTH RATE OF AVIAN SKELETAL MUSCLE: A CONSTRAINT ON EVOLUTIONARY RESPONSE. AB - In this study, we investigate whether a tissue-level constraint can explain the general inverse relationship between growth rate and precocity of development in birds. On the whole, altricial (dependent) chicks grow three to four times faster than the less dependent, more able chicks of precocial species of similar adult mass. We suggest that an antagonism between growth and acquisition of mature function in skeletal muscle constrains postnatal growth and development in most species of birds. Altricial species, represented by European starlings in this study, hatch with skeletal muscle having low capacity for generating force but grow rapidly. Conversely, precocial species (northern bobwhite quail and Japanese quail), hatch with relatively mature skeletal muscle, especially in their legs, but grow more slowly. As development proceeds in all species, exponential growth rates decrease as muscles acquire adult levels of function. Among four variables associated with muscle function, exponential growth rate (EGR) was negatively correlated with pyruvate kinase activity (glycolysis), potassium concentration (electrical potential), and dry weight fraction (contractile proteins) in both pectoral and leg muscles but not with citrate synthase activity (aerobic metabolism) in either set of muscles. For pectoral muscle, these variables accounted for 87% of the total variation in EGR in all three species combined despite a twofold difference in growth rates between the starling and quail. EGRs of leg muscle (51% of variation accounted for) were less than predicted by the pectoral-muscle equation in quail during the early part of the postnatal period and in starlings during the late postnatal period. This result would not contradict a growth rate/maturity constraint hypothesis if EGRs were down regulated for allometric or other considerations. PMID- 28564468 TI - SEX ALLOCATION IN THE ANT COLOBOPSIS NIPPONICUS (WHEELER). I. POPULATION SEX RATIO. AB - The relative power of queens and workers at controlling sex allocation in the ant Colobopsis nipponicus is investigated in this study. Results show that C. nipponicus completely satisfies Hamilton's assumptions concerning colony social structure: monogyny, monoandry, and no worker reproduction. A genetic survey of the population structure rejects possibilities of local mate competition, local resource enhancement, and local resource competition, which all can bias population-allocation ratios from 0.5. Although these factors are absent, the observed sex-allocation ratio (male investment/total sexual investment; 0.250 +/- 0.027) is significantly biased toward females and is not different from the estimated optimal ratio for workers (0.252). Thus, it appears that workers are likely to win in conflicts over sex allocation with queens. PMID- 28564467 TI - THE SIGNIFICANCE OF GENETIC EROSION IN THE PROCESS OF EXTINCTION. IV. INBREEDING LOAD AND HETEROSIS IN RELATION TO POPULATION SIZE IN THE MINT SALVIA PRATENSIS. AB - If, because of genetic erosion, the level of homozygosity in small populations is high, additional selfing will result in small reductions of fitness. In addition, in small populations with a long inbreeding history selection may have purged the population of its genetic load. Therefore, a positive relationship between population size (or level of genetic variation) and level of additional inbreeding depression, here referred to as inbreeding load, may be expected. In a previous study on the rare and threatened perennial Salvia pratensis, a positive correlation between population size and level of allozyme variation has been demonstrated. In the present study, the inbreeding load in six populations of varying size and allozyme variation was investigated. In the greenhouse, significant inbreeding load in mean seed weight, proportion of germination, plant size, regenerative capacity, and survival was demonstrated. In a field experiment with the two largest and the two smallest populations, survival of selfed progeny was 16% to 63% lower than survival of outcrossed progeny. In addition, survival of outcrossed progeny was, with the exception of the largest population, lower (16% to 37%) than of hybrid progeny, resulting from crosses between populations. Effects on plant size were qualitatively similar to the effects on survival, but these effects were variable in time because of differential survival of larger individuals. In all populations the total inbreeding load, that is, the effects on size and survival multiplicated, increased in time. It was demonstrated that inbreeding load in different characters may be independent. At no time and for no character was inbreeding load or the heterosis effect correlated to the mean number of alleles per locus, indicating that allozyme variation is not representative for variation at fitness loci in these populations. Combined with results of previous investigations, these results suggest that the small populations are in an early phase of the genetic erosion process. In this phase, allozyme variation, which is supposed to be (nearly) neutral, has been affected by genetic erosion but the selectively nonneutral variation is only slightly affected. These results stress the need for detailed information about the inbreeding history of small populations. The relative performance of selfed progeny was lowest in all populations, in the greenhouse as well as in the field, and inbreeding depression could still influence the extinction probabilities of the small populations. PMID- 28564469 TI - GENETICS OF MORTALITY IN THE BEAN BEETLE CALLOSOBRUCHUS MACULATUS. PMID- 28564470 TI - HIERARCHICAL GENETIC STRUCTURE AND GENE FLOW IN MACROGEOGRAPHIC POPULATIONS OF THE EASTERN TENT CATERPILLAR (MALACOSOMA AMERICANUM). AB - Genetic structure and inferred rates of gene flow in macrogeographic populations of the eastern tent caterpillar Malacosoma americanum were analyzed at two hierarchical scales: local demes and regional subpopulations. Wright's F statistics were used to estimate population genetic structure using multilocus genotypic data generated electrophoretically. Estimated values of FST and the distribution of private alleles were then used to obtain indirect estimates of gene flow. We found modest, though significant, genetic structure at both spatial scales, a pattern consistent with high rates of gene flow over the large distances involved. Modest values obtained for Nei's genetic distance also suggested high levels of gene flow across the range of this species, although some gene-flow restriction resulting from isolation by distance was suggested by a positive regression of genetic distance on geographic distance. The observed homogeneity at enzyme loci across the range of M. americanum parallels the reported uniformity in morphology, suggesting a general absence of local genetic differentiation in this widely distributed species. The genetic homogeneity observed in this wide-ranging insect is discussed in terms of organism-specific environmental experience at different spatial scales. Some organisms occupying apparently heterogeneous environments may ameliorate unsuitable local conditions through microhabitat selection or behavioral modification of their microenvironment. This may be accomplished in M. americanum through group shelter construction and behavioral thermoregulation, closely tying thermoregulation to social biology in this species. If in this way the tent helps produce an effectively homogeneous environment for this species across its extensive range, this system may provide a unique example of how social behavior can influence the distribution of genetic variation in a population. PMID- 28564471 TI - SEXUAL SELECTION IN AMERICAN TOADS: A TEST OF A GOOD-GENES HYPOTHESIS. AB - Adaptive mate choice in species lacking male resource control and/or paternal care might be maintained by selection because preferred males sire genetically superior offspring. For such a process to occur, some male phenotypic trait(s) must both reliably indicate male genetic quality and influence the pattern of mate choice by females. In American toads, Bufo americanus, male body length has been documented to influence female mating patterns: females usually mate with males that are larger than average. However, the relationship between male size and male genetic quality is unknown. We conducted a controlled breeding experiment using 48 sires and 19 dams to determine if larger males sire offspring with superior larval performance characteristics (greater survival to metamorphosis, larger mass at metamorphosis, and earlier metamorphosis). We also aged each sire to test the hypothesis that older males are, on average, genetically superior to younger males. We crossed each female with three sires representing three body size categories (mean and 1 SD +/- mean snout-ischium length). Hatchlings (500 from each cross) were reared to metamorphosis in seminatural ponds in the field. Metamorph weight (log transformed) and age at metamorphosis showed significant heritability and were genetically correlated with each other. Hence, sires differed in genetic quality. However, none of the three measures of offspring performance was correlated with sire body size or age. Thus, we obtained no support for the prediction that sire body size or age is related to genetic quality. PMID- 28564472 TI - FOOD PROVISIONING IN RELATION TO REPRODUCTIVE STRATEGY IN ALTRICIAL BIRDS: A COMPARISON OF TWO HYPOTHESES. PMID- 28564473 TI - HYBRIDIZATION AND CHLOROPLAST DNA VARIATION IN A PINUS SPECIES COMPLEX FROM ASIA. AB - Heterologous hybridization of chloroplast DNA (cpDNA) involving 30 endonucleaseprobe combinations was used to analyze cpDNA variation in multiple individuals and populations of Pinus tabulaeformis (Carr.), Pinus yunnanensis (Franchet) and Pinus massoniana (Lamb.). Restriction fragment patterns detected by several combinations distinguished among the three species. The obtained cpDNA markers were subsequently used to examine cpDNA variation of Pinus densata (Masters), a putative tertiary hybrid between P. tabulaeformis and P. yunnanensis. The analysis demonstrated that P. densata populations harbor three different haplotypes. Two of these haplotypes are characteristic of P. tabulaeformis and P. yunnanensis. However, the third haplotype found in P. densata appears to be absent in other extant Asian Pinus species. It is suggested that the observed cpDNA composition of P. densata populations is a result of past hybridization involving P. tabulaeformis, P. yunnanensis, and a third unknown or extinct taxon. Chloroplast DNA polymorphism in P. densata was much greater than that for nuclear allozyme markers in this and the other Pinus species. Population differentiation was also substantial in P. densata and exceeded that for allozyme markers. In contrast, no cpDNA polymorphism was detected in populations of P. tabulaeformis, P. yunnanensis, and P. massoniana. The study suggests that interspecific gene exchange may lead to the creation of stable cpDNA polymorphism in conifer hybrids. PMID- 28564474 TI - BIOCHEMICAL HETEROZYGOSITY AND MORPHOLOGIC VARIATION IN A COLONY OF PAPIO HAMADRYAS HAMADRYAS BABOONS. AB - This analysis examines the association between genetic heterozygosity and individual morphologic variation in a captive population of Papio hamadryas hamadryas consisting of 403 juveniles and adults. The population structure of the colony was artificially generated and maintained and is thus rigorously defined. Subpopulations delimited by age, sex, and degree of inbreeding are also explored. Heterozygosity, as enumerated from six simple Mendelian biochemical loci, is compared with the residual morphologic variation of each individual for each of 20 quantitative traits. Use of a sequential Bonferroni technique nullifies all significant correlations. Principal-components analysis reduces the morphometrics to a single or few significant axes in each population. The first axis of the total population contains 86.07% of the variation in the sample and the absolute values of the factor scores exhibit a significant positive correlation with heterozygosity at P < 0.05. Correcting for age- and sex-related variation in the total population with a linear model subsequently demonstrates that no significant correlation between heterozygosity and morphologic variation exists. No significant relationship is found in the inbred animals or subpopulations when age and sex are controlled. Previous studies have indicated that individuals proximal to the population mean for a specific polygenic trait exhibit a higher biochemical heterozygosity than individuals distant from the mean. The results presented here, which are based on more loci than many studies and a well-defined population, do not support this relationship. Substructuring of a population by age and sex can lead to spurious correlations with univariate or multivariate techniques. Comprehensive indices of genetic variation and rigorous statistical techniques should be used in future analyses. Studies that fail to recognize these design elements should be interpreted with caution. PMID- 28564475 TI - PROVINCIALISM IN PLANKTON: ENDEMISM AND ALLOPATRIC SPECIATION IN AUSTRALIAN DAPHNIA. AB - Zooplankton species are generally considered poor candidates for allopatric speciation because of their broad distributions and capabilities for long distance dispersal. We examined the validity of this conclusion by determining both species distributions and the extent of gene frequency divergence in the Daphnia fauna of southeastern Australia, a mature landscape dominated by members of the carinata complex. Although delimitation of species boundaries was complicated by the prevalence of interspecific hybrids and variation in breeding systems, allozyme analysis of 187 populations indicated the presence of at least seven species. All of these species had restricted distributions, and several were narrowly endemic. Gene frequency divergence was often apparent between populations separated by only a few kilometers but was least prominent in species from inland areas. The extent of regional gene frequency shifts varied among species-two narrowly distributed (projecta, thomsoni) and one broadly distributed (carinata) species showed little divergence between sites, but two other common species (cephalata, longicephala) showed marked gene frequency shifts coincident with physiographic barriers. Together, the limited species distributions and regional gene-pool fragmentation suggest that allopatric speciation has played an important role in the origin of taxon diversity in the Daphnia carinata complex. PMID- 28564476 TI - NATURAL SELECTION AND SEXUAL SIZE DIMORPHISM IN RED-WINGED BLACKBIRDS. AB - Patterns of overwinter mortality in the sexually dimorphic red-winged blackbird (Agelaius phoeniceus) were examined to test the predictions of the sexual selection hypothesis that male size is limited by directional selection favoring small males and that female size is maintained by stabilizing selection wherein extreme phenotypes experience higher mortality. Museum specimens collected from Ontario over a 95-yr period were used to compare the sizes of males and females collected in fall and spring. In a separate field study, body sizes of returning and nonreturning male and female red-winged blackbirds were compared over a 6-yr period. Overall, there was no evidence of higher overwinter mortality among larger males. Among adult (ASY) males, large individuals appeared to have higher survival than small individuals, although among subadult (SY) males, large size may have been disadvantageous. Weak evidence of stabilizing selection on female body size was found. Among adults, sexual size dimorphism seemed more pronounced after winter than before winter. Our results do not support the hypothesis that body size in male red-winged blackbirds is limited by selective mortality outside the breeding season. It is possible that size selection occurs earlier in life, when males are still in the nest. Our results suggest that caution should be exercised when interpreting interspecific evidence showing higher adult male than female mortality in sexually dimorphic species. Such patterns could arise as a cost to males of sexual selection and yet provide no insight into how natural selection opposes sexual selection for increased male size. PMID- 28564477 TI - EVOLUTION OF VEGETATIVE INCOMPATIBILITY IN FILAMENTOUS ASCOMYCETES. I. DETERMINISTIC MODELS. AB - In ascomycetes vegetative incompatibility can prevent the somatic exchange of genetic material between conspecifics. It must occur frequently in natural populations, since in all species studied many vegetative compatibility groups (VCGs) are found. Using a population-genetic approach, this paper explores two possible selective explanations for the evolution of vegetative incompatibility in asexual fungi: selection by a nuclear parasitic gene, and selection by a harmful cytoplasmic element. In a deterministic model, assuming a random spatial distribution of VCGs in an infinitely sized population, it is found that neither of these forms of frequency-dependent selection can explain the large number of VCGs found in nature. The selective pressure for more VCGs disappears once a limited number of VCGs exist, because the frequency of compatible interactions decreases when the number of VCGs increases. In comparing the two selective explanations, selection by a cytoplasmic element seems a more plausible explanation than selection by a nuclear gene. PMID- 28564478 TI - THE EFFECTS OF KIN-STRUCTURED COLONIZATION ON NUCLEAR AND CYTOPLASMIC GENETIC DIVERSITY. AB - We investigate kin-structured migration and its effects on patterns of genetic variation in cytoplasmic and nuclear genomes. We show that colonization events involving close relatives, such as those that might characterize range expansion and the invasion of new habitats, can change the patterns of nuclear and cytoplasmic genetic variation expected at equilibrium. The difference in the patterns of variation between the nuclear and mitochondrial genomes suggests that it may be possible to estimate the time of the effective kin-structured colonization event. Observations in several taxa are discussed in light of these findings and in relation to their known geological history. PMID- 28564479 TI - THE EVOLUTIONARY GENETICS AND DEVELOPMENTAL BASIS OF WING PATTERN VARIATION IN THE BUTTERFLY BICYCLUS ANYNANA. AB - We have studied interactions between developmental processes and genetic variation for the eyespot color pattern on the adult dorsal forewing of the nymphalid butterfly, Bicyclus anynana. Truncation selection was applied in both an upward and a downward direction to the size of a single eyespot consisting of rings with wing scales of differing color pigments. High heritabilities resulted in rapid responses to selection yielding divergent lines with very large or very small eyespots. Strong correlated responses occurred in most of the other eyespots on each wing surface. The cells at the center of a presumptive eyespot (the "focus") act in the early pupal stage to establish the adult wing pattern. The developmental fate of the scale cells within an eyespot is specified by the "signaling" properties of the focus and the "response" thresholds of the epidermis. The individual eyespots can be envisaged as developmental homologues. Grafting experiments performed with the eyespot foci of the selected lines showed that additive genetic variance exists for both the response and, in particular, the signaling components of the developmental system. The results are discussed in the context of how constraints on the evolution of this wing pattern may be related to the developmental organization. PMID- 28564480 TI - THE GENETICS OF VIABILITY IN DROSOPHILA MELANOGASTER: EFFECTS OF INBREEDING AND ARTIFICIAL SELECTION. AB - Inbreeding and artificial selection experiments were conducted to investigate the genetic properties of egg-to-pupa viability in a population of Drosophila melanogaster. The effect of different levels of inbreeding (F = 0, 0.25, 0.50, and 0.73) was studied. Up to F = 0.50, a linear depression of the mean viability was observed, accompanied by a significant increase of both within-line additive variance and between-line variance. At F = 0.73, no further changes were detected. This can be attributed to natural selection opposing high levels of homozygosity. In parallel, artificial selection to increase viability was performed for 27 generations in (1) a single undivided population (U) and (2) two populations with cycles of subdivision and between-line selection, followed by reconstitution of selected lines (SO and SI ). During the first cycle (generations 0-4), most of the final total response was achieved under all selection regimes. An advantage of the SO and SI strategies was observed after the completion of the first cycle. However, the same limit was reached in all cases because of a delayed response experienced by line U. Reverse selection for viability resulted in positive correlated responses for fecundity and mating success. Both inbreeding and selection results are compatible with the genetic variance of viability in the base population being generated by segregation at a few loci with substantial additive effects and several deleterious recessives at low initial frequencies. Possible reasons for the maintenance of that variance in natural populations are discussed. PMID- 28564481 TI - COSTS OF REPRODUCTION INFLUENCE THE EVOLUTION OF SEXUAL SIZE DIMORPHISM IN SNAKES. PMID- 28564482 TI - DIVERGENCE IN MORPHOLOGY AND MATING SIGNALS, AND ASSORTATIVE MATING AMONG POPULATIONS OF CHORTHIPPUS PARALLELUS (ORTHOPTERA: ACRIDIDAE). AB - Three geographically widely separated populations of the grasshopper Chorthippus parallelus (Orthoptera: Acrididae) have been examined for morphological divergence, divergence in characteristics of the acoustic sexual signals of males, and assortative mating. Significant assortative mating existed between two of the three pairwise combinations of populations in multiple-choice tests. This may be caused by divergence in three of the four acoustic signal parameters measured. The populations also differed in morphology, including characters associated with signal production. The results are discussed in relation to theories for the origin of premating isolation, and it is argued that the observed divergence has developed rapidly, possibly indicating the action of selection. However, this selection could not have been caused by interactions with closely related taxa. PMID- 28564483 TI - GENETIC, ACCLIMATIZATION, AND ONTOGENETIC EFFECTS ON HABITAT SELECTION BEHAVIOR IN DAPHNIA PULICARIA. AB - Daphnia pulicaria from three different populations were observed to express within-population variation in habitat-choice behavior in field assays. Individuals from different habitats (i.e., lake depths) were isolated and cultured as clonal lines under standard conditions. Habitat choices by clonal descendants were then estimated in the field, using replicate experimental columns. There was significant heritable and ontogenetic variation in habitat choice, but the heritable effect was small relative to the phenotypic variation of the original isolates. In a second set of experiments, D. pulicaria that were acclimatized to different habitats showed a strong tendency to choose the habitat to which they had been acclimatized. These data suggest that a given genotype can use a wide range of habitats, given appropriate acclimatization. Although genetic variation is significant, we hypothesize that natural selection on correlated ecological traits is more likely to maintain patterns of genotypic segregation among habitats in Daphnia. PMID- 28564484 TI - HOW TO COMPENSATE FOR COSTLY SEXUALLY SELECTED TAILS: THE ORIGIN OF SEXUALLY DIMORPHIC WINGS IN LONG-TAILED BIRDS. AB - Recent work on birds suggests that certain morphological differences between the sexes may have evolved as an indirect consequence of sexual selection because they offset the cost of bearing extravagant ornaments used for fighting or mate attraction. For example, long-tailed male sunbirds and widowbirds also have longer wings than females, perhaps to compensate for the aerodynamic costs of tail elaboration. We used comparative data from 57 species to investigate whether this link between sexual dimorphism in wing and tail length is widespread among long-tailed birds. We found that within long-tailed families, variation in the extent of tail dimorphism was associated with corresponding variation in wing dimorphism. One nonfunctional explanation of this result is simply that the growth of wings and tails is controlled by a common developmental mechanism, such that long-tailed individuals inevitably grow long wings as well. However, this hypothesis cannot account for a second pattern in our data set: as predicted by aerodynamic theory, we found that, comparing across long-tailed families, sexual dimorphism in wing length varied with tail shape as well as with sex differences in tail length. Thus, wing dimorphism was generally greater in species with aerodynamically costly graduated tails than in birds with cheaper, streamer shaped tails. This result was not caused by confounding phylogenetic effects, because it persisted when phylogeny was controlled for, using an independent comparisons method. Our findings therefore confirm that certain aspects of sexual dimorphism may sometimes have evolved through selection for traits that reduce the costs of elaborate sexually selected characters. We suggest that future work aimed at understanding sexual selection by investigating patterns of sexual dimorphism should attempt to differentiate between the direct and indirect consequences of sexual selection. PMID- 28564485 TI - LONG-TERM LABORATORY EVOLUTION OF A GENETIC LIFE-HISTORY TRADE-OFF IN DROSOPHILA MELANOGASTER. 1. THE ROLE OF GENOTYPE-BY-ENVIRONMENT INTERACTION. AB - Trade-offs among life-history traits are often thought to constrain the evolution of populations. Here we report the disappearance of a trade-off between early fecundity on the one hand, and late-life fecundity, starvation resistance, and longevity on the other, over 10 yr of laboratory selection for late-life reproduction. Whereas the selected populations showed an initial depression in early-life fecundity, they later converged upon the controls and then surpassed them. The evolutionary loss of the trade-off among life-history traits is considered attributable to the following factors: (1) the existence of differences in the culture regimes of the short- and long-generation populations other than the demographic differences deliberately imposed; (2) adaptation of one or both of these sets of populations to the unique aspects of their culture regimes; (3) the existence of an among-environment trade-off in the expression of early fecundity in the two culture regimes, as reflected in assays that mimic those regimes. The trade-off between early and late-life reproductive success, as manifest among divergently selected populations, is apparent or not depending on the assay environment. This demonstration that strong genotype-by-environment interactions can obscure a fundamental trade-off points to the importance of controlling all aspects of the culture regime of experimental populations and the difficulty of doing so even in the laboratory. PMID- 28564486 TI - HIGH INBREEDING DEPRESSION, SELECTIVE INTERFERENCE AMONG LOCI, AND THE THRESHOLD SELFING RATE FOR PURGING RECESSIVE LETHAL MUTATIONS. AB - The evolutionary dynamics of recessive or slightly dominant lethal mutations in partially self-fertilizing plants are analyzed using two models. In the identity equilibrium model, lethals occur at a finite number of unlinked loci among which genotype frequencies are independent in mature plants. In the Kondrashov model, lethals occur at an infinite number of unlinked loci with identity disequilibrium produced by partial selfing. If the genomic mutation rate to (nearly) recessive lethal alleles is sufficiently high, such that the mean number of lethals (or lethal equivalents) per mature plant maintained at equilibrium under complete outcrossing exceeds 10, selective interference among loci creates a sharp discontinuity in the mean number of lethals maintained as a function of the selfing rate. Virtually no purging of the lethals occurs unless the selfing rate closely approaches or exceeds a threshold selfing rate, at which there is a precipitous drop in the mean number of lethals maintained. Identity disequilibrium lowers the threshold selfing rate by increasing the ratio of variance to mean number of lethals per plant, increasing the opportunity for selection. This theory helps to explain observations on plant species that display very high inbreeding depression despite intermediate selfing rates. PMID- 28564487 TI - SUBSTITUTION PROCESSES IN MOLECULAR EVOLUTION. II. EXCHANGEABLE MODELS FROM POPULATION GENETICS. AB - Substitution processes are of two sorts: origination processes record the times at which nucleotide mutations that ultimately fix in the population first appear, and fixation processes record the times at which they actually fix. Substitution processes may be generated by combining models of population genetics-here the symmetrical-neutral, overdominance, underdominance, TIM, and SAS-CFF models-with the infinite-sites, no-recombination model of the gene. This paper is mainly concerned with a computer simulation study of these substitution processes. The rate of substitution is shown to be remarkably insensitive to the strength of selection for models with strong balancing selection caused by the genealogical drift of mutations through alleles held in the population by selection. The origination process is shown to be more regular than Poisson for the overdominance, TIM, and SAS-CFF models but more clustered for the underdominance model. A class of point processes called Sawyer processes is introduced to help explain these observations as well as the observation that the times between successive originations are nearly uncorrelated. Fixation processes are shown to be more complex than origination processes, with regularly spaced bursts of multiple fixations. An approximation to the fixation process is described. One important conclusion is that protein evolution is not easily reconciled with any of these models without adding perturbations that recur on a time scale that is commensurate with that of molecular evolution. PMID- 28564488 TI - Noninvasive beat-to-beat finger arterial pressure monitoring during orthostasis: a comprehensive review of normal and abnormal responses at different ages. AB - Over the past 30 years, noninvasive beat-to-beat blood pressure (BP) monitoring has provided great insight into cardiovascular autonomic regulation during standing. Although traditional sphygmomanometric measurement of BP may be sufficient for detection of sustained orthostatic hypotension, it fails to capture the complexity of the underlying dynamic BP and heart rate responses. With the emerging use of noninvasive beat-to-beat BP monitoring for the assessment of orthostatic BP control in clinical and population studies, various definitions for abnormal orthostatic BP patterns have been used. Here, age related changes in cardiovascular control in healthy subjects will be reviewed to define the spectrum of the most important abnormal orthostatic BP patterns within the first 180 s of standing. Abnormal orthostatic BP responses can be defined as initial orthostatic hypotension (a transient systolic BP fall of >40 mmHg within 15 s of standing), delayed BP recovery (an inability of systolic BP to recover to a value of >20 mmHg below baseline at 30 s after standing) and sustained orthostatic hypotension (a sustained decline in systolic BP of >=20 mmHg occurring 60-180 s after standing). In the evaluation of patients with light headedness, pre(syncope), (unexplained) falls or suspected autonomic dysfunction, it is essential to distinguish between normal cardiovascular autonomic regulation and these abnormal orthostatic BP responses. The prevalence, clinical relevance and underlying pathophysiological mechanisms of these patterns differ significantly across the lifespan. Initial orthostatic hypotension is important for identifying causes of syncope in younger adults, whereas delayed BP recovery and sustained orthostatic hypotension are essential for evaluating the risk of falls in older adults. PMID- 28564489 TI - Graphene Oxide/Ag Nanoparticles Cooperated with Simvastatin as a High Sensitive X Ray Computed Tomography Imaging Agent for Diagnosis of Renal Dysfunctions. AB - Graphene oxides (GO) are attracting much attention in the diagnosis and therapy of the subcutaneous tumor as a novel biomaterial, but its diagnosis to tissue dysfunction is yet to be found. Here, a novel application of GO for diagnosis of renal dysfunction via contrast-enhanced computed tomography (CT) is proposed. In order to serve as contrast-enhanced agent, Ag nanoparticles (AgNPs) are composited on the surface of GO to promote its X-ray absorption, and then simvastatin is coinjected for eliminating in vivo toxicity induced by AgNPs. It is found that GO/AgNPs can enhance the imaging of CT into the lung, liver, and kidney of mice for a long circulation time (~24 h) and a safety profile in vivo in the presence of simvastatin. Interestingly, the lower dose of GO/AgNPs (~0.5 mg per kg bw) shows an excellent performance for CT imaging of renal perfusion, and visually exhibits the right renal dysfunction in model mice. Hence, this work suggests that graphene nanoparticles will play a vital role for the future medical translational development including drug carrier, biosensing, and disease therapy. PMID- 28564490 TI - Effect of Comonomers on Physical Properties and Cell Attachment to Silica Methacrylate/Acrylate Hybrids for Bone Substitution. AB - Hybrids with a silica network covalently bonded to a polymer are promising materials for bone repair. Previous work on synthesizing methyl methacrylate (MMA) based copolymers by reversible addition-fragmentation chain transfer (RAFT) polymerization gives high tailorability of mechanical properties since sophisticated polymer structures can be designed. However, more flexible hybrids would be beneficial. Here, n-butyl methacrylate (BMA) and methyl acrylate (MA) based hybrids are produced. Unlike MMA, BMA and MA hybrids do not show plastic deformation, and BMA hybrid has strain to failure of 33%. Although the new hybrids are more flexible, preosteoblast cells do not adhere on their surfaces, due to higher hydrophobicity and lower stiffness. Comonomer choice is crucial for bone regenerative hybrids. PMID- 28564491 TI - Attenuation of Follicular Helper T Cell-Dependent B Cell Hyperactivity by Abatacept Treatment in Primary Sjogren's Syndrome. AB - OBJECTIVE: To assess the effect of abatacept (CTLA-4Ig), which limits T cell activation, on homeostasis of CD4+ T cell subsets and T cell-dependent B cell hyperactivity in patients with primary Sjogren's syndrome (SS). METHODS: Fifteen patients with primary SS treated with abatacept were included. Circulating CD4+ T cell and B cell subsets were analyzed by flow cytometry at baseline, during the treatment course, and after treatment was completed. CD4+ effector T cell subsets and Treg cells were identified based on expression of CD45RA, CXCR3, CCR6, CCR4, CXCR5, programmed death 1, inducible costimulator (ICOS), and FoxP3. Serum levels of anti-SSA/anti-SSB and several T cell-related cytokines were measured. Expression of ICOS and interleukin-21 (IL-21) protein was examined in parotid gland tissue at baseline and after treatment. Changes in laboratory parameters and associations with systemic disease activity (EULAR Sjogren's Syndrome Disease Activity Index [ESSDAI]) over time were analyzed using generalized estimating equations. RESULTS: Abatacept selectively reduced percentages and numbers of circulating follicular helper T (Tfh) cells and Treg cells. Other CD4+ effector T cell subsets were unaffected. Furthermore, expression of the activation marker ICOS by circulating CD4+ T cells and expression of ICOS protein in parotid gland tissue declined. Reduced ICOS expression on circulating Tfh cells correlated significantly with lower ESSDAI scores during treatment. Serum levels of IL-21, CXCL13, anti-SSA, and anti-SSB decreased. Among circulating B cells, plasmablasts were decreased by treatment. After cessation of treatment, all parameters gradually returned to baseline. CONCLUSION: Abatacept treatment in patients with primary SS reduces circulating Tfh cell numbers and expression of the activation marker ICOS on T cells. Lower numbers of activated circulating Tfh cells contribute to attenuated Tfh cell-dependent B cell hyperactivity and may underlie the efficacy of abatacept. PMID- 28564492 TI - Photoinitiated Polymerization-Induced Self-Assembly of Glycidyl Methacrylate for the Synthesis of Epoxy-Functionalized Block Copolymer Nano-Objects. AB - Herein, a novel photoinitiated polymerization-induced self-assembly formulation via photoinitiated reversible addition-fragmentation chain transfer dispersion polymerization of glycidyl methacrylate (PGMA) in ethanol-water at room temperature is reported. It is demonstrated that conducting polymerization induced self-assembly (PISA) at low temperatures is crucial for obtaining colloidal stable PGMA-based diblock copolymer nano-objects. Good control is maintained during the photo-PISA process with a high rate of polymerization. The polymerization can be switched between "ON" and "OFF" in response to visible light. A phase diagram is constructed by varying monomer concentration and degree of polymerization. The PGMA-based diblock copolymer nano-objects can be further cross-linked by using a bifunctional primary amine reagent. Finally, silver nanoparticles are loaded within cross-linked vesicles via in situ reduction, exhibiting good catalytic properties. PMID- 28564493 TI - Sustainable, Oxidative, and Metal-Free Annulation. AB - Annulation has received steadily growing interest in the interplay with the increasing emphasis towards selective C-H bond functionalization reactions. Metal free oxidative annulation through functionalization of inert and abundant C-H bonds offers great improvements in terms of atom- and step-economics as well as reduced waste production under mild reaction conditions. Annulation is considered to be a highly efficient strategy for the construction of cyclic molecules because at least two new bonds are formed within a single reaction step. The combination of annulation and direct C-H bond functionalization allows the efficient and straightforward synthesis of carbo- and heterocyclic molecules using simple and non-prefunctionalized precursors. This Concept highlights novel strategies and recent breakthroughs for metal-free annulation through C-H bond functionalization giving access to a variety of important structural motifs. PMID- 28564494 TI - How people from Chinese backgrounds make sense of and respond to the experiences of mental distress: Thematic analysis. AB - RATIONALE FOR THE STUDY: Many Chinese people do not contact mental health services when they first develop mental health problems. It is therefore important to find out reasons for low uptake of services so that strategies can be identified to promote early intervention. WHAT IS ALREADY KNOWN ABOUT THE TOPIC?: Most Chinese people only come into contact with mental health services during crisis situations. Language difference, lack of knowledge of mainstream services and stigma attached to mental health problems are barriers to access and utilize mental health services. WHAT THE STUDY ADDS TO THE INTERNATIONAL EVIDENCE?: Chinese people apply both Western medication and traditional healing to manage distress caused by mental health problems. Because of the extreme stigma associated with mental health problems, Chinese people are reluctant to accept support from their own cultural groups outside their family. Family plays a major role in caring for relatives with mental health problems. Families are prepared to travel across the world in search of folk healing if not available in Western societies. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: It is important to recognize the different approaches to understanding and managing mental health problems among Chinese people, otherwise they will be dissuaded from engaging with mental health services if their beliefs are disregarded and invalidated. Services that involve Chinese speaking mental health workers can address the issue of language differences and sensitive mental health issues within the Chinese community. ABSTRACT: Introduction Late presentation and low utilization of mental health services are common among Chinese populations. An understanding of their journey towards mental health care helps to identify timely and appropriate intervention. Aim We aimed to examine how Chinese populations make sense of the experiences of mental distress, and how this understanding influences their pathways to mental health care. Method We undertook in-depth interviews with fourteen people with mental health problems (MHPs) and sixteen family members. Thematic analysis was used to analyse data. Results/Discussions Different conceptualization of mental distress and the stigma attached to MHPs explained why most participants accessed services at crisis points. Because of mental illness stigma, they were reluctant to seek help outside of the family. Participants used a pragmatic pluralistic approach to incorporate ritual healing and Western interventions to manage mental distress as they travelled further on the pathway journey. Families play a key role in the journey and are prepared to visit different parts of the world to seek traditional healers. Implications for practice Mental health nurses need to adopt a transcultural working approach to address mental health issues so that family will get the support needed to continue their caring role. PMID- 28564496 TI - Acute chest pain in an adolescent with cystic fibrosis in September: Would you have thought about this? AB - Acute chest pain is common in patients with cystic fibrosis (CF). Here we report the case of an adolescent who suffered acute chest pain in September after an history of acute abdominal pain and fever. The reason for this clinical sceneriao was found to be Coxsackievirus B3, known to be responsible of Bornholm disease, a frequent but under recognized viral myositis. The diagnosis is mainly clinical, but evocating this diagnosis may avoid unnecessary exam. PMID- 28564497 TI - TEMPORAL VARIATION IN ALLELE FREQUENCIES: TESTING THE RIGHT HYPOTHESIS. AB - Although standard statistical tests (such as contingency chi-square or G tests) are not well suited to the analysis of temporal changes in allele frequencies, they continue to be used routinely in this context. Because the null hypothesis stipulated by the test is violated if samples are temporally spaced, the true probability of a significant test statistic will not equal the nominal alpha level, and conclusions drawn on the basis of such tests can be misleading. A generalized method, applicable to a wide variety of organisms and sampling schemes, is developed here to estimate the probability of a significant test statistic if the only forces acting on allele frequencies are stochastic ones (i.e., sampling error and genetic drift). Results from analyses and simulations indicate that the rate at which this probability increases with time is determined primarily by the ratio of sample size to effective population size. Because this ratio differs considerably among species, the seriousness of the error in using the standard test will also differ. Bias is particularly strong in cases in which a high percentage of the total population can be sampled (for example, endangered species). The model used here is also applicable to the analysis of parent-offspring data and to comparisons of replicate samples from the same generation. A generalized test of the hypothesis that observed changes in allele frequency can be satisfactorily explained by drift follows directly from the model, and simulation results indicate that the true alpha level of this adjusted test is close to the nominal one under most conditions. PMID- 28564495 TI - Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon-Induced Up-Regulation of Interferon Regulatory Factor 1. AB - OBJECTIVE: The inflammasome complex is a driver of organ damage in patients with systemic lupus erythematosus (SLE). Although type I interferons (IFNs) are well established as mediators of SLE pathogenesis, their role in inflammasome activation in SLE has not been assessed. The aim of this study was to examine type I IFNs as regulators of the inflammasome. METHODS: SLE patients fulfilled >=4 American College of Rheumatology criteria and were recruited from the University of Michigan Lupus Cohort. Primary monocytes were isolated from SLE patients or healthy controls by negative selection, treated with inflammasome activators in the presence or absence of IFNalpha, and IL-1beta secretion was measured by enzyme-linked immunosorbent assay. Expression levels of IFN and inflammasome-related molecules were assessed by real-time polymerase chain reaction and Western blotting. IFN regulatory factor 1 (IRF-1) expression was specifically down-regulated by small interfering RNA (siRNA) transfection and a chemical inhibitor. RESULTS: Monocytes from patients with SLE exhibited increased expression and enhanced activation of the inflammasome by ATP when compared with control monocytes. Expression of inflammasome and IFN-regulated genes was significantly correlated in monocytes from SLE patients but not in control monocytes. Inflammasome activity was increased after prolonged exposure to IFNalpha. Reduction of IRF-1 expression via siRNA blocked caspase 1 up-regulation after treatment with IFNalpha. Importantly, hyperactivity of the inflammasome in the monocytes of SLE patients was significantly reduced after knockdown or inhibition of IRF-1. CONCLUSION: Prolonged type I IFN exposure, as seen in SLE patients, primes monocytes for robust inflammasome activation in an IRF-1 dependent manner. IRF-1 inhibition may serve as a novel target for treatment of SLE-associated inflammation and organ damage. PMID- 28564498 TI - INFLUENCES OF MATERNAL BODY WEIGHT, AGE, AND PARITY ON SEX RATIO IN SEMIDOMESTICATED REINDEER (RANGIFER T. TARANDUS). PMID- 28564499 TI - LIFE-HISTORY EVOLUTION IN GUPPIES: 2. REPEATABILITY OF HELD OBSERVATIONS AND THE EFFECTS OF SEASON ON LIFE HISTORIES. AB - Natural populations of guppies that co-occur with the pike cichlid Crenicichla alta and associated predators mature at smaller body sizes, produce more and smaller offspring per litter reproduce more frequently, and have higher reproductive allotments (weight of developing embryos/total body weight) than guppies that co-occur with just the killifish Rivulus harti (Reznick and Endler, 1982). I here consider three forms of repeatability in these life-history patterns: i) among replicate samples collected on the same day from the same locality, ii) between Crenicichla and Rivulus communities among a new series of localities, and iii) among a smaller series of Crenicichla and Rivulus localities sampled in two wet and two dry seasons. In the analysis of replicate collections from two localities, seven of eight statistical comparisons revealed no significant difference. The usual methodology for estimating these variables therefore accurately represents guppy life-history patterns at a given locality. Differences among guppies from Rivulus and Crenicichla localities, covering a wider geographical area than considered by Reznick and Endler (1982), were virtually identical to the previous comparison. Wet-season samples were associated with significant decreases in reproductive allotment and fecundity and significant increases in the size of mature males and the minimum size of reproducing females. Differences between guppies from Rivulus and Crenicichla localities persisted across all samples and were consistent with all other observations, although they tended to be smaller during the wet season. Discriminant analyses on female reproductive traits showed that fecundity and offspring size made strong, independent contributions to discriminating between guppies from the two types of localities. The contribution from reproductive allotment was considerably smaller. There was more overlap between predator treatments during the wet season. Only 8.5% of the individuals were misclassified during the dry season, but 19.5% were misclassified during the wet season. PMID- 28564500 TI - GENE TREES AND ORGANISMAL HISTORIES: A PHYLOGENETIC APPROACH TO POPULATION BIOLOGY. AB - A "gene tree" is the phylogeny of alleles or haplotypes for any specified stretch of DNA. Gene trees are components of population trees or species trees; their analysis entails a shift in perspective from many of the familiar models and concepts of population genetics, which typically deal with frequencies of phylogenetically unordered alleles. Molecular surveys of haplotype diversity in mitochondrial DNA (mtDNA) have provided the first extensive empirical data suitable for estimation of gene trees on a microevolutionary (intraspecific) scale. The relationship between phylogeny and geographic distribution constitutes the phylogeographic pattern for any species. Observed phylogeographic trees can be interpreted in terms of historical demography by comparison to predictions derived from models of gene lineage sorting, such as inbreeding theory and branching-process theory. Results of such analyses for more than 20 vertebrate species strongly suggest that the demographies of populations have been remarkably dynamic and unsettled over space and recent evolutionary time. This conclusion is consistent with ecological observations documenting dramatic population-size fluctuations and range shifts in many contemporary species. By adding an historical perspective to population biology, the gene-lineage approach can help forge links between the disciplines of phylogenetic systematics (and macroevolutionary study) and population genetics (microevolution). Preliminary extensions of the "gene tree" methodology to haplotypes of nuclear genes (such as Adh in Drosophila melanogaster) demonstrate that the phylogenetic perspective can also help to illuminate molecular-genetic processes (such as recombination or gene conversion), as well as contribute to knowledge of the origin, age, and molecular basis of particular adaptations. PMID- 28564501 TI - DIVERGENCE IN CACTOPHILIC DROSOPHILA: THE EVOLUTIONARY SIGNIFICANCE OF ADULT ETHANOL METABOLISM. PMID- 28564502 TI - CAN GENE FLOW PREVENT REINFORCEMENT? AB - A model of reinforcement in a hybrid zone is developed in which an allele causing reinforcement may only be favored in the center of the hybrid zone and is selected against elsewhere. When reinforcement is favored only in the hybrid zone, the swamping effect of gene flow severely impedes the evolution of reinforcement: reinforcement can only occur when beta < sgamma2 /4 (s is selection against hybrids, gamma is the strength of reinforcement, and beta is the strength of selection against reinforcement). Although the region in which reinforcement can occur is narrower when selection against hybrids is stronger, strong selection is still more likely to be reinforced despite the effects of gene flow. Another modifier is considered which reduces postmating isolation. The conditions for increase in frequency of this modifier reduce to the same conditions as those for the reinforcing allele. Both kinds of modification reduce the strength of selection and, therefore, cause the cline to widen. Reinforcement causes an increase in premating isolation between races, while modification of selection reduces postmating isolation. PMID- 28564503 TI - ON THE EVOLUTION AND ECOLOGY OF ISLAND POPULATIONS OF CROSSBILLS. PMID- 28564504 TI - INBREEDING IN DARWIN'S MEDIUM GROUND FINCHES (GEOSPIZA FORTIS). AB - We studied the frequency and causes of inbreeding and its effect on reproductive success in a population of Darwin's Medium Ground Finches (Geospiza fortis) on Isla Daphne Major, Galapagos, during four breeding seasons (1981, 1983, 1984, and 1987). Pedigree analysis showed that levels of inbreeding were low but comparable with those observed in other passerine birds. For pairs with at least half of their grandparents known, approximately 20% of all pairings were between detectably related birds. The frequency of pairings between closely related birds (coefficient of kinship [phi] >= 0.250) among all pairs was 0.6%. We detected no effect of inbreeding on reproductive success, although sample sizes were small. The observed reproductive output of related pairs was not significantly different from the output of unrelated pairs, and there was no correlation between a pair's kinship coefficient and an estimate of the potential magnitude of inbreeding depression. Comparisons with a study of Great Tits (Parus major) by van Noordwijk and Scharloo (1981) suggest that, even if present, the fitness costs of inbreeding in this population of G. fortis would be low. Observed levels of inbreeding in each breeding episode were accurately predicted by simulations of random mating in which relatedness had no influence on pairing between individuals. This result suggests that levels of inbreeding in this population are determined more by demographic factors than by behavioral avoidance of mating with kin. PMID- 28564505 TI - COMPOSITE TRAITS, SELECTION RESPONSE, AND EVOLUTION. AB - It is very difficult to relate macroevolutionary patterns to the microevolutionary processes described by quantitative-genetic models. Quantitative-genetic parameters are statistical abstractions. Their long-term significance and evolution might be understood if they can be related to development, physiology, and other biological properties. Most continuous traits are composites of other traits that may contribute differentially to selection response and long-term divergence. The operation of selection on continuous traits can be indirect, with intermediate optima caused by correlated fitness components. Few realistic models are available, and heritable maternal effects can further complicate selection response. Examples involving allometry of brain and body size in mammals suggest that prenatal and postnatal growth have contributed differently to body-size evolution, with different correlated changes in brain size. Several different models could explain these patterns, and interpretation is further complicated by statistical difficulties in comparative biology. Quantitative-genetic models may become more informative and predictive if variation in their parameters can be explained by developmental and other biological processes that have been shaped by the previous history of the population. PMID- 28564506 TI - FEMALE RECEPTIVITY TO REMATING AND EARLY FECUNDITY IN DROSOPHILA MELANOGASTER. PMID- 28564507 TI - AN EXPERIMENTAL EVALUATION OF THE RECOVERY POTENTIAL OF RYEGRASS POPULATIONS FROM GENETIC STRESS RESULTING FROM RESTRICTION OF POPULATION SIZE. PMID- 28564508 TI - FITNESS CONSEQUENCES OF MATING SYSTEM, SEED WEIGHT, AND EMERGENCE DATE IN A WINTER ANNUAL, COLLINSIA VERNA. AB - Selfed and outcrossed progeny of 60 maternal parents were produced to investigate the joint and individual effects of mating system, seed weight, and emergence date on the expression of characters related to fitness and adult fecundity. A series of analyses of variance investigated these effects through time and indicated that 1) mating system explained 56% of the variance in seed weight, 2) seed weight explained 51% and mating system explained 38% of the variance in emergence date, and 3) mating system explained 71% and seed weight explained 15% of the variance in fecundity. Outcrossed-seed means differed significantly from selfed-seed means for all traits measured. On average, outcrossed seeds were larger, germinated earlier, had higher percentage emergence, and produced plants that were more fecund than selfed seeds. The coefficient of inbreeding depression increased through time in this study, from 0.05 for seed weight to 0.23 for fecundity. Seed weight and emergence date were positively correlated, both phenotypically and genetically, for both mating systems. Genetically, this indicates that genes that increase the value of seed weight also increase the value of emergence date and vice versa. Phenotypically, the positive correlation indicates that larger seeds germinate later. Outcrossed seeds were significantly larger but germinated earlier than selfed seeds, suggesting that mating system has an overriding effect in influencing fitness. In light of the selection on emergence date quantified in a previous study, seed weight, emergence date, and mating system may be functioning as a cluster of characters on which selection acts jointly in this species. PMID- 28564509 TI - THE ORIGIN OF MORPHOLOGICAL CHARACTERS AND THE BIOLOGICAL BASIS OF HOMOLOGY. AB - A homolog is a part of the phenotype that is homologous to equivalent parts in other species. A biological homology concept is expected to explain three properties of homologs: 1) the conservation of those features that are used to define a homolog, 2) the individualization of the homolog with regard to the rest of the body, and 3) the uniqueness of homologs, i.e., their specificity for monophyletic groups. The main obstacle to describing a mechanistic basis for homology is the variability of the developmental pathways of undoubtedly homologous characters. However, not all aspects of the developmental pathway are of equal importance. The only organizational features of the developmental system that matter are those that have been historically acquired and cause developmental constraints on the further evolutionary modification of the characters. Two main factors contribute to historically acquired developmental constraints: generative rules of pattern formation and ontogenetic networks. In particular, hierarchical and cyclical inductive networks have the required properties to explain homology. How common such networks are is an open empirical question. The development and variation of pectoral fin hooks in blenniid fishes is presented as a model for the study of a simple ontogenetic network. PMID- 28564510 TI - REPRODUCTIVE ISOLATION AS A CONSEQUENCE OF ADAPTIVE DIVERGENCE IN DROSOPHILA PSEUDOOBSCURA. PMID- 28564511 TI - THE EVOLUTION OF FLORAL COLOR CHANGE: POLLINATOR ATTRACTION VERSUS PHYSIOLOGICAL CONSTRAINTS IN FUCHSIA EXCORTICATA. AB - Field experiments showed that the green-to-red color change in the flowers of Fuchsia excorticata is age-dependent, rather than pollination-induced. Nectar is produced only in green and, to a lesser extent, intermediate-phase flowers; red flowers are postreproductive and are avoided by pollinators (bellbirds). Additional experiments suggested that the red flowers are retained because pollen tubes require at least three days to reach the ovaries, and abscission of the floral tube and accompanying style requires at least another 1.5 days. The change in color directs pollinators away from the postreproductive flowers while these physiological processes are occurring, thereby increasing foraging efficiency and visitation to flowers that are still capable of receiving and donating pollen. No evidence was found to suggest that red-phase flowers function to attract pollinators. Finally, we suggest that the color change evolved through neotenous retention of the green coloration of buds and is a derived trait reflecting an interaction between natural selection and physiological constraints. PMID- 28564512 TI - PHYLOGENIES AND THE ANALYSIS OF EVOLUTIONARY SEQUENCES, WITH EXAMPLES FROM SEED PLANTS. AB - Studies of character evolution have frequently relied on ahistorical correlations rather than on phylogenies. However, correlations do not estimate the number of times that a trait evolved, and they are insensitive to the direction or the temporal sequence of character transformation. In contrast, cladograms can provide this information. A cladistic test of the hypothesis that the evolution of dioecy is favored in animal-dispersed plants indicates that dioecy may have originated somewhat more often in such lineages. Nevertheless, differences in rates of speciation or extinction must largely account for the observed species level correlation between dispersal and breeding system. In considering the evolution of individual traits, cladograms help identify the context in which a feature evolved and specify which organisms should be compared in evaluating the causes of character change. Determining whether a feature and a performance advantage were strictly historically correlated or followed one another in sequence helps to distinguish whether the trait is an adaptation or an exaptation for the function. For example, cladograms of seed plants suggest that double fertilization arose incidentally prior to the origin of angiosperms and that the resulting product was later co-opted and elaborated as a nutritive tissue for the developing embryo. The order of character assembly in a lineage also bears on the evolution of functional and developmental interdependencies. In particular, it may be possible to trace the evolution of a character's "burden" from an initial period, during which change is more likely, through later stages, wherein successful modification is less likely owing to the evolution of dependent characters. The evolution of vessels and of floral phyllotaxis in angiosperms may exemplify this pattern. Recognition that the likelihood of character transformation may change during the evolution of a group warns against character weighting in phylogenetic analysis. PMID- 28564513 TI - GENETIC BASIS FOR ALTERNATIVE REPRODUCTIVE TACTICS IN THE PYGMY SWORDTAIL, XIPHOPHORUS NIGRENSIS. AB - Differences in adult male size and age at sexual maturity in the Rio Coy (Mexico) population of Xiphophorus nigrensis (Pisces; Poeciliidae) are controlled by genetic variation at a Y-linked locus. Four genetic size-classes have been identified. The mating behavior of the males of the three largest size-classes consists exclusively of an elaborate courtship display, whereas that of the genetically small males ranges from display to a sneak-chase attempt at copulation. In the presence of large males, small males switch to the sneak-chase behavior. Females prefer the display of large males. In mating-competition experiments (two females with one large male and one small male), the large males are dominant and deny the small males access to females. From 20 such experiments, 601 large-male and 200 small-male progeny were obtained, indicating that the switch to sneak-chase behavior by small males is not particularly effective in overcoming the large-male advantage. By using the largest males of the genetically smallest size class and the smallest males of the genetically next-larger size-class, size was kept constant, whereas genotype was varied. When these males were tested in competition with genetically large males, only the males of the genetically smallest size class showed sneak-chase behavior. These observations suggest that the difference in mating behavior is not an indirect developmental effect of size but, rather, is under direct genetic control. PMID- 28564514 TI - VISUALIZING MULTIVARIATE SELECTION. AB - Recent developments in quantitative-genetic theory have shown that natural selection can be viewed as the multivariate relationship between fitness and phenotype. This relationship can be described by a multidimensional surface depicting fitness as a function of phenotypic traits. We examine the connection between this surface and the coefficients of phenotypic selection that can be estimated by multiple regression and show how the interpretation of multivariate selection can be facilitated through the use of the method of canonical analysis. The results from this analysis can be used to visualize the surface implied by a set of selection coefficients. Such a visualization provides a compact summary of selection coefficients, can aid in the comparison of selection surfaces, and can help generate testable hypotheses as to the adaptive significance of the traits under study. Further, we discuss traditional definitions of directional, stabilizing, and disruptive selection and conclude that selection may be more usefully classified into two general modes, directional and nonlinear selection, with stabilizing and disruptive selection as special cases of nonlinear selection. PMID- 28564515 TI - Autoerotic Asphyxiation: A Case Report. PMID- 28564516 TI - Treatment of Hypersexuality in an Elderly Patient With Frontotemporal Dementia in a Long-Term Care Setting. PMID- 28564517 TI - Intestinal Bioengineering. AB - This review summarizes bioengineering innovations in the treatment of patients with short bowel syndrome. Bioengineering approaches aim to increase the overall intestinal tissue mass. While the morphology of the intestine is clearly altered by these interventions, it remains to be shown that the overall function of the intestine is improved. Continued innovations will likely bring about new therapeutic options for patients with short bowel syndrome. Careful evaluations of the impact of these interventions await controlled clinical trials. PMID- 28564518 TI - Long-term Outcomes in Intestinal Rehabilitation in Children. AB - Long-term outcomes for pediatric patients with intestinal failure have significantly improved with advances in management of parenteral nutrition and the associated comorbidities. These changes have been driven by the development of multidisciplinary intestinal rehabilitation teams. Overall survival and transplant-free survival rates have increased while the introduction of new management strategies has decreased complications such as central line infections and intestinal failure associated liver disease. Factors have been identified that aid in prediction of duration of parenteral nutrition and time to enteral autonomy. Close long-term monitoring of growth and early evaluation of development are needed as abnormalities in both areas are common. With the improved survival, an important focus going forward will be the study of and improvement in quality of life for both children with intestinal failure and their families. PMID- 28564519 TI - Donor-Specific HLA Antibodies: A Review of Data Published in 2016. AB - The results from continued research regarding the role of anti-human leukocyte antigen (anti-HLA) antibodies and donor-specific antibodies (DSA) in transplantation has strengthened the association between DSA and allograft rejection. The formation of de novo DSAs is particularly detrimental to allograft function and survival. Paradoxically, grafts of patients without DSA may fail and patients with DSA may continue to have extended post-transplant graft function. An explanation for this inconsistency in outcomes must be found to utilize anti HLA DSA as a biomarker of allograft rejection. This review highlights multiple studies regarding DSA and secondary characteristics of DSA, including C1q binding, mean fluorescence, and immunoglobulin G subtype, which have been useful in stratifying DSA-positive patients into low- and high-risk groups of allograft rejection. PMID- 28564520 TI - Cytokines as Biomarkers for Renal Transplant Recipients: What is New? AB - Poor long-term graft survival remains a major problem in the field of organ transplantation. This could be attributed at least in part, to the lack of reliable biomarkers that allow for accurate, noninvasive monitoring of graft status and individualized immunosuppressive therapy. To this end, cytokines and chemokines have been investigated in a number of studies to evaluate their potential to serve as diagnostic and prognostic markers for kidney transplantation. Based on our review of recent publications, urinary chemokine C C motif ligand 2, chemokine C-XC motif ligand (CXCL) 9, and CXCL10 are identified as potential novel biomarkers of renal graft outcomes. Although there are numerous considerations to accurately analyze cytokine and chemokine profiles of transplant patients, continuing efforts in this field of research hold promise for improving the long-term outcomes of renal transplant recipients. PMID- 28564521 TI - The Clinical Impact of Non-HLA Antibodies in Solid Organ Transplantation. AB - Antibody-mediated rejection in solid organ transplantation is associated with significant organ dysfunction and allograft loss. Donor-specific antibodies against human leukocyte antigens (HLAs) have been a major focus for research, clinical testing, and therapies. Recently, non-HLA autoantibodies to various endothelial antigens including angiotensin II type 1 receptor, endothelin-1 type A receptor, Major Histocompatibility Complex Class 1-Related Chain A, perlecan, and collagen V are emerging as both potential mediators of allograft dysfunction and targets for intervention. Incorporation of non-HLA antibodies into clinical practice is currently not standardized due to a lack of consensus regarding the pathogenic effects on the allograft. Treatment strategies for non-HLA antibodies are evolving and remain an area that warrants further investigation. PMID- 28564522 TI - Non-HLA Antibodies in Clinical Transplantation. AB - Organ transplantation overcomes conservative therapy to improve patient longevity. Despite the improvement of donor-recipient compatibility tests and intensified immunosuppressive agents, long-term graft survival remains poor because of acute and chronic injury driven by immunologic and non-immunologic factors. The significant immunological barrier for graft longevity is antibody mediated rejection. Antibodies reactive to donor-specific human leukocyte antigens (HLA) have been shown to have adverse effects on the transplanted organ. However, there is minimal or controversial data supporting a pathogenic effect of antibodies against non-HLAs. This review discusses non-HLA antibodies and relevant antigen targets that have been uncovered by molecular medicine and correspond with acute rejection and chronic allograft injury. Updated proteomic evaluation may improve our knowledge of the immune response by enhancing immunologic epitope determination outside the scope of HLA. PMID- 28564523 TI - HLA Epitopes - Are We Ready for Clinical Prime Time? Historic Perspective and Future Needs. AB - A significant barrier to long-term transplant success is the development of de novo donor-specific human leukocyte antigen (HLA) antibodies. The best approach to minimize the risk of developing such antibodies is an HLA identical transplant, but the likelihood of finding such an organ is very low. The alternative is to identify "permissible mismatches" - HLA antigen mismatches that are less likely to induce an immune response. In the past few years, it has become clear that matching at the "epitope level" is the likely solution; however, we are still struggling with how to define HLA epitopes. Herein, we provide a short review of the development of the epitope concept within the HLA field, with the hope that it sheds light on present knowledge. We follow with our personal opinion on where the future is leading us. PMID- 28564524 TI - HLA Epitopes and Shared Molecular Eplet Characterization and Their Implication on Transplant Outcome: The Experience of One Center. AB - We report three interesting cases concerning antibody-mediated rejection (AMR), associated or not with anti-donor-specific antibodies, and detection of implicated molecular epitopes. The first report presents a case of intra-allele sensitization. The second case presents an interesting case concerning Luminex mean fluorescence intensity (MFI) levels considered to be low risk antibodies (<1000), but producing AMR. The third case occurred after a second kidney transplantation mediated by antibodies directed against HLA-C antigens (MFI<1000) in the previous transplantation (which was considered to be an indicator of low risk of AMR). PMID- 28564525 TI - Acute Rejection, Kidney Allograft Function, and Graft Survival in Patients with Circulating Pre-Transplant IgG Antibodies Directed Against Donor HLA-A, -B, or -C Locus Determined Antigens. AB - The relationship between circulating pre-transplant immunoglobulin G (IgG) antibodies to donor human leukocyte antigen (HLA) -C locus determined antigens alone and acute rejection, kidney allograft function, and graft survival is not fully defined. Also, the impact of circulating pre-transplant IgG antibodies to donor HLA-C locus antigens alone on these outcomes has not been compared with the impact of circulating pre-transplant IgG antibodies to donor HLA-A or -B locus antigens. We conducted a retrospective review of records of 1252 kidney allograft recipients transplanted at our center between January 2010 and January 2016 to identify patients with circulating pre-transplant IgG antibodies directed at kidney donor HLA-A, -B, or -C locus determined antigens. Antibodies were detected and reported using the LABScreen Single Antigen Bead assay with microbeads coated with single HLA class I antigens. Pre-transplant and post-transplant data were collected and the graft outcomes of 16 kidney graft recipients with antibodies to HLA-C locus antigens were compared to the outcomes in 56 recipients with antibodies to HLA-A or -B locus determined antigens. The one-year acute rejection rate was 6% in those with donor-specific antibodies (DSA) to HLA-C locus antigens and 20% in those with DSA to HLA-A or -B locus antigens. The graft survival rate was 100% in those with DSA to HLA-C locus antigens and 95% in those with DSA to HLA-A or -B locus antigens. None of the numerical differences were statistically significant (p>0.05). The presence of circulating pre-transplant IgG antibodies directed at kidney donor HLA-C locus antigens alone may not be associated with an increased risk of acute rejection or a decreased graft survival rate. Our observations support the concept that circulating pre-transplant IgG antibodies directed at kidney donor HLA-C locus antigens alone do not negatively impact kidney allograft outcomes and that the mean fluorescence intensities of the antibodies directed at HLA-C locus alone should not be used to list unacceptable HLA-C locus antigens for kidney allocation. A study with a larger cohort is needed to investigate our hypothesis. PMID- 28564526 TI - Pre-empting Antibody-Mediated Rejection: A Program of DSA Monitoring and Treatment Can Effectively Prevent Antibody Mediated Rejection. AB - Antibody-mediated rejection (AMR) remains a problem without a reliable treatment in the care of kidney transplant patients. We proposed and tested a program of screening for donor specific antibodies (DSA) to initiate treatment of patients before AMR was detected and to prevent its occurrence. Starting in April 2012, we stratified patients into high-, medium-, and low-risk groups for the development of DSA and instituted a program of screening for and treatment of these antibodies. We used a historic control group of patients transplanted at our center as a comparator and looked at rates of DSA testing and development as well as rates of development of AMR, cell-mediated rejection, and graft loss. 614 patients were transplanted under the protocol compared with 266 patients in the control group. Length of follow-up was similar in both groups. The group undergoing DSA screening had lower rates of DSA development (17.6% versus 24.8%, p=0.016) and that DSA was found at a significantly earlier time post-transplant (147 versus 248 days, p=0.02). Incidence of AMR was dramatically lower in the screened group (1.3% versus 8.6%, p<0.0001) with no grafts lost due to AMR. AMR was found to occur at an average of 181 days post-transplant. Rates of acute cellular rejection did not decrease in a manner similar to AMR rates. In conclusion, a program of universal risk-stratified DSA testing in kidney transplant patients can dramatically reduce rates of AMR and virtually eliminate graft loss due to AMR. PMID- 28564527 TI - Incidence and Factors Associated with De Novo DSA After BK Viremia in Renal Transplant Recipients. AB - BK polyomavirus infection and de novo donor-human leukocyte antigen (HLA) specific antibodies (dnDSA) are two well-known and distinct complications occurring after kidney transplantation. Recent literature suggests an association between the two events. This study aims to examine the relationship between BK viremia (BKV) and dnDSA and to identify potential risk factors for dnDSA following BKV in kidney transplant recipients. A retrospective review of 1019 recipients from Houston Methodist Hospital was conducted. All patients underwent routine screening for BKV and dnDSA. Median follow-up was 44 months. BKV was detected in 186 (18%) patients at a median of 107 (82-205) days post-transplant. dnDSA occurred in 283 (28%) patients at a median of 272 (62-575) days post transplant. Of the 69 dnDSA-positive/BKV-positive patients, dnDSA detection occurred after BKV onset in 46 patients. Thus, 46 (28%) previously DSA-negative patients later became dnDSA-positive following BKV, not significantly different from the rate seen in BKV-negative patients (26%; p=0.5). Median time to DSA detection following BKV onset was 232 days (interquartile range, 119-460) post BKV detection. Multivariate analysis revealed a greater number of HLA mismatches and viral clearance as risk factors for development of dnDSA following BKV, whereas delayed graft function was associated with a lower risk of dnDSA. In conclusion, despite being considered a result of over-immunosuppression, BKV can still be followed by dnDSA in a substantial proportion of patients. Monitoring for dnDSA in patients being managed for BKV may be warranted. PMID- 28564528 TI - Late Antibody-Mediated Rejection in Kidney Transplant Recipients: Outcomes after Intravenous Immunoglobulin Therapy. AB - Development of acute antibody-mediated rejection (AMR) is associated with graft loss and can occur both early (<3 months) and late (>3 months) post-transplant. Treatment and prognosis differ in early and late AMR. Herein, we present a single center experience using high-dose intravenous immunoglobulin (IVIg) (2g/kg) for the treatment of late AMR. All kidney recipients with negative T- and B-cell flow crossmatch at transplant and biopsy-proven late AMR were included (2009-2013, n=126). All patients were treated with IVIg at 2g/kg over divided doses and high dose intravenous methylprednisolone. Variables collected included demographics, Banff 2007 renal allograft biopsy scoring criteria, and laboratory values. Multivariable Cox proportional hazard regression was used to identify factors predictive of graft loss. Median age was 46 years, with 60% male and 47.6% African American. Median time from transplant to rejection was 3.8 years. Baseline serum creatinine was 1.6 mg/dl and median serum creatinine at diagnosis was 2.6 mg/dl. Fifty-eight patients (46%) eventually lost their grafts at a median of 12 months (interquartile range: 4-21) from diagnosis. Serum creatinine >5.3 mg/dl at time of diagnosis was associated with a 94% probability of graft loss, and after controlling for multiple recipient and donor factors, only serum creatinine and urine protein creatinine ratio at diagnosis were predictive of graft loss. Late AMR has a poor prognosis, with 46% graft loss at a median follow up of 12 months. Serum creatinine was a better predictor of subsequent graft failure than histological characteristics in late AMR. These findings help inform treatment plans as well as prognosis. PMID- 28564529 TI - Outcomes in Simultaneous Liver Kidney Transplants in the Setting of a Positive Crossmatch: A Single Center Experience. AB - Recent literature suggests that a positive crossmatch adversely impacts outcomes in simultaneous liver-kidney transplant (SLKT). The aim of this study was to evaluate outcomes of SLKT with a positive flow crossmatch (+FCXM) at our center. We retrospectively analyzed all of the SLKTs between January 1, 2000, and September 30, 2010. A total of 2793 kidney transplants and 892 liver transplants were performed in this time period, of which, 31 were SLKT (3%). Seven of the 31 (22%) SLKTs had a +FCXM. There were 3 major adverse events: 1 patient mortality at 9 months with liver failure; 1 allograft nephrectomy for primary nonfunction secondary to hyper-acute rejection; and, 1 recurrent liver allograft rejection with eventual graft loss and death at 26 months post-transplant. The median follow-up time was 34 months. The 3-year overall SLKT patient survival in the negative FCXM (-FCXM) patients was 85% compared with 71% in the +FCXM group. The rates of acute liver and kidney rejection were 6% and 10%, respectively, in the FCXM group compared to 14% and 28%, respectively, in the +FCXM group. A very strongly +FCXM with a mean channel shift above 4 times the positive cut-off and the presence of multiple strong donor-specific antibodies (DSA) with mean fluorescence intensity (MFI) above 10,000 were associated with poorer outcome. In conclusion, in patients with very strongly +FCXM with high MFI DSA, proceeding with the transplantation leads to poor outcomes. PMID- 28564530 TI - C1q Donor-Specific Antibody Associates with Post-transplant Biopsy Findings in Highly- Sensitized Kidney Transplant Recipients. AB - Donor-specific anti-human leukocyte antigen antibodies (DSA) are associated with antibody-mediated rejection (AMR) in kidney transplantation, but the spectrum of graft injury seen in patients with DSA ranges from no damage to florid rejection. Since immunoglobulin G (IgG) antibodies with cytotoxic potential can be distinguished by their binding complement fraction C1q, the level of C1q-binding IgG (C1q+) DSA may be useful for stratifying risk or diagnosing AMR. We therefore investigated the value of IgG and C1q+ DSA in predicting pathologic features of AMR on kidney biopsies. We tested the associations between DSA at different cut off levels and pathologic features of AMR on biopsy in a cohort of consecutive, highly-sensitized patients transplanted after December 2014 who had 1-, 3-, and 6 month protocol kidney biopsies and monitoring for IgG and C1q+ DSA. Eight patients with cPRA >90% and negative flow crossmatch underwent kidney transplant and completed six months of follow-up contributing 23 pairs of biopsy/ serum samples for analysis. C1q+ DSA was significantly associated with C4d finding on biopsy at mean fluorescence intensity (MFI) cut-offs of >100 (p=0.046) and >300 (p=0.008) and showed superior positive and negative predictive value in comparison to conventional IgG DSA. C1q+ DSA also showed significant association and good predictive value for any AMR feature on biopsy (p=0.003, for >100 MFI; p=0.005 for >300 MFI), while IgG DSA showed no association. In a small cohort of high cPRA transplant recipients, C1q+ DSA outperformed IgG DSA as an indicator of AMR biopsy findings. Including C1q+ DSA testing in post-transplant DSA monitoring of highly-sensitized patients may aid the timely diagnosis of AMR. PMID- 28564531 TI - Acute Rejection in 6-Antigen HLA-Matched Kidney Transplant Recipients: Risk Factors and Outcomes from the Wisconsin Allograft Recipient Database (WisARD). AB - Acute rejection in human leukocyte antigen (HLA)-matched kidney transplant recipients is uncommon and the mechanisms involved are not well understood. Data from 6-antigen HLA-matched recipients transplanted between 1994 and 2014 were analyzed to identify the incidence, risk factors, and outcomes associated with biopsy-proven acute rejection (BPAR). A total of 278 HLA-matched recipients were identified, of which, 155 (55.8%) received a graft from a sibling donor. Ten patients (3.6%) experienced BPAR over a median follow-up of 10 years (0.41 cases per 100 person-years). Median time to rejection was 36.5 months (standard deviation +/-56.4). Recipients who experienced rejection did not differ from those who did not in terms of age, gender, ethnicity, induction agent, panel reactive antibody, or sensitizing events. Acute cellular, antibody-mediated, and mixed rejection occurred in 5, 3, and 2 patients, respectively. The most common biopsy classification was Banff IA (n=4). Four out of 10 patients had documented nonadherence to maintenance immunosuppression. Thirty percent of HLA-matched recipients who rejected had graft loss and 10% died, compared to 30.8% graft loss and 28.4% deaths in non-rejectors (p=0.57 and 0.20, respectively). In conclusion, acute cellular and antibody-mediated rejection are infrequent in HLA-matched kidney transplant recipients. Nonadherence appears to be relatively common among those experiencing rejection. Acute rejection was not associated with higher graft loss or death. The pathogenesis of acute rejection in HLA-matched recipients remains to be determined. PMID- 28564532 TI - Post-transplant Desensitization for Deceased Donor Kidney Transplant Recipients: A Single Center Experience. AB - The highly-sensitized kidney transplant candidate with no available living donors remains at a major disadvantage with decreased access and worse outcomes post transplant. We have previously reported our initial data on both pre-transplant and post-transplant desensitization. We observed only a modest decline in unacceptable antigens with pretransplant intravenous immunoglobin (IVIG) and rituximab. Due to these observations, we have focused on a peri-operative post transplant desensitization protocol in our program. Beginning in 2006, we implemented a simple point-based algorithm [variables included: panel reactive antibody (PRA) status; flow cytometric crossmatch (FCXM); and delayed graft function] to identify kidney transplant recipients who would undergo peri operative plasmapheresis/IVIG to abrogate preformed antibody-mediated allograft rejection (AMR). Our previous results suggested acceptable 5-year outcomes. Here, in an expanded population (N=66), we report an overall death-censored graft survival of 73% at a mean follow-up of 8.5 years post-transplant. Our patients were largely African American (85%) and regrafts (39%), with a median PRA of 88%, and a mean T- and B-FCXM of 97 mean channel shifts (MCS) and 117 MCS, respectively. Although acute AMR rates were acceptable (12%), 22% of patients developed chronic AMR. A pre-transplant T-cell FCXM of > 200 MCS (p=0.02) or presence of donor specific antibodies (DSA) at most recent follow-up (p=0.02) were associated with graft loss. Current studies with revised protocols utilizing additional DSA information, surveillance biopsies, and proteasome inhibition are ongoing. PMID- 28564533 TI - From Accurate Assessment of Anti-HLA Antibody MFI to Complement-Binding Assays. AB - Single antigen bead (SAB) and complement-binding assays are commonly used to monitor immunization in transplant patients. Like all new diagnostic assays, some considerations have to be appreciated to avoid a biased utilization. By truly decreasing antibody concentration, SAB monitoring in sensitized patients experiencing apheresis offers a good opportunity to explore analytical interference. We explored analytical artifacts by analyzing the role of prozone and saturation effects through a concrete example of a single patient who experienced immunoadsorption. We then assessed, on a larger cohort, the link between an accurate assessment of mean fluorescence intensity (MFI) and the C1q and C3d binding assays. Finally, we compared MFI with the two main available SAB assays. After immunoadsorption, the MFI of some antibodies unexpectedly rose. We showed that this increase was due, in part, to both a prozone effect and a saturation of the beads. Dithiothreitol treatment appeared to be an efficient way to avoid a prozone effect. The analysis of dilution profile was an interesting tool to detect a saturation effect. The comparison of the two main SABs revealed a systematic difference of 3000 MFI. MFI was a strong predictor of C1q and C3d positivity. Complement-positive antibodies had a higher MFI (p<0.01). Despite the great contribution of SAB assays in anti-HLA antibody assessment, the knowledge of analytical interference is necessary to avoid any misleading conclusions. With regard to the interference between MFI and complement-binding assays, their place in risk stratification has to be clarified. PMID- 28564534 TI - Influenza Immunization and the Generation of Anti-HLA and Anti-MICA Antibodies in Patients with Renal Failure and in Kidney Transplant Recipients. AB - The aim of this study was to determine whether the influenza vaccine induces the development of anti-human leukocyte antigen (HLA) and anti-major histocompatibility complex class I - chain A (MICA) antibodies. We determined the presence or de novo development of anti-HLA and anti-MICA antibodies in 3 groups of patients vaccinated against influenza: A) 42 healthy adults; B) 40 end-stage kidney disease patients; C) 25 kidney transplant recipients; and, D) 22 healthy adults who refused vaccination. Serum samples per subject were obtained: prior to vaccination, one week after vaccination, and on a monthly basis for 6 months. They were analyzed by LABScreen(r) Single Antigen, Luminex. The proportions of de novo antibodies (anti-HLA and anti-MICA) in the 4 groups were 2.4%, 17.5%, 20%, and 0%, respectively. Some patients developed the antibodies later, unrelated to the vaccine. We found preformed antibodies (anti-HLA and anti-MICA) in 67%, 78%, 88%, and 27% of cases in groups A, B, C, and D, respectively. The presence of preformed antibodies was the only predictive factor for the development of de novo antibodies. In conclusion, the development of de novo anti-HLA and anti-MICA antibodies after an external stimulus other than HLA antigens is possible. However, not all cases can be attributed to the vaccine. PMID- 28564535 TI - Clinical Relevance of Donor-Specific IgM Antibodies in HLA Incompatible Renal Transplantation: A Retrospective Single-Center Study. AB - Immunoglobulin G (IgG) antibodies against donor human leukocyte antigens (HLA) are monitored in the pre-and post-transplant period due to their established role in predicting rejection and renal allograft survival. However, the role of immunoglobulin M (IgM) anti-HLA donor-specific antibodies (DSA) is not fully understood, especially in highly-sensitized patients undergoing direct transplantation. We designed this study to determine whether IgM DSA predicts rejection episodes and/or graft failure. Samples from 92 patients who had undergone HLA-antibody incompatible transplants were tested at 5 time points: days -8 (pre-plasmapheresis), 0, 7, 14, and 30 using Luminex microbead assay with ethylenediaminetetraacetic acid containing wash buffer (LABScreen(r), One Lambda, Canoga Park, CA). IgM was defined positive if the mean fluorescence values were greater than 2000. Presence of pre- and post-transplant IgM was correlated with early antibody mediated rejection episodes (within 30 days post-transplantation) and graft failure. Statistical analyses were performed using SPSS IBM software. Graft survival estimates were death-censored. The presence of pre-transplant IgM DSA did not predict rejection (p=0.83) or graft failure (p=0.424). The post transplant IgM DSA levels peaked at day 14 (similar to IgG DSA levels). Presence of IgM DSA post-transplant (de novo and resynthesis) was not associated with rejection (p=0.83). However, post-transplant IgM was associated with graft failure (p=0.037). This study shows additional testing of post-transplant IgM DSA over and above IgG is important as post-transplant IgM DSA is associated with graft failure. PMID- 28564536 TI - Influence of Feed Composition on the Monomeric Structure of Free Bacterial Extracellular Polysaccharides in Anaerobic Digestion. AB - Six 5.0-L fill-and-draw batch reactors were used with different feed compositions containing a range of carbohydrates (glucose, sucrose, fructose) and nitrogen sources (urea, NH4Cl) at various concentrations to investigate free extracellular polysaccharide (EPS) production during anaerobic digestion (AD). This work analyzed not only their monosaccharide components, but also their specific linkage patterns and the change associated with different chemical nature in carbon substrates or nitrogen sources; all of these parameters can have profound biological consequences, and were correlated to macronutrients present in the feed. It is believed that feed composition is a major factor which determines the physicochemical characteristics of the free EPS. Our findings also suggest that the differences associated with the digestion of various carbon substrates and/or nitrogen sources could alter monomeric saccharide composition and concentrations of the free EPS. Such insights demonstrate that previous studies on feed C/N ratios tended to overestimate EPS production, while variations in the chemical nature of the nitrogen source were overlooked. Our results also link the physiochemical properties of free EPS with underlying biofouling mechanisms, and demonstrate that membrane fouling is to some extent dependent upon the prevailing nutritional environment and feed composition. PMID- 28564538 TI - Mechanism of Off-Target Interactions and Toxicity of Tamoxifen and Its Metabolites. AB - Tamoxifen is an estrogen modulator that acts to competitively inhibit the binding of endogenous estrogens. It is widely used for treatment of breast cancer; however, analogous with many antineoplastic agents, tamoxifen is associated with numerous adverse effects, most prominently nausea. We have identified several off target receptors of tamoxifen and 22 of its metabolites that include histamine H1 and H3, and muscarinic M1, M4, and M5 subtypes, and dopamine D2 receptor. We have shown how they are associated with tamoxifen and its metabolites' toxicity through a comprehensive computational analysis of their interaction modes, which were also compared to that of the related endogenous substrates of each receptor. The results were further evaluated using available in vivo and in vitro data. The presented work provides foundational knowledge toward the determination of the precise mechanism of nausea induction, and in particular, interactions of tamoxifen and its metabolites with the receptors involved in that biomolecular pathway. This study can assist in predicting the potential undesired effects of the chemicals with common pharmacophores or similar fragments to that of tamoxifen and its metabolites and serve drug discovery research in developing more effective and tolerable tamoxifen analogues or chemotherapeutic agents. PMID- 28564539 TI - Spherulitic Growth of Coral Skeletons and Synthetic Aragonite: Nature's Three Dimensional Printing. AB - Coral skeletons were long assumed to have a spherulitic structure, that is, a radial distribution of acicular aragonite (CaCO3) crystals with their c-axes radiating from series of points, termed centers of calcification (CoCs). This assumption was based on morphology alone, not on crystallography. Here we measure the orientation of crystals and nanocrystals and confirm that corals grow their skeletons in bundles of aragonite crystals, with their c-axes and long axes oriented radially and at an angle from the CoCs, thus precisely as expected for feather-like or "plumose" spherulites. Furthermore, we find that in both synthetic and coral aragonite spherulites at the nanoscale adjacent crystals have similar but not identical orientations, thus demonstrating by direct observation that even at nanoscale the mechanism of spherulite formation is non crystallographic branching (NCB), as predicted by theory. Finally, synthetic aragonite spherulites and coral skeletons have similar angle spreads, and angular distances of adjacent crystals, further confirming that coral skeletons are spherulites. This is important because aragonite grows anisotropically, 10 times faster along the c-axis than along the a-axis direction, and spherulites fill space with crystals growing almost exclusively along the c-axis, thus they can fill space faster than any other aragonite growth geometry, and create isotropic materials from anisotropic crystals. Greater space filling rate and isotropic mechanical behavior are key to the skeleton's supporting function and therefore to its evolutionary success. In this sense, spherulitic growth is Nature's 3D printing. PMID- 28564537 TI - Attach-Pull-Release Calculations of Ligand Binding and Conformational Changes on the First BRD4 Bromodomain. AB - Bromodomains, protein domains involved in epigenetic regulation, are able to bind small molecules with high affinity. In the present study, we report free energy calculations for the binding of seven ligands to the first BRD4 bromodomain, using the attach-pull-release (APR) method to compute the reversible work of removing the ligands from the binding site and then allowing the protein to relax conformationally. We test three different water models, TIP3P, TIP4PEw, and SPC/E, as well as the GAFF and GAFF2 parameter sets for the ligands. Our simulations show that the apo crystal structure of BRD4 is only metastable, with a structural transition happening in the absence of the ligand typically after 20 ns of simulation. We compute the free energy change for this transition with a separate APR calculation on the free protein and include its contribution to the ligand binding free energies, which generally causes an underestimation of the affinities. By testing different water models and ligand parameters, we are also able to assess their influence in our results and determine which one produces the best agreement with the experimental data. Both free energies associated with the conformational change and ligand binding are affected by the choice of water model, with the two sets of ligand parameters affecting their binding free energies to a lesser degree. Across all six combinations of water model and ligand potential function, the Pearson correlation coefficients between calculated and experimental binding free energies range from 0.55 to 0.83, and the root-mean-square errors range from 1.4-3.2 kcal/mol. The current protocol also yields encouraging preliminary results when used to assess the relative stability of ligand poses generated by docking or other methods, as illustrated for two different ligands. Our method takes advantage of the high performance provided by graphics processing units and can readily be applied to other ligands as well as other protein systems. PMID- 28564541 TI - Comparative Analysis of Methods for Enhancement of the Photostability of CdTe@TGA QD Colloid Solutions. AB - The employment of colloid quantum dots in a number of applications is limited by their instability under light irradiation. Additional methods of photostability enhancement of UV+visible-irradiated TGA-stabilized CdTe quantum dots are investigated. Photostability enhancement was observed via either addition of sodium sulphite in the role of chemical oxygen absorber or addition of 1% gelatin, or, finally, by additional stabilization by bovine serum albumine (BSA). The latter method is the most promising, since it not only enhances the quantum dots' photostability but also makes them more biocompatible and extends the possibilities of their biological applications. PMID- 28564543 TI - Improved pKa Prediction of Substituted Alcohols, Phenols, and Hydroperoxides in Aqueous Medium Using Density Functional Theory and a Cluster-Continuum Solvation Model. AB - Acid dissociation constants (pKa's) are key physicochemical properties that are needed to understand the structure and reactivity of molecules in solution. Theoretical pKa's have been calculated for a set of 72 organic compounds with -OH and -OOH groups (48 with known experimental pKa's). This test set includes 17 aliphatic alcohols, 25 substituted phenols, and 30 hydroperoxides. Calculations in aqueous medium have been carried out with SMD implicit solvation and three hybrid DFT functionals (B3LYP, omegaB97XD, and M06-2X) with two basis sets (6 31+G(d,p) and 6-311++G(d,p)). The effect of explicit water molecules on calculated pKa's was assessed by including up to three water molecules. pKa's calculated with only SMD implicit solvation are found to have average errors greater than 6 pKa units. Including one explicit water reduces the error by about 3 pKa units, but the error is still far from chemical accuracy. With B3LYP/6 311++G(d,p) and three explicit water molecules in SMD solvation, the mean signed error and standard deviation are only -0.02 +/- 0.55; a linear fit with zero intercept has a slope of 1.005 and R2 = 0.97. Thus, this level of theory can be used to calculate pKa's directly without the need for linear correlations or thermodynamic cycles. Estimated pKa values are reported for 24 hydroperoxides that have not yet been determined experimentally. PMID- 28564540 TI - A Continuum Poisson-Boltzmann Model for Membrane Channel Proteins. AB - Membrane proteins constitute a large portion of the human proteome and perform a variety of important functions as membrane receptors, transport proteins, enzymes, signaling proteins, and more. Computational studies of membrane proteins are usually much more complicated than those of globular proteins. Here, we propose a new continuum model for Poisson-Boltzmann calculations of membrane channel proteins. Major improvements over the existing continuum slab model are as follows: (1) The location and thickness of the slab model are fine-tuned based on explicit-solvent MD simulations. (2) The highly different accessibilities in the membrane and water regions are addressed with a two-step, two-probe grid labeling procedure. (3) The water pores/channels are automatically identified. The new continuum membrane model is optimized (by adjusting the membrane probe, as well as the slab thickness and center) to best reproduce the distributions of buried water molecules in the membrane region as sampled in explicit water simulations. Our optimization also shows that the widely adopted water probe of 1.4 A for globular proteins is a very reasonable default value for membrane protein simulations. It gives the best compromise in reproducing the explicit water distributions in membrane channel proteins, at least in the water accessible pore/channel regions. Finally, we validate the new membrane model by carrying out binding affinity calculations for a potassium channel, and we observe good agreement with the experimental results. PMID- 28564542 TI - Repurposing Suzuki Coupling Reagents as a Directed Fragment Library Targeting Serine Hydrolases and Related Enzymes. AB - Serine hydrolases are susceptible to potent reversible inhibition by boronic acids. Large collections of chemically diverse boronic acid fragments are commercially available because of their utility in coupling chemistry. We repurposed the approximately 650 boronic acid reagents in our collection as a directed fragment library targeting serine hydrolases and related enzymes. Highly efficient hits (LE > 0.6) often result. The utility of the approach is illustrated with the results against autotaxin, a phospholipase implicated in cardiovascular disease. PMID- 28564544 TI - Giant Enhancement of Defect-Bound Exciton Luminescence and Suppression of Band Edge Luminescence in Monolayer WSe2-Ag Plasmonic Hybrid Structures. AB - We have investigated how the photoluminescence (PL) of WSe2 is modified when coupled to Ag plasmonic structures at low temperature. Chemical vapor deposition (CVD) grown monolayer WSe2 flakes were transferred onto a Ag film and a Ag nanotriangle array that had a 1.5 nm Al2O3 capping layer. Using low-temperature (7.5 K) micro-PL mapping, we simultaneously observed enhancement of the defect bound exciton emission and quenching of the band edge exciton emission when the WSe2 was on a plasmonic structure. The enhancement of the defect-bound exciton emission was significant with enhancement factors of up to ~200 for WSe2 on the nanotriangle array when compared to WSe2 on a 1.5 nm Al2O3 capped Si substrate with a 300 nm SiO2 layer. The giant enhancement of the luminescence from the defect-bound excitons is understood in terms of the Purcell effect and increased light absorption. In contrast, the surprising result of luminescence quenching of the bright exciton state on the same plasmonic nanostructure is due to a rather unique electronic structure of WSe2: the existence of a dark state below the bright exciton state. PMID- 28564545 TI - Reaction Progress Kinetics Analysis of 1,3-Disiloxanediols as Hydrogen-Bonding Catalysts. AB - 1,3-Disiloxanediols are effective hydrogen-bonding catalysts that exhibit enhanced activity relative to silanediols and triarylsilanols. The catalytic activity for a series of 1,3-disiloxanediols, including naphthyl-substituted and unsymmetrical siloxanes, has been quantified and compared relative to other silanol and thiourea catalysts using the Friedel Crafts addition of indole to trans-beta-nitrostyrene. An in-depth kinetic study using reaction progress kinetic analysis (RPKA) has been performed to probe the catalyst behavior of 1,3 disiloxanediols. The data confirm that the disiloxanediol-catalyzed addition reaction is first order in catalyst over all concentrations studied with no evidence of catalyst self-association. 1,3-Disiloxanediols proved to be robust and recoverable catalysts with no deactivation under reaction conditions. No product inhibition is observed, and competitive binding studies with nitro containing additives suggest that 1,3-disiloxanediols bind weakly to nitro groups but are strongly activating for catalysis. PMID- 28564546 TI - Polyurethane Microgel Based Microtissue: Interface-Guided Assembly and Spreading. AB - Colloidal gels are three-dimensional networks of microgel particles and can be utilized to design microtissues where the differential adhesive interactions between the particles and cells, guided by their surface energetics, are engineered to spatially assemble the cellular and colloidal components into three dimensional microtissues. In this work we utilized a colloidal interaction approach to design cell-polyurethane (PU) microgel bimodal microtissues using endothelial cells (ECs) as a normal cell model and a nonmalignant breast cancer cell line (MCF-7) as a cancer cell model. PU microgels were developed from a library of segmental polyurethanes with poly(ethylene glycol) soft segment and aliphatic diisocyanate/l-tyrosine based chain extender as hard segment to modulate the interactions between PU colloidal particles and cells. The surface energies of the microgel particles and cells were estimated using Zisman's critical surface tension and van Oss-Good-Chaudhury theory (vOGCT) from liquid contact angle analysis. Binary interaction potentials between colloidal PU particles and cells and the ternary interaction between colloidal PU particle, cell, and collagen I/Matrigel were calculated to explain the formation of microtissues and their spreading in extraneous biomatrix respectively by using classical and extended DLVO theory (XDLVO). Furthermore, rheological analysis and in silico simulations were used to analyze the assembly and spreading of the PU microgel based microtissues. In vitro experiments showed that ECs and MCF-7 displayed more differentiated (EC spreading/MCF-7 lumen formation) character when mixed with microgel particles that were stable in aqueous medium and more undifferentiated character (EC nonspreading/MCF-7 spreading) when mixed with microgel particles unstable in aqueous medium. PMID- 28564547 TI - Challenges to the provision of community aged care services across rural Australia: perceptions of service managers. AB - INTRODUCTION: The Australian community aged care sector is facing a growing workforce crisis, particularly in rural and regional areas. Its predominantly female workforce is ageing, and recruiting younger, skilled workers is proving difficult. The service sector, too, is proving highly complex and diverse as a result of contemporary aged care service reforms as well as ongoing difficulties in providing services to the growing numbers of older people living in Australia's rural areas. Despite these multiple challenges, there is a gap in research that explores how rural aged care services manage their day-to-day requirements for skilled workers across the diverse service sector. To address this gap, this article reports on the experiences and perceptions of a small sample of service managers whose organisations represent this diversity, and who are accountable for care provision in regional and rural locations. In such areas, recruitment and skill needs are contoured by disproportionate aged populations, distance and reduced service availability. METHODS: Eleven service managers were interviewed as part of a larger project that examined the skill and training needs of community aged care workers within the Riverina, a rural region in New South Wales. Qualitative data drawn from semi-structured interviews were thematically analysed to identify the managers' individual needs for workers and skills in the context of location, service parameters and availability of other health and community services. RESULTS: Thematic analysis of the interview data elicited three themes: services, roles and skill deployment; older workers and gendered roles; and barriers to recruitment. The findings illustrate the complexities that characterise the community aged care sector as a whole and the impact of these on individual services located in regional and rural parts of Australia. The participants reported diverse needs for worker skills in keeping with the particular level of service they provide. Significantly, their varying perceptions and practices reflect their preference for older, female workers; their reluctance to take on younger workers is negatively skewed by a lack of capacity to compete for, recruit and retain such workers and to offer incentives in the form of enhanced roles and career development. CONCLUSIONS: The findings highlight the conceptual ambiguities inherent in definitions of community aged care work as broadly skilled and uniformly sought across the sector. On the one hand, demands for more and better trained workers to meet growing client complexity locate care work as skilled. On the other, managers of narrowly defined service activities may rely on a diminishing workforce whose skills they downplay in gendered and lay terms. This contradiction corresponds with long-held conclusions about the gendered, exploitative reputation of care work, a characterisation discursively constructed by privileging the moral dimensions of the job over the technical skills required for it. Significantly, the findings raise questions about the capacity of services, as they are currently structured and differentiated, to reshape and redefine aged care work as a 'good job', one that holds appeal and tangible rewards for new and younger skilled workers. PMID- 28564548 TI - Feasibility of developing a pediatric telehealth network in Honduras with international consultation support. AB - INTRODUCTION: Honduras is the second poorest country in Central America, and roughly 50% of the population lives in rural areas. A telehealth network linking these areas to larger health centers may improve patient access to care, and physician access to educational opportunities. This pilot study assessed the feasibility of establishing a pediatric telehealth network between underserved clinics in Honduras and the Medical University of South Carolina (MUSC). METHODS: Two underserved Honduran clinics were identified and invited to participate in the telehealth network. Providers from these clinics connected remotely to educational conferences at MUSC, and received teleconsults from MUSC physicians and physicians from the other Honduran site. Honduran providers completed five point Likert scale satisfaction surveys following participation in the conferences and teleconsults. RESULTS: Survey feedback was positive, with 100% of respondents stating they would utilize telemedicine in the future. Dissatisfaction was expressed subjectively in the survey comments with regards to poor Internet connectivity and unreliable electrical power. CONCLUSIONS: The establishment of a telehealth network between Honduras and MUSC is feasible, and rural providers were receptive to the clinical and educational opportunities this network provides. Future projects will expand telehealth capabilities to other Honduran sites and focus on intra-country collaboration to ensure sustainability. PMID- 28564549 TI - The Role of Science in Addressing the Opioid Crisis. PMID- 28564550 TI - Deja Vu: Introducing Operations Research to Health Care. PMID- 28564552 TI - Prospects for Health Care Reform in the U.S. Senate. PMID- 28564551 TI - A Framework for Treatment Decision Making at Prostate Cancer Recurrence. AB - BACKGROUND: Of the 50,000 men in the US who elect for radical prostatectomy for prostate cancer, 24% to 40% will have a prostate-specific antigen (PSA) recurrence (PSA-R) within 10 years. Deciding whether to administer salvage therapy (ST) at PSA-R presents challenges, as treatment reduces the risk of progression to clinical metastasis but incurs unnecessary side effects should the man die before metastasis. We have developed a new harm-benefit framework using a clinical cohort to inform shared decision making between patients and physicians at PSA-R. METHODS: Records of 1,045 Johns Hopkins University Hospital patients diagnosed between 1984 and 2013 who had PSA-R following radical prostatectomy were analyzed using marginal structural models to estimate the baseline risk of metastasis and the effect of ST (radiation therapy with or without hormone therapy) while accounting for selection into ST on the basis of PSA growth. The estimated model predicts the harm-benefit tradeoffs of ST within patient subgroups. The benefit of ST is the absolute reduction in the risk of metastasis within 10 years; the harm is the frequency of cancers that would not have metastasized in the patient's lifetime in the absence of ST (overtreatment). RESULTS: The adjusted hazard ratio associated with ST was 0.41 (95% CI, 0.31 to 0.55). Providing ST to all men at PSA-R reduced the risk of metastasis from 43% to 23% but led to 31% of men being overtreated (harm/benefit = 31/(43-23) = 1.6). Providing ST to men with Gleason score >7 reduced the risk of metastasis from 67% to 39%, with 13% of men being overtreated (harm/benefit = 13/(67-39) = 0.5). CONCLUSIONS: A quantitative framework that evaluates primary harms and benefits of ST after PSA-R will facilitate informed decision making. Immediate ST may be more appropriate in patient subgroups at elevated risk of metastasis. PMID- 28564553 TI - Structural and Mechanistic Insights into Protein Translocation. AB - Many proteins are translocated across the endoplasmic reticulum (ER) membrane in eukaryotes or the plasma membrane in prokaryotes. These proteins use hydrophobic signal sequences or transmembrane (TM) segments to trigger their translocation through the protein-conducting Sec61/SecY channel. Substrates are first directed to the channel by cytosolic targeting factors, which use hydrophobic pockets to bind diverse signal and TM sequences. Subsequently, these hydrophobic sequences insert into the channel, docking into a groove on the outside of the lateral gate of the channel, where they also interact with lipids. Structural data and biochemical experiments have elucidated how channel partners, the ribosome in cotranslational translocation, and the eukaryotic ER chaperone BiP or the prokaryotic cytosolic SecA ATPase in posttranslational translocation move polypeptides unidirectionally across the membrane. Structures of auxiliary components of the bacterial translocon, YidC and SecD/F, provide additional insight. Taken together, these recent advances result in mechanistic models of protein translocation. PMID- 28564555 TI - Holocarboxylase Synthetase: A Moonlighting Transcriptional Coregulator of Gene Expression and a Cytosolic Regulator of Biotin Utilization. AB - The vitamin biotin is an essential nutrient for the metabolism and survival of all organisms owing to its function as a cofactor of enzymes collectively known as biotin-dependent carboxylases. These enzymes use covalently attached biotin as a vector to transfer a carboxyl group between donor and acceptor molecules during carboxylation reactions. In human cells, biotin-dependent carboxylases catalyze key reactions in gluconeogenesis, fatty acid synthesis, and amino acid catabolism. Biotin is attached to apocarboxylases by a biotin ligase: holocarboxylase synthetase (HCS) in mammalian cells and BirA in microbes. Despite their evolutionary distance, these proteins share structural and sequence similarities, underscoring their importance across all life forms. However, beyond its role in metabolism, HCS participates in the regulation of biotin utilization and acts as a nuclear transcriptional coregulator of gene expression. In this review, we discuss the function of HCS and biotin in metabolism and human disease, a putative role for the enzyme in histone biotinylation, and its participation as a nuclear factor in chromatin dynamics. We suggest that HCS be classified as a moonlighting protein, with two biotin-dependent cytosolic metabolic roles and a distinct biotin-independent nuclear coregulatory function. PMID- 28564554 TI - The Nexus Between Nutrition and Early Childhood Development. AB - This article looks at both nutrition and early childhood stimulation interventions as part of an integrated life cycle approach to development. We build on recent systematic reviews of child development, which are comprehensive in regard to what is currently known about outcomes reported in key studies. We then focus particularly on implementation, scaling, and economic returns, drawing mainly on experience in low- and middle-income countries where undernutrition and poor child development remain significant public health challenges with implications across the life course. PMID- 28564556 TI - Brain on Fire: Incentive Salience, Hedonic Hot Spots, Dopamine, Obesity, and Other Hunger Games. AB - This review examines human feeding behavior in light of psychological motivational theory and highlights the importance of midbrain dopamine (DA). Prospective evidence of both reward surfeit and reward deficit pathways to increased body weight are evaluated, and we argue that it is more complex than an either/or scenario when examining DA's role in reward sensitivity, eating, and obesity. The Taq1A genotype is a common thread that ties the contrasting models of DA reward and obesity; this genotype related to striatal DA is not associated with obesity class per se but may nevertheless confer an increased risk of weight gain. We also critically examine the concept of so-called food addiction, and despite growing evidence, we argue that there is currently insufficient human data to warrant this diagnostic label. The surgical and pharmacological treatments of obesity are discussed, and evidence is presented for the selective use of DA-class drugs in obesity treatment. PMID- 28564558 TI - Spiraling Out of Control. PMID- 28564557 TI - Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis. AB - BACKGROUND: On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis. METHODS: During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2-weighted MRI, cumulative number of new lesions enhanced on T1-weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T1-weighted MRI plus new and newly enlarged lesions on T2-weighted MRI]). RESULTS: A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo. CONCLUSIONS: The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .). PMID- 28564559 TI - Minocycline in Multiple Sclerosis - Compelling Results but Too Early to Tell. PMID- 28564561 TI - A 1980 Letter on the Risk of Opioid Addiction. PMID- 28564562 TI - Health Policy Trials. PMID- 28564563 TI - The Other Victims of the Opioid Epidemic. PMID- 28564564 TI - Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. AB - BACKGROUND: Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2) negative breast cancer have poor prognoses. The benefit of adjuvant chemotherapy in these patients remains unclear. METHODS: We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival. RESULTS: The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval [CI], 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand-foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group. CONCLUSIONS: After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843 .). PMID- 28564565 TI - Myeloproliferative Neoplasms. PMID- 28564566 TI - Screening for Chlamydia trachomatis Infections in Women. PMID- 28564567 TI - Screening for Chlamydia trachomatis Infections in Women. PMID- 28564568 TI - Abuse-Deterrent Opioid Formulations - Putting the Potential Benefits into Perspective. PMID- 28564570 TI - Delegalizing Advance Directives - Facilitating Advance Care Planning. PMID- 28564571 TI - Radiation plus Temozolomide in Patients with Glioblastoma. PMID- 28564572 TI - Radiation plus Temozolomide in Patients with Glioblastoma. PMID- 28564569 TI - Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. AB - BACKGROUND: Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options. METHODS: We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir-voxilaprevir (163 patients) or sofosbuvir velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. RESULTS: In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir-velpatasvir-voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir-velpatasvir voxilaprevir and 90% with sofosbuvir-velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower. CONCLUSIONS: Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247 .). PMID- 28564573 TI - Dysphagia after Occipitocervical Fusion. PMID- 28564574 TI - Evolution of Purpura Fulminans. PMID- 28564575 TI - Seeing the Forest through the Phylogenetic Tree. PMID- 28564576 TI - The endocannabinoid system as a target for addiction treatment: Trials and tribulations. AB - Addiction remains a major public health concern, and while pharmacotherapies can be effective, clinicians are limited by the paucity of existing interventions. Endocannabinoid signaling is involved in reward and addiction, which raises the possibility that drugs targeting this system could be used to treat substance use disorders. This review discusses findings from randomized controlled trials evaluating cannabinergic medications for addiction. Current evidence suggests that pharmacotherapies containing delta-9-tetrahydrocannabinol, such as dronabinol and nabiximols, are effective for cannabis withdrawal. Dronabinol may also reduce symptoms of opioid withdrawal. The cannabinoid receptor 1 (CB1) inverse agonist rimonabant showed promising effects for smoking cessation but also caused psychiatric side effects and currently lacks regulatory approval. Few trials have investigated cannabinergic medications for alcohol use disorder. Overall, the endocannabinoid system remains a promising target for addiction treatment. Development of novel medications such as fatty acid amide hydrolase inhibitors and neutral CB1 antagonists promises to extend the range of available interventions. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". PMID- 28564577 TI - Gene therapy and editing: Novel potential treatments for neuronal channelopathies. AB - Pharmaceutical treatment can be inadequate, non-effective, or intolerable for many people suffering from a neuronal channelopathy. Development of novel treatment options, particularly those with the potential to be curative is warranted. Gene therapy approaches can permit cell-specific modification of neuronal and circuit excitability and have been investigated experimentally as a therapy for numerous neurological disorders, with clinical trials for several neurodegenerative diseases ongoing. Channelopathies can arise from a wide array of gene mutations; however they usually result in periods of aberrant network excitability. Therefore gene therapy strategies based on up or downregulation of genes that modulate neuronal excitability may be effective therapy for a wide range of neuronal channelopathies. As many channelopathies are paroxysmal in nature, optogenetic or chemogenetic approaches may be well suited to treat the symptoms of these diseases. Recent advances in gene-editing technologies such as the CRISPR-Cas9 system could in the future result in entirely novel treatment for a channelopathy by repairing disease-causing channel mutations at the germline level. As the brain may develop and wire abnormally as a consequence of an inherited or de novo channelopathy, the choice of optimal gene therapy or gene editing strategy will depend on the time of intervention (germline, neonatal or adult). This article is part of the Special Issue entitled 'Channelopathies.' PMID- 28564578 TI - Metabolic profiling of the hepatotoxicity and nephrotoxicity of Ginkgolic acids in rats using ultra-performance liquid chromatography-high-definition mass spectrometry. AB - Ginkgolic acids (GAs) are thought to be the potentially hazardous constituents corresponding to the toxic side effects of Ginkgo products. In this study, toxicological and metabolomics studies of GAs were carried out by ultra performance liquid chromatography-high-definition mass spectrometry (UPLC-HDMS). Significant changes in serum clinical chemistry were observed in the both low (100 mg/kg) and high (900 mg/kg) doses. Especially the serum enzyme of ALT, AST, LDH, and CK decreased in treated groups. The histopathological observation demonstrated hepatic steatosis in liver and tubular vacuolar degeneration in kidney. These results demonstrated the hepatotoxicity and nephrotoxicity of GAs. Functional disorders are more likely to be toxic induced by GAs. Metabolic profiling within seven days revealed the change of the body status after oral administration. The results indicated the body function was significantly influenced at the 3rd day and could recover in seven days. Metabolomic analysis showed alterations in 14 metabolites from plasma such as LysoPC(18:0), LysoPC(18:2) and other lipids. The results suggested that exposure to GAs could cause disturbances in liver and kidney function associated with the metabolisms of lipids, glucose and the enzyme activity. PMID- 28564579 TI - Lipid membranes catalyse the fibril formation of the amyloid-beta (1-42) peptide through lipid-fibril interactions that reinforce secondary pathways. AB - Alzheimer's disease is associated with the aggregation of amyloid-beta (Abeta) peptides into oligomers and fibrils. We have explored how model lipid membranes modulate the rate and mechanisms of Abeta(1-42) self-assembly, in order to shed light on how this pathological reaction may occur in the lipid-rich environments that the peptide encounters in the brain. Using a combination of in vitro biophysical experiments and theoretical approaches, we show that zwitterionic DOPC lipid vesicles accelerate the Abeta(1-42) fibril growth rate by interacting specifically with the growing fibrils. We probe this interaction with help of a purpose-developed Forster resonance energy transfer assay that monitors the proximity between a fibril-specific dye and fluorescent lipids in the lipid vesicle membrane. To further rationalise these findings we use mathematical models to fit the aggregation kinetics of Abeta(1-42) and find that lipid vesicles alter specific mechanistic steps in the aggregation reaction; they augment monomer-dependent secondary nucleation at the surface of existing fibrils and facilitate monomer-independent catalytic processes consistent with fibril fragmentation. We further show that DOPC vesicles have no effect on primary nucleation. This finding is consistent with experiments showing that Abeta(1-42) monomers do not directly bind to the lipid bilayer. Taken together, our results show that plain lipid membranes with charge and composition that is representative of outer cell membranes can significantly augment autocatalytic steps in the self-assembly of Abeta(1-42) into fibrils. This new insight suggests that strategies to reduce fibril-lipid interactions in the brain may have therapeutic value. PMID- 28564580 TI - The death pathways in mussel larval cells after a freeze-thaw cycle. AB - We analyzed cell viability, caspase activity, plasma membrane alterations and cell ultrastructure morphology to estimate the morphological and biochemical alterations that occur in bivalve molluscan cell cultures during cryopreservation. The use of 5% dymethyl sulfoxide as a cryoprotectant resulted in greater cell survival and a scarcity of destroyed cells lacking cytosol among dead cells. In this case, almost all cells died through necrosis or apoptosis, which appeared to increase in mussel cell cultures after a freeze-thaw cycle. Apoptosis was not a main death pathway in mussel cells, but it was induced in a significant part of these cells (up to 24%) immediately after thawing and depended mostly on the cryoprotectant used. Regardless of the type of the used cryoprotectant, we observed some nuclear aberrations in cells after freezing thawing, such as few multipolar mitoses or the absence of a division spindle in mitotic cells. After analyzing different methods for assessing cell damage, the best results were obtained from optimal approaches that could provide information regarding the cell disruption level after freezing-thawing and could be considered for future studies. PMID- 28564581 TI - Identification, characterization, and function analysis of the NF-kappaB repressing factor (NKRF) gene from Litopenaeus vannamei. AB - The NF-kappaB family transcription factors regulate a wide spectrum of biological processes, in particular immune responses. The studies in human suggest that the NF-kappaB repressing factor (NKRF) negatively regulates the activity of NF-kappaB through a direct protein-protein interaction. However, the function of NKRF has not been studied outside mammals up to now. The current study identified a NKRF gene (LvNKRF) from the Pacific white shrimp, Litopenaeus vannamei, which showed homology with NKRFs from insects, fishes and mammals. LvNKRF was high expressed in intestine, stomach and muscle tissues and was localized in the nucleus. LvNKRF could interact with both Dorsal and Relish, the two members of the shrimp NF kappaB family. Interestingly, although sharing a similar protein structure with that of human NKRF, LvNKRF showed no inhibitory but instead enhancing effects on activities of Dorsal and Relish, which was contrary to those of mammalian NKRFs. The expression of LvNKRF could not be induced by Gram-positive and -negative bacteria and immunostimulants lipopolysaccharide (LPS) and poly (I:C) but was significantly up-regulated after white spot syndrome virus (WSSV) infection. Silencing of LvNKRF significantly decreased the mortalities of shrimp caused by WSSV infection and down-regulated the WSSV copies and the expression of WSSV structural gene in tissues. These suggested that LvNKRF could facilitate the infection of shrimp by WSSV, which may be an additional strategy for WSSV to hijack the host NF-kappaB pathway to favor its own replication. The current study could provide a valuable context for further investigating the evolutionary derivation of NKRFs and facilitate the study of regulatory mechanisms of invertebrate NF-kappaB pathways. PMID- 28564582 TI - MicroRNA-145 protects follicular granulosa cells against oxidative stress-induced apoptosis by targeting Kruppel-like factor 4. AB - Oxidative stress-induced follicular granulosa cell (GC) apoptosis plays an essential role in abnormal follicular atresia, which may trigger ovarian dysfunction. To investigate the role of microRNA (miR)-145 in the regulation of GC apoptosis and modulation of the apoptotic pathway in the setting of oxidative stress, we employed an H2O2-induced in vitro model and a 3-nitropropionic acid (NP)-induced in vivo model of ovarian oxidative stress. We demonstrated in vitro that miR-145 expression was significantly down-regulated in KGN cells and mouse granulosa cells (mGCs) treated with H2O2, whereas miR-145 over-expression attenuated H2O2-induced apoptosis in GCs. Moreover, miR-145 protected GCs against H2O2-induced apoptosis by targeting KLF4, which promoted H2O2-induced GC apoptosis via the BAX/BCL-2 pathway. Importantly, decreased miR-145 expression in the in vivo ovarian oxidative stress model promoted apoptosis by up-regulating KLF4 expression, whereas GC-specific miR-145 over-expression attenuated apoptosis by targeting KLF4. In conclusion, miR-145 protects GCs against oxidative stress induced apoptosis by targeting KLF4. PMID- 28564583 TI - Fibroblast growth factors (FGFs) in cancer: FGF traps as a new therapeutic approach. AB - Originally characterized as angiogenic factors, fibroblast growth factors (FGFs) are pleiotropic factors that exert autocrine and paracrine functions on tumor and stromal cells. Thus, they may represent key players in the complex crosstalk among angiogenesis, inflammation, tumor growth, and drug resistance, all contributing to tumor progression. Given the multiple activities of FGFs, inhibitors of the FGF/FGFR system may act as "two compartment" targeting drugs able to exert a deep impact on the growth of FGF/FGFR-driven tumors. To date, the discovery of drugs targeting the FGF/FGFR system has focused mainly on the development of selective and non-selective tyrosine kinase FGFR inhibitors. Recently, a different approach has been emerging, aimed at the development of extracellular "FGF ligand traps" able to bind and sequester FGFs, thus preventing their interaction with cognate signaling receptors. This approach is based on the identification of natural FGF ligands followed by the development of small molecule mimetics endowed with a significant FGF binding/neutralizing capacity. Aim of this review is to provide an overview of the role of the FGF/FGFR system in cancer and a comprehensive analysis of the process, based on the study of the FGF interactome, which has led to the identification and characterization of FGF ligand traps. This approach has allowed the development of promising FGF targeting molecules with potential implications for the therapy of FGF-driven tumors. PMID- 28564584 TI - Hydroalcoholic extract from Nerium oleander L. (Apocynaceae) elicits arrhythmogenic activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Nerium oleander L. (OLE) has been used medicinally and is reported to possess a wide range of pharmacological activities. OLE effects are caused by different cardiac glycosides (CG), primarily oleandrin, found within the plant. CG can potentially impair sodium potassium ATPase (NKA) pump activity and cause positive inotropic effects on the heart. AIM OF THE STUDY: The aim of this study was to investigate the potential arrhythmogenic effects of hydroalcoholic extracts from N. oleander (OLE). MATERIALS AND METHODS: OLE hydroalcoholic extracts were obtained from N. oleander leaves and analyzed by HPLC. In vivo experiments with guinea pigs consisted if oral administration of water, 150mg/kg and 300mg/kg OLE extract. Clinical signs and ECG analysis were evaluated. Sample tissues from the heart were processed for histopathological and ultra-structural analysis. Autonomic effects were assessed through pharmacological blockade and ECG monitoring. In vitro experiments were conducted with isolated ventricular myocytes from adult mice. The effects of OLE extract on cardiac excitability, Na+/K+ pump current and global Ca2+ transients were evaluated. RESULTS: Our results demonstrated that OLE hydroalcoholic extract elicited severe cardiac arrhythmias that can lead to death with minimal tissue damage. In vitro experiments suggest that OLE causes electromechanical disturbances in the heart due to inhibition of Na+/K+ pump, mitochondrial swelling, and modulation of the sarco(endo)plasmic Ca2+ ATPase without interfering with the autonomic nervous system. Thus, arrhythmias and electrical conduction disturbances promoted by OLE are mainly associated with impaired cardiomyocyte dysfunction, rather than anatomical tissue remodeling and/or autonomic modulation. CONCLUSION: Our data revealed the potential cardiotoxicity and positive inotropic effect of OLE and its important role in modulation of electrophysiology in cardiomyocytes. PMID- 28564585 TI - Hunger, taste, and normative cues in predictions about food intake. AB - Normative eating cues (portion size, social factors) have a powerful impact on people's food intake, but people often fail to acknowledge the influence of these cues, instead explaining their food intake in terms of internal (hunger) or sensory (taste) cues. This study examined whether the same biases apply when making predictions about how much food a person would eat. Participants (n = 364) read a series of vignettes describing an eating scenario and predicted how much food the target person would eat in each situation. Some scenarios consisted of a single eating cue (hunger, taste, or a normative cue) that would be expected to increase intake (e.g., high hunger) or decrease intake (e.g., a companion who eats very little). Other scenarios combined two cues that were in conflict with one another (e.g., high hunger + a companion who eats very little). In the cue conflict scenarios involving an inhibitory internal/sensory cue (e.g., low hunger) with an augmenting normative cue (e.g., a companion who eats a lot), participants predicted a low level of food intake, suggesting a bias toward the internal/sensory cue. For scenarios involving an augmenting internal/sensory cue (e.g., high hunger) and an inhibitory normative cue (e.g., a companion who eats very little), participants predicted an intermediate level of food intake, suggesting that they were influenced by both the internal/sensory and normative cue. Overall, predictions about food intake tend to reflect a general bias toward internal/sensory cues, but also include normative cues when those cues are inhibitory. If people are systematically biased toward internal, sensory, and inhibitory cues, then they may underestimate how much food they or other people will eat in many situations, particularly when normative cues promoting eating are present. PMID- 28564586 TI - A 57-year-old chronic cougher with somatically evoked cough. PMID- 28564587 TI - Effects of low-frequency electrical stimulation of the anterior piriform cortex on kainate-induced seizures in rats. AB - OBJECTIVE: Recent evidence in animals and humans suggests that low-frequency stimulation (LFS) has significant antiepileptic properties. The anterior piriform cortex (APC) is a highly susceptible seizure-trigger zone and may be critical for the initiation and propagation of seizures originating from cortical and limbic foci. We used the kainic acid (KA) seizure model in rats to assess the therapeutic effect of LFS of the APC on seizures. METHODS: Adult male Sprague Dawley rats were implanted with electrodes in the left APC and recording electrodes bilaterally in the hippocampal CA3 regions. Rats were monitored continuously with video-EEG after the emergence of spontaneous recurrent seizures that followed induction of status epilepticus by intraperitoneal KA. After two weeks of baseline recordings to determine seizure frequency, LFS of the APC was applied 60-min On 15-min Off, for two weeks with 1Hz biphasic square waves, 0.2ms pulse width, at 200MUA. Another 2-week period of video-EEG monitoring was done after the cessation of LFS to study the carry-over effect. Changes in seizure frequency, severity, and duration between baseline, during LFS, and post-LFS were analyzed using the Poisson regression model. RESULTS: Overall seizure frequency decreased during the post-LFS period to 5% of that at baseline (p=0.003). Severe seizures (stages 4 and 5 on the Racine scale) decreased to 0% of the baseline during the post-LFS period. CONCLUSIONS: Two weeks of LFS of the APC reduced spontaneous seizure frequency and severity in the KA model with the effect outlasting the stimulation. Our findings suggest that the APC can be an important therapeutic target for stimulation in epilepsy. PMID- 28564588 TI - Social, proximal and conditioned threat. AB - Responding to threats in the environment is crucial for survival. Certain types of threat produce defensive responses without necessitating previous experience and are considered innate, whereas other threats are learned by experiencing aversive consequences. Two important innate threats are whether an encountered stimulus is a member of the same species (social threat) and whether a stimulus suddenly appears proximal to the body (proximal threat). These threats are manifested early in human development and robustly elicit defensive responses. Learned threat, on the other hand, enables adaptation to threats in the environment throughout the life span. A well-studied form of learned threat is fear conditioning, during which a neutral stimulus acquires the ability to eliciting defensive responses through pairings with an aversive stimulus. If innate threats can facilitate fear conditioning, and whether different types of innate threats can enhance each other, is largely unknown. We developed an immersive virtual reality paradigm to test how innate social and proximal threats are related to each other and how they influence conditioned fear. Skin conductance responses were used to index the autonomic component of the defensive response. We found that social threat modulates proximal threat, but that neither proximal nor social threat modulates conditioned fear. Our results suggest that distinct processes regulate autonomic activity in response to proximal and social threat on the one hand, and conditioned fear on the other. PMID- 28564589 TI - Functional monitoring of peripheral nerves from electrical impedance measurements. AB - Medical electrical stimulators adapted to peripheral nerves use multicontact cuff electrodes (MCC) to provide selective neural interfaces. However, neuroprostheses are currently limited by their inability to locate the regions of interest to focus. Intended until now either for stimulation or recording, MCC can also be used as a means of transduction to characterize the nerve by impedancemetry. In this study, we investigate the feasibility of using electrical impedance (EI) measurements as an in vivo functional nerve monitoring technique. The monitoring paradigm includes the synchronized recording of both the evoked endogenous activity as compound action potentials (CAP) and the superimposed sine signal from the EI probe. Measurements were conducted on the sciatic nerve of rodents, chosen for its branchings towards the peroneal and tibial nerves, with both mono- and multi-contact per section electrodes. During stimulation phases, recordings showed CAP with consistent fiber conduction velocities. During coupled phases of both stimulation and sine perturbation, impedance variations were extracted using the mono-contact electrode type for certain frequencies, e.g. 2.941kHz, and were temporally coherent with the previous recorded CAP. Using a MCC, localized evoked CAP were also recorded but the signal to noise ratio (SNR) was too low to distinguish the expected associated impedance variation and deduce an image of impedance spatial changes within the nerve. The conducted in vivo measurements allowed to distinguish both evoked CAP and associated impedance variations with a strong temporal correlation. This indicates the feasibility of functional EI monitoring, aiming at detecting the impedance variations in relation to neural activity. Further work is needed to improve the in vivo system, namely in terms of SNR, and to integrate new multicontact devices in order to move towards EI tomography with the detection of spatially-localized impedance variations. Eventually, regions that are interesting to be targeted by stimulation could be identified through these means. PMID- 28564590 TI - Long intergenic non-coding RNA 668 regulates VEGFA signaling through inhibition of miR-297 in oral squamous cell carcinoma. AB - Recently, long noncoding RNAs (lncRNAs) have been reported to have crucial regulatory efficiency in human cancer biology. Long intergenic non-coding RNA 668 (LINC00668) was regarded as an oncogene in multiple cancers. However, the underlying molecular mechanism of LINC00668 in oral squamous cell carcinoma (OSCC) has not been studied. In this study, we first demonstrated that LINC00668 expression was up-regulated, which was correlated with tumor progression, and miR 297 down-regulated in OSCC tissues and cells. Importantly, LINC00668 expression was negatively correlated with miR-297 expression in OSCC tissues. Loss-of function of LINC00668 revealed that LINC00668 functioned as a ceRNA for miR-297 to facilitate VEGFA expression, promoting OSCC progression. Furthermore, LINC00668 knockdown suppressed tumor growth and reduced the expression of proliferation antigen ki-67 in vivo. Finally, we confirmed that LINC00668 promoted OSCC activity through VEGFA signaling. In conclusion, these results suggest that LINC00668 promotes OSCC tumorigenesis via miR-297/VEGFA axis, which may provide a new target for the diagnosis and therapy of OSCC disease. PMID- 28564591 TI - Whole-transcriptome screening reveals the regulatory targets and functions of long non-coding RNA H19 in epileptic rats. AB - Understanding the molecular mechanisms mediating epileptogenesis may lead to the development of preventative therapies against epilepsy. Our previous study demonstrated that the long non-coding RNA H19 contributes to epileptogenesis by aggravating status epilepticus-induced neuronal loss, glial cell activation, mossy fiber sprouting, and cognitive impairments in epileptic rats. However, the systematic functions and downstream targets of H19 associated with epileptogenesis are still unknown. In the present study, high-throughput microarray analysis was used to explore the influence of H19 on gene expression in an epileptic rat model. A large number of genes were differentially expressed at the transcriptional level when H19 was overexpressed or knocked down. Series test of cluster analysis further distinguished genes associated with H19. Function and pathway analyses demonstrated that H19 has diverse functions related to epileptogenesis, including demyelination, immune and inflammatory responses, cell apoptosis, and activation of MAPK. This study implicates H19 in a broad spectrum of epileptogenic processes, thereby providing a range of targets for further mechanistic investigations. PMID- 28564592 TI - Alteration of mitochondrial protein PDHA1 in Lewy body disease and PARK14. AB - The histopathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) is the occurrence of insoluble fibrillary aggregates known as Lewy bodies. Mitochondria play a vital role in energy production, and the pathogenesis of PD is associated with altered cellular metabolism due to mitochondrial dysfunction. The pyruvate dehydrogenase (PDH) complex provides a primary step in aerobic glucose metabolism by catalyzing the oxidative decarboxylation of pyruvate to acetyl CoA. Pyruvate dehydrogenase alpha 1 (PDHA1) forms the core structure of the PDH complex. Dysfunction of the PDH complex leads to energy production failure, resulting in various neurological disorders. However, no study has investigated the involvement of PDHA1 in the pathogenesis of PD. In the present study, we performed immunohistochemistry and immunoblotting to clarify the involvement of PDHA1 in idiopathic PD, DLB, PARK14-linked parkinsonism (PARK14; a familial form of PD), and multiple system atrophy, in comparison with normal controls. Here we report PDHA1 as a new component of brainstem-type Lewy bodies in idiopathic PD, DLB and PARK14, the level of PDHA1 protein being significantly decreased in the putamen and substantia nigra of patients with idiopathic PD. Our findings suggest that alteration of glucose metabolism through dysfunction of the PDH complex might occur in the pathogenesis of Lewy body disease and PARK14. PMID- 28564593 TI - The occurrence of l-lactate dehydrogenase in the inner mitochondrial compartment of pig liver. AB - Although pig represents a model species in biomedical research including studies dealing with liver patho-physiology, some aspects of liver metabolism need to be addressed. In particular, whether and how pig mitochondria can metabolize l lactate remains to be established. We show here that pig liver mitochondria (PLM) possess their own l-lactate dehydrogenase (mL-LDH). This was shown both via immunological analysis and by assaying photometrically the L-LDH reaction in solubilised PLM. The mL-LDH reaction shows hyperbolic dependence on the substrate concentration, it is inhibited by oxamate and proves to differ from the cytosolic activity (cL-LDH), as revealed by the difference found in both pH profiles and temperature dependence of m- and cL-LDH. Titration experiments with digitonin show that mL-LDH is restricted in mitochondrial inner compartment. In agreement with the above findings, three genes in Sus scrofa genome encoded for L-LDH subunits which are predicted to have mitochondrial localization, as investigated by Target P 1.1 and PredSL analysis. PMID- 28564594 TI - Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS. AB - Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay that could guide future therapeutic strategies in ALS. PMID- 28564596 TI - The Histone Variant MacroH2A1 Is a BRCA1 Ubiquitin Ligase Substrate. AB - The breast- and ovarian-cancer-specific tumor suppressor BRCA1 and its heterodimeric partner BARD1 contain RING domains that implicate them as E3 ubiquitin ligases. Despite extensive efforts, the bona fide substrates of BRCA1/BARD1 remain elusive. Here, we used recombinant GST fused to four UBA domains to enrich ubiquitinated proteins followed by a Lys-epsilon-Gly-Gly (diGly) antibody to enrich ubiquitinated tryptic peptides. This tandem affinity purification method coupled with mass spectrometry identified 101 putative BRCA1/BARD1 E3 substrates. We identified the histone variant macroH2A1 from the screen and showed that BRCA1/BARD1 ubiquitinates macroH2A1 at lysine 123 in vitro and in vivo. Primary human fibroblasts stably expressing a ubiquitination deficient macroH2A1 mutant were defective in cellular senescence compared to their wild-type counterpart. Our study demonstrates that BRCA1/BARD1 is a macroH2A1 E3 ligase and implicates a role for macroH2A1 K123 ubiquitination in cellular senescence. PMID- 28564595 TI - Structural Basis for Regulation of ESCRT-III Complexes by Lgd. AB - The ESCRT-III complex induces outward membrane budding and fission through homotypic polymerization of its core component Shrub/CHMP4B. Shrub activity is regulated by its direct interaction with a protein called Lgd in flies, or CC2D1A or B in humans. Here, we report the structural basis for this interaction and propose a mechanism for regulation of polymer assembly. The isolated third DM14 repeat of Lgd binds Shrub, and an Lgd fragment containing only this DM14 repeat and its C-terminal C2 domain is sufficient for in vivo function. The DM14 domain forms a helical hairpin with a conserved, positively charged tip, that, in the structure of a DM14 domain-Shrub complex, occupies a negatively charged surface of Shrub that is otherwise used for homopolymerization. Lgd mutations at this interface disrupt its function in flies, confirming functional importance. Together, these data argue that Lgd regulates ESCRT activity by controlling access to the Shrub self-assembly surface. PMID- 28564597 TI - Synaptic Remodeling Depends on Signaling between Serotonin Receptors and the Extracellular Matrix. AB - Rewiring of synaptic circuitry pertinent to memory formation has been associated with morphological changes in dendritic spines and with extracellular matrix (ECM) remodeling. Here, we mechanistically link these processes by uncovering a signaling pathway involving the serotonin 5-HT7 receptor (5-HT7R), matrix metalloproteinase 9 (MMP-9), the hyaluronan receptor CD44, and the small GTPase Cdc42. We highlight a physical interaction between 5-HT7R and CD44 (identified as an MMP-9 substrate in neurons) and find that 5-HT7R stimulation increases local MMP-9 activity, triggering dendritic spine remodeling, synaptic pruning, and impairment of long-term potentiation (LTP). The underlying molecular machinery involves 5-HT7R-mediated activation of MMP-9, which leads to CD44 cleavage followed by Cdc42 activation. One important physiological consequence of this interaction includes an increase in neuronal outgrowth and elongation of dendritic spines, which might have a positive effect on complex neuronal processes (e.g., reversal learning and neuronal regeneration). PMID- 28564598 TI - A Glio-Protective Role of mir-263a by Tuning Sensitivity to Glutamate. AB - Glutamate is a ubiquitous neurotransmitter, mediating information flow between neurons. Defects in the regulation of glutamatergic transmission can result in glutamate toxicity, which is associated with neurodegeneration. Interestingly, glutamate receptors are expressed in glia, but little is known about their function, and the effects of their misregulation, in these non-neuronal cells. Here, we report a glio-protective role for Drosophila mir-263a mediated by its regulation of glutamate receptor levels in glia. mir-263a mutants exhibit a pronounced movement defect due to aberrant overexpression of CG5621/Grik, Nmdar1, and Nmdar2. mir-263a mutants exhibit excitotoxic death of a subset of astrocyte like and ensheathing glia in the CNS. Glial-specific normalization of glutamate receptor levels restores cell numbers and suppresses the movement defect. Therefore, microRNA-mediated regulation of glutamate receptor levels protects glia from excitotoxicity, ensuring CNS health. Chronic low-level glutamate receptor overexpression due to mutations affecting microRNA (miRNA) regulation might contribute to glial dysfunction and CNS impairment. PMID- 28564600 TI - Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System. AB - Lipoprotein cholesterol is delivered to the limiting membrane of late endosomes/lysosomes (LELs) by Niemann-Pick C1 (NPC1). However, the mechanism of cholesterol transport from LELs to the endoplasmic reticulum (ER) is poorly characterized. We report that oxysterol-binding protein-related protein 1L (ORP1L) is necessary for this stage of cholesterol export. CRISPR-mediated knockout of ORP1L in HeLa and HEK293 cells reduced esterification of cholesterol to the level in NPC1 knockout cells, and it increased the expression of sterol regulated genes and de novo cholesterol synthesis, indicative of a block in cholesterol transport to the ER. In the absence of this transport pathway, cholesterol-enriched LELs accumulated in the Golgi/perinuclear region. Cholesterol delivery to the ER required the sterol-, phosphatidylinositol 4 phosphate-, and vesicle-associated membrane protein-associated protein (VAP) binding activities of ORP1L, as well as NPC1 expression. These results suggest that ORP1L-dependent membrane contacts between LELs and the ER coordinate cholesterol transfer with the retrograde movement of endo-lysosomal vesicles. PMID- 28564599 TI - ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis. AB - The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6alpha. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress. PMID- 28564601 TI - Replication-Coupled Dilution of H4K20me2 Guides 53BP1 to Pre-replicative Chromatin. AB - The bivalent histone modification reader 53BP1 accumulates around DNA double strand breaks (DSBs), where it dictates repair pathway choice decisions by limiting DNA end resection. How this function is regulated locally and across the cell cycle to channel repair reactions toward non-homologous end joining (NHEJ) in G1 and promote homology-directed repair (HDR) in S/G2 is insufficiently understood. Here, we show that the ability of 53BP1 to accumulate around DSBs declines as cells progress through S phase and reveal that the inverse relationship between 53BP1 recruitment and replicated chromatin is linked to the replication-coupled dilution of 53BP1's target mark H4K20me2. Consistently, premature maturation of post-replicative chromatin restores H4K20me2 and rescues 53BP1 accumulation on replicated chromatin. The H4K20me2-mediated chromatin association of 53BP1 thus represents an inbuilt mechanism to distinguish DSBs in pre- versus post-replicative chromatin, allowing for localized repair pathway choice decisions based on the availability of replication-generated template strands for HDR. PMID- 28564602 TI - Mad2 Overexpression Uncovers a Critical Role for TRIP13 in Mitotic Exit. AB - The mitotic checkpoint ensures proper segregation of chromosomes by delaying anaphase until all kinetochores are bound to microtubules. This inhibitory signal is composed of a complex containing Mad2, which inhibits anaphase progression. The complex can be disassembled by p31comet and TRIP13; however, TRIP13 knockdown has been shown to cause only a mild mitotic delay. Overexpression of checkpoint genes, as well as TRIP13, is correlated with chromosomal instability (CIN) in cancer, but the initial effects of Mad2 overexpression are prolonged mitosis and decreased proliferation. Here, we show that TRIP13 overexpression significantly reduced, and TRIP13 reduction significantly exacerbated, the mitotic delay associated with Mad2 overexpression, but not that induced by microtubule depolymerization. The combination of Mad2 overexpression and TRIP13 loss reduced the ability of checkpoint complexes to disassemble and significantly inhibited the proliferation of cells in culture and tumor xenografts. These results identify an unexpected dependency on TRIP13 in cells overexpressing Mad2. PMID- 28564603 TI - 2-HG Inhibits Necroptosis by Stimulating DNMT1-Dependent Hypermethylation of the RIP3 Promoter. AB - 2-hydroxyglutarate-(2-HG)-mediated inhibition of TET2 activity influences DNA hypermethylation in cells harboring mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2). Here, we show that 2-HG also regulates DNA methylation mediated by DNA methyltransferase 1 (DNMT1). DNMT1-dependent hypermethylation of the RIP3 promoter occurred in both IDH1 R132Q knockin mutant mouse embryonic fibroblast (MEFs) and 2-HG-treated wild-type (WT) MEFs. We found that 2-HG bound to DNMT1 and stimulated its association with the RIP3 promoter, inducing hypermethylation that reduces RIP3 protein and consequently impaired RIP3-dependent necroptosis. In human glioma samples, RIP3 protein levels correlated negatively with IDH1 R132H levels. Furthermore, ectopic expression of RIP3 in transformed IDH1-mutated MEFs inhibited the growth of tumors derived from these cells following transplantation into nude mice. Thus, our research sheds light on a mechanism of 2-HG-induced DNA hypermethylation and suggests that impaired necroptosis contributes to the tumorigenesis driven by IDH1/2 mutations. PMID- 28564605 TI - A TLR3-Specific Adjuvant Relieves Innate Resistance to PD-L1 Blockade without Cytokine Toxicity in Tumor Vaccine Immunotherapy. AB - Cancer patients having anti-programmed cell death-1 (PD-1)/PD ligand 1 (L1) unresponsive tumors may benefit from advanced immunotherapy. Double-stranded RNA triggers dendritic cell (DC) maturation to cross-prime antigen-specific cytotoxic T lymphocytes (CTLs) via Toll-like receptor 3 (TLR3). The TLR3-specific RNA agonist, ARNAX, can induce anti-tumor CTLs without systemic cytokine/interferon (IFN) production. Here, we have developed a safe vaccine adjuvant for cancer that effectively implements anti-PD-L1 therapy. Co-administration of ARNAX with a tumor-associated antigen facilitated tumor regression in mouse models, and in combination with anti-PD-L1 antibody, activated tumor-specific CTLs in lymphoid tissues, enhanced CTL infiltration, and overcame anti-PD-1 resistance without cytokinemia. The TLR3-TICAM-1-interferon regulatory factor (IRF)3-IFN-beta axis in DCs exclusively participated in CD8+ T cell cross-priming. ARNAX therapy established Th1 immunity in the tumor microenvironment, upregulating genes involved in DC/T cell/natural killer (NK) cell recruitment and functionality. Human ex vivo studies disclosed that ARNAX+antigen induced antigen-specific CTL priming and proliferation in peripheral blood mononuclear cells (PBMCs), supporting the feasibility of ARNAX for potentiating anti-PD-1/PD-L1 therapy in human vaccine immunotherapy. PMID- 28564604 TI - Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation. AB - Oncogenic mutations in two isocitrate dehydrogenase (IDH)-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma (GBM). Our in silico and wet-bench analyses indicate that non-mutated IDH1 mRNA and protein are commonly overexpressed in primary GBMs. We show that genetic and pharmacologic inactivation of IDH1 decreases GBM cell growth, promotes a more differentiated tumor cell state, increases apoptosis in response to targeted therapies, and prolongs the survival of animal subjects bearing patient-derived xenografts (PDXs). On a molecular level, diminished IDH1 activity results in reduced alpha-ketoglutarate (alphaKG) and NADPH production, paralleled by deficient carbon flux from glucose or acetate into lipids, exhaustion of reduced glutathione, increased levels of reactive oxygen species (ROS), and enhanced histone methylation and differentiation marker expression. These findings suggest that IDH1 upregulation represents a common metabolic adaptation by GBMs to support macromolecular synthesis, aggressive growth, and therapy resistance. PMID- 28564606 TI - Genome-wide Analysis of STAT3-Mediated Transcription during Early Human Th17 Cell Differentiation. AB - The development of therapeutic strategies to combat immune-associated diseases requires the molecular mechanisms of human Th17 cell differentiation to be fully identified and understood. To investigate transcriptional control of Th17 cell differentiation, we used primary human CD4+ T cells in small interfering RNA (siRNA)-mediated gene silencing and chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) to identify both the early direct and indirect targets of STAT3. The integrated dataset presented in this study confirms that STAT3 is critical for transcriptional regulation of early human Th17 cell differentiation. Additionally, we found that a number of SNPs from loci associated with immune-mediated disorders were located at sites where STAT3 binds to induce Th17 cell specification. Importantly, introduction of such SNPs alters STAT3 binding in DNA affinity precipitation assays. Overall, our study provides important insights for modulating Th17-mediated pathogenic immune responses in humans. PMID- 28564607 TI - Specification and Diversification of Pericytes and Smooth Muscle Cells from Mesenchymoangioblasts. AB - Elucidating the pathways that lead to vasculogenic cells, and being able to identify their progenitors and lineage-restricted cells, is critical to the establishment of human pluripotent stem cell (hPSC) models for vascular diseases and development of vascular therapies. Here, we find that mesoderm-derived pericytes (PCs) and smooth muscle cells (SMCs) originate from a clonal mesenchymal progenitor mesenchymoangioblast (MB). In clonogenic cultures, MBs differentiate into primitive PDGFRbeta+CD271+CD73- mesenchymal progenitors, which give rise to proliferative PCs, SMCs, and mesenchymal stem/stromal cells. MB derived PCs can be further specified to CD274+ capillary and DLK1+ arteriolar PCs with a proinflammatory and contractile phenotype, respectively. SMC maturation was induced using a MEK inhibitor. Establishing the vasculogenic lineage tree, along with identification of stage- and lineage-specific markers, provides a platform for interrogating the molecular mechanisms that regulate vasculogenic cell specification and diversification and manufacturing well-defined mural cell populations for vascular engineering and cellular therapies from hPSCs. PMID- 28564608 TI - Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1. AB - Endoglin (ENG)/CD105 is an essential endothelial cell co-receptor of the transforming growth factor beta (TGF-beta) superfamily, mutated in hereditary hemorrhagic telangiectasia type 1 (HHT1) and involved in tumor angiogenesis and preeclampsia. Here, we present crystal structures of the ectodomain of human ENG and its complex with the ligand bone morphogenetic protein 9 (BMP9). BMP9 interacts with a hydrophobic surface of the N-terminal orphan domain of ENG, which adopts a new duplicated fold generated by circular permutation. The interface involves residues mutated in HHT1 and overlaps with the epitope of tumor-suppressing anti-ENG monoclonal TRC105. The structure of the C-terminal zona pellucida module suggests how two copies of ENG embrace homodimeric BMP9, whose binding is compatible with ligand recognition by type I but not type II receptors. These findings shed light on the molecular basis of the BMP signaling cascade, with implications for future therapeutic interventions in this fundamental pathway. PMID- 28564609 TI - Sequential Steps of CRAC Channel Activation. AB - Interaction between the endoplasmic reticulum protein STIM1 and the plasma membrane channel ORAI1 generates calcium signals that are central for diverse cellular functions. How STIM1 binds and activates ORAI1 remains poorly understood. Using electrophysiological, optical, and biochemical techniques, we examined the effects of mutations in the STIM1-ORAI1 activating region (SOAR) of STIM1. We find that SOAR mutants that are deficient in binding to resting ORAI1 channels are able to bind to and boost activation of partially activated ORAI1 channels. We further show that the STIM1 binding regions on ORAI1 undergo structural rearrangement during channel activation. The results suggest that activation of ORAI1 by SOAR occurs in multiple steps. In the first step, SOAR binds to ORAI1, partially activates the channel, and induces a rearrangement in the SOAR-binding site of ORAI1. That rearrangement of ORAI1 then permits sequential steps of SOAR binding, via distinct molecular interactions, to fully activate the channel. PMID- 28564610 TI - Effect of Human Genetic Variability on Gene Expression in Dorsal Root Ganglia and Association with Pain Phenotypes. AB - Dorsal root ganglia (DRG) relay sensory information to the brain, giving rise to the perception of pain, disorders of which are prevalent and burdensome. Here, we mapped expression quantitative trait loci (eQTLs) in a collection of human DRGs. DRG eQTLs were enriched within untranslated regions of coding genes of low abundance, with some overlapping with other brain regions and blood cell cis eQTLs. We confirm functionality of identified eQTLs through their significant enrichment within open chromatin and highly deleterious SNPs, particularly at the exon level, suggesting substantial contribution of eQTLs to alternative splicing regulation. We illustrate pain-related genetic association results explained by DRG eQTLs, with the strongest evidence for contribution of the human leukocyte antigen (HLA) locus, confirmed using a mouse inflammatory pain model. Finally, we show that DRG eQTLs are found among hits in numerous genome-wide association studies, suggesting that this dataset will help address pain components of non pain disorders. PMID- 28564611 TI - Quantitative Cell Cycle Analysis Based on an Endogenous All-in-One Reporter for Cell Tracking and Classification. AB - Cell cycle kinetics are crucial to cell fate decisions. Although live imaging has provided extensive insights into this relationship at the single-cell level, the limited number of fluorescent markers that can be used in a single experiment has hindered efforts to link the dynamics of individual proteins responsible for decision making directly to cell cycle progression. Here, we present fluorescently tagged endogenous proliferating cell nuclear antigen (PCNA) as an all-in-one cell cycle reporter that allows simultaneous analysis of cell cycle progression, including the transition into quiescence, and the dynamics of individual fate determinants. We also provide an image analysis pipeline for automated segmentation, tracking, and classification of all cell cycle phases. Combining the all-in-one reporter with labeled endogenous cyclin D1 and p21 as prime examples of cell-cycle-regulated fate determinants, we show how cell cycle and quantitative protein dynamics can be simultaneously extracted to gain insights into G1 phase regulation and responses to perturbations. PMID- 28564612 TI - Impact of food grade and nano-TiO2 particles on a human intestinal community. AB - Titanium dioxide (TiO2) nanoparticles (NPs) are used as an additive (E171 or INS171) in foods such as gum, candy and puddings. To address concerns about the potential hazardous effects of ingested NPs, the toxicity of these food-grade NPs was investigated with a defined model intestinal bacterial community. Each titania preparation (food-grade TiO2 formulations, E171-1 and E171-6a) was tested at concentrations equivalent to those found in the human intestine after sampling 1-2 pieces of gum or candy (100-250 ppm). At the low concentrations used, neither the TiO2 food additives nor control TiO2 NPs had an impact on gas production and only a minor effect on fatty acids profiles (C16:00, C18:00, 15:1 w5c, 18:1 w9c and 18:1 w9c, p < 0.05). DNA profiles and phylogenetic distributions confirmed limited effects on the bacterial community, with a modest decrease in the relative abundance of the dominant Bacteroides ovatus in favor of Clostridium cocleatum (-13% and +14% respectively, p < 0.05). Such minor shifts in the treated consortia suggest that food grade and nano-TiO2 particles do not have a major effect on human gut microbiota when tested in vitro at relevant low concentrations. However, the cumulative effects of chronic TiO2 NP ingestion remain to be tested. PMID- 28564613 TI - High dose tetrabromobisphenol A impairs hippocampal neurogenesis and memory retention. AB - Tetrabromobisphenol A (TBBPA) is a brominated flame retardant that is commonly used in commercial and household products, such as, computers, televisions, mobile phones, and electronic boards. TBBPA can accumulate in human body fluids, and it has been reported that TBBPA possesses endocrine disruptive activity. However, the neurotoxic effect of TBBPA on hippocampal neurogenesis has not yet been investigated. Accordingly, the present study was undertaken to evaluate the effect of TBBPA on adult hippocampal neurogenesis and cognitive function. Male C57BL/6 mice were orally administrated vehicle or TBBPA (20 mg/kg, 100 mg/kg, or 500 mg/kg daily) for two weeks. TBBPA was observed to significantly and dose dependently reduce the survival of newly generated cells in the hippocampus but not to affect the proliferation of newly generated cells. Numbers of hippocampal BrdU and NeuN positive cells were dose-dependently reduced by TBBPA, indicating impaired neurogenesis in the hippocampus. Interestingly, glial activation without neuronal death was observed in hippocampi exposed to TBBPA. Furthermore, memory retention was found to be adversely affected by TBBPA exposure by a mechanism involving suppression of the BDNF-CREB signaling pathway. The study suggests high dose TBBPA disrupts hippocampal neurogenesis and induces associated memory deficits. PMID- 28564614 TI - Enhanced barrier functions and anti-inflammatory effect of cultured coconut extract on human skin. AB - Natural plant oils have been used as a translational alternative to modern medicine. Particularly, virgin coconut oil (VCO) has gained popularity because of its potential benefits in pharmaceutical, nutritional, and cosmetic applications. Cultured coconut extract (CCE) is an alternative end product of VCO, which undergoes a further bacterial fermentation process. This study aimed to investigate the effects of CCE on human skin. We analyzed the expression of skin barrier molecules and collagens after applying CCE on human explanted skin. To evaluate the anti-inflammatory properties of CCE, the expression of inflammatory markers was analyzed after ultraviolet B (UVB) irradiation. The CCE-treated group showed increased expression of cornified cell envelope components, which contribute to protective barrier functions of the stratum corneum. Further, the expression of inflammatory markers was lower in the CCE-treated group after exposure to UVB radiation. These results suggest an anti-inflammatory effect of CCE against UVB irradiation-induced inflammation. Additionally, the CCE-treated group showed increased collagen and hyaluronan synthase-3 expression. In our study, CCE showed a barrier-enhancing effect and anti-inflammatory properties against ex vivo UVB irradiation-induced inflammation. The promising effect of CCE may be attributed to its high levels of polyphenols and fatty acid components. PMID- 28564615 TI - A comparison of untagged gamma-ray and tagged-neutron yields from 241AmBe and 238PuBe sources. AB - Untagged gamma-ray and tagged-neutron yields from 241AmBe and 238PuBe mixed-field sources have been measured. Gamma-ray spectroscopy measurements from 1 to 5MeV were performed in an open environment using a CeBr3 detector and the same experimental conditions for both sources. The shapes of the distributions are very similar and agree well with previous data. Tagged-neutron measurements from 2 to 6MeV were performed in a shielded environment using a NE-213 liquid scintillator detector for the neutrons and a YAP(Ce) detector to tag the 4.44MeVgamma-rays associated with the de-excitation of the first-excited state of 12C. Again, the same experimental conditions were used for both sources. The shapes of these distributions are also very similar and agree well with previous data, each other, and the ISO recommendation. Our 238PuBe source provides approximately 2.6 times more 4.44MeVgamma-rays and 2.4 times more neutrons over the tagged-neutron energy range, the latter in reasonable agreement with the original full-spectrum source-calibration measurements performed at the time of their acquisition. PMID- 28564616 TI - Comparative clinical characteristics and natural history of three variants of sclerosing cholangitis: IgG4-related SC, PSC/AIH and PSC alone. AB - There is increased interest and recognition of the clinical variants of Sclerosing Cholangitis (SC) namely IgG4-SC, PSC/AIH overlap and PSC. For most Centers, the characteristic of IgG4-SC has not been thoroughly clinically compared with other sclerosing cholangitis variants. Further there are relatively few PSC/AIH overlap patients and the clinical outcome is not well characterized, especially for the PSC/AIH overlap syndrome. Our objective herein is to clarify the differences and similarities of the natural history of IgG4-SC, the PSC/AIH overlap and PSC alone. We also place in perspective the diagnostic value of serum IgG4 for IgG4-SC and investigate biomarkers for predicting the prognosis of sclerosing cholangitis. In this study, we took advantage of our large and well defined patient cohort to perform a retrospective cohort study including 57 IgG4 SC, 36 PSC/AIH overlap patients, and 55 PSC patients. Firstly, as expected, we noted significant differences among immunoglobulin profiles and all patients exhibited similar cholestatic profiles at presentation. Cirrhotic events were found in 20 of total 57 IgG4-SC, 15 of 36 PSC/AIH overlap, and 18 of 55 PSC patients. Serum IgG4 was elevated in 92.65% of IgG4-SC patients with an 86% sensitivity and 98% specificity for diagnosis. IgG4-SC patients had a better treatment response at 6-month and 1-year than PSC/AIH patients, while the latter responded better with steroids than PSC patients. Importantly the adverse outcome free survival of IgG4-SC patients was reduced, unlike earlier reports, and therefore similar to the PSC/AIH overlap syndrome. Serum IgG and total bilirubin were useful to predict long-term survival of IgG4-SC and PSC/AIH, respectively. In conclusion, serum IgG4?1.25 ULN shows an excellent predictability to distinguish IgG4-SC among SC patients. IgG4-SC appears to be immune-mediated inflammatory process, while PSC/AIH overlap more tends to be cholestatic disease. PMID- 28564617 TI - Recent advances in our understanding of giant cell arteritis pathogenesis. AB - Giant cell arteritis (GCA) is a granulomatous vasculitis affecting large arteries, especially the aorta and the extracranial branches of the external carotid artery. Its exact pathogenesis is not fully understood but major progress has been made in recent years, leading to new therapeutic targets like inhibition of the interleukin-6 pathway or the modulation of immune checkpoints. The cause of GCA has not been clearly identified but it is thought that GCA occurs on a genetic background and is triggered by unknown environmental factors that could activate and lead to the maturation of dendritic cells localized in the adventitia of normal arteries. These activated dendritic cells then produce chemokines which trigger the recruitment of CD4+ T cells, which in turn become activated, proliferate and polarize into Th1 and Th17 cells, which produce IFN gamma and IL-17, respectively. Exposed to IFN-gamma, endothelial cells and vascular smooth muscle cells produce chemokines leading to the recruitment of further Th1 cells, CD8+ T cells and monocytes. The latter differentiate into macrophages, which, when persistently exposed to IFN-gamma, form giant cells, the histological hallmark of GCA. With the contribution of vascular smooth muscle cells, immune cells then trigger the destruction and remodeling of the arterial wall, thus leading to the formation of a neo-intima resulting in progressive occlusion of the arterial lumen, which is responsible for the ischemic symptoms of GCA. In this paper, we review recent progress in our understanding of GCA pathogenesis in the fields of genetics, epigenetics, infections, immunology and vascular remodeling. PMID- 28564619 TI - Repeated pulses of methyl-prednisolone with reduced doses of prednisone improve the outcome of class III, IV and V lupus nephritis: An observational comparative study of the Lupus-Cruces and lupus-Bordeaux cohorts. AB - OBJECTIVE: To compare the clinical course of patients with class III, IV and V lupus nephritis (LN) treated at Hospital Universitario Cruces (CC) and at Bordeaux University Hospital (BC). METHODS: The Lupus-Cruces nephritis protocol combines pulses of 125mg of methyl-prednisolone with each fortnightly pulse of cyclophosphamide and prednisone <=30mg/day with tapering over 12-14weeks until 2.5-5mg/day. The BC followed international lupus nephritis guidelines, combining high-dose prednisone and either mycophenolate mofetil or cyclophosphamide, followed by maintenance therapy with low dose prednisone and immunosuppressive drugs. The main outcomes were complete renal remission (CR) and glucocorticoid toxicity. RESULTS: 44 patients from BC and 29 from CC were included. The mean maximum prednisone dose was 42.5 (BC) vs. 21mg/day (CC), p<0.001. The average 6 month prednisone dose was 21 (BC) vs. 8.3mg/d (CC), p<0.001.The mean number of methyl-prednisolone pulses was 3 (BC) vs. 9.3 (CC), p<0.001. HCQ was used by 64% (BC) vs. 100% (CC), p<0.001. CR rates were 30% (BC) vs. 69% (CC), p=0.001, and 42% (BC) vs. 86% (CC), p<0.001, at 6 and 12months, respectively. Patients from the CC more frequently achieved CR (adjusted HR 3.8, 95%CI 2.05-7-09). The number of pulses of methyl-prednisolone were associated with CR (adjusted HR 1.09, 95%CI 1.03-1.15). Patients in the CC had a lower risk of GC-related side effects (adjusted HR 0.19, 95%CI 0.04-0.89). CONCLUSION: The Lupus-Cruces nephritis protocol improves the outcome of LN. Repeated methyl-prednisolone pulses help reduce the dose of oral glucocorticoids and enhance clinical response. PMID- 28564618 TI - Very early and early systemic sclerosis in the Spanish scleroderma Registry (RESCLE) cohort. AB - OBJECTIVES: According to the existence of subclinical organ involvement pre scleroderma should be divided into two subsets: very early and early disease. Pre scleroderma patients included in the Spanish Scleroderma Registry (RESCLE) Cohort were reclassified into subsets. Differences were evaluated and the risk of progression to definite systemic sclerosis was estimated. METHODS: The characteristics of very early and early SSc patients were compared. A logistic regression model was used to determine the risk factors of progression. RESULTS: 1632 patients were included, 36 (2.2%) in the very early subset and 111 (6.8%) in the early subset. There were no differences in sex, age at disease onset, duration of Raynaud's phenomenon, antinuclear antibodies or capillaroscopic findings. Three (8.3%) very early SSc patients evolved to definite SSc, 2 (5.6%) of them meeting the ACR/EULAR 2013 criteria, unlike 31 (28%) early SSc patients, 20 (24%) of them meeting the criteria (p=0.034). Digestive involvement was an independent risk factor of progression (OR 17; 95% CI, 6.1-47.2). CONCLUSIONS: The classification of early forms of scleroderma identifies patients with different prognostic risk of progression. The evolution to definite SSc is more frequent in early than in very early SSc patients. Digestive involvement is a risk factor of progression. An active assessment of organ damage in preclinical stages allows a correct classification and risk stratification, with implications for monitoring and treatment. PMID- 28564620 TI - Survivin in autoimmune diseases. AB - Survivin is a protein functionally important for cell division, apoptosis, and possibly, for micro-RNA biogenesis. It is an established marker of malignant cell transformation. In non-malignant conditions, the unique properties of survivin make it indispensable for homeostasis of the immune system. Indeed, it is required for the innate and adaptive immune responses, controlling differentiation and maintenance of CD4+ and CD8+ memory T-cells, and in B cell maturation. Recently, survivin has emerged as an important player in the pathogenesis of autoimmune diseases. Under the conditions of unreserved inflammation, survivin enhances antigen presentation, maintains persistence of autoreactive cells, and supports production of autoantibodies. In this context, survivin takes its place as a diagnostic and prognostic marker in rheumatoid arthritis, psoriasis, systemic sclerosis and pulmonary arterial hypertension, neuropathology and multiple sclerosis, inflammatory bowel diseases and oral lichen planus. In this review, we summarise the knowledge about non-malignant properties of survivin and focus on its engagement in cellular and molecular pathology of autoimmune diseases. The review highlights utility of survivin measures for clinical applications. It provides rational for the survivin inhibiting strategies and presents results of recent reports on survivin inhibition in modern therapies of cancers and autoimmune diseases. PMID- 28564621 TI - The characteristics and impact of source of infection on sepsis-related ICU outcomes. AB - BACKGROUND: Source of infection is an independent predictor of sepsis-related mortality. To date, studies have failed to evaluate differences in septic patients based on the source of infection. METHODS: Retrospective study of all patients with sepsis admitted to the ICU of a university hospital within a 12month time period. RESULTS: Sepsis due to intravascular device and multiple sources had the highest number of positive blood cultures and microbiology whereas lung and abdominal sepsis had the least. The observed hospital mortality was highest for sepsis due to multiple sources and unknown cause, and was lowest when due to abdominal, genitourinary (GU) or skin/soft tissue. Patients with sepsis due to lungs, unknown and multiple sources had the highest rates of multi organ failure, whereas those with sepsis due to GU and skin/soft tissue had the lowest rates. Those with multisource sepsis had a significantly higher median ICU length of stay and hospital cost. CONCLUSION: There are significant differences in patient characteristics, microbiology positivity, organs affected, mortality, length of stay and cost based on the source of sepsis. These differences should be considered in future studies to be able to deliver personalized care. PMID- 28564622 TI - Suitability of functional evaluation embedded in serious game rehabilitation exercises to assess motor development across lifespan. AB - The aim of this study was to determine if the results of activities performed using specially developed serious games for physical rehabilitation could be used as an indicator of the natural maturation and decline of motor control in healthy participants. Eighty-one participants (19 children (5-15 years old), 40 adults (18-65 years old) and 22 aged subjects (60-88 years old) participated in this study. Motions performed were recorded using the Kinect sensor. Three different exercises embedded in the games were used to assess upper limb, trunk and lower limb control. The trial duration and accuracy, measures of gross motor function and fine motor control, respectively, were computed for each participant. ANOVA tests shows statistically significant differences between the three groups for duration (53+/-15, 27+/-10 and 119+/-30s for children, adults and elderly subjects respectively) and accuracy (87+/-5, 89+/-10 and 70+/-8% for children, adults and elderly subjects respectively). The slopes of the curves that approximated the evolution of the performance over various ages are coherent with previous studies about motor control development and physiological decline. The proposed solution, i.e. serious games rehabilitation exercises coupled to motion analysis, seems to be an interesting tool to assess global motor function. Further studies are needed to study the influence of pathologies on the studied parameters. PMID- 28564623 TI - The challenges that parents of children with epilepsy face: A qualitative study. AB - OBJECTIVE: This qualitative study explored the challenges that Greek parents/caregivers of children with controlled epilepsy (CwE) face regarding the disorder. METHODS: Interviews were conducted based on open-ended questions guided by a review of the literature. A total of 91 parents/caregivers were recruited by neurologists at the neurology clinics of two Athens public hospitals. A hermeneutic phenomenological approach was used to explore parent/caregiver experiences. The data were grouped and analyzed through a textual interpretation. RESULTS: Two key challenges were identified for parents of CwE: the disclosure of epilepsy and the absence of adequate information about coping with epilepsy. Parents in Greece were hesitant to reveal their child's epilepsy to school staff and their wider social milieu. Also, although satisfied with the patient-centered approach they experienced with their hospital doctor, parents/caregivers found that they needed more education about the existing sources of psychosocial and emotional support to cope with their child's epilepsy personally and as a family. Finally, the parents/caregivers who let their child know about the epilepsy and discussed the implications with the child found that parent-child communication improved. CONCLUSION: This study provides valuable insight into the impact of epilepsy on parents of CwE, which might help hospital and school staff support families with greater understanding, sensitivity, and skill. The findings suggest that Greek authorities should staff hospitals and schools with experts and more systematically advertise sources of information about epilepsy and ways to cope with it. PMID- 28564624 TI - Dissolved rare earth elements in the central-western sector of the Ross Sea, Southern Ocean: Geochemical tracing of seawater masses. AB - The present essay contributes to the existing literature on rare earth elements (REEs) in the southern hemisphere by presenting the first data, to our knowledge, on the vertical profiles of dissolved REEs in 71 samples collected in the central western sector of the Ross Sea (Southern Ocean-SO). The REEs were measured in the water samples collected during the 2002-2003 and 2005-2006 austral summers. 4 samples were collected and analysed in the framework of a test experiment, as part of the WISSARD Project (Whillans Ice Stream Subglacial Access Research Drilling). Our results show significant differences between the REE patterns of the main water masses present in the SO: we could observe specific signature in the High Salinity Shelf Water (HSSW), Ice Shelf Water (ISW) and Low Salinity Shelf Water (LSSW). A significant increase in Terbium (Tb) concentration was observed in the HSSW and ISW, the two principal water masses contributing to the formation of Antarctic Bottom Water (AABW) in the Ross Sea area, and in LSSW. Some of the HSSW samples show enrichment in Neodymium (Nd). Dissolved REE could therefore be used as tracers to understand the deep circulation of the SO (Pacific sector). We hypothesize that: (I) the characteristic dissolved REE pattern may derive from the composition of source area and from the hydrothermal activity of the central-western area of the Ross Sea; (II) the Tb anomaly observed in the AABW on the South Australian platform could be partially explained by the contribution of AABW generated in the Ross Sea region. PMID- 28564625 TI - Dynamics of inorganic components in lake waters from Terra Nova Bay, Antarctica. AB - Water and Suspended Particulate Material (SPM) samples analysed in this work were collected in the austral summer 2011/12 from six shallow Antarctic lakes (Carezza, Edmonson Point 14 and 15a, Gondwana, Inexpressible Island 10b and Tarn Flat 20) of Terra Nova Bay (Northern Victoria Land, Antarctica). The total concentrations of a large suite of inorganic analytes were determined, in order to gain insight into the natural processes regulating species distribution, define natural background values and detect possible present or future local and/or global anthropogenic contamination. Lake water composition was found to be influenced by marine spray, lake geographical position and meltwater input. Seasonal variability was also evaluated for each analyte, and explained considering the natural transport processes involving each species. Multivariate chemometric techniques were used in order to identify groups of samples with similar characteristics and find out similarities and correlations among variables. The variability observed within the water samples is closely connected to the marine aerosol input; hence, it is primarily a consequence of geographical and meteorological factors, such as distance from the ocean and period of year. Higher element concentrations have been found in SPM than in water, suggesting that weathering plays an important role on the chemistry of these lakes or that adsorption processes take place. SPM samples were also examined with a Scanning Electron Microscope (SEM), and many diatoms belonging to different species were detected. No clear evidence of a relevant metal contamination was found in the investigated area. PMID- 28564626 TI - Pesticide incidence in poisoned baits: A 10-year report. AB - The incidence of pesticides in poisoned baits recovered from 2005 to 2014 in Italian northern regions of Emilia Romagna and Lombardy was analysed. A total of 956 baits tested positive for pesticides during the study period. In 9.3% (n=89) of the baits analysed more than one toxic compound was present. Insecticides (53.2%) proved to be the pesticides most commonly involved followed by rodenticides (34.3%), molluscicides (12.3%) and herbicides (0.2%). Among insecticides, the anticholinesterases (organophosphates and carbamates) were the most frequently detected (59.1%, n=412) followed by organochlorines (39.8%; n=277). Anticoagulants proved to be the rodenticides most commonly involved (78.5%; n=353) with many baits containing brodifacoum or bromadiolone, while metaldehyde was the most used molluscicide (88.2%; n=142). A high number of baits contained banned pesticides such as endosulfan, methamidophos, carbofuran and strychnine indicating that the restrictions and the bans on the use of toxic and highly toxic pesticides are not accompanied by a lower use in poisoned baits. The high incidence of banned pesticides detected in the present survey is extremely worrying and poses the question of where and how these compounds were obtained. Efforts have to be made to reduce this illegal practice and its environmental impact. Moreover, education and awareness campaigns should be instituted. PMID- 28564627 TI - Assessing the influence of confounding biological factors when estimating bioaccumulation of PCBs with passive samplers in aquatic ecosystems. AB - Passive samplers are promising surrogates for organisms, mimicking bioaccumulation. However, several biological characteristics disturb the passive partitioning process in organisms by accelerating or restraining bioaccumulation, resulting in species-specific body residues of hydrophobic organic contaminants (HOCs). In addition to site-specific characteristics and HOC concentrations, age, sex, diet, biotransformation capability and habitat-specific characteristics may affect body residues. Two passive sampler types, polyethylene (PE) and polydimethylsiloxane (PDMS) were deployed in a PCB-contaminated freshwater lake water and sediment, respectively, to assess their bioaccumulation prediction capacity. In order to understand the importance of biological characteristics in the bioaccumulation process, we explored bioaccumulation in biota from plants and plankton to mussels and fish. The PCB concentrations in the PE sheet reflected the bioavailable concentration of PCBs slightly better than those in the PDMS samplers. Passive samplers were good predictors of PCB concentrations in fish, whereas concentrations in algae and invertebrates were overestimated. When comparing the measured concentrations in biota to the estimated concentrations using the PE samplers, the average regression slope was 0.87 for all biota and 1.22 for fish, and average modeling efficiency (EF) was 3.02 for all biota and 0.6 for fish. The best model performance was achieved for fish in trophic levels 3-4. Bioaccumulation was species-specific and dependent on the trophic level and diet. Closer examination revealed that metabolic capability changes during the life span, and source of nutrition determined the biomagnification of HOCs, which differed between the fish species. Thus, species composition and available prey selection compose a unique bioaccumulation scenario and the resulting body residues. Due to the existing variation in body residues derived from passive samplers, extrapolating the results from one to another ecosystem must be done with caution. Passive samplers, however, offer a very powerful tool for risk assessment on the ecosystem level. PMID- 28564629 TI - Comparison between Roche and Xpert in HIV-1 RNA quantitation: A high concordance between the two techniques except for a CRF02_AG subtype variant with high viral load titters detected by Roche but undetected by Xpert. AB - BACKGROUND: HIV-1 viral load (VL) testing is important to predict viral progression and to monitor the response to antiretroviral therapy. New HIV-1 VL tests are continuously introduced to the market. Their performance is usually compared to Abbott and/or Roche HIV-1 VL assays, as reference. The Xpert HIV-1 VL test was recently introduced, but its performance compared to Roche has not been sufficiently studied. OBJECTIVES: To compare the Xpert assay with Roche and to assess its use in the HIV clinical laboratory. STUDY DESIGN: A total of 383 plasma samples of HIV-1 infected patients previously tested by Roche, were retrospectively tested by Xpert to determine concordance between the two assays. Samples included a diversity of HIV-1 subtypes and a wide range of VLs. RESULTS: There was a high concordance between the two assays, except for a CRF02_AG subtype variant with high VL titters, that was detected by Roche but undetected by Xpert. The 5' long terminal repeat gene region of this virus, targeted by the Xpert assay, was amplified and sequenced. A 25 nucleotide insert was identified, but was unmatched to any known sequences of HIV-1. This particular insert, however could not explain the false-negativity by the Xpert assay. CONCLUSIONS: This study underlines the challenge to routine VL testing due to the high genetic diversity of HIV-1. Clinicians should, therefore be advised that a negative VL in cases where the clinical picture does not match the laboratory report, might in fact be, a false-negative result of the VL assay. PMID- 28564628 TI - Severity of anxiety- but not depression- is associated with oxidative stress in Major Depressive Disorder. AB - BACKGROUND: Oxidative stress is implicated in both depression and anxiety, but it is currently unclear whether this relates to syndromal diagnoses or trans diagnostic dimensional symptoms. We examined the relationship between oxidative stress and severity of depression and anxiety symptoms in individuals with Major Depressive Disorder (MDD). METHODS: Plasma oxidative stress markers F2 isoprostanes and oxidized glutathione (GSSG), and the antioxidant reduced glutathione (GSH), were assessed in 69 physically healthy, medication-free MDD subjects. Symptoms of anxiety and depression were assessed using the Hamilton Anxiety (HAM-A) and Hamilton Depression (HAM-D) Rating Scales. Total HAM-A and HAM-D scores, along with "core" anxiety and depression subscales, and individual HAM-D items "psychic anxiety" and "depressed mood," were related to oxidative stress markers. Analyses controlled for age, sex, BMI, and smoking. RESULTS: Total HAM-A ratings were positively associated with F2-isoprostanes (beta=.26, p=.042) and GSSG (beta=.25, p=.049), but not GSH (beta=.05, p=.711). Core anxiety severity was positively associated with F2-isoprostanes (beta=.34, p=.012) and GSSG, although this did not reach significance (beta=.24, p=.074). None of the biological markers were significantly associated with total HAM-D or core depression ratings (all p>.13). Subjects scoring high on "psychic anxiety" had elevated F2-isoprostanes (p=.030) and GSSG (p=.020). This was not seen with "depressed mood" scores (all p>.12). LIMITATIONS: We assessed peripheral oxidative markers, but their relationship to the brain is unclear. CONCLUSIONS: Oxidative stress is more closely related to anxiety than depression symptoms in MDD. This highlights the importance of relating oxidative stress to specific symptoms and could provide new insights into the biological correlates of affective disorders. PMID- 28564631 TI - Perspectives on dendritic architectures and their biological applications: From core to cell. AB - The challenges of medicine today include the increasing stipulation for sensitive and effective systems that can improve the pathological responses with a simultaneous reduction in accumulation and drug side effects. The demand can be fulfilled through the advancements in nanomedicine that includes nanostructures and nanodevices for diagnosing, treating, and prevention of various diseases. In this respect, the nanoscience provides various novel techniques with carriers such as micelles, dendrimers, particles and vesicles for the transportation of active moieties. Further, an efficient way to improve these systems is through stimuli a responsive system that utilizes supramolecular hyperbranched structures to meet the above criteria. The stimuli-responsive dendritic architectures exhibit spatial, temporal, convenient, effective, safety and controlled drug release in response to specific trigger through electrostatic interactions plus pi stacking. The stimuli-responsive systems are capable of sequestering the drug molecules underneath a predefined set of conditions and discharge them in a different environment through either exogenous or endogenous stimulus. The incorporation of photoresponsive moieties at various components of dendrimer such as core, branches or at the peripheral end exaggerates its significance in various allied fields of nanotechnology which includes sensors, photoswitch, electronic widgets and in drug delivery systems. This is due to the light instigated geometrical modifications at the core or at the surface molecules which generates huge conformational changes throughout the hyperbranched structure. Further, numerous synthetic methodologies have been investigated for utilization of dendrimers in therapeutic drug delivery and its applicability towards stimuli responsive systems such as photo-instigated, thermal-instigated, and pH-instigated hyperbranched structures and their advancement in the field of nanomedicine. This paper highlights the fascinating theoretical advances and principal mechanisms of dendrimer synthesis and their ability to capture light that strengthens its applicability from radiant energy to medical photonics. PMID- 28564630 TI - Green chemical approach towards the synthesis of CeO2 doped with seashell and its bacterial applications intermediated with fruit extracts. AB - Nanomaterials of CeO2 with A. vera were synthesized by using simple chemical method. Grapes drops are used as an oxidizing agent. Structural and morphological studies of nanomaterials of cerium oxide (CeO2), were studied for combustion method of preparation. The precursor solution was initialized by a hydrothermal reaction. Cerium hydroxyl carbonate precursors which involves cerium (III) nitrate Ce(NO3)3. 6 H2O with (1.0M) of seashell powder, 3% A. vera, extracts, grapes and pomegranate drops and this complex solution was used to produce the CeO2 powder particles. We have prepared another sample with 5% of Aloe vera extract and found that 3% Aloe vera extract has lesser grain size and enhanced band gap values, so the article explained the sample analysis of combination with 3% extract of Aloe vera. The product has the rod pattern which was the unusual features appear to originate from the unique crystal chemistry aspects. From the optical absorption spectrum, it has been shown that the CeO2 rods have 3.847eV of direct band gap energy. The minimum inhibitory concentration (MIC) values of the synthesized compounds exhibited activity towards various microbial pathogens such as B. subtilis (15MUg/mL), S. aureus (50MUg/mL), S. epidermidis (20MUg/mL), E. faecalis (25MUg/mL) and towards E. coli (100MUg/mL), K. pneumoniae (50MUg/mL) and P. aeruginosa (75MUg/mL) respectively. The tests on bacterial activities confirmed that the CeO2 rods are suitable hand for the biological applications. The seashell structure and the phytochemical contents of A. vera might enhance its bacterial activities. PMID- 28564632 TI - Manganese in Drinking Water and Cognitive Abilities and Behavior at 10 Years of Age: A Prospective Cohort Study. AB - BACKGROUND: Cross-sectional studies have indicated impaired neurodevelopment with elevated drinking water manganese concentrations (W-Mn), but potential susceptible exposure windows are unknown. OBJECTIVES: We prospectively evaluated the effects of W-Mn, from fetal life to school age, on children's cognitive abilities and behavior. METHODS: We assessed cognitive abilities and behavior in 1,265 ten-year-old children in rural Bangladesh using the Wechsler Intelligence Scale for Children (WISC-IV) and the Strengths and Difficulties Questionnaire (SDQ), respectively. Manganese in drinking water used during pregnancy and by the children at 5 y and 10 y was measured using inductively coupled plasma mass spectrometry. RESULTS: The median W-Mn was 0.20 mg/L (range 0.001-6.6) during pregnancy and 0.34mg/L (<0.001-8.7) at 10 y. In multivariable-adjusted linear regression analyses, restricted to children with low arsenic (As) exposure, none of the W-Mn exposures was associated with the children's cognitive abilities. Stratifying by gender (p for interaction in general <0.081) showed that prenatal W-Mn (3 mg/L) was positively associated with cognitive ability measures in girls but not in boys. W-Mn at all time points was associated with an increased risk of conduct problems, particularly in boys (range 24-43% per mg/L). At the same time, the prenatal W-Mn was associated with a decreased risk of emotional problems [odds ratio (OR)=0.39 (95% CI: 0.19, 0.82)] in boys. In girls, W-Mn was mainly associated with low prosocial scores [prenatal W-Mn: OR=1.48 (95% CI: 1.06, 1.88)]. CONCLUSIONS: Elevated prenatal W-Mn exposure was positively associated with cognitive function in girls, whereas boys appeared to be unaffected. Early life W-Mn exposure appeared to adversely affect children's behavior. https://doi.org/10.1289/EHP631. PMID- 28564636 TI - Depot-specific differences in fat mass expansion in WT and ob/ob mice. AB - The study was designed to investigate the cellular mechanisms underlying the differential fat expansion in different fat depots in wild type (WT) and ob/ob (OB) mice. At 6 weeks old, no differences in fat mass were found between SAT and VAT in WT mice, while O-SAT showed significantly higher weight than that of O VAT. The average adipocyte size of SAT (~ 4133.47 MUm2) was smaller than that of VAT (~ 7438.91 MUm2) in OB mice. O-SAT preadipocytes gained higher triglyceride contents and higher levels of PPARgamma and C/EBPalpha than did O-VAT preadipocytes upon in vitro differentiation. W-SAT and W-VAT displayed no significant differences in fatty acid uptake, while 1.36 fold significantly higher fatty acid uptake was found in O-SAT compared to O-VAT. Approximately 52% of the radioactivity recovered in cellular lipids was found in TAG in O-SAT, which was significantly higher than the other three adipocyte types. Significantly more radiolabelled oleic acid was beta-oxidized to CO2 in adipocytes from O-VAT than that from O-SAT. ATP production was significantly lower in W-SAT compared with W-VAT, whereas no significantly ATP level was observed between O-SAT and O-VAT. Expression of UCP-1 in SAT from either WT or OB mice was significantly higher than the counterpart of VAT, which demonstrated higher uncoupled respiration and lower oxidative phosphorylation in SAT. Together, a combined increase in adipogenesis and FA uptake, and decreases in beta-oxidation and ATP production, contributed to greater expansion of SAT compared to VAT in obese mice. PMID- 28564633 TI - MicroRNA-145 down-regulates mucin 5AC to alleviate airway remodeling and targets EGFR to inhibit cytokine expression. AB - This study aims to explore how microRNA-145 (miR-145) affects airway remodeling and cytokine expression by targeting epidermal growth factor receptor (EGFR) to regulate mucin 5AC (MUC5AC).Mice alveolar epithelial cells (AECs) were divided into a control, blank, miR-145 mimics, mimic control, miR-145 inhibitors, inhibitor control, si-EGFR and miR-145 inhibitors + si-EGFR group. Asthma mice models with airway remodeling were induced with an Ovalbumin (OVA) solution and randomly divided into a normal, asthma, asthma + miR-145 mimics, asthma + miR-145 mimic control, asthma + si-EGFR or asthma + si-EGFR NC group. Airway remodeling degree and histomorphology was measured using hematoxylin-eosin (HE), Masson and periodic acid-Schiff (PAS) staining. Flow cytometry was used to detect Th2 and Th17 cells in peripheral blood, ELISA was used to measure inflammatory factors. qRT-PCR and western blotting was adapted to detect the expressions of EGFR and the relevant cytokines that are regulated by miR-145.The control, miR-145 mimics and si-EGFR groups showed a higher expression of miR-145 and a lower expression of EGFR and cytokines than the blank, mimic control, inhibitor control and miR 145 inhibitor + si-EGFR groups. Mice in the asthma + miR-145 mimics and asthma + si-EGFR groups showed lower WAt/Pbm, WAi/Pbm and WAm/Pbm, less inflammatory cells, less airway modeling and alleviated goblet cell hyperplasia and mucus obstruction than the asthma group. Furthermore, the expressions of EGFR and cytokines of transfected cells and lung tissues were negatively related to those of miR-145. MiR-145 can down-regulate MUC5AC by negatively targeting EGFR and thereby relieving airway remodeling. PMID- 28564637 TI - Efficacy and safety of neoadjuvant FOLFIRINOX for borderline resectable pancreatic adenocarcinoma: improved efficacy compared with gemcitabine-based regimen. AB - Borderline resectable pancreatic cancer (BRPC) is a potentially resectable disease but is associated with poorer survival compared to primary resectable disease. There has been no prospective trial that compare the efficacy of FOLFIRNOX and gemcitabine-based regimen for BRPC. Between February 2013 and December 2014, 18 patients with BRPC receiving FOLFIRINOX were reviewed retrospectively. For comparative analysis, data for all BRPC patients (n=18) in our previous phase 2 study of neoadjuvant fixed-dose rate-gemcitabine plus capecitabine were pooled. Patients received a median 6 cycles (range, 3-13) of FOLFIRINOX. Surgical resection was performed in 12 patients (67%) and R0 resection in 9 patients. Median progression-free survival (PFS) and overall survival (OS) were 16.8 (95% confidence interval [CI], 9.4-24.2) and 21.2 (95% CI, 14.2-28.2) months, respectively. Patients who underwent surgical resection showed significantly better PFS (p=0.01) and OS (p=0.003) than those unresected. In the exploratory analysis, patients receiving FOLFIRINOX showed significantly longer PFS compared to those receiving fixed-dose rate-gemcitabine plus capecitabine (median 16.8 months [95% CI, 9.4-24.2] vs. 6.5 months [1.6-11.3]; p = 0.04). There was a trend toward improved OS in patients who received FOLFIRINOX (median 21.2 months [95% CI, 14.2-28.2]) compared to those who received fixed dose rate-gemcitabine plus capecitabine (13.6 months [11.8-15.4]; p=0.12). FOLFIRINOX was feasible and effective as neoadjuvant chemotherapy for patients with BRPC and may have improved efficacy compared to a gemcitabine-based regimen. PMID- 28564640 TI - Impact of Diabetes on Extracellular Volume Status in Patients Initiating Peritoneal Dialysis. AB - BACKGROUND: Recent reports have highlighted that diabetic patients with kidney failure are at increased risk of technique failure and transfer to haemodialysis within 90 days of initiating peritoneal dialysis (PD). We wished to determine whether there were differences between diabetic and non-diabetic patients within the first 3 months of starting PD. METHODS: We reviewed results of corresponding bioimpedance and the 1st test of peritoneal membrane function (PET) in consecutive patients, 6-10 weeks after initiating PD electively. RESULTS: Adult patients numbering 386 - 230 males (59.6%), 152 (39.4%) diabetic, 188 (48.7%) white, mean age 57.3 +/-16.9 years - were studied. Although weight, residual renal function and peritoneal clearances were not different, diabetic patients had greater extracellular water to total body water (ECW/TBW; 40.4 +/- 1.1 vs. 39.2 +/- 1.4) and % ECW excess (9.6 [6.3-12.3] vs. 4.9 [0.7-8.9]), lower serum albumin (35.2 +/- 4.7 vs. 37.8 +/- 4.9 g/L), greater fat mass index (9.5 +/- 4.2 vs. 7.7 +/- 4.2), and although mean arterial blood pressure was similar, arterial pulse pressure was greater (66.9 +/- 10.8 vs. 54.3 +/- 17.3 mm Hg, all p < 0.001). On multivariate analysis, glycated haemoglobin was associated with pulse pressure (standardised beta 0.24, p < 0.001), N terminal brain natriuretic peptide (beta 0.24, p < 0.001), ECW/TBW (beta 0.19, p = 0.012) and negatively with serum albumin (beta -0.14, p = 0.033) and creatinine (beta -0.18, p = 0.02). CONCLUSION: Diabetic patients electively starting PD were found to have greater ECW/TBW ratios and ECW excess 6-10 weeks after starting PD compared to non diabetics, despite similar PET. Increased ECW could predispose diabetic patients to be at greater risk of volume overload. PMID- 28564641 TI - The Role of Self-Collection by Vaginal Lavage for the Detection of HPV and High Grade Intraepithelial Neoplasia. AB - OBJECTIVE: To compare the results of cervical cytology and high-risk HPV tests using samples obtained using two different collection modalities in a population of Brazilian women: self-collection (vaginal lavage) and cervical Pap testing. METHODS: We enrolled 204 women who were aged 18-64 years and had previously obtained abnormal cervical cytology test results; 83.8% of them agreed to participate. The sample was divided into two aliquots: one for the cytological study and one for the molecular analysis of high-risk HPV. RESULTS: Fifty-eight percent of the participants preferred to utilize self-collection as an alternative screening method. However, we noticed that the HPV positivity rate was significantly lower in self-collected samples when compared to those obtained using the conventional collection method (p = 0.035). The cytology tests of the samples obtained via self-collection were sensitive and had a positive predictive value and an area under the curve (AUC) that were significantly lower than those of the Pap test. However, the specificity and negative predictive value of these tests were similar. When compared with the HPV test, the self-collected samples demonstrated lower accuracy in predicting high-grade cervical intraepithelial neoplasia or worse, with a significantly lower sensitivity, positive predictive value, and AUC than the cervical Pap test samples. CONCLUSION: Self-collection by vaginal lavage is simple and well accepted by women. Due to its limitations, however, self-collection by lavage should be utilized with caution. PMID- 28564642 TI - Effectiveness of Endoscopic Hemostasis with Soft Coagulation for Non-Variceal Upper Gastrointestinal Bleeding over a 12-Year Period. AB - BACKGROUND/AIMS: In this study, investigations were carried out to ascertain whether soft coagulation hemostasis for non-variceal upper gastrointestinal bleeding (UGIB) has ever been performed in a time-dependent manner. METHODS: Medical records of 502 patients who had undergone emergency endoscopic hemostasis for non-variceal UGIB from 2003 to 2014 were checked and the modalities were used to achieve hemostasis compared between the first period from 2003 to 2008 (197 patients) and the second period from 2009 to 2014 (305 patients). RESULTS: Endoscopic hemostasis was successfully achieved in 96.0% of study patients. Peptic ulcers were the main cause of bleeding (89.4%). Endoscopic hemostasis was performed by soft coagulation significantly more frequently during the second (71.1%) than the first period (11.7%; p < 0.001). Endoscopic hemostasis was mainly achieved by trainees during the second period (76.1%); these trainees comprised a significantly greater proportion of endoscopists than during the first period (56.3%; p < 0.001). Endoscopic-related complications did not differ between the 2 periods. The only risk factor for rebleeding after hemostasis was Helicobacter pylori infection; the use of soft coagulation and the fact that endoscopists were just trainees were not risk factors. CONCLUSION: Our findings suggest that using soft coagulation to achieve endoscopic hemostasis for non variceal UGIB is safe and effective, even when it is performed by trainees. PMID- 28564643 TI - Prevent Pancreatic Fistula after Pancreatoduodenectomy: Possible Role of Ultrasound Elastography. AB - BACKGROUND: The purpose of the study is to evaluate the utility of acoustic radiation force impulse (ARFI) on pancreatic tissue as a preoperative predictor of postoperative pancreatic fistula (POPF). Studied patients underwent exclusively to pancreaticoduodenectomy (PD) surgery. METHODS: Shear wave velocity of pancreas was measured using ARFI in 71 patients scheduled for PD. An intraoperative pancreas palpation was made by surgeons. A postoperative clinical evaluation to detect occurrence of POPF was performed. Sensitivity, specificity, positive and negative predictive values together with the accuracy of the method were investigated. RESULTS: Incidence of fistula observed in 17 patients with soft pancreas was approximately 53% vs. 47% without fistula. Percentage of patients without fistula was higher (66%) among 24 patients with medium parenchymal texture values, and was even higher (69%) in 26 patients with hard pancreas. Comparing ARFI and intraoperative pancreatic palpation, low wave velocity values (<=1.40 m/s) match 60% with soft parenchyma assessed by palpation and high values (>2 m/s) match 59% with hard pancreas on palpation. CONCLUSIONS: This study shows that ARFI elastography may be clinically useful as a preoperative predictor of pancreatic fistula following PD. PMID- 28564645 TI - Chicken Microchromosomes in the Lampbrush Phase: A Cytogenetic Description. AB - Lampbrush chromosomes are giant, transcriptionally active, meiotic chromosomes found in oocytes of all vertebrates with the exception of mammals. Lampbrush chromosomes offer a convenient tool for cytogenetic mapping and, in particular, have been instrumental in mapping genes and linkage groups on chicken (GGA) chromosomes. Whereas cytogenetic maps of macrochromosome GGA1-10 and microchromosome GGA11-16 lampbrush bivalents have been established, identification and description of smaller microchromosome bivalents are still missing. In this work, we used specific FISH probes for the identification of 12 chicken lampbrush chromosomes formed by GGA17-28. Our observations on chromomere and lateral loop arrangement and chiasma position allowed us to construct the respective cytogenetic maps for these microchromosomes. For the 10 smallest chicken microchromosomes, GGA29-38, no individual molecular tags are available, yet they can be collectively marked using the PO41 repeat. The reported results contribute to building of working cytogenetic maps of the chicken karyotype. PMID- 28564644 TI - Erythropoietin Hyporesponsiveness in Dialysis Patients: Possible Role of Statins. AB - BACKGROUND: Hypothesizing that statins may be useful as adjuvant treatment for renal anemia, we examined the association between statin prescription (Rx) and erythropoiesis-stimulating agent (ESA) hyporesponsiveness in Japanese hemodialysis (HD) patients prescribed ESAs. METHODS: We examined 3,602 patients in 60 HD facilities dialyzed 3 times/week for >=4 months from the Japan Dialysis Outcomes and Practice Patterns Study phases 3-5 (2005-2015). Statin Rx was reported at the end of a 4-month interval (baseline) for each patient. ESA hyporesponsiveness in the subsequent 4 months was then defined as a binary indicator (mean hemoglobin [Hgb] level <10 g/dL and mean ESA dose >6,000 units/week) and separately as the ESA resistance index (ERI; mean ESA dose/[dry weight * mean Hgb]). We used adjusted logistic and linear regressions to evaluate the associations between statin Rx and ESA hyporesponsiveness. RESULTS: At baseline, 16.2% of patients reported statin Rx; 12.8% were classified as having ESA hyporesponsiveness during 4 months of follow-up. Compared to patients without statin Rx, patients with statin Rx had lower odds of ESA hyporesponsiveness (OR 0.87; 95% CI 0.66-1.15). Similarly, the ERI was lower for those with statin Rx than without (ratio of means, 0.94; 95% CI 0.89-0.99) after adjustment for possible confounders. CONCLUSIONS: Our results suggest that statins may slightly reduce ESA hyporesponsiveness in HD patients. However, any causal inference is limited by the observational study design and unmeasured compliance with statin Rx. PMID- 28564647 TI - 64th ORCA Congress. July 5-8, 2017, Oslo, Norway: Abstracts. PMID- 28564648 TI - Provocation of Migraine after Maximal Exercise: A Test-Retest Study. AB - BACKGROUND: Exercise is often recommended in migraine treatment, but strenuous physical activity is also reported as a migraine trigger. The main aim of this study was to evaluate whether migraine can be triggered by a maximal exercise test, using a prospective test-retest method. A secondary aim was to compare the participants who responded to the maximal exercise test with a migraine attack with those who did not suffer a migraine attack after the test. METHODS: A total of 19 patients reporting exercise as a potential trigger for their migraines were included in the study. After a baseline period of 1 month with measurements of migraine frequency, a cycle ergometer test until exhaustion was used twice on each patient. RESULTS: A total of 14 patients were test-retested, and of these, 3 reported migraine following both tests, 5 after one of the tests, and 6 did not report migraine after either test. We observed a higher risk of migraine after 1 or 2 tests in patients with a higher baseline migraine frequency (p = 0.036). CONCLUSION: In conclusion, the study showed that although maximal aerobic exercise can trigger migraine attacks, it does not always provoke an attack even in those who report exercise as a migraine trigger. PMID- 28564646 TI - Constitutive Activation of Smoothened in the Renal Collecting Ducts Leads to Renal Hypoplasia, Hydronephrosis, and Hydroureter. AB - Sonic Hedgehog (Shh) signaling plays a major role in and is essential for regulation, patterning, and proliferation during renal development. Smoothened (Smo) plays a pivot role in transducing the Shh-glioma-associated oncogene Kruppel family member. However, the cellular and molecular mechanism underlying the role of sustained Smo activation in postnatal kidney development is still not clearly understood. Using a conditional knockin mouse model that expresses a constitutively activated form of Smo (SmoM2) upon Homeobox-B7-mediated recombination (Hoxb7-Cre), the effects of Shh signaling were determined in postnatal kidney development. SmoM2;Hoxb7-Cre mutant mice showed growth retardation with a reduction of body weight. Constitutive activation of Smo in the renal collecting ducts caused renal hypoplasia, hydronephrosis, and hydroureter. The parenchymal area and glomerular numbers were reduced, but the glomerular density was increased in SmoM2;Hoxb7-Cre mutant mice. The expression of Patched 1, the receptor of Shh and a downstream target gene of the Shh signaling pathway, was highly restricted and it was upregulated in the inner medullary collecting ducts of the kidney. The proliferative cells in the mesenchyme and collecting ducts were decreased in SmoM2;Hoxb7-Cre mutant mice. This study showed for the first time that sustained Smo inhibits postnatal kidney development by suppressing the proliferation of the mesenchyme and medullary collecting ducts in mice. PMID- 28564649 TI - Oral Vancomycin and Gentamicin for Treatment of Very Early Onset Inflammatory Bowel Disease. AB - BACKGROUND: The pathogenesis of inflammatory bowel disease (IBD) is complex and involves the contribution of genetic and environmental factors. Many patients with very early onset IBD are difficult to treat. The current antibiotic medication that targets gram-negative and anaerobic bacteria provides only moderate efficacy in subsets of patients with IBD. METHODS: We report a case series of 5 children with a mean age of 1.6 years (range 6 months to 2.7 years) during IBD onset, who were previously refractory to standard treatments and who received oral vancomycin with or without gentamicin. RESULTS: Four out of 5 children demonstrated substantial therapeutic effect, and the effect was sustained in 3 children over a follow-up period of 12-33 months. CONCLUSION: Our findings are consistent with model systems and suggest that randomized trials are required to establish whether a change in therapeutic paradigm, that is, targeting gram-positive bacteria with nonabsorbable antibiotics, may have therapeutic benefits. PMID- 28564651 TI - Pro-Angiogenesis Therapy and Aging: A Mini-Review. AB - Apart from major illnesses and chronic afflictions, the elderly experience lesser ailments, such as muscle weakness, cold intolerance, and transient memory lapses. Physical signs in the aged include wrinkled skin and the slow healing of skin abrasions. These ailments and signs are grouped together because they may be due in part to an age-linked, waning microcirculation. A reduced capillary density (CD) throughout the body of aged people and animals has been reported in over 40 papers. The reduced CD is due in turn to declining levels of angiogenic growth factors (AGFs) throughout the body during old age, as documented in 7 reports in the literature. From this perspective, old age is a deficiency state of AGFs, much like the reduced testosterone levels in elderly males. The above data on reduced CD and AGFs are the basis for the "angiogenesis hypothesis of aging", whose corollary suggests pro-angiogenesis therapy for symptoms and signs of old age. Several AGFs are now available in recombinant forms (e.g., vascular endothelial growth factor) and have been used safely in animal experiments and in short-term clinical trials. PMID- 28564650 TI - The Metabolic Phenotype in Obesity: Fat Mass, Body Fat Distribution, and Adipose Tissue Function. AB - The current obesity epidemic poses a major public health issue since obesity predisposes towards several chronic diseases. BMI and total adiposity are positively correlated with cardiometabolic disease risk at the population level. However, body fat distribution and an impaired adipose tissue function, rather than total fat mass, better predict insulin resistance and related complications at the individual level. Adipose tissue dysfunction is determined by an impaired adipose tissue expandability, adipocyte hypertrophy, altered lipid metabolism, and local inflammation. Recent human studies suggest that adipose tissue oxygenation may be a key factor herein. A subgroup of obese individuals - the 'metabolically healthy obese' (MHO) - have a better adipose tissue function, less ectopic fat storage, and are more insulin sensitive than obese metabolically unhealthy persons, emphasizing the central role of adipose tissue function in metabolic health. However, controversy has surrounded the idea that metabolically healthy obesity may be considered really healthy since MHO individuals are at increased (cardio)metabolic disease risk and may have a lower quality of life than normal weight subjects due to other comorbidities. Detailed metabolic phenotyping of obese persons will be invaluable in understanding the pathophysiology of metabolic disturbances, and is needed to identify high-risk individuals or subgroups, thereby paving the way for optimization of prevention and treatment strategies to combat cardiometabolic diseases. PMID- 28564653 TI - Skin Perfusion Changes within 12 h after Axillary Plexus Block. AB - BACKGROUND/PURPOSE: An improvement of the blood flow would be beneficial in microvascular upper-extremity reconstruction and in digit replantation. In the present work, skin perfusion changes and their duration due to axillary plexus block were quantified. METHODS: The peripheral blood flow of the upper extremities in 20 patients undergoing trapeziectomy under axillary plexus block was analyzed. RESULTS: Laser Doppler spectrophotometry was used to measure perfusion factors over a 12-h period, with the contralateral hand acting as the control. Axillary plexus block produced a significant increase of peripheral oxygen saturation (117 +/- 35% vs. control 93 +/- 22%, p = 0.019), peripheral blood flow (220 +/- 166% vs. 130 +/- 77%, p = 0.037), and velocity (164 +/- 58% vs. 117 +/- 45%, p = 0.011). CONCLUSION: Axillary plexus block produces an improvement of peripheral tissue oxygen saturation of the upper extremities over the first 6 h after the inception of anesthesia. This suggests a potential benefit especially for critically perfused tissues. PMID- 28564652 TI - Roux-en-Y Gastric Bypass Improves Hepatic Glucose Metabolism Involving Down Regulation of Protein Tyrosine Phosphatase 1B in Obese Rats. AB - OBJECTIVE: This study was initiated to investigate the effects of Roux-en-Y gastric bypass (RYGB) surgery on hepatic glucose metabolism and hepatic expression of protein tyrosine phosphatase 1B (PTP1B) in obese rats. METHODS: Body weight, glucose, intraperitoneal glucose, insulin, and pyruvate tolerance tests were performed pre- and postoperatively, and plasma lipid, insulin and glucagon-like peptide 1 (GLP-1) were measured. The mRNA levels of G6Pase, Pepck, Gsk-3beta and Gys-2, and the expression levels of PTP1B mRNA, protein, and other components of the insulin signaling pathway were measured by using RT-PCR and western blotting. The intracellular localization of PTP1B and hepatic glycogen deposition was also observed. RESULTS: RYGB surgery-treated rats showed persistent weight loss, significantly improved glucose tolerance, pyruvate tolerance, and dyslipidemia, as well as increased insulin sensitivity, hepatic glycogen deposition and increased plasma GLP-1 in obese rats. RT-PCR analyses showed Pepck, G6Pase, and Gsk-3beta mRNA to be significantly decreased, and Gys-2 mRNA to be significantly increased in liver tissue in the RYGB group (p < 0.05 vs. high-fat diet (HFD) or HFD + sham group); in addition, the expression of PTP1B were significantly decreased and insulin signaling were improved in the RYGB group (p < 0.05 vs. HFD or HFD + sham group). CONCLUSION: RYGB can improve hepatic glucose metabolism and down-regulate PTP1B in obese rats. An increased circulating GLP-1 concentration may be correlated with the effects following RYGB in obese rats. PMID- 28564654 TI - High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in Piglets. AB - BACKGROUND: Cannabidiol (CBD) is considered a promising neuroprotectant after perinatal hypoxia-ischemia (HI). We have previously studied the effects of CBD 1 mg/kg in the early phase after global HI in piglets. In contrast to prior studies, we found no evidence of neuroprotection and hypothesized that higher doses might be required to demonstrate efficacy in this animal model. OBJECTIVE: To assess the safety and potential neuroprotective effects of high-dose CBD. METHODS: Anesthetized newborn piglets underwent global HI by ventilation with 8% O2 until the point of severe metabolic acidosis (base excess -20 mmol/L) and/or hypotension (mean arterial blood pressure <=20 mm Hg). Piglets were randomized to intravenous treatment with vehicle (n = 9) or CBD (n = 13). The starting dose, CBD 50 mg/kg, was reduced if adverse effects occurred. The piglets were euthanized 9.5 h after HI and tissue was collected for analysis. RESULTS: CBD 50 mg/kg (n = 4) induced significant hypotension in 2 out of 4 piglets, and 1 out of 4 piglets suffered a fatal cardiac arrest. CBD 25 mg/kg (n = 4) induced significant hypotension in 1 out of 4 piglets, while 10 mg/kg (n = 5) was well tolerated. A significant negative correlation between the plasma concentration of CBD and hypotension during drug infusion was observed (p < 0.005). Neuroprotective effects were evaluated in piglets that did not display significant hypotension (n = 9) and CBD did not alter the degree of neuronal damage as measured by a neuropathology score, levels of the astrocytic marker S100B in CSF, magnetic resonance spectroscopy markers (Lac/NAA and Glu/NAA ratios), or plasma troponin T. CONCLUSIONS: High-dose CBD can induce severe hypotension and did not offer neuroprotection in the early phase after global HI in piglets. PMID- 28564655 TI - Aqueous Humor Levels of Soluble Vascular Endothelial Growth Factor Receptor and Inflammatory Factors in Diabetic Macular Edema. AB - Aqueous levels of soluble vascular endothelial growth factor receptor (sVEGFR) and inflammatory factors were measured in 35 patients (37 eyes) with diabetic macular edema (DME) receiving anti-vascular endothelial growth factor (VEGF) therapy. Aqueous levels of growth factors (VEGF, placental growth factor [PlGF], and platelet-derived growth factor AA [PDGF-AA]), sVEGFR-1 and -2, soluble intercellular adhesion molecule 1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, -8, -12, and -13, and interferon-inducible 10-kDa protein (IP 10) were significantly higher in the DME group than in the nondiabetic control group. The sVEGFR-2 level was significantly correlated with the neurosensory retinal thickness, as well as with the levels of growth factors (VEGF and PDGF AA) and inflammatory factors (MCP-1, IL-6, and IL-8). Three growth factors (VEGF, PlGF, and PDGF-AA) were also significantly correlated with each other, as were sVEGFR-1 or -2 and the inflammatory factors (MCP-1, IL-6, IL-8, and IP-10). These findings suggest that sVEGFRs and growth/inflammatory factors have an important role in DME. PMID- 28564657 TI - Relationship between Elevated Intraocular Pressure and Divided Peripapillary Sector Retinal Nerve Fiber Layer Thickness in a Cynomolgus Monkey Laser-Induced Ocular Hypertension Model. AB - AIMS: We investigated the relationship between elevated intraocular pressure (IOP) and changes in global and peripapillary sector retinal nerve fiber layer (RNFL) thickness around the optic nerve head (ONH) in the laser-induced ocular hypertension monkey model. METHODS: To induce high IOP, green laser photocoagulation burns were applied around the trabecular meshwork of 1 eye from each of 12 cynomolgus monkeys. The animals had been acclimated to IOP measurement under conscious conditions for more than 2 months, and IOP was chronologically measured. RNFL thickness was measured for 6 peripapillary sectors and global area using spectral-domain optical coherence tomography. RESULTS: After model induction, marked IOP elevation and enlarged optic disk cupping were observed. Thinning of the RNFL associated with elevated IOP was observed around the ONH from 6 until 9 weeks after laser treatment, and the degree of reduction in RNFL thickness varied between the peripapillary sectors. Correlations between cumulative IOP elevation and RNFL thickness reduction were statistically significant for the temporal-superior (p = 0.024), nasal-inferior (p = 0.044), and temporal (p = 0.049) sectors, and global RNFL (p = 0.018). CONCLUSIONS: These results suggest that this model reflected the pathology of clinical glaucoma in terms of the specific pattern of RNFL thinning around the ONH. PMID- 28564656 TI - Association Study of Three Gene Polymorphisms Recently Identified by a Genome Wide Association Study with Obesity-Related Phenotypes in Chinese Children. AB - OBJECTIVE: This study aimed to examine associations of three single-nucleotide polymorphisms (SNPs) with obesity-related phenotypes in Chinese children. These SNPs were identified by a recent genome-wide association (GWA) study among European children. Given that varied genetic backgrounds across different ethnicity may result in different association, it is necessary to study these associations in a different ethnic population. METHODS: A total of 3,922 children, including 2,191 normal-weight, 873 overweight and 858 obese children, from three independent studies were included in the study. Logistic and linear regressions were performed, and meta-analyses were conducted to assess the associations between the SNPs and obesity-related phenotypes. RESULTS: The pooled odds ratios of the A-allele of rs564343 in PACS1 for obesity and severe obesity were 1.180 (p = 0.03) and 1.312 (p = 0.004), respectively. We also found that rs564343 was nominally associated with BMI, BMI standard deviation score (BMI SDS), waist circumference, and waist-to-height ratio (p < 0.05). CONCLUSIONS: We showed for the first time that the rs564343 in PACS1 was associated with risk of severe obesity in a non-European population. This SNP was also found to be associated with common obesity and various obesity-related phenotypes in Chinese children, which had not been reported in the original study. The results demonstrated the value of conducting genetic researches in populations with different ethnicity. PMID- 28564658 TI - The Upstream Determinants of Adult Obesity. AB - Over-consumption of high-energy foods and a lack of physical activity are the main behavioural risk factors for people to develop obesity. These behaviours are influenced by a range of individual-level factors which are nested within contexts that contain influencing characteristics further upstream. In this paper, we define these upstream determinants. We also provide a historical background, summarise the current evidence base regarding these determinants across various types of environments and put them in perspective. PMID- 28564659 TI - Life-Threatening Intracerebral Hemorrhage in Previously Undiagnosed Acute T-Cell Lymphoblastic Leukemia with Blast Crisis: A Nightmare in Neurosurgeon's Life? AB - Spontaneous, nontraumatic intracerebral hemorrhage is a significant cause of morbidity and mortality throughout the world. Acute lymphoblastic leukemia is the most common cancer diagnosed in children. According to the literature, only 6 cases of acute lymphoblastic leukemia presenting as intracerebral hemorrhage have been reported. Five out of the 6 patients were managed conservatively; 3 out of these 6 patients survived with correction of coagulopathy. Surgical intervention was performed in only 1 of the previously reported cases in which the patient could not be salvaged. We report a case of life-threatening intracerebral hemorrhage in previously undiagnosed acute T-cell lymphoblastic leukemia with blast crisis, in which the patient was salvaged from the catastrophic complication after surgical intervention. PMID- 28564660 TI - Crimes against humanity. PMID- 28564661 TI - Workplace violence in hospitals and measures to address it. PMID- 28564662 TI - Introduction to Recent Advances in Neurosurgery. PMID- 28564663 TI - Current Treatment of Metastatic Spine Tumors - Surgery and Stereotactic Radiosurgery. AB - There has been significant progress and innovation in the treatment of patients with metastatic spinal tumors over the last two to three decades that has impacted our ability to provide individualized care that improves a patient's quality of life and degree of neurologic impairment. Advances in surgical techniques and radiation delivery modalities have dramatically improved our ability to decrease local tumor recurrence rates, improve pain control, and provide more durable spinal stability. Modern day spine tumor resection and reconstruction techniques have been shown to improve and prolong patients' ability to ambulate, maintain continence, and reduce the need for pain medications. Spinal radiosurgery, the focused delivery of radiation to a target in the spine, has significantly enhanced the ability to provide a high degree of local tumor control in a non-invasive manner, even for tumors that are deemed radioresistant by conventional radiation therapy standards. In most patients, a combination of treatment modalities, including both surgery and radiation, is the mainstay of any comprehensive treatment plan for metastatic spinal tumors. [Full article available at http://rimed.org/rimedicaljournal-2017-06.asp]. PMID- 28564664 TI - The Role of Radiation Therapy in the Treatment of Metastatic Brain Disease. AB - Brain metastasis is the most frequent central nervous system malignancy. Although surgery and chemotherapy have roles to play in the treatment of brain metastasis, radiation therapy remains a mainstay of therapy. We will review the role of fractionated radiotherapy and stereotactic radiosurgery in the treatment of newly diagnosed and recurrent brain metastasis. [Full article available at http://rimed.org/rimedicaljournal-2017-06.asp]. PMID- 28564665 TI - Current Strategies in the Surgical Management of Ischemic Stroke. AB - Stroke is a major cause of death and disability in the United States and rapid evaluation and treatment of stroke patients are critical to good outcomes. Effective surgical treatments aim to restore adequate cerebral blood flow, prevent secondary brain injury, or reduce the likelihood of recurrent stroke. Patient evaluation in centers with a comprehensive stroke program and a dedicated neuro- vascular team is recommended. [Full article available at http://rimed.org/rimedicaljournal-2017-06.asp]. PMID- 28564666 TI - A Comprehensive Approach to Deep Brain Stimulation for Movement Disorders. AB - Deep brain stimulation (DBS) is a well-established form of neuromodulation, used primarily for movement disorders such as Parkinson's disease (PD) and Essential Tremor (ET). The selection of patients who will benefit most from DBS depends on a team of clinicians from various disciplines, including neurology, neurosurgery, psychiatry, neuropsychology and rehabilitation specialists. The actual surgical procedure can take many forms. We apply a combination of multidisciplinary, team based evaluations and intra-operative neurophysiology, test stimulation and imaging to optimize DBS therapy for individual patients. [Full article available at http://rimed.org/rimedicaljournal-2017-06.asp]. PMID- 28564667 TI - Rhode Island Hospital's Contribution to the Field of Endoscopic Spine Surgery. AB - The first academic program in endoscopic spine surgery in the United States opened its doors at Rhode Island Hospital in 2012. Published advances in the field since its inception have included treatments for a myriad of pathologies including lumbar and thoracic disc herniations, spondylolisthesis, spine tumors as well as treatments for complications of other spinal procedures including spinal fusion, kyphoplasty, and total disc replacement. In this issue of the Rhode Island Medical Journal we summarize the history of the procedure as well as some of the interesting progress going on in this field in Rhode Island. [Full article available at http://rimed.org/rimedicaljournal-2017-06.asp]. PMID- 28564668 TI - Updates On Chimeric Antigen Receptor-Mediated Glioblastoma Immunotherapy. AB - Glioblastoma multiforme (GBM) is the most malignant of the primary central nervous system (CNS) neoplasms, accounting for nearly 80% of all primary brain tumors and is associated with high morbidity and mortality. Immunotherapy is proving to be a fertile ground for next-generation GBM therapy, with large translational research projects and clinical trials currently underway. One particularly promising area is the chimeric antigen receptors (CARs) in the context of lymphocyte adoptive cell therapy (ACT), which has achieved success in the treatment of hematological malignancies. In this review, we will discuss CARs and review current challenges facing their use in GBM therapy. [Full article available at http://rimed.org/rimedicaljournal-2017-06.asp]. PMID- 28564669 TI - Recent Advances in the Treatment of Gliomas - Comprehensive Brain Tumor Center. AB - Gliomas are a class of primary brain tumors arising from the supporting structures of the brain, the astrocytes and oligodendrocytes, which range from benign lesions to its most malignant form, the glioblastoma. Treatment for these lesions includes maximal surgical resection, radiotherapy, and chemotherapy. Recently, novel therapies such as immune modulatory therapies and electrical field treatment of the most malignant form, the glioblastoma, have shown promise in improving survival. We will review recent advances in clinical trials, explore the role of multimodal care in brain tumor therapy, as well as explore advances in molecular biology and nanotechnology which offer new hope for treatment of this class of disease. [Full article available at http://rimed.org/rimedicaljournal-2017-06.asp]. PMID- 28564670 TI - Current Concepts in the Pathogenesis, Diagnosis, and Management of Type I Chiari Malformations. AB - Type 1 Chiari malformations (CMs) are a group of congenital or acquired disorders which include the abnormal presence of the cerebellar tonsils in the upper spinal canal, rather than the posterior fossa. The resulting anatomic abnormality causes crowding of the structures at the craniocervical junction and can impair the normal flow of cerebral spinal fluid (CSF) in this region. This impairment in CSF flow dynamics can led to the development of syringomyelia or hydrocephalus. Type 1 CMs have been associated with a wide array of symptoms resulting from either cerebellar and brainstem compression and distortion or disturbances in CSF dynamics, and can affect both children and adults. The clinical diagnosis may be difficult. Age usually matters in the clinical presentation, and in symptomatic patients, surgical intervention is usually required. [Full article available at http://rimed.org/rimedicaljournal-2017-06.asp]. PMID- 28564672 TI - The Myth of Patient Centeredness in the Trauma Bay. PMID- 28564671 TI - Effects of Smoking and Smoking Cessation during Pregnancy on Adverse Birth Outcomes in Rhode Island, 2012-2014. PMID- 28564673 TI - Postoperative Multimodal Analgesia Pain Management With Nonopioid Analgesics and Techniques: A Review. AB - Importance: Amid the current opioid epidemic in the United States, the enhanced recovery after surgery pathway (ERAS) has emerged as one of the best strategies to improve the value and quality of surgical care and has been increasingly adopted for a broad range of complex surgical procedures. The goal of this article was to outline important components of opioid-sparing analgesic regimens. Observations: Regional analgesia, acetaminophen, nonsteroidal anti-inflammatory agents, gabapentinoids, tramadol, lidocaine, and/or the N-methyl-d-aspartate class of glutamate receptor antagonists have been shown to be effective adjuncts to narcotic analgesia. Nonsteroidal anti-inflammatory agents are not associated with an increase in postoperative bleeding. A meta-analysis of 27 randomized clinical trials found no difference in postoperative bleeding between the groups taking ketorolac tromethamine (33 of 1304 patients [2.5%]) and the control groups (21 of 1010 [2.1%]) (odds ratio [OR], 1.1; 95% CI, 0.61-2.06; P = .72). After adoption of the multimodal analgesia approach for a colorectal ERAS pathway, most patients used less opioids while in the hospital and many did not need opioids after hospital discharge, although approximately 50% of patients received some opioid during their stay. Conclusions and Relevance: Multimodal analgesia is readily available and the evidence is strong to support its efficacy. Surgeons should use this effective approach for patients both using and not using the ERAS pathway to reduce opioid consumption. PMID- 28564675 TI - Incomplete Author Name in Byline. PMID- 28564676 TI - New Blood Pressure-Lowering Targets-Finding Clarity. PMID- 28564677 TI - Defining Treatment-Resistant Depression. PMID- 28564674 TI - Association of a Policy Mandating Physician-Patient Communication With Racial/Ethnic Disparities in Postmastectomy Breast Reconstruction. AB - Importance: With the stabilization of breast cancer incidence and substantial improvement in survival, more attention has focused on postmastectomy breast reconstruction (PBR). Despite its demonstrated benefits, wide disparities in the use of PBR remain. Physician-patient communication has an important role in disparities in health care, especially for elective surgical procedures. Recognizing this, the State of New York enacted Public Health Law (NY PBH Law) 2803-o in 2011 mandating that physicians communicate about reconstructive surgery with patients undergoing mastectomy. Objective: To evaluate whether mandated physician-patient communication is associated with reduced racial/ethnic disparities in immediate PBR (IPBR). Design, Setting, and Participants: This retrospective study used state inpatient data from January 1, 2008, through December 31, 2011, in New York and California to evaluate a final sample of 42 346 women aged 20 to 70 years, including 19 364 from New York (treatment group) and 22 982 from California (comparison group). The primary hypothesis tested the effect of the New York law on racial/ethnic disparities, using California as a comparator. The National Academy of Medicine's (formerly Institute of Medicine) definition of a disparity was applied, and a difference-in-differences method (before-and-after comparison design) was used to evaluate the association of NY PBH Law 2803-o mandating physician-patient communication with disparities in IPBR. Data were analyzed from July 1, 2016, to February 24, 2017. Exposures: New York PBH Law 2803-o was implemented on January 1, 2011. The preexposure period included January 1, 2008, through December 31, 2010 (3 years); the postexposure period, January 1 through December 31, 2011 (1 year). Main Outcomes and Measures: The primary outcome was use of IPBR among white, African American, Hispanic, and other minority groups before and after the implementation of NY PBH Law 2803-o. Results: Among the 42 346 women (mean [SD] age, 53 [10] years), 65.3% (27 654) were white, 12.7% (5365) were Hispanic, 9.4% (3976) were African American, and 12.6% (5351) were other minorities. The new legislation was not associated with the overall IPBR rate or disparity in IPBR between whites and African Americans (reduction of 1 percentage point; 95% CI, -0.02 to 0.04), but it was associated with a reduction in disparities in IPBR between Hispanic and white patients by 9 (95% CI, 0.06-0.11) percentage points and between other minorities and white patients by 13 (95% CI, 0.11-0.16) percentage points. Conclusions and Relevance: Physician-patient communication may help to address inequity in the use of elective surgical procedures, such as IPBR. However, lack of patient trust and/or effective physician-patient communication may reduce the potential effect of mandatory communication for some subpopulations, including African American individuals. PMID- 28564678 TI - Association Between Skin and Aortic Vascular Inflammation in Patients With Psoriasis: A Case-Cohort Study Using Positron Emission Tomography/Computed Tomography. AB - Importance: Inflammation is critical in the development of atherosclerosis. Psoriasis is a chronic inflammatory skin disease that is associated with increased vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography in vivo and future cardiovascular events. It provides a human model to understand the effect of treating inflammation in a target organ (eg, the skin) on vascular diseases. Objective: To investigate the association between change in skin disease severity and change in vascular inflammation at 1 year and to characterize the impact of 1 year of anti-tumor necrosis factor therapy on vascular inflammation. Design, Setting, and Participants: In this prospective cohort study, 220 participants from outpatient practices were recruited at the US National Institutes of Health. A total of 115 consecutively recruited patients with psoriasis were followed up at 1 year. The study was conducted from January 1, 2013, through October 31, 2016, with data analyzed in November 2016. Exposure: Skin inflammation measured as Psoriasis Area and Severity Index (PASI) score. Main Outcomes and Measures: Vascular inflammation assessed as target-to-background ratio by 18fluorodeoxyglucose positron emission tomography/computed tomography. Results: Among the 115 patients, the mean (SD) age at 1-year follow-up was 50.8 (12.8) years and 68 were men (59%). The cohort had a low cardiovascular risk by Framingham risk score and mild-to-moderate psoriasis, with a median PASI score of 5.2 (interquartile range, 3.0-8.9). At follow-up, the total cohort had a median improvement in PASI score of 33%, with use of topical therapy (60%), biological therapy (66%, mostly anti tumor necrosis factor) and phototherapy (15%) (P < .001). Moreover, improvement in PASI score was associated with improvement in target-to-background ratio of 6%, mainly driven by those with higher responses in PASI score (P < .001). This association persisted beyond traditional risk factors (beta = 0.19; 95% CI, 0.012 0.375; P = .03) and was the strongest in those initiated with anti-tumor necrosis factor therapy (beta = 0.79; 95% CI, 0.269-1.311; P = .03). Conclusions and Relevance: Improvement in psoriasis skin disease severity was associated with improvement in aortic vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography, with greater improvement in aortic vascular inflammation observed in those who had higher than 75% reduction in skin disease severity. These findings suggest that controlling remote target organ inflammation (eg, in the skin) may improve vascular diseases; however, randomized clinical trials are needed to confirm these findings. PMID- 28564680 TI - Suicide Risk After Psychiatric Hospital Discharge. PMID- 28564679 TI - Difficulties in Testing the Instrument Strength Independent of Direct Effect Assumption in Mendelian Randomization. PMID- 28564683 TI - Consciousness as Sequential Dynamics, Robustness, and Mental Disorders. PMID- 28564682 TI - Systolic Blood Pressure Reduction and Risk of Cardiovascular Disease and Mortality: A Systematic Review and Network Meta-analysis. AB - Importance: Clinical trials have documented that lowering blood pressure reduces cardiovascular disease and premature deaths. However, the optimal target for reduction of systolic blood pressure (SBP) is uncertain. Objective: To assess the association of mean achieved SBP levels with the risk of cardiovascular disease and all-cause mortality in adults with hypertension treated with antihypertensive therapy. Data Sources: MEDLINE and EMBASE were searched from inception to December 15, 2015, supplemented by manual searches of the bibliographies of retrieved articles. Study Selection: Studies included were clinical trials with random allocation to an antihypertensive medication, control, or treatment target. Studies had to have reported a difference in mean achieved SBP of 5 mm Hg or more between comparison groups. Data Extraction and Synthesis: Data were extracted from each study independently and in duplicate by at least 2 investigators according to a standardized protocol. Network meta-analysis was used to obtain pooled randomized results comparing the association of each 5-mm Hg SBP category with clinical outcomes after adjusting for baseline risk. Main Outcomes and Measures: Cardiovascular disease and all-cause mortality. Results: Forty-two trials, including 144 220 patients, met the eligibility criteria. In general, there were linear associations between mean achieved SBP and risk of cardiovascular disease and mortality, with the lowest risk at 120 to 124 mm Hg. Randomized groups with a mean achieved SBP of 120 to 124 mm Hg had a hazard ratio (HR) for major cardiovascular disease of 0.71 (95% CI, 0.60-0.83) compared with randomized groups with a mean achieved SBP of 130 to 134 mm Hg, an HR of 0.58 (95% CI, 0.48-0.72) compared with those with a mean achieved SBP of 140 to 144 mm Hg, an HR of 0.46 (95% CI, 0.34-0.63) compared with those with a mean achieved SBP of 150 to 154 mm Hg, and an HR of 0.36 (95% CI, 0.26-0.51) compared with those with a mean achieved SBP of 160 mm Hg or more. Likewise, randomized groups with a mean achieved SBP of 120 to 124 mm Hg had an HR for all-cause mortality of 0.73 (95% CI, 0.58-0.93) compared with randomized groups with a mean achieved SBP of 130 to 134 mm Hg, an HR of 0.59 (95% CI, 0.45-0.77) compared with those with a mean achieved SBP of 140 to 144 mm Hg, an HR of 0.51 (95% CI, 0.36-0.71) compared with those with a mean achieved SBP of 150 to 154 mm Hg, and an HR of 0.47 (95% CI, 0.32-0.67) compared with those with a mean achieved SBP of 160 mm Hg or more. Conclusions and Relevance: This study suggests that reducing SBP to levels below currently recommended targets significantly reduces the risk of cardiovascular disease and all-cause mortality. These findings support more intensive control of SBP among adults with hypertension. PMID- 28564684 TI - Skin and Vascular Disease-Inside-Out/Outside-In. PMID- 28564681 TI - Association of Microvascular Dysfunction With Late-Life Depression: A Systematic Review and Meta-analysis. AB - Importance: The etiologic factors of late-life depression are still poorly understood. Recent evidence suggests that microvascular dysfunction is associated with depression, which may have implications for prevention and treatment. However, this association has not been systematically reviewed. Objective: To examine the associations of peripheral and cerebral microvascular dysfunction with late-life depression. Data Sources: A systematic literature search was conducted in MEDLINE and EMBASE for and longitudinal studies published since inception to October 16, 2016, that assessed the associations between microvascular dysfunction and depression. Study Selection: Three independent researchers performed the study selection based on consensus. Inclusion criteria were a study population 40 years of age or older, a validated method of detecting depression, and validated measures of microvascular function. Data Extraction and Synthesis: This systematic review and meta-analysis has been registered at PROSPERO (CRD42016049158) and is reported in accordance with the PRISMA and MOOSE guidelines. Data extraction was performed by an independent researcher. Main Outcomes and Measures: The following 5 estimates of microvascular dysfunction were considered in participants with or without depression: plasma markers of endothelial function, albuminuria, measurements of skin and muscle microcirculation, retinal arteriolar and venular diameter, and markers for cerebral small vessel disease. Data are reported as pooled odds ratios (ORs) by use of the generic inverse variance method with the use of random-effects models. Results: A total of 712 studies were identified; 48 were included in the meta analysis, of which 8 described longitudinal data. Data from 43 600 participants, 9203 individuals with depression, and 72 441 person-years (mean follow-up, 3.7 years) were available. Higher levels of plasma endothelial biomarkers (soluble intercellular adhesion molecule-1: OR, 1.58; 95% CI, 1.28-1.96), white matter hyperintensities (OR, 1.29; 95% CI, 1.19-1.39), cerebral microbleeds (OR, 1.18; 95% CI, 1.03-1.34), and cerebral (micro)infarctions (OR, 1.30; 95% CI, 1.21-1.39) were associated with depression. Among the studies available, no significant associations of albuminuria and retinal vessel diameters with depression were reported. Longitudinal data showed a significant association of white matter hyperintensities with incident depression (OR, 1.19; 95% CI, 1.09-1.30). Conclusions and Relevance: This meta-analysis shows that both the peripheral and cerebral forms of microvascular dysfunction are associated with higher odds of (incident) late-life depression. This finding may have clinical implications because microvascular dysfunction might provide a potential target for the prevention and treatment of depression. PMID- 28564686 TI - Bayesian depth estimation from monocular natural images. AB - Estimating an accurate and naturalistic dense depth map from a single monocular photographic image is a difficult problem. Nevertheless, human observers have little difficulty understanding the depth structure implied by photographs. Two dimensional (2D) images of the real-world environment contain significant statistical information regarding the three-dimensional (3D) structure of the world that the vision system likely exploits to compute perceived depth, monocularly as well as binocularly. Toward understanding how this might be accomplished, we propose a Bayesian model of monocular depth computation that recovers detailed 3D scene structures by extracting reliable, robust, depth sensitive statistical features from single natural images. These features are derived using well-accepted univariate natural scene statistics (NSS) models and recent bivariate/correlation NSS models that describe the relationships between 2D photographic images and their associated depth maps. This is accomplished by building a dictionary of canonical local depth patterns from which NSS features are extracted as prior information. The dictionary is used to create a multivariate Gaussian mixture (MGM) likelihood model that associates local image features with depth patterns. A simple Bayesian predictor is then used to form spatial depth estimates. The depth results produced by the model, despite its simplicity, correlate well with ground-truth depths measured by a current generation terrestrial light detection and ranging (LIDAR) scanner. Such a strong form of statistical depth information could be used by the visual system when creating overall estimated depth maps incorporating stereopsis, accommodation, and other conditions. Indeed, even in isolation, the Bayesian predictor delivers depth estimates that are competitive with state-of-the-art "computer vision" methods that utilize highly engineered image features and sophisticated machine learning algorithms. PMID- 28564685 TI - Histopathologic and Immunohistochemical Correlates of Confocal Descriptors in Pigmented Facial Macules on Photodamaged Skin. AB - Importance: Pigmented facial macules on photodamaged skin are a clinical, dermoscopic, and histopathologic challenge. Objectives: To clinically and dermoscopically characterize, by means of reflectance confocal microscopy (RCM), ambiguous pigmented facial macules and establish a correlation between RCM, histopathologic, and immunohistochemical findings. Design, Setting, and Participants: A prospective study of ambiguous pigmented facial macules on photodamaged skin was conducted in a tertiary referral center for dermatology between January 1, 2009, and December 31, 2015. Sixty-one patients with 63 ambiguous pigmented facial macules and 12 control photodamaged facial areas were included in the study. Melanocyte density in 1-mm basal layers was determined in skin biopsy specimens from all lesions stained with hematoxylin-eosin and immunohistochemical markers (melan-A, microphthalmia-associated transcription factor, and SRY-related HMG-box gene 10). Dermoscopic, RCM images, and histopathologic preparations were systematically evaluated for the presence of lentigo maligna (LM) criteria. Confocal evaluation was blinded to clinical and dermoscopic diagnosis. Sensitivity and specificity of RCM for LM diagnosis and kappa value to establish correlations between dermoscopy, RCM, and histopathology were performed. Main Outcomes and Measures: Sensitivity and specificity of RCM for LM diagnosis. Results: Of the 61 patients included in the study, 31 (51%) were women; mean (SD) age was 71.8 (13.1) years. Twenty-four of the 63 (38%) lesions were diagnosed as LM or LM melanoma (LMM) and 39 (62%) as benign pigmented lesions. Reflectance confocal microscopy enhanced the diagnosis of pigmented facial macules with 91.7% sensitivity and 86.8% specificity. Multivariate analysis showed 2 dermoscopic and 2 confocal features associated with LM or LMM: (1) asymmetric follicular pigmentation and targetlike structures, and (2) round, large pagetoid cells and follicular localization of atypical cells, respectively. Continuous proliferation of atypical melanocytes was found in 21 (88%) LM or LMM and in 3 (77%) benign lesions. Asymmetric pigmented follicular openings by dermoscopy correlated with follicular localization of pagetoid cells by RCM (kappa = 0.499, P < .001). The presence of 3 or more atypical cells at the dermal-epidermal junction (DEJ) by RCM correlated with hyperplasia of melanocytes in hematoxylin-eosin sections (kappa = 0.422, P < .001). Conclusions and Relevance: Reflectance confocal microscopy improves LM diagnosis in photodamaged skin with good histopathologic correlation although false-positive and false-negative cases exist. False-positives obtained with RCM in photodamaged skin are due to the presence of basal melanocyte hyperplasia and intraepidermal Langerhans cells. Histopathologic features of these lesions sometimes are not enough for a definite diagnosis and immunohistochemical studies may be required. PMID- 28564687 TI - Scan patterns during real-world scene viewing predict individual differences in cognitive capacity. AB - From the earliest recordings of eye movements during active scene viewing to the present day, researchers have commonly reported individual differences in eye movement scan patterns under constant stimulus and task demands. These findings suggest viewer individual differences may be important for understanding gaze control during scene viewing. However, the relationship between scan patterns and viewer individual differences during scene viewing remains poorly understood because scan patterns are difficult to analyze. The present study uses a powerful technique called Successor Representation Scanpath Analysis (Hayes, Petrov, & Sederberg, 2011, 2015) to quantify the strength of the association between individual differences in scan patterns during real-world scene viewing and individual differences in viewer intelligence, working memory capacity, and speed of processing. The results of this analysis revealed individual differences in scan patterns that explained more than 40% of the variance in viewer intelligence and working memory capacity measures, and more than a third of the variance in speed of processing measures. The theoretical implications of our findings for models of gaze control and avenues for future individual differences research are discussed. PMID- 28564688 TI - Defining Treatment-Resistant Depression-Reply. PMID- 28564689 TI - Laser-induced micropore formation and modification of cartilage structure in osteoarthritis healing. AB - Pores are vital for functioning of avascular tissues. Laser-induced pores play an important role in the process of cartilage regeneration. The aim of any treatment for osteoarthritis is to repair hyaline-type cartilage. The aims of this study are to answer two questions: (1) How do laser-assisted pores affect the cartilaginous cells to synthesize hyaline cartilage (HC)? and (2) How can the size distribution of pores arising in the course of laser radiation be controlled? We have shown that in cartilage, the pores arise predominately near chondrocytes, which promote nutrition of cells and signal molecular transfer that activates regeneration of cartilage. In vivo laser treatment of damaged cartilage of miniature pig joints provides cellular transformation and formation of HC. We propose a simple model of pore formation in biopolymers that paves the way for going beyond the trial-and-error approach when choosing an optimal laser treatment regime. Our findings support the approach toward laser healing of osteoarthritis. PMID- 28564691 TI - Single-image structured illumination using Hilbert transform demodulation. AB - Structured illumination microscopy (SIM) achieves sectioning at depth by removing undesired light from out-of-focus planes within a specimen. However, it generally requires at least three modulated images with discrete phase shifts of 0, 120, and 240 deg to produce sectioning. Using a Hilbert transform demodulation, it is possible to produce both sectioning and depth information relative to a reference plane (i.e., a coverslip) using only a single image. The specimen is modulated at a known frequency, and the unmodulated portion of the image is estimated. These two components are used to provide a high-quality sectioned image containing both axial and lateral information of an object. The sectioning resolution with a single image is on par with that of a control three-image SIM. We are also able to show that when used with three images of discrete phase, this method produces better contrast within a turbid media than the traditional SIM technique. Because the traditional SIM requires alignment of three different phases, small differences in optical path length can introduce strong artifacts. Using the single-image technique removes this dependency, greatly improving sectioning in turbid media. Multiple targets with various depths and opaqueness are considered, including human skin in vivo, demonstrating a quick and useful way to provide noninvasive sectioning in real time. PMID- 28564690 TI - Volume holographic imaging endoscopic design and construction techniques. AB - A reflectance volume holographic imaging (VHI) endoscope has been designed for simultaneous in vivo imaging of surface and subsurface tissue structures. Prior utilization of VHI systems has been limited to ex vivo tissue imaging. The VHI system presented in this work is designed for laparoscopic use. It consists of a probe section that relays light from the tissue sample to a handheld unit that contains the VHI microscope. The probe section is constructed from gradient index (GRIN) lenses that form a 1:1 relay for image collection. The probe has an outer diameter of 3.8 mm and is capable of achieving 228.1 ?? lp / mm resolution with 660-nm Kohler illumination. The handheld optical section operates with a magnification of 13.9 and a field of view of 390 ?? ? m * 244 ?? ? m . System performance is assessed through imaging of 1951 USAF resolution targets and soft tissue samples. The system has also passed sterilization procedures required for surgical use and has been used in two laparoscopic surgical procedures. PMID- 28564693 TI - Vesicular Rash in a Neutropenic Infant. PMID- 28564692 TI - Simulated altitude exposure assessment by hyperspectral imaging. AB - Testing the human body's reaction to hypoxia (including the one generated by high altitude) is important in aeronautic medicine. This paper presents a method of monitoring blood oxygenation during experimental hypoxia using hyperspectral imaging (HSI) and a spectral unmixing model based on a modified Beer-Lambert law. A total of 20 healthy volunteers (males) aged 25 to 60 years were included in this study. A line-scan HSI system was used to acquire images of the faces of the subjects. The method generated oxyhemoglobin and deoxyhemoglobin distribution maps from the foreheads of the subjects at 5 and 10 min of hypoxia and after recovery in a high oxygen breathing mixture. The method also generated oxygen saturation maps that were validated using pulse oximetry. An interesting pattern of desaturation on the forehead was discovered during the study, showing one of the advantages of using HSI for skin oxygenation monitoring in hypoxic conditions. This could bring new insight into the physiological response to high altitude and may become a step forward in air crew testing. PMID- 28564694 TI - Background and Room Illumination in Color Identification of Skin Lesions: A Cross sectional Study. PMID- 28564696 TI - A Framework for the Assessment of Graduate Medical Education. PMID- 28564695 TI - Efficacy and Tolerance of Anti-Tumor Necrosis Factor alpha Agents in Cutaneous Sarcoidosis: A French Study of 46 Cases. AB - Importance: Evidence for the long-term efficacy and safety of anti-tumor necrosis factor alpha agents (anti-TNF) in treating cutaneous sarcoidosis is lacking. Objective: To determine the efficacy and safety of anti-TNF in treating cutaneous sarcoidosis in a large observational study. Design, Setting, and Participants: STAT (Sarcoidosis Treated with Anti-TNF) is a French retrospective and prospective multicenter observational database that receives data from teaching hospitals and referral centers, as well as several pneumology, dermatology, and internal medicine departments. Included patients had histologically proven sarcoidosis and received anti-TNF between January 2004 and January 2016. We extracted data for patients with skin involvement at anti-TNF initiation. Main Outcomes and Measures: Response to treatment was evaluated for skin and visceral involvement using the ePOST (extra-pulmonary Physician Organ Severity Tool) severity score (from 0 [not affected] to 6 [very severe involvement]). Epidemiological and cutaneous features at baseline, efficacy, steroid-sparing, safety, and relapses were recorded. The overall cutaneous response rate (OCRR) was defined as complete (final cutaneous ePOST score of 0 or 1) or partial response (ePOST drop >=2 points from baseline but >1 at last follow-up). Results: Among 140 patients in the STAT database, 46 had skin involvement. The most frequent lesions were lupus pernio (n = 21 [46%]) and nodules (n = 20 [43%]). The median cutaneous severity score was 5 and/or 6 at baseline. Twenty-one patients were treated for skin involvement and 25 patients for visceral involvement. Reasons for initiating anti-TNF were failure or adverse effects of previous therapy in 42 patients (93%). Most patients received infliximab (n = 40 [87%]), with systemic steroids in 28 cases (61%) and immunosuppressants in 32 cases (69.5%). The median (range) follow-up was 45 (3-103) months. Of the 46 patients with sarcoidosis and skin involvement who were treated with anti-TNF were included, median (range) age was 50 (14-78) years, and 33 patients (72%) were women. The OCRR was 24% after 3 months, 46% after 6 months, and 79% after 12 months. Steroid sparing was significant. Treatment was discontinued because of adverse events in 11 patients (24%), and 21 infectious events occurred in 14 patients (30%). Infections were more frequent in patients treated for visceral involvement than in those treated for skin involvement (n = 12 of 25 [48%] vs n = 2 of 21 [9.5%], respectively; P = .02). The relapse rate was 44% 18 months after discontinuation of treatment. Relapses during treatment occurred in 35% of cases, mostly during anti-TNF or concomitant treatment tapering. Conclusions and Relevance: Anti-TNF agents are effective but suspensive in cutaneous sarcoidosis. The risk of infectious events must be considered. PMID- 28564697 TI - Activation of Protein Kinase C epsilon in Merkel Cell Polyomavirus-Induced Merkel Cell Carcinoma. PMID- 28564698 TI - Intralesional Sodium Thiosulfate Treatment for Calcinosis Cutis in the Setting of Lupus Panniculitis. PMID- 28564700 TI - Nighttime Driving in Older Adults: Effects of Glare and Association With Mesopic Visual Function. AB - Purpose: To examine the associations between nighttime driving performance of older drivers and photopic, mesopic, and glare-based tests of visual function. Methods: Participants included 26 older drivers (71.8 +/- 6.3 years), with minimal or no eye disease, but who reported vision-related nighttime driving difficulties. Nighttime driving performance was assessed on a closed-road circuit, which included intermittent glare. An overall driving performance score was calculated based on detection of signs, pedestrians, wooden animals and road markings, lane-keeping, and avoidance of low contrast hazards. Visual function tests included photopic and mesopic visual acuity (VA) and contrast sensitivity (CS). Tests of glare (Berkeley Glare and Aston Halometer) and mesopic motion sensitivity were also assessed. Regression analyses were used to explore the associations between these vision measures and nighttime driving performance. Results: The overall driving performance score was significantly reduced by intermittent glare (P = 0.002); notably, pedestrian detection decreased by 38% in the presence of intermittent glare (P < 0.001). Overall driving scores were most strongly associated with motion sensitivity (P = 0.001) and mesopic high contrast VA (P = 0.002), rather than photopic or glare-based tests. Motion sensitivity accounted for more than twice the variation in driving performance compared to photopic high contrast VA (29% vs. 14%). Conclusions: Glare reduced several aspects of nighttime driving performance. Mesopic tests of visual function, including motion sensitivity and mesopic high contrast VA, were more strongly associated with nighttime driving performance than photopic high-contrast VA. These results highlight the potential importance of nonstandard vision tests for assessing older drivers' visual capacity to drive at night. PMID- 28564701 TI - The Impact of Lens Opacity on SD-OCT Retinal Nerve Fiber Layer and Bruch's Membrane Opening Measurements Using the Anatomical Positioning System (APS). AB - Purpose: To evaluate the impact of lens opacity on retinal nerve fiber layer thickness (RNFLT) and Bruch's membrane opening (BMO) measurements. Methods: Fifty nine randomly selected patients without any other relevant ocular pathology undergoing elective routine cataract surgery in two specialized eye clinics were enrolled. RNFLT, BMO area, and BMO minimum rim width (BMO-MRW) were assessed with the Heidelberg Engineering Spectralis OCT using the anatomical positioning system (APS) prior to and 1 day after cataract surgery using a ring scan at different eccentricities of the disc (3.5, 4.1 and 4.7 mm). Lens opacity was quantified using densitometry based on Scheimpflug images (Oculus Pentacam AXL). Results: RNFLT, BMO area, and BMO-MRW were virtually identical before and following removal of the cataractous lens. This held when assessed overall, within the six sectors for the 3.5-mm scan, or at any other eccentricity. Baseline RNFLT was not associated with lens opacity. Conclusions: Using the APS, RNFLT remained unchanged following cataract surgery, contrary to results reported by previous studies. Our results imply that the APS may have contributed to more precise spectral-domain optical coherence measurements, minimizing the influence of cataract on RNFLT and BMO assessments in our cohort. PMID- 28564699 TI - Suicide Rates After Discharge From Psychiatric Facilities: A Systematic Review and Meta-analysis. AB - Importance: High rates of suicide after psychiatric hospitalization are reported in many studies, yet the magnitude of the increases and the factors underlying them remain unclear. Objectives: To quantify the rates of suicide after discharge from psychiatric facilities and examine what moderates those rates. Data Sources: English-language, peer-reviewed publications published from January 1, 1946, to May 1, 2016, were located using MEDLINE, PsychINFO, and EMBASE with the search terms ((suicid*).ti AND (hospital or discharg* OR inpatient or in-patient OR admit*).ab and ((mortality OR outcome* OR death*) AND (psych* OR mental*)).ti AND (admit* OR admis* or hospital* OR inpatient* OR in-patient* OR discharg*).ab. Hand searching was also done. Study Selection: Studies reporting the number of suicides among patients discharged from psychiatric facilities and the number of exposed person-years and studies from which these data could be calculated. Data Extraction and Synthesis: The meta-analysis adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. A random-effects model was used to calculate a pooled estimate of postdischarge suicides per 100 000 person-years. Main Outcomes and Measures: The suicide rate after discharge from psychiatric facilities was the main outcome, and the association between the duration of follow-up and the year of the sampling were the main a priori moderators. Results: A total of 100 studies reported 183 patient samples (50 samples of females, 49 of males, and 84 of mixed sex; 129 of adults or unspecified patients, 20 of adolescents, 19 of older patients, and 15 from long term or forensic discharge facilities), including a total of 17 857 suicides during 4 725 445 person-years. The pooled estimate postdischarge suicide rate was 484 suicides per 100 000 person-years (95% CI, 422-555 suicides per 100 000 person-years; prediction interval, 89-2641), with high between-sample heterogeneity (I2 = 98%). The suicide rate was highest within 3 months after discharge (1132; 95% CI, 874-1467) and among patients admitted with suicidal ideas or behaviors (2078; 95% CI, 1512-2856). Pooled suicide rates per 100 000 patients-years were 654 for studies with follow-up periods of 3 months to 1 year, 494 for studies with follow-up periods of 1 to 5 years, 366 for studies with follow-up periods of 5 to 10 years, and 277 for studies with follow-up periods longer than 10 years. Suicide rates were higher among samples collected in the periods 1995-2004 (656; 95% CI, 518-831) and 2005-2016 (672; 95% CI, 428-1055) than in earlier samples. Conclusions and Relevance: The immediate postdischarge period is a time of marked risk, but rates of suicide remain high for many years after discharge. Patients admitted because of suicidal ideas or behaviors and those in the first months after discharge should be a particular focus of concern. Previously admitted patients should be able to access long-term care and assistance. PMID- 28564703 TI - Erratum. PMID- 28564704 TI - Erratum. PMID- 28564702 TI - Associations Between beta-Peripapillary Atrophy and Reticular Pseudodrusen in Early Age-Related Macular Degeneration. AB - Purpose: Choroidal thinning has been associated with reticular pseudodrusen (RPD) and beta-peripapillary atrophy (beta-PPA), which have been linked to normal tension glaucoma (NTG). This analysis sought to determine whether RPD are independently associated with beta-PPA in early AMD patients. Secondary outcomes included the association of RPD and preexisting diagnosis of glaucoma, cup-to disc ratio (CDR), subfoveal choroidal thickness (SFCT), and IOP. Methods: This prospective cross-sectional study examined 78 age- and sex-matched early AMD patients: 43 RPD patients (63 eyes) and 35 non-RPD patients (64 eyes). Exclusion criteria included advanced AMD, high myopia, and vitreoretinal conditions/surgery. RPD and non-RPD groups were identified by confocal scanning laser ophthalmoscopy. beta-PPA as well as CDR were graded on digital, nonstereoscopic fundus photos. SFCT was measured on spectral-domain optical coherence tomography for 69 patients (35 RPD and 34 non-RPD). IOP and glaucoma diagnosis were extracted from charts. Results: beta-PPA had a greater prevalence in RPD than non-RPD (44% vs. 19%, P = 0.002); however, this relationship was not significant when SFCT was added to the model (P = 0.150). A preexisting diagnosis of glaucoma (P = 0.156), CDR (P = 0.176), and IOP (P = 0.98) was not different between groups. Conclusions: RPD in early AMD are associated with presence of beta-PPA, but choroidal thickness is a confounder in this relationship. Because beta-PPA is a common finding in NTG, focusing on a potential shared pathway between RPD and NTG could improve the understanding of pathophysiology and expand therapies for each condition. PMID- 28564705 TI - A Histologic Categorization of Aqueous Outflow Routes in Familial Open-Angle Glaucoma and Associations With Mutations in the MYOC Gene in Japanese Patients. AB - Purpose: This study evaluated specific relationships between pathogenic mechanisms and genetic polymorphisms in primary open-angle glaucoma (POAG). We analyzed the morphologies of trabeculectomy specimens obtained from patients with familial POAG. Methods: We used light microscopy and transmission electron microscopy to examine specimens obtained from 17 eyes of 14 patients with familial POAG. We also conducted exome analyses of two families and used targeted Sanger sequencing to analyze samples obtained from the remaining patients. Results: The POAG cases examined in this study were divided into two groups based on morphologic characteristics. Group A eyes (7 eyes from 5 patients) had an abnormally thick trabecular meshwork (TM), whereas group B eyes (10 eyes from 9 patients) had a TM of normal thickness. The characteristics of the outflow routes in group A eyes were remarkable and included apoptotic TM cells, abnormally thickened TM basement membranes, fused TM beams, and occluded Schlemm's canals. All group A patients harbored mutations (F369L, P370L, T377M, and T448P) in the myocilin (MYOC) gene that were not found in group B patients. Conclusions: Although age matching of morphologic changes in the outflow routes was impossible due to the small sample size, this study suggests that abnormal TM cells may cause sequential damage in abnormally thickened TM basement membranes, TM cell apoptosis, TM beam fusion, and the occlusion of Schlemm's canals. The four detected MYOC mutations appeared to be associated with morphologic changes in the TM and the underlying pathogenesis of a subtype of familial POAG. PMID- 28564706 TI - Patient Experiences of Trauma Resuscitation. AB - Importance: Patient satisfaction is an increasingly common feature of quality measurement, and patient-centered care is a key aspect of high-quality clinical care. Incorporating patient preferences in an acute context, such as trauma resuscitation, presents distinct challenges; however, to our knowledge, patients' experiences of trauma resuscitation have not been explored. Objectives: To describe patient experiences of trauma resuscitation and to identify opportunities to improve patient experience without compromising speed or thoroughness. Design, Setting, and Participants: This qualitative, descriptive study was conducted at an urban, academic, level I trauma center. Semistructured interviews and video observations were conducted from May to December 2015. Interview participants were adult English-speaking patients who had experienced trauma resuscitation and were clinically stable with no alteration in consciousness. We recruited interview participants and conducted video observations until thematic saturation was reached, resulting in 30 interviews and 20 observations. Video observation patients did not overlap with interview participants. The purposive sample included equal numbers of violently and nonviolently injured patients. Data were analyzed for thematic content from June 2015 to April 2016. Main Outcomes and Measures: The main outcomes reported are themes of patient experience. Results: Of 30 interview participants, 25 were men (83.3%), and 21 were black (70.0%). Of 20 video observation patients, 16 were men (80.0%), and 17 were black (85.0%). Salient aspects of patient experience of trauma resuscitation included emotional responses, physical experience, nonclinical concerns, treatment and procedures, trauma team members' interactions, communication, and comfort. Participants drew satisfaction from trauma team members' demeanor, expertise, and efficiency and valued clear clinical communication, as well as words of reassurance. Dissatisfaction stemmed from the perceived absence of these attributes and from participants' emotional or physical discomfort. Observation data added insight into the components of care that may have contributed to participants' responses and those aspects of care that were not salient to participants. Conclusions and Relevance: Although the urgency of trauma care limits explicit discussion and consideration of patient priorities, we found that patient concerns corresponded well with trauma team goals. Patients perceived trauma team members as competent, efficient, and caring. Focusing on patient communication could further improve patient centeredness in this setting. PMID- 28564707 TI - Treatment of First-Time Perianal Abscess in Childhood, Balance Recurrence and Fistula Formation Rate with Medical Intervention. AB - PURPOSE: Because of differences in therapy for first-time perianal abscess, a wide range of recurrences and/or development of fistula-in-ano (RF) rates have been reported. The indication for determining when surgical intervention is needed remains obscure and controversial. This retrospective study sought to compare outcomes of conservative treatment with those after incision and drainage (ID) to determine the optimal time for surgical intervention. METHODS: A total of 697 patients with first-time perianal abscess were included in this study. The median patient age at the time of onset was 129 days (range: 5-5,110 days). The median follow-up period was 395 days (range: 120-760 days). RESULTS: Of the 697 patients with first-time perianal abscess, 355 (50.9%) patients who received conservative treatment had 12.7% (45/355) RF rate, which is less than that of abscesses treated with ID (24.6%, 72/297; p < 0.001). The median course was 23 (2,466) days, which did not differ significantly from that of abscesses with ID (18 [3,510] days) (p = 0.609). Forty-six (6.6%) patients with abscesses that perforated spontaneously had 10.9% (5/46) RF rate, which was less than that of abscesses with ID (p = 0.019), and the median course was 9 (3,316) days, which was shorter than that of abscesses with ID (p = 0.04). CONCLUSION: Conservative treatment is a safe and effective technique for most first-time perianal abscesses with less recurrence and a lower fistula formation rate. Incision must be performed when an abscess is likely to spread or shows no sign of spontaneous perforation. PMID- 28564708 TI - Modulation of the Early Host Response to Electrospun Polylactic Acid Matrices by Mesenchymal Stem Cells from the Amniotic Fluid. AB - PURPOSE: The reconstruction of congenital diaphragmatic hernia or other congenital soft tissue defects often requires implants. These can be either degradable or permanent, each having their advantages. Whatever type is being used, the host response induced by implants plays a crucial role to determine the outcome. Macrophages are pivotal during implant remodeling; they are plastic and acquire in response to environmental stimuli either an inflammatory status and mediate subsequent fibrosis or a regulatory status and facilitate functional remodeling. Matrices engineered with mesenchymal stem cells (MSCs) have the capacity to modulate the host immune reaction. MSCs are believed to promote constructive remodeling of the implant through a regulatory macrophage response among others. Herein, we evaluate this potential of MSC derived from the amniotic fluid (AF-MSC), an interesting MSC type for neonatal reconstruction, on electrospun polylactic acid (PLA) scaffolds. METHODS: We seeded AF-MSC at a density of 1.105/cm2 on electrospun PLA matrices and determined cell viability. In vivo, we used cell-seeded or cell-free PLA matrices for subcutaneous implantation in immune competent rats. The host immune response was evaluated by histomorphometry at 14 days postoperatively. RESULTS: The PLA matrix supported adherence and proliferation of AF-MSC. Fourteen days after implantation, PLA matrices were well penetrated by inflammatory cells, new blood vessels, and collagen fibers. AF-MSC-seeded scaffolds were associated with a similar response yet with a decreased number of eosinophils, increased matrix degradation and collagen fiber deposition compared with controls. The amount of total macrophages and of M2-subtype was similar for all animals. CONCLUSION: Electrospun PLA matrices are a suitable substrate for short-term culture of AF-MSC. In rats, addition of AF-MSC to PLA matrices modulates the host response after subcutaneous implantation, yet without a difference in macrophage profile compared with control. PMID- 28564709 TI - [Primary mixed adeno-neuroendocrine carcinoma (MANEC) of the urinary bladder: a rare entity]. AB - A 67-year-old male patient underwent transurethral resection for a bladder tumour at the lower posterior wall found incidentally on imaging for an unrelated disease. The initial histomorphological examination suggested an adenocarcinoma with partial neuroendocrine differentiation. Imaging of the thorax and the abdomen, showed no evidence of another primary tumour. Due to the unusual diagnosis, the case was sent to our department of pathology for expert consultation, which confirmed the diagnosis of a primary mixed adeno neuroendocrine carcinoma of the bladder (MANEC). Mixed adeno-neuroendocrine carcinomas are rare tumours that mostly occur in the colorectum. To our knowledge, this case is the fifth case report of a MANEC primarily arising in the urinary bladder. PMID- 28564710 TI - [Unreported Intentional Life-Ending Acts in Physicians and Nurses]. AB - Introduction Intentional life-ending acts (LA) including euthanasia and termination of life without explicit request are illegal in Germany and have not been extensively studied. In a pilot study, unreported LA administered by physicians and nurses in German health care were explored. Methods All hospitals and nursing homes registered in 2015 (n = 13 393) were contacted via mail or e mail and physician and nursing staff were asked to complete an anonymous online survey or the identical attached paper-pencil questionnaire. 4629 participants, including physicians (n = 356), nurses (n = 3121) und geriatric nurses (n = 1152) from a predominant in-patient working area responded to questions about LA at their workplace, requests for euthanasia and performance of LA. Results 2.25 - 4.01 % (172 participants) of all physicians and nurses indicated to have heard of euthanasia at their workplace in the last 12 months and 1.42 - 3.39 % (77 participants) indicated to have performed LA themselves. LA was more frequently administered by male participants, physicians and on intensive care units. More than one third of all participants who had administered LA (38.10 - 41.67 %) were never asked for it. Discussion This pilot study indicates that beside legal forms of passive and indirect euthanasia, illegal intentional life-ending acts are administered by physicians and nurses in all health-care areas under investigation. PMID- 28564711 TI - [Linkage Between Promotion of Employment and Promotion of Health in the Community Setting - Results of the Pilot Project of the Federal Employment Agency and the Statutory Health Insurance]. PMID- 28564712 TI - [Quality Controls in Hospitals by MDK Hessen: A Practice Report of Experiences and Outlook]. AB - INTRODUCTION: The Hospital Structure Act introduced S 275a SGB V into the German Social Code. It specifies and expands the legal requirements for future quality controls in hospitals performed by the Medical Review Board of the Statutory Health Insurance Funds (MDK). These controls are intended to ensure high-quality, patient-centered and needs-based medical care of the population. Based on 10 years of experience of the Hessian MDK, the practicability of the quality controls is to be demonstrated. METHODS: The hospital quality controls carried out so far concern either the examination of the structural quality according to the regulations of the Federal Joint Committee (G-BA) for the quality assurance of special care complexes/procedures or the specifications of the German Institute of Medical Documentation and Information (DIMDI) for complex procedures. All quality controls in the Hessian hospitals are performed as on site inspections by a specialized MDK-team of 2 medical examiners. The quality controls involve the responsible medical staff as well as members of the hospital management. RESULTS: From 2006-2016 a total of 357 quality controls were carried out according to the regulations of the G-BA for 10 different special care complexes/procedures. In about 20% of cases, the requirements were not fulfilled. During the same period, 1624 quality controls were carried out according to the specifications of the DIMDI for 33 different complex procedures. In about 40% of cases the required standards were not fulfilled. CONCLUSION: The deficits revealed demonstrate the need for quality control by an independent and qualified body. The quality controls contribute to quality assurance and thus to the quality of structures, processes and outcomes in hospitals. The quality control practice established by the Hessian MDK is transferable to nationwide quality controls to be performed in future. PMID- 28564713 TI - Direct peroral cholangioscopy for diagnosis of bile duct lesions using an I-SCAN ultraslim endoscope: a pilot study. AB - : Background and study aims I-SCAN is a computed virtual chromoendoscopy (CVC) system designed to enhance surface and vascular patterns. In this study, we evaluated the usefulness of direct peroral cholangioscopy (POC) using I-SCAN compared with a conventional white-light image (WLI) to diagnose bile duct lesions. Patients and methods Patients with mucosal lesions in the bile duct detected during direct POC were enrolled prospectively. The quality of endoscopic visualization and the visual diagnosis were assessed using I-SCAN and WLI modes, respectively, during direct POC. Results A total of 20 patients (9 malignant and 11 benign lesions) underwent I-SCAN to evaluate lesions in the bile duct using direct POC. The quality of endoscopic visualization using direct POC with I-SCAN was significantly higher than that of WLI for surface structure (P = 0.04), surface microvascular architecture (P = 0.01), and margins (P = 0.02). Overall diagnostic accuracy of the visual diagnosis was not different between I-SCAN and WLI (90.0 % vs. 75.0 %; P = 0.20). Conclusion Direct POC using CVC by I-SCAN seems to be helpful for evaluating mucosal lesions of the bile duct, without the interference from bile. CLINICAL TRIAL REGISTRATION: UMIN000021009. PMID- 28564714 TI - Endoscopic submucosal dissection for early gastric cancer: are expanded resection criteria safe for Western patients? AB - : Background and study aims Endoscopic submucosal dissection (ESD) is the standard treatment for early gastric cancer (EGC) fulfilling guideline resection criteria or the expanded resection criteria in Asia. It is unclear whether the expanded criteria can be transferred to European patients, and long-term follow up data are lacking. The aim of this study was to evaluate long-term follow-up data after ESD of EGCs in Europe. Patients and methods Patients with EGC who underwent ESD were included in this single-center study at a German referral center. Patient and lesion characteristics, procedure characteristics, and follow up data were recorded prospectively. Results A total of 179 patients with 191 EGCs were included over a period of 141 months, with 29.6 % of lesions meeting guideline criteria and 48.6 % meeting expanded criteria. The en bloc resection rate was 98.4 % for guideline criteria and 89.0 % for expanded criteria lesions (P = 0.09), and the R0 resection rate was 90.2 % and 73.6 %, respectively (P = 0.02). The main reason for the expanded criteria was a lesion diameter > 20 mm (81.6 %). COMPLICATIONS: perforation 1 %, delayed bleeding 6.3 %, stricture 2.1 %, procedure-related mortality 1.1 %. Local recurrence rate was 0 % for guideline criteria and 4.8 % for expanded criteria lesions (P = 0.06), and the rate of metachronous neoplasia was 15.1 % and 7.1 %, respectively (median follow-up 51 and 56 months, respectively); 92.9 % of metachronous neoplasia were treated curatively with repeat ESD. One patient developed lymph node metastasis after ESD of a submucosal invasive expanded criteria lesion. Long-term-survival was comparable between the two criteria (P = 0.58). No gastric cancer-related death was observed in either group. Conclusions ESD can achieve high rates of long-term curative treatment using the expanded criteria in EGCs in Western countries. We recommend ESD as treatment of choice not only for guideline criteria EGCs but also for intramucosal nonulcerated EGCs regardless of their diameter. PMID- 28564715 TI - Two-stage endoscopic mucosal resection is a safe and effective salvage therapy after a failed single-session approach. AB - Background and study aims Endoscopic mucosal resection (EMR) of laterally spreading colonic lesions >= 20 mm (LSLs) is ideally performed in a single session (ssEMR) and avoids surgery in > 90 % of patients. We investigated whether a second attempt is safe or useful when ssEMR fails at a tertiary center. Patients and methods In a multicenter prospective observational study of patients with LSL treated by EMR at four tertiary centers over 8 years, incompletely resected LSLs were referred for surgery or underwent two-stage EMR (tsEMR). At tsEMR, the scar was located and all visible residual tissue removed by snare, with thermal treatment permitted thereafter. Scheduled surveillance was performed at 5 months (SC1) and 18 months (SC2). The primary outcome was avoidance of surgery. Results A total of 1944 LSLs (median size 35 mm) underwent EMR. ssEMR was unsuccessful in 127 lesions, 43 of which underwent tsEMR, with success in 36 (83.7 %). Compared with ssEMR, tsEMR lesions were larger (median size 50 mm vs. 30 mm; P < 0.001), exhibited more submucosal fibrosis (P < 0.001), and histology was more often tubular adenoma and less often serrated (P = 0.005). Lesions mainly required tsEMR for nonlifting (41.9 %) or poor endoscopic access (37.2 %). Failure of tsEMR was predicted by larger LSL (P = 0.03). Safety was comparable to ssEMR. Of the 33 LSLs that underwent tsEMR for benign disease and completed first surveillance, 27 (81.8 %) avoided surgery to long term follow-up. Conclusions tsEMR shows promise as a salvage therapy for LSLs that cannot be resected in a single session for patients in whom other options such as surgery are not preferred or not possible.Trial registered at ClinicalTrials.gov (NCT01368289). PMID- 28564717 TI - The Importance of Facts and the Role of Academic Publishers in Today's World-A Publisher's View. PMID- 28564716 TI - Clinical utility of a functional lumen imaging probe in management of dysphagia following head and neck cancer therapies. AB - Background and aims Chemoradiotherapy for head and neck cancer (HNC) with/without laryngectomy commonly causes dysphagia. Pharyngoesophageal junction (PEJ) stricturing is an important contributor. We aimed to validate a functional lumen imaging probe (the EndoFLIP system) as a tool for quantitating pretreatment PEJ distensibility and treatment-related changes in HNC survivors with dysphagia and to evaluate the diagnostic accuracy of EndoFLIP-derived distensibility in detecting PEJ strictures. Methods We studied 34 consecutive HNC survivors with long-term (> 12 months) dysphagia who underwent endoscopic dilation for suspected strictures. Twenty non-dysphagic patients undergoing routine endoscopy served as controls. PEJ distensibility was measured at endoscopy with the EndoFLIP system pre- and post-dilation. PEJ stricture was defined as the presence of a mucosal tear post-dilation. Results PEJ stricture was confirmed in 22/34 HNC patients (65 %). During distension up to 60 mmHg, the mean EndoFLIP-derived narrowest cross sectional area (nCSA) in HNC patients with strictures, without strictures, and in controls were 58 mm2 (95 % confidence interval [CI] 22 to 118), 195 mm2 (95 %CI 129 to 334), and 227 mm2 (95 %CI 168 to 316), respectively. A cutoff of 114 mm2 for the nCSA at the PEJ had perfect diagnostic accuracy in detecting strictures (area under the receiver operating characteristic curve = 1). In patients with strictures, a single session of dilation increased the nCSA by 29 mm2 (95 %CI 20 to 37; P < 0.001). In patients with no strictures, dilation caused no change in the nCSA (mean difference 13 mm2 [95 %CI -4 to 30]; P = 0.13). Conclusions EndoFLIP is a highly accurate technique for the detection of PEJ strictures. EndoFLIP may complement conventional diagnostic tools in the detection of pharyngeal outflow obstruction. PMID- 28564718 TI - Clinical Trial Design for Immune-Based Therapy of Hepatitis B Virus. AB - The treatment paradigm in hepatitis B virus is on the cusp of major development, with a multitude of novel agents undergoing testing for clinical efficacy. Such new immune therapies are urgently required for the treatment of chronic hepatitis B virus. The current direct antiviral therapies, although able to control viral replication and limit the progression to cirrhosis, require lifelong administration due to frequent viral rebound on treatment cessation, and immune modulation with interferon is only effective in a subpopulation of patients. Here the authors discuss novel agents in the pipeline along with whom and how best to utilize these immune therapies to achieve functional cure with defined treatment endpoints in chronic hepatitis B virus. PMID- 28564719 TI - Immunotolerance in Liver Transplantation. PMID- 28564720 TI - Inflammasomes in Liver Fibrosis. AB - Cell death and inflammation are two central elements in the development of liver fibrosis. Inflammasomes are intracellular multiprotein complexes expressed in both hepatocytes and nonparenchymal cells in the liver that are key regulators of inflammation and cell fate. They respond to cellular danger signals by activating caspase 1, releasing the proinflammatory cytokines IL-1beta and IL-18, as well as initiating a novel pathway of programmed cell death termed "pyroptosis." These processes can initiate and perpetuate an abnormal wound-healing response with the principle cellular target being the activation of hepatic stellate cells. From the various inflammasomes, the NLRP3 inflammasome has been increasingly implicated in the pathogenesis of chronic inflammatory liver diseases, including nonalcoholic steatohepatitis, a disease process that is soaring and has evolved as a primary cause of liver fibrosis and need for liver transplantation. In this review, the authors highlight the growing evidence for both indirect and direct effects of inflammasomes in triggering liver fibrosis as well as potential novel targets for antifibrotic therapies. PMID- 28564721 TI - The Human Gut Microbiome in Liver Diseases. PMID- 28564723 TI - Emerging Concepts and Human Trials in Alpha-1-Antitrypsin Deficiency Liver Disease. PMID- 28564722 TI - Update on the Mechanisms of Liver Regeneration. AB - Liver possesses many critical functions such as synthesis, detoxification, and metabolism. It continually receives nutrient-rich blood from gut, which incidentally is also toxin-rich. That may be why liver is uniquely bestowed with a capacity to regenerate. A commonly studied procedure to understand the cellular and molecular basis of liver regeneration is that of surgical resection. Removal of two-thirds of the liver in rodents or patients instigates alterations in hepatic homeostasis, which are sensed by the deficient organ to drive the restoration process. Although the exact mechanisms that initiate regeneration are unknown, alterations in hemodynamics and metabolism have been suspected as important effectors. Key signaling pathways are activated that drive cell proliferation in various hepatic cell types through autocrine and paracrine mechanisms. Once the prehepatectomy mass is regained, the process of regeneration is adequately terminated. This review highlights recent discoveries in the cellular and molecular basis of liver regeneration. PMID- 28564725 TI - Disorders in Hepatic Copper Secretion: Wilson's Disease and Pleomorphic Syndromes. PMID- 28564726 TI - [Orphan diseases - on the way to better patient care]. PMID- 28564727 TI - [Management of Pregnancy-Associated Venous Thromboembolism - Current Recommendations]. PMID- 28564724 TI - Epigenetics in the Primary Biliary Cholangitis and Primary Sclerosing Cholangitis. PMID- 28564728 TI - [Recent Findings on Primary Hyperparathyroidism]. PMID- 28564729 TI - [Status of Ambulant Geriatrics]. PMID- 28564730 TI - [Current Aspects in Diagnosis and Therapy of Plasma Cell Myeloma]. PMID- 28564731 TI - [Update on Tick-Borne Diseases in Germany]. PMID- 28564732 TI - [Inotropic Support During Infarct-related Cardiogenic Shock]. PMID- 28564733 TI - [Update Dyslipidaemias - Comments on the 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias]. PMID- 28564734 TI - [Diagnostics and Non-Dialytic Management of AKI - Update]. PMID- 28564735 TI - [Sarcoidosis - Recent Advances]. PMID- 28564736 TI - [Primary Immunodeficiency in Adults]. PMID- 28564737 TI - [Hepatitis E - More than a Rare Travel-Associated Infectious Disease!] PMID- 28564738 TI - [31-year-old Male with Epigastric Pain]. PMID- 28564739 TI - [Histologic Remission following Neoadjuvant Immunotherapy in a Patient with Lynch Syndrome and Primarily Unresectable Relapse of Rectum Carcinoma]. AB - Clinical History A 43-year-old male patient was diagnosed to have rectum carcinoma cT4N2M0 with underlying Lynch-Syndrome. After initializing neoadjuvant radio-chemotherapy followed by operation, the patient presents with an extensive locoregional relapse within a short time. In order to achieve resectability, a second line treatment with FOLFOXIRI protocol in addition to Bevacizumab was conducted. However, after completing six cycles of this intensiv treatment protocol, the tumour showed further progression. Clinical Course Having no evidence of distance metastasis, we decided to initiate off-label use of Pembrolizumab, a PD-1-receptor inhibitor. Clinical symptoms decreased rapidly and after receiving six cycles, PET/CT imaging showed regression. The side effects were limited to subclinical autoimmune thyroiditis. After re-operation no evidence of malignancy were found in the resectates of exenteration of the pelvis. Currently the patient is capable of working with only limited symptoms. Conclusion Pembrolizumab offers new treatment options for patients with DNA repair-deficiency mismatch, e. g. Lynch-Syndrome. A phase II study already showed effectiveness in this particular group of patients. The striking and unexpected histo-pathologic results showing full remission should draw attention to the use of Pembrolizumab in neoadjuvant settings. PMID- 28564740 TI - Message for the Readers of European Journal of Pediatric Surgery. PMID- 28564741 TI - The Young Pediatric Surgeon. PMID- 28564742 TI - Prophylactic Bracing Has No Effect on Lower Extremity Alignment or Functional Performance. AB - Prophylactic ankle bracing is commonly used during physical activity. Understanding how bracing affects body mechanics is critically important when discussing both injury prevention and sport performance. The purpose is to determine if ankle bracing affects lower extremity mechanics during the Landing Error Scoring System test (LESS) and Sage Sway Index (SSI). Thirty physically active participants volunteered for this study. Participants completed the LESS and SSI in both a braced and unsupported conditions. Total errors were recorded for the LESS. Total errors and time (seconds) were recorded for the SSI. The Wilcoxon signed-rank test was utilized to evaluate any differences between the brace conditions for each dependent variable. A priori alpha level was set at p<0.05. The Wilcoxon signed-rank test yielded no significant difference between the braced and unsupported conditions for the LESS (Z=-0.35, p=0.72), SSI time (Z=-0.36, p=0.72), or SSI Errors (Z=-0.37, p=0.71). Ankle braces had no effect on subjective clinical assessments of lower extremity alignment or postural stability. Utilization of a prophylactic support at the ankle did not substantially alter the proximal components of the lower kinetic chain. PMID- 28564743 TI - Forced Retirement from Professional Rugby Union is Associated with Symptoms of Distress. AB - Rugby has a higher injury burden than other popular sports, such as football. Athletes who are forced to retire as a result of injury are associated with poor mental health. With its high injury burden, professional rugby players might be at risk of mental health conditions associated with injury-related forced retirement. This study aimed to compare mental health between former professional rugby players who were and weren't forced to retire. A questionnaire including the 4DSQ (distress), GHQ-12 (anxiety/depression), PROMIS short-form (sleep disturbance) and AUDIT-C (alcohol misuse) was completed by retired professional players from Ireland, France and South Africa. The questionnaire asked players whether or not they were forced to retire, as well as the reason for retirement. Players forced to retire were more than twice as likely to report symptoms of distress in comparison to those that retired voluntarily (odds ratio: 2.1, 95% confidence interval: 1.2-3.6, p<0.001). None of the other mental health measures (anxiety/depression, sleep disturbance or alcohol misuse) were associated with forced retirement. In conclusion, rugby players that were forced to retire may require support structures and longitudinal monitoring. Future studies should begin monitoring players during their careers to accurately assess the effect of retirement on mental health. PMID- 28564744 TI - Locomotion Mode Affects the Physiological Strain during Exercise at Walk-Run Transition Speed inElderly Men. AB - This study investigated cardiorespiratory responses and rating of perceived exertion (RPE) during prolonged walking and running exercise performed at the walk-run transition speed (WRTS) in untrained healthy elderly men. 20 volunteers (mean+/-SE, age: 68.4+/-1.2 yrs; height: 170.0+/-0.02 cm; body mass: 74.7+/-2.3 kg) performed the following bouts of exercise: a) maximal cardiopulmonary exercise test (CPET); b) specific protocol to detect WRTS; and c) two 30-min walking and running bouts at WRTS. Expired gases were collected during exercise bouts via the Ultima CardiO2 metabolic analyzer. Compared to walking, running at the WRTS resulted in higher oxygen uptake (>0.27 L.min-1), pulmonary ventilation (>7.7 L.min-1), carbon dioxide output (>0.23 L.min-1), heart rate (>15 beats.min 1), oxygen pulse (>0.88 15 mL.beats-1), energy expenditure (>27 kcal) and cost of oxygen transport (>43 mL.kg-1.km-1.bout-1). The increase of overall and local RPEs with exercise duration was similar across locomotion modes (P<0.001). In all participants, %HRR and %VO2R throughout walking and running bouts were around or above the gas exchange threshold. In conclusion, elderly men exhibited higher cardiorespiratory responses during 30-min bouts of running than walking at WRTS. Nevertheless, walking corresponded to relative metabolic intensities compatible with preservation or improvement of cardiorespiratory fitness and should be preferable over running at WRTS in the untrained elderly characterized by poor fitness and reduced exercise tolerance. PMID- 28564746 TI - THE BIOTA OF LONG-DISTANCE DISPERSAL. II. LOSS OF DISPERSIBILITY IN PACIFIC COMPOSITAE. PMID- 28564747 TI - ON THE ORIGIN OF THE JUMPING MECHANISM IN FROGS. PMID- 28564745 TI - Cardiorespiratory Responses of Adults and Children during Normoxic and Hypoxic Exercise. AB - We aimed to elucidate potential differential effects of hypoxia on cardiorespiratory responses during submaximal cycling and simulated skiing exercise between adults and pre-pubertal children. Healthy, low-altitude residents (adults, N=13, Age=40+/-4yrs.; children, N=13, age=8+/-2yrs.) were tested in normoxia (Nor: PiO2=134+/-0.4 mmHg; 940 m) and normobaric hypoxia (Hyp: PiO2=105+/-0.6 mmHg; ~3 000 m) following an overnight hypoxic acclimation (>=12 hrs). On both days, the participants underwent a graded cycling test and a simulated skiing protocol. Minute ventilation (VE), oxygen uptake (VO2), heart rate (HR) and capillary-oxygen saturation (SpO2) were measured throughout both tests. The cycling data were interpolated for 2 relative workload levels (1 W.kg 1 & 2 W.kg-1). Higher resting HR in hypoxia, compared to normoxia was only noted in children (Nor:78+/-17; Hyp:89+/-17 beats.min-1; p<0.05), while SpO2 was significantly lower in hypoxia (Nor:97+/-1%; Hyp:91+/-2%; p<0.01) with no between group differences. The VE, VO2 and HR responses were higher during hypoxic compared to normoxic cycling test in both groups (p<0.05). Except for greater HR during hypoxic compared to normoxic skiing in children (Nor:155+/-19; Hyp:167+/ 13 (beats.min-1); p<0.05), no other significant between-group differences were noted during the cycling and skiing protocols. In summary, these data suggest similar cardiorespiratory responses to submaximal hypoxic cycling and simulated skiing in adults and children. PMID- 28564748 TI - ECOLOGICAL AND CYTOGENETIC STUDIES OF DROSOPHILA FLAVOPILOSA, A NEOTROPICAL SPECIES LIVING IN CESTRUM FLOWERS. PMID- 28564749 TI - CHROMOSOMAL FITNESS CHANGES IN EXPERIMENTAL POPULATIONS OF DROSOPHILA PERSIMILIS FROM TIMBERLINE. II. RE-EXTRACTED CHROMOSOMES. PMID- 28564750 TI - INTRASPECIES COMPETITION, VIABILITY, AND LONGEVITY IN EXPERIMENTAL POPULATIONS. PMID- 28564751 TI - SELECTION FOR INCREASED FERTILITY OF FEMALE QUAIL WHEN MATED TO MALE CHICKENS. PMID- 28564752 TI - DEVELOPMENTAL RATE AND COMPETITIVE ABILITY IN TRIBOLIUM. PMID- 28564753 TI - MORPHOLOGICAL VARIATION IN NATURAL AND EXPERIMENTAL POPULATIONS OF DROSOPHILA PSEUDOOBSCURA AND DROSOPHILA PERSIMILIS. PMID- 28564754 TI - EXPERIMENTS ON RANDOM GENETIC DRIFT AND NATURAL SELECTION IN DROSOPHILA PSEUDOOBSCURA. PMID- 28564755 TI - ORIGIN OF DECIDUOUS AND EVERGREEN HABITS IN TEMPERATE FORESTS. PMID- 28564756 TI - METACHROMISM OR THE PRINCIPLE OF EVOLUTIONARY CHANGE IN MAMMALIAN TEGUMENTARY COLORS. PMID- 28564757 TI - ADAPTIVE SIGNIFICANCE OF PIGMENT POLYMORPHISMS IN COLIAS BUTTERFLIES. I. VARIATION OF MELANIN PIGMENT IN RELATION TO THERMOREGULATION. PMID- 28564758 TI - THE GENOME CONSTITUTIONS OF EASTERN NORTH AMERICAN PHLOX AMPHIPLOIDS. PMID- 28564759 TI - POPULATION STUDIES IN PREDOMINANTLY SELF-POLLINATED SPECIES. XI. GENETIC DIVERGENCE AMONG THE MEMBERS OF THE FESTUCA MICROSTACHYS COMPLEX. PMID- 28564760 TI - AN ANALYSIS OF THREE HYBRID POPULATIONS OF POCKET GOPHERS (GENUS THOMOMYS). PMID- 28564761 TI - CRETACEOUS DINOSAUR EXTINCTION. PMID- 28564762 TI - ADAPTATION TO HETEROGENEOUS ENVIRONMENTS. I. VARIATION IN HETEROPHYLLY IN RANUNCULUS FLAMMULA L. PMID- 28564763 TI - THE ROLE OF HETEROSTYLY IN NARCISSUS AND MIRABILIS. PMID- 28564764 TI - STUDIES ON COMPETITION IN RICE. III. THE MECHANISM OF COMPETITION AMONG PHENOTYPES. PMID- 28564765 TI - EVOLUTIONARY STATUS OF A RELICT POPULATION OF BUFO HEMIOPHRYS COPE. PMID- 28564766 TI - NATURAL SELECTION FOR AND AGAINST A POLYMORPHISM WHICH INTERACTS WITH SEX. PMID- 28564767 TI - CONSIDERATIONS ON SPECIATION IN CHALCIDOIDEA (HYMENOPTERA). PMID- 28564768 TI - BREAKDOWN OF ISOLATION MECHANISMS IN TWO SPECIES OF CAPTIVE JUNGLEFOWL (GALLUS GALLUS AND GALLUS SONNERATII). PMID- 28564769 TI - SELECTION MECHANISMS ASSOCIATED WITH INTRASPECIFIC SHELL VARIATION IN LITTORINA PICTA (PROSOBRANCHIA: MESOGASTROPODA). PMID- 28564770 TI - GENETIC STRUCTURE OF POPULATIONS. IV. SUMMER ENVIRONMENTAL VARIABLES AND LETHAL AND SEMILETHAL FREQUENCIES IN A NATURAL POPULATION OF DROSOPHILA MELANOGASTER. PMID- 28564771 TI - PROPENSITY FOR MULTIPLE MATING IN DROSOPHILA MELANOGASTER FEMALES. PMID- 28564772 TI - GENETIC VARIATION IN TRIDACNA MAXIMA, AN ECOLOGICAL ANALOG OF SOME UNSUCCESSFUL EVOLUTIONARY LINEAGES. PMID- 28564773 TI - INTRA- AND INTERSPECIES VARIATIONS IN GYPIDULID BRACHIOPODS. PMID- 28564774 TI - HYBRIDIZATION OF KARYOTYPICALLY DIFFERENTIATED POPULATIONS IN THE SCELOPORUS GRAMMICUS COMPLEX (IGUANIDAE). PMID- 28564776 TI - WEATHER, CLIMATE, AND THE EXTERNAL MORPHOLOGY OF PACIFIC TREE TOADS. PMID- 28564775 TI - PREFERENTIAL MATING AND THE MAINTENANCE OF THE SEX-LIMITED DIMORPHISM IN PAPILIO GLAUCUS: EVIDENCE FROM LABORATORY MATINGS. PMID- 28564777 TI - STUDIES OF LINKAGE IN POPULATIONS. VI. PERIODIC SELECTION FOR X-CHROMOSOME GENE ARRANGEMENT COMBINATIONS. PMID- 28564778 TI - CHANCE, HABITAT AND DISPERSAL IN THE DISTRIBUTION OF BIRDS IN THE WEST INDIES. PMID- 28564779 TI - GENETIC DIVERGENCE IN BODY SIZE AMONG EXPERIMENTAL POPULATIONS OF DROSOPHILA PSEUDOOBSCURA KEPT AT DIFFERENT TEMPERATURES. PMID- 28564780 TI - ENZYME DIFFERENTIATION AND PHYLOGENY IN CLARKIA FRANCISCANA, C. RUBICUNDA AND C. AMOENA. PMID- 28564781 TI - THE NUMBERS OF SPECIES OF HUMMINGBIRDS IN THE WEST INDIES. PMID- 28564782 TI - PREDATOR POLYMORPHISM AND APOSTATIC SELECTION. PMID- 28564783 TI - GENETIC DIFFERENTIATION WITHOUT ISOLATION IN THE AMERICAN EEL, ANGUILLA ROSTRATA. PMID- 28564785 TI - CHROMOSOMAL EVOLUTION IN HAPLOPAPPUS GRACILIS: A CENTRIC TRANSPOSITION RACE. PMID- 28564784 TI - COMPARATIVE EVOLUTION OF CEREALS. PMID- 28564786 TI - MODE OF POLLINATION AND FLORAL SEXUALITY IN THALICTRUM. PMID- 28564787 TI - DEMONSTRATION OF THE SELECTIVE ADVANTAGE OF MIMETIC LIMENITIS BUTTERFLIES PRESENTED TO CAGED AVIAN PREDATORS. PMID- 28564788 TI - DINOSAUR PHYSIOLOGY AND THE ORIGIN OF MAMMALS. PMID- 28564789 TI - RELATIONSHIPS BETWEEN WEEDY AND CULTIVATED FORMS IN SOME SPECIES OF CHILI PEPPERS (GENUS CAPSICUM). PMID- 28564790 TI - GROUP SELECTION AND THE EVOLUTION OF DISPERSAL. PMID- 28564791 TI - PHYLETIC DIVERGENCE DATES OF HOMINOID PRIMATES: A COMPARISON OF FOSSIL AND MOLECULAR DATA. PMID- 28564792 TI - AN EXAMPLE OF PARALLEL EVOLUTION IN EPILOBIUM (ONAGRACEAE). PMID- 28564793 TI - CYTOGENETICS OF THE SOUTH AMERICAN AKODONT RODENTS (CRICETIDAE). I. A PROGRESS REPORT OF ARGENTINIAN AND VENEZUELAN FORMS. PMID- 28564794 TI - VARIATION IN THE TARSUS LENGTH OF BIRDS IN ISLAND AND MAINLAND REGIONS. PMID- 28564795 TI - ANTHOCYANIDINS OF SOME IMPATIENS SPECIES. PMID- 28564796 TI - GENETIC CHANGES IN FLUCTUATING VOLE POPULATIONS. PMID- 28564797 TI - "GRYPHAEA," EVOLUTION, AND NATURAL SELECTION. PMID- 28564798 TI - THE STRUCTURE OF A POLYSPECIES HYBRID SWARM IN LIATRIS. PMID- 28564799 TI - GEOGRAPHICAL VARIATION AND EVOLUTION IN PSEUDOSINELLA HIRSUTA. PMID- 28564800 TI - EVOLUTIONARY RELATIONSHIPS THROUGH NUCLEIC ACID SIMILARITIES. PMID- 28564801 TI - A COMPARISON OF THE ESTIMATED SIZE AND THE "EFFECTIVE SIZE" OF BREEDING POPULATIONS OF THE LEOPARD FROG, RANA PIPIENS. PMID- 28564802 TI - COMPETITION AND CHARACTER DISPLACEMENT IN TWO SYMPATRIC PINE-DWELLING WARBLERS (DENDROICA, PARULIDAE). PMID- 28564803 TI - RELATION OF INFECTION TO POPULATION STRUCTURE IN DROSOPHILA MELANOGASTER. PMID- 28564804 TI - VARIATION AND SELECTION IN AN ISOLATED SERIES OF POPULATIONS OF LYSIMACHIA VOLKENSII ENGL. PMID- 28564805 TI - DIPLOID-TETRAPLOID-HAPLOID CYCLES AND THE ORIGIN OF VARIABILITY IN DICHANTHIUM AGAMOSPECIES. PMID- 28564806 TI - THE EFFECT OF DIFFERENTIAL VIABILITY ON THE POPULATION DYNAMICS OF t ALLELES IN THE HOUSE MOUSE. PMID- 28564807 TI - MIGRATION AND COMPETITION IN DROSOPHILA I. COMPETITION BETWEEN WILD AND VESTIGIAL STRAINS OF DROSOPHILA MELANOGASTER IN A CAGE AND MIGRATION-TUBE POPULATION. PMID- 28564808 TI - STUDIES ON COMPETITION IN RICE II. COMPETITION IN SEGREGATING POPULATIONS. PMID- 28564809 TI - PARTIAL UNILATERAL INCOMPATIBILITY IN LEAVENWORTHIA (CRUCIFERAE). PMID- 28564810 TI - THE POPULATION BIOLOGY OF THE BUTTERFLY, EUPHYDRYAS EDITH A VII. HAS E. EDITH A EVOLVED A SERPENTINE RACE? PMID- 28564811 TI - THE GENETICS OF POLYMORPHISM IN THE GOOSE ANSER CAERULESCENS. PMID- 28564812 TI - SOCIAL MIMICRY; CHARACTER CONVERGENCE VERSUS CHARACTER DISPLACEMENT. PMID- 28564813 TI - SIBLING SPECIES IN ARTEMIA (CRUSTACEA:BRANCHIOPODA). PMID- 28564814 TI - UNIFORM HETEROKARYOTYPIC SUPERIORITY FOR VIABILITY IN A COLORADO POPULATION OF DROSOPHILA PSEUDOOBSCURA. PMID- 28564815 TI - CUMULATIVE PARENTAL AGE EFFECTS IN DROSOPHILA SUBOBSCURA. PMID- 28564816 TI - SEASONAL SELECTION IN THE LEOPARD FROG, RANA PIPIENS. PMID- 28564817 TI - DEVELOPMENTAL AND GENETIC HOMEOSTASIS IN TWO SPECIES OF FLOUR BEETLES. PMID- 28564818 TI - THE EFFECT OF WATER ON POLLEN GERMINATION IN TWO SPECIES OF PRIMULA. PMID- 28564819 TI - THE CORRELATION OF CLIMATE AND HOST PLANT MORPHOLOGY WITH A GEOGRAPHIC GRADIENT OF AN INVERSION POLYMORPHISM IN DROSOPHILA PACHEA. PMID- 28564820 TI - GENETIC VARIABILITY IN EDAPHICALLY RESTRICTED AND WIDESPREAD PLANT SPECIES. PMID- 28564821 TI - INTERDEMIC SELECTION AND THE EVOLUTION OF ALTRUISM: A COMPUTER SIMULATION STUDY. PMID- 28564825 TI - COMPARATIVE GEOGRAPHIC VARIATION IN MENIDIA. PMID- 28564822 TI - ANALYSIS OF A GENERIC LEVEL TRANSITION IN CRETACEOUS AMMONITES. PMID- 28564823 TI - CHROMOSOMAL EVOLUTION IN PEROMYSCUS. PMID- 28564826 TI - MARINE FAUNAL DOMINANCE AND MOLLUSCAN SHELL FORM. PMID- 28564827 TI - LACK OF ALLOZYMIC VARIABILITY IN THREE BEE SPECIES. PMID- 28564828 TI - REPRODUCTIVE RELATIONSHIPS BETWEEN HOMOSEQUENTIAL SPECIES OF HAWAIIAN DROSOPHILA. PMID- 28564829 TI - EFFECTIVE POPULATION NUMBERS IN THE SNAIL CEPAEA NEMORALIS. PMID- 28564830 TI - SPATIAL SEGREGATION OF PINS AND THRUMS IN POPULATIONS OF HEDYOTIS NIGRICANS. PMID- 28564832 TI - GENETIC DIFFERENTIATION DURING THE SPECIATION PROCESS IN DROSOPHILA. PMID- 28564831 TI - GENIC AND CHROMOSOMAL DIFFERENTIATION IN POCKET GOPHERS OF THE GEOMYS BURSARIUS GROUP. PMID- 28564833 TI - CHANGES IN MATING BEHAVIOR PRODUCED BY SELECTION FOR ETHOLOGICAL ISOLATION BETWEEN EBONY AND VESTIGIAL MUTANTS OF DROSOPHILA MELANOGASTER. PMID- 28564834 TI - ENZYME VARIABILITY IN NATURAL POPULATIONS OF DAPHNIA MAGNA I. POPULATION STRUCTURE IN EAST ANGLIA. PMID- 28564835 TI - DARK CO2 FIXATION, HABITAT PREFERENCE AND EVOLUTION WITHIN THE BROMELIACEAE. PMID- 28564836 TI - INCHOATE SPECIATION IN CERATOPTERIS: AN ANALYSIS OF THE SYNTHESIZED HYBRID C. RICHARDII X C. PTERIDOIDES. PMID- 28564837 TI - REPLY TO "DINOSAURS AS REPTILES". PMID- 28564838 TI - BREEDING SYSTEMS AND RESISTANCE TO ENVIRONMENTAL STRESS IN CILIATES. PMID- 28564839 TI - GALAPAGOS SEA LIONS ARE PATERNAL. PMID- 28564840 TI - GENIC HETEROZYGOSITY IN THE 13-YEAR CICADA, MAGICICADA. PMID- 28564841 TI - EVOLUTION OF APPALACHIAN GYPIDULID BRACHIOPODS: A REPLY TO ELDREDGE (1974). PMID- 28564842 TI - THE INFLUENCE OF SEXUAL SELECTION AND INTERSPECIFIC COMPETITION ON MOCKINGBIRD SONG (MIMUS POLYGLOTTOS). PMID- 28564843 TI - POLYMORPHISM IN CRICKET FROGS: AN HYPOTHESIS. PMID- 28564844 TI - EVOLUTION OF THE WORLD FAUNA OF AQUATIC FREE-LIVING ARTHROPODS. PMID- 28564845 TI - A PATERNAL ROLE IN GALAPAGOS SEA LIONS? PMID- 28564846 TI - A FINAL WORD. PMID- 28564847 TI - TESTING EVOLUTIONARY HYPOTHESES IN PALEONTOLOGY: A COMMENT ON MAKURATH AND ANDERSON (1973). PMID- 28564848 TI - THE EVOLUTIONARY ORIGIN OF. HYBRID INVIABILITY. PMID- 28564849 TI - THE CONGRUENCE OF MORPHOMETRIC SHAPE IN RELATION TO GENETIC DIVERGENCE IN FOUR RACES OF MORABINE GRASSHOPPERS (ORTHOPTERA: EUMASTACIDAE). PMID- 28564850 TI - SCHOOLING BEHAVIOR IN THE GUPPY (POECILIA RETICULATA): AN EVOLUTIONARY RESPONSE TO PREDATION. PMID- 28564851 TI - PALEONTOLOGY AND EVOLUTIONARY THEORY. PMID- 28564852 TI - DINOSAUR BIOENERGETICS-A REPLY TO BENNETT AND DALZELL, AND FEDUCCIA. PMID- 28564853 TI - ENDOTHERMY, DINOSAURS, AND ARCHAEOPTERYX. PMID- 28564854 TI - ADULT MOVEMENTS AND POPULATION STRUCTURE IN EUPHYDRYAS EDITHA. PMID- 28564855 TI - POLYMORPHIC MIMICRY AND NATURAL SELECTION: A REPLY TO J. AND M. EDMUNDS. PMID- 28564856 TI - RELATIVE GROWTH OF THE TITANOTHERE HORN: A NEW APPROACH TO AN OLD PROBLEM. PMID- 28564857 TI - DINOSAURS AS DINOSAURS. PMID- 28564858 TI - THE ROLE OF GENETIC DRIFT IN THE DIFFERENTIATION OF ICELANDIC AND NORWEGIAN CATTLE. PMID- 28564859 TI - POLYMORPHIC MIMICRY AND NATURAL SELECTION: A REAPPRAISAL. PMID- 28564860 TI - THE UTILITY OF ELECTROPHORETIC ANALYSIS OF LONG-LIVED PLANTS AND SEEDS FOR THE STUDY OF EVOLUTION. PMID- 28564861 TI - EXPERIMENTAL EVIDENCE FOR THE EVOLUTIONARY SIGNIFICANCE OF TEMPERATURE-DEPENDENT SEX DETERMINATION. AB - The evolutionary significance of sex-determining mechanisms, particularly temperature-dependent sex determination (TSD) in reptiles, has remained unresolved despite extensive theoretical work. To investigate the evolutionary significance of this unusual sex-determining mechanism, I incubated eggs of the common snapping turtle (Chelydra serpentina) at a male-producing temperature (26 degrees C), a female-producing temperature (30 degrees C), and an intermediate temperature that produced both sexes about equally (28 degrees C). Laboratory experiments indicated that two performance variables, but no morphological measurements, were significantly influenced by incubation temperature (P <= 0.05): hatchlings from cooler incubation treatments swam faster than turtles from warmer incubation treatments, and hatchlings from 28 degrees C exhibited a greater propensity to run than did individuals from 26 degrees C and 30 degrees C. In the field, hatchlings from the all-male and all-female producing temperatures had significantly higher first-year survivorship than did consexuals from the incubation temperature that produced both sexes (G = 6.622, P = 0.03). Significant directional selection was detected on propensity of hatchlings to run (beta' = -0.758, P = 0.05): turtles that tended to remain immobile had a higher probability of first-year survivorship than did individuals that moved readily. Thus, the effects of the gender * incubation temperature interaction on survivorship of hatchling turtles observed in the field experiment may have been mediated by temperature-dependent antipredator behavior. These results provide a possible functional explanation for the evolutionary significance of TSD in turtles that is consistent with predictions of theoretical models. PMID- 28564863 TI - PERSPECTIVE A UNITS-OF-EVOLUTION PERSPECTIVE ON THE ENDOSYMBIONT THEORY OF THE ORIGIN OF THE MITOCHONDRION. AB - Discussions of mitochondria and their hosts often conceptualize this relationship in a more or less modern form, focusing on the metabolic benefits of mitochondria to the host cell or on the possibility of intragenomic conflict. A more inclusive units-of-evolution perspective recognizes that both costs and benefits must be viewed from the level of the cells that initiated this interaction, the protomitochondrion and the primitive host cell. From this perspective, ecological and physiological considerations become central to the characterization of initial and subsequent host-mitochondria associations. Foremost among these considerations is the generation of superoxide radicals by modern mitochondria and the deleterious effects of these endogenous oxidants on modern eukaryotic cells. Because of their photosynthetic and aerobic ecologies, protomitochondria likely were relatively tolerant of such oxidants; anaerobic, heterotrophic, primitive host cells, on the other hand, likely were not. In the initial association of host and symbiont, the latter may have manipulated the former's life history by means of both endogenous oxidants and a superabundance of ATP. A resolution of this units-of-evolution conflict was necessary to continue this association, and this resolution, in a ritualized form, may have shaped the evolution of many features of modern eukaryotic cells and mitochondria, for example, the messenger functions of calcium ions, the regulatory role of phosphorylation cascades in cell-division cycles, the absence from the mitochondrial genome of replication factors, transcription factors, and adenine nucleotide carrier genes. The initial host-mitochondria interaction may have further channeled the evolution of multicellular eukaryotes, particularly animals, resulting in the association of mitochondria and the germinal plasm and in the use of extracellular ATP and endogenous oxidants as developmental signals. Evolutionary explanations for "free-radical" theories of development and aging are thus suggested. PMID- 28564862 TI - INTERSEXUAL SELECTION IN THE MEDITERRANEAN FRUIT FLY: DOES FEMALE CHOICE ENHANCE FITNESS? AB - Adaptive hypotheses of female choice predict that females use male courtship displays as an indicator of male quality. A test of whether female choice is adaptive measuring direct and indirect effects of mate choice on females was made using a laboratory population of a lek-mating species, the Mediterranean fruit fly. The nonrandom mating observed in this species is thought to be strongly influenced by female choice. Whether female choice acts to increase fecundity or offspring quality was assessed using two different statistical tests. Multiple regression showed that females generally do not receive direct benefits as a result of mating with males which are successful in copulating with many females. However, in one trial the relationship between male quality and female benefit was nonlinear. Females which mate with males that obtain few matings (<2), and females which mate with males that obtain many matings (>6) enjoy increased fecundity. Mate choice does not, however, appear to enhance offspring quality as father/son correlation and sibling analysis showed no heritable component to male copulatory success. PMID- 28564864 TI - QUANTITATIVE GENETICS IN PLANTS: THE EFFECT OF THE BREEDING SYSTEM ON GENETIC VARIABILITY. AB - The expected effects of breeding system on quantitative genetic variation under various models for the maintenance of such variation are examined, with particular emphasis on the contrast between randomly mating and highly self fertilizing populations. Estimates of quantitative genetic parameters from plant populations are reviewed. There is some evidence for reduced within-population genetic variance in highly inbreeding populations, compared with outbreeders, but more empirical work appears necessary. Although the estimate of the magnitude of the effect of breeding system is subject to considerable error, the reduction in genetic variance in inbreeding populations appears greater than expected if the variation were maintained by overdominance, or if it were due to neutral mutations. It is more consistent with models involving mutation-selection balance, although a rather larger reduction in genetic variance is estimated than is expected theoretically. We discuss some possible reasons for the lower level of genetic variance in selfers than is predicted by such models. PMID- 28564865 TI - FINE-SCALE SPATIAL STRUCTURE: CORRELATIONS FOR INDIVIDUAL GENOTYPES DIFFER FROM THOSE FOR LOCAL GENE FREQUENCIES. PMID- 28564866 TI - EVOLUTIONARY ORIGIN OF A PARTHENOFORM, THE AMAZON MOLLY POECILIA FORMOSA, ON THE BASIS OF A MOLECULAR GENEALOGY. AB - The appearance of vertebrate species that reproduce without genetic recombination has been explained by their origin from a rare hybridization event between members of two distantly related species. For the first recognized vertebrate unisexual, the Amazon molly Poecilia formosa, mostly morphological and biochemical genetic information has been available so far with respect to its evolutionary origin. DNA sequence analyses of transcribed portions of the genome (tyrosine kinase proto-oncogenes) demonstrated its hybrid state unequivocally. Both alleles can be traced in a DNA sequence-based phylogenetic tree to extant species that represent the parental species or that are closely related to the corresponding extinct forms, namely P. mexicana limantouri and a so far taxonomically ill-defined north Mexican subspecies of the P. latipinna/P. velifera complex. A rough estimate from the mutation rates dates the hybridization event further back than would have been predicted on the basis of "Muller's ratchet" for an ecologically successful species. PMID- 28564867 TI - EVOLUTION OF SPRINT SPEED IN LACERTID LIZARDS: MORPHOLOGICAL, PHYSIOLOGICAL, AND BEHAVIORAL COVARIATION. AB - Organismal performance abilities occupy a central position in phenotypic evolution; they are determined by suites of interacting lower-level traits (e.g., morphology and physiology) and they are a primary focus of natural selection. The mechanisms by which higher levels of organismal performance are achieved during evolution are therefore fundamentally important for understanding correlated evolution in general and coadaptation in particular. Here we address correlated evolution of morphological, physiological, and behavioral characteristics that influence interspecific variation in sprint speed in a clade of lacertid lizards. Phylogenetic analyses using independent contrasts indicate that the evolution of high maximum sprinting abilities (measured on a photocell-timed racetrack) has occurred via the evolution of (1) longer hind limbs relative to body size, and (2) a higher physiologically optimum temperature for sprinting. For ectotherms, which experience variable body temperatures while active, sprinting abilities in nature depend on both maximum capacities and relative performance levels (i.e., percent of maximum) that can be attained. With respect to temperature effects, relative performance levels are determined by the interaction between thermal physiology and thermoregulatory behavior. Among the 13 species or subspecies of lizards in the present study, differences in the optimal temperature for sprinting (body temperature at which lizards run fastest) closely matched interspecific variation in median preferred body temperature (measured in a laboratory photothermal gradient), indicating correlated evolution of thermal physiology and thermal preferences. Variability of the preferred body temperatures maintained by each species is, across species, negatively correlated with the thermal-performance breadth (range of body temperatures over which lizards can run relatively fast). This pattern leads to interspecific differences in the levels of relative sprint speed that lizards are predicted to attain while active at their preferred temperatures. The highest levels of predicted relative performance are achieved by species that combine a narrow, precise distribution of preferred temperatures with the ability to sprint at near-maximum speeds over a wide range of body temperatures. The observed among-species differences in predicted relative speed were positively correlated with the interspecific variation in maximum sprinting capacities. Thus, species that attain the highest maximum speeds are (1) also able to run at near-maximum levels over a wide range of temperatures and (2) also maintain body temperatures within a narrow zone near the optimal temperature for sprinting. The observed pattern of correlated evolution therefore has involved traits at distinct levels of biological organization, that is, morphology, physiology, and behavior; and trade-offs are not evident. We hypothesize that this particular trait combination has evolved in response to coadaptational selection pressures. We also discuss our results in the context of possible evolutionary responses to global climatic change. PMID- 28564868 TI - PENGUINS, PETRELS, AND PARSIMONY: DOES CLADISTIC ANALYSIS OF BEHAVIOR REFLECT SEABIRD PHYLOGENY? AB - Whether or not behavior accurately reflects evolutionary relationships (phylogeny) has been hotly debated by ethologists and comparative psychologists. Previous studies attempting to resolve this question have generally lacked a quantitative, phylogenetic approach. In this study we used behavior and life history (BLH) information (72 characters) to generate phylogenetic trees for 18 seabird species (albatrosses, petrels, and penguins). We compared these trees with trees obtained from isozyme electrophoretic analysis of blood proteins (15 loci and 98 electromorphs) and partial mitochondrial 12S ribosomal DNA sequences (381 base pairs). Cladistic analysis of the BLH data set generated three MP trees (tree length = 243, CI = 0.52, RI = 0.57) with significant cladistic structure. The BLH characters were classified into four types (foraging, agonistic, reproductive, and life history) and levels of homoplasy for each type were measured. No significant differences were found among these categories. The BLH trees were shown to be significantly more congruent with the electrophoretic and 12S sequence trees than expected by chance. This indicates that seabird BLH data contains phylogenetic signal. Areas of incongruence between BLH trees and a phylogeny generated by combining the data sets were predicted to result from ecological constraints that did not covary with phylogeny. These predictions were supported by the results of a concentrated changes test. This study found that this BLH data set was no more homoplasious than molecular data and that BLH trees were significantly congruent with molecular trees. PMID- 28564869 TI - EARLY LIFE HISTORIES, OCEAN CURRENTS, AND THE POPULATION GENETICS OF CARIBBEAN REEF FISHES. AB - Tropical reef fishes, along with many benthic invertebrates, have a life cycle that includes a sedentary, bottom-dwelling reproductive phase and a planktonic stage that occurs early in development. The adult benthic populations occupy disjunct, patchy habitats; the extent of gene flow due to dispersal of the planktonic life stage is generally unknown. PMID- 28564870 TI - NATURAL SELECTION AGAINST WHITE PETALS IN PHLOX. PMID- 28564871 TI - MITOCHONDRIAL DNA PHYLOGEOGRAPHY OF PEROGNATHUS AMPLUS AND PEROGNATHUS LONGIMEMBRIS (RODENTIA: HETEROMYIDAE): A POSSIBLE MAMMALIAN RING SPECIES. AB - Substantiated cases of ring species in mammals are rare. I examined the variation in mitochondrial DNA (mtDNA) of Perognathus amplus and P. longimembris in and around Arizona to test the hypothesis proposed by Hoffmeister (1986) that these two taxa are members of a single ring species demonstrating circular overlap. Through digestion of purified mtDNA from 45 P. amplus and 35 P. longimembris with 16 type II restriction enzymes, I identified 38 distinct haplotypes that belong to eight different evolutionary lineages. I then amplified and directly sequenced a portion of the mitochondrial cytochrome-b region from individuals representative of the lineages identified by restriction fragments, and used these data for phylogeny reconstruction in both a parsimony and neighbor-joining setting. The resulting phylogeny was consistent with the ring hypothesis, but, based on the incompleteness of the ring of subspecies and the apparent timing of evolutionary events in this group, I conclude that P. amplus and P. longimembris are distinct lineages that have completed the speciation process. PMID- 28564872 TI - FITNESS CONSEQUENCES OF SEASONAL POLYPHENISM IN WESTERN WHITE BUTTERFLIES. AB - The western white butterfly, Pontia occidentalis, has distinctly different wing phenotypes during spring and summer generations as a result of phenotypic plasticity (seasonal polyphenism). We experimentally generated different seasonal phenotypes in the lab by altering photoperiodic conditions during rearing, and released the resulting butterflies in the field. Mark-recapture studies were then used to estimate the effects of the polyphenism on activity patterns and adult survival in both late-spring (one study) and summer (two studies) conditions. There were no significant effects of rearing treatment on temporal patterns of behavioral activity during either the late-spring or the summer field studies. Recapture probabilities were consistently higher for males than females in all three field studies; in the summer 1992 study, recapture probabilities were higher for long-day (LD) than for short-day (SD) treatment groups. During the late-spring 1992 study, there were no significant differences between LD and SD treatment groups for survival probabilities. In the two summer studies, there were significant effects of photoperiodic treatment on survival probabilities; in the summer 1992 study, LD individuals consistently had higher survival probabilities than SD individuals; in the summer 1991 study, there was a significant interaction between treatment and time period on survival probabilities, such that survival probabilities were higher for LD than for SD individuals in two of four time periods. The consistent differences in survival probabilities between treatment groups in the summer 1992 study can be accounted for by the differences in wing traits between the treatment groups. Micrometeorological data from the study site showed that midday ambient temperatures averaged ~3 degrees C hotter during the 1992 than the 1991 summer study and that ambient conditions during the late-spring 1992 study were relatively warm and sunny for the season. These results document the varying relationships between phenotype and fitness in the temporally fluctuating environments experienced by this population. PMID- 28564873 TI - THE EVOLUTION OF ENDOTHERMY: TESTING THE AEROBIC CAPACITY MODEL. AB - One of the most important events in vertebrate evolution was the acquisition of endothermy, the ability to use metabolic heat production to elevate body temperature above environmental temperature. Several verbal models have been proposed to explain the selective factors leading to the evolution of endothermy. Of these, the aerobic capacity model has received the most attention in recent years. The aerobic capacity model postulates that selection acted mainly to increase maximal aerobic capacity (or associated behavioral abilities) and that elevated resting metabolic rate evolved as a correlated response. Here we evaluate the implicit evolutionary and genetic assumptions of the aerobic capacity model. In light of this evaluation, we assess the utility of phenotypic and genetic correlations for testing the aerobic capacity model. Collectively, the available intraspecific data for terrestrial vertebrates support the notion of a positive phenotypic correlation between resting and maximal rates of oxygen consumption within species. Interspecific analyses provide mixed support for this phenotypic correlation. We argue, however, that assessments of phenotypic or genetic correlations within species and evolutionary correlations among species (from comparative data) are of limited utility, because they may not be able to distinguish between the aerobic capacity model and plausible alternatives, such as selection acting directly on aspects of thermoregulatory abilities. We suggest six sources of information that may help shed light on the selective factors important during the evolution of high aerobic metabolic rates and, ultimately, the attainment of endothermy. Of particular interest will be attempts to determine, using a combination of mechanistic physiological and quantitative genetic approaches, whether a positive genetic correlation between resting and maximal rates of oxygen consumption is an ineluctable feature of vertebrate physiology. PMID- 28564874 TI - MITOCHONDRIAL DNA HOMOGENEITY IN THE PHENOTYPICALLY DIVERSE REDPOLL FINCH COMPLEX (AVES: CARDUELINAE: CARDUELIS FLAMMEA-HORNEMANNI). AB - Breeding redpoll finches (Aves: Carduelinae) show extensive plumage and size variability and, in many cases, a plumage polymorphism that is not related to age or sex. This has been ascribed to extreme phenotypic variation within a single taxon or to moderate variability within distinct taxa coupled with hybridization. The predominant view favors the recognition of two largely sympatric species: Carduelis flammea, comprised of four well-marked subspecies-flammea, cabaret, islandica, and rostrata; and C. hornemanni, comprised of two subspecies hornemanni and exilipes. We studied representative samples of these putative subspecies (except islandica) for variation in mitochondrial DNA (mtDNA). Using 20 informative restriction enzymes that recognized 124 sites (642 base pairs [bp] of sequence or ~ 3.7% of the molecule), we identified 17 RFLP haplotypes in the 31 individuals surveyed. The haplotypes formed a simple phylogenetic network with most clones diverging by a single site difference from a common haplotype found in almost half of the individuals. Within populations and taxa, levels of mtDNA diversity were similar to those observed in other avian species. The pattern of mtDNA divergence among populations was statistically unrelated to their geographic or traditional taxonomic relationships, and the estimated distance between the two traditionally recognized species was very small relative to those typically observed among avian sister species. PMID- 28564875 TI - COLOR-PATTERN VARIATION IN LAKE ERIE WATER SNAKES: THE ROLE OF GENE FLOW. AB - In an effort to clarify the evolutionary processes influencing color-pattern variation in Lake Erie island water snake (Nerodia sipedon) populations, rates of gene flow among island and mainland populations were estimated from patterns of allozymic variation detected using electrophoresis. Rates of gene flow were high with Nm, the number of migrants per generation, averaging 25.5 among island sites, 9.2 between the Ontario mainland and the islands, and 3.6 between the Ohio mainland and the islands. Based on estimates of current population size from mark recapture work and of past population size extrapolated from the extent of shoreline habitat, values of m between island and mainland populations ranged from 0.0008-0.01. Synthesis of estimates of the rate of gene flow with information on inheritance of color pattern, the strength of natural selection, and population history supports the hypothesis that color-pattern variation in island populations results from a balance between gene flow and natural selection. However, depending on the mode of inheritance of color pattern, stochastic processes such as drift may have been important in the initial stages of differentiation between island and mainland populations. PMID- 28564876 TI - A HISTORY OF HOST ASSOCIATIONS AND EVOLUTIONARY DIVERSIFICATION FOR OPHRAELLA (COLEOPTERA: CHRYSOMELIDAE): NEW EVIDENCE FROM MITOCHONDRIAL DNA. PMID- 28564877 TI - LOCAL ADAPTATION AND AGENTS OF SELECTION IN A MOBILE INSECT. AB - The deme-formation hypothesis states that selection can produce adaptive genetic variation within and among phytophagous insect populations. We conducted three field experiments and tested this prediction by transferring eggs and measuring performance of a mobile leafmining insect, Stilbosis quadricustatella. In Experiment 1, we compared the rate of mine initiation of leafminers transferred to natal and novel sites. In Experiment 2, we compared mine-initiation rate of leafminers transferred to natal and novel host-plant species. In Experiment 3, we compared the mine-initiation rate, mine-completion rate, and sources of mortality of miners transferred to neighboring natal and novel Quercus geminata trees. In the first, second, and third experiments, leafminer larvae initiated significantly more mines at the natal site, on the natal plant species, and on the natal Q. geminata tree, evidence for adaptive differentiation. Furthermore, plant-mediated mortality was significantly lower among miners transferred to natal Q. geminata trees. This result supports a key assumption of the deme formation hypothesis: insects adapt to the defensive phenotypes of individual trees. However, natural-enemy mortality was significantly higher among miners transferred to natal trees, essentially reversing the plant effect. Therefore, rates of successful mine completion were similar on natal (19%) and novel (17%) trees. This experiment suggests that host plants and natural enemies may represent opposing forces of selection. Leafminers adapted to individual trees may realize a selective advantage only when natural-enemy densities are low. PMID- 28564878 TI - VIABILITY SELECTION ON SEASONALLY POLYPHENIC TRAITS: WING MELANIN PATTERN IN WESTERN WHITE BUTTERFLIES. AB - Wing melanin pattern varies seasonally among generations in many populations of the butterfly Pontia occidentalis, leading to distinctly different wing phenotypes during spring and summer generations. Estimates of directional selection on wing pattern can therefore quantify the imperfection of this phenotypically plastic (polyphenic) response in generating "optimal" phenotypes for each seasonal generation. Mark-release-recapture (MRR) studies were used to estimate directional selection on six wing traits in a natural population of P. occidentalis during both spring and summer weather conditions. Estimated survival and recapture probabilities varied substantially among the four MRR studies. When differences between males and females were detected, the survival and recapture probabilities were higher for males than for females. Estimated selection coefficients suggested that the direction of selection on one wing trait important for thermoregulation, melanin on the base of the dorsal hindwings (trait hb), fluctuated seasonally; there was evidence of directional selection for increased hb in the spring studies and for decreased hb in the summer studies. Such fluctuating seasonal selection on hb implies that the seasonal polyphenic response may not be sufficient to eliminate selection on this trait; the slope of the reaction-norm mapping hb onto seasonal environmental cues is too shallow, resulting in further selection on the reaction norm. Adaptive evolution of the reaction norm may be constrained by phenotypic and genetic correlations with other wing traits that experience different patterns of selection and by variable weather conditions within seasons and among years. PMID- 28564879 TI - RESOURCE ALLOCATION AND MATING SYSTEMS IN BUTTERFLIES. AB - A cross-taxonomic comparison of resources allocated to reproductive reserves at adult eclosion reveals that females belonging to polyandrous species receive more ejaculate material and allocate proportionally less of their total reserves to potential reproduction compared to females belonging to monandrous species. These results suggest that adult females of polyandrous species have a higher expected nutrient income and are consistent with the idea that females can benefit from male nutrient donations transferred during mating. Males show the opposite pattern: males of polyandrous species allocate proportionally more to reproduction. This is expected since males in polyandrous species have both proportionally heavier ejaculates and have a higher ejaculative production capacity than do males in monandrous species. Interestingly, adults of the genus Heliconius which can obtain nutrients crucial to reproduction by pollen feeding do not seem to follow these patterns as strong as only nectar-feeding butterflies. Instead, the association between degree of polyandry and resources allocated to reproduction is relaxed. PMID- 28564880 TI - MORPHOLOGICAL VARIATION IN THE LIMBS OF TARICHA GRANULOSA (CAUDATA: SALAMANDRIDAE): EVOLUTIONARY AND PHYLOGENETIC IMPLICATIONS. AB - Variation in the limb skeleton was studied in a large sample (452 individuals) of adult newts (Taricha granulosa) from a single population in central California. A standard morphology is found in the hands and feet in more than 70% of individuals, but there is important variation in the remainder of the sample. Although twice as many individuals express variant tarsal (18.9%) than carpal (9.3%) patterns, the carpus reveals a greater diversity of variant conditions. Only a few of the many possible arrangements (including loss, addition, and amalgamation) of the seven carpal and nine tarsal elements are encountered. Most of the observed patterns are readily classified on the basis of phylogenetic relationship and models of development. Five patterns are bilaterally symmetrical. Two of these five arrangements are atavisms that represent plesiomorphic states. The other three symmetrical variants duplicate patterns found elsewhere among derived urodele taxa. These homoplastic patterns correspond to apomorphies of other genera within the same family or apomorphies of deeply nested and highly specialized members of other families (e.g., several plethodontid genera). This variation reveals the potential of the generative system and suggests the existence of limited domains of phenotypic expression. Both the origin of novelty and the restoration of ancestral states reflect the action of design constraints that not only place limits but also provide opportunities during the morphologic and phyletic diversification of urodeles. PMID- 28564881 TI - POPULATION STRUCTURE AND DYNAMICS OF SELECTED GENES IN THE MOSQUITO CULEX PIPIENS. AB - To determine the outcome of the combined effects of gene flow, genetic drift, and selection on the evolution of insecticide-resistance genes in the mosquito Culex pipiens, samples were collected along three transects crossing treated and nontreated areas in northern Spain and southern France. Electrophoretic polymorphisms of five presumably neutral genes disclosed that differentiation among samples was low, and that both Wright F-statistics and Slatkin private alleles methods provided a high estimate for Nm. In contrast, there was a strong differentiation in the distribution of resistance genes closely associated with insecticide treatments. These divergent situations are explained in relation to both the very recent origin of some resistance genes that are still localized geographically (A2-B2 and C1), and the high fitness cost of the older and ubiquitous ones in nontreated areas (A1, A4-B4, and AceR ). PMID- 28564882 TI - GENETIC CONSTRAINTS ON MACROEVOLUTION: THE EVOLUTION OF HOST AFFILIATION IN THE LEAF BEETLE GENUS OPHRAELLA. AB - We hypothesize that the evolution of an ecologically important character, the host associations of specialized phytophagous insects, has been influenced by limitations on genetic variation. Using as a historical framework a phylogenetic reconstruction of the history of host associations in the beetle genus Ophraella (Chrysomelidae), we have employed quantitative-genetic methods to screen four species for genetic variation in larval survival, oviposition (in one species only), and feeding responses to their congeners' host plants, in the Asteraceae. We here report results of studies of one species and evaluate the results from all four. Analysis of half-sib/full-sib families and of progenies of wild females of O. notulata, a specialist on Iva (Ambrosiinae), provided evidence of genetic variation in larval consumption of five of six test plants and in adult consumption of four of six. Larval mortality was complete on five plants; only on Ambrosia, a close relative of the natural host, was there appreciable, and genetically variable, survival. Oviposition on Ambrosia showed marginally significant evidence of genetic variation; a more distantly related plant elicited no oviposition at all. In compiling results from four Ophraella species, reported in this and two other papers, we found no evidence of genetic variation in 18 of 39 tests of feeding responses and 14 of 16 tests of larval survival on congeners' hosts. This result is consistent with the hypothesis that absence or paucity of genetic variation may constrain or at least bias the evolution of host associations. The lower incidence of genetic variation in survival than in feeding behavior may imply, according to recent models, that avoidance is a more common evolutionary response to novel plants than adaptation. The usually great disparity between mean performance on congeners' hosts and the species' natural hosts, and an almost complete lack of evidence for negative genetic correlations, argue against the likelihood that speciation has occurred by sympatric host shift. The presence versus apparent absence of genetic variation in consumption was correlated with the propinquity of relationship between the beetle species tested and the species that normally feeds on the test plant, suggesting that the history of host shifts in Ophraella has been guided in part by restrictions on genetic variation. It was also correlated with the propinquity of relationship between a test plant and the beetle's natural host. The contributions of plant relationships and insect relationships, themselves correlated in part, to the pattern of genetic variation, are not readily distinguishable, but together accord with phylogenetic evidence that these and other phytophagous insects adapt most readily to related plants. In this instance, therefore, the macroevolution of an ecologically important character appears to have been influenced by genetic constraints. We hypothesize that absence of the structural prerequisites for genetic variation in complex characters may affect genetic variation and the trajectory of evolution. PMID- 28564883 TI - UNDERSTANDING THE POPULATION GENETIC STRUCTURE OF GLEDITSIA TRIACANTHOS L.: THE SCALE AND PATTERN OF POLLEN GENE FLOW. AB - Spatial and temporal patterns of gene flow determine the extent to which populations can differentiate from one another as a result of natural selection or genetic drift. In this study, we investigated pollen-mediated gene flow in two eastern Kansas populations of the subdioecious tree species, Gleditsia triacanthos L. (Leguminosae), or honeylocust. In 2 yr at each site, we used paternity-exclusion analysis to estimate the proportion of seeds sired by immigrant pollen. We also used a single-parent and parent-pair exclusion analysis on naturally established seedlings and saplings to estimate gene flow into one site over a 12-yr period and into the second site over a 22-yr period. Results of both analyses showed high minimum estimates of pollen gene flow into each site (17%-30%). In each population, we found significantly less gene flow in years of high fruit production than in years of low fruit production, but in one population, we observed little variation in gene-flow rates among age classes of seedlings and saplings. The level of pollen gene flow showed weak negative dependence on the relative isolation distances of the maternal trees sampled (140 240 m at one site vs. 85-120 m at the second site), and gene-flow estimates from naturally established juveniles were very similar at the two sites. Within populations, a multiple regression model showed that maximum-likelihood estimates of male fertility were negatively associated with distances between mates and positively associated with male size as measured by stem diameter. In neither population, however, did the regression explain more than 16% of the total variation in male fertilities. PMID- 28564884 TI - POPULATION STRUCTURE OF A HERBIVOROUS INSECT AND ITS HOST PLANT ON A MICROGEOGRAPHIC SCALE. PMID- 28564885 TI - CONSERVATION OF MOLECULAR PREPATTERNS DURING THE EVOLUTION OF CUTICLE MORPHOLOGY IN DROSOPHILA LARVAE. AB - We are using patterns of cuticle specialization in Drosophila larvae as models to investigate the molecular, genetic, and developmental bases of morphological evolution. Members of the virilis species group differ markedly from one another in the distribution of hairs on the dorsal surface of first instar larvae. In particular, characteristic bands of hairs cover about 20% of each trunk segment in some species but about 70% in others. These major types do not correlate with recently proposed phylogenetic relationships, suggesting that similar phenotypes have arisen independently in different lineages. The patterns of expression of several genes that control or reflect intrasegmental patterning are indistinguishable in species with very different cuticle morphologies. We conclude that, in this case, morphology probably has evolved via altered response to a conserved molecular prepattern. PMID- 28564886 TI - QUANTITATIVE GENETICS OF BRYOZOAN PHENOTYPIC EVOLUTION. I. RATE TESTS FOR RANDOM CHANGE VERSUS SELECTION IN DIFFERENTIATION OF LIVING SPECIES. AB - The possible roles of random genetic change and natural selection in bryozoan speciation were analyzed using quantitative genetic methods on breeding data for traits of skeletal morphology in two closely related species of the cheilostome Stylopoma. The hypothesis that morphologic differences between the species are caused entirely by mutation and genetic drift could not be rejected for reasonable rates of mutation maintained for as few as 103 to 104 generations. Divergence times this short or shorter are consistent with the abrupt appearances of many invertebrate species in the fossil record, commonly followed by millions of years of morphologic stasis. To produce these differences over 103 generations or fewer, directional selection acting alone would require unrealistically high levels of minimum selective mortality throughout divergence. Thus, selection is unnecessary to explain the divergence of these species, except as a means of accelerating the effects of random genetic change on shorter time scales (directional selection), or decelerating them over longer ones (stabilizing selection). These results are consistent with a variety of models of phenotypic evolution involving random shifts between multiple adaptive peaks. Similar results were obtained by substituting trait heritabilities and genetic covariances reconstructed by partitioning within- and among-colony phenotypic variance in place of the values based on breeding data. Quantitative genetic analysis of speciation in fossil bryozoan lineages is thus justified. PMID- 28564887 TI - PERSPECTIVE: THE EVOLUTIONARY BIOLOGY OF AGING, SEXUAL REPRODUCTION, AND DNA REPAIR. AB - Three recent books on the evolutionary biology of aging and sexual reproduction are reviewed, with particular attention focused on the provocative suggestion by Bernstein and Bernstein (1991) that senescence and genetic recombination are related epiphenomena stemming from the universal challenge to life posed by DNA damages and the need for damage repair. Embellishments to these theories on aging and sex are presented that consider two relevant topics neglected or underemphasized in the previous treatments. The first concerns discussion of cytoplasmic genomes (such as mtDNA), which are transmitted asexually and therefore do not abide by the recombinational rules of nuclear genomes; the second considers the varying degrees of cellular and molecular autonomy which distinguish unicellular from multicellular organisms, germ cells from somatic cells, and sexual from asexual genomes. Building on the Bernsteins' suggestions, two routes to immortality for cell lineages appear to be available to life: an asexual strategy (exemplified by some bacteria), whereby cell proliferation outpaces the accumulation of DNA damages, thereby circumventing Muller's ratchet; and a sexual strategy (exemplified by germlines in multicellular organisms), whereby recombinational repair of DNA damages in conjunction with cell proliferation and gametic selection counter the accumulation of nuclear DNA damages. If true, then elements of both the recombinational strategy (nuclear DNA) and replacement strategy (cytoplasmic DNA) may operate simultaneously in the germ-cell lineages of higher organisms, producing at least some gametes that are purged of the DNA damages accumulated during the lifetime of the somatic parent. For multicellular organisms, production of functionally autonomous and genetically screened gametic cells is a necessary and sufficient condition for the continuance of life. PMID- 28564888 TI - VARIATION IN REACTION NORMS AMONG POPULATIONS OF THE GRASS BOUTELOUA RIGIDISETA. AB - Recent research has emphasized the importance of investigating the reaction norms of quantitative traits to understand evolution in natural environments. In this study, genetic differences in reaction norms among eight populations of the grass Bouteloua rigidiseta were examined using clonal replicates of genotypes planted in a common garden with two levels of competition (single B. rigidiseta without competition and single B. rigidiseta surrounded by four Erioneuron pilosum). The populations were found to be genetically differentiated for a variety of traits. Differences in reaction norms of size-specific fecundity (spikelet clusters per tiller number) were detected among the populations: some showed little response to competition; in others size-specific fecundity was much greater in the absence of competition. This divergence in reaction norms among these populations may be the result of past selection (including the cost of plasticity), or genetic drift. PMID- 28564889 TI - PREFERENCE HIERARCHIES AND THE ORIGIN OF GEOGRAPHIC SPECIALIZATION IN HOST USE IN SWALLOWTAIL BUTTERFLIES. AB - Four allopatric populations of the widely distributed western anise swallowtail butterfly, Papilio zelicaon, use different plant genera as hosts, but simultaneous choice experiments showed that these populations have diverged only slightly in oviposition preference. Of the four populations-two from southeastern Washington State, one from coastal southwestern Washington State, and one from central California-three use hosts that are not available to any of the others. Although variation for the degree of preference for particular plant species occurred within and among populations, all four populations ranked hosts in the same overall order. Monophagy on a local, low-ranking host outside the range of high-ranking hosts did not necessarily lead to the loss of preference for those high-ranking hosts, thereby indicating that the high-ranking hosts would still be accepted, and in some cases even preferred, if a population encountered them again. Hence, the overall preference hierarchy among P. zelicaon populations appears to be evolutionarily conservative. Analyses of differences among families within the California population indicated that increased preference for some hosts is inversely correlated, whereas preference for other hosts may be uncorrelated. Positive correlations may also occur but were not observed among the plant species tested. Overall, the results indicate local monophagy on different plant species in P. zelicaon has not involved major reorganizations in the preference hierarchy of ovipositing females, even in populations that may have fed on a low-ranking host for many generations. Instead, small increases in preference for local hosts have occurred within an evolutionarily conservative preference hierarchy. PMID- 28564890 TI - THE ROLE OF DEME SIZE, REPRODUCTIVE PATTERNS, AND DISPERSAL IN THE DYNAMICS OF t LETHAL HAPLOTYPES. AB - The t-lethal haplotypes (t) found in house mouse (Mus musculus) populations are recessive lethals favored by gametic selection whereby male heterozygotes exhibit a non-Mendelian transmission ratio of about 95% t. The expected equilibrium frequency is 0.385; however, empirical values are lower, averaging close to 0.13. We examined the hypothesis that interdemic selection is the cause of the low empirical values by using a deme-structured simulation model that included overlapping generations, a realistic breeding system, differential deme productivity, and a large total population. We found that under some conditions interdemic selection could lower t frequency below 0.13 in the face of immigration rates up to 5%. Low frequencies were correlated with effective deme size (ne ), regardless of whether ne was changed through changing deme size (n) or through changing the proportion of breeding adults. Earlier workers showed how the first two phases of interdemic selection (random genetic differentiation and mass selection) interacted to reduce the haplotype frequency, but here we show the importance of the third phase (differential productivity of demes) once demes are linked by dispersal. The effect of this phase is not due to the (negative) covariation between deme productivity and haplotype frequency, but occurs when differential deme productivity generates a difference in t frequency between the population of juveniles recruited into their natal deme and the population of juvenile dispersers. This difference was maximized when the average productivity of demes was low, either because few adult females bred at any one time and/or because fecundity was low. Contrary to an earlier prediction, male-biased dispersal also reduced haplotype frequency, and this probably stems from the relative excess of wild-type genotypes among dispersers compared to the deme residents. Another unexpected finding was that the randomly generated excess of heterozygotes (FIS < 0) found in small demes favored t haplotypes; however, the effect was only seen when the more powerful influence of the third phase of interdemic selection was removed. Simulations of neutral polymorphisms showed that a deme structure giving FST <= 0.6 is inconsistent with a haplotype frequency below 0.13. Based on current empirical estimates of FST (about 0.2), we concluded that immigration rates in the field are too high for interdemic selection alone to cause the observed deficit of lethal haplotypes. One factor that could combine with population structure effects is the observation that the transmission ratio is lowered to around 0.6 in litters produced from postpartum estrus (PPE). Incorporating this factor, we showed that interdemic selection could be effective in lowering the frequency of t below 0.13 when FST was above 0.43 even when migration rates were up to 10%. These results suggest that if empirical haplotype and FST estimates are accurate, then additional factors such as a lowered fitness of heterozygotes may be involved. PMID- 28564891 TI - EXTREME KARYOTYPIC VARIATION IN A MUS MUSCULUS DOMESTICUS HYBRID ZONE: THE TOBACCO MOUSE STORY REVISITED. AB - The Robertsonian fusion is a common chromosomal mutation among mammal species and is especially prevalent in the West European house mouse, Mus musculus domesticus. More than 40 races of the house mouse exist in Europe, including the famous "tobacco mouse" (Poschiavo race) of Val Poschiavo, Switzerland. Documented here is the discovery of an extreme case of karyotypic variation in the neighboring Upper Valtellina, Italy. In a 20-km stretch of the valley, 32 karyotypes were observed, including five chromosomal races and 27 hybrid types. One previously unknown race is reported, the "Mid Valtellina" race, with a diploid number of 2n = 24 and the Robertsonian fusions Rb(1.3), Rb(4.6), Rb(5.15), Rb(7.18), Rb(8.12), Rb(9.14), Rb(11.13), and Rb(16.17). The Poschiavo race (2n = 26), Upper Valtellina race (2n = 24), Lower Valtellina race (2n = 22) and all-acrocentric race (2n = 40) were also present. The races form a patchy distribution, which we term a "mottled hybrid zone." Geographical position, isolation, extinction, recolonization, and selection against hybrids are all believed to be instrumental in the origin and evolution of this complex system. Previous studies of house mice from Upper Valtellina indicated that two of the races in the valley (the Upper Valtellina and Poschiavo races) may have speciated in the village of Migiondo. We discuss the possibility that there may have been a reinforcement event in this village. PMID- 28564892 TI - MALE MATE CHOICE AND THE EVOLUTION OF FEMALE PLUMAGE COLORATION IN THE HOUSE FINCH. AB - The house finch (Carpodacus mexicanus) is a sexually dichromatic passerine in which males display colorful plumage and females are generally drab brown. Some females, however, have a subdued version of the same pattern of ornamental coloration seen in males. In previous research, I found that female house finches use male coloration as an important criterion when choosing mates and that the plumage brightness of males is a reliable indicator of male nest attentiveness. Male house finches invest substantially in the care of young and, like females, stand to gain by choosing high-quality mates. I therefore hypothesized that a female's plumage brightness might be correlated with her quality and be the basis for male mate choice. In laboratory mate choice experiments, male house finches showed a significant preference for the most brightly plumaged females presented. Observations of a wild population of house finches, however, suggest that female age is the primary criterion in male choice and that female plumage coloration is a secondary criterion. In addition, yearling females tended to have more brightly colored plumage than older females, and there was no relationship between female plumage coloration and overwinter survival, reproductive success, or condition. These observations fail to support the idea that female plumage coloration is an indicator of individual quality. Male mate choice for brightly plumaged females may have evolved as a correlated response to selection on females to choose brightly colored males. PMID- 28564893 TI - WHAT METAZOAN PARASITES TELL US ABOUT THE EVOLUTION OF AMERICAN AND EUROPEAN EELS. PMID- 28564894 TI - ECOLOGICAL AND GENETIC ASSOCIATIONS IN AN IRIS HYBRID ZONE. AB - Chloroplast DNA (cpDNA) markers and 12 nuclear (random amplified polymorphic DNA, or RAPD) markers were used to examine the distribution of genetic variation among individuals and the genetic and ecological associations in a hybrid iris population. Plants in the population occurred at various distances from the edge of a bayou in a relatively undisturbed mixed hardwood forest and in an adjacent pasture dominated by herbaceous perennials with interspersed oak and cypress trees. The majority of plants sampled possessed combinations of markers from the different Iris species. Genetic markers diagnostic for Iris fulva and I. brevicaulis occurred at high frequencies, whereas markers diagnostic for I. hexagona were infrequent. For the majority of the nuclear markers, significant levels of cytonuclear disequilibria existed because of intraspecific associations among the markers in both the pasture and the forest. The distribution of nuclear markers among individuals was bimodal; intermediate genotypes were absent and the majority of RAPD markers were associated with their intraspecific cpDNA haplotypes. Strong intraspecific associations existed among RAPD markers in the forest, but associations tended to be weaker in the pasture area. Ecological correlations were detected for all but one of the I. fulva and I. brevicaulis RAPD markers. The ecological associations of hybrids similar to I. brevicaulis resembled associations of I. brevicaulis parental genotypes, suggesting that these hybrid genotypes may be relatively fit in the same habitats. The hybrids similar to I. fulva, however, were distributed in habitats that were unique relative to the parental species. The patterns of genetic and environmental associations along with other available data suggest that (1) only advanced generation hybrids were present in the population; (2) formation of F1 hybrids among Louisiana irises is rare, leading to sporadic formation of hybrid populations; and (3) selection and assortative mating have contributed to the formation of hybrid genotypes that tend to be similar to parental genotypes. The patterns of ecological and genetic associations detected in this population suggest that assortative mating and environmental and viability selection are important in the structuring and maintenance of this hybrid zone. PMID- 28564895 TI - THE EVOLUTION OF ALTERNATE MORPHOLOGIES: FITNESS AND WING MORPHOLOGY IN MALE SAND CRICKETS. AB - Many organisms show distinct morphological types. We argue that the evolution of these alternate morphologies depends upon both fitness differences between morphs within each sex and the genetic correlation between sexes. In this paper, we examine the evolution of alternate morphologies using wing dimorphism in insects as a model system. Many insect species are wing dimorphic, one morph having wings and being capable of flight, the other lacking functional wings. While there is a well established trade-off in females between macroptery and reproduction, there are few data on the possible costs in males. We examine trade-offs between macroptery and life-history traits in male sand crickets, Gryllus firmus, and estimate the genetic correlation of wing dimorphism between the sexes. Macropterous males develop faster than micropterous males and are either larger or the same size depending upon rearing conditions. There is no difference in absolute or relative testis size at eclosion or 7 d thereafter. Finally, there is no difference between macropterous and micropterous males in relative success at siring offspring. Thus, with respect to the above traits, there are no costs associated with being winged in male G. firmus. It is possible that there may be a trade-off between calling rate and macroptery. A comparison of the relative frequency of macroptery between males and female across different orders of insects supports this hypothesis. The genetic correlation of wing dimorphism between the sexes is high (r8 = 0.86), and hence the frequency of macroptery in males may be strongly influenced by selection acting on females. PMID- 28564896 TI - THE INFLUENCE OF MATING SYSTEM AND OVERLAPPING GENERATIONS ON EFFECTIVE POPULATION SIZE. AB - The effective population size (Ne ) depends strongly on mating system and generation time. These two factors interact such that, under many circumstances, Ne is close to N/2, where N is the number of adults. This is shown to be the case for both simple and highly polygynous mating systems. The random union of gametes (RUG) and monogamy are two simple systems previously used in estimating Ne , and here a third, lottery polygyny, is added. Lottery polygyny, in which all males compete equally for females, results in a lower Ne than either RUG or monogamy! Given nonoverlapping generations the reduction is 33% for autosomal loci and 25% for sex-linked loci. The highly polygynous mating systems, harem polygyny and dominance polygyny, can give very low values of Ne /N when the generation time (T) is short. However, as T is lengthened, Ne approaches N/2. The influence of a biased sex ratio depends on the mating system and, in general, is not symmetrical. Biases can occur because of sex differences in either survival or recruitment of adults, and the potential for a sex-ratio bias to change Ne is much reduced given a survival bias. The number of juveniles present also has some influence: as the maturation time is lengthened, Ne increases. PMID- 28564897 TI - INBREEDING EFFECTS IN A GYNODIOECIOUS POPULATION OF THE COLONIZING SPECIES TRIFOLIUM HIRTUM ALL. AB - The demographic consequences of one and two generations of selfing were examined in a gynodioecious population of rose clover (Trifolium hirtum). Seeds collected from a roadside population were used to create an experimental population that consisted of seeds of open-pollinated individuals (S0 ), and seeds obtained after one (S1 ) and two (S2 ) generations of selfing. Seeds from the three groups were equally likely to germinate. However, inbreeding effects were observed in the vigor and survivorship of the seedlings. The proportion of the transplanted seedlings that reached the reproductive stage was 0.42, 0.31, and 0.14 for the S0 , S1 , and S2 groups, indicating a reduction of 26% and 66% by one and two generations of selfing, respectively. Inbreeding effects on reproductive components of fitness were nonsignificant. Groups were compared by multiplicative fitness functions based on germination, survival to reproduction, and fecundity. The relative fitness of the S1 and S2 groups were 0.64 and 0.23 relative to the S0 group, representing a reduction in lifetime fitness of 36% and 77%, respectively. The differences in relative fitness among the groups were caused mainly by differences in survivorship. Thus, inbreeding depression is apparently an important factor in the maintenance of the gynodioecious breeding system in rose clover. PMID- 28564898 TI - ANNUAL DIFFERENCES IN FEMALE REPRODUCTIVE SUCCESS AFFECT SPATIAL AND COHORT SPECIFIC GENOTYPIC HETEROGENEITY IN PAINTED TURTLES. AB - Long-term ecological data were used to evaluate the relative importance of movements, breeding structure, and reproductive ecological factors to the degree of spatial and age-specific variation in genetic characteristics of painted turtles (Chrysemys picta) on the E. S. George Reserve in southeastern Michigan. Estimates of the degree of spatial genetic structuring were based on the proportion of total genotypic variance partitioned within and between subpopulations (inferred from hierarchical F-statistics based on variation at 18 protein loci), and in terms of gene correlations (co-ancestry among individuals derived from reproductive data on full-sib families of females nesting at specific nesting areas). Little variation in allele frequency was observed among turtles from different marshes (Fmt = 0.003), though significant variation was observed among turtles from different nesting areas associated with each marsh (Fnm = 0.046). Gene correlations among individuals within nesting areas varied greatly over years (0.032-0.171; mean = 0.069) and were negatively correlated to the proportion of females that successfully nested during each year. General concordance between independent estimates of genotypic correlations (i.e., Fnm derived from protein electrophoretic variation vs. mean co-ancestry) suggests that allozyme data, when collected over spatial scales consistent with species behavioral characteristics and reproductive ecology, may accurately reflect the apportionment of gene diversity within and among subpopulations. The magnitude and patterning of allelic variation among nesting areas and individuals appears to be primarily a function of gametic correlations among members of full-sib families, irrespective of the degree of gene flow or female nesting-site fidelity. Comparisons of genetic characteristics among 11 cohorts (1974-1984) revealed that heterozygosity (H) and inbreeding coefficients (F) varied greatly. Cohort estimates of H and F were correlated to female nesting success and to estimates of co-ancestry for the same years. Results clearly reflect the concomitant importance of ecological factors (principally the proportion of the female population that successfully produce offspring during each year) in determining the magnitude and patterning of gene correlations within and among groups, and to the genotypic composition of offspring born during each year. PMID- 28564899 TI - PHENOTYPIC VARIATION OF GROWTH TRAJECTORIES IN FINCHES. AB - Evolution cannot proceed without phenotypic variation for selection to act on. This is particularly true of ontogenetic parameters because it is changes in these parameters that give rise to new phenotypes. I analyzed the amount and dimensionality of phenotypic variation on growth trajectories in early ontogeny in three species of finches (Fringillidae) using the recently developed infinite dimensional model. For two species, eight traits were analyzed, and for a third, six traits. Growth data were analyzed only up to 6 d of age in two species and 8 d of age in the third. The results were very similar for all species and traits. A very large proportion of the phenotypic variation in growth trajectories was confined to a single dimension. This dimension corresponded to a simultaneous increase/decrease at all ages in early ontogeny. The eigenfunctions, each describing a family of similar-shaped growth trajectories, were highly collinear among traits. A high covariance existed among traits at the same and different ages. If some part of the phenotypic variation has an additive genetic basis, then any selection for a change in size at one age in one trait will lead to a response in a size at subsequent ages and in the other traits. This in turn suggests that morphological evolution frequently will move along a multivariate size axis, as has indeed been found in several taxa. PMID- 28564900 TI - GENETIC CONTROL OF THE RATE OF EMBRYONIC DEVELOPMENT: SELECTION FOR FASTER DEVELOPMENT AT ELEVATED TEMPERATURES. PMID- 28564901 TI - MAXIMUM-LIKELIHOOD ESTIMATES OF SELECTION COEFFICIENTS FROM DNA SEQUENCE DATA. AB - Selection can have a significant effect on sequence evolution and this will be reflected in the information contained within the phylogenetic relationships between species. Selection will reduce the frequency of any deleterious nucleotides, and this can be used to test for the presence of selection. The frequencies of different nucleotides can be predicted theoretically and compared to observed values. If a sample of sequences has an usually low frequency of a particular nucleotide then selection might be inferred to have acted upon these sequences. This conclusion can be true only if the sequences are not too closely related and if sufficient mutations have occurred during their evolution. Otherwise, the unusual pattern of nucleotides in the sequences may be caused by recent common ancestry. An algorithm is presented to obtain maximum-likelihood estimates of selection coefficients using the phylogenetic information contained within sequence data. A k-allele model is developed that uses the phylogeny to measure relative mutation rates and degrees of relatedness and to evaluate the likelihood in the presence of selection. The method is illustrated with examples from the NS2 genes of influenza viruses and the MHC genes of mice. It is shown that the maximum-likelihood estimate for mutation rates are very large for. influenza viruses and that statistically significant selection acts to maintain a specific coding sequence. Overall, the MHC genes also have significant selection to preserve the coding sequence, but at the antigen recognition site, this selection is reversed to promote genetic variation. Maximum-likelihood estimates of these selection coefficients are provided. PMID- 28564902 TI - CLADOGRAM VERSATILITY: EVOLUTION AND BIOGEOGRAPHY OF ACANTHUROID FISHES. AB - A highly corroborated cladogram of acanthuroid fishes is used to explore several aspects of the biogeographic and microevolutionary events during the evolution of the group. Five events in acanthuroid evolution are documented here, which demonstrate not only the power of cladograms to provide adaptational hypotheses, but also how they can be used to frame significant questions for further research. Biogeographic analysis indicates that basal cladogenesis of the acanthuroids must have occurred prior to the Eocene (50-55 mya), because at least the basal lineages of the Acanthuridae, one of the last acanthuroid families to have evolved, were present at that time. In addition, optimization of current distributions suggests that the ancestors of the Acanthurinae, of the Acanthuridae, and of the Acanthuroidei each had an Indo-West Pacific distribution. Subsequent dispersion and/or speciation in one or more of these lineages may have been related either to the closure of the Tethys (ca 20 mya), or to colonization from the Pacific of the Caribbean/Atlantic prior to the formation of the Panamanian isthmus. Hypotheses about adaptation in acanthuroids begin with a discussion of several cases of dietary plasticity. The importance of information from fossils is illustrated in an investigation of predorsal bone evolution. Morphologically divergent and convergent tendencies in the modification of the pelvic fins concludes the examples. The morphologically most derived genus, Ctenochaetus, seems the least active taxon evolutionarily in the characters investigated. PMID- 28564903 TI - GENETIC SUBDIVISIONS AMONG SMALL CANIDS: MITOCHONDRIAL DNA DIFFERENTIATION OF SWIFT, KIT, AND ARCTIC FOXES. AB - Gene flow can effectively suppress genetic divergence among widely separated populations in highly mobile species. However, the same may not be true of species that typically disperse over shorter distances. Using mtDNA restriction site and sequence analyses, we evaluate the extent of divergence among populations of two small relatively sedentary North American canids, the kit and swift foxes (genus Vulpes). We determine the significance of genetic differentiation among populations separated by distance and those separated by discrete topographic barriers. Our results show the among-population component of genetic variation in kit and swift foxes is large and similar to that of small rodents with limited dispersal ability. In addition, we found two distinct groupings of genotypes, separated by the Rocky Mountains, corresponding to the traditional division between kit and swift fox populations. Previous workers have characterized these morphologically similar populations either as separate species or subspecies. Our mtDNA data also suggest that kit and swift fox populations hybridize over a limited geographic area. However, the sequence divergence between kit and swift foxes is similar to that between these taxa and the arctic fox (Alopex lagopus), a morphologically distinct species commonly placed in a separate genus. This result presents a dilemma for species concepts, and we conclude that kit and swift foxes should be recognized as separate species. PMID- 28564904 TI - GENETIC CONSTRAINTS ON THE INDEPENDENT EVOLUTION OF MALE AND FEMALE REPRODUCTIVE CHARACTERS IN THE TRISTYLOUS PLANT LYTHRUM SALICARIA. AB - Here we test whether the potential exists for the independent evolution of allocation to male, female, and attractive functions within a flower. We employed half-sib and parent-offspring regression methods in the tristylous plant Lythrum salicaria to determine whether there is additive genetic variation for characters important to male and female reproductive success and whether genetic correlations could constrain the independent evolution of male and female function. Although significance levels were not consistent among morph types or between populations, there were significant narrow-sense heritabilities for several traits including stamen mass, pistil mass, perianth mass, petal length, and calyx length. Traits that might be under strong stabilizing selection to promote specific pollen transfer, such as stamen and style lengths, had little heritable variation. In the majority of cases in which heritable variation was present, there were positive genetic correlations among floral traits. A strong positive genetic correlation appeared between stamen and pistil mass in the short styled morph from one of the populations studied. This suggests that selection might not be able to act independently on biomass allocation to male and female flower parts. No evidence of negative genetic correlations appeared that would suggest trade-offs and that could augment a selection response towards sexual specialization. The observed positive correlations could be explained if we consider the "functional architecture" that underlies the covariance structure. If there is more covariance generated by pleiotropic loci controlling overall flower size than at loci controlling male versus female allocation, it could result in the observed positive covariance. At the phenotypic level, we did find significant negative partial correlations between male and female traits when flower size was controlled, but these trade-offs were among rather than within morphs. PMID- 28564905 TI - A MATHEMATICAL MODEL OF HALDANE'S RULE. PMID- 28564906 TI - EVOLUTION OF PLANT POLLINATION SYSTEMS: HYPOTHESES AND TESTS WITH THE NEOTROPICAL VINE DALECHAMPIA. AB - The results of pollination and mating-system studies were integrated with a phylogenetic study of 40 Neotropical species of Dalechampia L. (Euphorbiaceae) to reconstruct the history of evolutionary change in pollination systems. The results of this analysis were treated as a hypothesis and tested for circularity problems and robustness in the face of changes in the data set. The historical hypothesis was used to make specific predictions about details of pollination ecology and reward biochemistry; the predictions were supported by independent observations. I conclude that pollination systems in Dalechampia have been evolutionarily labile, relative to most morphological features, with repeated parallelisms and reversals. Transitions among the three pollination systems evolved by Dalechampia (pollination by resin-collecting bees, fragrance collecting male euglossine bees, and pollen-collecting bees) have been facilitated by biochemical exaptation (preadaptation). Pollination by male euglossine bees is relatively rare in the genus but has originated independently three to four times. In contrast, pollination by resin-collecting female bees is very common, but has originated only once. Eighty-six to 97% of transitions between pollination systems involved an intermediate phase during which both old and new pollinators were effective, but 3 to 14% of transitions may have been "instantaneous," lacking the intermediate phase. Clades of species secreting resin rewards are about 10 times as species rich as clades of species secreting fragrance rewards; circumstantial evidence suggests that different extinction rates may be responsible for this difference. Relatively allogamous (cross pollinating) species have evolved from more autogamous (self-pollinating) species up to 13 times, and autogamous species have evolved from more allogamous ones up to 11 times. Species occurring in disturbed habitats are facultatively autogamous, whereas species of undisturbed habitats are often highly allogamous. PMID- 28564907 TI - REPRODUCTIVE RELATIONSHIPS AMONG TEN SPECIES OF THE DROSOPHILA REPLETA GROUP FROM SOUTH AMERICA AND THE WEST INDIES. PMID- 28564908 TI - CHEMICAL COMMUNICATION IN HAWAIIAN DROSOPHILA. AB - We are interested in elucidating the extent to which lekking Hawaiian Drosophila species have diverged from their continental counterparts, which engage in sexual behavior at communal food sources, with regard to the chemical communication systems that the flies employ. Accordingly, we have analyzed flies from three closely related Hawaiian Drosophila species in the adiastola subgroup. These species are of interest because the males engage in a unique behavior: while courting, they raise their abdomens over their heads and emit anal droplets. Analysis of the flies' behavior, the hydrocarbons in males' anal droplets, and males' cuticular hydrocarbons suggest that females' responses to males may be mediated by cuticular pheromones and/or pheromones in males' extruded droplets that enable the females to distinguish conspecific from heterospeciflc males. Conversely, perception of cuticular hydrocarbons from conspecific females enables D. adiastola males to distinguish females from a closely related species from conspecific females. On the basis of these observations, we suggest that the adiastola subgroup species are unique among drosophilids in that they utilize an anal droplet-mediated pheromone communication system, some or all components of which are species specific. However, the lekking Hawaiian Drosophila species are similar to D. melanogaster and related continental species in that the Hawaiian flies employ a cuticular pheromone communication system, some components of which are sex and species-specific. PMID- 28564909 TI - MODERN AND HISTORICAL EVIDENCE FOR NATURAL HYBRIDIZATION BETWEEN SYMPATRIC SPECIES IN MANDARINA (PULMONATA: CAMAENIDAE). AB - Geographical and temporal variation in gene exchange between two endemic land snail species, Mandarina aureola and Mandarina ponderosa, was studied on Hahajima Island of the Bonin Islands. Allozyme variation in modern samples, and variation in the color and shell morphology of modern and fossil samples, suggest a complex geographical and historical pattern of hybridization. These two species occur in sympatry, and their shell morphologies and protein genotypes are markedly divergent. However, many specimens of M. aureola, collected from the middle region of the island, exhibit intermediate shell morphologies and possess marker alleles of M. ponderosa. Fossil samples of the two species strongly suggest that these intermediates were hybrids with M. ponderosa that were produced since the end of the Pleistocene. Each of these species, in addition, is subdivided into two genetically and morphologically divergent parapatric races. Interspecific hybridization appears to have produced genetical and morphological admixture among these four distinctive groups of populations. The past distribution and geographic variation of M. ponderosa can be traced in the distribution of M. ponderosa-derived genotypes in current populations of M. aureola. Temporal changes of the color pattern in the fossil populations of hybrids suggest that the traits introduced from M. ponderosa to M. aureola have been affected by natural selection and could replace traits of living species when advantageous. Moreover, these introgressed genes appeared to provide novel properties that enabled M. aureola to advance into a new environment. Relatively independent change in shell color and morphology further suggests mosaic evolution following the hybridization events. Connectively, these data reveal how hybridization events may be an important source of evolutionary novelties and make it clear that the phenomenon of reticulate evolution cannot be ignored. PMID- 28564910 TI - LONG-TERM COST OF REPRODUCTION WITH AND WITHOUT ACCELERATED SENESCENCE IN CALLOSOBRUCHUS MACULATUS: ANALYSIS OF AGE-SPECIFIC MORTALITY. AB - Age-specific mortality is measured to characterize the costs of reproduction in the beetle Callosobruchus maculatus, providing explicit details of the timing, duration, magnitude, and acceleration of mortality. We experimentally manipulated reproductive effort in four cohorts of 200 individually housed females by controlling exposure to males and to an artificial oviposition substrate. We demonstrate that (1) early reproduction produces long-term increases in age specific mortality; (2) egg-laying effort affects the onset of age-specific mortality but not its shape or rate of change; and (3) mating with subsequent reproduction increases the rate of change in age-specific mortality relative to virgins. Accelerated senescence is defined demographically as an increase in the rate of change of age-specific mortality. Our results challenge the hypothesis that reproductive effort accelerates senescence but provides evidence that mating itself may have this effect. PMID- 28564912 TI - AN UNUSUAL PATTERN OF GENE FLOW BETWEEN THE TWO SOCIAL FORMS OF THE FIRE ANT SOLENOPSIS INVICTA. AB - Uncertainty over the role of shifts in social behavior in the process of speciation in social insects has stimulated interest in determining the extent of gene flow between conspecific populations differing in colony social organization. Allele and genotype frequencies at 12 neutral polymorphic protein markers, as well as the numbers of alleles at the sex-determining locus (loci), are shown here to be consistent with significant ongoing gene flow between two geographically adjacent populations of Solenopsis invicta that differ in colony queen number. Data from a thirteenth protein marker that is under strong differential selection in the two social forms confirm that such gene flow occurs. Data from this selected locus, combined with knowledge of the reproductive biology of the two social forms, further suggest that interform gene flow is largely unidirectional and mediated through males only. This unusual pattern of gene flow results from the influence of the unique social enviroments of the two forms on the behavior of workers and on the reproductive physiology of sexuals. PMID- 28564913 TI - EFFECTS OF THIRTY YEARS HYBRIDIZATION ON THE TOADS BUFO AMERICANUS AND BUFO WOODHOUSII FOWLERI AT BLOOMINGTON, INDIANA. PMID- 28564914 TI - DEWLAP COLOR VARIATION AND ELECTROPHORETICALLY DETECTED SIBLING SPECIES IN A HAITIAN LIZARD, ANOLIS BREVIROSTRIS. PMID- 28564915 TI - FERTILITY GENES IN NATURAL POPULATIONS OF DROSOPHILA MELANOGASTER. III. SUPERIORITY OF INVERSION HETEROZYGOTES. PMID- 28564916 TI - CLARKIA RUBICUNDA: A MODEL OF PLANT EVOLUTION IN SEMIARID REGIONS. PMID- 28564917 TI - THE AGE STRUCTURE OF A HYBRID SWARM IN LIATRIS (COMPOSITAE). PMID- 28564918 TI - A FURTHER ANALYSIS OF BUMPUS' DATA: THE INTENSITY OF NATURAL SELECTION. PMID- 28564919 TI - INTERACTION EFFECTS OF TEMPERATURE AND HUMIDITY ON PUPAL SURVIVAL IN DROSOPHILA MELANICA. PMID- 28564920 TI - PHYLOGENETIC SIGNIFICANCE OF POLLEN NUCLEAR NUMBER IN THE EUPHORBIACEAE. PMID- 28564921 TI - ADAPTIVE COLOR POLYMORPHISM IN CRICKET FROGS. PMID- 28564922 TI - ON THE ETHOLOGICAL DIFFERENTIATION OF DROSOPHILA ANANASSAE AND DROSOPHILA PALLIDOSA IN SAMOA. PMID- 28564923 TI - ENVIRONMENTAL CONTROL OF SEASONAL VARIATION IN THE BUTTERFLY COLIAS EURYTHEME. I. ADAPTIVE ASPECTS OF A PHOTOPERIODIC RESPONSE. PMID- 28564924 TI - ADAPTIVE CHROMOSOMAL POLYMORPHISM IN DROSOPHILA MELANICA. PMID- 28564925 TI - A MODEL RELATING DEVELOPMENTAL INTERACTION AND DIFFERENTIAL EVOLUTIONARY REDUCTION OF TOOTH SIZE. PMID- 28564926 TI - BARRIERS TO HYBRIDIZATION BETWEEN THE HOUSE FLY, MUSCA DOMESTICA L., AND THE FACE FLY, M. AUTUMNALIS DE GEER (DIPTERA: MUSCIDAE). PMID- 28564927 TI - CHROMOSOMAL, ELECTROPHORETIC, AND BREEDING STUDIES OF SELECTED POPULATIONS OF DEER MICE (PEROMYSCUS MANICULATUS) AND BLACK-EARED MICE (P. MELANOTIS). PMID- 28564928 TI - STUDIES OF LINKAGE IN POPULATIONS. VII. TEMPORAL VARIATION AND X-CHROMOSOMAL LINKAGE DISEQUILIBRIUMS. PMID- 28564929 TI - ADAPTIVE VARIATION IN BODY SIZE AND SKELETAL PROPORTIONS OF HORNED LARKS OF THE SOUTHWESTERN UNITED STATES. PMID- 28564930 TI - EXTRAPOLATION OF THE PREDOMESTICATED HEXAPLOID CULTIVATED OATS. PMID- 28564931 TI - GENETIC VARIABILITY IN NATURAL POPULATIONS OF SOFTCHESS (BROMUS MOLLIS L.). PMID- 28564932 TI - THE REPRODUCTIVE BEHAVIOR AND THE NATURE OF SEXUAL SELECTION IN SCATOPHAGA STERCORARIA L. (DIPTERA: SCATOPHAGIDAE). VII. THE ORIGIN AND EVOLUTION OF THE PASSIVE PHASE. PMID- 28564934 TI - IMPORTANT NOTICE. PMID- 28564933 TI - REPRODUCTIVE ISOLATION IN STEGOMYIA MOSQUITOES. II. HYBRID BREAKDOWN BETWEEN AEDES AEGYPTI AND A. MASCARENSIS. PMID- 28564935 TI - A NEW PENTAPLOID MEXICAN WILD POTATO AND ITS PROGENY. PMID- 28564936 TI - EVOLUTION OF PAIR COOPERATION IN A TROPICAL HUMMINGBIRD. PMID- 28564937 TI - HOST SPECIFICITY OF FIG WASPS (AGAONIDAE). PMID- 28564938 TI - THE GENETICS OF DACUS OLEAE. IV. RELATION BETWEEN ADULT ESTERASE GENOTYPES AND SURVIVAL TO ORGANOPHOSPHATE INSECTICIDES. PMID- 28564939 TI - EXTRACHROMOSOMAL ELEMENT DELTA IN DROSOPHILA MELANOGASTER. IV. VARIATION AND PERSISTENCE OF DELTA-ASSOCIATING SECOND CHROMOSOMES IN A NATURAL POPULATION. PMID- 28564940 TI - ON THE RELATIONSHIP BETWEEN VARIATION AND CONSERVATISM. PMID- 28564941 TI - CYTOPLASMIC STERILITIES THAT SEPARATE THE CULTIVATED POTATO FROM ITS PUTATIVE DIPLOID ANCESTORS. PMID- 28564942 TI - ON ECOTYPIC VARIATION IN BIRDS. PMID- 28564943 TI - CYTOGENETIC RELATIONSHIPS OF KEY DIPLOID MEMBERS OF THE MIMULUS GLABRATUS COMPLEX (SCROPHULARIACEAE). PMID- 28564944 TI - MEASUREMENTS BY DNA RENATURATION OF THE GENETIC BASIS OF PARASITIC REDUCTION. PMID- 28564945 TI - RESPIRATION IN EARLY TETRAPODS-THE FROG IS A RED HERRING. PMID- 28564946 TI - COMMENT ON: "A POSSIBLE EVOLUTIONARY BASIS FOR AESTHETIC APPRECIATION IN MEN AND APES". PMID- 28564947 TI - EVOLUTION OF DIOECY FROM GYNODIOECY. PMID- 28564948 TI - THE DISTRIBUTION OF GENE FREQUENCIES IN POLYMORPHIC POPULATIONS OF DROSOPHILA MELANOGASTER. PMID- 28564950 TI - MICROEVOLUTIONARY SEQUENCES AS A FUNDAMENTAL CONCEPT IN MACROEVOLUTIONARY MODELS. PMID- 28564949 TI - DISTRIBUTION, ADAPTATION AND PROBABLE ORIGIN OF AN ALL-FEMALE FORM OF POECILIOPSIS (PISCES: POECILIIDAE) IN NORTHWESTERN MEXICO. PMID- 28564951 TI - CYTOGENETICS, DISTRIBUTION, AND AMPHITROPICAL AFFINITIES OF SOUTH AMERICAN CAMISSONIA (ONAGRACEAE). PMID- 28564952 TI - EVOLUTIONARY ADAPTATION TO TEMPERATURE. I. FITNESS RESPONSES OF ESCHERICHIA COLI TO CHANGES IN ITS THERMAL ENVIRONMENT. AB - We used bacteria to study experimentally the process of genetic adaptation to environmental temperature. Replicate lines of Escherichia coli, founded from a common ancestor, were propagated for 2,000 generations in 4 different thermal regimes as 4 experimental groups: constant 32, 37, or 42 degrees C (thermal specialists), or a daily alternation between 32 and 42 degrees C (32/42 degrees C: thermal generalists). The ancestor had previously been propagated at 37 degrees C for 2,000 generations. Adaptation of the groups to temperature was measured by improvement in fitness relative to the ancestor, as estimated by competition experiments. All four experimental groups showed improved relative fitness in their own thermal environment (direct response of fitness). However, rates of fitness improvement varied greatly among temperature groups. The 42 degrees C group responded most rapidly and extensively, followed by the 32 and 32/42 degrees C groups, whose fitness improvements were indistinguishable. The 37 degrees C group, which experienced the ancestral temperature, had the slowest and least extensive fitness improvement. The correlated fitness responses of each group, again relative to the common ancestor, were measured over the entire experimental range of temperatures. No necessary tradeoff between direct and correlated responses of fitness was apparent: for example, the improved fitness of the 42 degrees C group at 42 degrees C was not accompanied by a loss of fitness at 37 degrees C or 32 degrees C. However, the direct fitness responses were usually greater than the correlated responses, judged both by comparing direct and correlated responses of a single group at different temperatures and by comparing direct and correlated responses of different groups at a single temperature. These comparisons indicate that the observed adaptation was, in fact, largely temperature specific. Also, the fitness responses of the generalist group across a range of temperatures were less variable than those of the thermal specialist groups considered as whole. PMID- 28564953 TI - mtDNA PHYLOGENY OF ANDEAN MICE: A TEST OF DIVERSIFICATION ACROSS ECOLOGICAL GRADIENTS. AB - Parapatric speciation across sharp ecological gradients is an alternative to the more usual allopatric model as both a general explanation of organismal diversification and as an explicit statement regarding differentiation of tropical forest biotas (Endler, 1977, 1982a, 1982b). The relevance of this model to species of small mammals distributed across a 3,000 meter gradient on the eastern flank of the Peruvian Andes is examined here by phylogenetic analysis of comparative mitochondrial DNA sequences, relying on both freshly collected samples and extracts taken from skins preserved in museum collections. These analyses falsify the applicability of the gradient model in this case. Moreover, the phylogenetic approach employed here provides an explicit test of the feasibility of the gradient model for any other taxon, either plant or animal, of the lowland Amazonian forest. PMID- 28564954 TI - THE EVOLUTION OF REPRODUCTIVE EFFORT IN LIZARDS AND SNAKES. AB - Life history theory suggests that the optimal evolved level of reproductive effort (RE) for an organism depends upon the degree to which additional current reproductive investment reduces future reproductive output. Future reproduction can be decreased in two ways, through (i) decreases in the organism's survival rate, and/or (ii) decreases in the organism's growth (and hence subsequent fecundity). The latter tradeoff-that is, the "potential fecundity cost"-should affect the evolution of RE only in species with relatively high survival rate, a relatively high rate of fecundity increase with body size, or a relatively high reproductive frequency per annum. Unless these conditions are met, the probable benefit in future fecundity obtained from decreasing present reproductive output is too low for natural selection to favor any reduction in RE below the maximum physiologically possible. Published data on survival rate, reproductive frequency and relative clutch mass (RCM) suggest that many lizard species fall well below the level at which natural selection can be expected to influence RE through such "potential fecundity" tradeoffs. Hence, the relative allocation of resources between growth and reproduction is unlikely to be directly optimized by natural selection in these animals. Instead, energy allocation should influence the evolution of RE only indirectly, via effects on an organism's probability of survival during reproduction. Survival costs of reproduction may be the most important evolutionary determinants of RE in many reptiles, and information on the nature and extent of such costs is needed before valid measures of reptilian RE can be constructed. PMID- 28564955 TI - GENETIC AND ENVIRONMENTAL VARIATION IN FLORAL TRAITS AFFECTING OUTCROSSING RATE IN CLARKIA TEMBLORIENSIS (ONAGRACEAE). AB - Clarkia tembloriensis exhibits a wide range of variation among its natural populations in outcrossing rate and in separation of male and female function in space (anther-stigma separation or herkogamy) and in time (protandry). Here we show that outcrossing rate is highly correlated with protandry and anther-stigma separation. Both genetic and environmental variation contribute to inter- and intrapopulation variation in protandry and anther-stigma separation. Interpopulation differentiation for protandry and anther-stigma separation was found to be polygenic. Genetic variation for protandry and anther-stigma separation within populations was demonstrated by a significant among-family variance in two populations with contrasting breeding systems. Environmental effects on the expression of mating system traits were manifested in two ways. First, significant variation among lathhouse benches suggests that small-scale environmental heterogeneity may affect the development of floral traits. Second, protandry was shortened under hot summer conditions. Hence, hotter and drier habitats, typical of the more self-pollinating populations of C. tembloriensis, can promote self-pollination purely through environmental effects. PMID- 28564956 TI - GENETIC STRUCTURE OF MORPHOLOGICALLY DIFFERENTIATED POPULATIONS OF THE AMPHIPOD GAMMARUS MINUS. PMID- 28564957 TI - SEASONAL DECLINES IN OFFSPRING FITNESS AND SELECTION FOR EARLY REPRODUCTION IN NYMPH-OVERWINTERING GRASSHOPPERS. AB - In this study, I examine the effects of natural and experimentally induced variation in life cycle timing on offspring fitness in Arphia sulphurea and Chortophaga viridifasciata, to understand the selective pressures shaping phenology in these two species of nymph-overwintering grasshoppers. Because these species lack embryonic diapause, hatching varies over a two month range under natural conditions. I used a cold treatment to delay hatching of some egg pods and extend the natural range of hatching dates. Due to the shorter time for growth and poorer growing conditions late in the fall, late-hatching nymphs of both species grew to a smaller size before winter and suffered higher overwinter mortality, compared to early nymphs. In addition, late nymphs that did survive the winter became reproductive later in the following year's breeding season. Size- dependent mortality of offspring during the winter is a strong selective pressure favoring early reproduction in these species. Female adult life history traits appear responsive to the seasonal declines in offspring fitness, in that late-maturing females began reproducing sooner after adult maturation and reproduced at a more rapid rate, even at the expense of having shorter adult longevity and producing fewer total egg pods. Experimental manipulations were crucial in understanding the fitness consequences of intrapopulation variation in the timing of specific life-cycle events for these species. PMID- 28564958 TI - EVOLUTION OF beta-GLUCURONIDASE REGULATION IN THE GENUS MUS. AB - Despite the central role suggested for regulatory mutations in many evolutionary scenarios, there is relatively little information available about the type and extent of regulatory differences between species, or to what extent differences between species are independent of variation within species. To address this issue we have studied the regulatory system of beta-glucuronidase, a gene implicated in a murine androgen-inducible pheromone-signalling system. We examined the changes in beta-glucuronidase hormonal regulation which have occurred during the radiation of a group of 12 closely related species of mice by assaying beta-glucuronidase activity in six different tissues after treatment with estrogen, and with androgen alone and in combination with either estrogen or growth hormone. We also examined in some detail the extent of variation in regulatory responses within species. We found extensive variation in regulatory phenotypes both within and among the species surveyed, suggesting that many of the species examined are currently polymorphic for various regulatory factors that affect inducibility of beta-glucuronidase. The variation we observed reflects changes in the ability of the beta-glucuronidase gene to respond to hormonal influences, rather than changes in aspects of the hormonal signalling system exterior to the gene. The marked differences among species in the renal and uterine responses to hormonal induction of beta-glucuronidase are not easily related to the phylogeny of the genus Mus. If hormonal induction of the gene for beta-glucuronidase is subject to natural selection, it appears to be subject to widely fluctuating selective forces. We review evidence that the apparently disorderly evolution of the hormonal responsiveness of beta-glucuronidase does not appear to be a unique property of this regulatory system. In contrast to the evolution of many protein sequences, which are tightly correlated with phylogeny and proceed at a relatively constant rate, some, perhaps many, regulatory phenotypes are in rapid evolutionary flux, providing an extensive range of phenotypes upon which selection can act. PMID- 28564959 TI - PHYLOGENIES FROM RESTRICTION SITES: A MAXIMUM-LIKELIHOOD APPROACH. AB - Restriction sites data can be analyzed by maximum likelihood to obtain estimates of phylogenies. The likelihood methods of Smouse and Li, who were able to compute likelihoods for up to four species under a simplified model of base change, can be extended numerically to deal with any number of species. The computational methods for doing so are outlined. The resulting algorithms are slow but take multiple gains and losses of restriction sites fully into account, unlike parsimony methods. They allow for the failure to observe potential sites that are absent from all species. Analysis of the five-species hominoid data of Ferris and coworkers confirms the pattern found by Smouse and Li with four species-that a chimpanzee-gorilla clade is favored, but not statistically significantly over other tree topologies. A large data set produced by computer simulation has also been analyzed to confirm that the method works properly. The methods used here do not allow for different rates of transitions and transversions. They can be extended to do so, but only at a cost of considerably slower computations. The present method is available in a computer program. PMID- 28564960 TI - HYBRID ZONES AND HOST-PARASITE RELATIONSHIPS: EFFECT ON THE EVOLUTION OF PARASITIC SPECIFICITY. AB - In southern France, Diplozoon gracile (Monogenea, Polyopisthocotylea), parasitizes four sympatric cyprinids. One of these host species, Barbus meridionalis, naturally hybridizes with another species of barbel, Barbus barbus, which is never parasitized by D. gracile under natural conditions. This hybridization has previously been studied and described as an introgression of B. barbus by B. meridionalis. The hybrids are parasitized by D. gracile, and parasite prevalence increases in proportion to the introgression rate, i.e., the percentage of B. meridionalis genes. The causes for this preferential distribution of the parasite in the hybrid population are analysed on the basis of ecological and ethological differences between the two parent species. PMID- 28564961 TI - GENETIC EVIDENCE FOR MULTIPLE ORIGINS OF DIOECY IN THE HAWAIIAN SHRUB WIKSTROEMIA (THYMELAEACEAE). AB - Dioecy is unusually common in the Hawaiian Islands, yet little is known about the evolutionary biology of this breeding system. A native shrub, Wikstroemia, has an unusually diverse array of breeding systems: two forms of dioecy, cryptic and morphological dioecy, as well as hermaphroditism (perfect flowers). The existence of two forms of dioecy is significant for three reasons: 1) the presence of cryptic unisexuals that are functionally unisexual, but retain the appearance of hermaphroditism in both sexes, is strong evidence for the ancestral status of hermaphroditism; 2) the production of nonfunctional pollen, by female cryptic unisexuals, is a new instance of a phenomenon which has previously been reported for a few other species; 3) the two forms of dioecy are morphological markers which are useful in hybridization studies for tracing the genetic basis of their inheritance. Crosses were made between cryptically unisexual individuals (C), between morphologically unisexual individuals (M), and between the two types of unisexuality. The offspring of crosses between individuals with the same sex type usually resulted in offspring with that sex type, but most of the progeny of between-sex type crosses were, unexpectedly, perfect-flowered hermaphrodites. These results show that genetic control of sex determination is not homologous in all populations, suggesting that dioecy has evolved at least twice in Hawaiian Wikstroemia. The genetic data further suggest that males are the heterozygous sex. PMID- 28564962 TI - GENETIC STRUCTURE OF THICK-BILLED MURRE (URIA LOMVIA) POPULATIONS EXAMINED USING DIRECT SEQUENCE ANALYSIS OF AMPLIFIED DNA. PMID- 28564963 TI - LIFE-CYCLE COMPONENTS OF SELECTION IN ERIGERON ANNUUS: II. GENETIC VARIATION. AB - Genetic variation for seedling and adult fitness components was measured under natural conditions to determine the relative importance of the seedling stage for lifetime fitness in Erigeron annuus. Variation in lifetime reproductive success can result from both the persistent effects of genetic variation expressed among seedlings and from variation in adult fitness components. Analysis of covariance was used to separate the stage specific from the cumulative effects of genetic variance expressed earlier in the life cycle. E. annuus produces seeds through apomixis, which allowed measurement of the fitness of replicate genotypes from germination through the entire life cycle. There were significant differences among genotypes for date of emergence, seedling size, survivorship and fecundity, but heritabilities were low, indicating slow response to selection. For all characters, environmental components of variance were one to two orders of magnitude larger than genetic variance components, resulting in broad sense heritabilities less than 0.1. For seedling size and fecundity, all of the genetic variance was in the form of genotype-environment interactions, often with large negative genetic correlations across environments. In contrast, genotypes differed in mean survivorship through one year, but there were no genotype environment interactions for viability. Genetic differences in viability were primarily expressed as differences in overwinter survivorship. Genotype * environment interactions among sites and blocks were generated early in the life cycle while the genotype * environment interactions in response to competitive environment (open, annual cover, perennial cover) first appeared in adult fecundity. Genetic variation in lifetime fitness was not significant, despite a fourfold difference in mean fitness among genotypes. PMID- 28564964 TI - ASSOCIATION BETWEEN LATITUDINAL VARIATION FOR EMBRYONIC DEVELOPMENT TIME AND CHROMOSOME STRUCTURE IN THE GRASSHOPPER CALEDIA CAPTIVA (ORTHOPTERA: ACRIDIDAE). AB - From southeastern Queensland to southern Victoria, over a transect of 11 degrees latitude, the Moreton taxon of the Australian grasshopper Caledia captiva exhibits a cline in chromosome structure that involves change from a metacentric to an acrocentric genome. In this study, we show that embryonic development time covaries with chromosome structure along the transect. Both development time and chromosome short arm length exhibit an overall negative correlation with latitude, but with maxima just south of the northern limit of the taxon's distribution. Selection for such a pattern appears to arise from changes in voltinism along the cline in season length that exists along the transect. Populations with the highest temperature thresholds for avoidance of embryonic diapause also have the slowest development time and probably represent the northern extreme of a primarily univoltine life cycle. North of this region bivoltinism increases in frequency and, as expected from a split of the season length, development time decreases. Maximum chromosome short arm length occurs in the vicinity of the northern univoltine populations, rather than at the limit of distribution where bivoltinism prevails. We conclude that variation in chromosome structure could be contributing to the heritable variation for development time that forms the basis for adaptive change in this trait. These results provide justification for investigating causal relationships between chromosome structure and development time, with an ultimate aim of understanding the adaptive significance of chromosomal variation in C. captiva. PMID- 28564965 TI - MEASURING EVOLUTIONARY CONSTRAINTS: A MARKOV MODEL FOR PHYLOGENETIC TRANSITIONS AMONG SEED DISPERSAL SYNDROMES. AB - I introduce a Markov probabilistic model of transitions among discrete morphological states as a method for describing and testing nonrandom patterns of evolutionary change. The Markov model assumes one-generational dependency, i.e., that the future direction of evolutionary change depends on the current morphology of a species, not on any history of changes. This model is very flexible, allowing for any number of discrete states to describe morphology, yet permit rigorous testing of even complex evolutionary hypotheses. I apply this model to changes in seed dispersal mechanisms within 571 genera of Neotropical plants, using cladistic methods to infer the ancestral and derived states within each genus. I then test a series of progressively more complex hypotheses about the constraints that might shape the patterns of observed evolutionary transitions: 1) no transition constraints; 2) all dispersal mechanisms are equally labile evolutionarily; 3) the probability of particular evolutionary transitions among dispersal mechanisms depends on the descendant state but not on the ancestral state; 4) transition probabilities differ among pairs of dispersal mechanisms, but are reciprocal within such pairs. More complex hypotheses matched the data significantly better than did simpler hypotheses. However, only one of the hypotheses (reciprocal transitions) fit the observed data and then only for the most cautious interpretation of the frequencies of transitions within genera. These results suggest that evolutionary transitions among major adaptive syndromes are indeed ordered, and the observed patterns of transitions suggest possible reasons for such macroevolutionary structure. PMID- 28564966 TI - EXPERIMENTAL STUDIES ON THE FUNCTIONAL SIGNIFICANCE OF HETEROSTYLY. AB - Heterostyly has been viewed as both an antiselfing device and a mechanism that increases the proficiency of pollen transfer between plants. We used experimental manipulation of the morph structure of garden populations of self-compatible, tristylous Eichhornia paniculata to investigate the function of floral polymorphism. Outcrossing rates (t), levels of intermorph mating (d), and morph specific male and female reproductive success were compared in replicate trimorphic and monomorphic populations. In trimorphic populations, t and d averaged 0.81 (2 SE = 0.03) and 0.77 (2 SE = 0.03) respectively, with no difference in either parameter among morphs. Ninety-five percent of outcrossed seeds were therefore the result of intermorph fertilizations. Male reproductive success of the long-styled morph was low, especially in comparison with plants of the short-styled morph. Outcrossing rates for each morph were higher in trimorphic than monomorphic populations where t averaged 0.71 (2 SE = 0.01), 0.30 (2 SE = 0.04) and 0.43 (2 SE = 0.1) for the long-, mid-, and short-styled morphs, respectively. Seed set was lower in monomorphic populations, particularly those composed of the L morph, reflecting reduced pollen deposition. Floral polymorphism therefore increased both outcrossing rate and fecundity but the magnitude of the differences varied among morphs. If the ancestral condition in heterostylous groups resembled the L morph, as has been suggested, data from this study suggests that the selective basis for the establishment of floral polymorphism could have been increased pollen transfer rather than higher levels of outcrossing. PMID- 28564967 TI - MITOCHONDRIAL DNA VARIATION AND EVOLUTION OF THE DEATH VALLEY PUPFISHES (CYPRINODON, CYPRINODONTIDAE). AB - A phylogenetic analysis of mitochondrial DNA (mtDNA) restriction sites was used to examine the geographic history of the Cyprinodon nevadensis complex of pupfishes, a group of four species (seven extant subspp.) in two endorheic (closed) basins of the Death Valley System in California and Nevada (Owens River Valley and Ash Meadows-Death Valley). The mtDNA results suggest that the group contains mtDNAs from two divergent clades. One such clade is represented by the mtDNAs of the Owens Valley pupfish (C. radiosus) and the existing species in the Colorado River (C. macularius), while the other includes the mtDNAs of the Ash Meadows-Death Valley species (C. nevadensis, C. salinus, and C. diabolis) and a species located much farther to the east (C. fontinalis from the Guzman Basin, Chihuahua, Mexico). These results, together with evidence from other studies, suggest two separate invasions of the Death Valley System by pupfishes carrying phylogenetically divergent mtDNAs. The C. nevadensis complex apparently is either an artificial group or else it is monophyletic and its genetic history includes loss of the original mtDNA in either Owens Valley or Ash Meadows-Death Valley following genetic introgression after an invasion by a pupfish carrying a divergent mtDNA. PMID- 28564968 TI - POLLINATION SYSTEMS, DISPERSAL MODES, LIFE FORMS, AND DIVERSIFICATION RATES IN ANGIOSPERM FAMILIES. PMID- 28564969 TI - LIFE-CYCLE COMPONENTS OF SELECTION IN ERIGERON ANNUUS: I. PHENOTYPIC SELECTION. AB - The magnitude and direction of phenotypic selection on emergence date and seedling size in Erigeron annuus was measured to determine the heterogeneity of selection among sites and the proportion of fitness variance explained by seedling size and emergence date. Three disturbance treatments (open, annual vegetation, perennial vegetation) were imposed to test the hypothesis of stronger selection on seedlings in competitive environments. Selection was most heterogeneous early in the life cycle, with significant spatial heterogeneity in the magnitude of selection on a local scale. The disturbance treatments affected only fecundity selection gradients and selection was strongest in open plots. Significant variation in the sign of selection differentials on emergence date was observed for establishment and fall viability selection episodes; at later stages selection varied in magnitude but not direction. Seedlings in the earliest cohort experienced high mortality during establishment, but increased size and fecundity later in the life cycle. Both stabilizing and disruptive selection on emergence date were observed during establishment, but in general selection was purely directional. At Stony Brook most selection on emergence date operated indirectly through seedling size, whereas at the Weld Preserve direct selection was stronger. There were persistent effects of both seedling emergence date and rosette diameter on adult fitness components, and October rosette diameter explained 18% of the total phenotypic variance in fecundity. Overall, viability fitness components were much more important than fecundity selection. Winter survivorship was the single most important episode of selection. PMID- 28564970 TI - GENETIC AND SOCIAL INHERITANCE OF BODY AND EGG SIZE IN THE BARNACLE GOOSE (BRANTA LEUCOPSIS). AB - We present heritability estimates for final size of body traits and egg size as well as phenotypic and genetic correlations between body and egg traits in a recently established population of the barnacle goose (Branta leucopsis) in the Baltic area. Body traits as well as egg size were heritable and, hence, could respond evolutionarily to phenotypic selection. Genetic correlations between body size traits were significantly positive and of similar magnitude or higher than the corresponding phenotypic correlations. Heritability estimates for tarsus length obtained from full-sib analyses were higher than those obtained from midoffspring-midparent regressions, and this indicates common environment effects on siblings. Heritabilities for tarsus length obtained from midoffspring-mother regressions were significantly higher than estimates from midoffspring-father regressions. The results suggest that this discrepancy is not caused by maternal effects through egg size, nor by extra-pair fertilizations, but by a socially inherited foraging site fidelity in females. PMID- 28564971 TI - THE ROLE OF COURTSHIP SONGS IN REPRODUCTIVE ISOLATION AMONG POPULATIONS OF GREEN LACEWINGS OF THE GENUS CHRYSOPERLA (NEUROPTERA: CHRYSOPIDAE). AB - Male and female lacewings tremulate during courtship, establishing duets that always precede copulation. Three distinct courtship songs are found in populations of the green lacewing Chrysoperla plorabunda (P1, P2 and P3 song morphs). Analysis of five features of the songs for individuals collected from Connecticut, Idaho, Oregon and California showed few differences within song morphs, but sympatric song morphs differed significantly in temporal features of the songs and their mode of presentation. Playback experiments using recorded songs were performed on females with all possible sympatric and allopatric combinations of females and recorded songs. The results showed that females strongly prefer to duet with recordings of males of their own song type and usually showed no responses to songs of other types. Thus, song differences are effective barriers to reproduction between the sympatric morphs. Our results support the hypothesis that the three song morphs are true biological species. PMID- 28564972 TI - MITOCHONDRIAL DNA ANALYSES AND THE ORIGIN AND RELATIVE AGE OF PARTHENOGENETIC CNEMIDOPHORUS: PHYLOGENETIC CONSTRAINTS ON HYBRID ORIGINS. AB - Within the genus Cnemidophorus, parthenogenesis has arisen by hybridization several times. This provides the opportunity to investigate general features of hybridization events that result in the formation of parthenogenetic lineages. The relationships of mtDNA from all bisexual species of Cnemidophorus known to be parents of parthenogens were investigated to evaluate phylogenetic constraints on the hybrid-origin of parthenogenesis. No phylogenetic clustering of the parental species, either maternal or paternal, was apparent. However, the combination of bisexual species that have resulted in parthenogenetic lineages are generally distantly related or genetically divergent. This contrasts with the expectation if parthenogenesis in hybrids is due to the action of a single rare allele, but is consistent with the hypothesis that some minimal level of divergence is necessary to stimulate parthenogenetic reproduction in hybrids. PMID- 28564974 TI - QUANTITATIVE GENETICS OF SEXUAL DIMORPHISM IN HUMAN BODY SIZE. AB - A classical data set is used to predict the effect of selection on sexual dimorphism and on the population means of three characters-stature, span, and cubit-in humans. Given selection of equal intensity, the population means of stature and of cubit should respond more than 60 times as fast as dimorphism in these characters. The population mean of span should also respond far more rapidly than dimorphism, but no numerical estimate of the ratio of these rates was possible. These results imply that sexual dimorphism in these characters can evolve only very slowly. Consequently, hypotheses about the causes of sexual dimorphism cannot be tested by comparing the dimorphism of different human societies. It has been suggested that primate sexual dimorphism may be an allometric response to selection for larger body size. We show that such selection can indeed generate sexual dimorphism, but that this effect is too weak to account for the observed relationship between dimorphism and body size in primates. PMID- 28564973 TI - DIRECT AND CORRELATED RESPONSES TO SELECTION ON AGE AT REPRODUCTION IN DROSOPHILA MELANOGASTER. AB - Aging may be a consequence of mutation accumulation or of negative pleiotropic correlations between performance late and earlier in the lifespan. This study used artificial selection on flies derived from two different base stocks to produce "young" and "old" lines, propagated by breeding from young and old adults respectively. Virgin and mated adults of both sexes from the "old" lines lived longer than "young" line flies. "Young" and "old" mated females did not differ in fecundity or fertility early in the lifespan, but "old" line females had higher fecundity and fertility late in life. The results therefore suggested either that the response to selection had revealed the effect of mutation accumulation, or that pleiotropy involving characters other than early fecundity must have been involved. Development time from egg to adult was longer in the "old" lines. Competition of selected line larvae from one base stock against mutant marked larvae from the same base stock revealed that, at a wide range of larval densities, "old" line larvae showed lower survival rates than "young" line larvae. Thorax length and wet weight were significantly greater in the "old" line flies from one base stock. The results may imply that the selection regime in the "old" lines favored extended growth during development to produce a more durable adult soma, despite the cost in increased larval mortality and delayed reproduction, because the potential reproductive benefits later in life were increased. However, the differences between larvae from "old" and "young" lines could also be attributable to density differences, and this possibility needs systematic investigation. PMID- 28564975 TI - ON THE MAINTENANCE OF GENETIC VARIATION BY DISRUPTIVE SELECTION AMONG HOSTS IN A PHYTOPHAGOUS MITE. PMID- 28564976 TI - REPRODUCTIVE ISOLATING MECHANISMS IN THE BLUE-WINGED WARBLER - GOLDEN-WINGED WARBLER COMPLEX. PMID- 28564977 TI - TRANSLOCATION HETEROZYGOTES AND SUPERNUMERARY CHROMOSOMES IN WILD POPULATIONS OF CLARKIA WILLIAMSONII. PMID- 28564978 TI - THE ORIGIN OF VERTEBRATE FOETAL MEMBRANES. PMID- 28564979 TI - MONOPHYLY OR DIPHYLY IN THE ORIGIN OF WHALES. PMID- 28564980 TI - LOCAL GENE DISPERSAL IN PHLOX. PMID- 28564981 TI - THE SELECTIVE ADVANTAGE OF TEMPERATURE TOLERANCE AMONG THE PROGENY OF FROGS WITH VERTEBRAL FUSIONS. PMID- 28564982 TI - POLLINATION BY EUGLOSSINE BEES. PMID- 28564983 TI - THE BEGINNINGS OF PRIMATES. PMID- 28564984 TI - A MEASURE OF DISCRIMINATION IN MATING. PMID- 28564985 TI - EVOLUTION OF FITNESS. II. CORRELATED EFFECTS OF NATURAL SELECTION ON THE PRODUCTIVITY AND SIZE OF EXPERIMENTAL POPULATIONS OF DROSOPHILA SERRATA. PMID- 28564986 TI - BREAKDOWN OF POLYMORPHISM OF THE RED-BACKED SALAMANDER ON LONG ISLAND. PMID- 28564988 TI - ORIGIN AND EARLY EVOLUTION OF MARSUPIALS. PMID- 28564987 TI - DEFENSE OF FEEDING AREAS BY ADULT HERRING GULLS AND INTRUSION BY YOUNG. PMID- 28564989 TI - STUDIES ON COMPETITION IN RICE I. COMPETITION IN MIXTURES OF VARIETIES. PMID- 28564990 TI - THE POPULATION BIOLOGY OF THE BUTTERFLY EUPHYDRYAS EDITHA: VI. PHENETICS OF THE JASPER RIDGE COLONY, 1965-66. PMID- 28564991 TI - THE COMPOSITION OF A HYBRIDIZING POPULATION OF BAPTISIA SPHAEROCARPA AND BAPTISIA LEUCOPHAEA. PMID- 28564992 TI - POPULATION GENETICS IN THE AMERICAN TROPICS III. THE GENETIC ROLE OF HETEROZYGOUS INDIVIDUALS IN VARIOUS COLOMBIAN POPULATIONS OF D. MELANOGASTER. PMID- 28564993 TI - THE ROLE OF COMPETITION IN THE EVOLUTION OF MIGRATION. PMID- 28564994 TI - EVOLUTIONARY PROCESSES IN POPULATIONS OF COPPER TOLERANT AGROSTIS TENUIS Sibth. PMID- 28564995 TI - CHROMOSOME NUMBER DIFFERENCE IN THE AMPHIBIAN GENUS BUFO: THE BUFO REGULARIS SPECIES GROUP. PMID- 28564996 TI - INTROGRESSION BETWEEN CLOSELY RELATED SPECIES OF DROSOPHILA IN PANAMA. PMID- 28564997 TI - AN EMPIRICAL TEST OF PREDICTIONS OF TWO COMPETING MODELS FOR THE MAINTENANCE AND FATE OF HYBRID ZONES: BOTH MODELS ARE SUPPORTED IN A HARD-CLAM HYBRID ZONE. AB - Two models developed to discern the mode of selection in hybrid zones differ in some predictions. The tension-zone model predicts that selection acts against hybrids and independently of the environment (endogenous selection) and that selection is invariant throughout the hybrid zone. The ecological selection gradient, or ecotone, model maintains that fitness of different genotypes varies in response to environmental variation (exogenous selection) and thus, that in a region of the zone, fitness of hybrids is at least equal to that of the parental species. Therefore, to assess the predominant mode of selection operating in a hybrid zone, it is fundamental to evaluate whether selection is acting specifically against hybrid individuals, that is, whether hybridity alone is the basis for deficiencies of hybrids, and to evaluate whether the relative fitness of hybrids versus that of pure species varies across the zone. In a hardclam (genus Mercenaria) hybrid zone located in a polyhaline lagoon in east-central Florida, we used age-specific and location-specific analyses to determine that a hybrid deficit occurrs, that the deficit seems to be due to selection against hybrids, and that selection varies across the zone. Various measures of deviation from Hardy-Weinberg equilibrium, linkage disequilibrium analyses, and shifts in allele frequencies at semidiagnostic loci support the idea that selection is strongest in the northern region of the lagoon, the zone of sympatry and hybridization. Southward, into the range of M. mercenaria (the numerically predominant species), the percentage of hybrids remains relatively high and selection against hybrids decreases. For some genetic linkage groups, selection for M. mercenaria alleles seems to be occurring, but selection seems to be acting principally against alleles characteristic of M. mercenaria and, to a lesser degree, for alleles characteristic of M. campechiensis (the rarer species). These findings and others from previous analyses we have done on this hybrid zone demonstrate that selection in the zone is complex, and that characteristics of both the tension-zone and ecotone models are present. Supporting the tension-zone model, selection against hybrids per se clearly occurs, but specific genotypes seem to be at a selective disadvantage, whereas others have a selective advantage, and selection operates differentially on the two parental species within the zone. Supporting the ecotone model, the strength of overall selection varies throughout the zone, and environmentally mediated selection in which each species and hybrids have an advantage in specific habitats occurs, but some selection against hybrids is invariant throughout the zone. Thus, the structure and genetic architecture of this hybrid zone appear to be products of a complicated interaction between both types of selective forces cited in the two competing models. PMID- 28564998 TI - TREE BALANCE AND TREE COMPLETENESS. PMID- 28564999 TI - PHENOTYPIC SELECTION IN AN ARTIFICIAL POPULATION OF IMPATIENS PALLIDA: THE IMPORTANCE OF THE INVISIBLE FRACTION. AB - Multiple-regression techniques for measuring phenotypic selection have been used in a large number of recent field studies. One benefit of this technique is its ability to discern the direct action of selection on traits by removing effects of correlated traits. However, covariation among traits expressed at different stages in an organism's life history is often poorly estimated because individuals that die before reaching adulthood cannot be measured as adults. Accurate estimates of trait covariances are necessary for the correct interpretation of the direct action of selection on a trait. If phenotypic characters expressed at different life-history stages are of interest, and mortality occurs between stages, the components of the selection model will be biased by not including those individuals that died (the "invisible fraction"). PMID- 28565000 TI - NEW PERSPECTIVES ON COMPARATIVE TESTS OF ANTAGONISTIC PLEIOTROPY USING DROSOPHILA. PMID- 28565001 TI - VARIANCE-INDUCED PEAK SHIFTS. AB - The increase in phenotypic variance that occurs in some populations as a result of bottlenecks and founder events can cause a dramatic increase in the probability of a peak shift from one adaptive state to another. Periods of small population size allow drift in the amount of phenotypic variance. Increases in phenotypic variance, coupled with a constant individual fitness function with multiple peaks, can cause the mean fitness landscape to change from bimodal to unimodal, thereby allowing the population's mean phenotype to change deterministically by selection. As the amount of phenotypic variance is returned to an equilibrium state, the multiple peaks reemerge, but the population has moved from one stable state to another. These variance-induced peak shifts allow punctuational evolution from one peak to another at a rate that can be much higher than that predicted by Wright's shifting-balance process alone. PMID- 28565002 TI - MITOCHONDRIAL DNA VARIATION IN THE FUNGUS ATKINSONELLA HYPOXYLON INFECTING SYMPATRIC DANTHONIA GRASSES. AB - The purpose of this study was to determine how host identity and geographic proximity were related to genetic variation in the fungus Atkinsonella hypoxylon infecting four sympatric Danthonia grasses. We analyzed 192 A. hypoxylon isolates from 48 geographic sites for mitochondrial DNA (mtDNA) variation by restriction digestion of total DNA with EcoRI, BamHI, and PstI, and subsequent hybridization with purified A. hypoxylon mtDNA. Thirtynine haplotypes were identified. UPGMA cluster analysis showed that mtDNA type is highly correlated with host-species group; isolates from Danthonia compressa and D. spicata formed one branch of the phenogram, and isolates from D. epilis and D. sericea formed the other. Restriction maps of the most common mtDNA haplotypes infecting each host-species pair revealed a 30-kb size difference and a minimum of eight length changes and one restrictionsite change between them. Mapping of the mutation differences among all haplotypes occurring at North Carolina sites resulted in two distinct gene trees corresponding to the two Danthonia species groups, corroborating the phenetic analysis. The results indicate a high degree of host-dependent isolation and establish the existence of host races in A. hypoxylon. Possible mechanisms responsible for this isolation are discussed. Little differentiation existed between isolates from within a Danthonia species pair, and some variation was explained by geographic origin. Analysis of progeny from a natural sexual cross revealed that mitochondria are maternally inherited in A. hypoxylon. PMID- 28565003 TI - PROBABILISTIC OPTIMIZATION OF BODY SIZE: A DISCREPANCY BETWEEN GENETIC AND PHENOTYPIC OPTIMA. PMID- 28565004 TI - LIFETIME ESTIMATES OF BIPARENTAL INBREEDING DEPRESSION IN THE SELF-INCOMPATIBLE ANNUAL PLANT RAPHANUS SATIVUS. AB - Studies of inbreeding depression in plant populations have focused primarily on comparisons of selfing versus outcrossing in self-compatible species. Here we examine the effect of five naturally occurring levels of inbreeding (f ranging from 0 to 0.25 by pedigree) on components of lifetime fitness in a field population of the self-incompatible annual, Raphanus sativus. Pre- and postgermination survival and reproductive success were examined for offspring resulting from compatible cross-pollinations. Multiple linear regression of inbreeding level on rates of fruit and seed abortion as well as seed weight and total seed weight per fruit were not significant. Inbreeding level was not found to affect seed germination, offspring survival in the field, date of first flowering, or plant biomass (dry weight minus fruit). The effect of inbreeding on seedling viability in the greenhouse and viability to flowering was significant but small and inconsistently correlated with inbreeding level. Maternal fecundity, however, a measure of seed yield, was reduced almost 60% in offspring from full-sib crosses (f = 0.25) relative to offspring resulting from experimental outcross pollinations (f = 0). Water availability, a form of physiological stress, affected plant biomass but did not affect maternal fecundity, nor did it interact with inbreeding level to influence these characters. The delayed expression of strong inbreeding depression suggests that highly deleterious recessive alleles were not a primary cause of fitness loss with inbreeding. Highly deleterious recessives may have been purged by bottlenecks in population size associated with the introduction of Raphanus and its recent range expansions. In general, reductions in total relative fitness of greater than 50% associated with full-sib crosses should be sufficient to prohibit the evolution of self-compatibility via transmission advantage in Raphanus. PMID- 28565005 TI - ESTIMATING EFFECTIVE POPULATION SIZE: A REPLY TO NUNNEY. PMID- 28565006 TI - PREDICTING MICROEVOLUTIONARY RESPONSES TO DIRECTIONAL SELECTION ON HERITABLE VARIATION. AB - Microevolution of quantitative traits in the wild can be predicted from a knowledge of selection and genetic parameters. Testing the predictions requires measurement of the offspring of the selected group, a requirement that is difficult to meet. We present the results of a study of Darwin's finches on the Galapagos island of Daphne Major where this requirement is met. The study demonstrates microevolutionary consequences of natural selection. PMID- 28565007 TI - REPEATED REVERSALS OF HOST-PREFERENCE EVOLUTION IN A SPECIALIST INSECT HERBIVORE. AB - A tree of mitochondrial DNA (mtDNA) haplotypes was constructed to estimate the number of evolutionary changes of host-plant preference needed to account for variation among 24 populations of the butterfly Euphydryas editha. Using 17 restriction endonucleases, 22 mtDNA haplotypes were found among 24 populations of this butterfly species. We allowed for the possibility of haplotypes to acquire particular preferences either from evolutionary change at their local sites or from migration to populations where those preferences occurred. After we had taken these estimates of migration into account, a minimum of 10 evolutionary changes of host preference (reduced from 22) was needed to explain the pattern of use of five host-plant genera among these populations. Analysis of allozyme variation among a partially overlapping set of populations also suggested multiple host shifts. Although genetic variation of host preference is largely responsible for interpopulation variation of diet, repeated reversals of preference evolution have occurred. However, host preferences were not distributed randomly with respect to phylogeny, and some tendency toward evolutionary conservation of preference also was indicated. The haplotype of E. editha most closely related to the sister species, E. chalcedona, used a principal host of E. chalcedona. Our results suggest that host shifts occur frequently in E. editha, are a result of both migration and local evolution, and have not been associated with speciation in these insects. PMID- 28565008 TI - INBREEDING DEPRESSION IN MORPHOLOGICAL AND PHYSIOLOGICAL TRAITS OF SCHIEDEA LYDGATEI (CARYOPHYLLACEAE) IN TWO ENVIRONMENTS. AB - We compared inbreeding depression in hermaphroditic Schiedea lydgatei and its gynodioecious sister species, S. salicaria, to infer the level of inbreeding depression in their common ancestor. With measurements of selfing rates, this information can be used to assess the importance of inbreeding depression in the evolution of breeding systems in S. lydgatei and S. salicaria. Morphological and physiological characters related to fitness were compared for inbred and outcrossed S. lydgatei in high- and low-fertilizer environments in the greenhouse. Seed mass, number of seeds per capsule, germination, survival, biomass, number of flowers, and age at first flowering were compared for inbred versus outcrossed progeny. We also measured inbreeding depression in maximal rates of photosynthetic carbon assimilation and stomatal conductance to water vapor, traits that affect fitness through their influence on plant carbon balance and water-use efficiency (ratio of carbon gain to water loss). All traits except number of seeds per capsule in parents and survival showed inbreeding depression, with the magnitude depending on family and environment. High inbreeding depression is likely in the ancestor of S. lydgatei and S. salicaria, indicating that, with sufficiently high selfing rates, females could spread in populations. Hermaphroditism in S. lydgatei is probably favored by low selfing rates. In contrast, the evolution of gynodioecy in S. salicaria apparently has been favored by relatively high selfing rates in combination with high inbreeding depression. PMID- 28565009 TI - MEASURING THE RATIO OF EFFECTIVE POPULATION SIZE TO ADULT NUMBERS USING GENETIC AND ECOLOGICAL DATA. PMID- 28565010 TI - THE FOUNDING OF A NEW POPULATION OF DARWIN'S FINCHES. AB - We report the natural colonization of the small Galapagos island Daphne Major by the large ground finch (Geospiza magnirostris). Immigrants of this species were present in every year of a 22-yr study, 1973-1994. Typically they arrived after a breeding season and left at the beginning of the next one. Geospiza magnirostris bred on the island for the first time in the exceptionally wet El Nino year of 1982-1983, and bred in all subsequent years except drought years. In agreement with theoretical expectations the frequency of inbreeding was unusually high. Pronounced fluctuating asymmetry in tarsus length, together with slightly reduced breeding success of inbreeding pairs, suggests a low level of inbreeding depression. Despite this, the population increased from 5 breeding individuals in 1983 to 20 breeding individuals in 1992, and probably more than twice that number in 1993, largely through recruitment of locally born birds. PMID- 28565011 TI - THE EVOLUTIONARILY STABLE PHENOTYPE DISTRIBUTION IN A RANDOM ENVIRONMENT. AB - In an unpredictably changing environment, phenotypic variability may evolve as a "bet-hedging" strategy. We examine here two models for evolutionarily stable phenotype distributions resulting from stabilizing selection with a randomly fluctuating optimum. Both models include overlapping generations, either survival of adults or a dormant propagule pool. In the first model (mixed-strategies model) we assume that individuals can produce offspring with a distribution of phenotypes, in which case, the evolutionarily stable population always consists of a single genotype. We show that there is a unique evolutionarily stable strategy (ESS) distribution that does not depend on the amount of generational overlap, and that the ESS distribution generically is discrete rather than continuous; that is, there are distinct classes of offspring rather than a continuous distribution of offspring phenotypes. If the probability of extreme fluctuations in the optimum is sufficiently small, then the ESS distribution is monomorphic: a single type fitted to the mean environment. At higher levels of variability, the ESS distribution is polymorphic, and we find stability conditions for dimorphic distributions. For an exponential or similarly broad tailed distribution of the optimum phenotype, the ESS consists of an infinite number of distinct phenotypes. In the second model we assume that an individual produces offspring with a single, genetically determined phenotype (pure strategies model). The ESS population then contains multiple genotypes when the environmental variance is sufficiently high. However the phenotype distributions are similar to those in the mixed-strategies model: discrete, with an increasing number of distinct phenotypes as the environmental variance increases. PMID- 28565012 TI - SPATIAL POPULATION STRUCTURE IN THE WHIRLIGIG BEETLE DINEUTUS ASSIMILIS: EVOLUTIONARY INFERENCES BASED ON MITOCHONDRIAL DNA AND FIELD DATA. AB - The spatial population structure of the pond-living water beetle Dineutus assimilis (Coleoptera: Gyrinidae) was investigated through a field study of population dynamics and dispersal, with a concurrent assessment of the spatial distribution of mitochondrial DNA (mtDNA) restriction-fragment-length polymorphism (RFLP). A comprehensive 2-yr survey within a 60-km2 study area revealed pronounced fluctuations in local abundances, including extinctions and colonizations. The recapture of marked individuals showed that dispersal among ponds is frequent in both males and females and connects populations on a large geographic scale (maximum observed flight distance: 20 km). The population structure of D. assimilis is thus characterized by both pronounced genetic drift and frequent gene flow. Together, these two forces generate a pattern of very local and transient genetic differentiation. Mitochondrial DNA samples collected within a few kilometers indicate highly significant spatial structure, if newly founded demes or those that experienced recent bottlenecks are included. These results based on four demes within the study area were placed into a regional context by further samples collected at distances of 100 km and 200 km. Fst estimates computed on increasing spatial scales were variable but showed no increasing trend. Thus, gene flow exerts a strong homogenizing force over a wide geographic range but is counteracted locally by genetic drift. These findings highlight the need to supplement estimates of Fst with additional data to arrive at valid interpretations of the genetic information. More generally, this study raises questions about how to capture the relevant features of dynamic, subdivided populations to understand their evolutionary dynamics. PMID- 28565013 TI - QUANTITATIVE GENETICS OF BRYOZOAN PHENOTYPIC EVOLUTION. III. PHENOTYPIC PLASTICITY AND THE MAINTENANCE OF GENETIC VARIATION. AB - Cheilostome bryozoan species show long-term morphologic stasis, implying stabilizing selection sustained for millions of years, but nevertheless retain significant heritable variation in traits of skeletal morphology. The possible role of within-genotype (within-colony) phenotypic variability in preserving genetic diversity was analyzed using breeding data for two species of Stylopoma from sites along 110 km of the Caribbean coast of Panama. Variation among zooids within colonies accounts for nearly two-thirds of the phenotypic variance on average, increases with environmental heterogeneity, and includes significant genotype-environment interaction. Thus, within-colony variability apparently represents phenotypic plasticity, at least some of which is heritable, rather than random "developmental noise." Almost all of the among-colonies component of phenotypic variance is accounted for by additive genetic differences in trait means, suggesting that within-colony plasticity includes virtually all of the environmental component of phenotypic variance in these populations of Stylopoma. Thus, heritable within-colony plasticity could play a significant part in maintaining genetic diversity in cheilostomes, but it is also possible that rates of polygenic mutation alone are sufficient to balance the effects of selection. PMID- 28565014 TI - ESTIMATING SELECTION ON QUANTITATIVE TRAITS USING CAPTURE-RECAPTURE DATA. PMID- 28565015 TI - CLUTCH SIZE AND EGG SIZE IN FREE-LIVING AND PARASITIC COPEPODS: A COMPARATIVE ANALYSIS. AB - The evolution of reproductive strategies and the trade-off between number and size of eggs were investigated in a comparative analysis of free-living and parasitic copepods. Data from 1038 copepod species were used to obtain family averages for 105 families; the phylogenetic relationships among these families include 94 branching events or 94 independent contrasts on which the analysis was based. Transition from a free-living existence to parasitism on invertebrates resulted in small increases in body size. Transition from parasitism on invertebrates to parasitism on fish was associated with greater increases in body size. After controlling for body size, a switch to fish hosts resulted in an increase in the number of eggs produced and a reduction in egg size. Among all contrasts, there was a negative relationship between changes in relative clutch size and changes in relative egg size, suggesting the existence of a trade-off between egg size and numbers. However, opposite changes in these measures of clutch size and egg size were not quite more frequent than expected by chance, therefore indicating that investments into egg numbers are not necessarily made at the expense of egg size, and vice versa. Latitude affected copepod body size, clutch size, and egg size, whereas the effects of freshwater colonization or size of the fish host were not significant. Comparative analyses at either the genus or species levels within given taxa of copepods parasitic on fish provided limited support for a trade-off between clutch size and egg size, but were hampered by the small number of independent phylogenetic contrasts available. From the family-level comparative analysis, it appears that the evolutionary transition from a free life to parasitism on invertebrates, and the transition from parasitism on invertebrates to parasitism on fish, have led to changes in life-history traits in response to the different selective pressures associated with the different modes of life. PMID- 28565016 TI - POPULATION STRUCTURE, LOCAL MATE COMPETITION, AND SEX-ALLOCATION PATTERN IN THE ANT MESSOR ACICULATUS. AB - Population-genetic structure and sex-allocation ratios were investigated for the ant Messor aciculatus, a species that conducts mass nuptial flights. An electrophoretic survey on two polymorphic loci revealed excessive homozygosities in two populations. Because inbreeding inside nests does not occur, the heterozygote deficiency may result from population subdivision rather than assortative inbreeding during nuptial flights. Assuming no inbreeding, a simulation based on the observed genotype distribution in the study site suggested that, on average, a breeding swarm consists of alates from only 1.7 colonies. This population genetic structure seems to cause local mate competition (LMC), a factor that can shift population sex ratio toward females. The sex allocation ratio to males in the population (0.166 +/- 0.030; mean +/- SE) was significantly female biased and lower than the expected optima for queens (0.5) and for workers (0.25) without LMC. Sex-ratio variability among colonies was explained by a pattern of constant male investment, which is predictable assuming LMC. Thus, the study provides the first evidence of LMC in ants with mass nuptial flights and contradicts previous assumptions about breeding structure in swarming ants. The results suggest that LMC can affect sex-allocation patterns for ant colonies and populations. PMID- 28565017 TI - ASYNCHRONY OF INFECTION TIMING, HABITAT PREFERENCE, AND SYMPATRIC SPECIATION OF SCHISTOSOME PARASITES. PMID- 28565018 TI - PHENETIC ANALYSIS AND THE PHYLOGENY OF THE DIPLOID SPECIES OF GOSSYPIUM L. (MALVACEAE). PMID- 28565019 TI - PARALLELISM AND CONVERGENCE IN THE EVOLUTION OF SIZE AND SHAPE IN HOLARCTIC HYLA. PMID- 28565020 TI - AN EXAMPLE OF PARALLELISM IN CARNIVORE BRAIN EVOLUTION. PMID- 28565021 TI - THE GENETICS OF DACUS OLEAE. V. CHANGES OF ESTERASE POLYMORPHISM IN A NATURAL POPULATION FOLLOWING INSECTICIDE CONTROL-SELECTION OR DRIFT? PMID- 28565022 TI - THE MONOECIOUS AND DIOECIOUS CONDITIONS IN SAGITTARIA LATIFOLIA L. (ALISMATACEAE). PMID- 28565023 TI - THE RELATIONS BETWEEN POPULATION STRUCTURE AND RATE OF INBREEDING. PMID- 28565024 TI - A DEVELOPMENTAL BASIS FOR DIFFERENTIAL TOOTH REDUCTION DURING HOMINID EVOLUTION. PMID- 28565025 TI - LETHAL ALLELES NEAR LOCUS T IN HOUSE MOUSE POPULATIONS ON THE JUTLAND PENINSULA, DENMARK. PMID- 28565026 TI - REVERSIBLE TETRAPLOIDY AS AN EVOLUTIONARY MECHANISM. PMID- 28565027 TI - THE GENETICS OF POLYMORPHISM IN THE ROSS' GOOSE (ANSER ROSSII). PMID- 28565028 TI - CHANGES IN MICROGEOGRAPHIC VARIATION PATTERNS OF PEMPHIGUS POPULITRANSVERSUS OVER A SIX-YEAR SPAN. PMID- 28565029 TI - EXPERIMENTAL ANALYSIS OF RELATIVE FITNESS IN TRANSFERRIN GENOTYPES OF MICROTUS OCHROGASTER. PMID- 28565030 TI - GENETIC INTERPRETATION OF REGRESSIVE EVOLUTIONARY PROCESSES: STUDIES ON HYBRID EYES OF TWO ASTYANAX CAVE POPULATIONS (CHARACIDAE, PISCES). PMID- 28565031 TI - TWO THOUSAND GENERATIONS OF HYBRIDISATION IN A HELICONIUS BUTTERFLY. PMID- 28565032 TI - A COMPARATIVE STUDY OF THE CAUSE AND SIGNIFICANCE OF MORPHOLOGICAL VARIATION IN ADULTS AND PUPAE OF CULICOIDES: A FACTOR ANALYSIS AND MULTIPLE REGRESSION STUDY. PMID- 28565033 TI - TOWARD THE ORIGIN OF ARTIODACTYLS. PMID- 28565034 TI - MATING PROPENSITY OF GENE ARRANGEMENT CARRIERS FROM A REDWOODS POPULATION OF DROSOPHILA PERSIMILIS. PMID- 28565035 TI - Clinical experience with white blood cell-PET/CT in autosomal dominant polycystic kidney disease patients with suspected cyst infection: A prospective case series. AB - AIMS: Cyst infection (CI) is a common problem in patients with autosomal dominant polycystic kidney disease (ADPKD). Localization is of great importance in CI. We describe the clinical experience with [18F] FDG-labelled white-blood cell (WBC) PET/CT in detecting CI in ADPKD. METHODS: Nineteen ADPKD patients (M:F = 7:12) suspected of having CI were enrolled in this prospective study. All underwent WBC PET/CT and MRI or CT. The degree of their WBC accumulation was evaluated from the maximal standardized uptake value of cystic wall. RESULTS: Cyst infection was diagnosed in 14 cases [definite (n = 6), probable (n = 1), or possible (n = 7); kidney (n = 11), or liver (n = 3)]. There was no difference in fever or laboratory findings (White blood cell count, C-reactive protein, culture results, and eGFR). The blood culture was positive only in a subset of CI patients (n = 4). Cyst fluid culture yielded bacterial growth in 80% of aspirates. WBC-PET/CT detected 64% of CI cases, whereas conventional imaging, 50%. WBC-PET/CT showed false-positive results in two of five cases with no CI. The reasons for false negatives with WBC-PET/CT were poor host immune reaction, low virulence, or prior antibiotic therapy. Haemorrhagic cysts were the most common cause of false positivity in WBC-PET/CT. However, WBC-PET/CT detected CI in three cases, in which the conventional imaging failed to find CI. CONCLUSIONS: Clinical information may play little role in the diagnosis of CI. WBC-PET/CT can be used to detect CI with better sensitivity in ADPKD patients, circumventing the exposure to contrast media. PMID- 28565036 TI - GENETIC CHANGES IN NATURAL POPULATIONS OF DROSOPHILA MELANOGASTER. PMID- 28565037 TI - BUTTERFLY PALATABILITY AND MIMICRY: EXPERIMENTS WITH AMEIVA LIZARDS. PMID- 28565038 TI - INFLUENCE OF ENVIRONMENTAL FACTORS ON FREQUENCIES OF CERTAIN CHROMOSOMAL INVERSIONS IN CHIRONOMUS TENTANS FABRICIUS. PMID- 28565039 TI - THE INFLUENCE OF GENETIC VARIABILITY ON WING SYMMETRY IN HONEYBEES (APIS MELLIFERA). PMID- 28565040 TI - A COMMENT ON THE ROLE OF ENVIRONMENTAL VARIATION IN MAINTAINING POLYMORPHISMS IN NATURAL POPULATIONS. PMID- 28565041 TI - GEOGRAPHIC PROTEIN VARIATION AND DIVERGENCE IN POPULATIONS OF THE SALAMANDER PLETHODON CINEREUS. PMID- 28565042 TI - RELATIONSHIPS BETWEEN AGGRESSIVE BEHAVIOR AND GENIC HETEROZYGOSITY IN THE OLD FIELD MOUSE, PEROMYSCUS POLIONOTUS. PMID- 28565043 TI - CHROMOSOME EVOLUTION IN WOODRATS, GENUS NEOTOMA (RODENTIA: CRICETIDAE). PMID- 28565044 TI - POPULATION GENETIC STUDIES IN BEES. 2. SEX-LIMITED GENES. PMID- 28565045 TI - EVOLUTION OF THE BRAIN AND INTELLIGENCE: COMMENT ON RADINSKY'S REVIEW. PMID- 28565046 TI - POPULATION GENETICS OF MARINE PELECYPODS. IV. SELECTION, MIGRATION AND GENETIC DIFFERENTIATION IN THE BLUE MUSSEL MYTILUS EDULIS. PMID- 28565047 TI - SIB-MATING POPULATIONS IN AN UNPREDICTABLE ENVIRONMENT: EFFECTS ON COMPONENTS OF FITNESS. PMID- 28565048 TI - GENETIC DIFFERENTIATION IN SPECIOSE VERSUS DEPAUPERATE PHYLADS: EVIDENCE FROM THE CALIFORNIA MINNOWS. PMID- 28565049 TI - EFFECTS OF LARVAL BIOTIC RESIDUES ON CHROMOSOMAL POLYMORPHISM OF DROSOPHILA PAVANI. PMID- 28565050 TI - STUDIES IN WARNING COLORATION AND MIMICRY. VII. EVOLUTIONARY CONSEQUENCES OF A BATESIAN-MULLERIAN SPECTRUM: A MODEL FOR MULLERIAN MIMICRY. PMID- 28565051 TI - EFFECTIVE POPULATION NUMBER IN CEPAEA: A MODIFICATION. PMID- 28565052 TI - EFFECTS OF AGE, REARING AND MATING EXPERIENCES ON FREQUENCY DEPENDENT SEXUAL SELECTION IN DROSOPHILA PSEUDOOBSCURA. PMID- 28565053 TI - THE MAINTENANCE OF NON-MIMETIC FORMS IN A DIMORPHIC BATESIAN MIMIC SPECIES. PMID- 28565054 TI - THE INTERRELATION BETWEEN VARIABILITY OF CHARACTERS, EFFECTIVENESS OF ENERGY UTILISATION, AND KARYOTYPE STRUCTURE IN FISHES. PMID- 28565055 TI - POLYMORPHIC MIMICRY AND NATURAL SELECTION. PMID- 28565056 TI - CHARACTER CONVERGENCE IN MEXICAN FINCHES. PMID- 28565057 TI - COMPARATIVE STUDIES OF SEED PROTEINS OF SPECIES OF GOSSYPIUM BY GEL ELECTROPHORESIS. PMID- 28565058 TI - EXPERIMENTAL INTROGRESSION IN THE GENUS PHASEOLUS. I. EFFECT OF MATING SYSTEMS ON INTERSPECIFIC GENE FLOW. PMID- 28565059 TI - A POSSIBLE EVOLUTIONARY BASIS FOR AESTHETIC APPRECIATION IN MEN AND APES. PMID- 28565060 TI - CONVERGENT EVOLUTION OF MEDITERRANEAN-CLIMATE EVERGREEN SCLEROPHYLL SHRUBS. PMID- 28565062 TI - INTROGRESSION ACROSS ISOLATING BARRIERS IN WILD AND CULTIVATED ORYZA SPECIES. PMID- 28565061 TI - ELECTROPHORESIS OF PROTEINS IN NATURAL POPULATIONS OF PARTULA (GASTROPODA). PMID- 28565063 TI - STAGE OF TAXON CYCLE AND DISTRIBUTION OF BIRDS ON JAMAICA, GREATER ANTILLES. PMID- 28565064 TI - RAPID POPULATION DIFFERENTIATION IN A MOSAIC ENVIRONMENT. I. THE RESPONSE OF ANTHOXANTHUM ODORATUM POPULATIONS TO SOILS. PMID- 28565065 TI - THE POPULATION BIOLOGY OF ANNUAL GRASSLAND HEMIPARASITES. I. THE HOST ENVIRONMENT. PMID- 28565066 TI - POPULATION CONSEQUENCES OF NON-MENDELIAN SEGREGATION AMONG MULTIPLE ALLELES. PMID- 28565067 TI - PLASTICITY OF TAXONOMIC CHARACTERS OF THE QUEENSLAND FRUIT FLIES DACUS TRYONI AND DACUS NEOHUMERALIS (TEPHRITIDAE). PMID- 28565069 TI - THE GONADS AND REPRODUCTION OF THREE INTERGENERIC SUNFISH (FAMILY CENTRARCHIDAE) HYBRIDS. PMID- 28565068 TI - ANALYSIS OF SIMPLE CAVE COMMUNITIES I. CAVES AS ISLANDS. PMID- 28565070 TI - APOMIXIS, POLYPLOIDY, AND SPECIATION IN DICHANTHIUM. PMID- 28565071 TI - GENETIC VARIATION IN THE HORSESHOE CRAB (LIMULUS POLYPHEMUS), A PHYLOGENETIC "RELIC". PMID- 28565072 TI - SEXUAL SELECTION FOR SIZE DIFFERENCES IN TWO SPECIES OF SANDPIPERS. PMID- 28565073 TI - ORNITHISCHIAN DINOSAURS AND THE ORIGIN OF BIRDS. PMID- 28565074 TI - THE EXPLOITATION OF POLLINATORS BY SPECIES AND HYBRIDS OF PHLOX. PMID- 28565075 TI - ON THE EVOLUTIONARY STATE OF SOME REPRODUCTIVE ORGANS IN THE MAMMALIAN ORDER LAGOMORPHA. PMID- 28565076 TI - DEVELOPMENTAL MODE AND SPECIES GEOGRAPHIC RANGE IN REGULAR SEA URCHINS (ECHINODERMATA: ECHINOIDEA). AB - Among marine benthic organisms, the ability to disperse, primarily during the larval stage, is widely thought to influence the extent of species geographic range. Because related species often differ in their modes of larval development (pelagic, feeding larvae; pelagic, nonfeeding larvae; or brooded development), and these can have dramatically different planktonic intervals, the mode of development may influence geographic range. A global survey of 215 regular echinoids shows that species with pelagic, feeding larvae have significantly larger ranges than those with pelagic, nonfeeding larvae, but there is no difference in ranges between species with pelagic, nonfeeding larvae and those with brooded development. These patterns are maintained within the Cidaroida and the Temnopleuroida, which account for the great majority of species with pelagic, nonfeeding development and brooded development. This limited effect of developmental mode on geographic range is found among species occurring predominantly in waters shallower than 100 m. For species occurring deeper than 100 m, there is no significant difference in geographic range related to type of development. The relationship between developmental mode and species range was examined more closely for circa 30 species for which the developmental period was known from laboratory observations. Adjusting the developmental times to a common temperature, 20 degrees C, using realistic values for Q10 from 2.0 to 3.6, showed a highly significant, negative correlation between egg volume and developmental time, indicating the potential for developmental mode to influence the planktonic interval. However, there was no relationship between time in the plankton, estimated from unadjusted developmental times, and extent of species geographic range. These results suggest that developmental mode may influence extent of species geographic ranges indirectly through the consequences of dispersal for gene flow or recovery from disturbance. PMID- 28565077 TI - CLINAL VARIATION IN MALE-TO-MALE ANTAGONISM AND WEAPONRY IN A SUBSOCIAL MITE. AB - Male aggressiveness is highly variable among populations of a subsocial spider mite that occurs throughout Japan. The average level of aggressiveness is positively correlated with mean winter temperature and with the relative size among males of leg I, which is used as a weapon in this species. The relatedness of males within nests is influenced by rates of overwinter survival, with high survivorship leading to low relatedness, increased aggressiveness, and larger legs I. Within this species, variation in the intensity of sexual selection may therefore be influenced both by natural selection and by kin selection. PMID- 28565078 TI - THE EVOLUTIONARY GENETICS OF MALE LIFE-HISTORY CHARACTERS IN DROSOPHILA MELANOGASTER. AB - Alternative models of the maintenance of genetic variability, theories of life history evolution, and theories of sexual selection and mate choice can be tested by measuring additive and nonadditive genetic variances of components of fitness. A quantitative genetic breeding design was used to produce estimates of genetic variances for male life-history traits in Drosophila melanogaster. Additive genetic covariances and correlations between traits were also estimated. Flies from a large, outbred, laboratory population were assayed for age-specific competitive mating ability, age-specific survivorship, body mass, and fertility. Variance-component analysis then allowed the decomposition of phenotypic variation into components associated with additive genetic, nonadditive genetic, and environmental variability. A comparison of dominance and additive components of genetic variation provides little support for an important role for balancing selection in maintaining genetic variance in this suite of traits. The results provide support for the mutation-accumulation theory, but not the antagonistic pleiotropy theory of senescence. No evidence is found for the positive genetic correlations between mating success and offspring quality or quantity that are predicted by "good genes" models of sexual selection. Additive genetic coefficients of variation for life-history characters are larger than those for body weight. Finally, this set of male life-history characters exhibits a very low correspondence between estimates of genetic and phenotypic correlations. PMID- 28565079 TI - PHENOLOGICAL ISOLATION, GENE FLOW AND DEVELOPMENTAL DIFFERENCES AMONG LOW- AND HIGH-ELEVATION POPULATIONS OF EUPHILOTES ENOPTES (LEPIDOPTERA: LYCAENIDAE). AB - Populations of the specialist herbivore, Euphilotes enoptes (Lepidoptera: Lycaenidae), along three elevational transects in the mountains of central Washington state, differed markedly in the phenology of adult flight. In spite of this apparent limitation to gene flow, six allozyme loci revealed substantial gene exchange among populations along these gradients. The elevational difference, and thus the phenological difference, between populations has not influenced the extent of gene flow between them. Because the direct exchange of genes between low- and high-elevation populations is very unlikely, gene flow between them has probably occurred in a stepwise fashion via intermediate populations. It is hypothesized that such gene flow has been biased in an uphill direction due to the combined effects of source size and oviposition behavior. Adult emergence times of populations in the same region are positively correlated with elevation in a nonlinear fashion, consistent with the hypothesis that gene flow from low-elevation populations has been swamping selection at higher altitudes. PMID- 28565080 TI - LOCAL VARIATION IN THE GENETIC BASIS OF MORPHOLOGICAL TRAITS IN THE SALAMANDER AMBYSTOMA TALPOIDEUM. PMID- 28565081 TI - THE IMPORTANCE OF THE ENVIRONMENTAL VARIANCE-COVARIANCE STRUCTURE IN PREDICTING EVOLUTIONARY RESPONSES. PMID- 28565082 TI - A GENETIC PERSPECTIVE OF MAMMALIAN VARIATION AND EVOLUTION IN THE INDONESIAN ARCHIPELAGO: BIOGEOGRAPHIC CORRELATES IN THE FRUIT BAT GENUS CYNOPTERUS. AB - This study investigated allozyme and morphometric variability within the genus Cynopterus, with particular emphasis on C. nusatenggara, which is endemic to Wallacea, the area encompassing the Oriental-Australian biogeographic interface. The genetic distances between Cynopterus species are small by mammalian standards and suggest that this genus has undergone a recent series of speciation events. The genetic distance between populations of C. nusatenggara is strongly correlated with both the contemporary sea-crossing distance between islands and the estimated sea crossing at the time of the last Pleistocene glacial maximum, 18,000 b.p. This observation, together with low levels of population substructure within islands as shown by F-statistics, indicates that the sea is a primary and formidable barrier to gene exchange. The genetic distance and the great-circle geographical distance between the populations of C. nusatenggara are not correlated, although a principal-coordinates analysis of genetic distance reveals relationships between the populations that are similar to their geographical arrangement. A strong negative correlation exists between the level of heterozygosity within island populations of C. nusatenggara and the minimum sea crossing distance to the nearest large source population. This is interpreted as reflecting an isolation effect of the sea, leading to reduced heterozygosity in populations that have larger sea barriers between them and the large source islands. Independently of this, heterozygosity is negatively associated with longitude, which in turn is associated with systematic changes in the environment such as a gradual decline in rainfall from west to east. The association between heterozygosity and longitude is interpreted as reflecting an association between genetic and environmental variance and supports the niche-width theory of genetic variance. Morphometric variability did not show any of the main effects demonstrated in the genetic data. Furthermore, there was no evidence that, at the level of individuals, genetic and morphometric variability were associated. PMID- 28565083 TI - DELETERIOUS MUTATION AND THE EVOLUTION OF GENETIC LIFE CYCLES. AB - It is often proposed that the ability of diploids to mask deleterious mutations leads to an evolutionary advantage over haploidy. In this paper, we studied the evolution of the relative duration of haploid and diploid phases using a model of recurrent deleterious mutations across the entire genome. We found that a completely diploid life cycle is favored under biologically reasonable conditions, even when prolonging the diploid phase reduces a population's mean fitness. A haploid cycle is favored when there is complete linkage throughout the genome or when mutations are either highly deleterious or partially dominant. These results hold when loci interact multiplicatively and for synergistic epistasis. The strength of selection generated on the life cycle can be substantial because of the cumulative effect of selection against mutations across many loci. We did not find conditions that support cycles that retain both phases, such as those found in some plants and algae. Thus, selection against deleterious mutations may be an important force in the evolution of life cycles but may not be sufficient to explain all the patterns of life cycles seen in nature. PMID- 28565084 TI - THE POTENTIAL FOR COEVOLUTION IN A HOST-PARASITOID SYSTEM. II. GENETIC VARIATION WITHIN A POPULATION OF WASPS IN THE ABILITY TO PARASITIZE AN APHID HOST. AB - Much of the study of coevolution has focused on the adaptations that have resulted from interactions between species. For reciprocal evolution to occur, there must be genetic variation in each species for traits that directly affect their interaction. Here I report evidence of significant additive genetic variance within a population of parasitic wasps in the ability to successfully parasitize an aphid host. These data, combined with companion work documenting clonal variation in a population of aphids from the same site, provide evidence that within the same population both a host and its parasitoid have the potential for specific and reciprocal genetic interactions. PMID- 28565085 TI - EVOLUTIONARILY STABLE SELFING RATES OF HERMAPHRODITIC PLANTS IN COMPETING AND DELAYED SELFING MODES WITH ALLOCATION TO ATTRACTIVE STRUCTURES. AB - I present a resource-allocation model to analyze how patterns of allocation to reproductive structures influence the evolution of selfing rates in hermaphrodites subject to competing and delayed forms of self-fertilization. The evolutionarily stable state does not depend on the mode of pollination. In contrast to previous models in which the number and the size of flowers were not considered, intermediate selfing is not evolutionarily stable with linear constraints on flower number and size. In contrast, intermediate selfing can be evolutionarily stable with nonlinear constraints on flower number and size. Optimal allocations to attractive structures increase and selfing rates decrease in the presence of inbreeding depression. In particular, stable intermediate levels of selfing may be favored when flower number is strongly constrained. Thus, nonlinear constraints on flower number and size could favor the evolution of intermediate selfing in either the delayed or the competing modes of selfing. Outcrossing is not favored in the absence of inbreeding depression, a result inconsistent with Holsinger's results in which allocation to attractive structures was not considered. PMID- 28565086 TI - EPISTASIS AND THE INCREASE IN ADDITIVE GENETIC VARIANCE: IMPLICATIONS FOR PHASE 1 OF WRIGHT'S SHIFTING-BALANCE PROCESS. AB - Central to Wright's shifting-balance theory is the idea that genetic drift and selection in systems with gene interaction can lead to the formation of "adaptive gene complexes." The theory of genetic drift has been well developed over the last 60 years; however, nearly all of this theory is based on the assumption that only additive gene effects are acting. Wright's theory was developed recognizing that there was a "universality of interaction effects," which implies that additive theory may not be adequate to describe the process of differentiation that Wright was considering. The concept of an adaptive gene complex implies that an allele that is favored by individual selection in one deme may be removed by selection in another deme. In quantitative genetic terms, the average effects of an allele relative to other alleles changes from deme to deme. The model presented here examines the variance in local breeding values (LBVs) of a single individual and the covariance in the LBVs of a pair of individuals mated in the same deme relative to when they are mated in different demes. Local breeding value is a measure of the average effects of the alleles that make up that individual in a particular deme. I show that when there are only additive effects the covariance between the LBVs of individuals equals the variance in the LBV of an individual. As the amount of epistasis in the ancestral population increases, the variance in the LBV of an individual increases and the covariance between the LBVs of a pair of individuals decreases. The divergence in these two values is a measure of the extent to which the LBV of an individual varies independently of the LBVs of other individuals. When this value is large, it means that the relative ordering of the average effects of alleles will change from deme to deme. These results confirm an important component of Wright's shifting-balance theory: When there is gene interaction, genetic drift can lead to the reordering of the average effects of alleles and when coupled with selection this will lead to the formation of the adaptive gene complexes. PMID- 28565087 TI - THE POTENTIAL FOR COEVOLUTION IN A HOST-PARASITOID SYSTEM. I. GENETIC VARIATION WITHIN AN APHID POPULATION IN SUSCEPTIBILITY TO A PARASITIC WASP. AB - For coevolution to occur, there must be genetic variation in each species for traits relevant to their interaction. Here, statistically significant variation in susceptibility to a parasitic wasp was found among pea-aphid clones collected from a single population. In a subset of clones that was tested further, wasps were found to oviposit in aphids from both resistant and susceptible lines, but eggs failed to develop in resistant hosts. Significant genetic variance in susceptibility provides evidence that this aphid population has the potential to evolve resistance in response to selection by one of its major natural enemies. Predictions of an expected response to selection based on the experimental measures of variation and field parasitism rates suggested that there should be a detectable change in susceptibility over the course of a season. However, an experimental comparison of mean susceptibility of clones collected early and late in the summer, a period of several generations, revealed no response to selection by the wasps. Aphids collected late in the season were as susceptible, on the average, as those collected early in the summer. Possible constraints on the response of the aphids to selection by this natural enemy are considered. PMID- 28565088 TI - FLORAL CORRELATES AND FITNESS CONSEQUENCES OF MATING-SYSTEM VARIATION IN TURNERA ULMIFOLIA. AB - Outcrossing rates varied from 0% to 69% among Jamaican populations of Turnera ulmifolia. A correlation between increasing herkogamy and outcrossing rate occurred among populations. Predictions from sex-allocation theory were tested by estimating allocation to reproductive functions. Significant differences in allocation patterns occurred among populations, but they were not correlated with outcrossing rates. The fitness consequences of inbreeding were assessed in high- and low-density greenhouse experiments for nine populations with variable outcrossing rates. No evidence for inbreeding depression occurred in early portions of the life history, but multiplicative fitness functions provide evidence for inbreeding depression. We tested the prediction that selfing populations have lower levels of inbreeding depression than outcrossing populations but found no significant correlation. PMID- 28565089 TI - SYMPATRIC CONVERGENCE AND ENVIRONMENTAL CORRELATION BETWEEN TWO LAND-SNAIL SPECIES. AB - In the southern Appalachian region of North America, the phylogenetically convergent shells of the polygyrid snails Triodopsinae Neohelix major (Binney) and Polygyrinae Mesodon normalis (Pilsbry) are even more convergent in size and shape in sympatry (7 sites) than in allopatry (23 and 10 sites). Environmental correlations account for 34% and 30% of size and shape variations in N. major (larger, taller, and more loosely coiled at northern, high-altitude, sheltered sites), but for only 14% and 9% in M. normalis (larger, flatter, and more loosely coiled at south-facing, exposed sites). The statistical significance of the sympatric convergence dropped out when these correlations were removed. This phenomenon helps account for the many cases in eastern North America of nearly identical land-snail shells in sympatry and questions the importance of competitive character displacement in the evolution of land-snail shell morphology. This apparently nonmimetic case of sympatric convergence provides an unusually precise and well-delimited, naturally replicated experiment in evolutionary morphology, which is analyzed for controlling factors in a follow-up paper. PMID- 28565090 TI - THE SELECTION BARRIER BETWEEN POPULATIONS SUBJECT TO STABILIZING SELECTION. AB - The introgression of genes carried by a small group of immigrants is studied. The recipient and the donor populations differ at several autosomal loci subject to weak selection, and two allelic forms of each gene are considered. Fitness variation is determined by additive allelic effects, by dominance effects, and by two-locus additive-by-additive epistatic interaction of the effects of the alleles. The fate of the group of immigrants is quantified by the selection barrier that describes the cumulative mean fitness of the hybrids and hybrid descendants relative to the fitness of the resident population. The monomorphic and the polymorphic loci of the recipient population contribute differently to the selection barrier. If the genetic difference between recipient and donor population is small, then the contribution of the monomorphic loci is dominated by a positive term dependent on the difference in gene frequencies. The contribution of the polymorphic loci depends only on the difference of the leading order in the pairwise linkage disequilibria between the two populations. This contribution may be positive or negative; and, thus, polymorphic loci may either contribute to the barrier or inflate the introgression. PMID- 28565091 TI - LOWER MITE INFESTATIONS IN AN ASEXUAL GECKO COMPARED WITH ITS SEXUAL ANCESTORS. AB - What advantage do sexually reproducing organisms gain from their mode of reproduction that compensates for their twofold loss in reproductive rate relative to their asexual counterparts? One version of the Red Queen hypothesis suggests that selective pressure from parasites is strongest on the most common genotype in a population, and thus genetically identical clonal lineages are more vulnerable to parasitism over time than genetically diverse sexual lineages. Our surveys of the ectoparasites of an asexual gecko and its two sexual ancestral species show that the sexuals have a higher prevalence, abundance, and mean intensity of mites than asexuals sharing the same habitat. Our experimental data indicate that in one sexual/asexual pair this pattern is at least partly attributable to higher attachment rates of mites to sexuals. Such a difference may occur as a result of exceptionally high susceptibility of the sexuals to mites because of their low genetic diversity (relative to other more-outbred sexual species) and their potentially high stress levels, or as a result of exceptionally low susceptibility of the asexuals to mites because of their high levels of heterozygosity. PMID- 28565092 TI - RAPID LABORATORY EVOLUTION OF ADULT LIFE-HISTORY TRAITS IN DROSOPHILA MELANOGASTER IN RESPONSE TO TEMPERATURE. AB - Three replicate lines of Drosophila melanogaster were cultured at each of two temperatures (16.5 degrees C and 25 degrees C) in population cages for 4 yr. The lifespans of both sexes and the fecundity and fertility of the females were then measured at both experimental temperatures. The characters showed evidence of adaptation; flies of both sexes from each selection regime showed higher longevity, and females showed higher fecundity and fertility, than flies from the other selection regime when they were tested at the experimental temperature at which they had evolved. Calculation of intrinsic rates of increase under different assumptions about the rate of population increase showed that the difference between the lines from the two selection regimes became less the higher the rate of population increase, because the lines were more similar in early adulthood than they were later. Despite the increased adaptation of the low temperature lines to the low temperature, like the high temperature lines they produced progeny at a higher rate at the higher temperature. The lines may have independently evolved adaptations to their respective thermal regimes during the experiment, or there may have been a trade-off between adaptation to the two temperatures, or mutation pressure may have lowered adaptation to the temperature that the flies no longer encountered. PMID- 28565093 TI - GEOGRAPHIC VARIATION IN FEMALE PREFERENCES FOR MALE TRAITS IN POECILIA RETICULATA. AB - We examined the preferences of female guppies (Poecilia reticulata) from 11 localities in Trinidad with respect to male color-pattern elements, body shape and size, and overall color and brightness contrast. Females are on average more attracted to males from their own population than from alien populations, and populations appear to vary in the criteria used in female choice. Multiple regression analysis suggests that mate-preference criteria vary among localities in intensity, sign, and the number of traits used. Although preference estimators and color-pattern parameters are unique to each population, only orange, black, and color contrast showed a correlation between degree of male trait and degree of preference for that trait. There is a clear effect of water color and a possible effect of predation intensity. The results are discussed in light of various models of sexual selection and the early stages of speciation. PMID- 28565094 TI - HONEST SIGNALING AND THE SURVIVAL COST OF BADGES IN THE HOUSE SPARROW. PMID- 28565095 TI - KIN-MEDIATED MORPHOGENESIS IN FACULTATIVELY CANNIBALISTIC TADPOLES. AB - Inclusive fitness theory predicts that organisms can increase their fitness by helping or not harming relatives, and many animals modify their behavior toward kin in a manner consistent with this prediction. Morphogenesis also may be sensitive to kinship environment, particularly in species where certain individuals facultatively develop structures that can be used against conspecifics as weaponry. We tested this hypothesis by examining whether and how consanguinity affected the probability that a structurally distinctive carnivore phenotype, which is opportunistically cannibalistic, would be produced in plains spadefoot toad tadpoles (Spea bombifrons) and southern spadefoot toad tadpoles (S. multiplicata). For tadpoles of S. multiplicata, individuals were significantly more likely to express the carnivore phenotype in mixed sibship groups than in pure sibship groups. For tadpoles of S. bombifrons, individuals were significantly more likely to express the carnivore phenotype when reared alone than in pure sibship groups. Both outcomes were independent of food availability or sibship specific differences in size or growth rate, and waterborne chemical signals from nonkin were sufficient to trigger expression of the carnivore phenotype. Our results suggest that morphogenesis may be responsive to kinship environment in any species or population that occurs as multiple, environmentally induced forms (polyphenism) that differ in their ability to help or to harm others. PMID- 28565096 TI - POPULATION STRUCTURE OF MORPHOLOGICAL TRAITS IN CLARKIA DUDLEYANA. II. CONSTANCY OF WITHIN-POPULATION GENETIC VARIANCE. AB - Recent quantitative genetic studies have attempted to infer long-term selection responsible for differences in observed phenotypes. These analyses are greatly simplified by the assumption that the within-population genetic variance remains constant through time and over space, or for the multivariate case, that the matrix of additive genetic variances and covariances (G matrix) is constant. We examined differences in G matrices and the association of these differences with differences in multivariate means (Mahalanobis D2 ) among 11 populations of the California endemic annual plant, Clarkia dudleyana. Based on nine continuous morphological traits, the relationship between Mahalanobis D2 and a distance measure summarizing differences in G matrices reflected no concomitant change in (co)variances with changes in means. Based on both broad- and narrow-sense analyses, we found little evidence that G matrices differed between populations. These results suggest that both the additive and nonadditive (co)variances for traits have remained relatively constant despite changes in means. PMID- 28565097 TI - THE EVOLUTION OF THRESHOLD TRAITS: A QUANTITATIVE GENETIC ANALYSIS OF THE PHYSIOLOGICAL AND LIFE-HISTORY CORRELATES OF WING DIMORPHISM IN THE SAND CRICKET. AB - Many traits are phenotypically discrete but polygenically determined. Such traits can be understood using the threshold model of quantitative genetics that posits a continuously distributed underlying trait, called the liability, and a threshold of response, individuals above the threshold displaying one morph and individuals below the threshold displaying the alternate morph. For many threshold traits the liability probably consists of a hormone or a suite of hormones. Previous experiments have implicated juvenile hormone esterase (JHE), a degratory enzyme of juvenile hormone, as a physiological determinant of wing dimorphism in the crickets Gryllus rubens and G. firmus. The present study uses a half-sib experiment to measure the heritability of JHE in the last nymphal stadium of G. firmus and its genetic correlation with fecundity, a trait that is itself genetically correlated with wing morph. The phenotypic and genetic parameters are consistent with the hypothesis that JHE is a significant component of the liability. Comparison of sire and dam estimates suggest that nonadditive effects may be important. Two models have been proposed to account for the fitness differences between morphs: the dichotomy model, which assumes that each morph can be characterized by a particular suite of traits, and the continuous model, which assumes that the associated fitness traits are correlated with the liability rather than the morphs themselves. The latter model predicts that the fitness differences will not be constant but change with the morph frequencies. Variation in fecundity and flight muscle histolysis are shown to be more consistent with the continuous model. Data from the present experiment on JHE are inconclusive, but results from a previous selection experiment also suggest that variation in JHE is consistent only with the continuous model. PMID- 28565098 TI - THE GENETIC BASIS OF DEVELOPMENTAL STABILITY. III. HAPLO-DIPLOIDY: ARE MALES MORE UNSTABLE THAN FEMALES? PMID- 28565099 TI - THE INFLUENCE OF HOST DEMOGRAPHY ON THE EVOLUTION OF VIRULENCE OF A MICROSPORIDIAN GUT PARASITE. AB - It is predicted that host exploitation should evolve to maximize parasite fitness and that virulence (= parasite-induced host mortality) evolves along with the rate of host exploitation. If the life expectancy of a parasite is short, it is expected to evolve a higher rate of host exploitation and therefore higher virulence because the penalty to the parasite for killing the host is reduced. We tested this hypothesis by keeping for 14 months the horizontally transmitted microsporidian parasite Glugoides intestinalis in mono-clonal host cultures (Daphnia magna) under conditions of high and low host background mortality. High host mortality, and thus parasite mortality, was achieved by replacing weekly 70 80% of all hosts in a culture with uninfected hosts from stock cultures (Replacement lines). In the low-mortality treatment no replacement took place. Contrary to our expectation, parasites from the Replacement lines evolved a lower within-host growth rate and virulence than parasites from the Nonreplacement lines. Across lines we found a strong positive correlation between within-host growth rate and virulence. We did further experiments to answer the question why our data did not support the predictions. Sporophorous vesicles (SVs, spore clusters) were smaller in doubly infected than in singly infected host-gut cells, indicating that competition within cells bears costs for the parasite. Due to our experimental protocol, the average life span of infections had been much higher in the Nonreplacement lines. Since the number of parasites inside a host increases with the time since infection, long-lasting infections led to high frequencies of multiply infected host-gut cells. Therefore, we speculated that within-cell competition was more severe in the Nonreplacement lines and may have led to selection for accelerated within-host growth. SVs in the Nonreplacement lines were indeed significantly larger. Our results point out that single-factor explanations for the evolution of virulence can lead to wrong predictions and that multiple infections are an important factor in virulence evolution. PMID- 28565100 TI - PARALLEL EVOLUTION OF LAKE-STREAM PAIRS OF THREESPINE STICKLEBACKS (GASTEROSTEUS) INFERRED FROM MITOCHONDRIAL DNA VARIATION. AB - Three drainage systems in British Columbia, Canada, contain divergent parapatric lake-stream pairs of threespine sticklebacks (Gasterosteus aculeatus): Drizzle and Mayer Lakes on Graham Island, Queen Charlotte Islands, and Misty Lake on northeastern Vancouver Island. Ecological and morphological differences between members of all three lake-stream pairs are strikingly similar; lake fish are melanistic and slim bodied with smaller mouths and more gill rakers than the mottled-brown and robust-bodied stream sticklebacks. We estimated the level of genetic divergence between lake and stream fish in Misty Lake and tested hypotheses of single versus multiple origins of the pairs by assaying mitochondrial DNA (mtDNA) restriction site variation in samples from the three lake systems. MtDNA analysis revealed the existence of two highly divergent lineages differing by 2.7% in sequence. One lineage predominated in Misty stream fish (73%), whereas the other lineage predominated in Misty Lake samples (96%). Comparable forms (lake or stream) in the different lakes did not cluster together in terms of mtDNA nucleotide divergence, suggesting that the pairs have had independent origins. We concluded that: (1) divergent mtDNA lineages in North Pacific sticklebacks stem from historical isolation in the two major glacial refugia proposed for the North Pacific (Beringia and Cascadia); (2) the stream and lake pair in Misty Lake are distinct gene pools; (3) the divergence between parapatric lake and stream Gasterosteus represents parallel evolution having occurred at least twice in the North Pacific; and (4) different scales of evolutionary divergence exist in North Pacific Gasterosteus, that is, a relatively ancient divergence of mtDNA clades as well as recent (i.e., postglacial) divergence of ecotypes within major clades. PMID- 28565101 TI - TESTS FOR SEXUAL INCOMPATIBILITY BETWEEN TWO NEWT SPECIES, TRITURUS VULGARIS AND TRITURUS MONTANDONI: NO-CHOICE MATING DESIGN. PMID- 28565102 TI - PREY ADAPTATION AS A CAUSE OF PREDATOR-PREY CYCLES. AB - We analyze simple models of predator-prey systems in which there is adaptive change in a trait of the prey that determines the rate at which it is captured by searching predators. Two models of adaptive change are explored: (1) change within a single reproducing prey population that has genetic variation for vulnerability to capture by the predator; and (2) direct competition between two independently reproducing prey populations that differ in their vulnerability. When an individual predator's consumption increases at a decreasing rate with prey availability, prey adaptation via either of these mechanisms may produce sustained cycles in both species' population densities and in the prey's mean trait value. Sufficiently rapid adaptive change (e.g., behavioral adaptation or evolution of traits with a large additive genetic variance), or sufficiently low predator birth and death rates will produce sustained cycles or chaos, even when the predator-prey dynamics with fixed prey capture rates would have been stable. Adaptive dynamics can also stabilize a system that would exhibit limit cycles if traits were fixed at their equilibrium values. When evolution fails to stabilize inherently unstable population interactions, selection decreases the prey's escape ability, which further destabilizes population dynamics. When the predator has a linear functional response, evolution of prey vulnerability always promotes stability. The relevance of these results to observed predator-prey cycles is discussed. PMID- 28565103 TI - EVOLUTIONARY PREDICTABILITY IN NATURAL POPULATIONS: DO MATING SYSTEM AND NONADDITIVE GENETIC VARIANCE INTERACT TO AFFECT HERITABILITIES IN PLANTAGO LANCEOLATA? AB - Quantitative genetics has been an immensely powerful tool in manipulating the phenotypes of domesticated plants and animals. Much of the predictive power of quantitative genetics depends on the breeder's control over the context in which phenotype and mating are being expressed. In the natural world, these contexts are often difficult to describe, let alone control. We are left, therefore, with a poor understanding of the limits of quantitative genetics in natural populations. One of the crucial contextual elements for assessing breeding value is the genetic background in which an individual's genes are being assessed. When interacting genes are polymorphic within a population, the degree of mating among relatives can influence the correlations among mates and the predictions of a response to selection. Population structure can strongly influence the degree to which dominance and epistasis influences additive genetic variance and heritability. The extent of inbreeding can also influence heritabilities through its effect on the environmental component of phenotypic variance. The applicability of standard quantitative genetic breeding designs to the measurement of heritabilities in natural populations therefore depends in part on: (1) the mating system of the population; and (2) the importance of gene interactions in determining phenotypic variation. We tested for an effect of mating structure on the partitioning of phenotypic variance and heritability by comparing two breeding designs in a common environment. Both breeding designs used 139 pollen parents taken from mapped locations in a population of Plantago lanceolata L., and crossed to 280 seed parents from the same population. One design was random-mating, the second was biased toward near-neighbor matings to an extent determined by field measure of pollen-mediated gene flow distances. The offspring were grown randomly mixed in a common garden. Nine traits were measured: central corm diameter, number of leaves, area of the most recently fully expanded leaf, density of hairs (cm-2 ) on the leaves, dry weight per unit leaf area, photosynthetic capacity, transpiration rates, water use efficiency, and reproductive dry weight. Heritabilities and variance components from the two designs were compared using randomization tests. None of the variance components or the heritabilities differed significantly between breeding designs at the 0.05 level. The test could distinguish differences between the heritabilities measured in the two breeding designs as small as 0.11, on average. Thus, for the degree of inbreeding normally exhibited in P. lanceolata there is insufficient gene interaction present within populations to influence the partitioning of variance between additive and nonadditive components or to influence heritability estimates to a meaningful extent. We suggest that for Plantago other sources of variation in heritability estimates, such as maternal effects and genotype * environment interactions, are more important influences than the interaction between inbreeding and gene interactions, and standard heritability estimate based on random breeding is as accurate as one taking the natural mating structure into account. PMID- 28565104 TI - LABORATORY EVOLUTION OF LIFE-HISTORY TRAITS IN THE BEAN WEEVIL (ACANTHOSCELIDES OBTECTUS): THE EFFECTS OF DENSITY-DEPENDENT AND AGE-SPECIFIC SELECTION. AB - Four types of laboratory populations of the bean weevil (Acanthoscelides obtectus) have been developed to study the effects of density-dependent and age specific selection. These populations have been selected at high (K) and low larval densities (r) as well as for reproduction early (Y) and late (O) in life. The results presented here suggest that the r- and K-populations (density dependent selection regimes) have differentiated from each other with respect to the following life-history traits: egg-to-adult viability at high larval density (K > r), preadult developmental time (r > K), body weight (r > K), late fecundity (K > r), total realized fecundity (r > K), and longevity of males (r > K). It was also found that the following traits responded in statistically significant manner in populations subjected to different age-specific selection regimes: egg to-adult viability (O > Y), body weight (O > Y), early fecundity (Y > O), late fecundity (O > Y), and longevity of females and males (O > Y). Although several life-history traits (viability, body weight, late fecundity) responded in similar manner to both density-dependent and age-specific selection regimes, it appears that underlying genetic and physiological mechanisms responsible for differentiation of the r/K and Y/O populations are different. We have also tested quantitative genetic basis of the bean weevil life-history traits in the populations experiencing density-dependent and age-specific selection. Among the traits traded-off within age-specific selection regimes, only early fecundity showed directional dominance, whereas late fecundity and longevity data indicated additive inheritance. In contrast to age-specific selecton regimes, three life history traits (developmental time, body size, total fecundity) in the density sependent regimes exhibited significant dominance effects. Lastly, we have tested the congruence between short-term and long-term effects of larval densities. The comparisons of the outcomes of the r/K selection regimes and those obtained from the low- and high-larval densities revealed that there is no congruence between the selection results and phenotypic plasticity for the analyzed life-history traits in the bean weevil. PMID- 28565105 TI - FLUCTUATING POPULATION SIZE AND THE RATIO OF EFFECTIVE TO CENSUS POPULATION SIZE. PMID- 28565106 TI - RECENT EVOLUTION AND DIVERGENCE AMONG POPULATIONS OF A RARE MEXICAN ENDEMIC, CHIHUAHUA SPRUCE, FOLLOWING HOLOCENE CLIMATIC WARMING. AB - Fragmentation and reduction in population size are expected to reduce genetic diversity. However, examples from natural populations of forest trees are scarce. The range of Chihuahua spruce retreated northward and fragmented coincident with the warming climate that marked the early Holocene. The isolated populations vary from 15 to 2441 trees, which provided an opportunity to test whether census number is a good predictor of genetic diversity. Mean expected heterozygosity, He , based on 24 loci in 16 enzyme systems, was 0.093 for 10 sampled populations, which is within the range reported for conifers. However, estimates varied more than twofold among populations and He was closely related to the logarithm of the number of mature trees in the population (rHe,N = 0.93). Diversity among populations, FST , was 24.8% of the total diversity, which is higher than that observed in almost all conifer species studied. Nei's genetic distance, D, was not related to geographic distance between populations, and D was 0.033, which is higher than estimates for most wide-ranging species. Most populations had excess homozygosity and the fixation index, FIS , was higher than that reported for all but one species of conifer. Nm, the number of migrants per generation, was 0.43 to 0.76, depending on estimation procedure, and is the smallest observed in conifers. The data suggest that populations of Chihuahua spruce have differentiated by drift and that they are effectively isolated. The results illustrate how a combination of paleontological observation and molecular markers can be used to illuminate recent evolutionary events. Multilocus estimates of outcrossing for two small populations were zero (complete selfing) and 0.153, respectively, which are in striking contrast to the near complete outcrossing observed in most conifers. The high fixation index and a high proportion of empty seeds (45%) suggest that inbreeding may be a serious problem for conservation of Chihuahua spruce. PMID- 28565107 TI - OPTIMISTIC GROWTH: COMPETITION AND AN ONTOGENETIC NICHE-SHIFT SELECT FOR RAPID GROWTH IN PUMPKINSEED SUNFISH (LEPOMIS GIBBOSUS). AB - Intrinsic growth rate is emerging as an important life-history trait that can be modified by natural selection. One factor determining optimal intrinsic growth rates is the pattern of resource availability. Organisms that experience chronically low resource levels tend to have slow intrinsic growth rates. However, this does not necessarily hold if resource levels change as an organism grows. We present a theoretical model showing that rapid growth is favored when resource levels for small size classes are low relative to resource levels for large size classes. We call such a growth strategy "optimistic" because rapid growth is based on an expectation that resources will improve once a minimum size is reached. We provide empirical support for this hypothesis by examining the intrinsic growth rates of pumpkinseed sunfish derived from three populations sympatric with bluegill sunfish (an important competitor with small size classes) to three populations allopatric with bluegill sunfish raised under common conditions. Rapid growth has evolved in the sympatric fish to reach the size refuge from competition as quickly as possible. PMID- 28565108 TI - MAINTENANCE OF POLYMORPHISM PROMOTED BY SEX-SPECIFIC FITNESS PAYOFFS. PMID- 28565109 TI - THE EFFECTS OF WINTER LENGTH ON THE GENETICS OF APPLE AND HAWTHORN RACES OF RHAGOLETIS POMONELLA (DIPTERA: TEPHRITIDAE). AB - Host plant-associated fitness trade-offs are central to models of sympatric speciation proposed for certain phytophagous insects. But empirical evidence for such trade-offs is scant, which has called into question the likelihood of nonallopatric speciation. Here, we report on the second in a series of studies testing for host-related selection on pupal life-history characteristics of apple (Malus pumila L.) and hawthorn- (Crataegus mollis L. spp.) infesting races of the Tephritid fruit fly, Rhagoletis pomonella (Walsh). In particular, we examine the effects of winter length on the genetics of these flies. We have previously found that the earlier fruiting phenology of apple trees exposes apple-fly pupae to longer periods of warm weather preceding winter than hawthorn-fly pupae. Because R. pomonella has a facultative diapause, we hypothesized that this selects for pupae with more recalcitrant pupal diapauses (or slower metabolic/development rates) in the apple-fly race. A study in which we experimentally manipulated the length of the prewintering period for hawthorn origin pupae supported this prediction. If the period preceding winter is important for apple- and hawthorn-fly pupae, then so too should be the length (duration) of winter; the rationale for this prediction is that "fast developing" pupae that break diapause too early will deplete their energy reserves and disproportionately die during long winters. To test this possibility, we chilled apple- and hawthorn-origin pupae collected from a field site near Grant, Michigan, in a refrigerator at 4 degrees C for time periods ranging from one week to two years. Our a priori expectation was that longer periods of cold storage would select against allozyme markers that were associated with faster rates of development in our earlier study. Since these electromorphs are typically found at higher frequencies in hawthorn flies, extending the overwintering period should favor "apple-fly alleles" in both races. The results from this "overwinter" experiment supported the diapause hypothesis. The anticipated genetic response was observed in both apple and hawthorn races, as allele frequencies became significantly more "apple-fly-like" in eclosing adults surviving longer chilling periods. This indicates that it is the combination of environmental conditions before and during winter that selects on the host races. Many tests for trade-offs fail to adequately consider the interplay between insect development, host plant phenology, and local climatic conditions. Our findings suggest that such oversight may help to explain the paucity of reported fitness trade-offs. PMID- 28565110 TI - EVOLUTION OF DISPERSAL RATES IN METAPOPULATION MODELS: BRANCHING AND CYCLIC DYNAMICS IN PHENOTYPE SPACE. AB - We study the evolution of dispersal rates in a two patch metapopulation model. The local dynamics in each patch are given by difference equations, which, together with the rate of dispersal between the patches, determine the ecological dynamics of the metapopulation. We assume that phenotypes are given by their dispersal rate. The evolutionary dynamics in phenotype space are determined by invasion exponents, which describe whether a mutant can invade a given resident population. If the resident metapopulation is at a stable equilibrium, then selection on dispersal rates is neutral if the population sizes in the two patches are the same, while selection drives dispersal rates to zero if the local abundances are different. With non-equilibrium metapopulation dynamics, non-zero dispersal rates can be maintained by selection. In this case, and if the patches are ecologically identical, dispersal rates always evolve to values which induce synchronized metapopulation dynamics. If the patches are ecologically different, evolutionary branching into two coexisting dispersal phenotypes can be observed. Such branching can happen repeatedly, leading to polymorphisms with more than two phenotypes. If there is a cost to dispersal, evolutionary cycling in phenotype space can occur due to the dependence of selection pressures on the ecological attractor of the resident population, or because phenotypic branching alternates with the extinction of one of the branches. Our results extend those of Holt and McPeek (1996), and suggest that phenotypic branching is an important evolutionary process. This process may be relevant for sympatric speciation. PMID- 28565111 TI - THE EFFECTS OF GENE FLOW ON REINFORCEMENT. AB - We explore the possibility that differences in the pattern of gene flow between populations may affect the evolution of reinforcement by comparing pairs of populations undergoing one-way migration versus symmetric migration. The case of symmetric migration is modeled by a two-island model, where the two populations exchange equal proportions of migrants each generation. One-way migration is modeled by a continent-island model, where migration is in one direction from a large continental population with a fixed genotype to an island population whose genotype frequencies can vary. Hybrid inviability is assumed to be caused by epistatic interactions between background loci. We examine the spread of an introduced preference allele for a previously unpreferred male trait that characterizes one of the populations. Computer simulations indicate that with a weak introduced preference, reinforcement is possible under a wide range of parameter values in a symmetric migration model but cannot occur in a one-way migration model. Reinforcement with one-way migration can occur only with a very strong introduced preference and very strong selection against hybrids. Our results suggest that the speciation of a peripheral isolate, which undergoes essentially one-way migration, may be difficult to complete if secondary contact occurs before reproductive isolation is fully developed. PMID- 28565112 TI - THE SEX-RATIO TRAIT IN DROSOPHILA SIMULANS: GEOGRAPHICAL DISTRIBUTION OF DISTORTION AND RESISTANCE. AB - The sex-ratio trait we describe here in Drosophila simulans results from X-linked meiotic drive. Males bearing a driving X chromosome can produce a large excess of females (about 90%) in their progeny. This is, however, rarely the case in the wild, where resistance factors, including autosomal suppressors and insensitive Y chromosomes, prevent the expression of the driver. In this study, we searched for drive and resistance factors in strains of Drosophila simulans collected all over the world. Driving X chromosomes were found in all populations whenever a good sample size was available. Their frequency may reach up to 60%. However, the presence of driving X chromosomes never results in an excess of females, due to the systematic co-occurrence of resistance factors. The highest frequencies of driving X chromosomes were observed in islands, while populations from East and Central Africa (the supposed center of origin of the species) showed the highest level of resistance. The geographical pattern of drive and resistance factors, as well as the results of crosses between strains from different geographical areas, suggest that the sex-ratio system described here has a unique and ancient origin in the species. PMID- 28565113 TI - PLEIOTROPIC EFFECTS OF INDIVIDUAL GENE LOCI ON MANDIBULAR MORPHOLOGY. AB - The genotypic basis of morphological variation is largely unknown. In this study we examine patterns of pleiotropic effects on mandibular morphology at individual gene loci to determine whether the pleiotropic effects of individual genes are restricted to functionally and developmentally related traits. Mandibular measurements were obtained from 480 mice from the F2 generation of an intercross between the LG/J and SM/J mouse strains. DNA was also extracted from these animals, and 76 microsatellite loci covering the autosomes were scored. Interval mapping was used to detect chromosomal locations with significant effects on various mandibular measurements. Sets of traits mapping to a common chromosomal region were considered as being affected by a single quantitative trait locus (QTL) for mandibular morphology. Thirty-seven such chromosomal regions were identified spread throughout the autosomes. Gene effects were small to moderate with the allele derived from the LG/J strain typically leading to larger size. When dominance was present, the LG/J allele was typically dominant to the SM/J allele. Most loci affected restricted functional and developmental regions of the mandible. Of the 26 chromosomal regions affecting more than two traits, 50% affect the muscular processes of the ascending ramus, 27% affect the alveolar processes carrying the teeth, and 23% affect the whole mandible. Four additional locations affecting two traits had effects significantly associated with alveolar regions. Pleiotropic effects are typically restricted to morphologically integrated complexes. PMID- 28565114 TI - IS PINUS SYLVESTRIS RESISTANCE TO PINE TWIST RUST ASSOCIATED WITH FITNESS COSTS OR BENEFITS? AB - Seven-year-old Pinus sylvestris were studied in two field trials with respect to height growth and injury caused by the fungal pathogen Melampsora pinitorqua. Each trial comprised single-tree progenies from two to 11 parent trees from each of 45 pine populations in northern Sweden (open pollinated) and Finland (control pollinated with a pollen mixture from 22 north Swedish trees). Heritability estimates were in the range of 6-18%. Most of genetic variation in height growth and rust resistance in Swedish populations and in height growth in Finnish populations occurred within populations (86-100%). In populations of Finnish origin variation in rust resistance consisted of more equal among- and within population components (68% and 32%, respectively). Family genetic correlations between pathogen resistance and tree height the previous year (disease-free environment) were positive among Finnish populations and Swedish coast populations, suggesting that pathogen resistance confers fitness benefits even in the absence of disease, whereas Swedish inland populations showed a negative correlation indicative of fitness costs. Patterns of genetic correlations at the population level tended to be just the reverse compared with those found at the family level. No genotype * trial interactions were detected for any of the examined characters. Prerequisites for establishment of a genecological balance between host and parasite are discussed. PMID- 28565115 TI - SPECIATIONAL HISTORY IN A DIVERSE CLADE OF HABITAT-SPECIALIZED SPIDERS (ARANEAE: NESTICIDAE: NESTICUS): INFERENCES FROM GEOGRAPHIC-BASED SAMPLING. AB - This paper summarizes the results of an initial effort to reconstruct the speciational history of cave spiders (Nesticus) from the southern Appalachian Mountains of eastern North America. The Appalachian Nesticus fauna includes a large series of about 30 species distributed across islandlike cave and montane habitats. Many of the species are geographically restricted; all of the species are found in allopatry. Observed patterns of morphological variation and biogeographic evidence suggest that species diversification in this lineage may have occurred recently, perhaps in response to Pleistocene climatic fluctuations. To address questions about the spatial and temporal dynamics of Nesticus speciation, while accounting for potential phylogenetic difficulties, I have gathered nuclear and mitochondrial DNA sequences for a sample of individuals from 81 populations representing 28 Nesticus species. Analyses of these data indicate that considerable genetic divergence exists within and among currently recognized morphological species. Consistent with relatively deep species divergences, most of which likely predate the Pleistocene, is a prevailing pattern of phylogenetic concordance between taxonomic species and monophyletic gene tree lineages. The few deviations from monophyly detected can be tentatively attributed to a peripatric mode of speciation. Although species limits as inferred by the molecular data are generally concordant with patterns of morphological continuity and discontinuity in genitalia, there is evidence to suggest that cryptic phylogenetic lineages exist within some morphologically continuous units. This observation, in combination with the general depth of species lineages, makes any argument about rapid evolution in Nesticus genitalic characteristics unnecessary. PMID- 28565116 TI - CONSEQUENCES OF INBREEDING ON INVERTEBRATE HOST SUSCEPTIBILITY TO PARASITIC INFECTION. PMID- 28565117 TI - MOLECULAR PHYLOGENETIC ANALYSIS OF LIFE-HISTORY EVOLUTION IN ASTERINID STARFISH. AB - We analyzed phylogenetic relationships among 12 nominal species of starfish in the genera Patiriella and Asterina (Order Valvatida, Family Asterinidae), based on complete sequences for a mitochondrial protein coding gene (cytochrome oxidase subunit I) and five mitochondrial transfer RNA genes (alanine, leucine, asparagine, glutamine, and proline) (1923 bp total). The resulting phylogeny was used to test a series of hypotheses about the evolution of life-history traits. (1) A complex, feeding, planktonic larva is probably ancestral for these starfish, but this is not the most parsimonious reconstruction of ancestral larval states. (2) The feeding larval form was lost at least four times among these species, and three of these losses occurred among members of a single clade. (3) Small adult size evolved before both cases of hermaphroditism and viviparous brooding, but viviparity was not always preceded by an intermediate form of external brooding. (4) An ordered transformation series from feeding planktonic development to viviparous brooding has been predicted for starfish, but we could not find an example of this transformation series. (5) Viviparity evolved recently (< 2 Mya). (6) Both species selection and transformation of lineages may have contributed to the accumulation of species with nonfeeding development among these starfish. (7) Neither Asterina nor Patiriella are monophyletic genera. Larval forms and life-history traits of these starfish have evolved freely under no obvious constraints, contrary to the widely assumed evolutionary conservatism of early development. PMID- 28565118 TI - NATURAL SELECTION FOR ENVIRONMENTALLY INDUCED PHENOTYPES IN TADPOLES. AB - Models suggest that phenotypic plasticity is maintained in situations where the optimal phenotype differs through time or space, so that selection acts in different directions in different environments. Some empirical work supports the general premise of this prediction because phenotypes induced by a particular environment sometimes perform better than other phenotypes when tested in that environment. We have extended these results by estimating the targets of selection in Pseudacris triseriata tadpoles in environments without predators and with larval Anax dragonflies. Tadpoles displayed significant behavioral and morphological plasticity when reared in the presence and absence of nonlethal dragonflies for 32 days in cattle tanks. We measured selection in the absence of free predators by regressing growth and survival in the tanks against activity and several measures of tail and body shape. We measured selection in the presence of predators by exposing groups of 10 tadpoles to Anax in overnight predation trials and regressing the average phenotype of survivors against the number of tadpoles killed. Selection in the two environments acted in opposite directions on both tail and body shape, although the affected fitness components were different. In the presence of Anax, tadpoles with shallow and narrow body, deep tail fin, and wide tail muscle survived best. In the absence of free predators, tadpoles with narrow tail muscle grew significantly faster, and those with shallow tail fin and deep body grew somewhat faster. Activity was unrelated to survival or growth in either environment. Developmental plasticity in tail shape closely paralleled selection, because tail fin depth increased after long term exposure to Anax and tail muscle width tended to increase. In contrast, there was no plasticity in body shape in spite of strong selection for decreasing body depth. Thus, when confronted with a dragonfly predator, P. triseriata tadpoles adjusted their tail shape (but not body shape) almost exactly in the direction of selection imposed by Anax. These results suggest that phenotypic plasticity in some morphological traits, such as tail depth and tail muscle width, has evolved under intermittent selection by dragonflies. Other traits that undergo selection by dragonflies, such as body morphology, appear developmentally rigid, perhaps because of historically strong opposing selection in nature or other constraints. PMID- 28565119 TI - THE PRICE EQUATION, FISHER'S FUNDAMENTAL THEOREM, KIN SELECTION, AND CAUSAL ANALYSIS. AB - A general framework is presented to unify diverse models of natural selection. This framework is based on the Price Equation, with two additional steps. First, characters are described by their multiple regression on a set of predictor variables. The most common predictors in genetics are alleles and their interactions, but any predictor may be used. The second step is to describe fitness by multiple regression on characters. Once again, characters may be chosen arbitrarily. This expanded Price Equation provides an exact description of total evolutionary change under all conditions, and for all systems of inheritance and selection. The model is first used for a new proof of Fisher's fundamental theorem of natural selection. The relations are then made clear among Fisher's theorem, Robertson's covariance theorem for quantitative genetics, the Lande-Arnold model for the causal analysis of natural selection, and Hamilton's rule for kin selection. Each of these models is a partial analysis of total evolutionary change. The Price Equation extends each model to an exact, total analysis of evolutionary change for any system of inheritance and selection. This exact analysis is used to develop an expanded Hamilton's rule for total change. The expanded rule clarifies the distinction between two types of kin selection coefficients. The first measures components of selection caused by correlated phenotypes of social partners. The second measures components of heritability via transmission by direct and indirect components of fitness. PMID- 28565120 TI - THE GENETICS OF ADAPTATION: THE GENETIC BASIS OF RESISTANCE TO WASP PARASITISM IN DROSOPHILA MELANOGASTER. AB - There have been very few genetic analyses of "natural" adaptations, that is, those not involving artificial selection or responses to human disturbance. Here we analyze the genetic basis of geographic variation in Drosophila melanogaster's resistance to parasitism by a wasp, Asobara tabida. Our results suggest that population differences in ability to encapsulate parasitoid eggs have a fairly simple genetic basis: 60% of the D. melanogaster genome plays no role in differences between resistant and susceptible populations. Instead, resistance gene(s) are restricted to chromosome two, and may be further restricted to the centromeric region of this chromosome. This finding suggests that natural adaptations-like many responses to artificial selection and human disturbance sometimes have a simple genetic basis. PMID- 28565121 TI - SALIVARY ANDROGEN-BINDING PROTEIN (ABP) MEDIATES SEXUAL ISOLATION IN MUS MUSCULUS. AB - We wanted to determine whether the microevolution of the mouse salivary androgen binding protein (ABP) Alpha subunit gene (Abpa) could mediate sexual selection and thereby have a potential role in maintaining gene pool integrity where radiating mouse subspecies make secondary contact. This hypothesis is based upon previous work in this laboratory, which has shown that each subspecies apparently has its own allele and that these alleles have a 25-fold excess of nonsynonymous/synonymous base substitutions compared to an average protein under purifying selection. We provide direct evidence for ABP-assortative mate selection in a laboratory setting: Mus musculus domesticus and M. m. musculus female mice recognize and discriminate between the territories of male mice that essentially differ solely in their Abpa genotype and, when the males are present, the female prefers to mate with the one of her own ABP type. The observation that females could differentiate between the territories of the two males when those mice were absent suggests that the males marked their territories with ABP. In this study, we also detected ABP on the pelts of male mice and in their environment. It is likely that the animals apply the protein to their pelts by licking and that it is then deposited in their surroundings. We suggest that females of the two subspecies are able to discriminate between males of those subspecies on the basis of this protein molecule. Mouse salivary ABP might present a worthwhile system with which to study a prezygotic isolation mechanism in a mammal. PMID- 28565122 TI - THE EFFECTS OF FIVE GENERATIONS OF ENFORCED SELFING ON POTENTIAL MALE AND FEMALE FUNCTION IN MIMULUS GUTTATUS. AB - In prior work we detected no significant inbreeding depression for pollen and ovule production in the highly selfing Mimulus micranthus, but both characters showed high inbreeding depression in the mixed-mating M. guttatus. The goal of this study was to determine if the genetic load for these traits in M. guttatus could be purged in a program of enforced selfing. These characters should have been under much stronger selection in our artificial breeding program than previously reported characters such as biomass and total flower production because, for example, plants unable to produce viable pollen could not contribute to future generations. Purging of genetic load was investigated at the level of both the population and the individual maternal line within two populations of M. guttatus. Mean ovule number, pollen number, and pollen viability declined significantly as plants became more inbred. The mean performance of outcross progeny generated from crosses between pairs of maternal inbred lines always exceeded that of self progeny and was fairly constant for each trait through all five generations. The consistent performance of outcross progeny and the universally negative relationships between performance and degree of inbreeding are interpreted as evidence for the weakness of selection relative to the quick fixation of deleterious alleles due to drift during the inbreeding process. The selective removal (purging) of deleterious alleles from our population would have been revealed by an increase in performance of outcross progeny or an attenuation of the effects of increasing homozygosity. The relationships between the mean of each of these traits and the expected inbreeding coefficient were linear, but one population displayed a significant negative curvilinear relationship between the log of male fertility (a function of pollen number and viability) and the inbreeding coefficient. The generally linear form of the responses to inbreeding were taken as evidence consistent with an additive model of gene action, but the negative curvilinear relationship between male fertility and the inbreeding coefficient suggested reinforcing epistasis. Within both populations there was significant genetic variation among maternal lineages for the response to inbreeding in all traits. Although all inbred lineages declined at least somewhat in performance, several maternal lines maintained levels of performance just below outcross means even after four or five generations of selfing. We suggest that selection among maternal lines will have a greater effect than selecting within lines in lowering the genetic load of populations. PMID- 28565123 TI - THE EVOLUTION OF SOCIAL SIGNALS: MORPHOLOGICAL, FUNCTIONAL, AND GENETIC INTEGRATION OF THE SEX PHEROMONE IN NAUPHOETA CINEREA. AB - Social signals that mediate intraspecific interactions can be complex, conveying considerable information concerning the probable behavior of individuals and minimizing overt aggression and wasted energy. In the cockroach Nauphoeta cinerea, male-male competition and female mate choice are mediated by a multicomponent male-produced sex pheromone. In this study, I examine variation in this pheromone. First I measure differences among males in both individual pheromone compounds and the overall composition of the pheromone. Principal component analysis is used to quantify and describe pheromone composition. Next, I explore some of the causes and consequences of this variation by examining the pheromone of males with different social experiences. Compared to subordinate males, dominant males have significantly less variable quantities of the individual pheromone compounds and are significantly less variable in the composition of their pheromone. Because of an association between status and mating success, male-male competition can result in stabilizing sexual selection on the sex pheromone. Finally, I test the hypothesis that the pheromone compounds evolve in a manner consistent with their function. As predicted for morphologically integrated characters, the patterns of phenotypic, genetic, and environmental correlations among my measures of pheromone compounds and composition match functional patterns suggested by this study and the developmental patterns demonstrated in my previous studies. Based on these studies of the N. cinerea sex pheromone, I argue that stabilizing sexual selection shapes the evolution of pheromonal communication involved in social interactions among male N. cinerea. Further, I argue that coordinated evolution of social signals may be possible due to the morphological integration of their multiple compounds. PMID- 28565124 TI - EVOLUTION OF THERMAL SENSITIVITY OF PARASITIZATION CAPACITY IN EGG PARASITOIDS. PMID- 28565125 TI - THE MAINTENANCE OF A CLINE IN THE MARINE SNAIL LITTORINA SAXATILIS: THE ROLE OF HOME SITE ADVANTAGE AND HYBRID FITNESS. AB - Steep clinal transitions in one or several inherited characters between genetically distinct populations are usually referred to as hybrid zones. Essentially two different mechanisms may maintain steep genetic clines. Either selection acts against hybrids that are unfit over the entire zone due to their mixed genetic origin (endogenous selection), or hybrids and parental types attain different fitness values in different parts of the cline (exogenous selection). Survival rate estimates of hybrids and parental forms in different regions of the cline may be used to distinguish between these models to assess how the cline is maintained. We used reciprocal transplants to test the relative survival rates of two parental ecotypes and their hybrids over microscale hybrid zones in the direct-developing marine snail Littorina saxatilis (Olivi) on the rocky shores of Galicia, Spain. One of the parental forms occupies upper and the other lower shores, and the hybrids are found at various proportions (1-38%) along with both parental forms in a midshore zone a few meters wide. The survival rate over one month was 39-52% of the native ecotype on upper shores, but only 2-8% for the lower-shore ecotype. In contrast, only 4-8% of the upper-shore ecotype but 53% of large (> 6 mm) and 8% of small (3-6 mm) native lower-shore ecotype survived in the lower shores. In the midshores, both the two parental ecotypes and the hybrids survived about equally well. Thus there is a considerable advantage for the native ecotypes in the upper and lower shores, while in the hybrid zone none of the morphs, hybrids included, are favored. This indicates that the dimorphism of L. saxatilis is maintained by steep cross-shore selection gradients, thus supporting the selection-gradient model of hybrid zones. We performed field and laboratory experiments that suggest physical factors and predation as important selective agents. Earlier studies indicate assortative mating between the two ecotypes in the midshore. This is unexpected in a hybrid zone maintained by selection gradients, and it seems as if the reproductive barrier compresses the hybrid zone considerably. PMID- 28565126 TI - GEOGRAPHIC VARIATION AND PHENOTYPIC PLASTICITY OF NUMBER OF TRUNK VERTEBRAE IN SLENDER SALAMANDERS, BATRACHOSEPS (CAUDATA: PLETHODONTIDAE). AB - To understand the evolutionary significance of geographic variation, one must identify the factors that generate phenotypic differences among populations. I examined the causes of geographic variation in and evolutionary history of number of trunk vertebrae in slender salamanders, Batrachoseps (Caudata: Plethodontidae). Number of trunk vertebrae varies at many taxonomic levels within Batrachoseps. Parallel clines in number occur along an environmental gradient in three lineages in the Coast Ranges of California. These parallel clines may signal either adaptation or a shared phenotypically plastic response to the environmental gradient. By raising eggs from 10 populations representing four species of Batrachoseps, I demonstrated that number of trunk vertebrae can be altered by the developmental temperature; however, the degree of plasticity is insufficient to account for geographic variation. Thus, the geographic variation results largely from genetic variation. Number of trunk vertebrae covaries with body size and shape in diverse vertebrate taxa, including Batrachoseps. I hypothesize that selection for different degrees of elongation, possibly related to fossoriality, has led to the extensive evolution of number of trunk vertebrae in Batrachoseps. Analysis of intrapopulational variation revealed sexual dimorphism in both body shape and number of trunk vertebrae, but no correlation between these variables in either sex. Females are more elongate than males, a pattern that has been attributed to fecundity selection in other taxa. Patterns of covariation among different classes of vertebrae suggest that some intrapopulational variation in number results from changes in vertebral identity rather than changes in segmentation. PMID- 28565127 TI - BATESIAN MIMICRY AND SIGNAL ACCURACY. PMID- 28565128 TI - LIKELIHOOD OF ANCESTOR STATES IN ADAPTIVE RADIATION. AB - Theories of ecological diversification make predictions about the timing and ordering of character state changes through history. These theories are testable by "reconstructing" ancestor states using phylogenetic trees and measurements of contemporary species. Here we use maximum likelihood to estimate and evaluate the accuracy of ancestor reconstructions. We present likelihoods of discrete ancestor states and derive probability distributions for continuous ancestral traits. The methods are applied to several examples: diets of ancestral Darwin's finches; origin of inquilinism in gall wasps; microhabitat partitioning and body size evolution in scrubwrens; digestive enzyme evolution in artiodactyl mammals; origin of a sexually selected male trait, the sword, in platies and swordtails; and evolution of specialization in Anolis lizards. When changes between discrete character states are rare, the maximum-likelihood results are similar to parsimony estimates. In this case the accuracy of estimates is often high, with the exception of some nodes deep in the tree. If change is frequent then reconstructions are highly uncertain, especially of distant ancestors. Ancestor states for continuous traits are typically highly uncertain. We conclude that measures of uncertainty are useful and should always be provided, despite simplistic assumptions about the probabilistic models that underlie them. If uncertainty is too high, reconstruction should be abandoned in favor of approaches that fit different models of trait evolution to species data and phylogenetic trees, taking into account the range of ancestor states permitted by the data. PMID- 28565129 TI - SYMPATRIC SPECIATION VIA HABITAT SPECIALIZATION DRIVEN BY DELETERIOUS MUTATIONS. AB - Theoretical studies have suggested that the evolution of habitat (host) races, regarded as a prelude to sympatric speciation, requires strong trade-offs in adaptation to different habitats: alleles that improve fitness in some habitats and have deleterious effects of similar magnitude in other habitats must be segregating in the population. I argue that such trade-offs are not necessary; the evolution of habitat races can also be driven by genetic variation due to loci that affect fitness in one habitat and are neutral or nearly so in others, that is, when performance in different habitats is genetically independent. One source of such genetic variation are deleterious mutations with habitat-specific fitness effects. I use deterministic two-locus and multilocus models to show that the presence of such mutations in the gene pool results in indirect selection favoring habitat fidelity or habitat preference over acceptance of both suitable habitats. This leads to the evolution of largely genetically isolated populations that use different habitats, from a single panmictic population of individuals accepting both habitats. This study suggests that the conditions favoring habitat race formation, and thus possibly sympatric speciation, are much less stringent than previously thought. PMID- 28565130 TI - CHROMOSOMAL ANALYSIS OF HEAT-SHOCK TOLERANCE IN DROSOPHILA MELANOGASTER EVOLVING AT DIFFERENT TEMPERATURES IN THE LABORATORY. AB - We investigated the heat tolerance of adults of three replicated lines of Drosophila melanogaster that have been evolving independently by laboratory natural selection for 15 yr at "nonextreme" temperatures (18 degrees C, 25 degrees C, or 28 degrees C). These lines are known to have diverged in body size and in the thermal dependence of several life-history traits. Here we show that they differ also in tolerance of extreme high temperature as well as in induced thermotolerance ("heat hardening"). For example, the 28 degrees C flies had the highest probability of surviving a heat shock, whereas the 18 degrees C flies generally had the lowest probability. A short heat pretreatment increased the heat tolerance of the 18 degrees C and 25 degrees C lines, and the threshold temperature necessary to induce thermotolerance was lower for the 18 degrees C line than for the 25 degrees C line. However, neither heat pretreatment nor acclimation to different temperatures influenced heat tolerance of the 28 degrees C line, suggesting the loss of capacity for induced thermotolerance and for acclimation. Thus, patterns of tolerance of extreme heat, of acclimation, and of induced thermotolerance have evolved as correlated responses to natural selection at nonextreme temperatures. A genetic analysis of heat tolerance of a representative replicate population each from the 18 degrees C and 28 degrees C lines indicates that chromosomes 1, 2, and 3 have significant effects on heat tolerance. However, the cytoplasm has little influence, contrary to findings in an earlier study of other stocks that had been evolving for 7 yr at 14 degrees C versus 25 degrees C. Because genes for heat stress proteins (hsps) are concentrated on chromosome 3, the potential role of hsps in the heat tolerance and of induced thermotolerance in these naturally selected lines is currently unclear. In any case, species of Drosophila possess considerable genetic variation in thermal sensitivity and thus have the potential to evolve rapidly in response to climate change; but predicting that response may be difficult. PMID- 28565132 TI - WHEN DID EVE LIVE? AN EVOLUTIONARY DETECTIVE STORY. AB - Various estimates of the time at which the human mitochondrial Eve lived have ranged from as little as 60,000 yr to more than 500,000 yr ago. Because of this immense range, it is impossible to distinguish between single-origin and multiple origins hypotheses for the evolution of our species. In an attempt to reduce the uncertainty, I have examined the largest available body of sequence information, comprising the mitochondrial control region, for clues to how the observed diversity arose. In this region it is possible to show, by examining the distribution of polymorphic sites, that transitions have occurred at some sites at a much higher rate than at others. Computer simulations can, when two rates for transitions are postulated, provide close approximations to the distribution of substitutions seen in the actual data. The "best fit" was obtained when the rate at 3/4 of the sites was 4 times the transversion rate, and the rate at the remainder 160 times the transversion rate. The likelihood of such a high rate at some sites helps to explain why tree-building methods employing these data have provided so little phylogenetic information. Furthermore, it is possible to show that transversions do not appear to occur preferentially at these transition "hot spot" sites and that such huge differences in substitution rates are not seen for transversions, suggesting that the rules governing the mutation and acceptance or rejection of transversions are different from those governing transitions. The great majority of transversions appear to occur at a low rate throughout the region. Thus, methods for determining the age of Eve that are based on recent divergence in human populations, or on applying a mutation probability matrix based on an assumption of uniform mutation rates, are likely to result in underestimates. The rate of accumulation of transversions is shown to be a more accurate estimator of the age of Eve. The conclusion is reached that Eve probably lived (depending on when the ancestors of humans and chimpanzees diverged) between 436,000 and 806,000 yr ago. PMID- 28565131 TI - INFERRING PHYLOGENIES FROM mtDNA VARIATION: MITOCHONDRIAL-GENE TREES VERSUS NUCLEAR-GENE TREES. AB - An accurately resolved gene tree may not be congruent with the species tree because of lineage sorting of ancestral polymorphisms. DNA sequences from the mitochondrially encoded genes (mtDNA) are attractive sources of characters for estimating the phylogenies of recently evolved taxa because mtDNA evolves rapidly, but its utility is limited because the mitochondrial genes are inherited as a single linkage group (haplotype) and provide only one independent estimate of the species tree. In contrast, a set of nuclear genes can be selected from distinct chromosomes, such that each gene tree provides an independent estimate of the species tree. Another aspect of the gene-tree versus species-tree problem, however, favors the use of mtDNA for inferring species trees. For a three-species segment of a phylogeny, the branching order of a gene tree will correspond to that of the species tree if coalescence of the alleles or haplotypes occurred in the internode between the first and second bifurcation. From neutral theory, it is apparent that the probability of coalescence increases as effective population size decreases. Because the mitochondrial genome is maternally inherited and effectively haploid, its effective population size is one-fourth that of a nuclear-autosomal gene. Thus, the mitochondrial-haplotype tree has a substantially higher probability of accurately tracking a short internode than does a nuclear-autosomal-gene tree. When an internode is sufficiently long that the probability that the mitochondrial-haplotype tree will be congruent with the species tree is 0.95, the probability that a nuclear-autosomalgene tree will be congruent is only 0.62. If each of k independently sampled nuclear-gene trees has a probability of congruence with the species tree of 0.62, then a sample of 16 such trees would be required to be as confident of the inference based on the mitochondrial-haplotype tree. A survey of mtDNA-haplotype diversity in 34 species of birds indicates that coalescence is generally very recent, which suggests that coalescence times are typically much shorter than internodal branch lengths of the species tree, and that sorting of mtDNA lineages is not likely to confound the species tree. Hybridization resulting in transfer of mtDNA haplotypes among branches could also result in a haplotype tree that is incongruent with the species tree; if undetected, this could confound the species tree. However, hybridization is usually easy to detect and should be incorporated in the historical narrative of the group, because reticulation, as well as cladistic events, contributed to the evolution of the group. PMID- 28565133 TI - HOST POPULATION STRUCTURE AND THE EVOLUTION OF VIRULENCE: A "LAW OF DIMINISHING RETURNS". AB - Structure in a population of host individuals, whether spatial or temporal, can have important effects on the transmission and evolutionary dynamics of its pathogens. One of these is to limit dispersal of pathogens and thus increase the amount of contact between a given pair or within a small group of host individuals. We introduce a "law of diminishing returns" that predicts an evolutionary decline of pathogen virulence whenever there are on average more possibilities of pathogen transmission between the same pair of hosts. Thus, the effect of repeated contact between hosts will be to shift the balance of any trade-off between virulence and transmissibility toward lower virulence. PMID- 28565134 TI - PHENOTYPIC PLASTICITY AND REACTION NORMS IN TEMPERATE AND TROPICAL POPULATIONS OF DROSOPHILA MELANOGASTER: OVARIAN SIZE AND DEVELOPMENTAL TEMPERATURE. AB - The plasticity of ovariole number relative to developmental temperature was studied in three populations of Drosophila melanogaster at both ends of the cline: a temperate French population and two equatorial Congolese. Ovary size was much greater in the French flies, in agreement with an already known latitudinal cline. Among isofemale lines, significant differences in genetic variability were observed between populations with a maximum variability at intermediate temperatures. Parameters of phenotypic variability (CV and FA) were not statistically different among lines or populations, but a significant increase at low temperature was demonstrated for both. The shapes of the response curves (i.e., the norm of reaction) were analyzed by adjusting the data to a quadratic equation. The parameters of the equation were highly variable among lines. On the other hand, the temperature for maximum value of ovarioles (TMV) was much less variable and exhibited only a slightly significant difference between temperate and tropical flies (22.2 degrees C vs. 22.7 degrees C). During its geographic extension toward colder places, D. melanogaster underwent a large, presumably adaptative, increase in ovariole number but very little change in the norm of reaction of that trait. PMID- 28565135 TI - HYBRID BREAKDOWN BETWEEN TWO HAPLODIPLOID SPECIES: THE ROLE OF NUCLEAR AND CYTOPLASMIC GENES. AB - A central question in evolutionary biology concerns the population and genetic processes by which new species arise. Here, the genetic basis of hybrid breakdown between two haplodiploid species, Nasonia vitripennis and N. giraulti is investigated. Hybridization between the two species is normally prevented by microorganisms that cause bidirectional incompatibility. However, after elimination of microorganisms, F1 hybrids females are readily produced (due to haplodiploidy, males develop from unfertilized eggs and are therefore not hybrids). F1 hybrid females are viable and fecund, but recombinant (haploid) F2 male offspring suffer from severe hybrid breakdown (larval and pupal mortality). This is typically interpreted as evidence for the existence of different coadapted gene complexes in the two species, which are broken up by recombination. F2 recombinant eggs were rescued by fertilization with the complete chromosome complement from either species, supporting the view that hybrid lethality genes tend to be recessive. Negative epistatic interactions occur between nuclear genes of the two species, and between cytoplasmically inherited factors (cytoplasmic genes) of giraulti and nuclear genes of vitripennis. Interactions between nuclear genes and cytoplasmic genes are asymmetric. Experiments clearly demonstrate that the latter incompatibility is not due to maternal-effect genes, but to cytoplasmically inherited elements. Nuclear-mitochondrial interactions are possibly involved. PMID- 28565136 TI - THE IMPACT OF TREE SQUIRRELS (TAMIASCIURUS) ON LIMBER PINE SEED DISPERSAL ADAPTATIONS. AB - Tree squirrels (Tamiasciurus) are important selective agents on conifer reproductive strategies (Smith 1970, 1975). Although this is well established for wind-dispersed pines, the impact of tree squirrels on bird-dispersed pines has been largely ignored. I assessed the impact of tree squirrels on the allocation of reproductive energy in the bird-dispersed limber pine (Pinus flexilis) by comparing its cone and seed traits from three sites in the Rocky Mountains where tree squirrels (Tamiasciurus) are present to those from three mountain ranges in the Great Basin where tree squirrels are absent. As predicted, differences between the two regions in individual cone and seed traits are consistent with the hypothesis that tree squirrels are important selective agents on these traits. In the absence of tree squirrels, limber pine allocates more than twice as much energy to kernel compared with that invested in putative seed defenses (cone, resin, and seed coat) as does limber pine where tree squirrels are present. Such a large difference is particularly striking, because tree squirrels may have become extinct in the Great Basin in only the last 12,000 yr. Although many factors influence the allocation of energy to cones and seeds, no single factor other than the presence of tree squirrels is compatible with the large and consistent differences between limber pine in the Rocky Mountains and Great Basin. These results show that tree squirrels are an important constraint on the evolution of cone and seed traits that promote the dispersal of seeds by birds. PMID- 28565137 TI - AN ANALYSIS OF SELECTIONAL RESPONSE IN RELATION TO A POPULATION BOTTLENECK. AB - Selection for increased morphometric shape (ratio of wing length to thorax width) was compared between control (nonbottlenecked) populations and bottlenecked populations founded with two male-female pairs of flies. Contrary to neutral expectation, selectional response was not reduced in bottlenecked populations, and the mean realized heritabilities and additive genetic variances were higher for the bottlenecked lines than for the nonbottlenecked lines. Additive genetic variances based on these realized heritabilities were consistent with independent estimates of genetic variances based on parent-offspring covariances. Joint scaling tests applied to the crosses between selected lines and their controls revealed significant nonadditive components of genetic variance in the ancestor, which were not detected in the crosses involving bottlenecked lines. The nonbottlenecked lines responded principally by changes in one trait or the other (wing length or thorax width) but not in both, and regardless of which trait responded, larger trait size was dominant and epistatic to smaller size. Stabilizing selection for morphometric shape in the ancestor likely molded the genetic architecture to include nonadditive genetic effects. PMID- 28565138 TI - EFFECT OF ECTOPARASITIC MITES ON SEXUAL SELECTION IN A SONORAN DESERT FRUIT FLY. AB - We conducted a field study and a laboratory experiment to test whether ectoparasitic mites, Macrocheles subbadius, generate parasite-mediated sexual selection in the Sonoran desert endemic fruit fly, Drosophila nigrospiracula. Male flies gather on the outer surfaces of necrotic saguaro cacti where they engage in male-male competitive interactions and vigorous female-directed courtship. At these sites, operational sex ratios were significantly skewed toward males. The degree to which mites were aggregated among flies varied across the 25 fly populations sampled. The degree of mite aggregation across fly populations was strongly positively related to the mean number of mites per fly (intensity of infestation). Both the intensity and prevalence of infestation (fraction of flies infested) increased with the age of the cactus necrosis. Infested flies of both sexes were significantly less likely to be found in copula than uninfested flies, and mean intensity of infestation was significantly more pronounced in noncopulating than in copulating flies. The effect of attached mites on copulatory success exhibited dose-dependency, and this effect was more stringent in males: males or females with more than two and four mites, respectively, were never found in copula. The magnitude of parasite-mediated sexual selection was estimated for 12 fly populations by calculating selection differentials for each sex separately. The relation between intensity of infestation and magnitude of parasite-mediated sexual selection was stronger in males but significant for both sexes. We also assayed copulatory success of field caught males in the laboratory, both during infestation and after experimental removal of mites. Males infested with two mites copulated less frequently than uninfested individuals, and in mating trials after mites had been removed, previously infested males copulated as many times as flies with no history of infestation. These findings, and the lack of difference in the number of mite induced scars on copulating and single individuals in nature, strongly suggest that the reduced copulatory success of infested flies is attributable to an effect of mites per se, rather than to a character correlated with parasitism or previous parasite infestation. PMID- 28565139 TI - SELECTION ON FECUNDITY AND VARIATION IN THE DEGREE OF SEXUAL SIZE DIMORPHISM AMONG SPIDER SPECIES (CLASS ARANEAE). PMID- 28565140 TI - INFERRING THE RATES OF BRANCHING AND EXTINCTION FROM MOLECULAR PHYLOGENIES. AB - Molecular techniques provide ancestral phylogenies of extant taxa with estimated branching times. Here we studied the pattern of ancestral phylogeny of extant taxa produced by branching (or cladogenesis) and extinction of taxa, assuming branching processes with time-dependent rates. (1) If the branching rate b and extinction rate c are constant, the semilog plot of the number of ancestral lineages over time is not a straight line but is curvilinear, with increasing slope toward the end, implying that ancestral phylogeny shows apparent increase in the branching rate near the present. The estimate of b and c based on nonlinear fitting is examined by computer simulation. The estimate of branching rate can be usable for a large phylogeny if b is greater than c, but the estimate of extinction rate c is unreliable because of large bias and variance. (2) Gradual decrease in the slope of the semilog plot of the number of ancestral lineages over time, as was observed in a phylogeny of bird families based on DNA hybridization data, can be explained equally well by either the decreasing branching rate or the increasing extinction rate. Infinitely many pairs of branching and extinction rates as functions of time can produce the same ancestral phylogeny. (3) An explosive branching event in the past would appear as a quick increase in the number of ancestral lineages. In contrast, mass extinction occurring in a brief period, if not accompanied by an increase in branching rate, does not produce any rapid change in the number of ancestral lineages at the time. (4) The condition in which the number of ancestral lineages of extant species changes in parallel with the actual number of species in the past is derived. PMID- 28565141 TI - ALTERNATIVE ROUTES TO THE EVOLUTION OF COMPETITIVE ABILITY IN TWO COMPETING SPECIES OF DROSOPHILA. AB - The evolution of components of interspecific competitive ability was examined in three different environments for three replicate pairs of Drosophila melanogaster and D. simulans populations. Populations evolved enhanced competitive ability in three ways: (1) increased effectiveness at reducing the numbers of the competitor species; (2) increased resistance to the inhibitory effects of the competitor species; or (3) a combination of the two. Considerable variation was seen in the evolutionary outcomes of competition among environments, and also among replicate populations within environments. Significant replicate-by-environment interactions were also observed. The results suggest that the evolutionary routes to the evolution of enhanced competitive abilities can potentially differ among subdivided populations, creating a geographic mosaic of outcomes. PMID- 28565142 TI - DIRECT SELECTION ON LIFE SPAN IN DROSOPHILA MELANOGASTER. AB - An important issue in the study of the evolution of aging in Drosophila melanogaster is whether decreased early fecundity is inextricably coupled with increased life span in selection experiments on age at reproduction. Here, this problem has been tackled using an experimental design in which selection is applied directly to longevity. Selection appeared successful for short and long life, in females as well as males. Progeny production of females selected for long life was lower than for short-lived females throughout their whole life. No increase of late-life reproduction in long-lived females occurred, as has been found in selection experiments on age at reproduction. This discrepancy is explained in terms of the inadequacy of the latter design to separate selection on life span from selection on late-life fecundity. Moreover, starvation resistance and fat content were lower for adults selected for short life. In general, the data support the negative-pleiotropy-disposable-soma theory of aging, and it is hypothesized that the pleiotropic allocation of resources to maintenance versus to reproduction as implicated in the theory might involve lipid metabolism. It is argued that further research on this suggestion is urgent and should certainly comprise observations on male reproduction because these are for the greater part still lacking. In conclusion, the longevity of D. melanogaster can be genetically altered in a direct-selection design, and such an increase is accompanied by a decreased general reproduction and thus early reproduction. PMID- 28565143 TI - MAGPIE HOST MANIPULATION BY GREAT SPOTTED CUCKOOS: EVIDENCE FOR AN AVIAN MAFIA? AB - Why should the hosts of brood parasites accept and raise parasitic offspring that differ dramatically in appearance from their own? There are two solutions to this evolutionary enigma. (1) Hosts may not yet have evolved the capability to discriminate against the parasite, or (2) parasite-host systems have reached an evolutionary equilibrium. Avian brood parasites may either gain renesting opportunities or force their hosts to raise parasitic offspring by destroying or preying upon host eggs or nestlings following host ejection of parasite offspring. These hypotheses may explain why hosts do not remove parasite offspring because only then will hosts avoid clutch destruction by the cuckoo. Here we show experimentally that if the egg of the parasitic great spotted cuckoo Clamator glandarius is removed from nests of its magpie Pica pica host, nests suffer significantly higher predation rates than control nests in which parasite eggs have not been removed. Using plasticine model eggs resembling those of magpies and observations of parasites, we also confirm that great spotted cuckoos that have laid an ejected egg are indeed responsible for destruction of magpie nests with experimentally ejected parasite eggs. Cuckoos benefit from destroying host offspring because they thereby induce some magpies to renest and subsequently accept a cuckoo egg. PMID- 28565144 TI - UNPREDICTABILITY OF CORRELATED RESPONSE TO SELECTION: PLEIOTROPY AND SAMPLING INTERACT. AB - Given a set of loci that contribute additive genetic variation for a trait being selected, the pleiotropic effects of these loci on a second trait may vary. I simulated selection on genetic systems having different combinations of pleiotropic effects to investigate the variability of correlated responses to selection. The simulation shows that there are many possible combinations of pleiotropic effects that are characterized by the same value of the genetic correlation; the genetic correlation does not uniquely determine a set of pleiotropic effects. Furthermore, for a given value of the genetic correlation, differences in pleiotropic effects have a substantial impact on the variation in correlated responses. Some combinations of pleiotropic effects constrain correlated response to a narrow range of possible values; others allow a wide range, including some correlated responses in a direction opposite the sign of the genetic correlation. The genetic correlation is not a reliable predictor of pleiotropic constraint. Whereas it has been previously established that genetic correlations are not necessarily constraints, the alternative is also true: correlated response can be strictly constrained despite a genetic correlation of zero. Given the frequency of correlated responses in a direction opposite to the one predicted by the genetic correlation, it follows that correlated response is not a reliable predictor of genetic correlation in the base population. PMID- 28565145 TI - DISCORDANCE BETWEEN NUCLEAR AND CHLOROPLAST PHYLOGENIES IN THE HEUCHERA GROUP (SAXIFRAGACEAE). AB - Various factors, including taxon density, sampling error, convergence, and heterogeneity of evolutionary rates, can potentially lead to incongruence between phylogenetic trees based on different genomes. Particularly at the generic level and below, chloroplast capture resulting from hybridization may distort organismal relationships in phylogenetic analyses based on the chloroplast genome, or genes included therein. However, the extent of such discord between chloroplast DNA (cpDNA) trees and those trees based on nuclear genes has rarely been assessed. We therefore used sequences of the internal transcribed spacer regions (ITS-1 and ITS-2) of nuclear ribosomal DNA (rDNA) to reconstruct phylogenetic relationships among members of the Heuchera group of genera (Saxifragaceae). The Heuchera group presents an important model for the analysis of chloroplast capture and its impact on phylogenetic reconstruction because hybridization is well documented within genera (e.g., Heuchera), and intergeneric hybrids involving six of the nine genera have been reported. An earlier study provided a well-resolved phylogenetic hypothesis for the Heuchera group based on cpDNA restriction-site variation. However, trees based on ITS sequences are discordant with the cpDNA-based tree. Evidence from both morphology and nuclear encoded allozymes is consistent with the ITS trees, rather than the cpDNA tree, and several points of phylogenetic discord can clearly be attributed to chloroplast capture. Comparison of the organellar and ITS trees also raises the strong likelihood that ancient events of chloroplast capture occurred between lineages during the early diversification of the Heuchera group. Thus, despite the many advantages and widespread use of cpDNA data in phylogeny reconstruction, comparison of relationships based on cpDNA and ITS sequences for the Heuchera group underscores the need for caution in the use of organellar variation for retrieving phylogeny at lower taxonomic levels, particularly in groups noted for hybridization. PMID- 28565146 TI - GENETIC EVIDENCE FOR A PLEISTOCENE POPULATION EXPLOSION. AB - Expansions of population size leave characteristic signatures in mitochondrial "mismatch distributions." Consequently, these distributions can inform us about the history of changes in population size. Here, I study a simple model of population history that assumes that, t generations before the present, a population grows (or shrinks) suddenly from female size N0 to female size N1 . Although this model is simple, it often provides an accurate description of data generated by complex population histories. I develop statistical methods that estimate theta0 = 2uN0 , theta1 = 2uN1 , and tau = 2ut (where u is the mutation rate), and place a confidence region around these estimates. These estimators are well behaved, and insensitive to simplifying assumptions. Finally, I apply these methods to published mitochondrial data, and infer that a major expansion of the human population occurred during the late Pleistocene. PMID- 28565147 TI - ARTIFICIAL SELECTION FOR DEVELOPMENTAL TIME IN DROSOPHILA MELANOGASTER IN RELATION TO THE EVOLUTION OF AGING: DIRECT AND CORRELATED RESPONSES. AB - A wild-type strain of Drosophila melanogaster was successfully selected for both fast and slow larval development. The realized heritabilities (h2 ) ranged from 0.20 to 0.30 for the fast lines and 0.35 to 0.60 for the slow lines. The selection applied is relevant in relation to the evolution of aging. The longevity of adults, either virgin or mated, was not affected by selection for developmental time, indicating that developmental time is not a causal determinant of life span, thus confirming the results of the studies on environmental effects on aging (Zwaan et al. 1991, 1992). However, adult body weights were higher in the slow developmental lines and lower in the fast lines, relative to the control flies. Furthermore, slow females showed relatively high early fecundity and low late fecundity, as compared with control and fast females. Mated longevities and total lifetime progeny productions were not statistically different. Previous results obtained by other authors from selection experiments on age at reproduction either supported the mutation accumulation or the negative pleiotropy theory of aging (Luckinbill et al. 1984; Rose 1984b). The impact of the reported results on the interpretation of these studies is discussed, and it is noted that direct selection on adult longevity is needed to settle this issue. PMID- 28565148 TI - MORPHOLOGICAL EVOLUTION MEDIATED BY BEHAVIOR IN THE DAMSELFLIES OF TWO COMMUNITIES. AB - Behavior can play a mediating role in determining the selective pressures that influence the evolution of morphological structures. To examine this, I quantified patterns of morphological variation among larvae of Enallagma damselfly species (Odonata: Coenagrionidae) that use different behaviors to avoid the major predators found in each of two communities, lakes with and without fish. Specifically, I quantified the sizes and shapes of the abdomens and caudal lamellae (used for swimming) and legs for three species from fishless lakes and six species from lakes with fish. A preliminary cladistic analysis indicates that species within each lake type are not members of a single clade, which supports the conclusions of previous odonate taxonomists. Previous studies have shown that species in fishless lakes are very active, running and swimming frequently and at high rates of speed in the absence of predators, and they avoid their primary predators, large dragonflies, by swimming. These species have the widest abdomens, the largest caudal lamellae relative to overall body size, and the longest legs of the species studied, which should make them powerful swimmers and runners. Furthermore, species in fishless lakes are morphologically very similar to one another and differ greatly from fish-lake species, although each is more closely related to species in fish lakes. In contrast, species from lakes with fish move very slowly and infrequently in the absence of predators and do not attempt to evade attacking predators. However, despite their behavioral similarity, large interspecific variation in morphology exists among the fish lake species, and the only morphological patterns were differences associated with membership in the two primary clades identified in the cladistic analysis. A modification of Felsenstein's (1985) method of evolutionary contrasts which allows character change to be isolated along single branches is introduced and is used to reconstruct the evolutionary histories of these characters. This analysis suggests that large increases in caudal lamella size, abdominal segment lengths and widths, and leg length accompany speciation events associated with habitat shifts from fish-lakes to fishless lakes. Following habitat shifts selection pressures exerted by dragonfly predation apparently favored swimming as an escape tactic, which mediated selection pressures onto morphologies used in swimming to increase swimming performance; morphological patterns in extant species reflect this adaptation to a new environment. Mechanisms by which behaviorally mediated selection could have accelerated evolutionary dynamics following founder events are discussed. PMID- 28565149 TI - RUNAWAY EVOLUTION TO SELF-EXTINCTION UNDER ASYMMETRICAL COMPETITION. AB - We analyze a popular model of the evolution of traits related to performance in exploitative competition. This model has previously been used to explain a mechanism by which interspecific competition can cause taxon cycles. We show that purely intraspecific competition can cause evolution of extreme competitive abilities that ultimately result in extinction, without any influence from other species. The only change in the model required for this outcome is the assumption of a nonnormal distribution of resources of different sizes measured on a logarithmic scale. This suggests that taxon cycles, if they exist, may be driven by within- rather than between-species competition. Self-extinction does not occur when the advantage conferred by a large value of the competitive trait (e.g., size) is relatively small, or when the carrying capacity decreases at a comparatively rapid rate with increases in trait value. The evidence regarding these assumptions is discussed. The results suggest a need for more data on resource distributions and size-advantage in order to understand the evolution of competitive traits such as body size. PMID- 28565150 TI - INTRASPECIFIC MOLECULAR PHYLOGENY IN THE YELLOW WARBLER (DENDROICA PETECHIA), AND IMPLICATIONS FOR AVIAN BIOGEOGRAPHY IN THE WEST INDIES. AB - A phylogenetic analysis of mitochondrial DNA (mtDNA) restriction sites was used to examine the evolutionary history of populations of yellow warbler (Dendroica petechia) sampled from North America, Central America, South America, and the West Indies. Thirty-seven haplotypes were identified, and only one was found in more than one of these regions. Estimated sequence divergence among haplotypes ranged from 0.14 to 3.17%, and mtDNAs from North American migratory populations clearly were differentiated from those of most tropical sedentary populations. Parsimony analysis of haplotypes suggested multiple colonizations of the West Indies archipelago and of individual Caribbean islands. The inference of multiple colonizations has important implications for studies of avian ecology and evolution in this region. PMID- 28565151 TI - SINGLE- AND MULTIPLE-LOCUS GENOTYPES AND LIFE-HISTORY RESPONSES OF GAMBUSIA HOLBROOKI REARED AT TWO TEMPERATURES. AB - Eastern mosquitofish (Gambusia holbrooki) were reared from birth to 10 wk of age at 25 degrees C and 32 degrees C. Relationships of growth, time to maturity, and developmental stability to isozyme genotype were used to examine the hypothesis that more heterozygous individuals should exhibit superior performances, especially under thermally stressful (32 degrees C) conditions. More heterozygous fish grew faster than homozygous individuals, especially at 32 degrees C. Significant differences in time to maturity were detected among allozyme genotypes but not with heterozygosity. Multiple-locus heterozygosity was negatively related to fluctuating asymmetry. Thus, life-history traits were affected by both multiple-locus heterozygosity and single-locus genotype. PMID- 28565152 TI - COSTS AND BENEFITS OF PLANT RESPONSES TO DISEASE: RESISTANCE AND TOLERANCE. AB - A major assumption of models of the evolution of plant resistance to disease is that plant resistance involves fitness costs. To test this assumption, a field experiment was performed so that a quantitative-genetic analysis could be used to detect fitness costs to Ipomoea purpurea of resistance to different fungal isolates of Colletotrichum dematium, a pathogenic fungus causing the disease anthracnose. This experiment yielded no evidence that resistance to anthracnose involves direct fitness costs. Nevertheless, trade-offs in plant fitness that were unrelated to resistance were detected between different disease environments. Tolerance, defined as the ability to compensate in part for fitness decrements caused by disease, was found to involve fitness costs. Halfsib families that were more tolerant of disease had lower fitness in the absence of disease. The possibility that the cost of tolerance could obscure fitness costs of resistance is explored. PMID- 28565153 TI - MECHANISMS OF LARGE-SCALE EVOLUTIONARY TRENDS. AB - Large-scale evolutionary trends may result from driving forces or from passive diffusion in bounded spaces. Such trends are persistent directional changes in higher taxa spanning significant periods of geological time; examples include the frequently cited long-term trends in size, complexity, and fitness in life as a whole, as well as trends in lesser supraspecific taxa and trends in space. In a driven trend, the distribution mean increases on account of a force (which may manifest itself as a bias in the direction of change) that acts on lineages throughout the space in which diversification occurs. In a passive system, no pervasive force or bias exists, but the mean increases because change in one direction is blocked by a boundary, or other inhomogeneity, in some limited region of the space. Two tests have been used to distinguish these trend mechanisms: (1) the test based on the behavior of the minimum; and (2) the ancestor-descendant test, based on comparisons in a random sample of ancestor descendant pairs that lie far from any possible lower bound. For skewed distributions, a third test is introduced here: (3) the subclade test, based on the mean skewness of a sample of subclades drawn from the tail of a terminal distribution. With certain restrictions, a system is driven if the minimum increases, if increases significantly outnumber decreases among ancestor descendant pairs, and if the mean skew of subclades is significantly positive. A passive mechanism is more difficult to demonstrate but is the more likely mechanism if decreases outnumber increases and if the mean skew of subclades is negative. Unlike the other tests, the subclade test requires no detailed phylogeny or paleontological time series, but only terminal (e.g., modern) distributions. Monte Carlo simulations of the diversification of a clade are used to show how the subclade test works. In the empirical cases examined, the three tests gave concordant results, suggesting first, that they work, and second, that the passive and driven mechanisms may correspond to natural categories of causes of large-scale trends. PMID- 28565154 TI - USING HITCHHIKING GENES TO STUDY ADAPTATION AND DIVERGENCE DURING SPECIATION WITHIN THE DROSOPHILA MELANOGASTER SPECIES COMPLEX. AB - Several studies of intraspecific and interspecific DNA sequence variation from Drosophila loci have revealed a pattern of low intraspecific variation from genomic regions of low recombination. The mechanisms consistently invoked to explain these patterns are the selective sweep of advantageous mutations together with genetic hitchhiking of linked loci. To examine the effect of selective sweeps on genetic divergence during speciation, we studied two loci in different genomic regions thought to be subject to selective sweeps. We obtained DNA sequences from 1.1kb pair portions of the fourth chromosome locus cubitus interruptus Dominant (ciD ) and from the asense locus near the telomere of the X chromosome. At ciD , we found very low variation among multiple lines of Drosophila mauritiana and D. sechellia. This finding is consistent with an earlier report of very low variation in D. melanogaster and D. simulans at ciD and supports the conclusion of selective sweeps and genetic hitchhiking on the nonrecombining fourth chromosome. The pattern of variation found at asense suggests that a selective sweep has occurred recently at the tip of the X chromosome in D. simulans, but not in D. melanogaster or D. mauritiana. The data from ciD and asense are compared with data from three X chromosome loci (period, zeste, and yolk protein 2) that experience normal levels of recombination. By examining estimated genealogies and the rates at which different classes of mutations have accumulated, we conclude that selective sweeps are common occurrences on the fourth chromosome but less common near the tip of the X chromosome. An interesting pattern of low variation at ciD among D. simulans, D. mauritiana, and D. sechellia suggests that a selective sweep may have occurred among these forms even after divergence into separate species had begun. PMID- 28565155 TI - PARSIMONY, MOLECULAR EVOLUTION, AND BIOGEOGRAPHY: THE CASE OF THE NORTH AMERICAN GIANT SALAMANDER. AB - To draw biogeographic conclusions about the Central Highlands region of the United States, we reconstructed the phylogeny of hellbender (Cryptobranchus alleganiensis) populations from restriction-site variation in mtDNA. We were unable to root the phylogeny using an outgroup and therefore could not weight restriction-site gains more heavily than site losses. As a result, maximum parsimony results in low phylogenetic resolution because of high levels of homoplasy in the data set. Use of a recently published algorithm based on an explicit model of molecular evolution yielded much greater resolution of the mtDNA relationships. This phylogeny indicates the two subspecies of hellbenders are paraphyletic with respect to one another. Hellbenders found in the southern Ozarks (C. a. bishopi) are either most closely related to populations of C. a. alleganiensis inhabiting the Tennessee River drainage or are so divergent that phylogenetic affinities are undetectable. Extremely low levels of divergence among mtDNA haplotypes found in populations from Pennsylvania, Indiana, Illinois, and the northern Missouri Ozarks suggest a recent, probably post-Pleistocene, invasion of this region from a refugium in one of these areas. Biogeographic hypotheses of the causes and timing of hellbender distributions differ significantly from those postulated from analyses of fish species relationships. Possible reasons for the discrepancy are discussed. PMID- 28565156 TI - GENETIC CONSEQUENCES OF SEED DISPERSAL IN THREE SYMPATRIC FOREST HERBS. II. MICROSPATIAL GENETIC STRUCTURE WITHIN POPULATIONS. AB - Significant spatial genetic differentiation over short distances was detected by F-statistics and spatial autocorrelation within populations of the temperate forest herbs Cryptotaenia canadensis, Osmorhiza claytonii and Sanicula odorata (Apiaceae). Differences among the three species were consistent with estimates of their seed-dispersal abilities. Populations of Cryptotaenia, with the most limited seed dispersal, are characterized by genetic structure at smaller spatial scales than those of Osmorhiza or Sanicula, as indicated by higher estimates of theta(Fst ), larger autocorrelation coefficients, and correlograms with more distant x-intercepts. Although spatial autocorrelation was somewhat more sensitive to the distribution of rare alleles than F-statistics, the two methods were generally concordant. Genetic structure was more pronounced, and inbreeding coefficients larger, in low-density, patchy populations than in a high-density site. Observed patterns of spatial autocorrelation, particularly for Cryptotaenia, were in agreement with expectations based on simulations of isolation by distance. The magnitude of observed autocorrelations was less than those typically produced in computer-simulation studies, but this discrepancy between empirical and theoretical results probably is derived from a lack of genetic and demographic equilibrium in natural populations. Isolation by distance can be an important evolutionary force organizing spatial genetic structure in plant populations, particularly in predominantly self-fertilizing species such as those studied here. PMID- 28565157 TI - EVOLUTIONARY INTERACTIONS BETWEEN SEXUAL AND ALL-FEMALE TAXA OF CYPRINOTUS (OSTRACODA: CYPRIDIDAE). AB - Freshwater ostracodes show both an exceptionally high incidence of transitions to unisexuality and, in some cases, an extraordinary level of clonal diversity. There is no understanding of the agents promoting these transitions to thelytoky, although it has been suggested that their frequency may set the stage for sexual taxa to infuse clonal diversity into unisexuals. This study examines the nature and origins of clonal diversity in the unisexual ostracode Cyprinotus incongruens. A combination of allozyme and cytogenetic studies revealed the presence of two diploid clones of this species at three temperate sites and ten clones at one arctic site including three diploids, five triploids, and two tetraploids. The low heterozygosity (0%-20%) of its diploid clones suggests that parthenogenesis has arisen spontaneously in C. incongruens rather than through hybridization, as in vertebrate asexuals. Polyploid clones appear to owe their origin to genome additions from sexual taxa, although subsequent mutational divergence has played a role in further enhancing diversity. Two triploid clones have apparently originated from the incorporation of a haploid genome from the sexually reproducing C. glaucus, as evidenced by their high heterozygosity and possession of alleles otherwise found only in that species. Other polyploid clones have likely arisen as a result of interbreeding between bisexual and unisexual C. incongruens. These results suggest that both the incidence of spontaneous transitions to clonality and the frequency of interbreeding with relatives may be the key processes that govern clonal diversity in unisexual ostracodes. PMID- 28565158 TI - THE EVOLUTION OF DEVELOPMENT IN DROSOPHILA MELANOGASTER SELECTED FOR POSTPONED SENESCENCE. AB - The role of development in the evolution of postponed senescence is poorly understood despite the existence of a major gerontological theory connecting developmental rate to aging. We investigate the role of developmental rate in the laboratory evolution of aging using 24 distinct populations of Drosophila melanogaster. We have found a significant difference between the larval developmental rates of our Drosophila stocks selected for early (B) and late-life (O) fertility. This larval developmental time difference of approximately 12% (O > B) has been stable for at least 5 yr, occurs under a wide variety of rearing conditions, responds to reverse selection, and is shown for two other O-like selection treatments. Emerging adults from lines with different larval developmental rates show no significant differences in weight at emergence, thorax length, or starvation resistance. Long-developing lines (O, CO, and CB) have greater survivorship from egg to pupa and from pupa to adult, with and without strong larval competition. Crosses between slower developing populations, and a variety of other lines of evidence, indicate that neither mutation accumulation nor inbreeding depression are responsible for the extended development of our late-reproduced selection treatments. These results stand in striking contrast to other recent studies. We argue that inbreeding depression and inadvertent direct selection in other laboratories' culture regimes explain their results. We demonstrate antagonistic pleiotropy between developmental rate and preadult viability. The absence of any correlation between longevity and developmental time in our stocks refutes the developmental theory of aging. PMID- 28565159 TI - SEXUAL SELECTION AND SURVIVAL IN NORTH AMERICAN WATERFOWL. PMID- 28565160 TI - ADAPTATION AND CONSTRAINT IN THE EVOLUTION OF SPECIALIZATION OF BAHAMIAN ANOLIS LIZARDS. AB - Interspecific interactions affect habitat use and subsequent morphological adaptation in Anolis lizards. We examined populations of two species of Anolis lizards that evolved in the species-rich communities of Cuba and are now widespread in the Bahamas. Because the species occupy islands in the Bahamas that vary in the number of lizard species present and other characteristics, we predicted that directional selection should have led to morphological differentiation. In particular, we expected that populations on one-species islands should have evolved toward a generalist morphology because of the lack of competitors. Divergence in both species has been adaptive; populations that use wider perches have longer legs. Nonetheless, these differences are relatively minor, and none of the populations appears to have differentiated from its ancestral "ecomorph" type toward a more generalized morphology. This stasis mirrors a trend observed in the radiation of Caribbean anoles, which exhibits repeated instances of evolutionary specialization, but few or no cases of reversion to a more generalized condition. The explanation for this directionality of evolution is not obvious but probably involves the tendency of specialized species to continue using and further adapting the niches for which they are specialized even as conditions change. PMID- 28565161 TI - ASSORTATIVE MATING AND NATURAL SELECTION IN AN IRIS HYBRID ZONE. AB - The phenology of different genotypes and the distribution of genetic variation among flowering plants and their progeny were examined to assess the levels of assortative mating and selection in a hybrid population of Iris. This study and a previous survey of RAPD nuclear markers and chloroplast markers indicate that the population consists of parental genotypes and recombinant hybrid genotypes that are similar to the parental species (I. fulva and I. brevicaulis), although lacking intermediate genotypes. Early in the season only I. fulva genotypes produced flowers, but as flowering in these plants decreased, the hybrid genotypes and I. brevicaulis genotypes began flowering, resulting in a 24-d period of coincidental flowering. The genotypic distribution of seeds produced during the period of flowering overlap contained a high frequency of intermediate genotypes that were not present in the adult generation. The degree of effective assortative mating was examined by comparing the observed progeny genotypic distributions with expected distributions from a mixed-mating model. The model included selfing and random outcrossing to the nearest plants that had pollen bearing flowers on the day the recipient flower was receptive. The observed genotypic distribution of progeny from plants with I. brevicaulis chloroplast DNA (cpDNA) was not significantly different from the expected distribution. For I. fulva genotypes, however, there were higher than expected frequencies in the extreme genotypic classes, although intermediate genotypes were absent, indicating that these plants were preferentially mating with similar genotypes. Compared with the extreme genotypes, a larger proportion of the intermediate seed progeny produced were aborted, indicating that intermediate genotypes have lower viability. On the basis of the observed progeny genotypes and genetic disequilibria estimates for the adults and the progeny, there appears to be a pattern of effective asymmetrical mating in this population. This asymmetry is most likely due to pollen-style interactions that reduce the fertilization ability of genetically dissimilar pollen, or preferential abortion of genetically intermediate zygotes by I. fulva-like genotypes. The lack of any apparent discrimination by I. brevicaulis-like genotypes creates a directional exchange of nuclear genetic elements that will have implications for introgression and the evolution of hybrid genotypes. PMID- 28565162 TI - RELATIONSHIPS BETWEEN INFERRED LEVELS OF GENE FLOW AND GEOGRAPHIC DISTANCE IN A PHILOPATRIC CORAL, BALANOPHYLLIA ELEGANS. AB - When the dispersal capability of a species is considerably less than its geographic range, genetic differences between populations should increase with the distance separating those populations. This pattern should be most evident in linearly distributed species. The sessile solitary cup coral Balanophyllia elegans lives along nearly the entire Pacific coast of North America, yet its crawling larvae usually settle within 40 cm of their birthplace. In this paper, I document geographic patterns of allozyme differentiation within and among populations of B. elegans and estimate the proportion of observed geographic pattern attributable to gene flow between adjacent populations. Genetic subdivision among localities separated by up to 3000 km was high (FST = 0.283, SE = 0.038). Inferred gene flow between pairs of localities (M?, individuals per generation) correlated inversely with the geographic distance between those localities, consistent with the pattern expected for a species at equilibrium in which gene flow occurred exclusively between adjacent localities. Within localities, patches separated by 4 to 30 m were also significantly subdivided, but genetic differentiation between patches did not vary significantly with the distance separating them. Simulations revealed that the power to detect genetic pattern expected from gene flow between adjacent populations increased with both the number of loci used to infer gene flow and the heterozygosity of those loci. Simulations also verified that when geographic distance poorly approximated the number of steps between populations, reduced major-axis regression more accurately portrayed the structural relationship between gene flow and separation than did ordinary least-squares regression. Attenuation of gene flow with distance explained 15% of the between-locality pattern of genetic differentiation in B. elegans. The remaining variation appeared to be due to neither natural selection nor a recent rangewide recolonization. Loci from the northern sampled localities, however, had fewer alleles than those from the remainder of the range, suggesting these localities had been recolonized recently following Pleistocene cooling. PMID- 28565163 TI - FINE-SCALE GENETIC AND PHENOTYPIC STRUCTURE IN NATURAL POPULATIONS OF BACILLUS SUBTILIS AND BACILLUS LICHENIFORMIS: IMPLICATIONS FOR BACTERIAL EVOLUTION AND SPECIATION. AB - The genetic and phenotypic structure of sympatric populations of wild bacteria traditionally identified as Bacillus subtilis and B. licheniformis was analyzed. Small soil samples were taken from a single, tiny site in the Sonoran Desert of Arizona, USA, to provide a true population analysis, in contrast to many analyses of genetic structure using bacterial strain collections of widely heterogeneous origin. Genetic analyses of isolates used multilocus enzyme electrophoresis, mismatches in restriction fragment length polymorphism, and variants from Southern hybridization with B. subtilis DNA probes. Phenotypic analyses of isolates used the API test system for detection of growth and acid production on specific carbon sources. The two species were distinct both phenotypically and genetically, despite their known potential for genetic exchange in laboratory experiments. Genic and genotypic diversity were high in both species, and only 16% of observed allozyme variants might possibly be common to both species. Hence, there is probably modest genetic exchange, if any, between the species in nature. Clear hierarchies of population-genetic structure were found for both species. Different types of genetic data yield concordant population structures for B. subtilis. For both species, two-locus and multilocus statistical analyses of linkage demonstrated modest to strong disequilibrium at the species level but truly panmictic subunits within each species. The evidence for extensive genetic recombination within these fine-scale subdivisions is unequivocal, indicating that the sexuality of these bacteria can be well expressed in nature. The relation of these results to processes of bacterial evolution and speciation is discussed. PMID- 28565164 TI - THE EFFECTS OF THE RELATIVE GEOGRAPHIC SCALES OF GENE FLOW AND SELECTION ON MORPH FREQUENCIES IN THE WALKING-STICK TIMEMA CRISTINAE. AB - Gene frequencies in large populations are determined by a balance between selection and gene flow between neighborhoods of different selection regimes. This balance is affected by the area of the patches of a given selection regime relative to the gene-flow distance. If patches are small relative to gene-flow distance, similarity in the total area occupied by different patch types is a crucial condition for the stability of polymorphisms. However, if patches are larger than the gene-flow distance, then the relative area of different patch types is less important because of reduced gene flow resulting from isolation by distance. Two morphs (striped and unstriped) of the walking-stick Timema cristinae were each strongly associated with patches of distinct species of food plants on which they are most cryptic. The frequency of a morph was high on the plant on which it is most cryptic when either: (1) the area occupied by the food plant (patch) was very large; (2) the patch was completely isolated from other patches; or (3) the patch was larger than adjacent patches. Results (1) and (2) are consistent with isolation-by-distance models, and result (3) is consistent with Levene's multiple-niche polymorphism model. PMID- 28565165 TI - MOLECULAR HETEROCHRONY IN THE PATTERN OF FIBRONECTIN EXPRESSION DURING GASTRULATION IN AMPHIBIANS. PMID- 28565166 TI - GENETIC VARIATION FOR PHENOTYPIC PLASTICITY IN THE LARVAL LIFE HISTORY OF SPADEFOOT TOADS (SCAPHIOPUS COUCHII). AB - Phenotypic plasticity in life-history traits is common. The relationship between phenotype and environment, or reaction norm, associated with life-history plasticity can evolve by natural selection if there is genetic variation within a population for the reaction norm and if the traits involved affect fitness. As with other traits, selection on plasticity in a particular trait or in response to a particular environmental factor may be constrained by trade-offs with other traits that affect fitness. In this paper, I experimentally evaluated broad-sense genetic variation in the reaction norms of age and size at metamorphosis in response to two environmental factors, food level and temperature. Differences among full-sib families in one or both traits were evident in all treatments. However, variation among families in their responses to each treatment (genotype environment interaction) resulted in variation among treatments in estimated heritabilities and genetic correlations. Age at metamorphosis was equally sensitive to temperature in all families, but size at metamorphosis was more sensitive to temperature in some families than in others. Size at metamorphosis was equally sensitive to food level in all families, but age at metamorphosis was sensitive to food in some families but not in others. At high temperature or low food, the genetic correlation between age and size at metamorphosis was positive, generating a potential trade-off between metamorphosing early to attain higher larval survival and metamorphosing later to achieve larger size. This trade-off extends across treatments: families with the largest average size at metamorphosis achieved larger size with the longest average and greatest plasticity in age at metamorphosis. Other families achieved shorter average larval periods by exhibiting greater plasticity in size at metamorphosis but had the smallest average size at metamorphosis. This trade-off may reflect an underlying functional constraint on the ability to respond optimally to all environments, resulting in persistent genetic variation in reaction norms. PMID- 28565167 TI - NUCLEO-CYTOPLASMIC MALE STERILITY AND ALTERNATIVE ROUTES TO DIOECY. AB - Population-genetic models of nucleo-cytoplasmic gynodioecy are shown to allow invasion of males and conversion to dioecy in a single cytotype. Pleiotropic effects of restorer alleles on fertility through male or female function can maintain a cytoplasmic polymorphism in a population that prevents evolution to dioecy regardless of the pollen fertility of males. However, a cytoplasmic polymorphism has little effect on, and may even reduce, the minimum pollen fertility required for the spread of males into an equilibrium gynodioecious population. Where the thresholds for dioecy are similar, the presence of males during a transient preequilibrium high frequency of females can accelerate evolution to dioecy by more than 50 times relative to nuclear male sterility. However, the appearance of a nonrestorable male-sterile cytotype generally eliminates males from both subdioecious and dioecious populations, converting them to purely cytoplasmic gynodioecy. These models contradict the previously suggested notion that nucleo-cytoplasmic gynodioecy represents a "stable" intermediate breeding system and instead show that such gynodioecy can generally evolve to subdioecy, and often to dioecy, as easily as nuclear gynodioecy. PMID- 28565168 TI - GLOBAL PHYLOGEOGRAPHY OF THE LOGGERHEAD TURTLE (CARETTA CARETTA) AS INDICATED BY MITOCHONDRIAL DNA HAPLOTYPES. AB - Restriction-site analyses of mitochondrial DNA (mtDNA) from the loggerhead sea turtle (Caretta caretta) reveal substantial phylogeographic structure among major nesting populations in the Atlantic, Indian, and Pacific oceans and the Mediterranean sea. Based on 176 samples from eight nesting populations, most breeding colonies were distinguished from other assayed nesting locations by diagnostic and often fixed restriction-site differences, indicating a strong propensity for natal homing by nesting females. Phylogenetic analyses revealed two distinctive matrilines in the loggerhead turtle that differ by a mean estimated sequence divergence p = 0.009, a value similar in magnitude to the deepest intraspecific mtDNA node (p = 0.007) reported in a global survey of the green sea turtle Chelonia mydas. In contrast to the green turtle, where a fundamental phylogenetic split distinguished turtles in the Atlantic Ocean and the Mediterranean Sea from those in the Indian and Pacific oceans, genotypes representing the two primary loggerhead mtDNA lineages were observed in both Atlantic-Mediterranean and Indian-Pacific samples. We attribute this aspect of phylogeographic structure in Caretta caretta to recent interoceanic gene flow, probably mediated by the ability of this temperate-adapted species to utilize habitats around southern Africa. These results demonstrate how differences in the ecology and geographic ranges of marine turtle species can influence their comparative global population structures. PMID- 28565169 TI - A SPECIATIONAL HISTORY OF "LIVING FOSSILS": MOLECULAR EVOLUTIONARY PATTERNS IN HORSESHOE CRABS. AB - Horseshoe crabs' exceptional morphological conservatism over the past 150 My has led to their reputation as "living fossils," but also has served to obscure phylogenetic relationships within the complex. Here we employ nucleotide sequences from two mitochondrial genes to assess molecular evolutionary rates and patterns among all extant horseshoe crab species. The American species Limulus polyphemus proved to be the sister taxon to a clade composed of the Asiatic species Tachypleus gigas, T. tridentatus, and Carcinoscorpius rotundicauda, whose relationships inter se were not resolved definitively. Both absolute and relative rate tests suggest a moderate slowdown in sequence evolution in horseshoe crabs. Nonetheless, dates of the lineage separations remain uncertain primarily because of reservations about molecular-clock calibrations resulting from large rate variances at examined loci across Arthropods and other animal lineages, as inferred in this and prior studies. Thus, ironically, separation dates as estimated by molecular evidence in general may remain most insecure in taxonomic groups for which such information is needed most-those lacking strong biogeographic or fossil benchmarks for internal-clock calibrations. In any event, the current results show that large numbers of molecular characters distinguish even these most morphologically conservative of organisms. Furthermore, comparisons against previously published mitochondrial sequence data in the morphologically dynamic hermit crab-king crab complex demonstrates that striking heterogeneity in levels of morphotypic differentiation can characterize Arthropod lineages at similar magnitudes of molecular divergence. PMID- 28565170 TI - CENTRAL MOMENTS AND PROBABILITY DISTRIBUTION OF COLLESS'S COEFFICIENT OF TREE IMBALANCE. AB - The great increase in the number of phylogenetic studies of a wide variety of organisms in recent decades has focused considerable attention on the balance of phylogenetic trees-the degree to which sister clades within a tree tend to be of equal size-for at least two reasons: (1) the degree of balance of a tree may affect the accuracy of estimates of it; (2) the degree of balance, or imbalance, of a tree may reveal something about the macroevolutionary processes that produced it. In particular, variation among lineages in rates of speciation or extinction is expected to produce trees that are less balanced than those that result from phylogenetic evolution in which each extant species of a group has the same probability of speciation or extinction. Several coefficients for measuring the balance or imbalance of phylogenetic trees have been proposed. I focused on Colless's coefficient of imbalance (7) for its mathematical tractability and ease of interpretation. Earlier work on this statistic produced exact methods only for calculating the expected value. In those studies, the variance and confidence limits, which are necessary for testing the departure of observed values of I from the expected, were estimated by Monte Carlo simulation. I developed recursion equations that allow exact calculation of the mean, variance, skewness, and complete probability distribution of I for two different probability-generating models for bifurcating tree shapes. The Equal-Rates Markov (ERM) model assumes that trees grow by the random speciation and extinction of extant species, with all species that are extant at a given time having the same probability of speciation or extinction. The Equal Probability (EP) model assumes that all possible labeled trees for a given number of terminal taxa have the same probability of occurring. Examples illustrate how these theoretically derived probabilities and parameters may be used to test whether the evolution of a monophyletic group or set of monophyletic groups has proceeded according to a Markov model with equal rates of speciation and extinction among species, that is, whether there has been significant variation among lineages in expected rates of speciation or extinction. PMID- 28565171 TI - THE ROLES OF FLUCTUATING SELECTION AND LONG-TERM DIAPAUSE IN MICROEVOLUTION OF DIAPAUSE TIMING IN A FRESHWATER COPEPOD. AB - Direct observations of selection response in natural, unmanipulated populations in the wild are rare. Those that exist have resulted from major changes in environment during an ongoing study. Selection response should be more common and more readily observable in short-lived organisms where the direction of selection changes from year to year. We examined how the interaction of fluctuating selection, and emergence from long-term diapause, caused ongoing microevolutionary change over eight years in an important life-history trait (diapause timing) in the freshwater calanoid copepod Diaptomus sanguineus. Emergence from long-term diapause releases into the population lineages that did not experience the most recent bout of selection, thereby promoting the maintenance of the heritable trait variation that allows continual selection response. A mechanistic selection model was created on the basis of field and laboratory studies to predict how interannual variations in predation intensity generate year-to-year changes in mean diapause timing and in net reproductive success for alternate trait values. The predicted selection response and the estimated effect of emergence from diapause were both significantly correlated with observed changes in trait mean. A linear model combining selection response and emergence from diapause explained 59% of the variance in year-to-year changes in trait mean. According to this model, strong selection occurred in about half of the years studied, and the average annual contributions to changes in trait mean from selection and emergence were roughly equal. Thus, both fluctuating natural selection and emergence from prolonged diapause affect the expression of diapause timing by D. sanguineus. Fluctuating selection is ubiquitous in nature and may provide opportunities in other populations to witness ongoing natural selection without directional trends in mean phenotype. PMID- 28565172 TI - TRAIT MAPPING AND SALIENCE IN THE EVOLUTION OF EUSOCIAL VESPID WASPS. AB - The multiple independent origins of eusociality in the insect order Hymenoptera are clustered in only four of more than 80 families, and those four families are two pairs of closely related taxa in a single part of the order. Therefore, although ordinal-level characteristics can contribute to hymenopteran eusocial evolution, more important roles have been played by traits of infraordinal taxa that contain the eusocial forms. Many factors have been proposed and discussed, but assessments of traits' salience to eusocial evolution have heretofore not been joined to phylogenetics. In the present analysis, cladograms of superfamilies and families of Hymenoptera and of the family Vespidae are used to ordinate the appearance of traits that play roles in vespid eusociality. Proximity of traits' first appearance to the origin of eusocial Vespidae is taken as one measure of traits' salience to vespid eusocial evolution. Traits that subtend only eusocial taxa and that are uniquely associated with eusociality have foundations in more general traits that subtend more inclusive taxa. No single trait is uniquely causative of vespid eusocial evolution. High-salience traits that closely subtend vespid eusociality include nesting, oviposition into an empty nest cell, progressive provisioning of larvae, adult nourishment during larval provision malaxation, and inequitable food distribution among nestmates. The threshold characteristic of Polistes-grade eusociality is life-long alloparental brood care by first female offspring who remain, uninseminated, at their natal nest. Traits directly associated with occurrence of such workers are larva-adult trophallaxis, which can foster relatively low larval nourishment early in a colony cycle, and protogyny and direct larval development, which combine to yield restricted mating opportunities for female offspring that are the first to emerge in the colony cycle. Trait mapping suggests no role for asymmetry of relatedness due to haplodiploidy, but it suggests high salience for haplodiploidy as a mechanism enabling the production of all-female clutches of first offspring. PMID- 28565173 TI - COLOR PATTERN EVOLUTION, ASSORTATIVE MATING, AND GENETIC DIFFERENTIATION IN BRIGHTLY COLORED BUTTERFLYFISHES (CHAETODONTIDAE). AB - In butterflyfishes (Chaetodontidae), color pattern evolves rapidly and is often the only morphological trait separating closely related species. Vivid coloration is frequently assumed to provide critical signals for mate recognition and mate choice, but few direct experimental tests are available. Here we analyze the relationship between color pattern change, mate choice, and genetic differentiation in a group of three very closely related allopatric butterflyfishes. We found that in only one member of this group, Chaetodon multicinctus, is color pattern evolution associated with mate preference and genetic divergence. For its two sister species, C. punctatofasciatus and C. pelewensis, color pattern change has not resulted in assortative mating (based on laboratory pairing experiments and field observations) or in significant mtDNA or allozyme differentiation. In a contact zone on reefs in the Solomon Islands and Papua New Guinea, hybridization between the two forms has nearly homogenized color pattern differences. Outside these areas, however, color pattern remains distinct. Genetic variation is homogeneous over a much larger geographic scale. Sequence variation in the tRNA-proline end of the mitochondrial control region and allozyme variation was distributed widely within C. punctatofasciatus and C. pelewensis, which suggests few constraints to mitochondrial or nuclear gene flow across the color pattern boundary. These contrasting patterns strongly suggest that selection is maintaining color pattern differences in allopatry in the face of potentially homogenizing levels of gene flow. The mating pattern data show that this selection is not operating on mate recognition in the strictest sense, but probably on some other aspect of the social system of these territorial fish. In this case, divergence in mating preference can follow color pattern evolution, but is not contemporaneous with it. PMID- 28565174 TI - GENETICS OF SEX RATIO VARIATION AMONG NATURAL POPULATIONS OF A DIOECIOUS PLANT. AB - The female-biased sex ratio in the genus Silene is the most widely documented example of sex ratio bias in plants. It has recently been shown that the genetic basis of sex ratio in this species involves a system of sex ratio distorters and restorers, but it is not known if these genetic elements are of fundamental importance in natural populations. I crossed plants from natural populations with known testers to examine the frequencies of sex ratio distorters and restorers in eight populations of S. alba, and to determine the extent that these elements are responsible for the sex ratio variation in nature. The genetic basis of sex ratio varied from one population to another, suggesting that sex ratio evolution occurs over a relatively small spatial scale and is asynchronous among local demes. The resulting variation in the frequency of sex ratio alleles among populations explained most of the sex ratio variation seen in nature, which suggests that the ecology and evolution of this trait in natural populations is governed primarily by underlying dynamics of selfish genetic elements. The possible causes and the evolutionary consequences of population structure at genes controlling sex ratio are discussed, as are the implications of these results for the overall importance of selfish genetic elements in natural populations. PMID- 28565175 TI - COMPETITION AND GENOTYPE-BY-ENVIRONMENT INTERACTION IN NATURAL BREEDING SUBSTRATES OF DROSOPHILA. AB - Although empirical studies frequently suggest that genotype-by-environment (G X E) interaction can maintain genetic variation, very few data are available to test for the specific conditions necessary for the existence of a protected polymorphism (i.e., the property of persistence of an allele even when initially rare). Drosophila species live in patchy environments and their local population structure may be characterized to some extent by Levene's migration pattern, namely by a single pool of individuals that presumably mate at random and breed on discrete and ephemeral resources. We present here a field experiment that links Drosophila ecology and population genetics, which used the alcohol dehydrogenase (Adh) and alpha-glycerophosphate dehydrogenase (alphaGpdh) polymorphic loci in D. melanogaster flies raised from Opuntia ficus-indica fruits (prickly pears). The results show that there is density-dependent mortality in those fruits with a relatively high number of larvae (i.e., selection is "soft") and suggest that there is differential viability for alphaGpdh genotypes. Additionally, a pattern of G X E interaction for fitness values, which is fully compatible with the theoretical conditions required for the existence of a protected polymorphism, was found after weighting the fitness estimates by the relative contribution that each fruit makes to the total adult population. The strong association between AdhS and alphaGpdhF alleles suggests that the occurrence of the common cosmopolitan inversion In(2L)t in the population might be responsible for the negative frequency-dependent selection predicted by Levene's model when genetic variation persists in heterogeneous environments. PMID- 28565176 TI - CORRECTING FOR SAMPLING BIAS IN QUANTITATIVE MEASURES OF SELECTION WHEN FITNESS IS DISCRETE. AB - We show with a simulation that nonrepresentative sampling of two discrete fitness classes leads to biased estimates of selection. Systematic underestimation occurs if the selected class is overrepresented in the sample and overestimation if the unselected class is overrepresented. The bias is greater the stronger the selection intensity, the smaller the true fraction of individuals favored by selected, and the lower the sample size. We present a simple method that allows a posteriori statistical correction in cases of biased sampling given a separate estimate of the actual class representation, describe its practical implementation, and show that it works. PMID- 28565177 TI - THE QUANTITATIVE AND MOLECULAR GENETIC ARCHITECTURE OF A SUBDIVIDED SPECIES. AB - In an effort to elucidate the evolutionary mechanisms that determine the genetic architecture of a species, we have analyzed 17 populations of the microcrustacean Daphnia pulex for levels of genetic variation at the level of life-history characters and molecular markers in the nuclear and mitochondrial genomes. This species is highly subdivided, with approximately 30% of the variation for nuclear molecular markers and 50% of the variation for mitochondrial markers being distributed among populations. The average level of genetic subdivision for quantitative traits is essentially the same as that for nuclear markers, which superficially suggests that the life-history characters are diverging at the neutral rate. However, the existence of a strong correlation between the levels of population subdivision and broadsense heritabilities of individual traits argues against this interpretation, suggesting instead that the among-population divergence of some quantitative traits (most notably body size) is being driven by local adaptation to different environments. The fact that the mean phenotypes of the individual populations are also strongly correlated with local levels of homozygosity indicates that variation in local inbreeding plays a role in population differentiation. Rather than being a passive consequence of local founder effects, levels of homozygosity may be selected for directly for their effects on the phenotype (adaptive inbreeding depression). There is no relationship between the levels of variation within populations for molecular markers and quantitative characters, and this is explained by the fact that the average standing genetic variation for life-history characters in this species is equivalent to only 33 generations of variation generated by mutation. PMID- 28565178 TI - VARIATION IN GENETIC ARCHITECTURE OF CALLING SONG AMONG POPULATIONS OF ALLONEMOBIUS SOCIUS, A. FASCIATUS, AND A HYBRID POPULATION: DRIFT OR SELECTION? AB - Predictions using quantitative genetic models generally assume that the variance covariance matrices remain constant over time. This assumption is based on the supposition that selection is generally weak and hence variation lost through selection can be replaced by new mutations. Whether this is generally true can only be ascertained from empirical studies. Ideally for such a study we should be able to make a prediction concerning the relative strength of selection versus genetic drift. If the latter force is prevalent then the variance-covariances matrices should be proportional to each other. Previous studies have indicated that females in the two sibling cricket species Allonemobius socius and A. fasciatus do not discriminate between males of the two species by their calling song. Therefore, differences between the calling song of the two males most likely result from drift rather than sexual selection. We test this hypothesis by comparing the genetic architecture of calling song of three populations of A. fasciatus with two populations of A. socius. We found no differences among populations within species, but significant differences in the G (genetic) and P (phenotypic) matrices between species, with the matrices being proportional as predicted under the hypothesis of genetic drift. Because of the proportional change in the (co)variances no differences between species are evident in the heritabilities or genetic correlations. Comparison of the two species with a hybrid population from a zone of overlap showed highly significant nonproportional variation in genetic architecture. This variation is consistent with a general mixture of two separate genomes or selection. Qualitative conclusions reached using the phenotypic matrices are the same as those reached using the genetic matrices supporting the hypothesis that the former may be used as surrogate measures of the latter. PMID- 28565179 TI - REPLY TO COMMENTS ON THE CHASE-AWAY MODEL OF SEXUAL SELECTION. PMID- 28565180 TI - PATTERNS OF DESCENT IN CLONAL LINEAGES AND THEIR MULTILOCUS FINGERPRINTS ARE RESOLVED WITH COMBINED GENE GENEALOGIES. AB - Clonal lineages in the filamentous ascomycete (fungi) Sclerotinia sclerotiorum were determined by analysis of genealogies of four loci: the intergenic spacer of the nuclear ribosomal repeat (IGS; approximately 4 kb), the translation elongation factor (EF-1alpha; approximately 300 bp), an anonymous region (44.11; approximately 700 bp), and the calmodulin gene (CAL; approximately 400 bp). Three of the four loci are physically unlinked. The combined analysis of the four loci provided the best estimate of phylogeny, which is consistent with a pattern of some recombination among clonal lineages against a background of predominant clonality. Comparison of gene genealogies with a phylogeny inferred from DNA fingerprints and a combined phylogeny of the entire dataset identified convergent or parallel changes in fingerprints. Analysis of the entire data matrix allowed us to resolve patterns of descent among clonal lineages that could not be inferred from fingerprints alone and to discern recent episodes of divergence that were not detected in gene genealogies. Prerequisites for applying this approach to other systems are a haploid context for inferring multiple gene genealogies (such as the mitochondrial genome) that indicate limited recombination and another data matrix that identifies recently evolved genotypes. PMID- 28565181 TI - POPULATION GENETIC STRUCTURE AND GENE FLOW ACROSS ARID VERSUS MESIC ENVIRONMENTS: A COMPARATIVE STUDY OF TWO PARAPATRIC SENECIO SPECIES FROM THE NEAR EAST. AB - To shed light on the potential effects of xeric/arid versus mesic environments on plant population genetic structure and patterns of gene flow, we have compared allozyme and cpDNA haplotype variation in populations of two closely related, highly outcrossed, and largely wind-dispersed winter annuals of Senecio (Asteraceae). The species form a distinctive zone of parapatric distribution in the Near East by differing in their ecogeographical regimes. Senecio vernalis mainly thrives in the mesic Mediterranean life zone of Israel, whereas S. glaucus inhabits either xeric maritime or arid (semi-) desert sites. Significant differences in allozymic population subdivision among S. vernalis (thetan = 0.04; Nmn = 5.85) and S. glaucus (thetan = 0.12; Nmn = 1.85) largely resulted from topogeographical substructuring present within the latter species. Because of the similarity of within-region estimates of population structure for S. glaucus with those measured among populations of S. vernalis, it appears unlikely that ecological "aridity" factors per se are important in influencing levels of population differentiation in these species. Based on hierarchical F-statistics and tests of isolation by distance, we further conclude that geographical topologies influence the level and mode of nuclear gene flow (via pollen and/or seed) among and within subsets of S. glaucus populations, although without providing a complete barrier to interregional dispersal (dNmreg = 2.16) and without promoting allopatric differentiation via drift. The allozymic data further suggested that S. vernalis and S. glaucus form a zone of secondary contact in the Near East, accompanied by an almost complete interspecific barrier to nuclear gene flow (dnNmsp = 0.253). However, to account for the considerable sharing of cpDNA haplotypes, both at the intra- and interspecific level, it is necessary to invoke either (1) selection acting against alien nuclear but not cytoplasmic DNA; or (2) the sporadic immigration of cpDNA via seed with large homogenizing effects on cytoplasmic population structure over time. PMID- 28565182 TI - SUPPRESSION OF SEX-RATIO MEIOTIC DRIVE AND THE MAINTENANCE OF Y-CHROMOSOME POLYMORPHISM IN DROSOPHILA. AB - Like several other species of Drosophila, D. quinaria is polymorphic for X chromosome meiotic drive; matings involving males that carry a "sex-ratio" X chromosome (XSR ) result in the production of strongly female-biased offspring sex ratios (Jaenike 1996). A survey of isofemale lines of D. quinaria from several populations reveals that there is genetic variation for partial suppression of this meiotic drive. Crossing experiments show that there is Y linked, and probably autosomal, variation for suppression of drive. Y-linked suppressors of X-chromosome drive have now been described in several species of Diptera. I develop a simple model for the maintenance of Y-chromosome polymorphism in species polymorphic for X-linked meiotic drive. One interesting feature of this model is that, if there is a stable Y-chromosome polymorphism, then the equilibrium frequency of the standard and sex-ratio X chromosomes is determined solely by Y-chromosome parameters, not by the fitness effects of the different X chromosomes on their carriers. This model suggests that Y-chromosome polymorphism may be easier to maintain than previously thought, and I hypothesize that karyotypic variation in Y chromosomes will be found to be associated with suppression of sex-ratio meiotic drive in other species of Drosophila. PMID- 28565183 TI - MATERNAL EFFECTS AND THE PERVASIVE IMPACT OF NESTLING HISTORY ON EGG SIZE IN A PASSERINE BIRD. AB - Environmental conditions experienced during ontogeny may have important and permanent consequences for life-history traits of individuals. The aim of this work was to determine whether conditions experienced during early life, as expressed by prefledgling condition, have any bearing on the volume of eggs subsequently laid by females in a small passerine bird species, the pied flycatcher (Ficedula hypoleuca). I first show a genetic influence on egg volume by dam-offspring regression. The existence of maternal effects is shown by comparing resemblances between average egg volumes of offspring to those of their paternal and maternal grandmothers. Path analysis shows that when controlling for the influence of maternal egg volume, the average volume of eggs produced in a lifetime is positively related to the body condition of a female measured while she is still at the nest. Thus, body condition at fledgling affects egg volume beyond the ability of maternal egg volume to predict offspring egg volume. Although there may be a persistent maternal effect of egg volume on itself or linked to a property correlated with egg volume, the maternal performance trait involved remains unknown, except for maternal egg volume itself. Given the effects that egg volume may have on reproductive success, which are partly determined prior to leaving the nest, maternal effects may have important consequences for lifetime fitness of offspring. PMID- 28565184 TI - EVIDENCE FOR AN EXTREME BOTTLENECK IN A RARE MEXICAN PINYON: GENETIC DIVERSITY, DISEQUILIBRIUM, AND THE MATING SYSTEM IN PINUS MAXIMARTINEZII. AB - Maxipinon (Pinus maximartinezii Rzedowski), which is confined to a single population of approximately 2000 to 2500 mature trees, covers about 400 ha in southern Zacatecas, Mexico. Genetic diversity measured by expected heterozygosity was 0.122, which is moderate for pines. However, percentage polymorphic loci was low, 30.3%. The fixation index (F) of 0.081 indicated only slight heterozygote deficiency. Mating system analysis indicated a significant but low level of selling; the multilocus outcrossing rate, tm , was 0.816. The mean of single locus estimates, ts , was smaller (0.761), perhaps suggesting mating among relatives, although the difference between tm and ts was not statistically significant. The most striking features of maxipinon's genetic structure were that no polymorphic locus had more than two alleles and most alleles at polymorphic loci were at intermediate frequencies. This is in contrast to other pines, which often have three to five or more alleles at some loci and in which the distribution of allele frequencies is U-shaped, most alleles being present at frequencies less than 10% or greater than 90%. A population with only two alleles per locus and at intermediate frequencies could occur if the population had been reduced to an extreme bottleneck and then expanded rapidly before random drift modified allele frequencies. A novel origin from a hybridization event would also explain the results. Significant gametic disequilibrium was detected at several pairs of loci in both maternal and paternal gametes. The presence of disequilibrium is in agreement with an origin from an extreme bottleneck, perhaps even a single seed. Furthermore, it demands that the event be relatively recent. The number of generations, as calculated from the observed mean disequilibrium, suggested that maxipinon derived from an extreme bottleneck four to five generations ago, which is less than 1000 years in this species. PMID- 28565185 TI - SEXUAL SELECTION ON MATURATION TIME AND BODY SIZE IN SPHENARIUM PURPURASCENS (ORTHOPTERA: PYRGOMORPHIDAE): CORRELATED RESPONSE TO SELECTION. AB - We measured in the field the intensity and mode (i.e., directional, stabilizing) of sexual selection acting jointly on body size and time of sexual maturity in the univoltine, polygamous grasshopper Sphenarium purpurascens. Statistical analyses indicated that selection favored large and protandrous males in terms of a higher mating success. At the same time, evidence of correlational selection acting simultaneously on body size and time to sexual maturity was found. Thus, selection should strengthen the relationship between body size and the time of sexual maturity. Theoretical work suggests the existence of a trade-off between reaching a large size and early sexual maturation in insects. The present study does not support the existence of this kind of trade-off. Recent theoretical and empirical work like the one reported here suggests that such a trade-off may not be necessarily expected if growth rates (which are often assumed to be invariable) are affected by environmental and genetic factors. PMID- 28565186 TI - CHASE-AWAY SEXUAL SELECTION AS NOISY RELIABLE SIGNALING. PMID- 28565187 TI - THE EFFECTIVE SIZE OF A HIERARCHICALLY STRUCTURED POPULATION. AB - A knowledge of the effective size of a population (Ne ) is important in understanding its current and future evolutionary potential. Unfortunately, the effective size of a hierarchically structured population is not, in general, equal to the sum of its parts. In particular, the inbreeding structure has a major influence on Ne . Here I link Ne to Wright's hierarchical measures of inbreeding, FIS and FST , for an island-structured population (or metapopulation) of size NT . The influence of FST depends strongly on the degree to which island productivity is regulated. In the absence of local regulation (the interdemic model), interdemic genetic drift reduces Ne . When such drift is combined with local inbreeding under otherwise ideal conditions, the effects of FIS and FST are identical: increasing inbreeding either within or between islands reduces Ne , with Ne = NT /[(1 + FIS )(1 + FST ) - 2FIS FST ]. However, if islands are all equally productive because of local density regulation (the traditional island model), then Ne = NT /[(1 + FIS )(1 -FST )] and the effect of FST is reversed. Under the interdemic model, random variation in the habitat quality (and hence productivity) of islands act to markedly decrease Ne . This variation has no effect under the island model because, by definition, all islands are equally productive. Even when no permanent island structure exists, spatial differences in habitat quality can significantly increase the overall variance in reproductive success of both males and females and hence lower Ne . Each of these basic results holds when other nonideal factors are added to the model. These factors, deviations from a 1:1 sex ratio, greater than Poisson variance in female reproductive success, and variation in male mating success due to polygynous mating systems, all act to lower Ne . The effects of male and female variance on Ne have important differences because only females affect island productivity. Finally, it is noted that to use these relationships, FIS and FST must be estimated according to Wright's definition (and corrected to have a zero expectation under the null model). A commonly used partitioning (theta, thetag ) can be biased if either island size or the number of islands is small. PMID- 28565188 TI - INTERTIDAL MICROHABITAT AND SELECTION AT MPI: INTERLOCUS CONTRASTS IN THE NORTHERN ACORN BARNACLE, SEMIBALANUS BALANOIDES. AB - Barnacles were sampled from various microhabitats in the rocky intertidal at multiple sites in two years. At sites in which there were large differences among microhabitats in temperature profiles, Mpi genotype frequencies were consistently and significantly different. Genotype frequencies for another allozyme locus (Gpi) as well as a DNA marker shown to be neutral (the mtDNA control region) were statistically homogeneous among thermal microhabitats at all sites in both years. The data indicate that temperature and/or desiccation mediated selection is operating at Mpi or a linked locus and that Mpi genotypes experience differential mortality in the various habitat types. If the relative fitness of genotypes is dependent on habitat type, the Mpi polymorphism may be actively maintained by a Levene model of balancing selection (Levene 1953). Because barnacle larvae are produced in abundance each year and spend five to eight weeks dispersing in the water column, there is little opportunity for the accumulation of adaptive divergence over the environmental grain size relevant in intertidal habitats. The Mpi polymorphism may be an important component of a suite of traits involved in the adaptation of barnacles to heterogeneous environments. Due to the relatively high concentration of mannose in a variety of algal groups, the metabolism of mannose may substantially affect individual performance and fitness in this and other species that feed on algae and phytoplankton. Because the Mpi locus is one of the most strongly polymorphic in marine organisms, these findings may be relevant for a diversity of other such species. PMID- 28565189 TI - COST OF GLANDULAR TRICHOMES, A "RESISTANCE" CHARACTER IN DATURA WRIGHTII REGEL (SOLANACEAE). AB - Models regarding the evolution of plant resistance to herbivory often assume that the primary mechanism maintaining resistance polymorphisms is the balance between benefits of increased resistance to herbivores and costs associated with the production of a resistance character. However, rarely has it been demonstrated that genetically based resistance traits are costly. Here, we document costs associated with the production of glandular trichomes, a resistance character in Datura wrightii that is predominantly under the control of a single gene of large effect. In the absence of herbivores, plants with glandular trichomes (sticky) produced 45% fewer viable seeds than plants with nonglandular trichomes (velvety). Although both plant types flowered with similar frequency, sticky plants matured fewer capsules and fewer of their seeds germinated. The fitness difference between the types in herbivore-free conditions was not mitigated by the addition of water, a potentially limiting resource for sticky plants. Under herbivore pressure, there was no significant fitness difference between the types, although the fitness of velvety plants was still higher than that of sticky plants. This occurred even though velvety plants sustained more herbivore damage than sticky plants and were more likely to be attacked by most herbivore species present. The fitness difference between the plant types was especially reduced when herbivore-attacked plants were watered, which indicates that sticky plants may have higher tolerance for damage than velvety plants when supplied with a potentially limiting resource. Yet, the maintenance of a fitness deficit (albeit small and nonsignificant) for sticky plants when attacked by herbivores indicates no net benefit associated with the production of glandular trichomes in this first year of our study. These results add to our current understanding that herbivore resistance characters can be costly and raise the question of how this genetic polymorphism is maintained in wild populations. PMID- 28565190 TI - THE ONTOGENY OF ASYMMETRY IN EARWIG FORCEPS. AB - Fluctuating asymmetry may play an important role in the evolution of naturally selected and secondary sexual traits. However, very little is known about how asymmetries arise or how organisms maintain symmetry during development. Here I propose three mutually exclusive patterns for the development of asymmetries through consecutive growth stages: (1) compensatory growth, in which growth of the shorter side is greatest at the following growth stage; (2) persistent growth, in which growth of the longer side is greatest at the following growth stage; and (3) uncorrelated growth in which growth of the following stage is unrelated to the asymmetry at the previous one. I followed the growth in the forceps of male earwigs through four successive instars. Dyar's rule was used as a null model of insect growth. In the molt from the second to third instar, asymmetries increased through uncorrelated growth and with the magnitude but not the sign expected from Dyar's rule. However, following this, at the molts between instars 3-4 and 4-5, compensatory growth maintained asymmetries at a lower level than expected from Dyar's rule. Although there was no reduction in the absolute magnitude of asymmetry, relative asymmetry did decline. The net growth of forceps length did not follow Dyar's rule. The interpretation of patterns of growth were more sensitive and informative than the interpretation of the relations between asymmetries at consecutive instars. PMID- 28565192 TI - FINE-SCALE GENETIC STRUCTURE OF WHITEBARK PINE (PINUS ALBICAULIS): ASSOCIATIONS WITH WATERSHED AND GROWTH FORM. AB - The fine-scale genetic structure of a subalpine conifer, whitebark pine (Pinus albicaulis Engelm.), was studied at nested geographic levels from watershed to adjacent stems in the eastern Sierra Nevada Range of California. A combination of several characteristics contributed to unpredicted genetic structure in this species. This includes being one of only 20 pine species worldwide with wingless, bird-dispersed seeds; having the reputed capacity to reproduce vegetatively; and forming distinct growth morphologies at different elevations in this part of its natural range. Genetic differentiation, as measured with 21 allozyme loci, among the three studied watersheds is virtually negligible (FST = 0.004). This is a surprising result because the upper-elevation sites vary somewhat in slope aspect; thus, aspect was confounded with watershed effect. Differentiation between the upper-elevation prostrate krummholz thickets and lower-elevation upright tree clump growth forms is modest (FST = 0.051). Much stronger differentiation was measured among the individual thickets and clumps within their sample sites (FST = 0.334). Within krummholz thickets, multiple individuals are present and genetic relationships often resemble half- to full-sibling family structure (mean r = 0.320). Canonical trend surface analysis in two intensively sampled thickets indicates greatest genotypic variation in the direction of the prevailing wind. At lower elevations, most (72%) of the tree clumps contained more than one genotype; the remaining clumps are probably multistemmed trees. Within tree clumps, family relationships are closer than those for krummholz thickets-commonly full-sibling to selfed structure (mean r = 0.597). Genetic structure is apparently profoundly influenced by the seed-caching behavior of Clark's nutcracker (Nucifraga columbiana Wilson). Western pine species typically show little among-population differentiation and high levels of within-population genetic variation. In whitebark pine in the eastern Sierra Nevada of California, genetic variation is highly structured, especially within the natural groupings krummholz thickets and upright tree clumps. PMID- 28565191 TI - COMPARATIVE POPULATION STRUCTURE AND GENE FLOW OF A BROOD PARASITE, THE GREAT SPOTTED CUCKOO (CLAMATOR GLANDARIUS), AND ITS PRIMARY HOST, THE MAGPIE (PICA PICA). AB - The amount of gene flow is an important determinant of population structure and therefore of central importance for understanding coevolutionary processes. We used microsatellite markers to estimate population structure and gene flow rates of the great spotted cuckoo (Clamator glandarius) and its main host in Europe, the magpie (Pica pica), in a number of populations (seven and 15, respectively) across their distribution range in Europe. The genetic analysis shows that there exists a pattern of isolation by distance in both species, although the cuckoo data are only indicative due to a small sample size. Gene flow seems to be extensive between nearby populations, higher for magpies than cuckoos, and especially high for magpie populations within the area of distribution of the great spotted cuckoo. There is no correlation between genetic distances between magpie populations and genetic distances between cuckoo populations. We discuss the implications of extensive gene flow between magpie populations in sympatry with cuckoos for the population dynamics of hosts, in particular for the occurrence of egg rejection behavior in host populations and how the different rates of migration for both species can affect the dynamics of coevolutionary processes. PMID- 28565193 TI - GENETIC CORRELATIONS BETWEEN LIFE-HISTORY AND BEHAVIORAL TRAITS CAN CAUSE REPRODUCTIVE ISOLATION. AB - Reproductive isolation may often evolve as an indirect (pleiotropic) consequence of populations adapting to different environments or habitats. For example, niches that are temporally or seasonally offset can select for organisms with different developmental characteristics. These developmental differences can inadvertently cause reproductive isolation by a variety of means including shifts in mating activity patterns. Here, we show a genetic correlation between a life history trait (developmental period) and a behavioral trait (time of mating) that causes significant premating isolation in the melon fly, Bactrocera cucurbitae (Diptera: Tephritidae). Fly lines selected for short and long developmental periods differ in their preferred times of mating during the evening. This difference translates into significant prezygotic isolation, as measured by mate choice tests. If the time of mating between two populations differed more than one hour, the isolation index was significantly higher than zero. These indicate that premating isolation can be established if the developmental period is divergently selected for. If such genetic correlations are ubiquitous in many organisms, multifarious divergent selection for life-history traits would often accelerate the evolution of reproductive isolation. We speculate that reproductive isolation may have been evolved via genetic correlations among time related traits, for example, developmental period and time of mating, as in other organisms. PMID- 28565194 TI - CHASE-AWAY SEXUAL SELECTION: RESISTANCE TO "RESISTANCE". PMID- 28565195 TI - THE ZOOGEOGRAPHY AND CENTERS OF ORIGIN OF THE CRAYFISH SUBGENUS PROCERICAMBARUS (DECAPODA: CAMBARIDAE). AB - The Central Highlands region in the central United States is a taxonomically diverse region with a high incidence of stream endemism. Based on the distributions of the diverse ichthyofauna in the region, a pre-Pleistocene pattern of diversity due to vicariant events has been proposed to explain high levels of endemism and species richness. We tested this hypothesis using crayfish phylogenies and distributional patterns for species distributed in the Central Highlands region. We concluded that both pre-Pleistocene and Pleistocene hypotheses are compatible with the crayfish distributions and these distributions are likely due to a combination of both vicariant and dispersal events. Furthermore, we suggest a Pleistocene center of origin for the crayfish subgenus Procericambarus within the Ozark region and a pre-Pleistocene center of origin for the genus Orconectes within the Eastern Highlands region. PMID- 28565196 TI - DID VICARIANCE MOLD PHENOTYPES OF WESTERN NORTH AMERICAN FISHES? EVIDENCE FROM GILA RIVER CYPRINIDS. AB - Pairwise, two- and three-way Mantel tests were used to evaluate a null hypothesis of no significant covariation when morphological features of three cyprinid fish taxa of the genus Gila were compared. Tests involved ecological conditions and past and present hydrography in the Gila River Basin of western North America. A vicariance hypothesis was the only model statistically proficient in explaining diversity of fish phenotypes. Of paleohydrographic reconstructions compared, those of the mid-Miocene and Pliocene epochs were significantly associated with present-day distributions of phenotypes. Of these, the Pliocene was paramount. PMID- 28565197 TI - COPULATORY BEHAVIOR, GENITAL MORPHOLOGY, AND MALE FERTILIZATION SUCCESS IN WATER STRIDERS. AB - Recent theoretical and empirical interest in postmating processes have generated a need for increasing our understanding of the sources of variance in fertilization success among males. Of particular importance is whether such postmating sexual selection merely reinforces the effects of premating sexual selection or whether other types of male traits are involved. In the current study, we document large intraspecific variation in last male sperm precedence in the water strider Gerris lateralis. Male relative paternity success was repeatable across replicate females, showing that males differ consistently in their ability to achieve fertilizations. By analyzing shape variation in male genital morphology, we were able to demonstrate that the shape of male intromittent genitalia was related to relative paternity success. This is the first direct experimental support for the suggestion that male genitalia evolve by postmating sexual selection. A detailed analysis revealed that different components of male genitalia had different effects, some affecting male ability to achieve sperm precedence and others affecting male ability to avoid sperm precedence by subsequent males. Further, the effects of the shape of the male genitalia on paternity success was in part dependent on female morphology, suggesting that selection on male genitalia will depend on the frequency distribution of female phenotypes. We failed to find any effects of other morphological traits, such as male body size or the degree of asymmetry in leg length, on fertilization success. Although males differed consistently in their copulatory behavior, copulation duration was the only behavioral trait that had any significant effect on paternity. PMID- 28565198 TI - GENETIC VARIATION IN TIME AND SPACE: MICROSATELLITE ANALYSIS OF EXTINCT AND EXTANT POPULATIONS OF ATLANTIC SALMON. AB - Information on genetic composition of past and present populations may be obtained by analyzing DNA from archival samples. A study is presented on the genetic population structure of extant and extinct local populations of Atlantic salmon from 1913 to 1989 using dried scales as a source of DNA. Variation at six microsatellite loci was studied. Tests for differentiation among populations and among time series within populations showed that population structure was stable over time. This was also confirmed by a neighbor-joining dendrogram, which showed a clear clustering of samples from individual rivers that covered a time span of up to 76 years. These results suggest that salmon populations evolve as semi independent units connected by modest amounts of gene flow. Additionally, a clear association between geographic and genetic distance was found. This relationship has otherwise been difficult to establish in several recent studies. The discrepancy may be due to impact of human activities on the genetic structure of present populations, whereas old samples represent populations in a more unaffected state. However, other explanations related to differences in the sampling of past and present populations may be equally valid. PMID- 28565199 TI - THE INFLUENCE OF POPULATION SIZE AND ISOLATION ON GENE FLOW BY POLLEN IN SILENE ALBA. AB - In a series of experiments conducted over two seasons, we used arrays of experimental populations to examine the effects of flower number and distance between patches on gene flow by pollen. For this study we used the dioecious, short-lived perennial plant Silene alba (Caryophyllaceae). This species lives in disturbed roadside and agricultural habitats and displays a weedy population dynamic with high colonization and extinction rates. The motivation for the study was to understand what factors may be influencing genetic connectedness among newly colonized populations within a regional metapopulation. By using experimental populations composed of genotypes homozygous at a diagnostic locus, it was possible to identify explicitly pollen movement into a focal patch as a function of flower number and distance to the nearest neighboring patch. Overall, the mean immigration rate (measured as the fraction of seeds sired by males outside the focal patch) at 20 m was just over 47%, whereas at 80 m immigration rates were less than 6%. In addition, by knowing the context in which each of these gene-flow events occurred, it was possible to understand some of the factors that influenced the exchange of genes. Both the number of flowers in the focal population (target) and in the neighboring populations (source) had a significant effect on the frequency of gene flow. Our experimental data also demonstrate that factors that influence gene flow at one spatial scale may not act in the same way at another. Specifically, the influence of target size and the relative size of the target and source patches on rates of gene flow depended on whether the patches were separated by 20 m or 80 m. These data suggest that the patterns of gene flow within a metapopulation system can be complex and may vary within a growing season. PMID- 28565200 TI - A FIELD TEST FOR HOST-PLANT DEPENDENT SELECTION ON LARVAE OF THE APPLE MAGGOT FLY, RHAGOLETIS POMONELLA. AB - Host-plant dependent fitness trade-offs refer to traits that enhance the performance of an insect on one plant species to its detriment on others. Such trade-offs are central to models of sympatric speciation via host shifts, but have proven difficult to empirically demonstrate. Here, we test for host-plant dependent selection on larvae of apple (Malus pumila L.)- and hawthorn (Crataegus mollis L. spp.)-infesting races of Rhagoletis pomonella (Walsh). Samples of larvae were reared in the field and under protective conditions in a garage. Our rationale was that the garage should slow rates of fruit rot relative to the field, relaxing selection pressures associated with declining fruit quality. Four findings emerged from the study. (1) Larvae suffered higher mortality in fruits in the field than the garage. (2) The increase in mortality was greater for larvae in haws. (3) Larvae possessing the alleles Me 100, Acon-2 95, and Mpi 37, three allozymes displaying host-related differentiation in R. pomonella that map to linkage group II in the fly, left fruits earlier than other genotypes. (4) Allele frequencies for Me 100, Acon-2 95, and Mpi 37 were significantly higher in both apple and haw larvae surviving the field versus the garage treatment. Our results suggested that field conditions favored larvae that rapidly developed and left rotting fruits. Since these individuals tended to possess the alleles Me 100, Acon-2 95, and Mpi 37, frequencies of these allozymes were higher in the field. Selection on larvae was directional for Me 100, Acon-2 95, and Mpi 37 (or linked genes) in both host races. We previously showed that these same alleles can be disfavored in the pupal stage, especially in the apple race, where they correlate with premature diapause termination. Fitness trade-offs in Rhagoletis may therefore be due as much to differences in the relative strengths of directional selection pressures acting on different life stages as to disruptive selection affecting any one particular stage. The necessity to consider details of the entire life-cycle highlights one of the many challenges posed to documenting fitness trade-offs for phytophagous insects. PMID- 28565201 TI - EPISTATIC INTERACTIONS CAN LOWER THE COST OF RESISTANCE TO MULTIPLE CONSUMERS. AB - It is widely assumed that resistance to consumers (e.g., predators or pathogens) comes at a "cost," that is, when the consumer is absent the resistant organisms are less fit than their susceptible counterparts. It is unclear what factors determine this cost. We demonstrate that epistasis between genes that confer resistance to two different consumers can alter the cost of resistance. We used as a model system the bacterium Escherichia coli and two different viruses (bacteriophages), T4 and Lambda, that prey upon E. coli. Epistasis tended to reduce the costs of multiple resistance in this system. However, the extent of cost savings and its statistical significance depended on the environment in which fitness was measured, whether the null hypothesis for gene interaction was additive or multiplicative, and subtle differences among mutations that conferred the same resistance phenotype. PMID- 28565202 TI - DIFFERENTIATION OF MITOCHONDRIAL DNA POLYMORPHISMS IN POPULATIONS OF FIVE JAPANESE ABIES SPECIES. AB - Mitochondrial DNA polymorphism of 40 populations of five Abies species was investigated using PCR-amplified coxI and coxIII gene probes. Using four combinations of probe and restriction enzyme, we detected three major haplotypes and 15 total haplotypes. We also found varied levels of gene diversity for the different species: 0.741, 0.604, 0.039, 0.000, and 0.292 for A. firma, A. homolepis, A. veitchii, A. mariesii, and A. sachalinensis, respectively. The marginal and southern populations of A. firma and A. homolepis have unique haplotypes, especially the Kyushu, Shikoku, and Kii Peninsula populations, which inhabit areas coinciding with probable refugia of the last glacial period and possess high levels of mtDNA genetic diversity. The haplotypes in some populations suggested mtDNA capture also occurred between species through introgression/hybridization. The strong mtDNA population differentiation in Abies is most likely due to the maternal inheritance of mitochondria and restricted seed dispersal. A phenetic tree based on the genetic similarity of the mtDNA suggests that some species are polyphyletic. Based on mtDNA variation, the five Abies species could be divided roughly into three groups: (1) A. firma and A. homolepis, (2) A. veitchii and A. sachalinensis, and (3) A. mariesii. However, we found that all these Abies species, except A. mariesii, are genetically very closely related according to an analysis of their cpDNA sequences. This showed that the chloroplast rbcL gene differed by only one base substitutions among the four species. We believe that the mtDNA variation and cpDNA similarity clearly reflect relationships among, and the dissemination processes affecting these Abies species since the last glacial period. PMID- 28565203 TI - ANALYSIS OF MECHANISMS OF MICROEVOLUTIONARY CHANGE IN CEPPHUS GUILLEMOTS USING PATTERNS OF CONTROL REGION VARIATION. AB - We surveyed population-level sequence variation in part of the mitochondrial control region for three species including eight subspecies of Cepphus guillemots (Charadriiformes: Alcidae) to test specific predictions about mechanisms of population differentiation. We found that sequences of spectacled guillemots (C. carbo) were more closely related to those of pigeon guillemots (C. columba; both found in the Pacific Ocean) than to those of black guillemots (C. grylle; Arctic and Atlantic Oceans), despite dissimilarities in plumage between spectacled guillemots and the other species. Distributions of species and timing of divergence events suggest that speciation involved allopatric and microallopatric populations isolated by Pleistocene glaciers. Control region sequences were significantly differentiated among populations within species and suggest that gene flow is low; however, populations are probably not in genetic equilibrium, so these results probably reflect historical isolation of colonies. In contrast, phylogenetic relationships among sequences within species were poorly resolved, probably because of a combination of incomplete lineage sorting and contemporary gene flow. Indices of genetic diversity provided no suggestion of recent bottlenecks in most populations, although two populations apparently underwent recent severe bottlenecks. Genetic divergence among populations was not correlated with geographic distance, which argues against isolation by distance. Results of these analyses, combined with breeding distributions and timing of divergence events, suggest that populations diverged during isolation in glacial refugia. Our results are consistent with earlier hypotheses posed by Storer and Udvardy. PMID- 28565204 TI - AN EVOLUTIONARY ARGUMENT FOR TIME LIMITATION. PMID- 28565205 TI - ESTIMATING HIERARCHICAL F-STATISTICS. AB - This paper presents an analysis of variance (ANOVA) approach by which estimation of F-statistics can be made from data with an arbitrary s-level hierarchical population structure. Assuming a complete random-effect model, a general ANOVA procedure is developed to estimate F-statistics as ratios of different variance components for all levels of population subdivision in the hierarchy. A generalized relationship among F-statistics is also derived to extend the well known relationship originally found by Sewall Wright. Although not entirely free from the bias particular to small number of subdivisions at each hierarchy and extreme gene frequencies, the ANOVA estimators of F-statistics consider sampling effects at each level of hierarchy, thus removing the bias incurred in the other estimators that are commonly based on direct substitution of unknown gene frequencies by their sample estimates. Therefore, the ANOVA estimation procedure presented here may become increasingly useful in analyzing complex population structure because of increasing use of the estimated hierarchical F-statistics to infer genetic and demographic structures of natural populations within and among species. PMID- 28565206 TI - SEX AND SPECIATION: GENETIC ARCHITECTURE AND EVOLUTIONARY POTENTIAL OF SEXUAL VERSUS NONSEXUAL TRAITS IN THE SIBLING SPECIES OF THE DROSOPHILA MELANOGASTER COMPLEX. AB - Phenotypic divergence in the male reproductive system (genitalia and gonads) between species of the Drosophila melanogaster complex and their hybrids was quantified to decipher the role of these traits in species differentiation and speciation. Internal as well as external, sexual and nonsexual traits were analyzed with respect to genetic variation and trait asymmetry between strains within species, genetic divergence between species, and dominance and asymmetry in species and hybrids. The variation between strains within species was significant among sexual traits, and only external traits were less asymmetric than internal ones, which suggests that sexual traits are not strongly constrained within species. Three main findings show that sexual traits are most divergent between species: (1) testis length and area, and the area of the posterior lobe of the genital arch (sexual traits) showed the highest proportion of variation between species; (2) linear discriminant functions with the highest components associated to sexual traits were better predictors of species membership; and (3) testis length and area revealed a departure from a linear relationship between members of the species group. Examination of interspecific hybrids showed that sexual traits had higher asymmetry in species hybrids than in the parental species and that sexual traits showed additivity or dominance whereas nonsexual traits showed overdominance (with the exception of malpighian tubules length). These results suggest that sexual traits have undergone more genetic changes and, as a result, tend to show higher divergence and stronger hybrid breakdown between species than nonsexual traits. We propose that sexual selection in the broad sense, affecting all aspects of sexuality, may be responsible for the diversified appearance of sexual traits among closely related species and that the genetic architecture underlying sexual traits may be more prone to disruption during the early stages of speciation. PMID- 28565207 TI - DOES THE TRADE-OFF BETWEEN GROWTH AND REPRODUCTION SELECT FOR FEMALE-BIASED SEXUAL ALLOCATION IN COSEXUAL PLANTS? AB - We analyzed sexual allocation in cosexual plants while taking the trade-off between growth and reproduction into consideration and showed that this trade-off does not select for female-biased sexual allocation. There are two problems in sexual allocation: optimizing the amount of resources allocated to reproduction in a growing season and equalizing the resources allocated to the male and the female functions. If these two are possible at the same time, equal resource allocation to the male and the female functions is the evolutionarily stable strategy (ESS; given that the fitness gains through the male and the female functions are proportional to the amount of the resources allocated to these functions). Biased sexual allocation only occurs when constraints make it impossible to simultaneously optimize allocation to reproduction and allocation to male and female functions. However, even if female-biased sexual allocation occurs due to the addition of other constraints, the trade-off between growth and reproduction itself is not an important factor that selects for female-biased sexual allocation. PMID- 28565208 TI - ORIGIN AND BIOGEOGRAPHY OF AESCULUS L. (HIPPOCASTANACEAE): A MOLECULAR PHYLOGENETIC PERSPECTIVE. AB - Sequences of chloroplast gene matK and internal transcribed spacers of nuclear ribosomal RNA genes were used for phylogenetic analyses of Aesculus, a genus currently distributed in eastern Asia, eastern and western North America, and southeastern Europe. Phylogenetic relationships inferred from these molecular data are highly correlated with the geographic distributions of species. The identified lineages closely correspond to the five sections previously recognized on the basis of morphology. Ancestral character-state reconstruction, a molecular clock, and fossil evidence were used to infer the origin and biogeographic history of the genus within a phylogenetic framework. Based on the molecular phylogenetic reconstruction of the genus, sequence divergence, and paleontological evidence, we infer that the genus originated during the transition from the Cretaceous to the Tertiary (~65 M.Y.B.P.) at a high latitude in eastern Asia and spread into North America and Europe as an element of the "boreotropical flora"; the current disjunct distribution of the genus resulted from geological and climatic changes during the Tertiary. PMID- 28565209 TI - THE ORIGIN OF WEST EUROPEAN SUBSPECIES OF HONEYBEES (APIS MELLIFERA): NEW INSIGHTS FROM MICROSATELLITE AND MITOCHONDRIAL DATA. AB - Apis mellifera is composed of three evolutionary branches including mainly African (branch A), western and northern European (branch M), and southeastern European (branch C) populations. The existence of morphological clines extending from the equator to the Polar Circle through Morocco and Spain raised the hypothesis that the branch M originated in Africa. Mitochondrial DNA analysis revealed that branches A and M were characterized by highly diverged lineages implying very remote links between both branches. It also revealed that mtDNA haplotypes from lineages A coexisted with haplotypes M in the Iberian Peninsula and formed a south-north frequency cline, suggesting that this area could be a secondary contact zone between the two branches. By analyzing 11 populations sampled along a France-Spain/Portugal-Morocco-Guinea transect at 8 microsatellite loci and the DraI RFLP of the COI-COII mtDNA marker, we show that Iberian populations do not present any trace of "africanization" and are very similar to French populations when considering microsatellite markers. Therefore, the Iberian Peninsula is not a transition area. The higher haplotype A variability observed in Spanish and Portuguese samples compared to that found in Africa is explained by a higher mutation rate and multiple and recent introductions. Selection appears to be the best explanation to the morphological and allozymic clines and to the diffusion and maintenance of African haplotypes in Spain and Portugal. PMID- 28565210 TI - HETEROCHRONY AND DEVELOPMENTAL INNOVATION: EVOLUTION OF FEMALE GAMETOPHYTE ONTOGENY IN GNETUM, A HIGHLY APOMORPHIC SEED PLANT. AB - Seed plant female gametophytes are focal points for the evolutionary modification of development. From a structural perspective, the most divergent female gametophytes among all seed plants are found in Gnetum, a clade within Gnetales. Coenocytic organization at sexual maturity, absence of defined egg cells (free nuclei are fertilized), lack of centripetal cellularization, and postfertilization development of embryo-nourishing tissues are features of the female gametophytes of Gnetum unparalleled among seed plants. Although the female gametophyte of Gnetum retains the three basic phases of somatic development common to female gametophytes of plesiomorphic seed plants (free nuclear development, cellularization, cellular growth), the timing of fertilization has been accelerated relative to the rate of somatic development. As a consequence, the female gametophyte of Gnetum matures sexually (is fertilized) at a juvenile (compared with the ancestral somatic ontogeny) and free nuclear stage of somatic development, thereby precluding differentiation of egg cells. Unlike progenetic animals, where truncation of somatic ontogeny evolves in tandem with acceleration in the timing of sexual maturation, the female gametophyte of Gnetum completes the entire ancestral somatic ontogeny after precocious sexual maturation. This results in the evolution of postfertilization development of embryo-nourishing female gametophyte tissues, a phenomenon unique among seed plants. Nonheterochronic developmental innovations have also played important roles in the evolution of the female gametophyte of Gnetum. Centripetal cellularization, which is always associated with the phase change from coenocytic to cellular organization among plesiomorphic seed plant female gametophytes, is lacking in Gnetum. Instead, during early phases of development, apomorphic free nuclear organization is coupled with a highly anomalous pattern of cellularization. Stage specific innovations during early development in the female gametophyte of Gnetum do not affect plesiomorphic aspects of later phases of development. Thus, a complex array of heterochronic and nonheterochronic developmental innovations have played critical roles in the ontogenetic evolution of the highly apomorphic female gametophyte of Gnetum. PMID- 28565211 TI - GENETIC STRUCTURE OF THE FROGS GEOCRINIA LUTEA AND GEOCRINIA ROSEA REFLECTS EXTREME POPULATION DIVERGENCE AND RANGE CHANGES, NOT DISPERSAL BARRIERS. AB - I describe the genetic structure of two frog species, Geocrinia rosea and Geocrinia lutea, using allozyme electrophoresis to understand population structure and thereby possible mechanisms of divergence and speciation. The sampling regimes represented the entire range of both species and provided replicated tests of the impact of ridges, rivers, and dry forest on gene flow. Geocrinia rosea and G. lutea were highly genetically subdivided (FST = 0.69, 0.64, respectively). In the extreme, there were fixed allelic differences between populations that were only 4 km (G. rosea) or 1.25 km (G. lutea) apart. In addition to localized divergence, two-dimensional scaling of genetic distance allowed the recognition of broad-scale genetic groups, each consisting of several sample sites. Patterns of divergence were unrelated to the presence of ridges, rivers, or dry forest. I argue that range contraction and expansion, combined with extreme genetic divergence in single, isolated populations, best accounts for the genetic structure of these species. PMID- 28565212 TI - EFFECTS OF MORTALITY RISK AND GROWTH ON A MODEL OF REPRODUCTIVE EFFORT: WHY THE SHINE AND SCHWARZKOPF MODEL IS NOT GENERAL. AB - Using data and reanalysis of a model published by Shine and Schwarzkopf (1992) we reject the two unsubstantiated assertions made by Shine et al. (1996) about modeling the evolution of reproductive effort in squamate reptiles: (1) mortality schedules do not affect predictions of the Shine and Schwarzkopf (1992) model; and (2) growth rates that would affect the predictions of the original model are biologically unreasonable. On the basis of these two points alone, we strongly reject Shine et al.'s (1996) claim that a critique by Niewiarowski and Dunham (1994) actually reinforces the original conclusions of Shine and Schwarzkopf (1992). Furthermore, results and data presented here are strong enough to severely circumscribe the generality of the Shine and Schwarzkopf (1992) model. Though we do not provide data or new analyses of the potential effects of offspring size variation, we reaffirm the position of Niewiarowski and Dunham (1994) that the sensitivity of the Shine and Schwarzkopf (1992) model to such effects should be explored before using it as a basis for structuring future research on the evolution of reproductive effort in squamate reptiles. PMID- 28565213 TI - THE POPULATION GENETICS OF ADAPTATION: THE DISTRIBUTION OF FACTORS FIXED DURING ADAPTIVE EVOLUTION. AB - We know very little about the genetic basis of adaptation. Indeed, we can make no theoretical predictions, however heuristic, about the distribution of phenotypic effects among factors fixed during adaptation nor about the expected "size" of the largest factor fixed. Study of this problem requires taking into account that populations gradually approach a phenotypic optimum during adaptation via the stepwise substitution of favorable mutations. Using Fisher's geometric model of adaptation, I analyze this approach to the optimum, and derive an approximate solution to the size distribution of factors fixed during adaptation. I further generalize these results to allow the input of any distribution of mutational effects. The distribution of factors fixed during adaptation assumes a pleasingly simple, exponential form. This result is remarkably insensitive to changes in the fitness function and in the distribution of mutational effects. An exponential trend among factors fixed appears to be a general property of adaptation toward a fixed optimum. PMID- 28565214 TI - CYTOLOGICAL CHARACTERIZATION OF PREMEIOTIC VERSUS POSTMEIOTIC DEFECTS PRODUCING HYBRID MALE STERILITY AMONG SIBLING SPECIES OF THE DROSOPHILA MELANOGASTER COMPLEX. AB - In accordance with Haldane's rule, hybridizations between species of the Drosophila simulans clade produce fertile females but sterile males. In this study, a comprehensive characterization was undertaken on the six types of F1 males that were the result of the crosses between D. simulans, D. sechellia, and D. mauritiana. With the use of light and electron microscopy, it was shown that while each particular hybrid genotype exhibited a specific sterility phenotype, these phenotypes fell into two distinct classes. The two hybrid genotypes that possessed D. mauritiana X-chromosomes contained spermatogenic defects that caused arrests in premeiotic spermatogenic stages. The other four F1 hybrids possessed postmeiotic spermatogenic defects. Nonsynchronous cell divisions, underdeveloped mitochondrial derivative-axonemal associations, and microtubule abnormalities were common to all of these hybrids. Each particular postmeiotically defective hybrid genotype demonstrated characteristically distinct profiles in sperm bundle number in addition to characteristic spermiogenic arrests in the furthest developed spermatids. These results in species hybrids contrast with the absence of significant differences in spermatogenic characters between species of this clade. In addition, by utilizing an attached-X cross, we investigated the influence of maternal effects and cytoplasmic factors on the sterility of D. simulans F1 hybrids and found none. However, we discovered a strain of D. simulans (2119) that caused a large shift in sterility from postmeiotic to premeiotic when crossed to D. sechellia. This suggests that D. simulans is polymorphic for genes involving premeiotic and postmeiotic sterility and that the two types of sterilities between species may have a simple genetic basis. PMID- 28565215 TI - RANDOM TREES AND THE COMPARATIVE METHOD: A CAUTIONARY TALE. AB - One of the toughest problems facing comparative biology is the paucity of robust phylogenetic hypotheses for many taxonomic groups. Martins (1996) proposed a method to analyze comparative data in the absence of a known phylogeny using randomly generated trees. Before applying this method, however, researchers should be aware that (1) parameter estimates derived from this method essentially assume a star phylogeny, and thus, estimate the same evolutionary regression or correlation coefficient as traditional cross-species analyses; and (2) statistical conclusions derived from this method may be so conservative as to mask evolutionary patterns, such as Rensch's rule, and should be interpreted with caution. PMID- 28565216 TI - BEST-FIT MAXIMUM-LIKELIHOOD MODELS FOR PHYLOGENETIC INFERENCE: EMPIRICAL TESTS WITH KNOWN PHYLOGENIES. AB - Despite the proliferation of increasingly sophisticated models of DNA sequence evolution, choosing among models remains a major problem in phylogenetic reconstruction. The choice of appropriate models is thought to be especially important when there is large variation among branch lengths. We evaluated the ability of nested models to reconstruct experimentally generated, known phylogenies of bacteriophage T7 as we varied the terminal branch lengths. Then, for each phylogeny we determined the best-fit model by progressively adding parameters to simpler models. We found that in several cases the choice of best fit model was affected by the parameter addition sequence. In terms of phylogenetic performance, there was little difference between models when the ratio of short: long terminal branches was 1:3 or less. However, under conditions of extreme terminal branch-length variation, there were not only dramatic differences among models, but best-fit models were always among the best at overcoming long-branch attraction. The performance of minimum-evolution-distance methods was generally lower than that of discrete maximum-likelihood methods, even if maximum-likelihood methods were used to generate distance matrices. Correcting for among-site rate variation was especially important for overcoming long-branch attraction. The generality of our conclusions is supported by earlier simulation studies and by a preliminary analysis of mitochondrial and nuclear sequences from a well-supported four-taxon amniote phylogeny. PMID- 28565217 TI - THE GENETIC BASIS OF THE TRADE-OFF BETWEEN CALLING AND WING MORPH IN MALES OF THE CRICKET GRYLLUS FIRMUS. AB - Wing dimorphisms exist in a wide range of insects. In wing-dimorphic species one morph is winged has functional flight muscles (LW), and is flight-capable, whereas the other has reduced wings (SW) and cannot fly The evolution and maintenance of wing dimorphisms is believed to be due to trade-offs between flight capability and fitness-related traits. Although there are well-established phenotypic trade-offs associated with wing dimorphism in female insects, there only exist two studies that have established a genetic basis to these trade-offs. The present study provides the first evidence for a genetically based trade-off in male insects, specifically in the sand cricket Gryllus firmus. Because they have to expend energy to maintain the flight apparatus (especially flight muscles), LW males are predicted to call less and therefore to attract fewer females. To be of evolutionary significance, call duration wing morph, and wing muscle condition (size and functionality) should all have measurable heritabilities and all be genetically correlated. Differences between morphs in male G. firmus in the likelihood of attracting a female were tested in the laboratory using a T-maze where females chose between a LW male and a SW male. Call duration for each male was recorded on the sixth day of adult life. A significant difference in call duration was found between SW and LW males (SW = 0.86 +/- 0.01, LW = 0.64 +/- 0.01 h). SW males attracted significantly more females than did LW males (63% vs. to 37%). All the traits involved in the trade off had significant heritabilities (call = 0 75 +/- 0 33; wing morph = 0.22 +/- 007; muscle weight = 0.38 +/- 0.09) and genetic correlations (call and wing morph = -0.46 +/- 0.20 for SW, -0.68 +/- 0.16 for LW; LW call and muscle weight = -0.80 +/- 0.14). These results provide the first documented evidence that trade-offs between a dimorphic trait and a fitness-related character in males has a genetic basis and hence can be of evolutionary significance. PMID- 28565218 TI - A PHYLOGENETIC PERSPECTIVE ON THE EVOLUTION OF SEXUAL DICHROMATISM IN TANAGERS (THRAUPIDAE): THE ROLE OF FEMALE VERSUS MALE PLUMAGE. AB - The evolution of sexual dichromatism in tanagers (family Thraupidae) was studied from a phylogenetic perspective using a molecular-based phylogeny. Mapping patterns of sexual dimorphism in plumage onto the phylogeny reveals that changes in female plumage occur more frequently than changes in male plumage. Possible explanations for this pattern include sexual selection acting on female plumage and natural selection for background matching. The results of this study and other recent phylogenetic and comparative studies suggest that factors affecting female plumage are important in shaping patterns of sexual dimorphism. PMID- 28565219 TI - TESTS FOR ANCIENT SPECIES FLOCKS BASED ON MOLECULAR PHYLOGENETIC APPRAISALS OF SEBASTES ROCKFISHES AND OTHER MARINE FISHES. AB - The concept of species flocks has been central to previous interpretations of patterns and processes of explosive species radiations within several groups of freshwater fishes. Here, molecular phytogenies of species-rich Sebastes rockfishes from the northeastern Pacific Ocean were used to test predictions of null theoretical models that assume random temporal placements of phylogenetic nodes. Similar appraisals were conducted using molecular data previously published for particular cichlid fishes in Africa that epitomize, by virtue of a rapid and recent radiation of species, the traditional concept of an intralacustrine "species flock." As gauged by the magnitudes of genetic divergence in cytochrome b sequences from mitochondrial DNA, as well as in allozymes, most speciation events in the Sebastes complex were far more ancient than those in the cichlids. However, statistical tests of the nodal placements in the Sebastes phylogeny suggest that speciation events in the rockfishes were temporally nonrandom, with significant clustering of cladogenetic events in time. Similar conclusions also apply to an ancient complex of icefishes (within the Notothenioidei) analyzed in the same fashion. Thus, the rockfishes (and icefishes) may be interpreted as ancient species flocks in the marine realm. The analyses exemplified in this report introduce a conceptual and operational approach for extending the concept of species flocks to additional environmental settings and evolutionary timescales. PMID- 28565220 TI - BREEDING SYSTEM AND GENETIC VARIANCE IN THE MONOGAMOUS, SEMI-SOCIAL SHREW, CROCIDURA RUSSULA. AB - The population-genetic consequences of monogamy and male philopatry (a rare breeding system in mammals) were investigated using microsatellite markers in the semisocial and anthropophilic shrew Crocidura russula. A hierarchical sampling design over a 16-km geographical transect revealed a large genetic diversity (h = 0.813) with significant differentiation among subpopulations (FST = 5-6%), which suggests an exchange of 4.4 migrants per generation. Demic effective-size estimates were very high, due both to this limited gene inflow and to the inner structure of subpopulations. These were made of 13-20 smaller units (breeding groups), comprising an estimate of four breeding pairs each. Members of the same breeding groups displayed significant coancestries (FLS = 9-10%), which was essentially due to strong male kinship: syntopic males were on average related at the half-sib level. Female dispersal among breeding groups was not complete (~39%), and insufficient to prevent inbreeding. From our results, the breeding strategy of C. russula seems less efficient than classical mammalian systems (polygyny and male dispersal) in disentangling coancestry from inbreeding, but more so in retaining genetic variance. PMID- 28565221 TI - HOST-PARASITE COEVOLUTION: EVIDENCE FOR RARE ADVANTAGE AND TIME-LAGGED SELECTION IN A NATURAL POPULATION. AB - In theory, parasites can create time-lagged, frequency-dependent selection in their hosts, resulting in oscillatory gene-frequency dynamics in both the host and the parasite (the Red Queen hypothesis). However, oscillatory dynamics have not been observed in natural populations. In the present study, we evaluated the dynamics of asexual clones of a New Zealand snail, Potamopyrgus antipodarum, and its trematode parasites over a five-year period. During the summer of each year, we determined host-clone frequencies in random samples of the snail to track genetic changes in the snail population. Similarly, we monitored changes in the parasite population, focusing on the dominant parasite, Microphallus sp., by calculating the frequency of clones in samples of infected individuals from the same collections. We then compared these results to the results of a computer model that was designed to examine clone frequency dynamics for various levels of parasite virulence. Consistent with these simulations and with ideas regarding dynamic coevolution, parasites responded to common clones in a time-lagged fashion. Finally, in a laboratory experiment, we found that clones that had been rare during the previous five years were significantly less infectible by Microphallus when compared to the common clones. Taken together, these results confirm that rare host genotypes are more likely to escape infection by parasites; they also show that host-parasite interactions produce, in a natural population, some of the dynamics anticipated by the Red Queen hypothesis. PMID- 28565222 TI - LOW FREQUENCY OF t HAPLOTYPES IN NATURAL POPULATIONS OF HOUSE MICE (MUS MUSCULUS DOMESTICUS). AB - t haplotypes are a naturally occurring, autosomal, meiotic-drive system found on chromosome 17 of the house mouse. They show non-Mendelian transmission from heterozygous +/t males, such that 90% or more of the male's offspring inherit the t-bearing chromosome. Although they are expected to become rapidly fixed, surveys of natural populations typically report low overall frequencies of only ~15-25% +/t heterozygotes. Generally, such studies of t haplotypes in wild populations have sampled only small numbers of individuals due to the need to genotype mice by breeding, thus we have conducted a large survey of wild mice, Mus musculus domesticus, using DNA markers to examine the frequency and distribution of t haplotypes in natural populations. The overall frequency of +/t heterozygotes from our entire sample was 0.062, which is much lower than all previous estimates of t haplotype frequency. t haplotypes were patchily distributed and rare, and were present in only 46% of the populations we sampled. There were no significant sex-specific differences in the frequency of t haplotypes. Our data suggest that the frequency of +/t heterozygotes in independent populations varies with respect to population size and stability: t haplotypes were at low frequency in all large, relatively persistent populations, whereas they were at more variable, and often higher, frequencies in small, temporally unstable populations. The extinction and recolonization of many of the smaller populations may contribute to the greater variation in t haplotype frequency observed, and small populations may be important reservoirs of t haplotypes in the wild. The highest frequencies of t haplotypes were obtained from populations with semilethal, or complementing lethal, t haplotypes, where t/t homozygous mice were present. PMID- 28565223 TI - THE DETECTION OF PLASTICITY GENES IN HETEROGENEOUS ENVIRONMENTS. AB - The molecular genetic mechanisms for phenotypic plasticity across heterogeneous macro- and microenvironments were examined using the Populus genomic map constructed by DNA-based markers. Three hypotheses have been suggested to explain genetic variation in phenotypic response to varying environments (i.e., reaction norm): Lerner's homeostasis, allelic sensitivity, and gene regulation. The homeostasis hypothesis, which predicts that heterozygotes are less sensitive to the environment than homozygotes, was supported for phenotypic plasticity to unpredictable environments (microenvironmental plasticity) at the whole-genome level, but for phenotypic plasticity to predictable environments (macroenvironmental plasticity) the hypothesis was supported only at functioning quantitative trait loci (QTLs). For all growth traits studied, gene regulation was suggested to play a prevailing role in determining the norms of reaction to environments. Indirect evidence for gene regulation is that there tend to be more QTLs with larger effects on the phenotype in optimal growing conditions than suboptimal growing conditions because the expression of these QTLs identified is mediated by regulatory genes. Direct evidence for gene regulation is the identification of some loci that differ from QTLs for trait values within environments and exert an environmentally dependent control over structural gene expression. In this study, fewer environmentally sensitive QTLs were detected that display unparalleled allelic effects across environments. For stem height, there were more regulatory loci and more structural loci (whose expression is determined by gene regulation) affecting phenotypic plasticity than for basal area. It was found that microenvironmental plasticity was likely controlled by different genetic systems than those for macroenvironmental plasticity. PMID- 28565224 TI - GENETIC VARIATION IN CRICKET CALLING SONG ACROSS A HYBRID ZONE BETWEEN TWO SIBLING SPECIES. AB - The sibling ground crickets Allonemobius fasciatus and A. socius meet along a mosaic hybrid zone at ~ 40 degrees N latitude in eastern North America. In this paper we report the findings of a genetic analysis of calling-song variation within and among six cricket populations sampled along a transect through the hybrid zone in southern New Jersey. We compared aspects of the calling song of both wild-caught and laboratory-reared crickets to test the hypothesis that population differences in song observed in the wild were genetically based. We found significant, species-level differences in all aspects of the calling song, and these differences persisted even after a generation of common-garden rearing in the laboratory, supporting the hypothesis that interspecific variation observed in the wild largely reflects genetic differentiation between the two taxa. A discriminant function analysis indicated that individual crickets could be assigned to the proper taxon with less than 10% error, supporting the premise that calling song could be used by female crickets as a mechanism for species recognition. One population, collected from within the hybrid zone and containing significant numbers of hybrid individuals, was intermediate in its calling song, presumably reflecting this population's mixed genetic makeup. In this hybrid zone population, song phenotype was highly correlated to a hybrid index score generated using species-specific alleles at four diagnostic allozyme markers, suggesting a multigenic basis to calling-song variation in these crickets as well as linkage disequilibrium between markers and song. Based on an analysis of laboratory-reared full-sib families, broad-sense heritabilities for calling-song characteristics were generally significant in the two A. socius populations, whereas many components of song showed no significant family effects in the three A. fasciatus populations. The genotypically mixed, hybrid zone population showed very high heritabilities for most calling-song components, which likely reflect the influence of interspecific gene flow on genetic variation for quantitative traits. PMID- 28565225 TI - CRYPTIC FEMALE CHOICE: CRITERIA FOR ESTABLISHING FEMALE SPERM CHOICE. AB - In this paper, I consider the criteria necessary to demonstrate the postcopulatory ability of females to favor the sperm of one conspecific male over another, that is, sperm choice. In practice it is difficult to distinguish between sperm competition and sperm choice, and sperm choice can be demonstrated only if the effects of sperm competition can be controlled. Few studies have used experimental protocols that do this, so evidence for sperm choice is limited. Moreover, in those studies in which sperm choice occurs, it does so to avoid incompatible genetic combinations and is therefore unlikely to result in directional sexual selection. PMID- 28565226 TI - INTROGRESSIVE HYBRIDIZATION AND NONCONCORDANT EVOLUTIONARY HISTORY OF MATERNAL AND PATERNAL LINEAGES IN NORTH AMERICAN DEER. AB - Introgressive hybridization between mule deer (Odocoileus hemionus) and white tailed deer (O. virginianus) was studied using sequence analysis of the paternally inherited, Y-linked, Zfy gene. The distribution of Zfy genotypes indicate that male white-tailed deer disperse into the range of mule deer and successfully breed with mule deer does. In western Texas, F1 hybrids are rare, but a relatively high proportion of backcross individuals was observed. Phylogenetic analysis of Zfy among white-tailed, mule, and black-tailed deer was consistent with traditional systematic placement of the latter two being sister taxa, whereas previous mtDNA studies suggested mule and white-tailed deer were sister taxa. PMID- 28565227 TI - DOES BATEMAN'S PRINCIPLE APPLY TO BROADCAST-SPAWNING ORGANISMS? EGG TRAITS INFLUENCE IN SITU FERTILIZATION RATES AMONG CONGENERIC SEA URCHINS. AB - Evolutionary biologists generally invoke male competition and female choice as mechanisms driving sexual selection. However, in broadcast-spawning organisms sperm may be limiting and females may compete, in the Darwinian sense, for increased mating success. In this study, I investigate how species differences in egg and sperm traits result in different patterns of fertilization among three closely related sea urchins (Strongylocentrotus purpuratus, S. franciscanus, and S. droebachiensis). Field studies demonstrate that all three species achieve similar percentages of eggs fertilized when eggs and sperm are released simultaneously. However, when sperm must disperse before encountering eggs, differences arise among species such that those with the smaller eggs and faster but shorter-lived sperm achieve relatively fewer fertilizations than do species with larger eggs and slower but longer-lived sperm. A field hybridization experiment, field estimates of sperm dispersal, correlations of egg size to field rates of fertilization, laboratory studies of fertilization kinetics, and a simulation model all suggest that it is attributes of the egg (probably egg size) that are responsible for the differences. These patterns of fertilization match the species' patterns of dispersion; species that do well only when sperm and eggs are released in close proximity are more aggregated, species that do relatively well when sperm and eggs are released farther apart are more dispersed. These results are consistent with the notion that eggs of different species are adapted to maximize reproductive success under different degrees of sperm limitation and suggest that male competition and female choice may not be an appropriate dichotomy in broadcast-spawning organisms. PMID- 28565229 TI - RECENT BOOKS IN PRINT. PMID- 28565228 TI - BODY SIZE DECLINES DESPITE POSITIVE DIRECTIONAL SELECTION ON HERITABLE SIZE TRAITS IN A BARNACLE GOOSE POPULATION. AB - Analyses of more than 2000 marked barnacle geese (Branta leucopsis) in the largest Baltic colony, Sweden, showed that structurally large females generally produced larger clutches and larger eggs, hatched their broods earlier in the season, and produced more and heavier young than smaller females. In males, the corresponding relationships between reproductive parameters and structural body size were weaker or nonsignificant. Because structural body size traits have previously been found to be significantly heritable and positively genetically correlated, an increase in mean structural body size of individuals as a response to selection might have been expected. By contrast, we found that the mean adult head length and mean adult tarsus length decreased significantly in the largest colony by approximately 0.7 and 0.5 standard deviations, respectively, in both males and females during the 13-year study period. Environmental factors, such as the amount of rain in different years, were found to affect the availability of high-quality food for growing geese. As a consequence of this temporal variability in the availability of high-quality food, the mean adult structural body size of different cohorts differed by up to 1.3 standard deviations. Comparisons of mean body size of cohorts born in different colonies suggest that the most likely explanation for the body-size decline in the main study colony is that a density-dependent process, which mainly was in effect during the very early phase of colony growth, negatively affected juvenile growth and final size. We conclude that large environmental effects on growth and final structural body size easily can mask microevolutionary responses to selection. Analyses of environmental causes underlying temporal and spatial body size variation should always be considered in the reconstruction and prediction of evolutionary changes in natural populations. PMID- 28565230 TI - SAMPLING PROPERTIES OF GENEALOGICAL PATHWAYS UNDERLYING POPULATION PEDIGREES. AB - In sexual species, autosomal alleles are transmitted through multigeneration organismal pedigrees via pathways of descent involving both genders. Here, models assess the sampling properties of these gender-described transmission pathways. An isolation-by-distance model of mating was used to construct a series of computer population pedigrees by systematically varying neighborhood size and the timing of isolation events in sundered populations. For each known pedigree, a matrix of true coancestry coefficients between all individuals in the final generation was calculated and compared (using cophenetic correlations) to mean pairwise times to common ancestry as estimated by sampling varying numbers of gender-defined lineage routes available to individual alleles through that pedigree. When few lineage routes were sampled, agreement between the estimated and the true pedigree was poor and showed a large variance. Agreement improved as more lineage routes were incorporated and asymptotically approached plateau levels predictably relatable to the magnitude of population structure. Results underscore a distinction between the composite genealogical information in a population pedigree and the subsets of that information registered in allelic lineage pathways. PMID- 28565231 TI - A MOLECULAR PHYLOGENY OF THE DROSOPHILA WILLISTONI GROUP: CONFLICTS BETWEEN SPECIES CONCEPTS? AB - The six sibling species of the Neotropical Drosophila willistoni group have a long history in studies of evolutionary biology, yet to date only one molecular study, which used allozymes, has been published on the phylogeny of the group. Here we present a phylogeny of the siblings based on the sequences of two nuclear genes, period (per) and Alcohol dehydrogenase (Adh), as well as the mitochondrial gene Cytochrome oxidase I (COI). Taken individually, only per has a strong phylogenetic signal supporting a well-resolved phylogeny of the group, and this phylogeny is different from that obtained using allozymes. The COI dataset by itself produces trees that disagree with per, and neither that data nor the Adh data have a strong phylogenetic signal, as indicated by low bootstrap values for all analyses. Combining the Adh and COI datasets results in the same tree as per alone. Combining all three genes results in the same topology, which is strongly supported. Two problematic taxa, D. pavlovskiana and a "Carmody strain," which were identified as potentially separate species based on reproductive isolation, clearly cluster in the phylogenetic analyses within D. paulistorum and D. equinoxialis, respectively. Thus, there appears to be a conflict between the biological species concept and the phylogenetic species concept. PMID- 28565232 TI - CHANGES IN THE HERITABILITY OF FIVE MORPHOLOGICAL TRAITS UNDER COMBINED ENVIRONMENTAL STRESSES IN DROSOPHILA MELANOGASTER. AB - Heritabilities and evolvabilities for morphological traits were compared between two environments in Drosophila melanogaster using parent-offspring comparisons. One of the environments was favorable. The other stressful environment involved a combination of repeated cold shocks, poor nutrition, and ethanol added to the medium, which markedly decreased viability. For wing traits, heritabilities were relatively lower in the stressful environment, while heritabilities for bristle traits were not influenced by conditions. Heritability changes were largely due to an increase in the environmental variance under stress, whereas levels of additive genetic variance were relatively constant. Evolvabilities were similar between environments except for crossvein length. PMID- 28565233 TI - MATERNAL INHERITANCE AND ITS EFFECT ON ADAPTIVE EVOLUTION: A QUANTITATIVE GENETIC ANALYSIS OF MATERNAL EFFECTS IN A NATURAL PLANT POPULATION. AB - A mother can influence a trait in her offspring both by the genes she transmits (Mendelian inheritance) and by maternal attributes that directly affect that trait in her offspring (maternal inheritance). Maternal inheritance can alter the direction, rate, and duration of adaptive evolution from standard Mendelian models and its impact on adaptive evolution is virtually unexplored in natural populations. In a hierarchical quantitative genetic analysis to determine the magnitude and structure of maternal inheritance in the winter annual plant, Collinsia verna, I consider three potential models of inheritance. These range from a standard Mendelian model estimating only direct (i.e., Mendelian) additive and environmental variance components to a maternal inheritance model estimating six additive and environmental variance components: direct additive (sigmaAo2) and environmental (sigmaEo2) variances; maternal additive (sigmaAm2) and environmental (sigmaEm2) variances; and the direct-maternal additive (sigmaApAm) and environmental (sigmaEm2) covariances. The structure of maternal inheritance differs among the 10 traits considered at four stages in the life cycle. Early in the life cycle, seed weight and embryo weight display substantial sigmaAm2, a negative sigmaAoAm, and a positive sigmaEoEm. Subsequently, cotyledon diameter displays sigmaAo2 and sigmaAm2 of roughly the same magnitude and negative sigmaAoAm. For fall rosettes, leaf number and length are best described by a Mendelian model. In the spring, leaf length displays maternal inheritance with significant sigmaAo2 and sigmaAm2 and a negative sigmaAoAm. All maternally inherited traits show significant negative sigmaAoAm. Predicted response to selection under maternal inheritance depends on sigmaAo2 and sigmaAm2 as well as sigmaAoAm. Negative sigmaAoAm results in predicted responses in the opposite direction to selection for seed weight and embryo weight and predicted responses near zero for all subsequent maternally inherited traits. Maternal inheritance persists through the life cycle of this annual plant for a number of size-related traits and will alter the direction and rate of evolutionary response in this population. PMID- 28565234 TI - SELECTION ON THE COLOR POLYMORPHISM IN HAWAIIAN HAPPY-FACE SPIDERS: EVIDENCE FROM GENETIC STRUCTURE AND TEMPORAL FLUCTUATIONS. AB - Throughout this century genetic polymorphisms for color have been widely used as a research tool to allow insights into key evolutionary processes. Although color variants can often be diverse within populations, frequencies of different morphs may be similar across populations, either as a result of balancing selection or gene flow. Under these circumstances selection can be extremely difficult to demonstrate. Here we test for balancing selection on the naturally occurring color forms of the Hawaiian happy-face spider, Theridion grallator with two approaches. First, allozyme loci are used to generate a null model against which to test selection. Frequencies of alleles involved in the color polymorphism of T. grallator are used to generate another estimate for comparison. The results suggest that statistically similar frequencies of color morphs among populations of T. grallator may be maintained by some form of balancing selection. Second, we make use of an unusual event in which the normally stable frequencies of unpatterned and patterned morphs within a population were found to have shifted toward an excess of unpatterned morphs. We scored offspring of all fertilized, unpatterned (bottom-recessive) females found during this period of skewed morph frequencies and also in a year when morph frequencies were normal to deduce paternal color phenotypes. Mating was found to be random in the normal year, but in the perturbed year females had mated with rare (patterned) males twice as frequently as expected on the basis of the frequency of this morph type in the population. Both of these results are consistent with selection operating on the color polymorphism, and we speculate that apostatic selection, perhaps mediated by bird predators, may provide the mechanism. PMID- 28565235 TI - HIGHER FITNESS FOR PHILOPATRIC THAN FOR IMMIGRANT MALES IN A SEMI-ISOLATED POPULATION OF GREAT REED WARBLERS. AB - To compare the fitness of philopatric and immigrant individuals we examined the lifetime reproductive success of 116 male and 137 female great reed warblers. The study was carried out in a semi-isolated population in Sweden and covered breeding adults hatched between 1985 and 1993. Lifetime fitness, measured as life time number of fledglings and offspring recruits, was lower for immigrant than for philopatric males. We found no such relationships for females. The difference in reproductive success could not be explained by immigrant males having lower phenotypic quality because they had similar life span, spring arrival date, and territory quality as philopatric males. The lower lifetime fitness among immigrant than philopatric males appeared to result from reduced mating success. This suggests that females are reluctant to mate with immigrant males despite their apparently similar phenotypic quality. Though it is not known whether females gain in fitness by avoiding matings with immigrant males, it is notable that immigrant males have smaller song repertoires than philopatric males. Large repertoires, previously shown to sexually arouse great reed warbler females, correlate with the occurrence of extrapair paternity and postfledging survival of offspring in our population. PMID- 28565236 TI - ESTIMATING THE HERITABILITY OF FLUCTUATING ASYMMETRY IN FIELD DROSOPHILA. AB - Some studies have found intermediate heritabilities for fluctuating asymmetry (FA) in traits, but almost all of these are flawed and/or based on laboratory experiments. We therefore tested if there was heritable variation for FA in bristle and wing traits in three field collections of Drosophila melanogaster by rearing F1 s from field flies under laboratory conditions. One of the collections was reared to the F2 generation in the laboratory to compare heritability estimates from the laboratory with those from the field-laboratory comparison. Trait means indicated an increase in size under laboratory rearing. FAs increased in one collection, decreased in another collection, and showed no changes in the third collection under laboratory rearing. FAs from the collections tended to converge under laboratory conditions. Morphological traits were heritable under field conditions. However, FA was not significantly heritable for any of the individual traits or when FA was determined by combining traits. Comparisons of the two laboratory generations showed that FA heritability was low under laboratory conditions, in contrast to the morphological traits themselves. These findings suggest a very low heritability for FA in field and laboratory Drosophila. FA in bristle and wing traits may therefore be a poor indicator of genetic quality in Drosophila. PMID- 28565237 TI - TEMPORAL CHANGE OF MITOCHONDRIAL DNA HAPLOTYPE FREQUENCIES AND FEMALE EFFECTIVE SIZE IN A BROWN TROUT (SALMO TRUTTA) POPULATION. AB - We report data on genetic drift of mitochondrial DNA (mtDNA) haplotypes in a natural brown trout (Salmo trutta) population in Sweden. Large temporal frequency shifts were observed over the 14 consecutive year classes studied. The observed rate of drift was used to estimate the effective size of the population. This effective size applies to the female segment of the population as mtDNA is maternally inherited. The magnitude of mtDNA haplotype frequency change is compared with the corresponding allele frequency changes at 14 allozyme loci in the same population. The female effective size is estimated as 58, which is approximately half the effective size of 97 for the total population (both sexes) previously obtained from the shifts of allozyme allele frequencies. PMID- 28565238 TI - FINE-GRAINED SPATIAL AND TEMPORAL VARIATION IN SELECTION DOES NOT MAINTAIN GENETIC VARIATION IN ERIGERON ANNUUS. AB - Because interactions among plants are spatially local, the scale of environmental heterogeneity can have large effects on evolutionary dynamics. However, very little is known about the spatial patterns of variation in fitness and the relative magnitude of spatial and temporal variation in selection. Replicates of 12 genotypes of Erigeron annuus (Asteraceae) were planted in 288 locations within a field, separated by distances of 0.1 to 30.0 m, and replicated in two years. In a given year, most spatial variation in relative fitness (genotype-environment [G * E] interactions for fitness) occurred over distances of only 50 cm. Year effects were as large or larger than the spatial variation in fitness; in particular there was a large, three-way, genotype-year-environment interaction at the smallest spatial scale. The genetic correlation of fitness across years at a given location was near zero, 0.03. Thus, the relative fitness of genotypes is spatially unpredictable and a map of the selective environment has constantly shifting locations of peaks and valleys. Including measurements of soil nutrients as covariates in the analysis removed most of the spatial G * E interaction. Vegetation and microtopography had no effect on the G * E terms, suggesting that differential response to soil nutrients is the cause of spatial variation in fitness. However, the slope of response to NH4 and P04 was negative; therefore the soil nutrients are probably just indicators of other, unknown, environmental factors. We explored via simulation the evolutionary consequences of spatial and temporal variation in fitness and showed that, for this system, the spatial scale of variation was too fine grained (by a factor of 3 to 5) to be a powerful force maintaining genetic variation in the population. The inclusion of both spatial and temporal variation in fitness actually reduced the coexistence of genotypes compared to pure spatial models. Thus the presence of spatial or temporal variation in selection does not guarantee that it is an effective evolutionary force maintaining diversity. Instead the pattern of selection favors generalist genotypes. PMID- 28565239 TI - A MICROSATELLITE ASSESSMENT OF SNEAKED FERTILIZATIONS AND EGG THIEVERY IN THE FIFTEENSPINE STICKLEBACK. AB - Attempts by males to steal fertilizations from other males are common in many species. In some sticklebacks, males also are known to steal eggs from the nests of rivals and to carry them back to their own nests. However the genetic consequences of these nest-raiding behaviors seldom have been investigated. Here we assess genetically the prevalence of sneaked fertilizations and egg stealing, and we describe the mating system in a natural population of the fifteenspine stickleback. Six microsatellite markers were developed and employed to assay a total of 1307 embryos from 28 nests. Guardian males and all nest-holding males in the local area also were genotyped for two to six loci Analysis of male genotypes and those of embryos revealed that five of the 28 nests (18%) contained progeny from sneaked fertilizations, and that four of the 24 nests (17%) with resident males contained stolen egg clutches Comparisons of the composite DNA genotypes of nest-holding males against those of inferred sneakers implicated one nest holder as the sneaker of a nest seven meters from his own. Also, the genetic data demonstrated that nests of males frequently contain eggs from multiple females. The multilocus genotypes of inferred mothers indicated that females mate with multiple males, sometimes over distances greater than one kilometer. PMID- 28565240 TI - MUTATION, SELECTION, AND THE MAINTENANCE OF LIFE-HISTORY VARIATION IN A NATURAL POPULATION. AB - In an effort to provide insight into the role of mutation in the maintenance of genetic variance for life-history traits, we accumulated spontaneous mutations in 10 sets of clonal replicates of Daphnia pulex for approximately 30 generations and compared the variance generated by mutation with the standing level of variation in the wild population. Mutations for quantitative traits appear to arise at a fairly high rate in this species, on the order of at least 0.6 per character per generation, but have relatively small heterozygous effects, changing the phenotype by less than 2.5% of the mean. The mean persistence time of a new mutation affecting life-history/body-size traits is approximately 40 generations in the natural population, which requires an average selection coefficient against new mutations of approximately 3% in the heterozygous state. These data are consistent with the idea that the vast majority of standing genetic variance for life-history characters may be largely a consequence of the recurrent introduction of transient cohorts of mutations that are at least conditionally deleterious and raise issues about the meaning of conventional measures of standing levels of variation for fitness-related traits. PMID- 28565241 TI - HISTORICAL ALLOPATRY AND THE BIOGEOGRAPHY OF SPECIATION IN THE PROSOBRANCH SNAIL GENUS NUCELLA. AB - Two recently diverged northeastern Pacific sibling snail species, Nucella ostrina and N. emarginata, currently inhabit adjacent zoogeographic provinces. Their distributions overlap in central California to the north of a major faunal boundary at Point Conception, California (PC). To test the hypothesis that modern sympatry is due to a recent northward range expansion by N. emarginata, I analyzed the population structures of both species with nuclear (allozyme) and mitochondrial DNA (mtDNA) markers. Populations of N. emarginata in the region of overlap exhibit significantly lower heterozygosity and allelic diversity than either populations to the south of PC or populations of N. ostrina. A single mtDNA haplotype characterizes all but one population of N. emarginata sampled in this region, but no haplotype to the south of PC is found at more than one locality. MtDNA haplotypes and allozyme allele frequencies also indicate monophyly of central California populations of N. emarginata. Sharp differences in allelic diversity over small geographic distances may reflect the action of natural selection, but because both nuclear and mtDNA markers display concordant patterns, a range expansion across PC best explains patterns of genetic variation in N. emarginata. Allozymes and mtDNA also reveal that the geologically older N. ostrina is paraphyletic with respect to N. emarginata. This pattern is consistent with, but not indicative of, a peripheral isolation model of speciation. Low genetic diversity is also expected if a significant bottleneck occurred at speciation. However, low allelic diversity is not universal throughout the geographic range of N. emarginata; high allelic diversity at the southern end of the distribution of N. emarginata suggests that in the past N. emarginata has been geographically restricted much further south than PC. A northward range expansion across PC by N. emarginata may thus represent only the most recent postglacial movement by the species. The thermal and oceanographic discontinuities found at PC may not have been directly involved in geographic isolation if N. emarginata originated much further south of this modern boundary. Despite uncertainty regarding the exact spatial distribution of populations at speciation, genetic data indicate that even though N. ostrina and N. emarginata currently exhibit a broad range of geographic overlap, speciation was likely allopatric and was initiated by physical isolation of populations in different zoogeographic provinces. PMID- 28565242 TI - QUANTITATIVE GENETICS OF SEXUAL SIZE DIMORPHISM IN THE COLLARED FLYCATCHER, FICEDULA ALBICOLLIS. AB - Quantitative genetic theory predicts that evolution of sexual size dimorphism (SSD) will be a slow process if the genetic correlation in size between the sexes is close to unity, and the heritability of size is similar in both sexes. However, there are very few reliable estimates of genetic correlations and sex specific heritabilities from natural populations, the reasons for this being that (1) offspring have often been sexed retrospectively, and hence, selection acting differently with respect to body size in the two sexes between measuring and sex identification can bias estimates of SSD; and (2) in many taxa, parents may be incorrectly assigned to offspring either because of assignment errors or because of extrapair paternity. We used molecular sex and paternity identification to overcome these problems and estimated sex-specific heritabilities and the genetic correlation in body size between the two sexes in the collared flycatcher, Ficedula albicollis. After exclusion of the illegitimate offspring, the genetic correlation in body size between the sexes was 1.00 (SE = 0.22), implying a severe constraint on the evolution of SSD in this species. Furthermore, sex specific heritability estimates were very similar, indicating that neither sex will be able to evolve faster than the other. By using estimated genetic parameters, together with empirically derived estimates of sex-specific selection gradients, we further demonstrated that the predicted selection response in female tarsus length is displaced about 200% in the opposite direction from that to be expected if there were no genetic correlation between the sexes. The correspondence between the biochemically estimated rate of extrapair paternity (about 15 % of the young) and that estimated from the "heritability method" (11%) was good. However, the estimated rate of extrapair paternity with the heritability method after exclusion of the illegitimate young was 22%, adding to increasing evidence that factors other than extrapair paternity (e.g., maternal effects) may be resposible for the commonly observed higher mother-offspring than father-offspring resemblance. PMID- 28565243 TI - REPRODUCTIVE CHARACTERISTICS OF THE FLOWER BREEDING DROSOPHILA HIBISCI BOCK (DROSOPHILIDAE) IN EASTERN AUSTRALIA: GENETIC AND ENVIRONMENTAL DETERMINANTS OF OVARIOLE NUMBER. AB - Quantitative genetic analysis of the ovariole number of the Australian Hibiscus flower-breeding Drosophila hibisci Bock was conducted on populations from two localities along a latitudinal cline in ovariole number previously observed in the species (Starmer et al., in press). Parental strains, F1 , F1r (reciprocal), F2 , backcross, and backcross reciprocal generations were used in a line-cross (generation means) analysis. This analysis revealed both additive and epistatic effects as important determinants of variation in ovariole number when larvae were reared at 25 degrees C. Maternal effects and maternal-by-progeny genetic interactions were not significant. These results are comparable to previous studies that document epistatic components as genetic determinants of ovariole number in D. melanogaster. Parallel studies on ovariole number in D. hibisci parental and hybrid generations (F1 and F1r ) reared as larvae at three temperatures (18 degrees , 21.5 degrees , and 25 degrees C) showed environmental effects and genotype-by-environment interactions as significant influences on the phenotype. Maternal effects were present when temperature of larval development was considered and significant, nonlinear environmental effects were detected. Field collections of D. hibisci females showed that field conditions result in significant departure of ovariole number from comparable laboratory reared females. The significant epistatic genetic effects, genotype-by-environment interactions, and maternal effects indicate that the genetic architecture of traits, such as ovariole number, may be more complex than often acknowledged and thus may be compatible with Wright's view of a netlike relationship between the genome and complex characters (Wright 1968). PMID- 28565244 TI - EFFECTIVENESS OF SELECTION IN REDUCING THE GENETIC LOAD IN POPULATIONS OF PEROMYSCUS POLIONOTUS DURING GENERATIONS OF INBREEDING. AB - It has been hypothesized that natural selection reduces the "genetic load" of deleterious alleles from populations that inbreed during bottlenecks, thereby ameliorating impacts of future inbreeding. We tested the efficiency with which natural selection purges deleterious alleles from three subspecies of Peromyscus polionotus during 10 generations of laboratory inbreeding by monitoring pairing success, litter size, viability, and growth in 3604 litters produced from 3058 pairs. In P. p. subgriseus, there was no reduction across generations in inbreeding depression in any of the fitness components. Strongly deleterious recessive alleles may have been removed previously during episodes of local inbreeding in the wild, and the residual genetic load in this population was not further reduced by selection in the lab. In P. p. rhoadsi, four of seven fitness components did show a reduction of the genetic load with continued inbreeding. The average reduction in the genetic load was as expected if inbreeding depression in this population is caused by highly deleterious recessive alleles that are efficiently removed by selection. For P. p. leucocephalus a population that experiences periodic bottlenecks in the wild, the effect of further inbreeding in the laboratory was to exacerbate rather than reduce the genetic load. Recessive deleterious alleles may have been removed from this population during repeated bottlenecks in the wild; the population may be close to a threshold level of heterozygosity below which fitness declines rapidly. Thus, the effects of selection on inbreeding depression varied substantially among populations, perhaps due to different histories of inbreeding and selection. PMID- 28565245 TI - MAXIMUM-LIKELIHOOD ESTIMATION OF POPULATION DIVERGENCE TIMES AND POPULATION PHYLOGENY IN MODELS WITHOUT MUTATION. AB - In this paper we present a method for estimating population divergence times by maximum likelihood in models without mutation. The maximum-likelihood estimator is compared to a commonly applied estimator based on Wright's FST statistic. Simulations suggest that the maximum-likelihood estimator is less biased and has a lower variance than the FST -based estimator. The maximum-likelihood estimator provides a statistical framework for the analysis of population history given genetic data. We demonstrate how maximum-likelihood estimates of the branching pattern of divergence of multiple populations may be obtained. We also describe how the method may be applied to test hypotheses such as whether populations have maintained equal population sizes. We illustrate the method by applying it to two previously published sets of human restriction fragment length polymorphism (RFLP) data. PMID- 28565246 TI - HERITABILITY OF EXPRESSION OF THE 70KD HEAT-SHOCK PROTEIN IN DROSOPHILA MELANOGASTER AND ITS RELEVANCE TO THE EVOLUTION OF THERMOTOLERANCE. AB - The principle inducible heat-shock protein of Drosophila melanogaster, Hsp70, contributes to thermotolerance throughout the entire life cycle of the species but may also reduce fitness in some life stages. In principle, selection might maximize the benefits of Hsp70 expression relative to its costs by adjusting the magnitude of Hsp70 expression for each life-cycle stage independently. Therefore we examined whether the magnitude of Hsp70 expression varied during the life cycle and the relationship of this variation to several life-history traits. For 28 isofemale lines derived from a single natural population, estimates of heritable variation in Hsp70 expression ranged between 0.25 and 0.49, and the association among variation in first- and third-instar larvae and in adults correlated highly. Thus, Hsp70 expression is genetically coupled at these developmental stages. A line engineered with extra copies of the hsp70 gene produced more Hsp70 and survived heat shock much better than did a control strain. Among natural lines, Hsp70 expression was only weakly related to tolerance of heat shock and to larva-to-adult survival and developmental time at permissive temperatures. Additionally, lines with high adult survival developed slowly as larvae, which is a possible trade-off. These and other findings suggest that trade-offs may maintain quantitative variation both in heat-shock protein expression and in life-history traits that associate with thermotolerance. PMID- 28565247 TI - PATTERNS OF MATING IN WILD SUNFLOWER HYBRID ZONES. AB - Theory predicts that homoploid hybrid speciation will be facilitated by selfing, yet most well-documented hybrid species are outcrossers. One possible explanation for this puzzle is that conditions in hybrid populations may favor selfing, even in otherwise outcrossing species. For example, in self-incompatible plants, mixtures of self and interspecific pollen often induce selfing. Here, we examine patterns of mating in three hybrid zones and four "pure" populations of Helianthus annuus and H. petiolaris, wild, self-incompatible sunflower species that are thought to have parented three homoploid hybrid species. Fourteen to 16 maternal families from each pure population and 44-46 maternal families from each hybrid zone were analyzed for seven polymorphic isozyme loci. Maximum-likelihood (ML) methods were used to estimate multilocus outcrossing rates (Tm ) and hybridization frequencies for each maternal family, each phenotypic group within each hybrid zone (annuus-like, hybrid, and petiolaris-like), and each population. As predicted for self-incompatible species, all four parental populations have outcrossing rate ML estimates of 1.0. Within the hybrid zones, outcrossing rates were lowest in the H. annuus-like fraction of the population (0.73, 0.72, and 0.74 in the three hybrid zones, respectively), largely intermediate in the H. petiolaris-like group (0.94, 0.90, and 0.94), and highest in the hybrid group (0.97, 0.93, and 0.97). Although outcrossing rates are lower in hybrid zones than in pure populations, it is unlikely that the observed decrease facilitates hybrid speciation because outcrossing rates in the critical hybrid fraction of the population do not differ significantly from 1.0. Dividing the outcrossed pollen pool into intraspecific and interspecific components revealed that maternal plants are largely fertilized by conspecific pollen, confirming an important role for pollen competition as a reproductive barrier. Highly sterile hybrid plants do not appear to discriminate between parental species pollen, but hybrids with higher fertility tend to be fertilized by pollen from the parental group they resemble genetically. Thus, gametic selection leads to substantial assortative mating in these hybrid zones. PMID- 28565248 TI - SPECIATION AND FEATHER ORNAMENTATION IN BIRDS. AB - The hypothesis that sexual selection promotes speciation has rarely been tested. We identified 70 evolutionarily independent events of feather ornaments in birds. For each focal species we noted the number of ornamented and nonornamented species belonging to its genus and its number of subspecies, as well as its mating system and the extent of its geographic range. For purposes of comparison, we randomly chose a second, nonornamented species for which we obtained information on the number of subspecies, and in cases in which the nonornamented species was in the same genus, we chose a third, nonornamented species in a related genus and obtained the same information. We then noted the number of species in each genus and the difference in numbers of species, or species richness, between paired genera. For the genera of the focal ornamented species, we regressed number of ornamented species on number of nonornamented species and found a positive relationship. As number of species per genus rose, number of ornamented species per genus rose more rapidly, indicating that more speciose genera have a higher proportion of ornamented species than less speciose genera. We then took the deviations from this regression, the residual number of species, and regressed them on the differences in species richness between the paired genera. This relationship was positive indicating that ornamented genera with more than the expected number of ornamented species were more speciose with respect to their paired genera than were genera with fewer than the expected number of ornamented species. Finally, we compared the deviations from this regression, the residual number of ornamented species, with species' mating system and found a greater residual number of ornamented species among species whose mating system is associated with greater skew in male mating success and thus more intense sexual selection. Ornamented species had more subspecies than nonornamented species, even when controlling for geographic range, suggesting an association between subspeciation and ornaments. PMID- 28565249 TI - CONFLICTS OF INTEREST IN SOCIAL INSECTS: MALE PRODUCTION IN TWO SPECIES OF POLISTES. AB - In social insects, reproduction is often monopolized by queens even though in many species are workers capable of laying male eggs. Because it is difficult to see how one or a few queens can suppress the much more numerous workers, collective worker control, or policing, offers an attractive solution. When workers are less related to other workers than they are to queens, workers should be selected to suppress each other in favor of the queen's male offspring, if other things are equal. Otherwise, they should allow each other to lay male eggs. For two species of Polistes, we used DNA microsatellites to estimate these two relatednesses, to determine the sex of brood, and to determine whether male brood was produced by queens or workers. Workers were significantly more related to each other (0.63 and 0.73 for P. bellicosus and P. dorsalis, respectively) than they were to queens (0.40 and 0.54, respectively) so they were predicted to allow each other to lay the male eggs. However, workers did not lay male-destined eggs in either species, so the results do not support collective worker control. There are two possible explanations for this result. Queens may be able to physically dominate in these small colonies. Alternatively, this may be a conventional settlement that minimizes conflict and the attendant costs. PMID- 28565250 TI - HERITABILITIES OF DOMINANCE-RELATED TRAITS IN MALE BANK VOLES (CLETHRIONOMYS GLAREOLUS). AB - A number of studies have shown that in several animal species females prefer dominant males as mating partners, but fewer attempts have been made to measure possible indirect benefits of this choice. One reason for this may be that, even though dominance is a widely used concept, the definition of dominance still remains controversial Furthermore, defining and measuring the heritability of social behaviors is problematic because they are not individual traits but, by definition, involve interactions between at least two individuals. In this study we estimated heritabilities and coefficients of additive genetic variances (CVA ) for male traits that are closely associated with dominance and female mating preferences in bank voles (Clethrionomys glareolus). The heritability values were estimated using father-offspring regression. All heritability estimates were relatively high ranging from 0.531 (urine marking) to 0.767 (preputial glands). The CVA -values indicated high levels of additive genetic variance especially in the characters most closely related to dominance: the weight of preputial glands and urine marking behavior. All phenotypic correlations among the traits measured were significantly positive and the genetic correlations were of similar magnitude as the corresponding phenotypic counterparts. Even though heritabilities may be lower in the natural environment than under controlled laboratory conditions, our results suggest that characters closely related to dominance may be at least partly genetically determined. PMID- 28565251 TI - BAKER'S LAW REVISITED: REPRODUCTIVE ASSURANCE IN A METAPOPULATION. AB - Baker's Law states that it is more likely for self-compatible than for self incompatible individuals to establish sexually reproducing colonies after long distance dispersal, because only the former can do so with a single individual. This hypothesis, proposed by H. G. Baker 40 years ago is based largely on the observation that self-compatibility is particularly frequent among colonists of oceanic islands. Here we argue that the principle of Baker's Law applies equally in the context of a metapopulation in which frequent local extinction is balanced by recolonization of sites by seed dispersal: metapopulation dynamics will select for an ability to self-fertilize. We review several studies that support this hypothesis and present a metapopulation model in which the seed productivity required by obligate outcrossers for their maintenance in a metapopulation is compared with that of selfers. Our model also estimates the reduction in the advantage of reproductive assurance to selfers as a result of perenniality and seed dormancy. In general, selection for reproductive assurance is greatest when the colony occupancy rate, p, is low and is much reduced when p approaches its maximum. This provides an explanation for the observation that many highly successful colonizers, in which p is often high, are self-incompatible. The basic model we present also lends itself to comparisons of metapopulation effects between unisexuality and cosexuality and between different modes of self incompatibility. PMID- 28565252 TI - GENERAL-PURPOSE GENOTYPES FOR HOST SPECIES UTILIZATION IN A NEMATODE PARASITE OF DROSOPHILA. AB - The nematode Howardula aoronymphium parasitizes several species of mushroom feeding Drosophila. A survey of isofemale strains of H. aoronymphium and a 25 generation selection experiment revealed that this species does not comprise host races, and that it harbors little heritable variation for adaptation to specific hosts No tradeoffs in performance on the different host species were evident. General-purpose genotypes, which can utilize all host species, characterize H. aoronymphium. An important feature of the natural history of these nematodes correlated epidemiology across host species-is postulated to be both a cause and a consequence of the evolution of general-purpose genotypes in this species. PMID- 28565253 TI - EXPERIMENTAL EVOLUTION OF RESISTANCE IN BRASSICA RAPA: CORRELATED RESPONSE OF TOLERANCE IN LINES SELECTED FOR GLUCOSINOLATE CONTENT. AB - The evolutionary response of plant populations to selection for increased defense may be constrained by costs of defense. The purpose of this study was to investigate such constraints on the evolution of defense due to a cost of defense manifested as a trade-off between defense and tolerance. Variation in the response to artificial damage (tolerance) among lines of Brassica rapa that had been artificially selected for foliar glucosinolate content (defense) was examined. Leaf area was removed from replicates of three selection lines (high glucosinolates, control, and low glucosinolates) at three damage levels (0%, 20%, and 60% damage). An external cost of defense would result in a statistically significant selection line by damage treatment interaction, with those selected for high defense expressing less tolerance than those selected for low defense. Damage treatment had a significant overall effect on estimated total fitness, with fitness declining with increasing damage level. Further, selection line also had a significant overall effect on estimated total fitness, with low-defense selection lines having higher fitness compared to both control and high-defense selection lines. More importantly, a cost of defense in terms of tolerance was demonstrated by a significant selection line-by-damage treatment interaction. This interaction was in the direction to demonstrate a genetic trade-off between defense and tolerance, with low-defense selection lines decreasing estimated total fitness in response to damage less than both control and high-defense selection lines. Variation in tolerance among selection lines was due to the greater ability of low-defense lines to maintain fruit and seed production despite the presence of damage. In terms of tolerance, this cost of glucosinolate production in B. rapa could constrain the evolution of increased defense and, in so doing, maintain individuals within the population that are poorly defended yet tolerant. PMID- 28565254 TI - EVOLUTION OF ALLORECOGNITION IN BOTRYLLID ASCIDIANS INFERRED FROM A MOLECULAR PHYLOGENY. AB - Despite the functional and phyletic ubiquity of highly polymorphic genetic recognition systems, the evolution and maintenance of these remarkable loci remain an empirical and theoretical puzzle. Many clonal invertebrates use polymorphic genetic recognition systems to discriminate kin from unrelated individuals during behavioral interactions that mediate competition for space. Space competition may have been a selective force promoting the evolution of highly polymorphic recognition systems, or preexisting polymorphic loci may have been coopted for the purpose of mediating space competition. Ascidian species in the family Botryllidae have an allorecognition system in which fusion or rejection between neighboring colonies is controlled by allele-sharing at a single, highly polymorphic locus. The behavioral sequence involved in allorecognition varies in a species-specific fashion with some species requiring extensive intercolony tissue integration prior to the allorecognition response, while other species contact opposing colonies at only a few points on the outer surface before resolving space conflicts. Due to an apparent species-specific continuum of behavioral variation in the degree of intercolony tissue integration required for allorecognition, this system lends itself to a phylogenetic analysis of the evolution of an allorecognition system. We constructed a molecular phylogeny of the botryllids based on 18S rDNA sequence and mapped allorecognition behavioral variation onto the phylogeny. Our phylogeny shows the basal allorecognition condition for the group is the most internal form of the recognition reaction. More derived species show progressively more external allorecognition responses, and in some cases loss of some features of internal function. We suggest that external allorecognition appears to be a secondary function of a polymorphic discriminatory system that was already in place due to other selective pressures such as gamete, pathogen, or developmental cell lineage recognition. PMID- 28565255 TI - HYBRIDIZATION AND GEOGRAPHIC VARIATION IN TWO MEADOW KATYDID CONTACT ZONES. AB - In this study, previously unrecognized hybridization was documented between two meadow katydids in each of two disjunct contact zones, in the southeastern United States and along the Potomac River near Washington, DC. These two zones have very different histories and dynamics of interaction between the two taxa. Orchelimum nigripes and O. pulchellum (Tettigoniidae: Conocephalinae) are distributed west and east, respectively, of the Appalachian Mountains, from the Great Lakes to the Gulf Coast and along the Atlantic Coastal Plain from New York to the Florida Keys, but are not found in the Appalachians themselves. In addition, during this century O. nigripes has become established in a small area east of the Appalachians, in the Potomac River basin, where it has completely replaced O. pulchellum along the river corridor above Washington, DC. I sampled katydids from 40 sites across both hybrid zones and mapped geographic patterns of genetic variation (allele frequencies at two diagnostic loci) and variation in a morphometric index for males. Although the two taxa are quite distinct over most of their extensive distributions, there is clear evidence of introgression in both contact zones. In the Deep South, samples from a transect along the Gulf Coast define a broad hybrid zone of about 50-100 km, while samples from a transect 200 km to the north define a zone of about 150-250 km in width. Only one Deep South population shows a deviation from Hardy-Weinberg equilibrium at either locus, and there is no evidence of linkage disequilibrium in any Deep South population. In the Potomac region, there is a narrow upstream-downstream hybrid zone along the river. Within the Potomac River floodplains downriver from Washington, DC, as well as outside the floodplains throughout the region, O. pulchellum is present in abundance, but O. nigripes markers are virtually absent. Within the floodplains upriver from Washington, DC, O. nigripes is abundant, but O. pulch***ellum markers are virtually absent. All four mixed ancestry Potomac populations sampled show strong and highly significant linkage disequilibrium, although only one clearly deviates from single-locus Hardy-Weinberg equilibrium. The position of the Deep South hybrid zone is generally consistent with interspecific and intraspecific phylogeographic patterns previously reported for numerous taxa from the southeastern United States. The observed genetic and morphometric clines appear to be the result of neutral introgression over thousands of years. In the much younger Potomac hybrid zone, O. nigripes appears to be spreading downriver, interbreeding with O. pulchellum, and replacing it. The mechanism for this replacement remains uncertain, but may be clarified by ongoing behavioral, genetic, and breeding studies. PMID- 28565256 TI - RECOGNIZING AND TESTING HOMOLOGY OF COURTSHIP DISPLAYS IN STORKS (AVES: CICONIIFORMES: CICONIIDAE). AB - Ethological studies in the 1940s and 1950s, most notably those of Lorenz and Tinbergen, emphasized a historical perspective. By the 1970s, the notion that behavioral traits are too plastic to retain historical information became prevalent, and evolutionary approaches in behavioral studies were largely abandoned. However, several recent studies have demonstrated that behavioral characters are remarkably consistent with phylogenies obtained from other data and not particularly prone to homoplasy. In this study, I coded descriptions of courtship display behaviors in stork species (Aves: Ciconiiformes: Ciconiidae) as a matrix of discrete characters. I mapped each behavioral character onto a phylogeny based on DNA-DNA hybridization distances to test the homology of individual characters. Generally, displays occurring early in courtship were congruent with phylogenetic relationships and showed little homoplasy, while displays occurring late in courtship were more homoplastic. I also performed a phylogenetic analysis of the behavioral data matrix using maximum parsimony. The strict consensus of the 24 most-parsimonious trees was congruent with the DNA-DNA hybridization tree in all nodes having greater than 70% bootstrap support. PMID- 28565257 TI - THE EVOLUTION OF CANALIZATION AND THE BREAKING OF VON BAER'S LAWS: MODELING THE EVOLUTION OF DEVELOPMENT WITH EPISTASIS. AB - Evolution can change the developmental processes underlying a character without changing the average expression of the character itself. This sort of change must occur in both the evolution of canalization, in which a character becomes increasingly buffered against genetic or developmental variation, and in the phenomenon of closely related species that show similar adult phenotypes but different underlying developmental patterns. To study such phenomena, I develop a model that follows evolution on a surface representing adult phenotype as a function of underlying developmental characters. A contour on such a "phenotype landscape" is a set of states of developmental characters that produce the same adult phenotype. Epistasis induces curvature of this surface, and degree of canalization is represented by the slope along a contour. I first discuss the geometric properties of phenotype landscapes, relating epistasis to canalization. I then impose a fitness function on the phenotype and model evolution of developmental characters as a function of the fitness function and the local geometry of the surface. This model shows how canalization evolves as a population approaches an optimum phenotype. It further shows that under some circumstances, "decanalization" can occur, in which the expression of adult phenotype becomes increasingly sensitive to developmental variation. This process can cause very similar populations to diverge from one another developmentally even when their adult phenotypes experience identical selection regimes. PMID- 28565258 TI - DESICCATION AND STARVATION TOLERANCE OF ADULT DROSOPHILA: OPPOSITE LATITUDINAL CLINES IN NATURAL POPULATIONS OF THREE DIFFERENT SPECIES. AB - Desiccation and starvation tolerance were measured along latitudinal transects in three Drosophilid species (Drosophila ananassae, D. melanogaster, and Zaprionus indianus) of the Indian subcontinent. In each case, significant latitudinal clines were observed; desiccation tolerance increased with latitude while starvation tolerance decreased. Such field observations suggest that desiccation and starvation tolerance are fitness related traits that are independently selected in nature and genetically independent. It was, however, difficult to relate these genetic changes with precise climatic variables, except winter temperature. The overall negative correlation between the two traits, which was evidenced in natural populations, contrasts with a positive correlation generally observed in various laboratory selection experiments and that also seems to exist between different species. These observations point to the difficulty of interpreting correlations among fitness-related traits when different evolutionary levels are compared, and also different sets of data, that is, field versus laboratory studies. PMID- 28565259 TI - DNA HETEROZYGOSITY AND GROWTH RATE IN THE ATLANTIC COD GADUS MORHUA (L). AB - Relationships between growth rate and the degree of individual heterozygosity at ten nuclear RFLP loci were examined in two populations of the Atlantic cod, Gadus morhua, from northern Norway. A highly significant positive correlation was observed between growth rate and DNA heterozygosity in one population (Balsfjord) but not in the other (Barents Sea). Our results provide support for an important prediction of the associative overdominance hypothesis that heterozygosity fitness correlations can be detected at neutral genetic markers and suggest that environmental conditions might play a dominant role in the manifestation of the correlation. PMID- 28565260 TI - EFFECTS OF DIFFERENT LEVELS OF INBREEDING ON PROGENY FITNESS IN PLANTAGO CORONOPUS. AB - Inbreeding depression (delta) is a major selective force favoring outcrossing in flowering plants. Many phenotypic and genetic models of the evolution of selfing conclude that complete outcrossing should evolve whenever inbreeding depression is greater than one-half, otherwise selfing should evolve. Recent theoretical work, however, has challenged this view and emphasized (1) the importance of variation in inbreeding depression among individuals within a population; and (2) the nature of gene action between deleterious mutations at different loci (epistasis) as important determinants for the evolution of plant mating systems. The focus of this study was to examine the maintenance of inbreeding depression and the relationship between inbreeding level and inbreeding depression at both the population and the individual level in one population of the partially self fertilizing plant Plantago coronopus (L.). Maternal plants, randomly selected from an area of about 50 m2 in a natural population, were used to establish lines with expected inbreeding coefficients (f) of 0, 0.25, 0.50, 0.75, and 0.875. Inbreeding depression was estimated both in the greenhouse and at the site of origin of the maternal plants by comparing growth, survival, flowering, and seed production of the progeny with different inbreeding coefficients. No significant inbreeding depression for these fitness traits was detected in the greenhouse after 16 weeks. This was in strong contrast to the field, where the traits all displayed significant inbreeding depression and declined with increased inbreeding. The results were consistent with the view that mutation to mildly deleterious alleles is the primary cause of inbreeding depression. At the family level, significantly different maternal line responses (maternal parent * inbreeding level interaction) provide a mechanism for the invasion of a selfing variant into the population through any maternal line exhibiting purging of its genetic load. At the population level, evidence for synergistic epistasis was detected for the probability of flowering, but not for total seed production. At the family level, however, a significant interaction between inbreeding level and maternal families for both traits was observed, indicating that epistasis could play a role in the expression of inbreeding depression among maternal lines. PMID- 28565261 TI - INTRASPECIFIC PHYLOGEOGRAPHY ACROSS THE POINT CONCEPTION BIOGEOGRAPHIC BOUNDARY. AB - Recent studies of intraspecific phylogeography have suggested that the geographic location of genetic discontinuities, or phylogeographic breaks, may frequently coincide with biogeographic boundaries. The concordance is hypothesized to reflect similarity in the processes governing species boundaries and intraspecific lineage boundaries. This concordance has not, however, been widely tested. In the case of the Point Conception biogeographic boundary between the Oregonian and Californian marine biotas, only the supralittoral copepod Tigriopus californicus has been found to have a coincident phylogeographic break. Here I show that the apparent relationship between this break and Point Conception was, in fact, an artifact of insufficient geographic sampling. Mitochondrial DNA analyses of T. californicus populations between Morro Bay and San Diego reveal at least five equally deep phylogeographic breaks in the region (where only one biogeographic boundary is recognized). Limited nuclear DNA sequence data and allozyme data also support the occurrence of multiple genetic discontinuities along this geographic range. Lack of one-to-one correspondence between intraspecific phylogeography and biogeographic boundaries indicates that the processes affecting the genetic differentiation of populations of T. californicus differ from those responsible for determining species distributional limits at the Point Conception biogeographic boundary. A review of genetic data from other species also fails to provide evidence for concordance of biogeography and intraspecific phylogeography across Point Conception. I suggest that the concordance of phylogeography with biogeography will only be pronounced where the biogeographic boundary separates biotas that are phylogenetically related. The numerous cases of interspecific hybrid zones in the region of Cape Canaveral, for example, indicate that many sister-species pairs occur across this biogeographic boundary. Such hybrid zones are not common at Point Conception, and there appears to be no cases of intraspecific phylogeographic breaks associated with this well recognized biogeographic boundary. PMID- 28565262 TI - TOPIARY PRUNING AND WEIGHTING REINFORCE AN AFRICAN ORIGIN FOR THE HUMAN MITOCHONDRIAL DNA TREE. AB - A method is presented for removing recent homoplastic events from a phylogenetic tree. This "topiary pruning" method produces a series of progressively modified duplicates of the original set of data, from which more and more of the most recent substitutions have been removed. The edited sets of data have increased amounts of information per remaining taxon, while similar but randomized data sets subjected to topiary pruning do not. The ability of topiary pruning to "unscramble" artificial data sets that have high levels of homoplasy is demonstrated, and is shown to be similar in its effects to the weighting method of Kluge and Farris (1969), although with the additional advantage of reducing the number of taxa to the point where bootstrapping is feasible. Pruning and weighting used together produce closer approximations to the "true" tree than either method used separately. It is further shown that in these artificial data sets midpoint rooting is more likely to be accurate than outgroup rooting. When pruning and weighting are applied to the extensive sets of mitochondrial DNA data of Cann et al. (1987) and Vigilant et al. (1991), trees result that have deep branch points, some of which lead to entirely African branches. In the case of the Vigilant et al. data, the three African branches have bootstrap values between 0.94 and 1.0, and the consensus and bootstrap midpoint roots also have high bootstrap values and occur on these African branches near their junction. An African origin of the human mitochondrial tree is not proved by this approach, particularly since sequences from non-African groups are underrepresented in current data sets, but it is rendered more likely. PMID- 28565263 TI - ADAPTATION TO FINE-GRAINED ENVIRONMENTAL VARIATION: AN ANALYSIS OF WITHIN INDIVIDUAL LEAF VARIATION IN AN ANNUAL PLANT. AB - Recent studies of evolution in heterogeneous environments have concentrated on the role of coarse-grained environmental variation. Here I explore the potential for a modular organism to adapt to fine-grained environmental variation through within-individual variation among modules. I describe the pattern of variation among leaves of single individuals and report results of initial analyses of genetic variation for within-individual variability in leaf traits and of genetic correlations that could influence the rate of further evolution of within individual variation of these traits. Plants from 24 paternal half-sib families were raised in growth chambers, and five traits were measured for two leaves produced by each plant. Four of the five traits differed significantly between sampling times. Genetic analyses revealed significant additive genetic variation for within-individual variation in several traits. Estimates of family mean correlations between traits expressed at different times suggest few relationships that would be expected to impede response to selection for changes in the pattern of within-individual variation in leaf traits. These results support the possibility that within-individual variation could evolve as an adaptive response to fine-grained environmental variation and suggest a need for further investigation to improve understanding of evolution in heterogeneous environments. PMID- 28565264 TI - ARTIFICIAL SELECTION ON HORN LENGTH-BODY SIZE ALLOMETRY IN THE HORNED BEETLE ONTHOPHAGUS ACUMINATUS (COLEOPTERA: SCARABAEIDAE). AB - Males of the horned beetle Onthophagus acuminatus Har. (Coleoptera: Scarabaeidae) exhibit horn length dimorphism due to a sigmoidal allometric relationship between horn length and body size: the steep slope of the allometry around the inflection of the sigmoid curve separates males into two groups; those larger than this inflection possess long horns, and those smaller than this inflection have short horns or lack horns. I examined the genetic basis of the allometric relationship between horn length and body size by selecting males that produced unusually long horns, and males that produced unusually short horns, for their respective body sizes. After seven generations of selection, lines selected for relatively long horns had significantly longer horn lengths for a given body size than lines selected for relatively short horns, indicating a heritable component to variation in the allometry. The sigmoidal shape of the allometry was not affected by this selection regime. Rather, selected lines differed in the position of the allometry along the body size axis. One consequence of lateral shifts in this allometric relationship was that the body size separating horned from hornless males (the point of inflection of the sigmoid curve) differed between selection lines: lines in which males were selected for relatively long horns began horn production at smaller body sizes than lines selected for relatively short horns. These results suggest that populations can evolve in response to selection on male horn length through modification of the growth relationship between horn length and body size. PMID- 28565265 TI - MAINTENANCE OF POLYGENIC VARIATION VIA A MIGRATION-SELECTION BALANCE UNDER UNIFORM SELECTION. PMID- 28565266 TI - ON PHASE THREE OF THE SHIFTING-BALANCE THEORY. AB - A common conclusion in several recent publications devoted to the deterministic analysis of the third phase of Wright's shifting-balance theory is that under reasonable conditions phase three should proceed easily. I argue that the mathematical equations analyzed in these papers do not correspond to the biological situation they were meant to describe. I present a more appropriate study of the third phase of the shifting balance. My results show that the third phase can proceed only under much more restricted conditions than the previous studies suggested. Migration should be neither too strong not too weak relative to selection. The higher peak should be sufficiently dominant over the lower peak. Recombination can greatly reduce the plausibility of this phase or completely preclude peak shifts. A very important determinant of the ultimate outcome of the competition between different peaks is the topological structure of the network of demes. Peak shifts in two-dimensional networks of demes are more difficult than in one-dimensional networks. Phase three can be accomplished easiest if it is initiated in one of the peripheral demes. PMID- 28565267 TI - INTRASPECIFIC CHLOROPLAST DNA VARIATION AND BIOGEOGRAPHY OF NORTH AMERICAN LIRIODENDRON L. (MAGNOLIACEAE). AB - Restriction site variation in chloroplast DNA (cpDNA) was surveyed to analyze population dynamics in Liriodendron tulipifera L., a woody angiosperm found in eastern North America. Two cpDNA haplotypes, differing by the presence or absence of five restriction site changes (nucleotide sequence divergence estimated as approximately 0.15%) are geographically structured; 61 widespread populations possess the "northern" haplotype and three isolated populations of central Florida possess the "southern" haplotype. This geographic break in cpDNA distribution corresponds to patterns of geographic distribution revealed by a previous survey of allozyme variation, with the exception that analyses of allozyme data further divided the populations containing the northern cpDNA haplotype into two groups, a widespread upland group and a coastal intermediate group. Analyses of these two independent data sets together support the hypothesis that L. tulipifera survived the glacial advances of the Pleistocene in two distinct refugia, possibly as different taxa, and the intermediate coastal group was putatively formed from recent hybridizations between these entities. PMID- 28565268 TI - BERGMANN SIZE CLINES: A SIMPLE EXPLANATION FOR THEIR OCCURRENCE IN ECTOTHERMS. AB - In general ectothermic organisms grow larger at both lower temperatures and higher latitudes. Adult size in the soil nematode Caenorhabditis elegans reared at 10 degrees C was approximately 33% greater than worms grown at 25 degrees C. Nematode egg size and fish red blood cell size showed similar size increases at lower temperatures. These results indicate that body size differences in many ectotherms may simply be a consequence of developmental processes that cause cells to grow larger at lower temperatures. This would provide a general explanation for the increased size of ectotherms at lower temperatures independent of species-specific ecology. PMID- 28565269 TI - REACTION NORMS FOR AGE AND SIZE AT MATURITY IN LASIOMMATA BUTTERFLIES: PREDICTIONS AND TESTS. PMID- 28565270 TI - INFERENCES ABOUT QUANTITATIVE INHERITANCE BASED ON NATURAL POPULATION STRUCTURE IN THE YELLOW MONKEYFLOWER, MIMULUS GUTTATUS. AB - We used a nonmanipulative, marker-based method to study quantitative genetic inheritance in two habitats of a common monkeyflower population. The method involved regressing quantitative trait similarity on marker-estimated relatedness between individuals sampled in the field. We sampled 300 adult plants from each of two transects, one along a stream habitat and another through a meadow habitat. For each plant we measured 10 quantitative characters and assayed 10 polymorphic isozyme loci. In the meadow habitat, relatedness of plants within 1 m was moderate (r = 0.125, corresponding to half-sibs) as was actual variance of relatedness (Vr = 0.044). Significant heritabilities of 50-70% were found for corolla width and the fitness characters of flower number and plant weight. Genetic correlations were strongly positive, but sharing of environmental effects within 1 m was weak. In the stream habitat, levels of relatedness were lower and similar heritabilities were indicated. To detect dominance variance and the correlation of phenotypes due to shared inbreeding, we also estimated higher order coefficients of relationship and inbreeding, but these did not significantly differ from zero. Laboratory-based estimates of heritability in the field were lower than the marker-based estimates, indicating that natural heritabilities and genetic correlations may be stronger than indicated by controlled studies. PMID- 28565271 TI - ACCLIMATION, CROSS-GENERATION EFFECTS, AND THE RESPONSE TO SELECTION FOR INCREASED COLD RESISTANCE IN DROSOPHILA. AB - The way populations respond to selection can be altered when populations are acclimated prior to selection. To examine this possibility, the responses of replicate lines of Drosophila melanogaster and D. simulans to selection for increased resistance to cold were compared. Flies were selected without hardening or after they had been hardened by holding them at 4 degrees C for one hour. The selection response in both species was much greater when flies were not cold hardened. Cold resistance in both sets of selected lines reached a plateau after a few generations. Surprisingly, continued selection for increased resistance resulted in decreasing levels of resistance. This decrease was no longer evident after selection had been relaxed for a generation, suggesting cross-generation effects. The magnitude of the cross-generation effects increased with additional generations of selection. Cross-generation effects were also detected for fitness components. Relaxing selection for a generation increased fecundity, weight, viability, and development time. Comparisons of relaxed lines and control lines indicated that only fecundity was influenced by selection. Both sets of selected lines had a lower fecundity than control lines. Crosses between control and selected lines and among replicate selected lines indicated that this decrease in fecundity was not associated with inbreeding. The direct and correlated responses to selection for cold resistance can therefore be influenced by acclimation and cross-generation effects. PMID- 28565272 TI - SEX-SPECIFIC COSTS OF RESISTANCE TO THE FUNGAL PATHOGEN USTILAGO VIOLACEA (MICROBOTRYUM VIOLACEUM) IN SILENE ALBA. AB - Costs of resistance are often invoked to explain the maintenance of polymorphisms for resistance to fungal pathogens in natural plant populations. To investigate such costs, 27 half-sib families of Silene alba, collected from a single host population, were grown in experimental populations in the presence and absence of the anther-smut fungus Ustilago violacea, a host-sterilizing pathogen transmitted by insects that are both pollinators and vectors of the disease. Host families differed significantly in resistance to inoculation, indicating the presence of genetic variation for mechanisms that impede fungal growth once the disease is encountered ("biochemical" resistance) within the host population. In addition, host families differed significantly in onset of flowering and in flower production in the absence of the disease. Path analysis revealed that late onset of flowering in male host families made a direct contribution to high field resistance (P < 0.01), probably due to a reduced rate of contact between hosts and vectors carrying high spore loads (avoidance, or "phenological" resistance). The contribution of low flower production to field resistance only approached significance (P < 0.10). There was a significantly positive genetic association between biochemical and phenological resistance, suggesting that delayed flowering is either a pleiotropic effect of biochemical resistance, or that genes governing these traits are in linkage disequilibrium. Path analysis revealed that biochemical resistance made both a direct contribution to field resistance (P < 0.01) and a positive indirect contribution via its association with phenology and flower production (P < 0.05) in male hosts. Costs of resistance were sex specific. Male host families with high field resistance had significantly lower reproductive success in healthy populations, indicating a fitness cost of field resistance (P < 0.01), whereas no costs were detected for female hosts. Path analysis revealed that the biochemical component of field resistance made no direct contribution to the observed fitness cost in male hosts, whereas its indirect effect through phenology was only marginally significant (P < 0.10). This finding indicates that fitness costs were mainly due to the phenological component of field resistance. Because the host population had no known history of disease, it is not clear whether the fitness costs are responsible for maintenance of the resistance polymorphism or whether the polymorphism is present for reasons unrelated to pathogen infection. Interactions between host families and pathogen strains with respect to inoculation success were not significant. Hence, there was no evidence for indirect costs of biochemical resistance, that is, reduced resistance to alternative strains. Infection rates in experimental populations with an initially patchy distribution of the pathogen were lower than in populations with a uniform pathogen distribution, suggesting that the effective pathogen pressure and hence the relative success of susceptible and resistant individuals may, in addition to fitness costs of resistance, depend on the spatial population structure of the pathogen. PMID- 28565273 TI - WITHIN- AND BETWEEN-GENERATION EFFECTS OF TEMPERATURE ON THE MORPHOLOGY AND PHYSIOLOGY OF DROSOPHILA MELANOGASTER. AB - We investigated the effects of developmental and parental temperatures on several physiological and morphological traits of adult Drosophila melanogaster. Flies for the parental generation were raised at either low or moderate temperature (18 degrees C or 25 degrees C) and then mated in the four possible sex-by-parental temperature crosses. Their offspring were raised at either 18 degrees C or 25 degrees C and then scored as adults for morphological (dry body mass, wing size, and abdominal melanization [females only]), physiological (knock-down temperature, and thermal dependence of walking speed), and life history (egg size) traits. The experiment was replicated, and the factorial design allows us to determine whether and how paternal, maternal, and developmental temperatures (as well as offspring sex) influence the various traits. Sex and developmental temperature had major effects on all traits. Females had larger bodies and wings, higher knock-down temperatures, and slower speeds (but similar shaped performance curves) than males. Development at 25 degrees C (versus at 18 degrees C) increased knock-down temperature, increased maximal speed and thermal performance breadth, decreased the optimal temperature for walking, decreased body mass and wing size, reduced abdominal melanization, and reduced egg size. Parental temperatures influenced a few traits, but the effects were generally small relative to those of sex or developmental temperature. Flies whose mother had been raised at 25 degrees C (versus at 18 degrees C) had slightly higher knock down temperature and smaller body mass. Flies whose father had been raised at 25 degrees C had relatively longer wings. The effects of paternal, maternal, and developmental temperatures sometimes differed in direction. The existence of significant within- and between-generation effects suggests that comparative studies need to standardize thermal environments for at least two generations, that attempts to estimate "field" heritabilities may be unreliable for some traits, and that predictions of short-term evolutionary responses to selection will be difficult. PMID- 28565274 TI - PATERNAL GENOTYPE INFLUENCES INCUBATION PERIOD, OFFSPRING SIZE, AND OFFSPRING SHAPE IN AN OVIPAROUS REPTILE. AB - Theoretical models for the evolution of life-history traits assume a genetic basis for a significant proportion of the phenotypic variance observed in characteristics such as hatching date and offspring size. However, recent experimental work has shown that much of the phenotypic variance in hatchling reptiles is induced by nongenetic factors, such as maternal nutrition and thermoregulation, and the physical conditions experienced during embryogenesis. Thus, there is no unambiguous evidence for strictly genetic (intraspecific) influences on the phenotypes of hatchling reptiles. We report results from a technique that uses a genetic marker trait and DNA fingerprinting to determine paternity of offspring from multiply sired clutches of European sand lizards, Lacerta agilis. By focusing on paternal rather than maternal effects, we show that hatchling genotypes exert a direct influence on the duration of incubation, the size (mass, snout-vent length) and shape (relative tail length) of the hatchling, and subsequent growth rates of the lizard during the first 3 mo of life. Embryos with genes that code for a few days' delay in hatching are thereby larger when they hatch, having undergone further differentiation (and hence, have changed in bodily proportions), and are able to grow faster after hatching. Our data thus provide empirical support for a crucial but rarely tested assumption of life-history theory, and illuminate some of the proximate mechanisms that produce intraspecific variation in offspring phenotypes. PMID- 28565275 TI - THE EVOLUTION OF ASYMMETRY IN SEXUAL ISOLATION: A MODEL AND A TEST CASE. AB - We constructed a model for the evolution of sexual isolation by extending Lande's (1981) model of sexual selection. The model predicts that asymmetric sexual isolation is a transient phenomenon, characteristic of intermediate stages of divergence in sexually selected traits. Unlike the Kaneshiro (1976, 1980) proposal, our model does not depend upon drift and the loss of courtship elements to produce asymmetries in sexual isolation. According to our model, the direction of evolution cannot be predicted from asymmetry in sexual isolation. We tested some features of the model using data from an experimental study of sexual isolation in the salamander Desmognathus ochrophaeus. We tested for sexual isolation between 12 allopatric populations and found significant asymmetry in sexual isolation in about a quarter of the test cases. The highest degrees of asymmetry were associated with intermediate levels of divergence. A curvilinear relationship between isolation asymmetry and divergence was predicted by our model and was supported by statistical analysis of the salamander data. PMID- 28565276 TI - MEASUREMENTS OF NATURAL SELECTION ON FLORAL TRAITS IN WILD RADISH (RAPHANUS RAPHANISTRUM). II. SELECTION THROUGH LIFETIME MALE AND TOTAL FITNESS. AB - It has often been suggested that selection on floral traits in hermaphroditic plants should occur primarily through differences in male fitness. However, measurements of selection on floral traits through differences in lifetime male fitness have been lacking. We measured selection on a variety of wild radish floral traits using lifetime male fitness measures derived from genetic paternity analysis. These male fitness estimates were then combined with estimates of lifetime female fitness of the same plants to produce measurements of selection based on lifetime total fitness. Contrary to the prediction above, there was no strong evidence for selection on floral morphology through male fitness differences in any of the three years of the study, but there was strong selection for increased flower size through female fitness differences in one year. The main determinant of both male and female fitness in all years was flower number; this lead to moderately positive correlations between male and female fitness in all three years. PMID- 28565277 TI - ANDROGENETICS AND TRIPLOIDS FROM AN INTERACTING PARTHENOGENETIC HYBRID AND ITS ANCESTORS IN STICK INSECTS. AB - Populations of unisexual organisms are often assumed to be genetically invariant (clones) and destined to a short existence on an evolutionary timescale. Unisexual organisms are most often obligate parthenogens and, by definition, ought to be completely isolated reproductively from related bisexual organisms. The assumption of complete reproductive isolation between amphimictic ancestors and thelytokous hybrids is common to most hypotheses on the evolution of sex and its adaptive significance. Stick insects of the genus Bacillus however provide evidence for reproductive interactions between allodiploid parthenogens and their ancestors, because pure species progeny (androgenetics) and triploid descendants are produced. These findings demonstrate that, through androgenesis, offspring of parthenogenetic hybrid females can contribute specimens of both sexes to the fathering species when fertilized by syntopic ancestral males and the parthenogenetic egg of strictly clonal females, when fertilized, allows a third genome to be added to the allodiploid chromosome set. These triploid genomes promote further genetic diversification and evolution of the unisexual populations through the formation of new clones by recombination during the changed maturation mode of allotriploid eggs. All this argues for much more complex breeding systems and evolutionary pathways than are usually assumed for hybrid unisexual organisms. PMID- 28565278 TI - TEMPORAL CHANGES IN CHROMOSOMAL POLYMORPHISM OF DROSOPHILA SUBOBSCURA RELATED TO CLIMATIC CHANGES. PMID- 28565279 TI - A MARKER-BASED METHOD FOR INFERENCES ABOUT QUANTITATIVE INHERITANCE IN NATURAL POPULATIONS. AB - A marker-based method for studying quantitative genetic characters in natural populations is presented and evaluated. The method involves regressing quantitative trait similarity on marker-estimated relatedness between individuals. A procedure is first given for estimating the narrow sense heritability and additive genetic correlations among traits, incorporating shared environments. Estimation of the actual variance of relatedness is required for heritability, but not for genetic correlations. The approach is then extended to include isolation by distance of environments, dominance, and shared levels of inbreeding. Investigations of statistical properties show that good estimates do not require great marker polymorphism, but rather require significant variation of actual relatedness; optimal allocation generally favors sampling many individuals at the expense of assaying fewer marker loci; when relatedness declines with physical distance, it is optimal to restrict comparisons to within a certain distance; the power to estimate shared environments and inbreeding effects is reasonable, but estimates of dominance variance may be difficult under certain patterns of relationship; and any linkage of markers to quantitative trait loci does not cause significant problems. This marker-based method makes possible studies with long-lived organisms or with organisms difficult to culture, and opens the possibility that quantitative trait expression in natural environments can be analyzed in an unmanipulative way. PMID- 28565280 TI - GENETIC CONSTRAINTS TO LIFE-HISTORY EVOLUTION IN THE PITCHER-PLANT MOSQUITO, WYEOMYIA SMITHII. AB - Life-history theory relies heavily on the hypothesis that genetic tradeoffs among the components of fitness constrain their independent evolution and joint maximization. Herein we show that selection on preadult development time in the pitcher-plant mosquito, Wyeomyia smithii, leads to a correlated response in cohort mean generation time but no correlated response in survivorship, fecundity, or cohort replacement rate. Lines selected for fast development achieve a higher capacity for increase (rc ) than lines selected for slow development, independently of larval density. These results imply that tradeoffs due to underlying antagonistic pleiotropy affecting growth, development, survivorship, and reproduction are not necessary constraints to life-history evolution. Previous work with W. smithii has shown a positive genetic correlation between development time and a general, genetically coordinated diapause syndrome. We propose that the observed nontradeoffs among the components of rc may be subsumed into an even more fundamental tradeoff between performance during the summer generations and synchronization of development and reproduction with the changing seasons. Consequently, critical tests of genetic tradeoffs as a constraint to the independent evolution or simultaneous optimization of fitness components may need to consider the seasonal context. PMID- 28565281 TI - EVOLUTIONARY POTENTIAL AND LOCAL GENETIC DIFFERENTIATION IN A PHENOTYPICALLY PLASTIC TRAIT OF A CYCLICAL PARTHENOGEN, DAPHNIA MAGNA. AB - The frequent use of neutral markers to quantify genetic variation in natural populations emphasizes the role of stochastic events in explaining genetic differentiation between populations. Complementary studies on ecologically relevant traits are needed to assess the role of natural selection acting on adaptive variation in the development of local genetic differentiation. To test the hypothesis of local adaptation in the cyclical parthenogenetic species Daphnia magna, the phototactic behavior in the absence and presence of fish kairomone was assayed for 30 clones derived from resting eggs isolated from three habitats characterized by a different predation pressure by fish. Clones derived from populations in which fish are present were, on average, more negatively phototactic in and more responsive to the presence of fish kairomone than clones derived from a fishless habitat. In addition, the results show a high genetic diversity for the traits studied in all three gene pools investigated, indicating a high potential for microevolutionary changes in behavior of these Daphnia populations in the face of changes in predation pressure. The results of the present study indicate that working with large samples at the expense of having less precise estimates of genotypic values for specific genotypes may result in a loss of information with regard to the evolutionary potential of local populations. PMID- 28565282 TI - THE RESPONSE TO SELECTION FOR FAST LARVAL DEVELOPMENT IN DROSOPHILA MELANOGASTER AND ITS EFFECT ON ADULT WEIGHT: AN EXAMPLE OF A FITNESS TRADE-OFF. AB - A selection experiment using Drosophila melanogaster revealed a strong trade-off between adult weight and larval development time (LDT), supporting the view that antagonistic pleiotropy for these two fitness traits determines mean adult size. Two experimental lines of flies were selected for a shorter LDT (measured from egg laying to pupation). After 15 generations LDT was reduced by an average of 7.9%. The response appeared to be controlled primarily by autosomal loci. A correlated response to the selection was a reduction in adult dry weight: individuals from the selected populations were on average 15.1% lighter than the controls. The lighter females of the selected lines showed a 35% drop in fecundity, but no change in longevity. Thus, there is no direct relationship between LDT and adult longevity. The genetic correlation between weight and LDT, as measured from their joint response to selection, was 0.86. Although there was weak evidence for dominance in LDT, there was none for weight, making it unlikely that selection acting on this antagonistic pleiotropy could lead to a stable polymorphism. In all lines, sex differences in weight violated expectations based on intrasex genetic correlations: Females, being larger than males, ought to require a longer LDT, whereas there was a slight trend in the opposite direction. Because the sexual dimorphism in size was not significantly altered by selection, it appears that the controlling loci are either invariant or have very limited pleiotropic effect on developmental time. It is suggested that they probably control some intrinsic, energy-intensive developmental process in males. PMID- 28565283 TI - INTERACTIVE EFFECTS OF OFFSPRING SIZE AND TIMING OF REPRODUCTION ON OFFSPRING REPRODUCTION: EXPERIMENTAL, MATERNAL, AND QUANTITATIVE GENETIC ASPECTS. AB - We demonstrate that egg size in side-blotched lizards is heritable (parent offspring regressions) and thus will respond to natural selection. Because our estimate of heritability is derived from free-ranging lizards, it is useful for predicting evolutionary response to selection in wild populations. Moreover, our estimate for the heritability of egg size is not likely to be confounded by nongenetic maternal effects that might arise from egg size per se because we estimate a significant parent-offspring correlation for egg size in the face of dramatic experimental manipulation of yolk volume of the egg. Furthermore, we also demonstrate a significant correlation between egg size of the female parent and clutch size of her offspring. Because this correlation is not related to experimentally induced maternal effects, we suggest that it is indicative of a genetic correlation between egg size and clutch size. We synthesize our results from genetic analyses of the trade-off between egg size and clutch size with previously published experiments that document the mechanistic basis of this trade-off. Experimental manipulation of yolk volume has no effect on offspring reproductive traits such as egg size, clutch size, size at maturity, or oviposition date. However, egg size was related to offspring survival during adult phases of the life history. We partitioned survival of offspring during the adult phase of the life history into (1) survival of offspring from winter emergence to the production of the first clutch (i.e., the vitellogenic phase of the first clutch), and (2) survival of the offspring from the production of the first clutch to the end of the reproductive season. Offspring from the first clutch of the reproductive season in the previous year had higher survival during vitellogenesis of their first clutch if these offspring came from small eggs. We did not observe selection during these prelaying phases of adulthood for offspring from later clutches. However, we did find that later clutch offspring from large eggs had the highest survival over the first season of reproduction. The differences in selection on adult survival arising from maternal effects would reinforce previously documented selection that favors the production of small offspring early in the season and large offspring later in the season-a seasonal shift in maternal provisioning. We also report on a significant parent offspring correlation in lay date and thus significant heritable variation in lay date. We can rule out the possibility of yolk volume as a confounding maternal effect-experimental manipulation of yolk volume has no effect on lay date of offspring. However, we cannot distinguish between genetic effects (i.e., heritable) and nongenetic maternal effects acting on lay date that arise from the maternal trait lay date per se (or other unidentified maternal traits). Nevertheless, we demonstrate how the timing of female reproduction (e.g., date of oviposition and date of hatching) affect reproductive attributes of offspring. Notably, we find that date of hatching has effects on body size at maturity and fecundity of offspring from later clutches. We did not detect comparable effects of lay date on offspring from the first clutch. PMID- 28565284 TI - DOES EVOLUTIONARY PLASTICITY EVOLVE? AB - During the development of a multicellular organism from a zygote, a large number of epigenetic interactions take place on every level of suborganismal organization. This raises the possibility that the system of epigenetic interactions may compensate or "buffer" some of the changes that occur as mutations on its lowest levels, and thus stabilize the phenotype with respect to mutations. This hypothetical phenomenon will be called "epigenetic stability." Its potential importance stems from the fact that phenotypic variation with a genetic basis is an essential prerequisite for evolution. Thus, variation in epigenetic stability might profoundly affect attainable rates of evolution. While representing a systemic property of a developmental system, epigenetic stability might itself be genetically determined and thus be subject to evolutionary change. Whether or not this is the case should ideally be answered directly, that is, by experimentation. The time scale involved and our insufficient quantitative understanding of developmental pathways will probably preclude such an approach in the foreseeable future. Preliminary answers are sought here by using a biochemically motivated model of a small but central part of a developmental pathway. Modeled are sets of transcriptional regulators that mutually regulate each other's expression and thereby form stable gene expression patterns. Such gene-expression patterns, crucially involved in determining developmental pattern formation events, are most likely subject to strong stabilizing natural selection. After long periods of stabilizing selection, the fraction of mutations causing changes in gene-expression patterns is substantially reduced in the model. Epigenetic stability has increased. This phenomenon is found for widely varying regulatory scenarios among transcription factor genes. It is discussed that only epistatic (nonlinear) gene interactions can cause such change in epigenetic stability. Evidence from paleontology, molecular evolution, development, and genetics, consistent with the existence of variation in epigenetic stability, is discussed. The relation of epigenetic stability to developmental canalization is outlined. Experimental scenarios are suggested that may provide further evidence. PMID- 28565285 TI - MEASUREMENTS OF NATURAL SELECTION ON FLORAL TRAITS IN WILD RADISH (RAPHANUS RAPHANISTRUM). I. SELECTION THROUGH LIFETIME FEMALE FITNESS. AB - Although the role of natural selection in the evolution of floral traits has been of great interest to biologists since Darwin, studies of selection on floral traits through differences in lifetime fitness have been rare. We measured selection acting on flower number, flower size, stigma exsertion, and ovule number per flower using field data on lifetime female fitness (seed production) in wild radish, Raphanus raphanistrum. The patterns of selection were reasonably consistent across three field seasons, with strong directional selection for increased flower production in all three years, weaker selection for increased ovule number per flower in two years, and selection for increased flower size in one year. The causes of the selection were investigated using path analysis combined with multiplicative fitness components. Increased flower production increased fruit production directly, and increased numbers of ovules per flower increased the number of seeds per fruit in all three years; pollinator visitation did not influence either of these fitness components. Increased flower size was associated with increases in both the number of fruit and the number of seeds per fruit in one year, with the latter relationship being stronger. Total lifetime seed production was affected more strongly by differences in fruit production than by differences in either the number of seeds per fruit or the proportion of fertilized seeds that were viable, but all three fitness components were positively correlated with total seed production. PMID- 28565286 TI - THE EFFECT OF COEXISTENCE ON COMPETITIVE OUTCOME IN TRIBOLIUM CASTANEUM AND TRIBOLIUM CONFUSUM. AB - We describe an experiment exploring the effects of coexistence and population differentiation on the competitive outcome of two species of Tribolium flour beetles, T. castaneum and T. confusum. The only manipulation was whether the populations used in the competitive phase of the study were raised initially in mixed-species communities, single-species populations, or in the standard culture conditions used to maintain stocks in the laboratory. Any treatment effects observed were due to natural selection acting within populations and genetic drift. In the competitive phase, we examined 10 mixed-species communities and 10 pairs of single-species populations. We replicated each community 15 times to provide an assessment of the distribution of competitive outcome. Statistical analysis demonstrates the lineages within the treatments became highly differentiated for all measures of competitive outcome: the outcome of competition (which species won), time to extinction of one of the competing species, and census history. The fraction of the variance that is among lineages has been referred to as the group or community heritability. All of these measures of competitive outcome had high community level heritabilities indicating that competitive ability would evolve rapidly as a result of group or community level selection. In contrast, competitive outcome was not affected by whether the two species had coexisted prior to the competitive phase. This indicates that the outcome of competition was not systematically changed by processes acting within the two species communities. PMID- 28565287 TI - DEVELOPMENTAL BUFFERING AND SELECTION. PMID- 28565288 TI - THE EFFECTS OF PREDATION ON THE AGE AND SIZE OF MATURITY OF PREY. AB - The effects of nonselective predation on the optimal age and size of maturity of their prey are investigated using mathematical models of a simple life history with juvenile and adult stages. Fitness is measured by the product of survival to the adult stage and expected adult reproduction, which is usually an increasing function of size at maturity. Size is determined by both age at maturity and the value of costly traits that increase mean growth rate (growth effort). The analysis includes cases with fixed size but flexible time to maturity, fixed time but flexible size, and adaptively flexible values of both variables. In these analyses, growth effort is flexible. For comparison with previous theory, models with a fixed growth effort are analyzed. In each case, there may be indirect effects of predation on the prey's food supply. The effect of increased predation depends on (1) which variables are flexible; (2) whether increased growth effort requires increased exposure to predators; and (3) how increased predator density affects the abundance of food for juvenile prey. If there is no indirect effect of predators on prey food supply, size at maturity will generally decrease in response to increased predation. However, the indirect effect from increased food has the opposite effect, and the net result of predation is often increased size. Age at maturity may either increase or decrease, depending on functional forms and parameter values; this is true regardless of the presence of indirect effects. The results are compared with those of previous theoretical analyses. Observed shifts in life history in response to predation are reviewed, and the role of size-selective predation is reassessed. PMID- 28565289 TI - DEPENDENCE OF GENE FLOW ON GEOGRAPHIC DISTANCE IN TWO SOLITARY CORALS WITH DIFFERENT LARVAL DISPERSAL CAPABILITIES. AB - When the level of gene flow among populations depends upon the geographic distance separating them, genetic differentiation is relatively enhanced. Although the larval dispersal capabilities of marine organisms generally correlate with inferred levels of average gene flow, the effect of different modes of larval development on the association between gene flow and geographic distance remains unknown. In this paper, I examined the relationship between gene flow and distance in two co-occurring solitary corals. Balanophyllia elegans broods large, nonfeeding planulae that generally crawl only short distances from their place of birth before settling. In contrast, Paracyathus stearnsii free spawns and produces small planktonic larvae presumably capable of broad dispersal by oceanic currents. I calculated F-statistics using genetic variation at six (P. stearnsii) or seven (B. elegans) polymorphic allozyme loci revealed by starch gel electrophoresis, and used these F-statistics to infer levels of gene flow. Average levels of gene flow among twelve Californian localities agreed with previous studies: the species with planktonic, feeding larvae was less genetically subdivided than the brooding species. In addition, geographic isolation between populations appeared to affect gene flow between populations in very different ways in the two species. In the brooding B. elegans, gene flow declined with increasing separation, and distance explained 31% of the variation in gene flow. In the planktonically dispersed P. stearnsii distance of separation between populations at the scale studied (10-1000 km) explained only 1% of the variation in gene flow between populations. The mechanisms generating geographic genetic differentiation in species with different modes of larval development should vary fundamentally as a result of these qualitative differences in the dependence of gene flow on distance. PMID- 28565290 TI - EFFECTS OF INTRINSIC AND EXTRINSIC FACTORS ON POPULATION FRAGMENTATION IN THREE SPECIES OF NORTH AMERICAN MINNOWS (TELEOSTEI: CYPRINIDAE). AB - Geographic patterns of genetic variation (mitochondrial DNA [mtDNA] and allozymes) were used to examine effects of intrinsic characteristics (e.g., vagility, habitat specificity, and reproductive behaviors) and extrinsic factors (e.g., climatic and geological history) on population fragmentation. The three species of cyprinid fishes examined (Tiaroga cobitis, Meda fulgida, and Agosia chrysogaster) occupied similar historical ranges within the lower Colorado River drainage, but differ in intrinsic characteristics conducive to population fragmentation. Relationships among populations were similar across species, reflecting common historical influences, but results indicate the distribution of variation among species is strongly affected by intrinsic characteristics. Variation within two species (T. cobitis and M. fulgida) is subdivided among populations, suggesting little gene flow among rivers. In contrast, similarity of A. chrysogaster populations throughout the Gila River drainage supports the hypothesis that levels of gene flow are high for this species. Levels of mtDNA divergence were much higher than expected for both T. cobitis and A. chrysogaster suggesting long-term isolation of geographic regions. These results indicate that both long-term and short-term extrinsic factors have shaped basic patterns of variation within these fishes; however, the intrinsic characteristics of each species have strongly affected the population genetic structure of these fishes. PMID- 28565291 TI - PERSPECTIVE: COMPLEX ADAPTATIONS AND THE EVOLUTION OF EVOLVABILITY. AB - The problem of complex adaptations is studied in two largely disconnected research traditions: evolutionary biology and evolutionary computer science. This paper summarizes the results from both areas and compares their implications. In evolutionary computer science it was found that the Darwinian process of mutation, recombination and selection is not universally effective in improving complex systems like computer programs or chip designs. For adaptation to occur, these systems must possess "evolvability," i.e., the ability of random variations to sometimes produce improvement. It was found that evolvability critically depends on the way genetic variation maps onto phenotypic variation, an issue known as the representation problem. The genotype-phenotype map determines the variability of characters, which is the propensity to vary. Variability needs to be distinguished from variations, which are the actually realized differences between individuals. The genotype-phenotype map is the common theme underlying such varied biological phenomena as genetic canalization, developmental constraints, biological versatility, developmental dissociability, and morphological integration. For evolutionary biology the representation problem has important implications: how is it that extant species acquired a genotype phenotype map which allows improvement by mutation and selection? Is the genotype phenotype map able to change in evolution? What are the selective forces, if any, that shape the genotype-phenotype map? We propose that the genotype-phenotype map can evolve by two main routes: epistatic mutations, or the creation of new genes. A common result for organismic design is modularity. By modularity we mean a genotype-phenotype map in which there are few pleiotropic effects among characters serving different functions, with pleiotropic effects falling mainly among characters that are part of a single functional complex. Such a design is expected to improve evolvability by limiting the interference between the adaptation of different functions. Several population genetic models are reviewed that are intended to explain the evolutionary origin of a modular design. While our current knowledge is insufficient to assess the plausibility of these models, they form the beginning of a framework for understanding the evolution of the genotype-phenotype map. PMID- 28565292 TI - COSTS OF REPRODUCTION IN THE WILD: PATH ANALYSIS OF NATURAL SELECTION AND EXPERIMENTAL TESTS OF CAUSATION. AB - During 1991 through 1994, natural selection on reproductive effort in side blotched lizards was indexed by measuring total clutch mass produced on the first clutch of the reproductive season and assessing how such effort in current reproduction affects subsequent survival and clutch production. In addition, selection was also experimentally assessed in free-ranging female side-blotched lizards by (1) surgically decreasing total clutch mass (direct ovarian manipulation) and enhancing clutch mass using (2) exogenous gonadotropin, and (3) exogenous corticosterone. Surgical reduction of clutch mass uniformly enhanced survival. However, increasing clutch mass had more complex effects depending on year. Experimentally enhanced clutch mass enhanced survival in 1991, had no effect on survival in 1992, and decreased survival in 1993. Despite the complexity of these experimental results, they are corroborated by our comparative data. It is important to note that local environmental effects can obscure detection of costs arising from natural variation in reproductive effort, and we removed such effects using path analysis. The striking shift in natural selection favoring females laying a large clutch mass (1991) to selection against females laying a large clutch mass (1993) is associated with an end of a severe multiyear drought. Our natural-history observations suggest that the correlated increase in predatory snake activity on our study site, coincident with the end of the drought, is the agent of natural selection. Although the actual agents of selection (e.g., snake predation versus drought-related effects) are not resolved, the patterns of natural selection measured in our comparative and experimental data are also consistent with year-to-year changes in clutch mass and egg size that would be indicative of rapid short-term evolution in these traits. PMID- 28565293 TI - CONTRASTING THE UNDERLYING PATTERNS OF ACTIVE TRENDS IN MORPHOLOGIC EVOLUTION. AB - Gastropod evolution during the early Paleozoic featured active trends (i.e., differential replacement of morphologies) for at least three shell characters. Selective sorting, either of individual organisms or of whole species, is an obvious mechanism for such active trends. Sorting of individuals should result in a disproportionate number of ancestor to descendant transitions being in the same direction as the trend, whereas sorting of species should result in species with particular morphologies producing more daughter species. Sorting of species can occur over long periods of time or it can be concentrated over a particular interval, such as an extinction event. Constraints on morphologic evolution also can drive trends, especially in cases where it is easier to produce a particular morphology than it is to change it. Finally, active trends can be artifacts of unrelated differential diversification within a clade (i.e., species hitchhiking), which might result from sorting of species based on phylogenetically associated characters or simply by chance. Unlike other active trends, trends attributable to species hitchhiking do not support hypotheses about selection or evolutionary constraints. PMID- 28565294 TI - Rice, W. R., and S. D. Gaines. 1994. "Heads I win, tails you lose": Testing directional alternative hypotheses in ecological and evolutionary research. Trends Ecol. & Evol. 9:235-237. PMID- 28565295 TI - DROUGHT STRESS AND INBREEDING DEPRESSION IN LYCHNIS FLOS-CUCULI (CARYOPHYLLACEAE). AB - Interactions between drought stress and inbreeding depression were studied in Lychnis flos-cuculi. Four inbreeding levels (F = 0, 0.25, 0.50 and 0.75), and three watering treatments were used. Performance was scored for germination rate and proportion, survival, plant size, proportion of plants flowering, flowering date, stem height, number of flowers, flower size, anther weight, fruiting proportion and number of capsules. Multiplicative fitness values were estimated from these traits. Inbreeding affected most of the traits studied, and a severe inbreeding depression was found for the combined fitness estimates. The higher inbreeding depression found here relative to the same family groups in a former experiment may reflect greater dominance and suppression in the present experiment at higher density. PMID- 28565296 TI - ADAPTATION AND CONSTRAINT IN THE EVOLUTION OF THE PHYSIOLOGY AND BEHAVIOR OF THE NAMIB DESERT TENEBRIONID BEETLE GENUS ONYMACRIS. AB - A comparative phylogenetic approach was used to test the following adaptive hypotheses pertaining to the physiological abilities of the Namib desert tenebrionid beetle genus Onymacris to withstand the hot, dry desert environment: (1) Desert-interior species evolved longer legs (relative to body size) than beetles in the cooler coastal region to facilitate stilting, i.e., elevating their bodies out of the hot boundary layer of air close to the substrate. (2) Wax blooms on the exoskeleton, which reduce evaporative water loss, are more likely to evolve in desert-interior species than in coastal species. (3) The high costs of activity in the extreme climates select for perfect coadaptation of preferred body temperatures (i.e., optimal temperatures for activity) and those they achieve in the field. All three of these adaptive hypotheses were supported by the results of squared-change parsimony and independent-contrasts analyses. Additionally, a parsimony approach suggested that a novel means of obtaining water from periodic fogs, known as fog basking, has evolved independently on two occasions. PMID- 28565297 TI - ADAPTATION TO HEAVY METALS IN THE AQUATIC OLIGOCHAETE LIMNODRILUS HOFFMEISTERI: EVIDENCE FOR CONTROL BY ONE GENE. PMID- 28565298 TI - EPISTASIS AS A SOURCE OF INCREASED ADDITIVE GENETIC VARIANCE AT POPULATION BOTTLENECKS. AB - The role of epistasis in evolution and speciation has remained controversial. We use a new parameterization of physiological epistasis to examine the effects of epistasis on levels of additive genetic variance during a population bottleneck. We found that all forms of epistasis increase average additive genetic variance in finite populations derived from initial populations with intermediate allele frequencies. Average additive variance continues to increase over many generations, especially at larger population sizes (N = 32 to 64). Additive-by additive epistasis is the most potent source of additive genetic variance in this situation, whereas dominance-by-dominance epistasis contributes smaller amounts of additive genetic variance. With additive-by-dominance epistasis, additive genetic variance decreases at a relatively high rate immediately after a population bottleneck, rebounding to higher levels after several generations. Empirical examples of epistasis for murine adult body weight based on measured genotypes are provided illustrating the varying effects of epistasis on additive genetic variance during population bottlenecks. PMID- 28565299 TI - DEMOGRAPHIC GENETICS OF A PIONEER TROPICAL TREE SPECIES: PATCH DYNAMICS, SEED DISPERSAL, AND SEED BANKS. AB - We consider whether changes in population-genetic structure through the life cycle of Cecropia obtusifolia, a tropical pioneer tree, reflect its gap-dependent demography and the role of evolutionary processes that are important for this species. We asked whether the spatial scale at which population-genetic subdivision occurs corresponds to the scale of habitat patchiness created by gap dynamics; whether patterns of seed dispersal and storage in the soil affect spatial genetic patterns; and whether spatial genetic patterns change through the species life cycle. We estimated Wright's F-statistics for six successive life history stages for individuals grouped into subpopulations according to occurrence in natural gaps, physical proximity, or occurrence within large quadrats. For each life stage, FST -statistics were significantly higher when individuals were grouped by gaps, although concordant patterns across life stages for the three grouping methods were obtained. This supports the hypothesis that patchy recruitment in gaps or among-gap heterogeneity influences the species' genetic structure. F-statistics of seeds collected from females before dispersal (tree seeds), seed-rain seeds, soil seeds, seedlings, juveniles, and adults grouped by gaps, were, respectively: FIT = 0.004, 0.160, 0.121, 0.091, -0.0002, 0.081; FIS = -0.032, 0.124, 0.118, 0.029, -0.016, -0.083; and FST = 0.035, 0.041, 0.003, 0.063, 0.015, 0.002. Spatial genetic differentiation in rain seeds was not significantly lower than that of tree seeds. The loss of genetic structure in the soil seed bank, relative to that found in the seed rain may be due to sampling artifacts, but alternative explanations, such as microsite selection or temporal Wahlund effect are also discussed. If structure among soil seeds is unbiased, the peak in seedling FST may be due to microsite selection. FIS of seeds in the rain and soil were significantly greater than zero. A Wahlund effect is the most likely cause of these positive FIS values. Such fine-scale substructuring could be caused by correlated seed deposition by frugivores. The decrease in FIS from seedlings to adults could result from loss of fine-scale genetic structure during stand thinning or from selection. PMID- 28565300 TI - EVIDENCE FOR SYMPATRIC GENETIC DIVERGENCE OF ANADROMOUS AND NONANADROMOUS MORPHS OF SOCKEYE SALMON (ONCORHYNCHUS NERKA). AB - Anadromous and nonanadromous morphs of the Pacific salmon Oncorhynchus nerka spawn in close physical proximity in tributaries to Takla Lake, British Columbia, yet differ in morphology, gill raker number, allozyme allele frequencies, and reproductive traits. Both morphs are semelparous typically maturing at age four, the anadromous morph (sockeye) at fork lengths of 38-65 cm and the nonanadromous morph (kokanee) at 17-22 cm. When reared together, pure and hybrid morphs also exhibited different growth rates and maturity schedules. Collectively, these large differences between the morphs confirm that sockeye and kokanee exist as reproductively isolated populations. Average gene flow (m) was estimated to be 0.1-0.8% between morphs, 1.7-3.7% among tributaries for kokanee, and 0.3-5.6% among tributaries for sockeye. We conclude that divergence has occurred in sympatry and examine potential isolating mechanisms. PMID- 28565301 TI - QUANTITATIVE GENETIC AND OPTIMALITY ANALYSES OF LIFE-HISTORY PLASTICITY IN THE EASTERN MOSQUITOFISH, GAMBUSIA HOLBROOKI. PMID- 28565302 TI - ENVIRONMENT-DEPENDENCE OF QUANTITATIVE GENETIC PARAMETERS IN IMPATIENS PALLIDA. AB - Population response to selection depends on the presence of additive genetic variance for traits under selection. When a population enters an alien environment, environment-induced changes in the expression of genetic variance may occur. These could have large effects on the response to selection. To investigate the environment-dependence of genetic variance, we conducted a reciprocal transplant experiment between two ecotypically differentiated populations of Impatiens pallida using the progeny of a standard mating design. The floodplain site was characterized by high water availability, moderate temperatures, and continuous dense stands of Impatiens. The hillside site was drier, with larger temperature extremes and supported only scattered patches of Impatiens with significantly lower seed production and earlier mortality. Estimates of heritability were low for each of the 13 traits measured in each population and site (range from 0-28%). Additive genetic variance for life history traits tended to be larger than for morphological traits, but genetic variance in fitness was estimated to be not significantly different from zero in all cases. Significant heritability was detected in both populations for one trait (date of first cleistogamous flower) known to be closely related to fitness on the hillside. In general, heritability was reduced for populations when grown in the hillside site relative to the floodplain site, suggesting that stress acts to reduce the expression of genetic variance and the potential to respond to selection there. Consistent reductions in heritability associated with more stressful environments suggest that populations invading such sites may undergo little adaptive differentiation and be more prone to local extinction. PMID- 28565303 TI - BENEFITS OF MULTIPLE MATES IN THE CRICKET GRYLLUS BIMACULATUS. AB - Despite the importance of polyandry for sexual selection, the reasons why females frequently mate with several males remain poorly understood. A number of genetic benefits have been proposed, based on the idea that by taking multiple mates, females increase the likelihood that their offspring will be sired by genetically more compatible or superior males. If certain males have intrinsically "good genes," any female mating with them will produce superior offspring. Alternatively, if some males have genetic elements that are incompatible with a particular female, then she may benefit from polyandry if the sperm of such males are less likely to fertilize her eggs. We examined these hypotheses in the field cricket Gryllus bimaculatus (Orthoptera: Gryllidae). By allocating females identical numbers of matings but different numbers of mates we investigated the influence of number of mates on female fecundity, and both short- and long-term offspring fitness. This revealed no effect of number of mates on number of eggs laid. However, hatching success of eggs increased with number of mates. This effect could not be attributed to nongenetic effects such as the possibility that polyandry reduces variance in the quantity or fertilizing ability of sperm females receive, because a control group receiving half the number of copulations showed no drop in hatching success. Offspring did not differ in survival, adult mass, size, or development time with treatment. When males were mated to several different females there were no repeatable differences between individual males in the hatching success of their mate's eggs. This suggests that improved hatching success of polyandrous females is not due to certain males having genes that improve egg viability regardless of their mate. Instead, our results support the hypothesis that certain males are genetically more compatible with certain females, and that this drives polyandry through differential fertilization success of sperm from more compatible males. PMID- 28565304 TI - SINGLE FOUNDER-FLUSH EVENTS AND THE EVOLUTION OF REPRODUCTIVE ISOLATION. AB - By demonstrating the evolution of significant premating isolation, previous laboratory experiments have provided some evidence for the founder-flush model of speciation. However, these experiments are subject to a number of criticisms, including the use of hybrid populations recently collected from the wild and the use of multiple bottlenecks. Here we present the results of a test of founder flush speciation using a single, well-adapted laboratory stock of Drosophila melanogaster subjected to one founder-flush event. The experiment was replicated at larger scale than previous studies, and results indicate that none of 50 independent founder-flush lines evolved significant assortative mating relative to the control (base) population. This suggests a diminished emphasis on population bottlenecks in speciation of D. melanogaster and perhaps in general. PMID- 28565305 TI - BIOGEOGRAPHY OF A WIDESPREAD FRESHWATER CRUSTACEAN: PSEUDOCONGRUENCE AND CRYPTIC ENDEMISM IN THE NORTH AMERICAN DAPHNIA LAEVIS COMPLEX. AB - The lack of morphological variation in many freshwater invertebrates over vast distances has been cited as evidence for their frequent, long-distance dispersal. This scenario implies that vicariance will be an insignificant determinant of species distributions or diversity. We carried out a phylogeographic and population genetics study of one widespread crustacean group, the North American Daphnia laevis complex. Allozyme and sequence variation of two mtDNA genes (12S and 16S rRNA) clearly indicates the existence of five morphologically cryptic, largely allopatric groups (Daphnia dubia, D. laevis laevis, D. laevis gessneri, D. magniceps magniceps, and D. magniceps pacifica ssp. n.). Within each of these groups, there is weak or no genetic differentiation over large geographic areas suggesting their recent long-distance dispersal. The present-day distributions and phylogeography of the regional groups suggests the occurrence of both deep and shallow vicariance events. Although divergence times from mtDNA sequences do indicate both deep and shallow divergences, these estimates are incongruent with their proposed vicariance times. The results show that even within closely related freshwater invertebrates, a complex biogeography exists, whose analysis is made difficult by long-distance dispersal, cryptic endemism, and pseudocongruence. PMID- 28565306 TI - ECOLOGICAL AND HISTORICAL ASSOCIATIONS OF GENE FLOW IN DARTERS (TELEOSTEI: PERCIDAE). AB - Life history should relate to gene flow (Nm) through its influence on dispersal and effective population size. Comparative studies designed to elucidate this relationship must contend with historical events that can yield misleading estimates of gene flow and statistical problems associated with inclusion of life history traits correlated with phylogeny. We studied the relationships of life history characters and gene flow in 15 species of darters, a monophyletic group of stream fishes. Populations of coexisting species were sampled in three geographic regions with different Pleistocene glaciation histories. Gene flow was estimated indirectly from allozymes using two methods, 8 and private alleles. Isolation-by-distance was also tested using regression of pairwise estimates of gene flow (M) on distance. Theta and private-alleles methods produced congruent estimates of Nm, except in a study region hypothesized to have been historically fragmented and then united following Pleistocene glaciation. A relatively weak association between life-history traits and Nm (based on theta) was observed when species from the historically fragmented region were included in stepwise regression analysis, because Nm was low despite life-history differences among taxa in this region. Excluding observations from this region produced stronger associations between clutch size and Nm (r2 = 0.57), and between female size, egg size, and Nm (r2 = 0.95). Additional analyses that corrected for female body size and phylogenetic nonindependence agreed that darters with high fecundity and small eggs exhibited high gene flow, whereas darters with small clutches and large eggs had low gene flow. The latter combination of life-history traits primarily is exhibited in species from headwater habitats where parental investment presumably confers survivorship on offspring. Reduced gene flow and genetic divergence among demes appear to be evolutionary consequences of this strategy. PMID- 28565307 TI - INFECTIVITY, MULTIPLE INFECTIONS, AND THE GENETIC CORRELATION BETWEEN WITHIN-HOST GROWTH AND PARASITE VIRULENCE: A REPLY TO HOCHBERG. AB - Two experimental studies, Ebert (1994) and Ebert and Mangin (1997), described a genetic correlation between parasite virulence and the number of transmission stages found in the hosts. It was concluded that this correlation is evidence that within-host growth rate of the parasite is positively correlated with virulence. Hochberg (1998) has criticized this interpretation, arguing that differential infectivity and density-dependent parasite growth could confound the results. Here I point out that density dependence is unlikely to have confounded the results, but, at least for Ebert (1994), differential infectivity is likely to have been a confounding factor. However, Ebert and Mangin (1997) measured infectivity and showed that strains with higher infectivity had lower virulence, which is contrary to Hochberg's hypothesis. In summary, I conclude that differential infectivity played a role in the assessment of the correlation between parasite reproduction and virulence, but that differential within-host growth remains the most likely explanation for the correlation observed in Ebert and Mangin (1997). PMID- 28565308 TI - INBREEDING DEPRESSION IN GYNODIOECIOUS LOBELIA SIPHILITICA: AMONG-FAMILY DIFFERENCES OVERRIDE BETWEEN-MORPH DIFFERENCES. AB - If inbreeding depression is caused by deleterious recessive alleles, as suggested by the partial dominance hypothesis, a negative correlation between inbreeding and inbreeding depression is predicted. This hypothesis has been tested several times by comparisons of closely related species or comparisons of populations of the same species with different histories of inbreeding. However, if one is interested in whether this relationship contributes to mating-system evolution, which occurs within populations, comparisons among families within a population are needed; that is, inbreeding depression among individuals with genetically based differences in their rate of selfing should be compared. In gynodioecious species with self-compatible hermaphrodites, hermaphrodites will have a greater history of potential inbreeding via both selfing and biparental inbreeding as compared to females and may therefore express a lower level of inbreeding depression. We estimated the inbreeding depression of female and hermaphrodite lineages in gynodioecious Lobelia siphilitica in a greenhouse experiment by comparing the performance of selfed and outcrossed progeny, as well as sibling crosses and crosses among subpopulations. We did not find support for lower inbreeding depression in hermaphrodite lineages. Multiplicative inbreeding depression (based on seed germination, juvenile survival, survival to flowering, and flower production in the first growing season) was not significantly different between hermaphrodite lineages (delta = 0.30 +/- 0.08) and female lineages (delta = 0.15 +/- 0.18), although the trend was for higher inbreeding depression in the hermaphrodite lineages. The population-level estimate of inbreeding depression was relatively low for a gynodioecious species (delta = 0.25) and there was no significant inbreeding depression following biparental inbreeding (delta = 0.01). All measured traits showed significant variation among families, and there was a significant interaction between family and pollination treatment for four traits (germination date, date of first flowering, number of flowers, and aboveground biomass). Our results suggest that the families responded differently to selfing and outcrossing: Some families exhibited lower fitness following selfing whereas others seemed to benefit from selfing as compared to outcrossing. Our results support recent simulation results in that prior inbreeding of the lineages did not determine the level of inbreeding depression. These results also emphasize the importance of determining family level estimates of inbreeding depression, relative to population-level estimates, for studies of mating-system evolution. PMID- 28565309 TI - EFFECTS OF POSTGLACIAL RANGE EXPANSION ON ALLOZYME AND QUANTITATIVE GENETIC VARIATION OF THE PITCHER-PLANT MOSQUITO, WYEOMYIA SMITHII. AB - We determined allozyme variability of 34 populations of the pitcher-plant mosquito, Wyeomyia smithii, from Florida (30 degrees N) to northern Manitoba (54 degrees N) and compared allozyme variability with the additive genetic variance for preadult development time and photoperiodic response determined previously for six populations over a similar range (30-50 degrees N). Phylogenetic analysis of allozymes shows a well-defined split between Gulf Coast and lowland North Carolina populations, similar to previously observed phylogeographic patterns in a wide variety of taxa. A deeper split in the phylogeny of W. smithii coincides with the location of the maximum extent of the Laurentide Ice Sheet. Furthermore, both average heterozygosity and patterns of isolation-by-distance decline in populations north of the former glacial border. It is likely that northern populations are the result of a range expansion that occurred subsequent to the late-Wisconsin retreat of the Laurentide Ice Sheet and that these populations have not yet reached a drift-migration equilibrium. The northern decline in allozyme heterozygosity contrasts sharply with the northern increase in additive genetic variance of development time and photoperiodic response found in previous studies. These previous studies also showed that the genetic divergence of populations has involved stochastic variation in the contribution of dominance and epistasis to the genetic architecture underlying demographic traits, including preadult development time, and photoperiodic response. When taken together, the present and prior studies identify the genetic processes underlying the lack of concordance between geographic patterns of allozyme and quantitative genetic variation in natural populations of W. smithii. In the presence of nonadditive genetic variation, isolation and drift can result in opposite patterns of genetic variation for structural genes and quantitative traits. PMID- 28565310 TI - EVOLUTION OF A POLYMORPHISM FOR OUTCROSSING RATE IN SENECIO VULGARIS: INFLUENCE OF GERMINATION BEHAVIOR. AB - A difference in germination behavior between the highly selling, nonradiate variant of Senecio vulgaris and the more outcrossing, radiate form had a large effect on the relative female fitness of these two morphs raised in mixed stands under conditions similar to those experienced in the wild. Of particular significance was the finding that female fitness differences between morphs were reversed in early- and late-sown plots. This was because a greater proportion of nonradiate than radiate seed germinated directly after sowing, and in early-sown plots a relatively large proportion of early-germinated nonradiate seedlings survived winter to produce large, highly fecund plants the following summer, that contributed greatly to the total female fitness of the nonradiate morph. In contrast, in late-sown plots (i.e., sown two weeks later), survivorship of early germinated seedlings was much reduced, and the radiate morph had an advantage because most radiate seed delayed germination until spring, therefore avoiding seedling mortality during winter. The effect of the association between morph type and germination behavior on morph female fitness in S. vulgaris is clearly important in regard to the evolution of the polymorphism for outcrossing rate in the species. This, in turn, emphasizes the point that an understanding of factors responsible for the evolution and maintenance of polymorphisms for outcrossing rate in the wild should be based on a detailed examination of the ecological genetics of such polymorphisms that extend beyond traditional studies of pollen discounting and inbreeding depression. PMID- 28565311 TI - LABORATORY EVOLUTION OF LIFE-HISTORY TRAITS IN THE BEAN WEEVIL (ACANTHOSCELIDES OBTECTUS): THE EFFECTS OF SELECTION ON DEVELOPMENTAL TIME IN POPULATIONS WITH DIFFERENT PREVIOUS HISTORY. AB - In this study we examined the direct and correlated responses for fast and slow preadult development time in three laboratory populations of the bean weevil (Acanthoscelides obtectus). The first population ("base," B) has experienced laboratory conditions for more than 10 years; the second ("young," Y) and the third ("old," O) populations were selected for early and late reproduction, respectively, before the onset of the present experiments. All three populations are successfully selected for both fast and slow preadult development. The realized heritabilities are very similar in all populations, suggesting a similar level of the additive genetic variance for preadult development. We studied the correlated responses on the following life-history traits: egg-to-adult viability, wet body weight, early fecundity, late fecundity, total realized female fecundity, and adult longevity. All life-history traits examined here, except for the egg-to-adult viability, are affected by selection for preadult development in at least in one of the studied populations. In all three populations, beetles selected for slow preadult development are heavier and live longer than those from the fast-selected lines. The findings with respect to adult longevity are unexpected, because the control Y and O populations, selected for short- and long-lived beetles, respectively, do not show significant differences in preadult development. Thus, our results indicate that some kind of asymmetrical correlated responses occur for preadult development and adult longevity each time that direct selection has been imposed on one or the other of these two traits. In contrast to studies with Drosophila, it appears that for insect species that are aphagous as adults, selection for preadult development entails selection for alleles that also change the adult longevity, but that age specific selection (applied in the Y and O populations) mostly affects the alleles that have no significant influence on the preadult development. Implications of these findings on the developmental and evolutionary theories of aging are also discussed. PMID- 28565312 TI - EXPERIMENTAL EVOLUTION OF SENESCENCE: AN ANALYSIS USING A "HETEROGENEITY" MORTALITY MODEL. AB - A long-term laboratory selection experiment has produced replicated populations of fruit flies that differ in mean life span by more than twofold. An analysis of age-specific mortality rates indicated that differences in mean life span have been achieved principally by evolution of patterns of senescence. These results provide empirical confirmation that senescence can be modified within species by appropriate forms of natural selection, which is a fundamental prediction of theories regarding the genetic basis and evolution of senescence. Mortality data were fit to a model that accounts for the leveling off of cohort mortality rates at older ages, but that does not necessarily imply that very old individuals cease to senesce. PMID- 28565313 TI - INBREEDING AND FITNESS IN THE FRESHWATER SNAIL LYMNAEA PEREGRA: AN EVALUATION OVER TWO GENERATIONS OF SELF-FERTILIZATION. AB - Inbreeding depression was estimated from an outbreeding population of the freshwater snail Lymnaea peregra, on the basis of two successive generations of enforced selling and outcrossing, and 70 maternal lineages. Outcrossing was analyzed under two treatments, groups of two and five individuals. The fitness parameters measured included fecundity, growth, and survival. In the first generation, we contrasted three treatments (selfers vs. paired outcrossers and group outcrossers). Very similar results were obtained between the two outcrossing treatments. A strong self-fertilization depression (which includes parental fecundity and progeny fitness) was detected in the selling treatment (about 90%). In the second generation, there was again marked evidence for self fertilization depression, with the highest contributions coming from parental fecundity and progeny hatching rate. Our results suggest that the decreased parental fecundity is a consequence of the mating system in the previous generation, although the role of partial self-incompatibility and the copulation behavior could not be ruled out. Hatching rate and early survival data are suggestive of purging of lethal mutations. Significant variation in fitness among selfing lineages was found for most fitness traits. Our experimental design also allowed to test for interactions among fitness loci. Only one trait of the nine studied behaved as expected under synergistic interactions. However we cannot rule out some purging during the experiment, which could have biased results towards linearity. Inbreeding depression was also inferred from the change of inbreeding level across generations in the same population. We obtained a value similar to the experimental estimate. PMID- 28565314 TI - TESTING HYPOTHESES OF NEURAL EVOLUTION IN GYMNOTIFORM ELECTRIC FISHES USING PHYLOGENETIC CHARACTER DATA. AB - In this paper, we propose a method to test alternative hypotheses of phenotypic evolution. The method compares patterns observed in phylogenetic character data with patterns expected by explicit models of evolutionary process. Observed patterns of character-state diversity are assessed from four properties of character-state change derived from a phylogenetic analysis: the sequence and correlation of transformations on a cladogram and the spatial and functional localization of these transformations to parts of an organism. Patterns expressed in terms of the localization of transformations are compared with the expectations of null models that the number of transformations is proportional to measures of size or complexity. Deviations from the values expected by the null models are then compared with qualitative expectations of the models. The method is applied to characters in the nervous system of gymnotiform electric fishes. Patterns in the diversity of 63 reconstructed character-state changes are compared with the expectations of 10 published models of neural evolution. A total of 63 expectations are reviewed, of which 33 (52%) are found to be consistent with the gymnotiform neural data. In general, the models reviewed are not successful at making global predictions, in part because they have been cast in excessively general terms. The data support the conclusion that evolution in the nervous system of gymnotiforms has involved a mosaic of processes, each operating differentially on functional and developmental systems and at different spatial and temporal scales. The results also indicate that more refined models are required, each making more explicit predictions. PMID- 28565315 TI - ESTABLISHING GENETIC CORRELATIONS INVOLVING PARASITE VIRULENCE. AB - For many host-parasite interactions, virulence is necessarily affected by population densities, transmission biology of the parasite, and proliferation of the parasite at the expense of its host. Attempts to experimentally demonstrate genetic correlations involving virulence therefore need to employ protocols controlling for variation in the number of successful infections (i.e., the end point of transmissibility). If protocols are not controlled, then correlations may be spurious, as appears to be the case in recent experimental studies by Ebert (1994) and Ebert and Magnin (1997). There is a need to explore the modes of the evolution of each of the many sequential steps in nonsymbiotic and symbiotic phases of host-parasite associations and the implication of such evolution for overall virulence. I argue that it is the interdependence of these sequential steps (and not overall virulence) that should be at the center of attempts to establish genetic correlations. PMID- 28565316 TI - LOGISTIC REGRESSION FOR EMPIRICAL STUDIES OF MULTIVARIATE SELECTION. AB - Understanding the mechanics of adaptive evolution requires not only knowing the quantitative genetic bases of the traits of interest but also obtaining accurate measures of the strengths and modes of selection acting on these traits. Most recent empirical studies of multivariate selection have employed multiple linear regression to obtain estimates of the strength of selection. We reconsider the motivation for this approach, paying special attention to the effects of nonnormal traits and fitness measures. We apply an alternative statistical method, logistic regression, to estimate the strength of selection on multiple phenotypic traits. First, we argue that the logistic regression model is more suitable than linear regression for analyzing data from selection studies with dichotomous fitness outcomes. Subsequently, we show that estimates of selection obtained from the logistic regression analyses can be transformed easily to values that directly plug into equations describing adaptive microevolutionary change. Finally, we apply this methodology to two published datasets to demonstrate its utility. Because most statistical packages now provide options to conduct logistic regression analyses, we suggest that this approach should be widely adopted as an analytical tool for empirical studies of multivariate selection. PMID- 28565317 TI - COMPARATIVE ANALYSIS OF GALL MORPHOLOGY IN AUSTRALIAN GALL THRIPS: THE EVOLUTION OF EXTENDED PHENOTYPES. AB - We used a combination of morphometric, phylogenetic, and life-history information to analyze the evolution and possible adaptive significance of gall morphology in a clade of 24 species of gall-inducing thrips (Insecta: Thysanoptera) on Australian Acacia trees. Principal components analysis revealed that galls varied in morphology along two main axes, spherical versus elongate (PC1) and general size (PC2). A high degree of conservation of gall shape on an independently derived phylogeny of the insects and the presence of nine species of Acacia each bearing two or three morphologically disparate gall forms induced by different thrips species indicate that interspecific variation in gall form is determined predominantly by the insects. Character optimization of PC1 on the phylogeny of gall thrips suggested that the ancestral gall form was a simple roll or curl. The diversification of gall form involved four main processes: (1) the convergent evolution of relatively spherical galls in two clades; (2) the evolution of small elongate and hemispherical galls in one clade; (3) the evolution of a lobed interior in a species with a spherical gall and multiple within-gall generations; and (4) the evolution of intraspecific gall polymorphism in a clade of apparent sibling species. Comparative analyses indicated that gall sphericity was associated with the presence of physogastry (foundress hyperfecundity) and that small elongate and hemispherical forms may be associated with the presence of multiple generations in a gall and, perhaps, with the presence of soldier castes. The evolution of a lobed interior in one species, which greatly increases inner surface area, coincided with the evolution of multiple generations. In the clade with intraspecific gall polymorphism in some species, patterns of intraspecific variation mirror patterns of interspecific variation within the clade as a whole. This is the first study to analyze the evolution of gall size and shape in a phylogenetic context and to investigate the life-history correlates of evolutionary changes in gall form. Taken together, our findings indicate that the main selective pressures driving the evolution of gall form in Australian gall thrips on Acacia involve inner surface area to volume relationships, which change in concert with foundress fecundity and the number of within-gall generations. PMID- 28565318 TI - THE EVOLUTION OF FEMALE-BIASED SEXUAL SIZE DIMORPHISM: A POPULATION-LEVEL COMPARATIVE STUDY IN HORNED LIZARDS (PHRYNOSOMA). AB - Female-biased sexual size dimorphism is uncommon among vertebrates and traditionally has been attributed to asymmetric selective pressures favoring large fecund females (the fecundity-advantage hypothesis) and/or small mobile males (the small-male advantage hypothesis). I use a phylogenetically based comparative method to address these hypotheses for the evolution and maintenance of sexual size dimorphism among populations of three closely related lizard species (Phrynosoma douglasi, P. ditmarsi, and P. hernandezi). With independent contrasts I estimate evolutionary correlations among female body size, male body size, and sexual size dimorphism (SSD) to determine whether males have become small, females have become large, or both sexes have diverged concurrently in body size during the evolutionary Xhistory of this group. Population differences in degree of SSD are inversely correlated with average male body size, but are not correlated with average female body size. Thus, variation in SSD among populations has occurred predominantly through changes in male size, suggesting that selective pressures on small males may affect degree of SSD in this group. I explore three possible evolutionary mechanisms by which the mean male body size in a population could evolve: changes in size at maturity, changes in the variance of male body sizes, and changes in skewness of male body size distributions. Comparative analyses indicate that population differentiation in male body size is achieved by changes in male size at maturity, without changes in the variance or skewness of male and female size distributions. This study demonstrates the potential of comparative methods at lower taxonomic levels (among populations and closely related species) for studying microevolutionary processes that underlie population differentiation. PMID- 28565319 TI - APPEARANCE AND SWEEP OF A GENE DUPLICATION: ADAPTIVE RESPONSE AND POTENTIAL FOR NEW FUNCTIONS IN THE MOSQUITO CULEX PIPIENS. AB - Evolution of a new gene function is a fundamental process of adaptation. Gene duplication followed by divergence due to relaxed selection on redundant copies has been viewed as the predominant mechanism involved in this process. At a macroevolutionary scale, evidence for this scenario came from the analysis of sequences of genes families. However, even if several genetic models have described the different potential microevolutionary scenario for a new function to evolve, little is really known about the initial evolutionary dynamics of such processes. We analyze such early dynamics in natural populations of the mosquito Culex pipiens polymorphic for a duplication at Ace.1, a locus involved in insecticide resistance. The date of occurrence and the selective advantages of the duplication were estimated using frequency data. We propose a scenario where the spread of a duplication is driven, from the very beginning, by selection due to insecticide treatment. PMID- 28565320 TI - NEGATIVE MATERNAL EFFECT REVISITED: A TEST ON TWO POPULATIONS OF ORCHESELLA CINCTA L. (COLLEMBOLA: ENTOMOBRYIDAE). AB - A Dutch population of Orchesella cincta had been demonstrated to exhibit a negative maternal effect on age at first reproduction, which caused alternation of short and long generations. The adaptive significance of such a mechanism was assumed to be associated with the bivoltine life cycle of Dutch O. cincta. We expected that it would be absent in a non bivoltine population sampled in Siena, Italy. To test this hypothesis we performed a parent-offspring regression experiment with both populations simultaneously. The experiment showed that there was no negative maternal effect in both populations. We leave open the question of the cause of the discrepancy between the previous result with the Dutch population and the present result. The results of our experiment were also used to determine heritabilities of the traits age, mass and number of molts at first reproduction, and size of the first clutch. The estimates of heritabilities were often not significantly different from zero, especially in the Italian population which had only one significant heritability. PMID- 28565321 TI - SELECTION AND STRAIN SPECIFICITY OF COMPATIBILITY BETWEEN SNAIL INTERMEDIATE HOSTS AND THEIR PARASITIC SCHISTOSOMES. AB - Many theoretical models of host-parasite coevolution assume that variation in host resistance to parasite infection is, at least partially, genetically determined and specific to the strain of infecting parasite. However, very few experimental studies have been conducted to test this assumption in animal parasite systems. Biomphalaria glabrata snails serve as the intermediate hosts of Schistosoma mansoni. Although some snails are resistant to infection, there is no evidence of fixation of resistance in field populations. Two possible explanations for this are high fitness costs associated with resistance and a dynamic coevolution between parasite and host, perhaps involving matching alleles or gene-for-gene interactions. Two strains of B. glabrata were artificially selected for either resistance or susceptibility to each of two strains of S. mansoni parasite for three generations. Third-generation snails were then were exposed to either the parasite strain to which they had been selected or to a different parasite strain. In both host strains, resistance and susceptibility (compatibility) were found to be heritable. Moreover, compatibility to one parasite strain was not associated with compatibility to another strain, implying no genetic trade-off. Our results are discussed in terms of potential mechanisms of resistance in this host-parasite system and their implications to general coevolutionary theory. PMID- 28565322 TI - ISOLATING A ROLE FOR NATURAL SELECTION IN SPECIATION: HOST ADAPTATION AND SEXUAL ISOLATION IN NEOCHLAMISUS BEBBIANAE LEAF BEETLES. AB - Muller (1942) and Mayr (1963) hypothesized that natural selection indirectly causes the evolution of reproductive barriers between allopatric populations by causing adaptive genetic divergence that pleiotropically promotes prezygotic or postzygotic incompatibility. Under this mechanism, herbivorous insect populations should be more prone to speciate if they are adapting to different host plants, because the evolution of reproductive isolation will be accelerated above the rate promoted by genetic drift and host-independent sources of selection alone. Although the Muller-Mayr hypothesis is widely accepted, little direct evidence has been collected in support of selection's role in allopatric speciation. This paper offers a method for isolating and evaluating the contribution of host plant related natural selection pressures to the reproductive isolation between allopatric herbivore populations. The host-related selection hypothesis (HRSH) predicts that herbivore populations using different host plants should be more reproductively isolated than those using the same host, other things being equal. Here, I test this hypothesis using Neochlamisus bebbianae, an oligophagous leaf beetle with a geographically variable host range. In each of two sets of experiments (contrast I, contrast II), I compared two beetle populations (Georgia and New York) that use the same host (Acer) in nature and a third population that natively uses a different host (Betula in Oklahoma [CI], Salix in Ontario [CII]). Experiments showed that "different-host" populations were more strongly differentiated in host-use traits (oviposition, host fidelity, feeding response, larval performance) than were "same-host" populations and that each population most readily uses foliage from its native host. As predicted by the HRSH, sexual isolation was also greater between the adaptively divergent different-host populations (from Betula vs. Acer, from Salix vs. Acer) than between the same host populations (from Acer), which were undifferentiated in host-use traits. Interpreting these results in a historical context provided by mtDNA sequences from test populations indicated: (1) that Acer- and Betula-associated N. bebbianae represent separate sibling species whose causal origins have been lost to history, and whose incomplete sexual isolation is fortified by host-associated ecological and "physiological" isolation; and (2) that incipiently speciating Acer- and Salix-associated populations are more closely related to each other than are the two Acer-associated populations, which is consistent with the HRSH. This study thus illustrates the consequences of host-related selection for both the origin and maintenance of reproductive isolation. More important, it provides evidence that the pleiotropic effects of natural selection promote allopatric speciation. PMID- 28565323 TI - TIMING OF PARTURITION AS A MATERNAL CARE TACTIC IN AN ALPINE LIZARD SPECIES. AB - Lack of ability to buffer postparturient offspring mortality risks may put a female under strong selection to time the birth of her young with benign environmental conditions. We provide support for timing of parturition as an adaptation in Tasmanian snow skinks (Niveoscincus) by demonstration of (1) ongoing selection against poorly timed parturitions, (2) retention of full-term young through episodes of unfavorable conditions, and (3) phylogenetic shifts from autumn to spring parturition in taxa where costs of autumn parturition are expected to be relatively higher. PMID- 28565324 TI - CONSPIRATORIAL WHISPERS AND CONSPICUOUS DISPLAYS: GAMES OF SIGNAL DETECTION. AB - Recent models of signaling have assumed that the expenditure required to ensure detection of a display is negligible and have concentrated instead on the costs that may be necessary to maintain honesty. Such models predict that individuals who share the same interests are likely to communicate using "conspiratorial whispers," signals that are cheap and inconspicuous. Here, I present a game theoretical model of signal detection (in a noisy environment, in the presence of potential eavesdroppers), which demonstrates that the idea of conspiratorial whispers is far too simplistic. It is true that in "cooperative" signaling systems (where signalers attempt to elicit responses that are beneficial for receivers), signal cost is not required to maintain honesty. However, some level of expenditure is still needed to ensure that a signal is reliably detected. Moreover, there exists a conflict of interest between signalers and receivers over the division of this expenditure. To predict the stable level of display in such cases, one needs to know how this conflict of interest will be resolved. The model reveals that the outcome may range from a whisper to a conspicuous and costly (though still conspiratorial) display. The more closely related the receiver is to the signaler, the greater the level of signal exaggeration that is expected-the opposite prediction to that of honest signaling models. PMID- 28565325 TI - EVOLUTION OF STARVATION RESISTANCE IN DROSOPHILA MELANOGASTER: ASPECTS OF METABOLISM AND COUNTER-IMPACT SELECTION. AB - An artificial selection experiment for increased female starvation resistance employed five selected lines and five control lines of Drosophila melanogaster. Females responded to selection within the first five generations, but a substantial male response was not observed until starvation resistance was assessed at generation 15. By measuring respiration rate in selected and control lines, it was possible to test the hypothesis that reduced metabolic rate is a general mechanism for stress resistance. There was no association between starvation resistance and respiration rate and thus no support for the hypothesis. Studies using vertebrates have shown that starvation causes a decrease in intermediary metabolism enzyme activity, but this relationship is not well documented in invertebrates. In the present study, intermediary metabolism enzyme activities decreased in response to starvation in control-line females and males, and in selected-line males. However, the selected females showed no overall decrease in enzyme activities in response to starvation. One interpretation is that selected females evolved to resist the phenotypic impact of stress. The concept of "counter-impact selection" is discussed in relationship to the use of phenotypic manipulations for the study of evolution. PMID- 28565327 TI - RECENT BOOKS IN PRINT. PMID- 28565326 TI - PATTERNS OF POSTZYGOTIC ISOLATION IN FROGS. AB - From literature data on 116 taxa crosses involving 46 species of frogs, we found a positive correlation between degree of divergence (measured as Nei's genetic distance, D) and degree of postzygotic isolation. In anurans, hybrid sterility appears to evolve more quickly than inviability, which is consistent with the conclusions of other studies that involved Drosophila species. The lower threshold of D = 0.30 for evolution of hybrid inviability that we found is similar to that observed for Drosophila. This consistency suggests that there may be a general pattern in the acquisition of reproductive isolation in animals. PMID- 28565328 TI - A SPATIALLY EXPLICIT STOCHASTIC MODEL DEMONSTRATES THE FEASIBILITY OF WRIGHT'S SHIFTING BALANCE THEORY. AB - Recently there has been a resurgence of theoretical papers exploring Wright's Shifting Balance Theory (SBT) of evolution. The SBT explains how traits which must pass through an adaptive valley may evolve in substructured populations. It has been suggested that Phase III of the SBT (the spread of new advantageous traits through the populations) proceeds only under a very restricted set of conditions. We show that Phase III can proceed under a much broader set of conditions in models that properly incorporate a key feature of Wright's theory: local, random migration of discrete individuals. PMID- 28565329 TI - GENETIC STRUCTURE AND EVOLUTION OF SPECIES IN THE MANGROVE GENUS AVICENNIA (AVICENNIACEAE) IN THE INDO-WEST PACIFIC. AB - Allozyme variation in species of the mangrove genus Avicennia was screened in 25 populations collected from 22 locations in the Indo-West Pacific and eastern North America using 11 loci. Several fixed gene differences supported the specific status of Avicennia alba, A. integra, A. marina, and A. rumphiana from the Indo-West Pacific, and A. germinans from the Atlantic-East Pacific. The three varieties of A. marina, var. marina, var. eucalyptifolia, and van australasica, had higher genetic similarities (Nei's I) and no fixed gene differences, confirming their conspecific status. Strong genetic structuring was observed in A. marina, with sharp changes in gene frequencies at the geographical margins of varietal distributions. The occurrence of alleles found otherwise in only one variety, in only immediately adjacent populations of another variety, provided evidence of introgession between varieties. The varieties appear to have diverged recently in the Pleistocene and are apparently not of ancient Cretaceous origin, as suggested earlier. Despite evidence of high degrees of outcrossing, gene flow among populations was relatively low (Ne m < 1-2), except where populations were geographically continuous, questioning assumptions that these widespread mangrove species achieve high levels of long-distance dispersal. PMID- 28565330 TI - IS SPECIALIZATION A DEAD END? THE PHYLOGENY OF HOST USE IN DENDROCTONUS BARK BEETLES (SCOLYTIDAE). AB - Ecological explanations for the prevalence of resource specialists are abundant, whereas phylogenetic evidence on their origins is scarce. In this paper, we provide a molecular phylogenetic study of the 19 specialist or generalist species in the bark beetle genus Dendroctonus, which collectively attack species in four different genera in the conifer family Pinaceae. Given substantial variation in diet breadth, we asked two general questions concerning the evolution of resource use in this group. How conservative is the evolution of host use in these insects? Does specialization tend to be derived (i.e., a "dead end")? To answer these questions, we estimated the phylogeny of Dendroctonus using mitochondrial DNA sequences and mapped transitions in resource use on the resulting phylogeny estimate. The evolution of affiliations with Pinus and Picea hosts in Dendroctonus was conservative among beetle species (PTP test; P < 0.012), but there was no significant correspondence between the phylogeny of these beetles and the phylogeny among their Pinaceae hosts (among genera, P = 0.28; among Pinus species, P = 0.82). Degree of specialization, as measured in the proportion of hosts used, was bimodally distributed with "generalist" species utilizing < 60% of the congeneric hosts within their range and six specialist species utilizing < 40% of the available hosts. Among the generalists, we found a strong correlation between the number of hosts encountered and the number of hosts utilized (R = 0.97, P < 0.0001), whereas there was no significant correlation among the specialists (R = 0.27, P = 0.59). The evolution of specialization in Dendroctonus proved highly labile-specialists arose from generalists at least six separate times (without reversal) all in derived positions, and closer examination of some specialists revealed instances where they appear to have lost particular host species from their diet. However, evidence from the ecological literature also suggests that several Dendroctonus generalists may have increased their range of host genera within the Pinaceae. PMID- 28565331 TI - PHOSPHOGLUCONATE DEHYDROGENASE POLYMORPHISM AND SALINITY IN THE WHITE SANDS PUPFISH. AB - The phosphogluconate dehydrogenase (Pgdh) locus is the only polymorphic allozyme locus observed among 37 loci examined in all four populations of a New Mexico state Endangered species, the White Sands pupfish (Cyprinodon tularosa). We report evidence suggesting that this polymorphism may be associated with salinity. Salinity levels vary widely within and between habitats occupied by White Sands pupfish. The frequency of the Pgdh100 allozyme was correlated with salinity but not with temperature. Frequency of Pgdh100 differed between low (3.76 parts per thousand (ppt)) and high (9.23 ppt) salinity sites at Malpais Spring despite no obvious barriers to fish movement. Frequencies of Pgdh100 in two introduced populations differed from that of the presumptive founding stock and correlated with salinity in the current habitats. PMID- 28565332 TI - PERSPECTIVE: THE THEORIES OF FISHER AND WRIGHT IN THE CONTEXT OF METAPOPULATIONS: WHEN NATURE DOES MANY SMALL EXPERIMENTS. AB - We critically review the two major theories of adaptive evolution developed early in this century, Wright's shifting balance theory and Fisher's large population size theory, in light of novel findings from field observations, laboratory experiments, and theoretical research conducted over the past 15 years. Ecological studies of metapopulations have established that the processes of local extinction and colonization of demes are relatively common in natural populations of many species and theoretical population genetic models have shown that these ecological processes have genetic consequences within and among local demes. Within demes, random genetic drift converts nonadditive genetic variance into additive genetic variance, increasing, rather than limiting, the potential for adaptation to local environments. For this reason, the genetic differences that arise by drift among demes, can be augmented by local selection. The resulting adaptive differences in gene combinations potentially contribute to the genetic origin of new species. These and other recent findings were not discussed by either Wright or Fisher. For example, although Wright emphasized epistatic genetic variance, he did not discuss the conversion process. Similarly, Fisher did not discuss how the average additive effect of a gene varies among demes across a metapopulation whenever there is epistasis. We discuss the implications of such recent findings for the Wright-Fisher controversy and identify some critical open questions that require additional empirical and theoretical study. PMID- 28565333 TI - TESTS OF PHYLOGEOGRAPHIC MODELS WITH NUCLEAR AND MITOCHONDRIAL DNA SEQUENCE VARIATION IN THE STONE CRABS, MENIPPE ADINA AND MENIPPE MERCENARIA. AB - Evolutionary relationships among stone crabs (Menippe) from the Gulf of Mexico and western Atlantic were investigated by comparisons of restriction sites within anonymous nuclear DNA sequences and nucleotide sequences of both mitochondrial and a duplicated nuclear form of the mitochondrial large subunit ribosomal RNA (LSrDNA) gene. A survey of over 100 restriction sites by Southern blot analysis with 10 anonymous nuclear DNA sequence probes failed to reveal any differences between Menippe adina and M. mercenaria. Sequence comparisons of both mitochondrial and nuclear forms of the LSrDNA gene also did not distinguish these species. Although both LSrDNA gene sequences were variable, some haplotypes were shared by the two species, implying either incomplete gene lineage sorting or introgressive hybridization. Based on molecular clock calibrations, we estimate that all of the observed mitochondrial LSrDNA sequences share a common ancestor between 1.5 and 2.7 million years before present (M.Y.B.P.). However, because identical sequences are shared by the two species, these data are also compatible with a more recent common ancestry. These findings conflict with a previously proposed biogeographic scenario for North American Menippe, which featured a relict hybrid zone on the Atlantic Coast. We suggest an alternative scenario based on relatively recent events and ongoing, rather than historical, gene flow. PMID- 28565334 TI - MOLECULAR GENETIC DISSECTION OF SPAWNING, PARENTAGE, AND REPRODUCTIVE TACTICS IN A POPULATION OF REDBREAST SUNFISH, LEPOMIS AURITUS. AB - Despite a great diversity of reproductive behaviors in fishes, few studies have examined the genetic consequences of alternative reproductive tactics. Here we develop and employ microsatellite markers to assess genetic paternity and maternity of progeny cohorts in a population of redbreast sunfish (Lepomis auritus), a species in which males build and tend nests. Nearly 1000 progeny from 25 nests, plus nest-attendant males and nearby adults, were genotyped at microsatellite loci that displayed more than 18 alleles each. The genetic data demonstrate that multiple females (at least two to six) spawned in each nest, their offspring were spatially dispersed across a nest, and more than 90% of the young were sired by the attendant male. However, about 40% of the nests also showed genetic evidence of low-level reproductive parasitism, and two nests were tended by males that had fathered none of the sampled offspring. Genetically deduced reproductive behaviors in this population of redbreast sunfish contrast with those reported previously in bluegill sunfish (L. macrochirus) wherein heteromorphic males specialized for parasitism or for parental care coexist in high frequency. Thus, nest-parasitic reproductive behaviors in fishes appear to be evolutionary labile. PMID- 28565335 TI - PAIRWISE VERSUS DIFFUSE NATURAL SELECTION AND THE MULTIPLE HERBIVORES OF SCARLET GILIA, IPOMOPSIS AGGREGATA. AB - Recent theoretical studies have argued that plant-herbivore coevolution proceeds in a diffuse rather than a pairwise manner in multispecies interactions when at least one of two conditions are met: (1) genetic correlations exist between plant resistances to different herbivore species; and (2) ecological interactions between herbivores sharing a host plant cause nonadditive impacts of herbivory on plant fitness. We present results from manipulative field experiments investigating the single and interactive fitness effects of three types of herbivory on scarlet gilia (Ipomopsis aggregata) over two years of study. We utilize these data to test whether selection imposed by herbivore attack on date of first flowering is pairwise (independent) or diffuse (dependent) in nature. Our results reveal complex patterns of the fitness effect of herbivores. Simulated early season browsing had a strong negative fitness effect on plants and also reduced subsequent insect attack. Surprisingly, this ecological interaction did not translate into significant interactions between clipping and insect manipulations on plant fitness. However, we detected a significant interaction between seed fly and caterpillar herbivory on plant fitness, with the negative effect of either insect being greatest when occurring alone. These results suggest that herbivore-imposed selection may have pairwise and diffuse components. In our selection analysis of flowering phenology, we discovered significant pairwise linear selection imposed by clipping, diffuse linear selection imposed by insects, and diffuse nonlinear selection imposed by clipping and insect attack acting simultaneously. Our results reveal that the evolution of flowering phenology in scarlet gilia may be in response to diffuse and pairwise natural selection imposed by multiple herbivores. We discuss the evolution of resistance characters in light of diffuse versus pairwise forms of linear and nonlinear selection and stress the complexity of selection imposed by suites of interacting species. PMID- 28565336 TI - POLLEN TRANSFER BY NATURAL HYBRIDS AND PARENTAL SPECIES IN AN IPOMOPSIS HYBRID ZONE. AB - Models of hybrid zones differ in their assumptions about the relative fitnesses of hybrids and the parental species. These fitness relationships determine the form of selection across the hybrid zone and, along with gene flow, the evolutionary dynamics and eventual outcome of natural hybridization. We measured a component of fitness, export and receipt of pollen in single pollinator visits, for hybrids between the herbaceous plants Ipomopsis aggregata and I. tenuituba and for both parental species. In aviary experiments with captive hummingbirds, hybrid flowers outperformed flowers of both parental species by receiving more pollen on the stigma. Although hummingbirds were more effective at removing pollen from anthers of I. aggregata, hybrid flowers matched both parental species in the amount of pollen exported to stigmas of other flowers. These patterns of pollen transfer led to phenotypic stabilizing selection, during that stage of the life cycle, for a stigma position intermediate between that of the two species and to directional selection for exserted anthers. Pollen transfer between the species was high, with flowers of I. aggregata exporting pollen equally successfully to conspecific and I. tenuituba flowers. Although this study showed that natural hybrids enjoy the highest quality of pollinator visits, a previous study found that I. aggregata receives the highest quantity of pollinator visits. Thus, the relative fitness of hybrids changes over the life cycle. By combining the results of both studies, pollinator-mediated selection in this hybrid zone is predicted to be strong and directional, with hybrid fitness intermediate between that of the parental species. PMID- 28565337 TI - SELECTION ON A FLORAL COLOR POLYMORPHISM IN THE COMMON MORNING GLORY (IPOMOEA PURPUREA): THE EFFECTS OF OVERDOMINANCE IN SEED SIZE. PMID- 28565338 TI - EXTRAPAIR PATERNITY AND THE EFFECTIVE SIZE OF SOCIALLY MONOGAMOUS POPULATIONS. PMID- 28565339 TI - THE OCCURRENCE AND SIGNIFICANCE OF EPISTATIC VARIANCE FOR QUANTITATIVE CHARACTERS AND ITS MEASUREMENT IN HAPLOIDS. AB - Epistatic genetic variance for quantitative traits may play an important role in evolution, but detecting epistasis in diploid organisms is difficult and requires complex breeding programs and very large sample sizes. We develop a model for detecting epistasis in organisms with a free-living haploid stage in their life cycles. We show that epistasis is indicated by greater variance among families of haploid progeny derived from individual diploids than among clonally replicated haploid sibs from the same sporophyte. Simulations show that the power to detect epistasis is linearly related to the number of sporophytes and the number of haploids per sporophyte in the dataset. We illustrate the model with data from growth variation among gametophytes of the moss, Ceratodon purpureus. The experiment failed to detect epistatic variance for biomass production, although there was evidence of additive variance. PMID- 28565340 TI - EVOLUTION OF THE GENETIC ARCHITECTURE UNDERLYING FITNESS IN THE PITCHER-PLANT MOSQUITO, WYEOMYIA SMITHII. AB - We examined the genetic basis for evolutionary divergence among geographic populations of the pitcher-plant mosquito, Wyeomyia smithii, using protein electrophoresis and line-cross analysis. Line-cross experiments were performed under both low density, near-optimal conditions, and at high, limiting larval densities sufficient to reduce fitness (rc ) in parental populations by approximately 50%. We found high levels of electrophoretic divergence between ancestral and derived populations, but low levels of divergence between two ancestral populations and between two derived populations. Assessed under near optimal conditions, the genetic divergence of fitness (rc ) between ancestral and derived populations, but not between two derived populations or between two ancestral populations, has involved both allelic (dominance) and genic (epistatic) interactions. The role of dominance and epistasis in the divergence of rc among populations affects its component traits in a pattern that is unique to each cross. Patterns of genetic differentiation among populations of W. smithii provide evidence for a topographically complex "adaptive landscape" as envisioned by Wright in his "shifting balance" theory of evolution. Although we cannot definitively rule out the role of deterministic evolution in the divergence of populations on this landscape, ecological inference and genetic data are more consistent with a stochastic than a deterministic process. At high, limiting larval density, hybrid vigor is enhanced and the influence of epistasis disappears. Thus, under stressful conditions, the advantages to fitness due to hybrid heterozygosity can outweigh the deleterious effects of fragmented gene complexes. These results have important implications for the management of inbred populations. Outbreeding depression assessed in experimental crosses under benign lab, zoo, or farm conditions may not accurately reveal the increased advantages of heterozygosity in suboptimal or marginal conditions likely to be found in nature. PMID- 28565341 TI - AN EXPERIMENTAL STUDY OF PATERNITY AND TAIL ORNAMENTATION IN THE BARN SWALLOW (HIRUNDO RUSTICA). AB - Previous studies of the socially monogamous barn swallow (Hirundo rustica) have shown that males that most frequently engage in extrapair copulations and whose partners are least involved in copulations with extrapair males are those with long tail ornaments. In this study, through the use of three highly polymorphic microsatellite markers, we analyze the relationships between length of tail ornaments of male barn swallows and proportion of nestlings fathered in own broods, number of offspring fathered in broods of other pairs, and total number of offspring fathered, using both a correlational and an experimental approach. Consistent with our predictions, we show that males with either naturally long or experimentally elongated tails have higher paternity (proportion of biological offspring in own broods), and they produce more biological offspring during the whole breeding season than males with naturally short or experimentally shortened tails. Males with naturally long tails also had more offspring in extrapair broods than short-tailed males, but the effect of tail manipulation on the number of offspring fathered in extrapair broods, although being in the predicted direction, was not statistically significant. Cuckolded males that did not fertilize extrapair females had smaller postmanipulation tail length than cuckolders. We conclude that there is a causal, positive relationship between male tail length and paternity. Since female barn swallows have extensive control over copulation partners and heritability of tail length is high, this study shows that female choice is a component of selection for larger male ornaments. Benefits from extrapair fertilizations to females may arise because they acquire "good" genes for sexual attractiveness or high viability for their offspring. PMID- 28565342 TI - BERGMANN'S RULE IN ECTOTHERMS: IS IT ADAPTIVE? PMID- 28565343 TI - ANTHER SMUT DISEASE IN DIANTHUS SILVESTER (CARYOPHYLLACEAE): NATURAL SELECTION ON FLORAL TRAITS. AB - Mating opportunities, pollination intensity, and pollen dispersal ability may vary with variation in floral traits such as color, size, and shape. Where these traits are selected by pollinators for enhanced elaboration, they should evolve toward the equilibrium between selection for further elaboration and selection against this through reduced fecundity or vitality. Here we show that pollinator borne fungal diseases of plants may be a factor influencing the position of this equilibrium. Populations of the rock pink, Dianthus silvester often contain individuals infected with the anther smut fungus Microbotryum violaceum (= Ustilago violacea). In a naturally infected population in the Alps of eastern Switzerland we investigated how intrapopulation variation in flower size and nectar rewards influenced spore deposition and how floral traits varied with disease status. We found that spore deposition increased with increasing petal size, suggesting that large-flowered plants were at a greater risk of disease. Spore deposition was also higher for plants growing in patches with many or a high proportion of diseased neighbors. Multiple regression analyses showed that petal size or nectar reward influenced spore deposition when the effects of neighborhood disease abundance were controlled statistically. In sequential analyses, after removing the effects of disease density or frequency and plant gender, petal length explained significant variation in spore deposition. Diseased plants had reduced female reproductive organs, but calyx size was intermediate between that of healthy perfect and female flowers of this gynodioecious-gynomonoecious species, and diseased plants bore flowers with the largest petals. This may reflect a symptom of this disease or the cause, if larger-flowered plants are more likely to become infected. We conclude that investment to pollinator attraction may bring an enhanced risk of contracting this sterilizing pollinator-borne disease, so natural selection by the fungus M. violaceum acts to lower attractiveness to pollinators. PMID- 28565344 TI - CAN A PATCHY POPULATION STRUCTURE AFFECT THE EVOLUTION OF COMPETITION STRATEGIES? AB - Simulation models are described that examine the effect of a patchy population structure on the evolution of competition strategies. The results of the models suggest that a patchy population structure will make the evolution of scramble competition strategies more likely than in a single undivided population. The outcome of the models depends on the details of the population structure, in particular the number of individuals that found patches, the number of generations of competition within a patch, and the point at which founding females mate can all affect the evolutionary outcome. The results of the models are compared to those of previous models examining the effects of a structured population on the evolution of female-biased sex ratios, and altruistic behavior. The results of the model may help to explain the patterns of larval competition strategies observed in bruchid beetles. PMID- 28565345 TI - TESTING FOR HOMOGENEITY OF GAMETIC DISEQUILIBRIUM AMONG POPULATIONS. PMID- 28565346 TI - DENSITY-DEPENDENT NATURAL SELECTION IN DROSOPHILA: EVOLUTION OF GROWTH RATE AND BODY SIZE. AB - Drosophila melanogaster populations subjected to extreme larval crowding (CU lines) in our laboratory have evolved higher larval feeding rates than their corresponding controls (UU lines). It has been suggested that this genetically based behavior may involve an energetic cost, which precludes natural selection in a density-regulated population to simultaneously maximize food acquisition and food conversion into biomass. If true, this stands against some basic predictions of the general theory of density-dependent natural selection. Here we investigate the evolutionary consequences of density-dependent natural selection on growth rate and body size in D. melanogaster. The CU populations showed a higher growth rate during the postcritical period of larval life than UU populations, but the sustained differences in weight did not translate into the adult stage. The simplest explanation for these findings (that natural selection in a crowded larval environment favors a faster food acquisition for the individual to attain the same final body size in a shorter period of time) was tested and rejected by looking at the larva-to-adult development times. Larvae of CU populations starved for different periods of time develop into comparatively smaller adults, suggesting that food seeking behavior in a food depleted environment carries a higher cost to these larvae than to their UU counterparts. The results have important implications for understanding the evolution of body size in natural populations of Drosophila, and stand against some widespread beliefs that body size may represent a compromise between the conflicting effects of genetic variation in larval and adult performance. PMID- 28565347 TI - A POPULATION GENETIC THEORY OF CANALIZATION. AB - Canalization is the suppression of phenotypic variation. Depending on the causes of phenotypic variation, one speaks either of genetic or environmental canalization. Genetic canalization describes insensitivity of a character to mutations, and the insensitivity to environmental factors is called environmental canalization. Genetic canalization is of interest because it influences the availability of heritable phenotypic variation to natural selection, and is thus potentially important in determining the pattern of phenotypic evolution. In this paper a number of population genetic models are considered of a quantitative character under stabilizing selection. The main purpose of this study is to define the population genetic conditions and constraints for the evolution of canalization. Environmental canalization is modeled as genotype specific environmental variance. It is shown that stabilizing selection favors genes that decrease environmental variance of quantitative characters. However, the theoretical limit of zero environmental variance has never been observed. Of the many ways to explain this fact, two are addressed by our model. It is shown that a "canalization limit" is reached if canalizing effects of mutations are correlated with direct effects on the same character. This canalization limit is predicted to be independent of the strength of stabilizing selection, which is inconsistent with recent experimental data (Sterns et al. 1995). The second model assumes that the canalizing genes have deleterious pleiotropic effects. If these deleterious effects are of the same magnitude as all the other mutations affecting fitness very strong stabilizing selection is required to allow the evolution of environmental canalization. Genetic canalization is modeled as an influence on the average effect of mutations at a locus of other genes. It is found that the selection for genetic canalization critically depends on the amount of genetic variation present in the population. The more genetic variation, the stronger the selection for canalizing effects. All factors that increase genetic variation favor the evolution of genetic canalization (large population size, high mutation rate, large number of genes). If genetic variation is maintained by mutation-selection balance, strong stabilizing selection can inhibit the evolution of genetic canalization. Strong stabilizing selection eliminates genetic variation to a level where selection for canalization does not work anymore. It is predicted that the most important characters (in terms of fitness) are not necessarily the most canalized ones, if they are under very strong stabilizing selection (k > 0.2Ve ). The rate of decrease of mutational variance Vm is found to be less than 10% of the initial Vm . From this result it is concluded that characters with typical mutational variances of about 10-3 Ve are in a metastable state where further evolution of genetic canalization is too slow to be of importance at a microevolutionary time scale. The implications for the explanation of macroevolutionary patterns are discussed. PMID- 28565348 TI - COSTS AND BENEFITS OF MOSQUITO REFRACTORINESS TO MALARIA PARASITES: IMPLICATIONS FOR GENETIC VARIABILITY OF MOSQUITOES AND GENETIC CONTROL OF MALARIA. AB - The problem of fitness costs associated with host resistance to parasitism is related to the evolution of parasite virulence, population genetic diversity and the dynamics of host-parasite relationships, and proposed strategies for disease control through the genetic manipulation of mosquito vectors. Two Aedes aegypti populations, refractory and susceptible to Plasmodium gallinaceum, were previously selected from the Moyo-In-Dry strain (MOYO) through inbreeding (F = 0.5). Reproductive success and survivorship of the two populations were compared, and the influence of the parasite on mosquito fitness also was evaluated. Fitness components studied include fecundity, adult survivorship and egg-to-adult developmental time, blood-meal size, and adult body size. The refractory population has a significantly shorter egg-to-adult developmental time and a smaller body size, takes a smaller blood meal, and subsequently lays fewer eggs than the susceptible population. The mean longevity of the refractory population is significantly shorter than the susceptible population. Exposure to the parasite exhibited little effect on the survivorship and fecundity of either population. Several factors may contribute to the lower fitness of the refractory population, including founder effect, inbreeding depression, the effect of other uncharacterized genes linked to genes conferring refractoriness, and pleiotropic effects associated with these genes. The results are discussed in relation to the genetic diversity of natural mosquito populations and their implications for the genetic control of malaria. PMID- 28565349 TI - EVOLUTION OF BREEDING DISTRIBUTIONS IN THE OLD WORLD LEAF WARBLERS (GENUS PHYLLOSCOPUS). AB - Among Palearctic warblers of the genus Phylloscopus those species that breed farther north occupy larger geographical ranges than those which breed farther south (Rapoport's rule). We suggest that much of this pattern is a consequence of the differential ability of species to occupy areas rendered inhospitable during the Pleistocene. In support of this suggestion, the midpoint of breeding range in a north-south direction has been an exceptionally labile trait through evolutionary time. Comparisons of ecological attributes of those species breeding in the Himalayas with close relatives in Siberia implies a role for habitat tracking in determining which species have been able to colonize northern areas; hypotheses based on climate and climatic variability have less support. In addition there is a likely role for geographic barriers and/or biotic interactions in preventing some taxa from spreading from small southern ranges. PMID- 28565350 TI - ECTOTHERMS FOLLOW THE CONVERSE TO BERGMANN'S RULE. PMID- 28565351 TI - GENETIC AND ENVIRONMENTAL VARIATION IN LIFE-HISTORY TRAITS OF A MONOCARPIC PERENNIAL: A DECADE-LONG FIELD EXPERIMENT. AB - Directional and stabilizing selection tend to deplete additive genetic variance. On the other hand, genetic variance in traits related to fitness could be retained through polygenic mutation, spatially varying selection, genotype environment interaction, or antagonistic pleiotropy. Most estimates of genetic variance in fitness-related traits have come from laboratory studies, with few estimates of heritability made under natural conditions, particularly for longer lived organisms. Here I estimated additive genetic variance in life-history characters of a monocarpic herb, Ipomopsis aggregata, that lives for up to a decade. Experimental crosses yielded 229 full-sibships nested within 32 paternal half-sibships. More than 5000 offspring were planted as seeds into natural field sites and were followed in most cases through their entire life cycle. Survival showed substantial additive genetic variance (genetic coefficient of variation ~ 54%). Small differences at seedling emergence were magnified over time, such that the genetic variability in survival was only detectable by tracking the success of offspring for several years starting from seed. In contrast to survival, reproductive traits such as flower number, seeds per flower, and age at flowering showed little or no genetic variability. Despite relatively high levels of additive genetic variation for some life-history characters, high environmental variance in survival resulted in very low heritabilities (0-9%) for all of these characters. Maternal effects were evident in seed mass and remained strong throughout the lengthy vegetative period. No negative genetic correlations between major components of female fitness were detected. Mean corolla width for a paternal family was, however, negatively correlated with the finite rate of increase based on female fitness. That negative correlation could help to maintain additive genetic variance in the face of strong selection through male function for wide corollas. PMID- 28565352 TI - MICROSATELLITES REVEAL HIGH POPULATION VISCOSITY AND LIMITED DISPERSAL IN THE ANT FORMICA PARALUGUBRIS. AB - We used microsatellites to study the fine-scale genetic structure of a highly polygynous and largely unicolonial population of the ant Formica paralugubris. Genetic data indicate that long-distance gene flow between established nests is limited and new queens are primarily recruited from within their natal nest. Most matings occur between nestmates and are random at this level. In the center of the study area, budding and permanent connections between nests result in strong population viscosity, with close nests being more similar genetically than distant nests. In contrast, nests located outside of this supercolony show no isolation by distance, suggesting that they have been initiated by queens that participated in mating flights rather than by budding from nearby nests in our sample population. Recruitment of nestmates as new reproductive individuals and population viscosity in the supercolony increase genetic differentiation between nests. This in turn inflates relatedness estimates among worker nestmates (r = 0.17) above what is due to close pedigree links. Local spatial genetic differentiation may favor the maintenance of altruism when workers raise queens that will disperse on foot and compete with less related queens from neighboring nests or disperse on the wing and compete with unrelated queens. PMID- 28565353 TI - VARIABILITY OF A VESTIGIAL STRUCTURE: FIRST METACARPAL IN COLOBUS GUEREZA AND ATELES GEOFFROYI. AB - A tenet of evolutionary theory is that, under conditions of stabilizing selection, phenotypic variability is inversely related to selection intensity. Correspondingly, a nonfunctional, vestigial structure is expected to be highly variable relative to its functional homologue. This study tests the hypothesis that species with a vestigial pollex, Colobus guereza and Ateles geoffroyi, have a first metacarpal whose length is both highly variable relative to, and poorly correlated with, the lengths of the other metapodials. The results are consistent with the hypothesis, though this combination of traits is also found in Presbytis rubicunda and Presbytis cristata. The latter two species have functional, albeit miniature, pollices. This study also demonstrates a general, inverse relationship among anthropoid primates between relative length of the first metapodial and its relative variability. These results suggest that elevated variability accompanies structural reduction. PMID- 28565354 TI - STATISTICAL TESTS OF HOST-PARASITE COSPECIATION. AB - A history of cospeciation (synchronous speciation) among ecologically associated, but otherwise distantly related, species is often revealed by a strong correspondence of their phylogenies. In this paper, we present several tests of cospeciation that use maximum-likelihood and Bayesian methods of phylogenetic estimation. The hypotheses tested include: (1) topological agreement of phylogenies for coevolving groups; (2) identical speciation times of associated species; and (3) identical evolutionary rates in genes of associated species. These tests are applied to examine a possible instance of host-parasite coevolution among pocket gophers and lice using mitochondrial COI DNA sequences. The observed differences between gopher and louse trees cannot be explained by sampling error and are consistent with a rate of host switching about one-third the host speciation rate. A subset of the gopher-louse data is consistent with a common history of evolution (i.e., the topologies and speciation times are identical). However, the relative rate of nucleotide substitution is two to four times higher in the lice than in the gophers. PMID- 28565355 TI - LOCAL CYTONUCLEAR EXTINCTION OF THE GOLDEN-WINGED WARBLER. AB - I compared the mtDNA compositions of two adjacent populations of Vermivora chrysoptera (golden-winged warbler) at different stages of transient hybridization with its sister species V. pinus (blue-winged warbler). Pinus mtDNA introgresses asymmetrically and perhaps rapidly into chrysoptera phenotypes without comparable reverse introgression of chrysoptera mtDNA into replacing pinus populations. Pinus mtDNA was virtually fixed (98%) in an actively hybridizing lowland population with varied phenotypes. Pinus mtDNA increased from 27% (n = 11) in 1988 to 70% (n = 10) in 1992 in successive samples of a highland population in the initial stages of hybridization. This population comprised mostly pure and slightly introgressed chrysoptera phenotypes. The rapid pace of asymmetrical introgression may be the result of initial invasion of chrysoptera populations by pioneering female pinus and/or an unknown competitive advantage of pinus females and their daughters over chrysoptera females. PMID- 28565356 TI - MITOCHONDRIAL DNA PHYLOGENIES FOR THE DROSOPHILA OBSCURA GROUP. AB - Species belonging to the obscura group of the genus Drosophila have long held a central position in evolutionary studies, especially in experimental population genetics. Despite the considerable amount of accumulated knowledge, many of the phylogenetic relationships of the species in the group remain unclear. Here we present DNA sequence data for the mitochondrial gene cytochrome oxidase I (COI) for 13 species native to both the Old and New Worlds. We combine these data with seven other mitochondrial gene sequences from previous studies, for a total of over 3 kb per species. Strongly supported conclusions include: (1) the two North American subgroups, pseudoobscura and affinis, are each monophyletic; and (2) among Eurasian species two unambiguous clades are identified, one containing D. tristis, D. ambigua, and D. obscura and the other containing D. guanche, D. subobscura, and D. madeirensis. Constructing firm hypotheses connecting these four major clades is problematic with all datasets. Major ambiguities are the number of invasions giving rise to the North American obscura species and the relationships among the Eurasian species. The inadequacy of the mtDNA data to resolve these ambiguities does not reside in lack of changes; the transversions only parsimony tree has 283 informative characters. Rather, the problems are likely intrinsic to the history of the group: while radiating in temperate Eurasia, North America was colonized once or twice, followed by one or two radiations in the New World. PMID- 28565357 TI - A PERFORMANCE CONSTRAINT ON THE EVOLUTION OF TRILLED VOCALIZATIONS IN A SONGBIRD FAMILY (PASSERIFORMES: EMBERIZIDAE). AB - Behavioral evolution can be influenced by constraints, for example, of phylogeny and performance. In this paper I describe a pattern in the evolution of birdsongs that may reflect a constraint on vocal performance. Trilled vocalizations from 34 species of songbirds (Passeriformes: Emberizidae) were analyzed. Two acoustic variables, trill rate and frequency bandwidth, were measured for different trill types. In most species, maximal values of frequency bandwidth were found to decrease with increasing trill rates. Further, trills with low trill rates exhibited wide variance in frequency bandwidth, and trills with high trill rates exhibited only narrow frequency bandwidths. The bounded nature of this pattern suggests that performance constraints have limited the evolutionary diversification of trills. In particular, I explore the role of constraints associated with vocal tract modulations during song production and evolution. Identification of this constraint may enhance our ability to explain particular patterns of trill evolution. PMID- 28565358 TI - MITOCHONDRIAL-GENE TREES VERSUS NUCLEAR-GENE TREES, A REPLY TO HOELZER. PMID- 28565359 TI - THE RELATIONSHIP BETWEEN MATING-SYSTEM CHARACTERS AND INBREEDING DEPRESSION IN MIMULUS GUTTATUS. AB - Several recent theoretical considerations of mating-system evolution predict within-population covariation between levels of inbreeding depression and genetically controlled mating-system characters. If inbreeding depression is caused by deleterious recessive alleles, families with characters that promote self-pollination should show lower levels of inbreeding depression than families with characters that promote outcrossing. The converse is expected if inbreeding depression is due to overdominant allelic interactions. Whether these associations between mating-system and viability loci evolve will have important consequences for mating-system evolution. The evolution of selfing within the genus Mimulus is associated with a reduction in stigma-anther separation (i.e., a loss of herkogamy) and high autogamous seed set. In this study we compared families from two M. guttatus populations that differed genetically in their degree of stigma-anther separation. In one of these populations we also compared families that differed genetically in the degree to which they autogamously set seed in a pollinator-free greenhouse. Dams often differed significantly in levels of inbreeding depression for aboveground biomass and flower production, but variation in inbreeding depression was never explained by herkogamy class or autogamy class. Several factors might account for why families with traits associated with selfing did not show lower inbreeding depression, and these are discussed. Our study also demonstrated significant variation among self progeny from a given female likely due to differences in pollination date and position of fruit maturation. The detection of significant dam * sire interactions suggests biparental inbreeding or differences in combining ability for specific pairs of parents. PMID- 28565360 TI - SEXUAL SIZE DIMORPHISM AND SELECTION IN THE WILD IN THE WATERSTRIDER AQUARIUS REMIGIS: LIFETIME FECUNDITY SELECTION ON FEMALE TOTAL LENGTH AND ITS COMPONENTS. AB - Darwin's fecundity advantage model is often cited as the cause of female biased size dimorphism, however, the empirical studies of lifetime selection on male and female body size that would be required to demonstrate this are few. As a component of a study relating sexual size dimorphism to lifetime selection in natural populations of the female size-biased waterstrider Aquarius remigis (Hemiptera: Gerridae), we estimated coefficients for daily fecundity selection, longevity selection, and lifetime fecundity selection acting on female body size and components of body size for two consecutive generations. Daily fecundity was estimated using females confined in field enclosures and reproductive survival was estimated by twice-weekly recaptures. We found that daily fecundity selection favored females with longer total length through direct selection acting on abdomen length. Longevity selection favored females with smaller total length. When daily fecundity and reproductive longevity were combined to estimate lifetime fecundity we found significant balancing selection acting on total length in both years. The relationship between daily fecundity and reproductive longevity also reveals a significant cost of reproduction in one of two years. We relate these selection estimates to previous estimates of sexual selection on male body size and consider the relationship between contemporary selection and sexual size dimorphism. PMID- 28565361 TI - PHYLOGENETIC ANALYSIS OF PHENOTYPIC COVARIANCE STRUCTURE. II. RECONSTRUCTING MATRIX EVOLUTION. AB - A modified minimum evolution approach is used to estimate covariance matrices for hypothetical ancestors. Branch lengths are calculated as the mean disparity in corresponding ancestor-descendent covariances. Branches are longest leading to terminal populations and subspecies, while interspecific branches are relatively short, indicating a general conservation of covariance structure among species despite a high degree of intraspecific variability. Absolute deviations in covariance structure are not correlated with phenotypic divergence. Interpreted in light of other studies, the analyses suggest that deviations in covariance structure are most strongly associated with the formation of diagnosably distinct taxa and stochastic sampling of genotypes at the population level. There is no evidence for restructuring of phenotypic covariance structure in association with reproductive isolation. The results suggest that phenotypic covariances are dynamic over short time scales and do not support attempts to extrapolate genetic covariance structure to explain or predict macroevolutionary change. This study further demonstrates that branch lengths, which are not usually analyzed in detail, contain valuable evolutionary information complementary to that residing in the branching pattern. PMID- 28565362 TI - ALLOZYME VARIATION IN A SNAIL (LITTORINA SAXATILIS)-DECONFOUNDING THE EFFECTS OF MICROHABITAT AND GENE FLOW. AB - It is commonly observed that a restricted gene flow among populations of a species generates genetic differentiation in, for example, allozyme markers. However, recent studies suggest that microhabitat-specific variation may contribute to the total differentiation. To appreciate the relative contributions of geographic variation and habitat-specific variation, we sampled 42 subpopulations of the intertidal snail Littorina saxatilis from three different microhabitats (boulders, low and high rocky intertidal) on five small islands within a distance of 15 km. We used a modified orthogonal version of Nei's gene diversity analysis with a modified analysis of variance (ANOVA) that estimated the significance of habitat and geographic separation and the interaction between them. Between subpopulation differentiation (GST ) was usually in the range of 5% to 10% but was exceptionally high in one locus (Aat; 53%). Genetic differentiation attributable to different habitats accounted for 10% to 81% (mean 35%) of the between subpopulation variation and was significant (P < 0.05) in six loci. Differentiation due to geographic separation accounted for 11% to 61% (mean 36%) and was significant (P < 0.05) in seven loci. Furthermore, three loci showed interactions between habitat and island, suggesting varying effects of habitat in different islands. Microhabitat-specific variation, probably through spatially varying fitness, seems particularly likely in Aat and Pgm-2. Moderate levels of habitat associated variation added to the observed differentiation due to gene flow in Pgi, Pnp, and Pgm-1, whereas in the remaining three loci either the habitat effect was confused by strong habitat-island interaction (Ark) or was virtually absent (Pep and Mpi). PMID- 28565363 TI - EVOLUTION OF PUFFERFISH INFLATION BEHAVIOR. AB - The evolution of the extraordinary inflation mechanism of pufferfishes was studied in the light of an independently derived phylogenetic hypothesis of tetraodontiform fishes. Inflation behavior is found in all members of the puffer sister taxa Tetraodontidae and Diodontidae. However, most other tetraodontiform fishes exhibit two functionally similar behaviors. All taxa exhibit a "coughing" behavior and, with the exception of the sister-group to all other tetraodontiforms, represented by the Triacanthidae, all lineages "blow" strong jets of water out of their mouth to excavate prey. Functional specializations associated with the three behaviors were identified from anatomical analyses and electromyographic recordings of muscle activity in representatives of the major lineages of the order. The phylogenetic distribution of the three buccal compression behaviors and their functional bases indicates the following: (1) the evolution of inflation behavior involved major structural modifications of the head that function in a novel mechanism that links depression of the floor of the mouth to posterior expansion of the buccal cavity; (2) the contraction patterns of four key head muscles used in the three behaviors are generally similar both across behaviors and taxa; (3) however, the distribution of the two significant modifications of muscle activity are consistent with the hypothesis that the three behaviors represent a transformation series from coughing to water blowing to inflation. The motor pattern for water blowing is a slightly modified version of that seen in coughing, and the inflation motor pattern retains the blowing specialization and adds a single additional modification. The convergent evolution of a poorly developed inflation behavior in at least one genus of filefish provides evidence that tetraodontiform fishes are predisposed to the evolution of this unusual defensive behavior. The presence of a well developed water-blowing behavior in most tetraodontiform lineages may represent an intermediate functional specialization that increased the probability of the evolution of inflation. PMID- 28565364 TI - THE EFFECT OF INBREEDING ON POPULATION-LEVEL GENETIC CORRELATIONS IN THE RED FLOUR BEETLE TRIBOLIUM CASTANEUM. PMID- 28565365 TI - EXPRESSION OF GENETIC VARIATION IN BODY SIZE OF THE COLLARED FLYCATCHER UNDER DIFFERENT ENVIRONMENTAL CONDITIONS. AB - Heritability of body size in two experimentally created environments, representing good and poor feeding conditions, respectively, was estimated using cross-fostered collared flycatcher Ficedula albicollis nestlings. Young raised under poor feeding conditions attained smaller body size (tarsus length) than their full-sibs raised under good feeding conditions. Parent-offspring regressions revealed lower heritability (h2 ) of body size under poor than under good feeding conditions. Hence, as the same set of parents were used in the estimation of h2 in both environments, this suggests environment-dependent change in additive genetic component of variance (VA ), or that the genetic correlation between parental and poor offspring environment was less than that between parental and good offspring environment. However, full-sib analyses failed to find evidence for genotype-environment interactions, although the power of these tests might have been low. Full-sib heritabilities in both environments tended to be higher than estimates from parent-offspring regressions, indicating that prehatching or early posthatching common environment/maternal effects might have inflated full-sib estimates of VA . The effect of sibling competition on estimates of VA was probably small as the nestling size-hierarchy at day 2 posthatch was not generally correlated with size-hierarchy at fledging. Furthermore, there was no correlation between maternal body condition during the incubation and final size of offspring, indicating that direct maternal effects related to nutritional status were small. A review of earlier quantitative genetic studies of body size variation in birds revealed that in eight of nine cases, heritability of body size was lower in poor than in good environmental conditions. The main implication of this relationship will be a decreased evolutionary response to selection under poor environmental conditions. On the other hand, this will retard the loss of genetic variation by reducing the accuracy of selection and might help explain the moderate to high heritabilities of body-size traits under good environmental conditions. PMID- 28565366 TI - INFERRING PHYLOGENIES FROM mtDNA VARIATION: MITOCHONDRIAL-GENE TREES VERSUS NUCLEAR-GENE TREES REVISITED. PMID- 28565367 TI - INCREASED PROBABILITY OF EXTINCTION DUE TO DECREASED GENETIC EFFECTIVE POPULATION SIZE: EXPERIMENTAL POPULATIONS OF CLARKIA PULCHELLA. AB - We established replicated experimental populations of the annual plant Clarkia pulchella to evaluate the existence of a causal relationship between loss of genetic variation and population survival probability. Two treatments differing in the relatedness of the founders, and thus in the genetic effective population size (Ne ), were maintained as isolated populations in a natural environment. After three generations, the low Ne treatment had significantly lower germination and survival rates than did the high Ne treatment. These lower germination and survival rates led to decreased mean fitness in the low Ne populations: estimated mean fitness in the low Ne populations was only 21% of the estimated mean fitness in the high Ne populations. This inbreeding depression led to a reduction in population survival: at the conclusion of the experiment, 75% of the high Ne populations were still extant, whereas only 31% of the low Ne populations had survived. Decreased genetic effective population size, which leads to both inbreeding and the loss of alleles by genetic drift, increased the probability of population extinction over that expected from demographic and environmental stochasticity alone. This demonstrates that the genetic effective population size can strongly affect the probability of population persistence. PMID- 28565368 TI - MEASURING PHENOTYPIC SELECTION ON AN ADAPTATION: LAMELLAE OF DAMSELFLIES EXPERIENCING DRAGONFLY PREDATION. AB - Previous studies suggest that the evolution of increased caudal lamellae size to increase swimming speed was an adaptation of Enallagma damselflies for coexisting with large, predatory dragonflies in fishless lakes. To test whether dragonfly predation still exerts selection pressures for increased lamellae size, I performed a field experiment in which I manipulated the abilities of dragonfly larvae to inflict mortality on Enallagma boreale larvae and compared differences in lamellae size and shape between treatments. In cages where dragonflies were free to forage on damselflies, surviving E. boreale larvae had lamellae that were larger in lateral surface area, and that were wider relative to their length, as compared with larvae recovered from treatments in which dragonflies were not permitted to forage on damselflies. Selection differentials of about 0.25 phenotypic standard deviation units were measured for both of these characters. These results indicate that dragonfly predation still exerts significant selection pressures on damselfly antipredator adaptations. The results of this study are discussed in the context of studies of adaptation. PMID- 28565369 TI - PHYLOGENETIC ANALYSIS OF PHENOTYPIC COVARIANCE STRUCTURE. I. CONTRASTING RESULTS FROM MATRIX CORRELATION AND COMMON PRINCIPAL COMPONENT ANALYSES. AB - Applications of quantitative techniques to understanding macroevolutionary patterns typically assume that genetic variances and covariances remain constant. That assumption is tested among 28 populations of the Phyllotis darwini species group (leaf-eared mice). Phenotypic covariances are used as a surrogate for genetic covariances to allow much greater phylogenetic sampling. Two new approaches are applied that extend the comparative method to multivariate data. The efficacy of these techniques are compared, and their sensitivity to sampling error examined. Pairwise matrix correlations of correlation matrices are consistently very high (> 0.90) and show no significant association between matrix similarity and phylogenetic relatedness. Hierarchical decomposition of common principal component (CPC) analyses applied to each clade in the phylogeny rejects the hypothesis that common principal component structure is shared in clades more inclusive than subspecies. Most subspecies also lack a common covariance structure as described by the CPC model. The hypothesis of constant covariances must be rejected, but the magnitudes of divergence in covariance structure appear to be small. Matrix correlations are very sensitive to sampling error, while CPC is not. CPC is a powerful statistical tool that allows detailed testing of underlying patterns of covariation. PMID- 28565370 TI - ON THE ADAPTIVE NATURE OF BERGMANN SIZE CLINES: A REPLY TO MOUSSEAU, PARTRIDGE AND COYNE. PMID- 28565371 TI - HOST IMMUNE STATUS DETERMINES SEXUALITY IN A PARASITIC NEMATODE. AB - We examine the hypothesis that sexual reproduction by parasites is an adaptation to counter the somatic evolution of vertebrate immune responses. This is analogous to the idea that antagonistic coevolution between hosts and their parasites maintains sexual reproduction in host populations. Strongyloides ratti is a parasitic nematode of rats. It can have a direct life cycle, with clonal larvae of the wholly parthenogenetic parasites becoming infective, or an indirect life cycle, with clonal larvae developing into free-living dioecious adults. These free-living adults produce infective larvae by conventional meiosis and syngamy. The occurrence of the sexual cycle is determined by both environmental and genetic factors. By experimentally manipulating host immune status using hypothymic mutants, corticosteroids, whole-body gamma-irradiation and previous exposure to S. ratti, we show that larvae from hosts that have acquired immune protection are more likely to develop into sexual adults. This effect is independent of the method of manipulation, larval density, and the number of days postinfection. This immune-determined sexuality is consistent with the idea that sexual reproduction by parasites is adaptive in the face of specific immunity, an idea which, if true, has clinical and epidemiological consequences. PMID- 28565372 TI - PATTERNS OF VARIATION AND LINKAGE DISEQUILIBRIUM IN A FIELD CRICKET HYBRID ZONE. AB - The distribution of multilocus genotypes found within a natural hybrid zone is determined by the sample of genotypes present when the hybrid zone first formed, by subsequent patterns of genetic exchange between the hybridizing taxa, and by drift and selection within each of the hybrid zone populations. We have used anonymous nuclear DNA restriction fragment polymorphisms (RFLPs) to characterize the array of multilocus genotypes present within a well-studied hybrid zone between two eastern North American field crickets, Gryllus pennsylvanicus and Gryllus firmus. These crickets hybridize along a zone of contact that extends from New England to Virginia. Previous studies have shown that both premating and postmating barriers exist between the two cricket species, but the absence of diagnostic morphological and allozyme markers has made it difficult to assess the consequences of these barriers for genetic exchange. Analyses based on four diagnostic anonymous nuclear markers indicate that hybrid zone populations in Connecticut contain few F1 hybrids, and that nonrandom associations persist among nuclear gene markers, between nuclear and cytoplasmic markers, and between molecular markers and morphology. Field cricket populations within the hybrid zone are not "hybrid swarms" but consist primarily of crickets that are very much like one or the other of the parental species. Despite ample opportunity for genetic exchange and evidence for introgression at some loci, the two species remain quite distinct. Such a pattern appears to be characteristic of many natural hybrid zones. PMID- 28565373 TI - ABSOLUTE VERSUS RELATIVE MEASUREMENTS OF SEXUAL SELECTION: ASSESSING THE CONTRIBUTIONS OF ULTRASONIC SIGNAL CHARACTERS TO MATE ATTRACTION IN LESSER WAX MOTHS, ACHROIA GRISELLA (LEPIDOPTERA: PYRALIDAE). AB - When females choose a mate among a group of signaling males concentrated in a small area, a male's mating success is often determined not only by his absolute attractiveness but by the attractiveness of his neighbors as well. Multivariate analyses of sexual selection measurements based on absolute values of predictor variables are then misleading, because such analyses assume that the fitness of a given individual is not influenced by others. We addressed this problem of relative fitness in sexual selection by developing two adjustments of the predictor variables in the multivariate analyses by including group means in addition to absolute values and by using relative values, deviations from group means. In the lesser wax moth, Achroia grisella (Lepidoptera: Pyralidae), aggregated males produce ultrasonic signals attractive to females in the vicinity of honey bee colonies. Playback experiments showed that females prefer signals whose pulses are louder, longer, delivered at a faster rate, and include lengthy silent gaps within pulse pairs (long asynchrony intervals). To measure sexual selection on ultrasonic signals, attractiveness was assessed by observing the number of females orienting toward given males in four-choice trials. The various signal characters of the males were computed from ultrasound recordings. Multivariate regression and nonparametric analyses revealed that peak amplitude, asynchrony interval, and pulse rate were the direct targets of selection. Nonlinear stabilizing and correlational selection were also detected. Comparisons of results from multivariate analyses based on absolute values and on the two relative adjustments indicated that the quality of a four-male group did not affect the strength or direction of linear selection but changed the strength of nonlinear selection. Both relative adjustments improved the prediction of male attractiveness. Three-dimensional surface plots generated by the nonparametric regression analyses showed that attractiveness increased monotonically with any combination of the signal characters. This graphical technique also showed that female choice in A. grisella was based on a relative, as opposed to a threshold, decision rule. Overall, male attractiveness for the population remained consistent between testing days. However, attractiveness values for some individual males changed between successive testing days. In these cases, the change in attractiveness was related only to the change in peak amplitude. PMID- 28565375 TI - SYMPATRIC SEA SHELLS ALONG THE SEA'S SHORE: THE GEOGRAPHY OF SPECIATION IN THE MARINE GASTROPOD TEGULA. AB - Uncertainty and controversy surround the geographical and ecological circumstances that create genetic differences between populations that eventually lead to reproductive isolation. Two aspects of marine organisms further complicate this situation: (1) many species possess planktonic larvae capable of great dispersal; and (2) obvious barriers to movement between populations are rare. Past studies of speciation in the sea have focussed on identifying the effects of past land barriers and on biogeographical breakpoints. However, assessing the role such undeniable barriers actually play in the initial divergence leading to reproductive isolation requires phylogenetic studies of recent radiations living in varying degrees of sympatry and allopatry to see which barriers (if any) tend to separate sister species. Here I infer phylogenetic relationship between 23 species of the marine snail Tegula using DNA sequences from two regions of the mitochondrial genome: cytochrome c oxidase I (COI) and the small ribosomal subunit (12S) These snails possess planktonic larvae with moderate dispersal capabilities and have speciated rapidly with over 40 extant species arising since the genus first appeared in the mid-Miocene (about 15 M.Y.B.P.). Trees constructed from the COI and 12S regions (which yielded 205 and 137 phylogenetically informative sites, respectively) were robust with respect to tree-building method, bootstrapping, and the relative weightings of transitions, transversions, and gaps Within clades where all extant species have been sampled, five of six identified sister species pairs broadly coexist on the same side of biogeographical boundaries. These data suggest strong geographical barriers to gene flow may not always be required for speciation in the sea; transient allopatry or even ecological barriers may suffice. A survey of the geographic distributions of marine radiations suggests that coastal distributions may favor the sympatry of sister taxa more than island distributions do. PMID- 28565374 TI - EVOLUTION OF COURTSHIP SONG AND REPRODUCTIVE ISOLATION IN THE DROSOPHILA WILLISTONI SPECIES COMPLEX: DO SEXUAL SIGNALS DIVERGE THE MOST QUICKLY? AB - Reproductive isolation increases with genetic distance between species. Although sexual selection may drive divergence of sexual signals and traits, causing rapid evolution of sexual isolation, quantitative data supporting this idea are rare. We examine the rates of divergence of a species-specific courtship signal, sexual isolation, and postmating isolation in the Drosophila willistoni group. Both types of isolation increase with genetic distance and postmating isolation is the most strongly correlated with genetic divergence, suggesting this has the least variable divergence rate. Song divergence is not correlated with genetic divergence. Homoplasy in song pattern results in poorly resolved phylogenies that are different from molecular phylogenies. Song evolves more quickly than sexual isolation, which evolves more quickly than postmating isolation. PMID- 28565376 TI - CYTONUCLEAR THEORY FOR HAPLODIPLOID SPECIES AND X-LINKED GENES. II. STEPPING STONE MODELS OF GENE FLOW AND APPLICATION TO A FIRE ANT HYBRID ZONE. AB - We develop cytonuclear, hybrid zone models for haplodiploid species or X-linked genes in diploid species using a stepping-stone framework of migration, in which migration rates vary with both direction and sex. The equilibrium clines for the allele frequencies, cytonuclear disequilibria, and frequencies of pure parental types are examined for species with diagnostic markers, under four important migration schemes: uniform migration of both sexes in both directions, greater migration of both sexes from one direction, greater migration of females, and greater migration of males. Of the three cytonuclear variables examined, the allele frequency clines are the most informative in differentiating among the various migration patterns. The cytonuclear disequilibria and the frequency of the pure parental types tend to be useful only in revealing directional asymmetries in migration. The extent of hybrid zone subdivision has quantitative but not qualitative effects on the distribution of cytonuclear variables, in that the allele frequency clines become more gradual, the cytonuclear disequilibria decrease in magnitude, and the frequencies of pure parentals decline with increasing subpopulation number. Also, the only major difference between the X linked and haplodiploid frameworks is that a higher frequency of pure parentals is found when considering haplodiploids, in which male production does not require mating. The final important theoretical result is that censusing after migration yields greater disequilibria and parental frequencies than censusing after mating. We analyzed cytonuclear data from two transects from a naturally occurring hybrid zone between two haplodiploid fire ant species, Solenopsis invicta and S. richteri, using our stepping-stone framework. The frequency of S. invicta mtDNA exceeds the frequency of the S. invicta nuclear markers through much of this hybrid zone, indicating that sex differences in migration or selection may be occurring. Maximum-likelihood estimates for the migration rates are very high, due to an unexpectedly large number of pure parental types in the hybrid zone, and differ substantially between the two transects. Overall, our model does not provide a good fit, in part because the S. invicta-S. richteri hybrid zone has not yet reached equilibrium. PMID- 28565377 TI - ARE RATES OF DIVERSIFICATION IN SUBTERRANEAN SOUTH AMERICAN TUCO-TUCOS (GENUS CTENOMYS, RODENTIA: OCTODONTIDAE) UNUSUALLY HIGH? AB - Subterranean rodents have been used frequently as examples of explosive speciation in mammals. We tested for differential rates of diversification by using information from molecular phylogenies to focus primarily on tuco-tucos (Rodentia: Octodontidae), the most speciose lineage of subterranean rodents. Tuco tucos were not significantly more diverse than their sister taxon (octodontines); however, a lineages-through-time analysis suggests an increase in diversification at the base of the tuco-tuco clade. PMID- 28565379 TI - LATITUDINAL VARIATION OF WING:THORAX SIZE RATIO AND WING-ASPECT RATIO IN DROSOPHILA MELANOGASTER. AB - In dipterans, the wing-beat frequency, and, hence, the lift generated, increases linearly with ambient temperature. If flight performance is an important target of natural selection, higher wing:thorax size ratio and wing-aspect ratio should be favored at low temperatures because they increase the lift for a given body weight. We investigated this hypothesis by examining wing: thorax size ratio and wing-aspect ratio in Drosophila melanogaster collected from wild populations along a latitudinal gradient and in their descendants reared under standard laboratory conditions. In a subset of lines, we also studied the phenotypic plasticity of these traits in response to temperature. To examine whether the latitudinal trends in wing:thorax size ratio and wing-aspect ratio could have resulted from a correlated response to latitudinal selection on wing area, we investigated the correlated responses of these characters in lines artificially selected for wing area. In both the geographic and the artificially selected lines, wing:thorax size ratio and wing-aspect ratio decreased in response to increasing temperature during development. Phenotypic plasticity for either trait did not vary among latitudinal lines or selective regimes. Wing:thorax size ratio and wing-aspect ratio increased significantly with latitude in field-collected flies. The cline in wing:thorax size ratio had a genetic component, but the cline in wing-aspect ratio did not. Artificial selection for increased wing area led to a statistically insignificant correlated increase in wing:thorax size ratio and a decrease in wing-aspect ratio. Our observations are consistent with the hypotheses that high wing-thorax size ratio and wing aspect ratio are per se selectively advantageous at low temperatures. PMID- 28565378 TI - AN EIGENVECTOR METHOD FOR ESTIMATING PHYLOGENETIC INERTIA. AB - We propose a new method to estimate and correct for phylogenetic inertia in comparative data analysis. The method, called phylogenetic eigenvector regression (PVR) starts by performing a principal coordinate analysis on a pairwise phylogenetic distance matrix between species. Traits under analysis are regressed on eigenvectors retained by a broken-stick model in such a way that estimated values express phylogenetic trends in data and residuals express independent evolution of each species. This partitioning is similar to that realized by the spatial autoregressive method, but the method proposed here overcomes the problem of low statistical performance that occurs with autoregressive method when phylogenetic correlation is low or when sample size is too small to detect it. Also, PVR is easier to perform with large samples because it is based on well known techniques of multivariate and regression analyses. We evaluated the performance of PVR and compared it with the autoregressive method using real datasets and simulations. A detailed worked example using body size evolution of Carnivora mammals indicated that phylogenetic inertia in this trait is elevated and similarly estimated by both methods. In this example, Type I error at alpha = 0.05 of PVR was equal to 0.048, but an increase in the number of eigenvectors used in the regression increases the error. Also, similarity between PVR and the autoregressive method, defined by correlation between their residuals, decreased by overestimating the number of eigenvalues necessary to express the phylogenetic distance matrix. To evaluate the influence of cladogram topology on the distribution of eigenvalues extracted from the double-centered phylogenetic distance matrix, we analyzed 100 randomly generated cladograms (up to 100 species). Multiple linear regression of log transformed variables indicated that the number of eigenvalues extracted by the broken-stick model can be fully explained by cladogram topology. Therefore, the broken-stick model is an adequate criterion for determining the correct number of eigenvectors to be used by PVR. We also simulated distinct levels of phylogenetic inertia by producing a trend across 10, 25, and 50 species arranged in "comblike" cladograms and then adding random vectors with increased residual variances around this trend. In doing so, we provide an evaluation of the performance of both methods with data generated under different evolutionary models than tested previously. The results showed that both PVR and autoregressive method are efficient in detecting inertia in data when sample size is relatively high (more than 25 species) and when phylogenetic inertia is high. However, PVR is more efficient at smaller sample sizes and when level of phylogenetic inertia is low. These conclusions were also supported by the analysis of 10 real datasets regarding body size evolution in different animal clades. We concluded that PVR can be a useful alternative to an autoregressive method in comparative data analysis. PMID- 28565380 TI - A REEVALUATION OF THE ORIGIN OF PENTADACTYLY. AB - The hypothesis suggested by Coates that pentadactyly arose twice is based on the presumed affinities between Tulerpeton, embolomeres, and amniotes. Flaws were found in the coding of some characters that supported this clade and, once corrected, the matrix fails to support the proposed phylogeny. Furthermore, interpretation of the phylogeny of Coates is difficult because no amniotes and no lissamphibians were included in this analysis. A reappraisal of the affinities of Tulerpeton using a matrix composed of a greater range of taxa suggests that it is a stem-tetrapod, that pentadactyly arose only once, and that the first tetrapod was already pentadactyl. PMID- 28565381 TI - INHERITANCE OF MALE COURTSHIP BEHAVIOR, AGGRESSIVE SUCCESS, AND BODY SIZE IN DROSOPHILA SILVESTRIS. AB - We describe a combined phenotypic and quantitative genetic investigation of the traits that may contribute to reproductive success in the picture-winged fly, Drosophila silvestris. These were courtship behavior, aggressive success, and body size and shape. Behavioral tests were conducted on wild-caught sires and their laboratory-reared sons. Neither size, shape, nor aggressive success predicted mating success. In both generations, males that spent more time courting and in wing-vibration were more likely to mate. However, components of courtship, overall aggressive success, and overall mating success had very low and nonsignificant heritabilities. The genetic estimates did not depend on whether they were based on males reared in both environments or reared only in the laboratory. PMID- 28565382 TI - GENETIC INTERACTIONS AND NATURAL SELECTION IN LOUISIANA IRIS HYBRIDS. AB - Hybridization between divergent lineages has long been assumed to give rise to unfavorable interactions between the parental genomes. These deleterious genetic interactions are further assumed to result in the production of hybrid offspring with decreased levels of viability and/or fertility. To test this assumption, we investigated the role of both nuclear and cytonuclear epistatic interactions in determining the frequencies of F2 genotypes produced in crosses between two species of Louisiana iris, Iris fulva and I. brevicaulis. Overall, these crosses revealed a significant deficit of intermediate hybrid genotypes accompanied by an excess of parental-like genotypes, suggesting that genetic interactions may promote postmating reproductive isolation between these species. However, analyses of single and multilocus segregation patterns revealed a variety of negative and positive interactions between the genomes of the parental taxa at the nuclear and cytonuclear levels. Taken together, these results indicate that the traditional view that interactions between divergent genomes are always deleterious is an oversimplification. Rather, it seems likely that crosses between divergent lineages can lead to the production of both fit and unfit hybrid genotypes. PMID- 28565383 TI - A TEST OF QUEEN RECRUITMENT MODELS USING NUCLEAR AND MITOCHONDRIAL MARKERS IN THE FIRE ANT SOLENOPSIS INVICTA. AB - We assess nestmate queen relatedness and the genetic similarity of neighboring nests in the polygyne (multiple-queen) social form of the introduced fire ant Solenopsis invicta using both nuclear and mitochondrial markers. We find that estimates of queen relatedness calculated with both types of markers do not differ statistically from zero. Furthermore, there is no significant relationship between the genetic similarity and geographic proximity of nests in each of six study sites. In contrast to these findings, sites show strong mitochondrial, but no nuclear, genetic differentiation. Our results suggest that nonnestmate queen recruitment occurs at a high frequency in introduced populations of this species. Moreover, queens within nests seem to represent a random sample of the queens within the site in which they reside. Therefore, kin selection models that rely on the recruitment of only nestmate queens to explain the persistence of polygyny in ants do not apply to polygyne S. invicta in its introduced range. PMID- 28565384 TI - AMONG-FAMILY VARIATION FOR ENVIRONMENTAL SEX DETERMINATION IN REPTILES. AB - Unlike birds and mammals, in many reptiles the temperature experienced by a developing embryo determines its gonadal sex. To understand how temperature dependent sex determination (TSD) evolves, we must first determine the nature of genetic variation for sex ratio. Here, we analyze among-family variation for sex ratio in three TSD species: the American alligator (Alligator mississipiensis), the common snapping turtle (Chelydra serpentina) and the painted turtle (Chrysemys picta). Significant family effects and significant temperature effects were detected in all three species. In addition, family-by-temperature interactions were evident in the alligator and the snapping turtle, but not in the painted turtle. Overall, the among-family variation detected in this study indicates potential for sex-ratio evolution in at least three reptiles with TSD. Consequently, climate change scenarios that are posited on the presumption that sex-ratio evolution in TSD reptiles is genetically constrained may require reevaluation. PMID- 28565385 TI - RESOURCE ACQUISITION AND THE EVOLUTION OF STRESS RESISTANCE IN DROSOPHILA MELANOGASTER. AB - Resistance to environmental stress is one of the most important forces molding the distribution and abundance of species. We investigated the evolution of desiccation stress resistance using 20 outbred Drosophila melanogaster populations directly selected in the laboratory for adult desiccation resistance (D), postponed senescence (O), and their respective controls (C and B). Both aging and desiccation selection increased desiccation resistance relative to their controls, creating a spectrum of desiccation resistance levels across selection treatments. We employed an integrative approach, merging data on the life histories of these populations with a detailed physiology of water balance. The physiological basis of desiccation resistance may be mechanisms enhancing either resource conservation or resource acquisition and allocation. Desiccation resistant populations had increased water and carbohydrate stores, and showed age specific patterns of desiccation resistance consistent with the resource accumulation mechanism. A significant proportion of the resources relevant to resistance of the stress were accumulated in the larval stage. Males and females of desiccation-selected lines exhibited distinctly different patterns of desiccation resistance and resource acquisition, in a manner suggesting intersexual antagonism in the evolution of stress resistance. Preadult viability of stress-selected populations was lower than that of controls, and development was slowed. Our results suggest that there is a cost to preadult resource acquisition, pointing out a complex trade-off architecture involving characters distributed across distinct life-cycle stages. PMID- 28565386 TI - INTENSE NATURAL SELECTION ON BODY SIZE AND WING AND TAIL ASYMMETRY IN CLIFF SWALLOWS DURING SEVERE WEATHER. AB - Extreme climatic disturbances provide excellent opportunities to study natural selection in wild populations because they may cause measurable directional shifts in character traits. Insectivorous cliff swallows (Petrochelidon pyrrhonota) in the northern Great Plains must often endure periods of cold weather in late spring that reduce food availability, and if cold spells last four or more days, mortality due to starvation may result. We analyzed morphological shifts associated with viability selection, and how patterns of bilateral symmetry were affected by survival selection, during a four-day period of cold weather in 1992 and a six-day period in 1996 in southwestern Nebraska. Birds that died during the cold were compared to those still alive when the severe weather ended. The event in 1992 killed relatively few birds, but the cold spell in 1996 killed thousands of cliff swallows and reduced their population by about 53%. Climatological records suggest that mortality events comparable to that of 1996 have occurred in only one other year since 1875. Larger birds were favored in the 1996 event. Selection was more intense in 1996 than in 1992 because of more stressful conditions in 1996. Directional selection gradient analysis showed that measures of skeletal body size (tarsus length, culmen width and length) and wing length were targets of selection in 1996. Survivors had lower wing and outer tail asymmetry, and wing and tail asymmetry were targets of selection in both events. Mortality patterns did not differ by sex, but older birds suffered heavier mortality; morphological traits generally did not vary with age. Nonsurvivors were not in poorer apparent condition prior to the weather event than survivors, suggesting that selection acted directly on morphology independent of condition. Selection on body size in cliff swallows was more intense than in studies of body size evolution in other bird species. Larger swallows were probably favored in cold weather due to the thermal advantages of large size and the ability to store more fat. Swallows with low asymmetry were favored probably because low asymmetry in wing and tail made foraging more efficient and less costly, conferring survival advantages during cold weather. This population of cliff swallows may have undergone relatively recent body size evolution. PMID- 28565387 TI - NEUTRAL GENE FLOW ACROSS SINGLE LOCUS CLINES. AB - We study the strength of the genetic barrier to neutral gene flow in a general one-locus, two-allele model that includes viability selection as well as fertility selection and premating isolation. We have separately considered adult migration and pollen migration. Our theoretical results suggest that selection against hybrid formation in the form of fertility selection or assortative mating is more effective in preventing introgression of neutral alleles than is reduction in hybrid viability. We argue that in experimental studies of introgression testing of F1 hybrids is as important as testing of parental forms. To illustrate the utility of this approach, we estimate the strength of the barrier to neutral gene flow between Piriqueta caroliniana and P. viridis, between Iris hexagona and I. fulva, and between Chorthippus brunneus and C. biguttulus. PMID- 28565388 TI - ADAPTIVE SIGNIFICANCE OF FLOWER COLOR AND INTER-TRAIT CORRELATIONS IN AN IPOMOPSIS HYBRID ZONE. AB - Flower color is often viewed as a trait that signals rewards to pollinators, such that the relationship between flower color and plant fitness might result from its association with another trait. We used experimental manipulations of flower color and nectar reward to dissociate the natural character correlations present in a hybrid zone between Ipomopsis aggregata and Ipomopsis tenuituba. Isozyme markers were used to follow the male and female reproductive success of these engineered phenotypes. One field experiment compared fitnesses of I. aggregata plants that varied only in flower color. Plants with flowers painted red received more hummingbird visits and sired more seeds than did plants with flowers painted pink or white to match those of hybrids and I. tenuituba. Our second field experiment compared fitnesses of I. aggregata, I. tenuituba, and hybrid plants in an unmanipulated array and in a second array where all flowers were painted red. In the unmanipulated array, I. aggregata received more hummingbird visits, set more seeds per flower, and sired more seeds per flower. These fitness differences largely disappeared when the color differences were eliminated. The higher male fitness of I. aggregata was due to its very high success at siring seeds on conspecific recipients. On both I. tenuituba and hybrid recipients, hybrid plants sired the most seeds, despite showing lower pollen fertility than I. aggregata in mixed donor pollinations in the greenhouse. Ipomopsis tenuituba had a fitness of only 13% relative to I. aggregata when traits varied naturally, compared to a fitness of 36% for white relative to red flowers when other traits were held constant. PMID- 28565389 TI - THE EVOLUTION OF WORKER STERILITY IN HONEY BEES: AN INVESTIGATION INTO A BEHAVIORAL MUTANT CAUSING FAILURE OF WORKER POLICING. AB - Normally, worker honey bees (Apis mellifera) only lay eggs when their colony is queenless. When a queen is present, worker egg-laying is controlled by mutual "policing" behavior in which any rare worker-laid eggs are eaten by other workers. However, an extremely rare behavioral phenotype arises in which workers develop functional ovaries and lay large numbers of eggs despite the presence of the queen. In this study, microsatellite analysis was used to determine the maternity of drones produced in such a colony under various conditions. One subfamily was found to account for about 90% of drone progeny, with the remainder being laid by other subfamilies or the queen. No evidence of queen policing was found. After a one-month period of extreme worker oviposition in spring, the colony studied reverted to normal behavior and showed no signs of worker oviposition. However, upon removal of the queen, workers commenced oviposition very quickly. Significantly, the subfamily that laid eggs when the queen was present did not contribute to the drone production when the colony was queenless. However, another subfamily contributed a disproportionately large number of drones. The frequency of worker oviposition appears to be determined by opposing selective forces. Individual bees benefit from personal reproduction, whereas other bees and the colony are disadvantaged by it. Thus a behavioral polymorphism can be maintained in the population in which some workers can escape worker policing, with balancing selection at the colony level to detect and eliminate these mutations. PMID- 28565390 TI - GENITAL LOCK-AND-KEY AS A SELECTIVE AGENT AGAINST HYBRIDIZATION. AB - We demonstrate experimentally that differences in genital characters impose a direct cost of interspecific copulation on two closely related carabid species, Carabus (Ohomopterus) maiyasanus and C. (O.) iwawakianus, that share a narrow hybrid zone. Males of both species attempted copulation indiscriminately between conspecific and heterospecific females. Females experiencing heterospecific mating often suffered mortality due to rupture of their vaginal membranes. Those without fatal injury laid eggs which developed into F1 adults, but the fertilization rate was much lower than for intraspecific pairs. Males of C. maiyasanus, but not C. iwawakianus, often had broken genital parts (copulatory pieces) following interspecific copulations, which may prevent normal copulation in subsequent matings. Because of female mortality and low fertilization rate, the estimated fitness cost of interspecific mating was very large in terms of the reduction in the number of offspring (hatching larvae) for both sexes and both species. Thus, genital lock-and-key appears to exert significant selection against hybridization in the hybrid zone of these carabid beetles. PMID- 28565391 TI - INFERENCE OF SPERM COMPETITION FROM BROODS OF FIELD-CAUGHT DROSOPHILA. AB - In field studies of multiple mating and sperm competition there typically is no experimental control over the number of times that a female mates, the interval between matings, or the genetic identity of multiple fathers contributing to a brood. Irrespective of this complexity, high-resolution molecular markers can be used to assign paternity with considerable confidence. This study employed two highly heterozygous microsatellite loci to assess multiple paternity and sperm displacement in a sample of broods taken from a natural population of Drosophila melanogaster. The large number of alleles present at each of the loci makes it difficult to derive explicit maximum-likelihood estimates for multiple paternity and sperm displacement from brood samples. Monte Carlo simulations were used to estimate maximum-likelihood parameters for the distribution of female remating frequency and the proportion of offspring sired by the second or subsequent mating males. Estimates were made based on genotypes scored at two distinct marker loci because they were found to give statistically homogeneous results. Fitting a Poisson distribution of number of matings, the mean number of males mated by a female was 1.82. The sperm displacement parameter estimated from doubly mated females were 0.79 and 0.86 for the two loci (0.83 for the joint estimate). The overall probability that a multiply mated female will be misclassified as singly mated was only 0.006, which indicates that microsatellites can provide excellent resolution for identifying multiple mating. In addition, microsatellites can be used to generate relatively precise estimates of sperm precedence in brood-structured samples from a natural population. PMID- 28565392 TI - GENETIC, ENVIRONMENTAL, AND CONDITION-DEPENDENT EFFECTS ON FEMALE AND MALE ORNAMENTATION IN THE BARN OWL TYTO ALBA. AB - Secondary sexual characters are thought to indicate individual quality. Expression of sex-limited traits in an extravagant state may require both the underlying genes and the available nutrient resources. The assessment of the relative contribution of genes, environment, and body condition is relevant for understanding to that extent the extravagant trait may signal genotypic or phenotypic quality of the individual. In birds, usually only the males are ornamented. In the barn owl, Tyto alba, both females and males display sex limited plumage traits. Males are commonly lighter colored and females spottier. In an experiment with combined cross-fostering and brood size manipulation we determined the relative contribution of genes, environment, and body condition to the variation in plumage coloration and plumage spottiness. The partial cross fostering experiment tested the relative importance of shared genes and a shared environment for the resemblance of related birds. Siblings raised in different nests converged toward similar trait values, offspring resembled the true but not the foster parents, and plumage traits of unrelated nestlings sharing the same nest were not correlated. Results were not inflated by maternal effects detectable in the mother's phenotype, because middaughter to mother resemblance was not higher than midson to father resemblance. This suggests that plumage coloration and spottiness are largely genetically inherited traits, and that the rearing environment does not have a strong impact on the expression of these traits. To further investigate whether the two sex-limited traits are condition dependent, brood sizes were manipulated. Enlargement or reduction of broods by two nestlings resulted in lower and higher body mass of nestlings, respectively. However, nestlings raised in enlarged or reduced broods did not show either a significantly darker or lighter or a more or less spotted plumage. We did not detect any genotype-by-environment interaction. In conclusion, simultaneous cross fostering and brood size manipulation demonstrate that additive genetic variance for plumage coloration and spottiness is maintained and that both the rearing environment and body condition do not account for a large proportion of the phenotypic variance in female and male ornamentations. PMID- 28565393 TI - HIGH LEVELS OF COLICIN RESISTANCE IN ESCHERICHIA COLI. AB - Colicins are plasmid-encoded antibiotics that are produced by and kill Escherichia coli and other related species. The frequency of colicinogeny is high, on average 30% of E. coli isolates produce colicins. Initial observations from one collection of 72 strains of E. coli (the ECOR collection) suggest that resistance to colicin killing is also ubiquitous, with over 70% of strains resistant to one or more colicins. To determine whether resistance is a common trait in E. coli, three additional strain collections were surveyed. In each of these collections levels of colicin production were high (from 15 to 50% of the strains produce colicins). Levels of colicin resistance were even higher, with most strains resistant to over 10 colicins. A survey of 137 non-E. coli isolates revealed even higher levels of resistance. We discuss a mechanism (pleiotropy) that could result in the co-occurrence of such high levels of colicin production and colicin resistance. PMID- 28565394 TI - HOST SPECIFICITY AND THE GENETIC STRUCTURE OF TWO YUCCA MOTH SPECIES IN A YUCCA HYBRID ZONE. AB - Host specialization is an important mechanism of diversification among phytophagous insects, especially when they are tightly associated with their hosts. The well-known obligate pollination mutualism between yucca moths and yuccas represent such an association, but the degree of host specificity and modes of specialization in moth evolution is unclear. Here we use molecular tools to test the morphology-based hypothesis that the moths pollinating two yuccas, Yucca baccata and Y. schidigera, are distinct species. Host specificity was assessed in a zone of sympatry where the hosts are known to hybridize. Because the moths are the only pollinators, the plant hybrids are evidence that the moths occasionally perform heterospecific pollination. Nucleotide variation was assessed in a portion of the mitochondrial gene COI, and in an intron within a nuclear lysozyme gene. Moths pollinating Y. baccata and Y. schidigera were inferred to be genetically isolated because there was no overlap in alleles at either locus, and all but one of the moths was found on their native host in the hybrid zone. Moreover, genetic structure was very weak across the range of each moth species: estimates of FST for the lysozyme intron were 0.043 (SE = +/- 0.004) and 0.021 (SE = +/- 0.006) for the baccata and schidigera pollinators, respectively; estimated FST for COI in the baccata moths was 0.228 (+/- 0.012), whereas schidigera pollinators were fixed for a single allele. These results reveal a high level of migration among widely separated moth populations. We predict that pollen-mediated gene flow among conspecific yuccas is considerable and hypothesize that geographic separation is a limited barrier both for yuccas and for yucca moths. PMID- 28565395 TI - FLUCTUATING ASYMMETRY IN CENTRAL AND MARGINAL POPULATIONS OF LYCHNIS VISCARIA IN RELATION TO GENETIC AND ENVIRONMENTAL FACTORS. AB - Developmental instability in the form of increased fluctuating asymmetry can be caused by either genetic or environmental stress. Because extinctions can be attributed broadly to these factors, fluctuating asymmetry may provide a sensitive tool for detecting such stresses. We studied the level of fluctuating asymmetry of flowers of a perennial outcrossing plant species, Lychnis viscaria, both in natural and common-garden populations. The degree of flower asymmetry was higher in small, isolated, and marginal populations of the species range. These marginal populations also were the most homozygous. In the core area of the species' range, flowers were more symmetrical The level of asymmetry was correlated with both population size and heterozygosity. However, a partial correlation analysis revealed that when the impact of population size was controlled for, there was a negative relationship between fluctuating asymmetry and heterozygosity, whereas when controlling for heterozygosity, no relationship between population size and fluctuating asymmetry was found. This indicates that genetic consequences of small population size probably underlie the relationship between the level of asymmetry and population size. Results from a transplantation experiment showed that individuals subjected to a higher environmental stress had an increased level of asymmetry compared to control plants. In the common-garden conditions the level of fluctuating asymmetry did not differ between the central and marginal populations. This suggests that presumably both genetic and environmental factors affected to the higher level of asymmetry among marginal populations compared to central ones. In all we conclude that even though fluctuating asymmetry seems to be a sensitive tool for detecting stresses, results from studies focusing on only one factor should be interpreted with caution. PMID- 28565396 TI - ADAPTIVE PHENOTYPIC PLASTICITY IN GROWTH, DEVELOPMENT, AND BODY SIZE IN THE YELLOW DUNG FLY. AB - Life-history theory predicts that age and size at maturity of organisms should be influenced by time and food constraints on development. This study investigated phenotypic plasticity in growth, development, body size, and diapause in the yellow dung fly, Scathophaga stercoraria. Full-sib families were allowed to develop under predator-free field conditions. The time before the onset of winter was varied and each brood was split into three environments differing in the amount of dung a set number of larvae had as a resource. When resources were abundant and competition was minimal, individuals of both sexes grew to larger body sizes, took longer time to mature, and were able to increase their growth rates to attain large body sizes despite shorter effective development periods later in the season. In contrast, limited larval resources and strong competition constrained individuals to mature earlier at a smaller adult size, and growth rates could not be increased but were at least maintained. This outcome is predicted by only two life-history optimality models, which treat mortality due to long development periods and mortality due to fast growth as independent. Elevated preadult mortality indicated physiological costs of fast growth independent of predation. When larval resources were limited, mortality increased with heritable variation in development time for males, and toward the end of the season mortality increased as larval resources became more abundant because this induced longer development periods. Sexual and fecundity selection favoring large body size in this species is thus opposed by larval viability selection favoring slower growth in general and shorter development periods when time and resources are limited; this overall combination of selective pressures is presumably shaping the reaction norms obtained here. Flexible growth rates are facilitated by low genetic correlations between development time and body size, a possible consequence of selection for plasticity. Heritable variation was evident in all traits investigated, as well as in phenotypic plasticity of these traits (genotype X interactions). This is possibly maintained by unpredictable spatiotemporal variation in dung abundance, competition, and hence selection. PMID- 28565397 TI - DESCRIBING THE EVOLUTION OF REACTION NORM SHAPE: BODY PIGMENTATION IN DROSOPHILA. AB - If phenotypic plasticity is a trait subject to selection and evolution, we need to quantify reaction norms and to identify the potential target(s) of selection. Previously we proposed the use of polynomial coefficients as reaction norm descriptors. However, the interpretation of these coefficients is not straightforward if the reaction norm is not linear. Therefore, we instead propose the use of characteristic values to describe reaction norms. We depict such characteristic values for linear, quadratic, and logistic reaction norms, discuss how they might evolve, and illustrate their estimation using data on abdominal pigmentation of Drosophila simulans. PMID- 28565398 TI - INTENSE SELECTION OF MITE CLONES IN A HETEROGENEOUS ENVIRONMENT. AB - Genetic diversity within obligatorily parthenogenic species can be high, contrary to common views of the evolutionary consequences of this reproductive system. How this clonal diversity is maintained within populations is not clearly understood. Previous studies showing high clonal diversity have used parthenogenic organisms with known sexual forms or relatives. Here we report significant spatial and temporal clonal diversity within two populations of an obligatorily parthenogenic mite, Penthaleus major, which has no known sexual form or close sexual relative. Fitness estimates from temporal sampling at two sites and manipulated field plots reveal intense natural selection acting on ecologically different clones. We propose that environmental heterogeneity contributes to the maintenance of clonal diversity within populations of P. major and that selection is strong enough to overcome the problems of relative niche size. PMID- 28565399 TI - REPTILIAN VIVIPARITY AND DOLLO'S LAW. AB - It has been suggested repeatedly that the evolutionary transition from oviparity (egg-laying) to viviparity (live-bearing) in reptiles is irreversible. However, these adaptive arguments have yet to be tested by detailed examination of the phylogenetic distribution of oviparity and viviparity across a broad range of taxa. Using available data on reproductive modes and phylogenetic relationships within reptiles, we here quantify the numbers and directions of evolutionary transitions between oviparity and viviparity. Phylogenetic relationships among three diverse squamate groups (scincid lizards, colubrid snakes, elapid snakes) are currently inadequately known for inclusion in this study Among the remaining reptiles, oviparity has given rise to viviparity at least 35 times. Five possible instances of reversals (from viviparity to oviparity) are identified, but closer examination indicates that all have weak empirical support (i.e., they could be "unreversed" with little loss in parsimony, and/or are based on poorly substantiated phylogenetic hypotheses). Viviparity is clearly more frequently (and presumably easily) gained than lost in several disparate groups so far examined (reptiles, fishes, polychaete worms); this evolutionary bias should be considered when reproductive mode is optimized on a phylogeny or employed in phylogenetic reconstruction. PMID- 28565400 TI - QUORUM SENSING AND GROUP SELECTION. AB - Bacteria respond to cell density by expressing genes whose products are beneficial to the population as a whole. This response is brought about through the release into the medium of signaling molecules of the class N-acyl homoserine lactones, the concentration of which determines the level of gene expression. This form of communication between cells has been termed "quorum sensing," and has been found to operate in the control of many functions in a variety of gram negative bacteria. As with all signaling between individuals, if fitness costs are associated with the release of and response to the signal, the inclusive fitness of alleles responsible for the phenomenon depends upon genetic relatedness between signaler and responder. The situation is considered in explicit models for bacterial population genetics, in which the critical parameter determining the success of quorum sensing is the mean number of cells founding a population sharing a patch of resource. It is found that extensive polymorphism for the presence or absence of quorum sensing is expected for a wide range of parameter space. If local communities of bacteria contain diverse species, community stability may be the consequence of these interactions rather than polymorphism. PMID- 28565401 TI - GEOMETRIC MORPHOMETRICS OF DEVELOPMENTAL INSTABILITY: ANALYZING PATTERNS OF FLUCTUATING ASYMMETRY WITH PROCRUSTES METHODS. AB - Although fluctuating asymmetry has become popular as a measure of developmental instability, few studies have examined its developmental basis. We propose an approach to investigate the role of development for morphological asymmetry by means of morphometric methods. Our approach combines geometric morphometrics with the two-way ANOVA customary for conventional analyses of fluctuating asymmetry and can discover localized features of shape variation by examining the patterns of covariance among landmarks. This approach extends the notion of form used in studies of fluctuating asymmetry from collections of distances between morphological landmarks to an explicitly geometric concept of shape characterized by the configuration of landmarks. We demonstrate this approach with a study of asymmetry in the wings of tsetse flies (Glossina palpalis gambiensis). The analysis revealed significant fluctuating and directional asymmetry for shape as well as ample shape variation among individuals and between the offspring of young and old females. The morphological landmarks differed markedly in their degree of variability but multivariate patterns of landmark covariation identified by principal component analysis were generally similar between fluctuating asymmetry (within-individual variability) and variation among individuals. Therefore there is no evidence that special developmental processes control fluctuating asymmetry. We relate some of the morphometric patterns to processes known to be involved in the development of fly wings. PMID- 28565402 TI - ENVIRONMENTAL STRESS AND THE MAINTENANCE OF SEX IN A FRESHWATER SNAIL. AB - Synergism among mutations can lead to an advantage to sexual reproduction, provided mutation rates are high enough (the mutational deterministic hypothesis). Here we tested the idea that competition for food can increase the advantage to sexual reproduction, perhaps by increasing the synergism among mutations in asexual individuals. We compared the survivorship of sexual and asexual snails (Potamopyrgus antipodarum) under two treatments: starved and fed. We predicted higher mortality for asexual snails when starved, but found that sexual and asexual individuals survived at the same rate, independent of treatment. These results suggest that the distribution of sex in this snail may not be explained by variation in competition among populations. PMID- 28565403 TI - RESPONSE TO SELECTION IN PARTIALLY SELF-FERTILIZING POPULATIONS. I. SELECTION ON A SINGLE TRAIT. AB - Self-fertilization is a common form of reproduction in plants and it has important implications for quantitative trait evolution. Here, I present a model of selection on quantitative traits that can accommodate any level of self fertilization. The "structured linear model" (SLM) predicts the evolution of the mean phenotype as a function of three distinct quantities: the mean additive genetic value, the directional dominance, and the mean inbreeding coefficient. Stochastic simulations of truncation selection demonstrate the accuracy of the SLM in predicting changes in the mean and variance of a quantitative trait over the full range of selfing rates. They also illustrate how complex interactions between selection and mating system determine the population distribution of inbreeding coefficients and also the amount of linkage disequilibrium. Changes in the genetic variance due to linkage disequilibria, which are commonly referred to as the "Bulmer effect," are greatly magnified by selfing. This complicates the relationship between selfing rate and response to selection. Like the random mating theory, the parameters of the SLM can be estimated from phenotypic data. PMID- 28565404 TI - ACCELERATED EVOLUTION OF LAND SNAILS MANDARINA IN THE OCEANIC BONIN ISLANDS: EVIDENCE FROM MITOCHONDRIAL DNA SEQUENCES. AB - An endemic land snail genus Mandarina of the oceanic Bonin (Ogasawara) Islands shows exceptionally rapid evolution not only of morphological and ecological traits, but of DNA sequence. A phylogenetic relationship based on mitochondrial DNA (mtDNA) sequences suggests that morphological differences equivalent to the differences between families were produced between Mandarina and its ancestor during the Pleistocene. The inferred phylogeny shows that species with similar morphologies and life habitats appeared repeatedly and independently in different lineages and islands at different times. Sequential adaptive radiations occurred in different islands of the Bonin Islands and species occupying arboreal, semiarboreal, and terrestrial habitat arose independently in each island. Because of a close relationship between shell morphology and life habitat, independent evolution of the same life habitat in different islands created species possesing the same shell morphology in different islands and lineages. This rapid evolution produced some incongruences between phylogenetic relationship and species taxonomy. Levels of sequence divergence of mtDNA among the species of Mandarina is extremely high. The maximum level of sequence divergence at 16S and 12S ribosomal RNA sequence within Mandarina are 18.7% and 17.7%, respectively, and this suggests that evolution of mtDNA of Mandarina is extremely rapid, more than 20 times faster than the standard rate in other animals. The present examination reveals that evolution of morphological and ecological traits occurs at extremely high rates in the time of adaptive radiation, especially in fragmented environments. PMID- 28565405 TI - GEOGRAPHIC DISTRIBUTION OF MOLECULAR VARIANCE WITHIN THE BLUE MARLIN (MAKAIRA NIGRICANS): A HIERARCHICAL ANALYSIS OF ALLOZYME, SINGLE-COPY NUCLEAR DNA, AND MITOCHONDRIAL DNA MARKERS. AB - This study presents a comparative hierarchical analysis of variance applied to three classes of molecular markers within the blue marlin (Makaira nigricans). Results are reported from analyses of four polymorphic allozyme loci, four polymorphic anonymously chosen single-copy nuclear DNA (scnDNA) loci, and previously reported restriction fragment length polymorphisms (RFLPs) of mitochondrial DNA (mtDNA). Samples were collected within and among the Atlantic and Pacific Oceans over a period of several years. Although moderate levels of genetic variation were detected at both polymorphic allozyme (H = 0.30) and scnDNA loci (H = 0.37), mtDNA markers were much more diverse (h = 0.85). Allele frequencies were significantly different between Atlantic and Pacific Ocean samples at three of four allozyme loci and three of four scnDNA loci. Estimates of allozyme genetic differentiation (thetaO ) ranged from 0.00 to 0.15, with a mean of 0.08. The thetaO values for scnDNA loci were similar to those of allozymes, ranging from 0.00 to 0.12 with a mean of 0.09. MtDNA RFLP divergence between oceans (thetaO = 0.39) was significantly greater than divergence detected at nuclear loci (95% nuclear confidence interval = 0.04-0.11). The fourfold smaller effective population size of mtDNA and male-mediated gene flow may account for the difference observed between nuclear and mitochondrial divergence estimates. PMID- 28565406 TI - EVOLUTIONARY ADAPTATION TO TEMPERATURE. VII. EXTENSION OF THE UPPER THERMAL LIMIT OF ESCHERICHIA COLI. AB - What factors influence the ability of populations to adapt to extreme environments that lie outside their current tolerance limits? We investigated this question by exposing experimental populations of the bacterium Escherichia coli to lethally high temperatures. We asked: (1) whether we could obtain thermotolerant mutants with an extended upper thermal limit by this selective screen; (2) whether the propensity to obtain thermotolerant mutants depended on the prior selective history of the progenitor genotypes; and (3) how the fitness properties of these mutants compared to those of their progenitors within the ancestral thermal niche. Specifically, we subjected 15 independent populations founded from each of six progenitors to 44 degrees C; all of the progenitors had upper thermal limits between about 40 degrees C and 42 degrees C. Two of the progenitors were from populations that had previously adapted to 32 degrees C, two were from populations adapted to 37 degrees C, and two were from populations adapted to 41-42 degrees C. All 90 populations were screened for mutants that could survive and grow at 44 degrees C. We obtained three thermotolerant mutants, all derived from progenitors previously adapted to 41-42 degrees C. In an earlier study, we serendipitously found one other thermotolerant mutant derived from a population that had previously adapted to 32 degrees C. Thus, prior selection at an elevated but nonlethal temperature may predispose organisms to evolve more extreme thermotolerance, but this is not an absolute requirement. It is evidently possible to obtain mutants that tolerate more extreme temperatures, so why did they not become prevalent during prior selection at 41-42 degrees C, near the upper limit of the thermal niche? To address this question, we measured the fitness of the thermotolerant mutants at high temperatures just within the ancestral niche. None of the four thermotolerant mutants had an advantage relative to their progenitor even very near the upper limit of the thermal niche; in fact, all of the mutants showed a noticeable loss of fitness around 41 degrees C. Thus, the genetic adaptations that improve competitive fitness at high but nonlethal temperatures are distinct from those that permit tolerance of otherwise lethal temperatures. PMID- 28565407 TI - EVOLUTION OF DRIVING X CHROMOSOMES AND RESISTANCE FACTORS IN EXPERIMENTAL POPULATIONS OF DROSOPHILA SIMULANS. AB - Sex-ratio drive is a particular case of meiotic drive, described in several Drosophila species, that causes males bearing driving X chromosome to produce a large excess of females in their progeny. In Drosophila simulans, driving X chromosomes and resistance factors located on the Y chromosome and on the autosomes have been previously reported. In this paper, we report the study of the dynamics of sex-ratio factors in experimental populations. We followed the evolution in frequency of driving X chromosomes in the absence of resistance factors and the evolution of resistance factors in the presence of driving X chromosomes. The driving X chromosome was lost, contrarily to theoretical expectations that predict its rapid invasion. Autosomal resistances increased in frequency, and resistant Y chromosomes invaded the population very quickly, as predicted by theoretical models. Fitness measurements showed that the loss of the driving X chromosome was due to a strong deleterious effect that was expressed only when distorting males were in competition with standard males. However, the spread of autosomal resistances reduced this deleterious effect. Implications for the maintenance of polymorphism in natural populations are discussed. PMID- 28565408 TI - INVERSION POLYMORPHISM, LONGEVITY, AND BODY SIZE IN A NATURAL POPULATION OF DROSOPHILA BUZZATII. AB - In this study we present the results of an analysis of differential longevity associated with Drosophila buzzatii second chromosome inversion karyotypes based on the assessment of more than 1000 individuals collected in a natural population. Comparisons of inversion frequencies between emerged and bait collected flies showed not only that inversion arrangements were associated with differential longevity, but also that selection was sex specific. Because each individual fly was scored for thorax length and karyotype, we were able to show that longevity selection favoring larger flies coupled with the average effect of inversions on thorax length can account for the change of inversion frequencies due to longevity in females. The observed genotypic-by-sex interaction could be an important mechanism involved in the maintenance of the polymorphism. Arrangement 2Jz3 , which was shown to impaired fecundity in two independent previous studies, exhibited a positive effect on longevity. This pattern of negative pleiotropy may be another plausible mechanism accounting for the maintenance of the polymorphism. PMID- 28565409 TI - PERSPECTIVE: HIGHLY VARIABLE LOCI AND THEIR INTERPRETATION IN EVOLUTION AND CONSERVATION. AB - Although highly variable loci, such as microsatellite loci, are revolutionizing both evolutionary and conservation biology, data from these loci need to be carefully evaluated. First, because these loci often have very high within population heterozygosity, the magnitude of differentiation measures may be quite small. For example, maximum GST values for populations with no common alleles at highly variable loci may be small and are at maximum less than the average within population homozygosity. As a result, measures that are variation independent are recommended for highly variable loci. Second, bottlenecks or a reduction in population size can generate large genetic distances in a short time for these loci. In this case, the genetic distance may be corrected for low variation in a population and tests to detect bottlenecks are advised. Third, statistically significant differences may not reflect biologically meaningful differences both because the patterns of adaptive loci may not be correlated with highly variable loci and statistical power with these markers is so high. As an example of this latter effect, the statistical power to detect a one-generation bottleneck of different sizes for different numbers of highly variable loci is discussed. All of these concerns need to be incorporated in the utilization and interpretation of patterns of highly variable loci for both evolutionary and conservation biology. PMID- 28565410 TI - DYNAMIC AND GENETIC CONSEQUENCES OF VARIATION IN HORIZONTAL TRANSMISSION FOR A MICROPARASITIC INFECTION. AB - Transmission to a new host is a critical step in the life cycle of a parasite. Variation in the characteristics of the transmission process, for example, due to host demography, is assumed to select for different variants of the parasite. We have experimentally tested how variation in the time to transmission (early or late after infection) and exposure to adverse conditions outside the host (immediate or delayed contact with new host) interact to determine the success of the infection in the next host, using the trypanosome Crithidia bombi infecting its bumblebee host, Bombus terrestris. These two experimentally manageable steps mimic the processes of within- and among-host selection for the parasite. We found that early transmission led to higher infection success in the next host as did immediate contact with the new host. However, there was no interaction between the two parameters as would be expected if early-transmitted variants, resulting from rapid multiplication within the host, would be less adapted to the conditions encountered during the between-host transfer or infection of the next host. Furthermore, typing the genetic variability of the parasites with microsatellites showed that the four different transmission routes of our experiment selected for different degrees of allelic diversity of the infecting parasite populations. The results support the idea that variation in the transmission process selects for different genotypic variants of the parasite. At the same time, the relationship of allelic diversity with infection intensity suggested that the coinfection model of May and Nowak (1995) may be appropriate, where each parasite is able to infect and multiply independent of others within the same host. PMID- 28565411 TI - FEMALE-FEMALE COMPETITION IN KATYDIDS: SEXUAL SELECTION FOR INCREASED SENSITIVITY TO A MALE SIGNAL? AB - In contrast to studies of sex-specific weaponry and other sexually selected traits, there has been no examination of Darwin's (1871, p. 418) suggestion that elaborations or enlargements of "the organs of sense" function to enhance mating success. In certain katydids the size of thoracic spiracles, which are a main input into the hearing system, determines auditory sensitivity of females. Here we present evidence that sexual dimorphism in the spiracle size of a pollen katydid, Kawanaphila nartee, is a result of sexual selection on females competing to locate nuptial-gift giving males. In field experiments in which female K. nartee were attracted to a calling male, we show a pairing advantage to females with larger auditory spiracles. The spiracle-size advantage was not a correlated result of a larger body size or mass of winners. Finally, there was no spiracle size advantage or body-mass advantage for mating females in a later stage of competition when experimental females struggled for access to a silent male. We suggest that research on the detection of displays has lagged behind work on the displays themselves; the focus has been on the species specificity of signal perception rather than on the fitness consequences of variation in the ability to detect cues from mates or predators. PMID- 28565412 TI - INTEGRATING DEVELOPMENTAL EVOLUTIONARY PATTERNS AND MECHANISMS: A CASE STUDY USING THE GASTROPOD RADULA. AB - Determining the connection between ontogeny and phylogeny continues to be a major theme in biology. However, few studies have combined dissection of pattern and process that lead to transformation of complex morphological structures. Here we examine the patterns and processes of shape change in a model system-the gastropod radula. This system is a simple one having only two processes: initial secretion and postsecretional movement of teeth. However, it produces a tremendous amount of shape variability and fusion patterns. To determine both pattern and mechanism of shape change in an evolutionary context, we use three complementary approaches and datasets. First, we use a phylogenetic hypothesis to determine the polarity of developmental events. Second, we perform a morphometric analysis of shape change using relative warp analysis that allows us to locate and compare the direction and magnitude of ontogenetic and phylogenetic shape divergence. These comparisons are the basis for testing hyptheses of heterochrony and heterotopy, and we show how our results do not conform to expectations of pure heterochrony. The rejection of heterochrony as a hypothesis is based on empirically demonstrating (1) initial shape differs in each taxon; (2) a single dimension of shape variability does not simultaneously describe ontogenetic and evolutionary shape changes; and (3) a significantly different shape and size covariance between taxa. This rejection is probably based on spatial changes in initial conditions and not spatial changes caused by the process itself. Finally, we construct a mechanistic model that explains how shape change happens based on the sequence of events during ontogeny. By using the parameters in the model as characters in the phylogenetic dataset, we show that different parts of the system have arisen at different times and become co-opted into the process. By integrating our analyses together we show that spatial process parameters can be responsible for our nonspatial patterns and that different ontogenetic processes can create similar end morphologies. PMID- 28565413 TI - TESTS OF INBREEDING EFFECTS ON HOST-SHIFT POTENTIAL IN THE PHYTOPHAGOUS BEETLE OPHRAELLA COMMUNA. AB - Although inbreeding, on average, decreases additive genetic variance, some inbred populations may show an increase in phenotypic variance for some characters. In those populations with increased phenotypic variance, character changes by peak shifts may occur because of the effects of the higher variance on the adaptive landscape. A population's increased phenotypic variance may place it in the domain of attraction of a new adaptive peak or increase the likelihood of a selection-driven peak shift as the landscape of mean fitness flattens. The focus of this study was to test for increased variance, in inbred populations, in a behavioral character involved in adaptive diversification and probably speciation. We examined the effect of inbreeding on feeding responses of the leaf beetle Ophraella communa in a series of inbred lineages across a range of levels of inbreeding (f = 0.25, 0.375, 0.5). We measured the feeding response of inbred lineages of O. communa on its normal host, Ambrosia artemisiifolia, and on two novel plants, Chrysopsis villosa and Iva frutescens, that are the hosts of other Ophraella species. The results show that feeding responses on the different plants are not correlated, indicating that the feeding responses to the different plants are to some degree genetically independent. Despite apparent genetic variation in lineage feeding responses, we could not statistically demonstrate increases in phenotypic variance within the lineages. Thus, the experimental results do not support the idea that host shifts in this beetle evolved by peak shifts in bottlenecked populations. PMID- 28565414 TI - THE RELATIVE CONTRIBUTIONS OF TIME AND EGGS TO THE COST OF REPRODUCTION. AB - Whether the trade-off between current and future reproduction in insect parasitoids is mediated by the costs of time or eggs remains an issue of contention. Life-history models predict that parasitoids have some risk of exhausting their lifetime supply of oocytes. I develop a simple conceptual model that assesses the relative contributions of time and eggs to the cost of reproduction by placing them in a common currency: foregone future fitness returns. Although rates of egg limitation observed in nature are modest, eggs still often make the dominant contribution to the overall cost of oviposition. Therefore, models of parasitoid reproduction must recognize the costliness of both time and eggs. PMID- 28565415 TI - THE ASSOCIATION BETWEEN FLUCTUATING ASYMMETRY, TRAIT VARIABILITY, TRAIT HERITABILITY, AND STRESS: A MULTIPLY REPLICATED EXPERIMENT ON COMBINED STRESSES IN DROSOPHILA MELANOGASTER. AB - A number of hypotheses have been proposed about the association between developmental stability phenotypic variability, heritability, and environmental stress. Stress is often considered to increase both the asymmetry and phenotypic variability of bilateral traits, although this may depend on trait heritability. Empirical studies of such associations often yield inconsistent results. This may reflect the diversity of traits and conditions used or a low repeatability of any associations. To test for repeatable associations between these variables, multiply replicated experiments were undertaken on Drosophila melanogaster using a combination stress at the egg, larval and adult stages of reduced protein, ethanol in the medium, and a cold shock. Both metric and meristic traits were measured and levels of heritable variation for each trait estimated by maximum likelihood and parent-offspring regression over three generations. Trait means were reduced by stress, whereas among-individual variation increased Fluctuating asymmetry (FA) was increased by stress in some cases, but few comparisons were significant. Only one trait orbital bristle, showed consistent increases in FA. Changes in trait means, trait phenotypic variability, and developmental stability as a result of stress were not correlated. Extreme phenotypes tended to have higher levels of FA but only the results for orbital bristles were significant. All traits had low to intermediate heritabilities except orbital bristle, which showed no heritable variation. Only traits with low heritability and high levels of phenotypic variability may show consistent increases in FA under stress. Overall, the independence of phenotypic variability, plasticity, and the developmental stability of traits extend to changes in these measures under stressful conditions. PMID- 28565416 TI - KIN-STRUCTURED COLONIZATION AND SMALL-SCALE GENETIC DIFFERENTIATION IN SILENE DIOICA. AB - We investigated the genetic structure of a single island population of the dioecious plant Silene dioica in the Skeppsvik Archipelago, Umea, Sweden. The population is less than 10 years old and consists of approximately 700 individuals growing within an area of about 200 m2 . Despite the small scale of the study, levels of genetic differentiation among contiguous patches are greater than or comparable to what is observed over larger scales in the archipelago. The results suggest that the small-scale structuring occurs during population expansion, soon after island colonization, and that the observed patterns of genetic differentiation can be attributed to the population being substructured into family groups. This family structure results from kin-structured dispersal processes (colonization and migration) as the population expands over the island. As plant densities increase over time, either spatial fusion or temporal fusion of patches reduce the among patch variation. These processes, however, do not completely eradicate the genetic differentiation established by the kin structured dispersal processes. We discuss some implications of kin structuring for evolution through either kin or interdemic selection. PMID- 28565417 TI - RELATIONSHIP BETWEEN SELF-FERTILITY, ALLOCATION OF GROWTH, AND INBREEDING DEPRESSION IN THREE CONIFEROUS SPECIES. AB - Mortality and growth of self and outcross families of three wind-pollinated, mixed-mating, long-lived conifers, Douglas-fir (Pseudotsuga menziesii), ponderosa pine (Pinus ponderosa), and noble fir (Abies procera) were followed from outplanting to age 26 (25 for noble fir) in spaced plantings at a common test site. Response to inbreeding differed greatly among species over time and in all regards. Only Douglas-fir and noble fir will be contrasted here, because ponderosa pine usually was intermediate to the other two in its response to inbreeding. In earlier reports, compared to noble fir Douglas-fir had a higher rate of primary selfing and larger inbreeding depression in seed set. Douglas-fir continued to have higher inbreeding depression in nursery and early field survival. The species differed in time courses of inbreeding depression in height and in allocation of growth due to crowding. Between ages 6 and 12, the relative elongation rate (dm . dm-1 . yr-1 ) of Douglas-fir was significantly greater in the selfs than in the outcrosses. The response was not observed in noble fir. At final measurement, inbreeding depression in diameter relative to inbreeding depression in height was greater in Douglas-fir than in noble fir. At final measurement inbreeding depression in height was inversely related to inbreeding depression in survival. Cumulative inbreeding depressions from time of fertilization to final measurement were 0.98, 0.94, and 0.83 for Douglas-fir, ponderosa pine, and noble fir, respectively, which indicates that selfs will not contribute to the mature, reproductive populations. PMID- 28565418 TI - SEXUAL SELECTION ON BODY SIZE AND SHAPE IN THE WESTERN HARVESTER ANT, POGONOMYRMEX OCCIDENTALIS CRESSON. AB - Mating in social insects has generally been studied in relation to reproductive allocation and relatedness. Despite the tremendous morphological diversity in social insects, little is known about how individual morphology affects mating success. We examined the correlation of male size and shape with mating success in the western harvester ant, Pogonomyrmex occidentalis. Larger males had significantly higher mating success in two independent collections of males at mating aggregations. We also detected significant linear and nonlinear selection on aspects of male shape that were consistent across years. These shape components are independent of size, suggesting that male mating success is a complex function of size and shape. Successful males had elongate thoraxes and short mandibles relative to males collected at random at the lek. Overall, mated males also had longer postpetioles relative to body size, but there was also evidence of nonlinear selection on relative postpetiole length in both years. We found no evidence of assortative mating based on size or multivariate shape measures in either year, but in one year we found weak assortative mating based on some univariate traits. PMID- 28565419 TI - THE EVOLUTIONARY GENETICS OF AN ADAPTIVE MATERNAL EFFECT: EGG SIZE PLASTICITY IN A SEED BEETLE. AB - In many organisms, a female's environment provides a reliable indicator of the environmental conditions that her progeny will encounter. In such cases, maternal effects may evolve as mechanisms for transgenerational phenotypic plasticity whereby, in response to a predictive environmental cue, a mother can change the type of eggs that she makes or can program a developmental switch in her offspring, which produces offspring prepared for the environmental conditions predicted by the cue. One potentially common mechanism by which females manipulate the phenotype of their progeny is egg size plasticity, in which females vary egg size in response to environmental cues. We describe an experiment in which we quantify genetic variation in egg size and egg size plasticity in a seed beetle, Stator limbatus, and measure the genetic constraints on the evolution of egg size plasticity, quantified as the genetic correlation between the size of eggs laid across host plants. We found that genetic variation is present within populations for the size of eggs laid on seeds of two host plants (Acacia greggii and Cercidium floridum; h2 ranged between 0.217 and 0.908), and that the heritability of egg size differed between populations and hosts (higher on A. greggii than on C. floridum). We also found that the evolution of egg size plasticity (the maternal effect) is in part constrained by a high genetic correlation across host plants (rG > 0.6). However, the cross environment genetic correlation is less than 1.0, which indicates that the size of eggs laid on these two hosts can diverge in response to natural selection and that egg size plasticity is thus capable of evolving in response to natural selection. PMID- 28565420 TI - GENETICS OF FLUCTUATING ASYMMETRY: A DEVELOPMENTAL MODEL OF DEVELOPMENTAL INSTABILITY. AB - Although numerous studies have found that fluctuating asymmetry (FA) can have a heritable component, the genetic and developmental basis of FA is poorly understood. We used a developmental model of a trait, according to a diffusion threshold process, whose parameters are under genetic control. We added a small amount of random variation to the parameter values of this model to simulate developmental noise. As a result of the nonlinearity of the model, different genotypes differed in their sensitivity to developmental noise, even though the noise is completely random and independent of the genotype. The heritable component of FA can thus be understood as genetically modulated expression of variation that is itself entirely nongenetic. The loci responsible for this genetic variation of FA are the same that affect the left/right mean of the trait, showing that genetic variation for FA does not require genes that specifically control FA. Furthermore, the model offers alternative explanations for phenomena widely discussed in the literature on FA, for instance, the correlations between FA and heterozygosity and between FA and trait size. The model underscores the importance of dominance and epistasis, and therefore unites the study of FA with the classical theory of quantitative genetics. PMID- 28565421 TI - EXPERIMENTAL EVOLUTION OF HSP70 EXPRESSION AND THERMOTOLERANCE IN DROSOPHILA MELANOGASTER. AB - To examine whether recent evolutionary history affects the expression of Hsp70, the major heat-induced-heat shock protein in Drosophila melanogaster, we measured Hsp70 expression, thermotolerance, and hsp70 gene number in replicate populations undergoing laboratory evolution at different temperatures. Despite Hsp70's ancient and highly conserved nature, experimental evolution effectively and replicably modified its expression and phenotype (thermotolerance). Among five D. melanogaster populations founded from a common ancestral population and raised at three different temperatures (one at 18 degrees C, two each at 25 degrees C and 28 degrees C) for twenty years, Hsp70 expression varies in a consistent pattern: the replicate 28 degrees C lines expressed 30-50% less Hsp70 than the other lines at a range of inducing temperatures. This modification was refractory to acclimation, and correlated with thermotolerance: the 28 degrees C lines had significantly lower inducible tolerance of 38.5 degrees C and 39 degrees C. We verified the presence of five hsp70 genes in the genome of each line, excluding copy number variation as a candidate molecular basis of the evolved difference in expression. These findings support the ability of Hsp70 levels in D. melanogaster populations to change over microevolutionary time scales and implicate constancy of environmental temperature as a potentially important selective agent. PMID- 28565422 TI - APPLICABILITY OF THE HYPERGEOMETRIC PHENOTYPIC MODEL TO HAPLOID AND DIPLOID POPULATIONS. AB - We show that the phenotypic hypergeometric model of a quantitative trait can exactly describe both haploid and diploid populations. The condition necessary for this is equiprobability of genotypes within each phenotype. This requires equal allele frequencies across the loci, which may be the case when the population is under disruptive selection. PMID- 28565423 TI - FLUCTUATING ASYMMETRY IN A SALIX HYBRID SYSTEM: THE IMPORTANCE OF GENETIC VERSUS ENVIRONMENTAL CAUSES. AB - To examine the effects of hybridization and environmental stress on developmental instability, we examined fluctuating asymmetry (FA), the variance in random deviations from perfect symmetry in bilaterally symmetrical traits, for leaf symmetry in a Salix hybrid system. An abiotic environmental stress (water stress), an interspecific biotic stress (pathogen attack), and an intraspecific biotic stress (competition) were examined to determine which factors increase developmental instability. None of these three environmental stressors significantly increased FA. However, genetic stress through hybridization was detected; hybrid plants showed significantly higher levels of FA than parental species. In contrast to hybridization providing greater developmental stability through heterozygosity, these results suggest that complex, nonadditive interactions provided developmental stability and that developmental instability increased when coadapted gene complexes were disrupted through hybridization. In addition, plant biomass was significantly, negatively correlated with FA, suggesting that those individuals that were more able to buffer themselves against the disruptive effects of environmental stress may have a selective advantage over those that are less able to buffer themselves against these disruptive effects. PMID- 28565424 TI - SIZE, SYMMETRY, AND SEXUAL SELECTION IN THE HOUSEFLY, MUSCA DOMESTICA. AB - Relationships between measures of body size, asymmetry, courtship effort, and mating success were investigated in the housefly, Musca domestica (Diptera: Muscidae). A previous study indicated that both male and female flies with low fluctuating asymmetry enjoyed enhanced mating success. The aim of our investigations was to determine whether the greater success of symmetrical males is due to variation in male mating effort or to female choice and whether males exhibited mate choice. However, our study found directional rather than fluctuating asymmetry with both male and female flies having, on average, longer left wings than right. Also, asymmetry was not related to mating success in either sex. Rather, both males and females appeared to exhibit choice on the basis of the size of potential mates, with males preferring females with long bodies and females preferring heavy males. Possible benefits from choice of large mates are discussed. The initial mating strikes (in which the male leaps onto the back of the female) did not appear to be targeted according to female morphology, and their frequency did not vary according to male morphology. This indicates that mate choice by both sexes according to size probably occurs during the later stages of courtship, when the flies are in intimate contact. Possible reasons for the absence of choice according to asymmetry are discussed. PMID- 28565425 TI - COSTS OF EXPLOITING POISONOUS PREY: EVOLUTIONARY TRADE-OFFS IN A PREDATOR-PREY ARMS RACE. AB - Evolutionary trade-offs often are expected to arise between traits that share similar functions or resources. Such costs are well known from a variety of coevolutionary systems, but examples are conspicuously absent from predator-prey interactions. We present evidence of a trade-off between two disparate functions predatory and anti-predatory ability-in a species of garter snake that has evolved resistance to the neurotoxin of its prey. Patterns of among-family variation suggest a genetic basis to the trade-off. Both resistant and nonresistant populations of snakes exhibit the trade-off, suggesting that it stems from a fundamental aspect of organismal performance. This cost may help to explain the geographic mosaic of predator exploitative ability and prey defense that exists in this system. PMID- 28565426 TI - COINCIDENT BIOGEOGRAPHIC PATTERNS: INDO-WEST PACIFIC OCEAN. AB - The majority of tropical marine families demonstrate their greatest concentration of species within the relatively small East Indies Triangle. In every direction, the species diversity decreases with distance from the East Indies. Other patterns suggest that the East Indies is where the average generic age is youngest, where some historical routes of dispersal originate, where the most apomorphic species occur, where genetic diversity is the greatest, and where extinctions are likely to originate. These coincident patterns provide support for the hypothesis that the East Indies has been operating as a center of evolutionary radiation. The driving force for this dynamic system is apparently the predominance of successful speciation involving relatively large populations with higher genetic diversity. This mechanism fits the centrifugal speciation model that was proposed more than 50 years ago. PMID- 28565427 TI - SUPPRESSION OF SEX-RATIO MEIOTIC DRIVE AND THE MAINTENANCE OF Y-CHROMOSOME POLYMORPHISM IN DROSOPHILA. PMID- 28565428 TI - RESPONSE TO SELECTION IN PARTIALLY SELF-FERTILIZING POPULATIONS. II. SELECTION ON MULTIPLE TRAITS. AB - The structured linear model (SLM) is generalized to treat selection on multiple, correlated characters. Four different causes of phenotypic correlations are distinguished by the SLM: environmental covariance, identity disequilibrium, pleiotropy, and linkage disequilibrium. Each is characterized by distinct variables because they have different implications for character evolution. Correlations due to identity disequilibrium and linkage disequilibrium depend on both the mating system and the selection regime. As a consequence, they will evolve rapidly under selection. Correlations due to pleiotropy or environmental factors will evolve more slowly and are characterized by parameters that can be estimated from comparisons among relatives. These parameters include several novel "inbreeding covariance components" that emerge from the interaction of inbreeding and genetic dominance. Although data are limited, current estimates suggest that the expression of these components may substantially alter the pattern of multitrait evolution in self-fertilizing populations. PMID- 28565429 TI - INBREEDING DEPRESSION IN A SELF-COMPATIBLE, ANDRODIOECIOUS CRUSTACEAN, EULIMNADIA TEXANA. AB - The observation that offspring produced by the mating of close relatives are often less fit than those produced by matings between unrelated individuals (i.e., inbreeding depression) has commonly been explained in terms of the increased probability of expressing deleterious recessive alleles among inbred offspring (the partial dominance model). This model predicts that inbreeding depression should be limited in regularly inbreeding populations because the deleterious alleles that cause inbreeding depression (i.e., the genetic load) should be purged by regularly exposing these alleles to natural selection. We indirectly test the partial dominance model using four highly inbred populations of an androdioecious crustacean, the clam shrimp Eulimnadia texana. These shrimp are comprised of males and hermaphrodites, the latter capable of either self fertilizing or mating with a male (i.e., outcrossing between hermaphrodites is impossible). Hermaphrodites are further subdivided into monogenics (produced via self-fertilization) and amphigenics (produced via self-fertilization or outcrossing). Electrophoretic evidence suggests significant differences in heterozygosity among populations, but that selfing rates were not statistically different (average s = 0.67). Additional electrophoretic analyses reveal that three previously described sex-linked loci (Fum, Idh-1, and Idh-2) are all tightly linked to each other, with crossing over on the order of 1% per generation. Although selfing rates are clearly high, we present evidence that early inbreeding depression (hatching rates, juvenile survival, and age at sexual maturity) exists in all four populations. For all of these factors, inbreeding depression was inferred by the positive correlation of multilocus heterozygosity and fitness. Cumulative inbreeding depression (8) is between 0.41 and 0.47 across all populations, which appears to be too low to limit the effects of purging via identity disequilibrium. Instead, we suggest that the maintenance of inbreeding depression in these populations is due to the observed linkage group, which we suggest contains a large number of genes including many related to fitness. Segregation of such a large linkage group would explain our observations of the predominance of amphigenic hermaphrodites in our field samples and of survival differences between monogenics and amphigenics within selfed clutches. We propose that a modified form of the overdominance model for inbreeding depression operating at the level of linkage groups maintains the observed levels of inbreeding depression in these populations even in the face of high rates of selfing. PMID- 28565430 TI - LOCOMOTOR PERFORMANCE AT LOW TEMPERATURE AND THE EVOLUTION OF NOCTURNALITY IN GECKOS. AB - Nocturnal geckos are active at body temperatures 10-35 degrees C below the thermal optima for maximum rate of aerobic metabolism (V.O2max) of diurnal lizards. Therefore, given ancestral (diurnal) lizard physiology, nocturnality causes a substantial thermal handicap in locomotor performance. In prior studies, we hypothesized that a low minimum cost of locomotion (Cmin ) in geckos was an adaptation that increased locomotor endurance capacity at low, nocturnal temperatures. However, Cmin is only part of an integrated system that, in conjunction with the maximum rate of oxygen consumption, sets the maximum speed that can be sustained aerobically (termed the maximum aerobic speed or MAS). We conducted the first phylogenetic analysis of MAS and V.O2max lizards and found that the greatest changes in MAS, Cmin and V.O2max (at activity temperatures) in the evolutionary history of lizards all coincided with the evolution of nocturnality in geckos. Geckos active at 15-25 degrees C did not become optimized for nocturnal temperatures, or fully offset the thermal effects of nocturnality by evolving maximal rates of oxygen consumption comparable to diurnal lizards active at 35 degrees C. Geckos did evolve MAS twice that of diurnal lizards running at low temperatures by evolving a remarkably low Cmin . Allometric analysis and phylogenetically independent contrasts of V.O2max, Cmin , and MAS indicate a 72% evolutionary decrease in V.O2max, (at activity temperatures) and a 50% evolutionary decrease in Cmin concordant with the evolution of nocturnality in geckos. Experimental measurements show that decreased Cmin in six species of gecko increased MAS by 50-120% compared to diurnal lizards at low temperatures. Thus, geckos sufficiently overcame the near paralyzing effects of nocturnal temperatures, but only offset about 50% of the decrease in MAS resulting from the low maximum rate of oxygen consumption. Although the nocturnal environment remains severely suboptimal, the evolution of a low cost of locomotion in the ancestor of geckos was highly adaptive for nocturnality. We also present a generalized approach to ecophysiological evolution that integrates phylogeny with the causal relationships among environment, physiology, and performance capacity. With respect to a clade, two hypotheses are central to our integrative approach: (1) a change of an environmental variable (e.g., temperature) causes a performance handicap; and (2) evolution of a physiological variable (e.g., minimum cost of locomotion [Cmin ]) increases performance in the derived environment. To test the hypothesis that evolution of a physiological variable is adaptive in nature, we suggest determining if individuals in nature perform at levels exceeding the performance capacity of their hypothetical ancestors and if this additional performance capacity is due to the evolution of the physiological variable in question. PMID- 28565432 TI - RARER NEED NOT BE BETTER IF COMMONER IS WORSE: FREQUENCY-DEPENDENT SELECTION FOR DEVELOPMENTAL TIME AT THE ALCOHOL DEHYDROGENASE LOCUS OF THE OLIVE FRUIT FLY, BACTROCERA OLEAE. AB - Whereas the importance of frequency-dependent selection in life-history traits, behavioral characters and source allocation patterns is widely accepted, its role in governing biochemical and molecular polymorphisms remains poorly understood. Here we demonstrate a case of allozyme frequency-dependent selection. When olive fruit flies (Bactrocera oleae) are reared on an artificial larval medium, an allele at the alcohol dehydrogenase locus that is present in very low frequency in natural populations increases to about one-third in less than five generations. We show here that the time from the hatching of the egg to the eclosion of the adult is affected by the genotype composition of the larval population that grows in the same cup of food. Cultures consisting of one genotype only have the longest developmental time, and two-allele cultures in which the two homozygotes and the heterozygote occur in a 1:1:2 ratio show the shortest developmental time. Cultures with intermediate genotypic compositions show intermediate levels of developmental time. The results can be explained by assuming that the developmental time of a genotype depends on the frequency array of all genotypes in the larval population and is not merely a function of its own frequency. It is even possible that the developmental time of a genotype becomes longer as the genotype becomes rarer, yet the genotype will be favored because the developmental times of the competing genotypes become even longer owing to the associated increase of their frequencies. Given that developmental time is inversely related to fitness, this generates a frequency-dependent selection, with developmental times changing progressively until the population arrives at an equilibrium. One optimum population composition that provides a satisfactory fit to allele frequency changes in our experimental populations is when the two alleles occur in equal frequencies and genotypes are in Hardy-Weinberg proportions. We argue that this type of selection is consistent with the role of alcohol dehydrogenase as a detoxifying enzyme in a medium that undergoes continuous chemical changes during its use by the feeding larvae. PMID- 28565431 TI - LOCAL MALADAPTATION IN THE ANTHER-SMUT FUNGUS MICROBOTRYUM VIOLACEUM TO ITS HOST PLANT SILENE LATIFOLIA: EVIDENCE FROM A CROSS-INOCULATION EXPERIMENT. AB - Conventional wisdom holds that parasites evolve more rapidly than their hosts and are therefore locally adapted, that is, better at exploiting sympatric than allopatric hosts. We studied local adaptation in the insect-transmitted fungal pathogen Microbotryum violaceum and its host plant Silene latifolia. Infection success was tested in sympatric (local) and allopatric (foreign) combinations of pathogen and host from 14 natural populations from a metapopulation. Seedlings from up to 10 seed families from each population were exposed to sporidial suspensions from each of four fungal strains derived from the same population, from a near-by population (< 10 km distance), and from two populations at an intermediate (< 30 km) and remote (< 170 km) distance, respectively. We obtained significant pathogen X plant interactions in infection success (proportion of diseased plants) at both fungal population and strain level. There was an overall pattern of local maladaptation of this pathogen: average fungal infection success was significantly lower on sympatric hosts (mean proportion of diseased plants = 0.32 +/- 0.03 SE) than on allopatric hosts (0.40 +/- 0.02). Five of the 14 fungal populations showed no strong reduction in infection success on sympatric hosts, and three even tended to perform better on sympatric hosts. This pattern is consistent with models of time-lagged cycles predicting patterns of local adaptation in host-parasite systems to emerge only on average. Several factors may restrict the evolutionary potential of this pathogen relative to that of its host. First, a predominantly selfing breeding system may limit its ability to generate new virulence types by sexual recombination, whereas the obligately outcrossing host 5. latifolia may profit from rearrangement of resistance alleles by random mating. Second, populations often harbor only a few infected individuals, so virulence variation may be further reduced by drift. Third, migration rates among host plant populations are much higher than among pathogen populations, possibly because pollinators prefer healthy over diseased plants. Migration among partly isolated populations may therefore introduce novel host plant resistance variants more often than novel parasite virulence variants. That migration contributes to the coevolutionary dynamics in this system is supported by the geographic pattern of infectivity. Infection success increased over the first 10-km range of host-pathogen population distances, which is likely the natural range of gene exchange. PMID- 28565433 TI - SUCCESSFUL FATHERS SIRE SUCCESSFUL SONS. AB - The theory of sexual selection holds a central role in evolutionary biology. Its key assumption is the heritability of traits associated with reproductive success. Strong indirect evidence supporting this assumption comes from the numerous studies that have identified heritable traits associated with mating success. However, there remain only a handful of studies that have attempted to demonstrate directly that successful fathers have successful sons. We present the results of an experimental study of the mating success and phenotype of male field crickets Gryllus bimaculatus (Orthoptera: Gryllidae) and their offspring. These reveal that sons of successful males obtain significantly more copulations than sons of unsuccessful males. There was no difference in body size of sons of either group, but sons of successful males had significantly longer development times. This may represent a naturally selected cost to traits associated with success that could balance their sexually selected advantages. PMID- 28565434 TI - THE AGE AND RELATIONSHIPS OF THE MAJOR ANIMAL PHYLA. AB - Given the uncertainties in the fossil record and the paucity of informative morphological characters, there is still considerable uncertainty as to the phylogenetic affinities and times of origins of essentially all of the phyla of animals. A multilocus analysis of amino-acid sequence data for mitochondrial genes suggests that the major triploblast phyla began diverging approximately 630 million years ago. These results support the hypothesis that the so-called Cambrian radiation of animals actually initiated about 100 million years prior to the Cambrian, as the fossil evidence suggests. In addition, phylogenetic analysis supports the monophyly of animals, an early (~900 million years ago) branching off of the cnidarian lineage, the monophyly of deuterostomes and protostomes, and the inclusion of nematodes in the protostome lineage. The results of this study suggest that, with appropriate levels of taxon sampling and a focus on conserved regions of protein-coding sequence, complete mitochondrial genome analysis may be sufficiently powerful to elucidate the genealogical relationships of many of the animal phyla. PMID- 28565435 TI - GAMETE INTERACTIONS AND GENETIC DIFFERENTIATION AMONG THREE SYMPATRIC POLYCHAETES. AB - The evolution of gamete incompatibility between free-spawning marine invertebrate species has been explained by three hypotheses: (1) independent divergence at gamete recognition loci; (2) selection against hybrids; and (3) a process of sexual selection involving polymorphic gamete recognition loci (Metz and Palumbi 1996). The first two hypotheses predict that gamete incompatibility appears only after gene flow has been halted for other reasons and the third that gamete incompatibility appears simultanously with blocks to gene flow. Here I show that gametes of three sympatric polychaetes in the genus Arctonoe are compatible in all crosses, over a broad range of gamete concentrations and contact times. Although at least some hybrid crosses produce fertile adults, allozyme and mitochondrial DNA sequence data indicate that the three species do not regularly exchange genes. These data are consistent with predictions of the first two hypotheses for the evolution of gamete incompatibility, but allow rejection of the third hypothesis. Gametes of the three species are compatible despite estimated divergence times of 1-3 M.Y.B.P.; in several other marine invertebrates, divergence times of the same magnitude are associated with asymmetric or complete gamete incompatibility. It appears likely that segregation of symbiotic adults on their respective host species restricts mating opportunities, and thus gene flow, among Arctonoe species. PMID- 28565436 TI - COASTAL REFUGIA AND POSTGLACIAL RECOLONIZATION ROUTES: A REPLY TO DEMBOSKI, STONE, AND COOK. PMID- 28565437 TI - POPULATION SEX STRUCTURE AND REPRODUCTIVE FITNESS IN GYNODIOECIOUS SIDALCEA MALVIFLORA MALVIFLORA (MALVACEAE). AB - The spatial distribution of females and hermaphrodites within gynodioecious populations is expected to exert considerable selective pressure on gender fitness through pollen limitation of seed set. If pollen flow is predominantly local, seed set in individual plants may be sensitive to the proximity of pollen donors; pollen limitation of seed set may occur if hermaphrodites are locally rare. Under such circumstances, female fitness will be negatively frequency dependent and hermaphrodite fitness will be positively frequency dependent. Given local seed dispersal, a nonrandom clumped distribution of the genders is expected in gynodioecious populations due to the heritability of gender in gynodioecious species. If gender fitness is frequency dependent, such structure should favor hermaphrodites and select against females. To test this hypothesis, I quantified the distribution of the genders in terms of nearest neighbors and neighborhood sex ratio in two populations of gynodioecious Sidalcea malviflora malviflora. I then measured the effect of neighborhood sex ratio on open-pollinated seed set and pollen limitation in both manipulated and unmanipulated neighborhoods. Results indicate that the genders have a patchy distribution and that both genders are pollen limited and show an increase in seed set with an increase in neighborhood hermaphrodite frequency. The observed population sex structure favors hermaphrodites and disadvantages females. These results highlight the importance that population-level traits can have in determining individual fitness and the evolution of sex ratios in gynodioecious species. PMID- 28565438 TI - INSIGHT INTO SPECIATION FROM HISTORICAL DEMOGRAPHY IN THE PHYTOPHAGOUS BEETLE GENUS OPHRAELLA. AB - Speciation in phytophagous insects is commonly associated with shifts in host use. Using a phylogenetic framework to identify recently diverged taxa that have undergone a radical host shift, this study focuses on how reconstruction of the historical demography of a species, in conjunction with branching patterns between species, provides insight into mode of speciation. Analyses of mitochondrial cytochrome oxidase I sequences indicate that the leaf beetle Ophraella communa exhibits significant population structure, as shown by patterns of genealogical relationships among mitochondrial haplotypes and high FST values. However, the absence of regional localization of old clades of haplotypes, negative Tajima's D, and unimodal rather than bimodal frequency distribution of the number of pairwise differences between sequences suggests an absence of long-term barriers to gene flow. Furthermore, we found no evidence of isolation by distance. This pattern of genetic variation is consistent with episodes of gene flow on a large geographic scale, perhaps owing to Pleistocene changes in climate. Ophraella communa and its sister species O. bilineata diverged during the early Pleistocene. The evidence of dynamic population structure in O. communa, potentially including episodic but massive gene flow, suggests that reproductive isolation evolved quite rapidly on a localized geographic scale, because speciation would probably have been reversed by gene flow if the evolution of reproductive isolation had been prolonged. That is, gene flow occasioned by range shifts during the Pleistocene would likely have interrupted speciation unless it occurred very rapidly. Sequence diversity implies a large effective population size (> 106 ) in both O. communa and O. bilineata. However, a model based on a drastic bottleneck did not have a lower likelihood than a model with no bottleneck, simply because the time since speciation has been great enough for coalescence to a single ancestor that existed after the speciation event. Sequence diversity in itself, without reference to the time since speciation, cannot provide evidence on the demography of speciation. PMID- 28565439 TI - CYTOCHROME C OXIDASE ACTIVITY IN INTERPOPULATION HYBRIDS OF A MARINE COPEPOD: A TEST FOR NUCLEAR-NUCLEAR OR NUCLEAR-CYTOPLASMIC COADAPTATION. AB - The respiratory enzyme cytochrome c oxidase (COX) is composed of subunits encoded by both nuclear and mitochondrial genes; thus, COX activity reflects, to some extent, the coordinated function of the two genomes. Because extensive mtDNA differentiation exists between populations of the copepod Tigriopus californicus, we hypothesized that laboratory hybridizations that disrupt natural combinations of nuclear and mitochondrial genes might negatively impact COX activity. Although experimental results varied greatly among different crosses, replicate sets of crosses between two particular populations showed consistent evidence for nuclear cytoplasmic coadaptation. PMID- 28565440 TI - SEXUAL SIZE DIMORPHISM AND REPRODUCTIVE INVESTMENT BY FEMALE SPIDERS: A COMPARATIVE ANALYSIS. AB - We investigate the association between female reproductive investment, absolute size, and sexual size dimorphism in spiders to test the predictions of the fecundity-advantage hypothesis. The relationships between absolute size and sexual size dimorphism and aspects of female reproductive output are examined in comparative analyses using phylogenetically independent contrasts. We provide support for the idea that allometry for sexual dimorphism is the result of variation in female size more so than male size. Regression analyses suggest selection for increased fecundity in females. We argue that fecundity selection provides the only general explanation for the evolution of sexual size dimorphism in spiders. PMID- 28565441 TI - DO IMAGE-FORMING EYES PROMOTE EVOLUTIONARY DIVERSIFICATION? AB - It has been suggested that image-forming eyes promote the evolutionary diversification (measured by species richness) of the groups that possess them. Several different processes could give rise to this effect, including diversifying selection in a new adaptive zone (or zones) and a reduced rate of extinction due to enhanced competitive abilities. I tested the generality of the hypothesis that imaging eyes increase net speciation by comparing extant species numbers of 12 groups that have such eyes (as categorized by Land and Fernald 1992) with those of their cladistic sister groups that lack such organs. Even assuming the published hypotheses of phylogenetic relationships that most favor increased net speciation of visual groups, these comparisons show no significant association between imaging eyes and species richness. Increased activity, as indicated by published accounts of locomotory speed, is significantly associated with the evolution of image-forming eyes. This suggests that a large "visual adaptive zone" might be characterized by relatively high activity. However, when diversity comparisons are limited to eight cases in which the evolution of imaging eyes is associated with increased activity, there is still no significant association between such eyes and species richness. The fossil record indicates that the only visual groups that have undergone major evolutionary radiations evolved imaging eyes early in the history of metazoans (before the Silurian). The radiations of these early groups may have largely filled up niches for visual animals and thus prevented the subsequent proliferation of other groups with image-forming eyes. Alternatively, it may be that image-forming eyes have no exceptional effect on diversification or that their effects are obscured by other factors in the long run. PMID- 28565442 TI - MAJOR GENETIC DIFFERENCES BETWEEN CROWN-OF-THORNS STARFISH (ACANTHASTER PLANCI) POPULATIONS IN THE INDIAN AND PACIFIC OCEANS. AB - Spatial variation in allelic frequencies at nine allozyme loci were assayed in 20 populations of the crown-of-thorns starfish, Acanthaster planci, collected throughout the Pacific and Indian Oceans. These data were analyzed together with published data, for the same loci, from an additional 19 populations, giving a total sample size of approximately 1800 individuals. There was a marked discontinuity between the Indian and Pacific Ocean populations, but those off Western Australia and from the Southeast Asian region had a strong Pacific affinity. The genetic groups were congruent with the distributions of two color morph groups: gray-green to red-brown forms in the Pacific and a blue to pale red form in the Indian Ocean. These patterns of genetic structure are similar to those described for the starfish Linckia laevigata, which has similar life history characteristics. Vicariant events may have influenced some populations within the Pacific, but the allozyme data cannot resolve the effects of these events clearly. Patterns of variation within regions were consistent with isolation by distance, but, at larger scales, were obscured by regional vicariance and some outliers, particularly by apparently high levels of gene flow between Japan and the Great Barrier Reef, Australia. Apparent gene flow between population pairs was not closely related to present-day ocean currents. The results demonstrate a strong influence of allopatric separation on genetic divergence at large geographic scales, but also show evidence of slow rates of change in gene frequencies consistent with the large population sizes of this species. Low levels of divergence between groups demonstrate the genetic structure is recent (Pleistocene) and are likely responses to changes in climate and sea level. PMID- 28565443 TI - MORPHOLOGICAL AND MOLECULAR VARIATION ACROSS A MIGRATORY DIVIDE IN WILLOW WARBLERS, PHYLLOSCOPUS TROCHILUS. AB - A migratory divide is a narrow region in which two populations showing different migratory directions meet arid presumably also mate and hybridize. Banding of willow warblers, Phylloscopus trochilus, in Europe has demonstrated a migratory divide latitudinally across central Scandinavia. In autumn, southern birds migrate southwest to tropical West Africa, whereas northern birds migrate southeast to East and South Africa. The migratory divide is associated with concordant differences in size and plumage coloration. Based on morphology, we estimate the width of the transition zone between northern and southern willow warblers to be less than 350 km. We found indication of linkage disequilibria around the migratory divide, in that measures of body size were correlated with plumage coloration within the contact zone, but uncorrelated within the populations south or north of the contact zone. The presence of linkage disequilibria and the fact that several morphological clines occur together suggest that the hybrid zone is a result of secondary contact between populations that have differentiated in allopatry. This interpretation is in accord with the knowledge of the recolonization pattern of the Scandinavian peninsula after the last glaciation; animals and plants appeared to have colonized either from the south or from the north around the northern bay of the Baltic Sea. If northern and southern willow warblers resided in allopatric populations during late Pleistocene glaciations and the hybrid zone is a result of postglacial range expansions, we would expect some degree of genetic differentiation accumulated during the period in isolation. In contrast, northern and southern willow warblers are near panmictic in the frequencies of alleles of mitochondrial DNA and at two microsatellite loci. The observed pattern, clear morphological and behavioral differentiation without genetic differentiation at neutral loci, suggests either that the differences are maintained by strong selection on the expressed genes in combination with high levels of current gene flow or, in the case of weak gene flow, that the divergence in morphology and behavior is very recent. PMID- 28565444 TI - FURTHER PERSPECTIVES ON THE HAIDA GWAII GLACIAL REFUGIUM. PMID- 28565445 TI - MEASURING NATURAL SELECTION ON PHENOTYPIC PLASTICITY. AB - To understand natural selection we need to integrate its measure across environments. We present a method for measuring phenotypic selection that combines the potential for both environmental variation and phenotypic plasticity. The method uses path analysis and a measure of selection that is analogous to selection on breeding values. For individuals growing in alternative environments, paths are created that represent potential changes in the environment. The probabilities for these changes are then multiplied by the path coefficients to calculate selection coefficients. Selection on plasticity is measured as the difference in selection within each environment. We illustrate these methods using data on selection in an experimental population of Arabidopsis thaliana. Individuals from 36 families were grown in one of four environments, a factorial combination of shaded/open and early/late shading. For final height of the inflorescence, there was positive selection in both the open and shaded environments and negative selection on plasticity of height. For bolting time, there was also positive selection in both environments, but no selection on plasticity. We show how to use this information to examine how selection would change with changes in environmental frequencies and their transition probabilities. These methods can be expanded to encompass continuous traits and continuous environments as well as other complexities of natural selection. PMID- 28565446 TI - BIOCHEMICAL EVOLUTION ASSOCIATED WITH ANTIPREDATOR ADAPTATION IN DAMSELFLIES. AB - Previous studies have shown that at least two lineages of Enallagma damselflies (Odonata: Coenagrionidae) shifted from inhabiting lakes with fish as top predators to inhabiting ponds and lakes with large dragonflies as the top predators. In adapting to living with the new predator type, these lineages evolved much greater swimming speeds to avoid attacking dragonflies. In this paper, I test whether biochemical adaptations to fuel swimming arose in concert with previously identified morphological changes that increase swimming speed. I assayed the mass-specific enzyme activities of three enzymes involved in fueling strenuous activity: pyruvate kinase and lactate dehydrogenase (enzymes involved in glycolysis) and arginine kinase (the enzyme that recharges the ATP pool). Enzyme activities were determined for 14 Enallagma species from across the genus. Species that coexist with dragonfly predators had significantly higher mass specific arginine kinase activities than species that coexist with fish, and the results of evolutionary contrasts analyses indicate that this difference between the two groups is the result of evolutionary change associated with the habitat shifts of lineages from fish lakes to dragonfly lakes. Although significant evolution was documented for lactate dehydrogenase and pyruvate kinase across the genus, evolutionary change in the activities of these enzymes was not consistent with adaptation to coexisting with dragonfly predators. Swimming bouts to avoid dragonfly predators last for only a few seconds, and the action of arginine kinase to phosphorylate ADP to make ATP will extend the duration of maximal exertion for swimming for a few seconds. However, much longer time periods (over 45 sec) are required to generate ATP via glycolysis. Therefore, selection may have favored adaptation only at the arginine kinase locus. PMID- 28565447 TI - GENETIC LOAD OF THE YEAST SACCHAROMYCES CEREVISIAE UNDER DIVERSE ENVIRONMENTAL CONDITIONS. AB - Fitness effect of spontaneous mutations accumulated in mismatch-repair deficient strains of yeast was estimated by measuring their maximum growth rate. Several environments with different energetic substrates, nutritional conditions, and temperature were tested. Genetic load of haploid strains was about 20-30% under most of these conditions. Because such a pronounced effect was caused by relatively small lesions (point mutations) affecting probably less than 1% of genes, resistance of the yeast genome to DNA damage appears to be rather limited. Fitness transitions among environments were orderly, in the sense that some strains tended to be more or less fit than others in all circumstances. One of the environments (an extremely high temperature, 38 degrees C) was stressful to the strains that accumulated mutations, as some of them stopped to grow, whereas the mutation-free strains were only moderately affected. These results imply that the impact of random point mutations is substantial and generally not dependent on a particular environment. Under stressful conditions, however, natural selection may be especially effective in purging mutations that, if commonly met, could slow down the rate of mutation accumulation. PMID- 28565448 TI - NATURAL GENETIC VARIATION OF LIFE SPAN, REPRODUCTION, AND JUVENILE GROWTH IN DAPHNIA. AB - The evolutionary theory of senescence predicts that high extrinsic mortality in natural populations should select for accelerated reproductive investment and shortened life span. Here, we test the theory with natural populations of the Daphnia pulex-pulicaria species complex, a group of freshwater zooplankton that spans an environmental gradient of habitat permanence. We document substantial genetic variation in demographic life-history traits among parent and hybrid populations of this complex. Populations from temporary ponds have shorter life spans, earlier and faster increases of intrinsic mortality risk, and earlier and steeper declines in fecundity than populations from permanent lakes. We also examine the age-specific contribution to fitness, measured by reproductive value, and to expected lifetime reproduction; these traits decline faster in populations from temporary ponds. Despite having more rapid senescence, pond Daphnia exhibit faster juvenile growth and higher early fitness, measured as population growth rate (r). Among populations within this species complex we observed negative genetic correlations between r and indices of life-history timing, suggesting trade-offs between early- and late-life performance. Our results cannot be explained by a trade-off between survival and fecundity or by nonevolutionary theories of senescence. Instead, our data are consistent with the evolutionary theory of senescence because the genetic variation in life histories we observed is roughly congruent with the temporal scale of environmental change in the field. PMID- 28565449 TI - PERSPECTIVE: THE PACE OF MODERN LIFE: MEASURING RATES OF CONTEMPORARY MICROEVOLUTION. AB - We evaluate methods for measuring and specifying rates of microevolution in the wild, with particular regard to studies of contemporary, often deemed "rapid," evolution. A considerable amount of ambiguity and inconsistency persists within the field, and we provide a number of suggestions that should improve study design, inference, and clarity of presentation. (1) Some studies measure change over time within a population (allochronic) and others measure the difference between two populations that had a common ancestor in the past (synchronic). Allochronic studies can be used to estimate rates of "evolution," whereas synchronic studies more appropriately estimate rates of "divergence." Rates of divergence may range from a small fraction to many times the actual evolutionary rates in the component populations. (2) Some studies measure change using individuals captured from the wild, whereas others measure differences after rearing in a common environment. The first type of study can be used to specify "phenotypic" rates and the later "genetic" rates. (3) The most commonly used evolutionary rate metric, the darwin, has a number of theoretical shortcomings. Studies of microevolution would benefit from specifying rates in standard deviations per generation, the haldane. (4) Evolutionary rates are typically specified without an indication of their precision. Readily available methods for specifying confidence intervals and statistical significance (regression, bootstrapping, randomization) should be implemented. (5) Microevolutionists should strive to accumulate time series, which can reveal temporal shifts in the rate of evolution and can be used to identify evolutionary patterns. (6) Evolutionary rates provide a convenient way to compare the tempo of evolution across studies, traits, taxa, and time scales, but such comparisons are subject to varying degrees of confidence. Comparisons across different time scales are particularly tenuous. (7) A number of multivariate rate measures exist, but considerable theoretical development is required before their utility can be determined. We encourage the continued investigation of evolutionary rates because the information they provide is relevant to a wide range of theoretical and practical issues. PMID- 28565450 TI - AGE AND POLYPHYLETIC ORIGINS OF HYBRID AND SPONTANEOUS PARTHENOGENETIC CAMPELOMA (GASTROPODA: VIVIPARIDAE) FROM THE SOUTHEASTERN UNITED STATES. AB - We used mtDNA sequence variation to assess the origin, age, and spatial patterns of sequence divergence of triploid hybrid and diploid spontaneous parthenogens from southeastern United States populations of the freshwater snail Campeloma. There was strong support for multiple origins of both parthenogens using likelihood-ratio tests, and we argue that parthenogens are recently derived from sexuals. Atlantic coastal populations of C. limum or C. floridense were the maternal ancestors of Gulf Coast triploid hybrids in the Florida Panhandle. Sequence divergence within monophyletic groups of both parthenogens is similar to within-population divergence found in sympatric sexuals, and monophyletic clades of hybrid and spontaneous parthenogens are geographically widespread throughout the Atlantic and Gulf Coast rivers. These patterns are consistent with higher dispersal rates and recent range expansion of parthenogens, which should reduce the effects of mutation accumulation or parasitism. Range expansion may have occurred through interdrainage transfer during Pleistocene glacial periods. PMID- 28565451 TI - THE HISTORICAL PATTERN OF GENE FLOW AMONG MIGRATORY AND NONMIGRATORY POPULATIONS OF PRAIRIE WARBLERS (AVES: PARULINAE). AB - Within a group of interbreeding organisms, the balance of gene flow among populations and microevolutionary forces acting within populations is expected to result in clinal transitions in the phenotypes possessed by members of differentiated populations. Discontinuous variation between geographically adjacent populations suggests the presence of a significant barrier to gene flow. Here I present genetic evidence for restricted gene flow between migratory and nonmigratory populations of prairie warblers. The nonmigratory form of this species is restricted to coastal mangroves in Florida and is morphologically distinguishable from the typical, migratory form that occurs across the remainder of the eastern United States. Pairs of migratory populations exhibited little population subdivision (PhiST ? 0.09), whereas pairs of migratory and nonmigratory populations are much more differentiated (PhiST = 0.27-0.42). A phylogenetic analysis of mitochondrial DNA haplotypes did not offer evidence of long-term isolation of migratory and nonmigratory populations. Together with the population genetic analysis, the phylogenetic relationship of haplotypes suggests that isolation between these forms must have arisen relatively recently in their history. Evidence for significant population structure is unexpected, given the geographic proximity of migratory and nonmigratory populations, the capacity for long-distance movements (e.g., migration) by prairie warblers, and several previous studies of population structure in North American birds. However, the findings are consistent with the geographic distribution of morphological and behavioral variation and demonstrate that significant boundaries between populations of vagile organisms may be relatively cryptic. PMID- 28565452 TI - OPTIMAL SAMPLING DESIGNS FOR STUDIES OF GENE FLOW-A CHALLENGING TRADE-OFF: A REPLY TO KLEIN AND LAREDO. PMID- 28565453 TI - MUTATIONAL CONTRIBUTIONS TO GENETIC VARIANCE-COVARIANCE MATRICES: AN EXPERIMENTAL APPROACH USING INDUCED MUTATIONS IN ARABIDOPSIS THALIANA. AB - Genetic potential for evolutionary change and covariational constraints are typically summarized as the genetic variance-covariance matrix G, and there is currently debate over the extent to which G remains effectively constant during the course of adaptive evolution. However, G provides only a temporally restricted view of constraints that ignores possible biases in how new mutations affect multivariate phenotypes. We used chemical mutagenesis to study the effect of mutations as summarized by the mutational covariance matrix, M, in Arabidopsis thaliana. By introducing mutations into three isogenic strains of A. thaliana, we were able to quantify M directly as the genetic variance-covariance matrix of mutagenized lines. Induced mutations generally did not alter the means of the six morphology and life-history traits we measured, but they did affect the levels of available genetic variation and the covariances among traits. However, these effects were not consistent among the three isogenic lines; that is, there were significant differences among the lines in both the number of mutations produced by ethyl-methane-sulfonate treatment and the M matrices they induced. The evolutionary implications of the dependence of M on the number of mutations, the particular genetic background, and the mutagenic sampling of loci in the genome are discussed in light of commonly applied models of multivariate evolution and the potential for the genetic architecture itself to change in ways that facilitate the coordinated evolution of complex phenotypes. PMID- 28565454 TI - LIMITS TO THE SOUTHERN BORDER OF DROSOPHILA SERRATA: COLD RESISTANCE, HERITABLE VARIATION, AND TRADE-OFFS. AB - There are a number of evolutionary hypotheses about why species distributions are limited, but very little empirical information to test them. We present data examining whether the southern distribution of Drosophila serrata is limited by cold responses. Species comparisons were undertaken for cold resistance, development time, and viability at 15 degrees C and 25 degrees C for D. serrata and other species with a more southerly distribution (D. melanogaster, D. simulans, and D. immigrans). Relative to the other species, D. serrata had a long development time at both temperatures and a low level of cold resistance. Using isofemale lines collected in different seasons, central and marginal populations were compared for cold resistance, as well as development time and viability at 14 degrees C. The border population had a relatively higher resistance to cold shock in postwinter collections, but there was no population differentiation for prewinter collections or for the other traits. The presence of variation among isofemale lines within the border populations suggests that genetic variation as measured in the laboratory is unlikely to limit range expansion. Population cages were used in the field to determine if D. serrata persisted over winter at borders. Although all cages yielded adult offspring at northern sites, only a few produced offspring at or just south of the border. In contrast, all cages with D. simulans produced adult offspring, suggesting that climatic factors limited D. serrata numbers. Offspring from surviving adults showed a phenotypic trade-off between fecundity and cold resistance. Comparisons of the cold resistance of field males and females with their laboratory-reared offspring provided evidence for heritable variation in field-reared flies. Overall, the results suggest that cold stress is important in limiting the southern distribution of D. serrata, but it seems unlikely that a lack of genetic variation restricts range expansion. PMID- 28565455 TI - ENHANCING THE RETRDEVABILITY OF POPULATION GENETIC SURVEY DATA? AN ASSESSMENT OF ANIMAL MITOCHONDRIAL DNA STUDIES. AB - Surveys of genetic variation in natural populations represent a valuable and often irreplaceable resource. It may be desirable to reanalyze data as new methods are developed for comparisons with other populations or for comparisons with the same populations at different times. We evaluated existing mechanisms of data preservation in a survey of 627 published surveys of mitochondrial DNA variation in animal and found that over half of the datasets (56%) contained insufficient information for reanalysis. In many cases, publication of complete data would not have added excessively to the length of the publication. Because at present, publications represent the main archive of population genetic data, we offer recommendations for how the essential data from mtDNA surveys can be presented in a form that is complete and concise. PMID- 28565456 TI - THE EFFECT OF NUCLEAR AND CYTOPLASMIC GENES ON FITNESS AND LOCAL ADAPTATION IN AN ANNUAL LEGUME, CHAMAECRISTA FASCICULATA. AB - The role of nuclear genes in local adaptation has been well documented. However, the role of maternally inherited cytoplasmic genes to the evolution of natural populations has been relatively unstudied. To evaluate the contribution of cytoplasmic and nuclear genomes and their interactions to local adaptation we created second-generation backcross hybrids between a Maryland and an Illinois population of the annual legume Chamaecrista fasciculata. Backcross progeny were planted in the sites native to each population for two years and we quantified germination, survivorship, fruit production, vegetative biomass, and cumulative fitness. We found limited evidence for the contribution of either cytoplasmic or nuclear genes to local adaptation. In Maryland plants had greater survivorship, biomass, fruit production, and cumulative fitness if their nuclear genome was composed predominately of native Maryland genes; cytoplasmic genes did not affect fitness. In Illinois local cytoplasm marginally enhanced fitness, whereas Maryland nuclear genes outperformed local nuclear genes. Interactions between cytoplasmic and nuclear genes influenced seed weight, vegetative biomass, and fitness and therefore may affect evolution of these characters. Genetic effects were stronger acting through seed size than directly on characters. However, seed size differences between the two populations were largely genetic and therefore selection on fitness components is likely to result in evolutionary change. The contribution of nuclear and cytoplasmic genes to fitness components varied across sites and years, suggesting that experiments should be replicated and conducted under natural conditions to understand the influence of these genomes and their interactions to population differentiation. PMID- 28565457 TI - HYBRIDIZATION IN LEOPARD FROGS (RANA PIPIENS COMPLEX): LARVAL FITNESS COMPONENTS IN SINGLE-GENOTYPE POPULATIONS AND MIXTURES. AB - Recognizing the predominant mode of selection in hybrid systems is important in predicting the evolutionary fate of recombinant genotypes. Natural selection is endogenous if hybrid genotypes are at a disadvantage relative to parental species independent of environment. Alternatively, relative fitness can vary in response to environmental variation (exogenous selection), and hybrid genotypes can possess fitness values equal to or greater than that of parental species. I investigated the nature of natural selection in a leopard frog hybrid system by rearing larvae of hybrid and parental genotypes between Rana blairi and R. sphenocephala in 1000-L outdoor experimental ponds. Three hybrid (F1 , backcrossj [B1 ], backcross2 [B2 ]) and two parental (R. blairi [BB] and R. sphenocephala [SS]) larval genotypes were produced by artificial fertilzations using adult frogs from a natural population in central Missouri. Resultant larvae were reared in single-genotype populations and two-way mixtures at equal total numbers from hatching to metamorphosis. In single-genotype ponds, F1 hybrid larvae had highest survival and BB were largest at metamorphosis. When F1 and SS larvae were mixed together, F1 hybrids had reduced survival and both F1 and SS larvae metamorphosed at larger body masses than when reared separately. When mixed, both B1 and SS larvae had shorter larval period lengths than when reared alone. Higher proportion of B1 metamorphs were produced when larvae were mixed with either parental species than when reared alone. Larval fitness components as measured by survival, body mass at metamorphosis, proportion of survivors metamorphosing, and larval period length for B2 hybrid and BB larvae were similar in single-genotype populations and mixtures. Comparison of composite fitness component estimates indicated hybrid genotypes possess equivalent or higher larval fitness relative to both parental species for the life-history fitness components measured. Despite reduced survival of F1 hybrids in mixtures, backcross-generation hybrid genotypes demonstrated high levels of larval growth, survival, and metamorphosis in mixtures with parental species. Consequently, this study suggests natural hybridization and subsequent backcrossing between R. blairi and R. sphenocephala can produce novel and relatively fit hybrid genotypes capable of successful existence with parental species larvae. Thus, the evolutionary fate of hybrid and parental genotypes in this system may be influenced by exogenous selection mediated by genotypic composition of larval assemblages. PMID- 28565458 TI - HETEROSIS AND OUTBREEDING DEPRESSION IN INTERPOPULATION CROSSES SPANNING A WIDE RANGE OF DIVERGENCE. AB - The intertidal copepod Tigriopus californicus was used as a model organism to look at effects of crossing distance on fitness and to investigate the genetic mechanisms responsible. Crosses were conducted between 12 pairs of populations spanning a broad range of both geographic distance (5 m to 2007 km) and genetic distance (0.2% to 22.3% sequence divergence for a 606-bp segment of the mitochondrial COI gene). For each pair of populations, three fitness components (hatching number, survivorship number, and metamorphosis number) were measured in up to 16 cohorts including parentals, reciprocal F1 , F2 , F3 , and first generation backcross hybrids. Comparisons of each set of cohorts allowed estimation of within- and between-locus gene interaction. Relative to parentals, F1 hybrids showed a trend toward increased fitness, with no correspondence with population divergence, and a decrease in variance, which in some cases correlated with population divergence. In sharp contrast, F2 hybrids had a decrease in fitness and an increase in variance that both corresponded to population divergence. Genetic interpretation of these patterns suggests that both the beneficial effects of dominance and the detrimental effects of breaking up coadaptation are magnified by increasing evolutionary distance between populations. Because there is no recombination in T. californicus females, effects of recombination can be assessed by comparing F1 hybrid males and females backcrossed to parentals. Both recombinant and nonrecombinant backcross hybrids showed a decline in fitness correlated with population divergence, indicating that segregation among chromosomes contributes to the breakup of coadaptation. Although there was no difference in mean fitness between the two backcross types, recombinational backcrosses showed greater variance for fitness than nonrecombinational backcrosses, suggesting that the breakup of parental gene ombinations within chromosomes has both beneficial and detrimental effects. PMID- 28565459 TI - CORRELATION OF PAIRWISE GENETIC AND GEOGRAPHIC DISTANCE MEASURES: INFERRING THE RELATIVE INFLUENCES OF GENE FLOW AND DRIFT ON THE DISTRIBUTION OF GENETIC VARIABILITY. AB - Attempts to relate estimates of regional FST to gene flow and drift via Wright's (1931) equation FST ~ 1/ (4Nm + 1) are often inappropriate because most natural sets of populations probably are not at equilibrium (McCauley 1993), as assumed by the island model upon which the equation is based, or ineffective because the influences of gene flow and drift are confounded in the product Nm. Evaluations of the association between genetic (FST ) and geographic distances separating all pairwise populations combinations in a region allows one to test for regional equilibrium, to evaluate the relative influences of gene flow and drift on population structure both within and between regions, and to visualize the behavior of the association across all degrees of geographic separation. Tests of the model using microsatellite data from 51 populations of eastern collared lizards (Crotaphytus collaris collaris) collected from four distinct geographical regions gave results highly consistent with predicted patterns of association based on regional differences in various historical and ecological factors that affect the amount of drift and gene flow. The model provides a prerequisite for and an alternative to regional FST analyses, which often simply assume regional equilibrium, thus potentially leading to erroneous and misleading inferences regarding regional population structure. PMID- 28565460 TI - OPTIMAL SAMPLING DESIGNS FOR STUDIES OF GENE FLOW: A COMMENT ON ASSUNCAO AND JACOBI. PMID- 28565461 TI - THE ROLE OF GENES OF LARGE EFFECT ON INBREEDING DEPRESSION IN MIMULUS GUTTATUS. AB - Severe inbreeding depression is routinely observed in outcrossing species. If inbreeding load is due largely to deleterious alleles of large effect, such as recessive lethals or steriles, then most of it is expected to be purged during brief periods of inbreeding. In contrast, if inbreeding depression is due to the cumulative effects of many deleterious alleles of small effect, then it will be maintained in the face of periodic inbreeding. Whether or not inbreeding depression can be purged with inbreeding in the short term has important implications for the evolution of mating systems and the probability that a small population will go extinct. In this paper I evaluate the extent to which the tremendous inbreeding load in a primarily outcrossing population of the wildflower, Mimulus guttatus, is due to alleles of large effect. To do this, I first constructed a large outbred "ancestral" population by randomly mating plants collected as seeds from a natural population. From this population I formed 1200 lines that were maintained by self-fertilization and single seedling descent: after five generations of selling, 335 lines had survived the inbreeding process. Selection during the line formation is expected to have largely purged alleles of large effect from the collection of highly inbred lines. Because alleles with minor effects on fitness should have been effectively neutral, the inbreeding depression due to this class of genes should have been unchanged. The inbred lines were intercrossed to form a large, outcrossed "purged" population. Finally, I estimated the fitness of outbred and selfed progeny from the ancestral and purged populations to determine the contribution of major deleterious alleles on inbreeding depression. I found that although the average fitness of the outcrossed progeny nearly doubled following purging, the limited decline in inbreeding depression and limited increase in inbred fitness indicates that alleles of large effect are not the principle cause of inbreeding depression in this population. In aggregate, the data suggest that lethals and steriles make a minority contribution to inbreeding depression and that the increased outbred fitness is due primarily to adaptation to greenhouse conditions. PMID- 28565462 TI - EVOLUTION OF MULTIPLE KINDS OF FEMALE SPERM-STORAGE ORGANS IN DROSOPHILA. AB - Females of all species belonging to the family Drosophilidae have two kinds of sperm-storage organs: paired spherical spermathecae and a single elongate tubular seminal receptacle. We examined 113 species belonging to the genus Drosophila and closely allied genera and describe variation in female sperm-storage organ use and morphology. The macroevolutionary pattern of organ dysfunction and morphological divergence suggests that ancestrally both kinds of organs stored sperm. Loss of use of the spermathecae has evolved at least 13 times; evolutionary regain of spermathecal function has rarely if ever occurred. Loss of use of the seminal receptacle has likely occurred only once; in this case, all descendant species possess unusually elaborate spermathecae. Data further indicate that the seminal receptacle is the primary sperm-storage organ in Drosophila. This organ exhibits a pattern of strong correlated evolution with the length of sperm. The evolution of multiple kinds of female sperm-storage organs and the rapidly divergent and correlated evolution of sperm and female reproductive tract morphology are discussed. PMID- 28565463 TI - MICROSATELLITE LOCI REVEAL SEX-DEPENDENT RESPONSES TO INBREEDING AND OUTBREEDING IN RED DEER CALVES. AB - Mean d2 is a recently devised microsatellite-based measure that is hypothesised to allow the detection of inbreeding depression and heterosis in free-living populations. Two studies that have investigated the measure have both demonstrated an association between mean d2 and traits related to fitness. Here we present an association between mean d1 and an important component of fitness, first-year overwinter survival, in a population of red deer on the Isle of Rum, Scotland. The association between survival and mean d2 differed between males and females. As predicted, outbred female calves (high mean d2 ) survived better than those that were inbred (low mean d2 ). However, the association was in the opposite direction in male calves. We suggest that this difference is due to different early growth strategies between the sexes. The association between mean d2 and survival was not significantly influenced by any single locus. Decomposition of mean d2 into a recent inbreeding component and an outbreeding component showed that it was the degree of outbreeding that influenced survival in males and both the degree of outbreeding and recent inbreeding that influenced survival in females. Our analyses suggest that mean d2 is an easy-to-calculate measure of inbreeding and degree of outbreeding that can reveal interesting interactions between genetics and ecology. PMID- 28565464 TI - POLLINATOR-MEDIATED COMPETITION, REPRODUCTIVE CHARACTER DISPLACEMENT, AND THE EVOLUTION OF SELFING IN ARENARIA UNIFLORA (CARYOPHYLLACEAE). AB - Ecological factors that reduce the effectiveness of cross-pollination are likely to play a role in the frequent evolution of routine self-fertilization in flowering plants. However, we lack empirical evidence linking the reproductive assurance value of selfing in poor pollination environments to evolutionary shifts in mating system. Here, we investigated the adaptive significance of prior selfing in the polymorphic annual plant Arenaria uniflora (Caryophyllaceae), in which selfer populations occur only in areas of range overlap with congener A. glabra. To examine the hypothesis that secondary contact between the two species contributed to the evolution and maintenance of selfing, we used field competition experiments and controlled hand-pollinations to measure the female fitness consequences of pollinator-mediated interspecific interactions. Uniformly high fruit set by selfers in the naturally pollinated field arrays confirmed the reproductive assurance value of selfing, whereas substantial reductions in outcrosser fruit set (15%) and total seed production (20-35%) in the presence of A. glabra demonstrated that pollinator-mediated interactions can provide strong selection for self-pollination. Heterospecific pollen transfer, rather than competition for pollinator service, appears to be the primary mechanism of pollinator-mediated competition in Arenaria. Premating barriers to hybridization between outcrossers and A. glabra are extremely weak. The production of a few inviable hybrid seeds after heterospecific pollination and intermediate seed set after mixed pollinations indicates that A. glabra pollen can usurp A. uniflora ovules. Thus, any visit to A. uniflora by shared pollinators carries a potential female fitness cost. Moreover, patterns of fruit set and seed set in the competition arrays relative to controls were consistent with the receipt of mixed pollen loads, rather than a lack of pollinator visits. Competition through pollen transfer favors preemptive self-pollination and may be responsible for the evolution of a highly reduced floral morphology in A. uniflora selfers as well as their current geographical distribution. PMID- 28565465 TI - SPECIES FLOCK IN THE NORTH AMERICAN GREAT LAKES: MOLECULAR ECOLOGY OF LAKE NIPIGON CISCOES (TELEOSTEI: COREGONIDAE: COREGONUS). AB - Studies on north temperate fish species indicate that new habitat availability following the last ice sheet retreat has promoted ecological speciation in postglacial lakes. Extensive ecophenotypic polymorphisms observed among the North American Great Lakes ciscoes suggest that this fish group has radiated through trophic adaptation and reproductive isolation. This study aims at relating the ecomorphological and genetic polymorphisms expressed by the Lake Nipigon ciscoes to evaluate the likelihood of an intralacustrine divergence driven by the exploitation of alternative resources. Morphological variation and trophic and spatial niches are characterized and contrasted among 203 individuals. Genetic variation at six microsatellite loci is also analyzed to appraise the extent of genetic differentiation among these morphotypes. Ecomorphological data confirm the existence of four distinct morphotypes displaying various levels of trophic and depth niche overlap and specialization. However, ecological and morphological variations were not coupled as expected, suggesting that trophic morphology is not always predictive of ecology. Although extensive genetic variability was observed, little genetic differentiation was found among morphotypes, with only one morph being slightly but significantly differentiated. Contrasting patterns of morphological, ecological, and genetic polymorphisms did not support the hypothesis of ecological speciation: the most ecologically different forms were morphologically most similar, while the only genetically differentiated morph was the least ecologically specialized. The low levels of genetic differentiation and the congruence between theta and phi estimates altogether suggest a recent (most likely postglacial) process of divergence and/or high gene flow among morphs A, C, and D, whereas higher phi estimates for comparison involving morph B suggest that this morph may be derived from another colonizing lineage exchanging little genes with the other morphs. Patterns of ecophenotypic and genetic diversity are also compatible with a more complex evolutionary history involving hybridization and introgression. PMID- 28565466 TI - ADAPTIVE PHENOTYPIC PLASTICITY AND ITS DIFFERENCE BETWEEN UNIVOLTINE AND MULTIVOLTINE POPULATIONS IN A BRUCHID BEETLE, KYTORHINUS SHARPIANUS. AB - The multivoltine bruchid Kytorhinus sharpianus shows seasonal phenotypic plasticity in adult longevity, the preoviposition period, and the number of eggs laid without feeding between the diapausing and nondiapausing generations. This study compared the norms of reaction in three life-history traits between the univoltine Aomori and multivoltine Mitsuma populations. The directions of response in the norms of reaction were similar in both populations, although their response curves differed between populations. This result indicated a potential for variation in seasonal phenotypic plasticity in the univoltine population. However, the variation in the norms of reaction was small in both populations, suggesting strong selection pressure on the plasticity in the multivoltine population. These results also suggest that the univoltine Aomori population may have originated from a multivoltine population. PMID- 28565467 TI - MOLECULAR PHYLOGENETICS AND EVOLUTION OF SEXUAL DICHROMATISM AMONG POPULATIONS OF THE YARROW'S SPINY LIZARD (SCELOPORUS JARROVII). AB - Understanding evolution of geographic variation in sexually dimorphic traits is critical for understanding the role that sexual selection may play in speciation. We performed a phylogenetic analysis of geographic variation in sexual dichromatism in the Yarrow's spiny lizard (Sceloporus jarrovii), a taxon that exhibits remarkable diversity in male coloration among populations (e.g., black, red, green, yellow, blue, brown). An mtDNA phylogeny based on approximately 880 bp from the 12S ribosomal RNA gene and 890 bp from the ND4 gene was reconstructed for 30 populations of S. jarrovii and eight other species of the torquatus species group using maximum-likelihood and parsimony methods. The phylogeny suggests that S. jarrovii consists of at least five evolutionary species, none of which are sister taxa. Although intraspecific diversity in male coloration is less than indicated by previous taxonomy, two species formerly referred to as S. jarrovii exhibit impressive geographic variation in sexual dichromatism. In one of these species, the phylogeny shows the independent evolution of a distinctive blue color morph in different parts of the species range. This pattern suggests that sexual selection may lead to striking phenotypic divergence among conspecific populations and striking convergence. Results also demonstrate the importance of a phylogenetic perspective in studies of evolutionary processes within nominal species and the problematic nature of "polytypic" species recognized under the biological species concept. PMID- 28565468 TI - HIERARCHICAL PATTERNS OF GENETIC POPULATION STRUCTURE IN BLACK RAT SNAKES (ELAPHE OBSOLETA OBSOLETA) AS REVEALED BY MICROSATELLITE DNA ANALYSIS. AB - We investigated the distribution of variation at six microsatellite loci in the black rat snake (Elaphe obsoleta obsoleta). Sampling occurred at three hierarchical scales ranging from communal hibernacula to regional populations, with most locales situated within the Frontenac Axis region of eastern Ontario. We detected no statistically significant pairwise differentiation (FST and RST ) between hibernacula within the same subpopulations (interhibernaculum distance <6 km). However, isolation-by-distance was evident among locales within the Frontenac Axis (maximum of 50 km) and among regional populations (maximum of 1500 km). Conservative estimates of Nc derived from heterozygosity values ranged from approximately 600 to 2000. These values suggest relatively large genetic neighborhoods encompassing many communal hibernacula. Our results considered together suggest viscosity of gene flow over relatively short distances (tens of kilometers), but substantial genetic exchange among local hibernacula. PMID- 28565469 TI - EVIDENCE FOR LIMITED INTERCONTINENTAL GENE FLOW IN THE COSMOPOLITAN MUSHROOM, SCHIZOPHYLLUM COMMUNE. AB - The genetic structure of populations of Schizophyllum commune was inferred from electrophoretic variation among 136 individuals at 11 polymorphic allozyme loci to determine the extent of geographic differentiation in this widespread mushroom species. The majority of the genetic variation was contained within populations; however, considerable genetic differentiation was observed among populations (global GST = 0.214). Clustering analysis demonstrated that genetic distance was correlated with geographic distance and that a large component of the genetic variation was due to allele frequency differences among populations from the eastern and western hemispheres. Our results also suggest that populations are large and geographically widespread. The lack of fixed genetic differences among intercontinental populations at any of the allozyme loci suggests that long distance spore dispersal may counter the effects of genetic drift in this cosmopolitan species. These results are contrasted with a previous description of the same collection, in which the mating allele distribution of the species displayed no population substructure at any geographic scale (Raper et al. 1958). Broader implications of this study are that both species and mating allele distributions may not be correlated with long-distance gene flow in basidiomycete fungi. PMID- 28565470 TI - EVOLUTION OF HAPLODIPLOIDY IN DERMANYSSINE MITES (ACARI: MESOSTIGMATA). AB - Haplodiploidy, a widespread phenomenon in which males are haploid and females are diploid, can be caused by a number of different underlying genetic systems. In the most common of these, arrhenotoky, males arise from unfertilized eggs, whereas females arise from fertilized eggs. In another system, pseudoarrhenotoky, males arise from fertilized eggs, but they eliminate the paternal genome at some point prior to spermatogenesis, with the consequence that they do not pass this genome to their offspring. In 1931 Schrader and Hughes-Schrader suggested that arrhenotoky arises through a series of stages involving pseudoarrhenotokous systems such as those found in many scale insects (Homoptera: Coccoidea), however, their hypothesis has been largely ignored. We have used a phylogenetic analysis of 751 base pairs of 28S rDNA from a group of mites (Mesostigmata: Dermanyssina) that contains arrhenotokous, pseudoarrhenotokous, and ancestrally diplodiploid members to test this hypothesis. Neighbor-joining, maximum parsimony, and maximum-likelihood methods all indicate that the arrhenotokous members of this group form a clade that arose from a pseudoarrhenotokous ancestor, rather than directly from a diplodiploid one. This provides unequivocal support for the hypothesis of Schrader and Hughes-Schrader. The wider implications of this result for the evolution of uniparental genetic systems are discussed. PMID- 28565471 TI - A TEST OF THE GLACIAL REFUGIUM HYPOTHESIS USING PATTERNS OF MITOCHONDRIAL AND NUCLEAR DNA SEQUENCE VARIATION IN ROCK PTARMIGAN (LAGOPUS MUTUS). AB - The glacial refugium hypothesis (GRH) proposes that glaciers promoted differentiation and generation of intraspecific diversity by isolating populations in ice-free refugia. We tested three predictions of this hypothesis for the evolutionary divergence of rock ptarmigan (Lagopus mutus) during the Wisconsin glaciation of the late Pleistocene. To do this, we examined subspecies distributions, population genetic structure, and phylogenetic relationships in 26 populations across North America and the Bering Sea region. First, we analyzed sequence variation in the mitochondrial control region, in a nuclear intron (Gapdh), and in an internal transcribed spacer (ITS1). Control region sequences of 154 rock ptarmigan revealed strong population and phylogeographic structure. Variation in intron sequences of 114 rock ptarmigan also revealed significant population structure compatible with results for the control region. Rock ptarmigan were invariant for ITS1. Second, we show that five known Nearctic refugia and an Icelandic refugium are concordant with the current distribution of morphologically distinct subspecies; five of these six refugia are geographically concordant with the distribution of closely related control region haplotypes. Third, our estimates of the time since phylogenetic lineages diverged predated the last glacial maximum for all but two lineages. In addition, all lines of evidence suggest that two unknown refugia in the Bering Sea region supported rock ptarmigan during the Wisconsin glaciation. Overall, our results are most consistent with the hypothesis that isolated populations of rock ptarmigan diverged in multiple refugia during the Wisconsin and that geographic variation reflects patterns of recolonization of the Nearctic after the ice receded. The GRH may therefore offer the most plausible explanation for similar biogeographic patterns in a variety of Nearctic vertebrates. PMID- 28565472 TI - THE RATE AND EFFECTS DISTRIBUTION OF VIABILITY MUTATION IN DROSOPHILA: MINIMUM DISTANCE ESTIMATION. AB - The empirical distribution of the mean viability of mutation accumulation lines, obtained from three published experiments, was analyzed using minimum-distance estimation. In two cases (Mukai et al. 1972; Ohnishi 1977), mutations were allowed to accumulate in copies of chromosome II protected from natural selection and recombination. In the other one (Fernandez and Lopez-Fanjul 1996), they accumulated in inbred lines derived from an isogenic stock. In contrast with currently accepted hypotheses, we consistently estimated low (about 0.01) genomic viability mutation rates, lambda, and a small kurtosis of the distribution of mutational effects on viability (a) in the three datasets. Minimum-distance estimates of the per-generation mean viability change due to mutation (lambdaE[a]) were also obtained. These were very similar for both chromosomal datasets, their absolute values being about five times smaller than estimates obtained from the observed change in mean viability during the mutation process. It must be noted that, in both experiments, viability was measured relative to the Cy chromosome of a Cy/Pm stock. Thus, an unnoticed viability increase in this Cy chromosome may have resulted in overestimation of the mean viability reduction in the lines. In parallel, minimum-distance estimation of lambdaE(a) from inbred lines data (where the selective pressure during the accumulation process was larger) was even somewhat smaller, in absolute value, and very close to the estimate obtained by comparing the mean viability of the lines with that of the control isogenic line. The evolutionary importance of these results, as well as their relevance to the solution of the mutational load paradox, is discussed. PMID- 28565473 TI - ORIGIN AND MAINTENANCE OF A FEMALE MATING PREFERENCE. AB - We investigated the role of maintenance and origin of female mating preferences in three species of fish. Poecilia latipinna and P. mexicana are sexual species that hybridized to form the gynogenetic clonal P. formosa, which reproduces asexually but requires sperm to initiate embryogenesis. We demonstrate that all three species display almost identical and statistically indistinguishable preferences for large males. Although processes of good genes, runaway sexual selection, and direct selection could maintain preferences in the sexual species, good genes and runaway sexual selection are unlikely to operate in the asexual species. Furthermore, we found that the most likely direct selection benefit, an increase in fecundity, can also be excluded in the gynogens. We conclude that the most parsimonious explanation for this P. formosa preference is that it was inherited from the parental species and is maintained without forces generated by good genes, runaway selection, or direct selection for increased fecundity. This preference may be maintained because of pleiotropic effects (e.g., sensory bias) or mate searching costs. PMID- 28565474 TI - ANIMAL COMMUNICATION AND EVOLUTION. PMID- 28565475 TI - LONG-TERM EXPERIMENTAL EVOLUTION IN ESCHERICHIA COLI. VII. MECHANISMS MAINTAINING GENETIC VARIABILITY WITHIN POPULATIONS. AB - Six replicate populations of the bacterium Escherichia coli were propagated for more than 10,000 generations in a defined environment. We sought to quantify the variation among clones within these populations with respect to their relative fitness, and to evaluate the roles of three distinct population genetic processes in maintaining this variation. On average, a pair of clones from the same population differed from one another in their relative fitness by approximately 4%. This within-population variation was small compared with the average fitness gain relative to the common ancestor, but it was statistically significant. According to one hypothesis, the variation in fitness is transient and reflects the ongoing substitution of beneficial alleles. We used Fisher's fundamental theorem to compare the observed rate of each population's change in mean fitness with the extent of variation for fitness within that population, but we failed to discern any correspondence between these quantities. A second hypothesis supposes that the variation in fitness is maintained by recurrent deleterious mutations that give rise to a mutation-selection balance. To test this hypothesis, we made use of the fact that two of the six replicate populations had evolved mutator phenotypes, which gave them a genomic mutation rate approximately 100-fold higher than that of the other populations. There was a marginally significant correlation between a population's mutation rate and the extent of its within population variance for fitness, but this correlation was driven by only one population (whereas two of the populations had elevated mutation rates). Under a third hypothesis, this variation is maintained by frequency-dependent selection, whereby genotypes have an advantage when they are rare relative to when they are common. In all six populations, clones were more fit, on average, when they were rare than when they were common, although the magnitude of the advantage when rare was usually small (~1% in five populations and ~5% in the other). These three hypotheses are not mutually exclusive, but frequency-dependent selection appears to be the primary force maintaining the fitness variation within these experimental populations. PMID- 28565476 TI - AN INTERACTION BETWEEN ENVIRONMENTAL TEMPERATURE AND GENETIC VARIATION FOR BODY SIZE FOR THE FITNESS OF ADULT FEMALE DROSOPHILA MELANOGASTER. AB - - Drosophila and other ectotherms show geographic genetic variation in body size, with larger individuals at higher latitudes and altitudes. Temperature is implicated as an important selective agent because long-term laboratory culture of Drosophila leads to the evolution of larger body size at lower temperatures. In this paper, we tested the hypothesis that, in Drosophila melanogaster, larger size is favored at lower temperatures in part because of selection on adult females. We used replicated lines of D. melanogaster artificially selected for increased and decreased wing area with constant cell area. The resulting size differences between the selected lines were due solely to differences in cell number, and thereby were similar to the cellular basis of clinal variation in body size in nature. We examined life-history traits of adult females at 18 and 25 degrees C. Rearing for two generations at the two temperatures did not affect the extent of the size differences between lines from the different selection regimes. There was a strong interaction between temperature and size selection for both survival and lifetime reproductive success, with larger females living significantly longer and producing more offspring over their lifetime only when reared and tested in the colder environment. There was also an increase in average daily progeny production in large-line females relative to the control and small lines again, only in the colder environment. Thus, the females from the large selection lines were relatively fitter at the colder temperature. At both experimental temperatures, especially the lower one, the small- line females rescheduled their progeny production to later ages. Larger body size may have evolved at higher latitudes and altitudes because of the advantages to the adult female of being larger at lower temperatures. PMID- 28565477 TI - DEVELOPMENTAL STABILITY, FITNESS, AND TRAIT SIZE IN LABORATORY HYBRIDS BETWEEN EUROPEAN SUBSPECIES OF THE HOUSE MOUSE. AB - The effects of hybridization on developmental stability and size of tooth characters were investigated in intersubspecific crosses between random-bred wild strains of the house mouse (Mus musculus domesticus and M. m. musculus). Fluctuating asymmetry (FA) and trait size were compared within and between parental, F1 , backcross, and F2 hybrid groups. The relationship between FA and reproductive fitness within the F1 hybrids was also studied. The results indicated that both FA and character size levels differed significantly between the two subspecies. The F1 hybrids and the recombined groups (backcrosses and F2 hybrids) showed heterosis for both parameters. No significant differences in the FA of fertile and sterile F1 hybrid individuals were found. Comparison of the FA levels obtained in this study with those found in wild populations from the hybrid zone in Denmark showed that the levels of FA were lower in laboratory-bred samples than in the wild populations. This study provides further evidence that, in hybrids, the developmental processes underlying most of the morphological traits we studied benefit from a heterotic effect, despite the genomic incompatibilities between the two European house mice revealed by previous genetical and parasitological studies. PMID- 28565478 TI - FITNESS VARIATION ACROSS A SUBDIVIDED POPULATION OF THE ANNUAL PLANT IMPATIENS CAPENSIS. AB - The evolution of a subdivided population depends on whether subpopulations with high mean fitness make a greater per capita contribution to the next generation than subpopulations with lower mean fitness. I distinguish two different models of ecological population structure, denoted local compensation and global compensation. Local compensation restricts the differential contribution of subpopulations, whereas global compensation allows subpopulations to contribute in direct proportion to their mean fitness. I describe a simple regression-based method that distinguishes these alternatives as points on a continuum of possible population structures. The method is applied to field measurements of local abundance and reproduction in a subdivided population of the annual plant Impatiens capensis. These data suggest that the global compensation model is a more accurate description of the population studied. This result is surprising because local density effects on growth and reproduction occur in I. capensis. The implications of ecological population structure for both geographical variation in selection and kin selection are discussed. PMID- 28565480 TI - FINE-GRAINED SPATIAL AND TEMPORAL POPULATION GENETIC STRUCTURE IN THE MARINE BIVALVE SPISULA OVALIS. PMID- 28565479 TI - BUTTERFLY EYESPOTS: THE GENETICS AND DEVELOPMENT OF THE COLOR RINGS. AB - The butterfly Bicyclus anynana has a series of distal eyespots on its wings. Each eyespot is composed of a white pupil, a black disc, and a gold outer ring. We applied artificial selection to the large dorsal eyespot on the forewing to produce a line with the gold ring reduced or absent (BLACK) and another line with a reduced black disc and a broad gold ring (GOLD). High heritabilities, coupled with a rapid response to selection, produced two lines of butterflies with very different phenotypes. Other eyespots showed a correlated change in the proportion of their color rings. Surgical experiments were performed on pupal wings from the different lines at the time of eyespot pattern specification. They showed that the additive genetic variance for this trait was in the response of the wing epidermis to signaling from the organizing cells at the eyespot center (the focus). This response was found to vary across different regions of the wing and also between the sexes. The particular eyespot color composition found for each sex, as well as the maintenance of the high genetic variation, are discussed with reference to the ecology of the butterfly, sexual selection, and visual selection by predators. PMID- 28565481 TI - GENETIC AND COLOR INTERACTIONS AT A CONTACT ZONE OF ACANTHOCHROMIS POLYACANTHUS: A MARINE FISH LACKING PELAGIC LARVAE. AB - - Acanthochromis polyacanthus is an unusual tropical marine damselfish that uniquely lacks pelagic larvae and has lost the capacity for broad-scale dispersal among coral reefs. Different color morphs exist in different regions of the Great Barrier Reef, and morphs from northern and southern regions are genetically distinct. In the Hydrographers Passage area, which is a large break through the reef matrix in the central Great Barrier Reef that may have acted as a bottleneck on the migration of these animals during sea level rise, three morphs recognized from other regions were found on neighboring reefs. The transition between them is abrupt with three loci (AAT-2*, GPI-1*, and PGM*) showing allelic frequency patterns close to fixation between opposite alleles within a few kilometers. On two reefs (Hyde, Bebe), a pair of morphs was found to coexist and exhibited a habitat partitioning pattern with each morph restricted to one side on the reef and steep transitions in between. Outside these transition zones, phenotypes and genotypes matched those on surrounding reefs without coexistence and were little changed from reefs several hundred kilometers away. An electrophoretic survey across one transition zone on Hyde Reef showed steep genetic gradients along one kilometer of reef slope. Significant linkage disequilibria in samples collected in Hyde Reef as a result of dispersal of parental combinations of alleles into the center or because parental combinations of alleles confer greater fitness, allowed us to estimate the dispersal rate (189 m/generation) and the selection pressure on the marker loci (0.411). Finally, we investigated models that could lead to such a steep transition in genotypic and phenotypic combinations. Both contact zones on each side of Hyde Reef were associated with geomorphological discontinuities in the reef structure. We suggest that assortative mating may be a proximal mechanism for maintaining isolated each color morph, which could be reinforced by selective predation against hybrids outside the zone of their formation (i.e., the frequency-dependent selection model of Mallet and Barton (1989). Acanthochromis is a midwater planktivore and, when in coexistence, the two morphs forage in different habitats amid multispecific flocks of other damselfishes of matching colors. PMID- 28565482 TI - HABITAT CONTINUITY AND THE GENETIC STRUCTURE OF DROSOPHILA POPULATIONS. PMID- 28565483 TI - MODELING THE GENETIC BASIS OF HETEROSIS: TESTS OF ALTERNATIVE HYPOTHESES. AB - Houle (1994) showed that marker-associated heterosis due to general inbreeding depression could not be distinguished from direct overdominance at the marker locus by examining mean genotypic fitnesses, in the one-locus case. Indeed, both hypotheses equally fit the same regression model, referred to as the "adaptive distance model" (Smouse 1986). I here extend the analysis to several loci and to the relationship between marker genotype and variance in fitness. Several predictions differ between the overdominance and inbreeding hypotheses: (1) all locus-specific effects are equal under inbreeding, whereas they are not under overdominance; (2) the adaptive distance model has an increasingly low fit when the number of loci increases, under inbreeding, whereas it always explains the whole variance in fitness under overdominance; (3) a negative relationship is predicted between mean fitness and the variance in fitness, under inbreeding, which is not predicted under overdominance. Some statistical tests are derived from these predictions, that help to identify the genetic basis of heterosis. Simulations show that the power of these tests allows their application to real datasets. PMID- 28565484 TI - QUANTITATIVE GENETICS OF OVARIOLE NUMBER IN DROSOPHILA MELANOGASTER. I. SEGREGATING VARIATION AND FITNESS. AB - The number of ovarioles of the Drosophila melanogaster ovary is a trait thought to be associated with female fecundity, and therefore is expected to be under strong natural selection. This hypothesis may be tested by examining patterns of genetic and environmental variation for ovariole number in natural populations, and by determining the association between ovariole number and fitness in isogenic lines derived from a natural population. We measured ovariole number, and competitive fitness and its components, for 48 homozygous chromosome 3 substitution lines in a standard inbred background; and body size in a sample of 15 chromosome 3 substitution lines. We found significant segregating genetic variation for ovariole number, with a broad-sense heritability (H2 ) of 0.403 and correspondingly high coefficients of genetic variation (CVC = 20.8) and residual variation (CVR = 25.3). Estimates of quantitative genetic parameters for body size (H2 = 0.191, CVG = 2.15, and CVR = 3.87) are similar to those previously reported for this trait. Although the isogenic chromosome 3 substitution lines varied significantly for components of fitness, there was no significant linear or quadratic association of ovariole number and body size with fitness. There was, however, highly significant sex * genotype interaction for fitness among these lines. This special case of genotype * environment interaction for fitness may contribute to the maintenance of genetic variation for fitness in natural populations. PMID- 28565485 TI - NATURAL SELECTION ON AVIAN BREEDING TIME: CAUSALITY, FECUNDITY-DEPENDENT, AND FECUNDITY-INDEPENDENT SELECTION. AB - Natural selection on breeding time through postfledgling survival was investigated in a population of blue tits, Parus caeruleus, between 1993 and 1996. In particular, selection acting through large brood sizes among early breeders (fecundity-dependent selection) was separated from selection acting through fitness benefits unrelated to the numerical benefits of large brood sizes (fecundity-independent selection). There was evidence that natural selection favored early breeding in 1993 and 1995 (significantly so in 1993), whereas in 1994 there was a tendency for selection to be stabilizing. Analyses of selection gradients further showed that there was direct selection for both early breeding and large brood sizes in 1993. Experimentally delayed pairs produced a lower proportion of surviving young among their fledglings compared to early pairs, indicating that the seasonal fitness trend is a causal one and not caused by differences between early and late breeders in territory or individual quality. There was no evidence for significant heritability for four reproductive traits (clutch sizes, laying dates, hatching dates, and brood size at fledging) although repeatability values ranged from 0.26 to 0.53. The importance of year-specific selective regimes in the evolution of avian breedings times are discussed and a role for population density in this context is proposed. PMID- 28565486 TI - EVOLUTIONARY HISTORY OF THE MATING SYSTEM IN AMSINCKIA (BORAGINACEAE). AB - A survey of restriction site variation in the chloroplast genome of the annual plant genus Amsinckia, together with estimation of outcrossing rates, was conducted to analyze the evolutionary history of the mating system. Species, and in some cases populations within species, differ markedly in their mating system. Five taxa are distylous and predominantly outcrossing, or show mixed mating systems, while the remaining taxa are homostylous and predominantly self fertilizing. Reconstruction of the molecular phylogeny of the group places different distylous and homostylous taxa at four separate branch tips. When distyly is treated as ancestral in the group, or when the loss of distyly is assumed to be more common than its gain, the results of the phylogenetic analysis support the hypothesis that the self-fertilizing taxa are of recent origin from outcrossing relatives. These findings are discussed with respect to theory for the evolution and breakdown of distyly and the probability of extinction of selfing lineages. PMID- 28565487 TI - THE INFLUENCE OF INTRASPECIFIC VARIATION IN DISPERSAL STRATEGIES ON THE GENETIC STRUCTURE OF PLANTHOPPER POPULATIONS. AB - The hypothesis that levels of gene flow among populations are correlated with dispersal ability has typically been tested by comparing gene flow among species that differ in dispersal abilities, an approach that potentially confounds dispersal ability with other species-specific differences. In this study, we take advantage of geographic variation in the dispersal strategies of two wing dimorphic planthopper species, Prokelisia marginata and P. dolus, to examine for the first time whether levels of gene flow among populations are correlated with intraspecific variation in dispersal ability. We found that in both of these coastal salt marsh-inhabiting species, population-genetic subdivision, as assessed using allozyme electrophoresis, parallels geographic variation in the proportion of flight-capable adults (macropters) in a population; in regions where levels of macroptery are high, population genetic subdivision is less than in regions where levels of macroptery are low. We found no evidence that geographic variation in dispersal capability influences the degree to which gene flow declines with distance in either species. Thus, both species provided evidence that intraspecific variation in dispersal strategies influences the genetic structure of populations, and that this effect is manifested in population-genetic structure at the scale of large, coastal regions, rather than in genetic isolation by distance within a region. This conclusion was supported by interspecific comparisons revealing that: (1) population-genetic structure (GST ) of the two Prokelisia species correlated negatively with the mean proportion of flight-capable adults within a region; and (2) there was no evidence that the degree of isolation by distance increased with decreasing dispersal capability. Populations of the relatively sedentary P. dolus clustered by geographic region (using Nei's distances), but this was not the case for the more mobile P. marginata. Furthermore, gene flow among the two major regions we surveyed (Atlantic and Gulf Coasts) has been substantial in P. marginata, but relatively less in P. dolus. The results for P. marginata suggest that differences in the dispersal strategies of Atlantic and Gulf Coast populations occur despite extensive gene flow. We argue that gene flow is biased from Atlantic to Gulf Coast populations, indicating that selection favoring a reduction in flight capability must be intense along the Gulf. Together, the results of this study provide the first rigorous evidence of a negative relationship within a species between dispersal ability and the genetic structure of populations. Furthermore, regional variation in dispersal ability is apparently maintained by selective differences that outweigh high levels of gene flow among regions. PMID- 28565488 TI - HITCH-HIKER PARASITES OR HOW TO BENEFIT FROM THE STRATEGY OF ANOTHER PARASITE. PMID- 28565489 TI - HYBRID ZONES WITH DOBZHANSKY-TYPE EPISTATIC SELECTION. AB - Dobzhansky's model of epistatic selection assumes that viable genotypes form "clusters" in genotype space so that populations can evolve from one state to a reproductively isolated state following a "ridge" of well-fit genotypes without crossing any deep adaptive valleys. Recently, the importance of Dobzhansky-type models in evolutionary studies has been reemphasized by Gavrilets (1997a) and Gavrilets and Gravner (1997) who argue that the existence of "ridges" of well-fit genotypes connecting reproductively isolated genotypes is actually a general property of multidimensional adaptive landscapes. Using rigorous techniques and numerical simulations, I analyze clines in the frequencies of selected and neutral alleles maintained by a balance of migration and Dobzhansky-type epistatic selection acting on two diallelic loci. I show that Dobzhansky-type epistatic selection can build up a very strong barrier to neutral gene flow. I describe properties of clines that are indicative of Dobzhansky-type selection. PMID- 28565490 TI - FITNESS COSTS OF FEMALE REPRODUCTION. PMID- 28565491 TI - FOUNDER EFFECTS AND PEAK SHIFTS WITHOUT GENETIC DRIFT: ADAPTIVE PEAK SHIFTS OCCUR EASILY WHEN ENVIRONMENTS FLUCTUATE SLIGHTLY. AB - Two similar evolutionary theories, the shifting balance theory and founder-flush models, invoke random genetic drift to allow evolution on complex adaptive landscapes. These models, in their usual incarnations, deal with fitness as a static entity, and the probability of transition from one form to another is predicted to be quite small by analysis of these models. Fitness itself can change, however, and the amount of change in the parameters of the fitness functions required to allow deterministic evolution to new adaptive peaks is very small. The probability of environmental changes sufficient to allow substantial morphological evolution or reproductive isolation is large relative to the probability that similar changes could occur by processes requiring genetic drift, even with very small population sizes. The rapid evolution or speciation following a population founding event is more closely linked with environmental changes than genetic drift. PMID- 28565492 TI - INVERSION LENGTH AND BREAKPOINT DISTRIBUTION IN THE DROSOPHILA BUZZATII SPECIES COMPLEX: IS INVERSION LENGTH A SELECTED TRAIT? AB - Length and position of breakpoints are characteristics of inversions that can be precisely determined on the polytene chromosomes of Drosophila species, and they provide crucial information about the processes that govern the origin and evolution of inversions. Eighty-six paracentric inversions described in the Drosophila buzzatii species complex and 18 inversions induced by introgressive hybridization in D. buzzatii were analyzed. In contrast to previous studies, inversion length and breakpoint distribution have been considered simultaneously. We conclude that: (1) inversion length is a selected trait; rare inversions are predominantly small while evolutionarily successful inversions, polymorphic and fixed, are predominantly intermediate in length; a nearly continuous variation in length, from small to medium sized, is found between less and more successful inversions; (2) there exists a significant negative correlation between length and number of polymorphic inversions per species which explains 39% of the inversion length variance; (3) natural selection on inversion length seems the main factor determining the relative position of breakpoints along the chromosomes; (4) the distribution of breakpoints according to their band location is non-random, with chromosomal segments that accumulate up to eight breakpoints. PMID- 28565493 TI - MITOCHONDRIAL DNA SEQUENCE-BASED PHYLOGENY AND THE EVOLUTION OF VIVIPARITY IN THE SCELOPORUS SCALARIS GROUP (REPTILIA, SQUAMATA). AB - The lizard genus Sceloporus contains both oviparous and viviparous species. The scalaris complex is the only monophyletic group within the genus that includes both reproductive modes, thus it is particularly well suited for studies of the evolution of viviparity. Approximately 874 nucleotides of mtDNA sequence data, collected from 38 specimens, comprising 25 populations of all five recognized species within the group, were used in a phylogenetic analysis of the origin of viviparity. Viviparity appears to have evolved twice in this group: once in S. goldmani, included in a clade formed by a northern group consisting of S. scalaris, S. chaneyi, and S. goldmani, and one more time in S. bicanthalis, included in the southern group formed by S. bicanthalis and S. aeneus. An oviparous population of S. bicanthalis nested within that viviparous clade, indicates that reversal from viviparity to oviparity may be possible. Degree of sequence divergence among several S. bicanthalis individuals pertaining to a population in which both parity modes occur, was no larger between oviparous and viviparous lizards than among viviparous lizards. This suggests that this population is a single species, and it may represent a transition from oviparity to viviparity or vice-versa. PMID- 28565494 TI - LOCAL ADAPTATION IN TWO SUBSPECIES OF AN ANNUAL PLANT: IMPLICATIONS FOR MIGRATION AND GENE FLOW. AB - Plant populations often adapt to local environmental conditions. Here we demonstrate local adaptation in two subspecies of the California native annual Gilia capitata using standard reciprocal transplant techniques in two sites (coastal and inland) over three consecutive years. Subspecies performance in each site was measured in four ways: probability of seedling emergence, early vegetative size (length of longest leaf), probability of flowering, and total number of inflorescences produced per plant. Analysis of three of the four variables demonstrated local adaptation through site-by-subspecies interactions in which natives outperformed immigrants. The disparity between natives and immigrants in their probability of emergence and probability of flowering was greater at the coastal site than at the inland site. Treated in isolation, these two fitness components suggest that migration from the coast to the inland site may be less restricted by selection than migration in the opposite direction. Two measurements of individual size (leaf length and number of inflorescences), suggest (though not strongly) that immigrants may be subject to weaker selection at the coastal site than at the inland site. A standard cohort life table is used to compare replacement rates (R0 ) for each subspecies at each site. Comparisons of R0 s suggest that immigrants are under a severe demographic disadvantage at the coastal site, but only a small disadvantage at the inland site. The results point out the importance of integrating over several fitness components when documenting the magnitude of local adaptation. PMID- 28565495 TI - GENETIC DIFFERENTIATION OF FITNESS-ASSOCIATED TRAITS AMONG RAPIDLY EVOLVING POPULATIONS OF THE SOAPBERRY BUG. AB - In this study we used reciprocal rearing experiments to test the hypothesis that there is a genetic basis for the adaptive differences in host-use traits among host-associated soapberry bug populations (described in Carroll and Boyd 1992). These experiments were conducted on two host races from Florida, in which differences in beak length and development were found between natural populations on a native host plant species and those on a recently introduced plant species (colonized mainly post-1950). Performance was generally superior on the host species from which each lab population originated (i.e., on the "Home" host species): in analysis of variance, there was significant population-by-host interaction for size, development time, and growth rate. These results indicate that the population differences in nature are evolved rather than host induced. Increased performance on the introduced host was accompanied by reduced performance on the native host, a pattern that could theoretically promote further differentiation between the host races. PMID- 28565496 TI - EVOLUTION OF A BENEFICIAL ALLELE UNDER PARTIAL SELFING AND INBREEDING DEPRESSION. PMID- 28565497 TI - FLAT REACTION NORMS AND "FROZEN" PHENOTYPIC VARIATION IN CLONAL SNAILS (POTAMOPYRGUS ANTIPODARUM). AB - The Frozen Niche-Variation hypothesis (FNV) suggests that clones randomly sample and "freeze" the genotypes of their ancestral sexual populations. Hence, each clone expresses only a fraction of the total niche-use variation observed in the sexual population, which may lead to selection for ecological specialization and coexistence of clones. A generalized form of the FNV model suggests that the same is true for life-history (as well as other) traits that have important fitness consequences, but do not relate directly to niche use. We refer to the general form of the model as the Frozen Phenotypic Variation (FPV) model. A mixed population of sexual and parthenogenetic snails (Potamopyrgus antipodarum) in a New Zealand lake allowed us to examine the phenotypic variation expressed by coexisting clones in two benthic habitats, and to compare that variation to the sexual population. Three clones were found primarily in an aquatic macrophyte zone composed of Isoetes kirkii (1.5-3.0 m deep), and three additional clones were found in a deeper macrophyte zone composed of Elodea canadensis (4.0-6.0 m deep). These clones showed significant variation between habitats, which mirrored that observed in the sexual population. Specifically, clones and sexuals from the deeper habitat matured at a larger size and had larger broods. There was also significant among-clone variation within habitats; and as expected under the FPV model, the within-clone coefficients of variation for size at maturity were low in both habitats when compared to the sexual population. In addition, we found four clones that were common in both macrophyte zones. The reaction norms of these clones were flat across habitats, suggesting little phenotypic plasticity for morphology or life-history traits. Flat reaction norms, high among-clone variation, and low coefficients of variation (relative to the sexual population) are in accordance with the FPV model for the origin of clonal lineages. We also measured the prevalence of infection by trematode larvae to determine whether clones are inherently more or less infectable, or whether they are freezing phenotypic variation for resistance from the sexual population. We did this in the deep habitats of the lake where recycling of the parasite by the vertebrate host is unlikely, thereby reducing the complications raised by frequency dependent responses of parasites to host genotypes. We found no indication that clones are either more or less infectable than the resident sexual population. Taken together, our results suggest that phenotypic variation for both life history traits and resistance to parasites is frozen by clones from the local sexual population. PMID- 28565498 TI - WHAT DETERMINES FITNESS WHEN DISPERSAL IS LIMITED? AB - Simple evolutionary models typically assume a homogeneous environment in which all individuals have equal access to resources. However, when dispersal is limited this assumption is unlikely to correspond to reality. Instead, the offspring of relatively fecund parents can be expected to find that resources are scarce because of competition from their relatively large number of siblings. We show that these factors lead to selection for decreased variation in the number of offspring produced. We investigate the relationship between fitness and variation in fertility for a variety of different circumstances. Our results indicate that, in some cases, selection for reduced variation in fertility can be very substantial. PMID- 28565499 TI - REACTION NORMS OF MORPHOLOGICAL TRAITS IN DROSOPHILA: ADAPTIVE SHAPE CHANGES IN A STENOTHERM CIRCUMTROPICAL SPECIES? AB - Reaction norms of wing length, thorax length, and ovariole number were studied according to growth temperature in the circumtropical Drosophila ananassae, and compared to similar data from the cosmopolitan D. melanogaster. In the two species convex reaction norms were observed, but they were not parallel and sometimes exhibited intersections either at high (wing) or at low (thorax) temperature. On average, D. ananassae may be considered as a species with a bigger thorax but shorter wings than D. melanogaster. The shapes of reaction norms were analyzed and compared after quadratic polynomial adjustments. Significant differences were observed, in several cases between polynomial parameters, and in all cases between characteristic points that is, Maximum Value (MV) and Temperature of Maximum Value (TMV). The wing/thorax ratio may also be considered as a specific trait related to wing loading. Major differences were observed between the two species for the mean value and the shape of the response curves of this trait. The main observation of this work was however a shift of TMVs for wing and thorax length and ovariole number in D. ananassae toward higher temperatures. These variations in the reaction norms corresponded to a shift in the species thermal range, suggesting that temperature adaptation was accompanied by a modification of the shape of the response curves. PMID- 28565500 TI - COMPETITION AMONG TADPOLES OF COEXISTING HEMICLONES OF HYBRIDOGENETIC RANA ESCULENTA: SUPPORT FOR THE FROZEN NICHE VARIATION MODEL. AB - Vertebrate animals reproducing without genetic recombination typically are hybrids, which have large ranges, are locally abundant, and live in disturbed or harsh habitats. This holds for the hemiclonal hybridogenetic frog Rana esculenta: it is widespread in Europe and commonly is found in disturbed habitats such as gravel pits. We hypothesize that its widespread occurrence may either be the result of natural selection for a single hemiclone acting as a broadly adapted "general-purpose" genotype, or of interclonal selection, which maintains multiple hemiclones that each are relatively narrowly adapted and perform differently across environments, that is, the Frozen Niche Variation model. We tested these competing hypotheses using 1000-L outdoor artificial ponds to rear tadpoles of the parental species (Rana lessonae [LL] and Rana ridibunda [RR]) alone, and each of three hemiclones of Rana esculenta (GUT1, GUT2, GUT3) alone, and in mixed hemiclonal populations from hatching to metamorphosis. Tadpoles of three coexisting hemiclones from a single natural population (near Gutighausen, Switzerland) were reared in both two- and three-way mixtures in equal total numbers at high and low density. For each species and hemiclone, the proportion of tadpoles metamorphosing decreased as the density of tadpoles increased, with the three hemiclones spanning the range of values exhibited by the two parental species. LL and GUT1 tadpoles produced the highest proportion of metamorphs, whereas tadpoles of RR produced the fewest metamorphs at both densities. GUT1 tadpoles also produced the largest metamorphs at low density, GUT2 and GUT3 tadpoles produced smaller metamorphs than did GUT1 tadpoles at the low density, but the three hemiclones did not differ from each other at high density. The parental species (LL and RR) were intermediate in metamorphic size to the hemiclones at low density, but all genotypes converged on a similar size at high density. Length of the larval period also was affected by density, but its effect was dependent on genotype. GUT1 tadpoles had the shortest larval period at the low density, but larval period was longer and not different between GUT1, GUT3, and LL at high density. RR tadpoles had the longest larval period at both densities. The most dramatic results were that three genotypes (GUT1, GUT2, and RR) maintained rank order and increased days to metamorphosis from low to high density, whereas two genotypes (GUT3 and LL) changed rank order and decreased days to metamorphosis from low to high density. Mixtures of hemiclones in two- and three-way combinations facilitated the proportion of tadpoles metamorphosing for GUT1 and GUT2 at both densities, but only at the low density for GUT3 tadpoles. Results from this experiment are incompatible with the General-Purpose Genotype model as a global explanation of hybrid abundance in these frogs. Alternatively, the Frozen Niche Variation prediction of general performance superiority of clonal mixtures relative to single clone populations is strongly supported. The data confirm that fitness advantages of hemiclones change, depending on the environment, such that in temporally and spatially heterogeneous habitats like ponds, frequency-dependent selection among hemiclones may promote coexistence in hemiclonal assemblages. Yet, differential dispersal or colonization ability and historical factors affecting hemiclone distribution may also be important in shaping patterns of clonal coexistence. PMID- 28565501 TI - A BIG BOOK AND A SMALL BOOK ON SELECTION. PMID- 28565502 TI - THE EVOLUTION OF PARASITES FROM THEIR HOSTS: A CASE STUDY IN THE PARASITIC RED ALGAE. AB - Morphological similarities of many parasites and their hosts have led to speculation that some groups of plant, animal, fungal, and algal parasites may have evolved directly from their hosts. These parasites, which have been termed adelphoparasites in the botanical literature, and more recently, agastoparasites in the insect literature, may evolve monophyletically from one host and radiate secondarily to other hosts or, these parasites may arise polyphyletically, each arising from its own host. In this study we compare the internal transcribed spacer regions of the nuclear ribosomal repeats of species and formae specialis (host races) included in the red algal parasite genus Asterocolax with its hosts, which all belong to the Phycodrys group of the Delesseriaceae and with closely related nonhost taxa of the Delesseriaceae. These analyses reveal that species of Asterocolax have evolved polyphyletically. Asterocolax erythroglossi from the North Atlantic host Erythroglossum laciniatum appears to have evolved from its host, whereas taxa included in the north Pacific species Asterocolax gardneri have had two independent origins. Asterocolax gardneri from the host Polyneura latissima probably arose directly from this host. In contrast, all other A. gardneri formae specialis appear to have originated from either Phycodrys setchellii or P. isabelliae and radiated secondarily onto other closely related taxa of the Phycodrys group, including Nienburgia andersoniana and Anisocladella pacifica. Gamete crossing experiments confirm that A. gardneri from each host is genetically isolated from both its host, and from other A. gardneri and their hosts. Cross-infection experiments reveal that A. gardneri develops normally only on its natural host, although some abberrant growth may occur on alternate hosts. The ability of red algal parasites to radiate secondarily to other red algal taxa, where they may become isolated genetically and speciate, suggests that this process of speciation is not a "genetic dead end" but one that may give rise to related clusters of parasite species. PMID- 28565503 TI - INCIPIENT SPECIATION BY SEXUAL ISOLATION IN DROSOPHILA MELANOGASTER: VARIATION IN MATING PREFERENCE AND CORRELATION BETWEEN SEXES. AB - Genetic divergence for characters pertaining to reproductive isolation is of considerable interest in evolutionary biology. Since most studies concentrate on sibling species (for recent reviews, see Wu et al. 1996), we would like to know how much genetic variation exists between populations that are at an incipient stage of speciation. To answer this question, we have begun measuring variations in mating preference among natural isolates of Drosophila melanogaster, represented by the cosmopolitan and Zimbabwe sexual races. We quantify the variation in mating preference and success in both sexes by using a multiple choice design and an index that is suited to cases of strong asymmetry in mate choice. Different designs and indices for measuring sexual isolation are also discussed. These sexual traits are entirely genetically determined. Surveying four populations in southern Africa and additional cosmopolitan lines, we observe extensive genetic variation in sexual characters as well as strong correlation between sexes. The populations are highly differentiated and represent various stages of evolution between the African and the cosmopolitan type of sexual behaviors. The genetic variation and correlation for these sexual characters coupled with their geographical pattern have interesting implications for models of speciation by sexual selection. PMID- 28565504 TI - POPULATION STRUCTURE OF DIPODOMYS INGENS (HETEROMYIDAE): THE ROLE OF SPATIAL HETEROGENEITY IN MAINTAINING GENETIC DIVERSITY. AB - The giant kangaroo rat, Dipodomys ingens (Heteromyidae), is an endangered rodent that inhabits approximately 3% of its estimated historic range. Its current distribution is centered in two geographic areas, situated about 150 km apart, in south-central California. We sequenced a 293 base-pair fragment at the 5' end of the control region in 95 giant kangaroo rats from nine localities to examine the genetic structure of extant populations. We determine that mutations in this section of the control region follow a negative binominal distribution, rather than a Poisson. However, the distance between haplotypes is small enough that the difference between a tree that corrects for the non-Poisson distribution of mutations and one that does not, is minimal. This implies that the use of methods that assume a Poisson distribution of mutations, such as those based on coalescent theory, are justified. We find that the correlation between levels of genetic diversity and estimated census size is poor. This suggests that population sizes have fluctuated over time or that populations have not been isolated from one another, or both. We also examine the hierarchical structure of populations and find that the southern populations are not genetically subdivided but that there is significant subdivision between northern and southern populations and between some northern subpopulations. The phylogeographic relationship between northern and southern populations can primarily be attributed to isolation by distance, although the time since divergence between them appears to be less than the age of either. To examine the phylogeographic relationships in more detail we construct a minimum spanning tree based on Tamura Nei gamma-corrected distances and superimpose on it the geographic position of haplotypes. This reveals that there is more genetic distance between some northern haplotypes than between any northern and southern haplotypes, despite the geographic distance separating north from south and the larger size of the southern population. It also reveals that one northern population, in the Panoche Valley, contains old allelic lineages and shares ancestral polymorphism with several other populations. It also shows that two, small, geographically remote populations contain a surprising amount of genetic diversity, but that different population/geographic processes have affected the structure of that diversity. We estimate the average migration rate among all populations to be 7.5 per generation, and conclude that a disproportionate number of migration events involve gene flow with one northern population, the Panoche Valley. We find evidence for the hypothesis that there has been an increase in population size in the remaining populations in the north and suggest that the Panoche Valley could play a role in these expansions. Finally we discuss the probabilitiy that the genetic structure of the southern populations has been affected by fluctuations in size. These results are briefly compared to other studies on the genetic structure of rodent populations. PMID- 28565505 TI - THE EFFECT OF HABITAT ON PARENTAL AND HYBRID FITNESS: TRANSPLANT EXPERIMENTS WITH LOUISIANA IRISES. AB - We performed transplant experiments with Louisiana irises to test the assumptions of three models of hybrid zone structure: the bounded hybrid superiority model, the mosaic model, and the tension zone model. Rhizomes of Iris fulva, I. hexagona, and F1 and F2 hybrids were planted at four sites in southeastern Louisiana in 1994. Wild irises grew at all four sites, but differed in genotypic composition among sites. The sites were characterized by (1) pure I. fulva plants; (2) I. fulva-like hybrids; (3) I. hexagona-like hybrids; and (4) pure I. hexagona plants. The sites differed significantly in light availability, soil moisture and chemical composition, and vegetation. Survival of transplants was high in all sites and did not differ significantly among plant classes. Iris hexagona produced significantly more leaf material than I. fulva at the I. hexagona and I. hexagona hybrid sites. The two species did not differ in leaf production at the I. fulva and I. fulva hybrid sites. Leaf production by both classes of hybrid was as great as, or significantly greater than, both parental classes in all sites. Iris hexagona rhizomes gained mass in the I. hexagona and I. hexagona hybrid sites, but lost mass in the I. fulva and I. fulva hybrid sites. Iris fulva rhizomes lost mass in all sites. There were no significant differences in rhizome growth among classes at the I. fulva site. At all other sites, F1 rhizomes grew significantly more than all other classes except for I. hexagona at the I. hexagona hybrid site. There were no significant differences among classes in the production of new ramets. Overall blooming frequencies were 30% for I. fulva, 10% for F1 s, 3% for F2 s, and 0.7% for I. hexagona. Blooming frequency did not differ among sites for I. fulva, but significantly more F1 s bloomed at the I. hexagona site than at the I. fulva site. These results are inconsistent with all three models of hybrid zone structure. They suggest that once rhizomes become established, hybrids can reproduce by clonal growth as successfully as parents in all habitats, and can outperform them in some habitats. Clonal reproduction may ensure the long-term survival of early generation hybrids and allow the establishment of introgressed populations, despite the fact that F1 hybrids are rarely produced in nature. PMID- 28565506 TI - MATE CHOICE IN THE SAILFIN MOLLY, POECILIA LATIPINNA. AB - We examined both female and male mate choice in the sailfin molly, Poecilia latipinna. Female mollies preferred larger males over smaller ones when comparing males from their own populations. Although the expression of this preference depends on a female's receptive state, the level of female preference does not appear to be associated with any other attribute of the female or of the males. When presented with males of the same size from different populations, females preferred native over foreign males in some but not all population combinations. These results cannot be explained by a bias for higher size-specific rates of courtship displays that is shared by all females. Males preferred larger over smaller females; larger males exhibited stronger preferences, and preference for the larger female also increased as the disparity in size between the two object females increased. We found no evidence that males preferred native over foreign females when encountered singly or in size-matched combinations. These results indicate that discrimination among populations arises because females exercise divergent directional preferences for size-specific trait values that are associated with differences among males in these values. This result implies an active role for sexual selection in contributing to the maintenance of the behavioral or morphological distinctions among males observed within and among populations. PMID- 28565507 TI - ASSOCIATION BETWEEN FEEDING RATE AND PARASITOID RESISTANCE IN DROSOPHILA MELANOGASTER. AB - Replicate lines of Drosophila melanogaster have been selected for increased resistance against one of two species of parasitoid wasp, Asobara tabida and Leptopilina boulardi. In both cases, it has been shown that an improved ability to mount an immunological defense against the parasitoid's egg is associated with reduced survival when the larvae are reared under conditions of low resource availability and thus high competition. We show here that in both sets of selected lines, lower competitive ability is associated with reduced rates of larval feeding, as measured by the frequency of retractions of the cephalopharyngeal skeleton. This suggests that the same or similar physiological processes are involved in the trade-off between competition and resistance against either parasitoid and shows how the interaction between adaptations for competition and natural enemy resistance may be mediated. PMID- 28565508 TI - ADAPTIVE DYNAMICS IN ALLELE SPACE: EVOLUTION OF GENETIC POLYMORPHISM BY SMALL MUTATIONS IN A HETEROGENEOUS ENVIRONMENT. AB - We demonstrate how a genetic polymorphism of distinctly different alleles can develop during long-term frequency-dependent evolution in an initially monomorphic diploid population, if mutations have only small phenotypic effect. As a specific example, we use a version of Levene's (1953) soft selection model, where stabilizing selection acts on a continuous trait within each of two habitats. If the optimal phenotypes within the habitats are sufficiently different, then two distinctly different alleles evolve gradually from a single ancestral allele. In a wide range of parameter values, the two locally optimal phenotypes will be realized by one of the homozygotes and the heterozygote, rather than by the two homozygotes. Unlike in the haploid analogue of the model, there can be multiple polymorphic evolutionary attractors with different probabilities of convergence. Our results differ from the population genetic models of short-term evolution in two aspects: (1) a polymorphism that is population genetically stable may be invaded by a new mutant allele and, as a consequence, the population may fall back to monomorphism, (2) long-term evolution by allele substitutions may lead from a population where polymorphism is not possible into one where polymorphism is possible. PMID- 28565509 TI - PLANT POLYPLOIDY AND POLLINATION: FLORAL TRAITS AND INSECT VISITS TO DIPLOID AND TETRAPLOID HEUCHERA GROSSULARIIFOLIA. AB - In many polyploid species, polyploids often have different suites of floral traits and different flowering times than their diploid progenitor species. We hypothesized that such differences in floral traits in polyploids may subsequently affect their interactions with pollinating and other insect visitors. We measured floral morphology and flowering phenology in 14 populations of diploid and autotetraploid Heuchera grossulariifolia Rydb. (Saxifragaceae), determined if repeated evolution of independent polyploid lineages resulted in differentiation in floral morphology among those lineages, and ascertained if there was a consistent pattern of differentiation among genetically similar diploid and autotetraploid populations. In addition, we evaluated the differences in suites of floral visitors within a natural community where diploids and autotetraploids occur sympatrically. Overall, flowers of autotetraploid plants were larger and shaped differently than those of diploids, had a different flowering phenology than that of diploids, and attracted different suites of floral visitors. In comparison with flowers of diploids, tetraploid floral morphology varied widely from pronounced differences between cytotypes in some populations to similar flower shapes and sizes between ploidal levels in other populations. Observations of floral visitors to diploids and autotetraploids in a natural sympatric population demonstrated that the cytotypes had different suites of floral visitors and six of the 15 common visitors preferentially visited one ploidy more frequently. Moreover, we also found that floral morphology differed among independent autotetraploid origins, but there was no consistent pattern of differentiation between genetically similar diploid and autotetraploid populations. Hence, the results suggest that the process of polyploidization creates the potential for attraction of different suites of floral visitors. Multiple origins of polyploidy also presents the opportunity for new or different plant-insect interactions among independent polyploid lineages. These differences in turn may affect patterns of gene flow between diploids and polyploids and also among plants of independent polyploid origin. Polyploidy, therefore, may result in a geographic mosaic of interspecific interactions across a species' range, contributing to diversification in both plant and insect groups. PMID- 28565510 TI - NO EVIDENCE OF BOTTLENECK IN THE POSTGLACIAL RECOLONIZATION OF EUROPE BY THE NOCTULE BAT (NYCTALUS NOCTULA). AB - During the Pleistocene, the habitat of the noctule bat (Nyctalus noctula) was limited to small refuge areas located in Southern Europe, whereas the species is now widespread across this continent. Using mtDNA (control region and ND1 gene) polymorphisms, we asked whether this recolonization occurred through bottlenecks and whether it was accompanied by population growth. Sequences of the second hypervariable domain of the control region were obtained from 364 noctule bats representing 18 colonies sampled across Europe. This yielded 108 haplotypes that were depicted on a minimum spanning tree that showed a starlike structure with two long branches. Additional sequences obtained from the ND1 gene confirmed that the different parts of the MST correspond to three clades which diverged before the Last Glacial Maximum (18,000 yrC14 BP), leading to the conclusion that the noctule bat survived in several isolated refugia. Partitioning populations into coherent geographical groups divided our samples (phiCT = 0.17; P = 0.01) into a group of highly variable nursing colonies from central and eastern Europe and less variable, isolated colonies from western and southern Europe. Demographic analyses suggest that populations of the former group underwent demographic expansions either after the Younger Dryas (11,000-10,000 yrC14 BP), assuming a fast mutation rate for HV II, or during the Pleistocene, assuming a conventional mutation rate. We discuss the fact that the high genetic variability (h = 0.69 0.96; pi = 0.006-0.013) observed in nursing colonies that are located some distance from potential Pleistocene refugia is probably due to the combined effect of rapid evolution of the control region in growing populations and a range shift of noctule populations parallel to the recovery of forests in Europe after the last glaciations. PMID- 28565511 TI - RECENT BOOKS IN PRINT. PMID- 28565512 TI - PATTERNS OF HYBRIDIZATION IN THE PIRIQUETA CAROLINIANA COMPLEX IN CENTRAL FLORIDA: EVIDENCE FOR AN EXPANDING HYBRID ZONE. AB - We have identified a broad zone of hybridization between two morphologically and ecologically distinct herbaceous perennial taxa (morphotypes) within the Piriqueta caroliniana complex, which extends more than 300 km across the central Florida peninsula. Phylogeographic analyses indicate that the caroliniana morphotype has been present in north and central Florida since the early Pleistocene and that the viridis morphotype has immigrated into southern Florida much more recently. We examine the distribution of diagnostic morphological characters and nuclear genetic markers to assess the extent and patterns of introgression in this system. The results are consistent with the hypothesis that this hybrid zone has expanded north in recent history as viridis alleles have introgressed into regions that were previously occupied by populations of caroliniana. Genetic markers diagnostic for caroliniana have consistently high frequencies across the hybrid zone, whereas markers for viridis are extremely variable among populations with frequency reversals in adjacent populations. The latter pattern is probably the result of the combined stochastic effects of dispersal and drift on viridis alleles as they introgressed northward. Additional evidence for the recent expansion of this hybrid zone comes from patterns of variation for morphological and genetic markers. As expected for an expanding hybrid zone, within-population morphological variation was greatest toward the advancing front of introgression and levels of genetic variation for neutral diagnostic markers were greatest in the region of initial contact and lower in areas of recent expansion. The observed patterns of variation suggest that at least some hybrid genotypes have high fitnesses, which has led to the expansion of the hybrid zone via the displacement of parental genotypes in central Florida. PMID- 28565513 TI - MOLECULAR CHARACTERIZATION OF PgiC IN A TETRAPLOID PLANT AND ITS DIPLOID RELATIVES. AB - Allotetraploid plant species combine the genomes of related diploid species, but little is known about whether homologous genes from the diploid genomes are expressed, how they interact, or whether they evolve differently when in a common tetraploid nucleus. Polyploidy may lead to gene silencing, but few molecular characterizations of silenced genes encoding enzymes in polyploids and related diploids have been reported. Here we describe the PgiC genes in the tetraploid Clarkia gracilis and related diploid species, which are native from California to southern Washington. PgiC encodes the cytosolic isozyme of phosphoglucose isomerase (PGIC; EC 5.3.1.9). The gene was duplicated in the basal stock of Clarkia and now both genes, PgiC1 and PgiC2, are active in about half of the diploid species, whereas only PgiC1 is active in the others. Clarkia gracilis was found to have three PgiC genes: two PgiC1s and a PgiC2. Reverse-transcriptase polymerase chain reaction (RT-PCR) experiments, starting with mRNAs prepared from seedling leaves of C. gracilis, showed that the three genes are expressed. Analysis of their sequences showed they are evolving at similar rates to their homologues and that they have the same intron-exon structure. The presence of an expressed PgiC2 in C. gracilis was unexpected because all related diploid species, including one identified as a parent, have only active PgiC1s. The donor of the PgiC2 is now presumed extinct, but parsimony analysis identified its phylogenetic position. None of the PgiC genes that were active when C. gracilis arose were silenced. A possible example of gene conversion involving a 300 nuclectide region of one PgiC1 and PgiC2 was identified, but it probably occurred in the diploid parental species rather than in C. gracilis. PgiC2 is the first known example of an active locus in a tetraploid plant species that is no longer expressed in its diploid relatives. PMID- 28565514 TI - MOLECULAR MARKERS INDICATE RARE SEX IN A PREDOMINANTLY ASEXUAL PARASITOID WASP. AB - The parasitoid wasp genus Lysiphlebus (Hymenoptera: Braconidae: Aphidiinae) contains a taxonomically poorly resolved group of both sexual (arrhenotokous) species and asexual (thelytokous) clones. Maximum-parsimony and maximum likelihood analyses of mitochondrial DNA sequence data from specimens collected across Western Europe showed that asexuality, which does not appear to be caused by the bacterium Wolbachia, is concentrated in two geographically widespread lineages, the older of which diverged from the closest extant sexual taxa approximately 0.5 million years ago. However, the DNA sequences of a nuclear intron (elongation factor-1alpha) showed no congruence with this pattern, and a much higher frequency of heterozygotes with very high allelic diversity was observed among the asexual females compared to that among females from the sexual species. This pattern is consistent with maternally inherited asexuality coupled with a history of rare sex with members of several closely related sexual populations or species. Our observations reinforce recent arguments that rare sex may be more important for the persistence of otherwise asexual lineages than hitherto appreciated. PMID- 28565515 TI - BATHYMETRIC PATTERNS OF BODY SIZE IN DEEP-SEA GASTROPODS. AB - The shift to smaller body size in marine invertebrates at the deep-sea threshold and size-depth clines within the deep-sea ecosystem are global biogeographic phenomena that remain poorly understood. We present the first standardized measurements of larval and adult size among ecologically and phylogenetically similar species across a broad and continuous depth range, using the largest family of deep-sea gastropods (the Turridae). Size at all life stages increases significantly with depth from the upper bathyal region to the abyssal plain. These consistent clines may result from selection favoring larger size at greater depths because of its metabolic and competitive advantages. The unusually small size of deep-sea mollusks, in general, may represent an independent evolutionary process that favors invasion by inshore taxa composed of small organisms. PMID- 28565516 TI - ECOLOGICAL COSTS OF PLANT RESISTANCE TO HERBIVORES IN THE CURRENCY OF POLLINATION. AB - In this paper, we examine how ecological costs of resistance might be manifested through plant relationships with pollinators. If defensive compounds are incorporated into floral structures or if they are sufficiently costly that fewer rewards are offered to pollinators, pollinators may discriminate against more defended plants. Here we consider whether directional selection for increased resistance to herbivores could be constrained by opposing selection through pollinator discrimination against more defended plants. We used artificial selection to create two populations of Brassica rapa plants that had high and low myrosinase concentrations and, consequently, high and low resistance to flea beetle herbivores. We measured changes in floral characters of plants in both damaged and undamaged states from these populations with different resistances to flea beetle attack. We also measured pollinator visitation to plants, including numbers of pollinators and measures of visit quality (numbers of flowers visited and time spent per flower). Damage from herbivores resulted in reduced petal size, as did selection for high resistance to herbivores later in the plant lifetime. In addition, floral display (number of open flowers) was also altered by an interaction between these two effects. Changes in floral traits translated into overall greater use of low-resistance, undamaged plants based on total amount of time pollinators spent foraging on plants. Total numbers of pollinators attracted to plants did not differ among treatments; however, pollinators spent significantly more time per flower on plants from the low-resistance population and tended to visit more flowers on these plants as well. Previous work by other investigators on the same pollinator taxa has shown that longer visit times are associated with greater male and female plant fitness. Because initial numbers of pollinators did not differ between selection regimes, palatability and/or amount of rewards offered by high- and low-resistance populations are likely to be responsible for these patterns. During periods of pollinator limitation, less defended plants may have a selective advantage and pollinator preferences may mediate directional selection imposed by herbivores. In addition, if pollinator preferences limit seed set in highly defended plants, then lower seed set previously attributed to allocation costs of defense may also reflect greater pollinator limitation in these plants relative to less defended plants. PMID- 28565517 TI - POPULATION DIVERGENCE IN SEXUAL ORNAMENTS: THE WHITE FOREHEAD PATCH OF NORWEGIAN PIED FLYCATCHERS IS SMALL AND UNSEXY. AB - Models of sexual selection suggest that populations may easily diverge in male secondary sexual characters. Studies of a Spanish population of the pied flycatcher, Ficedula hypoleuca, and a Swedish population of the closely related collared flycatcher, F. albicollis, have indicated that the white forehead patch of males is a sexually selected trait. We studied the white forehead patch of male pied flycatchers (n = 487) in a Norwegian population over seven years. Males with large forehead patches were in general more brightly colored, but patch height was not correlated to body mass, body size, or parasite loads. Conditions during the nestling period did not seem to influence patch height as an adult. Patch height increased slightly from the first to the second year as adults, but then remained relatively constant at higher ages. Patch height was not related to survival. Year-to-year changes showed that males who increased in patch height also increased in body mass, suggesting that expression of the forehead patch may be partly condition dependent. However, changes in body mass explained only a small proportion of the variance in patch height between males. Thus, patch height would not be a good indicator of male quality. Furthermore, patch size was also not related to male ability to feed nestlings, indicating that females would not obtain direct benefits by choosing males with large patches. However, patch height could be a Fisher trait, but this requires heritability and there was no significant father-son resemblance in patch height. Comparisons of the males visited by each female during the mate sampling period indicated that chosen males did not have larger forehead patches than rejected males. Experimental manipulation of patch height did not affect male mating success. These results indicate that females do not use patch size as a mate choice cue. Finally, patch height did not predict the outcome of male contests for nestboxes, suggesting that the forehead patch is not an intrasexually selected cue of status. Norwegian pied flycatchers have smaller forehead patches than both Spanish pied flycatchers and Swedish collared flycatchers. We suggest that this pattern may be explained by the lack of sexual selection on the forehead patch in the Norwegian population as compared to the other populations, where the patch is apparently sexually selected. We discuss possible reasons for these population divergences, such as female choice on an alternative secondary sexual character (general plumage color) and speciation among Ficedula flycatchers. PMID- 28565518 TI - GENETIC DIVERSITY AND CAPILLARIA HEPATICA (NEMATODA) PREVALENCE IN MICHIGAN DEER MOUSE POPULATIONS. AB - There have been few field tests of the hypothesis that homozygous populations are prone to high levels of disease. I tested for a negative correlation between genetic diversity and parasitism by estimating the allozyme heterozygosity, population density, and proportion of individuals infected by Capillaria hepatica (Nematoda) in nine Michigan populations of deer mice (Peromyscus maniculatus). Parasite prevalence was correlated negatively with heterozygosity when the effects of density were held constant, but was not correlated with population density after controlling for the effects of genetic diversity. These data support the prediction that inbred populations will be more susceptible to parasite infestations. PMID- 28565519 TI - POLLEN PERFORMANCE AND SEX-RATIO EVOLUTION IN A DIOECIOUS PLANT. AB - There has been a proliferation of studies, in a variety of taxa, that have detected sex-linked or cytoplasmic genes that enhance their own transmission via sex-ratio distortion. One of the most important parameters influencing the dynamics of these elements is the magnitude of their transmission advantage. In many systems, the mechanism of sex-ratio distortion is to abort X- or Y-bearing gametes. With this mechanism, the transmission advantage associated with sex ratio distortion is diminished when the production of male gametes limits offspring production or when competition among the gametes of different males is intense. In this study, we analyzed the outcome of pollen competition between males that produced different sex ratios in the dioecious plant, Silene alba, and estimated how the sex-ratio bias influenced the transmission properties of the sex chromosomes. We varied the intensity of pollen competition by controlling the quantity of pollen used in crosses and used a combination of single-male pollinations and pollen mixtures to evaluate the effects of multiple paternity. Paternity in pollen mixtures was estimated using allozymes. Sex-ratio bias was directly influenced by the quantity of pollen, but the magnitude of this effect was small. The relative performance of pollen from different males varied substantially, especially when there was multiple paternity. Specifically, males with biased sex ratios sired far fewer offspring of either sex in pollen mixtures. In crosses involving single males, however, these "sex-ratio" males produced the same number of offspring as other males, so the female bias caused a significant transmission advantage for X-linked genes. X-linked genes could enhance their transmission via sex-ratio distortion in Silene populations, but the magnitude of this transmission advantage will depend on the ecological circumstances that influence the opportunity for multiple paternity. PMID- 28565520 TI - WOLBACHIA AND THE EVOLUTION OF REPRODUCTIVE ISOLATION BETWEEN DROSOPHILA RECENS AND DROSOPHILA SUBQUINARIA. AB - Endosymbiotic bacteria of the genus Wolbachia are widespread among insects and in many cases cause cytoplasmic incompatibility in crosses between infected males and uninfected females. Such findings have been used to argue that Wolbachia have played an important role in insect speciation. Theoretical models, however, indicate that Wolbachia alone are unlikely to lead to stable reproductive isolation between two formerly conspecific populations. Here we analyze the components of reproductive isolation between Drosophila recens, which is infected with Wolbachia, and its uninfected sister species Drosophila subquinaria. Laboratory pairings demonstrated that gene flow via matings between D. recens females and D. subquinaria males is hindered by behavioral isolation. Matings readily occurred in the reciprocal cross (D. quinaria females * D. recens males), but very few viable progeny were produced. The production of viable hybrids via this route was restored by antibiotic curing of D. recens of their Wolbachia symbionts, indicating that hybrid offspring production is greatly reduced by cytoplasmic incompatibility in the crosses involving infected D. recens males. Thus, behavioral isolation and Wolbachia-induced cytoplasmic incompatibility act as complementary asymmetrical isolating mechanisms between these two species. In accordance with Haldane's rule, hybrid females were fertile, whereas hybrid males invariably were sterile. Levels of mtDNA variation in D. recens are much lower than in either D. subquinaria or D. falleni, neither of which is infected with Wolbachia. The low haplotype diversity in D. recens is likely due to an mtDNA sweep associated with the spread of Wolbachia. Nevertheless, the existence of several mtDNA haplotypes in this species indicates that Wolbachia have been present as a potential isolating mechanism for a substantial period of evolutionary time. Finally, we argue that although Wolbachia by themselves are unlikely to bring about speciation, they can increase the rate of speciation in insects. PMID- 28565521 TI - ARE ENZYME LOCI SELECTIVELY NEUTRAL IN HAPLOID POPULATIONS OF NONVASCULAR PLANTS? AB - Enzyme data from 12 previously published studies of haploid bryophyte populations were subjected to tests of selective neutrality and population equilibrium. Altogether 280 samples were tested using the Ewens-Watterson test, the Ewens exact test, and Chakraborty's test. The Ewens-Watterson and the Ewens exact tests revealed neutrality in 84.6% of the cases, whereas the Chakraborty test revealed neutrality in 100% of the cases. Neutrality may thus explain the relatively high amounts of genetic variation found in these organisms. Possible hidden population sub-structuring and nonrandom field sampling of genotypes in many of the studies could make Chakraborty's test more reliable than the two others. PMID- 28565522 TI - GEOGRAPHIC VARIATION IN LIFE-HISTORY TRAITS OF THE ANT LION, MYRMELEON IMMACULATUS: EVOLUTIONARY IMPLICATIONS OF BERGMANN'S RULE. AB - In eastern North America, body size of the larval ant lion Myrmeleon immaculatus increases from south to north, following Bergmann's rule. We used a common-garden experiment and a reciprocal-transplant experiment to evaluate the effects of food and temperature on ant lion growth, body size, and survivorship. In the laboratory common-garden experiment, first-instar larvae from two southern (Georgia, South Carolina) and two northern (Connecticut, Rhode Island) populations were reared in incubators under high- and low-food and high- and low temperature regimes. For all populations, high food increased final body mass and growth rate and decreased development time. Growth rates were higher at low temperatures, but temperature did not affect larval or adult body mass. Survivorship was highest in high-food and low-temperature treatments. Across all food and temperature treatments, northern populations exhibited a larger final body mass, shorter development time, faster growth rate, and greater survivorship than did southern populations. Results were similar for a field reciprocal transplant experiment of third-instar larvae between populations in Connecticut and Oklahoma: Connecticut larvae grew faster than Oklahoma larvae, regardless of transplant site. Conversely, larvae transplanted to Oklahoma grew faster than larvae transplanted to Connecticut, regardless of population source. These results suggest that variation in food availability, not temperature, may account for differences in growth and body size of northern and southern ant lions. Although northern larvae grew faster and reached a larger body size in both experiments, northern environments should suppress growth because of reduced food availability and a limited growing season. This study provides the first example of countergradient selection causing Bergmann's rule in an ectotherm. PMID- 28565523 TI - BREEDING STRUCTURE OF A YUCCA FILAMENTOSA (AGAVACEAE) POPULATION. AB - Yucca filamentosa and its species-specific pollinator, the yucca moth, Tegeticula yuccasella (Lepidoptera: Prodoxidae), form a relationship that is often cited as a classic example of a coevolved plant-pollinator mutualism. Observations of the moth's behavior have led to predictions that moth dispersal is relatively limited and that, as a consequence, the self-compatible Y. filamentosa should experience relatively high rates of self-fertilization. In contrast, analyses of its mating system indicated that Y. filamentosa was predominantly outcrossed. To better understand effective breeding patterns in Y. filamentosa populations, 10 polymorphic allozyme loci were investigated to analyze the breeding structure of a natural Y. filamentosa population. Analyses revealed that Y. filamentosa is predominantly outcrossed, has multiply sired fruits, and that each fruit was sired by a different set of pollen donors. The effective number of pollen donors per fruit ranged from 1.56 to 3.13, indicating that some correlated mating exists within fruits. Paternity analyses revealed that pollen moved from 6 m to 293 m (mean = 118 m) within the study population and that a minimum of 10% of the progeny were sired by pollen originating outside of the population. These results are discussed in the context of the yucca-yucca moth mutualism. PMID- 28565525 TI - MORPHOLOGICAL DIVERSIFICATION AND ADAPTIVE RADIATION: A COMPARISON OF TWO DIVERSE LIZARD CLADES. AB - We compared the morphological diversity (i.e., the amount of morphological space occupied) of two similar clades, the lizard genera Anolis and Sceloporus. These species-rich monophyletic clades are similar in body size, age of origin, and many aspects of their natural history. We examined a number of morphological traits whose variation is likely to represent adaptation to different aspects of the environment, including body size, limb proportions, head dimensions, and tail length. Examination of the position of species in multidimensional space, based on a principal components analysis, indicates that the morphological diversity of Anolis, which we refer to as disparity, is significantly greater than that of Sceloporus. One potential explanation for this pattern is that morphological diversification in Anolis was facilitated by the evolution of subdigital toe pads, which allow anoles to use the environment in ways not available to Sceloporus. The geographic location of diversification (tropical and subtropical for Anolis, arid for Sceloporus) may also have been important. PMID- 28565524 TI - COSTS OF INDUCED RESPONSES AND TOLERANCE TO HERBIVORY IN MALE AND FEMALE FITNESS COMPONENTS OF WILD RADISH. AB - Theory predicts that plant defensive traits are costly due to trade-offs between allocation to defense and growth and reproduction. Most previous studies of costs of plant defense focused on female fitness costs of constitutively expressed defenses. Consideration of alternative plant strategies, such as induced defenses and tolerance to herbivory, and multiple types of costs, including allocation to male reproductive function, may increase our ability to detect costs of plant defense against herbivores. In this study we measured male and female reproductive costs associated with induced responses and tolerance to herbivory in annual wild radish plants (Raphanus raphanistrum). We induced resistance in the plants by subjecting them to herbivory by Pieris rapae caterpillars. We also induced resistance in plants without leaf tissue removal using a natural chemical elicitor, jasmonic acid; in addition, we removed leaf tissue without inducing plant responses using manual clipping. Induced responses included increased concentrations of indole glucosinolates, which are putative defense compounds. Induced responses, in the absence of leaf tissue removal, reduced plant fitness when five fitness components were considered together; costs of induction were individually detected for time to first flower and number of pollen grains produced per flower. In this system, induced responses appear to impose a cost, although this cost may not have been detected had we only quantified the traditionally measured fitness components, growth and seed production. In the absence of induced responses, 50% leaf tissue removal, reduced plant fitness in three out of the five fitness components measured. Induced responses to herbivory and leaf tissue removal had additive effects on plant fitness. Although plant sibships varied greatly (49-136%) in their level of tolerance to herbivory, costs of tolerance were not detected, as we did not find a negative association between the ability to compensate for damage and plant fitness in the absence of damage. We suggest that consideration of alternative plant defense strategies and multiple costs will result in a broader understanding of the evolutionary ecology of plant defense. PMID- 28565526 TI - THE FITNESS OF MANIPULATING PHENOTYPES: IMPLICATIONS FOR STUDIES OF FLUCTUATING ASYMMETRY AND MULTIVARIATE SELECTION. AB - Phenotypic manipulation (or phenotypic engineering) that alters trait distributions provides a way to increase the statistical power of detecting relationships between traits and fitness. Manipulations relying on plastic responses, however, assume a specific relationship between the perturbation and the alteration of the traits when multiple traits are involved. We measured several traits, including condition measured as fluctuating asymmetry, in the ladybird beetle Harmonia axyridis under six different diets to examine how altered environments affected multiple traits and their distributions. Although diet affected fluctuating asymmetry, we found no consistent relationship between degree of asymmetry and other phenotypic measures. As expected, individual traits were altered by our treatments. Contrary to expectation, relationships among traits were not constant among diets. Our results suggest that assumptions about the relationship between condition and trait values, especially fluctuating asymmetry, cannot be made. Further, studies that use manipulated phenotypes to statistically determine the form of selection must first demonstrate that the pattern of the phenotypic correlation matrix is not itself altered by the manipulation. If the phenotypic correlation matrix is not constant, then experimental estimates of selection coefficients may not reflect selection that occurs in the wild. PMID- 28565527 TI - THE PHENOTYPIC AND FITNESS EFFECTS OF COLICIN RESISTANCE IN ESCHERICHIA COLI K 12. AB - Previous studies indicate that most natural isolates of Escherichia coli are resistant to most or all colicins (antibiotics produced by E. coli) when assessed in the laboratory. Additionally, resistance to different colicin types appears to arise in a nonindependent manner. One possible mechanism to explain this nonindependence is pleiotropy: Multiple resistances are selected after exposure to a single colicin. This study, which was designed to address the role of pleiotropy in the generation of colicin resistance, revealed that 96% of colicin resistant mutants were resistant to two or more colicins. Mutational class was important because putative translocation mutants (Tol pathway mutants) resisted fewer colicins than putative receptor mutants. To determine whether colicin resistance is costly, the effects of colicin resistance mutations on maximal growth rate in a rich medium were also examined. Relative to the sensitive ancestor, translocation mutations lowered maximal growth rates by 17%, whereas putative receptor mutations did not significantly lower growth rates. Thus, when nutrients are abundant, the most advantageous forms of colicin resistance may not impose a cost. The ecological consequences of pleiotropic colicin resistance could involve population cycling between colicin sensitivity and resistance. Additionally, if the cost of resistance depends on the environment, ecological diversification could result. PMID- 28565528 TI - THE DISTRIBUTION OF PHENOTYPIC VARIANCE WITH INBREEDING. AB - Fifty-two inbred populations of Drosophila melanogaster, each founded from a single pair, and a large number of control, outbred flies were measured for fitness and a set of six traits. A survey of the literature on the effects of inbreeding and population bottlenecks demonstrates that the commonly observed pattern of an apparent variance among characters and among species in changes of phenotypic variance may in fact be largely the result of sampling error, given the pattern of change that we demonstrate within a species for the same character. In our study, population bottlenecks on average decrease the amount of phenotypic variance for a suite of wing characteristics and size, but there is large and significant variation among lines in the amount of phenotypic variance. As a result, several lines increased in variance in spite of the average decrease. Interestingly, the changes in phenotypic variance for fitness are in sharp contrast to those seen for phenotypic variance for morphological traits. The amount of phenotypic variance for fitness varies highly significantly among lines but, on average, is increased by bottlenecks. The changes in phenotypic variance as a result of population bottlenecks are large enough to significantly affect the probability of peak shifts by the variance-induced peak shift model. PMID- 28565529 TI - DEVELOPMENTAL INSTABILITY IN WILD CHROMOSOMAL HYBRIDS OF THE HOUSE MOUSE. AB - In wild populations of the house mouse from Tunisia, fluctuating asymmetry and character size of tooth traits were compared between chromosomal races (2n = 40, all acrocentric standard karyotype, and 2n = 22, with nine fixed Robertsonian fusions) and their natural hybrids. Developmental stability was impaired in hybrids compared to both parental groups. Because genetic divergence measured by allozyme markers was low, genomic incompatibilities were not expected between the chromosomal races. This suggests that differentiation of gene systems specifically involved in development may have occurred between the chromosomal races. Support for the latter was found in the study of character size which showed that the 2n = 22 mice had smaller teeth than either the hybrid or the standard mice. The study of Tunisian chromosomal races thus shows that chromosomal evolution may lead to important changes in coadapted gene systems without involving extensive genic differentiation. PMID- 28565530 TI - CONVERGENT EVOLUTION OF COURTSHIP SONGS AMONG CRYPTIC SPECIES OF THE CARNEA GROUP OF GREEN LACEWINGS (NEUROPTERA: CHRYSOPIDAE: CHRYSOPERLA). AB - Although traits of related species are likely to be similar due to common ancestry, mating signals are an exception. In singing insects, for example, song similarity has been documented only for allopatric or allochronic species pairs, and even then, not often. Where song similarity does occur, it has been logically attributed to the inheritance of ancestral traits rather than convergence. It is quite common for related, sympatric insect species to differ dramatically in calling song, which is predicted by evolutionary theory to maximize intraspecific mating success. Given that there are a limited number of ways to make sounds on anatomically similar organs and given that there would be no selective pressure for songs to differ in widely separated geographic areas, convergence in songs among related species living on different continents might be expected. Here we present the first well-documented case of such convergence, in a group of sibling, cryptic species characterized by substrate-borne vibrational mating songs. In this example from green lacewings of the carnea group of the genus Chrysoperla, a variety of statistical tests shows that one species in North America and another in Asia possess songs that are strikingly similar to each other. DNA data demonstrate that the species involved belong to divergent speciose lineages, and behavioral data demonstrate that the convergent songs are readily accepted by members of both species. PMID- 28565531 TI - A COMPARISON OF INBREEDING DEPRESSION IN LIFE-HISTORY AND MORPHOLOGICAL TRAITS IN ANIMALS. AB - The current study tests the hypothesis that life-history traits (closely related to fitness) show greater inbreeding depression than morphological traits (less closely related to fitness). The mean and median slope of the standardized coefficient of inbreeding depression (the slope of the linear relationship between F and the trait value) for life-history and morphological traits were compared. Slopes for life-history traits were higher than those for morphological traits. At F = 0.25 (full-sibling mating), life-history traits experienced a median reduction of 11.8% in trait value, whereas morphological traits showed a depression in trait value of approximately 2.2%. PMID- 28565532 TI - LOSS OF SEX IN CLONAL POPULATIONS OF A FLOWERING PLANT, DECODON VERTICILLATUS (LYTHRACEAE). AB - The loss of traits that no longer increase fitness is a pervasive feature of evolution, although detailed studies of the genetic, developmental, and evolutionary factors involved are few. Most perennial plants practice both sexual and clonal reproduction, and it has been hypothesized that populations with little sexual recruitment may lose the capacity for sexual reproduction by fixing mutations that disable one or more of the many processes involved in sex. The clonal, tristylous aquatic plant, Decodon verticillatus, exhibits marked geographical variation in sexual recruitment. Populations at the northern limit of the range are usually monomorphic for style length consist of single genotypes, and produce almost no seed, due, in part, to environmental conditions that inhibit pollination, fertilization, and seed maturation. Controlled crosses in a greenhouse provided evidence for greatly reduced sexual capacity in an exclusively clonal, monomorphic population. Plants from this infertile population produced only 3-18% as many seeds per pollination as fertile populations. Observations of pollen tube growth indicated that infertility is due to severe reductions in pollen tube numbers both early after pollination and later when pollen tubes were traversing the ovary, due primarily to the inability of pistils to support normal tube growth. A three-year greenhouse experiment comparing fertility, survival, and growth of F1 progenies produced from reciprocal crosses between plants from the infertile population and those from nearby fertile populations suggested that the genetic basis for infertility is simple and may involve a single recessive mutation. In addition, the results did not reveal any association between infertility and other aspects of survival and vegetative vigor. The infertile genotype was likely fixed in the population through founder effect rather than indirect selection resulting from antagonistic pleiotropy or direct selection of advantages associated with reduced investment in sexual reproduction. A broader comparison of sexual fertility in 15 clonal, monomorphic populations and five genotypically diverse, trimorphic populations under greenhouse conditions revealed substantial infertility in all but one monomorphic population. Populations varied somewhat in the stage at which infertility was expressed, however, pollen tube growth was impaired in all populations. These results provide strong support for the hypothesis that complex traits like sex are degraded by mutation when they no longer increase fitness. PMID- 28565533 TI - EVIDENCE THAT AN OUTCROSSING POPULATION IS A DERIVED LINEAGE IN A HERMAPHRODITIC FISH (RIVULUS MARMORATUS). AB - Rivulus marmoratus is the only known vertebrate with obligate, synchronous hermaphroditic fertilization. Males can be experimentally induced in the laboratory and are rare or absent in most populations, but at the isolated Twin Cays, Belize, locality, males are relatively abundant. At this locality, evidence of outcrossing has been documented in this otherwise automictic cloning species. Phylogenetic analysis of restriction sites and sequence characters revealed that all Florida and Belize western Caribbean populations (including Twin Cays) are phyletically indistinguishable yet divergent from eastern populations in Brazil and the Bahamas. Further, these western lineages shared a common ancestor more recently than all other populations. Therefore, the Twin Cays population is not a remnant ancestral outcrossing population. Outcrossing is suspected to have evolved as a phenotypically plastic character, and its expression in R. marmoratus may be dormant unless triggered by some ecological factor that is not well understood. PMID- 28565534 TI - COMPARATIVE PHYLOGEOGRAPHY OF A SIBLING PAIR OF RAINFOREST DROSOPHILA SPECIES (DROSOPHILA SERRATA AND D. BIRCHII). AB - Drosophila serrata and D. birchii are presumed sibling species; the former is a widespread generalist and the latter is restricted to rainforests. Comparison of the mtDNA sequence phylogeographies revealed two highly divergent, geographically distinct lineages of D. serrata that are as distinct from each other as either is from D. birchii. However, diversity in D. birchii is low and unstructured. The low diversity in D. birchii corresponds with a late-Pleistocene-Holocene contraction of lowland rainforests. We suggest that future studies of speciation and adaptation should compare the two lineages of D. serrata to each other as well as to D. birchii. PMID- 28565535 TI - EPISTASIS AND THE EVOLUTION OF ADDITIVE GENETIC VARIANCE IN POPULATIONS THAT PASS THROUGH A BOTTLENECK. AB - Traditional models of genetic drift predict a linear decrease in additive genetic variance for populations passing through a bottleneck. This perceived lack of heritable variance limits the scope of founder-effect models of speciation. We produced 55 replicate bottleneck populations maintained at two male-female pairs through four generations of inbreeding (average F = 0.39). These populations were formed from an F2 intercross of the LG/J and SM/J inbred mouse strains. Two contemporaneous control strains maintained with more than 60 mating pairs per generation were formed from this same source population. The average level of within-strain additive genetic variance for adult body weight was compared between the control and experimental lines. Additive genetic variance for adult body weight within experimental bottleneck strains was significantly higher than expected under an additive genetic model This enhancement of additive genetic variance under inbreeding is likely to be due to epistasis, which retards or reverses the loss of additive genetic variance under inbreeding for adult body weight in this population. Therefore, founder-effect speciation processes may not be constrained by a loss of heritable variance due to population bottlenecks. PMID- 28565536 TI - HYDROTHERMAL-VENT ALVINELLID POLYCHAETE DISPERSAL IN THE EASTERN PACIFIC. 2. A METAPOPULATION MODEL BASED ON HABITAT SHIFTS. AB - Marine organisms typically fall into two main categories: those with a high level of population structuring and those with a low one. The first are often found to be poor dispersers, following isolation by distance or stepping-stone theoretical predictions. The second are commonly associated with high-dispersal taxa and are best described by the island model. Deep-sea hydrothermal vent systems represent a good model for studying one-dimensional metapopulations. Whereas isolation by distance might be expected to be the rule in such a system for species with limited dispersal capabilities, a biological paradox can be observed: an apparent genetic homogeneity in some vent species with short-scale dispersal potential, in a one-dimensional fragmented habitat. This can be explained if one key assumption of the existing models is not met: gene flow between populations and genetic drift may not have the time to equilibrate. Geophysical models revealed that hydrothermal convection is intrinsically unstable, inducing processes of coalescence or splitting of venting areas in a chaotic manner. This is likely to generate frequent extinctions and recolonizations. Theoretical genetic predictions derived from extinctions/recolonizations cannot satisfactorily model a situation where habitat shifts are frequent and constantly affect the metapopulation equilibrium. Because neither the island and the stepping-stone models nor the classical metapopulation models resemble the hydrothermal vent reality, we present here a realistic model developed to provide a compromise between existing conceptual models and what is currently known of the biology and ecology of one of the most peculiar and best-studied vent species, the polychaete Alvinella pompejana. This model allows us to define the boundaries between which the metapopulation is evolutionary stable in an unstable context. Simulations show different patterns in which metapopulation size and recolonization vary but reach an equilibrium despite chaotic vent extinctions. In contrast, the model also shows that displacing habitat continuously affects the equilibrium between gene flow and drift. As a consequence, the time required to balance these evolutionary forces can never be attained, leading to chaotic fluctuations in F statistics. Those fluctuations are mainly due to stochastic changes of the interpatch distance which affect migration rates. The shifting of active zones of venting can episodically counterbalance differentiation and allow a long-term genetic homogenization at the ridge scale. These findings lead to a new concept in which the exchanges between populations would mainly depend on the habitat's movements along the ridge axis rather than the organim's dispersal. We therefore propose a new model based on patch-network displacements in which transient contact zones allow low levels of gene flow throughout the metapopulation. PMID- 28565538 TI - SUPPRESSION OF SEX-RATIO MEIOTIC DRIVE AND THE MAINTENANCE OF Y-CHROMOSOME POLYMORPHISM IN DROSOPHILA. PMID- 28565537 TI - PARASITE-MEDIATED SELECTION AGAINST INBRED SOAY SHEEP IN A FREE-LIVING ISLAND POPULATON. AB - Parasites are thought to provide a selective force capable of promoting genetic variation in natural populations. One rarely considered pathway for this action is via parasite-mediated selection against inbreeding. If parasites impose a fitness cost on their host and the offspring of close relatives have greater susceptibility to parasites due to the increased homozygosity that results from inbreeding, then parasite-mediated mortality may select against inbred individuals. This hypothesis has not yet been tested within a natural vertebrate population. Here we show that relatively inbred Soay sheep (Ovis aries), as assessed by microsatellite heterozygosity, are more susceptible to parasitism by gastrointestinal nematodes, with interactions indicating greatest susceptibility among adult sheep at high population density. During periods of high overwinter mortality on the island of Hirta, St. Kilda, Scotland, highly parasitised individuals were less likely to survive. More inbred individuals were also less likely to survive, which is due to their increased susceptibility to parasitism, because survival was random with respect to inbreeding among sheep that were experimentally cleared of their gastrointestinal parasite burden by anthelminthic treatment. As a consequence of this selection, average microsatellite heterozygosity increases with age in St. Kildan Soay sheep. We suggest that parasite-mediated selection acts to maintain genetic variation in this small island population by removing less heterozygous individuals. PMID- 28565539 TI - NATURAL SELECTION ON THERMOGENIC CAPACITY OF HIGH-ALTITUDE DEER MICE. AB - Adaptive explanations that rely on physiological arguments are common, but tests of hypotheses about the significance of whole-animal physiological performance (e.g., aerobic capacities) are rare. We studied phenotypic selection on the thermogenic capacity (i.e., maximal rate of oxygen consumption [VO2 max] elicited via cold exposure) of high-altitude (~3800 m) deer mice (Peromyscus maniculatus). A high VO2 max equates to a high capacity for heat production and should favor survival in the cold environments prevalent at high altitude. Strong directional selection favored high VO2 max, at least in one year. The selection for increased VO2 max is consistent with predictions derived from incorporating our physiological data into a biophysical model. During another year, we found weak evidence of selection for decreased body mass. Nonlinear selection was not significant for any of the selection episodes we studied. The strong directional selection for VO2 max that we observed suggests that-given ample genetic variation-aerobic metabolism and perhaps endothermy may have evolved rapidly on the geological time scale. PMID- 28565540 TI - SPATIAL GENETIC STRUCTURE OF CLONAL AND SEXUAL REPRODUCTION IN POPULATIONS OF ADENOPHORA GRANDIFLORA (CAMPANULACEAE). AB - The spatial distribution of clonal versus sexual reproduction in plant populations should generally have differing effects on the levels of biparental inbreeding and the apparent selfing rate, produced via mating by proximity through limited pollen dispersal. We used allozyme loci, join-count statistics, and Moran's spatial autocorrelation statistics to separate the spatial genetic structure caused by clonal reproduction from that maintained in sexually reproduced individuals in two populations of Adenophora grandiflora, a perennial herb. Join-count statistics showed that there were statistically significant clustering of clonal genotypes within distances less than 4 m. Both the entire populations and the sets of sexually reproduced individuals exhibited significant spatial autocorrelation at less than about 12 m, and the sexually reproduced individuals are substantially structured in an isolation-by-distance manner, consistent with a neighborhood size of about 50. PMID- 28565541 TI - THE EVOLUTION OF DIAPAUSE IN THE KILLIFISH FAMILY RIVULIDAE (ATHERINOMORPHA, CYPRINODONTIFORMES): A MOLECULAR PHYLOGENETIC AND BIOGEOGRAPHIC PERSPECTIVE. AB - Phylogenetic relationships within the family Rivulidae (order Cyprinodontiformes) are investigated using 1972 aligned base pairs of mitochondrial DNA (mtDNA) for samples representing 66 species. Genes analyzed include those encoding the 12S ribosomal RNA; transfer RNAs for valine, glutamine, methionine, tryptophan, alanine, asparagine, cysteine, and tyrosine; complete NADH dehydrogenase subunit II; and part of cytochrome oxidase I. Parsimony analysis of the aligned mtDNA sequences results in a single most parsimonious tree. The phylogeny reveals two independent origins of developmental diapause within the family Rivulidae. It is unlikely that diapause evolved de novo in each group, suggesting that the presence or absence of diapause is the result of developmental switches between alternative stabilized pathways. Phylogeny of the family Rivulidae shows high concordance with predictions derived from the geological history of South America and Central America. Basal lineages in the rivulid phylogeny are distributed primarily on geologically old areas, whereas more nested lineages occur in geologically younger areas. However, there is little concordance between the molecular phylogeny and currently available morphological hypotheses and existing taxonomies. Based on the mtDNA phylogeny, the genera Pterolebias, Rivulus, Pituna, and Plesiolebias are considered nonmonophyletic and warrant taxonomic reassessment. PMID- 28565542 TI - GENETIC BASIS OF INBREEDING DEPRESSION IN ARABIS PETRAEA. AB - Inbreeding depression may be caused by (partially) recessive or overdominant gene action. The relative evolutionary importance of these two modes has been debated; the former mode is emphasized in the "dominance hypothesis," the latter in the "overdominance hypothesis." We analyzed the genetic basis of inbreeding depression in the self-incompatible herb Arabis petraea (L.) Lam.: In the selfed progeny of twelve parental plants, we studied the proportion of chlorophyll deficient seedlings, the genotypic distributions of marker genes, and associations of marker genotypes with viability and quantitative traits. Early components of fitness were examined by scoring seed size, germination time, and early growth rate and by observing the proportion of chlorophyll-deficient seedlings. Later components of fitness, flowering, and root and aboveground biomass were also measured. Marker genotypes of young seedlings were scored for 11 enzyme loci and three microsatellite markers. We found a high proportion (about 70%) of families with chlorophyll-deficient seedlings, indicating a high mutational load. We found six significant deviations from 1:2:1 ratio at marker loci of 60 tests in seedlings, with three of these significant at the experimentwide level. Deviations from the expected ratio were assumed to be due to linked viability loci. A graphical and a Bayesian method were used to distinguish between the overdominance and dominance hypotheses. Most of the deviant segregation ratios suggested overdominance instead of recessivity of the deleterious allele. Neither the early (seed size, germination time, or early growth trait) nor the late quantitative traits (flowering, and root and aboveground biomass) showed significant linkage to markers at the experimentwide level. Presence of significant associations between markers and early viability, but lack thereof for quantitative traits expressed late, suggests either that there may be relatively low inbreeding depression in later life stages or that individual quantitative trait loci may have smaller effects than loci contributing to early viability. PMID- 28565543 TI - COLONY SEX RATIOS, CONFLICT BETWEEN QUEENS AND WORKERS, AND APPARENT QUEEN CONTROL IN THE ANT PHEIDOLE DESERTORUM. AB - Sex-ratio conflict between queens and workers was explored in a study of colony sex ratios, relatedness, and population investment in the ant Pheidole desertorum. Colony reproductive broods consist of only females, only males, or have a sex ratio that is extremely male biased. Colonies producing females (female specialists) and colonies producing males (male specialists) occur at near equal frequency in the population. Most colonies apparently specialize in producing one reproductive sex throughout their life. Allozyme analyses show that relatedness does not differ within male-specialist and female-specialist colonies and they do not appear to differ in available resources. In the population, workers are nearly three times more closely related to females than males; however, the investment sex ratio is near equal (1.01, female/male), which is consistent with queen control. Selection should be strong on workers to increase investment in reproductive females, so why do workers in male-specialist colonies produce only (or nearly only) males? One hypothesis is that queens in male specialist colonies prevent the occurrence of reproductive females, perhaps by producing worker-biased female eggs. An earlier simulation study of genetic evolution of sex ratios in social Hymenoptera (Pamilo 1982b) predicts that such mechanisms can result in the evolution of bimodal colony sex ratios and queen control. Results on P. desertorum are generally consistent with that study; however, information is not currently available to test some of the model's predictions and assumptions. PMID- 28565544 TI - THE DETERMINATION OF GENETIC COVARIANCES AND PREDICTION OF EVOLUTIONARY TRAJECTORIES BASED ON A GENETIC CORRELATION MATRIX. AB - There is much interest in measuring selection, quantifying evolutionary constraints, and predicting evolutionary trajectories in natural populations. For these studies, genetic (co)variances among fitness traits play a central role. We explore the conditions that determine the sign of genetic covariances and demonstrate a critical role of selection in shaping genetic covariances. In addition, we show that genetic covariance matrices rather than genetic correlation matrices should be characterized and studied in order to infer genetic basis of population differentiation and/or to predict evolutionary trajectories. PMID- 28565545 TI - ANALYSIS OF GENOTYPIC DIFFERENCES IN DEVELOPMENTAL STABILITY IN ANNONA CHERIMOLA. AB - The genetic basis of developmental stability, measured as asymmetry (fluctuating asymmetry in leaves), was analyzed in leaves and flowers of cherimoya (Annona cherimola Mill) and atemoya (A. cherimola * A. squamosa). The individuals analyzed belonged to a controlled collection of cultivars (clones) that had previously been characterized by means of isozymes. We used a nested design to analyze the differences in asymmetry at several sampling levels: individual leaves and flowers, individual trees, and genotypes. The clonal repeatability of developmental stability was not significantly different from zero, thus suggesting the absence of heritability of the asymmetry for leaves and flowers under these environmental conditions. No relationship between asymmetry and individual heterozygosity was found, but leaf fluctuating asymmetry was significantly related to particular isozymic genes. Petal and leaf size showed a phenotypically plastic response to the exposure zone of the tree (mainly due to light). Leaf fluctuating asymmetry also showed such a plastic response. No significant correlation was found between asymmetry and any pomological characters (some of these being fitness related). Finally, the hybrid species (atemoya) did not show larger developmental instability than did the parental species (cherimoya). All these data show that cherimoya asymmetry reveals the random nature of developmental noise, with developmental stability for leaves being possibly related to specific chromosome regions, but with weak evidence for genotypic differences in developmental stability. PMID- 28565546 TI - HIERARCHICAL COMPARISON OF GENETIC VARIANCE-COVARIANCE MATRICES. II COASTAL INLAND DIVERGENCE IN THE GARTER SNAKE, THAMNOPHIS ELEGANS. AB - The time-scale for the evolution of additive genetic variance-covariance matrices (G-matrices) is a crucial issue in evolutionary biology. If the evolution of G matrices is slow enough, we can use standard multivariate equations to model drift and selection response on evolutionary time scales. We compared the G matrices for meristic traits in two populations of gaiter snakes (Thamnophis elegans) with an apparent separation time of 2 million years. Despite considerable divergence in the meristic traits, foraging habits, and diet, these populations show conservation of structure in their G-matrices. Using Flury's hierarchial approach to matrix comparisons, we found that the populations have retained the principal components (eigenvectors) of their G-matrices, but their eigenvalues have diverged. In contrast, we were unable to reject the hypothesis of equal environmental matrices (E-matrices) for these populations. We propose that a conserved pattern of multivariate stabilizing selection may have contributed to conservation of G- and E-matrix structure during the divergence of these populations. PMID- 28565547 TI - MILDLY DELETERIOUS MUTATIONS IN AVIAN MITOCHONDRIAL DNA: EVIDENCE FROM NEUTRALITY TESTS. AB - To determine whether mildly deleterious mutations (MDMs) are present in nonrecombining genomes such as avian mitochondrial DNA (mtDNA), I analyzed molecular data from 14 studies using the neutrality tests of Tajima (1989a) and McDonald and Kreitman (1991). The presence of MDMs in mtDNA is inferred from trends observed across species in estimates of heterozygosity (theta and pi) and by comparisons of polymorphism and divergence using the neutrality index (NI). Assuming neutrality, theta equals pi and NI equals one. In this study, however, theta is greater than pi more often than expected by chance, which reflects an excess of low-frequency alleles, and NI values presented here and elsewhere are consistently greater than one, which suggests an excess of nonsynonymous mutations within species (polymorphism) relative to between species (divergence). These observations suggest that, within species, there is an excess of rare haplotypes and that these haplotypes are carrying MDMs. The excess rare haplotypes may need to be accounted for when estimating population genetic parameters that assume strict neutrality. PMID- 28565548 TI - EVOLUTION OF AN APHID-PARASITOID INTERACTION: VARIATION IN RESISTANCE TO PARASITISM AMONG APHID POPULATIONS SPECIALIZED ON DIFFERENT PLANTS. AB - The evolution of associations between herbivorous insects and their parasitoids is likely to be influenced by the relationship between the herbivore and its host plants. If populations of specialized herbivorous insects are structured by their host plants such that populations on different hosts are genetically differentiated, then the traits affecting insect-parasitoid interactions may exhibit an associated structure. The pea aphid (Acyrthosiphon pisum) is a herbivorous insect species comprised of genetically distinct groups that are specialized on different host plants (Via 1991a, 1994). Here, we examine how the genetic differentiation of pea aphid populations on different host plants affects their interaction with a parasitoid wasp, Aphidius ervi. We performed four experiments. (1) By exposing pea aphids from both alfalfa and clover to parasitoids from both crops, we demonstrate that pea aphid populations that are specialized on alfalfa are successfully parasitized less often than are populations specialized on clover. This difference in parasitism rate does not depend upon whether the wasps were collected from alfalfa or clover fields. (2) When we controlled for potential differences in aphid and parasitoid behavior between the two host plants and ensured that aphids were attacked, we found that pea aphids from alfalfa were still parasitized less often than pea aphids from clover. Thus, the difference in parasitism rates is not due to behavior of either aphids or wasps, but appears to be a physiologically based difference in resistance to parasitism. (3) Replicates of pea aphid clones reared on their own host plant and on a common host plant, fava bean, exhibited the same pattern of resistance as above. Thus, there do not appear to be nutritional or secondary chemical effects on the level of physiological resistance in the aphids due to feeding on clover or alfalfa, and therefore the difference in resistance on the two crops appears to be genetically based. (4) We assayed for genetic variation in resistance among individual pea aphid clones collected from clover fields and found no detectable genetic variation for resistance to parasitism within two populations sampled from clover. This is in contrast to Henter and Via's (1995) report of abundant genetic variation in resistance to this parasitoid within a pea aphid population on alfalfa. Low levels of genetic variation may be one factor that constrains the evolution of resistance to parasitism in the populations of pea aphids from clover, leading them to remain more susceptible than populations of the same species from alfalfa. PMID- 28565549 TI - GENOTYPE-BY-ENVIRONMENT INTERACTIONS IN THE DETERMINATION OF THE SIZE OF A SECONDARY SEXUAL CHARACTER IN THE COLLARED FLYCATCHER (FICEDULA ALBICOLLIS). AB - Although genetic variation in characters closely related to fitness is expected to either become depleted by selection or masked by environmental variation, "good gene" models of sexual selection require moderate to high heritabilities of secondary sexual characters to explain the occurrence of costly female mate preferences. In this study, I investigated whether the estimated heritability of a condition-dependent secondary sexual character (i.e., the white forehead badge) in the collared flycatcher varied depending on environmental conditions experienced during offspring growth. The data were collected over a period of 14 years making it possible to exploit natural variation in natal conditions. In addition, natal conditions were experimentally altered through brood size manipulations. During unfavorable conditions caused by generally poor weather or experimentally enlarged brood size, no significant heritability based on father sons regressions could be demonstrated (0.19 ? h2 ? 0.27). In contrast, sons reared during years with favorable weather or in experimentally reduced broods significantly resembled their fathers (0.44 ? h2 ? 0.65). In addition, the heritability estimates declined with increasing maternal age. The strong effect of natal environmental condition on the estimated heritability of forehead badge size suggests that the potential genetic benefit from mate choice vary according to environmental conditions (e.g., the benefit is reduced during unfavorable rearing conditions). Because sons reared during poor conditions have probably experienced a natal environment different from that experienced by their fathers, the low heritability estimates obtained under poor conditions seem to be caused by low additive genetic variation expressed in such environments and/or a low genetic correlation between the expression of the trait in the two different environments (i.e., good vs. bad). Both of these explanations imply the presence of genotype-by-environment interactions. If such interactions frequently affect the expression of secondary sexual characters, this may offer an explanation of the high heritabilites sometimes reported for such traits, despite their exposure to long-term directional selection. PMID- 28565550 TI - EVOLUTION IN A PUTATTVELY ANCIENT ASEXUAL APHID LINEAGE: RECOMBINATION AND RAPID KARYOTYPE CHANGE. AB - Ancient asexual lineages are of great potential significance for understanding the evolutionary biology of sex, but their existence is controversial. In part, this is because claims of ancient asexuality have rested on negative evidence-a mere absence of evidence for sexuality in a taxon. M. Meselson has suggested a method, discussed by Judson and Normark (1996) and by Birky (1996), that has the potential to uncover positive evidence of ancient asexuality. Phylogenetic relationships between alleles and interallelic divergences are predicted to be very different in diploid lineages that lack recombination from those in diploid lineages that undergo recombination. I have applied Meselson's method to the putatively ancient asexual aphid tribe Tramini (Homoptera: Aphidoidea: Lachnidae), using the intron-bearing nuclear protein-coding gene elongation factor 1alpha (EF-1alpha). I found heterozygosities much lower than intraspecific divergences, indicating that some recombination has occurred, but not discriminating between recombination within an asexual lineage (automixis or mitotic recombination) and outcrossing sex. Species of Tramini (especially in the genus Trama) typically have highly structurally heterozygous karyotypes that appear to be incompatible with regular successful meiosis, and have very high levels of karyotype variability within species. I found very high levels of karyotype variability within lineages with identical EF-1alpha and mitochondrial (cytochrome oxidase 1 and 2) genotypes, indicating a high rate of karyotype evolution compared to the rate of nucleotide substitution. PMID- 28565551 TI - GENETIC STRUCTURE AND MALE-MEDIATED GENE FLOW IN THE GHOST BAT (MACRODERMA GIGAS). AB - The Australian ghost bat is a large, opportunistic carnivorous species that has undergone a marked range contraction toward more mesic, tropical sites over the past century. Comparison of mitochondrial DNA (mtDNA) control region sequences and six nuclear microsatellite loci in 217 ghost bats from nine populations across subtropical and tropical Australia revealed strong population subdivision (mtDNA phiST = 0.80; microsatellites URST = 0.337). Low-latitude (tropical) populations had higher heterozygosity and less marked phylogeographic structure and lower subdivision among sites within regions (within Northern Territory [NT] and within North Queensland [NQ]) than did populations at higher latitudes (subtropical sites; central Queensland [CQ]), although sampling of geographically proximal breeding sites is unavoidably restricted for the latter. Gene flow among populations within each of the northern regions appears to be male biased in that the difference in population subdivision for mtDNA and microsatellites (NT phiST = 0.39, URST = 0.02; NQ phiST = 0.60, URST = -0.03) is greater than expected from differences in the effective population size of haploid versus diploid loci. The high level of population subdivision across the range of the ghost bat contrasts with evidence for high gene flow in other chiropteran species and may be due to narrow physiological tolerances and consequent limited availability of roosts for ghost bats, particularly across the subtropical and relatively arid regions. This observation is consistent with the hypothesis that the contraction of the species' range is associated with late Holocene climate change. The extreme isolation among higher-latitude populations may predispose them to additional local extinctions if the processes responsible for the range contraction continue to operate. PMID- 28565552 TI - MULTIPLE ORIGINS OF SELF-COMPATIBILITY IN LINANTHUS SECTION LEPTOSIPHON (POLEMONIACEAE): PHYLOGENETIC EVIDENCE FROM INTERNAL-TRANSCRIBED-SPACER SEQUENCE DATA. AB - Phylogenetic reconstruction based on sequence variation in the internal transcribed spacer (ITS) region of rDNA was used to investigate the evolutionary dynamics of homomorphic self-incompatibility in Linanthus section Leptosiphon (Polemoniaceae), a group of annual plant species. Hand-pollination experiments revealed that five species were self-incompatible and four were self-compatible. Optimization of breeding systems onto the tree resulting from maximum-likelihood analysis, with no assumptions made about the ancestral condition, indicated that self-incompatibility has been lost four times in this section. An alternative tree rearrangement conforming to the hypothesis of three losses of self incompatibility did not have a significantly lower likelihood than the maximum likelihood tree as determined by a paired-sites test, but all rearrangements resulting in fewer than three losses were statistically rejected. Linanthus bicolor, a selfing species, was found to be polyphyletic, with populations from different geographic regions occurring in three well-supported clades. Morphological similarity in these distinct lineages is likely to have resulted from convergent evolution of traits associated with self-fertilization. Selection for reproductive assurance is hypothesized to have played an important role in the recurrent transformations from self-incompatibility to selfing in this group of annual species. PMID- 28565553 TI - HIERARCHICAL COMPARISON OF GENETIC VARIANCE-COVARIANCE MATRICES. I. USING THE FLURY HIERARCHY. AB - The comparison of additive genetic variance-covariance matrices (G-matrices) is an increasingly popular exercise in evolutionary biology because the evolution of the G-matrix is central to the issue of persistence of genetic constraints and to the use of dynamic models in an evolutionary time frame. The comparison of G matrices is a nontrivial statistical problem because family structure induces nonindependence among the elements in each matrix. Past solutions to the problem of G-matrix comparison have dealt with this problem, with varying success, but have tested a single null hypothesis (matrix equality or matrix dissimilarity). Because matrices can differ in many ways, several hypotheses are of interest in matrix comparisons. Flury (1988) has provided an approach to matrix comparison in which a variety of hypotheses are tested, including the two extreme hypotheses prevalent in the evolutionary literature. The hypotheses are arranged in a hierarchy and involve comparisons of both the principal components (eigenvectors) and eigenvalues of the matrix. We adapt Flury's hierarchy of tests to the problem of comparing G-matrices by using randomization testing to account for nonindependence induced by family structure. Software has been developed for carrying out this analysis for both genetic and phenotypic data. The method is illustrated with a garter snake test case. PMID- 28565554 TI - HYBRID DYSFUNCTION IN FIRE-BELLIED TOADS (BOMBINA). AB - Reproductive isolation between two taxa may be due to endogenous selection, which is generated by incompatibilities between the respective genomes, to exogenous selection, which is generated by differential adaptations to alternative environments, or to both. The continuing debate over the relative importance of either mode of selection has highlighted the need for unambiguous data on the fitness of hybrid genotypes. The hybrid zone between the fire-bellied toad (Bombina bombina) and the yellow-bellied toad (B. variegata) in central Europe involves adaptation to different environments, but evidence of hybrid dysfunction is equivocal. In this study, we followed the development under laboratory conditions of naturally laid eggs collected from a transect across the Bombina hybrid zone in Croatia. Fitness was significantly reduced in hybrid populations: Egg batches from the center of the hybrid zone showed significantly higher embryonic and larval mortality and higher frequencies of morphological abnormalities relative to either parental type. Overall mortality from day of egg collection to three weeks after hatching reached 20% in central hybrid populations, compared to 2% in pure populations. There was no significant difference in fitness between two parental types. Within hybrid populations, there was considerable variation in fitness, with some genotypes showing no evidence of reduced viability. We discuss the implications of these findings for our understanding of barriers to gene flow between species. PMID- 28565555 TI - RAPID AND REPEATED INVASIONS OF FRESH WATER BY THE COPEPOD EURYTEMORA AFFINIS. AB - Invasions of fresh water by marine organisms have been of great interest to evolutionary biologists and paleontologists because they typically constitute major evolutionary transitions. Recent (< 200 years) invasions of fresh water by brackish or marine species offer an opportunity to understand mechanisms underlying these events, but pathways of invasion from salt water have not been confirmed using genetic data. This study employed mitochondrial DNA sequences (652 base pairs from the cytochrome oxidase I (COI) gene) to reconstruct the geographic and evolutionary history of freshwater invasion by the common estuarine and saltmarsh crustacean Eurytemora affinis (Copepoda; Poppe 1880). Phylogenetic analysis of populations from North America, Europe, and Asia revealed at least eight independent invasions of fresh water from genetically distinct lineages. At least five of these freshwater invasions most likely arose independently in different river drainages, recently from saltwater sources within each river drainage. An analysis of molecular variance (AMOVA) was performed at three geographic scales (among continents, among drainages, and within drainages) to assess the hierarchical distribution of genetic variance. Results indicated that 52% of the genetic variance was explained by differences among drainages, 43% by differences among continents, but only 5% by differences within drainages, thus supporting geographic patterns of invasions inferred from the phylogeny. Physiological experiments were performed to determine whether adults and larvae from saltwater populations could tolerate freshwater conditions. Transfer to zero salinity resulted in high mortalities, but with some survival to the second generation in one population. This study provides genetic evidence and physiological support for rapid transitions from a saline life history into fresh water, with repeated invasions on a global scale. PMID- 28565556 TI - THE MITOCHONDRIAL AND NUCLEAR GENETIC HOMOGENEITY OF THE PHENOTYPICALLY DIVERSE DARWIN'S GROUND FINCHES. AB - The most extensively studied group of Darwin's finches is the genus Geospiza, the ground finches, and yet little is known about the evolutionary history and genetic relationships of these birds. Studies using either allozyme or morphological data have been unable to resolve relationships between the six species and numerous populations of ground finches. In this paper we report the results of a study using mitochondrial control region and nuclear internal transcribed spacer (ITS) 1 sequence data. The differentiation of the ground finch species based on morphological data is not reflected in either mitochondrial or nuclear DNA sequence phylogenies. Furthermore, there is little concordance between the mitochondrial haplotypes and ITS alleles found within individuals. We suggest that the absence of species-specific lineages can be attributed to ongoing hybridization involving all six species of Geospiza. There are no long term selective pressures against hybridization within this genus, and therefore a genetically homogenous genus may be maintained indefinitely. Hybridization has apparently played a role in the adaptive radiation of Darwin's finches. PMID- 28565557 TI - EXPERIMENTAL TESTS OF GENETIC TRANSILIENCE. PMID- 28565558 TI - REINFORCING SELECTION IS EFFECTIVE UNDER A RELATIVELY BROAD SET OF CONDITIONS IN A MOSAIC HYBRID ZONE. AB - Many hybrid zones have a mosaic structure, yet we know of no theoretical work that examines the impact of mosaicism on the outcome of evolution. We developed a computer simulation model designed to test whether the outcome of reinforcing selection differs in a mosaic and a clinal hybrid zone. Our model was a one dimensional stepping-stone model. The mosaic and clinal hybrid zones that we modeled were, respectively, a mosaic maintained by differential fitness of the interacting taxa in patchy habitats and a tension zone. We modeled changes in gene frequency at two biallelic loci, A and B. Hybrids at the A locus were selected against. An allele at the B locus caused assortative mating at the A locus, which promoted reinforcement; there was a selective cost to this allele. In a mosaic hybrid zone, spatial variation in the fitness of A-locus homozygotes in different patches caused gene and genotype frequencies at the A and B loci to differ greatly from those in a tension zone. Compared to a tension zone, a mosaic hybrid zone had a broader region in which hybrids could be formed and, thus, a broader region in which the assortative-mating allele provided a net selective advantage (via decreased production of the less fit A-locus hybrids). This caused the assortative-mating allele to be favored under a broader set of conditions in a mosaic hybrid zone than in a tension zone. In mosaic and tension hybrid zones, both low and high levels of migration could prevent the establishment of the allele that promoted reinforcement, but the allele could establish under a wider range of migration rates in a mosaic than in a tension zone. In a tension zone, both low and high levels of selection against A-locus hybrids could prevent the establishment of the assortative-mating allele. In a mosaic hybrid zone, the assortative-mating allele established under lower levels of selection against hybrids than in a tension zone, and high levels of selection did not impede the establishment of this allele. Overall, our work illustrates how the structure of a hybrid zone can alter the outcome of an important evolutionary process, in this case, reinforcement. PMID- 28565559 TI - RAPID MORPHOLOGICAL CHANGE IN CHANNEL ISLAND DEER MICE. AB - Deer mice, Peromyscus maniculatus, collected over 90 years from three California Channel Islands, were examined for evidence of morphological change. Rapid morphological change has occurred in the endemic subspecies from Santa Barbara (P. m. elusus), Anacapa (P. m. anacapae), and Santa Cruz Island (P. m. santacruzae). Data were divided into two temporal classes, 1897-1941 and 1955 1988. Of the 16 morphological characters measured, between five and 10 measures changed significantly (P ? 0.05) with temporal class in each subspecies, and multivariate test statistics were significant (P ? 0.05) for all three subspecies. For each subspecies, depth of braincase, total length, tail length, and hind foot length became smaller over time, except depth of braincase, which became larger in P. m. elusus. The rates of change dramatically exceed those estimated from paleontological records and are even higher than those reported in some experimental selection studies. Temporal change in two characters exceeds differentiation between subspecies. Although changing, each subspecies remained well differentiated, and incorporation of temporal change allowed correct classification of most specimens. Unlike nearly all previous reports of rapid evolution, the changes in these populations were not associated with a founder events or recent introductions. This study demonstrates that rapid phenotypic change can occur in long-established natural populations and temporal stability of morphological characters in such populations, even over short evolutionary time periods, cannot be assumed. PMID- 28565560 TI - THE GENETIC ARCHITECTURE OF PLASTICITY TO DENSITY IN IMPATIENS CAPENSIS. AB - Plant responses to crowding may be mediated by resource availability and/or by a specific environmental cue, the ratio of red:far red wavelengths (R:FR) perceived by phytochrome. This study examined the contribution of phytochrome-mediated photomorphogenesis to genetic variation in plastic responses to density in the annual plant Impatiens capensis. Inbred lines derived from open and woodland populations were grown under low density high density, and high density with selective removal of FR wavelengths to block phytochrome-mediated perception of neighbor proximity. Genetic variation in plasticity to density and to the R:FR cue was detected for several traits Plants grown at high density displayed increased internode elongation; decreased branch, flower, and node production; increased menstem dormancy; and decreased leaf area and specific leaf weight compared to plants grown at low density. Stem elongation responses to density were suppressed when phytochrome perception was blocked at high density. For these phytochrome-mediated traits, a genotype's plasticity to density was strongly correlated with its response to R:FR. Phytochrome-mediated traits were tightly correlated with one another, regardless of the density environment. However, the responses to density of meristem allocation to branching and leaf traits were less strongly phytochrome-mediated. These traits differed in patterns of plasticity, and their genetic correlations often differed across environments. In particular, genetic trade-offs involving meristem allocation to branching were expressed only at low density. The observed density dependence of phenotypic and genetic correlations implies that indirect selection and the potential for correlated response to selection will depend upon the competitive environment. Thus the differential sensitivity of characters to the R:FR cue can influence the evolution of integrated plastic responses to density. PMID- 28565561 TI - CORRELATED TROPHIC SPECIALIZATION AND GENETIC DIVERGENCE IN SYMPATRIC LAKE WHITEFISH ECOTYPES (COREGONUS CLUPEAFORMIS): SUPPORT FOR THE ECOLOGICAL SPECIATION HYPOTHESIS. AB - There is ample empirical evidence that phenotypic diversification in an adaptive radiation is the outcome of divergent natural selection related to differential resource use. In contrast, the role of ecological forces in favoring and maintaining reproductive isolation in nature remains poorly understood. If the same forces driving phenotypic divergence are also responsible for speciation, one would predict a correlation between the extent of trophic specialization (reflecting variable intensity of divergent natural selection) and that of reproductive isolation being reached in a given environment. We tested this hypothesis by comparing the extent of morphological and genetic differentiation between sympatric dwarf and normal whitefish ecotypes (Coregonus sp.) from six lakes of the St. John River basin (eastern Canada and northern Maine). Eight meristic variables, 19 morphometric variables, and six microsatellite loci were used to quantify morphological and genetic differentiation, respectively. Dwarf and normal ecotypes in each lake differed primarily by traits related to trophic specialization, but the extent of differentiation varied among lakes. Significant but variable genetic divergence between ecotypes within lakes was also observed. A negative correlation was observed between the extent of gene flow between ecotypes within a lake and that of their morphological differentiation in trophic related traits. The extent of reproductive isolation reached between dwarf and normal whitefish ecotypes appears to be driven by the potential for occupying distinct trophic niches and, thus, by the same selective forces driving tropic specialization in each lake. These results therefore support the hypothesis of ecological speciation. PMID- 28565562 TI - MATERNAL EFFECTS ON OFFSPRING SIZE: VARIATION THROUGH EARLY DEVELOPMENT OF CHINOOK SALMON. AB - We performed two breeding experiments with chinook salmon (Oncorhynchus tshawytscha) to explore maternal effects on offspring size. We estimated the magnitude of maternal effects as the differences between sire-offspring and dam offspring regression slopes. Early in life, offspring size is largely influenced by maternal size, but this influence decreases through early development, with the maternal effect becoming negative at intermediate offspring ages (corresponding to a period of reduced growth of progeny hatching from large eggs) and converging on zero as offspring age. Also, egg size was positively correlated with early survival, but negatively correlated with maternal fecundity. PMID- 28565563 TI - DOES COSMOPOLITANISM RESULT FROM OVERCONSERVATIVE SYSTEMATICS? A CASE STUDY USING THE MARINE SPONGE CHONDRILLA NUCULA. AB - The sponge species Chondrilla nucula has a simple morphology and a very wide geographical distribution. To verify whether the latter might be an artifact of the former, samples of this species were collected across 10,000 km of its range, in the Mediterranean, the Caribbean, and the southwestern atlantic. The classical (spicule morphology) and molecular (allozymes) systematic approaches were compared, to try to define the geographic limits between populations and detect possible cryptic species. We found five distinct genetic forms within C. nucula that sometimes showed morphological homogeneity and other times plasticity. The difference in size of spicules could not be related to the clear-cut genetic differences, suggesting that the use of spicule sizes for sponge systematics should be reappraised. The population of one of the genetic forms along 3000 km of the Brazilian coast was highly structured (FST = 0.21; Ne m = 0.96). Our results reject the null hypothesis of cosmopolitanism of C. nucula and indicate that the putative worldwide distribution of some marine sponges, and possibly many other benthic invertebrates, may be the result of overly conservative systematics. Cryptic species appear to be particularly prevalent when genera are well defined but species are characterized by only a few morphological characters. PMID- 28565564 TI - DISPERSAL, VICARIANCE, AND CLOCKS: HISTORICAL BIOGEOGRAPHY AND SPECIATION IN A COSMOPOLITAN PASSERINE GENUS (ANTHUS: MOTACILLIDAE). AB - Dispersal and vicariant hypotheses have for decades been at odds with each other, notwithstanding the fact that both are well-established natural processes with important histories in biogeographic analyses. Despite their importance, neither dispersal nor vicariant methodologies are problem-free. The now widely used molecular techniques for generating phylogenies have provided a mechanism by which both dispersal- and vicariance-driven speciation can be better tested via the application of molecular clocks; unfortunately, substantial problems can also exist in the employment of those clocks. To begin to assess the relative roles of dispersal and vicariance in the establishment of avifaunas, especially intercontinental avifaunas, I applied a test for clocklike behavior in molecular data, as well as a program that infers ancestral areas and dispersal events, to a phylogeny of a speciose, cosmopolitan avian genus (Anthus; Motacillidae). Daughter-lineages above just 25 of 40 nodes in the Anthus phylogeny are evolving in a clocklike manner and are thus dateable by a molecular clock. Dating the applicable nodes suggests that Anthus arose nearly 7 million yr ago, probably in eastern Asia, and that between 6 and 5 million yr ago, Anthus species were present in Africa, the Palearctic, and North and South America. Speciation rates have been high throughout the Pliocene and quite low during the Pleistocene; further evidence that the Pleistocene may have had little effect in generating modern species. Intercontinental movements since 5 million yr ago have been few and largely restricted to interchange between Eurasia and Africa. Species swarms on North America, Africa, and Eurasia (but not South America or Australia) are the product of multiple invasions, rather than being solely the result of within continent speciation. Dispersal has clearly played an important role in the distribution of this group. PMID- 28565565 TI - DON'T FORGET THE BIOLOGY: A REPLY TO GREEN. PMID- 28565566 TI - DENSITY DEPENDENCE AND UNPREDICTABLE SELECTION IN A HETEROGENEOUS ENVIRONMENT: COMPROMISE AND POLYMORPHISM IN THE ESS REACTION NORM. AB - In quantitative genetic models of the evolution of reaction norms, an individual is selected in the habitat in which it develops; as a consequence, selection leads to the optimum phenotype in each habitat. Here, individuals are assumed to experience unpredictable habitat change between development and selection, so that the environment in which an individual is selected may differ from the environment in which it developed. The model reveals that unpredictability of the selection an individual actually faces leads to the evolutionarily stable bet hedging reaction norm constituting a compromise between the phenotypic optima in the different patches. We also examine the effect of local density regulation before selection, in the patches in which the individuals develop, and after selection, in the patches in which they are selected. Density regulation before selection has a much lower influence on the evolution of the reaction norm than density regulation after selection. The source-sink structure of the environment caused by differential productivity of patches strongly affects how the compromise bet-hedging strategy weighs the different phenotypic optima and might compromise the local evolutionary stability of the evolved reaction norm. If the strength and variability among patches of density regulation after selection is sufficiently large, no single reaction norm is evolutionary stable: Polymorphic reaction norms constitute the evolutionarily stable population. We also show that a polymorphic reaction norm is more likely to be observed in a less productive habitat. The relations between the present model and the Dempster and the Levene models are discussed. PMID- 28565567 TI - EXPERIMENTAL TESTS OF FOUNDER-FLUSH: A REPLY TO TEMPLETON. PMID- 28565568 TI - THE ROLE OF INBREEDING DEPRESSION IN MAINTAINING THE MIXED MATING SYSTEM OF THE COMMON MORNING GLORY, IPOMOEA PURPUREA. AB - Theoretical studies show that, although inbreeding depression (ID) will counterbalance the transmission advantage of selfing, it can only maintain a mixed mating system in plants when at least one of the following two conditions is met: (1) there is a positive association between selfing rates and the level of ID; and (2) ID is greater than 0.5 for the female component of fitness, while the average ID for male and female fitness is less than 0.5. This study tests whether these two conditions hold in the common morning glory, Ipomoea purpurea, which has a mixed mating system with 30% self-fertilization. Inbreeding depression was found in all but one fitness component measured in two groups of plants with distinct anther-stigma distances (ASD), a character that influences selfing rates. However, when examined separately, a negative association was found between selfing rates and ID; plants with large ASD (low-selfing-rate genotypes) tended to have higher ID than ones with small ASD (high-selfing-rate genotypes). Furthermore, the overall lifetime ID for male (12.5%) and female (24%) components of fitness, averaged across two ASD groups, were lower than what is necessary for ID to maintain an evolutionarily stable mixed mating system. Therefore, although inbreeding depression contributes to balancing the transmission advantage of selfing, it is not likely to be the primary mechanism maintaining the mixed mating system of I. purpurea. The contribution of other mechanisms is discussed. PMID- 28565569 TI - EXPERIMENTAL ANALYSES OF WING SIZE, FLIGHT, AND SURVIVAL IN THE WESTERN WHITE BUTTERFLY. AB - Butterflies have distinctively large wings relative to body size, but the functional and fitness consequences of wing size for butterflies are largely unknown. I use natural and experimentally generated variation in wing surface area to examine how decreased wing size affects flight and survival in a population of the western white butterfly, Pontia occidentalis. In the laboratory, experimental reductions in wing area (reduced-wings manipulation) significantly increased wingbeat frequencies of hovering butterflies, whereas a control manipulation had no detectable effects. In contrast, behavioral observations and mark-release-recapture (MRR) studies in the field detected no significant differences in flight activity, initial dispersal rates, or recapture probabilities among treatment groups. Estimated selection coefficients indicated that natural variation in wing size, body mass, and wing loading in the population were not significantly correlated with survival in the two MRR studies. In two mark-recapture studies with manipulated butterflies, survival probabilities were not significantly different for reduced-wings individuals compared with control or unmanipulated individuals. In summary, experimental reductions in wing area significantly altered aspects of flight in the laboratory, but did not detectably alter flight or survival in the field for this population. The large wing size typical of butterflies may reduce the functional and survival consequences of wing size variation within populations. PMID- 28565570 TI - ADAPTIVE SEX ALLOCATION IN A SIMULTANEOUS HERMAPHRODITE. AB - When applied to hermaphrodite organisms, the local mate competition hypothesis predicts an increase of the ratio of sperm to ova produced as the number of mates increases. Here we test this prediction using a hermaphroditic platyhelminth parasite (trematode), Echinostoma caproni. This worm inhabits the small intestine of vertebrates, inevitably inducing the formation of highly subdivided populations, a condition known to promote local mate competition. Moreover this echinostome exhibits an unrestricted mating pattern involving both selfing and outcrossing as well as multiple fertilizations. We quantified the investment in reproductive organs by estimations of testes, cirrus sac, ovary, and egg size and fecundity when echinostomes were isolated alone, in pairs, or in groups of 20 worms. Adult body size was also recorded as a covariate. When mating group size increases (singles, pairs, or groups) we observed a significant increase in resource allocation to male function in addition to a significant decrease in ovary size. Smaller ovaries do not seem to affect egg size, but do result in a reduction in fecundity. Finally, our results are in accordance with the expected theoretical relationship between male allocation and the number of potential mates given local mate competition. PMID- 28565571 TI - ARE CHLOROPLAST AND MITOCHONDRIAL DNA VARIATION SPECIES INDEPENDENT IN OAKS? AB - Extensive introgression of cytoplasmic genomes across oak species is now a well established fact. To distinguish between ancient hybridization events and ongoing introgression, a direct test for the existence of local exchanges is proposed. Such local exchanges must be comparatively recent, that is, contemporaneous with or later than the last postglacial recolonization. The test is applied to an extensive set of data comprising 377 pure or mixed populations (1744 individuals) of four white oak species in southern France. After demonstrating that local exchanges have occurred frequently between all species pairs, another test is performed to check if species status does nevertheless play some role in restricting cytoplasmic gene flow. The results vary according to the species pairs considered, and the observed pattern may be related to the ecology and/or compatibility of interspecific crosses. It is also shown that, for some of these oak species, the presence of related species in a population significantly influences the intraspecific diversity. Altogether, the results demonstrate that (1) intraspecific cytoplasmic gene flow varies according to the species, (2) interspecific cytoplasmic gene flow varies according to the species pair, and (3) both components of gene flow are at least partly related. PMID- 28565572 TI - EVOLUTIONARY RESPONSE OF PREDATORS TO DANGEROUS PREY: PREADAPTATION AND THE EVOLUTION OF TETRODOTOXIN RESISTANCE IN GARTER SNAKES. AB - Coevolutionary interactions typically involve only a few specialized taxa. The factors that cause some taxa and not others to respond evolutionarily to selection by another species are poorly understood. Preadaptation may render some species predisposed for evolutionary response to new pressures, whereas a lack of genetic variation may limit the evolutionary potential of other taxa. We evaluate these factors in the predator-prey interaction between toxic newts (Taricha granulosa) and their resistant garter snake predators (Thamnophis sirtalis). Using a bioassay of resistance to tetrodotoxin (TTX), the primary toxin in the prey, we examined phenotypic evolution in the genus Thamnophis. Reconstruction of ancestral character states suggests that the entire genus Thamnophis, and possibly natricine snakes in general, has slightly elevated TTX resistance compared to other lineages of snakes. While this suggests that T. sirtalis is indeed predisposed to evolving TTX resistance, it also indicates that the potential exists in sympatric congeners not expressing elevated levels of TTX resistance. We also detected significant family level variation for TTX resistance in a species of Thamnophis that does not exhibit elaborated levels of the trait. This finding suggests that evolutionary response in other taxa is not limited by genetic variability. In this predator-prey system, species and population differences in resistance appear to be largely determined by variation in the selective environment rather than preadaptation or constraint. PMID- 28565573 TI - ALLOMETRY OF GENITALIA IN INSECTS AND SPIDERS: ONE SIZE DOES NOT FIT ALL. PMID- 28565575 TI - RECENT BOOKS IN PRINT. PMID- 28565574 TI - REPRODUCTIVE ISOLATION BETWEEN SYMPATRIC RACES OF PEA APHIDS. I. GENE FLOW RESTRICTION AND HABITAT CHOICE. AB - Determining the extent and causes of barriers to gene flow between genetically divergent populations or races of single species is an important complement to post facto analyses of the causes of reproductive isolation between recognized species. Sympatric populations of pea aphids (Acyrthosiphon pisum Harris, Homoptera: Aphididae) on alfalfa and red clover are highly genetically divergent and locally adapted. Here, hierarchical estimates of population structure based on Fst suggest that gene exchange between closely adjacent aphid populations on the two hosts is highly restricted relative to that among fields of the same host plant. Although these host-associated races are presently considered to be the same subspecies, they appear to be significantly reproductively isolated, suggesting incipient speciation. Habitat (host) choice was investigated as the first in a temporal series of factors that could reduce gene exchange between these sympatric populations. Field studies of winged colonists to newly planted fields of each host suggest pronounced habitat fidelity. This result was verified using replicated observations of the host choice behavior of different aphid genotypes for which the relative demographic performance on each host was known. These laboratory observations of behavior revealed a strong genetic correlation between habitat choice (or acceptance) and the relative performance in each habitat. Because mating occurs on the host plant, habitat choice in this system leads to assortative mating and is therefore a major cause of reproductive isolation between the sympatric pea aphid populations on alfalfa and clover. However, the extent of dispersal between hosts estimated from the field study of winged colonists (9-11%) is too great to be consistent with the genetic divergence estimated between the races. This suggests that barriers to gene flow other than host choice also exist, such as selection against migrants or hybrids in the parental environments, hybrid sterility, or hybrid breakdown. PMID- 28565576 TI - THE EVOLUTION OF VIRULENCE IN PATHOGENS WITH VERTICAL AND HORIZONTAL TRANSMISSION. AB - The idea that vertical transmission of parasites selects for lower virulence is widely accepted. However, little theoretical work has considered the evolution of virulence for parasites with mixed horizontal plus vertical transmission. Many human, animal, and plant parasites are transmitted both vertically and horizontally, and some horizontal transmission is generally necessary to maintain parasites at all. We present a population-dynamical model for the evolution of virulence when both vertical and horizontal transmission are present. In the simplest such model, up to two infectious strains can coexist within one host population. Virulent, vertically transmitted pathogens can persist in a population when they provide protection against more virulent, horizontally transmitted strains. When virulence is maintained by a correlation with horizontal transmission rates, increased levels of vertical transmission always lower the evolutionarily stable (ESS) level of virulence. Contrary to existing theory, however, increases in opportunities for horizontal transmission also lower the ESS level of virulence. We explain these findings in light of earlier work and confirm them in simulations including imperfect vertical transmission. We describe further simulations, in which both vertical and horizontal transmission rates are allowed to evolve. The outcome of these simulations depends on whether high levels of vertical transmission are possible with low virulence. Finally, we argue against the notion of a virulence-avirulence continuum between horizontal and vertical transmission, and discuss our results in relation to empirical studies of transmission and virulence. PMID- 28565577 TI - PLEIOTROPY CAUSES LONG-TERM GENETIC CONSTRAINTS ON LIFE-HISTORY EVOLUTION IN BRASSICA RAPA. AB - Fundamental, long-term genetic trade-offs constrain life-history evolution in wild crucifer populations. I studied patterns of genetic constraint in Brassica rapa by estimating genetic correlations among life-history components by quantitative genetic analyses among ten wild populations, and within four populations. Genetic correlations between age and size at first reproduction were always greater than +0.8 within and among all populations studied. Although quantitative genetics might provide insight about genetic constraints if genetic parameters remain approximately constant, little evidence has been available to determine the constancy of genetic correlations. I found strong and consistent estimates of genetic correlations between life-history components, which were very similar within four natural populations. Population differentiation also showed these same trade-offs, resulting from long-term genetic constraint. For some traits, evolutionary changes among populations were incompatible with a model of genetic drift. Historical patterns of natural selection were inferred from population differentiation, suggesting that correlated response to selection has caused some traits to evolve opposite to the direct forces of natural selection. Comparison with Arabidopsis suggests that these life-history trade offs are caused by genes that regulate patterns of resource allocation to different components of fitness. Ecological and energetic models may correctly predict these trade-offs because there is little additive genetic variation for rates of resource acquisition, but resource allocation is genetically variable. PMID- 28565578 TI - INTRASEXUAL COMPETITION ALONE FAVORS A SEXUALLY DIMORPHIC ORNAMENT IN THE RUBYSPOT DAMSELFLY HETAERINA AMERICANA. AB - I studied the sex-limited red spots on the wings of male rubyspot damselflies (Hetaerina americana) in relation to territoriality and fitness in the wild. Both observational and experimental (wing spot manipulation) studies indicated that wing spots were selected through competition among males for mating territories, not through female choice or direct competition for females. Males with naturally or artificially large wing spots were more successful at holding territories and consequently mated at higher rates than males with relatively small wing spots. In contrast, sexual selection on male body size appeared to operate among nonterritorial males at the clasping stage of the mating sequence, perhaps because larger males were better at clasping females forcibly. Of four models proposed to explain the evolution of ornaments through territory competition, only the agonistic handicap model makes predictions consistent with the results of this study. PMID- 28565579 TI - MITOCHONDRIAL DNA VARIATION IN THE FIELD VOLE (MICROTUS AGRESTIS): REGIONAL POPULATION STRUCTURE AND COLONIZATION HISTORY. AB - Restriction fragment length polymorphism analysis of mitochondrial DNA (mtDNA) was used to examine the genetic structure among field voles (Microtus agrestis) from southern and central Sweden. A total of 57 haplotypes was identified in 158 voles from 60 localities. Overall mtDNA diversity was high, but both haplotype and nucleotide diversity exhibited pronounced geographic heterogeneity. Phylogenetic analyses revealed a shallow tree with seven primary mtDNA lineages separated by sequence divergences ranging from 0.6% to 1.0%. The geographic structure of mtDNA diversity and lineage distribution was complex but strongly structured and deviated significantly from an equilibrium situation. The extensive mtDNA diversity observed and the recent biogeographic history of the region suggests that the shallow mtDNA structure in the field vole cannot be explained solely by stochastic lineage sorting in situ or isolation by distance. Instead, the data suggest that the genetic imprints of historical demographic conditions and vicariant geographic events have been preserved and to a large extent determine the contemporary geographic distribution of mtDNA variation. A plausible historical scenario involves differentiation of mtDNA lineages in local populations in glacial refugia, a moving postglacial population structure, and bottlenecks and expansions of mtDNA lineages during the postglacial recolonization of Sweden. By combining the mtDNA data with an analysis of Y chromosome variation, a specific population unit was identified in southwestern Sweden. This population, defined by a unique mtDNA lineage and fixation of a Y chromosome variant, probably originated in a population bottleneck in southern Sweden about 12,000 to 13,000 calendar years ago. PMID- 28565580 TI - DENSITY-DEPENDENT SELECTION ON CONTINUOUS CHARACTERS: A QUANTITATIVE GENETIC MODEL. AB - A quantitative genetic model of density-dependent selection is presented and analysed with parameter values obtained from laboratory selection experiments conducted by Mueller and his coworkers. The ecological concept of r- and K selection is formulated in terms of selection gradients on underlying phenotypic characters that influence the density-dependent measure of fitness. Hence the selection gradients on traits are decomposed into two components, one that changes in the direction to increase r, and one that changes in the direction to increase K. The relative importance of the two components is determined by temporal fluctuations in population density. The evolutionary rate of r and K (per-generation changes in r and K due to the genetic responses of the underlying traits) is also formulated. Numerical simulation has shown that with moderate genetic variances of the underlying characters, r and K can evolve rapidly and the evolutionary rate is influenced by synergistic interaction between characters that contribute to r and K. But strong r-selection can occur only with severe and continuous disturbances of populations so that the population density is kept low enough to prevent K-selection. PMID- 28565581 TI - EVIDENCE FOR GENETIC DIFFERENTIATION BETWEEN CHOKE-INDUCING AND ASYMPTOMATIC STRAINS OF THE EPICHLOE GRASS ENDOPHYTE FROM BRACHYPODIUM SYLVATICUM. AB - Life cycle and breeding system variation in Epichloe grass endophytes (choke disease) is tightly linked to the degree of stroma formation. It is not known whether this variation results from differences in host resistance, fungal virulence, or environmental conditions. We found genetic differentiation between 173 asymptomatic (NS) and 93 stromata-forming (S) Epichloe strains isolated from one grass species, Brachypodium sylvaticum, based on 13 presumed allozyme loci, of which six were variable. The fungal strains originated from 10 sites in Switzerland, three sites of which were represented by both NS and S subpopulations. In total, 19 allozyme genotypes, that were nonrandomly distributed among S and NS were detected. Genetic variation measured as GST between S and NS strains isolated from the same site ranged from 0.73 to 0.98. Clonality, measured as linkage disequilibrium at one site, was significant in the NS subpopulation (P ? 0.001), but not in the S subpopulation (P = 0.21), implying asexual reproduction by NS strains as well as successful horizontal transmission of S strains. Since all seeds are usually infected vegetatively, horizontal transmission implies the occurrence of multiple host infections. Altogether, these results provide indirect evidence that NS and S strains do not belong to one panmictic population and that differentiation patterns of stroma formation found in nature are due to genetic differences among fungi in associations with their host plants. We discuss the direction of evolution of disease expression in this system. The distribution of genetic variability suggests that the asymptomatic strains were derived from stromata-forming populations. PMID- 28565582 TI - LONG-DISTANCE GENE FLOW IN THE SEDENTARY BUTTERFLY, EUPHILOTES ENOPTES (LEPIDOPTERA: LYCAENIDAE). AB - The relationship between gene flow and geographic proximity has been assessed for many insect species, but dispersal distances are poorly known for most of these. Thus, we are able to assess the concordance between vagility and gene flow for only a few species. In this study, I documented variation at six allozyme loci among Washington and Oregon populations of the sedentary, patchily distributed, lycaenid butterfly, Euphilotes enoptes (Boisduval) to assess whether the relationship between gene flow and geographic distance is consistent with the dispersal biology of this species. Both a phenogram based on genetic distances between populations and a regression analysis of gene flow estimates on geographic distances showed a pattern consistent with genetic isolation by distance. Many estimates of gene flow among pairs of populations separated by more than 100 km exceeded the equivalent of 10 individuals exchanged per generation, a value much greater than would be predicted from the limited dispersal ability of this species. However, based on the allozyme data, genetic neighborhood size was estimated to be approximately 39 individuals, a value that is consistent with poor vagility. The results of this study speak to the power of stepping-stone gene flow among populations and are compared to the results of other studies that have examined the relationship between dispersal and gene flow in sedentary insects. PMID- 28565583 TI - FACULTATIVE ADJUSTMENT OF THE SEX RATIO IN AN INSECT (PLANOCOCCUS CITRI, PSEUDOCOCCIDAE) WITH PATERNAL GENOME LOSS. PMID- 28565584 TI - ARE POPULATIONS ISLANDS? ANALYSIS OF CHLOROPLAST DNA VARIATION IN AQUILEGIA. AB - The degree to which conspecific populations are interconnected via ongoing gene flow remains an important focus of evolutionary biology. One major difficulty in distinguishing ongoing gene flow from historical subdivision is that either process can generate similar estimates of apparent gene flow. Thus, gene flow estimates themselves are insufficient to distinguish between these alternatives. However, genetic data coupled with additional information about demography and distribution do allow a distinction to be made. Here we address the specific question, does gene flow link populations of Aquilegia? In a survey of a 525 B.P. chloroplast DNA fragment sampled from 251 individual plants from 18 populations of three taxa, five haplotypes were identified. No significant relationship between geographic distance and apparent gene flow between population pairs existed. Further, the estimated level of gene flow was entirely compatible with a historical subdivision of Aquilegia populations during the late Pleistocene or early Holocene. Therefore, these patterns of variation are due not to ongoing gene flow, but rather to historical association among populations. Thus Aquilegia populations may be considered as distinct evolutionary entities with regard to seed-mediated processes. As a result, comparative analysis of ecological traits undergoing potentially rapid evolution (e.g., life histories, mating systems, inbreeding depression) should be possible in these taxa. PMID- 28565585 TI - THE DISTRIBUTION AMONG POPULATIONS IN PHENOTYPIC VARIANCE WITH INBREEDING. AB - The effects of inbreeding on the phenotypic variance within populations were measured in a set of 30 bottlenecked lines derived from a single source population of Drosophila melanogaster. Inbred lines had significant variance among lines in the amount of phenotypic variance within lines, for thorax length, and sternopleural bristle scores. When significance levels were corrected on an experimentwide basis, no line had significant increases in phenotypic variance for sternopleural bristle counts, although two lines had significant increases in thorax length variance. These results demonstrate that inbred lines cannot be treated as necessarily more uniform than outbred lines and that results on changes in variance due to inbreeding should be treated with caution unless there has been sufficient replication. These results also demonstrate the validity of an important assumption of models of evolution by variance-mediated mechanisms, such as the variance-induced peak-shift model. PMID- 28565586 TI - DOES INTERFERENCE COMPETITION AMONG POLLEN GRAINS OCCUR IN WILD RADISH? AB - Interest in the possibility of sexual selection in plants has focused primarily on competition among pollen donors based on the speed of pollen-tube growth. However, when pollen arrives on stigmas, there is the opportunity for both races for access to ovules (exploitation competition) and interference with the germination and growth of pollen from other donors (interference competition). We considered whether this second form of competition might occur among pollen grains of wild radish in two experiments. In the first, interference likely occurred because the amount of pollen germination was less in mixed-donor than in single-donor pollinations. This result was duplicated in a second experiment, which also showed that interference occurred only when pollen grains from different donors were in direct contact with each other. In addition, in the second experiment, the opportunity for interference affected the frequency of seeds sired by different pollen donors. Because pollen loads are often mixed in nature, interference competition among pollen grains may be important in the ecology and evolution of plant reproduction. PMID- 28565587 TI - SEXUAL SELECTION AND SURVIVAL SELECTION ON WING COLORATION AND BODY SIZE IN THE RUBYSPOT DAMSELFLY HETAERINA AMERICANA. AB - I review methodological problems that can lead to false evidence for selection on secondary sexual characters and present a study of selection in rubyspot damselflies (Hetaerina americana) that avoids these pitfalls. Male rubyspots have a large red spot on each wing that grows to a terminal size after sexual maturity. Selection gradient analyses revealed evidence for positive sexual and survival selection on both terminal wing spot size and body size. Phenotype manipulations confirmed that wing spot size was subject to direct sexual selection, but showed that the positive slope of survival on wing spot size was an indirect effect of selection on unmeasured traits. This study provides the strongest evidence yet for sexual selection on coloration in Odonata, but also provides clear examples of why phenotypic selection statistics must be calculated and interpreted cautiously. PMID- 28565588 TI - PARASITE VIRULENCE AND HOST IMMUNE DEFENSE: HOST IMMUNE RESPONSE IS RELATED TO NEST REUSE IN BIRDS. AB - The evolution of parasite virulence has been hypothesized to be related to the mode of parasite transmission; horizontally transmitted parasites can afford to damage their hosts more than vertically transmitted parasites because increased virulence does not reduce the probability of transmission to new hosts. This relationship between mode of transmission and virulence would particularly select for improved immune defense in hosts that are subject to horizontally transmitted parasites. Among avian hosts, hole nesters and colonial nesters frequently reuse nest sites because of nest-site limitation, and this results in an increased frequency of horizontal transmission. Comparison of the size of two organs involved in the immune defense between pairs of bird species being either hole or open nesters, or colonially or solitarily nesting birds, respectively, revealed that the size of the bursa of Fabricius and the spleen were consistently larger in hole nesters than in open nesters, and similarly in colonially breeding bird species than in solitarily breeding species. These results support the hypothesis that mode of parasite transmission affects the evolution of immune defence in hosts. PMID- 28565590 TI - EFFECTS OF DIFFERENTIAL POLLEN-TUBE GROWTH ON HYBRIDIZATION IN THE LOUISIANA IRISES. AB - To elucidate the importance of hybridization in evolution, it is necessary to understand the processes that affect hybridization frequency in nature. Here we focus on postpollination, prefertilization isolating mechanisms using two hybridizing species of Louisiana iris as a study system. We compared the effects of differential pollen-tube growth on the frequency of F1 hybrid formation in experimental crosses between Iris fulva and Iris hexagona. Analyses of seed production in fruits from pure conspecific and heterospecific pollinations revealed that more seeds were produced in the top half than the bottom half of fruits for all four crosses. Heterospecific pollen was applied to flowers of each species at zero to 24 h prior to conspecific pollen, thereby giving a head start to the foreign pollen. Using diagnostic isozyme markers, the frequency of hybrid progeny was examined at the level of the whole fruit and separately for the top and bottom halves of fruits. In both species, the proportion of hybrid seeds per fruit increased significantly with increasing head starts, suggesting that differences in pollen-tube growth rates affect the frequency of hybridization. In I. fulva fruits, the increase in hybrid seeds occurred in both halves of the fruits, but in I. hexagona an increase was only detected in the top half of fruits. These findings are consistent with a model that assumes attrition of pollen tubes due to the greater length of I. hexagona styles. While pollen-tube growth rate appears to be the most important factor affecting hybridization frequency in I. fulva, both pollen-tube growth rate and pollen-tube attrition appear to be important in I. hexagona. PMID- 28565589 TI - ADAPTIVE RADIATION ALONG GENETIC LINES OF LEAST RESISTANCE. AB - Are measurements of quantitative genetic variation useful for predicting long term adaptive evolution? To answer this question, I focus on gmax , the multivariate direction of greatest additive genetic variance within populations. Original data on threespine sticklebacks, together with published genetic measurements from other vertebrates, show that morphological differentiation between species has been biased in the direction of gmax for at least four million years, despite evidence that natural selection is the cause of differentiation. This bias toward the direction of evolution tends to decay with time. Rate of morphological divergence between species is inversely proportional to theta, the angle between the direction of divergence and the direction of greatest genetic variation. The direction of greatest phenotypic variance is not identical with gmax , but for these data is nearly as successful at predicting the direction of species divergence. I interpret the findings to mean that genetic variances and covariances constrain adaptive change in quantitative traits for reasonably long spans of time. An alternative hypothesis, however, cannot be ruled out: that morphological differentiation is biased in the direction gmax because divergence and gmax are both shaped by the same natural selection pressures. Either way, the results reveal that adaptive differentiation occurs principally along "genetic lines of least resistance." PMID- 28565591 TI - LACK OF CALLING SONG DISPLACEMENT BETWEEN TWO CLOSELY RELATED GROUND CRICKETS. AB - Thorough examinations of purported cases of reproductive character displacement are critical for reaching an understanding of the role of reinforcement in the evolution of reproductive barriers between closely related species. In this paper, we report the results of an extensive investigation of male calling song variation in the ground crickets, Allonemobius fasciatus and A. socius. Contrary to the results of an earlier study, we uncovered little evidence of displacement of songs in areas of overlap. We discuss explanations for the lack of displacement as well as for the discrepancies between the results of the current study and those of the earlier study. PMID- 28565592 TI - SEXUAL SELECTION OPERATING IN A WILD POPULATION OF DROSOPHILA ROBUSTA. PMID- 28565593 TI - THE EVOLVING GENETIC HISTORY OF A POPULATION OF LATHYRUS SYLVESTRIS: EVIDENCE FROM TEMPORAL AND SPATIAL GENETIC STRUCTURE. AB - We analyze patterns of genetic microdifferentiation within a natural population of Lathyrus sylvestris, a perennial herb with both sexual reproduction and clonal growth. In a population from the northern foothills of the Pyrenees in southwestern France, a combined demographic and genetic investigation enabled the study not only of spatial genetic structure of the population, but also of the history of the population's spatial genetic structure over time. Excavation of all individuals allowed identification of clonemates. Age of each individual was determined by counting annual growth rings in the taproot, a method tested with individuals of known age planted in experimental gardens. Each individual was mapped, and genotypes of all individuals were determined using allozyme markers for a number of polymorphic loci. Distribution patterns and spatial genetic structure, both for all individuals and for different age classes, were analyzed using spatial autocorrelation statistics (Geary's Index, Moran's Index). Patterns of gene flow within the population were also studied using F-statistics and tests for random associations of alleles. Because age, allele frequencies, and location were known for each individual, it was possible to study how spatial genetic structure changed over time. Results from all these diverse approaches are consistent with one another, and clearly show the following: (1) founder effects, with the study transect being first colonized by individuals at either end of the transect that were homozygous for different alleles at one marker locus; (2) a difference in spatial distribution of individuals originated from sexual reproduction (seedlings) and from clonal growth (connected individuals); (3) restricted gene flow, due to inbreeding among related, clumped individuals; and (4) increase in heterozygote deficit within the youngest cohort of individuals. The results indicate that genetic differentiation in time was much less marked than differentiation in space. Nevertheless, the results revealed that the studied population is experiencing demographic and genetic variation in time, suggesting that it is not at equilibrium. On the one hand, spatial structuring is becoming less marked due to the recombination of founder genotypes; on the other hand, as establishment of new individuals increases, a new spatial structure emerges due to mating between relatives. PMID- 28565594 TI - INBREEDING DEPRESSION, NEUTRAL POLYMORPHISM, AND COPULATORY BEHAVIOR IN FRESHWATER SNAILS: A SELF-FERTILIZATION SYNDROME. AB - This paper examines the consequences of self-fertilization on life-history traits and neutral genetic polymorphism in natural populations of three species of hermaphrodite freshwater snails: Biomphalaria straminea, Bulinus globosus, and the aphallic species Bulinus truncatus. Life-history traits (fecundity, growth, hatching rate, and survival of offspring) are compared under laboratory conditions between isolated (obligatory selfing) and paired (outcrossing possible) snails in one population of B. straminea and B. globosus and two populations of B. truncatus. The genetic polymorphism of the same four populations is analyzed using electrophoretic markers in B. straminea and B. globosus and microsatellite markers in B. truncatus. In B. truncatus and B. straminea, isolated snails have a higher fecundity than paired snails, whereas the contrary is observed in B. globosus. For all populations, no difference in hatching rate and offspring survival is detected between the two treatments. Genetic analyses using microsatellite markers conducted in B. truncatus on progeny of paired snails reveal a high selfing rate in spite of high copulation rates, highlighting the difficulties of obtaining outcrossing in highly selfing snails. The high survival of selfed offspring in B. truncatus and B. straminea indicates that inbreeding depression is limited. The extent of inbreeding depression in B. globosus is less clear. Overall, fitness decrease in this species is limited to fecundity. The extent of allozyme polymorphism is very limited whereas a much higher variability is observed with microsatellites. Biomphalaria straminea and B. truncatus populations are also characterized by very low observed heterozygosities and large heterozygote deficiencies, whereas the B. globosus population does not exhibit such a deficiency. Overall these results allow the definition of a self-fertilization syndrome in hermaphrodite freshwater snails: selfing populations (such as those of B. straminea and B. truncatus studied here) are characterized by high selfing rates in spite of copulations, limited deleterious effects of selfing, limited neutral genetic polymorphism, and large heterozygote deficiencies. PMID- 28565595 TI - LIFE-HISTORY VARIATION AND COMPARATIVE PHYLOGEOGRAPHY OF DARTERS (PISCES: PERCIDAE) FROM THE NORTH AMERICAN CENTRAL HIGHLANDS. AB - Phylogeography seeks to evaluate the relationship between genetic variation and geographic distribution of a species to examine the influence of historical events on divergence. Congruent phylogeographic patterns in codistributed species indicate historical association of the taxa being compared, and the uniform action of biogeographic events in shaping genetic variation. We sought to evaluate the congruence of patterns of genetic variation of five closely related fish species across a well-defined biogeographic boundary. We gathered allozymic and mitochondrial DNA (mtDNA) sequence data for five species of darters (Percidae: Etheostomatini) from populations distributed among biogeographic regions in the Ozark and Ouachita highlands of the south-central United States. Comparisons among species revealed noncongruence in the magnitude of genetic divergence in both allozymes and mtDNA sequences. We hypothesized that noncongruence resulted, in part, from differences in life histories of the species in our comparison. To address this hypothesis, we evaluated the association between gene flow (measured by Ne m) and variation in body size and fecundity variables because they have been shown to influence gene flow in fishes. Correlation analysis revealed an association between gene flow and fecundity (r = 0.88), but not with body size (r = 0.36) or reproductive investment per individual (r = -0.23). The result was similar when independent contrasts of the original variables were used in correlation analyses. Phylogeographic analysis of mtDNA sequence data indicated the importance of history, evident in gene trees of Percina nasuta and Percina phoxocephala. Divergence rates between these two taxa may differ because of historically persistent differences in population sizes, reflected in present-day abundance and fecundity differences. Conversely, Percina caprodes showed little evidence of divergence in mtDNA sequences and yielded the highest mean Ne m values from allozyme data. Comparisons among closely related, codistributed taxa may help discriminate among the possibilities for noncongruence in biogeographic studies by allowing evaluation of the influence of life history on patterns of gene flow. PMID- 28565596 TI - SEXUAL SIZE DIMORPHISM AS A CORRELATED RESPONSE TO SELECTION ON BODY SIZE: AN EMPIRICAL TEST OF THE QUANTITATIVE GENETIC MODEL. AB - We artificially selected for body size in Drosophila melanogaster to test Lande's quantitative genetic model for the evolution of sexual size dimorphism. Thorax width was used as an estimator of body size. Selection was maintained for 21 generations in both directions on males only, females only, or both sexes simultaneously. The correlated response of sexual size dimorphism in each selection regime was compared to the response predicted by four variants of the model, each of which differed only in assumptions about input parameters. Body size responded well to selection, but the correlated response of sexual size dimorphism was weaker than that predicted by any of the variants. Dimorphism decreased in most selection lines, contrary to the model predictions. We suggest that selection on body size acts primarily on growth trajectories. Changes in dimorphism are caused by the fact that male and female growth trajectories are not parallel and termination of growth at different points along the curves results in dimorphism levels that are difficult to predict without detailed knowledge of growth parameters. This may also explain many of the inconsistent results in dimorphism changes seen in earlier selection experiments. PMID- 28565597 TI - BODY SIZE AND HAREM SIZE IN MALE RED-WINGED BLACKBIRDS: MANIPULATING SELECTION WITH SEX-SPECIFIC FEEDERS. AB - We experimentally manipulated the strength of selection in the field on red winged blackbirds (Agelaius phoeniceus) to test hypotheses about contrasting selective forces that favor either large or small males in sexually size dimorphic birds. Selander (1972) argued that sexual selection favors larger males, while survival selection eventually stabilizes male size because larger males do not survive as well as smaller males during harsh winters. Searcy (1979a) proposed instead that sexual selection may be self limiting: male size might be stabilized not by overwinter mortality, but by breeding-season sexual selection that favors smaller males. Under conditions of energetic stress, smaller males should be able to display more and thus achieve higher reproductive success. Using feeders that provisioned males or females but not both, we produced conditions that mimicked the extremes of natural conditions. We found experimental support for the hypothesis that when food is abundant, sexual selection favors larger males. But even under conditions of severe energetic stress, smaller males did not gain larger harems, as the self-limiting hypothesis predicted. Larger males were more energetically stressed than smaller males, but in ways that affected their future reproductive output rather than their current reproductive performance. Stressed males that returned had smaller wings and tails than those that did not return; among returning stressed males, relative harem sizes were inversely related to wing and tail length. Thus, male body size may be stabilized not by survival costs during the non-breeding season, nor by energetic costs during the breeding season, but by costs of future reproduction that larger males pay for their increased breeding-season effort. PMID- 28565598 TI - PHYLOGENIES, SPATIAL AUTOREGRESSION, AND THE COMPARATIVE METHOD: A COMPUTER SIMULATION TEST. AB - Brownian motion computer simulation was used to test the statistical properties of a spatial autoregressive method in estimating evolutionary correlations between two traits using interspecific comparative data. When applied with a phylogeny of 42 species, the method exhibited reasonable Type I and II error rates. Estimation abilities were comparable to those of independent contrasts and minimum evolution (parsimony) methods, and generally superior to a traditional nonphylogenetic approach (not taking phylogenies into account at all). However, the autoregressive method performed extremely poorly with a smaller phylogeny (15 species) and with nearly independent ("star") phylogenies. In both of these situations, any phylogenetic autocorrelation present in the data was not detected by the method. Results show how diagnostic techniques (e.g., Moran's I) can be useful in detecting and avoiding such situations, but that such techniques should not be used as definitive evidence that phylogenetic correlation is not present in a set of comparative data. The correction factor (alpha) proposed by Gittleman and Kot (1990) for use in weighting phylogenetic information had little effect in most analyses of 15 or 42 species with incorrect phylogenetic information, and may require much larger sample sizes before significant improvement is shown. With the sample sizes tested in this study, however, the autoregressive method implemented with this correction factor and correct phylogenetic information led to downwardly biased estimates of the absolute magnitude of the evolutionary correlation between two traits. Cautions and recommendations for implemention of the spatial autoregressive method are given; computer programs to conduct the analyses are available on request. PMID- 28565599 TI - POLLEN-TUBE COMPETITION AND MALE FITNESS IN HIBISCUS MOSCHEUTOS. AB - The stigmas of animal-pollinated flowers often capture more pollen than is needed to fertilize all available ovules, and mixed-donor pollen loads are probably common. When this is the case, variation in average pollen-tube growth rates can potentially affect the number of seeds sired by a given plant. Despite considerable interest in effects of postpollination processes on male fitness, little is known about the extent of variation in pollen performance among plants from natural populations. To examine this question in Hibiscus moscheutos (rose mallow), we conducted mixed-donor hand-pollination experiments with 39 pollen donors bearing distinctive isozyme markers. Pairs of competing donors were compared on sets of 11 to 15 recipient plants per pair. These donors often differed in the proportions of seeds they sired, with the maximum deviation from an expected ratio of 50:50 being 68:32. Furthermore, three intensively studied plants exhibited consistent trends in relative pollen performance when each was tested against (1) the same three competitors, and (2) groups of 14 competitors chosen at random from the study population. In a separate experiment, we investigated the effects of salinity stress and high soil nutrients on pollen performance. These environmental factors had anticipated effects on leaf production, flower production, and petal length, but style length and (most importantly) the number of seeds sired relative to a standard pollen donor were not affected. In summary, this study provides the strongest evidence to date that pollen-tube competitive ability varies among coexisting plants and may be an important component of male fitness in plants. PMID- 28565601 TI - AN EVOLUTIONARY ARGUMENT FOR EGG LIMITATION. PMID- 28565600 TI - SEXUAL SELECTION IN A WOLF SPIDER: MALE DRUMMING ACTIVITY, BODY SIZE, AND VIABILITY. AB - Females are often believed to actively choose highly ornamented males (males with extravagant morphological signals or intense sexual display), and ornaments should be honest signals of male viability. However, this belief is relying only on some pieces of empirical evidence from birds. Our study reports active female choice on sexual display that indicates male viability in spiders. We established trials in which we studied female choice in relation to male courtship drumming activity and body size. Females chose the most actively drumming males as mating partners, but the body size of the males did not seem to be selected. Male drumming activity turned out to be a good predictor of male viability, whereas male viability was independent of male body mass. Our results suggest that by actively choosing mates according to male drumming performance, but independently of male body mass, females are preferring viable males as mates. Because Hygrolycosa rubrofasciata males do not provide obvious direct benefits to their offspring, females may gain some indirect benefits; offspring may have higher chance of survival, or the offspring may inherit the attractiveness of their father. PMID- 28565602 TI - THEORY OF MAST REPRODUCTION IN PLANTS: STORAGE-SIZE DEPENDENT STRATEGY. AB - The amount of available resource can be considered to restrict mast seeding behavior in plants, regardless of the cause of masting itself. The reproductive strategy of a plant that has stopped growing, but continues to maintain a constant size, is based on the allocation of assimilated resources between reproduction and storage. If both plant death and population growth rates are constant, the plant strategy is dependent only on its own storage size. Conditions for the evolution of mast reproduction were analyzed under both constant and varying environments, from the view point of storage-size dependent strategy, which is influenced by three parameters: the advantage coefficient of mast seeding, beta; the cost coefficient of delayed seeding, gamma; and the assimilation rate, P. The model indicated that: (1) mast seeding evolves only with a greater than linear increase in reproductive success with effort (beta > 1) under both constant and varying environments; (2) in mast seeding, a critical storage size, Sc *, occurs, above which plants utilize all storage for reproduction; (3) in a constant environment, Sc * increases with increasing beta and P and/or decreasing gamma; (4) concomitant with (3), an intermasting period, tau, also increases with increasing beta and decreasing 7, but is independent of P; (5) in a varying environment, Sc * and the average of tau increase with increasing variance of the assimilation rate, P; and (6) concomitant with (5), the intermasting period has a certain probability distribution. In addition, reproductive synchrony within the population and the relationship between mast seeding and species diversity are discussed. PMID- 28565603 TI - THE EFFECTS OF CONTRASTING MODES OF FERTILIZATION ON LEVELS OF INBREEDING IN THE MARINE INVERTEBRATE GENUS CORELLA. AB - A simple difference in the body design of two species of marine urochordates in the ascidian genus Corella suggested that these species may differ in their mating systems. The two coexisting species share common life-history traits and morphology with the exception of a difference in body design that affects site of fertilization and embryonic development. Corella inflata has internal fertilization and embryonic development, while C. willmeriana has external fertilization and embryonic development. The natural mating system of these two species of solitary ascidians was inferred by comparing the relative survival of selfed and outcrossed fertilizations in the laboratory. Corella inflata, the internal fertilizer, showed no difference in survival between selfed and outcrossed fertilizations at any developmental stage through metamorphosis and early juvenile development. In contrast, self-fertilized crosses of C. willmeriana had significantly lower survival than outcrossed fertilizations even at the earliest scorable developmental stages. These results suggest that C. inflata may inbreed frequently in nature, while viable C. willmeriana offspring are primarily a result of outcrossing. The internally-fertilizing species, C. inflata, showed approximately 10% male sterility in laboratory crosses despite apparent morphological hermaphroditism. The externally-fertilizing, commonly outcrossing species, C. willmeriana, showed no difference in fertility between genders. PMID- 28565604 TI - DEVELOPMENT OF THE HYBRID SWARM BETWEEN PECOS PUPFISH (CYPRINODONTIDAE: CYPRINODON PECOSENSIS) AND SHEEPSHEAD MINNOW (CYPRINODON VARIEGATUS): A PERSPECTIVE FROM ALLOZYMES AND mtDNA. AB - A comparison of allozyme and mtDNA frequencies was used for insight into a situation in the Pecos River, Texas where contact between the endemic pupfish (Cyprinodon pecosensis) and an introduced congener (C. variegatus) has resulted in rapid, geographically extensive genetic introgression. Temporal changes in mean frequencies of diagnostic allozyme markers indicate that the clinal pattern of introduced genetic material (Echelle and Connor 1989) is slowly decreasing in amplitude. Significant rank concordance in diagnostic allele frequencies among sites and across sampling years indicates directional influences upon temporal allele frequency change. These observations are consistent with the theory of gene flow in neutral clines. Levels of introgression indicated by each of four allozyme loci and mtDNA were roughly equivalent. The early history of the hybrid swarm is explained by genetic swamping, possibly mediated by selection for C. variegatus or C. variegatus * C. pecosensis, at a time when the normally abundant endemic species had been catastrophically depleted. High frequencies of an introduced GPI-A allele in all samples of intergrades suggests that the introduced genome originated with a single founding event. PMID- 28565605 TI - ENERGY, RISK, AND REPTILIAN REPRODUCTIVE EFFORT: A REPLY TO NIEWIAROWSKI AND DUNHAM. PMID- 28565606 TI - FROM FROND TO FAN: ARCHAEOPTERYX AND THE EVOLUTION OF SHORT-TAILED BIRDS. AB - Modern birds have extremely short tail skeletons relative to Archaeopteryx and nonavialian theropod dinosaurs. Long- and short-tailed birds also differ in the conformation of main tail feathers making up the flight surface: frond shaped in Archaeopteryx and fan shaped in extant fliers. Mechanisms of tail fanning were evaluated by electromyography in freely flying pigeons and turkeys and by electrical stimulation of caudal muscles in anesthetized birds. Results from these experiments reveal that the pygostyle, rectrices, rectricial bulbs, and bulbi rectricium musculature form a specialized fanning mechanism. Contrary to previous models, our data support the interpretation that the bulbi rectricium independently controls tail fanning; other muscles are neither capable of nor necessary for significant rectricial abduction. This bulb mechanism permits rapid changes in tail span, thereby allowing the exploitation of a wide range of lift forces. Isolation of the bulbs on the pygostyle effectively decouples tail fanning from fan movement, which is governed by the remaining caudal muscles. The tail of Archaeopteryx, however, differs from this arrangement in several important respects. Archaeopteryx probably had a limited range of lift forces and tight coupling between vertebral and rectricial movement. This would have made the tail of this primitive flier better suited to stabilization than maneuverability. The capacity to significantly alter lift and manipulate the flight surface without distortion may have been two factors favoring tail shortening and pygostyle development during avian evolution. PMID- 28565607 TI - WAITING FOR SPECIATION: THE EFFECT OF POPULATION SUBDIVISION ON THE TIME TO SPECIATION. AB - We study the time required for speciation in a species that is divided into small versus large populations. Following Dobzhansky and Muller, we assume that hybrid sterility or inviability is caused by "complementary genes," that is, by the accumulation of genes that cause sterility or inviability when brought together in hybrids but that have no deleterious effect on their normal species genetic background. When divergence between populations is caused by genetic drift, we show that the time to speciation is independent of population subdivision: speciation occurs just as quickly in a species split into a few large populations as into many small populations. When divergence is driven by natural selection, however, the time to speciation is very sensitive to population subdivision and speciation occurs most rapidly when a species is split into two large populations. These results contradict several popular intuitions about the effect of population size on speciation. PMID- 28565608 TI - GENETICS OF BRASSICA RAPA. 3. COSTS OF DISEASE RESISTANCE TO THREE FUNGAL PATHOGENS. AB - Genetic costs of resistance to pathogens may be an important factor maintaining heritable variation for resistance in natural populations. Pleiotropic fitness trade-offs occur when genetic resistance causes reduction in other components of fitness. Although costs of resistance have an important influence on plant pathogen interactions, few previous studies have detected pleiotropic costs of resistance in the absence of confounding effects of linkage disequilibrium. To avoid this potential problem, we performed artificial selection experiments on resistance to two fungal pathogens, Leptosphaeria maculans, and Peronospora parasitica, and compared growth rates of resistant and susceptible genotypes of Brassica rapa in the absence of pathogens. Leptosphaeria resistance had no effect on growth rate, indicating cost-free defense. In contrast, Peronospora-resistant genotypes grow 6% slower than Peronospora-susceptible genotypes in pathogen-free environments, indicating a significant genetic fitness cost to Peronospora resistance. Such genetic trade-offs could maintain genetic variation in the wild. Another factor that might explain heritable variation for resistance is ecological trade-offs, in which genetic resistance to one species causes susceptibility to another. Such ecological trade-offs do not exist for the pathogens studied in this system. PMID- 28565609 TI - GENETIC STRUCTURE AND EVOLUTION OF A FIRE ANT HYBRID ZONE. AB - Two introduced fire ants, Solenopsis invicta and S. richteri, hybridize over an extensive area in the United States spanning central Mississippi, Alabama, and western Georgia. We studied a portion of this hybrid zone in northwestern Mississippi in detail by sampling ants at many sites along two transects extending across the zone and examining gene frequency and size distributions at a large number of genetic and morphological markers. The distributional patterns at these markers are most consistent with the mosaic hybrid zone model, whereby the distribution of various fire ant genotypes is determined initially by the historical patterns of colonization of newly available habitats. However, these distributional patterns probably do not reflect the equilibrium state of interactions because of the very recent secondary contact of the species (< 60 yr) and the dynamic nature of available nesting habitats in this area. Our data suggest that, with prolonged contact and interaction, differential fitness of various hybrid genotypes due to intrinsic and extrinsic selective factors is important in structuring the hybrid zone. For instance, consistent differential introgression of morphological and genetic markers, combined with previous evidence of differences in developmental stability among genotypes, suggest reduced fitness of hybrids relative to parentals due to intrinsic selection (as may be caused by breakup of parental gene complexes). Furthermore, marked reductions in the occurrence of parental-like hybrids in areas where the similar parental species is common suggest reduced fitness of these parental-like hybrids in competition with the parentals (i.e., extrinsic selection). Because the relative roles of such deterministic as well as stochastic forces apparently vary both spatially and temporally, the eventual distribution of the various fire ant genotypes and the fate of the hybrid zone in the United States is difficult to predict. PMID- 28565610 TI - MALTHUS AND DARWIN: WORLD VIEWS APART. PMID- 28565611 TI - INBREEDING AND VARIANCE EFFECTIVE SIZES FOR NONRANDOM MATING POPULATIONS. AB - Following an inbreeding approach and assuming discrete generations and autosomal inheritance involving genes that do not affect viability or reproductive ability, I have derived expressions for the inbreeding effective size, NeI , for a finite diploid population with variable census sizes for three cases: monoecious populations with partial selfing; dioecious populations of equal numbers of males and females with partial sib mating; and unequal numbers of males and females with random mating. For the first two cases, recurrence equations for the inbreeding coefficient are also obtained, which allow inbreeding coefficients to be predicted exactly in both early and late generations. Following the variance of change in gene frequency approach, a general expression for variance effective size, NeV , is obtained for a population with unequal numbers of male and female individuals, arbitrary family size distribution, and nonrandom mating. All the parameters involved are allowed to change over generations. For some special cases, the equation reduces to the simple expressions approximately as derived by previous authors. Comparisons are made between equations derived by the present study and those obtained by previous authors. Some of the published equations for NeI and NeV are shown to be incomplete or incorrect. Stochastic simulations are run to check the results where disagreements with others are involved. PMID- 28565612 TI - IDENTICAL MAJOR GENE LOCI FOR HEAVY METAL TOLERANCES THAT HAVE INDEPENDENTLY EVOLVED IN DIFFERENT LOCAL POPULATIONS AND SUBSPECIES OF SILENE VULGARIS. AB - Heavy metal tolerant Silene vulgaris plants, originating from different metalliferous sites in Germany and one in Ireland, were crossed to each other and to nontolerant plants from a nonmetalliferous site in The Netherlands. Analysis of the crosses suggested that there were two distinct major gene loci for zinc tolerance among a total of five tolerant populations. The tolerance loci for zinc, copper, and cadmium in the Irish plants were shown to be identical with those in the German populations. It is argued that the occurrence of common major genes for tolerance among different geographically isolated populations must have resulted from independent parallel evolution in local nontolerant ancestral populations. Each of the tolerances studied seems to be controlled by only a few specific major genes. PMID- 28565613 TI - SEVERE INBREEDING DEPRESSION AND RAPID FITNESS REBOUND IN THE BUTTERFLY BICYCLUS ANYNANA (SATYRIDAE). AB - We established inbred laboratory lines of the satyrid Bicyclus anynana with one, three and 10 pairs of butterflies, which were subsequently allowed to increase freely to a maximum size of 300 butterflies. Minimally inbred control lines were established with 300 randomly selected virgin butterflies of equal sex ratio. We measured fecundity, egg weight, egg hatching, adult emergence, adult size, and the proportion of crippled adults in generations F2 , F3 , F5 , and F7 (the latter two for the one pair bottleneck lines only). The most striking result was an unexpectedly large decrease in egg hatching with increase in inbreeding (25% per 10% increase in inbreeding). Such a level of inbreeding depression has not been reported previously for any insect. The distribution of egg hatching rate for individual clutches within inbred lines was markedly skewed, with a large fraction of clutches producing no eggs at all. This is interpreted as a relatively lower ratio of detrimental to lethal (or sterile) mutation loads than is found in Drosophila, the only insects for which mutation loads have been well characterized. Possible explanations for this severe inbreeding depression include a relatively high rate of mutation to recessive alleles with substantial damaging effects and infrequent episodes of inbreeding in nature. In the experiments, average egg hatching rate recovered rapidly between F2 and F7 in three of the six one-pair lines. We discuss the implications of these results for survival of populations through extreme bottlenecks in nature and in captivity. PMID- 28565614 TI - THE SELECTION DIFFERENTIAL IN QUANTITATIVE GENETICS AND ESS MODELS. PMID- 28565615 TI - GENETIC COMPARISONS OF SEED BANK AND SEEDLING POPULATIONS OF A PERENNIAL DESERT MUSTARD, LESQUERELLA FENDLERI. AB - Soil seed banks may accumulate and store seed genotypes produced over many seasons. If germination and establishment of these soil seeds are influenced by seed genotypes, then seed bank and seedling populations may differ genetically. I compared the genetic structure of dormant but viable soil seeds of the desert mustard Lesquerella fendleri with the genetic structure of Lesquerella seedlings at the Sevilleta Long-Term Ecological Research Site. In 1991 and 1992, soil seeds and seedlings were mapped and genetically analyzed using starch gel electrophoresis. When data from all loci were lumped, there were highly significant differences in allele frequencies between soil seeds and seedlings at the population level (all plots) in both years, in all subpopulation (adjacent plots) comparisons in 1991, and three of five subpopulations in 1992. Differences at some individual loci were also detected in one or both years. Analysis of data pooled across both years revealed highly significant differences in the distribution of multilocus soil seed and seedling heterozygosity, but no significant differences in mean heterozygosity. Fst values showed small but statistically significant genetic differentiation within soil seeds and seedlings in both years. Fst values also showed significant genetic differentiation between these two groups at three of seven loci in 1991, and at one locus in 1992. Soil seeds and seedlings showed a general pattern of decreasing genetic relationship with distance, as estimated by the coefficient of coancestry analyses. In 1991, seedlings were roughly twice as genetically related to each other than were soil seeds at fine spatial scales (0-0.25 and 0.25-0.50 m). This study suggests that Lesquerella seedlings in this system represent a nonrandom genetic subset of the underlying Lesquerella seed bank. Such temporal genetic change may be an important yet frequently overlooked mechanism for generating population genetic structure. PMID- 28565616 TI - QUANTITATIVE GENETICS OF SEXUAL SELECTION IN THE FIELD CRICKET, GRYLLUS INTEGER. AB - Major theories of sexual selection predict heritable variation in female preferences and male traits and a positive genetic correlation between preference and trait. Here we show that female Texas field crickets, Gryllus integer, have heritable genetic variation for the male calling song stimulus level that produces the greatest phonotactic response. Approximately 34% of the variation in female preferences was due to additive genetic effects. Female choosiness, that is, the strength of the female response to her most preferred stimulus relative to her average response to all stimuli, did not show significant genetic effects. The male calling song character was not related to male size or age but did show significant genetic effects. Approximately 39% of the variation in the number of pulses per trill was due to additive genetic variation. The genetic correlation estimated for the field population was 0.51 +/- 0.17. The number of pulses per trill produced by males is under stabilizing sexual selection. PMID- 28565617 TI - SEXUALLY TRANSMITTED DISEASE AND PARASITE-MEDIATED SEXUAL SELECTION. AB - Few studies have investigated the consequences of parasite-mediated sexual selection on the parasites involved. In some cases parasite-mediated sexual selection could lead to increased virulence, but I develop a simple model that shows that, if a parasite is sexually transmitted (i.e., is a sexually transmitted disease, or STD) and if mating success of the host is adversely affected by the parasite, then less virulent STDs will be selected for because transmission of the STD depends on the mating success of the host. This selection for reduced virulence could have important consequences for the role of STDs in sexual selection. PMID- 28565618 TI - ECOLOGICAL SPECIATION IN STICKLEBACKS: ENVIRONMENT-DEPENDENT HYBRID FITNESS. AB - "Ecological" speciation occurs when reproductive isolation evolves as a consequence of divergent selection between populations exploiting different resources or environments. We tested this hypothesis of speciation in a young stickleback species pair by measuring the direct contribution of ecological selection pressures to hybrid fitness. The two species (limnetic and benthic) are strongly differentiated morphologically and ecologically, whereas hybrids are intermediate. Fitness of hybrids is high in the laboratory, especially F1 and F2 hybrids (backcrosses may show some breakdown). We transplanted F1 hybrids to enclosures in the two main habitats in the wild to test whether the distribution of resources available in the environment generates a hybrid disadvantage not detectable in the laboratory. Hybrids grew more slowly than limnetics in the open water habitat and more slowly than benthics in the littoral zone. Growth of F1 hybrids was inferior to the average of the parent species across both habitats, albeit not significantly. The contrast between laboratory and field results supports the hypothesis that mechanisms of F1 hybrid fitness in the wild are primarily ecological and do not result from intrinsic genetic incompatibilities. Direct selection on hybrids contributes to the maintenance of sympatric stickleback species and may have played an important role in their origin. PMID- 28565619 TI - CROSS-RESISTANCE FOLLOWING ARTIFICIAL SELECTION FOR INCREASED DEFENSE AGAINST PARASITOIDS IN DROSOPHILA MELANOGASTER. AB - An increase in resistance to one natural enemy may result in no correlated change, a positive correlated change, or a negative correlated change in the ability of the host or prey to resist other natural enemies. The type of specificity is important in understanding the evolutionary response to natural enemies and was studied here in a Drosophila-paxasitoid system. Drosophila melanogaster lines selected for increased larval resistance to the endoparasitoid wasps Asobara tabida or Leptopilina boulardi were exposed to attack by A. tabida, L. boulardi and Leptopilina heterotoma at 15 degrees C, 20 degrees C, and 25 degrees C. In general, encapsulation ability increased with temperature, with the exception of the lines selected against L. boulardi, which showed the opposite trend. Lines selected against L. boulardi showed large increases in resistance against all three parasitoid species, and showed similar levels of defense against A. tabida to the lines selected against that parasitoid. In contrast, lines selected against A. tabida showed a large increase in resistance to A. tabida and generally to L. heterotoma, but displayed only a small change in their ability to survive attack by L. boulardi. Such asymmetries in correlated responses to selection for increased resistance to natural enemies may influence host-parasitoid community structure. PMID- 28565620 TI - NEUTRAL GENETIC DIVERSITY IN A METAPOPULATION WITH RECURRENT LOCAL EXTINCTION AND RECOLONIZATION. AB - Many species exist as metapopulations in balance between local population extinction and recolonization, processes that may strongly affect the distribution of neutral genetic diversity within demes and in the metapopulation as a whole. In this paper we use both the infinite-alleles and the infinite-sites models to reframe Slatkin's propagulepool and migrant-pool models in terms of mean within-deme and among-deme genetic diversity; the infinite-sites model is particularly relevant to DNA sequence data. Population turnover causes a major reduction in neutral genetic diversity within demes, piS , and in the metapopulation as a whole, pit . This effect is particularly strong for propagulepool colonization, in which colonists are drawn from a single extant deme. Because metapopulation dynamics affect both within-deme and total metapopulation diversity similarly, comparisons between species with different ecologies on the basis of ratios such as FST are difficult to interpret and absolute measures of divergence between populations should be used as well. Although the value of FST in a metapopulation with local extinction depends strongly on the mode of colonization, this has almost no effect on the numerator of the FST ratio, pit - piS , so that FST is influenced mainly by the effect of the colonization mode on the denominator (pit ). Our results also indicate that it is inappropriate to use measures of average within-deme diversity in species with population turnover to estimate the scaled mutation rate, theta, because extinction can greatly reduce piS . Finally, we discuss the effect of population turnover on the effective size of a metapopulation. PMID- 28565621 TI - KIN INTERACTIONS IN A COLONIAL HYDROZOAN (HYDRACTINIA SYMBIOLONGICARPUS): POPULATION STRUCTURE ON A MOBILE LANDSCAPE. AB - Many sessile colonial organisms intensively compete with conspecifics for growing space. This competition can result in either cooperative fusion or aggressive rejection between colonies, and some species have evolved highly polymorphic genetic systems that mediate the outcome of these interactions. Here we demonstrate the potential for interactions among close kin as the basis for the evolutionary maintenance of a genetically polymorphic allorecognition system in the colonial hydroid Hydractinia symbiolongicarpus, which lives on gastropod shells occupied by hermit crabs. Fusion between hydroids in the laboratory is restricted mainly to encounters between full siblings, whereas other encounters result in aggressive rejection. Natural selection acting on the costs or benefits of fusion between colonies could be responsible for the present maintenance of such a highly specific behavioral response, but only if encounters between fusible colonies still occur in contemporary populations. The large size of these hydroid populations and the mobility of the crabs should limit the potential for interactions among closely related hydroids on the same shell. However, RAPD polymorphisms among a large sample of hydroids from a population off the coast of Massachusetts indicate that genetically similar colonies are often found together on the same shell. Some genetic distances between colonies on the same shell were low relative to genetic distances between colonies on different shells or genetic distances between known full siblings from laboratory matings. We conservatively estimate that 2-18% of co-occurring colonies may be full sibling pairs. These observations suggest that encounters between genetically similar hydroids are common, despite the mobile nature of their habitat, and these encounters may provide frequent opportunities for natural selection to influence the evolution of cooperative and agonistic behaviors and their polymorphic genetic basis. PMID- 28565622 TI - MORPHOMETRIC CORRELATION PATTERNS OF ADULT BIRDS (FRINGILLIDAE: PASSERIFORMES AND COLUMBIFORMES) MIRROR THE EXPRESSION OF DEVELOPMENTAL CONTROL GENES. AB - Stimulated by the rapid progress in developmental genetics, recent approaches to evolutionary theory focus on the interface function of developmental processes in the study of genotype-phenotype mapping. From this viewpoint, the main result of the present analysis is that the expression patterns of developmental control genes are reflected in the infraspecific correlation patterns of phenotypic characters in the adult stage. The study is based on 42 logarithmically scaled skeletal measurements of two avian clades, finches (43 species, n = 313) and pigeons (27 species, n = 219). First, for each clade an "observed correlation matrix" was calculated by computing a bias-reduced pooled-species correlation matrix based on the clade-specific pooled within-species variance-covariance matrix between measurements. Second, the expression domains of diverse developmental control genes, that is, Hox, Msx, Pax, Mhox, Shh, Bmp, and Gdf, in characters were represented by "theoretical matrices." Finally, the observed and the theoretical matrices were compared by Mantel's test to test hypotheses about pattern similarities between phenotypic correlations and the expression of developmental control genes. Seventeen percent of the single matrix comparisons revealed significant (P <= 0.05) pattern correspondences in finches, whereas 63% were significant in pigeons. The multiple comparisons revealed correspondences at the highest significance level (P <= 0.001) in both clades and disclosed that 15% of the observed matrix patterns are explained in finches versus 22% in pigeons. Presumably, as finches have less pronounced correspondences between gene expression and phenotypic correlation, they are more derived than pigeons. Out of the significant single matrix comparisons, four correspondences are common to both clades: one of them is connected with the Gdf gene expression concerning limb length relations and also harmonizes with the dominant pattern within the infraspecific correlation matrices. The general implication is that the significant correspondences detected here between observed and theoretical matrices are based on a correspondence between phenotypic and genetic modules. Because the phenotypic modules are potential candidates for a direct impact of selection, the important role of genotype-phenotype mapping in molding the body plan becomes apparent. PMID- 28565623 TI - RESPONSES OF FLORAL TRAITS TO SELECTION ON PRIMARY SEXUAL INVESTMENT IN SPERGULARIA MARINA: THE BATTLE BETWEEN THE SEXES. AB - Two widespread assumptions underlie theoretical models of the evolution of sex allocation in hermaphroditic species: (1) resource allocations to male and female function are heritable; and (2) there is an intrinsic, genetically based negative correlation between male and female reproductive function. These assumptions have not been adequately tested in wild species, although a few studies have detected either genetic variation in pollen and ovule production per flower or evidence of trade-offs between male and female investment at the whole plant level. It may also be argued, however, that in highly autogamous, perfect-flowered plant taxa that exhibit genetic variation in gamete production, strong stabilizing selection for an efficient pollen:ovule ratio should result in a positive correlation among genotypes with respect to mean ovule and mean pollen production per flower. Here we report the results of a three-generation artificial selection experiment conducted on a greenhouse population of the autogamous annual plant Spergularia marina. Starting with a base population of 1200 individuals, we conducted intense mass selection for two generations, creating four selected lines (high and low ovule production per flower; high and low anther production per flower) and a control line. By examining the direct and correlated responses of several floral traits to selection on gamete production per flower, we evaluated the expectations that primary sexual investment would exhibit heritable variation and that resource-sharing, variation in resource-garnering ability, or developmental constraints mold the genetic correlations expressed among floral organs. The observed direct and correlated responses to selection on male and female gamete production revealed significant heritabilities of both ovule and anther production per flower and a significant negative genetic correlation between them. When plants were selected for increased ovules per flower over two generations, ovule production increased and anther production declined relative to the control line. Among plants selected for decreased anthers per flower, we observed a decline in anther production and an increase in ovule production relative to the control line. In contrast, the lines selected for low ovules per flower and for high anthers per flower exhibited no evidence for significant genetic correlations between male and female primary investment. Correlated responses to selection also indicate a genetically based negative correlation between the production of normal versus developmentally abnormal anthers (staminoid organs); a positive correlation between the production of ovules versus staminoid organs; and a positive correlation between the production of anthers and petals. The negative relationship between male versus female primary investment supports classical sex allocation theory, although the asymmetrical correlated responses to selection indicate that this relationship is not always expressed. PMID- 28565624 TI - EVOLUTIONARY ENDOCRINOLOGY OF JUVENILE HORMONE ESTERASE: FUNCTIONAL RELATIONSHIP WITH WING POLYMORPHISM IN THE CRICKET, GRYLLUS FIRMUS. AB - The existence, nature, and physiological consequences of genetic variation for juvenile hormone esterase (JHE) activity was studied in the wing-polymorphic cricket, Gryllus firmus. Hemolymph (blood) JHE activity was sixfold lower in nascent short-winged (SW) females, relative to nascent long-winged (LW) females during the last juvenile stadium (stage). Morph-associated genetic variation for JHE activity had two causes, variation in loci: (1) regulating whole-organism enzyme activity; and (2) controlling the degree to which JHE is secreted into the blood Reduced JHE activity in nascent SW-selected individuals was associated with reduced in vivo juvenile hormone catabolism. This suggests that variation in JHE activity during juvenile development may have important physiological consequences with respect to the regulation of blood levels of juvenile hormone and consequent specification of wing morph. This is the first definitive demonstration of genetic variation for hormonal metabolism in any insect and a genetic association between hormone metabolism and the subsequent expression of morphological variation (wing morph). However, we have not yet firmly established whether these associations represent causal relationships In contrast to the clear association between JHE activity and wing morph development, we observed no evidence indicating that variation in JHE activity plays any direct or indirect role in causing the dramatic differences in ovarian growth between adult wing morphs. Variation in JHE activity also does not appear to be important in coordinating the development of wing morph with the subsequent expression of reproductive differences between adult morphs. Finally genetic variation for the developmental profiles of JHE activity during juvenile and adult stages are remarkably similar in three Gryllus species. This suggests that genetic correlations between JHE activities during different periods of development, which underlie these activity profiles, have been conserved since the divergence of the three Gryllus species. PMID- 28565625 TI - GENETIC AND GEOGRAPHIC VARIATION IN REJECTION BEHAVIOR OF CUCKOO EGGS BY EUROPEAN MAGPIE POPULATIONS: AN EXPERIMENTAL TEST OF REJECTER-GENE FLOW. AB - Host responses toward brood parasitism have been shown to differ among populations depending on the duration of sympatry between host and parasite, although populations not currently parasitized show rejection behavior against parasitic eggs. The persistence of rejection behavior in unparasitized host populations and rapid increases of rejection rate in parasitized ones have sometimes been explained as the result of gene flow of rejecter genes from sympatry to allopatry (rejecter-gene flow hypothesis). We present data on the rejection behavior of magpies (Pica pica) the main European host of the great spotted cuckoo (Clamator glandarius), in 15 populations (nine sympatric six allopatric) across their distribution range in Europe. Rejection rates of mimetic and nonmimetic model eggs were significantly higher in sympatric than in allopatric magpie populations, although differences in rejection rate of both mimetic and nonmimetic model eggs between magpie populations were significantly correlated even after controlling tor phylogenetic effects, with differences between sympatric and allopatric magpie populations being larger for mimetic than for nonmimetic model eggs. Differences in rejection of mimetic model eggs were related to both genetic and geographic distances between populations, but differences in rejection rate of nonmimetic model eggs were unrelated to these distances. However, when comparing only sympatric populations, differences in rejection rate of both mimetic and nonmimetic model eggs were related to geographic distances. A multiple autocorrelation analysis revealed that differences among populations in rejection rates of mimetic model eggs had a strong geographic component whereas the main component of rejection rate of nonmimetic model eggs was genetic rather than geographic. These results support the rejecter-gene flow hypothesis. We discuss differences in rejection rates of mimetic and nonmimetic model eggs that suggest the egg-recognition ability of the host is genetically based, but is affected by a learning process for fine tuning of recognition. PMID- 28565626 TI - A PHYLOGENETIC TEST OF ECOMORPHOLOGICAL ADAPTATION IN CANCER CRABS. AB - We used McPeek's (1995a) method of evolutionary contrasts, and phylogenetic trees derived from maximum-parsimony, neighbor-joining, and maximum-likelihood analyses of data from the cytochrome oxidase I (COI) gene to evaluate the hypothesis that macroevolutionary changes in habitat use have driven the morphological diversification of Cancer crabs. All of our analyses suggested that habitat shifts from structurally complex substrates (e.g., the rocky intertidal zone) to more homogeneous substrates (e.g., sand or mud) have occurred independently in three Cancer lineages. Evolutionary contrasts analyses indicated that these habitat shifts were accompanied by increased morphological change toward larger body sizes. These macroevolutionary patterns support the hypothesis that the morphological diversification of Cancer crabs is strongly related to size dependent habitat use; ancillary evidence suggests that increased predation pressure in homogeneous habitats represents the main selective agent for increased body size. PMID- 28565627 TI - PERSPECTIVE: SPONTANEOUS DELETERIOUS MUTATION. AB - Mildly deleterious mutation has been invoked as a leading explanation for a diverse array of observations in evolutionary genetics and molecular evolution and is thought to be a significant risk of extinction for small populations. However, much of the empirical evidence for the deleterious-mutation process derives from studies of Drosophila melanogaster, some of which have been called into question. We review a broad array of data that collectively support the hypothesis that deleterious mutations arise in flies at rate of about one per individual per generation, with the average mutation decreasing fitness by about only 2% in the heterozygous state. Empirical evidence from microbes, plants, and several other animal species provide further support for the idea that most mutations have only mildly deleterious effects on fitness, and several other species appear to have genomic mutation rates that are of the order of magnitude observed in Drosophila. However, there is mounting evidence that some organisms have genomic deleterious mutation rates that are substantially lower than one per individual per generation. These lower rates may be at least partially reconciled with the Drosophila data by taking into consideration the number of germline cell divisions per generation. To fully resolve the existing controversy over the properties of spontaneous mutations, a number of issues need to be clarified. These include the form of the distribution of mutational effects and the extent to which this is modified by the environmental and genetic background and the contribution of basic biological features such as generation length and genome size to interspecific differences in the genomic mutation rate. Once such information is available, it should be possible to make a refined statement about the long-term impact of mutation on the genetic integrity of human populations subject to relaxed selection resulting from modern medical procedures. PMID- 28565628 TI - HOLARCTIC PHYLOGEOGRAPHY OF AN ASEXUAL SPECIES COMPLEX I. MITOCHONDRIAL DNA VARIATION IN ARCTIC DAPHNIA. AB - Pleistocene glacial cycles undoubtedly altered the evolutionary trajectories of many taxa, yet few studies have examined the impact of such events on genetic differentiation and phylogeography at large geographic scales. Here we present the results of a circumarctic survey of mitochondrial DNA diversity in members of the Daphnia pulex complex. The analysis involved the survey of restriction site polymorphisms in a 2100-bp fragment of the NADH-4 (ND4) and NADH-5 (ND5) genes for 276 populations representing the two major groups (tenebrosa and pulicaria) in this complex across their Holarctic range. A comparison of the distribution patterns for seven clades in this complex revealed very clear phylogeographic structuring. Most notably, pulicaria group lineages were restricted primarily to the Nearctic, with some colonization of formerly glaciated portions of northern Europe. This group was not detected from vast expanses of northern Eurasia, including the Beringian glacial refuge. In contrast, tenebrosa group haplotypes showed considerable intercontinental divergence between Eurasian and North American lineages, but were absent from Greenland and Iceland, as well as the Canadian arctic archipelago. Dispersal in Eurasia was primarily in a westerly direction from Beringia, whereas dispersal in the Nearctic followed proglacial drainage patterns. Long-distance dispersal of certain lineages was observed in both groups, and variation in haplotype richness and nucleotide diversity allowed us to make inferences about the positioning of putative glacial refugia. Overall, the phylogeographic pattern of diversification in this arctic complex is characterized by the apparently unique postglacial histories for each clade, indicating that even closely allied taxa can respond independently to the allopatric effects of glacial cycles. This is in sharp contrast to other phylogeographic studies of species assemblages from more southern (unglaciated) latitudes, which are often characterized by concordant patterns. PMID- 28565629 TI - ADAPTIVE COLORATION AND GENE FLOW AS A CONSTRAINT TO LOCAL ADAPTATION IN THE STREAMSIDE SALAMANDER, AMBYSTOMA BARBOURI. AB - Predation is an important selective force that influences animal color patterns. Some larval populations of the streamside salamander, Ambystoma barbouri, inhabit streams with fish predators. Other larval salamanders are found in shallow, ephemeral streams that are predator-free. Quantitative melanophore cell counts and estimates of percent body area pigmented indicated that larval coloration is strongly correlated with stream type. Larvae that coexist with fish tend to be lighter than larvae from streams that are Ashless and ephemeral. Two approaches demonstrated that lightly pigmented salamander larvae better match the common background in relatively permanent streams and are less conspicuous to fish than dark larvae. First, using a model based on the spectral sensitivity of the fish and reflectance properties of salamanders and natural stream backgrounds, we showed that light larvae are three times more cryptic than dark larvae on rocks. Second, lighter larvae had higher survival than darker salamanders on rocks in a predator- choice experiment. It is not clear why larvae in ephemeral streams are darker. Larvae in ephemeral streams should be active to feed and develop rapidly and reach sufficient size to metamorphose before seasonal drying. Several hypotheses may explain why larvae tend to be darker in ephemeral streams, such as increased thermoregulatory ability, better screening of ultraviolet radiation (in these shallower streams), or better background matching to terrestrial predators. Among populations where salamander larvae coexist with fish, there are differences in relative crypsis. Larvae from populations with fish and relatively high gene flow from ephemeral populations (where larvae are dark) tend to be darker (with more melanophores) and more conspicuous to predators than those from more genetically isolated populations, where larvae are lighter and more cryptic. These differences illustrate the role of gene flow as a constraint to adaptive evolution. PMID- 28565630 TI - RESISTANCE AND VIRULENCE STRUCTURE IN TWO LINUM MARGINALE-MELAMPSORA LINI HOST PATHOGEN METAPOPULATIONS WITH DIFFERENT MATING SYSTEMS. AB - Different patterns of resistance to six pathotypes of Melampsora lini were detected in 11 populations of Linum marginale distributed across two metapopulations. The two metapopulations (mountains and plains of New South Wales, Australia) differed in the annual cycle of disease development, which barely overlapped, and in the growth cycle and mating system of the host. Host populations in the mountains metapopulation were highly inbred, whereas those on the plains showed appreciable levels of outcrossing. Within each metapopulation there was significant variation among component populations in (1) levels of host resistance to individual pathogen isolates; (2) mean levels of resistance to all six isolates; (3) the number of resistance phenotypes present and the evenness of their distribution within the population; and (4) the average number of pathogen lines to which individual hosts were resistant. A more limited comparison of pathogen populations from the two metapopulations (two from each) found greater similarities in the structure of populations and particular virulence frequencies within, rather than among, the two metapopulations. Differences in host outcrossing rates between the two metapopulations are reflected in marked differences in the overall level of resistance, its partitioning within and among populations, the number and distribution of resistance phenotypes in the two areas, and the level of polymorphism for specific virulence factors in the pathogen, with the plains metapopulation showing consistently higher values. However, these differences were not significant. In general, variation for all parameters was just as great among populations within a metapopulation as between the two metapopulations. PMID- 28565631 TI - GENETIC BASIS OF A BETWEEN-ENVIRONMENT TRADE-OFF INVOLVING RESISTANCE TO CADMIUM IN DROSOPHILA MELANOGASTER. AB - In a replicated, laboratory, natural selection experiment Drosophila melanogaster populations were maintained for 20 generations either on unpolluted medium or on polluted medium containing cadmium chloride at a concentration of 80 MUg/ml. Lines maintained on polluted medium evolved resistance. In comparison with unpolluted lines, their juvenile survivorship increased from 35% to 46%, developmental period decreased from 13.7 days to 13.0 days, and fecundity increased from 3 to 29 eggs per two-day period. Emergence weights, however, did not change. By contrast the "environmental" effect of moving susceptible flies onto polluted medium was that after two generations survivorship fell 62%, developmental period increased 40%, and fecundity fell 97%. Emergence weights fell 31% in females and 28% in males. Resistant lines paid a fitness cost in unpolluted environments, with fecundity being reduced by 44% and emergence weights being reduced by 4% in females and 6% in males. Developmental period, however, was unaffected. Analyses of crosses and backcrosses between the lines suggested that the evolved cadmium resistance was due to a single sex-linked gene. Levels of dominance were calculated, and in each life-history character the resistant allele was found to be completely dominant. Because the life-history effects appear to be produced by a single gene, it is probable that they all depend on the same metabolic pathway. Metallothionein production is a likely candidate because this is known to be controlled by genes on the X-chromosome. The study adds to a small number of examples of single or closely linked genes with large antagonistic pleiotropic effects on life histories. The result here is a between-environment trade-off, allowing animals increased fitness in polluted environments, but only at the cost of reduced growth and reproduction in unpolluted environments. PMID- 28565632 TI - EXTRAPAIR MATE CHOICE AND HONEST SIGNALING IN COOPERATIVELY BREEDING SUPERB FAIRY WRENS. AB - In many species of monogamous birds females copulate with males other than their social mates, resulting in extrapair fertilizations. Little is known about how females choose extrapair mates and whether the traits used to choose them are reliable indicators of male quality. Here we identify a novel male trait associated with extra-group mating success in the superb fairy-wren (Malurus cyaneus), a cooperatively breeding bird with one of the highest known frequencies of extra-group mating. Female fairy-wrens chose extra-group mates that molted earlier into breeding plumage. Males molted up to five months before the breeding season began, and only males that molted at least one month prior to its onset gained any extra-group fertilizations. This conclusion held after controlling statistically for the effect of age and social status on molt date. Once males acquired breeding plumage, they began courtship display to females on other territories. Thus, some males were displaying to females for several months before the breeding season began. This extraordinarily long period of advertisement by males may be facilitated by the long-term ownership of territories. We suggest that early acquisition of breeding plumage or the subsequent display behavior can be reliable cues for mate choice because they are costly to acquire or maintain. PMID- 28565634 TI - HISTORICAL SEPARATION AND PRESENT GENE FLOW THROUGH A ZONE OF SECONDARY CONTACT IN PONDEROSA PINE. AB - I examined the effects of historical division and secondary contact between eastern and western varieties of ponderosa pine (Pinus ponderosa Laws Pinaceae) on extant patterns of genetic variation. Fossil and biogeographic evidence both indicate that the current point of contact between these two varieties represents secondary contact following historical separation during the Wisconsin glaciation. Current gene flow was assessed by observing the degree of introgression of paternally inherited cpDNA and maternally inherited mtDNA polymorphisms. Both seeds and pollen are wind dispersed in ponderosa pine. Introgression was primarily from west to east, the direction of the prevailing wind, for both organelles, but introgression of cpDNA far exceeded that of mtDNA. Thus pollen is the main agent of contemporary gene flow between the two varieties. Neither seeds nor pollen showed enough introgression since secondary contact to have homogenized the two gene pools. However, allozyme differentiation was minimal. This calls into question assumptions of selective neutrality for at least some of the markers. Theory predicts that nuclear markers will show a high locus-to-locus variance of FST following historical separation. This prediction is confirmed by the allozyme data for ponderosa pine, and may provide a useful means of identifying historical separations from allele frequency data. PMID- 28565633 TI - MECHANISM OF SELECTION FAVORING A WIDE TUBULAR COROLLA IN CAMPANULA PUNCTATA. AB - A previous study of Campanula punctata pollinated by Bombus diversus showed greater male reproductive success in plants with wider corollas when male reproductive success was measured by paternity analysis. Pollen removal alone was not a good measure of male reproductive success. The aim of the current study is to elucidate the mechanism underlying the selection on corolla width in C. punctata. Multiple regression analysis of male reproductive success in experimental populations revealed that the advantage of a wide corolla to the male is independent of the corolla width of pollen recipients, indicating that the position of pollen deposited on Bombus may not be an important factor for selection. However, the number of pollen grains that fell on the petal or off the flower and were lost at the first visit of Bombus (pollen fall) decreased with increasing corolla width, so that most pollen grains removed from a wide flower were deposited onto the pollinator. In a narrow flower, a greater proportion of the pollen removed was wasted through pollen fall. Pollen removal does not reflect male reproductive success, at least in part because of the loss of pollen in some flowers through pollen fall. The positive relationship between wider corollas and reduced loss of pollen through pollen fall is likely to lead to greater male reproductive success of wider flowers under repeated visits of pollinators. Decreased pollen fall, probably due to more gentle contact between pollen and bees in flowers with wider corollas, may be one of the mechanisms underlying the selection on corolla width of C. punctata. PMID- 28565635 TI - INTERSPECIFIC RECOGNITION AND DISCRIMINATION BASED UPON OLFACTORY CUES IN NORTHERN SWORDTAILS. AB - Female Xiphophorus montezumae were attracted to olfactory cues from conspecific and heterospecific (X. cortezi and X. nigrensis) males when given a choice between the stimulus and water. When given a choice between conspecific and heterospecific cues, females only demonstrated a strong preference for the conspecific stimulus when it was matched against X. nigrensis. Female X. nigrensis were attracted to olfactory cues from their close relative, X. cortezi, but did not respond to cues from the more distantly related X. montezumae. They preferred the scent of their own males to the olfactory cues of both heterospecific species. Our results indicate that X. cortezi and X. nigrensis share an apomorphic change in some aspect of their olfactory cue-receiver system that is not shared with X. montezumae. We also uncovered an asymmetry in response based on olfactory stimuli in these fishes: X. montezumae is moderately attracted to the cue from X. nigrensis, whereas X. nigrensis does not respond to the cue from X. montezumae at all. PMID- 28565636 TI - THE ENDOCRINE GENETICS OF WING POLYMORPHISM IN GRYLLUS. A RESPONSE TO ZERA. PMID- 28565637 TI - GENETIC RELATIONSHIPS BETWEEN PARASITE VIRULENCE AND TRANSMISSION IN THE RODENT MALARIA PLASMODIUM CHABAUDI. AB - Many parasites evolve to become virulent rather than benign mutualists. One of the major theoretical models of parasite virulence postulates that this is because rapid within-host replication rates are necessary for successful transmission (parasite fitness) and that virulence (damage to the host) is an unavoidable consequence of this rapid replication. Two fundamental assumptions underlying this so-called evolutionary trade-off model have rarely been tested empirically: (1) that higher replication rates lead to higher levels of virulence; and (2) that higher replication rates lead to higher transmission. Both of these relationships must have a genetic basis for this evolutionary hypothesis to be relevant. These assumptions were tested in the rodent malaria parasite, Plasmodium chabaudi, by examining genetic relationships between virulence and transmission traits across a population of eight parasite clones isolated from the wild. Each clone was injected into groups of inbred mice in a controlled laboratory environment, and replication rate (measured by maximum asexual parasitemia), virulence (measured by live-weight loss and degree of anemia in the mouse), and transmission (measured by density of sexual forms, gametocytes, in the blood and proportion of mosquitoes infected after taking a blood-meal from the mouse) were assessed. It was found that clones differed widely in these traits and these clone differences were repeatable over successive blood passages. Virulence traits were strongly phenotypically and genetically (i.e., across clones) correlated to maximum parasitemia thus supporting the first assumption that rapid replication causes higher virulence. Transmission traits were also positively phenotypically and genetically correlated to parasitemia, which supports the second assumption that rapid replication leads to higher transmission. Thus, two assumptions of the parasite centered trade-off model of the evolution of virulence were shown to be justified in malaria parasites. PMID- 28565638 TI - COMPARATIVE GEOGRAPHIC STRUCTURES OF TWO PARASITOID-HOST INTERACTIONS. AB - Recent studies of parasitoid-host interactions have demonstrated that parasitoids and their hosts are geographically structured for traits such as virulence and encapsulation defenses, but no studies have yet compared the geographic structure of parasitoids and hosts using neutral genetic markers. Such studies of geographic structure are needed to evaluate the underlying geographic scale at which these interactions evolve and allow assessment of the relative effects of selection and gene flow on the geographic structure observed in traits under selection. We used sequence data from the mitochondrial DNA cytochrome oxidase I and II subunits to document and compare the geographic structures of the parasitoid Agathis thompsoni and its moth host Greya subalba. We also documented the geographic structure of G. enchrysa and compared it to the geographic structure of its parasitoid Agathis n. sp. The results demonstrated that parasitoids and their hosts may have incongruent patterns of geographic structure as assessed by molecular markers. As a consequence, the geographic scale at which the interaction evolves may be different for each species involved in the interaction. Depending on the interplay of selection and gene flow, there may not be a one-to-one correspondence of traits important in the interaction between parasitoids and their hosts at the level of local populations. The geographic structures of A. thompsoni and G. subalba and Agathis n. sp. and G. enchrysa provide further evidence of the potential importance of the formation of geographic mosaics in coevolving parasitoid-host interactions and evolving interactions in general. PMID- 28565639 TI - POLYTOMIES AND THE POWER OF PHYLOGENETIC INFERENCE. AB - Although phylogenetic hypotheses can provide insights into mechanisms of evolution, their utility is limited by our inability to differentiate simultaneous speciation events (hard polytomies) from rapid cladogenesis (soft polytomies). In the present paper, we tested the potential for statistical power analysis to differentiate between hard and soft polytomies in molecular phytogenies. Classical power analysis typically is used a priori to determine the sample size required to detect a particular effect size at a particular level of significance (a) with a certain power (1 - beta). A posteriori, power analysis is used to infer whether failure to reject a null hypothesis results from lack of an effect or from insufficient data (i.e., low power). We adapted this approach to molecular data to infer whether polytomies result from simultaneous branching events or from insufficient sequence information. We then used this approach to determine the amount of sequence data (sample size) required to detect a positive branch length (effect size). A worked example is provided based on the auklets (Charadriiformes: Alcidae), a group of seabirds among which relationships are represented by a polytomy, despite analyses of over 3000 bp of sequence data. We demonstrate the calculation of effect sizes and sample sizes from sequence data using a normal curve test for difference of a proportion from an expected value and a t-test for a difference of a mean from an expected value. Power analyses indicated that the data for the auklets should be sufficient to differentiate speciation events that occurred at least 100,000 yr apart (the duration of the shortest glacial and interglacial events of the Pleistocene), 2.6 million years ago. PMID- 28565640 TI - ECOLOGICAL GENETICS OF GYNODIOECY IN SILENE VULGARIS: RELATIVE FITNESS OF FEMALES AND HERMAPHRODITES DURING THE COLONIZATION PROCESS. AB - Recent theoretical models have addressed the influence of metapopulation dynamics on the fitness of females and hermaphrodites in gynodioecious plants. In particular, selection is thought to favor hermaphrodites during population establishment because that sex should be less prone to pollen limitation, especially if self-fertilization is possible. However, inbreeding depression could limit this advantage. In this experimental study of Silene vulgaris, a weedy gynodioecious plant, the fitness of females and hermaphrodites was estimated from seed production in both mixed-sex populations and for individuals isolated from these populations by 20, 40, 80, or 160 m. In mixed populations females display statistically significant greater per capita seed production owing to higher capsule production and higher rates of seed germination. The fitness of both sexes declines with increasing isolation, but at different rates, such that in the 160-m treatment hermaphrodites are by far the more fit sex. Allozyme studies suggest that this differential decline is because the selfing rate in hermaphrodites increases as a function of isolation, at least partially compensating for a decline in the availability of outcross pollen. Overall, the negative effects of pollen limitation on females far outweighs the negative effects of inbreeding depression following selfing in hermaphrodites. Thus, extinction/recolonization dynamics would appear to favor hermaphrodites as long as seed dispersal events exceed some critical distance. PMID- 28565641 TI - TEMPERATURE EFFECTS AND GENOTYPE-BY-ENVIRONMENT INTERACTIONS IN HYBRIDS: HALDANE'S RULE IN FLOUR BEETLES. AB - When males of the flour beetle, Tribolium castaneum, are crossed to females of its close relative T. freemani, the sex ratio of the hybrids is female biased, owing in part to hybrid male mortality. Morphological abnormalities are also frequent in the surviving hybrid males, but not in the hybrid females. The finding that the heterogametic sex (male) is more adversely affected in interspecific crosses than the homogametic sex is consistent with Haldane's rule, which predicts that hybrid dysfunction should emerge as an indirect byproduct of divergent adaptation to differing environments. If so, environmental effects and genotype-by-environment interactions (GEI) should characterize the expression of Haldane's rule and interspecific hybrid traits in general. We used two wild collected populations of T. castaneum (from Infantes, Spain, and Madagascar) to investigate the effects of environmental variation on the expression of Haldane's rule. Males from each population were mated to several T. freemani females and the half-sibling hybrid progenies were reared across a series of temperature regimes. For both populations, we found that hybrids raised at higher temperatures exhibited a more extreme expression of Haldane's rule: The hybrid sex ratios were more biased toward females and hybrid males had a much higher incidence of morphological abnormalities. The average response to temperature, the norm of reaction for Haldane's rule, varied between the two populations, and we found considerable and significant GEI for both hybrid traits within both populations. The evolutionary implications of these findings are discussed in the context of speciation arising as an indirect effect of local adaptation. PMID- 28565642 TI - MAGNITUDE AND TIMING OF INBREEDING DEPRESSION IN SCOTS PINE (PINUS SYLVESTRIS L.). AB - Inbreeding depression is a major selective force favoring outcrossing in flowering plants. However, some self-fertilization should weaken the harmful effects of inbreeding by exposing deleterious alleles to selection. This study examines the maintenance of inbreeding depression in the predominantly outcrossing species Pinus sylvestris L. (Scots pine). Open-pollinated and self fertilized progeny of 23 maternal trees, originating from a natural stand in southern Finland, were grown at two sites. We observed significant inbreeding depression in two of the four life stages measured. Inbreeding depression was largest for seed maturation (delta = 0.74), where seedset in open-pollinated strobili (70.9%) was about four times higher than in selfed strobili (18.3%). Inbreeding depression in postgermination survival (upto an age of 23 years) was also high (delta = 0.62-0.75). No significant differences in height (delta = 0.05) or flowering (delta = 0.14) of the trees after 23 years were observed. Cumulative inbreeding depression was high (delta = 0.90-0.94) and differed significantly among maternal families (range 0.45-1.00). The magnitude of inbreeding depression among the 23 maternal parents was not significantly correlated between early (seed maturation) and later (postgermination survival) life stages, suggesting that its genetic basis varies across the life cycle. Size differences among the progeny types diminished in time due to nonrandom size specific mortality, causing a decrease in the inbreeding depression estimates for height over time. Our results indicate that Scots pine exhibits high levels of inbreeding depression during both early and later stages of the life cycle. It is argued that self-fertilization in Scots pine is inefficient in purging the genetic load caused by highly deleterious mutations because of the nearly complete loss of selfed individuals over time. This results in an effectively random mating outcrossing population. PMID- 28565643 TI - SEXUAL SELECTION AGAINST HYBRIDS BETWEEN SYMPATRIC STICKLEBACK SPECIES: EVIDENCE FROM A FIELD EXPERIMENT. AB - Sexual selection against viable, fertile hybrids may contribute to reproductive isolation between recently diverged species. If so, then sexual selection may be implicated in the speciation process. Laboratory measures of the mating success of hybrids may underestimate the amount of sexual selection against them if selection pressures are habitat specific. Male F1 hybrids between sympatric benthic and limnetic sticklebacks (Gasterosteus aculeatus complex) do not suffer a mating disadvantage when tested in the laboratory. However, in the wild males choose different microhabitats and parental females tend to be found in the same habitats as conspecific males. This sets up the opportunity for sexual selection against male hybrids because they must compete with parental males for access to parental females. To test for sexual selection against adult F1 hybrid males, we examined their mating success in enclosures in their preferred habitat (open, unvegetated substrate) where limnetic males and females also predominate. We found significantly reduced mating success in F1 hybrid males compared with limnetic males. Thus, sexual selection, like other mechanisms of postzygotic isolation between young sister species, may be stronger in a wild setting than in the laboratory because of habitat-specific selection pressures. Our results are consistent with, but do not confirm, a role for sexual selection in stickleback speciation. PMID- 28565644 TI - THE ENDOCRINE GENETICS OF WING POLYMORPHISM IN GRYLLUS: CRITIQUE OF RECENT STUDIES AND STATE OF THE ART. PMID- 28565645 TI - OPTIMAL REPRODUCTIVE EFFORT IN STOCHASTIC, DENSITY-DEPENDENT ENVIRONMENTS. AB - The amount of effort organisms should put into reproducing at any given time has been a matter of debate for many years. Early models suggested a simple rule of thumb: iteroparity should be favored when juvenile survival is relatively variable and semelparity when adult survival is relatively variable. When more mathematically complex models were developed, these simple conclusions were found to be special cases. Variability can select toward iteroparity or semelparity depending on a number of factors irrespective of relative adult/juvenile survival (e.g, the density-independent models of Orzack and Tuljapurkar). Using new techniques, we estimate the ESS reproductive effort for stage-structured models in density-dependent and stochastic conditions. We find that variability causes significant changes in reproductive effort, these changes are often small (+/- 10% of determinstic ESS effort, but up to 50% change in some instances), and the amount that effort increases or decreases depends on many factors (e.g., the deterministic population dynamics, the vital rates affected by density, the amount of variation, the correlations between the vital rates, the distribution from which the variation is drawn, and the deterministic ESS effort). In a variable environment, semelparity is the ESS in only 3.5% of cases; iteroparity is the rule. PMID- 28565646 TI - PHYLOGEOGRAPHY OF THE PANTROPICAL SEA URCHIN EUCIDARIS IN RELATION TO LAND BARRIERS AND OCEAN CURRENTS. AB - The pantropical sea urchin genus Eucidaris contains four currently recognized species, all of them allopatric: E. metularia in the Indo-West Pacific, E. thouarsi in the eastern Pacific, E. tribuloides in both the western and eastern Atlantic, and E. clavata at the central Atlantic islands of Ascension and St. Helena. We sequenced a 640-bp region of the cytochrome oxidase I (COI) gene of mitochondrial DNA to determine whether this division of the genus into species was confirmed by molecular markers, to ascertain their phylogenetic relations, and to reconstruct the history of possible dispersal and vicariance events that led to present-day patterns of species distribution. We found that E. metularia split first from the rest of the extant species of the genus. If COI divergence is calibrated by the emergence of the Isthmus of Panama, the estimated date of the separation of the Indo-West Pacific species is 4.7-6.4 million years ago. This date suggests that the last available route of genetic contact between the Indo-Pacific and the rest of the tropics was from west to east through the Eastern Pacific Barrier, rather than through the Tethyan Sea or around the southern tip of Africa. The second cladogenic event was the separation of eastern Pacific and Atlantic populations by the Isthmus of Panama. Eucidaris at the outer eastern Pacific islands (Galapagos, Isla del Coco, Clipperton Atoll) belong to a separate clade, so distinct from mainland E. thouarsi as to suggest that this is a different species, for which the name E. galapagensis is revived from the older taxonomic literature. Complete lack of shared alleles in three allozyme loci between island and mainland populations support their separate specific status. Eucidaris galapagensis and E. thouarsi are estimated from their COI divergence to have split at about the same time that E. thouarsi and E. tribuloides were being separated by the Isthmus of Panama. Even though currents could easily convey larvae between the eastern Pacific islands and the American mainland, the two species do not appear to have invaded each other's ranges. Conversely, the central Atlantic E. clavata at St. Helena and Ascension is genetically similar to E. tribuloides from the American and African coasts. Populations on these islands are either genetically connected to the coasts of the Atlantic or have been colonized by extant mitochondrial DNA lineages of Eucidaris within the last 200,000 years. Although it is hard to explain how larvae can cross the entire width of the Atlantic within their competent lifetimes, COI sequences of Eucidaris from the west coast of Africa are very similar to those of E. tribuloides from the Caribbean. FST statistics indicate that gene flow between E. metularia from the Indian Ocean and from the western and central Pacific is restricted. Low gene flow is also evident between populations of E. clavata from Ascension and St. Helena. Rates of intraspecific exchange of genes in E. thouarsi, E. galapagensis, and E. tribuloides, on the other hand, are high. The phylogeny of Eucidaris confirms Ernst Mayr's conclusions that major barriers to the dispersal of tropical echinoids have been the wide stretch of deep water between central and eastern Pacific, the cold water off the southwest coast of Africa, and the Isthmus of Panama. It also suggests that a colonization event in the eastern Pacific has led to speciation between mainland and island populations. PMID- 28565648 TI - RECENT BOOKS IN PRINT. PMID- 28565647 TI - PHYLOGEOGRAPHY OF SPOTTED OWL (STRIX OCCIDENTALIS) POPULATIONS BASED ON MITOCHONDRIAL DNA SEQUENCES: GENE FLOW, GENETIC STRUCTURE, AND A NOVEL BIOGEOGRAPHIC PATTERN. AB - Mitochondrial DNA control region sequences of spotted owls (Strix occidentalis) allowed us to investigate gene flow, genetic structure, and biogeographic relationships among these forest-dwelling birds of western North America Estimates of gene flow based on genetic partitioning and the phylogeography of haplotypes indicate substantial dispersal within three long-recognized subspecies. However, patterns of individual phyletic relationships indicate a historical absence of gene flow among the subspecies, which are essentially monophyletic. The pattern of haplotype coalescence enabled us to identify the approximate timing and direction of a recent episode of gene flow from the Sierra Nevada to the northern coastal ranges. The three subspecies comprise phylogenetic species, and the northern spotted owl (S. o. caurina) is sister to a clade of California (S. o. occidentalis) plus Mexican spotted owls (S o lucida); this represents a novel biogeographic pattern within birds. The California spotted owl had substantially lower nucleotide diversity than the other two subspecies; this result is inconsistent with present patterns of population density A causal explanation requires postulating a severe bottleneck or a selective sweep, either of which was confined to only one geographic region. PMID- 28565649 TI - PHYLOGENETIC ANALYSIS OF TRAIT EVOLUTION AND SPECIES DIVERSITY VARIATION AMONG ANGIOSPERM FAMILIES. AB - Angiosperm families differ greatly from one another in species richness (S). Previous studies have attributed significant components of this variation to the influence of pollination mode (biotic/abiotic) and growth form (herbaceous/woody) on speciation rate, but these results suffer difficulties of interpretation because all the studies ignored the phylogenetic relationships among families. We use a molecular phylogeny of the angiosperm families to reanalyse correlations between S and family-level traits and use reconstructions of trait evolution to interpret the results. We confirm that pollination mode and growth form are correlated with S and show that the majority of changes in pollination mode involved a change from biotic to abiotic pollination with an associated fall in speciation rate. The majority of growth form changes involved the evolution of herbaceousness from woodiness with a correlated rise in speciation rate. We test the hypothesis of Ricklefs and Renner (1994) that "evolutionary flexibility" rather than other trait changes triggered increased speciation rates in some families, but find little support for the hypothesis. PMID- 28565650 TI - ALLOZYME AND ADVERTISEMENT CALL VARIATION IN THE TUNGARA FROG, PHYSALAEMUS PUSTULOSUS. AB - We analyzed variation in advertisement calls and allozymes in 30 populations along a 5000-km transect throughout most of the range of the tungara frog, Physalaemus pustulosus. All 12 call variables measured show significant differences among populations despite the importance of the advertisement call in species recognition. Some call variables exhibited clinal variation, whereas most others differed between the two major allozyme groups that have invaded Panama at different times, perhaps 4-4.5 million yr apart. Call variables that primarily affect discrimination among conspecifics tended to exhibit greater variation than call variables that are crucial for species recognition. The proximate mechanism of production underlying a call variable, however, is a better predictor of its variation. Contrary to predictions of some sexual selection models, call variation exhibits predictable patterns of geographical variation, although a substantial portion of variation among populations is not explained by geographic position. Although allozymes, calls, and geography usually covary, closer populations can have more similar calls independent of allozyme similarity. PMID- 28565651 TI - APPARENT DIRECTIONAL SELECTION OF BODY SIZE IN DROSOPHILA BUZZATII: LARVAL CROWDING AND MALE MATING SUCCESS. PMID- 28565653 TI - SELECTION FOR HEAT-SHOCK RESISTANCE IN LARVAL AND IN ADULT DROSOPHILA BUZZATII: COMPARING DIRECT AND INDIRECT RESPONSES. AB - Direct and correlated responses in selection for heat-shock resistance in adult and in larval Drosophila buzzatii were studied. Two lines were artificially selected for higher survival to heat stress as adults, and two other lines were reared under a fluctuating thermal environment as larvae, 35 degrees C for 6 h and 25 degrees C for 18 h, to "naturally" select for higher resistance as larvae. The latter two lines were duplicated after nine generations to yield additional lines to be "naturally" selected as larvae at a higher temperature, 38.2 degrees C for 6 h. Control lines were maintained separately for the adult and larval selection lines. A significant direct response to selection was found for the adult selection lines. However, larvae of these adult selection lines were no more heat resistant than were larvae of the control lines. One of the two larval selection lines increased significantly in heat resistance as larvae. However, adult heat resistance was similar for lines selected as larvae and the corresponding control lines maintained at 25 degrees C. Changes in developmental time accompanied changes in survival after stress in both sets of lines selected for increased heat resistance. PMID- 28565652 TI - EVOLUTIONARY GENETICS OF ALLORECOGNITION IN THE COLONIAL HYDROID HYDRACTINIA SYMBIOLONGICARPUS. AB - Many sedentary, clonal marine invertebrates compete intensively with conspecifics for habitable space. Allorecognition systems mediate the nature and outcome of these intraspecific competitive interactions, such that the initiation of agonistic behavior and the potential for intergenotypic fusion depend strongly on the relatedness of the contestants. The dependence of these behaviors on relatedness, along with the extraordinary precision with which self can be discriminated from nonself, suggest that allorecognition systems are highly polymorphic genetically. However, allotypic specificity of this sort could be produced by any number of genetic scenarios, ranging from relatively few loci with abundant allelic variation to numerous loci with relatively few alleles per locus. At this point, virtually nothing is known of the formal genetics of allorecognition in marine invertebrates; consequently, the evolutionary dynamics of such systems remain poorly understood. In this paper, we characterize the formal genetics of allorecognition in the marine hydrozoan Hydractinia symbiolongicarpus. Hydractinia symbiolongicarpus colonizes gastropod shells occupied by hermit crabs. When two or more individuals grow into contact, one of three outcomes ensues: fusion (compatibility), transitory fusion (a temporary state of compatibility), and rejection (incompatibility, often accompanied by the production of agonistic structures termed hyperplastic stolons). Observed patterns of compatibility between unrelated, half-sib pairs, and full-sib pairs show that unrelated and half-sib pairs under laboratory culture have a very low probability of being fusible, whereas full sibs have a roughly 30% rate of fusion in experimental pairings. The genetic simulations indicate that roughly five loci, with 5-7 alleles per locus, confer specificity in this species. In ecological terms, the reproductive ecology of H. symbiolongicarpus should promote the cosettlement of kin, some of which should be full sibs, and some half sibs. Thus, there is potential for kin selection to play a major role in the evolution of the H. symbiolongicarpus allorecognition system. In genetic terms, this system conforms to theoretical predictions for a recognition system selected to distinguish among classes of kin, in addition to self from nonself. PMID- 28565654 TI - COMPETITION BETWEEN SEGREGATION DISTORTERS: COEXISTENCE OF "SUPERIOR" AND "INFERIOR" HAPLOTYPES AT THE t COMPLEX. AB - By means of population genetical models, we investigate the competition between sex-specific segregation distorters. Although the models are quite general, they are motivated by a specific example, the t complex of the house mouse. Some variants at this gene complex, the t haplotypes, distort Mendelian segregation in heterozygous males in their favor. The selective advantage at the gamete level is counterbalanced by strong negative fitness effects at the individual level (male sterility or even lethality in both sexes). A plethora of different t haplotypes has been found, both in the field and in the lab. Up to now, however, models have focused on the equilibrium frequency of a single t haplotype. In contrast, we explicitly model the competition between several t haplotypes. A deterministic model for a large, well-mixed population predicts a surprisingly high degree of polymorphism. Haplotypes with seemingly inferior fitness characteristics may easily coexist with "superior" haplotypes. For instance, a lethal haplotype with a low segregation ratio may stably coexist with a sterile haplotype with a high segregation ratio. Stable coexistence is even possible for haplotypes with a segregation disadvantage. A simple stochastic model shows that the same principles apply in the context of a structured metapopulation. Although counterintuitive at first sight, all our results can be explained by the fact that segregation distorters have an inherent advantage when they are rare. We conclude that fitness comparisons are not sufficient to predict the outcome of competition when selective forces are acting at different levels. PMID- 28565655 TI - NATURAL HERITABILITIES: CAN THEY BE RELIABLY ESTIMATED IN THE LABORATORY? AB - The validity of the assumption, that laboratory estimates of heritabilities will tend to overestimate natural heritabilities, due to a reduction in environmental variability and thus the phenotypic variance of traits, is examined. One hundred sixty-five field estimates of narrow sense heritabilities derived from the literature are compared with 189 estimates from laboratory studies on wild, outbred animal populations derived from the data set of Mousseau and Roff. The results indicate that 84% of field heritabilities are significantly different from zero and that for morphological, behavioral, and life-history traits there are no significant differences between laboratory and field estimates of heritability. Unexpectedly, mean heritabilities for morphological and life history traits are actually higher in the field than in the lab. Twenty-two cases were found for which both laboratory and natural heritabilities had been estimated on the same traits. For this subset of the data, laboratory heritabilities tended to be higher than field estimates, but the difference was not significant. Also, the correlation between lab and field estimates was high (r = 0.6, P < 0.001), and the regression slope did not differ significantly from one. The major implications of this study are that laboratory estimates of heritability should generally provide reasonable estimations of both the magnitude and the significance of heritabilities in nature. PMID- 28565656 TI - MULTIPLE ORIGINS OF GENDER-ASSOCIATED MITOCHONDRIAL DNA LINEAGES IN BIVALVES (MOLLUSCA: BIVALVIA). AB - Previous studies have shown that marine mussels (genus Mytilus) and a freshwater mussel (Pyganodon grandis) contain two distinct gender-associated mitotypes, which is a characteristic feature of the phenomenon of doubly uniparental inheritance (DUI) of mitochondrial DNA (mtDNA). Here we present evidence for the presence of distinct male (M) and female (F) mitotypes in three other bivalve species, the mytilid Geukensia demissa, and the unionid species P. fragilis and Fusconaia flava. Nucleotide sequences of a segment of the COI gene from the M and F mitotypes from each of the three mytilid species (M. edulis, M. trossulus, G. demissa) and three unionid species (P. grandis, P. fragilis, F. flava) were used for phylogenetic analysis. The analysis suggests three independent origins of M and F mitotypes for the six species examined; one for the three unionid species, one for the two Mytilus species, and one for Geukensia. The first of these F/M divergence events, while of uncertain age, predates the divergence of the two unionid genera and is likely older than either of the two F/M divergence events in the mytilid taxa. The most parsimonious explanation of multiple F/M divergence events is that they represent independent origins of DUI. Another possibility is that, in a given taxon, an F or M mitotype assumes the role of the opposite mitotype (by virtue of a mechanism that remains to be clarified) and subsequently was fixed within its new gender. The fixation of a mtDNA lineage derived from a mitotype of switched function would reset the divergence of the gender-associated lineages to zero, thereby mimicking a de novo split of F and M lineages from a preexisting mtDNA genome that was not gender specific. Further broad-scale taxonomic studies of the occurrence of distinct M and F mitotypes may allow for the evaluation of the latter hypothesis. PMID- 28565657 TI - FEMALE CHOICE FOR AN INDICATOR OF MALE SIZE IN THE SONG OF THE BLACK-HORNED TREE CRICKET, OECANTHUS NIGRICORNIS (ORTHOPTERA: GRYLLIDAE: OECANTHINAE). AB - The calling song of male crickets, including Oecanthus nigricornis (Walker), attracts females for mating and provides a model system of sexual communication. We give the first conclusive identification of a feature of cricket song that is both attractive to females and indicates a phenotypic feature (body size) that determines male mating success and female reproductive benefits. We do this by first testing for correlations between song characteristics and aspects of male phenotype that are hypothesized to indicate male quality. We show that song is a reliable indicator of male size and male age, and that large male size is associated with increased female fecundity. We then use playbacks of synthetic songs that mimic natural variation in song parameters to study song preferences and we compare preferences under different presentation regimes to determine whether choices are based on relative song quality or some fixed criterion. Females show a preference for the lower frequency songs produced by large males, but only during simultaneous playbacks. Thus female choice is based on the relative quality of calls that can be sampled simultaneously. These results provide strong support for the hypothesis that females use variation in calling song to assess male mate quality. PMID- 28565658 TI - CHLOROPLAST DNA PHYLOGEOGRAPHY OF THE COMMON BEECH (FAGUS SYLVATICA L.) IN EUROPE. PMID- 28565659 TI - HIERARCHICAL ANALYSIS OF INBREEDING DEPRESSION IN PEROMYSCUS POLIONOTUS. AB - The severity of inbreeding depression appears to vary among taxa, but few ecological or other patterns have been identified that predict accurately which taxa are most sensitive to inbreeding. To examine the causes of heterogeneity in inbreeding depression, the effects of inbreeding on reproduction, survival, and growth were measured in three replicate experimental stocks for each of three subspecies of Peromyscus polionotus mice. Inbreeding of the dam reduced the probability of breeding, the probability of producing a second litter, and litter size. Inbreeding of the litter caused depression of litter size, juvenile viability, and mass at weaning, and caused an increase in the within-litter variance in mass. In spite of differences between the subspecies in natural population sizes, genetic variation, and mean rates of reproduction and survival, all variation observed between experimental populations in their responses to inbreeding could be attributed to random founder effects. The genetic load of deleterious alleles in each replicate was unequally partitioned among its founder pairs, and different founders contributed to the load affecting different fitness components. Thus, inbreeding depression for any one fitness component, in our experimental environment, must be due to relatively few deleterious alleles with major effects. Genetic loads so comprised would be expected to diverge among natural populations due to both random drift and selective removal of recessive deleterious alleles during population bottlenecks. The near universality of inbreeding depression would be maintained, however, if different alleles contribute to inbreeding depression of different fitness components and in different environments. PMID- 28565661 TI - LATITUDINAL VARIATION IN DEVELOPMENTAL TIME AND MASS IN DROSOPHILA MELANOGASTER. PMID- 28565662 TI - ECOLOGICAL AND GENETIC CONSEQUENCES OF POLLINATION BY SEXUAL DECEPTION IN THE ORCHID CALADENIA TENTACTULATA. AB - Only orchids affect pollination by the deceptive sexual attraction of male insects, a syndrome particularly well developed in Australia. We examined the ecological and genetic consequences of exclusive pollination by sexually attracted male thynnine wasps in the orchid Caladenia tentaculata. Male wasps respond rapidly to flowers artificially presented in 1 * 1 m2 experimental patches. Sixty of 287 wasps approached within centimeters of the flower, but did not land. Of the remaining 79% who made floral contact, only 7.5% attempted copulation, the step critical for pollination. Wasps only rarely moved among patches (19% of flights) and none attempted copulation a second time, resembling observations in natural populations. We confirmed outcrossing and long distance pollen flow by monitoring how colored pollen moved in natural populations. Pollen movements approximated a linear rather than a leptokurtic distribution (mean distance: 17 m; maximum: 58 m). Pollinator visits varied independently of flower density in three of four populations with most solitary flowers being visited. Allozyme analysis revealed within-population fixation indices (F) close to zero and low levels of differentiation (FST) among populations. Despite behavioral evidence for long distance pollen flow, significant local genetic structure exists, perhaps reflecting restricted seed dispersal. Long distance pollen flow in C. tentaculata may therefore promote outbreeding by minimizing pollen transfers among related neighbors. Although this species is self-compatible, outcrossed progeny develop significantly faster than selfed progeny. Effective pollination at low flower densities could accentuate this advantage. The data are consistent with the predictions that deceptive pollination will result in long distance pollen flow, which may be of selective advantage at low density. Comparative studies of how food reward, food deceptive, and sexual deceptive pollination systems vary within a phylogenetic framework could further illuminate the evolution of sexual deception. PMID- 28565663 TI - GROWTH TEMPERATURE AND ADULT PIGMENTATION IN TWO DROSOPHILA SIBLING SPECIES: AN ADAPTIVE CONVERGENCE OF REACTION NORMS IN SYMPATRIC POPULATIONS? AB - Phenotypic plasticity of abdomen pigmentation was investigated in populations of the sibling species Drosophila melanogaster and D. simulans, living in sympatry in two French localities. Ten isofemale lines of each population and species were grown at different constant temperatures spanning their complete thermal range from 12 to 31 degrees C. Genetic variability between isofemale lines was not affected by growth temperature, but was consistently less in D. simulans. For all traits, the dark pigmentation of the abdominal segments decreased according to growth temperature, in agreement with the thermal budget adaptive hypothesis. The shapes of the response curves were different between the abdominal segments, but for a given segment, quite similar in the two species. On average D. simulans was lighter than D. melanogaster, but the difference was mainly expressed at higher temperatures. An interesting result was the difference observed between the two localities: flies from the colder locality (Villeurbanne) were found to be darker than flies from the warmer locality (Bordeaux). Interestingly, this difference was expressed only at low temperatures, 21 degrees C and below, that is, at temperatures encountered in natural conditions. This suggests an adaptive response resulting in a change of the shape of reaction norm and involving genotype-environment interactions. When comparing the genetic structure of geographic populations for quantitative traits, several laboratory environments should be preferred to a single one. PMID- 28565664 TI - CULTURAL INHERITANCE OF SONG AND ITS ROLE IN THE EVOLUTION OF DARWIN'S FINCHES. AB - Songs of Darwin's finches were studied on the Galapagos Island of Daphne Major from 1976 to 1995. A single, structurally simple, and unvarying song is sung throughout life by each male of the two common species, Geospiza fortis (medium ground finch) and G. scandens (cactus finch). Songs of the two species differ strongly in quantitative features, and individual variation among males is much broader in G. fortis than in G. scandens. Although there are exceptions, songs of sons strongly resemble the songs of their fathers. They also resemble the songs of their paternal grandfathers, but not their maternal grandfathers, indicating that they are culturally inherited and not genetically inherited. Female G. fortis display a tendency to avoid mating with males that sing the same type of song as their father. They also avoid mating with males that sing heterospecific song, with very rare exceptions. Thus song, an evolving, culturally inherited trait, is an important factor in species recognition and mate choice. It constrains the mating of females to conspecifics, even when there is no genetic penalty to interbreeding, and thus may play a crucial role in species formation by promoting genetic isolation on secondary contact. The barrier is leaky in that occasional errors in song transmission result in misimprinting, which leads to a low incidence of hybridization and introgression. Introgression slows the rate of postzygotic isolation, but can produce individuals in novel genetic and morphological space that can provide the starting point of a new evolutionary trajectory. PMID- 28565665 TI - PATTERNS IN PHYLOGENETIC TREE BALANCE WITH VARIABLE AND EVOLVING SPECIATION RATES. AB - Aspects of phylogenetic tree shape, and in particular tree balance, provide clues to the workings of the macroevolutionary process. I use a simulation approach to explore patterns in tree balance for several models of the evolutionary process under which speciation rates vary through the history of diversifying clades. I demonstrate that when speciation rates depend on an evolving trait of individuals, and are therefore "heritable" along evolutionary lineages, the resulting phylogenies become imbalanced. However, imbalance also results from some (but not all) models of "nonheritable" speciation rate variation. The degree of imbalance increases with the magnitude of speciation rate variation, and then for gradual evolution (but not punctuated equilibria) reaches an asymptote short of the theoretical maximum. Very high levels of rate variation are required to produce imbalance matching that found in real data (estimated phylogenies from the systematic literature). I discuss implications of the simulation results for our understanding of macroevolution. PMID- 28565666 TI - GENETIC POPULATION STRUCTURE AND GRADUAL NORTHWARD DECLINE OF GENETIC VARIABILITY IN THE GREENFINCH (CARDUELIS CHLORIS). PMID- 28565667 TI - THE GEOGRAPHY OF COEVOLUTION: COMPARATIVE POPULATION STRUCTURES FOR A SNAIL AND ITS TREMATODE PARASITE. AB - Gene flow and the genetic structure of host and parasite populations are critical to the coevolutionary process, including the conditions under which antagonistic coevolution favors sexual reproduction. Here we compare the genetic structures of different populations of a freshwater New Zealand snail (Potamopyrgus antipodarum) with its trematode parasite (Microphallus sp.) using allozyme frequency data. Allozyme variation among snail populations was found to be highly structured among lakes; but for the parasite there was little allozyme structure among lake populations, suggesting much higher levels of parasite gene flow. The overall pattern of variation was confirmed with principal component analysis, which also showed that the organization of genetic differentiation for the snail (but not the parasite) was strongly related to the geographic arrangement of lakes. Some snail populations from different sides of the Alps near mountain passes were more similar to each other than to other snail populations on the same side of the Alps. Furthermore, genetic distances among parasite populations were correlated with the genetic distances among host populations, and genetic distances among both host and parasite populations were correlated with "stepping stone" distances among lakes. Hence, the host snail and its trematode parasite seem to be dispersing to adjacent lakes in a stepping-stone fashion, although parasite dispersal among lakes is clearly greater. High parasite gene flow should help to continuously reintroduce genetic diversity within local populations where strong selection might otherwise isolate "host races." Parasite gene flow can thereby facilitate the coevolutionary (Red Queen) dynamics that confer an advantage to sexual reproduction by restoring lost genetic variation. PMID- 28565668 TI - SIMPLE GENETIC BASIS FOR IMPORTANT SOCIAL TRAITS IN THE FIRE ANT SOLENOPSIS INVICTA. AB - Variation in queen phenotype and reproductive role in the fire ant Solenopsis invicta has been shown to have a simple genetic basis in a single introduced population in the United States. The evidence consists of an association between this variation and queen genotype at Pgm-3, a phosphoglucomutase-encoding gene. In the present study, we surveyed Pgm-3 allele and genotype frequencies in diverse populations from the native and introduced ranges of this ant to learn whether this simple genetic basis for reproductive traits is a general feature of the species or a genetic anomaly in introduced ants stemming from a recent bottleneck or the invasion of novel habitats. No egg-laying queens living in polygyne (multiple-queen) nests possessed the homozygous genotype Pgm-3a/a in any of the study populations, yet nonreproductive females from such nests (workers as well as queens that had not yet initiated oogenesis) possessed this genotype at moderate frequencies. Remarkably, Pgm-3a/a was the most common genotype among all classes of females, including egg-laying queens, in monogyne (single-queen) nests from all populations studied. Genotype proportions at Pgm-3 in polygyne populations typically departed strongly from the proportions expected under Hardy Weinberg equilibrium, whereas those in monogyne populations did not. These patterns establish that a single mendelian gene influences queen reproductive role in S. invicta and that this gene uniformly is under strong directional selection in the polygyne social form only. Moreover, the perfect association of Pgm-3 genotype and reproductive role in all populations, combined with the known function of phosphoglucomutase in insect metabolism, suggest that this gene may directly influence queen phenotypes rather than merely serving as a marker for a linked gene that causes the effects. PMID- 28565669 TI - TEMPORAL INSTABILITY OF GENETIC COMPONENTS OF FLORAL TRAIT VARIATION: MATERNAL FAMILY AND POPULATION EFFECTS IN SPERGULARIA MARINA (CARYOPHYLLACEAE). PMID- 28565670 TI - PATERNAL EFFECTS IN INHERITANCE OF A PATHOGEN RESISTANCE TRAIT IN IPOMOEA PURPUREA. AB - For continuously variable, polygenic characters, the response to selection depends upon the proportion of phenotypic variance that is caused by additive genetic variance, or narrow-sense heritability. Thus, a major goal of quantitative genetics is to partition phenotypic variance for a trait in a way that isolates additive genetic variance from other causes. The variance among paternal half-sib families, which is frequently used to estimate additive variance, is commonly recognized to include additive epistatic effects. However, this variance component can also include non-Mendelian paternal effects. We report here the results from a diallel crossing design used to isolate nonnuclear effects from the paternal nuclear contribution to disease resistance in the common morning glory, Ipomoea purpurea. In particular, we found that genetic variance for resistance to anthracnose, a disease caused by the fungal pathogen Colletotrichum dematium, was determined largely by a nonnuclear, additive paternal effect. We discuss potential mechanisms for this effect as well as some of their evolutionary implications. PMID- 28565671 TI - THE CONTRIBUTION OF NEW MUTATIONS TO GENOTYPE-ENVIRONMENT INTERACTION FOR FITNESS IN DROSOPHILA MELANOGASTER. AB - Many studies have documented the existence of genotype-environment interaction (GEI) for traits closely related to fitness in natural populations. A type of GEI that is commonly observed is changes in the fitness ranking of genetic groups (families, clones, or inbred lines) in different environments. We refer to such changes in ranking as crossing of reaction norms for fitness. A common interpretation of crossing of reaction norms for fitness is that selection favors different alleles in the different environments (i.e., that "trade-offs" exist). If this is the case, selection could maintain genetic variation, and even lead to reproductive isolation between subpopulations using different environments. Even if the same alleles are favored in every environment, however, deleterious mutations that vary in the magnitude of their effect depending on environment could cause reaction norms for fitness to cross. If deleterious mutations with environment-dependent effects are responsible for maintaining much of the variation leading to crossing of reaction norms for fitness in natural populations, it should be possible to observe crossing of reaction norms for fitness among otherwise genetically identical lines bearing newly arisen spontaneous mutations. We examined the contribution of new mutations to GEI for fitness in Drosophila melanogaster. Eighteen lines were derived from a common, highly inbred base stock, and maintained at a population size of 10 pairs for over 200 generations, to allow them to accumulate spontaneous mutations. Because of the small population size of the lines, selection against mildly deleterious mutations should have been relatively ineffective. The lines were tested for productivity (number of surviving adult progeny from a standard number of parents) in five different environmental treatments, comprising different food media, temperatures, and levels of competition. The lines showed highly significant GEI for productivity, owing largely to considerable changes in ranking in the different environments. We conclude that mutations that are deleterious on average, but whose quantitative effects depend on environment, could be responsible for maintaining much of the variation leading to crossing of reaction norms for fitness that has been observed in samples of D. melanogaster from the wild. PMID- 28565672 TI - POLLEN-TUBE COMPETITION, SIRING SUCCESS, AND CONSISTENT ASYMMETRIC HYBRIDIZATION IN LOUISIANA IRISES. AB - Postpollination mechanisms can play an important role in limiting natural hybridization in plants. Reciprocal hand pollination experiments were performed to study these mechanisms in two species of Louisiana iris: Iris brevicaulis and I. fulva. Relative pollen-tube growth rates changed significantly through time, with I. fulva tubes increasingly outperforming I. brevicaulis tubes in both conspecific and heterospecific styles. However, this pattern of change in relative performance was a poor predictor of siring success: the majority of seeds sired by both maternal species was conspecific rather than hybrid. Experimental crosses and field studies show consistent asymmetric hybridization in Louisiana irises, with I. fulva being a more successful father and a more selective mother than both I. brevicaulis and a third species, I. hexagona. The cause of this pattern is not yet clear, but the pattern itself is unusual. Typically, short-styled species tend to be less successful in reciprocal crosses than long-styled relatives, but I. fulva has shorter styles than either I. brevicaulis or I. hexagona. The effects of pollen-tube competition, differential fertilization, and selective abortion in causing this pattern of asymmetric hybridization is discussed. PMID- 28565673 TI - THERMAL EVOLUTION OF EGG SIZE IN DROSOPHILA MELANOGASTER. AB - We measured the size of eggs produced by populations of Drosophila melanogaster that had been collected along latitudinal gradients in different continents or that had undergone several years of culture at different temperatures in the laboratory. Australian and South American populations from higher latitudes produced larger eggs when all were compared at a standard temperature. Laboratory populations that had been evolving at 16.5 degrees C produced larger eggs than populations that had evolved at 25 degrees C or 29 degrees C, suggesting that temperature may be an important selective agent in producing the latitudinal clines. Flies from laboratory populations produced larger eggs at an experimental temperature of 16.5 degrees C than at 25 degrees C, and there was no indication of genotype-environment interaction for egg size. Evolution of egg size in response to temperature cannot be accounted for by differences in adult body size between populations. It is not clear which life-history traits are direct targets of thermal selection and which are showing correlated responses, and disentangling these is a task for the future. PMID- 28565674 TI - ECOLOGICAL DIVERSIFICATION AND COMMUNITY STRUCTURE IN THE OLD WORLD LEAF WARBLERS (GENUS PHYLLOSCOPUS): A PHYLOGENETIC PERSPECTIVE. AB - I investigated the historical basis for variation in regional species diversity. I used a molecular phylogenetic analysis within a single genus of birds (the Old World leaf warblers, genus Phylloscopus) in conjunction with ecological studies in Europe, the Himalayas, and Japan to evaluate the importance of historical events in shaping the present constellation of morphology and behavior in the three different regions. The relatively depauperate assemblages have different histories. In Japan, there was invasion of several lineages, which have more closely related species elsewhere in Asia, whereas in Europe there was also limited in situ speciation. Much of the structure of peripheral communities is attributable to invasions from species-rich Asia, with little in situ morphological diversification. Within the Phylloscopus there are several phylogenetic clades with nonoverlapping size distributions. Major ecological and morphological shifts occurred early in the history of diversification within the group, and rarely since. PMID- 28565675 TI - GOOD GENES AND DIRECT SELECTION IN THE EVOLUTION OF MATING PREFERENCES. AB - A model is used to study quantitatively the impact of a good genes process and direct natural selection on the evolution of a mating preference. The expression of a male display trait is proportional to genetic quality, which is determined by the number of deleterious mutations a male carries throughout his genome. Genetic variances and covariances, including the covariance between the preference and male trait that drives the good genes process, are allowed to evolve under an infinitesimal model. Results suggest that the good genes process generates only weak indirect selection on preferences, with an effective selection intensity of a few percent or less. If preferences are subject to direct natural selection of the intensity observed for other characters, the good genes process alone is not expected to exaggerate the male trait by more than a few phenotypic standard deviations, contrary to what is observed in highly sexually selected species. Good genes can, however, cause substantial exaggeration if preference genes are nearly selectively neutral. Alternatively, direct selection on preference genes, acting on mating behavior itself or on the genes' pleiotropic effects, can cause mating preferences and male display traits to be exaggerated by any degree. Direct selection of preference genes may therefore play an important role in species that show extreme sexual selection. PMID- 28565676 TI - EVOLUTION OF MALE PARENTAL CARE IN A BIRD WITH ALMOST COMPLETE CUCKOLDRY. PMID- 28565677 TI - PHYLOGENETIC ANALYSIS OF LEARNING-RELATED NEUROMODULATION IN MOLLUSCAN MECHANOSENSORY NEURONS. AB - In spite of significant advances in our understanding of mechanisms of learning and memory in a variety of organisms, little is known about how such mechanisms evolve. Even mechanisms of simple forms of learning, such as habituation and sensitization, have not been studied phylogenetically. Here we begin an evolutionary analysis of learning-related neuromodulation in species related to the well-studied opisthobranch gastropod, Aplysia californica. In Aplysia, increased spike duration and excitability in mechanosensory neurons contribute to several forms of learning-related changes to defensive withdrawal reflexes. The modulatory transmitter serotonin (5-hydroxytryptamine, or 5-HT), is thought to play a critical role in producing these firing property changes. In the present study, we tested mechanosensory homologs of the tail-withdrawal reflex in species related to Aplysia for 5-HT-mediated increases in spike duration and excitability. Criteria used to identify homologous tail-sensory neurons included position, relative size, resting electrical properties, expression of a sensory neuron-specific protein, neuroanatomy, and receptive field. The four ingroup species studied (Aplysia californica, Dolabella auricularia, Bursatella leachii, and Dolabrifera dolabrifera) belong to two clades (two species each) within the family Aplysiidae. In the first clade (Aplysia/Dolabella), we found that the tail sensory neurons of A. californica and tail-sensory homologs of a closely related species, D. auricularia, responded to bath-applied serotonin in essentially similar fashion: significant increases in spike duration as well as excitability. In the other clade (Dolabrifera/Bursatella), more distantly related to Aplysia, one species (B. leachii) showed spike broadening and increased excitability. However, the other species (D. dolabrifera) showed neither spike broadening nor increased excitability. The firing properties of tail-sensory homologs of D. dolabrifera were insensitive to 5-HT over a wide range of concentrations. We also performed experiments on two outgroup species (Akera bullata and Bulla gouldiana) and found that spike duration was unaffected by 5-HT, whereas excitability was increased. This study suggests that 5-HT-induced spike broadening arose more recently in opisthobranch evolution, whereas 5-HT-induced excitability increase is a more ancestral trait that may have been expressed in the earliest opisthobranchs. Both traits are absent in the aplysiid species D. dolabrifera, demonstrating that a lineage can lose learning-related mechanisms. The phylogenetic variation observed in the present study presents the opportunity to test general models about learning mechanisms and their evolution in unique ways. PMID- 28565678 TI - HOST-PLANT SWITCHES AND THE EVOLUTION OF CHEMICAL DEFENSE AND LIFE HISTORY IN THE LEAF BEETLE GENUS OREINA. AB - Insect-plant interactions have played a prominent role in investigating phylogenetic constraints in the evolution of ecological traits. The patterns of host association among specialized insects have often been described as highly conservative, yet not all specialized herbivorous insect lineages display the same degree of fidelity to their host plants. In this paper, we present an estimate of the evolutionary history of the leaf beetle genus Oreina. This genus displays an amazing flexibility in several aspects of its ecology and life history: (1) host plant switches in Oreina occurred between plant families or distantly related tribes within families and thereby to more distantly related plants than in several model systems that have contributed to the idea of parallel cladogenesis; (2) all species of the genus are chemically defended, but within the genus a transition between autogenous production of defensive toxins and sequestration of secondary plant compounds has occurred; and (3) reproductive strategies in the genus range from oviparity to viviparity including all intermediates that could allow the gradual evolution of viviparity. Cladistic analysis of 18 allozyme loci found two most parsimonious trees that differ only in the branching of one species. According to this phylogeny estimate, Oreina species were originally associated with Asteraceae, with an inclusion of Apiaceae in the diet of one oligophagous species and an independent switch to Apiaceae in a derived clade. The original mode of defense appears to be the autogenous production of cardenolides as previously postulated; the additional sequestration of pyrrolizidine alkaloids could have either originated at the base of the genus or have arisen three times independently in all species that switched to plants containing these compounds. Viviparity apparently evolved twice in the genus, once without matrotrophy, through a retention of the eggs inside the female's oviducts, and once in combination with matrotrophy. We hypothesize that the combination of autogenous defense and a life history that involves mobile externally feeding larvae allowed these beetles to switch host plants more readily than has been reported for highly conservative systems. PMID- 28565679 TI - NATURAL FORMATION OF IRIS HYBRIDS: EXPERIMENTAL EVIDENCE ON THE ESTABLISHMENT OF HYBRID ZONES. PMID- 28565680 TI - EVOLUTION OF INFLORESCENCE DESIGN: THEORY AND DATA. AB - Very low fruit set in milkweeds and other flowering plants often has been attributed to greater sexual selection on inflorescence size via male, rather than female, reproductive success. Although this explanation has been generally accepted, alternate explanations have been presented, and recently the "male function" or "pollen donation" hypothesis has been sharply criticized. In this paper, we make the distinction between selection on total flower number and on the size of inflorescence units, both of which have been termed "inflorescence size." We present an ESS model for the evolution of inflorescence design that considers reproductive success through male and female function. The model predicts that selection will balance the proportional changes in female and male reproductive success resulting from changes in inflorescence-unit size. We conducted a field study of selection on the size of inflorescence units (umbels) by manipulating umbel size and number in a natural population of Asclepias tuberosa, in southeastern Arizona, during two reproductive seasons. We found that the male fitness function reached a maximum at an intermediate umbel size in both years (although not significantly different from the smallest umbel size in either year), whereas the female fitness function was highest for the smallest umbel size in one year, but was constant across umbel sizes in the other year. We also found that pollinator visitation rate corresponded well with male, but not female, function, and that between-year variation in the male reproductive success of different umbel sizes corresponded with variation in the composition of the pollinator pool. Our empirical results, when inserted in the model, predict ESS umbel sizes similar to those observed in the study population and the species throughout its range. PMID- 28565681 TI - MOLECULAR GENETIC ANALYSIS OF A STEPPED MULTILOCUS CLINE IN THE AMERICAN OYSTER (CRASSOSTREA VIRGINICA). AB - Gulf of Mexico versus Atlantic populations of several coastal species in the southeastern United States are known to differ sharply in genetic composition, but most transitional zones have not previously been examined in detail. Here we employ molecular markers from mitochondrial and nuclear loci to characterize cytonuclear genetic associations at meso- and microgeographic scales along an eastern Florida transitional zone between genetically distinct Atlantic and Gulf populations of the American oyster, Crassostrea virginica. The single- and multilocus cytonuclear patterns display: (1) a cline extending along 340 km of the east Florida coastline; (2) a pronounced step in the cline centered at Cape Canaveral (shifts in allelic frequencies by 50-75% over a 20 km distance); (3) a close agreement of observed genotypic frequencies with Hardy-Weinberg expectations within locales; and (4) mild or nonexistent nuclear and cytonuclear disequilibria in most local population samples. These results imply: (1) considerable restrictions to interpopulational gene flow along the eastern Florida coastline; (2) within locales, free interbreeding (as opposed to mere population admixture) between Gulf and Atlantic forms of oysters; and (3) localized population recruitment in the transition zone localities. These findings demonstrate that marine organisms with high dispersal potential via long lived pelagic larvae can nonetheless display pronounced spatial population genetic structure, and more generally they exemplify the utility of pronounced genetic transition zones for the study of population level processes. PMID- 28565682 TI - A TEST FOR SEXUAL SELECTION ON HYBRIDS OF TWO SYMPATRIC STICKLEBACKS. AB - In this study we assessed whether sexual selection against hybrids contributes to reproductive isolation between two sympatric stickleback species. The species are recently diverged and possibly in the final stages of speciation. Our aim was to find whether mating discrimination of the parental species selects against F1 hybrids, and what conditions are necessary for such sexual selection to operate. We used conservative no-choice laboratory trials with reproductively naive, lab reared fish to measure female mating preferences. Females exhibited ranked preferences, preferring in order: conspecific, hybrid, then heterospecific males. However, intermediate attractiveness does not necessarily imply selection against hybrids: two-way ANOVAs suggested that limnetic, benthic, and hybrid males were statistically equivalent when averaged across females. Thus, this experiment found no evidence for a hybrid mating disadvantage. Our interpretation is that if sexual selection against hybrids is present in the wild, then some factor that biases encounter rates between hybrids and parental species (e.g., habitat selection) is necessary to produce it. PMID- 28565683 TI - PHYLOGENETIC ANALYSIS OF BREEDING SITE USE AND alpha-AMANITIN TOLERANCE WITHIN THE DROSOPHILA QUINARIA SPECIES GROUP. AB - The Drosophila quinaria group is unusual within the genus in that it comprises both mycophagous and nonmycophagous species. DNA sequence data from three regions of the mitochondrial genome were used to infer relationships among four mycophagous species and three that breed on decaying water plants. Phylogenetic analysis of these species show that breeding in mushrooms and tolerance of high levels of alpha-amanitin were the ancestral states within the group. Thus, breeding in decaying water plants and intolerance of alpha-amanitin are derived conditions. We also found that the D. quinaria species group does not comprise separate mycophagous and nonmycophagous clades, but rather that (1) the shift from mushrooms to decaying plants occurred on at least two occasions; or (2) mycophagy reevolved within a lineage that had previously shifted to breeding on plants. The correlation between mycophagy and alpha-amanitin tolerance is perfect across the species we have examined, indicating that there is no detectable time lag between an ecological shift to a new breeding site and correlated changes in biochemical adaptation. The genetic distance between the mycophagous D. recens and the nonmycophagous D. quinaria indicates that these species split only about 1 M.Y.B.P. In terms of alpha-amanitin tolerance, D. recens and D. quinaria are typical of other ecologically similar species within the group. Thus, evolutionary changes in alpha-amanitin tolerance can evidently occur on the order of about 1 million yr. Our data also indicate that, in comparison to other groups of Drosophila, the quinaria species group may be undergoing an adaptive radiation. PMID- 28565684 TI - SEXUAL DICHROMATISM IN BIRDS: IMPORTANCE OF NEST PREDATION AND NEST LOCATION FOR FEMALES VERSUS MALES. AB - Examinations of variation in plumage dichromatism in birds have focused on male plumage brightness and largely neglected variation in female plumage brightness. Nest predation previously was concluded to constrain male brightness and thereby reduce dimorphism in ground-nesting birds based on an incorrect assumption that nest predation is greater for ground nests. Correlations of plumage brightness and dichromatism with nest predation have never been tested directly and we do so here with data for warblers (Parulinae) and finches (Carduelinae). We show that male plumage brightness varies among nest heights, but in a pattern that is not correlated with nest predation. Female plumage brightness also varies among nest heights, but in a pattern that differs from males, and one in which variation in female plumage brightness was negatively correlated with nest predation. These results suggest that nest predation may place greater constraints on female than male plumage brightness, at least in taxa where only females incubate eggs and brood young. These results also show that female plumage patterns vary at least partly independently of male patterns and emphasize the need to include consideration of both female and male plumage variation in tests of plumage dimorphism. Plumage dimorphism differs between ground and off-ground nesters as previously described and, if anything, the relationship between plumage dimorphism and nest predation was positive rather than negative as previously argued. PMID- 28565685 TI - AN EXPERIMENTAL TEST FOR FOOD EFFECTS ON HEAD SIZE ALLOMETRY IN JUVENILE SNAKES. PMID- 28565686 TI - SUBOPTIMAL VIRULENCE OF AN INSECT-PARASITIC NEMATODE. AB - Recent considerations of parasite virulence have focused on the adverse effects that parasites can have on the survival of their hosts. Many parasites, however, reduce host fitness by an equally deleterious but different means, by causing partial or complete sterility of their hosts. A model of optimal parasite virulence is developed in which a quantity of host resources can be allocated to either host or parasite reproduction. Increases in parasite reproduction thus cause reductions in host fertility. The model shows that under a wide variety of ecological conditions, such parasites should completely sterilize their hosts. Only when opportunities for horizontal transmission are very limited should the parasites appropriate less than all of a host's reproductive resources. Field and laboratory evidence shows that the nematode parasite Howardula aoronymphium is relatively avirulent to one of its principal host species, Drosophila falleni, whereas it is much more virulent to D. putrida and D. neotestacea, suggesting that there may be substantial vertical transmission in D. falleni. However, epidemiological studies in the field and laboratory assays of host specificity strongly suggest that the three host species share a single parasite pool in natural populations, indicating that parasites in all three host species experience high levels of horizontal transmission. Thus, the low virulence of H. aoronymphium to D. falleni is not consistent with the model of optimal parasite virulence. It is proposed that this suboptimal virulence in D. falleni is a consequence of populations of H. aoronymphium being selected to exploit simultaneously several different host species. As a result, virulence may not be optimal in any one host. One must, therefore, consider the full range of host species in assessing a parasite's virulence. PMID- 28565687 TI - A COMPARISON OF TEMPERATURE-INDUCED POLYPHENISM IN AFRICAN BICYCLUS BUTTERFLIES FROM A SEASONAL SAVANNAH-RAINFOREST ECOTONE. AB - Temperature-induced variation and norms of reaction have been analyzed for wing pattern elements of six species belonging to the African butterfly genus Bicyclus (Lepidoptera, Nymphalidae, Satyrinae). Five of these species are sympatric in Malawi and exhibit seasonal polyphenism in the savannah-rainforest ecotone. The sixth species originated from Cameroonian equatorial rainforest. The organisms were laboratory reared under four different temperature conditions ranging from 17-28 degrees C. The variation in response to temperature is described by principal component analysis (PCA). Discrimination on the basis of plastic wing pattern characters was performed by discriminant function analysis (DFA) and unweighed pair-group method algorithm (UPGMA) clustering. A phylogenetic reconstruction based on adaptive plastic wing characters was compared with a cladogram built on "nonadaptive" characters. Results demonstrate that: (1) Phenotypic plasticity of wing pattern characters in response to temperature in laboratory-reared organisms is reminiscent of variation induced by seasonal change in the field. (2) Different wing pattern characters are under different control: "exposed" characters of butterflies at rest position are highly sensitive to temperature variation, whereas "hidden" characters, only visible during active behavior, are dominated by species differences. In general the sensitivity of the former can be attributed to their proposed function in deflecting predators. (3) The sexes differ especially in the size of those eyespots that are displayed during active behavior. (4) Species from seasonal and aseasonal environments react in a broadly similar manner to temperature variation. However, savannah species and species of aseasonal rainforest exhibit relatively shallow reaction norms, whereas reaction norms are steeper in species from the savannah-rainforest ecotone. Such a strong response was also apparent in so-called correlation networks between principal components for these species. (5) Phylogenetic distances are to some extent reflected in ordination in both PCA space and DFA-space: closely related species of the safitza group remain close in both ordinations. The more distantly related species differ in ordination from a pattern as suggested by a phylogenetic reconstruction. It is argued that the wing pattern variation of these species reflects both adaptive processes and historical relationships. PMID- 28565688 TI - MORPHOLOGICAL EVOLUTION IN RESPONSE TO FLUCTUATING SELECTION. PMID- 28565689 TI - META-ANALYSES OF THE ASSOCIATION BETWEEN MULTILOCUS HETEROZYGOSITY AND FITNESS. AB - Meta-analyses of published correlation coefficients between multilocus heterozygosity (MLH) and two fitness surrogates, growth rate and fluctuating asymmetry, suggested that the strength of these correlations are generally weak. A variety of plants and animals was included in the meta-analyses. A statistically homogeneous group of MLH-growth rate correlation coefficients that included both plants and animals yielded a common correlation of rz = 0.133. A common correlation of rz = -0.170 was estimated for correlations between MLH and fluctuating asymmetry in three species of salmonid fishes. These results suggest that selection, including overdominance, has at most a weak effect at allozyme loci and cast some doubt on the widely held notion that heterozygosity and individual fitness are strongly correlated. PMID- 28565690 TI - EVOLUTIONARY HISTORY OF NORTHERN HEMISPHERE NUCELLA (GASTROPODA, MURICIDAE): MOLECULAR, MORPHOLOGICAL, ECOLOGICAL, AND PALEONTOLOGICAL EVIDENCE. AB - By combining data from a variety of sources we explore patterns of evolution and speciation in Nucella, a widely studied genus of shallow-water marine neogastropods. We present a hypothesis of phylogenetic relationships for all of the currently recognized species of northern hemisphere Nucella, based on an analysis of 718 base pairs of nucleotide sequence from the mitochondrial cytochrome b gene. The order of appearance of species in the fossil record is congruent with this hypothesis. The topology of the inferred phylogeny of Nucella, coupled with ecological, morphological, and fossil evidence, was used to address three main questions: (1) At what time and by which route was the North Atlantic invaded from the North Pacific compared to prior studies of the trans Arctic interchange? (2) Do patterns of molecular variation within species corroborate the importance of climatic cycles in driving speciation in north temperate marine animals? (3) Was radiation in the direction of increased or decreased ecological specialization, body size, or vulnerability to predation? Molecular evidence confirmed that the sole North Atlantic species, N. lapillus, arose from a North Pacific ancestor. Biogeographic and paleontological evidence supported the dispersal of Nucella, and perhaps other interchange species, via the Eurasian Arctic. Rather intriguingly, the linkage of N. lapillus to a western as opposed to eastern Pacific clade, and the biogeographic origins of the eastern Pacific species, parallel closely similar patterns observed in another genus of rocky-shore gastropods, Littorina. This congruence, in conjunction with information on the climatic and geographic histories of the region, as well as the geographic arrangement of mtDNA haplotypes within Nucella species, supports a model of speciation in Nucella driven by cycles of climatic amelioration and deterioration that began during the Miocene. Calibrations from the fossil record of Nucella suggest that third position transitions and transversions accrue at a rate of 3-4% and 0.5% respectively per million yr. This supports an early participation by Nucella in the trans-Arctic interchange, as suggested by paleobiogeographic studies. Consistent with the unstable taxonomic history of species of Nucella, we found few nonmolecular traits to be phylogenetically informative. Among North Pacific species, more recently derived species (N. canaliculata and the N. emarginata clade) were more ecologically specialized (narrower diet and habitat range). Consistent with extensive intraspecific variation, shell traits were quite labile evolutionarily: neither overall size nor development of antipredatory traits exhibited consistent evolutionary trends over the history of the genus. Nurse eggs (unfertilized eggs consumed by developing embryos) were an ancestral trait that was lost evolutionarily in the two clades that also exhibited increased body size, suggesting that these two life-history traits may be coupled. The reduced number of chromosomes in N. lapillus is clearly a derived state and is consistent with White's (1978) observations on chromosome evolution in other clades. PMID- 28565691 TI - INDIVIDUAL VARIATION OF ONTOGENIES: A LONGITUDINAL STUDY OF GROWTH AND TIMING. AB - This study of growth and developmental time in the water strider Limnoporus canaliculatus (Heteroptera: Gerridae) is based on longitudinal data from specimens reared individually in the laboratory. I analyzed multivariate allometry using a common principal components approach. This technique identified patterns of variation that were uncorrelated both within and among instars and which remained fairly constant throughout the growth period; in contrast, the overall amount of variation increased from young to older instars. Negative correlations between size and subsequent growth increments indicated convergent growth in the first three instars, but there was a transition to positive correlations (divergent growth) in later instars. Analysis of covariation among measurements made in different instars showed strong ontogenetic autocorrelation and revealed patterns remarkably similar to those found in mammals and birds; yet corresponding analyses of growth increments showed mainly independent variation in different instars. Therefore, I conclude that the strong correlations among stage-specific measurements result from the part-whole relationships inherent to these cumulative size data, but do not reflect specific properties of the organisms studied. In contrast to size increments, instar durations of water striders were highly correlated throughout the larval period, indicating that individuals tended to develop at either relatively fast or relatively slow rates in all instars. The correlations between growth increments and instar durations were nil or negative, contrary to expectations from life-history theory. The results of these analyses of individual variation match the findings from other water striders and from interspecific comparisons in the genus Limnoporus, but information about physiological mechanisms of molting and growth in insects cannot completely explain the patterns observed. PMID- 28565692 TI - SEXUAL SIZE DIMORPHISM AND TRANSITION TO PARASITISM IN COPEPODS. PMID- 28565693 TI - PHENOTYPIC SELECTION BY PARASITOIDS ON THE TIMING OF LIFE HISTORY IN A LEAFMINING MOTH. AB - Direct measurements of phenotypic selection by parasitoids on quantitative traits in herbivorous insects have been rare. I analysed episodes of phenotypic selection on the timing of life-history events in a multivoltine leafmining moth, Phyllonorycter mespilella, and assessed the importance of hymenopterous parasitoids as selective influences. Phyllonorycter mespilella has two consecutive stages of larval development, the sap-feeding (SF) and tissue-feeding (TF) stages. Adult parasitoids host feed predominantly on SF larvae, and oviposit predominantly on TF larvae. Oviposition attack on TF larvae caused positive directional selection on the date of transition to the the TF stage (TF date) in the third generation of P. mespilella in one population in 1991. Overwinter mortality caused negative directional selection on TF date in the third generation in a second population in 1993. No directional or variance selection on TF date was detected in the second population in the second generation of 1993. Parasitoid females accepted SF larvae for oviposition more often in the fall generation than in summer generations in both populations. The relative frequencies of SF and TF larvae may alter the pattern of oviposition attack by parasitoids, and thus the form of phenotypic selection on TF date. PMID- 28565694 TI - CYTONUCLEAR DISEQUILIBRIA IN HYBRID ZONES USING RAPD MARKERS. PMID- 28565695 TI - MUTUAL MATE CHOICE AND SEX DIFFERENCES IN CHOOSINESS. AB - Sexual competition is associated closely with parental care because the sex providing less care has a higher potential rate of reproduction, and hence more to gain from competing for multiple mates. Sex differences in choosiness are not easily explained, however. The lower-caring sex (often males) has both higher costs of choice, because it is more difficult to find replacement mates, and higher direct benefits, because the sex providing more care (usually females) is likely to exhibit more variation in the quality of contributions to the young. Because both the costs and direct benefits of mate choice increase with increasing parental care by the opposite sex, general predictions about sex difference in choosiness are difficult. Furthermore, the level of choosiness of one sex will be influenced by the choosiness of the other. Here, we present an ESS model of mutual mate choice, which explicitly incorporates differences between males and females in life history traits that determine the costs and benefits of choice, and we illustrate our results with data from species with contrasting forms of parental care. The model demonstrates that sex differences in costs of choice are likely to have a much stronger effect on choosiness than are differences in quality variation, so that the less competitive sex will commonly be more choosy. However, when levels of male and female care are similar, differences in quality variation may lead to higher levels of both choice and competition in the same sex. PMID- 28565696 TI - MEASURES OF PHENOTYPIC SELECTION ARE BIASED BY PARTIAL INBREEDING. AB - When populations are partially inbred due to the population structure or to a mixed mating system like partial self-fertilization, some individuals will be more inbred than others. This heterogeneity among individuals in the history of inbreeding can greatly complicate the interpretation of measures of quantitative genetic variability when the traits studied exhibit inbreeding depression. Partial inbreeding can also bias measures of phenotypic selection toward the detection of strong directional and stabilizing selection. In this paper, data are presented from several inbreeding experiments conducted on two partially selfing, annual populations of the monkeyflower Mimulus guttatus that show that the means of many of the morphological and phenological traits measured were affected by inbreeding. These findings imply that estimates of heritabilities and additive genetic covariances would not reflect the potential for these populations to respond to selection. Phenotypic selection analyses conducted on naturally occurring plants, involving linear regressions of relative seed production on the traits, revealed significant directional selection on many of the same quantitative traits measured in the inbreeding studies. However, when the same selection analyses were performed on plants with known histories of inbreeding, part of the statistical relationship between relative seed number and the traits was found to be due to the mating system: inbred individuals had both lower seed production and different mean values for the traits than outcrossed individuals. It is also shown, with a hypothetical example, that partial inbreeding can bias measures of stabilizing selection toward the detection of strong stabilizing selection. Partial inbreeding therefore tends to make directional and stabilizing selection appear stronger than it is, and it may be that natural selection in the wild is actually weaker than many studies of partially inbred species suggest. PMID- 28565697 TI - PROBLEMS WITH TESTING INBREEDING AVOIDANCE: THE CASE OF THE COLLARED FLYCATCHER. AB - Four year's data on collared flycatchers, Ficedula albicollis, breeding in a nestbox plot on the island of Gotland, Sweden, was used to investigate whether individuals avoid mating with close kin (i.e., parents or sibs). Only one case of close inbreeding (0.5% of all pairs) was observed during the years of study. The observed frequency of close inbreeding was compared to expected frequencies based on two different null models. Assuming no inbreeding avoidance behaviors (e.g., dispersal or kin recognition), but taking into account the fact that mortality, and different arrival and pairing times of individuals reduce the probability of mating with close kin, the expected frequency of close inbreeding is 10% and 15% for female and male recruits (i.e., born in the study plot), respectively. However, assuming mating to be random within the study plot reduced the expected frequency of close inbreeding to 1% or less for both males and females. Consequently, conclusions drawn concerning inbreeding avoidance depend on the null model used. Contrasting estimated costs of tolerating close inbreeding with those of avoiding it (by dispersal to other plots), however, suggests that the costs of avoiding close inbreeding are substantially greater than those of tolerating it. Therefore, although inbreeding avoidance cannot be rejected as a cause of dispersal of this species, it is not the primary cause, and particularly not for sex-biased dispersal. The general problems of investigating inbreeding avoidance are discussed. It is argued that all previous null models based on random mating in finite populations produce expected frequencies of close inbreeding that in fact include inbreeding avoidance, since they implicitly assume random dispersal within a finite population. Thus, comparisons between observed and expected frequencies of close inbreeding based on random mating are inadequate. The most promising method of investigating inbreeding avoidance is to experimentally study individual movements and mating preferences in the presence and absence of close kin. PMID- 28565698 TI - REPLY TO: FEMALE MATE DISCRIMINATION OR MALE RESPONSES TO FEMALE STIMULATION? PMID- 28565699 TI - FIXATION PROBABILITIES OF SELFING RATE MODIFIERS IN SIMULATIONS WITH SEVERAL DELETERIOUS ALLELES WITH LINKAGE. AB - The fixation rates of selfing rate modifiers were found by stochastic simulation in an infinite site model, including effects of several deleterious alleles with variable effects, which were randomly distributed in the genome without assuming any pollen discounting. Previous results on the evolution of selfing obtained by more precise methods were in this study further validated, and it was concluded that the effect of genetic associations on the evolution of mating systems is small except in the case of full pollen discounting. Furthermore, attention was given to the uneven distribution of the genetic load in the population, and the accompanying large among-genome variation in fixation rates. This among-genome variation will be of significance for the evolution of mating systems. PMID- 28565700 TI - SEXUAL SELECTION AND THE EVOLUTION OF SEXUAL SIZE DIMORPHISM IN THE WATER STRIDER, AQUARIUS REMIGIS. AB - Sexual size dimorphism (SSD) is often attributed to sexual selection, particularly when males are the larger sex. However, sexual selection favoring large males is common even in taxa where females are the larger sex, and is therefore not a sufficient explanation of patterns of SSD. As part of a more extensive study of the evolution of SSD in water striders (Heteroptera, Gerridae), we examine patterns of sexual selection and SSD in 12 populations of Aquarius remigis. We calculate univariate and multivariate selection gradients from samples of mating and single males, for two sexually dimorphic traits (total length and profemoral width) and two sexually monomorphic traits (mesofemoral length and wing form). The multivariate analyses reveal strong selection favoring larger males, in spite of the female-biased SSD for this trait, and weaker selection favoring aptery and reduced mesofemoral length. Selection is weakest on the most dimorphic trait, profemoral width, and is stabilizing rather than directional. The pattern of sexual selection on morphological traits is therefore not concordant with the pattern of SSD. The univariate selection gradients reveal little net selection (direct + indirect) on any of the traits, and suggest that evolution away from the plesiomorphic pattern of SSD is constrained by antagonistic patterns of selection acting on this suite of positively correlated morphological traits. We hypothesize that SSD in A. remigis is not in equilibrium, a hypothesis that is consistent with both theoretical models of the evolution of SSD and our previous studies of allometry for SSD. A negative interpopulation correlation between the intensity of sexual selection and the operational sex ratio supports the hypothesis that, as in several other water strider species, sexual selection in A. remigis occurs through generalized female reluctance rather than active female choice. The implications of this for patterns of sexual selection are discussed. PMID- 28565701 TI - TESTING HISTORICAL HYPOTHESES OF MORPHOLOGICAL CHANGE: BIOMECHANICAL DECOUPLING IN LORICARIOID CATFISHES. AB - The "decoupling hypothesis" has been proposed as a mechanistic basis for the evolution of novel structure and function. Decoupling derives from the release of functional constraints via loss of linkages and/or repetition of individual elements as redundant design components, followed by specialization of one or more elements. Examples of apomorphic decoupling have been suggested for several groups of organisms, however there have been few empirical tests of explicit statements concerning functional and morphological consequences of decoupling. Using the loricarioid catfishes, we tested one particular consequence of decoupling, the prediction that clades possessing decoupled systems having increased biomechanical complexity will exhibit greater morphological variability of associated structures than outgroups having no such decoupled systems. Morphometric procedures based on interlandmark distances were used to quantify morphological variance at three levels of design at successive nodes in the loricarioid cladogram. Additional landmark-based procedures were used to localize major patterns of shape change between clades. We report significantly greater within-group morphometric variance at all three morphological levels in those lineages associated with decoupling events, confirming our predictions under the decoupling hypothesis. Two of 12 comparisons, however, yielded significant variance effects where none were predicted. Localization of the major patterns of shape change suggests that disassociation between morphological and functional evolution may contribute to the lack of fit between variance predictions and decoupling in these two comparisons. PMID- 28565702 TI - QUANTITATIVE GENETICS OF SPRINT RUNNING SPEED AND SWIMMING ENDURANCE IN LABORATORY HOUSE MICE (MUS DOMESTICUS). AB - We tested the hypothesis that locomotor speed and endurance show a negative genetic correlation using a genetically variable laboratory strain of house mice (Hsd:ICR: Mus domesticus). A negative genetic correlation would qualify as an evolutionary "constraint," because both aspects of locomotor performance are generally expected to be under positive directional selection in wild populations. We also tested whether speed or endurance showed any genetic correlation with body mass. For all traits, residuals from multiple regression equations were computed to remove effects of possible confounding variables such as age at testing, measurement block, observer, and sex. Estimates of quantitative genetic parameters were then obtained using Shaw's (1987) restricted maximum-likelihood programs, modified to account for our breeding design, which incorporated cross-fostering. Both speed and endurance were measured on two consecutive trial days, and both were repeatable. We initially analyzed performances on each trial day and the maximal value. For endurance, the three estimates of narrow-sense heritabilities ranged from 0.17 to 0.33 (full ADCE model), and some were statistically significantly different from zero using likelihood ratio tests. The heritability estimate for sprint speed measured on trial day 1 was 0.17, but negative for all other measures. Moreover, the additive genetic covariance between speeds measured on the two days was near zero, indicating that the two measures are to some extent different traits. The additive genetic covariance between speed on trial day 1 and any of the four measures of endurance was negative, large, and always statistically significant. None of the measures of speed or endurance was significantly genetically correlated with body mass. Thus, we predict that artificial selection for increased locomotor speed in these mice would result in a decrease in endurance, but no change in body mass. Such experiments could lead to a better understanding of the physiological mechanisms leading to trade-offs in aspects of locomotor abilities. PMID- 28565703 TI - PERSPECTIVE: INDIRECT MATE CHOICE, COMPETITION FOR MATES, AND COEVOLUTION OF THE SEXES. AB - When Darwin first proposed the possibility of sexual selection, he identified two mechanisms, male competition for mates and female choice of mates. Extending this classification, we distinguish two forms of mate choice, direct and indirect. This distinction clarifies the relationship between Darwin's two mechanisms and, furthermore, indicates that the potential scope for sexual selection is much wider than thus far realized. Direct mate choice, the focus of most research on sexual selection in recent decades, requires discrimination between attributes of individuals of the opposite sex. Indirect mate choice includes all other behavior or morphology that restricts an individual's set of potential mates. Possibilities for indirect mate choice include advertisement of fertility or copulation, evasive behavior, aggregation or synchronization with other individuals of the same sex, and preferences for mating in particular locations. In each of these cases, indirect mate choice sets the conditions for competition among individuals of the opposite sex and increases the chances of mating with a successful competitor. Like direct mate choice, indirect mate choice produces assortative mating. As a consequence, the genetic correlation between alleles affecting indirect choice and those affecting success in competition for mates can produce self-accelerating evolution of these complementary features of the sexes. The broad possibilities for indirect mate choice indicate that sexual selection has more pervasive influences on the coevolution of male and female characteristics than previously realized. PMID- 28565704 TI - TWO HERBIVORES AND CONSTRAINTS ON SELECTION FOR RESISTANCE IN BRASSICA RAPA. AB - Although most plants experience herbivory by several insect species, there has been little empirical work directed toward understanding plant responses to these simultaneous selection pressures. In an experiment in which herbivory by flea beetles (Phyllotreta cruciferae) and diamondback moths (Plutella xylostella) was manipulated in a factorial design, I found that selection for resistance to these herbivores is not independent in Brassica rapa. Specifically, the effect of flea beetle damage on B. rapa fitness depends on the amount of diamondback moth damage a plant experiences: damage by these herbivores has a nonadditive effect on plant fitness. When diamondbacks are abundant, plants that sustain high levels of damage by flea beetles are favored by natural selection, but when diamondbacks are rare, a low level of damage by flea beetles is favored. However, resistance to the later-feeding diamondback moth is not affected by the presence or absence of damage by early-feeding flea beetles. Thus, there are no plant-mediated ecological interactions between these herbivores that affect the outcome of selection for resistance. Because these herbivores do not independently affect plant fitness, neither is likely to develop a pairwise coevolutionary relationship with its host. Instead, coevolution is diffuse. PMID- 28565705 TI - HISTORICAL DIVERSIFICATION OF BIRDS IN NORTHWESTERN SOUTH AMERICA: A MOLECULAR PERSPECTIVE ON THE ROLE OF VICARIANT EVENTS. AB - Studies of South American biodiversity have identified several areas of endemism that may have enhanced historical diversification of South American organisms. Hypotheses concerning the derivation of birds in the Choco area of endemism in northwestern South America were evaluated using protein electrophoretic data from 14 taxonomically diverse species groups of birds. Nine of these groups demonstrated that the Choco area of endemism has a closer historical relationship to Central America than to Amazonia, a result that is consistent with phytogeographic evidence. Within species groups, genetic distances between cis Andean (east of the Andes) and trans-Andean (west of the Andes) taxa are, on average, roughly twice that between Choco and Central American taxa. The genetic data are consistent with the hypotheses that the divergence of most cis-Andean and trans-Andean taxa was the result of either the Andean uplift fragmenting a once continuous Amazonian-Pacific population (Andean Uplift Hypothesis), the isolation of the two faunas in forest refugia on opposite sides of the Andes during arid climates (Forest Refugia Hypothesis), or dispersal of Amazonian forms directly across the Andes into the trans-Andean region (Across-Andes Dispersal Hypothesis). Disentangling these hypotheses is difficult due to the complexity of the Andean uplift and to the scant geologic and paleoclimatic information that elucidates diversification events in northwestern South America. Regarding the divergence of cis- and trans-Andean taxa, the genetic, geologic, and paleoclimatic data allow weak rejection of the Andean Uplift Hypothesis and weak support for the Forest Refugia and Andean Dispersal Hypotheses. The subsequent diversification of Choco and Central American taxa was the result of Pleistocene forest refugia, marine transgressions, or parapatric speciation. PMID- 28565706 TI - FEMALE MATE DISCRIMINATION OR MALE RESPONSES TO FEMALE STIMULATION? PMID- 28565707 TI - DO PHYLOGENETIC METHODS PRODUCE TREES WITH BIASED SHAPES? AB - We examine whether phylogenetic methods provide biased estimates of tree shape with respect to the random branching model. We investigate the performance of five commonly used phylogenetic methods using computer simulation: (1) maximum parsimony; (2) neighbor joining; (3) UPGMA with an outgroup taxon; (4) UPGMA without an outgroup taxon; and (5) maximum likelihood. All methods provide estimates of tree shape that are, on average, more asymmetrical than the true tree, especially when rates of evolution are high. We suggest a simple explanation for the bias and propose a modified test of tree shape that corrects for it. PMID- 28565708 TI - GENETIC STRUCTURE OF COEXISTING SEXUAL AND CLONAL SUBPOPULATIONS IN A FRESHWATER SNAIL (POTAMOPYRGUS ANTIPODARUM). AB - We examined clonal diversity and the distribution of both clonal and sexual genotypes in a single population of freshwater snails (Potamopyrgus antipodarum) in which diploid sexual individuals and triploid parthenogens coexist. A genetic analysis of individuals from three habitat zones in Lake Alexandrina, New Zealand revealed extremely high clonal diversity: 165 genotypes among 605 clonal individuals. The frequency of triploid clonal individuals increased with increasing depth in the lake, and most of the individual clones were habitat specific, suggesting that differences among habitats are important in structuring the clonal subpopulation. There were also high levels of clonal diversity within habitats, suggesting frequent origins of habitat-specific clones. In contrast, diploid sexual individuals were proportionately more common in the shallow regions of the lake (where infection by trematode larvae is highest), and there was no significant spatial structure in the sexual subpopulation. We suggest that habitat specialization by clones, as well as parasite-mediated selection against common clones, are important factors affecting the structure of this mixed population of sexual and clonal snails. PMID- 28565709 TI - LIFE-HISTORY EVOLUTION IN GUPPIES (POECILIA RETICULATA) 6. DIFFERENTIAL MORTALITY AS A MECHANISM FOR NATURAL SELECTION. AB - We have previously reported a correlation between the life-history patterns of guppies and the types of predators with which they coexist. Guppies from localities with an abundance of large predators (high predation localities) mature at an earlier age and devote more resources to reproduction than those found in localities with only a single, small species of predator (low predation localities). We also found that when guppies were introduced from a high to low predation locality, the guppy life history evolved to resemble what was normally found in this low predation locality. The presumed mechanism of natural selection is differences among localities in age/size-specific mortality (the age/size specific mortality hypothesis); in high predation localities we assumed that guppies experienced high adult mortality rates while in the low predation localities we assumed that guppies experienced high juvenile mortality rates. These assumptions were based on stomach content analyses of wild-caught predators and on laboratory experiments. Here, we evaluate these assumptions by directly estimating the mortality rates of guppies in natural populations. We found that guppies from high predation localities experience significantly higher mortality rates than their counterparts from low predation localities, but that these higher mortality rates are uniformly distributed across all size classes, rather than being concentrated in the larger size classes. This result appears to contradict the predictions of the age/size-specific predation hypothesis. However, we argue, using additional data on growth rates and the probabilities of survival to maturity in each type of locality, that the age-specific mortality hypothesis remains plausible. This is because the probability of survival to first reproduction is very similar in each type of locality, but the guppies from high predation localities have a much lower probability of survival per unit time after maturity. We also argue for the plausibility of two other mechanisms of natural selection. These results thus reveal mortality patterns that provide a potential cause of natural selection, but expand, rather than narrow, the number of possible mechanisms responsible for life-history evolution in guppies. PMID- 28565710 TI - RECONSTRUCTION OF THE EVOLUTION OF REPRODUCTIVE CHARACTERS IN PONTEDERIACEAE USING PHYLOGENETIC EVIDENCE FROM CHLOROPLAST DNA RESTRICTION-SITE VARIATION. AB - We reconstructed the phylogenetic history of Pontederiaceae using chloroplast DNA restriction-site variation from approximately two-thirds of the species in this family of aquatic monocotyledons. The molecular phylogeny was used to evaluate hypotheses concerning the evolution of reproductive characters associated with the breeding system. The family has four main genera, two of which (Eichhornia and Pontederia) have tristylous, predominantly outcrossing species, while two (Monochoria and Heteranthera) have enantiostylous taxa. Self-incompatibility is restricted to some but not all tristylous species. In Eichhornia and Pontederia, predominantly selfing species with small monomorphic flowers (homostyly) have been hypothesized to result from the multiple breakdown of tristyly. Restriction site variation provided a well supported phylogeny of ingroup taxa, enabling the mapping of reproductive characters onto trees. Two contrasting optimization schemes were assessed, differing in the relative weights assigned to shifts in character states. The reconstructed sequence of floral character-state change was used to assess competing hypotheses concerning the origin and breakdown of tristyly, and the relationships between tristylous and enantiostylous syndromes. Our results indicate that the class of optimization scheme used was the most critical factor in reconstructing character evolution. Despite some topological uncertainties and difficulty in reconstructing the primitive floral form in the family, several broad conclusions were possible when an unordered, unequally weighted optimization scheme was used: (1) tristyly originated either once or twice, while the occurrence of enantiostyly in Monochoria and Heteranthera was always found to have independent origins; (2) tristyly has repeatedly broken down leading to selfing, homostylous taxa; and (3) self-incompatibility probably arose after the origin of floral trimorphism, a sequence of events that conflicts with some evolutionary models. PMID- 28565711 TI - CORRELATED EVOLUTION OF SELF-FERTILIZATION AND INBREEDING DEPRESSION: AN EXPERIMENTAL STUDY OF NINE POPULATIONS OF AMSINCKIA (BORAGINACEAE). AB - The relation between inbreeding depression and rate of self-fertilization was studied in nine natural populations of the annual genus Amsinckia. The study included two clades (phylogenetic lineages) in which small-flowered, homostylous populations or species are believed to have evolved from large-flowered, heterostylous, self-compatible ones. In one lineage the small-flowered species is tetraploid with disomic inheritance. Rates of self-fertilization were 25% to 55% in the four large-flowered, heterostylous populations; 72% in a large-flowered but homostylous population; and greater than 99.5% in the four small-flowered, homostylous populations, which produce seed autonomously. When present, inbreeding depression occurred in the fertility but not the survival components of fitness. Using a cumulative fitness measure incorporating both survival and fertility (flower number), we found inbreeding depression to be lower in the four very highly self-fertilizing populations than in the five intermediate ones. The Spearman rank correlation between inbreeding depression and selfing rate for the nine populations was -0.50, but was not statistically significant (P = 0.12). Inbreeding depression was greater in the two tetraploid populations than in the very highly self-fertilizing, diploid ones. Phenotypic stability of progeny from self-fertilization tended to be higher in populations with lower inbreeding depression. We conclude that levels of self-fertilization and inbreeding depression in Amsinckia are determined more by other factors than by each other. Estimates of mutation rates and dominance coefficients of deleterious alleles, obtained from a companion study of the four highly self-fertilizing populations, suggest that a strong relationship may not be expected. We discuss the relationship of the present results to current theory of the coevolution of self fertilization and inbreeding depression. PMID- 28565712 TI - POSTMATING REPRODUCTIVE ISOLATION BETWEEN CHRYSOPA QUADRIPUNCTATA AND CHRYSOPA SLOSSONAE: MECHANISMS AND GEOGRAPHIC VARIATION. AB - In laboratory tests, Chrysopa quadripunctata showed geographic variation in a postmating, prezygotic barrier to interbreeding with its sister species, C. slossonae. When paired with C. slossonae males, C. quadripunctata females from populations that are sympatric with C. slossonae (i.e. from New York and Florida) had lower incidences of fertile oviposition than those from allopatric populations (i.e. from Kansas and California). Chrysopa quadripunctata females in all interspecific pairings were inseminated, but absence of fertile oviposition was associated with the lack of sperm transfer from the bursa copulatrix to the spermatheca. The C. quadripunctata females that failed to lay fertile eggs when crossed with C. slossonae males, invariably produced viable C. quadripunctata offspring (no hybrids) within one day after the heterospecific male was replaced with a conspecific one. Thus, the barrier to hybridization may involve the ability of females to (a) distinguish between heterospecific and conspecific sperm and (b) allow the transfer of only conspecific sperm to the spermatheca. When C. slossonae females were paired with C. quadripunctata males, the incidences of fertile oviposition were high and there was no apparent geographic variation in the degree of hybridization. As with C. quadripunctata females, unsuccessful hybridization of C. slossonae females was associated with retention of sperm in the bursa copulatrix. Hybrids did not differ from intraspecific offspring in their viability or sex ratios. However, hybrids whose parents originated from sympatric populations had low fertility; thus hybrid infertility may constitute an additional barrier to hybridization. The patterns of inter- and intraspecific variation in hybridization are consistent with the notions that C. quadripunctata harbors variation in the mechanism that controls sperm movement to the spermatheca and that the evolution of reproductive isolation between C. quadripunctata and C. slossonae may include natural selection for increased expression of this mechanism. PMID- 28565713 TI - TESTING COLD FUSION OF PHYLA: MATERNITY IN A TUNICATE * SEA URCHIN HYBRID DETERMINED FROM DNA COMPARISONS. PMID- 28565714 TI - TRANSLATING BETWEEN MICROEVOLUTIONARY PROCESS AND MACROEVOLUTIONARY PATTERNS: THE CORRELATION STRUCTURE OF INTERSPECIFIC DATA. AB - As species evolve along a phylogenetic tree, we expect closely related species to retain some phenotypic similarities due to their shared evolutionary histories. The amount of expected similarity depends both on the hierarchical phylogenetic structure, and on the specific magnitude and types of evolutionary changes that accumulate during each generation. In this study, we show how models of microevolutionary change can be translated into the resulting macroevolutionary patterns. We illustrate how the structure of phenotypic covariances expected in interspecific measurements can be derived, and how this structure depends on the microevolutionary forces guiding phenotypic change at each generation. We then explore the covariance structure expected from several simple microevolutionary models of phenotypic evolution, including various combinations of random genetic drift, directional selection, stabilizing selection, and environmental change, as well as models of punctuated or burst-like evolution. We find that stabilizing selection leads to patterns of exponential decrease of between species covariance with phylogenetic distance. This is different from the usual linear patterns of decrease assumed in most comparative and systematic methods. Nevertheless, linear patterns of decrease can result from many processes in addition to random genetic drift, such as directional and fluctuating selection as well as modes of punctuated change. Our framework can be used to develop methods for (1) phylogenetic reconstruction; (2) inference of the evolutionary process from comparative data; and (3) conducting or evaluating statistical analyses of comparative data while taking phylogenetic history into account. PMID- 28565715 TI - CLEAVAGE PATTERNS AND MESENTOBLAST FORMATION IN THE GASTROPODA: AN EVOLUTIONARY PERSPECTIVE. AB - The larger gastropod taxa are characterized by distinctive cleavage patterns. The cell stage at which the mesentoblast is formed appears to be crucial. In none of the taxa is it formed earlier than the 24- and not later than the 63-cell stage. A heterochronic shift from late to early mesentoblast formation appears to coincide with successive steps in gastropod evolution. Comparison of the early cleavage patterns appears to be a powerful method for investigating the evolutionary relations between major gastropod taxa. PMID- 28565716 TI - METABOLIC AND DIGESTIVE RESPONSES TO ARTIFICIAL SELECTION IN CHICKENS. AB - Compared to ancestral wild jungle fowl, domestic broiler chickens have been consciously selected for large body size, relatively large pectoral muscles, rapid growth, and high feed efficiency. Hence intraspecific comparisons of these two strains could help identify consequences of unconscious artificial selection, trade-offs in energy allocation, and factors limiting energy budgets. We therefore compared our measurements of many corresponding parameters in both strains: growth rate, energy intake, digestive efficiency, metabolic rate and its components, organ masses, and intestinal brush-border nutrient transporter and hydrolase activities and capacities, as functions of age and body mass in zero- to nine-week-old chicks. Both strains prove to have the same digestive efficiency. Compared to equal-sized jungle fowl, broilers have higher daily energy intake and activity costs. Broilers have relatively longer and wider, hence heavier, small intestines, and their other gut compartments are also relatively larger. Offsetting these increases, broilers have relatively smaller brains and leg bones, these being much less important to a captive bird than to a wild bird exposed to predators. Broilers have generally lower intestinal transporter activities, but relatively higher transporter capacities because of their larger guts. Among domestic chicken strains, comparison of broilers with layers, the former having been consciously selected for much higher growth rates, yields generally similar conclusions. Thus, as recognized in broad outline by Darwin, domestication provides clear examples of conscious selection, of unconscious selection for traits prerequisite to the consciously selected traits, and of unconscious selection against traits rendered less important or competing for space or energy. PMID- 28565717 TI - RECENT BOOKS IN PRINT. PMID- 28565718 TI - EVOLUTION OF FLORAL TRAITS IN A HERMAPHRODITIC PLANT: FIELD MEASUREMENTS OF HERITABILITIES AND GENETIC CORRELATIONS. AB - Genetic variances, heritabilities, and genetic correlations of floral traits were measured in the monocarpic perennial Ipomopsis aggregata (Polemoniaceae). A paternal half-sib design was employed to generate seeds in each of four years, and seeds were planted back in the field near the parental site. The progeny were followed for up to eight years to estimate quantitative genetic parameters subject to natural levels of environmental variation over the entire life cycle. Narrow-sense heritabilities of 0.2-0.8 were detected for the morphometric traits of corolla length, corolla width, stigma position, and anther position. The proportion of time spent by the protandrous flowers in the pistillate phase ("proportion pistillate") also exhibited detectable heritability of near 0.3. In contrast, heritability estimates for nectar reward traits were low and not significantly different from zero, due to high environmental variance between and within flowering years. The estimates of genetic parameters were combined with phenotypic selection gradients to predict evolutionary responses to selection mediated by the hummingbird pollinators. One trait, corolla width, showed the potential for a rapid response to ongoing selection through male function, as it experienced both direct selection, by influencing pollen export, and relatively high heritability. Predicted responses were lower for proportion pistillate and corolla length, even though these traits also experienced direct selection. Stigma position was expected to respond positively to indirect selection of proportion pistillate but negatively to selection of corolla length, with the net effect sensitive to variation in the selection estimates. Anther position also was not directly selected but could respond to indirect selection of genetically correlated traits. PMID- 28565719 TI - STABILIZING SELECTION DETECTED FOR BRISTLE NUMBER IN DROSOPHILA MELANOGASTER. AB - Stabilizing selection, which favors intermediate phenotypes, is frequently invoked as the selective force maintaining a population's status quo. Two main alternative reasons for stabilizing selection on a quantitative trait are possible: (1) intermediate trait values can be favored through the causal effect of the trait on fitness (direct stabilizing selection); or (2) through a pleiotropic, deleterious side effect on fitness of mutants affecting the trait (apparent stabilizing selection). Up to now, these alternatives have never been experimentally disentangled. Here we measure fitness as a function of the number of abdominal bristles within four Drosophila melanogaster lines, one with high, one with low, and two with intermediate average bristle number. The four were inbred nonsegregating lines, so that apparent selection due to pleiotropy is not possible. Individual fitness significantly increased (decreased) with bristles number in the low (high) line. No significant fitness-trait association was detected within each intermediate line. These results reveal substantial direct stabilizing selection on the trait. PMID- 28565720 TI - DIVERGENCE IN SYMBIOTIC COMPATIBILITY IN A LEGUME-BRADYRHIZOBIUM MUTUALISM. AB - Geographic variation in the mutualism between the legume Amphicarpaea bracteata and its nitrogen-fixing root nodule bacteria (Bradyrhizobium sp.) was analyzed by sampling genotypes from 11 sites separated by distances ranging from 0.6 km to more than 1000 km. Cross inoculation experiments revealed that plants were genetically differentiated in traits determining compatibility with mutualist partners from different sites. Combinations of plant and bacterial genotypes native to the same local habitat yielded 26% higher plant growth relative to non native combinations (range across 4 experiments; 9% to 48%). Among non-native symbioses, plant growth was unrelated to the geographic distance between sites of plant and bacterial origin. However, compatibility varied significantly with the genetic distance among host populations (inferred by multilocus enzyme electrophoresis): genetically similar plants from separate sites showed superior growth with each other's mutualist partners. Nevertheless, the tree structure of population genetic similarity was not congruent in plants versus bacteria. This implies that adaptive variation in symbiotic compatibility has evolved without strictly parallel divergence in the two species. PMID- 28565721 TI - QUANTITATIVE GENETICS OF THE WING COLOR PATTERN IN THE BUCKEYE BUTTERFLY (PRECIS COENIA AND PRECIS EVARETE): EVIDENCE AGAINST THE CONSTANCY OF G. AB - Models for the evolution of continuously varying traits use heritabilities, genetic correlations, and the G-matrix to quantify the genetic variation upon which selection acts. Given estimates of these parameters, it is possible to predict the long-term effects of selection, infer past selective forces responsible for observed differences between populations or species, and distinguish the effects of drift from selection. Application of these methods, however, requires the unproven assumption that the G-matrix remains constant from one generation to the next. This study examines the assumption of constancy for the wing pattern characteristics of two sibling species of butterflies, Precis coenia and P. evarete (Lepidoptera: Nymphalidae). Quantitative genetic parameters were estimated from parent-offspring regression. Two approaches were taken to test the null hypothesis of equality between species. First, pairwise tests between corresponding elements of G and between heritabilities and genetic correlations for the two species were constructed. Second, a modification of Bartlett's modified likelihood-ratio test was used to test for equality between the G-matrices. The matrix test failed to detect any between species differences. In contrast, pairwise comparision revealed significant differences. Thus, it appears that constancy cannot be assumed at the species level in quantitative genetic studies. In particular, the assumption of constancy was violated for the trait with the greatest difference in mean phenotype. PMID- 28565722 TI - THE ECOLOGY AND GENETICS OF FITNESS IN CHLAMYDOMONAS. VII. THE EFFECT OF SEX ON THE VARIANCE IN FITNESS AND MEAN FITNESS. PMID- 28565723 TI - THE EVOLUTION OF GENETIC CORRELATIONS: AN ANALYSIS OF PATTERNS. AB - The genetic correlation is a central parameter of quantitative genetics, providing a measure of the rate at which traits respond to indirect selection (i.e., selection that does not act upon the traits under study, but some other trait with which they have genes in common). In this paper, I review the pattern of variation among four combinations of traits: life history * life history (L * L), morphological * morphological (M * M), life history * morphological (L * M), and behavioral * behavioral (B * B). A few other combinations were investigated, but insufficient data were obtained for separate analysis. A total of 1798 correlations, distributed over 51 different animal and plant species, were analyzed. The analysis was conducted at two levels: first by dividing the data set solely by trait combination, and second by blocking the data by trait combination and species. Because selection will tend to fix alleles that show positive correlations with fitness traits faster than those that are negative and because the latter are expected to arise more frequently by mutation, correlations between life-history traits are predicted to be more often negative than those between morphological traits. This prediction was supported, with the ranking in decreasing proportion of negative correlations being: L * L > L * M > B * B > M * M. The mean magnitude of the genetic correlation shows little variation among morphological and life-history combinations, and the distribution of values is remarkably flat. However, the estimated standard errors and the coefficient of variation (SE/rG ) are large, making it difficult to separate biological factors influencing the pattern of dispersion from experimental error. Analysis of the phenotypic and genetic correlations suggest that for the combinations M * M and L * M, but not L * L or B * B, the phenotypic correlation is an adequate estimate of the genetic correlation. PMID- 28565724 TI - GENETIC DRIFT AND FOUNDER EFFECT IN NATIVE VERSUS INTRODUCED POPULATIONS OF AN INVADING PLANT, LYTHRUM SALICARIA (LYTHRACEAE). AB - There are few convincing examples of genetic drift at loci under selection in natural populations. The plant sexual polymorphism tristyly provides an opportunity to investigate genetic drift because stochastic processes interacting with frequency-dependent selection give rise to a diagnostic pattern of morph frequency variation. A previous study of 102 Ontario populations of the introduced tristylous wetland herb Lythrum salicaria provided evidence for the role of stochastic processes during colonization. However, whether stochastic effects are greater in these recently introduced populations compared to native Eurasian populations remains unclear. The propensity of this species to invade disturbed habitats suggests that episodes of colonization and periods of small population size must also occur in the native range. A survey of 102 populations in southwestern France indicated reduced stochastic effects in native populations. Populations exhibited significantly lower morph loss than in Ontario (5% vs. 23%) and significantly higher values of morph evenness. The greater incidence of trimorphism in French populations was not associated with larger population sizes; populations were significantly smaller than those in Ontario (means: 266 vs. 487). Morph evenness was positively correlated with population size among French but not Ontario populations, providing further evidence of nonequilibrium conditions in introduced compared to native populations. The incidence of trimorphism was unexpectedly high in small native populations (N <= 25; 22 of 27 populations trimorphic). Computer simulations indicated that levels of gene flow on the order of m >= 0.05 can account for the maintenance of tristyly in small populations. The high connectivity of populations within the agricultural landscape typical of southwestern France may facilitate levels of gene flow sufficient to maintain trimorphism in small populations. PMID- 28565725 TI - MICROGEOGRAPHIC PATTERNS OF GENETIC AND MORPHOLOGICAL VARIATION IN SAVANNAH SPARROWS (PASSERCULUS SANDWICHENSIS). AB - Surveys of genetic population structure are often limited to large geographic scales because geographically close populations are indistinguishable. Genetic uniformity across adjacent demes can be interpreted as evidence for cohesion (panmixia) or recent divergence. However, poor genetic resolution at microgeographic scales can also arise from the use of overly conservative (slowly evolving) markers. This study examines the ability of hypervariable, minisatellite loci to discriminate among geographically close populations of Savannah sparrows (Passerculus sandwichensis) and to track morphological differentiation at a microgeographic scale (interregional distance < 55 km). Savannah sparrows breeding at five island and two mainland sites in the Bay of Fundy, New Brunswick, Canada, show concordant patterns of variation in external morphology (seven characters) and multilocus DNA fingerprinting profiles (Sxy ): island sparrows are phenotypically larger and genetically more similar to each other than they are to mainland sparrows. This pattern of variation is consistent with both adaptive (natural selection) and nonadaptive (genetic drift) mechanisms of population divergence. Based on minisatellite diversity, the effective size of both island and mainland populations is 37, an estimate substantially lower than census population sizes. These data are discordant with observations of sparrow vagility and abundance and suggest a closer examination of microgeographic patterns in avian systems. PMID- 28565726 TI - CYCLICAL ENVIRONMENTAL CHANGES AS A FACTOR MAINTAINING GENETIC POLYMORPHISM. 2. DIPLOID SELECTION FOR AN ADDITIVE TRAIT. AB - The subject of this paper is polymorphism maintenance due to stabilizing selection with a moving optimum. It was shown that in case of two-locus additive control of the selected trait, global polymorphism is possible only when the geometric mean fitnesses of double homozygotes averaged over the period are lower than that of the single heterozygotes and of the double heterozygote (with a multiplier [1 - r]p , which depends on recombination rate r and period length p). But local stability of polymorphism cannot be excluded even if geometric mean fitnesses of all double homozygotes are higher than that of all heterozygotes. We proved, that for logarithmically convex fitness functions, cyclical changes of the optimum cannot help in polymorphism maintenance in case of additive control of the selected trait by two equal loci. However, within the same class of fitness functions, nonequal gene action and/or dominance effect for one or both loci may lead to local polymorphism stability with large enough polymorphism attracting domain. The higher the intensity of selection and closer the linkage between selected loci the larger is this domain. Note that even simple cyclical selection could result in two forms of polymorphic limiting behavior: (a) usually expected forced cycle with a period equal to that of environmental changes; and (b) "supercycles," nondumping auto-oscillations with a period comprising of hundreds of forced oscillation periods. PMID- 28565727 TI - A QUANTITATIVE GENETIC ANALYSIS OF THERMAL SENSITIVITY IN THE LOCOMOTOR PERFORMANCE CURVE OF APHIDIUS ERVI. AB - The thermal sensitivity of locomotor performance in Aphidius ervi, a parasitic hymenopteran, conforms to the "jack-of-all-trades is master of none" model of specialist-generalist trade-offs. Performance breadth and maximal performance at the phenotypic level are negatively correlated in both sexes. A strong, negative genetic correlation was found for males, but not for females. In males, the broad sense heritability of performance breadth was about 0.16, and that of maximum walking velocity was about 0.29. Neither heritability was significantly different from zero in females. The broad-sense heritability of body mass was about 0.3 in females and 0.6 in males, with a strong negative genetic correlation between size and maximum velocity in males only. These data provide the first quantitative genetic analysis of performance curves in eukaryotic animals, and one of the few demonstrations of the specialist-generalist trade-off that underlies much theory in evolutionary ecology. PMID- 28565728 TI - GEOLOGICALLY DATED SEA BARRIERS CALIBRATE A PROTEIN CLOCK FOR AEGEAN WATER FROGS. AB - Reliable estimates of phylogenetic relationships and divergence times are a crucial requirement for many evolutionary studies, but are usually difficult because fossils are scarce and their interpretation is often uncertain. Frogs are fresh water animals that generally are unable to cross salt water barriers (their skin is readily permeable to both salt and water). The geologically determined ages of salt water barriers that isolate related frog populations thus provide an independent measure of the minimum date of genetic divergence between pairs of such populations. For the genetically well-studied western Palearctic water frogs (Rana esculenta group), the Aegean region provides an ideal area for determining the relationship between genetic divergence and time of spatial isolation, using a nested set of geologically determined isolation times (12,000 yr, 200,000 yr, 1.8 Myr, 2-3 Myr, and 5.2 Myr). Using 31 electrophoretic loci for 33 pairs of neighboring frog populations, a linear relationship between geologically determined isolation time and Hillis' modified Nei genetic distance was found: D*Nei = (0.04 +/- 0.01) + (0.10 +/- 0.01) isolation time [Myr] corresponding to an average divergence rate ("molecular clock" pace) of 0.10 D*Nei /Myr (0.10 DNei /Myr). This rate is in the range of previous estimates reported for protein electrophoretic data; the value is conservative because relatively few of the loci used are "fast evolvers" (13%; sAAT, ALB, EST-5, MPI). Removing these fast evolvers from the analysis results in 0.08 D*Nei /Myr (0.08 DNei /Myr). The confidence limits for estimation of the divergence time given the genetic distance are large, but unusually narrow for this kind of study; they permit us to estimate divergence times during the Pliocene and Miocene. Few previous studies, including sequence analyses, have provided reasonable estimates of divergence time for the Pliocene. A test using the outgroup taxa Rana perezi and Rana saharica (also isolated for 5.2 Myr by the Strait of Gibraltar) fits the calibration well: observed genetic Nei distance D*Nei = 0.55, expected D*Nei = 0.56. The calculated divergence times, based on this absolute molecular clock, suggest a series of speciation events after the Messinian (5.2 Myr), possibly triggered by the rapid ecological changes accompanying the desiccation and refilling of the Mediterranean Basin. PMID- 28565729 TI - Combined Endoscopic and Surgical Treatment of Severe Gastrointestinal Bleeding in a Patient with Heart Assist Device under Therapeutic Anticoagulation. AB - Gastrointestinal (GI) bleeding is a common complication after heart assist device placement. Reasons for bleeding are multifactorial. Endoscopic therapy is the treatment of choice, whereas invasive procedures are avoided in these critically ill patients. We present the case of a 65-year-old male patient experiencing severe GI bleeding after left ventricular assist device (LVAD) and right ventricular assist device (RVAD) placement with therapeutic anticoagulation. Endoscopically, multiple gastric bleeding sources were found but could not be treated effectively due to a large blood clot. A combined endoscopic and surgical treatment was initiated, including gastrotomy for blood clot removal, surgical transgastric suturing, endoscopic over-the-scope clip (OTSC) placement and hemospray application. Postoperative endoscopic visualization showed effective bleeding control. The patient unfortunately died due to causes unrelated to the treatment. This case shows that a minimal invasive combination of endoscopic and surgical techniques can be an alternative treatment for severe upper GI bleeding in critically ill and anticoagulated patients. PMID- 28565730 TI - Gallbladder Volume Indicated for Gallbladder Dysmotility. PMID- 28565731 TI - [Consensus of Chinese experts on diagnosis of disseminated intravascular coagulation (version 2017)]. PMID- 28565732 TI - [Consensus of Chinese expert on the diagnosis and treatment of hemophilia (version 2017)]. PMID- 28565733 TI - [How I treat disseminated intravascular coagulation]. PMID- 28565734 TI - [How I treat corticosteroid-resistant or relapsed adult patients with primary immune thrombocytopenia]. PMID- 28565735 TI - [A prospective study of the efficacy and safety of maintenance therapy with recombinant human thrombopoietin in patients with primary immune thrombocytopenia: a multicenter study]. AB - Objective: To evaluate the efficacy and safety of maintenance therapy with reduced dose of rhTPO in the patients with primary immune thrombocytopenia (ITP) who attained stable platelet (PLT) counts after daily administration of rhTPO. Methods: Treatment was started with a daily administration of rhTPO (300 U/kg) for 2 consecutive weeks. Patients who attained stable PLT>=50*10(9)/L were enrolled to maintenance therapy starting with every other day administration of rhTPO, then adjusted dose interval to maintain platelet count (30-100) *10(9)/L. Results: A total of 91 eligible patients were enrolled. Fourteen patients discontinued the study due to noncompliance (12/14) and investigator decision (2/14) . Among 77 patients who completed the study, 38 patients with the administration of rhTPO at every other day or less could maintain PLT>=30*10(9)/L for 12 weeks. The percentage of patients with a platelet response (PLT>=30*10(9)/L) at 4(th) week, 8(th) week and 12(th) week of maintain therapy was 92.6% (63/68) , 82.7% (43/52) and 85.0% (34/40) , respectively. Median platelet counts remained in the range of (70-124) *10(9)/L. The overall incidence of rhTPO-related adverse events was 7.7%. All the adverse events were generally mild. Conclusion: Extending the dose interval of rhTPO is feasible to maintain stable platelet count in the patients with ITP, but the optimal dose interval is uncertain and might vary with individuals. PMID- 28565736 TI - [Predictors of fatigue among individuals with primary immune thrombocytopenia in China]. AB - Objective: To study the fatigue symptoms of adult patients with primary immune thrombocytopenia (ITP) and to analyze the possible factors that affect the severity of fatigue. Methods: Eligible adult patients with ITP who admitted to Institute of Hematology & Blood Diseases Hospital were enrolled in this study and the questionnaires including a Chinese version of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) , the Pittsburgh sleep quality index (PSQI) , the Hospital Anxiety and Depression scale (HADS) and demographic information were completed. The predictors of fatigue were determined with multiple linear regression analyses. Results: A total of 207 patients with ITP were enrolled, including 70 males (33.8%) and 137 females (66.2%) , the median age was 42 (18-72) years old. The FACIT-F score in ITP patients was (37.50+/ 9.05) . The FACIT-F severity of ITP patients was positively correlated with the platelet count (r=0.307, P<0.001) . The FACIT-F severity was negatively correlated with bleeding severity (r=-0.276, P<0.001) , sleep quality (r=-0.654, P<0.001) , depression (r=-0.598, P<0.001) and anxiety (r=-0.616, P<0.001) . A multiple linear regression analysis revealed that the severity of ITP-related fatigue was significantly correlated with platelet count (P<0.001) , bleeding severity (P=0.004) , sleep quality (P<0.001) and depression (P<0.001) . Conclusion: Fatigue was determined by complicated factors in adult ITP patients. Interventions addressing depressive symptoms, sleep quality, bleeding symptoms and platelet count could be potential avenues for treatment of fatigue in patients with ITP. PMID- 28565737 TI - [A Study on the establishment of immune thrombocytopenia model induced by anti platelet GPIbalpha antibodies]. AB - Objective: To establish primary immune thrombocytopenia (ITP) animal model induced by anti-platelet membrane glycoprotein GPIbalpha antibodies AN51 and R300. Methods: Twenty guinea pigs (6-8 week) were divided into 4 groups. Five guinea pigs in each group were intravenously injected with different doses of AN51 (0.05, 0.1, 0.2 MUg/g) and 0.2 MUg/g IgG as control. The whole blood was collected from inner angular venous plexus. Platelets number was determined by an automated cell counter and Swiss-Jim method. Then, the similar protocol was used to establish ITP nude mice model by intraperitoneal injection of different concentrations of anti-platelet GPIbalpha antibody R300, respectively. Results: 1Five minutes after intravenous injection of AN51 at 0.05, 0.1 and 0.2 MUg/g, the platelet counts of guinea pigs reduced about 0-5%, 50%-60% and 70%-80% compared to the control group, respectively. The difference was statistically significant (P<0.01) . 2Six hours after intraperitoneal injection of R300 at 0.05, 0.1, 0.2 MUg/g, the platelet counts of nude mice decreased about 20%-30%, 60%-70% and 80% 90% compared to the control group, respectively. The difference was statistically significant (P<0.01) . The nude mice, injected 0.2 MUg/g R300 once a day for 2 weeks, showed typical ITP clinical manifestations including large number of petechiaes or ecchymoses on limbs, head and abdomen. Conclusion: AN51 at 0.2 MUg/g and R300 at 0.2 MUg/g could establish stable ITP model in guinea pigs and nude mice respectively. PMID- 28565738 TI - [Comparative study between two bleeding grading systems of primary immune thrombocytopenia]. AB - Objective: To evaluate prospectively the clinical significance of immune thrombocytopenia (ITP) bleeding scale (version 2016 of ITP bleeding scale) recommended in consensus of Chinese experts on diagnosis and treatment of adult primary immune thrombocytopenia (version 2016) by Chinese Medical Association. Methods: A total of 88 patients were assessed by ITP bleeding scale (version 2016) and ITP specific bleeding assessment tool (ITP-BAT) to analyze the association between bleeding score of ITP bleeding scale (version 2016) and platelet counts, gender, disease stage, also to evaluate interinstrument consistency between two bleeding grading systems. Among 47 newly diagnosed ITP patients treated with high dose dexamethasone, bleeding score of ITP bleeding scale (version 2016) and platelet counts were assessed before treatment, one week and two weeks after treatment, respectively, and the responsiveness of ITP bleeding scale (version 2016) was evaluated. Results: Bleeding score of ITP patients was negatively correlated with platelet counts (r=-0.515, P<0.001) . Gender and disease stage had no significant influence on bleeding score (F=4.255, P=0.382; F=5.251, P=0.753) . ITP bleeding scale was in excellent agreement with ITP-BAT. Change of bleeding score of 47 ITP patients before and after high dose dexamethasone treatment had significant difference (z=-5.612, P<0.001) , also, the same result was observed in patients who didn't get complete response (z= 3.969, P<0.001) . Back-to-back scoring consistency of two doctors was 94.4% (k=0.918) . It took less time to accomplish ITP bleeding scale (version 2016) than that of ITP-BAT [3 (2-6) min vs 7 (4-13) min, z=-8.213, P<0.001]. Conclusion: ITP bleeding scale (version 2016) has good responsiveness, strong assessment consistency, close correlation with ITP-BAT and less time-consuming in clinical application. It can be used as an effective tool of condition judgement, risk assessment and efficacy evaluation of ITP patients. PMID- 28565739 TI - [Research on the negative immune regulation of NK cells in patients with primary immune thrombocytopenia]. AB - Objective: To investigate the levels of NK cells and their relevant cytokines (IL 10, TGF-beta and IFN-gamma) in patients with primary immune thrombocytopenia (ITP) . Methods: All samples were obtained from 42 patients (22 newly diagnosed and 20 in remission) and 20 healthy volunteers. The levels of IL-10 and IFN-gamma in blood serum were detected by enzyme-linked immunosorbent assay (ELISA) . The percentage of CD3(-) CD56(+) NK cell, CD3(-) CD56(bright) CD16(-) NK cell, CD3(-) CD56(dim) CD16(+) NK cell in peripheral blood lymphocyte were detected by flow cytometry. The NK cells were isolated by immunomagnetic microbeads. The mRNA expression levels of IL-10, TGF-beta, and IFN-gamma in NK cells were detected by real-time fluorescent quantitative PCR. Correlation between the above measured results was analyzed. Results: 1 The blood serum level of IFN-gamma in newly diagnosed ITP patients [ (653.0+/-221.6) ng/L] was higher than that in remission ITP patients [ (484.4+/-219.5) ng/L] and healthy control [ (390.9+/-253.5) ng/L] (P=0.022, P=0.001) . The blood serum level of IL-10 in newly diagnosed ITP patients was lower than that in healthy control [ (52.09+/-26.66) ng/L vs (79.44+/-38.43) ng/L, P=0.007]. 2The percentage of NK cell in newly diagnosed and remission ITP patients [ (9.53+/-3.93) %, (9.03+/-3.78) %] were significantly lower than that in healthy control [ (13.72+/-7.42) %] (P=0.013, P=0.007) . The ratio of CD3(-) CD56(bright) CD16(-) NK cell/total NK cells in newly diagnosed ITP patients was higher than that in healthy control [ (6.85+/-4.43) % vs (4.05+/ 2.81) %, P=0.032]. The ratio of CD3(-)CD56(dim) CD16(-) NK cell/total NK cells in newly diagnosed ITP patients was lower than that in healthy control [ (93.14+/ 4.43) % vs (95.94+/-2.81) %, P=0.032]. 3 There was no significant difference in the mRNA expression level of IFN-gamma in NK cells of ITP patients and healthy control (all P>0.05) . The mRNA expression levels of IL-10 and TGF-beta in NK cells in newly diagnosed ITP patients were significantly higher than that in healthy control (1.82+/-1.32 vs 1.02+/-1.03, P=0.023; 2.80+/-2.31 vs 1.46+/-1.37, P=0.028) . The ratio of CD3(-)CD56(bright) CD16(-) NK cell/total NK cells was positively correlated with the mRNA expression levels of IL-10, TGF-beta in NK cells (r=0.424, P=0.001; r=0.432, P<0.001) . Conclusion: NK cells may compensate for the deficiency of the number by enhancing the secretion of negative regulation cytokines, acting as "protective" roles in the disease. PMID- 28565740 TI - [Retrospectively analysis of the difference of bleeding frequency and hemophilic arthropathy between hemophilia A and hemophilia B patients]. AB - Objective: To analyze the difference of bleeding frequency, plain radiographic (X ray) , risk factors in hemophilic arthropathy progression and the Arnold Hilgartner classification. Methods: A retrospective study was conducted in 211 hemophilia patients hospitalized in our medical center between January 2007 and December 2010, some patients with hemarthrosis were followed up for 5 years. Results: All patients were male, including 150 hemophilia A (HA) and 61 hemophilia B (HB) . The HA patients bled more frequently than HB patients with annualized total bleeding rate 20.5 (0-48) vs 13 (1-40) ; annualized joint bleeding rate 13.5 (0-38) vs 8 (0-33) , especially in moderate hemophilia [26 (1 48) vs 12 (1-36) , P<0.001; 18 (0-36) vs 7.5 (0-26) , P=0.001], but severe hemophilia had no difference in bleeding frequency [33 (1-41) vs 26 (1-40) , P=0.702; 22 (0-36) vs 18 (0-33) , P=0.429]. The condition of the affected joints of 108 HA and 54 HB was evaluated on roentgenography. In HA patients, the Arnold Hilgartner classification increased with the severity ratings (r=0.063, P=0.004) . However, similar associations were not found in HB patients (r=0.045, P=0.082) . Five years later, 36 HA and 19 HB patients received the same joint X-ray, there were no significant differences in joints radiographic progression between the total HA and HB groups (z=1.941, P=0.052) . However, significant difference between moderate HA and HB was observed (z=0.076, P=0.002) . Multivariate unconditioned Logistic analysis showed that annualized joint bleeding rate [P<0.001, OR=1.166 (95%CI 1.097-1.239) ] and articular structural injuries [P=0.018, OR=2.842 (95% CI 1.196-6.755) ] were independent risk factors for the joints radiographic progression. Conclusion: The study suggests that there was a difference in bleeding phenotype between HA and HB, especially in moderate hemophilia. HB patients showed mild but progressive development over time, compared with HA patients. Annualized joint bleeding rate and articular structural injuries were independent risk factors for the joints radiographic progression. PMID- 28565741 TI - [Analysis of clinical efficacy of recombinant activated factor VII on bleeding in patients with hematologic disorders]. AB - Objective: To investigate the treatment efficacy of recombinant activated factor VII (rFVIIa) for bleeding among patients with hematologic disorders. Methods: A total of 38 times of bleeding in 31 patients with hematological disease treated with rFVIIa were analyzed retrospectively. Results: The clinical effective rate of rFVIIa for bleeding management in acquired hemophilia A (AHA) patients/hemophilia patients with inhibitor, acute promyelocytic leukemia (APL) patients and patients with non-APL leukemia was 90% (9/10) , 71.4% (5/7) and 60.0% (3/5) , respectively, which was higher than that in patients following HSCT (30.8%) . The clinical effective rate of rFVIIa for patients with bleeding score of 2 (100.0%) was higher than that with 3 (66.7%) and 4 (54.1%) . The effective rate of rFVIIa was 25.0% (2/5) in 5 patients with cerebral hemorrhage, 66.7% (6/9) in 9 patients with hematuria and 41.7% in 12 patients with gastrointestinal hemorrhage. The curative effect for 3 patients with joints and muscle bleeding and 5 patients with skin, nasal, pharyngeal and gum bleeding was excellent. Following HSCT, among patients with bleeding score of 4 points, high dose and repeated use of rFVIIa did not necessarily achieve a good effect. Among AHA/hemophilia patients with inhibitors and patients with acute leukemia who had bleeding score of 4 points, the use of low dose FVIIa could achieve good therapeutic effect, however the efficacy of lowest dose (22.5 MUg/kg) rFVIIa was poor. Conclusions: The hemostasis efficacy of rFVIIa is affected by various factors such as diseases, bleeding sites, bleeding score and so on. The use of rFVIIa can achieve good efficacy for bleeding management in AHA patients/hemophilia patients with inhibitor, APL patients and patients with non APL leukemia. However the efficacy of rFVIIa for bleeding of patients after HSCT is poor. Early use of rFVIIa is important for successful hemostatic treatment. Management of underlying condition is as important as hemostatic treatment. PMID- 28565742 TI - [Sorafenib in combination with chemotherapy as first-line therapy for FLT3-ITD positive acute myeloid leukemia]. AB - Objective: To analyze the clinical features of acute myeloid leukemia patients with Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation and the therapeutic effect of sorafenib in combination with chemotherapy as first line therapy for these patients. Methods: Clinical features and therapeutic effect were retrospectively analyzed in 53 AML patients with FLT3-ITD mutation diagnosed in Henan Cancer Hospital from January 2013 to August 2016. The biological characteristics and clinical efficacy of chemotherapy in combination with or without Sorafeinb were analyzed. Results: FLT3-ITD mutation was identified in 53 AML patients, 22 cases (41.5%) were M(5) subtype. The median of the peripheral WBC was 61.00 (0.98-920.00) *10(9)/L, and there were 50 (94.3%) patients with WBC>10*10(9)/L. The median of blast cell in bone marrow was 0.730 (0.234-0.966) . The total remission rate of all these 53 patients was 56.6% (30/53) . The complete remission (CR) rates in patients treated with chemotherapy in combination with sorafenib and patients with chemotherapy alone were 86.4% (19/22) and 35.5% (11/31) , respectively. The 1-year overall survival rates of the two groups were 78.3%% and 50.0% (P=0.041) , and 1-year progression free survival rates were 75.9% and 42.4% (P=0.044) , respectively. Conclusion: AML patients with FLT3-ITD mutation have the characteristics of high peripheral WBC, high blast cells in bone marrow and accompanying with M(5) subtype. Sorafeinb combined with chemotherapy can significantly improve CR rate and short term survival. PMID- 28565743 TI - [Distribution of donor-specific aKIR after unrelated allogeneic hematopoietic stem cell transplantation]. AB - Objective: To analyze the distribution and proportion of donor-specific activated killer cell immunoglobulin like receptor (aKIR) genes and their clinical application values in unrelated allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: Retrospective analyses of KIR genotyping using polymerase chain reaction with sequence specific primers (PCR-SSP) were performed in 216 pairs of donors and recipients. Results: The frequency of donor specific KIR genes was 53.7% (116/216) in 216 patients receiving unrelated allo HSCT, with the frequency of 78.3% (112/143) in the KIR genes mismatched group and 5.5% (4/73) in matched group. Of the 116 patients with detectable donor-specific KIR genes, 99.1% (115/116) patients had various donor-specific aKIR genes. Among 55 pairs of donors' KIR-Bx genotype and patients' KIR-AA genotype group, the most commonly observed genotypes were Bx1, Bx2, Bx3, Bx4, in which the donor-specific KIR genes were respectively KIR 3DS1, 2DL5A, 2DS5, 2DS1; KIR 3DS1, 2DL5A, 2DS3, 2DS1; KIR 2DS2, 2DL2; KIR 2DS2, 2DL2, 3DS1, 2DL5A, 2DS5, 2DS1. Of 44 pairs of donors' KIR-AA genotype and patients' KIR-Bx (AB) genotype group, 36.4% (16/44) recipients had donor-specific KIR2DS4 (FUL) gene. In 143 pairs of KIR mismatched group, the frequencies of donor-specific KIR genes were KIR2DS1 (35.7%) , KIR3DS1 (32.9%) , KIR2DS5 (29.4%) , KIR2DS4 (FUL) (25.9%) , KIR2DL2 (25.2%) , KIR2DS2 (24.5%) , KIR2DS3 (21.7%) and KIR3DL1 (8.4%) , respectively. Conclusion: The donor-specific aKIR genes mainly existed in KIR mismatched group after unrelated allo-HSCT, and the different pairs of donors' and patients' KIR genotypes led to the diverse donor-specific aKIR. But there were higher specific aKIR genes in higher frequency of KIR AA, Bx1, Bx2, Bx3, Bx4 genotypes. All these can provide the experimental basis for studying the role of the donor-specific aKIR genes on the prognosis of HSCT. PMID- 28565744 TI - [Chromosomal large fragment deletion induced by CRISPR/Cas9 gene editing system]. AB - Objective: Using CRISPR-Cas9 gene editing technology to achieve a number of genes co-deletion on the same chromosome. Methods: CRISPR-Cas9 lentiviral plasmid that could induce deletion of Aloxe3-Alox12b-Alox8 cluster genes located on mouse 11B3 chromosome was constructed via molecular clone. HEK293T cells were transfected to package lentivirus of CRISPR or Cas9 cDNA, then mouse NIH3T3 cells were infected by lentivirus and genomic DNA of these cells was extracted. The deleted fragment was amplified by PCR, TA clone, Sanger sequencing and other techniques were used to confirm the deletion of Aloxe3-Alox12b-Alox8 cluster genes. Results: The CRISPR-Cas9 lentiviral plasmid, which could induce deletion of Aloxe3-Alox12b Alox8 cluster genes, was successfully constructed. Deletion of target chromosome fragment (Aloxe3-Alox12b-Alox8 cluster genes) was verified by PCR. The deletion of Aloxe3-Alox12b-Alox8 cluster genes was affirmed by TA clone, Sanger sequencing, and the breakpoint junctions of the CRISPR-Cas9 system mediate cutting events were accurately recombined, insertion mutation did not occur between two cleavage sites at all. Conclusion: Large fragment deletion of Aloxe3 Alox12b-Alox8 cluster genes located on mouse chromosome 11B3 was successfully induced by CRISPR-Cas9 gene editing system. PMID- 28565745 TI - [Study on autophagy in nucleated red blood cells in patients with myelodysplastic syndromes]. AB - Objective: To investigate the change of autophagy level of bone marrow nucleated red blood cell (RBC) in patients with myelodysplastic syndromes (MDS) . Methods: Fifty-four MDS patients and thirty-three controls were enrolled in this study. The mitophagy were observed by transmission electron microscopy (TEM) . The level of autophagy-associated protein LC3B in GlycoA(+) nucleated RBC was measured by flow cytometry. The expressions of ULK1 and mTOR mRNA in GlycoA(+) nucleated RBC were measured by real-time PCR. The expression of the mitochondrial outer membrane protein TOM20 in GlycoA(+) nucleated RBC was detected by Western blot. Results: Autophagosomes or autolysosomes were scarcely observed by TEM in MDS patients. The expression of LC3B in GlycoA(+) nucleated RBC in high-risk MDS patients (0.22+/-0.12) was significantly lower than that in normal controls (0.43+/-0.22, P<0.001) , and lower than that in low-risk MDS patients (0.40+/ 0.16, P=0.001) . The expression of AMPK [0.26 (0.60) ] in GlycoA(+) nucleated RBC in high-risk MDS patients was significantly lower than that in controls [1.00 (2.07) , P<0.017) . The expression of ULK1 mRNA in GlycoA(+) nucleated RBC in high-risk MDS patients [0.27 (3.31) ] was significantly lower than that in controls [1.07 (4.41) , P<0.017]. The level of mTOR mRNA in GlycoA(+) nucleated RBC in high-risk MDS patients [1.82 (3.74) ] was significantly higher than that in controls [1.26 (1.38) , P<0.017]. The level of LC3B in GlycoA(+) nucleated RBC was negatively correlated with the HGB (r=0.529, P=0.009) in high-risk MDS patients. The expression of mitochondrial outer membrane protein TOM20 in high risk MDS patients was 9.42+/-4.42. Conclusion: Autophagy is impaired in nucleated RBC of MDS patients. PMID- 28565746 TI - [Clinical analysis of staphylococcus septicemia-associated hemophagocytic lymphohistiocytosis: seven case reports]. PMID- 28565747 TI - [Progress of acquired thrombotic thrombocytopenic purpura]. PMID- 28565748 TI - [Advances in Hemophilia A inhibitors]. PMID- 28565749 TI - Main constituents of polyphenol complex from seagrasses of the genus Zostera, their antidiabetic properties and mechanisms of action. AB - The present review analyzed the recent experimental studies of the alleviating activity of main constituents of the polyphenol complex from seagrasses of the genus Zostera, namely rosmarinic acid, luteolin and its sulfated derivatives, on carbohydrate and lipid metabolism disorders. A number of studies by our group and others, in which various experimental models of diabetes and hyperlipidemia were used, show a therapeutic action of the polyphenol complex and the abovementioned phenolic constituents, when applied separately and in combination. Based on the analysis of the results of these studies, the probable mechanisms of the therapeutic action of these compounds in diabetes and hyperlipidemia were proposed. PMID- 28565750 TI - Myocardial fibrosis in congenital and pediatric heart disease. AB - Cardiac fibrosis is a common phenomenon in different types of heart diseases, such as ischemic heart disease, inherited cardiomyopathy mutations, diabetes, and ageing and is associated with morbidity and mortality. Increased accumulation of extracellular matrix (ECM) that impacts cardiac function, is the underlying cause of fibrotic heart disease. There are four different types of cardiac fibrosis, including, reactive interstitial fibrosis, replacement fibrosis, infiltrative interstitial fibrosis and endomyocardial fibrosis. They are involved in the activation and transformation of cardiac fibroblasts to myofibroblasts, which participate in ECM production and fibrotic process and several inflammatory pathways. Besides the ECM proteins, myofibroblasts also express smooth muscle alpha-actin, SM22 and caldesmon and other markers related to fibrotic process. Most commonly employed techniques to assess myocardial fibrosis include stress echocardiography, cardiac magnetic resonance imaging and positron emission tomography. Because of the involvement of renin-angiotensin-II-aldosterone system, transforming growth factor-beta signaling and activin-linked kinase 5 in the mechanisms of cardiac fibrosis, these pathways and the involved proteins are useful as therapeutic targets. However, because of the importance of these pathways in many other physiological functions, their therapeutic targeting needs to be approached with caution. PMID- 28565751 TI - Application of high-field magnetic resonance imaging in Parkinson's disease. AB - The present study aimed to observe the structural changes of the extracorticospinal tract in Parkinson's disease (PD) using susceptibility weighted imaging (SWI) and diffusion tensor imaging (DTI) magnetic resonance (MR) scans. The association of DTI parameters and brain-iron accumulation with PD was examined and imaging signs useful in the diagnosis of PD were explored. The study included 30 patients with PD and 30 age- and gender-matched healthy controls who underwent routine MR, SWI and DTI scans. The corrected phase (CP) values of the substantia nigra (SN), red nucleus (RN), globus pallidus (GP) and putamen (PUT) were measured, and fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained. Significant differences were found in the CP values between the PD and control groups in the SN, RN and PUT, but there were no differences in other regions of interest (ROIs). The FA values of the SN and PUT in the PD group were significantly decreased compared with those of the control group, but there was no significant difference in the FA values of the GP. Furthermore, there was no significant inter-group difference in the ADC values of any ROIs. In conclusion, SWI is a method useful for evaluating brain-iron deposition in PD. Increasing iron storage levels have previously been shown to be associated with PD pathogenesis but not with the degree of PD severity. FA values may be useful for diagnosing PD, and DTI may offer some insight into PD pathomechanisms and clinical diagnosis. PMID- 28565752 TI - Hepatoprotective activity of chrysin is mediated through TNF-alpha in chemically induced acute liver damage: An in vivo study and molecular modeling. AB - Chrysin (5,7-dihydroxyflavone) is a naturally occurring flavonoid present at high levels in honey, propolis and numerous plant extracts. Chrysin is known to have hepatoprotective activity, however, the mechanisms by which it exerts this effect remain unclear. In the present study, the effects of chrysin in carbon tetrachloride (CCl4)-induced acute liver damage were investigated and the results used to infer a possible mechanism behind chrysin's hepatoprotective activity. Prior to an intraperitoneal injection of CCl4 (1 ml/kg) to induce acute liver damage, chrysin (50 mg/kg) was administered orally to mice for 7 days. The positive control group was given 50 mg/kg standardized silymarin, a well-studied hepatoprotective flavonoid. Twenty-four h following CCl4 administration, an increase in the activity levels of serum aspartate-amino-transferase and alanine amino-transferase was found. This was accompanied by extended centrilobular necrosis, steatosis and an altered hepatocyte ultrastructure. In addition, CCl4 induced acute hepatotoxicity was associated with an increase in hepatic tumor necrosis factor-alpha (TNF-alpha) and alpha-smooth muscle actin (alpha-SMA) protein expression, which was significantly decreased in the livers of mice pre treated with chrysin (P<0.001), similar to the results of the silymarin pre treated group (P<0.001). Treatment with chrysin prior to CCl4 exposure significantly reduced the activity of enzymes used as biochemical markers of poor liver function compared with the group which did not receive pre-treatment (P<0.001). In addition, the results of histopathological and electron microscopy liver examination showed chrysin pre-treatment reduced the effects of CCl4 treatment. Molecular modeling results demonstrated that the hepatoprotective activity of chrysin is mediated through TNF-alpha, as it reduces soluble TNF alpha generation via blocking TNF-alpha-converting enzyme activity. In conclusion, the results of the present study suggest that inflammatory pathways are activated in CCl4-induced acute liver damage, which are ameliorated by chrysin pre-treatment. This indicates that chrysin is a potent hepatoprotective agent, similarly to silymarin at the same dose, which has the potential to be a viable alternative to conventional hepatoprotective treatments. PMID- 28565753 TI - Clinical and genomic responses to ultra-short course chemotherapy in spinal tuberculosis. AB - Traditional treatments for spinal tuberculosis (TB) involve chemotherapy and surgery. In the present study, it has been identified that chemotherapy lasting <6 months [ultra-short course chemotherapy (UCCT)], rather than the 6-18 months of the traditional regimen, is effective in sustaining TB clearance following complete surgical debridement. This current study aims to compare the changes in peripheral blood gene expression prior to and following UCCT, subsequent to complete debridement of spinal TB lesions. The study includes 5 patients without TB and 27 patients with spinal, divided into three groups: Group 1 (untreated group, n=8); group 2 (UCCT treatment group, n=9); and group 3 (UCCT treatment 1 year follow-up group, n=10). Gene changes were detected using DNA microarray analysis, confirmed through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and the results were examined using the DAVID Knowledgebase to identify the pathways and functions of differentially expressed genes. TB lesions were active in group 1, while groups 2 and 3 showed no signs of active TB, as indicated by clinical manifestations and imaging. Comparison of the transcription profiles of the control and study groups showed that treatment of spinal TB resulted in upregulation of genes that are associated with immune response pathways; RT-qPCR produced similar findings. In conclusion, these results indicate that UCCT is an effective treatment against TB following complete surgical debridement. Furthermore, DNA microarray analysis proved a useful tool to evaluate the effects of spinal TB treatment on the expression of genes associated with immune response pathways. PMID- 28565754 TI - Identification of potential biomarkers of sepsis using bioinformatics analysis. AB - Sepsis is defined as the systemic inflammatory response to infection and is one of the leading causes of mortality in critically ill patients. The goal of the present study is to elucidate the molecular mechanism of sepsis. Transcription profile data (GSE12624) were downloaded that had a total of 70 samples (36 sepsis samples and 34 non-sepsis samples) from the Gene Expression Omnibus database. Protein-protein interaction network analysis was conducted in order to comprehensively understand the interactions of genes in all samples. Hierarchical clustering and analysis of covariance (ANCOVA) global test were performed to identify the differentially expressed clusters in the networks, followed by function and pathway enrichment analyses. Finally, a support vector machine (SVM) was performed to classify the clusters, and 10-fold cross-validation method was performed to evaluate the classification results. A total of 7,672 genes were obtained after preprocessing of the mRNA expression profile data. The PPI network of genes under sepsis and non-sepsis status collected 1,996/2,147 genes and 2,645/2,783 interactions. Moreover, following the ANCOVA global test (P<0.05), 24 differentially expressed clusters with 12 clusters in septic and 12 clusters in non-septic samples were identified. Finally, 207 biomarker genes, including CDC42, CSF3R, GCA, HMGB2, RHOG, SERPINB1, TYROBP SERPINA1, FCER1 G and S100P in the top six clusters, were collected using the SVM method. The SERPINA1, FCER1 G and S100P genes are thought to be potential biomarkers. Furthermore, Gene oncology terms, including the intracellular signaling cascade, regulation of programmed cell death, regulation of cell death, regulation of apoptosis and leukocyte activation may participate in sepsis. PMID- 28565755 TI - MitoKATP regulating HIF/miR210/ISCU signaling axis and formation of a positive feedback loop in chronic hypoxia-induced PAH rat model. AB - In the present study, we studied the mechanism of mitochondrial ATP-sensitive potassium (mitoKATP) channels regulating hypoxia-inducible factor (HIF) 1alpha/microRNA (miR)-210/mitochondrial iron-sulfur protein integrin (ISCU) signaling axis and forming a positive feedback loop in chronic hypoxia-induced pulmonary arterial hypertension (PAH) by using in vivo animal model. Two hundred healthy adult SPF Sprague-Dawley rats were randomly divided into five groups: Control, a mimic miR-210 agent (mimic-210) intervention, a miR-210 inhibitor (anti-210) intervention, a chronic PAH and an anti-210 intervention PAH groups, with 40 rats in each group. After the chronic PAH rat model was successfully established, the rats were intervened with mimic-210 and anti-210. The pulmonary artery smooth muscle cells (PASMCs) of rats in each group were acutely isolated and the activity of mitoKATP and mitochondria-derived oxygen free radicals reactive oxygen species (ROS) was detected. RT-qPCR was used to detect the gene of HIF-1alpha/miR-210/ISCU and western blot analysis was used to detect the protein of HIF-1alpha and ISCU. The gene and protein expression were detected again after mitoKATP-specific opener diazoxide and blocker 5-HD was given via tail vein and took effect on each group of rats, respectively. Additionally, the indicators were detected again after ISCU recombinant protein was given via tail vein and ISCU small interfering RNA (siRNA) via nasal feeding and took effect on each group of rats, respectively. It was found that the activity of mitoKATP and ROS and the gene and protein levels of HIF-1alpha/miR-210/ISCU of the mimic-210 group were significantly higher than those of the control group while that of the anti-210 group was significantly reduced (P<0.05). The indicators in the chronic PAH group were significantly higher than those of the control group while those of the anti-210 intervention PAH group were significantly reduced (P<0.05). The indicators of all the groups were increased after being given mitoKATP specific opener diazoxide. The indicators of all the groups were significantly reduced after receiving blocker 5-HD (P<0.05). The indicators of all the groups were significantly reduced after given ISCU recombinant protein. The indicators of all the groups increased following ISCU siRNA, and there was a statistically significant difference (P<0.05). In conclusion, the mechanism of mitoKATP regulating the HIF-1alpha/miR-210/ISCU signaling axis and formation of a positive feedback loop exists in the PAH rat model. PMID- 28565756 TI - MicroRNA-98 rescues proliferation and alleviates ox-LDL-induced apoptosis in HUVECs by targeting LOX-1. AB - Oxidized low-density lipoprotein (ox-LDL) is a major and critical mediator of atherosclerosis, and the underlying mechanism is thought to involve the ox-LDL induced dysfunction of endothelial cells (ECs). MicroRNAs (miRNAs), which are a group of small non-coding RNA molecules that post-transcriptionally regulate the expression of target genes, have been associated with diverse cellular functions and the pathogenesis of various diseases, including atherosclerosis. miRNA-98 (miR-98) has been demonstrated to be involved in the regulation of cellular apoptosis; however, the role of miR-98 in ox-LDL-induced dysfunction of ECs and atherosclerosis has yet to be elucidated. Therefore, the present study aimed to investigate the role of miR-98 in ox-LDL-induced dysfunction of ECs and the underlying mechanism. It was demonstrated that miR-98 expression was markedly downregulated in ox-LDL-treated human umbilical vein ECs (HUVECs) and that miR-98 promoted the proliferation and alleviated apoptosis of HUVECs exposed to ox-LDL. In addition, the results demonstrated that lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) was a direct target of miR-98 in HUVECs, as indicated by a luciferase assay. The results of the present study suggested that miR-98 may inhibit the uptake of toxic ox-LDL, maintain HUVEC proliferation and protect HUVECs against apoptosis via the suppression of LOX-1. PMID- 28565757 TI - An exploratory study into the role of miR-204-5p in pregnancy-induced hypertension. AB - The molecular mechanism that leads to pregnancy-induced hypertension (PIH), a pregnancy-specific syndrome, remains poorly understood. It has been suggested that microRNAs (miRNAs) may be potentially useful biomarkers for severe preeclampsia (PE), which is an important condition associated with PIH. The aim of the present study was to identify miR-204 by verifying differentially expressed serum miRNAs in patients with PIH during pregnancy compared with normal controls. Subsequently, the effects of miR-204 on proliferation and apoptosis of human choriocarcinoma (JAR) cells in hypoxic microenvironment were investigated. Previous studies indicated a number of miRNA candidates and the present study validated the expression of eight miRNAs in serum samples using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A higher expression of miR-204 was identified in patients with PIH. To assess the impact of miR-204 inhibition on hypoxic JAR cells function in vitro, cell proliferation was detected using a Cell Counting Kit-8 assay. The rate of apoptosis and cell cycle progression was then examined by flow cytometry. RT-qPCR confirmed that serum miR-204-5p is more highly expressed in patients with PIH. Further statistical analysis indicated that the survival ratio of JAR cells in hypoxic microenvironments was increased in the miR-204-5p inhibitor group. However, the miR-204-5p inhibitor protected hypoxic JAR cells from apoptosis. The analysis of cell-cycle status demonstrated that the percentage of cells in the G2/G1 phase was larger compared with the control group. The results of the present study suggest that low levels of miR-204-5p may increase cell proliferation and reduce cell apoptosis with cell cycle changes in vitro. Therefore, serum miR-204-5p may be used as a notable biomarker for the diagnosis, prevention and treatment of PIH. PMID- 28565758 TI - Apigenin in the regulation of cholesterol metabolism and protection of blood vessels. AB - Hyperlipidemia is a major independent risk factor for atherosclerosis. Seeking natural compounds in medicinal plants capable of reducing blood fat and studying their mechanisms of action has been the focus of research in recent years. The aim of the present study was to analyze the mechanisms of apigenin in regulating cholesterol metabolism and protecting blood vessels, and to provide a theoretical basis for the clinical application of apigenin. The mouse model of hyperlipidemia was established to verify the efficacy of apigenin in improving hyperlipidemia and to observe the mechanism of action of apigenin in reducing cholesterol content. In vitro cell experiments were conducted to evaluate the role of apigenin in mediating reverse cholesterol transport. Additionally, H2O2-injured human umbilical venous endothelial cells (EA.hy926 cells) were used for further study on the roles of apigenin in resisting oxidization and protecting vascular endothelial cells. Apigenin significantly regulated blood fat, reduced animal weight, and reduced total cholesterol (P=0.024), triglyceride (P=0.031) and low density lipoprotein cholesterol (P=0.014) in the serum of the high-fat diet mice. Apigenin improved the blood lipid metabolism of the hyper-lipidemia model mice. Body weight and serum cholesterol content increased abnormally (P=0.003) as a consequence of high-fat diet. Apigenin increased the activity of superoxide dismutase in EA.hy926 cells (P=0.043) and increased the amount of nitric oxide secreted by the cells (P=0.038). Apigenin also inhibited the proliferation of vascular smooth muscle cells in a dose-dependent manner (P=0.036). In conclusion, apigenin can regulate cholesterol metabolism in vivo and plays a role in reducing the level of blood fat by promoting cholesterol absorption and conversion, and accelerating reverse cholesterol transport. Apigenin also has a role in resisting oxidization and protecting blood vessels. PMID- 28565759 TI - Oral administration of ampelopsin protects against acute brain injury in rats following focal cerebral ischemia. AB - Ampelopsin (AMP) is isolated from the Chinese medicinal herb Ampelopsis grossedentata (Hand-Mazz) and has been associated with numerous biological and pharmacological activities. However, it is not clear whether AMP has a direct protective effect on cerebral ischemia reperfusion injury. Therefore, the present study investigated its role in acute brain injury following focal cerebral ischemia in rats. The current study induced transient focal cerebral ischemia by performing middle cerebral artery occlusion (MCAO) for 60 min, followed by 24 h of reperfusion. Rats were exposed to 40, 80 and 160 mg/kg AMP by oral administration 30 min prior to MCAO and the cysteinyl leukotriene receptor 1 antagonist, pranlukast (0.1 mg/kg, i.p.) was used as a positive control. Neurological deficit scores were observed and an inclined board test was used to assess behavioral dysfunction. The coronal slices were stained with 3,5 triphenyltetrazolium chloride to determine the infarct volume and brain edema. Neuronal morphology was assessed in brain sections stained with cresyl violet and degenerating neurons were identified using Fluoro-Jade B staining. Blood-brain barrier permeability was determined with immunoglobulin (Ig)G immunohistochemistry. Interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF alpha) in serum and cerebrospinal fluid were measured using ELISA kits. AMP at 80 and 160 mg/kg attenuated neurological deficits, reduced infarct volume, brain edema, IgG exudation and neuron degeneration and loss. Similar to pranlukast, AMP also inhibited the MCAO-induced IL-1beta and TNF-alpha release. Thus, AMP has a neuroprotective effect on acute brain injury following focal cerebral ischemia in rats at an effective oral dose of 80-160 mg/kg. The results of the current study indicate a therapeutic role for AMP in the treatment of ischemic stroke. PMID- 28565760 TI - In silico insight into EGFR treatment in patients with lung carcinoma and T790M mutations. AB - The T790M mutational basis of treatment failure, following treatment via alteration of the epidermal growth factor receptor (EGFR) pathway, is a well known anomaly in patients with non-small cell lung cancer (NSCLC). The T790M mutation activates the kinase domain, causing tyrosine kinase inhibitors, such as gefitinib, to elicit little or no response. To overcome this acquired resistance in NSCLC cells, the present study utilized a structure-based drug designing method to identify a novel lead compound. An in-house traditional Chinese medicinal compound database was used and following initial virtual screening, pre absorption, distribution, metabolism and excretion/Tox and automated docking analyses, nardosinon was selected as the most appropriate candidate for further analysis. Two NSCLC cell lines, PC9GR4 and H2347, were used to test nardosinon and the results were compared with gefitinib. Results from an initial cell death assay revealed that nardosinon was able to induce cell death in NSCLC cells with and without the T790M mutation. These findings suggest that nardosinon may be an effective pharmacological compound for NSCLC treatment, including T790M EGFR mutant NSCLC cells. PMID- 28565761 TI - Clinical application of intra-aortic balloon pump in patients with cardiogenic shock during the perioperative period of cardiac surgery. AB - Intra-aortic balloon pumps (IABP) have saved many patients with cardiogenic shock during the perioperative period of cardiac surgery. However, the ideal insertion timing is controversial. In the present study, we aimed to optimize the insertion timing, in order to increase the survival rate of the patients. A total of 197 patients with cardiogenic shock during the perioperative period of cardiac surgery and implemented IABP from January 2011 to October 2015 were selected for the study. Patients were divided into five groups on the basis of application timing of IABP: 0-60, 61-120, 121-180, 181-240 and >240 min. The 30-day mortality, application rate of continuous renal replacement therapy (CRRT), duration of mechanical ventilation, duration of hospital stay and hospitalization charges were analyzed in the above groups. The risk factors related to mortality and the occurrence of IABP complications were also analyzed. The mortality in the 0-60, 61-120, 121-180, 181-240 and >240 min groups were 42.17, 36.6, 77.3, 72.7 and 79.3%, respectively. Earlier IABP insertion resulted in less patients receiving CRRT from acute renal failure and less daily hospitalization charges. However, the IABP application timing had no effect on indexes such as hospitalization duration, duration of mechanical ventilation and total hospitalization charges. Multifactor logistic regression analysis indicated that the independent risk factors of death in patients with cardiogenic shock during cardiac surgery were related to IABP support timing and vasoactive-inotropic score (VIS) before balloon insertion. In the first 120 min of cardiogenic shock during the perioperative period of cardiac surgery, IABP application decreased 30 day mortality. Mortality was related with VIS score of patients, which can be used to predict the prognosis of patients with cardiogenic shock. PMID- 28565762 TI - Technique and results in total laparoscopic radical cystectomy with sigmoidorectal pouch (Mainz pouch II) - an initial experience. AB - We used laparoscopic radical cystectomy (LRC) with urinary diversion for muscle invasive bladder cancer. A series of total LRC is presented with Mainz pouch II after we had gained experience of nearly 200 open radical cystectomy and 23 LRC. Since from October 2010 to April 2012, we performed totally LRC in 5 patients with muscle-invasive bladder cancer with Mainz pouch II as a urinary diversion. We analyzed age, pathological staging, continence, operative time, blood loss, blood transfusion volume, and complications. The mean age of the patients was 58.8+/-7.6 years (range, 49-69 years), and the follow-up time was 15.4+/-4.72 months. The mean operative time was 577.0+/-126.4 min for total LRC, with a mean blood loss of 280.0+/-130.38 ml and a mean hospital stay of 29.4+/-9.2 days. Blood transfusion was required in two cases, and immediate and late complications were observed in 2 cases. In conclusion, total LRC with urinary diversion is feasible for the management of muscle-invasive bladder cancer, by experienced surgeons, and despite the high level of difficulty of these procedures. PMID- 28565763 TI - Effects of glucocorticoid on the expression and regulation of aquaporin 5 in the paranasal sinus of rats with chronic rhinosinusitis. AB - Aquaporins (AQPs) are water-specific membrane channel proteins that regulate water homeostasis for cells and organisms. AQP5 serves an important role in the maintenance of mucosal water homeostasis, and potentially contributes to mucosal edema and inflammation formation in chronic rhinosinusitis (CRS). The aim of the present study was to explore the expression pattern of AQP5 and the effect of glucocorticoids on AQP5 expression in rats with CRS. The rats were randomly divided into three equal groups, as follows: CRS, dexamethasone (dexa) treatment and control groups. A polyvinyl acetal material containing Staphylococcus aureus was inserted into the left nasal cavity of each rat from the CRS and dexa groups. On the 90th post-operative day, the dexa group received dexamethasone (2 mg/kg/day) via intraperitoneal injection for 7 days. The controls did not receive any treatment. The expression of AQP5 in the sinonasal mucosa was determined using immunohistochemistry and quantitative PCR. The immunoreactivities of AQP5 were primarily noted in the epithelial lining and glandular cells, the vascular endothelium and in the goblet cells in the sinonasal mucosa. The AQP5 mRNA expression level was significantly higher in the dexa group than in the control and CRS groups (P=0.006 and P=0.014, respectively). However, no significant difference was indicated between the CRS and control groups (P=0.760). In conclusion, the current study suggests that glucocorticoids induce AQP5 expression in the sinonasal mucosa of CRS rats, which highlights AQP5 as a potential target in the diagnosis and treatment of CRS. PMID- 28565764 TI - Evaluation of the maintenance of stemness, viability, and differentiation potential of gingiva-derived stem-cell spheroids. AB - Gingiva-derived stem cells have been applied for tissue-engineering purposes and may be considered a favorable source of mesenchymal stem cells as harvesting stem cells from the mandible or maxilla may be performed with ease under local anesthesia. The present study was performed to fabricate stem-cell spheroids using concave microwells and to evaluate the maintenance of stemness, viability, and differentiation potential. Gingiva-derived stem cells were isolated, and the stem cells of 4*105 (group A) or 8*105 (group B) cells were seeded into polydimethylsiloxane-based, concave micromolds with 600 um diameters. The morphology of the microspheres and the change of the diameters of the spheroids were evaluated. The viability of spheroids was qualitatively analyzed via Live/Dead kit assay. A cell viability analysis was performed on days 1, 3, 6, and 12 with Cell Counting Kit-8. The maintenance of stemness was evaluated with immunocytochemical staining using SSEA-4, TRA-1-60(R) (positive markers), and SSEA-1 (negative marker). Osteogenic, adipogenic, and chondrogenic differentiation potential was evaluated by incubating spheroids in osteogenic, adipogenic and chondrogenic induction medium, respectively. The gingiva-derived stem cells formed spheroids in the concave microwells. The diameters of the spheroids were larger in group A than in group B. The majority of cells in the spheroids emitted green fluorescence, indicating the presence of live cells at day 6. At day 12, the majority of cells in the spheroids emitted green fluorescence, and a small portion of red fluorescence was also noted, which indicated the presence of dead cells. The spheroids were positive for the stem cell markers SSEA-4 and TRA-1-60(R) and were negative for SSEA-1, suggesting that these spheroids primarily contained undifferentiated human stem cells. Osteogenic, adipogenic, and chondrogenic differentiation was more evident with an increase of incubation time: Mineralized extracellular deposits were observed following Alizarin Red S staining at days 14 and 21; oil globules were increased at day 18 when compared with day 6; and Alcian blue staining was more evident at day 18 when compared with day 6. Within the limits of this study, stem-cell spheroids from gingival cells maintained the stemness, viability, and differentiation potential during the experimental periods. This method may be applied for a promising strategy for stem-cell therapy. PMID- 28565765 TI - Pravastatin reduces radiation-induced damage in normal tissues. AB - Pravastatin is an inhibitor of 3-hydroxy-3-methyl- glutaryl-coenzyme A reductase that has been reported to have therapeutic applications in a range of inflammatory conditions. The aim of the present study was to assess the radioprotective effects of pravastatin in an experimental animal model. Mice were divided into two groups: The control group received ionizing radiation with no prior medication, while the pravastatin group received pravastatin prior to ionizing radiation. Pravastatin was administered orally at 30 mg/kg body weight in drinking water at 24 and 4 h before irradiation. Intestinal crypt epithelial cell survival and the incidence of apoptosis in the intestine and lung were measured post-irradiation. The effect of pravastatin on intestinal DNA damage was determined by immunohistochemistry. Finally, the effect of pravastatin on tumor response to radiotherapy was examined in a mouse mesothelioma xenograft model. Pravastatin increased the number of viable intestinal crypts and this effect was statistically significant in the ileum (P<0.0001). The pravastatin group showed significantly lower apoptotic indices in all examined parts of the intestine (P<0.0001) and tended to show reduced apoptosis in the lung. Pravastatin reduced the intestinal expression of ataxia-telangiectasia mutated and gamma-H2AX after irradiation. No apparent pravastatin-related differences were observed in the response of xenograft tumors to irradiation. In conclusion, pravastatin had radioprotective effects on the intestine and lung and reduced radiation-induced DNA double-strand breaks. Pravastatin may increase the therapeutic index of radiotherapy. PMID- 28565766 TI - A recurrent mutation in bone morphogenetic proteins-2-inducible kinase gene is associated with developmental dysplasia of the hip. AB - Developmental dysplasia of the hip (DDH) is a complex disorder of the hip joint affecting 1-50/00 of newborns. While genetic influence on DDH has been long known, DDH has not been ascribed to any specific genetic event. The present study reported on variants contributing to DDH susceptibility in a family with four individuals affected across three generations. Whole-exome sequencing was performed in three affected and two unaffected individuals of a pedigree with DDH. Candidate variants were confirmed by Sanger sequencing and then validated in available family members and 37 sporadic DDH patients. Two novel heterozygous, inframe mutations causing multi-nucleotide substitution polymorphisms (c.1432_1440delCAGCAGCAG corresponding with p.Gln478_480del and c.1440_1441insCAG corresponding with p.Gln480ins) in exon 11 of chromosome 4 in bone morphogenetic proteins-2-inducible kinase (BMP2K) were identified; these were found in members of the pedigree affected by DDH and in the unaffected grandmother of the proband, who was deemed to be the carrier of potential mutations, but not in the unaffected normal control saunt of the proband. These two variants shared the same genomic coordinate but with different types of mutation in BMP2K. BMP2K is known to be associated with bone and cartridge development and heterozygous mutations were found to be present in 4/4 (100%) of the affected family members, 4/15 (26.7%) of the unaffected family members and 0/7 (0%) of the unaffected unrelated family members. Genotyping of 37 unrelated, sporadic DDH patients showed that three cases were positive for the BMP2K c.1432_1440delCAGCAGCAG variants (8.12%). These findings provided strong evidence for the role of BMP2K variants in causing DDH and demonstrated that the combination of pedigree information and next-generation sequencing is an effective method for identifying pathogenic sites associated with DDH. PMID- 28565768 TI - Raman spectrum: A potential biomarker for embryo assessment during in vitro fertilization. AB - The aim of the study was to investigate whether Raman spectrum is consistent with the morphological scoring of the embryo of day 3 during in vitro fertilization (IVF). The spent culture media of embryo of day 3 from 10 patients were collected and analyzed. The samples were analyzed using Raman spectroscopy and graded according to the standard embryo scoring system simultaneously. Data showed that the Raman spectra obtained from the droplet of media were useful, as they can act as the characteristic signature for protein and amino acids. The Raman biospectroscopy-based metabonomics profiling of spent media was consistent with the result of conventional morphological evaluation. In conclusion, this technology offers great potential for the development of tools allowing rapid non invasive assessment of the quality of embryo of day 3 during IVF. PMID- 28565767 TI - Hair follicle-derived mesenchymal cells support undifferentiated growth of embryonic stem cells. AB - The aim of the present study was to investigate whether feeder layers composed of human hair follicle-derived mesenchymal stem cells (hHFDCs) are able to support human embryonic stem cells (hESCs). hHFDCs and mouse embryonic fibroblasts (MEFs) were isolated and cultured in Dulbecco's modified Eagle's medium (DMEM)/F-12 and low-glucose DMEM, respectively. hHFDCs were passaged three times and subsequently characterized. hHFDCs and MEFs were mitotically inactivated with mitomycin C for 3 h prior to co-culture with H9-hESCs. hESCs were initially established on a mouse feeder layer, subsequently transferred onto a human feeder layer and split every 5 days. Cell morphology, expression of specific 'undifferentiation' markers and growth factors, and the differentiation capacity of hESCs grown on the hHFDC feeder layer were analyzed. hHFDCs are adherent to plastic, possess the classic mesenchymal stem cell phenotype [they express cluster of differentiation (CD)90, CD73 and CD105] and are able to differentiate into adipocytes, chondroblasts and osteocytes, indicating that these cells are multipotent. Population-doubling time analysis revealed that hHFDCs rapidly proliferate over 34.5 h. As a feeder layer, hHFDC behaved similarly to MEF in maintaining the morphology of hESCs. The results of alkaline phosphatase activity, reverse transcription-quantitative polymerase chain reaction analysis of the expression of pluripotency transcription factors [octamer-binding transcription factor 4 (Oct4), Nanog and sex determining region Y-box 2], and immunofluorescence assays of markers (stage specific embryonic antigen-4 and Oct4) in hESCs co-cultured over hHFDC, indicated that the undifferentiated state of hESCs was preserved. No change in the level of growth factor transcripts (bone morphogenetic protein 4, fibroblast growth factor 2, vascular endothelial growth factor, Pigment epithelium-derived factor and transforming growth factor-beta1) was detected for either feeder layer prior to or following inactivation. Similar phenotypes of embryoid body formation, size and morphology were observed in the hHFDC and MEF feeders. In conclusion, hHFDC maintained hESCs in an undifferentiated state comparable to MEF in standard conditions, which may be an important finding regarding the establishment of stem cell-based translational applications. PMID- 28565769 TI - A micro-CT study of microstructure change of alveolar bone during orthodontic tooth movement under different force magnitudes in rats. AB - The dynamic changes of the microstructure of alveolar bone during orthodontic tooth movement in rats was explored by employing micro-computed tomography (micro CT) system and to provide theoretical reference for clinical orthodontic treatment. Ten rats were selected randomly as control among 70 adult female Wistar rats, and the other 60 rats were divided into 25-g and 75-g groups of equal number. Orthodontic appliance with force of 25 g and 75 g was installed to perform the molar mesial movement. Microstructural parameters for trabecular bone mesial to the distobuccal root were evaluated at different time points using micro-CT system. Moreover, distance for mesial movement of the molar were measured. Microstructural parameters for trabecular bone of two groups showed no significant changes from day 0 to day 3 (P>0.05); from day 3 to day 7, bone mineral density (BMD), bone volume/total volume (BV/TV) and trabecular thickness (Tb.Th) decreased significantly (P<0.05), whereas trabecular separation (Tb.Sp) and structure model index (SMI) increased significantly (P<0.05); from day 7 to day 14, in 25-g group, BMD, BV/TV and Tb.Th increased significantly (P<0.05), while Tb.Sp and SMI decreased significantly (P<0.05). Correspondingly, in 75-g group, changes of parameters did not carry any statistical significance (P>0.05). Furthermore, the 75-g group showed larger distance than 25-g group only at day 14 (P<0.05). In conclusion, in order to maintain the health of periodontal tissues, adequate time for repair and recovery is needed to ensure reasonable remolding of alveolar bone and healthy movement of the orthodontic tooth. PMID- 28565770 TI - Dose-dependent effect of Curcuma longa for the treatment of Parkinson's disease. AB - Curcuma longa is a plant that belongs to the ginger family, Zingiberaceae. It has been used in Siddha medicine for thousands of years in Asia. Parkinson's disease (PD) is a degenerative disorder of the central nervous system that affects the motor system of the brain. Death of dopamine-producing cells in the substantia nigra leads to PD. Exposure to salsolinol, which is an endogenous neurotoxin, has been associated with damage to dopamine-producing cells. The present study assessed the toxicity of salsolinol in SH-SY5Y human neuroblastoma cells and subsequently investigated the neuroprotective potential of C. longa extract in salsolinol-induced toxic conditions in SH-SY5Y cells. Sulphorhodamine-B assay showed the protective effect of the anti-apoptotic effect of treated SH-SY5Y cells. Fluorescence microscopy and confocal laser scanning microscope analysis indicated the anti-apoptotic impact of the C. longa extract. Mitochondria-derived reactive oxygen species were reduced in C. longa extract-treated SH-SY5Y cells. Downregulated mRNA expression levels of p53, Bcl-2-associated X protein and caspase 3 were observed in the C. longa extract-treated SH-SY5Y cells. Caspase 3 activity was reduced in the C. longa extract-treated SH-SY5Y cells. In conclusion, the present findings demonstrated that solsolinol is neurotoxic to SH SY5Y cells, and C. longa extract may be useful in the treatment of PD. PMID- 28565771 TI - Erythropoietin facilitates the recruitment of bone marrow mesenchymal stem cells to sites of spinal cord injury. AB - Despite the successes of bone marrow mesenchymal stem cell (BMSC) transplantation for the treatment of spinal cord injuries, only a small fraction of grafted cells migrate to the target areas. Therefore, there remains a need for more efficient strategies of BMSC delivery. The present study was designed to explore this. Rat models of spinal cord injury (SCI) were established and exposed to phosphate buffered saline (control), BMSCs or BMSCs + erythropoietin (EPO). Basso, Beattie and Bresnahan (BBB) locomotor scale and grid walk tests were then utilized to estimate neurological rehabilitation. Additionally, the following assays were performed: Immunofluorescence localization of BMSCs to the site of SCI; the transwell migration assay to detect in vitro cellular migration; the terminal deoxynucleotidyl transferase dUTP nick end labeling assay to determine the apoptotic index of the lesion; and western blotting analysis to evaluate the expression of vascular endothelial growth factor (VEGF) and brain derived neurotrophic factor (BDNF) at the site of SCI. The BBB scores of the BMSC + EPO treated group were significantly increased compared with the BMSC treatment group (P<0.05). For example, BMSC + EPO treated rats had a significantly decreased number of hind limb slips compared with the BMSC treatment group (P<0.05). Furthermore, EPO significantly increased the migration capacity of BMSCs compared with the control group (P<0.001). In addition, the apoptotic index of the BMSC + EPO group was significantly decreased compared with the BMSC group (P<0.05). Green fluorescent protein-labeled BMSCs were detected at the site of SCI in the BMSC and BMSCs + EPO groups, with the signal being notably stronger in the latter. Moreover, the expression of VEGF and BDNF in the BMSCs + EPO group was significantly increased compared with the BMSC group (P<0.05). In conclusion, the results of the present study indicate that EPO can facilitate the recruitment of BMSCs to sites of SCI, increase expression of BDNF and VEGF, and accelerate recovery of neurological function following SCI. PMID- 28565772 TI - Association of Mycoplasma pneumoniae infection with increased risk of asthma in children. AB - The present study was conducted to investigate the relationship between Mycoplasma pneumoniae (MP) infection and the risk of asthma among children by detecting the rate of MP immunoglobulin M (MP-IgM) and the eosinophil (EOS) count. A total of 139 asthmatic children were enrolled as the case group and assigned into three groups: Group A (aged <3 years, n=42), group B (aged 3-8 years, n=45) and group C (aged >8 years, n=52). Additionally, 115 healthy children were enrolled in the control group. Enzyme-linked immunosorbent assay was used to measure the MP-IgM-positive rate. EOS count was detected in the experimental and control groups by using a hemocytometer analyzer. A meta analysis was performed by using the Comprehensive Meta-Analysis version 2.0 software. The positive rates of the MP-IgM and EOS count in the experimental group were significantly higher than those in control group (both P<0.001). Furthermore, the asthmatic children in group C had a higher MP-IgM-positive rate and EOS count as compared to those in groups A and B, respectively (all P<0.05). Results from groups A and B were not statistically significant (all P>0.05). The meta-analysis further confirmed that asthmatic children had a higher MP-IgM positive rate as compared to the healthy controls (P<0.001). Age-stratified analysis revealed that the MP-IgM-positive rate in asthmatic children aged >=8 and <8 years was significantly higher than that in the healthy controls (P=0.003 and P<0.001). Asthmatic children had a higher MP-IgM-positive rate and EOS count as compared with controls, suggesting that the MP infection may be closely associated with the risk of asthma. Additionally, the positive rate of MP-IgM may indicate an important biological marker in predicting the development of asthma. PMID- 28565773 TI - Pien Tze Huang Gan Bao ameliorates carbon tetrachloride-induced hepatic injury, oxidative stress and inflammation in rats. AB - Liver damage results from a variety of insults, including hepatitis and chemical toxicity from alcohol, drugs and other toxins. The present study evaluated the hepatoprotective effects and potential mechanisms of action of the Traditional Chinese Medicine Pien Tze Huang Gan Bao (GB) in a rat model of carbon tetrachloride (CCl4)-induced liver injury. Sixty male Sprague-Dawley rats were randomly divided into six different groups: i) Control, ii) CCl4 injury model and groups treated with iii) silymarin as a positive drug control, iv) 150 mg/kg GB, v) 300 mg/kg GB and vi) 600 mg/kg GB. Control rats received no treatment, while the remaining ones were intraperitoneally injected with CCl4 (2 ml/kg) to induce acute liver disease. Silymarin or GB was orally administered prior to CCl4 treatment in various treatment groups for 7 days. Animals were sacrificed 24 h post-CCl4 injection. It was revealed that GB significantly reduced serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase and total bilirubin levels in the serum induced by CCl4. BG also prevented CCl4-induced changes in liver tissues, as revealed by histopathological analysis. CCl4-induced reductions in endogenous liver antioxidant enzyme activities of superoxide dismutase, glutathione and glutathione peroxidase as well as increases in malondialdehyde and thiobarbituric acid reactive substances were inhibited by GB treatment. Activated NF-kappaB in liver tissues was also significantly increased by CCl4, which was attenuated by GB as indicated by immunohistochemical and PCR analysis. Furthermore, CCl4 mediated increases in the inflammatory factors tumor necrosis factor-alpha and interleukin-1beta secretion into the serum and their expression in liver tissues were reversed following GB treatment, as revealed by ELISA and PCR, respectively. These findings suggested that GB protects against CCl4-induced hepatic injury, inflammation and oxidative damage in rats and may be useful in future clinical application of liver injury and disease. PMID- 28565774 TI - Effects of Ankaferd BloodStopper on bone healing in an ovariectomized osteoporotic rat model. AB - Bone defects resulting from oncological surgical resections, congenital facial anomalies, trauma or infection represent a significant and common clinical problem. The present study aimed to evaluate the effects of a commercially available medicinal plant extract product, Ankaferd BloodStopper (ABS), on bone healing. The present study was performed on 24 female ovariectomized (OVX) rats. A defect on each rat calvarium was created using a trephine burr prior to the rats being divided into two groups. Defects were grafted with a gelatin sponge soaked with normal saline (control group) or plant extract (experimental group). Half of the animals were sacrificed after 2 weeks and the others after 4 weeks. In the control group, the defects were not filled with regenerated bone. By contrast, in the experimental group, all defect areas had an increased amount of regenerated bone and connective tissue. Osteoblastic activity appeared to be greater in the experimental group however, osteoclastic activity was observed to be higher in the control group. At 2 and 4 weeks, there was a significant difference in the amount of newly regenerated bone observed in the experimental group compared with the control group (P<0.05). Therefore, the results of the present study indicated that local ABS application had a positive effect on bone healing in the OVX rat model. PMID- 28565775 TI - Identification of key genes and pathways for peri-implantitis through the analysis of gene expression data. AB - The present study attempted to identify potential key genes and pathways of peri implantitis, and to investigate the possible mechanisms associated with it. An array data of GSE57631 was downloaded, including six samples of peri-implantitis tissue and two samples of normal tissue from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) in the peri-implantitis samples compared with normal ones were analyzed with the limma package. Moreover, Gene Ontology annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for DEGs were performed by DAVID. A protein-protein interaction (PPI) network was established using Cytoscape software, and significant modules were analyzed using Molecular Complex Detection. A total of 819 DEGs (759 upregulated and 60 downregulated) were identified in the peri implantitis samples compared with normal ones. Moreover, the PPI network was constructed with 413 nodes and 1,114 protein pairs. Heat shock protein HSP90AA1 (90 kDa alpha, member 1), a hub node with higher node degrees in module 4, was significantly enriched in antigen processing, in the presentation pathway and nucleotide-binding oligomerization domain (NOD)-like receptor-signaling pathway. In addition, nuclear factor-kappa-B1 (NFKB1) was enriched in the NOD-like receptor-signaling pathway in KEGG pathway enrichment analysis for upregulated genes. The proteasome is the most significant pathway in module 1 with the highest P-value. Therefore, the results of the present study suggested that HSP90AA1 and NFKB1 may be potential key genes, and the NOD-like receptor signaling pathway and proteasome may be potential pathways associated with peri implantitis development. PMID- 28565776 TI - (+)-Cholesten-3-one induces osteogenic differentiation of bone marrow mesenchymal stem cells by activating vitamin D receptor. AB - In our previous reports, it was revealed that steroids in traditional Chinese medicine (TCM) have the therapeutic potential to treat bone disease. In the present study, an in vitro model of a vitamin D receptor response element (VDRE) reporter gene assay in mesenchymal stem cells (MSCs) was used to identify steroids that enhanced osteogenic differentiation of MSCs. (+)-cholesten-3-one (CN), which possesses a ketone group that is modified in cholesterol and cholesterol myristate, effectively promoted the activity of the VDRE promoter. Phenotypic cellular analysis indicated that CN induced differentiation of MSCs into osteogenic cells and increased expression of specific osteogenesis markers, including alkaline phosphatase, collagen II and Runt-related transcription factor 2. Furthermore, CN significantly increased the expression of osteopontin, the target of the vitamin D receptor (VDR), which indicated that CN may activate vitamin D receptor signaling. Over-expression of VDR or knockdown studies with VDR-small interfering RNA revealed that the pro-differentiation effects induced by CN required VDR. Furthermore, the present study determined that the C-terminal region of the VDR is responsible for the action of CN. Taken together, the present findings demonstrated that CN induced osteogenic differentiation of MSCs by activating VDR. The present study explored the regulation of stem cells by using a series of similar steroids and provided evidence to support a potential strategy for the screening of novel drugs to treat bone disease in the future. PMID- 28565777 TI - Expression of pericardial fluid T-cells and related inflammatory cytokines in patients with chronic heart failure. AB - Pericardial fluid, as a biochemical indicator of heart status, directly indicates pathological alteration to the heart. The accumulation of pericardial fluid can be attributed to an underlying systemic or local inflammatory process. However, the pericardial fluid expression of cellular surface markers, as well as several cytokines in chronic heart failure (CHF), remain unclear. In order to evaluate these issues further the pericardial fluid expression of several cytokines and the surface expression of activity markers between CHF patients and non-heart failure (NHF) patients were analyzed. The pericardial fluid expression of cytokines was measured by immunofluorescence and biomarker of plasma N-terminal propeptide of B-type natriuretic peptide (NT-proBNP), while pericardial fluid levels of soluble glycoprotein 130 (sgp130) were analyzed by ELISA in 50 CHF and 24 NHF patients. In addition, the surface expression of activation markers for T cells was measured by immunohistochemistry. Patients with CHF demonstrated increased levels of plasma NT-proBNP and pericardial fluid sgp130. Surface expression of cellular activation markers CD25 and Foxp3 in the pericardial fluid was increased in patients with CHF. Moreover, the pro- and anti-inflammatory cytokines interferon (IFN)-gamma, interleukin (IL)-6 and IL-10 in patients with CHF also demonstrated an increased expression within its pericardial fluid. In addition, there was infiltration of inflammatory cells and enhanced expression of inflammatory cytokines in the pericardial fluid of patients with CHF, which may reflect T cell activation, suggesting that systemic inflammation is important in the progression of CHF. This evidence could indicate a possible novel target for future therapeutics and prevention of CHF. PMID- 28565778 TI - Value of a new pathological classification of lumbar intervertebral disc herniation based on transforaminal endoscopic observations. AB - Removal of herniated disc materials based on an imaging only method may not relieve symptoms in many patients. Therefore, the aim of the present study was to develop a transforaminal endoscopic method of classifying the pathological type of lumber intervertebral disc herniation and to compare the outcomes of surgery based on the pathological type with those of conventional endoscopic disc removal. The records of patients who received endoscopic transforaminal nucleotomy with foraminoplasty for symptomatic lumbar disc herniation between 2009 and 2013 were retrospectively reviewed. Patients were then divided into two groups: Group A, which consisted of 275 patients who received conventional endoscopic transforaminal nucleotomy with foraminoplasty between 2009 and 2011 and group B, which consisted of 316 patients who received 'targeted' endoscopic transforaminal nucleotomy with foraminoplasty between 2011 and 2013 (based on the pathological type of disc herniation identified at surgery, including fresh, calcified and scar type based on intraoperative observations). The results showed that there were no significant differences in age, gender, body mass index, symptom duration, operated segments or previous invasive therapies between the two groups. Moreover, evaluation of visual analogue scale pain scores and Oswestry disability index scores revealed that the patients in group B had a greater improvement in symptoms than those in group A (P<0.05). In addition, an age >40 years and a longer symptom duration were associated with the calcified type, and previous invasive therapy was associated with the scar type. Therefore, specific surgical treatment based on the transforaminal endoscopic pathological type can result in better outcomes for patients with lumbar disc herniation. PMID- 28565779 TI - Expression of integrin-linked kinase improves cardiac function in a swine model of myocardial infarction. AB - Previous studies have described the beneficial effects of overexpressing integrin linked kinase (ILK) after myocardial infarction (MI) in small animal models. However, the effects of ILK in pre-clinical large animals are not known. To move closer to clinical translation, we examined the effects of ILK gene transfer in a swine model of ischemic heart disease. Swine received percutaneous intracoronary injections of adenoviral vector expressing ILK (n=10) or empty ad-null (n=10) in the left anterior descending coronary artery (LAD) following LAD occlusion. Four weeks after transfection, we confirmed that transgene expression was restricted to the infarcted area in the cardiac tissue. Imaging studies demonstrated preserved cardiac function in the ILK group. ILK treatment was associated with reduced infarcted scar size and preserved left ventricular (LV) geometry (LV diameter and LV wall thickness). Enhanced angiogenesis was preserved in the ILK animals, along with reduction of apoptosis. ILK gene therapy improves cardiac remodeling and function in swine following MI associated with increased angiogenesis, reduced apoptosis, and increased cardiomyocyte proliferation with no signs of toxicity. These results may deliver a new approach to treat post infarct remodeling and subsequent heart failure. PMID- 28565780 TI - Comparison of the purity and vitality of natural killer cells with different isolation kits. AB - Natural killer (NK) cells are innate lymphocytes that aid in the protection of the host from infectious diseases and cancer. In vitro studies of NK cells have provided a foundation for developing clinical adoptive NK-cell transferred immunotherapy against human tumors. To elucidate the functions and mechanisms of NK cell populations, it is important to develop an optimal, highly reproducible and reliable isolation method. The present comparative study was performed with four different NK cell isolation kits of magnetic bead labeling made by Miltenyi and Stemcell companies, including positive selection kits [cluster of differentiation (CD)-49b, using the monoclonal antibody DX5) MicroBeads] and negative selection kits. In addition, the viability of NK cells isinterleukin-2 (IL-2)-dependent in vitro and thus the concentration of IL-2 is critical for maintaining longer cell viability of NK cells. NK cell purity and viability after culturing, for 24, 48 or 72 h, with or without IL-2 (0, 100, 300 or 500 U/ml) was investigated in the present study. Purity of NK cells varied depending on the purification kit used, despite the same method being applied. Furthermore, more granulocytes were present in purified NK cells using Miltenyi sorting kits, particularly when using the negative selection kit. The main disadvantage of DX5 positive selection using the Stemcell and Miltenyi kits was that a high percentage of CD3epsilon+ cells were mixed into the isolated NK cells. Additionally, a significant difference of NK cell purity (P=0.003) was observed while purification was performed using different surface markers. As a consequence, the use of the positive selection kit was modified and subsequently a significantly higher purity (P=0.002) and yield (P=0.004) of NK cells was obtained. Moreover, the purity of NK cells and viability with or without a range of concentrations of IL-2 was compared. Results indicated that with a higher IL-2 concentration, the NK cell purity and viability were significantly higher (P<0.05). To our knowledge, this is the first report that has compared the disadvantages of four commercial NK cell isolation kits from two well-known companies, and identified the effect of NK cell purity and viability, using different concentrations of IL-2. To conclude, the results of the present study are fundamental in aiding the further development of NK cell therapy protocols for murine in vivo models. PMID- 28565781 TI - Design and implementation of fast allergy skin test detector for traditional Chinese medicine injections. AB - Traditional Chinese medicine (TCM) injections are prepared from active substances extracted from TCMs and other natural medicines to establish scientific and technological methods, based on TCM hypotheses and experiences. A device was designed to provide a fast allergy skin test detector for TCM injections that could be applied to drugs of a single component or complex components. A novel fast allergy skin test detector for TCM injections was developed combining direct current main, drug solution permeation devices of various shape that were compatible with the skin test electrode, nano-sponge patch adsorption, and flexible liposome coverage technologies with high-amplitude pulse. The detector was characterized by simple structure, easy manipulation, low dose of drug required for the skin test, no irritation to human skin, and low-false positive rate. According to the pilot clinical use, it was able to meet the clinical demand and was promising for the prevention of allergy to TCM injections. PMID- 28565784 TI - Molecular mechanisms in microRNA-mediated TRB3 gene and hypertension left ventricular hypertrophy. AB - The present study investigated the relationship between microRNA-mediated TRB3 gene and hypertension left ventricular hypertrophy at the molecular level. Polymorphic site in TRB3 gene was identified by direct PCR method, and the correlation between the SNP site and ventricular hypertrophy was determined. MicroRNAs target gene sequence interacting on the TRB3 polymorphic site was screened by bioinformatics, and the effect of microRNAs on the TRB3 polymorphic site was finally verified by luciferase test. Two polymorphic sites rs6186912 and rs6186923 were found in the TRB3 gene, and the direct relationship between rs6186923 polymorphic site and the hypertension left ventricular hypertrophy in patients with myocardial hypertrophy was compared and analyzed. Pictar software was used to analyze the effect of miR-100 on rs6186923, and the argumentation was verified by luciferase test. In conclusion, the study showed that the TRB3 gene polymorphism rs6186923 was able to affect the TRB3 gene by affecting the binding of miR-100, which indirectly caused the formation of hypertension left ventricular hypertrophy. PMID- 28565783 TI - Traditional Chinese medicine baoxin decoction improves cardiac fibrosis of rats with dilated cardiomyopathy. AB - We investigated the effect of baoxin decoction (BXD) on myocardial fibrosis and clarified the possible mechanism of action. Dilated myocardiopathy was induced by doxorubicin injected intraperitoneally for 6 weeks. Rats that demonstrated dilated myocardiopathy were randomly divided into five groups plus a control group. Three groups were treated with BXD (7.5/kg, 15 g/kg and 30 g/kg) daily for 4 weeks. One group was treated with 8.75 g/kg of captopril (positive control), and with physiologic saline (negative control). Cardiac function was evaluated using echocardiography. Hematoxylin and eosin, and Massons trichrome staining were performed, PICP and PIIINP were assessed by ELISA, the expression of galectin-3 and collagen types I and III was evaluated with reverse transcription quantitative PCR, and interrelated proteins were detected by western blot analysis. BXD downregulated galectin-3, collagen I and III and was correlated with a high expression of fibrosis markers. It also significantly decreased myocardial collagen volume fraction (CVF), together with markedly preventing the upregulation of collagen I and III. In addition, BXD downregulated the expression of TGF-beta1 and Smad3 in the myocardial fibrosis rats. Therefore, BXD treatment significantly improved cardiac function and alleviated myocardial fibrosis in a rat model of doxorubicin-induced dilated cardiomyopathy (DCM), which is the mechanism that may be associated with inhibiting the TGF-beta1 signaling pathway. PMID- 28565782 TI - Hybrid composites of mesenchymal stem cell sheets, hydroxyapatite, and platelet rich fibrin granules for bone regeneration in a rabbit calvarial critical-size defect model. AB - The reconstruction of large bone defects remains a major clinical challenge, and tissue engineering is a promising technique for resolving this problem. Many attempts have been made to optimize bone tissue engineering protocols. The aim of the present study was to develop a process incorporating mesenchymal stem cell (MSC) sheets with nanoscale hydroxyapatite (nano-HA) and autologous platelet-rich fibrin (PRF) granules for enhanced bone formation within a critical-sized rabbit cranial defect. MSC sheets and PRF were prepared prior to in vivo experiments. The osteogenic differentiation ability of MSCs and the ultrastructure of PRF were also studied. A total of 15 New Zealand white rabbits were used in the current study and critical-size defects (CSDs) were surgically introduced in the cranium (diameter, 15 mm). The surgical defects were treated with MSC/PRF composites, MSC composites or left empty. Animals were euthanized at week 8 post-surgery. Iconography, histological and histomorphometric analysis were performed to assess de novo bone formation. The percentage of new bone in the MSC/PRF group (35.7+/ 5.1%) was significantly higher than that in the MSC (18.3+/-3.2%; P<0.05) and empty defect groups (4.7+/-1.5%; P<0.05). The results of the present study suggest that combined application of an MSC sheet with nano-HA and granular PRF enhances bone regeneration in a rabbit calvarial CSD model, and provides a novel insight into bone tissue regeneration for large bone defects. PMID- 28565785 TI - Comparison of the iCare rebound tonometer and the Goldmann applanation tonometer. AB - Tonometry is a fundamental procedure in routine ophthalmologic examination. Although regarded as the reference standard, the Goldmann applanation tonometer (GAT) has its limitations. A new portable alternative to the GAT is the iCare rebound tonometer (RT). The aim of the present study was to compare the intraocular pressure (IOP) results obtained using the RT and GAT and then correlate the results with the central corneal thickness (CCT). Moreover, the tolerability and safety of the RT were evaluated. The IOP of 336 patients (672 eyes) was determined by the RT and GAT. The patients were divided into three groups (group A, 7-15 mmHg, n=74; group B, 16-22 mmHg, n=218; and group C, 23-50 mmHg, n=44), based on the GAT IOP readings. Pachymetry and slit lamp inspection were also performed. To establish an agreement between the devices, a Bland Altman analysis and paired t-test were performed. The correlation between CCT and IOP readings obtained by the two devices were assessed using linear regression correlation analysis. The mean IOP values of the RT and the GAT were 18.30+/-5.10 and 18.52+/-4.46 mmHg, respectively. There were no significant differences between them (t=-1.31, P=0.19). The 95% confidence interval of the differences between the two devices was -5.80-6.24 mmHg. The RT readings are correlated well with those of GAT (r=0.806, P=0.001). However, the RT measurements were significantly (t=-2.84, P=0.007) lower (-1.66+/-3.87 mmHg) than those obtained with GAT when GAT >=23 mmHg. Both the RT (r=0.390, P=0.001) and the GAT (r=0.191, P=0.001) showed positive correlations with CCT. The IOP measurement with RT was well tolerated. None of the corneal epithelial defects was detected and all subjects denied discomfort. The RT is well tolerated and safe, and can be considered a reliable alternative to GAT for patients in a low to moderate IOP range. However, in patients with high IOP values, the measurements obtained with RT did not correlate well with those obtained by GAT. The RT readings are influenced more by CCT compared to GAT. PMID- 28565786 TI - Expression of S100beta protein in patients with vascular dementia after basal ganglia hemorrhage and its clinical significance. AB - We investigated the expression levels and clinical significance of S100beta protein in patients with vascular dementia (VD) after basal ganglia hemorrhage. From June 2014 to December 2015, in 138 patients with basal ganglia hemorrhage, we carried out the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) in patients on the day before the operation, the day after the operation and 9 days after the operation. Thirty-two patients (blood vessel group) had cognitive dysfunction and 106 patients (control group) had VD. One hundred thirty-eight cases of healthy adult volunteers were treated in Henan Provincial People's Hospital and were selected in the same period as healthy controls. The expression levels of serum S100beta in the three groups were tested through the ELISA method and the statistical analysis was carried out. In VD patients, the serum S100beta levels of patients were significantly higher than VD and healthy control groups; differences were statistically significant (P<0.05). However, there was no significant difference between those without VD after operation and the healthy control group (P>0.05). The correlation analysis was carried out with serum S100beta as an independent variable and mean arterial pressure, BMI, MMSE and MoCA scores as dependent variables. Our results suggest that S100beta expression levels were negatively correlated to the MMSE score (rs= 4.19) and the difference was statistically significant (P<0.05). The length of hospital stay of patients with basal ganglia hemorrhage associated with VD was significantly extended, with a mean of 23.4+/-2.8 days. The expression levels of S100beta protein in the serum of patients with VD after basal ganglia hemorrhage was significantly increased and negatively correlated to the cognitive function of patients. Therefore, it can be used as a differential diagnosis indicator of VD after the basal ganglia hemorrhage and treatment target point of the VD. PMID- 28565787 TI - Clinical observation of umbilical cord mesenchymal stem cell treatment of severe idiopathic pulmonary fibrosis: A case report. AB - Idiopathic pulmonary fibrosis (IPF) is a degenerative disease characterized by fibrosis. Cell therapy has been considered within the therapeutic options for IPF. In this study, we explored the potential benefits of human umbilical cord derived mesenchymal stem cell (HUC-MSC) intravenous infusion in the management of IPF. We describe a case of a 56-year-old man with IPF who was receiving long-term oxygen therapy (LTOT). The patient underwent HUC-MSC intravenous infusion and was followed up for 12 months. Clinical and motor tests, as well as questionnaires assessing quality of life, were performed prior to and following the transplantation. At the end of 12 months, a relevant reduction of LTOT requirement was registered; improvements in terms of physical performance, quality of life, and respiratory parameters were observed in our patient. In conclusion, a program of HUC-MSC intravenous infusion appears to be beneficial to patients with IPF and may be considered as an additional therapeutic option. PMID- 28565789 TI - Abdominal ultrasonography for patients with abdominal pain as a first-line diagnostic imaging modality. AB - The utility and limitations of abdominal ultrasonography (US) were retrospectively evaluated as a first-line diagnostic imaging modality in patients with abdominal pain. Hospital records from patients subjected to abdominal US as a first-line diagnostic imaging examination at the National Hospital Organization Shimoshizu Hospital (Yotsukaido, Japan) from April 2010 to April 2015 were analyzed. Only those patients who underwent abdominal US to diagnose abdominal symptoms were included in the present study. All patients with prior diagnostic imaging examination findings were excluded from the study in order to reduce bias of results. The analyzed patients included 39 males with an average (mean +/- standard deviation) age of 65.8+/-18.8 years and 37 females with an average age of 53.7+/-19.3 years. Diagnosis with abdominal US was in agreement with the final diagnosis in 66 of the 76 patients. Final diagnosis of symptoms by abdominal US was not successful in the remaining 10 patients who required further investigation. Acute cholangitis, acute cholecystitis, acute pancreatitis, acute appendicitis, colonic diverticulitis and spleen rupture were correctly diagnosed. Different types of cancer, including colorectal cancer, were also successfully diagnosed. Bile duct cancer and sigmoid colon volvulus could not be diagnosed by abdominal US due to the presence of intestinal gas. Abnormal findings were detected using abdominal US, but the diagnosis required additional consultation with gynecologists. Abdominal US was suitable for patients with abdominal symptoms. It is recommended that patients undergo further diagnostic imaging or consultation with gynecologists when large gas bubbles are present or gynecological conditions are suspected. PMID- 28565788 TI - Immunosuppressive agents are associated with peptic ulcer bleeding. AB - Peptic ulcer bleeding can be fatal. Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids and immunosuppressive agents are administered for long term usage. The present study assessed the association between peptic ulcer bleeding and administration of NSAIDs, corticosteroids and immunosuppressive agents. Furthermore, the efficacy of lowering the risk of peptic ulcer bleeding with proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA) was evaluated. Medical records were retrospectively analyzed for patients subjected to an upper gastrointestinal (GI) endoscopy performed at the National Hospital Organization Shimoshizu Hospital (Yotsukaido, Japan) from October 2014 to September 2015. During this period, a total of 1,023 patients underwent an upper GI endoscopy. A total of 1,023 patients, including 431 males (age, 68.1+/-12.9 years) and 592 females (age, 66.4+/-12.3 years), who had been administered NSAIDs, corticosteroids, immunosuppressive agents, PPIs and H2RAs, were respectively enrolled. Endoscopic findings of the patients were reviewed and their data were statistically analyzed. Logistic regression analysis was used to determine the odds ratio of peptic ulcer bleeding for each medication; immunosuppressive agents had an odds ratio of 5.83, which was larger than that for NSAIDs (4.77). The Wald test was applied to confirm the correlation between immunosuppressive agents and peptic ulcer bleeding. Furthermore, chi2 tests were applied to the correlation between peptic ulcer bleeding and administration of PPIs or H2RAs. Immunosuppressive agents had the largest chi2, and the P-value was 0.03. Administration of PPIs was significantly correlated with non-peptic ulcer bleeding (P=0.02); furthermore, a tendency toward non-peptic ulcer bleeding with administration of H2RA was indicated, but it was not statistically significant (P=0.12). In conclusion, immunosuppressive agents were correlated with peptic ulcer bleeding and PPIs were effective at lowering the risk of peptic ulcer bleeding. PMID- 28565790 TI - Level of serum undercarboxylated osteocalcin correlates with bone quality assessed by calcaneal quantitative ultrasound sonometry in young Japanese females. AB - The diagnostic criteria of osteoporosis were established based on bone mineral density (BMD). Therefore, BMD measured by dual energy X-ray absorptiometry has been recognized as the gold standard to diagnose osteoporosis. However, discrepancies between fracture risk and BMD have been recognized. Bone is composed of collagen scaffold reinforced by hydroxyapatite. Both protein scaffold and hydroxyapatite are involved in bone quality. BMD may indicate bone mineralization but potentially fail to assess the protein scaffold. Vitamin K contributes to bone mineralization and as a protein scaffold. A deficiency of vitamin K upregulates the level of serum undercarboxylated osteocalcin (ucOC), and serum ucOC correlates with fracture risk. However, direct association of ucOC and bone quality has not been demonstrated. For the present study, a total of 49 healthy young Japanese female college students underwent calcaneal; quantitative ultrasound sonometry (QUS) and determination of serological bone metabolic markers. QUS parameters were significantly correlated with serum 25 hydroxyvitamin D (25-OH-D) concentrations (P<0.05). A significant negative correlation was also identified between log transformed serum ucOC concentrations [Ln(ucOC)] and a QUS parameter, speed of sound (SOS) (P<0.05). Stepwise multiple regression analysis indicated that Ln(ucOC) was an independent determinant of SOS, and 25-OH-D was an independent determinant of the other two QUS parameters, transmission index (TI) and synthetic parameter osteo-sono-assessment index. As vitamin D is involved in bone mineralization, TI may reflect the mineralization. Correlation of vitamin K status, indicated by ucOC, with SOS may clarify the correlation between vitamin K status and bone quality, although the material factors that connect them have not been identified. PMID- 28565791 TI - Endobronchial ultrasound-guided transbronchial needle aspiration for thyroid cyst therapy: A case report. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is of limited usefulness for diagnosing thyroid disease, and few studies have reported its use in diagnosing and treating thyroid cysts. The present study investigated a unique case of diagnosis and treatment of a thyroid cyst by EBUS TBNA. A 67-year-old male presented with back pain. Positron emission tomography/computed tomography scanning revealed low-density signals in the right lobe of the thyroid. Needle aspiration biopsies and drainage at this site was performed, and EBUS was used for guidance in diagnosing the thyroid cyst. A follow-up chest computed tomography scan indicated that the thyroid lesion had subsequently disappeared. The present study concludes that EBUS-TBNA provides an alternative approach for diagnosing and treating deep thyroid cysts located close to the airway. In all other cases, percutaneous needle aspiration or surgery should be the first choice. PMID- 28565792 TI - Effect of ozone oxidative preconditioning on oxidative stress injury in a rat model of kidney transplantation. AB - The aim of the present study was to investigate the protective effect of ozone oxidative preconditioning (OOP) on renal oxidative stress injury in a rat model of kidney transplantation. Thirty-six male Sprague Dawley (SD) rats were randomly divided into three groups: A sham (S) group, a kidney transplantation (KT) group and an OOP and kidney transplantation (OOP+KT) group. In the S group, the rats' abdomens were opened and closed without transplantation. In the KT group, the rats received a left kidney from donor SD rats. In the OOP+KT group, donor SD rats received 15 OOP treatments by transrectal insufflations (1 mg/kg), once a day, at an ozone concentration of 50 ug/ml, before the kidney transplantation. Twenty-four hours after transplantation, the parameters of renal function of the recipients were measured. The morphology and pathological effects of renal allograft were examined using hematoxylin and eosin staining, periodic acid Schiff staining, a terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry. Markers of oxidative stress were also detected using the thiobarbituric acid method, and expression levels of Nrf-2 and HO-1 were determined by western blot analysis. Blood urea nitrogen and creatinine levels were significantly decreased in the OOP+KT group compared with the KT group, and the morphology and pathological changes of renal allograft were also less severe. Meanwhile, the renal allograft cell apoptosis index was significantly higher in the KT group compared to the OOP+KT group (P<0.05). Levels of superoxide dismutase, glutathione and catalase in the renal allografts were significantly higher in the OOP+KT group compared to those in the KT group (P<0.05), while malondialdehyde levels were significantly lower in the OOP+KT group compared to those in the KT group (P<0.05). Western blot analysis indicated that the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1) were significantly higher in the OOP+KT compared to the KT group (P<0.05). In conclusion, the mechanism by which OOP alleviates oxidative stress injury in renal transplantation may be related to the activation of the signaling pathways of Nrf-2/HO-1 and inhibition of renal tubular epithelial cell apoptosis. PMID- 28565793 TI - Involvement of neuronal pathways in the protective effects of hindlimb perconditioning during renal ischemia. AB - Remote ischemic perconditioning (RPEC) is a therapeutic intervention that has been demonstrated to reduce renal ischemia/reperfusion (I/R) injury. However, the underlying renal protective mechanism remains unclear. The present study hypothesized that RPEC may utilize neural pathways to transfer the protective signal from the perconditioned hindlimb to the kidney. Following a right nephrectomy, rats were randomly allocated into five groups (n=6). The sham group underwent the surgical protocol only. In all other groups, the left renal pedicle was clamped for 45 min and reperfused for 24 h. The I/R control group then underwent 45 min ischemia and 24 h reperfusion (I/R) with no more intervention but the I/R-NR control group underwent the ischemia and reperfusion followed by left femoral nerve (FN) and sciatic nerve (SN) resection. The RPEC group underwent ischemia and reperfusion followed by four cycles of 5 min occlusions of the left femoral artery and 5 min reperfusion. Finally, the RPEC-NR group underwent ischemia and reperfusion followed by left FN and SN resection. Following 24 h, renal functional indices, plasma blood urea nitrogen (BUN) and creatinine (Cr) levels, urinary N-acetyl-beta-glucosaminidase (NAG) release and histopathological changes were assessed. Compared with the sham group, ischemia and reperfusion in the sham and I/R control groups resulted in renal dysfunction, indicated by significantly increased levels of BUN and Cr. This was accompanied by increased urinary NAG activity and morphological damage observed in control groups. In the RPEC group, renal histology and function were significantly improved compared with the control groups. However, FN and SN resection eliminated the protection of the kidney, which was induced by RPEC. In conclusion, remote hindlimb ischemic perconditioning reduced renal I/R injury in the rat kidney in a manner that potentially involves a neural pathway. PMID- 28565794 TI - Novel two-step derivation method for the synchronous analysis of inherited metabolic disorders using urine. AB - The aim of the present study was to conduct preliminary clinical screening and monitoring using a novel two-step derivatization process of urine in five categories of inherited metabolic disease (IMD). Urine samples (100 ul, containing 2.5 mmol/l creatinine) were taken from patients with IMDs. The collected urine was then treated using a two-step derivatization method (with oximation and silylation at room temperature), where urea and protein were removed. In the first step of the derivatization, alpha-ketoacids and alpha aldehyde acids were prepared by oximation using novel oximation reagents. The second-step of the derivatization was that residues were silylated for analysis. Urine samples were examined using gas chromatography/mass spectrometry (GC/MS) and a retention time-locking technique. The simultaneous analysis and identification of >400 metabolites in >130 types of IMD was possible from the GC/MS results, where the IMDs included phenylketonuria, ornithine transcarbamylase deficiency, neonatal intrahepatic cholestasis caused by citrin deficiency, beta-ureidopropionase deficiency and mitochondrial metabolic disorders. This method was demonstrated to have good repeatability. Considering alpha-ketoglutarate (alpha-KG) as an example, the relative standard deviations (RSDs) of the alpha-KG retention time and peak area were 0.8 and 3.9%, respectively, the blank spiked recovery rate was between 89.6 and 99.8%, and the RSD was <=7.5% (n=5). The method facilitates the analysis of thermally non-stable and semi-volatile metabolites in urine, and greatly expands the range of materials that can be synchronously screened by GC/MS. Furthermore, it provides a comprehensive, effective and reliable biochemical analysis platform for the pathological research of IMDs. PMID- 28565795 TI - 1,25-(OH)2D3 and its analogue BXL-628 inhibit high glucose-induced activation of RhoA/ROCK pathway in HK-2 cells. AB - It has previously been reported that 1,25-(OH)2D3 inhibits high glucose-induced epithelial-to-mesenchymal transition (EMT) in HK-2 cells. However, the mechanism of this renoprotective action remains unclear. Elocalcitol (BXL-628), a vitamin D analog, has been suggested to be effective on the RhoA/Rho associated protein kinase (ROCK) pathway, which serves a crucial role in high glucose-induced EMT. The aim of the present study was to investigate the effect of 1,25-(OH)2D3 and its analogue BXL-628 on high glucose-induced activation of the RhoA/ROCK pathway in human renal proximal tubular cells. HK-2 cells were co-treated with high glucose and either 1,25-(OH)2D3 or BXL-628. The RhoA expression levels and ROCK activity of the membrane were assessed via western blot analysis or immunofluorescence. alpha-smooth muscle actin (alpha-SMA) and epithelial (E) cadherin were detected using western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR), whereas collagen I and fibronectin levels were measured by ELISA and RT-qPCR. The results demonstrated that 1,25-(OH)2D3 and BXL-628 both significantly downregulated the expression of active RhoA and ROCK activity induced by high glucose (P<0.05). Furthermore, the expressions of alpha-SMA, collagen I, and fibronectin were significantly downregulated at both protein and mRNA (P<0.05) levels, whereas the expression of E-cadherin was significantly increased (P<0.05) by 1,25-(OH)2D3 or BXL-628 treatment. In conclusion, the vitamin D receptor agonist 1,25-(OH)2D3 and its analogue BXL-628 were both able to attenuate high glucose-induced EMT and extracellular matrix accumulation of HK-2 cells by suppressing the RhoA/ROCK signaling pathway in vitro. PMID- 28565797 TI - Factors affecting the accuracy and safety of computed tomography-guided biopsy of intrapulmonary solitary nodules <=30 mm in a retrospective study of 155 patients. AB - Computed tomography (CT)-guided percutaneous fine needle biopsy is a common method for lung biopsy. The objective of this study was to investigate factors affecting the accuracy and safety of CT-guided percutaneous lung biopsy of nodules <=30 mm in diameter. Between January 2013 and March 2014, 155 patients underwent a CT-guided percutaneous biopsy procedure on an intrapulmonary solitary nodule measuring <=30 mm in diameter. Prospectively collected data were retrospectively reviewed and examined for the influence of clinical and pathological characteristics (age, gender, smoking status, adhesion of nodule to the pleura, puncture depth, nodule size and time of biopsy) on the accuracy of biopsy and incidence of pneumothorax and hemorrhage. The accuracy of CT-guided biopsy was 90.3% (140/155). Biopsies predominantly contained lung adenocarcinoma (114/140; 81.4%) or squamous cell carcinoma of the lung (10/140; 7.1%). Accuracy was significantly dependent on nodule size, ranging in accuracy from 85 to 97% for patients with nodule diameters of <=20 or 21-30 mm, respectively (P<0.05). Pleural adherence of the nodule significantly increased the accuracy of the biopsy (P<0.05). Patients with a nodule of 11-20 mm in diameter had a significantly higher incidence of pneumothorax compared with patients with a smaller nodule (P=0.013). In conclusion, the nodule size and adhesion to the pleura influenced the accuracy of CT-guided biopsy of intrapulmonary nodules that were <=30 mm in diameter. Nodule size may also affect the incidence of severe complications. CT-guided percutaneous lung biopsy has a high accuracy and is easy and safe to conduct for intrapulmonary solitary nodules of <=30 mm in diameter. PMID- 28565796 TI - Hemodynamic effects of renin-angiotensin-aldosterone inhibitor and beta-blocker combination therapy vs. beta-blocker monotherapy for portal hypertension in cirrhosis: A meta-analysis. AB - beta-blockers are commonly used for the treatment of acute variceal bleeding in cirrhosis. Renin-angiotensin-aldosterone antagonists (angiotensin I-converting enzyme inhibitors, angiotensin receptor blockers and aldosterone antagonists) are potential therapies for portal hypertension. Several studies have compared the renin-angiotensin-aldosterone system (RAAS) inhibitor and beta-blocker combination therapy vs. beta-blocker monotherapy, with inconsistent results. The aim of the present study was to assess the efficacy of the RAAS inhibitor and beta-blocker combination therapy vs. beta-blocker monotherapy for hepatic vein pressure gradient (HVPG) reduction in cirrhosis. Studies were obtained using PubMed, Embase, Medline and Cochrane library databases up to July 2015, and the weighted mean difference (WMD) in HVPG reduction was used as a measure of treatment efficacy. In total, three studies (91 patients) were included. When compared to the beta-blocker monotherapy, the RAAS inhibitor and beta-blocker combination therapy resulted in a significant HVPG reduction [WMD 1.70; 95% confidence interval (CI): 0.52-2.88]. However, there was no significant difference in the heart rate reduction between the monotherapy and combination therapy groups (WMD -0.11; 95% CI: -3.51-3.29). In addition, no significant difference in the hemodynamic response was observed between the two groups (WMD 1.46; 95% CI: 0.93-2.30). In conclusion, the RAAS inhibitor and beta-blocker combination therapy reduces portal hypertension significantly and to a greater extent than beta-blocker monotherapy. Both therapies reduced the heart rate to similar levels; however, the RAAS inhibitor and beta-blocker combination therapy reduced the mean arterial pressure to a greater extent. Due to the limited number of studies included, the data available do not allow a satisfactory comparison of adverse events. Moreover, further larger-scale trials are required in order to strengthen the results of the present study. PMID- 28565799 TI - Phthiriasis palpebrarum: A case of eyelash infestation with Pthirus pubis. AB - Phthiriasis palpebrarum is a rare type of eyelid infestation. In the present study, a 63-year-old woman presented with a case of phthiriasis palpebrarum, which was initially misdiagnosed as anterior blepharitis. The patient had a 2 month history of repeated episodes of itching and burning sensations and moderate pain in both eyes that were not improved by antibiotic and corticosteroid eye drops. Slit lamp examination revealed lice and nits anchored to the eyelashes. All eyelashes were removed from the base along with lice and nits. The patient recovered fully within 2 weeks with no further management, and no evidence of lice or nits was found at the follow up. In conclusion, the findings of the present study suggests that patients presenting with itching of the eyelids and with clinical findings resembling seborrhea accumulation on the eyelashes should be carefully examined by prolonged observation with a slit lamp. PMID- 28565798 TI - PCSK9 regulates apoptosis in human lung adenocarcinoma A549 cells via endoplasmic reticulum stress and mitochondrial signaling pathways. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the subtilisin family of PCs that encodes a neural apoptosis-regulated convertase 1. However, the precise role of PCSK9 in lung cancer cell apoptosis has remained elusive. In the present study, A549 human lung adenocarcinoma cells were transfected with PCSK9 small interfering (si)RNA to investigate the underlying mechanisms of apoptosis. The results indicated that PCSK9 siRNA exhibited anti tumor activity by inducing apoptosis as determined by a Cell Counting Kit-8 and Hoechst staining analysis. In addition, PCSK9 siRNA significantly increased apoptosis of A549 cells in part via activation of caspase-3 and downregulation of the anti-apoptotic proteins survivin and X-linked inhibitor of apoptosis protein. Moreover, the results demonstrated that perturbations in the mitochondrial membrane were associated with the deregulation of the Bax/Bcl-2 ratio, which led to the release of cytochrome c after PCSK9 siRNA transfection. In addition, PCSK9 siRNA also induced endoplasmic reticulum stress (ERS) by increasing the levels of 78 kDa glucose-regulated protein (GRP78), GRP94, phosphorylated protein kinase R like ER kinase and phosphorylated eukaryotic initiation factor 2alpha. Therefore, these results demonstrated that PCSK9 siRNA may exert its anti-tumor activity through inducing mitochondrial dysfunction and ERS-associated cell death in A549 cells. PMID- 28565801 TI - Inflammatory response associated with choke vessel remodeling in the extended perforator flap model. AB - Ischemic necrosis of the surgical flap is a common complication. The behavior of choke vessels has an important role in skin flap survival. However, the mechanism of choke vessel remodeling has remained elusive. The purpose of the present study was to investigate the possible association between inflammatory responses and choke vessel remodeling in the extended perforator flap model in rats. After flap elevation, the animals were randomly divided into three groups (n=6 in each) for tissue analysis at three, five or seven days after flap surgery. Six additional rats served as a control group (no flap elevation). Tissue samples were collected from the choke zone for histological, western blot and PCR analyses. Monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) as inflammatory cytokines were examined in the present study. Histopathological analysis showed that dilation of choke vessels and increased vessel wall thickness was obvious after flap elevation. It also showed edema, inflammation cell aggregation after the operation. Compared with the control group, the protein and mRNA expression levels of MCP-1 and TNF-alpha were significantly increased at days 3, 5 and 7 after flap elevation, while reaching a maximum at day 5. These findings indicated that inflammatory responses may have an important role in choke vessel remodeling. MCP-1 and TNF-alpha may be considered as potential targets for modulating the behavior of choke vessels. PMID- 28565800 TI - MicroRNA-93 promotes cell proliferation by directly targeting P21 in osteosarcoma cells. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that are key regulators of gene expression by directly binding to the 3'-untranslated region of their target mRNAs, resulting in translational repression or degradation of mRNA. It has been demonstrated that miRNAs have key roles in a variety of human malignancies, including osteosarcoma. The present study aimed to assess the molecular mechanism of miR-93 in the regulation of osteosarcoma cell proliferation. Reverse transcription quantitative PCR and western blot assays were used to examine mRNA and protein expression. An MTT assay and flow cytometry were performed to determine the cell proliferation and cell cycle distribution. A luciferase reporter assay was performed to confirm the direct targeting of cyclin-dependent kinase inhibitor 1A (CDKN1A), also known as P21, by miR-93, which was suggested by a bioinformatics analysis. The results showed that the expression of miR-93 was frequently and significantly increased in a total of 19 osteosarcoma tissues compared to their matched adjacent non-tumor tissues, and the upregulation of miR 93 was associated with the malignant progression of osteosarcoma. Furthermore, miR-93 was also upregulated in the human osteosarcoma cell lines Saos-2, U2OS, SW1353 and MG63 when compared with that in the human osteoblast cell line hFOB1.19. Transfection with miR-93 inhibitor significantly reduced the miR-93 levels and inhibited the proliferation of U2OS and MG63 osteosarcoma cells. The protein levels of P21 were negatively regulated by miR-93 in U2OS and MG63 cells. Knockdown of miR-93 caused cell cycle arrest at G1 stage in U2OS and MG63 cells, identical to the effect of P21 overexpression. Finally, P21 was found to be significantly downregulated in osteosarcoma tissues compared to their matched adjacent non-tumor tissues, suggesting that the inhibition of P21 may be due to increased miR-93 expression in osteosarcoma tissues. In conclusion, the present study demonstrated that miR-93 enhances the proliferation of osteosarcoma cells, at least in part via inhibiting P21 expression and thus promoting cell cycle progression. PMID- 28565802 TI - Continuous-type splenogonadal fusion: A case report. AB - Splenogonadal fusion (SGF) is a rare congenital malformation. Since it lacks characteristic features, very few cases of SGF have been diagnosed preoperatively. Laparoscopy was effective in both diagnosing and surgically treating this condition. Herein, we reported left side SGF in a male patient who was diagnosed during laparoscopic exploration, and Fowler-Stephens orchidopexy was implemented at the same time. The patient was followed up for one year. At a 6-month follow-up, the left scrotum demonstrated swelling and the internal contents were hard. An ultrasound of this testicle indicated non-uniform, splenic like organization. However, at the one-year follow-up, the volume of splenic-like organization was reduced but the testicular size did not exhibit further atrophy. PMID- 28565803 TI - Endovascular treatment and morphology typing of chronic ostial occlusion of the subclavian artery. AB - Chronic obstructive lesions of the subclavian artery (SCA) often result in subclavian steal syndrome, which leads to arm claudication, transient cerebral ischemia, and other serious complications. The lesions are classified as stenosis and occlusion, according to the degree of obstruction. Unlike totally occlusive lesions, including ostial occlusions, stenotic lesions have an excellent technical success rate. In the present study, ostial occlusions were classified into 4 types according to their angiographic appearance. A total of 8 patients (6 male, 2 female) with SCA occlusions were treated with percutaneous transluminal angioplasty and stenting over a 4-year period. Mean patient age was 65.6 years (range, 60-72 years). In total, 9 self-expanding and 1 balloon-expandable stent were implanted at the ostia of the SCA in 7 of the patients. One female patient did not undergo stenting. Bleeding at the access site was noted in 2 patients and was controlled by gauze pressure. The patient that did not undergo stenting was lost to follow-up with symptoms of a transient ischemic attack at 3 months. The mean follow-up time for the remaining 7 patients was 15.7 months (range, 1-36 months). No ischemic symptoms, neointimal hyperplasia, or restenosis was observed in these patients. The transfemoral artery operation approach is preferred for rat-tail and peak type occlusions, whereas the dual approach involving both femoral and radial arteries is preferred for hilly and plain type occlusions. The angiographic morphology typing used in the present study may serve as a reference to decide upon the interventional operation strategy to be used for improving the technical success rate. PMID- 28565804 TI - Schwann cells promote the capability of neural stem cells to differentiate into neurons and secret neurotrophic factors. AB - The present study investigated whether co-culturing Schwann cells (SCs) with neural stem cells (NSCs) improves viability, direction of differentiation and secretion of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in NSCs. The three groups assessed were as follows: SCs, NSCs, and a co-culture of SCs and NSCs. Cellular morphological changes were observed under an inverted phase contrast microscope and quantified. Cells were identified by immunofluorescence staining: S100 for SCs, Nestin for NSCs, microtubule associated protein (Map) 2 and NeuN for neurons and glial fibrillary acidic protein for astrocytes. Cell viability was evaluated by MTT assay. Secretion of BDNF and GDNF was quantified; mRNA expression was quantified by reverse transcription-quantitative polymerase chain reaction. The majority of NSCs in the co-cultured group differentiated into neurons. The cell survival rate of the co-culture group was significantly higher than the other groups on days 3, 5 and 10 (P<0.01). The secretion of BDNF in the co-culture group was significantly higher than NSCs on days 3, 5 and 7 (P<0.05), while the amount of GDNF in co-culture was significantly higher than both NSCs and SCs on day 1 (P<0.05). BDNF and GDNF gene expression in the co-culture group was significantly higher than SCs (P<0.01). Gene expression of Map2 in co-culture group was also significantly higher than both NSC and SC groups (P<0.01). Therefore, co-cultured SCs and NSCs promote differentiation of NSCs into neurons and secrete higher levels of neurotropic factors including BDNF and GDNF. PMID- 28565805 TI - Effects of dual modified resistant indica rice starch on azoxymethane-induced incipient colon cancer in mice. AB - In this study, the effects of different doses of dual modification-treated (DMT) indica rice resistant starch (IR-RS) on azoxymethane (AOM)-induced early colon cancer in mice were investigated. The investigated factors included body weight, gastrointestinal emptying rate, the number and morphology of aberrant crypt foci (ACFs) and the specific expressions of adenomatous polyposis coli (APC), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and cytochrome c genes. The results demonstrated that DMT IR-RS controlled the increase in the body weights of the mice, increased the gastrointestinal emptying rates and reduced the numbers of ACFs and aberrant crypts. Reverse transcription-polymerase chain reaction revealed that DMT IR-RS promoted the expression of APC, Bax and cytochrome c and inhibited the expression of Bcl-2. These results demonstrate that a DMT IR-RS diet may induce apoptosis and has beneficial health effects in AOM-induced early colon cancer in mice. PMID- 28565806 TI - Prokinetic effects of LD02GIFRO on functional gastrointestinal disorder in rats. AB - LD02GIFRO is a novel prokinetic agent formulated with Poncirus fructus and Zanthoxylum sp. fruits. The aim of the present study was to evaluate the effect of LD02GIFRO on delayed gastrointestinal transit (GIT) and colorectal hypersensitivity. To investigate the effect of LD02GIFRO, a rat model of delayed GIT was induced via three mechanisms; postoperative ileus (POI), morphine, and POI plus morphine. Visceromotor responses (VMR) to colorectal distension (CRD) were also evaluated. POI was induced by laparotomy surgery and manipulation of the small intestine under anesthesia, and GIT was calculated by measuring the length that Evans Blue travelled through the gastrointestinal tract in a given time. Oral administration of 260 mg/kg LD02GIFRO caused Evans Blue to migrate significantly further in the delayed GIT models induced by POI, morphine and POI plus morphine compared with the control (P<0.05). This effect was inhibited by atropine, a muscarinic receptor antagonist, and completely abolished by GR125487, a 5-HT4-receptor antagonist. Furthermore, intraperitoneal administration of 600 and 900 mg/kg LD02GIFRO significantly reduced VMR to CRD in acute and chronic colorectal hypersensitive rat models, induced by acetic acid and trinitrobenzenesulfonic acid, to almost normal levels (P<0.01). In the present study, LD02GIFRO successfully ameliorated delayed GIT models and colorectal hypersensitivity models, suggesting that LD02GIFRO may be an effective therapeutic treatment for patients with functional gastrointestinal disorders and abnormalities in GIT. PMID- 28565807 TI - Arsenic trioxide increases expression of secreted frizzled-related protein 1 gene and inhibits the WNT/beta-catenin signaling pathway in Jurkat cells. AB - The aim of the present study was to investigate the demethylation effect of arsenic trioxide (As2O3) on the secreted frizzled-related protein 1 (SFRP1) gene and its ability to inhibit the Wingless-type MMTV integration site family (WNT) pathway in Jurkat cells. Methylation-specific polymerase chain reaction was used to examine the CpG island methylation status of the SFRP1 gene in leukemia cell lines. In addition, the effects on Jurkat cells of treatment with different concentrations of As2O3 for 48 h were investigated. Reverse transcription quantitative polymerase chain reaction was employed to measure the expression of mRNAs, while western blot analysis was used to examine protein expression in cells. The SFRP1 gene was methylated in Jurkat cells. However, both methylated and unmethylated SFRP1 genes were detected in HL60 and K562 cells. In normal bone marrow mononuclear cells, the SFRP1 gene was unmethylated. Following treatment with As2O3 for 48 h, the SFRP1 gene was demethylated, and the mRNA and protein expression levels of the SFRP1 gene were increased. By contrast, the mRNA and protein expression levels of beta-catenin and cyclin Dl were downregulated. The protein expression of c-myc was also downregulated, but As2O3 exhibited no significant effect on the mRNA expression of c-myc. Abnormal methylation of the SFRP1 gene was detected in Jurkat cells. These results suggest that As2O3 activates SFRP1 gene expression at the mRNA and protein levels in Jurkat cells by demethylation of the SFRP1 gene. Furthermore, they indicate that As2O3 regulates WNT target genes and controls the growth of Jurkat cells through the WNT/beta catenin signaling pathway. PMID- 28565808 TI - Rutin attenuates isoflurane-induced neuroapoptosis via modulating JNK and p38 MAPK pathways in the hippocampi of neonatal rats. AB - An increasing number of infants and children undergo surgery and are exposed to anesthesia as a part of medical care each year. Isoflurane is a commonly used anesthetic in the pediatric population. However, previous studies have reported widespread isoflurane-induced neuroapoptosis and cognitive impairments in neonatal animal models, raising concerns over the administration of isoflurane in the pediatric population. The current study investigated the effects of rutin, a flavonoid, on isoflurane-induced neuroapoptosis in a neonatal rodent model. Groups of neonatal rat pups were administered rutin at doses of 10, 20 or 40 mg/kg body weight from postnatal day 1 (P1) to P15. On P7, pups were exposed to 0.75% isoflurane for 6 h. Rat pups in the control groups did not receive rutin, and did not receive anesthesia in one group. Neuroapoptosis following isoflurane exposure was determined by TUNEL assay. The expression levels of cleaved caspase 3, apoptotic pathway proteins [Bcl2-associated agonist of cell death (Bad), phospho-Bad, Bax, B-cell lymphoma 2 (Bcl-2) and Bcl-xL and mitogen-activated protein kinases (MAPK)] signalling pathway proteins [c-Jun N-terminal kinase (JNK), phospho-JNK, extracellular-signal-regulated kinase 1/2 (ERK1/2), phosphoERK1/2, p38, phospho-p38 and phospho-c-Jun], were determined by western blot analysis. The Morris water maze test was used to assess the learning and memory of pups on P30 and P31. The present study found that rutin at the tested doses of 10, 20 and 40 mg significantly reduced (P<0.05) the isoflurane-induced elevation in apoptotic cell count. The expression levels of caspase-3, Bad, Bax and MAPK proteins, which were increased following isoflurane treatment, were rescued by rutin treatment. Furthermore, rutin prevented the increase in Bcl-xL, Bcl-2 and phospho-Bad expression following isoflurane treatment, and enhanced the memory of the rats. Rutin provided neuroprotection against isoflurane-induced neuronal apoptosis and improved the learning and memory of rats by effectively regulating the expression levels of proteins in the MAPK pathway. PMID- 28565809 TI - Clinical study on the association between pregnancy-induced hypertension and insulin resistance. AB - The aim of the present study was to explore the association between pregnancy induced hypertension (PIH) and insulin resistance (IR). A total of 50 cases of PIH and 50 healthy pregnant women with a similar gestational age were enrolled. The hyperinsulinemic-euglycemic clamp technique was used to evaluate the degree of IR and all 100 subjects were divided into an IR and a non-IR group accordingly. Subsequently, the correlation between the systolic or diastolic blood pressure was assessed; furthermore, a homeostasis model assessment of IR (HOMA-IR), a HOMA of the insulin sensitivity index (HOMA-ISI) and a HOMA of beta cell function (HOMA-beta%) were performed. Moreover, the effect of IR on PIH was assessed and the protein expression of insulin receptor substrate (IRS)-1, phosphorylated (p)-IRS-1, AKT and p-AKT were detected in the placental plasma by western blot analysis. The results showed that in the PIH group, the p-IRS-1/IRS 1 and p-AKT/AKT ratios were decreased compared with those in the control group. Blood flow parameters, including perfusion index, retinal resistive index and systolic maximum velocity/end-diastolic velocity ratio in the IR group were higher, while time averaged velocity was lower compared with that in the non-IR group. Furthermore, the HOMA-ISI and HOMA-beta% were decreased, while the HOMA-IR was increased in the PIH group compared to that in the control group; alongside the blockage of the insulin signaling pathway, these factors may therefore cause PIH. The present study may provide novel therapeutic approaches for PIH. PMID- 28565810 TI - Anti-atherogenic properties of resveratrol: 4-week resveratrol administration associated with serum concentrations of SIRT1, adiponectin, S100A8/A9 and VSMCs contractility in a rat model. AB - Resveratrol (3, 4', 5-trihydroxy-trans-stilbene) is a natural, non-flavonoid polyphenol that exerts protective properties against atherosclerosis-associated endothelial dysfunction and senescence. The present study aimed to assess the influence of resveratrol on vascular contractility and molecular factors including sirtuin-1 (SIRT1), adiponectin and calprotectin (S100A8/A9) that are considered to be important elements of atherogenesis. A total of 17 male rats were divided into a control and treatment group and administered resveratrol or a placebo. Pharmacometrics were performed on an isolated and perfused tail artery. Serum SIRT1, adiponectin and S100A8/A9 levels were quantified using an ELISA assay. The level of SIRT1 in the control and treatment groups at time 0 was 4.26 and 4.45 ng/ml, respectively. SIRT1 in the control and treatment groups following 2 weeks of treatment was 4.59 and 6.86 ng/ml, respectively (P<0.05) and following 4 weeks of treatment was 4.15 and 6.38 ng/ml, respectively (P<0.05). The level of adiponectin in the control and treatment groups at time 0 was 1.24 and 1.21 ng/ml, respectively. Following 2 weeks of treatment, the level of adiponectin in the control and treatment groups was 1.22 and 1.2 ng/ml, respectively (P>0.05) and following 4 weeks of treatment was 1.26 and 1.58 ng/ml, respectively (P<0.05). The S100A8/A9 level in control and treatment groups at time 0 was 0.39 and 0.33 ng/ml, respectively. The level of S100A8/A9 in control and treatment groups following 2 weeks of treatment was 0.37 and 0.35 ng/ml, respectively (P>0.05) and following 4 weeks of treatment was 0.34 and 0.32 ng/ml, respectively (P>0.05). EC50 values obtained for phenylephrine in resveratrol-pretreated arteries were significantly higher than controls in the presence and absence of A7-hydrochloride (P<0.05). The results of the present study indicate a significant increase in the concentration of SIRT1 and adiponectin in the resveratrol-pretreated group (P<0.05). S100A8/A9 serum concentrations remained unchanged. Reactivity of resistant arteries was significantly reduced for resveratrol-pretreated vessels and this effect was partially independent of phosphodiesterase (PDE1). Additionally, there was a synergistic interaction observed between resveratrol and the PDE1 inhibitor. PMID- 28565811 TI - Severity and distribution of cartilage damage and bone marrow edema in the patellofemoral and tibiofemoral joints in knee osteoarthritis determined by MRI. AB - The aim of the present study was to analyze the distribution and severity of cartilage damage (CD) and bone marrow edema (BME) of the patellofemoral and tibiofemoral joints (PFJ and TFJ, respectively) in patients with knee osteoarthritis (OA), and to determine whether a correlation exists between BME and CD in knee OA, using magnetic resonance imaging (MRI). Forty-five patients diagnosed with knee OA (KOA group) and 20 healthy individuals (control group) underwent sagittal multi-echo recalled gradient echo sequence scans, in addition to four conventional MR sequence scans. Knee joints were divided into 15 subregions by the whole-organ MRI scoring method. MRIs of each subregion were analyzed for the presence of CD, CD score and BME score. The knee joint activity functional score was determined using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) in the KOA group. Statistical analyses were used to compare the CD incidence; CD score and BME score between the PFJ and TFJ. Whether a correlation existed among body mass index, BME score, WOMAC pain score and CD score was also examined. Among the 675 subregions analyzed in the KOA group, 131 exhibited CD (CD score, 1-6). These 131 subregions were primarily in the PFJ (80/131, 61.07%), with the remainder in the TFJ (51/131, 38.93%). Thirty three subregions had a CD score of 1, including 24 PFJ subregions (72.73%) and 9 TFJ subregions (27.27%). Among the 103 subregions with BME, the PFJ accounted for 60 (58.25%) and the TFJ for 43 (41.75%). A significant positive correlation was found between the BME and CD scores. In conclusion, CD and BME occurred earlier and more often in the PFJ compared to the TFJ in knee OA, and BME is an indirect sign of CD. PMID- 28565812 TI - Increased Runx2 expression associated with enhanced Wnt signaling in PDLLA internal fixation for fracture treatment. AB - Poly-D-L lactide (PDLLA) biodegradable implants to heal fractures are widely applied in orthopedic surgeries. However, whether the process of fracture healing is regulated differently when PDLLA is used compared with traditional metal materials remains unclear. Runt-related transcription factor 2 (Runx2) and canonical Wnt signaling are essential and may interact reciprocally in the regulation of osteogenesis during bone repair. In the present study, a rat femoral open osteotomy model was used to compare the curative efficacy of a PDLLA rod and Kirschner wire under intramedullary fixation for fracture treatment. The dynamic expression of Runx2 and key components of the canonical Wnt signaling in callus tissue during fracture healing was also investigated. The results of the current study indicate that at weeks 4 and 6 following fixation, the callus bone structural parameters of microCT were significantly improved by PDLLA rod compared to that of Kirschner wire. In addition, at weeks 4 and 6 after fixation, the protein and mRNA expression of Runx2 and the positive regulators of canonical Wnt signaling, such as Wnts and beta-catenin, were significantly increased. However, the protein and mRNA expression levels of the negative regulators of canonical Wnt signaling, such as glycogen synthase kinase-3beta, were significantly decreased in callus tissue when treated with PDLLA rod compared with Kirschner wire. Collectively, these data indicate that compared to the traditional metal material, using PDLLA internal fixation for fracture treatment may further improve bone formation, which is associated with the increased expression of Runx2 and the enhancement of canonical Wnt signaling. PMID- 28565813 TI - Successful treatment of diffuse panbronchiolitis in a child from Western China: A case report. AB - The present report describes a case of diffuse panbronchiolitis (DPB) in a child from Western China and the favorable outcome associated with early diagnosis. DPB is an uncommon presentation in pediatric patients. A 13-year-old Chinese boy was admitted to the respiratory outpatient department due to recurrent cough and progressive exertional dyspnea that had persisted for 1 year. An initial diagnosis of bronchial asthma was made, and the patient was prescribed inhaled fluticasone combined with salmeterol (50/250 ug, twice daily), and montelukast (4 mg daily). However, 2 months later no clinical improvement was observed. The disease was re-diagnosed as DPB following the identification of features such as centrilobular small nodular opacities, a 'tree-in-bud appearance' and thickening of the bronchial walls meeting the diagnostic criteria for DPB. Complete resolution of the disease and sustained alleviation of the patient's respiratory symptoms were achieved following the early institution of erythromycin therapy, and the exacerbation of chronic bronchitis was reduced. In conclusion, it is essential to consider that successful treatment for DPB lies in early diagnosis and early treatment. DPB may be treated well by use of erythromycin. PMID- 28565814 TI - Refractory hypotension induced by Sheehan syndrome with pituitary crisis: A case report. AB - The present study reported on an unusual case of refractory hypotension induced by Sheehan syndrome with pituitary crisis and explored the causes and treatment of hypotension in hypopiptuitarism. Refractory hypotension is a rare and severe complication of longstanding hypopituitarism induced by Sheehan syndrome with pituitary crisis. A 48-year-old Chinese woman with pituitary crisis due to Sheehan syndrome developed refractory hypotension and received longstanding vasopressor blood pressure support and hormone replacement therapy. Besides normalized blood pressure, echocardiography over 3 months revealed partial reversibility of her cardiac function with hormone replacement therapy. Consistent numerous studies reviewed, hormone replacement therapy may improve cardiac function in patients with cardiomyopathy linked to Sheehan syndrome. A retrospective study of 77 cases with hypopituitarism encountered at Qilu Hospital of Shandong University (Jinan, China) was also performed and the incidence rate of hypotension was analyzed, revealing that the present case was the first of refractory hypotension induced by Sheehan syndrome with pituitary crisis at this institution in 16 years. PMID- 28565815 TI - Epidemiology and management of splenic injury: An analysis of a Chinese military registry. AB - In China, there have been few meta-analyses of the epidemiology and management of splenic injury. Due to the success of Chinese military hospitals in the domestic treatment of splenic injury, the present study conducted a systematic review of such cases, identifying a high occurrence rate of splenic trauma, as well as a number of strategies of managing splenic injury in China. Data were collected from sixteen Chinese military hospitals between July 2000 and March 2009, and retrospectively reviewed. It was observed that between July 2000 and March 2009 a total of 7,807 patients (84.32% male and 15.68% female) with splenic injury were admitted to hospital. The mean duration of hospital stay was 17.9+/-18.6 days and the gender distribution of splenic injury over the successive years did not differ significantly (P>0.05, c=0.034). However, there was a significant difference in the gender distribution of splenic injury patients in different months (P<0.05, c=0.063). In addition, admission numbers for splenic injury were highest in September, October and November. It was also found that splenic injury may occur at all ages, though patients of working age (20-50 years), which comprises 85.59% of patients, the highest proportion of all recorded cases. Associations between mortality rate and each management strategy were as follows: Operative management, 0.11% and non-operative management, 0.15%. Furthermore, multivariate analysis demonstrated that transfusion, New Injury Severity Score and management strategies were all correlated with mortality rate. Thus, despite a lack of data for inpatients from civilian hospitals, the present study has, in part, identified the epidemiology and management strategies of splenic injury in China. These findings may supplement those from previous analyses of splenic injury in other countries and regions. PMID- 28565816 TI - MicroRNA-212 targets FOXA1 and suppresses the proliferation and invasion of intrahepatic cholangiocarcinoma cells. AB - [This retracts the article DOI: 10.3892/etm.2016.3824.]. PMID- 28565818 TI - Transforming growth factor beta and its role in heart disease. AB - Myocardial infarction (MI) is a major form of heart disease that leads to immediate cardiomyocyte death due to ischemia and eventually fibrosis and scar formation and further dysfunction of myocardium and heart failure. Extracellular matrix (ECM) production and tissue repair is conducted by myofibroblasts, which are formed from the normal quiescent cardiac fibroblasts following transformational changes, through the active participation of transforming growth factor beta (TGFbeta) and its signaling pathways. TGFbeta appears to be a 'Master of all trades', with respect to cardiac fibrosis, as it can promote cardiomyocyte apoptosis and cardiac hypertrophy. TGFbeta signaling involves its binding to TGFbeta receptor type II (TGFbetaRII), which recruits TGFbeta receptor type I (TGFbetaRI), which are also known as activin receptor-like kinase (ALK) in five different isoforms. In canonical signaling pathways, ALK5 activates Smads 2 and 3, and ALK1 activates Smads 1 and 5. These pairs of Smads form a corresponding complex and then bind to Smad 4, to translocate into the nucleus, where transcriptional reprogramming is carried out to promote myofibroblast formation and ECM production, eventually leading to cardiac fibrosis. TGFbeta levels are elevated in MI, thereby aggravating the myocardial injury further. Several microRNAs are involved in the regulation of TGFbeta signaling at different steps, affecting different components. Therapeutic targeting of TGFbeta signaling at ALK1-5 receptor activity level has met with limited success and extensive research is needed to develop therapies based on the components of TGFbeta signaling pathway, for instance cardiac dysfunction and heart failure. PMID- 28565817 TI - Medical perspective in testicular ischemia-reperfusion injury. AB - Testicular torsion or torsion of the spermatic cord is one of the most serious urological conditions. It causes testicular injury, which potentially leads to male subfertility. The turning of the spermatic cord and spermatic structures around themselves results in biochemical and histological changes; however, following testicular detorsion, tissues undergo reperfusion that causes more severe damage than that induced by ischemia. Since the primary causes of testicular damage are reactive oxygen species production, an increase in intra mitochondrial calcium concentration and an increased rate of cellular apoptosis, different medications may potentially be effective. It seems that several medications, experimentally and sometimes clinically, serve an adjuvant role in the cellular damage that occurs following ischemia-reperfusion. Antioxidants, calcium channel blockers, phytotherapeutical medicinals, anaesthetics, hormones and platelet inhibitors may potentially create a solid basis for an adjuvant restoring therapy and ameliorate testicular function following torsion. The current study aimed to review the relevant literature and discuss the actions of a number of molecules that may protect the testes during ischemia/reperfusion injury. PMID- 28565819 TI - Genetic basis of pediatric epilepsy syndromes. AB - Childhood epilepsy affects ~0.5-1% in the general population worldwide. Early onset epileptic encephalopathies are considered to be severe neurological disorders, which lead to impaired motor, cognitive, and sensory development due to recurrence of seizures. Many of the observed epilepsy phenotypes are associated with specific chromosomal imbalances and thus display gene dosage effects, and also specific mutations of a variety of genes ranging from ion channels to transcription factors. High throughput sequencing technologies and whole exome sequencing have led to the recognition of several new candidate genes with a possible role in the pathogenesis of epileptic encephalopathies. The mutations causing channelopathies can be either a gain or a loss of ion channel function and contribute to the pathogenesis of epilepsy syndrome. Nearly 300 mutations of SCN1A gene coding for the Nav1.1 channel protein have been identified that contribute to the pathology of epilepsy. Besides Na, potassium and calcium channels are also implicated in epileptic encephalopathies. Therapeutic management of epileptic encephalopathies has been challenging as the majority of the medications are not efficient and often have many undesirable side effects. A better understanding of the molecular nature of epilepsy in an individual is important to design a personalized medication, considering the number of possible genetic mutations that can contribute to epileptic encephalopathies. PMID- 28565820 TI - Beneficial effects of Jiawei Shenqi-wan and treadmill training on deficits associated with neonatal hypoxic-ischemia in rats. AB - Jiawei Shenqi-wan (JSQW), which comprises Shenqi-wan and two additional medicinal herbs, has been widely used for the treatment of various growth impairments, including cerebral palsy. In the present study, JSQW was administered to hypoxic ischemic Sprague-Dawley rats that underwent treadmill training from 4-7 weeks of age to examine the beneficial effects of combined JSQW and treadmill therapy. Behavioral examinations were performed and a significant improvement in cylinder test performance was observed in rats treated with treadmill training compared with hypoxic-ischemia rats (P<0.05), as well as a significant improvement in passive avoidance test performance for rats treated with JSQW (P<0.05). The thickness of the corpus callosum and the integrated optical density (IOD) of myelin basic protein (MBP) were significantly increased by treatment with treadmill therapy alone (P<0.01 and P<0.001, respectively) and treatment with both JSQW and treadmill significantly increased the IOD of MBP compared with hypoxic-ischemia rats (P<0.001). Western blot analysis revealed that the expression of neuronal nuclei (NeuN) and doublecortin (Dcx) significantly decreased (P<0.001 and P<0.05, respectively) and MBP expression markedly decreased in the ipsilateral subventricular zone of hypoxic-ischemic rats compared with the control group; however, the expression of NeuN was significantly recovered by treatment with both JSQW and treadmill training (P<0.05). Furthermore, Dcx expression was significantly recovered by treatment with JSQW (P<0.05), and MBP expression was significantly restored by treatment with treadmill training (P<0.01). In the immunohistochemical analyses, a significant increase in the number of bromodeoxyuridine (BrdU) positive cells in this region was observed in treadmill-treated rats (P<0.05), whereas significant increases in the number of Brdu/Dcx or NeuN or glial fibrillary acidic protein double-positive cells were observed only in the group co-treated with JSQW and treadmill (P<0.01, P<0.05 and P<0.001, respectively). These results suggest that JSQW and treadmill training may contribute to behavior recovery following hypoxic ischemia, and JSQW treatment was particularly effective in promoting memory function via enhancing the differentiation of neuronal progenitor cells. The results of the present study therefore suggest that JSQW may provide an additional treatment option for functional recovery with treadmill training in cerebral palsy. PMID- 28565821 TI - Berberis vulgaris extract/beta-cyclodextrin complex increases protection of hepatic cells via suppression of apoptosis and lipogenesis pathways. AB - Berberis vulgaris (Bv) is well known worldwide for its healing properties. However, limited information is available concerning its mechanism of action and the increased hepatoprotective activity of formulated extracts. This study evaluated the protective effect of Bv bark extract against CCl4-induced cytotoxicity in Huh7 cells, as well whether beta-cyclodextrin complexation of the extract resulted in increased hepatoprotective effects. Huh7 cells were incubated for 48 h with 5, 7.5 and 10 ug/ml of unformulated or formulated Bv extract alone and in co-treatment with CCl4. The effects on Huh7 cell growth and apoptosis were evaluated by MTT assay, caspase-3/7 activity and caspase-3 expression, whereas fatty acid changes were investigated by Oil red O staining and the detection of peroxisome proliferator-activated receptor-gamma (PPARgamma) expression using immunofluorescence. Ultrastructural alterations were observed by electron microscopy. The MTT assay showed that co-exposure to CCl4 and 7.5 ug/ml formulated extract led to a 1.25-fold increase in cell viability compared with the non-formulated extract. Caspase-3/7 activity decreased by 50% and 70% following co-treatment with unformulated or formulated extract, compared with that in cells treated with CCl4 alone. Furthermore, hepatocyte ultrastructure was protected from CCl4-induced injury in the two co-treated groups, intracytoplasmic lipid accumulation decreased significantly and PPARgamma expression was restored, in comparison with CCl4-treated cells alone. Formulated and unformulated extracts were efficient against the anti-proliferative and pro-apoptotic actions of CCl4 through suppression of CCl4-induced caspase-3 activation and lipid accumulation. The protective effect of the formulated extract was more pronounced than that of the unformulated one, which may be due to its increased solubility. PMID- 28565823 TI - Corticosterone suppresses IL-1beta-induced mPGE2 expression through regulation of the 11beta-HSD1 bioactivity of synovial fibroblasts in vitro. AB - The aim of the present study was to investigate the correlation between glucocorticoid activity regulation, prostaglandin E2 (PGE2) synthesis, and synovial inflammation inhibition activity, through microsomal prostaglandin E synthase-1 (mPGES-1) expression regulated by the glucocorticoid pre-receptor regulator, 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1). In the present study, fibroblast-like synovial cells of rats were studied as a cell model. Cells were stimulated with 10 ng/ml interleukin (IL)-1beta for 24 h, and were subsequently, within the next 24 h, treated with or without 10-6 mmol/l corticosterone alone or with 100 nmol/l PF915275. At the end of the second 24 h, PGE2 levels in culture supernatants were assayed. Cells were harvested for mRNA evaluation of 11beta-HSD1, mPGES-1, IL-1beta and tumor necrosis factor (TNF) alpha, and protein detection of 11beta-HSD1 and mPGES-1 using reverse transcription-qualitative polymerase chain reaction and western blot analysis, respectively. Corticosterone was demonstrated to suppress the mRNA expression levels of inflammatory factors, such as TNF-alpha and PGE2, induced by IL-1beta in vitro. Simultaneously, expression levels of 11beta-HSD1 decreased significantly at the mRNA and protein levels (P<0.05). Cortisol concentration in the medium of the group treated with corticosterone was significantly increased (P<0.05) compared with that of the control group; however, the cortisol concentration was decreased in the medium when the conversion bioactivity of 11beta-HSD1 was inhibited by PF915275, while the changes in 11beta-HSD1 and mPGES 1 mRNA expression levels and PGE2 content were reversed in the medium. These results indicated that a significant positive correlation (P<0.01) may exist between mRNA and protein expression levels. To conclude, 11beta-HSD1 is a key regulator for the synthesis of mPGES-1 and PGE2 in the inflammatory synovial cells in vitro, suggesting a potential interference target for osteoarthritis. PMID- 28565822 TI - Molecular and cellular impact of Psoriasin (S100A7) on the healing of human wounds. AB - Psoriasin, which is also known as S100A7, is a member of the S100 protein family, a group of calcium-responsive signalling proteins. Psoriasin expression remains high in patients with psoriasis, whereas it is downregulated in patients with invasive breast carcinoma. This observation suggests that this protein may be a notable marker of keratinocyte function and differentiation during wound healing. The aim of the present study was to determine the cellular impact of Psoriasin in keratinocytes, which are the primary cell type associated with wound healing. Psoriasin expression in wound tissues was examined using reverse transcription quantitative polymerase chain reaction and immunochemical staining. Knockdown of Psoriasin in HaCaT cells was performed using anti-Psoriasin ribozyme transgenes and the effect on growth, adhesion and migration of keratinocytes was subsequently determined using in vitro cellular functional assays. Psoriasin expression is upregulated in wounds, particularly at the wound edges. The present study demonstrated that Psoriasin is expressed in keratinocytes and is a fundamental regulator of keratinocyte migration. Significant increases in the rate of keratinocyte adhesion, migration and growth were observed in Psoriasin deficient cells (P<0.01 vs. control). Application of small inhibitors identified the potential association of neural Wiskott-Aldrich syndrome protein, focal adhesion primase and rho-associated protein kinase signalling pathways with Psoriasin-regulated cell adhesion and motility. In conclusion, Psoriasin serves an important role in the wound healing process, suggesting that it may be utilized as a potential wound healing biomarker. PMID- 28565824 TI - Roscovitine protects murine Leydig cells from lipopolysaccharide-induced inflammation. AB - Roscovitine is a cyclin-dependent kinase inhibitor, which has been previously investigated for its anticancer effects. It has also been confirmed that roscovitine can downregulate the expression of myeloid cell leukemia-1 protein to inhibit inflammation. In the present study, roscovitine was used to treat inflammation in lipopolysaccharide (LPS)-induced model mice. At the cellular level, Leydig cells isolated from mouse testis were assessed for inflammatory factors. It was revealed that roscovitine successfully reduced inflammation associated injury induced by LPS pretreatment. At the molecular level, roscovitine was found to exert this effect through promotion of adenosine monophosphate-activated protein kinase phosphorylation. To the best of our knowledge, the present study was the first to suggest that roscovitine has a protective role in Leydig cells through its anti-inflammatory action. PMID- 28565825 TI - A comparison of adeB gene expression levels under conditions of induced resistance by different drugs in vitro in Acinetobacter baumannii. AB - The present study was designed to analyze the difference of the adeB gene expression levels under conditions of induced resistance and to verify the significance of the AdeABC efflux pump in the in vitro induction of Acinetobacter baumannii (A. baumannii). Strains were isolated from blood or drainage samples in the First Hospital of China Medical University. The minimum inhibitory concentration (MIC) was determined by a broth microdilution method. In addition, an in vitro induction of drug-resistance tests was confirmed with the three drugs. The expression level of the adeB was determined by quantitative polymerase chain reaction (qPCR), and there were 19, 17 and 25 strains isolated from this test that were susceptible to amikacin, netilmicin and imipenem, respectively. Furthermore, 11, 15 and 8 stably resistant strains generated against amikacin, netilmicin and imipenem, respectively, by in vitro induction. The MIC values of all the imipenem-sensitive and imipenem-resistant strains decreased by no more than 2-fold under carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-containing conditions. The MIC values of 10 amikacin-resistant and 14 netilmicin-resistant strains decreased 4-fold or more under CCCP-containing conditions. Furthermore, qPCR revealed that none of the imipenem-sensitive or the imipenem-resistant strains expressed the adeB gene, but there were 10 amikacin-resistant and 5 netilmicin-resistant strains that expressed the adeB gene. In conclusion, the present study confirmed that in vitro induction of drug-resistance tests in sensitive A. baumannii strains could produce drug-resistance following long-term exposure to low doses of antibacterial drugs. In addition, amikacin and netilmicin are more prone to producing drug-resistance compared to imipenem in vitro. The results of the efflux phenotype indicate the possible application of CCCP in the inhibition of the efflux system in some drugs. The inconsistency between efflux phenotype and qPCR of adeB indicates that other mechanisms may also be included in the induction of drug-resistance that work with the active mechanism in order to increase drug resistance to common clinically-used antimicrobial drugs. PMID- 28565826 TI - Transcriptional profiling of leukocytes from rheumatoid arthritis patients before and after anti-tumor necrosis factor therapy: A comparison of anti-nuclear antibody positive and negative subsets. AB - Anti-nuclear antibodies (ANAs) may be induced in patients with rheumatoid arthritis (RA) receiving anti-tumor necrosis factor (TNF) therapy with TNF inhibitors (TNFi), etanercept, infliximab or adalimumab. In the present study, 11 patients who were TNFi drug naive were started on TNFi at a time of high disease activity. Of these, all cases were positive for rheumatoid factor and 9 cases tested were positive for anti-citrullinated peptide (anti-CCP) antibodies prior to TNFi treatment. Peripheral blood mononuclear cells (PBMCs) and serum were collected from all patients before and after TNFi therapy. Serum was assayed for ANAs over time. Total cellular RNA was extracted from PBMCs and assessed using Illumina arrays. Gene expression profiles were examined for alterations in key effector pathways. After 3 or more months on TNFi, 6 patients converted to ANA positivity. Analysis of transcripts from patients with RA who converted to ANA positivity after 3 months on TNFi identified complex gene expression profiles that reflected a reduction in cell adhesion, cell stress and lipid metabolism transcripts. In summary, unique transcriptional profiles in PBMCs from patients with RA were observed after TNFi therapy. This pilot study suggests that transcriptional profiling is a precise method of measuring the impact of TNFi therapies and reveals novel pathways that likely influence the immune response. PMID- 28565828 TI - Effect of sacral slope on the biomechanical behavior of the low lumbar spine. AB - The present study investigated the influence of sacral slope (SS) on the biomechanical responses of the lumbar spine under specific physiological conditions. Firstly, based on computed tomography scan images of a 30-year-old healthy male volunteer (SS, 55 degrees ), a three-dimensional finite element (FE) model including the L4-S1 segment was established. Flexion, extension, lateral bending and torsion motions were simulated and compared with cadaveric test data in the literature to validate the lumbar spine FE model. The model was then modified with different SS values (40 and 25 degrees ) for the same simulations to describe the process of structural compensation. Numerical results showed that with the reduction of SS, the range of motions (ROMs) reduced for flexion and lateral bending, but increased for extension and torsion. For displacement, the maximum magnitudes of L4/5 annulus fibrosus (AF) reduced by 10-25% in flexion, lateral bending and torsion, but less effect was observed for extension with only a 4% drop. Nearly the same displacement distribution appeared on the L5/S1 AF with small changes in the four motions. For the stress field of L4/5 AF, in contrast to flexion, the magnitudes for extension and lateral bending varied markedly, and under torsion the value increased by ~10%. For L5/S1 AF, the stresses changed little under flexion, extension and lateral bending, but strongly declined for torsion by ~71.8%. In conclusion, the present study indicates that the change in SS due to structural compensation affects the biomechanical behavior of the spine structure, and attention should be paid to SS when conducting surgical procedures or selecting intervertebral fusion implants. PMID- 28565827 TI - Neuroprotective effect of combining tanshinone IIA with low-dose methylprednisolone following acute spinal cord injury in rats. AB - The present study compared the potential neuroprotective effect of tanshinone IIA (TIIA) monotherapy, methylprednisolone (MP) monotherapy and combined treatment in an adult acute spinal cord injury (ASCI) rat model. The current study used the weight-drop method (Allen's Impactor) in the rat model and the mechanical scratch method in primary spinal cord neuron culture to determine whether the combined treatment was able to reduce the required dosage of MP in the treatment of ASCI to produce a similar or improved therapeutic effect. In vivo male Sprague Dawley rats (n=60) were randomly divided into 5 groups, of which 12 rats were selected for the sham group and T9-T11 laminectomies, leading to ASCI, were performed on 48 of the 60 rats using a 10 g *25 mm weight-drop at the level of T10 spinal cord. Therefore, the ASCI group (n=12) included the 'laminectomy and weight drop'. The remaining 36 ASCI model animals were subdivided into 3 groups (n=12 each group): TIIA group (30 mg/kg/day), MP group (30 mg/kg) and combined treatment group (TIIA 30 mg/kg/day + MP 20 mg/kg). Neuronal function following ASCI was evaluated using the Basso Beattie Bresnahan (BBB) locomotor rating scale. Levels of the anti-apoptotic factor B-cell lymphoma-2 (Bcl-2), the pro apoptotic factors Bcl-2 associated protein X (Bax) and caspase-3, and the inflammatory associated factor nuclear factor-kappaB, were analyzed by western blot analysis. Immunohistochemistry was used to detect caspase-3. To investigate the underlying mechanism, the anti-oxidative effect of combination TIIA and MP treatment was assessed by measuring the activity of malondialdehyde (MDA) and superoxide dismutase (SOD) in ASCI. In agreement with the experiment in vivo, primary neurons were prepared from the spinal cord of one-day-old Sprague-Dawley rats' and co-cultured with astrocytes from the brain cortex. The injury of neurons was induced by mechanical scratch and levels of apoptosis factors were analyzed by western blot analysis. The results of the current study indicated that injured animals in the combined treatment group exhibited a significant increase in BBB scores (P<0.05). TIIA + MP combined treatment and MP treatment was observed to reduce the expression of pro-apoptotic factors and promote neuron survival in vivo and in vitro. Combined treatment may promote neuroprotection through reduced apoptosis and inflammation caused by ASCI, similar to MP alone. Combined treatment reversed the decrease of SOD and the increase of MDA level caused by ASCI. In addition, combined treatment decreased the expression of caspase-3 in the neurons following ASCI in rats, as indicated by immunofluorescence double labeling. Overall, the present study indicates that the combined treatment of TIIA and MP may protect the neurons by stimulating the rapid initiation of neuroprotection following ASCI and reduce the dosage of MP in the treatment of ASCI required to produce the same or improved neuroprotective effects in vivo and in vitro. PMID- 28565829 TI - Effects of negative-pressure wound therapy combinedwith microplasma on treating wounds of ulcer and the expression of heat shock protein 90. AB - The effects of negative pressure wound therapy (NPWT) combined with microplasma on treating wounds of ulcer, and blood perfusion of wound-healing of interface, angiogenesis and the expressions of heat shock protein 90 (HSP90) were explored. We selected continuously 64 patients with wounds of ulcer. The patients were divided into the conventional treatment group (just medical foam dressing and 1% silver sulfadiazine cream for dressing changes) (n=20 cases), the NPWT group (n=22 cases) and the combination group (NPWT combined with microplasma) (n=22 cases), and compared the effects. It was found that in the 7 and 14 day combination group, maturity of granulation tissues and growth degree of epithelium were significantly higher than those in other two groups, and the areas of ulcer reduced significantly, the healing rate increased significantly (P<0.05). In the 7 and 14 day combination group, blood perfusion of wounds and density of new vessels were significantly higher than the other two groups (P<0.05). In the 7 and 14 day combination group, the expression of HSP90 was significantly higher than the other two groups (P<0.05). In conclusion, NPWT combined with microplasma can improve the healing of woulds of ulcers, and it is related to the upregulated expression of HSP90. PMID- 28565830 TI - Correlation between PKB/Akt, GSK-3beta expression and tubular epithelial mesenchymal transition in renal allografts with chronic active antibody-mediated rejection. AB - Chronic antibody-mediated rejection (ABMR) is a major cause of the transplant renal interstitial fibrosis and transplanted kidney epithelial cell transdifferentiation is one of the main mechanisms. The transforming growth factor (TGF)-beta1/integrin-linked kinase (ILK) signaling pathway has a significant role in the epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells; however, the molecular mechanisms of this process have remained elusive. The present study confirmed that Akt and glycogen synthase kinase (GSK) 3beta, as TGF-beta1 downstream signaling factors, are involved in fibrotic processes caused by kidney disease, which, however, has been rarely reported in the kidney transplant field. Based on the Banff 2009 standard, transplanted kidney specimens were classified according to the fibrosis level. The results showed that with the reduction of the interstitial fibrosis level, E-cadherin expression was gradually reduced, while alpha-smooth muscle actin expression progressively increased. The expression of Akt and GSK-3beta in normal human kidney tissue was not obvious but showed a marked increase with the aggravation of the interstitial fibrosis level, which confirmed the occurrence of EMT during the fibrosis process, and that phosphorylated (p)-Akt and GSK-3beta have an important role in the EMT process in the transplanted kidney. A correlation analysis of p-Akt, GSK-3beta, TGF-beta1 and ILK suggested that overexpression of p-Akt and GSK-3beta may induce and mediate the transdifferentiation of renal tubular epithelial cells to myofibroblasts and that this proceeds via TGFbeta1/ILK signaling pathways. PMID- 28565831 TI - Clinical characteristics and epilepsy outcomes following surgery caused by focal cortical dysplasia (type IIa) in 110 adult epileptic patients. AB - The aim of the present study was to investigate the effects of surgical intervention of focal cortical dysplasia (FCD) IIa on the outcome of epilepsy, and to evaluate the prognostic factors of seizure freedom. Patient data from epilepsy surgeries were retrospectively reviewed at the Second Affiliated Hospital of Dalian Medical University between 2007 and 2015. A total of 110 patients with a definite pathological diagnosis of FCD IIa were included. Moreover, the clinical characteristics, seizure outcome and quality of life in adults with FCD IIa were evaluated. The Engel seizure outcome achievements were class I in 72, class II in 20, class III in 11 and class IV in 7 patients. In addition, the Engel seizure outcome was relevant with the resection range of the lesions (P=0.028). The assessments of electrocorticography (ECoG) patterns and magnetic resonance imaging (MRI) are relevant to determining the extent of the resection, which may influence the surgery outcome (P=0.001 and P=0.023). Using multivariate regression analyses, the extent of resection, seizure frequency, preoperative ECoG and location of resection were the most important risk factors for seizure recurrence. The results of quality of life in epilepsy-10 scoring revealed that the quality of life improved significantly following surgery (P<0.01). Moreover, surgical intervention, EcoG, MRI positioning and complete resection helped to have improved seizure control, relief of anxiety and quality of life. All these observations strongly recommend an early consideration of epilepsy surgery in FCD IIa patients. PMID- 28565832 TI - Leptin is overexpressed in the tumor microenvironment of obese patients with estrogen receptor positive breast cancer. AB - The present study aimed to investigate the potential role of leptin in the progression of breast cancer and the associated cell proliferation signalling pathway(s). A total of 44 female patients diagnosed with breast cancer and 24 healthy donors from Ain Shams University Hospitals (Cairo, Egypt) were enrolled in the present study. The present study assessed leptin expression in breast cancer tissues at the gene and protein level using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry. The results demonstrate that the expression of leptin was significantly higher in tissue of breast cancer samples from obese patients than overweight and control samples (P<0.001). ELISA results indicated a significant increase (P<0.001) of leptin expression in obese patients. To investigate whether there is any difference in leptin expression between the peripheral and tumor microenvironment blood of patients with breast cancer, the concentration of leptin was assessed in plasma from both using ELISA assays. The results demonstrated a statistically significant increase in the level of leptin in plasma samples from the tumor microenvironment of obese patients with estrogen receptor positive (ER+) breast cancer, compared with peripheral plasma samples. Furthermore, the leptin gene was overexpressed in obese ER+ breast cancer tissue. RT-qPCR was also performed to assess the expression of genes involved in proliferation pathways including leptin receptor (LEPR), aromatase, mitogen activated protein kinase (MAPK) and signal transducer and activator of transcription-3 (STAT3). A positive association between leptin expression, LEPR, aromatase, MAPK and STAT3 was detected in tissue samples of patients with breast cancer. The current study concluded that leptin may enhance breast cancer progression by inducing the expression of JAK/STAT3, ERK1/2 and estrogen pathways in obese patients breast cancer. PMID- 28565833 TI - High-frequency repetitive transcranial magnetic stimulation for treating moderate traumatic brain injury in rats: A pilot study. AB - Transcranial magnetic stimulation (TMS) is a method of noninvasive brain stimulation that causes neuromodulation by activating neurons or changing excitability in a certain brain area. Considering the known effects of TMS and the pathophysiology of traumatic brain injury (TBI), TMS was proposed to have potential for treating this condition. Moderate TBI was induced in adult male Sprague Dawley rats using Feeney's weight-dropping method. Injured rats were divided into a TMS group and a control group. Repetitive TMS (rTMS) was administered to rats in the TMS group from post-TBI day 2. At post-TBI days 7, 14 and 28, three or four of the rats were sacrificed, and harvested brains were embedded in paraffin and sectioned. Sections were then treated with hematoxylin and eosin and immunohistochemical staining. Three rats from each group underwent fludeoxyglucose F 18 micro-positron emission tomography scanning on post-TBI day 2 and 13. The unexpected mortality rate after injury was lower in the TMS group than in the control group. The modified neurological severity score of the TMS group was lower compared with the control group at post-TBI day 14. According to the results of hematoxylin eosin staining, relative cerebral parenchyma loss was lower at post-TBI day 28 in the TMS group compared with the control group. However, the aforementioned differences were not found to be statistically significant. There was also no significant difference in glucose metabolism between the two groups. According to immunohistochemical staining, the TMS group showed a significantly higher level of proliferation (indicated by bromodeoxyuridine) in the subventricular zone, as compared with the control group (P<0.05). A significantly higher rate of neuron survival at day 28 (P<0.05; indicated by NeuN) and a significantly reduced rate of apoptosis at days 7 and 14 (P<0.05; indicated by caspase-3) were observed in the perilesional zone of the TMS group, as compared with the control group. The current findings suggest that high-frequency rTMS may promote neurogenesis and provide a basis for further studies in this area. PMID- 28565834 TI - Intravenous infusion umbilical cord-derived mesenchymal stem cell in primary immune thrombocytopenia: A two-year follow-up. AB - Four patients with chronic refractory immune thrombocytopenic purpura (ITP) received human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). The hUC MSC dose was 5*107 to 1*108. Complete remission (CR) was achieved in three patients in 12 months and one patient in 24 months. Three patients received the second hUC-MSC transplantation with the same dose. The median time between hUC MSC transplantation and response was 12.5 days (range, 7-16). There were no severe adverse events during and post hUC-MSC transplantation. During follow-up (median, 17 months; range, 13-24) no other immunosuppressive drugs were used post first hUC-MSCs transplantation. In conclusion, hUC-MSC transplantation is a reasonable salvage treatment in chronic refractory ITP. Prospective randomized large-scale clinical trials are needed to further elucidate the efficacy of hUC MSCs transplantation therapy on ITP. PMID- 28565835 TI - Intervention treatment on massive hemoptysis of pulmonary aspergilloma. AB - Retrospective analysis was carried out on intervention treatment and the effects of massive hemoptysis of pulmonary aspergilloma. Twenty-five cases diagnosed as massive hemoptysis of pulmonary aspergilloma were performed with imaging of bronchial arteries and other related blood vessels in order to assess blood vessel type and the number involved in the disease and perform embolotherapy on the offending artery. There were 68 bleeding arteries in 25 cases, of which there were 36 bronchial arteries (52.94%), 15 intercostal arteries (22.06%), 9 internal thoracic arteries (16.17%), 5 inferior phrenic arteries (7.35%), and 3 pulmonary arterial branches (4.41%) and all of them were in embolism condition. For 25 cases, 21 bleeding cases were stopped immediately (84.00%), 3 bleeding cases were stopped after the 2nd embolism, and 1 case had a small amount of hemoptysis after surgery discontinuously, which was stopped after corresponding treatment with no severe complications. Ten cases used polyvinyl alcohol (PVA) particulate embolization solely, 12 cases used PVA with spring coil and 3 cases used PVA, spring coil and N-butyl cyanoacrylate (NBCA) glue. In conclusion, patients who suffer from massive hemoptysis of pulmonary aspergilloma and whose medical treatments are not effective and who are not willing to receive surgical removal, intervention treatment is an effective method. PVA, spring coil and NBCA glue can be effectively used in hemoptysis embolism and pulmonary artery embolism can be considered when systemic embolism is not effective. PMID- 28565836 TI - The immune mechanism of intestinal tract Toll-like receptor in mediating EV71 virus type severe hand-foot-and-mouth disease and the MAPK pathway. AB - Immunological response is thought to play a crucial role in the development of a severe hand-foot-and-mouth disease (HFMD) infection in children, but the mechanisms remain largely unknown. This study was designed to help in elucidating the immunopathological pathways involved in the disease by quantifying Toll-like receptor (TLR) mRNAs, MAPK factors and cytokine levels in children experiencing the disease. A total of 86 enterovirus 71 (EV71)-infected HFMD children (49 with mild and 27 with severe disease), along with 30 healthy children were involved in the study. Peripheral vein blood samples were collected from each individual, and used to isolate peripheral blood mononuclear cells (PBMCs) for mRNA extraction and sera for measuring levels of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-6 and IL-10. The average expression levels of TLR3, TLR4, TLR7 and TLR8 mRNA in PBMCs of children with severe HFMD were significantly higher than those in the other children, the lowest values were found in the healthy control group (P<0.05). The expression levels of TLR2 and TLR9 mRNA were not significantly different (P>0.05) among the groups. Additionally, the expression levels of TNF-alpha, IFN-gamma, IL-6 and IL-10 in the serum of the children in the severe group were significantly higher than those in the other two groups, and the lowest values were again found in the control group (P<0.05). Pearson correlation analysis showed that the TLR3, TLR4, TLR7 and TLR8 mRNA levels in PBMCs were positively correlated with the TNF-alpha, IFN-gamma, IL-6 and IL-10 levels in the serum (P<0.05). Furthermore, the expression levels of the ERK, JNK and p38 mRNA in PBMCs of children in the severe group were significantly higher than those in the other two groups, with the lowest values being in the control group (P<0.05). Pearson correlation analysis showed that the TLR3, TLR4, TLR7 and TLR8 mRNA levels in PBMCs were positively correlated with ERK, JNK and p38 mRNA levels (P<0.05). The results of our study seem to indicate that the high expression levels of TLR3, TLR4, TLR7 and TLR8 induced in severe EV71 HFMD regulate the expression of cytokines by MAPK signaling pathway and negatively affect the ability of the organism to resolve the infection. Further studies are needed to test the hypothesis that immuno-modulation would be an effective treatment approach in pediatric cases of severe HFMD. PMID- 28565837 TI - Artesunate influences Th17/Treg lymphocyte balance by modulating Treg apoptosis and Th17 proliferation in a murine model of rheumatoid arthritis. AB - CD4+ regulatory T (Treg) cells and T-helper 17 (Th17) cells have been shown to have important roles in rheumatoid arthritis (RA). In our previous study, it was demonstrated that artesunate was able to alter the Treg/Th17 ratio in patients with RA; however, the underlying mechanisms remain unclear. The present study established a male Sprague Dawley (SD) rat model of type II collagen-induced arthritis (CIA). SD rats were divided into normal control, CIA model and artesunate-treated (5, 10 or 20 mg/kg/day) groups. Treg and Th17 cells were detected in the synovium by immunohistochemical analysis of forkhead/winged helix transcription factor (Foxp3) and interleukin (IL)-17 expression. Subsequently, lymphocytes were extracted from the rat spleens, and the proportions of Treg/Th17 cells were detected by flow cytometry. The results demonstrated that the expression levels of Foxp3 were significantly decreased, and those of IL-17 were significantly increased, in the CIA model group, as compared with the normal control group. The results demonstrated that artesunate decreased the frequency of Th17 cells and increased the frequency of Treg cells in CIA rats in a dose dependent manner. In conclusion, the present study suggested that artesunate may regulate the Th17/Treg balance by inducing Th17-mediated apoptosis. Therefore, artesunate may be considered a novel therapeutic agent for the treatment of patients with RA. PMID- 28565838 TI - HOTAIR is a promising novel biomarker in patients with thyroid cancer. AB - Thyroid cancer (TC) is the most common endocrine malignancy. Lack of effective early diagnostic tools is one of the clinical obstacles for TC treatment. Thus, enhanced comprehension of the molecular changes in TC tumorigenesis is urgently needed to develop novel strategies for the diagnosis and treatment of TC. Long non-coding RNAs (lncRNAs) manage fundamental biochemical and cellular processes in tumorigenesis and development. One of the best-described lncRNAs, HOX transcript antisense RNA (HOTAIR), functions as a regulatory molecule in a wide variety of biological processes, and represses gene expression through recruitment of the chromatin modifying complex. However, the function of HOTAIR in TC remains unclear. In the current study, the expression of HOTAIR is elevated in TC and correlates with metastasis and poor prognosis. Furthermore, the expression of HOTAIR is significantly upregulated in human thyroid carcinoma cells compared with normal human thyroid cells. Furthermore, knockdown of HOTAIR significantly inhibited cell growth and invasion in TPC-1 and SW579 human thyroid carcinoma. In summary, HOTAIR is a promising novel biomarker in patients with TC. PMID- 28565839 TI - miR-365 induces hepatocellular carcinoma cell apoptosis through targeting Bcl-2. AB - Hepatocellular carcinoma (HCC) is currently ranked as the third leading cause of cancer-related mortality worldwide. microRNAs (miRs) serve important roles in the development and progression of HCC. miR-365 has been demonstrated to function as a tumor suppressor in several types of cancer, including HCC; however, the mechanisms by which miR-365 regulates HCC apoptosis remains to be elucidated. In the present study, reverse transcription-quantitative polymerase chain reaction was performed to determine miR-365 expression levels in HCC and normal liver (LO2) cells. miR-365 overexpression was induced in SMC7721 cells using a plasmid based system, and Cell Counting Kit-8 and TUNEL assays were performed to detect cell activity and apoptosis following miR-365 transfection. A luciferase assay was performed to determine the direct target of miR-365 in apoptosis regulation. Furthermore, a subcutaneously transplanted tumor model was established to evaluate the effects of miR-365 on tumor growth in vivo. The tumor tissue was used for further proliferation and apoptosis detection. The results of the present study indicated that miR-365 expression was significantly lower in HCC cells compared with LO2 cells (P<0.01). Transfection of SMC7721 cells with miR 365 plasmid significantly inhibited cell activity by inducing apoptosis (P<0.01). Luciferase assay indicated that miR-365 targets B-cell lymphoma 2 (Bcl-2) directly and therefore induces the downstream expression of pro-apoptotic proteins. The SMC7721 primary tumor growth was significantly reduced by miR-365 transfection (P<0.01). Further investigation demonstrated that the miR-365 group contained significantly fewer cells that were positive for proliferating cell nuclear antigen (P<0.01) and significantly more apoptotic cells (P<0.01). In conclusion, the results of the present study demonstrated that miR-365 may serve a role in inducing HCC apoptosis via directly targeting Bcl-2. This may provide a novel diagnosis and therapy target for the treatment of patients with HCC. PMID- 28565840 TI - Overexpression of miR-155 in clear-cell renal cell carcinoma and its oncogenic effect through targeting FOXO3a. AB - MicroRNA-155 (miR-155) is overexpressed in numerous human cancer types and has an oncogenic role. Previous study has revealed that miR-155 serves an important role in the progression of clear-cell renal cell carcinoma (ccRCC); however, the underlying mechanism was not completely clarified. The present study aimed to investigate the biological role of miR-155 in ccRCC and the underlying molecular mechanisms. The expression of miR-155 in 20 ccRCC and adjacent normal kidney tissues was determined by PCR. After downregulation of miR-155 expression by miR 155 inhibitor, cell growth was assessed by MTT and colony formation assays. Apoptosis and cell cycle distribution were analyzed by flow cytometry. Cell invasion and migration was detected by wound healing and Transwell assays. Furthermore, forkhead box O3a (FOXO3a) mRNA and protein expression were detected by PCR and immunoblotting. The expression of FOXO3a in 20 ccRCC tissues was also examined by immunohistochemistry. The expression of miR-155 was upregulated in ccRCC tissues compared to that in adjacent normal tissues. Inhibition of miR-155 significantly suppressed the proliferation, colony formation, migration and invasion, and induced G1 arrest and apoptosis of ccRCC cells in vitro. Moreover, inhibition of miR-155 significantly upregulated FOXO3a expression, and miR-155 expression was inversely correlated with FOXO3a expression in ccRCC tissues. In conclusion, miR-155 may have an important role in the genesis of ccRCC through targeting FOXO3a and may be a potential target for ccRCC therapy. PMID- 28565841 TI - Ultrasound combined with targeted cationic microbubble-mediated angiogenesis gene transfection improves ischemic heart function. AB - The present study aimed to construct targeted cationic microbubbles (TCMBs) by synthesizing cationic microbubbles conjugated to an intercellular adhesion molecule-1 (ICAM-1) antibody, and then to use the TCMBs to deliver the angiopoietin-1 (Ang-1) gene into infarcted heart tissue using ultrasound-mediated microbubble destruction. It was hypothesized that the TCMBs would accumulate in higher numbers than non-targeted cationic microbubbles (CMBs) in the infarcted heart, and would therefore increase the efficiency of targeted Ang-1 gene transfection and promote angiogenesis. The results of the study demonstrated that the ability of TCMBs to target inflammatory endothelial cells was 18.4-fold higher than that of the CMBs in vitro. The accumulation of TCMBs was greater than that of CMBs in TNF-alpha-stimulated human umbilical cord veins, indicated by a 212% higher acoustic intensity. In vivo, the TCMBs specifically accumulated in the myocardial infarct area in a rabbit model. Three days after ultrasound microbubble-mediated gene transfection, Ang-1 protein expression in the TCMB group was 2.7-fold higher than that of the CMB group. Angiogenesis, the thickness of the infarct region and the heart function of the TCMB group were all significantly improved compared with those in the CMB and control groups at 4 weeks following gene transfection (all P<0.01). Therefore, the results of the current study demonstrate that ultrasound-mediated TCMB destruction effectively delivered the Ang-1 gene to the infarcted myocardium, resulting in improved cardiac morphology and function in the animal model. Ultrasound-mediated TCMB destruction is a promising strategy for improving gene therapy in the future. PMID- 28565842 TI - Detection of trisomies 13, 18 and 21 using non-invasive prenatal testing. AB - The clinical performance of non-invasive prenatal testing (NIPT) in the Down's syndrome screening based on 1,901 pregnant women in a Chinese hospital was investigated. This was a retrospective analysis of NIPT study in singleton pregnancy (n=1,901). The NIPT test is offered routinely as a prenatal screening test for common fetal aneuploidies, including trisomy 13 (T13), T18 and T21 to pregnant women with risk factors of one or more anomalies. Maternal peripheral blood (5 ml) was collected in an ethylenediaminetetraacetic acid (EDTA) tube at a gestational age of 12+0 to 32+6 weeks. The samples were delivered at -80 degrees C to the certified Shenzhen BGI Clinical Laboratory Center. Sequencing data were analyzed using a proprietary algorithm. Women with positive NIPT results were recommended to receive karyotype analysis and amniotic fluid puncture for further validation. The cases were followed up for 56 days after delivery. All the patients underwent ultrasound examination, and the majority of patients (91.16%) showed normal findings. In contrast, 136 (7.15%) showed ultrasound anomalies. The most common anomaly was echogenic heart focus (n=80), accounting for 4.21% of the patients. Twenty-two cases were classified by the NIPT to be positive for the T21 (n=15), T18 (n=5) and T13 (n=2), respectively, while the others (n=1,879) were classified to be NIPT negative cases. Among these cases, the fetal outcome data were obtained in 1,483 cases, while 396 were lost to follow-up. The majority of cases (75.47%) were normal at birth. Neonatal death was observed in 1 case. Five pregnant women decided termination of pregnancy despite the presence of NIPT negativity. In conclusion, NIPT technique is feasible for the prenatal screening of T18 and T21 with higher sensitivity and specificity compared with conventional methods. PMID- 28565843 TI - Inhibition of centrosomal protein 164 sensitizes rhabdomyosarcoma cells to radiotherapy. AB - Rhabdomyosarcoma is the second most common malignant tumor of the heart in infants and children and cannot often be resected completely. Chemotherapy and radiotherapy have a critical role in relieving symptoms and prolonging survival; therefore, enhancing the sensitivity of rhabdomyosarcoma to radiotherapy is an important area of investigation in order to improve the prognosis of patients. It has been reported that centrosomal protein 164 (CEP164) has a key role in the DNA damage-activated signaling cascade. CEP164 is often overexpressed in tumors and is associated with poor prognosis in various types of cancer. In the present study, the influence of CEP164 on the radiosensitivity of rhabdomyosarcoma cells was investigated. Results demonstrated that CEP164 is involved in the radiation induced cellular response. CEP164 is increased upon radiation and influences the cell cycle, cell viability and cell apoptosis. CEP164 depletion enhanced cellular sensitivity to radiation, promoted cell apoptosis, decreased cell viability and induced gap 2/mitosis arrest of the cell cycle. The present study identified the function of CEP164 in radiation resistance in rhabdomyosarcoma, providing a potential therapeutic target for rhabdomyosarcoma treatment by disrupting CEP164. PMID- 28565845 TI - Significance of new blood vessels in the pathogenesis of temporomandibular joint osteoarthritis. AB - We studied the significance of new blood vessels in the pathogenesis of temporomandibular joint osteoarthritis (TMJOA). Fifteen 8-week-old female Sprague Dawley rats were selected to establish TMJOA models of gradually induced occlusal disorders. Five rats were sacrificed at 4, 8 and 16 weeks, and histological exam was conducted along with micro-computed tomography observation on the condyle specimen. The distribution and number of new blood vessels breaking were observed through the tidemark through CD34 immunofluorescence staining. The proliferation of chondrocytes were detected through Ki67 immunohistochemical staining, and the differentiation functions of chondrocytes were observed through PTHrP and IHH immunohistochemical staining. The degradation functions of cartilage matrix were observed through matrix metalloproteinase (MMP)-9 immunohistochemical staining to detect the expression of vascular growth promotion and inhibition factors with vascular endothelial growth factor (VEGF), CTGF and CHM-1 immunohistochemical staining and screen differentially expressed genes through gene chip analysis method. It was found that the condyle tissue full thickness, fiber layer thickness and calcified cartilage layer thickness were significantly increased with time (P<0.05). Bone mineral density, trabecular thickness and Tb.Sp were also increased significantly with time, BS/BV and trabecular number were decreased significantly with time (P<0.05). The new blood vessels reached the deep layer of calcified cartilage until the tide line was broken and non calcified cartilage was invaded. The number of vessels were increased significantly with time (P<0.05). Ki67, PTHrP and IHH-positive rates were increased significantly (P<0.05). MMP-9, VEGF, CTGF and CHM-1 were increased significantly (P<0.05). VEGF, CTGF and CHM-1 mRNA were upregulated differentially with the expressed genes. In conclusion, the new blood vessels may be important in the pathogenesis of TMJOA. PMID- 28565844 TI - Protective effects of choline against hypoxia-induced injuries of vessels and endothelial cells. AB - The current study aimed to lay a theoretical foundation for further development of choline as an anti-hypoxia damage drug. Wild-type, 3- to 5-month-old male Sprague-Dawley rats, weighing 180-220 g, were used in this study. The rats were randomly divided into a normoxic control group (n=16) and a chronic intermittent hypoxia (CIH) group (n=16). The effects of CIH on acetylcholine (ACh)-mediated endothelium-dependent vasodilatation in the rat cerebral basilar arterioles and mesenteric arterioles, as well as the protective effects of choline on the arterioles damaged by hypoxia were observed. Moreover, the effects of choline on endothelial cell proliferation during hypoxia were observed, and choline's functional mechanism further explored. The ACh-mediated vasodilatation of rat cerebral basilar and mesenteric arterioles significantly reduced during hypoxia (P<0.01). Choline significantly increased dilation in the rat cerebral basilar (P<0.01) and mesenteric arterioles (P<0.05) damaged by CIH compared with those in the control group. In addition, under hypoxic conditions, choline significantly promoted the proliferation of rat aortic endothelial cells (P<0.05) and significantly reduced lactate dehydrogenase activity in the cell culture supernatant in vitro (P<0.05). Furthermore, the effect of choline could be related to its ability to significantly increase the secretion of vascular endothelial growth factor (P<0.01) and activation of alpha7 non-neuronal nicotinic acetylcholine receptors under hypoxia (P<0.01). This study demonstrated that choline could have protective effects against hypoxic injuries. PMID- 28565846 TI - Use of DNA microarray chips for the rapid detection of Mycobacterium tuberculosis resistance to rifampicin and isoniazid. AB - The objective of the present study was to evaluate the potential development of DNA microarray chips to detect rifampicin (RFP) and isoniazid (INH) resistance in Mycobacterium tuberculosis (MTB), using samples from clinical tuberculosis (TB) patients in Soochow City, China. The sputum samples of 42 patients with TB in the Affiliated Hospital of Infectious Diseases of Soochow University (Soochow, China) were collected. The conventional Lowenstein-Jensen culture medium (Gold Standard) was used to assess drug sensitivity using the absolute concentration method. GeeDom MTB drug detection kits were also used to create a DNA microarray chip and examine the RFP-resistance associated gene mutation points rpoB-RRDR 511, 513, 516, 526, 531 and 533, and the INH-resistance associated gene mutation points katG315 and inhA-15 of the sputum samples. Compared with the results from the absolute concentration method, the susceptibility and specificity of RFP sensitivity detected by the DNA microarray chip were 92.8 and 93.8%, respectively. The susceptibility and specificity of INH sensitivity detected were 66.7 and 81%, respectively. The rpoB-RRDR 526, 531 mutations were the primary causes of MTB RFP resistance and the katG315 mutation was the primary cause of INH resistance. The detection of rpoB and katG gene mutation points by a DNA microarray chip may be used as a rapid, accurate and bulk clinical detection method for RFP and INH resistance in MTB. This is very valuable for the control of TB epidemics. PMID- 28565847 TI - Recombinant Bacille Calmette-Guerin coexpressing Ag85B-IFN-gamma enhances the cell-mediated immunity in C57BL/6 mice. AB - The only available vaccine against pulmonary tuberculosis is Bacille Calmette Guerin (BCG). As the efficacy reported of the vaccine is not up to the mark, there is an urgent need to develop improved anti-tuberculosis vaccines. Antigen 85B (Ag85B) is a very promising vaccine candidate molecule of Mycobacterium tuberculosis and interferon (IFN)-gamma and has been considered the most attractive correlate of protective immunity. The aim of this study was to construct a novel recombinant BCG (rBCG) to secrete Ag85B and mouse IFN-gamma under control of the Mycobacterial heat shock protein 60 (hsp60) promoter and the antigen signal sequence. Second aim of the present study is to evaluate the immune response in C57BL/6 elicted by the new rBCG. Expression of the fusion protein was readily detectable by western blotting and IFN-gamma bioactivity was detected indirectly by enzyme-linked immunosorbent assay (ELISA). Compared with BCG, rBCG::Ag85B-IFN-gamma was substantially more active in inducing the production of IFN-gamma and tumor necrosis factor (TNF)-alpha from mouse splenocytes. ELISA analysis for IgG, IgG1 and IgG2c showed that rBCG::Ag85B-IFN gamma induced higher titer of Ag85B and facilitated Th1 type immune response. rBCG::Ag85B-IFN-gamma also improved nitric oxide production levels and enhanced antigen-specific splenocyte proliferation. Moreover, rBCG::Ag85B-IFN-gamma induced human monocytes such as THP-1 cells to enhance expression of CD80, CD86, CD40 and HLA-DR. Flow cytometry analysis confirmed that rBCG::Ag85B-IFN-gamma significantly activated CD4+ T cells. Assessing combinations of IFN-gamma, TNF alpha and interleukin-2 at the single-cell level by multiparameter flow cytometry, we found that rBCG::Ag85B-IFN-gamma improved the multifunctional T cells level in comparison to BCG. In conclusion, the present study indicates that rBCG::Ag85B-IFN-gamma increases cell mediated immune response and is a potential candidate vaccine for immunotherapeutic protocols against pulmonary tuberculosis. PMID- 28565848 TI - Autophagy activated by the c-Jun N-terminal kinase-mediated pathway protects human prostate cancer PC3 cells from celecoxib-induced apoptosis. AB - The aim of the present study was to investigate the role of autophagy in celecoxib-induced apoptosis in human hormone-insensitive prostate cancer cell line PC3 cells and to explore the underlying molecular mechanism leading to autophagic activation. A cell viability assay was applied to investigate the effect of various concentrations of celecoxib (0, 40, 60, 80, 100 and 120 umol/l) on PC3 cells for 24 and 48 h, respectively. The 50% inhibitory concentration of celecoxib for 24 h was chosen for subsequent experiments. Annexin V-fluorescein isothiocyanate/propidium iodide double staining flow cytometry, as well as caspase 3 and poly (ADP-ribose) polymerase proteins detected by western blotting, were applied to analyze cellular apoptosis induced by celecoxib. Ultrastructural cellular changes observed by transmission electron microscopy and the level of LC 3 II and P62 detected by western blotting were used to determine the activation of autophagy. It was demonstrated that celecoxib induced apoptosis and activated autophagy in PC3 cells in a dose- and time-dependent manner. Furthermore, flow cytometry and western blotting were applied to elucidate whether the role of autophagy in celecoxib-induced apoptosis is protective or destructive. Blockade of autophagy markedly increased apoptosis, suggesting that celecoxib-activated autophagy was cytoprotective. Additionally, c-jun-N-terminal kinase (JNK) was demonstrated to have a role in autophagic activation, and suppression of JNK was able to reduce autophagy and increase apoptosis. In conclusion, the results of the present study indicate that celecoxib induces apoptosis in PC3 cells; however, celecoxib also activates JNK-mediated autophagy, which exerts cytoprotective effects in prostate cancer PC3 cells. Blockade of autophagy via the JNK-mediated pathway may provide a promising strategy for prostate cancer therapy. PMID- 28565849 TI - Myocardial protective effects of dexmedetomidine in patients undergoing cardiac surgery: A meta-analysis and systematic review. AB - Arrhythmias are the common complications following cardiac surgery and contribute to hemodynamic instability, cognitive impairment, thromboembolic events, and congestive heart failure. Prevention of atrial fibrillation following cardiac surgery reduces morbidity and among the many available preventive approaches dexmedetomidine shows many positive effects on cardiovascular stability. Even though many studies indicated the beneficial effects of dexmedetomidine, the power of the analysis and conclusion of these studies is rather weak due to relatively smaller number of patients in these studies. In the present meta analysis, we included a large number of patients, both children and adults, undergoing cardiac surgery, to address the efficacy of dexmedetomidine. Several databases were searched to identify clinical studies comparing the efficacy of dexmedetomidine in myocardial protection in patients undergoing cardiac surgery. Cardiac function related parameters including heart rate, blood pressure, tachycardia, arrhthmias, and bradycardia were measured. In accordance with the selection criteria, a total of 18 studies published between 2003 and 2016, with a total of 19,225 patients were included in the present meta-analysis. Dosage of dexmedetomidine was in the range of 0.5-1 ug/kg body weight loading followed by continuous infusion at a rate of 0.2-0.7 ug/kg/h. Dexmedetomidine treatment was found to lower heart rate, systolic blood pressure, incidence of tachycardia and arrhythmias in both adult and pediatric patients, but elevated the risk of bradycardia. In conclusion, results of this meta-analysis indicate that dexmedetomidine is an efficacious cardioprotective drug in adults and children undergoing cardiac surgery. PMID- 28565850 TI - Metabolic acidosis as a risk factor for the development of acute kidney injury and hospital mortality. AB - Metabolic acidosis has been proved to be a risk factor for the progression of chronic kidney disease, but its relation to acute kidney injury (AKI) has not been investigated. In general, a diagnosis of metabolic acidosis is based on arterial blood gas (ABG) analysis, but the diagnostic role of carbon dioxide combining power (CO2CP) in the venous blood may also be valuable to non respiratory patients. This retrospective study included all adult non-respiratory patients admitted consecutively to our hospital between October 01, 2014 and September 30, 2015. A total of 71,089 non-respiratory patients were included, and only 4,873 patients were evaluated by ABG analysis at admission. In patients with ABG, acidosis, metabolic acidosis, decreased HCO3- and hypocapnia at admission was associated with the development of AKI, while acidosis and hypocapnia were independent predictors of hospital mortality. Among non-respiratory patients, decreased CO2CP at admission was an independent risk factor for AKI and hospital mortality. ROC curves indicated that CO2CP was a reasonable biomarker to exclude metabolic acidosis, dual and triple acid-base disturbances. The effect sizes of decreased CO2CP on AKI and hospital mortality varied according to age and different underlying diseases. Metabolic acidosis is an independent risk factor for the development of AKI and hospital mortality. In non-respiratory patient, decreased CO2CP is also an independent contributor to AKI and mortality and can be used as an indicator of metabolic acidosis. PMID- 28565851 TI - Pharmacological management of non-alcoholic fatty liver disease: Atorvastatin versus pentoxifylline. AB - In this study, we aimed to evaluate the efficacy of pentoxifylline and atorvastatin in the treatment of non-alcoholic fatty liver disease (NAFLD). The study included 98 patients with histologically confirmed NAFLD divided into 2 groups as follows: group I (57 dyslipidemic patients, receiving atorvastatin 20 mg/day and group II (41 non-dyslipidemic patients, treated with pentoxifylline, 800 mg/day). The present study was conducted for a mean of 32.8+/-3.4 weeks. For all patients, we determined the body mass index, a liver biopsy was performed, and we measured the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total cholesterol (TC) and triglycerides (TG) at the beginning and at the end of the study period. The NAFLD activity score (NAS) was used to evaluate the liver biopsies for steatosis, fibrosis and necroinflammation. The patients in group I exhibited a considerable reduction in ALT, AST, GGT, TC, AP and TG levels (P<0.0001). Histologically, there were no changes in fibrosis and necroinflammation, although the extent steatosis was reduced. The improvement in the ALT, AST and GGT values (P<0.05) in group II were similar to those in group I; however, no statistically significant decrease was noted in the levels of ALP, TC and TG in this group. Our results thus demonstrated that atorvastatin attenuated steatosis and improved liver function parameters in patients with NAFLD associated with dyslipidemia. Similar results were obtained in the non dyslipidemic patients administered pentoxifylline. PMID- 28565852 TI - Oxidation of human serum albumin exhibits inter-individual variability after an ultra-marathon mountain race. AB - The aim of this study was to examine the oxidation of human serum albumin (HSA) caused by oxidative stress following exhaustive and demanding exercise, such as an ultra-marathon race. For this purpose, blood samples from 12 adult runners who underwent a 103 km mountain ultra-marathon race were collected before the race, and also at 24, 48 and 72 h post-race. HSA was partially purified using affinity chromatography and consequently subjected to western blot analysis in order to determine the levels of disulfide dimers indicating oxidation. For reasons of comparison, the results were correlated with those from a previous study, in which the same samples were analyzed using different oxidative stress markers. The results revealed a good correlation between albumin dimers and protein carbonyls at all time points, while there was also a significant correlation with static oxidation reduction potential at 24 h, and a negative correlation with capacity oxidation reduction potential at 24 and 48 h. In addition, an individual analysis of albumin dimers exhibited great inter-individual differences, indicating the variation of HSA oxidation between different athletes. Namely, in some athletes, HSA seemed to be the main oxidation target of serum proteins, while in other athletes, there was even a reduction of HSA. This inter-individual variability in the oxidation of HSA may suggest that different interventions (e.g., through diet) may be required in order to confront the effects on athletes following strenuous exercise. On the whole, this study suggests the importance of the assessment of albumin dimers as a predictive marker for exercise-induced oxidative stress. PMID- 28565853 TI - Comparison of acute phase protein and hemodynamic variables in dogs undergoing video-assisted thoracoscopic vs. open pneumonectomy. AB - It has been demonstrated that video-assisted thoracoscopic surgery (VATS) is feasible and safe in humans and animal models. The aim of the present study was to compare the surgical outcome using VATS with that of the standard transthoracic approach for pneumonectomy in dogs, to determine the acute-phase reaction in VATS pneumonectomy, and to analyze the difference between VATS and the standard transthoracic approach. A total of 14 dogs were divided into two groups (n=7); one group underwent VATS and the other group underwent a transthoracic pneumonectomy. Pre-, intra- and post-operative physiologic parameters were monitored, in addition to the blood cell count and serum acute phase protein (APP) concentrations. The APP and hemodynamic changes between the two approaches were analyzed. Mean surgical time in the VATS group (176.7 min) was significantly longer compared with the open group (132.4 min). All APP concentrations were significantly increased at day 1 postoperation and gradually decreased to preoperative concentrations. The serum concentration of C-reactive protein on day 3 and the white blood cell count on day 1 were significantly higher following surgery in the open group compared with the VATS group (P<0.05). No differences were observed in the physiological parameters between the two groups. Although VATS took longer, animals experienced smaller incision and less stress. Therefore, the VATS approach was satisfactory for total pneumonectomy. PMID- 28565854 TI - Effect of icariin on fracture healing in an ovariectomized rat model of osteoporosis. AB - Osteoporosis is frequently asymptomatic, presenting a significant clinical and economic burden, particularly following an osteoporosis-associated fracture. Icariin has been reported to inhibit osteoporosis in vitro, and the present study investigated whether icariin also promoted bone fracture healing in ovariectomized osteoporotic (OVX) rats in vivo. A total of 30 female rats were randomly divided into three groups (n=10 per group): i) Sham surgery; ii) OVX; and iii) OVX with icariin (OVX + ICA) groups. At 3 months after the ovariectomy, a unilateral cross-tibia fracture was made at the proximal right tibia. Animals were then sacrificed after 5 weeks of oral treatment. X-rays were taken at 1 week, 3 weeks and 5 weeks of treatment, and dual energy X-ray absorptiometry was used to measure the bone mineral density (BMD). Changes to the osteocalcin (BGLAP), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) and estradiol levels in blood were measured. Callus formation and bone union were observed, the BMD was significantly higher and the BGLAP, ALP and TRAP levels were reduced, but no significant increase was observed in the blood estradiol level in the OVX + ICA group compared with the OVX group. The present findings indicate that icariin has potential as a novel alternative therapeutic agent for fracture healing in postmenopausal osteoporosis. PMID- 28565855 TI - Immunosuppressive effect of sinomenine in an allergic rhinitis mouse model. AB - Allergic rhinitis (AR) is a chronic allergic airway disease that has become a significant global public health issue. Sinomenine (SN), a natural phytochemical found in Sinomenium acutum, showed anti-inflammatory and immunosuppressive effect in previous studies. In order to explore the role of SN in the treatment of AR, mice were sensitized and challenged by ovalbumin (OVA) to establish an AR mouse model. SN was administered to AR mice orally, and compared with dexamethasone treatment as a positive control. Nasal symptoms and histopathological changes were used to evaluate the effect of SN treatment in the AR mice model. In addition, the levels of anti-OVA specific IgE and various cytokines in the serum were measured by enzyme-linked immunosorbent assay, while the levels of transforming growth factor-beta (TGF-beta) in the mucosa were also detected by western blot analysis and reverse transcription-quantitative polymerase chain reaction. AR mice that received SN treatment had reduced symptom scores and milder eosinophil infiltration. The serum levels of anti-OVA specific IgE and interleukin-4 significantly decreased following SN treatment. Furthermore, TGF beta expression levels in the serum and nasal mucosa tissue in AR mice increased when compared with those in AR mice without treatment. In conclusion, SN treatment alleviated the symptoms of AR in mice and had an immunosuppressive effect on AR, which may result from the upregulation of TGF-beta. PMID- 28565856 TI - Blocking fatty acid synthase inhibits tumor progression of human osteosarcoma by regulating the human epidermal growth factor receptor 2/phosphoinositide 3 kinase/protein kinase B signaling pathway in xenograft models. AB - Previous studies have demonstrated that fatty acid synthase (FASN) is overexpressed in osteosarcoma (OS) cells and tissues and, therefore, knockdown of FASN may inhibit OS cell proliferation, migration and invasion via regulation of the human epidermal growth factor receptor 2 (HER2)/phosphoinositide 3-kinase (PI3K)/protein kinase B(Akt) signaling pathway in vitro. However, the tumor microenvironment has a crucial role in the determination of tumor malignant phenotype. The aim of the present study was to investigate the effect of knockdown of FASN on OS progression and the potential molecular mechanism in nude mice with orthotopic tumor implants in vivo. Results demonstrated that the knockdown of FASN markedly suppressed the growth and metastasis of OS, at least partially, by blocking the HER2/PI3K/Akt signal pathway in mice with intratibial 143B OS xenografts. These results suggest that the FASN/HER2/PI3K/Akt signaling pathway may be a potential therapeutic target for OS management. PMID- 28565857 TI - Role of the PI3K/AKT signalling pathway in apoptotic cell death in the cerebral cortex of streptozotocin-induced diabetic rats. AB - Diabetes mellitus is associated with cognitive dysfunction. Numerous previous studies have shown that type 1 diabetes-induced hyperglycaemia causes structural brain damage, such as a decrease in whole-brain grey matter. The impact of diabetes mellitus on the cerebral cortex is poorly understood and requires further clarification. In the present study, diabetes was induced via an intraperitoneal injection of streptozotocin (50 mg/kg). Hematoxylin and eosin (H&E) staining was performed to detect the morphological changes in the cerebral cortex, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining was used to detect neuronal apoptosis and western blotting was performed to determine protein expression levels. Nine weeks after the induction of diabetes, the body weight was significantly lower and the blood glucose levels were significantly higher in the diabetic rats than in the control rats (P<0.05). H&E staining revealed nuclear chromatin condensation and cytoplasmic shrinkage in the cerebral cortex of the diabetic rats and TUNEL staining further indicated apoptotic changes in the cerebral cortex of the diabetic rats. The ratio of B cell lymphoma 2 (Bcl-2) -associated X protein/Bcl-2 and the expression of cytochrome c and activated caspase-3 (cleaved caspase-3) were significantly increased, whereas the ratio of phosphorylated AKT/AKT was significantly decreased in the diabetic rats compared with that in the control rats (P<0.05). Taken together, these results suggested that diabetes mellitus may induce neuronal apoptosis in the cerebral cortex by downregulating AKT phosphorylation. PMID- 28565858 TI - Neuroprotective effects of phenylethanoid glycosides in an in vitro model of Alzheimer's disease. AB - The present study aimed to investigate the neuroprotective effects of phenylethanol glycosides (PhGs) on H2O2- and beta-amyloid peptide (Abeta)1-42 induced injury of PC12 cells as an in vitro model of Alzheimer's disease (AD). The optimal induction conditions were established through screening of various incubation times and concentrations. PC12 cells were treated with 0.5 uM Abeta1 42 and H2O2 in the presence of PhGs for 24 h and the cell viability was then evaluated by an MTT assay; lactate dehydrogenase (LDH) release and malondialdehyde (MDA) content were also measured. The optimal conditions for establishing the AD model were the treatment of PC12 cells with 0.5 uM Abeta1-42 for 48 h, or with 25 uM H2O2 dissolved in DMEM with PBS. PhGs at concentrations of 5, 25 and 50 ug/ml increased the viability and decreased LDH and MDA release by PC12 cells injured with Abeta1-42 or H2O2. In conclusion, the model of Abeta1 42- and H2O2-induced PC12 cell injury was successfully established. PhGs were shown to have a significant neuroprotective effect against Abeta1-42- or H2O2 induced cell injury. PMID- 28565859 TI - Protective effect of a novel antifungal peptide derived from human chromogranin a on the immunity of mice infected with Candida krusei. AB - Invasive fungal infections threat the life of immunocompromised patients. Chromogranin A N-46 (CGA-N46), corresponding to the 31st to 76th amino acids of the N-terminus of human chromogranin A, is an antifungal peptide. In order to elucidate the antifungal effects of CGA-N46 in vivo, we studied its effects on cell-mediated immunity in Candida krusei-infected mice. The results showed that the treatment with CGA-N46 increased the average body weight and decreased the mortality of the immunocompromised mice model infected with Candida krusei. The spleen and thymus indices of treated mice has markedly increased compared with that of the control group (P<0.05), and the immune cell levels in peripheral blood also increased significantly (P<0.05). The immuno-modulatory effect of CGA N46 (60 mg/kg/day) was found to be comparable to that of terbinafine. Additionally, CGA-N46 could alleviate or eliminate histopathological symptoms in the liver, spleen, kidney, and lung tissues. In conclusion, the present study suggests that CGA-N46 may offer a new strategy for antifungal therapeutic option. This study is an essential step in elucidating the effect of CGA-N46 in vivo. PMID- 28565860 TI - Development of a sustained-release microcapsule for delivery of metoprolol succinate. AB - Sustained-release (SR) formulations of metoprolol succinate (MS) may minimize fluctuations in plasma concentration and decrease the resulting adverse events. The aim of the present study was to optimize the loading capacity of microcapsules and the SR of MS. A uniform design method was applied to optimize the formulation of SR microcapsules, composed of ethyl cellulose and polyethylene glycol 6,000, in one step via emulsion-solvent diffusion. In vitro release was studied, and the in vivo bioavailability of MS following dosing with novel microcapsules was compared with a commercially available MS formulation in beagle dogs. The present methodology achieved an entrapment efficiency of 83.2%, with 96.1% of drug released in vitro in 18 h, and the release was close to linear over a 12-h period. Pharmacokinetic studies of MS microcapsules in beagle dogs demonstrated a superior SR profile compared with conventional SR tablets. MS microcapsules were developed with high encapsulation efficiency, which had desirable SR properties in vitro and in vivo. PMID- 28565861 TI - Global methylation and promoter-specific methylation of the P16, SOCS-1, E cadherin, P73 and SHP-1 genes and their expression in patients with multiple myeloma during active disease and remission. AB - Tumor suppressor gene promoter CpG island methylation is a well-recognized mechanism in cancer pathogenesis, but its role in multiple myeloma (MM) is controversial. The present study investigated the methylation status and expression of P16, suppressor of cytokine signaling 1 (SOCS-1), P73, E-cadherin and Src homology region 2 domain-containing phosphatase 1 (SHP-1), as well as global methylation in patients with MM during active disease and remission. Bone marrow samples were obtained from 43 patients at the Multiple Myeloma Clinic, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (Mexico City, Mexico) during active disease and remission. Methylation-specific polymerase chain reaction and ELISA were performed on bisulfite-treated or untreated DNA to determine promoter-specific or genomic methylation, respectively. Gene expression was measured using reverse-transcription polymerase chain reaction. The results indicated that SOCS-1 methylation occurred more frequently during active disease than remission [29 vs. 3.2% (P=0.021)] and was associated with more advanced forms of the disease [international staging system (ISS) 3, 16.67% vs. ISS 1, 8.3% (P=0.037)]. SHP-1 methylation during active disease was associated with a lower probability of survival at 39-month follow up (median), 52.5 vs. 87.5% (P=0.025). The percentage of methylation was associated with active disease at remission, but this was not significant. Global hypomethylation at remission was a negative predictor factor for overall survival (OS). The results indicated that methylated P16, SOCS-1 and SHP-1 were associated with clinical variables of poor prognosis in MM, likewise the persistence of global hypomethylation at remission. The negative impact on OS of global hypomethylation at remission must be confirmed in a larger sample. Future studies are necessary to investigate whether patients with global hypermethylation at remission should receive more aggressive treatments to improve their OS. PMID- 28565862 TI - Preliminary evaluation of cone beam computed tomography in three-dimensional cephalometry for clinical application. AB - The present study was conducted to evaluate the three-dimensional (3D) cephalometry accuracy of cone-beam computed tomography (CBCT). A total of 40 newly diagnosed orthodontic patients (including 18 males and 22 females; age range, 12-18 years) were subjected to CBCT scanning and X-ray imaging in order to obtain lateral cephalograms. The 3D CBCT cephalograms were reconstructed and measured with in vivo 5.1 software, and compared with the results from the conventional 2D lateral cephalograms. Measurements in the two images were performed twice using the Steiner and Tweed standards and a single analyzer paired t-test was used to analyze the differences between the two cephalometric methods. The results indicated that the two methods showed significant differences in all 12 angle and 5 linear measurements (P<0.05). These findings indicated that CBCT is a more accurate technique compared with the conventional 2D method. In conclusion, CBCT may provide diagnostic and treatment information for maxillofacial deformities by using fast computer-aided analysis platform. PMID- 28565863 TI - Gambogenic acid induces cell growth inhibition, cell cycle arrest and metastasis inhibition in choroidal melanoma in a dose-dependent manner. AB - The aim of the present study was to explore the effects of gambogenic acid (GNA) on the malignant behaviors of choroidal melanoma cells, including cell viability, cell cycle, migration and invasion, and to elucidate the underlying regulatory mechanism. The human choroidal melanoma cell line OCM-1 was treated with different concentrations of GNA and cell viability, colony formation ability, cell cycle, migration and invasion were analyzed. Additionally, cells were incubated with or without LY294002, a specific inhibitor of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, for 24 h. Levels of cell cycle-associated proteins (cyclin D1, cyclin E, cyclin-dependent kinase 2 and P21), epithelial-mesenchymal transition (EMT)-associated molecules (epithelial-cadherin, alpha-smooth muscle actin and vimentin) and phosphorylated (p)-AKT/AKT were determined using reverse transcription-quantitative polymerase chain reaction and western blot analysis. The results demonstrated that GNA significantly inhibited cell viability and induced cell cycle arrest at the G0/G1 phase in a dose-dependent manner (P<0.01). Furthermore, GNA administration significantly suppressed cell migration and invasion in a dose-dependent manner (P<0.01). Treatment with GNA or LY294002 induced a marked decrease in the expression of p-AKT/AKT, a significant downregulation in cell cycle-associated molecules (P<0.01), and a significant decrease in cell viability (P<0.01). Co treatment with LY294002 and GNA had an additive effect on the growth of OCM-1 cells. In conclusion, the results of the present study suggest that treatment with GNA may inhibit cell viability and induce G0/G1 arrest. Furthermore, GNA may also inhibit cell metastasis via regulating EMT-associated molecules. The PI3K/Akt signaling pathway may be a key mechanism involved in the progression of choroidal melanoma, and GNA may serve as a potential therapeutic reagent for the treatment of this disease. PMID- 28565864 TI - Expression of Kruppel-like factor 4 in breast cancer tissues and its effects on the proliferation of breast cancer MDA-MB-231 cells. AB - The aim of the present study was to detect the expression of Kruppel-like factor 4 (KLF4) in breast cancer tissues and to evaluate the effect on the proliferation of breast cancer MDA-MB-231 cells. The expression of KLF4 protein in 239 breast cancer tissues and 40 paracancerous tissues were detected by an immunohistochemical assay, and its correlation with clinical pathological parameters was analyzed. A eukaryotic expression vector, pcDNA3.1-KLF4, was constructed by transient transfection of breast cancer MDA-MB-231 cells with liposomes (experimental group). The untransfected cells and those transfected with empty plasmid pcDNA3.1 were used as the blank and negative control groups, respectively. The expression of the KLF4 gene and protein in the three groups were detected by reverse transcription polymerase chain reaction and western blotting, respectively. Furthermore, the cell proliferative capacity was detected by an MTT assay. The positive expression rate of KLF4 protein in breast cancer tissues (39.0%, 93/239) was significantly lower than that of paracancerous tissues (77.5%, 31/40) (P<0.05). In addition, KLF4 protein expression in breast cancer tissues was correlated with pathological type, histological grade and lymphatic metastasis (P<0.05). KLF4 mRNA and protein were both expressed by the experimental group, but not by the two control groups. Meanwhile, the proliferative capacity of the experimental group was also significantly decreased. A significant decrease in the positive expression rate of KLF4 protein in breast cancer tissues was correlated with several clinical pathological parameters. In addition, transfection of the KLF4 gene inhibited the proliferation of breast cancer cells, suggesting that this gene is important in the onset and progression of this type of cancer. PMID- 28565865 TI - Alterations of Caspr2 and Nav1.6 on myelinated axon damage in a rat model of chronic cerebral hypoperfusion. AB - Myelinated axons require the correct localization of key proteins that are essential for nerve conduction and cognitive function. Little is known regarding the altered expression of contactin-associated protein 2 (Caspr2) at the juxtaparanodal regions and Nav1.6 at the node of Ranvier in response to chronic cerebral hypoperfusion (CCH). The aim of the present study was to examine the alterations in the key protein of myelinated axons and the potential mechanisms that may follow CCH. We established a rat model of CCH by controllable partial narrowing of bilateral common carotid arteries. Then, we detected cerebral blood flow (CBF) after surgery. We also evaluated motor-evoked potentials (MEPs), assessed the Morris water maze test, analyzed Caspr2 expression through immunohistochemistry and Nav1.6 protein expression through western blot analysis at 2, 4 and 12 weeks. The results revealed that the mean CBF value was significantly decreased to 33.90+/-5.48%. The MEP latencies and the escaping latencies were significantly prolonged. There was also an elongation of the first time passing of the hidden platform with a reduction of crossing platform times in spatial probing. Furthermore, the Caspr2 immunoreactivity demonstrated that the Caspr2 level was significantly downregulated with abnormal locations in the corpus callosum. The western blot analysis of Nav1.6 protein revealed that the level was reduced significantly over time. The results demonstrate that CCH leads to central conductive function loss, cognitive function damage and alterations in the key protein of myelinated axons, which may provide a molecular basis and key link for white matter damage. PMID- 28565867 TI - Hemophagocytic lymphohistiocytosis in a patient with human immunodeficiency virus infection: A case report. AB - Hemophagocytic lymphohistiocytosis (HLH), also termed hemophagocytic syndrome, is a severe, life-threatening inflammatory condition that results from an excessive, prolonged and ineffective immune response. The syndrome occurs due to overactive macrophages from the bone marrow or lymph tissue that phagocytose erythrocytes leukocytes and platelets. HLH in a patient with human immunodeficiency virus infection has rarely been studied. The present case study described an uncommon case of this syndrome in combination with human immunodeficiency virus infection in a patient, who eventually succumbed to severe infection and multiple organ failure following the refusal of medical treatment. PMID- 28565866 TI - Inhibition of PKCalpha reduces the ability of migration of kidney cancer cells but has no impact on cell apoptosis. AB - Kidney cancer is among the most important causes of cancer-associated mortality worldwide. The present study aimed to evaluate protein kinase C alpha (PKCalpha) expression in kidney cancer tissues and cell lines, and its significance in apoptosis and migration. Expression of PKCalpha was analyzed using quantitative polymerase chain reaction and western blotting. In addition, the inhibitor of PKCalpha (calphostin C and GO6976) was used to treat kidney cancer cells. The ACHN cell line was generated with PKCalpha-small-interfering RNA (siRNA) and a stable expression of PKCalpha, in order to facilitate the analysis of apoptosis and migration of PKCalpha during knockdown and inactivation. Flow cytometry was used to determine the rates of apoptosis. Immunohistochemical staining was used to identify the localization of PKCalpha in renal clear cell carcinoma and normal sections. PKCalpha expression in normal tissues was found to be greater than in cancerous tissues. Furthermore, apoptosis was not promoted with PKCalpha inhibitors or PKCalpha-siRNA treatment, and a decrease of the migration ability was observed following transfection with PKCalpha-dominant negative. The results indicated that inhibition of PKCalpha might not contribute to apoptosis progression in kidney carcinoma. PMID- 28565868 TI - Proliferative myositis in the right brachioradialis: A case report. AB - Proliferative myositis is a rare, self-limiting, benign disease. Its diagnosis can be difficult and in many cases is not confirmed until after surgical resection. Herein, we report a case of proliferative myositis of the right brachioradialis in a 64-year-old man. The patient presented with a rapidly growing, painless mass in his right forearm. Magnetic resonance imaging and fine needle aspiration biopsy led to a diagnosis of proliferative myositis. Complete surgical resection of the mass was performed. Postoperative pathological examination confirmed the diagnosis. To the best of our knowledge, this is the first report of proliferative myositis in the right brachioradialis. Fine-needle biopsy is helpful in the diagnosis of proliferative myositis, thus avoiding unnecessary surgical trauma and costs. PMID- 28565869 TI - Mitochondrial dysfunction on sinoatrial node and pulmonary vein electrophysiological activities. AB - Atrial fibrillation (AF) is associated with mitochondrial dysfunction. Sinoatrial node (SAN) dysfunction increases arrhythmogenesis of pulmonary veins (PVs), which is the most important trigger of AF; however, it is not clear whether mitochondrial dysfunction differentially regulates electrical activity of SANs and PVs. In the present study, conventional microelectrodes were used to record the action potentials (APs) in isolated rabbit PVs, SANs, left atrium (LA) and right atrium (RA) before and after application of trifluorocarbonylcyanide phenylhydrazone (FCCP; a mitochondrial uncoupling agent) at 10, 100 and 300 nM. FCCP application at 100 and 300 nM decreased spontaneous rates in PVs and in SANs at 10, 100 and 300 nM. FCCP shortened the 20, 50 and 90% AP durations in the LA, and shortened only the 20% AP duration in the RA. FCCP caused a greater rate reduction in SANs than in PVs; however, in the presence of coenzyme-Q10 (10 uM), FCCP reduced the beating rate in PVs and SANs to a similar extent. In SAN-PV preparations with intact electrical connections, FCCP (100 nM) application shifted the SAN-PV electrical conduction into PV-SAN conduction in 5 (62.5%) of 8 preparations. In conclusion, mitochondrial dysfunction modulates PV and SAN electrical activities, which may contribute to atrial arrhythmogenesis. PMID- 28565870 TI - C1QBP is upregulated in colon cancer and binds to apolipoprotein A-I. AB - The present study aimed to investigate the expression of complement component 1, q subcomponent-binding protein (C1QBP) in colon cancer cells, and identify proteins that interact with C1QBP. Total proteins were extracted from both the tumor and normal tissues of 22 patients with colon cancer and analyzed using liquid chromatography-mass spectrometry (LC-MS) to identify proteins that were differentially-expressed in tumor tissues. C1QBP overexpression was induced in 293T cells using a pFLAG-CMV2 expression vector. Overexpressed FLAG-tagged C1QBP protein was then immunoprecipitated using anti-FLAG antibodies and C1QBP interacting proteins were screened using LC-MS analysis of the immunoprecipitates. The C1QBP-interacting proteins were confirmed using reverse immunoprecipitation and the differential expression of C1QBP in tissues and cell lines was confirmed using western blot analysis. LC-MS analysis revealed that C1QBP exhibited a typical tumor expression pattern. Two immune-reactive signals (33 and 14 kDa) were detected in normal and tumor tissues from 19 patients. Furthermore, 14 kDa C1QBP protein was upregulated in the tumors of 15 patients. In total, 39 proteins were identified as candidate C1QBP-interacting proteins, and an interaction between C1QBP and apolipoprotein A-I was confirmed. The present study indicates that C1QBP is involved in colon cancer carcinogenesis, and that the mechanisms underlying the established anti-tumor properties of apolipoprotein A-I may include interacting with and inhibiting the activity of C1QBP. PMID- 28565871 TI - Propofol inhibits hepatocellular carcinoma growth and invasion through the HMGA2 mediated Wnt/beta-catenin pathway. AB - Propofol is a commonly used intravenous anesthetic in tumor surgery. Recently, studies have confirmed that propofol has an antitumor effect on hepatocellular carcinoma (HCC); however, the molecular mechanism underlying this effect has not been elucidated until now. The present study aimed to investigate the mechanism of propofol on HepG2 cell proliferation, apoptosis and invasion, focusing on High Mobility Group AT-Hook 2 (HMGA2)-mediated Wnt/beta-catenin pathway. The HepG2 cells were treated with various concentrations of propofol for 24 h, the relative protein levels of HMGA2, Wnt3a, beta-catenin, Snail Family Zinc Finger 1 and c myc were determined by western blot analysis. HMGA2-pcDNA3.1 plasmid was transfected into the HepG2 cells to overexpress HMGA2. Cell proliferation, apoptosis and invasion were examined by MTT assays, flow cytometry and Transwell matrigel invasion assays, respectively. The results showed that propofol suppressed HMGA2 expression and Wnt/beta-catenin signaling in a dose-dependent manner. Propofol was able to inhibit cell proliferation and invasion, and induce cell apoptosis of HepG2 cells; however, these effects were attenuated by HMGA2 overexpression. The suppressed Wnt/beta-catenin signaling in HepG2 cells by treatment with propofol was also reversed by HMGA2 overexpression. In conclusion, this study provided a novel mechanism underlying the anti-tumor function of propofol on HCC. To the best of our knowledge, the present study is the first to demonstrate that propofol could downregulate the expression of HMGA2, which inhibited the Wnt/beta-catenin pathway, thus leading to the inhibition of cell proliferation and invasion, as well as the apoptosis of HepG2 cells. PMID- 28565872 TI - MicroRNA-33a promotes cell proliferation and inhibits apoptosis by targeting PPARalpha in human hepatocellular carcinoma. AB - MicroRNA-33a (miR-33a) is dysregulated in a number of human cancers, where it functions as an oncogenic miRNA. However, the clinical significance of miR-33a and its underlying molecular pathways regarding the progression of hepatocellular carcinoma (HCC) are currently unknown. In the present study, it was observed that the level of miR-33a expression was significantly increased in HCC tissues, relative to adjacent non-tumor tissues. Increased miR-33a expression was significantly correlated with poor prognostic features of HCC, including larger tumor size, higher Edmondson-Steiner grading and higher tumor-node-metastasis tumor stage. Furthermore, high levels of miR-33a expression were associated with decreases in the 5-year overall survival rate and recurrence-free survival of patients with HCC. In addition, functional experiments indicated that overexpression of miR-33a led to increased proliferation and reduced apoptosis of the HCC cell line Huh7, while knockdown of miR-33a decreased proliferation and induced apoptosis in the HCC cell line HepG2. Furthermore, peroxisome proliferator activated receptor alpha (PPARalpha) was identified as a direct target of miR-33a in HCC. Upregulation of miR-33a was found to reduce the levels of PPARalpha expression in Huh7 cells, while inhibition of miR-33a lead to a downregulation in PPARalpha expression in HepG2 cells. Collectively, these results suggest that miR-33a regulates the proliferation and apoptosis of HCC cells, and is a potential prognostic marker of HCC. PMID- 28565873 TI - miR-148a Suppresses estrogen-induced viability and migration of breast cancer cells via inhibition of estrogen receptor alpha expression. AB - MicroRNAs (miRs) play critical roles in the development and malignant progression of human cancers. miR-148a has previously been found to inhibit the migration and invasion of breast cancer cells. However, the underlying mechanism of miR-148a in regulating the viability and migration of estrogen receptor (ER) alpha-positive breast cancer cells is still unknown. In this study, ERalpha-positive breast cancer MCF7 cells were treated with estradiol (E2). Data from MTT and wound healing assays showed that E2 treatment promoted the viability and migration of MCF7 cells. A bioinformatics analysis and luciferase reporter assay identified ERalpha as a direct target of miR-148a. Ectopic expression of miR-148a significantly decreased the protein expression of ERalpha (P<0.01), while knockdown of miR-148a significantly increased the ERalpha protein level in MCF7 cells (P<0.01). Furthermore, miR-148a overexpression significantly inhibited the E2-induced viability and migration of MCF7 cells (P<0.01), similar to the effect of silencing ERalpha. However, overexpression of ERalpha rescued the suppressed viability and migration caused by miR-148a upregulation. Finally, it was found that E2 treatment led to a significant decrease in the miR-148a level in MCF7 cells (P<0.01). These results suggest that miR-148a can suppress the E2-induced viability and migration of MCF7 breast cancer cells via inhibition of ERalpha protein expression, expanding the understanding of miR function in ERalpha positive breast cancer. PMID- 28565874 TI - Resistin increases the expression of NOD2 in mouse monocytes. AB - Previous studies have indicated that resistin, a type of adipokine, contributes to the development of insulin resistance and type 2 diabetes mellitus, and mediates inflammatory reactions. However, a specific receptor for resistin has not yet been identified. In this study, the relationship between resistin and nucleotide-binding oligomerization domain-like receptors, as well as resistin signal transduction, was examined through transfection, quantitative polymerase chain reaction, western blot analysis and ELISA. The mRNA expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a key immune receptor related to insulin resistance, was significantly increased by resistin treatment at concentrations of 100, 150 and 200 ng/ml (P<0.05, P<0.01 and P<0.01, respectively). The mRNA expression of downstream signaling molecules in the NOD2 signaling pathway, receptor-interacting serine/threonine-protein kinase 2 (RIP2; P<0.01 at 6, 12 and 24 h) and inhibitor of NF-kappaB kinase subunit beta (P<0.01 at 3, 6, 12 and 24 h) were significantly increased by resistin treatment compared with the control. The mRNA expression of key proinflammatory cytokines, tumor necrosis factor alpha, IL (interleukin)-6 and IL 1beta, were also significantly increased by resistin treatment compared with the control (P<0.01). NOD2 knockdown by small interfering RNA (siRNA) significantly decreased the expression of NOD2 and RIP2 (P<0.01), and there was no significant increase in the levels of cytokines, as compared with treatment with control siRNA. These findings indicate that the inflammatory reaction induced by resistin involves the NOD2-nuclear factor (NF)-kappaB signaling pathway. The inhibition of NF-kappaB significantly decreased the secretion of key inflammatory cytokines (P<0.01), suggesting that NF-kappaB signaling mechanisms are essential to the resistin-induced inflammatory response. PMID- 28565875 TI - Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines. AB - The sonic hedgehog (Shh) pathway has been proven to be involved in embryonic development and cancer growth. GDC-0449, an antagonist of the hedgehog signaling receptor Smoothened (Smo), was recently approved by the US Food and Drug Administration as a prescription for skin basal cell carcinoma. However, the efficacy of GDC-0449 in the treatment of colon cancer and other malignancies, such as basal cell carcinoma and pancreatic cancer, has remained to be proven. The present study assessed the effect of GDC-0449 on the colon cancer cell lines Caco-2 and Ht-29. A Cell Counting Kit-8 assay was applied to assess the cell proliferation rate and apoptosis was tested by flow cytometry. Reverse transcription quantitative PCR and western blot analysis were used for analyzing expression levels of target genes. Cell proliferation was inhibited, while apoptosis was increased by GDC-0449, whereas the expression of B-cell lymphoma 2 (Bcl-2), a downstream target of Shh signaling, was decreased. Consistent with the inhibition of Gli1 expression, the cancer stem cell markers CD44 and ALDH were decreased in the presence of GDC-0449. In conclusion, GDC-0449 was shown to inhibit the replication of colon cancer cells and trigger apoptosis through downregulating Bcl-2. This may also influence the stemness of cancer stem cells as indicated by the decreased stem cell surface markers. PMID- 28565876 TI - Effects of 17beta-estradiol and 2-methoxyestradiol on the oxidative stress hypoxia inducible factor-1 pathway in hypoxic pulmonary hypertensive rats. AB - The present study aimed to investigate the effects of 17beta-estradiol (E2) and 2 methoxyestradiol (2ME) on the oxidative stress-hypoxia inducible factor-1 (OS-HIF 1) pathway in hypoxic pulmonary hypertensive rats. Female Sprague-Dawley rats were divided randomly into 4 groups, as follows: i) Control (Group A); ii) ovariectomy (OVX) + hypoxia (Group B); iii) OVX + hypoxia + E2 injection (Group C); and iv) 2ME injection (Group D). The rats were maintained under hypoxic conditions for 8 weeks, and mean pulmonary artery pressure (mPAP) and pulmonary arteriole morphology were measured. The reactive oxygen species, superoxide dismutase (SOD), manganese superoxide dismutase (MnSOD), and copper-zinc superoxide dismutase (Cu/ZnSOD) levels in serum were also measured. MnSOD and HIF 1alpha expression levels in lung tissue were determined by western blotting and reverse transcription-quantitative polymerase chain reaction. The mPAP and arterial remodeling index were significantly elevated following chronic hypoxia exposure; however, experimental data revealed a reduced response in E2 and 2ME intervention rats. Compared with Group A, Group B had significantly elevated oxidative stress levels, as illustrated by increased serum ROS levels, decreased serum SOD and MnSOD levels and decreased MnSOD mRNA and protein expression levels in lung tissue. Furthermore, HIF-1alpha mRNA and protein expression in Group B was significantly elevated compared with Group A. E2 and 2ME intervention significantly attenuated the aforementioned parameter changes, suggesting that E2 and 2ME partially ameliorate hypoxic pulmonary hypertension. The underlying mechanism of this may be associated with the increase in MnSOD activity and expression and reduction in ROS level, which reduces the levels of transcription and translation of HIF-1alpha. PMID- 28565877 TI - Elucidating the mechanism of miRNA-214 in the regulation of gingival carcinoma. AB - The aim of the present study was to evaluate the expression levels of microRNA (miRNA)-214 in tumor tissue, blood and saliva of patients with gingival carcinoma, and to investigate the mechanisms underlying the infiltration and invasion of gingival carcinoma. Between January 2013 and March 2015, blood and saliva samples, gingival carcinoma tumor specimens and peritumoral tumor tissues were harvested from 56 patients with gingival carcinoma. Blood and saliva samples were also harvested from 33 control patients without gingival carcinoma. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to detect miRNA-214 and protein tyrosine phosphatase gene (PTEN) mRNA levels. Western blotting and ELISA were performed to detect PTEN protein levels. The results of RT-qPCR demonstrated that the expression of PTEN mRNA in tumor tissues, blood and saliva of patients with gingival carcinoma were significantly decreased compared with that of the control group (P<0.05). These findings were consistent were consistent with the results of PTEN protein expression detected via western blotting and ELISA in these samples (P<0.05). Conversely, the expression levels of miRNA-214 in these samples were significantly increased (P<0.05) in patients with gingival carcinoma compared with the control group. The decreased expression of PTEN may be associated with the expression of miRNA-214. miRNA-214 may regulate infiltration and invasion of gingival carcinoma via PTEN. These results suggest that miRNA-214 may be used as a marker of gingival carcinoma. PMID- 28565878 TI - Ginsenoside Rb3 strengthens the hypoglycemic effect through AMPK for inhibition of hepatic gluconeogenesis. AB - Ginsenoside Rb3 is one of the major active components in protopanaxdiol type ginsenosides, and has demonstrated anti-diabetic activity. However, the mechanism of this action has yet to be elucidated. The present study investigated the effects of ginsenoside Rb3 on the AMP-activated protein kinase (AMPK) gluconeogenesis pathway. The present study involved the use of HepG2 cells and western blot analysis to systematically evaluate the effect of ginsenoside Rb3 on AMPK signaling proteins and key factors of gluconeogenesis [phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase, forkhead transcription factor 1 (FOXO1) and hepatic nuclear receptor 4alpha (HNF4alpha)]. The results indicated that 25 uM ginsenoside Rb3 significantly activated AMPK activity, increased the ratio of p-AMPK/total-AMPK, and had synergistic effects with the activator of AICAR on the activation of AMPK. Further analysis indicated that the expression of the transcription factor FOXO1 and HNF4alpha protein, two important factors in the pathway of HepG2 cell gluconeogenesis, was significantly suppressed by ginsenoside Rb3. PEPCK and G6Pase were subsequently inhibited, which led to the suppression of gluconeogenesis. These effects were partially blocked by the AMPK inhibitor, Compound C, which indicated that the inhibition effects of ginsenoside Rb3 on hepatic gluconeogenesis were predominantly due to the activation of the AMPK signaling pathway. These data suggested that ginsenoside Rb3 can suppress hepatic gluconeogenesis, at least partially through stimulation of AMPK activity. PMID- 28565879 TI - Difference in protective effects of GIP and GLP-1 on endothelial cells according to cyclic adenosine monophosphate response. AB - Receptors for glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide 1 (GLP-1) are present in vascular endothelial cells. Previous studies investigating euglycemic status have demonstrated that GIP is directly involved in the physiology of blood vessels by controlling the blood flow rate of portal veins and that GLP-1 has a protective effect on blood vessels by acting on endothelial cells. However, to the best of our knowledge, the effects of GIP and GLP-1 on endothelial cells in patients with hyperglycemia remain unknown. Therefore, the present study investigated whether the effect of the incretin hormones GLP-1 and GIP differed with regards to the reversal of endothelial cell dysfunction caused by hyperglycemia. The production of nitric oxide (NO) was measured using the Griess reagent system kit and the expression of cyclic adenosine monophosphate (cAMP) in the cell was measured at a wavelength of 405 nm with the ELISA reader using the cyclic AMP EIA kit. Exposure of human umbilical vein endothelial cells (HUVEC) to a high glucose concentration decreased NO and endothelial nitric oxide synthase (eNOS) levels but increased inducible NOS (iNOS) levels. However, when HUVECs were pretreated with GLP-1, a reduction of iNOS expression was observed and the expression of eNOS and NO were increased, as opposed to pretreatment with GIP. The results differed according to the response of cAMP, the second messenger of incretin hormones: The GIP pretreatment group did not exhibit an increase in cAMP levels while the GLP-1 pretreatment group did. The results of the present study provide evidence that GLP-1, but not GIP, has a protective effect on endothelial function associated with cardiovascular disease, as it is associated with increased eNOS expression and the levels of NO. This effect may be due to an increase in the cAMP concentration during hyperglycemic events. PMID- 28565880 TI - Etanercept attenuates thermal and mechanical hyperalgesia induced by bone cancer. AB - Bone cancer pain commonly occurs when tumors originating in the breast, prostate or lung metastasize to long bones, spinal vertebrae and/or the pelvis. However, the underlying mechanisms of bone cancer pain remain largely unknown. The present study aimed to determine the role of spinal tumor necrosis factor-alpha (TNF alpha) in the development of bone cancer pain. Osteosarcoma NCTC 2472 cells were implanted into the femoral intramedullary space of C3H/HeJ mice to establish a bone cancer model. Resulting pain-related behaviors, namely spontaneous foot lifting, paw withdrawal mechanical threshold and paw withdrawal thermal latency were observed prior to inoculation and on days 3, 5, 7, 10 and 14 thereafter. Reverse transcription-quantitative polymerase chain reaction was also performed to assess the levels of TNF-alpha mRNA within the spinal cord. In addition, the effects of the TNF-alpha antagonist etanercept on TNF-alpha levels and pain behaviors were evaluated. It was observed that the levels of TNF-alpha mRNA in the spinal cord were significantly higher in tumor-bearing mice 10 days post inoculation, which was accompanied by increases in spontaneous flinching, mechanical hyperalgesia and thermal hyperalgesia, relative to control mice. Etanercept attenuated the bone cancer-induced increase in TNF-alpha and pain related behaviors. These results suggest that etanercept may be a potential therapeutic for the treatment of bone cancer pain. PMID- 28565881 TI - A pilot study: Screening target miRNAs in tissue of nonsyndromic cleft lip with or without cleft palate. AB - Nonsyndromic cleft lip with or without cleft palate (NSCLP) has been recognized as a condition resulting from a combination of environmental and genetic factors. Studies have demonstrated that microRNAs (miRNAs) are involved in embryonic development. However, few studies have focused on screening potential target miRNAs in human NSCLP tissue. Using microarray-based miRNA expression profiling, miRNA expression was compared in tissue samples from 4 NSCLP patients and 4 healthy control subjects. Two hundred and fifty-four miRNAs were found to be differentially expressed. Changes in Homo sapiens (hsa)-miR-24-3p, hsa-miR-27b 3p, hsa-miR-205-5p, hsa-miR-1260b and hsa-miR-720 were of particular interest with respect to Wnt signaling (fold-changes were 12.5, 12.2, 12.1, 12.3 and 10.5, respectively; P<0.005 for all). The levels of hsa-miR-24-3p, hsa-miR-1260b and hsa-miR-205-5p were higher in tissues from NSCLP patients than in those from controls according to PCR analysis. Hsa-miR-24-3p, hsa-miR-1260b and hsa-miR-205 5p may be candidate miRNAs involved in the etiology of NSCLP via Wnt signaling. PMID- 28565882 TI - Association of calreticulin expression with disease activity and organ damage in systemic lupus erythematosus patients. AB - Measurement of disease activity in patients with systemic lupus erythematosus (SLE) is important for monitoring disease progression and evaluating the therapeutic effects. The severity of organ damage correlates with clinical status and prognosis. Therefore, it is imperative to find an effective biomarker measuring disease activity and organ damage for SLE management. The present study investigated the possibility of serum calreticulin (CRT) in the assessment of disease activity and organ damage in SLE patients. Serum CRT levels from 80 patients with SLE, 55 patients with other autoimmune diseases and 60 healthy controls (HC) were measured by ELISA. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores. Organ damage was evaluated with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. CRT levels in SLE were significantly higher than that in other autoimmune diseases and HC. CRT was correlated with SLEDAI-2K score (r=0.3345, P=0.0024), and with anti-double stranded DNA (anti-dsDNA) (r=0.4483, P<0.0001). A significant negative correlation of CRT levels with complement 3 (r=-0.3635, P=0.0009) and complement 4 (r=-0.3507, P=0.0014) was observed in patients with SLE. Furthermore, the patients with SLE and a positive anti-Ro52 result had higher levels of CRT compared with those with a negative anti-Ro52 result (P<0.001). Elevated levels of CRT were also reported among patients with SLE who also indicated the presence of cumulative organ damage. In addition, increased expression of CRT correlated with the presence of lupus nephritis. In conclusion, the results of the current report provided that CRT may be used as a potential biomarker for clinical diagnosis and of prognosis, providing additional information regarding disease activity and organ damage alongside other traditional indices. PMID- 28565883 TI - Hydrogen-rich water alleviates the toxicities of different stresses to mycelial growth in Hypsizygus marmoreus. AB - In plants, hydrogen gas (H2) enhances tolerance to several abiotic stresses, including salinity and heavy metals. However, the effect of H2 on fungal growth under different stresses remains largely unclear. In this study, hydrogen-rich water (HRW) was employed to characterize physiological roles and molecular mechanisms of H2 in the alleviation of three different stresses in basidiomycete Hypsizygus marmoreus. Our results showed that HRW treatment, of which the H2 concentration was 0.8 mM, significantly reduced the toxicities of CdCl2, NaCl and H2O2, leading to significantly improved mycelial growth and biomass. These beneficial effects could be attributed to a significantly decreased formation of malondialdehyde (MDA). Besides, HRW treatment significantly increased the activities of antioxidants (SOD, CAT and GR) as well as the gene expressions of these antioxidants (SOD, CAT, and GR) at the mRNA level. In vivo detection of reactive oxygen species (ROS), including H2O2 and O2-, as well as lipid peroxidation provided further evidence that HRW could significantly improve tolerances of CdCl2, NaCl and H2O2. Furthermore, pyruvate kinase was activated in the mycelia treated with HRW, along with its induced gene expression, suggesting that HRW treatment enhanced the glucose metabolism. Taken together, our findings suggested that the usage of HRW could be an effective approach for contaminant detoxification in H. marmoreus, which was similar with the effects of HRW in plants, and such effects could be also beneficial in entire agricultural system. PMID- 28565884 TI - Mechanical Composite of LiNi0.8Co0.15Al0.05O2/Carbon Nanotubes with Enhanced Electrochemical Performance for Lithium-Ion Batteries. AB - LiNi0.8Co0.15Al0.05O2/carbon nanotube (NCA/CNT) composite cathode materials are prepared by a facile mechanical grinding method, without damage to the crystal structure and morphology of the bulk. The NCA/CNT composite exhibits enhanced cycling and rate performance compared with pristine NCA. After 60 cycles at a current rate of 0.25 C, the reversible capacity of NCA/CNT composite cathode is 181 mAh/g with a discharge retention rate of 96%, considerably higher than the value of pristine NCA (153 mAh/g with a retention rate of 90%). At a high current rate of 5 C, it also can deliver a reversible capacity of 160 mAh/g, while only 140 mAh/g is maintained for the unmodified NCA. Highly electrical conductive CNTs rather than common inert insulating materials are for the first time employed as surface modifiers for NCA, which are dispersed homogenously on the surface of NCA particles, not only improving the electrical conductivity but also providing effective protection to the side reactions with liquid electrolyte of the battery. PMID- 28565885 TI - Facile Synthesis of Heterostructured WS2/Bi2MoO6 as High-Performance Visible Light-Driven Photocatalysts. AB - In this paper, novel WS2/Bi2MoO6 heterostructured photocatalysts were successfully fabricated via a facile solvothermal growth method using pre exfoliated layered WS2 nanoslices as a substrate. The structure, morphology, and optical properties of the as-prepared WS2/Bi2MoO6 samples were characterized by XRD, XPS, SEM, TEM (HRTEM), and UV-vis diffuse reflectance spectra (DRS). Results confirmed the existence of an excellent nanojunction interface between layered WS2 nanoslices and Bi2MoO6 nanoflakes. Under visible light (>420 nm), the WS2/Bi2MoO6 composites exhibit significantly enhanced photocatalytic activity compared with pure Bi2MoO6 toward the decomposition of rhodamine B (RhB). Meanwhile, the active species trapping experiments indicated that holes (h+) were the main active species during the photocatalytic reaction. The enhanced photocatalytic performance can be ascribed to the effective light harvesting, fast photogenerated electron-hole pairs separation, and excellent charge carrier transport of the WS2/Bi2MoO6 heterostructures. Moreover, the prepared WS2/Bi2MoO6 composites also show good structural and activity stability in repeatability experiments. PMID- 28565886 TI - Effects of Cholecalciferol Supplementation in Patients with stable heart failure and LOw vITamin D levels (ECSPLOIT-D): a double-blind, randomized, placebo controlled pilot study. AB - BACKGROUND: The aim of this study was to investigate the effects of vitamin D (VD) on the interaction among functional, echocardiographic and hormonal parameters in patients with heart failure (HF) and VD deficiency. METHODS: In a randomized, double blind trial, 35 patients with HF and VD<20 ng/mL, received either 300,000 U of oral cholecalciferol followed by 50,000 U/month for 6 months, or placebo treatment. RESULTS: Changes in the 6 Minute Walking Test (6MWT) assessed at 3 and 6 months in treatment group was the primary end point. Secondary endpoints were echocardiographic and hormonal changes. The same targets were compared in treated and placebo groups as secondary endpoints. In the treatment group the 6MWT improved at 3 (from 210+/-104 mt to 225+/-94 mt; P=0.033) but not at 6 months (from 210+/-104 mt to 217+/-94 mt; P=0.288) while PTH dropped at 3 (from 76.8+/-50.5 to 50.2+/-20.3 pg/mL; P=0.025), but not at 6 months. 6MWT improvement was negatively related to baseline VD levels. Variation in 6MWT did not significantly differ among groups at 3 (13.6+/-23.3 vs. 3.6+/ 17.3; P 0.175) and 6 months (12.1+/-31.4 vs. 0.2+/-23.2; P 0.225). Left atrial size increased in the placebo group (from 50.8+/-20.7 to 61.7+/-36.0 mL/m2; P=0.010). Other hormonal parameters remained unchanged. CONCLUSIONS: In summary, the treatment of VD deficiency in patients with HF improved 6MWT after 3 months along with a decrease in PTH levels. However when compared with the placebo arm, treatment of VD deficiency did not influence the final outcomes. PMID- 28565887 TI - Safety and efficacy of catheter-based left atrial appendage closure in patients with contraindications for long-term anticoagulation. AB - BACKGROUND: Percutaneous left atrial appendage closure (LAAC) and the role of postinterventional anticoagulation often evokes controversy in daily practice. This study aimed to evaluate LAAC in patients with non-rheumatic atrial fibrillation, high thromboembolic risk and contraindications for long-term anticoagulation in a clinical scenario. METHODS: Between 2010-2015, LAAC was attempted in 118 patients (47 women). RESULTS: Devices were successfully implanted in 95% (WatchmanTM device: N.=97; AmplatzerTM Cardiac Plug/Amulet: N.=14; Amplatzer PFO Occluder: N.=1). Mean age was 75+/-8.35 years. Mean HAS-BLED and CHA2DS2VASc scores were 4.3 and 4.9, respectively. Median follow-up was 447 days (IQR: 183-789 days). The primary safety endpoint was defined as major bleeding according to the International Society on Thrombosis and Hemostasis. The combined efficacy endpoint included ischemic strokes, transitory ischemic attacks (TIA) and systemic embolisms. Procedural complication rate was 3.4%. After successful intervention, either a therapy with anticoagulants (N.=62) or dual antiplatelet therapy (DAPT, N.=50) was prescribed temporarily. Medication was reduced if implantation proved satisfying in a 6-week follow-up transesophageal echocardiography, which was the case in 79% of these patients. During follow-up, one patient suffered a TIA (0.6%/year). No other efficacy event was observed. Eleven major bleedings occurred (6.6%/year): one each under DAPT plus phenprocoumon, DAPT plus rivaroxaban, acetylsalicylic acid (ASA) plus rivaroxaban, two under DAPT, two under ASA plus low molecular weight heparin, and four under ASA only. CONCLUSIONS: In the present study, catheter-based LAA occlusion prevented thromboembolisms with high efficacy. Major bleedings were however common in patients with, but also without anticoagulation, independent from time course. PMID- 28565888 TI - Role of adipokines and inflammatory markers in postmenopausal hypertension. AB - BACKGROUND: The role of inflammatory markers and adipokines contributing to the development of postmenopausal hypertension, has not been established. The aim of our study was to assess the complex association between blood pressure, obesity, menopausal status, adipokines and inflammatory mediators in postmenopausal women. METHODS: We recruited 38 women seen at our Endocrinology Clinic and collected anthropometric measures and blood pressure and obtained serum samples for inflammatory markers and adipokine levels. Out of 38 women, 23 (60%) were postmenopausal. RESULTS: In the pre-menopausal and postmenopausal women, there were no significant differences in measured adipokines and inflammatory markers based on hypertensive status. When obesity was eliminated, significantly higher levels of EGF, IL-8, MCP1 and TNF-alpha and lower levels of IL-1alpha and IL-3 were observed in the postmenopausal group (P<0.05). Women with higher waist-to hip ratio (WHR) had a significant trend towards lower adiponectin levels as compared to those with lower WHR (P=0.014 and P=0.04, respectively). CONCLUSIONS: There was a significant difference in pro-inflammatory markers in non-obese, pre- and post-menopausal women. These higher inflammatory markers might play a role in the development of post-menopausal hypertension. PMID- 28565889 TI - Renal function markers and metformin eligibility. AB - BACKGROUND: Metformin is the cornerstone of the pharmacological therapy for type 2 diabetes mellitus (T2DM). It belongs to the biguanide class of drugs and it improves hepatic insulin resistance and enhances GLP-1 and peptide YY secretion. Despite being considered safe regarding hypoglycemic risk, renal dysfunction remains the main obstacle to its use due to the underlying risk of lactic acidosis. In the recent past many authors used creatinine values as the decisive marker when it came to choose between pharmacological agents in DM. Serum creatinine values equal or above 1.4 and 1.5 mg/dL were considered contraindications for metformin use in women and men respectively. Nowadays, creatinine is not the only surrogate of renal dysfunction and formulas such as the MDRD and CKD-EPI, that besides serum creatinine also include variables such as gender, age and race, have replaced serum creatinine as the standard for renal function assessment. Furthermore, since the associations between metformin and lactic acidosis in renal disease are not straightforward, its use has been considered safe down to creatinine clearances of 30 mL/min/1.73 m2. The authors describe a population with T2DM being treated with metformin and evaluate the impact of the solo evaluation of serum creatinine or CKD-EPI on biguanide prescription. METHODS: Retrospective, observational, single-center study. All type 2 diabetic patients with regular follow up in a Central University Hospital Endocrinology-Diabetology Outpatient Clinic who were being treated with metformin and had at least 2 creatinine and estimated glomerular filtration rate (eGFR) measurements in the last decade were included. Patients were stratified according to renal function-based metformin contraindication criteria: creatinine group included patients with serum creatinine levels above 1.4 and 1.5 mg/dL in women and men respectively, and eGFR group included patients with eGFR below 30 mL/min/1.73 m2. The entire population and both groups are described and compared regarding comorbidities, demographic and laboratory data. The authors report the impact of each renal function marker (serum creatinine or eGFR) when used solo regarding metformin prescription eligibility. RESULTS: A total of 2218 patients (61.3% females) with a mean age of 70+/-12 years is studied. Mean diabetes duration was 11.8+/-8.8 years. No cases with an eGFR below 30 mL/min/1.73 m2 were identified. On the other hand, in patients with GFR greater than 30 mL/min/1.73 m2, creatinine alone would contraindicate therapy in 274 patients (12.4% of the study population). Comparing Stage 3 chronic kidney disease patients without creatinine contraindication criteria with those with creatinine based contraindication, the data reveals that a higher prevalence of males, with longer diabetes duration, higher target organ damage (cerebrovascular disease, peripheral artery disease, heart failure, neuropathy and retinopathy) and with worse glycemic control were prevalent more in the elevated creatinine group. The use of serum creatinine as the single marker for renal function would significantly reduce metformin eligibility (OR=0.88, 95% CI: 0.8-0.95, P=0.002). CONCLUSIONS: Metformin is the first line pharmacological agent in type 2 diabetes mellitus patients, being associated with significant HbA1c reductions and improvements in both micro and macrovascular outcomes. Avoiding its use due to imprecise renal function markers would potentially render the patient deprived of optimal pharmacological therapy for T2DM. Creatinine contraindication criteria alone are associated with unnecessary under prescription of metformin. PMID- 28565890 TI - Influence of nodal status on the surgical outcome for bronchogenic carcinoma involving the carina: a systematic review and meta-analysis. AB - INTRODUCTION: Bronchogenic carcinomas involving the carina or the tracheo bronchial angle represents a challenging surgical procedure because of difficult surgical techniques and complex ventilation procedures. Even though surgical outcomes for this type of procedure has improved over time, the need for surgical management of patients with metastatic mediastinal nodes, that is those that are graded N2 or higher according to the TNM classification, is still controversial. EVIDENCE ACQUISITION: We searched PubMed, Embase, and CNKI for literature in English or Chinese reporting on this subject, with information on survival rates or survival curves for groups with different grades of nodal status. We then performed a meta-analysis by grouping N0 and N1 patients and compared the surgical outcomes to those graded as N2 or higher. Hazard Ratios for each study were derived from the Kaplan-Meier survival curve. EVIDENCE SYNTHESIS: Seven studies were included in this meta-analysis. The calculated hazard ratios ranged from 0.146 to 0.455. The weighted average hazard ratio for the N0/N1 group as compared to the N2/N3 group was 0.261 (CI: 0.154-0.441). The Galbraith plot confirmed the homogeneity of the studies included. CONCLUSIONS: Carinal resection and reconstruction remains a challenging surgical procedure and the rather poor surgical outcomes for patients graded as N2 or higher, according to nodal involvement points to the fact that better pre-operative management is required in terms of tumor grading, induction chemotherapy and radiotherapy to decrease the risks associated with metastatic mediastinal nodal status. PMID- 28565891 TI - The role of surgery in cystic lesions of the pancreas. AB - The incidence of cystic neoplasms of the pancreas (CNP) is steadily increasing, most likely due to the commonly increased use of cross-sectional abdominal imaging. Most of these lesions are benign at the time of initial presentation, but some harbor malignant potential that either requires constant surveillance or surgical resection. However, it is still unclear when resection is mandated and when observation is sufficient. Moreover, the extent of resection and the technique used are also a matter of debate since limited resection and minimally invasive procedures are becoming more popular. Therefore, the aim of this review was to assess the role of surgery for the management of CNPs with an emphasis on novel procedures. PMID- 28565892 TI - Metabolic surgery and nutritional deficiencies. AB - The increasing prevalence of morbid obesity in Germany is associated with an increasing number of metabolic surgical interventions. Short-term surgical and long-term metabolic complications such as nutrient deficiencies can be considered as the main risks of metabolic surgery with its malabsorptive but also restrictive procedures. The aim of this review was to characterize the most relevant metabolic complications specific for the various bariatric procedures, which, subsequently, require a permanent surveillance and supplementation, respectively. Furthermore, we aimed to identify if there are diagnostic and therapeutic measures that can prevent those complications. Restrictive bariatric surgery such as "gastric banding" and "sleeve gastrectomy" can be associated with deficiencies related to B-vitamins whereas iron, folate, vitamin B1, B12 and D deficiencies are associated with the malabsorptive procedure such as "biliopancreatic diversion," "duodenal switch" and "Roux-en-Y gastric bypass". Due to possible metabolic and surgical complications after bariatric surgery, patients need to undergo life-long medical and dietetic surveillance. The recently published guidelines of the "American Association of Bariatric and Metabolic Surgery" are the basis for recommendations on supplementation and treatment following weight loss surgery. PMID- 28565893 TI - Positron emission tomography/computer tomography in gastrointestinal malignancies: current potential and challenges. AB - The use of 18F-Fluoro-D-deoxy-glucose -positron emission tomography/computed tomography (FDG-PET/CT) in gastrointestinal (GI)-malignancies may not be as straightforward as in many other cancers, but the potential is clearly there in select clinical settings. The challenges include the relative non-specificity of FDG, the variable degrees of physiologic FDG-uptake, and the heterogeneous FDG uptake in different cell types within the GI-domain, which all together hamper the use in primary diagnostics. In general, the literature is older, heterogeneous, and based on stand-alone PET, which is now largely considered obsolete. There is emerging evidence for use of hybrid PET/CT, but the literature is still relatively sparse. The main indications are preoperative staging of distant metastases, not only in limited disease but also before curative treatment of limited metastatic disease. Controversies remain concerning liver metastases but improved technology boast well for the future role of FDG-PET/CT not least concerning equivocal findings on conventional imaging. In our opinion, an important upcoming indication is early response assessment, perhaps mostly in the neoadjuvant settings of upper GI-malignancies, but standardization of response assessment criteria is lacking before a more widespread implementation is feasible. Finally, there seems to be a significant role in recurrence detection, especially in CRC. PMID- 28565894 TI - Contemporary strategies to improve the outcome in locally advanced pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of less than 7%. After many years of basic and clinical research efforts, pancreatic cancer patients presenting with locally advanced, unresectable tumors remain a therapeutic challenge. Despite the lack of high quality randomized controlled trials, perioperative/neoadjuvant treatment strategies seem to be beneficial in these patients. At present the FOLFIRINOX regimen, which was established in the palliative setting, is increasingly recognized as the backbone of neoadjuvant therapy for locally advanced PDAC. Surgical resection follows the same principles and guidelines as upfront surgery specifically regarding the extent of resection including lymphadenectomy, vascular resections and multivisceral resections. Because of the limited diagnostic accuracy of restaging after neoadjuvant treatment, an adjusted intraoperative strategy is necessary to minimize the risk of debulking procedures and maximize the chance of a potential curative resection. Locally advanced PDAC requires a multidisciplinary and individualized treatment approach, and further research efforts for novel and innovative therapies. This article provides an updated overview on strategies to improve the outcome in locally advanced PDAC. PMID- 28565896 TI - Effects of magnetically controlled growing rods surgery on pulmonary function in young subjects with spinal muscular atrophy type 2 and other neuromuscular scoliosis. AB - BACKGROUND: The aim of this study was to determine the effects of magnetically controlled growing rods surgery (MCGRS) of the scoliosis on pulmonary function in children with neuromuscular scoliosis. METHODS: Seven patients, 85.7% female (mean +/- SD age: 6.7+/-1.2 years), with neuromuscular scoliosis (4 SMA II, 2 congenital myopathies and 1 VACTER syndrome), received MCGRS of the spine in the thoraco-lumbar area. The outcome measures were clinical features and pulmonary function (forced vital capacity [FVC] and forced expiratory volume in 1st second [FEV1], were collected. All measures were collected at pre-, post-intervention and follow-up (short-term [0-6 months], mid-term [7-12 months], and long-term [13 24 months]). RESULTS: MCGRS reduced Cobb angle after intervention in 100% in subjects and this result was maintained at 24-month follow-up (all, P=0.001). There was no significant difference in FVC or FEV1 between preoperative and each postoperative period, (P>0.05). Analyses of the correlation coefficients indicated no significant associations between changes in pulmonary function and scoliosis. CONCLUSIONS: The current study found that MCGRS addressed to the scoliosis maintained pulmonary function during long-term follow-up; However, pulmonary function was not associated with scoiosis in children with neuromuscular scoliosis. PMID- 28565895 TI - Quality of the tools used to assess aerobic capacity in people with multiple sclerosis. AB - INTRODUCTION: Assessments of physical fitness, including exercise tolerance functions, are valuable in persons with multiple sclerosis (MS). Many tools with widely varying advantages and disadvantages have been used to assess physical fitness in research and clinical practice. To date, there are no recommendations regarding the best tools to use for this purpose in persons with MS. This study aims to systematically review the psychometric properties of the tools used to assess exercise tolerance functions in persons with MS, and to propose recommendations regarding the best test to use. EVIDENCE ACQUISITION: The literature was searched (PubMed, SPORTdiscus, PEDro, MEDLINE, Embase via Scopus, CINAHL, and PsycInfo) to identify the tools most frequently used to assess exercise tolerance functions. These tools were systematically analyzed. EVIDENCE SYNTHESIS: Forty-eight articles were selected. Six tools or categories of tools concerning exercise tolerance functions were identified. Whole-body exercise tests combined with gas exchange analysis had the best psychometric properties (e.g., validity, reliability) for assessing aerobic capacity in pwMS with mild to moderate disability (Expanded Disability Status Scale [EDSS] <=6.5). Although sometimes used for this purpose, walk tests seemed to assess walking performance rather than exercise tolerance functions. The psychometric properties of other tests had scarcely been studied. CONCLUSIONS: The tools vary widely in quality. Whole-body exercise testing combined with gas exchange analysis has the best psychometric properties of the reviewed tools. If gas exchange analysis is feasible, whole-body exercise tests combined with gas exchange analysis, with maximal exercise effort for pwMS with EDSS <=4 and submaximal exercise effort for pwMS with EDSS >=4.5, should be recommended to assess exercise tolerance, both in research and in clinical practice. A selection algorithm is proposed. PMID- 28565897 TI - Management of patients with an unruptured intracranial aneurysm and a history of malignancy. AB - BACKGROUND: Management of a patient with an unruptured intracranial aneurysm (UIA) who has a history of malignancy can be challenging due to considerations related to the natural history of the aneurysm and risk of recurrence or progression of malignancy. The current study presents our experience with both conservative management and interventional treatment of patients with UIAs and a remote or recent history of cancer. METHODS: Consecutive patients with a history of malignancy and UIA were classified into the following groups: Group I (diagnoses of both UIA and cancer within 3 years) and Group II (known cancer with new UIA diagnosed >= 3 years after cancer). Patient demographics, clinical characteristics, aneurysm/treatment characteristics, and outcomes were collected prospectively. We studied the following outcomes: perioperative and mid-/long term complications, aneurysm rupture, retreatment/recurrence rates, long-term neurological outcome, and possible impact of cancer history on decision-making for treatment. RESULTS: A total of 122 patients were included in this study (55 in Group I and 67 in Group II). Patients in Group I underwent aneurysm treatment significantly less often than those in Group II (20.0% versus 46.3%, P=0.002). There was no difference in neurological morbidity rates between the two groups after a mean follow-up of 22.3 months (3.6% versus 3.0%, P=0.29). Overall, untreated patients experienced an annualized rupture rate of 1.6% (95% CI=0.0% 3.4%, 3/187.6 ruptures/person years). CONCLUSIONS: Patients with an UIA and a history of cancer should be considered for management with either conservative management or invasive techniques. The optimal UIA management is defined on a case-by-case basis carefully comparing the prognosis of the patient's malignancy with the natural history of the aneurysm and the risk of interventional treatment. PMID- 28565898 TI - Vitamin B12, folate and homocysteine status in obese and atopic children: a preliminary study. PMID- 28565899 TI - Post-infectious persistent cough: pathogenesis and therapeutic options. AB - Post-infectious cough is a common symptom associated with common colds and/or upper respiratory tract infection. This cough is expected to last for only for few days and resolve spontaneously, whilst when persists for longer than three weeks is defined "persistent" and is associated tickling or an irritating sensation in the throat which often leads to paroxysms of coughing. Persistent post-infectious cough can cause morbidity since it may interfere with usual living. Despite the recent advances in understanding the mechanisms that regulate cough, in physiological and pathological conditions, current therapeutic options for post-infectious cough are little or only moderately effective. PMID- 28565900 TI - The impact of intrauterine growth restriction on respiratory outcomes. AB - BACKGROUND: Intrauterine growth restriction (IUGR) is caused by fetal growth below what is normal for its genetic potential. Recent studies have shown a distinct association between changes in umbilical artery flow in IUGR subjects and an increased risk of respiratory morbidity and was to find the impact of IUGR on the respiratory outcomes of premature neonates born with less than 32 weeks gestational age. METHODS: This retrospective cohort study targeted infants born with less than 32 weeks of gestation, admitted at NCIU, between January 2010 and December 2016. Each selected IUGR case was matched according to gestational age and sex with an appropriate birthweight newborn at a 1:2 ratio, within a 12-month period. RESULTS: The study involved 126 neonates, 42 with IUGR, and 84 control subjects. IUGR was not identified as a predictor of Bronchopulmonary Dysplasia (BDP) (OR 4.80, 95% CI 1.14-20.21, p = 0.033). Abnormal umbilical artery flow (OR 4.80, 95% CI 1.14-20.21, p = 0.033) and late onset sepsis (OR 3.31, 95% CI 1.04 10.56, p = 0.044) were significantly associated with BDP. CONCLUSIONS: It is essential to recognize changes in the umbilical artery flow, especially in high risk pregnancies such as IUGR, since these represent an a priori risk marker for the development of BDP. The individual and combined effect of IUGR, alterations on umbilical artery flow and extreme prematurity has not yet been completely clarified on the impact on lung morbidity, requiring a larger number of studies. PMID- 28565901 TI - The influence of extra-curricular physical activities in the development of coordination in pre-school children. AB - BACKGROUND: The aim of this study is to provide information in relation to the coordination ability of pre-school children. The study aimed to investigate the influence of pre-school physical activity, as part of the enrichment curriculum, on the coordination of the pupils. METHODS: A sample of 120 preschool children (M=63; F=58) aged 4 and 5 years old (M = 4.47, SD = 0.5), with differing levels of physical activity carried out by the Children Body Coordination Test instrument (TCCI), Soares (1993). Proceeded to descriptive statistical analysis of coordinative benefits students, depending on the variables gender, age group, practical activities, years of practice, number of workouts and total weekly sessions of physical activity. We conducted an inferential analysis of data for comparison of means in the variables under study. RESULTS: Practicing enrichment activities has been demonstrated to assist in the development of children's motor skills with those having engaged in such activities achieving a higher level of performance. CONCLUSIONS: The practice of extracurricular physical activities significantly enhances the general coordinative abilities in children aged 4 and 5 years of age, but it was found that 5 year old children had a significantly higher performance compared to 4 year old children. PMID- 28565902 TI - The significance of genetics in pathophysiologic models of premature birth. AB - INTRODUCTION: Prematurity is a major health problem in all countries, especially in certain ethnic groups and increasing recurrence imply the influence of genetic factors. Published genetic polymorphisms are identified in relation to the 4 pathophysiological models of prematurity described: chorioamniotic-decidual inflammation, premature contraction pathway, decidual hemorrhage and susceptibility to environmental toxins. EVIDENCE ACQUISITION: The research identified 240 articles, 52 articles are excluded because they are not original, not written in English or duplicated. From them 125 articles were included in qualitative analysis This review aims to update recent knowledge about genes associated with premature birth. EVIDENCE SYNTHESIS: Polymorphisms in specific genes are responsible, in varying degrees, for prematurity and the different pathogenetic mechanisms are involved. CONCLUSIONS: The fetus is genetically different from its mother and is recognized as such by the immune system. Generality has shown that maternal physiology adapts to tolerate and nourish the fetus and that both mother and fetus play an active role in the birth process. PMID- 28565903 TI - Uncatalyzed Carboboration of Seven-Membered-Ring trans-Alkenes: Formation of Air Stable Trialkylboranes. AB - Seven-membered-ring trans-alkenes undergo rapid, uncatalyzed carboboration reactions to form trialkylboranes as single diastereomers. In contrast with other trialkylboranes, which can ignite in the presence of oxygen, these trialkylboranes are stable in air. Hindered trialkylboranes can undergo reverse hydroboration reactions to form allylic silanes or can be oxidized to afford highly substituted triols. This reaction sequence permits the construction of compounds with up to five consecutive stereocenters. Control experiments and computational studies support a concerted mechanism for the migratory insertion of the alkene into the carbon-boron bond, similar to the mechanism for hydroboration. PMID- 28565904 TI - Correction to Development of Comparative Toxicity Potentials of TiO2 Nanoparticles for Use in Life Cycle Assessment. PMID- 28565906 TI - Reversible Generation of Labile Secondary Carbocations from Alcohols in the Nanospace of H-Mordenite and Their Long-Lasting Preservation at Ambient Temperature. AB - Secondary carbocations are rarely observed spectrometrically for prolonged durations at ambient temperatures because of their instability. In this study, when 4,4'-difluorobenzhydrol (1) was mixed with H-mordenite (H-Mor), the 4,4' difluorodiphenylmethyl cation (2) was generated as the main product, identified by UV-vis and 13C-MAS NMR spectroscopies, and was preserved for over 1 week at ambient temperature. Surprisingly, the polymerization and disproportionation of 1 barely proceeded within the micropores of H-Mor. However, these side reactions prevailed in TfOH and formation of 2 was not observed. Preservation of other secondary carbocations from benzhydrol, 4,4'-dichlorobenzhydrol, and 9-fluorenol was also realized in H-Mor. It was confirmed that the generation of 2 from 1 was controlled by thermodynamic equilibrium rather than kinetic regulations. The equilibrium between 2 and 1 was accompanied by reversible chromism, which could be easily controlled by altering the moisture content in H-Mor. Moreover, novel insights into specific acid catalysis in zeolites densely populated with acid sites on the inner surface of micropores are described herein. PMID- 28565905 TI - Enantioselective CuH-Catalyzed Hydroacylation Employing Unsaturated Carboxylic Acids as Aldehyde Surrogates. AB - The direct asymmetric copper hydride (CuH)-catalyzed coupling of alpha,beta unsaturated carboxylic acids to aryl alkenes to access chiral alpha-aryl dialkyl ketones is reported. A variety of substrate substitution patterns, sensitive functional groups, and heterocycles are tolerated in this reaction, which significantly expands the range of accessible products compared with existing hydroacylation methodology. Although mechanistic studies are ongoing, we propose that CuH-catalyzed silylation of unsaturated acids occurs to access a uniquely effective acyl electrophilic coupling partner. PMID- 28565907 TI - Thermodynamic Characterization of Hydration Sites from Integral Equation-Derived Free Energy Densities: Application to Protein Binding Sites and Ligand Series. AB - Water molecules play an essential role for mediating interactions between ligands and protein binding sites. Displacement of specific water molecules can favorably modulate the free energy of binding of protein-ligand complexes. Here, the nature of water interactions in protein binding sites is investigated by 3D RISM (three dimensional reference interaction site model) integral equation theory to understand and exploit local thermodynamic features of water molecules by ranking their possible displacement in structure-based design. Unlike molecular dynamics based approaches, 3D RISM theory allows for fast and noise-free calculations using the same detailed level of solute-solvent interaction description. Here we correlate molecular water entities instead of mere site density maxima with local contributions to the solvation free energy using novel algorithms. Distinct water molecules and hydration sites are investigated in multiple protein-ligand X-ray structures, namely streptavidin, factor Xa, and factor VIIa, based on 3D RISM derived free energy density fields. Our approach allows the semiquantitative assessment of whether a given structural water molecule can potentially be targeted for replacement in structure-based design. Finally, PLS-based regression models from free energy density fields used within a 3D-QSAR approach (CARMa - comparative analysis of 3D RISM Maps) are shown to be able to extract relevant information for the interpretation of structure-activity relationship (SAR) trends, as demonstrated for a series of serine protease inhibitors. PMID- 28565909 TI - Virtual Issue in Memory of David Chandler. PMID- 28565911 TI - Spotlights: Volume 8, Issue 11. PMID- 28565912 TI - Are Electron Affinity and Ionization Potential Intrinsic Parameters to Predict the Electron or Hole Acceptor Character of Amorphous Molecular Materials? PMID- 28565908 TI - Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7 ((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2 carboxamide, for Imaging of Metabotropic Glutamate Receptor 2. AB - Metabotropic glutamate 2 receptors (mGlu2) are involved in the pathogenesis of several CNS disorders and neurodegenerative diseases. Pharmacological modulation of this target represents a potential disease-modifying approach for the treatment of substance abuse, depression, schizophrenia, and dementias. While quantification of mGlu2 receptors in the living brain by positron emission tomography (PET) would help us better understand signaling pathways relevant to these conditions, few successful examples have been demonstrated to image mGlu2 in vivo, and a suitable PET tracer is yet to be identified. Herein we report the design and synthesis of a radiolabeled negative allosteric modulator (NAM) for mGlu2 PET tracer development based on a quinoline 2-carboxamide scaffold. The most promising candidate, 7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4 [11C]methoxyphenyl) quinoline-2-carboxamide ([11C]QCA) was prepared in 13% radiochemical yield (non-decay-corrected at the end of synthesis) with >99% radiochemical purity and >74 GBq/MUmol (2 Ci/MUmol) specific activity. While the tracer showed limited brain uptake (0.3 SUV), probably attributable to effects on PgP/Bcrp efflux pump, in vitro autoradiography studies demonstrated heterogeneous brain distribution and specific binding. Thus, [11C]QCA is a chemical probe that provides the basis for the development of a new generation mGlu2 PET tracers. PMID- 28565910 TI - Photochemical Energy Storage and Electrochemically Triggered Energy Release in the Norbornadiene-Quadricyclane System: UV Photochemistry and IR Spectroelectrochemistry in a Combined Experiment. AB - The two valence isomers norbornadiene (NBD) and quadricyclane (QC) enable solar energy storage in a single molecule system. We present a new photoelectrochemical infrared reflection absorption spectroscopy (PEC-IRRAS) experiment, which allows monitoring of the complete energy storage and release cycle by in situ vibrational spectroscopy. Both processes were investigated, the photochemical conversion from NBD to QC using the photosensitizer 4,4' bis(dimethylamino)benzophenone (Michler's ketone, MK) and the electrochemically triggered cycloreversion from QC to NBD. Photochemical conversion was obtained with characteristic conversion times on the order of 500 ms. All experiments were performed under full potential control in a thin-layer configuration with a Pt(111) working electrode. The vibrational spectra of NBD, QC, and MK were analyzed in the fingerprint region, permitting quantitative analysis of the spectroscopic data. We determined selectivities for both the photochemical conversion and the electrochemical cycloreversion and identified the critical steps that limit the reversibility of the storage cycle. PMID- 28565913 TI - Outer membrane cytochromes/flavin interactions in Shewanella spp.-A molecular perspective. AB - Extracellular electron transfer (EET) is intrinsically associated with the core phenomena of energy harvesting/energy conversion in natural ecosystems and biotechnology applications. However, the mechanisms associated with EET are complex and involve molecular interactions that take place at the "bionano interface" where biotic/abiotic interactions are usually explored. This work provides molecular perspective on the electron transfer mechanism(s) employed by Shewanella oneidensis MR-1. Molecular docking simulations were used to explain the interfacial relationships between two outer-membrane cytochromes (OMC) OmcA and MtrC and riboflavin (RF) and flavin mononucleotide (FMN), respectively. OMC flavin interactions were analyzed by studying the electrostatic potential, the hydrophilic/hydrophobic surface properties, and the van der Waals surface of the OMC proteins. As a result, it was proposed that the interactions between flavins and OMCs are based on geometrical recognition event. The possible docking positions of RF and FMN to OmcA and MtrC were also shown. PMID- 28565915 TI - In vitro mineralization of dual grafted polytetrafluoroethylene membranes. AB - The modification of biomaterials by radiation induced grafting is a promising method to improve their bioactivity. Successful introduction of carboxyl and amine functional groups on the surface of a polytetrafluoroethylene membrane was achieved by grafting of acrylic acid (AA) and 2-aminoethyl methacrylate hydrochloride (AEMA) using simultaneous gamma irradiation grafting. Chemical characterization by attenuated total reflectance Fourier transform infrared spectroscopy and x-ray photoelectron spectroscopy confirmed the presence of amine and carboxylate functionalities and indicated that all protonated amines formed ion pairs with carboxyl groups, but not all carboxyl are involved in ion pairing. It was found that the irradiation doses (2, 5, or 10 kGy) affected the grafting outcome only when sulfuric acid (0.5 or 0.9 M) was added as a polymerization enhancer. The use of the inorganic acid successfully enhanced the total graft yield (GY), but the changes in the graft extent (GE) were not conclusive. Dual functional films were produced by either a one- or a two-step process. Generally, higher GY and GE values were observed for the samples produced by the two-step grafting of AA and AEMA. The in vitro mineralization in 1.5* simulated body fluid (SBF) induced the formation of carbonated hydroxyapatite as verified by FITR. All samples showed an increase in weight after mineralization with significantly larger increases observed for the samples which had the 1.5* SBF changed every third day compared to every seventh. For the dual functional samples, it was found that the sample grafted by the one-step method shows a significantly higher increase in weight despite a much lower GY compared to the sample prepared by the two-step method and this was attributed to the different architecture of grafted chains. PMID- 28565914 TI - Human melanoma inhibitory protein binds to the FN12-14 Hep II domain of fibronectin. AB - The heparin binding site (Hep II) of fibronectin plays a major role in tumor cell metastasis. Its interaction with heparan sulfate proteoglycans occurs in a variety of physiological processes including focal adhesion and migration. The melanoma inhibitory activity (MIA) is an important protein that is functionally involved in melanoma development, progression, and tumor cell invasion. After its secretion by malignant melanoma cells, MIA interacts with fibronectin and thereby actively facilitates focal cell detachment from surrounding structures and strongly promotes tumor cell invasion and the formation of metastases. In this report, the authors have determined the molecular basis of the interaction of MIA with the Hep II domain of fibronectin based on nuclear magnetic resonance spectroscopic binding assays. The authors have identified the type III modules 12 to 14 of fibronectin's Hep II as the major MIA binding sites. These results now provide a new target protein-protein binding interface for the discovery of novel antimetastatic agents against malignant melanoma in the future. PMID- 28565917 TI - Differences in carbon source utilization of Salmonella Oranienburg and Saintpaul isolated from river water. AB - Long-term exposure to river water by non-indigenous micro-organisms such as Salmonella may affect metabolic adaptation to carbon sources. This study was conducted to determine differences in carbon source utilization of Salmonella Oranienburg and Salmonella Saintpaul (isolated from tropical river water) as well as the control strain Salmonella Typhimurium exposed to laboratory, river water, and host cells (Hep-2 cell line) growth conditions. Results showed that Salmonella Oranienburg and Salmonella Saintpaul showed better ability for carbon source utilization under the three growth conditions evaluated; however, S. Oranienburg showed the fastest and highest utilization on different carbon sources, including D-Glucosaminic acid, N-acetyl-D-Glucosamine, Glucose-1 phosphate, and D-Galactonic acid, while Salmonella Saintpaul and S. Typhimurium showed a limited utilization of carbon sources. In conclusion, this study suggests that environmental Salmonella strains show better survival and preconditioning abilities to external environments than the control strain based on their plasticity on diverse carbon sources use. PMID- 28565916 TI - Ubiquitin immobilized on mesoporous MCM41 silica surfaces - Analysis by solid state NMR with biophysical and surface characterization. AB - Deriving the conformation of adsorbed proteins is important in the assessment of their functional activity when immobilized. This has particularly important bearings on the design of contemporary and new encapsulated enzyme-based drugs, biosensors, and other bioanalytical devices. Solid-state nuclear magnetic resonance (NMR) measurements can expand our molecular view of proteins in this state and of the molecular interactions governing protein immobilization on popular biocompatible surfaces such as silica. Here, the authors study the immobilization of ubiquitin on the mesoporous silica MCM41 by NMR and other techniques. Protein molecules are shown to bind efficiently at pH 5 through electrostatic interactions to individual MCM41 particles, causing their agglutination. The strong attraction of ubiquitin to MCM41 surface is given molecular context through evidence of proximity of basic, carbonyl and polar groups on the protein to groups on the silica surface using NMR measurements. The immobilized protein exhibits broad peaks in two-dimensional 13C dipolar-assisted rotational resonance spectra, an indication of structural multiplicity. At the same time, cross-peaks related to Tyr and Phe sidechains are missing due to motional averaging. Overall, the favorable adsorption of ubiquitin to MCM41 is accompanied by conformational heterogeneity and by a major loss of motional degrees of freedom as inferred from the marked entropy decrease. Nevertheless, local motions of the aromatic rings are retained in the immobilized state. PMID- 28565918 TI - Role for Thrombin Receptor Antagonism With Vorapaxar in Secondary Prevention of Atherothrombotic Events: From Bench to Bedside. AB - In spite of treatment with the current standard of care antiplatelet regimens including dual antiplatelet therapy, recurrence rates of ischemic events remain elevated for high-risk patients with atherosclerotic disease. This may be in part attributed to the fact that other key platelet activation pathways remain uninhibited and can thus continue to trigger platelet activation and lead to thrombotic complications. Thrombin is a powerful inducer of platelet activation and mediates its effects directly on platelets through protease activator receptors (PARs), particularly the PAR-1 subtype, making PAR-1 inhibition an attractive approach for reducing atherothrombotic events. These observations have led to the development of several PAR-1 antagonists. Vorapaxar is a direct inhibitor of PAR-1 and the only agent of this class approved for the prevention of recurrent ischemic events in patients with prior myocardial infarction or peripheral artery disease. In the present manuscript, we present a review of the pathophysiologic role of thrombin on thrombotic complications, the impact of vorapaxar on outcomes, including the most recent updates deriving from clinical trials, as well as future perspectives in the field. PMID- 28565919 TI - Age and Anatomical Location-Related Dermoscopic Patterns of 210 Acral Melanocytic Nevi in a Turkish Population. AB - BACKGROUND: Dermoscopy is a useful tool for earlier diagnosis and differentiating benign lesions from melanoma. OBJECTIVES: We aim to investigate dermoscopic features of acral nevi, age, and localisation-related findings of these lesions. METHODS: This was an observational, descriptive study. Patients were retrospectively collected from the Department of Dermatology. The patients with acral nevi were included in the study. Inclusion criteria were Turkish nationality and the presence of at least 1 acral nevus diagnosed both clinically and dermoscopically. Lesions in dorsal and subungual areas were excluded. All nevi were examined by the same dermatologist. RESULTS: The most common dermoscopic patterns were as follows: parallel furrow (87 patients; 41.4%), globular (24 patients; 11.4%), fibrillar (22 patients; 10.5%), combination patterns (19 patients; 9.1%), globulostreak-like (16 patients; 7.6%), lattice like (15 patients; 7.1%), homogeneous (12 patients; 5.7%), nontypical (8 patients; 3.8%), parallel ridge (4 patients; 1.9%), reticular (2 patients; 1.0%), and crista dotted pattern (1 patient; 0.5%). The parallel furrow pattern was the most common pattern in all localisations. The number of parallel furrow patterns (5 lesions) was equal to the globulostreak-like pattern (5 lesions) on the thenar area. The number of parallel furrow patterns (4 lesions) was equal to the fibrillar pattern (4 lesions) on the heel. Parallel furrow (dotted variants) (11 lesions) and globulostreak-like patterns (5 lesions) were the most common patterns in the pediatric population (0-15 years old). The fibrillar pattern showed a tendency for soles (12 lesions), while a lattice-like pattern was seen more often in the plantar arch (3 lesions). CONCLUSIONS: Description of the dermoscopic features of acral nevi is important to improve management and reduce the number of unnecessary excisions. The most common patterns were parallel furrow, globular, and fibrillar in our study. Parallel furrow (dotted variants) and globulostreak-like patterns were the most common patterns in the pediatric population. The fibrillar pattern showed a tendency for soles, while a lattice like pattern was seen more often on the plantar arch. Therefore, there may be a relation between anatomic localisation, age, and dermoscopic pattern. PMID- 28565920 TI - Vulvar Basal Cell Carcinoma: Four Case Reports With Immunohistochemical Study. AB - Basal cell carcinomas (BCC) are the most frequent tumours in humans and normally appear in photoexposed areas of the skin. It is widely accepted that BCCs originate at follicular stem cells and consequently are very rare in nonhairy areas. Here, we report 4 cases of vulvar BCC, 3 of which were located in a vulvar semimucous area, a nonphotoexposed area, and a nonhairy area. We have determined the CK7 and CK19 profile of all cases; both are markers of simple epithelium with glandular differentiation. Interestingly, all cases were positively stained for CK7 and CK19. Considering that the vulvar region is rich in sebaceous and apocrine units, we hypothesise a glandular origin of BCCs situated in the vulvar region. PMID- 28565921 TI - Interpretation of environmental tracer data for conceptual understanding of groundwater flow: an application for fractured aquifer systems in the Klodzko Basin, Sudetes, Poland. AB - Environmental isotopes and hydrogeological data have been used for the construction of a conceptual model of fresh groundwater flow in the Klodzko Basin, Sudetes, Poland. The model has allowed the verification of a groundwater circulation scheme resulting from the general morphological assumptions and the recharge role to the surrounding mountains. Combined interpretation of the tritium ages and the isotopic altitude effect allowed determining the volume of water-bearing rock Vr and hydrogeological parameters of systems drained by springs and wells. Prior to the final determination of the recharge zone of individual objects, calculations were made for the thickness of the flow zone (h) and the distance from the recharge zone to the drainage point (L). The recharge areas for springs are located within a distance of 1-1.5 km and are characterized by a width of 0.75-1.65 km. The recharge area of wells is located in significantly longer distances of 2.1-12 km but yet definitely lower width. The recharge of groundwater from the Western direction seems to be obvious for all the wells and springs located westward from Nysa Klodzka River. The eastern component of the recharge appeared during the interpretation of the well in Dlugopole. Dedicated to Professor Peter Fritz on the occasion of his 80th birthday. PMID- 28565922 TI - God, heresy trials and psychiatry. PMID- 28565923 TI - Cost of high prevalence mental disorders: Findings from the 2007 Australian National Survey of Mental Health and Wellbeing. AB - OBJECTIVE: The aim of this project was to detail the costs associated with the high prevalence mental disorders (depression, anxiety-related and substance use) in Australia, using community-based, nationally representative survey data. METHODS: Respondents diagnosed, within the preceding 12 months, with high prevalence mental disorders using the Confidentialised Unit Record Files of the 2007 National Survey of Mental Health and Wellbeing were analysed. The use of healthcare resources (hospitalisations, consultations and medications), productivity loss, income tax loss and welfare benefits were estimated. Unit costs of healthcare services were obtained from the Independent Hospital Pricing Authority, Medicare and Pharmaceutical Benefits Scheme. Labour participation rates and unemployment rates were determined from the National Survey of Mental Health and Wellbeing. Daily wage rates adjusted by age and sex were obtained from Australian Bureau of Statistics and used to estimate productivity losses. Income tax loss was estimated based on the Australian Taxation Office rates. The average cost of commonly received Government welfare benefits adjusted by age was used to estimate welfare payments. All estimates were expressed in 2013-2014 AUD and presented from multiple perspectives including public sector, individuals, private insurers, health sector and societal. RESULTS: The average annual treatment cost for people seeking treatment was AUD660 (public), AUD195 (individual), AUD1058 (private) and AUD845 from the health sector's perspective. The total annual healthcare cost was estimated at AUD974m, consisting of AUD700m to the public sector, AUD168m to individuals, and AUD107m to the private sector. The total annual productivity loss attributed to the population with high prevalence mental disorders was estimated at AUD11.8b, coupled with the yearly income tax loss at AUD1.23b and welfare payments at AUD12.9b. CONCLUSION: The population with high prevalence mental disorders not only incurs substantial cost to the Australian healthcare system but also large economic losses to society. PMID- 28565924 TI - The securitization of health in the context of the war on terror. National security and global health: the conflict of imperatives. AB - In this article, I want to show that the securitization of health issues in the name of national interests led to the militarization of health care in the context of the war against terrorism. However, the connection between health and security also gave way to the emergence of the notion of human security, thus, converging with the human right to health approach and the cosmopolitan discourse on global health. These two perspectives on the relation between health and security lead to conflicting imperatives in the current state of counter terrorism operations. I argue that when the securitization of health concerns in the name of national security conflicts with the provision of health care in the name of universal human rights, the higher moral end must trump the prudential one. Moreover, it is a duty to promote the human right to health when liberal democracies in foreign policies directly violate this moral ideal in the name of national security. PMID- 28565925 TI - Sexual minority youth and depressive symptoms or depressive disorder: A systematic review and meta-analysis of population-based studies. AB - OBJECTIVE: Research has suggested that sexual minority young people are more likely to have depressive symptoms or depressive disorder, but to date most studies in the field have relied on convenience-based samples. This study overcomes this limitation by systematically reviewing the literature from population-based studies and conducting a meta-analysis to identify whether depressive disorder and depressive symptoms are elevated in sexual minority youth. METHOD: A systematic review and meta-analysis were conducted and informed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement to determine if rates of depressive symptoms or depressive disorder differ for sexual minority youth, relative to heterosexual adolescents. MEDLINE, PsycINFO, EMBASE and ERIC databases were searched. Studies reporting depressive symptom data or the prevalence of depressive disorder in population-based samples of adolescents, which included sexual minority youth and heterosexual young people, were included in the review. A meta-analysis was conducted to examine differences between groups. RESULTS: Twenty-three articles met the inclusion criteria. The proportion of sexual minority youth in the studies ranged from 2.3% to 12%. Sexual minority youth reported higher rates of depressive symptoms and depressive disorder (odds ratio = 2.94, p < 0.001 and standardized mean difference, d = 0.39, p < 0.001) in comparison to heterosexual young people. Female sexual minority youth were more likely to report depressive symptoms when compared to male sexual minority youth (standardized mean difference, d = 0.34, p < 0.001). Limitations included variations in how sexuality was operationalized and how depressive symptoms or depressive disorder was measured. CONCLUSIONS: There is robust evidence that rates of depressive disorder and depressive symptoms are elevated in sexual minority youth in comparison to heterosexual young people. Despite the elevated risk of depressive symptoms or depressive disorder for sexual minority youth, the treatment for this group of young people has received little attention. PMID- 28565926 TI - C-peptide: A predictor of cardiovascular mortality in subjects with established atherosclerotic disease. AB - AIM: Insulin resistance and type 2 diabetes are independent risk factors for cardiovascular diseases. Levels of C-peptide are increased in these patients and its role in the atherosclerosis progression was studied in vitro and in vivo over the past years. To evaluate the possible use of C-peptide as cardiovascular biomarkers, we designed an observational study in which we enrolled patients with mono- or poly-vascular atherosclerotic disease. METHODS: We recruited 431 patients with stable atherosclerosis and performed a yearly follow-up to estimate the cardiovascular and total mortality and cardiovascular events. RESULTS: We performed a mean follow-up of 56 months on 268 patients. A multivariate Cox analysis showed that C-peptide significantly increased the risk of cardiovascular mortality [Hazard Ratio: 1.29 (95% confidence interval: 1.02-1.65, p < 0.03513)] after adjustment for age, sex, diabetes treatment, estimated glomerular filtration rate and known diabetes status. Furthermore, levels of C-peptide were significantly correlated with metabolic parameters and atherogenic factors. CONCLUSION: C-peptide was associated with cardiovascular mortality independently of known diabetes status in a cohort of patients with chronic atherosclerotic disease. Future studies using C-peptide into a reclassification approach might be undertaken to consider its potential as a cardiovascular disease biomarker. PMID- 28565927 TI - Human Papilloma Virus-Associated Lips Verrucous Carcinoma in HIV-Infected Male. AB - Human papillomavirus (HPV) infection, widely known as the necessary cause of cervical cancer, has been established as a major etiologic factor for head and neck cancer (HNC). HIV-infected individuals are at higher risk of HPV-associated cancers than the general population. We describe a 45-year-old man with HIV and HPV coinfection, who presented progressively enlarging verrucous neoformations of the lips. The final diagnosis of verrucous carcinoma was delayed. Early detection of HPV lesions in oral mucosa and HPV screening activities could be important in improving the diagnostic sensitivity for the HIV-infected patients with oral cancer. PMID- 28565928 TI - Iron oxide magnetic nanoparticles as antimicrobials for therapeutics. AB - The use of iron oxide magnetic nanoparticles (IMNP) in medical and pharmaceutical areas dates to the beginning of the 1970s, as carriers. Some other uses to these nanoparticles are in vitro separation, magnetic resonance imaging and drug targeting agent. Many preparations containing IMNP have been described and used in drug delivery, hyperthermia, in vitro separation, tissue repair, cellular therapy, for magnetic separation, magnetic resonance imaging, as spoilers for magnetic resonance spectroscopy, and more recently as sensors for metabolites and other biomolecules. The use of these nanostructures as antibacterial agents has also been reported, which could kill some bacteria species causing no damage to the human host cells. Recently, they have been used as hyperthermia agents to treat infections or cancer, which are more susceptible than the healthy host's cells. Engineering designs, physiochemical characteristics, biomedical applications of IMNP, toxicity and magnetic nanotoxicology have been discussed. However, the application of IMNP as antimicrobials is very important. Thus, this review explores the therapeutic activities of IMNP and their use as antimicrobial agents. These nanoparticles can be efficient for the treatment of microbial infections, probably acting as membrane permeability enhancer, damaging the cell wall or by generating reactive oxygen species. PMID- 28565929 TI - Effects of acute and chronic exposure to both 900 MHz and 2100 MHz electromagnetic radiation on glutamate receptor signaling pathway. AB - PURPOSE: To demonstrate the molecular effects of acute and chronic exposure to both 900 and 2100 MHz radiofrequency electromagnetic radiation (RF-EMR) on the hippocampal level/activity of some of the enzymes - including PKA, CaMKIIalpha, CREB, and p44/42 MAPK - from N-methyl-D-aspartate receptor (NMDAR)-related signaling pathways. MATERIALS AND METHODS: Rats were divided into the following groups: sham rats, and rats exposed to 900 and 2100 MHz RF-EMR for 2 h/day for acute (1 week) or chronic (10 weeks), respectively. Western blotting and activity measurement assays were used to assess the level/activity of the selected enzymes. RESULTS: The obtained results revealed that the hippocampal level/activity of selected enzymes was significantly higher in the chronic groups as compared to the acute groups at both 900 and 2100 MHz RF-EMR exposure. In addition, hippocampal level/activity of selected enzymes was significantly higher at 2100 MHz RF-EMR than 900 MHz RF-EMR in both acute and chronic groups. CONCLUSIONS: The present study provides experimental evidence that both exposure duration (1 week versus 10 weeks) and different carrier frequencies (900 vs. 2100 MHz) had different effects on the protein expression of hippocampus in Wistar rats, which might encourage further research on protection against RF-EMR exposure. PMID- 28565930 TI - Current perspectives on the role of chemotherapy in chronic lymphocytic leukemia. AB - Chemotherapy has long been integral to the treatment of chronic lymphocytic leukemia (CLL). Fludarabine/cyclophosphamide, chlorambucil and bendamustine are commonly used as a backbone, depending on the patient's age and general health. The advent of the anti-CD20 monoclonal antibodies, such as rituximab and obinutuzumab, altered the face of treatment, and chemoimmunotherapy still forms the current standard first-line approach. However, the landscape is changing following the emergence of novel targeted agents, such as ibrutinib, idelalisib and venetoclax, which offer the chance for improved efficacy over standard therapy alone, with no substantial increase in toxicity. This review focuses on the role of chemotherapy in CLL, discussing the characteristics that define a state-of-the art chemotherapy, the current role of chemotherapy in the treatment of CLL, within the context of guidelines, and its future role in a setting in which chemotherapy-free regimens are being increasingly investigated. PMID- 28565931 TI - Histopathology and analyses of inflammation intensity in the gills of mussels exposed to silver nanoparticles: role of nanoparticle size, exposure time, and uptake pathways. AB - Environmentally induced perturbation of health parameters lead to morphological changes associated to the inflammatory response. Hematoxyline and eosin (H&E) stained gill filaments sections were examined for such changes and inflammation intensity was scored according to a quantitative model in order to evaluate the health status of in vivo exposed (for 3, 6, and 12 h) mussels to silver nanoparticles (Ag-NPs <50 nm and Ag-NPs <100 nm) prior and after the inhibition of two potential uptake pathways (clathrin- and caveolae-mediated endocytosis) with the aid of pharmaceutical inhibitors (amantadine and nystatin). The impacts of the nanoparticles (NPs) size, as well as their uptake routes within different time of exposure on the inflammatory response were assessed. The results showed that Ag-NPs clearly induced morphological changes associated to the inflammatory response in gill tissues (Mann-Whitney p values were <.05). It is also clear that the length of the exposure as well as the NP size highly impacted inflammation intensity (highest histopathological indices recorded with Ag-NPs <100 nm). Also, the routes of NPs entry noticed to be major factor underlying inflammatory response (significant inflammation intensity reported with Ag-NPs <50 nm after blockade of uptake routes; p <.05). Throughout, it was concluded that inflammation intensity was related to NPs size and exposure time. Overall, uptake routes are shown to be the major factor underlying nanotoxicity. PMID- 28565932 TI - Information Transfer Capacity of Articulators in American Sign Language. AB - The ability to convey information is a fundamental property of communicative signals. For sign languages, which are overtly produced with multiple, completely visible articulators, the question arises as to how the various channels co ordinate and interact with each other. We analyze motion capture data of American Sign Language (ASL) narratives, and show that the capacity of information throughput, mathematically defined, is highest on the dominant hand (DH). We further demonstrate that information transfer capacity is also significant for the non-dominant hand (NDH), and the head channel too, as compared to control channels (ankles). We discuss both redundancy and independence in articulator motion in sign language, and argue that the NDH and the head articulators contribute to the overall information transfer capacity, indicating that they are neither completely redundant to, nor completely independent of, the DH. PMID- 28565934 TI - Aceclofenac oil drops: characterization and evaluation against ocular inflammation. AB - Ocular inflammatory diseases, such as uveitis, scleritis, episcleritis and dry eye syndrome are commonly treated with eye drop formulations. In the present study, attempts were made to prepare aceclofenac oil formulations to evaluate its transcorneal permeation and anti-inflammatory effect. Ophthalmic solutions of aceclofenac with or without (0.5% v/v) benzyl alcohol were formulated in different vegetable oils and permeation studies were carried out. Aceclofenac ophthalmic solution in linseed oil containing benzyl alcohol exhibited maximum permeation (4.42% in goat, 4.26% in sheep and 3.94% in buffalo) through corneas under study. The partition characteristics of aceclofenac in linseed oil reinforced the results of permeation studies. The optimized formulation (linseed oil containing benzyl alcohol) showed better stability profile. Linseed oil aceclofenac formulation showed significant inhibitory effect on ocular inflammation induced by arachidonic acid in rabbit eyes (p < .05) and hence it can be considered as a potential approach for treatment of ocular inflammatory conditions. PMID- 28565933 TI - Comparing executive function, evoked hemodynamic response, and gait as predictors of variations in mobility for older adults. AB - OBJECTIVE: Falls represent a major concern for older adults and may serve as clinically salient index events for those presenting in the prodromal stages of mild cognitive impairment. Declines in executive function performance and in gait consistency have shown promise in predicting fall risk; however, associated neurophysiological underpinnings have received less attention. In this study, we used a multimodal approach to assess fall risk in a group of older adults with and without a previous fall history. METHOD: Processing speed, inductive reasoning, verbal fluency, crystallized ability, episodic memory, and executive functioning were assessed using standardized neuropsychological tests. Cognitive interference was assessed using the Multi-Source Interference Task. Spatiotemporal gait parameters were assessed with and without cognitive load using a 6.4-m instrumented walkway. Hemodynamic responses were measured using functional near-infrared spectroscopy. RESULTS: Whereas no group differences were observed in cognitive behavioral performance, during a cognitive interference task fallers displayed more oxygenated hemoglobin across the prefrontal cortex than nonfallers, suggesting that engaging in the cognitive task was more effortful for them overall, therefore eliciting greater cortical activation. Between-group differences in spatial as well as temporal gait parameters were also observed. CONCLUSIONS: These results are in keeping with assertions that diminished executive control is related to fall risk. Notably, the group differences observed in prefrontal cortical activation and in gait parameters may ultimately precede those observed in cognitive behavioral performance, with implications for measurement sensitivity and early identification. PMID- 28565935 TI - Why overall survival and not progression free survival improves in era of program death inhibitors. PMID- 28565936 TI - Osimertinib: A third-generation tyrosine kinase inhibitor for treatment of epidermal growth factor receptor-mutated non-small cell lung cancer with the acquired Thr790Met mutation. AB - Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for the treatment of metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) in patients failing previous TKI therapy. The T790M mutation is an acquired resistance mechanism found in over half of patients with NSCLC progressing on first-generation TKIs. First- and second-generation TKIs do not inhibit the T790M mutation at clinically relevant concentrations. Osimertinib is selective for mutated forms of EGFR, including the TKI-sensitizing mutations L858R and exon 19 deletions, as well as the acquired T790M resistance mutation. In a trial comparing osimertinib to platinum doublet therapy among patients with the T790M mutation progressing on first-line TKI therapy, median progression-free survival was significantly longer in patients receiving osimertinib. Osimertinib has a favorable safety profile compared to platinum-doublet chemotherapy. Common adverse events include diarrhea, skin rash, dry skin, and paronychia; however, because it spares wild type EGFR, these toxicities appear to occur with less frequency and severity compared to other TKIs. Serious, but rare, adverse events include pneumonitis, interstitial lung disease-like events, QT interval prolongation, and reduced ejection fraction. Osimertinib has the unique ability to distribute readily into brain tissue compared with other TKIs, giving it a potential role in the treatment and/or prevention of CNS metastases; future studies are warranted in this area. An ongoing study evaluating osimertinib versus first-generation TKIs as first-line treatment for patients with EGFR mutation-positive NSCLC may help to define the role of osimertinib as front-line therapy. PMID- 28565937 TI - App-guided exposure and response prevention for obsessive compulsive disorder: an open pilot trial. AB - Although effective treatments for obsessive-compulsive disorder (OCD) exist, there are significant barriers to receiving evidence-based care. Mobile health applications (Apps) offer a promising way of overcoming these barriers by increasing access to treatment. The current study investigated the feasibility, acceptability, and preliminary efficacy of LiveOCDFree, an App designed to help OCD patients conduct exposure and response prevention (ERP). Twenty-one participants with mild to moderate symptoms of OCD were enrolled in a 12-week open trial of App-guided self-help ERP. Self-report assessments of OCD, depression, anxiety, and quality of life were completed at baseline, mid treatment, and post-treatment. App-guided ERP was a feasible and acceptable self help intervention for individuals with OCD, with high rates of retention and satisfaction. Participants reported significant improvement in OCD and anxiety symptoms pre- to post-treatment. Findings suggest that LiveOCDFree is a feasible and acceptable self-help intervention for OCD. Preliminary efficacy results are encouraging and point to the potential utility of mobile Apps in expanding the reach of existing empirically supported treatments. PMID- 28565938 TI - N-(4-Hydroxyphenyl)-3,4,5-trimethoxybenzamide derivatives as potential memory enhancers: synthesis, biological evaluation and molecular simulation studies. AB - The present paper describes the synthesis, biological evaluation and molecular simulation studies of a series of N-(4-hydroxyphenyl)-3,4,5-trimethoxybenzamide derivatives with N,N-dialkylaminoethoxy/propoxy moiety as potential memory enhancers with acetylcholinesterase-inhibiting activity having IC50 in low micromolar range (4.0-16.5 MUM). All the compounds showed a good degree of agreement between in vivo and in vitro results as most of these derivatives showed dose-dependent increase in percent retention. Compound 10a showed significant % retention of 84.73 +/- 4.51 as compared to piracetam (46.88 +/- 5.42) at 3 mg kg-1 and also exhibited a maximal percent inhibition of 97% at 50 MUM. Molecular docking, MM-GBSA and molecular simulation studies were performed establishing a correlation between the experimental biology and in silico results. In silico results indicate that all the compounds have better docking scores and predicted binding free energies as compared to cocrystallized ligand with the best potent ligand retaining conserved hydrophobic interactions with residues of catalytic triad (HIS447), catalytic anionic site (CAS) (TRP86, TYR337, PHE338) and peripheral anionic site (PAS) (TYR72, TYR124, TRP286 and TYR341). Root mean square deviation (RMSD = 2.4 A) and root mean square fluctuations of 10a-AChE complex during simulation proved its stable nature in binding toward acetylcholinesterase. The docked conformation of 10a and other analogs at the binding site have also been simulated with polar and nonpolar interactions interlining the gorge residues from PAS to catalytic triad. PMID- 28565939 TI - Homicide in the western family and background factors of a perpetrator. AB - AIMS: Familicide is a multiple-victim homicide incident in which the killer's spouse and one or more children are slain. A systematic review was conducted to reveal the background factors of western homicide perpetrators. METHODS: The systematic search was performed in the Arto, Medic, Cinahl, Medline, EBSCOhost Academic Search Premier and Social Services abstracts databases. The keywords were familicide, family homicide, familicide-suicide, filicide-suicide, extended suicide, child, murder, family, filicide and infanticide. The searches revealed 4139 references from the databases. The references were filtered and 32 peer reviewed research articles revealed in years 2004-2014 were selected as data. The articles were analysed using inductive content analysis, by finding all possible background factors related to homicide. RESULTS: The factors were described as percentages of the range. The background factors of familicide perpetrators were categorised as follows: perpetrators who had committed homicide of a child and intimate partner and possibly committed suicide; a father had who killed a child; a mother who had killed a child; a father who had committed a filicide-suicide; and a mother who had committed a filicide-suicide. CONCLUSIONS: Psychological instability, violence and crime were found in all these categories of familicides. Perpetrators who had committed a suicide in addition to the familicide had more often been diagnosed with depression, but they sought treatment for mental health problems less often and had violence and self destructiveness less often in their background than in other familicide categories. Social and healthcare professionals should be more sensitive to emerging family problems and be prepared for intervention. PMID- 28565940 TI - Exposure to suicide behaviour and individual risk of self-harm: Findings from a nationally representative New Zealand high school survey. AB - PURPOSE: To examine whether there is an association between students self reported suicide attempts and non-suicidal self-injury and exposure to suicidal behaviour among friends, family members or within school communities. METHODS: A cross-sectional analysis of a nationally representative health and well-being survey of 8500 New Zealand high school students conducted from March through November 2012. Students' self-reported suicide attempts and repeated non-suicidal self-injury was examined in relation to student reports of self-harming behaviour among friends and family as well as data from school administrators of completed suicides within the school community. RESULTS: Almost 1 in 20 (4.5%) students reported a suicide attempt in the last 12 months and 7.9% reported repeated non suicidal self-injury in the last 12 months. The risk of both suicide attempts and repeated non-suicidal self-injury was highest among females, students from homes with economic deprivation and among students reporting an episode of low mood in the previous 12 months. Students exposed to suicide attempts or completed suicide among friends and/or family members were at increased risk of reporting attempted suicide and repeated non-suicidal self-injury in the last year. There was no association between completed suicide in school community and students self reported suicide attempts or repeated non-suicidal self-injury. CONCLUSIONS: Low mood and exposure to suicide attempts of friends and family members are associated with suicide attempts and repeated non-suicidal self-injury in New Zealand high school students. This research highlights importance of supporting adolescents with low mood and exposed to suicide of friends and family. PMID- 28565942 TI - Recurrent administration of the nitric oxide donor, isosorbide dinitrate, induces a persistent cephalic cutaneous hypersensitivity: A model for migraine progression. AB - Background A subgroup of migraineurs experience an increase in attack frequency leading to chronic migraine. Methods We assessed in rats the roles of dose and repeat administration of systemic isosorbide dinitrate (ISDN), a nitric oxide donor, on the occurrence and development of cephalic/face and extracephalic/hindpaw mechanical allodynia as a surrogate of migraine pain, and the effect of acute systemic sumatriptan and olcegepant and chronic systemic propranolol on these behavioral changes. Results A single high (H-ISDN) but not low (L-ISDN) dose of ISDN induces a reversible cephalic and extracephalic mechanical allodynia. However, with repeat administration, L-ISDN produces reversible cephalic but never extracephalic allodynia, whereas H-ISDN induces cephalic and extracephalic allodynia that are both potentiated. H-ISDN-induced cephalic allodynia thus gains persistency. Sumatriptan and olcegepant block single H-ISDN-induced behavioral changes, but only olcegepant reduces these acute changes when potentiated by repeat administration. Neither sumatriptan nor olcegepant prevent chronic cephalic hypersensitivity. Conversely, propranolol blocks repeat H-ISDN-induced chronic, but not acute, behavioral changes. Conclusions Repeated ISDN administration appears to be a naturalistic rat model for migraine progression, suitable for screening acute and preventive migraine therapies. It suggests frequent and severe migraine attacks associated with allodynia may be a risk factor for disease progression. PMID- 28565941 TI - Insulin replacement limits progression of diabetic cardiomyopathy in the low-dose streptozotocin-induced diabetic rat. AB - Diabetic cardiomyopathy is a major contributor to the increasing burden of heart failure globally. Effective therapies remain elusive, in part due to the incomplete understanding of the mechanisms underlying diabetes-induced myocardial injury. The objective of this study was to assess the direct impact of insulin replacement on left ventricle structure and function in a rat model of diabetes. Male Sprague-Dawley rats were administered streptozotocin (55 mg/kg i.v.) or citrate vehicle and were followed for 8 weeks. A subset of diabetic rats were allocated to insulin replacement (6 IU/day insulin s.c.) for the final 4 weeks of the 8-week time period. Diabetes induced the characteristic systemic complications of diabetes (hyperglycaemia, polyuria, kidney hypertrophy) and was accompanied by marked left ventricle remodelling (cardiomyocyte hypertrophy, left ventricle collagen content) and diastolic dysfunction (transmitral E/A, left ventricle-dP/dt). Importantly, these systemic and cardiac impairments were ameliorated markedly following insulin replacement, and moreover, markers of the diabetic cardiomyopathy phenotype were significantly correlated with the extent of hyperglycaemia. In summary, these data suggest that poor glucose control directly contributes towards the underlying features of experimental diabetic cardiomyopathy, at least in the early stages, and that adequate replacement ameliorates this. PMID- 28565943 TI - An analytical GC-MS method to quantify methyl dihydrojasmonate in biocompatible oil-in-water microemulsions: physicochemical characterization and in vitro release studies. AB - Microemulsions (MEs) loaded with methyl dihydrojasmonate (MJ) were developed to improve the aqueous solubility of this drug. The composition of the formulations ranged according to the oil/surfactant ratio (O/S). The MEs were characterized according to diameter of droplets, X-ray diffraction and polarized light microscopy. The MJ identification and quantification was performed by gas chromatography-mass spectrometry (GC-MS). The MJ showed a retention time of ~16.7 min for all samples. The obtained correlation coefficient from the calibration graph was 0.991. The developed analytical method was effective enough to quantify low and high concentrations of MJ. The increase of the O/S ME ratio led to a reduction of the droplet diameter. All formulations showed an amorphous structure and the behavior varied between isotropic and anisotropic systems. A decrease in the release of MJ with the increase of the O/S ratio in the formulations was observed. The analytical method developed for the quantitative determination of MJ is suitable to detect and quantify the drug compound from different compositions of MEs in the in vitro release test, and by analogy in other prolonged effects related to the drug reservoir effect of these systems was observed, revealing that ME can be a promising nanocarrier for MJ delivery to tumor cells. PMID- 28565944 TI - Linus Pauling, Ph.D. (1901-1994): From Chemical Bond to Civilization. PMID- 28565946 TI - OCD in College Athletes. PMID- 28565948 TI - Collaboration to Reduce Tragedy and Improve Outcomes: Law Enforcement, Psychiatry, and People Living With Mental Illness. PMID- 28565945 TI - Association and Causation in Brain Imaging in the Case of OCD: Response to McKay et al. PMID- 28565949 TI - Cortical Pyramidal Neurons Show a Selective Loss of New Synapses in Chronic Schizophrenia. PMID- 28565951 TI - CORRECTIONS. PMID- 28565952 TI - CORRECTIONS. PMID- 28565953 TI - CORRECTIONS. PMID- 28565954 TI - The Paradoxes of Unexpected Reward in Anorexia Nervosa. PMID- 28565955 TI - Association and Causation in Brain Imaging: The Case of OCD. PMID- 28565957 TI - Getting Personalized: Brain Scan Biomarkers for Guiding Depression Interventions. PMID- 28565958 TI - Engaging Depressed Patients: An Essential Step in Optimizing Care. PMID- 28565959 TI - Grief Process Following the Sudden Death of a Patient. PMID- 28565960 TI - Comparison of subjective and fully automated methods for measuring mammographic density. AB - Background Breast radiologists of the Norwegian Breast Cancer Screening Program subjectively classified mammographic density using a three-point scale between 1996 and 2012 and changed into the fourth edition of the BI-RADS classification since 2013. In 2015, an automated volumetric breast density assessment software was installed at two screening units. Purpose To compare volumetric breast density measurements from the automated method with two subjective methods: the three-point scale and the BI-RADS density classification. Material and Methods Information on subjective and automated density assessment was obtained from screening examinations of 3635 women recalled for further assessment due to positive screening mammography between 2007 and 2015. The score of the three point scale (I = fatty; II = medium dense; III = dense) was available for 2310 women. The BI-RADS density score was provided for 1325 women. Mean volumetric breast density was estimated for each category of the subjective classifications. The automated software assigned volumetric breast density to four categories. The agreement between BI-RADS and volumetric breast density categories was assessed using weighted kappa (kw). Results Mean volumetric breast density was 4.5%, 7.5%, and 13.4% for categories I, II, and III of the three-point scale, respectively, and 4.4%, 7.5%, 9.9%, and 13.9% for the BI-RADS density categories, respectively ( P for trend < 0.001 for both subjective classifications). The agreement between BI-RADS and volumetric breast density categories was kw = 0.5 (95% CI = 0.47 0.53; P < 0.001). Conclusion Mean values of volumetric breast density increased with increasing density category of the subjective classifications. The agreement between BI-RADS and volumetric breast density categories was moderate. PMID- 28565961 TI - Non-penetrating traumatic injuries of the aortic arch. AB - Background In severely injured trauma patients, non-penetrating aortic arch injuries (NAAI) have a remarkable incidence and mortality. Both diagnostics and therapy of NAAI recently underwent significant changes. Purpose To assess mortality, morbidity, and the risk factors associated with NAAI in severely injured patients (Injury Severity Score [ISS] >=16) under the light of recent technical and procedural advances in trauma care. Material and Methods A total of 230 consecutive trauma patients with ISS >=16 admitted to our level-I trauma center during a 24-month period, were prospectively included and underwent standardized whole-body computed tomography (CT) in a 2 * 128-detector-row scanner. Incidence, mortality, patient and trauma characteristics, and concomitant injuries were recorded for patients with NAAI. Localization of NAAI was described referring to Mitchell and Ishimaru; severity was graded according to the proposal of Heneghan et al. Results Thirteen of 230 patients had a NAAI, yielding an incidence of 5.6%. Mean age and ISS was not elevated in NAAI (44.4 +/ 14.8 years, ISS = 38 +/- 12.4). Mortality was 23.1%. One patient had severe neurologic sequelae from a stroke; all surviving patients had to undergo (transient) anticoagulant therapy. Trauma mechanism was of high kinetic energy in all cases. Concomitant injuries were predominantly thoracic (rib fractures = 76.9%, thoracic spine fracture = 38.5%). Conclusion Whenever an individual possibly encountered a deceleration-acceleration trauma mechanism, a high level of suspicion for NAAI should be maintained. It remains to be determined whether recent advances in mortality are due to changes in trauma care or due to improved vehicle and road safety. PMID- 28565962 TI - The role of pro-/anti-inflammation imbalance in Abeta42 accumulation of rat brain co-exposed to fine particle matter and sulfur dioxide. AB - Taiyuan is a center of coal-based electricity production and many chemicals industries, where mixtures of sulfur dioxide (SO2) and particulate matter may be more prominent. The focus of the present study was to determine if there is a link between adverse effects in the brain and the combined-exposure to SO2 and fine particulate matter (PM2.5). Rats were exposed alternately to PM2.5 with different dosages (1.5, 6.0 and 24.0 mg/kg body weight) and SO2 at the level of 5.6 mg/m3. The results showed that the combined exposure to PM2.5 and SO2 enhanced the mRNA expression and protein level of TNF-alpha and IL-6 in rat cortex and hippocampus relative to the control, SO2 and PM2.5 alone. Instead, TGF beta1 mRNA and protein level were down-regulated in the brain. Additionally, PM2.5 at medium and/or high dose caused marked increase in Abeta42 level and PM2.5 + SO2 induced further increase of Abeta42 level in the cortex and hippocampus. It suggests that SO2 and PM2.5 can synergistically exert inflammation responses and induce Abeta42 accumulation in the brain. Also, it is notable that the Abeta42 accumulation of rat cortex and hippocampus were closely associated with pro-/anti-inflammatory cytokines ratio. These results clearly demonstrated that the combined exposure to PM2.5 and SO2 can induce the imbalance of pro-/anti-inflammatory cytokine, resulting in Abeta42 accumulation of rat brain cortex and hippocampus. PMID- 28565964 TI - Reporting on self-care in research studies: Guidance to improve knowledge building. PMID- 28565963 TI - Genomic instability induced in distant progeny of bystander cells depends on the connexins expressed in the irradiated cells. AB - PURPOSE: To examine the time window during which intercellular signaling though gap junctions mediates non-targeted (bystander) effects induced by moderate doses of ionizing radiation; and to investigate the impact of gap junction communication on genomic instability in distant progeny of bystander cells. MATERIALS AND METHODS: A layered cell culture system was developed to investigate the propagation of harmful effects from irradiated normal or tumor cells that express specific connexins to contiguous bystander normal human fibroblasts. Irradiated cells were exposed to moderate mean absorbed doses from 3.7 MeV alpha particle, 1000 MeV/u iron ions, 600 MeV/u silicon ions, or 137Cs gamma rays. Following 5 h of co-culture, pure populations of bystander cells, unexposed to secondary radiation, were isolated and DNA damage and oxidative stress was assessed in them and in their distant progeny (20-25 population doublings). RESULTS: Increased frequency of micronucleus formation and enhanced oxidative changes were observed in bystander cells co-cultured with confluent cells exposed to either sparsely ionizing (137Cs gamma rays) or densely ionizing (alpha particles, energetic iron or silicon ions) radiations. The irradiated cells propagated signals leading to biological changes in bystander cells within 1 h of irradiation, and the effect required cellular coupling by gap junctions. Notably, the distant progeny of isolated bystander cells also exhibited increased levels of spontaneous micronuclei. This effect was dependent on the type of junctional channels that coupled the irradiated donor cells with the bystander cells. Previous work showed that gap junctions composed of connexin26 (Cx26) or connexin43 (Cx43) mediate toxic bystander effects within 5 h of co-culture, whereas gap junctions composed of connexin32 (Cx32) mediate protective effects. In contrast, the long-term progeny of bystander cells expressing Cx26 or Cx43 did not display elevated DNA damage, whereas those coupled by Cx32 had enhanced DNA damage. CONCLUSIONS: In response to moderate doses from either sparsely or densely ionizing radiations, toxic and protective effects are rapidly communicated to bystander cells through gap junctions. We infer that bystander cells damaged by the initial co-culture (expressing Cx26 or Cx43) die or undergo proliferative arrest, but that the bystander cells that were initially protected (expressing Cx32) express DNA damage upon sequential passaging. Together, the results inform the roles that intercellular communication play under stress conditions, and aid assessment of the health risks of exposure to ionizing radiation. Identification of the communicated molecules may enhance the efficacy of radiotherapy and help attenuate its debilitating side-effects. PMID- 28565965 TI - Challenges in secondary prevention after acute myocardial infarction: A call for action. AB - Worldwide, each year more than 7 million people experience myocardial infarction, in which one-year mortality rates are now in the range of 10%, but vary with patient characteristics. The consequences are even more dramatic: among patients who survive, 20% suffer a second cardiovascular event in the first year and approximately 50% of major coronary events occur in those with a previous hospital discharge diagnosis of ischaemic heart disease. The people behind these numbers spur this call for action. Prevention after myocardial infarction is crucial to reduce risk and suffering. Evidence-based interventions include optimal medical treatment with anti-platelets and statins, achieve-ment of blood pressure, lipid and blood glucose targets, and appropriate lifestyle changes. The European Society of Cardiology and its constituent bodies are determined to embrace this challenge by developing a consensus document in which the existing gaps for secondary prevention strategies are reviewed. Effective interventions in relation to the patients, healthcare providers and healthcare systems are proposed and discussed. Finally, innovative strategies in hospital as well as in outpatient and long-term settings are endorsed. PMID- 28565966 TI - A Vascular Complications Risk (VASCOR) score for patients undergoing invasive cardiac procedures in the catheterization laboratory setting: A prospective cohort study. AB - BACKGROUND: Vascular complications are still common in the catheterization laboratory setting. However, no risk scores for their prediction have been described. With a view to bridging this gap, the present study sought to develop and validate a score for prediction of vascular complications associated with arterial access in patients undergoing interventional cardiology procedures. METHODS: This prospective multicenter cohort study included adult patients who underwent cardiac catheterization via the femoral or radial route. The outcomes of interest were: access site hematoma; major and minor bleeding; and retroperitoneal hemorrhage, pseudoaneurysm, or arteriovenous fistula requiring surgical repair. Past medical history as well as pre-procedural, intra procedural, and post-procedural variables were collected. Patients were randomly allocated to the derivation or validation cohorts at a 2:1 ratio. The following equation constituted the score: (>6F introducer sheath*4.0)+(percutaneous coronary intervention*2.5)+(history of vascular complication after prior interventional cardiology procedure*2.0)+(prior use of warfarin or phenprocoumon*2.0)+(female sex*1.5)+(age?60 years*1.5). The maximum score is 13.5 points. RESULTS: A score dichotomized at ?3 (best cutoff for balancing sensitivity and specificity) was moderately accurate (sensitivity=0.66 (95% confidence interval: 0.59-0.73); specificity=0.59 (95% confidence interval: 0.56 0.61)). Patients with a score ?3 were at increased risk of complications (odds ratio: 2.95; 95% confidence interval: 2.22-3.91). CONCLUSIONS: This study yielded a score that is capable of predicting vascular complications and easily applied in daily practice by providers working in the catheterization laboratory setting. PMID- 28565968 TI - HRT in women with cardiovascular disease: Can we start, should we stop? PMID- 28565967 TI - Quality of chest compressions by healthcare professionals using real-time audiovisual feedback during in-hospital cardiopulmonary resuscitation. AB - INTRODUCTION: A high quality of chest compressions, e.g. sufficient depth (5-6 cm) and rate (100-120 per min), has been associated with survival. The patient's underlay affects chest compression depth. Depth and rate can be assessed by feedback systems to guide rescuers during cardiopulmonary resuscitation. AIM: The purpose of this study was to describe the quality of chest compressions by healthcare professionals using real-time audiovisual feedback during in-hospital cardiopulmonary resuscitation. METHOD: An observational descriptive study was performed including 63 cardiac arrest events with a resuscitation attempt. Data files were recorded by Zoll AED Pro, and reviewed by RescueNet Code Review software. The events were analysed according to depth, rate, quality of chest compressions and underlay. RESULTS: Across events, 12.7% (median) of the compressions had a depth of 5-6 cm. Compression depth of >6 cm was measured in 70.1% (median). The underlay could be identified from the electronic patient records in 54 events. The median compression depth was 4.5 cm (floor) and 6.7 cm (mattress). Across events, 57.5% (median) of the compressions were performed with a median frequency of 100-120 compressions/min and the most common problem was a compression rate of <100 (median=22.3%). CONCLUSIONS: Chest compression quality was poor according to the feedback system. However, the distribution of compression depth with regard to underlay points towards overestimation of depth when treating patients on a mattress. Audiovisual feedback devices ought to be further developed. Healthcare professionals need to be aware of the strengths and weaknesses of their devices. PMID- 28565969 TI - Effectiveness of endurance exercise training in patients with coronary artery disease: A meta-analysis of randomised controlled trials. AB - BACKGROUND: Exercise interventions apparently reduce the risks of and prevent coronary artery disease (CAD). Developing an exercise intervention for patients with CAD is a rapidly expanding focus worldwide. The results of previous studies are inconsistent and difficult to interpret across various types of exercise programme. AIM: This study aimed to update prior systemic reviews and meta analyses in order to determine the overall effects of endurance exercise training on patients with CAD. METHODS: The databases (PubMed, Medline, CINAHL, EMBASE and Cochrane Library) were searched for the interventions published between January 1, 2000, and May 31, 2015. Comprehensive meta-analysis software was used to evaluate the heterogeneity of the selected studies and to calculate mean differences (MDs) while considering effect size. RESULTS: A total of 18 studies with 1286 participants were included. Endurance exercise interventions at a moderate to high training intensity significantly reduced resting systolic blood pressure (MD: -3.8 mmHg, p = 0.01) and low-density lipoprotein cholesterol (MD: 5.5 mg/dL, p = 0.02), and increased high-density lipoprotein cholesterol (MD: 3.8 mg/dL, p < 0.001). There were also significant positive changes in peak oxygen consumption (MD: 3.47 mL/kg/min, p < 0.001) and left ventricular ejection fraction (MD: 2.6%, p = 0.03) after the interventions. Subgroup analysis results revealed that exercise interventions of 60-90 minutes per week with a programme duration of >12 weeks had beneficial effects on functional capacity, cardiac function and a number of cardiovascular risk factors. CONCLUSIONS: Endurance exercise training has a positive effect on major modifiable cardiovascular risk factors and functional capacity. Nurses can develop endurance exercise recommendations for incorporation into care plans of clinically stable CAD patients following an acute cardiac event or revascularisation procedure. PMID- 28565970 TI - Baclofen systemic toxicity: Experimental histopathological and biochemical study. AB - OBJECTIVE: The present study was designed to highlight the toxic impact of baclofen on both biochemical and histopathological aspects in rats' liver, gastric, lung, kidney, and brain tissues. METHODS: The study was performed on 30 healthy adult male albino rats divided into four groups with 5 rats in each control group, and 10 rats in either experimental groups (two experimental and two control groups). Five rats (negative control) were kept in a quite non stressful environment, provided with food ad libitum and free access to water. Normal saline (1 ml) was given orally as placebo in the positive control group ( n = 5). Experimental group III, baclofen acute toxicity group (10 rats): Each animal received a single dose of lethal dose (LD50) of baclofen orally by gavage. It equals 145 mg/kg body weight. The rats were observed for acute toxicity manifestations as well as for LD50 deaths. Group IV, (baclofen-dependent group, 10 rats): Each animal received baclofen (1/10th LD50) in gradually increasing doses for 1 month. RESULTS: The levels of blood urea nitrogen, creatinine kinase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, cardiac troponin I, and prothrombin time in both baclofen-treated groups showed significant elevation when compared to controls. There were brain, lung, gastric, hepatic, and renal histopathological changes in baclofen-treated rats whose severity varied between the two experimental groups. CONCLUSION AND RECOMMENDATION: Baclofen toxicity is an under diagnosed emergency. Physicians should consider baclofen toxicity in users having hepatorenal dysfunction, presenting with altered mental status, bradycardia, and hypotension. PMID- 28565971 TI - Monodora myristica (African nutmeg) modulates redox homeostasis and alters functional chemistry in sickled erythrocytes. AB - The antioxidative effect of Monodora myristica seed acetone extract and its effect on chemical functional groups were investigated in sickled erythrocytes as well as molecular modeling of the antisickling potentials of its secondary metabolites. The extract was subjected to gas chromatography-mass spectrometry to identify the compounds present, which were then docked into the allosteric binding site of deoxy-hemoglobin. The extract was incubated with sickled erythrocytes at 37 degrees C for 6, 12, and 24 h and were subjected to antioxidative analysis for reduced glutathione (GSH), superoxide dismutase (SOD), catalase, and lipid peroxidation (LPO). Chemical functional group of the treated cells was analyzed via Fourier transform infrared spectroscopy (FTIR). The predominant compounds identified were 17-octadecynoic acid; oleic acid, androstan 3-one, 17-hydroxy-2-methyl- (2.beta.,5.beta.,17.beta.)-; estran-3-one, 17 (acetyloxy)-2-methyl-, (2.alpha., 5.alpha., 17.beta.), and (+)-3-carene, 10 (acetylmethyl)-. They all fitted well within the active site of Hb with good binding affinity, as evidenced by the negative CDocker interaction energies of their complexes ranging between -54.4 and -26.7 kcal/mol. Treatment with the extract exacerbated SOD and catalase activities as well as GSH level, while LPO was suppressed. This antioxidative activity was time and/or dose dependent, with 6 and 12 h incubation showing the optimum activity. FTIR analysis of the treated cells showed the presence of hydrophobic functional groups. The synergetic molecular interaction of the major compounds of the extract with the alpha-dimer of Hb depicts an antisickling effect of M. myristica acetone extract. This is accompanied by exacerbation of endogenous antioxidant enzymes activity and modification of the functional chemistry of the cells. PMID- 28565972 TI - Effects of insulin+glucose pretreatment on bupivacaine cardiotoxicity in rats. AB - A mistaken overdose of bupivacaine into systemic circulation may cause severe cardiovascular side effects. The aim of this study was to assess the effects of pretreatment with combined intra venous lipid emulsion (ILE) and high-dose insulin therapy against cardiotoxicity caused by bupivacaine intoxication. The rats were divided into the following three groups: Group B received a saline pretreatment plus a bupivacaine, group L received ILE pretreatment plus a bupivacaine, and in group I, insulin with glucose was infused intravenously, plus ILE pretreatment plus a bupivacaine. The electrocardiogram tracing, invasive arterial pressure, and heart rate (HR) of rats were monitored continuously. Arterial blood gas analysis was performed in all groups. Arterial blood gas analysis revealed that the baseline pH, PaO2, and PaCO2 values were similar between groups ( p > 0.05). Widening of Q, R, and S wave complex was found 46.8 +/- 16.7, 92.0 +/- 5.80, and 106.5 +/- 17.9 s after initiation of bupivacaine infusion in groups B, L, and I, respectively. Time elapsed until 25% reduction of HR 127.3 +/- 17.7, 248.4 +/- 34.1, and 260.1 +/- 51.3 s for groups B, L, and I, and 25% reduction of mean arterial pressure 107.6 +/- 14.1, 253.2 +/- 36.3, and 292 +/- 57.7 s for groups B, L, and I, respectively. Arrhythmia was observed after 142.2 +/- 27.5, 180.7 +/- 17.8, and 190.7 +/- 19.2 s for groups B, L, and I, respectively. Finally, asystole occurred after 560.1 +/- 76.4, 782.4 +/- 63.0, and 882.5 +/- 105.1 s for groups B, L, and I, respectively. This finding indicates that the survival time of rats administered pretreatment with ILE plus insulin+glucose and those given ILE was observed to be longer. PMID- 28565973 TI - The dimensionality of disclosure of HIV status amongst post-partum women in Cape Town, South Africa. AB - Disclosure of HIV status to sexual partners and others has been presented as positive health behaviour and is widely encouraged by antiretroviral treatment (ART) programmes, providers and policies. However, disclosure is also highly contextual and its positive effects are not universal. We explore the dimensions of disclosure amongst post-partum women who initiated ART during pregnancy in Cape Town, South Africa. Forty-seven semi-structured interviews with post-partum women were conducted as part of the Maternal Child Health-Antiretroviral Therapy (MCH-ART) study. Primary elements of disclosure were coded and interpreted according to dominant themes and subthemes. Disclosure was commonplace in the sample, ranging from widely disclosing status (rare); to disclosing to some family, friends and partners; to tacit disclosure, where participants took medication in front of others without explicitly discussing their status. Women described reasons for non-disclosure in terms of not being ready, fear of negative reactions (including violence and loss of financial support), and fear of their status being widely known. Self-reported adherence was uniformly high throughout the range of disclosure. Even those who made special efforts to avoid disclosure, such as attending clinics distant from their homes, reported good adherence. Those who disclosed experienced a range of responses to their disclosure, from support to shunning. Despite access to ART, stigma remained a persistent feature in descriptions of disclosure, particularly in relation to partner disclosure. Our findings suggest that disclosure is not always positive and adherence can be maintained within a wide range of disclosure behaviours. It is important that clinic settings allow women to retain control over their disclosure process. PMID- 28565974 TI - PNC27 anticancer peptide as targeting ligand significantly improved antitumor efficacy of Doxil in HDM2-expressing cells. AB - AIM: To investigate the potential of PNC27 peptide, 12-26 of p53 with high affinity for HDM2 protein, as targeting ligand for Doxil to improve its antitumor activity. MATERIALS & METHODS: Doxil postinserted with 25, 50, 100 and 200 PNC27 peptides per liposome. Flow cytometry and confocal analysis were performed on C26 colon carcinoma (HDM2 positive) and B16F0 melanoma (HDM2 negative) cells. In vivo studies were performed on BALB/c mice bearing C26 and C57BL/6 mice bearing B16F0 tumor models. RESULTS: PNC27-Doxil showed significant cellular uptake and cytotoxicity in C26 cells compared with Doxil. PNC27-Doxil (100 PNC27 peptide) significantly improved therapeutic efficacy of Doxil without compromising its biodistribution in C26 tumor. However, these results were not observed in B16F0 cells. CONCLUSION: PNC27 is a promising targeting ligand for Doxil against HDM2 positive cancers. PMID- 28565975 TI - Stress, Emotions, and Motivational States Among Traditional Dancers in New Zealand and Japan. AB - This study used a reversal theory framework to examine motivational dominance and changes in motivational state, arousal, stress, and emotions among members of traditional Japanese (Nihon Odori Sports Science (NOSS)) and New Zealand (Kapa Haka) dance groups. Eighty-four participants (50 in Japan and 34 in New Zealand) completed questionnaires on each variable before and after a dance class. The findings indicated that the Kapa Haka dancers were significantly more playful and arousal-seeking than the NOSS dancers. They also reported higher overall arousal, preferred arousal, and effort during performance while the NOSS dancers became more serious afterward. Data on emotions matched those of arousal in that the Kapa Haka dancers felt significantly more excited and provocative after the session. The NOSS dancers were more relaxed and placid, both overall and after dancing. These patterns were consistent with the dancers' respective motivational states and motivational dominance, and suggest that both dances can be effective in reducing negative affect. They also suggest that psychological effects are dependent upon performers' personal and cultural affiliation with the two dance forms. PMID- 28565976 TI - Differences in labour force participation by motherhood status among second generation Turkish and majority women across Europe. AB - Second-generation Turkish immigrants make up an increasingly important segment of European labour markets. These young adults are entering the prime working ages and forming families. However, we have only a limited understanding of the relationship between labour force participation and parenthood among second generation Turkish women. Using unique data from the Integration of the European Second Generation survey (2007/08), we compared the labour force participation of second-generation Turkish women with their majority-group counterparts by motherhood status in four countries. We found evidence that motherhood gaps, with respect to labour force participation, were similar for majority and second generation Turkish women in Germany and in Sweden; however, there may be larger gaps for second-generation mothers than for majority women in the Netherlands and France. Cross-national findings were consistent with the view that national normative and social policy contexts are relevant for the labour force participation of all women, regardless of migrant background. PMID- 28565977 TI - Endovascular treatment of blister aneurysms. AB - Blister aneurysms are rare cerebrovascular lesions for which the treatment methods are reviewed here, with a focus on endovascular options. The reported pathogenesis of blister aneurysms varies, and hemodynamic stress, arterial dissection, and arteriosclerotic ulceration have all been described. There is consensus on the excessive fragility of blister aneurysms and their parent vessels, which makes clipping technically difficult. Open surgical treatment is associated with high rates of complications, morbidity, and mortality; endovascular treatment is a promising alternative. Among endovascular treatment options, deconstructive treatment has been associated with higher morbidity compared with reconstructive methods such as direct embolization, stent- or balloon-assisted direct embolization, stent monotherapy, and flow diversion. Flow diversion has been associated with higher technical success rates and similar clinical outcomes compared with non-flow diverting treatment methods. However, delayed aneurysm occlusion and the need for antiplatelet therapy are potential drawbacks to flow diversion that must be considered when choosing among treatment methods for blister aneurysms. PMID- 28565978 TI - Off-label uses of the Pipeline embolization device: a review of the literature. AB - The Pipeline embolization device (PED) is the most widely used flow diverter in endovascular neurosurgery. In 2011, the device received FDA approval for the treatment of large and giant aneurysms in the internal carotid artery extending from the petrous to the superior hypophyseal segments. However, as popularity of the device grew and neurosurgeons gained more experience, its use has extended to several other indications. Some of these off-label uses include previously treated aneurysms, acutely ruptured aneurysms, small aneurysms, distal circulation aneurysms, posterior circulation aneurysms, fusiform aneurysms, dissecting aneurysms, pseudoaneurysms, and even carotid-cavernous fistulas. The authors present a literature review of the safety and efficacy of the PED in these off-label uses. PMID- 28565979 TI - Flow diversion of tandem cerebral aneurysms: a multi-institutional retrospective study. AB - OBJECTIVE Flow diversion has proven to be an efficacious means of treating cerebral aneurysms that are refractory to other therapeutic means. Patients with tandem aneurysms treated with flow diversion have been included in larger, previously reported series; however, there are no dedicated reports on using this technique during a single session to treat this unique subset of patients. Therefore, the authors analyzed the outcomes of patients who had undergone single session flow diversion for the treatment of tandem aneurysms. METHODS The authors conducted a retrospective review of flow diversion with the Pipeline embolization device (PED) for the treatment of tandem aneurysms in a single session at 2 participating medical centers: University of Utah, Salt Lake City, Utah, and Barrow Neurological Institute, Phoenix, Arizona. Patient demographic data, aneurysm characteristics, treatment strategy and results, complications, and follow-up data were collected from the medical record and analyzed. RESULTS Between January 2011 and December 2015, 17 patients (12 female, 5 male) with a total of 38 aneurysms (mean size 4.7 +/- 2.7 mm, mean +/- SD) were treated. Sixteen patients had aneurysms in the anterior circulation, and 1 patient had tandem aneurysms in the posterior circulation. Twelve patients underwent only placement of a PED, whereas 5 underwent adjunctive coil embolization of at least 1 aneurysm. One PED was used in each of 9 patients, and 2 PEDs were required in each of 8 patients. There were 2 intraprocedural complications; however, in both instances, the patients were asymptomatic at the last follow-up. The follow-up imaging studies were available for 15 patients at a mean of 7 months after treatment (216 days, range 0-540 days). The mean initial Raymond score after treatment was 2.7 +/- 0.7, and the mean final score was 1.3 +/- 0.7. CONCLUSIONS In this series, the use of flow diversion for the treatment of tandem cerebral aneurysms had an acceptable safety profile, indicating that it should be considered as an effective therapy for this complicated subset of patients. Further prospective studies must be performed before more definitive conclusions can be made. PMID- 28565980 TI - Update on flow diverters for the endovascular management of cerebral aneurysms. AB - Flow diversion has become a well-accepted option for the treatment of cerebral aneurysms. Given the significant treatment effect of flow diverters, numerous options have emerged since the initial Pipeline embolization device studies. In this review, the authors describe the available flow diverters, both endoluminal and intrasaccular, addressing nuances of device design and function and presenting data on complications and outcomes, where available. They also discuss possible future directions of flow diversion. PMID- 28565981 TI - Complications associated with the use of flow-diverting devices for cerebral aneurysms: a systematic review and meta-analysis. AB - OBJECTIVE The objective of this study was to review the literature on the use of flow-diverting devices (FDDs) to treat intracranial aneurysms (IAs) and to investigate the safety and complications related to FDD treatment for IAs by performing a meta-analysis of published studies. METHODS A systematic electronic database search was conducted using the Springer, EBSCO, PubMed, Medline, and Cochrane databases on all accessible articles published up to January 2016, with no restriction on the publication year. Abstracts, full-text manuscripts, and the reference lists of retrieved articles were analyzed. Random-effects meta-analysis was used to pool the complication rates across studies. RESULTS Sixty studies were included, which involved retrospectively collected data on 3125 patients. The use of FDDs was associated with an overall complication rate of 17.0% (95% confidence interval [CI] 13.6%-20.5%) and a low mortality rate of 2.8% (95% CI 1.2%-4.4%). The neurological morbidity rate was 4.5% (95% CI 3.2%-5.8%). No significant difference in the complication or mortality rate was observed between 2 commonly used devices (the Pipeline embolization device and the Silk flow diverter device). A significantly higher overall complication rate was found in the case of ruptured IAs than in unruptured IA (odds ratio 2.3, 95% CI 1.2-4.3). CONCLUSIONS The use of FDDs in the treatment of IAs yielded satisfactory results with regard to complications and the mortality rate. The risk of complications should be considered when deciding on treatment with FDDs. Further studies on the mechanism underlying the occurrence of adverse events are required. PMID- 28565982 TI - Introduction. The treatment of cerebral aneurysms: flow diversion and beyond. PMID- 28565983 TI - Vision outcomes in patients with paraclinoid aneurysms treated with clipping, coiling, or flow diversion: a systematic review and meta-analysis. AB - OBJECTIVE Patients with paraclinoid aneurysms commonly present with visual impairment. They have traditionally been treated with clipping or coiling, but flow diversion (FD) has recently been introduced as an alternative treatment modality. Although there is still initial aneurysm thrombosis, FD is hypothesized to reduce mass effect, which may decompress the optic nerve when treating patients with visually symptomatic paraclinoid aneurysms. The authors performed a meta-analysis to compare vision outcomes following clipping, coiling, or FD of paraclinoid aneurysms in patients who presented with visual impairment. METHODS A systematic literature review was performed using the PubMed and Web of Science databases. Studies published in English between 1980 and 2016 were included if they reported preoperative and postoperative visual function in at least 5 patients with visually symptomatic paraclinoid aneurysms (cavernous segment through ophthalmic segment) treated with clipping, coiling, or FD. Neuroophthalmological assessment was used when reported, but subjective patient reports or objective visual examination findings were also acceptable. RESULTS Thirty-nine studies that included a total of 2458 patients (520 of whom presented with visual symptoms) met the inclusion criteria, including 307 visually symptomatic cases treated with clipping (mean follow-up 26 months), 149 treated with coiling (mean follow-up 17 months), and 64 treated with FD (mean follow-up 11 months). Postoperative vision in these patients was classified as improved, unchanged, or worsened compared with preoperative vision. A pooled analysis showed preoperative visual symptoms in 38% (95% CI 28%-50%) of patients with paraclinoid aneurysms. The authors found that vision improved in 58% (95% CI 48% 68%) of patients after clipping, 49% (95% CI 38%-59%) after coiling, and 71% (95% CI 55%-84%) after FD. Vision worsened in 11% (95% CI 7%-17%) of patients after clipping, 9% (95% CI 2%-18%) after coiling, and 5% (95% CI 0%-20%) after FD. New visual deficits were found in patients with intact baseline vision at a rate of 1% (95% CI 0%-3%) for clipping, 0% (95% CI 0%-2%) for coiling, and 0% (95% CI 0% 2%) for FD. CONCLUSIONS To the authors' knowledge, this is the first meta analysis to assess vision outcomes after treatment for paraclinoid aneurysms. The authors found that 38% of patients with these aneurysms presented with visual impairment. These data also demonstrated a high rate of visual improvement after FD without a significant difference in the rate of worsened vision or iatrogenic visual impairment compared with clipping and coiling. These findings suggest that FD is an effective option for treatment of visually symptomatic paraclinoid aneurysms. PMID- 28565984 TI - Novel use of flow diversion for the treatment of aneurysms associated with arteriovenous malformations. AB - The use of flow-diverting stents for intracranial aneurysms has become more prevalent, and flow diverters are now routinely used beyond their initial scope of approval at the proximal internal carotid artery. Although flow diversion for the treatment of cerebral aneurysms is becoming more commonplace, there have been no reports of its use to treat flow-related cerebral aneurysms associated with arteriovenous malformations (AVMs). The authors report the cases of 2 patients whose AVM-associated aneurysms were managed with flow diversion. A 40-year-old woman presented with a history of headaches that led to the identification of an unruptured Spetzler-Martin Grade V, right parietooccipital AVM associated with 3 aneurysms of the ipsilateral internal carotid artery. Initial attempts at balloon assisted coil embolization of the aneurysms were unsuccessful. The patient underwent placement of a flow-diverting stent across the diseased vessel; a 6 month follow-up angiogram demonstrated complete occlusion of the aneurysms. In the second case, a 57-year-old man presented with new-onset seizures, and an unruptured Spetzler-Martin Grade V, right frontal AVM associated with an irregular, wide-necked anterior communicating artery aneurysm was identified. The patient underwent placement of a flow-diverting stent, and complete occlusion of the aneurysm was observed on a 7-month follow-up angiogram. These 2 cases illustrate the potential for use of flow diversion as a treatment strategy for feeding artery aneurysms associated with AVMs. Because of the need for dual antiplatelet medications after flow diversion in this patient population, however, this strategy should be used judiciously. PMID- 28565985 TI - Endovascular management of fusiform aneurysms in the posterior circulation: the era of flow diversion. AB - Fusiform aneurysms are uncommon compared with their saccular counterparts, yet they remain very challenging to treat and are associated with high rates of rebleeding and morbidity. Lack of a true aneurysm neck renders simple clip reconstruction or coil embolization usually impossible, and more advanced techniques are required, including bypass, stent-assisted coiling, and, more recently, flow diversion. In this article, the authors review posterior circulation fusiform aneurysms, including pathogenesis, natural history, and endovascular treatment, including the role of flow diversion. In addition, the authors propose an algorithm for treatment based on their practice. PMID- 28565986 TI - Pipeline embolization device versus coiling for the treatment of large and giant unruptured intracranial aneurysms: a cost-effectiveness analysis. AB - OBJECTIVE Rupture of large or giant intracranial aneurysms leads to significant morbidity, mortality, and health care costs. Both coiling and the Pipeline embolization device (PED) have been shown to be safe and clinically effective for the treatment of unruptured large and giant intracranial aneurysms; however, the relative cost-to-outcome ratio is unknown. The authors present the first cost effectiveness analysis to compare the economic impact of the PED compared with coiling or no treatment for the endovascular management of large or giant intracranial aneurysms. METHODS A Markov model was constructed to simulate a 60 year-old woman with a large or giant intracranial aneurysm considering a PED, endovascular coiling, or no treatment in terms of neurological outcome, angiographic outcome, retreatment rates, procedural and rehabilitation costs, and rupture rates. Transition probabilities were derived from prior literature reporting outcomes and costs of PED, coiling, and no treatment for the management of aneurysms. Cost-effectiveness was defined, with the incremental cost effectiveness ratios (ICERs) defined as difference in costs divided by the difference in quality-adjusted life years (QALYs). The ICERs < $50,000/QALY gained were considered cost-effective. To study parameter uncertainty, 1-way, 2 way, and probabilistic sensitivity analyses were performed. RESULTS The base-case model demonstrated lifetime QALYs of 12.72 for patients in the PED cohort, 12.89 for the endovascular coiling cohort, and 9.7 for patients in the no-treatment cohort. Lifetime rehabilitation and treatment costs were $59,837.52 for PED; $79,025.42 for endovascular coiling; and $193,531.29 in the no-treatment cohort. Patients who did not undergo elective treatment were subject to increased rates of aneurysm rupture and high treatment and rehabilitation costs. One-way sensitivity analysis demonstrated that the model was most sensitive to assumptions about the costs and mortality risks for PED and coiling. Probabilistic sampling demonstrated that PED was the cost-effective strategy in 58.4% of iterations, coiling was the cost-effective strategy in 41.4% of iterations, and the no-treatment option was the cost-effective strategy in only 0.2% of iterations. CONCLUSIONS The authors' cost-effective model demonstrated that elective endovascular techniques such as PED and endovascular coiling are cost-effective strategies for improving health outcomes and lifetime quality of life measures in patients with large or giant unruptured intracranial aneurysm. PMID- 28565987 TI - Prolapse of the Pipeline embolization device in aneurysms: incidence, management, and outcomes. AB - OBJECTIVE The Pipeline embolization device (PED) is frequently used in the treatment of anterior circulation aneurysms, especially around the carotid siphon, with generally excellent results. However, the PED has its own unique technical challenges, including the occurrence of device foreshortening or migration leading to prolapse into the aneurysm. The authors sought to determine the incidence of this phenomenon, the rescue strategies, and outcomes. METHODS Four institutional databases of neuroendovascular procedures were reviewed for cases of intracranial aneurysms treated with PEDs. Patient and aneurysm data as well as angiographic imaging were reviewed for all cases involving device prolapse into the aneurysm. RESULTS A total of 413 intracranial aneurysms were treated with PEDs during the study period, by 5 neurointerventionalists. Large and giant aneurysms (>= 2 cm) accounted for 32 of these aneurysms. Among these 32 PEDs, prolapse into the aneurysm occurred in 3 patients, with 1 of these PEDs successfully rescued and the other 2 left in situ. No patients suffered any severe complications. The 2 patients in whom the PEDs were left in situ remained on antiplatelet therapy. CONCLUSIONS The PED may foreshorten or migrate during or after deployment, leading to prolapse into the aneurysm. This phenomenon appears to be associated with large and giant aneurysms, vessel tortuosity, short landing zones, and use of balloon angioplasty. Future study and follow-up is needed to further evaluate this phenomenon, but some of the observations and techniques described in this paper may help to prevent or salvage prolapsed devices. PMID- 28565988 TI - Postprocedural, midterm, and long-term results of cerebral aneurysms treated with flow-diverter devices: 7-year experience at a single center. AB - OBJECTIVE Flow diversion has emerged as a viable treatment option for selected intracranial aneurysms and recently has been gaining traction. The aim of this study was to evaluate the safety and effectiveness of flow-diverter devices (FDDs) over a long-term follow-up period. METHODS The authors retrospectively reviewed all cerebral aneurysm cases that had been admitted to the Division of Neurosurgery of the Universita degli Studi di Napoli between November 2008 and November 2015 and treated with an FDD. The records of 60 patients (48 females and 12 males) harboring 69 cerebral aneurysms were analyzed. The study end points were angiographic evidence of complete aneurysm occlusion, recanalization rate, occlusion of the parent artery, and clinical and radiological evidence of brain ischemia. The occlusion rate was evaluated according to the O'Kelly-Marotta (OKM) Scale for flow diversion, based on the degree of filling (A, total filling; B, subtotal filling; C, entry remnant; D, no filling). Postprocedural, midterm, and long-term results were strictly analyzed. RESULTS Complete occlusion (OKM D) was achieved in 63 (91%) of 69 aneurysms, partial occlusion (OKM C) in 4 (6%), occlusion of the parent artery in 2 (3%). Intraprocedural technical complications occurred in 3 patients (5%). Postprocedural complications occurred in 6 patients (10%), without neurological deficits. At the 12-month follow-up, 3 patients (5%) experienced asymptomatic cerebral infarction. No further complications were observed at later follow-up evaluations (> 24 months). There were no reports of any delayed aneurysm rupture, subarachnoid or intraparenchymal hemorrhage, ischemic complications, or procedure- or device-related deaths. CONCLUSIONS Endovascular treatment with an FDD is a safe treatment for unruptured cerebral aneurysms, resulting in a high rate of occlusion. In the present study, the authors observed effective and stable aneurysm occlusion, even at the long-term follow-up. Data in this study also suggest that ischemic complications can occur at a later stage, particularly at 12-18 months. On the other hand, no other ischemic or hemorrhagic complications occurred beyond 24 months. PMID- 28565989 TI - Pipeline embolization device for recurrence of previously treated aneurysms. AB - OBJECTIVE The utilization of the Pipeline embolization device (PED) has increased significantly since its inception and original approval for use in large, broad necked aneurysms of the internal carotid artery. While microsurgical clipping and advances in endovascular techniques have improved overall efficacy in achieving complete occlusion, recurrences still occur, and the best modality for retreatment remains controversial. Despite its efficacy in this setting, the role of PED utilization in the setting of recurrent aneurysms has not yet been well defined. This study was designed to assess the safety and efficacy of PED in the recurrence of previously treated aneurysms. METHODS The authors reviewed a total of 13 cases in which patients underwent secondary placement of a PED for aneurysm recurrence following prior treatment with another modality. The PEDs were used to treat aneurysm recurrence or residual following endovascular coiling in 7 cases, flow diversion in 2, and microsurgical clipping in 4. The mean time between initial treatment and retreatment with a PED was 28.1 months, 12 months, and 88.7 months, respectively. Clinical outcomes, including complications and modified Rankin Scale (mRS) scores, and angiographic evidence of complete occlusion were tabulated for each treatment group. RESULTS All PEDs were successfully placed without periprocedural complications. The rate of complete occlusion was 80% at 6 months after PED placement and 100% at 12 months in these patients who underwent PED placement following failed endovascular coiling; there were no adverse clinical sequelae at a mean follow-up of 26.1 months. In the 2 cases in which PEDs were placed for treatment of residual aneurysms following prior flow diversion, 1 patient demonstrated asymptomatic vessel occlusion at 6 months, and the other exhibited complete aneurysm occlusion at 12 months. In patients with aneurysm recurrence following prior microsurgical clipping, the rate of complete occlusion was 100% at 6 and 12 months, with no adverse sequelae noted at a mean clinical follow-up of 27.7 months. CONCLUSIONS The treatment of recurrent aneurysms with the PED following previous endovascular coiling, flow diversion, or microsurgical clipping is associated with a high rate of complete occlusion and minimal morbidity. PMID- 28565990 TI - Transcirculation Pipeline embolization device deployment: a rescue technique. AB - The Pipeline embolization device (PED) has become a very important tool in the treatment of nonruptured cerebral aneurysms. However, a patient's difficult anatomy or vascular stenosis may affect the device delivery. The purpose of this article was to describe an alternate technique for PED deployment when ipsilateral anatomy is not amenable for catheter navigation. A 44-year-old woman with a symptomatic 6-mm right superior hypophyseal artery aneurysm and a known history of right internal carotid artery dissection presented for PED treatment of her aneurysm. An angiogram showed persistence of the arterial dissection with luminal stenosis after 6 months of dual antiplatelet treatment. The contralateral internal carotid artery was catheterized and the PED was deployed via a transcirculation approach, using the anterior communicating artery. Transcirculation deployment of a PED is a viable option when ipsilateral anatomy is difficult or contraindicated for this treatment. PMID- 28565991 TI - Platelet testing in flow diversion: a review of the evidence. AB - OBJECTIVE Although the use of dual antiplatelet therapy with flow diversion is recommended and commonplace, the testing of platelet inhibition is more controversial. METHODS The authors reviewed the medical literature to establish and describe the physiology of platelet adhesion, the pharmacology of antiplatelet medications, and the mechanisms of the available platelet function tests. Additionally, they present a review of the pertinent neurointerventional and interventional cardiology literature. RESULTS Competing reports in the neurointerventional literature argue for and against the use of routine platelet function testing, with adjustments to the dosage or medications based on the results. The interventional cardiology literature has also wrestled with this dilemma after percutaneous coronary interventions, with conflicting reports of the benefits of platelet function testing. CONCLUSIONS Despite its prevalence, the benefits of platelet function testing prior to flow diversion are unproven. This practice will likely remain controversial until the level of evidence improves through more rigorous testing and reporting. PMID- 28565992 TI - Pipeline flow diversion of ruptured blister aneurysms of the supraclinoid carotid artery using a single-device strategy. AB - OBJECTIVE Ruptured blister aneurysms remain challenging lesions for treatment due to their broad, shallow anatomy and thin, fragile wall. Historical challenges with both open microsurgical approaches and intrasaccular endovascular approaches have led to increased use of flow diversion for management of these aneurysms. However, the optimum paradigm, including timing of treatment, use of dual antiplatelet therapy, and number of flow-diverter devices to use remains unknown. The authors describe their experience with ruptured blister aneurysms treated with flow diversion at their institution, and discuss rates of rebleeding and number of devices used. METHODS All patients presenting with subarachnoid hemorrhage from a ruptured blister aneurysm and treated with Pipeline flow diversion were identified. Patient demographic data, clinical status and course, need for external ventricular drain (EVD), timing of treatment, and angiographic details and follow-up were recorded. RESULTS There were 13 patients identified (11 women and 2 men), and 4 had multiple aneurysms. Two aneurysms were treated on initial angiography, with average time to treatment of 3.1 days for the remainder, after discussion with the family and institution of dual antiplatelet therapy. Device placement was technically successful in all patients, with 2 patients receiving 2 devices and the remainder receiving 1 device. There was 1 intraoperative complication, of a wire perforation causing intracerebral hemorrhage requiring decompressive craniectomy. Three patients had required EVD placement for management of hydrocephalus. There was no rebleeding from the target lesion; however, one patient had worsening intraventricular hemorrhage and another had rupture of an unrecognized additional aneurysm, and both died. Of the other 11 patients, 10 made a good recovery, with 1 remaining in a vegetative state. Nine underwent follow-up angiography, with 5 achieving complete occlusion, 2 with reduced aneurysm size, and 2 requiring retreatment for aneurysm persistence or enlargement. There were no episodes of delayed rupture. CONCLUSIONS Pipeline flow diversion is a technically feasible and effective treatment for ruptured blister aneurysms, particularly in good-grade patients without hydrocephalus. Patients with a worse grade on presentation and requiring EVDs may have higher risk for bleeding complications and poor outcome. There was no rebleeding from the target lesion with use of a single device in this series. PMID- 28565993 TI - Use of the Pipeline embolization device in the treatment of iatrogenic intracranial vascular injuries: a bi-institutional experience. AB - OBJECTIVE Flow-diverting devices have been used for the treatment of complex intracranial vascular pathology with success, but the role of these devices in treating iatrogenic intracranial vascular injuries has yet to be clearly defined. Here, the authors report their bi-institutional experience with the use of the Pipeline embolization device (PED) for the treatment of iatrogenic intracranial vascular injuries. METHODS The authors reviewed a retrospective cohort of patients with iatrogenic injuries to the intracranial vasculature that were treated with the PED between 2012 and 2016. Data collection included demographic data, indications for treatment, number and sizes of PEDs used, and immediate and follow-up angiographic and clinical outcomes. RESULTS Four patients with a mean age of 47.5 years (range 18-63 years) underwent PED placement for iatrogenic vessel injuries. In 3 patients, the intracranial internal carotid artery (ICA) was injured during transnasal tumor resection. In 1 patient, a basilar apex injury occurred during endoscopic third ventriculostomy. Three patients had a pseudoaneurysm as a result of vessel injury, and 1 patient had frank ICA laceration and extravasation. All 3 pseudoaneurysms were successfully treated with PED deployment. The ICA laceration was refractory to PED placement, and the vessel was subsequently occluded endovascularly. All 4 patients had a good clinical outcome (modified Rankin Scale score of 0 or 1). CONCLUSIONS The use of the PED is feasible in the management of iatrogenic pseudoaneurysms of the intracranial vasculature. In cases of frank vessel perforation, an alternative strategy such as covered stent placement should be considered. Endovascular or surgical vessel occlusion remains the definitive treatment in cases of refractory hemorrhage. PMID- 28565994 TI - The effects of silver nanoparticles on behavior, apoptosis and nitro-oxidative stress in offspring Wistar rats. AB - AIM: To investigate the comparative effects of prenatal exposure to silver nanoparticles (AgNPs) functionalized with citrate and polyphenols on spatial cognition and also on nitro-oxidative stress and apoptosis in the hippocampus and cerebellum of offsprings. MATERIALS & METHODS: Pregnant Wistar rats were orally administered substances from day 10 of gestation until day 21. Six weeks postpartum, six male offsprings from each group were used for behavioral evaluation and determination of oxidative stress and apoptosis. RESULTS: Both groups exhibited hyperactivity and anxiety especially after AgNPs-Sambucus nigra L. administration. AgNPs-S. nigra L. group showed increase in induced nitric oxide synthase activity and decrease in superoxide dismutase activity and apoptosis in the hippocampus, while AgNPs-citrate coated administration exerted a moderate toxicity and induced apoptosis. CONCLUSION: AgNPs functionalized with natural extracts had a lower toxicity than citrate-coated silver particles. PMID- 28565995 TI - Intervention study on school meal habits in Norwegian 10-12-year-old children. AB - AIM: The aim of this study was to investigate whether a free school meal every day was associated with children's intake of healthy food during school. METHODS: A non-randomized study design with an intervention and a control group was used to measure change in children's meal habits at lunchtime. In total, 164 children participated; 55 in the intervention group and 109 in the control group. Children in the intervention group were served a free, healthy school meal every school day. Participating children completed a questionnaire at baseline and at 6 months' follow up. Possible associations were evaluated with a healthy food score, which was calculated based on a food frequency questionnaire on lunch habits at school. Chi-square and Independent Samples t-test were used to analyse the data. RESULTS: At baseline, there was no significant difference in the healthy food score between the intervention and the control group ( p = 0.08). Children in the intervention group increased their healthy food score significantly compared with children in the control group after 6 months ( p ? 0.01). Change in the healthy food score was mainly due to an increase in the intake of fruit ( p ? 0.01), vegetables ( p ? 0.01) and fish spread ( p = 0.02); all in favour of the intervention group. CONCLUSIONS: A serving of a free school meal every day for 6 months increased children's intake of healthy food at lunchtime compared with the control group. Further studies are needed to establish possible long-term effects. PMID- 28565996 TI - Task utility and norms for the Preschool Executive Task Assessment (PETA). AB - Earlier identification of executive deficits in preschool children using an ecological approach would give more scope for intervention. The Preschool Executive Task Assessment (PETA) was developed to resemble an everyday age appropriate task in order to examine the self-direction and integration of executive functions during a multistep task. It was designed so that performance can be evaluated in a microanalytic way and so individualized feedback and support can be easily communicated. The utility of the PETA was assessed with 166 three-to five-year olds. Results showed improved performance with increasing age and verbal intellectual quotient as well as good task reliability and utility. Evidence for influence of socioeconomic status, gender, and use of self-talk was also observed. Clinical applications and future directions of this novel measure are discussed. PMID- 28565997 TI - Safety of radiofrequency ablation of benign thyroid nodules and recurrent thyroid cancers: a systematic review and meta-analysis. AB - OBJECTIVE: We performed a systematic review and meta-analysis to evaluate the safety of radiofrequency ablation (RFA) for the treatment of benign thyroid nodules and recurrent thyroid cancers. MATERIALS AND METHODS: Ovid-MEDLINE, EMBASE, and Library of Cochrane databases were searched up to 12 July 2016 for studies on the safety of RFA for treating benign thyroid nodules or recurrent thyroid cancers. Pooled proportions of overall and major complications were assessed using random-effects modelling. Heterogeneity among studies was determined using the chi2 statistic for the pooled estimates and the inconsistency index I2. RESULTS: A total of 24 eligible studies were included, giving a sample size of 2421 patients and 2786 thyroid nodules. 41 major complications and 48 minor complications of RFA were reported, giving a pooled proportion of 2.38% for overall RFA complications [95% confidence interval (CI): 1.42%-3.34%] and 1.35% for major RFA complications (95% CI: 0.89%-1.81%). There were no heterogeneities in either overall or major complications (I2 = 1.24% 21.79%). On subgroup analysis, the overall and major complication rates were significantly higher for malignant thyroid nodules than for benign thyroid nodules (p = 0.0011 and 0.0038, respectively). CONCLUSIONS: RFA was found to be safe for the treatment of benign thyroid nodules and recurrent thyroid cancers. PMID- 28565999 TI - Ryk receptors on unmyelinated nerve fibers mediate excitatory synaptic transmission and CCL2 release during neuropathic pain induced by peripheral nerve injury. AB - Background Neuropathic pain is a major pathology of the central nervous system associated with neuroinflammation. Ryk (receptor-like tyrosine kinase) receptors act as repulsive axon-guidance molecules during development of central nervous system and neural injury. Increasing evidence suggests the potential involvement of Wnt/Ryk (wingless and Int) signaling in the pathogenesis of neuropathic pain. However, its underlying mechanism remains unknown. Results The expression and location of Ryk receptor as well as its ligand Wnt1 were detected by qPCR, Western blot, and immunohistochemistry. We found that Ryk, a specific Wnt receptor, was expressed in IB4+ (Isolectin B4) and CGRP+ (calcitonin gene-related peptide) dorsal root ganglia neurons and their ascending unmyelinated fibers in the dorsal horn of the spinal cord. Ryk was upregulated after spinal nerve ligation surgery. Wnt1 was also increased in activated astrocytes in the dorsal horn after spinal nerve ligation. The presynaptic mechanism of Ryk in regulation of neuropathic pain was determined by electrophysiology in spinal slice. Spinal nerve ligation model was established, and the therapeutic potential of inhibiting Ryk receptor was determined. Spine-specific blocking of the Wnt/Ryk receptor signaling attenuated the spinal nerve ligation-induced mechanical allodynia but not thermal hyperalgesia. Further, it also blocked Ca2+-dependent signals including CaMKII and PKCgamma, subsequent release of CCL2 (CCR-like protein) in the dorsal horn. An in vitro study showed that inactivating Ryk receptors with anti-Ryk antibodies or lentiviral Ryk shRNA led to the inactivation of Wnt1 for excitatory synaptic transmission in spinal slices and subsequent decrease in CCL2 expression in the dorsal root ganglia neurons. Conclusion These studies demonstrate the existence of critical crosstalk between astrocytes and unmyelinated fibers, which indicate the presynaptic mechanism of Ryk in cytokine transmission of neuropathic pain and the therapeutic potential for Wnt/Ryk signaling pathway in the treatment of neuropathic pain. PMID- 28565998 TI - GABAB receptors-mediated tonic inhibition of glutamate release from Abeta fibers in rat laminae III/IV of the spinal cord dorsal horn. AB - Presynaptic GABAB receptors (GABABRs) are highly expressed in dorsal root ganglion neurons and spinal cord dorsal horn. GABABRs located in superficial dorsal horn play an important antinociceptive role, by acting at both pre- and postsynaptic sites. GABABRs expressed in deep dorsal horn could be involved in the processing of touch sensation and possibly in the generation of tactile allodynia in chronic pain. The objective of this study was to characterize the morphological and functional properties of GABABRs expressed on Abeta fibers projecting to lamina III/IV and to understand their role in modulating excitatory synaptic transmission. We performed high-resolution electron microscopic analysis, showing that GABAB2 subunit is expressed on 71.9% of terminals in rat lamina III-IV. These terminals were engaged in axodendritic synapses and, for the 46%, also expressed glutamate immunoreactivity. Monosynaptic excitatory postsynaptic currents, evoked by Abeta fiber stimulation and recorded from lamina III/IV neurons in spinal cord slices, were strongly depressed by application of baclofen (0.1-2.5 uM), acting as a presynaptic modulator. Application of the GABABR antagonist CGP 55845 caused, in a subpopulation of neurons, the potentiation of the first of two excitatory postsynaptic currents recorded with the paired-pulse protocol, showing that GABABRs are endogenously activated. A decrease in the paired-pulse ratio accompanied the effect of CGP 55845, implying the involvement of presynaptic GABABRs. CGP 55845 facilitated only the first excitatory postsynaptic current also during a train of four consecutive stimuli applied to Abeta fibers. These results suggest that GABABRs tonically inhibit glutamate release from Abeta fibers at a subset of synapses in deep dorsal horn. This modulation specifically affects only the early phase of synaptic excitation in lamina III-IV neurons. PMID- 28566001 TI - Exploring encapsulation mechanism of DNA and mononucleotides in sol-gel derived silica. AB - The encapsulation mechanism of DNA in sol-gel derived silica has been explored in order to elucidate the effect of DNA conformation on encapsulation and to identify the nature of chemical/physical interaction of DNA with silica during and after sol-gel transition. In this respect, double stranded DNA and dAMP (2' deoxyadenosine 5'-monophosphate) were encapsulated in silica using an alkoxide based sol-gel route. Biomolecule-encapsulating gels have been characterized using UV-Vis, 29Si NMR, FTIR spectroscopy and gas adsorption (BET) to investigate chemical interactions of biomolecules with the porous silica network and to examine the extent of sol-gel reactions upon encapsulation. Ethidium bromide intercalation and leach out tests showed that helix conformation of DNA was preserved after encapsulation. For both biomolecules, high water-to-alkoxide ratio promoted water-producing condensation and prevented alcoholic denaturation. NMR and FTIR analyses confirmed high hydraulic reactivity (water adsorption) for more silanol groups-containing DNA and dAMP encapsulated gels than plain silica gel. No chemical binding/interaction occurred between biomolecules and silica network. DNA and dAMP encapsulated silica gelled faster than plain silica due to basic nature of DNA or dAMP containing buffer solutions. DNA was not released from silica gels to aqueous environment up to 9 days. The chemical association between DNA/dAMP and silica host was through phosphate groups and molecular water attached to silanols, acting as a barrier around biomolecules. The helix morphology was found not to be essential for such interaction. BET analyses showed that interconnected, inkbottle-shaped mesoporous silica network was condensed around DNA and dAMP molecules. PMID- 28566000 TI - Peripheral KV7 channels regulate visceral sensory function in mouse and human colon. AB - Background Chronic visceral pain is a defining symptom of many gastrointestinal disorders. The KV7 family (KV7.1-KV7.5) of voltage-gated potassium channels mediates the M current that regulates excitability in peripheral sensory nociceptors and central pain pathways. Here, we use a combination of immunohistochemistry, gut-nerve electrophysiological recordings in both mouse and human tissues, and single-cell qualitative real-time polymerase chain reaction of gut-projecting sensory neurons, to investigate the contribution of peripheral KV7 channels to visceral nociception. Results Immunohistochemical staining of mouse colon revealed labelling of KV7 subtypes (KV7.3 and KV7.5) with CGRP around intrinsic enteric neurons of the myenteric plexuses and within extrinsic sensory fibres along mesenteric blood vessels. Treatment with the KV7 opener retigabine almost completely abolished visceral afferent firing evoked by the algogen bradykinin, in agreement with significant co-expression of mRNA transcripts by single-cell qualitative real-time polymerase chain reaction for KCNQ subtypes and the B2 bradykinin receptor in retrogradely labelled extrinsic sensory neurons from the colon. Retigabine also attenuated responses to mechanical stimulation of the bowel following noxious distension (0-80 mmHg) in a concentration-dependent manner, whereas the KV7 blocker XE991 potentiated such responses. In human bowel tissues, KV7.3 and KV7.5 were expressed in neuronal varicosities co-labelled with synaptophysin and CGRP, and retigabine inhibited bradykinin-induced afferent activation in afferent recordings from human colon. Conclusions We show that KV7 channels contribute to the sensitivity of visceral sensory neurons to noxious chemical and mechanical stimuli in both mouse and human gut tissues. As such, peripherally restricted KV7 openers may represent a viable therapeutic modality for the treatment of gastrointestinal pathologies. PMID- 28566002 TI - A two-stage cold isostatic pressing and gelling approach for fabricating a therapeutically loaded amorphous calcium polyphosphate local delivery system. AB - Local delivery systems have taken on a greater clinical focus for osteomyelitis therapy owing to their ability to overcome many disadvantages of systemic delivery. This study reports for the first time the capacity to fabricate strontium- and vancomycin-doped calcium polyphosphate beads using a two-stage cold isostatic pressing and gelling approach. The fabricated beads were of uniform shape and diameter, and upon gelling exhibited reduced porosity. Of greatest significance in the subsequent in vitro study was the improvement of bead long-term structural stability upon vancomycin incorporation; a characteristic that further encourages the extended release of therapeutically relevant levels of antibiotic. Overall, this study provides support for the inclusion of a cold isostatic pressing step in the fabrication of a therapeutically loaded calcium polyphosphate bead-based local delivery system intended for osteomyelitis treatment. PMID- 28566004 TI - Prevention of heart failure mortality and hospitalizations in SPRINT, EMPA-REG, ALLHAT and HYVET: are diuretics the clue? PMID- 28566003 TI - Memory and executive functions correlates of self-awareness in traumatic brain injury. AB - OBJECTIVE: The purpose of this study was to investigate the contribution of executive functions (EF) components and episodic and working memory variables, as well as clinical and demographic factors, to awareness of cognitive ability in traumatic brain injury (TBI). METHODS: Sixty-five TBI patients (mild: n = 26; moderate/severe: n = 39) took part in the study. Independent stepwise regression models were calculated for EF and memory predictors, with awareness being measured by patient/informant discrepancy in the Patient Competency Rating Scale. RESULTS: Models with EF variables indicated that semantic verbal fluency and age are the best predictors of awareness, whereas models including mnemonic functions suggested verbal delayed episodic recall and TBI severity as predictors. CONCLUSIONS: These results are discussed in relation to clinical implications, such as the need to focus efforts of rehabilitation in the cognitive abilities related to awareness, and theoretical models. PMID- 28566005 TI - Solid-state fermentation and composting as alternatives to treat hair waste: A life-cycle assessment comparative approach. AB - One of the wastes associated with leather production in tannery industries is the hair residue generated during the dehairing process. Hair wastes are mainly dumped or managed through composting but recent studies propose the treatment of hair wastes through solid-state fermentation (SSF) to obtain proteases and compost. These enzymes are suitable for its use in an enzymatic dehairing process, as an alternative to the current chemical dehairing process. In the present work, two different scenarios for the valorization of the hair waste are proposed and assessed by means of life-cycle assessment: composting and SSF for protease production. Detailed data on hair waste composting and on SSF protease production are gathered from previous studies performed by our research group and from a literature survey. Background inventory data are mainly based on Ecoinvent version 3 from software SimaPro(r) 8. The main aim of this study was to identify which process results in the highest environmental impact. The SSF process was found to have lower environmental impacts than composting, due to the fact that the enzyme use in the dehairing process prevents the use of chemicals traditionally used in the dehairing process. This permits to reformulate an industrial process from the classical approach of waste management to a novel alternative based on circular economy. PMID- 28566006 TI - Arousal (but not valence) amplifies the impact of salience. AB - Previous findings indicate that negative arousal enhances bottom-up attention biases favouring perceptual salient stimuli over less salient stimuli. The current study tests whether those effects were driven by emotional arousal or by negative valence by comparing how well participants could identify visually presented letters after hearing either a negative arousing, positive arousing or neutral sound. On each trial, some letters were presented in a high contrast font and some in a low contrast font, creating a set of targets that differed in perceptual salience. Sounds rated as more emotionally arousing led to more identification of highly salient letters but not of less salient letters, whereas sounds' valence ratings did not impact salience biases. Thus, arousal, rather than valence, is a key factor enhancing visual processing of perceptually salient targets. PMID- 28566007 TI - Aging With a Physical Disability in Medicaid Managed Care. AB - This study examines health services appraisal (HSA) and unmet health-care needs for adults (age 50 and over) with physical disabilities in Medicaid managed care (MMC) versus Medicaid fee for service (FFS). Surveys from 309 individuals in MMC and 349 in FFS 2 years after MMC implementation included demographics, MMC processes, HSA, and unmet health-care needs. Regression analyses with HSA and unmet health-care needs as outcomes included demographics and group status (MMC or FFS) for the entire sample, and demographics and MMC processes (continuity of care, experience with care coordinators and primary care physicians) as independent variables for only MMC enrollees. Group status was not associated with HSA or unmet needs. Among MMC enrollees, better health and more positive MMC processes related to higher HSA and lower unmet needs. It is important to consider the perspectives of people aging with disabilities in MMC to better serve their needs. PMID- 28566008 TI - Aging With Disability: Advancement of a Cross-Disciplinary Research Network. PMID- 28566009 TI - Health and Health-Care Utilization of the Older Population of Ireland: Comparing the Intellectual Disability Population and the General Population. AB - BACKGROUND/OBJECTIVES: Largely unresearched are the similarities and differences compared to the general population in the aging of people with an intellectual disability (ID). Data reported here compare the health and health-care utilization of the general aging population in Ireland with those who are aging with ID. DESIGN: Data for comparisons were drawn from the 2010 The Irish Longitudinal Study on Ageing (TILDA) and the Intellectual Disability Supplement (IDS)-TILDA Wave 1 data sets. SETTING: TILDA participants were community dwelling only while IDS-TILDA participants were drawn from community and institutional settings. PARTICIPANTS: TILDA consists of a sample of 8,178 individuals aged 50 years and older who were representative of the Irish population. The IDS-TILDA consists of a random sample of 753 persons aged 40 and older. Using age 50 as the initial criterion, 478 persons with ID were matched with TILDA participants on age, sex, and geographic location to create the sample for this comparison. MEASUREMENTS: Both studies gathered self-reported data on physical and mental health, behavioral health, functional limitations, and health-care utilization. RESULTS: Rates of chronic disease appeared higher overall for people with ID as compared to the general population. There were also age-related differences in the prevalence of diabetes and cancer and different rates of engagement between the two groups in relevant behavioral health activities such as smoking. There were higher utilization levels among IDS-TILDA participants for allied health and general practitioner visits. CONCLUSION: Different disease trajectories found among IDS-TILDA participants raise concerns. The longitudinal comparison of data for people with ID and for the general population offered a better opportunity for the unique experiences of people with ID to be included in data that inform health planning. PMID- 28566010 TI - Extending the Promise of the Older Americans Act to Persons Aging With Long-Term Disability. AB - This article discusses the need for Older Americans Act (OAA) programs to evaluate and develop where needed the capacity to serve persons aging with long term disabilities such as intellectual and/or developmental disabilities and physical disabilities including polio, spinal cord injury, and multiple sclerosis. The rationale for this work is the universal access to OAA programs for all adults over 60, regardless of the disability type, age of onset, or severity, acknowledging that other needs-based criteria often need to be met to receive services. Recommendations for increasing OAA and aging network capacity include addressing long-standing divisions between the fields of aging and disability, a comprehensive review of all Administration for Community Living programs and policies, engaging in program adaptation to build capacity, advancing knowledge and skills of the professional workforce, creating new knowledge to support delivery of evidence-based interventions to all older adults including those with lifelong and early and midlife onset of disability. PMID- 28566011 TI - Types of Family Caregiving and Daily Experiences in Midlife and Late Adulthood: The Moderating Influences of Marital Status and Age. AB - Guided by the life-course perspective, this study contributes to the family caregiving, aging, and disability literature by examining the daily experiences of three types of family caregivers in midlife and late adulthood. A sample of 162 caregivers from the National Survey of Midlife in the United States study completed interviews, questionnaires, and a Daily Diary Study. Multilevel models showed the patterns of daily time use did not differ by caregiver types. Caregivers of sons/daughters with developmental disabilities (DD) experienced more daily stressors than caregivers of parents with health conditions (HC) and caregivers of spouses with HC. Unmarried caregivers of sons/daughters with DD reported spending more time on daily leisure activities and exhibited greater daily stressor exposure than other family caregivers. Age did not moderate the associations between caregiver types and daily experiences. Findings highlight the important consideration of the caregivers' characteristics to better determine the quality of their daily experiences in midlife and late adulthood. PMID- 28566012 TI - Aging With Disability for Midlife and Older Adults. AB - This analysis brings "aging with disability" into middle and older ages. We study U.S. adults ages 51+ and ages 65+ with persistent disability (physical, household management, personal care; physical limitations, instrumental activities of daily living [IADLs], activities of daily living [ADLs]), using Health and Retirement Study data. Two complementary approaches are used to identify persons with persistent disability, one based directly on observed data and the other on latent classes. Both approaches show that persistent disability is more common for persons ages 65+ than ages 51+ and more common for physical limitations than IADLs and ADLs. People with persistent disability have social and health disadvantages compared to people with other longitudinal experiences. The analysis integrates two research avenues, aging with disability and disability trajectories. It gives empirical heft to government efforts to make aging with disability an age-free (all ages) rather than age-targeted (children and youths) perspective. PMID- 28566013 TI - Sexual harassment and menstrual disorders among Italian university women: A cross sectional observational study. AB - AIMS: Menstrual disorders and sexual harassment are common among young women and interfere with their life and activities. We aimed to describe the association of sexual harassment and menstrual disorders among female university students. METHODS: This cross-sectional, observational study examined the association between sexual harassment and menstrual disorders in a sample of 349 university students in Italy. Students answered an anonymous self-administered questionnaire. Descriptive bivariate analyses and logistic regression analyses were performed. Main outcome measures were associations between levels of exposure to sexual harassment (none, levels 1 and 2) and five menstrual disorders (premenstrual symptoms, heavy bleeding, pain, irregular cycles, and amenorrhea). RESULTS: Among the women interviewed (mean age 20.4 +/- 1.45 years), 146 (41.8%) had experienced sexual harassment in the previous 12 months: 91 (26.1%) level 1 and 55 (15.7%) level 2. The frequency of premenstrual symptoms was 31.9% ( n=110); heavy bleeding, 35.3% ( n=124); pain, 51.4% ( n=181); irregular cycles, 55.5% ( n=195); and amenorrhea, 6.7% ( n=23). After adjustment for age, place of birth, being in a couple relationship and receiving hormone therapy, the frequency of menstrual disorders, except for amenorrhea, was increased with sexual harassment, with a regular gradient from no harassment to level 2 harassment. Introducing factors of depression, specific gynaecological problems and lifetime sexual violence did not change the results. For instance, the adjusted odds ratios of premenstrual symptoms were 2.10 [1.19-3.68] for women with level 1 harassment and 3.58 [1.83-7.03] for women with level 2 compared with women without harassment exposure. CONCLUSIONS: Sexual harassment is related to the prevalence of menstrual disorders. Healthcare providers should encourage dialogue with patients and address the issue of sexual violence or harassment. PMID- 28566014 TI - Assessing the culture of safety in cardiovascular perfusion: attitudes and perceptions. AB - INTRODUCTION: The Hospital Survey on Patient Safety Culture was developed by the Agency for Healthcare Research and Quality (AHRQ) to assess the culture of safety in hospitals. The purpose of this study was to identify specific domains of perfusion that are indicators of a high quality culture of safety. METHODS: Perfusionists were recruited to participate in the survey through email invitation through Perflist, Perfmail and LinkedIn. The survey consisted of 37 questions across six safety domains. Questions were developed using the AHRQ Hospital Survey on Patient Safety Culture. 'Positive scores' were defined as a response that either agreed or strongly agreed with a safety standard. Survey responses that resulted in a 75 percent or higher positive response rate were identified as vital components of a high culture of safety. Logistic regression analysis was used to determine importance components of perceived safety. RESULTS: Four responses were found to have a significant predictive level of a positive safety environment in the work unit: (1) in this unit, we discuss ways to prevent errors from happening again; OR=3.09, (2) in this unit, we treat others with respect; OR=1.09 (3) my supervisor/manager seriously considers staff suggestions for improving patient safety; OR=1.89 and (4) there is good cooperation among hospital units that need to work together; OR=1.77. There were two predictors of a negative work unit safety environment: (1) staff are afraid to ask questions when something does not seem right; OR=0.62 and (2) it is just by chance that more serious mistakes don't happen around here; OR=0.55. CONCLUSIONS: The results from this survey indicate that effective communication secondary to both incident and near-miss reporting is associated with a higher perceived culture of safety. A positive safety environment is associated with being able to speak up regarding safety issues without fear of negative repercussions. PMID- 28566015 TI - Judging Total Volumes Of Silhouetted Spheres In Different Numerosities. AB - Volume and number are addressed separately rather than combined in perception research. Yet, our everyday problems often involve summed continuous volumes of countable solid objects with partial depth cues (e.g., food items). The participants were presented with a set of black-and-white silhouettes of spheres that independently varied in numerosity (from 1 to 6) and total volume (2, 4, 6, or 8), and an adjacent silhouette of a partially filled cylinder. They judged how much the silhouetted sphere(s) in the set would raise the level of the cylinder content if the spheres were immersed into that content. Higher total volumes and numerosities of the spheres were judged slower and underestimated. Lower total volumes and numerosities were judged faster and overestimated. These effects strongly reflected the total silhouette area of the spheres in a set. The discontinuous effect of numerosity on judgment accuracy and speed suggested separate judgment modes below and above Numerosity 3. PMID- 28566016 TI - A computational study to identify the key residues of peroxisome proliferator activated receptor gamma in the interactions with its antagonists. AB - Peroxisome proliferator-activated receptors (PPARs) compose a family of nuclear receptors, PPARalpha, PPARbeta, and PPARgamma, which mediate the effects of lipidic ligands at the transcriptional level. Among these, the PPARgamma has been known to regulate adipocyte differentiation, fatty acid storage and glucose metabolism, and is a target of antidiabetic drugs. In this work, the interactions between PPARgamma and its six known antagonists were investigated using computational methods such as molecular docking, molecular dynamics (MD) simulations, and the hybrid quantum mechanics/molecular mechanics (QM/MM). The binding energies evaluated by molecular docking varied between -22.59 and -35.15 kJ mol- 1. In addition, MD simulations were performed to investigate the binding modes and PPARgamma conformational changes upon binding of antagonists. Analysis of the root-mean-square fluctuations (RMSF) of backbone atoms shows that H3 of PPARgamma has a higher mobility in the absence of antagonists and moderate conformational changes were observed. The interaction energies between antagonists and each PPARgamma residue involved in the interactions were studied by QM/MM calculations. These calculations reveal that antagonists with different structures show different interaction energies with the same residue of PPARgamma. Therefore, it can be concluded that the key residues vary depending on the structure of the ligand, which binds to PPARgamma. PMID- 28566018 TI - Autoimmune abnormality affects ovulation and oocyte-pick-up in MRL/MpJ-Fas lpr/lpr mice. AB - Ovulation and oocyte-pick-up are essential processes in fertilization. Herein, we found associations between autoimmune disease and the aforementioned processes in mice. At three and six months, along with the evaluation of autoimmune disease indices, the ovary, mesosalpinx, and oviducts were histologically examined in C57BL/6, MRL/MpJ, and MRL/MpJ-Fas lpr/lpr mice as healthy control, mild and severe models of autoimmune disease, respectively. In superovulated mice, the number of "oocyte cumulus complexes" found in the ampulla was macroscopically counted, and that of "ovulated oocytes" was histologically evaluated, as indicated by ruptured follicles or corpora hemorrhagica in ovaries. Finally, the oocyte-pick-up rate was calculated. In MRL/MpJ-Fas lpr/lpr mice, the oocyte-pick up rate decreased with disease-related deterioration, unlike in other mouse strains. Further, more ovulated oocytes were found in MRL/MpJ mice than in C57BL/6 mice, and this number significantly decreased with aging in MRL/MpJ-Fas lpr/lpr mice. Numerous T-cells infiltrated into the infundibulum or a part of the mesosalpinx in aged MRL/MpJ-Fas lpr/lpr mice, and their infundibulum showed swelling and fewer ciliated epithelial cells compared to that of C57BL/6 mice. In conclusion, the progression of severe autoimmune disease affected the oocyte-pick up process through histopathological changes in the infundibulum. These results provide important insights into female infertility associated with autoimmune disease. PMID- 28566017 TI - Efficacy and safety of tacrolimus in systemic lupus erythematosus patients with refractory thrombocytopenia: a retrospective study. AB - Objective We evaluated the efficacy and safety of tacrolimus in systemic lupus erythematosus patients with refractory thrombocytopenia. Methods We retrospectively reviewed the data for 20 systemic lupus erythematosus patients with refractory thrombocytopenia and treated with tacrolimus during the period January 2013 to January 2015. In addition to glucocorticoids, all patients were treated with tacrolimus, 1 mg taken twice daily. The clinical effect of tacrolimus treatment in patients was evaluated by analysis of platelet counts at baseline and after one, three and six months of tacrolimus treatment. Levels of anti-double-stranded DNA antibodies and complement C3, C4 were determined individually. Results After one month of tacrolimus treatment, three patients (15%) did not respond, three patients (15%) achieved a complete response and the other 14 patients (75%) achieved a partial response. After three months of tacrolimus treatment, the platelet counts of all patients were significantly improved. A partial response was seen in 14 patients (75%) and the complete response rate increased to 25% (five patients). After six months, all patients attained partial response or complete response without relapse, and the rate of complete response increased to 75%. Compared to pretreatment, anti-double stranded DNA antibody levels and the disease activity index score were markedly decreased after tacrolimus treatment. The levels of serum C3 and C4 were increased significantly ( P < 0.05). Conclusions Our survey revealed that a six month course of tacrolimus is a safe and effective treatment for systemic lupus erythematosus patients with refractory thrombocytopenia. PMID- 28566020 TI - Do parents of adolescents request the same universal parental support as parents of younger children? A random sample of Swedish parents. AB - : Universal parental support intended to enhance parents' capacity for parenting is an important aspect of public health strategies. However, support has mostly been aimed at parents, especially mothers, of younger children. There is a gap in the research concerning parents of adolescents and fathers' interest in parenting support. AIM: To investigate and compare the interest in parenting support of parents of adolescents and younger children, potential differences between mothers and fathers, and their knowledge of what is being offered to them already, and to explore their requirements for future universal parental support. METHODS: Telephone interviews were conducted with a random sample of 1336 parents. Quantitative methods were used to analyze differences between groups and qualitative methods were used to analyze open-ended questions in regard to parents' requirements for future universal parental support. RESULTS: About 82% of the parents of adolescents interviewed think that offering universal parental support is most important during child's adolescence. There is a substantial interest, particularly among mothers, in most forms of support. Despite their interest, parents have limited awareness of the support available. Only 7% knew about the local municipality website, although 70% reported a possible interest in such a website. Similarly, 3% knew that a parent phone line was available to them, while 59% reported a possible interest. CONCLUSIONS: It poses a challenge but is nevertheless important for municipalities to develop support targeted at parents of adolescents which is tailored to their needs, and to reach out with information. PMID- 28566019 TI - Using Evidence To Inform Practice and Policy To Enhance the Quality of Care for Persons with Traumatic Spinal Cord Injury. AB - In today's economic climate, there is a need to demonstrate a return on investment for healthcare spending and for clinical practice and policy to be informed by evidence. Navigating this process is difficult for decision-makers, clinicians, and researchers alike. This article will describe how a knowledge translation framework and an evidence-based policy-making process were integrated to clarify the problem, frame options, and plan implementation, to impact clinical practice and policy in the area of traumatic spinal cord injury (tSCI). The Access to Care and Timing (ACT) project is focused on optimizing the access and timing of specialized healthcare delivery for persons sustaining a tSCI in Canada. A simulation model was developed that uses current patient data to address complex problems faced by the healthcare system. At a workshop, participants stressed the importance of linking interventions to short- and long term outcomes to drive change. Presently, there are no national, system level indicators to monitor performance after tSCI. Although the ideal system of care after tSCI is unknown, indicator collection will establish a baseline to measure improvement. The workshop participants prioritized two indicators important from the clinician and patient perspective-timely admission to rehabilitation and meaningful community participation. The ACT simulation model for tSCI care will be used to promote the uptake of identified indicators and provide a predictive link between interventions on potential outcomes. The standardized collection of outcome-oriented indicators will help to evaluate the access and timing of care and to define the ideal system of care after SCI. PMID- 28566021 TI - First-Person Perspectives on Prescriber-Service User Relationships in Community Mental Health Centers. AB - OBJECTIVE: Because of changes in health care, there is a greater focus on brief medication management visits as the primary method of providing psychiatric care in community mental health settings. Research on the first-person perspectives of service users and prescribers in these settings is limited. The objective of this study was to describe first-person perspectives on medication management visits and the service user-prescriber relationship. METHODS: Researchers conducted qualitative interviews as part of a larger comparative effectiveness trial at 15 community mental health centers, researchers interviewed service users (N=44) and prescribers (N=25) about their perspectives on the typical elements of a medication management visit and asked service users about their relationship with their prescriber. RESULTS: Both service users and prescribers described medication management visits as very brief encounters focused on medication and symptoms. Most service users reflected on the service user-prescriber relationship in positive or neutral terms; they did not describe the development of a strong therapeutic relationship or a meaningful clinical encounter with prescribing clinicians. CONCLUSIONS: Service users described the service user prescriber relationship and medication management visit as largely transactional. Despite the transactional nature of these encounters, most service users described relationships with prescribing clinicians in positive or neutral terms. Their satisfaction with the visit did not necessarily mean that they were receiving high-quality care. Satisfaction may instead suggest service users' disengagement from care. They may need more support to fully participate in their own care. PMID- 28566022 TI - Six-Month Follow-Up of Recovery-Oriented Cognitive Therapy for Low-Functioning Individuals With Schizophrenia. AB - OBJECTIVE: The study examined six-month follow-up results and the impact of length of illness on treatment outcomes of recovery-oriented cognitive therapy (CT-R). METHODS: Sixty outpatients (mean age 38.4 years, 33% female, 65% African American) with schizophrenia or schizoaffective disorder and elevated negative symptoms were randomly assigned to CT-R or standard treatment. Assessments were conducted at baseline, midtreatment (six and 12 months), end of treatment (18 months), and follow-up (24 months, N=46 after attrition) by assessors blind to treatment condition. Global functioning, measured with the Global Assessment Scale, was the primary outcome. Secondary outcomes were negative symptoms (avolition-apathy score on the Scale for the Assessment of Negative Symptoms) and positive symptoms (total score on the Scale for the Assessment of Positive Symptoms). Length of illness indexed chronicity (less chronic, one to 12 years; more chronic, 13 to 40 years). RESULTS: Intent-to-treat analyses (hierarchal linear modeling) at follow-up indicated significant benefits for individuals assigned to CT-R compared with standard treatment: higher global functioning scores (between-group Cohen's d=.53), lower scores for negative symptoms (d= .66), and lower scores for positive symptoms (d=-1.36). Length of illness moderated treatment effects on global functioning, such that those with a less chronic illness began to show improvements earlier (at the trend level by six months and reaching significance by the end of treatment), whereas the group with a more chronic illness did not show significant improvements until later (at follow-up). CONCLUSIONS: CT-R produced durable effects that were present even among individuals with the most chronic illness. PMID- 28566023 TI - Second-Generation Antipsychotic Prescribing Patterns for Pediatric Patients Enrolled in West Virginia Medicaid. AB - OBJECTIVE: The prescribing of second-generation antipsychotics for young people has increased dramatically. Studies have shown that children enrolled in Medicaid are more likely than those with private insurance to receive antipsychotics, leading many states to require prior authorization (PA) for their use. However, little is known about how PA programs affect prescribing patterns for antipsychotics or other psychotropic medications. This study examined a PA program for second-generation antipsychotic use for children under 18 in West Virginia Medicaid. Prescribing rates for antipsychotics and other psychotropic classes were assessed. METHODS: Administrative claims from West Virginia Medicaid and the Children's Health Insurance Program for September 2014 to July 2016 were examined (N=273,369 prescriptions) with an interrupted time-series design. Segmented linear regression was used to model both immediate effects and trends in prescribing rates before and after implementation of the PA program in August 2015. RESULTS: After PA program implementation, the prescribing rate for second generation antipsychotics immediately dropped by 17% from prior levels, adjusted for preexisting trends, and further declined in the following months. Prescribing rates for all second-generation antipsychotics except for aripiprazole decreased significantly. Benzodiazepine prescribing increased in the month after PA program implementation but immediately returned to prepolicy rates, and sustained compensatory prescribing was not observed for any psychotropic drug class. CONCLUSIONS: Implementation of a second-generation antipsychotic PA program for children under age 18 resulted in a significant decrease in the prescribing rate for this class of medication, without sustained compensatory prescribing of other psychotropic classes. PMID- 28566024 TI - Fostering Activation Among Latino Parents of Children With Mental Health Needs: An RCT. AB - OBJECTIVE: Latino families raising children with mental health and other special health care needs report greater dissatisfaction with care compared with other families. Activation is a promising strategy to eliminate disparities. This study examined the comparative effectiveness of MePrEPA, an activation intervention for Latino parents whose children receive mental health services. METHODS: A randomized controlled trial (N=172) was conducted in a Spanish-language mental health clinic to assess the effectiveness of MePrEPA, a four-week group psychoeducational intervention to enhance parent activation among Latino parents, compared with a parent-support control group. Inclusion criteria were raising a child who receives services for mental health needs and ability to attend weekly sessions. Outcomes were parent activation, education activation, quality of school interaction, and parent mental health. Effectiveness of the intervention was tested with a difference-in-difference approach estimating linear mixed models. Heterogeneity of treatment effect was examined. RESULTS: MePrEPA enhanced parent activation (beta=5.98, 95% confidence interval [CI]=1.42-10.53), education activation (beta=7.98, CI=3.01-12.94), and quality of school interaction (beta=1.83, CI=.14-3.52) to a greater degree than did a parent-support control group. The intervention's impact on parent activation and education outcomes was greater for participants whose children were covered by Medicaid and were novices to therapy and those with low activation at baseline. No statistically significant effects were observed in parent mental health. CONCLUSIONS: Activation among Latino parents was improved with MePrEPA, which can be readily incorporated in current practices by mental health clinics. Future work should replicate findings in a large number of sites, adding behavioral measures and distal impacts while examining MePrEPA's effects across settings and populations. PMID- 28566025 TI - Management of Mental Health Crises Among Youths With and Without ASD: A National Survey of Child Psychiatrists. AB - OBJECTIVE: This study compared management by child psychiatrists of mental health crises among youths with and without autism spectrum disorder (ASD). METHODS: A custom online mental health crisis services survey was administered to members of the American Academy of Child and Adolescent Psychiatry. The survey probed three domains of crisis management: willingness to work with youths with a history of mental health crisis, comfort level in managing a mental health crisis, and availability of external resources during a crisis. Child psychiatrists reporting on management of youths with ASD (N=492) and without ASD (N=374) completed the survey. RESULTS: About 75% of psychiatrists in both groups were willing to accept a child with a history of a mental health crisis in their practice. During a crisis, psychiatrists caring for youths with ASD had less access to external consultation resources, such as a crisis evaluation center or other mental health professionals, compared with those caring for youths without ASD. Psychiatrists also expressed concerns about the ability of emergency department professionals and emergency responders to manage mental health crises among youths in a safe and developmentally appropriate manner, particularly among those with ASD. CONCLUSIONS: Child psychiatrists are in need of more external resources to manage youths with ASD who are experiencing a mental health crisis. There is also a need to develop best practice procedures for emergency responders who are working with youths experiencing a mental health crisis. PMID- 28566026 TI - Gun Violence Following Inpatient Psychiatric Treatment: Offense Characteristics, Sources of Guns, and Number of Victims. AB - OBJECTIVE: This study presents data on the relative contribution to gun violence by people with a history of inpatient psychiatric treatment and on federal efforts to deter presumptively dangerous persons from obtaining firearms, information useful for analyzing the potential public health benefits of gun policies targeting people with serious mental illness. The study also estimates the reduction in gun violence victims that would be expected if individuals with a previous psychiatric hospitalization were prohibited from purchasing firearms. METHODS: Data from 838 violent gun offenders from a nationally representative sample of state prison inmates were analyzed. Those with and without a history of psychiatric hospitalization were compared on a range of offense characteristics, including relationship to the victim, number of victims, location of the offense, and source of firearms. RESULTS: Inmates with a history of hospitalization constituted 12% of all violent gun offenders and accounted for 13% of the sample's victims. They were less likely than those without a previous hospitalization to victimize strangers (odds ratio=.52) and were no more likely to commit gun violence in public or to have multiple victims. Among those with previous hospitalizations, 78% obtained guns from sources not subject to federal background checks. Of the total 1,041 victims of gun violence, only 3% were victimized by participants with a history of hospitalization who obtained guns from currently regulated sources. CONCLUSIONS: Prohibiting all individuals with a history of psychiatric hospitalization from purchasing firearms, absent expanded background checks, was estimated to reduce the number of gun violence victims by only 3%. PMID- 28566027 TI - Perceived Autonomy Support in the NIMH RAISE Early Treatment Program. AB - OBJECTIVE: This study examined perceived support for autonomy-the extent to which individuals feel empowered and supported to make informed choices-among participants in the Recovery After an Initial Schizophrenia Episode Early Treatment Program (RAISE ETP). The aims of this study were to evaluate whether NAVIGATE, the active treatment studied in RAISE ETP, was associated with greater improvements in perceived autonomy support over the two-year intervention, compared with community care, and to examine associations between perceived autonomy support and quality of life and symptoms over time and across treatment groups. METHODS: This study examined perceived autonomy support among the 404 individuals with first-episode psychosis who participated in the RAISE ETP trial (NAVIGATE, N=223; community care, N=181). Three-level conditional linear growth modeling was used given the nested data structure. RESULTS: The results indicated that perceived autonomy support increased significantly over time for those in NAVIGATE but not in community care. Once treatment began, higher perceived autonomy support was related to higher quality of life at six, 12, and 18 months in NAVIGATE and at 12, 18, and 24 months in community care. Higher perceived autonomy support was related to improved scores on total symptoms and on excited symptoms regardless of treatment group and time. CONCLUSIONS: Overall, perceived autonomy support increased in NAVIGATE but not for those in community care and was related to improved quality of life and symptoms across both treatment groups. Future research should examine the impact of perceived autonomy support on a wider array of outcomes, including engagement, medication adherence, and functioning. PMID- 28566028 TI - A Randomized Controlled Trial of the Rochester Forensic Assertive Community Treatment Model. AB - OBJECTIVE: Forensic assertive community treatment (FACT) is an adaptation of the assertive community treatment model and is designed to serve justice-involved adults with serious mental illness. This study compared the effectiveness of a standardized FACT model and enhanced treatment as usual in reducing jail and hospital use and in promoting engagement in outpatient mental health services. METHODS: Seventy adults with psychotic disorders who were arrested for misdemeanor crimes and who were eligible for conditional discharge were recruited from the Monroe County, New York, court system. Participants were randomly assigned to receive either FACT (N=35) or enhanced treatment as usual (N=35) for one year. Criminal justice and mental health service utilization outcomes were measured by using state and county databases. RESULTS: Forty-nine participants (70%) completed the full one-year intervention period. Nineteen (27%) were removed early by judicial order, one was removed by county health authorities, and one died of a medical illness. Intent-to-treat analysis for all 70 participants showed that those receiving the FACT intervention had fewer mean+/ SD convictions (.4+/-.7 versus .9+/-1.3, p=.023), fewer mean days in jail (21.5+/ 25.9 versus 43.5+/-59.2, p=.025), fewer mean days in the hospital (4.4+/-15.1 versus 23.8+/-64.2, p=.025), and more mean days in outpatient mental health treatment (305.5+/-92.1 versus 169.4+/-139.6, p<.001) compared with participants who received treatment as usual. CONCLUSIONS: The Rochester FACT model was associated with fewer convictions for new crimes, less time in jail and hospitals, and more time in outpatient treatment among justice-involved adults with psychotic disorders compared with treatment as usual. PMID- 28566029 TI - Trainer Fidelity as a Predictor of Crisis Counselors' Behaviors With Callers Who Express Suicidal Thoughts. AB - OBJECTIVE: The relationship between trainer fidelity during a two-day suicide prevention program for counselors at crisis centers and counselors' behaviors during calls from individuals with suicidal thoughts was examined. METHODS: The study used two data sets from a randomized control trial of a suicide prevention program delivered by counselors at 17 crisis centers who had previously received training (train-the-trainer [TTT] approach). One data set examined counselors' behaviors by silently monitoring calls (N=764) to the crisis lines, and one assessed adherence to manual content and competence in delivery among trainers (N=34) by coding training videotapes. Multilevel modeling was used to account for nested data. RESULTS: Use of recommended behaviors by counselors was primarily related to trainers' competence in delivery of the program rather than adherence to the program content. CONCLUSIONS: Trainer selection for competence may be particularly critical for group-based TTT programs involving experienced counselors and the use of experiential activities. PMID- 28566030 TI - Treatment of alumina refinery waste (red mud) through neutralization techniques: A review. AB - In the Bayer process of extraction of alumina from bauxite, the insoluble product generated after bauxite digestion with sodium hydroxide at elevated temperature and pressure is known as 'red mud' or 'bauxite residue'. This alumina refinery waste is highly alkaline in nature with a pH of 10.5-12.5 and is conventionally disposed of in mostly clay-lined land-based impoundments. The alkaline constituents in the red mud impose severe and alarming environmental problems, such as soil and air pollution. Keeping in view sustainable re-vegetation and residue management, neutralization/treatment of red mud using different techniques is the only alternative to make the bauxite residue environmentally benign. Hence, neutralization techniques, such as using mineral acids, acidic waste (pickling liquor waste), coal dust, superphosphate and gypsum as amenders, CO2, sintering with silicate material and seawater for treatment of red mud have been studied in detail. This paper is based upon and emphasizes the experimental work carried out for all the neutralization techniques along with a comprehensive review of each of the processes. The scope, applicability, limitations and feasibility of these processes have been compared exhaustively. Merits and demerits have been discussed using flow diagrams. All the techniques described are technically feasible, wherein findings obtained with seawater neutralization can be set as a benchmark for future work. Further studies should be focused on exploring the economical viability of these processes for better waste management and disposal of red mud. PMID- 28566031 TI - The link between waste management, climate change and bioeconomy. PMID- 28566032 TI - Estimation of construction and demolition waste using waste generation rates in Chennai, India. AB - A large amount of construction and demolition waste is being generated owing to rapid urbanisation in Indian cities. A reliable estimate of construction and demolition waste generation is essential to create awareness about this stream of solid waste among the government bodies in India. However, the required data to estimate construction and demolition waste generation in India are unavailable or not explicitly documented. This study proposed an approach to estimate construction and demolition waste generation using waste generation rates and demonstrated it by estimating construction and demolition waste generation in Chennai city. The demolition waste generation rates of primary materials were determined through regression analysis using waste generation data from 45 case studies. Materials, such as wood, electrical wires, doors, windows and reinforcement steel, were found to be salvaged and sold on the secondary market. Concrete and masonry debris were dumped in either landfills or unauthorised places. The total quantity of construction and demolition debris generated in Chennai city in 2013 was estimated to be 1.14 million tonnes. The proportion of masonry debris was found to be 76% of the total quantity of demolition debris. Construction and demolition debris forms about 36% of the total solid waste generated in Chennai city. A gross underestimation of construction and demolition waste generation in some earlier studies in India has also been shown. The methodology proposed could be utilised by government bodies, policymakers and researchers to generate reliable estimates of construction and demolition waste in other developing countries facing similar challenges of limited data availability. PMID- 28566033 TI - Hospital waste management in developing countries: A mini review. AB - Health care activities can generate different kinds of hazardous wastes. Mismanagement of these wastes can result in environmental and occupational health risks. Developing countries are resource-constrained when it comes to safe management of hospital wastes. This study summarizes the main issues faced in hospital waste management in developing countries. A review of the existing literature suggests that regulations and legislations focusing on hospital waste management are recent accomplishments in many of these countries. Implementation of these rules varies from one hospital to another. Moreover, wide variations exist in waste generation rates within as well as across these countries. This is mainly attributable to a lack of an agreement on the definitions and the methodology among the researchers to measure such wastes. Furthermore, hospitals in these countries suffer from poor waste segregation, collection, storage, transportation and disposal practices, which can lead to occupational and environmental risks. Knowledge and awareness regarding proper waste management remain low in the absence of training for hospital staff. Moreover, hospital sanitary workers, and scavengers, operate without the provision of safety equipment or immunization. Unsegregated waste is illegally recycled, leading to further safety risks. Overall, hospital waste management in developing countries faces several challenges. Sustainable waste management practices can go a long way in reducing the harmful effects of hospital wastes. PMID- 28566034 TI - Hunting for valuables from landfills and assessing their market opportunities A case study with Kudjape landfill in Estonia. AB - Landfill mining is an alternative technology that merges the ideas of material recycling and sustainable waste management. This paper reports a case study to estimate the value of landfilled materials and their respective market opportunities, based on a full-scale landfill mining project in Estonia. During the project, a dump site (Kudjape, Estonia) was excavated with the main objectives of extracting soil-like final cover material with the function of methane degradation. In total, about 57,777 m3 of waste was processed, particularly the uppermost 10-year layer of waste. Manual sorting was performed in four test pits to determine the detailed composition of wastes. 11,610 kg of waste was screened on site, resulting in fine (<40 mm) and coarse (>40 mm) fractions with the share of 54% and 46%, respectively. Some portion of the fine fraction was sieved further to obtain a very fine grained fraction of <10 mm and analyzed for its potential for metals recovery. The average chemical composition of the <10 mm soil-like fraction suggests that it offers opportunities for metal (Cr, Cu, Ni, Pb, and Zn) extraction and recovery. The findings from this study highlight the importance of implementing best available site-specific technologies for on-site separation up to 10 mm grain size, and the importance of developing and implementing innovative extraction methods for materials recovery from soil-like fractions. PMID- 28566035 TI - Pilot-scale steam aging of steel slags. AB - Solid waste management has gained importance in the steel industry in view of rising environmental concerns and scarcity of raw materials. In spite of significant developments in reducing waste generation and development of recycling technologies, steel slag is still a concern for the industry as most of it is dumped. Steel slag is similar to stone aggregates in strength, but its volumetric instability in contact with water hinders its application as aggregates in construction. A part of steel slag is normally exposed to rain and sun for natural aging and stabilization for months before use. The natural aging process is slow and time-consuming, and thus restricts its usage. The steelmaking slag can be put to effective use as coarse aggregates if quickly aged and stabilized by pre-reacting the free expansive phases. In the present work, a new process has been developed to accelerate the steel slag aging process using steam in a 30 T pilot scale facility. The setup has controlled steam injection, distribution, and process control system for steam, temperature, flow, and pressure. Steam percolates through the minute pores in the slag lumps and hydrates the expansive free lime and MgO phases, making it stable. The aged slag expansion properties were tested using an in-house developed expansion testing apparatus. The process is capable of reducing the expansion of steel slag from 3.5% to <1.5% (standard requirement) in 7 days. The aged steel slag is currently being used in roads at JSW Steel, Vijayanagar Works. PMID- 28566036 TI - Relationship Between Supervisor Factors and Therapist Knowledge, Attitudes, and Use of EBP in a Large Public Behavioral Health System. PMID- 28566038 TI - Public Psychiatry's Accomplishments: Bound for Nowhere? PMID- 28566037 TI - Mental Health, Substance Use, and Socioeconomic Needs of Older Persons Paroled or Placed on Probation. PMID- 28566039 TI - Maintaining ACA's Gains in Insurance Coverage and Improving Access to Behavioral Health Care. PMID- 28566040 TI - Quality of Inpatient Psychiatric Care and Consumers' Trust in the Mental Health Care System. PMID- 28566042 TI - 2017: The Year Otolaryngology Had to "Scramble". PMID- 28566041 TI - Long-term operational studies of lab-scale pumice-woodchip packed stormwater biofilters. AB - The performance of three pumice-woodchip packed stormwater biofilter (PWSWBF) systems with three packing volume ratios of pumice to woodchip (1:2, 1:1 and 2:1) were compared. The results show that the PWSWBF system packed with a lower percentage of woodchip attained a higher removal efficiency of TCOD, TN, NH4-N and TP, whereas all three systems completely removed nitrate. The highest removal efficiencies for TCOD, TN, NH4-N, NO3-N and TP were 95%, 70%, 86%, 100% and 100%, respectively. In the biofilter with a lower percentage of woodchip, the pollutants that get removed through aerobic biological processes were removed more significantly, which is attributed to less oxygen depletion via woodchip decomposition, which is common under wet conditions. Nitrate was significantly removed via denitrification in all three systems, indicating that the woodchip that occupied one-third of the main media was sufficient for denitrification, and also that the oxygen condition inside the column was proper for denitrification to proceed. A smaller amount of woodchip as the packing material also mitigated the adverse effect of the release of organics from the media during the initial period. In addition, the system showed very good buffering capacity, in that the outflow pH was constant within the optimal range for microorganism growth. PMID- 28566043 TI - Highlights from the Current Issue: June 2017. PMID- 28566044 TI - Residency Education in Otolaryngology. PMID- 28566045 TI - Inpatient Rounding Practices in Otolaryngology Residency Programs. AB - Inpatient rounding is an agelong tradition in the field of medicine. Among recent changes in health care, rounding is understudied as an area of research. The purpose of this study was to assess current methods of inpatient rounding in otolaryngology residency programs and assess satisfaction with current practices. Survey questions were designed by members of the resident committee of the Society of University Otolaryngologists. Surveys were sent to all 450 members, and we obtained a 32% response rate. Sixty-four percent of attendings perform bedside rounds; 44% of subjects reported that attending physicians participate in rounds at least once a week; and 21% reported daily participation. When asked if attending participation in rounding is adequate, attendings did not have a strong opinion (mean = 3.8). There is a paucity of research on inpatient rounding, and future studies should examine specific practices with the goal of maximizing patient safety and resident education. PMID- 28566046 TI - Are All Manikins Created Equal? A Pilot Study of Simulator Upper Airway Anatomic Fidelity. AB - This study evaluates the anatomic fidelity of several commercially available pediatric and adult manikins, including airway task trainers, which could be used in aerodigestive procedure training. Twenty-three experienced otolaryngologists assessed the aerodigestive anatomy of 5 adult and 5 pediatric manikins in a passive state, using rigid and flexible endoscopy. Anatomic fidelity was rated on a 5-point scale for the following: nasal cavity, nasopharynx, oral cavity, oropharynx, larynx, trachea, esophagus, and neck. Mean scores and standard deviations were tabulated for each manikin at each anatomic site. Ratings by survey participants demonstrated variation in the anatomic fidelity of the aerodigestive tract in a range of manikins. Radar chart display of the results allows comparison of manikin fidelity by anatomic site. Differences in scores may allow instructors to select manikins with the best anatomic fidelity for specific educational purposes, and they may contribute to recommendations to improve future manikin design. PMID- 28566047 TI - Implementation of an Intramural Competitive Resident Research Grant. AB - Experience with procurement of research funding and grantsmanship is an essential skill and one that is rarely taught in a manner that adequately prepares trainees for the magnitude of this professional requirement. The aims of the program described in this article are (1) to provide a mentored experience in grantsmanship through designing and concisely outlining an individual research study and (2) to supplement extramural funding mechanisms for clinical trainees to produce meaningful and substantive clinical and/or basic science research. A total of $10,000 of departmental chair discretionary funds is allocated for resident research annually. The first 2 cycles have successfully allocated the allotted funding through a competitive, scored grant evaluation process. Awardees have already produced meaningful data that have been nationally presented, submitted for publication, and integrated into an National Institutes of Health grant submission. The feasibility of implementing an intramural competitive resident research grant may have broad application within varied training environments. PMID- 28566048 TI - The P Value Problem in Otolaryngology: Shifting to Effect Sizes and Confidence Intervals. AB - There is a lack of reporting effect sizes and confidence intervals in the current biomedical literature. The objective of this article is to present a discussion of the recent paradigm shift encouraging the use of reporting effect sizes and confidence intervals. Although P values help to inform us about whether an effect exists due to chance, effect sizes inform us about the magnitude of the effect (clinical significance), and confidence intervals inform us about the range of plausible estimates for the general population mean (precision). Reporting effect sizes and confidence intervals is a necessary addition to the biomedical literature, and these concepts are reviewed in this article. PMID- 28566049 TI - Molecular dynamics simulations of apo and holo forms of fatty acid binding protein 5 and cellular retinoic acid binding protein II reveal highly mobile protein, retinoic acid ligand, and water molecules. AB - Structural and dynamic properties from a series of 300 ns molecular dynamics, MD, simulations of two intracellular lipid binding proteins, iLBPs, (Fatty Acid Binding Protein 5, FABP5, and Cellular Retinoic Acid Binding Protein II, CRABP II) in both the apo form and when bound with retinoic acid reveal a high degree of protein and ligand flexibility. The ratio of FABP5 to CRABP-II in a cell may determine whether it undergoes natural apoptosis or unrestricted cell growth in the presence of retinoic acid. As a result, FABP5 is a promising target for cancer therapy. The MD simulations presented here reveal distinct differences in the two proteins and provide insight into the binding mechanism. CRABP-II is a much larger, more flexible protein that closes upon ligand binding, where FABP5 transitions to an open state in the holo form. The traditional understanding obtained from crystal structures of the gap between two beta-sheets of the beta barrel common to iLBPs and the alpha-helix cap that forms the portal to the binding pocket is insufficient for describing protein conformation (open vs. closed) or ligand entry and exit. When the high degree of mobility between multiple conformations of both the ligand and protein are examined via MD simulation, a new mode of ligand motion that improves understanding of binding dynamics is revealed. PMID- 28566050 TI - Running and Osteoarthritis: Does Recreational or Competitive Running Increase the Risk? AB - Exercise, like running, is good for overall health and, specifically, our hearts, lungs, muscles, bones, and brains. However, some people are concerned about the impact of running on longterm joint health. Does running lead to higher rates of arthritis in knees and hips? While many researchers find that running protects bone health, others are concerned that this exercise poses a high risk for age related changes to hips and knees. A study published in the June 2017 issue of JOSPT suggests that the difference in these outcomes depends on the frequency and intensity of running. J Orthop Sports Phys Ther 2017;47(6):391. doi:10.2519/jospt.2017.0505. PMID- 28566051 TI - Osteoarthritis Management: Time to Change the Deck. AB - This Viewpoint highlights the shortcomings of existing osteoarthritis (OA) clinical practices and emphasizes the opportunity that can come about by virtue of adherence to appropriate management. In an effort to emphasize optimism, there are huge missed opportunities with existing efficacious treatments and tremendous developments that are currently going on that will positively influence future care. How we respond to that opportunity will not only impact the individuals disabled by the disease but also make a massive difference to our society through reducing underemployment and health care waste. J Orthop Sports Phys Ther 2017;47(6):370-372. doi:10.2519/jospt.2017.0605. PMID- 28566052 TI - Buttock Pain and Sciatica Caused by a Femoral Osteochondroma. AB - A 26-year-old woman was referred to physical therapy with lower back pain extending into the right buttock. Palpation of the right buttock revealed a firm, immobile mass of considerable size, which the patient identified as her locus of symptoms. Due to the noted palpable mass, her pain, her inability to sit normally, and the longevity of symptoms, the physical therapist ordered radiographs, which identified multiple osteochondromas. J Orthop Sports Phys Ther 2017;47(6):442. doi:10.2519/jospt.2017.6877. PMID- 28566053 TI - Hip Pain and Mobility Deficits-Hip Osteoarthritis: Revision 2017. AB - The Orthopaedic Section of the American Physical Therapy Association (APTA) has an ongoing effort to create evidence-based practice guidelines for orthopaedic physical therapy management of patients with musculoskeletal impairments described in the World Health Organization's International Classification of Functioning, Disability, and Health (ICF). The purpose of these revised clinical practice guidelines is to review recent peer-reviewed literature and make recommendations related to hip pain and mobility deficits. J Orthop Sports Phys Ther. 2017;47(6):A1-A37. doi:10.2519/jospt.2017.0301. PMID- 28566054 TI - Biologics for psoriasis : maintenance treatment and true disease modification. PMID- 28566055 TI - Motor behavior of masticatory muscles in individuals with unilateral trans incisive foramen cleft lip and palate. AB - OBJECTIVE: To investigate whether children with complete unilateral cleft lip and palate (CLP) have altered control of masticatory muscles. METHODS: The muscular activity of 66 children with CLP (n = 33) and without CLP (n = 33), aged 6-12 years was assessed during different tasks (rest, isometry, mastication) using electromyography. RESULTS: The activation for the analyzed muscles was higher in children with CLP at rest (R) and inactive period (IP) (p < 0.05). The muscles of children with CLP remained active for longer than those without CLP (p < 0.05), and the length of the masticatory cycle was higher in children with CLP (p < 0.05). CONCLUSION: Children with CLP have longer muscle activation and increased cycle time during the chewing cycle, which might be a consequence of malocclusion, resulting in difficulty chewing. PMID- 28566056 TI - The impact of depression and PTSD symptom severity on trauma memory. AB - Posttraumatic stress disorder (PTSD) and depression frequently co-occur following a traumatic event. Differences in the processing of autobiographical memory have been observed in both disorders in the form of overgeneralised memories and negative intrusive memories. The current study examined how symptoms of PTSD and depression influence the phenomenological characteristics of trauma memories. Undergraduate students who had experienced a traumatic event (n = 696) completed questionnaires online including measures of PTSD and depressive symptom severity. They rated their trauma memory on several phenomenological characteristics using the Memory Experiences Questionnaire [Sutin, A. R., & Robins, R. W. (2007). Phenomenology of autobiographical memories: The memory experiences questionnaire. Memory.]. Moderated multiple regression was used to examine how PTSD and depressive symptom severity related to each phenomenological characteristic. Symptoms of PTSD and depression were related separately and uniquely to the phenomenological characteristics of the trauma memory. PTSD severity predicted trauma memories that were more negative, contained higher sensory detail, and were more vivid. In contrast, depressive symptom severity predicted trauma memories that were less accessible and less coherent. These findings suggest that depressive and PTSD symptomatology affect traumatic memory differently and support a distinction between these two disorders. PMID- 28566058 TI - Recognition of facial expressions is moderated by Islamic cues. AB - Recognising emotions from faces that are partly covered is more difficult than from fully visible faces. The focus of the present study is on the role of an Islamic versus non-Islamic context, i.e. Islamic versus non-Islamic headdress in perceiving emotions. We report an experiment that investigates whether briefly presented (40 ms) facial expressions of anger, fear, happiness and sadness are perceived differently when covered by a niqab or turban, compared to a cap and shawl. In addition, we examined whether oxytocin, a neuropeptide regulating affection, bonding and cooperation between ingroup members and fostering outgroup vigilance and derogation, would differentially impact on emotion recognition from wearers of Islamic versus non-Islamic headdresses. The results first of all show that the recognition of happiness was more accurate when the face was covered by a Western compared to Islamic headdress. Second, participants more often incorrectly assigned sadness to a face covered by an Islamic headdress compared to a cap and shawl. Third, when correctly recognising sadness, they did so faster when the face was covered by an Islamic compared to Western headdress. Fourth, oxytocin did not modulate any of these effects. Implications for theorising about the role of group membership on emotion perception are discussed. PMID- 28566057 TI - Sinecatechins and imiquimod as proactive sequential therapy of external genital and perianal warts in adults. AB - This review about the proactive sequential therapy (PST) of external genital and perianal warts (EGW) is based on the most current available clinical literature and on the broad clinical experience of a group of international experts, physicians who are well versed in the treatment of human papillomavirus associated diseases. It provides a practical guide for the treatment of EGW, including epidemiology, etiology, clinical appearance, and diagnostic procedures for these viral infections. Furthermore, the treatment goals and current treatment options, elucidating provider- and patient-applied therapies, and the parameters driving treatment decisions are summarized. Specifically, the mode of action of the topical treatments sinecatechins and imiquimod, as well as the PST for EGW to achieve rapid and sustained clearance is discussed. The group of experts has developed a treatment algorithm giving healthcare providers a practical tool for the treatment of EGW which is very valuable in the presence of many different treatment options. PMID- 28566059 TI - The effect of endograft device on patient outcomes in endovascular repair of ruptured abdominal aortic aneurysms. AB - Objective Endovascular aneurysm repair for ruptured abdominal aortic aneurysm is being increasingly applied as the intervention of choice. The purpose of this study was to determine whether survival and reintervention rates after ruptured abdominal aortic aneurysm vary between endograft devices. Methods This cohort study identified all ruptured abdominal aortic aneurysms performed at The Ottawa Hospital from January 1999 to May 2015. Data collected included patient demographics, stability index at presentation, adherence to device instructions for use, endoleaks, reinterventions, and mortality. Kruskal-Wallis test was used to compare outcomes between groups. Mortality outcomes were assessed using Kaplan Meier survival analysis, and multivariate Cox regression modeling. Results One thousand sixty endovascular aneurysm repairs were performed using nine unique devices. Ninety-six ruptured abdominal aortic aneurysms were performed using three devices: Cook Zenith ( n = 46), Medtronic Endurant ( n = 33), and Medtronic Talent ( n = 17). The percent of patients presented in unstable or extremis condition was 30.2, which did not differ between devices. Overall 30-day mortality was 18.8%, and was not statistically different between devices ( p = 0.16), although Medtronic Talent had markedly higher mortality (35.3%) than Cook Zenith (15.2%) and Medtronic Endurant (15.2%). AUI configuration was associated with increased 30-day mortality (33.3% vs. 12.1%, p = 0.02). Long-term mortality and graft-related reintervention rates at 30 days and 5 years were similar between devices. Instructions for use adherence was similar across devices, but differed between the ruptured abdominal aortic aneurysm and elective endovascular aneurysm repair cohorts (47.7% vs. 79.0%, p < 0.01). Notably, two patients who received Medtronic Talent grafts underwent open conversion >30 days post endovascular aneurysm repair ( p = 0.01). Type 1 endoleak rates differed significantly across devices (Cook Zenith 0.0%, Medtronic Endurant 18.2%, Medtronic Talent 17.6%, p = 0.01). Conclusion Although we identified device related differences in endoleak rates, there were no significant differences in reintervention rates or mortality outcomes. Favorable outcomes of Cook Zenith and Medtronic Endurant over Medtronic Talent reflect advances in endograft technology and improvements in operator experience over time. Results support selection of endograft by operator preference for ruptured abdominal aortic aneurysm. PMID- 28566061 TI - Primum non nocere: rethinking our policies on out-of-home care in Australia. PMID- 28566060 TI - Topical application of the hematostatic agent Surgiflo(r) could attenuate brain injury in experimental TBI mice. AB - OBJECT: The pathologies resulting from traumatic brain injury (TBI) have been thoroughly studied, but rarely have the effects of bleeding and coagulation in the early stage of TBI been considered. In this study, we investigated the effects of topical Surgiflo(r) application on brain injury in experimental TBI mice using S100beta, MAP-2 and mNSS scores. METHODS: TBI was induced by modified weight drop injury in male C57BL/6 mice. The mice were then randomly divided into (i) the sham group, (ii) TBI mice applied with saline (vehicle), and (iii) TBI mice applied with Surgiflo(r) in the same volume. Modified neurological severity scores (mNSS) were measured on days 0 (before surgery), 1, 3, 7, and 28 to evaluate neurologic functional deficits. At day 28, the mice were sacrificed, and the forebrains were sliced. The effects of Surgiflo(r) on microtubule-associated protein 2 and serum S100beta protein were examined by immunohistochemistry and electro-chemiluminescence immunoassay. RESULTS: Serum S100beta protein levels were significantly elevated at different time points (24 h, 3 days, 7 days) in the TBI groups (p < 0.01) compared to normal control groups. Surgiflo(r) induced a lower concentration of serum S100beta protein levels at day 3 (p < 0.05) and day 7 (p < 0.05) compared to the TBI group applied with saline. H&E staining showed that Surgiflo(r) treatment led to a 45% decrease in cortical brain lesion volume and in subcortical white matter 28 days after TBI. Compared with the saline-treated group, the number of MAP2-positive cells was significantly increased in the perilesional area of the Surgiflo(r)-treated group. The Surgiflo(r)-treated group exhibited lower mNSS scores on days 7 and 28 than did the saline-treated group. DISCUSSION: Surgiflo(r) treatment produced a significant decrease in serum S100beta protein levels in TBI mouse models, which may lead to an improvement in the recovery of TBI models. PMID- 28566064 TI - Hip arthroscopy for femoroacetabular impingement: use escalating beyond the evidence. PMID- 28566062 TI - Premature deaths of nursing home residents: an epidemiological analysis. AB - OBJECTIVES: To conduct a descriptive epidemiological analysis of external cause deaths (premature, usually injury-related, and potentially preventable) of nursing home residents in Australia. DESIGN: Retrospective study of a cohort of nursing home residents, using coronial data routinely recorded by the National Coronial Information System. SETTING AND PARTICIPANTS: Residents of accredited Australian nursing homes, whose deaths were reported to coroners between 1 July 2000 and 30 June 2013, and determined to have resulted from external causes. MAIN OUTCOME MEASURES: Causes of death, analysed by sex and age group, and by location of incidents leading to death and location of death. Rates of death were estimated on the basis of Australian Bureau of Statistics population and Australian Institute of Health and Welfare nursing home data. RESULTS: Of 21672 deaths of nursing home residents, 3289 (15.2%) resulted from external causes. The most frequent mechanisms of death were falls (2679 cases, 81.5%), choking (261 cases, 7.9%) and suicide (146 cases, 4.4%). The incidents leading to death usually occurred in the nursing home (95.8%), but the deaths more frequently occurred outside the nursing home (67.1%). The annual number of external cause deaths in nursing homes increased during the study period (from 1.2 per 1000 admissions in 2001-02 to 5.3 per 1000 admissions in 2011-12). CONCLUSION: The incidence of premature and potentially preventable deaths of nursing home residents has increased over the past decade. A national policy framework is needed to reduce the incidence of premature deaths among Australians living in nursing homes. PMID- 28566065 TI - Clinical quality registries for clinician-level reporting: strengths and limitations. PMID- 28566066 TI - The benefits of international health experiences for Australian and New Zealand medical education. PMID- 28566068 TI - Work-readiness and workforce numbers: the challenges. PMID- 28566067 TI - Expectorate the unexpected. PMID- 28566069 TI - Averting avoidable deaths of nursing home residents. PMID- 28566071 TI - Preparedness for practice: the perceptions of graduates of a regional clinical school. AB - OBJECTIVE: To assess graduates' self-reported preparedness with reference to a range of clinical practice capabilities, including those related to patient centred care. DESIGN: A retrospective survey of self-reported preparedness for practice, based on a survey developed by the Peninsula Medical School (United Kingdom) and adapted to account for Australian circumstances and to provide more information about patient-centred care-related capabilities. SETTING AND PARTICIPANTS: Launceston Clinical School, a regional clinical school for undergraduate medical students. Medical students who had graduated during 2005 2014 and were contactable by email were invited to participate in the study. MAIN OUTCOME MEASURES: Graduates' self-reported preparedness for practice in 44 practice areas, measured on a 5-point Likert scale. RESULTS: Responses from 135 graduates (50% of invited graduates, 38% of the eligible graduate population) were received. Most graduates felt prepared in 41 of the 44 practice areas; 80% felt at least well prepared in 17 areas. After clustering the 44 areas into six thematic groups, no differences were found between men and women who had graduated in the past 4 years. As male graduates become more experienced (5-10 years after graduation), retrospective perceptions of preparedness in some areas differed from those of more recent graduates; this was not found for female graduates. CONCLUSION: The survey identified strengths and weaknesses in the preparation of doctors for practice. It could be more broadly applied in Australia to obtain longitudinal data for assessing the quality of learning for curriculum planning purposes, and for aligning graduates' needs and expectations with those of the medical training and health care employment sectors. PMID- 28566072 TI - The sugar content of soft drinks in Australia, Europe and the United States. PMID- 28566070 TI - Reducing cardiovascular disease risk in diabetes: a randomised controlled trial of a quality improvement initiative. AB - OBJECTIVES: To describe the management of cardiovascular disease (CVD) risk in Australian patients with diabetes; to compare the effectiveness of a quality improvement initiative for people with and without diabetes. RESEARCH DESIGN AND METHODS: Subgroup analyses of patients with and without diabetes participating in a cluster randomised trial. SETTING AND PARTICIPANTS: Indigenous people (>= 35 years old) and non-Indigenous people (>= 45 years old) who had attended one of 60 Australian primary health care services at least three times during the preceding 24 months and at least once during the past 6 months. INTERVENTION: Quality improvement initiative comprising point-of-care electronic decision support with audit and feedback tools. MAIN OUTCOME MEASURES: Adherence to CVD risk screening and prescribing guidelines. RESULTS: Baseline rates of guideline-recommended screening were higher for 8829 patients with diabetes than for 44 335 without diabetes (62.0% v 39.5%; P < 0.001). Baseline rates of guideline-recommended prescribing were greater for patients with diabetes than for other patients at high risk of CVD (55.5% v 39.6%; P < 0.001). The proportions of patients with diabetes not attaining recommended treatment targets for blood pressure, low density lipoprotein-cholesterol or HbA1c levels who were not prescribed the corresponding therapy at baseline were 28%, 44% and 24% respectively. The intervention was associated with improved screening rates, but the effect was smaller for patients with diabetes than for those without diabetes (rate ratio [RR], 1.14 v 1.28; P = 0.01). It was associated with improved guideline recommended prescribing only for undertreated individuals at high risk; the effect size was similar for those with and without diabetes (RR, 1.63 v 1.53; P = 0.28). CONCLUSIONS: Adherence to CVD risk management guidelines was better for people with diabetes, but there is room for improvement. The intervention was modestly effective in people with diabetes, but further strategies are needed to close evidence-practice gaps.Australian and New Zealand Clinical Trials Registry number: ACTRN12611000478910. PMID- 28566073 TI - Emerging infectious disease agents and blood safety in Australia: spotlight on Zika virus. AB - Emerging infectious diseases (EIDs) are infectious diseases whose incidence has increased in humans in the past 20 years or could increase in the near future. EID agents may represent a threat to blood safety if they infect humans, cause a clinically significant illness, include an asymptomatic blood phase in the course of infection, and are transmissible by transfusion. EID agents are typically not well characterised, but there is a consensus that we can expect ongoing outbreaks. Strategies to manage the risk to blood safety from EIDs include ongoing surveillance, regular risk assessments, modelling transfusion transmission risk, and deferral of donors with a recent travel history to outbreak areas. The 2015-16 Zika virus (ZIKV) outbreak in the Americas is the largest reported ZIKV outbreak to date, and it highlights the unpredictable nature of EID outbreaks and how quickly they can become a major public health problem. This ZIKV outbreak has provided evidence of a causal link between the virus and microcephaly in newborns. In assessing the potential risk of ZIKV to blood safety in Australia, it should be noted that a relatively small number of imported ZIKV infections have been reported in Australia, there have been no reported cases of local ZIKV transmission, and the geographical distribution of the potential ZIKV mosquito vector in Australia (Aedes aegypti) is limited to northern Queensland. Moreover, reported transfusion-transmitted ZIKV cases worldwide are rare. At present, ZIKV represents a low risk to blood safety in Australia. PMID- 28566074 TI - [Evaluation of virulence factors in enterococcus species]. AB - Enterococci have recently become important due to their increased isolation rates in community-based and nosocomial infections and resistance to many antibiotics, including glycopeptides. The aim of this study was to evaluate the antimicrobial susceptible patterns and virulence factors of various clinical specimens; urine (n= 149), blood (n= 38), wound (n= 17), stool (n= 13), and other (n= 12) with a total of 229 enterococci including 138 E.faecalis and 91 E.faecium isolates. Aggregation factor (AF), enterococcus surface protein (esp), cytolysins and gelatinase encoding genes (asa1, esp, cylM, cylBcyl A, cylll, cylls, gelE, respectively) were investigated by molecular methods. Haemolysin production and gelatinase were studied phenotypically. A total of 30 isolates, 29 of E.faecium and one of E.faecalis isolates were resistant to vancomycin. High-level gentamicin and high-level streptomycin resistance in E.faecalis were 40.7% and 63.7% however, they were 47.1% and 55.8% in E.faecalis isolates. All strains were susceptible to linezolid. Ampicillin, penicillin and vancomycin resistance in E.faecium isolates were found to be higher than E.faecalis isolates (p= 0.001, p= 0.008 and p< 0.001). Asa1 (p< 0.001), cylll (p= 0.002) and cylls (p< 0.001) as well as gelatinase activity in isolates of E.faecalis were significantly higher than the isolates of E.faecium (p< 0.001). The most common virulence genes in our study were asa1 gene (45%), cyLs gene (33.2%) and esp gene (32.3%). Ciprofloxacin resistance in cylLL and cyLs gene positive isolates of E.faecalis were significantly higher compared to isolates that do not contain these genes (p= 0.035 and p= 0.047). Likewise, haemolysin producing E.faecium isolates were significantly more resistant to vancomycin compared to isolates that do not produce hemolysin (p< 0.001). When the virulence factors of vancomycin resistant and susceptible isolates were compared, the esp gene level in VRE E.faecium isolates was found to be 24.1%, while no esp gene was found in VRE E.faecalis isolates. The existence of asa1was negative in both VRE E.faecium and VRE E.faecalis isolates. The activity of hemolysin was found 42.3% for E.faecalis and 19.3% for E.faecium. In vancomycin-sensitive enterococcus (VSE) species, esp gene activity was 35.1% for E.faecalis, 29.4% for E.faecium, asa1 gene activity was 60.8% for E.faecalis and 47.1% for E.faecium, hemolysin activity was 52.8% for E.faecalis and 23.5% for E.faecium. In our study, it was found that VSE isolates have more virulence genes than VRE isolates. It should be kept in mind that VRE can causeinfections which are difficult-to-treat especially in hospitalized patients and VSE have significant virulence factors that can cause severe infections. PMID- 28566075 TI - [Evaluation of QuantiFERON(r)-TB Gold in Tube Test and Tuberculin Skin Test in the diagnosis of Mycobacterium tuberculosis infection]. AB - The aims of this study were to evaluate the sensitivity of QuantiFERON(r)-TB Gold in Tube (QFT) test and its agreement with the tuberculin skin test (TST), to investigate possible factors associated with indeterminate QFT test results and to explore the relationship between latent tuberculosis infection (LTBE) prevalence and the rate of tuberculosis (TB) cases in our region. 1455 cases with QFT test performed in Ege University Faculty of Medicine Hospital between 2013 and 2015 were included in the study and simultaneously TST results of 268 of 1455 cases were reached. TST results were evaluated according to both >= 10 mm and >= 15 mm cut-off values. The QFT results of the cases were compared according to their gender, age groups and clinical characteristics with chi-square test. Stratified analyses were also conducted according to age groups. Multivariate logistic regression was used to analyse factors associated with QFT positivity and indeterminate QFT results. Cohen's kappa was used to test the agreement between QFT and TDT, overall and stratified according to age groups. Among 1455 cases, 396 (27.2%) were QFT positive and 120 (8.2%) had an indeterminate QFT result. When the indeterminate results were excluded, QFT positivity was found as 29.7%. The highest indeterminate results were determined among 0-4 year-old and >= 65 year-old groups as 17.6% and 12.1%, respectively and lowest among the 55-64 age group as 4%. The comparison of the cases without any cellular immunity defect and the patients with hematologic malignancies or immune deficiency and patients under immunosuppressive treatment had two and 2.44 times more indeterminate QFT results, respectively. Among 268 cases with TST results reached, QFT positivity was 30.6%; 38.1% for TST >= 10 mm and 25.7% for TST >= 15. After the exclusion of indeterminate results, the agreement between QFT and TST >= 10 mm was 71.3% for positive cases and 75.5% for negative cases. The highest agreement between QFT and TST >= 10 mm was in the age group 35-64 and lowest in the age group >= 65. Among 43 culture-positive cases, 32 had QFT positive, six negative and five indeterminate results. When indeterminate results were excluded, the sensitivity of thetest was 84.2% (32/38) among culture-positive active TB cases. TST results were available for 17 of the culture-positive cases, among them QFT sensitivity was 76.5% (13/17), TST sensitivity 70.6% (12/17) and the sensitivity of both tests was 88.2% (15/17). The ratio of QFT positivity has increased as the age increased. Interestingly, QFT positivity was higher among females than males in the 15-34 age group and higher among males in the 35-64 age group. The rates of QFT positivity were lower among immunocompromised patients. When QFT and TST positivities were compared with the rate of TB cases among age groups, QFT positivity was observed as parallel to the rate of TB cases. In conclusion, although the sensitivity of QFT was higher than TST, it was found that it could not be considered as a gold standard in LTBE diagnosis. As active TB cases originate from the LTBE pool, QFT test results might be considered a better indicator of active TB development risk. PMID- 28566076 TI - [Evaluation of viral etiology in central nervous system infections from a university hospital point of view in Izmir based on seven years data]. AB - The serious diseases of the central nervous system (CNS); encephalitis and meningitis, have high mortality and morbidity rate especially not diagnosed and treated in time. Nucleic acid testing (NAT) is the tool of choice for viral diagnosis in CNS infections. In this study, viral etiological agents found in cerebrospinal fluid (CSF) samples sent to our university hospital virology laboratory for laboratory diagnosis of CNS infections were retrospectively evaluated and results were compared with other reports from our country. Viral etiological agents found in cerebrospinal fluid (CSF) samples sent to Ege University Faculty of Medicine Department of Medical Microbiology Virology Laboratories for laboratory diagnosis of CNS infection between 01.01.2009 31.12.2015 were evaluated retrospectively. A total of 3778 CSF tests were performed for cell culture of enterovirus (EV) in 487 samples and 3291 tests for nucleic acid testing (NAT) by real time polymerase chain reaction (PCR) in herpes simplex virus 1 (HSV1), herpes simplex virus 2 (HSV2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes virus 6 (HHV6) and EV. VZV and EV NAT's were performed during the last one and five years period, respectively. NAT positive results for HSV1, HSV2, CMV, EBV, VZV, HHV6 and EV were 1.80% (24/1333), 0.08% (1/1333), 3.28% (19/580), 4.35% (22/506), 0.46% (1/216), 1.05% (5/478) and 3.37% (6/178), respectively. EV was isolated in 30 (6.20%) of 487 CSF samples by viral culture. Positive samples were mainly from pediatric, neurology and infectious diseases clinics as expected. The number of higher positive results were found in samples sentin december (35.3%), july (12.9%) and november (10.6%). Overall 80% of positive samples belonged to patients over 18 years old. When the results of other studies reported from Turkey are examined, although the positivity rates are generally similar, it is seen that the rates specific to certain factors are higher in selected smaller patient groups like HSV1 and EV. Rapid nucleic acid tests like multiplex PCR and microarray will provide more practical and effective laboratory diagnosis approach in CNS infections, since many more microorganisms may be causative agents. PMID- 28566077 TI - [The significance and place of HBsAg neutralization test in the diagnosis and algorithm of hepatitis B infection]. AB - The diagnosis of hepatitis B virus infection is evaluated serologically, virologically, biochemically, and with histologic liver indicators. The aim of this study was to investigate the place and significance of the HBsAg neutralization test in the diagnostic algorithm for hepatitis Binfection. From the venous blood samples sent to Ankara Numune Education and Research Hospital Medical Microbiology Laboratory between September 2014 and May 2016 for HBsAg test, serum samples regarded each patient as reactive (>= 0.9 S?CO) , 9 <= S <= CO <= 30) were studied twice. A total of 105 samples which were reactive in both analyses were included in the study. After the evaluation of these samples by neutralization confirmation test, which is routinely performed in our laboratory, the samples were stored under optimal conditions and studied for HBV DNA with the real-time PCR and for HBeAg, anti-HBeAg, anti-HBc IgM, and anti-HBc total antibody assays by ELISA. The 105 samples, in which HBsAg was detected, were analyzed with the neutralization test. The presence of HBsAg was confirmed by neutralization test in 67 of 105 samples (63.8%), and of these patients, two patients (2.3%) had negative HBV DNA and anti-HBc total antibody test (false positive neutralization test). Of the 105 samples included in the study, the anti HBc total antibody test was positive in 78 patients (74.3%). However, out of these 78 patients who were positive for the anti-HBc total antibody test, there were 13 patients (16.7%) with negative neutralization and HBV DNA test results (false positive anti-HBc total antibody test). The HBV DNA positivity was detected significantly lower in samples with HBsAg level <= 5 S/CO compared to the samples with HBsAg level > 5 S/CO (p= 0.020). Also, if the unit price of the neutralization test used in our study was considered, the cost was 17,00 TL while the unit price of HBV DNA test was 55,00 TL. Utilization of the neutralization test instead of HBV DNA test provides a saving of 38,00 TL per patient. The use of the neutralization test as a validation test when the HBsAg titre was less than or equal to 5S/CO will significantly reduce the cost of the test without the need for HBV DNA test. We suggest that if both the neutralization test and the anti-HBc total antibody test is negative in a sample with an HBsAg titration higher than 5 S/CO, the decision can be made without the need for HBV DNA test. However; if the neutralization test is negative, but the anti-HBc total antibody test is positive, then HBV DNA needs to be determined to eliminate the inconsistency between neutralization and anti-HBc total antibody assays. At the same time, we found that the use of anti-HBc total antibody test along with HBsAg as a screening test did not provide any advantage since the anti-HBc total antibody test was detected to have a high false positivity (16.7%) rate. PMID- 28566078 TI - [Determination of drug resistance mutations of NS3 inhibitors in chronic hepatitis C patients infected with genotype 1]. AB - Direct-acting antiviral agents (DAA) such as NS3 protease inhibitors is the first class of drugs used for chronic hepatitis C (CHC) treatment. NS3 inhibitors (PI) with low genetic barrier have been approved to be used in the CHC genotype 1 infections, and in the treatment of compensated liver disease including cirrhosis together with pegile interferon and ribavirin. Consequently, the development of drug resistance during DAA treatment of CHC is a major problem. NS3 resistant variants can be detected before treatment as they can occurnaturally. The aim of this study was to investigate new and old generation NS3 inhibitors resistance mutations before DAA treatment in hepatitis C virus (HCV) that were isolated from CHC. The present study was conducted in 2015 and included 97 naive DAA patients infected with HCV genotype 1, who were diagnosed in Manisa and Kocaeli cities of Turkey. Magnetic particle based HCV RNA extraction and than RNA detection and quantification were performed using commercial real-time PCR assay QIASypmhony + Rotorgene Q/ArtusHCV QS-RGQ and COBAS Ampliprep/COBAS TaqMan HCV Tests. HCV NS3 viral protease genome region was amplified with PCR and mutation analysis was performed by Sanger dideoxy sequencing technique of NS3 protease codons (codon 32 185). HCV NS3 protease inhibitors; asunaprevir, boceprevir, faldaprevir, grazoprevir, pariteprevir, simeprevir and telaprevir were analysed for resistant mutations by Geno2pheno-HCV resistance tool. HCV was genotyped in all patients and 88 patients (n= 88/97, 91%) had genotype 1. Eight (n= 8/97, 8.2%) and 80 (n= 80/97, 82.4%) HCC patients were subgenotyped as 1a and 1b, respectively. Many aminoacid substitutions and resistance mutations were determined in 39/88 (44%) patients in the study group. Q80L, S122C/N, S138W were defined as potential substitutions (6/88 patients; 7%); R109K, R117C, S122G, I132V, I170V, N174S were described as potential resistance (34/88 patients; 39%); V36L, T54S, V55A, Q80H were characterized as resistance (7/88 patients; 8%) and Q80K, A156S were defined as high resistance (3/88 patients; 3%) mutations. Based on resistance and high resistance mutations, clinically significant mutations were defined in 10/88 (11%) of the patients. Our study shows that it is essential to analyse HCV NS3 protease inhibitors drug resistance before DAA treatment of CHC patients. On the other hand, our results pointed out that analysis of NS5A and NS5B genome region mutations may also be required in the near future. PMID- 28566079 TI - [Investigation of cytokine responses and variations in the expression of beta defensin-3 of Caco-2 human colon epidermal adenocarsinoma and THP-1 human leukemia monocyte cell lines in response to Toxoplasma gondii under various conditions]. AB - Mononuclear phogocytic cells and epithelial cells are effective during the initiation and regulation of the innate immune response. They have an active role in mucosal immune response both mechanically and by interaction with other cells with cytokine release. Defensins are microbicidal peptides that are expressed in various cells and are thought to be effective in the first line defense against pathogens. IL-12 and IL-10, showing proinflamatory and antiinflamatory activities, respectively, are actors of the cellular immunity and limit the infection of the host without causing immunopathology. The aim of this study was to observe the differences in the release of IL-12 and IL-10 and the expression of human beta-defensin-3 (hBD-3) inCaco-2 (human colon epidermal adenocarcinoma cell) and THP-1 (human leukemia monocytic cell) cell lines cultured alone or in co-culture, by the stimulation of Toxoplasma gondii tachyzoites either in direct contact with the cells or separated by an insert filter from the cells. Twenty four hours after the addition of RH strain tachyzoites to the cells, the supernatants were collected from the experiment wells, and commercial ELISA kits (Invitrogen) were used according to the manufacturers instructions to measure IL 12 and IL-10 levels. HBD-3 expression of cells collected from the experiment wells afterfour and 24 hourswere analyzed by using real time PCR. For this procedure, complementary c-DNA was obtained (Transcriptor High Fidelity cDNA Synthesis Kit, Roche Diagnostics, Germany)after the extraction of RNA with a commercial kit (High pure RNA isolation kit, Roche Diagnostics, Germany). IL-12 was higher than IL-10 in all experiment wells. IL-12 was induced more in the co culture wells where Caco-2 and THP-1 cells were challenged together, than the wells in which the cells infected with T.gondii tachyzoites alone. No differences in respect to cytokine response were observed between the cells with which tachyzoites were in contact and the cells which were separated from the parasites with an insert. In hBD-3 experiments, Caco-2 and THP-1 cells interacted in co culture wells when infected with tachyzoites and displayed a higher level of hBD 3 expression than the condition when they were infected alone. This study showed that, IL-12 release and hBD-3 expression, which play a role in innate immunity, are greater when various antigens of T.gondii interacted with stimulated mononuclear cell and epithelial cells. PMID- 28566080 TI - [Molecular epidemiology of human Mycobacterium bovis infection in Aegean Region, Turkey]. AB - Mycobacterium bovis, which has a broader host spectrum as opposed to Mycobacterium tuberculosis that generally causes disease in humans, mainly leads to chronic progressive pulmonary disease in a large number of domestic and wild mammals, particularly cattle. The term "zoonotic tuberculosis (TB)" is used to describe M.bovis infection in humans. "Zoonotic TB" can not be differentiated clinically, radiologically or pathologically from TB caused by M.tuberculosis. The aim of this study was to evaluate the role of M.bovis in epidemiology of human TB in Aegean Region, Turkey and to determine M.bovis genotypes responsible for human TB. Thirteen M.bovis isolates identified by spoligotyping from 482 M.tuberculosis complex isolates obtained from clinical specimens sent for routine mycobacteriological examination to the Mycobacteriology Laboratory in Medical Microbiology Department of Ege University Faculty of Medicine Hospital between 2009 and 2014 were included in the study. Drug susceptibility tests of the isolates were performed by the BACTEC MGIT 960 automated system. It was determined that 9 (63.6%) of the 13 spoligotyped M.bovis isolates in this study were ST685 (SB0288), 1 (7.7%) was ST 1118 (SB0989) and 1 (7.7%) was ST820 (SB0856), for two isolates there were no registered data in SpolDB4 and Mbovis.org databases. All the isolates were susceptible to first-line antituberculosis drugs. It was determined that 13 M.bovis isolates examined in the study accounted for 2.7% of the 482 M.tuberculosis complex isolates spoligotyped in the same period. In this study, it was determined that 8 (%61.5) of 13 patients was male, 5 (38.5%) of them was female, 9 (69.2%) of the 13 patients had pulmonary TB and 4 (30.8%) had extra pulmonary TB. Seven of nine patients with pulmonary TB and two of the four patients with extrapulmonary TB were living in the rural area, and two patients with pulmonary TB had occupational exposure. Although ST683 (SB0140) is widely seen in the world among human isolates, it was not detectedin this study and other studies conducted in Turkey. In contrast, ST685 (SB0288) and ST1118 (SB0989), which have been reported very few in the world, found to be predominant in this study. This result suggested that they may be unique spoligotypes emerging in Anatolia. In conclusion, collaborative molecular epidemiological studies are needed in conjunction with researchers working in medicine and veterinary fields to determine precisely the importance of zoonotic TB in human TB in our country, to determine the route of transmission to humans and risk factors for zoonotic TB infections, to identify the dominant types between humans and animals and to understand the phylogeographic relationships of the strains in our country. PMID- 28566081 TI - [A rarely isolated bacterium in microbiology laboratories: Streptococcus uberis]. AB - Streptococcus uberis is a gram-positive bacterium that is mostly responsible for mastitis in cattle. The bacterium rarely has been associated with human infections. Conventional phenotyphic methods can be inadequate for the identification of S.uberis; and in microbiology laboratories S.uberis is confused with the other streptococci and enterococci isolates. Recently, molecular methods are recommended for the accurate identification of S.uberis isolates. The aim of this report is to present a lower respiratory tract infection case caused by S.uberis and the microbiological methods for identification of this bacterium. A 66-year-old male patient with squamous cell lung cancer who received radiotherapy was admitted in our hospital for the control. According to the chest X-Ray, patient was hospitalized with the prediagnosis of ''cavitary tumor, pulmonary abscess''. In the first day of the hospitalization, blood and sputum cultures were drawn. Blood culture was negative, however, Candida albicans was isolated in the sputum culture and it was estimated to be due to oral lesions. After two weeks from the hospitalization, sputum sample was taken from the patient since he had abnormal respiratory sounds and cough complaint. In the Gram stained smear of the sputum there were abundant leucocytes and gram-positive cocci, and S.uberis was isolated in both 5% sheep blood and chocolate agar media. Bacterial identification and antibiotic susceptibility tests were performed by VITEK 2 (Biomerieux, France) and also, the bacterium was identified by matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) based VITEK MS system as S.uberis. The isolate was determined susceptible to ampicillin, erythromycin, clindamycin, levofloxacin, linezolid, penicillin, cefotaxime, ceftriaxone, tetracycline and vancomycin. 16S, 23S ribosomal RNA and 16S-23S intergenic spacer gene regions were amplified with specific primers and partial DNA sequence analysis of 16S rRNA polymerase chain reaction (PCR) products were performed by 3500xL Genetic Analyzer (Applied Biosystems, USA). According to the partial 16S rRNA gene sequencing results, bacterium was confirmed as S.uberis. This report makes a significant contribution to the number of case reports of human infections caused by S.uberis as the identification was performed by current microbiological methods in our case. In conclusion, S.uberis should be evaluated as an opportunistic pathogen among the immunosuppressed patients and in addition to phenotypic bacteriological methods, the other recent microbiological methods should also be utilized for the identification. PMID- 28566082 TI - [Femoral hemodialysis catheter-related bacteremia due to Globicatella sanguinis: challenges in species identification]. AB - In this case, catheter-related bacteremia due to Globicatella sanguinis in a 43 years old female patient undergoing hemodialysis with the diagnosis of diabetic nephropathy was presented and the methods in the laboratory diagnosis of the rare opportunistic pathogen, Globicatella cins, were nvestigated. A set of peripheral blood cultures and simultaneous catheter culture was obtained from the patient in third of May 2016. Biochemical tests, Phoenix (Becton Dickinson, USA) and MicroScan (Beckman Coulter, USA) automated systems and matrix assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF MS) based Microflex MS (Bruker, Daltonics, Germany) and VITEK MS (database v2.0) (bioMerieux, France) systems were used for the identification of the cultured bacteria. Partial 16S rDNA sequencing was done by using specific p8FPL 5'-AGT TTG ATC ATG GCT CAG-3' and p806R 5'-GGA CTA CCA GGG TAT CTA AT-3' primers. Minimal inhibitory concentrations (MICs) for vancomycin, erythromycin, imipenem, cefotaxime and benzypenicillin were determined by agar gradient method. The blood and catheter cultures yielded the same type of bacterial colonies. Alfa hemolytic, catalase negative colonies observed on blood agar plates after an over night incubation yielded gram-positive cocci on Gram staining. In Sisli Hamidiye Etfal Hospital, the isolate was identifed as G.sulfidifaciens (score value > 2) by Bruker MS system and as G.sanguinis by Phoenix automated system. In Inonu University, the isolate could not be identified by Microscan automated system while VITEK MS named the isolate as 99.9% G.sanguinis and 98.3% G.sulfidifaciens. The 16S rDNA sequencing identifed the isolate as 100% G.sanguinis (GenBank accessionno. KJ680157.1). The MIC values were 0.38 ug/ml, 1.5 ug/ml, 0.38 ug/ml, > 32 ug/ml and 64 ug/ml for vancomycin, eryrthromycin, imipenem, cefotaxime and benzylpenicillin, respectively. The patient was diagnosed as catheter-related bacteremia and vancomycin (1 x 1 g IV/72 h) was used for up to 10 days. No fever and bacterial growth in cultures were present in her control visits. As G.sanguinis is not among the commonly encountered pathogens and due to difficulties in laboratory diagnosis, it may be missedor mis-identified in clinical laboratories. BD Phoenix and Bruker MS data bases lack G.sulfidifaciens and G.sanguinis, respectively, while the Globicatella genus is not present in MicroScan database. The increased number of medical implementations and the increasing number of immunosuppressed patient populations in recenty ears will lead to the emergence of rare bacteria. Increasing the diagnostic power of clinical microbiology laboratories by conventional and molecular methods and renewal of the databases of commercial identification systems by expanding the pathogen spectrum are significantly important for the prevention and control of infections caused by these agents. PMID- 28566083 TI - [A case of coccidioidomycosis in Turkey imported from the United States of America]. AB - Coccidioidomycosis caused by Coccidioides immitis or Coccidioides posadasii is a rare infectious disease except in endemic regions. In this report the third documented imported case of coccidioidomycosis in Turkey was presented. A thirty year-old male patient was admitted to our hospital with fever and purulent drainage from his chest tube. He had worked in Arizona, USA, until 4 months before this presentation. While in Arizona, he experienced cough and hemoptysis and was diagnosed as pulmonary coccidioidomycosis. He was treated with itraconazole for two months and he had no symptoms for 3 years. He then returned to Turkey and 2 months after his return to Turkey, he was admitted to another hospital in Istanbul with dyspnea and diagnosed as hydro-pneumothorax, and pleural fluid obtained from the inserted chest tube was found to be purulent. One gram of BID amoxicillin-clavulanate was given. Physical examination on admission revealed a purulent drainage on the right side chest tube, a temperature of 38.5 degrees C and decreased breath sounds on the right lung. Piperacillin-tazobactam 3 x 4.5 g intravenous and fluconazole 400 mg intravenous once daily were started. Human immunodeficiency virus test was negative. Gram-negative diplococci and rods, gram-positive cocci and septate hyphae were seen in the Gram stain of his pleural fluid. Pleural fluid culture revealed Moraxella catarrhalis after 24 hours incubation and a mold after 72 hours of incubation. Anti-coccidioidal antibodies were found positive in a titer of 1/2. Hydro-pneumothorax, atelectasis and a 3 mm nodules in the right lung were seen in his thorax CT. The patient's pleural fluid and the culture plates were sent to the Public Health Institute of Turkey, Mycology Reference Laboratory (PHIT-MRL), with a clinical suspicion of coccidioidomycosis. The specimen and plates were submitted to the PHIT-MRL Bio Safety Level-3 laboratory for mycological evaluation. The microscopic examination of 15% KOH preparations of pleural fluid specimens revealed septate hyphae which appear to be in the early stages of forming arthroconidia. The pleural fluid culture grew buff-white coloured colonies with aerial hyphae, which were suspected of being a Coccidioides spp. The strain was identified as C.immitis/posadasii by direct microscopy and culture, and subsequently confirmed by the FDA-approved DNA probe. DNA sequence analysis of the ITS and D1/D2 rDNA regions confirmed the isolate to be C.posadasii species [ITS 100% match to GenBank Accession No. AB232901 (630/630 base pair match), and D1/D2 100% match to GenBank Accession No. AB232884 (617/617 base pair match)]. ITS1 and ITS2 barcode analysis also confirmed the species to be C.posadasii, which is the species endemic in Arizona. Susceptibility testing was performed according to Clinical and Laboratory Standards Institute M38-A2 guidelines in the Fungus Testing Laboratory of the University of Texas Health Science Center at San Antonio and minimal inhibitory concentration values were; 0.125 ug/ml for amphotericin B, posaconazole and voriconazole, 0.5 ug/ml for itraconazole and 8 ug/ml for fluconazole. He had decortication of the pleura and was discharged from hospital after six weeks treatment with intravenous fluconazole which was continued orally for one year. Anti-coccidioidal antibodies were negative after two months of treatment. The patient is currently asymptomatic. The presented case is the third case reported from Turkey and provides additional contribution to the existing literature with regard to the appearance of arthroconidium, which is the unusual hyphal form, instead of the expected spherules in the infected tissue. PMID- 28566084 TI - [Multicenter investigation of bufavirus in the etiology of viral central nervous system infections of adults and children]. AB - Bufavirus (BuV) is a newly-identified parvovirus in the family of Parvoviridae. Metagenomic analysis of fecal samples from children in Burkina Faso with acute diarrhea showed a highly divergent parvovirus, which was named bufavirus (BuV). The global distribution, epidemiology and genetic characteristics of BuVs infections are obscure. It was first discovered as an agent causing gastroenteritis but the association of BuV infections with various clinical presentations mostly remain to be explored. The aims of this study were to investigate probable impact of BuV in central nervous system infections in a region where it was previously reported to cause human infections and to detect enteroviruses (EV) which are reported as a cause of central nervous system infections in our country. The study was undertaken in three institutions in Ankara province, Central Anatolia, Turkey. Patients, clinically diagnosed with febrile disease and/or central nervous system infections of presumed viral etiology, were enrolled in the study with informed consent. Cerebrospinal fluid specimens were collected from 93 children attended to Gazi University Hospital and Diskapi Yildirim Beyazit Hospital from October 2011-April 2015 and 33 adult patients, attended to Hacettepe University Hospital from June 2012 to March 2013. Clinical history and follow-up, physical examination and standard laboratory findings of the patients were recorded. Nucleic acid extraction was performed via commercially available spin-column assays and complementery DNA (cDNA) synthesis was performed by using commercially available cDNA synthesis kit with randomised hexamer primers. BuV detection was carried out by in house nested-polymerase chain reaction (PCR) utilized with previously-described primers. EV detection was carried out by in house PCR with pan-enterovirus primers. Seventy-four percent (93/126) and 26% (33/126) of the patients were children (0-18) and adults (19 86), respectively. In all patients, bacterial, mycobacterial and fungal cultures were negative, as well as PCR for herpes simplex virus (HSV) types 1 and 2. PCR results of all samples were negative for BuV and EV. This is the first study that evaluates a probable association of BuV and central nervous system infections. Although Parvovirus B19, a well-characterized human pathogen can rarely cause encephalitis, our findings did not confirm such an association for BuV in this preliminary investigation. However, long-term evaluation of individual cases with unknown etiology is required to reveal the relationship of the virus with specific environments. PMID- 28566085 TI - Prevalence of autoantibodies against cellular antigens in patients with HIV and leprosy coinfection in the Amazon region. AB - BACKGROUND: Infectious agents can activate self-reactive T cells. In general, infections trigger various mechanisms, including a lack of auto-tolerance, induction of costimulatory molecules on antigen presenting cells, and molecular simulation, in addition to cross-reactions between microbial antigens and self antigens. HIV and leprosy coinfections lead to self-immunity with the production of autoantibodies. However, not enough data on the immune behaviour associated with this coinfection are available. Therefore, this study focused on the detection of autoantibodies against cellular antigens (AACA) in individuals with HIV and leprosy coinfection in the Amazon region. METHODS: Patients were distributed into four groups according to their infections: (i) coinfection with HIV and leprosy (n = 23), (ii) infection with leprosy (n = 33), (iii) infection with HIV/AIDS (n = 25), and (iv) healthy blood donor controls (n = 100). AACA were identified by indirect immunofluorescence and the samples were tested using a commercial diagnosis kit containing the antinuclear antibody HEp-2. RESULTS: Morphologically, all stages of cell division were assessed in addition to the morphological features associated with the nuclear matrix, nucleolus, mitotic spindle, and cytoplasm. There was a high prevalence of AACA in the coinfection group (47.8%, n = 11) when compared with the control group of healthy blood donors (2.0%). The results showed predominantly cytoplasmic staining in all groups analysed, and no difference was observed between the presence or absence of AACA and the leprosy forms (paucibacillary and multibacillary) in the coinfection group. CONCLUSIONS: The results of this study show that despite the tendency of coinfected patients to have higher levels of autoantibodies, no correlation was observed between clinical and laboratorial variables and morbidity associated with HIV and leprosy coinfections or the levels of AACA in the serum of coinfected patients. These data are important to elucidate this complex relationship between HIV and leprosy and thus improve the follow-up of these patients. PMID- 28566087 TI - Development and evaluation of an "emergency access button" in Danish out-of-hours primary care: a study protocol of a randomized controlled trial. AB - BACKGROUND: Out-of-hours (OOH) health care for acute medical problems is often challenged by long waiting time for callers in need of advice and triage. Allowing patients to bypass the OOH telephone waiting line may increase patient satisfaction and provide them with a feeling of safety. We aimed to develop an "emergency access button" enabling patients to bypass the normal telephone waiting line in out-of-hours primary care (OOH-PC) if they perceive their condition to be critical and to evaluate the effect of introducing the button in terms of patient satisfaction and their feeling of safety. METHODS: All patients calling the OOH-PC in two different Danish health care regions during three months will be included in this randomized controlled trial. Data will be collected through two questionnaires developed for this study: a pop-up questionnaire on the relevance of bypassing the normal waiting line to be completed by triage professionals after patient contact and a paper/electronic questionnaire on perceived safety and satisfaction with the emergency access button to be completed by the callers. These questionnaires were developed and validated using external and internal expert feedback, focus group interviews and a two-week field test. The study will be conducted over three months with an estimated user-rate of the emergency access button of 3%. DISCUSSION: We have developed an emergency access button and we now want to investigate whether this new option will influence upon the level of satisfaction and the feeling of safety in the calling patients. Additionally, the study will reveal the assessed relevance of the decision to bypass the line by triage professionals. TRIAL REGISTRATION: Registered as NCT02572115 at Clinicaltrials.gov on October 5th 2015. PMID- 28566086 TI - The genetics of gout: towards personalised medicine? AB - Over the last decade, there have been major advances in the understanding of the genetic basis of hyperuricaemia and gout as well as of the pharmacogenetics of urate-lowering therapy. Key findings include the reporting of 28 urate-associated loci, the discovery that ABCG2 plays a central role on extra-renal uric acid excretion, the identification of genes associated with development of gout in the context of hyperuricaemia, recognition that ABCG2 variants influence allopurinol response, and the impact of HLA-B*5801 testing in reducing the prevalence of allopurinol hypersensitivity in high-risk populations. These advances, together with the reducing cost of whole genome sequencing, mean that integrated personalised medicine approaches may soon be possible in clinical practice. Genetic data may inform assessment of disease prognosis in individuals with hyperuricaemia or established gout, personalised lifestyle advice, selection and dosing of urate-lowering therapy, and prevention of serious medication adverse effects. In this article, we summarise the discoveries from genome-wide association studies and discuss the potential for translation of these findings into clinical practice. PMID- 28566088 TI - Factors associated with utilization of skilled service delivery among women in rural Northern Ghana: a cross sectional study. AB - BACKGROUND: Ghana's current Maternal Mortality Ratio (MMR) of 319 per 100,000 live births makes achievement of the Sustainable Development Goal of 70 maternal deaths per 100,000 live births or less by 2030 appear to be illusory. Skilled assistance during childbirth is a critical strategy to reducing maternal mortality, yet the proportion of deliveries taking place within health facilities where such assistance is provided is very low in Ghana, with huge disparity between urban and rural women. To address the gap in skilled attendance in rural Upper East Region, the Ghana Health Service (GHS) in 2005 piloted a program that involved training of Community Health Officers (CHOs) as midwives. This study explored factors associated with skilled delivery services utilization in a predominantly rural district in Ghana. METHODS: A cross-sectional study, data was collected from a sample of 400 women between the ages of 15 and 49 years who had given birth a year prior to the study. We used frequencies and percentages for descriptive analysis and chi-square (chi 2 ) test for relationship between independents factors and utilization of skilled delivery services. RESULTS: Of the 400 women included in the analysis, 93.3% of them delivered in a health facility. Almost all of the mothers (97.3%) attended or received antenatal care at their last pregnancy with 75.0% of them having four or more ANC visits. The proportion of women who received ANC and utilized skilled delivery services was high (91.5%). Mother's educational attainment, ANC attendance, frequency of ANC visits, satisfaction with ANC services and possession of valid NHIS card significantly associated with utilisation of skilled delivery services. CONCLUSION: For a predominantly rural district, the percentage of women who deliver within health facilities where skilled assistance is available is very encouraging and a significant stride towards reducing Ghana's overall MMR. Having four or more ANC visits and improving on the quality of care provided has a great potential of improving uptake of skilled delivery services. PMID- 28566089 TI - Histone H3 lysine 36 methylation affects temperature-induced alternative splicing and flowering in plants. AB - BACKGROUND: Global warming severely affects flowering time and reproductive success of plants. Alternative splicing of pre-messenger RNA (mRNA) is an important mechanism underlying ambient temperature-controlled responses in plants, yet its regulation is poorly understood. An increase in temperature promotes changes in plant morphology as well as the transition from the vegetative to the reproductive phase in Arabidopsis thaliana via changes in splicing of key regulatory genes. Here we investigate whether a particular histone modification affects ambient temperature-induced alternative splicing and flowering time. RESULTS: We use a genome-wide approach and perform RNA-sequencing (RNA-seq) analyses and histone H3 lysine 36 tri-methylation (H3K36me3) chromatin immunoprecipitation sequencing (ChIP-seq) in plants exposed to different ambient temperatures. Analysis and comparison of these datasets reveal that temperature induced differentially spliced genes are enriched in H3K36me3. Moreover, we find that reduction of H3K36me3 deposition causes alteration in temperature-induced alternative splicing. We also show that plants with mutations in H3K36me3 writers, eraser, or readers have altered high ambient temperature-induced flowering. CONCLUSIONS: Our results show a key role for the histone mark H3K36me3 in splicing regulation and plant plasticity to fluctuating ambient temperature. Our findings open new perspectives for the breeding of crops that can better cope with environmental changes due to climate change. PMID- 28566090 TI - Lymphatic delivery of etanercept via nanotopography improves response to collagen induced arthritis. AB - BACKGROUND: Evidence suggests lymphatic function mediates local rheumatoid arthritis (RA) flares. Yet biologics that target the immune system are dosed systemically via the subcutaneous (SC) administration route, thereby inefficiently reaching local lymphatic compartments. Nanotopography has previously been shown to disrupt tight cellular junctions, potentially enhancing local lymphatic delivery and potentially improving overall therapeutic efficacy. METHOD: We first characterized nanotopography (SOFUSATM) delivery of an anti-TNF drug, etanercept, by comparing pharmacokinetic profiles to those obtained by conventional SC, intravenous (IV), and intradermal (ID) routes of administration, and assessed uptake of radiolabeled etanercept in draining lymph nodes (LNs) in single dosing studies. We then compared etanercept efficacy in a progressive rat model of collagen-induced arthritis (CIA), administered systemically via SC route of administration; via the regional lymphatics through ID delivery; or through a nanotopography (SOFUSATM) device at 10, 12, and 14 days post CIA induction. Measurements of hind limb swelling and near-infrared fluorescence (NIRF) imaging of afferent lymph pumping function and reflux were conducted on days 11, 13, and 18 post CIA induction and compared to untreated CIA animals. Univariate and multivariate analysis of variance were used to compare the group differences for percentage swelling and lymphatic contractile activity. RESULTS: Even though all three modes of administration delivered an equal amount of etanercept, SOFUSATM delivery resulted in increased lymphatic pumping and significantly reduced swelling as compared to untreated, ID, and SC groups. Pharmacokinetic profiles in serum and LN uptake studies showed that using the nanotopography device resulted in the greatest uptake and retention in draining LNs. CONCLUSIONS: Locoregional lymphatic delivery of biologics that target the immune system may have more favorable pharmacodynamics than SC or IV administration. Nanotopography may provide a more efficient method for delivery of anti-TNF drugs to reverse impairment of lymphatic function and reduce swelling associated with RA flares. PMID- 28566091 TI - Health care professionals from developing countries report educational benefits after an online diabetes course. AB - BACKGROUND: Medical education is a cornerstone in the global combat against diseases such as diabetes and obesity which together affect more than 500 million humans. Massive Open Online Courses (MOOCs) are educational tools for institutions to teach and share their research worldwide. Currently, millions of people have participated in evidence-based MOOCs, however educational and professional benefit(s) for course participants of such initiatives have not been addressed sufficiently. We therefore investigated if participation in a 6 week open online course in the prevention and treatment of diabetes and obesity had any impact on the knowledge, skills, and career of health care professionals contrasting participants from developing countries versus developed countries. METHODS: 52.006 participants signed up and 29.469 participants were active in one of the three sessions (2014-2015) of Diabetes - a Global Challenge. Using an online based questionnaire (nine sections) software (Survey Monkey), email invitations were send out using a Coursera based database to the 29.469 course participants. Responses were analyzed and stratified, according to the United Nations stratification method, by developing and developed countries. RESULTS: 1.303 (4.4%) of the 29.469 completed the questionnaire. 845 of the 1303 were defined as health care professionals, including medical doctors (34%), researchers (15%), nurses (11%) and medical students (8%). Over 80% of the health care participants report educational benefits, improved knowledge about the prevention and treatment therapies of diabetes and furthermore improved professional life and practice. Over 40% reported that their professional network expanded after course participation. Study participants who did not complete all modules of the course reported similar impact as the ones that completed the entire course(P = 0.9). Participants from developing countries gained more impact on their clinical practice (94%) compared to health care professionals from developed regions (88%) (Mean of differences = 6%, P = 0.03. CONCLUSIONS: Based on self-reports from course participants, MOOC based medical education seems promising with respect to providing accessible and free research-based education to health professionals in both developing and developed countries. Course participants from developing countries report more benefits from course participation than their counterparts in the developed world. PMID- 28566092 TI - Increased fragility fracture risk in Korean women who snore: a 10-year population based prospective cohort study. AB - BACKGROUND: Snoring is frequently associated with obstructive sleep apnea (OSA). Previous studies have shown that bone mineral density was significantly lower in patients with OSA than in controls; however, these studies did not focus on fractures. Fragility fractures can lead to long-term disabilities and a decrease in quality of life. The present study aimed to investigate the association between snoring and fragility fractures. METHODS: This study included 2969 men and 3220 women aged 40 years and older from the Ansung and Ansan cohort studies in Korea. During a 10-year follow-up period, 129 and 273 fracture cases were reported in men and women, respectively. RESULTS: Severe snoring (6-7 nights per week or sleep disturbance by snoring in the next room) was a statistically significant risk factor for fracture (p = 0.006, hazard ratio 1.68, 95% confidence interval 1.16-2.43) after adjusting for covariates related to fragility fracture in women. However, both snoring and severe snoring groups did not show significant associations with the fracture risk in men. CONCLUSIONS: Thus, information on the frequency of snoring in women may improve the accuracy of fragility fracture risk prediction, which can help in deciding whether intervention or treatment is necessary. PMID- 28566093 TI - Efficacy and short-term outcomes of preoperative chemoradiotherapy with intermittent oral tegafur-uracil plus leucovorin in Japanese rectal cancer patients: a single center experience retrospective analysis. AB - BACKGROUND: Various types of preoperative chemoradiotherapy (CRT) have been established for rectal cancer; thus, Physicians will need to refine the selection of appropriate preoperative CRT for different patients since there are various treatment regimens. Oral tegafur-uracil (UFT) plus leucovorin (LV) is commonly used to treat rectal cancer in Japan. Oral chemotherapy offers patients many potential advantages. Since 2008, we have been performing preoperative CRT with intermittent oral UFT plus LV in locally advanced rectal cancer patients to prevent postoperative local recurrence. Here, in a retrospective analysis, we evaluated the efficacy and short-term outcomes of preoperative CRT with intermittent oral UFT plus LV. METHODS: We analyzed data from 62 patients with locally advanced rectal cancer, including 31 patients who underwent preoperative CRT between 2009 and 2013 (the CRT group) and 31 patients who were treated with surgery alone between 2001 and 2008 (the non-CRT group). Clinicopathologically, both groups included patients with rectal cancer at clinical tumor stages III-IV or clinical node stages 0-III. In the CRT group, curative operations were performed >=8 weeks after CRT. Patients were concomitantly treated with 2 cycles of oral UFT (300 mg/m2/day, days 1-14 and 29-42) plus LV (75 mg/day, days 1-14 and 29-42) and 45 Gy of radiotherapy. Chemotherapy was repeated every 28 days, followed by a 2-week break. RESULTS: The completion rate of CRT was high at 94% (n = 29/31). The downstaging rate of CRT was 61% (n = 19/31). The pathological complete response rate was 6.5% (n = 2/31). Significant differences were observed in the 3-year local recurrence rate between the two groups (P < 0.05). CONCLUSIONS: Preoperative CRT with intermittent oral UFT plus LV appears to be a tolerable and effective treatment for Japanese patients with rectal cancer. A further investigation of a diversification of preoperative CRT for Japanese rectal cancer patients is required. PMID- 28566095 TI - Health-related outcomes of new grocery store interventions: a systematic review. AB - OBJECTIVE: To assess the evidence of the impact of new food store (supermarket/grocery store) interventions on selected health-related outcomes. DESIGN: A systematic review following the Effective Public Health Practice Project guidelines. All quantitative studies were assessed for their methodological quality. Results were synthesized narratively. SETTING: Eight electronic databases - MEDLINE, EMBASE, CINAHL, ProQuest Public Health, Web of Science, Scopus, PsycINFO and Cochrane Library - were searched to identify relevant records. SUBJECTS: Peer-reviewed scholarly journal articles on new grocery store/supermarket interventions with adult study populations, published in the English language after 1995. RESULTS: Eleven records representing seven new grocery store interventions were identified. Six were assessed having 'weak' methodological quality, one as 'moderate' and two as 'strong'. All studies reported fruit and vegetable consumption but results were not consistent, some studies reporting significantly more and others no increase in consumption. BMI and self-rated health did not show significant improvements. Perceptions of food access, neighbourhood satisfaction and psychological health showed significant improvements. CONCLUSIONS: Improved food access through establishment of a full service food retailer, by itself, does not show strong evidence towards enhancing health-related outcomes over short durations. Presently the field is developing and the complex linking pathways/mechanisms are yet to be elucidated. Further evidence, in the form of high-quality research in different communities with longer follow-up periods, is needed to inform policy decisions. PMID- 28566094 TI - Assessment of cerebral blood flow in adult patients with aortic coarctation. AB - BACKGROUND: Survival into adult life in patients with aortic coarctation is typical following surgical and catheter-based techniques to relieve obstruction. Late sequelae are recognised, including stroke, hypertension, and intracerebral aneurysm formation, with the underlying mechanisms being unclear. We hypothesised that patients with a history of aortic coarctation may have abnormalities of cerebral blood flow compared with controls. METHODS: Patients with a history of aortic coarctation underwent assessment of cerebral vascular function. Vascular responsiveness of intracranial vessels to hypercapnia and degree of cerebral artery stiffness using Doppler-derived pulsatility indices were used. Response to photic stimuli was used to assess neurovascular coupling, which reflects endothelial function in response to neuronal activation. Patient results were compared with age- and sex-matched controls. RESULTS: A total of 13 adult patients (males=10; 77%) along with 13 controls underwent evaluation. The mean age was 36.1+/-3.7 years in the patient group. Patients with a background of aortic coarctation were noted to have increased pulse pressure on blood pressure assessment at baseline with increased intracranial artery stiffness compared with controls. Patients with a history of aortic coarctation had less reactive cerebral vasculature to hypercapnic stimuli and impaired neurovascular coupling compared with controls. RESULTS: Adult patients with aortic coarctation had increased intracranial artery stiffness compared with controls, in addition to cerebral vasculature showing less responsiveness to hypercapnic and photic stimuli. Further studies are required to assess the aetiology and consequences of these documented abnormalities in cerebral blood flow in terms of stroke risk, cerebral aneurysm formation, and cognitive dysfunction. PMID- 28566096 TI - Attributable Mortality of Healthcare-Associated Infections Due to Multidrug Resistant Gram-Negative Bacteria and Methicillin-Resistant Staphylococcus Aureus. AB - OBJECTIVE The purpose of this study was to quantify the effect of multidrug resistant (MDR) gram-negative bacteria and methicillin-resistant Staphylococcus aureus (MRSA) healthcare-associated infections (HAIs) on mortality following infection, regardless of patient location. METHODS We conducted a retrospective cohort study of patients with an inpatient admission in the US Department of Veterans Affairs (VA) system between October 1, 2007, and November 30, 2010. We constructed multivariate log-binomial regressions to assess the impact of a positive culture on mortality in the 30- and 90-day periods following the first positive culture, using a propensity-score-matched subsample. RESULTS Patients identified with positive cultures due to MDR Acinetobacter (n=218), MDR Pseudomonas aeruginosa (n=1,026), and MDR Enterobacteriaceae (n=3,498) were propensity-score matched to 14,591 patients without positive cultures due to these organisms. In addition, 3,471 patients with positive cultures due to MRSA were propensity-score matched to 12,499 patients without positive MRSA cultures. Multidrug-resistant gram-negative bacteria were associated with a significantly elevated risk of mortality both for invasive (RR, 2.32; 95% CI, 1.85-2.92) and noninvasive cultures (RR, 1.33; 95% CI, 1.22-1.44) during the 30-day period. Similarly, patients with MRSA HAIs (RR, 2.77; 95% CI, 2.39-3.21) and colonizations (RR, 1.32; 95% CI, 1.22-1.50) had an increased risk of death at 30 days. CONCLUSIONS We found that HAIs due to gram-negative bacteria and MRSA conferred significantly elevated 30- and 90-day risks of mortality. This finding held true both for invasive cultures, which are likely to be true infections, and noninvasive infections, which are possibly colonizations. Infect Control Hosp Epidemiol 2017;38:848-856. PMID- 28566098 TI - Fish parasites as indicators of organic pollution in southern Brazil. AB - Increasing urbanization along riverbanks is a constant source of stressors to the aquatic community, and the use of bioindicators is suitable to detect and monitor the effect of each stressor. We investigated the parasites of the 'cara' fish (Geophagus brasiliensis) as potential bioindicators in a river whose banks are subject to increasing anthropogenic pressure. Samples were taken at four points of the Sangradouro River, in Florianopolis, southern Brazil, bimonthly for 12 months. Water temperature, pH, dissolved oxygen, conductivity and salinity were measured at each point and water samples were taken for nutrient analysis (total nitrogen, nitrite, total ammonia nitrogen, total phosphorus, phosphate), and total and faecal coliforms. A generalized linear model (GLM) was constructed using the abundance of each parasite species as the response variable and biometric characteristic of the fish and water variables as possible predictors. Among the 137 fish examined, 114 (83.2%) were parasitized by at least one parasite species. Two species of ectoparasites (Sciadicleithrum guanduensis and Neascus-type metacercariae) and two species of endoparasites (Pandosentis aff. iracundus and Homalometron pseudopallidum) were observed. This is the first record of the genus Pandosentis in Brazilian waters and the first record of the species G. brasiliensis as a host for this parasite. Among the analysed groups of parasites, monogeneans and acanthocephalans proved to be the most sensitive to the concentrations of dissolved oxygen, faecal coliforms and total ammonia nitrogen in the water. Our study suggests that the abundance of both monoxenic and heteroxenous parasites can be negatively affected by organic pollution in the aquatic environment, reinforcing the potential of fish parasites as indicators of water quality. PMID- 28566097 TI - Bony cochlear nerve canal and internal auditory canal measures predict cochlear nerve status. AB - OBJECTIVES: The bony cochlear nerve canal is the space between the fundus of the internal auditory canal and the base of the cochlear modiolus that carries cochlear nerve fibres. This study aimed to determine the distribution of bony labyrinth anomalies and cochlear nerve anomalies in patients with bony cochlear nerve canal and internal auditory canal atresia and stenosis, and then to compare the diameter of the bony cochlear nerve canal and internal auditory canal with cochlear nerve status. METHODS: The study included 38 sensorineural hearing loss patients (59 ears) in whom the bony cochlear nerve canal diameter at the mid modiolus was 1.5 mm or less. Atretic and stenotic bony cochlear nerve canals were examined separately, and internal auditory canals with a mid-point diameter of less than 2 mm were considered stenotic. Temporal bone computed tomography and magnetic resonance imaging scans were reviewed to determine cochlear nerve status. RESULTS: Cochlear hypoplasia was noted in 44 out of 59 ears (75 per cent) with a bony cochlear nerve canal diameter at the mid-modiolus of 1.5 mm or less. Approximately 33 per cent of ears with bony cochlear nerve canal stenosis also had a stenotic internal auditory canal and 84 per cent had a hypoplastic or aplastic cochlear nerve. All patients with bony cochlear nerve canal atresia had cochlear nerve deficiency. The cochlear nerve was hypoplastic or aplastic when the diameter of the bony cochlear nerve canal was less than 1.5 mm and the diameter of the internal auditory canal was less than 2 mm. CONCLUSION: The cochlear nerve may be aplastic or hypoplastic even if temporal bone computed tomography findings indicate a normal cochlea. If possible, patients scheduled to receive a cochlear implant should undergo both computed tomography and magnetic resonance imaging of the temporal bone. The bony cochlear nerve canal and internal auditory canal are complementary structures, and both should be assessed to determine cochlear nerve status. PMID- 28566099 TI - HEALTH TECHNOLOGY ASSESSMENT: THE SCIENTIFIC CAREER OF A POLICY CONCEPT. AB - OBJECTIVES: The aim of this work was to provide a comprehensive overview of the evolution of the health technology assessment (HTA) concept in the scientific literature through a scientometric approach. METHODS: A literature search was conducted, by selecting publications, as well as news from the media, containing "health technology assessment" in their title, abstracts, or keywords. We then undertook a bibliometric and network analysis on the corpus of 2,865 publications thus obtained. RESULTS: Since a first publication in 1978, interest in HTA remained marginal until a turning point in the late 1980s, when growth of the number of publications took off alongside the creation of the U.K.'s NICE agency. Since then, publications have spread across several journals. The ranking of the organizations that publish such articles does not reflect any hegemonic position. However, HTA-related scientific production is strongly concentrated in Commonwealth and Nordic countries. Despite its transnational aspects, research on HTA has been framed within a small number of scientific networks and by a few opinion leaders. CONCLUSIONS: The "career" of the HTA concept may be seen as a scientific-knowledge based institutionalization of a public policy. To succeed in a country, HTA first needs scientific prerequisites, such as an organized scientific community working on the health sector and health services. Then, it appears that the recognition of this research by decision makers plays a key role in the development of the field. PMID- 28566100 TI - Understanding the beta-Lactam/Inhibitor of beta-Lactamase Combinations: Reassessment for Better Antimicrobial Stewardship. PMID- 28566101 TI - FROM MOTIVES THROUGH DESIRES TO INTENTIONS: INVESTIGATING THE REPRODUCTIVE CHOICES OF CHILDLESS MEN AND WOMEN IN POLAND. AB - SummaryThis study examined the potential of the theoretical model proposed by Warren Miller (the Traits/Motives-Desires-Intentions-Behaviour or TDIB model) for investigating the involuntary-voluntary childlessness continuum. The first three stages of the theoretical motivational sequence (motives to desires to intentions) were examined using a purposive sample of 314 childless Polish men and women aged 30-39 (at the time of data collection in September 2013). In Poland, this is the age range when the final decision for or against parenthood is taken. To model the motivational sequence, the Structural Equation Modelling (SEM) technique was applied. The results confirmed the hypothesized relations between the constructs for childless individuals in the analysed age group. Their childbearing desires were found to be good predictors of reproductive intentions, while negative and positive childbearing motives (independently) underpinned their desires. Moreover, positive motives appeared to have a stronger effect on desires than negative ones. The study also documented the psychometric properties of the Polish adaptation of the Childbearing Questionnaire, which was originally developed by Miller to measure childbearing motives. The advantages of using this tool for investigating the involuntary-voluntary childlessness continuum are discussed. Overall, the study validated the theoretical model as well as the adaptation of the Childbearing Questionnaire in the new research context: in the new cultural setting and for examining reproductive choices of a specific subpopulation. Directions for future research that could build on the TDIB model and allow for a deeper understanding of permanent childlessness are outlined. PMID- 28566102 TI - Real-time parameter estimation of Zika outbreaks using model averaging. AB - Early prediction of the final size of any epidemic and in particular for Zika disease outbreaks can be useful for health authorities in order to plan the response to the outbreak. The Richards model is often been used to estimate epidemiological parameters for arboviral diseases based on the reported cumulative cases in single- and multi-wave outbreaks. However, other non-linear models can also fit the data as well. Typically, one follows the so called post selection estimation procedure, i.e., selects the best fitting model out of the set of candidate models and ignores the model uncertainty in both estimation and inference since these procedures are based on a single model. In this paper we focus on the estimation of the final size and the turning point of the epidemic and conduct a real-time prediction for the final size of the outbreak using several non-linear models in which these parameters are estimated via model averaging. The proposed method is applied to Zika outbreak data in four cities from Colombia, during the outbreak ocurred in 2015-2016. PMID- 28566103 TI - Developing a "toolkit" to measure implementation of concurrent palliative care in rural community cancer centers. AB - OBJECTIVE: Despite national guidelines recommending early concurrent palliative care for individuals newly diagnosed with metastatic cancer, few community cancer centers, especially those in underserved rural areas do so. We are implementing an early concurrent palliative care model, ENABLE (Educate, Nurture, Advise, Before Life Ends) in four, rural-serving community cancer centers. Our objective was to develop a "toolkit" to assist community cancer centers that wish to integrate early palliative care for patients with newly diagnosed advanced cancer and their family caregivers. METHOD: Guided by the RE-AIM (Reach, Effectiveness Adoption, Implementation, Maintenance) framework, we undertook an instrument development process based on the literature, expert and site stakeholder review and feedback, and pilot testing during site visits. RESULTS: We developed four instruments to measure ENABLE implementation: (1) the ENABLE RE-AIM Self Assessment Tool to assess reach, adoption, implementation, and maintenance; (2) the ENABLE General Organizational Index to assess institutional implementation; (3) an Implementation Costs Tool; and (4) an Oncology Clinicians' Perceptions of Early Concurrent Oncology Palliative Care survey. SIGNIFICANCE OF RESULTS: We developed four measures to determine early palliative care implementation. These measures have been pilot-tested, and will be integrated into a comprehensive "toolkit" to assist community cancer centers to measure implementation outcomes. We describe the lessons learned and recommend strategies for promoting long-term program sustainability. PMID- 28566104 TI - Attention and Regional Gray Matter Development in Very Preterm Children at Age 12 Years. AB - OBJECTIVES: This study examines the selective, sustained, and executive attention abilities of very preterm (VPT) born children in relation to concurrent structural magnetic resonance imaging (MRI) measures of regional gray matter development at age 12 years. METHODS: A regional cohort of 110 VPT (<=32 weeks gestation) and 113 full term (FT) born children were assessed at corrected age 12 years on the Test of Everyday Attention-Children. They also had a structural MRI scan that was subsequently analyzed using voxel-based morphometry to quantify regional between-group differences in cerebral gray matter development, which were then related to attention measures using multivariate methods. RESULTS: VPT children obtained similar selective (p=.85), but poorer sustained (p=.02) and executive attention (p=.01) scores than FT children. VPT children were also characterized by reduced gray matter in the bilateral parietal, temporal, prefrontal and posterior cingulate cortices, bilateral thalami, and left hippocampus; and increased gray matter in the occipital and anterior cingulate cortices (family-wise error-corrected p<.05). Poorer sustained auditory attention was associated with increased gray matter in the anterior cingulate cortex (p=.04). Poor executive shifting attention was associated with reduced gray matter in the right superior temporal cortex (p=.04) and bilateral thalami (p=.05). Poorer executive divided attention was associated with reduced gray matter in the occipital (p=.001), posterior cingulate (p=.02), and left temporal (p=.01) cortices; and increased gray matter in the anterior cingulate cortex (p=.001). CONCLUSIONS: Disturbances in regional gray matter development appear to contribute, at least in part, to the poorer attentional performance of VPT children at school age. (JINS, 2017, 23, 539-550). PMID- 28566105 TI - Regional differences in dendritic spine density confer resilience to chronic social defeat stress. AB - OBJECTIVE: Although alterations in the dendritic spine density in the brain regions may play a role in the stress-induced depression-like phenotype, the precise mechanisms are unknown. The aim was to investigate the role of spine density in the brain regions after chronic social defeat stress (CSDS). METHODS: We examined dendritic spine density in the medial prefrontal cortex (mPFC), CA1, CA3, dentate gyrus (DG) of hippocampus, nucleus accumbens (NAc), and ventral tegmental area (VTA) of susceptible and resilient mice after CSDS. RESULTS: Spine density in the prelimbic area of mPFC, CA3, and DG in the susceptible group, but not resilient group, was significantly lower than control group. In contrast, spine density in the NAc and VTA in the susceptible group, but not resilient group, was significantly higher than control group. CONCLUSIONS: The results suggest that regional differences in spine density may contribute to resilience versus susceptibility in mice subjected to CSDS. PMID- 28566106 TI - Burns associated with e-cigarette batteries: A case series and literature review. AB - Electronic cigarettes, often referred to as e-cigarettes, have established a considerable market in North America over the last decade. In parallel to this trend, there has been a surge of e-cigarette battery explosions reported in the general media. Given the growing number of such events, acute care physicians should recognize the associated risks and injury patterns and initiate appropriate treatment. This report presents two cases of burn injuries from e cigarette battery explosions requiring surgical management. The accompanying comprehensive literature review highlights the emerging importance of e cigarettes as an aetiology of burn injury. PMID- 28566107 TI - Comparison of outcomes in Australian indigenous and non-indigenous children and adolescents undergoing cardiac surgery. AB - BACKGROUND: Population-based registries report 95% 5-year survival for children undergoing surgery for CHD. This study investigated paediatric cardiac surgical outcomes in the Australian indigenous population. METHODS: All children who underwent cardiac surgery between May, 2008 and August, 2014 were studied. Demographic information including socio-economic status, diagnoses and co morbidities, and treatment and outcome data were collected at time of surgery and at last follow-up. RESULTS: A total of 1528 children with a mean age 3.4+/-4.6 years were studied. Among them, 123 (8.1%) children were identified as indigenous, and 52.7% (62) of indigenous patients were in the lowest third of the socio-economic index compared with 28.2% (456) of non-indigenous patients (p?0.001). The indigenous sample had a significantly higher Comprehensive Aristotle Complexity score (indigenous 9.4+/-4.2 versus non-indigenous 8.7+/-3.9, p=0.04). The probability of having long-term follow-up did not differ between groups (indigenous 93.8% versus non-indigenous 95.6%, p=0.17). No difference was noted in 30-day mortality (indigenous 3.2% versus non-indigenous 1.4%, p=0.13). The 6-year survival for the entire cohort was 95.9%. The Cox survival analysis demonstrated higher 6-year mortality in the indigenous group - indigenous 8.1% versus non-indigenous 5.0%; hazard ratio (HR)=2.1; 95% confidence intervals (CI): 1.1, 4.2; p=0.03. Freedom from surgical re-intervention was 79%, and was not significantly associated with the indigenous status (HR=1.4; 95% CI: 0.9, 1.9; p=0.11). When long-term survival was adjusted for the Comprehensive Aristotle Complexity score, no difference in outcomes between the populations was demonstrated (HR=1.6; 95% CI: 0.8, 3.2; p=0.19). CONCLUSION: The indigenous population experienced higher late mortality. This apparent relationship is explained by increased patient complexity, which may reflect negative social and environmental factors. PMID- 28566109 TI - The role of inorganic nitrate and nitrite in CVD. AB - CVD is the leading cause of death worldwide, a consequence of mostly poor lifestyle and dietary behaviours. Although whole fruit and vegetable consumption has been consistently shown to reduce CVD risk, the exact protective constituents of these foods are yet to be clearly identified. A recent and biologically plausible hypothesis supporting the cardioprotective effects of vegetables has been linked to their inorganic nitrate content. Approximately 60-80 % inorganic nitrate exposure in the human diet is contributed by vegetable consumption. Although inorganic nitrate is a relatively stable molecule, under specific conditions it can be metabolised in the body to produce NO via the newly discovered nitrate-nitrite-NO pathway. NO is a major signalling molecule in the human body, and has a key role in maintaining vascular tone, smooth muscle cell proliferation, platelet activity and inflammation. Currently, there is accumulating evidence demonstrating that inorganic nitrate can lead to lower blood pressure and improved vascular compliance in humans. The aim of this review is to present an informative, balanced and critical review of the current evidence investigating the role of inorganic nitrate and nitrite in the development, prevention and/or treatment of CVD. Although there is evidence supporting short-term inorganic nitrate intakes for reduced blood pressure, there is a severe lack of research examining the role of long-term nitrate intakes in the treatment and/or prevention of hard CVD outcomes, such as myocardial infarction and cardiovascular mortality. Epidemiological evidence is needed in this field to justify continued research efforts. PMID- 28566110 TI - Society for the Advancement of Disaster Nursing: Exploring the Path to Excellence. AB - OBJECTIVE: Major disasters occurring within the Unites States require nursing participation as a component of a successful response. Disaster nursing includes the care of populations affected by disasters, public health emergencies, and mass casualty events, both natural and man-made. A unique knowledge base, abilities, and skills are needed to respond appropriately to health care and human service needs resulting from these events. METHODS: Despite prior efforts to advance disaster nursing as a specialty, none were sustainable and a professional framework for establishing standards and guidelines remains lacking. RESULTS: Disaster nursing is a complex arena where the intersection of competence, scope of practice, regulation, and clinical guidelines continues to evolve. Professional credibility and our contribution to disaster response lie in our ability to articulate and advance professionalism. Disaster nursing as a specialty practice requires a similar foundational framework to nursing specialties recognized by the American Nurses Association within a model of professional practice in order to ensure population outcomes that are reflective of safe, quality, evidence-based practice. CONCLUSIONS: It is time to define a disaster nursing scope of practice, establish standards for care, identify best practices, and pursue the establishment of an independent professional organization within the field of disaster nursing. This will establish the necessary foundation for optimizing nursing's contribution to and support of the National Health Security Strategy. (Disaster Med Public Health Preparedness. 2017;11:641-646). PMID- 28566112 TI - Erratum. PMID- 28566108 TI - Cognitive performance of community-dwelling oldest-old individuals with major depression: the Pieta study. AB - BACKGROUND: Individuals with late-life depression (LLD) may present cognitive symptoms. We sought to determine whether a brief cognitive battery (BCB) could identify cognitive and functional deficits in oldest-old individuals with LLD and a low level of education. METHODS: We evaluated 639 community-dwelling individuals aged 75+ years in Caete (MG), Brazil. We used the MINI and GDS-15 to diagnose major depression and evaluate its severity, respectively. The cognitive evaluation comprised the Mini-Mental State Examination (MMSE), BCB, clock-drawing test, category fluency test (animals) and Pfeffer's Functional Activities Questionnaire (FAQ). RESULTS: Fifty-four (11.6%) of the included individuals were diagnosed with LLD; on average, these participants were aged 81.0 +/- 4.8 years and had 3.9 +/- 3.4 years of schooling, and 77.8% of the subjects with LLD were female. Depressed individuals scored lower than subjects without dementia/depression on the MMSE overall (p < 0.001) and on several of the MMSE subscales, namely, time (p < 0.001) and spatial orientation (p = 0.021), attention/calculation (p = 0.019), and language (p = 0.004). Individuals with LLD performed worse on the incidental and (p = 0.011) immediate memory (p = 0.046) and learning tasks (p = 0.039) of the BCB. Individuals with LLD also performed worse on the category fluency test (p = 0.006), clock-drawing test (p = 0.011) and FAQ (p < 0.001). Depression severity was negatively correlated with incidental memory (rho = -0.412; p = 0.003) and positively correlated with FAQ score (rho = 0.308; p = 0.035). In the multiple regression analysis, only temporal orientation and FAQ score remained independently associated with LLD. CONCLUSION: Individuals with depression and a low level of education presented several cognitive and functional deficits. Depression severity was negatively correlated with incidental memory and functionality. Our findings serve as a description of the presence of cognitive dysfunction in individuals with LLD and suggest that these deficits may be identified based on the results of a BCB. PMID- 28566113 TI - Group-based education for patients with type 2 diabetes: a survey of Australian dietitians. AB - Group-based education has the potential to substantially improve the outcomes of individuals with type 2 diabetes mellitus (T2DM) and reduce the enormous burden that chronic diseases place on healthcare systems worldwide. Despite this proven effectiveness, the utilisation of group services for the management of T2DM by Australian dietitians is surprisingly low. This study surveyed a sample of 263 Australian dietitians to explore the utilisation of group-based education for T2DM, as well as dietitians' preferences for practice and training. The results of this study indicate that Australian dietitians are currently under-utilising group-based education programs for the management of T2DM, with the primary reasons identified as a lack of training provided to dietitians in the area, limited access to facilities suitable for conducting group education, the perceived poor cost-effectiveness of these programs, and the lack of evidence based practice guidelines for the group-based management of persons with T2DM. Additionally, the majority of preferences for further training were for either face-to-face or web-based formal training conducted over 3-6h. Clear, evidence based practice guidelines and training resources for group education for the management of T2DM are needed in order to encourage better utilisation of group based education by Australian dietitians. PMID- 28566114 TI - Effects of ovarian disaggregation on adult murine follicle yield and viability. AB - Follicles are isolated from ovaries for numerous reasons, including IVM, but adult murine yields are <2 folliclesmg-1. The aim of the present study was to optimise ovarian disaggregation and develop methods applicable to the rapid screening of follicle viability. Ovaries from adult mice (n=7) were halved and disaggregated mechanically, or by using collagenase IV (Col-IV; 590UmL-1) or animal origin-free collagenase IV (AOF) at 590 or 1180UmL-1. Isolated follicles were stained with 4',6'-diamidino-2-phenylindole (DAPI; nuclei), chloromethyl-X rosamine (CMXRos; mitochondria) or fluorescein isothiocyanate-conjugated anti alpha-tubulin antibody. Follicle diameters and staining were measured and analysed using ImageJ, and data analysed using GraphPad Prism. Col-IV disaggregation yielded the highest number of follicles (17+/-10 folliclesmg-1 ovarian tissue). All disaggregation methods released more secondary follicles (86+/-20 per ovary; P<0.05) than any other size cohort. Mechanical and Col-IV disaggregation yielded similar numbers of morphologically intact follicles, whereas AOF disaggregation caused more damage (P<0.01). As the morphological disruption increased, DAPI and CMXRos staining decreased (P<0.05), and tubulin localisation became more heterogeneous. Col-IV disaggregation gave the best yield of morphologically intact follicles containing viable granulosa cells. In conclusion, we improved adult murine follicle yields and applied molecular markers to assess follicle morphology, cellular cytoskeleton and mitochondrial function. PMID- 28566115 TI - Development and evaluation of an endoscopic surgery course for medical students. AB - INTRODUCTION: Surgical training has changed with the introduction of endoscopic surgery. However, a gap in undergraduate medical training has become evident regarding theoretical principles of and basic skills training in endoscopic surgery. The objective of this study was to develop and evaluate a course in endoscopic surgery for medical students. METHODS: Kern's six-step approach in curriculum development was used. A course including interactive, faculty-led didactic sessions (14 hours, distributed over three days) and simulation-based basic skills training in endoscopic surgery (nine hours, distributed over four sessions) was developed. Knowledge was tested using a 35-item test before and after the course, and finally the course was evaluated electronically. The project group in cooperation with the faculty -developed the goals and objectives, the test and the evaluation questionnaire. RESULTS: The test-scores significantly improved after the course, p < 0.0001, with a mean difference of 12.95 (95% confidence interval: 11.47-14.44). A total of 74% (14/19) responded that the course increased their interest in a career in a surgical specialty and 58% (11/19) were considering specialising in a surgical specialty. CONCLUSIONS: A course in endoscopic surgery was developed based on Kern's six-step approach. The course was positively perceived by the students in terms of contents as well as structure and relevance. FUNDING: University of Copenhagen, Aase og Ejner Danielsen Fonden, The Juliane Marie Centre for Children, Women and Reproduction, Rigshospitalet. TRIAL REGISTRATION: not relevant. PMID- 28566116 TI - Adherence to local antimicrobial guidelines for initial treatment of community acquired infections. AB - INTRODUCTION: Adherence to antimicrobial guidelines is key to ensuring a correct treatment of severe infections and to lessening misuse of broad-spectrum antimicrobials. We conducted a retrospective cross-sectional study at the Emergency Department of Aalborg University Hospital, North Denmark Region. Our aim was to examine adherence to local antimicrobial guidelines in the empirical treatment of community-acquired infections and to identity any predictors of guideline non-adherence. METHODS: We identified 1,555 patients who had blood cultures performed and were admitted to the medical emergency department in 2016. We reviewed the medical charts of 755 patients and included those who received at least one antibiotic prescription within the first 24 hours of admission. We excluded patients with known immunodeficiency, severe renal failure or hospitalisation within the previous month. RESULTS: Of the 383 included patients, 203 (53%) received guideline-concordant antibiotic treatment. The treatment was guideline-concordant in 41% of patients with suspected sepsis of unknown origin, in 44% with pneumonia and in 37% with urinary tract infections. Patients with underlying chronic obstructive pulmonary disease (25%) received guideline concordant treatment significantly more often (83%, p < 0.01) than other groups. CONCLUSIONS: Adherence to local antimicrobial guidelines was not high. Further studies are needed to identify barriers to guideline adherence. FUNDING: None. TRIAL REGISTRATION: The study was registered with the Danish Data Protection Agency (R. no. 2008-58-0028). PMID- 28566117 TI - The impact of acute high-risk abdominal surgery on quality of life in elderly patients. AB - INTRODUCTION: Undergoing acute high-risk abdominal (AHA) surgery is associated with reduced survival and a great risk of an adverse outcome, especially in the elderly. The primary aim of this study was to investigate the residential status and quality of life in elderly patients undergoing AHA surgery. METHODS: From 1 November 2014 to 30 April 2015, consecutive patients (>= 75 years) undergoing AHA surgery were included for follow-up after six months. The patients included answered a health-related quality-of-life questionnaire and a supplemental questionnaire regarding residential status. The results were compared with an age matched national control group. RESULTS: A total of 52 patients matched the inclusion crit-eria. Mortality at six months after surgery was 46%. Out of the 28 survivors, 22 participated in the study. Quality of life was estimated as good in 77% of the survivors and they were willing to undergo surgery again, if necessary. All study participants were admitted from their own home, and 95% had no change in residential status after six months. CONCLUSIONS: The self-reported quality of life in elderly survivors six months after AHA surgery was surprisingly good in a small study where all findings should be interpreted with precaution. The majority had no change in residential status. Our study may provide useful information for surgeons advising elderly patients and their families about realistic outcomes following AHA surgery. FUNDING: none. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency and registered with clinicaltrials.gov. PMID- 28566118 TI - NBOMe hallucinogenic drug exposures reported to the Danish Poison Information Centre. AB - INTRODUCTION: N-benzylmethoxy (NBOMe) is a new class of hallucinogenic designer drugs sold on cheap blotter papers. They are potent 5-hydroxytryptamine-2A receptor agonists, and since their recent entry into the drug market there have been worldwide reports of severe intoxications and even fatalities. This study reviews suspected NBOMe drug exposures reported to the Danish Poison Information Centre (DPIC). METHODS: Data from the DPIC database were extracted, including all enquiries with NBOMe exposures reported from 1 January 2013 to 30 June 2016. The following data were extracted: age, sex, date of exposure, risk assessment, co exposures, geography and reported symptoms. RESULTS: A total of 43 cases were identified: one in 2013, five in 2014, 32 in 2015 and five in the first six months of 2016. The mean patient age was 21 years (range: 15-34 years) with 32 (74%) male and 11 (26%) female patients. The patients most frequently presented with hallucinations/psychosis (n = 18), tachycardia (n = 18) and agitation (n = 15). A total of 16 patients were admitted with co-exposures to other drugs such as alcohol (n = 9), cannabis (n = 7), amphetamine (n = 5) cocaine (n = 3), benzodiazepines (n = 1) and 3,4-methylenedioxymethamphetamine (n = 1). The cases were distributed evenly across the entire country with only ten cases having a postal address in one of the three major cities of Denmark. CONCLUSIONS: This study has shown a steep and sudden rise in reported NBOMe exposures in Denmark within 3-4 years. Geographical data demonstrate an even distribution throughout the country. However, our results also suggest that the use has started to decline. FUNDING: none. TRIAL REGISTRATION: This study was approved by the Danish Data Protection Agency. (BFH-2016-070/04985). PMID- 28566119 TI - Consultation expectations among patients with respiratory tract infection symptoms. AB - INTRODUCTION: Antibiotic resistance is a growing threat to public health, and antibiotic prescribing increases. About 90% of antibiotics are prescribed in general practice, mostly for acute respiratory tract infections. It is well known that patient expectations and general practitioners' misinterpretation of patients' expectations are associated with antibiotic overuse. The aim of this study was to explore Danish patients' expectations when consulting a general practitioner with symptoms of acute respiratory tract infection, and to determine predictors for these expectations. METHODS: A questionnaire survey was conducted in Danish primary care during 2014. Patients aged >= 18 years were asked about their expectations to the consultation when consulting with symptoms of acute respiratory tract infections. Associations between socio-demographic characteristics, self-reported antibiotic prescription and patients' expectations were also explored. RESULTS: A total of 567 patients with symptoms of acute respiratory tract infections were recorded as interested in receiving a questionnaire, 361 of whom responded. The majority expected an examination (94.6%) and an explanation (85.9%). About one third expected antibiotic treatment (32.3%). Patients who expected an antibiotic were more than eight times more likely to be prescribed one than were patients not expecting an antibiotic (odds ratio = 8.6 (95% confidence interval: 4.63-16.03); p < 0.001). CONCLUSIONS: Most Danish patients expected an examination and/or an explanation of their symptoms when consulting with their general practitioner. FUNDING: The study was, in part, funded by The Council for Quality Assurance in Primary Care in both The Region of Southern Denmark and Region Zealand. Malene Plejdrup Hansen received a postdoctoral scholarship in general practice and family medicine from The Novo Nordic Foundation. The sponsors have not been involved in the design or the development of the study. TRIAL REGISTRATION: This study was registered with the Danish Data Protection Agency (R. no. 2013-41-2582). PMID- 28566120 TI - A simple high-dose gentamicin regimen showed no side effects among neonates. AB - INTRODUCTION: Treatment of infections in neonates with gentamicin is a balance between optimising bactericidal effect and minimising adverse effects. Previously, at the Neonatal Intensive Care Unit (NICU) at Kolding Hospital, Denmark, neonates suspected of having infections were treated daily with gentamicin 5 mg/kg for the first three days, thus exposing the smallest neonates to double gentamicin amounts compared with those used in most Danish NICUs. We aimed to evaluate if this regimen increased the trough values and oto- and nephrotoxicity. METHODS: Neonates admitted to the NICU between 2008 and 2012 and treated with gentamicin were included retrospectively in the study. Neonates with trough serum (S)-gentamicin level >= 2.0 mg/l before the third dose were reviewed in detail. RESULTS: In total, S-gentamicin level was measured in 253 treated neonates of whom 7% displayed elevated trough values. Neonates < 32 weeks of age had a slightly higher incidence of S-gentamicin level >= 2.0 mg/l compared with less premature and mature infants (16%, 13%, and 2%, respectively). No oto- or nephrotoxicity was found despite the high-dose gentamicin regimen. CONCLUSIONS: The incidence of elevated S-gentamicin trough levels was increased among very premature neonates. However, no evidence of oto- or nephrotoxicity was observed. This simple regimen of gentamicin 5 mg/kg for the first three days should be considered for all neonates as it potentially minimises the risk of dosing errors and bacterial breakthrough infection. FUNDING: none. TRIAL REGISTRATION: Danish Data Protection Agency (2008-58-0035). PMID- 28566121 TI - Danish national guideline: Diagnosis and treatment of Irritable Bowel Syndrome. AB - National Danish guidelines for the diagnosis and treatment of irritable bowel syndrome (IBS) in adult patients in secondary and tertiary care have been approved by the Danish Society for Gastroenterology and Hepatology. IBS can be a positive diagnosis in patients fulfilling the Rome III criteria for IBS with no alarm signals, a normal physical examination and a normal CRP and hemoglobin. In patients < 40 years with IBS and diarrhea, a normal fecal calprotectin excludes inflammatory bowel disease with a high probability. Patients with IBS and diarrhea should be tested for celiac disease. Endoscopy is not routinely recommended. The therapeutic gain of various treatment modalities is small and most likely overestimated in older studies. However, side effects are usually mild which may justify empirical treatment. The choice of therapy based on IBS subtyping is pragmatic and there are only few trials as guidance. The significance of previous failure with another treatment modality is unclear. There is a lack of long-term treatment trials. The generalizability of the trials is poor, mainly due to selection bias. PMID- 28566122 TI - Necrotizing enterocolitis - classification and two initial steps towards prevention. AB - The premature infant suffers from immaturity of all organ systems, one of them being the gastrointestinal tract. When the infant is born, the immature gastrointestinal tract is exposed to milk and simultaneously colonized by high densities of bacteria. The combination of milk, microbiota and an immature gut, leaves the infant vulnerable to developing the dreaded intestinal emergency necrotizing enterocolitis (NEC). NEC is often very aggressive and no cure exists, which means that prevention is an utmost important topic to researchers, physicians, parents - and infants. Despite immense research during the last decades, no specific test to determine if an infant suffers from NEC exists. Most neonatal units use Bell's staging criteria, which are based on clinical and radiographic findings, as a diagnostic tool; however the diagnosis given according to Bell's stages has not been validated. In study I, we aimed to determine the validity of the NEC diagnosis given at discharge. An expert panel consisting of a neonatologist, a paediatric surgeon and a paediatric radiologist served as the golden standard. We found that the diagnosis given at discharge had a poor validity which significantly affected the reported incidence of NEC in the neonatal department at Rigshospitalet, Denmark. The validity of the NEC diagnosis was worse than the validity of most other paediatric diagnoses that had been investigated. In studies II and III, we aimed to explore possible means of NEC prevention. The role of nutrition in NEC development is well established with mother's milk as the best option to avoid NEC in the preterm infant. Maternal milk is, however, most often not available in sufficient amounts during the first days of life, and preterm infant formula or human donor milk is used in its absence. Studies in preterm piglets showed that bovine colostrum equally to human donor milk protected against NEC compared to infant formula. Furthermore, bovine colostrum was superior to human donor milk in stimulating gut immunity and digestive functions. Hence, in study II we aimed to design a pilot study of bovine colostrum used as a supplement to maternal milk in the first days of life and to determine if the study was feasible. In the paper, we present the protocol and the results of the first two phases of the Precolos study in which 12 infants were included and received pasteurized, spray-dried and reconstituted bovine colostrum during the first days of life as the first infants in the world. We found that the infants tolerated bovine colostrum without clinical adverse effects, but we also observed a transient hypertyrosinemia on day seven of life in five infants. The results were evaluated by a safety management board which encouraged us to continue the pilot study with the last phase, which was a randomized controlled trial of 20+20 infants comparing supplementation with bovine colostrum to supplementation with standard nutrition. The randomized trial has just finished recruitment. At last, we wanted to shed light on a possible microbiological angle of NEC prevention. Dysbiosis and bacterial translocation are believed to play a crucial role in the development of NEC as intestinal pneumatosis, which occurs when bacteria produce gas inside the intestinal wall, is a pathognomonic radiographic finding. In a quality improvement study from the US published in 2014, NEC incidence was significantly reduced after the implementation of several quality improvement interventions. Standardized weekly exchange of nasogastric feeding tubes was suggested as one of the potential NEC reducing interventions. In the neonatal unit at Rigshospitalet, Denmark, preterm infants are fed 8-12 times daily through a resident nasogastric feeding tube which is exposed to body temperature, contains milk residuals from the last meal and is handled by both parents and personnel. Since bacterial pollution of milk given through the nasogastric feeding tube might be NEC-inducing, we aimed in study III to determine the bacterial load given to the infants when feeding them through a tube. We collected 92 used nasogastric feeding tubes and flushed them with one ml saline each to imitate a meal given through them. Eighty-nine percent of the tubes contaminated the meals with more than 1000 colony-forming units of bacteria and fifty-five percent contaminated the meals with the possible pathogens Enterobacteriaceae or Staphylococcus aureus. The concentration of bacteria in the saline flushed through the tubes was as high as 109 colony forming units per ml; however, neither the risk of contamination nor the concentration of bacteria in the flush was associated with the duration of use. Implementation of standardized weekly exchange of feeding tubes would therefore not prevent the contamination of meals. In conclusion, the studies included in this thesis serve as a base for future studies investigating the prevention of NEC. We found a poor validity of the NEC diagnosis given at discharge. This should be kept in mind when conducting epidemiological studies of NEC and especially when conducting interventional trials with NEC as an outcome. If the findings of the randomized part of the Precolos study indicate a positive effect of bovine colostrum and do not give rise to concerns regarding feasibility, safety or tolerability, a large-scale randomized controlled study with NEC as the primary outcome will be planned. Based on the high concentrations of bacteria found in the nasogastric feeding tubes, a randomized controlled trial investigating whether the frequency of feeding tube exchange affects the early colonization has been commenced in the neonatal department at Rigshospitalet. Hopefully, the results of these studies will bring us closer to preventing NEC in the future. PMID- 28566123 TI - Funen Anorexia Nervosa Study - a follow-up study on outcome, mortality, quality of life and body composition. AB - Eating disorders (EDs) comprise a wide range of symptoms, with severe psychological and physical implications for the patient. EDs include anorexia nervosa (AN), bulimia nervosa (BN) and until 2013 eating disorder not otherwise specified (EDNOS), if criteria for AN or BN were not met. Patients suffering from an ED have poor prognosis, with more than half of AN patients not obtaining complete remission. One-fifth develops a chronic disease. EDs have an increased risk of premature death and patients with EDs report poorer quality of life (QoL) compared to both the general population and other psychiatric/somatic diseases. Patients who, apparently, obtain complete remission will still be affected in QoL when compared to a healthy reference group. Treatment is complicated by high drop out rates, hence making large retrospective follow-up studies difficult to conduct. The multiple endocrine disturbances as a result of the severe malnourishment in AN often result in amenorrhea and a weight goal for remenorrhea has been ambiguous. This thesis encompasses results from four studies examining the abovementioned challenges and is based on a large retrospective cohort of ED patients referred to a highly specialized ED treatment unit. Study 1: QoL in EDs was reported for a large retrospective Danish cohort. Furthermore, meta-analysis on existing published literature was performed to determine potential differences between the diagnostic groups. QoL in EDs was significantly decreased compared to the general population and no difference between the diagnostic groups was established. Study 2: ED pathology (measured by the Eating Disorder Inventory - 2 (EDI-2)) and outcome (measured by the Morgan Russell Outcome Schedule (MROS)) was reported for a large retrospective Danish cohort. The correlation between the patient-reported measurements (SF-36 & EDI-2) and clinician-assessed characteristics (BMI and remission status) was investigated in a group of ED patients (n=383). A high association between EDI scores and BMI was observed in AN and EDNOS, despite remission status, representing an increase in symptomatology with increasing BMI. This was not present in BN. We found no association between HRQoL and BMI in any of the diagnostic groups. Study 3: Mortality rates were calculated in a large group of ED patients (n=998) including AN, BN and EDNOS with a long follow-up time. We found a SMR of 2.9 for AN, which was considerably lower than previous published results. We compared the results to data from the same catchment area published prior to the establishment of a multidisciplinary ED center. Patients with EDs had a significantly increased risk of premature death compared to the general population; however the mortality rates had decreased since the formation of the ED unit. Study 4: The association between body composition measures and amenorrhea was studied in a cohort of adult patients with a history of AN (n=113) and predicted probabilities for the resumption of menses was determined. We found a high association between DXA scans and BMI in predicting the resumption of menses. Half of the patients were predicted to resume their menstrual status at BMI 19/fat percentage 23, however at BMI 14/fat percentage 11 still 25% of patients were predicted to resume their menses. PMID- 28566124 TI - Melatonin for prevention of erythema and oxidative stress in response to ultraviolet radiation. AB - Skin damage induced by UVR is an escalating problem in dermatology, and increasing incidence of skin cancer, especially for non-melanoma skin cancer, has been reported worldwide. UVR from sun exposure and the production of reactive oxygen species (ROS) is known to be a pivotal factor in the aetiology of skin cancer. The pineal hormone melatonin is recognized as the most potent endogenous antioxidant. Melatonin conducts its antioxidant effects acting directly as a radical scavenger and indirectly by up regulation of antioxidant enzymes. It has been proposed, that melatonin may have a protective effect against UVR-induced skin damage. The aim of this thesis was to: - Clarify melatonin's protective effect against UVR-induced skin damage in laboratory and clinical settings trough a systematic review of the literature. - To clinically assess the protective effect of topical treatment with melatonin against natural sun exposure, and determine the optimal concentration. - To clinically evaluate the degree of cognitive dysfunction with full body application of topical melatonin. Study 1: This was a systematic review using the databases Pubmed, EM-BASE and Cinahl. The databases were searched up to January 2013 to identify studies evaluating melatonin's protective effect against UVR-induced erythema in humans, and damage on a cellular level. Twenty studies were included, four human and 16 experimental. The results indicated that melatonin had a protective effect against UVR-induced erythema if applied before exposure, and this effect was probably obtained by melatonin acting directly as an antioxidant, and indirectly by regulating gene expression and inducing a DNA stabilizing effect. As these results were obtained using artificial UVR-sources and without investigating possible side effects, studies using natural sunlight and evaluating possible side effects of topical melatonin administration were warranted. Study 2: This study was a randomized, double-blind, placebo-controlled study. We evaluated the protective effect of three different doses of topical melatonin against erythema induced by natural sun-light. The primary outcome was reduction in erythema, evaluated by chromatography, after sun exposure, when treated with topi-cal melatonin (0.5%, 2.5%, 12.5%) versus placebo and no treatment. A significant difference in erythema formation was found between areas treated with melatonin 12.5% and areas receiving placebo or no treatment. However, this was only seen in participants with an erythema reaction to the sun exposure. Further-more, the treated skin areas were very small and studies assessing any potential adverse effects were necessary. Study 3: This also was a randomized, double-blind, placebo-controlled, cross-over study. We assessed the degree of cognitive dysfunction with full body application of topical melatonin 12.5%. Cognition was evaluated using a neuropsychological test battery consisting of Karolinska sleepiness scale (KSS), finger tapping test (FTT) and continuous reaction time (CRT). The impact on KSS was the primary outcome. We found no significant effect on cognition, however, large inter-individual variation was observed. These results support that melatonin is a safe drug for dermal application. The studies in this thesis may be valuable in the research field of melatonin's protective potential against UVR-induced oxidative skin damage. Increasing incidence of skin cancer is reported worldwide, and experts have suggested that the problem will only increase further, due to depletion of the ozone layer and the aging population. Furthermore, high-risk patient groups are emerging with the widely use of immunosuppressive medicine in various diseases, and this high-risk is in spite of use of protective measures known today. Therefore, development of new and more effective sun protective agents, with other qualities than simple chemical reflection of the UVR, is more important than ever. We have supported the suggestion of melatonin as a sun protective agent, and added the clinical relevant feature, that melatonin also has a protective effect against natural sunlight. Furthermore, we have supported the idea of melatonin being a safe drug for topical treatment, even in previous unknown high dosages. However, before any clinical implementation of melatonin as a sun protective agent can take place, further studies evaluating the long-term effects are warranted. PMID- 28566125 TI - Weight Changes in General Practice. AB - INTRODUCTION: This PhD thesis is about weight changes. What determines long-term weight changes in the adult general population? Is it possible that weight loss may not always be healthy? The present clinical guidelines for general practice advice most overweight persons and patients with type 2 diabetes to lose weight. Are the guidelines based on firm evidence? METHODS: The back-bone of the thesis is constituted by three scientific articles based on three different population based cohort studies. Multivariable modeling and other epidemiological methods were used. RESULTS: Article 1 examined weight changes in the general population in relation to smoking status, and proposed a graphical 'smoking cessation weight change model', demonstrating the importance of time, age and smoking status in relation to long-term weight changes. Article 2 suggested new methods to improve the processing of dietary data. It was demonstrated how median imputation for missing values and assumptions about standard portion sizes were inferior to stochastic methods conditioning on information about physiology of the individual. Article 3 evaluated the influence of prospectively planned intentional weight loss on long-term morbidity and mortality in patients with type 2 diabetes. Therapeutic intentional weight loss supervised by a medical doctor was not associated with reduced morbidity or mortality. In the general population the dietary intake of fructose and soft drinks sweetened with sugar was not associated with weight change over 9 years. Weight gain rates were large in young adults and incrementally smaller in middle aged adults. Subjects more than 60 years lost weight on average. Historical weight data suggest that the body weight increases throughout life to the age of 60-65years. A study with simulated data indicates that bias in baseline BMI may misleadingly have favored weight loss in earlier cohort studies of intentional weight loss and mortality. DISCUSSION: The findings regarding weight loss and mortality in patients with type 2 diabetes are in opposition to the prevailing observational literature. Harrington's meta-analysis of intentional weight loss and the underlying studies are evaluated along with the Look AHEAD trial and a number of diabetes prevention studies. Difficulties in conducting and interpreting weight change studies are discussed. CONCLUSIONS: Surprisingly, intentional therapeutic weight loss in patients with type 2 diabetes, supervised by a medical doctor, did not seem to reduce the long-term risk for CVD, CVD-mortality or all-cause mortality. The contradictions between our results and the prevailing observational evidence may be explained by methodological weaknesses favoring weight loss in earlier studies. Consequently, there is no good evidence to support that intentional weight loss will reduce the risk of CVD or mortality in any group of patients in general practice or in the general population. Age was a powerful determinant of weight changes and the 'normal weight development' can be taken into consideration when evaluating weight studies, and when general practitioners are following their patients over time. Compared with age, sex, education, and comorbidity, lifestyle factors like the dietary intake and physical activity seemed to be of less importance for long-term weight development. An exception to this was smoking or smoking cessation. Based on the scientific literature in the field and on the results of article 3, it seems uncertain whether weight loss is beneficial or harmful in terms of mortality and cardiovascular morbidity in patients with diabetes and in overweight people in general. Improvements in for instance psychosocial factors and diabetes prevention may well be short term as only few are able to a maintain weight loss. Rather than going for weight loss in overweight high risk patients, it seems more rational for general practitioners to focus on other lifestyle changes like for instance Mediterranean diet and increased exercise. PMID- 28566126 TI - Survey on knowledge, attitude and practice about blood donation among continuing medical education (CME) students in Sichuan province, China. AB - The study was to assess the knowledge, attitude and practice of blood donation among continuing medical education students in Sichuan.This study was carried out on 841 continuing medical education students using a self-administered structured questionnaire. The statistical analysis was done by using the SPSS software.Among the 800 students, 424 were donors and 417 were non-donors The score of knowledge (mean11.71+/-2.22 VS 8.46+/-3.27) and attitude (mean 9.19+/-2.42 VS 7.08+/-2.02) in donors were statistically significant higher than the non-donors. The moral responsibility of altruism was the major reason for donating blood and worrying of the sanitation and getting infectious disease during donation was the major reason for not donating blood. Being male, aged more than 40, worked in grassroots hospital were predictors of being a blood donor.Blood services should take more efforts to improve donation experience and reinforce the positive KAP of CME students through blood donation training could help more grassroots people to know the blood donation and abandon the prejudice of blood donation. PMID- 28566127 TI - Retraction notice to" Modification of TAK1 by O-linked N-acetylglucosamine facilitates TAK1 activation and promotes M1 macrophage polarization" Cellular Signalling 28 (2016) 1742-1752. PMID- 28566128 TI - If a butterfly flaps its wings in the Amazon, do we form an Inflammasome? PMID- 28566129 TI - Foreword: Endocrine Disrupting Chemicals in Consumer Products. PMID- 28566130 TI - Novel Approaches to Analyze Immunoglobulin Repertoires. AB - Analysis of immunoglobulin (Ig) repertoires aims to comprehend Ig diversity with the goal of predicting humoral immune responses in the context of infection, vaccination, autoimmunity, and malignancies. The first next-generation sequencing (NGS) analyses of bulk B cell populations dramatically advanced sampling depth over previous low-throughput single-cell-based protocols, albeit at the expense of accuracy and loss of chain-pairing information. In recent years the field has substantially differentiated, with bulk analyses becoming more accurate while single-cell approaches have gained in throughput. Additionally, new platforms striving to combine high throughput and chain pairing have been developed as well as various computational tools for analysis. Here we review the developments of the past 4-5 years and discuss the open challenges. PMID- 28566131 TI - Autoantibodies in antimithocondrial antibodies negative primary biliary cholangitis. PMID- 28566132 TI - Early Diagnostic Performance of Heart-Type Fatty Acid Binding Protein in Suspected Acute Myocardial Infarction: Evidence From a Meta-Analysis of Contemporary Studies. AB - BACKGROUND: Although cardiac troponin is the cornerstone in diagnosis of acute myocardial infarction (AMI), the accuracy is still suboptimal in the early hours after chest pain onset. Due to its small size, heart-type fatty acid-binding protein (H-FABP) has been reported accurate in diagnosis of AMI, however, this remains undetermined. The aim is to investigate the diagnostic performance of H FABP alone and in conjunction with high-sensitivity troponin (hs-Tn) within 6 hours of symptom onset. Furthermore, accuracy in 0h/3h algorithm was also assessed. METHODS: Medline and EMBASE databases were searched; sensitivity, specificity and area under ROC curve (AUC) were used as measures of the diagnostic accuracy. We pooled data on bivariate modelling, threshold effect and publication bias was applied for heterogeneity analysis. RESULTS: Twenty-two studies with 6602 populations were included, pooled sensitivity, specificity and AUC of H-FABP were 0.75 (0.68-0.81), 0.81 (0.75-0.86) and 0.85 (0.82-0.88) within 6 hours. Similar sensitivity (0.76, 0.69-0.82), specificity (0.80, 0.71-0.87) and AUC (0.85, 0.82-0.88) of H-FABP were observed in 4185 (63%) patients in 0h/3h algorithm. The additional use of H-FABP improved the sensitivity of hs-Tn alone but worsened its specificity (all p<0.001), and resulted in no improvement of AUC (p>0.99). There was no threshold effect (p=0.18) and publication bias (p=0.31) in this study. CONCLUSIONS: H-FABP has modest accuracy for early diagnosis of AMI within 3 and 6 hours of symptom onset. The incremental value of H-FABP seemed much smaller and was of uncertain clinical significance in addition to hs-Tn in patients with suspected AMI. Routine use of H-FABP in early presentation does not seem warranted. PMID- 28566133 TI - Variation in Screening Mammography Rates Among Medicare Advantage Plans. AB - PURPOSE: Prior studies have shown higher screening mammography rates for beneficiaries in capitated managed care Medicare Advantage (MA) plans compared with traditional fee-for-service Medicare. The aim of this study was to explore variation in screening mammography rates at the level of MA managed care plans. METHODS: Using the 2016 MA Healthcare Effectiveness Data and Information Set Public Use File, screening mammography rates were identified for all 385 reporting MA plans. Associations were explored with a range of plan characteristics from this file, as well as from the CMS Part C and Part D Medicare Star Ratings Data File, Medicare Advantage Plan Directory, and Medicare Monthly Enrollment by Plan File. RESULTS: Overall MA plan screening rates were high (mean, 72.6 +/- 9.4%) but varied substantially among plans (range, 14.3% 91.8%). Screening rates were higher in nonprofit versus for-profit plans (77.3% versus 71.8%, P < .001), as well as in health maintenance organization or local preferred provider organization plans versus private fee-for-service or regional preferred provider organization plans (71.9%-73.2% versus 65.5%-66.8%, P = .001). Among parent organizations with five or more plans, screening rates were highest for Kaiser Foundation (median, 88.4%) and lowest for Molina Healthcare (median, 65.3%). Screening rates showed small but significant associations with plans' contract lengths, enrolled populations, and counties served. Screening rates showed strong associations (r = 0.796-0.798) with colorectal cancer screening and annual flu vaccine rates and showed moderate associations (r = 0.283-0.365) with ambulatory and preventive care visits, osteoporosis screenings, body mass index assessments, and nonrecommended prostate-specific antigen screenings after age 70. CONCLUSIONS: Screening mammography rates vary considerably among MA plans. With increased federal interest in promoting the MA program, enhanced transparency will be necessary to ensure appropriate Medicare beneficiary participation decision making. PMID- 28566134 TI - Medicare Claims Data Resources: A Primer for Policy-Focused Radiology Health Services Researchers. AB - As societal stakeholders call for increased evidence-based health policy, considerable attention has focused on Medicare, the country's largest payer. Concurrently, medical imaging has come under considerable scrutiny as a contributor to rising health care expenditures. Accordingly, many recent studies have focused on multiple factors related to the utilization of imaging among Medicare beneficiaries. This article summarizes several national Medicare fee-for service data sources relevant to supporting ongoing investigations. Aggregated 100% data sets include the Physician/Supplier Procedure Summary Master Files and the Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File. The former focuses on services, specialties, and sites of service; the latter focuses on providers. Both permit high-level national assessments of imaging utilization and spending. Individual 5% random-sample claims-level data sources include the Carrier Standard Analytical File Limited Data Set and the Research Identifiable File, which contain greater beneficiary level information. Both facilitate more robust patient- and encounter-level analyses and some assessment of downstream outcomes but involve greater costs and require greater privacy oversight. More recently, Medicare data are being merged with registry data (eg, Surveillance, Epidemiology, and End Results-Medicare Linked Database files), creating opportunities for even more robust analyses given richer clinical information. Understanding these data sets and trade-offs in their use will aid policy-focused imaging health services researchers in most effectively conducting their investigations. PMID- 28566135 TI - How to set up a robotic-assisted laparoscopic surgery center and training of staff. AB - The use of computers to assist surgeons in the operating room has been an inevitable evolution in the modern practice of surgery. Robotic-assisted surgery has been evolving now for over two decades and has finally matured into a technology that has caused a monumental shift in the way gynecologic surgeries are performed. Prior to robotics, the only minimally invasive options for most Gynecologic (GYN) procedures including hysterectomies were either vaginal or laparoscopic approaches. However, even with over 100 years of vaginal surgery experience and more than 20 years of laparoscopic advancements, most gynecologic surgeries in the United States were still performed through an open incision. However, this changed in 2005 when the FDA approved the da Vinci Surgical Robotic Systemtm for use in gynecologic surgery. Over the last decade, the trend for gynecologic surgeries has now dramatically shifted to less open and more minimally invasive procedures. Robotic-assisted surgeries now include not only hysterectomy but also most all other commonly performed gynecologic procedures including myomectomies, pelvic support procedures, and reproductive surgeries. This success, however, has not been without controversies, particularly around costs and complications. The evolution of computers to assist surgeons and make minimally invasive procedures more common is clearly a trend that is not going away. It is now incumbent on surgeons, hospitals, and medical societies to determine the most cost-efficient and productive use for this technology. This process is best accomplished by developing a Robotics Program in each hospital that utilizes robotic surgery. PMID- 28566136 TI - Extraordinary Cases of Miraculous Healing. PMID- 28566137 TI - Eosinophilic Esophagitis: Latent Disease in Patients with Anaphylactic Reaction to Cow's Milk. AB - BACKGROUND: Food allergy and eosinophilic esophagitis are a substantial and evolving public health issue. Clinicians should know the relationship between these diseases and how one may predispose to the other. This can help minimize misdiagnosis. OBJECTIVE: The objective of this study was to assess esophageal eosinophilia and eosinophilic esophagitis frequency in patients with persistent cow's milk allergy and anaphylaxis manifestations. METHODS: Patients with persistent cow's milk allergy with anaphylaxis manifestations were enrolled from 2012 through 2016 at the Sao Paulo University Hospital, Brazil. All of them were submitted to endoscopy despite the presence or absence of gastrointestinal symptoms. Demographics data, atopic comorbidities, medication use, endoscopic findings, and esophageal eosinophilia frequency were evaluated. RESULTS: Eighty nine patients were selected. The median age was 8 years. It was observed that 34 of 89 patients (38.2%; 95% confidence interval [CI]: 28.14%-49.16%) presented with esophageal eosinophilia. Five patients (7.1%) presented proton pump inhibitor-responsive esophageal eosinophilia, and 10 patients (14.2%) presented eosinophilic esophagitis. We found that 29.4% were asymptomatic patients, 23.5% had nonspecific symptoms, 23.5% had persistent typical symptoms, and 23.5% had intermittent typical symptoms. There was an association with inflammatory endoscopy findings in 21 patients (61.7%). CONCLUSIONS: This description demands scientific attention because it is the highest frequency of esophageal eosinophilia yet described in a group of patients with cow's milk allergy presenting with anaphylaxis. Eosinophilic esophagitis is a condition that can coexist "silently" with an IgE-mediated food allergy and is most often underestimated and underdiagnosed. PMID- 28566138 TI - A newly developed ultraminiature wearable electromyogram system useful for analyses of masseteric activity during the whole day. AB - PURPOSE: We describe the characteristics of a new data-logger-type ultraminiature electromyogram (EMG) system (FLA-500-SD) and methods used for recording and we show its potential in clinical applications by presenting an example of a clinical case. METHOD: FLA contains electrodes, an amplifier, 12-bit analog-to digital (A/D) converter at a sampling frequency of 1kHz, 16-bit CPU, a 3.7-V coin shaped lithium battery, and a micro SD card. The size of FLA is 37.0*23.5*8.6mm, and its weight is 6g (9g with a battery inserted). The device is wearable and patients can attach the device and operate it by themselves in daily life. Data recorded in the micro SD card are transferred to a personal computer and analyzed. Although the device is ultraminiature and wearable, it has the capacity for recording a precise and clear masseteric surface electromyogram that is not inferior to that recorded by conventional stationary-type EMG recording systems. CONCLUSIONS: To our knowledge, the device is the smallest and lightest device with capacity for the longest consecutive measuring time as a data-logger-type electromyograph with built-in electrodes and memory. The device is useful for analyses of masseteric activity during the whole day. In the future, it is expected that applications of the device will expanded to observation, evaluation and diagnosis of normal or abnormal gnathic functions, e.g., assessment of sleep and awake bruxism and observation of the chewing state in daily life. PMID- 28566139 TI - Arithmetic in the developing brain: A review of brain imaging studies. AB - Brain imaging studies on academic achievement offer an exciting window on experience-dependent cortical plasticity, as they allow us to understand how developing brains change when children acquire culturally transmitted skills. This contribution focuses on the learning of arithmetic, which is quintessential to mathematical development. The nascent body of brain imaging studies reveals that arithmetic recruits a large set of interconnected areas, including prefrontal, posterior parietal, occipito-temporal and hippocampal areas. This network undergoes developmental changes in its function, connectivity and structure, which are not yet fully understood. This network only partially overlaps with what has been found in adults, and clear differences are observed in the recruitment of the hippocampus, which are related to the development of arithmetic fact retrieval. Despite these emerging trends, the literature remains scattered, particularly in the context of atypical development. Acknowledging the distributed nature of the arithmetic network, future studies should focus on connectivity and analytic approaches that investigate patterns of brain activity, coupled with a careful design of the arithmetic tasks and assessments of arithmetic strategies. Such studies will produce a more comprehensive understanding of how the arithmetical brain unfolds, how it changes over time, and how it is impaired in atypical development. PMID- 28566140 TI - Computer-assisted orthognathic surgery: evaluation of mandible registration accuracy and report of the first clinical cases of navigated sagittal split ramus osteotomy. AB - Intraoperative navigation is a helpful tool in complex anatomical regions or procedures. The mobility of the mandible in relation to the skull base limits the use of navigation tools on the lower jaw if the reference device is installed on the forehead. A new workflow that allows navigation-assisted sagittal split osteotomy in orthognathic surgery using a separate non-invasive mandibular registration technique has been developed. An evaluation of accuracy in different anatomical regions and with different registration techniques was performed on skull models and skulls with movable mandibles. The mean inaccuracy was 1.51mm, with no significant difference between anatomical sites. Using a splint-based reference device allows the movable mandible to be registered independently from the midface. Registration using metal points in the splint provides higher accuracy than using interdental anatomical landmarks. The workflow could be transferred successfully to patient treatment. Navigation-assisted osteotomy by Obwegeser-Dal Pont technique was performed without any complication in six patients. The mean deviation from the planned osteotomy line was 1.52mm. The navigated sagittal split ramus osteotomy seems to be a suitable technique to increase patient safety. PMID- 28566141 TI - Bibrachial plegia due to Lyme radiculopoliomyelitis-myelitis. AB - Nervous system involvement occurs in up to 15% of patients with Lyme disease, most commonly manifested as cranial neuropathy, lymphocytic meningitis, and or radiculoneuritis. We describe a patient with subacute radiculopoliomyelitis myelitis matching the selective involvement of the anterior horns and roots of the cervical spinal cord seen on MRI and on electrodiagnostic studies. We demonstrate positive CSF Lyme antibodies and document a near-complete recovery with antibiotics. This case highlights the importance of recognizing an atypical presentation of Lyme disease in the setting of initial radiculitis and or myelitis, particularly given the potential for favorable outcomes with appropriate treatment. PMID- 28566142 TI - Three dimensional video-oculography and thin-slice magnetic resonance imaging in a patient with superior oblique myokymia. PMID- 28566143 TI - Intracerebral haemorrhage risk in microbleed-positive ischaemic stroke patients with atrial fibrillation: Preliminary meta-analysis of cohorts and anticoagulation decision schema. AB - INTRODUCTION: Whether ischaemic stroke patients with atrial fibrillation (AF) and cerebral microbleeds (CMBs) on MRI can be safely anticoagulated is a hotly debated topic. We performed a systematic review and meta-analysis of published aggregate data, to investigate the risk of subsequent intracerebral haemorrhage (ICH) based on CMBs presence in this stroke population, generally considered for oral anticoagulation. We also suggest a decision-making schema for anticoagulation use in this setting. METHODS: We searched PubMed for relevant observational studies. Random effects models with DerSimonian-Laird weights were used to investigated the association between CMBs presence at baseline MRI and ICH or ischaemic stroke during follow-up. RESULTS: Four studies, with slightly heterogeneous design, including 990 ischaemic stroke patients were pooled in a meta-analysis (crude CMBs prevalence: 25%; 95%CI: 17%-33%). The median follow-up ranged between 17 and 37months. The future symptomatic ICH rate was 1.6% (16/990), while recurrent ischaemic stroke rate was 5.9% (58/990). Baseline CMB presence was associated with increased risk of symptomatic ICH during follow-up compared to patients without CMBs (OR: 4.16; 95%CI: 1.54-11.25; p=0.005). There was no association between CMBs presence and recurrent ischaemic stroke risk. CONCLUSION: We have shown that the presence of CMBs in cohorts of ischaemic stroke patients, most with AF on warfarin, is associated with a 4-fold increase in subsequent ICH (but not ischaemic stroke) risk (Class III evidence). These pooled estimates are useful for future trials design. We propose a simple data driven anticoagulation schema which awaits validation and refinement as new prospective data are accumulated. PMID- 28566146 TI - Marcel Proust's contacts with neurology. Did mistrust in doctors lead him to refuse life-saving therapies? PMID- 28566145 TI - The brain of Rene Descartes (1650): A neuro-anatomical analysis. AB - The skull of Rene Descartes is held in the National Museum of Natural History since the 19th c. Up to date, only anthropological examinations were carried out, focusing on the cranial capacity and phrenological interpretation of the skull morphology. Using CT-scan based 3D technology, a reconstruction of the endocast was performed, allowing for its first complete description and inter-disciplinary analysis: assessment of metrical and non-metrical features, retrospective diagnosis of anatomical anomalies, and confrontation with neuro-psychological abilities of this well-identified individual. PMID- 28566147 TI - The man behind Duchenne de Boulogne. PMID- 28566144 TI - The anteroposterior and primary-to-posterior limbic ratios as MRI-derived volumetric markers of Alzheimer's disease. AB - BACKGROUND/AIMS: Alzheimer's disease (AD) shows a characteristic pattern of brain atrophy, with predominant involvement of posterior limbic structures, and relative preservation of rostral limbic and primary cortical regions. We aimed to investigate the diagnostic utility of two gray matter volume ratios based on this pattern, and to develop a fully automated method to calculate them from unprocessed MRI files. PATIENTS AND METHODS: Cross-sectional study of 118 subjects from the ADNI database, including normal controls and patients with mild cognitive impairment (MCI) and AD. Clinical variables and 3T T1-weighted MRI files were analyzed. Regional gray matter and total intracranial volumes were calculated with a shell script (gm_extractor) based on FSL. Anteroposterior and primary-to-posterior limbic ratios (APL and PPL) were calculated from these values. Diagnostic utility of variables was tested in logistic regression models using Bayesian model averaging for variable selection. External validity was evaluated with bootstrap sampling and a test set of 60 subjects. RESULTS: gm_extractor showed high test-retest reliability and high concurrent validity with FSL's FIRST. Volumetric measurements agreed with the expected anatomical pattern associated with AD. APL and PPL ratios were significantly different between groups, and were selected instead of hippocampal and entorhinal volumes to differentiate normal from MCI or cognitively impaired (MCI plus AD) subjects. CONCLUSION: APL and PPL ratios may be useful components of models aimed to differentiate normal subjects from patients with MCI or AD. These values, and other gray matter volumes, may be reliably calculated with gm_extractor. PMID- 28566148 TI - Assessment of the general public's knowledge of stroke: A cross-sectional study in Yaounde, Cameroon. AB - BACKGROUND: Stroke knowledge and awareness in the general public is important to improve stroke prevention and ensure prompt response to disease onset. Addressing the dearth of data in Africa, this study aimed to determine the level of knowledge on stroke definition, symptoms, risk factors and complications in the general population living in Yaounde, Cameroon. METHODS: From February to April 2015, we conducted a cross-sectional study at the Nicolas Barre Hospital Centre. With the exception of the health personnel, we recruited all individuals aged >=18years who visited the Centre for one reason or another and who volunteered to answer our questionnaire. The level of knowledge on stroke was evaluated on 28 points corresponding to 28 questions addressing either stroke definition, warning signs and symptoms, risk factors or complications. RESULTS: In total, 1.025 participants (57.4% females) were enrolled. The median age was 34years (interquartile range: 26-48); 14.9% and 9.8% of the participants were known hypertensive and diabetes patients, respectively. Overall, 99% of participants had already heard about stroke. The mean score of knowledge was 81.3+/-11.1%. The main sources of information on stroke were the close entourage (83.0%) and the health personnel (73.0%); media (television (16.4%), newspaper (8.0%), internet (7.7%), and radio (2.2%)) and school (8.0%) were the least represented. Speech disturbances (98.3%) and weakness, numbness or paralysis of one part of the body (98.0%) were the major warning signs and symptoms cited. Hypertension (98.5%) and overweight/obesity (97.8%) were the most known risk factors; 98.7% of people were aware of stroke common complications. Younger age (<45years), male sex, lower level of education and previous experience of stroke education were independently associated with a lower level of knowledge on stroke. CONCLUSION: The general public's level of knowledge on stroke in Yaounde is good, though still needing to be improved. Media and schools should be capitalized to communicate on stroke, as these means will help to reach the youngest and the least educated who seem to have lower levels of knowledge. PMID- 28566150 TI - Deep brain stimulation for Parkinson's disease: Subcutaneous apomorphine as an alternative for patients unable to tolerate surgery under local anesthesia. PMID- 28566149 TI - Clinical profile of motor neuron disease patients with lower urinary tract symptoms and neurogenic bladder. AB - INTRODUCTION: Lower urinary tract symptoms (LUTS) are frequent in motor neuron disease (MND) patients, but clinical factors related to them are unknown. We describe differences in LUTS among MND phenotypes and their relationship with other clinical characteristics, including prognosis. METHODS: For this study, we collected clinical data of a previously published cohort of patients diagnosed with classical amyotrophic lateral sclerosis (cALS), progressive muscular atrophy (PMA) or primary lateral sclerosis (PLS) with and without LUTS. Familial history was recorded and the C9ORF72 expansion was analysed in the entire cohort. Patients were followed-up for survival until August 2016. RESULTS: Fifty-five ALS patients (37 cALS, 10 PMA and 8 PLS) were recruited. Twenty-four reported LUTS and neurogenic bladder (NB) could be demonstrated in nine of them. LUTS were not influenced by age, phenotype, disability, cognitive or behavioural impairment, or disease progression, but female sex appeared to be a protective factor (OR=0.39, p=0.06). Neither family history nor the C9ORF72 expansion was linked to LUTS or NB. In the multivariate analysis, patients reporting LUTS early in the disease course tended to show poorer survival. CONCLUSIONS: In this study, LUTS appear to be more frequent in male MND patients, but are not related to age, clinical or genetic characteristics. When reported early, LUTS could be a sign of rapid disease spread and poor prognosis. Further prospective longitudinal and neuroimaging studies are warranted to confirm this hypothesis. PMID- 28566151 TI - Mobile health as a viable strategy to enhance stroke risk factor control: A systematic review and meta-analysis. AB - BACKGROUND: With the rapid growth worldwide in cell-phone use, Internet connectivity, and digital health technology, mobile health (mHealth) technology may offer a promising approach to bridge evidence-treatment gaps in stroke prevention. We aimed to evaluate the effectiveness of mHealth for stroke risk factor control through a systematic review and meta-analysis. METHODS: We searched PubMed from January 1, 2000 to May 17, 2016 using the following keywords: mobile health, mHealth, short message, cellular phone, mobile phone, stroke prevention and control, diabetes mellitus, hypertension, hyperlipidemia and smoking cessation. We performed a meta-analysis of all eligible randomized control clinical trials that assessed a sustained (at least 6months) effect of mHealth. RESULTS: Of 78 articles identified, 13 met eligibility criteria (6 for glycemic control and 7 for smoking cessation) and were included for the final meta-analysis. There were no eligible studies for dyslipidemia or hypertension. mHealth resulted in greater Hemoglobin A1c reduction at 6months (6 studies; 663 subjects; SMD: -0.44; 95% CI: [-0.82, -0.06], P=0.02; Mean difference of decrease in HbA1c: -0.39%; 95% CI: [-0.74, -0.04], P=0.03). mHealth also lead to relatively higher smoking abstinence rates at 6months (7 studies; 9514 subjects; OR: 1.54; 95% CI: [1.24, 1.90], P<0.0001). CONCLUSIONS: Our meta-analysis supports that use of mHealth improves glycemic control and smoking abstinence rates. PMID- 28566153 TI - Concerning the article "Interleukins 17 and 10 in a sample of Egyptian relapsing remitting multiple sclerosis patients". PMID- 28566152 TI - Sonographic evaluation of atherosclerosis burden in carotid arteries of ischemic stroke patients and its relation to paraoxonase 1 and 2, MTHFR and AT1R genetic variants. AB - OBJECTIVE: Common variants of the Paraoxonase (PON), 5-Methyl-Tetrahydrofolate Reductase (MTHFR) and Angiotensin-II receptor 1 (AT1R) genes have been associated with ischemic stroke (IS) risk. Moreover, carotid atherosclerosis is a common cause of IS. The aim of this study is to explore whether variants in these genes associate with the severity of ultrasonographic determined atherosclerosis assessed in carotid arteries. PATIENTS AND METHODS: Etiologic subtype of cerebral ischemia was determined according to the TOAST classification. Genotypes were detected by PCR and restriction analysis. An ultrasonographic supra-aortic trunks study was performed to all patients to assess their atherosclerotic involvement based on predefined criteria. RESULTS: In IS patients, none of the analyzed gene distributions differed concerning the stenosis degree. Nevertheless, a trend was observed for the rs662 and rs7493 variants of the PON1 and PON2 genes respectively. When evaluated the results based on different inheritance models, a significant contribution of rs7493 variant according to a dominant (OR=2.397, 95% CI (1.001-5.376); p=0.045) and log-additive inheritance forms (OR=1.85, 95% CI (1.07-3.2); p=0.03) was observed. Only rs7493 reached statistical significance (p=0.013), when genotype distribution was analyzed according to carotid intima media thickness (cIMT) and remain significant in multivariate logistic regression analysis (OR=2.66, 95% CI (1.1 to 6.4); p=0.03). CONCLUSION: In IS patients of the north area of the Gran Canaria island the PON2 (rs7493) gene variant associates with a worse ultrasonographic profile. Conversely, the Cys311Cys homozygosis of the rs7493 variant was also related to a better ultrasonographic profile in our study. PMID- 28566154 TI - Usefulness of the superior cerebellar peduncle for differential diagnosis of progressive supranuclear palsy: A meta-analysis. AB - Previous studies have reported the usefulness of superior cerebellar peduncle (SCP) abnormalities in diagnosing progressive supranuclear palsy. However, the results of these studies were heterogeneous. In the present meta-analysis, we aimed to establish more robust evidence of SCP abnormalities in progressive supranuclear palsy, and to determine the cause of the previously reported heterogeneity. We identified six studies on SCP size and three studies on apparent diffusion coefficient. Key features of each study were extracted and standardized differences in size and apparent diffusion coefficient values were calculated. There was some heterogeneity in terms of the reduction in SCP size in patients with progressive supranuclear palsy compared to those with Parkinson's disease. Moreover, age and Hoehn-Yahr stage negatively correlated with standardized mean difference in SCP size between patients with progressive supranuclear palsy and Parkinson's disease. There was homogenous agreement that the SCP was smaller in patients with progressive supranuclear palsy compared to those with multiple system atrophy. Finally, in terms of apparent diffusion coefficient, there was no significant difference between patients with progressive supranuclear palsy, Parkinson's disease, or multiple system atrophy. Together, these findings suggest that SCP size, when corrected for age and disease severity, could be a diagnostic tool for progressive supranuclear palsy. PMID- 28566155 TI - DNA damage, DNA susceptibility to oxidation and glutathione redox status in patients with Alzheimer's disease treated with and without memantine. AB - The aim of the current study was to compare oxidative DNA damage, DNA susceptibility to oxidation, and ratio of GSH/GSSG in patients with Alzheimer's disease (AD) treated with acetylcholinesterase inhibitor (AChEI) and combined AChEI+memantine. The study included 67 patients with AD and 42 volunteers as control. DNA damage parameters (strand breaks, oxidized purines, H2O2-induced DNA damage) in lymphocyte DNA and GSH/GSSG ratio in erythrocytes were determined by the comet assay and spectrophotometric assay, respectively. DNA damage was found to be higher, GSH/GSSG ratio was found to be lower in the AD group than those in the control group. DNA strand breaks and H2O2-induced DNA damage were lower in the patients taking AChEI+memantine than those in the patients taking AChEI but no significant difference was determined between the groups for oxidized purines and GSH/GSSG ratio. In conclusion, increased systemic oxidative DNA damage and DNA susceptibility to oxidation may be resulted from diminished GSH/GSSG ratio in AD patients. Although DNA strand breaks and H2O2-induced DNA damage are lower in the AD patients treated with combined AChEI and memantine, this may not indicate protective effect of memantine against DNA oxidation due to similar levels of oxidized purines in the patients treated with AChEI and AChEI+memantine. PMID- 28566156 TI - A preliminary investigation of sleep quality in functional neurological disorders: Poor sleep appears common, and is associated with functional impairment. AB - PURPOSE: Functional neurological disorders (FND) are disabling conditions for which there are few empirically-supported treatments. Disturbed sleep appears to be part of the FND context; however, the clinical importance of sleep disturbance (extent, characteristics and impact) remains largely unknown. We described sleep quality in two samples, and investigated the relationship between sleep and FND related functional impairment. METHODS: We included a sample recruited online via patient charities (N=205) and a consecutive clinical sample (N=20). Participants completed validated measures of sleep quality and sleep characteristics (e.g. total sleep time, sleep efficiency), mood, and FND-related functional impairment. RESULTS: Poor sleep was common in both samples (89% in the clinical range), which was characterised by low sleep efficiency (M=65.40%) and low total sleep time (M=6.05h). In regression analysis, sleep quality was negatively associated with FND-related functional impairment, accounting for 16% of the variance and remaining significant after the introduction of mood variables. CONCLUSIONS: These preliminary analyses suggest that subjective sleep disturbance (low efficiency, short sleep) is common in FND. Sleep quality was negatively associated with the functional impairment attributed to FND, independent of depression. Therefore, sleep disturbance may be a clinically important feature of FND. PMID- 28566157 TI - Functional brain neuroimaging-guided repetitive transcranial magnetic stimulation in neurodevelopmental disorders: The case of a schizencephaly-related spastic dystonia. PMID- 28566158 TI - Diagnostic challenges in POEMS syndrome presenting with polyneuropathy: A case series. AB - OBJECTIVE: To analyze the clinical characteristics of patients with POEMS presenting with polyneuropathy and discuss associated diagnostic challenges. METHOD: Retrospective analysis of 6 patients from 2 tertiary-care institutions. RESULTS: Six patients presented with progressive sensorimotor deficits predominantly or exclusively in the lower extremities and were diagnosed with POEMS syndrome. In 4 patients, a diagnosis of chronic inflammatory demyelinating polyradiculopathy (CIDP) was mistakenly made. Low concentration of serum paraprotein and elevated vascular endothelial growth factor (VEGF) were detected in all 6 patients. Initial serum immunofixation and skeletal survey were normal in 2 patients each. On nerve conduction studies, motor and sensory responses were absent in the lower extremity in all 6 patients. Conduction velocity slowing and F-wave latency prolongation appear slightly more pronounced than distal motor latency prolongation in the upper extremity. Spinal MRI showed diffuse lumbosacral nerve root enhancement in all. In 3 patients, targeted bone marrow biopsy was needed for confirming the POEMS diagnosis. Treatment with corticosteroids, chemotherapy agent, focal radiation and/or autologous stem cell transplantation led to significant improvement in 5 of 6 patients. CONCLUSION: Diagnosis of POEMS should be considered in patients with progressive polyneuropathies of mixed demyelinating and axon loss features, including CIDP patients not responding to standard treatment. A polyradiculoneuropathy rather than a pure polyneuropathy seems to exist in POEMS. PMID- 28566159 TI - Paroxysmal sensory (spinal) attacks without hyperexplexia in a patient with a variant in the GLRA1 gene. PMID- 28566160 TI - Bilateral striatal necrosis caused by a founder mitochondrial 14459G>A mutation in two independent Japanese families. AB - Bilateral striatal necrosis (BSN) has many causes and is characterized by unique clinical and neuroradiological features. Herein, we report a clinical and genetic analysis of three BSN cases from two independent Japanese families harboring a mitochondrial DNA (mtDNA) 14459G>A mutation located in a coding region of the NADH dehydrogenase subunit 6 gene. In the first family, two male siblings from non-consanguineous parents exhibited similar phenotypes, with infantile-onset generalized dystonia. A third sporadic case involved a male patient with a comparatively milder phenotype characterized by juvenile-onset mild truncal ataxia and parkinsonism. Cerebral magnetic resonance imaging of these cases revealed abnormal signal intensities along the bilateral putaminal area and enlarged lateral ventricle anterior horns caused by caudate nuclear atrophy, particularly in the sibling pair. The sibling-pair cases shared a homoplasmic 14459G>A mutation, and the sporadic case showed heteroplasmy of the same mutation. Additionally, all three cases harbored the 14605A>G single nucleotide polymorphism, which was previously reported as a rare synonymous variation (4.3%) in a Japanese population. Plasmid sequencing revealed a genetic linkage of these two DNA substitutions, suggesting that the three patients shared a genetic founder. Although our mtDNA analysis was only accessible using leukocytes, clinical severity might be associated with homoplasmy or heteroplasmy. In summary, it is important to evaluate potential mtDNA defects in BSN cases, regardless of familial occurrence. PMID- 28566161 TI - Long-term safety of repeated high doses of incobotulinumtoxinA injections for the treatment of upper and lower limb spasticity after stroke. AB - Current guidelines suggested a dosage up to 600units (U) of botulinum toxin type A (BoNT-A) (onabotulinumtoxinA or incobotulinumtoxinA) in reducing spastic hypertonia with low prevalence of complications, although a growing body of evidence showed efficacy with the use of high doses (>800U). The available evidence mainly referred to a single set of injections evaluating the efficacy and safety of the neurotoxin 30days after the treatment. In a prospective, non randomized, open-label study, we studied the safety of repeated higher doses of incobotulinumtoxinA in post-stroke upper and lower limb spasticity. Two years after the first set of injections, we evaluated in 20 stroke survivors with upper and lower limb spasticity the long-term safety of repeated high doses of incobotulinumtoxinA (up to 840U) for a total of eight sets of injections. Patients reported an improvement of their clinical picture concerning a reduction of spasticity measured with the Asworth Scale (AS) for elbow, wrist, fingers and ankle flexor muscles and disability measured with the Disability Assessment Scale (DAS) 30days after the last set of injections (eighth set) compared to the baseline (p<0.0001). No difference in AS and DAS scores has been found between t1 (30days after the first injection set) and t2 (30days after the eighth set of injections), with also similar safety. In a two-year follow-up, repeated high doses of incobotulinumtoxinA, administered for eight sets of injections, appeared to be safe in patients with upper and lower limb spasticity after stroke without general adverse effects. PMID- 28566162 TI - Brain positron emission tomography in patients with myotonic dystrophy type 1 and type 2. AB - AIM: To determine regions of reduced brain metabolism in patients with myotonic dystrophy type 1 (DM1) and type 2 (DM2) using 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), and to analyse their potential association with cognitive deficit. METHOD: Study included 29 patients (16 DM1 and 13 DM2). FDG-PET and detailed neuropsychological testing were performed in both groups. RESULTS: The most common cognitive findings were executive, visuospatial, and naming dysfunction in DM1, and executive and naming dysfunction in DM2. FDG-PET showed the most prominent glucose hypometabolism in prefrontal, temporal, and pericentral regions in both DM1 and DM2 patients, with additional affection of insula and subcortical grey matter in DM2. In DM1 patients, we found association between right frontotemporal hypometabolism and executive dysfunction (p<0.05). In DM2 patients attention deficit was in association with prefrontal, insular, and striatal hypometabolism, as well as right frontotemporal hypometabolism (p<0.05). Executive dysfunction in DM2 was more common in patients with prefrontal and insular hypometabolism, right parietotemporal and frontotemporal hypometabolism, as well as left striatal hypometabolism (p<0.05). Patients with parietotemporal defect on FDG-PET were more likely to have naming dysfunction (p<0.01). CONCLUSION: FDG-PET findings corresponded well with the results of neuropsychological testing. FDG-PET may be a good biomarker of central nervous system involvement in DM1 and DM2, but this hypothesis will have to be more strongly supported by larger studies. PMID- 28566163 TI - Subcutaneous immunoglobulin treatment in CIDP and MMN. Efficacy, treatment satisfaction and costs. AB - Subcutaneous administration of immunoglobulin (SCIG) in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) has been reported in several case reports and in a few randomized trials during the last decade. In this review we present the studies on SCIG in CIDP and MMN with special focus on the clinical effects. Moreover, the effect on quality of life, side effects to SCIG and the health economic perspectives are reviewed. Nine case studies, three randomized trials and six long-term, follow-up studies were identified. Most of the studies are conducted in patients switched from regular IVIG to SCIG treatment; one study involves treatment-naive patients. The review shows that none of the studies have been powered to demonstrate an effect on disability. SCIG can maintain muscle strength for a period of 1 to 2years and ability seems preserved for a similar period. Quality of life is generally unchanged or improved after switch to SCIG and generalized side-effects seem fewer, whereas local reactions at the injection site occur. Health economic analyses favour SCIG at the doses used in the reviewed studies. PMID- 28566164 TI - Cervical spinal cord and motor unit pathology in a canine model of SOD1 associated amyotrophic lateral sclerosis. AB - Development of effective treatments for amyotrophic lateral sclerosis (ALS) would be facilitated by identification of early events in the pathological cascade of disease progression. Degenerative myelopathy (DM), a naturally occurring disease in dogs, is quite similar to forms of ALS associated with SOD1 mutations and is likely to be a good model for these forms of the human disease. The sequence of histopathological changes that occur in DM was characterized by analyzing tissue samples obtained from affected dogs euthanized at various stages of disease progression. Cervical spinal cord and the associated spinal nerve roots, ulnar nerve, and the extensor carpi radialis (ECR) muscle were obtained from Pembroke Welsh Corgi dogs (PWCs) with early and late stage DM and from age-matched unaffected PWCs. In early stage disease there was a substantial change in the ratio of the two main muscle fiber types and an increase in mean muscle fiber area in the ECR. DM, even in late stage disease, was not accompanied by changes in the number of motor neuron cell bodies, in the number of axons in the motor or sensory nerve roots, or in the ulnar nerve. In addition, no disease-related denervation of the acetylcholine receptors of the ECR was observed at any stage of the disease. On the other hand, axon densities in both motor and sensory nerve tracts in the cervical cord were reduced in affected dogs. SOD1-immunoreactive aggregates were observed in spinal cord motor neuron cell bodies only in late stage disease. These findings suggest that some of the earliest pathological changes in DM occur in the muscle fibers and upper motor and sensory neuron tracts in the spinal cord. Targeting therapeutic interventions to these early events in the disease are most likely to be effective in slowing disease progression for DM and may translate to therapy of SOD1-related forms of ALS. PMID- 28566165 TI - Peripheral neuropathy in idiopathic Parkinson's disease: A systematic review. AB - BACKGROUND: Parkinson's disease (PD) has been associated with peripheral neuropathy (PN). PN has been demonstrated in some rare genetic forms of PD (e.g. PARK2 mutations) but has also been linked to levodopa exposure. OBJECTIVE: The aim of this systematic review is to clarify any evidence of peripheral nervous system involvement in idiopathic PD. METHODS: A systematic computer-based literature search was conducted on PubMed database. FINDINGS: The pooled estimate of the prevalence of large fiber PN in PD was 16.3% (based on 1376 patients). The pooled estimate of the prevalence of biopsy-proven small fiber neuropathy was 56.9% (based on 72 patients). Large fiber PN in PD is in the majority of cases distal, symmetrical, axonal and predominantly sensory. There are, however, few reports of chronic idiopathic demyelinating polyneuropathy and very occasional cases of acute neuropathies. Although nerve conduction studies have been performed in the majority of the studies, they included only a limited number of nerves, mainly in the lower limbs. There is little evidence to support a direct link between levodopa treatment and the development of PN in idiopathic PD. In the majority of the cases PN has been linked to abnormalities in vitamin B12, methylmalonic acid or fasting homocysteine levels. Additional aetiological risk factors for PN may be responsible for any apparent link between PD and PN. CONCLUSIONS: Large-scale prospective studies with long-term follow-up with detailed baseline assessments are needed in order to understand the natural history of PN in PD, both on clinical and neurophysiological parameters. PMID- 28566166 TI - Expanding the clinical phenotype of CAPN1-associated mutations: A new case with congenital-onset pure spastic paraplegia. PMID- 28566168 TI - Management of post-stroke depression in the Middle East and North Africa: Too little is known. AB - Stroke is among the most common disabilities among adults and most stroke victims live in developing countries. However, little is known about services delivered in these countries for post-stroke depression, a common comorbidity that influences functional outcomes of stroke. In this paper, a physician from Syria reviews the literature on post-stroke depression among patients living in countries of the Middle East and North Africa region in order to examine whether current practices can be improved. Studies of prevalence were found in six of the region's countries and only four studies described interventions for stroke patients with clinical depression. The limited studies on prevalence confirmed that stroke incidence and post-stroke depression are common although diagnosed depression appears to vary depending on the economic environment of the country. Hence, additional interventions in MENA countries may be warranted to increase recognition of depression in stroke patients and to ensure health professionals are prepared to deliver appropriate services to stroke patients and their family caregivers for depression when it occurs. PMID- 28566167 TI - In-vivo reflectance confocal microscopy of Meissner's corpuscles in diabetic distal symmetric polyneuropathy. AB - OBJECTIVE: To evaluate in-vivo reflectance confocal microscopy (RCM) of Meissner's corpuscles (MC) in diabetic distal symmetric polyneuropathy (DSP). METHODS: Forty-three adults with diabetes and 21 control subjects underwent RCM of MC density at the fingertip of digit V, thenar eminence (TE), and arch of the foot, ankle skin biopsy for epidermal nerve fiber density (ENFD), electrophysiological studies, monofilament threshold testing, and timed vibration at the toe. Subjects with diabetes were subdivided into groups with and without clinical DSP using the American Academy of Neurology (AAN) case definition and neuropathy outcomes were compared across groups. RESULTS: Both diabetic groups (with and without AAN clinical DSP criteria) had objective evidence of peripheral sensory involvement using conventional sensory measures, although those with clinical DSP criteria had greater abnormalities. MC densities were lower in the entire diabetic group at the TE and digit V relative to controls. MC densities at all imaging sites were associated with corresponding conventional sensory measures. MC densities were reduced in subjects without AAN clinical DSP criteria at the TE and digit V compared to controls whereas conventional upper limb sensory measures did not differ between these groups. CONCLUSIONS: In-vivo RCM of MC density at digit V is a non-invasive, painless, objective marker in diabetes that offers a window into early large fiber sensory nerve terminal loss. Further studies are needed to determine whether RCM of MCs can identify quantitative changes in DSP associated with disease progression or treatment. PMID- 28566169 TI - Transcranial direct current stimulation over the primary motor vs prefrontal cortex in refractory chronic migraine: A pilot randomized controlled trial. AB - Although transcranial direct current stimulation (tDCS) represents a therapeutic option for the prophylaxis of chronic migraine, the target area for application of the electrical current to the cortex has not yet been well established. Here we sought to determine whether a treatment protocol involving 12 sessions of 2mA, 20min anodal stimulation of the left primary motor (M1) or dorsolateral prefrontal cortex (DLPFC) could offer clinical benefits in the management of pain from migraine. Thirteen participants were assessed before and after treatment, using the Headache Impact Test-6, Visual Analogue Scale and Medical Outcomes Study 36 - Item Short - Form Health Survey. After treatment, group DLPFC exhibited a better performance compared with groups M1 and sham. On intragroup comparison, groups DLPFC and M1 exhibited a greater reduction in headache impact and pain intensity and a higher quality of life after treatment. No significant change was found in group sham. The participants in group M1 exhibited more adverse effects, especially headache, heartburn, and sleepiness, than did those in the other two groups. Transcranial direct current stimulation is a safe and efficacious technique for treating chronic migraine. However, it should be kept in mind that the site of cortical stimulation might modulate the patient's response to treatment. PMID- 28566170 TI - Is maraviroc useful in multiple sclerosis patients with natalizumab-related progressive multifocal leukoencephalopathy? AB - BACKGROUND: Despite the recent advances in the understanding of natalizumab (NTZ) related progressive multifocal leukoencephalopathy (PML) and its associated immune reconstitution inflammatory syndrome (PML-IRIS), the therapeutic options are still under investigated. In this context, the beneficial use of maraviroc is still an anecdotal observation. OBJECTIVE: To evaluate the impact of maraviroc in modifying the course of PML preventing IRIS or blunting IRIS manifestations. METHODS: Three patients with NTZ PML included in the Italian dataset of PML were treated with maraviroc. Their longitudinal clinical and radiological course was described in detail. RESULTS: The three patients were characterized by a steady clinical worsening not controlled by maraviroc. All the three patients manifested PML-IRIS, which emerged, respectively, at 62, 64 and 90days post NTZ withdrawal. This is in accordance with the data of the Italian dataset. Clinical and radiological stabilization of PML-IRIS occurred only after corticosteroids administration. CONCLUSION: In these three cases, maraviroc did not show any clear effect in modulating the clinical course of PML preventing IRIS. Moreover, once PML-IRIS emerged, the clinical stabilization was achieved only with the use of corticosteroids. Thus, the use of maraviroc should be regarded with extreme caution due the potential adverse events associated with its use. PMID- 28566171 TI - Achieving low density lipoprotein-cholesterol<70mg/dL may be associated with a trend of reduced progression of carotid artery atherosclerosis in ischemic stroke patients. AB - OBJECTIVE: To assess whether an intensive lipid-lowering strategy is more beneficial on atherosclerotic plaque progression in the stroke survivors. METHODS: We retrospectively assessed data that was prospectively collected on 106 ischemic stroke patients from one academic stroke center. Patients with various degrees of common carotid artery atherosclerosis were followed for one year. Patients were classified into intensive lipid-lowering therapy (ILLT) group if they achieve low-density lipoprotein cholesterol (LDL-c)<70mg/dL (n=38) and conventional lipid-lowering therapy (CLLT) group if their LDL-c is within 70 120mg/dL (n=68) at end of one year. Carotid ultrasound was performed at baseline lipid-lowering therapy and at one year to characterize the plaques. RESULTS: Mean change in atherosclerotic plaque length was -1.4mm (95% CI: [-4.1, 1, 2]; P=0.27) in ILLT and 1.1mm in CLLP group (95% CI: [-0.9, 3.1]; P=0.27); no difference between groups (P=0.40). Atherosclerotic plaque thickness decreased by 0.2mm (95% CI: [-0.4, 0.03]; P=0.09) in ILLT group; while in CLLT group, thickness increased by 0.02mm after 1-year therapy (95%CI: [-0.1, 0.2]; P=0.77); no difference between groups (P=0.28). CONCLUSIONS: Achieving LDL-c<70mg/dL in ischemic stroke patients was associated with a trend of reducing atherosclerotic plaque progression at one year. Future larger studies are warranted. PMID- 28566172 TI - Pattern of care and outcome in elderly patients with glioblastoma: Data in 151 patients from 3 Lombardia Hospitals. AB - The appropriate treatment approach for elderly patients with glioblastoma multiforme (GBM) is unclear, although different studies suggest survival benefit in fit patients treated with radiotherapy and chemiotherapy after surgery. We performed a retrospective analysis of 151 patients older than 65years with GBM treated in 3 Lombardia Hospitals. In univariate regression analysis higher KPS (p=0.02), macroscopical total resection (p<0.003), radiotherapy (p<0.0001), chemotherapy (p<0.0001) and second line chemotheraphy (p=0.02) were of positive prognostic value. On the contrary older age (>70years), presence of seizure at onset and additional resection after tumor recurrence did not influence OS. Multivariate analysis revealed radiotherapy (HR 0.2 p<0.0001) and extent of surgery (HR 0.3, p=0,0063) as positive independent prognostic factors. Patients receiving radio-chemiotherapy displayed more treatment-related toxicities with a slightly prolonged OS versus those receiving hypofractionated radiotherapy. With the limits of a retrospective study, our data suggest that in elderly fit patients extensive surgery should be considered, moreover adjuvant treatments led to an increase in OS. Randomized controlled study are needed to develop treatment guidelines for elderly GBM patients and to assess whether the combination of post surgical radio and chemiotherapy may be superior to hypofractionated radiotherapy and chemiotherapy in fit patients. PMID- 28566173 TI - Vitamin D3 supplementation in multiple sclerosis: Symptoms and biomarkers of depression. AB - Depressive symptoms are common in multiple sclerosis (MS), and both depression and MS have been associated with a poor vitamin D status. As cytokine-mediated inflammatory processes play a role in the pathogenesis of both disorders, we hypothesized that vitamin D3 supplementation reduces depressive symptoms in MS via its immunomodulatory properties. In this randomized pilot study relapsing remitting (RR) MS patients received either vitamin D3 supplementation (n=20; 14.000IU/day) or placebo (n=20) during 48weeks. Pre- and post-supplementation depression scores, measured using the Hospital Anxiety Depression Scale (HADS) depression subscale (HADS-D), showed a significant decrease within the vitamin D3 group (median HADS-D 4.0 to 3.0, p=0.02), a trend towards a decrease within the placebo group (median HADS-D 3.0 to 2.0, p=0.06), but no significantly different reductions between groups (p=0.78). Furthermore, no reductions in pro- and anti inflammatory cytokine balances, secreted by stimulated leukocytes and CD8+ T cells, were found in the vitamin D3 compared to the placebo arm. Therefore, we found no evidence for a reduction of depressive symptoms or related biomarkers upon vitamin D3 supplementation in RRMS patients in this exploratory study. Whether vitamin D3 supplementation is of benefit in manifest depression in MS needs to be assessed by additional studies. PMID- 28566174 TI - Role of the "other Babinski sign" in hyperkinetic facial disorders. AB - BACKGROUND: The "other Babinski sign" consists in the co-contraction of the orbicularis and frontalis muscles, causing an eyebrow elevation during ipsilateral eye closure. It cannot be voluntarily reproduced. AIMS OF THE STUDY: To determine the utility of this sign in the differential diagnosis of hyperkinetic facial disorders. METHODS: The presence of the sign was assessed in consecutive patients with blepharospasm, primary hemifacial spasm or post paralytic facial syndrome treated in a botulinum toxin outpatient clinic. RESULTS: Of the 99 patients identified, 86 were included, 41 with blepharospasm (32 female, mean age 71+/-11years), 28 with hemifacial spasm (16 female, mean age 65+/-12years) and 17 with post-paralytic facial syndrome (14 female, mean age 50+/-17years). The sign was detected in 67.9% of the patients with hemifacial spasm, in 23.5% of the post-paralytic facial syndrome group and in none of the patients with blepharospasm, exhibiting a sensitivity of 51% and a specificity of 100% for the diagnosis of hemifacial spasm/post-paralytic facial syndrome and a specificity of 76% for hemifacial spasm, compared to post-paralytic facial syndrome. CONCLUSIONS: This sign is highly specific for the diagnosis of peripherally induced hyperkinetic facial disorders. Its assessment should integrate the routine examination of patients with abnormal facial movements. PMID- 28566176 TI - Effects of age and glucose levels on lactate levels in cerebrospinal fluid examination of neurodegenerative diseases. AB - Despite recent studies examining the association between neurodegenerative diseases and mitochondrial dysfunction, there are not sufficient data on factors that influence cerebrospinal fluid (CSF) lactate levels. Thus, we investigated factors that affect CSF lactate levels in neurodegenerative diseases. We extracted laboratory findings, including CSF lactate, glucose, and protein levels, and demographic and background information, including age and gender, from the electronic medical records of patients with neurodegenerative diseases in order to explore factors that have an impact CSF lactate levels. These patients had been admitted to our department and underwent a CSF examination between April 2007 and March 2015. Data from 83 patients (average age 64.5years; 45 males and 38 females) were analyzed. The patients' diagnoses included amyotrophic lateral sclerosis, multiple system atrophy, spinocerebellar degeneration, corticobasal syndrome, Parkinson's disease, and Huntington's disease. CSF lactate levels were higher in patients with a neurodegenerative disease who were aged 65years and older relative to those who were aged under 65years (p<0.05), and CSF lactate and glucose levels showed a moderate positive correlation (r=0.487). Age and CSF glucose levels influenced CSF lactate levels even after adjusting for gender, age, CSF protein levels, and CSF glucose levels. When investigating CSF lactate levels in neurodegenerative diseases, it is necessary to consider patients' age and CSF glucose levels. PMID- 28566177 TI - C9ORF72 and parkinsonism: Weak link, innocent bystander, or central player in neurodegeneration? PMID- 28566178 TI - Expanding the phenotype of phosphomannomutase-2 gene congenital disorder of glycosylation: Cervical dystonia. PMID- 28566175 TI - Brain iron concentrations in regions of interest and relation with serum iron levels in Parkinson disease. AB - Brain iron has been previously found elevated in the substantia nigra pars compacta (SNpc), but not in other brain regions, of Parkinson's disease (PD) patients. However, iron in circulation has been recently observed to be lower than normal in PD patients. The regional selectivity of iron deposition in brain as well as the relationship between SNpc brain iron and serum iron within PD patients has not been completely elucidated. In this pilot study we measured brain iron in six regions of interest (ROIs) as well as serum iron and serum ferritin, in 24 PD patients and 27 age- gender-matched controls. Brain iron was measured on magnetic resonance imaging (MRI) with a T2 prime (T2') method. Difference in brain iron deposition between PD cases and controls for the six ROIs were calculated. SNpc/white matter brain iron ratios and SNpc/serum iron ratios were calculated for each study participant, and differences between PD patients and controls were tested. PD patients overall had higher brain iron than controls in the SNpc. PD patients had significantly higher SNpc/white matter brain iron ratios than controls, and significantly higher brain SNpc iron/serum iron ratios than controls. These results indicate that PD patients' iron metabolism is disrupted toward a higher partitioning of iron to the brain SNpc at the expenses of iron in the circulation. PMID- 28566179 TI - Acute unilateral peripheral vestibulopathy in neurosyphilis. AB - INTRODUCTION: Neurosyphilis producing basal meningitis presenting as sequential transient cranial nerve palsies was well recognized before the antibiotic era. OBJECTIVE: To report two patients presenting with acute unilateral peripheral vestibulopathy due to syphilitic basal meningitis. RESULTS: In Case 1 basal meningitis occurred early in the secondary phase of the infection, in Case 2 in the late latent phase. The diagnosis was not made immediately in either case; in Case 1 after previous presentation with increasing hearing loss and then with facial palsy and then a subsequent presentation with optic neuritis; in Case 2 after investigation for possible lymphoma. CONCLUSION: Syphilitic basal meningitis in either the secondary or in the latent phase can present as acute unilateral peripheral vestibulopathy with transient involvement of the facial or auditory nerve. PMID- 28566180 TI - Improved strength on 5-hydroxytryptophan and carbidopa in spinal cord atrophy. AB - There is ample evidence of an important role of descending serotonergic projections in modulating spinal motor neuron activation and firing, and experimental studies suggest that 5-HT receptor stimulation can improve motor function after spinal cord injury; however, relevant clinical data is sorely lacking. We describe two sisters with hemiplegic migraine, low CSF and platelet serotonin levels, and progressive spastic paraparesis associated with profound spinal cord atrophy whose lower extremity strength and ambulation responded to a precursor replacement strategy (5-hydroxytryptophan and carbidopa administration), an approach that may have broader applicability in myelopathies of diverse etiology where descending serotonergic projections are compromised. PMID- 28566181 TI - Interleukin 17 and 10 in relapsing remitting multiple sclerosis. PMID- 28566182 TI - NUDT15 p.R139C variant is common and strongly associated with azathioprine induced early leukopenia and severe alopecia in Korean patients with various neurological diseases. AB - Azathioprine (AZA)-induced leukopenia is a relatively common complication in Korean patients. In addition to variation in TPMT (thiopurine S methyltransferase), the NUDT15 p.R139C variant was recently identified to have a strong association with AZA-induced leukopenia. We investigated these associations in Korean patients undergoing AZA treatment with various neurological diseases. Among 84 enrolled patients, 20 (23.8%; 7 early, 13 late) exhibited leukopenia. The NUDT15 p.R139C variant was associated with leukopenia (OR: 11.844, 95% CI 3.984-36.024, p=1.327 * 10-5). The allelic frequency of NUDT15 p.R139C was as high as 10.7% and the frequency of the C/C, C/T, and T/T genotypes was 84.5, 10.7, and 5.9%, respectively. All T/T homozygous patients (5/5) developed early severe-grade leukopenia (white blood cells <1000mm-3) and severe alopecia. NUDT15 p.R139C was strongly associated with early leukopenia and severe alopecia (OR for early leukopenia: 107.624, 95% CI 18.857-614.250, p=1.403 * 10-7, OR for severe alopecia: 77.152, 95% CI 17.378-342.526, p=1.101 * 10-8). The sensitivity and specificity for predicting AZA-induced early leukopenia were 85.7% and 92.2%, respectively. Therefore, the NUDT15 p.R139C variant is common and strongly associated with AZA-induced early leukopenia and severe alopecia in Korean patients with various neurological diseases. PMID- 28566183 TI - Profile of 26 HIV Seropositive individuals with Cerebral Venous Thrombosis. AB - BACKGROUND: HIV infection has been found to be prothrombotic condition. However, venous thromboembolism associated with HIV is restricted to peripheral vasculature with few reports of cerebral venous thrombosis (CVT). OBJECTIVE: To examine the clinical manifestations of CVT among HIV seropositive individuals and explore the possible etiological factors. METHODS AND RESULTS: It is a prospective study of 26 (M:F-18:8) patients of CVT associated with HIV seropositive status. Their age and duration of illness was 33.8+/-6.8years and 11.3+/-8.5days respectively. Headache and vomiting was the most common symptom followed by seizures. Drowsiness with GCS (Glasgow coma score) ranging from 9-14 was present in two-thirds of the patients. Serum homocysteine was elevated in 70% of patients. Vitamin B12 was low in 12.5% and insufficient levels in 25%. 88.5% of the patients recovered completely to GCS 15/15 in 2-7days during follow up; 11.5% patients expired during the acute state. CONCLUSION: This study represents the largest series of CVT in HIV seropositive individuals. There is increased risk of thrombosis due to elevated homocysteine and low Vitamin B12. They have better sensorium inspite of extensive radiological involvement. PMID- 28566184 TI - Unexpectedly mild phenotype in an ataxic family with a two-base deletion in the APTX gene. AB - INTRODUCTION: Early onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia 1 (AOA1) is an autosomal recessive disorder caused by mutations in the APTX gene. In contrast to the recent progress on the molecular mechanism of aprataxin in DNA repair, the genotype and phenotype correlation has not been fully established. A previous study demonstrated that patients with truncation mutations had earlier onset of disease than those with missense mutations METHODS: Genomic DNA analysis was performed in a consanguineous family with relatively late-onset EAOH/AOA1. In addition, mRNA and protein analyses were performed. RESULTS: The proband of the family had a homozygous two-base deletion in the middle of exon 3. Reverse-transcriptase polymerase-chain-reaction (RT-PCR) assays of mRNA revealed an aberrantly spliced mRNA with a cryptic splice site located four bases upstream of the deletion site. The newly identified mRNA retained a frameshift mutation and encoded a truncated protein. Immunoblot analysis did not detect the truncated protein in the patient's fibroblasts, possibly because it was unstable. CONCLUSIONS: Although patients with truncation mutations had an earlier onset of disease, our findings suggest that patients with a truncation mutation resulting in an undetectable protein level can also have a later onset of disease. PMID- 28566185 TI - Trends in vascular risk factors, stroke performance measures, and outcomes in patients with first-ever ischemic stroke in Taiwan between 2000 and 2012. AB - BACKGROUND: With the aging of the population in Taiwan, the financial burden of stroke on the healthcare system is expected to rise. We aimed to investigate the trends in vascular risk factors, adherence to stroke performance measures, and stroke outcomes based on a nationwide representative sample. METHODS: Adult patients hospitalized for first-ever ischemic stroke between 2000 and 2012 were identified from a nationwide administrative database. The study period was divided into 1-year intervals. The Cuzick test and the Cochran-Armitage test were used to determine the significance of changes over time. Trends in stroke outcomes as a function of year were assessed using logistic regression, controlling for age, sex, comorbidity, and stroke severity. RESULTS: A total of 11,462 patients (mean age 67.3years, female 40.9%) were hospitalized. Between 2000 and 2012, the prevalence of hypertension, diabetes mellitus, hyperlipidemia, and atrial fibrillation increased while the prevalence of coronary artery disease decreased. The proportion of patients taking antihypertensive or antidiabetic medication prior to stroke decreased, whereas the proportion of patients taking lipid lowering medication increased. Adherence to the five selected performance measures significantly improved. A significant decreasing trend in the proportion of recurrent stroke or all-cause death within one year was observed regardless of whether adjustment for age, sex, comorbidity, and stroke severity was made. CONCLUSIONS: Despite the rising prevalence of vascular risk factors, improved adherence to stroke performance measures was accompanied by better stroke outcomes. PMID- 28566186 TI - Detection of LGI1 and CASPR2 antibodies with a commercial cell-based assay in patients with very high VGKC-complex antibody levels. AB - BACKGROUND: The presence of VGKC-complex antibodies, without LGI1/CASPR2 antibodies, as a standalone marker for neurological autoimmunity remains controversial. Additionally, the lack of an unequivocal VGKC-complex antibody cut off level defining neurological autoimmunity makes it important to test for monospecific antibodies. We aim to determine the performance characteristics of a commercial assay (Euroimmun, Lubeck, Germany) for LGI1/CASPR2 antibody detection in patients with very high VGKC-complex antibody levels and report their clinico serological associations. METHODS: We identified 8 patients in our cohort with the highest VGKC-complex antibody levels (median 2663.5pM, range 933-6730pM) with VGKC-complex antibody related syndromes (Group A). Two other groups were identified; 1 group with suspected neuronal surface antibody syndromes and negative for VGKC-complex antibodies (Group B, n=8), and another group with cerebellar ataxia and negative for onconeuronal antibodies (Group C, n=8). RESULTS: Seven out of 8 patients (87.5%) in Group A had LGI1 and/or CASPR2 antibodies. One Group B patient had LGI1 antibodies but was negative on re testing with a live cell assay. No Group C patients had monospecific antibodies. Inter-rater reliability was high; combining Groups A and B patients, the kappa statistic was 0.87 and 1.0 for LGI1 and CASPR2 antibodies respectively. CONCLUSION: We demonstrated that a high proportion of patients with very high VGKC-complex antibody levels and relevant clinical syndromes have LGI1 and/or CASPR2 antibodies detected by the commercial assay. Our findings lend support to the use of the assay for rapid and reliable detection of LGI1 and CASPR2 antibodies. PMID- 28566187 TI - VEMPs in a patient with cerebellar ataxia, neuropathy and vestibular areflexia (CANVAS). PMID- 28566188 TI - Neuroendocrine lung cancer in a patient with limbic encephalopathy due to anti-Hu antibodies: A rare association not to be missed. PMID- 28566189 TI - Association between leukoaraiosis and hemorrhagic transformation after cardioembolic stroke due to atrial fibrillation and/or rheumatic heart disease. AB - Cardioembolic stroke due to atrial fibrillation (AF) and/or rheumatic heart disease (RHD) often involves hemorrhagic transformation (HT), and we examined whether leukoaraiosis (LA) was associated with HT in these cases. We prospectively enrolled 251 patients who were admitted to two hospitals within one month of experiencing cardioembolic stroke due to AF/RHD. LA severity was assessed using three visual rating scales. HT was identified in 99 patients (39.4%) based on baseline computed tomography (CT) and post-admission magnetic resonance imaging or second CT. Univariate analysis identified risk of HT as higher in the presence of frontal LA based on the age-related white matter changes scale and in the presence of anterior LA based on the VSS scale. Multivariate analysis confirmed that moderate to severe LA was independently associated with higher HT risk. Of the various sites affected in LA, frontal LA correlated with highest risk of HT (OR 3.199, 95%CI 1.555-6.580). These results suggest that moderate to severe LA, especially at periventricular and anterior sites, is associated with HT after cardioembolic stroke due to AF/RHD. These findings suggest the need to take LA into account as a HT risk factor when considering the use of anticoagulation and thrombolysis in these patients. PMID- 28566190 TI - The promise of telemedicine for chronic neurological disorders: the example of Parkinson's disease. AB - Disparities in access to health care, particularly specialist care, exist worldwide. As the prevalence of chronic neurological disorders increases with ageing populations, access to neurologist care is likely to worsen in many regions if there are no changes to models of care. Telemedicine-defined here as the use of real-time, synchronous videoconferencing to deliver medical care-could be used to improve access to neurologist care for patients with a range of chronic neurological disorders. In Parkinson's disease, several studies have shown the feasibility and potential benefits of telemedicine-delivered care. Further research is needed to establish whether telemedicine can deliver on the promise of improved access to neurologist care and whether telemedicine-delivered care is comparable to in-person care in terms of clinical outcomes. Many barriers to widespread implementation of telemedicine services remain to be addressed, including reimbursement, legal considerations, and technological issues. PMID- 28566191 TI - Th2 and Th1 Responses: Clear and Hidden Sides of Immunity Against Intestinal Helminths. AB - Intestinal helminthiases affect millions of people worldwide, mainly in developing regions, where they cause a significant negative impact on human health and socioeconomic growth of affected populations. However, intestinal helminthiases are still among the most neglected tropical diseases. Protective immunity against intestinal helminths is associated with development of type 2 responses. Nevertheless, in some host-intestinal helminth combinations, local Th1 responses are initiated, inducing chronicity. The usage of helminth-mouse models is useful for elucidating the mechanisms behind the initiation of each type of response. Herein, the current knowledge on these topics is reviewed, paying particular attention to the earliest events of the immune cascade which eventually lead to either susceptibility or resistance to infection. PMID- 28566192 TI - Association of a synonymous SCN1B variant affecting splicing efficiency with Benign Familial Infantile Epilepsy (BFIE). AB - Benign Familial Infantile Epilepsy (BFIE) is clinically characterized by clusters of brief partial seizures progressing to secondarily generalized seizures with onset at the age of 3-7 months and with favorable outcome. PRRT2 mutations are the most common cause of BFIE, and found in about 80% of BFIE families. In this study, we analyzed a large multiplex BFIE family by linkage and whole exome sequencing (WES) analyses. Genome-wide linkage analysis revealed significant evidence for linkage in the chromosomal region 19p12-q13 (LOD score 3.48). Mutation screening of positional candidate genes identified a synonymous SCN1B variant (c.492T>C, p.Tyr164Tyr) affecting splicing by the removal of a splicing silencer sequence, shown by in silico analysis, as the most likely causative mutation. In addition, the PRRT2 frameshift mutation (c.649dupC/p.Arg217Profs*8) was observed, showing incomplete, but high segregation with the phenotype. In vitro splicing assay of SCN1B expression confirmed the in silico findings showing a splicing imbalance between wild type and mutant exons. Herein, the involvement of the SCN1B gene in the etiology of BFIE, contributing to the disease phenotype as a modifier or part of an oligogenic predisposition, is shown for the first time. PMID- 28566194 TI - Non-invasive vagus nerve stimulation acutely improves spontaneous cardiac baroreflex sensitivity in healthy young men: A randomized placebo-controlled trial. AB - BACKGROUND: Despite positive outcomes of transcutaneous vagus nerve stimulation (tVNS) via the auricular branch of the vagus nerve (ABVN), the mechanisms underlying these outcomes remain unclear. Additionally, previous studies have not been controlled the possible placebo effects of tVNS. OBJECTIVE: To test the hypothesis that tVNS acutely improves spontaneous cardiac baroreflex sensitivity (cBRS) and autonomic modulation, and that these effects are specific to stimulation of ABVN. METHODS: Thirteen healthy men (23+/-1yrs) were randomized across three experimental visits. In active tVNS, electrodes were placed on the tragus of the ear and electrical current was applied by using a Transcutaneous Electrical Nerve Stimulation device. A time-control visit was performed with the electrodes placed on tragus, but no current was applied (sham-T). Additionally, to avoid a placebo effect, another sham protocol was performed with same electrical current of the active visit, but the electrodes were placed on the ear lobe (an area without cutaneous nerve endings from the vagus - tLS). Beat-to-beat heart rate (HR) and blood pressure (BP) were monitored at rest, during stimulation (active, sham-T and tLS) and recovery. cBRS was measured via sequence technique. Both HR (HRV) and BP variability (BPV) were also measured. RESULTS: Arterial BP and BPV were not affected by any active or sham protocols (P > 0.05). Resting HR and LF/HF ratio of HRV decreased (Delta-3.4 +/- 1% and Delta-15 +/- 12%, P < 0.05, respectively) and cBRS increased (Delta24 +/- 8%, P < 0.05) during active tVNS, but were unchanged during both sham protocols. CONCLUSION: tVNS acutely improves cBRS and autonomic modulation in healthy young men. PMID- 28566193 TI - Efficacy of transcranial direct current stimulation over primary motor cortex (anode) and contralateral supraorbital area (cathode) on clinical pain severity and mobility performance in persons with knee osteoarthritis: An experimenter- and participant-blinded, randomized, sham-controlled pilot clinical study. AB - BACKGROUND: Previous studies indicate that transcranial direct current stimulation (tDCS) with anode over motor cortex (M1) and cathode over contralateral supraorbital region (SO) may be effective in reducing pain, but these studies are limited in number and have not focused on older adults with osteoarthritis (OA). OBJECTIVE: To evaluate the preliminary efficacy and safety of M1-SO applied tDCS on clinical pain severity and mobility performance in adults with knee OA pain. METHODS: Forty 50- to 70-year-old community-dwelling participants with knee OA were randomly assigned to receive five daily sessions of 2 mA tDCS for 20 min (n = 20) or sham tDCS (n = 20). We measured clinical pain severity via Numeric Rating Scale, Western Ontario and McMaster Universities Osteoarthritis Index, and Short-Form McGill Pain Questionnaire. In addition, we measured mobility performance using the 6-Minute Walk Test and the Short Physical Performance Battery. Moreover, we obtained a sensation/safety questionnaire and measured cognition changes using the PROMIS-Applied Cognition-Abilities-Short Form 8a. RESULTS: Active tDCS over M1-SO significantly reduced Numeric Rating Scale of pain compared to sham tDCS after completion of the five daily sessions, and remained up to three weeks. No other measures were significantly different from sham. Participants tolerated tDCS over M1-SO well without serious adverse effects or cognition changes. CONCLUSION: Although not consistent in all pain measurements, our findings demonstrate promising clinical efficacy for reduction in pain perception for older adults with knee OA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02512393. PMID- 28566196 TI - Ataluren and similar compounds (specific therapies for premature termination codon class I mutations) for cystic fibrosis. PMID- 28566195 TI - Parenting stress in parents of children with refractory epilepsy before and after vagus nerve stimulation implantation. AB - OBJECTIVES: The purpose of this study was to evaluate parenting stress in parents of children with refractory epilepsy before and after their children received vagus nerve stimulation (VNS) implantation. METHODS: Parents of children with refractory epilepsy completed the Parenting Stress Index (PSI) under a psychologist's assessment before and at least 12 months after their children received VNS implantation. The PSI questionnaire measures parenting stress in two domains; a parent domain with seven subscales, and a child domain with six. Age, gender, epilepsy comorbidity, VNS implantation date, seizure frequency, and anticonvulsant history before and after VNS implantation were obtained from reviews of medical charts. RESULTS: In total, 30 parents completed the first and follow-up PSI questionnaires. Seventeen of their children (56.7%) were boys. The children aged from 1 to 12 years (7.43 +/- 3.59 years, mean +/- SD). After VNS implantation, the mean total parenting stress scores decreased from 282.1 +/- 38.0 to 272.4 +/- 42.9. A significant decrease was found on the spouse subscale of the parent domain. For the parents of boys, the mean total parenting stress scores decreased significantly. The mean total parenting stress scores also decreased significantly for parents of epileptic children without autism and who did not taper off the number of different anticonvulsants used after VNS. CONCLUSIONS: VNS is an advisable choice to treat refractory epilepsy. Our study showed that 12 months or more after VNS implantation, seizure frequency and parenting stress typically decreased. However, in some special cases the parenting stress may increase, and external help may be required to support these patients and their parents. PMID- 28566197 TI - Cardiac sarcoidosis: Diagnosis, therapeutic management and prognostic factors. AB - BACKGROUND: Cardiac sarcoidosis (CS) is a severe localization, observed mostly in cardiology departments. Despite appropriate cardiological treatment, CS is a potentially life-threatening condition, and accounts for 13-85% of sarcoidosis related deaths. AIMS: This retrospective study aimed to give an overview of CS in a non-cardiac unit, to analyse the effect of first-line immunosuppressive treatment on outcome and survival and to evaluate factors associated with relapses. METHODS: From 534 cases of sarcoidosis, we selected 59 patients with CS according to "2006 international criteria". We performed an in-depth analysis regarding symptoms, physical signs and cardiac investigation results. Patients were followed for a median period of 60 months. RESULTS: The median age at cardiac signs was 42 years. Echocardiography abnormalities, isotopic defects and abnormal magnetic resonance imaging findings were observed in 81%, 84% and 92% of patients, respectively. First-line treatment included steroids alone in 24 patients and steroids plus immunosuppressive therapy in 35 patients. Forty-seven (80%) patients recovered; 12 stabilized or worsened. The recovery rate was 75% in the steroids alone group versus 83% in the steroids plus immunosuppressive therapy group. Five (9%) patients died during follow-up, with two deaths attributed to CS. The overall 1- and 5-year survival rates were 98% and 92%, respectively. CONCLUSION: Our series of patients with CS who received steroids alone or combined with immunosuppressive therapy had a good prognosis, with an overall 5-year survival rate of 92%. The recovery rate was 85%, with no significant difference between patients treated with steroids alone or plus immunosuppressive therapy. PMID- 28566198 TI - Ebstein's anomaly in adults: Modified cone reconstruction of the tricuspid valve is associated with promising outcomes. AB - BACKGROUND: Ebstein's anomaly is a complex malformation. Justification of a procedure in mildly symptomatic adults is debatable: repair techniques are demanding and valve replacement is associated with poorer outcome. OBJECTIVES: We report our initial experience with the cone procedure versus medical follow-up. METHODS: Patients aged>=15years with Ebstein's anomaly were enrolled during 2007 2014. The cone procedure was performed in consecutive patients with severe tricuspid regurgitation (TR); those with less severe disease did not undergo surgery, although some underwent percutaneous catheter atrial septal defect closure. RESULTS: The cone procedure was performed in 20 patients (mean age 34.3+/-14.4years; TR grade 3.3+/-0.7) because of impaired functional capacity: six New York Heart Association (NYHA) class II, 14 class III. No surgical patient died during a mean (range) follow-up of 2.8 (0.5-5.0) years. One patient required subsequent repair for suture dehiscence 6 months postoperatively. All patients presented with mild or less TR at last echocardiographic follow-up. NYHA functional class was significantly improved at follow-up (P<0.0001): 16 NYHA class I and four class II. Of 24 non-surgical patients (mean age 37.3+/-16.9 years; TR grade 2.2+/-0.8), seven underwent percutaneous ASD closure. During a mean (range) follow-up of 4.8 (3.6-5.0) years, two patients died: one sudden death and one stroke. CONCLUSION: The cone repair of the tricuspid valve in adults with Ebstein's anomaly provided excellent mid-term results and significantly improved functional status. This procedure might be considered even in mildly symptomatic patients in the presence of severe valve regurgitation. PMID- 28566199 TI - Determinants of left atrial volume index in patients with aortic stenosis: A multicentre pilot study. AB - BACKGROUND: Left atrial (LA) enlargement is frequent in patients with aortic stenosis (AS), yet its determinants and prognostic implications are poorly understood. AIMS: To identify the echocardiographic variables associated with increased LA volume index (LAVI), and test the prognostic value of LAVI in AS. METHODS: We prospectively included 715 patients with AS in sinus rhythm at enrolment. Echocardiography was performed at baseline. Median follow-up was 22.0 (9-34) months. Patients were divided into two groups according to the best cut off for event prediction during follow-up (45mL/m2). RESULTS: Compared with LAVI<45mL/m2, patients with LAVI>=45mL/m2 had a lower stroke volume, cardiac output and left ventricular (LV) ejection fraction, greater LV volumes and mass and higher filling pressures. By linear regression, LAVI was best correlated with E wave mitral velocity (r=0.34), E/A ratio (r=0.34), E/e' ratio (r=0.28), indexed LV mass (r=0.29), systolic pulmonary artery pressure (r=0.34) and LV longitudinal strain (r=-0.28). Multivariable analysis confirmed the independent association of LAVI with age (P<0.001), indexed aortic valve area (P=0.04), indexed LV mass (P<0.001), LV ejection fraction (P=0.007), LV end-diastolic volume (P=0.001), E/A ratio (P<0.001) and E/e' ratio (P<0.001). LAVI>=45mL/m2 was independently predictive of the combined endpoint of cardiovascular death or hospitalization for heart failure (adjusted hazard ratio 1.69, 95% confidence interval 1.04 2.73). CONCLUSION: LA enlargement is correlated with AS severity, but also with variables reflecting LV systolic and diastolic dysfunction. Further studies are needed to investigate the outcome implication of LA enlargement in patients with AS. PMID- 28566200 TI - Performance of new automated transthoracic three-dimensional echocardiographic software for left ventricular volumes and function assessment in routine clinical practice: Comparison with 3 Tesla cardiac magnetic resonance. AB - BACKGROUND: Three-dimensional (3D) transthoracic echocardiography (TTE) is superior to two-dimensional Simpson's method for assessment of left ventricular (LV) volumes and LV ejection fraction (LVEF). Nevertheless, 3D TTE is not incorporated into everyday practice, as current LV chamber quantification software products are time-consuming. AIMS: To evaluate the feasibility, accuracy and reproducibility of new fully automated fast 3D TTE software (HeartModelA.I.; Philips Healthcare, Andover, MA, USA) for quantification of LV volumes and LVEF in routine practice; to compare the 3D LV volumes and LVEF obtained with a cardiac magnetic resonance (CMR) reference; and to optimize automated default border settings with CMR as reference. METHODS: Sixty-three consecutive patients, who had comprehensive 3D TTE and CMR examinations within 24hours, were eligible for inclusion. Nine patients (14%) were excluded because of insufficient echogenicity in the 3D TTE. Thus, 54 patients (40 men; mean age 63+/-13 years) were prospectively included into the study. RESULTS: The inter- and intraobserver reproducibilities of 3D TTE were excellent (coefficient of variation<10%) for end diastolic volume (EDV), end-systolic volume (ESV) and LVEF. Despite a slight underestimation of EDV using 3D TTE compared with CMR (bias=-22+/-34mL; P<0.0001), a significant correlation was found between the two measurements (r=0.93; P=0.0001). Enlarging default border detection settings leads to frequent volume overestimation in the general population, but improved agreement with CMR in patients with LVEF<=50%. Correlations between 3D TTE and CMR for ESV and LVEF were excellent (r=0.93 and r=0.91, respectively; P<0.0001). CONCLUSION: 3D TTE using new-generation fully automated software is a feasible, fast, reproducible and accurate imaging modality for LV volumetric quantification in routine practice. Optimization of border detection settings may increase agreement with CMR for EDV assessment in dilated ventricles. PMID- 28566201 TI - Racial Variation in the Outcome of Subsequent Prostate Biopsies in Men With an Initial Diagnosis of Atypical Small Acinar Proliferation. AB - BACKGROUND: African American (AA) men are known to have more aggressive prostate cancer (PCa) compared with Caucasian American men. We sought to determine predictors of subsequent detection and risk stratification of PCa in a racially diverse group of men with atypical small acinar proliferation (ASAP) on initial prostate biopsy. MATERIALS AND METHODS: A retrospective analysis was conducted on data from men with ASAP on initial prostate biopsy who subsequently received confirmatory biopsies between September 2000 and July 2015. Biopsies with more than 3 years between initial and confirmatory biopsies were excluded. Race, age, body mass index, transrectal ultrasound volume, serum prostate-specific antigen (PSA), PSA velocity, PSA density, and elapsed time between biopsies were assessed for predictive value in subsequent PCa diagnosis after an initial finding of ASAP. RESULTS: Of 106 men analyzed, 75 (71%) were AA and 31 (29%) were non-AA. Baseline variables revealed AA men had higher PSA levels, PSA velocity, and PSA density (all P < .05). PCa was diagnosed in subsequent biopsy in 42 (40%) patients without significant racial variation; 30 (40%) AA versus 12 (39%) non AA. Of the 42 PCa patients, 25 (24%) met Epstein criteria for significant disease without racial variation; 18 (24%) AA versus 7 (23%) non-AA. Only 10 (9%) patients had any component of Gleason 4; 7 (9%) AA versus 3 (10%) non-AA. In multivariate analysis, increasing age, PSA level, and PSA density were significant predictors of PCa. CONCLUSION: AA men diagnosed with ASAP on initial prostate biopsy do not have increased risk of PCa on confirmatory biopsy compared with non-AA men. PMID- 28566203 TI - Physical Model of Clear-Cell Renal Carcinoma With Inferior Vena Cava Extension Created From a 3-Dimensional Printer to Aid in Surgical Resection: A Case Report. PMID- 28566202 TI - Management of Renal Masses in an Octogenarian Cohort: Is There a Right Approach? AB - BACKGROUND: We reviewed the outcomes for an octogenarian population to investigate whether active surveillance (AS) provides comparable survival to partial nephrectomy (PN) or radical nephrectomy (RN). PATIENTS AND METHODS: Data were collected from 115 octogenarian patients referred for management of renal masses at Moffitt Cancer Center from 2000 to 2013. Patients were treated with AS, PN, or RN. Univariable and multivariable Cox regression models measured the association between management modality and survival. Kaplan-Meier survival analysis was used to calculate survival, and log-rank tests were used to compare survival curves. RESULTS: The median age was 82 years (interquartile range, 81-85 years). The median follow-up period was 51 months (interquartile range, 23-81 months). Of the 115 patients, 31 (27%) underwent AS, 31 (27%) underwent PN, and 53 (46%) underwent RN. The patients who underwent RN had a larger mean tumor size at 5.5 cm, with 19 patients (36%) having stage >= pT3 (P < .001). We found no difference in overall survival or disease-specific survival among the 3 management strategies on univariable analysis (P = .39 and P = .1, respectively). On multivariable analysis for overall survival, only the Charlson comorbidity index was associated with worse survival (hazard ratio, 1.2; 95% confidence interval, 1.1-1.3; P = .002). In a subgroup analysis of cT1a patients, we also found no difference in overall or disease-specific survival among the treatment arms on univariable analysis (P = .74 and P = .9, respectively). CONCLUSION: Active treatment with PN and RN might not provide a survival advantage compared with AS in the octogenarian population with a small renal mass. However, larger renal masses should undergo active treatment in appropriately selected patients. PMID- 28566204 TI - Is it possible to calculate surface areas of intraoral structures from preoperative CT scan? AB - Microsurgical reconstruction of intraoral structures requires accurate planning of flap shape and dimensions. The goal of this study is to describe a method that allows to calculate surfaces of oral structures from preoperative CT-scan in order to determine a precise flap design before the surgery. We created casts of the human mouth from cadavers with a head and neck CT-scan available using an impression material. We digitalized the mouth casts and unwrapped the surfaces of the different structures of the mouth in a bi-dimensional plane in order to measure the area. Furthermore, we measured distances from pre-determined bony landmarks using the CT-scan 3D reconstruction model and we correlated the two type of measurements. We performed a simple regression analysis and afterwards a multivariate analysis using the more statistically correlated measurements. We found a statistical correlation between the surface of the tongue and the surface floor of the mouth with three bone distances that let us to create three mathematical formulas. With those formulas, we can calculate the surfaces of the tongue and the floor of the mouth using simple bony distances that can be easily measured from the head and neck preoperative CT scan. Using standard template's layouts, we can create a precise preoperative flap design in the reconstruction of the tongue and of the floor of the mouth. PMID- 28566205 TI - Internationally adopted children with cleft lip and/or palate: A retrospective cohort study. AB - OBJECTIVE: The treatment approach for internationally adopted children with cleft lip and/or palate differs from locally born children with cleft lip and/or palate. They are older at initial presentation, may have had treatment abroad of different quality, and are establishing new and still fragile relationships with their adoptive parents. The aim of this study was to describe the characteristics and initial care and treatment of this group. METHODS: A retrospective cohort study was performed including all internationally adopted children with cleft lip and/or palate presenting to the cleft team outpatient clinic in the Wilhelmina Children's Hospital between January 1994 and December 2014. Medical records of all patients were reviewed; information concerning demographic characteristics, characteristics at initial presentation, and treatment were obtained. RESULTS: A total number of 132 adopted patients were included: 15% had cleft lip, 7% had cleft palate, and 78% had cleft lip and palate. The average age at the time of adoption was 26.5 months. In most cases, China was the country of origin. Seventy eight percent had surgery in their country of origin, primarily lip repair. Fistulae in need of revision surgery were found in 8% of the patients. Pharyngoplasty was needed in 48% of the patients. No significant differences were found for mean age at adoption, gender, cleft type, and one- or two-stage palatal closure. CONCLUSION: Internationally adopted children with cleft lip and/or palate are a very diverse group of patients with challenging treatment. These children undergo surgery late and frequently need additional surgery. PMID- 28566206 TI - Quality of reporting for randomized controlled trials in the hypospadias literature: Where do we stand? AB - INTRODUCTION: To assess the quality of reporting of randomized controlled trials (RCTs) in the hypospadias literature using the 2010 Consolidated Standards of Reporting Trials (CONSORT) statement. It was hypothesized that hypospadias RCTs that contained clear descriptions of key methodological items, allocation concealment, blinding, and sample size justification would have higher overall quality of reporting scores (OQS). MATERIALS AND METHODS: A comprehensive search was conducted through MEDLINE to identify RCTs in hypospadias surgical techniques and postoperative management during the period 1990-2014. Two reviewers independently selected articles, which were evaluated using the CONSORT checklist. An overall quality score (%) was calculated to assess the quality of reporting. In addition, a methodological index score out of 4 was calculated based on the following items: use of intention to treat/sample size justification, allocation concealment, specification of randomization type, and blinding of outcome assessors. RESULTS: Of the 76 initial results, 39 (51%) were excluded due to their predominant focus on anesthesia. After full-text screening, 10 (13%) citations were further excluded because they were case control studies or did not focus on hypospadias techniques, resulting in 27 (36%) studies included for analysis. The mean overall quality score was 37 +/- 12% and a median of 36% (range: 14-61%). Fifteen (56%) studies were identified as low quality (score <40%) and 12 (44%) as moderate quality (40-70%). No studies were classified as high quality (>70%). Hypospadias RCTs published between 2007 and 2014 versus those reported before 2007 (44 +/- 9% vs 33 +/- 11%, P = 0.01), RCTs with a sample size >100 patients versus those <100 (47 +/- 8% vs 36 +/- 11%, P = 0.01), RCTs that disclosed having received funding versus those that did not (56 +/- 4% vs 38 +/- 10%, P < 0.01) and RCTs that had proof of biostatistician/epidemiologist support versus those that did not (58 +/- 5% vs 36 +/- 11%, P = 0.01) had a higher mean OQS. The number of articles that met specific 2010 CONSORT criteria is illustrated in Summary Fig. DISCUSSION: It was found that the contemporary hypospadias literature continues to suffer from suboptimal reporting standards. There seems to be an improvement in the OQS for studies published after 2007 and those with larger sample sizes, usually >100 patients. Nevertheless, none of the studies obtained high quality of reporting (OQS >70%) as per the CONSORT statement checklist. The inadequacies in reporting were related to sample size justifications, randomization method, allocation concealment strategy, blinding, description of subjects lost to follow-up and Intention To Treat (ITT) analysis. These findings were consistent with the poor quality of reporting observed in other surgical fields. CONCLUSIONS: The current overall quality score in hypospadias literature is suboptimal and efforts must be made to improve quality. PMID- 28566207 TI - Aberrations in sperm DNA methylation patterns are associated with abnormalities in semen parameters of subfertile males. AB - Infertility affects about 15% of couples worldwide, with approximately 7% of males suffering from infertility problems. This study was designed to assess the relationship between alterations in sperm DNA methylation patterns and semen parameters in subfertile males. Of a total of 108 males, 30 samples were subjected to 450K BeadChip arrays to evaluate the variation in DNA methylation level between cases and controls. Three CpG sites showed the highest difference in methylation levels (cg09737095, cg14271023, and cg17662493), which are located in the KCNJ5, MLPH, and SMC1beta genes, respectively; these were selected for further analysis using deep bisulfite sequencing in 78 independent samples (21 proven fertile "controls", and 57 subfertile "cases"). The results of a validation study showed that variation in methylation levels was found in more than one CpG site: there was a significant decrease in methylation levels at six CpGs (CpG1, CpG3, CpG4, CpG6, CpG7, and CpG8) in the KCNJ5 gene-related amplicon (p<=0.001, p<=0.009, p<=0.007, p<=0.007, p<=0.020, and p<=0.016, respectively), and at (CpG1, CpG2, and CpG4) in the MLPH gene-related amplicon (p<=0.003, p<=0.005, and p<=0.0001, respectively), while there was a significant increase in the methylation level at six out of eight CpGs in the SMC1beta gene-related amplicon in cases compared to controls. Our results show that three CpGs have a significant difference in sperm DNA methylation levels in subfertile males compared to proven fertile males. PMID- 28566208 TI - Development of WNK signaling inhibitors as a new class of antihypertensive drugs. AB - Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia and hypertension despite a normal glomerular filtration rate. Abnormal activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress responsive kinase 1)/SPAK (STE20/SPS1-related proline/alanine-rich kinase) and NCC (NaCl cotransporter) results in characteristic salt-sensitive hypertension. Thus, inhibitors of the WNK-OSR1/SPAK-NCC cascade are candidates for a new class of antihypertensive drugs. In this study, we developed novel inhibitors of this signal cascade from the 9-aminoacridine lead compound 1, one of the hit compounds obtained by screening our chemical library for WNK-SPAK binding inhibitors. Among the synthesized acridine derivatives, several acridine-3-amide and 3-urea derivatives, such as 10 (IC50: 6.9MUM), 13 (IC50: 2.6MUM), and 20 (IC50: 4.8MUM), showed more potent inhibitory activity than the lead compound 1 (IC50: 15.4MUM). Compounds 10 and 20 were confirmed to inhibit phosphorylation of NCC in vivo. PMID- 28566209 TI - De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial. AB - BACKGROUND: Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia with deep molecular responses; however, patients with stable major molecular response (MMR), but not MR4, have not been studied, nor has the effect of treatment de-escalation rather than outright cessation. We aimed to examine the effects of treatment de escalation as a prelude to complete cessation, not only in patients with MR4 or greater, but also in those with MMR but not MR4. METHODS: We did this interim analysis of a non-randomised, phase 2 trial at 20 hospitals in the UK. We recruited patients (aged >=18 years) with chronic myeloid leukaemia in first chronic phase who had received TKI for 3 years or more and were either in stable MR4 (BCR-ABL1:ABL1 ratio <0.01%; MR4 cohort) or in stable MMR (BCR-ABL1:ABL1 ratio consistently <0.1%) but not MR4 (MMR cohort) for 12 months or longer. Participants received half their standard TKI dose (imatinib 200 mg daily, dasatinib 50 mg daily, or nilotinib 200 mg twice daily) for 12 months. Molecular recurrence was defined as loss of MMR (BCR-ABL1:ABL1 ratio >0.1%) on two consecutive samples. The primary endpoint of this interim analysis was the proportion of patients who lost MMR on de-escalation and regained MMR on TKI resumption. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985. FINDINGS: Between Dec 16, 2013 and April 10, 2015, we enrolled 174 patients into the MMR cohort (n=49) or the MR4 cohort (n=125). During the 12 months of half-dose therapy, 12 patients (7%) had molecular recurrence, all of whom regained MMR within 4 months of full-dose TKI resumption (median time to recovery 77 days). Recurrence was significantly lower in the MR4 cohort (three [2%; 90% CI 0.2-4.8] of 121 evaluable patients) than in the MMR cohort (nine [19%; 90% CI 9.5-28.0] of 48 evaluable patients; hazard ratio 0.12, 90% CI 0.04-0.37; p=0.0007), but was unrelated to previous TKI or TKI therapy duration. Adverse events (eg, lethargy, diarrhoea, rash, and nausea) improved during the first 3 months of de-escalation, though not thereafter. 16 serious adverse events were reported, including one fatality due to worsening pre existing peripheral arterial occlusive disease in a patient who had received only imatinib. INTERPRETATION: TKI de-escalation is safe for most patients with excellent responses to TKI therapy, and is associated with improvement in symptoms. These findings show that lower TKI doses might maintain responses in these patients, implying that such patients could be unnecessarily overtreated. Studies of more ambitious de-escalation are warranted. FUNDING: Newcastle University and Bloodwise. PMID- 28566210 TI - The DESTINY of chronic myeloid leukeamia. PMID- 28566211 TI - Carcinogenicity, efficiency and biosafety analysis in xeno-free human amniotic stem cells for regenerative medical therapies. AB - BACKGROUND AIMS: Human amniotic mesenchymal stromal cells (hAMSCs) are a potent and attractive stem cell source for use in regenerative medicine. However, the safe uses of therapeutic-grade MSCs are equally as important as the efficiency of MSCs. To provide efficient, clinic-compliant (safe for therapeutic use) MSCs, hAMSC lines that completely eliminate the use of animal products and have been characterized for carcinogenicity and biosafety are required. METHODS: Here, we have efficiently generated 10 hAMSC lines under human umbilical cord blood serum (hUCS)-supplemented medium (xeno-free culture) and fetal bovine serum (FBS) supplemented medium (standard culture) and investigated carcinogenicity and immunosuppressive properties in the resultant hAMSC lines. All hAMSC lines were examined for efficiency (growth kinetics, cryopreservation, telomere length, phenotypic characterization, differentiation potential), carcinogenicity (proto oncogene and tumor suppressor gene and epigenomic stability) and safety (immunosuppressive properties). RESULTS: Stem cell characteristics between the xeno-free hAMSC lines and the cell lines generated using the standard culture system showed no differences. Xeno-free hAMSC lines displayed normal growth proliferation potential, morphological, karyotypic, phenotypic differentiation properties and telomere lengths. Additionally, they retained normal immunosuppressive effects. As a marker of carcinogenicity and biosafety, proto oncogenes expression levels showed no differences in xeno-free hAMSCs, and we detected no SNP mutations on hotspot codons of the P53 tumor suppressor gene and stable epigenomic imprinting in xeno-free hAMSC lines. CONCLUSIONS: Xeno-free hAMSC lines retain essential stem cell characteristics, with a high degree of certainty for meeting biosafety and carcinogenicity standards for a xeno-free system supplemented with allogenic hUCS. The cell lines are suitable and valuable for therapeutic purposes. PMID- 28566212 TI - Correction to Lancet Glob Health 2017; 5: e593-603. PMID- 28566213 TI - Role of mass drug administration in elimination of Plasmodium falciparum malaria: a consensus modelling study. AB - BACKGROUND: Mass drug administration for elimination of Plasmodium falciparum malaria is recommended by WHO in some settings. We used consensus modelling to understand how to optimise the effects of mass drug administration in areas with low malaria transmission. METHODS: We collaborated with researchers doing field trials to establish a standard intervention scenario and standard transmission setting, and we input these parameters into four previously published models. We then varied the number of rounds of mass drug administration, coverage, duration, timing, importation of infection, and pre-administration transmission levels. The outcome of interest was the percentage reduction in annual mean prevalence of P falciparum parasite rate as measured by PCR in the third year after the final round of mass drug administration. FINDINGS: The models predicted differing magnitude of the effects of mass drug administration, but consensus answers were reached for several factors. Mass drug administration was predicted to reduce transmission over a longer timescale than accounted for by the prophylactic effect alone. Percentage reduction in transmission was predicted to be higher and last longer at lower baseline transmission levels. Reduction in transmission resulting from mass drug administration was predicted to be temporary, and in the absence of scale-up of other interventions, such as vector control, transmission would return to pre-administration levels. The proportion of the population treated in a year was a key determinant of simulated effectiveness, irrespective of whether people are treated through high coverage in a single round or new individuals are reached by implementation of several rounds. Mass drug administration was predicted to be more effective if continued over 2 years rather than 1 year, and if done at the time of year when transmission is lowest. INTERPRETATION: Mass drug administration has the potential to reduce transmission for a limited time, but is not an effective replacement for existing vector control. Unless elimination is achieved, mass drug administration has to be repeated regularly for sustained effect. FUNDING: Bill & Melinda Gates Foundation. PMID- 28566215 TI - Close Encounters - Probing Proximal Proteins in Live or Fixed Cells. AB - The well-oiled machinery of the cellular proteome operates via variable expression, modifications, and interactions of proteins, relaying genomic and transcriptomic information to coordinate cellular functions. In recent years, a number of techniques have emerged that serve to identify sets of proteins acting in close proximity in the course of orchestrating cellular activities. These proximity-dependent assays, including BiFC, BioID, APEX, FRET, and isPLA, have opened up new avenues to examine protein interactions in live or fixed cells. We review herein the current status of proximity-dependent in situ techniques. We compare the advantages and limitations of the methods, underlining recent progress and the growing importance of these techniques in basic research, and we discuss their potential as tools for drug development and diagnostics. PMID- 28566214 TI - The Growing Toolbox for Protein Synthesis Studies. AB - Protein synthesis stands at the last stage of the central dogma of molecular biology, providing a final regulatory layer for gene expression. Reacting to environmental cues and internal signals, the translation machinery can quickly tune the translatome from a pre-existing pool of RNAs, before the transcriptome changes. Although the translation reaction itself has been known since the 1950s, the quantitative or even qualitative measurement of its efficacy in cells has posed experimental and analytic hurdles. In this review, we outline the array of state-of-the-art methods that have emerged to tackle the hidden aspects of translational control. PMID- 28566216 TI - Molecular quantitative assay for esterase-mediated organophosphate resistance in Rhipicephalus microplus. AB - The use of pesticides is the main tool to control infestations of the cattle tick Rhipicephalus microplus, and organophosphate (OP) is one of the most used compounds for this purpose. Carboxylesterases (ChEs) are targets for OP pesticides in arthropods, and acetylcholinesterase 2 (AChE2) and esterase 1 (EST1) are metabolic enzymes involved in the xenobiotic detoxification process. The increase in the synthesis of these enzymes can be detected by the quantitative polymerase chain reaction (qPCR) assay, which was used to identify cattle tick populations resistant to OP pesticides. For that, two field populations of R. microplus were used, one previously identified by the larval packet test (LPT) as OP -sensitive (LC50=0.13MUg/cm2) and the other OP-resistant (LC50=8.14MUg/cm2). To promote the OP enzyme detoxification, groups of 10 females of the resistant strain were immersed in solutions of diazinon in technical grade at concentrations of 1.0mg/ml, 2.5mg/ml, and 5.0mg/ml. The ticks that survived diazinon exposure were submitted to qPCR assay, which enabled observing an increase in AChE2 and EST1 synthesis in the OP-resistant strain when compared to the susceptible strain. The initial results of expression analysis suggest that the qPCR assay can discriminate OP-resistant and susceptible populations. The development and improvement of molecular diagnostic tests to identify pesticide resistant R. microplus populations are priorities and in the near future it will be important to expand the molecular targets involved in OP resistance, which could be used for better selection of effective strategies to control cattle tick populations. PMID- 28566217 TI - Integration of Hands-On Team Training into Existing Curriculum Improves Both Technical and Nontechnical Skills in Laparoscopic Cholecystectomy. AB - OBJECTIVE: Nontechnical skills are an essential component of surgical education and a major competency assessed by the ACGME milestones project. However, the optimal way to integrate nontechnical skills training into existing curricula and then objectively evaluate the outcome is still unknown. The aim of this study was to determine the effect laparoscopic team-based task training would have on the nontechnical skills needed for laparoscopic surgery. DESIGN: 9 PGY-1 residents underwent an established training curriculum for teaching the knowledge and technical skills involved in laparoscopic cholecystectomy. Initial training involved a didactic session, expert-led practice on a porcine model in a simulated operating room and laparoscopic skills practice on a virtual reality trainer. Residents then performed a laparoscopic cholecystectomy on the same porcine model as a preintervention test. Three to four months following this, residents were subjected to specific nontechnical skills training involving 2 simple team-based laparoscopic tasks. They then practiced a further 4 to 6 hours on the virtual reality trainer. A repeat postintervention laparoscopic cholecystectomy was then performed 3 to 4 months after nontechnical skills training. Both the preintervention and postintervention laparoscopic cholecystectomies were audiovisually recorded and then evaluated by 2 independent surgeons in a blinded fashion. Technical skills were assessed using objective structured assessment of technical skills (OSATS) and a technique specific rating scale (TRS) that we developed for laparoscopic cholecystectomy. Nontechnical skills were assessed using nontechnical skills for surgeons (NOTSS). Residents also completed a survey at the beginning and end of the training. SETTING: Tertiary care, university based teaching institution. PARTICIPANTS: A total of 9 general surgery residents at the intern level. RESULTS: The mean OSATS score improved from 13.7 +/- 1.24 to 26.7 +/- 0.31 (p < 0.001), the mean TRS score improved from 6 +/- 0.46 to 13.1 +/- 0.36 (p < 0.001) and the mean NOTSS score improved from 21.7 +/- 1.83 to 36.3 +/- 0.87 (p < 0.001) following the training. There was a strong correlation between OSATS and NOTSS scores (Pearson's R = 0.98) and TRS and NOTSS (R = 0.94). The inter-rater agreement was 0.79 for NOTSS, 0.9 for OSATS, and 0.82 for TRS. Following completion of the training, residents self-reported improvements in exchanging information (p < 0.01), coordinating activities (p < 0.01) and coping with pressure in the operating room (p < 0.001). CONCLUSION: Simple, team-based nontechnical skills training for laparoscopic cholecystectomy that was separate from technical skills training led to a sustained increase in residents' nontechnical skills 3 to 4 months after training. This was associated with a self-reported improvement in many nontechnical skills based on resident survey. Based on these results, we recommend that such designated nontechnical skills training is a valid alternative to other methods such as coaching and debriefing. We, therefore, plan to continue our efforts to develop team-based simulation tasks aimed at improving nontechnical skills for multiple surgical modalities. PMID- 28566219 TI - Lipoprotein(a) and cardiovascular mortality: mystery still unsolved. PMID- 28566220 TI - The relationship between tumour stage, systemic inflammation, body composition and survival in patients with colorectal cancer. AB - BACKGROUND: Disease progression in cancer is often associated with loss of weight and lean tissue and the development of a systemic inflammatory response (SIR) and these have prognostic value. The present study investigated the relationship between these factors in patients with operable colorectal cancer. METHODS: The study included 322 patients with primary operable colorectal cancer. In addition to BMI, pre-operative CT scans were used to define the presence of visceral obesity, sarcopenia and myosteatosis. Tumour and patient characteristics were recorded. Survival was analysed using univariate and multivariate Cox regression. RESULTS: There was no significant association between TNM stage and any measure of body composition. The modified Glasgow Prognostic Score (mGPS), was associated with greater BMI (p = 0.021), sarcopenia (p < 0.001), and myosteatosis (p = 0.004). On univariate analysis, there was a significant association between age (p = 0.002), ASA grade (p = 0.010), TNM stage (p < 0.001), mGPS (p = 0.001) and myosteatosis (p = 0.017) and disease specific survival. On multivariate analysis, age (HR 1.89, 95% CI 1.27-2.79, p = 0.002), TNM stage (HR 2.27, 95% CI 1.45-3.55, p < 0.001) and mGPS (HR 1.48, 95% CI 1.08-2.03, p = 0.016) remained prognostic. CONCLUSIONS: The SIR is a key hallmark of progressive nutritional and functional decline leading to poorer survival in patients with cancer. PMID- 28566222 TI - Tissue-specific transcriptomic profiling provides new insights into the reproductive ecology and biology of the iconic seagrass species Posidonia oceanica. AB - Seagrasses form extensive meadows in shallow coastal waters and are among the world's most productive ecosystems. Seagrasses can produce both clonally and sexually, and flowering has long been considered infrequent, but important for maintaining genetically diverse stands. Here we investigate the molecular mechanisms involved in flowering of the seagrass Posidonia oceanica, an iconic species endemic to the Mediterranean. We generated a de novo transcriptome of this non-model species for leaf, male and female flower tissue of three individuals, and present molecular evidence for genes that may be involved in the flowering process and on the reproductive biology of the species. We present evidence that suggests that P. oceanica exhibits a strategy of protogyny, where the female part of the hermaphroditic flower develops before the male part, in order to avoid self-fertilization. We found photosynthetic genes to be up regulated in the female flower tissues, indicating that this may be capable of photosynthesis. Finally, we detected a number of interesting genes, previously known to be involved in flowering pathways responding to light and temperature cues and in pathways involved in anthocyanin and exine synthesis. This first comparative transcriptomic approach of leaf, male and female tissue provides a basis for functional genomics research on flower development in P. oceanica and other seagrass species. PMID- 28566218 TI - Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study. AB - BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. FINDINGS: The median follow-up was 9.9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1.44, 95% CI 1.14-1.83) and the presence of either LPA SNP (1.88, 1.40-2.53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0.95, 0.81-1.11 and either LPA SNP 1.10, 0.92-1.31) or cardiovascular mortality (0.99, 0.81-1.2 and 1.13, 0.90-1.40, respectively) or in the validation studies. INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung fur Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny. PMID- 28566223 TI - Oxidative and biochemical responses in Brycon amazonicus anesthetized and sedated with Myrcia sylvatica (G. Mey.) DC. and Curcuma longa L. essential oils. AB - OBJECTIVE: To investigate the effects of rapid anesthesia and long-term sedation with the essential oils (EOs) of Myrcia sylvatica (EOMS) and Curcuma longa (EOCL) on biochemical and oxidative parameters in matrinxa. STUDY DESIGN: Prospective, randomized, laboratory experiment. ANIMALS: A total of 72 matrinxa (Brycon amazonicus) adults weighing 404.8 +/- 27.9 g were divided into eight groups of nine fish. METHODS: Biochemical and oxidative effects were investigated in plasma and tissues of matrinxa subjected to rapid anesthesia (5 minutes) or long-term sedation (360 minutes, simulating the practice of transport) with EOMS (200 MUL L 1 and 10 MUL L-1, respectively) and EOCL (500 MUL L-1 and 40 MUL L-1, respectively). RESULTS: Transport simulation without sedation or anesthesia increased lipid peroxidation levels in the gills and kidney of fish in the control group. Anesthesia and sedation with EOs decreased cortisol concentrations and increased lactate concentrations compared with controls. Lipid peroxidation was lower in the brain, gills, liver and kidney of sedated and anesthetized fish, than in the control group. Anesthesia with EOs increased the activity of superoxide dismutase and glutathione-S-transferase in the brain, and catalase in the liver and gills, compared with controls. Long-term sedation with EOs increased superoxide dismutase, glutathione peroxidase and glutathione reductase activities in the brain, catalase in the liver, glutathione peroxidase and glutathione reductase in the gills and superoxide dismutase in the kidney. In general, nonprotein thiols content and total reactive antioxidant potential of tissues were higher after anesthesia and sedation with EOs compared with the control group. CONCLUSIONS AND CLINICAL RELEVANCE: The concentrations of EOMS and EOCL used were effective at preventing a stress response and excess of reactive oxygen species formation. For these reasons, these substances may be recommended for use in the transportation of fish to improve survival and animal welfare. PMID- 28566221 TI - Sentinel lymph node mapping and staging in endometrial cancer: A Society of Gynecologic Oncology literature review with consensus recommendations. AB - The emphasis in contemporary medical oncology has been "precision" or "personalized" medicine, terms that imply a strategy to improve efficacy through targeted therapies. Similar attempts at precision are occurring in surgical oncology. Sentinel lymph node (SLN) mapping has recently been introduced into the surgical staging of endometrial cancer with the goal to reduce morbidity associated with comprehensive lymphadenectomy, yet obtain prognostic information from lymph node status. The Society of Gynecologic Oncology's (SGO) Clinical Practice Committee and SLN Working Group reviewed the current literature for preparation of this document. Literature-based recommendations for the inclusion of SLN assessment in the treatment of patients with endometrial cancer are presented. This article examines. PMID- 28566224 TI - Response to "Diagnosis of exocrine pancreatic insufficiency in chronic pancreatitis: 13C-mixed Triglyceride Breath Test versus Fecal Elastase: Methodological issues". PMID- 28566225 TI - Treatment and retreatment with omalizumab in chronic spontaneous urticaria: Real life experience with twenty-five patients. AB - BACKGROUND: Previous data have shown the high efficacy of omalizumab in chronic spontaneous urticaria (CSU). However, factors that may be effective on the response to therapy, relapse rates after drug discontinuation, and efficacy of retreatment remain unclear. This study aimed to determine the efficacy of omalizumab in CSU refractory to conventional therapy, to identify possible factors affecting treatment response and relapse, and also to evaluate the efficacy of retreatment on relapsed disease. METHODS: The data of CSU patients treated with 300 mg/month omalizumab for at least 3 months were retrospectively analyzed. In order to evaluate the efficacy of treatment and retreatment, baseline and follow-up concomitant medication score (CMS) and urticaria activity score (UAS) were calculated. Possible factors affecting treatment response and relapse were identified. RESULTS: Twenty-five patients were included. The median duration of omalizumab therapy was 6 (6-12) months. Of the patients with baseline UAS 6 (5.5-6) and CMS 13 (10-15), 8 (32%) had complete response (UAS = 0) and 2 (8%) were non-responders after 3 months of therapy. None of the complete responders were positive for IgG-anti-TPO. After discontinuation of omalizumab therapy, 11 (61%) patients experienced relapse and 10 of them received retreatment with omalizumab. Half of the patients had complete response, and half had partial response (UAS = 1-4) after retreatment. No treatment related adverse events were documented. CONCLUSIONS: Omalizumab has high efficacy in both the treatment and retreatment of CSU; however, relapse rates after discontinuation are high. Autoimmune markers may be helpful in predicting treatment response and relapse. PMID- 28566228 TI - Viable dual therapy second-line antiretroviral regimen for Africa? PMID- 28566226 TI - Optimization of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Due to RPGR Mutations. AB - X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is an early onset and severe cause of blindness. Successful proof-of-concept studies in a canine model have recently shown that development of a corrective gene therapy for RPGR-XLRP may now be an attainable goal. In preparation for a future clinical trial, we have here optimized the therapeutic AAV vector construct by showing that GRK1 (rather than IRBP) is a more efficient promoter for targeting gene expression to both rods and cones in non-human primates. Two transgenes were used in RPGR mutant (XLPRA2) dogs under the control of the GRK1 promoter. First was the previously developed stabilized human RPGR (hRPGRstb). Second was a new full length stabilized and codon-optimized human RPGR (hRPGRco). Long-term (>2 years) studies with an AAV2/5 vector carrying hRPGRstb under control of the GRK1 promoter showed rescue of rods and cones from degeneration and retention of vision. Shorter term (3 months) studies demonstrated comparable preservation of photoreceptors in canine eyes treated with an AAV2/5 vector carrying either transgene under the control of the GRK1 promoter. These results provide the critical molecular components (GRK1 promoter, hRPGRco transgene) to now construct a therapeutic viral vector optimized for RPGR-XLRP patients. PMID- 28566229 TI - [Cardiovascular risk and cardiovascular events in the general population of the sanitary area of Toledo. RICARTO Study]. AB - INTRODUCTION: The main aim of this study is to ascertain the prevalence of cardiovascular risk factors (CVRF), target organ damage (TOD), cardiovascular disease (CVD), as well as life habits (physical exercise, alcohol consumption, and Mediterranean diet) in the population of a Health Area in Toledo, Spain, to assess cardiovascular risk (CVR). MATERIAL AND METHODS: Epidemiological and observational study that will analyse a sample from the general population aged 18 years or older, randomly selected from a database of health cards, and stratified by age and gender. Clinical history, physical examination, and complementary tests will be performed. Aliquots of whole blood and serum samples will be stored at a temperature of-85 degrees C to evaluate future genetic studies. CVR will be estimated by using SCORE project scales calibrated for Spanish population and the Framingham Heart Study scale. When the estimated sample size has been achieved and after a minimum follow-up of 5 years, a final visit will performed in which CVRF, TOD, CVD, CVRF control, and fatal and non fatal outcomes will be evaluated. DISCUSSION: The RICARTO study is aimed to assess the prevalence of the main CVRF, TOD and CVD in order to determine the CVR in the general population of a health area of Toledo. An analysis will be repeated on the final sample after at least 5 years of follow-up to ascertain the incidence of CV outcomes and the temporal trends of life style, as well as the prevalence of CVRF, TOD, and CVD. PMID- 28566231 TI - Representing the sublime in the VIMAP and empirical aesthetics: Reviving Edmund Burke's A Philosophical Enquiry into the Origins of Our Ideas of the Sublime and Beautiful: Comment on "Move me, astonish me... delight my eyes and brain: The Vienna Integrated Model of top-down and bottom-up processes in Art Perception (VIMAP) and corresponding affective, evaluative, and neurophysiological correlates" by Matthew Pelowski et al. PMID- 28566227 TI - Boosted protease inhibitor monotherapy versus boosted protease inhibitor plus lamivudine dual therapy as second-line maintenance treatment for HIV-1-infected patients in sub-Saharan Africa (ANRS12 286/MOBIDIP): a multicentre, randomised, parallel, open-label, superiority trial. AB - BACKGROUND: Despite satisfactory efficacy of WHO-recommended second-line antiretroviral treatment for patients with HIV in low-income countries, the need for simplified, low-cost, and less-toxic maintenance strategies remains high. We compared boosted protease inhibitor monotherapy with dual therapy with boosted protease inhibitor plus lamivudine in patients on second-line antiretrovial therapy (ART). METHODS: We did a multicentre, randomised, parallel, open-label, superiority, trial in the HIV services of five hospitals in sub-Saharan Africa (Yaounde, Cameroon; Dakar, Senegal; and Bobo Dioulasso, Burkina Faso). We recruited patients from the long-term, post-trial cohort of the ANRS 12169/2LADY study that compared the efficacy of three second-line combinations based on boosted protease inhibitors. Participants for our study were HIV-1 infected with multiple mutations including M184V, at first-line failure, aged 18 years and older, on boosted protease inhibitor plus two nucleoside reverse transcriptase inhibitors (NRTI) for at least 48 weeks with at least 48 weeks follow-up in the 2LADY trial, with two viral load measurements of less than 200 copies per mL in the previous 6 months, CD4 counts of more than 100 cells per MUL, adherence of at least 90%, and no change to ART in the past 3 months. We randomly assigned participants (1:1) to receive either monotherapy with their boosted protease inhibitor (once-daily darunavir 800 mg [two 400 mg tablets] boosted with ritonavir 100 mg [one tablet] or coformulation of lopinavir 200 mg with ritonavir 50 mg [two tablets taken twice per day]) or to boosted protease inhibitor plus once-daily lamivudine 300 mg (one 300 mg tablet or two 150 mg tablets). Computer generated randomisation was stratified by study site and viral load at screening (< 50 copies per mL, and 50-200 copies per mL), and concealed from study personnel throughout the inclusion period. After randomisation, treatment allocation was not masked from clinicians or patients]. Patients had follow-up visits at weeks 4 and 12, and every 3 months until 96 weeks; if viral load exceeded 500 copies per mL at any visit, NRTI (tenofovir and lamivudine) were reintroduced into treatment. The primary outcome was the proportion of participants who had treatment failure at 96 weeks in the intention-to-treat analysis, where treatment failure was defined as one of the following: a confirmed viral load of more than 500 copies per mL, reintroduction of NRTI, or interruption of boosted protease inhibitor. We designed the study to detect a difference of 12% between groups in the primary outcome, with an expected 20% of patients having treatment failure in the monotherapy group. This study is registered with ClinicalTrials.gov, number NCT01905059. FINDINGS: Between March 5, 2014, and Jan 26, 2015, 265 participants were assigned to receive monotherapy (133) or boosted protease inhibitor plus lamivudine (132). At week 48, an independent data safety monitoring board reviewed data, and advised discontinuation of the monotherapy group because the number of failures had exceeded the expected 20%; therefore results here are for week 48. At this point, treatment failure occurred in four (3.0%; 95% CI 0.8-7.6) of 132 participants on dual therapy and 33 (24.8%; 17.7-33.0) of 133 participants on monotherapy (relative risk 8.2, 95% CI 3.0-22.5; odds ratio 10.6, 95% CI 3.6-42.1). The difference between groups (21.8%, 95% CI 13.9-29.7; p<0.0001) showed superiority of dual therapy compared with monotherapy. We recorded 46 severe adverse events of grade 3 or 4 (29 in the monotherapy group, 17 in the boosted protease inhibitor plus lamivudine group); one event in the montherapy group (intoxication resulting from co-administration of ritonavir-boosted lopinavir with an ergotamine derivate) was deemed related to study drug. Two participants in the monotherapy group and one in the dual therapy group died, all from causes not related to study drugs or procedures (one from complications from gastric cancer surgery, one in a work accident, and one from a lung disease of unknown cause). INTERPRETATION: After viral suppression with boosted protease inhibitor plus NRTI in second-line ART, maintenance therapy with boosted protease inhibitor plus lamivudine was associated with a high rate of success, despite the presence of M184V mutations at first-line treatment failure. Results indicated that boosted protease inhibitor monotherapy cannot be recommended for these patients. FUNDING: Agence National de Recherche sur le Sida et les hepatites and Janssen Pharmaceutica. PMID- 28566230 TI - Efficacy and safety of indacaterol in patients with chronic obstructive pulmonary disease aged over 65 years: A pooled analysis. AB - BACKGROUND: Although the prevalence of chronic obstructive pulmonary disease (COPD) increases with age, no specific therapeutic approaches are available till date for the elderly population. AIM: To assess the efficacy and safety of once daily indacaterol 150 and 300 MUg in elderly patients with moderate to severe COPD. METHODS: Data were pooled from 11 randomized, double-blind, placebo- and active-controlled studies (8445 patients with COPD). The patient population was stratified into age groups: young (>=40-<65 years; 52.3%), elderly (>=65-<75 years; 36.4%), and very elderly (>=75 years; 11.4%). The efficacy outcomes included improvements in trough forced expiratory volume in 1 s (FEV1), transition dyspnea index (TDI), and health status (St. George's Respiratory Questionnaire [SGRQ]); safety was also assessed at 12 weeks. RESULTS: At Week 12, the mean improvement in FEV1 with indacaterol 150 MUg versus placebo was comparable in the elderly (150 mL), very elderly (160 mL), and young (170 mL) groups (p < 0.001 for all comparisons). Similar improvement in FEV1 was observed with indacaterol 300 MUg versus placebo in each group (p < 0.001). This improvement was also significantly higher with indacaterol than formoterol, salmeterol, and tiotropium in all groups (p < 0.01). Both TDI and SGRQ scores significantly improved with indacaterol versus placebo across age groups (p < 0.001) and were significantly higher than that for tiotropium (p < 0.001). Incidences of adverse events among indacaterol- or placebo-treated patients were similar, regardless of the age group. CONCLUSIONS: This pooled analysis suggests that the efficacy and safety of indacaterol treatment is similar between elderly and younger patients with COPD. PMID- 28566232 TI - Identification and diagnostic value of phytanoyl- and pristanoyl-carnitine in plasma from patients with peroxisomal disorders. AB - Phytanic acid is a branched-chain fatty acid, the level of which is elevated in patients with a variety of peroxisomal disorders, including Refsum disease, and Rhizomelic chondrodysplasia punctata type 1 and 5. Elevated levels of both phytanic and pristanic acid are found in patients with Zellweger Spectrum Disorders, and pristanic acid is elevated in patients with alpha-methylacyl-CoA racemase deficiency. For the diagnosis of peroxisomal disorders, a variety of metabolites can be measured in blood samples from suspected patients, including very long-chain fatty acids, phytanic and pristanic acid. Based on the fact that very long-chain fatty acylcarnitines are elevated in tissues and plasma from patients with certain peroxisomal disorders, we investigated whether phytanoyl- and pristanoyl-carnitine are also present in plasma from patients with different peroxisomal disorders. Our study shows that phytanoyl- and pristanoyl-carnitine are indeed present in plasma samples from patients with different types of peroxisomal disorders, but only when the total plasma levels of their corresponding fatty acids, phytanic acid and pristanic acid, are markedly elevated. We conclude that the measurement of phytanoyl- and pristanoyl-carnitine is not sensitive and specific enough to use these acylcarnitines as conclusive diagnostic markers for peroxisomal disorders. PMID- 28566233 TI - Expanding the genetic cause of multiple sulfatase deficiency: A novel SUMF1 variant in a patient displaying a severe late infantile form of the disease. AB - Multiple sulfatase deficiency (MSD) is a rare inherited metabolic disease caused by defective cellular sulfatases. Activity of sulfatases depends on post translational modification catalyzed by formylglycine-generating enzyme (FGE), encoded by the SUMF1 gene. SUMF1 pathologic variants cause MSD, a syndrome presenting with a complex phenotype. We describe the first Polish patient with MSD caused by a yet undescribed pathologic variant c.337G>A [p.Glu113Lys] (i.e. p.E113K) in heterozygous combination with the known deletion allele c.519+5_519+8del [p.Ala149_Ala173del]. The clinical picture of the patient initially suggested late infantile metachromatic leukodystrophy, with developmental delay followed by regression of visual, hearing and motor abilities as the most apparent clinical symptoms. Transient signs of ichthyosis and minor dysmorphic features guided the laboratory workup towards MSD. Since MSD is a rare disease and there is a variable clinical spectrum, we thoroughly describe the clinical outcome of our patient. The FGE-E113K variant, expressed in cell culture, correctly localized to the endoplasmic reticulum but was retained intracellularly in contrast to the wild type FGE. Analysis of FGE-mediated activation of steroid sulfatase in immortalized MSD cells revealed that FGE-E113K exhibited only approx. 15% of the activity of wild type FGE. Based on the crystal structure we predict that the exchange of glutamate-113 against lysine should induce a strong destabilization of the secondary structure, possibly affecting the folding for correct disulfide bridging between C235-C346 as well as distortion of the active site groove that could affect both the intracellular stability as well as the activity of FGE. Thus, the novel variant of the SUMF1 gene obviously results in functionally impaired FGE protein leading to a severe late infantile type of MSD. PMID- 28566235 TI - Investigation of storage time-dependent alterations of enantioselective amino acid profiles in kimchi using liquid chromatography-time of flight mass spectrometry. AB - Although naturally abundant amino acids are represented mainly by l-enantiomers, fermented foods are known to contain various d-amino acids. Enantiospecific profiles of food products can vary due to fermentation by bacteria, and such alterations may contribute to changes in food properties that would not be dependent exclusively on l-amino acids. Therefore, more attention should be paid to the study of temporal alterations of d-amino acid profiles during fermentation process. However, there have been very few studies reporting time-dependent profiling of d-amino acids because enantioseparation of widely targeted d-amino acids is technically difficult. This study aimed to achieve high throughput profiling of amino acids enantiomers. Enantioselective profiling of amino acids using CROWNPAK CR-I(+) column, liquid chromatography, time of flight mass spectrometry, and principle component analysis was performed to investigate time dependent alterations in concentrations of free d- and l-amino acids in kimchi stored at 4 degrees C or 25 degrees C. We demonstrated significant changes in d- and l-amino acid profiles in kimchi stored at 25 degrees C. In particular, concentrations of the amino acids d-Ala, d-Ser, d-allo-Ile, d-Leu, d-Asp, d-Glu, and d-Met became higher in kimchi with storage time. This is the first report of time-dependent alterations of d- and l-amino acid contents in kimchi. This study showed that our analytical method of enantioselective detection of amino acids using liquid chromatography time-of-flight mass spectrometry (LC-TOFMS) with CROWNPAK CR-I(+) enables high throughput food screening and can be recommended for advanced studies of the relationship between d-amino acid content and food properties. PMID- 28566234 TI - Enhancement of butanol production by sequential introduction of mutations conferring butanol tolerance and streptomycin resistance. AB - Ribosome engineering, originally applied to Streptomyces lividans, has been widely utilized for strain improvement, especially for the activation of bacterial secondary metabolism. This study assessed ribosome engineering technology to modulate primary metabolism, taking butanol production as a representative example. The introduction into Clostridium saccharoperbutylacetonicum of mutations conferring resistance to butanol (ButR) and of the str mutation (SmR; a mutation in the rpsL gene encoding ribosomal protein S12), conferring high-level resistance to streptomycin, increased butanol production 1.6-fold, to 16.5 g butanol/L. Real-time qPCR analysis demonstrated that the genes involved in butanol metabolism by C. saccharoperbutylacetonicum were activated at the transcriptional level in the drug-resistant mutants, providing a mechanism for the higher yields of butanol by the mutants. Moreover, the activity of enzymes butyraldehyde dehydrogenase (AdhE) and butanol dehydrogenases (BdhAB), the key enzymes involved in butanol synthesis, was both markedly increased in the ButR SmR mutant, reflecting the significant up regulation of adhE and bdhA at transcriptional level in this mutant strain. These results demonstrate the efficacy of ribosome engineering for the production of not only secondary metabolites but of industrially important primary metabolites. The possible ways to overcome the reduced growth rate and/or fitness cost caused by the mutation were also discussed. PMID- 28566236 TI - Renaming all spinal autonomic outflows as sympathetic is a mistake. PMID- 28566237 TI - Comparing indices of median nerve among diabetic patients with or without metabolic syndrome. AB - BACKGROUND: Metabolic syndrome is highly prevalent among patients with type II diabetes and is reported as a strong risk factor for cardiovascular diseases as well as carpal tunnel syndrome (CTS). The aim of the current study was to compare median nerve indices among diabetic patients with and without metabolic syndrome. METHODS: This cross-sectional study was conducted on 105 patients with type II diabetes whom participated in the coronary artery disease risk factor study in Kerman, Iran (KERCARDS). Patients with type II diabetes were called and those with clinical symptoms of CTS were included in the study, and median nerve indices were measured according to standard electro diagnosis tests. GEE statistical model was used to compare median nerve indices among diabetic patients with and without metabolic syndrome. All statistical analysis was done using SPSS 20.0. RESULTS: The mean age of participants was 57.57+/-9.53. There was no significant difference between the left and right hand regarding median nerve indices except median nerve motor amplitude (MA). Furthermore, components of metabolic syndrome including BMI and LDL were determined as risk factors for CTS according to several indices. CONCLUSION: Components of metabolic syndrome had more influence on sensory indices than motor indices and primary control of these components might prevent dysfunction of sensory neurons and also motor neurons in advanced stages among diabetic patients. PMID- 28566238 TI - Correlation of Resistin Serum Level with Fat Mass and Obesity-Associated Gene (FTO) rs9939609 Polymorphism in Obese Women with Type 2 Diabetes. AB - AIMS: The aim of this study was to detect any association of fat mass and obesity associated (FTO) rs9939609 variant to metabolic and anthropometric parameters and resistin level as adipokines in Iranian obese women with type 2 diabetes mellitus. MATERIAL AND METHODS: Totally, 42 diabetic and 36 non-diabetic women were selected. The PCR amplicons of FTO gene were sequenced and metabolic, anthropometric parameters and resistin level were measured. RESULTS: Serum resistin concentrations were not different between diabetic and non-diabetic subjects (p>0.05), while resistin level in diabetic group with AA genotype was lower than that with other genotypes in the same group. In rs9939609 SNP adjusted analysis, insulin and HOMA levels were high in AA genotype. While levels of FBS and HbA1c were higher in AA and AT genotypes. In diabetic group, only TG showed significant difference among three genotypes and mean of TG was higher in TA genotype. No significant correlation between resistin and anthropometric and metabolic parameters was found except for DBP in diabetic patients. CONCLUSION: There was no significant association between rs9939609 and resistin serum level in type 2 obese diabetic women while percentile ranges (25th, 50th and 75th) of resistin concentrations was high in diabetic group. PMID- 28566240 TI - Frontiers in planning optimization for lung SBRT. AB - Emerging data are showing the safety and the efficacy of Stereotactic Body Radiation therapy (SBRT) in lung cancer management. In this context, the very high doses delivered to the Planning Target Volume, make the planning phase essential for achieving high dose levels conformed to the shape of the target in order to have a good prognosis for tumor control and to avoid an overdose in relevant healthy adjacent tissue. In this non-systematic review we analyzed the technological and the physics aspects of SBRT planning for lung cancer. In particular, the aims of the study were: (i) to evaluate prescription strategies (homogeneous or inhomogeneous), (ii) to outline possible geometrical solutions by comparing the dosimetric results (iii) to describe the technological possibilities for a safe and effective treatment, (iv) to present the issues concerning radiobiological planning and the automation of the planning process. PMID- 28566239 TI - A reduced time to surgery within a 'fast track' pathway for periampullary malignancy is associated with an increased rate of pancreatoduodenectomy. AB - INTRODUCTION: Pancreatoduodenectomy (PD) typically follows preoperative biliary drainage (PBD) despite PBD being potentially harmful. This study evaluated a pathway to avoid PBD within the framework of the UK's NHS. METHOD: A prospective observational study of jaundiced patients undergoing PD for periampullary cancer. A pathway to provide early surgery without PBD was introduced at the start of the study period. RESULTS: Over 12 months 61 and 32 patients underwent surgery with and without PBD respectively; 95% of patients in the PBD group had been stented before referral. The time from CT scan to surgery was shorter in the no PBD group (16 vs 65 days, p < 0.0001). Significantly more patients underwent PD in the no PBD group (31/32 vs 46/61, p = 0.009) and venous resection (10/31 vs 4/46, p = 0.014). The sensitivity of initial CT scan to define borderline resectable disease was worse in the PBD group (91 vs 50%, p = 0.042). CONCLUSIONS: Early surgery to avoid PBD is possible within the NHS. By reducing the time to surgery it appears that more patients undergo potentially curative resection. It is desirable to understand why surgery without PBD is not performed routinely as are the development of strategies to support its more widespread practice. PMID- 28566241 TI - The global HIV epidemic: What the pathologist needs to know. AB - The World Health Organization estimates that at the end of 2015, approximately 36.7 million people were living with HIV worldwide. An estimated 0.8% of adults aged 15-49 years are infected with HIV with women representing a little over half of these infections. The burden of the epidemic varies considerably between regions of the world and within countries. Sub-Saharan Africa is the region of the world with most infections accounting for approximately 70% of people living with HIV. In the United States the number of new infections decreased by 19% between 2005 and 2014 yet, close to 40,000 new infections occurred in 2015 and, as people with HIV live longer and new infections continue, the number of people living with HIV in the US now stands at nearly 1.2 million and continues to rise. Unprecedented funding initiatives for antiretroviral therapy have resulted in coverage of up to 46% of those in need globally. In recent years, studies have demonstrated that HIV-infected persons who are on antiretroviral therapy and suppressed do not transmit HIV thus the United Nations AIDS Program (UNAIDS) initiative of "treatment is prevention". The UNAIDS goals for 2020 are to have diagnosis of 90% of those infected, 90% of those infected will be on treatment and in 90% there will be viral suppression. Of note, for two of the goals, laboratory system strengthening is paramount. PMID- 28566242 TI - Clinical and Genetic Diagnosis of Nonischemic Sudden Cardiac Death. AB - INTRODUCTION AND OBJECTIVES: Nonischemic sudden cardiac death (SCD) is predominantly caused by cardiomyopathies and channelopathies. There are many diagnostic tests, including some complex techniques. Our aim was to analyze the diagnostic yield of a systematic diagnostic protocol in a specialized unit. METHODS: The study included 56 families with at least 1 index case of SCD (resuscitated or not). Survivors were studied with electrocardiogram, advanced cardiac imaging, exercise testing, familial study, genetic testing and, in some cases, pharmacological testing. Families with deceased probands were studied using the postmortem findings, familial evaluation, and molecular autopsy with next-generation sequencing (NGS). RESULTS: A positive diagnosis was obtained in 80.4% of the cases, with no differences between survivors and nonsurvivors (P=.53). Cardiac channelopathies were more prevalent among survivors than nonsurvivors (66.6% vs 40%, P=.03). Among the 30 deceased probands, the definitive diagnosis was given by autopsy in 7. A diagnosis of cardiomyopathy tended to be associated with a higher event rate in the family. Genetic testing with NGS was performed in 42 index cases, with a positive result in 28 (66.6%), with no differences between survivors and nonsurvivors (P=.21). CONCLUSIONS: There is a strong likelihood of reaching a diagnosis in SCD after a rigorous protocol, with a more prevalent diagnosis of channelopathy among survivors and a worse familial prognosis in cardiomyopathies. Genetic testing with NGS is useful and its value is increasing with respect to the Sanger method. PMID- 28566243 TI - Timing of Onset and Outcome of New Conduction Abnormalities Following Transcatheter Aortic Valve Implantation: Role of Balloon Aortic Valvuloplasty. AB - INTRODUCTION AND OBJECTIVES: Little is known about the timing of onset and outcome of conduction abnormalities (CA) following balloon-expandable transcatheter aortic valve implantation. The aim of this study was to examine the timing of CA and determine the impact of balloon aortic valvuloplasty (BAV) on the persistence of these abnormalities. METHODS: A total of 347 patients were included. Of these, 75 had a continuous electrocardiogram recording and a 6-lead electrocardiogram at each step of the procedure. RESULTS: In the transcatheter aortic valve implantation population undergoing continuous electrocardiogram monitoring, new-onset left bundle branch block (LBBB) or third-degree atrioventricular block occurred in 48 (64%) and 16 (21.3%) patients, with 51.5% of CA occurring before valve implantation. Left bundle branch block persisted more frequently at hospital discharge (53.8 vs 22.7%; P=.028) and at 1-month follow-up (38.5 vs 13.6%; P=.054) when occurring before valve implantation. Balloon aortic valvuloplasty prior to valve implantation was used in 264 (76.1%) patients, and 78 (22.5%) had persistent LBBB or complete atrioventricular block requiring pacemaker implantation. Persistent LBBB or unresolved atrioventricular block at 1 month occurred more frequently in the BAV group (76.1 vs 47.6%; P=.021), and the use of BAV was associated with a lack of CA resolution (OR, 3.5; 95%CI, 1.17-10.43; P=.021). CONCLUSIONS: In patients undergoing a balloon expandable transcatheter aortic valve implantation, more than half of CA occurred before valve implantation. Early occurrence of CA was associated with a higher rate of persistence at 1-month follow-up. The use of BAV was associated with an increased risk of CA persistence. PMID- 28566244 TI - Paravalvular Leak Correction: Searching for a Balance Between Surgical and Percutaneous Techniques. PMID- 28566246 TI - Conversion of atrial dissociation with lidocaine in a dog. AB - A 3-year-old healthy dog was presented for abdominal surgery following ingestion of razor blades. An electrocardiogram revealed a regular sinus bradycardia with normal P waves at a heart rate of 45 bpm. In addition, low-amplitude positive deflections (p' waves) were visualized at a regular interval and rapid rate of 250 bpm, dissociated from the normal sinus P waves. A tentative diagnosis of atrial dissociation was proposed. Administration of lidocaine abolished the p' waves. This case describes atrial dissociation observed following premedication that was successfully terminated using lidocaine in a healthy dog. PMID- 28566245 TI - Validity Assessment of Low-risk SCORE Function and SCORE Function Calibrated to the Spanish Population in the FRESCO Cohorts. AB - INTRODUCTION AND OBJECTIVES: To assess the validity of the original low-risk SCORE function without and with high-density lipoprotein cholesterol and SCORE calibrated to the Spanish population. METHODS: Pooled analysis with individual data from 12 Spanish population-based cohort studies. We included 30 919 individuals aged 40 to 64 years with no history of cardiovascular disease at baseline, who were followed up for 10 years for the causes of death included in the SCORE project. The validity of the risk functions was analyzed with the area under the ROC curve (discrimination) and the Hosmer-Lemeshow test (calibration), respectively. RESULTS: Follow-up comprised 286 105 persons/y. Ten-year cardiovascular mortality was 0.6%. The ratio between estimated/observed cases ranged from 9.1, 6.5, and 9.1 in men and 3.3, 1.3, and 1.9 in women with original low-risk SCORE risk function without and with high-density lipoprotein cholesterol and calibrated SCORE, respectively; differences were statistically significant with the Hosmer-Lemeshow test between predicted and observed mortality with SCORE (P < .001 in both sexes and with all functions). The area under the ROC curve with the original SCORE was 0.68 in men and 0.69 in women. CONCLUSIONS: All versions of the SCORE functions available in Spain significantly overestimate the cardiovascular mortality observed in the Spanish population. Despite the acceptable discrimination capacity, prediction of the number of fatal cardiovascular events (calibration) was significantly inaccurate. PMID- 28566248 TI - [Prognostic factors for head and neck cancer reirradiation: A systematic review]. AB - PURPOSE: To specify the effectiveness of head and neck cancer reirradiation and make a synthesis of prognostic factors established by published series of patients. MATERIALS AND METHODS: Original series of external reirradiation of head and neck cancer with at least ten patients were sought in Medline database. RESULTS: Exclusive reirradiation with or without concurrent chemotherapy offers 11 months of median overall survival, versus 6 months for chemotherapy alone, and 20 to 40% of the patients are still alive two years after treatment. Postoperative reirradiation allows 3 years overall survival from 40 to 60%. However, side effects of grade 3 or more arise in more than half of patients. Patient-related good prognostic factors are male, young age, good performance status without comorbidities. Those related to the disease are low rT and rN stage, poor differentiation, other than squamous cell carcinomas and a nasopharyngeal, oropharyngeal or laryngeal location. Concerning the treatment, surgical resection, a dose higher than 50 to 60Gy in a smaller-irradiated volume, an interval between the two treatments of more than 2 years and the use of an innovating technology are the most commonly highlighted prognostic factors. Concurrent chemotherapy is often associated with higher toxicity rates, without improving overall survival, unless using cisplatin for selected patients. CONCLUSIONS: Head and neck cancer reirradiation achieves long-term survival outcomes. However, regarding to its associated side effects, patients need to be carefully selected based on prognostic factors. PMID- 28566249 TI - Is palliative care included in care of renal disease? PMID- 28566250 TI - Local Somatodendritic Translation and Hyperphosphorylation of Tau Protein Triggered by AMPA and NMDA Receptor Stimulation. AB - Tau is a major component of the neurofibrillary tangles (NFT) that represent a pathological hallmark of Alzheimer's disease (AD). Although generally considered an axonal protein, Tau is found in the somato-dendritic compartment of degenerating neurons and this redistribution is thought to be a trigger of neurodegeneration in AD. Here, we show the presence of tau mRNA in a dendritic ribonucleoprotein (RNP) complex that includes Ca2+-calmodulin dependent protein kinase (CaMK)IIalpha mRNA and that is translated locally in response to glutamate stimulation. Further, we show that Tau mRNA is a component of mRNP granules that contain RNA-binding proteins, and that it interacts with Myosin Va, a postsynaptic motor protein; these findings suggest that tau mRNA is transported into dendritic spines. We also report that tau mRNA localized in the somato dendritic component of primary hippocampal cells and that a sub-toxic concentration of glutamate enhances local translation and hyperphosphorylation of tau, effects that are blocked by the gluatamatergic antagonists MK801 and NBQX. These data thus demonstrate that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-d-aspartate (NMDA) stimulation redistributes tau to the somato-dendritic region of neurons where it may trigger neurodegeneration. PMID- 28566252 TI - Stop measles in Switzerland - The importance of travel medicine. AB - BACKGROUND: In line with the worldwide strive to combat measles, the Swiss Federal Office of Public Heath (FOPH) launched a National Strategy for measles elimination 2011-2015. In this study, we highlight the importance of travel medicine consultations to complement measles vaccination programmes based on data from the Travel Clinic of the University of Zurich. METHOD: We analysed measles vaccination data from the Zurich Travel Clinic between July 2010 and February 2016 and focused on three groups: (i) all clients who received the measles vaccination, (ii) all clients aged>two years who received the measles vaccination ("catch-up vaccination"), and (iii) all clients aged>two years and born after 1963 ("FOPH recommended catch-up vaccination"). RESULTS: 107,669 consultations were performed from 2010 to 2016. In 12,470 (11.6%) of these, a measles vaccination was administered; 90.9% measles vaccinations were given during a pre travel consultation, and 99.4% were administered to individuals aged>two years ("catch-up vaccinations"). An "FOPH recommended catch-up vaccination" was received by 13.6% of all Zurich Travel Clinic clients aged >2years and born after 1963. CONCLUSIONS: In this study, we highlight the importance of travel medicine consultations to enhance the measles vaccination coverage in the adult Swiss population. PMID- 28566251 TI - Tenomodulin is Required for Tendon Endurance Running and Collagen I Fibril Adaptation to Mechanical Load. AB - Tendons are dense connective tissues that attach muscles to bone with an indispensable role in locomotion because of their intrinsic properties of storing and releasing muscle- generated elastic energy. Tenomodulin (Tnmd) is a well accepted gene marker for the mature tendon/ligament lineage and its loss-of function in mice leads to a phenotype with distinct signs of premature aging on tissue and stem/progenitor cell levels. Based on these findings, we hypothesized that Tnmd might be an important factor in the functional performance of tendons. Firstly, we revealed that Tnmd is a mechanosensitive gene and that the C-terminus of the protein co-localize with collagen I-type fibers in the extracellular matrix. Secondly, using an endurance training protocol, we compared Tnmd knockout mice with wild types and showed that Tnmd deficiency leads to significantly inferior running performance that further worsens with training. In these mice, endurance running was hindered due to abnormal response of collagen I cross linking and proteoglycan genes leading to an inadequate collagen I fiber thickness and elasticity. In sum, our study demonstrates that Tnmd is required for proper tendon tissue adaptation to endurance running and aids in better understanding of the structural-functional relationships of tendon tissues. PMID- 28566253 TI - A thermostable presentation of the live, attenuated peste des petits ruminants vaccine in use in Africa and Asia. AB - The research objective was to develop a thermostable vaccine against peste des petits ruminants (PPR), a morbilliviral disease of small ruminants targeted for eradication that is a major constraint on the livelihoods of the rural poor throughout much of Africa and Asia. Although existing PPR vaccines provide life long immunity, they require continuous refrigeration. This limits their utility in developing countries. Methods for the lyophilization of a related morbillivirus, rinderpest (RP), resulted in vaccine that could be used in the field for up to 30days without refrigeration which was a major contribution to the global eradication of RP completed in 2011. The present research applied the rinderpest lyophilization method to the attenuated Nigeria 75/1 PPR vaccine strain, and measured thermostability in accelerated stability tests (AST) at 37 degrees C. The shelf-life of the vaccine was determined as the time a vial retained the minimum dose required as a 25-dose presentation at the specified temperature. A lactalbumin hydrolysate and sucrose (LS) stabilizer was compared to stabilizers based on trehalose. PPR vaccine produced using the Xerovac drying method was compared to vaccine produced using the rinderpest lyophilization method in AST. LS vaccine was evaluated in AST at 37, 45 and 56 degrees C and an Arrhenius plot was constructed for estimation of stability at temperatures not tested. Vaccines produced using LS and the rinderpest method of lyophilization were the most stable. The shelf-life of the Xerovac preparation was 22.2days at 37 degrees C. The three LS vaccine batches had shelf-lives at 37 degrees C of 177.6, 105.0 and 148.9days, respectively, at 37 degrees C. At 56 degrees C, the shelf-life was 13.7days. The projected half-life at 25 degrees C was 1.3years. This is sufficient thermostability for use without a cold chain for up to 30days which will greatly facilitate the delivery of vaccination in the global eradication of PPR. PMID- 28566254 TI - Challenges of vaccine presentation and delivery: How can we design vaccines to have optimal programmatic impact? AB - Immunization program delivery strategies that enable high vaccine coverage, particularly in inaccessible and remote areas, are critical to achieving optimal vaccine impact. In addition to demonstration of safety and efficacy, there are many factors that influence whether a newly licensed vaccine will be introduced into a country's national immunization program, particularly in resource constrained environments. This paper describes three case studies of novel approaches that represent the potential for improved programmatic impact by increasing vaccine accessibility in different ways. However, the pathway to regulatory approval, policy recommendation, and program introduction in low- and middle-income countries is complex, requiring engagement with multiple, diverse stakeholders. Consideration of aspects that affect uptake in low- and middle income countries, during the product development stage, will help better position new or second-generation vaccine products for successful implementation to achieve public health impact. PMID- 28566255 TI - Learning From Experience: Development of a Cognitive Task List to Perform a Caesarean Section in the Obese Parturient. PMID- 28566256 TI - Validating the Performance of the Modified Early Obstetric Warning System Multivariable Model to Predict Maternal Intensive Care Unit Admission. AB - OBJECTIVES: To evaluate the performance of the Modified Early Obstetric Warning System (MEOWS) to predict maternal ICU admission in an obstetric population. DESIGN: Case-control study. SETTING: Two maternity units in Vancouver, Canada, one with ICU facilities, between January 1, 2000, and December 31, 2011. PATIENTS: Pregnant or recently delivered (<=6 weeks) women admitted to the hospital for >24 hours. Three control patients were randomly selected per case and matched for year of admission. MEASUREMENTS AND MAIN RESULTS: Retrospective, observational, case-control validation study investigating the physiologic predictors of admission in the 24-hour period preceding either ICU admission >24 hours (cases) or following admission (control patients). Model performance was assessed based on sensitivity, specificity, and predictive values. Forty-six women were admitted to the ICU for >24 hours (0.51/1000 deliveries); the study included 138 randomly selected control patients. There were no maternal deaths in the cohort. MEOWS had high sensitivity (0.96) but low specificity (0.54) for ICU admission >24 hours, whereas >=1 one red trigger maintained sensitivity (0.96) and improved specificity (0.73). CONCLUSION: Altering MEOWS trigger parameters may improve the accuracy of MEOWS in predicting ICU admission. Formal modelling of a MEOWS scoring system is required to support evidence-based care. PMID- 28566257 TI - Maternal Blood Biomarkers of Placentation to Predict Low-Birth-Weight Newborns: A Meta-Analysis. AB - OBJECTIVE: The development of methods for pre-delivery prediction of low-birth weight newborns would be clinically advantageous because low birth weight contributes to a high infant mortality rate. This study was performed to examine whether maternal blood biomarkers of placentation can be used to predict low birth-weight newborns. METHODS: Ten databases, including PubMed/Medline, were searched. Any English language study that provided all of the true- and false positive and true- and false-negative results of this prediction was included in the analysis. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies. Bivariate diagnostic meta-analysis was performed to construct hierarchical summary receiver operating characteristic curves. RESULTS: Based on relatively good quality studies, alpha fetoprotein (AFP), human chorionic gonadotropin (hCG), and pregnancy-associated plasma protein A (PAPP-A) (n = 73, 19, and 7, respectively) showed low sensitivity and specificity and low diagnostic odds ratio. The informational usability was categorized as "no exclusion or confirmation" (i.e., positive likelihood ratio <10 and negative likelihood ratio >0.1). The diagnostic accuracy of AFP and hCG or PAPP-A was categorized as low (i.e., 0.5 <= area under the curve <=0.7) or could not be categorized (i.e., area under the curve <0.5). CONCLUSION: There is no evidence that maternal blood levels of AFP, hCG, or PAPP-A used as a single predictor are useful to predict low-birth-weight newborns. PMID- 28566258 TI - Isolated hepatosplenic sarcoidosis: A pitfall for lymphoma evaluation by 18F-FDG PET/CT. PMID- 28566259 TI - Multimodal approach in radioguided surgery in a case of multiple paraganglioma. AB - The case involves a 34-year-old woman who underwent surgical removal of a retroperitoneal paraganglioma adjacent to the left kidney's lower pole, previously visualized by CT and MRI. The 123I-MIBG scan was positive for this lesion and, in addition, another uptake was observed located caudally at the level of L5 and of smaller size and less intensity. The second lesion was not considered for surgical removal, due to its lack of morphological definition. One week after surgical intervention, the patient presented difficult-to-control high blood pressure. A second 123I-MIBG scan was performed. The previously described second image was more intense in this study, and surgery was planned to remove it. A combination of techniques including freehand-SPECT and a portable hybrid gamma camera (with optical camera) were used pre-operatively to identify the location of the lesion. The combination of intra-operative laparoscopic gamma probe and portable hybrid gamma camera enabled the tumor to be located, excised, and its complete removal to be monitored. The histopathology analysis confirmed a second paraganglioma. PMID- 28566260 TI - 18F-FDG PET/CT in lung cancer. The added value of quantification. AB - OBJECTIVE: To test a software application for the quantification of metabolic heterogeneity and to evaluate its superiority in relation to visual interpretation. To investigate if a quantitative analysis adds information to the interpretation of 18F-FDG-PET/CT. MATERIAL AND METHODS: The study analyzed 215 patients with a 18F-FDG-PET/CT done for the initial staging of lung cancer between March 2011 and December 2015. The study included 57 (26.5%) women and 158 (73.5%) men, with ages ranging from 34 to 88 years (mean+/-SD: 67.23+/-10.04). There were 82 surgical stages (I, II, IIIA), and 133 non-surgical stages (IIIB, IV). The primary tumour was analyzed quantitatively by obtaining the following parameters: SUVmax, metabolic active tumour volume (MATV), total lesion glycolysis (TLG), and the entropy heterogeneity index (ET). Heterogeneity was assessed visually. Death dates and/or the follow-up time were registered, ranging from 0.70 to 67.60 months (mean+/-SD: 23.20+/-17.68). RESULTS: In multivariate analysis, ET emerged as a better predictor of survival than visual analysis of heterogeneity that was not statistically significant. The C-index determination demonstrated that all quantitative parameters were statistically-significant predictors of survival. Cut-offs were obtained in order to compare survival times. A multivariate analysis was performed. In the total population, the best predictor was the TNM stage, but MATV, ET, and male gender were statistically significant and independent predictors of survival. In stages without surgical indication, the best predictor was the TNM stage, but the MATV and male gender were statistically significant and independent predictors of survival. In the surgical stages, ET was the only statistically significant and independent predictor of survival. CONCLUSIONS: Quantification adds prognostic information to the visual analysis of 18F-FDG-PET/CT. PMID- 28566261 TI - Fatty thymic involution uptake mimicking a thymic epithelial tumour in a 18F-FDG PET/CT study. PMID- 28566262 TI - Effect of phosphodiesterase-5 inhibition with Tadalafil on SystEmic Right VEntricular size and function - A multi-center, double-blind, randomized, placebo controlled clinical trial - SERVE trial - Rational and design. AB - BACKGROUND: Patients with a systemic right ventricle (RV) have a compromised late outcome caused by ventricular dysfunction. Standard medical heart failure therapy has not been shown to improve RV function and survival in these patients. Phosphodiesterase (PDE)-5 inhibition increases contractility in experimental models of RV hypertrophy, but not in the normal RV. In clinical practice, the effects of PDE-5 inhibition on systemic RV function and exercise capacity in adults with a systemic RV have not been tested. METHODS: The SERVE protocol is a double-blind, randomized placebo-controlled multicenter superiority trial to study the effect of PDE-5 inhibition with Tadalafil on RV volumes and function in patients with either D-transposition of the great arteries repaired with an atrial switch procedure or with congenitally corrected transposition of the great arteries. Tadalafil 20mg or placebo will be given over a study period of 3years. The primary endpoint is the change in mean end-systolic RV volumes from baseline to study end at 3years of follow-up (or at the time of permanent discontinuation of the randomized treatment if stopped before 3- years of follow-up), and will be measured by cardiovascular magnetic resonance imaging (CMR) or by cardiac computed tomography in patients with contraindications for CMR. Secondary endpoints are changes in RV ejection fraction, VO2max and NT-proBNP. CONCLUSION: The objective of this study is to assess the effect of PDE-5 inhibition with Tadalafil on RV size and function, exercise capacity and neurohumoral activation in adults with a systemic RV over a 3-year follow-up period. PMID- 28566263 TI - PREventive Care Infrastructure based On Ubiquitous Sensing (PRECIOUS): A Study Protocol. AB - BACKGROUND: mHealth has experienced a huge growth during the last decade. It has been presented as a new and promising pathway to increase self-management of health and chronic conditions in several populations. One of the most prolific areas of mHealth has been healthy lifestyles promotion. However, few mobile apps have succeeded in engaging people and ensuring sustained use. OBJECTIVE: This paper describes the pilot test protocol of the PReventive Care Infrastructure based on Ubiquitous Sensing (PRECIOUS) project, aimed at validating the PRECIOUS system with end users. This system includes, within a motivational framework, the Bodyguard2 sensor (accelerometer with heart rate monitoring) and the PRECIOUS app. METHODS: This is a pilot experimental study targeting morbidly obese prediabetic patients who will be randomized to three conditions: (1) Group 1 - Control group (Treatment as usual with the endocrinologist and the nurse + Bodyguard2), (2) Group 2 - PRECIOUS system (Bodyguard2 + PRECIOUS app), and (3) Group 3 - PRECIOUS system (Bodyguard2 + PRECIOUS app + Motivational Interviewing). The duration of the study will be 3 months with scheduled follow up appointments within the scope of the project at Weeks 3, 5, 8, and 12. During the study, several measures related to healthy lifestyles, weight management, and health-related quality of life will be collected to explore the effectiveness of PRECIOUS to foster behavior change, as well as user acceptance, usability, and satisfaction with the solution. RESULTS: Because of the encouraging results shown in similar scientific work analyzing health apps acceptance in clinical settings, we expect patients to widely accept and express satisfaction with PRECIOUS. We also expect to find acceptable usability of the preventive health solution. The recruitment of the pilot study has concluded with the inclusion of 31 morbidly obese prediabetic patients. Results are expected to be available in mid-2017. CONCLUSIONS: Adopting and maintaining healthy habits may be challenging in people with chronic conditions who usually need regular support to ensure mid/long-term adherence to recommendations and behavior change. Thus, mHealth could become a powerful and efficient tool since it allows continuous communication with users and immediate feedback. The PRECIOUS system is an innovative preventive health care solution aimed at enhancing inner motivation from users to change their lifestyles and adopt healthier habits. PRECIOUS includes ubiquitous sensors and a scientifically grounded app to address three main components of health: physical activity, diet, and stress levels. TRIAL REGISTRATION: Clinicaltrials.gov NCT02818790; https://clinicaltrials.gov/ct2/show/NCT02818790 (Archived by WebCite at http://www.webcitation.org/6qfzdfMoU). PMID- 28566264 TI - Understanding Environmental and Contextual Influences of Physical Activity During First-Year University: The Feasibility of Using Ecological Momentary Assessment in the MovingU Study. AB - BACKGROUND: It is well established that drastic declines in physical activity (PA) occur during young adults' transition into university; however, our understanding of contextual and environmental factors as it relates to young adults' PA is limited. OBJECTIVE: The purpose of our study was to examine the feasibility of using wrist-worn accelerometers and the use of ecological momentary assessment (EMA) to assess the context and momentary correlates of PA on multiple occasions each day during first-year university. METHODS: First-year university students were asked to participate in the study. The participants completed a brief questionnaire and were subsequently asked to wear an ActiGraph GT9X-Link accelerometer and respond to a series of EMA prompts (7/day) via their phones for 5 consecutive days. RESULTS: A total of 96 first-year university students with smartphones agreed to participate in the study (mean age 18.3 [SD 0.51]; n=45 females). Overall, there was good compliance for wearing the accelerometers, with 91% (78/86) of the participants having >=2 days of >=10 hours of wear time (mean=3.53 valid days). Students were generally active, averaging 10,895 steps/day (SD 3413) or 1123.23 activity counts/min (SD 356.10). Compliance to EMA prompts was less desirable, with 64% (55/86) of the participants having usable EMA data (responding to a minimum of >=3 days of 3 prompts/day or >=4 days of 2 prompts/day), and only 47% (26/55) of these participants were considered to have excellent EMA compliance (responding to >=5 days of 4 prompts/day or >= 4 days of 5 prompts/day). CONCLUSIONS: This study represents one of the first studies to use an intensive real-time data capture strategy to examine time-varying correlates of PA among first-year university students. These data will aim to describe the physical and social contexts in which PA occurs and examine the relationships between momentary correlates of PA among the first-year university students. Overall, current results suggest that wrist-worn accelerometers and EMA are feasible methods for data collection among the young adult population; however, more work is needed to understand how to improve upon compliance to a real-time data capture method such as EMA. PMID- 28566265 TI - Computerized Cognitive Behavioral Therapy to Treat Emotional Distress After Stroke: A Feasibility Randomized Controlled Trial. AB - BACKGROUND: Depression and anxiety are common complications following stroke. Symptoms could be treatable with psychological therapy, but there is little research on its efficacy. OBJECTIVES: The aim of this study was to investigate (1) the acceptability and feasibility of computerized cognitive behavioral therapy (cCBT) to treat symptoms of depression and anxiety and (2) a trial design for comparing the efficacy of cCBT compared with an active comparator. METHODS: Of the total 134 people screened for symptoms of depression and anxiety following stroke, 28 were cluster randomized in blocks with an allocation ratio 2:1 to cCBT (n=19) or an active comparator of computerized cognitive remediation therapy (cCRT, n=9). Qualitative and quantitative feedback was sought on the acceptability and feasibility of both interventions, alongside measuring levels of depression, anxiety, and activities of daily living before, immediately after, and 3 months post treatment. RESULTS: Both cCBT and cCRT groups were rated as near equally useful (mean = 6.4 vs 6.5, d=0.05), while cCBT was somewhat less relevant (mean = 5.5 vs 6.5, d=0.45) but somewhat easier to use (mean = 7.0 vs 6.3, d=0.31). Participants tolerated randomization and dropout rates were comparable with similar trials, with only 3 participants discontinuing due to potential adverse effects; however, dropout was higher from the cCBT arm (7/19, 37% vs 1/9, 11% for cCRT). The trial design required small alterations and highlighted that future-related studies should control for participants receiving antidepressant medication, which significantly differed between groups (P=.05). Descriptive statistics of the proposed outcome measures and qualitative feedback about the cCBT intervention are reported. CONCLUSIONS: A pragmatic approach is required to deliver computerized interventions to accommodate individual needs. We report a preliminary investigation to inform the development of a full randomized controlled trial for testing the efficacy of computerized interventions for people with long-term neurological conditions such as stroke and conclude that this is a potentially promising way of improving accessibility of psychological support. PMID- 28566266 TI - The Development of a Web-Based Program to Reduce Dietary Salt Intake in Schoolchildren: Study Protocol. AB - BACKGROUND: Salt intake of schoolchildren in the Australian state of Victoria is high. To protect future cardiovascular health, interventions that seek to reduce the amount of salt in children's diets are required. OBJECTIVE: We sought to develop and pilot test a Web-based program (Digital Education to Limit Salt Intake in the Home [DELISH]) that aims to reduce dietary salt intake among schoolchildren and to improve child and parent knowledge, attitudes, and behaviors related to salt intake. This paper presents the DELISH study protocol, along with pilot findings used to inform the development of the program. METHODS: The DELISH program is a 5-week Web-based intervention that targets schoolchildren aged 7-10 years and their parents. This is a single-arm study with a pretest and posttest design. We will assess change in salt intake through analysis of 24-hour urinary sodium excretion. Children and parents will complete online surveys assessing knowledge, attitudes, and behaviors related to salt intake. We will assess feasibility of the program via process measures, which include metrics to describe intervention uptake (eg, number of children who complete Web-based sessions and of parents who view online newsletters) and evaluation surveys and interviews conducted with children, parents, and schoolteachers. The first 2 Web sessions developed for children were pilot tested in 19 children aged 8-12 years. RESULTS: Findings from pilot testing indicated that most children (session 1: 18/19, 95%; and session 2: 19/19, 100%) enjoyed completing each session and liked the inclusion of comic strips and interactive games. Commonly reported areas of improvement related to sessions being text and content heavy. Based on these findings, we simplified sessions and developed 3 additional sessions for use in the DELISH program. The DELISH program was implemented during June-December 2016. We expect to have results from this study at the end of 2017. CONCLUSIONS: To our knowledge, this is the first Australian study to examine the effectiveness of a Web-based program to reduce salt intake among children in primary school. If shown to be acceptable and effective in lowering salt intake, the DELISH program could be tested using a more rigorous randomized controlled trial design. PMID- 28566269 TI - Ranjit Singh: A geek at heart. PMID- 28566270 TI - Halting Zika's resurgence with new rapid tests for the virus. PMID- 28566268 TI - High Level of Integration in Integrated Disease Management Leads to Higher Usage in the e-Vita Study: Self-Management of Chronic Obstructive Pulmonary Disease With Web-Based Platforms in a Parallel Cohort Design. AB - BACKGROUND: Worldwide, nearly 3 million people die of chronic obstructive pulmonary disease (COPD) every year. Integrated disease management (IDM) improves disease-specific quality of life and exercise capacity for people with COPD, but can also reduce hospital admissions and hospital days. Self-management of COPD through eHealth interventions has shown to be an effective method to improve the quality and efficiency of IDM in several settings, but it remains unknown which factors influence usage of eHealth and change in behavior of patients. OBJECTIVE: Our study, e-Vita COPD, compares different levels of integration of Web-based self-management platforms in IDM in three primary care settings. The main aim of this study is to analyze the factors that successfully promote the use of a self management platform for COPD patients. METHODS: The e-Vita COPD study compares three different approaches to incorporating eHealth via Web-based self-management platforms into IDM of COPD using a parallel cohort design. Three groups integrated the platforms to different levels. In groups 1 (high integration) and 2 (medium integration), randomization was performed to two levels of personal assistance for patients (high and low assistance); in group 3 there was no integration into disease management (none integration). Every visit to the e-Vita and Zorgdraad COPD Web platforms was tracked objectively by collecting log data (sessions and services). At the first log-in, patients completed a baseline questionnaire. Baseline characteristics were automatically extracted from the log files including age, gender, education level, scores on the Clinical COPD Questionnaire (CCQ), dyspnea scale (MRC), and quality of life questionnaire (EQ5D). To predict the use of the platforms, multiple linear regression analyses for the different independent variables were performed: integration in IDM (high, medium, none), personal assistance for the participants (high vs low), educational level, and self-efficacy level (General Self-Efficacy Scale [GSES]). All analyses were adjusted for age and gender. RESULTS: Of the 702 invited COPD patients, 215 (30.6%) registered to a platform. Of the 82 patients in group 1 (high integration IDM), 36 were in group 1A (personal assistance) and 46 in group 1B (low assistance). Of the 96 patients in group 2 (medium integration IDM), 44 were in group 2A (telephone assistance) and 52 in group 2B (low assistance). A total of 37 patients participated in group 3 (no integration IDM). In all, 107 users (49.8%) visited the platform at least once in the 15-month period. The mean number of sessions differed between the three groups (group 1: mean 10.5, SD 1.3; group 2: mean 8.8, SD 1.4; group 3: mean 3.7, SD 1.8; P=.01). The mean number of sessions differed between the high-assistance and low-assistance groups in groups 1 and 2 (high: mean 11.8, SD 1.3; low: mean 6.7, SD 1.4; F1,80=6.55, P=.01). High assistance participants used more services (mean 45.4, SD 6.2) than low assistance participants (mean 21.2, SD 6.8; F1,80=6.82, P=.01). No association was found between educational level and usage and between GSES and usage. CONCLUSIONS: Use of a self-management platform is higher when participants receive adequate personal assistance about how to use the platform. Blended care, where digital health and usual care are integrated, will likely lead to increased use of the online program. Future research should provide additional insights into the preferences of different patient groups. TRIAL REGISTRATION: Nederlands Trial Register NTR4098; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4098 (Archived by WebCite at http://www.webcitation.org/6qO1hqiJ1). PMID- 28566267 TI - Toward the Design of Evidence-Based Mental Health Information Systems for People With Depression: A Systematic Literature Review and Meta-Analysis. AB - BACKGROUND: Existing research postulates a variety of components that show an impact on utilization of technology-mediated mental health information systems (MHIS) and treatment outcome. Although researchers assessed the effect of isolated design elements on the results of Web-based interventions and the associations between symptom reduction and use of components across computer and mobile phone platforms, there remains uncertainty with regard to which components of technology-mediated interventions for mental health exert the greatest therapeutic gain. Until now, no studies have presented results on the therapeutic benefit associated with specific service components of technology-mediated MHIS for depression. OBJECTIVE: This systematic review aims at identifying components of technology-mediated MHIS for patients with depression. Consequently, all randomized controlled trials comparing technology-mediated treatments for depression to either waiting-list control, treatment as usual, or any other form of treatment for depression were reviewed. Updating prior reviews, this study aims to (1) assess the effectiveness of technology-supported interventions for the treatment of depression and (2) add to the debate on what components in technology-mediated MHIS for the treatment of depression should be standard of care. METHODS: Systematic searches in MEDLINE, PsycINFO, and the Cochrane Library were conducted. Effect sizes for each comparison between a technology-enabled intervention and a control condition were computed using the standard mean difference (SMD). Chi-square tests were used to test for heterogeneity. Using subgroup analysis, potential sources of heterogeneity were analyzed. Publication bias was examined using visual inspection of funnel plots and Begg's test. Qualitative data analysis was also used. In an explorative approach, a list of relevant components was extracted from the body of literature by consensus between two researchers. RESULTS: Of 6387 studies initially identified, 45 met all inclusion criteria. Programs analyzed showed a significant trend toward reduced depressive symptoms (SMD -0.58, 95% CI -0.71 to -0.45, P<.001). Heterogeneity was large (I2>=76). A total of 15 components were identified. CONCLUSIONS: Technology-mediated MHIS for the treatment of depression has a consistent positive overall effect compared to controls. A total of 15 components have been identified. Further studies are needed to quantify the impact of individual components on treatment effects and to identify further components that are relevant for the design of future technology-mediated interventions for the treatment of depression and other mental disorders. PMID- 28566271 TI - The making of a WHO director general. PMID- 28566272 TI - Shining the light of hope. PMID- 28566274 TI - Prenatal antidepressant use and risk of attention-deficit/hyperactivity disorder in offspring: population based cohort study. AB - Objective To assess the potential association between prenatal use of antidepressants and the risk of attention-deficit/hyperactivity disorder (ADHD) in offspring.Design Population based cohort study.Setting Data from the Hong Kong population based electronic medical records on the Clinical Data Analysis and Reporting System.Participants 190 618 children born in Hong Kong public hospitals between January 2001 and December 2009 and followed-up to December 2015.Main outcome measure Hazard ratio of maternal antidepressant use during pregnancy and ADHD in children aged 6 to 14 years, with an average follow-up time of 9.3 years (range 7.4-11.0 years).Results Among 190 618 children, 1252 had a mother who used prenatal antidepressants. 5659 children (3.0%) were given a diagnosis of ADHD or received treatment for ADHD. The crude hazard ratio of maternal antidepressant use during pregnancy was 2.26 (P<0.01) compared with non-use. After adjustment for potential confounding factors, including maternal psychiatric disorders and use of other psychiatric drugs, the adjusted hazard ratio was reduced to 1.39 (95% confidence interval 1.07 to 1.82, P=0.01). Likewise, similar results were observed when comparing children of mothers who had used antidepressants before pregnancy with those who were never users (1.76, 1.36 to 2.30, P<0.01). The risk of ADHD in the children of mothers with psychiatric disorders was higher compared with the children of mothers without psychiatric disorders even if the mothers had never used antidepressants (1.84, 1.54 to 2.18, P<0.01). All sensitivity analyses yielded similar results. Sibling matched analysis identified no significant difference in risk of ADHD in siblings exposed to antidepressants during gestation and those not exposed during gestation (0.54, 0.17 to 1.74, P=0.30).Conclusions The findings suggest that the association between prenatal use of antidepressants and risk of ADHD in offspring can be partially explained by confounding by indication of antidepressants. If there is a causal association, the size of the effect is probably smaller than that reported previously. PMID- 28566275 TI - Fibroblast-adapted human CMV vaccines elicit predominantly conventional CD8 T cell responses in humans. AB - Cytomegalovirus (CMV)-based vaccines have shown remarkable efficacy in the rhesus macaque model of acquired immune deficiency syndrome, enabling 50% of vaccinated monkeys to clear a subsequent virulent simian immunodeficiency virus challenge. The protective vaccine elicited unconventional CD8 T cell responses that were entirely restricted by MHC II or the nonclassical MHC I molecule, MHC-E. These unconventional responses were only elicited by a fibroblast-adapted rhesus CMV vector with limited tissue tropism; a repaired vector with normal tropism elicited conventional responses. Testing whether these unusual protective CD8 T responses could be elicited in humans requires vaccinating human subjects with a fibroblast-adapted mutant of human CMV (HCMV). In this study, we describe the CD8 T cell responses of human subjects vaccinated with two fibroblast-adapted HCMV vaccines. Most responses were identified as conventional classically MHC I restricted, and we found no evidence for MHC II or HLA-E restriction. These results indicate that fibroblast adaptation alone is unlikely to explain the unconventional responses observed in macaques. PMID- 28566276 TI - Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription. AB - The role of AP-1 transcription factors in early B cell development and function is still incompletely characterized. Here we address the role of Fra-2 in B cell differentiation. Deletion of Fra-2 leads to impaired B cell proliferation in the bone marrow. In addition, IL-7-stimulated pro-B cell cultures revealed a reduced differentiation from large pre-B cells to small B cells and immature B cells. Gene profiling and chromatin immunoprecipitation sequencing analyses unraveled a transcriptional reduction of the transcription factors Foxo1, Irf4, Ikaros, and Aiolos in Fra-2-deficient B cells. Moreover, expression of IL7Ralpha and Rag 1/2, downstream targets of Irf4 and Foxo1, were also reduced in the absence of Fra-2. Pro-B cell proliferation and small pre-B cell differentiation were fully rescued by expression of Foxo1 and Irf4 in Fra-2-deficient pro-B cells. Hence, Fra-2 is a key upstream regulator of Foxo1 and Irf4 expression and influences proliferation and differentiation of B cells at multiple stages. PMID- 28566278 TI - Emergency departments are struggling to meet asthma care standards, audit shows. PMID- 28566280 TI - Erratum for Killiny et al., "A Plant Bacterial Pathogen Manipulates Its Insect Vector's Energy Metabolism". PMID- 28566277 TI - Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease. AB - Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase-derived hydroxyeicosatetraenoic acid-phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease. PMID- 28566282 TI - GMC wins right to appeal ruling that registrar's fitness to practise was not impaired. PMID- 28566283 TI - The safety of antidepressants in pregnancy. PMID- 28566281 TI - Double burden or double counting of child malnutrition? The methodological and theoretical implications of stuntingoverweight in low and middle income countries. AB - BACKGROUND: There is increasing concern at research and policy levels about the double burden of child malnutrition (DBCM)-with stunting and overweight found across different groups of children. Despite some case studies suggesting that stunting and overweight can occur concurrently in children, here known as 'stuntingoverweight', and major drives to reduce all forms of malnutrition in low and middle income countries (LMICs), stuntingoverweight is continually overlooked. This research evidences the prevalence of stuntingoverweight across LMICs, exploring the theoretical and methodological implications of failing to acknowledge this form of malnutrition. METHODS: Prevalence estimates of stuntingoverweight are constructed from 79 LMICs with nationally representative anthropometric survey data. Stunting and overweight estimates are amended to exclude stuntedoverweight children. These estimates are compared with those published in the Joint Child Malnutrition Estimates (JMEs)-evidencing overestimation and double counting of stuntedoverweight children. RESULTS: Children can be concurrently stunted and overweight. Stuntedoverweight children are found in all LMICs, from 0.3% to 11.7% of under-fives and are included in both stunting and overweight rates. Analysed together, this leads to double counting of stuntedoverweight children. This artificial inflation of stunting and overweight rates can give a false impression of a DBCM, obscuring the true diversity of malnutrition present. Over 10 million children are stuntedoverweight in the world. CONCLUSIONS: Stuntingoverweight is a newly recognised, understudied phenomenon. Affected children are included in both stunting and overweight prevalence estimates, introducing unobserved heterogeneity to both individual level and population-level research and double counting to population-level research. Overlooking stuntedoverweight children has great implications for methodology, theory, policies, programmes and the health of affected children. PMID- 28566284 TI - Diagnosis and management of deep vein thrombosis in pregnancy. PMID- 28566285 TI - Comparison of 19F NMR and 14C Measurements for the Assessment of ADME of BYL719 (Alpelisib) in Humans. AB - The human mass balance study is the definitive study for the assessment of absorption, distribution, metabolism, and excretion (ADME) properties of a new chemical entity in humans. Traditionally this has been carried out by the administration of radiolabeled drug substances, typically 14C or occasionally 3H, as detection methods for these isotopes allow the absolute quantification of drug related material (DRM) in blood, plasma, and excreta. Coupled with the use of analytical techniques such as liquid chromatography-mass spectrometry, a picture of the metabolic fate of a compound can be elucidated. In this study, we demonstrate the capabilities of 19F nuclear magnetic resonance (NMR) spectroscopy, applied as an alternative to radiolabeling, for the determination of mass balance and for metabolite profiling of an orally administered fluorinated drug. To demonstrate the capabilities of NMR, the study was conducted on remaining samples from a 14C human mass balance study conducted on Alpelisib (BYL719), a compound in late stage development at Novartis for the treatment of solid tumors. Quantitative 14C data were used to cross-validate the data obtained by NMR. The data show that, using 19F NMR, comparable data can be obtained for key human ADME endpoints including mass balance, total DRM determination in plasma and metabolite profiling and identification in plasma and excreta. Potential scenarios where NMR could be employed as an alternative to radiolabeling for the conduct of an early human ADME study are discussed. PMID- 28566273 TI - An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. AB - To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D associated loci (P < 5 * 10-8), including variants near the GLP2R, GIP, and HLA DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology. PMID- 28566286 TI - Rab35 protein regulates evoked exocytosis of endothelial Weibel-Palade bodies. AB - Weibel-Palade bodies (WPB) are secretory organelles of endothelial cells that undergo evoked exocytosis following intracellular Ca2+ or cAMP elevation, thereby supplying the vasculature with factors controlling hemostasis. Several cytosolic and membrane-associated proteins, including the Rab family members Rab3, Rab15, and Rab27a, have been implicated in regulating the acute exocytosis of WPB. Here, we carried out a genome-wide screen to identify Rab pathways affecting WPB exocytosis. Overexpression of a specific subset of Rab GTPase-activating proteins (RabGAPs) inhibited histamine-evoked, Ca2+-dependent WPB exocytosis, presumably by inactivating the target Rab GTPases. Among these RabGAPs, we concentrated on TBC1D10A and showed that the inhibitory effect depends on its GAP activity. We confirmed that Rab35 was a target Rab of TBC1D10A in human endothelial cells; Rab35 interacted with TBC1D10A, and expression of the GAP-insensitive Rab35(Q67A) mutant rescued the inhibitory effect of TBC1D10A overexpression on WPB exocytosis. Furthermore, knockdown of Rab35 and expression of a dominant-negative Rab35 mutant both inhibited histamine-evoked secretion of the WPB cargos von Willebrand factor and P-selectin. Pulldown and co-immunoprecipitation experiments identified the ArfGAP with coiled-coil, Ank repeat, and pleckstrin homology domain-containing protein ACAP2 as an Rab35 effector in endothelial cells, and depletion as well as overexpression approaches revealed that ACAP2 acts as a negative regulator of WPB exocytosis. Interestingly, a known ACAP2 target, the small GTPase Arf6, supported histamine-evoked WPB exocytosis, as shown by knockdown and overexpression of a dominant-negative Arf6 mutant. Our data identify Rab35 as a novel regulator of WPB exocytosis, most likely acting through the downstream effectors ACAP2 and Arf6. PMID- 28566287 TI - The prolyl isomerase Pin1 increases beta-cell proliferation and enhances insulin secretion. AB - The prolyl isomerase Pin1 binds to the phosphorylated Ser/Thr-Pro motif of target proteins and enhances their cis-trans conversion. This report is the first to show that Pin1 expression in pancreatic beta cells is markedly elevated by high fat diet feeding and in ob/ob mice. To elucidate the role of Pin1 in pancreatic beta cells, we generated beta-cell-specific Pin1 KO (betaPin1 KO) mice. These mutant mice showed exacerbation of glucose intolerance but had normal insulin sensitivity. We identified two independent factors underlying impaired insulin secretion in the betaPin1 KO mice. Pin1 enhanced pancreatic beta-cell proliferation, as indicated by a reduced beta-cell mass in betaPin1 KO mice compared with control mice. Moreover, a diet high in fat and sucrose failed to increase pancreatic beta-cell growth in the betaPin1 KO mice, an observation to which up-regulation of the cell cycle protein cyclin D appeared to contribute. The other role of Pin1 was to activate the insulin-secretory step: Pin1 KO beta cells showed impairments in glucose- and KCl-induced elevation of the intracellular Ca2+ concentration and insulin secretion. We also identified salt inducible kinase 2 (SIK2) as a Pin1-binding protein that affected the regulation of Ca2+ influx and found Pin1 to enhance SIK2 kinase activity, resulting in a decrease in p35 protein, a negative regulator of Ca2+ influx. Taken together, our observations demonstrate critical roles of Pin1 in pancreatic beta cells and that Pin1 both promotes beta-cell proliferation and activates insulin secretion. PMID- 28566290 TI - Outcome With the Repositionable and Retrievable Boston Scientific Lotus Valve Compared With the Balloon-Expandable Edwards Sapien 3 Valve in Patients Undergoing Transfemoral Aortic Valve Replacement. AB - BACKGROUND: New generation devices for transfemoral aortic valve replacement were optimized on valve positioning and reduction of residual aortic regurgitation. We compared 30-day, 12-month, and 24-month outcomes of the Boston Scientific Lotus valve (Lotus) and the balloon-expandable Edwards Sapien 3 (ES3) valve. Primary end point was all-cause mortality or disabling stroke within 12 months. METHODS AND RESULTS: Between 2014 and 2016, 537 patients were enrolled at our center, and 202 patients received Lotus and 335 ES3. There was no residual moderate or severe aortic regurgitation. Rate of mild aortic regurgitation was lower with the repositionable and retrievable Lotus valve compared with the ES3. Rate of pacemaker implantation was significantly higher with the Lotus valve compared with the ES3 valve (36.1% versus 14.9%, P<0.01). Valve Academic Research Consortium-2 early safety end point at 30 days was 7.4% with both devices with no difference in all-cause mortality (Lotus, 1.9%; ES3, 1.8%; P=0.87), rate of disabling stroke (Lotus, 1.5%; ES3, 2.1%; P=0.62), or major vascular complications (Lotus, 2.9%; ES3, 2.4%; P=0.69). The primary end point at 12 months was similar between groups. In a propensity score-matched comparison, there was no difference in the primary end point within 12 months (Lotus, 15.5%; ES3, 18.6%; P=0.69) and 24 months (Lotus, 21.9%; ES3, 26.4%; P=0.49). CONCLUSIONS: Transfemoral aortic valve replacement with the ES3 and the Lotus were associated with similar 30-day, 12-month, and 24-month clinical outcomes. Need for permanent pacemaker implantation was significantly higher with the repositionable Lotus device. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02162069. PMID- 28566291 TI - Transcatheter Mitral Valve Replacement With a Novel Dual Stent Bioprosthesis. PMID- 28566288 TI - Point mutations in the N-terminal domain of transactive response DNA-binding protein 43 kDa (TDP-43) compromise its stability, dimerization, and functions. AB - Transactive response DNA-binding protein 43 (TDP-43) performs multiple tasks in mRNA processing, transport, and translational regulation, but it also forms aggregates implicated in amyotrophic lateral sclerosis. TDP-43's N-terminal domain (NTD) is important for these activities and dysfunctions; however, there is an open debate about whether or not it adopts a specifically folded, stable structure. Here, we studied NTD mutations designed to destabilize its structure utilizing NMR and fluorescence spectroscopies, analytical ultracentrifugation, splicing assays, and cell microscopy. The substitutions V31R and T32R abolished TDP-43 activity in splicing and aggregation processes, and even the rather mild L28A mutation severely destabilized the NTD, drastically reducing TDP-43's in vitro splicing activity and inducing aberrant localization and aggregation in cells. These findings strongly support the idea that a stably folded NTD is essential for correct TDP-43 function. The stably folded NTD also promotes dimerization, which is pertinent to the protein's activities and pathological aggregation, and we present an atomic-level structural model for the TDP-43 dimer based on NMR data. Leu-27 is evolutionarily well conserved even though it is exposed in the monomeric NTD. We found here that Leu-27 is buried in the dimer and that the L27A mutation promotes monomerization. In conclusion, our study sheds light on the structural and biological properties of the TDP-43 NTD, indicating that the NTD must be stably folded for TDP-43's physiological functions, and has implications for understanding the mechanisms promoting the pathological aggregation of this protein. PMID- 28566289 TI - Microtubule-assisted altered trafficking of astrocytic gap junction protein connexin 43 is associated with depletion of connexin 47 during mouse hepatitis virus infection. AB - Gap junctions (GJs) are important for maintenance of CNS homeostasis. GJ proteins, connexin 43 (Cx43) and connexin 47 (Cx47), play a crucial role in production and maintenance of CNS myelin. Cx43 is mainly expressed by astrocytes in the CNS and forms gap junction intercellular communications between astrocytes astrocytes (Cx43-Cx43) and between astrocytes-oligodendrocytes (Cx43-Cx47). Mutations of these connexin (Cx) proteins cause dysmyelinating diseases in humans. Previously, it has been shown that Cx43 localization and expression is altered due to mouse hepatitis virus (MHV)-A59 infection both in vivo and in vitro; however, its mechanism and association with loss of myelin protein was not elaborated. Thus, we explored potential mechanisms by which MHV-A59 infection alters Cx43 localization and examined the effects of viral infection on Cx47 expression and its association with loss of the myelin marker proteolipid protein. Immunofluorescence and total internal reflection fluorescence microscopy confirmed that MHV-A59 used microtubules (MTs) as a conduit to reach the cell surface and restricted MT-mediated Cx43 delivery to the cell membrane. Co immunoprecipitation experiments demonstrated that Cx43-beta-tubulin molecular interaction was depleted due to protein-protein interaction between viral particles and MTs. During acute MHV-A59 infection, oligodendrocytic Cx47, which is mainly stabilized by Cx43 in vivo, was down-regulated, and its characteristic staining remained disrupted even at chronic phase. The loss of Cx47 was associated with loss of proteolipid protein at the chronic stage of MHV-A59 infection. PMID- 28566292 TI - Effect of Permanent Right Internal Mammary Artery Closure on Coronary Collateral Function and Myocardial Ischemia. AB - BACKGROUND: The objective of this study is to test the effect of permanent right internal mammary artery device closure on coronary collateral function and myocardial ischemia. METHODS AND RESULTS: This was a prospective, open-label clinical trial in 50 patients with coronary artery disease. The primary study end point was coronary collateral flow index as obtained during a 1-minute proximal right coronary artery (RCA) and left coronary artery balloon occlusion at baseline before and at follow-up examination 6 weeks after distal right internal mammary artery device closure. Collateral flow index is the ratio between simultaneously recorded mean coronary occlusive pressure divided by mean aortic pressure, both subtracted by central venous pressure. Secondary study end points were fractional flow reserve during vessel patency, the quantitative intracoronary ECG ST-segment elevation, and angina pectoris during the same 1 minute coronary occlusion. Collateral flow index in the untreated RCA and left coronary artery changed from 0.071+/-0.082 at baseline to 0.132+/-0.117 (P<0.0001) at follow-up examination and from 0.106+/-0.092 to 0.081+/-0.079 (P=0.29), respectively. RCA fractional flow reserve increased significantly (P=0.0029) from baseline to follow-up examination, despite deferral of coronary intervention in all patients. There was a decrease in intracoronary ECG ST elevation during RCA occlusion from baseline to follow-up examination (P=0.0015); it did not change in the left coronary artery. Angina pectoris during RCA occlusion tended to occur in fewer patients at follow-up versus baseline examination (P=0.06). CONCLUSIONS: Permanent right internal mammary artery device closure seems to augment extracardiac ipsilateral coronary supply to the effect of reducing ischemia in the dependent myocardial region. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02475408. PMID- 28566293 TI - Stimulating Extracardiac Collaterals via Right Internal Mammary Artery Occlusion: Another Step Into an Undiscovered Country. PMID- 28566294 TI - "The NHS is on its knees, someone needs to stand up"--why doctors are running for parliament. PMID- 28566295 TI - Significance of Microvascular Function in Visual-Functional Mismatch Between Invasive Coronary Angiography and Fractional Flow Reserve. AB - BACKGROUND: Despite a moderate correlation between angiographical stenosis and physiological significance, the mechanism of discordance has not been fully elucidated, particularly regarding the significance of microvascular function. This study sought to clarify whether microvascular function affects visual functional mismatch between quantitative coronary angiography (QCA) and fractional flow reserve (FFR). METHODS AND RESULTS: We assessed QCA, FFR, coronary flow reserve, and the index of microcirculatory resistance in 849 non left-main coronary lesions with visually estimated intermediate stenoses from 532 patients. Clinical and lesion-specific characteristics and physiological parameters associated with mismatch and reverse mismatch were studied. Coronary flow reserve and index of microcirculatory resistance showed a weak, but significant, correlation with FFR (R=0.306, P<0.001 and R=0.158, P<0.001, respectively). Four hundred twenty-two lesions were visually nonsignificant (diameter stenosis assessed by QCA [QCA-DS] <=50%) and 427 lesions were visually significant (QCA-DS >50%). Among visually nonsignificant lesions, FFR <=0.80 (reverse mismatch) was observed in 129 lesions (30.6%). Among visually significant lesions, FFR >0.80 (mismatch) were observed in 179 lesions (41.9%). The significant predictors of reverse mismatch were male sex, nonculprit lesions of acute coronary syndrome, left anterior descending artery location, smaller QCA reference diameter, greater QCA-DS, lower coronary flow reserve, and lower index of microcirculatory resistance. Mismatch was associated with right coronary artery location, greater QCA reference diameter, smaller QCA-DS, lesion length, higher coronary flow reserve, and higher index of microcirculatory resistance. CONCLUSIONS: There was a high prevalence of visual-functional mismatches between QCA and FFR. The discrepancy was related to clinical characteristics, lesion specific factors, and microvascular resistance that was undistinguishable by coronary angiography, thus suggesting the importance of physiological lesion assessment. PMID- 28566296 TI - Shortening of the Short Refractory Periods in Short QT Syndrome. AB - BACKGROUND: Diagnosis of short QT syndrome (SQTS) remains difficult in case of borderline QT values as often found in normal populations. Whether some shortening of refractory periods (RP) may help in differentiating SQTS from normal subjects is unknown. METHODS AND RESULTS: Atrial and right ventricular RP at the apex and right ventricular outflow tract as determined during standard electrophysiological study were compared between 16 SQTS patients (QTc 324+/-24 ms) and 15 controls with similar clinical characteristics (QTc 417+/-32 ms). Atrial RP were significantly shorter in SQTS compared with controls at 600- and 500-ms basic cycle lengths. Baseline ventricular RP were significantly shorter in SQTS patients than in controls, both at the apex and right ventricular outflow tract and for any cycle length. Differences remained significant for RP of any subsequent extrastimulus at any cycle length and any pacing site. A cut-off value of baseline RP <200 ms at the right ventricular outflow tract either at 600- or 500-ms cycle length had a sensitivity of 86% and a specificity of 100% for the diagnosis of SQTS. CONCLUSIONS: Patients with SQTS have shorter ventricular RP than controls, both at baseline during various cycle lengths and after premature extrastimuli. A cut-off value of 200 ms at the right ventricular outflow tract during 600- and 500-ms basic cycle length may help in detecting true SQTS from normal subjects with borderline QT values. PMID- 28566297 TI - Effect of Coronary Revascularization on the Prognostic Value of Stress Myocardial Contrast Wall Motion and Perfusion Imaging. AB - BACKGROUND: The assessment of myocardial perfusion (MP) and wall motion (WM) using contrast dipyridamole echocardiography (cSE-WMP) improves the sensitivity to detect coronary artery disease and the stratification of cardiac events, but its long-term value for fatal and nonfatal ischemic cardiac events, also with respect to patients undergoing revascularization or not, remains to be determined. METHODS AND RESULTS: One-thousand three-hundred and twenty-nine patients with suspect or known CAD who underwent cSE-WMP were followed for a median 5.5 years. The independent prognostic value of cSE-WMP regarding cardiac death or nonfatal myocardial infarction was related to stress WM and MP, rest ejection fraction, clinical risk factors, and medications. Patients revascularized after cSE-WMP were separately analyzed to determine whether the procedure influenced outcome and whether this depends on cSE-WMP results. A total of 125 cardiac fatal and nonfatal ischemic events (9.4%) occurred during the follow-up (61 deaths, 64 myocardial infarctions). The 5-year event rate with normal MP and WM was 5.9%, 9.9% with isolated MP defects (normal WM), and 15.5% with both MP and WM abnormalities. In patients not undergoing revascularization (n=1111), reversible MP defects added discrimination value over WM response and clinical factors/medication data (P=0.001), while in the cohort undergoing revascularization (n=218), cSE-WMP results did not influence outcome. CONCLUSIONS: cSE-WMP, with both contrast MP and WM assessments, provides independent, incremental prognostic information regarding ischemic cardiac events at 5 years in patients with known or suspected coronary artery disease. Revascularization reduces cardiac events after an abnormal cSE-WMP, resulting in outcomes not different from those in patients with normal cSE-WMP. PMID- 28566298 TI - Colchicine Depolymerizes Microtubules, Increases Junctophilin-2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a lethal disease characterized by obstructive pulmonary vascular remodeling and right ventricular (RV) dysfunction. Although RV function predicts outcomes in PAH, mechanisms of RV dysfunction are poorly understood, and RV-targeted therapies are lacking. We hypothesized that in PAH, abnormal microtubular structure in RV cardiomyocytes impairs RV function by reducing junctophilin-2 (JPH2) expression, resulting in t tubule derangements. Conversely, we assessed whether colchicine, a microtubule depolymerizing agent, could increase JPH2 expression and enhance RV function in monocrotaline-induced PAH. METHODS AND RESULTS: Immunoblots, confocal microscopy, echocardiography, cardiac catheterization, and treadmill testing were used to examine colchicine's (0.5 mg/kg 3 times/week) effects on pulmonary hemodynamics, RV function, and functional capacity. Rats were treated with saline (n=28) or colchicine (n=24) for 3 weeks, beginning 1 week after monocrotaline (60 mg/kg, subcutaneous). In the monocrotaline RV, but not the left ventricle, microtubule density is increased, and JPH2 expression is reduced, with loss of t-tubule localization and t-tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves t-tubule morphology in RV cardiomyocytes. Colchicine therapy diminishes RV hypertrophy, improves RV function, and enhances RV-pulmonary artery coupling. Colchicine reduces small pulmonary arteriolar thickness and improves pulmonary hemodynamics. Finally, colchicine increases exercise capacity. CONCLUSIONS: Monocrotaline-induced PAH causes RV-specific derangement of microtubules marked by reduction in JPH2 and t-tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves both t-tubule architecture and RV function. Colchicine also reduces adverse pulmonary vascular remodeling. These results provide biological plausibility for a clinical trial to repurpose colchicine as a RV-directed therapy for PAH. PMID- 28566299 TI - Predicting Coronary Artery Aneurysms in Kawasaki Disease at a North American Center: An Assessment of Baseline z Scores. AB - BACKGROUND: Accurate risk prediction of coronary artery aneurysms (CAAs) in North American children with Kawasaki disease remains a clinical challenge. We sought to determine the predictive utility of baseline coronary dimensions adjusted for body surface area (z scores) for future CAAs in Kawasaki disease and explored the extent to which addition of established Japanese risk scores to baseline coronary artery z scores improved discrimination for CAA development. METHODS AND RESULTS: We explored the relationships of CAA with baseline z scores; with Kobayashi, Sano, Egami, and Harada risk scores; and with the combination of baseline z scores and risk scores. We defined CAA as a maximum z score (zMax) >=2.5 of the left anterior descending or right coronary artery at 4 to 8 weeks of illness. Of 261 patients, 77 patients (29%) had a baseline zMax >=2.0. CAAs occurred in 15 patients (6%). CAAs were strongly associated with baseline zMax >=2.0 versus <2.0 (12 [16%] versus 3 [2%], respectively, P<0.001). Baseline zMax >=2.0 had a C statistic of 0.77, good sensitivity (80%), and excellent negative predictive value (98%). None of the risk scores alone had adequate discrimination. When high risk status per the Japanese risk scores was added to models containing baseline zMax >=2.0, none were significantly better than baseline zMax >=2.0 alone. CONCLUSIONS: In a North American center, baseline zMax >=2.0 in children with Kawasaki disease demonstrated high predictive utility for later development of CAA. Future studies should validate the utility of our findings. PMID- 28566300 TI - Sphingolipids: membrane microdomains in brain development, function and neurological diseases. AB - Sphingolipids are highly enriched in the nervous system where they are pivotal constituents of the plasma membranes and are important for proper brain development and functions. Sphingolipids are not merely structural elements, but are also recognized as regulators of cellular events by their ability to form microdomains in the plasma membrane. The significance of such compartmentalization spans broadly from being involved in differentiation of neurons and synaptic transmission to neuronal-glial interactions and myelin stability. Thus, perturbations of the sphingolipid metabolism can lead to rearrangements in the plasma membrane, which has been linked to the development of various neurological diseases. Studying microdomains and their functions has for a long time been synonymous with studying the role of cholesterol. However, it is becoming increasingly clear that microdomains are very heterogeneous, which among others can be ascribed to the vast number of sphingolipids. In this review, we discuss the importance of microdomains with emphasis on sphingolipids in brain development and function as well as how disruption of the sphingolipid metabolism (and hence microdomains) contributes to the pathogenesis of several neurological diseases. PMID- 28566303 TI - Sustained increases in skin blood flow are not a prerequisite to initiate sweating during passive heat exposure. AB - Some studies have observed a functional relationship between sweating and skin blood flow. However, the implications of this relationship during physiologically relevant conditions remain unclear. We manipulated sudomotor activity through changes in sweating efficiency to determine if parallel changes in vasomotor activity are observed. Eight young men completed two trials at 36 degrees C and two trials at 42 degrees C. During these trials, air temperature remained constant while ambient vapor pressure increased from 1.6 to 5.6 kPa over 2 h. Forced airflow across the skin was used to create conditions of high (HiSeff) or low (LoSeff) sweating efficiency. Local sweat rate (LSR), local skin blood flow (SkBF), as well as mean skin and esophageal temperatures were measured continuously. It took longer for LSR to increase during HiSeff at 36 degrees C (HiSeff: 99 +/- 11 vs. LoSeff: 77 +/- 11 min, P < 0.01) and 42 degrees C (HiSeff: 72 +/- 16 vs. LoSeff: 51 +/- 15 min, P < 0.01). In general, an increase in LSR preceded the increase in SkBF when expressed as ambient vapor pressure and time for all conditions (P < 0.05). However, both responses were activated at a similar change in mean body temperature (average across all trials, LSR: 0.26 +/- 0.15 vs. SkBF: 0.30 +/- 0.18 degrees C, P = 0.26). These results demonstrate that altering the point at which LSR is initiated during heat exposure is paralleled by similar shifts for the increase in SkBF. However, local sweat production occurs before an increase in SkBF, suggesting that SkBF is not necessarily a prerequisite for sweating. PMID- 28566304 TI - Circulating motilin, ghrelin, and GLP-1 and their correlations with gastric slow waves in patients with chronic kidney disease. AB - Patients with chronic kidney disease (CKD) commonly complain upper gastrointestinal (GI) symptoms, especially anorexia. Hemodialysis (HD) has been noted to improve GI symptoms; however, the underlying mechanisms are unclear. This study was designed 1) to study effects of HD on GI symptoms and gastric slow waves; and 2) to investigate possible roles of ghrelin and glucagon-like peptide 1 (GLP-1): the study recruited 13 healthy controls, 20 CKD patients without HD (CKD group), and 18 CKD patients with HD (HD group). Dyspeptic symptoms, autonomic functions, gastric slow waves, and plasma level of ghrelin and GLP-1 were analyzed. First, the CKD patients with HD showed markedly lower scores of anorexia (0.6 +/- 0.2 vs. 3.2 +/- 0.4, P < 0.001) compared with patients without HD. Second, the CKD group but not HD group showed a significant reduction (25.6%) in the percentage of normal gastric slow waves, compared with controls. Third, the CKD group exhibited a significantly lower ghrelin level compared with the HD group (26.8 +/- 0.9 vs. 34.1 +/- 2.3 ng/l, P < 0.02) and a higher GLP-1 level (29.4 +/- 2.8 vs. 20.0 +/- 2.1 pmol/l, P < 0.05) compared with controls. Moreover, the percentage of normal slow waves was positively correlated with ghrelin (r = 0.385, P = 0.019) but negatively correlated with GLP-1 (r = -0.558, P < 0.001) in all CKD patients. Hemodialysis improves upper GI symptoms and gastric slow waves in CKD patients. An increase in ghrelin and a decrease in GLP 1 might be involved in the HD-induced improvement in gastric slow waves. PMID- 28566305 TI - Tissue-specific seasonal changes in mitochondrial function of a mammalian hibernator. AB - Mammalian hibernators, such as golden-mantled ground squirrels (Callospermophilus lateralis; GMGS), cease to feed while reducing metabolic rate and body temperature during winter months, surviving exclusively on endogenous fuels stored before hibernation. We hypothesized that mitochondria, the cellular sites of oxidative metabolism, undergo tissue-specific seasonal adjustments in carbohydrate and fatty acid utilization to facilitate or complement this remarkable phenotype. To address this, we performed high-resolution respirometry of mitochondria isolated from GMGS liver, heart, skeletal muscle, and brown adipose tissue (BAT) sampled during summer (active), fall (prehibernation), and winter (hibernation) seasons using multisubstrate titration protocols. Mitochondrial phospholipid composition was examined as a postulated intrinsic modulator of respiratory function across tissues and seasons. Respirometry revealed seasonal variations in mitochondrial oxidative phosphorylation capacity, substrate utilization, and coupling efficiency that reflected the distinct functions and metabolic demands of the tissues they support. A consistent finding across tissues was a greater influence of fatty acids (palmitoylcarnitine) on respiratory parameters during the prehibernation and hibernation seasons. In particular, fatty acids had a greater suppressive effect on pyruvate-supported oxidative phosphorylation in heart, muscle, and liver mitochondria and enhanced uncoupled respiration in BAT and muscle mitochondria in the colder seasons. Seasonal variations in the mitochondrial membrane composition reflected changes in the supply and utilization of polyunsaturated fatty acids but were generally mild and inconsistent with functional variations. In conclusion, mitochondria respond to seasonal variations in physical activity, temperature, and nutrient availability in a tissue-specific manner that complements circannual shifts in the bioenergetic and thermoregulatory demands of mammalian hibernators. PMID- 28566301 TI - Understanding RNA modifications: the promises and technological bottlenecks of the 'epitranscriptome'. AB - The discovery of mechanisms that alter genetic information via RNA editing or introducing covalent RNA modifications points towards a complexity in gene expression that challenges long-standing concepts. Understanding the biology of RNA modifications represents one of the next frontiers in molecular biology. To this date, over 130 different RNA modifications have been identified, and improved mass spectrometry approaches are still adding to this list. However, only recently has it been possible to map selected RNA modifications at single nucleotide resolution, which has created a number of exciting hypotheses about the biological function of RNA modifications, culminating in the proposition of the 'epitranscriptome'. Here, we review some of the technological advances in this rapidly developing field, identify the conceptual challenges and discuss approaches that are needed to rigorously test the biological function of specific RNA modifications. PMID- 28566306 TI - Association of dietary nitrate with atherosclerotic vascular disease mortality: a prospective cohort study of older adult women. AB - Background: Nitrate-rich vegetables lower blood pressure and improve endothelial function in humans. It is not known, however, whether increased consumption of nitrate-rich vegetables translates to a lower risk of atherosclerotic vascular disease (ASVD) mortality.Objective: The objective was to investigate the association of nitrate intake from vegetables with ASVD mortality.Design: A total of 1226 Australian women aged 70-85 y without prevalent ASVD and/or diabetes were recruited in 1998 and were studied for 15 y. We assessed demographic and ASVD risk factors at baseline (1998), and we used a validated food-frequency questionnaire to evaluate dietary intake. Nitrate intake from vegetables was calculated by use of a newly developed comprehensive database. The primary outcome was any death attributed to ASVD ascertained by using linked data that were provided via the Western Australian Data Linkage system. We used Cox proportional hazards modeling to examine the association between nitrate intake and ASVD mortality before and after adjustment for lifestyle and cardiovascular disease risk factors.Results: During a follow-up period of 15,947 person-years, 238 of 1226 (19.4%) women died of ASVD-related causes. The mean +/- SD vegetable nitrate intake was 67.0 +/- 29.2 mg/d. Each SD higher vegetable nitrate intake was associated with a lower risk of ASVD mortality in both unadjusted [HR: 0.80 (95% CI: 0.70, 0.92), P = 0.002] and multivariable-adjusted [HR: 0.79 (95% CI: 0.68, 0.93), P = 0.004] analyses. This relation was attenuated after further adjustment for diet quality [HR: 0.85 (95% CI: 0.72, 1.01), P = 0.072]. Higher vegetable nitrate intake (per SD) also was associated with a lower risk of all cause mortality [multivariable-adjusted HR: 0.87 (95% CI: 0.78, 0.97), P = 0.011].Conclusions: Nitrate intake from vegetables was inversely associated with ASVD mortality independent of lifestyle and cardiovascular disease risk factors in this population of older adult women without prevalent ASVD or diabetes. These results support the concept that nitrate-rich vegetables may reduce the risk of age-related ASVD mortality. This trial was registered at www.anzctr.org.au as ACTRN12617000640303. PMID- 28566309 TI - In Memoriam. PMID- 28566307 TI - Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants. AB - Background: For older groups, being overweight [body mass index (BMI; in kg/m2): 25 to <30] is reportedly associated with a lower or similar risk of mortality than being normal weight (BMI: 18.5 to <25). However, this "risk paradox" is partly explained by smoking and disease-associated weight loss. This paradox may also arise from BMI failing to measure fat redistribution to a centralized position in later life.Objective: This study aimed to estimate associations between combined measurements of BMI and waist-to-hip ratio (WHR) with mortality and incident coronary artery disease (CAD).Design: This study followed 130,473 UK Biobank participants aged 60-69 y (baseline 2006-2010) for <=8.3 y (n = 2974 deaths). Current smokers and individuals with recent or disease-associated (e.g., from dementia, heart failure, or cancer) weight loss were excluded, yielding a "healthier agers" group. Survival models were adjusted for age, sex, alcohol intake, smoking history, and educational attainment. Population and sex-specific lower and higher WHR tertiles were <0.91 and >=0.96 for men and <0.79 and >=0.85 for women, respectively.Results: Ignoring WHR, the risk of mortality for overweight subjects was similar to that for normal-weight subjects (HR: 1.09; 95% CI: 0.99, 1.19; P = 0.066). However, among normal-weight subjects, mortality increased for those with a higher WHR (HR: 1.33; 95% CI: 1.08, 1.65) compared with a lower WHR. Being overweight with a higher WHR was associated with substantial excess mortality (HR: 1.41; 95% CI: 1.25, 1.61) and greatly increased CAD incidence (sub-HR: 1.64; 95% CI: 1.39, 1.93) compared with being normal weight with a lower WHR. There was no interaction between physical activity and BMI plus WHR groups with respect to mortality.Conclusions: For healthier agers (i.e., nonsmokers without disease-associated weight loss), having central adiposity and a BMI corresponding to normal weight or overweight is associated with substantial excess mortality. The claimed BMI-defined overweight risk paradox may result in part from failing to account for central adiposity, rather than reflecting a protective physiologic effect of higher body-fat content in later life. PMID- 28566308 TI - Changes in dietary glycemic index and glycemic load in Australian adults from 1995 to 2012. AB - Background: Australians have used the glycemic index (GI) since 1995; however, there are no data on changes in carbohydrate quality over time.Objectives: The aim was to compare average dietary GI and glycemic load (GL), and contributing carbohydrate foods, in the 2 most recent national dietary surveys.Design: Dietary data from adult participants of national nutrition surveys conducted in 1995 (the 1995 Australian National Nutrition Survey; n = 8703) and 2012 (the 2011-2012 National Nutrition and Physical Activity Survey; n = 6278), collected by a single 24-h recall, were analyzed. The differences in mean dietary GI and GL between surveys were compared by using 1-factor ANOVA. The main sources of dietary GL in the 2 surveys were also assessed. Multiple linear regression was performed to examine the contributions of the food groups to interindividual variations in dietary GI and GL.Results: Overall, dietary GI and GL decreased by 5% and 12%, respectively, from 1995 to 2012 (GI on glucose standard: 56.5 +/- 6.2 compared with 53.9 +/- 6.8, respectively; GL: 153.3 +/- 62.1 compared with 135.4 +/- 58.5, respectively; both P < 0.001). Breads were the main contributor to GL at both time points. Potatoes and sweetened beverages contributed less, whereas cereal based dishes contributed more in 2012 than in 1995. The top 20 GL-contributing food groups explained less interindividual variation in dietary GI (R2: 0.376 compared with 0.290) and GL (R2: 0.825 compared with 0.770) in 2012 than in 1995.Conclusion: Although the average dietary GI and GL declined between 1995 and 2012, trends in specific carbohydrate foods suggest that Australians are avoiding potatoes and sugary beverages in favor of a greater variety of carbohydrate foods, particularly cereal products. PMID- 28566310 TI - Higher densities of fast-food and full-service restaurants are not associated with obesity prevalence. AB - Background: The obesity epidemic in the United States has been mirrored by an increase in calories consumed outside of the home and by expansions in the numbers of, and portion sizes at, both fast-food restaurants (FFRs) and full service restaurants (FSRs), leading some to blame the epidemic on the restaurant industry. If this were indeed true, one would predict that greater per capita densities of FFRs and FSRs would lead to greater obesity prevalence.Objective: We evaluated the population-level association between both FSRs and FFRs and the prevalence of obesity and calculated the proportion of calories consumed in these establishments.Design: In this ecological cross-sectional study, we used county level data (aggregate-level data) for obesity prevalence across the mainland United States in 2012 and matched these data to county-level per capita densities of FFRs and FSRs in the same year. Multiple linear regression was used to determine the relation between the prevalence of obesity and the densities of FFRs and FSRs after adjustment for confounding factors.Results: Contrary to expectations, obesity prevalence was highly significantly negatively related to the densities of both FFRs and FSRs (combined-effect R2 = 0.195). This was principally because greater numbers of both FFRs and FSRs were located in areas in which individuals were on average wealthier and more educated. When we normalized for these factors (and additional socioeconomic variables), the associations between restaurant densities and obesity effectively disappeared (pooled R2 = 0.008). Our calculations showed that the percentage of total calories consumed in FFRs and FSRs is a mean of only 15.9% of the total intake (maximum: 22.6%).Conclusions: Variations in the densities of FFRs and FSRs are not linked to the prevalence of obesity in the United States, and food consumed in these establishments is responsible for <20% of total energy intake. This finding has implications for policy decisions regarding how we aim to tackle the obesity epidemic. PMID- 28566312 TI - Michael John Rennie, MSc, PhD, FRSE, FHEA, 1946-2017: an appreciation of his work on protein metabolism in human muscle. PMID- 28566311 TI - Comparing effectiveness of mass media campaigns with price reductions targeting fruit and vegetable intake on US cardiovascular disease mortality and race disparities. AB - Background: A low intake of fruits and vegetables (F&Vs) is a major risk factor for cardiovascular disease (CVD) in the United States. Both mass media campaigns (MMCs) and economic incentives may increase F&V consumption. Few data exist on their comparative effectiveness.Objective: We estimated CVD mortality reductions potentially achievable by price reductions and MMC interventions targeting F&V intake in the US population.Design: We developed a US IMPACT Food Policy Model to compare 3 policies targeting F&V intake across US adults from 2015 to 2030: national MMCs and national F&V price reductions of 10% and 30%. We accounted for differences in baseline diets, CVD rates, MMC coverage, MMC duration, and declining effects over time. Outcomes included cumulative CVD (coronary heart disease and stroke) deaths prevented or postponed and life-years gained (LYGs) over the study period, stratified by age, sex, and race.Results: A 1-y MMC in 2015 would increase the average national F&V consumption by 7% for 1 y and prevent ~18,600 CVD deaths (95% CI: 17,600, 19,500), gaining ~280,100 LYGs by 2030. With a 15-y MMC, increased F&V consumption would be sustained, yielding a 3 fold larger reduction (56,100; 95% CI: 52,400, 57,700) in CVD deaths. In comparison, a 10% decrease in F&V prices would increase F&V consumption by ~14%. This would prevent ~153,300 deaths (95% CI: 146,400, 159,200), gaining ~2.51 million LYGs. For a 30% price decrease, resulting in a 42% increase in F&V consumption, corresponding values would be 451,900 CVD deaths prevented or postponed (95% CI: 433,100, 467,500) and 7.3 million LYGs gained. Effects were similar by sex, with a smaller proportional effect and larger absolute effects at older ages. A 1-y MMC would be 35% less effective in preventing CVD deaths in non Hispanic blacks than in whites. In comparison, price-reduction policies would have equitable proportional effects.Conclusion: Both national MMCs and price reduction policies could reduce US CVD mortality, with price reduction being more powerful and sustainable. PMID- 28566313 TI - Evaluation of a Real-Time Reverse Transcription-PCR (RT-PCR) Assay for Detection of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Clinical Samples from an Outbreak in South Korea in 2015. PMID- 28566314 TI - T2 Magnetic Resonance Assay-Based Direct Detection of Three Lyme Disease-Related Borrelia Species in Whole-Blood Samples. AB - In early Lyme disease (LD), serologic testing is insensitive and seroreactivity may reflect active or past infection. In this study, we evaluated a novel assay for the direct detection of three species of Borrelia spirochetes in whole blood. The T2 magnetic resonance (T2MR) assay platform was used to amplify Borrelia DNA released from intact spirochetes and to detect amplicon. Analytical sensitivity was determined from blood spiked with known concentrations of spirochetes, and the assay's limit of detection was found to be in the single-cell-per-milliliter range: 5 cells/ml for B. afzelii and 8 cells/ml for Borrelia burgdorferi and Borrelia garinii Clinical samples (n = 66) from confirmed or suspected early LD patients were also analyzed. B. burgdorferi was detected using T2MR in 2/2 (100%) of blood samples from patients with confirmed early LD, based on the presence of erythema migrans and documentation of seroconversion or a positive real-time blood PCR. T2MR detected B. burgdorferi in blood samples from 17/54 (31%) of patients with probable LD, based on the presence of erythema migrans without documented seroconversion or of documented seroconversion in patients with a compatible clinical syndrome but without erythema migrans. Out of 21 clinical samples tested by real-time PCR, only 1 was positive and 13 were negative with agreement with T2MR. An additional 7 samples that were negative by real-time PCR were positive with T2MR. Therefore, T2MR enables a low limit of detection (LoD) for Borrelia spp. in whole blood samples and is able to detect B. burgdorferi in clinical samples. PMID- 28566317 TI - WHO targets medication-related errors. PMID- 28566315 TI - Low Cryptococcus Antigen Titers as Determined by Lateral Flow Assay Should Be Interpreted Cautiously in Patients without Prior Diagnosis of Cryptococcal Infection. AB - Detection of Cryptococcus antigen (CrAg) is invaluable for establishing cryptococcal disease. Multiple different methods for CrAg detection are available, including a lateral flow assay (LFA). Despite excellent performance of the CrAg LFA, we have observed multiple cases of low-titer (<=1:5) positive CrAg LFA results in patients for whom cryptococcosis was ultimately excluded. To investigate the accuracy of low-titer positive CrAg LFA results, we performed chart reviews for all patients with positive CrAg LFA results between June 2014 and December 2016. During this period, serum and/or cerebrospinal fluid (CSF) samples from 3,969 patients were tested with the CrAg LFA, and 55 patients (1.5%) tested positive. Thirty-eight of those patients lacked a history of cryptococcal disease and were the focus of this study. Fungal culture or histopathology confirmed Cryptococcus infection for 20 patients (52.6%), and CrAg LFA titers in serum and CSF samples ranged from 1:5 to >=1:2,560. For the 18 patients (47.4%) without culture or histopathological confirmation, the CrAg LFA results were considered true-positive results for 5 patients (titer range, 1:10 to >=1:2,560), due to clinical improvement with targeted therapy and decreasing CrAg LFA titers. The remaining 13 patients had CrAg LFA titers of 1:2 (n = 11) or 1:5 (n = 2) and were ultimately diagnosed with an alternative condition (n = 11) or began therapy for possible cryptococcosis without improvement (n = 2), leading to an overall CrAg LFA false-positive rate of 34%. We recommend careful clinical correlation prior to establishing a diagnosis of cryptococcal infection for patients with first-time positive CrAg LFA titers of 1:2. PMID- 28566319 TI - What next for the cardiovascular polypill? PMID- 28566318 TI - Febrile seizures in children: benefits and risks of prophylactic drug management. PMID- 28566316 TI - Evaluation of Euroimmun Anti-Zika Virus IgM and IgG Enzyme-Linked Immunosorbent Assays for Zika Virus Serologic Testing. AB - With the emerging Zika virus (ZIKV) epidemic, serologic diagnosis relies on a labor-intensive IgM antibody capture enzyme-linked immunosorbent assay (MAC ELISA) and confirmation by a plaque reduction neutralization test (PRNT). To streamline serologic testing, several commercial assays have been developed. Our aim was to compare the commercial Euroimmun anti-ZIKV IgM and IgG assays to the reference MAC-ELISA and PRNT currently in use. Serum specimens submitted to Public Health Ontario Laboratory, Canada, were tested for IgM and IgG using the Euroimmun assays and the results were compared with those from MAC-ELISA. The PRNT was performed on positive or equivocal specimens using either MAC-ELISA or Euroimmun assays, MAC-ELISA-inconclusive specimens, and a convenience sample of specimens negative by both assays (cohort 1). Another set of specimens selected on the basis of PRNT results was subsequently tested by the Euroimmun assays (cohort 2). MAC-ELISA was positive, equivocal, negative, and inconclusive in 57/223, 15/223, 147/223, and 4/223 specimens, respectively. Among the 76 specimens that were MAC-ELISA positive, equivocal, or inconclusive, 30 (39.5%) were Euroimmun IgM and/or IgG positive or equivocal. Among the 147 MAC-ELISA negative specimens, 136 (92.5%) were Euroimmun IgM and IgG negative. The sensitivity of the combined Euroimmun IgM/IgG against the PRNT was 83% (cohort 1) and 92% (cohort 2), whereas the specificity was 81% (cohort 1) and 65% (cohort 2). The combined Euroimmun IgM/IgG showed good specificity (92.5%) but suboptimal sensitivity (39.5%) compared with that of the MAC-ELISA. However, the sensitivity of the combined Euroimmun IgM/IgG against the PRNT was significantly higher (83 to 92%). More studies are needed before commercial assays are implemented for routine ZIKV serologic diagnosis. PMID- 28566320 TI - EMA recommends suspension of some generic drugs. PMID- 28566322 TI - More on gastric acid suppression and C. difficile risk. PMID- 28566321 TI - Effect of intensive glucose control on microvascular events in people with type 2 diabetes. AB - Effect of intensive glucose control on microvascular events in people with type 2 diabetes ? Febrile seizures in children: benefits and risks of prophylactic drug management More on gastric acid suppression and C difficile risk ? What next for the cardiovascular polypill? ? EMA recommends suspension of some generic drugs ? Phototherapy for vitiligo ? WHO targets medication-related errors. PMID- 28566323 TI - Phototherapy for vitiligo. PMID- 28566326 TI - Retrieval analysis of metal and ceramic femoral heads on a single CoCr stem design. AB - OBJECTIVES: The use of ceramic femoral heads in total hip arthroplasty (THA) has increased due to their proven low bearing wear characteristics. Ceramic femoral heads are also thought to reduce wear and corrosion at the head-stem junction with titanium (Ti) stems when compared with metal heads. We sought to evaluate taper damage of ceramic compared with metal heads when paired with cobalt chromium (CoCr) alloy stems in a single stem design. METHODS: This retrieval study involved 48 total hip arthroplasties (THAs) with CoCr V40 trunnions paired with either CoCr (n = 21) or ceramic (n = 27) heads. The taper junction of all hips was evaluated for fretting/corrosion damage and volumetric material loss using a roundness-measuring machine. We used linear regression analysis to investigate taper damage differences after adjusting for potential confounding variables. RESULTS: We measured median taper material loss rates of 0.210 mm3/year (0.030 to 0.448) for the metal head group and 0.084 mm3/year (0.059 to 0.108) for the ceramic group. The difference was not significant (p = 0.58). Moreover, no significant correlation between material loss and implant or patient factors (p > 0.05) was found. CONCLUSIONS: Metal heads did not increase taper damage on CoCr trunnions compared with ceramic heads from the same hip design. The amount of material released at the taper junctions was very low when compared with available data regarding CoCr/Ti coupling in metal-on-metal bearings.Cite this article: A. Di Laura, H. Hothi, J. Henckel, I. Swiatkowska, M. H. L. Liow, Y M. Kwon, J. A. Skinner, A. J. Hart. Retrieval analysis of metal and ceramic femoral heads on a single CoCr stem design. Bone Joint Res 2017;6:-350. DOI: 10.1302/2046-3758.65.BJR-2016-0325.R1. PMID- 28566325 TI - Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing. AB - Mammalian target of rapamycin complex 1 (mTORC1) and cell senescence are intimately linked to each other and to organismal aging. Inhibition of mTORC1 is the best-known intervention to extend lifespan, and recent evidence suggests that clearance of senescent cells can also improve health and lifespan. Enhanced mTORC1 activity drives characteristic phenotypes of senescence, although the underlying mechanisms responsible for increased activity are not well understood. We have identified that in human fibroblasts rendered senescent by stress, replicative exhaustion, or oncogene activation, mTORC1 is constitutively active and resistant to serum and amino acid starvation. This is driven in part by depolarization of senescent cell plasma membrane, which leads to primary cilia defects and a resultant failure to inhibit growth factor signaling. Further, increased autophagy and high levels of intracellular amino acids may act to support mTORC1 activity in starvation conditions. Interventions to correct these phenotypes restore sensitivity to the mTORC1 signaling pathway and cause death, indicating that persistent signaling supports senescent cell survival. PMID- 28566327 TI - The influence of cement thickness on stem subsidence and cement creep in a collarless polished tapered stem: When are thick cement mantles detrimental? AB - OBJECTIVES: Favourable results for collarless polished tapered stems have been reported, and cement creep due to taper slip may be a contributing factor. However, the ideal cement thickness around polished stems remains unknown. We investigated the influence of cement thickness on stem subsidence and cement creep. METHODS: We cemented six collarless polished tapered (CPT) stems (two stems each of small, medium and large sizes) into composite femurs that had been reamed with a large CPT rasp to achieve various thicknesses of the cement mantle. Two or three tantalum balls were implanted in the proximal cement in each femur. A cyclic loading test was then performed for each stem. The migration of the balls was measured three-dimensionally, using a micro-computed tomography (CT) scanner, before and after loading. A digital displacement gauge was positioned at the stem shoulder, and stem subsidence was measured continuously by the gauge. Final stem subsidence was measured at the balls at the end of each stem. RESULTS: A strong positive correlation was observed between mean cement thickness and stem subsidence in the CT slices on the balls. In the small stems, the balls moved downward to almost the same extent as the stem. There was a significant negative correlation between cement thickness and the horizontal:downward ratio of ball movement. CONCLUSION: Collarless polished tapered stems with thicker cement mantles resulted in greater subsidence of both stem and cement. This suggests that excessive thickness of the cement mantle may interfere with effective radial cement creep.Cite this article: E. Takahashi, A. Kaneuji, R. Tsuda, Y. Numata, T. Ichiseki, K. Fukui, N. Kawahara. The influence of cement thickness on stem subsidence and cement creep in a collarless polished tapered stem: When are thick cement mantles detrimental? Bone Joint Res 2017;6:-357. DOI: 10.1302/2046 3758.65.BJR-2017-0028.R1. PMID- 28566324 TI - Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. AB - Mitochondrial stress activates a mitonuclear response to safeguard and repair mitochondrial function and to adapt cellular metabolism to stress. Using a multiomics approach in mammalian cells treated with four types of mitochondrial stressors, we identify activating transcription factor 4 (ATF4) as the main regulator of the stress response. Surprisingly, canonical mitochondrial unfolded protein response genes mediated by ATF5 are not activated. Instead, ATF4 activates the expression of cytoprotective genes, which reprogram cellular metabolism through activation of the integrated stress response (ISR). Mitochondrial stress promotes a local proteostatic response by reducing mitochondrial ribosomal proteins, inhibiting mitochondrial translation, and coupling the activation of the ISR with the attenuation of mitochondrial function. Through a trans-expression quantitative trait locus analysis, we provide genetic evidence supporting a role for Fh1 in the control of Atf4 expression in mammals. Using gene expression data from mice and humans with mitochondrial diseases, we show that the ATF4 pathway is activated in vivo upon mitochondrial stress. Our data illustrate the value of a multiomics approach to characterize complex cellular networks and provide a versatile resource to identify new regulators of mitochondrial-related diseases. PMID- 28566328 TI - Somatic Mutations Drive Distinct Imaging Phenotypes in Lung Cancer. AB - Tumors are characterized by somatic mutations that drive biological processes ultimately reflected in tumor phenotype. With regard to radiographic phenotypes, generally unconnected through present understanding to the presence of specific mutations, artificial intelligence methods can automatically quantify phenotypic characters by using predefined, engineered algorithms or automatic deep-learning methods, a process also known as radiomics. Here we demonstrate how imaging phenotypes can be connected to somatic mutations through an integrated analysis of independent datasets of 763 lung adenocarcinoma patients with somatic mutation testing and engineered CT image analytics. We developed radiomic signatures capable of distinguishing between tumor genotypes in a discovery cohort (n = 353) and verified them in an independent validation cohort (n = 352). All radiomic signatures significantly outperformed conventional radiographic predictors (tumor volume and maximum diameter). We found a radiomic signature related to radiographic heterogeneity that successfully discriminated between EGFR+ and EGFR cases (AUC = 0.69). Combining this signature with a clinical model of EGFR status (AUC = 0.70) significantly improved prediction accuracy (AUC = 0.75). The highest performing signature was capable of distinguishing between EGFR+ and KRAS+ tumors (AUC = 0.80) and, when combined with a clinical model (AUC = 0.81), substantially improved its performance (AUC = 0.86). A KRAS+/KRAS- radiomic signature also showed significant albeit lower performance (AUC = 0.63) and did not improve the accuracy of a clinical predictor of KRAS status. Our results argue that somatic mutations drive distinct radiographic phenotypes that can be predicted by radiomics. This work has implications for the use of imaging-based biomarkers in the clinic, as applied noninvasively, repeatedly, and at low cost. Cancer Res; 77(14); 3922-30. (c)2017 AACR. PMID- 28566329 TI - Venetoclax Synergizes with Radiotherapy for Treatment of B-cell Lymphomas. AB - Constitutive B-cell receptor signaling leads to overexpression of the antiapoptotic BCL-2 protein and is implicated in the pathogenesis of many types of B-cell non-Hodgkin lymphoma (B-NHL). The BCL-2 small-molecule inhibitor venetoclax shows promising clinical response rates in several lymphomas, but is not curative as monotherapy. Radiotherapy is a rational candidate for combining with BCL-2 inhibition, as DNA damage caused by radiotherapy increases the activity of pro-apoptotic BCL-2 pathway proteins, and lymphomas are exquisitely sensitive to radiation. We tested B-NHL responses to venetoclax combined with either external beam radiotherapy or radioimmunotherapy (RIT), which joins the selectivity of antibody targeting with the effectiveness of irradiation. We first tested cytotoxicity of cesium-137 irradiation plus venetoclax in 14 B-NHL cell lines representing five lymphoma subtypes. Combination treatment synergistically increased cell death in 10 of 14 lines. Lack of synergy was predicted by resistance to single-agent venetoclax and high BCL-XL expression. We then assessed the efficacy of external beam radiotherapy plus venetoclax in murine xenograft models of mantle cell (MCL), germinal-center diffuse large B-cell (GCB DLBCL), and activated B-cell (ABC-DLBCL) lymphomas. In each model, external beam radiotherapy plus venetoclax synergistically increased mouse survival time, curing up to 10%. We finally combined venetoclax treatment of MCL and ABC-DLBCL xenografts with a pretargeted RIT (PRIT) system directed against the CD20 antigen. Optimal dosing of PRIT plus venetoclax cured 100% of mice with no detectable toxicity. Venetoclax combined with radiotherapy may be a promising treatment for a wide range of lymphomas Cancer Res; 77(14); 3885-93. (c)2017 AACR. PMID- 28566330 TI - Monitoring the Vascular Response and Resistance to Sunitinib in Renal Cell Carcinoma In Vivo with Susceptibility Contrast MRI. AB - Antiangiogenic therapy is efficacious in metastatic renal cell carcinoma (mRCC). However, the ability of antiangiogenic drugs to delay tumor progression and extend survival is limited, due to either innate or acquired drug resistance. Furthermore, there are currently no validated biomarkers that predict which mRCC patients will benefit from antiangiogenic therapy. Here, we exploit susceptibility contrast MRI (SC-MRI) using intravascular ultrasmall superparamagnetic iron oxide particles to quantify and evaluate tumor fractional blood volume (fBV) as a noninvasive imaging biomarker of response to the antiangiogenic drug sunitinib. We also interrogate the vascular phenotype of RCC xenografts exhibiting acquired resistance to sunitinib. SC-MRI of 786-0 xenografts prior to and 2 weeks after daily treatment with 40 mg/kg sunitinib revealed a 71% (P < 0.01) reduction in fBV in the absence of any change in tumor volume. This response was associated with significantly lower microvessel density (P < 0.01) and lower uptake of the perfusion marker Hoechst 33342 (P < 0.05). The average pretreatment tumor fBV was negatively correlated (R2 = 0.92, P < 0.0001) with sunitinib-induced changes in tumor fBV across the cohort. SC-MRI also revealed suppressed fBV in tumors that acquired resistance to sunitinib. In conclusion, SC-MRI enabled monitoring of the antiangiogenic response of 786-0 RCC xenografts to sunitinib, which revealed that pretreatment tumor fBV was found to be a predictive biomarker of subsequent reduction in tumor blood volume in response to sunitinib, and acquired resistance to sunitinib was not associated with a parallel increase in tumor blood volume. Cancer Res; 77(15); 4127-34. (c)2017 AACR. PMID- 28566331 TI - Pharmacokinetics and Drug Interactions Determine Optimum Combination Strategies in Computational Models of Cancer Evolution. AB - The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes. Here we developed the first computational strategy to explore pharmacokinetic and drug interaction effects in evolutionary models of cancer progression, a crucial step towards making clinically relevant predictions. We found that incorporating these phenomena into our multiscale stochastic modeling framework significantly changes the optimum drug administration schedules identified, often predicting nonintuitive strategies for combination therapies. We applied our approach to an ongoing phase Ib clinical trial (TATTON) administering AZD9291 and selumetinib to EGFR-mutant lung cancer patients. Our results suggest that the schedules used in the three trial arms have almost identical efficacies, but slight modifications in the dosing frequencies of the two drugs can significantly increase tumor cell eradication. Interestingly, we also predict that drug concentrations lower than the MTD are as efficacious, suggesting that lowering the total amount of drug administered could lower toxicities while not compromising on the effectiveness of the drugs. Our approach highlights the fact that quantitative knowledge of pharmacokinetic, drug interaction, and evolutionary processes is essential for identifying best intervention strategies. Our method is applicable to diverse cancer and treatment types and allows for a rational design of clinical trials. Cancer Res; 77(14); 3908-21. (c)2017 AACR. PMID- 28566332 TI - Oncolytic Adenovirus and Tumor-Targeting Immune Modulatory Therapy Improve Autologous Cancer Vaccination. AB - Oncolytic viruses selectively lyse tumor cells, disrupt immunosuppression within the tumor, and reactivate antitumor immunity, but they have yet to live up to their therapeutic potential. Immune checkpoint modulation has been efficacious in a variety of cancer with an immunogenic microenvironment, but is associated with toxicity due to nonspecific T-cell activation. Therefore, combining these two strategies would likely result in both effective and specific cancer therapy. To test the hypothesis, we first constructed oncolytic adenovirus Delta-24-RGDOX expressing the immune costimulator OX40 ligand (OX40L). Like its predecessor Delta-24-RGD, Delta-24-RGDOX induced immunogenic cell death and recruit lymphocytes to the tumor site. Compared with Delta-24-RGD, Delta-24-RGDOX exhibited superior tumor-specific activation of lymphocytes and proliferation of CD8+ T cells specific to tumor-associated antigens, resulting in cancer-specific immunity. Delta-24-RGDOX mediated more potent antiglioma activity in immunocompetent C57BL/6 but not immunodeficient athymic mice, leading to specific immune memory against the tumor. To further overcome the immune suppression mediated by programmed death-ligand 1 (PD-L1) expression on cancer cells accompanied with virotherapy, intratumoral injection of Delta-24-RGDOX and an anti-PD-L1 antibody showed synergistic inhibition of gliomas and significantly increased survival in mice. Our data demonstrate that combining an oncolytic virus with tumor-targeting immune checkpoint modulators elicits potent in situ autologous cancer vaccination, resulting in an efficacious, tumor-specific, and long-lasting therapeutic effect. Cancer Res; 77(14); 3894-907. (c)2017 AACR. PMID- 28566334 TI - Antibody-Based Correlates of Protection Against Cholera Analysis of a Challenge Study in a Cholera-Naive Population. AB - Immunologic correlates of protection can be used to infer vaccine efficacy for populations in which challenge trials or field studies are infeasible. In a recent cholera challenge trial (WH Cohen et al, Clinical Infectious Disease 62: 1329-1335, 2016), 134 North American cholera-naive volunteers were randomized to receive either the live, attenuated single-dose cholera vaccine CVD 103-HgR or placebo, and titers of vibriocidal antibodies against classical Inaba were assessed 10 days after treatment. Subsequent to the immunologic evaluation, each subject ingested a fixed quantity of virulent V. cholerae O1 El Tor Inaba. Data from this trial suggest that vaccine-induced increase in vibriocidal antibody titer prior to challenge is tightly linked with protection: 51/51 vaccinees with post-vaccination vibriocidal titers >= 2560 were protected against moderate/severe cholera, and 60/62 vaccinees who seroconverted, or experienced a 4-fold or greater increase in vibriocidal titer relative to pre-vaccination levels, were similarly protected. Atypically high vibriocidal titers were observed in some placebo subjects; protection was limited in these individuals and differed substantially from the level of protection experienced by vaccinees with the same post-vaccination titers. Since only 1 of 66 placebo recipients experienced seroconversion, seroconversion was found to be uniquely associated with vaccination and insensitive to the effects of factors that can cause titers to be elevated but are weakly associated with protection. Thus, vibriocidal seroconversion was found to be better than vibriocidal titer for inferring vaccine efficacy in cholera-naive populations for which studies based upon exposure to V. cholerae are impractical. PMID- 28566333 TI - CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib. AB - Cyclin D-CDK4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER-positive breast tumors. Unfortunately, no reliable predictive tools are available for identifying potentially responsive or insensitive tumors. We had shown that the activating T172 phosphorylation of CDK4 is the central rate limiting event that initiates the cell cycle decision and signals the presence of active CDK4. Here, we report that the profile of post-translational modification including T172 phosphorylation of CDK4 differs among breast tumors and associates with their subtypes and risk. A gene expression signature faithfully predicted CDK4 modification profiles in tumors and cell lines. Moreover, in breast cancer cell lines, the CDK4 T172 phosphorylation best correlated with sensitivity to PD0332991. This gene expression signature identifies tumors that are unlikely to respond to CDK4/6 inhibitors and could help to select a subset of patients with HER2-positive and basal-like tumors for clinical studies on this class of drugs. PMID- 28566335 TI - Breadth and Duration of Meningococcal Serum Bactericidal Activity in Health Care Workers and Microbiologists Immunized with the MenB-FHbp Vaccine. AB - MenB-FHbp is a meningococcal serogroup B vaccine with two factor H binding protein (FHbp) antigens from subfamilies A and B. For licensure, efficacy was inferred from serum bactericidal antibody (SBA) responses to four reference strains. Only limited information is available on the breadth or duration of protective SBA responses to genetically diverse disease-causing strains. Seventeen health care or laboratory workers were immunized with two (n = 2) or three (n = 15) doses of MenB-FHbp at 0, 2, and 6 months. SBA levels were measured against 14 serogroup B case isolates, including 6 from U.S. college outbreaks and 2 from Quebec during hyperendemic disease. Compared with preimmunization titers, the proportion of subjects with >=4-fold increases in SBA titer 1 month after 2 doses of vaccine ranged from 35% to 94% for six isolates with FHbp subfamily A and from 24% to 76% for eight isolates with subfamily B FHbp. The respective proportions with >=4-fold titer increases at 1 month after dose 3 were 73% to 100% and 67% to 100%. At that time point, the proportion of subjects with titers of >=1:4 (presumed sufficient for short-term protection) ranged from 93% to 100% for all 14 isolates. By 9 to 11 months after dose 3, 50% or fewer of the subjects with follow-up sera had protective titers of >=1:4 for 4 of 9 isolates tested. Three doses of MenB-FHbp elicited short-term protective SBA responses to diverse disease-causing serogroup B strains. For some strains, serum titers declined to <1:4 by 9 to 11 months, which raises concerns about the duration of broad, long term protection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02569632.). PMID- 28566336 TI - Maternal Humoral Immune Correlates of Peripartum Transmission of Clade C HIV-1 in the Setting of Peripartum Antiretrovirals. AB - Despite the widespread use of antiretrovirals (ARV), more than 150,000 pediatric HIV-1 infections continue to occur annually. Supplemental strategies are necessary to eliminate pediatric HIV infections. We previously reported that maternal HIV envelope-specific anti-V3 IgG and CD4 binding site-directed antibodies, as well as tier 1 virus neutralization, predicted a reduced risk of mother-to-child transmission (MTCT) of HIV-1 in the pre-ARV era U.S.-based Women and Infants Transmission Study (WITS) cohort. As the majority of ongoing pediatric HIV infections occur in sub-Saharan Africa, we sought to determine if the same maternal humoral immune correlates predicted MTCT in a subset of the Malawian Breastfeeding, Antiretrovirals, and Nutrition (BAN) cohort of HIV infected mothers (n = 88, with 45 transmitting and 43 nontransmitting). Women and infants received ARV at delivery; thus, the majority of MTCT was in utero (91%). In a multivariable logistic regression model, neither maternal anti-V3 IgG nor clade C tier 1 virus neutralization was associated with MTCT. Unexpectedly, maternal CD4 binding-site antibodies and anti-variable loop 1 and 2 (V1V2) IgG were associated with increased MTCT, independent of maternal viral load. Neither infant envelope (Env)-specific IgG levels nor maternal IgG transplacental transfer efficiency was associated with transmission. Distinct humoral immune correlates of MTCT in the BAN and WITS cohorts could be due to differences between transmission modes, virus clades, or maternal antiretroviral use. The association between specific maternal antibody responses and in utero transmission, which is distinct from potentially protective maternal antibodies in the WITS cohort, underlines the importance of investigating additional cohorts with well-defined transmission modes to understand the role of antibodies during HIV-1 MTCT. PMID- 28566337 TI - Age-Related Autonomous Aldosteronism. AB - BACKGROUND: Both aging and inappropriate secretion of aldosterone increase the risk for developing cardiovascular disease; however, the influence of aging on aldosterone secretion and physiology is not well understood. METHODS: The relationship between age and adrenal aldosterone synthase (CYP11B2) expression was evaluated in 127 normal adrenal glands from deceased kidney donors (age, 9 months to 68 years). Following immunohistochemistry, CYP11B2-expressing area and areas of abnormal foci of CYP11B2-expressing cells, called aldosterone-producing cell clusters, were analyzed. In a separate ancillary clinical study of 677 participants without primary aldosteronism, who were studied on both high and restricted sodium diets (age, 18-71 years), we used multivariable linear regression to assess the independent associations between age and renin angiotensin-aldosterone system physiology. RESULTS: In adrenal tissue, the total CYP11B2-expressing area was negatively correlated with age (r=-0.431, P<0.0001), whereas the total aldosterone-producing cell cluster area was positively correlated with age (r=0.390, P<0.0001). The integrated ratio of aldosterone producing cell cluster to CYP11B2-expressing area was most strongly and positively correlated with age (r=0.587, P<0.0001). When participants in the clinical study were maintained on a high sodium balance, renin activity progressively declined with older age, whereas serum and urinary aldosterone did not significantly decline. Correspondingly, the aldosterone-to-renin ratio was positively and independently associated with older age (adjusted beta=+5.54 ng/dL per ng/mL per hour per 10 years, P<0.001). In contrast, when participants were assessed under sodium-restricted conditions, physiological stimulation of aldosterone was blunted with older age (beta=-4.6 ng/dL per 10 years, P<0.0001). CONCLUSIONS: Aging is associated with a pattern of decreased normal zona glomerulosa CYP11B2 expression and increased aldosterone-producing cell cluster expression. This histopathologic finding parallels an age-related autonomous aldosteronism and abnormal aldosterone physiology that provides 1 potential explanation for age-related cardiovascular risk. PMID- 28566338 TI - Associations Between Adding a Radial Artery Graft to Single and Bilateral Internal Thoracic Artery Grafts and Outcomes: Insights From the Arterial Revascularization Trial. AB - BACKGROUND: Whether the use of the radial artery (RA) can improve clinical outcomes in coronary artery bypass graft surgery remains unclear. The ART (Arterial Revascularization Trial) was designed to compare survival after bilateral internal thoracic artery (BITA) over single left internal thoracic artery (SITA). In the ART, a large proportion of patients (~20%) also received an RA graft instead of a saphenous vein graft (SVG). We aimed to investigate the associations between using the RA instead of an SVG to supplement SITA or BITA grafts and outcomes by performing a post hoc analysis of the ART. METHODS: Patients enrolled in the ART (n=3102) were classified on the basis of conduits actually received (as treated). The analysis included 2737 patients who received an RA graft (RA group; n=632) or SVG only (SVG group; n=2105) in addition to SITA or BITA grafts. The primary end point was the composite of myocardial infarction, cardiovascular death, and repeat revascularization at 5 years. Propensity score matching and stratified Cox regression were used to compare the 2 strategies. RESULTS: Myocardial infarction, cardiovascular death, and repeat revascularization cumulative incidence was 2.3% (95% confidence interval [CI], 1.1-3.4), 3.5% (95% CI, 2.1-5.0), and 4.4% (95% CI, 2.8-6.0) in the RA group and 3.4% (95% CI, 2.0-4.8), 4.0% (95% CI, 2.5-5.6), and 7.6% (95% CI, 5.5-9.7) in the SVG group, respectively. The composite end point was significantly lower in the RA group (8.8%; 95% CI, 6.5-11.0) compared with the SVG group (13.6%; 95% CI, 10.8-16.3; P=0.005). This association was present when an RA graft was used to supplement both SITA and BITA grafts (interaction P=0.62). CONCLUSIONS: This post hoc ART analysis showed that an additional RA was associated with lower risk for midterm major adverse cardiac events when used to supplement SITA or BITA grafts. CLINICAL TRIAL REGISTRATION: URL: https://www.situ.ox.ac.uk/surgical-trials/art. Unique identifier: ISRCTN46552265. PMID- 28566339 TI - Myelodysplasia in younger adults: outlier or unique molecular entity? PMID- 28566340 TI - Immunoglobulin genes in chronic lymphocytic leukemia: key to understanding the disease and improving risk stratification. PMID- 28566341 TI - Unmet needs in the scientific approach to older patients with lymphoma. PMID- 28566352 TI - Mechanisms underlying the control of responses to predator odours in aquatic prey. AB - In aquatic systems, chemical cues are a major source of information through which animals are able to assess the current state of their environment to gain information about local predation risk. Prey use chemicals released by predators (including cues from a predator's diet) and other prey (such as alarm cues and disturbance cues) to mediate a range of behavioural, morphological and life history antipredator defences. Despite the wealth of knowledge on the ecology of antipredator defences, we know surprisingly little about the physiological mechanisms that control the expression of these defensive traits. Here, we summarise the current literature on the mechanisms known to specifically mediate responses to predator odours, including dietary cues. Interestingly, these studies suggest that independent pathways may control predator-specific responses, highlighting the need for greater focus on predator-derived cues when looking at the mechanistic control of responses. Thus, we urge researchers to tease apart the effects of predator-specific cues (i.e. chemicals representing a predator's identity) from those of diet-mediated cues (i.e. chemicals released from a predator's diet), which are known to mediate different ecological endpoints. Finally, we suggest some key areas of research that would greatly benefit from a more mechanistic approach. PMID- 28566353 TI - Sex reversal induces size and performance differences among females of the African pygmy mouse, Mus minutoides. AB - Differences in biological performance, at both intra- and inter-specific levels, have often been linked to morphology but seldom to behavioural or genotypic effects. We tested performance at the intraspecific level by measuring bite force in the African pygmy mouse, Mus minutoides. This species displays an unusual sex determination system, with sex-reversed, X*Y females carrying a feminizing X* chromosome. X*Y females cannot be differentiated from XX females based on external or gonadal morphology; however, they are known to be more aggressive. We found that bite force was higher in X*Y females than in other females and males. We then performed geometric morphometric analyses on their skulls and mandibles and found that the higher performance of X*Y females was mainly explained by a greater overall skull size. The effects of the X* chromosome thus go beyond feminization, and extend to whole-organism performance and morphology. Our results also suggest limited effects of behaviour on bite force. PMID- 28566354 TI - Disruptive colouration in reef fish: does matching the background reduce predation risk? AB - Animals use disruptive colouration to prevent detection or recognition by potential predators or prey. Highly contrasting elements within colour patterns, including vertical or horizontal bars, are thought to be effective at distracting attention away from body form and reducing detection likelihood. However, it is unclear whether such patterns need to be a good match to the spatial characteristics of the background to gain cryptic benefits. We tested this hypothesis using the iconic vertically barred humbug damselfish, Dascyllus aruanus (Linneaus 1758), a small reef fish that lives among the finger-like projections of branching coral colonies. Using behavioural experiments, we demonstrated that the spatial frequency of the humbug pattern does not need to exactly match the spatial frequency of the coral background to reduce the likelihood of being attacked by two typical reef fish predators: slingjaw wrasse, Epibulus insidiator (Pallas 1770), and coral trout, Plectropomus leopardus (Lacepede 1802). Indeed, backgrounds with a slightly higher spatial frequency than the humbug body pattern provided more protection from predation than well matched backgrounds. These results were consistent for both predator species, despite differences in their mode of foraging and visual acuity, which was measured using anatomical techniques. We also showed that a slight mismatch in the orientation of the vertical bars did not increase the chances of detection. However, the likelihood of attack did increase significantly when the bars were perpendicular to the background. Our results provide evidence that fish camouflage is more complex than it initially appears, with likely many factors influencing the detection likelihood of prey by relevant predators. PMID- 28566355 TI - Spiders have rich pigmentary and structural colour palettes. AB - Elucidating the mechanisms of colour production in organisms is important for understanding how selection acts upon a variety of behaviours. Spiders provide many spectacular examples of colours used in courtship, predation, defence and thermoregulation, but are thought to lack many types of pigments common in other animals. Ommochromes, bilins and eumelanin have been identified in spiders, but not carotenoids or melanosomes. Here, we combined optical microscopy, refractive index matching, confocal Raman microspectroscopy and electron microscopy to investigate the basis of several types of colourful patches in spiders. We obtained four major results. First, we show that spiders use carotenoids to produce yellow, suggesting that such colours may be used for condition-dependent courtship signalling. Second, we established the Raman signature spectrum for ommochromes, facilitating the identification of ommochromes in a variety of organisms in the future. Third, we describe a potential new pigmentary-structural colour interaction that is unusual because of the use of long wavelength structural colour in combination with a slightly shorter wavelength pigment in the production of red. Finally, we present the first evidence for the presence of melanosomes in arthropods, using both scanning and transmission electron microscopy, overturning the assumption that melanosomes are a synapomorphy of vertebrates. Our research shows that spiders have a much richer colour production palette than previously thought, and this has implications for colour diversification and function in spiders and other arthropods. PMID- 28566342 TI - Predictors of clinical recovery from concussion: a systematic review. AB - OBJECTIVE: A systematic review of factors that might be associated with, or influence, clinical recovery from sport-related concussion. Clinical recovery was defined functionally as a return to normal activities, including school and sports, following injury. DESIGN: Systematic review. DATA SOURCES: PubMed, PsycINFO, MEDLINE, CINAHL, Cochrane Library, EMBASE, SPORTDiscus, Scopus and Web of Science. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies published by June of 2016 that addressed clinical recovery from concussion. RESULTS: A total of 7617 articles were identified using the search strategy, and 101 articles were included. There are major methodological differences across the studies. Many different clinical outcomes were measured, such as symptoms, cognition, balance, return to school and return to sports, although symptom outcomes were the most frequently measured. The most consistent predictor of slower recovery from concussion is the severity of a person's acute and subacute symptoms. The development of subacute problems with headaches or depression is likely a risk factor for persistent symptoms lasting greater than a month. Those with a preinjury history of mental health problems appear to be at greater risk for having persistent symptoms. Those with attention deficit hyperactivity disorder (ADHD) or learning disabilities do not appear to be at substantially greater risk. There is some evidence that the teenage years, particularly high school, might be the most vulnerable time period for having persistent symptoms-with greater risk for girls than boys. CONCLUSION: The literature on clinical recovery from sport-related concussion has grown dramatically, is mostly mixed, but some factors have emerged as being related to outcome. PMID- 28566356 TI - Functional morphology of tarsal adhesive pads and attachment ability in ticks Ixodes ricinus (Arachnida, Acari, Ixodidae). AB - The presence of well-developed, elastic claws on ticks and widely pilose hosts led us to hypothesise that ticks are mostly adapted to attachment and locomotion on rough, strongly corrugated and hairy, felt-like substrates. However, by using a combination of morphological and experimental approaches, we visualised the ultrastructure of attachment devices of Ixodes ricinus and showed that this species adheres more strongly to smooth surfaces than to rough ones. Between paired, elongated, curved, elastic claws, I. ricinus bears a large, flexible, foldable adhesive pad, which represents an adaptation to adhesion on smooth surfaces. Accordingly, ticks attached strongest to glass and to surface profiles similar to those of the human skin, generating safety factors (attachment force relative to body weight) up to 534 (females). Considerably lower attachment force was found on silicone substrates and as a result of thanatosis after jolting. PMID- 28566357 TI - Living with a leaky skin: upregulation of ion transport proteins during sloughing. AB - Amphibian skin is a multifunctional organ providing protection from the external environment and facilitating the physiological exchange of gases, water and salts with the environment. In order to maintain these functions, the outer layer of skin is regularly replaced in a process called sloughing. During sloughing, the outermost layer of the skin is removed in its entirety, which has the potential to interfere with skin permeability and ion transport, disrupting homeostasis. In this study, we measured, in vivo, the effects of sloughing on the cutaneous efflux of ions in toads Rhinella marina kept in freshwater conditions. We also measured transepithelial potential, cutaneous resistance, active ion transport and the distribution, abundance and gene expression of the key ion transport proteins sodium-potassium ATPase (NKA) and epithelial sodium channel (ENaC) during sloughing. We hypothesised that the increase in transepithelial efflux of ions during sloughing is a consequence of increased permeability and/or a reduction in the abundance or expression of cutaneous ion transport proteins, resulting in disruption of internal ion homeostasis. There was a significant increase in sodium and chloride efflux during sloughing in R. marina However, although in vitro skin resistance decreased after sloughing, active sodium transport increased commensurate with an increase in NKA and ENaC protein abundance in the skin. These changes in skin function associated with sloughing did not affect the maintenance of internal electrolyte homeostasis. These results suggest that during sloughing, amphibians actively maintain internal homeostasis by increasing cutaneous rates of ion uptake. PMID- 28566358 TI - Heat-resistant cytosolic malate dehydrogenases (cMDHs) of thermophilic intertidal snails (genus Echinolittorina): protein underpinnings of tolerance to body temperatures reaching 55 degrees C. AB - Snails of the genus Echinolittorina are among the most heat-tolerant animals; they experience average body temperatures near 41-44 degrees C in summer and withstand temperatures up to at least 55 degrees C. Here, we demonstrate that heat stability of function (indexed by the Michaelis-Menten constant of the cofactor NADH, KMNADH) and structure (indexed by rate of denaturation) of cytosolic malate dehydrogenases (cMDHs) of two congeners (E. malaccana and E. radiata) exceeds values previously found for orthologs of this protein from less thermophilic species. The ortholog of E. malaccana is more heat stable than that of E. radiata, in keeping with the congeners' thermal environments. Only two inter-congener differences in amino acid sequence in these 332 residue proteins were identified. In both cases (positions 48 and 114), a glycine in the E. malaccana ortholog is replaced by a serine in the E. radiata protein. To explore the relationship between structure and function and to characterize how amino acid substitutions alter stability of different regions of the enzyme, we used molecular dynamics simulation methods. These computational methods allow determination of thermal effects on fine-scale movements of protein components, for example, by estimating the root mean square deviation in atom position over time and the root mean square fluctuation for individual residues. The minor changes in amino acid sequence favor temperature-adaptive change in flexibility of regions in and around the active sites. Interspecific differences in effects of temperature on fine-scale protein movements are consistent with the differences in thermal effects on binding and rates of heat denaturation. PMID- 28566359 TI - Three Zika cases are found in India after random tests. PMID- 28566360 TI - Social Information Is Integrated into Value and Confidence Judgments According to Its Reliability. AB - How much we like something, whether it be a bottle of wine or a new film, is affected by the opinions of others. However, the social information that we receive can be contradictory and vary in its reliability. Here, we tested whether the brain incorporates these statistics when judging value and confidence. Participants provided value judgments about consumer goods in the presence of online reviews. We found that participants updated their initial value and confidence judgments in a Bayesian fashion, taking into account both the uncertainty of their initial beliefs and the reliability of the social information. Activity in dorsomedial prefrontal cortex tracked the degree of belief update. Analogous to how lower-level perceptual information is integrated, we found that the human brain integrates social information according to its reliability when judging value and confidence.SIGNIFICANCE STATEMENT The field of perceptual decision making has shown that the sensory system integrates different sources of information according to their respective reliability, as predicted by a Bayesian inference scheme. In this work, we hypothesized that a similar coding scheme is implemented by the human brain to process social signals and guide complex, value-based decisions. We provide experimental evidence that the human prefrontal cortex's activity is consistent with a Bayesian computation that integrates social information that differs in reliability and that this integration affects the neural representation of value and confidence. PMID- 28566361 TI - Effectiveness of alpha2agonists for sedation in paediatric critical care: study protocol for a retrospective cohort observational study. AB - INTRODUCTION: Mechanically ventilated children in paediatric intensive care units are commonly administered analgesics and sedative agents to minimise pain and distress and facilitate cooperation with medical interventions. Opioids and benzodiazepines are the most common analgesic and sedative agents but have safety concerns. The alpha2 agonists clonidine and dexmedetomidine are alternative sedatives in use despite neither having robust evidence to support their use. Studies evaluating effectiveness of alpha2 agonists to date have not focused on sedation-based outcomes instead focusing on opioid-sparing properties and ventilation outcomes. The aim of this study is to evaluate if an opioid-based sedation regimen, with an alpha2 agonist adjunct (clonidine or dexmedetomidine), produces a non-inferior proportion of time adequately sedated compared with a control group without an alpha2 agonist adjunct, while conferring potential additional benefits such as reduced opioid administration and less exposure to potential additional agents such as benzodiazepines. METHODS AND ANALYSIS: We will conduct a retrospective cohort study in two Irish paediatric intensive care units using clinical information on patient characteristics, sedation scores and drug use. Eligible children admitted between January 2014 and June 2016 who were mechanically ventilated and received an opioid infusion will be included. Patients will be categorised into two exposure categories (received an alpha2 agonist or did not receive an alpha2 agonist) and the time adequately sedated (measured using the COMFORT Behaviour Score) will be calculated using interpolation of nursing sedation scores at each recorded time point. At least 150 per group is planned for inclusion to ensure adequate study power. Propensity score matching will be used in analysis to account for potential confounding by indication. ETHICS AND DISSEMINATION: The study has been approved by the ethics committees of both hospitals. Dissemination will occur via local, national and international presentations for academic and healthcare audiences as well as through peer reviewed publications. PMID- 28566362 TI - Importance and added value of functional impairment to predict mortality: a cohort study in Swedish medical inpatients. AB - BACKGROUND: Accurate estimation of prognosis in multimorbid hospital patients could improve quality of care. This study aims to determine the relative importance and added value of a performance-based activities of daily living (ADL) measure with regard to mortality prediction. METHODS: 200 inpatients, aged over 60 years, were recruited at the Department of General Internal Medicine at a tertiary university hospital. Two nested survival models were built, one with established risk factors (age, sex, Charlson comorbidity index, haemoglobin, albumin, body mass index and glomerular filtration rate), and one using the same covariates with the Gottfries-Brane-Steen (GBS)-ADL measure added. The relative importance of GBS-ADL was evaluated in the full model. The added value of GBS-ADL was determined by comparing the nested models using four approaches: difference in overall chi2, discrimination, continuous net reclassification index (NRI >0) and integrated discrimination improvement (IDI). RESULTS: In the full model, GBS ADL was the single most important predictor of mortality (chi2-df=30, p<0.001). The likelihood ratio chi2 test showed significant added value of ADL (p<0.001). The C-statistic was 0.78 with ADL and 0.72 without (difference 0.058, 95% CI 0.022 to 0.094). The NRI >0 was 0.42 (95% CI 0.20 to 0.58) and IDI 0.15 (95% CI 0.07 to 0.22). CONCLUSIONS: Compared with a set of available clinical risk factors, impairment in ADL was a stronger predictor of all-cause mortality, showing substantial added value. Implementing quantitative ADL measurements could enable more appropriate and individual care for the elderly. PMID- 28566363 TI - Randomised healthcare policy evaluation of organised primary human papillomavirus screening of women aged 56-60. AB - OBJECTIVE: The aim of this research is to implement and reliably evaluate primary human papillomavirus (HPV) screening in an established and routinely running organised, large-scale population-based screening programme. PARTICIPANTS: Resident women in the Stockholm/Gotland region of Sweden, aged 56-60 years were randomised to either (1) screening with cervical cytology, with HPV test in triage of low-grade cytological abnormalities (old policy) or (2) screening with HPV testing, with cytology in triage of HPV positives (new policy). OUTCOME: The primary evaluation was the detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). RESULTS: During January 2012-May 2014, the organised screening programme sent 42 752 blinded invitations with a prebooked appointment time to the women in the target age group. 7325 women attended in the HPV policy arm and 7438 women attended in the cytology arm. In the new policy, the population HPV prevalence was 5.5%, using an accredited HPV test (Cobas 4800). HPV16 prevalence was 1.0% (73/7325) and HPV18 prevalence was 0.3% (22/7325). In the HPV policy arm, 78/405 (19%) HPV-positive women were also cytology positive. There were 19 cases of CIN2+ in histopathology, all among women who were both HPV positive and cytology positive. The positive predictive value for CIN2+ in this group was 33.3% (19/57). In the cytology policy, 153 women were cytology positive and there were 18 cases of CIN2+ in histopathology. Both the total number of cervical biopsies and the number of cervical biopsies with benign histopathology were much lower in thepositive predictive value policy (49 benign, 87 total vs 105 benign, 132 total). CONCLUSION: Primary HPV screening had a similar detection rate for CIN2+ as cytology-based screening, already before follow-up of HPV positive, cytology-negative women with new HPV test and referral of women with persistence. TRIAL REGISTRATION NUMBER: NCT01511328. PMID- 28566365 TI - Exploring an adapted Risk Behaviour Diagnosis Scale among Indigenous Australian women who had experiences of smoking during pregnancy: a cross-sectional survey in regional New South Wales, Australia. AB - OBJECTIVES: Explore Aboriginal women's responses to an adapted Risk Behaviour Diagnosis (RBD) Scale about smoking in pregnancy. METHODS AND DESIGN: An Aboriginal researcher interviewed women and completed a cross-sectional survey including 20 Likert scales. SETTING: Aboriginal Community Controlled Health Services, community groups and playgroups and Aboriginal Maternity Services in regional New South Wales, Australia. PARTICIPANTS: Aboriginal women (n=20) who were pregnant or gave birth in the preceding 18 months; included if they had experiences of smoking or quitting during pregnancy. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes: RBD constructs of perceived threat and perceived efficacy, dichotomised into high versus low. Women who had quit smoking, answered retrospectively. SECONDARY OUTCOME MEASURES: smoking status, intentions to quit smoking (danger control), protection responses (to babies/others) and fear control responses (denial/refutation). Scales were assessed for internal consistency. A chart plotted responses from low to high efficacy and low to high threat. RESULTS: RBD Scales had moderate-to-good consistency (0.67-0.89 Cronbach's alpha). Nine women had quit and 11 were smoking; 6 currently pregnant and 14 recently pregnant. Mean efficacy level 3.9 (SD=0.7); mean threat 4.3 (SD=0.7). On inspection, a scatter plot revealed a cluster of 12 women in the high efficacy-high threat quadrant-of these 11 had quit or had a high intention of quitting. Conversely, a group with low threat-low efficacy (5 women) were all smokers and had high fear control responses: of these, 4 had low protection responses. Pregnant women had a non-significant trend for higher threat and lower efficacy, than those previously pregnant. CONCLUSION: Findings were consistent with a previously validated RBD Scale showing Aboriginal smokers with high efficacy-high threat had greater intentions to quit smoking. The RBD Scale could have diagnostic potential to tailor health messages. Longitudinal research required with a larger sample to explore associations with the RBD Scale and quitting. PMID- 28566364 TI - Randomised trial of mitral valve repair with leaflet resection versus leaflet preservation on functional mitral stenosis (The CAMRA CardioLink-2 Trial). AB - BACKGROUND: The gold-standard treatment of severe mitral regurgitation (MR) due to degenerative disease is valve repair, which is surgically performed with either a leaflet resection or leaflet preservation approach. Recent data suggest that functional mitral stenosis (MS) may occur following valve repair using a leaflet resection strategy, which adversely affects patient prognosis. A randomised comparison of these two approaches to mitral repair on functional MS has not been conducted. METHODS AND ANALYSIS: This is a prospective, multicentre randomised controlled trial designed to test the hypothesis that leaflet preservation leads to better preservation of mitral valve geometry, and therefore, will be superior to leaflet resection for the primary outcome of functional MS as assessed by 12-month mean mitral valve gradient at peak exercise. Eighty-eight patients with posterior leaflet prolapse will be randomised intraoperatively once deemed by the operating surgeon to feasibly undergo mitral repair using either a leaflet resection or leaflet preservation approach. Secondary end points include comparison of repair strategies with regard to mitral valve orifice area, leaflet coaptation height, 6 min walk test and a composite major adverse event end point consisting of recurrent MR >=2+, death or hospital readmission for congestive heart failure within 12 months of surgery. ETHICS AND DISSEMINATION: Institutional ethics approval has been obtained from all enrolling sites. Overall, there remains clinical equipoise regarding the mitral valve repair strategy that is associated with the least likelihood of functional MS. This trial hopes to introduce high-quality evidence to help surgical decision making in this context. TRIAL REGISTRATION NUMBER: NCT02552771. PMID- 28566366 TI - Healthcare costs of asthma comorbidities: a systematic review protocol. AB - INTRODUCTION: Asthma is associated with many comorbid conditions that have the potential to impact on its management, control and outcomes. These comorbid conditions have the potential to impact on healthcare expenditure. We plan to undertake a systematic review to synthesise the evidence on the healthcare costs associated with asthma comorbidity. METHODS AND ANALYSIS: We will systematically search the following electronic databases between January 2000 and January 2017: National Health Service (NHS) Economic Evaluation Database, Google Scholar, Allied and Complementary Medicine Database (AMED), Global Health, PsychINFO, Medline, Embase, Institute for Scientific Information Web of Science and Cumulative Index to Nursing and Allied Health Literature. We will search the references in the identified studies for additional potential papers. Additional literature will be identified by contacting experts in the field and through searching of registers of ongoing studies. The review will include cost effectiveness and economic modelling/evaluation studies and analytical observational epidemiology studies that have investigated the healthcare costs of asthma comorbidity. Two reviewers will independently screen studies and extract relevant data from included studies. Methodological quality of epidemiological studies will be assessed using the Effective Public Health Practice Project tool, while that of economic evaluation studies will be assessed using the Drummond checklist. This protocol has been published in International Prospective Register of Systematic Reviews (PROSPERO) database (No. CRD42016051005). ETHICS AND DISSEMINATION: As there are no primary data collected, formal NHS ethical review is not necessary. The findings of this systematic review will be disseminated in a peer-reviewed journal and presented at relevant conferences. PROSPEROREGISTRATION NUMBER: CRD42016051005. PMID- 28566367 TI - Heme Oxygenase-1 Modulates Human Respiratory Syncytial Virus Replication and Lung Pathogenesis during Infection. AB - Human respiratory syncytial virus (hRSV) is the leading cause of severe lower respiratory tract infections in children. The development of novel prophylactic and therapeutic antiviral drugs against hRSV is imperative to control the burden of disease in the susceptible population. In this study, we examined the effects of inducing the activity of the host enzyme heme oxygenase-1 (HO-1) on hRSV replication and pathogenesis on lung inflammation induced by this virus. Our results show that after hRSV infection, HO-1 induction with metalloporphyrin cobalt protoporphyrin IX significantly reduces the loss of body weight due to hRSV-induced disease. Further, HO-1 induction also decreased viral replication and lung inflammation, as evidenced by a reduced neutrophil infiltration into the airways, with diminished cytokine and chemokine production and reduced T cell function. Concomitantly, upon cobalt protoporphyrin IX treatment, there is a significant upregulation in the production of IFN-alpha/beta mRNAs in the lungs. Furthermore, similar antiviral and protective effects occur by inducing the expression of human HO-1 in MHC class II+ cells in transgenic mice. Finally, in vitro data suggest that HO-1 induction can modulate the susceptibility of cells, especially the airway epithelial cells, to hRSV infection. PMID- 28566369 TI - T Cell-Mediated Humoral Immune Responses to Type 3 Capsular Polysaccharide of Streptococcus pneumoniae. AB - Most pathogenic bacteria express surface carbohydrates called capsular polysaccharides (CPSs). CPSs are important vaccine targets because they are easily accessible and recognizable by the immune system. However, CPS-specific adaptive humoral immune responses can only be achieved by the covalent conjugation of CPSs with carrier proteins to produce glycoconjugate vaccines. We previously described a mechanism by which a model glycoconjugate vaccine can activate the adaptive immune system and demonstrated that the mammalian CD4+ T cell repertoire contains a population of carbohydrate-specific T cells. In this study, we use glycoconjugates of type 3 Streptococcus pneumoniae CPS (Pn3P) to assess whether the carbohydrate-specific adaptive immune response exemplified in our previous study can be applied to the conjugates of this lethal pathogen. In this article, we provide evidence for the functional roles of Pn3P-specific CD4+ T cells utilizing mouse immunization schemes that induce Pn3P-specific IgG responses in a carbohydrate-specific T cell-dependent manner. PMID- 28566370 TI - Enhanced Effector Functions Due to Antibody Defucosylation Depend on the Effector Cell Fcgamma Receptor Profile. AB - Abs of the IgG isotype are glycosylated in their Fc domain at a conserved asparagine at position 297. Removal of the core fucose of this glycan greatly increases the affinity for FcgammaRIII, resulting in enhanced FcgammaRIII mediated effector functions. Normal plasma IgG contains ~94% fucosylated Abs, but alloantibodies against, for example, Rhesus D (RhD) and platelet Ags frequently have reduced fucosylation that enhances their pathogenicity. The increased FcgammaRIII-mediated effector functions have been put to use in various afucosylated therapeutic Abs in anticancer treatment. To test the functional consequences of Ab fucosylation, we produced V-gene-matched recombinant anti-RhD IgG Abs of the four different subclasses (IgG1-4) with and without core fucose (i.e., 20% fucose remaining). Binding to all human FcgammaR types and their functional isoforms was assessed with surface plasmon resonance. All hypofucosylated anti-RhD IgGs of all IgG subclasses indeed showed enhanced binding affinity for isolated FcgammaRIII isoforms, without affecting binding affinity to other FcgammaRs. In contrast, when testing hypofucosylated anti-RhD Abs with FcgammaRIIIa-expressing NK cells, a 12- and 7-fold increased erythrocyte lysis was observed with the IgG1 and IgG3, respectively, but no increase with IgG2 and IgG4 anti-RhD Abs. Notably, none of the hypofucosylated IgGs enhanced effector function of macrophages, which, in contrast to NK cells, express a complex set of FcgammaRs, including FcgammaRIIIa. Our data suggest that the beneficial effects of afucosylated biologicals for clinical use can be particularly anticipated when there is a substantial involvement of FcgammaRIIIa expressing cells, such as NK cells. PMID- 28566368 TI - Caspofungin Increases Fungal Chitin and Eosinophil and gammadelta T Cell Dependent Pathology in Invasive Aspergillosis. AB - The polysaccharide-rich fungal cell wall provides pathogen-specific targets for antifungal therapy and distinct molecular patterns that stimulate protective or detrimental host immunity. The echinocandin antifungal caspofungin inhibits synthesis of cell wall beta-1,3-glucan and is used for prophylactic therapy in immune-suppressed individuals. However, breakthrough infections with fungal pathogen Aspergillus fumigatus are associated with caspofungin prophylaxis. In this study, we report in vitro and in vivo increases in fungal surface chitin in A. fumigatus induced by caspofungin that was associated with airway eosinophil recruitment in neutropenic mice with invasive pulmonary aspergillosis (IA). More importantly, caspofungin treatment of mice with IA resulted in a pattern of increased fungal burden and severity of disease that was reversed in eosinophil deficient mice. Additionally, the eosinophil granule proteins major basic protein and eosinophil peroxidase were more frequently detected in the bronchoalveolar lavage fluid of lung transplant patients diagnosed with IA that received caspofungin therapy when compared with azole-treated patients. Eosinophil recruitment and inhibition of fungal clearance in caspofungin-treated mice with IA required RAG1 expression and gammadelta T cells. These results identify an eosinophil-mediated mechanism for paradoxical caspofungin activity and support the future investigation of the potential of eosinophil or fungal chitin-targeted inhibition in the treatment of IA. PMID- 28566372 TI - Occludin Expression in Epidermal gammadelta T Cells in Response to Epidermal Stress Causes Them To Migrate into Draining Lymph Nodes. AB - Epidermal gammadelta T cells that reside in the front line of the skin play a pivotal role in stress immune surveillance. However, it is not clear whether these cells are involved in further induction of immune responses after they are activated in dysregulated epidermis. In this study, we found that activated gammadelta T cells expressed occludin and migrated into draining lymph nodes in an occludin-dependent manner. Epidermal gammadelta T cells in occludin-deficient mice exhibited impairments in morphology changes and motility, although they expressed activation markers at levels comparable to those in wild-type cells. Occludin deficiency weakened the induction of allergen-induced contact hypersensitivity, primarily as the result of the impaired migration of epidermal gammadelta T cells. Thus, occludin expression by epidermal gammadelta T cells upon activation in response to epidermal stress allows them to move, which could be important for augmentation of immune responses via collaboration with other cells. PMID- 28566371 TI - Single-Cell RNA Sequencing Reveals Expanded Clones of Islet Antigen-Reactive CD4+ T Cells in Peripheral Blood of Subjects with Type 1 Diabetes. AB - The significance of islet Ag-reactive T cells found in peripheral blood of type 1 diabetes (T1D) subjects is unclear, partly because similar cells are also found in healthy control (HC) subjects. We hypothesized that key disease-associated cells would show evidence of prior Ag exposure, inferred from expanded TCR clonotypes, and essential phenotypic properties in their transcriptomes. To test this, we developed single-cell RNA sequencing procedures for identifying TCR clonotypes and transcript phenotypes in individual T cells. We applied these procedures to analysis of islet Ag-reactive CD4+ memory T cells from the blood of T1D and HC individuals after activation with pooled immunodominant islet peptides. We found extensive TCR clonotype sharing in Ag-activated cells, especially from individual T1D subjects, consistent with in vivo T cell expansion during disease progression. The expanded clonotype from one T1D subject was detected at repeat visits spanning >15 mo, demonstrating clonotype stability. Notably, we found no clonotype sharing between subjects, indicating a predominance of "private" TCR specificities. Expanded clones from two T1D subjects recognized distinct IGRP peptides, implicating this molecule as a trigger for CD4+ T cell expansion. Although overall transcript profiles of cells from HC and T1D subjects were similar, profiles from the most expanded clones were distinctive. Our findings demonstrate that islet Ag-reactive CD4+ memory T cells with unique Ag specificities and phenotypes are expanded during disease progression and can be detected by single-cell analysis of peripheral blood. PMID- 28566373 TI - Vimentin Modulates Infectious Internalization of Human Papillomavirus 16 Pseudovirions. AB - Human papillomavirus (HPV) infection is the most common viral infection of the reproductive tract, with virtually all cases of cervical cancer being attributable to infection by oncogenic HPVs. However, the exact mechanism and receptors used by HPV to infect epithelial cells are controversial. The current entry model suggests that HPV initially attaches to heparan sulfate proteoglycans (HSPGs) at the cell surface, followed by conformational changes, cleavage by furin convertase, and subsequent transfer of the virus to an as-yet-unidentified high-affinity receptor. In line with this model, we established an in vitro infection system using the HSPG-deficient cell line pgsD677 together with HPV16 pseudovirions (HPV16-PsVs). While pgsD677 cells were nonpermissive for untreated HPV16-PsVs, furin cleavage of the particles led to a substantial increase in infection. Biochemical pulldown assays followed by mass spectrometry analysis showed that furin-precleaved HPV16-PsVs specifically interacted with surface expressed vimentin on pgsD677 cells. We further demonstrated that both furin precleaved and uncleaved HPV16-PsVs colocalized with surface-expressed vimentin on pgsD677, HeLa, HaCaT, and NIKS cells, while binding of incoming viral particles to soluble vimentin protein before infection led to a substantial decrease in viral uptake. Interestingly, decreasing cell surface vimentin by small interfering RNA (siRNA) knockdown in HeLa and NIKS cells significantly increased HPV16-PsV infectious internalization, while overexpression of vimentin had the opposite effect. The identification of vimentin as an HPV restriction factor enhances our understanding of the initial steps of HPV-host interaction and may lay the basis for the design of novel antiviral drugs preventing HPV internalization into epithelial cells.IMPORTANCE Despite HPV being a highly prevalent sexually transmitted virus causing significant disease burden worldwide, particularly cancer of the cervix, cell surface events preceding oncogenic HPV internalization are poorly understood. We herein describe the identification of surface-expressed vimentin as a novel molecule not previously implicated in the infectious internalization of HPV16. Contrary to our expectations, vimentin was found to act not as a receptor but rather as a restriction factor dampening the initial steps of HPV16 infection. These results importantly contribute to our current understanding of the molecular events during the infectious internalization of HPV16 and open a new direction in the development of alternative drugs to prevent HPV infection. PMID- 28566374 TI - The SAT Protein of Porcine Parvovirus Accelerates Viral Spreading through Induction of Irreversible Endoplasmic Reticulum Stress. AB - The SAT protein (SATp) of porcine parvovirus (PPV) accumulates in the endoplasmic reticulum (ER), and SAT deletion induces the slow-spreading phenotype. The in vitro comparison of the wild-type Kresse strain and its SAT knockout (SAT-) mutant revealed that prolonged cell integrity and late viral release are responsible for the slower spreading of the SAT- virus. During PPV infection, regardless of the presence or absence of SATp, the expression of downstream ER stress response proteins (Xbp1 and CHOP) was induced. However, in the absence of SATp, significant differences in the quantity and the localization of CHOP were detected, suggesting a role of SATp in the induction of irreversible ER stress in infected cells. The involvement of the induction of irreversible ER stress in porcine testis (PT) cell necrosis and viral egress was confirmed by treatment of infected cells by ER stress-inducing chemicals (MG132, dithiothreitol, and thapsigargin), which accelerated the egress and spreading of both the wild-type and the SAT- viruses. UV stress induction had no beneficial effect on PPV infection, underscoring the specificity of ER stress pathways in the process. However, induction of CHOP and its nuclear translocation cannot alone be responsible for the biological effect of SAT, since nuclear CHOP could not complement the lack of SAT in a coexpression experiment.IMPORTANCE SATp is encoded by an alternative open reading frame of the PPV genome. Earlier we showed that SATp of the attenuated PPV NADL-2 strain accumulates in the ER and accelerates virus release and spreading. Our present work revealed that slow spreading is a general feature of SAT- PPVs and is the consequence of prolonged cell integrity. PPV infection induced ER stress in infected cells regardless of the presence of SATp, as demonstrated by the morphological changes of the ER and expression of the stress response proteins Xbp1 and CHOP. However, the presence of SATp made the ER stress more severe and accelerated cell death during infection, as shown by the higher rate of expression of CHOP and alteration of the localization of CHOP. The beneficial effect of irreversible ER stress on PPV spread was confirmed by treatment of infected cells with ER stress-inducing chemicals. PMID- 28566375 TI - Rapid Engineering of Foot-and-Mouth Disease Vaccine and Challenge Viruses. AB - There are seven antigenically distinct serotypes of foot-and-mouth disease virus (FMDV), each of which has intratypic variants. In the present study, we have developed methods to efficiently generate promising vaccines against seven serotypes or subtypes. The capsid-encoding gene (P1) of the vaccine strain O1/Manisa/Turkey/69 was replaced with the amplified or synthetic genes from the O, A, Asia1, C, SAT1, SAT2, and SAT3 serotypes. Viruses of the seven serotype were rescued successfully. Each chimeric FMDV with a replacement of P1 showed serotype-specific antigenicity and varied in terms of pathogenesis in pigs and mice. Vaccination of pigs with an experimental trivalent vaccine containing the inactivated recombinants based on the main serotypes O, A, and Asia1 effectively protected them from virus challenge. This technology could be a potential strategy for a customized vaccine with challenge tools to protect against epizootic disease caused by specific serotypes or subtypes of FMDV.IMPORTANCE Foot-and-mouth disease (FMD) virus (FMDV) causes significant economic losses. For vaccine preparation, the selection of vaccine strains was complicated by high antigenic variation. In the present study, we suggested an effective strategy to rapidly prepare and evaluate mass-produced customized vaccines against epidemic strains. The P1 gene encoding the structural proteins of the well-known vaccine virus was replaced by the synthetic or amplified genes of viruses of seven representative serotypes. These chimeric viruses generally replicated readily in cell culture and had a particle size similar to that of the original vaccine strain. Their antigenicity mirrored that of the original serotype from which their P1 gene was derived. Animal infection experiments revealed that the recombinants varied in terms of pathogenicity. This strategy will be a useful tool for rapidly generating customized FMD vaccines or challenge viruses for all serotypes, especially for FMD-free countries, which have prohibited the import of FMDVs. PMID- 28566377 TI - Structural Insight into Nucleoprotein Conformation Change Chaperoned by VP35 Peptide in Marburg Virus. AB - Marburg virus (MARV) encodes a nucleoprotein (NP) to encapsidate its genome by oligomerization and form a ribonucleoprotein complex (RNP). According to previous investigation on nonsegmented negative-sense RNA viruses (nsNSV), the newly synthesized NPs must be prevented from indiscriminately binding to noncognate RNAs. During the viral RNA synthesis process, the RNPs undergo a transition from an RNA-bound form to a template-free form, to open access for the interaction between the viral polymerase and the RNA template. In filoviruses, this transition is regulated by VP35 peptide and other viral components. To further understand the dynamic process of filovirus RNP formation, we report here the structure of MARV NPcore, both in the apo form and in the VP35 peptide-chaperoned form. These structures reveal a typical bilobed structure, with a positive charged RNA binding groove between two lobes. In the apo form, the MARV NP exists in an interesting hexameric state formed by the hydrophobic interaction within the long helix of the NPcore C-terminal region, which shows high structural flexibility among filoviruses and may imply critical function during RNP formation. Moreover, the VP35 peptide-chaperoned NPcore remains in a monomeric state and completely loses its affinity for single-stranded RNA (ssRNA). The structural comparison reveals that the RNA binding groove undergoes a transition from closed state to open state, chaperoned by VP35 peptide, thus preventing the interaction for viral RNA. Our investigation provides considerable structural insight into the filovirus RNP working mechanism and may support the development of antiviral therapies targeting the RNP formation of filovirus.IMPORTANCE Marburg virus is one of the most dangerous viruses, with high morbidity and mortality. A recent outbreak in Angola in 2005 caused the deaths of 272 persons. NP is one of the most essential proteins, as it encapsidates and protects the whole virus genome simultaneously with self-assembly oligomerization. Here we report the structures of MARV NPcore in two different forms. In the MARV NP apo form, we identify an interesting hexamer formed by hydrophobic interaction within a long helix, which is highly conserved and flexible among filoviruses and may indicate its critical function during the virus RNP formation. Moreover, the structural comparison with the NP-VP35 peptide complex reveals a structural transition chaperoned by VP35, in which the RNA binding groove undergoes a transition from closed state to open state. Finally, we discussed the high conservation and critical role of the VP35 binding pocket and its potential use for therapeutic development. PMID- 28566376 TI - Ruxolitinib and Polycation Combination Treatment Overcomes Multiple Mechanisms of Resistance of Pancreatic Cancer Cells to Oncolytic Vesicular Stomatitis Virus. AB - Vesicular stomatitis virus (VSV) is a promising oncolytic virus (OV). Although VSV is effective against a majority of pancreatic ductal adenocarcinoma cell (PDAC) cell lines, some PDAC cell lines are highly resistant to VSV, and the mechanisms of resistance are still unclear. JAK1/2 inhibitors (such as ruxolitinib and JAK inhibitor I) strongly stimulate VSV replication and oncolysis in all resistant cell lines but only partially improve the susceptibility of resistant PDACs to VSV. VSV tumor tropism is generally dependent on the permissiveness of malignant cells to viral replication rather than on receptor specificity, with several ubiquitously expressed cell surface molecules playing a role in VSV attachment to host cells. However, as VSV attachment to PDAC cells has never been tested before, here we examined if it was possibly inhibited in resistant PDAC cells. Our data show a dramatically weaker attachment of VSV to HPAF-II cells, the most resistant human PDAC cell line. Although sequence analysis of low-density lipoprotein (LDL) receptor (LDLR) mRNA did not reveal any amino acid substitutions in this cell line, HPAF-II cells displayed the lowest level of LDLR expression and dramatically lower LDL uptake. Treatment of cells with various statins strongly increased LDLR expression levels but did not improve VSV attachment or LDL uptake in HPAF-II cells. However, LDLR-independent attachment of VSV to HPAF-II cells was dramatically improved by treating cells with Polybrene or DEAE-dextran. Moreover, combining VSV with ruxolitinib and Polybrene or DEAE-dextran successfully broke the resistance of HPAF-II cells to VSV by simultaneously improving VSV attachment and replication.IMPORTANCE Oncolytic virus (OV) therapy is an anticancer approach that uses viruses that selectively infect and kill cancer cells. This study focuses on oncolytic vesicular stomatitis virus (VSV) against pancreatic ductal adenocarcinoma (PDAC) cells. Although VSV is effective against most PDAC cells, some are highly resistant to VSV, and the mechanisms are still unclear. Here we examined if VSV attachment to cells was inhibited in resistant PDAC cells. Our data show very inefficient attachment of VSV to the most resistant human PDAC cell line, HPAF II. However, VSV attachment to HPAF-II cells was dramatically improved by treating cells with polycations. Moreover, combining VSV with polycations and ruxolitinib (which inhibits antiviral signaling) successfully broke the resistance of HPAF-II cells to VSV by simultaneously improving VSV attachment and replication. We envision that this novel triple-combination approach could be used in the future to treat PDAC tumors that are highly resistant to OV therapy. PMID- 28566378 TI - Critical Role for Monocytes/Macrophages in Rapid Progression to AIDS in Pediatric Simian Immunodeficiency Virus-Infected Rhesus Macaques. AB - Infant humans and rhesus macaques infected with the human or simian immunodeficiency virus (HIV or SIV), respectively, express higher viral loads and progress more rapidly to AIDS than infected adults. Activated memory CD4+ T cells in intestinal tissues are major primary target cells for SIV/HIV infection, and massive depletion of these cells is considered a major cause of immunodeficiency. Monocytes and macrophages are important cells of innate immunity and also are targets of HIV/SIV infection. We reported previously that a high peripheral blood monocyte turnover rate was predictive for the onset of disease progression to AIDS in SIV-infected adult macaques. The purpose of this study was to determine if earlier or higher infection of monocytes/macrophages contributes to the more rapid progression to AIDS in infants. We observed that uninfected infant rhesus macaques exhibited higher physiologic baseline monocyte turnover than adults. Early after SIV infection, the monocyte turnover further increased, and it remained high during progression to AIDS. A high percentage of terminal deoxynucleotidyltransferase dUTP nick end label (TUNEL)-positive macrophages in the lymph nodes (LNs) and intestine corresponded with an increasing number of macrophages derived from circulating monocytes (bromodeoxyuridine positive [BrdU+] CD163+), suggesting that the increased blood monocyte turnover was required to rapidly replenish destroyed tissue macrophages. Immunofluorescence analysis further demonstrated that macrophages were a significant portion of the virus-producing cells found in LNs, intestinal tissues, and lungs. The higher baseline monocyte turnover in infant macaques and subsequent macrophage damage by SIV infection may help explain the basis of more rapid disease progression to AIDS in infants.IMPORTANCE HIV infection progresses much more rapidly in pediatric cases than in adults; however, the mechanism for this difference is unclear. Using the rhesus macaque model, this work was performed to address why infants infected with SIV progress more quickly to AIDS than do adults. Earlier we reported that in adult rhesus macaques, increasing monocyte turnover reflected tissue macrophage damage by SIV and was predictive of terminal disease progression to AIDS. Here we report that uninfected infant rhesus macaques exhibited a higher physiological baseline monocyte turnover rate than adults. Furthermore, once infected with SIV, infants displayed further increased monocyte turnover that may have facilitated the accelerated progression to AIDS. These results support a role for monocytes and macrophages in the pathogenesis of SIV/HIV and begin to explain why infants are more prone to rapid disease progression. PMID- 28566379 TI - Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly. AB - Chronic hepatitis B virus (HBV) infection is a global public health problem. Although the currently approved medications can reliably reduce the viral load and prevent the progression of liver diseases, they fail to cure the viral infection. In an effort toward discovery of novel antiviral agents against HBV, a group of benzamide (BA) derivatives that significantly reduced the amount of cytoplasmic HBV DNA were discovered. The initial lead optimization efforts identified two BA derivatives with improved antiviral activity for further mechanistic studies. Interestingly, similar to our previously reported sulfamoylbenzamides (SBAs), the BAs promote the formation of empty capsids through specific interaction with HBV core protein but not other viral and host cellular components. Genetic evidence suggested that both SBAs and BAs inhibited HBV nucleocapsid assembly by binding to the heteroaryldihydropyrimidine (HAP) pocket between core protein dimer-dimer interfaces. However, unlike SBAs, BA compounds uniquely induced the formation of empty capsids that migrated more slowly in native agarose gel electrophoresis from A36V mutant than from the wild type core protein. Moreover, we showed that the assembly of chimeric capsids from wild-type and drug-resistant core proteins was susceptible to multiple capsid assembly modulators. Hence, HBV core protein is a dominant antiviral target that may suppress the selection of drug-resistant viruses during core protein targeting antiviral therapy. Our studies thus indicate that BAs are a chemically and mechanistically unique type of HBV capsid assembly modulators and warranted for further development as antiviral agents against HBV.IMPORTANCE HBV core protein plays essential roles in many steps of the viral replication cycle. In addition to packaging viral pregenomic RNA (pgRNA) and DNA polymerase complex into nucleocapsids for reverse transcriptional DNA replication to take place, the core protein dimers, existing in several different quaternary structures in infected hepatocytes, participate in and regulate HBV virion assembly, capsid uncoating, and covalently closed circular DNA (cccDNA) formation. It is anticipated that small molecular core protein assembly modulators may disrupt one or multiple steps of HBV replication, depending on their interaction with the distinct quaternary structures of core protein. The discovery of novel core protein-targeting antivirals, such as benzamide derivatives reported here, and investigation of their antiviral mechanism may lead to the identification of antiviral therapeutics for the cure of chronic hepatitis B. PMID- 28566380 TI - Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage. AB - Seneca Valley virus (SVV) is an oncolytic RNA virus belonging to the Picornaviridae family. Its nucleotide sequence is highly similar to those of members of the Cardiovirus genus. SVV is also a neuroendocrine cancer-selective oncolytic picornavirus that can be used for anticancer therapy. However, the interaction between SVV and its host is yet to be fully characterized. In this study, SVV inhibited antiviral type I interferon (IFN) responses by targeting different host adaptors, including mitochondrial antiviral signaling (MAVS), Toll/interleukin 1 (IL-1) receptor domain-containing adaptor inducing IFN-beta (TRIF), and TRAF family member-associated NF-kappaB activator (TANK), via viral 3C protease (3Cpro). SVV 3Cpro mediated the cleavage of MAVS, TRIF, and TANK at specific sites, which required its protease activity. The cleaved MAVS, TRIF, and TANK lost the ability to regulate pattern recognition receptor (PRR)-mediated IFN production. The cleavage of TANK also facilitated TRAF6-induced NF-kappaB activation. SVV was also found to be sensitive to IFN-beta. Therefore, SVV suppressed antiviral IFN production to escape host antiviral innate immune responses by cleaving host adaptor molecules.IMPORTANCE Host cells have developed various defenses against microbial pathogen infection. The production of IFN is the first line of defense against microbial infection. However, viruses have evolved many strategies to disrupt this host defense. SVV, a member of the Picornavirus genus, is an oncolytic virus that shows potential functions in anticancer therapy. It has been demonstrated that IFN can be used in anticancer therapy for certain tumors. However, the relationship between oncolytic virus and innate immune response in anticancer therapy is still not well known. In this study, we showed that SVV has evolved as an effective mechanism to inhibit host type I IFN production by using its 3Cpro to cleave the molecules MAVS, TRIF, and TANK directly. These molecules are crucial for the Toll-like receptor 3 (TLR3) mediated and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated signaling pathway. We also found that SVV is sensitive to IFN-beta. These findings increase our understanding of the interaction between SVV and host innate immunity. PMID- 28566381 TI - Hepatitis C Virus Subverts Human Choline Kinase-alpha To Bridge Phosphatidylinositol-4-Kinase IIIalpha (PI4KIIIalpha) and NS5A and Upregulates PI4KIIIalpha Activation, Thereby Promoting the Translocation of the Ternary Complex to the Endoplasmic Reticulum for Viral Replication. AB - In this study, we elucidated the mechanism by which human choline kinase-alpha (hCKalpha) interacts with nonstructural protein 5A (NS5A) and phosphatidylinositol-4-kinase IIIalpha (PI4KIIIalpha), the lipid kinase crucial for maintaining the integrity of virus-induced membranous webs, and modulates hepatitis C virus (HCV) replication. hCKalpha activity positively modulated phosphatidylinositol-4-phosphate (PI4P) levels in HCV-expressing cells, and hCKalpha-mediated PI4P accumulation was abolished by AL-9, a PI4KIIIalpha specific inhibitor. hCKalpha colocalized with NS5A and PI4KIIIalpha or PI4P; NS5A expression increased hCKalpha and PI4KIIIalpha colocalization; and hCKalpha formed a ternary complex with PI4KIIIalpha and NS5A, supporting the functional interplay of hCKalpha with PI4KIIIalpha and NS5A. PI4KIIIalpha inactivation by AL 9 or hCKalpha inactivation by CK37, a specific hCKalpha inhibitor, impaired the endoplasmic reticulum (ER) localization and colocalization of these three molecules. Interestingly, hCKalpha knockdown or inactivation inhibited PI4KIIIalpha-NS5A binding. In an in vitro PI4KIIIalpha activity assay, hCKalpha activity slightly increased PI4KIIIalpha basal activity but greatly augmented NS5A-induced PI4KIIIalpha activity, supporting the essential role of ternary complex formation in robust PI4KIIIalpha activation. Concurring with the upregulation of PI4P production and viral replication, overexpression of active hCKalpha-R (but not the D288A mutant) restored PI4KIIIalpha and NS5A translocation to the ER in hCKalpha stable knockdown cells. Furthermore, active PI4KIIIalpha overexpression restored PI4P production, PI4KIIIalpha and NS5A translocation to the ER, and viral replication in CK37-treated cells. Based on our results, hCKalpha functions as an indispensable regulator that bridges PI4KIIIalpha and NS5A and potentiates NS5A-stimulated PI4KIIIalpha activity, which then facilitates the targeting of the ternary complex to the ER for viral replication.IMPORTANCE The mechanisms by which hCKalpha activity modulates the transport of the hCKalpha-NS5A complex to the ER are not understood. In the present study, we investigated how hCKalpha interacts with PI4KIIIalpha (a key element that maintains the integrity of the "membranous web" structure) and NS5A to regulate viral replication. We demonstrated that HCV hijacks hCKalpha to bridge PI4KIIIalpha and NS5A, forming a ternary complex, which then stimulates PI4KIIIalpha activity to produce PI4P. Pronounced PI4P synthesis then redirects the translocation of the ternary complex to the ER-derived, PI4P-enriched membrane for assembly of the viral replication complex and viral replication. Our study provides novel insights into the indispensable modulatory role of hCKalpha in the recruitment of PI4KIIIalpha to NS5A and in NS5A-stimulated PI4P production and reveals a new perspective for understanding the impact of profound PI4KIIIalpha activation on the targeting of PI4KIIIalpha and NS5A to the PI4P enriched membrane for viral replication complex formation. PMID- 28566385 TI - Correction. PMID- 28566384 TI - The number of target molecules of the amplification step limits accuracy and sensitivity in ultra deep sequencing viral population studies. AB - The invention of next generation sequencing techniques (NGS) marked the coming of a new era in the detection of genetic diversity of intra-host viral populations. A good understanding of the genetic structure of these populations first requires being able to identify the different isolates or variants, and second to accurately quantify them. However, the initial amplification step of NGS studies can impose potential quantitative biases modifying the variant relative frequencies. In particular, the number of target molecules (NTM) used during the amplification step is vastly overlooked, though of primary importance as it sets the limit of the accuracy and the sensitivity of the sequencing procedure. In the present article, we investigated quantitative biases in the NGS study of populations of a multipartite ssDNA virus at different steps of the procedure. We studied 20 independent populations of the ssDNA Faba Bean Necrotic Stunt Virus (FBNSV) virus in two host plants, Faba bean and Medicago. The FBNSV is a multipartite virus composed of eight genomic segments, whose specific and host dependent relative frequencies are defined as the "genome formula". Our results show significant distortion of the FBNSV genome formula after the amplification and the sequencing steps. We also quantified the genetic bottleneck occurring at the amplification step by documenting the NTM of two genomic segments of the FBNSV. We argue that the NTM must be documented and carefully considered when interpreting the sensitivity and accuracy of NGS studies.Importance The advent of next generation sequencing techniques (NGS) now enables studying the genetic diversity of viral populations. A good understanding of the genetic structure of these populations first requires being able to identify the different isolates or variants, and second to accurately quantify them. Prior to sequencing, viral genomes need to be amplified, a step that potentially imposes quantitative biases and modifies the viral population structure. In particular, the number of target molecules (NTM) used during the amplification step is of primary importance as it sets the limit of the accuracy and the sensitivity of the sequencing procedure. In this work, we used 20 replicated populations of the multipartite Faba Bean Necrotic Stunt Virus (FBNSV) to estimate the various limitations of ultra deep sequencing studies performed on intra-host viral populations. We report quantitative biases during Rolling Circle Amplification and the NTM of two genomic segments of the FBNSV. PMID- 28566382 TI - Human papillomavirus major capsid protein L1 remains associated with the incoming viral genome throughout the entry process. AB - During infectious entry, acidification within the endosome triggers uncoating of the HPV capsid whereupon host cyclophilins facilitate the release of most of the major capsid protein, L1, from the minor capsid protein L2 and the viral genome. The L2/DNA complex traffics to the trans-Golgi network (TGN). Following the onset of mitosis, HPV-harboring transport vesicles bud from the TGN followed by association with mitotic chromosomes. During this time, the HPV genome remains in a vesicular compartment until the nucleus has completely reformed. Recent data suggests that while most of L1 protein dissociates and is degraded in the endosome, some L1 protein remains associated with the viral genome. The L1 protein has DNA binding activity and L2 protein has multiple domains capable of interacting with L1 capsomeres. In this study, we report that some L1 protein traffics with L2 and viral genome to the nucleus. The accompanying L1 protein is mostly full-length and retains conformation-dependent epitopes, which are recognized by neutralizing antibodies. Since more than one L1 molecule contributes to these epitopes and require assembly into capsomeres, we propose that L1 protein is present in form of pentamers. Furthermore, we provide evidence that L1 protein interacts directly with viral DNA within the capsid. Based on our findings, we propose that the L1 protein, likely arranged as capsomeres, stabilizes the viral genome within the subviral complex during intracellular trafficking.IMPORTANCE After internalization, the non-enveloped human papillomavirus virion uncoats in the endosome whereupon conformational changes result in a dissociation of a subset of the major capsid protein L1 from the minor capsid protein L2, which remains in complex with the viral DNA. Recent data suggests that some L1 protein may accompany the viral genome beyond the endosomal compartment. Herein, we demonstrate that conformationally intact L1 protein, likely still arranged as capsomeres, remains associated with the incoming viral genome throughout mitosis and transiently resides in the nucleus until after the viral DNA is released from the transport vesicle. PMID- 28566383 TI - Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation. AB - Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block B cell receptor (BCR) signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction. Further investigation shows that mammalian target of rapamycin complex 2 (mTORC2) contributes to BCR-mediated lytic induction and that FK506-binding protein 12 (FKBP12) binding alone is not adequate to block activation. Finally, we show that BCR signaling can activate EBV lytic induction in freshly isolated B cells from peripheral blood mononuclear cells (PBMCs) and that activation can be inhibited by ibrutinib or idelalisib.IMPORTANCE EBV establishes viral latency in B cells. Activation of the B cell receptor pathway activates lytic viral expression in cell lines. Here we show that drugs that inhibit important kinases in the BCR signaling pathway inhibit activation of lytic viral expression but do not inhibit several other lytic activation pathways. Immunosuppressant drugs such as cyclosporine and tacrolimus but not rapamycin also inhibit BCR-mediated EBV activation. Finally, we show that BCR activation of lytic infection occurs not only in tumor cell lines but also in freshly isolated B cells from patients and that this activation can be blocked by BCR inhibitors. PMID- 28566386 TI - Cost and efficacy examination of alvimopan for the prevention of postoperative ileus. AB - Opioid analgesics exacerbate ileus through peripheral MU-opioid receptor action. Alvimopan, a MU-opioid receptor antagonist, has been proposed to alleviate postoperative ileus, leading to decreased time to return of gastrointestinal function and hospital discharge. As opioid-induced motility issues are only one factor affecting postoperative ileus, continued examination of the cost of the use and efficacy of the drug is needed. Data for this study were collected retrospectively from the charts of 55 patients who received an anastomosis and were given alvimopan at Morristown Medical Center between 2010 and 2013 as well as from 58 appropriately matched controls. The billing record and chart for each patient was examined, and information on total hospital charges, age, sex, body mas index, primary diagnosis, procedure type, length of stay (days), time to return of bowel function (hours), and outcomes were recorded for analysis. No difference between patients given alvimopan and controls was observed for the length of hospital stay (4.6 vs 4.8 days) or for time to return of bowel function (68.5 vs 67.3 hours). Total hospital charges were higher for treated patients (p=0.0080), averaging $48 705.15 and $41 068.80, respectively. Alvimopan was not associated with improved clinical outcome but was associated with an increase in hospital charges within this population. PMID- 28566387 TI - Acetabular dysplasia: multiple pathologies and myriad solutions. PMID- 28566388 TI - Magnetically controlled growing rods in the treatment of early-onset scoliosis: a note of caution. AB - The MAGnetic Expansion Control (MAGEC) system is used increasingly in the management of early-onset scoliosis. Good results have been published, but there have been recent reports identifying implant failures that may be associated with significant metallosis surrounding the implants. This article aims to present the current knowledge regarding the performance of this implant, and the potential implications and strategies that may be employed to identify and limit any problems. We urge surgeons to apply caution to patient and construct selection; engage in prospective patient registration using a spine registry; ensure close clinical monitoring until growth has ceased; and send all explanted MAGEC rods for independent analysis. The MAGEC system may be a good instrumentation system for the treatment of early-onset scoliosis. However, it is innovative and like all new technology, especially when deployed in a paediatric population, robust systems to assess long-term outcome are required to ensure that patient safety is maintained. Cite this article: Bone Joint J 2017;99-B:708-13. PMID- 28566389 TI - Does the type of graft affect the outcome of revision anterior cruciate ligament reconstruction? a meta-analysis of 32 studies. AB - AIMS: Our aim was to perform a meta-analysis of the outcomes of revision anterior cruciate ligament (ACL) reconstruction, comparing the use of different types of graft. MATERIALS AND METHODS: A search was performed of Medline and Pubmed using the terms "Anterior Cruciate Ligament" and "ACL" combined with "revision", "re operation" and "failure". Only studies that reported the outcome at a minimum follow-up of two years were included. Two authors reviewed the papers, and outcomes were subdivided into autograft and allograft. Autograft was subdivided into hamstring (HS) and bone-patellar tendon-bone (BPTB). Subjective and objective outcome measures were analysed and odds ratios with confidence intervals were calculated. RESULTS: A total of 32 studies met the inclusion criteria. Five studies used HS autografts, eight reported using BPTB autografts, two used quadriceps tendon autografts and eight used various types. Seven studies reported using allografts, while the two remaining used both BPTB autografts and allografts. Overall, 1192 patients with a mean age of 28.7 years (22.5 to 39) and a mean follow-up of 5.4 years (2.0 to 9.6) were treated with autografts, while 269 patients with a mean age of 28.4 years (25 to 34.6) and a mean follow-up of 4.0 years (2.3 to 6.0) were treated with allografts. Regarding allografts, irradiation with 2.5 mrad was used in two studies while the graft was not irradiated in the seven remaining studies. Reconstructions following the use of autografts had better outcomes than those using allograft with respect to laxity, measured by KT-1000/2000 (MEDmetric Corporation) and the rates of complications and re-operations. Those following the use of allografts had better mean Lysholm and Tegner activity scores compared with autografts. If irradiated allografts were excluded from the analysis, outcomes no longer differed between the use of autografts and allografts. Comparing the types of autograft, all outcomes were similar except for HS grafts which had better International Knee Documentation Committee scores compared with BPTB grafts. CONCLUSION: Autografts had better outcomes than allografts in revision ACL reconstruction, with lower post operative laxity and rates of complications and re-operations. However, after excluding irradiated allografts, outcomes were similar between autografts and allografts. Overall, the choice of graft at revision ACL reconstruction should be on an individual basis considering, for instance, the preferred technique of the surgeon, whether a combined reconstruction is required, the type of graft that was previously used, whether the tunnels are enlarged and the availability of allograft. Cite this article: Bone Joint J 2017;99-B:714-23. PMID- 28566390 TI - The Birmingham Interlocking Pelvic Osteotomy for acetabular dysplasia: 13- to 21 year survival outcomes. AB - AIMS: The aim of this study was to evaluate the long-term clinical and radiographic outcomes of the Birmingham Interlocking Pelvic Osteotomy (BIPO). PATIENTS AND METHODS: In this prospective study, we report the mid- to long-term clinical outcomes of the first 100 consecutive patients (116 hips; 88 in women, 28 in men) undergoing BIPO, reflecting the surgeon's learning curve. Failure was defined as conversion to hip arthroplasty. The mean age at operation was 31 years (7 to 57). Three patients (three hips) were lost to follow-up. RESULTS: Survivorship was 76% at ten years and 57% at a mean of 17 years. Younger patients (< 20 years) had the best survivorship (20 hips at risk; 90% at 17 years; 95% confidence interval 65 to 97). Post-operative complications occurred after 12 operations (10.4%) over the duration of the study. Increasing patient age and hip arthritis grade were primary determinants of surgical failure. CONCLUSION: BIPO provides good to excellent survivorship in appropriately selected patients, with a relatively low rate of complications. Our results are comparable with other established methods of periacetabular osteotomy (PAO), such as the Bernese PAO, even during the surgeon's initial learning curve. Cite this article: Bone Joint J 2017;99-B:724-31. PMID- 28566391 TI - The direct anterior approach in total hip arthroplasty: a systematic review of the literature. AB - AIMS: The most effective surgical approach for total hip arthroplasty (THA) remains controversial. The direct anterior approach may be associated with a reduced risk of dislocation, faster recovery, reduced pain and fewer surgical complications. This systematic review aims to evaluate the current evidence for the use of this approach in THA. MATERIALS AND METHODS: Following the Cochrane collaboration, an extensive literature search of PubMed, Medline, Embase and OvidSP was conducted. Randomised controlled trials, comparative studies, and cohort studies were included. Outcomes included the length of the incision, blood loss, operating time, length of stay, complications, and gait analysis. RESULTS: A total of 42 studies met the inclusion criteria. Most were of medium to low quality. There was no difference between the direct anterior, anterolateral or posterior approaches with regards to length of stay and gait analysis. Papers comparing the length of the incision found similar lengths compared with the lateral approach, and conflicting results when comparing the direct anterior and posterior approaches. Most studies found the mean operating time to be significantly longer when the direct anterior approach was used, with a steep learning curve reported by many. Many authors used validated scores including the Harris hip score, and the Western Ontario and McMaster Universities Arthritis Index. These mean scores were better following the use of the direct anterior approach for the first six weeks post-operatively. Subsequently there was no difference between these scores and those for the posterior approach. CONCLUSION: There is little evidence for improved kinematics or better long-term outcomes following the use of the direct anterior approach for THA. There is a steep learning curve with similar rates of complications, length of stay and outcomes. Well-designed, multi-centre, prospective randomised controlled trials are required to provide evidence as to whether the direct anterior approach is better than the lateral or posterior approaches when undertaking THA. Cite this article: Bone JointJ 2017;99-B:732-40. PMID- 28566392 TI - Mid-term results of the BIOLOX delta ceramic-on-ceramic total hip arthroplasty. AB - AIMS: We conducted a prospective study of a delta ceramic total hip arthroplasty (THA) to determine the rate of ceramic fracture, to characterise post-operative noise, and to evaluate the mid-term results and survivorship. PATIENTS AND METHODS: Between March 2009 and March 2011, 274 patients (310 hips) underwent cementless THA using a delta ceramic femoral head and liner. At each follow-up, clinical and radiological outcomes were recorded. A Kaplan-Meier analysis was undertaken to estimate survival. RESULTS: Four patients (four hips) died and 18 patients (20 hips) were lost to follow-up within five years. The remaining 252 patients (286 hips) were followed for a mean of 66.5 months (60 to 84). There were 144 men (166 hips) and 108 women (120 hips) with a mean age of 49.7 years (16 to 83) at surgery. The mean pre-operative Harris Hip Score of 47.1 points improved to 93.8 points at final follow-up. Six patients reported squeaking in seven hips; however, none were audible. Radiolucent lines involving Gruen zones one and/or seven were seen in 52 hips (18.2%). No hip had detectable wear, focal osteolysis or signs of loosening. One hip was revised because of fracture of the ceramic liner, which occurred due to an undetected malseating of the ceramic liner at the time of surgery. One hip was revised for a periprosthetic fracture of the femur, and one hip was treated for periprosthetic joint infection. The six year survivorship with re-operation for any reason as the endpoint was 99.0% (95% confidence interval 97.8% to 100%). DISCUSSION: The rate of delta ceramic fracture was 0.3% (one of 286). While ceramic head fracture was dominant in previous ceramic-on-ceramic THA, fracture of the delta ceramic liner due to malseating is a concern. Cite this article: Bone Joint J 2017;99-B:741-8. PMID- 28566393 TI - The evolution of an uncemented acetabular component in alumina-on-alumina total hip arthroplasty has improved clinical outcome: a prospective, comparative five- to 15-year follow-up study. AB - AIMS: To determine the effect of a change in design of a cementless ceramic acetabular component in fixation and clinical outcome after total hip arthroplasty PATIENTS AND METHODS: We compared 342 hips (302 patients) operated between 1999 and 2005 with a relatively smooth hydroxyapatite coated acetabular component (group 1), and 337 hips (310 patients) operated between 2006 and 2011 using a similar acetabular component with a macrotexture on the entire outer surface of the component (group 2). The mean age of the patients was 53.5 (14 to 70) in group 1 and 53.0 (15 to 70) in group 2. The mean follow-up was 12.7 years (10 to 17) for group 1 and 7.2 years (4 to 10) for group 2. RESULTS: No hips were revised due to complications related to bearing fracture or to stem loosening. A total of 15 acetabular components were revised for aseptic loosening in group 1 and two in group 2. The survival rate for acetabular component aseptic loosening at eight years was 96.8% (95% confidence interval (CI) 94.8 to 98.7) for group 1 and 99.2% (95% CI 98.0 to 100) for group 2. The risk for aseptic loosening of the acetabular component was higher in group 1 (p = 0.04, Hazard Ratio (HR) 4.99), dysplastic acetabula (p = 0.01, HR 4.12), components outside Lewinnek's zone (p < 0.001, HR 6.13) and in those with a hip rotation centre distance greater than 5 mm (p = 0.005, HR 4.09). CONCLUSION: Alumina ceramic-on-ceramic THA is an excellent option for young patients. Although newer components appeared to improve fixation, acetabular reconstruction is essential to obtain a satisfactory outcome. Cite this article: Bone Joint J 2017;99-B:749-58. PMID- 28566394 TI - Lumbar surgery prior to total hip arthroplasty is associated with worse patient reported outcomes. AB - AIMS: The aims of this study were to describe the prevalence of previous lumbar surgery in patients who undergo total hip arthroplasty (THA) and to investigate their patient-reported outcomes (PROMs) one year post-operatively. PATIENTS AND METHODS: Data from the Swedish Hip Arthroplasty Register and the Swedish Spine Register gathered between 2002 and 2012 were merged to identify a group of patients who had undergone lumbar surgery before THA (n = 997) and a carefully matched one-to-one control group. We investigated differences in the one-year post-operative PROMs between the groups. Linear regression analyses were used to explore the associations between previous lumbar surgery and these PROMs following THA. The prevalence of prior lumbar surgery was calculated as the ratio of patients identified with previous lumbar surgery between 2002 and 2012, and divided by the total number of patients who underwent a THA in 2012. RESULTS: The prevalence of lumbar surgery prior to THA in 2012 was 3.5% (351 of 10 082). Linear regression analyses showed an association with more pain (B = 4.35, 95% confidence interval (CI) 2.57 to 6.12), worse EuroQol (EQ)-5D index, (B = -0.089, 95% CI -0.112 to -0.066), worse EQ VAS (B = -6.75, 95% CI -8.58 to -4.92), and less satisfaction (B = 6.04, 95% CI 4.05 to 8.02). CONCLUSION: Lumbar spinal surgery prior to THA is associated with less reduction of pain, worse health related quality of life, and less satisfaction one year after THA. This is useful information to share in the decision-making process and may help establish realistic expectations of the outcomes of THA in patients who also have previously undergone lumbar spinal surgery. Cite this article: Bone Joint J 2017;99-B:759-65. PMID- 28566395 TI - The use of femoral stems with exchangeable necks in primary total hip arthroplasty increases the rate of revision. AB - AIMS: Femoral stems with exchangeable (modular) necks were introduced to offer surgeons an increased choice when determining the version, offset and length of the femoral neck during total hip arthroplasty (THA). It was hoped that this would improve outcomes and reduce complications, particularly dislocation. In 2010, the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) first reported an increased rate of revision after primary THA using femoral stems with an exchangeable neck. The aim of this study was to provide a more comprehensive up-to-date analysis of primary THA using femoral stems with exchangeable and fixed necks. MATERIALS AND METHODS: The data included all primary THA procedures performed for osteoarthritis (OA), reported to the AOANJRR between 01 September 1999 and 31 December 2014. There were 9289 femoral stems with an exchangeable neck and 253 165 femoral stems with a fixed neck. The characteristics of the patients and prostheses including the bearing surface and stem/neck metal combinations were examined using Cox proportional hazard ratios (HRs) and Kaplan-Meier estimates of survivorship. RESULTS: It was found that prostheses with an exchangeable neck had a higher rate of revision and this was evident regardless of the bearing surface or the size of the femoral head. Exchangeable neck prostheses with a titanium stem and a cobalt-chromium neck had a significantly higher rate of revision compared with titanium stem/titanium neck combinations (HR 1.83, 95% confidence interval 1.49 to 2.23, p < 0.001). Revisions were higher for these combinations compared with femoral stems with a fixed neck. CONCLUSION: There appears to be little evidence to support the continued use of prostheses with an exchangeable neck in primary THA undertaken for OA. Cite this article: Bone Joint J 2017;99-B:766-73. PMID- 28566396 TI - Successful return to sports in athletes following non-operative management of acute isolated posterior cruciate ligament injuries: medium-term follow-up. AB - AIMS: The aim of this study was to report the outcome of the non-operative treatment of high-grade posterior cruciate ligament (PCL) injuries, particularly Hughston grade III injuries, which have not previously been described. PATIENTS AND METHODS: This was a prospective study involving 46 consecutive patients who were athletes with MRI-confirmed isolated PCL injuries presenting within four weeks of injury. All had Hughston grade II (25 athletes) or III (21 athletes) injuries. Our non-operative treatment regimen involved initial bracing, followed by an individualised rehabilitation programme determined by the symptoms and physical signs. The patients were reviewed until they had returned to sports specific training, and were reviewed again at a mean of 5.2 years (3 to 9). RESULTS: The mean time to return to sports-specific training was 10.6 weeks and the mean time to return to full competitive sport was 16.4 weeks (10 to 40). A total of 42 patients (91.3%) were playing at the same or higher level of sport two years after the injury, with a mean Tegner activity score of 9 (5 to 10). At five years, 32 patients (69.5%) were playing at the same or higher level of sport, and 38 patients (82.6%) were playing at a competitive level, with a mean Tegner activity score of 9 (5 to 10). CONCLUSIONS: Medium-term review of a series of athletes suggests that commencing the non-operative management of isolated, Hughston grade II and III PCL injuries within four weeks of injury gives excellent functional outcomes with a high proportion returning to the same or higher level of sport. Cite this article: Bone Joint J 2017;99-B:774-8. PMID- 28566397 TI - Mediolateral force distribution at the knee joint shifts across activities and is driven by tibiofemoral alignment. AB - AIMS: Tibiofemoral alignment is important to determine the rate of progression of osteoarthritis and implant survival after total knee arthroplasty (TKA). Normally, surgeons aim for neutral tibiofemoral alignment following TKA, but this has been questioned in recent years. The aim of this study was to evaluate whether varus or valgus alignment indeed leads to increased medial or lateral tibiofemoral forces during static and dynamic weight-bearing activities. PATIENTS AND METHODS: Tibiofemoral contact forces and moments were measured in nine patients with instrumented knee implants. Medial force ratios were analysed during nine daily activities, including activities with single-limb support (e.g. walking) and double-limb support (e.g. knee bend). Hip-knee-ankle angles in the frontal plane were analysed using full-leg coronal radiographs. RESULTS: The medial force ratio strongly correlated with the tibiofemoral alignment in the static condition of one-legged stance (R2 = 0.88) and dynamic single-limb loading (R2 = 0.59) with varus malalignment leading to increased medial force ratios of up to 88%. In contrast, the correlation between leg alignment and magnitude of medial compartment force was much less pronounced. A lateral shift of force occurred during activities with double-limb support and higher knee flexion angles. CONCLUSION: The medial force ratio depends on both the tibiofemoral alignment and the nature of the activity involved. It cannot be generalised to a single value. Higher medial ratios during single-limb loading are associated with varus malalignment in TKA. The current trend towards a 'constitutional varus' after joint replacement, in terms of overall tibiofemoral alignment, should be considered carefully with respect to the increased medial force ratio. Cite this article: Bone Joint J 2017;99-B:779-87. PMID- 28566398 TI - Discharge on the day of surgery following unicompartmental knee arthroplasty within the United Kingdom NHS. AB - AIMS: Unicompartmental knee arthroplasty (UKA) has been successfully performed in the United States healthcare system on outpatients. Despite differences in healthcare structure and financial environment, we hypothesised that it would be feasible to replicate this success and perform UKA with safe day of surgery discharge within the NHS, in the United Kingdom. This has not been reported in any other United Kingdom centres. PATIENTS AND METHODS: We report our experience of implementing a pathway to allow safe day of surgery discharge following UKA. Data were prospectively collected on 72 patients who underwent UKA as a day case between December 2011 and September 2015. RESULTS: A total of 61 patients (85%) were discharged on the same day. The most common reason for failure was logistical; five patients had their operation too late in the day. Three patients failed to mobilise safely, two had inadequate control of pain and one had a leaking wound. The mean length of stay for those who were not discharged on the same day was 1.2 nights (1 to 3). During the same time, 58 patients underwent planned inpatient UKA, as they were deemed inappropriate for discharge on the day of surgery. However, three of these were safely discharged on the same day. Follow-up data, 24 hours post-operatively, were available for 70 patients; 51 (73%) reported no or mild pain, 14 (20%) had moderate pain and five (7%) had severe pain. There were no re-admissions. All patients had a high level of satisfaction. CONCLUSION: We found that patients can be safely and effectively discharged on the day of surgery after UKA, with high levels of satisfaction. This clearly offers improved management of resources and financial savings to healthcare trusts. Cite this article: Bone Joint J 2017;99-B:788-92. PMID- 28566399 TI - Oxidised zirconium versus cobalt alloy bearing surfaces in total knee arthroplasty: 3D laser scanning of retrieved polyethylene inserts. AB - AIMS: We sought to establish whether an oxidised zirconium (OxZr) femoral component causes less loss of polyethylene volume than a cobalt alloy (CoCr) femoral component in total knee arthroplasty. MATERIALS AND METHODS: A total of 20 retrieved tibial inserts that had articulated with OxZr components were matched with 20 inserts from CoCr articulations for patient age, body mass index, length of implantation, and revision diagnosis. Changes in dimensions of the articular surfaces were compared with those of pristine inserts using laser scanning. The differences in volume between the retrieved and pristine surfaces of the two groups were calculated and compared. RESULTS: The loss of polyethylene volume was 122 mm3 (standard deviation (sd) 87) in the OxZr group and 170 mm3 (sd 96) in the CoCr group (p = 0.033). The volume loss in the OxZr group was also lower in the medial (72 mm3 (sd 67) versus 92 mm3 (sd 60); p = 0.096) and lateral (49 mm3 (sd 36) versus 79 mm3 (sd 61); p = 0.096) compartments separately, but these differences were not significant. CONCLUSION: Our results corroborate earlier findings from in vitro testing and visual retrieval analysis which suggest that polyethylene volume loss is lower with OxZr femoral components. Since both OxZr and CoCr are hard surfaces that would be expected to create comparable amounts of polyethylene creep, the differences in volume loss may reflect differences in the in vivo wear of these inserts. Cite this article: Bone Joint J 2017;99-B:793-8. PMID- 28566400 TI - Arthroscopic decompression not recommended in the treatment of rotator cuff tendinopathy: a final review of a randomised controlled trial at a minimum follow up of ten years. AB - AIMS: Rotator cuff tendinopathy has a multifactorial origin. Rejecting the mechanistic theory has also led to abandoning operative treatment at initial presentation in the first line. Physiotherapy exercise programmes are the accepted first line treatment. The aim of this study was to assess the long-term additional benefits of subacromial decompression in the treatment of rotator cuff tendinopathy. PATIENTS AND METHODS: This randomised controlled trial of 140 patients (52 men, 88 women, mean age 47.1 years; 18 to 60) with rotator cuff tendinopathy extended previous work up to a maximum of 13 years. The patients were randomised into two treatment groups: arthroscopic acromioplasty and a supervised exercise treatment and a similar supervised exercise treatment alone. Self-reported pain on a visual analogue scale (VAS) was the primary outcome measure. Secondary measures were disability, working ability, pain at night, Shoulder Disability Questionnaire score and the number of painful days during the three months preceding the final assessment. RESULTS: A total of 90 patients (64%) returned questionnaires at a mean 12 years after randomisation. On an intention-to-treat basis, both treatment groups reached statistically significant improvement compared with the initial VAS for pain, but there was no significant difference between groups. The same was true in the secondary outcome measures. Due to group changes, the results were also analysed per protocol: operated or not. No significant differences between the groups were found. CONCLUSION: The natural history of rotator cuff tendinopathy probably plays a significant role in the results in the long-term. Even though the patients who underwent operative treatment had a stronger belief in recovery, which is likely to be surgical and the effect of placebo, the exercise group obtained similar results. In the future, an optimum exercise regime should be searched for, as the most clinically and cost-effective conservative treatment for rotator cuff tendinopathy. Cite this article: Bone Joint J 2017;99-B:799-805. PMID- 28566401 TI - Hypertrophy of the extra-articular tendon of the long head of biceps correlates with the location and size of a rotator cuff tear. AB - AIMS: The aim of this study was to assess hypertrophy of the extra-articular tendon of the long head of biceps (LHB) in patients with a rotator cuff tear. PATIENTS AND METHODS: The study involved 638 shoulders in 334 patients (175 men, 159 women, mean age 62.6 years; 25 to 81) with unilateral symptomatic rotator cuff tears. The cross-sectional area (CSA) of the LHB tendon in the bicipital groove was measured pre-operatively in both shoulders using ultrasound. There were 154 asymptomatic rotator cuff tears in the contralateral shoulder. Comparisons were made between those with a symptomatic tear, an asymptomatic tear and those with no rotator cuff tear. In the affected shoulders, the CSAs were compared in relation to the location and size of the rotator cuff tear. RESULTS: The mean CSA was 21.0 mm2 (4 to 71) in those with a symptomatic rotator cuff tear, 19.9 mm2 (4 to 75) in those with an asymptomatic rotator cuff tear and 14.1 mm2 (5 to 43) in those with no rotator cuff tear. The mean CSA in patients with both symptomatic and asymptomatic rotator cuff tears was significantly larger than in those with no rotator cuff tear (p < 0.001). In the affected shoulders, there were significant differences between patients with more than a medium sized posterosuperior cuff tear and those with an antero-superior cuff tear. CONCLUSION: Regardless of the symptoms, there was significant hypertrophy of the extra-articular LHB tendon in patients with a rotator cuff tear. The values were significantly related to the size of the tear. Cite this article: Bone Joint J 2017;99-B:806-11. PMID- 28566403 TI - Kudo type-5 total elbow arthroplasty for patients with rheumatoid arthritis: a minimum ten-year follow-up study. AB - AIMS: We assessed the long-term (more than ten-year) outcomes of the Kudo type-5 elbow prosthesis in patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: We reviewed 41 elbows (Larsen Grade IV, n = 21; Grade V, n = 20) in 31 patients with RA who had undergone a Kudo type-5 total elbow arthroplasty (TEA) between 1994 and 2003, and had been followed up for more than ten years. The humeral component was cementless and the all-polyethylene ulnar component cemented in every patient. Clinical outcome was assessed using the Mayo elbow performance score. We calculated the revision rate and evaluated potential risk factors for revision. The duration of follow-up was a mean 141 months (120 to 203). RESULTS: Aseptic loosening of the ulnar component occurred in 11 elbows. There was no radiolucency around any humeral component. There was one deep infection. The survival rate according to Kaplan-Meier survivorship analysis was 87.8% after five years and 70.7% after ten years. The range of extension/flexion was a mean -38 degrees (-80 degrees to 0 degrees )/105 degrees (30 degrees to 150 degrees ) before surgery and -40 degrees (-70 degrees to -20 degrees )/132 degrees (100 degrees to 150 degrees ) at the final follow-up, while the mean Mayo elbow performance score was 43 before surgery and 80 at final follow-up. Disease duration of RA up to the TEA of < 15 years and a pre-operative range of movement (ROM) of > 85 degrees were significant risk factors for revision or aseptic loosening. CONCLUSION: Although Kudo type-5 prostheses gave satisfactory results in the short-term, aseptic loosening increased after five years. In most cases, elbow function was maintained in the long-term without loosening of the implant. A short duration from the onset of RA to TEA and a large pre-operative ROM were significant risk factors for revision or aseptic loosening. Cite this article: Bone Joint J 2017;99-B:818-23. PMID- 28566402 TI - Recurrence of frozen shoulder after manipulation under anaesthetic (MUA): the results of repeating the MUA. AB - AIMS: Manipulation under anaesthetic (MUA) is a recognised form of treatment for patients with a frozen shoulder. However, not all patients benefit. Some have persistent or recurrent symptoms. There are no clear recommendations in the literature on the optimal management of recurrent frozen shoulder after a MUA. We aimed to address this issue in this study. PATIENTS AND METHODS: We analysed a prospectively collected, single-surgeon, consecutive series of patients who underwent MUA for frozen shoulder between January 1999 and December 2015. The Oxford Shoulder Scores (OSS) and range of movement were the outcome measures. RESULTS: A total of 730 patients (792 shoulders) underwent MUA during the study period. A further MUA was undertaken in 141 shoulders (17.8%), for which we had complete data for 126. The mean improvement in OSS for all patients undergoing MUA was 16 (26 to 42), and the mean post-operative OSS in those requiring a further MUA was 14 (28 to 42; t-test, no difference between mean improvements, p = 0.57). Improvement was seen after a further MUA, regardless both of the outcome of the initial MUA, and of the time of recurrence. Patients with type-1 diabetes mellitus were at a 38% increased risk of requiring a further MUA, compared with the 18% increased risk of the group as a whole (p < 0.0001). CONCLUSION: Patients with a poor outcome or recurrent symptoms of a frozen shoulder after a MUA should be offered a further MUA with the expectation of a good outcome and a low complication rate. Cite this article: Bone Joint J 2017;99-B:812-17. PMID- 28566405 TI - Intraspinal anomalies in early-onset idiopathic scoliosis. AB - AIMS: In the United Kingdom, lower incidences of intraspinal abnormalities in patients with early onset idiopathic scoliosis have been observed than in studies in other countries. We aimed to determine the rates of these abnormalities in United Kingdom patients diagnosed with idiopathic scoliosis before the age of 11 years. PATIENTS AND METHODS: This retrospective study of patients attending an urban scoliosis clinic identified 71 patients satisfying a criteria of: clinical diagnosis of idiopathic scoliosis; age of onset ten years and 11 months or less; MRI screening for intraspinal abnormalities. United Kingdom census data combined with patient referral data was used to calculate incidence. RESULTS: Mean age at diagnosis was six years with 39 right-sided and 32 left-sided curves. Four patients (5.6%) were found to have intraspinal abnormalities on MRI. These consisted of: two combined Arnold-Chiari type 1 malformations with syrinx; one syrinx with a low lying conus; and one isolated syrinx. Overall annual incidence of early onset idiopathic scoliosis was one out of 182 000 (0.0006%). CONCLUSION: This study reports the lowest rates to date of intraspinal anomalies in patients with early onset idiopathic scoliosis, adding to knowledge regarding current incidences of these abnormalities as well as any geographical variation in the nature of the disease. Cite this article: Bone Joint J 2017;99-B:829-33. PMID- 28566404 TI - Pre-operative functional status as a predictor of morbidity and mortality after elective cervical spine surgery. AB - AIMS: Patients seeking cervical spine surgery are thought to be increasing in age, comorbidities and functional debilitation. The changing demographics of this population may significantly impact the outcomes of their care, specifically with regards to complications. In this study, our goals were to determine the rates of functionally dependent patients undergoing elective cervical spine procedures and to assess the effect of functional dependence on 30-day morbidity and mortality using a large, validated national cohort. PATIENTS AND METHODS: A retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program data files from 2006 to 2013 was conducted to identify patients undergoing common cervical spine procedures. Multivariate logistic regression models were generated to analyse the independent association of functional dependence with 30-day outcomes of interest. RESULTS: Patients with lower functional status had significantly higher rates of medical comorbidities. Even after accounting for these comorbidities, type of procedure and pre operative diagnosis, analyses demonstrated that functional dependence was independently associated with significantly increased odds of sepsis (odds ratio (OR) 5.04), pulmonary (OR 4.61), renal (OR 3.33) and cardiac complications (OR 4.35) as well as mortality (OR 11.08). CONCLUSIONS: Spine surgeons should be aware of the inherent risks of these procedures with the functionally dependent patient population when deciding on whether to perform cervical spine surgery, delivering pre-operative patient counselling, and providing peri-operative management and surveillance. Cite this article: Bone Joint J 2017;99-B:824-8. PMID- 28566406 TI - Long-term survival and risk factors for failure of the native hip joint after operatively treated displaced acetabular fractures. AB - AIMS: Our aim in this study was to describe the long-term survival of the native hip joint after open reduction and internal fixation of a displaced fracture of the acetabulum. We also present long-term clinical outcomes and risk factors associated with a poor outcome. PATIENTS AND METHODS: A total of 285 patients underwent surgery for a displaced acetabular fracture between 1993 and 2005. For the survival analysis 253 were included, there were 197 men and 56 women with a mean age of 42 years (12 to 78). The mean follow-up of 11 years (1 to 20) was identified from our pelvic fracture registry. There were 99 elementary and 154 associated fracture types. For the long-term clinical follow-up, 192 patients with complete data were included. Their mean age was 40 years (13 to 78) with a mean follow-up of 12 years (5 to 20). Injury to the femoral head and acetabular impaction were assessed with CT scans and patients with an ipsilateral fracture of the femoral head were excluded. RESULTS: A total of 36 patients underwent total hip arthroplasty (THA). The overall ten-year survival of the hip joint was 86% (95% confidence interval (CI) 81% to 90%) and the 20-year survival was 82% (95% CI 76% to 87%). Injury to the femoral head and acetabular impaction were the strongest predictors of failure, with the long-term survival rate falling towards 50% in these patients. The survival fell to 0% at three years when both these risk factors were present in patients aged > 60 years. CONCLUSION: The long-term survival of the native hip joint after acetabular fractures was good, but the presence of injury to the femoral head and acetabular impaction proved to be strong predictors of failure, especially in patients aged > 60 years. These patients may be better treated with a combination of open reduction and internal fixation and primary arthroplasty. Cite this article: Bone Joint J 2017;99-B:834 40. PMID- 28566407 TI - Pelvic reconstruction following resection of malignant bone tumours using a stemmed acetabular pedestal cup. AB - AIMS: Pelvic reconstruction after the resection of a tumour around the acetabulum is a challenging procedure due to the complex anatomy and biomechanics. Several pelvic endoprostheses have been introduced, but the rates of complication remain high. Our aim was to review the use of a stemmed acetabular pedestal cup in the management of these patients. PATIENTS AND METHODS: The study involved 48 patients who underwent periacetabular reconstruction using a stemmed pedestal cup (Schoellner cup; Zimmer Biomet Inc., Warsaw, Indiana) between 2000 and 2013. The indications for treatment included a primary bone tumour in 27 patients and metastatic disease in 21 patients. The mean age of the patients at the time of surgery was 52 years (16 to 83). RESULTS: At a median follow-up of 6.6 years (95% confidence interval 4.6 to 8.2), local control was achieved in all patients; 19 patients had died (16 of disease). Complications occurred in 19 patients (40%), of which deep infection was the most common, affecting eight patients (17%). Seven patients (15%) had a dislocation of the hip. Aseptic loosening was found in three patients (6%). Two (4%) underwent hindquarter amputation for non oncological reasons. The risk of revision, with death being treated as a competing event, was 28% at one year, 39% at five years and 48% at ten years post operatively. The mean Musculoskeletal Tumour Society Score at final follow-up was 71% (27% to 93%). CONCLUSION: This type of reconstruction is a satisfactory option for the treatment of patients with a periacetabular tumour. There remains, however, a high rate of complication, which may be reduced by future modifications of the device such as silver coating and tripolar articulation. Cite this article: Bone Joint J 2017;99-B:841-8. PMID- 28566408 TI - 5-ALA ameliorates hepatic steatosis through AMPK signaling pathway. AB - 5-Aminolevulinic acid (5-ALA), the first compound in the porphyrin synthesis pathway, has been reported to ameliorate the diabetic state in Otsuka Long-Evans Tokushima Fatty rats by reducing fat pad weight in the retroperitoneal region. Dietary supplementation with 5-ALA has additionally demonstrated the capacity to lower blood glucose and HbA1c levels among subjects with diabetes. The etiology of nonalcoholic fatty liver disease (NAFLD) is complex and its typical characteristics include obesity and insulin resistance. As 5-ALA supplementation has previously normalized glucose and insulin resistance, we sought to investigate whether 5-ALA had potential therapeutic effects on NAFLD and elucidate the signal pathway mediating these effects. To explore these questions, we fed C57BL/6J mice a high-fat diet (HFD) to induce a fatty liver disease and supplemented the diet-induced obese (DIO) mice with 5-ALA. The mice in the presence of 5-ALA demonstrated a decrease in body weight and hepatic lipid content and moderate improvement in glucose homeostasis compared to untreated controls. Further, we found that 5-ALA activated AMPK signaling pathway, which was correlated with enhanced lipolysis and fatty acid beta-oxidation. Human hepatocarcinoma cells (HepG2 cells) treated with 5-ALA were additionally used to investigate the mechanics of 5-ALA. Treated cells had a higher expression of lipolysis-related genes, including PGC-1alpha. Our data indicated that 5-ALA might represent a novel compound that could be useful for the treatment of nonalcoholic fatty liver disease (NAFLD), likely through the restoration of phosphorylation levels of AMPK (Thr172) and acetyl-CoA (ACC) (Ser79), further enhanced PGC1alpha and CPT1alpha expression. PMID- 28566409 TI - Emphysematous gastritis with hepatic portal venous gas: a shift towards conservative management. PMID- 28566410 TI - Postoperative drug-induced priapism. AB - We presented a case of a postoperative patient with low-flow priapism, possibly initiated by propofol-based anaesthesia or epidural anaesthesia. The delay in diagnosing priapism resulted in emergency interventions with a partially successful effect and eventually permanent erectile dysfunction. Due to the delay in treatment, erectile dysfunction ensued and was manageable with medication; hence, the patient decided against a penile prosthesis. PMID- 28566411 TI - Incidental finding of a filamentous mass in the left atrium in a patient investigated for endocarditis. PMID- 28566412 TI - Rectosigmoid malakoplakia. AB - We present a rare case of rectosigmoid malakoplakia treated with fluoroquinolone. PMID- 28566413 TI - Hypercalcaemic encephalopathy due to metastatic parathyroid carcinoma. AB - A 49-year-old man presented in the emergency department with altered sensorium and renal failure and was placed on a ventilator. Evaluation with MRI of the brain showed enhancing lesion in the occipital lobe. Biochemical tests revealed elevated calcium and parathyroid hormone (PTH) levels. Further evaluation revealed multiple lesions at both lobes of the lungs and nodular lesion in the right inferior pole of the thyroid. Diagnosis of metastatic parathyroid carcinoma was suspected. Patient was stabilised with bisphosphonates and haemodialysis and planned for surgery. Intraoperatively a hard lesion was found in the right inferior parathyroid infiltrating the surrounding structures. En bloc resection was done. General condition of the patient improved and he was weaned from the ventilator. Histopathology confirmed the diagnosis of parathyroid carcinoma. Postoperatively, there was persistent elevation of PTH in spite of a fall in calcium levels indicating functioning brain and pulmonary metastases. Due to extensive metastases, the patient was given palliative cinacalcet and was kept under follow-up. PMID- 28566414 TI - Linagliptin-associated blistering and ulceration. AB - We present the case of 60-year-old man with type 2 diabetes who developed blistering after two sequential exposures to linagliptin. Linagliptin is one of the dipeptidyl peptidase 4 (DPP-4) inhibitors, a group of oral hypoglycaemic agents used commonly for the treatment of type 2 diabetes. On the first exposure to linagliptin, he developed blisters on the hands which resolved after stopping the drug. After repeat exposure, he developed two large blisters on the left foot, which burst giving rise to secondary infection, requiring hospital admission for treatment. We discuss the latest research linking DPP-4 inhibitors with adverse skin reactions and the effect of ulcers on the morbidity and mortality of patients with diabetes. This case report highlights skin reactions as an important, rare and lesser known side effect of DPP-4 inhibitors. PMID- 28566415 TI - A rare cause of anuria in a case of pre-B acute lymphoblastic leukaemia. AB - Renal failure in cases of acute lymphoblastic leukaemia during induction is mainly because of sepsis and tumour lysis syndrome. This 18-year-old man had sudden onset anuria with increase in creatine. At this time, patient did not have any overt signs or laboratory features suggestive of sepsis. Imaging studies documented bilateral hydronephrosis. Ureteroscopy was done, and it showed presence of soft tissue mass obstructing the ureter. On the the left side, it was noted in its middle part and on the right, at the ureteropelvic junction. The mass on the left side was removed under ureteroscopic guidance and was sent for histopathology examination. It was confirmed to be fungal ball on histopathology examination. Though rare, even in immunocompromised patients, bilateral fungal ball should be considered in differential diagnosis in cases of acute leukaemia with sudden onset anuria. We share our experience in managing this case for which there are no clear guidelines. PMID- 28566416 TI - Alport's syndrome with type 4 renal tubular acidosis. AB - This case report details a 51-year-old man with Alport's syndrome resulting in chronic nephritis with stable renal function and sensorineural deafness. The patient was being investigated for persistently raised potassium refractory to dietary and pharmacological modification. Subsequently, the patient was found to have type 4 renal tubular acidosis, and potassium normalised with the addition of fludrocortisone. PMID- 28566417 TI - Fascioliasis-a rare cause of hepatic nodules. AB - Fascioliasis is a zoonotic disease that can sometimes affect humans. It presents with non-specific signs and symptoms which makes it difficult to establish an early definitive diagnosis. This can be particularly true in non-endemic countries where a high degree of suspicion is needed to make the diagnosis. Another confounding factor is that many of the initial complains and findings are very similar to those of malignancy. We report a case of an otherwise healthy 47 year-old male presenting with abdominal pain, night-time sweating, anorexia, weight loss and loose stools that had several hepatic nodules visible in the abdominal CT scan. Although the initial hypothesis was hepatic malignancy or liver metastasis of unknown primary neoplasm, the workup performed led us to the correct diagnosis. He was treated successfully for hepatic fascioliasis, with a full recovery. PMID- 28566418 TI - Radiographic imaging of an intra-aortic balloon pump impersonating a misplacement in the superior vena cava due to a right-sided aortic arch. PMID- 28566419 TI - Cortical Predictive Mechanisms of Auditory Response Attenuation to Self-Generated Sounds. PMID- 28566420 TI - Correction: Mittner et al., "When the Brain Takes a Break: A Model-Based Analysis of Mind Wandering". PMID- 28566421 TI - Correction: Milivojevic, et al., "Coding of Event Nodes and Narrative Context in the Hippocampus". PMID- 28566423 TI - Radiation therapy primes tumors for nanotherapeutic delivery via macrophage mediated vascular bursts. AB - Efficient delivery of therapeutic nanoparticles (TNPs) to tumors is critical in improving efficacy, yet strategies that universally maximize tumoral targeting by TNP modification have been difficult to achieve in the clinic. Instead of focusing on TNP optimization, we show that the tumor microenvironment itself can be therapeutically primed to facilitate accumulation of multiple clinically relevant TNPs. Building on the recent finding that tumor-associated macrophages (TAM) can serve as nanoparticle drug depots, we demonstrate that local tumor irradiation substantially increases TAM relative to tumor cells and, thus, TNP delivery. High-resolution intravital imaging reveals that after radiation, TAM primarily accumulate adjacent to microvasculature, elicit dynamic bursts of extravasation, and subsequently enhance drug uptake in neighboring tumor cells. TAM depletion eliminates otherwise beneficial radiation effects on TNP accumulation and efficacy, and controls with unencapsulated drug show that radiation effects are more pronounced with TNPs. Priming with combined radiation and cyclophosphamide enhances vascular bursting and tumoral TNP concentration, in some cases leading to a sixfold increase of TNP accumulation in the tumor, reaching 6% of the injected dose per gram of tissue. Radiation therapy alters tumors for enhanced TNP delivery in a TAM-dependent fashion, and these observations have implications for the design of next-generation tumor-targeted nanomaterials and clinical trials for adjuvant strategies. PMID- 28566425 TI - Rapamycin keeps the reproductive clock ticking. AB - Two weeks of rapamycin administration in young and old female mice leads to long term improvements in ovarian function and reproductive longevity. PMID- 28566426 TI - A new therapeutic target for myelofibrosis is cause for Gli. AB - Myeloproliferative neoplasm cells recruit Gli1 positive mesenchymal stromal cells to transdifferentiate into fibrosis-causing myofibroblasts, a process that can be inhibited by a Gli inhibitor. PMID- 28566427 TI - Say good night to your pain. AB - Sleep deprivation induces pain hypersensitivity that can be reversed by increasing alertness. PMID- 28566424 TI - Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief. AB - Typically considered to be cell surface sensors of extracellular signals, heterotrimeric GTP-binding protein (G protein)-coupled receptors (GPCRs) control many pathophysiological processes and are the target of 30% of therapeutic drugs. Activated receptors redistribute to endosomes, but researchers have yet to explore whether endosomal receptors generate signals that control complex processes in vivo and are viable therapeutic targets. We report that the substance P (SP) neurokinin 1 receptor (NK1R) signals from endosomes to induce sustained excitation of spinal neurons and pain transmission and that specific antagonism of the NK1R in endosomes with membrane-anchored drug conjugates provides more effective and sustained pain relief than conventional plasma membrane-targeted antagonists. Pharmacological and genetic disruption of clathrin, dynamin, and beta-arrestin blocked SP-induced NK1R endocytosis and prevented SP-stimulated activation of cytosolic protein kinase C and nuclear extracellular signal-regulated kinase, as well as transcription. Endocytosis inhibitors prevented sustained SP-induced excitation of neurons in spinal cord slices in vitro and attenuated nociception in vivo. When conjugated to cholestanol to promote endosomal targeting, NK1R antagonists selectively inhibited endosomal signaling and sustained neuronal excitation. Cholestanol conjugation amplified and prolonged the antinociceptive actions of NK1R antagonists. These results reveal a critical role for endosomal signaling of the NK1R in the complex pathophysiology of pain and demonstrate the use of endosomally targeted GPCR antagonists. PMID- 28566430 TI - Erratum for the Research Article: "The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia" by G. Brumatti, C. Ma, N. Lalaoui, N.-Y. Nguyen, M. Navarro, M. C. Tanzer, J. Richmond, M. Ghisi, J. M. Salmon, N. Silke, G. Pomilio, S. P. Glaser, E. de Valle, R. Gugasyan, M. A. Gurthridge, S. M. Condon, R. W. Johnstone, R. Lock, G. Salvesen, A. Wei, D. L. Vaux, P. G. Ekert, J. Silke. PMID- 28566428 TI - Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers. AB - Mutant RAS has remained recalcitrant to targeted therapy efforts. We demonstrate that combined treatment with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple RAS mutant tumor models across tumor lineages where RAS mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of BRCA1/2 and p53 mutation status, suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in RAS mutant tumors is associated with (i) induction of BIM mediated apoptosis, (ii) decrease in expression of components of the homologous recombination DNA repair pathway, (iii) decrease in homologous recombination DNA damage repair capacity, (iv) decrease in DNA damage checkpoint activity, (v) increase in PARP inhibitor-induced DNA damage, (vi) decrease in vascularity that could increase PARP inhibitor efficacy by inducing hypoxia, and (vii) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus, the ability of mutant RAS to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in RAS mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with RAS mutant tumors where there are few effective therapeutic options. PMID- 28566431 TI - A trust approach for sharing research reagents. AB - The core feature of trusts-holding property for the benefit of others-is well suited to constructing a research community that treats reagents as public goods. PMID- 28566429 TI - Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. AB - The complement cascade not only is an innate immune response that enables removal of pathogens but also plays an important role in microglia-mediated synaptic refinement during brain development. Complement C3 is elevated in Alzheimer's disease (AD), colocalizing with neuritic plaques, and appears to contribute to clearance of Abeta by microglia in the brain. Previously, we reported that C3 deficient C57BL/6 mice were protected against age-related and region-specific loss of hippocampal synapses and cognitive decline during normal aging. Furthermore, blocking complement and downstream iC3b/CR3 signaling rescued synapses from Abeta-induced loss in young AD mice before amyloid plaques had accumulated. We assessed the effects of C3 deficiency in aged, plaque-rich APPswe/PS1dE9 transgenic mice (APP/PS1;C3 KO). We examined the effects of C3 deficiency on cognition, Abeta plaque deposition, and plaque-related neuropathology at later AD stages in these mice. We found that 16-month-old APP/PS1;C3 KO mice performed better on a learning and memory task than did APP/PS1 mice, despite having more cerebral Abeta plaques. Aged APP/PS1;C3 KO mice also had fewer microglia and astrocytes localized within the center of hippocampal Abeta plaques compared to APP/PS1 mice. Several proinflammatory cytokines in the brain were reduced in APP/PS1;C3 KO mice, consistent with an altered microglial phenotype. C3 deficiency also protected APP/PS1 mice against age-dependent loss of synapses and neurons. Our study suggests that complement C3 or downstream complement activation fragments may play an important role in Abeta plaque pathology, glial responses to plaques, and neuronal dysfunction in the brains of APP/PS1 mice. PMID- 28566432 TI - The innate and adaptive infiltrating immune systems as targets for breast cancer immunotherapy. PMID- 28566433 TI - mTORC1 Inhibition Induces Resistance to Methotrexate and 6-Mercaptopurine in Ph+ and Ph-like B-ALL. AB - Elevated activity of mTOR is associated with poor prognosis and higher incidence of relapse in B-cell acute lymphoblastic leukemia (B-ALL). Thus, ongoing clinical trials are testing mTOR inhibitors in combination with chemotherapy in B-ALL. However, the combination of mTOR inhibitors with standard of care chemotherapy drugs has not been studied extensively in high-risk B-ALL subtypes. Therefore, we tested whether mTOR inhibition can augment the efficacy of current chemotherapy agents in Ph+ and Ph-like B-ALL models. Surprisingly, inhibiting mTOR complex 1 (mTORC1) protected B-ALL cells from killing by methotrexate and 6-mercaptopurine, two antimetabolite drugs used in maintenance chemotherapy. The cytoprotective effects correlated with decreased cell-cycle progression and were recapitulated using cell-cycle inhibitors, palbociclib or aphidicolin. Dasatinib, a tyrosine kinase inhibitor currently used in Ph+ patients, inhibits ABL kinase upstream of mTOR. Dasatinib resistance is mainly caused by ABL kinase mutations, but is also observed in a subset of ABL unmutated cases. We identified dasatinib-resistant Ph+ cell lines and patient samples in which dasatinib can effectively reduce ABL kinase activity and mTORC1 signaling without causing cell death. In these cases, dasatinib protected leukemia cells from killing by 6-mercaptopurine. Using xenograft models, we observed that mTOR inhibition or dasatinib increased the numbers of leukemia cells that emerge after cessation of chemotherapy treatment. These results demonstrate that inhibitors targeting mTOR or upstream signaling nodes should be used with caution when combined with chemotherapeutic agents that rely on cell-cycle progression to kill B-ALL cells. Mol Cancer Ther; 16(9); 1942 53. (c)2017 AACR. PMID- 28566434 TI - JUN-Mediated Downregulation of EGFR Signaling Is Associated with Resistance to Gefitinib in EGFR-mutant NSCLC Cell Lines. AB - Mutations or deletions in exons 18-21 in the EGFR) are present in approximately 15% of tumors in patients with non-small cell lung cancer (NSCLC). They lead to activation of the EGFR kinase domain and sensitivity to molecularly targeted therapeutics aimed at this domain (gefitinib or erlotinib). These drugs have demonstrated objective clinical response in many of these patients; however, invariably, all patients acquire resistance. To examine the molecular origins of resistance, we derived a set of gefitinib-resistant cells by exposing lung adenocarcinoma cell line, HCC827, with an activating mutation in the EGFR tyrosine kinase domain, to increasing gefitinib concentrations. Gefitinib resistant cells acquired an increased expression and activation of JUN, a known oncogene involved in cancer progression. Ectopic overexpression of JUN in HCC827 cells increased gefitinib IC50 from 49 nmol/L to 8 MUmol/L (P < 0.001). Downregulation of JUN expression through shRNA resensitized HCC827 cells to gefitinib (IC50 from 49 nmol/L to 2 nmol/L; P < 0.01). Inhibitors targeting JUN were 3-fold more effective in the gefitinib-resistant cells than in the parental cell line (P < 0.01). Analysis of gene expression in patient tumors with EGFR activating mutations and poor response to erlotinib revealed a similar pattern as the top 260 differentially expressed genes in the gefitinib-resistant cells (Spearman correlation coefficient of 0.78, P < 0.01). These findings suggest that increased JUN expression and activity may contribute to gefitinib resistance in NSCLC and that JUN pathway therapeutics merit investigation as an alternate treatment strategy. Mol Cancer Ther; 16(8); 1645-57. (c)2017 AACR. PMID- 28566435 TI - Efficacy of AKT Inhibitor ARQ 092 Compared with Sorafenib in a Cirrhotic Rat Model with Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide. The AKT pathway has been found activated in 50% of HCC cases, making it a promising target. Therefore, we assess efficacy of the allosteric AKT inhibitor ARQ 092 compared with untreated control and standard treatment, sorafenib, in vitro and in vivo ARQ 092 blocked phosphorylation of AKT in vitro and strongly inhibited cell growth with significantly higher potency than sorafenib. Similarly, apoptosis and cell migration were strongly reduced by ARQ 092 in vitro To mimic human advanced HCC, we used a diethylnitrosamine induced cirrhotic rat model with fully developed HCC. MRI analyses showed that ARQ 092 significantly reduced overall tumor size. Furthermore, number of tumors was decreased by ARQ 092, which was associated with increased apoptosis and decreased proliferation. Tumor contrast enhancement was significantly decreased in the ARQ 092 group. Moreover, on tumor tissue sections, we observed a vascular normalization and a significant decrease in fibrosis in the surrounding liver of animals treated with ARQ 092. Finally, pAKT/AKT levels in ARQ 092-treated tumors were reduced, followed by downregulation of actors of AKT downstream signaling pathway: pmTOR, pPRAS40, pPLCgamma1, and pS6K1. In conclusion, we demonstrated that ARQ 092 blocks AKT phosphorylation in vitro and in vivo In the HCC-rat model, ARQ 092 was well tolerated, showed antifibrotic effect, and had stronger antitumor effect than sorafenib. Our results confirm the importance of targeting AKT in HCC. Mol Cancer Ther; 16(10); 2157-65. (c)2017 AACR. PMID- 28566438 TI - In Vivo Antitumoral Efficacy of PhAc-ALGP-Doxorubicin, an Enzyme-Activated Doxorubicin Prodrug, in Patient-Derived Soft Tissue Sarcoma Xenograft Models. AB - Given the very limited efficacy of doxorubicin (doxo) in soft tissue sarcoma, there is a clear need for more active and less toxic treatments for this family of diseases. However, due to the rarity of these malignancies and lack of reliable preclinical models, development of new therapies has lagged behind. We evaluated the efficacy of PhAc-ALGP-doxorubicin (ALGP-doxo), a prodrug metabolized to doxo by peptidases present in tumor cells and/or tumor microenvironment, in a synovial sarcoma (SynSa) and two dedifferentiated liposarcoma (DDLPS) patient-derived xenograft models. Sixty-eight mice were engrafted bilaterally with human DDLPS or SynSa and randomized to control, doxo, or ALGP-doxo treatment, which were administered using an intraperitoneal minipump. Tumor volume measurement, histopathology, and Western blotting were used to assess treatment efficacy. Tumor regrowth was evaluated in a subset of mice over a period of 2 weeks after treatment cessation. Although tumor volume in the control and doxo groups increased steadily, ALGP-doxo caused tumor volume stabilization in the DDLPS xenografts and significant tumor shrinkage in the SynSa model, continuing after treatment cessation. A significant decrease in proliferation and increase in apoptosis compared with control and doxo was observed during and after treatment with ALGP-doxo in all models. In conclusion, ALGP-doxo shows considerably higher antitumoral efficacy compared with doxo in all patient-derived xenograft models tested. Administration of a 30- to 40-fold higher dose of ALGP-doxo than doxo is tolerated without significant adverse events. These results warrant further testing of this prodrug in anthracycline sensitive and -resistant models of soft tissue sarcoma. Mol Cancer Ther; 16(8); 1566-75. (c)2017 AACR. PMID- 28566436 TI - Reactivation of the p90RSK-CDC25C Pathway Leads to Bypass of the Ganetespib Induced G2-M Arrest and Mediates Acquired Resistance to Ganetespib in KRAS-Mutant NSCLC. AB - A subset of non-small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations, including the most frequently observed driver mutant KRAS, which is associated with a poor prognosis. As direct RAS targeting in the clinic has been unsuccessful to date, use of Hsp90 inhibitors appeared to be a promising therapy for KRAS-mutant NSCLC; however, limited clinical efficacy was observed due to rapid resistance. Furthermore, the combination of the Hsp90 inhibitor (Hsp90i), ganetespib, and docetaxel was tested in a phase III clinical trial and failed to demonstrate benefit. Here, we investigated the mechanism(s) of resistance to ganetespib and explored why the combination with docetaxel failed in the clinic. We have not only identified a critical role for the bypass of the G2-M cell-cycle checkpoint as a mechanism of ganetespib resistance (GR) but have also found that GR leads to cross-resistance to docetaxel. Reactivation of p90RSK and its downstream target, CDC25C, was critical for GR and mediated the bypass of a G2-M arrest. Overexpression of either p90RSK or CDC25C lead to bypass of G2-M arrest and induced ganetespib resistance in vitro and in vivo Moreover, resistance was dependent on p90RSK/CDC25C signaling, as synthetic lethality to ERK1/2, p90RSK, or CDC25C inhibitors was observed. Importantly, the combination of ganetespib and p90RSK or CDC25C inhibitors was highly efficacious in parental cells. These studies provide a way forward for Hsp90 inhibitors through the development of novel rationally designed Hsp90 inhibitor combinations that may prevent or overcome resistance to Hsp90i. Mol Cancer Ther; 16(8); 1658-68. (c)2017 AACR. PMID- 28566440 TI - DIAGNOSIS OF ENDOCRINE DISEASE: Diagnostic approach to TSH-producing pituitary adenoma. AB - Thyrotropin (TSH)-secreting adenomas (TSHomas) are the rarest form of pituitary adenomas, and most endocrinologists will see few cases in a lifetime, if any. In most cases, the diagnostic approach is complicated and cases may be referred after being presented as a syndrome of inappropriate TSH secretion or as a pituitary mass. This review aims to cover the past, present and possible future diagnostic approaches to TSHomas, including different clinical presentations, laboratory assessment and imaging advances. The differential diagnoses will be discussed, as well as possible coexisting disorders. By evaluating the existing reports and reviews describing this rare condition, this review aims to present a clinically practical suggestion on the diagnosic workup for TSHomas, Major advances and scientific breakthroughs in the imaging area in recent years, facilitating diagnosis of TSHomas, support the belief that future progress within the imaging field will play an important role in providing methods for a more efficient diagnosis of this rare condition. PMID- 28566437 TI - Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas. AB - High-grade gliomas, such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG), are characterized by an aggressive phenotype with nearly universal local disease progression despite multimodal treatment, which typically includes chemotherapy, radiotherapy, and possibly surgery. Radiosensitizers that have improved the effects of radiotherapy for extracranial tumors have been ineffective for the treatment of GBM and DIPG, in part due to poor blood-brain barrier penetration and rapid intracranial clearance of small molecules. Here, we demonstrate that nanoparticles can provide sustained drug release and minimal toxicity. When administered locally, these nanoparticles conferred radiosensitization in vitro and improved survival in rats with intracranial gliomas when delivered concurrently with a 5-day course of fractionated radiotherapy. Compared with previous work using locally delivered radiosensitizers and cranial radiation, our approach, based on the rational selection of agents and a clinically relevant radiation dosing schedule, produces the strongest synergistic effects between chemo- and radiotherapy approaches to the treatment of high-grade gliomas. Mol Cancer Ther; 16(8); 1456-69. (c)2017 AACR. PMID- 28566441 TI - Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies. AB - OBJECTIVE: We assessed the efficacy and safety of a weekly pegylated human growth hormone (PEG-rhGH) (Jintrolong) vs daily rhGH for children with growth hormone deficiency (GHD). DESIGN: Phase II and III, multicenter, open-label, randomized controlled trials. METHODS: 108 and 343 children with treatment-naive GHD from 6 hospitals in China were enrolled in the phase II and III studies respectively. Patients in the phase II study were randomized 1:1:1 to weekly Jintrolong (0.1 mg/kg/week PEG-rhGH complex), weekly Jintrolong (0.2 mg/kg/week PEG-rhGH complex) or daily rhGH (0.25 mg/kg/week) for 25 weeks. Patients in the phase III study were randomized in a 2:1 ratio to weekly Jintrolong (0.2 mg/kg/week) or daily rhGH (0.25 mg/kg/week) for 25 weeks. The primary endpoint for both studies was height velocity (HV) increase at the end of treatment. Other growth-related parameters, safety and compliance were also monitored. RESULTS: The phase II study established the preliminary efficacy, safety and recommended dose of Jintrolong PEG-rhGH. In the phase III study, we demonstrated significantly greater HV increases in patients receiving Jintrolong treatment (from 2.26 +/- 0.87 cm/year to 13.41 +/- 3.72 cm/year) vs daily rhGH (from 2.25 +/- 0.82 cm/year to 12.55 +/- 2.99 cm/year) at the end of treatment (P < 0.05). Additionally, significantly greater improvement in the height standard deviation scores was associated with Jintrolong throughout the treatment (P < 0.05). Adverse event rates and treatment compliance were comparable between the two groups. CONCLUSION: Jintrolong PEG-rhGH at a dose of 0.2 mg/kg/week for 25 weeks is effective and safe for GHD treatment and is non-inferior to daily rhGH. PMID- 28566439 TI - MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease. AB - Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance. PMID- 28566442 TI - Improving risk estimates for metabolically healthy obesity and mortality using a refined healthy reference group. AB - OBJECTIVE: We aimed to re-examine mortality risk estimates for metabolically healthy obesity by using a 'stable' healthy non-obese referent group. DESIGN: Prospective cohort study. METHODS: Participants were 5427 men and women (aged 65.9 +/- 9.4 years, 45.9% men) from the English Longitudinal Study of Ageing. Obesity was defined as body mass index >=30 kg/m2 (vs non-obese as below this threshold). Based on blood pressure, HDL cholesterol, triglycerides, glycated hemoglobin and C-reactive protein, participants were classified as 'healthy' (0 or 1 metabolic abnormality) or 'unhealthy' (>=2 metabolic abnormalities). RESULTS: Totally, 671 deaths were observed over an average follow-up of 8 years. When defining the referent group based on 1 clinical assessment, the unhealthy non-obese (hazard ratio (HR) = 1.22; 95% CI: 1.01, 1.45) and unhealthy obese (HR = 1.29; CI: 1.05, 1.60) were at greater risk of all-cause mortality compared to the healthy non-obese, yet no excess risk was seen in the healthy obese (HR = 1.14; CI: 0.83, 1.52). When we re-defined the referent group based on 2 clinical assessments, effect estimates were accentuated and healthy obesity was at increased risk of mortality (HR = 2.67; CI: 1.64, 4.34). CONCLUSION: An unstable healthy referent group may make 'healthy obesity' appear less harmful by obscuring the benefits of remaining never obese without metabolic dysfunction. PMID- 28566443 TI - Hypoinsulinaemic, hypoketotic hypoglycaemia due to mosaic genetic activation of PI3-kinase. AB - OBJECTIVE: Genetic activation of the insulin signal-transducing kinase AKT2 causes syndromic hypoketotic hypoglycaemia without elevated insulin. Mosaic activating mutations in class 1A phospatidylinositol-3-kinase (PI3K), upstream from AKT2 in insulin signalling, are known to cause segmental overgrowth, but the metabolic consequences have not been systematically reported. We assess the metabolic phenotype of 22 patients with mosaic activating mutations affecting PI3K, thereby providing new insight into the metabolic function of this complex node in insulin signal transduction. METHODS: Three patients with megalencephaly, diffuse asymmetric overgrowth, hypoketotic, hypoinsulinaemic hypoglycaemia and no AKT2 mutation underwent further genetic, clinical and metabolic investigation. Signalling in dermal fibroblasts from one patient and efficacy of the mTOR inhibitor Sirolimus on pathway activation were examined. Finally, the metabolic profile of a cohort of 19 further patients with mosaic activating mutations in PI3K was assessed. RESULTS: In the first three patients, mosaic mutations in PIK3CA (p.Gly118Asp or p.Glu726Lys) or PIK3R2 (p.Gly373Arg) were found. In different tissue samples available from one patient, the PIK3CA p.Glu726Lys mutation was present at burdens from 24% to 42%, with the highest level in the liver. Dermal fibroblasts showed increased basal AKT phosphorylation which was potently suppressed by Sirolimus. Nineteen further patients with mosaic mutations in PIK3CA had neither clinical nor biochemical evidence of hypoglycaemia. CONCLUSIONS: Mosaic mutations activating class 1A PI3K cause severe non-ketotic hypoglycaemia in a subset of patients, with the metabolic phenotype presumably related to the extent of mosaicism within the liver. mTOR or PI3K inhibitors offer the prospect for future therapy. PMID- 28566444 TI - Prognostic impact of vascular invasion in differentiated thyroid carcinoma: a systematic review and meta-analysis. AB - BACKGROUND: The role of vascular invasion (VI) as a prognostic marker in thyroid cancer is continuously debated among investigators. In this systematic review and meta-analysis, we aimed to investigate the association of VI with tumor recurrence and patient mortality in differentiated thyroid cancers (DTCs). METHODS: We searched five electronic databases for cases of DTC matching our criteria. Data of tumor persistence, locoregional recurrence (LRR), distant recurrence (DR) and overall recurrence/persistence (RP) were extracted and pooled into odds ratios (OR) and corresponding 95% confidence intervals (CIs) using random effect model. Pooled hazard ratio (HR) for disease-specific survival (DSS) was calculated using random effect model weighted by inverse variance method. Publication bias was examined by using Egger's test and funnel plot. RESULTS: From 1650 studies, we included 26 studies comprising 11 961 DTCs for meta analyses. In DTC patients, we found significant associations of VI with tumor persistence (OR = 2.75; 95% CI = 1.46-5.18), LRR (OR = 4.44; 95% CI = 2.94-6.71), DR (OR = 5.08; 95% CI = 2.95-8.75), overall RP (OR = 3.53; 95% CI = 2.09-5.96) and worse DSS (HR = 2.47; 95% CI = 1.45-4.21). Our results also demonstrated that the presence of extensive VI is associated with a significantly higher risk for DR in follicular thyroid carcinomas as compared with focal VI. CONCLUSION: Our study demonstrated a significant impact of VI on tumor recurrence and patient survival in DTC patients. The presence and extent of VI should be considered an adverse prognostic factor in DTCs. PMID- 28566445 TI - Muscle strength in patients with acromegaly at diagnosis and during long-term follow-up. AB - OBJECTIVE: Patients with acromegaly have decreased body fat (BF) and increased extracellular water (ECW) and muscle mass. Although there is a lack of systematic studies on muscle function, it is believed that patients with acromegaly may suffer from proximal muscle weakness despite their increased muscle mass. We studied body composition and muscle function in untreated acromegaly and after biochemical remission. DESIGN: Prospective observational study. METHODS: Patients with acromegaly underwent measurements of muscle strength (dynamometers) and body composition (four-compartment model) at diagnosis (n = 48), 1 year after surgery (n = 29) and after long-term follow-up (median 11 years) (n = 24). Results were compared to healthy subjects. RESULTS: Untreated patients had increased body cell mass (113 +/- 9% of predicted) and ECW (110 +/- 20%) and decreased BF (67 +/- 7.6%). At one-year follow-up, serum concentration of IGF-I was reduced and body composition had normalized. At baseline, isometric muscle strength in knee flexors and extensors was normal and concentric strength was modestly increased whereas grip strength and endurance was reduced. After one year, muscle strength was normal in both patients with still active disease and patients in remission. At long-term follow-up, all patients were in remission. Most muscle function tests remained normal, but isometric flexion and the fatigue index were increased to 153 +/- 42% and 139 +/- 28% of predicted values, respectively. CONCLUSIONS: Patients with untreated acromegaly had increased body cell mass and normal or modestly increased proximal muscle strength, whereas their grip strength was reduced. After biochemical improvement and remission, body composition was normalized, hand grip strength was increased, whereas proximal muscle fatigue increased. PMID- 28566447 TI - MANAGEMENT OF ENDOCRINE DISEASE: l-Thyroxine replacement therapy in the frail elderly: a challenge in clinical practice. AB - The number of elderly people, mostly aged over 85 years (the 'oldest old'), is increasing worldwide. As a consequence, accompanying morbidity and disability have been increasing, and frailty, defined as an age-related condition of decline of physiological reserves and vulnerability, represents an emerging problem. Caring for older frail people may represent a challenge, since the elderly differ significantly from younger adults in terms of comorbidity, polypharmacy, pharmacokinetics and greater vulnerability to adverse drug reactions. Specific criteria of therapeutic appropriateness and modified goals of care are needed in such patients, also in endocrine care settings. Indeed, thyroid dysfunctions are among the most common conditions in older, multimorbid populations. The prevalence of overt and subclinical hypothyroidism is as high as 20% and thyroid hormone prescription is common in the elderly, with a trend toward levothyroxine treatment of more marginal degrees of hypothyroidism. In addition, older patients have the highest rate of overtreatment during replacement therapy and are more susceptible to developing adverse effects from thyroid hormone excess. Recently, results of a multicentric randomized controlled trial, the TRUST-IEMO collaboration trial, added further insights to the debated question of whether and when levothyroxine treatment is required and if it is beneficial in the elderly. With this in mind, we revised the relevant literature on the impact of thyroid dysfunction and replacement therapy among older people, with the aim to better define indications, benefits and risks of l-T4 replacement therapy in the frail elderly. PMID- 28566446 TI - Cortisol-related metabolic alterations assessed by mass spectrometry assay in patients with Cushing's syndrome. AB - OBJECTIVE: Endogenous hypercortisolism is a chronic condition associated with severe metabolic disturbances and cardiovascular sequela. The aim of this study was to characterize metabolic alterations in patients with different degrees of hypercortisolism by mass-spectrometry-based targeted plasma metabolomic profiling and correlate the metabolomic profile with clinical and hormonal data. DESIGN: Cross-sectional study. METHODS: Subjects (n = 149) were classified according to clinical and hormonal characteristics: Cushing's syndrome (n = 46), adrenocortical adenomas with autonomous cortisol secretion (n = 31) or without hypercortisolism (n = 27). Subjects with suspicion of hypercortisolism, but normal hormonal/imaging testing, served as controls (n = 42). Clinical and hormonal data were retrieved for all patients and targeted metabolomic profiling was performed. RESULTS: Patients with hypercortisolism showed lower levels of short-/medium-chain acylcarnitines and branched-chain and aromatic amino acids, but higher polyamines levels, in comparison to controls. These alterations were confirmed after excluding diabetic patients. Regression models showed significant correlation between cortisol after dexamethasone suppression test (DST) and 31 metabolites, independently of confounding/contributing factors. Among those, histidine and spermidine were also significantly associated with catabolic signs and symptoms of hypercortisolism. According to an discriminant analysis, the panel of metabolites was able to correctly classify subjects into the main diagnostic categories and to distinguish between subjects with/without altered post-DST cortisol and with/without diabetes in >80% of the cases. CONCLUSIONS: Metabolomic profiling revealed alterations of intermediate metabolism independently associated with the severity of hypercortisolism, consistent with disturbed protein synthesis/catabolism and incomplete beta-oxidation, providing evidence for the occurrence of metabolic inflexibility in hypercortisolism. PMID- 28566448 TI - Disease progression and regression in sporadic small vessel disease-insights from neuroimaging. AB - Cerebral small vessel disease (SVD) is considered the most important vascular contributor to the development of dementia. Comprehensive characterization of the time course of disease progression will result in better understanding of aetiology and clinical consequences of SVD. SVD progression has been studied extensively over the years, usually describing change in SVD markers over time using neuroimaging at two time points. As a consequence, SVD is usually seen as a rather linear, continuously progressive process. This assumption of continuous progression of SVD markers was recently challenged by several studies that showed regression of SVD markers. Here, we provide a review on disease progression in sporadic SVD, thereby taking into account both progression and regression of SVD markers with emphasis on white matter hyperintensities (WMH), lacunes and microbleeds. We will elaborate on temporal dynamics of SVD progression and discuss the view of SVD progression as a dynamic process, rather than the traditional view of SVD as a continuous progressive process, that might better fit evidence from longitudinal neuroimaging studies. We will discuss possible mechanisms and clinical implications of a dynamic time course of SVD, with both progression and regression of SVD markers. PMID- 28566449 TI - The role of perivascular innervation and neurally mediated vasoreactivity in the pathophysiology of Alzheimer's disease. AB - Neuronal death is a hallmark of Alzheimer's disease (AD) and considerable work has been done to understand how the loss of interconnectivity between neurons contributes to the associated dementia. Often overlooked however, is how the loss of neuronal innervation of blood vessels, termed perivascular innervation, may also contribute to the pathogenesis of AD. There is now considerable evidence supporting a crucial role for the neurovascular unit (NVU) in mediating the clearance of the beta-amyloid (Abeta) peptide, one of the main pathological constituents of AD, from the brain. Moreover, efficient removal appears to be dependent on the communication of cells within the NVU to maintain adequate vascular tone and pulsatility. This review summarizes the composition of the NVU, including the sources of perivascular innervation and how the NVU mediates Abeta clearance from the brain. It also explores evidence supporting the hypothesis that loss of neurally mediated vasoreactivity contributes to Abeta pathology in the AD brain. PMID- 28566450 TI - Monocyte subtypes and the CCR2 chemokine receptor in cardiovascular disease. AB - Monocytes circulate in the blood and migrate to inflammatory tissues, but their functions can be either detrimental or beneficial, depending on their phenotypes. In humans, classical monocytes are inflammatory cluster of differentiation (CD)14++CD16-CCR2++ cells originated from the bone marrow or spleen reservoirs and comprise >=92% of monocytes. Intermediate monocytes (CD14++CD16+CCR2+) are involved in the production of anti-inflammatory cytokines [such as interleukin (IL)-10], reactive oxygen species (ROS), and proinflammatory mediators [such as tumor necrosis factor-alpha (TNF-alpha) and IL-1beta). Nonclassical monocytes (CD14+CD16++CCR2-) are patrolling cells involved in tissue repair and debris removal from the vasculature. Many studies in both humans and animals have shown the importance of monocyte chemoattractant protein-1 (MCP-1) and its receptor [chemokine receptor of MCP-1 (CCR2)] in pathologies, such as atherosclerosis and myocardial infarction (MI). This review presents the importance of these monocyte subsets in cardiovascular diseases (CVDs), and sheds light on new strategies for the blocking of the MCP-1/CCR2 axis as a therapeutic goal for treating vascular disorders. PMID- 28566451 TI - Nuclear factor-kappaB and advanced glycation end-products expression in lacrimal glands of aging rats. PMID- 28566452 TI - Correction for Zhu et al., "Utp14 Recruits and Activates the RNA Helicase Dhr1 To Undock U3 snoRNA from the Preribosome". PMID- 28566453 TI - Correction for Sardana et al., "Physical and Functional Interaction between the Methyltransferase Bud23 and the Essential DEAH-Box RNA Helicase Ecm16". PMID- 28566454 TI - Correction for Kirkham et al., "Dynein Light Chain LC8 Is Required for RNA Polymerase I-Mediated Transcription in Trypanosoma brucei, Facilitating Assembly and Promoter Binding of Class I Transcription Factor A". PMID- 28566455 TI - Correction for Nakano et al., "Rad51-Dependent Aberrant Chromosome Structures at Telomeres and Ribosomal DNA Activate the Spindle Assembly Checkpoint". PMID- 28566456 TI - Correction for Erker et al., "Arkadia, a Novel SUMO-Targeted Ubiquitin Ligase Involved in PML Degradation". PMID- 28566459 TI - Development and aging of human spinal cord circuitries. AB - The neural motor circuitries in the spinal cord receive information from our senses and the rest of the nervous system and translate it into purposeful movements, which allow us to interact with the rest of the world. In this review, we discuss how these circuitries are established during early development and the extent to which they are shaped according to the demands of the body that they control and the environment with which the body has to interact. We also discuss how aging processes and physiological changes in our body are reflected in adaptations of activity in the spinal cord motor circuitries. The complex, multifaceted connectivity of the spinal cord motor circuitries allows them to generate vastly different movements and to adapt their activity to meet new challenges imposed by bodily changes or a changing environment. There are thus plenty of possibilities for adaptive changes in the spinal motor circuitries both early and late in life. PMID- 28566458 TI - Diverse effects of stimulus history in waking mouse auditory cortex. AB - Responses to auditory stimuli are often strongly influenced by recent stimulus history. For example, in a paradigm called forward suppression, brief sounds can suppress the perception of, and the neural responses to, a subsequent sound, with the magnitude of this suppression depending on both the spectral and temporal distances between the sounds. As a step towards understanding the mechanisms that generate these adaptive representations in awake animals, we quantitatively characterize responses to two-tone sequences in the auditory cortex of waking mice. We find that cortical responses in a forward suppression paradigm are more diverse in waking mice than previously appreciated, that these responses vary between cells with different firing characteristics and waveform shapes, but that the variability in these responses is not substantially related to cortical depth or columnar location. Moreover, responses to the first tone in the sequence are often not linearly related to the suppression of the second tone response, suggesting that spike-frequency adaptation of cortical cells is not a large contributor to forward suppression or its variability. Instead, we use a simple multilayered model to show that cell-to-cell differences in the balance of intracortical inhibition and excitation will naturally produce such a diversity of forward interactions. We propose that diverse inhibitory connectivity allows the cortex to encode spectro-temporally fluctuating stimuli in multiple parallel ways.NEW & NOTEWORTHY Behavioral and neural responses to auditory stimuli are profoundly influenced by recent sounds, yet how this occurs is not known. Here, the authors show in the auditory cortex of awake mice that the quality of history dependent effects is diverse and related to cell type, response latency, firing rates, and receptive field bandwidth. In a cortical model, differences in excitatory-inhibitory balance can produce this diversity, providing the cortex with multiple ways of representing temporally complex information. PMID- 28566460 TI - Mesoscale-duration activated states gate spiking in response to fast rises in membrane voltage in the awake brain. AB - Seconds-scale network states, affecting many neurons within a network, modulate neural activity by complementing fast integration of neuron-specific inputs that arrive in the milliseconds before spiking. Nonrhythmic subthreshold dynamics at intermediate timescales, however, are less well characterized. We found, using automated whole cell patch clamping in vivo, that spikes recorded in CA1 and barrel cortex in awake mice are often preceded not only by monotonic voltage rises lasting milliseconds but also by more gradual (lasting tens to hundreds of milliseconds) depolarizations. The latter exert a gating function on spiking, in a fashion that depends on the gradual rise duration: the probability of spiking was higher for longer gradual rises, even when controlled for the amplitude of the gradual rises. Barrel cortex double-autopatch recordings show that gradual rises are shared across some, but not all, neurons. The gradual rises may represent a new kind of state, intermediate both in timescale and in proportion of neurons participating, which gates a neuron's ability to respond to subsequent inputs.NEW & NOTEWORTHY We analyzed subthreshold activity preceding spikes in hippocampus and barrel cortex of awake mice. Aperiodic voltage ramps extending over tens to hundreds of milliseconds consistently precede and facilitate spikes, in a manner dependent on both their amplitude and their duration. These voltage ramps represent a "mesoscale" activated state that gates spike production in vivo. PMID- 28566461 TI - Separable systems for recovery of finger strength and control after stroke. AB - Impaired hand function after stroke is a major cause of long-term disability. We developed a novel paradigm that quantifies two critical aspects of hand function, strength, and independent control of fingers (individuation), and also removes any obligatory dependence between them. Hand recovery was tracked in 54 patients with hemiparesis over the first year after stroke. Most recovery of strength and individuation occurred within the first 3 mo. A novel time-invariant recovery function was identified: recovery of strength and individuation were tightly correlated up to a strength level of ~60% of estimated premorbid strength; beyond this threshold, strength improvement was not accompanied by further improvement in individuation. Any additional improvement in individuation was attributable instead to a second process that superimposed on the recovery function. We conclude that two separate systems are responsible for poststroke hand recovery: one contributes almost all of strength and some individuation; the other contributes additional individuation.NEW & NOTEWORTHY We tracked recovery of the hand over a 1-yr period after stroke in a large cohort of patients, using a novel paradigm that enabled independent measurement of finger strength and control. Most recovery of strength and control occurs in the first 3 mo after stroke. We found that two separable systems are responsible for motor recovery of hand: one contributes strength and some dexterity, whereas a second contributes additional dexterity. PMID- 28566463 TI - Functional connectivity between somatosensory and motor brain areas predicts individual differences in motor learning by observing. AB - Action observation can facilitate the acquisition of novel motor skills; however, there is considerable individual variability in the extent to which observation promotes motor learning. Here we tested the hypothesis that individual differences in brain function or structure can predict subsequent observation related gains in motor learning. Subjects underwent an anatomical MRI scan and resting-state fMRI scans to assess preobservation gray matter volume and preobservation resting-state functional connectivity (FC), respectively. On the following day, subjects observed a video of a tutor adapting her reaches to a novel force field. After observation, subjects performed reaches in a force field as a behavioral assessment of gains in motor learning resulting from observation. We found that individual differences in resting-state FC, but not gray matter volume, predicted postobservation gains in motor learning. Preobservation resting state FC between left primary somatosensory cortex and bilateral dorsal premotor cortex, primary motor cortex, and primary somatosensory cortex and left superior parietal lobule was positively correlated with behavioral measures of postobservation motor learning. Sensory-motor resting-state FC can thus predict the extent to which observation will promote subsequent motor learning.NEW & NOTEWORTHY We show that individual differences in preobservation brain function can predict subsequent observation-related gains in motor learning. Preobservation resting-state functional connectivity within a sensory-motor network may be used as a biomarker for the extent to which observation promotes motor learning. This kind of information may be useful if observation is to be used as a way to boost neuroplasticity and sensory-motor recovery for patients undergoing rehabilitation for diseases that impair movement such as stroke. PMID- 28566464 TI - Activation of ganglion cells and axon bundles using epiretinal electrical stimulation. AB - Epiretinal prostheses for treating blindness activate axon bundles, causing large, arc-shaped visual percepts that limit the quality of artificial vision. Improving the function of epiretinal prostheses therefore requires understanding and avoiding axon bundle activation. This study introduces a method to detect axon bundle activation on the basis of its electrical signature and uses the method to test whether epiretinal stimulation can directly elicit spikes in individual retinal ganglion cells without activating nearby axon bundles. Combined electrical stimulation and recording from isolated primate retina were performed using a custom multielectrode system (512 electrodes, 10-MUm diameter, 60-MUm pitch). Axon bundle signals were identified by their bidirectional propagation, speed, and increasing amplitude as a function of stimulation current. The threshold for bundle activation varied across electrodes and retinas, and was in the same range as the threshold for activating retinal ganglion cells near their somas. In the peripheral retina, 45% of electrodes that activated individual ganglion cells (17% of all electrodes) did so without activating bundles. This permitted selective activation of 21% of recorded ganglion cells (7% of expected ganglion cells) over the array. In one recording in the central retina, 75% of electrodes that activated individual ganglion cells (16% of all electrodes) did so without activating bundles. The ability to selectively activate a subset of retinal ganglion cells without axon bundles suggests a possible novel architecture for future epiretinal prostheses.NEW & NOTEWORTHY Large-scale multielectrode recording and stimulation were used to test how selectively retinal ganglion cells can be electrically activated without activating axon bundles. A novel method was developed to identify axon activation on the basis of its unique electrical signature and was used to find that a subset of ganglion cells can be activated at single-cell, single-spike resolution without producing bundle activity in peripheral and central retina. These findings have implications for the development of advanced retinal prostheses. PMID- 28566465 TI - The stochastic nature of action potential backpropagation in apical tuft dendrites. AB - In cortical pyramidal neurons, backpropagating action potentials (bAPs) supply Ca2+ to synaptic contacts on dendrites. To determine whether the efficacy of AP backpropagation into apical tuft dendrites is stable over time, we performed dendritic Ca2+ and voltage imaging in rat brain slices. We found that the amplitude of bAP-Ca2+ in apical tuft branches was unstable, given that it varied from trial to trial (termed "bAP-Ca2+ flickering"). Small perturbations in dendritic physiology, such as spontaneous synaptic inputs, channel inactivation, or temperature-induced changes in channel kinetics, can cause bAP flickering. In the tuft branches, the density of Na+ and K+ channels was sufficient to support local initiation of fast spikelets by glutamate iontophoresis. We quantified the time delay between the somatic AP burst and the peak of dendritic Ca2+ transient in the apical tuft, because this delay is important for induction of spike-timing dependent plasticity. Depending on the frequency of the somatic AP triplets, Ca2+ signals peaked in the apical tuft 20-50 ms after the 1st AP in the soma. Interestingly, at low frequency (<20 Hz), the Ca2+ peaked sooner than at high frequency, because only the 1st AP invaded tuft. Activation of dendritic voltage gated Ca2+ channels is sensitive to the duration of the dendritic voltage transient. In apical tuft branches, small changes in the duration of bAP voltage waveforms cause disproportionately large increases in dendritic Ca2+ influx (bAP Ca2+ flickering). The stochastic nature of bAP-Ca2+ adds a new perspective on the mechanisms by which pyramidal neurons combine inputs arriving at different cortical layers.NEW & NOTEWORTHY The bAP-Ca2+ signal amplitudes in some apical tuft branches randomly vary from moment to moment. In repetitive measurements, successful AP invasions are followed by complete failures. Passive spread of voltage from the apical trunk into the tuft occasionally reaches the threshold for local Na+ spike, resulting in stronger Ca2+ influx. During a burst of three somatic APs, the peak of dendritic Ca2+ in the apical tuft occurs with a delay of 20-50 ms depending on AP frequency. PMID- 28566462 TI - Neurophysiology and neural engineering: a review. AB - Neurophysiology is the branch of physiology concerned with understanding the function of neural systems. Neural engineering (also known as neuroengineering) is a discipline within biomedical engineering that uses engineering techniques to understand, repair, replace, enhance, or otherwise exploit the properties and functions of neural systems. In most cases neural engineering involves the development of an interface between electronic devices and living neural tissue. This review describes the origins of neural engineering, the explosive development of methods and devices commencing in the late 1950s, and the present day devices that have resulted. The barriers to interfacing electronic devices with living neural tissues are many and varied, and consequently there have been numerous stops and starts along the way. Representative examples are discussed. None of this could have happened without a basic understanding of the relevant neurophysiology. I also consider examples of how neural engineering is repaying the debt to basic neurophysiology with new knowledge and insight. PMID- 28566466 TI - The Ecology of Prions. AB - Chronic wasting disease (CWD) affects cervids and is the only known prion disease readily transmitted among free-ranging wild animal populations in nature. The increasing spread and prevalence of CWD among cervid populations threaten the survival of deer and elk herds in North America, and potentially beyond. This review focuses on prion ecology, specifically that of CWD, and the current understanding of the role that the environment may play in disease propagation. We recount the discovery of CWD, discuss the role of the environment in indirect CWD transmission, and consider potentially relevant environmental reservoirs and vectors. We conclude by discussing how understanding the environmental persistence of CWD lends insight into transmission dynamics and potential management and mitigation strategies. PMID- 28566467 TI - Diagnosis and management of inflammatory bowel disease in children. AB - Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are lifelong conditions that often begin in childhood. The implications of IBD are of particular importance in children because of the potential negative effects on growth, development, psychosocial function, and overall wellbeing. The key management strategy is to achieve sustained control of intestinal inflammation and monitor for potential complications of the disease and side effects of therapies. Overall, the evidence on the management of IBD in children is less extensive than in adults, but good quality multicenter studies and various guidelines and society consensus statements are available. This review summarizes the evidence on the pathophysiology, diagnosis, and approaches to management of children and adolescents with IBD. PMID- 28566468 TI - Smad7 protects against acute kidney injury by rescuing tubular epithelial cells from the G1 cell cycle arrest. AB - Smad7 plays a protective role in chronic kidney disease; however, its role in acute kidney injury (AKI) remains unexplored. Here, we report that Smad7 protects against AKI by rescuing the G1 cell cycle arrest of tubular epithelial cells (TECs) in ischemia/reperfusion-induced AKI in mice in which Smad7 gene is disrupted or restored locally into the kidney. In Smad7 gene knockout (KO) mice, more severe renal impairment including higher levels of serum creatinine and massive tubular necrosis was developed at 48 h after AKI. In contrast, restored renal Smad7 gene locally into the kidney of Smad7 KO mice protected against AKI by promoting TEC proliferation identified by PCNA+ and BrdU+ cells. Mechanistic studies revealed that worsen AKI in Smad7 KO mice was associated with a marked activation of TGF-beta/Smad3-p21/p27 signaling and a loss of CDK2/cyclin E activities, thereby impairing TEC regeneration at the G1 cell cycle arrest. In contrast, restored Smad7 locally into the kidneys of Smad7 KO mice protected TECs from the G1 cell cycle arrest and promoted TEC G1/S transition via a CDK2/cyclin E-dependent mechanism. In conclusion, Smad7 plays a protective role in AKI. Blockade of TGF-beta/Smad3-p21/p27-induced G1 cell cycle arrest may be a key mechanism by which Smad7 treatment inhibits AKI. Thus, Smad7 may be a novel therapeutic agent for AKI. PMID- 28566469 TI - Visceral adipose tissue activated macrophage content and inflammatory adipokine secretion is higher in pre-eclampsia than in healthy pregnancys. AB - Obesity increases pre-eclampsia (PE) risk. Adipose tissue inflammation may contribute to the clinical syndrome of PE. We compared adipose tissue macrophage infiltration and release of pro-inflammatory adipokines in PE and healthy pregnancy. Subcutaneous and visceral adipose tissue biopsies were collected from healthy (n=13) and PE (n=13) mothers. Basal and lipopolysaccharide (LPS) stimulated adipocyte TNFalpha, IL-6, CCL-2, and CRP release was measured. Adipose tissue cell densities of activated (cfms+) and total (CD68+) macrophages were determined. In PE only, visceral adipose tissue TNFalpha release was increased after LPS stimulation (57 [76] versus 81 [97] pg/ml/ug DNA, P=0.030). Basal TNFalpha release was negatively correlated insulin sensitivity of visceral adipocytes (r = -0.61, P=0.030) in PE. Visceral adipocyte IL-6 release was increased after LPS stimulation in PE only (566 [696] versus 852 [914] pg/ml/ug DNA, P=0.019). Visceral adipocyte CCL-2 basal (67 [61] versus 187 [219] pg/ml/ugDNA, P=0.049) and stimulated (46 [46] versus 224 [271] pg/ml/ug DNA, P=0.003) release was greater than in subcutaneous adipocytes in PE only. In PE, median TNF mRNA expression in visceral adipose tissue was higher than controls (1.94 [1.13-4.14] versus 0.8 [0.00-1.27] TNF/PPIA ratio, P=0.006). In visceral adipose tissue, CSF1R (a marker of activated macrophages) mRNA expression (24.8[11.0] versus 51.0[29.9] CSF1R/PPIA ratio, P=0.011) and activated (cfms+) macrophage count (6.7[2.6] versus 15.2[8.8] % cfms+/adipocyte, P=0.031) were higher in PE than in controls. In conclusion, our study demonstrates dysregulation of inflammatory pathways predominantly in visceral adipose tissue in PE. Inflammation of visceral adipose tissue may mediate many of the adverse metabolic effects associated with PE. PMID- 28566470 TI - Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion. AB - Pulmonary neuroendocrine cells (PNECs) are the only innervated airway epithelial cells. To what extent neural innervation regulates PNEC secretion and function is unknown. Here, we discover that neurotrophin 4 (NT4) plays an essential role in mucus overproduction after early life allergen exposure by orchestrating PNEC innervation and secretion of GABA. We found that PNECs were the only cellular source of GABA in airways. In addition, PNECs expressed NT4 as a target-derived mechanism underlying PNEC innervation during development. Early life allergen exposure elevated the level of NT4 and caused PNEC hyperinnervation and nodose neuron hyperactivity. Associated with aberrant PNEC innervation, the authors discovered that GABA hypersecretion was required for the induction of mucin Muc5ac expression. In contrast, NT4-/- mice were protected from allergen-induced mucus overproduction and changes along the nerve-PNEC axis without any defects in inflammation. Last, GABA installation restored mucus overproduction in NT4-/- mice after early life allergen exposure. Together, our findings provide the first evidence for NT4-dependent neural regulation of PNEC secretion of GABA in a neonatal disease model. Targeting the nerve-PNEC axis may be a valid treatment strategy for mucus overproduction in airway diseases, such as childhood asthma. Barrios, J., Patel, K. R., Aven, L., Achey, R., Minns, M. S., Lee, Y., Trinkaus Randall, V. E., Ai, X. Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion. PMID- 28566471 TI - Emergency treatment of decompensated aortic stenosis. AB - OBJECTIVE: The optimal treatment of patients with acute and severe decompensation of aortic stenosis is unclear due to recent advances in transcatheter interventions and supportive therapies. Our aim was to assess the early outcome of emergency transcatheter aortic valve implantation (eTAVI) versus emergency balloon aortic valvuloplasty (eBAV) followed by TAVI under elective circumstances. METHODS: Emergency conditions were defined as: cardiogenic shock with requirement of catecholamine therapy, severe acute dyspnoea (NYHA IV), cardiac resuscitation or mechanic respiratory support. The data were collected according to the Valve Academic Research Consortium 2 (VARC-2) criteria. RESULTS: In five German centres, 23 patients (logistic Euroscore 37.7%+/-18.1) underwent eTAVI and 118 patients underwent eBAV (logistic Euroscore 35.3%+/-20.8). In the eTAVI group, immediate procedural mortality was 8.7%, compared with 20.3% for the eBAV group (p=0.19). After 30 days, cardiovascular mortality for the eTAVI group was 23.8% and for the eBAV group 33.0% (p=0.40). Analyses adjusting for potential confounders did not provide evidence of a difference between groups. Of note, the elective TAVI performed after eBAV (n=32, logistic Euroscore 25.9%+/-13.9) displayed an immediate procedural mortality of 9.4% and a cardiovascular mortality after 30 days of 15.6%. Major vascular complications were significantly more likely to occur after eTAVI (p=0.01) as well as stroke (p=0.01). CONCLUSION: In this multicentre cohort, immediate procedural and 30-day mortality of eTAVI and eBAV were high, and mortality of secondary TAVI subsequent to eBAV was higher than expected. Randomised study data are required to define the role of emergency TAVI in tertiary care centres with current device generations. PMID- 28566472 TI - Pacemaker reuse in low-income/middle-income countries: moral duty or dangerous precedent? PMID- 28566473 TI - Declining incidence and prevalence of Eisenmenger syndrome in the developed world: a triumph of modern medicine. PMID- 28566474 TI - Mitral valve repair for degenerative mitral valve disease: surgical approach, patient selection and long-term outcomes. AB - Mitral valve repair (MVRepair) has become the procedure of choice to correct severe degenerative mitral regurgitation (MR), due to its documented superiority to valve replacement regarding long-term survival, freedom from valve-related adverse events and preservation of left ventricular (LV) function. The refinement of MVRepair techniques has rendered almost all valves (more than 95%) amenable to repair with a 15-year freedom from reoperation of 90%. The concept of 'centres of excellence for MVRepair' has emerged, encouraging referring doctors to select the most experienced institutions or individual surgeons to deal with the most complex cases, based on repair volume, appropriate peri-procedural imaging and data regarding expected outcomes (repair, mortality and durability of repair). Based on the good results, operating on asymptomatic patients with severe MR is now widely accepted, prophylactically avoiding the dire consequences of chronic MR, such as LV function deterioration/enlargement, and development of atrial fibrillation and pulmonary hypertension. In reference centres, where the repair rate is over 95% for all types of disease with <1% mortality, it has become standard practice in nearly 50%-60% of all patients submitted to MVRepair. Finally, recent advances in the surgical treatment with the purpose of reducing invasiveness and surgical trauma, through partial sternotomy or mini-thoracotomy (video-assisted with or without robotics), are now being increasingly performed in 20%-30% of centres, claiming comparable results to conventional surgery. In addition, transcatheter technology, particularly the MitraClip, is evolving and treading its way in the treatment of high-risk patients with severe MR, but the results are still short of ideal. PMID- 28566476 TI - A case of metronidazole-induced neurotoxicity. PMID- 28566475 TI - The Pacemaker and ICD Reuse Programme of the Pan-African Society of Cardiology. PMID- 28566478 TI - ILC2: There's a New Cell in Town. PMID- 28566477 TI - Long-Term Outcome of Steroid-Resistant Nephrotic Syndrome in Children. AB - We investigated the value of genetic, histopathologic, and early treatment response information in prognosing long-term renal outcome in children with primary steroid-resistant nephrotic syndrome. From the PodoNet Registry, we obtained longitudinal clinical information for 1354 patients (disease onset at >3 months and <20 years of age): 612 had documented responsiveness to intensified immunosuppression (IIS), 1155 had kidney biopsy results, and 212 had an established genetic diagnosis. We assessed risk factors for ESRD using multivariate Cox regression models. Complete and partial remission of proteinuria within 12 months of disease onset occurred in 24.5% and 16.5% of children, respectively, with the highest remission rates achieved with calcineurin inhibitor-based protocols. Ten-year ESRD-free survival rates were 43%, 94%, and 72% in children with IIS resistance, complete remission, and partial remission, respectively; 27% in children with a genetic diagnosis; and 79% and 52% in children with histopathologic findings of minimal change glomerulopathy and FSGS, respectively. Five-year ESRD-free survival rate was 21% for diffuse mesangial sclerosis. IIS responsiveness, presence of a genetic diagnosis, and FSGS or diffuse mesangial sclerosis on initial biopsy as well as age, serum albumin concentration, and CKD stage at onset affected ESRD risk. Our findings suggest that responsiveness to initial IIS and detection of a hereditary podocytopathy are prognostic indicators of favorable and poor long-term outcome, respectively, in children with steroid-resistant nephrotic syndrome. Children with multidrug resistant sporadic disease show better renal survival than those with genetic disease. Furthermore, histopathologic findings may retain prognostic relevance when a genetic diagnosis is established. PMID- 28566479 TI - Targeted Exome Sequencing Identifies PBX1 as Involved in Monogenic Congenital Anomalies of the Kidney and Urinary Tract. AB - Congenital anomalies of the kidney and urinary tract (CAKUT) occur in three to six of 1000 live births, represent about 20% of the prenatally detected anomalies, and constitute the main cause of CKD in children. These disorders are phenotypically and genetically heterogeneous. Monogenic causes of CAKUT in humans and mice have been identified. However, despite high-throughput sequencing studies, the cause of the disease remains unknown in most patients, and several studies support more complex inheritance and the role of environmental factors and/or epigenetics in the pathophysiology of CAKUT. Here, we report the targeted exome sequencing of 330 genes, including genes known to be involved in CAKUT and candidate genes, in a cohort of 204 unrelated patients with CAKUT; 45% of the patients were severe fetal cases. We identified pathogenic mutations in 36 of 204 (17.6%) patients. These mutations included five de novo heterozygous loss of function mutations/deletions in the PBX homeobox 1 gene (PBX1), a gene known to have a crucial role in kidney development. In contrast, the frequency of SOX17 and DSTYK variants recently reported as pathogenic in CAKUT did not indicate causality. These findings suggest that PBX1 is involved in monogenic CAKUT in humans and call into question the role of some gene variants recently reported as pathogenic in CAKUT. Targeted exome sequencing also proved to be an efficient and cost-effective strategy to identify pathogenic mutations and deletions in known CAKUT genes. PMID- 28566480 TI - Autoantibodies against C-Reactive Protein Influence Complement Activation and Clinical Course in Lupus Nephritis. AB - Autoantibodies against the major acute-phase reactant C-reactive protein (CRP) are frequently found in patients with lupus nephritis. Further defining the autoimmune epitopes on CRP may not only improve patient stratification but also, hint at mechanisms of CRP action. Herein, we show that amino acids 35-47 constitute the major epitope recognized by anti-CRP autoantibodies in patients with lupus nephritis. Notably, the presence of autoantibodies against amino acids 35-47 associated with more severe renal damage and predicted worse outcome. This epitope is exposed on CRP only after irreversible structure changes, yielding a conformationally altered form termed modified or monomeric CRP (mCRP). ELISA and surface plasmon resonance assays showed that amino acids 35-47 mediate the interaction of mCRP with complement factor H, an inhibitor of alternative pathway activation, and this interaction greatly enhanced the in vitro cofactor activity of complement factor H. In contrast, autoantibodies against amino acids 35-47 inhibited these actions of mCRP. Our results thus provide evidence for the in vivo generation of mCRP in a human disease and suggest that mCRP actively controls the pathogenesis of lupus nephritis by regulating complement activation. Therefore, amino acids 35-47 constitute a functional autoimmune epitope on CRP that can be targeted therapeutically and diagnostically. PMID- 28566481 TI - Defaunation effects on plant recruitment depend on size matching and size trade offs in seed-dispersal networks. AB - Defaunation by humans causes a loss of large animals in many ecosystems globally. Recent work has emphasized the consequences of downsizing in animal communities for ecosystem functioning. However, no study so far has integrated network theory and life-history trade-offs to mechanistically evaluate the functional consequences of defaunation in plant-animal networks. Here, we simulated an avian seed-dispersal network and its derived ecosystem function seedling recruitment to assess the relative importance of different size-related mechanisms. Specifically, we considered size matching (between bird size and seed size) and size trade-offs, which are driven by differences in plant or animal species abundance (negative size-quantity relationship) as well as in recruitment probability and disperser quality (positive size-quality relationship). Defaunation led to impoverished seedling communities in terms of diversity and seed size, but only if models accounted for size matching. In addition, size trade-off in plants, in concert with size matching, provoked rapid decays in seedling abundance in response to defaunation. These results underscore a disproportional importance of large animals for ecosystem functions. Downsizing in ecological networks will have severe consequences for ecosystem functioning, especially in interaction networks that are structured by size matching between plants and animals. PMID- 28566482 TI - Species contributions to ecosystem process and function can be population dependent and modified by biotic and abiotic setting. AB - There is unequivocal evidence that altered biodiversity, through changes in the expression and distribution of functional traits, can have large impacts on ecosystem properties. However, trait-based summaries of how organisms affect ecosystem properties often assume that traits show constancy within and between populations and that species contributions to ecosystem functioning are not overly affected by the presence of other species or variations in abiotic conditions. Here, we evaluate the validity of these assumptions using an experiment in which three geographically distinct populations of intertidal sediment-dwelling invertebrates are reciprocally substituted. We find that the mediation of macronutrient generation by these species can vary between different populations and show that changes in biotic and/or abiotic conditions can further modify functionally important aspects of the behaviour of individuals within a population. Our results demonstrate the importance of knowing how, when, and why traits are expressed and suggest that these dimensions of species functionality are not sufficiently well-constrained to facilitate the accurate projection of the functional consequences of change. Information regarding the ecological role of key species and assumptions about the form of species-environment interactions needs urgent refinement. PMID- 28566484 TI - Response of bats to light with different spectra: light-shy and agile bat presence is affected by white and green, but not red light. AB - Artificial light at night has shown a remarkable increase over the past decades. Effects are reported for many species groups, and include changes in presence, behaviour, physiology and life-history traits. Among these, bats are strongly affected, and how bat species react to light is likely to vary with light colour. Different spectra may therefore be applied to reduce negative impacts. We used a unique set-up of eight field sites to study the response of bats to three different experimental light spectra in an otherwise dark and undisturbed natural habitat. We measured activity of three bat species groups around transects with light posts emitting white, green and red light with an intensity commonly used to illuminate countryside roads. The results reveal a strong and spectrum dependent response for the slow-flying Myotis and Plecotus and more agile Pipistrellus species, but not for Nyctalus and Eptesicus species. Plecotus and Myotis species avoided white and green light, but were equally abundant in red light and darkness. The agile, opportunistically feeding Pipistrellus species were significantly more abundant around white and green light, most likely because of accumulation of insects, but equally abundant in red illuminated transects compared to dark control. Forest-dwelling Myotis and Plecotus species and more synanthropic Pipistrellus species are thus least disturbed by red light. Hence, in order to limit the negative impact of light at night on bats, white and green light should be avoided in or close to natural habitat, but red lights may be used if illumination is needed. PMID- 28566485 TI - Adhesion enhancement of cribellate capture threads by epicuticular waxes of the insect prey sheds new light on spider web evolution. AB - To survive, web-building spiders rely on their capture threads to restrain prey. Many species use special adhesives for this task, and again the majority of those species cover their threads with viscoelastic glue droplets. Cribellate spiders, by contrast, use a wool of nanofibres as adhesive. Previous studies hypothesized that prey is restrained by van der Waals' forces and entrapment in the nanofibres. A large discrepancy when comparing the adhesive force on artificial surfaces versus prey implied that the real mechanism was still elusive. We observed that insect prey's epicuticular waxes infiltrate the wool of nanofibres, probably induced by capillary forces. The fibre-reinforced composite thus formed led to an adhesion between prey and thread eight times stronger than that between thread and wax-free surfaces. Thus, cribellate spiders employ the originally protective coating of their insect prey as a fatal component of their adhesive and the insect promotes its own capture. We suggest an evolutionary arms race with prey changing the properties of their cuticular waxes to escape the cribellate capture threads that eventually favoured spider threads with viscous glue. PMID- 28566483 TI - The sources of adaptive variation. AB - The role of natural selection in the evolution of adaptive phenotypes has undergone constant probing by evolutionary biologists, employing both theoretical and empirical approaches. As Darwin noted, natural selection can act together with other processes, including random changes in the frequencies of phenotypic differences that are not under strong selection, and changes in the environment, which may reflect evolutionary changes in the organisms themselves. As understanding of genetics developed after 1900, the new genetic discoveries were incorporated into evolutionary biology. The resulting general principles were summarized by Julian Huxley in his 1942 book Evolution: the modern synthesis Here, we examine how recent advances in genetics, developmental biology and molecular biology, including epigenetics, relate to today's understanding of the evolution of adaptations. We illustrate how careful genetic studies have repeatedly shown that apparently puzzling results in a wide diversity of organisms involve processes that are consistent with neo-Darwinism. They do not support important roles in adaptation for processes such as directed mutation or the inheritance of acquired characters, and therefore no radical revision of our understanding of the mechanism of adaptive evolution is needed. PMID- 28566486 TI - Ecological drift and the distribution of species diversity. AB - Ecological drift causes species abundances to fluctuate randomly, lowering diversity within communities and increasing differences among otherwise equivalent communities. Despite broad interest in ecological drift, ecologists have little experimental evidence of its consequences in nature, where competitive forces modulate species abundances. We manipulated drift by imposing 40-fold variation in the size of experimentally assembled annual plant communities and holding their edge-to-interior ratios comparable. Drift over three generations was greater than predicted by neutral models, causing high extinction rates and fast divergence in composition among smaller communities. Competitive asymmetries drove populations of most species to small enough sizes that demographic stochasticity could markedly influence dynamics, increasing the importance of drift in communities. The strong effects of drift occurred despite stabilizing niche differences, which cause species to have greater population growth rates when at low local abundance. Overall, the importance of ecological drift appears greater in non-neutral communities than previously recognized, and varies with community size and the type and strength of density dependence. PMID- 28566487 TI - Local neighbourhood and regional climatic contexts interact to explain tree performance. AB - Tree neighbourhood modelling has significantly contributed to our understanding of the mechanisms structuring communities. Investigations into the impact of neighbouring crowding on tree performance have generally been conducted at local scales, missing important regional-scale context such as the suitability of the climate for each species. Favourable climates may enhance tree performance, but this may come at the cost of increased neighbourhood crowding and competition negatively impacting survival and growth. Through the synthesis of continental scale forest inventory and trait datasets from the northeast USA and Puerto Rico we present an analytical approach that elucidates the important interactions between local competitive and regional climatic contexts. Our results show strong asymmetries in competitive interactions and significant niche differences that are dependent on habitat suitability. The strong interaction between local neighbourhood and regional climate highlights the need for models that consider the interaction between these two processes that have been previously ignored. PMID- 28566488 TI - A fossil protein chimera; difficulties in discriminating dinosaur peptide sequences from modern cross-contamination. AB - A decade ago, reports that organic-rich soft tissue survived from dinosaur fossils were apparently supported by proteomics-derived sequence information of exceptionally well-preserved bone. This initial claim to the sequencing of endogenous collagen peptides from an approximately 68 Myr Tyrannosaurus rex fossil was highly controversial, largely on the grounds of potential contamination from either bacterial biofilms or from laboratory practice. In a subsequent study, collagen peptide sequences from an approximately 78 Myr Brachylophosaurus canadensis fossil were reported that have remained largely unchallenged. However, the endogeneity of these sequences relies heavily on a single peptide sequence, apparently unique to both dinosaurs. Given the potential for cross-contamination from modern bone analysed by the same team, here we extract collagen from bone samples of three individuals of ostrich, Struthio camelus The resulting LC-MS/MS data were found to match all of the proposed sequences for both the original Tyrannosaurus and Brachylophosaurus studies. Regardless of the true nature of the dinosaur peptides, our finding highlights the difficulty of differentiating such sequences with confidence. Our results not only imply that cross-contamination cannot be ruled out, but that appropriate measures to test for endogeneity should be further evaluated. PMID- 28566489 TI - An evolutionary model to predict the frequency of antibiotic resistance under seasonal antibiotic use, and an application to Streptococcus pneumoniae. AB - The frequency of resistance to antibiotics in Streptococcus pneumoniae has been stable over recent decades. For example, penicillin non-susceptibility in Europe has fluctuated between 12% and 16% without any major time trend. In spite of long term stability, resistance fluctuates over short time scales, presumably in part due to seasonal fluctuations in antibiotic prescriptions. Here, we develop a model that describes the evolution of antibiotic resistance under selection by multiple antibiotics prescribed at seasonally changing rates. This model was inspired by, and fitted to, published data on monthly antibiotics prescriptions and frequency of resistance in two communities in Israel over 5 years. Seasonal fluctuations in antibiotic usage translate into small fluctuations of the frequency of resistance around the average value. We describe these dynamics using a perturbation approach that encapsulates all ecological and evolutionary forces into a generic model, whose parameters quantify a force stabilizing the frequency of resistance around the equilibrium and the sensitivity of the population to antibiotic selection. Fitting the model to the data revealed a strong stabilizing force, typically two to five times stronger than direct selection due to antibiotics. The strong stabilizing force explains that resistance fluctuates in phase with usage, as antibiotic selection alone would result in resistance fluctuating behind usage with a lag of three months when antibiotic use is seasonal. While most antibiotics selected for increased resistance, intriguingly, cephalosporins selected for decreased resistance to penicillins and macrolides, an effect consistent in the two communities. One extra monthly prescription of cephalosporins per 1000 children decreased the frequency of penicillin-resistant strains by 1.7%. This model emerges under minimal assumptions, quantifies the forces acting on resistance and explains up to 43% of the temporal variation in resistance. PMID- 28566490 TI - The activation of N-methyl-d-aspartate receptors downregulates transient outward potassium and L-type calcium currents in rat models of depression. AB - Major depression is an important clinical factor in ventricular arrhythmia. Patients diagnosed with major depression overexpress N-methyl-d-aspartate receptors (NMDARs). Previous studies found that chronic NMDAR activation increases susceptibility to ventricular arrhythmias. We aimed to explore the mechanisms by which NMDAR activation may increase susceptibility to ventricular arrhythmias. Male rats were randomly assigned to either normal environments as control (CTL) group or 4 wk of chronic mild stress (CMS) to produce a major depression disorder (MDD) model group. After 4 wk of CMS, depression-like behaviors were measured in both groups. Varying doses (1-100 MUM) of NMDA and 10 MUM NMDA antagonist (MK-801) were perfused through ventricular myocytes isolated from MDD rats to measure the L-type calcium current (ICa-L) and transient outward potassium current (Ito). Structural remodeling was assessed using serial histopathology including Masson's trichrome dye. Electrophysiological characteristics were evaluated using Langendorff perfusion. Depression-like behaviors were observed in MDD rats. MDD rats showed longer action potential durations at 90% repolarization and higher susceptibility to ventricular arrhythmias than CTL rats. MDD rats showed lower ICa-L and Ito current densities than CTL rats. Additionally, NMDA reduced both currents in a concentration dependent manner, whereas there was no significant impact on the currents when perfused with MK-801. MDD rats exhibited significantly more fibrosis areas in heart tissue and reduced expression of Kv4.2, Kv4.3, and Cav1.2. We observed that acute NMDAR activation led to downregulation of potassium and L-type calcium currents in a rat model of depression, which may be the mechanism underlying ventricular arrhythmia promotion by depression. PMID- 28566492 TI - Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells. AB - Langerhans cell histiocytosis (LCH) and the non-LCH neoplasm Erdheim-Chester disease (ECD) are heterogeneous neoplastic disorders marked by infiltration of pathologic macrophage-, dendritic cell-, or monocyte-derived cells in tissues driven by recurrent mutations activating MAPK signaling. Although recent data indicate that at least a proportion of LCH and ECD patients have detectable activating kinase mutations in circulating hematopoietic cells and bone marrow based hematopoietic progenitors, functional evidence of the cell of origin of histiocytosis from actual patient materials has long been elusive. Here, we provide evidence for mutations in MAPK signaling intermediates in CD34+ cells from patients with ECD and LCH/ECD, including detection of shared origin of LCH and acute myelomonocytic leukemia driven by TET2-mutant CD34+ cell progenitors in one patient. We also demonstrate functional self-renewal capacity for CD34+ cells to drive the development of histiocytosis in xenotransplantation assays in vivo. These data indicate that the cell of origin of at least a proportion of patients with systemic histiocytoses resides in hematopoietic progenitor cells prior to committed monocyte/macrophage or dendritic cell differentiation and provide the first example of a patient-derived xenotransplantation model for a human histiocytic neoplasm. PMID- 28566491 TI - Chronic hypoxia alters fetal cerebrovascular responses to endothelin-1. AB - In utero hypoxia influences the structure and function of most fetal arteries, including those of the developing cerebral circulation. Whereas the signals that initiate this hypoxic remodeling remain uncertain, these appear to be distinct from the mechanisms that maintain the remodeled vascular state. The present study explores the hypothesis that chronic hypoxia elicits sustained changes in fetal cerebrovascular reactivity to endothelin-1 (ET-1), a potent vascular contractant and mitogen. In fetal lambs, chronic hypoxia (3,820-m altitude for the last 110 days of gestation) had no significant effect on plasma ET-1 levels or ETA receptor density in cerebral arteries but enhanced contractile responses to ET-1 in an ETA-dependent manner. In organ culture (24 h), 10 nM ET-1 increased medial thicknesses less in hypoxic than in normoxic arteries, and these increases were ablated by inhibition of PKC (chelerythrine) in both normoxic and hypoxic arteries but were attenuated by inhibition of CaMKII (KN93) and p38 (SB203580) in normoxic but not hypoxic arteries. As indicated by Ki-67 immunostaining, ET-1 increased medial thicknesses via hypertrophy. Measurements of colocalization between MLCK and SMalphaA revealed that organ culture with ET-1 also promoted contractile dedifferentiation in normoxic, but not hypoxic, arteries through mechanisms attenuated by inhibitors of PKC, CaMKII, and p38. These results support the hypothesis that chronic hypoxia elicits sustained changes in fetal cerebrovascular reactivity to ET-1 through pathways dependent upon PKC, CaMKII, and p38 that cause increased ET-1-mediated contractility, decreased ET-1-mediated smooth muscle hypertrophy, and a depressed ability of ET-1 to promote contractile dedifferentiation. PMID- 28566493 TI - Urinary sampling for 5HIAA and metanephrines determination: revisiting the recommendations. AB - CONTEXT: Biogenic amines such as 5-hydroxy-indole acetic acid (5HIAA) the main metabolite of serotonin or metanephrines (catecholamines metabolites) are used as biomarkers of neuroendocrine tumours. OBJECTIVE: To re-evaluate the recommendations for urinary sampling (preservatives, diet, drugs, etc.) as many of the reported analytical interferences supporting these recommendations are related to obsolete assays. METHODS: Bibliographic analysis of old and modern assays concerning preservation, extraction, assay and interferences. RESULTS: 5HIAA may degrade as soon as urine is excreted. Thus, acids as preservatives (hydrochloric or acetic acid) have to be immediately added. Care should be taken not to decrease the pH under 2. Urine preservative for metanephrine assays is not mandatory. Diets including serotonin-, tryptophan- and dopamine-rich foods have to be avoided depending on the biomarkers investigated (bananas, plantain, nuts, etc.). Tryptophan-rich over-the-counter formulas have to be prohibited when 5HIAA has to be assayed. Acetaminophen may interfere with electrochemical detection depending on high-pressure liquid chromatography (HPLC) parameters. No interference is known with mass spectrometric assays but with the one described for metanephrines determination. Some drugs interfere however with serotonin and catecholamines secretion and/or metabolism (monoamine oxidase inhibitors, serotonin or dopamine recapture inhibitors, etc.). CONCLUSION: Revisited recommendations are provided for the diet, the drugs and the preservatives before HPLC coupled with electrochemical and mass spectrometry assays. PMID- 28566494 TI - Zinc-binding structure of a catalytic amyloid from solid-state NMR. AB - Throughout biology, amyloids are key structures in both functional proteins and the end product of pathologic protein misfolding. Amyloids might also represent an early precursor in the evolution of life because of their small molecular size and their ability to self-purify and catalyze chemical reactions. They also provide attractive backbones for advanced materials. When beta-strands of an amyloid are arranged parallel and in register, side chains from the same position of each chain align, facilitating metal chelation when the residues are good ligands such as histidine. High-resolution structures of metalloamyloids are needed to understand the molecular bases of metal-amyloid interactions. Here we combine solid-state NMR and structural bioinformatics to determine the structure of a zinc-bound metalloamyloid that catalyzes ester hydrolysis. The peptide forms amphiphilic parallel beta-sheets that assemble into stacked bilayers with alternating hydrophobic and polar interfaces. The hydrophobic interface is stabilized by apolar side chains from adjacent sheets, whereas the hydrated polar interface houses the Zn2+-binding histidines with binding geometries unusual in proteins. Each Zn2+ has two bis-coordinated histidine ligands, which bridge adjacent strands to form an infinite metal-ligand chain along the fibril axis. A third histidine completes the protein ligand environment, leaving a free site on the Zn2+ for water activation. This structure defines a class of materials, which we call metal-peptide frameworks. The structure reveals a delicate interplay through which metal ions stabilize the amyloid structure, which in turn shapes the ligand geometry and catalytic reactivity of Zn2. PMID- 28566495 TI - Hidden role of intermolecular proton transfer in the anomalously diffuse vibrational spectrum of a trapped hydronium ion. AB - We report the vibrational spectra of the hydronium and methyl-ammonium ions captured in the C3v binding pocket of the 18-crown-6 ether ionophore. Although the NH stretching bands of the CH3NH3+ ion are consistent with harmonic expectations, the OH stretching bands of H3O+ are surprisingly broad, appearing as a diffuse background absorption with little intensity modulation over 800 cm-1 with an onset ~400 cm-1 below the harmonic prediction. This structure persists even when only a single OH group is present in the HD2O+ isotopologue, while the OD stretching region displays a regular progression involving a soft mode at about 85 cm-1 These results are rationalized in a vibrationally adiabatic (VA) model in which the motion of the H3O+ ion in the crown pocket is strongly coupled with its OH stretches. In this picture, H3O+ resides in the center of the crown in the vibrational zero-point level, while the minima in the VA potentials associated with the excited OH vibrational states are shifted away from the symmetrical configuration displayed by the ground state. Infrared excitation between these strongly H/D isotope-dependent VA potentials then accounts for most of the broadening in the OH stretching manifold. Specifically, low-frequency motions involving concerted motions of the crown scaffold and the H3O+ ion are driven by a Franck-Condon-like mechanism. In essence, vibrational spectroscopy of these systems can be viewed from the perspective of photochemical interconversion between transient, isomeric forms of the complexes corresponding to the initial stage of intermolecular proton transfer. PMID- 28566497 TI - Unique aqueous Li-ion/sulfur chemistry with high energy density and reversibility. AB - Leveraging the most recent success in expanding the electrochemical stability window of aqueous electrolytes, in this work we create a unique Li-ion/sulfur chemistry of both high energy density and safety. We show that in the superconcentrated aqueous electrolyte, lithiation of sulfur experiences phase change from a high-order polysulfide to low-order polysulfides through solid liquid two-phase reaction pathway, where the liquid polysulfide phase in the sulfide electrode is thermodynamically phase-separated from the superconcentrated aqueous electrolyte. The sulfur with solid-liquid two-phase exhibits a reversible capacity of 1,327 mAh/(g of S), along with fast reaction kinetics and negligible polysulfide dissolution. By coupling a sulfur anode with different Li-ion cathode materials, the aqueous Li-ion/sulfur full cell delivers record-high energy densities up to 200 Wh/(kg of total electrode mass) for >1,000 cycles at ~100% coulombic efficiency. These performances already approach that of commercial lithium-ion batteries (LIBs) using a nonaqueous electrolyte, along with intrinsic safety not possessed by the latter. The excellent performance of this aqueous battery chemistry significantly promotes the practical possibility of aqueous LIBs in large-format applications. PMID- 28566496 TI - Phosphate is the third nutrient monitored by TOR in Candida albicans and provides a target for fungal-specific indirect TOR inhibition. AB - The Target of Rapamycin (TOR) pathway regulates morphogenesis and responses to host cells in the fungal pathogen Candida albicans Eukaryotic Target of Rapamycin complex 1 (TORC1) induces growth and proliferation in response to nitrogen and carbon source availability. Our unbiased genetic approach seeking unknown components of TORC1 signaling in C. albicans revealed that the phosphate transporter Pho84 is required for normal TORC1 activity. We found that mutants in PHO84 are hypersensitive to rapamycin and in response to phosphate feeding, generate less phosphorylated ribosomal protein S6 (P-S6) than the WT. The small GTPase Gtr1, a component of the TORC1-activating EGO complex, links Pho84 to TORC1. Mutants in Gtr1 but not in another TORC1-activating GTPase, Rhb1, are defective in the P-S6 response to phosphate. Overexpression of Gtr1 and a constitutively active Gtr1Q67L mutant suppresses TORC1-related defects. In Saccharomyces cerevisiae pho84 mutants, constitutively active Gtr1 suppresses a TORC1 signaling defect but does not rescue rapamycin hypersensitivity. Hence, connections from phosphate homeostasis (PHO) to TORC1 may differ between C. albicans and S. cerevisiae The converse direction of signaling from TORC1 to the PHO regulon previously observed in S. cerevisiae was genetically shown in C. albicans using conditional TOR1 alleles. A small molecule inhibitor of Pho84, a Food and Drug Administration-approved drug, inhibits TORC1 signaling and potentiates the activity of the antifungals amphotericin B and micafungin. Anabolic TORC1-dependent processes require significant amounts of phosphate. Our study shows that phosphate availability is monitored and also controlled by TORC1 and that TORC1 can be indirectly targeted by inhibiting Pho84. PMID- 28566499 TI - Finally making sense of the double-slit experiment. AB - Feynman stated that the double-slit experiment "...has in it the heart of quantum mechanics. In reality, it contains the only mystery" and that "nobody can give you a deeper explanation of this phenomenon than I have given; that is, a description of it" [Feynman R, Leighton R, Sands M (1965) The Feynman Lectures on Physics]. We rise to the challenge with an alternative to the wave function centered interpretations: instead of a quantum wave passing through both slits, we have a localized particle with nonlocal interactions with the other slit. Key to this explanation is dynamical nonlocality, which naturally appears in the Heisenberg picture as nonlocal equations of motion. This insight led us to develop an approach to quantum mechanics which relies on pre- and postselection, weak measurements, deterministic, and modular variables. We consider those properties of a single particle that are deterministic to be primal. The Heisenberg picture allows us to specify the most complete enumeration of such deterministic properties in contrast to the Schrodinger wave function, which remains an ensemble property. We exercise this approach by analyzing a version of the double-slit experiment augmented with postselection, showing that only it and not the wave function approach can be accommodated within a time-symmetric interpretation, where interference appears even when the particle is localized. Although the Heisenberg and Schrodinger pictures are equivalent formulations, nevertheless, the framework presented here has led to insights, intuitions, and experiments that were missed from the old perspective. PMID- 28566498 TI - Thermal combination therapies for local drug delivery by magnetic resonance guided high-intensity focused ultrasound. AB - Several thermal-therapy strategies such as thermal ablation, hyperthermia triggered drug delivery from temperature-sensitive liposomes (TSLs), and combinations of the above were investigated in a rhabdomyosarcoma rat tumor model (n = 113). Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) was used as a noninvasive heating device with precise temperature control for image-guided drug delivery. For the latter, TSLs were prepared, coencapsulating doxorubicin (dox) and [Gd(HPDO3A)(H2O)], and injected in tumor-bearing rats before MR-HIFU treatment. Four treatment groups were defined: hyperthermia, ablation, hyperthermia followed by ablation, or no HIFU. The intratumoral TSL and dox distribution were analyzed by single-photon emission computed tomography (SPECT)/computed tomography (CT), autoradiography, and fluorescence microscopy. Dox biodistribution was quantified and compared with that of nonliposomal dox. Finally, the treatment efficacy of all heating strategies plus additional control groups (saline, free dox, and Caelyx) was assessed by tumor growth measurements. All HIFU heating strategies combined with TSLs resulted in cellular uptake of dox deep into the interstitial space and a significant increase of tumor drug concentrations compared with a treatment with free dox. Ablation after TSL injection showed [Gd(HPDO3A)(H2O)] and dox release along the tumor rim, mirroring the TSL distribution pattern. Hyperthermia either as standalone treatment or before ablation ensured homogeneous TSL, [Gd(HPDO3A)(H2O)], and dox delivery across the tumor. The combination of hyperthermia-triggered drug delivery followed by ablation showed the best therapeutic outcome compared with all other treatment groups due to direct induction of thermal necrosis in the tumor core and efficient drug delivery to the tumor rim. PMID- 28566501 TI - Prevention of contrast-induced nephropathy by limb ischemic preconditioning: underlying mechanisms and clinical effects. AB - Contrast-induced nephropathy (CIN) is an important complication following diagnostic radiographic imaging and interventional therapy. It results from administration of intravascular iodinated contrast media (CM) and is currently the third most common cause of hospital-acquired acute kidney injury. CIN is associated with increased morbidity, prolonged hospitalization, and higher mortality. Although the importance of CIN is widely appreciated, and its occurrence can be mitigated by the use of pre- and posthydration protocols and low osmolar instead of high osmolar iodine-containing CM, specific prophylactic therapy is lacking. Remote ischemic preconditioning (RIPC), induced through short cycles of ischemia-reperfusion applied to the limb, is an intriguing new strategy that has been shown to reduce myocardial infarction size in patients undergoing emergency percutaneous coronary intervention. Furthermore, multiple proof-of principle clinical studies have suggested benefit in several other ischemia reperfusion syndromes, including stroke. Perhaps somewhat surprisingly, RIPC also is emerging as a promising strategy for CIN prevention. In this review, we discuss current clinical and experimental developments regarding the biology of CIN, concentrating on the pathophysiology of CIN, and cellular and molecular mechanisms by which limb ischemic preconditioning may confer renal protection in clinical and experimental models of CIN. PMID- 28566500 TI - Gender difference in kidney electrolyte transport. I. Role of AT1a receptor in thiazide-sensitive Na+-Cl- cotransporter activity and expression in male and female mice. AB - We studied gender differences in Na+-Cl- cotransporter (NCC) activity and expression in wild-type (WT) and AT1a receptor knockout (KO) mice. In renal clearance experiments, urine volume (UV), glomerular filtration rate, absolute Na+ (ENa) and K+ (EK), and fractional Na+ (FENa) and K+ excretion were measured and compared at peak changes after bolus intravenous injection of hydrochlorothiazide (HCTZ; 30 mg/kg). In WT, females responded more strongly than males to HCTZ, with larger fractional increases of UV (7.8- vs. 3.4-fold), ENa (11.7- vs. 5.7-fold), FENa (7.9- vs. 4.9-fold), and EK (2.8- vs. 1.4-fold). In contrast, there were no gender differences in the responses to the diuretic in KO mice; HCTZ produced greater effects on male KO than on WT but similar effects on females. In WT, total (tNCC) and phosphorylated (pNCC) NCC protein expressions were 1.8- and 4.6-fold higher in females compared with males (P < 0.05), consistent with the larger response to HCTZ. In KO mice, tNCC and pNCC increased significantly in males to levels not different from those in females. There were no gender differences in the expression of the Na+/H+ exchanger (NHE3) in WT; NHE3 protein decreased to similar extents in male and female KO animals, suggesting AT1a-mediated NHE3 expression in proximal tubules. The resulting increase in delivery of NaCl to the distal nephron may underlie increased NCC expression and activity in mice lacking the AT1a receptor. PMID- 28566503 TI - Heavy metal suicide. PMID- 28566504 TI - Apigenin ameliorates streptozotocin-induced diabetic nephropathy in rats via MAPK NF-kappaB-TNF-alpha and TGF-beta1-MAPK-fibronectin pathways. AB - Diabetic nephropathy (DN), a microvascular complication of diabetes, has emerged as an important health problem worldwide. There is strong evidence to suggest that oxidative stress, inflammation, and fibrosis play a pivotal role in the progression of DN. Apigenin has been shown to possess antioxidant, anti inflammatory, antiapoptotic, antifibrotic, as well as antidiabetic properties. Hence, we evaluated whether apigenin halts the development and progression of DN in streptozotocin (STZ)-induced diabetic rats. Male albino Wistar rats were divided into control, diabetic control, and apigenin treatment groups (5-20 mg/kg po, respectively), apigenin per se (20 mg/kg po), and ramipril treatment group (2 mg/kg po). A single injection of STZ (55 mg/kg ip) was administered to all of the groups except control and per se groups to induce type 1 diabetes mellitus. Rats with fasting blood glucose >250 mg/dl were included in the study and randomized to different groups. Thereafter, the protocol was continued for 8 mo in all of the groups. Apigenin (20 mg/kg) treatment attenuated renal dysfunction, oxidative stress, and fibrosis (decreased transforming growth factor-beta1, fibronectin, and type IV collagen) in the diabetic rats. It also significantly prevented MAPK activation, which inhibited inflammation (reduced TNF-alpha, IL-6, and NF-kappaB expression) and apoptosis (increased expression of Bcl-2 and decreased Bax and caspase-3). Furthermore, histopathological examination demonstrated reduced inflammation, collagen deposition, and glomerulosclerosis in the renal tissue. In addition, all of these changes were comparable with those produced by ramipril. Hence, apigenin ameliorated renal damage due to DN by suppressing oxidative stress and fibrosis and by inhibiting MAPK pathway. PMID- 28566502 TI - Inhibition of HDAC enhances STAT acetylation, blocks NF-kappaB, and suppresses the renal inflammation and fibrosis in Npr1 haplotype male mice. AB - Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) plays a critical role in the regulation of blood pressure and fluid volume homeostasis. Mice lacking functional Npr1 (coding for GC-A/NPRA) exhibit hypertension and congestive heart failure. However, the underlying mechanisms remain largely less clear. The objective of the present study was to determine the physiological efficacy and impact of all-trans-retinoic acid (ATRA) and sodium butyrate (NaBu) in ameliorating the renal fibrosis, inflammation, and hypertension in Npr1 gene disrupted haplotype (1-copy; +/-) mice (50% expression levels of NPRA). Both ATRA and NaBu, either alone or in combination, decreased the elevated levels of renal proinflammatory and profibrotic cytokines and lowered blood pressure in Npr1+/- mice compared with untreated controls. The treatment with ATRA-NaBu facilitated the dissociation of histone deacetylase (HDAC) 1 and 2 from signal transducer and activator of transcription 1 (STAT1) and enhanced its acetylation in the kidneys of Npr1+/- mice. The acetylated STAT1 formed a complex with nuclear factor-kappaB (NF-kappaB) p65, thereby inhibiting its DNA-binding activity and downstream proinflammatory and profibrotic signaling cascades. The present results demonstrate that the treatment of the haplotype Npr1+/- mice with ATRA-NaBu significantly lowered blood pressure and reduced the renal inflammation and fibrosis involving the interactive roles of HDAC, NF-kappaB (p65), and STAT1. The current findings will help in developing the molecular therapeutic targets and new treatment strategies for hypertension and renal dysfunction in humans. PMID- 28566506 TI - The balanced and introspective brain. AB - Transfers of large-scale neural activity into, within and between corticothalamic neural populations and brain hemispheres are analysed using time-integrated transfer functions and state parameters obtained from neural field theory for a variety of arousal states. It is shown that the great majority of activity results from feedbacks within the corticothalamic system, including significant transfer between hemispheres, but only a small minority arises via net input from the external world, with the brain thus in a near-critical, highly introspective state. Notably, the total excitatory and inhibitory influences on cortical neurons are balanced to within a few per cent across arousal states. Strong negative intrahemispheric feedforward exists to the cortex, and even larger interhemispheric positive feedforward, but these are modified by feedback loops to yield near-critical positive overall gain. The results underline the utility of transfer functions for the analysis of brain activity. PMID- 28566508 TI - Curvature-induced stiffening of a fish fin. AB - How fish modulate their fin stiffness during locomotive manoeuvres remains unknown. We show that changing the fin's curvature modulates its stiffness. Modelling the fin as bendable bony rays held together by a membrane, we deduce that fin curvature is manifested as a misalignment of the principal bending axes between neighbouring rays. An external force causes neighbouring rays to bend and splay apart, and thus stretches the membrane. This coupling between bending the rays and stretching the membrane underlies the increase in stiffness. Using three dimensional reconstruction of a mackerel (Scomber japonicus) pectoral fin for illustration, we calculate the range of stiffnesses this fin is expected to span by changing curvature. The three-dimensional reconstruction shows that, even in its geometrically flat state, a functional curvature is embedded within the fin microstructure owing to the morphology of individual rays. As the ability of a propulsive surface to transmit force to the surrounding fluid is limited by its stiffness, the fin curvature controls the coupling between the fish and its surrounding fluid. Thereby, our results provide mechanical underpinnings and morphological predictions for the hypothesis that the spanned range of fin stiffnesses correlates with the behaviour and the ecological niche of the fish. PMID- 28566507 TI - Flagella bending affects macroscopic properties of bacterial suspensions. AB - To survive in harsh conditions, motile bacteria swim in complex environments and respond to the surrounding flow. Here, we develop a mathematical model describing how flagella bending affects macroscopic properties of bacterial suspensions. First, we show how the flagella bending contributes to the decrease in the effective viscosity observed in dilute suspension. Our results do not impose tumbling (random reorientation) as was previously done to explain the viscosity reduction. Second, we demonstrate how a bacterium escapes from wall entrapment due to the self-induced buckling of flagella. Our results shed light on the role of flexible bacterial flagella in interactions of bacteria with shear flow and walls or obstacles. PMID- 28566509 TI - Gene flow and metacommunity arrangement affects coevolutionary dynamics at the mutualism-antagonism interface. AB - Interspecific interactions are affected by community context and, as a consequence, show spatial variation in magnitude and sign. The selective forces imposed by interactions at the mutualism-antagonism interface are a consequence of the traits involved and their matching between species. If mutualistic and antagonistic communities are linked by gene flow, coevolution between a pair of interacting species is influenced by how selection varies in space. Here we investigate the effects of metacommunity arrangement, i.e. patterns of connection between communities and the number of communities, on the coevolutionary dynamics between two species for which the sign and magnitude of the interaction varies across the landscape. We quantify coevolutionary outcome as an index that can be decomposed into the contribution of intraspecific genetic diversity and interspecific interaction. We show that polymorphisms and mismatches are an expected outcome, which is influenced by spatial structure, interaction strength and the degree of gene flow. The index describes how variation is distributed within and between species, and provides information on the directionality of the mismatches and polymorphisms. Finally, we argue that depending on metacommunity arrangement, some communities have disproportionate roles in maintaining genetic diversity, with implications for the coevolution of interacting species in a fragmented landscape. PMID- 28566511 TI - Covert linear polarization signatures from brilliant white two-dimensional disordered wing structures of the phoenix damselfly. AB - The damselfly Pseudolestes mirabilis reflects brilliant white on the ventral side of its hindwings and a copper-gold colour on the dorsal side. Unlike many previous investigations of odonate wings, in which colour appearances arise either from multilayer interference or from wing-membrane pigmentation, the whiteness on the wings of P. mirabilis results from light scattered by a specialized arrangement of flattened waxy fibres and the copper-gold colour is produced by pigment-based filtering of this light scatter. The waxy fibres responsible for this optical signature effectively form a structure that is disordered in two dimensions and this also gives rise to distinct optical linear polarization. It is a structure that provides a mechanism enabling P. mirabilis to display its bright wing colours efficiently for territorial signalling, both passively while perched, in which the sunlit copper-gold upperside is presented against a highly contrasting background of foliage, and actively in territorial contests in which the white underside is also presented. It also offers a template for biomimetic high-intensity broadband reflectors that have a pronounced polarization signature. PMID- 28566510 TI - Gradual loading ameliorates maladaptation in computational simulations of vein graft growth and remodelling. AB - Vein graft failure is a prevalent problem in vascular surgeries, including bypass grafting and arteriovenous fistula procedures in which veins are subjected to severe changes in pressure and flow. Animal and clinical studies provide significant insight, but understanding the complex underlying coupled mechanisms can be advanced using computational models. Towards this end, we propose a new model of venous growth and remodelling (G&R) based on a constrained mixture theory. First, we identify constitutive relations and parameters that enable venous adaptations to moderate perturbations in haemodynamics. We then fix these relations and parameters, and subject the vein to a range of combined loads (pressure and flow), from moderate to severe, and identify plausible mechanisms of adaptation versus maladaptation. We also explore the beneficial effects of gradual increases in load on adaptation. A gradual change in flow over 3 days plus an initial step change in pressure results in fewer maladaptations compared with step changes in both flow and pressure, or even a gradual change in pressure and flow over 3 days. A gradual change in flow and pressure over 8 days also enabled a successful venous adaptation for loads as severe as the arterial loads. Optimization is used to accelerate parameter estimation and the proposed framework is general enough to provide a good starting point for parameter estimations in G&R simulations. PMID- 28566512 TI - Serpentine locomotion through elastic energy release. AB - A model for serpentine locomotion is derived from a novel perspective based on concepts from configurational mechanics. The motion is realized through the release of the elastic energy of a deformable rod, sliding inside a frictionless channel, which represents a snake moving against lateral restraints. A new formulation is presented, correcting previous results and including situations never analysed so far, as in the cases when the serpent's body lies only partially inside the restraining channel or when the body has a muscle relaxation localized in a small zone. Micromechanical considerations show that propulsion is the result of reactions tangential to the frictionless constraint and acting on the snake's body, a counter-intuitive feature in mechanics. It is also experimentally demonstrated that the propulsive force driving serpentine motion can be directly measured on a designed apparatus in which flexible bars sweep a frictionless channel. Experiments fully confirm the theoretical modelling, so that the presented results open the way to exploration of effects, such as variability in the bending stiffness or channel geometry or friction, on the propulsive force of snake models made up of elastic rods. PMID- 28566513 TI - Recursively constructing analytic expressions for equilibrium distributions of stochastic biochemical reaction networks. AB - Noise is often indispensable to key cellular activities, such as gene expression, necessitating the use of stochastic models to capture its dynamics. The chemical master equation (CME) is a commonly used stochastic model of Kolmogorov forward equations that describe how the probability distribution of a chemically reacting system varies with time. Finding analytic solutions to the CME can have benefits, such as expediting simulations of multiscale biochemical reaction networks and aiding the design of distributional responses. However, analytic solutions are rarely known. A recent method of computing analytic stationary solutions relies on gluing simple state spaces together recursively at one or two states. We explore the capabilities of this method and introduce algorithms to derive analytic stationary solutions to the CME. We first formally characterize state spaces that can be constructed by performing single-state gluing of paths, cycles or both sequentially. We then study stochastic biochemical reaction networks that consist of reversible, elementary reactions with two-dimensional state spaces. We also discuss extending the method to infinite state spaces and designing the stationary behaviour of stochastic biochemical reaction networks. Finally, we illustrate the aforementioned ideas using examples that include two interconnected transcriptional components and biochemical reactions with two dimensional state spaces. PMID- 28566514 TI - Modelling human skull growth: a validated computational model. AB - During the first year of life, the brain grows rapidly and the neurocranium increases to about 65% of its adult size. Our understanding of the relationship between the biomechanical forces, especially from the growing brain, the craniofacial soft tissue structures and the individual bone plates of the skull vault is still limited. This basic knowledge could help in the future planning of craniofacial surgical operations. The aim of this study was to develop a validated computational model of skull growth, based on the finite-element (FE) method, to help understand the biomechanics of skull growth. To do this, a two step validation study was carried out. First, an in vitro physical three dimensional printed model and an in silico FE model were created from the same micro-CT scan of an infant skull and loaded with forces from the growing brain from zero to two months of age. The results from the in vitro model validated the FE model before it was further developed to expand from 0 to 12 months of age. This second FE model was compared directly with in vivo clinical CT scans of infants without craniofacial conditions (n = 56). The various models were compared in terms of predicted skull width, length and circumference, while the overall shape was quantified using three-dimensional distance plots. Statistical analysis yielded no significant differences between the male skull models. All size measurements from the FE model versus the in vitro physical model were within 5%, with one exception showing a 7.6% difference. The FE model and in vivo data also correlated well, with the largest percentage difference in size being 8.3%. Overall, the FE model results matched well with both the in vitro and in vivo data. With further development and model refinement, this modelling method could be used to assist in preoperative planning of craniofacial surgery procedures and could help to reduce reoperation rates. PMID- 28566517 TI - Heartbeat: Text messaging to improve health. PMID- 28566516 TI - The counterbend dynamics of cross-linked filament bundles and flagella. AB - Cross-linked filament bundles, such as in cilia and flagella, are ubiquitous in biology. They are considered in textbooks as simple filaments with larger stiffness. Recent observations of flagellar counterbend, however, show that induction of curvature in one section of a passive flagellum instigates a compensatory counter-curvature elsewhere, exposing the intricate role of the diminutive cross-linking proteins at large scales. We show that this effect, a material property of the cross-linking mechanics, modifies the bundle dynamics and induces a bimodal L2 - L3 length-dependent material response that departs from the Euler-Bernoulli theory. Hence, the use of simpler theories to analyse experiments can result in paradoxical interpretations. Remarkably, the counterbend dynamics instigates counter-waves in opposition to driven oscillations in distant parts of the bundle, with potential impact on the regulation of flagellar bending waves. These results have a range of physical and biological applications, including the empirical disentanglement of material quantities via counterbend dynamics. PMID- 28566515 TI - A microfluidics assay to study invasion of human placental trophoblast cells. AB - Pre-eclampsia, fetal growth restriction and stillbirth are major pregnancy disorders throughout the world. The underlying pathogenesis of these diseases is defective placentation characterized by inadequate invasion of extravillous placental trophoblast cells into the uterine arteries. How trophoblast invasion is controlled remains an unanswered question but is influenced by maternal uterine immune cells called decidual natural killer cells. Here, we describe an in vitro microfluidic invasion assay to study the migration of primary human trophoblast cells. Each experiment can be performed with a small number of cells making it possible to conduct research on human samples despite the challenges of isolating primary trophoblast cells. Cells are exposed to a chemical gradient and tracked in a three-dimensional microenvironment using real-time high-resolution imaging, so that dynamic readouts on cell migration such as directionality, motility and velocity are obtained. The microfluidic system was validated using isolated trophoblast and a gradient of granulocyte-macrophage colony-stimulating factor, a cytokine produced by activated decidual natural killer cells. This microfluidic model provides detailed analysis of the dynamics of trophoblast migration compared to previous assays and can be modified in future to study in vitro how human trophoblast behaves during placentation. PMID- 28566518 TI - A case for palliative percutaneous coronary intervention. PMID- 28566519 TI - Re: A case for palliative percutaneous coronary intervention. PMID- 28566521 TI - Optical and chemical discoveries recognized for impact on biology and psychiatry. PMID- 28566522 TI - Understanding the brain in health and disease: An interview with Karl Deisseroth, Professor of Bioengineering and Psychiatry at Stanford University. PMID- 28566520 TI - Mitochondrial permeability transition involves dissociation of F1FO ATP synthase dimers and C-ring conformation. AB - The impact of the mitochondrial permeability transition (MPT) on cellular physiology is well characterized. In contrast, the composition and mode of action of the permeability transition pore complex (PTPC), the supramolecular entity that initiates MPT, remain to be elucidated. Specifically, the precise contribution of the mitochondrial F1FO ATP synthase (or subunits thereof) to MPT is a matter of debate. We demonstrate that F1FO ATP synthase dimers dissociate as the PTPC opens upon MPT induction. Stabilizing F1FO ATP synthase dimers by genetic approaches inhibits PTPC opening and MPT Specific mutations in the F1FO ATP synthase c subunit that alter C-ring conformation sensitize cells to MPT induction, which can be reverted by stabilizing F1FO ATP synthase dimers. Destabilizing F1FO ATP synthase dimers fails to trigger PTPC opening in the presence of mutants of the c subunit that inhibit MPT The current study does not provide direct evidence that the C-ring is the long-sought pore-forming subunit of the PTPC, but reveals that PTPC opening requires the dissociation of F1FO ATP synthase dimers and involves the C-ring. PMID- 28566523 TI - Gastric and Postgastric Processing of 13C Markers Renders the 13C Breath Test an Inappropriate Measurement Method for the Gastric Emptying of Lipid Emulsions in Healthy Adults. AB - Background: Breath tests (BTs) present an alternative gastric-emptying (GE) measure. However, their efficacy in the measurement of the GE rate of lipid emulsions (LEs) is unknown.Objective: The objective of this work was to investigate the validity of 13C BTs as a measure of fat GE rate in LEs.Methods: The lipophilic 13C octanoate (OCC) BT marker was investigated for fat GE with the hydrophilic 13C sodium acetate (ACC) and the triglyceride 13C trioctanoin (TCC) markers as comparators. Data from 2 randomized studies were combined [50 healthy participants; 25 men, mean +/- SD age: 23 +/- 2.8 y; mean +/- SD body mass index (in kg/m2): 22.4 +/- 1.7]. Each participant was given either an acid-stable LE (LE1) or an acid-unstable LE (LE4) at each visit. Twenty-three participants underwent simultaneous MRI. The effect of LEs on 13CO2 excretion profiles was determined. The BT half-emptying times (BT T50) were validated with the MRI half emptying time of the ingested fat volume (MRI T50).Results: The effect of LEs on 13CO2 excretion depended on the properties of the 13C marker. T50 for OCC was shorter by 98 min for LE1 than for LE4 (P < 0.001). Other markers showed either no LE dependency or a longer T50 for LE1 than for LE4. No difference in T50 between OCC and ACC was detected in LE1. In LE4, the T50 was longer by 154 min (P < 0.0001). There was some concordance between MRI T50 and OCC BT T50 for LE1 (rc = 0.7). No other marker showed any concordance with fat GE. 13C-Nuclear magnetic resonance in vitro findings were compatible with changes in the kinetics of phase transfer of OCC dependent on its protonation state.Conclusions: The structure of fat present in the stomach affects 13CO2 excretion. The chemical properties of the 13C marker and their gastric and postgastric interaction with fat renders 13CO2 excretion an inappropriate measure of LE emptying in healthy adults. This trial was registered at clinicaltrials.gov as NCT02226029 and NCT02602158. PMID- 28566524 TI - A Mediterranean Diet Reduces F2-Isoprostanes and Triglycerides among Older Australian Men and Women after 6 Months. AB - Background: Health benefits of a Mediterranean dietary pattern have been shown. However, there are few data on the effects of increased adherence to a Mediterranean diet (MedDiet) in non-Mediterranean countries.Objective: We aimed to determine whether adherence to a MedDiet would result in changes in plasma lipids, glucose and insulin, high-sensitivity C-reactive protein (hs-CRP), and F2 isoprostanes (F2-IsoPs) in an Australian population.Methods: The study was a 6-mo parallel, randomized, controlled dietary intervention trial. We recruited 166 participants aged >=65 y. Participants were stratified on body mass index, sex, and age and assigned to receive either a MedDiet or a habitual diet (HabDiet). The primary outcome was cognitive function, reported elsewhere. As secondary outcomes, assessment of fasting total, LDL, and HDL cholesterol; triglycerides (TGs); glucose; insulin; hs-CRP; and F2-IsoPs was completed at baseline and at 3 and 6 mo. The MedDiet group followed a prescribed diet containing 15-45 mL extra virgin olive oil/d, abundant vegetables, fruit, nuts, legumes, and whole grains, as well as moderate fish, poultry, and dairy foods. Dietary intake was measured by 3-d weighed food records at baseline and at 2 and 4 mo. Results were analyzed by using linear mixed-effects models.Results: Compared with the HabDiet, the MedDiet resulted in lower TGs at 3 mo (mean difference: -0.15 mmol/L; 95% CI: 0.23, -0.07 mmol/L; P < 0.001) and 6 mo (mean difference: -0.09 mmol/L; 95% CI: 0.18, -0.01 mmol/L; P = 0.03) and lower F2-IsoPs at 3 mo (mean difference: -103.5 pmol/L; 95% CI: -154.2, -52.7 pmol/L; P < 0.001) and 6 mo (-65.4 pmol/L; 95% CI: 117.1, -13.7 pmol/L; P < 0.001). Lipoprotein, glucose and insulin, and hs-CRP concentrations were not significantly different between groups.Conclusion: A high adherence to a MedDiet for 6 mo resulted in a significant reduction in TGs and F2 IsoPs among older Australians. This trial was registered at clinicaltrials.gov as ACTRN12613000602729. PMID- 28566526 TI - Modeling Optimal Cutoffs for the Brazilian Household Food Insecurity Measurement Scale in a Nationwide Representative Sample. AB - Background: This is the second part of a model-based approach to examine the suitability of the current cutoffs applied to the raw score of the Brazilian Household Food Insecurity Measurement Scale [Escala Brasileira de Inseguranca Alimentar (EBIA)]. The approach allows identification of homogeneous groups who correspond to severity levels of food insecurity (FI) and, by extension, discriminant cutoffs able to accurately distinguish these groups.Objective: This study aims to examine whether the model-based approach for identifying optimal cutoffs first implemented in a local sample is replicated in a countrywide representative sample.Methods: Data were derived from the Brazilian National Household Sample Survey of 2013 (n = 116,543 households). Latent class factor analysis (LCFA) models from 2 to 5 classes were applied to the scale's items to identify the number of underlying FI latent classes. Next, identification of optimal cutoffs on the overall raw score was ascertained from these identified classes. Analyses were conducted in the aggregate data and by macroregions. Finally, model-based classifications (latent classes and groupings identified thereafter) were contrasted to the traditionally used classification.Results: LCFA identified 4 homogeneous groups with a very high degree of class separation (entropy = 0.934-0.975). The following cutoffs were identified in the aggregate data: between 1 and 2 (1/2), 5 and 6 (5/6), and 10 and 11 (10/11) in households with children and/or adolescents <18 y of age (score range: 0-14), and 1/2, between 4 and 5 (4/5), and between 6 and 7 (6/7) in adult-only households (range: 0-8). With minor variations, the same cutoffs were also identified in the macroregions. Although our findings confirm, in general, the classification currently used, the limit of 1/2 (compared with 0/1) for separating the milder from the baseline category emerged consistently in all analyses.Conclusions: Nationwide findings corroborate previous local evidence that households with an overall score of 1 are more akin to those scoring negative on all items. These results may contribute to guide experts' and policymakers' decisions on the most appropriate EBIA cutoffs. PMID- 28566525 TI - Supplementation with RRR- or all-rac-alpha-Tocopherol Differentially Affects the alpha-Tocopherol Stereoisomer Profile in the Milk and Plasma of Lactating Women. AB - Background: The naturally occurring alpha-tocopherol stereoisomer RRR-alpha tocopherol is known to be more bioactive than synthetic alpha-tocopherol (all-rac alpha-tocopherol). However, the influence of this difference on the alpha tocopherol stereoisomer profile of human milk is not understood.Objective: We investigated whether supplemental RRR-alpha-tocopherol or all-rac-alpha tocopherol differentially affected the distribution of alpha-tocopherol stereoisomers in milk and plasma from lactating women.Methods: Eighty-nine lactating women aged 19-40 y and with a body mass index (in kg/m2) <=30 were randomly assigned at 4-6 wk postpartum to receive a daily supplement containing 45.5 mg all-rac-alpha-tocopherol acetate (ARAC), 22.8 mg all-rac-alpha-tocopherol acetate + 20.1 mg RRR-alpha-tocopherol (MIX), or 40.2 mg RRR-alpha-tocopherol (RRR). Milk and plasma were analyzed for alpha-tocopherol structural isomers and alpha-tocopherol stereoisomers at baseline and after 6 wk supplementation with the use of chiral HPLC.Results: There were no significant treatment group or time dependent changes in milk or plasma alpha, gamma, or delta-tocopherol. RRR-alpha tocopherol was the most abundant stereoisomer in both milk and plasma in each group. Supplementation changed both milk and plasma percentage RRR-alpha tocopherol (RRR > MIX > ARAC) (P < 0.05) and percentage non-RRR-alpha-tocopherol (ARAC > MIX > RRR) (P < 0.05). In the RRR group, percentage RRR-alpha-tocopherol increased in milk (mean +/- SEM: 78% +/- 2.3% compared with 82% +/- 1.7%) (P < 0.05) and plasma (mean +/- SEM: 77% +/- 1.8% compared with 87% +/- 1%) (P < 0.05). In contrast, the percentage RRR-alpha-tocopherol decreased in the MIX and ARAC groups (MIX, P < 0.05; ARAC, P < 0.0001), and percentage non-RRR-alpha tocopherol stereoisomers increased (MIX, P < 0.05; ARAC, P < 0.0001) commensurate with an accumulation of 2S-alpha-tocopherol stereoisomers (P < 0.05) in both milk and plasma. Milk and plasma RRR-alpha-tocopherol was positively correlated at baseline (r = 0.67; P < 0.0001) and 6 wk (r = 0.80; P < 0.0001).Conclusion: The alpha-tocopherol supplementation strategy differentially affected the alpha tocopherol milk and plasma stereoisomer profile in lactating women. RRR-alpha tocopherol increased milk and plasma percentage RRR-alpha-tocopherol, whereas all rac-alpha-tocopherol acetate reduced these percentages. Because RRR-alpha tocopherol is the most bioactive stereoisomer, investigating the impact of supplement-driven changes in the milk alpha-tocopherol stereoisomer profile on the alpha-tocopherol status of breastfed infants is warranted. PMID- 28566527 TI - Interactions between 5-Lipoxygenase Polymorphisms and Adipose Tissue Contents of Arachidonic and Eicosapentaenoic Acids Do Not Affect Risk of Myocardial Infarction in Middle-Aged Men and Women in a Danish Case-Cohort Study. AB - Background: The 5-lipoxygenase pathway has been linked to atherothrombotic disease, and a functional tandem repeat polymorphism in the arachidonate lipoxygenase-5 (ALOX-5) gene has been associated with the risk of myocardial infarction (MI). Interestingly, 2 studies have reported an interaction between dietary intakes of the ALOX-5 substrates, arachidonic acid (AA) and eicosapentaenoic acid (EPA), and genotype.Objective: We investigated whether the interactions between the ALOX-5 tandem repeat polymorphism (rs59439148) and adipose tissue AA and EPA were associated with incident MI.Methods: In the Danish Diet, Cancer and Health study, we conducted a case-cohort study including 3089 participants with incident MI identified from national registries and a randomly selected subcohort of 3000 participants. Participants were men and women with a median age of 56 y at baseline and no previous history of cancer. Adipose tissue and blood samples were collected at baseline along with comprehensive questionnaires on lifestyle and demographic data. The ALOX-5 tandem repeat polymorphism was genotyped by multititer plate sequencing. Associations were analyzed by using Cox proportional hazards models.Results: We observed a higher risk of MI for homozygous carriers of the variant alleles in the fifth quintile of AA content than for the reference group with the lowest quintile of AA and carrying the wild-type allele (HR: 3.02; 95% CI: 1.41, 6.44). In contrast, homozygotes for the variant alleles tended to have a higher risk of MI when comparing the lowest quintile of EPA content with the reference group with the highest quintile of EPA and carrying the wild-type allele (HR: 2.15; 95% CI: 0.91, 5.09; P = 0.08). Although our results suggested interactions between the polymorphism and adipose tissue AA and EPA, a quantitative evaluation of interaction by calculating the relative excess risk due to interactions was not significant.Conclusions: Adipose tissue EPA and AA and the ALOX-5 tandem repeat polymorphism did not significantly interact to affect the risk of MI. However, the results should be replicated in larger, heterogeneous populations. PMID- 28566528 TI - Vegetables and Mixed Dishes Are Top Contributors to Phylloquinone Intake in US Adults: Data from the 2011-2012 NHANES. AB - Background: Phylloquinone is the most abundant form of vitamin K in US diets. Green vegetables are considered the predominant dietary source of phylloquinone. As our food supply diversifies and expands, the food groups that contribute to phylloquinone intake are also changing, which may change absolute intakes. Thus, it is important to identify the contributors to dietary vitamin K estimates to guide recommendations on intakes and food sources.Objective: The purpose of this study was to estimate 1) the amount of phylloquinone consumed in the diet of US adults, 2) to estimate the contribution of different food groups to phylloquinone intake in individuals with a high or low vegetable intake (>=2 or <2 cups vegetables/d), and 3) to characterize the contribution of different mixed dishes to phylloquinone intake.Methods: Usual phylloquinone intake was determined from NHANES 2011-2012 (>=20 y old; 2092 men and 2214 women) and the National Cancer Institute Method by utilizing a complex, stratified, multistage probability cluster sampling design.Results: On average, 43.0% of men and 62.5% of women met the adequate intake (120 and 90 MUg/d, respectively) for phylloquinone, with the lowest self-reported intakes noted among men, especially in the older age groups (51-70 and >=71 y). Vegetables were the highest contributor to phylloquinone intake, contributing 60.0% in the high-vegetable-intake group and 36.1% in the low-vegetable-intake group. Mixed dishes were the second-highest contributor to phylloquinone intake, contributing 16.0% in the high-vegetable-intake group and 28.0% in the low-vegetable-intake group.Conclusion: Self-reported phylloquinone intakes from updated food composition data applied to NHANES 2011-2012 reveal that fewer men than women are meeting the current adequate intake. Application of current food composition data confirms that vegetables continue to be the primary dietary source of phylloquinone in the US diet. However, mixed dishes and convenience foods have emerged as previously unrecognized but important contributors to phylloquinone intake in the United States, which challenges the assumption that phylloquinone intake is a marker of a healthy diet. These findings emphasize the need for the expansion of food composition databases that consider how mixed dishes are compiled and defined. PMID- 28566529 TI - Unconditional Seasonal Cash Transfer Increases Intake of High-Nutritional-Value Foods in Young Burkinabe Children: Results of 24-Hour Dietary Recall Surveys within the Moderate Acute Malnutrition Out (MAM'Out) Randomized Controlled Trial. AB - Background: Cash transfer programs have the potential to improve dietary intake by improving accessibility to food. However, quantitative data on the impact of cash transfer programs on children's energy and nutrient intakes are lacking.Objective: The aim of this study was to evaluate the effect of seasonal unconditional cash transfers on children's energy, micro- and macronutrient, and food group intakes during the lean season in Burkina Faso.Methods: Within the framework of the MAM'Out (Moderate Acute Malnutrition Out) cluster-randomized controlled trial, two 24-h dietary recall surveys were conducted in July and August 2014. Daily energy and macro- and micronutrient intakes, breastfeeding practices, and food group consumption were analyzed for 322 children aged 14-27 mo from an intervention group (benefiting from unconditional cash transfer during the lean season in 2013 and 2014) and a control group by using mixed linear, logistic, and Poisson regression models or a gamma-generalized linear model with log-link. A dietary diversity score was calculated on the basis of 7 food groups.Results: Unconditional cash transfers during the lean season improved the diets of rural children through a higher consumption of eggs (11.3 +/- 1.55 compared with 3.25 +/- 0.79 g; P < 0.001), fat (20.6 +/- 0.80 compared with 16.5 +/- 0.89 g; P < 0.01), and vitamin B-12 (0.40 +/- 0.02 compared with 0.34 +/- 0.02 mg; P < 0.001) compared with controls and higher proportions of children consuming dairy products (OR: 4.14; 95% CI: 1.48, 11.6; P < 0.05), flesh foods (OR: 2.09; 95% CI: 1.18, 3.70; P < 0.05), and iron-rich or iron-fortified foods (OR: 2.23; 95% CI: 1.20, 4.13; P < 0.05). No difference was found in energy intake between the 2 groups. The minimum dietary diversity of two-thirds of the children who benefited from cash transfers was adequate compared with only one third in the control group (P < 0.001).Conclusions: Unconditional seasonal cash transfer increases intakes of high-nutritional-value foods in Burkinabe children aged 14-27 mo. As such, their use can be recommended in actions addressing children's dietary intake during the lean season. This trial was registered at clinicaltrials.gov as NCT01866124. PMID- 28566531 TI - SDHB mutation carriers with malignant pheochromocytoma respond better to CVD. PMID- 28566532 TI - Risk and protective factors for the occurrence of sporadic pancreatic endocrine neoplasms. AB - Pancreatic neuroendocrine neoplasms (PNENs) represent 10% of all pancreatic tumors by prevalence. Their incidence has reportedly increased over recent decades in parallel with that of pancreatic adenocarcinoma. PNENs are relatively rare, and of the few institutions that have published potential risk factors, findings have been heterogeneous. Our objective was to investigate the association between potential risk and protective factors for the occurrence of sporadic PNENs across a European population from several institutions. A multinational European case-control study was conducted to examine the association of selected environmental, family and medical exposure factors using a standardized questionnaire in face-to-face interviews. A ratio of 1:3 cases to controls were sex and age matched at each study site. Adjusted univariate and multivariate logistic regression analysis were performed for statistically significant factors. The following results were obtained: In 201 cases and 603 controls, non-recent onset diabetes (OR 2.09, CI 1.27-3.46) was associated with an increased occurrence of PNENs. The prevalence of non-recent onset diabetes was higher both in cases with metastatic disease (TNM stage III-IV) or advanced grade (G3) at the time of diagnosis. The use of metformin in combination with insulin was also associated with a more aggressive phenotype. Drinking coffee was more frequent in cases with localized disease at diagnosis. Our study concluded that non-recent onset diabetes was associated with an increased occurrence of PNENs and the combination of metformin and insulin was consistent with a more aggressive PNEN phenotype. In contrast to previous studies, smoking, alcohol and first-degree family history of cancer were not associated with PNEN occurrence. PMID- 28566530 TI - Rationale for the development of alternative forms of androgen deprivation therapy. AB - With few exceptions, the almost 30,000 prostate cancer deaths annually in the United States are due to failure of androgen deprivation therapy. Androgen deprivation therapy prevents ligand-activation of the androgen receptor. Despite initial remission after androgen deprivation therapy, prostate cancer almost invariably progresses while continuing to rely on androgen receptor action. Androgen receptor's transcriptional output, which ultimately controls prostate cancer behavior, is an alternative therapeutic target, but its molecular regulation is poorly understood. Recent insights in the molecular mechanisms by which the androgen receptor controls transcription of its target genes are uncovering gene specificity as well as context-dependency. Heterogeneity in the androgen receptor's transcriptional output is reflected both in its recruitment to diverse cognate DNA binding motifs and in its preferential interaction with associated pioneering factors, other secondary transcription factors and coregulators at those sites. This variability suggests that multiple, distinct modes of androgen receptor action that regulate diverse aspects of prostate cancer biology and contribute differentially to prostate cancer's clinical progression are active simultaneously in prostate cancer cells. Recent progress in the development of peptidomimetics and small molecules, and application of Chem-Seq approaches indicate the feasibility for selective disruption of critical protein-protein and protein-DNA interactions in transcriptional complexes. Here, we review the recent literature on the different molecular mechanisms by which the androgen receptor transcriptionally controls prostate cancer progression, and we explore the potential to translate these insights into novel, more selective forms of therapies that may bypass prostate cancer's resistance to conventional androgen deprivation therapy. PMID- 28566534 TI - Enhanced self-efficacy after a self-management programme in pituitary disease: a randomized controlled trial. AB - CONTEXT: Patients with pituitary disease report impairments in Quality of Life (QoL) despite optimal biomedical care. Until now, the effects of a self management intervention (SMI) addressing psychological and social issues for these patients and their partners have not been studied. OBJECTIVE: To examine the effects of a SMI i.e. Patient and Partner Education Programme for Pituitary disease (PPEP-Pituitary). DESIGN AND SUBJECTS: A multicentre randomized controlled trial included 174 patients with pituitary disease, and 63 partners were allocated to either PPEP-Pituitary or a control group. PPEP-Pituitary included eight weekly sessions (90 min). Self-efficacy, bother and needs for support, illness perceptions, coping and QoL were assessed before the intervention (T0), directly after (T1) and after six months (T2). Mood was assessed before and after each session. RESULTS: Patients in PPEP-Pituitary reported improved mood after each session (except for session 1). In partners, mood only improved after the last three sessions. Patients reported higher self efficacy at T1 (P = 0.016) which persisted up to T2 (P = 0.033), and less bother by mood problems directly after PPEP-Pituitary (P = 0.01), but more bother after six months (P = 0.001), although this increase was not different from baseline (P = 0.346). Partners in PPEP-Pituitary reported more vitality (P = 0.008) which persisted up to T2 (P = 0.034). At T2, partners also reported less anxiety and depressive symptoms (P <= 0.014). CONCLUSION: This first study evaluating the effects of a SMI targeting psychosocial issues in patients with pituitary disease and their partners demonstrated promising positive results. Future research should focus on the refinement and implementation of this SMI into clinical practice. PMID- 28566533 TI - Brown adipose tissue is associated with systemic concentrations of peptides secreted from the gastrointestinal system and involved in appetite regulation. AB - OBJECTIVE: Brown adipose tissue (BAT) has been proposed as a potential therapeutic target against obesity and its related metabolic conditions. Data from studies in rodents support a cross talk between BAT and other distal tissues. The relation between BAT and peptide hormones secreted from the gastrointestinal system (GI) and involved in appetite regulation is not known in humans. DESIGN: We studied 18 men during thermoneutral conditions and mild non shivering cold exposure (CE). METHODS: 2-Deoxy-2-(18F)fluoro-d-glucose positron emission tomography-computed tomography scans were conducted after mild cold to measure BAT volume. Fasting serum concentration of GI-secreted peptides and peptides involved in appetite regulation were measured during thermoneutral conditions and mild CE. RESULTS: During thermoneutral conditions, BAT volume was associated with lower serum concentration of leptin (P = 0.006), gastric inhibitory polypeptide (P = 0.016) and glucagon (P = 0.048) after adjusting for age and body fat percent. CE significantly decreased serum leptin (P = 0.004) and glucagon concentration (P = 0.020), while cold-induced BAT activation was significantly associated with lower serum ghrelin concentration (P = 0.029). CONCLUSIONS: BAT is associated with systemic concentrations of GI-secreted peptides and peptides involved in appetite regulation, suggesting a potential cross talk between BAT and the enteropancreatic axis. Further studies are needed to elucidate the potential link of BAT with the postprandial levels of appetite regulating peptides and the putative role of BAT in appetite regulation in humans. PMID- 28566535 TI - Right time, right place: the temporal regulation of developmental gene expression. AB - Many studies have focused on defining the critical transcription factors that specify tissue morphogenesis and differentiation. Our understanding of how these spatial regulators are deployed in the proper temporal order, however, has remained less clear. In this issue of Genes & Development, Uyehara and colleagues (pp. 862-875) provide new insights into the mechanisms by which temporal and spatial regulators are coordinated to control Drosophila wing development during metamorphosis. PMID- 28566537 TI - Corrigendum: Mutations in genes encoding condensins cause microcephaly through decatenation failure at mitosis. PMID- 28566538 TI - The Plasma Membrane Calcium ATPases and Their Role as Major New Players in Human Disease. AB - The Ca2+ extrusion function of the four mammalian isoforms of the plasma membrane calcium ATPases (PMCAs) is well established. There is also ever-increasing detail known of their roles in global and local Ca2+ homeostasis and intracellular Ca2+ signaling in a wide variety of cell types and tissues. It is becoming clear that the spatiotemporal patterns of expression of the PMCAs and the fact that their abundances and relative expression levels vary from cell type to cell type both reflect and impact on their specific functions in these cells. Over recent years it has become increasingly apparent that these genes have potentially significant roles in human health and disease, with PMCAs1-4 being associated with cardiovascular diseases, deafness, autism, ataxia, adenoma, and malarial resistance. This review will bring together evidence of the variety of tissue specific functions of PMCAs and will highlight the roles these genes play in regulating normal physiological functions and the considerable impact the genes have on human disease. PMID- 28566536 TI - How does Zika virus cause microcephaly? AB - The re-emergence of Zika virus (ZIKV), a mosquito-borne and sexually transmitted flavivirus circulating in >70 countries and territories, poses a significant global threat to public health due to its ability to cause severe developmental defects in the human brain, such as microcephaly. Since the World Health Organization declared the ZIKV outbreak a Public Health Emergency of International Concern, remarkable progress has been made to gain insight into cellular targets, pathogenesis, and underlying biological mechanisms of ZIKV infection. Here we review the current knowledge and progress in understanding the impact of ZIKV exposure on the mammalian brain development and discuss potential underlying mechanisms. PMID- 28566540 TI - The exon junction complex senses energetic stress and regulates contractility and cell architecture in cardiac myocytes. AB - The exon junction complex (EJC) is the main mechanism by which cells select specific mRNAs for translation into protein. We hypothesized that the EJC is involved in the regulation of gene expression during the stress response in cardiac myocytes, with implications for the failing heart. In cultured rat neonatal myocytes, we examined the cellular distribution of two EJC components eukaryotic translation initiation factor 4A isoform 3 (eIF4A3) and mago nashi homologue (Mago) in response to metabolic stress. There was significant relocalization of eIF4A3 and Mago from the nucleus to cytoplasm following 18 h of hypoxia. Treating myocytes with 50 mM NaN3 for 4 h to mimic the metabolic stress induced by hypoxia also resulted in significant relocalization of eIF4A3 and Mago to the cytoplasm. To examine whether the effects of metabolic stress on the EJC proteins were dependent on the metabolic sensor AMP kinase (AMPK), we treated myocytes with 1 MUM dorsomorphin (DM) in combination with NaN3 DM augmented the translocation of Mago and eIF4A3 from the nucleus to the cytoplasm. Knockdown of eIF4A3 resulted in cessation of cell contractility 96 h post-treatment and a significant reduction in the number of intact sarcomeres. Cell area was significantly reduced by both hypoxia and eIF4A3 knockdown, whilst eIF4A3 knockdown also significantly reduced nuclear size. The reduction in nuclear size is unlikely to be related to apoptosis as it was reversed in combination with hypoxia. These data suggest for the first time that eIF4A3 and potentially other EJC members play an important role in the myocyte stress response, cell contractility and morphology. PMID- 28566541 TI - Establishment and maintenance of aphid endosymbionts after horizontal transfer is dependent on host genotype. AB - Animal-associated microbial communities have important effects on host phenotypes. Individuals within and among species differ in the strains and species of microbes that they harbour, but how natural selection shapes the distribution and abundance of symbionts in natural populations is not well understood. Symbionts can be beneficial in certain environments but also impose costs on their hosts. Consequently, individuals that can or cannot associate with symbionts will be favoured under different ecological circumstances. As a result, we predict that individuals within a species vary in terms of how well they accept and maintain symbionts. In pea aphids, the frequency of endosymbionts varies among host-plant-associated populations ('biotypes'). We show that aphid genotypes from different biotypes vary in how well they accept and maintain symbionts after horizontal transfer. We find that aphids from biotypes that frequently harbour symbionts are better able to associate with novel symbionts than those from biotypes that less frequently harbour symbionts. Intraspecific variation in the ability of hosts to interact with symbionts is an understudied factor explaining patterns of host-symbiont association. PMID- 28566542 TI - Wolbachia-induced meiotic drive and feminization is associated with an independent occurrence of selective mitochondrial sweep in a butterfly. AB - Maternally inherited Wolbachia endosymbionts manipulate arthropod reproduction in various ways. In the butterfly Eurema mandarina, a cytoplasmic incompatibility inducing Wolbachia strain wCI and the associated mtDNA haplotypes are known to originate from the sister species Eurema hecabe, which offered a good case study for microbe-mediated hybrid introgression. Besides wCI, some females with the Z0 karyotype harbour a distinct Wolbachia strain wFem, which causes all-female production by meiotic drive and feminization. We report that a considerable proportion of E. mandarina females (65.7%) were infected with both wCI and wFem (CF) on Tanegashima Island. While females singly infected with wCI (C) produced offspring at a 1 : 1 sex ratio, CF females produced only females. Although Z linked sequence polymorphism showed no signs of divergence between C and CF females, mtDNA split into two discrete clades; one consisted of C females and the other CF females, both of which formed a clade with E. hecabe but not with uninfected E. mandarina This suggests that CF matrilines also, but independently, experienced a selective sweep after hybrid introgression from E. hecabe Distinct evolutionary forces were suggested to have caused C and CF matrilines to diverge, which would be irreversible because of the particular phenotype of wFem. PMID- 28566543 TI - Climate and sex ratio variation in a viviparous lizard. AB - The extent to which key biological processes, such as sex determination, respond to environmental fluctuations is fundamental for assessing species' susceptibility to ongoing climate change. Few studies, however, address how climate affects offspring sex in the wild. We monitored two climatically distinct populations of the viviparous skink Niveoscincus ocellatus for 16 years, recording environmental temperatures, offspring sex and date of birth. We found strong population-specific effects of temperature on offspring sex, with female offspring more common in warm years at the lowland site but no effect at the highland site. In contrast, date of birth advanced similarly in response to temperature at both sites. These results suggest strong population-specific effects of temperature on offspring sex that are independent of climatic effects on other physiological processes. These results have significant implications for our understanding of the ecological and evolutionary consequences of variation in sex ratios under climate change. PMID- 28566544 TI - Polyneuropathy relates to impairment in daily activities, worse gait, and fall related injuries. AB - OBJECTIVE: To extensively investigate the association of chronic polyneuropathy with basic and instrumental activities of daily living (BADL and IADL), falls, and gait. METHODS: A total of 1,445 participants of the population-based Rotterdam Study (mean age 71 years, 54% women) underwent a polyneuropathy screening involving a symptom questionnaire, neurologic examination, and nerve conduction studies. Screening yielded 4 groups: no, possible, probable, and definite polyneuropathy. Participants were interviewed about BADL (Stanford Health Assessment questionnaire), IADL (Instrumental Activities of Daily Living scale), and frequency of falling in the previous year. In a random subset of 977 participants, gait was assessed with an electronic walkway. Associations of polyneuropathy with BADL and IADL were analyzed continuously with linear regression and dichotomously with logistic regression. History of falling was evaluated with logistic regression, and gait changes were evaluated with linear regression. RESULTS: Participants with definite polyneuropathy had more difficulty in performing BADL and IADL than participants without polyneuropathy. Polyneuropathy related to worse scores of all BADL components (especially walking) and 3 IADL components (housekeeping, traveling, and shopping). Participants with definite polyneuropathy were more likely to fall, and these falls more often resulted in injury. Participants with polyneuropathy had worse gait parameters on the walkway, including lower walking speed and cadence, and more errors in tandem walking. CONCLUSIONS: Chronic polyneuropathy strongly associates with impairment in the ability to perform daily activities and relates to worse gait and an increased history of falling. PMID- 28566545 TI - Long-term unmet needs and associated factors in stroke or TIA survivors: An observational study. AB - OBJECTIVE: To extensively investigate long-term unmet needs in survivors of stroke or TIA and to identify factors associated with these unmet needs. METHODS: Community-dwelling adults were invited to participate in a survey >=2 years after discharge for stroke/TIA. Unmet needs were assessed across 5 domains: activities and participation, environmental factors, body functions, post-acute care, and secondary prevention. Factors associated with unmet needs were determined with multivariable negative binomial regression. RESULTS: Of 485 participants invited to complete the survey, 391 (81%) responded (median age 73 years, 67% male). Most responders (87%) reported unmet needs in >=1 of the measured domains, particularly in secondary prevention (71%). Factors associated with fewer unmet needs included older age (incident rate ratio [IRR] 0.62, 95% confidence interval [CI] 0.50-0.77), greater functional ability (IRR 0.33, 95% CI 0.17-0.67), and reporting that the general practitioner was the most important in care (IRR 0.69, 95% CI 0.57-0.84). Being depressed (IRR 1.61, 95% CI 1.23-2.10) and receiving community services after stroke (IRR 1.45, 95% CI 1.16-1.82) were associated with more unmet needs. CONCLUSIONS: Survivors of stroke/TIA reported considerable unmet needs >=2 years after discharge, particularly in secondary prevention. The factors associated with unmet needs could help guide policy decisions, particularly for tailoring care and support services provided after discharge. PMID- 28566546 TI - Familial aggregation of focal seizure semiology in the Epilepsy Phenome/Genome Project. AB - OBJECTIVE: To improve phenotype definition in genetic studies of epilepsy, we assessed the familial aggregation of focal seizure types and of specific seizure symptoms within the focal epilepsies in families from the Epilepsy Phenome/Genome Project. METHODS: We studied 302 individuals with nonacquired focal epilepsy from 149 families. Familial aggregation was assessed by logistic regression analysis of relatives' traits (dependent variable) by probands' traits (independent variable), estimating the odds ratio for each symptom in a relative given presence vs absence of the symptom in the proband. RESULTS: In families containing multiple individuals with nonacquired focal epilepsy, we found significant evidence for familial aggregation of ictal motor, autonomic, psychic, and aphasic symptoms. Within these categories, ictal whole body posturing, diaphoresis, dyspnea, fear/anxiety, and deja vu/jamais vu showed significant familial aggregation. Focal seizure type aggregated as well, including complex partial, simple partial, and secondarily generalized tonic-clonic seizures. CONCLUSION: Our results provide insight into genotype-phenotype correlation in the nonacquired focal epilepsies and a framework for identifying subgroups of patients likely to share susceptibility genes. PMID- 28566547 TI - Rapid transitions in the epidemiology of stroke and its risk factors in China from 2002 to 2013. AB - OBJECTIVE: To estimate the current prevalence, temporal incidence trends, and contribution of risk factors for stroke in China. METHODS: The China National Stroke Screening Survey (CNSSS) is an ongoing nationwide population-based program. A representative sample of 1,292,010 adults over 40 years old with 31,188 identified stroke cases from the 2013 and 2014 CNSSS database was analyzed to provide descriptive statistics of the prevalence and risk factors for stroke in 2014. In addition, a retrospective evaluation of 12,526 first-ever stroke cases in 2002-2013 and stroke mortality data from the 2002-2013 China Public Health Statistical Yearbook was conducted to estimate the incidence rates. RESULTS: In 2014, the adjusted stroke prevalence was 2.06% in adults aged 40 years and older. After full adjustments, all risk factors assessed showed significant associations with stroke (p < 0.01); the largest contributor was hypertension (population-attributable risk 53.2%), followed by family history, dyslipidemia, atrial fibrillation, diabetes, physical inactivity, smoking, and overweight/obesity. The incidence of first-ever stroke in adults aged 40-74 years increased from 189/100,000 individuals in 2002 to 379/100,000 in 2013-an overall annual increase of 8.3%. Stroke-specific mortality in adults aged 40-74 years has remained stable, at approximately 124 deaths/100,000 individuals in both 2002 and 2013. CONCLUSIONS: In 2002-2013, the incidence of stroke in China increased rapidly. Combined with a high prevalence, a trend toward a younger age, and stable mortality, this finding suggests that additional clinical and behavioral interventions for metabolic and lifestyle risk factors are necessary to prevent stroke, particularly in certain populations. PMID- 28566548 TI - White matter changes and social cognitive function in MS: When all is no longer in the eyes. PMID- 28566539 TI - Role of the Immune System in Hypertension. AB - High blood pressure is present in more than one billion adults worldwide and is the most important modifiable risk factor of death resulting from cardiovascular disease. While many factors contribute to the pathogenesis of hypertension, a role of the immune system has been firmly established by a large number of investigations from many laboratories around the world. Immunosuppressive drugs and inhibition of individual cytokines prevent or ameliorate experimental hypertension, and studies in genetically-modified mouse strains have demonstrated that lymphocytes are necessary participants in the development of hypertension and in hypertensive organ injury. Furthermore, immune reactivity may be the driving force of hypertension in autoimmune diseases. Infiltration of immune cells, oxidative stress, and stimulation of the intrarenal angiotensin system are induced by activation of the innate and adaptive immunity. High blood pressure results from the combined effects of inflammation-induced impairment in the pressure natriuresis relationship, dysfunctional vascular relaxation, and overactivity of the sympathetic nervous system. Imbalances between proinflammatory effector responses and anti-inflammatory responses of regulatory T cells to a large extent determine the severity of inflammation. Experimental and human studies have uncovered autoantigens (isoketal-modified proteins and heat shock protein 70) of potential clinical relevance. Further investigations on the immune reactivity in hypertension may result in the identification of new strategies for the treatment of the disease. PMID- 28566549 TI - Physical activity monitoring: A promising outcome measure in idiopathic inflammatory myopathies. PMID- 28566550 TI - Disconnection as a mechanism for social cognition impairment in multiple sclerosis. AB - OBJECTIVE: To assess the contribution of microstructural normal-appearing white matter (NAWM) damage to social cognition impairment, specifically in the theory of mind (ToM), in multiple sclerosis (MS). METHODS: We enrolled consecutively 60 patients with MS and 60 healthy controls (HC) matched on age, sex, and education level. All participants underwent ToM testing (Eyes Test, Videos Test) and 3T brain MRI including conventional and diffusion tensor imaging sequences. Tract based spatial statistics (TBSS) were applied for whole-brain voxel-wise analysis of fractional anisotropy (FA) and mean diffusivity (MD) on NAWM. RESULTS: Patients with MS performed worse on both tasks of ToM compared to HC (Eyes Test 58.7 +/- 13.8 vs 81.9 +/- 10.4, p < 0.001, Hedges g -1.886; Videos Test 75.3 +/- 9.3 vs 88.1 +/- 7.1, p < 0.001, Hedges g -1.537). Performance on ToM tests was correlated with higher values of FA and lower values of MD across widespread white matter tracts. The largest effects (>=90% of voxels with statistical significance) for the Eyes Test were body and genu of corpus callosum, fornix, tapetum, uncinate fasciculus, and left inferior cerebellar peduncle, and for the Videos Test genu and splenium of corpus callosum, fornix, uncinate fasciculus, left tapetum, and right superior fronto-occipital fasciculus. CONCLUSIONS: These results indicate that a diffuse pattern of NAWM damage in MS contributes to social cognition impairment in the ToM domain, probably due to a mechanism of disconnection within the social brain network. Gray matter pathology is also expected to have an important role; thus further research is required to clarify the neural basis of social cognition impairment in MS. PMID- 28566551 TI - Outcome measures in the idiopathic inflammatory myopathies: On the search for the holy grail. PMID- 28566552 TI - Advancing the phenome alongside the genome in epilepsy studies. PMID- 28566553 TI - Systematic analysis of Ca2+ homeostasis in Saccharomyces cerevisiae based on chemical-genetic interaction profiles. AB - We investigated the global landscape of Ca2+ homeostasis in budding yeast based on high-dimensional chemical-genetic interaction profiles. The morphological responses of 62 Ca2+-sensitive (cls) mutants were quantitatively analyzed with the image processing program CalMorph after exposure to a high concentration of Ca2+ After a generalized linear model was applied, an analysis of covariance model was used to detect significant Ca2+-cls interactions. We found that high dimensional, morphological Ca2+-cls interactions were mixed with positive (86%) and negative (14%) chemical-genetic interactions, whereas one-dimensional fitness Ca2+-cls interactions were all negative in principle. Clustering analysis with the interaction profiles revealed nine distinct gene groups, six of which were functionally associated. In addition, characterization of Ca2+-cls interactions revealed that morphology-based negative interactions are unique signatures of sensitized cellular processes and pathways. Principal component analysis was used to discriminate between suppression and enhancement of the Ca2+-sensitive phenotypes triggered by inactivation of calcineurin, a Ca2+-dependent phosphatase. Finally, similarity of the interaction profiles was used to reveal a connected network among the Ca2+ homeostasis units acting in different cellular compartments. Our analyses of high-dimensional chemical-genetic interaction profiles provide novel insights into the intracellular network of yeast Ca2+ homeostasis. PMID- 28566556 TI - Estimation of clinical parameters of chronic kidney disease by exhaled breath full-scan mass spectrometry data and iterative PCA with intensity screening algorithm. AB - Breath mass spectrometry is a useful tool for identifying important compounds associated with health. However, there have been few studies that have explored human exhaled breath by full-scan mass spectrometry as a non-invasive method for medical diagnosis, which may be attributed to the difficulties resulting from multicollinearity and small sample sizes relative to a large number of product ions. In this study, breath samples from 54 chronic kidney disease patients were analyzed by selected ion flow tube mass spectrometry in the full-scan mode. With the signal intensities of product ions, we developed a novel and robust algorithm, iterative PCA with intensity screening (IPS), to build linear models for estimating important clinical parameters of chronic kidney disease. It has been shown that IPS provided good estimations in cross-validated samples, and furthermore the identified product ions could have direct medical relevance to the disease. The study demonstrated the potential of quantitative breath analysis using mass spectrometry for medical diagnosis, and the importance of applying appropriate statistical tools to unveil the rich information in this type of data. PMID- 28566557 TI - The prognostic significance of ING4 expression on gastric gastrointestinal stromal tumors by immunohistochemistry. AB - OBJECTIVE: Inhibitor of growth 4 (ING4) is a novel tumor suppressor gene that is reported to be down-regulated in various tumors including gastrointestinal stromal tumors (GISTs) originated from different locations, recently. Herein, we aimed to evaluate ING4 expression and its prognostic significance on gastric GISTs in order to add further data to the current literature. MATERIAL AND METHODS: ING4 was evaluated in samples of gastric GISTs from 62 patients, by immunohistochemistry. The association between ING4 expression and clinicopathological features related with prognosis and overall survival (OS) were analyzed statistically. RESULTS: There was statistically significant inverse correlation between ING4 expression and risk groups according to both NIH and AFIP, Ki67 index, tumor diameter, and mitotic count by univarite analysis (p=0.000, p=0.000, p=0.08, p=0.01, and p=0.028, respectively). The negative association between ING4 expression and risk groups according to both NIH (p=0.002, beta=-0.263, t=-3.166) and AFIP (p=0.016, beta=-0.244, t=-2.492) was supported by multivariate analysis. There was statistically significant direct correlation between low levels of ING4 expression and shorter OS by univariate (p=0.000) and multivariate analysis (p=0.000, beta=0.769, t=9.798), as well as Kaplan-Meier method (p=0.035). CONCLUSIONS: The low ING4 expression level was found to be related with unfavorable prognosis. Thus, we suggest that loss of ING4 expression might play a role in the progression of GISTs and might be used as a potential prognostic tool. Additionally, this is the first study that has evaluated the association of ING4 expression on gastric GISTs, to the best of our knowledge. Therefore, we claim that more comprehensive future studies including higher number of patients and longer follow-up might clarify the potential role of ING4 on pathogenesis and prognosis of GISTs. KEY WORDS: Clinicopathological features, Gastrointestinal stromal tumor, ING4, Immunohistochemistry. PMID- 28566554 TI - PI3K class II alpha regulates delta-opioid receptor export from the trans-Golgi network. AB - The interplay between signaling and trafficking by G protein-coupled receptors (GPCRs) has focused mainly on endocytic trafficking. Whether and how surface delivery of newly synthesized GPCRs is regulated by extracellular signals is less understood. Here we define a signaling-regulated checkpoint at the trans-Golgi network (TGN) that controls the surface delivery of the delta opioid receptor (deltaR). In PC12 cells, inhibition of phosphoinositide-3 kinase (PI3K) activity blocked export of newly synthesized deltaR from the Golgi and delivery to the cell surface, similar to treatment with nerve growth factor (NGF). Depletion of class II phosphoinositide-3 kinase alpha (PI3K C2A), but not inhibition of class I PI3K, blocked deltaR export to comparable levels and attenuated deltaR-mediated cAMP inhibition. NGF treatment displaced PI3K C2A from the Golgi and optogenetic recruitment of the PI3K C2A kinase domain to the TGN-induced deltaR export downstream of NGF. Of importance, PI3K C2A expression promotes export of endogenous deltaR in primary trigeminal ganglion neurons. Taken together, our results identify PI3K C2A as being required and sufficient for deltaR export and surface delivery in neuronal cells and suggest that it could be a key modulator of a novel Golgi export checkpoint that coordinates GPCR delivery to the surface. PMID- 28566555 TI - Cross-linked matrix rigidity and soluble retinoids synergize in nuclear lamina regulation of stem cell differentiation. AB - Synergistic cues from extracellular matrix and soluble factors are often obscure in differentiation. Here the rigidity of cross-linked collagen synergizes with retinoids in the osteogenesis of human marrow mesenchymal stem cells (MSCs). Collagen nanofilms serve as a model matrix that MSCs can easily deform unless the film is enzymatically cross-linked, which promotes the spreading of cells and the stiffening of nuclei as both actomyosin assembly and nucleoskeletal lamin-A increase. Expression of lamin-A is known to be controlled by retinoic acid receptor (RAR) transcription factors, but soft matrix prevents any response to any retinoids. Rigid matrix is needed to induce rapid nuclear accumulation of the RARG isoform and for RARG-specific antagonist to increase or maintain expression of lamin-A as well as for RARG-agonist to repress expression. A progerin allele of lamin-A is regulated in the same manner in iPSC-derived MSCs. Rigid matrices are further required for eventual expression of osteogenic markers, and RARG antagonist strongly drives lamin-A-dependent osteogenesis on rigid substrates, with pretreated xenografts calcifying in vivo to a similar extent as native bone. Proteomics-detected targets of mechanosensitive lamin-A and retinoids underscore the convergent synergy of insoluble and soluble cues in differentiation. PMID- 28566559 TI - MRI feature analysis of uncommon prostatic malignant tumors. PMID- 28566558 TI - Testosterone treatment in older men: glass half empty or half full? PMID- 28566560 TI - Congenital hypertrichosis lanuginosa. PMID- 28566561 TI - A protruding nodule on the upper lip. PMID- 28566562 TI - Low plasma zinc levels in androgenetic alopecia. PMID- 28566563 TI - Isolation of Dihydroartemisinic Acid from Artemisia annua L. By-Product by Combining Ultrasound-Assisted Extraction with Response Surface Methodology. AB - Malaria is the most devastating parasitic disease worldwide. Artemisinin is the only drug that can cure malaria that is resistant to quinine-derived drugs. After the commercial extraction of artemisinin from Artemisia annua, the recovery of dihydroartemisinic acid (DHAA) from artemisinin extraction by-product has the potential to increase artemisinin commercial yield. Here we describe the development and optimization of an ultrasound-assisted alkaline procedure for the extraction of DHAA from artemisinin production waste using response surface methodology. Our results using this methodology established that NaOH at 0.36%, extraction time of 67.96 min, liquid-solid ratio of 5.89, and ultrasonic power of 83.9 W were the optimal conditions to extract DHAA from artemisinin production waste. Under these optimal conditions, we achieved a DHAA yield of 2.7%. Finally, we conducted a validation experiment, and the results confirmed the prediction generated by the regression model developed in this study. This work provides a novel way to increase the production of artemisinin per cultivated area and to reduce artemisinin production costs by recycling its commercial waste to obtain DHAA, an immediate precursor of artemisinin. The use of this technology may reduce the costs of artemisinin-based antimalarial medicines. PMID- 28566565 TI - GATA Transcription Factors: Basic Principles and Related Human Disorders. AB - The development of mature blood cell from hematopoietic stem cells is regulated by transcription factors that coordinate the expression of lineage-specific genes. GATA transcription factors are zinc finger DNA-binding proteins that play crucial roles in various biological processes, including hematopoiesis. Among GATA family proteins, GATA-1, GATA-2, and GATA-3 are essential for hematopoiesis. GATA-1 functions to promote development of erythrocytes, megakaryocytes, eosinophils, and mast cells. Mutations in GATA-1 are associated with acute megakaryoblastic leukemia (AMKL), congenital erythroid hypoplasia (Diamond Blackfan anemia; DBA), and X-linked anemia and/or thrombocytopenia. Conversely, GATA-2 functions early in hematopoiesis and is required for maintenance and expansion of hematopoietic stem cells (HSCs) and/or multipotent progenitors. GATA 2 mutations are associated with immunodeficiency, lymphedema, myelodysplastic syndrome (MDS), and leukemia. Furthermore, decreased GATA-2 expression may contribute to the pathophysiology of aplastic anemia. GATA-3 has an important role in T cell development, and has been suggested to be involved in the pathophysiology of acute lymphoblastic leukemias. This review summarizes current knowledge on hematological disorders associated with GATA-1 and GATA-2 mutations. PMID- 28566564 TI - Effect of Thyroxin Treatment on Carotid Intima-Media Thickness (CIMT) Reduction in Patients with Subclinical Hypothyroidism (SCH): a Meta-Analysis of Clinical Trials. AB - AIM: Research shows that subclinical hypothyroidism (SCH) is related to an increased carotid intima-media thickness (CIMT), a surrogate marker of subclinical cardiovascular disease (CVD). It is controversial whether or not SCH should be treated to reduce CVD morbidity and mortality. This meta-analysis aimed to determine whether SCH is associated with an increase in CIMT as compared to Euthyroidism (EU) and whether thyroxin (T4) treatment in SCH can reverse the change in CIMT. METHODS: Two independent reviewers conducted an extensive database research up to December 2016. A total of 12 clinical trials discussed the effect of Thyroxin on CIMT values at pre- and post-treatment in subjects with SCH. RESULTS: CIMT was significantly higher among SCH (n=280) as compared to EU controls (n=263) at baseline; the pooled weighted mean difference (WMD) of CIMT was 0.44 mm [95% confidence interval (CI) 0.14, 0.74], p=0.004; I2=65%. After treatment with thyroxin in subjects with SCH (n=314), there was a statistically significant decrease in CIMT from pre- to post-treatment; the pooled WMD of CIMT decrease was [WMD -0.32; 95% CI (-0.47, -0.16), p=<0.0001; I2=2%], and it was no longer different from EU controls [WMD 0.13 mm; 95% CI (-0.04, 0.30); p=0.14; I2=27%]. The total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) were higher in SCH as compared to EU controls and decreased significantly after treatment with thyroxin. CONCLUSION: This meta-analysis shows that thyroxin therapy in subjects with SCH significantly decreases CIMT and improves lipid profile, modifiable CVD risk factors. Thyroid hormone replacement in subjects with SCH may play a role in slowing down or preventing the progression of atherosclerosis. PMID- 28566566 TI - Measurements of clothing evaporative resistance using a sweating thermal manikin: an overview. AB - Evaporative resistance has been widely used to describe the evaporative heat transfer property of clothing. It is also a critical variable in heat stress models for predicting human physiological responses in various environmental conditions. At present, sweating thermal manikins provide a fast and cost effective way to determine clothing evaporative resistance. Unfortunately, the measurement repeatability and reproducibility of evaporative resistance are rather low due to the complicated moisture transfer processes through clothing. This review article presents a systematical overview on major influential factors affecting the measurement precision of clothing evaporative resistance measurements. It also illustrates the state-of-the-art knowledge on the development of test protocol to measure clothing evaporative resistance by means of a sweating manikin. Some feasible and robust test procedures for measurement of clothing evaporative resistance using a sweating manikin are described. Recommendations on how to improve the measurement accuracy of clothing evaporative resistance are addressed and expected future trends on development of advanced sweating thermal manikins are finally presented. PMID- 28566568 TI - What Is Qualitative Research? AB - The article is an in-depth explanation of qualitative research, an approach increasingly prevalent among today's research communities. After discussing its present spread within the health sciences, the author addresses: 1. Its definition. 2. Its characteristics, as well as its theoretical and procedural background. 3. Its procedures. 4. Differences between qualitative and quantitative approaches. 5. Mixed methods incorporating quantitative research. And in conclusion: 6. The importance of establishing an epistemological perspective in qualitative research. PMID- 28566567 TI - Utilization of Qualitative Data on Pharmacy Education Study. PMID- 28566569 TI - Influence on Learning of a Collaborative Learning Method Comprising the Jigsaw Method and Problem-based Learning (PBL). AB - Recently, the practice of active learning has spread, increasingly recognized as an essential component of academic studies. Classes incorporating small group discussion (SGD) are conducted at many universities. At present, assessments of the effectiveness of SGD have mostly involved evaluation by questionnaires conducted by teachers, by peer assessment, and by self-evaluation of students. However, qualitative data, such as open-ended descriptions by students, have not been widely evaluated. As a result, we have been unable to analyze the processes and methods involved in how students acquire knowledge in SGD. In recent years, due to advances in information and communication technology (ICT), text mining has enabled the analysis of qualitative data. We therefore investigated whether the introduction of a learning system comprising the jigsaw method and problem based learning (PBL) would improve student attitudes toward learning; we did this by text mining analysis of the content of student reports. We found that by applying the jigsaw method before PBL, we were able to improve student attitudes toward learning and increase the depth of their understanding of the area of study as a result of working with others. The use of text mining to analyze qualitative data also allowed us to understand the processes and methods by which students acquired knowledge in SGD and also changes in students' understanding and performance based on improvements to the class. This finding suggests that the use of text mining to analyze qualitative data could enable teachers to evaluate the effectiveness of various methods employed to improve learning. PMID- 28566570 TI - Research Using the Roter Method of Interaction Process Analysis (RIAS) for Communication Education in the Pharmaceutical Sciences. AB - The ability to communicate effectively as a healthcare professional has come into greater focus as the role of pharmacists expands from "medicine-based" to "client based" (e.g., working with patients, their families, and in multidisciplinary interactions). The ability to communicate cannot be acquired solely in the classroom; a large part of acquiring such skill is based on practical experience. Role-playing with simulated patients has already been implemented in pharmaceutical education; in that sense, opportunities to receive education in practical communication are increasing. However, in order to assure that these educational opportunities are more than "experiences" in theory alone, aspects of communications training that are satisfactory or need improvement must be clarified through empirical studies. While data used in pharmaceutical studies have mainly been quantitative in nature, data required for medical communication studies is generally more qualitative. Only recently the importance of qualitative research has been recognized in pharmaceutical studies, a field in which any aspect difficult to express numerically has been considered subjective, and thus less acceptable. Against this backdrop, this report introduces an aspect of communication research that employs the Roter method of interaction process analysis (RIAS), a medical communication analyzing method by Professor Debra Roter at Johns Hopkins University. RIAS is a quantitative analysis of qualitative data. I want to discuss the significance of using results of research based on qualitative data to improve the quality of communication. PMID- 28566571 TI - Pharmaceutical Sciences in the Future: The Bridge Linking between Basic and Clinical Research. PMID- 28566572 TI - Importance of Reverse Translational Research (rTR). AB - When events lead to clinical problems, the mechanisms involved often remain unclear. This is true for medications and therapies, in addition to problems inherent in an underlying disease. However, the recent development of modeling and metric methods makes it possible to estimate the relationship between side effects and various factors to explain inter-individual differences, such as genetic polymorphisms, co-administered drugs, age, gender, dysfunction of the liver/kidney based upon the database for side effects [such as Food and Drug Administration-Adverse Event Reporting System (FDA-AERS)] and the database in a patient's medical records. Once the mechanisms for such clinical problems have been clarified, and after revisiting preclinical studies (animal models, in vitro cell systems, etc.), those outcomes may lead to drug discovery, the development of new therapies, and methods to prevent unique drug induced side effects. Reverse translational research (rTR) is such an approach, and a worthy aim of pharmaceutical scientists skilled at basic research. In this presentation, I would like to share with you our following recent studies: (1) rTR aimed at a therapy for progressive familial intrahepatic cholestasis 2 (PFIC 2). (2) rTR aimed at developing methods to predict drug-induced side effects based on single nucleotide polymorphisms (SNPs) information and a patient's medical records database. And (3) rTR aimed at predicting drug-drug interactions in which clinical outcomes have not been obtained, yet based upon previous clinically relevant drug interaction databases. PMID- 28566573 TI - From a Viewpoint of Clinical Settings: Pharmacoepidemiology as Reverse Translational Research (rTR). AB - Clinical pharmacology and pharmacoepidemiology research may converge in practise. Pharmacoepidemiology is the study of pharmacotherapy and risk management in patient groups. For many drugs, adverse reaction(s) that were not seen and/or clarified during research and development stages have been reported in the real world. Pharmacoepidemiology can detect and verify adverse drug reactions as reverse translational research. Recently, development and effective use of medical information databases (MID) have been conducted in Japan and elsewhere for the purpose of post-marketing safety of drugs. The Ministry of Health, Labour and Welfare, Japan has been promoting the development of 10-million scale database in 10 hospitals and hospital groups as "the infrastructure project of medical information database (MID-NET)". This project enables estimation of the frequency of adverse reactions, the distinction between drug-induced reactions and basal health-condition changes, and usefulness verification of administrative measures of drug safety. However, because the database information is different from detailed medical records, construction of methodologies for the detection and evaluation of adverse reactions is required. We have been performing database research using medical information system in some hospitals to establish and demonstrate useful methods for post-marketing safety. In this symposium, we aim to discuss the possibility of reverse translational research from clinical settings and provide an introduction to our research. PMID- 28566574 TI - Quantitative Targeted Absolute Proteomics (QTAP)-based Pharmacoproteomics: The Importance of International Collaboration. AB - Proteins such as membrane transporters, enzymes, receptors and channels play key roles in drug absorption, distribution, metabolism, and elimination, and also influence efficacy and the likelihood of adverse reactions. Therefore, if we can quantify the activities of these molecules, it may be possible to predict the behavior of candidate drugs in humans in disease states; such methodology would be extremely helpful for efficient drug development. We have developed an in silico method to select appropriate peptides within amino acid sequences in order to quantify targeted proteins by LC-MS/MS in selected reaction monitoring (SRM) mode. We have applied this method for the quantification of functional proteins in order to validate various in vitro and in vivo models. We found fairly good correlation between protein amounts and the enzymatic activities of microsomal cytochrome P450 (CYP) isoforms and uridine 5'-diphospho-glucuronosyltransferase (UGT) in human liver, as well as between protein amounts and the transport activities of multiple transporters in human lung cells. These results suggest that protein quantification can be useful in predicting activity. We have applied this approach to evaluate the usefulness and limitations of an immortalized human brain capillary endothelial cell line (D3 cells) and a P-glycoprotein humanized (hMDR1) mouse model by comparing the amounts of functional proteins in the models with those in isolated capillaries from human brain. In order to obtain sufficient human tissue specimens for further studies leading to clinical applications, we believe that international collaboration will be crucial. PMID- 28566575 TI - In Silico Approaches Accelerate Reverse Translational Research from Bedside to Bench. AB - Corresponding with accelerated computing power, such as that found in supercomputers, simulation and big data are becoming increasingly important to modern science, second only to experimental and theoretical sciences research. The field of medicine is said to have entered the era of big data, with significant progress in recent years in the development of increasingly sophisticated equipment for measurement, observation, and information and communication technology (ICT). In particular, greater precision in personalized medicine will require the analysis of a large quantity of individual genome sequences. Research and development of techniques to analyze big data with respect to individual genome sequences are an urgent need. In clinical medicine and epidemiology, the analysis of clinical big data or real-world data has attracted attention as a new approach, which can be applied to examining occurrences at an actual clinical site. In this review, we have discussed the challenges and potential of an in silico approach for reverse translational research. PMID- 28566576 TI - From the Viewpoint of Drug Metabolism Research. AB - Since more than 70% of clinically used drugs are excreted from the body through metabolic processes, drug metabolism is a key determinant of pharmacokinetics, drug response and drug toxicity. Much progress has been made in understanding drug-drug interactions via the inhibition or induction of cytochrome P450s (P450, CYP), as well as the effects of genetic polymorphisms of P450s on pharmacokinetics, and this has facilitated the progress of optimized pharmacotherapy in the clinic. Now, similar information is needed for non-CYP enzymes, especially concerning Phase I enzymes, based on advanced basic and clinical studies. Recently, it was revealed that post-transcriptional regulation by microRNAs or RNA editing plays a significant role in regulating the expression of drug-metabolizing enzymes, thus conferring variability in the detoxification and metabolic activation of drugs or chemicals. Changes in the expression profile of microRNAs in tissues or body fluids can be a biomarker of drug response and toxicity; therefore, such studies could also be useful for drug repositioning. In addition, microRNAs are involved in pharmacogenetics, because single nucleotide polymorphisms in microRNA binding sites of mRNAs, or microRNAs themselves, may cause changes in gene expression. Some microRNA-related polymorphisms could be biomarkers of the clinical outcome of pharmacotherapy. In this review article, recent progress and future directions for drug metabolism studies are discussed. PMID- 28566577 TI - Biofilms and Oxidizing Biocides; Evaluation of Disinfection and Removal Effects by Using Established Microbial Systems. AB - The formation of bacterial biofilms and their disinfection and removal have been important subjects in the maintenance of water quality in areas such as public spas, swimming pools, food processing lines, industrial water systems, and in the hygienic control of medical devices, hospital procedures, etc. Presented here is an outline of biofilm formation, as well as studies on the disinfection and removal of biofilms by oxidizing biocides using established biofilms. These studies using established biofilms may increase the understanding of the variable response of biofilms to planktonic bacteria, and the unique aspects of oxidizing biocides in the disinfection and removal of biofilms. PMID- 28566578 TI - Functional Modulation of Tight Junction to Enhance the Permeability of Biological Products (Biologics) in Biomembranes. AB - In recent years, biological products (biologics), including blood components, recombinant therapeutic proteins, antibodies, gene therapeutic materials, and so on, have been produced by biotechnology methods and other novel technologies. These products are essential therapeutic materials in progressive medicine. However, we often encounter the lower permeability of these biologics through biomembranes, due to their high molecular mass. In the last three decades, we have investigated drug delivery systems, including several enhancement methods for the permeability of biologics such as recombinant therapeutic proteins and viral vectors in epithelial cells. This review focuses the development of novel delivery systems for biologics in rectal and nasal administration, and includes an interesting observation of modulators of the tight junction (TJ) function. From cellular biology perspective, the interaction between permeability enhancing materials and targeted molecules in the TJ of epithelial cells was investigated. We elucidated that a TJ modulator will interact with a major constituent protein, for instance claudins, in playing an essential role in the tissue-specific barrier function of the TJ. Furthermore, useful enhancement of gene transfer in cells (for instance, in Caco-2 cells) was found in the combination of an adenovirus vector and capric acid sodium salt (C10), a TJ modulator. PMID- 28566579 TI - Usefulness of Interprofessional Education (Tsurumai-Meijo IPE) in Program Collaborating with Simulated Patients. AB - Collaboration with multiple healthcare professionals is important to provide safer and higher quality care. Interprofessional education (IPE) promotes the practice of team-based care. The establishment of Tsurumai-Meijo IPE, including interprofessional education and practice (IPEP) and video-teaching materials, was conducted in collaboration with school of medicine/nursing in Nagoya University and Fujita Health University, because Meijo University does not have its own clinical settings and faculties except for pharmacy. In the established Tsurumai Meijo IPE, pharmacy, medicine, and nursing students interviewed simulated patients (SP) together or separately and practiced team-based care through Tsurumai-Meijo IPEP. Students could learn in advance and on their own about each professional's knowledge related to patient care by using video-teaching materials from the Meijo IPE homepage. Using a questionnaire survey at the end of program, this study was examined whether Tsurumai-Meijo IPEP, and video-teaching materials were useful for understanding importance of team-based care. More than 83% of students indicated that Tsurumai-Meijo IPE is useful on future clinical practice. This suggests that the program and materials are beneficial to the medical student education. In the optional survey of some clinical pharmacists, who had participated in Tsurumai-Meijo IPE before graduation, they utilized it in their work and it facilitated their work related to team-based care. Tsurumai Meijo IPE collaborating with SP is likely to contribute to provide high quality and safe team-based care by taking advantage of specialized professional ability of healthcare professionals. PMID- 28566580 TI - Determination of Density Distribution of Tablets Using Synchrotron X-ray Computed Tomography. AB - The purpose of this study was to determine the density distribution of scored and round-faced tablets using synchrotron X-ray computed tomography. The tablets were made by direct compression of standard formulations. The density distribution of scored flat-faced tablets was uniform in the whole cross-sectional image. However, the tablet formulated using microcrystalline cellulose (MCC) was very dense at the tip of the score only. It is caused by the poor fluidity of MCC particles. In the case of round-faced tablets, the density in the central section of the tablet was relatively low, compared with those of peripheral areas. These observations correlated well with the results obtained by the finite element method simulation using appropriate material models. PMID- 28566582 TI - Evaluation of the Effects of Pharmacist Intervention for Adverse Drug Reaction Detection and Exacerbation Avoidance. AB - We evaluated the effects of pharmacist intervention for adverse drug reaction detection and exacerbation avoidance, as well as the severity and outcome of reactions based on analyses of pharmacist involvement in a collaborative approach to medicine. Of 5436 cases with pharmacist involvement, adverse drug reaction prevention was seen in 440, accounting for 8.1%, and exacerbation avoidance in 213, accounting for 3.9%. We concluded that pharmacist involvement contributes to detect adverse drug reactions and avoid exacerbation, and improves pharmacotherapy safety. We also analyzed 131 cases in which the course after intervention was followed. When categorized by adverse drug reaction severity, Grade 1 and 2 were the same at 45.8%, Grade 3 at 8.4%, respectively. Those findings suggested that pharmacist intervention contributes to early detection of an adverse drug reaction. Also, the relationship between clues for detecting adverse drug reactions by a pharmacist and their severity showed that objective evaluations such as clinical laboratory test results, physical assessments and medication history were important for detecting reactions that became more serious. Patients recovered or recovering from an adverse reaction comprised 76.4%, indicating that pharmacist intervention contributed to exacerbation avoidance and improvement. Our findings revealed the effects of pharmacist intervention for adverse drug reaction detection and exacerbation avoidance, and for safety improvement of pharmacotherapy. Additionally, we considered it necessary for the future pharmacist intervention to improve skills of assessing an adverse drug reaction objectively. PMID- 28566581 TI - Evaluation of Moisturizing Effect of Heparinoid Ointment (Hirudoid Soft Ointment) Diluted by White Petrolatum (Propeto). AB - Steroid ointments are frequently mixed with moisturizer. It was reported that steroid ointments mixed with moisturizer increase permeability. There are only few studies done on the permeability of the moisturizer. We researched moisturizing effect of heparinoid ointment (Hirudoid Soft ointment) diluted with white petrolatum (Propeto) on the dry skin models by measuring water content of stratum. Two to four fold dilution of Hirudoid to white petrolatum resulted in a significant decrease in the moisturizing effect of the active ingredient. There was no significant difference in moisturizing effect between four times diluted mixture and white petrolatum alone. This leads to the conclusion that steroid ointment mixture with moisturizer is frequently used, but we should take more caution regarding the decrease of moisturizing effect. PMID- 28566583 TI - Bergamottin Promotes Adipocyte Differentiation and Inhibits Tumor Necrosis Factor alpha-induced Inflammatory Cytokines Induction in 3T3-L1 Cells. AB - Nowadays, a lot of food ingredients are marketed as dietary supplements for health. Because the effectiveness and mechanisms of these compounds have not been fully characterized, they might have unknown functions. Therefore, we investigated the effect of several food ingredients (Bergamottin, Chrysin, L Citrulline and beta-Carotene) known as health foods on adipocyte differentiation by using 3T3-L1 preadipocytes. In this study, we found that Bergamottin, a furanocoumarin isolated from grapefruit juice, promotes adipocyte differentiation. In addition, Bergamottin increases the expression of adiponectin, an anti-inflammatory adipokine, and peroxisome proliferator activated receptor gamma (PPARgamma), a nuclear receptor regulating adipocyte differentiation. Furthermore, the anti-inflammatory activity of Bergamottin was demonstrated by its inhibition of the activation of nuclear factor-kappaB (NF kappaB), an inflammatory transcription factor. Stimulation of mature 3T3-L1 adipocytes by tumor necrosis factor-alpha (TNF-alpha) decreased the expression of the endogeneous NF-kappaB inhibitor, IkappaBalpha. Treatment with Bergamottin further decreased the TNF-alpha-induced change in IkappaBalpha expression, suggesting that Bergamottin mediated the inhibition of NF-kappaB activation. In addition, Bergamottin decreased the TNF-alpha-induced increase in the mRNA levels of pro-inflammatory adipokines, monocyte chemoattractant protein-1 and interleukin-6. Taken together, our results show that Bergamottin treatment could inhibit inflammatory activity through promoting adipocyte differentiation, which in turn suggests that Bergamottin has the potential to minimize the risk factors of metabolic syndrome. PMID- 28566584 TI - Investigation into Differences in Level of Knowledge about Hypertension between High School Students and Elderly People. AB - As a major chronic non-communicable disease, hypertension is the most important risk factor for cardiovascular disease, chronic kidney disease, stroke and, if not treated appropriately, premature death. A population-based approach aimed at decreasing high blood pressure among the general population is an important component of any comprehensive plan to prevent hypertension. However, few studies have investigated generational differences in knowledge about, and consciousness of, hypertension. Thus, we conducted a questionnaire survey about hypertension, with the aim of clarifying differences of understanding about hypertension between high school students and elderly people. The results of this investigation suggested that there is indeed a generational difference: knowledge about hypertension, and awareness of its relationship with salt intake, was higher in elderly people than in high school students. Furthermore, our study showed that among high school students, salt intake consciousness correlated with a family history of hypertension. By contrast, in elderly people, salt intake consciousness is related to age and to an awareness of recommended daily salt intake. This study strongly showed that knowledge and consciousness of hypertension varied among generations, with the elderly being more aware and conscientious about salt intake. Acknowledgement of this generational diversity is critical to developing an effective overall preventive strategy for hypertension. PMID- 28566585 TI - Ovarian Large Cell Neuroendocrine Carcinoma Associated with Serous Carcinoma: Correlation of Pathology with MR Imaging. PMID- 28566586 TI - B1 Power Optimization for Chemical Exchange Saturation Transfer Imaging: A Phantom Study Using Egg White for Amide Proton Transfer Imaging Applications in the Human Brain. AB - The chemical exchange saturation transfer (CEST) effect on an egg white (EW) suspension was investigated for optimization of magnetization transfer (MT) power (B1,rms) and pH dependency with the addition of lactic acid. Applying a higher MT pulse, B1,rms, Z-spectrum shows higher asymmetry and the magnetisation transfer ratio (MTR)asym signal increases to around 1-3.5 ppm, indicating a higher CEST effect. Amide proton transfer (APT) at 3.5 ppm shows a signal elevation in MTRasym with the application of higher B1,rms power and high pH. In addition, the hydroxyl proton signal in MTRasym increases as pH is reduced by lactic acid. In Z spectrum of B1,rms at 1.0 MUT and 2.0 MUT, the dependence on CEST effect of amide proton and hydroxyl proton could be observed by using an EW suspension phantom. The CEST MT power was optimized on the EW suspension phantom with pH dependency and further confirmed on volunteers. In addition, APT imaging at 3.5 ppm using B1,rms at 1.0 MUT performed on two human brains with different pathophysiological conditions indicated appropriate ATP effect. PMID- 28566587 TI - The Superiority of Vonoprazan-based First-line Triple Therapy with Clarithromycin: A Prospective Multi-center Cohort Study on Helicobacter pylori Eradication. AB - Objective We evaluated the safety and efficacy of vonoprazan-based amoxicillin and clarithromycin 7-day triple therapy (VAC) in comparison to proton pump inhibitor (PPI)-based (PAC) as a first-line treatment and vonoprazan-based amoxicillin and metronidazole 7-day triple therapy (VAM) in comparison to PPI based (PAM) as a second-line treatment for the eradication of Helicobacter pylori in Japan. Methods We performed a non-randomized, multi-center, parallel-group study to compare first-line VAC to PAC and second-line VAM to PAM. A pre-planned subgroup analysis on CAM resistance was also performed. Safety was evaluated with an adverse effects questionnaire (AEQ), which was completed by patients during therapy. Results The first-line eradication rates (ER) in the intention-to-treat (ITT) and per protocol (PP) analyses were 84.9% (95% CI: 81.9-87.6%, n=623) and 86.4% (83.5-89.1%, n=612), respectively, for VAC and 78.8% (75.3-82.0%, n=608) and 79.4% (76.0-82.6%, n=603), respectively, for PAC. The ER of VAC was higher than that of PAC in the ITT (p=0.0061) and PP analyses (p=0.0013). The ERs for VAC in patients with CAM-resistant and CAM-susceptible bacteria were 73.2% (59.7 84.2%, n=56) and 88.9% (83.4-93.1%, n=180), respectively. PAC was associated with higher AEQ scores for diarrhea, nausea, headache, and general malaise. In the second-line ITT and PP analyses VAM achieved ERs of 80.5% (74.6-85.6%, n=216) and 82.4% (76.6-87.3%, n=211), respectively, while PAM achieved ERs of 81.5% (74.2 87.4%, n=146) and 82.1% (74.8-87.9%, n=145), respectively. No significant differences were observed in the ITT (p=0.89) or PP (p=1.0) analyses. Conclusion The ER of first-line VAC was higher than that of PAC, but still <90%. No difference was observed between second-line VAM and PAM. Vonoprazan-based triple therapy was safe and well tolerated. PMID- 28566588 TI - Limited Identification of Dual-time-point Positron Emission Tomography/Computed Tomography in Advanced Colorectal Neoplasms. AB - Objective We investigated whether dual-time-point 18-Fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) could improve the positive predictive value for detecting advanced colorectal neoplasms (cancer, adenoma >=10 mm or adenoma with high-grade dysplasia). Methods We retrospectively searched for consecutive patients with a known primary cancer, who had a colonic 18FDG uptake incidentally found by PET/CT, followed by colonoscopy between January 2013 and August 2014. The clinical characteristics including the maximum standardized uptake value (SUVmax) were compared between advanced colorectal neoplasms and non-advanced lesions. Results Forty-eight patients had 51 foci with an incidental focal colorectal uptake of 18FDG. Among these 51 foci, 28 foci were judged as being advanced neoplasms, whereas 23 foci identified as non-advanced lesions. Four cases were missed by PET/CT: two laterally spreading tumors (LSTs) with intramucosal cancer and two severe adenomas (<10 mm). The positive predictive value for the detection of advanced neoplasms was 55%. The per-spot performance of PET/CT showed that SUVmax was significantly higher in advanced neoplasms than in non-advanced lesions for the early-phase (10.1+/-4.9 vs. 6.5+/ 3.2, p=0.029) and the delayed-phase (12.0+/-6.0 vs. 7.4+/-4.0, p=0.022). However, more importantly, there was a significant overlap of the SUVmax and no significant difference was found in the retention index (19.2+/-20.1 vs. 16.6+/ 29.4, p=0.767). Conclusion Dual-time-point PET/CT was found to have limited impact for identifying advanced colorectal neoplasms in spite of its high sensitivity and it might therefore not be able to identify either LSTs or small advanced neoplasms. PMID- 28566589 TI - Clinical Characteristics of Severe Erosive Esophagitis among Patients with Erosive Esophagitis: A Case-control Study. AB - Objective The risk factors associated with severe erosive esophagitis are not well defined in Japan. We aimed to evaluate the risk factors associated with the endoscopic severity of esophageal mucosal injury. Methods Eighty consecutive Japanese patients with severe erosive esophagitis [Los Angeles (LA) classification grade C or D] who had undergone upper endoscopies in the Gastroenterology Division of Omori Red Cross Hospital between June 2010 and March 2013 were retrospectively analyzed. For each case, a control with mild erosive esophagitis (LA classification grade A or B) who was matched by sex and age was randomly selected during the same period. Among the endoscopic findings, the condition of the gastroesophageal flap valve (GEFV) was graded according to Hill's classification. We identified the risk factors for severe erosive esophagitis using a multivariable logistic regression model. Results A poor performance status (PS) (odds ratio [OR]=17.1201, 95% confidence interval [CI]=3.0268-140.3121, p=0.0008) and an abnormal GEFV (OR=3.0176, 95% CI=1.0589 9.4939, p=0.0385) were risk factors for severe erosive esophagitis, while the presence of open-type gastric mucosal atrophy (GMA) was inversely associated with severe erosive esophagitis (OR=0.2772, 95% CI=0.1087-0.6675, p=0.0040). Conclusion Among patients with erosive esophagitis, a poor PS and an abnormal GEFV were associated while GMA was inversely associated with severe erosive esophagitis. Drug therapy alone or in combination with physical therapy may improve the therapeutic effect on severe erosive esophagitis in patients with a poor PS. PMID- 28566590 TI - The Effects of Pioglitazone on Bone Formation and Resorption Markers in Type 2 Diabetes Mellitus. AB - Objective The use of thiazolidinediones is reported to be associated with an increased frequency of fractures, especially in women; however, the underlying mechanism is not clear. In this prospective study, we compared the effects of pioglitazone and metformin on bone metabolism in Japanese patients with type 2 diabetes mellitus. Methods A total of 58 patients with type 2 diabetes (24 men and 34 women) were randomly assigned to receive either pioglitazone (30 and 15 mg/day for men and women, respectively) or metformin (750 mg/day). The changes in serum and urinary type 1 cross-linked N-telopeptide (NTX), type 1 cross-linked C telopeptide (CTX), bone alkaline phosphatase (BAP), homocysteine, and serum pentosidine were evaluated before and after three months of treatment. The primary endpoint was changes in bone resorption markers after three months. Patients The subjects of this research were male and female type 2 diabetes patients, less than 80 years of age. Results Pioglitazone significantly increased the serum and urinary NTX and serum and urinary CTX levels. The rates of changes in the serum and urinary NTX and CTX were significantly greater in the pioglitazone group than in the metformin group. Although the BAP levels decreased significantly in the pioglitazone group, the rates of change were similar between the two groups. In the pioglitazone group, the changes in fasting insulin levels correlated significantly with increased bone resorption, independent of age and gender. Conclusion The results demonstrated that pioglitazone increased bone resorption independent of age and gender in Japanese patients with type 2 diabetes. PMID- 28566592 TI - A Prospective Study of the Efficacy, Safety and Pharmacokinetics of Enteral Moxifloxacin in the Treatment of Hemodialysis Patients with Pneumonia. AB - Objectives To investigate the efficacy of oral moxifloxacin (MFLX) as a treatment for pneumonia in hemodialysis (HD) patients and the pharmacokinetic (PK) profile of MFLX after oral administration. Methods Thirteen adult patients who required HD due to chronic renal failure were enrolled in the present study, which was performed to investigate the treatment of community-acquired pneumonia in HD patients. A standard dose of MFLX (400 mg, once daily) was administered. The therapy was continued, discontinued, or switched to another antibiotic depending on the response of the pneumonia to MFLX. A population PK model was developed using the post-hoc method. Results In total, 13 HD patients with pneumonia (male, n=7; female, n=6) were enrolled in the present study. The evaluation on the 3rd day showed that treatment was successful in 11 patients (84.6%) and that 10 patients were cured (76.9%). In the one case in which MFLX treatment failed, the patient was cured by switching to ceftriaxone (CTRX) (2 g, intravenously) plus levofloxacin (LVFX) (250 mg, orally). The causative bacterium in this male patient was P. aeruginosa. It did not display resistance to fluoroquinolones. One patient had liver dysfunction due to MFLX. The estimated PK parameters of MFLX were as follows: AUC0->24, 61.04+/-17.74 MUg h/mL; Cmax, 5.25+/-1.12 MUg/mL; and Ctrough, 1.15+/-0.45 MUg/mL. The PK parameters of MFLX among the patients in whom adverse events occurred or in whom a cure was not achieved did not differ from those of the other patients to a statistically significant extent. Conclusion MFLX showed good efficacy and safety in HD patients with community-acquired pneumonia and the results of the PK analysis were favorable. Further prospective studies with larger numbers of patients will be needed to draw definitive conclusions. PMID- 28566591 TI - Dual Therapy with Aspirin and Cilostazol May Improve Platelet Aggregation in Noncardioembolic Stroke Patients: A Pilot Study. AB - Objective Some previous studies have found clinical benefit of dual antiplatelet therapy with aspirin and cilostazol for prevention of secondary stroke, but the physiological mechanism involved remains unknown. We aimed to clarify the effects of aspirin/cilostazol therapy on the platelet and endothelial functions of patients with acute noncardioembolic ischemic stroke, in comparison to patients who were treated with aspirin alone. Methods The present randomized prospective pilot study enrolled 24 patients within a week after the onset of noncardioembolic ischemic stroke. The patients were randomly allocated to receive aspirin (100 mg/day) (A group; 11 patients) or cilostazol (200 mg/day) plus aspirin (100 mg/day) (CA group; 13 patients). We measured platelet aggregation, platelet activation, and the thrombomodulin (TM), highly sensitive C-reactive protein (hs-CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand (vWF) antigen levels and vWF activity over a 4-week period after enrollment. Results There was no significant difference in the platelet functions of the A and CA groups. However, the platelet aggregation induced by adenosine diphosphate (ADP) was decreased at 2 and 4 weeks (p<0.05) after treatment in comparison to the pre-treatment values in the CA group, but not in the A group. Platelet activation, and the hs-CRP, TM, ICAM-1, VCAM-1 and vWF values did not significantly decrease after treatment in either group. Conclusion Although there were no significant differences in platelet aggregation, platelet activation or the endothelial biomarker levels of the A and CA groups, dual therapy with aspirin and cilostazol inhibited platelet aggregation in comparison to the pre-treatment values, similarly to patients who received aspirin alone. This may suggest the clinical usefulness of dual therapy with aspirin and cilostazol in the treatment of patients with noncardioembolic ischemic stroke. PMID- 28566593 TI - Seasonal Variation in the Daily Urinary Sodium Excretion in Outpatients from the Morioka Region of Northern Japan. AB - Objective Although the daily urinary sodium excretion (UNaV) is considered to provide the most reliable estimate of the daily sodium intake, it may be affected by salt loss due to sweating in summer. However, the seasonal variation in the daily UNaV associated with a normal lifestyle is unknown. Methods This study was performed in 348 outpatients from the Morioka region during three seasons: summer (summer 1), winter, and the following summer (summer 2). The daily UNaV (g salt/day) was estimated by the second morning urine method three times during each season. Seasonal variation was defined as a significant trend across the three seasons together with a significant difference between winter and both summers. Results In women, the daily UNaV was higher in winter (11.8+/-3.0 g salt/day) than in summer 1 (11.2+/-2.9 g salt/day) or summer 2 (11.0+/-2.9 g salt/day). In contrast, there was no marked seasonal variation in men. An analysis stratified by age (4 quartiles) identified seasonal variation in the older 2 quartiles of women (aged >=68 years). In these women, the mean seasonal difference in the daily UNaV was 0.9 g of salt/day for both winter vs. summer 1 and winter vs. summer 2, while it was 0.1-0.8 g of salt/day in the other groups. Conclusion Seasonal variation in the daily UNaV only occurred in older female patients and was relatively small. This is evidence for restricting salt intake throughout the year and should reassure patients who are anxious about salt loss due to sweating in summer. PMID- 28566594 TI - The Effective Treatment with Cyclosporine of a Ulcerative Colitis Patient with Concurrent Idiopathic Thrombocytopenic Purpura Who Subsequently Developed Spontaneous Pneumomediastinum. AB - Although extraintestinal manifestations of inflammatory bowel diseases are not uncommon, few reports have described concurrent idiopathic thrombocytopenic purpura (ITP). Spontaneous pneumomediastinum is also a rare complication of ulcerative colitis (UC). This report describes the case of a 14-year-old boy who experienced recurrent ulcerative colitis 3 months after temporary improvement following treatment with prednisolone (20 mg/day) and granulocyte/monocyte adsorption apheresis. His platelet counts decreased, suggesting ITP. The dosage of prednisolone was increased to 60 mg/day; however, his thrombocytopenia did not improve and he suddenly developed pneumomediastinum. A continuous infusion of cyclosporine increased his platelet counts and improved his ulcerative colitis. Cyclosporine should be considered when steroid-resistant ITP accompanies UC. PMID- 28566595 TI - Gastroesophageal Variceal Bleeding Successfully Controlled by Partial Splenic Embolization. AB - A 53-year-old male patient with a history of hepatocellular carcinoma developed gastroesophageal varices refractory to endoscopic injection sclerotherapy (EIS). He required EIS six times in 2 years for recurring variceal bleeding. After hepatic resection, he developed massive splenomegaly. Partial splenic embolization (PSE) was performed to reduce the portal pressure. Varices and variceal bleeding were not detected during 13-year follow up, until the patient died of hepatocellular carcinoma. This is a unique case of gastroesophageal varices controlled by PSE and improved portal hypertension. PMID- 28566596 TI - Paraneoplastic Hypocalcemia Developed in Gastric Cancer Accompanied by Osteoblastic Metastasis. AB - Paraneoplastic syndromes are generally defined as clinical disorders associated with malignant diseases, and hypocalcemia associated with cancer is a rare condition. A woman in her 60s was referred to our hospital for the further examination of massive ascites due to carcinoma of unknown primary origin. She complained of numbness around her lips, and marked hypocalcemia of 5.0 mg/dL was noted. After two courses of chemotherapy, computed tomography showed a decrease in the ascites, and her serum calcium level increased. Although hypocalcemia is a very rare condition in patients with gastric cancer, serum calcium values should be evaluated when neurological symptoms are observed. PMID- 28566597 TI - Intravascular Images of Coronary Stenosis with Multiple Channels in a Patient with Antiphospholipid Syndrome: The Optical Coherence Tomography Findings. AB - Intravascular images of coronary stenosis by antiphospholipid syndrome (APS) would be beneficial to understand the mechanism of this disease. A 59-year-old woman with APS/systemic lupus erythematosis (SLE) underwent emergent coronary angiography which revealed stenosis with micro channels in the proximal left anterior descending artery. According to optical coherence tomography (OCT), the central lumen was surrounded by a thick septum with a homogenous and high intensity. Multiple small channels existed near the vessel wall with diffuse intimal hyperplasia. White thrombi were floating distal to the stenosis. Intravascular images obtained by optical coherence tomography (OCT) revealed the microstructure of complex coronary stenosis, which had ambiguous findings on angiography and intravascular ultrasound (IVUS) in an acute coronary syndrome (ACS) patient with APS/SLE. PMID- 28566598 TI - Late-onset Mitochondrial Cardiomyopathy Triggered by Anticancer Treatment. AB - We report the case of a 62-year-old woman with a history of bilateral hearing impairment, who developed mitochondrial cardiomyopathy after chemotherapy. The patient underwent postoperative cisplatin chemotherapy after the surgical treatment of cervical cancer. The systolic function of her left ventricle decreased significantly. A tissue examination of the left ventricle revealed mitochondrial cardiomyopathy. Genetic testing revealed mutations in mitochondrial 3,243 A->G. Nine hundred fifty-five individual mutations were identified by next generation sequencing. Since cardiovascular complications are the second leading cause of morbidity and mortality in patients undergoing cancer treatment, mitochondrial cardiomyopathy should be considered a potential cause of heart failure. PMID- 28566599 TI - Simultaneous Idiopathic Dissections of the Coronary and Superior Mesenteric Arteries. AB - A 49-year-old man complained of sudden upper abdominal pain but was not given a definitive diagnosis. The day after he was discharged, he noticed left chest pain. An in-depth electrocardiogram indicated acute myocardial infarction, and emergent coronary angiography revealed 99% stenosis of his left coronary artery. An intravascular ultrasound revealed spontaneous coronary artery dissection (SCAD), and the lesion was successfully stented. In an atherosclerosis screening, superior mesenteric artery dissection (SMAD) was confirmed, after which the lesion was successfully stented. This case suggests that SCAD and SMAD might have similar pathological backgrounds. PMID- 28566600 TI - Thrombolytic Therapy and Aspiration of Clots were Effective in the Removal of a Transient Inferior Vena Cava (IVC) Filter that Captured a Large Thrombus. AB - A 37-year-old woman presented at 37 weeks of gestation with a history of heaviness in her left leg. Enhanced computed tomography revealed a left extensive ileofemoral thrombus, and we employed a transient inferior vena cava (IVC) filter (t-IVCF) before delivery. Although we attempted to remove the t-IVCF on the day after delivery, a large thrombus was captured in the filter. We therefore performed thrombolytic therapy for one week, but a few small clots remained within the t-IVCF. We were ultimately able to remove the t-IVCF under constant negative pressure by aspiration from a side-hole of the sheath. We herein describe the effectiveness of this aspiration technique in our case. PMID- 28566601 TI - Challenging Differential Diagnosis of Hypergastremia and Hyperglucagonemia with Chronic Renal Failure: Report of a Case with Multiple Endocrine Neoplasia Type 1. AB - A 53-year-old woman developed end-stage renal failure during a 15-year clinical course of primary hyperparathyroidism and was referred to our hospital for evaluation of suspected multiple endocrine neoplasia type 1 (MEN1). Genetic testing revealed a novel deletion mutation at codon 467 in exon 10 of the MEN1 gene. Systemic and selective arterial calcium injection (SACI) testing revealed hyperglucagonemia and hypergastrinemia with positive gastrin responses. A pathological examination revealed glucagonoma and a lymph node gastrinoma. The findings in this case indicate the importance of early diagnosis of MEN1 and demonstrate the utility of systemic and SACI testing in renal failure cases. PMID- 28566602 TI - An Impaired Awareness of Hypoglycemia Improved After Vitamin B12 Treatment in a Type 1 Diabetic Patient. AB - An impaired awareness of hypoglycemia is a serious problem in diabetic patients, which can lead to life-threatening severe hypoglycemia. Recurrent hypoglycemia attenuates the function of the central, mainly hypothalamic, nervous system and it causes an impaired awareness of hypoglycemia. Vitamin B12 deficiency is also associated with the dysfunction of central nervous system. We report a 72-year old type 1 diabetic patient with vitamin B12 deficiency whose impaired awareness of hypoglycemia improved after 4 weeks of vitamin B12 administration with an increased counter-hormone secretion in response to hypoglycemia. We should recognize vitamin B12 deficiency as one of the causes of an impaired awareness of hypoglycemia in diabetic patients. PMID- 28566603 TI - Febuxostat for the Prevention of Recurrent 2,8-dihydroxyadenine Nephropathy due to Adenine Phosphoribosyltransferase Deficiency Following Kidney Transplantation. AB - Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder that results in irreversible renal damage due to 2,8-dihydroxyadenine (DHA) nephropathy. A 28-year-old man underwent living-related kidney transplantation for chronic kidney disease of unknown etiology. Numerous spherical brownish crystals observed in his urinary sediment on postoperative day 3 and were observed within the tubular lumen of renal allograft biopsy specimens on postoperative day 7. After a genetic diagnosis, febuxostat treatment was started on postoperative day 7, with the dosage gradually increased to 80 mg/day until complete the disappearance of 2,8-DHA crystals. Febuxostat prevented secondary 2,8-DHA nephropathy after kidney transplantation. PMID- 28566604 TI - Unusual Proliferative Glomerulonephritis in a Patient Diagnosed to Have Hypoparathyroidism, Sensorineural Deafness, and Renal Dysplasia (HDR) Syndrome with a Novel Mutation in the GATA3 Gene. AB - Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant disease caused by GATA3 mutations. Although several cases with variable renal features have been reported, the presence of histological changes within the glomeruli in adult patients is unclear. We herein report an adult case of HDR syndrome with a novel p.C288W (TGC>TGG) missense mutation in GATA3. His renal histology showed a membranoproliferative glomerulonephritis-like glomerular lesion. Additional renal histological analyses of HDR syndrome patients will be needed to clarify the role of GATA3 in both the developing and adult kidney. PMID- 28566605 TI - Dermatomyositis with Rapidly Progressive Interstitial Lung Disease Treated with Rituximab: A Report of 3 Cases in Japan. AB - We performed a retrospective chart review of three patients with hypomyopathic dermatomyositis and rapidly progressive interstitial lung disease. The patients were Japanese women of 71, 69, and 65 years of age. Two patients were anti melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive and 1 was anti-aminoacyl-tRNA synthetase (anti-ARS) antibody-positive. Their respiratory statuses deteriorated despite the administration of glucocorticoid, calcineurin inhibitors, and intravenous cyclophosphamide therapy. We subsequently administered rituximab. The anti-ARS antibody-positive patient survived, while 2 anti-MDA5 antibody-positive patients died. PMID- 28566606 TI - Pulmonary Endometriosis which Probably Occurred through Hematogenous Metastasis after Artificial Abortion. AB - Pulmonary endometriosis (PEM) is a rare disease characterized by the proliferation of ectopic endometrial tissue in the lungs, which presents as catamenial hemoptysis. A 20-year-old-woman was admitted for repeated hemoptysis. Chest CT revealed a ground-glass opacity that appeared consistently with her menstrual cycle. Our detailed inquiry revealed a history of artificial abortion, which was followed by the use of oral contraceptives and catamenial hemoptysis after the discontinuation of these medications. Surgical removal was performed and histopathological examinations confirmed PEM. This clinical course suggested hematogenous metastasis. An inquiry regarding the patient's history of uterine procedures and use of oral contraceptives was suggestive for the diagnosis of this disease. PMID- 28566607 TI - Development of Extranodal NK/T-cell Lymphoma Nasal Type in Cerebrum Following Epstein-Barr Virus-positive Uveitis. AB - A 74-year-old woman developed bilateral uveitis with high Epstein-Barr virus (EBV) DNA load in the vitreous fluid without lymphoma cells. Four years after the onset, T2-weighted contrast-enhanced MRI revealed hyperintense lesions in the right occipital and parietal lobe. A biopsy resulted in the diagnosis of extranodal NK/T-cell lymphoma nasal type (ENKL). The repeat region of LMP1, an EBV gene, detected in the brain lesion was identical to that detected in the vitreous fluid. ENKL of the central nervous system is quite rare, and the pathogenesis has not been determined. The lymphoma in this case might have been closely associated with the EBV-positive uveitis. PMID- 28566608 TI - A Rare Case of Adult Autoimmune Neutropenia Successfully Treated with Prednisolone. AB - Autoimmune neutropenia (AIN) is a rare disorder that may cause life-threatening infections. In adults, most cases are secondary to other pathological conditions, and primary AIN is extremely rare. We herein report a case involving a 57-year old woman diagnosed with AIN. A granulocyte immunofluorescence test detected autoantibodies against human neutrophil antigens in her serum, while various examinations revealed no other causes of neutropenia, suggesting her AIN was primary. She was refractory to granulocyte-colony-stimulating factor but responded to prednisolone. Her neutrophil count remained normal after gradual discontinuation of prednisolone. Diagnostic procedures and optimal treatments for this disorder need to be established. PMID- 28566609 TI - Progressive Balint's Syndrome in a Patient Demonstrating Dementia with Lewy Bodies. AB - We herein report a 65-year-old man demonstrating dementia with Lewy bodies who first presented with Balint's syndrome. Two years later, a mild cognitive impairment was noted. From three years after onset, he developed progressive parkinsonism, visual hallucination, and autonomic dysfunction, in line with the deterioration of the cognitive function. Single photon emission computed tomography with a 99mTc-ethylcysteinate dimer performed two years after onset revealed hypoperfusion in the restricted area of the bilateral superior parietal lobule, which extended to the lateral occipital cortices within two years. It is suggested that the pathological process can extend from the parietal to occipital lobes. PMID- 28566610 TI - An Autopsy Case of Respiratory Failure Induced by Repetitive Cervical Spinal Cord Damage due to Abnormal Movement of the Neck in Athetoid Cerebral Palsy. AB - We herein report the clinical and autopsy findings of a 48-year-old right-handed man with athetoid cerebral palsy who suffered from cervical myelopathy due to abnormal neck movement, and who died of respiratory failure. Pathologically, the external appearance of the ventral surface of the cervical spinal cord revealed a linear indentation running obliquely at the level between the C4 and C5 segments. In the most severely compressed lesion, the gray matter was predominantly affected and severely atrophic. Microscopically, clusters of oligodendrocytes associated with thinly myelinated axons were also observed in the lateral funiculus. The latter findings are unique, and could be interpreted as regenerative and/or restorative phenomena of the central nervous system following chronic repetitive spinal cord compression. PMID- 28566611 TI - Vasculitic Neuropathy Following Exposure to a Glyphosate-based Herbicide. AB - We herein report a case of peripheral neuropathy following exposure to large amounts of glyphosate-based herbicide. A 70-year-old man suffered from pain and purpura in the left sole following exposure to glyphosate-based herbicide. Pain and purpura spread to the opposite side and increased in severity. Mild weakness of the lower limbs was also observed. A sural nerve biopsy revealed the infiltration of lymphocytes around small vessels in the epineurium with numerous eosinophils, deposition of hemosiderins and focal axonal degeneration, compatible with findings of vasculitic neuropathy. Glyphosate-based herbicides should be recognized as a causative agent of vasculitic neuropathy. PMID- 28566612 TI - The Successful Treatment of Refractory Polyarteritis Nodosa Using Infliximab. AB - Polyarteritis nodosa (PAN), characterized by arteritis of medium-sized blood vessels, is usually treated with a combination of glucocorticoids and immunosuppressants; however, some cases are refractory to these treatments. We herein report the case of a man with PAN that was refractory to various immunosuppressive treatments, including cyclophosphamide, methotrexate, and rituximab. After infliximab (IFX) treatment was initiated, his symptoms improved dramatically and remission was maintained. IFX is considered to be an effective alternative treatment for PAN which proves to be refractory to several immunosuppressive treatments. PMID- 28566613 TI - Acute Carpal Tunnel Syndrome Due to Pyogenic Flexor Tenosynovitis without Any Antecedent Injury. AB - We herein report a case of acute carpal tunnel syndrome due to pyogenic flexor tenosynovitis in the absence of any antecedent injury whose rapid progression and course was similar to that seen with necrotizing fasciitis. This potentially disastrous clinical condition must be promptly recognized, since it needs early surgical management to prevent morbidity. PMID- 28566615 TI - Diffuse Esophageal Spasm. PMID- 28566614 TI - Conjunctivitis Caused by a Strain of Neisseria gonorrhoeae That Was Less Susceptible to Ceftriaxone. AB - A 20-year-old man presented with bilateral ocular discharge and conjunctival injection. An ocular culture revealed Neisseria gonorrhoeae with decreased susceptibility to multiple drugs, including ceftriaxone. The patient was successfully treated with doxycycline (100 mg), which was administered orally, twice a day, for 7 days. PMID- 28566616 TI - Macro-CK and CK-BB Contributing to Sham CK-MB Elevation. PMID- 28566617 TI - Biliary Pneumonia due to the Presence of a Bronchobiliary Fistula. PMID- 28566618 TI - Underlying Mechanisms and Therapeutic Strategies for Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ). AB - Bisphosphonates (BPs), with a non-hydrolysable P-C-P structure, are cytotoxic analogues of pyrophosphate, bind strongly to bone, are taken into osteoclasts during bone-resorption and exhibit long-acting anti-bone-resorptive effects. Among the BPs, nitrogen-containing BPs (N-BPs) have far stronger anti-bone resorptive effects than non-N-BPs. In addition to their pyrogenic and digestive organ-injuring side effects, BP-related osteonecrosis of jaws (BRONJ), mostly caused by N-BPs, has been a serious concern since 2003. The mechanism underlying BRONJ has proved difficult to unravel, and there are no solid strategies for treating and/or preventing BRONJ. Our mouse experiments have yielded the following results. (a) N-BPs, but not non-N-BPs, exhibit direct inflammatory and/or necrotic effects on soft tissues. (b) These effects are augmented by lipopolysaccharide, a bacterial-cell-wall component. (c) N-BPs are transported into cells via phosphate transporters. (d) The non-N-BPs etidronate (Eti) and clodronate (Clo) competitively inhibit this transportation (potencies, Clo>Eti) and reduce and/or prevent the N-BP-induced inflammation and/or necrosis. (e) Eti, but not Clo, can expel N-BPs that have accumulated within bones. (f) Eti and Clo each have an analgesic effect (potencies, Clo>Eti) via inhibition of phosphate transporters involved in pain transmission. From these findings, we propose that phosphate-transporter-mediated and inflammation/infection-promoted mechanisms underlie BRONJ. To treat and/or prevent BRONJ, we propose (i) Eti as a substitution drug for N-BPs and (ii) Clo as a combination drug with N-BPs while retaining their anti-bone-resorptive effects. Our clinical trials support this role for Eti (we cannot perform such trials using Clo because Clo is not clinically approved in Japan). PMID- 28566620 TI - Cooperative Behavior of Fluoroquinolone Combinations against Escherichia coli and Staphylococcus aureus. AB - The effects of different combinations of ciprofloxacin (CIP) and norfloxacin (NOR) against Escherichia coli and Staphylococcus aureus were studied using checkerboard, fractional inhibitory concentration (FIC) and time-kill analysis methods. Results obtained by the checkerboard method showed that the more effectives combinations against Escherichia coli were 0.0009 ug/mL CIP+0.0312 ug/mL NOR and 0.0037 ug/mL CIP+0.0075 ug/mL NOR with a FIC index of 0.62. For Staphylococcus aureus, the combination of 0.0625 ug/mL CIP+0.2500 ug/mL NOR showed a synergistic effect, with a FIC index of 0.50. The results of the time kill method demonstrated either indifference or additivity of the combinations 0.0009 ug/mL CIP+0.0312 ug/mL NOR, 0.0018 ug/mL CIP+0.0312 ug/mL NOR, 0.0037 ug/mL CIP+0.0075 ug/mL NOR and 0.0037 ug/mL CIP+0.0156 ug/mL NOR at 24 h against E. coli. The combination 0.0037 ug/mL CIP+0.0312 ug/mL NOR showed synergistic activity. All the analyzed combinations evidenced bactericidal effects at 4 h. The combinations 0.0625 ug/mL CIP+0.2500 ug/mL NOR and 0.0625 ug/mL CIP+0.0625 ug/mL NOR showed indifference or additivity against S. aureus. None of them generated bactericidal effect at 4 h. Moreover, this last equimolecular combination (equivalent to 1/4 minimum inhibitory concentration (MIC) CIP+1/16 MIC NOR) generated higher reduction of nitro blue tetrazolium than drugs alone. By another way, combinations not equimolecular of CIP and NOR assayed, generated less levels of reactive oxygen species (ROS) than the components alone. PMID- 28566619 TI - Berberine Induces Cell Cycle Arrest in Cholangiocarcinoma Cell Lines via Inhibition of NF-kappaB and STAT3 Pathways. AB - Berberine is a natural compound found in several herbs. Anticancer activity of berberine was reported in several cancers, however, little is known regarding the effects of berberine against cholangiocarcinoma (CCA). In this study, the growth inhibitory effects of berberine on CCA cell lines and its molecular mechanisms were explored. Cell growth and cell cycle distribution were examined by the 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. The expression levels of cell cycle regulatory proteins were determined by Western blot analysis. Berberine significantly inhibited growth of CCA cell lines in a dose and time dependent fashion. The inhibition was largely attributed to cell cycle arrest at the G1 phase through the reduction of cyclin D1, and cyclin E. Moreover, berberine could reduce the expression and activation of signal transducers and activator of transcription 3 (STAT3) and probably nuclear factor-kappaB (NF-kappaB) via suppression of extracellular signal regulated kinase (ERK) 1/2 action. These results highlight the potential of berberine to be a multi-target agent for CCA treatment. PMID- 28566621 TI - Dual Protective Effects of Flavonoids from Petasites japonicus against UVB Induced Apoptosis Mediated via HSF-1 Activated Heat Shock Proteins and Nrf2 Activated Heme Oxygenase-1 Pathways. AB - The leaves of Petasites japonicus are used for their anti-allergic properties in traditional Korean, Japanese, and Chinese medicine. This study aimed to identify bioactive compounds isolated from P. japonicus leaves. All compounds were assessed for their ability of transcriptional activation, induction of phase 2 enzymes and heat shock proteins (HSPs), as well as protection against the UVB induced apoptotic cell death. Bioactive compounds were isolated from P. japonicus leaves. All compounds were evaluated for their protective effect using human dermal fibroblasts (HDF) and human epidermal keratinocyte cells (HEKC) treated with UVB radiation. Four flavonoids were isolated from the leaves of P. japonicus and identified as kaempferol-3-O-(6"-acetyl)-beta-D-glucoside (1), quercetin-3-O (6"-acetyl)-beta-D-glucoside (2), kaempferol-3-O-beta-D-glucoside (3), and quercetin-3-O-beta-D-glucoside (4). These compounds activated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heat-shock response transcription elements (HSE) that resulted in the induction of heme oxygenase-1 (HO-1) and HSP70, respectively. Activation of these pathways provided protection to the skin cells against UVB radiation. The isolated compounds activated the Nrf2 and HSE pathways and could protect against UVB-induced apoptosis. PMID- 28566622 TI - Factorial Analysis of Hepatitis B Virus Reactivation-Induced Hepatitis B Using JADER. AB - Hepatitis B caused by chemotherapy- and immunosuppression-associated hepatitis B virus reactivation is likely to become fulminant, and a high mortality rate has been reported. In this study, using the Japanese adverse drug event report database (JADER), factorial analysis of patients who developed hepatitis B as an adverse event was performed. The number of reported cases of hepatitis B during the survey period was 781 and 185 of them (24%) died. Rituximab and prednisolone were administered to many cases (233, 216 cases, respectively), and the reporting odds ratios were high (65.35, 13.40, respectively), suggesting their strong association with the development of hepatitis B. Regarding the onset time, rituximab-induced hepatitis B developed within one year after administration in 83%, being a high frequency. Prednisolone-induced hepatitis B developed even after one year in 36%. Since prednisolone is used to treat rheumatoid arthritis at a dose <=10 mg/d, the patients were divided based on the prednisolone dose into the groups treated at >10 and <=10 mg/d, and the onset time was investigated in each group. The median onset time was 113 and 330 d, respectively, showing a significant difference. On time-to-event analysis using the Weibull distribution, rituximab was classified as the early failure type, and prednisolone and methotrexate for rheumatoid arthritis were classified as the wear out failure type. These findings are important information which may lead to early discovery of and taking actions against hepatitis B being helpful for providing appropriate medical care. PMID- 28566623 TI - Moutan Cortex Protects Hepatocytes against Oxidative Injury through AMP-Activated Protein Kinase Pathway. AB - Moutan Cortex, the root bark of Paeonia suffruticosa ANDREWS in Ranunculaceae, has widely demonstrated analgesic, anti-spasmodic, and anti-inflammatory effects in various cancer and immune cell lines. Oxidative stress is associated with development of several diseases, including liver disease. We prepared the water extract of Moutan Cortex (MCE) to investigate the cytoprotective activities and its mechanism. MCE protected hepatocytes from arachidonic acid (AA)+iron induced oxidative stress, as indicated by reactive oxygen species (ROS) production and cell viability analysis. MCE also suppressed mitochondrial dysfunction in AA+iron treated human hepatocyte-derived hepatocellular carcinoma cell line, HepG2 cells. In addition, MCE treatment induces AMP-activated protein kinase (AMPK) and liver kinase B1 phosphorylation, which play a role in inhibition of oxidative stress induced cell death. Moreover, one of the MCE compounds, chlorogenic acid, exerted protective effects against oxidative stress and apoptosis. Taken together, MCE protected hepatocytes against AA+iron-induced oxidative stress through AMPK activation, and may be a candidate for the treatment of liver disease. PMID- 28566624 TI - Distigmine Bromide Produces Sustained Potentiation of Guinea-Pig Urinary Bladder Motility by Inhibiting Cholinesterase Activity. AB - Distigmine is a cholinesterase (ChE) inhibitor used for the treatment of detrusor underactivity in Japan. Distigmine's pharmacological effects are known to be long lasting, but the duration of its effect on urinary bladder contractile function has not been fully elucidated. The present study aimed to determine these effects in relation to the plasma concentrations of distigmine and its inhibition of ChE activities in blood, plasma, and bladder tissue. Intravesical pressures were recorded in anesthetized guinea-pigs for 12 h after the intravenous administration of saline or distigmine (0.01-0.1 mg/kg). Plasma distigmine concentrations were measured by liquid chromatograph-tandem mass spectrometry (LC MS/MS), while ChE activities were assayed using 5,5'-dithiobis(2-nitrobenzoic acid). Distigmine (0.1 mg/kg) significantly increased the maximum intravesical pressure at micturition reflex for 12 h post-administration. In contrast, plasma distigmine was only detectable for 6 h post-administration in these animals and a one-compartment model calculated an elimination half-life of 0.7 h. However, bladder and blood acetylcholinesterase activities were significantly inhibited for 12 h after distigmine administration, although plasma ChE activities were not affected. The pharmacodynamic effects of distigmine thus persisted after its elimination from the circulation, indicating that it may bind to bladder acetylcholinesterase, producing sustained enzyme inhibition and enhancement of bladder contractility. PMID- 28566625 TI - Effective-Loading of Platinum-Chloroquine into PEGylated Neutral and Cationic Liposomes as a Drug Delivery System for Resistant Malaria Parasites. AB - The trans platinum-chloroquine diphosphate dichloride (PtCQ) is a new type of antimalarial drug used to fight parasites resistant to traditional drugs. PtCQ is synthesized by mixing platinum and chloroquine diphosphate (CQ). This study examines two efficient methods for forming a nanodrug, PtCQ-loaded liposomes, for use as a potential antimalarial drug-delivery system: the thin drug-lipid film method to incorporate the drug into a liposomal membrane, and a remote-loading method to load the drug into the interior of a cationic liposome. The membranes accordingly comprised PEGylated neutral or cationic liposomes. PtCQ was efficiently loaded into PEGylated neutral and cationic liposomes using the thin drug-lipid film method (encapsulation efficiency, EE: 76.1+/-6.7% for neutral liposomes, 1 : 14 drug-to-lipid weight ratio; 70.4+/-9.8% for cationic liposomes, 1 : 14 drug-to-lipid weight ratio). More PtCQ was loaded into PEGylated neutral liposomes using the remote-loading method than by the thin drug-lipid film method and the EE was maximum (96.1+/-4.5% for neutral liposomes, 1 : 7 (w/w)). PtCQ was encapsulated in PEGylated cationic liposomes comprising various amounts of cationic lipids (0-20 mol%; EE: 96.9-92.3%) using the remote-loading method. PEGylated neutral liposomes and cationic liposomes exhibited minimum leakage of PtCQ after two months' storage at 4 degrees C, and further exhibited little release under in vitro culture conditions at 37 degrees C for 72 h. These results provide a useful framework for the design of future liposome-based in vivo drug delivery systems targeting the malaria parasite. PMID- 28566626 TI - Analysis of Adverse Drug Reaction Risk in Elderly Patients Using the Japanese Adverse Drug Event Report (JADER) Database. AB - In general, the risk of adverse drug reactions (ADRs) is higher in elderly patients than in younger patients. In this study, we performed a comprehensive assessment of the risks of possible drug-ADR combinations in elderly patients using the Japanese Adverse Drug Event Report (JADER) database of the Pharmaceutical and Medical Devices Agency (PMDA, Japan) using the reporting odds ratio (ROR) as an index. Data recorded from April 2004 to September 2015 in the JADER database were downloaded from the PMDA website. The patients were classified into younger (<=69 years old) and elderly (>=70 years old) groups. The ROR and 95% confidence interval (CI) were calculated for all combinations of drugs and ADRs for which there were three or more reports in the database, focusing particularly on the combinations where more than 100 cases had been reported in elderly and younger patients. The most frequently reported drug-ADR combination was methotrexate with interstitial lung disease (646 cases). The combination with the highest ROR was methotrexate with lymphoproliferative disorder (ROR: 484.6, 95% CI: 334.1-702.9). In total, 27 drug-ADR combinations were found to have high risk in elderly patients. In conclusion, the findings of this comprehensive assessment of drug-ADR combinations using the JADER database will be valuable for updating the ADR risks for elderly patients in clinical setting. PMID- 28566627 TI - Analysis of Clinical Efficacy and Adverse Effects of beta-Blocking Agents Used Clinically for Chronic Heart Failure. AB - Clinical efficacy and adverse effects of the beta-blocking agents, carvedilol, bisoprolol, and metoprolol were analyzed theoretically, and then compared quantitatively, for the purpose of determining their proper use for chronic heart failure. Initially, we evaluated occupancy binding to the beta1 and beta2 receptors (Fssbeta1 and Fssbeta2) by these drugs. Thereafter, we examined the relationship between Fssbeta1 values and left ventricular ejection fraction (LVEF) increase rate to determine efficacy. The result showed that the efficacy with carvedilol could be attained with a lower Fssbeta1 value than the others. Therefore, we constructed a model under the assumption that beta-blocking agents exert both indirect action of LVEF increase through the beta1 receptor and direct action on ryanodine receptor 2. Using the model, it was suggested that these drugs have no differences in regard to the efficacy, while it was clarified theoretically that only carvedilol produces an effect that directly involves ryanodine receptor 2 at clinical doses. We also investigated decreases in heart rate and forced expiratory volume in 1 s as adverse effects of beta-blocking agents using a ternary complex model. It was indicated that carvedilol is less likely to induce a heart rate decrease. Meanwhile, it was also suggested that the risk of an asthmatic attack was higher for carvedilol at clinical doses. Our results are considered useful for selection of a proper beta-blocking agent and its administration at a reasonable dose for successful heart failure therapy. PMID- 28566628 TI - Histone Deacetylase Inhibitors Sensitize Murine B16F10 Melanoma Cells to Carbon Ion Irradiation by Inducing G1 Phase Arrest. AB - Epigenetic processes, in addition to genetic abnormalities, play a critical role in refractory malignant diseases and cause the unresponsiveness to various chemotherapeutic regimens and radiotherapy. Herein we demonstrate that histone deacetylase inhibitors (HDACis) can be used to sensitize malignant melanoma B16F10 cells to carbon ion irradiation. The cells were first treated with HDACis (romidepsin [FK228, depsipeptide], trichostatin A [TSA], valproic acid [VPA], and suberanilohydroxamic acid [SAHA, vorinostat]) and were then exposed to two types of radiation (carbon ions and gamma-rays). We found that HDACis enhanced the radiation-induced apoptosis and suppression of clonogenicity that was induced by irradiation, having a greater effect with carbon ion irradiation than with gamma rays. Carbon ion irradiation and the HDACi treatment induced G2/M and G0/G1 cell cycle arrest, respectively. Thus, it is considered that HDACi treatment enhanced the killing effects of carbon ion irradiation against melanoma cells by inducing the arrest of G1 phase cells, which are sensitive to radiation due to a lack of DNA homologous recombination repair. Based on these findings, we propose that pretreatment with HDACis as radiosensitizers to induce G1 arrest combined with carbon ion irradiation may have clinical efficacy against refractory cancer. PMID- 28566629 TI - Activation of PPARgamma at an Early Stage of Differentiation Enhances Adipocyte Differentiation of MEFs Derived from Type II Diabetic TSOD Mice and Alters Lipid Droplet Morphology. AB - Type 2 diabetic Tsumura, Suzuki, obese, diabetes (TSOD) mice gradually gain weight as compared to corresponding Tsumura, Suzuki, non-obesity (TSNO) control mice, and develop insulin resistance. Although development of type 2 diabetes mellitus is associated with dysfunction of adipocytes, little is known about the properties of adipocytes from TSOD mice. Therefore, we attempted to remove intracorporeal factors and elucidate inherent properties of adipocytes of TSOD mice using adipocytes differentiated from mouse embryonic fibroblasts (MEFs) in vitro. Here, we show that MEFs of TSOD have low potency for differentiation into adipocytes. The percentage of Oil red O-stained cells and levels of adipogenic markers in cells differentiated from MEFs of TSOD are lower than those in cells differentiated from MEFs of TSNO. We further show that treatment with an agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma) (rosiglitazone) at an early stage of differentiation increases the percentage of Oil red O stained cells in TSOD-MEFs differentiated into adipocytes. Moreover, the lipid droplet size in those adipocytes is larger than that in the adipocytes differentiated from MEFs of TSNO. Although persistent treatment of MEFs of TSOD with rosiglitazone during differentiation increases the percentage of Oil red O stained cells, the lipid droplet size in adipocytes treated as such does not reach the size of those treated in early stage only. Thus, activation of PPARgamma by its agonist at an early stage of differentiation compensates for the low potency toward adipogenic differentiation of, and accelerates formation of enlarged lipid droplets in adipocytes derived from, MEFs of TSOD mice. PMID- 28566630 TI - Insulin Represses Fasting-Induced Expression of Hepatic Fat-Specific Protein 27. AB - The fat-specific protein 27 (Fsp27) gene belongs to the cell death-inducing DNA fragmentation factor 45-like effector family. Fsp27 is highly expressed in adipose tissue as well as the fatty liver of ob/ob mice. Fsp27 is directly regulated by the peroxisome proliferator-activated receptor gamma (PPARgamma) in livers of genetically obese leptin deficient ob/ob mice. In the present study, Fsp27 was markedly induced by 24 h fasting in genetically normal mouse livers and repressed by refeeding a high sucrose diet. In contrast with the liver, Fsp27 expression was decreased in adipose tissue by fasting and increased by refeeding. Interestingly, fasting-induced Fsp27 liver expression was independent of PPARgamma. Moreover, Fsp27 expression was induced in the insulin-depleted livers of streptozotocin-treated mice. Finally, Fsp27 expression was repressed by direct injection of glucose or insulin in fasting mice. These results suggest that insulin represses Fsp27 expression in the fasting liver. PMID- 28566631 TI - An Empirical Study of the Prescription Pattern of Drugs for Hematological Malignancies in Japan from 2010-2014. AB - The number of elderly patients with hematologic malignancies has been steadily increasing with the aging of society. However, little research has been conducted to evaluate the prescription status of drugs for such diseases in Japan. Therefore, the aims of this study were to identify the patient population currently being prescribed drugs for hematologic malignancies in Japan and the direction of drug development. To examine the prescription pattern of drugs for the treatment of hematological malignancies in Japan from 2010-2014, we used the IMS Japan Pharmaceutical Market database and the Japanese Society of Hematology Clinical Practice Guidelines, and for drug development status, we used ClinicalTrials.gov and the University Hospital Medical Information Network Clinical Trials Registry. We found a significant upward trend in prescriptions for molecular-targeted agents, which are typically prescribed over the long term, and a significant downward trend in chemotherapeutic agents, which are usually prescribed for the short term. We also found that recent drug development in hematological malignancies has focused on molecular-targeted agents. These results suggest that drug development should be directed toward anti-tumor agents in hematological malignancies that can help maintain and improve patients' QOL. PMID- 28566632 TI - Anti-stress Effect of Green Tea with Lowered Caffeine on Humans: A Pilot Study. AB - Theanine, an amino acid in tea, has significant anti-stress effects on animals and humans. However, the effect of theanine was blocked by caffeine and gallate type catechins, which are the main components in tea. We examined the anti-stress effect of green tea with lowered caffeine, low-caffeine green tea, on humans. The study design was a single-blind group comparison and participants (n=20) were randomly assigned to low-caffeine or placebo tea groups. These teas (>=500 mL/d), which were eluted with room temperature water, were taken from 1 week prior to pharmacy practice and continued for 10 d in the practice period. The participants ingested theanine (ca. 15 mg/d) in low-caffeine green tea. To assess the anxiety of participants, the state-trait anxiety inventory test was used before pharmacy practice. The subjective stress of students was significantly lower in the low caffeine-group than in the placebo-group during pharmacy practice. The level of salivary alpha-amylase activity, a stress marker, increased significantly after daily pharmacy practice in the placebo-group but not in the low-caffeine-group. These results suggested that the ingestion of low-caffeine green tea suppressed the excessive stress response of students. This study was registered at the University Hospital Medical Information Network (ID No. UMIN14942). PMID- 28566633 TI - Co-administration of Magnesium Ion Prevents Indomethacin-Induced Intestinal Ulcerogenic Lesions in Adjuvant-Induced Arthritis Rats. AB - In a study to find ways to prevent the side effects of indomethacin (IMC), we previously reported that magnesium ion (Mg2+) can prevent the onset of IMC induced gastric mucosa in adjuvant-induced arthritis (AA) rats, a model for rheumatoid arthritis (RA). In this study we investigated whether the co administration of IMC and Mg2+ prevents the formation and aggravation of intestinal ulcerogenic lesions in AA rats. The single oral administration of an excessive dose of IMC (40 mg/kg) induces hemorrhagic lesions and nitric oxide (NO) production via inducible nitric oxide synthase (iNOS) in the jejunal and ileal mucosa of AA rats, and the extent of the lesions, as well as iNOS and NO levels in AA rats are higher than in normal rats. On the other hand, the co administration of 200 mg/kg Mg2+ attenuates intestinal ulceration and the elevation in the iNOS and NO levels in AA rats. Further, hemorrhagic lesioning and enhanced iNOS and NO levels in AA rats also result from the repetitive oral administration of 3 mg/kg IMC (therapeutic dose) for 42 d (once a day), and these changes are also prevented by the co-administration of 200 mg/kg Mg2+. In conclusion, the co-administration of Mg2+ suppresses the ulcerogenic response to IMC in the jejunal and ileal mucosa of AA rats, probably by preventing the elevation of iNOS and NO levels in the region. PMID- 28566635 TI - Concentration of Sulfate and Glucuronide Conjugates of Ritodrine in Twin Pregnancy. AB - Ritodrine, a drug for the treatment of threatened premature labor, is a highly selective beta-2 agonist with the major metabolites of sulfate and glucuronide conjugates. This study investigated the continuous evaluation of the concentration of ritodrine conjugates in relation to the clinical course in twin pregnancy. The subjects were 9 twin-pregnancy mothers who delivered after receiving ritodrine treatment between April 2012 and December 2013. Serum ritodrine sulfate and glucuronide conjugates were deconjugated using their specific enzymes. Ritodrine concentration was measured by liquid chromatography tandem mass spectrometry. The continuous infusion rate of ritodrine was 2.66+/ 0.67 (0.8-3.54) ug/min/kg, and the average concentration of unchanged ritodrine was 118.8+/-33.2 (63.8-194.0) ng/mL. During the study period between week 32 and week 36 of gestation, the average ratio of unchanged ritodrine concentration and sulfate ritodrine conjugate concentration for weeks 32, 33, 34, 35, and 36 were 1.7, 1.9, 1.5, 1.7, and 1.7 not significant (N.S.), respectively. The average ratio of unchanged ritodrine concentration and glucuronide ritodrine conjugate concentration were 1.8, 2.2, 1.9, 1.8, and 2.1 (N.S.), respectively. No statistical difference was identified in the ratios of unchanged ritodrine concentration and sulfate or glucuronide ritodrine conjugate concentrations. Large individual differences were shown in the concentration of sulfate and glucuronide during the gestational period. No change in the ratio of the formation of ritodrine metabolites was identified as the gestational age progressed. PMID- 28566634 TI - Effect of Docosahexaenoic Acid on Voltage-Independent Ca2+ Entry Pathways in Cultured Vascular Smooth Muscle Cells Stimulated with 5-Hydroxytryptamine. AB - We previously reported that docosahexaenoic acid (DHA) inhibits an increase in intracellular Ca2+ concentration ([Ca2+]i) in cultured rat vascular smooth muscle cells (VSMCs) through a mechanism involving mainly voltage-dependent Ca2+ channels; however, the effect of DHA on voltage-independent pathways, such as store-operated and receptor-operated Ca2+ entry, and Ca2+ entry through Na+/Ca2+ exchanger (NCX), has not been clarified. In the present study, we investigated the effect of DHA treatment on the expression of transient receptor potential canonical (TRPC) channels, capacitative Ca2+ entry, and Ca2+ entry through NCX in rat cultured VSMCs stimulated with 5-hydroxytryptamine (5-HT). RT-PCR analysis detected TRPC1, TRPC4, and TRPC6 mRNA in cultured VSMCs. DHA treatment for 2 d slightly but significantly decreased TRPC1, but not TRPC4 and TRPC6, mRNA expression. Sarpogrelate, a selective serotonin 5-HT2A receptor inhibitor, completely inhibited the 5-HT-induced increase in [Ca2+]i in cultured VSMCs. Ca2+ influx by adding extracellular Ca2+ (1.3 mM) to the Ca2+-free condition in the presence of 5-HT was partially but significantly inhibited by sarpogrelate. DHA treatment for 2 d had no effect on Ca2+ influx when extracellular Ca2+ was added to the Ca2+-free condition in the presence of either 5-HT alone or 5-HT with sarpogrelate. KB-R7943, a selective inhibitor of reverse mode NCX, significantly suppressed the 5-HT-induced increase of [Ca2+]i. Furthermore, DHA treatment for 2 d significantly decreased NCX1 mRNA expression. These results suggest that DHA seems to have little effect on capacitative Ca2+ entry. Through decreasing NCX1 expression, DHA may suppress the 5-HT-induced increase in [Ca2+]i. PMID- 28566636 TI - Inhibition of Methotrexate Uptake via Organic Anion Transporters OAT1 and OAT3 by Glucuronides of Nonsteroidal Anti-inflammatory Drugs. AB - Combination therapy of non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate (MTX) sometimes triggers adverse effects, such as liver injury, renal failure, gastrointestinal disorders, and myelosuppression, owing to the reduction of MTX clearance. Previous reports have suggested that NSAIDs inhibit renal MTX uptake via organic anion transporters (OATs) and reduced folate transporter (RFC)-1 and efflux via multidrug resistance-associated proteins (MRPs). Recently, our laboratory found inhibitory effects of NSAIDs-glucuronide (NSAIDs-Glu), a major metabolite of NSAIDs, on MRP-mediated MTX transport as a new site of interaction between MTX and NSAIDs. However, it remains unclear that whether NSAIDs-Glu inhibit renal uptake of MTX. Therefore, the present study aimed to evaluate inhibitory effects of several NSAIDs-Glu (diclofenac, R- and S ibuprofen, R- and S-flurbiprofen, and R- and S-naproxen) on human OAT1 and OAT3 mediated MTX transport. In this study, [3H]MTX uptake was observed by using human OAT1 and OAT3-overexpressing HEK293 cells in the presence or absence of NSAIDs Glu. All examined NSAIDs-Glu exhibited concentration-dependent inhibitory effects on MTX uptake via OAT1 and OAT3. Our results indicated that NSAIDs-Glu are more potent (5- to 15-fold) inhibitors of OAT3 than OAT1. Moreover, stereoselective inhibitory effects of NSAIDs-Glu on OATs-mediated MTX uptake were not observed, unlike on MRPs-mediated transport. These findings suggest that inhibition of OAT1 and OAT3-mediated renal uptake of MTX by plasma NSAIDs-Glu may be one of the competitive sites underlying complex drug interaction between MTX and NSAIDs. PMID- 28566637 TI - 2,4-Bis(1,1-dimethylethyl)phenol from Cinnamomum loureirii Improves Cognitive Deficit, Cholinergic Dysfunction, and Oxidative Damage in TMT-Treated Mice. AB - We previously reported that the extract of Cinnamomum loureirii (C. loureirii) significantly inhibited acetylcholinesterase (AChE), and identified 2,4-bis(1,1 dimethylethyl)phenol (BP) from C. loureirii as a potential AChE inhibitor. The present study, therefore was undertaken to demonstrate the effects of BP from C. loureirii on learning and memory impairment in trimethyltin (TMT)-treated ICR mice. Y-maze and passive avoidance tests were used to test cognitive ability. Further, changes in biochemical parameters in the brain tissue were also assessed in response to TMT injection and BP intervention. BP pre-administration (20, 40 mg/kg/d) in mice significantly protected cognitive dysfunction induced by TMT (p<0.05). Moreover, BP reduced AChE activity and lipid peroxidation but increased acetylcholine levels in the brain. In conclusion, we suggested that BP protected against TMT-induced cognitive dysfunction, and might be a potential agent for alleviating symptoms of neurodegenerative disorders, such as Alzheimer's disease, via modulating cholinergic functions. PMID- 28566639 TI - Errata for Biological and Pharmaceutical Bulletin. PMID- 28566638 TI - Prevention of UV-Induced Melanin Production by Accumulation of Redox Nanoparticles in the Epidermal Layer via Iontophoresis. AB - UV rays induce melanin production in the skin, which, from a cosmetic point of view, is problematic. Reactive oxygen species (ROS) generated in the skin upon UV irradiation are thought to be responsible for melanin production. Thus, effective antioxidants are recognized as useful tools for prevention of UV-induced melanin production. Redox nanoparticles (RNPs) containing nitroxide radicals as free radical scavengers were previously developed, and shown to be effective ROS scavengers in the body. RNPs are therefore expected to be useful for effective protection against UV-induced melanin production. However, as the sizes of RNPs are typically larger than the intercellular spaces of the skin, transdermal penetration is difficult. We recently demonstrated effective transdermal delivery and accumulation of nanoparticles in the epidermal layer via faint electric treatment, i.e., iontophoresis, suggesting that iontophoresis of RNPs may be a useful strategy for prevention of UV-induced melanin production in the skin. Herein, we performed iontophoresis of RNPs on the dorsal skin of hairless mice that produce melanin in response to light exposure. RNPs accumulated in the epidermal layer upon application of iontophoresis. Further, the combination of RNPs with iontophoresis decreased UV-induced melanin spots and melanin content in the skin. Taken together, we successfully demonstrated that iontophoresis mediated accumulation of RNPs in the epidermis prevented melanin production. PMID- 28566640 TI - Special Issue : ICRBO 2016 (The 3rd International Conference on Rice Bran Oil). PMID- 28566641 TI - Rice Bran Oil: A Versatile Source for Edible and Industrial Applications. AB - Rice bran oil (RBO) is healthy gift generously given by nature to mankind. RBO is obtained from rice husk, a byproduct of rice milling industry and is gaining lot of importance as cooking oil due to presence of important micronutrient, gamma oryzanol. Its high smoke point is beneficial for its use for frying and deep frying of food stuff. It is popular because of balanced fatty acid profile (most ideal ratio of saturated, monounsaturated and polyunsaturated fatty acids), antioxidant capacity, and cholesterollowering abilities. Rice bran wax which is secondary by-product obtained as tank settling from RBO is used as a substitute for carnauba wax in cosmetics, confectionery, shoe creams etc. It can be also used as a source for fatty acid and fatty alcohol. The article is intended to highlight for the importance of RBO and its applications. PMID- 28566642 TI - Modulatory Effect of an Isolated Triglyceride from Fenugreek Seed Oil on of alpha Amylase, Lipase and ACE Activities, Liver-Kidney Functions and Metabolic Disorders of Diabetic Rats. AB - This study was designed to examine physicochemical characteristics, chemical compositions and biological activities of fenugreek seed oil (FSO) and its pure triglyceride (TG). One fenugreek TG was purified using a bioassay-guided fractionation and administrated to surviving diabetic rats. The free fatty acids percentage as well as, the peroxide, the saponification and the iodine values were 2%, 12 mequiv. O2/kg of oil, 189 (mg KOH/g) and 110 (g/100 g of oil), respectively. Linolenic acid (C18:3 26.14%), Linoleic acid (C18:2 41.13%) and Oleic acid (C18:1 17.07%) were the dominant fatty acids in the FSO. beta sitosterol was the major sterol (85.3%) in the FSO. LnLnO (17.1%), LLL (16.6%), OLL and OOLn (8.4%), were the abundant triglycerides. The hexane extract of fenugreek seed (exhibiting the powerful inhibitory activity against alpha amylase) was purified using a bioassay-guided fractionation affording one fenugreek TG: (11Z)-11- eicosenoic acid 2, 3- bis[((9Z, 12Z, 15Z)-1-oxo-9, 12, 15 octadecatrien-1-yl)oxy] propyl ester. In diabetic rats, the administration of the fenugreek TG inhibited alpha-amylase activity in small intestine by 36% as compared to untreated diabetic rats. Moreover, fenugreek TG increased insulin sensibility which leads to decrease in blood glucose level by 43%. In addition, this study demonstrated that administration of pure fenugreek TG to diabetic rats ameliorated the glycogen rate in liver and muscle. In addition, the administration of fenugreek TG reverted back the activity of angiotensin converting enzyme respectively in kidney and plasma by 33 and 29%. Interestingly, the fenugreek TG inhibited lipase activity in small intestine by 33% which leads to the regulation of lipid profile. Moreover, the fenugreek TG protected liver kidney function evidenced by histological study. In conclusion, our finding demonstrates that the administration of fenugreek TG to diabetic rats can make it a potential candidate for industrial application as a pharmacological agent for the treatment of hyperglycemia. PMID- 28566644 TI - Creation of Novel Cyclization Methods Using sp-Hybridized Carbon Units and Syntheses of Bioactive Compounds. AB - Some recent results on the development of new and reliable procedures for the construction of diverse ring systems based on the chemistry of sp-hybridized species, especially allene functionality, are described. This review includes: (i) synthesis of the multi-cyclic skeletons by combination of the pi-component of allene with suitable other pi-components such as alkyne, alkene, or additional allene under Rh-catalyzed conditions; (ii) synthesis of heterocycles as well as carbocycles by reaction of the sp-hybridized center of allene with some nucleophiles in an endo-mode manner; and (iii) total syntheses of natural products and related compounds from the sp-hybridized starting materials. PMID- 28566643 TI - Prolapse Volume to Prolapse Height Ratio for Differentiating Barlow's Disease From Fibroelastic Deficiency. AB - BACKGROUND: As mitral valve (MV) repair for Barlow's disease remains surgically challenging, it is important to distinguish Barlow's disease from fibroelastic deficiency (FED) preoperatively. We hypothesized that the prolapse volume to prolapse height ratio (PV-PH ratio) may be useful to differentiate Barlow's disease and FED.Methods and Results:In 76 patients with MV prolapse who underwent presurgical transesophageal echocardiography, the 3D MV morphology was quantified: 19 patients were diagnosed with Barlow's disease and 57 with FED. The patients with Barlow's disease had greater prolapse volume and height than the patients with FED, as well as greater PV-PH ratio (0.61+/-0.35 vs. 0.17+/-0.10, P<0.001). Receiver-operating characteristic analysis revealed that with a cutoff value of 0.27, the PV-PH ratio differentiated Barlow's disease from FED with 84.2% sensitivity and 84.2% specificity. Net reclassification improvement showed that the differentiating ability of the PV-PH ratio was significantly superior to prolapse volume (1.30, P<0.001). After being adjusted by each of prolapse volume and height, annular area and shape, and the number of prolapsed segments, the PV PH ratio had an independent association with Barlow's disease. CONCLUSIONS: The PV-PH ratio was able to differentiate Barlow's disease from FED with high accuracy. 3D quantification including this value should be performed before MV repair. PMID- 28566645 TI - Preparation and Characterizations of RSPP050-Loaded Polymeric Micelles Using Poly(ethylene glycol)-b-Poly(epsilon-caprolactone) and Poly(ethylene glycol)-b Poly(D,L-lactide). AB - RSPP050 (AG50) is one of the semi-synthetic andrographolide that is isolated from Andrographis paniculata NEES (Acanthaceae). The anti-proliferation effects of AG50 against cholangiocarcinoma (HuCCT1) were displayed high cytotoxicity. Unfortunately, poor water solubility of AG50 limited its clinical applications. This study aimed to increase the concentration of AG50 in water and drug loading and release study in phosphate-buffered saline (PBS) in the absence/presence of pig liver esterase enzyme. Cytotoxicity of AG50-loaded polymeric micelles was evaluated against HuCCT1. AG50 loaded micelles were prepared by film sonication and encapsulated by polymers including poly(ethylene glycol)-b-poly(epsilon caprolactone) (PEG-b-PCL) or poly(ethylene glycol)-b-poly(D,L-lactide) (PEG-b PLA). Micelle properties were characterized such as solubility, drug loading, drug release and in vitro cytotoxicity against HuCTT1. AG50 was successfully loaded into both types of polymeric micelles. The best drug-polymer (D/P) ratio was 1 : 9. AG50/PCL and AG50/PLA-micelles had small particle size (36.4+/-5.1, 49.0+/-2.7 nm, respectively) and high yield (58.2+/-1.8, 58.8+/-2.9, respectively). AG50/PLA-micelles (IC50=2.42 ug/mL) showed higher cytotoxicity against HuCCT1 than AG50/PCL-micelles (IC50=4.40 ug/mL) due to the higher amount of AG50 released. Nanoencapsulation of AG50 could provide a promising development in clinical use for cholangiocarcinoma treatment. PMID- 28566646 TI - Morin Moderates the Biotoxicity of Pneumococcal Pneumolysin by Weakening the Oligomers' Formation. AB - Streptococcus pneumoniae (pneumococcus) is an important causative agent of acute invasive and non-invasive infections. Pneumolysin is one of a considerable number of virulence traits produced by pneumococcus that exhibits a variety of biological activities, thus making it a target of small molecule drug development. In this study, we aimed to evaluate the effect of morin, a natural compound that has no antimicrobial activity against S. pneumonia, is a potent neutralizer of pneumolysin-mediated cytotoxicity and genotoxicity by impairing oligomer formation, and possesses the capability of mitigating tissue damage caused by pneumococcus. These findings indicate that morin could be a potent candidate for a novel therapeutic or auxiliary substance to treat infections for which there are inadequate vaccines and that are resistant to traditional antibiotics. PMID- 28566648 TI - Three New Methods for Resolving Ternary Mixture with Overlapping Spectra: Comparative Study. AB - In this study three new spectrophotometric methods have been developed and validated for simultaneous determination of ternary mixture of metronidazole (MET), diloxanide (DLX) and mebeverine HCl (MEB) without prior separation steps. The newly introduced methods consisted of several steps utilizing either zero order or ratio spectra without the need for derivatization steps. The developed methods are called area under the curve ("AUC"), modified absorption factor (MAFM) and modified amplitude center (MACM) spectrophotometric methods. Selectivity and validity of the methods were checked by using different synthetic mixtures and by analysis of their combined dosage form where low standard deviation values and good percentage recoveries were obtained. Additionally, methods linearity, accuracy and precision were determined following United States Pharmacopoeia (USP) recommendations. The obtained results were found to agree with the reported ones when they were statistically compared using One Way ANOVA test. These methods are easily applied during drug quality control studies and in laboratories lacking the facilities of chromatographic methods of analysis. Data manipulation steps are very simple, hence these methods can be considered as time and money saving methods comparing to chromatographic methods of analysis. PMID- 28566647 TI - Potential Use of Polyvinyl Acetate-Polyvinylpyrrolidone Mixture for the Development of Atenolol Sustained Release Matrix Tablets: Optimization of Formulation through in Vitro-in Vivo Assessment Study. AB - The objective of this study was to develop sustained release matrix tablets of atenolol (AT) using different concentrations of polyvinyl acetate polyvinylpyrrolidone mixture (KSR) (20, 30, or 40%) with various types of fillers such as spray dried lactose (SP.D.L), avicel pH 101 (AV), and emcompress (EMS). The physical characteristics of the prepared tablets were evaluated. Characterization of the optimized formulation was performed using Fourier transform (FT)-IR spectroscopy and differential scanning calorimetry (DSC). Moreover, the in vitro release profiles of AT formulations were investigated in different pH dissolution media. Drug release kinetics and mechanisms were also determined. The results revealed that there was no potential incompatibility of the drug with the polymer. The release profiles of AT were affected by the concentration of KSR, fillers used, and pH of the dissolution media. The drug release kinetic from most of the formulations obeyed Higuchi diffusion model. The selected formulae were investigated for their stability by storage at 30 and 40 degrees C with atmospheric humidity and 75% relative humidity (RH), respectively. The results demonstrated that no change in the physicochemical properties of the tablets stored at 30 degrees C/atmospheric RH in comparison with some changes at 40 degrees C/75% RH. Finally, the in vivo study provided an evidence that the optimized AT tablet containing 40% KSR and SP.D.L exhibited prominent higher oral bioavailability and more efficient sustained-release effect than the drug alone or the commercial tablet product. It is noteworthy that KSR could be considered as a promising useful release retardant for the production of AT sustained release matrix tablets. PMID- 28566649 TI - Concise and Versatile Synthesis of Sulfoquinovosyl Acyl Glycerol Derivatives for Biological Applications. AB - Sulfoquinovosyl acylpropanediol (SQAP), a chemically modified analogue of sulfoquinovosyl acylglycerol (SQAG) that occurs in sea algae, has been reported to show a variety of biological activities, including accumulation in tumor cells and the inhibition of tumor cell growth. We report herein on a new concise and versatile synthesis of SQAP itself and derivatives bearing iodoaryl groups and boronclusters. This method should be useful for the design and synthesis of SQAG/SQAP derivatives for diagnosis and the treatment of cancer and related diseases. PMID- 28566650 TI - A Convenient Method for Preparation of alpha-Imino Carboxylic Acid Derivatives and Application to the Asymmetric Synthesis of Unnatural alpha-Amino Acid Derivative. AB - We describe herein a manganese(IV) oxide-mediated oxidation of N-p-methoxyphenyl (PMP)-protected glycine derivatives for the synthesis of alpha-imino carboxylic acid derivatives. Using this methodology, utilization of unstable glyoxic acid derivatives was avoided. Furthermore, using this methodology we synthesized novel alpha-imino carboxylic acid derivatives such as alpha-imino phenyl ester, perfluoroalkyl etsers, imides, and thioester. The asymmetric Mannich reaction of those novel imine derivatives with 1,3-dicarbonyl compound is also described, and the novel alpha-imino imide gave improved chemical yield and stereoselectivity compared with those obtained by the use of the conventional alpha-imino ester type substrate. PMID- 28566651 TI - A New Pyranonaphtoquinone Derivative, 4-Oxo-rhinacanthin A, from Roots of Indonesian Rhinacanthus nasutus. AB - A new pyranonaphthoquinone derivative, named 4-oxo-rhinacanthin A (1), was isolated from the roots of the Indonesian Rhinacanthus nasutus together with two known congeners, rhinacanthin A (2) and 3,4-dihydro-3,3-dimethyl-2H-naphtho[2,3 b]pyran-5,10-dione (3). The structure of 1 was elucidated based on its spectroscopic data. The absolute configuration of 1 was assigned by comparing its experimental Electronic Circular Dichroism (ECD) spectrum with the calculated ECD spectrum. Compounds 2 and 3 inhibited the growth of Staphylococcus aureus with inhibition zones of 16 and 20 mm at 25 ug/disc, respectively. Compound 3 also exhibited inhibitory activity against Mycobacterium smegmatis (20 mm at 25 ug/disc). PMID- 28566652 TI - Conformational Change and Epimerization of Diketopiperazines Containing Proline Residue in Water. AB - In water, diketopiperazines cyclo(L-Pro-L-Xxx) and cyclo(L-Pro-D-Xxx) (Xxx=Phe, Tyr) formed an intramolecular hydrophobic interaction between the main skeleton part and their benzene ring, and both cyclo(L-Pro-L-Xxx) and cyclo(L-Pro-D-Xxx) took a folded conformation. The conformational changes from folded to extended conformation by addition of several deuterated organic solvents (acetone-d6, metanol-d4, dimethyl sulfoxide-d6 (DMSO-d6)) and the temperature rise were investigated using 1H-NMR spectra. The results suggested that the intrarmolecular hydrophobic interaction of cyclo(L-Pro-D-Xxx) formed more strongtly than that of cyclo(L-Pro-L-Xxx). Under a basic condition of 1.0*10-1 mol/L potassium deuteroxide, enolization of O1-C1-C9-H9 moiety of cyclo(L-Pro-L-Xxx) occurred, while that of the O4-C4-C3-H3 moiety did not. Cyclo(L-Pro-L-Xxx) epimerized to cyclo(D-Pro-L-Xxx), while cyclo(L-Pro-D-Xxx) did not change. PMID- 28566653 TI - Errata for Chemical and Pharmaceutical Bulletin. PMID- 28566654 TI - Slow-Flow Phenomenon After Stent Deployment in Lipid Rich Plaque Harboring Cholesterol Crystals. PMID- 28566655 TI - Translational Study of Hydrogen Gas Inhalation as Adjuncts to Reperfusion Therapy for Acute Myocardial Infarction. PMID- 28566656 TI - Low Heart Rate Variability and Sympathetic Dominance Modifies the Association Between Insulin Resistance and Metabolic Syndrome - The Toon Health Study. AB - BACKGROUND: Insulin resistance is strongly associated with metabolic syndrome (MetS), but it is not known how this association is influenced by the autonomic nervous system, which controls insulin secretion.Methods and Results:The subjects were 2,016 individuals aged 30-79 years enrolled between 2009 and 2012. MetS was determined using the harmonized MetS definition, which includes waist circumference, blood pressure, triglycerides, high-density lipoprotein cholesterol, and fasting glucose. The homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt's insulin sensitivity index (ISI) were calculated based on fasting and 2 h-post-load glucose and insulin concentrations in a 75-g oral glucose tolerance test. The 5-min heart rate variability (HRV) was evaluated using time-domain indices of standard deviations of NN intervals (SDNN) and root mean square of successive differences (RMSSD). Power spectral analysis yielded frequency-domain measures for HRV: high-frequency (HF) power, low frequency (LF) power and LF/HF. Multivariable adjusted logistic models showed that the highest quartiles for SDNN, RMSSD, LF, and HF vs. the lowest quartiles had a significant association with MetS. RMSSD, HF, and LF/HF remained significantly associated with MetS after adjustment for HOMA-IR (or ISI). Additive interactions between the levels of high LF/HF and high HOMA-IR (or low ISI) were significantly positive. CONCLUSIONS: Sympathovagal imbalance as evidenced by low HF and high LF/HF modified the association of insulin resistance or low insulin sensitivity with MetS. PMID- 28566658 TI - Erratum. PMID- 28566657 TI - Performance of Leadless Pacemaker in Japanese Patients vs. Rest of the World - Results From a Global Clinical Trial. AB - BACKGROUND: A global study designed to demonstrate the safety and efficacy of a transcatheter pacing system included 38 Japanese patients enrolled at 4 sites. Subgroup analysis to evaluate the performance of the leadless intracardiac transcatheter pacing system in Japanese patients was performed.Methods and Results:Safety and efficacy outcomes, patient and implant procedure characteristics, and patient and physician acceptability from the Japanese population were compared with those from outside Japan. Differences in patient characteristics, implant procedure characteristics and patient acceptability were observed. There were no major complications in Japanese patients and pacing thresholds remained low and stable throughout follow-up. There were no observable differences between Japanese patients and patients from outside Japan in the freedom from major complication rate at 12-months post-implant (100.0% vs. 95.7%, P=0.211) or physician acceptability. CONCLUSIONS: Although some differences in specific baseline characteristics, such as body size and pacing indication, and in implant procedure characteristics, including anticoagulation strategy and hospitalization period, were observed in the Japanese patients, transcatheter pacemaker performance was similar to that in the global trial. (Clinical Trial Registration: ClinicalTrials.gov ID NCT02004873.). PMID- 28566659 TI - Effects of Natural and Chemically Defined Nutrients on Candida albicans Water soluble Fraction (CAWS) Vasculitis in Mice. AB - Kawasaki disease (KD) is an inflammatory disease that was identified by Professor Tomisaku Kawasaki in 1961. Candida albicans-derived substances, such as C. albicans water-soluble fraction (CAWS) , induce coronary arteritis similar to KD in mice. CAWS functions as a pathogen-associated molecular pattern (PAMP) by acting as a ligand for dectin-2. A gut-associated immunological system has developed specifically to segregate advantageous and detrimental stimuli, and the microbial flora has been found to markedly affect the development and severity of diseases. We herein investigated whether diet affects the onset and progression of CAWS vasculitis in mice. A standard diet, CE-2, and chemically defined diet, AIN93G, which is free of beta-glucan, were used. Although all mice administered with CAWS died, the mean number of survival days was smaller in the AIN93G group because vasculitis was induced earlier than in the CE-2 group. Bacteroides, which are inflammatory flora, were enriched in the microbial flora of the AIN93G group. The results of the present study suggest that diet quality affects not only microbial flora changes, but also the progression of systemic disease. PMID- 28566660 TI - A Giant Dermatophyte Abscess Caused by Trichophyton rubrum in an Immunocompromised Patient. AB - A 73-year-old male who had been receiving immunosuppressive drugs for 15 years developed a nodule on the left buttock region. The nodule slowly grew into a 15 cm fluctuant multilocular subcutaneous cyst. Serum beta-D-glucan levels were high, and the yellow purulent fluid obtained from the cyst was positive for Trichophyton rubrum. Granuloma formation in the cyst wall and large abscesses in the central cystic area were found, and septated hyphae were observed in both tissues. The cyst was surgically removed, and followed by itraconazole treatment. Notably, the clinical manifestations closely resembled those of a huge atheroma. PMID- 28566661 TI - Azole-resistant Aspergillus fumigatus Containing a 34-bp Tandem Repeat in cyp51A Promoter is Isolated from the Environment in Japan. AB - Azole-resistant strains of Aspergillus fumigatus containing a tandem repeat in the cyp51A promoter and amino acid substitution(s) have been isolated in the environment worldwide; however, this type of resistant strain had never been isolated from the environment in Japan. Our previous study indicated that an azole-resistant A. fumigatus strain OKH50 containing a 34-bp tandem repeat in cyp51A promoter with L98H substitution in Cyp51A was isolated from a patient in Obihiro of Hokkaido, Japan. In this study, we collected azole-resistant Aspergillus spp. by air sampling from the environment in Japan. One Aspergillus like colony was isolated from one of 10 sampling sites surveyed. The strain Env1 was confirmed as A. fumigatus by nucleotide sequencing and possessed a 34-bp tandem repeat in the promoter region of cyp51A with L98H substitution in Cyp51A. A. fumigatus Env1 has the identical short tandem repeat pattern with the OKH50 strain, indicating that these strains are closely related with each other. Additionally, the short tandem repeat pattern is closely related to Danish and Iranian environmental isolates, suggesting that azole-resistant strains have crossed transnational boundaries and are now present in Japan, and therefore, further analysis throughout Japan is required to determine the distribution of this type of azole-resistant A. fumigatus. PMID- 28566662 TI - Practical Management of Deep Cutaneous Fungal Infections. AB - Understanding deep cutaneous fungal infection requires not only reading many case reports and checking the typical clinical images of skin lesions, but also managing the patients properly to prevent misdiagnosis. Herein, I review my recent experiences with eight typical cases of deep cutaneous infections (including protothecosis and nocardiosis) in Japan. It is very important to do the four management processes; namely, KOH direct microscopic examination, skin biopsy, fungal culture, and microscopic examination of the histopathological specimen of PAS and Grocott staining. Also, to aid in memorizing the names of important diseases, I recommend the mnemonic "AC PPPS MD" (Aspergillosis, Cryptococcosis, Phaeohyphomycosis, Protothecosis, Pseudoallescheriosis, Sporotrichosis, Mycetoma, and Dermatophytosis). Isolation of the fungus by culturing from the skin lesion is the best way to carry out quick and correct diagnosis. PMID- 28566663 TI - Promising Therapies for Fungal Infection Based on the Study to Elucidate Mechanisms to Cope with Stress in Candida Species [Translated Article]. AB - In recent years, the incidence of fungal infections has been increasing, particularly among patients with immune systems compromised by human immunodeficiency virus infection, organ transplantation, and/or chemotherapy for cancer. Current therapies for treating systemic fungal infection have limited effectiveness and have created problems of adverse reactions and drug resistance. These issues therefore motivate us to develop novel antifungals. Elucidation of stress response mechanisms and virulence factors in pathogenic fungi is required in developing an effective antifungal strategy. There are actually numerous studies concerning various stress responses in several important fungal pathogens. Among these responses, we focused on stress response for iron starvation to identify potential targets for novel antifungals because iron starvation occurs in blood, where pathogenic fungi often infect. Here we show recent progress of studies on iron homeostasis in Candida species, especially focusing on Candida glabrata, and propose novel antifungal targets. PMID- 28566665 TI - Treatment of Tinea Pedis in Elderly Patients Using External Preparations. AB - Infection rate of tinea pedis is high in the elderly, wherein treatment by a dermatologist should be considered to prevent infecting their family members. About 90 percent of cases with tinea pedis is treated only using external preparations. In treating the elderly with tinea pedis using external preparation, we should take into consideration that the elderly have thinner and weaker skin compared to younger people. There are many kinds of dosage form (cream, ointments, lotion, spray, and so on) for external preparations to treat tinea pedis. Generally, liquid forms such as lotions and sprays cause stronger irritation compared to ointments and creams, thus, caution should be taken for side effects when applying them to the elderly. Contact dermatitis is the most frequent side effect of external preparations. Caution should also be taken for the type of additives used. The composition of the preparation should be checked when changing dosage forms, or when switching brand-name drugs to generic drugs. Since the adherence rate of external preparations is low, it is preferable to use those with strong antibacterial activity and only have to be applied once a day. PMID- 28566664 TI - Remarkable Works and Cases in the History of Medical Mycology in Japan. AB - Several pathogenic fungi and cases related to Japanese medical mycologists were reviewed. Trichosporon inkin (as Sarcinomyces inkin) was reported as a pathogen of scrotal lesion by Oho in 1921, and Trichosporon asahii was isolated from generalized keratotic lesions in 1922 by Akagi in Japan. They were once included in Trichophyton beigelii, but then based on revision using DNA molecular technology, were returned to their original names.Microsporum ferrugineum was reported by Ota as a causative dermatophyte of tinea capitis in Japan and surrounding areas. It was once classified under the genus Trichophyton, but after the discovery of characteristic rough-walled macroconidia belonging to genus Microsporum, the fungus was again assigned to the original name. PMID- 28566666 TI - Treatment and Prevention of Oral Candidiasis in Elderly Patients. AB - The incidence of oral candidiasis has increased in the elderly in recent years. Although the increase of the elderly population plays a big role in this rise of oral candidiasis, the broader recognition that elderly people have higher infection rates for oral candidiasis is considered to be also an important factor. Oral candidiasis can be categorized into three types. Pseudomembranous oral candidiasis is characterized by the appearance of white moss, erythematous oral candidiasis by the eruption of erythema, and hyperplastic oral candidiasis by mucosal hyperplasia. Miconazole has been commonly used when treating oral candidiasis. Elderly patients, however, have a tendency to develop oral candidiasis repeatedly. It is therefore critical to take measures to prevent recurrence. We recommend the use an oral moisturizer containing hinokitiol, an antifungal substance, on a regular basis, to help prevent recurrence of oral candidiasis. PMID- 28566668 TI - Term 14. PMID- 28566667 TI - Dermatophyte Antigen Kit. AB - The dermatophyte antigen kit uses monoclonal antibodies that react with polysaccharides present in the dermatophyte cell wall to detect dermatophyte antigens in specimens based on the principle of immunochromatography. Clinical studies showed that the kit was very useful in the diagnosis of tinea unguium but not tinea pedis. The kit was therefore further developed as an in vitro diagnostic tool for tinea unguium and was approved by the Pharmaceuticals and Medical Devices Agency of Japan. The kit's extraction solution can extract antigens from nail specimens quickly and efficiently. When direct microscopy fails to detect fungal elements in a specimen of suspected tinea unguium, the kit can be used so that positive samples are re-examined by direct microscopy, in order to reduce the likelihood of false-negative detection. In addition, in settings where direct microscopy is unavailable, the kit can be used so that treatment for dermatophytes is withheld when results are negative. Such an approach can reduce both wasteful treatment and medical costs. It is important to note that the kit is used to complement conventional fungus testing methods and that direct microscopy must be used to confirm the final morphological diagnosis of the pathogenic fungal infection. Use of a combination of direct microscopy and this kit should improve the accuracy of diagnosis of tinea unguium. PMID- 28566669 TI - Effect of enamel matrix derivative on the angiogenic behaviors of human umbilical vein endothelial cells on different titanium surfaces. AB - Angiogenesis play a crucial role in the regeneration of hard and soft tissue around dental titanium (Ti) implant. Enamel matrix derivative (EMD) promotes tissue regeneration and stimulates angiogenesis but its effect on the angiogenesis on Ti surfaces was never investigated. The effect of EMD on the angiogenic activity of endothelial cells cultured on pre-treated smooth Ti (PT), acidetched (A), coarse-grit blasted and acid-etched (SLA) surfaces and tissue culture plastic (TCP) in the presence or absence of EMD was investigated. EMD inhibited the proliferation/viability of human umbilical vein endothelial cells (HUVECs) growing on A and SLA Ti surfaces. EMD induced an increase in the expression of all these genes in HUVECs grown on SLA surface but not on other surfaces. Summarizing, our data show that EMD influences proliferation and expression of angiogenesis associated gene in HUVECs grown on moderately rough SLA surfaces, suggesting that EMD might promote angiogenesis following implantation. PMID- 28566670 TI - Micro computed tomography evaluation of the Self-adjusting file and ProTaper Universal system on curved mandibular molars. AB - The aim of this investigation was to compare the cleaning and shaping efficiency of Self-adjusting file and Protaper, and to assess the correlation between root canal curvature and working time in mandibular molars using micro-computed tomography. Twenty extracted mandibular molars instrumented with Protaper and Self-adjusting file and the total working time was measured in mesial canals. The changes in canal volume, surface area and structure model index, transportation, uninstrumented area and the correlation between working-time and the curvature were analyzed. Although no statistically significant difference was observed between two systems in distal canals (p>0.05), a significantly higher amount of removed dentin volume and lower uninstrumented area were provided by Protaper in mesial canals (p<0.0001). A correlation between working-time and the canal curvature was also observed in mesial canals for both groups (SAFr2 =0.792, p<0.0004, PTUr2=0.9098, p<0.0001). PMID- 28566671 TI - Effect of polyimide addition on mechanical properties of PMMA-based denture material. AB - The aim of the study was to evaluate the effect of modifying polymethyl methacrylate (PMMA) denture base material with polyimide (PI) on its flexural property and biocompatibility. Low molecular weight (1,500 g/mol) PI was synthesized and small amount of PI (0.4, 0.6, 0.8 and 1 wt%) was dispersed into the PMMA matrix. Three-point bending tests, scanning electron microscopy and thermal cycling were used to measure the mechanical properties, while MTT assay was used to evaluate the biocompatibility of the denture base material. The results showed that 0.6% addition of PI significantly increased flexural strength of PMMA denture base material by 13.5%, compared with the control group (p<0.05). Even after 5,000 hydrothermal cycling the reinforce effect still existed. However, when the PI content further increased, flexural strength of the denture base material decreased due to particle agglomeration. The MTT assay confirmed that the addition of PI did not change the biocompatibility of the PMMA denture base material. The present study suggested that blending polyimide in the proper proportion can be a potential method to strengthen the PMMA-based denture base material. PMID- 28566672 TI - Effects of various etching protocols on the flexural properties and surface topography of fiber-reinforced composite dental posts. AB - The purpose of this study was to evaluate the flexural properties and surface topography of fiber posts surface-treated with various etching protocols. Seventy each of three types of fiber posts: RelyX Fiber Post, Tenax Fiber Trans, and D.T. Light-Post Illusion X-Ro, were randomly divided into 7 groups: no surface treatment, surface treated with hydrofluoric acid (HF) 4.5% for 60 s, HF 4.5% for 120 s, HF 9.6% for 15 s, HF 9.6% for 60 s, HF 9.6% for 120 s, and treated with H2O2 24% for 10 min. The specimens were then subjected to a three-point bending test. Surface topographies of the posts were observed using a SEM. The results indicate that fiber post surface pretreatments had no adverse effects on the flexural properties. However, the fiber posts treated with high HF concentrations or long etching times seemed to have more surface irregularities. PMID- 28566673 TI - Resin adhesion strengths to zirconia ceramics after primer treatment with silane coupling monomer or oligomer. AB - Resin bonding to zirconia ceramics is difficult to achieve using the standard methods for conventional silica-based dental ceramics, which employ silane coupling monomers as primers. The hypothesis in this study was that a silane coupling oligomer -a condensed product of silane coupling monomers- would be a more suitable primer for zirconia. To prove this hypothesis, the shear bond strengths between a composite resin and zirconia were compared after applying either a silane coupling monomer or oligomer. The shear bond strength increased after applying a non-activated ethanol solution of the silane coupling oligomer compared with that achieved when applying the monomer. Thermal treatment of the zirconia at 110 degrees C after application of the silane coupling agents was essential to improve the shear bond strength between the composite resin cement and zirconia. PMID- 28566674 TI - A stability evaluation of a novel titanium dental implant/interconnected porous hydroxyapatite complex under functional loading conditions. AB - The aim of this study was to evaluate the stability of implant/interconnected porous calcium hydroxyapatite complex (implant/IPCHA-complex) under functional loading. Implant/IP-CHA-complexes were placed into the mandibles of four Beagle Labrador hybrid dogs (complex-group). On the other side, an implant was placed directly (control-group). To subject the loading, the animals were fed a hard diet throughout the loading phase of 5 months. The implant stability quotients (ISQs) and bone implant contact (BIC), and histological evaluations were performed. The ISQs of implant/IP-CHA-complex was significantly lower at placement than that of the control-implant. On the other hand, there was no significant difference between in the groups during loading. The BIC measurements, there was no significantly difference between in both groups. Histologically, newly formed bone was observed in contact with most of the implant surface in the complex-group. An IP-CHA/implant-complex would be able to achieve both bone reconstruction and implant stability under functional loading conditions. PMID- 28566675 TI - Effects of calcium hydroxide reagent on the bond strength of resin cements to root dentin and the retention force of FRC posts. AB - The aim of this study was to determine the effects of calcium hydroxide (Ca(OH)2) treatment on bond strength of resin cements to root dentin and retention force of fiber-reinforced composite (FRC) posts. Bovine root dentin was endodontically prepared and treated with Ca(OH)2 for 7 days. Root dentin for bond strength test was adhered to resin-composite with resin cements. For pull-out test, posts consisting of FRC posts and resin-composites were fabricated and cemented to root. Shear bond and pull-out tests were performed using a universal testing machine. No significant differences in bond strength and post retention force were found between Ca(OH)2 treated and untreated groups. Significant differences were found among the cements. A positive correlation was indicated between bond strength of cements and retention force of FRC posts. In conclusion, Ca(OH)2 treatment on root dentin did not affect bond strength of resin cements and retention force of FRC posts. PMID- 28566676 TI - Comparing the Curative Efficacy of Different Skin Grafting Methods for Third Degree Burn Wounds. AB - BACKGROUND Our research purpose was to compare the curative efficacy of different skin grafting methods for treating third-degree burn wounds. MATERIAL AND METHODS A total of 105 patients with third-degree burns were involved in this study. The burn wounds of these patients were treated using three different methods: Meek skin grafting, Stamp skin grafting, and Microskin grafting. Patients treated with different methods were placed in different groups. The skin graft survival rate, skin graft fusion time, wound healing time, total time of surgery, and 1% total body surface area (TBSA) treatment costs in each group were evaluated during and after the grafting procedures. After the operations, patients were followed up for 3 to 18 months in order to evaluate the postoperative outcomes. RESULTS The skin graft survival rate was significantly higher in the Meek group compared to the rates in the Stamp and Microskin groups (both P<0.01). In addition, the skin graft fusion time, wound healing time, and 1% TBSA treatment costs were significantly lower in the Meek group compared to those in the Stamp and Microskin groups (both P<0.01). Furthermore, the Meek group exhibited better results with respect to curative efficacy, scarring status, and joint activity in comparison to the other two groups (both P<0.05). CONCLUSIONS The Meek skin grafting method showed better clinical efficacy for treating large wound areas in third-degree burn patients compared to the Stamp and Microskin skin grafting methods. PMID- 28566678 TI - The relation between human hair follicle density and touch perception. AB - Unmyelinated low threshold C-tactile fibers moderate pleasant aspects of touch. These fibers respond optimally to stroking stimulation of the skin with slow velocities (1-10 cm/s). Low threshold mechanoreceptors are arranged around hair follicles in rodent skin. If valid also in humans, hair follicle density (HFD) may relate to the perceived pleasantness of stroking tactile stimulation. We conducted two studies that examined the relation between HFD and affective touch perception in humans. In total, 138 healthy volunteers were stroked on the forearm and rated the pleasantness and intensity. Stimulation was performed by a robotic tactile stimulator delivering C-tactile optimal (1, 3, 10 cm/s) and non optimal (0.1, 0.3, 30 cm/s) stroking velocities. Additionally, a measure of discriminative touch was applied in study 2. HFD of the same forearm was determined using the Cyanoacrylate Skin Stripping Method (CSSM), which we validated in a pretest. Women had higher HFD than men, which was explained by body size and weight. Furthermore, women rated affective touch stimuli as more pleasant and had higher tactile acuity. Depilation did not affect touch perception. A weak relationship was found between the C-tactile specific aspects of affective touch perception and HFD, and the hypothesis of HFD relating to pleasant aspects of stroking only received weak support. PMID- 28566677 TI - High-Grade Transformation in a Splenic Marginal Zone Lymphoma with a Cerebral Manifestation. AB - BACKGROUND Splenic marginal zone lymphomas (SMZLs) are generally uncommon, indolent lymphomas that typically affect older adults, but the development of the transformation to high-grade lymphoma may occur in a small proportion of patients and represents a rare event with blastic cell infiltration in the lymph nodes and bone marrow. CASE REPORT Here, we present a young adult patient who was diagnosed with a SMZL and developed a high-grade transformation to diffuse large B cell lymphoma (DLBCL) with central nervous system involvement. The patient was a 31 year-old woman whose hematologic medical history began with severe anemia and thrombocytopenia associated with atypical lymphoid infiltrate in the bone marrow and massive splenomegaly. A splenectomy was performed and revealed the SMZL. She was first treated with the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) and subsequently with the R-FMD regimen (rituximab, fludarabine, mitoxantrone, and dexamethasone) because the peripheral blood leukocytes were remarkably increased postoperatively. Six months after the splenectomy, she complained of headaches. A magnetic resonance imaging scan of her brain revealed intracerebral tumorous lesions from which a biopsy was taken. On morphological and immunohistochemical examination, the tumor fulfilled the criteria for a DLBCL. Treatment with pulse-dose intravenous methylprednisolone followed by high-dose methotrexate was promptly initiated, but the patient's condition continued to deteriorate and she died of the disease 13 months after the splenectomy. CONCLUSIONS Although there is a general tendency for SMZL to display low aggressiveness, central nervous system involvement associated with a histological transformation to high-grade lymphoma, as presented here, can occur in advanced stage of the disease. PMID- 28566679 TI - Combined magnetron sputtering and pulsed laser deposition of TiO 2 and BFCO thin films. AB - We report the successful demonstration of a hybrid system that combines pulsed laser deposition (PLD) and magnetron sputtering (MS) to deposit high quality thin films. The PLD and MS simultaneously use the same target, leading to an enhanced deposition rate. The performance of this technique is demonstrated through the deposition of titanium dioxide and bismuth-based perovskite oxide Bi2FeCrO6 (BFCO) thin films on Si(100) and LaAlO3 (LAO) (100). These specific oxides were chosen due to their functionalities, such as multiferroic and photovoltaic properties (BFCO) and photocatalysis (TiO2). We compare films deposited by conventional PLD, MS and PLD combined with MS, and show that under all conditions the latter technique offers an increased deposition rate (+50%) and produces films denser (+20%) than those produced by MS or PLD alone, and without the large clusters found in the PLD-deposited films. Under optimized conditions, the hybrid technique produces films that are two times smoother than either technique alone. PMID- 28566680 TI - Dibutyl phthalate induced testicular dysgenesis originates after seminiferous cord formation in rats. AB - Administration of dibutyl phthalate (DBP) to pregnant rats causes reproductive disorders in male offspring, resulting from suppression of intratesticular testosterone, and is used as a model for human testicular dysgenesis syndrome (TDS). DBP exposure in pregnancy induces focal dysgenetic areas in fetal testes that appear between e19.5-e21.5, manifesting as focal aggregation of Leydig cells and ectopic Sertoli cells (SC). Our aim was to identify the origins of the ectopic SC. Time-mated female rats were administered 750 mg/kg/day DBP in three different time windows: full window (FW; e13.5-e20.5), masculinisation programming window (MPW; e15.5-e18.5), late window (LW; e19.5-e20.5). We show that DBP-MPW treatment produces more extensive and severe dysgenetic areas, with more ectopic SC and germ cells (GC) than DBP-FW treatment; DBP-LW induces no dysgenesis. Our findings demonstrate that ectopic SC do not differentiate de novo, but result from rupture of normally formed seminiferous cords beyond e20.5. The more severe testis dysgenesis in DBP-MPW animals may result from the presence of basally migrating GC and a weakened basal lamina, whereas GC migration was minimal in DBP-FW animals. Our findings provide the first evidence for how testicular dysgenesis can result after normal testis differentiation/development and may be relevant to understanding TDS in human patients. PMID- 28566681 TI - Dimethyl Sulfide is a Chemical Attractant for Reef Fish Larvae. AB - Transport of coral reef fish larvae is driven by advection in ocean currents and larval swimming. However, for swimming to be advantageous, larvae must use external stimuli as guides. One potential stimulus is "odor" emanating from settlement sites (e.g., coral reefs), signaling the upstream location of desirable settlement habitat. However, specific chemicals used by fish larvae have not been identified. Dimethyl sulfide (DMS) is produced in large quantities at coral reefs and may be important in larval orientation. In this study, a choice-chamber (shuttle box) was used to assess preference of 28 pre-settlement stage larvae from reef fish species for seawater with DMS. Swimming behavior was examined by video-tracking of larval swimming patterns in control and DMS seawater. We found common responses to DMS across reef fish taxa - a preference for water with DMS and change in swimming behavior - reflecting a switch to "exploratory behavior". An open water species displayed no response to DMS. Affinity for and swimming response to DMS would allow a fish larva to locate its source and enhance its ability to find settlement habitat. Moreover, it may help them locate prey accumulating in fronts, eddies, and thin layers, where DMS is also produced. PMID- 28566682 TI - Solitonic conduction of electrotonic signals in neuronal branchlets with polarized microstructure. AB - A model of solitonic conduction in neuronal branchlets with microstructure is presented. The application of cable theory to neurons with microstructure results in a nonlinear cable equation that is solved using a direct method to obtain analytical approximations of traveling wave solutions. It is shown that a linear superposition of two oppositely directed traveling waves demonstrate solitonic interaction: colliding waves can penetrate through each other, and continue fully intact as the exact pulses that entered the collision. These findings indicate that microstructure when polarized can sustain solitary waves that propagate at a constant velocity without attenuation or distortion in the absence of synaptic transmission. Solitonic conduction in a neuronal branchlet arising from polarizability of its microstructure is a novel signaling mode of electrotonic signals in thin processes (<0.5 MUm diameter). PMID- 28566684 TI - Quantitative refractive index distribution of single cell by combining phase shifting interferometry and AFM imaging. AB - Cell refractive index, an intrinsic optical parameter, is closely correlated with the intracellular mass and concentration. By combining optical phase-shifting interferometry (PSI) and atomic force microscope (AFM) imaging, we constructed a label free, non-invasive and quantitative refractive index of single cell measurement system, in which the accurate phase map of single cell was retrieved with PSI technique and the cell morphology with nanoscale resolution was achieved with AFM imaging. Based on the proposed AFM/PSI system, we achieved quantitative refractive index distributions of single red blood cell and Jurkat cell, respectively. Further, the quantitative change of refractive index distribution during Daunorubicin (DNR)-induced Jurkat cell apoptosis was presented, and then the content changes of intracellular biochemical components were achieved. Importantly, these results were consistent with Raman spectral analysis, indicating that the proposed PSI/AFM based refractive index system is likely to become a useful tool for intracellular biochemical components analysis measurement, and this will facilitate its application for revealing cell structure and pathological state from a new perspective. PMID- 28566683 TI - Combinatorial Delivery of Dual and Triple TLR Agonists via Polymeric Pathogen like Particles Synergistically Enhances Innate and Adaptive Immune Responses. AB - Despite decades of research very few vaccine-adjuvants have received FDA approval. Two fundamental challenges plague clinical translation of vaccine adjuvants: reducing acute toxicities that result from systemic diffusion of many soluble adjuvants, and delivering multiple adjuvants at the same time to mimic the synergistic immune-stimulation of pathogens, while being safe. In order to address these barriers, we evaluated combinations of four clinically relevant immune-agonists, specifically Toll-like receptor (TLR) ligands, using biodegradable, polymer microparticles. We tested them alone and in combinations of 2 or 3, for a total of 10 unique conditions. We evaluated primary bone-marrow derived Dendritic Cell phenotypes and functionality, and identified several synergistic combinations. We picked a dual and a triple adjuvant combination, TLR4/TLR9 and TLR4/TLR7/TLR9, for further evaluation and found that both combinations promoted antigen cross-presentation in vitro. Studies in mice using the model antigen Ovalbumin, showed that both combinations enhanced lymph node germinal center and T follicular helper cell responses. The triple adjuvant combination showed increased antigen-specific antibody titer with an overall balanced Th1/Th2 response, while the dual combination promoted Th1-polarized IgG responses. Our results show how polymeric particulate-carriers can be adopted to safely deliver combinatorial adjuvants and selectively synergize specific types of immune responses for vaccine applications. PMID- 28566685 TI - Monitoring ZEO apoptotic potential in 2D and 3D cell cultures and associated spectroscopic evidence on mode of interaction with DNA. AB - Recognizing new anticancer compounds to improve Breast cancer treatment seems crucial. Essential oil of Zataria Multiflora (ZEO) is a secondary metabolite with some biological properties, yet underlying cellular and molecular anticancer properties of ZEO is unclear. GC/MS analysis revealed that carvacrol is the major ingredient of the essential oil. ZEO increasingly suppressed viability in MDA-MB 231, MCF-7 and T47D Breast cancer cells while nontoxic to L929 normal cells in monolayer cell cultures (2D), whereas MDA-MB-231 multicellular spheroids (3D) were more resistant to inhibition. ZEO significantly induced cell apoptosis confirmed by fluorescent staining, flow cytometry analysis and DNA fragmentation in MDA-MB-231 2D and 3D cell cultures. ZEO increased ROS generation and subsequent loss of DeltaPsim, caspase 3 activation and DNA damage which consequently caused G1 and G2/M cell cycle arrest in a dose- and time-dependent manner in 2D. S phase arrest occurred in cell spheroids therefore ZEO possible DNA interaction with gDNA was investigated and revealed ZEO binds DNA via intercalation. Altogether, these data corroborate anticancer properties of ZEO and suggest that cell culture format (2D monolayer vs. 3D spheroid) plays a critical role in drug response and provides new insights into the mechanisms underlying ZEO cytotoxicity effect on Breast cancer cells. PMID- 28566686 TI - The structural and magnetic properties of dual phase cobalt ferrite. AB - The bismuth (Bi3+)-doped cobalt ferrite nanostructures with dual phase, i.e. cubic spinel with space group Fd3m and perovskite with space group R3c, have been successfully engineered via self-ignited sol-gel combustion route. To obtain information about the phase analysis and structural parameters, like lattice constant, Rietveld refinement process is applied. The replacement of divalent Co2+ by trivalent Bi3+ cations have been confirmed from energy dispersive analysis of the ferrite samples. The micro-structural evolution of cobalt ferrite powders at room temperature under various Bi3+ doping levels have been identified from the digital photoimages recorded using scanning electron microscopy. The hyperfine interactions, like isomer shift, quadrupole splitting and magnetic hyperfine fields, and cation distribution are confirmed from the Mossbauer spectra. Saturation magnetization is increased with Bi3+-addition up to x = 0.15 and then is decreased when x = 0.2. The coercivity is increased from 1457 to 2277 G with increasing Bi3+-doping level. The saturation magnetization, coercivity and remanent ratio for x = 0.15 sample is found to be the highest, indicating the potential of Bi3+-doping in enhancing the magnetic properties of cobalt ferrite. PMID- 28566687 TI - Iterative Sequencing and Variant Screening (ISVS) as a novel pathogenic mutations search strategy - application for TMPRSS3 mutations screen. AB - Autosomal recessive diseases (ARD) are typically caused by a limited number of mutations whose identification is challenged by their low prevalence. Our purpose was to develop a novel approach allowing an efficient search for mutations causing ARD and evaluation of their pathogenicity without a control group. We developed Iterative Sequencing and Variant Screening (ISVS) approach based on iterative cycles of gene sequencing and mutation screening, and ISVS Simulator software ( http://zsibio.ii.pw.edu.pl/shiny/isvs/ ) for assessment of detected variants' significance. As shown by simulations, ISVS efficiently identifies and correctly classifies pathogenic mutations except for cases where the gene of interest has extremely high number of low frequency nonpathogenic variants. By applying ISVS, we found 4 known and 9 novel (p.C73Y, p.S124L, p.C194Mfs*17, c.782 + 2 T > A, c.953-5 A > G, p.L325Q, p.D334Mfs*24, p.R436G, p.M448T) TMPRSS3 variants among deaf patients. For 3 known and 5 novel variants the disease association was supported by ISVS Simulator odds >90:1. Pathogenicity of 6 novel mutations has been supported by in-silico predictions of variants' deleteriousness. By directly comparing variant prevalence in patients and controls, disease association was demonstrated only for two variants and it was relatively weak (P < 0.05). Summarizing, ISVS strategy and ISVS Simulator are useful for detection of genetic variants causing AR diseases. PMID- 28566688 TI - Sublingual house dust mite immunotherapy has no impact on decrease of circulating erythrocytes upon airway allergen challenge in allergic rhinitis. AB - House dust mite (HDM) allergy is a predominant cause for perennial allergic rhinitis (AR) in Europe. We recently reported that circulating erythrocyte numbers decrease after airway allergen challenge in a murine asthma model and in grass-pollen sensitized AR subjects. Consequently, we aimed to evaluate these findings in HDM sensitized AR subjects and the influence of preceding allergen immunotherapy. Seventy-seven (age 26.8 +/- 7.3 years; 54.5% female) HDM-allergic rhinitis subjects previously enrolled in a randomized, monocentric sublingual immunotherapy (SLIT) trial at the Vienna Challenge Chamber (VCC) were included. Subjects had either received placebo (n = 22), low-dose HDM (n = 29) or high-dose HDM specific sublingual immunotherapy (n = 26) daily for 24 weeks. Blood sampling was performed before and after 6 hours of HDM allergen exposure. Overall, specific airway allergen challenge resulted in a significant decrease in circulating erythrocytes and hematocrit (p < 0.001), and elevation of leukocytes (p < 0.001), particularly segmented neutrophils (p < 0.001). Gender had no significant effect on the observed changes in circulating blood cells. Erythrocytes decreased and neutrophil counts increased significantly after airway allergen challenge regardless of preceding immunotherapy. These findings imply a rapid systemic mobilization of neutrophils occurring within immediate type hypersensitivity response upon a specific allergen challenge, which is possibly inversely linked with the erythrocyte numbers. PMID- 28566689 TI - Bone marrow niche-mimetics modulate HSPC function via integrin signaling. AB - The bone marrow (BM) microenvironment provides critical physical cues for hematopoietic stem and progenitor cell (HSPC) maintenance and fate decision mediated by cell-matrix interactions. However, the mechanisms underlying matrix communication and signal transduction are less well understood. Contrary, stem cell culture is mainly facilitated in suspension cultures. Here, we used bone marrow-mimetic decellularized extracellular matrix (ECM) scaffolds derived from mesenchymal stromal cells (MSCs) to study HSPC-ECM interaction. Seeding freshly isolated HSPCs adherent (AT) and non-adherent (SN) cells were found. We detected enhanced expansion and active migration of AT-cells mediated by ECM incorporated stromal derived factor one. Probing cell mechanics, AT-cells displayed naive cell deformation compared to SN-cells indicating physical recognition of ECM material properties by focal adhesion. Integrin alphaIIb (CD41), alphaV (CD51) and beta3 (CD61) were found to be induced. Signaling focal contacts via ITGbeta3 were identified to facilitate cell adhesion, migration and mediate ECM-physical cues to modulate HSPC function. PMID- 28566690 TI - FastGT: an alignment-free method for calling common SNVs directly from raw sequencing reads. AB - We have developed a computational method that counts the frequencies of unique k mers in FASTQ-formatted genome data and uses this information to infer the genotypes of known variants. FastGT can detect the variants in a 30x genome in less than 1 hour using ordinary low-cost server hardware. The overall concordance with the genotypes of two Illumina "Platinum" genomes is 99.96%, and the concordance with the genotypes of the Illumina HumanOmniExpress is 99.82%. Our method provides k-mer database that can be used for the simultaneous genotyping of approximately 30 million single nucleotide variants (SNVs), including >23,000 SNVs from Y chromosome. The source code of FastGT software is available at GitHub (https://github.com/bioinfo-ut/GenomeTester4/). PMID- 28566691 TI - Substrate Rigidity Controls Activation and Durotaxis in Pancreatic Stellate Cells. AB - Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive malignancy characterised by the presence of extensive desmoplasia, thought to be responsible for the poor response of patients to systemic therapies. Pancreatic stellate cells (PSCs) are key mediators in the production of this fibrotic stroma, upon activation transitioning to a myofibroblast-like, high matrix secreting phenotype. Given their importance in disease progression, characterisation of PSC activation has been extensive, however one aspect that has been overlooked is the mechano sensing properties of the cell. Here, through the use of a physiomimetic system that recapitulates the mechanical microenvironment found within healthy and fibrotic pancreas, we demonstrate that matrix stiffness regulates activation and mechanotaxis in PSCs. We show the ability of PSCs to undergo phenotypic transition solely as a result of changes in extracellular matrix stiffness, whilst observing the ability of PSCs to durotactically respond to stiffness variations within their local environment. Our findings implicate the mechanical microenvironment as a potent contributor to PDAC progression and survival via induction of PSC activation and fibrosis, suggesting that direct mechanical reprogramming of PSCs may be a viable alternative in the treatment of this lethal disease. PMID- 28566692 TI - Pilot Study of 64Cu(I) for PET Imaging of Melanoma. AB - At present, 64Cu(II) labeled tracers including 64CuCl2 have been widely applied in the research of molecular imaging and therapy. Human copper transporter 1 (hCTR1) is the major high affinity copper influx transporter in mammalian cells, and specially responsible for the transportation of Cu(I) not Cu(II). Thus, we investigated the feasible application of 64Cu(I) for PET imaging. 64Cu(II) was reduced to 64Cu(I) with the existence of sodium L-ascorbate, DL-Dithiothreitol or cysteine. Cell uptake and efflux assay was investigated using B16F10 and A375 cell lines, respectively. Small animal PET and biodistribution studies were performed in both B16F10 and A375 tumor-bearing mice. Compared with 64Cu(II), 64Cu(I) exhibited higher cellular uptake by melanoma, which testified CTR1 specially influx of Cu(I). However, due to oxidation reaction in vivo, no significant difference between 64Cu(I) and 64Cu(II) was observed through PET images and biodistribution. Additionally, radiation absorbed doses for major tissues of human were calculated based on the mouse biodistribution. Radiodosimetry calculations for 64/67Cu(I) and 64/67Cu(II) were similar, which suggested that although melanoma were with high radiation absorbed doses, high radioactivity accumulation by liver and kidney should be noticed for the further application. Thus, 64Cu(I) should be further studied to evaluate it as a PET imaging radiotracer. PMID- 28566693 TI - Photoacoustic imaging of voltage responses beyond the optical diffusion limit. AB - Non-invasive optical imaging of neuronal voltage response signals in live brains is constrained in depth by the optical diffusion limit, which is due primarily to optical scattering by brain tissues. Although photoacoustic tomography breaks this limit by exciting the targets with diffused photons and detecting the resulting acoustic responses, it has not been demonstrated as a modality for imaging voltage responses. In this communication, we report the first demonstration of photoacoustic voltage response imaging in both in vitro HEK-293 cell cultures and in vivo mouse brain surfaces. Using spectroscopic photoacoustic tomography at isosbestic wavelengths, we can separate voltage response signals and hemodynamic signals on live brain surfaces. By imaging HEK-293 cell clusters through 4.5 mm thick ex vivo rat brain tissue, we demonstrate photoacoustic tomography of cell membrane voltage responses beyond the optical diffusion limit. Although the current voltage dye does not immediately allow in vivo deep brain voltage response imaging, we believe our method opens up a feasible technical path for deep brain studies in the future. PMID- 28566695 TI - Molecular alignment in degenerated dissociation channels in strong laser fields. AB - In this work, we study strong-field molecular alignment in, for the first time, degenerated channels following the same charged states of molecules. By measuring the angular distribution of dissociation fragments from two degenerated N+ + N+ channels of N2, we observe an opposite angular distribution development in these two channels, one expanding and one contracting, when the laser intensity increases. Our further study shows that the expanding channel comes from a nonsequential transition, while the contracting channel involves a sequential transition. We also study the time sequence of the sequential and nonsequential transitions and find that the opposite angular distribution development is due to the different degrees of molecular alignment in these two degenerated channels. PMID- 28566694 TI - Production of three phenylethanoids, tyrosol, hydroxytyrosol, and salidroside, using plant genes expressing in Escherichia coli. AB - Polyphenols, which include phenolic acids, flavonoids, stilbenes, and phenylethanoids, are generally known as useful antioxidants. Tyrosol, hydroxytyrosol, and salidroside are typical phenylethanoids. Phenylethanoids are found in plants such as olive, green tea, and Rhodiola and have various biological activities, including the prevention of cardiovascular diseases, cancer, and brain damage. We used Escherichia coli to synthesize three phenylethanoids, tyrosol, hydroxytyrosol, and salidroside. To synthesize tyrosol, the aromatic aldehyde synthase (AAS) was expressed in E. coli. Hydroxytyrosol was synthesized using E. coli harboring AAS and HpaBC, which encodes hydroxylase. In order to synthesize salidroside, 12 uridine diphosphate-dependent glycosyltransferases (UGTs) were screened and UGT85A1 was found to convert tyrosol to salidroside. Using E. coli harboring AAS and UGT85A1, salidroside was synthesized. Through the optimization of these three E. coli strains, we were able to synthesize 531 mg/L tyrosol, 208 mg/L hydroxytyrosol, and 288 mg/L salidroside, respectively. PMID- 28566696 TI - Ag-Mg antisite defect induced high thermoelectric performance of alpha-MgAgSb. AB - Engineering atomic-scale native point defects has become an attractive strategy to improve the performance of thermoelectric materials. Here, we theoretically predict that Ag-Mg antisite defects as shallow acceptors can be more stable than other intrinsic defects under Mg-poor-Ag/Sb-rich conditions. Under more Mg-rich conditions, Ag vacancy dominates the intrinsic defects. The p-type conduction behavior of experimentally synthesized alpha-MgAgSb mainly comes from Ag vacancies and Ag antisites (Ag on Mg sites), which act as shallow acceptors. Ag Mg antisite defects significantly increase the thermoelectric performance of alpha-MgAgSb by increasing the number of band valleys near the Fermi level. For Li-doped alpha-MgAgSb, under more Mg-rich conditions, Li will substitute on Ag sites rather than on Mg sites and may achieve high thermoelectric performance. A secondary valence band is revealed in alpha-MgAgSb with 14 conducting carrier pockets. PMID- 28566697 TI - Down-regulated GATA-1 up-regulates interferon regulatory factor 3 in lung adenocarcinoma. AB - Interferon regulatory factor 3 (IRF-3) is widely known for its prompt response against viral infection by activating the interferon system. We previously reported that E2F1, Sp1 and Sp3 regulated transcriptional activity of IRF-3. Recently, different expression patterns of IRF-3 were found in lung cancer, leading to the alternation of the immunomodulatory function in tumorigenesis. However, the mechanism of transcriptional regulation of IRF-3 in lung cancer has not been extensively studied. Here, we investigated the characterization of IRF-3 promoter and found that GATA-1 bound to a specific domain of IRF-3 promoter in vitro and in vivo. We found elevated IRF-3 and decreased GATA-1 gene expression in lung adenocarcinoma in Oncomine database. Additionally, higher IRF-3 gene expression was observed in human lung adenocarcinoma, accompanied by aberrant GATA-1 protein expression. We further analyzed the relationship of GATA-1 and IRF 3 expression in lung adenocarcinoma cell lines and found that inhibition of GATA 1 by siRNA increased the promoter activity, mRNA and protein levels of IRF-3, while over-expression of GATA-1 down-regulated IRF-3 gene expression. Taken together, we conclude that reduced GATA-1 could be responsible for the upregulation of IRF-3 in lung adenocarcinoma cells through binding with a specific domain of IRF-3 promoter. PMID- 28566698 TI - Insight into climate change from the carbon exchange of biocrusts utilizing non rainfall water. AB - Biocrusts are model ecosystems of global change studies. However, light and non rainfall water (NRW) were previously few considered. Different biocrust types further aggravated the inconsistence. So carbon-exchange of biocrusts (cyanobacteria crusts-AC1/AC2; cyanolichen crust-LC1; chlorolichen crust-LC2; moss crust-MC) utilizing NRW at various temperatures and light-intensities were determined under simulated and insitu mesocosm experiments. Carbon input of all biocrusts were negatively correlated with experimental temperature under all light-intensity with saturated water and stronger light with equivalent NRW, but positively correlated with temperature under weak light with equivalent NRW. LCPs and R/Pg of AC1 were lowest, followed in turn by AC2, LC2 and MC. Thus AC1 had most opportunities to use NRW, and 2.5 degrees C warming did cause significant changes of carbon exchange. Structural equation models further revealed that air temperature was most important for carbon-exchange of ACs, but equally important as NRW for LC2 and MC; positive influence of warming on carbon-input in ACs was much stronger than the latter. Therefore, temperature effect on biocrust carbon input depends on both moisture and light. Meanwhile, the role of NRW, transitional states between ACs, and obvious carbon-fixation differences between lichen crusts should be fully considered in the future study of biocrusts responding to climate change. PMID- 28566699 TI - Host-specific assembly of sponge-associated prokaryotes at high taxonomic ranks. AB - Sponges (Porifera) are abundant and diverse members of benthic filter feeding communities in most marine ecosystems, from the deep sea to tropical reefs. A characteristic feature is the associated dense and diverse prokaryotic community present within the sponge mesohyl. Previous molecular genetic studies revealed the importance of host identity for the community composition of the sponge associated microbiota. However, little is known whether sponge host-specific prokaryotic community patterns observed at 97% 16S rRNA gene sequence similarity are consistent at high taxonomic ranks (from genus to phylum level). In the present study, we investigated the prokaryotic community structure and variation of 24 sponge specimens (seven taxa) and three seawater samples from Sweden. Results show that the resemblance of prokaryotic communities at different taxonomic ranks is consistent with patterns present at 97% operational taxonomic unit level. PMID- 28566700 TI - Controlling Light Transmission Through Highly Scattering Media Using Semi Definite Programming as a Phase Retrieval Computation Method. AB - Complex Semi-Definite Programming (SDP) is introduced as a novel approach to phase retrieval enabled control of monochromatic light transmission through highly scattering media. In a simple optical setup, a spatial light modulator is used to generate a random sequence of phase-modulated wavefronts, and the resulting intensity speckle patterns in the transmitted light are acquired on a camera. The SDP algorithm allows computation of the complex transmission matrix of the system from this sequence of intensity-only measurements, without need for a reference beam. Once the transmission matrix is determined, optimal wavefronts are computed that focus the incident beam to any position or sequence of positions on the far side of the scattering medium, without the need for any subsequent measurements or wavefront shaping iterations. The number of measurements required and the degree of enhancement of the intensity at focus is determined by the number of pixels controlled by the spatial light modulator. PMID- 28566701 TI - Mathematical Analysis of Glioma Growth in a Murine Model. AB - Five immunocompetent C57BL/6-cBrd/cBrd/Cr (albino C57BL/6) mice were injected with GL261-luc2 cells, a cell line sharing characteristics of human glioblastoma multiforme (GBM). The mice were imaged using magnetic resonance (MR) at five separate time points to characterize growth and development of the tumor. After 25 days, the final tumor volumes of the mice varied from 12 mm3 to 62 mm3, even though mice were inoculated from the same tumor cell line under carefully controlled conditions. We generated hypotheses to explore large variances in final tumor size and tested them with our simple reaction-diffusion model in both a 3-dimensional (3D) finite difference method and a 2-dimensional (2D) level set method. The parameters obtained from a best-fit procedure, designed to yield simulated tumors as close as possible to the observed ones, vary by an order of magnitude between the three mice analyzed in detail. These differences may reflect morphological and biological variability in tumor growth, as well as errors in the mathematical model, perhaps from an oversimplification of the tumor dynamics or nonidentifiability of parameters. Our results generate parameters that match other experimental in vitro and in vivo measurements. Additionally, we calculate wave speed, which matches with other rat and human measurements. PMID- 28566702 TI - Colitis promotes neuronal differentiation of Sox2+ and PLP1+ enteric cells. AB - Mechanisms mediating adult enteric neurogenesis are largely unknown. Using inflammation-associated neurogenesis models and a transgenic approach, we aimed to understand the cell-source for new neurons in infectious and inflammatory colitis. Dextran sodium sulfate (DSS) and Citrobacter rodentium colitis (CC) was induced in adult mice and colonic neurons were quantified. Sox2GFP and PLP1GFP mice confirmed the cell-type specificity of these markers. Sox2CreER:YFP and PLP1creER:tdT mice were used to determine the fate of these cells after colitis. Sox2 expression was investigated in colonic neurons of human patients with Clostridium difficile or ulcerative colitis. Both DSS and CC led to increased colonic neurons. Following colitis in adult Sox2CreER:YFP mice, YFP initially expressed predominantly by glia becomes expressed by neurons following colitis, without observable DNA replication. Similarly in PLP1CreER:tdT mice, PLP1 cells that co-express S100b but not RET also give rise to neurons following colitis. In human colitis, Sox2-expressing neurons increase from 1-2% to an average 14% in colitis. The new neurons predominantly express calretinin, thus appear to be excitatory. These results suggest that colitis promotes rapid enteric neurogenesis in adult mice and humans through differentiation of Sox2- and PLP1 expressing cells, which represent enteric glia and/or neural progenitors. Further defining neurogenesis will improve understanding and treatment of injury associated intestinal motility/sensory disorders. PMID- 28566704 TI - Inclusions properties at 1673 K and room temperature with Ce addition in SS400 steel. AB - Inclusion species formed in SS400 steel with Ce-addition was predicted by thermodynamic calculation. The analysis of the inclusion morphology and size distribution was carried out by applying Scanning Electron Microscopy (SEM) and Transmission Electron Microscope (TEM). Nano-Fe3O4 particles were also found in cerium-deoxidized and -desulfurized steel and their shapes were nearly spherical. The complex Ce2O3 inclusions covering a layer of 218 nm composed by several MnS particles with similar diffraction pattern. Most importantly, the complex Ce2O3 characterized by using TEM diffraction is amorphous in the steel, indicating that Ce2O3 formed in the liquid iron and then MnS segregated cling to it. PMID- 28566703 TI - Astronomical age constraints and extinction mechanisms of the Late Triassic Carnian crisis. AB - The geological record contains evidence for numerous pronounced perturbations in the global carbon cycle, some of which are associated with mass extinction. In the Carnian (Late Triassic), evidence from sedimentology and fossil pollen points to a significant change in climate, resulting in biotic turnover, during a time termed the 'Carnian Pluvial Episode' (CPE). Evidence from the marine realm suggests a causal relationship between the CPE, a global 'wet' period, and the injection of light carbon into the atmosphere. Here we provide the first evidence from a terrestrial stratigraphic succession of at least five significant negative C-isotope excursions (CIE)'s through the CPE recorded in both bulk organic carbon and compound specific plant leaf waxes. Furthermore, construction of a floating astronomical timescale for 1.09 Ma of the Late Triassic, based on the recognition of 405 ka eccentricity cycles in elemental abundance and gamma ray (GR) data, allows for the estimation of a duration for the isotope excursion(s). Source mixing calculations reveal that the observed substantial shift(s) in delta13C was most likely caused by a combination of volcanic emissions, subsequent warming and the dissociation of methane clathrates. PMID- 28566705 TI - Nitrogen isotopes provide clues to amino acid metabolism in human colorectal cancer cells. AB - Glutamic acid and alanine make up more than 60 per cent of the total amino acids in the human body. Glutamine is a significant source of energy for cells and also a prime donor of nitrogen in the biosynthesis of many amino acids. Several studies have advocated the role of glutamic acid in cancer therapy. Identification of metabolic signatures in cancer cells will be crucial for advancement of cancer therapies based on the cell's metabolic state. Stable nitrogen isotope ratios (15N/14N, delta15N) are of particular advantage to understand the metabolic state of cancer cells, since most biochemical reactions involve transfer of nitrogen. In our study, we used the natural abundances of nitrogen isotopes (delta15N values) of individual amino acids from human colorectal cancer cell lines to investigate isotope discrimination among amino acids. Significant effects were noticed in the case of glutamic acid, alanine, aspartic acid and proline between cancer and healthy cells. The data suggest that glutamic acid is a nitrogen acceptor while alanine, aspartic acid and proline are nitrogen donors in cancerous cells. One plausible explanation is the transamination of the three acids to produce glutamic acid in cancerous cells. PMID- 28566707 TI - Insights into the complexation of N-Allyl-4-(4-(N-phenylureido)benzylamino)-1,8 naphthalimide with various anions. AB - A new urea functionalised 4-amino-1,8-naphthalimide based fluorescent anion sensor was synthesised in 64% yield over three steps. Fluorescence and 1H NMR titrations showed that the sensor complexes strongly with acetate and dihydrogen phosphate and to a lesser extent bromide. The corresponding binding stoichiometries were examined using 1H NMR titrations. Results show that the sensor molecule initially forms 1:1 complexes through hydrogen bonding to the urea moiety, followed by secondary complexation to form higher order host:guest stoichiometries. Specifically, oxyanions complex to the sensor via hydrogen bonding through synergistic aryl C-H and N-H anion interactions in a 1:2 sensor:oxyanion arrangement. Furthermore, 2:1 sensor:oxyanion complexes are formed through an oxyanion linkage between two urea functionalities on different host molecules. This contrasts the majority of previous reports for similar hosts, which indicate 1:1 binding stoichiometry. PMID- 28566706 TI - Adaptation to Progressive Additive Lenses: Potential Factors to Consider. AB - People develop presbyopia as part of the normal aging process. Most presbyopes adapt to progressive additive lens (PALs), while others do not. This investigation sought to determine whether the ability to modify disparity vergence or phoria was correlated to PALs adaptation. In experiment 1, a double step paradigm quantified the ability to modify convergence responses in sixteen presbyopes. In experiment 2, thirty-one incipient presbyopes participated in a 5 minute sustained fixation task to evoke phoria adaptation where the magnitude and rate of phoria adaptation were measured. Then, the experiment was repeated after wearing PALs for one month. Linear regression analyses were conducted between the following parameters: near point of convergence, positive fusional vergence at near, vergence facility, net change in the magnitude of phoria adaptation, and the rate of phoria adaptation. The ability to change convergence average peak velocity was significantly greater (p < 0.03) in presbyopic PALs adapters compared to presbyopic PALs non-adapters. The rate of phoria adaptation and vergence facility were significantly greater (p < 0.03) in incipient presbyopic PALs adapters compared to incipient presbyopic PALs non-adapters. Vergence facility and the rate of phoria adaptation may have potential clinical utility in differentiating which patients may adapt to PALs and which ones will have more difficulty. PMID- 28566708 TI - Reverse Anti-solvent Crystallization Process for the Facile Synthesis of Zinc Tetra(4-pyridyl)porphyrin Single Crystalline Cubes. AB - Synthesis of morphologically well-defined crystals of metalloporphyrin by direct crystallization based on conventional anti-solvent crystallization method without using any additives has been rarely reported. Herein, we demonstrate an unconventional and additive-free synthetic method named reverse anti-solvent crystallization method to achieve well-defined zinc-porphyrin cube crystals by reversing the order of the addition of solvents. The extended first solvation shell effect mechanism is therefore suggested to support the synthetic process by providing a novel kinetic route for reaching the local supersaturation environment depending on the order of addition of solvents, which turned out to be critical to achieve clean cube morphology of the crystal. We believe that our work not only extends fundamental knowledge about the kinetic process in binary solvent systems, but also enables great opportunities for shape-directing crystallization of various organic and organometallic compounds. PMID- 28566709 TI - Targeted radionuclide therapy with astatine-211: Oxidative dehalogenation of astatobenzoate conjugates. AB - 211At is a most promising radionuclide for targeted alpha therapy. However, its limited availability and poorly known basic chemistry hamper its use. Based on the analogy with iodine, labelling is performed via astatobenzoate conjugates, but in vivo deastatination occurs, particularly when the conjugates are internalized in cells. Actually, the chemical or biological mechanism responsible for deastatination is unknown. In this work, we show that the C-At "organometalloid" bond can be cleaved by oxidative dehalogenation induced by oxidants such as permanganates, peroxides or hydroxyl radicals. Quantum mechanical calculations demonstrate that astatobenzoates are more sensitive to oxidation than iodobenzoates, and the oxidative deastatination rate is estimated to be about 6 * 106 faster at 37 degrees C than the oxidative deiodination one. Therefore, we attribute the "internal" deastatination mechanism to oxidative dehalogenation in biological compartments, in particular lysosomes. PMID- 28566711 TI - Comparison of pediatric and adult lymphomas involving the mediastinum characterized by distinctive clinicopathological and radiological features. AB - Lymphomas involving the mediastinum occur in a wide age range and represent heterogeneous histological subtypes with various clinical symptoms and complex radiological findings. However, studies that describe the clinical and radiological features of different subtypes among Chinese pediatric and adult patients are limited. We analyzed the clinical, radiological and pathological features of 31 pediatric lymphomas involving the mediastinum, and compared them to the features of 21 adult patients. Although several histological subtypes were identified in adults, pediatric patients presented with T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/T-ALL) and classical Hodgkin lymphomas (CHL) in 24 and 7 cases, respectively. Compared to adults, pediatric patients were more likely to be male (P = 0.089) and showed a higher incidence of T-LBL/T-ALL (P = 0.001), prevalence of dyspnea (P = 0.001), frequency of stage IV tumors (P = 0.008), and ratio of tumor diameter to maximum transthoracic diameter (P = 0.015). T-LBL/T-ALL patients presented with a higher frequency with stage IV disease (P = 0.000 and P = 0.001), compression of the blood vessels (P = 0.005 and P = 0.017), and pleural effusions (P = 0.001, for both) than CHL and PMBL patients. Compared to adults, pediatric patients with mediastinal lymphomas presented with exclusive histological subtypes of T-LBL/T-ALL and CHL, which showed distinctive characteristics of histological distribution, clinical presentation and radiological assessments. PMID- 28566710 TI - Massive expansion and differential evolution of small heat shock proteins with wheat (Triticum aestivum L.) polyploidization. AB - Wheat (Triticum aestivum), one of the world's most important crops, is facing unprecedented challenges due to global warming. To evaluate the gene resources for heat adaptation in hexaploid wheat, small heat shock proteins (sHSPs), the key plant heat protection genes, were comprehensively analysed in wheat and related species. We found that the sHSPs of hexaploid wheat were massively expanded in A and B subgenomes with intrachromosomal duplications during polyploidization. These expanded sHSPs were under similar purifying selection and kept the expressional patterns with the original copies. Generally, a strong purifying selection acted on the alpha-crystallin domain (ACD) and theoretically constrain conserved function. Meanwhile, weaker purifying selection and strong positive selection acted on the N-terminal region, which conferred sHSP flexibility, allowing adjustments to a wider range of substrates in response to genomic and environmental changes. Notably, in CI, CV, ER, MI and MII subfamilies, gene duplications, expression variations and functional divergence occurred before wheat polyploidization. Our results indicate the massive expansion of active sHSPs in hexaploid wheat may also provide more raw materials for evolving functional novelties and generating genetic diversity to face future global climate changes, and highlight the expansion of stress response genes with wheat polyploidization. PMID- 28566712 TI - Developmental changes in social attention and oxytocin levels in infants and children. AB - Oxytocin (OT) signalling represents one of the most critical systems involved in human social behaviour. Although several studies have examined the relationship between social functioning and peripheral OT levels, the association between OT and the development of social attention has not been well studied. Therefore, we investigated the developmental relationship between gaze fixation for social cues and OT levels during young childhood. We examined visual attention using an eye tracking system in infants and children (5-90 months of age) and measured the concentration of OT in saliva samples. We observed a negative association between age and both attention toward social cues and salivary OT levels, and a positive association between age and attention for non-social cues. We also observed that salivary OT levels were modulated by polymorphisms in oxytocin receptor (OXTR) rs53576. Our results suggest that there is an age-dependent association between visual attention for social cues and OT levels in infants and children, and that the development of visual attention to the eyes as social cues is associated with both OXTR polymorphisms and OT levels. Such findings indicate that OT and OXTR status may provide insight into the atypical development of social attention in infants and young children. PMID- 28566713 TI - A PPARgamma-dependent miR-424/503-CD40 axis regulates inflammation mediated angiogenesis. AB - Activation of the endothelium by pro-inflammatory stimuli plays a key role in the pathogenesis of a multitude of vascular diseases. Angiogenesis is a crucial component of the vascular response associated with inflammatory signaling. The CD40/CD40 ligand dyad in endothelial cells (EC) has a central role in promoting vascular inflammatory response; however, the molecular mechanism underlying this component of inflammation and angiogenesis is not fully understood. Here we report a novel microRNA mediated suppression of endothelial CD40 expression. We found that CD40 is closely regulated by miR-424 and miR-503, which directly target its 3' untranslated region. Pro-inflammatory stimuli led to increased endothelial CD40 expression, at least in part due to decreased miR-424 and miR 503 expression. In addition, miR-424 and miR-503 reduced LPS induced EC sprouting, migration and tube formation. Moreover, we found that miR-424 and miR 503 expression is directly regulated by peroxisome proliferator-activated receptor gamma (PPARgamma), whose endothelial expression and activity are decreased in response to inflammatory factors. Finally, we demonstrate that mice with endothelial-specific deletion of miR-322 (miR-424 ortholog) and miR-503 have augmented angiogenic response to LPS in a Matrigel plug assay. Overall, these studies identify a PPARgamma-dependent miR-424/503-CD40 signaling axis that is critical for regulation of inflammation mediated angiogenesis. PMID- 28566714 TI - The role of flavin-containing enzymes in mitochondrial membrane hyperpolarization and ROS production in respiring Saccharomyces cerevisiae cells under heat-shock conditions. AB - Heat shock is known to accelerate mitochondrial ROS production in Saccharomyces cerevisiae cells. But how yeast mitochondria produce ROS under heat-shock condition is not completely clear. Previously, it was shown that ROS production in heat-stressed fermenting yeast cells was accompanied by mitochondrial membrane potential (MMP) increase. In the current investigation the relationship between ROS production and MMP was studied in respiring yeast cells in stationary phase, using diphenyleneiodonium chloride (DPI), an inhibitor of flavin-containing proteins, as well as the mutants deleted for NDE1, NDE2 and NDI1 genes, encoding flavin-containing external and internal NADH dehydrogenases. It was shown that heat shock induced a transient burst in mitochondrial ROS production, which was paralleled by MMP rise. ROS production and MMP was significantly suppressed by DPI addition and deletion of NDE1. The effect of DPI on ROS production and MMP rise was specific for respiring cells. The results obtained suggest that the functioning of mitochondrial flavin-binding enzymes, Nde1p for instance, is required for the hyperpolarization of inner mitochondrial membrane and ROS production in respiring S. cerevisiae cells under heat-shock conditions. PMID- 28566715 TI - Classical-to-quantum transition behavior between two oscillators separated in space under the action of optomechanical interaction. AB - We propose a scheme to show that the system consisting of two macroscopic oscillators separated in space which are coupled through Coulomb interaction displays the classical-to-quantum transition behavior under the action of optomechanical coupling interaction. Once the optomechanical coupling interaction disappears, the entanglement between the two separated oscillators disappears accordingly and the system will return to classical world even though there exists sufficiently strong Coulomb coupling between the oscillators. In addition, resorting to the squeezing of the cavity field generated by an optical parametric amplifier inside the cavity, we discuss the effect of squeezed light driving on this classical-to-quantum transition behavior instead of injecting the squeezed field directly. The results of numerical simulation show that the present scheme is feasible and practical and has stronger robustness against the environment temperature compared with previous schemes in current experimentally feasible regimes. The scheme might possibly help us to further clarify and grasp the classical-quantum boundary. PMID- 28566716 TI - Glycogen synthase kinase 3beta inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism. AB - Direct acting antivirals against hepatitis C virus (HCV) have markedly improved cure rates in the past few years. However, they are expensive, with only few targeting host cell factors, and affecting virus assembly and release. Huh7.5 cells infected with a JFH-1 clone of HCV were treated with two different glycogen synthase kinase (GSK3)-beta inhibitors; AR-A014418 and lithium chloride. Intra- and extracellular HCV virions and specific infectivity was determined using real time RT-PCR and TCID50, and changes in lipid production were identified by enzyme linked immunoassay and mass spectrometry analyses. Similarly, effect on two HCV replicon cells were identified by the luciferase activity. Although there was limited effect on virus replication in Huh7.5 cells and replicons, Huh7.5 cells treated with GSK3beta inhibitors produced significantly less viral particles in comparison to untreated cells. In addition, the treated cells synthesized significantly lower amounts of ApoB and trapped the ApoE lipoproteins in the cells. In conclusion, our study suggests that GSK3beta plays a pivotal role in HCV virion assembly and release mediated in part through inhibition of apolipoprotein synthesis. PMID- 28566717 TI - Metabolomic profiling in a Hedgehog Interacting Protein (Hhip) murine model of chronic obstructive pulmonary disease. AB - Genetic variants annotated to the hedgehog interacting protein (HHIP) are robustly associated with chronic obstructive pulmonary disease (COPD). Hhip haploinsufficiency in mice leads to increased susceptibility towards the development of emphysema following exposure to chronic cigarette smoke (CS). To explore the molecular pathways which contribute to increased susceptibility, we performed metabolomic profiling using high performance liquid chromatography tandem mass spectroscopy (LC/MS-MS) on plasma, urine, and lung tissue of Hhip +/- heterozygotes and wild type (Hhip +/+) C57/BL6 mice exposed to either room-air or CS for six months. Univariate comparisons between groups were made with a combined fold change >=2 and Student's t-test p-value < 0.05 to denote significance; associations with mean alveolar chord length (MACL), a quantitative measure of emphysema, and gene-by-environment interactions were examined using empiric Bayes-mediated linear models. Decreased urinary excretion of cotinine despite comparable plasma levels was observed in Hhip +/- heterozygotes; a strong gene-by-smoking association was also observed. Correlations between MACL and markers of oxidative stress such as urinary methionine sulfoxide were observed in Hhip +/- but not in Hhip +/+ mice. Metabolite set enrichment analyses suggest reduced antioxidant capacity and alterations in macronutrient metabolism contribute to increased susceptibility to chronic CS-induced oxidative stress in Hhip haploinsufficiency states. PMID- 28566718 TI - Investigation of optimal weight gain during pregnancy for Japanese Women. AB - This study aims to compare the US Institute of Medicine (IOM) and Japanese guidelines proposed by the Ministry and the Japan Society for the Study of Obesity on gestational weight gain (GWG), and to explore the optimal GWG range in Japanese women. We investigated 8,152 Japanese women who had full-term singleton babies between 2010 and 2013 at a single center in Tokyo. Logistic regression models showed that GWG below the recommendation of the IOM and Japanese guidelines was similarly associated with an increased risk of light-for-date (LFD), whereas GWG above these guidelines was similarly associated with an increased risk of heavy-for-date (HFD) in pre-pregnancy body mass index categories of underweight (<18.5 kg/m2, n = 1559), normal-weight (18.5-24.9 kg/m2, n = 4998), overweight (25.0-29.9 kg/m2, n = 270), and obese (30 <= kg/m2, n = 60). The receiver-operating characteristic curve demonstrated that the optimal cutoffs for LFD and HFD were 9.7 and 10.4 kg, respectively in normal weight mothers. The IOM and Japanese guidelines identified the risk of LFD or HFD equally well. The optimal GWG range in normal-weight women observed in this study was more close to Japanese guideline (i.e., 7-12 kg) compared to the IOM guideline (i.e., 11.5-16 kg). PMID- 28566719 TI - Chronic Alcohol Consumption Promotes Diethylnitrosamine-Induced Hepatocarcinogenesis via Immune Disturbances. AB - Chronic alcohol consumption increases the risk of hepatocellular carcinoma (HCC). However, little is known about the potential immunological mechanisms by which ethanol affects tumor progression. Here, adult male mice were administered multiple doses of diethylnitrosamine (DEN). Four and a half months later, the DEN treated mice were placed on a liquid Lieber-DeCarli control diet or diet containing 5% ethanol for 2.5 months. At the end of the study, liver tissue samples were obtained to analyze pathology, gene expression, and hepatic mononuclear cells (MNCs). Results showed that ethanol feeding exacerbates the progression of hepatic tumors (characterized by the ratio of liver weight to body weight, and the tumor volume and diameter) in DEN-treated mice. Mechanistically, chronic alcohol consumption decreased the number of antitumor CD8+ T cells but increased the number of tumor-associated macrophages (TAMs) in the liver in DEN initiated tumorigenesis. Besides, TAMs were prone to be M2 phenotype after alcohol consumption. Moreover, chronic alcohol consumption aggravated inflammation, fibrosis, and epithelial-mesenchymal transition (EMT) in the pathological process of HCC. These data demonstrate that chronic alcohol consumption exacerbates DEN-induced hepatocarcinogenesis by enhancing protumor immunity, impairing antitumor immunity and aggravating hepatic pathological injury. Targeting the immune system is a potential therapeutic regimen for alcohol-promoted HCC. PMID- 28566720 TI - Exosomes derived from human umbilical cord mesenchymal stem cells protect against cisplatin-induced ovarian granulosa cell stress and apoptosis in vitro. AB - Human umbilical cord mesenchymal stem cells (huMSCs) can treat primary ovarian insufficiency (POI) related to ovarian granulosa cell (OGC) apoptosis caused by cisplatin chemotherapy. Exosomes are a class of membranous vesicles with diameters of 30-200 nm that are constitutively released by eukaryotic cells. Exosomes mediate local cell-to-cell communication by transferring microRNAs and proteins. In the present study, we demonstrated the effects of exosomes derived from huMSCs (huMSC-EXOs) on a cisplatin-induced OGC model in vitro and discussed the preliminary mechanisms involved in these effects. We successfully extracted huMSC-EXOs from huMSC culture supernatant and observed the effective uptake of exosomes by cells with fluorescent staining. Using flow cytometry (with annexin V/PI labelling), we found that huMSC-EXOs increased the number of living cells. Western blotting showed that the expression of Bcl-2 and caspase-3 were upregulated, whilst the expression of Bax, cleaved caspase-3 and cleaved PARP were downregulated to protect OGCs. These results suggest that huMSC-EXOs can be used to prevent and treat chemotherapy-induced OGC apoptosis in vitro. Therefore, this work provides insight and further evidence of stem cell function and indicates that huMSC-EXOs protect OGCs from cisplatin-induced injury in vitro. PMID- 28566721 TI - A novel CXCR4-targeted near-infrared (NIR) fluorescent probe (Peptide R-NIR750) specifically detects CXCR4 expressing tumors. AB - C-X-C chemokine receptor 4 (CXCR4) is over-expressed in multiple human cancers and correlates with tumor aggressiveness, poor prognosis and increased risk for distant metastases. Imaging agents for CXCR4 are thus highly desirable. We developed a novel CXCR4-targeted near-infrared (NIR) fluorescent probe (Peptide R NIR750) conjugating the new developed CXCR4 peptidic antagonist Peptide R with the NIR fluorescent dye VivoTag-S750. Specific CXCR4 binding was obtained in cells overexpressing human CXCR4 (B16-hCXCR4 and human melanoma cells PES43), but not in CXCR4 low expressing cells (FB-1). Ex vivo evaluation demonstrated that PepR-NIR750 specifically detects B16-hCXCR4-derived subcutaneous tumors and lung metastases. Fluorescence Molecular Tomography (FMT) in vivo imaging was performed on mice carrying subcutaneous CHO and CHO-CXCR4 tumors. PepR-NIR750 accumulates only in CXCR4-positive expressing subcutaneous tumors. Additionally, an intense NIR fluorescence signal was detected in PES43-derived lung metastases of nude mice injected with PepR-NIR750 versus mice injected with VivoTag-S750. With a therapeutic intent, mice bearing PES43-derived lung metastases were treated with Peptide R. A the dramatic reduction in PES43-derived lung metastases was detected through a decrease of the PepR-NIR750 signal. PepR-NIR750 is a specific probe for non-invasive detection of human high CXCR4-expressing tumors and metastatic lesion and thus a valuable tool for cancer molecular imaging. PMID- 28566722 TI - Community and species-specific responses of plant traits to 23 years of experimental warming across subarctic tundra plant communities. AB - To improve understanding of how global warming may affect competitive interactions among plants, information on the responses of plant functional traits across species to long-term warming is needed. Here we report the effect of 23 years of experimental warming on plant traits across four different alpine subarctic plant communities: tussock tundra, Dryas heath, dry heath and wet meadow. Open-top chambers (OTCs) were used to passively warm the vegetation by 1.5-3 degrees C. Changes in leaf width, leaf length and plant height of 22 vascular plant species were measured. Long-term warming significantly affected all plant traits. Overall, plant species were taller, with longer and wider leaves, compared with control plots, indicating an increase in biomass in warmed plots, with 13 species having significant increases in at least one trait and only three species having negative responses. The response varied among species and plant community in which the species was sampled, indicating community warming interactions. Thus, plant trait responses are both species- and community specific. Importantly, we show that there is likely to be great variation between plant species in their ability to maintain positive growth responses over the longer term, which might cause shifts in their relative competitive ability. PMID- 28566723 TI - Requirement for Jagged1-Notch2 signaling in patterning the bones of the mouse and human middle ear. AB - Whereas Jagged1-Notch2 signaling is known to pattern the sensorineural components of the inner ear, its role in middle ear development has been less clear. We previously reported a role for Jagged-Notch signaling in shaping skeletal elements derived from the first two pharyngeal arches of zebrafish. Here we show a conserved requirement for Jagged1-Notch2 signaling in patterning the stapes and incus middle ear bones derived from the equivalent pharyngeal arches of mammals. Mice lacking Jagged1 or Notch2 in neural crest-derived cells (NCCs) of the pharyngeal arches display a malformed stapes. Heterozygous Jagged1 knockout mice, a model for Alagille Syndrome (AGS), also display stapes and incus defects. We find that Jagged1-Notch2 signaling functions early to pattern the stapes cartilage template, with stapes malformations correlating with hearing loss across all frequencies. We observe similar stapes defects and hearing loss in one patient with heterozygous JAGGED1 loss, and a diversity of conductive and sensorineural hearing loss in nearly half of AGS patients, many of which carry JAGGED1 mutations. Our findings reveal deep conservation of Jagged1-Notch2 signaling in patterning the pharyngeal arches from fish to mouse to man, despite the very different functions of their skeletal derivatives in jaw support and sound transduction. PMID- 28566725 TI - Low-field electron mobility of InSb nanowires: Numerical efforts to larger cross sections. AB - Within the framework of Boltzmann equation, we present a k . p theory based study for the low-field mobilities of InSb nanowires (InSb NWs) with relatively large cross sectional sizes (with diameters up to 51.8 nm). For such type of large size nanowires, the intersubband electron-phonon scattering is of crucial importance to affect the scattering rate and then the mobility. In our simulation, the lowest 15 electron subbands and 50 transverse modes of phonons are carefully accounted for. We find that, up to the 51.84 nm diameter, the mobility monotonously increases with the diameter, not yet showing any saturated behavior. We also find that, while the bulk InSb mobility is considerably higher than the bulk Si, the small size (e.g. ~3 nm diameter) nanowires from both materials have similar magnitude of mobilities. This implies, importantly, that the mobility of the InSb NWs would decrease faster than the SiNWs as we reduce the cross sectional size of the nanowires. PMID- 28566724 TI - Aberrant Intra- and Internetwork Functional Connectivity in Depressed Parkinson's Disease. AB - Much is known concerning the underlying mechanisms of Parkinson's disease (PD) with depression, but our understanding of this disease at the neural-system level remains incomplete. This study used resting-state functional MRI (rs-fMRI) and independent component analysis (ICA) to investigate intrinsic functional connectivity (FC) within and between large-scale neural networks in 20 depressed PD (dPD) patients, 35 non-depressed PD (ndPD) patients, and 34 healthy controls (HC). To alleviate the influence caused by ICA model order selection, this work reported results from analyses at 2 levels (low and high model order). Within these two analyses, similar results were obtained: 1) dPD and ndPD patients relative to HC had reduced FC in basal ganglia network (BGN); 2) dPD compared with ndPD patients exhibited increased FC in left frontoparietal network (LFPN) and salience network (SN), and decreased FC in default-mode network (DMN); 3) dPD patients compared to HC showed increased FC between DMN and LFPN. Additionally, connectivity anomalies in the DMN, LFPN and SN correlated with the depression severity in patients with PD. Our findings confirm the involvement of BGN, DMN, LFPN and SN in depression in PD, facilitating the development of more detailed and integrative neural models of PD with depression. PMID- 28566726 TI - Efficacy and Tolerability of Second and Third Generation Anti-epileptic Drugs in Refractory Epilepsy: A Network Meta-Analysis. AB - This study was proposed to compare the relative efficacy and tolerability of the second and third generation AEDs for refractory epilepsy. The 50% responder rate (RR) was selected as the efficacy outcome whereas the incidence of dizziness and somnolence were considered to evaluate the tolerability of AEDs. Odds ratio (OR) and their 95% credible interval (CrI) were obtained using a consistency model and surface under the cumulative ranking curve (SUCRA) value was calculated to rank AEDs. Topiramate appeared to be significantly more effective than placebo, eslicarbazepine acetate, perampanel, pregabalin, zonisamide, gabapentin and lamotrigine with respect to the 50% RR (all OR > 1). Patients who were managed by eslicarbazepine acetate, perampanel, oxcarbazepine, topiramate and pregabalin were more likely to suffer from dizziness compared to those who receive placebo (all OR > 1). Perampanel, topiramate and pregabalin were related to elevated risks of somnolence compared to placebo (all OR > 1). Moreover, topiramate ranked highest with respect to 50% RR (SUCRA = 0.968) whereas levetiracetam appeared to have balanced efficacy and tolerability (SUCRA = 0.769, 0.743, 0.604 and 0.659). In conclusion, topiramate was the most efficacious AED, while levetiracetam was able to provide patients with balanced efficacy and tolerability. PMID- 28566728 TI - Evaluation of riparian condition of Songhua River by integration of remote sensing and field measurements. AB - Riparian zone is crucial to the health of streams and their surrounding environment. Evaluation of riparian condition is essential to achieve and maintain good stream health, as well as to sustain ecological functions that riparian areas provide. This manuscript is aimed to evaluate riparian conditions of Songhua River, the fifth longest river in China, using physical structural integrality (PSI) values derived from remote sensing and validated by field measurements. The variation and clusters of PSI values were discriminated by the spatial statistics to quantify variation of riparian condition in each measurement section. Evaluation results derived from 13 measurement sections indicated that over 60% of the riparian zones have been disturbed by human activities. Analysis of land use patterns of riparian zone in the cold and hot spots found that land-use patterns had an important effect on riparian condition. The build-up and farmland areas had been the main human disturbances to the riparian condition, which were increased from 1976 to 2013. The low-low clusters (low PSI values with low neighbors) of PSI values can be implemented to identify the vulnerability of the riparian zone. PMID- 28566727 TI - Persistent spatial structuring of coastal ocean acidification in the California Current System. AB - The near-term progression of ocean acidification (OA) is projected to bring about sharp changes in the chemistry of coastal upwelling ecosystems. The distribution of OA exposure across these early-impact systems, however, is highly uncertain and limits our understanding of whether and how spatial management actions can be deployed to ameliorate future impacts. Through a novel coastal OA observing network, we have uncovered a remarkably persistent spatial mosaic in the penetration of acidified waters into ecologically-important nearshore habitats across 1,000 km of the California Current Large Marine Ecosystem. In the most severe exposure hotspots, suboptimal conditions for calcifying organisms encompassed up to 56% of the summer season, and were accompanied by some of the lowest and most variable pH environments known for the surface ocean. Persistent refuge areas were also found, highlighting new opportunities for local adaptation to address the global challenge of OA in productive coastal systems. PMID- 28566729 TI - Potent anti-cancer effects of less polar Curcumin analogues on gastric adenocarcinoma and esophageal squamous cell carcinoma cells. AB - Curcumin and its chalcone derivatives inhibit the growth of human cancer cells. It is reported that replacement of two OH groups in curcumin with less polar groups like methoxy increases its anti-proliferative activity. In this study, we explored benzylidine cyclohexanone derivatives with non-polar groups, to see if they possess increased anti-cancer activity. Novel 2,6-bis benzylidine cyclohexanone analogues of curcumin were synthesized, and their inhibitory effects on gastric adenocarcinoma (AGS) and esophageal squamous cell carcinoma (KYSE30) cancer cells were studied using an MTT assay. Cell apoptosis was detected by EB/AO staining, and cell cycle was analyzed by flow cytometry. Real time PCR was performed for gene expression analysis. All synthesized analogues were cytotoxic toward gastric and esophageal cancer cells and showed lower IC50 values than curcumin. Treatment with 2,6-Bis-(3-methoxy-4-propoxy-benzylidene) cyclohexanone (BM2) was 17 times more toxic than curcumin after 48 h incubation. All novel compounds were more effective than curcumin in apoptosis induction and cell cycle arrest at G1 phase. These results suggest that less polar analogues of curcumin have potent cytotoxicity in vitro. However, they need to be investigated further, especially with animal tumor models, to confirm their chemotherapeutic activity in vivo. PMID- 28566730 TI - Building early-larval sexing systems for genetic control of the Australian sheep blow fly Lucilia cuprina using two constitutive promoters. AB - Transgenic sexing strains (TSS) that carry conditional female lethal genes are advantageous for genetic control programs based on the sterile insect technique (SIT). It is desirable if females die early in development as larval diet is a major cost for mass production facilities. This can be achieved by using a gene promoter that is only active in embryos to drive expression of the tetracycline transactivator (tTA), the transcription factor commonly used in two-component TSS. While an embryo-specific promoter is ideal it may not be essential for assembling an effective TSS as tTA can be repressed by addition of tetracycline to the diet at larval and/or adult stages. Here we have investigated this idea by isolating and employing the promoters from the Lucilia spitting image and actin 5C genes to drive tTA expression in embryos and later stages. L. cuprina TSS with the tTA drivers and tTA-regulated tetO-Lshid effectors produced only females when raised on a limited tetracycline diet. The Lshid transgene contains a sex specific intron and as a consequence only females produce LsHID protein. TSS females died at early larval stages, which makes the lines advantageous for an SIT program. PMID- 28566731 TI - Experimental investigation of quantum entropic uncertainty relations for multiple measurements in pure diamond. AB - One unique feature of quantum mechanics is the Heisenberg uncertainty principle, which states that the outcomes of two incompatible measurements cannot simultaneously achieve arbitrary precision. In an information-theoretic context of quantum information, the uncertainty principle can be formulated as entropic uncertainty relations with two measurements for a quantum bit (qubit) in two dimensional system. New entropic uncertainty relations are studied for a higher dimensional quantum state with multiple measurements, and the uncertainty bounds can be tighter than that expected from two measurements settings and cannot result from qubits system with or without a quantum memory. Here we report the first room-temperature experimental testing of the entropic uncertainty relations with three measurements in a natural three-dimensional solid-state system: the nitrogen-vacancy center in pure diamond. The experimental results confirm the entropic uncertainty relations for multiple measurements. Our result represents a more precise demonstrating of the fundamental uncertainty principle of quantum mechanics. PMID- 28566732 TI - Peptide Markers for Rapid Detection of KPC Carbapenemase by LC-MS/MS. AB - Carbapenemase producing organisms (CPOs) represent an urgent public health threat, and the need for new rapid methods to detect these organisms has been widely recognized. CPOs carrying the Klebsiella pneumoniae carbapenemase (bla KPC ) gene have caused outbreaks globally with substantial attributable mortality. Here we describe the validation of a rapid MS method for the direct detection of unique tryptic peptides of the KPC protein in clinical bacterial isolates with an isolate-to-result time of less than 90 minutes. Using a genoproteomic discovery approach that combines theoretical peptidome analysis and liquid chromatography tandem MS (LC-MS/MS), we selected three high abundance peptide markers of the KPC protein that can be robustly detected following rapid tryptic digestion. Protein BLAST analysis confirmed that the chosen peptide markers were unique to KPC. A blinded validation set containing 20 KPC-positive and 80 KPC-negative clinical isolates, performed in triplicate (300 runs) demonstrated 100% sensitivity and 100% specificity (60/60 positive identifications, 240/240 negative identifications) using defined rules for positive calls. The most robust tryptic peptide marker in the validation was LTLGSALAAPQR. The peptide discovery and detection methods validated here are general and should be broadly applicable to allow the direct and rapid detection of other resistance determinants. PMID- 28566734 TI - Quantum realization of the bilinear interpolation method for NEQR. AB - In recent years, quantum image processing is one of the most active fields in quantum computation and quantum information. Image scaling as a kind of image geometric transformation has been widely studied and applied in the classical image processing, however, the quantum version of which does not exist. This paper is concerned with the feasibility of the classical bilinear interpolation based on novel enhanced quantum image representation (NEQR). Firstly, the feasibility of the bilinear interpolation for NEQR is proven. Then the concrete quantum circuits of the bilinear interpolation including scaling up and scaling down for NEQR are given by using the multiply Control-Not operation, special adding one operation, the reverse parallel adder, parallel subtractor, multiplier and division operations. Finally, the complexity analysis of the quantum network circuit based on the basic quantum gates is deduced. Simulation result shows that the scaled-up image using bilinear interpolation is clearer and less distorted than nearest interpolation. PMID- 28566733 TI - A Benzothiazole Derivative (5g) Induces DNA Damage And Potent G2/M Arrest In Cancer Cells. AB - Chemically synthesized small molecules play important role in anticancer therapy. Several chemical compounds have been reported to damage the DNA, either directly or indirectly slowing down the cancer cell progression by causing a cell cycle arrest. Direct or indirect reactive oxygen species formation causes DNA damage leading to cell cycle arrest and subsequent cell death. Therefore, identification of chemically synthesized compounds with anticancer potential is important. Here we investigate the effect of benzothiazole derivative (5g) for its ability to inhibit cell proliferation in different cancer models. Interestingly, 5g interfered with cell proliferation in both, cell lines and tumor cells leading to significant G2/M arrest. 5g treatment resulted in elevated levels of ROS and subsequently, DNA double-strand breaks (DSBs) explaining observed G2/M arrest. Consistently, we observed deregulation of many cell cycle associated proteins such as CDK1, BCL2 and their phosphorylated form, CyclinB1, CDC25c etc. Besides, 5g treatment led to decreased levels of mitochondrial membrane potential and activation of apoptosis. Interestingly, 5g administration inhibited tumor growth in mice without significant side effects. Thus, our study identifies 5g as a potent biochemical inhibitor to induce G2/M phase arrest of the cell cycle, and demonstrates its anticancer properties both ex vivo and in vivo. PMID- 28566735 TI - Interaction processes of ciprofloxacin with graphene oxide and reduced graphene oxide in the presence of montmorillonite in simulated gastrointestinal fluids. AB - This study investigated the interaction processes of ciprofloxacin (CIP) with graphene oxide (GO) and reduced GO (rGO) in presence of montmorillonite (Mont) in simulated gastrointestinal fluids. The order of CIP adsorption affinity was rGO+Mont > GO+Mont > rGO+Mont+pepsin > rGO > GO+Mont+pepsin > Mont > Mont+pepsin > GO > rGO+pepsin > GO+pepsin in simulated gastric fluid. Mont enhanced the adsorption of CIP on GO and rGO due to hydrated Si species coating on GO and rGO in the simulated gastric fluid. Meanwhile, pi-pi interaction between CIP and graphene caused the great shift of two cyclopropyl CH2 and one cyclopropyl in CIP molecules. And GO, rGO, and Mont interacted mainly with CIP by COOH groups. CIP and pepsin molecules could intercalate and increase the basal spacing of Mont as well. After the various interaction systems of adsorbent-adsorbate transferring to the simulated intestinal fluid, CIP was continuously adsorbed by GO and rGO. In addition, adsorbed CIP was released from Mont into the solution through electrostatic repulsion. The decrease ratio of CIP was the lowest in the GO/rGO+Mont+pepsin systems. Therefore, the mixture of Mont and GO/rGO decreased the CIP concentration in gastrointestinal fluid to weaken further antibiotic activity of CIP. PMID- 28566736 TI - Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-kappaB signaling. AB - The pathogenesis of chronic lymphocytic leukemia (CLL) has been linked to constitutive NF-kappaB activation but the underlying mechanisms are poorly understood. Here we show that alternative splicing of the negative regulator of NF-kappaB and tumor suppressor gene CYLD regulates the pool of CD5+ B cells through sustained canonical NF-kappaB signaling. Reinforced canonical NF-kappaB activity leads to the development of B1 cell-associated tumor formation in aging mice by promoting survival and proliferation of CD5+ B cells, highly reminiscent of human B-CLL. We show that a substantial number of CLL patient samples express sCYLD, strongly implicating a role for it in human B-CLL. We propose that our new CLL-like mouse model represents an appropriate tool for studying ubiquitination driven canonical NF-kappaB activation in CLL. Thus, inhibition of alternative splicing of this negative regulator is essential for preventing NF-kappaB-driven clonal CD5+ B-cell expansion and ultimately CLL-like disease. PMID- 28566737 TI - Sex-specific cardiopulmonary exercise testing parameters as predictors in patients with idiopathic pulmonary arterial hypertension. AB - Cardiopulmonary exercise testing (CPET) has been used for prognosis in idiopathic pulmonary arterial hypertension (IPAH). We explored whether sex differences had an impact on prognostic assessments of CPET in IPAH. Data were retrieved from 21 male and 36 female incident IPAH patients who underwent both right heart catheterization and CPET from 2010 to 2016 at Shanghai Pulmonary Hospital. Cox proportional hazards analysis was used to assess the prognostic value of CPET. The mean duration of follow-up was 22+/-15 months. Nine men and 15 women had an event. The differences in clinical parameters in the whole population were not the same as the inter-subgroup differences. Event-free women had significantly higher cardiac output, lower pulmonary vascular resistance and percentage of predicted FVC compared with event men (all P<0.05). Event-free men had significantly higher end-tidal partial pressure of CO2 (PETCO2) at anaerobic threshold (AT), peak workload, PETCO2, maximum oxygen consumption (VO2)/minute ventilation (VE), and oxygen uptake efficiency slope and lower end-tidal partial pressure of O2 (PETO2) at AT, peak PETO2, and lowest VE/VCO2 compared with event men. Event-free women had dramatically higher peak VO2, VCO2, VE and O2 pulse than event women (all P<0.05). Peak PETCO2 was the independent predictor of event free survival in all patients and males, whereas peak O2 pulse was the independent predictor of event-free survival in females. Men with peak PETCO2?20.50 mm Hg, women with peak O2 pulse ?6.25 ml per beat and all patients with peak PETCO2?27.03 mm Hg had significantly better event-free survival. Sex specific CPET parameters are predictors of poor outcomes. Decreased peak PETCO2 in men and peak O2 pulse in women were associated with lower event-free survival in IPAH. PMID- 28566738 TI - Structural insights into the elevator-like mechanism of the sodium/citrate symporter CitS. AB - The sodium-dependent citrate transporter of Klebsiella pneumoniae (KpCitS) belongs to the 2-hydroxycarboxylate transporter (2-HCT) family and allows the cell to use citrate as sole carbon and energy source in anaerobic conditions. Here we present crystal structures of KpCitS in citrate-bound outward-facing, citrate-bound asymmetric, and citrate-free inward-facing state. The structures reveal that the KpCitS dimerization domain remains stationary throughout the transport cycle due to a hydrogen bond network as well as extensive hydrophobic interactions. In contrast, its transport domain undergoes a ~35 degrees rigid body rotation and a ~17 A translocation perpendicular to the membrane to expose the substrate-binding site alternately to either side of the membrane. Furthermore, homology models of two other 2-HCT proteins based on the KpCitS structure offer structural insights into their differences in substrate specificity at a molecular level. On the basis of our results and previous biochemical data, we propose that the activity of the 2-HCT CitS involves an elevator-like movement in which the transport domain itself traverses the lipid bilayer, carrying the substrate into the cell in a sodium-dependent manner. PMID- 28566739 TI - Structural Color Filters Enabled by a Dielectric Metasurface Incorporating Hydrogenated Amorphous Silicon Nanodisks. AB - It is advantageous to construct a dielectric metasurface in silicon due to its compatibility with cost-effective, mature processes for complementary metal-oxide semiconductor devices. However, high-quality crystalline-silicon films are difficult to grow on foreign substrates. In this work, we propose and realize highly efficient structural color filters based on a dielectric metasurface exploiting hydrogenated amorphous silicon (a-Si:H), known to be lossy in the visible regime. The metasurface is comprised of an array of a-Si:H nanodisks embedded in a polymer, providing a homogeneously planarized surface that is crucial for practical applications. The a-Si:H nanodisk element is deemed to individually support an electric dipole (ED) and magnetic dipole (MD) resonance via Mie scattering, thereby leading to wavelength-dependent filtering characteristics. The ED and MD can be precisely identified by observing the resonant field profiles with the assistance of finite-difference time-domain simulations. The completed color filters provide a high transmission of around 90% in the off-resonance band longer than their resonant wavelengths, exhibiting vivid subtractive colors. A wide range of colors can be facilitated by tuning the resonance by adjusting the structural parameters like the period and diameter of the a-Si:H nanodisk. The proposed devices will be actively utilized to implement color displays, imaging devices, and photorealistic color printing. PMID- 28566740 TI - Quaternary fluvial terraces of the Tiber Valley: geochronologic and geometric constraints on the back-arc magmatism-related uplift in central Italy. AB - Through a geomorphological study relying on statistically assessed classes of hilltop elevations, we reconstruct a suite of paleo-surfaces along the Tiber River Valley north of Rome that we identify as fluvial terraces formed by interplay between global sea-level fluctuations and regional upift. Using biostratigraphic constraints provided by marine through continental deposits of Santernian age, we recognize the oldest terrace in this area, corresponding to an early coastal plain of late Santernian-Emilian age. By assuming the simple chronological principle of a staircase geometry we correlate the sea-level highstands of MIS 21 through MIS 5 with the lowest eight paleo-surfaces. By plotting against time the cumulated terrace elevations and the average elevation of the Santernian coastline in the investigated area, we detect rates of uplift during the last 1.8 Ma. Two major pulses of uplift are recognized 0.86 through 0.5 Ma, and 0.25 Ma through the Present, which are interpreted as driven by the subduction process and uprising of metasomatized magma bodies on the Tyrrhenian Sea Margin of central Italy, superimposied on a smaller isostatic component of uplift. PMID- 28566741 TI - Endometriosis foci differentiation by rapid lipid profiling using tissue spray ionization and high resolution mass spectrometry. AB - Obtaining fast screening information on molecular composition of a tissue sample is of great importance for a disease biomarkers search and for online surgery control. In this study, high resolution mass spectrometry analysis of eutopic and ectopic endometrium tissues (90 samples) is done using direct tissue spray mass spectrometry in both positive and negative ion modes. The most abundant peaks in the both ion modes are those corresponding to lipids. Species of three lipid classes are observed, phosphatidylcholines (PC), sphingomyelins (SM) and phosphoethanolamines (PE). Direct tissue analysis gives mainly information on PC and SM lipids (29 species) in positive ion mode and PC, SM and PE lipids (50 species) in negative ion mode which gives complementary data for endometriosis foci differentiation. The biggest differences were found for phospholipids with polyunsaturated acyls and alkils. Although, tissue spray shows itself as appropriate tool for tissue investigation, caution should be paid to the interpretation of mass spectra because of their higher complexity with more possible adducts formation and multiple interferences must be taken into account. The present work extends the application of direct tissue analysis for the rapid differentiation between endometriotic tissues of different foci. PMID- 28566742 TI - Dynamic control of coherent pulses via destructive interference in graphene under Landau quantization. AB - We analyze the destructive interference in monolayer graphene under Landau quantization in a time-dependent way by using the Bloch-Maxwell formalism. Based on this analysis, we investigate the dynamics control of an infrared probe and a terahertz (THz) switch pulses in graphene. In presence of the THz switch pulse, the destructive interference take places and can be optimized so that the monolayer graphene is completely transparent to the infrared probe pulse. In absence of the THz switch pulse, however, the infrared probe pulse is absorbed due to such a interference does not take place. Furthermore, we provide a clear physics insight of this destructive interference by using the classical dressed state theory. Conversely, the present model may be rendered either absorbing or transparent to the THz switch pulse. By choosing appropriate wave form of the probe and switch pulses, we show that both infrared probe and THz switch pulses exhibit the steplike transitions between absorption and transparency. Such steplike transitions can be used to devise a versatile quantum interference-based solid-state optical switching with distinct wave-lengths for optical communication devices. PMID- 28566743 TI - Pharmacokinetic Evaluation of Empagliflozin in Healthy Egyptian Volunteers Using LC-MS/MS and Comparison with Other Ethnic Populations. AB - The present study considered the pharmacokinetic evaluation of empagliflozin after administration to Egyptian volunteers, and the results were compared with other ethnic populations. The FDA recognizes that standard methods of defining racial subgroups are necessary to compare results across pharmacokinetic studies and to assess potential subgroup differences. The design of the study was as an open labeled, randomized, one treatment, one period, single dose pharmacokinetic study. The main pharmacokinetic parameters estimated were Cmax, Tmax, t1/2, elimination rate constant, AUC0-t and AUC0-inf. The insignificant difference in pharmacokinetic parameters between Egyptians and white German subjects suggests that no dose adjustment should be considered with administration of 25 mg empagliflozin to Egyptian population. A new LC-MS/MS method was developed and validated, allowing sensitive estimation of empagliflozin (25-600 ng mL-1) in human plasma using dapagliflozin as an internal standard (IS). The method was applied successfully on the underlying pharmacokinetic study with enhanced sample preparation that involved liquid-liquid extraction. Multiple Reaction Monitoring (MRM) of the transition pairs of m/z 449.01 to 371.21 for empagliflozin and m/z 407.00 to 328.81 for dapagliflozin (IS) was employed utilizing negative mode Electro Spray Ionization (ESI). The validated LC-MS/MS method is suitable for further toxicodynamic and bioequivalence studies. PMID- 28566744 TI - MRI tracking of autologous pancreatic progenitor-derived insulin-producing cells in monkeys. AB - Insulin-producing cells (IPCs) derived from a patient's own stem cells offer great potential for autologous transplantation in diabetic patients. However, the limited survival of engrafted cells remains a bottleneck in the application of this strategy. The present study aimed to investigate whether nanoparticle-based magnetic resonance (MR) tracking can be used to detect the loss of grafted stem cell-derived IPCs in a sensitive and timely manner in a diabetic monkey model. Pancreatic progenitor cells (PPCs) were isolated from diabetic monkeys and labeled with superparamagnetic iron oxide nanoparticles (SPIONs). The SPION labeled cells presented as hypointense signals on MR imaging (MRI). The labeling procedure did not affect the viability or IPC differentiation of PPCs. Importantly, the total area of the hypointense signal caused by SPION-labeled IPCs on liver MRI decreased before the decline in C-peptide levels after autotransplantation. Histological analysis revealed no detectable immune response to the grafts and many surviving insulin- and Prussian blue-positive cell clusters on liver sections at one year post-transplantation. Collectively, this study demonstrates that SPIO nanoparticles can be used to label stem cells for noninvasive, sensitive, longitudinal monitoring of stem cell-derived IPCs in large animal models using a conventional MR imager. PMID- 28566745 TI - Serum miRNA signature diagnoses and discriminates murine colitis subtypes and predicts ulcerative colitis in humans. AB - Inflammatory bowel disease (IBD) is difficult to diagnose due to nonspecific and variable symptoms, and lack of reliable diagnostic tests. Current methods are invasive, non-sensitive, non-predictive, and do not easily discriminate between its two main forms. Consequently, there remains a great need for reliable serum markers for IBD. Here, using a longitudinal study of various mouse models of colitis, we identified a serum miRNA signature that indicated the development of colitis and discriminated between inflammations of various origins (colitis from arthritis). Unlike the existing biomarkers, the newly identified signature also serves to distinguish individuals at risk, predict the type of inflammation, and evaluate the response to therapeutics. Moreover, the miRNA signature identified in mice predicted ulcerative colitis with 83.3% accuracy. In future, the signature identified herein could play a central role in monitoring inflammatory disorders and therapeutic responses in patients, thereby paving the way for personalized medicine. PMID- 28566746 TI - Thermally evaporated indium-free, transparent, flexible SnO2/AgPdCu/SnO2 electrodes for flexible and transparent thin film heaters. AB - We investigated the characteristics of themally evaporated SnO2/Ag-Pd-Cu (APC)/SnO2 multilayer films for applications as damage-free, indium-free, flexible, and transparent electrodes for high performance flexible and transparent thin film heaters (TFHs). The top and bottom SnO2 layers and APC interlayer were prepared by a multi-source evaporation process, and the effect of the thickness of each layer on the resistivity, optical transmittance, and mechanical flexibility of the SnO2/APC/SnO2 electrodes was investigated in detail. Based on a figure of merit value, we obtained a SnO2/APC/SnO2 electrode with a low sheet resistance of 9.42 Ohm/square and a high optical transmittance of 91.14%. In addition, we examined the mechanical properties of the SnO2/APC/SnO2 electrode using various bending tests such as inner bending, outer bending, dynamic fatigue, and a twisting test. By comparing the crack shape of the SnO2/APC/SnO2 electrode bent beyond the critical bending radius (2~3 mm), we suggest a possible crack formation mechanism for the SnO2/APC/SnO2 electrodes. Furthermore, we evaluated the feasibility of the SnO2/APC/SnO2 electrodes for flexible and transparent TFHs. By correlating the sheet resistance of the SnO2/APC/SnO2 electrode and the performance of TFHs, we show the importance of transparent electrodes for high performance flexible and transparent TFHs. PMID- 28566747 TI - Novel Locally Active Estrogens Accelerate Cutaneous Wound Healing-Part 2. AB - Estrogen deprivation is associated with delayed healing, while estrogen replacement therapy (ERT) accelerates acute wound healing and protects against development of chronic wounds. However, current estrogenic molecules have undesired systemic effects, thus the aim of our studies is to generate new molecules for topic administration that are devoid of systemic effects. Following a preliminary study, the new 17beta-estradiol derivatives 1 were synthesized. The estrogenic activity of these novel compounds was evaluated in vitro using the cell line ERE-Luc B17 stably transfected with an ERE-Luc reporter. Among the 17beta-estradiol derivatives synthesized, compounds 1e and 1f showed the highest transactivation potency and were therefore selected for the study of their systemic estrogenic activity. The study of these compounds in the ERE-Luc mouse model demonstrated that both compounds lack systemic effects when administered in the wound area. Furthermore, wound-healing experiments showed that 1e displays a significant regenerative and anti-inflammatory activity. It is therefore confirmed that this class of compounds are suitable for topical administration and have a clear beneficial effect on wound healing. PMID- 28566748 TI - A pathway for protective quenching in antenna proteins of Photosystem II. AB - Photosynthesis is common in nature, converting sunlight energy into proton motive force and reducing power. The increased spectral range absorption of light exerted by pigments (i.e. chlorophylls, Chls) within Light Harvesting Complexes (LHCs) proves an important advantage under low light conditions. However, in the exposure to excess light, oxidative damages and ultimately cell death can occur. A down-regulatory mechanism, thus, has been evolved (non-photochemical quenching, NPQ). The mechanistic details of its major component (qE) are missing at the atomic scale. The research herein, initiates on solid evidence from the current NPQ state of the art, and reveals a detailed atomistic view by large scale Molecular Dynamics, Metadynamics and ab initio Simulations. The results demonstrate a complete picture of an elaborate common molecular design. All probed antenna proteins (major LHCII from spinach-pea, CP29 from spinach) show striking plasticity in helix-D, under NPQ conditions. This induces changes in Qy bands in excitation and absorption spectra of the near-by pigment pair (Chl613 614) that could emerge as a new quenching site. Zeaxanthin enhances this plasticity (and possibly the quenching) even at milder NPQ conditions. PMID- 28566749 TI - Longitudinal associations between television in the bedroom and body fatness in a UK cohort study. AB - OBJECTIVE: To assess longitudinal associations between screen-based media use (television (TV) and computer hours, having a TV in the bedroom) and body fatness among UK children. METHODS: Participants were 12 556 children from the UK Millennium Cohort Study who were followed from age 7 to age 11 years. Associations were assessed between screen-based media use and the following outcomes: body mass index (BMI), fat mass index (FMI), and overweight. RESULTS: In fully adjusted models, having a bedroom TV at age 7 years was associated with significantly higher BMI and FMI (excess BMI for boys=0.29, 95% confidence interval (CI) 0.06-0.52; excess BMI for girls=0.57, 95% CI 0.31-0.84; excess FMI for boys=0.20, 95% CI 0.04-0.37; excess FMI for girls=0.39, 95% CI 0.21-0.57) and increased risk of being overweight (relative risk (RR) for boys=1.21, 95% CI 1.07 1.36; RR for girls=1.31, 95% CI 1.15-1.48) at age 11 years, compared with having no bedroom TV. Hours spent watching TV or digital versatile disks were associated with increased risk of overweight among girls only. Computer use at age 7 years was not related to later body fatness for either gender. CONCLUSION: Having a TV in the child's bedroom was an independent risk factor for overweight and increased body fatness in this nationally representative sample of UK children. Childhood obesity prevention strategies should consider TVs in children's bedrooms as a risk factor for obesity. PMID- 28566750 TI - Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia. AB - Episodic ataxia is an autosomal dominant ion channel disorder characterized by episodes of imbalance and incoordination. The disease is genetically heterogeneous and is classified as episodic ataxia type 2 (EA2) when it is caused by a mutation in the CACNA1A gene, encoding the alpha1A subunit of the P/Q-type voltage-gated calcium channel Cav2.1. The vast majority of EA2 disease-causing variants are loss-of-function (LoF) point changes leading to decreased channel currents. CACNA1A exonic deletions have also been reported in EA2 using quantitative approaches. We performed a mutational screening of the CACNA1A gene, including the promoter and 3'UTR regions, in 49 unrelated patients diagnosed with episodic ataxia. When pathogenic variants were not found by sequencing, we performed a copy number variant (CNV) analysis to screen for duplications or deletions. Overall, sequencing screening allowed identification of six different point variants (three nonsense and three missense changes) and two coding indels, one of them found in two unrelated patients. Additionally, CNV analysis identified a deletion in a patient spanning exon 35 as a result of a recombination event between flanking intronic Alu sequences. This study allowed identification of potentially pathogenic alterations in our sample, five of them novel, which cover 20% of the patients (10/49). Our data suggest that most of these variants are disease-causing, although functional studies are required. PMID- 28566751 TI - Establishment of the model system between phytochemicals and gene expression profiles in Macrosclereid cells of Medicago truncatula. AB - Macrosclereid cells, which are a layer in the seed coat of Medicago truncatula, accumulate large amounts of phytochemicals during their development. But little is known about the complex and dynamic changes during macrosclereid cell development. To characterize the phytochemicals and the related gene expression during the development of M. truncatula macrosclereid cells, a high performance liquid chromatography-mass spectrometry (HPLC-MS) assay and microarray study were conducted on transcriptome changes from macrosclereid cell during seed development. A total of 16 flavonoids by HPLC-MS and 4861 genes exhibited significant differences at transcript levels by microarray analysis were identified for macrosclerid cells at six different time points during seed development. 815 abiotic and biotic stress genes, 223 transcriptional factors (TFs), and 155 annotated transporter proteins exhibited differential expression during the development of macrosclereid cells. A total of 102 genes were identified as involved in flavonoid biosynthesis, phenypropanoid biosynthesis, and flavone and flavonol biosynthesis. We performed a weighted gene co-regulatory network (WGCNA) to analyze the gene-flavonoid association and rebuilt the gene regulatory network during macrosclereid cell development. Our studies revealed that macrosclereid cells are, beside as the first barrier of defense against diseases, an excellent model system to investigate the regulatory network that governs flavonoid biosynthesis. PMID- 28566752 TI - Metabolomics biomarkers to predict acamprosate treatment response in alcohol dependent subjects. AB - Precision medicine for alcohol use disorder (AUD) allows optimal treatment of the right patient with the right drug at the right time. Here, we generated multivariable models incorporating clinical information and serum metabolite levels to predict acamprosate treatment response. The sample of 120 patients was randomly split into a training set (n = 80) and test set (n = 40) five independent times. Treatment response was defined as complete abstinence (no alcohol consumption during 3 months of acamprosate treatment) while nonresponse was defined as any alcohol consumption during this period. In each of the five training sets, we built a predictive model using a least absolute shrinkage and section operator (LASSO) penalized selection method and then evaluated the predictive performance of each model in the corresponding test set. The models predicted acamprosate treatment response with a mean sensitivity and specificity in the test sets of 0.83 and 0.31, respectively, suggesting our model performed well at predicting responders, but not non-responders (i.e. many non-responders were predicted to respond). Studies with larger sample sizes and additional biomarkers will expand the clinical utility of predictive algorithms for pharmaceutical response in AUD. PMID- 28566753 TI - An integrated analysis revealed different microRNA-mRNA profiles during skeletal muscle development between Landrace and Lantang pigs. AB - Pigs supply vital dietary proteins for human consumption, and their economic value depends largely on muscle production. MicroRNAs are known to play important roles in skeletal muscle development. However, their relationship to distinct muscle production between pig breeds remains unknown. Here, we performed an integrated analysis of microRNA-mRNA expression profiles for Landrace (LR, lean) pigs and the Chinese indigenous Lantang pig (LT, lard-type) during 8 stages of skeletal muscle developmental, including at 35, 49, 63, 77 dpc (days post coitum) and 2, 28, 90, 180 dpn (days postnatal). As differentially expressed-miRNA expression profiles can be well classified into two clusters by PCA analysis, we grouped the embryonic stages as G1 and the postnatal stages as G2. A total of 203 genes were predicted miRNA targets, and a STEM analysis showed distinct expression patterns between G1 and G2 in both breeds based on their transcriptomic data. Furthermore, a STRING analysis predicted interactions between 22 genes and 35 miRNAs, including some crucial myogenic factors and myofibrillar genes. Thus, it can be reasonably speculated that myogenic miRNAs may regulate myofibrillar genes in myofiber formation during embryonic stages and muscle hypertrophy during postnatal stages, leading to distinct differences in muscle production between breeds. PMID- 28566754 TI - Stroke triggers nigrostriatal plasticity and increases alcohol consumption in rats. AB - Excessive alcohol consumption is a known risk factor for stroke, but the effect of stroke on alcohol intake is unknown. The dorsomedial striatum (DMS) and midbrain areas of the nigrostriatal circuit are critically associated to stroke and alcohol addiction. Here we sought to explore the influence of stroke on alcohol consumption and to uncover the underlying nigrostriatal mechanism. Rats were trained to consume alcohol using a two-bottle choice or operant self administration procedure. Retrograde beads were infused into the DMS or midbrain to label specific neuronal types, and ischemic stroke was induced in the dorsolateral striatum (DLS). Slice electrophysiology was employed to measure excitability and synaptic transmission in DMS and midbrain neurons. We found that ischemic stroke-induced DLS infarction produced significant increases in alcohol preference, operant self-administration, and relapse. These increases were accompanied by enhanced excitability of DMS and midbrain neurons. In addition, glutamatergic inputs onto DMS D1-neurons was potentiated, whereas GABAergic inputs onto DMS-projecting midbrain dopaminergic neurons was suppressed. Importantly, systemic inhibition of dopamine D1 receptors attenuated the stroke induced increase in operant alcohol self-administration. Our results suggest that the stroke-induced DLS infarction evoked abnormal plasticity in nigrostriatal dopaminergic neurons and DMS D1-neurons, contributing to increased post-stroke alcohol-seeking and relapse. PMID- 28566755 TI - Merlin is required for coordinating proliferation of two stem cell lineages in the Drosophila testis. AB - Although the mechanisms that balance self-renewal and differentiation of a stem cell lineage have been extensively studied, it remains poorly understood how tissues that contain multiple stem cell lineages maintain balanced proliferation among distinct lineages: when stem cells of a particular lineage proliferate, how do the other lineages respond to maintain the correct ratio of cells among linages? Here, we show that Merlin (Mer), a homolog of the human tumor suppressor neurofibromatosis 2, is required to coordinate proliferation of germline stem cells (GSCs) and somatic cyst stem cells (CySCs) in the Drosophila testis. Mer mutant CySCs fail to coordinate their proliferation with that of GSCs in multiple settings, and can be triggered to undergo tumorous overproliferation. Mer executes its function by stabilizing adherens junctions. Given the known role of Mer in contact-dependent inhibition of proliferation, we propose that the proliferation of CySCs are regulated by crowdedness, or confluency, of cells in their lineage with respect to that of germline, thereby coordinating the proliferation of two lineages. PMID- 28566756 TI - Layer-dependent semiconductor-metal transition of SnO/Si(001) heterostructure and device application. AB - As the downscaling of electronic devices continues, the problems of leakage currents and heat dissipation become more and more serious. To address these issues, new materials and new structures are explored. Here, we propose an interesting heterostructure made of ultrathin SnO layers on Si(001) surface. Our first-principle calculations show that a single layer of SnO on Si(001) surface is a semiconductor, but a bilayer SnO on the same surface is metallic. This metal semiconductor dichotomy allows construction of single-2D-material-based electronic devices with low contact resistance and low leakage currents. In particular, due to the interaction between Sn and the Si substrate, the semiconducting monolayer-SnO/Si(001) has a highly anisotropic band structure with a much lighter hole effective mass along one direction than that of Si and most other 2D materials, indicating a high carrier mobility. Furthermore, by combining density functional theory and nonequilibrium Green's function method, we directly investigate the transport characteristics of a field effect transistor based on the proposed heterostructures, which shows very low contact resistance, negligible leakage current, and easy gate control at a compact channel length. PMID- 28566757 TI - Association of body mass index with mortality and functional outcome after acute ischemic stroke. AB - The relation between obesity and stroke outcome has been disputed. This study was aimed to determine the association of body mass index (BMI) with mortality and functional outcome in patients with acute ischemic stroke. Data were from a national, multi-centre, prospective, hospital-based register: the ChinaQUEST (Quality Evaluation of Stroke Care and Treatment) study. Of 4782 acute ischemic stroke patients, 282 were underweight (BMI < 18.5 kg/m2), 2306 were normal-weight (BMI 18.5 to < 24 kg/m2), 1677 were overweight (BMI 24 to <28 kg/m2) and 517 were obese (BMI >= 28 kg/m2). The risks of death at 12 months and death or high dependency at 3 and 12 months in overweight (HR: 0.97, 95% CI: 0.78-1.20; OR: 0.93, 95% CI: 0.80-1.09; OR: 0.95, 95% CI: 0.81-1.12) and obese patients (HR: 1.07, 95% CI: 0.78-1.48; OR: 0.96, 95% CI: 0.75-1.22; OR: 1.06, 95% CI: 0.83 1.35) did not differ from normal-weight patients significantly after adjusting for baseline characteristics. Underweight patients had significantly increased risks of these three outcomes. In ischemic stroke patients, being overweight or obese was not associated with decreased mortality or better functional recovery but being underweight predicted unfavourable outcomes. PMID- 28566758 TI - Dielectric meta-atom with tunable resonant frequency temperature coefficient. AB - In this paper, we present a proof-of-concept of a new approach to achieving tailored resonant frequency temperature coefficients in dielectric meta-atoms. The technique involves introducing a thermally expanding or contracting material joining the active high permittivity dielectric absorbers. Both simulation and experiment show that by careful design of the element size and appropriate choice of thermomechanical intermediate layer material, increased or decreased resonant frequency shift temperature sensitivity is possible. Once the active dielectric material is chosen, and a meta-atom design determined, we show the resonant frequency shift depends on the thermal expansion coefficient of the intermediate layer. This work demonstrates the feasibility of manipulating the blue or red shift of metamaterial devices by introducing temperature responsive intermediate layers into meta-atoms. PMID- 28566759 TI - Sex-specific responses to winter flooding, spring waterlogging and post-flooding recovery in Populus deltoides. AB - Winter flooding events are common in some rivers and streams due to dam constructions, and flooding and waterlogging inhibit the growth of trees in riparian zones. This study investigated sex-specific morphological, physiological and ultrastructural responses to various durations of winter flooding and spring waterlogging stresses, and post-flooding recovery characteristics in Populus deltoides. There were no significant differences in the morphological, ultrastructural and the majority of physiological traits in trees subjected to medium and severe winter flooding stresses, suggesting that males and females of P. deltoides were winter flooding tolerant, and insensitive to winter flooding duration. Males were more tolerant to winter flooding stress in terms of photosynthesis and chlorophyll fluorescence than females. Females displayed greater oxidative damage due to flooding stress than males. Males developed more efficient antioxidant enzymatic systems to control reactive oxygen species. Both sexes had similarly strong post-flooding recovery capabilities in terms of plant growth, and physiological and ultrastructural parameters. However, Males had better recovery capabilities in terms of pigment content. These results increase the understanding of poplars's adaptation to winter flooding stress. They also elucidate sex-specific differences in response to flooding stress during the dormant season, and during post-flooding recovery periods. PMID- 28566760 TI - Determinants of Quantitative Optical Coherence Tomography Angiography Metrics in Patients with Diabetes. AB - Early microvascular damage in diabetes (e.g. capillary nonperfusion and ischemia) can now be assessed and quantified with optical coherence tomography-angiography (OCT-A). The morphology of vascular tissue is indeed affected by different factors; however, there is a paucity of data examining whether OCT-A metrics are influenced by ocular, systemic and demographic variables in subjects with diabetes. We conducted an observational cross-sectional study and included 434 eyes from 286 patients with diabetes. Foveal avascular zone (FAZ) area, FAZ circularity, total and parafoveal vessel density (VD), fractal dimension (FD), and vessel diameter index (VDI) from the superficial capillary plexus OCT angiogram were measured by a customized automated image analysis program. We found that diabetic retinopathy (DR) severity was associated with increased FAZ area, decreased FAZ circularity, lower VD, lower FD, and increased VDI. Enlarged FAZ area was correlated with shorter axial length and thinner central subfield macular thickness. Decreased FAZ circularity was correlated with a reduction in visual function. Decreased VD was correlated with thinner macular ganglion-cell inner plexiform layer. Increased VDI was correlated with higher fasting glucose level. We concluded that the effects of ocular and systemic factors in diabetics should be taken into consideration when assessing microvascular alterations via OCT-A. PMID- 28566761 TI - Proof-of-Concept Gene Editing for the Murine Model of Inducible Arginase-1 Deficiency. AB - Arginase-1 deficiency in humans is a rare genetic disorder of metabolism resulting from a loss of arginase-1, leading to impaired ureagenesis, hyperargininemia and neurological deficits. Previously, we generated a tamoxifen inducible arginase-1 deficient mouse model harboring a deletion of Arg1 exons 7 and 8 that leads to similar biochemical defects, along with a wasting phenotype and death within two weeks. Here, we report a strategy utilizing the Clustered, Regularly Interspaced, Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system in conjunction with piggyBac technology to target and reincorporate exons 7 and 8 at the specific Arg1 locus in attempts to restore the function of arginase-1 in induced pluripotent stem cell (iPSC)-derived hepatocyte like cells (iHLCs) and macrophages in vitro. While successful gene targeted repair was achieved, minimal urea cycle function was observed in the targeted iHLCs compared to adult hepatocytes likely due to inadequate maturation of the cells. On the other hand, iPSC-derived macrophages expressed substantial amounts of "repaired" arginase. Our studies provide proof-of-concept for gene-editing at the Arg1 locus and highlight the challenges that lie ahead to restore sufficient liver-based urea cycle function in patients with urea cycle disorders. PMID- 28566763 TI - Analysis of soil water movement inside a footslope and a depression in a karst catchment, Southwest China. AB - Soil water movement is difficult to explain with event-scale approaches, especially in karst regions. This paper focuses on investigating seasonal recharge and mean residence time (MRT) of soil water based on temporal variation of stable isotopes (deltaD and delta18O) and a dispersion model (DM), and discussing their differences along a footslope and a depression in a small karst catchment of southwest China. Temporal variations of the stable isotopes in precipitation and soil water within 0-100 cm profiles were monitored weekly for approximately 43 and 99 weeks. Results show that the seasonal recharge of soil water inside the footslope and the depression were similar, but the vertical flow velocity was higher implying a faster hydrological process in the footslope. The MRT of soil water (2-64 weeks) increased roughly, suggesting decreasing velocity of water displacement with increasing depth. However, the MRT at 60-100 cm depths in the depression (47-64 weeks) was obviously longer than at other sites, revealing more intensive water mixing. Furthermore, a shallower isotopic damping depth was found in the depression, indicating stronger delay and attenuation effects on base flow recharge. These results provide new insights into research on hydrological processes in karst areas. PMID- 28566762 TI - Tracking Real-Time Changes in Working Memory Updating and Gating with the Event Based Eye-Blink Rate. AB - Effective working memory (WM) functioning depends on the gating process that regulates the balance between maintenance and updating of WM. The present study used the event-based eye-blink rate (ebEBR), which presumably reflects phasic striatal dopamine activity, to examine how the cognitive processes of gating and updating separately facilitate flexible updating of WM contents and the potential involvement of dopamine in these processes. Real-time changes in eye blinks were tracked during performance on the reference-back task, in which demands on these two processes were independently manipulated. In all three experiments, trials that required WM updating and trials that required gate switching were both associated with increased ebEBR. These results may support the prefrontal cortex basal ganglia WM model (PBWM) by linking updating and gating to striatal dopaminergic activity. In Experiment 3, the ebEBR was used to determine what triggers gate switching. We found that switching to an updating mode (gate opening) was more stimulus driven and retroactive than switching to a maintenance mode, which was more context driven. Together, these findings show that the ebEBR - an inexpensive, non-invasive, easy-to-use measure - can be used to track changes in WM demands during task performance and, hence, possibly striatal dopamine activity. PMID- 28566764 TI - Difference in Cerebral Circulation Time between Subtypes of Moyamoya Disease and Moyamoya Syndrome. AB - In this study, we evaluated the differences in hemodynamics between hemorrhagic and non-hemorrhagic moyamoya disease (MMD) and moyamoya syndrome (MMS) by measuring cerebral circulation time (CCT). This case-control study included 136 patients with MMD or MMS diagnosed between April 2015 and July 2016 at Beijing Tian Tan Hospital. Each hemisphere was analyzed separately. The difference in clinical, radiological characteristics and CCT between subtypes of MMD and MMS were analyzed statistically. The results showed that total CCT between hemorrhagic and non-hemorrhagic sides was not statistically different (16.55 s vs. 16.06 s, P = 0.562). The cerebral filling circulation time (CFCT) of hemorrhagic sides was significantly shorter than that of non-hemorrhagic sides (4.52 s vs. 5.41 s, P < 0.001), and the cerebral venous circulation time (CVCT) of hemorrhagic sides was significantly longer than that of non-hemorrhagic sides (12.02 s, vs. 10.64 s, P < 0.001). The ratio of CFCT to CVCT (F-V ratio) was inversely correlated with the possibility of hemorrhagic stroke. Therefore, we conclude that the rapid filling and poor venous drainage of cerebral circulation are likely risk factors of hemorrhagic stroke secondary to MMD or MMS. The F-V ratio can be used to identify individuals at high risk of hemorrhagic stroke. PMID- 28566765 TI - All-fiber spatial rotation manipulation for radially asymmetric modes. AB - We propose and experimentally demonstrate spatial rotation manipulation for radially asymmetric modes based on two kinds of polarization maintaining few-mode fibers (PM-FMFs). Theoretical finding shows that due to successful suppression of both polarization and spatial mode coupling, the spatial rotation of radially asymmetric modes has an excellent linear relationship with the twist angle of PM FMF. Both elliptical core and panda type FMFs are fabricated, in order to realize manageable spatial rotation of LP11 mode within +/-360 degrees range. Finally, we characterize individual PM-FMF based spatial orientation rotator and present comprehensive performance comparison between two PM-FMFs in terms of insertion loss, temperature sensitivity, linear polarization maintenance, and mode scalability. PMID- 28566766 TI - Identification of a small molecule that primes the type I interferon response to cytosolic DNA. AB - The type I interferon response plays a pivotal role in host defense against infectious agents and tumors, and promising therapeutic approaches rely on small molecules designed to boost this system. To identify such compounds, we developed a high-throughput screening assay based on HEK-293 cells expressing luciferase under the control of Interferon-Stimulated Response Elements (ISRE). An original library of 10,000 synthetic compounds was screened, and we identified a series of 1H-benzimidazole-4-carboxamide compounds inducing the ISRE promoter sequence, specific cellular Interferon-Stimulated Genes (ISGs), and the phosphorylation of Interferon Regulatory Factor (IRF) 3. ISRE induction by ChX710, a prototypical member of this chemical series, was dependent on the adaptor MAVS and IRF1, but was IRF3 independent. Although it was unable to trigger type I IFN secretion per se, ChX710 efficiently primed cellular response to transfected plasmid DNA as assessed by potent synergistic effects on IFN-beta secretion and ISG expression levels. This cellular response was dependent on STING, a key adaptor involved in the sensing of cytosolic DNA and immune activation by various pathogens, stress signals and tumorigenesis. Our results demonstrate that cellular response to cytosolic DNA can be boosted with a small molecule, and potential applications in antimicrobial and cancer therapies are discussed. PMID- 28566767 TI - Independent effects of ADH1B and ALDH2 common dysfunctional variants on gout risk. AB - Gout is caused by hyperuricemia, with alcohol consumption being an established risk factor. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are crucial enzymes for alcohol metabolism. We recently performed a genome-wide association study of gout and a subsequent fine-mapping study which identified rs671 of ALDH2 as a gout locus. However, the association between gout and common variants of ADH1B has hitherto remained unreported, prompting us to investigate the association between gout and common dysfunctional variants of ADH1B (rs1229984) and ALDH2 (rs671). We used 1,048 clinically defined gout cases and 1,334 controls of Japanese male. The "His carrier" (His/His or His/Arg) of rs1229984 (His48Arg) of ADH1B significantly increased gout risk (P = 4.3 * 10-4, odds ratio = 1.76), as did the "non-Lys carrier (Glu/Glu)" of rs671 (Glu504Lys) of ALDH2. Furthermore, common variants of ADH1B and ALDH2 are independently associated with gout. Our findings likewise suggest that genotyping these variants can be useful for the evaluation of gout risk. PMID- 28566769 TI - A commentary on ANKRD11 variants cause variable clinical features associated with KBG syndrome and Coffin-Siris-like syndrome. PMID- 28566768 TI - Moving towards successful exon-skipping therapy for Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is an X chromosome-linked lethal muscular disorder with progressing muscle wasting and weakness caused by mutations in the gene encoding a subsarcolemmal protein dystrophin. For a long time, there was no effective cure; however, advances in molecular biology have allowed the development of radical treatment approaches. Among them, exon-skipping therapy using antisense oligonucleotides is very promising, because it corrects the reading frame of the dystrophin-encoding gene and restores protein expression, resulting in the conversion of DMD to a clinically milder form, Becker muscular dystrophy (BMD). However, clinical trials in exon-skipping therapy did not provide satisfactory results, which may be attributed to inefficient exon skipping, low expression level of restored dystrophin and inadequate methods of muscle function evaluation. To date, exon-skipping approaches have particularly focused on the correction of the gene-reading frame. However, the problem is that the relationship between the resultant and expected phenotypes in terms of definite symptomatic improvement has not yet been elucidated. In other words, previously conducted clinical trials have not been planned based on the comprehensive assessment of genotype-phenotype relationship in BMD, which demonstrates a broad range of symptom severity depending on the functional activity of the truncated dystrophin. The analysis I present in this review strongly suggests that the development of exon-skipping therapy and its clinical trials should be based on large-cohort studies of BMD. PMID- 28566770 TI - Phylogeny of Y-chromosome haplogroup C3b-F1756, an important paternal lineage in Altaic-speaking populations. AB - In previous studies, a specific paternal lineage with a null value for the Y chromosome short tandem repeat (Y-STR) marker DYS448 was identified as common among Mongolic- and Turkic-speaking populations. This paternal lineage (temporarily named C3*-DYS448del) was determined to be M217+, M93-, P39-, M48-, M407-, and P53.1-, and its origin and phylogeny remain ambiguous. Here, we analyzed Y-chromosome sequences of 10 male that are related this paternal lineage and redefined it as C3b1a1a1a-F1756 (C3b-F1756). We generated a highly revised phylogenetic tree of haplogroup C3b-F1756, including 21 sub-clades and 360 non private Y-chromosome polymorphisms. Additionally, we performed a comprehensive analysis of the C3*-DYS448del lineage in eastern Eurasia, including 18 270 samples from 297 populations. Whole Y-chromosome sequences, Y-STR haplotypes, and frequency data were used to generate a distribution map, a network, and age estimations for lineage C3*-DYS448del and its sub-lineages. Considering the historical records of the studied populations, we propose that two major sub branches of C3b-F1756 may correspond to early expansions of ancestors of modern Mongolic- and Turkic-speaking populations. The large number of newly defined Y chromosome polymorphisms and the revised phylogenetic tree for C3b-F1756 will assist in investigation of the early history of Altaic-speaking populations in the future. PMID- 28566771 TI - The agglomeration, coalescence and sliding of nanoparticles, leading to the rapid sintering of zirconia nanoceramics. AB - Conventional sintering is a time- and energy-consuming process used for the densification of consolidated particles facilitated by atomic diffusion at high temperatures. Nanoparticles, with their increased surface free energy, can promote sintering; however, size reduction also promotes agglomeration, so hampering particle packing and complete densification. Here we show how the ordered agglomeration of zirconia primary crystallites into secondary particle assemblies ensures their homogeneous packing, while also preserving the high surface energy to higher temperatures, increasing the sintering activity. When exposed to intense electromagnetic radiation, providing rapid heating, the assembled crystallites are subjected to further agglomeration, coalescence and sliding, leading to rapid densification in the absence of extensive diffusional processes, cancelling out the grain growth during the initial sintering stages and providing a zirconia nanoceramic in only 2 minutes at 1300 degrees C. PMID- 28566773 TI - [Characteristics of mother-child collaboration at 48 months in two number-related tasks]. AB - Preschoolers' number related skills and maternal guidance used to introduce and foster the acquisition of these skills were examined in 193 48-month-olds. Mother child collaboration was observed during two number-related tasks: a dot-to-dot drawing task and a matching number representations task. Patterns of responsibility sharing in task resolution were coded from videos, using a cross classification strategy adapted from Parent et al. (2000). Using mother-child interactions as a means to assess early numeracy skills, we replicated past findings obtained when child numeracy skills were assessed autonomously (Baroody & Dowker, 2003; Sinclair, 1988). Results also indicate that mothers adjust their support and the demands of the task to meet their child's skill level. In addition, promoting an enjoyable affective climate and fostering child motivation to complete the task appeared to be a predominant aspect of maternal guidance. Together, these results support the relevance of evaluating children's numeracy skills in a social context and emphasize the importance of taking into account affective dimensions of mother-child interactions when evaluating the development of new cognitive skills. PMID- 28566772 TI - Serum extracellular vesicle depletion processes affect release and infectivity of HIV-1 in culture. AB - Extracellular vesicles (EVs) are involved in intercellular communication and affect processes including immune and antiviral responses. Blood serum, a common cell culture medium component, is replete with EVs and must be depleted prior to EV-related experiments. The extent to which depletion processes deplete non-EV particles is incompletely understood, but depleted serum is associated with reduced viability and growth in cell culture. Here, we examined whether serum depleted by two methods affected HIV-1 replication. In cell lines, including HIV 1 latency models, increased HIV-1 production was observed, along with changes in cell behavior and viability. Add-back of ultracentrifuge pellets (enriched in EVs but possibly other particles) rescued baseline HIV-1 production. Primary cells were less sensitive to serum depletion processes. Virus produced under processed serum conditions was more infectious. Finally, changes in cellular metabolism, surface markers, and gene expression, but not miRNA profiles, were associated with depleted serum culture. In conclusion, depleted serum conditions have a substantial effect on HIV-1 production and infectivity. Dependence of cell cultures on "whole serum" must be examined carefully along with other experimental variables, keeping in mind that the effects of EVs may be accompanied by or confused with those of closely associated or physically similar particles. PMID- 28566774 TI - Effective medical writing: How to write a case report which Editors would publish. PMID- 28566775 TI - Orthopedic surgery in cerebral palsy: Instructional course lecture. AB - Orthopedic surgery (OS) plays an important role in the management of cerebral palsy (CP). The objectives of OS are to optimize functions and prevent deformity. Newer developments in OS for CP include emphasis on hip surveillance, minimally invasive procedures, use of external fixators instead of plates and screws, better understanding of lever arm dysfunctions (that can only be corrected by bony OS), orthopedic selective spasticity-control surgery, and single-event multilevel lever arm restoration and anti spasticity surgery, which have led to significant improvements in gross motor function and ambulation, especially in spastic quadriplegia, athetosis, and dystonia. The results of OS can be dramatic and life altering for the person with CP and their caregivers if it is performed meticulously by a specialized surgical team, at the appropriate age, for the correct indications, employing sound biomechanical principles and is followed by physician-led, protocol based, intensive, multidisciplinary, institutional rehabilitation, and long term followup. However, OS can be a double-edged sword, and if performed less than optimally, and without the supporting multidisciplinary medical and rehabilitation team, expertise and infrastructure, it often leads to significant functional worsening of the person with CP, including irretrievable loss of previous ambulatory capacity. OS must be integrated into the long term management of the person with CP and should be anticipated and planned at the optimal time and not viewed as a "last resort" intervention or failure of rehabilitation. This instructional course lecture reviews the relevant contemporary principles and techniques of OS in CP. PMID- 28566777 TI - Surgical treatment of secondary fractures after percutaneous vertebroplasty: A retrospective study. AB - BACKGROUND: Percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) are effective procedures for the treatment of vertebral compression fractures (VCFs). However, recent studies have reported that secondary VCFs develop in patients after PVP or PKP treatment. This study aimed to investigate the clinical characteristics and management of secondary fractures after PVP or PKP. MATERIALS AND METHODS: 599 cases who had vertebral compression fracture and underwent PVP or PKP between September 2008 and June 2014 were enrolled, including 121 males and 478 females. Secondary fractures were observed in 52 cases, including 3 males and 49 females, who were treated by re-operation with PVP or PKP. RESULTS: The ratio of secondary fracture after PVP or PKP was 8.68% in all cases. The age ranged from 59 to 92 years (74.41 +/- 6.83 average). A composition of 44.44% of the secondary fracture occurred near the initial fracture vertebrae. After re operation with PVP or PKP, visual analog scale score significantly decreased to 2.72 +/- 0.88 or 2.52 +/- 1.12, respectively, anterior height of vertebral bodies increased to 24.69 +/- 4.59 or 24.54 +/- 5.97 mm, respectively, and middle height of vertebral bodies increased to 20.90 +/- 3.72 or 20.36 +/- 6.33 mm, respectively. CONCLUSIONS: There is a high chance of secondary fracture near the initially operated vertebrae after PVP or PKP. Re-operation with PVP or PKP achieves satisfactory outcomes in these patients such as pain relief and the recovery of the vertebrae height. PMID- 28566776 TI - Infected nonunion of tibia. AB - Infected nonunions of tibia pose many challenges to the treating surgeon and the patient. Challenges include recalcitrant infection, complex deformities, sclerotic bone ends, large bone gaps, shortening, and joint stiffness. They are easy to diagnose and difficult to treat. The ASAMI classification helps decide treatment. The nonunion severity score proposed by Calori measures many parameters to give a prognosis. The infection severity score uses simple clinical signs to grade severity of infection. This determines number of surgeries and allows choice of hardware, either external or internal for definitive treatment. Co-morbid factors such as smoking, diabetes, nonsteroidal anti-inflammatory drug use, and hypovitaminosis D influence the choice and duration of treatment. Thorough debridement is the mainstay of treatment. Removal of all necrotic bone and soft tissue is needed. Care is exercised in shaping bone ends. Internal fixation can help achieve union if infection was mild. Severe infections need external fixation use in a second stage. Compression at nonunion site achieves union. It can be combined with a corticotomy lengthening at a distant site for equalization. Soft tissue deficit has to be covered by flaps, either local or microvascular. Bone gaps are best filled with the reliable technique of bone transport. Regenerate bone may be formed proximally, distally, or at both sites. Acute compression can fill bone gaps and may need a fibular resection. Gradual reduction of bone gap happens with bone transport, without need for fibulectomy. When bone ends dock, union may be achieved by vertical or horizontal compression. Biological stimulus from iliac crest bone grafts, bone marrow aspirate injections, and platelet concentrates hasten union. Bone graft substitutes add volume to graft and help fill defects. Addition of rh-BMP-7 may help in healing albeit at a much higher cost. Regeneration may need stimulation and augmentation. Induced membrane technique is an alternative to bone transport to fill gaps. It needs large amounts of bone graft from iliac crest or femoral canal. This is an expensive method physiologically and economically. Infection can resorb the graft and cause failure of treatment. It can be done in select cases after thorough eradication of infection. Patience and perseverance are needed for successful resolution of infection and achieving union. PMID- 28566778 TI - Nonunion of greater trochanter following total hip arthroplasty: Treated by an articulated hook plate and bone grafting. AB - BACKGROUND: Trochanteric osteotomy still has an important role in hip arthroplasty in cases of (1) preexisting developmental hip dysplasia with superior subluxation, (2) revision arthroplasty, specifically with acetabular component revision in the face of well-fixed femoral component, and (3) recurrent dislocation without component loosening or malalignment, in treatment of complicated trochanteric fixation in osteoporotic bone and nonunions may be difficult. This study reports the clinical outcomes of trochanteric fixation following total hip arthroplasty (THA) utilizing a hook plate construct in a cohort of ten patients. MATERIALS AND METHODS: The Arbeitsgemeinschaft fur Osteosynthesefragen (AO) articulated hook plate was used in nine cases of established approach related nonunion following THA and in one case of osteopenic bone during primary THA. All ten patients returned for interviews and clinical examination. The average time for clinical followup was 35 months (range 5-48 months). The mean age of the study cohort was 65 years (range 56-74 years). Time to union and incidence of postoperative complications were assessed. RESULTS: Union occurred in all ten cases at an average of 3.3 months postoperatively. One patient developed symptomatic trochanteric bursitis and required plate removal. Another patient developed a superficial infection which was successfully treated with local wound debridement and antibiotics. A third patient developed a symptomatic neuroma at the site of the iliac crest bone harvest and was successfully treated with excision of the neuroma. No catastrophic implant failures occurred. CONCLUSIONS: The articulated design of the plate allows for ease in application and functional construct stability. The articulated hook plate is an option for fixation of osteopenic bone fragments and established nonunions of the greater trochanter. PMID- 28566779 TI - Pain management in total knee arthroplasty by intraoperative local anesthetic application and one-shot femoral block. AB - BACKGROUND: Pain after total knee arthroplasty (TKA) is a big problem in orthopaedic surgery. Although opioids and continuous epidural analgesia remain the major options for the postoperative pain management of TKA, they have some undesirable side effects. Epidural analgesia is technically demanding, and the patient requires close monitoring. Different types of local anesthetic applications can successfully treat TKA pain. Local anesthetics have the advantage of minimizing pain at the source. This study investigates the efficacy of different local anesthetic application methods on early, (1st day) pain control after total knee arthroplasty. MATERIALS AND METHODS: 200 patients who underwent unilateral TKA surgery under spinal anesthesia were randomly assigned into four different groups (fifty in each group) and were administered pain control by different peri- and postoperative regimens. Group A was the control group wherein no postsurgical analgesia was administered to assess spinal anesthesia efficacy; in Group B, only postsurgical one-shot femoral block was applied; in Group C, intraoperative periarticular local anesthetic was applied; in Group D, a combination of the one-shot femoral block and intraoperative periarticular local anesthetics were applied. Demographic data consisting of age, weight, gender and type of deformity of patients were collected. The data did not differ significantly between the four groups. RESULTS: Group D patients experienced significantly better postoperative pain relief (P < 0.05) and were therefore more relaxed in pain (painless time, VAS score) and knee flexion (degrees) than the other patient groups in the 1st postoperative day followup. Painless time of Group D was 10.5 hours and was better than Group C (6.8 hours), Group B (6.2 hours) and Group A (3.0 hours) (P < 0.05). Group A got the best pain Vas score degrees in the 1st postoperative day which showed the success of combined periarticular local anesthetic injection and femoral nerve block. CONCLUSION: The intraoperative periarticular application of local anesthetics in addition to one-shot femoral block is an efficient way of controlling postsurgical pain after TKA. PMID- 28566780 TI - Radiologic assessment of femoral and tibial tunnel placement based on anatomic landmarks in arthroscopic single bundle anterior cruciate ligament reconstruction. AB - BACKGROUND: Accurate tibial and femoral tunnel placement has a significant effect on outcomes after anterior cruciate ligament reconstruction (ACLR). Postoperative radiographs provide a reliable and valid way for the assessment of anatomical tunnel placement after ACLR. The aim of this study was to examine the radiographic location of tibial and femoral tunnels in patients who underwent arthroscopic ACLR using anatomic landmarks. Patients who underwent arthroscopic ACLR from January 2014 to March 2016 were included in this retrospective cohort study. MATERIALS AND METHODS: 45 patients who underwent arthroscopic ACLR, postoperative radiographs were studied. Femoral and tibial tunnel positions on sagittal and coronal radiographic views, graft impingement, and femoral roof angle were measured. Radiological parameters were summarized as mean +/- standard deviation and proportions as applicable. Interobserver agreement was measured using intraclass correlation coefficient. RESULTS: The position of the tibial tunnel was found to be at an average of 35.1% +/- 7.4% posterior from the anterior edge of the tibia. The femoral tunnel was found at an average of 30% +/- 1% anterior to the posterior femoral cortex along the Blumensaat's line. Radiographic impingement was found in 34% of the patients. The roof angle averaged 34.3 degrees +/- 4.3 degrees . The position of the tibial tunnel was found at an average of 44.16% +/- 3.98% from the medial edge of the tibial plateau. The coronal tibial tunnel angle averaged 67.5 degrees +/- 8.9 degrees . The coronal angle of the femoral tunnel averaged 41.9 degrees +/- 8.5 degrees . CONCLUSIONS: The femoral and tibial tunnel placements correlated well with anatomic landmarks except for radiographic impingement which was present in 34% of the patients. PMID- 28566781 TI - A comparative study of intramedullary interlocking nailing and minimally invasive plate osteosynthesis in extra articular distal tibial fractures. AB - BACKGROUND: Extraarticular distal tibial fractures are among the most challenging fractures encountered by an orthopedician for treatment because of its subcutaneous location, poor blood supply and decreased muscular cover anteriorly, complications such as delayed union, nonunion, wound infection, and wound dehiscence are often seen as a great challenge to the surgeon. Minimally invasive plate osteosynthesis (MIPO) and intramedullary interlocking nail (IMLN) are two well-accepted and effective methods, but each has been historically related to complications. This study compares clinical and radiological outcome in extraarticular distal tibia fractures treated by intramedullary interlocking nail (IMLN) and minimally invasive plate osteosynthesis (MIPO). MATERIALS AND METHODS: 42 patients included in this study, 21 underwent IMLN and 21 were treated with MIPO who met the inclusion criteria and operated between June 2014 and May 2015. Patients were followed up for clinical and radiological evaluation. RESULTS: In IMLN group, average union time was 18.26 weeks compared to 21.70 weeks in plating group which was significant (P < 0.0001). Average time required for partial and full weight bearing in the nailing group was 4.95 weeks and 10.09 weeks respectively which was significantly less (P < 0.0001) as compared to 6.90 weeks and 13.38 weeks in the plating group. Lesser complications in terms of implant irritation, ankle stiffness, and infection, were seen in interlocking group as compared to plating group. Average functional outcome according to American Orthopedic Foot and Ankle Society score was measured which came out to be 96.67. CONCLUSION: IMLN group was associated with lesser duration of surgery, earlier weight bearing and union rate, lesser incidence of infection and implant irritation which makes it a preferable choice for fixation of extra-articular distal tibial fractures. However, larger randomized controlled trials are required for confirming the results. PMID- 28566782 TI - Early results of an intraosseous device for arthrodesis of the hallux metatarsophalangeal joint. AB - BACKGROUND: Arthrodesis of the hallux metatarsophalangeal (MTP) joint is commonly done as a primary procedure either to correct severe hallux valgus deformities or for rheumatoid arthritis, hallux rigidus, in patients with neuromuscular disorders and as a salvage procedure for failed bunion surgery or infection. Prominent metalwork frequently can cause soft tissue impingement and thus require removal. In contrast, osteosynthesis with a completely intraosseous implant has the advantage of less damage to the periosteal circulation. We describe a surgical technique and the early results of arthrodesis of the hallux metatarsophalangeal (MTP) joint using an intraosseous fixation device. MATERIALS AND METHODS: Twelve consecutive patients operated with this method were retrospectively reviewed. The average age was 57 years (range 44-88 years). A retrospective review of radiographs and electronic medical notes was conducted. The patients were also asked to fill a satisfaction questionnaire. RESULTS: Overall fusion rate was 91% with a mean hallux valgus angle of 15 degrees (range 4-20 degrees ) and a mean dorsiflexion angle of 20 degrees (range 7-30 degrees ). Complications included a case of failed fusion, a delayed union, and a case of persisting transfer metatarsalgia. At a mean followup of 14 months (range 5-28 months), the mean visual analog scale improved significantly from a mean of 8.4 (range 7-10) preoperatively, to a mean of 3.1 (range 0-7) postoperatively (P < 0.0001). The mean American Orthopaedic Foot and Ankle Society hallux score also significantly improved from 29.4 (range 10-54) to a mean of 73.3 (range 59-90) (P < 0.0001). The final result was satisfactory for 83% of the patients. CONCLUSIONS: The early results show intraosseous fixation to be a safe and efficient method for the fusion of the hallux MTP joint providing relief from pain and patient satisfaction. PMID- 28566783 TI - A comparative study to evaluate the efficacy of platelet-rich plasma and triamcinolone to treat tennis elbow. AB - BACKGROUND: Lateral elbow pain is common with a population prevalence of 1%-3%. The study was a comparative trial to validate the efficacy of single injection of platelet-rich plasma (PRP) for tennis elbow as compared with single injections of triamcinolone and placebo (normal saline) over a short term period. MATERIALS AND METHODS: Comparative trial with 3- and 6-month followup evaluated with visual analog scale (VAS) and facial pain scale (FPS). Our study included a total of eighty patients with unilateral or bilateral tennis elbows. The study population included patients between 20 and 40 years age group belonging to either sex with seventy unilateral and ten bilateral affections for more than 3-month duration. Patients suffering from elbow pain due to other problems or those who have received any form of injection were excluded from the study. One milliliter of 2% Xylocaine injection was given before injecting the proposed formulation under trial. VAS and FPS were used for scoring pain. Kruskal-Wallis test and Mann Whitney U-tests were used for statistical analyses at 12 and 24 weeks. RESULTS: Overall, 49 females and 31 males were included with thirty elbows in each group. Both the PRP and triamcinolone groups had better pain relief at 3 and 6 months as compared to normal saline group (P < 0.05), but at 6 months followup, the PRP group had statistically significant better pain relief than triamcinolone group. In the triamcinolone group, 13 patients had injection site hypopigmentation and 3 patients had subdermal atrophy. CONCLUSION: Over a short term period, PRP gives better pain relief than triamcinolone or normal saline in tennis elbow which needs to be validated over long term period by further studies. PMID- 28566784 TI - Management of open fractures using a noncontact locking plate as an internal fixator. AB - BACKGROUND: The treatment of open fractures leads to major problems which may be due to various reasons. It mainly causes soft tissue problems due to the absorption of a large amount of energy by the soft tissues and bone tissues. Although some recent treatment protocols have eliminated many problems regarding delayed soft tissue closure, it still remains a big challange. This study uses a method called the internal fixator technique with noncontact locking plate (NC LP) which involves the use of a combination of advantages of open and closed fixation techniques. MATERIALS AND METHODS: 42 patients (32 men and 10 women) having a mean age of 34.11 years (range 17-56 years) with open fractures operated using internal fixator technique between 2007 and 2012 were included in this study. A retrospective chart review was conducted to record the following: age, gender, anatomic region of fractures, fracture etiology, classification of open fractures by Gustilo-Anderson and AO classification, surgeries, length of hospitalization, location and pattern of fracture, length of followup, and complications. RESULTS: The fractures were caused by traffic accidents, shotgun injuries, falls from heights, and industrial crush injuries. Based on the Gustilo Anderson classification, 31 fractures were Type III and 11 were Type II, where 23 were localized in the tibia and 19 in the femur. Patients delay for a mean of 13.5 h (range 6-24 h) for operation and the mean followup interval was 27.8 months (range 16-44 months). The mean union time was 19.7 weeks (range 16-29 weeks). One patient had delayed union and implant failure, one patient had osteomyelitis, five suffered from surface skin necrosis, and one patient had an angulation of 17 degrees in the sagittal plane, for which no additional intervention was performed. CONCLUSIONS: This case series demonstrates that an "internal fixator technique" is an acceptable alternative to the management of open fractures of the femur or tibia in adult patients. The NC-LP method provided opportunities to achieve a stable fixation with noncontact between the implant and the bone tissues, and the fractures were sufficiently stabilized to allow union with a low complication rate. PMID- 28566785 TI - Combined negative pressure wound therapy with open bone graft for infected wounds with bone defects: An experimental study. AB - BACKGROUND: Bone and soft-tissue defects in infected wound have been an intractable problem to many surgical consultations. Infected wounds with bone defects are physical and financial burden to society. Nowadays, infected wounds with compound defect of bone and soft tissues are common in orthopedics department. Currently, no simple and efficient treatment has been found to solve this problem. This study investigates the effects of combining negative pressure wound therapy (NPWT) with open bone graft on this focus. MATERIALS AND METHODS: Twenty four rabbits with bone and soft tissue defects accompanied infected wounds were randomized into experimental (combined NPWT with open bone graft) and contrast group (only open bone graft). Treatment efficacy was assessed by the wound condition; wound healing time, bacterial bioburden, and bony callus were evaluated by X-ray. Furthermore, samples of granulation tissue from wounds on the 3rd, 7th, and 14th days of healing were evaluated for blood vessels and expression of vascular endothelial growth factor. RESULTS: Wounds in the experimental group tended to have shorter healing time, healthier wound conditions, lower bacterial bioburden, better bony callus, and more blood supply than those in the controlled group. CONCLUSIONS: In conclusion, NPWT combined open bone graft can act as a feasible and valuable method to treat combined infected bone and soft-tissue defects. PMID- 28566786 TI - Short and mid term results of revision total knee arthroplasty with Global Modular Replacement System. AB - BACKGROUND: The original knee megaprostheses with fixed or rotating hinge articulation were custom made and only used for reconstruction of the knee following distal femoral or proximal tibial tumor resections. The aim of the study was to analyze the short- and mid-term results of revision total knee arthroplasty with Global Modular Replacement System (GMRS) used in difficult situations not amenable to reconstruction with standard total knee replacement implants. MATERIALS AND METHODS: Nine patients (9 knees) were treated with this comprehensive modular implant system, with a mean age of 73.7 years (range 56-83 years) and a mean followup of 5 years (range 3-8 years). Two patients were treated for distal femoral nonunion, five for distal femur periprosthetic fracture and two for periprosthetic joint infection. RESULTS: The mean Knee Society Score: Knee and functional scores were 77.9 and 40 points, respectively. All demonstrated full extension and flexion was at least 90 degrees . Recurrence of infection was present in one patient. No signs of loosening, dislocation, or implant failure were observed. CONCLUSIONS: Based on our small series of patients that represent severe cases, GMRS provides relatively good mid-term functional results, pain relief, and good implant survivorship with a low complication rate. This salvage procedure allows elderly, infirm patients to regain early ambulatory ability. PMID- 28566787 TI - Acute flaccid paraparesis (cauda equina syndrome) in a patient with Bardet-Biedl syndrome. AB - Bardet-Biedl syndrome (BBS) is a rare, autosomal-recessive, debilitating genetic disorder, which can present with multitudinous systemic clinical features including rod-cone dystrophy, polydactyly, Frohlich-like central obesity, mental retardation, hypogonadism, and renal anomalies. Diverse neuromuscular manifestations in patients afflicted by this heterogeneous disorder include ataxia, cervical, and thoracic canal stenoses, presenting as spastic quadriparesis and other gait disturbances. We report a young patient with BBS, who had presented with acute flaccid paraparesis due to severe primary lumbar canal stenosis. She underwent immediate lumbar decompression and discectomy following which she recovered significantly. Acute cauda equina syndrome due to primary lumbar canal stenosis has not been reported as a clinical feature of BBS previously. PMID- 28566788 TI - Patellar tendon re-rupture on the opposite end of the previous site of surgical repair. AB - We describe a rare case of a patellar tendon "re-rupture" at the opposite end of a previous proximal tendon repair. A 32-year-old male with a history of surgically repaired right proximal patellar tendon rupture presented with an acute non-traumatic right knee pain and instability during sports. Magnetic resonance imaging confirmed a complete rupture of his distal patellar tendon at the tibial tuberosity. The patellar tendon was repaired using two 5.5 mm BioCorkscrews (Arthrex) inserted into the tibial tuberosity; the tendon was stitched with the No. 2 fiberwires using Krackow technique. As the patellar tendon was degenerative, the repair was augmented with a semitendinosus tendon harvested using an open tendon stripper, leaving the distal attachment intact. At 2.6 years followup he had mild anterior knee pain, range of motion 0-130 degrees and was able to squat. MRI scan done at followup revealed good healing of repaired patellar tendon. PMID- 28566789 TI - Prosthetic knee joint infection due to Mycobacterium abscessus. AB - Infected total knee arthroplasty (TKA) due to Mycobacterium abscessus is very rare with only three such cases described in literature. Only one case was managed successfully, however, with a prolonged course of anti tubercular therapy. In this case report, we present an elderly lady with infected TKA after 2 years of the primary procedure. Although initially it grew different bacteriae, M. abscessus was isolated during the second debridement. She was successfully treated with total of 5 months of second line anti tubercular drugs with revision prosthesis performed during chemotherapy. Two years followup revealed satisfactory outcome with no relapse. PMID- 28566790 TI - One stage revision single-bundle anterior cruciate ligament reconstruction with impacted morselized bone graft following a failed double-bundle reconstruction. AB - Although double-bundle anterior cruciate ligament (ACL) reconstruction has theoretical benefits such as more accurate reproduction of ACL anatomy, it is technically more demanding surgery. This report describes the case of a one stage revision single-bundle ACL reconstruction after primary double-bundle ACL reconstruction. A professional dancer had an ACL previously reconstructed with a double-bundle technique, but the femoral tunnels were malpositioned resulting in residual laxity and rotational instability. The previous femoral tunnel positions were vertical and widened. The previous vertical tunnels were filled with impacted bone graft and a revision single-bundle ACL reconstruction was performed via the new femoral tunnel with a 2 O'clock position between the previous two tunnels. After 10 months of postoperative rehabilitation, the patient returned to professional dancing with sound bony union and without any residual instability. PMID- 28566792 TI - Author's reply. PMID- 28566791 TI - Reverse distal femoral locking compression plate a salvage option in nonunion of proximal femoral fractures. PMID- 28566793 TI - Current state of orthopedic education in India. PMID- 28566794 TI - Author's reply. PMID- 28566795 TI - Legends of Indian Orthopedics: Prof. M. Natarajan. PMID- 28566796 TI - Joint volumetric extraction and enhancement of vasculature from low-SNR 3-D fluorescence microscopy images. AB - To simultaneously overcome the challenges imposed by the nature of optical imaging characterized by a range of artifacts including space-varying signal to noise ratio (SNR), scattered light, and non-uniform illumination, we developed a novel method that segments the 3-D vasculature directly from original fluorescence microscopy images eliminating the need for employing pre- and post processing steps such as noise removal and segmentation refinement as used with the majority of segmentation techniques. Our method comprises two initialization and constrained recovery and enhancement stages. The initialization approach is fully automated using features derived from bi-scale statistical measures and produces seed points robust to non-uniform illumination, low SNR, and local structural variations. This algorithm achieves the goal of segmentation via design of an iterative approach that extracts the structure through voting of feature vectors formed by distance, local intensity gradient, and median measures. Qualitative and quantitative analysis of the experimental results obtained from synthetic and real data prove the effcacy of this method in comparison to the state-of-the-art enhancing-segmenting methods. The algorithmic simplicity, freedom from having a priori probabilistic information about the noise, and structural definition gives this algorithm a wide potential range of applications where i.e. structural complexity significantly complicates the segmentation problem. PMID- 28566797 TI - Allochthonous matter: an important factor shaping the phytoplankton community in the Baltic Sea. AB - It is well-known that nutrients shape phytoplankton communities in marine systems, but in coastal waters allochthonous dissolved organic matter (ADOM) may also be of central importance. We studied how humic substances (proxy of ADOM) and other variables influenced the nutritional strategies, size structure and pigment content of the phytoplankton community along a south-north gradient in the Baltic Sea. During the summer, the proportion of mixotrophs increased gradually from the phosphorus-rich south to the ADOM-rich north, probably due to ADOM-fueled microbes. The opposite trend was observed for autotrophs. The chlorophyll a (Chl a): carbon (C) ratio increased while the levels of photoprotective pigments decreased from south to north, indicating adaptation to the darker humic-rich water in the north. Picocyanobacteria dominated in phosphorus-rich areas while nanoplankton increased in ADOM-rich areas. During the winter-spring the phytoplankton biomass and concentrations of photoprotective pigments were low, and no trends with respect to autotrophs and mixotrophs were observed. Microplankton was the dominant size group in the entire study area. We conclude that changes in the size structure of the phytoplankton community, the Chl a:C ratio and the concentrations of photoprotective pigments are indicative of changes in ADOM, a factor of particular importance in a changing climate. PMID- 28566798 TI - Occurrence of the siphonophore Muggiaea atlantica in Scottish coastal waters: source or sink? AB - We applied the concept of source-sink dynamics to investigate a recent (1999 2013) increase in the occurrence of the siphonophore Muggiaea atlantica in Scottish coastal waters. Our aim was to determine whether this change represented the establishment of resident populations (i.e. "sources"), or transient populations reliant on immigration (i.e. "sinks"). First, we show that local production was not always sufficient to account for recruitment (a "source" prerequisite), suggesting reliance on immigration (a "sink" prerequisite). Using variation partitioning, we then discriminated between the exclusive effects of immigration [indexed by the European Slope Current (ESC)] and local production (indexed by local sea temperature and food availability). On the west coast (Loch Ewe), interannual variability in the species' abundance was determined by, in order of increasing importance: (i) suitable local environmental conditions (13%); (ii) the role of the ESC in modulating these conditions (20%); and (iii) immigration via the ESC (29%). These results provided a strong indication that Loch Ewe represents a sink habitat for M. atlantica. However, on the east coast (Stonehaven) our results were less conclusive, probably due to the less direct influence of the ESC. For both locations, we suggest that low winter temperatures prevented overwintering, necessitating annual re-colonization via immigration. PMID- 28566799 TI - Focused Information Criterion and Model Averaging with Generalized Rank Regression. AB - Generalized rank regression, which is a class of weighted rank regression with weights based on factor space, provides a powerful tool for conducting robust estimation. In this article, we first establish the asymptotic properties of generalized rank regression under local model misspecification. We then apply the generalized rank regression to the focus information criterion and frequentist model averaging and establish their properties. PMID- 28566800 TI - Serum Soluble ST2 and Diastolic Dysfunction in Hypertensive Patients. AB - BACKGROUND: Echocardiographic evaluation of left ventricular (LV) structural and functional alterations in hypertension has some limitations, potentially overcome by using biomarkers. ST2, a prognostic biomarker for heart failure and myocardial infarction patients, was less studied in hypertension. AIM: To analyze the relationship between serum ST2 levels and diastolic dysfunction (DD) in hypertension. METHOD: We enrolled 88 hypertensive outpatients (average age 65 years, 69.3% females) in a prospective study, stratified for presence of LV hypertrophy (LVH). For each patient clinical examination, lab workup (routine and serum ST2 levels) and echocardiography were performed. RESULTS: Hypertensive patients with LVH had higher age, pulse pressure, mean arterial pressure, and serum ST2, while having lower serum albumin than those without LVH. Serum ST2 levels correlate with parameters of LV remodeling and DD. We found that 5.3% of ST2 level variability was caused by a 1-unit variation of cardiovascular risk. We identified cut-off values for discriminating hypertension with LVH versus that without LVH and grade 2 DD versus normal diastolic performance. CONCLUSION: ST2 could be used as diagnostic biomarker for cardiac remodeling and altered diastolic performance in hypertension, providing additional data to echocardiography. It could represent a milestone in early detection of cardiac performance alteration. PMID- 28566801 TI - [How a Diversity of Preschool Literary Experiences Contribute to Emergent Literacy Skills]. AB - Past studies show that language and cognitive factors among young children do not explain individual differences in written language skill acquisition (Senechal et LeFevre, 2002). Working from the principles of ethology and sociology, Pellegrini (2001) suggests that exposure to a larger variety of social contacts and contexts promotes the acquisition of literary language and reading/writing skills. The purpose of this study is to check the contribution of a variety of social writing related opportunities to the acquisition of emerging literacy skills in 5 year olds. This contribution is examined alongside family financial resources, parental education, frequency of mother-child reading/writing activities, and the child's verbal and mnemonic skills. The results partially confirm Pellegrini's hypothesis and support the relevance of considering several dimensions of preschool social experience. The unique contribution of diverse literary activities for 4 year-olds (48 months) seems to be as important as receptive vocabulary and short term memory, evaluated at 42 months. However, a larger variety of contacts was not added to the model. PMID- 28566802 TI - Are genes encoding proteoglycans really associated with the risk of anterior cruciate ligament rupture? AB - Proteoglycans are considered integral structural components of tendon and ligament and have been implicated in the resistance of compressive forces, collagen fibrillogenesis, matrix remodelling and cell signalling. Several sequence variants within genes encoding proteoglycans were recently implicated in modulating anterior cruciate ligament ruptures (ACLR). This study aimed to test the previously implicated variants in proteoglycan and vascular epithelial growth factor encoding genes with risk of ACLR in a population from Poland. A case control genetic association study was conducted using DNA samples from 143 healthy participants without a history of ACL injuries (99 male and 44 females) (CON group) and 229 surgically diagnosed ACLR participants (158 males and 71 females). All samples were genotyped for the ACAN: rs1516797, BGN: rs1042103, rs1126499, DCN: rs516115 and VEGFA: rs699947 variants. Main findings included the (i) ACAN rs1516797 G/T genotype which was underrepresented in the CON group (CON: 36%, n=52, ACLR: 49%, n=112, p=0.017, OR=1.68, 95% CI 1.09 to 2.57) when all participants were investigated and (ii) the BGN rs1042103 A allele was significantly under-represented in the male CON group compared to the male ACLR group (CON: 39%, n=78, ACLR: 49%, n=156, p=0.029, OR=1.5, 95% CI 1.05 to 2.15). Furthermore, BGN inferred haplotypes were highlighted with altered ACLR susceptibility. Although the study implicated the ACAN and BGN genes (combination of genotype, allele and haplotype) in modulating ACLR susceptibility, several differences were noted with previous published findings. PMID- 28566803 TI - Greater muscle damage in athletes with ACTN3 R577X (RS1815739) gene polymorphism after an ultra-endurance race: a pilot study. AB - In this study, we aimed to investigate the influence of ACTN3 R577X gene polymorphism on muscle damage responses in athletes competing in an ultra endurance race. Twenty moderate to well-trained ultra-runners who had entered in an official 37.1 km adventure race (22.1 km mountain biking, 10.9 km trekking, 4.1 km water trekking, 30 m rope course, and orienteering) volunteered for the study. Blood samples were collected for genotyping and analysis of muscle protein levels before and after the race. Percentage changes (pre- to post-race) of serum myoglobin [XX = 5,377% vs. RX/RR = 1,666%; P = 0.005, effect size (ES) = 1.73], creatine kinase (XX = 836.5% vs. RX/RR = 455%; P = 0.04, ES = 1.29), lactate dehydrogenase (XX = 82% vs. RX/RR = 65%; P = 0.002, ES = 1.61), and aspartate aminotransferase (XX = 148% vs. RX/RR = 75%; P = 0.02, ES = 1.77) were significantly greater for XX than RX/RR genotypes. ES analysis confirmed a large magnitude of muscle damage in XX genotype ultra-runners. Therefore, athletes with the ACTN3 577XX genotype experienced more muscle damage after an adventure race. This suggests that ultra-runners with alpha-actinin-3 deficiency may be more susceptible to rhabdomyolysis and associated health complications during ultra endurance competitions. PMID- 28566804 TI - Reticulocyte and erythrocyte hypochromia markers in detection of iron deficiency in adolescent female athletes. AB - The aim of this study was to analyse the effectiveness of new haematology parameters related to reticulocytes and mature red blood cells to differentiate pre latent and latent iron deficiency. The study included 219 female athletes (aged 15-20 years) representing volleyball, handball, cycling, canoeing, cross country skiing, swimming and judo. To assess iron status the concentration of ferritin, soluble transferrin receptor (sTfR), iron and total iron binding capacity (TIBC) were determined in serum. In addition to blood morphology, the mean cellular haemoglobin content in erythrocytes (CH) and reticulocytes (CHr), mean cellular haemoglobin concentration in reticulocytes (CHCMr), the percentage of erythrocytes (HYPOm) and reticulocytes (HYPOr) with decreased cellular haemoglobin concentration, the percentage of erythrocytes (LowCHm) and reticulocytes (LowCHr) with decreased cellular haemoglobin content, and percentage of erythrocytes with decreased volume (MICROm) were determined. Subjects with ferritin <30 ng/ml were classified as having stage I (pre-latent) iron deficiency (ID). The second stage (latent ID) was diagnosed when low ferritin was accompanied by elevated sTfR and/or elevated TIBC values. The frequency of ID (without anaemia symptoms) was high, amounting to 60% (stage I in 45%, stage II in 15% of subjects). In subjects with stage I ID significant changes in haematological variables concerned mainly reticulocytes: CHCMr (p<.001), CHr (p<.05), LowCHr (p<.05), HYPOr (p<.001) in comparison to normal iron stores. In athletes with latent ID, there were also significant changes (p<.001) in many indices of mature red blood cells, i.e. haemoglobin concentration (Hb), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), CH, %LowCHm, as well as %MICROm (p<.01) in relation to the group without iron deficiency. The main finding of this study was that the diminished or exhausted iron stores had already caused changes in reticulocytes, and intensified iron deficiency (stage II) increased changes in both reticulocytes' and erythrocytes' hypochromia indices, while microcythaemia symptoms appeared later. This suggests that the markers of hypochromia relating especially to reticulocytes are useful for diagnosis of early ID in athletes with absence of an acute phase reaction. PMID- 28566805 TI - Association of arch height with ankle muscle strength and physical performance in adult men. AB - Differences in arch height may have a certain impact on lower extremity muscle strength and physical performance. However, there is little evidence from investigation of the possible correlation of arch height with ankle muscle strength and physical performance measures. Sixty-seven participants took part in this study. Arch height index (AHI) was assessed and categorized using a 3 dimension foot scanner. Ankle muscle strength was measured employing a dynamometer. Physical performance measures including agility, force and proprioception were randomly tested. Compared to the medium AHI, the high AHI had lower plantarflexion and inversion peak torque. The high AHI also had lower peak torque per body weight value for plantarflexion and inversion at 120 degrees /s (P = 0.026 and 0.006, respectively), and dorsiflexion at 30 degrees /s (P = 0.042). No significant ankle muscle strength difference was observed between the low and medium AHI. Additionally, AHI was negatively correlated with eversion and inversion peak torque at 120 degrees /s, and negatively associated with plantarflexion, eversion and inversion peak torque per body weight at both 30 degrees /s and 120 degrees /s (r ranged from -0.26 to -0.36, P values < 0.050). However, no significant relationship was found between arch height and physical performance measures. The results showed that high arches had lower ankle muscle strength while low arches exhibited greater ankle muscle strength. Arch height was negatively associated with ankle muscle strength but not related to physical performance. We suggest that the lower arch with greater ankle muscle strength may be an adaptation to weight support and shock absorption. PMID- 28566806 TI - The effect of the training with the different combinations of frequency and peak to-peak vibration displacement of whole-body vibration on the strength of knee flexors and extensors. AB - Whole-body vibration training has become a popular method used in sports and physiotherapy. The study aimed to evaluate the effect of different vibration frequency and peak-to-peak displacement combinations on men knee flexors and extensors strength in isokinetic conditions. The sample consisted of 49 male subjects randomly allocated to seven comparative groups, six of which exercised on a vibration platform with parameters set individually for the groups. The experimental groups were exposed to vibrations 3 times a week for 4 weeks. The pre- and post- isokinetic strength tests, with the angular velocities of 240 degrees /s and 30 degrees /s, were recorded prior to and 2 days after the training. After 4 weeks of whole-body vibration training, a significant increase was noted regarding the mean values of peak torque, average peak torque and total work for knee flexors at high angular velocity in Groups I (60 Hz/4 mm) and V (40 Hz/2 mm) (p<0.05). The mean percentage values of post-training changes to study parameters suggest that the training had the most beneficial effect in Groups I (60 Hz/4 mm) and IV (60 Hz/2 mm) (p<0.05). Whole-body vibrations during static exercise beneficially affected knee flexor strength profile in young men at high angular velocity. The combinations of 60 Hz/4 mm seem to have the most advantageous effects on muscle strength parameters. PMID- 28566807 TI - Specific physical trainability in elite young soccer players: efficiency over 6 weeks' in-season training. AB - The aim of the present study was to compare the effects of 3 training protocols (plyometric [PLYO], agility [AG], or repeated shuttle sprints [RS]) on physical performance in the same population of young soccer players. Forty-two youth-level male players (13.6+/-0.3-years; 1.65+/-0.07 m; 54.1+/-6.5 kg; body fat: 12.8+/ 2.6%) participated in a short-term (6-week) randomized parallel fully controlled training study (pre-to-post measurements): PLYO group, n=10; AG group, n=10; RS group, n=12; and control group [CON] n=10. PLYO training = 9 lower limb exercises (2-3 sets of 8-12 repetitions). The AG group performed planned AG drills and direction changes. RS training consisted of 2-4 sets of 5-6x 20 to 30 m shuttle sprints (20 seconds recovery in between). Progressive overload principles were incorporated into the programme by increasing the number of foot contacts and varying the complexity of the exercises. Pre/post-training tests were: bilateral standing horizontal jump, and unilateral horizontal jumps, sprint (30 m with 10 m lap time), agility (20 m zigzag), and repeated sprint ability (RSA) (i.e. 6x30 m shuttle sprints: 2x15 m with 180 degrees turns). Significant main effects for time (i.e. training application) and group (training type) were detected. Improvements in horizontal jumping were higher (p<0.01: ES=large) in PLYO. The RS group improved significantly more (p<0.01; ES=large) than other groups: 30 m sprint, RSAbest and RSAmean performances. Significantly greater increases in 20 m zigzag performance were observed following AG and RS training (4.0 and 3.8%, respectively) compared with PLYO (2.0%) and CON training (0.8%). No significant differences were reported in the RSAdec between groups. Elite young male soccer players' physical performances can be significantly and specifically improved either using PLYO or AG or RSA training over short-term in-season training. PMID- 28566808 TI - In-season training periodization of professional soccer players. AB - The aim of this study was to quantify the seasonal perceived respiratory and muscular training loads (i.e., sRPEres-TL and sRPEmus-TL) completed by elite oriented young professional soccer players. Twenty-four players (20.3 +/- 2.0 years) belonging to the same reserve team of a Spanish La Liga club participated in this study. Only the players that were available to train for a whole week with the team and also to play the weekly game were considered: Starters, players that participated in the match for at least 45 min and Non-Starters, players that did not participate or played less than 45 minutes in the match. The competitive period was analysed after the division into 5x6-8 week blocks and 35x1 week microcycles. Data were also analysed with respect to number of days before the immediate match. Weekly TL variation across the in-season blocks was trivial small for both groups except between Block 2 and Block 3 (ES= moderate). Substantial TL differences (ES= small-very likely) were found between training days, the TL pattern being a progressive increase up to MD-3 followed by a decrease until MD-1. Except for the match, sRPEres-/sRPEmus-TL was very similar between Starters and Non-Starters. In summary, perceived TL across the season displayed limited variation. Coaches periodized training contents to attain the highest weekly TL 72 hours before the match to progressively unload the players between MD-3 and the match day. The data revealed that the TL arising from the weekly game was solely responsible for the observed higher weekly TL of Starters in comparison with Non-Starters. PMID- 28566809 TI - The effects of game types on intensity of small-sided games among pre-adolescent youth football players. AB - The aim of this study was to examine the effects of variations in pitch dimensions on pre-adolescent youth soccer players' physiological responses during two different types of small-sided games (SSG). Sixteen young soccer players (age: 13.2 +/- 0.6 years; body mass: 52.5 +/- 7 kg; height: 163.4 +/- 6 cm) participated in this study. They performed 4 vs. 4 stop-ball SSG (SB-SSG) vs. small-goals SSG (SG-SSG) with 4*4 min and 2 min of passive recovery in between, using 3 different pitch sizes (small: 10*15, medium: 15*20, and large: 20*25 m). Heart rate (HR), lactate concentration ([La-]), and rating of perceived exertion (RPE) were measured during each session. The results show that SB-SSG induced higher HR responses than SG-SSG for the 3 pitch sizes: for HR (167.2+/-3.0 vs. 164.5+/-3.0, 172.3+/-2.9 vs. 169.2+/-3.1, and 175.4+/-3.1 vs. 171.1+/-2.7 bpm; P<0.05, for small, medium, and large, respectively) and [La-] (7.1+/-1.0 vs. 6.5+/-1.04, 7.3+/-1.0 vs. 6.8+/-1.2, and 7.8+/-0.9 vs. 7.1+/-0.8 mmol.l-1; P<0.05 on small, medium, and large pitches, respectively), whereas RPE scores were significantly higher during SB-SSG compared to SG-SSG (6.2+/-1.0 vs. 5.8+/-0.9; P<0.05, respectively) on the small pitch. In the present study higher physiological responses were observed in SSG in pre-adolescent young soccer players when using the stop-ball conditions in comparison with the small-goal rule for all pitch sizes - small, medium, and large. Stop-ball conditions in comparison with the small-goal rule for all pitch sizes - small, medium, and large. PMID- 28566810 TI - Soccer small-sided games in young players: rule modification to induce higher physiological responses. AB - The aim of this study was to identify the physiological responses of 3 forms of players' numbers during two different games rules of small-sided games (SSG: stop ball vs. small-goals rules). Eighteen youth amateur soccer players (age 13.5+/ 0.7 years; height 168.9+/-6.1cm; body mass 63.1+/-7.7 kg) participated in this study and performed 3 SSGs with varying players' number (2vs.2; 3vs.3 and 4vs.4): stop-ball SSG (SB-SSG) vs. small-goals SSG (SG-SSG) in a randomized and counter balanced order on a constant pitch dimension (20*25m). The players performed 4*4 min SSG with 2-min of passive recovery in-between. Heart rate (HR), (expressed in bpm and % HRmax), lactate ([La-]), and rating of perceived exertion (RPE) were collected during each session. SB-SSG induced the higher HR values in comparison with the SG-SSG for the 3 game formats (2vs.2; 3vs.3 and 4vs.4). Also, compared with SG-SSG, SB-SSG induced the higher HR values during 2vs.2 compared with 4vs.4 games rules (178 vs. 174 and 175 vs. 171 bpm, respectively). However, the SB-SSG was more intense compared with SG-SSG in the 2 vs. 2 game rule compared with the two others (3 vs.3 and 4 vs. 4) for [La-] and RPE (7.58 vs. 7; 7.25 vs. 6.75 and 6.5 vs. 6.16 mmol ? L-1, and 7.75 vs. 7.33; 7.41 vs. 7.08 and 7.16 vs. 6.83, respectively). Therefore, the use of 2 vs. 2 and 3 vs. 3 SSG with SB-SSG seems to represent an alternative to coaches to increase cardiovascular and metabolic demands in youth soccer players. PMID- 28566811 TI - The effect of combined supplementation of carbohydrates and creatine on anaerobic performance. AB - The purpose of the study was to examine the effect of creatine (Cr) supplementation on anaerobic performance when ingesting creatine and carbohydrates (CHO) together. Twenty male physical education students comprised the two experimental (CR and CRCHO) and one control (CON) groups of the study. All groups performed three 30 s anaerobic Wingate tests (AWTs) interspersed with 6 minutes of recovery. The CR group (n = 7) ingested 5 g of Cr 5 times per day for 4 days. Subjects in the CRCHO group (n = 6) ingested the same quantity but additionally after each 5 g dose of Cr consumed 500 ml of a commercially available energy drink containing 100 g of simple sugars. Over all three AWTs average mean power improved significantly compared to baseline for the CR group (5.51%) but not for the CRCHO group (3.06%). Mean power for the second AWT was improved following the acute loading for the CR group only (4.54%) and for the third AWT for both CR (8.49%) and CRCHO (5.75%) groups. Over all three AWTs a significant change was recorded in average peak power following the acute loading for the CR group (8.26%) but not for the CRCHO group (4.11%). Peak power was significantly improved following the loading only for the CR group during the third AWT (19.79%). No changes in AWT performance were recorded for the CON group after intervention. The findings of the present study suggest that ingesting creatine together with carbohydrates will not further improve performance compared to the ingestion of creatine only. PMID- 28566812 TI - Determinants of the effectiveness of fast break actions in elite and sub-elite Italian men's basketball games. AB - The aim of this study was to examine the determinants of successful and unsuccessful fast-break (FB) actions in elite and sub-elite basketball games. Fifteen 1st-division (elite) and fifteen 3rd-division (sub-elite) Italian men's championship games were analysed across two seasons (2012/2013 and 2013/2014). A binary logistic regression analysis was performed, and the fast-break outcome (successful vs. unsuccessful) was adopted as the dependent variable separately in both elite and sub-elite games. FB execution (initiation, advance and completion phases), typology (primary and secondary break) and the number of players involved (equal number or superiority) were used as independent variables. The results showed that the rate of success of FB actions was 63.5% and 59.7% in elite and sub-elite games, respectively. Moreover, successful FBs were more likely to be completed in the lane in relation to unsuccessful ones in both elite and sub-elite games (p<0.05). Finally, descriptive statistics showed that both elite and sub-elite teams executed FBs similarly. This study highlighted that completion zone was the only predictor of a successful fast break in basketball, while the typology and number of players involved did not predict fast break effectiveness. Moreover, elite and sub-elite teams executed fast break actions similarly. These findings might be useful for basketball coaches to optimize the training of FB actions. PMID- 28566813 TI - Kickboxing review: anthropometric, psychophysiological and activity profiles and injury epidemiology. AB - Kickboxing is one of the modern combat sports. The psychophysiological demands of a kickboxing competition require athletes to achieve high thresholds of several aspects of physical fitness. The aim of the current review is to critically analyse and appraise the kickboxer's anthropometric, physiological, physical and psychological attributes with the activity profile and injury epidemiology in order to provide practical recommendations for training as well as new areas of scientific research. The available information shows that both amateur and elite level male kickboxers are characterized by a higher proportion of mesomorphy with a well-developed muscle mass and low body fat percentage. While there is some variation in the maximum oxygen uptake of kickboxers, moderate to high cardio respiratory levels are reported for these athletes. Regardless of kickboxers' level, a high peak and mean anaerobic power output were reported. High-level kickboxing performance also requires well-developed muscle power in both the upper and lower limbs. Psychological factors contribute to success that requires high levels of self-confidence, motivation, dispositional hope and optimism, mental toughness/resiliency, and adaptive perfectionism. Psychological attributes also distinguished successful from less successful kickboxers. The activity-to rest ratio was higher in elite (1:1) than both amateur and national-level (from 1:2 to 1:5) kickboxers, with no significant differences between rounds (round 1=1:4, and rounds 2 and 3=1:5) as well as between winners and losers in amateur and national-level simulated combats. These particular psychophysiological characteristics and performance aspects of kickboxers influence performance and could serve as guidance for training. Finally, kickboxing is characterized by chronic repetitive head trauma, which causes hypopituitarism due to traumatic brain injury (TBI). Future investigations into the physical, physiological and psychological characteristics related to age, gender and competitive levels of kickboxers are required to enrich the current knowledge and to help create the most suitable training programme. PMID- 28566814 TI - Endocrine responses and acute mTOR pathway phosphorylation to resistance exercise with leucine and whey. AB - Leucine ingestion reportedly activates the mTOR pathway in skeletal muscle, contributing to a hypertrophy response. The purpose of the study was to compare the post-resistance exercise effects of leucine and whey protein supplementation on endocrine responses and muscle mTOR pathway phosphorylation. On visit 1, subjects (X+/-SD; n=20; age=27.8+/-2.8yrs) provided baseline blood samples for analysis of cortisol, glucose and insulin; a muscle biopsy of the vastus lateralis muscle to assess mTOR signaling pathway phosphorylation; and were tested for maximum strength on the leg press and leg extension exercises. For visits 2 and 3, subjects were randomized in a double-blind crossover design to ingest either leucine and whey protein (10g+10g; supplement) or a non-caloric placebo. During these visits, 5 sets of 10 repetitions were performed on both exercises, immediately followed by ingestion of the supplement or placebo. Blood was sampled 30 min post-, and a muscle biopsy 45 min post-exercise. Western blots quantified total and phosphorylated proteins. Insulin increased (alpha<.05) with supplementation with no change in glucose compared to placebo. Relative phosphorylation of AKT and rpS6 were greater with leucine and whey supplementation compared to placebo. Supplementation of leucine and whey protein immediately after heavy resistance exercise increases anabolic signaling in human skeletal muscle. PMID- 28566816 TI - A roadmap for the aspiring interventional pediatric cardiologist. PMID- 28566815 TI - Training-induced changes in physical performance can be achieved without body mass reduction after eight week of strength and injury prevention oriented programme in volleyball female players. AB - The purpose of the study was to analyse the changes in muscle strength, power, and somatic parameters in elite volleyball players after a specific pre-season training programme aimed at improving jumping and strength performance and injury prevention. Twelve junior female volleyball players participated in an 8-week training programme. Anthropometric characteristics, isokinetic peak torque (PT) single-joint knee flexion (H) and extension (Q) at 60o/s and 180o/s, counter movement jump (CMJ), squat jump (SJ), and reactive strength index (RSI) were measured before and after intervention. Significant moderate effects were found in flexor concentric PT at 60o/s and at 180 o/s in the dominant leg (DL) (18.3+/ 15.1%, likely; 17.8+/-11.2%, very likely) and in extensor concentric PT at 180o/s (7.4%+/-7.8%, very likely) in the DL. In the non-dominant leg (NL) significant moderate effects were found in flexor concentric PT at 60o/s and at 180o/s (13.7+/-11.3%, likely; 13.4+/-8.0%, very likely) and in extensor concentric PT at 180o/s (10.7+/-11.5%, very likely). Small to moderate changes were observed for H/QCONV in the DL at 60o/s and 180o/s (15.9+/-14.1%; 9.6+/-10.4%, both likely) and in the NL at 60o/s (moderate change, 9.6+/-11.8%, likely), and small to moderate decreases were detected for H/QFUNC at 180o/s, in both the DL and NL ( 7.0+/-8.3%, likely; -9.5+/-10.0%, likely). Training-induced changes in jumping performance were trivial (for RSI) to small (for CMJ and SJ). The applied pre season training programme induced a number of positive changes in physical performance and risk of injury, despite a lack of changes in body mass and composition. PMID- 28566817 TI - Three-dimensional-printed cardiac prototypes in complex congenital cardiac defects: New technology with exciting possibilities. PMID- 28566818 TI - Three-dimensional-printed cardiac prototypes aid surgical decision-making and preoperative planning in selected cases of complex congenital heart diseases: Early experience and proof of concept in a resource-limited environment. AB - INTRODUCTION: Three-dimensional. (3D) printing is an innovative manufacturing process that allows computer-assisted conversion of 3D imaging data into physical "printouts" Healthcare applications are currently in evolution. OBJECTIVE: The objective of this study was to explore the feasibility and impact of using patient-specific 3D-printed cardiac prototypes derived from high-resolution medical imaging data (cardiac magnetic resonance imaging/computed tomography [MRI/CT]) on surgical decision-making and preoperative planning in selected cases of complex congenital heart diseases (CHDs). MATERIALS AND METHODS: Five patients with complex CHD with previously unresolved management decisions were chosen. These included two patients with complex double-outlet right ventricle, two patients with criss-cross atrioventricular connections, and one patient with congenitally corrected transposition of great arteries with pulmonary atresia. Cardiac MRI was done for all patients, cardiac CT for one; specific surgical challenges were identified. Volumetric data were used to generate patient specific 3D models. All cases were reviewed along with their 3D models, and the impact on surgical decision-making and preoperative planning was assessed. RESULTS: Accurate life-sized 3D cardiac prototypes were successfully created for all patients. The models enabled radically improved 3D understanding of anatomy, identification of specific technical challenges, and precise surgical planning. Augmentation of existing clinical and imaging data by 3D prototypes allowed successful execution of complex surgeries for all five patients, in accordance with the preoperative planning. CONCLUSIONS: 3D-printed cardiac prototypes can radically assist decision-making, planning, and safe execution of complex congenital heart surgery by improving understanding of 3D anatomy and allowing anticipation of technical challenges. PMID- 28566819 TI - Neonates with critical congenital heart defects: Impact of fetal diagnosis on immediate and short-term outcomes. AB - BACKGROUND: Fetal echocardiography is being increasingly used for prenatal diagnosis of congenital cardiac malformations, but its impact on the neonatal outcomes in low- and middle-income countries is still unknown. AIMS: The objective of this study is to determine the impact of fetal echocardiography on immediate postnatal and short-term outcome in a tertiary pediatric cardiac center. STUDY DESIGN: This is a prospective study. MATERIALS AND METHODS: One hundred consecutive patients with critical congenital heart defects (CHD) requiring active medical or surgical interventions in the 1st month of life were included in the study. The detailed history, postnatal examination findings, and fetal echocardiogram report were recorded. They were divided into two groups as antenatally diagnosed and postnatally diagnosed. Pre- and post-procedural variables were compared between the two groups. RESULTS: Twenty-nine neonates were diagnosed antenatally while 71 were diagnosed postnatally. Totally, 10 babies (34.5%) among the antenatally diagnosed group were delivered in a tertiary health-care setup. The mean age at presentation was 0 day in the antenatally diagnosed group while 10 days (0-30 days) in the postnatally diagnosed group (P = 0.01). A total of 17 (58.6%) patients in the antenatal group had duct dependent CHD, and 15 (88.2%) of these patients were transported on prostaglandin E1. In comparison, 19/34 (55.9%) patients in the postnatal group were transported on prostaglandin. The pH on admission in the antenatal group was 7.32 +/- 0.05 as compared to 7.28 +/- 0.05 in the postnatal group (P = 0.0004). There were 4 (5.6%) deaths in the postnatal group during transfer. There was no significant difference in the postoperative variables in both groups. CONCLUSIONS: Fetal echocardiography identifies patients with complex CHD resulting in better parental counseling, thus facilitating delivery at a tertiary care center and preoperative stabilization. This results in improved preoperative mortality and better stabilization. PMID- 28566820 TI - Patent ductus arteriosus closure using Occlutech(r) Duct Occluder, experience in Port Elizabeth, South Africa. AB - BACKGROUND: Percutaneous closure of patent ductus arteriosus (PDA) has become standard therapy. Experience with the Occlutech(r) Duct Occluder is limited. METHODS: Data regarding ductal closure using Occlutech(r) Duct Occluder were reviewed and prospectively collected. Demographics, hemodynamic and angiographic characteristics, complications, and outcomes were documented. RESULTS: From March 2013 to June 2016, 65 patients (43 females and 22 males) underwent percutaneous closure of the PDA using Occlutech(r) Duct Occluder. The median age of the patients was 11 months (range, 1-454 months) and the median weight was 8.5 kg (range 2.5-78 kg). The mean pulmonary artery median pressure was 27 mmHg (range, 12-100 mmHg) and the QP: Qs ratio median was 1.8 (range, 1-7.5), with a pulmonary vascular resistance mean of 2.7 WU (standard deviation [SD] +/-2.1). Thirty-two patients had Krichenko Type A duct (49%); 7, Type C (11%); 4, Type D (6%); and 22, Type E (34%). The ductal size (narrowest diameter at the pulmonic end) mean was 3.5 mm (SD +/- 1.9 mm). The screening time mean was 17.3 min (SD +/- 11.6). Out of 63 patients with successful closure of the PDA using Occlutech(r) Duct Occluder, there were 15 patients with small PDAs; 25 with moderate PDAs, and 23 with large PDAs. In one patient, the device dislodged to the descending aorta, and in two patients, to the right pulmonary artery immediately following deployment, with successful percutaneous (two) and surgical (one) retrieval. Complete ductal occlusion was achieved in all 63 patients on day one. CONCLUSION: The Occlutech(r) Duct Occluder is a safe and effective device for closure of ducts in appropriately selected patients. PMID- 28566821 TI - Mid-term outcomes of surgical repair for anomalous origin of the left coronary artery from the pulmonary artery: In infants, children and adults. AB - BACKGROUND: Anomalous origin of left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital malformation. We sought to evaluate in-hospital and mid-term outcomes of patients with a diagnosis of ALCAPA who underwent surgical repair. OBJECTIVES: The objective of this study is to evaluate the mid-term outcomes of surgical repair of ALCAPA at our center and to analyze the surgical techniques used. MATERIALS AND METHODS: In a retrospective study, we analyzed early and mid-term clinical and echocardiographic data to determine the outcomes of patients who underwent surgical repair of ALCAPA in our institution between 2005 and 2015. RESULTS: Twenty-one patients underwent surgical repair for ALCAPA using aortic reimplantation (n = 10, 47.6%), ostial closure (n = 8, 38.1%), or ligation (n = 3, 14.3%). The median age of patients was 24 months (range 22 days to 51 years). There were 2 (9.5%) in-hospital mortalities in infants undergoing the reimplantation technique. All patients were followed up for a median of 21 months (range 1-60 months). No patients required reoperation, and there was no mortality from discharge to mid-term follow-up. Severe early postoperative mitral regurgitation (MR) was associated with composite end-point, defined as a combination of mortality after surgery, moderate to severe MR, and moderate to severe left ventricular dysfunction at late follow-up (P = 0.019) while mitral valve repair was not (P = 0.469). CONCLUSION: The surgical management of ALCAPA can be associated with good in-hospital and mid-term outcomes regardless of the age, at which the patient has been operated. PMID- 28566822 TI - Cost-effectiveness analysis of different devices used for the closure of small-to medium-sized patent ductus arteriosus in pediatric patients. AB - AIMS: In this study, we examined the differences in cost and effectiveness of various devices used for the closure of small to medium sized patent ductus arteriosus (PDA). SETTING AND DESIGN: We retrospectively studied 116 patients who underwent closure of small PDAs between January 2010 and January 2015. SUBJECTS AND METHODS: Three types of devices were used: the Amplatzer duct occluder (ADO) II, the cook detachable coil and the Nit Occlud coil (NOC). Immediate and late complications were recorded and patients were followed up for 3 months after the procedure. STATISTICAL METHODS: All statistical calculations were performed using Statistical Package for the Social Science software. P <0.05 were considered significant. RESULTS: We successfully deployed ADO II devices in 33 out of 35 cases, cook detachable coils in 36 out of 40 cases and NOCs in 38 out of 41 cases. In the remaining nine cases, the first device was unsuitable or embolized and required retrieval and replacement with another device. Eleven patients (9.5%) developed vascular complications and required anticoagulation therapy. Patients who had hemolysis or vascular complications remained longer in the intensive care unit, with consequently higher total cost (P = 0.016). Also, the need for a second device increased the cost per patient. CONCLUSIONS: The cook detachable coil is the most cost-effective device for closure of small-to medium sized PDAs. Calculations of the incremental cost-effectiveness. (ICE) revealed that the Cook detachable coil had less ICE than the ADO II and NOC. The NOC was more effective with fewer complications. PMID- 28566823 TI - Correlation of electrocardiogram parameters and hemodynamic outcomes in patients with isolated secundum atrial septal defects. AB - OBJECTIVE: The characteristic rSR' pattern in lead V1 on electrocardiogram (ECG) has been described in association with atrial septal defect (ASD) and right ventricular dilation. We aimed to determine if temporal ECG changes can guide a more discriminate and cost-effective screening during follow-up of isolated secundum ASD. METHODS: Our study population included all pediatric patients followed at the Stollery Children's Hospital with a secundum ASD, not associated with other significant heart disease, between 2004 and 2010. We collected clinical as well as serial echocardiographic and ECG data. RESULTS: We identified 141 patients with ASD, 95% were asymptomatic and 88% referred for a murmur. Moderate-to-large (>5 mm) ASDs were present in 52%. The prevalence of an rSR' pattern was 26% in the overall cohort and 54% in the large ASD group. During median follow-up of 28.7 months, 37 patients underwent surgical or transcatheter closure. Among patients with rSR' on ECG, 78% had moderate-to-large ASD size. In that group, the presence versus the absence of rSR' correlated with lower positive predictive value (PPV) for spontaneous closure (7% vs. 36%; P = 0.01) and higher PPV for device or surgical closure (71% vs. 38%; P = 0.02). CONCLUSION: We observed a lower prevalence of rSR' pattern in patients with isolated ASD than previously reported. However, an rSR' pattern had incremental value in predicting the need for surgical or device intervention for closure in moderate-large groups. This can be used to tailor patient echocardiographic screening and caregiver counseling. PMID- 28566824 TI - Use of strain, strain rate, tissue velocity imaging, and endothelial function for early detection of cardiovascular involvement in patients with beta-thalassemia. AB - BACKGROUND: Global ventricular function often remains normal in patients with beta-thalassemia major (beta-TM) until late. Tissue Doppler and strain imaging may be useful to assess regional myocardial function abnormalities in these patients. METHODS: Systolic (Sm), early diastolic (Em), and late diastolic (Am) (Em/Am) myocardial velocities at basal lateral and septal left ventricular (LV) segments, strain (S), and strain rate (SR) in basal and mid LV, right ventricular (RV) and septum were measured in 30 patients (beta-TM, 12.4 +/- 5.2 years, serum ferritin 2603.1 MUg/L) and twenty controls (12.5 +/- 5.2 years). Flow-mediated dilatation (FMD) vasodilatation as a measure of endothelial function was also assessed. RESULTS: Patients had significantly higher LV mass index (169.45 +/- 61.14 vs. 104.66 +/- 24.42; P = 0.009) while global LV Sm and diastolic function was similar to controls. Patients had significantly lower lateral Em velocity, Em (10.12 +/- 1.16 vs. 17.9 +/- 2.11; P = 0.002), Em/Am ratio (0.811 +/- 0.192 vs. 2.06 +/- 0.62; P = 0.001) at the basal lateral LV, lower strain values at the basal lateral LV (19.5 +/- 4.17 vs. 24.196 +/- 1.81; P = 0.002), mid lateral LV (19.07 +/- 3.98 vs. 25.56 +/- 2.62; P = 0.042), basal septum (17.04 +/- 3.44 vs. 25.43 +/- 2.53; P = 0.001), and mid septum (20.49 +/- 5.34 vs. 24.45 +/- 2.20; P = 0.001) as compared to controls. SR at the basal and mid segment of the lateral LV wall and at the basal and mid septum was also significantly lower in patients. SR in basal and mid RV although lower was not significantly different from controls. Patients also had significantly lower FMD (7.57 +/- 3.16 vs. 18.08 +/- 1.9, P = 0.018) implying endothelial dysfunction. CONCLUSIONS: Tissue Doppler, strain and SR imaging are useful to quantify regional myocardial function in asymptomatic beta-TM patients with preserved global Sm and diastolic function. PMID- 28566825 TI - Catheter hemodynamic assessment of the univentricular circulation. AB - Children with very complex congenital heart disease not amenable to biventricular repair are increasingly being considered for a palliative univentricular care pathway. This involves a staged surgical approach culminating in the Fontan circulation with passive pulmonary blood flow and added resistances. The catheter based hemodynamic assessment at all three stages of this palliation is described in detail. Frequent pitfalls, inherent limitations and potential errors are discussed and clinical examples are illustrated. PMID- 28566827 TI - A North African perspective on pediatric cardiac services: A focused interview with Dr. Sulafa Ali. PMID- 28566826 TI - Isomerism in the setting of the so-called "heterotaxy": The usefulness of computed tomographic analysis. AB - The most complex combinations of congenital cardiac malformations are found in the setting of bodily isomerism. The question remains, however, as to whether evidence of cardiac isomerism is always to be found in the setting of bodily isomerism, also known as "heterotaxy." We have previously shown that, when assessed on the basis of the extent of the pectinate muscles relative to the atrioventricular junctions, there is always isomerism of the atrial appendages in this setting. Doubt has been remained, however, as to whether these cardiac features can accurately be recognized during life. We have now encountered two patients showing features of the left and right bodily isomerism. Examinations of these patients made using computed tomography show that all features of isomerism, no matter how complex, can now be visualized during life. The images currently presented show, furthermore, that the features of the so-called "heterotaxy" can be seen during life, not only within the heart but also in all the thoracic and abdominal organs, albeit that the isomeric features are confined to the thoracic organs. Based on the images presented, we argue that if each system of organs is analyzed and described in independent fashion; then it is possible for clinicians to exclude any suggestion of ambiguity and to provide accurate descriptions of the overall arrangement. We further discuss the appropriate terminology to describe the entity we prefer to call isomerism, along with the indications and usefulness of computed tomography in revealing the anatomic features of the congenitally malformed heart. PMID- 28566828 TI - Aberrant right subclavian artery presenting as tracheoesophagial fistula in a 50 year-old lady: Case report of a rare presentation of a common arch anomaly. AB - A 50-year-old, woman with a 2-year history of progressive dysphagia and 2-month history of chronic cough was referred to our center in a state of generalized sepsis. Provisional diagnosis of carcinoma esophagus with tracheoesophagial fistula was made. Evaluation of the patient revealed an aberrant right subclavian artery with retroesophageal course with compression of the esophagus and trachea with fistulous communication in between. The patient was managed with medical stabilization and with feeding jejunostomy, but she succumbed to underlying severe sepsis. This presentation of aberrant subclavian artery at this advanced age rare and is therefore reported. PMID- 28566829 TI - Pitfalls of stenting coarctation of an angulated right circumflex aortic arch in Goldenhar syndrome. AB - We report stenting of coarctation of an angulated right circumflex aortic arch (RCAA) using four Cheatham Platinum stents in a child with Goldenhar syndrome. Difficulties in measuring the accurate length of the curved and narrowed transverse aortic arch marked discrepancy between the luminal diameters of the long narrow transverse arch and wide descending thoracic aorta, increased displacement force caused by the 90 degrees bend between the two parts resulted in repeated stent migrations. We discuss the tips to avoid distal stent migration in the setting of an angulated RCAA. PMID- 28566830 TI - Modified transjugular approach for percutaneous atrial septal defect closure. AB - Femoral venous route is routinely used for percutaneous closure of atrial septal defects (ASDs). However, a situation may arise where transfemoral approach is not feasible. We describe a successful transjugular closure of a moderate-sized ASD in a 49-year-old symptomatic man with interrupted inferior vena cava, using a novel deployment technique, which helped in overcoming difficulties such as maintaining stable sheath position and minimizing risk of air embolism. PMID- 28566831 TI - Repair of anomalous mitral arcade in a child. AB - A 13-year-old girl presented with exertional dyspnea and congestive heart failure. Echocardiography revealed severe congenital mitral stenosis due to anomalous mitral arcade with severe pulmonary hypertension. She underwent successful mitral valve repair. The case is reported for its rarity. PMID- 28566832 TI - Recanalization of an occluded left pulmonary artery: A case report and review of the literature. AB - We report an 8-year-old male child with tetralogy of Fallot (TOF), who developed left pulmonary artery (LPA) atresia, following surgical repair of TOF and left pulmonary arterioplasty at the age of 6 years. He underwent successful radiofrequency recanalization and stenting of the LPA. The LPA exhibited satisfactory growth for 3 months, following recanalization and stenting. PMID- 28566833 TI - Stent migration after right ventricular outflow tract stenting in the severe cyanotic Tetralogy of Fallot case. AB - We report our experience with a stent migration after right ventricle outflow tract stenting and converted to patent ductus arteriosus stenting in Tetralogy of Fallot (TOF) with severe infundibular stenosis. Finally, the patient achieved to TOF repair, and the migrated stent was removed without any complication. PMID- 28566834 TI - The utility of computed tomographic angiography in a neonate on extracorporeal membrane oxygenation with extreme cyanosis after Blalock-Taussig shunt. AB - A modified Blalock-Taussig shunt (mBTS) is often employed to provide pulmonary blood flow in neonates that are born with cyanotic congenital heart defects. However, acute shunt thrombosis can occur in the postoperative period, resulting in profound cyanosis. In this case report, we describe the utility of computed tomographic angiography (CTA) in the management of a neonate with extreme cyanosis after placement of a mBTS while on extracorporeal membrane oxygenation. Using CTA, several small clots were identified in the shunt as well as stenosis of the left pulmonary artery; neither of which were identified with echocardiography. The CTA allowed for quick identification of the disorder and helped direct prompt surgical intervention. PMID- 28566835 TI - Anomalous origin of right coronary artery causing myocardial ischemia in a young patient. AB - Anomalous right coronary artery from left coronary sinus can have dynamic narrowing and kinking causing symptoms of myocardial ischemia and sudden cardiac death. Surgical repair of the anomaly is required in the symptomatic patient because of risk of ischemia or ventricular arrhythmia. Asymptomatic incidentally diagnosed low-risk patients can be closely followed up with exercise restriction as per present guideline. PMID- 28566836 TI - Apparent normal arrangement pattern of three-vessel view in a fetus with transposition of great arteries and L-malposed aorta. AB - Transposition of great arteries (TGA) is more commonly associated with D malposition of great arteries where anterior aorta produces characteristic "I" sign in the three-vessel view (3VV) in fetal heart imaging. We describe two cases with TGA and L-malposition of aorta where 3VV imaging showed an apparently normal arrangement of vessels while outflow tract imaging proved vital in diagnosing transposition anatomy. Apparently, normal 3VV in the presence of disproportionate vessel caliber and inability to produce normal outflow images should raise the suspicion. Attempts should be made to produce views to show great arteries originating from respective ventricles to rule out ventriculoarterial discordance and to complete segmental analysis. PMID- 28566837 TI - Massive biventricular rhabdomyoma in a neonate. AB - Rhabdomyoma is a well characterised entity in a neonate. Herein, we report a massive biventricular rhabdomyoma in a neonate presenting with cyanosis and congestive heart failure which was confirmed on autopsy. The report is for documentation of an unusually large tumour. PMID- 28566838 TI - Birth prevalence of congenital heart disease: A cross-sectional observational study from North India. PMID- 28566839 TI - Author's Response. PMID- 28566840 TI - Spontaneous pneumoperitoneum: A rare entity. PMID- 28566841 TI - New Hope in Fight against Sickle Cell Anemia? PMID- 28566842 TI - Interprofessional Education: A Reform Plan for Collaborative. PMID- 28566843 TI - Worldwide Use of Triclosan: Can Dentistry Do Without this Antimicrobial? PMID- 28566844 TI - Peeling Back the Onion: An Outsider's Observations. PMID- 28566846 TI - Deproteinization of Fluorosed Enamel with Sodium Hypochlorite Enhances the Shear Bond Strength of Orthodontic Brackets: An In vitro Study. AB - CONTEXT: Improving bonding strength to fluorosed teeh. AIMS: To determine the effect of deproteinization using 5.25% sodium hypochlorite (NaOCl) prior to acid etching on shear bond strength of orthodontic brackets bonded to fluorosed teeth. SETTINGS AND DESIGN: In vitro experimental study. METHODS AND MATERIAL: Forty freshly extracted human mandibular first premolars with TFI 4 were selected and divided into two groups of 20 each. In Group I the teeth were acid etched with 37% phosphoric acid and bonded with composite. In Group II the teeth were deproteinized with 5.25% NaOCl prior to acid etching with 37% phosphoric acid and were bonded with composite. Samples were then subjected to shear bond test by Instron Universal Testing machine. The sample from each group were selected for the SEM study (prior to bonding) to analyze the etching patterns achieved. STATISTICAL ANALYSIS USED: Data was checked for normality by Shapiro Wilk Test, to compare the two groups unpaired t test was used. P value was predetermined at <= 0.05. RESULTS: The S BS of Group II (11.75 +/- 2.83 MPa) was higher than Group I (7.44 +/- 2.43 MPa) and the difference was statistically significant (P = 0.000). On SEM the etching pattern was more of type 1 and 2 in Group II. CONCLUSIONS: Deproteinization using 5.25% NaOCl prior to acid etching significantly increases the shear bond strength of brackets bonded to fluorosed teeth and can be used as a convenient and effective option in orthodontic bonding to fluorosed teeth. PMID- 28566845 TI - Prevention and Treatment of White Spot Lesions in Orthodontic Patients. AB - Decalcification of enamel, appearing as white spot lesions (WSLs), around fixed orthodontic appliances is a major challenge during and after fixed orthodontic treatment by considering the fact that the goal of orthodontic treatment is to enhance facial and dental esthetic appearance. Banded or bonded teeth exhibit a significantly higher rate of WSLs compared to the controls with no braces as fixed appliances and the bonding materials promote retention of biofilms. These lesions are managed in the first step by establishing good oral hygiene habits and prophylaxis with topical fluorides, including high-fluoride toothpastes, fluoride mouthwashes, gels, varnishes, fluoride-containing bonding materials, and elastic ligatures. Recently, other materials and methods have been recommended, including the application of casein phosphopeptides-amorphous calcium phosphate, antiseptics, probiotics, polyols, sealants, laser, tooth bleaching agents, resin infiltration, and microabrasion. This article reviews the currently used methods to manage enamel demineralization during and after orthodontic treatment and the risk factors and preventive measures based on the latest evidence. PMID- 28566848 TI - In Vitro Comparative Evaluation of Cleaning Efficacy and Volumetric Filling in Primary Molars: Cone Beam Computed Tomography Evaluation. AB - INTRODUCTION: Pulpectomy of primary teeth is mostly carried out with hand files and broaches which is tricky and time consuming procedure. The development of new design features like varying tapers, non-cutting safety tips and varying length of cutting blades have resulted in new generation of rotary instruments. AIM: To compare and evaluate cleaning efficacy, canal preparation and volumetric filling using conventional files and rotary V Taper files through cone beam computed tomography. MATERIALS AND METHOD: Thirty extracted primary molars were selected. The teeth were randomly divided into three groups each containing 10 teeth i.e. 30 canals in each group. Group A was instrumented with K files; Group B rotary V Taper files and Group C was Hybrid group. Sodium hypochlorite (1%) was used for irrigation. Root canal filling was done with Zinc Oxide Eugenol cement in all groups. The volumetric analysis i.e. Percentage of Volume (POV) of the root canal filling in primary molars was done through CBCT Software. RESULT: In present study, p- value was found to be significant (<0.05). Almost 100% of canals of hybrid group were fully filled and 63.3% of canals of hand filing group were partially filled. The filling was found to be dense and no. of voids was least in hybrid group. CONCLUSION: Clinical time required in primary molar endodontics, especially with unpredictability and difficulty of canal morphology, is inevitable. The study confirms superior ability of rotary-file systems to shape severely curved canals with less time and significant decrease in procedural errors like partial filling, voids and inappropriate canal preparation. PMID- 28566847 TI - Evaluation of Micronutrient (Zinc, Magnesium, and Copper) Levels in Serum and Glycemic Status after Nonsurgical Periodontal Therapy in Type 2 Diabetic Patients with Chronic Periodontitis. AB - AIMS AND OBJECTIVES: To find out the effect of nonsurgical periodontal therapy on serum zinc (Zn), magnesium (Mg), and copper (Cu) concentration and glycemic status in type 2 diabetes with chronic periodontitis (CP). MATERIALS AND METHODS: One hundred and twenty patients were included in this study, which was further divided into three groups. Group 1 consisted of forty patients with CP, Group 2 consisted of forty patients of CP with controlled diabetes, and Group 3 consisted of forty patients of CP with uncontrolled diabetes. Periodontal parameters such as plaque index, gingival index, bleeding on probing, pocket depth, and clinical attachment levels (CALs) were evaluated. Blood samples were collected to assess the levels of fasting blood sugar, glycosylated hemoglobin, Zn, Mg, and Cu. All parameters were evaluated at baseline and 3 months after nonsurgical periodontal therapy. RESULTS: The results showed statistically significant reduction in all the clinical parameters within the groups except for the CAL in group 1 patients (P = 0.05). The glycemic status also showed a statistically significant reduction after treatment (P < 0.001). The intragroup comparison was taken between the values of micronutrients, showed substantial increase in the levels of both Zn and Mg and decrease in the level of Cu after nonsurgical periodontal treatment (P < 0.001). CONCLUSION: Patients with diabetes and periodontitis had altered metabolism of Zn, Mg, and Cu contributing to the progression and complication of diabetes mellitus and periodontitis. Nonsurgical periodontal treatment improved the variation and concentration of plasma micronutrients and also the periodontal status and glycemic level. PMID- 28566849 TI - Prevalence of Three Rooted Permanent Mandibular First Molars in Haryana (North Indian) Population. AB - BACKGROUND: Mandibular first molars typically have two roots but sometimes a supernumerary root presents distolingually called as radix entomolaris (RE). AIM: The present study evaluated the prevalence of permanent mandibular first molars featuring a distolingual root in Haryana (North India). MATERIALS AND METHODS: Five hundred patients possessing bilateral mandibular first molars were selected for this study. The intraoral periapical radiographs were taken. The radiographs of these patients were evaluated under optimal conditions. A total of 1000 mandibular first molars were screened, and the incidence of three-rooted mandibular first molars, RE and the correlation between left and right side occurrence and between either gender were recorded. STATISTICAL ANALYSIS: The binary logistic regression test and Pearson's Chi-square test were used for statistical analysis. RESULTS: The prevalence of three-rooted permanent mandibular first molars was 13% of the patients examined and 8.3% of the teeth examined. There was no statistically significant difference between gender and side of occurrence (P >= 0.05). The bilateral incidence of a symmetric distribution was 27.6 (18/65) among the RE teeth examined. CONCLUSION: RE is considered as an Asiatic trait. The occurrence of this macrostructure in the Haryana (North India) population was found to be 13%. The clinician must thoroughly examine the radiographs before the initiation of endodontic therapy. PMID- 28566851 TI - An In vitro Evaluation of Microleakage Associated with Three Different Compomer Placement Techniques in Primary Molars. AB - BACKGROUND: Microleakage is one of the most frequently encountered problems in posterior tooth-colored restorations. Efforts to decrease this problem with resin restorations include techniques for reducing the ratio of bonded to unbonded restoration surfaces and following strategic incremental placement techniques to reduce residual stress at tooth-restoration interface which reduces the C-factor, hence microleakage. AIM: The present study aimed to evaluate microleakage associated with three placement techniques for compomer restorations in primary molars. DESIGN AND METHODOLOGY: This in vitro experimental study assessed the microleakage associated with bulk-fill, horizontal-incremental, and oblique incremental compomer placement techniques in primary molars. Ninety specimens were divided into three groups of thirty for each of the placement techniques. RESULTS: Nearly 86.6% of the specimens presented with microleakage involving the entire axial wall and pulpal floor in the bulk-fill group, whereas 56.6% and 46.6% of the specimens in the horizontal-incremental and oblique-incremental groups showed microleakage up to two-third and one-third of the axial walls, respectively. A significant difference in scores was observed between groups (P < 0.001). CONCLUSION: Microleakage was observed with all the three techniques but was comparatively lower with the incremental placement techniques. The oblique incremental technique offered the least microleakage. PMID- 28566850 TI - Antiplaque Efficacy of Tooth and Gums Tonic, Hiora-GA Gel, and Spirogyl Gum Paint in Comparison with Chlorhexidine M Gel: A Double-blind Randomized Control Trial. AB - OBJECTIVE: To compare the efficacy of three different herbal products (Tooth and Gums Tonic, Hiora-GA gel, and Spirogyl Gum paint) in reducing plaque, gingival inflammation and bacterial count in comparison with chlorhexidine M gel among participants with moderate to severe periodontitis. MATERIALS AND METHODS: A total of eighty participants with moderate to severe periodontitis were initially recruited after obtaining their informed consent. All participants were offered scaling and polishing on the first visit to remove visible calculus. Then, these participants were randomly divided into four groups of twenty participants each using block randomization method. Participants in Group 1, 2, 3, and 4 were given chlorhexidine M gel, Hiora-GA gel, Spirogyl Gum paint, and Tooth and Gums Tonic, respectively. All participants were instructed to brush their teeth twice day with a soft bristled toothbrush and their regular fluoridated toothpaste. They were instructed to apply the respective gels twice a day according to the manufacturer's guidelines. The posttreatment follow-up examinations for gingival and plaque changes were assessed after 30, 60, and 90 days by three trained and calibrated investigators using gingival and plaque index. The investigators and statistician were blind about group allocation. The supragingival plaque samples were collected before and 90 days after treatment from the buccal surfaces of maxillary right first permanent molar of each participant for microbial analysis. RESULTS: The mean plaque, gingival scores significantly decreased at different intervals following intervention in all groups. The bacterial counts also significantly reduced postintervention with no significant difference in the efficacy of these products compared to chlorhexidine. CONCLUSION: All three herbal products were found to be effective when used along with oral prophylaxis. Hence, they can all be used as alternates to chlorhexidine in the management of periodontal diseases. PMID- 28566852 TI - Correlation of Mandibular Radiomorphometric Indices with Serum Calcium and Serum Estradiol in Pre- and Post-menopausal Women. AB - BACKGROUND: Osteoporosis is a disease that is seen commonly with increasing age. The purpose of this study was to compare the bone quality of pre- and post menopausal women using the quantitative indices determined by measurements on panoramic radiographs (mental index, inferior and superior panoramic mandibular indices, antegonion index [AGI], and gonion index) and to determine the effects of serum calcium and serum estradiol levels on alveolar bone loss. MATERIALS AND METHODS: Sixty female patients in the age group of 25-55 years were included in the study. The patients were divided into three equal groups, i.e., control Group A (twenty - premenopausal women), study Group B (twenty - postmenopausal women with healthy periodontium), study Group C (twenty - postmenopausal women with periodontitis). Quantitative indices were measured on digital panoramic radiographs of the patients and serum calcium and estradiol levels were determined. RESULTS: Correlation of serum calcium with radiomorphometric indices of all the groups showed statistically nonsignificant differences. On correlating mean estradiol levels with radiographic indices of patients of Group A and Group B showed statistically nonsignificant differences. On correlating mean estradiol levels with radiographic indices of patients of Group C patients showed statistically significant difference with positive correlation with cortical width (P = 0.04) and AGI (P = 0.02) while statistically nonsignificant correlation with other indices. The statistical tests used for the analysis of the result were one-way ANOVA, multiple comparison Tukey test, Chi-square test, Student's t-test. CONCLUSION: There is a little evidence of correlation of these indices with serum estradiol and calcium levels, and therefore, detailed further research about this correlation is required. PMID- 28566853 TI - Bacteriostatic Effect of Simvastatin on Selected Oral Streptococci in Vitro. AB - CONTEXT AND OBJECTIVE: Simvastatin is a widely used cholesterol-lowering drug, which has been found to have a number of pleiotropic effects. The aim of this study was to evaluate the antimicrobial effectiveness of simvastatin against selected oral streptococci as determined by the minimum inhibitory concentration (MIC). METHODS: Streptococcus mutans, Streptococcus sanguis, Streptococcus anginosus, and Streptococcus salivarius were the test microorganisms. The serial dilution method was used to determine the MIC of simvastatin against these organisms. The MIC was defined as the lowest concentration of simvastatin that completely inhibited growth of the test organisms. RESULTS: The data indicate that simvastatin inhibits the growth of the test organisms, with MIC's ranging from 7.8 to 15.6 MUg/ml. CONCLUSIONS: Simvastatin has MIC's against the selected bacteria that compare favorably with reported values for topical agents such as essential oil, chlorhexidine gluconate, and triclosan. The levels of simvastatin required to inhibit bacterial growth of oral bacteria exceed the reported levels of the drug found in plasma or crevicular fluid of patients who are treated with this cholesterol-lowering drug. However, clinical studies are warranted to investigate the potential use of simvastatin as a novel antiplaque agent that could be used in local drug delivery to the oral cavity of those patients who are prescribed this cholesterol-lowering drug. PMID- 28566854 TI - Assessment of the dental and skeletal effects of fan-type rapid maxillary expansion screw and Hyrax screw on craniofacial structures. AB - AIMS AND OBJECTIVES: The purpose of the study was to assess the skeletal and dental effects of fan-type rapid maxillary expansion (RME) appliance and Hyrax RME appliance on the craniofacial structures. MATERIALS AND METHODS: The sample of the study included 12 patients with constricted maxillary arches. Acrylic bonded type of attachment was used for both groups. Changes in sagittal, vertical, and transverse relationship were assessed with lateral and frontal cephalograms, respectively. Intercanine and intermolar widths were measured with stone models. Pre- and immediate post-treatment records were statistically analyzed with Wilcoxon signed-rank test. The differences between the groups were evaluated using Mann-Whitney U-test. Since the data pertaining to intercanine width and intermolar width were normally distributed, parametric test of significance (unpaired t-test) was used to compare them. RESULTS: Results showed that Hyrax presented with significantly greater increments for both nasal cavity width and maxillary width when compared to fan-type RME. Both groups had retroclination of incisors. The increase in the intercanine width was almost similar in both groups. CONCLUSION: Fan-type RME caused only minimal expansion of the intermolar width when compared to the Hyrax. The ratio between the intercanine and intermolar width expansion was nearly 4:1 in the fan-type RME and 0.75:1 in Hyrax. PMID- 28566855 TI - Assessment of Bracket Surface Morphology and Dimensional Change. AB - OBJECTIVE: The objective of this study was to compare the surface morphology and dimensional stability of the bracket slot at the onset of treatment and after 12 months of intraoral exposure. The study also compared the amount of calcium at the bracket base which indicates enamel loss among the three orthodontic brackets following debonding after 12 months of intraoral exposure. MATERIALS AND METHODS: The sample consisted of 60 (0.022" MBT) canine brackets. They were divided into three groups: self-ligating, ceramic bracket with metal slot, and stainless steel (SS) brackets. The slot dimensions, micromorphologic characteristics of as received and retrieved brackets were measured with a stereomicroscope and scanning electron microscope (SEM), respectively. The amount of calcium at the bracket base which indicates enamel damage was quantified using energy-dispersive X-ray spectrometry (EDX). RESULTS: The results showed statistically significant alterations (P < 0.05) in the right vertical dimension, internal tie wing width (cervical), right and left depth of the slot (Kruskal-Wallis test). Multiple comparison using Mann-Whitney test showed that ceramic brackets underwent (P < 0.05) minimal alterations in the right vertical dimension, internal tie wing width (cervical), right and left depth of the slot (0.01 mm, -0.003 mm, 0.006 mm, -0.002 mm, respectively) when compared with the changes seen in SS and self ligating brackets. SEM analysis revealed an increase in the surface roughness of ceramic with metal slot brackets and self-ligating bracket showed the least irregularity. The presence of calcium was noted on all evaluated brackets under EDX, but ceramic with metal slot brackets showed a significantly greater amount of enamel loss (P = 0.001). CONCLUSION: Ceramic brackets were found to be dimensionally stable when compared to SS and self-ligating. Self-ligating bracket showed minimal surface irregularity. Ceramic with metal slot brackets showed a greater amount of enamel loss following debonding. PMID- 28566856 TI - Immunophenotypic and Molecular Analysis of Human Dental Pulp Stem Cells Potential for Neurogenic Differentiation. AB - BACKGROUND: Growing evidence shows that dental pulp (DP) tissues could be a potential source of adult stem cells for the treatment of devastating neurological diseases and several other conditions. AIMS: Exploration of the expression profile of several key molecular markers to evaluate the molecular dynamics in undifferentiated and differentiated DP-derived stem cells (DPSCs) in vitro. SETTINGS AND DESIGN: The characteristics and multilineage differentiation ability of DPSCs were determined by cellular and molecular kinetics. DPSCs were further induced to form adherent (ADH) and non-ADH (NADH) neurospheres under serum-free condition which was further induced into neurogenic lineage cells and characterized for their molecular and cellular diversity at each stage. STATISTICAL ANALYSIS USED: Statistical analysis used one-way analysis of variance, Student's t-test, Livak method for relative quantification, and R programming. RESULTS: Immunophenotypic analysis of DPSCs revealed >80% cells positive for mesenchymal markers CD90 and CD105, >70% positive for transferring receptor (CD71), and >30% for chemotactic factor (CXCR3). These cells showed mesodermal differentiation also and confirmed by specific staining and molecular analysis. Activation of neuronal lineage markers and neurogenic growth factors was observed during lineage differentiation of cells derived from NADH and ADH spheroids. Greater than 80% of cells were found to express beta-tubulin III in both differentiation conditions. CONCLUSIONS: The present study reported a cascade of immunophenotypic and molecular markers to characterize neurogenic differentiation of DPSCs under serum-free condition. These findings trigger the future analyses for clinical applicability of DP-derived cells in regenerative applications. PMID- 28566857 TI - Comparative Evaluation of Gingival Depigmentation by Tetrafluroethane Cryosurgery and Surgical Scalpel Technique. A Randomized Clinical Study. AB - INTRODUCTION: Importance of good smile cannot be underestimated in enhancement of beauty, self-confidence and personality of a person. Health and appearance of gingiva is an essential part of attractive smile. Gingival pigmentation gives rise to unesthetic smile line. In present world, with increasing awareness to esthetic, people have become highly concerned about black gums. Various treatment modalities like abrasion, scrapping, scalpel technique, cryosurgery, electrosurgery and laser are available for treatment of gingival pigmentation. The present study was conducted with an objective of comparing efficacy of gingival depigmentation by cryosurgery and scalpel technique. METHOD: A Randomized control split mouth study was conducted for 25 patients with gingival pigmentation. Gingival pigmentation Index (GPI) for pigmentation and Visual Analoug Scale (VAS) for pain was evaluated for both test (Cryosurgery) and control sites (Scalpel technique) at baseline, 1month, 3months and 6 months. RESULTS: GPI score was 3 and 2 for 21/25 and 4/25 control sites and was 22/25 and 3/25 test sites respectively at baseline. Both the groups showed significant reduction in GPI score i.e., 0 at 1 and 3 months interval after treatment. GPI score increased to 1 for 5/25 sites treated with scalpel technique and 2/25 sites treated with cryosurgery at 6 months interval (P =0.0691). This indicates recurrence rate for pigmentation is higher after scalpel treatment. VAS Score was 3 for 10/25 sites treated with scalpel and was 2 for 12/25 sites treated with cryosurgery (P <0.001). CONCLUSION: It can be concluded that cryosurgery can be effectively and efficiently used for depigmentation by keeping patients acceptance and comfort in mind and also the long term results and ease of use when compared to scalpel technique. PMID- 28566858 TI - Comparative Evaluation of the Lipid Profile in the Serum of Patients with Type II Diabetes Mellitus and Healthy Individuals with Periodontitis. AB - CONTEXT: Periodontal disease is an immuno-inflammatory disease that is initiated by the interaction between microbial plaque and the periodontal tissues. The data available on the association of periodontal diseases with the lipid profile are conflicting. Therefore, a need for a study in this area was felt. AIMS: To evaluate the lipid profile in the serum of patients with chronic periodontitis and chronic periodontitis with Type II diabetes mellitus (DM) patients and to compare it with healthy controls, to see whether they can serve as potential markers for chronic periodontitis and also to assess whether periodontitis can have systemic effects. SETTINGS AND DESIGN: This study is a cross-sectional study. SUBJECTS AND METHODS: This cross-sectional study was conducted involving 300 participants in the age group of 30-60 years from October 2010 to May 2015. Five milliliters of venous blood was collected from each of the study participants, from the antecubital vein. Lipid profile was assessed using the ERBA commercially available kit. STATISTICAL ANALYSIS: Statistical analysis was carried out using SPSS software version 17. Multigroup comparison was carried out using ANOVA. The honest significant difference Tukey's test was used in conjunction with ANOVA to find means which are significantly different from each other. RESULTS: When the lipid profile was estimated, total cholesterol (TC) levels were seen to be significantly higher (P < 0.001) in the DM with periodontitis group. High-density lipoprotein (HDL) levels were seen to be significantly higher (P < 0.001) in the control group. Mean serum low-density lipoprotein (LDL) and very LDL (VLDL) levels were seen to be significantly higher (P < 0.001) in the DM with periodontitis group. The triglyceride (TGL) values were also significantly higher (P < 0.001) in the DM with periodontitis group. The HDL and LDL levels were seen to be nonsignificant between chronic periodontitis and chronic periodontitis with diabetic group. CONCLUSIONS: The findings of the study showed that the lipid profile was significantly altered in patients with chronic periodontitis as compared to healthy controls. There was a potentiated difference in the values for TC, VLDL cholesterol, and TGL in patients with chronic periodontitis when compared to patients with Type II DM. HDL cholesterol and LDL cholesterol did not show a significant difference. PMID- 28566859 TI - Interleukin 1beta (+3954; -511) Genotype Polymorphism and its Association with Severe Chronic Generalized Periodontitis in the Malaysian Population. AB - INTRODUCTION: Single-nucleotide polymorphisms (SNPs) in interleukin 1beta (IL 1beta) gene have been known to be associated with increased susceptibility to chronic periodontitis among various ethnic populations. SNPs are more commonly observed at loci + 3954 and - 511. The aim of this study was to evaluate the role of IL-1beta gene polymorphism at loci +3954 and - 511, and its association with severe chronic generalized periodontitis among the ethnic Malay, Chinese, and Indians within the Malaysian population. MATERIALS AND METHODS: Saliva samples from 120 subjects (60 cases and 60 controls) in the age group of 25-50 years were collected for isolation of genetic material using Norgen technique. Clinical attachment loss of >=5 mm was considered as severe chronic generalized periodontitis. SNP's at loci +3954 and - 511 were identified and analyzed using Kompetitive Allele Specific Polymerase Chain Reaction Genotyping System (KASPTM). Differences in the allele/genotype frequencies were assessed by Chi-square test (P < 0.05). RESULTS: On the comparison between cases and controls of IL-1beta genotype polymorphism (+3954 and - 511), the difference in the genotype frequencies was statistically insignificant in all the three ethnicities. The genotype frequency in both groups in all three ethnicities of the Malaysian population was similar. CONCLUSION: IL-1beta genotype polymorphism at +3954 and - 511 was found to be not associated with severe chronic generalized periodontitis among the three ethnicities in Malaysia. Studies with larger sample size should be done to confirm the findings of this study. PMID- 28566860 TI - Comparative Evaluation of Fresh Aloe barbadensis Plant Extract and Mineral Trioxide Aggregate as Pulpotomy Agents in Primary Molars: A 12-month Follow-up Study. AB - BACKGROUND: The purpose of this study was to compare the clinical and radiographic outcomes of fresh Aloe vera barbadensis plant extract and mineral trioxide aggregate (MTA) as pulpotomy agents in primary molar teeth. MATERIALS AND METHODS: Pulpotomy procedure was performed in sixty primary molar teeth which were randomly allocated to two groups, i.e., Aloe vera pulpotomy (Group A) and MTA pulpotomy (Group B). All the pulpotomized teeth were evaluated clinically and radiographically at 1, 3, 6, 9, and 12 months of time interval using predetermined criteria. RESULTS: The success rates between Groups A and B at the end of the 1st month were 24.1% and 96.4%, at the end of 3rd month were 57.1% and 100%, at the end of 6th month were 75% and 100%, at the end of 9th month were 66.6% and 100%, and at the end of 12 months were 100% and 100% respectively. The overall success rates at the end of 12-month follow-up period were 6.9% and 71.4%, respectively, after taking dropout patients into consideration, and the difference was statistically significant (P < 0.001). CONCLUSIONS: MTA pulpotomy was found to be superior when compared to fresh A. barbadensis plant extract pulpotomy in primary molars. PMID- 28566861 TI - Needlestick and Sharp Instruments Injuries among Brazilian Dentistry Students. AB - BACKGROUND: The occurrence of occupational accidents is common among students and dentists. The present study is aimed to evaluate the prevalence and characteristics of needlestick and sharp instrument injuries among dentistry students. MATERIALS AND METHODS: A documentary research was carried out with data being obtained from the analysis of 137 medical records of injuries caused by needlestick and sharp instruments occurring in the period from 2012 to 2016 and were analyzed regarding the characteristics of the victim (gender and age) and the accident (year, time, environment, and time interval between exposure and search for care). Data were organized in the Statistical Package for Social Sciences software version 18 and were presented through descriptive statistics. RESULTS: The occurrence of accidents was high (43.1%), with the predominance of female victims (66.1%) and aged up to 23 years (55.9%). The majority of events occurred in the afternoon (54.4%), in the clinical setting (70.7%), and in 75% of the cases, the search for care occurred within 2 h after exposure. CONCLUSION: Accidents with needlestick and sharp instruments have high frequency and involve mainly female students. They are more common in the afternoon and in the clinical setting and the time interval was between exposure and the search for care complied with recommendations of the Brazilian legislation. PMID- 28566862 TI - Effect of Freeze Dried Powdered Probiotics on Gingival Status and Plaque Inhibition: A Randomized, Double-blind, Parallel Study. AB - OBJECTIVE: The study aimed to evaluate the effectiveness of freeze dried powdered probiotics on gingival status and plaque inhibition among 12-15-year-old schoolchildren. MATERIALS AND METHODS: This randomized controlled trial was conducted among 12-15-year-old schoolchildren in Jaipur. Commercially available freeze dried probiotics containing Lactobacillus acidophilus, Bifidobacterium longum, Bifidobacterium bifidum and Bifidobacterium lactis (Prowel, Alkem Laboratories), lactic acid bacillus only (Sporolac, Sangyo), and a placebo powder calcium carbonate 250 g (Calcium Sandoz, Novartis) were assigned to two intervention groups and a placebo group each comprising 11 schoolchildren. All subjects were instructed to mix the powder in 30 ml of water and swish once daily for 3 min, for 3 weeks. Periodontal clinical parameters were assessed by examining the subjects for Turesky-Gilmore-Glickman plaque index (PI) (Modification of Quigley-Hein PI) and gingival index at baseline, 7th day, 14th day, and 21st day. RESULTS: For both the probiotic groups, a statistically significant reduction (P < 0.05) in gingival status and plaque inhibition was recorded up to 2nd week of probiotic ingestion. However, no significant difference was observed in the placebo group. CONCLUSION: The use of probiotic mouth rinses improves the oral health in children by significantly reducing the plaque and gingival scores. Further studies are warranted to prove or refute the long-term effects, means of administering probiotics and the dosages needed to achieve different preventive or therapeutic purposes. PMID- 28566863 TI - In vivo Comparative Evaluation of Mineral Trioxide Aggregate and Formocresol Pulpotomy in Primary Molars: A 60-month Follow-up Study. AB - INTRODUCTION: Pulpotomy is a regular procedure in the management of inflamed primary teeth. Diverse materials have been reviewed for the pulpotomy, some of them being formocresol, glutaraldehyde, ferric sulfate, and mineral trioxide aggregate (MTA). AIMS: The aim was to evaluate and compare clinically and radiographically the effects of MTA as a pulp dressing after coronal pulp amputation (pulpotomy) in primary molars. SETTINGS AND DESIGN: Sixty primary molars of thirty healthy children using split mouth design aged between 4 and 6 years were treated by pulpotomy technique. SUBJECTS AND METHODS: Sixty primary mandibular molars of thirty healthy children aged between 4 and 6 years were treated by pulpotomy technique. The teeth on the right side were assigned to MTA (Group A) and the left side for the formocresol (Group B). The children were then examined clinically and radiographically every 6 months. Statistical analysis used: Chi-square test using the SPSS version 19.0 was used to compare between the two groups. RESULTS: Results showed that both MTA and formocresol have the same outcome on the primary molars, with Chi-square value being 1.1483 (P >= 0.05). None of the teeth in any children in the study showed any clinical pathology. CONCLUSION: The principle conclusions of this study are that there are no significant differences in MTA and formocresol. The success rate of MTA and formocresol pulpotomy can be considered comparable till this therapy influences the development and growth of the permanent teeth. PMID- 28566865 TI - Pycnodysostosis: Clinicoradiographic Report of a Rare Case. AB - Pycnodysostosis is an uncommon autosomal recessive sclerosing bone disorder which is characterized by short stature and generalized diffuse osteosclerosis. Patients usually have a large head with separated sutures, open fontanels, aplasia of frontal sinuses, obtuse mandibular gonial angle, and acroosteolysis of the distal phalanges. This case report showed a 25-year-old female with features pathognomonic of pycnodysostosis. The emphasis is mainly on the early diagnosis as it has an important role in the general health of such patients and prevention of complications. PMID- 28566864 TI - Comparative Evaluation of Caries Status in Primary and Permanent Molars in 7-8 year-old Schoolchildren of Shimla Using Caries Assessment Spectrum and Treatment Index. AB - BACKGROUND: A new epidemiological index is introduced for full assessment of dental caries which is known as caries assessment spectrum and treatment (CAST). "Spectrum" is considered backbone of this index as it covers from no lesion to advanced stage progression of caries. We aimed to evaluate and compare the status of caries in primary and permanent molars of 7-8-year-old schoolchildren of Shimla using CAST index and to find if any correlation exists between the status of caries in evaluated teeth. METHODS: Three hundred and one schoolchildren with age group of 7-8 years were selected from schools in Shimla. CAST codes were determined for primary molars and first permanent molars. The distribution of CAST codes in the examined molars is correlated with the help of Spearman's rank correlation coefficient. The level of statistical significance was established at P < 0.05. The intraexaminer reliability was determined by the unweighted kappa coefficient. RESULTS: Caries was assessed in 6.3%-12.3% of the permanent molars in contrast to primary molars, in which caries was near about 50%. The correlation was stronger for first and second deciduous molars for the right side of the mouth than the left side (r = 0.293 and 0.257 in the maxilla and 0.503 and 0.319 in the mandible [P < 0.001], respectively, while correlation for teeth in opposite jaws was moderate [r = 0.20-0.47]). The intraexaminer reliability was examined (k = 0.90 for the primary and 0.85 for permanent molars). CONCLUSION: The correlation between primary and permanent molars regarding the caries status in primary molars is weak while strongest correlation was present on the right side of the mouth for first and second deciduous molars. The study also showed the applicability of the CAST index in epidemiological surveys. PMID- 28566866 TI - Management of Developing Skeletal Class III Malocclusion in a Prepubertal Girl with Prognathic Mandible in Late Mixed Dentition. AB - Treatment of skeletal Class III patients at younger age is highly unpredictable. The patient may respond well to the treatment or may show excessive mandibular growth during growth spurt which may require orthognathic surgery later on. If not treated at earlier stages of life, the condition may worsen with time. This case report will present the comprehensive orthodontic management of a 9-year-old prepubertal girl in late mixed dentition with prognathic mandible. Chin cup therapy was started and continued for 3 years. After chin cup therapy, maxillary and mandibular dentition were bonded with standard edgewise appliance. After leveling and alignment, Class III elastics were started. Fixed orthodontic treatment was completed in 3 years. At the end, good Class I molar and canine relationship with normal overjet and overbite were achieved. The total treatment time of orthopedic and orthodontic correction was 6 years, 2 months. The patient revealed the same Class I molar and canine relationship after 6 years of treatment. Redirection of mandibular growth pattern from hyperdivergent to normodivergent advocates the use of chin cup as a viable treatment regimen for the management of prognathic mandible in prepubertal patients. PMID- 28566867 TI - Effectiveness of Osteopathic Therapy in the Treatment of Oral Submucous Fibrosis. AB - Oral submucous fibrosis (OSMF) is a chronic progressive debilitating disease of oral cavity leading to the stiffness of oral mucosa, burning and trismus resulting in marked rigidity, and an inability to open the mouth. As the medical treatment of OSMF is yet not standardized, the purpose of the present case study was to explore the effectiveness of osteopathic manipulative treatment (OMT) in patients with OSMF. A 30-year-old male presented with a complaint of reduced mouth opening with burning sensation while eating spicy food for 4 years. The patient had undergone pharmacological treatment for the same in the past, got relief in the burning sensation, but did not get any significant improvement in mouth opening. Radiological features were noncontributory. The patient was treated with OMT techniques for twice a week for 4 weeks followed by the home exercise program. The patient showed a significant increase in mouth opening from approximately 10 mm to 22 mm of mouth opening at the end of the treatment sessions. PMID- 28566868 TI - Oral Subcutaneous Midline Leiomyomatous Hamartoma Presenting as Congenital Incisive Papilla Overgrowth in a Toddler. AB - Congenital soft-tissue tumors of oral cavity are mostly hyperplastic and benign in nature. This article presents an unusual case of congenital subcutaneous hamartoma of incisive papilla in a 2-year-old female child causing feeding and breathing difficulty. Total excisional biopsy was done under local anesthesia. Histopathology of tissue in reticulin-stained slide showed the presence of immature muscle fibers whereas Masson's trichrome stain revealed collagen fibers and smooth muscles confirming the diagnosis of oral midline subcutaneous smooth muscle (leiomyomatous) hamartoma of incisive papilla. It is important for dental professionals to be aware of this oral lesion present from birth mimicking overgrowth of incisive papilla, by its presentation, differential diagnosis, histopathology, and management. PMID- 28566869 TI - Bilateral Second Premolars Agenesia Together with a Unilateral Canine Radiculomegaly. AB - Congenitally missing teeth is a common feature for the third molars. However, missing teeth, macrodontia and radiculomegaly occurring in a single patient is very rare. This article describes a case of agenesis of mandibular second premolars, radiculomegaly with dilacerations of a canine tooth together with elongated roots of other canines. All these features had been discerned through diagnostic radiographs taken during a routine treatment planning. PMID- 28566870 TI - Temporomandibular Joint Dislocation in an 18-month-old Child. AB - Temporomandibular joint (TMJ) dislocation in children is extremely rare. In our case, an 18-month-old child presented with a history of inability to close her mouth. To confirm the clinical diagnosis, a computed tomogram was taken. Clinical examination and X-ray of the TMJ revealed bilateral TMJ dislocation. Bilateral TMJ reduction was achieved manually after giving analgesia and procedural sedation. This is one of the few case reports of an acute dislocation in a toddler. PMID- 28566871 TI - Endo-restorative Management of a Type II Dens Invaginatus in Mandibular Premolar Associated with a Large Cyst. AB - We present the management of a case of Type II dens invaginatus in a mandibular premolar with a large invagination in the coronal third of the root on mesial aspect of the crown in proximity of cementoenamel junction significantly compromising the strength of the crown structure. We describe in detail the various measures taken to assess the internal tooth structure destruction and enhance the fracture resistance of the involved premolar. The case has a long term follow-up of 36 months showing clinical and radiographic signs of healing. We highlight use of a simple "foil coated fiber postblocker technique" for root reinforcement in the first premolar. Successful management of teeth with dens invaginatus can be effectively done using with careful treatment planning and selection of reinforcing adhesive restorative materials. PMID- 28566872 TI - Treatment of Class II Malocclusion and Impacted Canines with Two-phase Orthodontic Treatment. AB - Twin Block appliance has been widely used for the treatment of Class II malocclusions in growing subjects, due to its versatility and its highly compliance nature. There are certain clinical indications where functional appliances can be used successfully in Class II malocclusion as in a growing patient. In using these appliances, the main concern is compliance of patients. This appliance simplifies the progression of treatment with fixed orthodontic braces later on. In this case, a 14-year-old adolescent was treated with Twin Block appliance followed by fixed appliances for finishing and detailing. The design and treatment effects are demonstrated in this case report. PMID- 28566873 TI - Hollow Bulb One Piece Maxillary Definitive Obturator - A Simplified Approach. AB - In maxillary defects, role of a prosthodontist is to rehabilitate the intra- and extra-oral structures and to endow with the normal function of mastication, speech, deglutition, and esthetics. Malignancies are common in the oral region and are treated usually through surgical intervention. Surgical intervention creates anatomical defects creating communication between oral and nasal cavity. Patients pose difficulties while performing normal functions such as swallowing and speaking, due to this communication. To overcome the problems encountered by the patient, obturators are fabricated. The main problem with rehabilitation of large defect is the weight of prosthesis; the prosthesis becomes very bulky and nonretentive due to its weight. Hollow obturators are fabricated to conquer this tribulation by different techniques. This case report describes a simplified method of fabrication of a definitive hollow bulb obturator for rehabilitation of a maxillary defect (Aramany's class I) by insertion of balloon. PMID- 28566874 TI - Bilateral Complete and Incomplete Fusion of Incisors and its Management. AB - This case report highlights the management of a case of bilateral complete and incomplete fusion of maxillary incisors in a 10-year-old child. A mock-up was done on the diagnostic cast. Pretreatment esthetic evaluation was done using bis acryl composite temporaries which were transferred intraorally from the diagnostic cast using a putty index. An incisal overlap veneer preparation was done, following which, an IPS e-max veneer was cemented. A digital mock-up was carried out using the Adobe Photoshop and Corel Draw softwares to aid in laboratorial fabrication of the veneer. PMID- 28566875 TI - Intermediate Type of Juvenile Paget's Disease: A Rare Case in Indian Population. AB - Juvenile Paget's disease (JPD), a rare genetic skeletal disorder characterized by accelerated bone turnover with elevated levels of serum alkaline phosphatase, presents in early childhood. We report a female patient with typical features of JPD with dental finding who remained undiagnosed until 18 years of age. Scarcity of this disease in the Indian literature and need for timely diagnosis to avert progression of disease thus incited us to report this case. PMID- 28566876 TI - Trabecular Variant: A Rare Entity of Juvenile Ossifying Fibroma of the Mandible. AB - One of the rarest entities of fibro-osseous lesions that arise within the craniofacial bones is Juvenile ossifying fibroma (JOF). It is an intraosseous expansile lesion of the jaw that imitate odontogenic lesions. WHO has described two distinct histopathological variants of JOF; trabecular and psammomatoid. Histologically, they are characterized by the presence of fibrous connective tissue stroma along with osteoblastic and osteoclastic cells. Clinical, characteristics show an early age of onset, typical histological patterns, high rate of aggressive behavior and recurrence. This article presents a rare clinical case of the trabecular variant of JOF, its clinical, radiological, histological, and treatment aspects. PMID- 28566877 TI - Actinomyces-associated Lesions Located in the Gingiva: Case Report of Rare Gingival Lesions. AB - Actinomyces spp. are located without displaying any pathogenic effect in the oral flora. However, the disruption of oral microenvironmental balance, mucosal tissue integrity, and defense system can cause microorganisms to settle on deep periodontal tissues and to induce pathologic reactions. The present case report describes erythematous and desquamative lesions with pseudomembrane limited to the gingiva. In the histopathologic examination, Actinomyces colonies were isolated from the gingiva. On the basis of histopathologic and laboratory findings, the lesions were diagnosed as Actinomyces- associated lesions of the gingiva. No condition that caused immuno suppression was present in the patient. Nevertheless, local effect of the chlorhexidine mouthwash usage for a period may induce irritation of the oral keratinized tissue. The localized form of actinomycotic lesions occurs seldom in the gingival tissues. In rare cases like this, the practice of differential diagnosis with a multi-disciplinary approach is very important for the accurate diagnosis and appropriate treatment planning. PMID- 28566878 TI - Consequences of Facial Hemangioma with Regard to Dental Treatment. AB - Hemangioma is a benign vascular tumor that affects 3%-10% of the population and usually does not require specific treatment due to spontaneous regression. The purpose of this paper is to present a case report of a child having been born prematurely and diagnosed with hemangioma in the head and neck, emphasizing the dentofacial changes and treatment used to provide care. Severe fibrous scars were found in the perioral region and below the ear that limited the patient's ability to open her mouth. The child exhibited anterior open bite as well as dental caries in the lower jaw, hypomineralization, and enamel hypoplasia. Treatment consisted of dietary and oral hygiene orientations, dental prophylaxis, topical 1:23% acidulated phosphate fluoride gel, removal of the carious tissue, sealing with glass ionomer cement, and extraction. Dentists need to have knowledge on hemangioma for a proper diagnosis and the optimization of dental treatment. PMID- 28566879 TI - Liver transplantation for intermediate hepatocellular carcinoma: An adaptive approach. AB - Hepatocellular carcinoma is becoming an increasing indication for liver transplantation, but selection and allocation of patients are challenging because of organ shortages. Conventional Milan criteria are the reference for the selection of patients worldwide, but many expanded criteria, like University of California San Francisco criteria and up-to-7 criteria, have demonstrated that survival and recurrence results are lower than those for restricted indications. Correct staging is crucial and should include surrogate markers of biological aggressiveness (alpha-fetoprotein, response to loco-regional treatments). Successful down-staging can select between patients with tumor burden initially beyond transplantation criteria those with a more favorable biology, provided a 3 mo stability in meeting the transplantation criteria. Allocation rules are constantly adjusted to minimize the imbalance between the priorities of candidates with and without hepatocellular carcinoma, and take into account local donor rate and waitlist dynamics. Recently, Mazzaferro et al proposed a benefit oriented "adaptive approach", in which the selection and allocation of patients are based on their response to non-transplantation treatments: low priority for transplantation in case of complete response, high priority in case of partial response or recurrence, and no listing in case of progression beyond transplantation criteria. PMID- 28566880 TI - Immune response to vaccines in children with celiac disease. AB - Celiac disease (CD) is an immune-mediated systemic condition evoked by ingestion of gluten and related prolamines in genetically susceptible subjects. The disease is featured by a variable combination of clinical signs, specific antibodies, HLA DQ2 and HLA-DQ8 haplotypes, and enteropathy. Vaccination is the most potent intervention for infectious disease prevention. Several factors including age, gender, ethnicity, quality and quantity of vaccine antigen, doses, and route of administration can influence immune response to vaccination, although the main cause of variation in the responsiveness among vaccine recipients is host genetic variability. The HLA system has a fundamental role in identifying the antigens introduced into the host with the vaccines and in the development of specific antibodies, and some HLA phenotypes have been associated with a less effective immunological response. The available literature indicates that the immunological response to vaccines in CD children does not differ markedly from that of general population and antibody titres are high enough to provide long-term protection, except for hepatitis B virus vaccine. In this article, we review and discuss the scarce literature in this field in order to provide clinical practice guidelines to achieve the most efficient monitoring of the response to vaccines in pediatric CD patients. PMID- 28566881 TI - Inflammatory bowel disease in liver transplanted patients. AB - Most common hepatobiliary manifestation of inflammatory bowel disease (IBD) are primary sclerosing cholangitis (PSC) and autoimmune hepatitis, ranking them as the main cause of liver transplantation (LT) in IBD setting. Course of pre existing IBD after LT differs depending on many transplant related factors. Potential risk factors related to IBD deterioration after LT are tacrolimus-based immunosuppressive regimens, active IBD and cessation of 5-aminosalicylates at the time of LT. About 30% patients experience improvement of IBD after LT, while approximately the same percentage of patients worsens. Occurrence of de novo IBD may develop in 14%-30% of patients with PSC. Recommended IBD therapy after LT is equivalent to recommendations to overall IBD patients. Anti-tumor necrosis factor alpha appears to be efficient for refractory IBD. Due to potential side effects it needs to be applied with caution. In average 9% of patients require proctocolectomy due to medically refractory IBD or colorectal carcinoma. The most frequent complication in patients who undergo proctocolectomy with ileal-pouch anal anastomosis is pouchitis. It is still undeterminable if LT adds to risk of developing pouchitis in PSC patients. Annual colonoscopies are recommended as surveillance and precaution of colonic malignancies. PMID- 28566882 TI - Platelets in liver disease, cancer and regeneration. AB - Although viral hepatitis treatments have evolved over the years, the resultant liver cirrhosis still does not completely heal. Platelets contain proteins required for hemostasis, as well as many growth factors required for organ development, tissue regeneration and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD) and cirrhosis, can manifest from decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis, as well as the role of platelets in CLD, is poorly understood. In this paper, experimental evidence of platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. In addition, we describe our current perspective based on the results of these studies. Platelets improve liver fibrosis by inactivating hepatic stellate cells, which decreases collagen production. The regenerative effect of platelets in the liver involves a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these observations, we ascertained the direct effect of platelet transfusion on improving several indicators of liver function in patients with CLD and liver cirrhosis. However, unlike the results of our previous clinical study, the smaller incremental changes in liver function in patients with CLD who received eltrombopag for 6 mo were due to patient selection from a heterogeneous population. We highlight the current knowledge concerning the role of platelets in CLD and cancer and anticipate a novel application of platelet-based clinical therapies to treat liver disease. PMID- 28566883 TI - Thiopurine use associated with reduced B and natural killer cells in inflammatory bowel disease. AB - AIM: To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo. METHODS: The thiopurines azathioprine and 6 mercaptopurine have been a mainstay of inflammatory bowel disease (IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy recipients. RESULTS: Complete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the time of sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer (NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells (Tregs) or naive CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iNKT and MAIT cells than healthy controls. CONCLUSION: Thiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients. PMID- 28566884 TI - Hepatitis B virus X protein induces hepatic stem cell-like features in hepatocellular carcinoma by activating KDM5B. AB - AIM: To determine the role of hepatitis B virus X protein (HBx), HBx in regulating hepatic progenitor cell (HPC)-like features in hepatocellular carcinoma (HCC) and the underlying molecular mechanisms. METHODS: We used a retrovirus vector to introduce wild type HBx or empty vector into HepG2 cells. We then used these cells to analyze cell proliferation, senescence, transformation, and stem-like features. Gene expression profiling was carried out on Affymetrix GeneChip Human U133A2.0 ver.2 arrays according to the manufacturer's protocol. Unsupervised hierarchical clustering analysis and Class Comparison analysis were performed by BRB-Array Tools software Version 4.2.2. A total of 238 hepatitis B virus (HBV)-related HCC patients' array data were used for analyzing clinical features. RESULTS: The histone demethylase KDM5B was significantly highly expressed in HBV-related HCC cases (P < 0.01). In HBV proteins, only HBx up regulated KDM5B by activating c-myc. Hepatic stem cell (HpSC) markers (EpCAM, AFP, PROM1, and NANOG) were significantly highly expressed in KDM5B-high HCC cases (P < 0.01). KDM5B played an important role in maintaining HpSC-like features and was associated with a poor prognosis. Moreover, inhibition of KDM5B suppressed spheroid formation and cell invasion in vitro. CONCLUSION: HBx activates the histone demethylase KDM5B and induces HPC-like features in HCC. Histone demethylases KDM5B may be an important therapeutic target against HBV related HCC cases. PMID- 28566885 TI - Artificial liver support in pigs with acetaminophen-induced acute liver failure. AB - AIM: To establish a reversible porcine model of acute liver failure (ALF) and treat it with an artificial liver system. METHODS: Sixteen pigs weighing 30-35 kg were chosen and administered with acetaminophen (APAP) to induce ALF. ALF pigs were then randomly assigned to either an experimental group (n = 11), in which a treatment procedure was performed, or a control group (n = 5). Treatment was started 20 h after APAP administration and continued for 8 h. Clinical manifestations of all animals, including liver and kidney functions, serum biochemical parameters and survival times were analyzed. RESULTS: Twenty hours after APAP administration, the levels of serum aspartate aminotransferase, total bilirubin, creatinine and ammonia were significantly increased, while albumin levels were decreased (P < 0.05). Prothrombin time was found to be extended with progression of ALF. After continuous treatment for 8 h (at 28 h), aspartate aminotransferase, total bilirubin, creatinine, and ammonia showed a decrease in comparison with the control group (P < 0.05). A cross-section of livers revealed signs of vacuolar degeneration, nuclear fragmentation and dissolution. Concerning survival, porcine models in the treatment group survived for longer times with artificial liver system treatment (P < 0.05). CONCLUSION: This model is reproducible and allows for quantitative evaluation of new liver systems, such as a bioartificial liver. The artificial liver system (ZHJ-3) is safe and effective for the APAP-induced porcine ALF model. PMID- 28566886 TI - Effects of sleeve gastrectomy plus trunk vagotomy compared with sleeve gastrectomy on glucose metabolism in diabetic rats. AB - AIM: To investigate the effects of sleeve gastrectomy plus trunk vagotomy (SGTV) compared with sleeve gastrectomy (SG) in a diabetic rat model. METHODS: SGTV, SG, TV and Sham operations were performed on rats with diabetes induced by high-fat diet and streptozotocin. Body weight, food intake, oral glucose tolerance test, homeostasis model assessment of insulin resistance (HOMA-IR), hepatic insulin signaling (IR, IRS1, IRS2, PI3K and AKT), oral glucose stimulated insulin secretion, GLP-1 and ghrelin were compared at various postoperative times. RESULTS: Both SG and SGTV resulted in better glucose tolerance, lower HOMA-IR, up regulated hepatic insulin signaling, higher levels of oral glucose-stimulated insulin secretion, higher postprandial GLP-1 and lower fasting ghrelin levels than the TV and Sham groups. No significant differences were observed between the SG and SGTV groups. In addition, no significant differences were found between the TV and Sham groups in terms of glucose tolerance, HOMA-IR, hepatic insulin signaling, oral glucose-stimulated insulin secretion, postprandial GLP-1 and fasting ghrelin levels. No differences in body weight and food intake were noted between the four groups. CONCLUSION: SGTV is feasible for diabetes control and is independent of weight loss. However, SGTV did not result in a better improvement in diabetes than SG alone. PMID- 28566888 TI - Risk of progression of Barrett's esophagus in patients with cirrhosis. AB - AIM: To study Barrett's esophagus (BE) in cirrhosis and assess progression to esophageal adenocarcinoma (EAC) compared to non-cirrhotic BE controls. METHODS: Cirrhotic patients who were found to have endoscopic evidence of BE confirmed by the presence of intestinal metaplasia on histology from 1/1/2000 to 12/1/2015 at Cleveland Clinic were included. Cirrhotic patients were matched 1:4 to BE controls without cirrhosis. Age, gender, race, BE length, hiatal hernia size, Child-Pugh (CP) class and histological findings were recorded. Cases and controls without high-grade dysplasia (HGD)/EAC and who had follow-up endoscopies were studied for incidence of dysplasia/EAC and to assess progression rates. Univariable conditional logistic regression was done to assess differences in baseline characteristics between the two groups. RESULTS: A total of 57 patients with cirrhosis and BE were matched with 228 controls (BE without cirrhosis). The prevalence of dysplasia in cirrhosis and controls were similar with 8.8% vs 12% with low grade dysplasia (LGD) and 12.3 % vs 19.7% with HGD or EAC (P = 0.1). In the incidence cohort of 44 patients with median follow-up time of 2.7 years [interquartile range 1.0, 4.8], there were 7 cases of LGD, 2 cases of HGD, and 2 cases of EAC. There were no differences in incidence rates of HGD/EAC in nondysplastic BE between cirrhotic cases and noncirrhotic controls (1.4 vs 1.1 per 100 person- years, P = 0.8). In LGD, cirrhotic patients were found to have higher rates of progression to HGD/EAC compared to control group though this did not reach statistical significance (13.7 vs 8.1 per 100 person- years, P = 0.51). A significant association was found between a higher CP class and neoplastic progression of BE in cirrhotic patients (HR =7.9, 95%CI: 2.0-30.9, P = 0.003). CONCLUSION: Cirrhotics with worsening liver function are at increased risk of progression of BE. More frequent endoscopic surveillance might be warranted in such patients. PMID- 28566887 TI - Wall shear stress in portal vein of cirrhotic patients with portal hypertension. AB - AIM: To investigate wall shear stress (WSS) magnitude and distribution in cirrhotic patients with portal hypertension using computational fluid dynamics. METHODS: Idealized portal vein (PV) system models were reconstructed with different angles of the PV-splenic vein (SV) and superior mesenteric vein (SMV) SV. Patient-specific models were created according to enhanced computed tomography images. WSS was simulated by using a finite-element analyzer, regarding the blood as a Newtonian fluid and the vessel as a rigid wall. Analysis was carried out to compare the WSS in the portal hypertension group with that in healthy controls. RESULTS: For the idealized models, WSS in the portal hypertension group (0-10 dyn/cm2) was significantly lower than that in the healthy controls (10-20 dyn/cm2), and low WSS area (0-1 dyn/cm2) only occurred in the left wall of the PV in the portal hypertension group. Different angles of PV SV and SMV-SV had different effects on the magnitude and distribution of WSS, and low WSS area often occurred in smaller PV-SV angle and larger SMV-SV angle. In the patient-specific models, WSS in the cirrhotic patients with portal hypertension (10.13 +/- 1.34 dyn/cm2) was also significantly lower than that in the healthy controls (P < 0.05). Low WSS area often occurred in the junction area of SV and SMV into the PV, in the area of the division of PV into left and right PV, and in the outer wall of the curving SV in the control group. In the cirrhotic patients with portal hypertension, the low WSS area extended to wider levels and the magnitude of WSS reached lower levels, thereby being more prone to disturbed flow occurrence. CONCLUSION: Cirrhotic patients with portal hypertension show dramatic hemodynamic changes with lower WSS and greater potential for disturbed flow, representing a possible causative factor of PV thrombosis. PMID- 28566889 TI - Clinical significance of hypoechoic submandibular gland lesions in type 1 autoimmune pancreatitis. AB - AIM: To assess the role of ultrasonography of submandibular glands (SGs) in the diagnosis of type 1 autoimmune pancreatitis (AIP). METHODS: Thirty-seven patients who were definitively diagnosed with type 1 AIP according to the international consensus diagnostic criteria (ICDC) for AIP at our institution between December 1990 and April 2016 were retrospectively reviewed. Findings by physical examination, ultrasonography, and scintigraphy of SGs were analyzed to reach a diagnosis based on the ICDC for AIP. The efficacy of corticosteroid treatment in the resolution of hypoechoic lesions in SGs was also evaluated by assessment with ultrasonography before and after treatment in 18 cases. RESULTS: The sensitivity of multiple hypoechoic lesions in SGs by ultrasonography for the diagnosis of sialadenitis in type 1 AIP (84%) was higher than that of physical examination (46%), scintigraphy (28%), and SGs thickness (49%). Ultrasonographic evidence of hypoechoic lesions in SGs improved the definitive diagnosis of sialadenitis and type 1 AIP by the ICDC criteria in 11 (30%) and 2 (5.4%) cases, respectively. Multiple hypoechoic lesions in SGs were resolved or disappear by corticosteroid administration in 14 of 16 cases with hypoechoic lesions in SGs, whereas the ultrasonographic findings in the remaining 2 cases with hypoechoic lesions in SGs and the 2 cases with homogenous SG parenchyma remained unchanged after corticosteroid administration. CONCLUSION: SG ultrasonography to detect multiple hypoechoic lesions might be useful for type 1 AIP diagnosis by improving diagnostic accuracy together with the ICDC sialadenitis criteria. PMID- 28566890 TI - Benefit of neoadjuvant concurrent chemoradiotherapy for locally advanced perihilar cholangiocarcinoma. AB - AIM: To clarify the role of neoadjuvant concurrent chemoradiotherapy (NACCRT) followed by surgical resection for localized or locally advanced perihilar cholangiocarcinoma (CCA). METHODS: We retrospectively reviewed 57 patients who underwent surgical resection with or without NACCRT for perihilar CCA; 12 patients received NACCRT and 45 patients did not received NACCRT. Patients with locally advanced perihilar CCA requiring NACCRT were defined as follows: (1) a mass involving unilateral branches of the portal vein or hepatic artery with insufficient volume of the anticipated remnant lobe; or (2) an infiltrating mass in the main portal vein that was too long for reconstruction, identified at preoperative staging. RESULTS: The median disease-free survival (DFS) durations of the neoadjuvant and non-neoadjuvant CCRT groups were 26.0 and 15.1 mo, respectively (P = 0.91). The median overall survival (OS) durations of the neoadjuvant and non-neoadjuvant CCRT groups were 32.9 and 27.1 mo, respectively (P = 0.26). The NACCRT group showed a downstaging tendency compared to the non NACCRT group as compared with the tumor stage confirmed by histological examination after surgery and the tumor stage confirmed by imaging test at the time of diagnosis (P = 0.01). CONCLUSION: NACCRT does not prolong DFS and OS in localized or locally advanced perihilar CCA. However, NACCRT may allow tumor downstaging and improve tumor resectability. PMID- 28566891 TI - Ling classification describes endoscopic progressive process of achalasia and successful peroral endoscopy myotomy prevents endoscopic progression of achalasia. AB - AIM: To verify the hypothesis that the Ling classification describes the endoscopic progressive process of achalasia and determine the ability of successful peroral endoscopic myotomy (POEM) to prevent endoscopic progression of achalasia. METHODS: We retrospectively reviewed the endoscopic findings, symptom duration, and manometric data in patients with achalasia. A total of 359 patients (197 women, 162 men) with a mean age of 42.1 years (range, 12-75 years) were evaluated. Symptom duration ranged from 2 to 360 mo, with a median of 36 mo. Patients were classified with Ling type I (n = 119), IIa (n = 106), IIb (n = 60), IIc (n = 60), or III (n = 14), according to the Ling classification. Of the 359 patients, 349 underwent POEM, among whom 21 had an endoscopic follow-up for more than 2 years. Pre-treatment and post-treatment Ling classifications of these 21 patients were compared. RESULTS: Symptom duration increased significantly with increasing Ling classification (from I to III) (P < 0.05), whereas lower esophageal sphincter pressure decreased with increasing Ling type (from I to III) (P < 0.05). There was no difference in sex ratio or onset age among the Ling types, although the age at time of diagnosis was higher in Ling types IIc and III than in Ling types I, IIa, and IIb. Of the 21 patients, 19 underwent high resolution manometry both before and after treatment. The mean preoperative and postoperative lower esophageal sphincter pressure were 34.6 mmHg (range, 15.3 59.4 mmHg) and 15.0 mmHg (range, 2.1-21.6 mmHg), respectively, indicating a statistically significant decrease after POEM. All of the 21 patients were treated successfully by POEM (postoperative Eckardt score <= 3) and still had the same Ling type during a mean follow-up period of 37.8 mo (range, 24-51 mo). CONCLUSION: The Ling classification represents the endoscopic progressive process of achalasia and may be able to serve as an endoscopic assessment criterion for achalasia. Successful POEM (Eckardt score <= 3) seems to have the ability to prevent endoscopic evolvement of achalasia. However, studies with larger populations are warranted to confirm our findings. PMID- 28566893 TI - Correlation of endoscopic disease severity with pediatric ulcerative colitis activity index score in children and young adults with ulcerative colitis. AB - AIM: To investigate of pediatric ulcerative colitis activity index (PUCAI) in ulcerative colitis correlate with mucosal inflammation and endoscopic assessment of disease activity (Mayo endoscopic score). METHODS: We reviewed charts from ulcerative colitis patients who had undergone both colonoscopy over 3 years. Clinical assessment of disease severity within 35 d (either before or after) the colonoscopy were included. Patients were excluded if they had significant therapeutic interventions (such as the start of corticosteroids or immunosuppressive agents) between the colonoscopy and the clinical assessment. Mayo endoscopic score of the rectum and sigmoid were done by two gastroenterologists. Inter-observer variability in Mayo score was assessed. RESULTS: We identified 99 patients (53% female, 74% pancolitis) that met inclusion criteria. The indications for colonoscopy included ongoing disease activity (62%), consideration of medication change (10%), assessment of medication efficacy (14%), and cancer screening (14%). Based on PUCAI scores, 33% of patients were in remission, 39% had mild disease, 23% had moderate disease, and 4% had severe disease. There was "moderate-substantial" agreement between the two reviewers in assessing rectal Mayo scores (kappa = 0.54, 95%CI: 0.41-0.68). CONCLUSION: Endoscopic disease severity (Mayo score) assessed by reviewing photographs of pediatric colonoscopy has moderate inter-rater reliability, and agreement was less robust in assessing patients with mild disease activity. Endoscopic disease severity generally correlates with clinical disease severity as measured by PUCAI score. However, children with inflamed colons can have significant variation in their reported clinical symptoms. Thus, assessment of both clinical symptoms and endoscopic disease severity may be required in future clinical studies. PMID- 28566892 TI - Disruptive behavior in the workplace: Challenges for gastroenterology fellows. AB - AIM: To assess first-year gastroenterology fellows' ability to address difficult interpersonal situations in the workplace using objective structured clinical examinations (OSCE). METHODS: Two OSCEs ("distracted care team" and "frazzled intern") were created to assess response to disruptive behavior. In case 1, a fellow used a colonoscopy simulator while interacting with a standardized patient (SP), nurse, and attending physician all played by actors. The nurse and attending were instructed to display specific disruptive behavior and disregard the fellow unless requested to stop the disruptive behavior and focus on the patient and procedure. In case 2, the fellow was to calm an intern managing a patient with massive gastrointestinal bleeding. The objective in both scenarios was to assess the fellows' ability to perform their duties while managing the disruptive behavior displayed by the actor. The SPs used checklists to rate fellows' performances. The fellows completed a self-assessment survey. RESULTS: Twelve fellows from four gastrointestinal fellowship training programs participated in the OSCE. In the "distracted care team" case, one-third of the fellows interrupted the conflict and refocused attention to the patient. Half of the fellows were able to display professionalism despite the heated discussion nearby. Fellows scored lowest in the interprofessionalism portion of post-OSCE surveys, measuring their ability to handle the conflict. In the "frazzled intern" case, 68% of fellows were able to establish a calm and professional relationship with the SP. Despite this success, only half of the fellows were successfully communicate a plan to the SP and only a third scored "well done" in a domain that focused on allowing the intern to think through the case with the fellow's guidance. CONCLUSION: Fellows must receive training on how to approach disruptive behavior. OSCEs are a tool that can assess fellow skills and set a culture for open discussion. PMID- 28566894 TI - Stress and sleep quality in doctors working on-call shifts are associated with functional gastrointestinal disorders. AB - AIM: To investigate the role of sleep quality and psychosocial problems as predictors of functional gastrointestinal disorders (FGIDs) in doctors that work 24 hour-on-call shifts. METHODS: In this cross-sectional observation study, using the Rome III Questionnaire and Pittsburgh Sleep Quality Index (PSQI), we analyzed 170 doctors with 24 hour-on-call shifts. RESULTS: Among the participants that had experienced a 24 hour-on-call shift within the last 6 mo, 48 (28.2%) had FGIDs. Overall prevalence of irritable bowel syndrome (IBS) and functional dyspepsia (FD) were 16.5% and 17.1%, respectively, with 5.3% exhibiting both. Sleep scores (PSQI) (8.79 +/- 2.71 vs 7.30 +/- 3.43, P = 0.008), the presence of serious psychosocial alarm (83.3% vs 56.6%, P = 0.004), and the proportion of doctors who experienced over two months of recent on-call work (81.2% vs 68.9%, P = 0.044) were significantly different between individuals with or without FGIDs. Multivariate analysis revealed that presenting serious psychosocial alarm was an independent risk factor for prevalence of FD (OR = 5.47, 95%CI: 1.06-28.15, P = 0.042) and poor sleep quality (PSQI >= 6) was a predictor of IBS (OR = 4.17, 95%CI: 1.92-19.02, P = 0.016). CONCLUSION: Physicians should recognize the role of sleep impairment and psychological stress in the development of FGIDs and a comprehensive approach should be considered to manage patients with FGIDs. PMID- 28566895 TI - In vivo and ex vivo confocal endomicroscopy of pancreatic cystic lesions: A prospective study. AB - AIM: To investigate the reproducibility of the in vivo endoscopic ultrasound (EUS) - guided needle based confocal endomicroscopy (nCLE) image patterns in an ex vivo setting and compare these to surgical histopathology for characterizing pancreatic cystic lesions (PCLs). METHODS: In a prospective study evaluating EUS nCLE for evaluation of PCLs, 10 subjects underwent an in vivo nCLE (AQ-Flex nCLE miniprobe; Cellvizio, MaunaKea, Paris, France) during EUS and ex vivo probe based CLE (pCLE) of the PCL (Gastroflex ultrahigh definition probe, Cellvizio) after surgical resection. Biopsies were obtained from ex vivo CLE-imaged areas for comparative histopathology. All subjects received intravenous fluorescein prior to EUS and pancreatic surgery for in vivo and ex vivo CLE imaging respectively. RESULTS: A total of 10 subjects (mean age 53 +/- 12 years; 5 female) with a mean PCL size of 34.8 +/- 14.3 mm were enrolled. Surgical histopathology confirmed 2 intraductal papillary mucinous neoplasms (IPMNs), 3 mucinous cystic neoplasms (MCNs), 2 cystic neuroendocrine tumors (cystic-NETs), 1 serous cystadenoma (SCA), and 2 squamous lined PCLs. Characteristic in vivo nCLE image patterns included papillary projections for IPMNs, horizon-type epithelial bands for MCNs, nests and trabeculae of cells for cystic-NETs, and a "fern pattern" of vascularity for SCA. Identical image patterns were observed during ex vivo pCLE imaging of the surgically resected PCLs. Both in vivo and ex vivo CLE imaging findings correlated with surgical histopathology. CONCLUSION: In vivo nCLE patterns are reproducible in ex vivo pCLE for all major neoplastic PCLs. These findings add further support the application of EUS-nCLE as an imaging biomarker in the diagnosis of PCLs. PMID- 28566896 TI - Chronological age when healthcare transition skills are mastered in adolescents/young adults with inflammatory bowel disease. AB - AIM: To describe the longitudinal course of acquisition of healthcare transition skills among adolescents and young adults with inflammatory bowel diseases. METHODS: We recruited adolescents and young adults (AYA) with inflammatory bowel diseases (IBD), from the pediatric IBD clinic at the University of North Carolina. Participants completed the TRxANSITION ScaleTM at least once during the study period (2006-2015). We used the electronic medical record to extract participants' clinical and demographic data. We used ordinary least square regressions with robust standard error clustered at patient level to explore the variations in the levels and growths of healthcare transition readiness. RESULTS: Our sample (n = 144) ranged in age from 14-22 years. Age was significantly and positively associated with both the level and growth of TRxANSITION ScaleTM scores (P < 0.01). Many healthcare transition (HCT) skills were acquired between ages 12 and 14 years, but others were not mastered until after age 18, including self-management skills. CONCLUSION: This is one of the first studies to describe the longitudinal course of HCT skill acquisition among AYA with IBD, providing benchmarks for evaluating transition interventions. PMID- 28566898 TI - Antimicrobial susceptibility testing before first-line treatment for Helicobacter pylori infection in patients with dual or triple antibiotic resistance. AB - AIM: To evaluate the efficacy of antimicrobial susceptibility-guided therapy before first-line treatment for infection in patients with dual or triple antibiotic resistance. METHODS: A total of 1034 patients infected by Helicobacter pylori (H. pylori) during 2013-2014 were tested for antimicrobial susceptibility. 157 of 1034 (15%) patients showed resistance to two (127/1034; 12%) and to three (30/1034; 3%) antibiotics. Sixty-eight patients with dual H. pylori-resistance (clarithromycin, metronidazole or levofloxacin) were treated for 10 d with triple therapies: OAL (omeprazole 20 mg b.i.d., amoxicillin 1 g b.i.d., and levofloxacin 500 mg b.i.d.) 43 cases, OAM (omeprazole 20 mg b.i.d., amoxicillin 1 g b.i.d., and metronidazole 500 mg b.i.d.) 12 cases and OAC (omeprazole 20 mg b.id., amoxicillin 1 g b.i.d., and clarithromycin 500 mg b.i.d.) 13 cases based on the antimicrobial susceptibility testing. Twelve patients showed triple H. pylori resistance (clarithromycin, metronidazole and levofloxacin) and received for 10 d triple therapy with OAR (omeprazole 20 mg b.id., amoxicillin 1 g b.i.d., and rifabutin 150 mg b.i.d.). Eradication was confirmed by 13C-urea breath test. Adverse effects and compliance were assessed by a questionnaire. RESULTS: Intention-to-treat eradication rates were: OAL (97.6%), OAM (91.6%), OAC (92.3%) and OAR (58.3%). Cure rate was significantly higher in naive patients treated with OAR-10 compared to patients who had two or three previous treatment failures (83% vs 33%). Adverse events rates for OAL, OAM, OAC and OAR were 22%, 25%, 23% and 17%, respectively, all of them mild-moderate. CONCLUSION: Antimicrobial susceptibility-guided triple therapies during 10 d for first-line treatment leads to an eradication rate superior to 90% in patients with dual antibiotic H. pylori resistance. PMID- 28566897 TI - Low-FODMAP diet reduces irritable bowel symptoms in patients with inflammatory bowel disease. AB - AIM: To investigate the effect of a low-FODMAP diet on irritable bowel syndrome (IBS)-like symptoms in patients with inflammatory bowel disease (IBD). METHODS: This was a randomised controlled open-label trial of patients with IBD in remission or with mild-to-moderate disease and coexisting IBS-like symptoms (Rome III) randomly assigned to a Low-FODMAP diet (LFD) or a normal diet (ND) for 6 wk between June 2012 and December 2013. Patients completed the IBS symptom severity system (IBS-SSS) and short IBD quality of life questionnaire (SIBDQ) at weeks 0 and 6. The primary end-point was response rates (at least 50-point reduction) in IBS-SSS at week 6 between groups; secondary end-point was the impact on quality of life. RESULTS: Eighty-nine patients, 67 (75%) women, median age 40, range 20 70 years were randomised: 44 to LFD group and 45 to ND, from which 78 patients completed the study period and were included in the final analysis (37 LFD and 41 ND). There was a significantly larger proportion of responders in the LFD group (n = 30, 81%) than in the ND group (n = 19, 46%); (OR = 5.30; 95%CI: 1.81-15.55, P < 0.01). At week 6, the LFD group showed a significantly lower median IBS-SSS (median 115; inter-quartile range [IQR] 33-169) than ND group (median 170, IQR 91 288), P = 0.02. Furthermore, the LFD group had a significantly greater increase in SIBDQ (median 60, IQR 51-65) than the ND group (median 50, IQR 39-60), P < 0.01. CONCLUSION: In a prospective study, a low-FODMAP diet reduced IBS-like symptoms and increased quality of life in patients with IBD in remission. PMID- 28566899 TI - Severe esophageal injury after radiofrequency ablation - a deadly complication. AB - Various degrees of esophageal injury have been described after radiofrequency ablation performed for treatment of atrial fibrillation. The main mechanism of injury is thermal and may lead to a range of esophageal mucosal changes, some clinically insignificant, however when deep ulceration occurs, this may be further complicated by perforation and mediastinitis, a rare but life threatening sequelae. We present a case of a severe esophageal injury leading to mediastinitis, with interesting endoscopic findings. PMID- 28566900 TI - Low-Dose Systemic Methotrexate Therapy for Recalcitrant Alopecia Areata. AB - BACKGROUND: Alopecia areata (AA) is an autoimmune skin disease difficult to manage and treat. The pathogenesis of AA features a T-cell-associated autoimmune process, and systemic immunosuppressive therapy is prescribed widely for AA. OBJECTIVE: To evaluate the efficacy and tolerance of systemic low-dose methotrexate (LD-MTX) therapy in treatment of recalcitrant AA multiplex. METHODS: In a retrospective, non-controlled study, we evaluated 29 patients with recalcitrant AA treated with LD-MTX and assessed the therapeutic response according to severity of disease, disease duration, cumulative dose of MTX, and drug safety. RESULTS: MTX was administered twice weekly, and the mean maximum weekly dose was 14.48 mg. The response was A5 (regrowth=100.0%) in 14 (48.3%) patients and A4 (regrowth of 75%~90%) in 12 (41.4%) patients. Three patients had poor response to LD-MTX treatment (A2: n=2 [6.9%], A1: n=1 [3.4%]). All three of the patients showing a poor response had disease durations exceeding 24 months. Relapse was observed in 31% of patients with more than 75% regrowth. Common side effects were elevated liver enzyme levels and gastrointestinal discomfort. CONCLUSION: LD-MTX appears to be an effective and well-tolerated treatment for recalcitrant AA multiplex. PMID- 28566901 TI - Periostin in Mature Stage Localized Scleroderma. AB - BACKGROUND: Periostin is a novel matricellular protein expressed in many tissues, including bone, periodontal ligament, and skin. Although its expression is prominent in various fibrotic conditions, studies of periostin in localized scleroderma are rare. OBJECTIVE: To investigate the expression of periostin and other molecules in localized scleroderma. METHODS: A retrospective study of 14 patients with confirmed mature stage localized scleroderma was undertaken. Fourteen age-matched and biopsy site-matched subjects with normal skin were included as controls. Collagen fiber deposition, periostin, procollagen, transforming growth factor-beta, and matrix metalloproteinase (MMP)-1 expression were assessed and compared between the two groups. Co-localization of alpha smooth muscle actin and periostin was evaluated using confocal microscopy. RESULTS: Periostin was predominantly expressed along the dermo-epidermal junction in the controls. Conversely, patients with localized scleroderma demonstrated increased collagen fiber deposition and periostin expression that was more widely distributed along the entire dermis. MMP-1 staining showed increased expression in the epidermis and dermis of patients compared to scanty expression in the controls. A semi-quantitative evaluation showed a higher proportion of excessive collagen bundle deposition (57.1% vs. 7.1%, p=0.013), diffuse periostin positivity (42.9% vs. 0%, p=0.016), and moderate MMP-1 positivity (71.4% vs. 7.1%, p=0.001) in patients than in the controls. CONCLUSION: Compared to the controls, patients with localized scleroderma had enhanced periostin expression corresponding to increased collagen fiber deposition and unexpected overexpression of MMP-1. The results of this human in vivo study may implicate the pathogenesis of localized scleroderma. PMID- 28566902 TI - Therapeutic Efficacy of a Combination Therapy of Topical 17alpha-Estradiol and Topical Minoxidil on Female Pattern Hair Loss: A Noncomparative, Retrospective Evaluation. AB - BACKGROUND: A variety of agents have been used to treat female pattern hair loss (FPHL), including topical minoxidil, topical 17alpha-estradiol, oral anti androgen agents, and mineral supplements. Compared with these single agent regimens, combination therapies could be a better therapeutic option in expectation of superior treatment outcome. OBJECTIVE: This study was designed to determine the efficacy of a combination therapy consisting of topical 0.025% 17alpha-estradiol and 3% minoxidil in Korean patients with FPHL. METHODS: Therapeutic efficacy was evaluated in 34 women who applied topical 0.025% 17alpha estradiol and 3% minoxidil once daily for more than 6 months. Phototrichogram analysis was performed before and after therapy. The efficacy was evaluated with respect to total hair count, hair caliber (as assessed by phototrichogram analysis), and photographic assessment. RESULTS: Total hair count and hair caliber both increased from baseline to 6 months in patients treated with the combination therapy of topical 0.025% 17alpha-estradiol and 3% minoxidil (p<0.001). Photographic assessment also revealed significant disease improvement, thus supporting the therapeutic efficacy. CONCLUSION: A combination therapy consisting of topical 0.025% 17alpha-estradiol and 3% minoxidil can be tried as an effective treatment for FPHL. PMID- 28566903 TI - Risk Factors for Aseptic Meningitis in Herpes Zoster Patients. AB - BACKGROUND: Herpes zoster (HZ) is caused by reactivation of latent varicella zoster virus (VZV) infection. HZ-associated aseptic meningitis, a rare complication of HZ, can require hospitalization and a long treatment period. OBJECTIVE: A retrospective study was performed to identify potential factors associated with HZ-associated aseptic meningitis development. METHODS: We included all outpatients and patients admitted in the neurology and dermatology departments of a single tertiary center, who were diagnosed with HZ for two years. Among 818 patients, 578 patients were eligible for analysis. RESULTS: The demographics and potential risk factors were compared between the uncomplicated HZ group (n=554) and aseptic meningitis group (n=24). Among the potential factors, the dermatological distribution of skin rash and gender showed statistically significantly different between the two groups. Patients with craniocervical distribution of HZ accounted for 87.5% (n=21) of the aseptic meningitis group and 54.3% (n=301) of the uncomplicated HZ group (p=0.043). The aseptic meningitis group had more men (66.7%, n=16) than the uncomplicated HZ group (42.8%, n=237, p=0.033). Patients with craniocervical distribution had an odds ratio (OR) of 5.884 (p=0.001) for developing aseptic meningitis when compared with the other dermatome involvements. Additional logistic regression analysis resulted in a fading between gender difference (p=0.050) and craniocervical involvement having an OR of 5.667 for aseptic meningitis (p=0.006). CONCLUSION: In HZ patients, skin rash with craniocervical distribution and male gender were associated with a higher risk of aseptic meningitis. PMID- 28566904 TI - Arborizing Vessels on Dermoscopy in Various Skin Diseases Other Than Basal Cell Carcinoma. AB - BACKGROUND: Arborizing vessels (AVs) are dermoscopically defined as telangiectasias with distinct treelike branching, and are a characteristic feature of basal cell carcinoma (BCC). However, AVs are observed in various conditions other than BCC. OBJECTIVE: The aim of this study was to investigate skin diseases showing AV and investigates dermoscopic differences between BCC and non-BCC. METHODS: Dermoscopic images showing AV were prospectively collected and classified into BCC/non-BCC. Non-BCC was further classified into tumors (benign cystic, benign non-cystic, premalignant, and malignant) and non-tumors. We compared AV focusing, widest diameter of stem vessels, widest diameter ratio of stem vessel to first branch, and number of ramifications between groups. RESULTS: Among 124 images, 54.0% were BCC and 46.0% were non-BCC. Non-BCC included epidermal cysts, hypertrophic scars/keloids, intradermal nevi, actinic keratoses, etc. The proportion of focused AV in BCC was significantly higher and the proportion of unfocused AV in BCC was lower than that of premalignant and malignant non-BCC. The widest diameter ratio of stem vessel to first branch was higher in non-BCC. Number of ramifications was significantly less in benign cystic non-BCC than BCC. CONCLUSION: Various skin diseases showed AV, so that diagnoses other than BCC should be considered. The findings in this study could help discriminate BCC from non-BCC. PMID- 28566905 TI - The Effect of Rhus verniciflua Stokes Extracts on Photo-Aged Mouse Skin. AB - BACKGROUND: Rhus verniciflua Stokes (RV) has traditionally been used in Korea as an indigenous food (Rhus chicken soup) and as an herbal medicinal plant. While the anticancer, antimicrobial, and anti-inflammatory properties of RV have been actively studied in the medical field, its antioxidant effects in the skin that resist the reactive oxygen species in keratinocytes and fibroblasts is less understood. OBJECTIVE: We designed to evaluate the effects of R. verniciflua Stokes extract (RVE) on the photo-aged skin by an in vitro experiment using human fibroblasts and an in vivo experiment using a photo-aged murine model. METHODS: For the in vitro experiments, human fibroblasts irradiated with ultraviolet (UV) B were treated with RVE or vehicle, and the growth levels and the expression level of type 1 procollagen were compared. For the in vivo experiment, photo-aged mice irradiated with UVB and UVA were administered drinking water with or without RVE, and histological changes and the expression level of type 1 procollagen and matrix metalloprotease (MMP)-13 were compared. RESULTS: In vitro experiments using fibroblasts irradiated with UVB showed that RVE promoted growth and significantly increased the expression of type 1 procollagen as compared to the control group. In the photo-aged mice, RVE increased collagen content in the dermis and promoted the synthesis of type 1 procollagen without any visible decrease in MMP-13 as compared to control group. CONCLUSION: In addition to the previously reported antioxidant effects of RVE, oral intake of RVE effectively inhibited photo-aging in hairless mice by enhancing collagen synthesis. PMID- 28566907 TI - The Delivery Rates of Pathology Test Results to Patients: A Single-Center Experience in a Secondary Referral Center. AB - BACKGROUND: Delivery of pathology reports to the patient is a key step in the biopsy pathway, which is important for patient safety in dermatology. Automated systems for facilitating such medical process began in 2010 in our hospital, sending short message service to scheduled patients. OBJECTIVE: The purpose of this study was to evaluate the delivery of pathology reports to patients and investigate factors that influence this process and annual trends. METHODS: We retrospectively reviewed the medical records of all outpatients (n=2,452) who underwent skin biopsy at our department of dermatology in 2009 and 2014. In each year group, we analyzed the proportion of revisiting patients in terms of year, sex, age, season, biopsy method and diagnosis. RESULTS: In 2009, a smaller proportion of patients (205; 91.5%) who had undergone shave or excisional biopsy than of those who had undergone punch biopsy returned (781; 98.0%; p<0.001). This trend was not significant in 2014. Whereas there was no significant difference of return visit ratio between men and women in 2009, a higher proportion of women (754; 98.0%) than men (633; 95.6%) re-visited after skin biopsy to confirm their diagnosis in 2014 (p=0.008). Three patients with either a malignant tumor or suspected malignant lesion that required complete excision did not return to our clinic. CONCLUSION: Pathology report delivery rates were fairly satisfactory, regardless of year, age, season, and diagnosis. Sex and biopsy method influenced the return visit ratio. More organized follow-up protocols are required to strengthen patient safety and prevent critical patient drop-out. PMID- 28566906 TI - Multivariate Analysis of Factors Associated with the Koebner Phenomenon in Vitiligo: An Observational Study of 381 Patients. AB - BACKGROUND: The Koebner phenomenon (KP) is a common entity observed in dermatological disorders. The reported incidence of KP in vitiligo varies widely. Although the KP is frequently observed in patients with viltiligo, the associated factors with KP has not been established yet. OBJECTIVE: The aim is to estimate the prevalence of KP in vitiligo patients and to investigate the associated factors with KP among vitiligo characteristics. METHODS: A cross-sectional observational study was conducted using 381 vitiligo patients. Demographic and clinical information was obtained via the completion of Vitiligo European Task Force (VETF) questionnaires. Patients with positive history of KP were extracted from this vitiligo database. Multivariate analysis was performed to assess associations with KP. RESULTS: The median age of cases was 24 years (range, 0.6~76). In total, 237 of the patients were male (62.2%). Vitiligo vulgaris was the most common type observed (152/381, 39.9%). Seventy-two percent (274/381) patients did not exhibit KP, whereas 28.1% (107/381) of patients exhibited this condition. Multivariable analysis showed the following to be independent factors with KP in patients with vitiligo: the progressive disease (odds ratio [OR], 1.82; 95% confidence interval [95% CI], 1.17~2.92; p=0.041), disease duration longer than 5 years (OR, 1.92; 95% CI, 1.22~2.11; p=0.003), and body surface area more than 2% (OR, 2.20; 95% CI, 1.26~3.24; p<0.001). CONCLUSION: Our results suggest that KP may be used to evaluate disease activity and investigate different associations between the clinical profile and course of vitiligo. Further studies are needed to predict the relationship between KP and responsiveness to therapy. PMID- 28566909 TI - In Vitro Anti-Malassezia Activity of Castanea crenata Shell and Oil-Soluble Glycyrrhiza Extracts. AB - BACKGROUND: A new shampoo with anti-Malassezia properties obtained from various plants is required to provide seborrheic dermatitis patients with a wider range of treatment options. OBJECTIVE: The aim of this study was to obtain in vitro susceptibility profiles of Malassezia restricta and M. globosa, the most important pathogenic organisms in the development of seborrheic dermatitis, to the plant extracts used in commercial anti-dandruff shampoos. METHODS: Minimal inhibitory concentrations (MICs) were determined for eight candidate plant extracts and two plant-derived natural products diluted with Leeming and Notman medium to final concentrations of 0.016 to 1 mg/ml. RESULTS: Castanea crenata shell, Camellia sinensis leaf, and oil-soluble Glycyrrhiza extracts presented relatively low MIC values (<=0.5 mg/ml) against both strains. The C. crenata shell and oil-soluble Glycyrrhiza extracts demonstrated especially high anti Malassezia activity, suggesting their potential use in the treatment of seborrheic dermatitis. The extracts also showed fungistatic activity against other common facultative pathogenic yeasts, Cryptococcus and Candida. CONCLUSION: C. crenata shell and oil-soluble Glycyrrhiza extracts could potentially be used as active ingredients in anti-seborrheic and anti-dandruff shampoo formulations. They could be helpful for repeated treatments and regular prophylaxis of scalp seborrheic dermatitis. PMID- 28566908 TI - The Effects of Multi-Growth Factors-Containing Cream on Post-Thyroidectomy Scars: A Preliminary Study. AB - BACKGROUND: Growth factors play important roles in wound healing. However, the evidence for the effects of growth factors on post-thyroidectomy scars is limited. OBJECTIVE: We performed a prospective study to assess the preventive and therapeutic effect of a multi-growth factor (MGF)-containing cream on post thyroidectomy scars. METHODS: Twenty-one patients with thyroidectomy scars applied MGF cream twice a day. We assessed the changes in erythema, pigmentation, skin elasticity, and skin hydration status using the erythema index, melanin index, cutometer, and corneometer, respectively. In addition, Vancouver scar scale (VSS) and patient satisfaction were assessed at 10 days after surgery (baseline), 2 weeks, 6 weeks, and 12 weeks after baseline. RESULTS: The mean total VSS scores were significantly lower at 6 weeks (3.24+/-1.51 vs. 1.91+/ 1.38) and 12 weeks (3.24+/-1.51 vs. 1.71+/-1.59) compared to the baseline. The degree of pigmentation was significantly lower at 12 weeks compared to the baseline, and the skin elasticity, and the skin hydration status were significantly higher at 12 weeks compared to the baseline. Over 85% of the patients were satisfied with the use of MGF cream without any adverse effect. CONCLUSION: MGF cream might have additive or supportive effect for scar formation after thyroidectomy. PMID- 28566910 TI - Acral Lentiginous Melanoma, Indolent Subtype Diagnosed by En Bloc Excision: A Case Report. AB - Nail unit melanoma is a type of acral lentiginous melanoma and requires histopathologic examination for a confirmed diagnosis. However, inadequate biopsy techniques make definitive diagnosis difficult. A 61-year-old man presented with progressive nail pigmentation for 15 years, which was clinically highly suspicious for malignancy. Acral lentiginous melanoma was not detected in punch and longitudinal biopsy specimens, but en bloc excision tissue revealed melanoma. Acral lentiginous melanoma is known to have a heterogeneous pathologic manifestation depending on the pigmented region and the time it takes to progress. In this regard, en bloc excision can be considered as a first-line biopsy technique to diagnose acral lentiginous melanoma, indolent subtype. PMID- 28566911 TI - Intense Pulsed Light and Q-Switched 1,064-nm Neodymium-Doped Yttrium Aluminum Garnet Laser Treatment for the Scarring Lesion of Discoid Lupus Erythematosus. AB - Discoid lupus erythematosus (DLE) is a chronic form of cutaneous lupus that can cause permanent scarring. Treatment of DLE includes protection from sunlight and artificial sources of ultraviolet light, as well as systemic and topical medications. The first-line standard therapies are antimalarials and topical steroids. Other systemic therapies include systemic steroid, azathioprine, dapsone, and immunosuppressive agents. Topical tacrolimus and pimecrolimus have also been evaluated. Recent studies reported that several treatments, including pulsed dye laser, CO2 laser, intense pulsed light (IPL), and 1,064-nm long-pulse neodymium-doped yttrium aluminum (Nd:YAG) have been used for the cosmetic treatment of DLE. Here, we report a case of a DLE scar that was successfully treated with a combination therapy of IPL and Q-switched 1,064-nm Nd:YAG laser. PMID- 28566912 TI - Eccrine Squamous Syringometaplasia Associated with Pelubiprofen Therapy. AB - Eccrine squamous syringometaplasia (ESS) is a histologically distinctive skin eruption occurring predominantly in acral or intertriginous areas presenting as erythematous macules, papules or patches. The etiology of ESS remains unclear, but it is usually reported in patients receiving chemotherapy for various malignant neoplasms. To date, only two cases of ESS associated with non-steroidal anti-inflammatory drugs (NSAIDs), which has distinctive clinical features and pathogenesis, have been reported in the literature. Herein, we report a rare and interesting case of ESS associated with pelubiprofen, a recently developed NSAID, which appeared after pelubiprofen therapy and resolved spontaneously after discontinuing the medication. PMID- 28566913 TI - Interstitial Granulomatous Dermatitis in a Patient with Prostate Cancer. AB - Interstitial granulomatous dermatitis (IGD) is a rare dermatosis, histologically characterized by an interstitial granulomatous infiltrate. It is associated with inflammatory arthritis, various medications, and autoimmune conditions. It is also associated with malignancies such as breast, endometrial, lung, and esophageal cancers as well as hematologic malignancies such as lymphoma and myelodysplastic syndrome. Herein we describe a case of IGD associated with prostate cancer, which has not been reported in the literature. PMID- 28566914 TI - Aquagenic Urticaria Diagnosed by the Water Provocation Test and the Results of Histopathologic Examination. AB - An 18-year-old male visited our department complaining of recurrent episodes of an itchy rash after hand washing, showering/bathing, drinking water, and getting rain-soaked. He was diagnosed with aquagenic urticaria after a water provocation test and histopathologic examination. Five months of antihistamine treatment successfully prevented further wheal formation. Aquagenic urticaria is a very unusual form of physical urticaria caused by contact with water. It manifests as pruritic small wheals surrounded by erythema within 30 minutes of exposure. The condition can be diagnosed by a water provocation test. Systemic antihistamines are the first-line treatment, with anticholinergics, phototherapy, or barrier cream used alternatively or additionally. Four cases of aquagenic urticaria have been reported in Korea, but no histopathologic evaluation was reported in the English or Korean literature. Herein, we provide both a case report of aquagenic urticaria diagnosed by the water provocation test and histopathologic examination results for this patient. PMID- 28566915 TI - Methotrexate in a Real-World Psoriasis Treatment: Is It Really a Dangerous Medication for All? PMID- 28566916 TI - Multiple Interdigital Nodular Amyloidosis of the Toe: A Unique Presentation of Localized Cutaneous Amyloidosis. PMID- 28566917 TI - Some Becker's Nevus Melanocytes Remain Alive after Treatment with Q-Switched Alexandrite Laser. PMID- 28566918 TI - Onychocytic Matricoma: Report of an Asian Case. PMID- 28566919 TI - Xanthoma Striatum Palmare in a Patient of Primary Biliary Cirrhosis with Autoimmune Hepatitis. PMID- 28566920 TI - The Effectiveness of Tailored Education on the Usage of Moisturizers in Atopic Dermatitis: A Pilot Study. PMID- 28566921 TI - Papular Acantholytic Dyskeratosis of the Inguinal Area in a 49-Year-Old Man. PMID- 28566922 TI - Dermoscopy as a Supportive Instrument in the Early Recognition of Erosive Adenomatosis of the Nipple and Mammary Paget's Disease. PMID- 28566923 TI - Attenuated Nuclear Factor Kappa B Activity by E7 Protein of Human Papillomavirus Type 2 in Human Epidermal Keratinocytes. PMID- 28566924 TI - Localized Grouped Basaloid Follicular Hamartoma on the Chest of an Adult. PMID- 28566925 TI - p16INK4a Expression in Porokeratosis. PMID- 28566926 TI - Intense Pulsed Light Increases Hyaluronan and CD44 in Epidermal Keratinocytes and Improves Age-Related Epidermal Structure Defects in Mice. PMID- 28566927 TI - Hunter Syndrome with Extensive Mongolian Spots. PMID- 28566928 TI - A Case of Cholesterol Granuloma Presenting as a Cutaneous Nodule. PMID- 28566929 TI - Acitretin as a Therapeutic Option for Chronic Hand Eczema. PMID- 28566930 TI - Fournier's Gangrene: A Rare Complication of Sweet's Syndrome. PMID- 28566931 TI - Is There an Ideal Low-Density Lipoprotein Cholesterol Level? Confusion regarding Lipid Guidelines, Low-Density Lipoprotein Cholesterol Targets, and Medical Management. AB - There are multiple guidelines for managing patients with high-risk cardiovascular disease, and unfortunately for the practicing clinician, these guidelines are quite variable. Some are fairly specific whereas others are not, resulting in a great deal of confusion regarding whether management of low-density lipoprotein cholesterol (LDL-C) should be tailored only, targeted only, or managed by a combination of both. In the management of cardiovascular disease, favorable cardiovascular outcomes can be obtained by simply lowering the LDL-C in the absence of any other medications. The advent of statins, the most potent LDL-C lowering medication yet when developed, provided benefits augmented by the presence of multiple pleiotropic effects. Tailoring and/or targeting the decrease in LDL-C is also an issue of concern. Then, in 2016, the new proprotein convertase sutilisin-like/kexin type 9 (PCSK9) inhibitors appeared, providing a solution to patients with high-risk cardiovascular disease with statin intolerance and those who did not attain a desired LDL-C level while on a high dose statin. These new PCSK9 inhibitors necessitate a determination of how low the LDL-C can and should go, most likely safely down to a beneficial level of 25 mg/dL for the highest-risk patient. These issues are documented and discussed with an attempt to help the reader make an informed risk management decision. PMID- 28566932 TI - Postural Changes in Measures of Arterial Stiffness in Hypertensive Subjects on Antihypertensive Drug Therapy: A Prospective, Pilot Study. AB - Prospective study with a controlled arm to know if there are variations of measures of arterial stiffness with posture in subjects with hypertension on antihypertensive medications. We studied postural variations of measures of arterial stiffness in 21 subjects with diagnosed hypertension on antihypertensive medications and compared them with 21 normotensive subjects. All subjects underwent pulse-wave analysis on SphygmoCor in the morning between 8 am to 10 am initially in supine and then in sitting position after 3 minutes. Summary measures on demographics, and blood pressure characteristics at sitting and supine positions are obtained. Differences between characteristics at supine and sitting position are compared using nonparametric paired test of Wilcoxon signed rank test. A value of p < 0.05 was accepted as statistically significant. Antihypertensive medications decreased the supine aortic augmentation pressure (AAP) and augmentation index (AI) but not significantly. When subgroups of patients with antihypertensive treatment were analyzed, it was noted that angiotensin-converting enzyme inhibitor and angiotensin receptor blocker group (12) decreased AAP and AI significantly in supine position compared with patients on other antihypertensive medications (9) (p-value 0.034 and 0.038, respectively). There was no significant difference in other groups of calcium channel blockers, beta-blockers, or diuretics. However, in normotensive control arm, there was an increase in AAP and AI in the supine position. In hypertensive subjects, on antihypertensive, there was reduction in AAP and AI in supine position compared with those of normotensives. The significance of the decrease in AAP and AI in supine position on antihypertensive needs to be studied further. PMID- 28566933 TI - Outcomes of Carotid Endarterectomy with Primary Closure. AB - Carotid endarterectomy (CEA) reduces the risk of stroke in patients with internal carotid artery stenosis, although the optimal surgical technique is debated. The literature suggests that patch angioplasty reduces complication risk, although primary closure shortens cross-clamp time and eliminates complications associated with grafts. The objective of this study was to assess the complication rate after CEA with primary closure. Retrospective review of 240 consecutive patients between 2002 and 2010. Of these patients, 70% returned for follow-up visits for at least 2 or more years. Primary closure was used in all patients. The average cross-clamp time was 18 minutes. Complications in the immediate postoperative period within 30 days were as follows: stroke (n = 3; 1.1%), transient ischemic attack (TIA; n = 4; 1.5%), myocardial infarction (MI; n = 3; 1.1%), and death (n = 1; 0.4%). Short-term follow-up revealed eight patients who were found to have significant restenosis (>80%) by carotid duplex imaging. Two to ten year postoperative complication rates were as follows: stroke (n = 7; 4.2%), TIA (n = 7; 4.2%), amaurosis fugax (n = 1; 0.6%), MI (n = 8; 4.8%), and death (n = 28; 17%). Mortality was due to stroke or heart attack (n = 2; 1.2%), cancer (n = 7; 4.2%), and unknown causes (n = 19; 11%). This study presents our experience with complications after primary closure after CEA. In our experience, CEA is a safe and effective surgical means of preventing stroke in the short term. Well designed prospective studies are needed to confirm specific patient characteristics in which primary closure and patch angioplasty are indicated. PMID- 28566934 TI - A Novel Risk Score in Predicting Failure or Success for Antegrade Approach to Percutaneous Coronary Intervention of Chronic Total Occlusion: Antegrade CTO Score. AB - Total occlusion of a coronary artery for more than 3 months is defined as chronic total occlusion (CTO). The goal of this study was to develop a risk score in predicting failure or success during attempted percutaneous coronary intervention (PCI) of CTO lesions using antegrade approach. This study was based on retrospective analyses of clinical and angiographic characteristics of CTO lesions that were assessed between February 2012 and February 2014. Success rate was defined as passing through occlusion with successful stent deployment using an antegrade approach. A total of 188 patients were studied. Mean +/- SD age was 59 +/- 9 years. Failure rate was 33%. In a stepwise multivariate regression analysis, bridging collaterals (OR = 6.7, CI = 1.97-23.17, score = 2), absence of stump (OR = 5.8, CI = 1.95-17.9, score = 2), presence of calcification (OR = 3.21, CI = 1.46-7.07, score = 1), presence of bending (OR = 2.8, CI = 1.28-6.10, score = 1), presence of near side branch (OR = 2.7, CI = 1.08-6.57, score = 1), and absence of retrograde filling (OR = 2.5, CI = 1.03-6.17, score = 1) were independent predictors of PCI failure. A score of 7 or more was associated with 100% failure rate whereas a score of 2 or less was associated with over 80% success rate. Most factors associated with failure of CTO-PCI are related to lesion characteristics. A new risk score (range 0-8) is developed to predict CTO PCI success or failure rate during antegrade approach as a guide before attempting PCI of CTO lesions. PMID- 28566935 TI - Variations in Echogenicity in Carotid and Femoral Atherosclerotic Plaques with Pycnogenol + Centella Asiatica Supplementation. AB - This registry study evaluated echogenicity of carotid-femoral plaques in asymptomatic subjects with increased oxidative stress and risk factors (mild hypertension, hypercholesterolemia). Supplementation with the combination Pycnogenol-CA (centella asiatica) on the echogenicity of plaques was assessed at 6 months (79 subjects). A standard management (SM) plan was used in all subjects (control of risk factors, lifestyle changes); 36 subjects used the supplements +SM; 43 SM only. The groups were comparable. High-resolution ultrasound evaluated echogenicity and plaque structure. Pycnogenol (150 mg/day) and CA (Centellicum, 450 mg/day) were used. At 6 months, cholesterol was reduced (p < 0.05) in both groups (difference between groups not significant). At 6 months, plasma free radicals were decreased with the supplements (17.64%; p < 0.05; vs <2% in controls). The plaque stability index increased from 11.22;2.3 to 22.4;1.1 (p < 0.05) with the supplements; no significant changes were seen in controls. Plaque echogenicity (% of "whiter" component in images) increased with supplementation from 16.7;1.7% to 34.2;2% (p < 0.05); no variations were observed in controls. The maximum plaque height decreased (p < 0.05) with the supplements. No significant variations were observed in controls. Plaque length was decreased (p < 0.05) in the supplement group with no changes in controls. The number of plaques (carotid, femoral bifurcations) decreased with supplementation; no significant changes were observed in controls. No adverse events, tolerability problems, or variations in routine blood tests were recorded. The combination Pycnogenol-CA appears to improve echogenicity and stability of complex plaques in 6 months. PMID- 28566936 TI - Interaction of Serum Phosphate with Age as Predictors of Cardiovascular Risk Scores in Stable Renal Transplant Recipients. AB - We calculated rate of changes in the cardiovascular risk calculator for renal transplant recipients (CRCRTR) major adverse cardiac events (MACE) in clinically stable renal transplant recipients (RTRs) to identify covariables that associate with fast cardiovascular (CV) risk progression. CRCRTR-MACE scores were calculated on 139 patients in 2011 and 2014. Score changes above and below median changes in scores were labeled fast or slow CV risk progression. Multivariate analysis (MVA) was performed to identify variables significant to percentage changes in scores. Receiver-operating characteristic (ROC) analysis was performed to define sensitivity and specificity of factors significant to fast score progression. Follow-up was 2.61 (2.02-4.47) years. Slow and fast progressions were present in 50.4 and 49.6% of patients, with a median change of 25.8% (- 92.1 to 1,444.7%). MVA showed percentage changes in age and serum phosphate were the only significant variables impacting fast progression in scores. ROC showed 2011 serum phosphate of 1.15 mmol/L to predict fast progression (area under the curve [AUC] of 0.628, p > 0.0126). Age older than 45 years combined with 2011 serum phosphate above 1.15 mmol/L had a significant AUC of 0.781, p < 0.0010 interleukin (IL)-1A and IL-28A were significant associates with serum phosphate above 1.1 mmol/L in the MVA. Changes in CV risk in RTR over time are highly variable. Serum phosphate, even within upper normal levels, predicts worsening of CV risk scores in stable RTR. PMID- 28566937 TI - Shear Stress Induces Change in Extracellular Signal-Regulated Kinase 5 Levels with Sustained Activation under Disturbed and Continuous Laminar Flow. AB - Extracellular signal-regulated kinase 5 (ERK5) has been reported to regulate endothelial integrity and protect from vascular dysfunction under laminar flow. Previously reported research indicates that under laminar flow ERK5 is activated with production of atheroprotective molecules. However, the characterization of ERK5 activation and levels under different flow patterns has not been investigated. Confluent HUVECs were serum-starved then seeded on glass slides. HUVECs incubated in 1% FBS were exposed to continuous laminar flow (CLF), to-and fro flow (TFF), or pulsatile forward flow (PFF) in a parallel plate flow chamber. At the end of experimentation, cell lysates were immunoblotted with antibodies to phospho-ERK5 and total ERK5. ERK5 activation was assessed by the levels of phosphorylated ERK5. The densitometric mean +/- SEM is calculated and analyzed by ANOVA. p < 0.05 is considered significant. Levels of ERK5 decreased with all flow conditions with the largest decrease in TFF flow condition. TFF and CLF exhibited sustained ERK5 phosphorylation in HUVECs stimulated for up to 4 hours. PFF had transient phosphorylation of ERK5 at 2 hours, which then became undetectable at 4 hours of exposure to flow. Also, TFF and CLF both showed decreased levels at 4 hours, suggesting a decrease in activation for these flow conditions. Exposure of HUVEC to different types of shear stress results in varying patterns of activation of ERK5. Activation of ERK5 with TFF suggests a role in the pathogenesis of atherosclerosis and vascular remodeling under disturbed flow conditions. PMID- 28566938 TI - Safety and Efficacy of a Novel "Hybrid Closure" Technique in Large-Bore Arteriotomies. AB - The "preclose" technique employing two Perclose (P) devices is well established for large-bore artery (LBA) hemostasis. Occasionally, only one Perclose deploys successfully during the initial preclose because of arterial calcification necessitating the use of the crossover balloon technique to achieve hemostasis at the LBA. We sought to determine if the combined use of one Perclose and either one Angioseal or one Mynx vascular closure device (VCD) is a safe alternative closure technique large-bore arteriotomy closure. In total, 40 patients underwent high-risk percutaneous coronary intervention (HRPCI) with Impella support, of whom 38 had common femoral artery (CFA) arteriotomies and 2 underwent percutaneous axillary arteriotomy (AA). Prior to Impella insertion, one Perclose device was predeployed. At the end of HRPCI, Impella was removed and a 0.035" wire was inserted through the Impella sheath. This sheath was then withdrawn over the wire, and partially deployed Perclose was fully deployed. A 6-Fr sheath was advanced over a 0.035" wire into the CFA or AA, achieving hemostasis and reducing the LBA to a 6-Fr size. The 6-Fr arteriotomy was closed with a 6-Fr Mynx or Angioseal VCD. Patients were followed at day 1 and day 30. Hybrid closure was successful in 38 of 40 cases. In one case of Mynx balloon rupture, hemostasis was achieved with heparin reversal and manual compression. In the case of Perclose failure, crossover balloon tamponade at arteriotomy site and external manual compression achieved hemostasis. Patients were free of complications at day 1 and day 30. Hybrid closure with one Perclose and either one Mynx or one Angioseal VCD is safe and effective for LBA closure. PMID- 28566939 TI - Variation of a Persistent Primitive Hypoglossal Artery (PPHA) as Incidental Finding in the Diagnostic Clarification of Cerebral Vasculopathy Associated with Intracranial Vasculitis. AB - We present a very rare variation of a persistent primitive hypoglossal artery (PPHA) arising from the internal carotid artery, detected during a diagnostic angiography. A 50-year-old female patient was admitted with an atypical intracranial hematoma in the left frontal lobe. Catheter angiography revealed intracranial vasculopathy with segmental stenoses, a small aneurysm of the right internal carotid artery bifurcation and a "string of beads" appearance of the left carotid artery, consistent with fibromuscular disease. On the left side, a vertebral artery ending in the posterior inferior cerebellar artery (PICA) was detected, whereas on the right side the vertebral artery was aplastic. During selective angiography of the right common carotid artery, a persistent hypoglossal artery was seen supplying the basilar artery. The literature of persistent embryonal carotid-vertebrobasilar anastomosis and their anatomical variations is discussed with respect to clinical importance for ischemia, interventional procedures, and surgery. PMID- 28566940 TI - High-Output Cardiac Failure Due to Hereditary Hemorrhagic Telangiectasia: A Case of an Extra-Cardiac Left to Right Shunt. AB - High-output cardiac failure is a rare complication of hereditary hemorrhagic telangiectasia and can potentially be mistaken for other entities. We present a case of high-output cardiac failure because of large hepatic arteriovenous malformations, review the literature regarding the cardiac manifestations of the disease, and discuss the possible differential diagnoses. PMID- 28566941 TI - Embolic Protection using the WIRION Embolic Protection System with JetStream Atherectomy in a Patient with Superficial Femoral Artery Chronic total Occlusion. AB - Distal embolization is a common occurrence with peripheral arterial interventions and is more frequent with the use of atherectomy devices. We report the first case of JetStream atherectomy (Boston Scientific, Maple Grove, MN) with the use of the novel WIRION embolic protection system filter. The procedure was performed successfully with no distal embolizations beyond the filter and with no complications in the delivery or retrieval of the filter. The pros and cons of the off label use of this filter with JetStream atherectomy are discussed. PMID- 28566942 TI - Neuroinflammation: new vistas for neuropsychiatric research. AB - In psychiatric diseases such as mood disorders or schizophrenia, the inflammatory response system is activated. Microglia has gradually emerged as a key interface between stress-related signals and neuroimnune consequences of stress, with stressors leading to elevated microglial activity. PMID- 28566943 TI - Affective immunology: where emotions and the immune response converge. AB - Affect and emotion are defined as "an essential part of the process of an organism's interaction with stimuli." Similar to affect, the immune response is the "tool" the body uses to interact with the external environment. Thanks to the emotional and immunological response, we learn to distinguish between what we like and what we do not like, to counteract a broad range of challenges, and to adjust to the environment we are living in. Recent compelling evidence has shown that the emotional and immunological systems share more than a similarity of functions. This review article will discuss the crosstalk between these two systems and the need for a new scientific area of research called affective immunology. Research in this field will allow a better understanding and appreciation of the immunological basis of mental disorders and the emotional side of immune diseases. PMID- 28566944 TI - In immune defense: redefining the role of the immune system in chronic disease. AB - The recognition of altered immune system function in many chronic disease states has proven to be a pivotal advance in biomedical research over the past decade. For many metabolic and mood disorders, this altered immune activity has been characterized as inflammation, with the attendant assumption that the immune response is aberrant. However, accumulating evidence challenges this assumption and suggests that the immune system may be mounting adaptive responses to chronic stressors. Further, the inordinate complexity of immune function renders a simplistic, binary model incapable of capturing critical mechanistic insights. In this perspective article, we propose alternative paradigms for understanding the role of the immune system in chronic disease. By invoking allostasis or systems biology rather than inflammation, we can ascribe greater functional significance to immune mediators, gain newfound appreciation of the adaptive facets of altered immune activity, and better avoid the potentially disastrous effects of translating erroneous assumptions into novel therapeutic strategies. PMID- 28566945 TI - Inflammation: opportunities for treatment stratification among individuals diagnosed with mood disorders. AB - Mood disorders continue to be a significant burden to those affected, resulting in significant illness-associated disability and premature mortality. In addition to mood disturbance, individuals also suffer from other transdiagnostic impairments (eg, anhedonia and cognitive impairment). Although there have been significant advancements in psychiatric treatment over the last few decades, treatment efficacy (eg, symptom remission, lack of functional recovery, and disease modification) continues to be an important limitation. Consequently, there is an urgent need to identify novel approaches capable of addressing the foregoing needs, providing the basis for the exploration of conceptual models and treatment opportunities that consider inflammation to be a key factor in mood disorder development. In part driven by metabolic comorbidities, a large proportion of individuals with mood disorders also have an imbalance in the inflammatory milieu. The aim of this review is to highlight evidence implicating inflammation in various effector systems in mood disorders, with a particular focus on the intercommunication with glutamatergic signaling, immune system signaling, as well as metabolic parameters (eg, L-methyl folate bioavailability). This article also briefly reviews novel and repurposed agents that are capable of targeting the innate immune inflammatory system and possibly correcting an abnormal immune/inflammatory milieu (eg, infliximab). PMID- 28566946 TI - A multispecies approach for understanding neuroimmune mechanisms of stress. AB - The relationship between stress challenges and adverse health outcomes, particularly for the development of affective disorders, is now well established. The highly conserved neuroimmune mechanisms through which responses to stressors are transcribed into effects on males and females have recently garnered much attention from researchers and clinicians alike. The use of animal models, from mice to guinea pigs to primates, has greatly increased our understanding of these mechanisms on the molecular, cellular, and behavioral levels, and research in humans has identified particular brain regions and connections of interest, as well as associations between stress-induced inflammation and psychiatric disorders. This review brings together findings from multiple species in order to better understand how the mechanisms of the neuroimmune response to stress contribute to stress-related psychopathologies, such as major depressive disorder, schizophrenia, and bipolar disorder. PMID- 28566948 TI - Clinical and autoimmune features of a patient with autism spectrum disorder seropositive for anti-NMDA-receptor autoantibody. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by dysfunctions in social interactions resulting from a complex interplay between immunogenetic and environmental risk factors. Autoimmunity has been proposed as a major etiological component of ASD. Whether specific autoantibodies directed against brain targets are involved in ASD remains an open question. Here, we identified within a cohort an ASD patient with multiple circulating autoantibodies, including the well-characterized one against glutamate NMDA receptor (NMDAR-Ab). The patient exhibited alexithymia and previously suffered from two major depressive episodes without psychotic symptoms. Using a single molecule-based imaging approach, we demonstrate that neither NMDAR-Ab type G immunoglobulin purified from the ASD patient serum, nor that from a seropositive healthy subject, disorganize membrane NMDAR complexes at synapses. These findings suggest that the autistic patient NMDAR-Abs do not play a direct role in the etiology of ASD and that other autoantibodies directed against neuronal targets should be investigated. PMID- 28566950 TI - Neuronal Autoantibodies Call for Attention in Epilepsy. PMID- 28566947 TI - Immunological aspects of the treatment of depression and schizophrenia. AB - Schizophrenia and major depression (MD) have been associated with immune system dysfunction. One example of this is the altered level of cytokines-important inflammatory mediators-in blood, and a proinflammatory immune state has been described in some subgroups of patients. A knock to the immune system in early life might trigger a life-long increased immune reactivity, and infections and autoimmune disorders are now known to be risk factors for development of schizophrenia and MD. Pro- and anti-inflammatory cytokines mediate indoleamine 2,3-dioxygenase activity; this enzyme drives metabolism of tryptophan and kynurenin in the central nervous system and degrades serotonin. Alterations of serotonergic, noradrenergic, and glutamatergic neurotransmission have been associated with low-level neuroinflammation, and anti-inflammatory compounds have a therapeutic benefit in MD and schizophrenia, as shown in meta-analyses. Moreover, antidepressants and antipsychotics have intrinsic immunomodulatory effects. With evidence pointing to the role inflammatory processes play in the pathogenesis of major psychiatric disorders, this review will look at various immunological aspects of treatment of such disorders. PMID- 28566949 TI - The potential role of neuroinflammation and transcription factors in Parkinson disease. AB - Parkinson disease (PD) is a neurodegenerative disorder characterized by dopaminergic neurons affected by inflammatory processes. Post-mortem analyses of brain and cerebrospinal fluid from PD patients show the accumulation of proinflammatory cytokines, confirming an ongoing neuroinflammation in the affected brain regions. These inflammatory mediators may activate transcription factors-notably nuclear factor kappaB, Ying-Yang 1 (YY1), fibroblast growth factor 20 (FGF20), and mammalian target of rapamycin (mTOR)-which then regulate downstream signaling pathways that in turn promote death of dopaminergic neurons through death domain-containing receptors. Dopaminergic neurons are vulnerable to oxidative stress and inflammatory attack. An increased level of inducible nitric oxide synthase observed in the substantia nigra and striatum of PD patients suggests that both cytokine-and chemokine-induced toxicity and inflammation lead to oxidative stress that contributes to degeneration of dopaminergic neurons and to disease progression. Lipopolysaccharide activation of microglia in the proximity of dopaminergic neurons in the substantia nigra causes their degeneration, and this appears to be a selective vulnerability of dopaminergic neurons to inflammation. In this review, we will look at the role of various transcription factors and signaling pathways in the development of PD. PMID- 28566951 TI - Psychological and Biological Validation of a Novel Digital Social Peer Evaluation Experiment (digi-SPEE). AB - INTRODUCTION: Negative social evaluation is associated with psychopathology. Given the frequency of evaluation through increasingly prevalent virtual social networks, increased understanding of the effects of this social evaluation is urgently required. METHODS: A new digital social peer evaluation experiment (digi SPEE) was developed to mimic everyday online social interactions between peers. Participants received mildly negative feedback on their appearance, intelligence, and congeniality. Two hundred and forty-one young people [58.9% female, aged 18.9 years (15 to 34)] from an ongoing novel general population twin study participated in this study. Positive affect (PA), negative affect (NA), implicit self-esteem, and cortisol were assessed before and after exposure to the social evaluation experiment. RESULTS: The social evaluation experiment decreased PA (B= 5.25, p<.001) and implicit self-esteem (B=-.19; p<.001), whereas it increased NA (B=5.99; p<.001) and cortisol levels (B=.07; p<.001). Females (PA: B=-7.62; p<.001; NA: B=8.28; p<.001) and participants with higher levels of general psychological distress (PA: B=-.04, p=.035; NA: B=.06; p=.028) showed stronger affective responses. Stressor-induced cortisol increase was stronger in adolescents under the age of 18 than in participants 18 years and older (B=-.06, p=.002). CONCLUSION: The digi-SPEE represents a social evaluation stressor that elicits biological and implicit and explicit mental changes that are relevant to mechanisms of psychopathology. PMID- 28566952 TI - Prevalence of Multiple Sclerosis in the Middle Black Sea Region of Turkey and Demographic Characteristics of Patients. AB - INTRODUCTION: Multiple sclerosis (MS), a demyelinating disease of the central nervous system, is increasing in prevalence worldwide. Other than small-scale studies, there is a scarcity of data on the prevalence of MS in Turkey. The present study aimed to elucidate the prevalence of MS in the Middle Black Sea Region and the demographic characteristics of patients. METHODS: Patients living in the Middle Black Sea Region and who were diagnosed with MS were included. The study was designed based hospital of Turkey. RESULTS: A total of 1,787 patients were interviewed, and a diagnosis of MS was confirmed in 1,584. The prevalence of MS was found to be 43.2/100,000 in the Middle Black Sea Region; this was calculated based on the total population and number of patients in the provinces and districts in this region. The mean age at the disease onset was 29.39+/-7.6 years. Among the patients, 1,299 (81.9%) had relapsing-remitting MS, 74 had secondary progressive MS, 77 had relapsing-progressive MS, 47 had primary progressive MS, and 87 had clinically isolated syndrome. CONCLUSION: The Middle Black Sea Region was found to have a high risk for the prevalence of MS. This study is the most comprehensive epidemiologic study having the largest geographical distribution on the prevalence of MS in Turkey. PMID- 28566953 TI - Conversion Disorder Comorbidity and Childhood Trauma. AB - INTRODUCTION: The aim of this study is to examine the socio-demographic and clinical characteristics, the presence of comorbidity, and the link with childhood traumatic experiences in patients with conversion disorder (CD) in a psychiatric outpatient clinic. METHODS: A total of 60 literate, female patients between 18 and 65 years of age who were referred to the general psychiatry outpatient clinic and who were diagnosed with conversion disorder according to the DSM-IV diagnostic criteria were included in the study. A questionnaire on sociodemographic and clinical characteristics, the Brief Psychiatric Rating Scale (BPRS), the Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS), the Childhood Trauma Questionnaire (CTQ), and the Dissociative Events Scale (DES) were used to assess the cases. RESULTS: The mean age of the participants was 36.27+/-11.18 years. 72% of the patients were married and 63% were primary school graduates. The most common symptoms were asthenia (100%), aphasia (96.7%), and crying-convulsions (93%). The most common co-morbidities were depression (50%) and dissociative disorders (48.3%). Among the patients, 53.3% reported a history of exposure to physical violence and 25% reported a history of sexual assault in childhood. Assessment of the Childhood Traumatic Questionnaire revealed a significant positive relation between emotional, physical, and sexual abuse scores and DES score. CONCLUSION: CD has not yet been fully analyzed in detail in health institutions; co-existence of another mental disorder and the presence of traumatic experiences in the past further complicate the issue. Consideration of these factors during treatment will have a positive impact on the course and prognosis of the disorder. PMID- 28566954 TI - Demonstration of Early Cognitive Impairment in Parkinson's Disease with Visual P300 Responses. AB - INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Cognitive changes in PD are less observable than motor symptoms; thus, research on cognitive processes, which are known to be impaired from the early stages of PD, is minimal. The purpose of this study is to research the brain dynamics of cognitively normal PD patients and healthy elderly controls using event-related potentials (ERPs) and to evaluate their relationships with neuropsychological tests. METHODS: Eighteen cognitively normal PD patients and 18 age-, gender-, and education-matched healthy controls were included in the study. Detailed neuropsychological tests were applied to all participants. Electroencephalography (EEG) was performed according to the international 10-20 system, and a classical visual oddball paradigm was used in the experiments. ERP responses in the 0.5 to 25 Hz frequency range were examined. P300 amplitude and latency values were measured from the F3, Fz, F4, C3, Cz, C4, P3, Pz, P4, O1, Oz, and O2 electrode sites. In addition, the correlations between P300 responses and neuropsychological test scores were analyzed. RESULTS: Significant differences were found between the P300 amplitudes of cognitively normal PD patients and healthy elderly controls [F(1,31)=9.265; p=0.005]. P300 amplitudes were significantly lower for PD patients at the F3, FZ, Cz, C4, Pz, and P4 electrode sites than for healthy elderly controls. Moderate correlations were found between Stroop test score and P4 amplitude, digit span forward and C3 and Pz amplitude, and digit span backward and O1 amplitude. CONCLUSION: The major finding of this study was the detection of cognitive changes by electrophysiological methods in PD patients who were indicated to be cognitively normal by neuropsychological tests. These finding suggests that cognitive changes in PD patients, which are not yet reflected in neuropsychological tests, may be detected by electrophysiological methods in earlier stages. PMID- 28566955 TI - A Clinically Neglected Topic: Risk of Suicide in Transgender Individuals. AB - INTRODUCTION: The aim of this study was to determine whether adolescence of transgender individuals is characterized by a high risk of suicide. METHODS: In total, 141 participants with transgenderism were questioned using a semi structured interview to determine whether participants had current suicidal thoughts, had a lifetime history of such thoughts, or had attempted suicide. These findings were cross-referenced to the participants' sociodemographic characteristics, and information about their families' general attitudes toward sexuality, gender identity, and commitment to religious views. In total, 101 participants attended group psychotherapy sessions for at least a year. In these sessions, family and partner relationships, occupational problems, financial problems, medical issues, and religious concerns were discussed. RESULTS: The incidence of suicide attempts, current suicidal thoughts, and lifetime suicidal thoughts were 29.8%, 9.2%, and 55.3%, respectively. In total, 76.7% of the suicide attempts occurred before the age of 21. CONCLUSION: Transsexual individuals present a high risk of suicide, particularly during adolescence. This finding may be considered a sign for taking action to prevent suicide when working with transgender individuals, particularly during adolescence. PMID- 28566956 TI - Intelligence, Functioning, and Related Factors in Children with Cerebral Palsy. AB - INTRODUCTION: Cerebral palsy (CP) is the most common significant motor impairment in childhood. CP is defined as a primary disorder of posture and movement; however, intellectual impairment is prevalent in children with CP. The purpose of this study was to examine the intelligence level associated with gross motor function and hand function, type of CP, the presence of comorbid disorders such as epilepsy, and other factors. METHODS: In total, 107 children with CP were included. Age, gender, prenatal/natal/postnatal risk factors, type of CP, and presence of other neurodevelopmental disorders were recorded as demographic findings. Intellectual functions of the patients were determined by clinical assessment, adaptive function of daily life, and individualized, standardized intelligence testing. The gross motor function and hand function of the patients were classified using the "Gross Motor Function Classification System" and "Bimanual Fine Motor Function" measurements, respectively. RESULTS: The mean age of the patients was 8.10+/-3.43 years (2-16 years). The study included 63 (58.9%) male patients and 44 (41.1%) female patients. During clinical typing, 80.4% of the patients were spastic, 11.2% were mixed, 4.7% were dyskinetic, and 3.7% were ataxic. Intellectual functioning tests found 26.2% of the children within the intellectual norm and that 10% of the children had a borderline intellectual disability, 16% of them had a mild intellectual disability, 17% of them had a moderate intellectual disability, and 30.8% of them had a severe intellectual disability. No significant relationship was determined between the CP type and intellectual functioning (p>0.05). Intellectual functioning was found to be significantly correlated with hand functions and motor levels (p<0.001). Factors related with intellectual functioning were neonatal convulsion, epilepsy, and speech disorders. CONCLUSION: Intelligence assessment should be an essential part of CP evaluation and research. There is not enough reliable knowledge, unanimity regarding validity data, and population-specific norms in the intelligence assessments of children with CP. Research is required to assess properly intelligence for children with CP. PMID- 28566957 TI - Additive Effects of Former Methylenedioxymethamphetamine and Cannabis Use on Subclinical Psychotic Symptoms. AB - INTRODUCTION: Methylenedioxymethamphetamine (MDMA) is an amphetamine-derived psychostimulant, usually known as "ecstasy." The long-term neuropsychological effects of MDMA are examined in several studies with conflicting results. The most common findings reported are depression, anxiety, and memory and attention deficits. In addition to acute psychotic reactions observed after MDMA use, serotonergic and dopaminergic toxicities may increase the psychosis risk in the long-term. Cannabis usage among MDMA users is very high. The aim of this study was, therefore, to examine the additive effects of cannabis and MDMA on subclinical psychotic symptoms (SPS). METHODS: Here, 131 healthy controls (hC), 54 former cannabis and MDMA users (C&M), and 46 former cannabis users (C) were evaluated for SPS. The definition of former user was based on the Munich Composite International Diagnostic Interview. The SPS scores were assessed by using the Schizotypal Personality Questionnaire (SPQ). The relationship between substance-free periods and total MDMA exposure with SPS was also examined. RESULTS: The C&M group had higher levels of SPS than both C and hC groups. This is true not only for the total SPQ scores but both positive and negative schizotypy scores as well as cognitive-perceptual, disorganized, and interpersonal schizotypy scores aligned hierarchically in the 3 study groups (C&M>C>hC). The total MDMA exposure was positively correlated and MDMA-free period was negatively correlated with the SPS score. CONCLUSION: We found that the former use of cannabis and MDMA is associated with marked elevation in SPS. Moreover, the exposure amount of MDMA and MDMA-free periods are important determinants of SPS. The longer the cannabis and ecstasy free periods, the larger is the waning of SPS. PMID- 28566958 TI - Cognitive Outcome after Surgery in Patients with Mesial Temporal Lobe Epilepsy. AB - INTRODUCTION: The aim of the present study was to evaluate the neuropsychological outcomes of patients with medically intractable unilateral mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis (HS) treated either by anterior temporal lobectomy (ATL) or selective amygdalohippocampectomy (SAH). METHODS: This was a retrospective study where 67 patients who had undergone surgery for MTLE were evaluated. Thirty-two patients underwent ATL and 35 underwent SAH. All patients underwent a detailed neuropsychological evaluation before and 1 year after surgery. RESULTS: The verbal memory outcome was unchanged after left-sided surgery, whereas learning capacity increased after right-sided surgery (p=0.038). The visual memory outcome improved after right-sided surgery. Improvement of executive functions, particularly in the resistance of interference pattern in the Stroop Test, shortened 5th card time (p=0.000), and decreased corrections (p=0.003), after right-sided surgery and increased attention (p=0.027) after left sided surgery were observed. After both surgery types, although statistically insignificant, there was a marked decrease in incorrect answers in the Stroop Test, which also showed an improvement in the resistance of interference pattern. Moreover, there was a significant decrease in switching errors with word pairs in the Verbal Fluency Test (p=0.008) after right-sided surgery. When the two sides were compared, we observed that the recall phase of the verbal memory worsened (p=0.018); however, the recognition phase improved (p=0.015) after left-sided surgery. Additionally, the short-term visual memory was better for both sides (p=0.035). CONCLUSION: Our results showed that patients with left MTLE were not worsened in verbal memory, but despite improved recognition, they have some problems in recalling information and only a minor improvement in attention. Patients with right MTLE improved in their verbal learning capacity, visual memory, and resistance of interference pattern 1 year after surgery. It was thus shown that while epilepsy surgery is associated with some negative cognitive changes, it may also improve some cognitive functions. PMID- 28566959 TI - Metabolic Effects of Antidepressant Treatment. AB - INTRODUCTION: This study aimed to investigate body measurements, glucose-insulin metabolism, and lipid profile in patients with anxiety and depressive symptoms and also the effects of antidepressant drugs on these metabolic parameters. METHODS: The study included 40 outpatients and 32 healthy controls. The patients received antidepressant treatment (sertraline, escitalopram, fluoxetine, and venlafaxine) for 8 weeks. Body measurements were performed, and lipid, fasting blood glucose, and insulin levels were measured before and after treatment in patients and once in healthy controls. Insulin resistance was evaluated using the homeostasis model assessment (HOMA) index. RESULTS: Body mass index was higher in patients than in healthy controls, and there was no change in patients after treatment. In patients, high-density lipoprotein (HDL) cholesterol levels increased owing to the antidepressant treatment. Insulin level and HOMA index had a tendency to decrease with the treatment in patients and were similar to those of healthy controls before the treatment; however, they became lower than those of healthy controls after the treatment. There was an increase in waist circumference and total and HDL cholesterol levels, whereas there was a decrease in fasting blood glucose levels with treatment in patients using escitalopram. There was no change in body measurements and biochemical and hormone values in patients using fluoxetine, sertraline, and venlafaxine. There was an increase in weight, body mass index, and waist circumference after treatment in patients with depression; however, there was no change in patients with anxiety. CONCLUSION: In patients with psychiatric disorders having anxiety and depressive symptoms, metabolic changes independent of drugs and the metabolic effects of drugs are present. PMID- 28566960 TI - Efficacy of Different Durations of Intravenous Methylprednisolone Treatment in Relapses of Multiple Sclerosis. AB - INTRODUCTION: Relapses of multiple sclerosis (MS) are usually treated with high dose intravenous methylprednisolone (IVMP), given over 3-10 days. There is no consensus on the optimal duration of treatment. In this study, we aimed to investigate whether longer treatment provides additional short-term clinical benefits assessed by the change in plasma cytokine levels and EDSS scores in patients with relapsing-remitting MS (RRMS). METHODS: Forty RRMS patients during relapse were grouped into 3 and treated with 1 g/day of IVMP for either 5, 7, or 10 consecutive days. RESULTS: Levels of IL-10 and IL-12 were analyzed, and EDSS scores were noted before treatment, after treatment (on days 6, 8, or 11) and at the 4th week. IVMP treatment significantly induced anti-inflammatory IL-10 levels but had no effect on IL-12 levels. IVMP treatment for 7 or 10 consecutive days was not significantly different than that for 5 days in terms of the change in IL 12, IL-10 levels or clinical outcome. CONCLUSION: In conclusion, pulse high-dose IVMP treatment enhances functional recovery in patients with acute relapses of RRMS. In addition, IVMP treatment significantly increases the levels of IL-10 but has no effect on the levels of IL-12 in the short term. PMID- 28566961 TI - Retinal Nerve Fiber Layer Thickness Measurement by Spectral-Domain Optical Coherence Tomography in Patients with Major Depressive Disorder. AB - INTRODUCTION: In recent years, an increasing number of studies have researched retinal nerve fiber layer (RNFL) changes in neurodegenerative disorders. In this study, our aim was to determine structural RNFL changes in patients with major depressive disorder. METHODS: A total of 30 patients with major depressive disorder and 30 age- and sex-matched controls were recruited. Using optical coherence tomography (OCT), the peripapillary RNFL thickness in major depressive disorder patients and control subjects was measured and compared at each location. RESULTS: Patients with major depressive disorder did not show a statistically significant reduction in overall peripapillary RNFL thickness. CONCLUSION: Our study showed that RNFL thickness is not reduced in major depressive disorder patients and that OCT is not a useful tool for diagnosing and monitoring the progression of major depressive disorder. This study suggests that the pathophysiology of unipolar depression is different than in neurodegenerative disorders, pervasive developmental disorders, schizophrenia, and bipolar disorder. PMID- 28566962 TI - Impact of Neuro-Behcet Disease Immunoglobulin G on Neuronal Apoptosis. AB - INTRODUCTION: Parenchymal neuro-Behcet disease (NBD) is encountered in 5%-15% of Behcet disease (BD) patients and is characterized by inflammation of the brainstem and diencephalon structures. Neuronal apoptosis has been shown to participate in neuronal cell loss. Anti-neuronal antibodies have been identified in NBD patients. However, the pathogenic properties of these antibodies have not been studied. METHODS: To delineate the potential pathogenic activity of serum antibodies on neurons, pooled sera from seven NBD patients and seven healthy controls were divided into purified immunoglobulin G (IgG) and IgG-depleted serum fractions, and each fraction was administered to cultured SH-SY5Y neuroblastoma cells. Cell death was evaluated with a toxicity assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Moreover, expression levels of several apoptosis markers were evaluated with real time polymerase chain reaction (PCR). RESULTS: Administration of NBD IgG to cultured SH-SY5Y cells induced significantly increased cell death and apoptosis compared with other treatments. NBD IgG also enhanced the mRNA expression levels of major apoptosis and cell survival pathway factors. CONCLUSION: Our results suggest that IgGs isolated from the sera of NBD patients have a neurotoxic activity that is presumably mediated by apoptotic mechanisms. PMID- 28566963 TI - The Investigation of Symptoms and Diagnoses of Adult-Attention Deficit/ Hyperactivity Disorder in Women with Iron Deficiency Anemia. AB - INTRODUCTION: The aim of this study was to investigate symptoms and diagnoses of Adult-Attention Deficit/Hyperactivity Disorder (ADHD) in women with iron deficiency anemia, to evaluate relationship between ADHD with clinical features and to compare with the women without iron deficiency anemia. METHODS: Eighty three newly diagnosed iron deficiency anemia patients and 70 healthy controls were included in this study. All participants were assessed using a sociodemographic form, Structured Clinical Interview I (SCID-I), Wender Utah Rating Scale (WURS); Moreover, participants having WURS scores 36 and above were also assessed using the Adult ADD/ADHD Evaluation Scale and interviewed according to DSM-5 criteria. RESULTS: In the study, 22.9% of patients with iron deficiency anemia and 12.9% of healthy controls were found to have WURS scores 36 and above. Fifteen patients (18.1%) in iron deficiency anemia group and two patients (2.9%) in control group had adult ADHD, when they were evaluated with Adult ADD/ADHD Evaluation Scale and interviewed according to DSM-5 criteria (p=0.007). The patients with iron deficiency anemia had significantly higher WURS scores compared to controls (p=0.002). The levels of iron and ferritin had negative correlation (r=-0.166, p<0.05; r=-0.255, p<0.01, respectively) and the levels of serum iron binding capacity had positive correlation (r=0.255, p<0.01) with the scores of WURS. CONCLUSION: The prevalence of adult ADHD is higher than those reported for general population in patients with iron deficiency anemia. Early diagnose and treatment of adult ADHD may positively contribute to the patients with iron deficiency anemia. PMID- 28566964 TI - Brainstem Reflexes in Systemic Lupus Erythematosus Patients Without Clinical Neurological Manifestations. AB - INTRODUCTION: We aimed to assess central and peripheral nervous system involvement in systemic lupus erythematosus (SLE) patients without any neurological signs and symptoms by performing electrophysiological investigations. METHODS: Thirty-eight SLE patients and 35 healthy volunteers participated in this study. Peripheral nerve conduction and brainstem reflexes were evaluated by performing nerve conduction studies (NCSs) and blink reflex (BR) and masseter inhibitory reflex (MIR) recordings. RESULTS: Eleven patients (29%) had an abnormality in at least 1 NCS parameter, and 1 (2.6%) patient was diagnosed with polyneuropathy. The number of patients with abnormal BR and MIR was 23 (60.5%) and 14 (37%), respectively. The contralateral R2 latency of BR and the silent period 1 (SP1) latency of MIR were significantly prolonged in the patients compared with the controls (p=0.015 and p<0.001, respectively). CONCLUSION: This study showed that irrespective of peripheral nervous system involvement, brainstem reflexes could be affected in SLE patients even without clinical neurological findings. Brainstem reflex abnormalities suggested that the functional integrity of the inhibitory or excitatory interneurons in the lateral caudal pons and lateral medulla is disturbed in SLE patients. PMID- 28566966 TI - Factitious Disorder Presenting with Stuttering in Two Adolescents: The Importance of Psychoeducation. AB - A factitious disorder (FD) is a diagnostic entity in which patients intentionally act physically or mentally ill without obvious benefits and without being consciously aware of a clear underlying motive. Most pediatric FD cases have been reported as Munchausen syndrome by Proxy; however, pediatric disease symptoms can also be intentionally falsified by child and adolescent patients. To our knowledge, in the medical literature, an FD patient presenting with stuttering has not been previously reported. In this case report, we aimed to discuss the diagnosis and treatment process of FDs in children and adolescents by reporting the cases of two FD patients presenting with stuttering according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition. Both patients improved with psychoeducation and early confrontation. PMID- 28566967 TI - Clinical and Electrophysiological Findings in Two Siblings with Familial Hyperekplexia. PMID- 28566965 TI - Caregiver Burden in Different Stages of Alzheimer's Disease. AB - With an increasing number of patients being diagnosed with Alzheimer's disease (AD) daily, it has become one of the major problems in public health. The increase in the number of dementia patients in low- and middle-income countries is expected to be much more than that in developed countries. As a result, the economic burden of dementia, both worldwide and in Turkey, is growing. Moreover, AD leads to emotional burdens and psychological distress in family member(s) and caregiver(s) alongside the patient. Each stage of AD imposes different responsibilities on caregivers, increasing their burden. The suffering and emotional burdens of caregivers from these responsibilities lead to a decreased quality of life and disturbed body physiology. Incapacity, despair, weariness, and loneliness are the hidden emotions of this iceberg. This review aims to gather the results of studies on caregiver burden in different stages of AD, attract attention to those results that may have been ignored in Turkey, and shed light on the solutions required to overcome the problems in caregiving of AD patients. PMID- 28566968 TI - Autism Spectrum Disorder and Phenylketonuria: Dyzygotic Twins with Double Syndrome. PMID- 28566969 TI - Anterior Cerebral Artery Dissection Due to Sildenafil Use. PMID- 28566970 TI - Parents' perceptions about child abuse and their impact on physical and emotional child abuse: A study from primary health care centers in Riyadh, Saudi Arabia. AB - OBJECTIVE: To determine perceptions of parents about child abuse, and their impact on physical and emotional child abuse. MATERIALS AND METHODS: Two hundred parents attending three primary health care centers (PHCCs) in Riyadh serving National Guard employes and their families, were requested to participate in this survey. Data was collected by self administered questionnaire. Five main risk factors areas/domains were explored; three were parent related (personal factors, history of parents' childhood abuse, and parental attitude toward punishment), and two were family/community effects and factors specific to the child. SPSS was used for data entry and analysis. Descriptive analysis included computation of mean, median, mode, frequencies, and percentages; Chi-square test and t-test were used to test for statistical significance, and regression analysis performed to explore relationships between child abuse and various risk factors. RESULTS: Thirty-four percent of the parents reported a childhood history of physical abuse. Almost 18% of the parents used physical punishment. The risk factors associated significantly with child abuse were parents' history of physical abuse, young parent, witness to domestic violence, and poor self-control. Child related factors included a child who is difficult to control or has attention deficit hyperactivity disorder (ADHD). Parents who did not own a house were more likely to use physical punishment. Abusive beliefs of parent as risk factors were: physical punishment as an effective educational tool for a noisy child; parents' assent to physical punishment for children; it is difficult to differentiate between physical punishment and child abuse; parents have the right to discipline their child as they deem necessary; and there is no need for a system for the prevention of child abuse. CONCLUSION: The causes of child abuse and neglect are complex. Though detecting child abuse may be difficult in primary care practice, many risk factors can be identified early. Parents' attitudes can be measured, and prevention initiatives, such as screening and counseling for parents of children at risk, can be developed and incorporated into primary care practice. PMID- 28566971 TI - Prevalence and spectrum of functional disability of urban elderly subjects: A community-based study from Central India. AB - INTRODUCTION: One of the major determinants of the quality of life of elderly subjects is their functional status, which refers to their ability to perform normal daily activities. This study was carried out to determine the prevalence of functional disability in terms of restriction in the activities of daily livings (ADLs) in elderly subjects. MATERIALS AND METHODS: This community-based cross-sectional study was conducted in an urban area of Varanasi, India, with 616 elderly subjects (60 years and above) selected for the study by an appropriate sampling procedure. A predesigned and pretested questionnaire was used to elicit the desired information after taking consent from the study subjects. Statistical Package for Social Sciences (SPSS 21st version) was used for analysis; Chi-square test and z-test were used to test for statistical significance. RESULTS: Prevalence of functional disability in elderly subjects was 53.6% (95% confidence interval: 49.67-57.5%). Restriction of any ADL with maximum severity was observed in 13.5% of the subjects. Independence in ADLs was maximum (100%) for bowel continence and lowest for climbing stairs (47.4%). On the basis of Barthel Index score, 25.2% and 4.4% of the subjects had moderate and severe dependency, respectively. In comparison to mobility restriction, the proportion of subjects whose ADLs were not affected was significantly (P < 0.01) more in the self-care domain. CONCLUSION: Nearly half of the elderly subjects were functionally disabled on the basis of ADL performance. The number of persons of this age group in the domain of restricted mobility is quite high. It is necessary and also possible to design and implement programs that will involve all persons concerned with their care to improve the functional status of the geriatric population. PMID- 28566972 TI - To what extent are Arab pilgrims to Makkah aware of the middle east respiratory syndrome coronavirus and the precautions against it? AB - BACKGROUND: Approximately, 80% of the many cases of the Middle East respiratory syndrome coronavirus (MERS-CoV) confirmed worldwide were diagnosed in the Kingdom of Saudi Arabia (KSA). The risk of the disease spreading internationally is especially worrying given the role of KSA as the home of the most important Islamic pilgrimage sites. This means the need to assess Arab pilgrims' awareness of MERS-CoV is of paramount importance. MATERIALS AND METHODS: A cross-sectional study was carried out during Ramadan 2015 in the Holy Mosque in Makkah, Saudi Arabia. Self-administered questionnaires were distributed to 417 Arab participants at King Fahad Extension, King Abdullah Prayer Extension and, King Abdullah Piazza Extension after Taraweeh and Fajr prayers. RESULTS: The mean MERS CoV knowledge score was 52.56. Majority of the respondents (91.3%) were familiar with MERS-CoV. Saudis had significantly higher knowledge of MERS-CoV than non Saudis (56.92 +/- 18.55 vs. 44.91 +/- 25.46, p = 0.001). Females had significantly more knowledge about consanguineous MERS-CoV than males (55.82 +/- 19.35 vs. 49.93 +/- 23.66, p = 0.006). The average knowledge was significantly higher in respondents who had received health advice on MERS-CoV (56.08 +/- 20.86 vs. 50.65 +/- 22.51, p = 0.024). With respect to stepwise linear regression, knowledge of MERS-CoV tended to increase by 14.23 (B = 14.23%, p = 0.001) in participants who were familiar with MERS-CoV, and by 8.50 (B = 8.50, p = 0.001) in those who perceived MERS-CoV as a very serious disease. CONCLUSION: There is a great need for educational programs to increase awareness about MERS-CoV. PMID- 28566973 TI - Perspective of Saudi women in the Makkah region on breast cancer awareness. AB - OBJECTIVE: To assess the perspective of Saudi women in the Makkah region on breast cancer awareness and early detection. MATERIALS AND METHODS: A mixed method study was conducted among 25-65 years old healthy Saudi females from Makkah region during the awareness campaign in October 2014. The participants were recruited by personal invitations at the women's places of work and social gatherings. The initial invitations were issued by either the research coordinator or the investigator. All women were asked to complete a short questionnaire on basic knowledge on breast cancer. This was followed by focus group discussions. All interviews were carried out by female breast cancer consultant oncologists. All discussion transcripts were summarized and categorized into main themes; data presented as frequencies and percentages. RESULTS: Forty Saudi females, aged 25-65 years, were included in the study. Nearly 38% of them had never attended any awareness campaign on breast cancer. Only 10% of the participants correctly answered all five basic questions on the risk and early detection of breast cancer; 63% of the women had never been taught breast self-examination. Participants' perception was discussed in five focus groups. Four themes were identified during the discussions: knowledge about breast cancer and screening; resources of breast cancer awareness; social support for access to awareness program; and beliefs on breast cancer and early detection. CONCLUSION: We recommend that strategies on breast cancer awareness in our population should focus on early detection by improving the knowledge and skills of women. These strategies should include programs widely accessible through primary health-care centers and other health-care institutions. In addition, we recommend that physicians and family members should be involved in these programs. PMID- 28566974 TI - Mild respiratory symptoms in asthmatic patients might not be due to bronchoconstriction. AB - BACKGROUND: Although respiratory symptoms in asthmatic patients are likely to be caused by bronchoconstriction, this should be confirmed by spirometry. In this study, our aim was to determine the percentage of asthmatic patients who present with mild respiratory symptoms but fail to show any evidence of bronchoconstriction in spirometry. MATERIALS AND METHODS: A total of 428 known asthmatic patients (57.5% females) participated in the study. Inclusion criteria were age >=16 years, known asthmatics for at least 1 year, presenting with mild respiratory symptoms including cough, wheezes, shortness of breath, and chest tightness. Patients presenting with moderate or severe asthma exacerbations were excluded from the study. Spirometry measurements were performed according to the guidelines of the American Thoracic Society. SPSS was used for data analysis. The percentage of patients who did not show any evidence of airway obstruction was calculated. For spirometry variables, mean and standard deviation were calculated. For the categorical variables, Chi-square test was performed to determine statistical significance at alpha=0.05. RESULTS: Typical obstructive pattern was found in 38 (or 9%) of all participants. Evidence of obstruction within small or middle airways was found in all those who showed an obstructive pattern and more than 90% of those who showed restrictive or mixed patterns. About 11% of the participants showed a normal spirometric pattern with no evidence of small airway obstruction. Statistical analysis showed an insignificant relation between patterns of spirometry and gender or body mass index of the participants. CONCLUSION: About 11% of asthmatic patients with mild respiratory symptoms who attended the respiratory clinic have no evidence of bronchoconstriction. Spirometry is an essential step for evaluation of every asthmatic patient who presents with respiratory symptoms. PMID- 28566975 TI - Doctors' knowledge of patients' rights at King Fahd Hospital of the University. AB - OBJECTIVES: To assess the level of physicians' knowledge about the contents of patients' bill of rights (PBR) and its implementation. MATERIALS AND METHODS: This cross-sectional study was carried out at a university hospital in the Eastern Province of Saudi Arabia. All physicians working in the hospital received a self-administered questionnaire to measure their level of knowledge of PBR. Scoring was done to determine the knowledge of the details. The study was approved by the Institutional Review Board of the University Hospital and permission sought from the administration. Data analysis performed with SPSS; descriptive analyses included frequency and percentages for categorical variables, and mean and standard deviations for continuous variables. Bivariate analyses were carried out to determine association between sociodemographic variables and the level of knowledge (adequate/inadequate). Logistic regression analysis were performed to calculate adjusted odds ratio at 0.05 significance level. RESULTS: Most (52.7%) of the physicians were females, were aged between 25 and 30 years (58.5%), and Saudi (80.2%). The majority of the physicians belonged to the residency program (44.9%) and had work experience of 1-5 years (45.4%). About 44% physicians had adequate knowledge about PBR and 55.56% had inadequate knowledge. Regarding physician's response to each item of PBR, the majority (98.1%) gave correct answer to Item 2: "Patients should know the identity and professional status of the healthcare providers responsible for their treatment" (98.1%). Item 25: "Doctors are entitled to withhold any procedures related to a patient's condition if the patient refuses their choice of treatment" was the item with the least correct response (15.5%). CONCLUSION: Reinforcement and strict implementation of PBR are necessary. The institution should provide training and motivate physicians, especially younger doctors regarding PBR to ensure good health for all and safeguard the integrity of both the physician and the hospital. PMID- 28566977 TI - Cochlear implants in children: A cross-sectional investigation on the influence of geographic location in Saudi Arabia. AB - INTRODUCTION: The role of the family in detecting a child's hearing difficulty and the age at which an implantation is done have been identified as strong predictors of the outcomes of pediatric cochlear implantation. In the absence of screening programs for hearing loss in Saudi neonates, the family's role is of paramount importance. The aim of this study was to investigate the influence of geographic location on the course of identification, examination, and cochlear implantation in children in Saudi Arabia. MATERIALS AND METHODS: Pediatric patients who had received either unilateral or bilateral cochlear implantation at King Abdulaziz University Hospital in Riyadh, Saudi Arabia, between January 1, 2012, and December 31, 2014, were surveyed. RESULTS: A total of 156 pediatric patients have had a cochlear implant between January 1, 2012, and December 31, 2014. The one-way analysis of variance test to compare the means of the independent sample groups in various geographic zones showed that with a hundred percent access to primary health care, the geographic location of the population had an influence on the detection of hearing loss but not on the cochlear implantation. CONCLUSION: This study found that the geographic location of the population has an influence on the time of detection of hearing loss in children but not on the time of cochlear implantation. Raising parental awareness of the importance of early detection of hearing loss is necessary. Further research is also required to define the role of factors such as the income and the educational level of parents on the early detection of neonatal hearing loss. PMID- 28566976 TI - Health education to diabetic patients before the start of Ramadan: Experience from a teaching hospital in Dammam. AB - BACKGROUND AND OBJECTIVE: Studies have shown that pre-Ramadan structured educational program for patients with diabetes mellitus (DM) is beneficial. In this study, our aim was to evaluate the degree of adherence of treating physicians to such programs and their influence on the patient's knowledge and behavior. MATERIALS AND METHODS: This cross-sectional study was carried out on adult patients with DM attending a university hospital, who were observed while fasting during Ramadan 1436/2015. Data was collected using a questionnaire-based interview. Baseline characteristics were obtained, and patients were asked whether they had had pre-Ramadan education or not and who the provider was. Patients' knowledge of the components of the recommended structured pre-Ramadan educational program was also tested. Comparison between patients who had the education and those who did not was done using Chi-square test and independent samples Student's t-test; p <= 0.05 was considered statistically significant. RESULTS: A total of 298 patients with type 1 or type 2 DM were included in the study; 75.5% of the patients were aged 40 years or older. Only 30% had pre Ramadan education delivered mainly by diabetic educators or the treating physicians (52% and 44%, respectively). Patients who had the education were younger (mean age: 45.6 +/- 17.4 vs. 50.3 +/- 14.4, respectively, p = 0.0048), had higher educational qualifications, were more likely to be employed, and self monitored their blood glucose more frequently (p = 0.0001). There was no difference between the two groups with regard to their knowledge of diet and exercise. CONCLUSION: The adherence to the pre-Ramadan educational program by the treating physician was low. It is necessary to increase the awareness about the importance of these programs among health-care professionals. The programs should target the less educated, the unemployed, and older patients. PMID- 28566978 TI - Satisfaction with a 2-day communication skills course culturally tailored for medical specialists in Qatar. AB - OBJECTIVE: Health-care communication skills training may be particularly needed in the Arabian Gulf countries because of the variety of cultures within the physician and patient populations. This study describes the implementation and results of a communication skills training program for physicians in Qatar that assessed previous training, and effect of previous training on participants' course evaluations. MATERIALS AND METHODS: We conducted a 2-day communication skills training course covering seven culturally adapted modules. Educational strategies included large and small group work with the standardized patient, demonstration videos, and lectures. At the end, participants completed a course evaluation survey. Data analysis performed with SPSS; frequencies and percentages were calculated, and Chi-square test applied to evaluate statistical significance. RESULTS: A total of 410 physicians in Qatar have participated in the course over a period of 2 years. Evaluation ratings of the course were high. Participants rated the module on Breaking Bad News as the most useful, and the small group role-play as the most helpful course component. One-third of participants had previously participated in experiential communication skills training. There was no association between previous experience and evaluation of the course. CONCLUSION: Physicians in Qatar positively evaluated a 2-day communication skills course, though the majority of participants did not have any previous exposure to experiential communication skills training. PMID- 28566979 TI - Eagle's syndrome with facial palsy. AB - Eagle's syndrome (ES) is a rare disease in which the styloid process is elongated and compressing adjacent structures. We describe a rare presentation of ES in which the patient presented with facial palsy. Facial palsy as a presentation of ES is very rare. A review of the English literature revealed only one previously reported case. Our case is a 39-year-old male who presented with left facial palsy. He also reported a 9-year history of the classical symptoms of ES. A computed tomography scan with three-dimensional reconstruction confirmed the diagnoses. He was started on conservative management but without significant improvement. Surgical intervention was offered, but the patient refused. It is important for otolaryngologists, dentists, and other specialists who deal with head and neck problems to be able to recognize ES despite its rarity. Although the patient responded to a treatment similar to that of Bell's palsy because of the clinical features and imaging, ES was most likely the cause of his facial palsy. PMID- 28566980 TI - Use of International Physical Activity Questionnaire-short form for assessment of physical activity of children. PMID- 28566981 TI - Isolated eyelid Schwannoma: A rare differential diagnosis of lid tumor. AB - Primary Schwannomas of the eyelid are extremely uncommon. It accounts for one percent of orbital tumors. We present a case of isolated eyelid Schwannoma in the lateral canthus of the left eye with no systemic diseases associated. Surgical excisional biopsy was done. In two years follow up, no recurrence or malignant conversion was detected. PMID- 28566982 TI - Successful management of choroidal neovascular membrane secondary to choroidal osteoma with intravitreal bevacizumab. PMID- 28566983 TI - The Radioprotective Effect of Resveratrol Against Genotoxicity Induced by gamma Irradiation in Mice Blood Lymphocytes. AB - In this study, we evaluated whether the protective potential of resveratrol (RSV; 3,5,4'-trihydroxy-trans-stilbene) against gamma-radiation caused damages in peripheral blood lymphocyte of mice. Resveratrol as a polyphenolic compound scavenges free radicals. Various doses of RSV were administered intraperitoneally 2 hours to adult male mice before a single dose of whole-body gamma-irradiation (2 Gy). To assess the protective ability of RSV, the alkaline comet assay in blood lymphocyte of mice was performed and the total comet score was evaluated. The results of the alkaline comet assay showed that RSV significantly inhibited radiation-induced DNA damage. We observed that RSV protects blood lymphocyte against radiation-induced damage in mice. PMID- 28566984 TI - Can mHealth Revolutionize the Way We Manage Adult Obesity? AB - Obesity is the largest driver of chronic preventable diseases, accounting for an estimated $147 billion or 10 percent of total US healthcare costs in 2008. It has been forecasted that 42 percent of Americans will be obese by 2030. Mobile health (mHealth) technologies target and may modify the behavioral factors that lead to obesity to promote a healthy lifestyle. These technologies could potentially reduce the cost and the morbidity and mortality burden of obesity because of their inexpensive and portable nature. This study aimed to analyze the efficacy and cost-effectiveness of mHealth interventions for adult obesity in the United States. The methodology used in this study was a literature review of 54 articles. Weight, body mass index (BMI), waist circumference reductions, and favorable lifestyle behavior changes were noted across most studies. Existing data and research on efficacy and linked costs indicated that mHealth technologies were more effective than other methods and could be inexpensively delivered remotely to manage adult obesity, offering significant benefits over conventional care. Further studies on the costs and benefits of adapting such mHealth interventions in clinical settings are needed. PMID- 28566985 TI - Development of a Novel Tablet-based Approach to Reduce HIV Stigma among Healthcare Staff in India. AB - Although stigma is considered to be one of the major barriers to reducing the AIDS epidemic in India, efforts to reduce stigma have not been sufficiently examined. In response, a partially computer-administered three-session stigma reduction intervention was developed and is currently being tested. This paper describes the technological design, development, implementation, and management of these in-person tablet-administered assessment and intervention sessions that are being used to evaluate the efficacy of this innovative stigma reduction intervention among nursing students and ward attendants in India. PMID- 28566986 TI - Differences in Sociocognitive Beliefs between Involved and Noninvolved Employees during the Implementation of an Electronic Health Record System. AB - BACKGROUND: Electronic health records (EHRs) can improve quality and efficiency in patient care. However, the intention to work with such a new system is often relatively low among employees because the work processes of the healthcare organization may change. Involving employees in an EHR implementation may increase their beliefs and perceived capabilities concerning the new system. The current study aimed to assess the role of involvement and its effects on sociocognitive beliefs regarding the implementation of a new EHR system. METHODS: The study was performed in June 2015 among all eligible employees of a hospital in the Netherlands. Both involved and noninvolved employees were invited to complete a paper-based questionnaire concerning their sociocognitive beliefs (i.e., attitude, social influence, self-efficacy, and intention) related to the EHR implementation. Independent sample t-tests were used to assess potential differences in sociocognitive beliefs between employees who were involved in the implementation process and those who were not. Effect sizes (Cohen's d) were calculated to indicate the standardized difference between the means. RESULTS: A total of 359 participants completed the paper-based questionnaire and were included in the analyses. Involved employees (n = 94) reported significantly higher levels of attitude (p < .001, d = .62), perceived self-efficacy (p = .01, d = .31), social support (p < .001, d = .68), and a higher intention to work with the new EHR system (p < .001, d = .60), compared with the group of employees who were not involved in the implementation process (n = 265). CONCLUSION: Involving employees during an EHR implementation appears to enhance employees' sociocognitive beliefs and increases their intention to work with the new system. PMID- 28566987 TI - Evaluating Motivation for the Use of an Electronic Health Record Simulation Game. AB - Experiential learning via simulation offers a variety of benefits including reduced risks, repetitive exposure, and mastery of complex processes. How to motivate people to engage in and enjoy playing games is an important concept in the creation of serious games focused on learning new skills. This study sought to determine the motivators that increase users' pleasurable experience when playing an electronic health record simulation game. To examine how intrinsic and extrinsic motivation affected both engagement and enjoyment, we surveyed students of health professions at one university. Results indicate that while both forms of motivation are significant in increasing engagement and enjoyment, extrinsic motivation such as badges, points, and scoreboards were much more important than internal motivations for our participants. These findings have implications for the development of an electronic health record simulation game. PMID- 28566989 TI - Potential Effects of the Electronic Health Record on the Small Physician Practice: A Delphi Study. AB - The Health Information Technology for Economic and Clinical Health (HITECH) Act established the requirement of all medical practices to have certified electronic health records (EHRs). Some primary concerns that have been delaying implementation are issues of cost, revenue impact, and the effect on the patient encounter. Small physician practices (one to four physicians) account for 46 percent of all physicians. The purpose of this qualitative study using a modified Delphi research design was to examine the potential effect of the adoption of the EHR on revenue, unintended costs or savings, and changes in the patient encounter. Fifteen expert panelists completed the three-round survey process. The expert panelists reached a consensus that EHRs would reduce the number of patients seen per day, thereby reducing their revenue. Although the panelists limited their discussion on the effect of patient outcomes, their most dominant concern was the loss of face-to-face time with the patient. They felt that the use of an EHR would reduce the focus on the patient and potentially cause physicians to miss medical conditions. The results of this study indicate an avenue for EHR vendors to develop educational avenues to teach physicians how to optimize the EHR as well as to share success stories that demonstrate improved financial impact. PMID- 28566988 TI - The Impact of Order Source Misattribution on Computerized Provider Order Entry (CPOE) Performance Metrics. AB - BACKGROUND: One strategy to foster adoption of computerized provider order entry (CPOE) by physicians is the monthly distribution of a list identifying the number and use rate percentage of orders entered electronically versus on paper by each physician in the facility. Physicians care about CPOE use rate reports because they support the patient safety and quality improvement objectives of CPOE implementation. Certain physician groups are also motivated because they participate in contracted financial and performance arrangements that include incentive payments or financial penalties for meeting (or failing to meet) a specified CPOE use rate target. Misattribution of order sources can hinder accurate measurement of individual physician CPOE use and can thereby undermine providers' confidence in their reported performance, as well as their motivation to utilize CPOE. Misattribution of order sources also has significant patient safety, quality, and medicolegal implications. OBJECTIVE: This analysis sought to evaluate the magnitude and sources of misattribution among hospitalists with high CPOE use and, if misattribution was found, to formulate strategies to prevent and reduce its recurrence, thereby ensuring the integrity and credibility of individual and facility CPOE use rate reporting. METHODS: A detailed manual order source review and validation of all orders issued by one hospitalist group at a midsize community hospital was conducted for a one-month study period. RESULTS: We found that a small but not dismissible percentage of orders issued by hospitalists-up to 4.18 percent (95 percent confidence interval, 3.84-4.56 percent) per month-were attributed inaccurately. Sources of misattribution by department or function were as follows: nursing, 42 percent; pharmacy, 38 percent; laboratory, 15 percent; unit clerk, 3 percent; and radiology, 2 percent. Order management and protocol were the most common correct order sources that were incorrectly attributed. CONCLUSION: Order source misattribution can negatively affect reported provider CPOE use rates and should be investigated if providers perceive discrepancies between reported rates and their actual performance. Preventive education and communication efforts across departments can help prevent and reduce misattribution. PMID- 28566990 TI - Development of a Web-Based Registry to Support Diabetes Care in Free Medical Clinics. AB - The United States has more than 1,000 free medical clinics. Because these clinics do not bill Medicare or Medicaid, they are not eligible for federal reimbursement for electronic health record (EHR) adoption. As a result, most do not have EHRs or electronic disease registries. A web-based diabetes registry was created with all open-source components for use in an urban free clinic to manage patients with type 2 diabetes and comorbidities. The registry was modeled after the Chronic Disease Electronic Management System and recommendations of the American Diabetes Association. The software was enhanced to include multiple other features, such as progress notes, so that it can function as a simple EHR. The configuration permits other free clinics to join securely, and the software can be shared. PMID- 28566991 TI - Future Research in Health Information Technology: A Review. AB - INTRODUCTION: Currently, information technology is considered an important tool to improve healthcare services. To adopt the right technologies, policy makers should have adequate information about present and future advances. This study aimed to review and compare studies with a focus on the future of health information technology. METHOD: This review study was completed in 2015. The databases used were Scopus, Web of Science, ProQuest, Ovid Medline, and PubMed. Keyword searches were used to identify papers and materials published between 2000 and 2015. Initially, 407 papers were obtained, and they were reduced to 11 papers at the final stage. The selected papers were described and compared in terms of the country of origin, objective, methodology, and time horizon. RESULTS: The papers were divided into two groups: those forecasting the future of health information technology (seven papers) and those providing health information technology foresight (four papers). The results showed that papers related to forecasting the future of health information technology were mostly a literature review, and the time horizon was up to 10 years in most of these studies. In the health information technology foresight group, most of the studies used a combination of techniques, such as scenario building and Delphi methods, and had long-term objectives. CONCLUSION: To make the most of an investment and to improve planning and successful implementation of health information technology, a strategic plan for the future needs to be set. To achieve this aim, methods such as forecasting the future of health information technology and offering health information technology foresight can be applied. The forecasting method is used when the objectives are not very large, and the foresight approach is recommended when large-scale objectives are set to be achieved. In the field of health information technology, the results of foresight studies can help to establish realistic long-term expectations of the future of health information technology. PMID- 28566992 TI - Mobile Device Security: Perspectives of Future Healthcare Workers. AB - Healthcare data breaches on mobile devices continue to increase, yet the healthcare industry has not adopted mobile device security standards. This increase is disturbing because individuals are often accessing patients' protected health information on personal mobile devices, which could lead to a data breach. This deficiency led the researchers to explore the perceptions of future healthcare workers regarding mobile device security. To determine healthcare students' perspectives on mobile device security, the investigators designed and distributed a survey based on the Technology Threat Avoidance Theory. Three hundred thirty-five students participated in the survey. The data were analyzed to determine participants' perceptions about security threats, effectiveness and costs of safeguards, self-efficacy, susceptibility, severity, and their motivation and actions to secure their mobile devices. Awareness of interventions to protect mobile devices was also examined. Results indicate that while future healthcare professionals perceive the severity of threats to their mobile data, they do not feel personally susceptible. Additionally, participants were knowledgeable about security safeguards, but their knowledge of costs and problems related to the adoption of these measures was mixed. These findings indicate that increasing security awareness of healthcare professionals should be a priority. PMID- 28566993 TI - Secure Clinical Texting: Patient Risk in High-Acuity Care. AB - The Joint Commission recently reversed its prior authorization of the use of secure clinical texting to issue patient care orders, now again prohibiting texting of orders. However, the potential sole or exclusive use of clinical texts to transmit other patient care information beyond care orders still poses a risk to patient safety in high acuity care because of text transmission delays resulting from carrier-dependent latency. Although texting in routine patient care may deliver high value to clinicians, the risk of latency and delayed receipt of clinically urgent or time-sensitive texted patient information in high acuity care settings can harm patients. We completed a review of 19 secure clinical text vendor websites, finding that 16 of 19 (84 percent) market their products for use specifically in high-acuity and critical patient care. The secure clinical texting industry needs the policy guidance of The Joint Commission and health information technology professionals to minimize risk to patients, clinicians, and hospital systems as secure clinical texting becomes standard accepted practice. PMID- 28566994 TI - The Odds of Success: Predicting Registered Health Information Administrator Exam Success. AB - The purpose of this study was to craft a predictive model to examine the relationship between grades in specific academic courses, overall grade point average (GPA), on-campus versus online course delivery, and success in passing the Registered Health Information Administrator (RHIA) exam on the first attempt. Because student success in passing the exam on the first attempt is assessed as part of the accreditation process, this study is important to health information management (HIM) programs. Furthermore, passing the exam greatly expands the graduate's job possibilities because the demand for credentialed graduates far exceeds the supply of credentialed graduates. Binary logistic regression was utilized to explore the relationships between the predictor variables and success in passing the RHIA exam on the first attempt. Results indicate that the student's cumulative GPA, specific HIM course grades, and course delivery method were predictive of success. PMID- 28566995 TI - The Use of Automated SNOMED CT Clinical Coding in Clinical Decision Support Systems for Preventive Care. AB - OBJECTIVE: The objective of this study is to discuss and analyze the use of automated SNOMED CT clinical coding in clinical decision support systems (CDSSs) for preventive care. The central question that this study seeks to answer is whether the utilization of SNOMED CT in CDSSs can improve preventive care. METHOD: PubMed, Google Scholar, and Cochrane Library were searched for articles published in English between 2001 and 2012 on SNOMED CT, CDSS, and preventive care. OUTCOME MEASURES: Outcome measures were the sensitivity or specificity of SNOMED CT coded data and the positive predictive value or negative predictive value of SNOMED CT coded data. Additionally, we documented the publication year, research question, study design, results, and conclusions of these studies. RESULTS: The reviewed studies suggested that SNOMED CT successfully represents clinical terms and negated clinical terms. CONCLUSION: The use of SNOMED CT in CDSS can be considered to provide an answer to the problem of medical errors as well as for preventive care in general. Enhancement of the modifiers and synonyms found in SNOMED CT will be necessary to improve the expected outcome of the integration of SNOMED CT with CDSS. Moreover, the application of the tree augmented naive (TAN) Bayesian network method can be considered the best technique to search SNOMED CT data and, consequently, to help improve preventive health services. PMID- 28566996 TI - Working with an Electronic Medical Record in Ambulatory Care: A Study of Patient Perceptions of Intrusiveness AB - OBJECTIVE: To assess patient perceptions of electronic medical record (EMR) intrusiveness during ambulatory visits to clinics associated with a large academic medical center. METHOD: We conducted a survey of patients seen at any of 98 academic medical center clinics. The survey assessed demographics, visit satisfaction, computer use, and perceived intrusiveness of the computer. RESULTS: Of 7,058 patients, slightly more than 80 percent reported that the physician had used the computer while in the room, but only 24 percent were shown results in the EMR. Most patients were very satisfied or satisfied with their visit and did not find the computer intrusive (83 percent). Younger respondents, those shown results, and those who reported that the physician used the computer were more likely to perceive the computer as intrusive. Qualitative comments suggest different perceptions related to computer intrusiveness than to EMR use more generally. DISCUSSION: Patients were generally accepting of EMRs and therefore use of computers in the exam room. However, subgroups of patients may require greater study to better understand patient perceptions related to EMR use and intrusiveness. CONCLUSION: Results suggest the need for greater focus on how physicians use computers in the exam room in a manner that facilitates maintaining good rapport with patients. PMID- 28566997 TI - EEG-Based Quantification of Cortical Current Density and Dynamic Causal Connectivity Generalized across Subjects Performing BCI-Monitored Cognitive Tasks. AB - Quantification of dynamic causal interactions among brain regions constitutes an important component of conducting research and developing applications in experimental and translational neuroscience. Furthermore, cortical networks with dynamic causal connectivity in brain-computer interface (BCI) applications offer a more comprehensive view of brain states implicated in behavior than do individual brain regions. However, models of cortical network dynamics are difficult to generalize across subjects because current electroencephalography (EEG) signal analysis techniques are limited in their ability to reliably localize sources across subjects. We propose an algorithmic and computational framework for identifying cortical networks across subjects in which dynamic causal connectivity is modeled among user-selected cortical regions of interest (ROIs). We demonstrate the strength of the proposed framework using a "reach/saccade to spatial target" cognitive task performed by 10 right-handed individuals. Modeling of causal cortical interactions was accomplished through measurement of cortical activity using (EEG), application of independent component clustering to identify cortical ROIs as network nodes, estimation of cortical current density using cortically constrained low resolution electromagnetic brain tomography (cLORETA), multivariate autoregressive (MVAR) modeling of representative cortical activity signals from each ROI, and quantification of the dynamic causal interaction among the identified ROIs using the Short-time direct Directed Transfer function (SdDTF). The resulting cortical network and the computed causal dynamics among its nodes exhibited physiologically plausible behavior, consistent with past results reported in the literature. This physiological plausibility of the results strengthens the framework's applicability in reliably capturing complex brain functionality, which is required by applications, such as diagnostics and BCI. PMID- 28566998 TI - Relative Contribution of Prolyl Hydroxylase-Dependent and -Independent Degradation of HIF-1alpha by Proteasomal Pathways in Cerebral Ischemia. AB - Hypoxia inducible factor-1 (HIF-1) is a key regulator in hypoxia and can determine the fate of brain cells during ischemia. However, the mechanism of HIF 1 regulation is still not fully understood in ischemic brains. We tested a hypothesis that both the 26S and the 20S proteasomal pathways were involved in HIF-1alpha degradation under ischemic conditions. Using in vitro ischemic model (oxygen and glucose deprivation) and a mouse model of middle cerebral artery occlusion, we tested effects of inhibitors of proteasomes and prolyl hydroxylase (PHD) on HIF-1alpha stability and brain injury in cerebral ischemia. We observed that 30 and 60 min of oxygen-glucose deprivation significantly increased the 20S proteasomal activity. We demonstrated that proteasome inhibitors increased HIF 1alpha stabilization and cell viability and were more effective than PHD inhibitors in primary cultured cortical neurons exposed to oxygen and glucose deprivation. Furthermore, the administration of the proteasome inhibitor, epoxomicin, to mice resulted in smaller infarct size and brain edema than a PHD inhibitor. Our results indicate that 20S proteasomes are involved in HIF-1alpha degradation in ischemic neurons and that proteasomal inhibition provides more HIF 1alpha stabilization and neuroprotection than PHD inhibition in cerebral ischemia. PMID- 28566999 TI - Communication Impairment in Ultrasonic Vocal Repertoire during the Suckling Period of Cd157 Knockout Mice: Transient Improvement by Oxytocin. AB - Communication consists of social interaction, recognition, and information transmission. Communication ability is the most affected component in children with autism spectrum disorder (ASD). Recently, we reported that the CD157/BST1 gene is associated with ASD, and that CD157 knockout (Cd157-/-) mice display severe impairments in social behavior that are improved by oxytocin (OXT) treatment. Here, we sought to determine whether Cd157-/- mice can be used as a suitable model for communication deficits by measuring ultrasonic vocalizations (USVs), especially in the early developmental stage. Call number produced in pups due to isolation from dams was higher at postnatal day (PND) 3 in knockout pups than wild-type mice, but was lower at PNDs 7 and 10. Pups of both genotypes had similarly limited voice repertoires at PND 3. Later on, at PNDs 7 and 10, while wild-type pups emitted USVs consisting of six different syllable types, knockout pups vocalized with only two types. This developmental impairment in USV emission was rescued within 30 min by intraperitoneal OXT treatment, but quickly returned to control levels after 120 min, showing a transient effect of OXT. USV impairment was partially observed in Cd157+/- heterozygous mice, but not in Cd157 /- adult male mice examined while under courtship. These results demonstrate that CD157 gene deletion results in social communication insufficiencies, and suggests that CD157 is likely involved in acoustic communication. This unique OXT sensitive developmental delay in Cd157-/- pups may be a useful model of communicative interaction impairment in ASD. PMID- 28567001 TI - Time to Amyloid Positivity and Preclinical Changes in Brain Metabolism, Atrophy, and Cognition: Evidence for Emerging Amyloid Pathology in Alzheimer's Disease. AB - Background: Abeta pathology is associated with longitudinal changes of brain metabolism, atrophy, and cognition, in cognitively healthy elders. However, Abeta information is usually measured cross-sectionally and dichotomized to classify subjects as Abeta-positive or Abeta-negative, making it difficult to evaluate when brain and cognitive changes occur with respect to emerging Abeta pathology. In this study, we use longitudinal Abeta information to combine the level and rate of change of Abeta to estimate the time to Abeta-positivity for each subject and test this temporal proximity to significant Abeta pathology for associations with brain structure, metabolism, and cognition. Methods: In 89 cognitively healthy elders with up to 10 years of follow-up, we estimated the points at which rates of fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to the time to Abeta-positivity. Points of initial acceleration in rates of decline were estimated using mixed-effects models with penalized regression splines. Results: Acceleration of rates of FDG PET were observed to occur 20+ years before the conventional threshold for Abeta positivity. Subtle signs of cognitive dysfunction were observed 10+ years before Abeta-positivity. Conclusions: Abeta may have subtle associations with other hallmarks of Alzheimer's disease before Abeta biomarkers reach conventional thresholds for Abeta-positivity. Therefore, we propose that emerging Abeta pathology occurs many years before cognitively healthy elders reach the current threshold for Abeta positivity (preclinical AD). To allow prevention in the earliest disease stages, AD clinical trials may be designed to also include subjects with Abeta biomarkers in the sub-threshold range. PMID- 28567000 TI - Exosomes from NSC-34 Cells Transfected with hSOD1-G93A Are Enriched in miR-124 and Drive Alterations in Microglia Phenotype. AB - Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder affecting motor neurons (MNs). Evidences indicate that ALS is a non-cell autonomous disease in which glial cells participate in both disease onset and progression. Exosomal transfer of mutant copper-zinc superoxide dismutase 1 (mSOD1) from cell-to-cell was suggested to contribute to disease dissemination. Data from our group and others showed that exosomes from activated cells contain inflammatory-related microRNAs (inflamma-miRNAs) that recapitulate the donor cell. While glia-derived exosomes and their effects in neurons have been addressed by several studies, only a few investigated the influence of motor neuron (MN)-derived exosomes in other cell function, the aim of the present study. We assessed a set of inflamma-miRs in NSC-34 MN-like cells transfected with mutant SOD1(G93A) and extended the study into their derived exosomes (mSOD1 exosomes). Then, the effects produced by mSOD1 exosomes in the activation and polarization of the recipient N9 microglial cells were investigated. Exosomes in coculture with N9 microglia and NSC-34 cells [either transfected with either wild type (wt) human SOD1 or mutant SOD1(G93A)] showed to be transferred into N9 cells. Increased miR-124 expression was found in mSOD1 NSC-34 cells and in their derived exosomes. Incubation of mSOD1 exosomes with N9 cells determined a sustained 50% reduction in the cell phagocytic ability. It also caused a persistent NF-kB activation and an acute generation of NO, MMP-2, and MMP-9 activation, as well as upregulation of IL-1beta, TNF-alpha, MHC-II, and iNOS gene expression, suggestive of induced M1 polarization. Marked elevation of IL-10, Arginase 1, TREM2, RAGE, and TLR4 mRNA levels, together with increased miR-124, miR-146a, and miR-155, at 24 h incubation, suggest the switch to mixed M1 and M2 subpopulations in the exosome-treated N9 microglial cells. Exosomes from mSOD1 NSC-34 MNs also enhanced the number of senescent-like positive N9 cells. Data suggest that miR-124 is translocated from the mSOD1 MNs to exosomes, which determine early and late phenotypic alterations in the recipient N9-microglial cells. In conclusion, modulation of the inflammatory-associated miR-124, in mSOD1 NSC-34 MNs, with potential benefits in the cargo of their exosomes may reveal a promising therapeutic strategy in halting microglia activation and associated effects in MN degeneration. PMID- 28567002 TI - Iron-Restricted Diet Affects Brain Ferritin Levels, Dopamine Metabolism and Cellular Prion Protein in a Region-Specific Manner. AB - Iron is an essential micronutrient for several physiological functions, including the regulation of dopaminergic neurotransmission. On the other hand, both iron, and dopamine can affect the folding and aggregation of proteins related with neurodegenerative diseases, such as cellular prion protein (PrPC) and alpha synuclein, suggesting that deregulation of iron homeostasis and the consequential disturbance of dopamine metabolism can be a risk factor for conformational diseases. These proteins, in turn, are known to participate in the regulation of iron and dopamine metabolism. In this study, we evaluated the effects of dietary iron restriction on brain ferritin levels, dopamine metabolism, and the expression levels of PrPC and alpha-synuclein. To achieve this goal, C57BL/6 mice were fed with iron restricted diet (IR) or with normal diet (CTL) for 1 month. IR reduced iron and ferritin levels in liver. Ferritin reduction was also observed in the hippocampus. However, in the striatum of IR group, ferritin level was increased, suggesting that under iron-deficient condition, each brain area might acquire distinct capacity to store iron. Increased lipid peroxidation was observed only in hippocampus of IR group, where ferritin level was reduced. IR also generated discrete results regarding dopamine metabolism of distinct brain regions: in striatum, the level of dopamine metabolites (DOPAC and HVA) was reduced; in prefrontal cortex, only HVA was increased along with the enhanced MAO A activity; in hippocampus, no alterations were observed. PrPC levels were increased only in the striatum of IR group, where ferritin level was also increased. PrPC is known to play roles in iron uptake. Thus, the increase of PrPC in striatum of IR group might be related to the increased ferritin level. alpha synuclein was not altered in any regions. Abnormal accumulation of ferritin, increased MAO-A activity or lipid peroxidation are molecular features observed in several neurological disorders. Our findings show that nutritional iron deficiency produces these molecular alterations in a region-specific manner and provide new insight into the variety of molecular pathways that can lead to distinct neurological symptoms upon iron deficiency. Thus, adequate iron supplementation is essential for brain health and prevention of neurological diseases. PMID- 28567003 TI - Evidence of a Cell Surface Role for Hsp90 Complex Proteins Mediating Neuroblast Migration in the Subventricular Zone. AB - In most mammalian brains, the subventricular zone (SVZ) is a germinative layer that maintains neurogenic activity throughout adulthood. Neuronal precursors arising from this region migrate through the rostral migratory stream (RMS) and reach the olfactory bulbs where they differentiate and integrate into the local circuitry. Recently, studies have shown that heat shock proteins have an important role in cancer cell migration and blocking Hsp90 function was shown to hinder cell migration in the developing cerebellum. In this work, we hypothesize that chaperone complexes may have an important function regulating migration of neuronal precursors from the subventricular zone. Proteins from the Hsp90 complex are present in the postnatal SVZ as well as in the RMS. Using an in vitro SVZ explant model, we have demonstrated the expression of Hsp90 and Hop/STI1 by migrating neuroblasts. Treatment with antibodies against Hsp90 and co-chaperone Hop/STI1, as well as Hsp90 and Hsp70 inhibitors hinder neuroblast chain migration. Time-lapse videomicroscopy analysis revealed that cell motility and average migratory speed was decreased after exposure to both antibodies and inhibitors. Antibodies recognizing Hsp90, Hsp70, and Hop/STI1 were found bound to the membranes of cells from primary SVZ cultures and biotinylation assays demonstrated that Hsp70 and Hop/STI1 could be found on the external leaflet of neuroblast membranes. The latter could also be detected in conditioned medium samples obtained from cultivated SVZ cells. Our results suggest that chaperones Hsp90, Hsp70, and co-chaperone Hop/STI1, components of the Hsp90 complex, regulate SVZ neuroblast migration in a concerted manner through an extracellular mechanism. PMID- 28567004 TI - Differentiation of Human Induced Pluripotent Stem Cell (hiPSC)-Derived Neurons in Mouse Hippocampal Slice Cultures. AB - Potential clinical applications of neurons derived from human induced pluripotent stem cells (hiPSC-neurons) for drug screening and transplantation therapies have received considerable attention. However, it remains unclear whether and how transplanted hiPSC-neurons are incorporated into pre-existing neural circuits. Here we developed a co-culture system of hiPSC-neurons and mouse hippocampal slices to examine the differentiation of hiPSC-neurons in pre-existing neural circuits. hiPSC-neurons transplanted in mouse hippocampal slices expressed the hippocampal neuron-specific markers HuB and Prox1 after 7 days of culture, while those markers were scarcely expressed in hiPSC-neurons cultured on glass dishes. Furthermore, hiPSC-neurons transplanted in the dentate gyrus (DG) of slice cultures grew to exhibit dentate granule cell-like morphologies, including besom shaped dendrites. Similarly, hiPSC-neurons transplanted in the CA1 region of slice cultures grew to exhibit CA1 pyramidal cell-like morphologies, including primary apical and multiple basal dendrites with synaptic spines. Additionally, these cells projected axons toward the entorhinal cortex (EC) as observed in vivo. These data suggest that hiPSC-neurons were anatomically integrated into pre existing neural circuits in a region-specific manner. Thus, the co-culture system will be useful for the study of efficient strategies to differentiate transplanted hiPSC-neurons. PMID- 28567006 TI - Lateral Entorhinal Cortex Lesions Impair Local Spatial Frameworks. AB - A prominent theory in the neurobiology of memory processing is that episodic memory is supported by contextually gated spatial representations in the hippocampus formed by combining spatial information from medial entorhinal cortex (MEC) with non-spatial information from lateral entorhinal cortex (LEC). However, there is a growing body of evidence from lesion and single-unit recording studies in rodents suggesting that LEC might have a role in encoding space, particularly the current and previous locations of objects within the local environment. Landmarks, both local and global, have been shown to control the spatial representations hypothesized to underlie cognitive maps. Consequently, it has recently been suggested that information processing within this network might be organized with reference to spatial scale with LEC and MEC providing information about local and global spatial frameworks respectively. In the present study, we trained animals to search for food using either a local or global spatial framework. Animals were re-tested on both tasks after receiving excitotoxic lesions of either the MEC or LEC. LEC lesioned animals were impaired in their ability to learn a local spatial framework task. LEC lesioned animals were also impaired on an object recognition (OR) task involving multiple local features but unimpaired at recognizing a single familiar object. Together, this suggests that LEC is involved in associating features of the local environment. However, neither LEC nor MEC lesions impaired performance on the global spatial framework task. PMID- 28567007 TI - Involvement of the CXCL12 System in the Stimulatory Effects of Prenatal Exposure to High-Fat Diet on Hypothalamic Orexigenic Peptides and Behavior in Offspring. AB - Exposure to a high fat diet (HFD) during gestation stimulates neurogenesis and expression of hypothalamic orexigenic neuropeptides that affect consummatory and emotional behaviors. With recent studies showing a HFD to increase inflammation, this report investigated the neuroinflammatory chemokine, CXCL12, and compared the effects of prenatal CXCL12 injection to those of prenatal HFD exposure, first, by testing whether the HFD affects circulating CXCL12 in the dam and the CXCL12 system in the offspring brain, and then by examining whether prenatal exposure to CXCL12 itself mimics the effects of a HFD on hypothalamic neuropeptides and emotional behaviors. Our results showed that prenatal exposure to a HFD significantly increased circulating levels of CXCL12 in the dam, and that daily injections of CXCL12 induced a similar increase in CXCL12 levels as the HFD. In addition, prenatal HFD exposure significantly increased the expression of CXCL12 and its receptors, CXCR4 and CXCR7, in the hypothalamic paraventricular nucleus (PVN) of the offspring. Finally, the results revealed strong similarities in the effects of prenatal HFD and CXCL12 administration, which both stimulated neurogenesis and enkephalin (ENK) expression in the PVN, while having inconsistent or no effect in other regions of the hypothalamus, and also increased anxiety as measured by several behavioral tests. These results focus attention specifically on the CXCL12 chemokine system in the PVN of the offspring as being possibly involved in the stimulatory effects of prenatal HFD exposure on ENK-expressing neurons in the PVN and their associated changes in emotional behavior. PMID- 28567005 TI - The Long Journey of Pontine Nuclei Neurons: From Rhombic Lip to Cortico-Ponto Cerebellar Circuitry. AB - The pontine nuclei (PN) are the largest of the precerebellar nuclei, neuronal assemblies in the hindbrain providing principal input to the cerebellum. The PN are predominantly innervated by the cerebral cortex and project as mossy fibers to the cerebellar hemispheres. Here, we comprehensively review the development of the PN from specification to migration, nucleogenesis and circuit formation. PN neurons originate at the posterior rhombic lip and migrate tangentially crossing several rhombomere derived territories to reach their final position in ventral part of the pons. The developing PN provide a classical example of tangential neuronal migration and a study system for understanding its molecular underpinnings. We anticipate that understanding the mechanisms of PN migration and assembly will also permit a deeper understanding of the molecular and cellular basis of cortico-cerebellar circuit formation and function. PMID- 28567008 TI - Interoception and Autonomic Correlates during Social Interactions. Implications for Anorexia. AB - The aim of this study is to investigate the bodily-self in Restrictive Anorexia, focusing on two basic aspects related to the bodily self: autonomic strategies in social behavior, in which others' social desirability features, and social cues (e.g., gaze) are modulated, and interoception (i.e., the sensitivity to stimuli originating inside the body). Furthermore, since previous studies carried out on healthy individuals found that interoception seems to contribute to the autonomic regulation of social behavior, as measured by Respiratory Sinus Arrhythmia (RSA), we aimed to explore this link in anorexia patients, whose ability to perceive their bodily signal seems to be impaired. To this purpose, we compared a group of anorexia patients (ANg; restrictive type) with a group of Healthy Controls (HCg) for RSA responses during both a resting state and a social proxemics task, for their explicit judgments of comfort in social distances during a behavioral proxemics task, and for their Interoceptive Accuracy (IA). The results showed that ANg displayed significantly lower social disposition and a flattened autonomic reactivity during the proxemics task, irrespective of the presence of others' socially desirable features or social cues. Moreover, unlike HCg, the autonomic arousal of ANg did not guide behavioral judgments of social distances. Finally, IA was strictly related to social disposition in both groups, but with opposite trends in ANg. We conclude that autonomic imbalance and its altered relationship with interoception might have a crucial role in anorexia disturbances. PMID- 28567009 TI - Anatomical Modularity of Verbal Working Memory? Functional Anatomical Evidence from a Famous Patient with Short-Term Memory Deficits. AB - Cognitive skills are the emergent property of distributed neural networks. The distributed nature of these networks does not necessarily imply a lack of specialization of the individual brain structures involved. However, it remains questionable whether discrete aspects of high-level behavior might be the result of localized brain activity of individual nodes within such networks. The phonological loop of working memory, with its simplicity, seems ideally suited for testing this possibility. Central to the development of the phonological loop model has been the description of patients with focal lesions and specific deficits. As much as the detailed description of their behavior has served to refine the phonological loop model, a classical anatomoclinical correlation approach with such cases falls short in telling whether the observed behavior is based on the functions of a neural system resembling that seen in normal subjects challenged with phonological loop tasks or whether different systems have taken over. This is a crucial issue for the cross correlation of normal cognition, normal physiology, and cognitive neuropsychology. Here we describe the functional anatomical patterns of JB, a historical patient originally described by Warrington et al. (1971), a patient with a left temporo-parietal lesion and selective short phonological store deficit. JB was studied with the H215O PET activation technique during a rhyming task, which primarily depends on the rehearsal system of the phonological loop. No residual function was observed in the left temporo-parietal junction, a region previously associated with the phonological buffer of working memory. However, Broca's area, the major counterpart of the rehearsal system, was the major site of activation during the rhyming task. Specific and autonomous activation of Broca's area in the absence of afferent inputs from the other major anatomical component of the phonological loop shows that a certain degree of functional independence or modularity exists in this distributed anatomical-cognitive system. PMID- 28567010 TI - The What, the When, and the Whether of Intentional Action in the Brain: A Meta Analytical Review. AB - In their attempt to define discrete subcomponents of intentionality, Brass and Haggard (2008) proposed their What, When, and Whether model (www-model) which postulates that the content, the timing and the possibility of generating an action can be partially independent both at the cognitive level and at the level of their neural implementation. The original proposal was based on a limited number of studies, which were reviewed with a discursive approach. To assess whether the model stands in front of the more recently published data, we performed a systematic review of the literature with a meta-analytic method based on a hierarchical clustering (HC) algorithm. We identified 15 PET/fMRI studies well-suited for this quest. HC revealed the existence of a rostro-caudal gradient within the medial prefrontal cortex, with the more anterior regions (the anterior cingulum) involved in more abstract decisions of whether to execute an action and the more posterior ones (the middle cingulum or the SMA) recruited in specifying the content and the timing components of actions. However, in contrast with the original www-model, this dissociation involves also brain regions well outside the median wall of the frontal lobe, in a component specific manner: the supramarginal gyrus for the what component, the pallidum and the thalamus for the when component, the putamen and the insula for the whether component. We then calculated co-activation maps on the three component-specific www clusters of the medial wall of the frontal/limbic lobe: to this end, we used the activation likelihood approach that we applied on the imaging studies on action contained in the BrainMap.org database. This analysis confirmed the main findings of the HC analyses. However, the BrainMap.org data analyses also showed that the aforementioned segregations are generated by paradigms in which subjects act in response to conditional stimuli rather than while driven by their own intentions. We conclude that the available data confirm that the neural underpinnings of intentionality can be fractionated in discrete components that are partially independent. We also suggest that intentionality manifests itself in discrete components through the boosting of general purpose action-related regions specialized for different aspects of action selection and inhibition. PMID- 28567011 TI - Imaging Brain Function with Functional Near-Infrared Spectroscopy in Unconstrained Environments. AB - Assessing the neural correlates of motor and cognitive processes under naturalistic experimentation is challenging due to the movement constraints of traditional brain imaging technologies. The recent advent of portable technologies that are less sensitive to motion artifacts such as Functional Near Infrared Spectroscopy (fNIRS) have been made possible the study of brain function in freely-moving participants. In this paper, we describe a series of proof-of concept experiments examining the potential of fNIRS in assessing the neural correlates of cognitive and motor processes in unconstrained environments. We show illustrative applications for practicing a sport (i.e., table tennis), playing a musical instrument (i.e., piano and violin) alone or in duo and performing daily activities for many hours (i.e., continuous monitoring). Our results expand upon previous research on the feasibility and robustness of fNIRS to monitor brain hemodynamic changes in different real life settings. We believe that these preliminary results showing the flexibility and robustness of fNIRS measurements may contribute by inspiring future work in the field of applied neuroscience. PMID- 28567012 TI - Age-Dependent Protein Aggregation Initiates Amyloid-beta Aggregation. AB - Aging is the most important risk factor for neurodegenerative diseases associated with pathological protein aggregation such as Alzheimer's disease. Although aging is an important player, it remains unknown which molecular changes are relevant for disease initiation. Recently, it has become apparent that widespread protein aggregation is a common feature of aging. Indeed, several studies demonstrate that 100s of proteins become highly insoluble with age, in the absence of obvious disease processes. Yet it remains unclear how these misfolded proteins aggregating with age affect neurodegenerative diseases. Importantly, several of these aggregation-prone proteins are found as minor components in disease associated hallmark aggregates such as amyloid-beta plaques or neurofibrillary tangles. This co-localization raises the possibility that age-dependent protein aggregation directly contributes to pathological aggregation. Here, we show for the first time that highly insoluble proteins from aged Caenorhabditis elegans or aged mouse brains, but not from young individuals, can initiate amyloid-beta aggregation in vitro. We tested the seeding potential at four different ages across the adult lifespan of C. elegans. Significantly, protein aggregates formed during the early stages of aging did not act as seeds for amyloid-beta aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-beta aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-beta plaques and neurofibrillary tangles such as 14-3 3, Ubiquitin-like modifier-activating enzyme 1 and Lamin A/C, highlighting these as strong candidates for cross-seeding. Overall, we demonstrate that widespread protein misfolding and aggregation with age could be critical for the initiation of pathogenesis, and thus should be targeted by therapeutic strategies to alleviate neurodegenerative diseases. PMID- 28567014 TI - Metabolic Profiling Analysis of the Alleviation Effect of Treatment with Baicalin on Cinnabar Induced Toxicity in Rats Urine and Serum. AB - Objectives: Baicalin is the main bioactive flavonoid constituent isolated from Scutellaria baicalensis Georgi. The mechanisms of protection of liver remain unclear. In this study, 1H NMR-based metabonomics approach has been used to investigate the alleviation effect of Baicalin. Method:1H NMR metabolomics analyses of urine and serum from rats, was performed to illuminate the alleviation effect of Baicalin on mineral medicine (cinnabar)-induced liver and kidney toxicity. Results: The metabolic profiles of groups receiving Baicalin at a dose of 80 mg/kg were remarkably different from cinnabar, and meanwhile, the level of endogenous metabolites returned to normal compared to group cinnabar. PLS-DA scores plots demonstrated that the variation tendency of control and Baicalein are apart from Cinnabar. The metabolic profiles of group Baicalein were similar to those of group control. Statistics results were confirmed by the histopathological examination and biochemical assay. Conclusion: Baicalin have the alleviation effect to the liver and kidney damage induced by cinnabar. The Baicalin could regulate endogenous metabolites associated with the energy metabolism, choline metabolism, amino acid metabolism, and gut flora. PMID- 28567013 TI - The Effect of Apolipoprotein E epsilon4 (APOE epsilon4) on Visuospatial Working Memory in Healthy Elderly and Amnestic Mild Cognitive Impairment Patients: An Event-Related Potentials Study. AB - Background: Apolipoprotein E (APOE) epsilon4 is the only established risk gene for late-onset, sporadic Alzheimer's disease (AD). Previous studies have provided inconsistent evidence for the effect of APOE epsilon4 status on the visuospatial working memory (VSWM). Objective: The aim was to investigate the effect of APOE epsilon4 on VSWM with an event-related potential (ERP) study in healthy controls (HC) and amnestic mild cognitive impairment (aMCI) patients. Methods: The study recorded 39 aMCI patients (27 APOE epsilon4 non-carriers and 12 APOE epsilon4 carriers) and their 43 matched controls (25 APOE epsilon4 non-carriers and 18 APOE epsilon4 carriers) with an 64-channel electroencephalogram. Participants performed an N-back task, a VSWM paradigm that manipulated the number of items to be stored in memory. Results: The present study detected reduced accuracy and delayed mean correct response time (RT) in aMCI patients compared to HC. P300, a positive component that peaks between 300 and 500 ms, was elicited by the VSWM task. In addition, aMCI patients showed decreased P300 amplitude at the central parietal (CP1, CPz, and CP2) and parietal (P1, Pz, and P2) electrodes in 0- and 1 back task compared to HC. In both HC and aMCI patients, APOE epsilon4 carriers showed reduced P300 amplitude with respect to non-carriers, whereas no significant differences in accuracy or RT were detected between APOE epsilon4 carriers and non-carriers. Additionally, standardized low-resolution brain electromagnetic tomography analysis (s-LORETA) showed enhanced brain activation in the right parahippocampal gyrus (PHG) during P300 time range in APOE epsilon4 carriers with respect to non-carriers in aMCI patients. Conclusion: It demonstrated that P300 amplitude could predict VSWM deficits in aMCI patients and contribute to early detection of VSWM deficits in APOE epsilon4 carriers. PMID- 28567015 TI - USP22 Induces Cisplatin Resistance in Lung Adenocarcinoma by Regulating gammaH2AX Mediated DNA Damage Repair and Ku70/Bax-Mediated Apoptosis. AB - Resistance to platinum-based chemotherapy is one of the most important reasons for treatment failure in advanced non-small cell lung cancer, but the underlying mechanism is extremely complex and unclear. The present study aimed to investigate the correlation of ubiquitin-specific peptidase 22 (USP22) with acquired resistance to cisplatin in lung adenocarcinoma. In this study, we found that overexpression of USP22 could lead to cisplatin resistance in A549 cells. USP22 and its downstream proteins gammaH2AX and Sirt1 levels are upregulated in the cisplatin- resistant A549/CDDP cell line. USP22 enhances DNA damage repair and induce cisplatin resistance by promoting the phosphorylation of histone H2AX via deubiquitinating histone H2A. In addition, USP22 decreases the acetylation of Ku70 by stabilizing Sirt1, thus inhibiting Bax-mediated apoptosis and inducing cisplatin resistance. The cisplatin sensitivity in cisplatin-resistant A549/CDDP cells was restored by USP22 inhibition in vivo and vitro. In summary, our findings reveal the dual mechanism of USP22 involvement in cisplatin resistance that USP22 can regulate gammaH2AX-mediated DNA damage repair and Ku70/Bax mediated apoptosis. USP22 is a potential target in cisplatin-resistant lung adenocarcinoma and should be considered in future therapeutic practice. PMID- 28567017 TI - Azoxystrobin Induces Apoptosis of Human Esophageal Squamous Cell Carcinoma KYSE 150 Cells through Triggering of the Mitochondrial Pathway. AB - Recent studies indicate that mitochondrial pathways of apoptosis are potential chemotherapeutic target for the treatment of esophageal cancer. Azoxystrobin (AZOX), a methoxyacrylate derived from the naturally occurring strobilurins, is a known fungicide acting as a ubiquinol oxidation (Qo) inhibitor of mitochondrial respiratory complex III. In this study, the effects of AZOX on human esophageal squamous cell carcinoma KYSE-150 cells were examined and the underlying mechanisms were investigated. AZOX exhibited inhibitory effects on the proliferation of KYSE-150 cells with inhibitory concentration 50% (IC50) of 2.42 MUg/ml by 48 h treatment. Flow cytometry assessment revealed that the inhibitory effect of AZOX on KYSE-150 cell proliferation occurred with cell cycle arrest at S phase and increased cell apoptosis in time-dependent and dose-dependent manners. Cleaved poly ADP ribose polymerase (PARP), caspase-3 and caspase-9 were increased significantly by AZOX. It is worth noted that the Bcl-2/Bax ratios were decreased because of the down-regulated Bcl-2 and up-regulated Bax expression level. Meanwhile, the cytochrome c release was increased by AZOX in KYSE-150 cells. AZOX-induced cytochrome c expression and caspase-3 activation was significantly blocked by Bax Channel Blocker. Intragastric administration of AZOX effectively decreased the tumor size generated by subcutaneous inoculation of KYSE-150 cells in nude mice. Consistently, decreased Bcl-2 expression, increased cytochrome c and PARP level, and activated caspase-3 and caspase-9 were observed in the tumor samples. These results indicate that AZOX can effectively induce esophageal cancer cell apoptosis through the mitochondrial pathways of apoptosis, suggesting AZOX or its derivatives may be developed as potential chemotherapeutic agents for the treatment of esophageal cancer. PMID- 28567016 TI - Streptomyces sp. MUM212 as a Source of Antioxidants with Radical Scavenging and Metal Chelating Properties. AB - Reactive oxygen species and other radicals potentially cause oxidative damage to proteins, lipids, and DNA which may ultimately lead to various complications including mutations, carcinogenesis, neurodegeneration, cardiovascular disease, aging, and inflammatory disease. Recent reports demonstrate that Streptomyces bacteria produce metabolites with potent antioxidant activity that may be developed into therapeutic drugs to combat oxidative stress. This study shows that Streptomyces sp. MUM212 which was isolated from mangrove soil in Kuala Selangor, Malaysia, could be a potential source of antioxidants. Strain MUM212 was characterized and determined as belonging to the genus Streptomyces using 16S rRNA gene phylogenetic analysis. The MUM212 extract demonstrated significant antioxidant activity through DPPH, ABTS and superoxide radical scavenging assays and also metal-chelating activity of 22.03 +/- 3.01%, 61.52 +/- 3.13%, 37.47 +/- 1.79%, and 41.98 +/- 0.73% at 4 mg/mL, respectively. Moreover, MUM212 extract was demonstrated to inhibit lipid peroxidation up to 16.72 +/- 2.64% at 4 mg/mL and restore survival of Vero cells from H2O2-induced oxidative damages. The antioxidant activities from the MUM212 extract correlated well with its total phenolic contents; and this in turn was in keeping with the gas chromatography mass spectrometry analysis which revealed the presence of phenolic compounds that could be responsible for the antioxidant properties of the extract. Other chemical constituents detected included hydrocarbons, alcohols and cyclic dipeptides which may have contributed to the overall antioxidant capacity of MUM212 extract. As a whole, strain MUM212 seems to have potential as a promising source of novel molecules for future development of antioxidative therapeutic agents against oxidative stress-related diseases. PMID- 28567018 TI - Acute Normobaric Hypoxia Increases Post-exercise Lipid Oxidation in Healthy Males. AB - The primary objective of the current study was to determine the effect of moderate normobaric hypoxia exposure during constant load cycling on post exercise energy metabolism recorded in normoxia. Indirect calorimetry was used to examine whole body substrate oxidation before, during, 40-60 min post, and 22 h after performing 60 min of cycling exercise at two different fractions of inspired oxygen (FIO2): (i) FIO2 = 0.2091 (normoxia) and (ii) FIO2 = 0.15 (hypoxia). Seven active healthy male participants (26 +/- 4 years of age) completed both experimental trials in randomized order with a 7-day washout period to avoid carryover effects between conditions. Resting energy expenditure was initially elevated following cycling exercise in normoxia and hypoxia (Delta 0.14 +/- 0.05, kcal min-1, p = 0.037; Delta 0.19 +/- 0.03 kcal min-1, p < 0.001, respectively), but returned to baseline levels the next morning in both conditions. Although, the same absolute workload was used in both environmental conditions (157 +/- 10 W), a shift in resting substrate oxidation occurred after exercise performed in hypoxia while post-exercise measurements were similar to baseline after cycling exercise in normoxia. The additional metabolic stress of hypoxia exposure was sufficient to increase the rate of lipid oxidation (Delta 42 +/- 11 mg min-1, p = 0.019) and tended to suppress carbohydrate oxidation (Delta 55 +/- 26 mg min-1, p = 0.076) 40-60 min post-exercise. This shift in substrate oxidation persisted the next morning, where lipid oxidation remained elevated (Delta 9 +/- 3 mg min-1, p = 0.0357) and carbohydrate oxidation was suppressed (Delta -22 +/- 6 mg min-1, p = 0.019). In conclusion, prior exercise performed under moderate normobaric hypoxia alters post-exercise energy metabolism. This is an important consideration when evaluating the metabolic consequences of hypoxia exposure during prolonged exercise, and future studies should evaluate its role in the beneficial effects of intermittent hypoxia training observed in persons with obesity and insulin resistance. PMID- 28567019 TI - Down-Regulation of Cough during Exercise Is Less Frequent in Healthy Children than Adults. Role of the Development and/or Atopy? AB - Cough is typically associated with physical activity in children with asthma, but the characteristics of the relationship between cough and exercise has not been established under physiological conditions. The aim of the study was to describe the effect of exercise on the reflex cough response elicited by a single breath of capsaicin in non-asthmatic children. A group of non-asthmatic adults was studied as reference. Thirty children and 29 adults were recruited. The cough reflex sensitivity to capsaicin was first determined to establish the dose that provokes 5 cough efforts (C5). The number of coughs elicited by C5 (NC5) was then compared at baseline and during a standardized submaximal treadmill exercise. Data are expressed as median (interquartile range). Children and adults showed a significant decrease in NC5 (respectively from 5.0 (4.0-6.0) to 2.5 (2.0-4.0), p < 0.0005 and from 6.0 (5.0-7.0) to 2.0 (0.0-3.0, p < 0.0005). During exercise, NC5 was observed to decrease in all adult subjects, but in only 24/30 children (80%, p = 0.02). A trend for a higher incidence of personal and familial atopy was observed in children that lacked cough down-regulation during exercise compared with other children. It is concluded that the cough reflex response to capsaicin is down regulated by exercise in both children and adults. The effect however is less consistently observed in the former. The difference may reflect maturation of descending inhibitory pathways of the cough reflex, but may also be associated to atopy. The data stress the importance of assessing the time relationship of cough and exercise in questionnaire studies of asthma. PMID- 28567020 TI - Dietary Effect on the Proteome of the Common Octopus (Octopus vulgaris) Paralarvae. AB - Nowadays, the common octopus (Octopus vulgaris) culture is hampered by massive mortalities occurring during early life-cycle stages (paralarvae). Despite the causes of the high paralarvae mortality are not yet well-defined and understood, the nutritional stress caused by inadequate diets is pointed out as one of the main factors. In this study, the effects of diet on paralarvae is analyzed through a proteomic approach, to search for novel biomarkers of nutritional stress. A total of 43 proteins showing differential expression in the different conditions studied have been identified. The analysis highlights proteins related with the carbohydrate metabolism: glyceraldehyde-3-phosphate-dedydrogenase (GAPDH), triosephosphate isomerase; other ways of energetic metabolism: NADP+ specific isocitrate dehydrogenase, arginine kinase; detoxification: glutathione-S transferase (GST); stress: heat shock proteins (HSP70); structural constituent of eye lens: S-crystallin 3; and cytoskeleton: actin, actin-beta/gamma1, beta actin. These results allow defining characteristic proteomes of paralarvae depending on the diet; as well as the use of several of these proteins as novel biomarkers to evaluate their welfare linked to nutritional stress. Notably, the changes of proteins like S-crystallin 3, arginine kinase and NAD+ specific isocitrate dehydrogenase, may be related to fed vs. starving paralarvae, particularly in the first 4 days of development. PMID- 28567022 TI - The Impact of Gender Stereotypes on the Self-Concept of Female Students in STEM Subjects with an Under-Representation of Females. AB - It's possible to assume that women who study STEM topics with a low proportion of females have successfully overcome barriers in school and the family, making them less prone to stereotypic views, and influences. The present study focuses on these kinds of factors and analyzes to which degree family factors, school related factors, and individual stereotypes may influence a woman's academic self concept. The following study presents a latent regression model which is based on a survey of 296 women from different German universities, all of whom are part of STEM programs of study that have <30% females. It was investigated to which degree individual stereotypes, support in school, and family support contribute to the self-concept in STEM. Gender stereotypes were negatively related to students' STEM-specific self-concept in the selected sample. This study also reveals negative family-related influences that lower a woman's self-concept. Positive predictors on the other hand included school aspects that are found in the students' favorite subjects at school. The results of the study provide important aspects for STEM education. Even though the students participating in the study presumably had good grades in STEM, stereotypes still corrupted their self-concept. One of the reasons for this might lie in stereotypes that attribute girls' achievements to diligence instead of talent. The results also point out that direct support, particularly by parents, can have a negative impact on female students' self-concept. Activities that are meant to support pupils directly may actually backfire and transport stereotypes instead. This stresses the need for indirect support during socialization, e.g., by providing opportunities for children to have positive experiences or by giving them the chance to meet role models that are enthusiastic about their STEM professions. These kinds of measures have the potential to spur students' interest in STEM subjects-something that in the present study proved to be especially beneficial for women's positive self-concept when studying STEM topics. PMID- 28567023 TI - Respiratory Constraints in Verbal and Non-verbal Communication. AB - In the present paper we address the old question of respiratory planning in speech production. We recast the problem in terms of speakers' communicative goals and propose that speakers try to minimize respiratory effort in line with the H&H theory. We analyze respiratory cycles coinciding with no speech (i.e., silence), short verbal feedback expressions (SFE's) as well as longer vocalizations in terms of parameters of the respiratory cycle and find little evidence for respiratory planning in feedback production. We also investigate timing of speech and SFEs in the exhalation and contrast it with nods. We find that while speech is strongly tied to the exhalation onset, SFEs are distributed much more uniformly throughout the exhalation and are often produced on residual air. Given that nods, which do not have any respiratory constraints, tend to be more frequent toward the end of an exhalation, we propose a mechanism whereby respiratory patterns are determined by the trade-off between speakers' communicative goals and respiratory constraints. PMID- 28567024 TI - Dissociating Attention and Eye Movements in a Quantitative Analysis of Attention Allocation. AB - In a recent paper, we introduced a method and equation for inferring the allocation of attention on a continuous scale. The size of the stimuli, the estimated size of the fovea, and the pattern of results implied that the subjects' responses reflected shifts in covert attention rather than shifts in eye movements. This report describes an experiment that tests this implication. We measured eye movements. The monitor briefly displayed (e.g., 130 ms) two small stimuli (~1.0 degrees * 1.2 degrees ), situated one atop another. When the stimuli were close together, as in the previous study, fixations that supported correct responses at one stimulus also supported correct responses at the other stimulus, as measured over the entire session. Yet, on any particular trial, correct responses were limited to just one stimulus. This pattern suggests that the constraints on responding within a trial were due to limits on cognitive processing, whereas the ability to respond correctly to either stimulus on different trials must have entailed shifts in attention (that were not accompanied by eye movements). In contrast, when the stimuli were far apart, fixations that had a high probability of supporting correct responses at one stimulus had a low probability of supporting correct responses at the other stimulus. Thus, conditions could be arranged so that correct responses depended on eye movements, whereas in the "standard" procedure, correct responses were independent of eye movements. The results dissociate covert and overt attention and support the claim that our procedure measures covert attention. PMID- 28567021 TI - Assessment of Fetal Development Using Cardiac Valve Intervals. AB - An automated method to assess the fetal physiological development is introduced which uses the component intervals between fetal cardiac valve timings and the Q wave of fetal electrocardiogram (fECG). These intervals were estimated automatically from one-dimensional Doppler Ultrasound and noninvasive fECG. We hypothesize that the fetal growth can be estimated by the cardiac valve intervals. This hypothesis was evaluated by modeling the fetal development using the cardiac intervals and validating against the gold standard gestational age identified by Crown-Rump Length (CRL). Among the intervals, electromechanical delay time, isovolumic contraction time, ventricular filling time and their interactions were selected in a stepwise regression process that used gestational age as the target in a cohort of 57 fetuses. Compared with the gold standard age, the newly proposed regression model resulted in a mean absolute error of 3.8 weeks for all recordings and 2.7 weeks after excluding the low quality recordings. Since Fetal Heart Rate Variability (FHRV) has been proposed in the literature for assessing the fetal development, we compared the performance of gestational age estimation by our new valve-interval based method, vs. FHRV, while assuming the CRL as the gold standard. The valve interval-based method outperformed both the model based on FHRV. Results of evaluation for 30 abnormal cases showed that the new method is less affected by arrhythmias such as tachycardia and bradycardia compared to FHRV, however certain types of heart anomalies cause large errors (more than 10 weeks) with respect to the CRL-based gold standard age. Therefore, discrepancies between the regression based estimation and CRL age estimation could indicate the abnormalities. The cardiac valve intervals have been known to reflect the autonomic function. Therefore the new method potentially provides a novel approach for assessing the development of fetal autonomic nervous system, which may be growth curve independent. PMID- 28567025 TI - A Proposal for a Scientifically-Informed and Instrumentalist Account of Free Will and Voluntary Action. AB - The ability to choose freely is captured under the umbrella concept of "free will," which designates an ability that plays a crucial role in most understandings of autonomy and responsibility and, thus, bears significance for moral practice and moral theory. Some claim that neuroscience research challenges the existence of free will/voluntary action while some who adopt stronger eliminativist stances have gone as far as describing free will as an illusion. Contrary to that, those relying on realist stances have restated the foundational value and role of folk psychological concepts of voluntary action and free will in, for example, the domains of ethics and law. An emerging body of research in cognitive science and social psychology has generated results suggesting that the phenomena captured by the concepts describing free will and voluntary action are dynamic and responsive to priming and framing effects. We propose that this body of research suggests the existence of dynamic and consequential properties of free will better captured following pragmatist theory and instrumentalist epistemology. This contrasts the simpler static concept of free will and the related metaphysics that was at the basis of earlier debates and structured around the poles of realism and eliminativism. This paper contextualizes ontological and epistemological debates about free will, describes a scientifically-informed and instrumentalist account of the concept of free will and voluntary action consistent with recent research in cognitive science, and discusses its implications for research (e.g., theoretical assumptions of research paradigms, interdisciplinary research) and practice (e.g., impact on self-image and social behavior). PMID- 28567026 TI - FMRI Study of Neural Responses to Implicit Infant Emotion in Anorexia Nervosa. AB - Difficulties in social-emotional processing have been proposed to play an important role in the development and maintenance of anorexia nervosa (AN). Few studies, thus far, have investigated neural processes that underlie these difficulties, including processing emotional facial expressions. However, the majority of these studies have investigated neural responses to adult emotional display, which may be confounded by elevated sensitivity to social rank and threat in AN. Therefore, the aim of this study was to investigate the neural processes underlying implicit processing of positively and negatively valenced infant emotional display in AN. Twenty-one adult women with AN and twenty-six healthy comparison (HC) women were presented with images of positively valenced, negatively valenced, and neutral infant faces during a fMRI scan. Significant differences between the groups in positive > neutral and negative > neutral contrasts were investigated in a priori regions of interest, including the bilateral amygdala, insula, and lateral prefrontal cortex (PFC). The findings revealed that the AN participants showed relatively increased recruitment while the HC participants showed relatively reduced recruitment of the bilateral amygdala and the right dorsolateral PFC in the positive > neutral contrast. In the negative > neutral contrast, the AN group showed relatively increased recruitment of the left posterior insula while the HC groups showed relatively reduced recruitment of this region. These findings suggest that people with AN may engage in implicit prefrontal down-regulation of elevated limbic reactivity to positively social-emotional stimuli. PMID- 28567027 TI - Transient Vestibulopathy in Wallenberg's Syndrome: Pathologic Analysis. AB - OBJECTIVE: To report an unusual lateral medullary stroke (LMS) associated with transient unidirectional horizontal, nystagmus, and decreased horizontal vestibulo-ocular reflex (h-VOR) gain that mimicked a peripheral vestibulopathy. MRI suggested involvement of caudal medial vestibular nucleus (MVN); however, the rapid resolution of the nystagmus and improved h-VOR gain favored transient ischemia without infarction. Decreased h-VOR gain is expected with peripheral vestibular lesions within the labyrinth or superior vestibular nerve; less frequently lateral pontine strokes involving the vestibular root entry, the vestibular fascicle, or neurons within the MVN may be responsible. The h-VOR is typically normal in LMS. METHODS: Clinicopathologic examination of a 61-year-old man with an acute vestibular syndrome (AVS) and left LMS who died 3 weeks after the stroke. Postmortem brainstem analysis was performed. RESULTS: The stroke involved the lateral medulla and pontomedullary junction, near the MVN, sparing the cerebellum and pons. To explain transient vestibular findings there are two possible hypotheses; the first would be that the MVN survived the ischemic process and would be histologically intact, and the second that vestibular afferents in the horizontal semicircular canal were ischemic and recovered after the ischemic process. Neuropathological examination showed a left LMS whose extent matched that seen by imaging. Non-ocular motor signs correlated well with structures affected by the infarction. Neurons and glia within nearby MVN were spared, as predicted by the rapid normalization of the ocular motor signs. Although unlikely, the possibility of transient intralabyrinthine arteriolar ischemia cannot be excluded. Additionally, truncal lateropulsion was due to combined lateral vestibulospinal tract and lateral reticular nucleus infarction. CONCLUSION: LMS may rarely be associated with an AVS that either represents or mimics a peripheral vestibulopathy. To our knowledge, this is the first neuropathologic examination of the brainstem of an LMS associated with transient vestibular findings occurring in the context of an anterior/posterior (AICA/PICA) cerebellar arterial variant stroke. PMID- 28567028 TI - Gelsemium elegans Poisoning: A Case with 8 Months of Follow-up and Review of the Literature. AB - BACKGROUND: Gelsemium elegans (G. elegans) is a toxic plant indigenous to Southeast Asia. It is highly poisonous due to its strong respiratory depressive effect. However, G. elegans poisoning cases have not been summarized comprehensively and are rarely reported in English journals. Furthermore, none of the present reports present prognosis in detail. CASE PRESENTATION: A 26-year-old female was found comatose at home and brought to the hospital with deep coma, hypoxia, and acidosis. After mechanical ventilation for hours, the patient recovered from coma with sequelae of impaired short-term memory, disorientation, and childish behaviors. Brain magnetic resonance imaging (MRI) showed bilateral hippocampus and basal ganglia damage due to hypoxia. During 8 months of follow up, both her symptoms and brain MRI scan improved significantly. CONCLUSION: G. elegans is highly toxic. Although patients may die within 30 min due to its strong respiratory depressive effect, they can survive with timely respiratory support and enjoy gradual improvement without delayed postanoxic encephalopathy. PMID- 28567029 TI - Long-term Developmental Trends of Pediatric Mitochondrial Diseases: The Five Stages of Developmental Decline. AB - Mitochondrial diseases (MDs) are a heterogeneous group of progressive multisystem disorders caused by impaired mitochondrial function. This study aimed to evaluate the clinical course and long-term development of 53 pediatric patients with MDs. Developmental function was evaluated at nine time points (two pre-diagnosis, one at diagnosis, and six post-diagnosis), with the developmental quotient (DQ) from the Korean infant and child development test (KICDT) assessing a child's developmental age (rather than chronological age). Additionally, disease-related clinical variables were reviewed, and clinical progress was determined through observation. Subgroup analyses by epilepsy severity, syndromic diagnosis, diffuse brain atrophy, and clinical rating were performed. The pre- and post-diagnosis results were compared by the paired t-test and Bonferroni correction. The pre diagnostic, diagnostic, and post-diagnostic evaluations were compared using repeated measures ANOVA. Patients with diffuse brain atrophy at the first pre diagnostic and second post-diagnostic evaluations showed lower DQs. Compared with patients with a mildly or severely deteriorating clinical course, those with an improving or static clinical course presented higher DQs at the pre-diagnostic and diagnostic evaluations. The age at onset of the first symptom correlated positively with the DQ post-diagnosis. Follow-up revealed consistent patterns of significant developmental deterioration during the lead time to diagnosis, with no significant decline post-diagnosis. The DQ is a feasible predictor and a measure of long-term functional development in children with MD. Early initiation of treatment may minimize developmental regression. PMID- 28567030 TI - A New Rabbit-Skin Model to Evaluate Protective Efficacy of Tuberculosis Vaccines. AB - Background: BCG protection is suboptimal and there is significant interest to develop new tuberculosis (TB) vaccines. However, there are significant limitations of the current vaccine evaluation systems in the mouse model. Here, we developed a BCG-challenge rabbit skin model as a new way to evaluate the protective efficacy of selected TB subunit vaccine candidates. Methods: Rabbits were immunized with subunit vaccines, including EAMM (ESAT6-Ag85B-MPT64<190-198> Mtb8.4), MH (Mtb10.4-HspX), and LT70 (ESAT6-Ag85B-MPT64<190-198>-Mtb8.4-Rv2626c) three times subcutaneously every 3-weeks and challenged with the attenuated Mycobacterium bovis BCG intradermally 6-weeks after last immunization. The immune response induced by the vaccine candidates was measured, the histopathology induced by the BCG challenge was studied, and the number of bacilli in the liquefied caseum was determined. Results: The subunit vaccines generated high antigen-specific IgG antibodies and fastened the liquefaction and healing process, and significantly reduced the viable BCG load. The subunit vaccine LT70 and EAMM-MH reduced BCG bacterial load in comparison to proteins EAMM, MH, Rv2626c, and also BCG itself. The Koch phenomena induced by the LT70 and combination of EAMM-MH were the same as that produced by BCG itself and were more rapid than those induced by the other proteins and the saline controls. Conclusions: The subunit vaccines LT70 and the combination of EAMM-MH showed promising protective efficacy as expected in the rabbit skin model, which can serve as a visual and convenient new model for evaluating TB vaccines. PMID- 28567031 TI - Impact of Nutrient Restriction on the Structure of Listeria monocytogenes Biofilm Grown in a Microfluidic System. AB - Biofilm formation by the pathogen Listeria monocytogenes is a major concern in food industries. The aim of this work was to elucidate the effect of nutrient limitation on both biofilm architecture and on the viability of the bacteria in microfluidic growth conditions. Biofilm formation by two L. monocytogenes strains was performed in a rich medium (BHI) and in a 10-fold diluted BHI (BHI/10) at 30 degrees C for 24 h by using both static conditions and the microfluidic system Bioflux. In dynamic conditions, biofilms grown in rich and poor medium showed significant differences as well in structure and in the resulting biovolume. In BHI/10, biofilm was organized in a knitted network where cells formed long chains, whereas in the rich medium, the observed structure was homogeneous cellular multilayers. Biofilm biovolume production in BHI/10 was significantly higher than in BHI in these dynamic conditions. Interestingly, biovolume of dead cells in biofilms formed under limited nutrient conditions (BHI/10) was significantly higher than in biofilms formed in the BHI medium. In the other hand, in static conditions, biofilm is organized in a multilayer cells and dispersed cells in a rich medium BHI and poor medium BHI/10 respectively. There was significantly more biomass in the rich medium compared to BHI/10 but no difference was noted in the dead/damaged subpopulation showing how L. monocytogenes biofilm could be affected by the growth conditions. This work demonstrated that nutrient concentration affects biofilm structure and the proportion of dead cells in biofilms under microfluidic condition. Our study also showed that limited nutrients play an important role in the structural stability of L. monocytogenes biofilm by enhancing cell death and liberating extracellular DNA. PMID- 28567032 TI - Recurring Necrotic Enteritis Outbreaks in Commercial Broiler Chicken Flocks Strongly Influence Toxin Gene Carriage and Species Richness in the Resident Clostridium perfringens Population. AB - Extensive use of antibiotic growth promoters (AGPs) in food animals has been questioned due to the globally increasing problem of antibiotic resistance. For the poultry industry, digestive health management following AGP withdrawal in Europe has been a challenge, especially the control of necrotic enteritis. Much research work has focused on gut health in commercial broiler chicken husbandry. Understanding the behavior of Clostridium perfringens in its ecological niche, the poultry barn, is key to a sustainable and cost-effective production in the absence of AGPs. Using polymerase chain reaction and pulsed-field gel electrophoresis, we evaluated how the C. perfringens population evolved in drug free commercial broiler chicken farms, either healthy or affected with recurring clinical necrotic enteritis outbreaks, over a 14-month period. We show that a high genotypic richness was associated with an increased risk of clinical necrotic enteritis. Also, necrotic enteritis-affected farms had a significant reduction of C. perfringens genotypic richness over time, an increase in the proportion of C. perfringens strains harboring the cpb2 gene, the netB gene, or both. Thus, necrotic enteritis occurrence is correlated with the presence of an initial highly diverse C. perfringens population, increasing the opportunity for the selective sweep of particularly virulent genotypes. Disease outbreaks also appear to largely influence the evolution of this bacterial species in poultry farms over time. PMID- 28567033 TI - Detection of Androgenic-Mutagenic Compounds and Potential Autochthonous Bacterial Communities during In Situ Bioremediation of Post-methanated Distillery Sludge. AB - Sugarcane-molasses-based post-methanated distillery waste is well known for its toxicity, causing adverse effects on aquatic flora and fauna. Here, it has been demonstrated that there is an abundant mixture of androgenic and mutagenic compounds both in distillery sludge and leachate. Gas chromatography-mass spectrometry (GC-MS) analysis showed dodecanoic acid, octadecanoic acid, n pentadecanoic acid, hexadecanoic acid, beta-sitosterol, stigmasterol, beta sitosterol trimethyl ether, heptacosane, dotriacontane, lanosta-8, 24-dien-3-one, 1-methylene-3-methyl butanol, 1-phenyl-1-propanol, 5-methyl-2-(1-methylethyl) cyclohexanol, and 2-ethylthio-10-hydroxy-9-methoxy-1,4 anthraquinone as major organic pollutants along with heavy metals (all mg kg-1): Fe (2403), Zn (210.15), Mn (126.30, Cu (73.62), Cr (21.825), Pb (16.33) and Ni (13.425). In a simultaneous analysis of bacterial communities using the restriction fragment length polymorphism (RFLP) method the dominance of Bacillus sp. followed by Enterococcus sp. as autochthonous bacterial communities growing in this extremely toxic environment was shown, indicating a primary community for bioremediation. A toxicity evaluation showed a reduction of toxicity in degraded samples of sludge and leachate, confirming the role of autochthonous bacterial communities in the bioremediation of distillery waste in situ. PMID- 28567035 TI - Evaluating the Detection of Hydrocarbon-Degrading Bacteria in 16S rRNA Gene Sequencing Surveys. AB - Hydrocarbonoclastic bacteria (HCB) play a key role in the biodegradation of oil hydrocarbons in marine and other environments. A small number of taxa have been identified as obligate HCB, notably the Gammaproteobacterial genera Alcanivorax, Cycloclasticus, Marinobacter, Neptumonas, Oleiphilus, Oleispira, and Thalassolituus, as well as the Alphaproteobacterial genus Thalassospira. Detection of HCB in amplicon-based sequencing surveys relies on high coverage by PCR primers and accurate taxonomic classification. In this study, we performed a phylogenetic analysis to identify 16S rRNA gene sequence regions that represent the breadth of sequence diversity within these taxa. Using validated sequences, we evaluated 449 universal 16S rRNA gene-targeted bacterial PCR primer pairs for their coverage of these taxa. The results of this analysis provide a practical framework for selection of suitable primer sets for optimal detection of HCB in sequencing surveys. PMID- 28567034 TI - Transcriptional Responses of Candida albicans to Antimicrobial Peptide MAF-1A. AB - Candida albicans is a major fungal pathogen in humans. Novel antifungal agents are urgent demanded due to the challenges of the resistance. Antimicrobial peptides (AMPs) are critical components of the innate immune system against pathogenic microorganism infection. MAF-1A is a novel cationic AMP that comes from Musca domestica and is effective against C. albicans, but the antifungal mechanism remains unclear. In this study, we performed a transcriptomics analysis in C. albicans using RNA-seq technique under the treatment of MAF-1A. A total of 5654 genes were identified. Among these, 1032 were differentially expressed genes (DEGs), including 575 up-regulated genes and 457 down-regulated genes. In these DEGs, genes encoding ergosterol metabolism and fatty acid biosynthesis were identified to be significantly down-regulated, while genes associated with oxidative stress response and cell wall were identified to be significantly up regulated. Using pathway enrichment analysis, 12 significant metabolic pathways were identified, and ribosome, oxidative phosphorylation, citrate cycle were mainly involved. The results revealed that MAF-1A induces complex responses in C. albicans. This study provides evidence that MAF-1A may inhibit the growth through affect multi-targets in C. albicans cells. PMID- 28567036 TI - Nasal IgA Provides Protection against Human Influenza Challenge in Volunteers with Low Serum Influenza Antibody Titre. AB - In spite of there being a number of vaccines, influenza remains a significant global cause of morbidity and mortality. Understanding more about natural and vaccine induced immune protection against influenza infection would help to develop better vaccines. Virus specific IgG is a known correlate of protection, but other factors may help to reduce viral load or disease severity, for example IgA. In the current study we measured influenza specific responses in a controlled human infection model using influenza A/California/2009 (H1N1) as the challenge agent. Volunteers were pre-selected with low haemagglutination inhibition (HAI) titres in order to ensure a higher proportion of infection; this allowed us to explore the role of other immune correlates. In spite of HAI being uniformly low, there were variable levels of H1N1 specific IgG and IgA prior to infection. There was also a range of disease severity in volunteers allowing us to compare whether differences in systemic and local H1N1 specific IgG and IgA prior to infection affected disease outcome. H1N1 specific IgG level before challenge did not correlate with protection, probably due to the pre-screening for individuals with low HAI. However, the length of time infectious virus was recovered from the nose was reduced in patients with higher pre-existing H1N1 influenza specific nasal IgA or serum IgA. Therefore, IgA contributes to protection against influenza and should be targeted in vaccines. PMID- 28567037 TI - Modulation of the Gut Microbiota by Krill Oil in Mice Fed a High-Sugar High-Fat Diet. AB - Multiple lines of evidence suggest that the gut microbiota plays vital roles in metabolic diseases such as hyperlipidemia. Previous studies have confirmed that krill oil can alleviate hyperlipidemia, but the underlying mechanism remains unclear. To discern whether krill oil changes the structure of the gut microbiota during the hyperlipidemia treatment, 72 mice were acclimatized with a standard chow diet for 2 weeks and then randomly allocated to receive a standard chow diet (control group, n = 12) or a high-sugar-high-fat (HSHF) diet supplemented with a low (100 MUg/g.d, HSHF+LD group, n = 12), moderate (200 MUg/g.d, HSHF+MD group, n = 12) or high dosage of krill oil (600 MUg/g.d, HSHF+HD group, n = 12), simvastatin (HSHF+S group, n = 12) or saline (HSHF group, n = 12) continuously for 12 weeks. The resulting weight gains were attenuated, the liver index and the low-density lipoprotein, total cholesterol and triglyceride concentrations showed a stepwise reduction in the treated groups compared with those of the control group. A dose-dependent modulation of the gut microbiota was observed after treatment with krill oil. Low- and moderate- doses of krill oil increased the similarity between the composition of the HSHF diet-induced gut microbiota and that of the control, whereas the mice fed the high-dose exhibited a unique gut microbiota structure that was different from that of the control and HSHF groups. Sixty-five key operational taxonomic units (OTUs) that responded to the krill oil treatment were identified using redundancy analysis, of which 26 OTUs were increased and 39 OTUs were decreased compared with those of the HSHF group. In conclusion, the results obtained in this study suggest that the structural alterations in the gut microbiota induced by krill oil treatment were dose dependent and associated with the alleviation of hyperlipidemia. Additionally, the high-dose krill oil treatment showed combined effects on the alleviation of hyperlipidemia and obesity. PMID- 28567038 TI - Assessing the Challenges in the Application of Potential Probiotic Lactic Acid Bacteria in the Large-Scale Fermentation of Spanish-Style Table Olives. AB - This work studies the inoculation conditions for allowing the survival/predominance of a potential probiotic strain (Lactobacillus pentosus TOMC-LAB2) when used as a starter culture in large-scale fermentations of green Spanish-style olives. The study was performed in two successive seasons (2011/2012 and 2012/2013), using about 150 tons of olives. Inoculation immediately after brining (to prevent wild initial microbiota growth) followed by re-inoculation 24 h later (to improve competitiveness) was essential for inoculum predominance. Processing early in the season (September) showed a favorable effect on fermentation and strain predominance on olives (particularly when using acidified brines containing 25 L HCl/vessel) but caused the disappearance of the target strain from both brines and olives during the storage phase. On the contrary, processing in October slightly reduced the target strain predominance on olives (70-90%) but allowed longer survival. The type of inoculum used (laboratory vs. industry pre-adapted) never had significant effects. Thus, this investigation discloses key issues for the survival and predominance of starter cultures in large-scale industrial fermentations of green Spanish-style olives. Results can be of interest for producing probiotic table olives and open new research challenges on the causes of inoculum vanishing during the storage phase. PMID- 28567039 TI - Neutrophil Extracellular Traps Reprogram IL-4/GM-CSF-Induced Monocyte Differentiation to Anti-inflammatory Macrophages. AB - Monocyte-derived dendritic cells (mo-DCs) are essential for the development of a Th1 protective immune response against Leishmania parasites. It is well known that IL-4 and GM-CSF drive differentiation of human monocytes to dendritic cells (DCs). Here, we investigate if neutrophil extracellular traps (NETs) disrupt this process. NETs-enriched supernatants, generated after human neutrophil activation by Leishmania promastigotes, were added to monocytes and differentiation monitored by expression of molecules associated with macrophage and DCs phenotypes, cytokine production, and parasite killing. We found that NETs addition to IL-4/GM-CSF-treated monocytes prevented then to fully differentiate into DCs. No effect was observed if NETs were treated with DNase or by filtering the traps. Moreover, NETs closely interact with monocytes and downregulate the expression of the IL-4 receptor, which in turn disrupts fully differentiation of monocytes into DCs. Neutrophil elastase inhibition rescues the monocytes to DCs differentiation. Monocytes cultured with IL-4/GM-CSF and NETs differentiated into macrophages, as observed by the increased expression of CD68, CD32, and CD163, and decreased expression of CD80. Moreover, NET addition to IL-4/GM-CSF-treated monocytes rendered these cells less efficient to kill Leishmania parasites. Altogether, our results show that NETs interfere with IL-4/GM-CSF driven differentiation, reprogramming the generation of mo-DCs to an anti-inflammatory macrophage. PMID- 28567040 TI - A Unique Cellular and Molecular Microenvironment Is Present in Tertiary Lymphoid Organs of Patients with Spontaneous Prostate Cancer Regression. AB - OBJECTIVE: Multiple solid cancers contain tertiary lymphoid organs (TLO). However, it is unclear whether they promote tumor rejection, facilitate tumor evasion, or simply whether they are a byproduct of chronic inflammation. We hypothesize that although chronic inflammation induces TLO formation, the tumor milieu can modulate TLO organization and functions in prostate cancer. Therefore, our study seeks to elucidate the cellular and molecular signatures in unique prostatectomy specimens from evanescent carcinoma patients to identify markers of cancer regression, which could be harnessed to modulate local immunosuppression or potentially enhance TLO function. METHODS: We used multicolor immunofluorescence to stain prostate tissues, collected at different stages of cancer progression (prostatic intraepithelial neoplasia, intermediate and advanced cancer) or from patients with evanescent prostate carcinoma. Tissues were stained with antibodies specific for pro-inflammatory molecules (cyclooxygenase 2, CXCL10, IL17), tumor-infiltrating immune cells (mature DC LAMP+ dendritic cells, CD3+ T cells, CD3+Foxp3+ regulatory T cells (Treg), T bet+ Th1 cells, granzyme B+ cytotoxic cells), and stromal cell populations (lymphatic vessels, tumor neovessels, high endothelial venules (HEV), stromal cells), which promote prostate tumor growth or are critical components of tumor-associated TLO. RESULTS: Generally, inflammatory cells are located at the margins of tumors. Unexpectedly, we found TLO within prostate tumors from patients at different stages of cancer and in unique samples from patients with spontaneous cancer remission. In evanescent prostate carcinomas, accumulation of Treg was compromised, while Tbet+ T cells and CD8 T cells were abundant in tumor associated TLO. In addition, we found a global decrease in tumor neovascularization and the coverage by cells positive for cyclooxygenase 2 (COX2). Finally, consistent with tumor regression, prostate stem cell antigen was considerably reduced in TLO and tumor areas from evanescent carcinoma patients. CONCLUSION: Collectively, our results suggest that COX2 and Treg are attractive therapeutic targets that can be harnessed to enhance TLO-driven tumor immunity against prostate cancer. Specially, the presence of HEV and lymphatics indicate that TLO can be used as a platform for delivery of cell-based and/or COX2 blocking therapies to improve control of tumor growth in prostate cancer. PMID- 28567041 TI - Pathogen-Reactive T Helper Cell Analysis in the Pig. AB - There is growing interest in studying host-pathogen interactions in human relevant large animal models such as the pig. Despite the progress in developing immunological reagents for porcine T cell research, there is an urgent need to directly assess pathogen-specific T cells-an extremely rare population of cells, but of upmost importance in orchestrating the host immune response to a given pathogen. Here, we established that the activation marker CD154 (CD40L), known from human and mouse studies, identifies also porcine antigen-reactive CD4+ T lymphocytes. CD154 expression was upregulated early after antigen encounter and CD4+CD154+ antigen-reactive T cells coexpressed cytokines. Antigen-induced expansion and autologous restimulation enabled a time- and dose-resolved analysis of CD154 regulation and a significantly increased resolution in phenotypic profiling of antigen-responsive cells. CD154 expression identified T cells responding to staphylococcal Enterotoxin B superantigen stimulation as well as T cells responding to the fungus Candida albicans and T cells specific for a highly prevalent intestinal parasite, the nematode Ascaris suum during acute and trickle infection. Antigen-reactive T cells were further detected after immunization of pigs with a single recombinant bacterial antigen of Streptococcus suis only. Thus, our study offers new ways to study antigen-specific T lymphocytes in the pig and their contribution to host-pathogen interactions. PMID- 28567042 TI - Hepatitis C Virus and Human Cytomegalovirus-Natural Killer Cell Subsets in Persistent Viral Infections. AB - Hepatitis C virus (HCV) and human cytomegalovirus (HCMV) are prominent examples of RNA and DNA viruses, respectively, that establish a persistent infection in their host. HCV affects over 185 million patients worldwide, who are at high risk for developing liver fibrosis, liver cirrhosis, and ultimately hepatocellular carcinoma. Recent breakthroughs in HCV therapy, using direct-acting antivirals have provided the opportunity to monitor natural killer (NK) cells after clearance of a chronic infection. There is now increasing evidence that the individual NK cell repertoire before infection is predictive for the course of disease. HCMV affects the majority of the global population. While being asymptomatic in healthy individuals, HCMV represents a severe clinical challenge in immunocompromised patients. Both viral infections, HCV and HCMV, lead to long lasting and profound alterations within the entire NK cell compartment. This review article, will discuss the diverse range of changes in the NK cell compartment as well as potential consequences for the course of disease. PMID- 28567044 TI - Curcumin Promotes the Clearance of Listeria monocytogenes both In Vitro and In Vivo by Reducing Listeriolysin O Oligomers. AB - The pore-forming toxin listeriolysin O (LLO), an essential virulence factor that is secreted by Listeria monocytogenes (L. monocytogenes), is responsible for bacterial breaching at the phagosomal membranes and subsequent release into the cytoplasm; it cannot be recognized by the host immune system. The vital role that LLO plays in bacterial pathogenicity and evading host immune clearance makes this virulence a promising target for addressing L. monocytogenes infection. In this study, we hypothesized that curcumin, a polyphenol derived from turmeric that could effectively inhibit LLO pore-forming activity, might be useful in the prevention or treatment of L. monocytogenes infection. Thus, the in vitro protective effects of curcumin against L. monocytogenes infection by targeting LLO were assessed via hemolytic activity assays, cytotoxicity tests, intracellular growth assays, and confocal microscopy. Our results revealed that treating infected macrophages with curcumin can lead to a decrease in LLO mediated bacteria phagosomal escape and limit the intracellular growth of L. monocytogenes. Moreover, results from animal experiments show that this natural compound effectively increases protection against bacterial infection and helps the host to clear the invading pathogen completely from an animal model, establishing it as a potent antagonist of L. monocytogenes. The results from our molecular modeling and mutational analysis demonstrated that curcumin directly engages with domains 2 and 4 of LLO, thereby decreasing the hemolytic activity of LLO by influencing its oligomerization. Taken together, these results suggest that, as an antitoxin agent, curcumin can be further developed into a novel therapy against L. monocytogenes infections by targeting LLO. PMID- 28567045 TI - Exploring Relationships between Canopy Architecture, Light Distribution, and Photosynthesis in Contrasting Rice Genotypes Using 3D Canopy Reconstruction. AB - The arrangement of leaf material is critical in determining the light environment, and subsequently the photosynthetic productivity of complex crop canopies. However, links between specific canopy architectural traits and photosynthetic productivity across a wide genetic background are poorly understood for field grown crops. The architecture of five genetically diverse rice varieties-four parental founders of a multi-parent advanced generation intercross (MAGIC) population plus a high yielding Philippine variety (IR64)-was captured at two different growth stages using a method for digital plant reconstruction based on stereocameras. Ray tracing was employed to explore the effects of canopy architecture on the resulting light environment in high resolution, whilst gas exchange measurements were combined with an empirical model of photosynthesis to calculate an estimated carbon gain and total light interception. To further test the impact of different dynamic light patterns on photosynthetic properties, an empirical model of photosynthetic acclimation was employed to predict the optimal light-saturated photosynthesis rate (Pmax ) throughout canopy depth, hypothesizing that light is the sole determinant of productivity in these conditions. First, we show that a plant type with steeper leaf angles allows more efficient penetration of light into lower canopy layers and this, in turn, leads to a greater photosynthetic potential. Second the predicted optimal Pmax responds in a manner that is consistent with fractional interception and leaf area index across this germplasm. However, measured Pmax , especially in lower layers, was consistently higher than the optimal Pmax indicating factors other than light determine photosynthesis profiles. Lastly, varieties with more upright architecture exhibit higher maximum quantum yield of photosynthesis indicating a canopy-level impact on photosynthetic efficiency. PMID- 28567043 TI - Simultaneous Subcutaneous and Intranasal Administration of a CAF01-Adjuvanted Chlamydia Vaccine Elicits Elevated IgA and Protective Th1/Th17 Responses in the Genital Tract. AB - The selection of any specific immunization route is critical when defining future vaccine strategies against a genital infection like Chlamydia trachomatis (C.t.). An optimal Chlamydia vaccine needs to elicit mucosal immunity comprising both neutralizing IgA/IgG antibodies and strong Th1/Th17 responses. A strategic tool to modulate this immune profile and mucosal localization of vaccine responses is to combine parenteral and mucosal immunizations routes. In this study, we investigate whether this strategy can be adapted into a two-visit strategy by simultaneous subcutaneous (SC) and nasal immunization. Using a subunit vaccine composed of C.t. antigens (Ags) adjuvanted with CAF01, a Th1/Th17 promoting adjuvant, we comparatively evaluated Ag-specific B and T cell responses and efficacy in mice following SC and simultaneous SC and nasal immunization (SIM). We found similar peripheral responses with regard to interferon gamma and IL-17 producing Ag-specific splenocytes and IgG serum levels in both vaccine strategies but in addition, the SIM protocol also led to Ag-specific IgA responses and increased B and CD4+ T cells in the lung parenchyma, and in lower numbers also in the genital tract (GT). Following vaginal infection with C.t., we observed that SIM immunization gave rise to an early IgA response and IgA-secreting plasma cells in the GT in contrast to SC immunization, but we were not able to detect more rapid recruitment of mucosal T cells. Interestingly, although SIM vaccination in general improved mucosal immunity we observed no improved efficacy against genital infection compared to SC, a finding that warrants for further investigation. In conclusion, we demonstrate a novel vaccination strategy that combines systemic and mucosal immunity in a two-visit strategy. PMID- 28567046 TI - Transcriptome Analysis of Salicylic Acid Treatment in Rehmannia glutinosa Hairy Roots Using RNA-seq Technique for Identification of Genes Involved in Acteoside Biosynthesis. AB - Rehmannia glutinosa is a common bulk medicinal material that has been widely used in China due to its active ingredients. Acteoside, one of the ingredients, has antioxidant, antinephritic, anti-inflammatory, hepatoprotective, immunomodulatory, and neuroprotective effects, is usually selected as a quality control component for R. glutinosa herb in the Chinese Pharmacopeia. The acteoside biosynthesis pathway in R. glutinosa has not yet been clearly established. Herein, we describe the establishment of a genetic transformation system for R. glutinosa mediated by Agrobacterium rhizogenes. We screened the optimal elicitors that markedly increased acteoside accumulation in R. glutinosa hairy roots. We found that acteoside accumulation dramatically increased with the addition of salicylic acid (SA); the optimal SA dose was 25 MUmol/L for hairy roots. RNA-seq was applied to analyze the transcriptomic changes in hairy roots treated with SA for 24 h in comparison with an untreated control. A total of 3,716, 4,018, and 2,715 differentially expressed transcripts (DETs) were identified in 0 h-vs.-12 h, 0 h-vs.-24 h, and 12 h-vs.-24 h libraries, respectively. KEGG pathway-based analysis revealed that 127 DETs were enriched in "phenylpropanoid biosynthesis." Of 219 putative unigenes involved in acteoside biosynthesis, 54 were found to be up-regulated at at least one of the time points after SA treatment. Selected candidate genes were analyzed by quantitative real time PCR (qRT-PCR) in hairy roots with SA, methyl jasmonate (MeJA), AgNO3 (Ag+), and putrescine (Put) treatment. All genes investigated were up-regulated by SA treatment, and most candidate genes were weakly increased by MeJA to some degree. Furthermore, transcription abundance of eight candidate genes in tuberous roots of the high-acteoside-content (HA) cultivar QH were higher than those of the low acteoside-content (LA) cultivar Wen 85-5. These results will pave the way for understanding the molecular basis of acteoside biosynthesis in R. glutinosa, and can serve as a basis for future validation studies. PMID- 28567047 TI - Brassinosteroid Mediated Cell Wall Remodeling in Grasses under Abiotic Stress. AB - Unlike animals, plants, being sessile, cannot escape from exposure to severe abiotic stresses such as extreme temperature and water deficit. The dynamic structure of plant cell wall enables them to undergo compensatory changes, as well as maintain physical strength, with changing environments. Plant hormones known as brassinosteroids (BRs) play a key role in determining cell wall expansion during stress responses. Cell wall deposition differs between grasses (Poaceae) and dicots. Grass species include many important food, fiber, and biofuel crops. In this article, we focus on recent advances in BR-regulated cell wall biosynthesis and remodeling in response to stresses, comparing our understanding of the mechanisms in grass species with those in the more studied dicots. A more comprehensive understanding of BR-mediated changes in cell wall integrity in grass species will benefit the development of genetic tools to improve crop productivity, fiber quality and plant biomass recalcitrance. PMID- 28567048 TI - Genetic Gains in Yield and Yield Related Traits under Drought Stress and Favorable Environments in a Maize Population Improved Using Marker Assisted Recurrent Selection. AB - The objective of marker assisted recurrent selection (MARS) is to increase the frequency of favorable marker alleles in a population before inbred line extraction. This approach was used to improve drought tolerance and grain yield (GY) in a biparental cross of two elite drought tolerant lines. The testcrosses of randomly selected 50 S1 lines from each of the three selection cycles (C0, C1, C2) of the MARS population, parental testcrosses and the cross between the two parents (F1) were evaluated under drought stress (DS) and well watered (WW) well as under rainfed conditions to determine genetic gains in GY and other agronomic traits. Also, the S1 lines derived from each selection types were genotyped with single nucleotide polymorphism (SNP) markers. Testcrosses derived from C2 produced significantly higher grain field under DS than those derived from C0 with a relative genetic gain of 7% per cycle. Also, the testcrosses of S1 lines from C2 showed an average genetic gain of 1% per cycle under WW condition and 3% per cycle under rainfed condition. Molecular analysis revealed that the frequency of favorable marker alleles increased from 0.510 at C0 to 0.515 at C2, while the effective number of alleles (Ne) per locus decreased from C0 (1.93) to C2 (1.87). Our results underscore the effectiveness of MARS for improvement of GY under DS condition. PMID- 28567049 TI - Quantitative Trait Loci Associated with Drought Tolerance in Brachypodium distachyon. AB - The temperate wild grass Brachypodium distachyon (Brachypodium) serves as model system for studying turf and forage grasses. Brachypodium collections show diverse responses to drought stress, but little is known about the genetic mechanisms of drought tolerance of this species. The objective of this study was to identify quantitative trait loci (QTLs) associated with drought tolerance traits in Brachypodium. We assessed leaf fresh weight (LFW), leaf dry weight (LDW), leaf water content (LWC), leaf wilting (WT), and chlorophyll fluorescence (Fv/Fm) under well-watered and drought conditions on a recombinant inbred line (RIL) population from two parents (Bd3-1 and Bd1-1) known to differ in their drought adaptation. A linkage map of the RIL population was constructed using 467 single nucleotide polymorphism (SNP) markers obtained from genotyping-by sequencing. The Bd3-1/Bd1-1 map spanned 1,618 cM and had an average distance of 3.5 cM between adjacent single nucleotide polymorphisms (SNPs). Twenty-six QTLs were identified in chromosome 1, 2, and 3 in two experiments, with 14 of the QTLs under well-watered conditions and 12 QTLs under drought stress. In Experiment 1, a QTL located on chromosome 2 with a peak at 182 cM appeared to simultaneously control WT, LWC, and Fv/Fm under drought stress, accounting for 11-18.7% of the phenotypic variation. Allelic diversity of candidate genes DREB2B, MYB, and SPK, which reside in one multi-QTL region, may play a role in the natural variation in whole plant drought tolerance in Brachypodium. Co-localization of QTLs for multiple drought-related traits suggest that the gene(s) involved are important regulators of drought tolerance in Brachypodium. PMID- 28567050 TI - New Genetic Insights into Pearl Millet Diversity As Revealed by Characterization of Early- and Late-Flowering Landraces from Senegal. AB - Pearl millet (Pennisetum glaucum (L.) R. Br.) is a staple food and a drought tolerant cereal well adapted to Sub-Saharan Africa agro-ecosystems. An important diversity of pearl millet landraces has been widely conserved by farmers and therefore could help copping with climate changes and contribute to future food security. Hence, characterizing its genetic diversity and population structure can contribute to better assist breeding programs for a sustainable agricultural productivity enhancement. Toward this goal, a comprehensive panel of 404 accessions were used that correspond to 12 improved varieties, 306 early flowering and 86 late-flowering cultivated landraces from Senegal. Twelve highly polymorphic SSR markers were used to study diversity and population structure. Two genes, PgMADS11 and PgPHYC, were genotyped to assess their association to flowering phenotypic difference in landraces. Results indicate a large diversity and untapped potential of Senegalese pearl millet germplasm as well as a genetic differentiation between early- and late-flowering landraces. Further, a fine scale genetic difference of PgPHYC and PgMADS11 (SNP and indel, respectively) and co-variation of their alleles with flowering time were found among landraces. These findings highlight new genetic insights of pearl millet useful to define heterotic populations for breeding, genomic association panel, or crosses for trait-specific mapping. PMID- 28567051 TI - Trichoderma-Induced Acidification Is an Early Trigger for Changes in Arabidopsis Root Growth and Determines Fungal Phytostimulation. AB - Trichoderma spp. are common rhizosphere inhabitants widely used as biological control agents and their role as plant growth promoting fungi has been established. Although soil pH influences several fungal and plant functional traits such as growth and nutrition, little is known about its influence in rhizospheric or mutualistic interactions. The role of pH in the Trichoderma Arabidopsis interaction was studied by determining primary root growth and lateral root formation, root meristem status and cell viability, quiescent center (QC) integrity, and auxin inducible gene expression. Primary root growth phenotypes in wild type seedlings and STOP1 mutants allowed identification of a putative root pH sensing pathway likely operating in plant-fungus recognition. Acidification by Trichoderma induced auxin redistribution within Arabidopsis columella root cap cells, causing root tip bending and growth inhibition. Root growth stoppage correlated with decreased cell division and with the loss of QC integrity and cell viability, which were reversed by buffering the medium. In addition, stop1, an Arabidopsis mutant sensitive to low pH, was oversensitive to T. atroviride primary root growth repression, providing genetic evidence that a pH root sensing mechanism reprograms root architecture during the interaction. Our results indicate that root sensing of pH mediates the interaction of Trichoderma with plants. PMID- 28567052 TI - How Single Molecule Real-Time Sequencing and Haplotype Phasing Have Enabled Reference-Grade Diploid Genome Assembly of Wine Grapes. PMID- 28567053 TI - Comparative Physiological and Molecular Analyses of Two Contrasting Flue-Cured Tobacco Genotypes under Progressive Drought Stress. AB - Drought is a major environmental factor that limits crop growth and productivity. Flue-cured tobacco (Nicotiana tabacum) is one of the most important commercial crops worldwide and its productivity is vulnerable to drought. However, comparative analyses of physiological, biochemical and gene expression changes in flue-cured tobacco varieties differing in drought tolerance under long-term drought stress are scarce. In this study, drought stress responses of two flue cured tobacco varieties, LJ851 and JX6007, were comparatively studied at the physiological and transcriptional levels. After exposing to progressive drought stress, the drought-tolerant LJ851 showed less growth inhibition and chlorophyll reduction than the drought-sensitive JX6007. Moreover, higher antioxidant enzyme activities and lower levels of H2O2, Malondialdehyde (MDA), and electrolyte leakage after drought stress were found in LJ851 when compared with JX6007. Further analysis showed that LJ851 plants had much less reductions than the JX6007 in the net photosynthesis rate and stomatal conductance during drought stress; indicating that LJ851 had better photosynthetic performance than JX6007 during drought. In addition, transcriptional expression analysis revealed that LJ851 exhibited significantly increased transcripts of several categories of drought-responsive genes in leaves and roots under drought conditions. Together, these results indicated that LJ851 was more drought-tolerant than JX6007 as evidenced by better photosynthetic performance, more powerful antioxidant system, and higher expression of stress defense genes during drought stress. This study will be valuable for the development of novel flue-cured tobacco varieties with improved drought tolerance by exploitation of natural genetic variations in the future. PMID- 28567054 TI - Monte Carlo Simulation for Polychromatic X-Ray Fluorescence Computed Tomography with Sheet-Beam Geometry. AB - X-ray fluorescence computed tomography (XFCT) based on sheet beam can save a huge amount of time to obtain a whole set of projections using synchrotron. However, it is clearly unpractical for most biomedical research laboratories. In this paper, polychromatic X-ray fluorescence computed tomography with sheet-beam geometry is tested by Monte Carlo simulation. First, two phantoms (A and B) filled with PMMA are used to simulate imaging process through GEANT 4. Phantom A contains several GNP-loaded regions with the same size (10 mm) in height and diameter but different Au weight concentration ranging from 0.3% to 1.8%. Phantom B contains twelve GNP-loaded regions with the same Au weight concentration (1.6%) but different diameter ranging from 1 mm to 9 mm. Second, discretized presentation of imaging model is established to reconstruct more accurate XFCT images. Third, XFCT images of phantoms A and B are reconstructed by filter back projection (FBP) and maximum likelihood expectation maximization (MLEM) with and without correction, respectively. Contrast-to-noise ratio (CNR) is calculated to evaluate all the reconstructed images. Our results show that it is feasible for sheet-beam XFCT system based on polychromatic X-ray source and the discretized imaging model can be used to reconstruct more accurate images. PMID- 28567055 TI - Surface Characteristics and Biofilm Development on Selected Dental Ceramic Materials. AB - BACKGROUND: Intraoral adjustment and polishing of dental ceramics often affect their surface characteristics, promoting increased roughness and consequent biofilm growth. This study correlated surface roughness to biofilm development with four commercially available ceramic materials. METHODS: Four ceramic materials (Vita Enamic(r), LavaTM Ultimate, Vitablocs Mark II, and Wieland Reflex(r)) were prepared as per manufacturer instructions. Seventeen specimens of each material were adjusted and polished to simulate clinical intraoral procedures and another seventeen remained unaltered. Specimens were analysed by SEM imaging, confocal microscopy, and crystal violet assay. RESULTS: SEM images showed more irregular surface topography in adjusted specimens than their respective controls. Surface roughness (Ra ) values were greater in all materials following adjustments. All adjusted materials with the exception of Vitablocs Mark II promoted significantly greater biofilm growth relative to controls. CONCLUSION: Simulated intraoral polishing methods resulted in greater surface roughness and increased biofilm accumulation. PMID- 28567056 TI - Rapid Determination of Isomeric Benzoylpaeoniflorin and Benzoylalbiflorin in Rat Plasma by LC-MS/MS Method. AB - Benzoylpaeoniflorin (BP) is a potential therapeutic agent against oxidative stress related Alzheimer's disease. In this study, a more rapid, selective, and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed to determine BP in rat plasma distinguishing with a monoterpene isomer, benzoylalbiflorin (BA). The method showed a linear response from 1 to 1000 ng/mL (r > 0.9950). The precision of the interday and intraday ranged from 2.03 to 12.48% and the accuracy values ranged from -8.00 to 10.33%. Each running of the method could be finished in 4 minutes. The LC-MS/MS method was validated for specificity, linearity, precision, accuracy, recovery, and stability and was found to be acceptable for bioanalytical application. Finally, this fully validated method was successfully applied to a pharmacokinetic study in rats following oral administration. PMID- 28567057 TI - Molecular Study of Acinetobacter baumannii Isolates for Metallo-beta-Lactamases and Extended-Spectrum-beta-Lactamases Genes in Intensive Care Unit, Mansoura University Hospital, Egypt. AB - Acinetobacter baumannii (A. baumannii) has been known as a causative pathogen of hospital acquired infections. The aim of this study is to examine the presence of A. baumannii among clinical isolates from intensive care unit (ICU) in Mansoura University Hospital (MUH), its antibiotic resistance pattern, and prevalence of antibiotic resistance genes metallo-beta-lactamases (MBLs) and extended-spectrum beta-lactamases (ESBLs) among A. baumannii isolates. A. baumannii was identified by colony morphology, API 20E, and confirmed by detecting the bla OXA-51-like carbapenemase gene by PCR. Phenotypic expression of MBLs resistance was demonstrated by Combined Disk Test (CDT) in 273 isolates (97.5%) and of ESBLs was demonstrated by double disc synergy method (DDST) in 6 isolates (2.1%). MBLs genes were positive in 266 isolates (95%) and ESBLs genes were positive in 8 isolates (2.9%). The most frequent genes of MBLs studied genes were IMP (95.7%) followed by SIM and GIM (47.1% and 42.9%; resp.). For ESBL genes, the most frequent gene was TEM (2.9%). From this study, we conclude that multidrug resistant (MDR) A. baumannii with MBLs activity was the most common isolate. Careful monitoring for the presence of MDR A. baumannii among hospitalized patients is recommended to avoid wide dissemination of antibiotic resistance. PMID- 28567058 TI - Implementation and Monitoring of a Gestational Trophoblastic Disease Management Program in a Tertiary Hospital in Morocco: Opportunities and Challenges. AB - Objective. Gestational Trophoblastic Disease (GTD) management requires clear guidelines for diagnosis, treatment, and follow-up. Unequal management skills among practitioners, inadequate treatment, irregular surveillance, and drop-out are common in resource-limited settings and can lead to life-threatening complications and morbidities. To address these challenges, we implemented a GTD Management Program at the National Center for Reproductive Health in Rabat, Morocco. Methods and Program Description. In-depth review of management protocols was carried out, and concise guidelines were developed, with targeted training for physicians. A physical space and a weekly fixed GTD consultation were set, and personalized follow-up was established for each patient. An electronic database documenting patients' surveillance was created, allowing immediate outreach in case of irregularities. Results. During the period from October 2013 to June 2016, 50 patients were included in this program. Patients' mean age was 33 years; 92% were illiterate and 82% had a low socioeconomic status. 68% had a positive evolution, while 32% developed gestational trophoblastic neoplasia, requiring 2 to 6 chemotherapy sessions. An average of 2.8 outreach reminders were necessary for each patient. 94% fully adhered to the program of care and completed properly their follow-up. Conclusion. Implementation and thorough monitoring of this program helped optimize patients' care, avoiding drop-outs and delays in diagnosing and treating complications. PMID- 28567059 TI - Intraplacental Choriocarcinoma: Rare or Underdiagnosed? Report of 2 Cases Diagnosed after an Incomplete Miscarriage and a Preterm Spontaneous Vaginal Delivery. AB - Intraplacental choriocarcinoma is a rare malignant tumor diagnosed after an abortion, an ectopic pregnancy, or a term or preterm pregnancy or following the diagnosis of a hydatidiform mole. During pregnancy, it may be more common than reported, as most patients are asymptomatic and placental choriocarcinomas are usually inconspicuous macroscopically and are often mistaken for an infarct. Based upon a case study methodology, we describe 2 cases of intraplacental choriocarcinoma: the first case was identified in the product of a uterine curettage following an incomplete miscarriage and the second in one of the placentas of a bichorionic twin pregnancy. Maternal investigation did not reveal evidence of metastatic disease and neither did the infants' one in the second case. The two cases underwent maternal surveillance with serum hCG and remained disease-free until the present. In conclusion, intraplacental choriocarcinoma is easily underdiagnosed but with current treatment, even in the presence of metastasis, the prognosis is excellent. A routine microscopic examination of all the placentas and products of miscarriage can increase the real incidence of this entity and consequently improve its management. PMID- 28567060 TI - Analysing the Influence of Health Insurance Status on Peoples' Health Seeking Behaviour in Rural Ghana. AB - This paper examines the influence of health insurance status on healthcare use in rural Ghana using 286 sampled respondents from four rural communities in the Bekwai Municipality. Data were obtained using structured interview and Pearson's Chi square and bivariate regressions were used to analyse data. The results show low healthcare utilization among study participants, with most respondents having irregular use (43.5%) or rare use (43.3%). Respondents with health insurance utilized healthcare more than those without health insurance, the results being statistically significant (df = 4; n = 283, p = 0.000). The bivariate analysis revealed that health insurance status has a positive and significant influence on utilization (beta = 1.284; p value = 0.000). The study recommends promotion and improvement of services of the National Health Insurance Scheme as effective strategy to improve healthcare consumption by the rural people. The expansion of health insurance services to all sections of the population is also recommended. PMID- 28567061 TI - Therapeutic Hypothermia in Asphyxiated Neonates: Experience from Neonatal Intensive Care Unit of University Hospital of Marrakech. AB - INTRODUCTION: Therapeutic hypothermia (TH) is now recommended for the treatment neonates with hypoxic-ischemic encephalopathy (HIE). This treatment protocol is applied in our department since June 2012. The aim of this study is to report the first experience with head cooling in asphyxiated neonates in Morocco. PATIENTS AND METHODS: Prospective study of newborns admitted for HIE from July 18, 2012, to May 15, 2014, in Neonatal Intensive Care Unit (NICU) of Mohamed VI University Hospital. The results were studied by comparing a newborn group who received hypothermia to a control group. RESULTS: Seventy-two cases of neonates with perinatal asphyxia were admitted in the unit. According to inclusion criteria thirty-eight cases were eligible for the study. Only 19 cases have received the hypothermia protocol for different reason; the arrival beyond six hours of life was the main cause accounting for 41%. Complications of asphyxia were comparable in both groups with greater pulmonary hypertension recorded in the control group. The long-term follow-up of protocol group was normal in almost half of cases. CONCLUSION: Our first experience with the controlled TH supports its beneficial effect in newborns with HIE. This treatment must be available in all the centers involved in the neonatal care in Morocco. PMID- 28567062 TI - [The mediating role of family functioning in the relationship between family adversity and preschoolers' social adjustment]. AB - Preschoolers' social adaptation is related to their degree of exposure to environnemental risks. However, the mechanisms through which the environmental risks operate their influence on social adaptation are still poorly documented. Thus, the first goal of this study is to investigate the main effect of family adversity on preschoolers' behavioral problems and attachment security. The second goal is to test the mediating effect of family functionning in the relationship between family adversity and behavioral problems or attachment security. Five hundred and seventy-two participants (n=572) were assessed on family adversity between the age of 5 and 42 months. Behavioral problems and family functionning were assesed at 42 months. Eighty of the participants were assessed on attachment security at the age of 48 months. The results show a main effect of family adversity on behavioral problems as well as a mediating effect of family functionning in the relationship of family adversity and behavioral problems. No significant effect was found for security of attachment. PMID- 28567063 TI - A review of case and case series reports on Henoch-Schonlein syndrome-related pancreatitis. AB - To summarize the experience of diagnosing and treating patients with Henoch Schonlein purpura (HSP)-related pancreatitis, a systematic review of previously published cases was conducted. Among 13 reported cases, there were six males and seven females whose age from 3 to 70 years. The clinical features of these patients indicated that acute pancreatitis could be the initial manifestation of HSP, the radiological change was atypical, and most cases were alleviated with steroidal treatment. Good outcomes can be achieved in patients who are diagnosed early with HSP-related pancreatitis, and it is vital to begin timely treatment of HSP-related pancreatitis with corticosteroid. PMID- 28567064 TI - Validity and reliability of the ankle-brachial index by oscillometric blood pressure and automated ankle-brachial index. AB - BACKGROUND: This study was conducted to assess the validity and reliability of ankle-brachial index (ABI) by oscillometric blood pressure (BP) measurement as compared with an automated ABI as a gold standard. MATERIALS AND METHODS: This study was conducted at Golden Jubilee Medical Center, Thailand. All the data were collected from 303 patients at risk of peripheral arterial disease (PAD) who were 45 years of age or above and who underwent treatment at the outpatient medical clinic between June and December 2015. Patients who were followed up at the medical clinic had both oscillometric BP measurement (Terumo, ES-P600) and an automated ABI (oscillometric method) at the same time. Sensitivity, specificity, positive predictive value, and negative predictive value of the oscillometric BP measurements to predict an abnormal ABI (<0.90) were determined using the automated ABI as the gold standard. RESULTS: ABI values were similar between the two methods. The oscillometric BP method for determining an ABI (cutoff point <0.90) on the right side had a sensitivity of 88.89%, specificity of 99.32%, an accuracy of 99.01%, a positive predictive value of 80%, and a negative predictive value of 99.32% whereas ABI on the left side had a sensitivity of 69.23%, a specificity of 99.66%, an accuracy of 98.35%, a positive predictive value of 90%, and a negative predictive value of 98.63%. Reliability of the oscillometric BP method by Kappa statistics was 0.84 on the right side and 0.77 on the left side (P = 0.000). CONCLUSION: The oscillometric BP method is a reliable and useful alternative to conventional automated ABI determination in patients with no severe arterial occlusion for estimation of the prevalence and screening of PAD in primary health-care settings. PMID- 28567065 TI - The psychoneuroendocrine-immunotherapy of cancer: Historical evolution and clinical results. AB - The prognosis of the neoplastic diseases depends not only on the biogenetic characteristics of cancer cells but also on the immunological response of patients, which may influence the biological features of cancer cells themselves as well as the angiogenic processes. Moreover, the immune system in vivo is under a physiological psychoneuroendocrine (PNE) regulation, mainly mediated by the brain opioid system and the pineal gland. In more detail, the anticancer immunity is stimulated by the pineal hormone melatonin (MLT) and inhibited by the opioid system, namely, through a mu-opioid receptor. Several alterations involving the pineal endocrine function and the opioid system have been described in cancer patients, which could play a role in tumor progression itself. Therefore, the pharmacological correction of cancer progression-related anomalies could contribute to control cancer diffusion, namely, the pineal endocrine deficiency and the hyperactivity of brain opioid system. In fact, the administration of pharmacological doses of the only MLT has already been proven to prolong the 1 year survival in untreatable metastatic cancer patients. Better results may be achieved by associating other pineal indoles to MLT, mu-opioid antagonists, cannabinoids, beta-carbolines. Moreover, these neuroendocrine combinations may be successfully associated with antitumor cytokines, such as interleukin (IL)-2 and IL-12, as a PNE-immune cancer therapy as well as with antitumor plants as PNE phytotherapy of cancer in an attempt to propose possible anticancer treatments also to patients with disseminated cancer and untreatable according to the standard oncology. PMID- 28567066 TI - Level of inflammatory factors in chronic hemodialysis patients with and without cardiovascular disease. AB - BACKGROUND: Considering the existence of controversies about the predictive value of inflammatory markers for cardiovascular disease (CVD), we aimed to compare the level of high-sensitivity C-reactive protein (hs-CRP) and interlukin-6 (IL-6) level in chronic hemodialysis (HD) patients with and without CVD. MATERIALS AND METHODS: In this historical cohort study, HD patients with and without CVD disease were enrolled. The presence of CVD risk factors, level of inflammatory factors including IL-6 and hs-CRP as well as lipid levels, fasting blood sugar, and other biochemical factors were compared in two studied groups. RESULTS: During the study, eighty HD patients with (n = 40) and without (n = 40) CVD were enrolled. Diabetes was more prevalent among HD patients with CVD than those without CVD (P < 0.05). The level of IL-6 and hs-CRP were not different in two studied groups (P > 0.05). Univariate analysis of variance test indicated that there was not any significant relationship between hs-CRP and CVD (P > 0.05). CONCLUSION: The findings indicated that the level of inflammatory factors including hs-CRP and IL-6 are not significantly different in HD patients with and without CVD. However, for obtaining more definite conclusion in this field and evaluation their predicting role in this field, it is recommended to study other novel inflammatory markers as well as the additive effect of the inflammatory factors with traditional ones in larger sample size and longer follow-up. PMID- 28567067 TI - Medication adherence in patients with hypertension: Does satisfaction with doctor patient relationship work? AB - BACKGROUND: It is assumed that doctor-patient relationship plays an effective role in patients' satisfaction, medication adherence, and health outcomes since exploring different aspects of this relationship, such as addressing medication adherence, has rarely been investigated. Therefore, the main aim of the present study was to assess the impact of patients' satisfaction derived from communicating with doctors on medication adherence in hypertensive patients. MATERIALS AND METHODS: This cross-sectional survey was conducted on three hundred patients with hypertension, using multistage sampling technique in health care centers in Isfahan, Iran. Data were collected by two questionnaires comprised (1) patients' satisfaction derived from the relationship with doctors and (2) medication adherence named "Morisky Medication Adherence Scale" with 8 items. Multivariate logistic regression model was applied to test the odds ratio (OR) of patients' satisfaction resulting from the relationship with physicians in numerous aspects in two groups: appropriate and inappropriate medication adherence. RESULTS: A lower level of satisfaction derived from building the relationship (confidence interval [CI] =0.95, 0.06-0.71 and OR = 0.20) and empathy subscales (CI = 0.95, 13-0.80 and OR = 0.33) was associated with nonadherence to treatment after controlling the physicians' gender and patients' age, gender, education, and duration of disease. CONCLUSION: Patients' satisfaction resulting from building the relationship and empathy with physicians appeared to be associated with medication adherence among hypertensive patients. PMID- 28567068 TI - Serum enolase-2, high-sensitivity C-reactive protein, and serum cholesterol in smear-positive drug-naive pulmonary tuberculosis. AB - BACKGROUND: Pulmonary tuberculosis (PTB) is a chronic granulomatous disease caused by Mycobacterium tuberculosis. The present study determined the serum human enolase-2 (ENO-2), high-sensitive C-reactive protein (hs-CRP), and serum cholesterol levels as biological marker of disease activity and treatment response in smear-positive drug-naive PTB. MATERIALS AND METHODS: This case control study was done in the Department of Medicine, Liaquat University of Medical and Health Sciences (LUMHS), Jamshoro/Hyderabad, Sindh, from January 2015 to April 2016. Thirty-five sputum smear-positive drug-naive PTB patients and thirty controls were studied. MTB culture and drug sensitivity were performed at the Diagnostic and Research Laboratory of LUMHS. Serum ENO-2, hs-CRP, and serum cholesterol were estimated at baseline, 3rd and 6th month of antituberculosis (TB) therapy. RESULTS: Serum ENO-2 and hs-CRP were found raised in PTB compared to controls and showed decrease of 13% and 21.55%, 19.6% and 31.5% at 3rd and 6th month, respectively (P = 0.0001). Serum ENO-2 revealed positive correlation with hs-CRP (r = 0.734, P = 0.0001), and serum cholesterol revealed negative correlation with ENO-2 and hs-CRP (r = -0.509, P = 0.0001) and (r = -0.566, P = 0.0001), respectively. CONCLUSION: The present study reports the baseline ENO-2 and hs-CRP were raised, and serum cholesterol was low in smear-positive PTB patients and the ENO-2 and hs-CRP were reduced by anti-TB drug therapy. PMID- 28567069 TI - Evaluation of Thompson's quadricepsplasty results in patients with knee stiffness resulted from femoral fracture. AB - BACKGROUND: Posttraumatic and/or postsurgical knee stiffness is one of the orthopedic complications which is difficult to be treated and can affect individual's life negatively. The aim of this study is to investigate the results of quadricepsplasty in patients with knee stiffness resulted from femoral fracture. MATERIALS AND METHODS: This is a cross-sectional study on all patients with femoral fracture which has caused knee flexion limitation referred to Kashani and Al-Zahra Hospitals in Isfahan from January 2010 to March 2013. The type and site of fracture, joint extension, and fracture fixation technique were recorded. Moreover, the range of motion (ROM) before surgery, under general anesthesia, and 3- and 6-month postoperation were measured. RESULTS: Among the patients, 13 had a simple fracture (48%) and 14 had a segmental fracture (51.9%). Considering the fracture site, 11, 10, and 6 patients had femoral (40.74%), supracondylar (37.3%), and femoral supracondylar (22.2%) fractures, respectively. The fracture fixation was performed by the plate, external, and Wagner fixation techniques for 24 (88.9%), 2 (7.4%), and 1 (3.7%) patients, respectively. The mean ROM before operation, under general anesthesia, and 3- and 6-month postoperation were determined to be 33.15 degrees +/- 24.73 degrees , 122.60 degrees +/- 10.22 degrees , 99.63 degrees +/- 16.52 degrees , and 100.74 degrees +/- 15.67 degrees , respectively. The mean ROM value at various stages was not similar (P < 0.001). The mean changes in the ROM were 79.2 degrees +/- 24.6 degrees and 62.1 degrees +/- 19.7 degrees in the cases with simple and segmental fractures, respectively. The mean changes in the knee ROM were significantly higher in simple fractures in comparison with the segmental femoral fracture (P = 0.03). CONCLUSION: We found Thompson's quadricepsplasty may successfully increase the range of knee flexion in knee fracture and also regardless of quadriceps time. PMID- 28567070 TI - The cutting-edge training modalities and educational platforms for accredited surgical training: A systematic review. AB - BACKGROUND: Historically, operating room (OR) has always been considered as a stand-alone trusted platform for surgical education and training. However, concerns about financial constraints, quality control, and patient safety have urged the surgical educators to develop more cost-effective, surgical educational platforms that can be employed outside the OR. Furthermore, trained surgeons need to regularly update their surgical skills to keep abreast with the emerging surgical technologies. This research aimed to explore the value of currently available modern surgical tools that can be used outside the OR and also elaborates the existing laparoscopic surgical training programs in world-class centers across the globe with a view to formulate a blended and unified structured surgical training program. MATERIALS AND METHODS: Several data sources were searched using MeSH terms "Laparoscopic surgery" and "Surgical training" and "Surgical curriculum" and "fundamentals of endoscopic surgery" and "fundamentals of laparoscopic surgery" and "Telementoring" and "Box trainer." The eligibility criteria used in data extraction searched for original and review articles and by excluding the editorial articles, short communications, conference proceedings, personal view, and commentaries. Data synthesis and data analysis were done by reviewing the initially retrieved 211 articles. Irrelevant and duplicate and redundant articles were excluded from the study. RESULTS: Finally, 12 articles were selected for this systematic review. Data results showed that a myriad of cutting-edge technical innovations have provided modern surgical training tools such as the simulation-based mechanical and virtual reality simulators, animal and cadaveric labs, telementoring, telerobotic-assisted surgery, and video games. Surgical simulators allow the trainees to acquire surgical skills in a tension free environment without supervision or time constraints. CONCLUSION: The existing world-renowned surgical training centers employ various clusters of training tools that essentially endeavor to embed the acquisition of knowledge and technical skills. However, a unified training curriculum that may be accepted worldwide is currently not available. PMID- 28567071 TI - Associating liver partition and portal vein ligation for staged hepatectomy: A surgical technique for liver resections. AB - BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a novel surgical technique liver resection in traditionally nonresectable primary intrahepatic tumors or colorectal liver metastases. MATERIALS AND METHODS: From June 2013 to March 2014, patients with primary tumor of liver or colorectal tumors with liver metastasis were selected to evaluate whether they met the initial criteria for ALPPS procedure. RESULTS: Nine patients enrolled in the study with primary diagnoses of colon and rectosigmoid cancer, carcinoid tumor, gastrointestinal stromal tumor of small intestine, hepatocellular carcinoma, and pancreatic neuroendocrine tumor (PNET). Four candidates excluded from the study prior or during the first step operation due to fatty liver, hepatic fibrosis, peritoneal seeding, and multiple small intestine metastases. Five patients underwent two stages of ALPPS with the interval of about 1 week. Liver hypertrophy was 100% among our candidates after the initial step. One postoperative death happened because of massive pulmonary thromboembolism Recurrence of liver metastasis was seen in one patient. Hepatic failure Class B and A were observed in two patients which did not progress during follow-up period. One patient developed an enterocutaneous fistula. DISCUSSION: We recommend to use 2 organ bags, one for wrapping right lobe and the other one for covering visceral organs and also do liver biopsy in suspicious cases of damaged liver parenchyma and laparoscopic exploration of abdomen for seeding and multiple metastases prior to laparotomy. CONCLUSION: As the procedure has not been well established and verified by oncologists yet, further studies are required to define the exact indications of ALPPS. PMID- 28567073 TI - Quantitative assessment of Wilms tumor 1 expression by real-time quantitative polymerase chain reaction in patients with acute myeloblastic leukemia. AB - BACKGROUND: The Wilms tumor 1 (WT1) gene is originally defined as a tumor suppressor gene and a transcription factor that overexpressed in leukemic cells. It is highly expressed in more than 80% of acute myeloid leukemia (AML) patients, both in bone marrow (BM) and in peripheral blood (PB), and it is used as a powerful and independent marker of minimal residual disease (MRD); we have determined the expression levels of the WT1 by real-time quantitative polymerase chain reaction (RQ-PCR) in PB and BM in 126 newly diagnosed AML patients. MATERIALS AND METHODS: This study was done in molecular pathology and cancer research center from April 2014 to June 2015, RQ-PCR method was used to determine the WT1 gene expression in BM and/or PB samples from 126 patients of AML, we cloned both WT1 and ABL genes for creating a standard curve, and we calculate copy number of WT1 genes in patients. RESULTS: A total of 126 AML patients consist of 70 males (55.6%) and 56 females (44.4%), with a median age of 26 years; 104 (81%) patients out of 126 show overexpression of WT1 gene. We also concomitant monitoring of fusion transcripts (PML RARa, AML1-ETO, MLL-MLL, CBFb MYH11, or DEK-CAN) in our patients, the AML1-ETO group showing remarkably low levels of WT1 compared with other fusion transcript and the CBFB-MYH11 showing high levels of WT1. CONCLUSION: We conclude that WT1 expression by RQ-PCR in AML patients may be employed as an independent tool to detect MRD in the majority of normal karyotype AML patients. PMID- 28567072 TI - Hyperimmunoglobulin E syndrome: Genetics, immunopathogenesis, clinical findings, and treatment modalities. AB - The hyperimmunoglobulin E syndromes (HIESs) are very rare immunodeficiency syndromes with multisystem involvement, including immune system, skeleton, connective tissue, and dentition. HIES are characterized by the classic triad of high serum levels of immunoglobulin E (IgE), recurrent staphylococcal cold skin abscess, and recurrent pneumonia with pneumatocele formation. Most cases of HIES are sporadic although can be inherited as autosomal dominant and autosomal recessive traits. A fundamental immunologic defect in HIES is not clearly elucidated but abnormal neutrophil chemotaxis due to decreased production or secretion of interferon gamma has main role in the immunopathogenesis of syndrome, also distorted Th1/Th2 cytokine profile toward a Th2 bias contributes to the impaired cellular immunity and a specific pattern of infection susceptibility as well as atopic-allergic constitution of syndrome. The ophthalmic manifestations of this disorder include conjunctivitis, keratitis, spontaneous corneal perforation, recurrent giant chalazia, extensive xanthelasma, tumors of the eyelid, strabismus, and bilateral keratoconus. The diagnosis of HIES is inconclusive, dependent on the evolution of a constellation of complex multisystemic symptoms and signs which develop over the years. Until time, no treatment modality is curative for basic defect in HIES, in terms of cytokines/chemokines derangement. Of note, bone marrow transplant and a monoclonal anti-IgE (omalizumab) are hoped to be successful treatment in future. PMID- 28567074 TI - Knee Injury and Osteoarthritis Outcome Score in patients with isolated meniscus injury; Validity and reliability. AB - BACKGROUND: The aim of this study is evaluation of the validity and reliability of the Persian version of Knee Injury and Osteoarthritis Outcome Score (KOOS) in patients with isolated meniscus injury. MATERIALS AND METHODS: One hundred people with isolated meniscal injury (29 females and 71 males with a mean age +/- standard deviation [SD] = 32.37 +/- 9.97 years) and fifty normal people with no knee problems (34 females and 16 males with a mean age +/- SD = 28.42 +/- 8.84 years) participated in this study. In patients, the duration of meniscus injury ranged from 1 month to 4 years. For evaluation of discriminate validity, we compared scores of KOOS questionnaire between patients and healthy people, and for concurrent validity, in addition to filling KOOS questionnaire, patients completed Short Form (SF-36) questionnaire, test-retest reliability with intraclass correlation coefficient) ICC), and internal consistency with Cronbach's alpha was calculated. RESULTS: Mean scores of patients (49.51 +/- 17.13) and healthy people (86.01 +/- 13.44) were different significantly (P < 0.001). The correlation between total score of SF-36 and KOOS was significant (r = 0.77, P < 0.001). ICC was 0.80 (ranged from 0.64-0.75) and Cronbach's alpha was 0.96 (ranged from 0.72 to 0.94). CONCLUSION: The Iranian version of KOOS is a reliable and valid tool for patients with isolated meniscus injury, so the clinicians and investigators may use this questionnaire in clinical settings and their researches. PMID- 28567075 TI - Aspects of quality of life affected in morbidly obese patients who decided to undergo bariatric surgery: A qualitative study to design a native questionnaire. AB - BACKGROUND: Obesity is a known prevalent major health issue. The aim of this study is to assay Iranian patients' problems with obesity and their expectations of bariatric surgery. MATERIALS AND METHODS: In this study, we included patients who have used different medical noninvasive treatments and were unsuccessful in losing weight from the obesity clinic in Al Zahra Hospital, Isfahan, from 2014 to 2015. Morbidly obese patients were interviewed using some open-ended questions, and then, directional content analysis of data was done. RESULTS: Analysis of data showed five main categories including (1) physical health, (2) psychological health, (3) social relationships, (4) environment, and (5) "about the causes of obesity" with some subcategories for each category. CONCLUSION: This study is the first step of designing a quality of life questionnaire while we focused on spiritual and cultural states of Iranian people. PMID- 28567076 TI - Hereditary Dilated Cardiomyopathy: Recent Advances in Genetic Diagnostics. AB - Dilated cardiomyopathy (DCM) is the most common cause of heart failure in young adults and up to 50% of idiopathic DCM is thought to be caused by genetic mutations in candidate genes. Although a genetic diagnosis can confirm a clinical diagnosis of hereditary DCM, genetic testing has not been easily accessible due to genetic heterogeneity and complexity. Next-generation sequencing (NGS) technologies have recently been introduced, and genetic testing for multiple genes is currently available and more than 40 different genes have been associated with DCM. In Korea, the government has supported genetic diagnosis for patients with idiopathic DCM. When a targeted gene panel with NGS technology was used, the detection rate was about 40%. MYBPC3, LMNA, and MYH7 were the most frequently identified genes, and the pattern of causative genes was different from previous reports. In the analysis, a significant number of subjects (42.0%) had rare or novel unspecified variants in DCM candidate genes, which should be assessed as potential causative mutations. Developing a more comprehensive test panel with additional DCM genes and whole exome sequencing will improve the detection rate, and allow genetic testing to be an option for patients with idiopathic DCM. However, all genetic variations are not pathogenic mutations, and the majority of reported mutations in DCM are unique to a single family, which makes genetic data interpretation more difficult. Therefore, clinical features and familial history integration are needed to improve clinical decision making. PMID- 28567077 TI - Idiopathic Polymorphic Ventricular Tachycardia: a "Benign Disease" with a Touch of Bad Luck? AB - Ventricular extrasystole originating from the right ventricular outflow tract or the left ventricular outflow tract are the most commonly encountered ventricular arrhythmias recorded in ostensibly healthy individuals with no evidence of heart disease. These ventricular arrhythmias have a distinctive electrocardiographic morphology. The morphology is so distinctive that it is common practice to accept the diagnosis of "idiopathic benign ventricular arrhythmias from the outflow tract" based on this unique morphology when the electrocardiogram during sinus rhythm and the echocardiogram are normal, sometimes removing the need to perform invasive tests in patients. Even if the outflow ventricular extrasystole ultimately triggers sustained ventricular arrhythmia, the resulting ventricular tachycardia (VT) will be a monomorphic VT originating from the outflow tract, which is known to be hemodynamically well tolerated. Thus, idiopathic ventricular arrhythmias originating from outflow tracts are universally considered benign. In 2005, we described a rare form of malignant polymorphic VT resulting in syncope or cardiac arrest. Here, we review the literature on this topic since the emergence of initial descriptions of this intriguing phenomenon. PMID- 28567078 TI - Data Sharing: a New Editorial Initiative from the International Committee of Medical Journal Editors. Implications for the Editors' Network. AB - The International Committee of Medical Journal Editors (ICMJE) provides recommendations to improve the editorial standards and scientific quality of biomedical journals. These recommendations range from uniform technical requirements to more complex and elusive editorial issues including ethical aspects of the scientific process. Recently, registration of clinical trials, conflicts of interest disclosure, and new criteria for authorship-emphasizing the importance of responsibility and accountability-, have been proposed. This year a new editorial initiative to foster sharing of clinical trial data has been launched. This review discusses this novel initiative with the aim of increasing awareness among readers, investigators, authors and Editors of the Editors' Network of the European Society of Cardiology. PMID- 28567079 TI - Inflammation in Cardiovascular Disease. PMID- 28567080 TI - Toward a New Heart Failure Registry in Korea. PMID- 28567081 TI - PCI or CABG, That is the Question! PMID- 28567082 TI - The Practice Pattern of Percutaneous Coronary Intervention in Korea: Based on Year 2014 Cohort of Korean Percutaneous Coronary Intervention (K-PCI) Registry. AB - BACKGROUND AND OBJECTIVES: Appropriate use criteria (AUC) was developed to improve the quality of percutaneous coronary intervention (PCI). However, these criteria should consider the current practice pattern in the country where they are being applied. MATERIALS AND METHODS: The algorithm for the Korean PCI practice pattern (KP3) was developed by modifying the United States-derived AUC in expert consensus meetings. KP3 class A was defined as any strategy with evidence from randomized trials that was more conservative for PCI than medical therapy or coronary artery bypass graft (CABG). Class C was defined as any strategy with less evidence from randomized trials and more aggressive for PCI than medical therapy or CABG. Class B was defined as a strategy that was partly class A and partly class C. We applied the KP3 classification system to the Korean PCI registry. RESULTS: The KP3 class A was noted in 67.7% of patients, class B in 28.8%, and class C in 3.5%. The median proportion of class C cases per center was 2.0%. The distribution of KP3 classes varied significantly depending on clinical and angiographic characteristics. The proportion of KP3 class C cases per center was not significantly dependent on PCI volume, but rather on the percentage of ACS cases in each center. CONCLUSION: We report the current PCI practice pattern by applying the new KP3 classification in a nationwide PCI registry. The results should be interpreted carefully with due regard for the complex relationships between the determining variables and the healthcare system in Korea. PMID- 28567083 TI - The Current Status of Percutaneous Coronary Intervention in Korea: Based on Year 2014 Cohort of Korean Percutaneous Coronary Intervention (K-PCI) Registry. AB - BACKGROUND AND OBJECTIVES: Although several multicenter registries have evaluated percutaneous coronary intervention (PCI) procedures in Korea, those databases have been limited by non-standardized data collection and lack of uniform reporting methods. We aimed to collect and report data from a standardized database to analyze PCI procedures throughout the country. MATERIALS AND METHODS: Both clinical and procedural data, as well as clinical outcomes data during hospital stay, were collected based on case report forms that used a standard set of 54 data elements. This report is based on 2014 Korean PCI registry cohort data. RESULTS: A total of 92 hospitals offered data on 44967 PCI procedures. The median age was 66.0 interquartile range 57.0-74.0 years, and 70.3% were men. Thirty-eight percent of patients presented with acute myocardial infarction and one-third of all PCI procedures were performed in an urgent or emergency setting. Non-invasive stress tests were performed in 13.9% of cases, while coronary computed tomography angiography was used in 13.7% of cases prior to PCI. Radial artery access was used in 56.1% of all PCI procedures. Devices that used PCI included drug-eluting stent, plain old balloon angioplasty, drug-eluting balloon, and bare-metal stent (around 91%, 19%, 6%, and 1% of all procedures, respectively). The incidences of in-hospital death, non-fatal myocardial infarction, and stroke were 2.3%, 1.6%, and 0.2%, respectively. CONCLUSION: These data may provide an overview of the current PCI practices and in-hospital outcomes in Korea and could be used as a foundation for developing treatment guidelines and nationwide clinical research. PMID- 28567084 TI - Clinical Characteristics and Outcome of Acute Heart Failure in Korea: Results from the Korean Acute Heart Failure Registry (KorAHF). AB - BACKGROUND AND OBJECTIVES: The burden of heart failure has increased in Korea. This registry aims to evaluate demographics, clinical characteristics, management, and long-term outcomes in patients hospitalized for acute heart failure (AHF). SUBJECTS AND METHODS: We prospectively enrolled a total of 5625 consecutive subjects hospitalized for AHF in one of 10 tertiary university hospitals from March 2011 to February 2014. Descriptive statistics were used to determine the baseline characteristics of the study population and to compare them with those from other registries. RESULTS: The mean age was 68.5+/-14.5 years, 53.2% were male, and 52.2% had de novo heart failure. The mean systolic and diastolic blood pressures were 131.2+/-30.3 mmHg and 78.6+/-18.8 mmHg at admission, respectively. The left ventricular ejection fraction was <=40% in 60.5% of patients. Ischemia was the most frequent etiology (37.6%) and aggravating factor (26.3%). Angiotensin converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers, and aldosterone antagonists were prescribed in 68.8%, 52.2%, and 46.6% of the patients at discharge, respectively. Compared with the previous registry performed in Korea a decade ago, extracorporeal membrane oxygenation (ECMO) and heart transplantation have been performed more frequently (ECMO 0.8% vs. 2.8%, heart transplantation 0.3% vs. 1.2%), and in-hospital mortality decreased from 7.6% to 4.8%. However, the total cost of hospital care increased by 40%, and one-year follow-up mortality remained high. CONCLUSION: While the quality of acute clinical care and AHF-related outcomes have improved over the last decade, the long-term prognosis of heart failure is still poor in Korea. Therefore, additional research is needed to improve long-term outcomes and implement cost-effective care. PMID- 28567085 TI - Coronary Artery Bypass Grafting vs. Drug-Eluting Stent Implantation for Multivessel Disease in Patients with Chronic Kidney Disease. AB - BACKGROUND AND OBJECTIVES: There is currently a limited amount of data that demonstrate the optimal revascularization strategy for chronic kidney disease (CKD) patients with multivessel coronary artery disease (CAD). We compared the long-term outcomes of percutaneous coronary intervention (PCI) with drug-eluting stents (DES) versus coronary artery bypass graft surgery (CABG) for multivessel CAD in patients with CKD. SUBJECTS AND METHODS: We analyzed 2108 CKD patients (estimated glomerular filtration rate <60 mL/min/1.73 m2) with multivessel CAD that were treated with PCI with DES (n=1165) or CABG (n=943). The primary outcome was a composite of all causes of mortality, myocardial infarction, or stroke. The mean age was 66.9+/-9.1 years. RESULTS: Median follow-up duration was 41.4 (interquartile range 12.1-75.5) months. The primary outcome occurred in 307 (26.4%) patients in the PCI group compared with 304 (32.2%) patients in the CABG group (adjusted hazard ratio [HR], 0.941; 95% confidence interval [CI], 0.79 1.12; p=0.493). The two groups exhibited similar rates of all-cause mortality (adjusted HR, 0.91; 95% CI, 0.77-1.09; p=0.295), myocardial infarction (adjusted HR, 1.86; 95% CI, 0.85-4.07; p=0.120) and stroke (3.2% vs. 4.8%; HR, 0.93; 95% CI, 0.57-1.61; p=0.758). However, PCI was associated with significantly increased rates of repeat revascularization (adjusted HR, 4.72; 95% CI, 3.20-6.96; p<0.001). CONCLUSION: Among patients with CKD and multivessel CAD, PCI with DES when compared with CABG resulted in similar rates of composite outcome of mortality from any cause, MI, or stroke; however, a higher risk of repeat revascularization was observed. PMID- 28567086 TI - Predicting Intermittent Atrial Fibrillation in Outpatient Clinics. AB - BACKGROUND AND OBJECTIVES: Palpitations are the most common complaint in cardiology outpatient clinics. These palpitations may be derived from paroxysmal atrial fibrillation (AF) and can be easily overlooked. It is unclear whether inter-atrial conduction time (ICT) may predict the paroxysmal AF in out-patients that present with palpitations. We evaluated the ability of the ICT to predict paroxysmal AF in these patients. SUBJECTS AND METHODS: The study group consisted of 199 patients (110 female). All patients underwent 24-hour Holter electrocardiogram (ECG) monitoring (total of 327 Holter ECG monitorings, mean: 1.64 times per patient). Brief episodes of AF were documented in 35 patients (20 female, Group 1). The remaining patients without AF were designated as Group 2 (90 female). All patients underwent routine transthoracic echocardiographic examination. ICT was also measured by echocardiography. RESULTS: The mean age in Group 1 was greater than in Group 2 (63.02+/-14 vs. 51.27+/-16 years, p<0.001). The left atrium was larger in Group 1 than in Group 2 (39.7+/-3.4 vs. 37.29+/-4.3 mm, p<0.001). The other echocardiographic variables were comparable between the two groups. The mean ICT was significantly higher in Group 1 than in Group 2 (138+/-14 vs. 114+/-12 msn, p<0.001). The ICT of 127 ms was predictive for AF with a sensitivity of 86% and specificity of 87% (p<0.001). CONCLUSION: Our findings show that ICT was prolonged in patients with palpitations who developed a brief episode of AF in Holter ECG monitoring. ICT prolongation may be used to identify patients with palpitation that are at risk of an AF episode. Holter ECG monitoring should be repeated to detect AF episodes in patients with prolonged ICT. PMID- 28567087 TI - Antiplatelet Therapy Combinations and Thrombogenicity in Patients with Non Valvular Atrial Fibrillation. AB - BACKGROUND AND OBJECTIVES: Combination antiplatelet therapy reduces the risk of ischemic stroke compared with aspirin monotherapy in non-valvular atrial fibrillation (NVAF) patients. The underlying mechanism, however, remains unclear. In addition, the association between platelet inhibition and thrombogenicity in NVAF has not been evaluated. SUBJECTS AND METHODS: We randomized 60 patients with NVAF that were taking 100 mg of aspirin daily (>1 month) to adding 75 mg of clopidogrel daily (CLPD group), 100 mg of cilostazol twice daily (CILO group), or 1000 mg of omega-3 polyunsaturated fatty acid twice daily (PUFA group). Biomarkers (von Willebrand factor antigen [vWF:Ag], fibrinogen, D-dimer, and high sensitivity C-reactive protein [hs-CRP]) and platelet reactivity (PR), which were the levels stimulated by adenosine diphosphate (ADP), thrombin-receptor agonist peptide, collagen, and arachidonic acid, were measured at baseline and 30-day follow-up. RESULTS: Combination antiplatelet therapy significantly reduced vWF:Ag and fibrinogen levels (7.7 IU/dL, p=0.015 and 15.7 mg/dL, p=0.005, respectively), but no changes were found in D-dimer and hs-CRP levels. The CLPD and CILO groups showed fibrinogen and vWF:Ag level reductions (24.9 mg/dL, p=0.015 and 9.3 IU/dL, p=0.044, respectively), whereas the PUFA group did not show any differences in biomarkers. Irrespective of regimen, the changes in fibrinogen and vWF:Ag levels were mainly associated with the change in ADP-mediated PR (r=0.339, p=0.008 and r=0.322, p=0.012, respectively). CONCLUSION: In patients with NVAF, combination antiplatelet therapy showed reductions for vWF:Ag and fibrinogen levels, which may be associated with the inhibitory levels of ADP-mediated PR. The clinical implications of these findings need to be evaluated in future trials. PMID- 28567088 TI - Changes in 11beta-Hydroxysteroid Dehydrogenase and Glucocorticoid Receptor Expression in Kawasaki Disease. AB - BACKGROUND AND OBJECTIVES: This study aims to investigate the significance of changes in the expression 11beta-hydroxysteroid dehydrogenase (11beta-HSD) and glucocorticoid receptor (GR) for the development of Kawasaki disease (KD). SUBJECTS AND METHODS: Real-time polymerase chain reaction was performed to determine the mRNA expression levels of GR and 11beta-HSD in peripheral blood monocytes, both in the acute phase of the disease and after treatment. Western blotting was performed to determine the protein expression levels of GR and 11beta-HSD. RESULTS: The expression levels of GRbeta, GRbeta, and 11beta-HSD1 mRNA in the acute phase were significantly higher than levels at baseline (p<0.01) and after treatment (p<0.05). The 11beta-HSD2 mRNA levels were lower in the acute phase than in the normal group (p<0.01), and they were significantly higher after treatment than before (p<0.01). Western blot results were consistent with the real-time PCR results. The coronary artery lesion group exhibited significantly different 11beta-HSD2 expression levels from that of the group with normal coronary arteries (p<0.01). CONCLUSION: GR and 11beta-HSD expression changes in the acute phase of KD are important factors for regulating inflammatory responses in KD. PMID- 28567089 TI - Combined Use of Neutrophil to Lymphocyte Ratio and C-Reactive Protein Level to Predict Clinical Outcomes in Acute Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention. AB - BACKGROUND AND OBJECTIVES: Both neutrophil to lymphocyte ratio (NLR) and C reactive protein (CRP) are biomarkers associated with poor prognosis of patients with acute myocardial infarction (AMI). However, the combined usefulness of NLR and CRP in predicting adverse outcomes has not been investigated. SUBJECTS AND METHODS: We analyzed 381 consecutive AMI patients who underwent percutaneous coronary intervention (PCI) from January 2012 to January 2014. The endpoints were all-cause mortality, recurrent myocardial infarction (MI), stent thrombosis, repeat revascularization, stroke, and major adverse cardiac and cerebrovascular events (MACCE) at 2-year follow-up. Included patients were divided into 4 groups according to the optimal cut-off values for NLR and CRP on receiver operating characteristic analysis predicting mortality. RESULTS: Patients with both high NLR (>6.30) and high CRP (>0.76) had significantly greater risk of all-cause death and MACCE at 24 months, with no significant increase in the risk of recurrent MI, stent thrombosis, or stroke compared with patients with either low NLR or low CRP, as well as those with low NLR and low CRP. Kaplan-Meier analysis revealed significantly lower survival in patients with high NLR-CRP. On Cox multivariate analysis, high NLR-CRP (hazard ratio 23.172, 95% confidence interval 6.575 to 81.671, p<0.001) was an independent predictor of all-cause death. CONCLUSION: Elevated levels of both NLR and CRP are associated with increased risk of long-term mortality in AMI patients who have undergone PCI. PMID- 28567090 TI - Expression of Class I and Class II a/b Histone Deacetylase is Dysregulated in Hypertensive Animal Models. AB - BACKGROUND AND OBJECTIVES: Dysregulation of histone deacetylase expression and enzymatic activity is associated with a number of diseases. It has been reported that protein levels of histone deacetylase (HDAC)1 and HDAC5 increase during human pulmonary hypertension, and that the enzymatic activity of HDAC6 is induced in a chronic hypertensive animal model. This study investigated the protein expression profiles of class I and II a/b HDACs in three systemic hypertension models. SUBJECTS AND METHODS: We used three different hypertensive animal models: (i) Wistar-Kyoto rats (n=8) and spontaneously hypertensive rats (SHR; n=8), (ii) mice infused with saline or angiotensin II to induce hypertension, via osmotic mini-pump for 2 weeks, and (iii) mice that were allowed to drink L-NG-nitro-L arginine methyl ester (L-NAME) to induce hypertension. RESULTS: SHR showed high systolic, diastolic, and mean blood pressures. Similar increases in systolic blood pressure were observed in angiotensin II or L-NAME-induced hypertensive mice. In SHR, class IIa HDAC (HDAC4, 5, and 7) and class IIb HDAC (HDAC6 and 10) protein expression were significantly increased. In addition, a HDAC3 protein expression was induced in SHR. However, in L-NAME mice, class IIa HDAC protein levels (HDAC4, 5, 7, and 9) were significantly reduced. HDAC8 protein levels were significantly reduced both in angiotensin II mice and in SHR. CONCLUSION: These results indicate that dysregulation of class I and class II HDAC protein is closely associated with chronic hypertension. PMID- 28567091 TI - Effect of Rosuvastatin on Bovine Pericardial Aortic Tissue Valve Calcification in a Rat Subdermal Implantation Model. AB - BACKGROUND AND OBJECTIVES: There are pathophysiologic similarities between calcification and atherosclerosis because both are the product of an active inflammatory process. The aim of this study was to examine the effects of statin treatment on calcification in bovine pericardial tissue valves. MATERIALS AND METHODS: Forty Sprague-Dawley rats were randomly divided into 4 groups according to hypercholesterolemia induction and statin intake (Group 1, n=10: normal diet without statin treatment, Group 2, n=10: normal diet with statin treatment, Group 3, n=10: high fat diet without statin treatment, Group 4, n=10: high fat diet with statin treatment). Serum lipid levels were measured just before the experiment and after 4 and 12 weeks. Bovine pericardial tissue valve cusps were surgically implanted in rat dorsal subcutis at 4 weeks. After the surgery, statin was administered daily to Groups 2 and 4. Serum interleukin-6 (IL-6) level was measured at 5 weeks. Cusps were explanted at 12 weeks and calcium levels were determined by atomic absorption spectroscopy. RESULTS: Mean IL-6 was significantly higher in Group 3 at 5 weeks (7.14, 2.03, 31.70, and 6.90 pg/dL for each group, respectively). Mean calcium level in Group 3 was significantly higher among groups but Group 4 was significantly lower compared to Group 3 and was similar to Group 1, 2 (1.86, 1.92, 2.55, and 1.80 mg/g for each group, respectively, p<0.01). CONCLUSION: Hypercholesterolemia may be a significant risk factor for bovine pericardial valve calcification. Statin treatment significantly attenuated calcification of bovine pericardial valve tissue in a rat subdermal implantation model and might prolong the durability of bioprostheses. PMID- 28567092 TI - Additive Role of Coronary Magnetic Resonance Angiography for the Evaluation of Coronary Artery Disease. AB - Coronary magnetic resonance angiography (CMRA) allows a noninvasive assessment of the coronary anatomy without exposing the patients to radiation. It is also superior to coronary computed tomography angiography (CCTA) for the evaluation of luminal narrowing in heavily calcified coronary segments. We report a case with triple-vessel disease, but it could not be accurately assessed by CCTA because of calcification and lack of a significant perfusion defect or myocardial scarring on cardiac magnetic resonance imaging (MRI). However, whole-heart CMRA performed as part of the cardiac MRI protocol demonstrated significant triple-vessel disease with left main involvement, confirmed by subsequent invasive angiography with a fractional flow reserve measurement. PMID- 28567093 TI - Cardiomyopathies with Mixed and Inapparent Morphological Features in Cardiac Troponin I3 Mutation. AB - The fact that different types of cardiomyopathies can be manifested by the same sarcomere protein gene mutation in a single family is well known. However, mixed features of different types of cardiomyopathies in a single patient have not been well appreciated. We identified a novel mutation in cardiac troponin I3 (Arg186Gly) in the present case, and two of the family members showed mixed morphologic features of hypertrophic cardiomyopathy and left ventricular non compaction. Moreover, both the features of cardiomyopathies were not apparent for each type of cardiomyopathy. In the patient's family, four other members had unexpected deaths before the age of 30. PMID- 28567095 TI - Embolic Myocardial Infarction in a Patient with Massive Pulmonary Thromboembolism. PMID- 28567094 TI - A Giant Isolated Cardiac Hydatid Cyst in the Interventricular Septum. PMID- 28567096 TI - Invasive Aspergillosis of the Abdominal Aorta with Multiple Peripheral Embolic Lesions. PMID- 28567097 TI - The Antigastric Cancer Activity of San Leng Powder Extract Induces Apoptosis in Balb/C Bearing-SGC-7901 Mice. AB - San Leng powder extract has been used as medicinal compound for the prevention and treatment of cancers. The antitumor activity of SLPE was determined by treating BALB/C mice harboring a human gastric cancer xenograft with SPLE for 17 days. Mice were also treated with fluorouracil (5-Fu, 25 mg/kg) or a combination of SLPE and 5-Fu. Our results indicate that the inhibition of tumor growth by SLPE might be due to a block in the cell cycle and the induction of apoptosis. These results suggest that SLPE might be useful in the treatment of gastric cancer. PMID- 28567100 TI - Editorial. PMID- 28567098 TI - Barley Seedling Extracts Inhibit RANKL-Induced Differentiation, Fusion, and Maturation of Osteoclasts in the Early-to-Late Stages of Osteoclastogenesis. AB - The number of patients with osteoporosis is increasing worldwide, and a decrease in bone mass is a main risk factor for fracture. The prevention of bone loss is critical for improving the quality of life for patients. However, the long-term use of antiosteoporotic agents is limited due to their side effects. Barley has been traditionally ingested for thousands of years as a safe, natural food with pharmaceutical properties, and its seedling can enhance the biological activity of the medicinal components found in food. This study aimed to clarify the antiresorptive activity of barley seedling and its mode of action. Barley seedling extracts (BSE) dose-dependently inhibited RANKL-induced osteoclast differentiation with alteration of IkappaB degradation, c-Fos, and NFATc1 molecules in the early-to-middle stages of osteoclastogenesis. In the late phase of osteoclastogenesis, BSE also prevented DC-STAMP and cathepsin K, which are required for cell fusion and bone degradation, such as osteoclast function. In conclusion, barley seedling from natural foods may provide long-term safety and be useful for the prevention or treatment of osteoclast-mediated bone metabolic diseases, including osteoporosis. PMID- 28567099 TI - A Chinese Medicine Formula "Xian-Jia-Tang" for Treating Bladder Outlet Obstruction by Improving Urodynamics and Inhibiting Oxidative Stress through Potassium Channels. AB - The aim of this study is to investigate efficacy of a traditional Chinese medicine formula (named Xian-Jia-Tang, XJT) on bladder outlet obstruction (BOO) in rats and explore its mechanisms. Total 80 BOO model rats were established and randomly divided into 4 groups: physiological saline, XJT, Cesium Chloride (CC), and XJT and CC groups. Meanwhile, 12 rats were used as normal control. Bladder weight and urodynamics were measured. Oxidative stress level and mRNA expressions of potassium channels gene were detected in detrusor. The mRNA and protein levels of hypoxia inducible factor-alpha (HIF-alpha) in detrusor were detected by RT-PCR and Western blot. BOO model rats showed significantly higher bladder weight and abnormal urodynamics. XJT significantly improved the abnormal urodynamics and inhibited the oxidative stress and changes of mRNA levels of potassium channels genes in detrusor of BOO model rats. Moreover, KATP and SK2/3 mRNA were overexpressed in BOO model rats treated by XJT. Besides, the significantly increased levels of HIF-alpha mRNA and protein were also inhibited by XJT. However, these inhibition effects of XJT were weakened by CC. XJT could effectively improve the urodynamics and inhibit the oxidative stress caused by hypoxia through suppressing the role of potassium channels in BOO model rats. PMID- 28567101 TI - Ascites matters. AB - The excess accumulation of intra-peritoneal fluid, referred to as ascites, is an important clue that points to a significant underlying illness. This may be due to a pathological event within the peritoneal cavity or secondary to an underlying systemic condition. Ascites is broadly classified into transudate and exudate, based on protein content, with a potential wide range of differential diagnoses. Traditionally, computed tomography has been regarded as the imaging modality of choice to demonstrate ascites and diagnose the underlying cause. However, ultrasound can reliably detect small volumes of fluid and is a useful first-line imaging modality for clinical triage. For instance, in the emergency setting, the detection of a trace of ascites may be the earliest indicator of an acute abdomen needing surgery. Ultrasound can quantify the volume of ascites and aid in the decision process for fluid drainage. Ultrasound is superior to computed tomography in the qualitative assessment of fluid. Broadly, simple fluid is anechoic, whereas complex fluid may appear particulate, layered or contain septations. On computed tomography, both have a uniform hypo-dense appearance and are often indistinguishable. Given ultrasound, in comparison to computed tomography, is safe, relatively inexpensive and readily available, it is a valuable tool in the assessment of ascites. Once ascites is detected on ultrasound, it is imperative for the operator to have a systematic approach to attempt to provide an underlying diagnosis. Through a series of cases, this article aims to increase awareness and reaffirm the role of ultrasound in the assessment of ascites. PMID- 28567102 TI - Neonatal respiratory distress syndrome: Chest X-ray or lung ultrasound? A systematic review. AB - BACKGROUND AND AIM: Neonatal respiratory distress syndrome is a leading cause of morbidity in preterm new-born babies (<37 weeks gestation age). The current diagnostic reference standard includes clinical testing and chest radiography with associated exposure to ionising radiation. The aim of this review was to compare the diagnostic accuracy of lung ultrasound against the reference standard in symptomatic neonates of <=42 weeks gestation age. METHODS: A systematic search of literature published between 1990 and 2016 identified 803 potentially relevant studies. Six studies met the review inclusion criteria and were retrieved for analysis. Quality assessment was performed before data extraction and meta analysis. RESULTS: Four prospective cohort studies and two case control studies included 480 neonates. All studies were of moderate methodological quality although heterogeneity was evident across the studies. The pooled sensitivity and specificity of lung ultrasound were 97% (95% confidence interval [CI] 94-99%) and 91% (CI: 86-95%) respectively. False positive diagnoses were made in 16 cases due to pneumonia (n = 8), transient tachypnoea (n = 3), pneumothorax (n = 1) and meconium aspiration syndrome (n = 1); the diagnoses of the remaining three false positive results were not specified. False negatives diagnoses occurred in nine cases, only two were specified as air-leak syndromes. CONCLUSIONS: Lung ultrasound was highly sensitive for the detection of neonatal respiratory distress syndrome although there is potential to miss co-morbid air-leak syndromes. Further research into lung ultrasound diagnostic accuracy for neonatal air-leak syndrome and economic modelling for service integration is required before lung ultrasound can replace chest radiography as the imaging component of the reference standard. PMID- 28567103 TI - Can breast ultrasound reduce patient's level of anxiety and pain? AB - BACKGROUND: Breast pain is one of the most common complaints of women attending a gynecology clinic and general practitioners. This pain can cause anxiety and, consequently, reduce the woman's quality of life. The objective of this study was to assess the severity of pain and anxiety in patients with breast pain and normal examination, before and after breast sonography. MATERIALS AND METHODS: Among the patients with breast pain and normal examination who came for breast sonography in three centers in Shiraz during 2011-2012, 51 patients agreed to cooperate in this project. These patients filled out the questionnaire for evaluation of pain and anxiety before and after breast sonography. RESULTS: Sonography findings indicated that 88% of patients have normal sonography without any finding. The average amounts of pain severity before and after sonography were 3.3 and 2.4, respectively (p < 0.005). The average amounts of anxiety severity in patients before and after sonography were 51.9 and 37.9, respectively (p < 0.005). CONCLUSION: This study shows the severity of pain and anxiety after ultrasonography decreased significantly. It can be concluded that ultrasound findings, which reassure the patients that they do not have specific pathology, can reduce the pain and anxiety by its impact on psychological status of the patient. PMID- 28567104 TI - The diagnostic performance of leak-plugging automated segmentation versus manual tracing of breast lesions on ultrasound images. AB - PURPOSE: To assess the diagnostic performance of a leak-plugging segmentation method that we have developed for delineating breast masses on ultrasound images. MATERIALS AND METHODS: Fifty-two biopsy-proven breast lesion images were analyzed by three observers using the leak-plugging and manual segmentation methods. From each segmentation method, grayscale and morphological features were extracted and classified as malignant or benign by logistic regression analysis. The performance of leak-plugging and manual segmentations was compared by: size of the lesion, overlap area (Oa ) between the margins, and area under the ROC curves (Az ). RESULTS: The lesion size from leak-plugging segmentation correlated closely with that from manual tracing (R2 of 0.91). Oa was higher for leak plugging, 0.92 +/- 0.01 and 0.86 +/- 0.06 for benign and malignant masses, respectively, compared to 0.80 +/- 0.04 and 0.73 +/- 0.02 for manual tracings. Overall Oa between leak-plugging and manual segmentations was 0.79 +/- 0.14 for benign and 0.73 +/- 0.14 for malignant lesions. Az for leak plugging was consistently higher (0.910 +/- 0.003) compared to 0.888 +/- 0.012 for manual tracings. The coefficient of variation of Az between three observers was 0.29% for leak plugging compared to 1.3% for manual tracings. CONCLUSION: The diagnostic performance, size measurements, and observer variability for automated leak-plugging segmentations were either comparable to or better than those of manual tracings. PMID- 28567105 TI - Cerebral haemodynamics in early puerperium: A prospective study. AB - AIM: Prospective study on 900 consecutive puerperae to assess normal values and range of the blood flow velocity in the middle cerebral artery in both hemispheres. MATERIAL AND METHOD: M1 and M2 segments of both middle cerebral arteries were assessed in all subjects within 96 hours of delivery. Mean flow velocity was recorded after adjusting for insonation angle. Lindegaard index (LI = middle cerebral artery-Internal Carotid Artery mean flow velocity ratio) was calculated whenever the mean flow velocity exceeded 100 cm/second. Asymmetry indexes were calculated inter hemispherically for M1 and M2 segments separately. RESULTS: Mean flow velocities were 74 +/- 17 and 72 +/- 17 in right and 73 +/- 17 and 72 +/- 17 cm/second in the left M1 and M2, respectively. A total of 136 subjects (12.1%) exceeded the threshold of 100 cm/second, but LI was consistently <3 in all of them. Mean flow velocity was inversely and independently correlated to haemoglobin levels and to parity. Mean asymmetry indexes were 0.25 +/- 23 in M1 and 0.45 +/- 25 in M2. CONCLUSION: Mean flow velocity in the middle cerebral artery of healthy subjects in early puerperium is higher than in age-matched non puerperal women and may exceed the threshold of 100 cm/second with no evidence of intracranial spasm, because of blood loss during delivery. Mean flow velocity is independently correlated with parity. Right-to-left mean flow velocity asymmetry may reach 50% as a consequence of a transient imbalance in vascular tone regulation. PMID- 28567106 TI - Antenatal ultrasonography findings and magnetic resonance imaging in a case of Pena-Shokeir phenotype. AB - Pena-Shokeir phenotype is a lethal anomaly characterized by neurogenic arthrogryposis, craniofacial anomalies, and pulmonary hypoplasia. This syndrome should be distinguished from trisomy 18 and arthrogryposis multiplex congenita for better counseling and establishing fetal prognosis. We present the case of a pregnant woman diagnosed with a Pena-Shokeir phenotype affected fetus at 24 weeks of gestation. Prenatal ultrasonography and fetal magnetic resonance imaging detected persistent hyperextension of the lumbar spine, micrognathia, absent septum pellucidum, and all characteristic features of Pena-Shokeir phenotype. Karyotyping was performed to exclude fetal chromosomal anomalies. Antenatal ultrasonography is an essential tool in the diagnosis of Pena-Shokeir phenotype while fetal magnetic resonance imaging is necessary to identify any associated anomalies of central nervous system. PMID- 28567107 TI - A case of adult intussusception with greyscale, contrast-enhanced ultrasound and computerised tomography correlation. AB - Intussusception is often misdiagnosed as a cause of bowel ischemia and obstruction among adults due to its relatively rare presentation outside of the paediatric population. Ultrasound is often the first-line investigation for non specific abdominal pain and can identify the presence of intussusception. In the adult population, it is essential to evaluate for causes and consequences of intussusception; as a result, computerised tomography is often deemed necessary. However, contrast-enhanced ultrasound allows for evaluation of potential causes and complications, including a neoplastic lead point and ischaemia of the bowel, whilst avoiding ionising radiation or nephrotoxic iodinated contrast. We report a case of adult intussusception with a polyp lead point with ultrasound, contrast enhanced ultrasound and computerised tomography correlation. PMID- 28567109 TI - Ultrasound-guided fine-needle aspiration of hyperenhancing lesion suspicious for pancreatic neuroendocrine tumor in the tail of pancreas-potential pitfalls. PMID- 28567110 TI - Indian visceral leishmaniasis with extensive lymphadenopathy - An unusual presentation: A case report with literature review. AB - Visceral leishmaniasis (VL), also known as kala-azar, is a life-threatening systemic disease caused by the obligate intracellular protozoan, Leishmania, and transmitted to humans by the female phlebotomine sand fly (Phlebotomus argentipes). The disease is fatal, if left untreated. We report a case of a patient clinically suspected of disseminated tuberculosis, but fine needle aspiration cytology of cervical and axillary lymph nodes yielded a diagnosis of leishmaniasis. Diagnosis of VL was challenging as the disease closely mimicked tuberculosis in the setting of extensive lymphadenopathy including conglomerate of mesenteric lymph nodes, on and off fever, and granulomatous lymphadenitis on aspiration. Bone marrow examination was further performed. A detailed workup revealed patient to be severely immunocompromised and newly diagnosed human immunodeficiency virus (HIV) positive. Worldwide, India has the largest number of VL cases, accounting for 40%-50% of world's disease burden and the second largest HIV-infected population, accounting for approximately 10% of the global disease burden. HIV increases the risk of developing VL by 100-2320 times in endemic areas and concurrently VL promotes the clinical progression of HIV disease. Co infection with HIV alters the body's immune response to leishmaniasis thus leading to unusual presentations. This case highlights the diagnostic problem in the aforesaid setting. Moreover, co-infection with HIV in VL can be a potential source of drug resistance. An early diagnosis and intensified treatment is the key to patient management. PMID- 28567111 TI - Cytomorphologic features distinguishing Bethesda category IV thyroid lesions from parathyroid. AB - BACKGROUND: Thyroid follicular cells share similar cytomorphological features with parathyroid. Without a clinical suspicion, the distinction between a thyroid neoplasm and an intrathyroidal parathyroid can be challenging. The aim of this study was to assess the distinguishing cytomorphological features of parathyroid (including intrathyroidal) and Bethesda category IV (Beth-IV) thyroid follicular lesions, which carry a 15%-30% risk of malignancy and are often followed up with surgical resection. METHODS: A search was performed to identify "parathyroid" diagnoses in parathyroid/thyroid-designated fine-needle aspirations (FNAs) and Beth-IV thyroid FNAs (follicular and Hurthle cell), all with diagnostic confirmation through surgical pathology, immunocytochemical stains, Afirma(r) analysis, and/or clinical correlation. Unique cytomorphologic features were scored (0-3) or noted as present versus absent. Statistical analysis was performed using R 3.3.1 software. RESULTS: We identified five FNA cases with clinical suspicion of parathyroid neoplasm, hyperthyroidism, or thyroid lesion that had an eventual final diagnosis of the parathyroid lesion (all female; age 20-69 years) and 12 Beth-IV diagnoses (11 female, 1 male; age 13-64 years). The following cytomorphologic features are useful distinguishing features (P value): overall pattern (0.001), single cells (0.001), cell size compared to red blood cell (0.01), nuclear irregularity (0.001), presence of nucleoli (0.001), nuclear to-cytoplasmic ratio (0.007), and nuclear chromatin quality (0.028). CONCLUSIONS: There are cytomorphologic features that distinguish Beth-IV thyroid lesions and (intrathyroidal) parathyroid. These features can aid in rendering correct diagnoses and appropriate management. PMID- 28567112 TI - Box-Counting Method of 2D Neuronal Image: Method Modification and Quantitative Analysis Demonstrated on Images from the Monkey and Human Brain. AB - This study calls attention to the difference between traditional box-counting method and its modification. The appropriate scaling factor, influence on image size and resolution, and image rotation, as well as different image presentation, are showed on the sample of asymmetrical neurons from the monkey dentate nucleus. The standard BC method and its modification were evaluated on the sample of 2D neuronal images from the human neostriatum. In addition, three box dimensions (which estimate the space-filling property, the shape, complexity, and the irregularity of dendritic tree) were used to evaluate differences in the morphology of type III aspiny neurons between two parts of the neostriatum. PMID- 28567113 TI - Research Ethics Governance in Times of Ebola. AB - The Medecins Sans Frontieres (MSF) ethics review board (ERB) has been solicited in an unprecedented way to provide advice and review research protocols in an 'emergency' mode during the recent Ebola epidemic. Twenty-seven Ebola-related study protocols were reviewed between March 2014 and August 2015, ranging from epidemiological research, to behavioural research, infectivity studies and clinical trials with investigational products at (very) early development stages. This article examines the MSF ERB's experience addressing issues related to both the process of review and substantive ethical issues in this context. These topics include lack of policies regarding blood sample collection and use, and engaging communities regarding their storage and future use; exclusion of pregnant women from clinical and vaccine trials; and the difficulty of implementing timely and high-quality qualitative/anthropological research to consider potential upfront harms. Having noticed different standards across ethics committees (ECs), we propose that when multiple ethics reviews of clinical and vaccine trials are carried out during a public health emergency they should be accompanied by transparent communication between the ECs involved. The MSF ERB experience should trigger a broader discussion on the 'optimal' ethics review in an emergency outbreak and what enduring structural changes are needed to improve the ethics review process. PMID- 28567114 TI - A randomized, double-blind study to evaluate the acid-inhibitory effect of vonoprazan (20 mg and 40 mg) in patients with proton-pump inhibitor-resistant erosive esophagitis. AB - BACKGROUND: Standard treatment for patients with erosive esophagitis (EE) is proton-pump inhibitors (PPIs), but some patients are resistant to PPIs. We aimed to evaluate the acid-inhibitory effects and efficacy of a novel potassium competitive acid blocker (vonoprazan) in patients with PPI-resistant EE. METHODS: This randomized, double-blind, multicenter study of vonoprazan evaluated gastric and esophageal pH over a 24-hour period as the primary endpoint and EE healing rate as the secondary endpoint. Following a 7 to 14-day run-in period (lansoprazole 30 mg treatment), patients with endoscopically confirmed PPI resistant EE received vonoprazan 20 mg or 40 mg for 8 weeks. RESULTS: Patients were randomized to receive vonoprazan 20 mg (n = 9) or 40 mg (n = 10). Over a 24 hour period; both groups showed a significant increase from baseline in the percentage of time gastric pH >= 4, referred to as pH 4 holding time ratio (HTR): an increase from 73.21% to 96.46% in the 20 mg group, and from 69.97% to 100.00% in the 40 mg group. Increases from baseline in esophageal pH 4 HTRs were not significant. The 40 mg group showed greater increases in gastric and esophageal pH 4 HTRs compared with the 20 mg group, but differences between groups were not significant. After 8 weeks' treatment, the healing rate in subjects with baseline EE grades A-D was 60.0% (3/5 patients) in the 20 mg group and 71.4% (5/7 patients) in the 40 mg group. Vonoprazan was generally well tolerated. One patient (40 mg group) experienced four treatment-emergent adverse events (TEAEs) (unrelated to study drug), leading to study discontinuation. CONCLUSIONS: Vonoprazan 20 mg and 40 mg effectively inhibited gastric acid secretion over a 24 hour period with significantly increased gastric pH 4 HTR, and resulted in an EE healing rate > 60.0% in this study. Vonoprazan treatment may be valuable for patients with PPI-resistant EE. PMID- 28567115 TI - Factors associated with the achievement of mucosal healing in Crohn's disease: the benefit of endoscopic monitoring in treating to target. AB - BACKGROUND: Mucosal healing (MH), the proposed treat to target in Crohn's disease (CD), is associated with improved disease outcomes. There are still scant data on factors associated with achieving MH in clinical practice. We evaluated the probability of achieving MH and identified factors predictive of subsequent MH in patients with CD. METHODS: This was a retrospective, observational cohort study. A total of 272 patients with CD with serial endoscopy assessment and subsequent therapeutic management were reviewed. The primary outcome was MH. The cumulative incidence of MH and endoscopic improvement was estimated using the Kaplan-Meier method. Factors independently associated with MH were identified using the Cox proportional hazards model. RESULTS: Of the 272 patients, 126 (46.32%) achieved MH after a median follow-up period of 33 months (interquartile range: 27-38 months). Factors independently associated with MH by multivariate analysis were time between endoscopic procedures within 26 weeks (hazard ratio [HR]: 1.56; 95% confidence interval [CI]: 1.05-3.39), adjustment of medical therapy when MH was not achieved (HR: 2.07; 95% CI: 1.26-2.33), prior enteric fistula (HR: 0.22; 95% CI: 0.06-0.91), perianal disease at CD diagnosis (HR: 0.58; 95% CI: 0.35-0.95), and C-reactive protein normalization within 12 weeks (HR: 3.23; 95% CI: 1.82 5.88). Similar factors have also been identified for endoscopic improvement. CONCLUSIONS: Performing serial endoscopic procedures at a 26-week interval and subsequent adjustment in medical treatment are helpful in achieving MH. Endoscopic monitoring plays an important role in the treating to target of CD. PMID- 28567116 TI - Efficacy of double-balloon enteroscopy for small-bowel polypectomy: clinical and economic evaluation. AB - BACKGROUND: We evaluated first the feasibility of endoscopic small-bowel polypectomy and second, the economic aspects, by comparing the cost of endoscopic and surgical polyp resection. METHODS: A prospective, observational, multicenter study included 494 patients with positive capsule endoscopy (CE) before double balloon enteroscopy (DBE). We selected only CE with at least one polyp. The retrospective economic evaluation compared patients treated by DBE or surgery for small-bowel polypectomy. Hospital readmission because of repeat polyp resection or complication-related interventions was noted. The 1-year cost was estimated from the viewpoint of the healthcare system and included procedures, hospital admissions and follow up. RESULTS: CE indicated one or more polyps in 62 (12.5%) patients (32 males, 49 +/- 5 years), all of whom underwent a successful DBE exploration. The DBE polyp diagnostic yield was 58%. There were no major complications. A total of 26 (42%) patients in the DBE group and 19 (39%) in the control group required hospital readmission. All readmissions in the DBE group were for repeat procedures to remove all polyps, and in the control group, for surgical complications. The total cost of the initial hospitalization (?4014 +/- 2239 DBE versus ?11,620 +/- 7183 surgery, p < 0.0001) and the 1-year total cost (?8438 +/- 9227 DBE versus ?13,402 +/- 7919 surgery, p < 0.0001) were lower in the DBE group. CONCLUSIONS: Endoscopic polypectomy was efficient and safe. The total cost at 1 year was less for endoscopy than surgery. DBE should be proposed as the first-line treatment for small-bowel polyp resection. PMID- 28567117 TI - Commercially available glutenases: a potential hazard in coeliac disease. AB - BACKGROUND: The only treatment for celiac disease (CD) is a gluten-free diet (GFD). However, there is interest among patients in a medical therapy to replace or help with a GFD. Therapies include gluten-degrading enzymes (glutenases). There are glutenases available marketed as dietary supplements that have not been demonstrated to digest the toxic epitopes of gluten. METHODS: We investigated the contents, claims, and disclaimers of glutenase products and assessed patient interest using Google AdWords to obtain Google search frequencies. RESULTS: Among 14 glutenase product, all contained proteases, eight contained X-prolyl exopeptidase dipeptidyl peptidase IV, two did not state the protease contents, and eight failed to specify the name or origin of all proteases. Eleven contained carbohydrases and lipases and three probiotics. One declared wheat and milk as allergens, two contained herbal products (type not stated) and one Carica papaya. Thirteen claimed to degrade immunogenic gluten fragments, four claimed to help alleviate gastrointestinal symptoms associated with eating gluten. Disclaimers included not being evaluated by the US Food and Drug Administration and products not intended to diagnose, treat, cure, or prevent any disease. On Google AdWords, the search frequency for the product names and the search terms was 3173 searches per month. CONCLUSIONS: The names of these products make implicit claims that appear to be supported by the claims on the labels and websites for which there is no scientific basis. Google search data suggest great interest and therefore possible use by patients with CD. There needs to be greater oversight of these 'drugs'. PMID- 28567118 TI - Endoscopic ultrasound-guided hepaticogastrostomy versus percutaneous transhepatic drainage for malignant biliary obstruction after failed endoscopic retrograde cholangiopancreatography: a retrospective expertise-based study from two centers. AB - BACKGROUND: Percutaneous transhepatic biliary drainage (PTBD) is widely performed as a salvage procedure in patients with unresectable malignant obstruction of the common bile duct (CBD) after failed endoscopic retrograde cholangiopancreatography (ERCP) or in case of surgically altered anatomy. Endoscopic ultrasound-guided hepaticogastrostomy (EU-HGS) is a more recently introduced alternative to relieve malignant obstructive jaundice. The aim of this prospective observational study was to compare the outcome, efficacy and adverse events of EU-HGS and PTBD. METHODS: From April 2012 to August 2015, consecutive patients with malignant CBD obstruction who underwent EU-HGS or PTBD in two tertiary-care referral centers were included. The primary endpoint was the clinical success rate. Secondary endpoints were technical success, overall survival, procedure-related adverse events, incidence of adverse events, and reintervention rate. RESULTS: A total of 51 patients (EU-HGS, n = 31; PTBD, n = 20) were included. Median survival was 71 days (range 25-75th percentile; 30-95) for the EU-HGS group and 78 days (range 25-75th percentile; 42-108) for the PTBD group (p = 0.99). Technical success was achieved in all patients in both groups. Clinical success was achieved in 25 (86%) of 31 patients in the EU-HGS group and in 15 (83%) of 20 patients in the PTBD group (p = 0.88). There was no difference in adverse events rates between the two groups (EU-HGS: 16%; PTBD: 10%) (p = 0.69). Four deaths within 1 month (two hemorrhagic and two septic) were considered procedure related (two in the EU-HGS group and two in the PTBD group). Overall reintervention rate was significantly lower after EU-HGS (n = 2) than after PTBD (n = 21) (p = 0.0001). Length of hospital stay was shorter after EU HGS (8 days versus 15 days; p = 0.002). CONCLUSIONS: EU-HGS can be an effective and safe mini invasive-procedure alternative to PTBD, with similar success and adverse-event rates, but with lower rates of reintervention and length of hospitalization. PMID- 28567119 TI - Direct oral anticoagulants and digestive bleeding: therapeutic management and preventive measures. AB - The use of direct oral anticoagulants (DOACs) was an important step forward in the management of atrial fibrillation and venous thromboembolism (VTE). The DOACs, anti-IIa for dabigatran and anti-Xa for rivaroxaban, apixaban and edoxaban, all have a rapid onset of action and a short half life. There is no need for routine hemostasis testing for treatment monitoring of a DOAC. Compared with vitamin K antagonists (VKAs), DOACs may increase the risk of gastrointestinal bleeding (relative risk 1.25). Withholding the DOAC treatment, evaluating the time of the last intake and estimating the patient's renal function are the first steps in the management of gastrointestinal bleeding. For patients without impaired renal function, achieving low coagulation takes around 24 h after the last intake of a DOAC. The use of DOAC antagonists will be helpful in controlling bleeding in the most severe and urgent situations. Idarucizumab is available for clinical use for dabigatran and andexanet is currently being reviewed by drug agencies for rivaroxaban, apixaban and edoxaban. It is important to assess the bleeding risk associated with the planned procedure, and the patient's renal function before withholding DOAC therapy for a scheduled intervention. It is mandatory to strengthen the local hemostasis strategies in DOAC-treated patients undergoing a therapeutic endoscopic procedure. Resuming or not resuming anticoagulation with a DOAC after bleeding or a risky procedure depends on the thrombotic and bleeding risk as well as the procedure involved. This discussion should always involve the cardiologist and decisions should be taken by a pluridisciplinary team. PMID- 28567121 TI - An alternative treatment for biliary injuries characterized by complete transection of the common bile duct: intraperitoneal rendezvous. PMID- 28567122 TI - A Functional Role for the Monomethylated Gln-51 and Lys-53 Residues of the 49GGQTK53 Motif of eL42 from Human 80S Ribosomes. AB - BACKGROUND: We have previously demonstrated that the eukaryote-specific ribosomal protein eL42 of the human 80S ribosome contains seven monomethylated residues, among which are the Gln-51 and Lys-53 residues contained in the 47GFGGQTK53 sequence conserved in all eukaryotic 80S ribosomes. This sequence contains the methylated and universally conserved GGQ motif common for all class-1 translation termination factors responsible for stop codon recognition and for triggering the hydrolysis of the P site-bound peptidyl-tRNA. We have also recently reported a model of ribosomal ternary eL42-tRNA-eRF1 complex where specific regions of all three macromolecules (the comparably flexible GGQ domains of eRF1 and eL42 and the CCA-arm of tRNA) are involved in interactions. METHOD: Here, we have studied the interactions between recombinant eL42 and eRF1 proteins and the tRNA substrate by means of the Biacore assay, using the wild-type eL42 protein, the eL42-Delta(GGQTK) mutant (the eL42 protein whose GGQTK motif has been deleted), the single Q51E and K53Q mutants (eL42-Q51E and eL42-K53Q, respectively), as well as the double Q51A/K53A mutant (eL42-Q51A/K53A). RESULTS: Our results show that the monomethylated Gln-51 and Lys-53 residues contained in the 47GFGGQTK53 sequence of eL42 and the monomethylated GGQ motif of eRF1 represents the sites of interaction between these two proteins through hydrophobic contacts between methyl groups. We also demonstrate that the interactions between eL42 and tRNA or 28S rRNA are characterized by strong binding affinities (KD values in the nanomolar or picomolar range, respectively) which argue for specific interactions. Strong interactions between eL42 and tRNA are likely to be responsible for the decrease in the poly(U)-dependent poly(Phe) synthesis activity of human 80S or E. coli 70S ribosomes in the presence of added human recombinant eL42. It is proposed that the decrease of the activity of the ribosome is caused by the sequestration of the substrate Phe-tRNAPhe by the added eL42 protein. CONCLUSION: Interactions between the monomethylated Gln-51 and Lys 53 residues of the 49GGQTK53 motif of the human eL42 protein and the methylated GGQ motif of eRF1 are likely to play a functional role on translating human 80S ribosomes. PMID- 28567120 TI - The potential role of comprehensive genomic profiling to guide targeted therapy for patients with biliary cancer. AB - Remarkable advancements in techniques of genomic profiling and bioinformatics have led to the accumulation of vast amounts of knowledge on the genomic profiles of biliary tract cancer (BTC). Recent largescale molecular profiling studies have not only highlighted genomic differences characterizing tumors of the intrahepatic and extrahepatic bile ducts and gallbladder, but have also revealed differences in genomic profiles pertaining to associated risk factors. Novel genomic alterations such as FGFR2 fusions and IDH1/2 mutations in intrahepatic cholangiocarcinoma (ICC) and ERBB2 alterations in gallbladder cancer (GBCA) are emerging as targeted therapy options capable of advancing precision medicine for the care of these patients. Moreover, variable genomic alterations also appear to impact prognosis and overall disease outcome independent from their therapy selection value. High mutational burden and increased expression of immune checkpoint-related proteins observed in a subset of BTC also show a potential for guidance of immunotherapy. Thus, comprehensive genomic profiling (CGP) is rapidly achieving status as an integral component of precision medicine and is starting to become invaluable in guiding the management of patients with BTC, a rare disease with dismal outcome. PMID- 28567123 TI - Identification of Protease Specificity Using Biotin-Labeled Substrates. AB - BACKGROUND: Proteolysis constitutes a major post-translational modification. For example, proteases regulate the activation or inactivation of various proteins, such as enzymes, growth factors, and peptide hormones. Proteases have substrate specificity, and protease expression regulates the specific and regional activation or inactivation of several functional proteins. METHODS: We demonstrate a novel method for determining protease specificity through the use of MALDI-TOF mass spectrometry with biotin-labeled substrates. RESULTS: This method was able to determine the specificity of TPCK-trypsin, V8 protease, elastase and cyanogen bromide cleavage, and the results were similar to previous reports. In addition, the method can be used to measure crude samples, such as tumor extracts. CONCLUSION: We demonstrated that this method could identify protease specificity after simple processing, even for crude samples. PMID- 28567124 TI - Monitoring the Level of 14C-Labelled Selegiline Following Oral Administration. AB - BACKGROUND: Selegiline [(-)-deprenyl] is widely used for the treatment of Parkinson's disease in humans. OBJECTIVE: Time-dependence of tissue distribution of selegiline following per os administration to rats. METHOD: Oral administration of radiolabeled selegiline to rats resulted in a pattern of tissue distribution similar to that following intraperitoneal injection. Analyses were done using both reversed-phase HPLC and also by counting radioactivity in various body compartments of rats. RESULTS: As a consequence of oral administration of 30 mg/kg of selegiline, its level in the stomach was extremely high (179.57 ug/g tissue through 54.67 ug/g at 15 min to 120 min), that is one magnitude higher than that in the serum level. High selegiline concentrations were also detected in the lacrimal glands (7.45 ug/g), kidneys (6.87 ug/g), livers (6.01 ug/g) and lungs (3.47 ug/g) after 30 minutes of application, which were higher than after intraperitoneal injections. CONCLUSION: The relatively high tissue levels remained for 120 min monitoring. Selegiline levels in the brain (1.69 ug/g) and in the testes (1.88 ug/g) were also considerably higher than following intraperitoneal administration during the entire period of observation (15 to 120 min). PMID- 28567125 TI - Synthesis and Functional Evaluation of Novel Aldose Reductase Inhibitors Bearing a Spirobenzopyran Scaffold. AB - BACKGROUND: Aldose reductase, the first enzyme of the polyol pathway, is the key determinant for the pathogenesis of long term diabetic complications. Accordingly, its inhibition represents the major therapeutic strategy to treat this kind of pathologies. OBJECTIVES: In this work we describe the synthesis and the functional evaluation of a number of spiro-oxazolidinone and spiro morpholinone acetic acid derivatives, and their benzyloxy analogs, developed as aldose reductase inhibitors. RESULTS: Most of them proved to inhibit the target enzyme, showing IC50 values in the micromolar/low micromolar range. SARs observed among the three different series allowed to highlight their key pharmacophoric elements, thus creating sound basis for the design of novel and more effective inhibitors. CONCLUSION: Although further substitution patterns are needed, the novel compounds here proposed represent a good starting point for the development of novel and effective ARIs. PMID- 28567127 TI - Path Loss Measurement and Channel Modeling with Muscular Tissue Characteristics. AB - BACKGROUND: The galvanic coupling intra-body communication has low radiation and strong anti-interference ability, so it has many advantages in the wireless communication. METHOD: In order to analyze the effect of muscle tissue's characteristics upon the communication channel, we selected the muscle of pig buttock as the experimental sample, and used it to study the attenuation property with the galvanic coupling intra-body communication channel along the parallel direction and the transverse direction relative to the muscular fibre line as well as on the surface of destroyed muscular fibre; the study frequency ranges from 1kHz to 10MHz.In the isotropic experiment, in order to destroy muscle's fibre characteristics, we grinded the muscle four times, at least five minutes for each time. 0dbm sine-wave signal was input to measure the channel attenuation parameter S21 when the transmitter and the receiver were placed at different positions and different distances d1 and d2 (20mm, 40mm, 60mm), so as to analyze channel loss. CONCLUSION: Within the same frequency range and at the same communication distance, the maximum error of channel attenuation was 10dB; within the same frequency, as the communication distance was increased, the channel attenuation rose gradually, with 4dB increased every 20mm. The conclusion provides the basis for building the theoretical model in the future. PMID- 28567126 TI - Tacrine, Trolox and Tryptoline as Lead Compounds for the Design and Synthesis of Multi-target Agents for Alzheimer's Disease Therapy. AB - The versatile biological activities of tacrine, trolox and beta-carboline derivatives make them promising lead structures for the development of multifunctional Alzheimer's disease (AD) agents. Based on the topology of the active site of cholinesterases and other target proteins involved in the pathogenesis of AD, we have designed and synthesized tacrine-trolox and tacrine tryptoline hybrids with various linker chain lengths. The hybrids containing the trolox moiety (8a-8d) showed moderate to high TcAChE inhibition (IC50: 17.37 - 2200 nM), eqBuChE inhibition (IC50: 3.16 - 128.82 nM) and free radical scavenging activities (IC50: 11.48 - 49.23 uM). The hybrids with longer linker chain lengths in general showed better ChE inhibitory activity. As expected, free radical scavenging activities were not significantly affected by varying linker chain lengths. The hybrid compound containing the tryptoline moiety linked with a 7 carbon spacer to tacrine (14) displayed the best AChE and BuChE inhibitory activity (IC50 = 17.37 and 3.16 nM). Docking experiments exhibited that compounds 8d and 14 were able to bind to both the CAS and PAS of TcAChE and eqBuChE, suggesting that they will be able to inhibit ChE induced Abeta aggregation. Novel multi-target agents that exhibit good ChE inhibition (8d and 14) and anti-oxidant (8d) activity were identified as suitable candidates for further investigation. PMID- 28567128 TI - Noninvasive Fetal Electrocardiography Part I: Pan-Tompkins' Algorithm Adaptation to Fetal R-peak Identification. AB - BACKGROUND: Indirect fetal electrocardiography is preferable to direct fetal electrocardiography because of being noninvasive and is applicable also during the end of pregnancy, besides labor. Still, the former is strongly affected by noise so that even R-peak detection (which is essential for fetal heart-rate evaluations and subsequent processing procedures) is challenging. Some fetal studies have applied the Pan-Tompkins' algorithm that, however, was originally designed for adult applications. Thus, this work evaluated the Pan-Tompkins' algorithm suitability for fetal applications, and proposed fetal adjustments and optimizations to improve it. METHOD: Both Pan-Tompkins' algorithm and its improved version were applied to the "Abdominal and Direct Fetal Electrocardiogram Database" and to the "Noninvasive Fetal Electrocardiography Database" of Physionet. R-peak detection accuracy was quantified by computation of positive-predictive value, sensitivity and F1 score. RESULTS: When applied to "Abdominal and Direct Fetal Electrocardiogram Database", the accuracy of the improved fetal Pan-Tompkins' algorithm was significantly higher than the standard (positive-predictive value: 0.94 vs. 0.79; sensitivity: 0.95 vs. 0.80; F1 score: 0.94 vs. 0.79; P<0.05 in all cases) on indirect fetal electrocardiograms, whereas both methods performed similarly on direct fetal electrocardiograms (positive predictive value, sensitivity and F1 score all close to 1). Improved fetal Pan Tompkins' algorithm was found to be superior to the standard also when applied to "Noninvasive Fetal Electrocardiography Database" (positive-predictive value: 0.68 vs. 0.55, P<0.05; sensitivity: 0.56 vs. 0.46, P=0.23; F1 score: 0.60 vs. 0.47, P=0.11). CONCLUSION: In indirect fetal electrocardiographic applications, improved fetal Pan-Tompkins' algorithm is to be preferred over the standard, since it provides higher R-peak detection accuracy for heart-rate evaluations and subsequent processing. PMID- 28567129 TI - Noninvasive Fetal Electrocardiography Part II: Segmented-Beat Modulation Method for Signal Denoising. AB - BACKGROUND: Fetal well-being evaluation may be accomplished by monitoring cardiac activity through fetal electrocardiography. Direct fetal electrocardiography (acquired through scalp electrodes) is the gold standard but its invasiveness limits its clinical applicability. Instead, clinical use of indirect fetal electrocardiography (acquired through abdominal electrodes) is limited by its poor signal quality. OBJECTIVE: Aim of this study was to evaluate the suitability of the Segmented-Beat Modulation Method to denoise indirect fetal electrocardiograms in order to achieve a signal-quality at least comparable to the direct ones. METHOD: Direct and indirect recordings, simultaneously acquired from 5 pregnant women during labor, were filtered with the Segmented-Beat Modulation Method and correlated in order to assess their morphological correspondence. Signal-to-noise ratio was used to quantify their quality. RESULTS: Amplitude was higher in direct than indirect fetal electrocardiograms (median:104 uV vs. 22 uV; P=7.66.10-4), whereas noise was comparable (median:70 uV vs. 49 uV, P=0.45). Moreover, fetal electrocardiogram amplitude was significantly higher than affecting noise in direct recording (P=3.17.10-2) and significantly in indirect recording (P=1.90.10-3). Consequently, signal-to-noise ratio was initially higher for direct than indirect recordings (median:3.3 dB vs. -2.3 dB; P=3.90.10-3), but became lower after denoising of indirect ones (median:9.6 dB; P=9.84.10-4). Eventually, direct and indirect recordings were highly correlated (median: rho=0.78; P<10-208), indicating that the two electrocardiograms were morphologically equivalent. CONCLUSION: Segmented-Beat Modulation Method is particularly useful for denoising of indirect fetal electrocardiogram and may contribute to the spread of this noninvasive technique in the clinical practice. PMID- 28567130 TI - Villous Tree Model with Active Contractions for Estimating Blood Flow Conditions in the Human Placenta. AB - BACKGROUND: In the human placenta, maternal and fetal bloods exchange substances through the surface of the villous trees: the fetal blood circulates in the villous trees, around which the maternal blood circulates. The blood flows directly influence fetal growth. Stem villi, the main supports of the villous tree, have contractile cells along the axes, whose contractions are expected to influence the blood circulations in the placenta. The displacement is neither measurable nor predictable while non-invasive measurements such as umbilical Doppler waveforms are helpful to predict the histological changes of the villous trees and vascularization in the placenta. OBJECTIVE: The displacement caused by the contraction of the villous tree is necessary to predict the blood flows in the placenta. Hence, a computational villous tree model, which actively contracts, was developed in this study. METHOD: The villous tree model was based on the previous reports: shear moduli of the human placenta; branching patterns in the stem villi. The displacement pattern in the placenta was estimated by the computational model when the shear elastic moduli were changed. RESULTS: The results show that the displacement caused by the contraction was influenced by the shear elastic moduli, but kept useful for the blood flows in the placenta. The characteristics agreed with the robustness of the blood flows in the placenta. CONCLUSION: The villous tree model, which actively contracts, was developed in this study. The combination of this computational model and non invasive measurements will be useful to evaluate the condition of the placenta. PMID- 28567131 TI - The Predictive Value of the Syntax Score in Patients With Chronic Coronary Artery Disease Undergoing Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting: A Pilot Study. AB - OBJECTIVES: To evaluate the usefulness of the SYNTAX score (SS) in predicting 1 year clinical outcomes in a population of patients with chronic coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). BACKGROUND: Despite the proven prognostic value of the SS in patients with multivessel and/or left main (LM) CAD, its usefulness in other patient subsets remains uncertain. METHODS: This was a prospective single centre cohort study conducted from September 2012 to November 2014 at the Nicosia General Hospital, Cyprus. Patients (n=140; 94% men and 6% women) with chronic CAD undergoing revascularization with either PCI or CABG were evaluated. RESULTS: At 1-year, angina occurred in 20 patients (14.3%), myocardial infarction (MI) in 3 patients (2.1%), repeat revascularization procedures in 9 patients (6.4%) and death in 12 patients (8.6%). The SS independently predicted angina (p=0.024) but was not predictive of MI (p=0.964), death (p=0.292) or repeat revascularization (p=0.069). CONCLUSION: In this patient population, the SS predicted angina in the year following revascularization but was not predictive of MI, death or repeat revascularization. PMID- 28567133 TI - Case Series Using Montelukast in Patients with Memory Loss and Dementia. AB - Cognitive decline and dementia are a growing problem as the population ages. Effective therapies to prevent and treat these problems are limited. Neuro inflammation has been suggested as a cause of dementia [1]. Montelukast is a leukotriene receptor antagonist used to treat seasonal allergies and asthma. It acts as a cysteinyl leukotriene (CysLT1) receptor antagonist blocking the action of leukotrienes and decreasing inflammation [2]. Animal studies have shown that administering Montelukast improves memory function [3]. This case series of patients in a private Internal Medicine practice between 2013-2014 used Montelukast in patients with various levels of memory impairment and dementia. Patients were given Montelukast 80 mg daily in 4 divided doses every 2-3 hours. Memory impaired patients had subjective improvement in the memory and recall. Patients with dementia were noted by family members to be less agitated, but had no memory improvement at the doses used. Montelukast may be useful to treat memory impairment and dementia. Long term use might act as a prophylactic to prevent dementia. PMID- 28567134 TI - "Doctor, I Hear Music": A Brief Review About Musical Hallucinations. AB - Auditory hallucinations are defined as the abnormal perception of sound in the absence of an external auditory stimulus. Musical hallucinations constitute a complex type of auditory hallucination characterized by perception of melodies, music, or songs. Musical hallucinations are infrequent and have been described in 0.16% of a general hospital population. The auditory hallucinations are popularly associated with psychiatric disorders or degenerative neurological diseases but there may be other causes in which the patient evolves favorably with treatment. With this clinical case we want to stress the importance of knowing the causes of musical hallucinations due to the unpredictable social consequences that they can have. PMID- 28567132 TI - Nitric Oxide and Related Aspects Underlying Angina. AB - Increased number of patients affected by metabolic syndrome (MS) has prompted the necessity of better understanding what is involved in such syndrome. Nevertheless, the establishment of promising therapies depends on the knowledge about the interaction of molecules within MS. In such context, Nitric Oxide (NO) emerges from a bulk of works relating its roles on aspects of MS, including cardiovascular diseases, their symptoms and comorbidities, which are thought to be triggered by similar sources. NO, nitric oxide synthase and enzymatic chains are keys for those disease and symptoms processes. NO has been separately described as part of hypertensive, ischemic and pain signaling. Although there are similar pathways likely shared for generating cardiovascular symptoms such angina, they are barely associated to NO in literature. The present review aims to clarify the patterns of NO alteration in metabolic syndrome directly concerned to cardiovascular symptoms, especially angina. PMID- 28567135 TI - Specific Effects of Anti-Hypertensive Treatment in an Older Patient with Dementia. AB - Dementia is one of the most common health problems in the world. Alzheimer's disease (AD) is the most common form of dementia. The presence of vascular risk factors such as hypertension (HT) may increase the risk of AD [1,2]. The relation between blood pressure (BP) and dementia has been the subject of numerous epidemiological studies, midlife HT is a risk factor for dementia and AD [3-7] but the association between HT and risk of dementia is lower in the older population [8]. A fair modulation of an antihypertensive treatment, based on the cognitive status of the elderly, can avoid multiple complications. A case of an older for whom cognitive improvement and reduced risk of falls were noticed after mild blood pressure elevation is reported. PMID- 28567136 TI - Pulp Revascularization: A Literature Review. AB - Reestablishing blood flow and allowing the continuation of root development are some of the objectives of pulp revascularization. This procedure is currently indicated for teeth with incomplete root formation as an alternative to the traditional treatment of apecification, which consists of inserting calcium hydroxide paste into the root canal for a determined time period in order to induce the formation of a calcified barrier. Although it is considered as the most classically employed therapy, the permanence of the paste for long time periods may lead to the weakening of the root due to hygroscopic properties, as well as proteolytic activities of calcium hydroxide. Therefore, there has been a permanent search for alternatives which allow the full development of immature teeth. Revascularization has emerged as such an alternative, and a range of treatment protocols can be found in the scientific literature. The aim of this paper is to accomplish a literature review concerning this issue. PMID- 28567137 TI - Social and Psychological Aspects of Dental Trauma, Behavior Management of Young Patients Who have Suffered Dental Trauma. AB - INTRODUCTION: Injuries concerning the skull, the mouth and thus potentially involving the mouth and teeth are characterized as major public health problems due to their high prevalence and very serious functional and aesthetic consequences. Pain, aesthetic and functional problems arising from dental trauma significantly disrupt normal function, and impact, often dramatically, on young patients' quality of life. PROCEDURE: With regards to the behavior management approach to a child who has suffered a dental trauma, dentist's first step is to be to reassure child and parents. They should feel that the emergency is being properly treated on the part of the dentist and feel safe. The dentist should offer psychological support to child and parents and focus on alleviating any possible pain the child may feel. But, before that, a good level of communication with the child should be established. CONCLUSION: This can be achieved through the tell-show-do technique, a presentation of the special session's structure, the positive reinforcement method, the attention distraction method and exploiting the child's imagination. The detailed description of the treatment to be followed is crucial for reducing the child's level of stress, as well as that of the parents. Immediately after the completion of treatment, dentist should give listening time to the parents for any queries and include the child who probably wants to share their experience. PMID- 28567138 TI - A 5-week Non-Surgical Approach towards Denture Induced Hyperplasia. AB - BACKGROUND: Despite the standard approach towards denture-induced hyperplasia being surgery, as elderly population increases the systemic problems are carried along. Thus, surgery might be risky for patients with medical conditions. OBJECTIVE: In this report, a patient with severe inflammatory papillary hyperplasia, medical problems and dental fear was treated with a 5-week nonsurgical protocol. METHOD: Once in a week, the upper denture was relined with a zinc enolic paste, for four weeks. In the fifth week, the denture was relined with fast set polymethyl methacrylate resin instead of zinc enolic paste so that the material would last longer than only a week until the new pair of dentures was manufactured. RESULTS AND CONCLUSION: The generated pressure combined with antioxidant and anti-inflammatory properties of the paste led to the elimination of the inflammatory papillary hyperplasia completely, satisfying the patient and allowing the manufacturing of a new set of complete dentures. PMID- 28567139 TI - Xerostomia and Salivary Gland Hypofunction in Patients with Oral Lichen Planus Before and After Treatment with Topical Corticosteroids. AB - BACKGROUND: Oral lichen planus and mouth dryness are common pathoses, yet not entirely understood. These two conditions may be associated, with a few studies investigating the relationship between mouth dryness and oral lichen planus providing conflicting results. None of the studies have explored the specific impact of disease treatment on mouth dryness. OBJECTIVE: The purpose of this observational before and after comparison study was to examine the effect of treatment of oral lichen planus with topical corticosteroids on mouth dryness. METHODS: Nineteen subjects with oral lichen planus were evaluated for the severity of xerostomia using a xerostomia inventory and a visual analogue scale. Stimulated and unstimulated whole salivary flow rates, unstimulated salivary pH and buffering capacity were also measured. All subjects were evaluated before and after treatment with topical corticosteroids. RESULTS: All subjects reported xerostomia before treatment with topical corticosteroids, with 79% reporting a significant improvement (P = 0.03) after treatment. Topical corticosteroid treatment was not associated with statistically significant differences in stimulated or unstimulated salivary flow rates, unstimulated salivary pH or buffering capacity. CONCLUSION: The results of this study suggest that treatment of oral lichen planus with topical corticosteroids may decrease the severity of dry mouth symptoms. PMID- 28567140 TI - Bioactive-glass in Endodontic Therapy and Associated Microsurgery. AB - INTRODUCTION: Bioactive-glass (B-G) has become a valuable adjunct to promote hard tissue healing in many clinical situations and is of particular interest for endodontic care because of its biocompatibility, regenerative and antimicrobial properties as well as chemical composition that closely resembles the mineral make-up of human bone and dentine. THERAPY: Initial studies suggested that bacteria-tight sealing within the entire root canal system can be achieved and successfully maintained after orthograde treatment. Promising results have also been obtained in conjunction with microsurgical techniques, with the aim of enhancing wound healing and positively influencing bone regeneration. CONCLUSION: Here, relevant literature was explored to present a comprehensive review of the rationale, development, and current applications of B-G in Endodontology illustrating them with case reports. PMID- 28567141 TI - Reproducibility of a Digital Method to Evaluate Soft Tissue Modifications: A study of Inter and Intra-Operative Measurement Concordance. AB - BACKGROUND: The soft tissue healing and quality around dental implant is a current debated topic in the recent literature. The free gingival margin and the quantity and quality of the mucosa around teeth and surrounding dental implants still determine the hard and soft tissue healing status. OBJECTIVE: The aim of this study is to assess inter and intra-operative measurement concordance of a method aimed at evaluating the apico-coronal migration of free gingival margin, using intra-oral photography. METHODS: The method was tested on peri-implant tissues that were treated with a connective tissue graft on the second stage surgery. Thirty-eight measurements on 13 implants in 8 patients were recorded. An intra-oral photograph was taken for the graft and the provisional crown, which enclosed a circular landmark with a previously determined diameter. The landmark was prepared with a red-resin by the same technician. Before crown cementation, the landmark was calibrated with a digital calibrator by the main investigator, to determine the precise diameter up to two decimal numbers. RESULTS: On the intra-oral photograph, the distance was measured from the most apical point of the determined landmark to the zenith of the gingiva, using an image-processing program designed for scientific multidimensional images (Image J). Three independent examiners took these measurements. CONCLUSION: The main advantage of the present non-invasive technique is that the spatial plane of the prosthetic landmarks is the same of the tooth unlike the utilization of periodontal probe, which is generally positioned on different plans in the space (generally more vestibular). PMID- 28567142 TI - Clinical Analysis of Analgesics and Steroids Use for Extraction of Teeth in Patients with Intellectual Disability Under General Anesthesia. AB - BACKGROUND: The extraction of lower wisdom teeth is often performed under general anesthesia in patients with intellectual disabilities. However, the choice of analgesics has not yet been investigated. OBJECTIVE: To analyze the use of analgesics during general anesthesia for extraction including lower wisdom teeth in patients with intellectual disabilities. METHODS: This research is a retrospective observational study. The study population was composed of all patients presenting for extraction of lower wisdom teeth under ambulatory general anesthesia in the clinic of Special Needs Dentistry in Okayama University Hospital from April 2011 to March 2016. The distribution of the combination of analgesics and the relationship between the use of analgesics and the type of extraction were investigated. RESULTS: One hundred and twelve cases were enrolled in this study. Intravenous injections of flurbiprofen, acetaminophen and betamethasone were used in 96 (85.7%), 12 (10.7%) and 26 cases (23.2%), respectively. Flurbiprofen is a non-steroid anti-inflammatory drugs (NSAIDs). Acetaminophen is an old analgesic, but an injection of acetaminophen is new, which was released in 2013 in Japan. And betamethasone is not an analgesic, but a steroid. Betamethasone was used in combination with other analgesics, and was used at a higher dose in a case in which four wisdom teeth were extracted. CONCLUSION: Flurbiprofen was the main analgesic used for extraction of wisdom teeth under general anesthesia in patients with intellectual disabilities. Betamethasone was used to support flurbiprofen or acetaminophen for extractions of multiple wisdom teeth, with the aim of controlling swelling rather than relieving pain. PMID- 28567143 TI - A New Transalveolar Sinus Lift Procedure for Single Implant Placement: The Ebanist Technique. A Technical Description and Case Series. AB - BACKGROUND: Nowadays, there are many techniques to compensate bone atrophies of the posterior maxilla in order to obtain an implant-supported rehabilitation. OBJECTIVE: This case series describes the Ebanist technique: a sinus lift procedure to be used in case of extremely resorbed bone crests (<=3 mm) allowing simultaneous implant placement. METHODS: With a dedicated cylindrical trephine bur, it is possible to harvest a cylinder of bone from a fresh mineralized frozen homologous bone block graft and to simultaneously create a trapdoor on the recipient site. The trapdoor cortical bone is detached from the sinus membrane and removed. Dental implant is placed into the graft before the grafting procedure since the cylindrical block, once inserted in the recipient area, is not able to oppose sufficient resistance to the torque needed for implant placement. RESULTS: Second-stage surgery and following prosthetic rehabilitation were performed after 5 months. In all cases, implant stability was manually checked and no pathological symptoms or signs were recovered at any follow-up visit. CONCLUSION: This technique can be considered a valid procedure for implant therapy on atrophic posterior upper maxillae, when the residual bone crest is extremely resorbed. PMID- 28567144 TI - Pretreatment Effect of Folic Acid on 13-Cis-RA-Induced Cellular Damage of Developing Midfacial Processes in Cultured Rat Embryos. AB - OBJECTIVE: Excess treatment of 13-cis-RA (Accutane(r)) on pregnant women induces craniofacial malformation found in infants. However, the effect of folic acid on 13-cis-RA-induced cellular damages of developing midfacial processes is still unknown. The purpose of this study was to investigate the pretreatment effect of folic acid (FA) on 13-cis-RA-induced cellular damage in developing midfacial processes in rat embryos. MATERIALS AND METHODS: The rat embryos at developing midfacial processes were performed by whole embryo culture in vitro, in the presence of 13-cis-RA (20 uM) with or without pre-treatment of FA (100 uM). The midfacial morphogenesis score, PCNA and TUNEL assay staining were evaluated for morphogenesis, cell proliferation and apoptosis of the midfacial processes, respectively. RESULTS: The 13-cis-RA-treated embryos at 24h showed atrophy of midfacial processes with significantly decreased morphogenesis score and cell proliferation, and increased apoptotic cell death. In contrast, the embryos pre treated with FA for 18h, followed by 13-cis-RA treatment for 24h (FA-RA) showed significantly greater morphogenesis score, increased cell proliferation and lower apoptotic cell death compared to those of the 13-cis-RA-treated embryos. CONCLUSION: The results suggest that FA reduced the teratogenic effects of 13-cis RA on midfacial process tissue. Future investigations regarding the anti teratogenic mechanism of FA on the prevention of damages in midface processes induced by 13-cis-RA on pregnant woman are warranted. PMID- 28567145 TI - Applicability of the Moyers' Probability Tables in Adolescents with Different Facial Biotypes. AB - INTRODUCTION: The Moyers' probability tables are used in mixed dentition analysis to estimate the extent of space required for the alignment of canines and premolars, by correlating the mesiodistal size of lower incisors with the size of permanent canines and premolars. OBJECTIVE: This study intended to evaluate the applicability of the Moyer's probability tables for predicting the mesiodistal space needed for the correct location of premolars and permanent canines non erupted, in adolescents of the city of Cordoba, Argentina, who show different facial biotypes. MATERIALS AND METHODS: Models and tele-radiographies of 478 adolescents of both genders from 10 to 15 years of age were analyzed. The tele radiographies were measured manually in order to determine the facial biotype. The models were scanned with a gauged scanner (HP 3670) and measured by using Image Pro Plus 4.5 software. RESULTS: According to this study, the comparison between the Moyer's probability table, and the table created at the National University of Cordoba (UNC) (at 95%, 75%, and 50%) shows that, in both tables, a higher value of mesiodistal width of lower incisors corresponds to a bigger difference in the space needed for permanent canines and premolars; being the need for space for permanents canines and premolars bigger in the UNC's table. On the other hand, when contrasting the values of mesiodistal space for permanent canines and premolars associated with each facial biotype, the discrepancies between groups were not statistically significant (P >0.05). However, we found differences in the size of the space required according to the mesiodistal width range of the lower incisors for each biotype: a) The comparison of lower-range values, with a mesialdistal width of lower incisors less than 22 mm, the space required for permanent canines and premolars resulted smaller in patients with dolichofacial biotype than in patients with mesofacial and braquifacial biotypes. The latter biotypes have meager differences between them. b) The comparison of mid-range values, with a mesialdistal width of lower incisors from 22 to 25 millimeters, shows that the values of required alignment space are similar in the three facial biotypes. c) Finally, the comparison of upper range values, with a mesialdistal width of lower incisors greater than 25 millimeters, indicates that the space required for dolichofacial biotypes tends to be higher than in mesofacial and brachyfacial biotypes. CONCLUSION: The Moyer's probability tables should be created to meet the needs of the population under study, with no consideration of patients' facial biotypes. PMID- 28567146 TI - Virulence Factors Associated with Enterococcus Faecalis Infective Endocarditis: A Mini Review. AB - INTRODUCTION: The enterococci are accountable for up to 20% of all cases of infective endocarditis, with Enterococcus faecalis being the primary causative isolate. Infective endocarditis is a life-threatening infection of the endocardium that results in the formation of vegetations. Based on a literature review, this paper provides an overview of the virulence factors associated with E. faecalis infective endocarditis. Furthermore, it reports the effects of active or passive immunization against some of these involved factors. INDIVIDUAL VIRULENCE FACTORS: Nine virulence factors have in particular been associated with E. faecalis infective endocarditis. Absence of these factors entailed attenuation of strains in both mixed- and mono-bacterial infection endocarditis models as well as in in vitro and ex vivo assays when compared to their virulence factor expressing parental strains. PATHOGENESIS: The virulence factors promote a broad spectrum of events that together allow for disease development and progression. The infection is initiated through bacterial binding to ligands present at the site of infection after which the colonization can be accelerated through inter bacterial attachment and modulation of the host immune response. The formation and growth of the vegetation provide protection and promote growth. Controlled degeneration of the vegetation appears to increase the likelihood of embolization and dissemination, without exposing protected bacteria. PROPHYLACTIC IMMUNIZATION: In most cases, active and passive immunization against associated virulence factors provided partial protection. FUTURE PROSPECTS: There is a need for further evaluation of the known virulence factors. Immunization against two or more virulence factors might be an effective prophylactic tool. PMID- 28567147 TI - Ozone Sensitivity and Catalase Activity in Pigmented and Non-Pigmented Strains of Serratia Marcescens. AB - BACKGROUND: Ozone exposure rapidly leads to bacterial death, making ozone an effective disinfectant in food industry and health care arena. However, microbial defenses may moderate this effect and play a role in the effective use of oxidizing agents for disinfection. Serratia marcescens is an opportunistic pathogen, expressing genes differentially during infection of a human host. A better understanding of regulatory systems that control expression of Serratia's virulence genes and defenses is therefore valuable. OBJECTIVE: Here, we investigated the role of pigmentation and catalase in Serratia marcescens on survival to ozone exposure. METHOD: Pigmented and non-pigmented strains of Serratia marcescens were cultured to exponential or stationary phase and exposed to 5 ppm of gaseous ozone for 2.5 - 10 minutes. Survival was calculated via plate counts. Catalase activity was measured photometrically and tolerance to hydrogen peroxide was assayed by disk-diffusion. RESULTS: Exposure of S. marcescens to 5 ppm gaseous ozone kills > 90% of cells within 10 minutes in a time and concentration-dependent manner. Although pigmented Serratia (grown at 28 degrees C) survived ozonation better than unpigmented Serratia (grown at 35 degrees C), non-pigmented mutant strains of Serratia had similar ozone survival rates, catalase activity and H2O2 tolerance as wild type strains. Rather, ozone survival and catalase activity were elevated in 6 hour cultures compared to 48 hour cultures. CONCLUSION: Our studies did not bear out a role for prodigiosin in ozone survival. Rather, induction of oxidative stress responses during exponential growth increased both catalase activity and ozone survival in both pigmented and unpigmented S. marcescens. PMID- 28567148 TI - Hip Abductor Strengthening Improves Physical Function Following Total Knee Replacement: One-Year Follow-Up of a Randomized Pilot Study. AB - BACKGROUND: Total knee replacement (TKR) is the commonest surgical procedure for patients with severe pain and impaired physical function following end stage knee osteoarthritis. The hip abductors are well renowned in stabilization of the trunk and hip during walking, maintaining the lower limb position, and transferring the forces from the lower limbs to the pelvis. OBJECTIVE: To assess the efficacy of hip abductor strengthening exercise on functional outcome using performance based outcome measures following total knee replacement. METHODS: An observer blinded randomized pilot trial design was conducted at Manipal hospital, Bangalore, India. Participants designated for elective TKR were randomized to experimental group hip abductor strengthening along with standard rehabilitation (n=10) or control group standard rehabilitation alone (n=10). Participants followed for one year to assess physical function using performance based outcomes, such as timed up and go test, single leg stance test, six minute walk test, knee extensor strength and hip abductor strength. RESULT: Eighteen participants with a mean age of 63.1 +/- 5.5 years (8 Males and 10 Females) completed the study. Improvement in hip abduction strength, single leg stand test was superior in hip abductor strengthening group at 3 months and 1 year when compared to standard rehabilitation alone. CONCLUSION: Hip abductor strengthening showed superior improvements in single leg stance test and six minute walk test. Hip abductor strengthening exercises has the potential to improve physical function following total knee replacement. PMID- 28567150 TI - Cortical Fenestration for Megaprosthesis Stem Revision. AB - BACKGROUND: The most common modes of failure for megaprostheses are aseptic loosening followed by periprosthetic infection and stem fracture. Surgical technique for bone and implant exposure is controversial and may influence the success of revision and the need for additional future revisions. The purpose of this study was to evaluate the effectiveness of cortical fenestration for megaprosthesis revision, particularly for stem fracture. METHODS: From 1985-2014, 196 adult and pediatric patients underwent limb salvage with a distal femoral or proximal tibial megaprosthesis (109 cemented, 87 pressfit). A retrospective chart review was performed to assess the rate of revision based on cemented or pressfit fixation and the use of a cortical window to extract the failed stem. Results: 27% (29 of 109) of cemented and 18% (16 of 87) of pressfit implants were revised for stem failure. The reasons for revision in the cemented group were loosening (62%), infection (24%), and stem fracture (13%). In the pressfit group, the reasons were loosening (43%), infection (31%), stem fracture (6%), limb-length discrepancy (6%), malrotation (6%), and local recurrence (6%). A cortical window was used in 10 of 45 initial revisions (7 cemented, 3 pressfit) including all of the stem fractures, and in 2 of 15 subsequent re-revisions. CONCLUSION: Cortical fenestration is an effective, bone-preserving method of implant extraction, particularly for broken or cemented stems. It is associated with low rates of loosening and no increase in periprosthetic fractures. PMID- 28567149 TI - Comparison of Meniscal Cell-Mediated and Chondrocyte-Mediated Calcification. AB - BACKGROUND: Chondrocytes have been traditionally thought to be responsible for calcium crystal deposits within osteoarthritic knees. Increasing recent experimental evidence suggests that menisci may also play a role. However, the calcifying potential of chondrocytes and meniscal cells derived from same OA patients, and the genes associated with meniscal calcification have never been fully examined. OBJECTIVE: Examine and compare the calcifying potential of articular chondrocytes and meniscal cells derived from same OA patients and identify the calcium crystal type(s) and selected gene expression in OA menisci. METHODS: Chondrocytes and meniscal cells were isolated from articular cartilage and menisci of OA patients undergoing total knee arthroplasty. Chondrocyte- and meniscal cell-mediated calcification was examined using both monolayer and micromass culture-based assays. Crustal types were examined with histological staining. Levels of Type X Collagen, MMP-13, and ANKH in OA menisci were examined using immunohistochemistry. RESULTS: Primary human OA meniscal cells produced calcified deposits at a similar rate compared to OA chondrocytes in-vitro. Histological examinations indicate that both BCP crystals and CPPD crystals are present in the meniscal tissue. Type X collagen, MMP-13, and ANKH were found in human OA menisci and their levels increased with OA severity. In addition, type X collagen was co-localized with calcium crystals. CONCLUSION: These findings suggest that OA meniscal cells have a similar calcifying potential as OA chondrocytes, supporting a pathogenic role of OA menisci in OA. PMID- 28567151 TI - Trends in Management of Radial Head and Olecranon Fractures. AB - BACKGROUND: Advancement in surgical techniques and implants has improved the ability to manage radial head and olecranon fractures. However, trends in management of these fractures are largely unstudied. OBJECTIVE: This purpose of this study is to evaluate management trends for these common fractures. METHODS: A retrospective review of a comprehensive Humana database was performed using Pearl Diver supercomputer (Warsaw, IN, USA) for radial head and neck (RHNF) and olecranon fractures (OF) between 2007 and 2014. Treatment methods including open reduction internal fixation (ORIF), radial head arthroplasty (RHA), and non operative treatment were reviewed. Total reported incidence of office visits and utilization of each treatment modality were investigated. Sub-analysis with stratification by age 15-74 and greater than 75-years was performed for OF. RESULTS: A total of 10,609 OF and 20,400 RHNF were identified between 2007 and 2014. A significant trend increase in the annual incidence of RHNF (266 cases/year, p<0.001) and OF (133.9 cases/year, p=0.001) was observed. A significant trend increase in annual percent utilization of RHA (0.22% per year, p=0.011) and a significant trend decrease in the annual percent utilization of ORIF (-1.0% per year, p=0.004) and non-operative management (-0.53% per year, p=0.046) was observed for RHNF. A significant trend increase was observed in percent utilization (0.40% per year, p=0.022) for OF non-operative management, especially in patients over 75 years (66% per year, p=0.034). CONCLUSION: The percentage of patients being treated with RHA is increasing. Non-operative management of OF has increased, specifically in the patients who are over 75 years. PMID- 28567152 TI - A Complicated Course of a Coronal Shear Fracture Type IV of the Distal Part of Humerus Resulting in Resurfacing Radiocapitellar Joint Replacement. AB - BACKGROUND: Coronal shear fracture type IV of the distal part of humerus is a very rare injury with articular complexity potentially leading to posttraumatic osteoarthritis. One option for surgical treatment of advanced unicompartmental radiocapitellar osteoarthritis is resurfacing radiocapitellar joint replacement. METHOD: A 62-year- old female sustained a coronal shear fracture type IV of the distal part of left humerus that was primarily treated with open reduction and internal fixation using headless compression screws. Three years postoperatively, there was a migration of one screw into radiocapitellar joint that led to circular deep cartilage defect of radial head. Four years after ORIF, a distinctive radiocapitellar osteoarthritis has evolved leading to a resurfacing radiocapitellar joint replacement using the Lateral Resurfacing ElbowTM (LRE) system. RESULT: At the 2-year follow-up after that procedure, there was an excellent subjective and functional outcome. Radiographically, no loosening or subsidence of implant without any signs of overstuffing could be found. The patient reported that she would have the same procedure again. CONCLUSION: The goal of unicompartmental radiocapitellar replacement is to obtain stability in elbow joint by avoiding cubitus valgus with subsequent instability of the distal radioulnar joint, and it does not alter the unaffected ulnohumeral joint. Additionally, the feature of the LRETM system is that the radial head is not excised, and so will receive the anatomical length of the overall radius articulating with the capitellum by preserving the annular ligament. In the literature only three publications could be found in which short-term results with the use of the LRETM system have been described. Hence, further studies are needed to validate this concept. PMID- 28567153 TI - Comparison of Post-Operative Muscular Strength Between Gamma Nailing and Hemiarthroplasty System in Femoral Intertrochanteric Fractures. AB - BACKGROUND: The current study focuses on the comparison of postoperative muscular strength around the hip joint of patients with femoral intertrochanteric fractures treated either by cephalo-medullary (CM) nailing or a new bipolar hip prosthesis (BHP), an especially attached device to secure displaced greater trochanteric fragment. METHODS: Twenty patients treated with CM nailing were age- and sex- matched with a control group of 20 patients treated with BHP. Maximum isometric forces at the bilateral hip joint were measured during the follow up period. Means of 3 measurements were represented. RESULTS: The mean and standard deviation values (kg) of muscle strength at the non-operative/ operative side in the CM nailing group were as follows: flexion strength 9.5+/-4.7/8.5+/-4.9 (P=0.06), extension strength 6.2+/-3.5/5.5+/-3.7 (P=0.08), abduction strength at 0 degrees 7.7+/-3.5/6.2+/-2.8 (p=0.002), abduction strength at 10 degrees 5.5+/ 2.0/4.2+/-2.0 (p=0.001). In the BHP group, mean and standard deviation values of muscle strength at the non-operative/ operative side were as follows: flexion strength 6.5+/-2.8/6.0+/-3.4 (P=0.08), extension strength 4.4+/-0.9/4.4+/-0.6 (P=0.83), abduction strength at 0 degrees 5.1+/-1.9/5.0+/-1.6 (p=0.12), and that at 10 degrees 4.7+/-1.4/4.6+/-1.3 (p=0.10). CONCLUSION: Our results demonstrate that CM nailing may cause a 25-30% decrease in postoperative muscle strength around the hip joint, particularly during hip abduction. With the new BHP, greater trochanter reduction is achieved allowing early weight bearing and maintaining strength in abduction. Surgeons should consider postoperative muscular strength as one of the necessary factors for selection of the appropriate surgical procedure. LEVEL OF EVIDENCE: Therapeutic Level III. PMID- 28567154 TI - Angulating-Distraction Ulnar Osteotomy and Interpositional Phosphocalcic Ceramic Wedge Graft for a Chronic Monteggia Lesion. AB - BACKGROUND: Various types of osteotomies have been used to facilitate reduction of the radial head and to prevent recurrent subluxation. The Bouyala technique - open reduction of radial head associated with open wedge ulnar osteotomy with or without annular ligament reconstruction, is presently the most widely used treatment for long- standing traumatic dislocation of the radial head, independently of age, in the absence of osteoarthritis remodeling, and should preferably be performed within 1 year of trauma. METHOD: In this article, we present a similar case operated by same technique, but we used synthetic phosphocalcic ceramic wedge graft instead of auto bone graft as described in many other studies. We believe that, this will limit the donor site morbidity and also aid in achieving better stability at osteotomy site, which in turn help in proceeding with early active mobilization protocol. RESULT: We achieved union of the osteotomy by three months. Clinically, there was no deformity and she achieved full pain-free range of motion of elbow joint. CONCLUSION: We believe that, use of synthetic phosphocalcic ceramic wedge graft allow rigid fixation of osteotomy, provides additional stability, decrease the risk of secondary displacement and allow early mobilization, which may minimize contracture and we could achieve fairly good clinical outcome. PMID- 28567155 TI - Ballistic Trauma of Limbs. AB - : The objective of our study was to report the management and follow-up of a particular case of ballistic trauma and to do the literature review. OBSERVATION: A 35-year-old patient, a trader who was the victim of a firearm accident under not very clear circumstances. He was admitted to the emergency department after 3 hours. Clinically, the patient had significant bleeding in the arm and was in a state of clouding of consciousness. We could notice on the right arm, a posterior large transfixing wound of 1 cm and a 6 cm one on the antero-internal side. The limb was cold with a small and thready pulse. Sensitivity was decreased in the radial nerve area. The radiograph showed bone comminution from the middle 1/3 to the superior 1/3 of the humeral diaphysis. The treatment was orthopedic (after debridement) by scapula-brachio-ante-brachiopalmar plaster splint with thoracic strap. The wound healed in 46 days and the patient resumed his activities after 11 months and 2 weeks. CONCLUSION: The authors presented the value of using the scapulo-brachio-palmar plaster splints with thoracic strap in some severe upper limb trauma in the absence of the external fixator. PMID- 28567156 TI - Surgical Treatment of Angular Pott's Kyphosis with Posterior Approach, Pedicular Wedge Osteotomy and Canal Widening. AB - BACKGROUND: It has been observed that the correction of severe posttuberculous angular kyphosis is still a challenge, mainly because of the neurologic risk. METHODS: Nine patients were reviewed after surgery (mean follow-up 18 months). There were 2 thoracic, 4 thoraco-lumbar and 3 lumbar kyphosis. The mean age at surgery was 23. Clinical results were evaluated by the Oswestry Disability Index (ODI) and by the neurologic evaluation. Preoperative, postoperative and final follow-up X-rays were assessed. The surgery included a posterior approach with cord release and correction by transpedicular wedge osteotomy and widening of the spinal canal. RESULTS: Average kyphotic angulation was 72 degrees before surgery, 10 degrees after surgery and 12 degrees at follow-up. Three out of four patients with neural deficit showed improvement. Neurologic complications included a transitory quadriceps paralysis, likely by foraminal compression of the root. CONCLUSION: A posterior transpedicular wedge osteotomy allows a substantial correction of the kyphosis, more by deflexion than by elongation, with limited neurologic risks. However it is mandatory to widely enlarge the spinal canal on the levels adjacent to the osteotomy, in order to allow the dura to expand backwards. PMID- 28567157 TI - Modified Open Suprapectoral EndoButton Tension Slide Tenodesis Technique of Long Head of Biceps with Restored Tendon Tension-Length. AB - BACKGROUND: The vast majority of biceps tendon ruptures occurs at the proximal insertion and almost always involves the long head. There are several options for long head of biceps (LHB) tenodesis with advantage and disadvantages of each technique. We believe that the suprapectoral LHB tenodesis described in this article enables the restoration of the anatomic length-tension relation in a technically reproducible manner, when following the guidelines set forth in this article, and restores biceps contour and function adequately with a low risk of complications. METHOD: We present a case of a young man who had a sudden jerk of his flexed right elbow, while involved in water skiing sports and sustained complete rupture of proximal end of long head of biceps tendon. In this article, we describe a modified surgical technique of open supra-pectoral long head of biceps tenodesis using an EndoButton tension slide technique, reproducing an anatomic length-tension relationship. RESULTS: By the end of one year, patient regained symmetrical muscle bulk, shape and contour of biceps compared to other side. There were no signs of dislodgement or loosening of the EndoButton on follow-up radiographs. He regained full muscle power in the biceps without any possible complications, such as humeral fracture, infection, or nerve injury, associated with this technique. CONCLUSION: This technique is a safe, easy to reproduce, cost-effective, less time consuming and an effective method that uses a small drill hole, conserving bone, minimizing trauma to the tendon, and decreasing postoperative complications. It does not need any special instrumentation and is suitable especially for use in centers where arthroscopy facility or training is not available. PMID- 28567158 TI - Plaster of Paris-Short History of Casting and Injured Limb Immobilzation. AB - Various materials have been used since ancient times to help immobilise fractures. In this review, we discuss the history and developments of these materials as well as plaster of Paris. There has been a recent trend away from non-operative management of fractures, and skills in the use of plaster of Paris are declining. For the successful treatment of patients, it is important to appreciate how plaster works, how it should be used, and what can go wrong. In this review, we also discuss principles of applications and complications of plaster of Paris. PMID- 28567161 TI - Serial Femoral Fractures in An Amputation Stump: A Case Report. AB - We report a case of an above-knee amputee who underwent dynamic hip screw fixation for a proximal femoral fracture and then open reduction and internal fixation a few years later for a further femoral fracture in the same stump. The patient had a good outcome. We aim to discuss the challenges in decision making, surgical technique and potential complications for the patient. PMID- 28567159 TI - Humeral Tip-apex-distance as a Prognostic Marker for Proximal Humeral Fractures in 203 Patients. AB - BACKGROUND: Humeral head fractures and their postoperative outcome remain a challenging problem in surgical daily routine. Predictive factors for loss of fixation are rare. OBJECTIVE: Determination of predictive factors for the failure of osteosynthesis with the loss of fixation or migration of screws in humeral head fractures. METHOD: From 1995 to 2011, 408 patients with proximal humeral fractures [mean age 66.6 years, 50.9-82.3 years] and osteosynthesis were analyzed. Two hundred and three received open reduction internal fixation (ORIF) with the PHILOS(r) plate. The non-locking plate was used in 80, the locking plate in 16 and humeral head prosthesis in 26 patients, in addition to 23 patients undergoing other procedures. Intraoperative reduction that achieved an anatomical alignment of the medial aspect of the humerus (humeral calcar) was assessed in 94 patients by postoperative X-ray analysis. The loss of fixation was evaluated by a follow-up of three to five X-rays and measurement of the humeral tip-apex distance (HTAD). RESULTS: For stable fixed fractures with an intact calcar, percentual HTAD was significantly higher than for unstable fixed fractures (p=0.04). Morbidity, such as hypertension, orthopedic operations or diabetes, strongly influenced the HTAD, while postoperative passive motion treatment modestly affected the HTAD over time. CONCLUSION: The anatomic reconstruction of the calcar, leading to stable fixation of humeral head fractures, can significantly prevent an overproportioned decrease in the HTAD in postoperative X rays and seems to be vital in multimorbid patients. Measurement of the HTAD over time delivers a tool for early detection of secondary loss of fixation. PMID- 28567160 TI - The Introduction of a Multidisciplinary Hip Fracture Pathway to Optimise Patient Care and Reduce Mortality: A Prospective Audit of 161 Patients. AB - INTRODUCTION: Hip fractures are a major cause of morbidity and mortality in the elderly. A new patient pathway was introduced in our institution to facilitate rapid preoperative assessment, acute physician involvement and early surgery for patients with hip fractures. We sought to assess its impact on patient care and outcomes. MATERIALS AND METHODS: Prospective audit of 161 patients admitted with a proximal femoral fracture in the six months before (92 patients) and after (69 patients) implementation of the pathway. Data included: time to orthogeriatric assessment (TtG); time to surgery (TtS); length of hospital stay (LOS); return to original accommodation; inpatient mortality rate. RESULTS: In the six months after introduction of the pathway, there was an increase in patients who received pre-operative medical assessment (85% after vs. 19% before, p=0.0001). Average TtG decreased (19 vs. 91 hours, p=0.0001), as did LOS (19.5 vs. 24.8 days, p=0.029) and mortality (4 vs. 14%, p=0.0336). There was an increase in patients returning to their original place of accommodation (80% vs. 57%, p=0.0069). There was a reduction in mean TtS (31 vs. 37 hours, p=0.0663), although this was not statistically significant. DISCUSSION AND CONCLUSIONS: Rapid medical optimisation and prompt surgery significantly improve outcomes in patients with hip fractures. By involving an acute medical team in patient care from the point of admission, we have significantly improved our inpatient mortality and increased the proportion of patients returning to their preoperative place of accommodation, thereby maintaining patient independence and reducing the financial and logistical burden on social care. PMID- 28567162 TI - Cytomegalovirus, Macrophages and Breast Cancer. AB - The human cytomegalovirus (HCMV) is a betaherpesvirus that is highly host specific, infects among others epithelial cells and macrophages, and has been recently mentioned as having oncomodulatory properties. HCMV is detected in the breast tumor tissue where macrophages, especially tumor associated macrophages, are associated with a poor prognosis. In this review, we will discuss the potential implication of HCMV in breast cancer with emphasis on the role played by macrophages. PMID- 28567164 TI - Pars Plana Vitrectomy with Internal Limiting Membrane Peeling for Nontractional Diabetic Macular Edema. AB - BACKGROUND: Diabetes mellitus remains the leading cause of blindness among working age Americans with diabetic macular edema being the most common cause for moderate and severe vision loss. OBJECTIVE: To investigate the anatomical and visual benefits of pars plana vitrectomy with inner limiting membrane peeling in patients with nontractional diabetic macular edema as well as correlation of integrity of outer retinal layers on spectral domain optical coherence tomography to visual outcomes. METHODS: We retrospectively reviewed the charts of 42 diabetic patients that underwent vitrectomy with internal limiting membrane peeling for nontractional diabetic macula edema. The integrity of outer retinal layers was evaluated and preoperative central macular thickness and visual acuity were compared with data at 1 month, 3 months and 6 months postoperatively. The student t-test was used to compare the groups. RESULTS: 31 eyes were included. While no differences were seen at 1 and 3 months, there was significant improvement of both central macular thickness and visual acuity at the 6 months follow up visit compared to preoperatively (357, 427 microns; p=0.03. 20/49, 20/82; p=0.03) . Patients with intact external limiting membrane and ellipsoid zone had better preoperative vision than patients with outer retinal layer irregularities (20/54, 20/100; p=0.03) and greater visual gains postoperatively (20/33, p<0.001 versus 20/81; p=non-significant). CONCLUSION: Pars plana vitrectomy with internal limiting membrane peeling can improve retinal anatomy and visual acuity in patients with nontractional diabetic macular edema. Spectral domain optical coherence tomography may help identify patients with potential for visual improvement. PMID- 28567165 TI - Letter to the Editor: Corneoscleral Melt 50 Years after Excision of Pterygium. AB - PURPOSE: To report a case of corneoscleral melt that occurred 50 years after resection of pterygium with postoperative administration of mitomycin C (MMC). RESULTS: A 93-year-old woman developed acute corneal perforation and scleral melt in her left eye at 50 years after pterygium surgery with postoperative topical MMC. She underwent limbal transplantation. The anterior chamber reformed postoperatively and her intraocular pressure was normal. At 12 months after transplantation, best-corrected visual acuity was 20/500 and the graft-host junction was well apposed. CONCLUSION: This case shows that corneoscleral melt can occur even 50 years after resection of pterygium combined with postoperative topical MMC. PMID- 28567163 TI - Targeting Melanoma with Cancer-Killing Viruses. AB - Melanoma is the deadliest skin cancer with ever-increasing incidence. Despite the development in diagnostics and therapies, metastatic melanoma is still associated with significant morbidity and mortality. Oncolytic viruses (OVs) represent a class of novel therapeutic agents for cancer by possessing two closely related properties for tumor reduction: virus-induced lysis of tumor cells and induction of host anti-tumor immune responses. A variety of viruses, either in "natural" or in genetically modified forms, have exhibited a remarkable therapeutic efficacy in regressing melanoma in experimental and/or clinical studies. This review provides a comprehensive summary of the molecular and cellular mechanisms of action of these viruses, which involve manipulating and targeting the abnormalities of melanoma, and can be categorized as enhancing viral tropism, targeting the tumor microenvironment and increasing the innate and adaptive antitumor responses. Additionally, this review describes the "biomarkers" and deregulated pathways of melanoma that are responsible for melanoma initiation, progression and metastasis. Advances in understanding these abnormalities of melanoma have resulted in effective targeted and immuno-therapies, and could potentially be applied for engineering OVs with enhanced oncolytic activity in future. PMID- 28567166 TI - The Effect of Vitamin E on Oxidative Stress Indicated by Serum Malondialdehyde in Insulin-dependent Type 2 Diabetes Mellitus Patients with Retinopathy. AB - BACKGROUND: Several studies have focused on oxidative stress on diabetes mellitus (DM). Our purpose was to investigate the impact of oxidative stress on progression of diabetic retinopathy (DR) in insulin-dependent type 2 DM patients, measuring serum malondialdehyde (MDA), as well as to examine the effect of vitamin E on DR progression in the above-mentioned patients. METHODS: Participants in the study were 282 insulin-dependent type 2 DM patients with DR. All participants underwent a thorough ophthalmological examination, so as to grade DR, along with serum MDA measurement. All participants received 300mg vitamin E daily for 3 months and were examined again. Serum MDA pre- and post intake of Vitamin E was the main outcome. RESULTS: Serum MDA was positively associated with DR stage, while there was a statistically significant difference pre- and post-intake of vitamin E in all DR stages. In a subgroup analysis of patients with proliferative DR, there was a significant difference at baseline between patients who have received prior laser photocoagulation and the treatment naive patients, while after intake of vitamin E, no statistically significant difference was noticed. CONCLUSION: Oxidative stress has been found to play significant role in the pathogenesis and progression of DR, while vitamin E seems to reduce MDA levels and subsequent oxidative stress, suggesting that it might have protective role in DR progression. PMID- 28567167 TI - Nurse Competence on Physiologic Monitors Use: Toward Eliminating Alarm Fatigue in Intensive Care Units. AB - BACKGROUND: Studies on nurse competence on alarm management are a few and tend to be focused on limited skills. In response to Phase II of implementing the National Patient Safety Goal on clinical alarm systems safety, this study assessed nurses' perceived competence on physiologic monitors use in intensive care units (ICUs) and developed and validated a tool for this purpose. METHODS: This descriptive study took place in a Magnet hospital in a Southwestern state of the U.S. A Nurse Competence on Philips Physiologic Monitors Use Survey was created and went through validation by 13 expert ICU nurses. The survey included 5 subscales with 59 rated items and two open-ended questions. Items on the first 4 subscales reflect most common tasks nurses perform using physiologic monitors. Items on the fifth subscale (advanced functions) reflect rarely used skills and were included to understand the scope of utilizing advanced physiologic monitors' features. Thirty nurses from 4 adult ICUs were invited to respond to the survey. RESULTS: Thirty nurses (100%) responded to the survey. The majority of nurses were from Neuro (47%) and Surgical Trauma (37%) ICUs. The data supported the high reliability and construct validity of the survey. At least one (3%) to 8 nurses (27%) reported lack of confidence on each item on the survey. On the first four subscales, 3% - 40% of the nurses reported they had never heard of or used 27 features/functions on the monitors. No relationships were found between subscales' scores and demographic characteristics (p > .05). Nurses asked for training on navigating the central-station monitor and troubleshooting alarms, and the use of unit-specific super users to tailor training to users' needs. CONCLUSION: This is the first study to create and test a list of competencies for physiologic monitors use. Rigorous, periodic and individualized training is essential for safe and appropriate use of physiologic monitors and to decrease alarm fatigue. Training should be comprehensive to include all necessary skills and should not assume proficiency on basic skills. Special attention should be focused on managing technical alarms. Increasing the number of super users is a recommended strategy for individualized and unit-specific training. There is a need for a usability testing of complex IT-equipped medical devices, such as physiologic monitors, for effective, efficient and safe navigation of the monitors. PMID- 28567168 TI - Nurses' Knowledge toward Hepatitis B and Hepatitis C in Guilan, Iran. AB - BACKGROUND: Health care workers (HCWs) represent high risk population for viral hepatitis infection. OBJECTIVES: This study sought to assess the knowledge of HCWs regarding hepatitis B (HBV) and hepatitis C (HCV) infection. METHODS: In a multi-center cross sectional study, all HCWs from eight teaching hospitals were invited to participate in the study and to fill in a self-administered questionnaire. RESULTS: A total of 1008 eligible HCWs have responded to the study. A high proportion of the study participants (55.4% and 52.9%) had unsatisfactory knowledge about HBV and HCV. Mean knowledge score toward HBV was significantly higher among more educated staff, p <0.001 and vaccinated personnel, P=0.02. Majority of responders answered correctly to transmission questions toward HBV and HCV (90% and 80%, respectively). There was statistically significant difference in only transmission domain score between various hospitals (p<0.05). The highest scores were related to surgical hospital. CONCLUSION: Although more than ninety percent of our participants were educated about HBV and HCV, knowledge about nature of disease, prevention, treatment and vaccine availability was unsatisfactory. Continuous training program toward viral infection is a matter of necessity. PMID- 28567169 TI - Patients' Variations of Reflection About and Understanding of Long-Term Illness- Impact of Illness Perception on Trust in Oneself or Others. AB - BACKGROUND: Patients' understanding of their illness is of great importance for recovery. Lacking understanding of the illness is linked with the patients' level of reflection about and interest in understanding their illness. OBJECTIVE: To describe patients' variations of reflection about and understanding of their illness and how this understanding affects their trust in themselves or others. METHOD: The study is based on the "Illness perception" model. Latent content analysis was used for the data analysis. Individual, semi-structured, open-ended and face-to-face interviews were conducted with patients (n=11) suffering from a long-term illness diagnosed at least six months prior to the interview. Data collection took place in the three primary healthcare centres treating the participants. RESULTS: The results show variations in the degree of reflection about illness. Patients search for deeper understanding of the illness for causal explanations, compare different perspectives for preventing complication of their illness, trust healthcare providers, and develop own strategies to manage life. CONCLUSION: Whereas some patients search for deeper understanding of their illness, other patients are less reflective and feel they can manage the illness without further understanding. Patients' understanding of their illness is related to their degree of trust in themselves or others. Patients whose illness poses an existential threat are more likely to reflect more about their illness and what treatment methods are available. PMID- 28567170 TI - Acceptability Among Community Healthcare Nurses of Intelligent Wireless Sensor system Technology for the Rapid Detection of Health Issues in Home-dwelling Older Adults. AB - BACKGROUND: The effective care and support of community healthcare nurses (CHNs) contribute greatly to the healthy aging of older adults living at home. Integrating innovative technologies into CHNs' daily practice offers new opportunities and perspectives for early detection of health issues and interventions among home-dwelling older adults. AIM: To explore the perception of acceptability among CHNs of an intelligent wireless sensor system (IWSS) for use in daily practice for the detection of health issues in home-dwelling older adults receiving home healthcare. METHOD: Descriptive and qualitative data were sourced from a pilot randomized controlled trial involving 17 CHNs using an IWSS in their daily practice to rapidly detect falls and other health issues in patients' homes. IWSS alerts indicating behavior changes were sent to CHNs. Their perceived usefulness (PU) and perceived ease of use (PEOU) were assessed. The acceptability of IWSS technology was explored using a questionnaire and focus group discussions. RESULTS: The PU and PEOU of the IWSS technology were low to moderate. A majority of the CHNs were dissatisfied with its performance and intrusiveness; they reported multiple obstacles in the usefulness and ease of use of the IWSS technology in daily practice. CONCLUSION: To improve the IWSS technology's low to moderate acceptability among CHNs, we recommend a more user centered implementation strategy and an embedded model of nursing care. PMID- 28567171 TI - A Functional MRI-Based Model for Individual Memory Assessment in Patients Eligible for Anterior Temporal Lobe Resection. AB - TITLE: A functional (f) MRI-based model for individual memory assessment in patients eligible for temporal lobe resection. AIM: To investigate if pre operative fMRI memory paradigms, add predictive information with regard to post surgical memory deficits. METHODS: Fourteen pharmacoresistant Temporal Lobe Epilepsy (TLE) patients accepted for Anterior Temporal Lobe Resection (ATLR) were included. A clinical risk assessment score (RAS 0-3) was constructed from structural MRI, neuropsychological testing and hemisphere dominance. fMRI lateralization indices (LIs) over frontal language and medial temporal regions were calculated. Predictive value from clinical risk scoring and added value from fMRI LIs were correlated to post-surgical memory change scores (significant decline -1 SD). Verbal memory outcome was classified either as expected (RAS 2-3 and post-operative decline; RAS 0-1 and intact post-operative verbal memory) or as unexpected (RAS 2-3 and intact post-operative verbal memory post-surgery; RAS 0-1 and post-operative decline). RESULTS: RAS for verbal memory decline exhibited a specificity of 67% and a sensitivity of 75%. Significant correlations were found between frontal language LIs and post-operative verbal memory (r = -0.802; p = 0.017) for left (L) TLE and between medial temporal lobe LIs and visuospatial memory (r = 0.829; p = 0.021), as well as verbal memory (r = 0.714; p = 0.055) for right (R) TLE. Ten patients had expected outcome and four patients had an unexpected outcome. In two MRI-negative RTLE patients that suffered significant verbal memory decline post-operatively, fMRI identified bilateral language and right lateralized medial temporal verbal encoding. In two LTLE patients with MRI pathology and verbal memory dysfunction, neither RAS nor fMRI identified the risk for aggravated verbal memory decline following ATLR. CONCLUSION: fMRI visualization of temporal-frontal network activation may add value to the pre surgical work-up in epilepsy patients eligible for ATLR. Frontal language patterns are important for prediction in both L and RTLE. Strong left lateralized language in LTLE, as well as bilateral language combined with right lateralized encoding in RTLE, seems to indicate an increased risk for post-operative verbal memory decline. PMID- 28567172 TI - Forms of Stigma and Discrimination in the Daily Lives of HIV-Positive Individuals in Mauritania. AB - SUMMARY: People living with HIV/AIDS (PLWHA) are often discriminated against in their daily lives. The objective of this descriptive and transversal study was to describe the experiences of PLWHA followed at a specialized outpatient center in Nouakchott to assess the forms of stigma from the perspective of those who suffer from discrimination. METHODS: All HIV-positive patients over the age of 18 years who were aware of their HIV status and provided consent to participate in the study were included from June 1 to 29, 2015. Data collection was conducted using a pre-tested questionnaire. RESULTS: A total of 210 PLWHA were interviewed. Men accounted for 54% of the sample population with a sex ratio of 1.2. About half of respondents were married (51%) and resided in Nouakchott (55%). Subjects who had never attended school represented 42% of the cases. Among our respondents, 64% knew their HIV status for over a year and admitted that they refused to reveal this information to any person. The distribution of forms of stigma experienced by PLWHA by demographic category was, in descending order, stigma in interpersonal relationships (78%), self-stigma (20%), and stigma in health services (2%). There was a significant association between the form of stigma and marital status (p = 0.007) and between the form of stigma and knowledge of HIV status for a period greater than one year (p = 0.02). CONCLUSION: The forms of stigma can be sources of discrimination and are a major obstacle to reintegration and support of PLWHA. This creates a vicious circle that, on the one hand, leads to the suffering, marginalization, and isolation of PLWHA, and on the other hand, has deleterious effects on their family and social relationships, self-esteem and self-confidence. PMID- 28567173 TI - Tensorial elastic properties and stability of interface states associated with Sigma5(210) grain boundaries in Ni3(Al,Si). AB - Grain boundaries (GBs) represent one of the most important types of defects in solids and their instability leads to catastrophic failures in materials. Grain boundaries are challenging for theoretical studies because of their distorted atomic structure. Fortunately, quantum-mechanical methods can reliably compute their properties. We calculate and analyze (tensorial) anisotropic elastic properties of periodic approximants of interface states associated with GBs in one of the most important intermetallic compounds for industrial applications, Ni3Al, appearing in Ni-based superalloys. Focusing on the Sigma5(210) GBs as a case study, we assess the mechanical stability of the corresponding interface states by checking rigorous elasticity-based Born stability criteria. The critical elastic constant is found three-/five-fold softer contributing thus to the reduction of the mechanical stability of Ni3Al polycrystals (experiments show their GB-related failure). The tensorial elasto-chemical complexity of interface states associated with the studied GBs exemplifies itself in high sensitivity of elastic constants to the GB composition. As another example we study the impact caused by Si atoms segregating into the atomic layers close to the GB and substituting Al atoms. If wisely exploited, our study paves the way towards solute-controlled design of GB-related interface states with controlled stability and/or tensorial properties. PMID- 28567174 TI - A new material platform of Si photonics for implementing architecture of dense wavelength division multiplexing on Si bulk wafer. AB - A new materials group to implement dense wavelength division multiplexing (DWDM) in Si photonics is proposed. A large thermo-optic (TO) coefficient of Si malfunctions multiplexer/demultiplexer (MUX/DEMUX) on a chip under thermal fluctuation, and thus DWDM implementation, has been one of the most challenging targets in Si photonics. The present study specifies an optical materials group for DWDM by a systematic survey of their TO coefficients and refractive indices. The group is classified as mid-index contrast optics (MiDex) materials, and non stoichiometric silicon nitride (SiNx) is chosen to demonstrate its significant thermal stability. The TO coefficient of non-stoichiometric SiNx is precisely measured in the temperature range 24-76 degrees C using the SiNx rings prepared by two methods: chemical vapor deposition (CVD) and physical vapor deposition (PVD). The CVD-SiNx ring reveals nearly the same TO coefficient reported for stoichiometric CVD-Si3N4, while the value for the PVD-SiNx ring is slightly higher. Both SiNx rings lock their resonance frequencies within 100 GHz in this temperature range. Since CVD-SiNx needs a high temperature annealing to reduce N H bond absorption, it is concluded that PVD-SiNx is suited as a MiDex material introduced in the CMOS back-end-of-line. Further stabilization is required, considering the crosstalk between two channels; a 'silicone' polymer is employed to compensate for the temperature fluctuation using its negative TO coefficient, called athermalization. This demonstrates that the resonance of these SiNx rings is locked within 50 GHz at the same temperature range in the wavelength range 1460-1620 nm (the so-called S, C, and L bands in optical fiber communication networks). A further survey on the MiDex materials strongly suggests that Al2O3, Ga2O3 Ta2O5, HfO2 and their alloys should provide even more stable platforms for DWDM implementation in MiDex photonics. It is discussed that the MiDex photonics will find various applications such as medical and environmental sensing and in vehicle data-communication. PMID- 28567175 TI - Carrier properties of B atomic-layer-doped Si films grown by ECR Ar plasma enhanced CVD without substrate heating. AB - The atomic-layer (AL) doping technique in epitaxy has attracted attention as a low-resistive ultrathin semiconductor film as well as a two-dimensional (2-D) carrier transport system. In this paper, we report carrier properties for B AL doped Si films with suppressed thermal diffusion. B AL-doped Si films were formed on Si(100) by B AL formation followed by Si cap layer deposition in low-energy Ar plasma-enhanced chemical-vapor deposition without substrate heating. After fabrication of Hall-effect devices with the B AL-doped Si films on unstrained and 0.8%-tensile-strained Si(100)-on-insulator substrates (maximum process temperature 350 degrees C), carrier properties were electrically measured at room temperature. Typically for the initial B amount of 2 * 1014 cm-2 and 7 * 1014 cm 2, B concentration depth profiles showed a clear decay slope as steep as 1.3 nm/decade. Dominant carrier was a hole and the maximum sheet carrier densities as high as 4 * 1013 cm-2 and 2 * 1013 cm-2 (electrical activity ratio of about 7% and 3.5%) were measured respectively for the unstrained and 0.8%-tensile-strained Si with Hall mobility around 10-13 cm2 V-1 s-1. Moreover, mobility degradation was not observed even when sheet carrier density was increased by heat treatment at 500-700 degrees C. There is a possibility that the local carrier (ionized B atom) concentration around the B AL in Si reaches around 1021 cm-3 and 2-D impurity-band formation with strong Coulomb interaction is expected. The behavior of carrier properties for heat treatment at 500-700 degrees C implies that thermal diffusion causes broadening of the B AL in Si and decrease of local B concentration. PMID- 28567176 TI - Combinatorial screening of halide perovskite thin films and solar cells by mask defined IR laser molecular beam epitaxy. AB - As an extension of combinatorial molecular layer epitaxy via ablation of perovskite oxides by a pulsed excimer laser, we have developed a laser molecular beam epitaxy (MBE) system for parallel integration of nano-scaled thin films of organic-inorganic hybrid materials. A pulsed infrared (IR) semiconductor laser was adopted for thermal evaporation of organic halide (A-site: CH3NH3I) and inorganic halide (B-site: PbI2) powder targets to deposit repeated A/B bilayer films where the thickness of each layer was controlled on molecular layer scale by programming the evaporation IR laser pulse number, length, or power. The layer thickness was monitored with an in situ quartz crystal microbalance and calibrated against ex situ stylus profilometer measurements. A computer controlled movable mask system enabled the deposition of combinatorial thin film libraries, where each library contains a vertically homogeneous film with spatially programmable A- and B-layer thicknesses. On the composition gradient film, a hole transport Spiro-OMeTAD layer was spin-coated and dried followed by the vacuum evaporation of Ag electrodes to form the solar cell. The preliminary cell performance was evaluated by measuring I-V characteristics at seven different positions on the 12.5 mm * 12.5 mm combinatorial library sample with seven 2 mm * 4 mm slits under a solar simulator irradiation. The combinatorial solar cell library clearly demonstrated that the energy conversion efficiency sharply changes from nearly zero to 10.2% as a function of the illumination area in the library. The exploration of deposition parameters for obtaining optimum performance could thus be greatly accelerated. Since the thickness ratio of PbI2 and CH3NH3I can be freely chosen along the shadow mask movement, these experiments show the potential of this system for high-throughput screening of optimum chemical composition in the binary film library and application to halide perovskite solar cell. PMID- 28567177 TI - Suppressing the coffee-ring effect of colloidal droplets by dispersed cellulose nanofibers. AB - We report that the addition of a small amount of cellulose nanofibers (CNFs) into an aqueous dispersion of colloidal particles suppresses the coffee-ring effect when the dispersion dries on a solid substrate, as revealed by the computational analysis of experimental time-series images and by particle image velocimetry. The addition of CNFs is much more effective than the increase of colloidal particle concentration at the same weight percentage; it is also more environment friendly than the use of typical molecular surfactants. This finding is promising for the fabrication of metamaterials from colloidal dispersions and for ink printing in electronics, where CNFs can also serve as a substrate for flexible devices. PMID- 28567178 TI - Novel magnetic properties of CoTe nanorods and diversified CoTe2 nanostructures obtained at different NaOH concentrations. AB - CoTe and CoTe2 nanorods with average diameter of 100 nm were synthesized by a simple hydrothermal process, and different CoTe2 nanostructures were obtained by changing the NaOH concentration. CoTe nanorods exhibit weak ferromagnetism while CoTe2 nanorods present paramagnetic behavior. Different magnetic behaviors occur in the other CoTe2 nanostructures due to Na+ entrance into CoTe2 crystals. A first-principles study on Na-doped CoTe2 confirms the magnetic characteristics. PMID- 28567180 TI - Bilateral persistent primitive hypoglossal arteries associated with unilateral symptomatic carotid thromboembolism. AB - We report the fifth case of bilateral persistent primitive hypoglossal arteries in the literature. This is also the first such case to be demonstrated on computerized tomography angiogram (CTA) and the first case to be associated with a symptomatic carotid thrombus. The sub-occlusive thrombus was distal to the take off of the dominant persistent hypoglossal artery (PHA) from the internal carotid artery, thus sparing involvement of posterior circulation. Timely identification of the internal carotid artery thromboembolism in the setting of a PHA is important to allow for thrombectomy. Any intervention was not done in this case as the patient was out of the window and at an additional risk of inducing intracranial thromboembolism. Symptomatic carotid stenosis at the PHA take-off is typically treated with endovascular angioplasty and stenting due to the typically high level of the bifurcation in the neck. PMID- 28567181 TI - Incidental finding - the discovery of a bronchopulmonary foregut malformation through investigations for Crohn's disease. AB - Pulmonary sequestration (PMS) is a rare bronchopulmonary malformation. It has an incidence of between 0.15% to 1.7%. Likewise, cystic adenomatoid malformation (CCAM) is another relatively rare category of a bronchopulmonary malformation with a reported incidence of between 1 in 25,000 to 1 in 35,000. Moreover, a bronchopulmonary malformation with features allied to both of these forms is considered an even rarer entity. In general, bronchopulmonary malformations present with a range of non-specific symptoms. Radiological features can be non specific yet distinctive when related to clinical features. Ultimately, definitive diagnosis depends upon histological assessment of lung tissue. We present an adult female with radiological features of both pulmonary sequestration and cystic adenomatoid malformation. This was an incidental finding unrelated to the patients presenting complaint. This case highlights the importance of using a structured and systematic approach when interpreting medical imagery. PMID- 28567182 TI - Adenocarcinoma of the Appendix Presenting as a Palpable Right Thigh Mass. AB - Intra-abdominal and intra-pelvic pathologies initially presenting in extra abdominal/pelvic locations is unusual. This spread predominantly occurs with infectious processes to sites including the buttock, thigh, and calf. The routes of extension into adjacent anatomically weak compartments include the pelvic outlet, greater sciatic foramen, obturator foramen, inguinal or femoral canal, weak bones, or along nerves and blood vessels. Malignant neoplasms of the appendix, while extremely rare and accounting for only 0.4% of all gastrointestinal cancers, is one of the intra-abdominal pathologies that can spread via these routes. Adenocarcinoma of the appendix accounts for 10-20% of primary appendiceal tumors. They usually present as acute appendicitis or as a right lower quadrant abdominal mass when associated with a mucocele. We report the unique case of mucinous appendiceal adenocarcinoma in a 57-year-old male who initially presented with a right thigh mass secondary to extension of the neoplasm from the right lower quadrant through the femoral canal. A similar presentation of a mucinous appendiceal cystadenoma has been previously reported, however, to our knowledge, this is the first case of a malignant appendiceal tumor extending into the thigh. We review the literature and discuss imaging findings and treatment of this tumor. PMID- 28567179 TI - Understanding chemically processed solar cells based on quantum dots. AB - Photovoltaic energy conversion is one of the best alternatives to fossil fuel combustion. Petroleum resources are now close to depletion and their combustion is known to be responsible for the release of a considerable amount of greenhouse gases and carcinogenic airborne particles. Novel third-generation solar cells include a vast range of device designs and materials aiming to overcome the factors limiting the current technologies. Among them, quantum dot-based devices showed promising potential both as sensitizers and as colloidal nanoparticle films. A good example is the p-type PbS colloidal quantum dots (CQDs) forming a heterojunction with a n-type wide-band-gap semiconductor such as TiO2 or ZnO. The confinement in these nanostructures is also expected to result in marginal mechanisms, such as the collection of hot carriers and generation of multiple excitons, which would increase the theoretical conversion efficiency limit. Ultimately, this technology could also lead to the assembly of a tandem-type cell with CQD films absorbing in different regions of the solar spectrum. PMID- 28567183 TI - Radiologic Findings in Gabapentin-Induced Myositis. AB - Throughout recent years, Gabapentin has become increasingly used for the treatment of neuropathic pain. We report on a case of a 31 year old female who presented to the emergency department with unilateral leg pain, weakness, and swelling after increasingly titrating her Gabapentin dosage over three weeks. Magnetic resonance imaging confirmed the presence of myositis confined to the left thigh and the patient's symptoms and laboratory abnormalities resolved following Gabapentin cessation. While Gabapentin-induced myositis and rhabdomyolysis is a rare entity, it should be a diagnostic consideration for radiologists, particularly in the absence of infection or trauma. PMID- 28567185 TI - Extramural vascular invasion and response to neoadjuvant chemoradiotherapy in rectal cancer: Influence of the CpG island methylator phenotype. AB - AIM: To identify whether CpG island methylator phenotype (CIMP) is predictive of response to neoadjuvant chemoradiotherapy (NACRT) and outcomes in rectal cancer. METHODS: Patients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified. Pre-treatment tumour biopsies were analysed for CIMP status (high, intermediate or low) using methylation specific PCR. KRAS and BRAF status were also determined using pyrosequencing analysis. Clinical information was extracted from case records and cancer services databases. Response to radiotherapy was measured by tumour regression scores determined upon histological examination of the resected specimen. The relationship between these molecular features, response to NACRT and oncological outcomes were analysed. RESULTS: There were 160 patients analysed with a median follow-up time of 46.4 mo. Twenty-one (13%) patients demonstrated high levels of CIMP methylation (CIMP-H) and this was significantly associated with increased risk of extramural vascular invasion (EMVI) compared with CIMP-L [8/21 (38%) vs 15/99 (15%), P = 0.028]. CIMP status was not related to tumour regression after radiotherapy or survival, however EMVI was significantly associated with adverse survival (P < 0.001). Intermediate CIMP status was significantly associated with KRAS mutation (P = 0.01). There were 14 (9%) patients with a pathological complete response (pCR) compared to 116 (73%) patients having no or minimal regression after neoadjuvant chemoradiotherapy. Those patients with pCR had median survival of 106 mo compared to 65.8 mo with minimal regression, although this was not statistically significant (P = 0.26). Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed, EMVI positivity was associated with poor overall survival, advanced "T" stage and CIMP-H but not nodal status, age, sex, KRAS mutation status and presence of local or systemic recurrence. CONCLUSION: We report a novel association of pre-treatment characterisation of CIMP-H with EMVI status which has prognostic implications and is not readily detectable on pre treatment histological examination. PMID- 28567184 TI - Molecular classifications of gastric cancers: Novel insights and possible future applications. AB - Despite some notable advances in the systemic management of gastric cancer (GC), the prognosis of patients with advanced disease remains overall poor and their chance of cure is anecdotic. In a molecularly selected population, a median overall survival of 13.8 mo has been reached with the use of human epidermal growth factor 2 (HER2) inhibitors in combination with chemotherapy, which has soon after become the standard of care for patients with HER2-overexpressing GC. Moreover, oncologists have recognized the clinical utility of conceiving cancers as a collection of different molecularly-driven entities rather than a single disease. Several molecular drivers have been identified as having crucial roles in other tumors and new molecular classifications have been recently proposed for gastric cancer as well. Not only these classifications allow the identification of different tumor subtypes with unique features, but also they serve as springboard for the development of different therapeutic strategies. Hopefully, the application of standard systemic chemotherapy, specific targeted agents, immunotherapy or even surgery in specific cancer subgroups will help maximizing treatment outcomes and will avoid treating patients with minimal chance to respond, therefore diluting the average benefit. In this review, we aim at elucidating the aspects of GC molecular subtypes, and the possible future applications of such molecular analyses. PMID- 28567187 TI - Introduction of laparoscopic gastrectomy for gastric cancer in a Western tertiary referral centre: A prospective cost analysis during the learning curve. AB - AIM: To evaluate the costs of the introduction of a laparoscopic surgery program for gastric cancer in a Western community training hospital and tertiary referral centre for gastric cancer surgery. METHODS: All patients who underwent surgery for gastric cancer with curative intent in 2013 and 2014 were prospectively included. Primary outcomes were costs regarding surgery and hospital stay. RESULTS: Laparoscopic gastrectomy was used in 52 patients [mean age 68 years (+/- 9, range 50 to 87)] and open gastrectomy was used in 25 patients [mean age 70 years (+/- 10, range 46 to 85)]. Mean costs (in euro's) of surgical instrumentation were significantly higher for laparoscopic surgery: 2270 +/- 670 vs 1181 +/- 680 in the open approach (P < 0.001). Costs of theatre use were higher in the laparoscopic group: mean 3819 +/- 865 vs 2545 +/- 1268 in the open surgery (P < 0.001). Total costs of hospitalization (i.e., costs of surgery and admission) were not different between laparoscopic and open surgery, 8187 +/- 4864 and 7673 +/- 8064 respectively (P = 0.729). Mean length of hospital stay was 9 +/- 12 d in the laparoscopic group vs 14 +/- 14 d in the open group (P = 0.044). CONCLUSION: The introduction of laparoscopic gastrectomy for gastric cancer coincided with higher costs for theatre use and surgical instrumentation compared to the open technique. Total costs were not significantly different due to shorter length of stay and less intensive care unit (ICU) admissions and shorter ICU stay in the laparoscopic group. PMID- 28567186 TI - Critical evaluation of contemporary management in a new Pelvic Exenteration Unit: The first 25 consecutive cases. AB - AIM: To critically appraise short-term outcomes in patients treated in a new Pelvic Exenteration (PE) Unit. METHODS: This retrospective observational study was conducted by analysing prospectively collected data for the first 25 patients (16 males, 9 females) who underwent PE for advanced pelvic tumours in our PE Unit between January 2012 and October 2016. Data evaluated included age, co morbidities, American Society of Anesthesiologists (ASA) score, Eastern Cooperative Oncology Group (ECOG) status, preoperative adjuvant treatment, intra operative blood loss, procedural duration, perioperative adverse event, lengths of intensive care unit (ICU) stay and hospital stay, and oncological outcome. Quantitative data were summarized as percentage or median and range, and statistically assessed by the chi2 test or Fisher's exact test, as applicable. RESULTS: All 25 patients received comprehensive preoperative assessment via our dedicated multidisciplinary team approach. Long-course neoadjuvant chemoradiotherapy was provided, if indicated. The median age of the patients was 61.9-year-old. The median ASA and ECOG scores were 2 and 0, respectively. The indications for PE were locally invasive rectal adenocarcinoma (n = 13), advanced colonic adenocarcinoma (n = 5), recurrent cervical carcinoma (n = 3) and malignant sacral chordoma (n = 3). The procedures comprised 10 total PEs, 4 anterior PEs, 7 posterior PEs and 4 isolated lateral PEs. The median follow-up period was 17.6 mo. The median operative time was 11.5 h. The median volume of blood loss was 3306 mL, and the median volume of red cell transfusion was 1475 mL. The median lengths of ICU stay and of hospital stay were 1 d and 21 d, respectively. There was no case of mortality related to surgery. There were a total of 20 surgical morbidities, which occurred in 12 patients. The majority of the complications were grade 2 Clavien-Dindo. Only 2 patients experienced grade 3 Clavien-Dindo complications, and both required procedural interventions. One patient experienced grade 4a Clavien-Dindo complication, requiring temporary renal dialysis without long-term disability. The R0 resection rate was 64%. There were 7 post-exenteration recurrences during the follow-up period. No statistically significant relationship was found among histological origin of tumour, microscopic resection margin status and postoperative recurrence (P = 0.67). Four patients died from sequelae of recurrent disease during follow-up. CONCLUSION: By utilizing modern assessment and surgical techniques, our PE Unit can manage complex pelvic cancers with acceptable morbidities, zero-rate mortality and equivalent oncologic outcomes. PMID- 28567188 TI - Challenges facing young African scientists in their research careers: A qualitative exploratory study. AB - BACKGROUND: Africa accounts for 14% of world's population, and the economies of most African countries are considered to be growing, but this is not reflected in the amount of research published by Africans. This study aimed at identifying the challenges that young African scientists face in their career development. METHODS: This was a qualitative exploratory study involving young researchers who attended the Teaching and Research in Natural Sciences for Development (TReND) in Africa scientific writing and communication workshop, which was held in Malawi in September 2015. A semi-structured questionnaire was sent to all workshop participants who consented to taking part in the survey. In total, 28 questionnaires were sent via email and 15 were returned, representing a response rate of 53.6%. Data were analysed using thematic analysis. RESULTS: Young Africans develop their research interests various ways. The most common career promoting factors identified by the study participants included formal classroom learning, aspirations to attain academic qualifications, work satisfaction, and the desire to fulfill parents' dreams. Challenges cited by survey respondents included a lack of mentorship, funds, and research and writing skills. Lack of interest in research by policymakers, lack of motivation by peers, and heavy workload (leaving little time for research) were also reported as challenges. Respondents suggested that grants specifically targeting young scientists would be beneficial. Participants also urged for the establishment of mentorship programmes, increasing motivation for research, and more frequent training opportunities. CONCLUSIONS: There is need for improved funding for institutional and research network strengthening in Africa, with particular attention given to expanding opportunities for young researchers. PMID- 28567190 TI - Experiences of caregivers of infants who have been on bubble continuous positive airway pressure at Queen Elizabeth Central Hospital, Malawi: A descriptive qualitative study. AB - BACKGROUND: An innovative, low-cost bubble continuous positive airway pressure (bCPAP) device has recently been introduced in Malawi for the treatment of respiratory distress in infants. While this novel bCPAP system has been shown to be safe and effective in reducing infant mortality, caregivers' experiences have not been investigated. The purpose of this study was to explore experiences of parents and guardians of infants who had been on bCPAP at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi. METHODS: This was a descriptive phenomenological study that was carried out at the Chatinkha nursery unit and the paediatric nursery ward at QECH, from January to February 2015. Purposive sampling was used to select participants for in-depth interviews. Data saturation was reached with 12 caregivers. Data were analysed using Colaizzi's framework. RESULTS: Caregivers received inadequate, inconsistent, and sporadic information about bCPAP. Student nurses and doctors were best able to answer caregivers' questions and concerns. When their infants were on bCPAP, caregivers felt anxious and fearful. However, upon implementation of bCPAP treatment for their children, the caregivers were satisfied with it. The main sources of psychological stress were limited parent-child interaction and the constraints of prescribed visiting hours. Family, friends, and caregiver involvement in the care of infants provided some psychological comfort. CONCLUSIONS: The results show gaps in the information and psychological support that mothers of infants on bCPAP receive in hospital. We recommend that psychological support be given to the mothers of infants on bCPAP at QECH. PMID- 28567189 TI - Polymerase chain reaction identification of Trypanosoma brucei rhodesiense in wild tsetse flies from Nkhotakota Wildlife Reserve, Malawi. AB - BACKGROUND: Trypanosoma brucei rhodesiense is the causative agent of acute human African trypanosomiasis. Identification of T. b. rhodesiense in tsetse populations is essential for understanding transmission dynamics, assessng human disease risk, and monitoring spatiotemporal trends and impact of control interventions. Accurate detection and characterisation of trypanosomes in vectors relies on molecular techniques. For the first time in Malawi, a molecular technique has been used to detect trypanosomes in tsetse flies in Nkhotakota Wildlife Reserve. METHODS: A polymerase chain reaction (PCR) technique was used to identify the serum resistance associated (SRA) gene of T. b. rhodesiense in tsetse flies. Of 257 tsetse flies that were randomly caught, 42 flies were dissected for microscopic examination. The midguts of 206 flies were positive and were individually put in eppendorf tubes containing phosphate-buffered saline (PBS buffer) for DNA extraction. Internal transcribed spacer (ITS)-PCR was first used to isolate all trypanosome species from the flies. TBR PCR was then used to isolate the Trypanozoon group. T. brucei-positive samples were further evaluated by SRA PCR for the presence of the SRA gene. RESULTS: Of 257 flies caught, 185 (72%) were Glossina morsitans morsitans and 72 (28%) were Glossina pallidipes. Three were tenerals and 242 were mature live flies. Of the 242 flies dissected, 206 were positive, representing an 85.1% infection rate. From 206 infected flies, 106 (51.5%) were positive using ITS-PCR, 68 (33.0%) being mixed infections, 18 (8.7%) T. brucei, 9 (4.4%) Trypanosoma vivax, 4 (1.9%) Trypanosoma godfrey, 3 (1.5%) Trypanosoma congolense savanna, 3 (1.5%) Trypanosoma simae, and 1 (0.4%) Trypanosoma simaetsavo. When subjected to TBR PCR, 107(51.9%) were positive for T. brucei. Of the 107 T. brucei-positive samples, 5 (4.7%) were found to have the SRA gene. CONCLUSIONS: These results suggest that wild tsetse flies in Malawi are infected with human-infective trypanosomes that put communities around wildlife reserves at risk of human African trypanosomiasis outbreaks. Further studies need to be done to identify sources of blood meals for the flies and for surveillance of communities around wildlife reserves. PMID- 28567191 TI - Prevalence and distribution of Schistosoma haematobium infection among school children living in southwestern shores of Lake Malawi. AB - BACKGROUND: The prevalence of Schistosoma haematobium infection has been shown to be about 23.7% among children living in the lakeshore areas of Malawi, with reinfection rates of about 30% to 40%. This study aimed to determine the current prevalence and distribution of S. haematobium infection in school children along the southwestern shores of Lake Malawi and examine the control interventions present in the area. METHODS: This prospective cross-sectional study was conducted in primary schools. School children were enrolled, demographic data were collected, and urine samples were submitted for analysis on macrohaematuria, microhaematuria, and S. haematobium eggs. A questionnaire was administered to 3 health facilities on diagnosis and treatment of schistosomiasis, as well as the control interventions against it. RESULTS: Four hundred children (174 males and 226 females) were enrolled from 7 primary schools. Mean participant age was 9.57 years (range 7 to 12 years). Fifty children (12.5%) had S. haematobium eggs detected in their urine, with the mean egg count being 15/10 mL. The highest infection intensity category (>= 50 eggs/10mL) was seen in 10 children (2.5%). Prevalence varied significantly between the schools, with rates ranging from 0% to 20%. Schools with higher prevalence rates were located farther away from the nearest public hospital that provides treatment free of charge. Prevalence correlated with previous history of mass chemotherapy in schools. Mass chemotherapy, health education, and improved water supply and sanitation were some of the interventions that contributed to lower prevalence rates in some areas. CONCLUSIONS: Schistosomiasis prevalence around southwestern Lake Malawi was lower than previously reported, owing to control interventions focusing on health education, improved water supply, sanitation, and mass chemotherapy. Consistent and uniform interventions can reduce prevalence further and sustain control. As prevalence falls, diagnostics can identify high transmission areas, monitor disease trends, and guide evidence-based control strategies. PMID- 28567192 TI - Rotavirus antigen, cytokine, and neutralising antibody profiles in sera of children with and without HIV infection in Blantyre, Malawi. AB - BACKGROUND: Rotavirus and HIV infection are major causes of death among children in sub-Saharan Africa. A previous study reported no association between concomitant HIV infection and rotavirus disease severity among hospitalised children in Malawi. This study examined rotavirus antigenaemia and broader immune responses among HIV-infected and uninfected children. METHODS: Stored (-80 degrees C), paired sera from acute and convalescent phases of Malawian children less than 5 years old, hospitalised for acute gastroenteritis in the primary study, collected from July 1997 to June 1999, were utilised. Among children older than 15 months, HIV infection was defined as the presence of HIV antibody in the blood, when confirmed by at least 2 established methods. For those younger than 15 months, nested polymerase chain reaction (PCR) amplification of proviral DNA was used for verification. All were followed for up to 4 weeks after hospital discharge. Rotavirus antigen levels in sera were measured with PremierTM Rotaclone(r) rotavirus enzyme immunoassay (EIA) kit. Acute-phase sera were examined for 17 cytokines, using Luminex fluorescent bead human cytokine immunoassay kit. Rotavirus-specific IgA and neutralising activity were determined by EIA and microneutralisation (MN) assay, respectively. Human strains and bovine human reassortants were propagated in MA104 cells with serum-free Iscove's Modified Dulbecco's Medium (IMDM). Differences in results, from specimens with and without HIV infection, were analysed for statistical significance using the chi-square test. RESULTS: We detected rotavirus antigen in 30% of the HIV infected and 21% HIV-uninfected, in the acute-phase sera. HIV-infected children developed slightly prolonged rotavirus antigenaemia compared to HIV-uninfected children. CONCLUSIONS: Rotavirus-specific IgA seroconversion rates and neutralising titres were similar in HIV-infected and HIV-uninfected children, thus, HIV infection had no major effect on immune responses to rotavirus infection. PMID- 28567193 TI - Hepatitis B virus seroprevalence among Malawian medical students: A cross sectional study. AB - BACKGROUND: Hepatitis B virus (HBV) predominantly spreads through contact with infected blood or other body fluids and causes liver disease. HBV vaccination for students at the College of Medicine, University of Malawi, is done without screening for the virus. It is important to assess the prevalence of HBV antigens among foundation-year students in order to consolidate evidence in support of HBV screening before vaccination. The aim of this study was to determine the seroprevalence of HBV antigens among 2013-2014 foundation-year students at the University of Malawi College of Medicine. METHODS: A prospective cross-sectional descriptive study was conducted among 2013-2014 foundation year students at the Malawi College of Medicine. Out of the 234 foundation-year students, written consent was obtained from 89 students. Venous blood samples were collected and tested for HBV surface antigen using SD Bioline immunochromatographic rapid assays. RESULTS: Out of the 62 (69.7%) male students, none tested HBV-positive, and out of 27 (30.3%) female students, none were seropositive. This suggested the absence of HBsAg among students or presence of HBsAg levels below detectable limits. CONCLUSIONS: This study showed levels of HBsAg below detectable limits among healthy young adults in Malawi. HBV screening for medical students should further be assessed to ensure adequate protection before they are assigned clinical duties. These findings provide enough grounds to agitate for further surveys to support the establishment of a universal HBV immunisation programme in Malawi. PMID- 28567195 TI - Abdominal myomectomy: A retrospective review of determinants and outcomes of complications at the University of Ilorin Teaching Hospital, Ilorin, Nigeria. AB - BACKGROUND: The aim of this study was to describe the pattern, outcomes, and determinants of perioperative complications of abdominal myomectomy at the University of Ilorin Teaching Hospital, Ilorin, Nigeria. METHODS: This was a retrospective review of cases of abdominal myomectomy between January 2010 and December 2013. Data were obtained from ward and operating theatre case records and analysed using SPSS version 20. The continuous variables were analysed with Student's t-test. The categorical variables were analysed with the chi-square test. P-values of 0.05 or less was taken to be significant. RESULTS: Total sampling yielded 204 cases, of which 170 records (80%) were adequate for analysis. Using criteria developed by Garry et al., major and minor complications occurred in 43.6% and 32.9% of procedures, respectively, while 23.5% of the patients had no complications. The commonest complication was intraoperative haemorrhage requiring blood transfusion. Mean estimated blood loss was 630.88 +/- 392.42 mL. There were no cases converted to hysterectomy, and no deaths were recorded. Uterine size equivalent to 16 weeks' gestation or more was significantly associated with heavier blood loss, blood transfusion, and fever (P = 0.034). Other significant determinants of major intraoperative haemorrhage with or without blood transfusion were menstrual flow of 6 days or more, preoperative anaemia, previous surgery, posterior incision, and surgery duration longer than 4 hours (P < 0.05). CONCLUSIONS: Outcome of abdominal myomectomy is generally favourable even if uterine size is greater than 16 weeks by palpation. Nevertheless, patients should be counselled preoperatively on the risk of blood loss and the possibility of blood transfusion. PMID- 28567194 TI - Prevalence of antibody to hepatitis B core antigen among hepatitis B surface antigen-negative blood donors in Ilorin, Nigeria: A cross-sectional study. AB - BACKGROUND: Post-transfusion hepatitis occurs even with stringent donor selection criteria and screening for hepatitis B surface antigen (HBsAg). The objective of this study was to determine the prevalence of antibody to hepatitis B core antigen (anti-HBc) in HBsAg-negative blood donors. METHODS: This was a cross sectional study in which 200 HBsAg-negative blood donors were recruited. Screening for viral markers was done using both a rapid test kit and enzyme linked immunosorbent assay (ELISA) for anti-HBc IgM. Quantitative and qualitative analysis of anti-HBc IgM was done by "capture" enzyme immunoassay using DIA.PRO HBc IgM test kits. The other viral markers were investigated using one step cassette style HBV tests. SPSS version 16 was used for data analysis. A P-value of 0.05 or less was considered significant. RESULTS: There were 190 male (95%) and 10 female (5%) blood donors, with a mean age of 31.7 +/- 7.9 years. The prevalence of anti-HBc IgM was 4%. The other viral markers (HBeAg, anti-HBeAg, anti-HBs and total anti-HBc) had a prevalence of 1.5%, 23%, 2.5%, and 32.5%, respectively. CONCLUSIONS: The prevalence of anti-HBc IgM in this study was high, and this supports the fact that screening blood donors for HBsAg alone is not sufficient to prevent transmission of HBV. PMID- 28567197 TI - Assessing the feasibility of mobile phones for follow-up of acutely unwell children presenting to village clinics in rural northern Malawi. AB - BACKGROUND: Patient follow-up is a routine component of clinical practice and valuable for evaluating the effectiveness of interventions, but because of the broad dispersion of health facilities and lack of standardised medical reporting in Malawi, collecting patient outcome data can be challenging. Increasing accessibility and affordability of mobile technology in resource-poor settings may facilitate patient follow-up in the community. The objective of this study was to evaluate the potential utility of mobile phones for collecting follow-up clinical data from parents or caregivers of acutely unwell under-5 children, for intervention evaluation purposes. METHODS: Parents' or caregivers' mobile phone numbers were obtained by health surveillance assistants (HSAs) during study enrollment. Guardians who provided a telephone number were contacted by the study team to establish re-consultations or hospitalisations of their child(ren) within 14 days of recruitment. Health records at village clinics and higher-level health facilities were hand-searched to identify or confirm presentations and abstract clinical data. RESULTS: 87 out of 149 (58.4%) guardians provided a mobile telephone number, of whom the study team could contact 44 (29.5%). Seven guardians stated they took their child for further treatment: three of these returned to village clinics and four presented to secondary care facilities; attendance could only be confirmed from health records for one child. CONCLUSIONS: With continued expansion of cellular network coverage and mobile ownership in Malawi, mobile phones may facilitate collection of patient outcomes for intervention evaluation purposes. Future consideration should also be given to integrating mobile technologies into HSA clinical practice. PMID- 28567196 TI - Cytopenias among ART-naive patients with advanced HIV disease on enrolment to care and treatment services at a tertiary hospital in Tanzania: A cross-sectional study. AB - BACKGROUND: HIV/AIDS causes high morbidity and mortality through both immunosuppression and complications not directly related to immunosuppression. Haematological abnormalities, including various cytopenias, occur commonly in HIV through immune and non-immune pathways. Though these complications could potentially cause serious clinical implications, published literature on the magnitude of this problem and its associated factors in Tanzania is scarce. This study aimed at determining the prevalence and risk factors of HIV-associated cytopenias among ART-naive patients enrolling for care and treatment services at Bugando Care and Treatment Centre (CTC) in Mwanza, Tanzania. METHODS: This was a cross-sectional clinic-based study done between March 2015 and February 2016, involving all antiretroviral therapy (ART)-naive adult HIV-positive patients enrolling for care and treatment services at Bugando CTC. Patients younger than 18 years and those with missing data were excluded. Data were analysed using Stata version 11 to determine the prevalence and risk factors of cytopenias. RESULTS: A total of 1205 ART-naive patients were included. Median age was 41 years (interquartile range [IQR] 32 to 48). Most participants were female (n = 789; 65.6%), with a female-to-male ratio of 2:1. The median baseline CD4 count was 200 cells/uL (IQR 113 to 439). About half (49%) of the study participants had baseline CD4 counts less than 200 cells/uL. Anaemia, leucopenia, and thrombocytopenia were found in 704 (58.4%), 285 (23.6%), and 174 (14.4%) participants, respectively, and these were strongly associated with advanced HIV infection. CONCLUSIONS: The magnitude of cytopenias is high among ART-naive HIV positive adults, and cytopenias are more marked with advanced HIV infection. Early diagnosis of HIV and timely initiation of ART could potentially reduce the number of people living with advanced HIV disease and its associated complications, including the cytopenias investigated in this study. Patients with cytopenias should undergo thorough screening for tuberculosis, which is an important and treatable correlate of cytopenia, in addition to close follow-up for any potential negative outcomes. PMID- 28567198 TI - Biochemical derangements prior to emergency laparotomy at Queen Elizabeth Central Hospital, Blantyre, Malawi: A cross-sectional pilot study. AB - BACKGROUND: The aim of this study was to examine biochemical investigations not routinely performed prior to emergency laparotomy in patients at Queen Elizabeth Central Hospital, a low-resource public hospital in Blantyre, Malawi. METHODS: A prospective cross-sectional study of adults (N = 15) needing emergency laparotomy over a 4-week period were studied at Queen Elizabeth Central Hospital. Biochemical investigations, not routinely performed for economic reasons, were performed preoperatively; these included sodium, potassium, chloride, carbon dioxide, urea, and calcium levels. RESULTS: Gastrointestinal pathology was predominant among the emergency laparotomies performed. Large bowel obstruction and bowel perforation secondary to typhoid were most frequent. Clinically significant biochemical derangements among the study patients were as follows: cases of moderate-to-severe hypokalaemia (n = 2), severe hyponatraemia (n = 1), moderate hypernatraemia (n = 1), and severe hypocalcaemia (n = 1). The most frequent abnormalities seen were uraemia and hypochloraemia (n = 11). CONCLUSIONS: Accurate electrolyte estimation in critically ill preoperative patients is desireable for optimal perioperative management but frequently absent in resource-challenged environments. PMID- 28567199 TI - Frequent malaria illness episodes in two Malawian patients on antiretroviral therapy soon after stopping cotrimoxazole preventive therapy. AB - We describe two Malawian adults on successful antiretroviral therapy who experienced frequent malaria episodes after stopping cotrimoxazole prophylaxis. We argue that, in addition to stopping cotrimoxazole, diminished malaria immunity and drug interactions between efavirenz and artemether-lumefantrine may have played a causative role in the recurrent malaria our patients experienced. PMID- 28567200 TI - Thoracic epidural for modified radical mastectomy in a high-risk patient. PMID- 28567201 TI - Discrepancy between statistical analysis method and study design in medical research: Examples, implications, and potential solutions. PMID- 28567202 TI - Adherence to iron supplementation in pregnancy. PMID- 28567203 TI - Background on the Termination of Pregnancy Bill Debate in Malawi. PMID- 28567204 TI - Proposed Termination of Pregnancy Bill in Malawi: Doctors use the best of what they have. PMID- 28567205 TI - The proposed legislation on termination of pregnancy does not protect women or children in Malawi and is not fit for the intended purpose: Christian Medical and Dental Fellowship position. PMID- 28567206 TI - An ethicist's thoughts on the Termination of Pregnancy Bill debate in Malawi. PMID- 28567207 TI - Fanuel Bickton talks to Desiree Witte on her clinical research experience with vaccines in Malawi. PMID- 28567208 TI - They are people too (an Ob-Gyn intern's perspective). PMID- 28567209 TI - Modelling human Puumala hantavirus infection in relation to bank vole abundance and masting intensity in the Netherlands. AB - This paper deals with modelling the relationship between human Puumala hantavirus (PUUV) infection, the abundance and prevalence of infection of the host (the bank vole), mast, and temperature. These data were used to build and parametrise generalised regression models, and parametrise them using datasets on these factors pertaining to the Netherlands. The performance of the models was assessed by considering their predictive power. Models including mast and monthly temperature performed well, and showed that mast intensity influences vole abundance and hence human exposure for the following year. Thus, the model can aid in forecasting of human illness cases, since (1) mast intensity influences the vole abundance and hence human exposure for the following year and (2) monitoring of mast is much more feasible than determining bank vole abundance. PMID- 28567211 TI - Methicillin-resistant Staphylococcus aureus not detected in Swedish nucleus and multiplying pig herds. AB - Introduction: Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) has emerged among pigs in many countries. MRSA in the pig population constitute a reservoir with risk for transmission to humans in close contact with pigs. Absence of MRSA in the top of the breeding pyramid would prevent spread to the rest of the pig population. The aim of this study was to investigate the occurrence of MRSA in nucleus and multiplying pig herds in Sweden. Materials and methods: All nucleus and multiplying pig herds in Sweden present in 2011 (n = 53) and 2014 (n = 39) were sampled for MRSA. Results and discussion: MRSA was not detected either in 2011 or in 2014. That MRSA was not detected in the top of the breeding pyramid indicates a favourable MRSA situation in the Swedish pig population. Abbreviations: MRSA: methicillin-resistant Staphylococcus aureus; LA MRSA: livestock-associated MRSA; CC: clonal complex. PMID- 28567212 TI - Is binding decline the main source of the ageing effect on prospective memory? A ride in a virtual town. AB - Objective: This study was designed to improve our understanding of prospective memory (PM) changes in ageing, and to identify the cognitive correlates of PM decline, using a virtual environment, to provide a more realistic assessment than traditional laboratory tasks. Design: Thirty-five young and 29 older individuals exposed to a virtual town were asked to recall three event-based intentions with a strong link between prospective and retrospective components, three event-based intentions with a weak link, and three time-based intentions. They also underwent retrospective episodic memory, executive functions, binding in working memory, processing speed, and time estimation assessments. Results: Older individuals recalled fewer intentions than young adults. While age-related PM decline affected the recall of both prospective and retrospective components, the recall of the latter seemed more challenging for older individuals when the link was weak. This PM decline was linked to an age-related decline in the binding process in working memory, as well as in processing speed, executive functioning, and episodic memory, depending on the nature of intentions. Conclusion: PM appears to be sensitive to ageing, even when the device is thought to be ecological. This decline is particularly pronounced when controlled processes are needed. PMID- 28567210 TI - Potential disease transmission from wild geese and swans to livestock, poultry and humans: a review of the scientific literature from a One Health perspective. AB - There are more herbivorous waterfowl (swans and geese) close to humans, livestock and poultry than ever before. This creates widespread conflict with agriculture and other human interests, but also debate about the role of swans and geese as potential vectors of disease of relevance for human and animal health. Using a One Health perspective, we provide the first comprehensive review of the scientific literature about the most relevant viral, bacterial, and unicellular pathogens occurring in wild geese and swans. Research thus far suggests that these birds may play a role in transmission of avian influenza virus, Salmonella, Campylobacter, and antibiotic resistance. On the other hand, at present there is no evidence that geese and swans play a role in transmission of Newcastle disease, duck plague, West Nile virus, Vibrio, Yersinia, Clostridium, Chlamydophila, and Borrelia. Finally, based on present knowledge it is not possible to say if geese and swans play a role in transmission of Escherichia coli, Pasteurella, Helicobacter, Brachyspira, Cryptosporidium, Giardia, and Microsporidia. This is largely due to changes in classification and taxonomy, rapid development of identification methods and lack of knowledge about host specificity. Previous research tends to overrate the role of geese and swans as disease vectors; we do not find any evidence that they are significant transmitters to humans or livestock of any of the pathogens considered in this review. Nevertheless, it is wise to keep poultry and livestock separated from small volume waters used by many wild waterfowl, but there is no need to discourage livestock grazing in nature reserves or pastures where geese and swans are present. Under some circumstances it is warranted to discourage swans and geese from using wastewater ponds, drinking water reservoirs, and public beaches. Intensified screening of swans and geese for AIV, West Nile virus and anatid herpesvirus is warranted. PMID- 28567213 TI - Rotational Acetabular Osteotomy. AB - Hip dysplasia is the most common cause of secondary osteoarthritis (OA). To prevent the early onset of secondary OA, Nishio's transposition osteotomy, Steel's triple osteotomy, Eppright's dial osteotomy, Wagner's spherical acetabular osteotomy, Tagawa's rotational acetabular osteotomy (RAO), and Ganz' periacetabular osteotomy (PAO) have been proposed. PAO and RAO are now commonly used in surgical treatment of symptomatic acetabular dysplasia in Europe, North America, and Asia. The aim of this paper is to present the followings: the patient selection criteria for RAO; the surgical technique of RAO; the long-term outcome of RAO; and the future perspectives. PMID- 28567214 TI - Surgical Treatment of Piriformis Syndrome. AB - BACKGROUND: Piriformis syndrome (PS) is an uncommon disease characterized by symptoms resulting from compression/irritation of the sciatic nerve by the piriformis muscle. Uncertainty and controversy remain regarding the proper diagnosis and most effective form of treatment for PS. This study analyzes the diagnostic methods and efficacy of conservative and surgical treatments for PS. METHODS: From March 2006 to February 2013, we retrospectively reviewed 239 patients who were diagnosed with PS and screened them for eligibility according to our inclusion/exclusion criteria. All patients underwent various conservative treatments initially including activity modification, medications, physical therapy, local steroid injections into the piriformis muscle, and extracorporeal shock wave therapy for at least 3 months. We resected the piriformis muscle with/without neurolysis of the sciatic nerve in 12 patients who had intractable sciatica despite conservative treatment at least for 3 months. The average age of the patients (4 males and 8 females) was 61 years (range, 45 to 71 years). The average duration of symptoms before surgery was 22.1 months (range, 4 to 72 months), and the mean follow-up period was 22.7 months (range, 12 to 43 months). We evaluated the degree of pain and recorded the responses using a visual analog scale (VAS) preoperatively and 3 days and 12 months postoperatively. RESULTS: Buttock pain was more improved than sciatica with various conservative treatments. Compared with preoperatively, the VAS score was significantly decreased after the operation. Overall, satisfactory results were obtained in 10 patients (83%) after surgery. CONCLUSIONS: PS is thought to be an exclusively clinical diagnosis, and if the diagnosis is performed correctly, surgery can be a good treatment option in patients with refractory sciatica despite appropriate conservative treatments. PMID- 28567215 TI - Comparison of Postoperative Infection-Related Complications between Cemented and Cementless Hemiarthroplasty in Elderly Patients: A Meta-Analysis. AB - BACKGROUND: The purpose of this review was to assess the risk of infection related complications following cemented and cementless hemiarthroplasty in elderly patients. METHODS: We searched PubMed, EMBASE, and Cochrane Library databases for published randomized clinical trials comparing cemented hemiarthroplasty with cementless hemiarthroplasty in patients with a femoral neck fracture and more than 65 years of age. Eight randomized controlled trials were available for analysis. A meta-analysis (with a fixed-effects model) and a meta regression analysis (with continuous variables) were performed. RESULTS: The 8 trials included 1,204 hips (608 cemented and 596 cementless). There was no significant difference between the cemented and cementless groups regarding the incidence of deep infection, superficial infection, pneumonia, and urinary tract infection. The overall incidence of postoperative deep infection was 2.3% (14/608) in the cemented group and 1.2% (7/596) in the cementless group (relative risk, 1.74; 95% confidence interval, 0.74 to 4.14; I2 = 0%; p = 0.206). No publication bias was found in the funnel plot. CONCLUSIONS: Results of our meta analysis suggest that when selecting a fixation method for hemiarthroplasty, infection-related postoperative complications are not the determinant factor to consider. PMID- 28567216 TI - The Need for an Implant Identification Card at Airport Security Check. AB - BACKGROUND: Joint replacement surgery is having an increasing demand as national healthcare systems confront an ever ageing population. Surgical complications associated with lower limb arthroplasty are well known but less investigation has been performed examining its effect on air travel, more specifically, unwanted and significant inconvenience caused to travelers going through airport security. METHODS: In lower limb arthroplasty clinics, 50 patients who met our selection criteria were given questionnaires. Ten airport security officers from 4 international airports (London Stansted, London Gatwick, London Heathrow, and Amsterdam Schiphol International Airport) were also given a separate questionnaire. The opinion of the Civil Aviation Authority was also sought. RESULTS: All 50 patients (mean age, 70.4 years; range, 55 to 84 years) who were presenting in lower limb arthroplasty clinics and who met our selection criteria volunteered to enter the study. Twenty-eight of these patients were female (mean age, 69.1 years; range, 55 to 84 years) and 22 were male (mean age, 71.2 years; range, 58 to 81 years). Of the patients, 14% stated that their joint replacements did not set off the airport security alarm. Responses were received from 10 airport security officers as well. Six airport security officers were male and 4 were female. All of the airport officers were aware of some form of implant identification card with 90% stating that these were useful to them at airport security. Eight-four percent of the patients stated that an implant identification card outlining what joint replacement they possessed and when this had been done would be very useful. Sixteen percent of the patients did not think a card would be beneficial since all of them had set off the airport alarm system only once or less in their lifetime. CONCLUSIONS: It is the opinion of airport security officers and patients that joint replacement implant identification cards streamline airport security checks and decrease the need for more invasive searches at airport security. PMID- 28567217 TI - Comparison of Surgical Parameters and Results between Curved Varus Osteotomy and Rotational Osteotomy for Osteonecrosis of the Femoral Head. AB - BACKGROUND: Various osteotomies have been introduced to treat osteonecrosis of the femoral head. The purpose of this study was to compare surgical parameters, postoperative limb length discrepancy, and minimum 5-year clinical and radiological results between transtrochanteric curved varus osteotomy (TCVO) and transtrochanteric rotational osteotomy (TRO) for osteonecrosis of the femoral head. METHODS: From 2004 to 2009, 103 consecutive TROs (97 patients) followed by 72 consecutive TCVOs (64 patients) were performed for the treatment of osteonecrosis of the femoral head. Of these, 85 patients (91 hips) in the TRO group and 58 patients (65 hips) in the TCVO group completed minimum 5-year clinical and radiological follow-up. The Kaplan-Meier product-limit method was used to estimate survival. RESULTS: The TCVO group had shorter operation time (p < 0.05) and less estimated blood loss (p = 0.026). Postoperative collapse developed in 26 hips (28.6%) in the TRO group and 7 hips (10.8%) in the TCVO group (p = 0.007). Osteophyte formation was observed in 34 hips (37.4%) in the TRO group and 13 hips (20%) in the TCVO group (p = 0.020). Fifteen hips (16.5%) in the TRO group and 7 hips (10.8%) in the TCVO group underwent conversion total hip arthroplasty (THA). The survival rate at 9 years with radiographic collapse as the endpoint was 68.7% (95% confidence interval [CI], 58.1% to 79.3%) in the TRO group, and 84.7% (95% CI, 71.5% to 97.9%) in the TCVO group. With conversion to THA as the endpoint, the survival rate was 82.2% (95% CI, 73.1% to 91.3%) in the TRO group and 89.2% (95% CI, 81.7% to 96.7%) in the TCVO group. CONCLUSIONS: The comparison indicates that TCVO was better than TRO in terms of surgical parameters including operation time and estimated blood loss while the 9-year survival rates were similar. PMID- 28567218 TI - Robotic Total Knee Arthroplasty with a Cruciate-Retaining Implant: A 10-Year Follow-up Study. AB - BACKGROUND: This study compared clinical and radiological results between robotic total knee arthroplasty (TKA) and conventional TKA with a cruciate-retaining implant at 10-year follow-up. The hypothesis was that robotic TKA would allow for more accurate leg alignment and component placement, and thus enhance clinical and radiological results and long-term survival rates. METHODS: A total of 113 primary TKAs performed using a cruciate-retaining implant in 102 patients from 2004 to 2007 were reviewed retrospectively. Of the 113 TKAs, 71 were robotic TKAs and 42 were conventional TKAs. Clinical outcomes (visual analogue scale pain score, Hospital for Special Surgery score, Western Ontario and McMaster University score, range of motion, and complications), radiological outcomes, and long-term survival rates were evaluated at a mean follow-up of 10 years. RESULTS: Clinical outcomes and long-term survival rates were similar between the two groups. Regarding the radiological outcomes, the robotic TKA group had significantly fewer postoperative leg alignment outliers (femoral coronal inclination, tibial coronal inclination, femoral sagittal inclination, tibial sagittal inclination, and mechanical axis) and fewer radiolucent lines than the conventional TKA group. CONCLUSIONS: Both robotic and conventional TKAs resulted in good clinical outcomes and postoperative leg alignments. Robotic TKA appeared to reduce the incidence of leg alignment outliers and radiolucent lines compared to conventional TKA. PMID- 28567219 TI - The Effect of Anxiety, Depression, and Optimism on Postoperative Satisfaction and Clinical Outcomes in Lumbar Spinal Stenosis and Degenerative Spondylolisthesis Patients: Cohort Study. AB - BACKGROUND: The aim of this study is to evaluate the effect of depression, anxiety, and optimism on postoperative satisfaction and clinical outcomes in patients who underwent less than two-level posterior instrumented fusions for lumbar spinal stenosis and degenerative spondylolisthesis. METHODS: Preoperative psychological status of subjects, such as depression, anxiety, and optimism, was evaluated using the Hospital Anxiety and Depression Scale (HADS) and the Revised Life Orientation Test (LOT-R). Clinical evaluation was determined by measuring changes in a visual analogue scale (VAS) and the Oswestry Disability Index (ODI) before and after surgery. Postoperative satisfaction of subjects assessed using the North American Spine Society lumbar spine questionnaire was comparatively analyzed against the preoperative psychological status. The correlation between patient's preoperative psychological status (depression, anxiety, and optimism) and clinical outcomes (VAS and ODI) was evaluated. RESULTS: VAS and ODI scores significantly decreased after surgery (p < 0.001), suggesting clinically favorable outcomes. Preoperative psychological status of patients (anxiety, depression, and optimism) was not related to the degree of improvement in clinical outcomes (VAS and ODI) after surgery. However, postoperative satisfaction was moderately correlated with optimism. CONCLUSIONS: Anxiety and optimism were more correlated with patient satisfaction than clinical outcomes. Accordingly, the surgeon can predict postoperative satisfaction of patients based on careful evaluation of psychological status before surgery. PMID- 28567220 TI - Should We Check the Routine Postoperative MRI for Hematoma in Spinal Decompression Surgery? AB - BACKGROUND: A postoperative magnetic resonance imaging (MRI) is performed as a routine to assess decompression of the spinal cord as well as to evaluate postoperative complications. The purpose of this study is to analyze the efficacy of postoperative MRI for hematoma in spinal decompression surgery. METHODS: Between January 1, 2008 and January 31, 2015, 185 patients who underwent postoperative MRI after spinal decompression surgery were included in this study. We checked the history of the use of an anticoagulant or antiplatelet agent, withdrawal period, blood platelet count, and prothrombin time (international normalized ratio [INR]). We measured the total amount of suction drainage and duration until removal. We retrospectively reviewed the presence of hematoma and thecal sac compression. Postoperative prognosis was evaluated by a visual analog scale (VAS) and the Oswestry Disability Index (ODI). RESULTS: Hematomas were found on postoperative MRI scans in 97 out of 185 patients (52.4%). Thirty patients had a thecal sac compressing hematoma: 7 in the cervical spine, 1 in the thoracic spine, and 22 in the lumbar spine. The occurrence of hematoma did not show significant difference according to the use of an anticoagulant (p = 0.157). The blood platelet count, prothrombin time (INR), and suction drainage duration did not have a statistically significant correlation with the occurrence of hematoma (p = 0.562, p = 0.506, and p = 0.429, respectively). The total amount of suction drainage was significantly different according to the presence of hematoma (p = 0.022). The total 185 patients had a significant decrease in the postoperative VAS score (p < 0.001), and the diminution of VAS score was not significantly different according to the occurrence of hematoma (p = 0.243). Even in the cases of thecal sac compressing hematoma, the reduction of VAS score was not significantly different (p = 0.689). CONCLUSIONS: Postoperative MRI for hematoma in spinal decompression surgery has little effect on prognosis or management. Therefore, indiscriminate postoperative MRI should be avoided and MRI should be performed depending on the patient's status. PMID- 28567221 TI - The Use of Contrast in Caudal Epidural Injections under Image Intensifier Guidance: Is It Necessary? AB - BACKGROUND: We investigated the value of using contrast as an additional aid to confirm the accuracy of needle placement for caudal epidural injections under intraoperative image intensifier guidance. METHODS: A total of 252 consecutive patients were included in this study. Their mean age was 46.7 years (range, 32 to 76 years). There were 133 males (53%) and 119 females (47%) over a 12-month period. RESULTS: Of the 252 consecutive procedures, the contrast enhanced image intensifier confirmed accurate needle placement on first attempt in 252 cases (100%). Needle resiting following the infiltration of contrast was required in 0 case. CONCLUSIONS: The results from this study demonstrate that a surgeon beyond the learning curve can accurately place caudal epidural injections using image intensification only, without the use of contrast. PMID- 28567222 TI - Comparison of the Extent of Degeneration among the Normal Disc, Immobilized Disc, and Immobilized Disc with an Endplate Fracture. AB - BACKGROUND: This study attempts to prove a cause and effect relationship between spine immobilization following posterior fixation for unstable burst fractures and degeneration observed following hardware removal. METHODS: We enrolled 57 patients (259 intervertebral discs [IVDs]) who underwent only posterior instrumentation without fusion for thoracolumbar and lumbar unstable burst fractures. We arbitrarily named the IVD that has an endplate fracture after immobilization using pedicle screws as the fractured endplate and immobilized disc (FEID), the IVD that has no endplate fracture after immobilization using pedicle screws as the nonfractured endplate and immobilized disc (NFEID), and the IVD that has no endplate fracture and no immobilization instrumentation as the normal disc (ND). At 2 years after implant removal, magnetic resonance imaging (MRI) was performed again for comparison. The extent of disc degeneration was classified using the Pfirrmann classification system. RESULTS: FEIDs were present in 67 levels, NFEIDs in 78 levels, and NDs in 114 levels. According to the Pfirrmann classification, 7.9% of the NDs, 32.1% of the NFEIDs, and 43.3% of the FEIDs were more degenerated at 2 years after implant removal. The FEIDs and NFEIDs were more degenerated than the NDs and the FEIDs were more degenerated than the NFEIDs at statistically significant levels (p < 0.001 for both). CONCLUSIONS: Spine immobilization with transpedicular screws has a significant influence on disc degeneration, and an endplate fracture accelerates the degeneration process. PMID- 28567223 TI - Reverse Total Shoulder Arthroplasty: Salvage Procedure for Failed Prior Arthroplasty. AB - BACKGROUND: To evaluate the clinical outcome of revision of primary shoulder replacement by using reverse total shoulder arthroplasty (RTSA). METHODS: Seven patients underwent revision RTSA with a mean follow-up of 22.1 months (range, 12 to 54 months). Their mean age at the time of operation was 75.5 years (range, 70 to 80 years). Assessments were performed on the preoperative and postoperative visual analogue scale (VAS) score, muscle strength, range of motion, University of California at Los Angeles (UCLA) score, Constant score, subjective satisfaction and the anteroposterior and axillary views of the glenohumeral joint. The primary operation was hemiarthroplasty in 5 patients, total shoulder replacement in 1 patient, and reverse shoulder arthroplasty in 1 patient. The cause of revision surgery was infection in 2 patients, humeral stem loosening in 2 patients, glenoid arthropathy in 2 patients, and glenoid loosening in 1 patient. The mean duration from primary operation to revision surgery was 52 months (range, 27 to 120 months). RESULTS: The VAS score for pain during motion was improved from 7.3 preoperatively to 2.1 postoperatively (p = 0.03). There were increases in the mean active forward flexion (from 62.1 degrees to 92.8 degrees ), abduction (from 70 degrees to 87.1 degrees ), external rotation (from 44.2 degrees to 47.4 degrees ), and internal rotation (from L5 to L4; p > 0.05) postoperatively. Performance in activities of daily living improved (p > 0.05), except for lifting 10 lb above the shoulder (from 1.2 to 1.1; p = 0.434). Overall, 5 of 7 patients were satisfied with the results of revision surgery. The mean Constant score improved from 44.8 preoperatively to 57.1 postoperatively (p = 0.018). The mean UCLA score improved from 12.8 preoperatively to 22.8 postoperatively (p = 0.027). In the postoperative radiological evaluation, no radiolucency was observed around the base plate or humeral stem. CONCLUSIONS: Pain could be reduced after revision RTSA, but improvements in range of motion and function were difficult to achieve. We think that the patients' satisfaction was relatively high despite the low function score due to the preoperative severe pain and marked limitation of range of motion. PMID- 28567224 TI - The Dimensions of the Scapula Glenoid in Japanese Rotator Cuff Tear Patients. AB - BACKGROUND: Reverse total shoulder arthroplasty has become a widely accepted surgical procedure in Japan since the time when the implants were approved for use in 2014. There is a doubt, however, as to whether the implants designed for Western people are suitable for Japanese people, particularly for females of relatively small stature. The purpose of this study was to investigate the glenoid dimension, with special focus on the length after glenoid reaming, in Japanese rotator cuff tear patients. METHODS: Fifty-six shoulders of 55 patients (35 males and 20 females; mean age, 63.8 years) were studied. Using the three dimensional computed tomography images of the entire scapula before shoulder surgery, we measured the glenoid height and width, and calculated the correlation between these measurements and the patient's height. Further, we measured the anteroposterior length of the scapular neck at the subchondral bone and the length at 15 mm medial to the subchondral bone, to simulate both the glenoid width after reaming (width of the 'virtual reamed surface') and the space available for the end of the center post of a standard glenoid baseplate. RESULTS: The average glenoid height and width were 35.8 mm and 28.1 mm in males and 30.8 mm and 23.4 mm in females, respectively. There was a significant correlation between patient height and glenoid size (glenoid height, r = 0.69; width, r = 0.75; p < 0.01). The mean value of the width of the virtual reamed surface was 27.0 mm in males and 22.5 mm in females. The mean anteroposterior length at 15 mm medial to the subchondral bone was 12.4 mm in males and 9.5 mm in females; the length was shorter than 8 mm in 6 female shoulders. CONCLUSIONS: There was a significant correlation between patient height and glenoid size. Considering that the common diameter of the commercially available baseplates and their center posts is greater than 25 mm and 8 mm, respectively, these prosthetic parts would be too large, especially for the Japanese female glenoid. Given that the current results of Japanese shoulder dimensions are similar to those of Asian people, 'Asian size implants' should be developed. PMID- 28567225 TI - Clinical Outcomes and Complications during the Learning Curve for Reverse Total Shoulder Arthroplasty: An Analysis of the First 40 Cases. AB - BACKGROUND: The purpose of this study was to investigate the results and complications during the learning curve of reverse total shoulder arthroplasty (RTSA) for rotator cuff deficiency. METHODS: We retrospectively reviewed the first 40 cases of RTSA performed by a single surgeon. The mean age of patients was 72.7 years (range, 63 to 81 years) and mean follow-up period was 26.7 months (range, 9 to 57 months). Clinical outcomes were evaluated using a visual analog scale (VAS) for pain, the University of California at Los Angeles (UCLA) shoulder score, American Shoulder and Elbow Surgeon (ASES) score, subjective shoulder value (SSV), and active range of motion (ROM). Intraoperative and postoperative complications were also evaluated. RESULTS: The average VAS pain score, UCLA score, ASES score, and SSV improved from 6.9%, 12.8%, 29.0%, and 29.0% before surgery to 1.6%, 27.0%, 73.3%, and 71.5% after surgery, respectively (p < 0.001). The mean forward flexion, abduction, and external rotation improved from 68.0 degrees , 56.9 degrees , and 28.0 degrees before surgery to 131.0 degrees , 112.3 degrees , and 38.8 degrees after surgery, respectively (p < 0.001, p < 0.001, and p = 0.021). However, the mean internal rotation did not improve after surgery (p = 0.889). Scapular notching was observed in 33 patients (51.5%). Eight shoulders (20%) had complications, including 2 major (1 deep infection and 1 glenoid fixation failure) and 6 minor complications (3 brachial plexus injuries, 2 acromial fractures, and 1 intraoperative periprosthetic fracture). CONCLUSIONS: The first 40 cases of RTSA performed by a single surgeon during the learning curve period showed satisfactory short-term follow-up results with an acceptable complication rate. PMID- 28567227 TI - Measurement Methods for Humeral Retroversion Using Two-Dimensional Computed Tomography Scans: Which Is Most Concordant with the Standard Method? AB - BACKGROUND: Humeral retroversion is variable among individuals, and there are several measurement methods. This study was conducted to compare the concordance and reliability between the standard method and 5 other measurement methods on two-dimensional (2D) computed tomography (CT) scans. METHODS: CT scans from 21 patients who underwent shoulder arthroplasty (19 women and 2 men; mean age, 70.1 years [range, 42 to 81 years]) were analyzed. The elbow transepicondylar axis was used as a distal reference. Proximal reference points included the central humeral head axis (standard method), the axis of the humeral center to 9 mm posterior to the posterior margin of the bicipital groove (method 1), the central axis of the bicipital groove -30 degrees (method 2), the base axis of the triangular shaped metaphysis +2.5 degrees (method 3), the distal humeral head central axis +2.4 degrees (method 4), and contralateral humeral head retroversion (method 5). Measurements were conducted independently by two orthopedic surgeons. RESULTS: The mean humeral retroversion was 31.42 degrees +/ 12.10 degrees using the standard method, and 29.70 degrees +/- 11.66 degrees (method 1), 30.64 degrees +/- 11.24 degrees (method 2), 30.41 degrees +/- 11.17 degrees (method 3), 32.14 degrees +/- 11.70 degrees (method 4), and 34.15 degrees +/- 11.47 degrees (method 5) for the other methods. Interobserver reliability and intraobserver reliability exceeded 0.75 for all methods. On the test to evaluate the equality of the standard method to the other methods, the intraclass correlation coefficients (ICCs) of method 2 and method 4 were different from the ICC of the standard method in surgeon A (p < 0.05), and the ICCs of method 2 and method 3 were different form the ICC of the standard method in surgeon B (p < 0.05). CONCLUSIONS: Humeral version measurement using the posterior margin of the bicipital groove (method 1) would be most concordant with the standard method even though all 5 methods showed excellent agreements. PMID- 28567226 TI - Acromion Index in Korean Population and Its Relationship with Rotator Cuff Tears. AB - BACKGROUND: Among the many causes of rotator cuff tears, scapular morphology is associated with the accelerating degenerative process of the rotator cuff. Acromion index (AI) was previously introduced and compared in two populations. METHODS: We enrolled 100 Korean patients diagnosed with full-thickness rotator cuff tears by magnetic resonance imaging and intraoperative arthroscopic findings between January and December 2013. Another 100 Korean patients with an intact rotator cuff tendon identified on magnetic resonance imaging and other shoulder diseases, such as frozen shoulder and instability, were enrolled as controls. We retrospectively compared these 100 rotator cuff tear patients (mean age, 63 years) and 100 controls (mean age, 51 years) in this study. Two independent orthopedic surgeons assessed the AI on radiographs. We performed an interobserver reliability test of the AI assessment, and then compared the AI between two groups. RESULTS: The measurement of the AI showed excellent reliability (intraclass correlation coefficient, 0.82). The mean AI in the rotator cuff tear group was 0.68 and it was significantly different between groups (p<0.001, 95% confidence interval). The AI was not related to tear size. CONCLUSIONS: Our study showed that the AI was an effective predictive factor for rotator cuff tears in a Korean population. PMID- 28567228 TI - Revision Surgery for Recurrent Pain after Excision of the Accessory Navicular and Relocation of the Tibialis Posterior Tendon. AB - BACKGROUND: The results of operative treatments for symptomatic accessory navicular are debatable. In some cases, recurrent pain may develop after the Kidner procedure. The purpose of this study is to review the reasons for recurrent pain after the Kidner procedure and to suggest possible options for revision surgery. METHODS: We reviewed the clinical and radiological outcomes in 9 patients who underwent revision surgery for recurrent pain after the Kidner procedure. During the revision surgery, the tibialis posterior tendon was reattached to the navicular either by advancing the tendon in 4 patients or by lengthening the tendon in another 4 patients. In the other 1 patient, the flexor digitorum longus tendon was transferred. Surgeries for the accompanying deformities were performed simultaneously in all patients. The results were evaluated using the American Orthopaedic Foot and Ankle Society ankle-hindfoot score and a visual analog scale. The mean follow-up was 2.3 years (range, 1 to 5 years). RESULTS: The mean American Orthopedic Foot and Ankle Society ankle hindfoot score improved from 71.25 to 81.50 in the advancement group, and 71.75 to 90.00 in the lengthening group. The mean visual analog scale improved from 7.75 to 4.25 in the advancement group and from 7.50 to 1.75 in the lengthening group. CONCLUSIONS: Recurrent pain after the Kidner procedure was associated with pes planovalgus or hindfoot valgus deformity. In revision surgery, correction of the associated deformities and reattachment of the tibialis posterior tendon after lengthening may need to be considered. PMID- 28567229 TI - Platelet-Derived Growth Factor Receptor-Positive Pericytic Cells of White Adipose Tissue from Critical Limb Ischemia Patients Display Mesenchymal Stem Cell-Like Properties. AB - BACKGROUND: The pericytes in the blood vessel wall have recently been identified to be important in regulating vascular formation, stabilization, remodeling, and function. We isolated and identified pericyte-like platelet-derived growth factor receptor beta-positive (PDGFRbeta+) cells from the stromal vascular fraction (SVF) of adipose tissue from critical limb ischemia (CLI) patients and investigated their potential as a reliable source of stem cells for cell-based therapy. METHODS: De-identified subcutaneous fat tissues were harvested after amputation in CLI patients. Freshly isolated SVF cells and culture-expanded adipose-derived stem cells (ADSCs) were quantified using flow cytometry. A matrigel tube formation assay and multi-lineage differentiation were performed to assess pericytic and mesenchymal stem cell (MSC)-like characteristics of PDGFRbeta+ ADSCs. RESULTS: PDGFRbeta+ cells were located in the pericytic area of various sizes of blood vessels and coexpressed mesenchymal stem cell markers. PDGFRbeta+ cells in freshly isolated SVF cells expressed a higher level of stem cell markers (CD34 and CXCR4) and mesenchymal markers (CD13, CD44, CD54, and CD90) than PDGFRbeta- cells. In vitro expansion of PDGFRbeta+ cells resulted in enrichment of the perivascular mesenchymal stem-like (PDGFRbeta+/CD90+/CD45-/CD31 ) cell fractions. The Matrigel tube formation assay revealed that PDGFRbeta+ cells were located in the peritubular area. CONCLUSIONS: PDGFRbeta+ ADSCs cells demonstrated a good multilineage differentiation potential. Pericyte-like PDGFRbeta+ cells from the SVF of adipose tissue from CLI patients had MSC-like characteristics and could be amplified by in vitro culture with preservation of their cell characteristics. We believe PDGFRbeta+ cells in the SVF of adipose tissue can be used as a reliable source of stem cells even in CLI patients. PMID- 28567230 TI - Secondary Chondrosarcoma from an Osteochondroma of the Proximal Tibia Involving the Fibula. AB - There are few reports on the surgical treatment of secondary malignancy arising from an osteochondroma on the lateral side of the proximal tibia. From March 2008 to December 2011, 3 patients were treated for a secondary chondrosarcoma from an osteochondroma of the proximal tibia involving the fibula. The operative procedure can be summed up as follows: (1) resection of the tumor including the fibula; (2) preservation of the peroneal nerve and the fibular head; and (3) arthrodesis of the proximal tibiofibular joint. Serial radiological studies showed successful fusion in the proximal tibiofibular joint in all patients. The Musculoskeletal Tumor Society functional scores were excellent in all 3 patients. No patients showed instability of the ipsilateral knee joint in any direction. All 3 patients could return to sports activities. Until the last follow-up, there was no evidence of disease recurrence. We suggest that the operative procedure described in this article would provide satisfactory oncological and functional outcomes. PMID- 28567232 TI - Using Virtual Social Networks for Case Finding in Clinical Studies: An Experiment from Adolescence, Brain, Cognition, and Diabetes Study. AB - BACKGROUND: One of the main usages of social networks in clinical studies is facilitating the process of sampling and case finding for scientists. The main focus of this study is on comparing two different methods of sampling through phone calls and using social network, for study purposes. METHODS: One of the researchers started calling 214 families of children with diabetes during 90 days. After this period, phone calls stopped, and the team started communicating with families through telegram, a virtual social network for 30 days. The number of children who participated in the study was evaluated. RESULTS: Although the telegram method was 60 days shorter than the phone call method, researchers found that the number of participants from telegram (17.6%) did not have any significant differences compared with the ones being phone called (12.9%). CONCLUSIONS: Using social networks can be suggested as a beneficial method for local researchers who look for easier sampling methods, winning their samples' trust, following up with the procedure, and an easy-access database. PMID- 28567231 TI - Effect of Lavender Oil Aroma in the Early Hours of Postpartum Period on Maternal Pains, Fatigue, and Mood: A Randomized Clinical Trial. AB - BACKGROUND: Busy care providers focus on the serious complications of postpartum period. This issue causes the seemingly trivial complications, such as mother's pains, fatigue, and psychological status, to be less taken into account. The study aimed to determine the effect of lavender oil aroma in the early hours of postpartum period on maternal pains, fatigue, and mood in primiparous mothers. METHODS: This randomized clinical trial was conducted on 56 participants; 29 in intervention group and 27 in control group. The intervention group received lavender oil in three doses during the first 24 h after delivery. Sesame oil was used in the control group. Intensity of pain, fatigue, and distress level was measured by visual analog scale before and after the interventions. Besides, mood status was assessed through the positive and negative affect schedule. RESULTS: The mean age of all the participants was 23.88 +/- 3.88 years. After the first intervention and also in the tomorrow morning assessment, significant differences were found between the two groups regarding perineal pain (P = 0.004, P < 0.001), physical pain (P < 0.001), fatigue (P = 0.02, P < 0.001), and distress scores (P < 0.001). In addition, significant differences were found concerning the mean scores of positive (P < 0.001) and negative (P = 0.007, P < 0.001) moods between the two groups after the interventions. Repeated measures analyses showed that the two groups were significantly different over time in all the evaluated variables. CONCLUSIONS: Lavender oil aromatherapy starting in the first hours of postpartum period resulted in better physical and mood status compared to nonaromatic group. PMID- 28567233 TI - Factors Associated with Screen Time in Iranian Children and Adolescents: The CASPIAN-IV Study. AB - BACKGROUND: Prolonged screen time is frequent in children and adolescents. Implementing interventions to reduce physical inactivity needs to assess related determinants. This study aims to assess factors associated with screen time in a national sample of children and adolescents. METHODS: This nationwide study was conducted among 14,880 students aged 6-18 years. Data collection was performed using questionnaires and physical examination. The World Health Organization Global School Health Survey questionnaire was used. Logistic regression analysis was used to examine the relationship between demographic variables, socioeconomic status (SES), family structure, physical activity, unhealthy eating habits, body mass index, and mental distress with screen time. RESULTS: The participation rate was 90.6% (n = 13,486), 50.8% were male, and 75.6% lived in urban areas. Mean (standard deviation) age of participants was 12.47 (3.36) years. The SES, eating junk foods, urban residence, and age had significant association with screen time, watching television (TV), and computer use (P < 0.05). With increasing number of children, the odds ratio of watching TV reduced (P < 0.001). Statistically, significant association existed between obesity and increased time spent watching TV (P < 0.001). Girls spent less likely to use computer and to have prolonged screen time (P < 0.001). Participants in the sense of worthlessness were less likely to watch TV (P = 0.005). Screen time, watching TV, and using computer were higher in students with aggressive behaviors (P < 0.001); screen time was higher in those with insomnia. CONCLUSIONS: In this study, higher SES, unhealthy food habits, and living in urban areas, as well as aggressive behaviors and insomnia increased the risk of physical inactivity. PMID- 28567235 TI - Investigating Idiopathic Inflammatory Myopathy; Initial Cross Speciality Experience with Use of the Extended Myositis Antibody Panel. AB - The discovery of unique autoantibodies has informed and altered our approach to the diagnosis and management of the inflammatory myopathies. This study reports the initial clinical experience of use of the Extended Myositis Antibody (EMA) panel in the largest university teaching hospital in Ireland. We conducted a retrospective review of all patients who had serum samples tested for myositis specific antibodies and myositis associated antibodies from April 2014 to March 2015. A positive EMA panel was of significant clinical utility in facilitating decisions on appropriate investigations, and need for onward referral to other physicians. Furthermore, this paper highlights the diversity of possible presentations of idiopathic inflammatory myopathy with subsequent need for multi speciality involvement, and serves to heighten awareness among clinicians of the diagnostic use of extended myositis antibody testing in these cases. PMID- 28567236 TI - Emphysematous Cystitis: Mortality, Risk Factors, and Pathogens of a Rare Disease. AB - Although high mortality rates have been reported for emphysematous pyelonephritis (EP), information on emphysematous cystitis (EC), which is less common, is sparse. Here, we report one new case of severe EC and 136 cases of EC that occurred between 2007 and 2016, and review information about the characteristics, diagnosis, treatment and mortality of these patients, and the pathogens found in these patients. The mean age of the 136 patients was 67.9+/-14.2 years. Concurrent emphysematous infections of other organs were found in 21 patients (15.4%), with emphysematous pyelonephritis being the most common of these infections. The primary pathogen identified was Escherichia coli (54.4%). Patients were mainly treated by conservative management that included antibiotics (n=105; 77.2%). Ten of the 136 patients with EC died, yielding a mortality rate of 7.4%. Despite the relatively low mortality rate of EC compared with that of EP, a high degree of suspicion must be maintained to facilitate successful and conservative management. PMID- 28567237 TI - Level of Headaches After Surgical Aneurysm Clipping Decreases Significantly Faster Compared to Endovascular Coiled Patients. AB - In incidental aneurysms, endovascular treatment can lead to post-procedural headaches. We studied the difference of surgical clipping vs. endovascular coiling in concern to post-procedural headaches in patients with ruptured aneurysms. Sixty-seven patients with aneurysmal subarachnoidal haemorrhage were treated in our department from September 1st 2015 - September 1st 2016. 43 Patients were included in the study and the rest was excluded because of late recovery or high-grade subarachnoid bleedings. Twenty-two were surgical treated and twenty-one were interventionally treated. We compared the post-procedural headaches at the time points of 24 h, 21 days, and 3 months after treatment using the visual analog scale (VAS) for pain. After surgical clipping the headache score decreased for 8.8 points in the VAS, whereas the endovascular treated population showed a decrease of headaches of 3.3 points. This difference was highly statistical significant and remained significant even after 3 weeks where the pain score for the surgically treated patients was 0.68 and for the endovascular treated 1.8. After 3 months the pain was less than 1 for both groups with surgically treated patients scoring 0.1 and endovascular treated patients 0.9 (not significant). Clipping is relieving the headaches of patients with aneurysm rupture faster and more effective than endovascular coiling. This effect stays significant for at least 3 weeks and plays a crucial role in stress relieve during the acute and subacute ICU care of such patients. PMID- 28567234 TI - Penile Inflammatory Skin Disorders and the Preventive Role of Circumcision. AB - Penile inflammatory skin conditions such as balanitis and posthitis are common, especially in uncircumcised males, and feature prominently in medical consultations. We conducted a systematic review of the medical literature on PubMed, EMBASE, and Cohrane databases using keywords "balanitis," "posthitis," "balanoposthitis," "lichen sclerosus," "penile inflammation," and "inflammation penis," along with "circumcision," "circumcised," and "uncircumcised." Balanitis is the most common inflammatory disease of the penis. The accumulation of yeasts and other microorganisms under the foreskin contributes to inflammation of the surrounding penile tissue. The clinical presentation of inflammatory penile conditions includes itching, tenderness, and pain. Penile inflammation is responsible for significant morbidity, including acquired phimosis, balanoposthitis, and lichen sclerosus. Medical treatment can be challenging and a cost burden to the health system. Reducing prevalence is therefore important. While topical antifungal creams can be used, usually accompanied by advice on hygiene, the definitive treatment is circumcision. Data from meta-analyses showed that circumcised males have a 68% lower prevalence of balanitis than uncircumcised males and that balanitis is accompanied by a 3.8-fold increase in risk of penile cancer. Because of the high prevalence and morbidity of penile inflammation, especially in immunocompromised and diabetic patients, circumcision should be more widely adopted globally and is best performed early in infancy. PMID- 28567238 TI - Vosaroxin in relapsed/refractory acute myeloid leukemia: efficacy and safety in the context of the current treatment landscape. AB - Treatment for acute myeloid leukemia (AML) generally consists of a combination of cytarabine and an anthracycline. Although induction therapy leads to complete remission (CR) for most patients, refractoriness to chemotherapy or relapse after initial response is associated with poor outcomes. The 1-year survival rates after first relapse have been reported at 29%, declining to 11% at 5 years. Prognosis is particularly poor among older patients whose higher prevalence of unfavorable cytogenetics and high frequency of comorbidities diminish their ability to tolerate intensive chemotherapy. There is no standard of care for relapsed/refractory (R/R) AML, and no new therapies have shown consistently superior outcomes in this setting in over two decades. Vosaroxin is an anticancer quinolone derivative (AQD) that was evaluated in combination with cytarabine for the treatment of R/R AML in the randomized, double-blind, placebo-controlled, phase III VALOR study (n = 711). Compared with placebo/cytarabine, the vosaroxin/cytarabine regimen demonstrated favorable CR rates and survival in patients ?60 years of age, with toxicities similar to other AML regimens. Here we review outcomes of recent studies of commonly used chemotherapy regimens for the treatment of R/R AML and evaluate the results of the VALOR trial in the context of the current treatment landscape. PMID- 28567239 TI - Bendamustine and its role in the treatment of unfit patients with chronic lymphocytic leukaemia: a perspective review. AB - With a median age of 72 years at first diagnosis, chronic lymphocytic leukaemia (CLL) is a disease of the elderly. At this age, many patients cannot bear an intensive chemoimmunotherapy like fludarabine, cyclophosphamide and rituximab (FCR), and therapeutic decisions are commonly complicated by a high burden of accompanying comorbidities. Clinical trials, on the other hand, are mostly designed to include a far healthier and younger trial population, with a median age in most studies well below 70 years, leading to an insufficient reflection of clinical reality. With the introduction of new targeted therapies, treatment of CLL is currently undergoing a profound change. New compounds like ibrutinib or idelalisib have enlarged the therapeutic options in treating CLL. However, so far, these oral medications imply continuous intake by the patient, which will at some point lead to the issue of adherence in most patients. In addition, long term experiences are largely missing. In this setting, one of the oldest chemoactive substances remains a viable option for many CLL patients and their treating physicians: bendamustine, a nitrogen-mustard derivative, has proven to be a safe and efficient agent for treatment of CLL in the first- and second-line setting. In particular, there is some evidence that the substance is relatively well tolerated in elderly and unfit patients. In this review, we summarize the current data on bendamustine in the treatment of elderly and unfit patients with CLL and aim to provide a concise analysis and outlook on the current and future role of this substance in the era of new targeted agents. PMID- 28567240 TI - Phylogeography, genetic diversity and population structure in a Patagonian endemic plant. AB - Phylogeographical patterns provide valuable insight into the historical processes underlying diversification, and may provide a better understanding of biodiversity, dispersal modes, diversification times, extinctions, refuge areas and other species-/population-level processes. Here, we examine the genetic structure of Oxalis laciniata, a representative of Oxalis, which is an important emerging model in evolutionary biology and phylogenetic studies. We analyse genetic correlation, haplotype diversity and genetic structure. In this study, cpDNA reveals the presence of 16 haplotypes, connected in tree networks. Genetic diversity is high and polymorphism is low among populations based on ISSR markers. Both clustering and analysis of the structure of the population indicate two different groups. Distribution modelling predicts two potential distribution areas. Our main conclusions are: (i) The phylogeographical pattern demonstrates non-random organization of genetic variability since two distinct groups can be distinguished; (ii) two refugia are proposed: one is situated in the SE, holding the most ancestral haplotypes; and the second one is situated in the SW; (iii) we propose an in situ diversification hypothesis for the populations located in the steppe; (iv) the centre of diversification coincides with the centre of the distribution; (v) distribution modelling shows a strong correspondence with the distribution of the species but it also suggests the possibility of occurrence in the Central Andes. PMID- 28567242 TI - Design principles of spectroscopic probes for biological applications. AB - Spectroscopic (chromogenic, fluorescent, or chemiluminescent) probes have been widely used in many fields due to their high sensitivity and unrivaled spatiotemporal resolution. This area is an old one but always full of activity, because the rapid development of science and technology requires not only new probes for specific purposes (e.g., subcellular imaging) but also the update of current probes with more satisfactory properties. Based on our experiences and including existing knowledge, in this mini-review we briefly discuss the design strategies, response modes, and bioapplications of small molecular spectroscopic probes, in particular their advantages and disadvantages as well as possible research trends, which may be helpful to those who are interested in this continually growing research area. PMID- 28567241 TI - Click-chemistry approaches to pi-conjugated polymers for organic electronics applications. AB - Given the wide utility of click-chemistry reactions for the preparation of simple moieties within large architecturally complex materials, this minireview article aims at surveying papers exploring their scope in the area of pi-conjugated polymers for application in organic electronics to enable advanced functional properties. PMID- 28567243 TI - Organised chaos: entropy in hybrid inorganic-organic systems and other materials. AB - Entropy is one of the fundamental quantities which links emerging research areas like flexibility and defect engineering in inorganic-organic hybrid materials. Additionally, a delicate balance between entropy and enthalpy can lead to intriguing temperature-driven transitions in such materials. Here, we briefly overview traditional material design principles, highlight the role of entropy in the past and discuss how computational methods can help us to understand and quantify entropic effects in inorganic-organic hybrid materials in the future. PMID- 28567244 TI - Foldable glycoprobes capable of fluorogenic crosslinking of biomacromolecules. AB - Small-molecular probes capable of monitoring and interfering with the activity of biomacromolecules - such as polysaccharides, nucleotides and proteins - are of paramount importance to the advancement of life science. However, such probes that can detect and simultaneously modulate the construction of biomacromolecules are elusive. Here we report a fluorogenic, foldable glycoprobe that can recognize and assemble a protein receptor in a synchronous fashion. The glycoprobe synthesized by introducing a glycoligand (for protein recognition) to a bola-type bis-fluorophore conjugate shows a "self-shielded" fluorescence in the folded state. Association with a receptor protein rapidly unfolds the probe, releasing a fluorophore capable of crosslinking the proteins - as determined using small angle X-ray scattering - thereby producing a unique fluorescent supramolecular construct. We have demonstrated the use of the foldable glycoprobe in order to track the endocytic cycle of a transmembrane receptor. PMID- 28567245 TI - Confined-space synthesis of nanostructured anatase, directed by genetically engineered living organisms for lithium-ion batteries. AB - Biomineral formation processes in nature are temporally and spatially regulated under the functions of biomolecules in a confined space. It is potentially very productive to rationally design a mineralized system by taking into account confined space as well as biomolecules. The laboratory technique of "bacterial cell surface display" is an ideal platform to host catalytically active proteins in a three-dimensionally confined space. In the present study, aiming to regulate the synthesis of nanostructured TiO2 anatase, repeating segments of silaffin were displayed on Escherichia coli surfaces through genetic manipulation. The displayed protein electrostatically interacted with a titanium source and catalyzed the hydrolysis of titanium dioxide precursors through hydrogen bonding interactions on the cell surface. In the subsequent calcination process, the genetically modified cells not only served as a framework for producing rod shaped TiO2 assembled by nanoparticles, but also provided a carbon source in situ. The size of nanoparticles was controlled by changing the number of tandem repeats of the protein segment. The as prepared TiO2 anatase exhibited unique characteristics including nanosized anatase crystals, mesoporous structure and carbon coating. When tested as the anode electrode of a lithium-ion battery, it showed excellent lithium storage performance. The carbon coated anatase anode shows a higher specific capacity of 207 mA h g-1 after 200 cycles at a current rate of 1C and an ultra-long cycling lifetime of 5000 cycles with an outstanding retention capacity of 149 mA h g-1 at a higher rate of 10C. This bioprocess inspired approach may help broaden the scope and impact of nanosized biominerals. PMID- 28567246 TI - Identification of dipole disorder in low temperature solution processed oxides: its utility and suppression for transparent high performance solution-processed hybrid electronics. AB - The ability to deposit high-quality inorganic semiconductors and dielectrics from solution at low process temperatures (~200 degrees C) has become a very important research focus. During the course of our investigation, we identify the presence of an induced dipole present in solid state solution processed inorganic oxide insulator layers processed at reduced temperature (200-350 degrees C) from either molecular precursors, or well-dispersed metal oxide nanoparticles. Chemical composition analysis coupled with electrical measurements shows that the dielectric instability occurs due to proton migration via the Grotthuss mechanism inducing a long lived dipole disorder. Thus we established conditions for suppressing this effect to afford "ideal" high-k dielectric layer. Using this methodology, solution processed all inorganic thin film transistors (TFTs) with charge carrier mobilities exceeding 6 cm2 V-1 s-1 operating at low voltage (5 V) have been achieved. In addition, we show the broad utility of the perovskite high k dielectric when processed with state of the art polymer and single crystal organic semiconductors yielding mobilities of approx. 7 cm2 V-1 s-1 at only 4 V. These transparent devices demonstrate excellent electrical device stability and a threshold voltage shift of only 0.41 V over 14 h, which is comparable, or better than sputtered oxide films. PMID- 28567247 TI - Polysulfide-1-oxides react with peroxyl radicals as quickly as hindered phenolic antioxidants and do so by a surprising concerted homolytic substitution. AB - Polysulfides are important additives to a wide variety of industrial and consumer products and figure prominently in the chemistry and biology of garlic and related medicinal plants. Although their antioxidant activity in biological contexts has received only recent attention, they have long been ascribed 'secondary antioxidant' activity in the chemical industry, where they are believed to react with the hydroperoxide products of autoxidation to slow the auto-initiation of new autoxidative chain reactions. Herein we demonstrate that the initial products of trisulfide oxidation, trisulfide-1-oxides, are surprisingly reactive 'primary antioxidants', which slow autoxidation by trapping chain-carrying peroxyl radicals. In fact, they do so with rate constants (k = 1-2 * 104 M-1 s-1 at 37 degrees C) that are indistinguishable from those of the most common primary antioxidants, i.e. hindered phenols, such as BHT. Experimental and computational studies demonstrate that the reaction occurs by a concerted bimolecular homolytic substitution (SH2), liberating a perthiyl radical - which is ca. 16 kcal mol-1 more stable than a peroxyl radical. Interestingly, the (electrophilic) peroxyl radical nominally reacts as a nucleophile - attacking the of the trisulfide-1-oxide - a role hitherto suspected only for its reactions at metal atoms. The analogous reactions of trisulfides are readily reversible and not kinetically competent to inhibit hydrocarbon autoxidation, consistent with the longstanding view that organosulfur compounds must be oxidized to afford significant antioxidant activity. The reactivity of trisulfides and their oxides are contrasted with what is known of their shorter cousins and predictions are made and tested with regards to the reactivity of higher polysulfides and their 1 oxides - the insights from which may be exploited in the design of future antioxidants. PMID- 28567248 TI - Sequence-defined oligo(ortho-arylene) foldamers derived from the benzannulation of ortho(arylene ethynylene)s. AB - A Cu-catalyzed benzannulation reaction transforms ortho(arylene ethynylene) oligomers into ortho-arylenes. This approach circumvents iterative Suzuki cross coupling reactions previously used to assemble hindered ortho-arylene backbones. These derivatives form helical folded structures in the solid-state and in solution, as demonstrated by X-ray crystallography and solution-state NMR analysis. DFT calculations of misfolded conformations are correlated with variable-temperature 1H and EXSY NMR to reveal that folding is cooperative and more favorable in halide-substituted naphthalenes. Helical ortho-arylene foldamers with specific aromatic sequences organize functional pi-electron systems into arrangements ideal for ambipolar charge transport and show preliminary promise for the surface-mediated synthesis of structurally defined graphene nanoribbons. PMID- 28567249 TI - Observing single nanoparticle events at the orifice of a nanopipet. AB - Single nanoparticle (NP) events are successfully observed at the orifice of a nanopipet by blocking the ionic current with a single NP. In addition to the traditional translocation events, we observe both staircase and blip current transients by controlling the radius ratio of NPs to nanopipet or bias potential. Confocal fluorescence microscopy and finite element simulation are used to simultaneously monitor and quantitatively understand these events, respectively. The frequency of the staircase and blip events is proportional to the NP concentration, and could be used for the quantification of NPs. This study offers a new method for NP determination and single NP behavior study. PMID- 28567250 TI - Mononuclear ruthenium polypyridine complexes that catalyze water oxidation. AB - Over the past decade, significant advances have been made in the development of molecular water oxidation catalysts (WOCs) in the context of developing a system that would accomplish artificial photosynthesis. Mononuclear ruthenium complexes with polypyridine ligands have drawn considerable attention in this regard, due to their high catalytic activity and relatively simple structure. In this perspective review, we will discuss mononuclear Ru polypyridine WOCs by organizing them into four groups according to their ligand environments. Each group will be discussed with regard to three fundamental questions: first, how does the catalyst initiate O-O bond formation? Second, which step in the catalytic cycle is rate-determining? Third, how efficient is the catalyst according to the specific descriptors such as turnover frequency? All discussion is based on the high-valent ruthenium intermediates that are proposed in the catalytic cycle according to experimental observation and theoretical simulation. Two fundamental mechanisms are set forth. An acid-base mechanism that involves the attack of a water molecule on the oxo of a high valent Ru 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 O species to form the O-O bond. Subsequent steps lead to dissociation of O2 and rehydration of the metal center. A second mechanism involves the formation of a Ru-O radical species, two of which then couple to form a Ru-O-O-Ru species that can release O2 afterwards. The acid-base mechanism appears to be more common and mechanistic differences could result from variation directly related to polypyridine ligand structures. Understanding how electronic, steric, and conformational properties can effect catalyst performance will lead to the rational design of more effective WOCs with not only ruthenium but also other transition metals. PMID- 28567252 TI - Solvation and surface effects on polymorph stabilities at the nanoscale. AB - We explore the effects of particle size and solvent environment on the thermodynamic stability of two pairs of polymorphs subjected to ball-mill neat grinding (NG) and liquid assisted grinding (LAG). Two systems were studied: (i) forms I and II of a 1 : 1 theophylline : benzamide cocrystal and (ii) forms A and B of an aromatic disulfide compound. For both systems, the most stable-bulk polymorph converted to the metastable-bulk polymorph upon NG. LAG experiments yielded different outcomes depending on the amount of solvent used. This was further investigated by performing carefully controlled LAG experiments with increasing MUL amounts of solvents of different nature. With these experiments, we were able to monitor form A to B and form I to II conversions as a function of solvent concentration and derive polymorph equilibrium curves. The concentration required for a switch in polymorphic outcome was found to be dependent on solvent nature. We propose that these experiments demonstrate a switch in thermodynamic stability of the polymorphs in the milling jar. Form B, the stable-bulk polymorph, has less stable surfaces than form A, thus becoming metastable at the nanoscale when surface effects become important. Ex situ diffraction and electron microscopy data confirm crystal sizes in the order of tens of nanometers after the ball mill grinding experiments reach equilibrium. DFT-d computations of the polymorph particles stabilities support these findings and were used to calculate cross-over sizes of forms A and B as a function of solvent. Attachment energies and surface stabilities of the various crystalline faces exposed were found to be very sensitive to the solvent environment. Our findings suggest that surface effects are significant in polymorphism at the nanoscale and that the outcomes of equilibrium ball-mill NG and LAG experiments are in general controlled by thermodynamics. PMID- 28567251 TI - Atmospheric chemistry of bioaerosols: heterogeneous and multiphase reactions with atmospheric oxidants and other trace gases. AB - Advances in analytical techniques and instrumentation have now established methods for detecting, quantifying, and identifying the chemical and microbial constituents of particulate matter in the atmosphere. For example, recent cryo TEM studies of sea spray have identified whole bacteria and viruses ejected from ocean seawater into air. A focal point of this perspective is directed towards the reactivity of aerosol particles of biological origin with oxidants (OH, NO3, and O3) present in the atmosphere. Complementary information on the reactivity of aerosol particles is obtained from field investigations and laboratory studies. Laboratory studies of different types of biologically-derived particles offer important information related to their impacts on the local and global environment. These studies can also unravel a range of different chemistries and reactivity afforded by the complexity and diversity of the chemical make-up of these particles. Laboratory experiments as the ones reviewed herein can elucidate the chemistry of biological aerosols. PMID- 28567253 TI - Photomodulation of bacterial growth and biofilm formation using carbohydrate based surfactants. AB - Naturally occurring and synthetic carbohydrate amphiphiles have emerged as a promising class of antimicrobial and antiadhesive agents that act through a number of dynamic and often poorly understood mechanisms. In this paper, we provide the first report on the application of azobenzene trans-cis photoisomerization for effecting spatial and temporal control over bacterial growth and biofilm formation using carbohydrate-based surfactants. Photocontrollable surface tension studies and small angle neutron scattering (SANS) revealed the diverse geometries and dimensions of self-assemblies (micelles) made possible through variation of the head group and UV-visible light irradiation. Using these light-addressable amphiphiles, we demonstrate optical control over the antibacterial activity and formation of biofilms against multi drug resistant (MDR) Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative Escherichia coli. To probe the mechanism of bioactivity further, we evaluated the impact of trans-cis photoisomerization in these surfactants on bacterial motility and revealed photomodulated enhancement in swarming motility in P. aeruginosa. These light-responsive amphiphiles should attract significant interest as a new class of antibacterial agents and as investigational tools for probing the complex mechanisms underpinning bacterial adhesion and biofilm formation. PMID- 28567255 TI - Enhancement of charge transport properties of small molecule semiconductors by controlling fluorine substitution and effects on photovoltaic properties of organic solar cells and perovskite solar cells. AB - We prepared a series of small molecules based on 7,7'-(4,4-bis(2-ethylhexyl)-4H silolo[3,2-b:4,5-b']dithiophene-2,6-diyl)bis(4-(5'-hexyl-[2,2'-bithiophene]-5 yl)benzo[c][1,2,5]thiadiazole) with different fluorine substitution patterns (0F 4F). Depending on symmetricity and numbers of fluorine atoms incorporated in the benzo[c][1,2,5]thiadiazole unit, they show very different optical and morphological properties in a film. 2F and 4F, which featured symmetric and even numbered fluorine substitution patterns, display improved molecular packing structures and higher crystalline properties in a film compared with 1F and 3F and thus, 2F achieved the highest OTFT mobility, which is followed by 4F. In the bulk heterojunction solar cell fabricated with PC71BM, 2F achieves the highest photovoltaic performance with an 8.14% efficiency and 0F shows the lowest efficiency of 1.28%. Moreover, the planar-type perovskite solar cell (PSC) prepared with 2F as a dopant-free hole transport material shows a high power conversion efficiency of 14.5% due to its high charge transporting properties, which were significantly improved compared with the corresponding PSC device obtained from 0F (8.5%). From the studies, it is demonstrated that low variation in the local dipole moment and the narrow distribution of 2F conformers make intermolecular interactions favorable, which may effectively drive crystal formations in the solid state and thus, higher charge transport properties compared with 1F and 3F. PMID- 28567256 TI - The reactivity and conformational control of cyclic tetrapeptides derived from aziridine-containing amino acids. AB - Among the smallest of the macrocyclic peptides, 12- and 13-membered cyclic tetrapeptides are particularly noteworthy because they exhibit a broad spectrum of biological activities due to their innate capacity to mimic beta-turns in proteins. In this report, we demonstrate that aziridine-containing cyclic tetrapeptides offer a platform to interrogate the conformational properties of tetrapeptides. We show that aziridine ring-opening of 12-membered cyclic tetrapeptides yields exclusively 13-membered alpha3beta macrocycles, regardless of peptide sequence, nucleophile, aziridine beta-carbon substitution, or stereochemistry. NMR and computational studies on two related aziridine containing cyclic tetrapeptides revealed that the amide conformations of their N acyl aziridines are similar, and are likely the determinant of the observed ring opening regioselectivity. Interestingly, some of the resulting 13-membered alpha3beta macrocycles were found to be conformationally heterogeneous. This study on the reactivity and conformational control of aziridine-containing cyclic tetrapeptides provides useful insight on the design and development of macrocyclic therapeutics. PMID- 28567254 TI - Circulatory zinc transport is controlled by distinct interdomain sites on mammalian albumins. AB - Zinc is an essential nutrient in the body; it is required for the catalytic activity of many hundreds of human enzymes and virtually all biological processes, therefore its homeostasis and trafficking is of crucial interest. Serum albumin is the major carrier of Zn2+ in the blood and is required for its systemic distribution. Here we present the first crystal structures of human serum albumin (HSA) and equine serum albumin (ESA) in complex with Zn2+. The structures allow unambiguous identification of the major zinc binding site on these two albumins, as well as several further, weaker zinc binding sites. The major site in both HSA and ESA has tetrahedral geometry and comprises three protein ligands from the sidechains of His67, His247 and Asp249 and a water molecule. Isothermal titration calorimetric studies of a HSA H67A mutant confirm this to be the highest affinity Zn2+ site. Furthermore, analysis of Zn2+ binding to HSA and ESA proved the presence of secondary sites with 20-50-fold weaker affinities, which may become of importance under particular physiological conditions. Both calorimetry and crystallography suggest that ESA possesses an additional site compared to HSA, involving Glu153, His157 and His288. The His157 residue is replaced by Phe in HSA, incapable of metal coordination. Collectively, these findings are critical to our understanding of the role serum albumin plays in circulatory Zn2+ handling and cellular delivery. PMID- 28567257 TI - Ferrocenyl chiral bisphosphorus ligands for highly enantioselective asymmetric hydrogenation via noncovalent ion pair interaction. AB - A new class of ferrocenyl chiral bisphosphorus ligand, Wudaphos, was developed, and exhibits excellent ee and activity (ee up to 99%, TON up to 20 000) for the asymmetric hydrogenation of both 2-aryl and 2-alkyl acrylic acids through ion pair noncovalent interaction under base free and mild reaction conditions. Well known anti-inflammatory drugs such as naproxen and ibuprofen together with the intermediate for the preparation of Roche ester and some bioactive compounds were also efficiently obtained with excellent ee. Control experiments were conducted and revealed that the ion pair noncovalent interaction and chain length played important roles. PMID- 28567258 TI - Templated dewetting: designing entirely self-organized platforms for photocatalysis. AB - Formation and dispersion of metal nanoparticles on oxide surfaces in site specific or even arrayed configuration are key in various technological processes such as catalysis, photonics, electrochemistry and for fabricating electrodes, sensors, memory devices, and magnetic, optical, and plasmonic platforms. A crucial aspect towards an efficient performance of many of these metal/metal oxide arrangements is a reliable fabrication approach. Since the early works on graphoepitaxy in the 70s, solid state dewetting of metal films on patterned surfaces has been much explored and regarded as a most effective tool to form defined arrays of ordered metal particles on a desired substrate. While templated dewetting has been studied in detail, particularly from a mechanistic perspective on lithographically patterned Si surfaces, the resulting outstanding potential of its applications on metal oxide semiconductors, such as titania, has received only limited attention. In this perspective we illustrate how dewetting and particularly templated dewetting can be used to fabricate highly efficient metal/TiO2 photocatalyst assemblies e.g. for green hydrogen evolution. A remarkable advantage is that the synthesis of such photocatalysts is completely based on self-ordering principles: anodic self-organized TiO2 nanotube arrays that self-align to a highest degree of hexagonal ordering are an ideal topographical substrate for a second self-ordering process, that is, templated dewetting of sputter-deposited metal thin films. The controllable metal/semiconductor coupling delivers intriguing features and functionalities. We review concepts inherent to dewetting and particularly templated dewetting, and outline a series of effective tools that can be synergistically interlaced to reach fine control with nanoscopic precision over the resulting metal/TiO2 structures (in terms of e.g. high ordering, size distribution, site specific placement, alloy formation) to maximize their photocatalytic efficiency. These processes are easy to scale up and have a high throughput and great potential to be applied to fabricate not only (photo)catalytic materials but also a large palette of other functional nanostructured elements and devices. PMID- 28567259 TI - Photothermal-enhanced catalysis in core-shell plasmonic hierarchical Cu7S4 microsphere@zeolitic imidazole framework-8. AB - Conventional semiconductor photocatalysis based on band-edge absorption remains inefficient due to the limited harvesting of solar irradiation and the complicated surface/interface chemistry. Herein, novel photothermal-enhanced catalysis was achieved in a core-shell hierarchical Cu7S4 nano-heater@ZIF-8 heterostructures via near-infrared localized surface plasmon resonance. Our results demonstrated that both the high surface temperature of the photothermal Cu7S4 core and the close-adjacency of catalytic ZIF-8 shell contributed to the extremely enhanced catalytic activity. Under laser irradiation (1450 nm, 500 mW), the cyclocondensation reaction rate increased 4.5-5.4 fold compared to that of the process at room temperature, in which the 1.6-1.8 fold enhancement was due to the localized heating effect. The simulated sunlight experiments showed a photothermal activation efficiency (PTAE) of 0.07%, further indicating the validity of photothermal catalysis based on the plasmonic semiconductor nanomaterials. More generally, this approach provides a platform to improve reaction activity with efficient utilization of solar energy, which can be readily extended to other green-chemistry processes. PMID- 28567260 TI - Cross-linked cationic diblock copolymer worms are superflocculants for micrometer sized silica particles. AB - A series of linear cationic diblock copolymer nanoparticles are prepared by polymerization-induced self-assembly (PISA) via reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization of 2-hydroxypropyl methacrylate (HPMA) using a binary mixture of non-ionic and cationic macromolecular RAFT agents, namely poly(ethylene oxide) (PEO113, Mn = 4400 g mol 1; Mw/Mn = 1.08) and poly([2-(methacryloyloxy)ethyl]trimethylammonium chloride) (PQDMA125, Mn = 31 800 g mol-1, Mw/Mn = 1.19). A detailed phase diagram was constructed to determine the maximum amount of PQDMA125 stabilizer block that could be incorporated while still allowing access to a pure worm copolymer morphology. Aqueous electrophoresis studies indicated that zeta potentials of +35 mV could be achieved for such cationic worms over a wide pH range. Core cross linked worms were prepared via statistical copolymerization of glycidyl methacrylate (GlyMA) with HPMA using a slightly modified PISA formulation, followed by reacting the epoxy groups of the GlyMA residues located within the worm cores with 3-aminopropyl triethoxysilane (APTES), and concomitant hydrolysis/condensation of the pendent silanol groups with the secondary alcohol on the HPMA residues. TEM and DLS studies confirmed that such core cross-linked cationic worms remained colloidally stable when challenged with either excess methanol or a cationic surfactant. These cross-linked cationic worms are shown to be much more effective bridging flocculants for 1.0 MUm silica particles at pH 9 than the corresponding linear cationic worms (and also various commercial high molecular weight water-soluble polymers.). Laser diffraction studies indicated silica aggregates of around 25-28 MUm diameter when using the former worms but only 3-5 MUm diameter when employing the latter worms. Moreover, SEM studies confirmed that the cross-linked worms remained intact after their adsorption onto the silica particles, whereas the much more delicate linear worms underwent fragmentation under the same conditions. Similar results were obtained with 4 MUm silica particles. PMID- 28567261 TI - Amplifying undetectable NMR signals to study host-guest interactions and exchange. AB - The characteristics of host-guest systems, such as molecular recognition, complexation, encapsulation, guest composition, and dynamic exchange, are manifested by changes in the chemical shifts (Deltaomega) in the NMR spectrum. However, in cases where NMR signals cannot be detected, due to low concentrations, poor solubility, or relatively fast exchange, an alternative is needed. Here, we show that by using the magnetization transfer (MT) method, the undetectable NMR signals of host-guest assemblies can be amplified by two orders of magnitude. It is shown that the binding kinetics characteristics of a fluorinated guest and cucurbit[n]uril (CB[n]) hosts in aqueous solutions determine the NMR signal amplification of host-guest assemblies. In addition, by using the MT technique within the 19F-NMR framework, one can detect MUM concentrations of the complex and study the effect of different solutes on the resulting host-guest system. The results expand the "NMR toolbox" available to explore a wider range of dynamic host-guest systems in which NMR signals cannot be detected. PMID- 28567263 TI - Non-bonding 1,5-S...O interactions govern chemo- and enantioselectivity in isothiourea-catalyzed annulations of benzazoles. AB - Isothiourea-catalyzed annulations between 2-acyl benzazoles and alpha,beta unsaturated acyl ammonium intermediates are selectively tuned to form either lactam or lactone heterocycles in good yields (up to 95%) and high ee (up to 99%) using benzothiazole or benzoxazole derivatives, respectively. Computation gives insight into the significant role of two 1,5-S...O interactions in controlling the structural preorganization and chemoselectivity observed within the lactam synthesis with benzothiazoles as nucleophiles. When using benzazoles the absence of a second stabilizing non-bonding 1,5-S...O interaction leads to a dominant C H...O interaction in determining structural preorganization and lactone formation. PMID- 28567262 TI - A magnetic look into the protecting layer of Au25 clusters. AB - The field of molecular metal clusters protected by organothiolates is experiencing a very rapid growth. So far, however, a clear understanding of the fine interactions between the cluster core and the capping monolayer has remained elusive, despite the importance of the latter in interfacing the former to the surrounding medium. Here, we describe a very sensitive methodology that enables comprehensive assessment of these interactions. Pulse electron nuclear double resonance (ENDOR) was employed to study the interaction of the unpaired electron with the protons of the alkanethiolate ligands in four structurally related paramagnetic Au25(SR)018 clusters (R = ethyl, propyl, butyl, 2-methylpropyl). Whereas some of these structures were known, we present the first structural description of the highly symmetric Au25(SPr)018 cluster. Through knowledge of the structural data, the ENDOR signals could be successfully related to the types of ligand and the distance of the relevant protons from the central gold core. We found that orbital distribution affects atoms that can be as far as 6 A from the icosahedral core. Simulations of the spectra provided the values of the hyperfine coupling constants. The resulting information was compared with that provided by 1H NMR spectroscopy, and molecular dynamics calculations provided useful hints to understanding differences between the ENDOR and NMR results. It is shown that the unpaired electron can be used as a very precise probe of the main structural features of the interface between the metal core and the capping ligands. PMID- 28567264 TI - Multi-electron reactivity of a cofacial di-tin(ii) cryptand: partial reduction of sulfur and selenium and reversible generation of S3. AB - Cofacial bimetallic tin(ii) ([Sn2(mBDCA-5t)]2-, 1) and lead(ii) ([Pb2(mBDCA-5t)]2 , 2) complexes have been prepared by hexadeprotonation of hexacarboxamide cryptand mBDCA-5t-H6 together with double Sn(ii) or Pb(ii) insertion. Reaction of 1 with elemental sulfur or selenium generates di-tin polychalcogenide complexes containing MU-E and bridging MU-E5 ligands where E = S or Se, and the Sn(ii) centers have both been oxidized to Sn(iv). Solution and solid-state UV-Vis spectra of [(MU-S5)Sn2(MU-S)(mBDCA-5t)]2- (4) indicate that the complex acts reversibly as a source of S3- in DMF solution with a Keq = 0.012 +/- 0.002. Reductive removal of all six chalcogen atoms is achieved through treatment of [(MU-E5)Sn2(MU-E)(mBDCA-5t)]2- with PR3 (R = t Bu, Ph, OiPr) to produce six equiv. of the corresponding EPR3 compound with regeneration of di-tin(ii) cryptand complex 1. PMID- 28567265 TI - Competitive coordination strategy for the synthesis of hierarchical-pore metal organic framework nanostructures. AB - Metal-organic frameworks (MOFs) usually have micropores smaller than 2 nm, which may restrict their applications in some cases. Hierarchical-pore MOFs (H-MOFs) are a new family of MOF materials, possessing both micro- and mesopores to address this problem. Here we demonstrate a competitive coordination strategy for the synthesis of H-MOF nanostructures, such as two-dimensional (2D) H-MOF nanosheets and H-MOF nanocubes, evolving through an etching process tuned by a competitive ligand. The as-synthesized 2D H-MOF nanosheets can serve as a substrate to in situ immobilize Pd nanoparticles to achieve a surfactant-free Pd catalyst, by means of a simple soaking method of Pd2+ precursors. Combined with the unique structure and gas adsorption capacity of H-MOF-5, the Pd-H-MOF-5 catalyst exhibits superior catalytic performance. PMID- 28567266 TI - A Lewis acid beta-diiminato-zinc-complex as all-rounder for co- and terpolymerisation of various epoxides with carbon dioxide. AB - A beta-diiminato-zinc-N(SiMe3)2 complex (1) was synthesised and fully characterised, including an X-ray diffraction study. The activity of catalyst 1 towards the coupling reaction of CO2 and various epoxides, including propylene oxide (PO), cyclohexene oxide (CHO), styrene oxide (SO), limonene oxide (LO), octene oxide (OO) and epichlorohydrin (ECH), was investigated. Terpolymerisation of CO2, PO and LO, as well as CO2, CHO and PO, was successfully realised, resulting in polymers with adjustable glass transition temperatures and transparencies. Reaction conditions such as temperature, pressure and catalyst concentration were varied to find the optimal reaction values, especially regarding LO/CO2. In situ IR experiments hinted that at 60 degrees C and a critical LO concentration, polymerisation and depolymerisation are in an equilibrium (ceiling effect). Pressurising catalyst 1 with carbon dioxide resulted in a dimeric catalyst (2) with a OSiMe3 group as a new initiator. Homopolymerisation of different epoxides was carried out in order to explain the reactivity concerning copolymerisation reaction of CO2 and epoxides. PMID- 28567268 TI - Measuring Early Cortical Visual Processing in the Clinic. AB - We describe a mobile app that measures early cortical visual processing suitable for use in clinics. The app is called Component Extraction and Motion Integration Test (CEMIT). Observers are asked to respond to the direction of translating plaids that move in one of two very different directions. The plaids have been selected so that the plaid components move in one of the directions and the plaid pattern moves in the other direction. In addition to correctly responding to the pattern motion, observers demonstrate their ability to correctly extract the movement (and therefore the orientation) of the underlying components at specific spatial frequencies. We wanted to test CEMIT by seeing if we could replicate the broader tuning observed at low spatial frequencies for this type of plaid. Results from CEMIT were robust and successfully replicated this result for 50 typical observers. We envisage that it will be of use to researchers and clinicians by allowing them to investigate specific deficits at this fundamental level of cortical visual processing. CEMIT may also be used for screening purposes where visual information plays an important role, for example, air traffic controllers. PMID- 28567267 TI - PdII2L4-type coordination cages up to three nanometers in size. AB - The utilization of large ligands in coordination-based self-assembly represents an attractive strategy for the construction of supramolecular assemblies more than two nanometers in size. However, the implementation of this strategy is hampered by the fact that the preparation of such ligands often requires substantial synthetic effort. Herein, we describe a simple one-step protocol, which allows large bipyridyl ligands with a bent shape to be synthesized from easily accessible and/or commercially available starting materials. The ligands were used to construct PdII2L4-type coordination cages of unprecedented size. Furthermore, we provide evidence that these cages may be stabilized by close intramolecular packing of lipophilic ligand side chains. Packing effects of this kind are frequently encountered in protein assemblies, but they are seldom used as a design element in metallasupramolecular chemistry. PMID- 28567270 TI - Perceiving Animacy From Deformation and Translation. AB - In a cartoon, we often receive an animacy impression from a dynamic nonanimate object, such as a sponge or a flour sack, which does not have an animal-like shape. We hypothesize that the animacy impression of a nonanimal object could stem from dynamic patterns that are possibly fundamental for biological motion perception. Here we show that observers recognize the animacy of human jump actions from the combination of deformation and translation. We extracted vertical motion vectors from the uppermost and lowermost points in point-light jumper stimuli and assigned the vectors to a uniform rectangle. The participants' task was to rate the animacy and jump impressions for the rectangle. Results showed that both animacy and jump impressions for the rectangle movements were comparable to those for the original point-light movements. The impressions decreased for stimuli having a deformation or translation component alone, which was extracted from the original motion vectors. By mathematically simulating deformation and translation in a human jump, we also found that the temporal relation between deformation and translation plays a critical role in the determination of jump impressions but only has a moderate effect for animacy impressions. On the basis of the results, we discuss how cartoon techniques take advantage of the properties of biological motion perception. PMID- 28567271 TI - The Accuracy and Precision of Position and Orientation Tracking in the HTC Vive Virtual Reality System for Scientific Research. AB - The advent of inexpensive consumer virtual reality equipment enables many more researchers to study perception with naturally moving observers. One such system, the HTC Vive, offers a large field-of-view, high-resolution head mounted display together with a room-scale tracking system for less than a thousand U.S. dollars. If the position and orientation tracking of this system is of sufficient accuracy and precision, it could be suitable for much research that is currently done with far more expensive systems. Here we present a quantitative test of the HTC Vive's position and orientation tracking as well as its end-to-end system latency. We report that while the precision of the Vive's tracking measurements is high and its system latency (22 ms) is low, its position and orientation measurements are provided in a coordinate system that is tilted with respect to the physical ground plane. Because large changes in offset were found whenever tracking was briefly lost, it cannot be corrected for with a one-time calibration procedure. We conclude that the varying offset between the virtual and the physical tracking space makes the HTC Vive at present unsuitable for scientific experiments that require accurate visual stimulation of self-motion through a virtual world. It may however be suited for other experiments that do not have this requirement. PMID- 28567269 TI - Spatial Frequency Shifts From Counterphase Flicker and From Simultaneous Contrast. AB - In simultaneous contrast of spatial frequency (SF), a test grating surrounded by a coarser inducing grating looks apparently finer. We combined this effect with another visual illusion; the fact that flickering the inducing grating raises its apparent SF. We found that the inducer's apparent, not physical spatial frequency, drove the simultaneous contrast that it induced into a test grating. Thus, when the inducer was made to flicker, its SF appeared to be higher and consequently, the test's SF appeared lower than before. This suggests that simultaneous contrast of spatial frequency exists further downstream than the flicker-induced increase in perceived SF. PMID- 28567272 TI - Accuracy and Tuning of Flow Parsing for Visual Perception of Object Motion During Self-Motion. AB - How do we perceive object motion during self-motion using visual information alone? Previous studies have reported that the visual system can use optic flow to identify and globally subtract the retinal motion component resulting from self-motion to recover scene-relative object motion, a process called flow parsing. In this article, we developed a retinal motion nulling method to directly measure and quantify the magnitude of flow parsing (i.e., flow parsing gain) in various scenarios to examine the accuracy and tuning of flow parsing for the visual perception of object motion during self-motion. We found that flow parsing gains were below unity for all displays in all experiments; and that increasing self-motion and object motion speed did not alter flow parsing gain. We conclude that visual information alone is not sufficient for the accurate perception of scene-relative motion during self-motion. Although flow parsing performs global subtraction, its accuracy also depends on local motion information in the retinal vicinity of the moving object. Furthermore, the flow parsing gain was constant across common self-motion or object motion speeds. These results can be used to inform and validate computational models of flow parsing. PMID- 28567274 TI - A new paradigm on health care accountability to improve the quality of the system: four parameters to achieve individual and collective accountability. PMID- 28567275 TI - Does SDG 3 have an adequate theory of change for improving health systems performance? PMID- 28567276 TI - Stopping female feticide in India: the failure and unintended consequence of ultrasound restriction. PMID- 28567273 TI - Bone and cartilage differentiation of a single stem cell population driven by material interface. AB - Adult stem cells, such as mesenchymal stem cells, are a multipotent cell source able to differentiate towards multiple cell types. While used widely in tissue engineering and biomaterials research, they present inherent donor variability and functionalities. In addition, their potential to form multiple tissues is rarely exploited. Here, we combine an osteogenic nanotopography and a chondrogenic hyaluronan hydrogel with the hypothesis that we can make a complex tissue from a single multipotent cell source with the exemplar of creating a three-dimensional bone-cartilage boundary environment. Marrow stromal cells were seeded onto the topographical surface and the temperature gelling hydrogel laid on top. Cells that remained on the nanotopography spread and formed osteoblast like cells, while those that were seeded into or migrated into the gel remained rounded and expressed chondrogenic markers. This novel, simple interfacial environment provides a platform for anisotropic differentiation of cells from a single source, which could ultimately be exploited to sort osteogenic and chondrogenic progenitor cells from a marrow stromal cell population and to develop a tissue engineered interface. PMID- 28567277 TI - Reducing maternal mortality in sub-Saharan Africa: the role of ethical consumerism. PMID- 28567278 TI - Psychosocial stimulation interventions for children with severe acute malnutrition: a systematic review. AB - BACKGROUND: The WHO Guidelines for the inpatient treatment of severely malnourished children include a recommendation to provide sensory stimulation or play therapy for children with severe acute malnutrition (SAM). This systematic review was performed to synthesize evidence around this recommendation. Specifically, the objective was to answer the question: "In children with severe acute malnutrition, does psychosocial stimulation improve child developmental, nutritional, or other outcomes?" METHODS: A review protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO 2016: CRD42016036403). MEDLINE, Embase, CINAHL, and PsycINFO were searched with terms related to SAM and psychosocial stimulation. Studies were selected if they applied a stimulation intervention in children with SAM and child developmental and nutritional outcomes were assessed. Findings were presented within a narrative synthesis and a summary of findings table. Quality of the evidence was evaluated using the Cochrane risk of bias tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. FINDINGS: Only two studies, both non-randomized controlled trials, met the selection criteria for this review. One was conducted in Jamaica (1975) with a follow-up period of 14 years; the other was done in Bangladesh (2002) with a six-month follow-up. At the individual study level, each of the included studies demonstrated significant differences in child development outcomes between intervention and control groups. Only the study conducted in Bangladesh demonstrated a clinically significant increase in weight-for-age z-scores in the intervention group compared to the control group. CONCLUSIONS: The evidence supporting the recommendation of psychosocial stimulation for children with SAM is not only sparse, but also of very low quality across important outcomes. High-quality trials are needed to determine the effects of psychosocial stimulation interventions on outcomes in children with SAM. PMID- 28567279 TI - Evolving treatment implementation among HIV-infected pregnant women and their partners: results from a national surveillance study in Italy, 2001-2015. AB - BACKGROUND: The current global and national indications for antiretroviral treatment (ART, usually triple combination therapy) in adolescent and adults, including pregnant women, recommend early ART before immunologic decline, pre exposure chemoprophylaxis (PrEP), and treatment of HIV-negative partners in serodiscordant couples. There is limited information on the implementation of these recommendations among pregnant women with HIV and their partners. METHODS: The present analysis was performed in 2016, using data from clinical records of pregnant women with HIV, followed between 2001 and 2015 at hospital or university clinics within a large, nationally representative Italian cohort study. The study period was divided in three intervals of five years each (2001-2005, 2006-2010, 2011-2015), and the analysis evaluated temporal trends in rates of HIV diagnosis in pregnancy, maternal antiretroviral treatment at conception, prevalence of HIV infection among partners of pregnant women with HIV, and proportion of seronegative and seropositive male partners receiving antiretroviral treatment. RESULTS: The analysis included 2755 pregnancies in women with HIV. During the three time intervals considered the rate of HIV diagnosis in pregnancy (overall 23.3%), and the distribution of HIV status among male partners (overall 48.7% HIV negative, 28.6% HIV-positive and 22.8% unknown) remained substantially unchanged. Significant increases were observed in the proportion of women with HIV diagnosed before pregnancy who were on antiretroviral treatment at conception (from 62.0% in 2001-2005 to 81.3% in 2011-2015, P < 0.001), and in the proportion of HIV positive partners on antiretroviral treatment (from 73.3% in 2001-2005 to 95.8% in 2011-2015, P = 0.002). Antiretroviral treatment was administered in 99.1% of the pregnancies that did not end early because of miscarriage, termination, or intrauterine death, and in 75.3% of those not ending in a live birth. No implementation of antiretroviral treatment was introduced among male HIV-negative partners. CONCLUSIONS: The results suggest good implementation of antiretroviral treatment among HIV-positive women and their HIV-positive partners, but no implementation, even in recent years, of Pre-Exposure Prophylaxis (PrEP) among uninfected male partners. Further studies should assess the determinants of this occurrence and clarify the attitudes and the potential barriers to PrEP use. PMID- 28567280 TI - Solar powered oxygen systems in remote health centers in Papua New Guinea: a large scale implementation effectiveness trial. AB - BACKGROUND: Pneumonia is the largest cause of child deaths in Papua New Guinea (PNG), and hypoxaemia is the major complication causing death in childhood pneumonia, and hypoxaemia is a major factor in deaths from many other common conditions, including bronchiolitis, asthma, sepsis, malaria, trauma, perinatal problems, and obstetric emergencies. A reliable source of oxygen therapy can reduce mortality from pneumonia by up to 35%. However, in low and middle income countries throughout the world, improved oxygen systems have not been implemented at large scale in remote, difficult to access health care settings, and oxygen is often unavailable at smaller rural hospitals or district health centers which serve as the first point of referral for childhood illnesses. These hospitals are hampered by lack of reliable power, staff training and other basic services. METHODS: We report the methodology of a large implementation effectiveness trial involving sustainable and renewable oxygen and power systems in 36 health facilities in remote rural areas of PNG. The methodology is a before-and after evaluation involving continuous quality improvement, and a health systems approach. We describe this model of implementation as the considerations and steps involved have wider implications in health systems in other countries. RESULTS: The implementation steps include: defining the criteria for where such an intervention is appropriate, assessment of power supplies and power requirements, the optimal design of a solar power system, specifications for oxygen concentrators and other oxygen equipment that will function in remote environments, installation logistics in remote settings, the role of oxygen analyzers in monitoring oxygen concentrator performance, the engineering capacity required to sustain a program at scale, clinical guidelines and training on oxygen equipment and the treatment of children with severe respiratory infection and other critical illnesses, program costs, and measurement of processes and outcomes to support continuous quality improvement. CONCLUSIONS: This study will evaluate the feasibility and sustainability issues in improving oxygen systems and providing reliable power on a large scale in remote rural settings in PNG, and the impact of this on child mortality from pneumonia over 3 years post intervention. Taking a continuous quality improvement approach can be transformational for remote health services. PMID- 28567281 TI - Toward elimination of mother-to-child transmission of HIV in South Africa: how best to monitor early infant infections within the Prevention of Mother-to-Child Transmission Program. AB - BACKGROUND: South Africa has utilized three independent data sources to measure the impact of its program for the prevention of mother-to-child transmission (PMTCT) of HIV. These include the South African National Health Laboratory Service (NHLS), the District Health Information System (DHIS), and South African PMTCT Evaluation (SAPMTCTE) surveys. We compare the results of each, outlining advantages and limitations, and make recommendations for monitoring transmission rates as South Africa works toward achieving elimination of mother-to-child transmission (eMTCT). METHODS: HIV polymerase chain reaction (PCR) test data, collected between 1 January 2010 to 31 December 2014, from the NHLS, DHIS and SAPMTCTE surveys were used to compare early mother-to-child transmission (MTCT) rates in South Africa. Data from the NHLS and DHIS were also used to compare early infant diagnosis (EID) coverage. RESULTS: The age-adjusted NHLS early MTCT rates of 4.1% in 2010, 2.6% in 2011 and 2.3% in 2012 consistently fall within the 95% confidence interval as measured by three SAPMTCTE surveys in corresponding time periods. Although DHIS data over-estimated MTCT rates in 2010, the MTCT rate declines thereafter to converge with age-adjusted NHLS MTCT rates by 2012. National EID coverage from NHLS data increases from around 52% in 2010 to 87% in 2014. DHIS data over-estimates EID coverage, but this can be corrected by employing an alternative estimate of the HIV-exposed infant population. CONCLUSION: NHLS and DHIS, two routine data sources, provide very similar early MTCT rate estimates that fall within the SAPMTCTE survey confidence intervals for 2012. This analysis validates the usefulness of routine data sources to track eMTCT in South Africa. PMID- 28567282 TI - Quantitative assessment of left ventricular mechanical dyssynchrony using cine cardiovascular magnetic resonance imaging: Inter-study reproducibility. AB - OBJECTIVES: To determine the inter-study reproducibility of left ventricular (LV) mechanical dyssynchrony measures based on standard cardiovascular magnetic resonance (CMR) cine images. DESIGN: Steady-state free precession (SSFP) LV short axis stacks and three long-axes were acquired on the same day at three time points. Circumferential strain systolic dyssynchrony indexes (SDI), area-SDI as well as circumferential and radial uniformity ratio estimates (CURE and RURE, respectively) were derived from CMR myocardial feature-tracking (CMR-FT) based on the tracking of three SSFP short-axis planes. Furthermore, 4D-LV-analysis based on SSFP short-axis stacks and longitudinal planes was performed to quantify 4D volume-SDI. SETTING: A single-centre London teaching hospital. PARTICIPANTS: 16 healthy volunteers. MAIN OUTCOME MEASURES: Inter-study reproducibility between the repeated exams. RESULTS: CURE and RURE as well as 4D-volume-SDI showed good inter-study reproducibility (coefficient of variation [CoV] 6.4%-12.9%). Circumferential strain and area-SDI showed higher variability between the repeated measurements (CoV 24.9%-37.5%). Uniformity ratio estimates showed the lowest inter-study variability (CoV 6.4%-8.5%). CONCLUSIONS: Derivation of LV mechanical dyssynchrony measures from standard cine images is feasible using CMR FT and 4D-LV-analysis tools. Uniformity ratio estimates and 4D-volume-SDI showed good inter-study reproducibility. Their clinical value should next be explored in patients who potentially benefit from cardiac resynchronization therapy. PMID- 28567283 TI - Dyslipidemia management in overweight or obese adolescents: A mixed-methods clinical trial of motivational interviewing. AB - BACKGROUND: Lifestyle management for dyslipidemic adolescents often occurs in the context of family-centered care, which necessitates adaptation of counseling strategies. OBJECTIVE: To determine the effectiveness of motivational interviewing for lifestyle behavior change for dyslipidemic adolescents in a dyad with a parent versus alone. METHODS: A total number of 32 adolescents were randomized 1:1 to receive a series of motivational interviewing sessions either together with a parent or alone for a 6-month intervention, with both quantitative and qualitative assessment of outcomes. RESULTS: Both groups were similar at baseline. Following the intervention, there were no significant differences between groups in physical, laboratory, lifestyle or psychosocial measures, except for a reduction in dietary fats/sugars (p = 0.02) and in screen time (p = 0.02) in the alone group. When both groups were combined, significant reductions at 6 months were noted for body mass index (p < 0.001), waist circumference (p < 0.001), total cholesterol (p < 0.001), low-density lipoprotein cholesterol (p < 0.001), triglycerides (p = 0.01), non-high-density lipoprotein cholesterol (p < 0.001), fasting insulin (p = 0.01), and homeostatic model (p = 0.02). Reduced screen time and increased fruit and vegetable intake were also noted for both groups combined. These changes were also reflected in self efficacy (p = 0.004), self-esteem (p = 0.03), and improvement in quality of life measures. Interview data provided insights into the utility and acceptability of the motivational interviewing intervention. CONCLUSION: Motivational interviewing was an efficient strategy for inspiring healthy lifestyle and physiological changes among adolescents in both groups. Family centered pediatric approaches should consider the autonomy and individual preferences of the adolescent prior to counseling. PMID- 28567284 TI - Ethnically Tibetan women in Nepal with low hemoglobin concentration have better reproductive outcomes. AB - Background and objectives: Tibetans have distinctively low hemoglobin concentrations at high altitudes compared with visitors and Andean highlanders. This study hypothesized that natural selection favors an unelevated hemoglobin concentration among Tibetans. It considered nonheritable sociocultural factors affecting reproductive success and tested the hypotheses that a higher percent of oxygen saturation of hemoglobin (indicating less stress) or lower hemoglobin concentration (indicating dampened response) associated with higher lifetime reproductive success. Methodology: We sampled 1006 post-reproductive ethnically Tibetan women residing at 3000-4100 m in Nepal. We collected reproductive histories by interviews in native dialects and noninvasive physiological measurements. Regression analyses selected influential covariates of measures of reproductive success: the numbers of pregnancies, live births and children surviving to age 15. Results: Taking factors such as marriage status, age of first birth and access to health care into account, we found a higher percent of oxygen saturation associated weakly and an unelevated hemoglobin concentration associated strongly with better reproductive success. Women who lost all their pregnancies or all their live births had hemoglobin concentrations significantly higher than the sample mean. Elevated hemoglobin concentration associated with a lower probability a pregnancy progressed to a live birth. Conclusions and implications: These findings are consistent with the hypothesis that unelevated hemoglobin concentration is an adaptation shaped by natural selection resulting in the relatively low hemoglobin concentration of Tibetans compared with visitors and Andean highlanders. PMID- 28567285 TI - Substrate roughening improves swimming performance in two small-bodied riverine fishes: implications for culvert remediation and design. AB - Worldwide declines in riverine fish abundance and diversity have been linked to the fragmentation of aquatic habitats through the installation of instream structures (e.g. culverts, dams, weirs and barrages). Restoring riverine connectivity can be achieved by remediating structures impeding fish movements by, for example, replacing smooth substrates of pipe culverts with naturalistic substrates (i.e. river stones; culvert roughening). However, empirical evaluations of the efficacy of such remediation efforts are often lacking despite the high economic cost. We assessed the effectiveness of substrate roughening in improving fish swimming performance and linked this to estimates of upstream passage success. Critical swimming speeds (Ucrit) of two small-bodied fish, purple-spotted gudgeon (Mogurnda adspersa; 7.7-11.6 cm total length, BL) and crimson-spotted rainbowfish (Melanotaenia duboulayi; 4.2-8.7 cm BL) were examined. Swimming trials were conducted in a hydraulic flume fitted with either a smooth acrylic substrate (control) or a rough substrate with fixed river stones. Swimming performance was improved on the rough compared to the smooth substrate, with Mo. adspersa (Ucrit-smooth = 0.28 +/- 0.0 m s-1, 2.89 +/- 0.1 BL s-1, Ucrit-rough = 0.36 +/- 0.02 m s-1, 3.66 +/- 0.22 BL s-1, mean +/- s.e) and Me. duboulayi (Ucrit-smooth = 0.46 +/- 0.01 m s-1, 7.79 +/- 0.33 BL s-1; Ucrit rough = = 0.55 +/- 0.03 m s-1, 9.83 +/- 0.67 BL s-1, mean +/- s.e.) both experiencing a 26% increase in relative Ucrit. Traversable water velocity models predicted maximum water speeds allowing successful upstream passage of both species to substantially increase following roughening remediation. Together these findings suggest culvert roughening may be a solution which allows hydraulic efficiency goals to be met, without compromising fish passage. PMID- 28567288 TI - GAD antibody-associated limbic encephalitis in a young woman with APECED. AB - : The autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a genetic disorder caused by a mutation in the autoimmune regulator (AIRE) gene. Immune deficiency, hypoparathyroidism and Addison's disease due to autoimmune dysfunction are the major clinical signs of APECED. We report on a 21 year-old female APECED patient with two inactivating mutations in the AIRE gene. She presented with sudden onset of periodic nausea. Adrenal insufficiency was diagnosed by means of the ACTH stimulation test. Despite initiation of hormone replacement therapy with hydrocortisone and fludrocortisone, nausea persisted and the patient developed cognitive deficits and a loss of interest which led to the diagnosis of depression. She was admitted to the psychiatric department for further diagnostic assessment. An EEG showed a focal epileptic pattern. Glutamic acid decarboxylase (GAD) antibodies, which had been negative eight years earlier, were now elevated in serum and in the cerebrospinal fluid. Oligoclonal bands were positive indicating an inflammatory process with intrathecal antibody production in the central nervous system (CNS). The periodic nausea was identified as dialeptic seizures, which clinically presented as gastrointestinal aura followed by episodes of reduced consciousness that occurred about 3-4 times per day. GAD antibody-associated limbic encephalitis (LE) was diagnosed. Besides antiepileptic therapy, an immunosuppressive treatment with corticosteroids was initiated followed by azathioprine. The presence of nausea and vomiting in endocrine patients with autoimmune disorders is indicative of adrenal insufficiency. However, our case report shows that episodic nausea may be a symptom of epileptic seizures due to GAD antibodies-associated LE in patients with APECED. LEARNING POINTS: Episodic nausea cannot only be a sign of Addison's disease, but can also be caused by epileptic seizures with gastrointestinal aura due to limbic encephalitis.GAD antibodies are not only found in diabetes mellitus type 1, but they are also associated with autoimmune limbic encephalitis and can appear over time.Limbic encephalitis can be another manifestation of autoimmune disease in patients with APECED/APS-1 that presents over the time course of the disease. PMID- 28567286 TI - Re-appraisal and consideration of minimally invasive surgery in colorectal cancer. AB - Throughout history, surgeons have been on a quest to refine the surgical treatment options for their patients and to minimize operative trauma. During the last three decades, there have been tremendous advances in the field of minimally invasive colorectal surgery, with an explosion of different technologies and approaches offered to treat well-known diseases. Laparoscopic surgery has been shown to be equal or superior to open surgery. The boundaries of laparoscopy have been pushed further, in the form of single-incision laparoscopy, natural-orifice transluminal endoscopic surgery and robotics. This paper critically reviews the pathway of development of minimally invasive surgery, and appraises the different minimally invasive colorectal surgical approaches available to date. PMID- 28567290 TI - ACTH-secreting medullary thyroid cancer: a case series. AB - : Medullary thyroid cancer (MTC) is a rare neuroendocrine tumour that originates from the parafollicular cells of the thyroid gland. The most common presentation of MTC is with a single nodule; however, by the time of diagnosis, most have spread to the surrounding cervical lymph nodes. Cushing's syndrome is a rare complication of MTC and is due to ectopic adrenocorticotrophic hormone (ACTH) secretion by tumour cells. Cushing's syndrome presents a challenging diagnostic and management issue in patients with MTC. Tyrosine kinase inhibitors (TKI) previously used for the management of metastatic MTC have become an important therapeutic option for the management of ectopic ACTH in metastatic MTC. The article describes three cases of ectopic ACTH secretion in MTC and addresses the significant diagnostic and management challenges related to Cushing's syndrome in metastatic MTC. LEARNING POINTS: Medullary thyroid cancer (MTC) is a rare neuroendocrine tumour.Cushing's syndrome is a rare complication of MTC that has a significant impact on patients' morbidity and mortality.Tyrosine kinase inhibitors (TKI) provide an important therapeutic option for the management of ectopic ACTH in metastatic MTC. PMID- 28567289 TI - Primary cutaneous B-cell lymphoma and chronic leg ulcers in a patient with type 2 diabetes. AB - : The incidences of type 2 diabetes mellitus and many cancers are rapidly increasing worldwide. Diabetes is a strong risk factor for some cancers (including lymphomas) and is also associated with adverse cancer outcomes. After gastrointestinal tract, the skin is the second most frequent extranodal site involved by non-Hodgkin lymphomas and the cutaneous B-cell lymphomas (CBCLs) range from 25% to 30% of all primary cutaneous lymphomas. The primary cutaneous diffuse large B-cell lymphoma (PCDLBCL) is an aggressive lymphoma with a poor prognosis, representing roughly 20% of all primary CBCLs. Classically, the cutaneous manifestation of this lymphoma is a red or violaceous tumors arising on a leg. To date, despite the large body of evidence suggesting that diabetes is strongly associated with an increased risk of some cancers, very little information is available regarding a possible association between type 2 diabetes and primary cutaneous diffuse large B-cell lymphoma. In this report, we will present the case of a white adult patient with type 2 diabetes with chronic leg ulcers complicated by a primary cutaneous diffuse large B-cell lymphoma. LEARNING POINTS: Diabetes mellitus is increasing worldwide as well as the incidence of many cancers.Diabetes mellitus is a powerful risk factor for some cancers (including lymphomas) and is strongly associated with adverse cancer outcomes.Seen that diabetes is strongly associated with an increased risk of cancers (including cutaneous lymphomas), clinicians should always keep in mind this complication in elderly patients with type 2 diabetes, even in a chronic leg ulcer with hypertrophy of the wound edge, which is hard to heal and does not have the typical characteristics of a diabetic or vascular ulcer. In these cases, a biopsy should be performed to rule out a neoplasm.Early diagnosis and correct management of cancer in a patient with type 2 diabetes are crucial to improve clinical outcomes. PMID- 28567291 TI - Pachydermoperiostosis: a rare mimicker of acromegaly. AB - : Pachydermoperiostosis is a very rare osteoarthrodermopathic disorder whose clinical and radiographic presentations may mimic those of acromegaly. In the evaluation of patients with acromegaloid appearances, pachydermoperiostosis should be considered as a differential diagnosis. In this article, we report a 17 year-old boy who presented with 2-year history of acral enlargement and facial appearance changes associated with joint pain and excessive sweating. He had been investigated extensively for acromegaly, and the final diagnosis was pachydermoperiostosis. LEARNING POINTS: There is a broad range of differential diagnosis for acromegaloid features such as acromegaly, pseudoacromegaly with severe insulin resistance, Marfan's syndrome, McCune-Albright and a rare condition called pachydermoperiostosis.Once a patient is suspected to have acromegaly, the first step is biochemical testing to confirm the clinical diagnosis, followed by radiologic testing to determine the cause of the excess growth hormone (GH) secretion. The cause is a somatotroph adenoma of the pituitary in over 95 percent of cases.The first step is measurement of a serum insulin-like growth factor 1 (IGF1). A normal serum IGF1 concentration is strong evidence that the patient does not have acromegaly.If the serum IGF1 concentration is high (or equivocal), serum GH should be measured after oral glucose administration. Inadequate suppression of GH after a glucose load confirms the diagnosis of acromegaly.Once the presence of excess GH secretion is confirmed, the next step is pituitary magnetic resonance imaging (MRI).Atypical presentation warrants revision of the diagnosis. This patient presented with clubbing with no gigantism, which is expected in adolescent acromegalics as the growth spurt and epiphyseal plate closure have not taken place yet. PMID- 28567292 TI - Euthyroid athyroxinemia - a novel endocrine syndrome. AB - : A 55-year-old female was referred with abnormal thyroid function tests (TFTs); the free thyroxine level (FT4) was undetectable <3.3 pmol/L (normal: 7.9-14.4), while her FT3, TSH and urinary iodine levels were normal. She was clinically euthyroid with a large soft lobulated goitre that had been present for more than thirty years. She received an injection of recombinant human TSH (rhTSH) following which there was a progressive rise of the FT3 and TSH levels to 23 pmol/L and >100 mIU/L respectively at 24 h, The FT4 however remained undetectable throughout. Being on thyroxine 100 ug/day for one month, her FT4 level increased to 15 pmol/L and TSH fell to 0.08 mIU/L. Four years earlier at another hospital, her FT4 level had been low (6.8 pmol/L) with a normal TSH and a raised Tc-99 uptake of 20% (normal<4%). We checked the TFTs and Tc-99 scans in 3 of her children; one was completely normal and 2 had euthyroid with soft lobulated goitres. Their Tc-99 scan uptakes were raised at 17% and 15%, with normal TFTs apart from a low FT4 7.2 pmol/L in the son with the largest thyroid nodule. This is a previously unreported form of dyshormonogenesis in which, with time, patients gradually lose their ability to synthesize thyroxine (T4) but not triiodothyroxine (T3). LEARNING POINTS: This is a previously unreported form of dyshormonogenetic goitre.This goitre progressively loses its ability to synthesize T4 but not T3.The inability to synthesize T4 was demonstrated by giving rhTSH. PMID- 28567293 TI - Pro-IGF2-induced hypoglycaemia associated with hepatocellular carcinoma. AB - : We present a patient (87 years, female) who was admitted to the emergency department because of loss of consciousness. Previous medical history included advanced-stage hepatocellular carcinoma and associated weight loss. She was found on the ground in an unresponsive state by her daughter and was determined to be hypoglycaemic. Upon bolus administration of 100 mL intravenous glucose (10%), glucose levels increased to 2.9 mmol/L and the patient regained full consciousness. She was admitted to the hospital for further examination, and treatment and continuous intravenous glucose infusion was initiated. As the patient was known to suffer from advanced-stage hepatocellular carcinoma, tumour associated hypoglycaemia was suspected. Insulin, c-peptide and IGF1 concentrations were indeed low, cortisol concentration was high and IGF2 and Pro IGF2 were borderline low and borderline high normal respectively. IGF2:IGF1 ratio was 23, confirming the diagnosis of non-islet cell tumour hypoglycaemia. During the initial phase of treatment, euglycaemia was maintained by continuous variable glucose infusion (5%, varying between 1 and 2 L/24 h), and the patient was advised to eat small snacks throughout the day. After euglycaemia was established and the diagnosis was confirmed, prednisolone was started (30 mg, 1 dd) and glucose infusions were halted. Under prednisolone treatment, glucose levels were slightly increased and no further hypoglycaemic episodes occurred. At her request, no surgery was performed. After 19 days, the patient was discharged to a hospice and died 3 weeks later. LEARNING POINTS: Hepatocellular carcinoma may be associated with non-islet cell tumour hypoglycaemia (NICTH).NICTH-induced hypoglycaemia is associated with low insulin and IGF1.Measurement of IGF2 only (without measurement of Pro-IGF2 and IGF1) may be insufficient to prove NICTH. PMID- 28567294 TI - Pheochromocytomatosis associated with a novel TMEM127 mutation. AB - : Pheochromocytomatosis, a very rare form of pheochromocytoma recurrence, refers to new, multiple, and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma. We here report a case of pheochromocytomatosis in a 70-year-old female. At age 64 years, she was diagnosed with a 6-cm right pheochromocytoma. She underwent laparoscopic right adrenalectomy, during which the tumor capsule was ruptured. At age 67 years, CT of abdomen did not detect recurrence. At age 69 years, she began experiencing episodes of headache and diaphoresis. At age 70 years, biochemical markers of pheochromocytoma became elevated with normal calcitonin level. CT revealed multiple nodules of various sizes in the right adrenal fossa, some of which were positive on metaiodobenzylguanidine (MIBG) scan. She underwent open resection of pheochromocytomatosis. Histological examination confirmed numerous pheochromocytomas ranging 0.1-1.2 cm in size. Next generation sequencing of a panel of genes found a novel heterozygous germline c.570delC mutation in TMEM127, one of the genes that, if mutated, confers susceptibility to syndromic pheochromocytoma. Molecular analysis showed that the c.570delC mutation is likely pathogenic. Our case highlights the typical presentation of pheochromocytomatosis, a rare complication of adrenalectomy for pheochromocytoma. Previous cases and ours collectively demonstrate that tumor capsule rupture during adrenalectomy is a risk factor for pheochromocytomatosis. We also report a novel TMEM127 mutation in this case. LEARNING POINTS: Pheochromocytomatosis is a very rare form of pheochromocytoma recurrence.Pheochromocytomatosis refers to new, multiple and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma.Tumor capsule rupture during adrenalectomy predisposes a patient to develop pheochromocytomatosis.Surgical resection of the multiple tumors of pheochromocytomatosis is recommended.Pheochromocytoma recurrence should prompt genetic testing for syndromic pheochromocytoma. PMID- 28567295 TI - Stubborn hiccups as a sign of massive apoplexy in a naive acromegaly patient with pituitary macroadenoma. AB - : Pituitary apoplexy (PA) may very rarely present with hiccups. A 32-year-old man with classical acromegaloid features was admitted with headache, nausea, vomiting and stubborn hiccups. Pituitary magnetic resonance imaging (MRI) demonstrated apoplexy of a macroadenoma with suprasellar extension abutting the optic chiasm. Plasma growth hormone (GH) levels exhibited suppression (below <1 ng/mL) at all time points during GH suppression test with 75 g oral glucose. After treatment with corticosteroid agents, he underwent transsphenoidal pituitary surgery and hiccups disappeared postoperatively. The GH secretion potential of the tumor was clearly demonstrated immunohistochemically. We conclude that stubborn hiccups in a patient with a pituitary macroadenoma may be a sign of massive apoplexy that may result in hormonal remission. LEARNING POINTS: Patients with pituitary apoplexy may rarely present with hiccups.Stubborn hiccupping may be a sign of generalized infarction of a large tumor irritating the midbrain.Infarction can be so massive that it may cause cessation of hormonal overproduction and result in remission. PMID- 28567296 TI - Thyrotoxicosis leading to adrenal crises reveals primary bilateral adrenal lymphoma. AB - : Primary adrenal lymphoma is a rare malignancy. It frequently presents bilaterally and with symptoms of adrenal insufficiency. Amiodarone may induce secondary organ dysfunction, and thyrotoxicosis develops in 15% of cases. The symptomatology of both conditions is nonspecific, especially in the elderly, and a high suspicion index is necessary for appropriate diagnosis. A 78-year-old female presented to the emergency department with confusion, nausea and vomiting. She had recently been to the emergency department with urinary tract infection, vomiting and acute hypochloremic hyponatremia. Upon re-evaluation, the leukocyturia persisted and because of TSH 0.01 uU/mL and free-T4 68 (10-18) pmol/L, she was admitted to the Endocrinology ward. Further evaluation supported amiodarone-induced thyroiditis type 2. Sepsis ensued, in the setting of nosocomial pneumonia. Hemodynamic instability, hyponatremia, hypoglycemia and vomiting raised the suspicion of adrenocortical insufficiency. Fluid resuscitation and hydrocortisone led to clinical improvement, and adrenal insufficiency was admitted. The thoracoabdominal tomography suggested an endobronchic primary lesion with hepatic and adrenal secondary deposits (6.6 and 7 cm), but this was confirmed neither on pleural effusion nor on bronchofibroscopic fluid analyses. The adrenals were not accessible for biopsy. Despite high-dose hydrocortisone maintenance, the patient died before definite diagnosis. The autopsy confirmed primary non-Hodgkin lymphoma. LEARNING POINTS: Primary adrenal lymphoma is a rare cause of adrenal insufficiency, but progression can be fast and fatal.Hyperpigmentation is frequently absent.The presenting symptoms are nonspecific and might mimic infection. Disproportion of the general state with signs of specific organ symptomatology is a diagnostic clue.Infection may precipitate adrenal crisis and worsen thyroid function with further adrenal insufficiency exacerbation.In the context of thyrotoxicosis, there may be little clinical response to a therapeutic trial with standard dose glucocorticoids.High-dose glucocorticoid substitution may be required to achieve clinical stability in thyrotoxic patients. PMID- 28567297 TI - Pasireotide in an insulin-requiring diabetic acromegalic patient without worsening of hyperglycemia. AB - : Long-acting pasireotide is an effective treatment option for acromegaly, but it is associated with hyperglycemia, which could impact its use in patients with diabetes. We present a case of a 53-year-old man with acromegaly and type 2 diabetes mellitus (glycated hemoglobin (HbA1c): 7.5%), who refused surgery to remove a pituitary macroadenoma and enrolled in a Phase 3 clinical trial comparing long-acting pasireotide and long-acting octreotide in acromegalic patients. The patient initially received octreotide, but insulin-like growth factor 1 (IGF-1) levels remained elevated after 12 months (383.9 ng/mL; 193.0 ng/mL; reference range: 86.5-223.8 ng/mL), indicating uncontrolled acromegaly. He switched to pasireotide 40 mg and subsequently increased to 60 mg. Within 6 months, IGF-1 levels normalized (193.0 ng/mL), and they were mostly normal for the next 62 months of treatment with pasireotide (median IGF-1: 190.7 ng/mL). Additionally, HbA1c levels remained similar to or lower than baseline levels (range, 6.7% to 7.8%) during treatment with pasireotide despite major changes to the patient's antidiabetic regimen, which included insulin and metformin. Uncontrolled acromegaly can result in hyperglycemia due to an increase in insulin resistance. Despite having insulin-requiring type 2 diabetes, the patient presented here did not experience a long-term increase in HbA1c levels upon initiating pasireotide, likely because long-term control of acromegaly resulted in increased insulin sensitivity. This case highlights the utility of long-acting pasireotide to treat acromegaly in patients whose levels were uncontrolled after long-acting octreotide and who manage diabetes with insulin. LEARNING POINTS: Long-acting pasireotide provided adequate, long-term biochemical control of acromegaly in a patient with insulin-requiring type 2 diabetes mellitus who was unresponsive to long-acting octreotide.Glycemic levels initially increased after starting treatment with pasireotide but quickly stabilized as acromegaly became controlled.Long-acting pasireotide, along with an appropriate antidiabetic regimen, may be a suitable therapy for patients with acromegaly who also have insulin-requiring type 2 diabetes mellitus. PMID- 28567298 TI - Recurrent insulinoma in a 10-year-old boy with Down's syndrome. AB - : An insulinoma is a rare tumour with an incidence of four cases per million per year in adults. The incidence in children is not established. There is limited literature available in children with insulinoma, and only one case is reported in association with Down's syndrome in adults. Insulinoma diagnosis is frequently missed in adults as well as in children. The Whipple triad is the most striking feature although it has limited application in young children. Hypoglycaemia with elevated insulin, C-peptide and absent ketones is highly suggestive of hyperinsulinism. We present a case of 10-year-old boy with Down's syndrome with recurrent insulinoma. He was initially misdiagnosed as having an adrenal insufficiency and developed cushingoid features and obesity secondary to hydrocortisone treatment and excessive sugar intake. The tumour was successfully localised in the head of the pancreas with an MRI and octreotide scan on first presentation. Medical treatment with diazoxide and octreotide could not achieve normal blood glucose levels. The insulinoma was laparoscopically enucleated and pathological examination confirmed a neuroendocrine tumour. Subsequently, he had complete resolution of symptoms. He had a recurrence after 2 years with frequent episodes of hypoglycaemia. The biochemical workup was suggestive of hyperinsulinism. MRI and PET scan confirmed the recurrence at the same site (head of the pancreas). He had an open laparotomy for insulinoma resection. The pathology was consistent with benign insulinoma, and subsequently, he had complete resolution of symptoms. LEARNING POINTS: Insulinoma is a very rare tumour in children; it should be considered in the differential diagnosis of hypoglycaemia with absent ketones.Refractory neurological symptoms like seizure, migraine, mood changes and regression of learning abilities should suggest evaluation for hypoglycaemia.MRI with contrast and PET scan would localise the majority of pancreatic beta islet cell lesions.Medical treatment with diazoxide, octreotide and the addition of corn starch in feeds is not curative but can be supportive to maintain normoglycemia until the surgical resection.Surgical resection is the only curative treatment. The surgical procedure of choice (laparoscopic/open laparotomy) depends on local expertise, preoperative localisation, tumour size and number.Surgical treatment results in complete resolution of symptoms, but all cases should be closely followed up to monitor for recurrence. The recurrence rate is four times higher in MEN1 cases. PMID- 28567299 TI - Evaluation of an online injecting drug use stigma intervention targeted at health providers in New South Wales, Australia. AB - People who inject drugs are highly stigmatised. Discriminatory experiences are commonly reported, particularly in health care settings. This article evaluates an online stigma reduction training module targeting health providers working with people who inject drugs. A total of 139 participants completed a pre- and post-survey including attitude items and items depicting hypothetical scenarios and concerns around client behaviours. Participants' attitudes towards people who inject drugs were more positive and they showed less concerns about client behaviours after completing the online training module. Findings highlight the benefits of online training in reducing discriminatory attitudes towards people who inject drugs and improving confidence in working with this client group. PMID- 28567300 TI - Quality of primary health care and autonomous motivation for effective diabetes self-management among patients with type 2 diabetes. AB - This study showed, in line with self-determination theory, that of the six central quality dimensions of primary health care (access to care, continuity of care, diabetes counseling, autonomy support from one's physician, trust, patient centered care), autonomy support from one's physician was most strongly associated with autonomous motivation (self-regulation) for effective diabetes self-management among patients with type 2 diabetes (n = 2866). However, overall support for diabetes care received from friends, family members, other patients with diabetes, and health care professionals may even play a greater role. PMID- 28567301 TI - Designing behavioral self-regulation application for preventive personal mental healthcare. AB - Most of computerized cognitive behavioral therapy targeted restoration and few have targeted primary prevention. The purpose of this study is to obtain the knowledge for further development on preventive mental healthcare application. We developed a personal mental healthcare application which aimed to give users the chance to manage their mental health by self-monitoring and regulating their behavior. Through the 30-day field trial, the results showed improvement of mood score through conducting of suggested action, and the depressive mood of the participants was significantly decreased after the trial. The possibility of application and further problem was confirmed. PMID- 28567302 TI - Prevalence of substance abuse and socio-economic differences in substance abuse in an Australian community-dwelling elderly sample. AB - A sample of 324 55-90-year-old Australian adults participated in a survey on elderly substance abuse using the Clinical Assessment Scales for the Elderly. Overall, males had a higher prevalence rate of substance abuse than females. Significant differences in substance abuse mean scores were found for gender, age, income, community involvement, and retirement. The findings also reveal that being a female, involved in community groups, being a retiree, and being a non baby boomer are protective factors of substance abuse. Being an upper medium income earner appears to be a risk factor of substance abuse. PMID- 28567304 TI - Rising prevalence of non-B HIV-1 subtypes in North Carolina and evidence for local onward transmission. AB - HIV-1 diversity is increasing in North American and European cohorts which may have public health implications. However, little is known about non-B subtype diversity in the southern United States, despite the region being the epicenter of the nation's epidemic. We characterized HIV-1 diversity and transmission clusters to identify the extent to which non-B strains are transmitted locally. We conducted cross-sectional analyses of HIV-1 partial pol sequences collected from 1997 to 2014 from adults accessing routine clinical care in North Carolina (NC). Subtypes were evaluated using COMET and phylogenetic analysis. Putative transmission clusters were identified using maximum-likelihood trees. Clusters involving non-B strains were confirmed and their dates of origin were estimated using Bayesian phylogenetics. Data were combined with demographic information collected at the time of sample collection and country of origin for a subset of patients. Among 24,972 sequences from 15,246 persons, the non-B subtype prevalence increased from 0% to 3.46% over the study period. Of 325 persons with non-B subtypes, diversity was high with over 15 pure subtypes and recombinants; subtype C (28.9%) and CRF02_AG (24.0%) were most common. While identification of transmission clusters was lower for persons with non-B versus B subtypes, several local transmission clusters (>=3 persons) involving non-B subtypes were identified and all were presumably due to heterosexual transmission. Prevalence of non-B subtype diversity remains low in NC but a statistically significant rise was identified over time which likely reflects multiple importation. However, the combined phylogenetic clustering analysis reveals evidence for local onward transmission. Detection of these non-B clusters suggests heterosexual transmission and may guide diagnostic and prevention interventions. PMID- 28567305 TI - Characterization of Ex Vivo Expanded Oral Mucosal Epithelium Cells on Acellular Porcine Corneal Stroma for Ocular Surface Reconstruction. AB - PURPOSE: To ex vivo expand oral mucosal epithelium cells (OMECs) on acellular porcine corneal stroma (APCS) without using feeder cells and serum and to compare the morphologic and phenotypic characteristics of cultured oral cells on APCS to those of cells on deluded human amniotic membrane (HAM). METHODS: SD rat oral mucosal biopsies were cultured on APCS and HAM. Reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were used to analyze the characterization of stem cells and epithelial differentiation of the outgrowth products. RESULTS: Stratified and optimal transplantable OMECs were obtained after being cultured three to four weeks. Both RT-PCR and immunohistochemistry showed that cultured OMECs expressed markers of epithelial differentiation cytokeratin K3 and epithelial stem cell markers of p63 and ABCG2. CONCLUSIONS: OMECs can be successfully cultured on APCS without using xenobiotic feeder cells and serum. Characterization showed that these sheets retain the morphologic and phenotypic characteristics of OMECs within differentiated cells and stem cells. The optimal transplantable sheets can prove to be particularly beneficial to both bilateral limbal stem cell deficiency and deep corneal lesions. PMID- 28567303 TI - Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine. AB - The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. Whole genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilized WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counseling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis. PMID- 28567307 TI - Corrigendum to "Unmet Supportive Care Needs among Breast Cancer Survivors of Community-Based Support Group in Kuching, Sarawak". AB - [This corrects the article DOI: 10.1155/2016/7297813.]. PMID- 28567306 TI - MR Micro-Neurography and a Segmentation Protocol Applied to Diabetic Neuropathy. AB - The aim of this study was to assess with MRI morphometric ultrastructural changes in nerves affected by diabetic peripheral neuropathy (DPN). We used an MR micro neurography imaging protocol and a semiautomated technique of tissue segmentation to visualize and measure the volume of internal nerve components, such as the epineurium and nerve fascicles. The tibial nerves of 16 patients affected by DPN and of 15 healthy volunteers were imaged. Nerves volume (NV), fascicles volume (FV), fascicles to nerve ratio (FNR), and nerves cross-sectional areas (CSA) were obtained. In patients with DPN the NV was increased and the FNR was decreased, as a result of an increase of the epineurium (FNR in diabetic neuropathy 0,665; in controls 0,699, p = 0,040). CSA was increased in subjects with DPN (12,84 mm2 versus 10,22 mm2, p = 0,003). The FV was increased in patients with moderate to severe DPN. We have demonstrated structural changes occurring in nerves affected by DPN, which otherwise are assessable only with an invasive biopsy. MR micro neurography appears to be suitable for the study of microscopic changes in tibial nerves of diabetic patients. PMID- 28567308 TI - Cut-Off Value of Medial Meniscal Extrusion for Knee Pain. AB - Purpose. Medial meniscal extrusion (MME) has attracted attention as an index of knee pain in conjunction with clinical symptoms that could be more useful than the diagnosis of knee osteoarthritis on X-ray. However, the size of MME that would cause knee pain has not been clarified. The aim of the present study was to investigate the cut-off value of MME for knee pain. Methods. A total of 318 knees were evaluated. The presence of current or past knee pain was confirmed by interview. Next, MME was measured using vertical sonographic images of the medial joint spaces during weightbearing. Results. Overall, 71 knees were painful (P group), and 247 knees were not (N-group). MME was 5.9 +/- 1.8 mm in the P-group and 2.9 +/- 1.5 mm in the N-group (P < 0.0001). Analysis of the receiver operating characteristic curve showed that the cut-off value of MME for knee pain was 4.3 mm, with sensitivity of 0.8451 and specificity of 0.8502. In addition, 64% of knees without pain cases at the time of examination whose MME exceeded this cut-off value had past knee pain. Conclusions. The sensitivity and specificity of MME for knee pain were very high with a cut-off value of 4.3 mm. PMID- 28567309 TI - Left Atrial Myxoma in Pregnancy: Management Strategy Using Minimally Invasive Surgical Approach. AB - This case report concerns a young woman who, during her pregnancy, suffered severe mitral regurgitation. It was discovered at the same time that she had a left atrial myxoma. During the early postpartum period she successfully underwent an anterior minithoracotomy to remove the left atrial myxoma in conjunction with repair of the mitral valve. The thoracotomy approach in this specific patient was chosen as it would give a better chance of successful mother-child bonding because the patient would be able to avoid the precautions which would have been necessary following a sternotomy, especially the limitation of her ability to hold her child during the first 4-6 weeks postoperatively. PMID- 28567310 TI - Absence of Left Circumflex Artery: A Rare Congenital Disorder of Coronary Arteries. AB - Congenital absence of left circumflex artery is a rare occurrence and very few cases have been reported in literature. It is a benign incidental finding; however some patients present with sudden onset chest pain mimicking acute coronary syndrome often resulting in detection of this rare anatomy on coronary angiography. Coronary computed tomography angiography is a relatively new noninvasive imaging modality which can be used to confirm this suspicion and diagnose this unique morphology reliably. PMID- 28567311 TI - Retrieval of Embolized Amplatzer Patent Foramen Ovale Occlusion Device: Issues Related to Late Recognition. AB - Embolization of a percutaneous patent foramen ovale (PFO) closure device is a rare but serious complication. While early, periprocedural device embolization can normally be managed with snare and percutaneous retrieval, late embolization requires a different management strategy due to inability of the device to deform to allow passage into a large caliber sheath. We present a case of asymptomatic device embolization recognized six months following implantation and discuss the challenges encountered in successfully retrieving the device. PMID- 28567312 TI - Intracorneal Hematoma Showing Clinical and Dermoscopic Features of Acral Lentiginous Melanoma. AB - Intra- and subcorneal hematoma, a skin alteration seen palmar and plantar after trauma or physical exercise, can be challenging to distinguish from in situ or invasive acral lentiginous melanoma. Thus, careful examination including dermoscopic and histologic assessment may be necessary to make the correct diagnosis. We here present a case of a 67-year-old healthy female patient who presented with a pigmented plantar skin alteration. Differential diagnoses included benign skin lesions, for example, hematoma or melanocytic nevus, and also acral lentiginous melanoma or melanoma in situ. Since clinical and dermoscopic examinations did not rule out a malignant skin lesion, surgical excision was performed and confirmed an intracorneal hematoma. In summary, without adequate physical trigger, it may be clinically and dermoscopically challenging to make the correct diagnosis in pigmented palmar and plantar skin alterations. Thus, biopsy or surgical excision of the skin alteration may be necessary to rule out melanoma. PMID- 28567313 TI - PUVA Induced Bullous Pemphigoid in a Patient with Mycosis Fungoides. AB - Background. Bullous pemphigoid is an autoimmune subepidermal blistering skin disease in which autoantibodies are directed against components of the basement membrane. The disease primarily affects the elderly people and in most of the patients inducing factors cannot be identified. Herein, we report a case of BP that occurred in a patient who was receiving PUVA therapy for the treatment of mycosis fungoides. Main Observation. A 26-year-old woman with mycosis fungoides developed blisters while receiving PUVA therapy. On physical examination tense bullae on the normal skin, remnants of blisters, and erosions were observed on her breasts, the chest wall, and the upper abdomen. Histopathological investigations revealed subepidermal blisters with eosinophilic infiltration and in direct immunofluorescence examination linear deposition of IgG along the basement membrane zone was observed. The diagnosis of bullous pemphigoid was also confirmed by ELISA and BIOCHIP mosaic-based indirect immunofluorescence test. Conclusions. PUVA therapy is an extremely rare physical factor capable of inducing bullous pemphigoid. So the development of blistering lesions during PUVA therapy may be suggestive sign of a bullous disease such as bullous pemphigoid and it should be excluded with proper clinical and laboratory approaches immediately after withdrawal of PUVA therapy. PMID- 28567314 TI - Subacute Hypophysitis with Panhypopituitarism as First Presentation of HIV and Syphilis Coinfection. AB - Infection by Treponema pallidum still represents a clinical challenge due to its various forms of presentation. HIV coinfection added diversity and changed the natural history of syphilis as a systemic infection. We present a rare case of subacute hypophysitis and panhypopituitarism due to an early active neurosyphilis in a previously unknown HIV coinfected patient. PMID- 28567315 TI - Respiratory Syncytial Virus Associated Myocarditis Requiring Venoarterial Extracorporeal Membrane Oxygenation. AB - Severe fulminant myocarditis causing cardiogenic shock can be a rapidly progressing, life threatening condition. Respiratory syncytial virus (RSV) is a very rare infectious culprit infrequently described in medical literature as a cause of myocarditis, particularly in adults. We present a case of acute fulminant myocarditis in a patient with PCR positive RSV infection requiring venoarterial extracorporeal membrane oxygenation (VA-ECMO). PMID- 28567316 TI - Spontaneous Nosocomial Pseudomonas aeruginosa Meningitis Presenting as Trismus. AB - We describe the case of a 78-year-old female receiving adjuvant postsurgical chemotherapy for colon adenocarcinoma who spontaneously developed nosocomial Pseudomonas meningitis causing severe trismus. The patient was initially admitted for ileus, developing neck stiffness and trismus on the thirteenth day of admission. Cerebrospinal fluid grew pansensitive Pseudomonas aeruginosa. Magnetic resonance imaging of the brain was consistent with bilateral subacute infarcts secondary to meningitis. The patient responded well to 21 days of broad spectrum antimicrobial therapy modified to ceftazidime alone following speciation and sensitivity. Outpatient follow-up at 46 days revealed normal maximal mouth opening with the ability to chew and tolerate a full diet. Trismus is a motor disturbance of the trigeminal nerve with difficulty in opening the mouth. Infectious etiologies commonly described include tetanus, odontogenic infections, or deep neck space infections. This is the first reported case of simultaneous nosocomial Pseudomonas meningitis and trismus in a patient with no history of neurosurgery or lumbar spinal manipulation. PMID- 28567317 TI - Open-Label Fosmetpantotenate, a Phosphopantothenate Replacement Therapy in a Single Patient with Atypical PKAN. AB - Objective. Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder with variable onset, rate of progression, and phenotypic expression. Later-onset, more slowly progressive PKAN often presents with neuropsychiatric as well as motor manifestations that include speech difficulties, progressive dystonia, rigidity, and parkinsonism. PKAN is caused by biallelic PANK2 mutations, a gene that encodes pantothenate kinase 2, a regulatory enzyme in coenzyme A biosynthesis. Current therapeutic strategies rely on symptomatic relief. We describe the treatment of the first, later-onset PKAN patient with oral fosmetpantotenate (previously known as RE-024), a novel replacement therapy developed to bypass the enzymatic defect. Methods. This was an open-label, uncontrolled, 12-month treatment with fosmetpantotenate of a single patient with a later-onset, moderately severe, and slowly progressive form of PKAN. Results. The patient showed improvement in all clinical parameters including the Unified Parkinson's Disease Rating Scale (UPDRS), Barry-Albright Dystonia Scale, the EuroQol five-dimensional three-level (EQ-5D-3L) scale, timed 25-foot walk test, and electroglottographic speech analysis. Fosmetpantotenate was well-tolerated with only transient liver enzyme elevation which normalized after dose reduction and did not recur after subsequent dose increases. Conclusions. Fosmetpantotenate showed promising results in a single PKAN patient and should be further studied in controlled trials. PMID- 28567319 TI - Anterior Interosseous Nerve Neuropraxia Secondary to Shoulder Arthroscopy and Open Subpectoral Long Head Biceps Tenodesis. AB - Arthroscopic rotator cuff tendon repair is a common elective procedure performed by trained orthopaedic surgeons with a relatively low complication rate. Specifically, isolated neuropraxia of the anterior interosseous nerve (AIN) is a very rare complication of shoulder arthroscopy. An analysis of peer-reviewed published literature revealed only three articles reporting a total of seven cases that describe this specific complication following standard shoulder arthroscopic procedures. This article reports on three patients diagnosed with AIN neuropraxia following routine shoulder arthroscopy done by a single surgeon within a three-year period. All three patients also underwent open biceps tenodesis immediately following completion of the arthroscopic procedures. The exact causal mechanism of AIN neuropraxia following shoulder arthroscopy with biceps tenodesis is not known. This case report reviews possible mechanisms with emphasis on specific factors that make a traction injury the most likely etiology in these cases. We critically analyze our operating room setup and patient positioning practices in light of the existing biomechanical and cadaveric research to propose changes to our standard practices that may help to reduce the incidence of this specific postoperative complication in patients undergoing elective shoulder arthroscopy with biceps tenodesis. PMID- 28567318 TI - Hemolysis, Elevated Liver Enzymes, and Low Platelets, Severe Fetal Growth Restriction, Postpartum Subarachnoid Hemorrhage, and Craniotomy: A Rare Case Report and Systematic Review. AB - Introduction. Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome is a relatively uncommon but traumatic condition occurring in the later stage of pregnancy as a complication of severe preeclampsia or eclampsia. Prompt brain computed tomography (CT) or magnetic resonance imaging (MRI) and a multidisciplinary management approach are required to improve perinatal outcome. Case. A 37-year-old, Gravida 6, Para 1-0-4-1, Hispanic female with a history of chronic hypertension presented at 26 weeks and 6 days of gestational age. She was noted to have hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome accompanied by fetal growth restriction (FGR), during ultrasound evaluation, warranting premature delivery. The infant was delivered in stable condition suffering no permanent neurological deficit. Conclusion. HELLP syndrome is an uncommon and traumatic obstetric event which can lead to neurological deficits if not managed in a responsive and rapid manner. The central aggravating factor seems to be hypertension induced preeclamptic or eclamptic episode and complications thereof. The syndrome itself is manifested by hemolytic anemia, increased liver enzymes, and decreasing platelet counts with a majority of neurological defects resulting from hemorrhagic stroke or subarachnoid hemorrhage (SAH). To minimize adverse perinatal outcomes, obstetric management of this medical complication must include rapid clinical assessment, diagnostic examination, and neurosurgery consultation. PMID- 28567320 TI - Pneumoperitoneum without Intestinal Perforation in a Neonate: Case Report and Literature Review. AB - Pneumoperitoneum in a preterm neonate usually indicates perforation of the intestine and is considered a surgical emergency. However, there are cases of pneumoperitoneum with no evidence of rupture of the intestine reported in the literature. We report a case of pneumoperitoneum with no intestinal perforation in a preterm neonate with respiratory distress syndrome who was on high frequency oscillatory ventilation (HFOV). He developed bilateral pulmonary interstitial emphysema with localized cystic lesion, likely localized pulmonary interstitial emphysema, and recurrent pneumothoraces. He was treated with dexamethasone to wean from the ventilator. Pneumoperitoneum developed in association with left sided pneumothorax following mechanical ventilation and cardiopulmonary resuscitation. Pneumoperitoneum resolved after the pneumothorax was resolved with chest tube drainage. He died from acute cardiorespiratory failure. At autopsy, there was no evidence of intestinal perforation. This case highlights the fact that pneumoperitoneum can develop secondary to pneumothorax and does not always indicate intestinal perforation or require exploratory laparotomy. PMID- 28567321 TI - Neuropsychiatric Manifestations in a Patient with Panhypopituitarism. AB - We present a case of an incidental diagnosis of panhypopituitarism in a 68-year old African American man admitted to our psychiatric inpatient unit with symptoms suggestive of schizophrenia. The case was unusual as a first-episode psychosis given the patient's age. In the course of his admission, the patient's clinical condition deteriorated culminating in a sudden altered mental status which prompted a transfer to the medical floors and further investigations. A head CT scan and a pituitary MRI revealed a near total resection of the pituitary while laboratory investigations revealed hyponatremia and a grossly low hormone profile. The progression of these events casts doubts on our admitting diagnosis as the primary cause of the patient's symptoms. The patient's clinical condition improved only when his endocrinopathy was treated with hormone replacement, fluids, and electrolyte correction in addition to antipsychotics. An inability to verify the patient's psychiatric history and a remote history of pituitary resection several decades earlier, unknown to the treating team, added to the diagnostic conundrum. We revised the diagnosis to neuropsychiatric manifestations secondary to an organic brain syndrome due to a partial pituitary resection. The patient was discharged with no symptoms of psychosis, good insight, judgment, and good reality testing. PMID- 28567322 TI - Contralateral Ovarian Metastasis of Clear-Cell Renal Carcinoma: A Rare Case Report and Review of the Literature. AB - Renal cell carcinoma (RCC) constitutes 2-3% of all types of cancers. RCCs metastasize into lungs (50-60%), lymph nodes (36%), bones (30-40%), liver (30 40%), and brain (5%) in respective percentages. RCC rarely metastasizes into ovary. Only 25 cases of ovarian tumor, which metastasized into kidneys, have been presented. In the literature, a kidney-ovary axis has been defined, and its interrelationship begins with embryological life. With this case report, we aimed both to present a very rarely seen metastasis of RCC into contralateral ovary and also to review the literature. PMID- 28567323 TI - Comparative Neuroprotective Effects of Dietary Curcumin and Solid Lipid Curcumin Particles in Cultured Mouse Neuroblastoma Cells after Exposure to Abeta42. AB - Aggregation of amyloid beta protein (Abeta) and phosphorylated tau (p-Tau) plays critical roles in pathogenesis of Alzheimer's disease (AD). As an antiamyloid natural polyphenol, curcumin (Cur) has a potential role in prevention of neurodegeneration in AD. However, due to limited absorption of the dietary Cur, the solid lipid Cur particles (SLCP) have been suggested as being more effective for AD therapy. In the present study, we compared the role of dietary Cur and SLCP on oxidative stress, neuronal death, p-Tau level, and certain cell survival markers in vitro, after exposure to Abeta42. Mouse neuroblastoma cells were exposed to Abeta42 for 24 h and incubated with or without dietary Cur and/or SLCP. Reactive oxygen species (ROS), apoptotic cell death, p-Tau, and tau kinase (including GSK-3beta and cell survival markers, such as total Akt, phosphorylated Akt, and PSD95 levels) were investigated. SLCP showed greater permeability than dietary Cur in vitro, decreased ROS production, and prevented apoptotic death. In addition, SLCP also inhibited p-Tau formation and significantly decreased GSK 3beta levels. Further, the cell survival markers, such as total Akt, p-Akt, and PSD95 levels, were more effectively maintained by SLCP than dietary Cur in Abeta42 exposed cells. Therefore, SLCP may provide greater neuroprotection than dietary Cur in Alzheimer's disease. PMID- 28567324 TI - Adenocarcinoma in a Koff Urinary Ileal Diversion. AB - The use of an ileal conduit as a means of treatment for bladder cancer or dysfunction is widely used and understood. However, long term surveillance of that conduit has not been strongly established and set forth as a means of screening. We present a 76yo female with a history of neurogenic bladder secondary to paraplegia who underwent the formation of a "Koff" pouch as a conduit. Nineteen years later she presents with hematuria and was found to have adenocarcinoma originating in her conduit. PMID- 28567325 TI - Metastatic Adenocarcinoma of the Prostate Presenting as Supraclavicular and Bulky Generalized Lymphadenopathy with a Benign Digital Rectal Exam. AB - A 63-year-old male presented with complaints of an enlarging left supraclavicular mass and weight loss. Computed tomography demonstrated a large retroperitoneal mass causing displacement of the adjacent organs, and moderate left hydroureteronephrosis. Multiple pulmonary nodules, lytic spinal lesions, and generalized lymphadenopathy including the left supraclavicular region were seen. Serum prostate-specific antigen level was 2064.0 ng/mL. Digital rectal exam revealed an enlarged prostate without nodularity. Biopsy of the supraclavicular node demonstrated prostatic adenocarcinoma. The diagnosis of lymphoma may be initially suggested, however, prostatic origin should be considered even when the prostate exam is not grossly abnormal. PMID- 28567326 TI - Renal Myxoma, an Incidental Finding. AB - Myxomas are mesenchymal tumors commonly found in the heart and skin. Renal myxomas are rare, having only been documented 14 times. Our case is a 55-year-old woman who presented to our clinic after a right renal mass was incidentally found on CT. Evaluation with MRI showed a mass that appeared to arise from the supero medial cortex of the right kidney. As the imaging was concerning for renal cell carcinoma, the patient underwent a partial nephrectomy. Microscopic examination showed a well-circumscribed mass with polygonal to spindle-shaped cells in a granular eosinophilic cytoplasm. Immunohistochemical staining for CD-10, Desmin, HMB-45, and Pankeratin were negative. PMID- 28567327 TI - Robot-Assisted Laparoscopic Management of Caliceal Diverticular Calculi. AB - Standard treatment modalities of caliceal diverticular calculi range from extracorporal shockwave lithotripsy (SWL) over retrograde intrarenal surgery (RIRS), percutaneous nephrolithotomy (PNL) and laparoscopic stone removal. A 55 year-old woman presented with a history of pyelonephritis based on a caliceal diverticular calculus. Due to the narrow infundibulum and anterior location, a robot-assisted laparoscopic calicotomy with extraction of the calculi and fulguration of the diverticulum was performed, with no specific perioperative problems and good stone-free results. This article shows technical feasibility with minimal morbidity of robot-assisted laparoscopic stone removal and obliteration of a caliceal diverticulum. PMID- 28567328 TI - Squamous Cell Carcinoma of the Renal Pelvis: Atypical Presentation of a Rare Malignancy. AB - Primary squamous cell carcinoma (SCC) of the renal pelvis is exceedingly rare and is associated with advanced stage at diagnosis and a poor prognosis. Diagnosis is often difficult due to vague presenting symptoms and nonspecific radiologic findings. The mainstay of treatment is nephrectomy, with cisplatin based chemotherapy and palliative radiation reserved for metastatic disease. We report a SCC of the renal pelvis in a 72 year-old female who presented with abdominal pain. To date, this is the largest SCC originating from the renal pelvis reported in the literature, made even more exceptional by the lack of antecedent risk factors. PMID- 28567329 TI - Carcinosarcoma of the Tunica Vaginalis Following Radiation Therapy for Localized Prostate Cancer. AB - Spermatic cord tumors (SCTs) are rare neoplasms with 80% exhibiting benign pathology. Of the malignant SCTs, 90% are sarcomas. To date there has only been one documented case of primary CS of the spermatic cord which occurred in a 40 year old with no reported medical history. A 76-year-old male with a history of biopsy proven Gleason score 7 (3 + 4) prostatic adenocarcinoma underwent external beam radiation therapy (7920 cGy) in 44 fractions in 2004. He presented with a 3 year history of an asymptomatic right hydrocele. Several scrotal ultrasounds had been performed confirming a hydrocele, with the most recent revealing a hydrocele measuring 10 * 14 cm and several epididymal cysts. During the hydrocelectomy a firm suspicious mass was noted inside the tunica vaginalis and involving the spermatic cord. Given the intraoperative findings, decision was made to proceed with radical orchiectomy. Final pathologic examination revealed the tumor to have a biphasic pattern composed of spindled cells and also cells with an epithelioid morphology. Five months following orchiectomy he patient presented with a painful, enlarging right upper scrotal mass. A CT scan revealed new soft tissue lesions suspicious for necrotic lymph nodes within the right inguinal canal. Additional metastatic evaluation revealed multiple new pleural and parenchymal lung nodules. CT guided needle biopsy of a left lung nodule demonstrated spindle cells with high cellularity and areas of necrosis which were histomorphologically similar to the previous scrotal CS. Gemcitabine therapy was subsequently started. Four months following the diagnosis of metastatic CS, the patient expired. Dedifferentiation of prostatic adenocarcinoma to prostatic CS should be considered as a treatment outcome after localized radiation therapy to the prostate due to the highly aggressive nature of metastatic CS. PMID- 28567330 TI - Cystic Dysplasia of the Testis in an Intraabdominal Undescended Testicle. AB - Cystic dysplasia of the testis is a rare, benign pathologic finding. We present two recent cases of cystic dysplasia of the testis to our practice. The first case involves an 11 month old male presenting with a non-palpable, intra abdominal left testis. The second case involves a 7 year old male with left scrotal swelling and a history of left renal agenesis. After review of the literature, the first case represents the first report of cystic dysplasia of the testis in an undescended, intra-abdominal testicle. PMID- 28567331 TI - Laparoscopic Management of Pelvic Organ Prolapse in a Kidney Transplant Recipient. AB - This is a report of a laparoscopic double mesh sacrocolpopexy performed in the setting of a 73-year-old woman carrying a grafted kidney. The patient had a vaginal prolapse of the anterior and posterior floor without urinary incontinence. Despite immunosuppression due to anti-rejection treatments and the presence of kidney transplant in left iliac fossa, laparoscopic intervention with the introduction of prosthetic material was conducted. The intervention showed no major difficulty in its implementation and the postoperative course was uneventful. The long-term follow-up will confirm the tolerance of a prosthetic material. PMID- 28567332 TI - Successful Radiotherapy for Advanced Small Cell Carcinoma of the Prostate with Syndrome of Inappropriate Secretion of Antidiuretic Hormone. AB - Small cell carcinoma of the prostate (SCCP) is rare in clinical practice. It is often accompanied with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). We present a case of SCCP with SIADH that was successfully treated with radiotherapy in the metastatic lymphnodes and prostate. The patient was an 81-year-old male with a castrate-resistant prostate cancer (CRPC) with invaded rectum and multiple metastases of pelvic lymphnodes. Hyponatremia was present. After radiotherapy, serum sodium increased and neuron-specific enolase (NSE) decreased. To our knowledge, this is the first case of SCCP with SIADH treated with radiotherapy to improve hyponatremia. PMID- 28567333 TI - Post Incisional Hernia Meshplasty Vesicocutaneous Fistula - A Rare Complication. AB - Laparoscopic meshplasty is gold standard in hernia surgery. Mesh migration into bowel/bladder has been documented after laparoscopic repair, though migration into bowel is more common than bladder. Only 12 cases of migration into bladder have been described post inguinal meshplasty. We report the 1st case of mesh migration into bladder post Incisional hernia meshplasty, presenting as vesicocutaneous fistula. The objectives of this report are highlighting important points enabling earlier diagnosis, treatment. We would also like to suggest important preventive measures during meshplasty which we believe will go a long way in avoiding this important complication, thus immensely benefiting patients. PMID- 28567334 TI - Case Presentation: Lung Consolidation as Sequelae of BCG Sepsis After Combined Intravesical and Intraurethral BCG. AB - BCG sepsis is rarely seen with modern intravesical therapy and therefore its presentation may not be apparent to recently trained urologists. We describe BCG sepsis occurring in a patient treated with combined intravesical and intraurethral BCG which resulted in lung consolidation with acid-fast bacilli requiring cessation of BCG and initiation of systemic antibiotic therapy. PMID- 28567335 TI - Rare Presentation of Metastatic Cystic Trophoblastic Tumor in a Patient Without Prior Chemotherapy. AB - Cystic trophoblastic tumor (CTT) is a rare testicular germ cell tumor (GCT) predominantly seen in post-chemotherapy patients. It is prognostically similar to teratoma and requires no additional chemotherapy in the absence of a nonteratomatous GCT component. We report a case of metastatic CTT in a patient with primary testicular teratoma without prior chemotherapy. Retroperitoneal lymph node metastases contained teratoma, embryonal carcinoma, and CTT. The CTT was beta-hCG positive and SALL4 negative by immunohistochemistry (IHC). CTT can arise in metastatic testicular GCT in treatment naive patients. An important differential diagnosis is choriocarcinoma due to treatment implications, and SALL4 IHC may help. PMID- 28567336 TI - Management of Hepatic Granulomatous Tuberculosis After BCG Therapy for Bladder Cancer. AB - BCG therapy is used as a treatment in bladder cancer. Intravesical administration of Bacillus Calmette-Guerin is used as a treatment method in superficial bladder cancer. While it is commonly effective, some serious side effects may occur. We hereby report a 65-year-old man who developed granulomatous hepatitis as a complication following BCG therapy. He was treated successfully with antitubercular therapy and prednisolone. PMID- 28567337 TI - Body mass index is associated with region-dependent metabolic reprogramming of adipose tissue. AB - Adipose tissue (AT) is involved in dysmetabolism pathogenesis. Regional fat distribution and functioning may contribute to obesity-related metabolic disorders and adverse health outcomes. Specific fat depots are suggested to possess unique biological properties, but specific metabolic profiles of subcutaneous (SAT) and visceral adipose tissue (VAT) remain unknown. We aimed to characterize VAT and SAT glucose metabolism, and their correlation with body mass index (BMI). AT samples from patients (n = 12; F:M, 9:3) with a mean age of 46 years (26-83 years) and an average BMI of 29.6 kg/m2 (18-37 kg/m2) were used. VAT and SAT explants were obtained during elective laparoscopy, either cholecystectomy for uncomplicated cholelithiasis or gastric bypass for severe obesity. Explants were placed in insulin-free cell culture media and their metabolic profile was established by proton nuclear magnetic resonance. AT explants display a glucose and pyruvate consumption and acetate production that is region-dependent according to the patients BMI. In VAT, glucose consumption was positively correlated with BMI, while alanine and lactate production were negatively correlated with BMI, whereas in SAT the patients BMI did not affect AT secretome suggesting that increased BMI promotes a metabolic reprogramming of VAT towards de novo lipogenesis. This region-dependent metabolic reprogramming of AT associated with BMI was autonomous of insulin. This data, although preliminary, suggests that there is a BMI-related remodeling of glucose metabolism in VAT. Targeting this BMI-induced metabolic shift may represent a potential target to counteract unwanted consequences derived from visceral adiposity. PMID- 28567338 TI - Rapid diagnosis and intraoperative margin assessment of human lung cancer with fluorescence lifetime imaging microscopy. AB - A method of rapidly differentiating lung tumor from healthy tissue is extraordinarily needed for both the diagnosis and the intraoperative margin assessment. We assessed the ability of fluorescence lifetime imaging microscopy (FLIM) for differentiating human lung cancer and normal tissues with the autofluorescence, and also elucidated the mechanism in tissue studies and cell studies. A 15-patient testing group was used to compare FLIM results with traditional histopathology diagnosis. Based on the endogenous fluorescence lifetimes of the testing group, a criterion line was proposed to distinguish normal and cancerous tissues. Then by blinded examined 41 sections from the validation group of other 16 patients, the sensitivity and specificity of FLIM were determined. The cellular metabolism was studied with specific perturbations of oxidative phosphorylation and glycolysis in cell studies. The fluorescence lifetime of cancerous lung tissues is consistently lower than normal tissues, and this is due to the both decrease of reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) lifetimes. A criterion line of lifetime at 1920 ps can be given for differentiating human lung cancer and normal tissues.The sensitivity and specificity of FLIM for lung cancer diagnosis were determined as 92.9% and 92.3%. These findings suggest that NADH and FAD can be used to rapidly diagnose lung cancer. FLIM is a rapid, accurate and highly sensitive technique in the judgment during lung cancer surgery and it can be potential in earlier cancer detection. PMID- 28567339 TI - Hallux rigidus: How do I approach it? AB - Hallux rigidus is a degenerative disease of the first metatarsalphalangeal (MTP) joint and affects 2.5% of people over age 50. Dorsal osteophytes and narrowed joint space leads to debilitating pain and limited range of motion. Altered gait mechanics often ensued as 119% of the body force transmit through the 1st MTP joint during gait cycle. Precise etiology remains under debate with trauma being often cited in the literature. Hallux valgus interphalangeus, female gender, inflammatory and metabolic conditions have all been identified as associative factors. Clinical symptoms, physical exam and radiographic evidence are important in assessing and grading the disease. Non-operative managements including nonsteroidal antiinflammatory drugs, intra-articular injections, shoe modification, activity modification and physical therapy, should always be attempted for all hallux rigidus patients. The goal of surgery is to relieve pain, maintain stability of the first MTP joint, and improve function and quality of life. Operative treatments can be divided into joint-sparing vs joint sacrificing. Cheilectomy and moberg osteotomy are examples of joint-sparing techniques that have demonstrated great success in early stages of hallux rigidus. Arthrodesis is a joint-sacrificing procedure that has been the gold standard for advanced hallux rigidus. Other newer procedures such as implant arthroplasty, interpositional arthroplasty and arthroscopy, have demonstrated promising early patient outcomes. However, future studies are still needed to validate its long-term efficacy and safety. The choice of procedure should be based on the condition of the joint, patient's goal and expectations, and surgeon's experience with the technique. PMID- 28567340 TI - Light and electron microscopic study of the medial collateral ligament epiligament tissue in human knees. AB - AIM: To examine the normal morphology of the epiligament tissue of the knee medial collateral ligament (MCL) in humans. METHODS: Several samples of the mid substance of the MCL of the knee joint from 7 fresh human cadavers (3 females and 4 males) were taken. Examination of the epiligament tissue was conducted by light microscopy and photomicrography on semi-thin sections of formalin fixed paraffin embedded blocks that were routinely stained with haematoxylin and eosin, Mallory stain and Van Gieson's stain. Electron microscopy of the epiligament tissue was performed on ultra-thin sections incubated in 1% osmium tetroxide and contrasted with 2.5% uranyl acetate, lead nitrate, and sodium citrate. RESULTS: The current light microscopic study demonstrated that the epiligament of the MCL consisted of fibroblasts, fibrocytes, adipocytes, neuro-vascular bundles and numerous multidirectional collagen fibers. In contrast, the ligament body was poorly vascularised, composed of hypo-cellular fascicles which were formed of longitudinal groups of collagen fibers. Moreover, most of the vessels of the epiligament-ligament complex were situated in the epiligament tissue. The electron microscopic study revealed fibroblasts with various shapes in the epiligament substance. All of them had the ultrastructural characteristics of active cells with large nuclei, well developed rough endoplasmic reticulum, multiple ribosomes, poorly developed Golgi apparatus, elliptical mitochondria and oval lysosomes. The electron microscopy also confirmed the presence of adipocytes, mast cells, myelinated and unmyelinated nerve fibers and chaotically oriented collagen fibers. CONCLUSION: Significant differences exist between the normal structure of the ligament and the epiligament whose morphology and function is to be studied further. PMID- 28567341 TI - Technical note: Anterior cruciate ligament reconstruction in the presence of an intramedullary femoral nail using anteromedial drilling. AB - AIM: To describe an approach to anterior cruciate ligament (ACL) reconstruction using autologous hamstring by drilling via the anteromedial portal in the presence of an intramedullary (IM) femoral nail. METHODS: Once preoperative imagining has characterized the proposed location of the femoral tunnel preparations are made to remove all of the hardware (locking bolts and IM nail). A diagnostic arthroscopy is performed in the usual fashion addressing all intra articular pathology. The ACL remnant and lateral wall soft tissues are removed from the intercondylar, to provide adequate visualization of the ACL footprint. Femoral tunnel placement is performed using a transportal ACL guide with desired offset and the knee flexed to 2.09 rad. The Beath pin is placed through the guide starting at the ACL's anatomic footprint using arthroscopic visualization and/or fluoroscopic guidance. If resistance is met while placing the Beath pin, the arthroscopy should be discontinued and the obstructing hardware should be removed under fluoroscopic guidance. When the Beath pin is successfully placed through the lateral femur, it is overdrilled with a 4.5 mm Endobutton drill. If the Endobutton drill is obstructed, the obstructing hardware should be removed under fluoroscopic guidance. In this case, the obstruction is more likely during Endobutton drilling due to its larger diameter and increased rigidity compared to the Beath pin. The femoral tunnel is then drilled using a best approximation of the graft's outer diameter. We recommend at least 7 mm diameter to minimize the risk of graft failure. Autologous hamstring grafts are generally between 6.8 and 8.6 mm in diameter. After reaming, the knee is flexed to 1.57 rad, the arthroscope placed through the anteromedial portal to confirm the femoral tunnel position, referencing the posterior wall and lateral cortex. For a quadrupled hamstring graft, the gracilis and semitendinosus tendons are then harvested in the standard fashion. The tendons are whip stitched, quadrupled and shaped to match the diameter of the prepared femoral tunnel. If the diameter of the patient's autologous hamstring graft is insufficient to fill the prepared femoral tunnel, the autograft may be supplemented with an allograft. The remainder of the reconstruction is performed according to surgeon preference. RESULTS: The presence of retained hardware presents a challenge for surgeons treating patients with knee instability. In cruciate ligament reconstruction, distal femoral and proximal tibial implants hardware may confound tunnel placement, making removal of hardware necessary, unless techniques are adopted to allow for anatomic placement of the graft. CONCLUSION: This report demonstrates how the femoral tunnel can be created using the anteromedial portal instead of a transtibial approach for reconstruction of the ACL. PMID- 28567342 TI - Functional outcome of tibial fracture with acute compartment syndrome and correlation to deep posterior compartment pressure. AB - AIM: To measure single baseline deep posterior compartment pressure in tibial fracture complicated by acute compartment syndrome (ACS) and to correlate it with functional outcome. METHODS: Thirty-two tibial fractures with ACS were evaluated clinically and the deep posterior compartment pressure was measured. Urgent fasciotomy was needed in 30 patients. Definite surgical fixation was performed either primarily or once fasciotomy wound was healthy. The patients were followed up at 3 mo, 6 mo and one year. At one year, the functional outcome [lower extremity functional scale (LEFS)] and complications were assessed. RESULTS: Three limbs were amputated. In remaining 29 patients, the average times for clinical and radiological union were 25.2 +/- 10.9 wk (10 to 54 wk) and 23.8 +/- 9.2 wk (12 to 52 wk) respectively. Nine patients had delayed union and 2 had nonunion who needed bone grafting to augment healing. Most common complaint at follow up was ankle stiffness (76%) that caused difficulty in walking, running and squatting. Of 21 patients who had paralysis at diagnosis, 13 (62%) did not recover and additional five patients developed paralysis at follow-up. On LEFS evaluation, there were 14 patients (48.3%) with severe disability, 10 patients (34.5%) with moderate disability and 5 patients (17.2%) with minimal disability. The mean pressures in patients with minimal disability, moderate disability and severe disability were 37.8, 48.4 and 58.79 mmHg respectively (P < 0.001). CONCLUSION: ACS in tibial fractures causes severe functional disability in majority of patients. These patients are prone for delayed union and nonunion; however, long term disability is mainly because of severe soft tissue contracture. Intra-compartmental pressure (ICP) correlates with functional disability; patients with relatively high ICP are prone for poor functional outcome. PMID- 28567343 TI - Frozen shoulder - A prospective randomized clinical trial. AB - AIM: To compare the results of arthroscopic capsular release with intra-articular steroid injections in patients of frozen shoulder. METHODS: Fifty-six patients with frozen shoulder were randomised to one of two treatment groups: Group 1, complete 360 degree arthroscopic capsular release and group 2, intra-articular corticosteroid injection (40 mg methyl prednisolone acetate). Both groups were put on active and passive range of motion exercises following the intervention. The outcome parameters were visual analogue scale (VAS) score for pain, range of motion and Constant score which were measured at baseline, 4, 8, 12, 16 and 20 wk after intervention. RESULTS: All the parameters improved in both the groups. The mean VAS score improved significantly more in the group 1 as compared to group 2 at 8 wk. This greater improvement was maintained at 20 wk with P value of 0.007 at 8 wk, 0.006 at 12 wk, 0.006 at 16 wk and 0.019 at 20 wk. The Constant score showed a more significant improvement in group 1 compared to group 2 at 4 wk, which was again maintained at 20 wk with P value of 0.01 at 4, 8, 12 and 16 wk. The gain in abduction movement was statistically significantly more in arthroscopy group with P value of 0.001 at 4, 8, 12, 16 wk and 0.005 at 20 wk. The gain in external rotation was statistically significantly more in arthroscopy group with P value of 0.007 at 4 wk, 0.001 at 8, 12, and 16 wk and 0.003 at 20 wk. There was no statistically significant difference in extension and internal rotation between the two groups at any time. CONCLUSION: Arthroscopic capsular release provides subjective and objective improvement earlier than intra articular steroid injection. PMID- 28567344 TI - Predicting lower limb periprosthetic joint infections: A review of risk factors and their classification. AB - AIM: To undertook a systematic review to determine factors that increase a patient's risk of developing lower limb periprosthetic joint infections (PJI). METHODS: This systematic review included full-text studies that reviewed risk factors of developing either a hip or knee PJI following a primary arthroplasty published from January 1998 to November 2016. A variety of keywords were used to identify studies through international databases referencing hip arthroplasty, knee arthroplasty, infection, and risk factors. Studies were only included if they included greater than 20 patients in their study cohort, and there was clear documentation of the statistical parameter used; specifically P-value, hazard ratio, relative risk, or/and odds ratio (OR). Furthermore a quality assessment criteria for the individual studies was undertaken to evaluate the presence of record and reporting bias. RESULTS: Twenty-seven original studies reviewing risk factors relating to primary total hip and knee arthroplasty infections were included. Four studies (14.8%) reviewed PJI of the hip, 3 (11.21%) of the knee, and 20 (74.1%) reviewed both joints. Nineteen studies (70.4%) were retrospective and 8 (29.6%) prospective. Record bias was identified in the majority of studies (66.7%). The definition of PJI varied amongst the studies but there was a general consensus to define infection by previously validated methods. The most significant risks were the use of preoperative high dose steroids (OR = 21.0, 95%CI: 3.5-127.2, P < 0.001), a BMI above 50 (OR = 18.3, P < 0.001), tobacco use (OR = 12.76, 95%CI: 2.47-66.16, P = 0.017), body mass index below 20 (OR = 6.00, 95%CI: 1.2-30.9, P = 0.033), diabetes (OR = 5.47, 95%CI: 1.77-16.97, P = 0.003), and coronary artery disease (OR = 5.10, 95%CI: 1.3-19.8, P = 0.017). CONCLUSION: We have highlighted the need for the provider to optimise modifiable risk factors, and develop strategies to limit the impact of non-modifiable factors. PMID- 28567347 TI - Effect of lengthening along the anatomical axis of the femur and its clinical impact. AB - AIM: To review and study the effect of lengthening along the anatomical axis of long bones and its relation to the mechanical axis deviation. METHODS: We try in this review to calculate and discuss the exact clinical impact of lengthening along the anatomical axis of the femur on affecting the limb alignment. Also we used a trigonometric formula to predict the change of the femoral distal anatomical mechanical angle (AMA) after lengthening along the anatomical axis. RESULTS: Lengthening along the anatomical axis of the femur by 10% of its original length results in reduction in the distal femoral AMA by 0.57 degrees. There is no objective experimental scientific data to prove that the Mechanical axis is passing via the center of the hip to the center of the knee. There is wide variation in normal anatomical axis for different populations. In deformity correction, surgeons try to reproduce the normal usual bone shape to regain normal function, which is mainly anatomical axis. CONCLUSION: Lengthening of the femur along its anatomical axis results in mild reduction of the distal femoral AMA. This may partially compensate for the expected mechanical axis lateralisation and hence justify its minimal clinical impact. PMID- 28567345 TI - Dementia and osteoporosis in a geriatric population: Is there a common link? AB - AIM: To determine the existence of a common pathological link between dementia and osteoporosis through reviewing the current evidence base. METHODS: This paper reviews the current literature on osteoporosis and dementia in order to ascertain evidence of a common predisposing aetiology. A literature search of Ovid MED-LINE (1950 to June 2016) was conducted. The keywords "osteoporosis", "osteoporotic fracture", "dementia" and "Alzheimer's disease" (AD) were used to determine the theoretical links with the most significant evidence base behind them. The key links were found to be vitamins D and K, calcium, thyroid disease, statins, alcohol and sex steroids. These subjects were then searched in combination with the previous terms and the resulting papers manually examined. Theoretical, in vitro and in vivo research were all used to inform this review which focuses on the most well developed theoretical common causes for dementia (predominantly Alzheimer's type) and osteoporosis. RESULTS: Dementia and osteoporosis are multifaceted disease processes with similar epidemiology and a marked increase in prevalence in elderly populations. The existence of a common link between the two has been suggested despite a lack of clear pathological overlap in our current understanding. Research to date has tended to be fragmented and relatively weak in nature with multiple confounding factors reflecting the difficulties of in vivo experimentation in the population of interest. Despite exploration of various possible mechanisms in search for a link between the two pathologies, this paper found that it is possible that these associations are coincidental due to the nature of the evidence available. One finding in this review is that prior investigation into common aetiologies has found raised amyloid beta peptide levels in osteoporotic bone tissue, with a hypothesis that amyloid beta disorders are systemic disorders resulting in differing tissue manifestations. However, our findings were that the most compelling evidence of a common yet independent aetiology lies in the APOE4 allele, which is a well-established risk for AD but also carries an independent association with fracture risk. The mechanism behind this is thought to be the reduced plasma vitamin K levels in individuals exhibiting the APOE4 allele which may be amplified by the nutritional deficiencies associated with dementia, which are known to include vitamins K and D. The vitamin theory postulates that malnutrition and reduced exposure to sunlight in patients with AD leads to vitamin deficiencies. CONCLUSION: Robust evidence remains to be produced regarding potential links and regarding the exact aetiology of these diseases and remains relevant given the burden of dementia and osteoporosis in our ageing population. Future research into amyloid beta, APOE4 and vitamins K and D as the most promising aetiological links should be welcomed. PMID- 28567346 TI - Surgery for calcifying tendinitis of the shoulder: A systematic review. AB - AIM: To systematically search literature and determine a preferable surgical procedure in patients with failed conservative treatment of calcifying tendinitis of the shoulder. METHODS: The electronic online databases MEDLINE (through PubMed), EMBASE (through OVID), CINAHL (through EB- SCO), Web of Science and Cochrane Central Register of Controlled Trials were systematically searched in May 2016. Eligible for inclusion were all available studies with level II and level III evidence (LoE). Data was assessed and extracted by two independent review authors using a specifically for this study designed data extraction form. RESULTS: Six studies (294 surgically treated shoulders) were included in this review. No significant differences between the three available treatment options (acromioplasty with the removal of the calcific deposits, acromioplasty or solely the removal of the calcific deposits) were detected regarding the functional and clinical outcome. The follow-up ranged from 12 mo to 5 years. Complication rates were low. No reoperations were necessary and the only reported complication was adhesive capsulitis, which in all cases could be treated conservatively with full recovery. CONCLUSION: We found that all three available treatment options show good functional and clinical outcomes in the short and midterm. However, a favorable procedure is difficult to determine due to the lack of high-quality comparing studies. PMID- 28567349 TI - Screening echocardiograms in a senior focused value based primary care improves systolic heart failure detection and clinical management. AB - BACKGROUND: Screening echocardiograms are not indicated. Our aim is to evaluate the impact of screening echocardiograms on improving clinical management among older adults. METHODS: We performed screening echocardiograms for all consecutive patients and defined incident systolic heart failure (HF) as an ejection fraction of less than 50% among patients without a previous HF diagnosis. We reviewed medical record data to determine if the new cases where Stage B or C. We obtained prescribed medications and vital signs from the electronic health record to determine absolute changes before and after the echocardiogram. RESULTS: We performed an echocardiogram in 6,417 patients with a mean age of 71.4+/-6. The echocardiogram identified 292 seniors with new cases of systolic HF (5.34%; 95% CI: 4.7-5.9) and 239 were stage B HF. The increase in the use of ace-inhibitor, beta blocker when comparing the pre and post echocardiogram periods was highest in those with Stage C and those with ejection fraction lower than 40%. Systolic blood pressure (SBP) decreased from 140+/-19 to 136+/-15 (P<0.01) and low density lipoprotein (LDL) from 105+/-36 to 97+/-33 (P<0.01). CONCLUSIONS: Performing echocardiograms in senior-focused value-based primary care improves evidence based cardiovascular treatment and short-term clinical outcomes, including lowering SBP and LDL. PMID- 28567348 TI - Chest pain caused by multiple exostoses of the ribs: A case report and a review of literature. AB - The aim of this paper is to report an exceptional case of multiple internal exostoses of the ribs in a young patient affected by multiple hereditary exostoses (MHE) coming to our observation for chest pain as the only symptom of an intra-thoracic localization. A 16 years old patient with familiar history of MHE came to our observation complaining a left-sided chest pain. This pain had increased in the last months with no correlation to a traumatic event. The computed tomography (CT) scan revealed the presence of three exostoses located on the left third, fourth and sixth ribs, all protruding into the thoracic cavity, directly in contact with visceral pleura. Moreover, the apex of the one located on the sixth rib revealed to be only 12 mm away from pericardium. Patient underwent video-assisted thoracoscopy with an additional 4-cm mini toracotomy approach. At the last 1-year follow-up, patient was very satisfied and no signs of recurrence or major complication had occured. In conclusion, chest pain could be the only symptom of an intra-thoracic exostoses localization, possibly leading to serious complications. Thoracic localization in MHE must be suspected when patients complain chest pain. A chest CT scan is indicated to confirm exostoses and to clarify relationship with surrounding structures. Video-assisted thoracoscopic surgery can be considered a valuable option for exostoses removal, alone or in addiction to a mini-thoracotomy approach, in order to reduce thoracotomy morbidity. PMID- 28567350 TI - A comparison of Cornell and Sokolow-Lyon electrocardiographic criteria for left ventricular hypertrophy in a military male population in Taiwan: the Cardiorespiratory fitness and HospItalization Events in armed Forces study. AB - BACKGROUND: The Cornell and Sokolow-Lyon electrocardiography (ECG) criteria have been widely used for diagnosing left ventricular hypertrophy (LVH) in patients with hypertension. However, the correlations of these ECG criteria with LVH were rarely compared in military members who received rigorous training, particularly of the Asian male population. METHODS: We compared the Cornell voltage and product criteria with the Sokolow-Lyon criteria for the echocardiographic LVH in 539 military male members, ages 18-50 years and free of hypertension in the Cardiorespiratory fitness and HospItalization Events in armed Forces (CHIEF) study in Taiwan. Pearson's correlation coefficient was used to determine the association of each ECG criterion with the index of left ventricular mass (LVM, g)/height (m)2.7. The sensitivities and specificities were estimated using a receiver-operating characteristics (ROC) curve in relation to the echocardiographic LVH which was defined as LVM index >=49 g/m2.7. RESULTS: The correlations of the Cornell voltage and product criteria (r=0.24 and 0.26 respectively, both P<0.0001) were stronger than that of the Sokolow-Lyon criteria (r=0.049 and 0.095, and P=0.26 and 0.03 respectively) with the LVM index. Similarly the performances of the Cornell voltage and product criteria for the echocardiographic LVH [area under curve (AUC): 0.66 and 0.68, both P<0.0001] were superior to that of the Sokolow-Lyon criteria (AUC: 0.54 and 0.53, both P>0.1) in the area under the ROC curve analysis. CONCLUSIONS: The Cornell ECG criteria for the echocardiographic LVH had better performance than the Sokolow-Lyon criteria in a young military male cohort in Taiwan. PMID- 28567351 TI - Regression of coronary atherosclerosis with infusions of the high-density lipoprotein mimetic CER-001 in patients with more extensive plaque burden. AB - BACKGROUND: CER-001 is an engineered pre-beta high-density lipoprotein (HDL) mimetic, which rapidly mobilizes cholesterol. Infusion of CER-001 3 mg/kg exhibited a potentially favorable effect on plaque burden in the CHI-SQUARE (Can HDL Infusions Significantly Quicken Atherosclerosis Regression) study. Since baseline atheroma burden has been shown as a determinant for the efficacy of HDL infusions, the degree of baseline atheroma burden might influence the effect of CER-001. METHODS: CHI-SQUARE compared the effect of 6 weekly infusions of CER-001 (3, 6 and 12 mg/kg) vs. placebo on coronary atherosclerosis in 369 patients with acute coronary syndrome (ACS) using serial intravascular ultrasound (IVUS). Baseline percent atheroma volume (B-PAV) cutoff associated with atheroma regression following CER-001 infusions was determined by receiver-operating characteristics curve analysis. 369 subjects were stratified according to the cutoff. The effect of CER-001 at different doses was compared to placebo in each group. RESULTS: A B-PAV >=30% was the optimal cutoff associated with PAV regression following CER-001 infusions. CER-001 induced PAV regression in patients with B-PAV >=30% but not in those with B-PAV <30% (-0.45%+/-2.65% vs. +0.34%+/-1.69%, P=0.01). Compared to placebo, the greatest PAV regression was observed with CER-001 3mg/kg in patients with B-PAV >=30% (-0.96%+/-0.34% vs. 0.25%+/-0.31%, P=0.01), whereas there were no differences between placebo (+0.09%+/-0.36%) versus CER-001 in patients with B-PAV <30% (3 mg/kg; +0.41%+/ 0.32%, P=0.39; 6 mg/kg; +0.27%+/-0.36%, P=0.76; 12 mg/kg; +0.32%+/-0.37%, P=0.97). CONCLUSIONS: Infusions of CER-001 3 mg/kg induced the greatest atheroma regression in ACS patients with higher B-PAV. These findings identify ACS patients with more extensive disease as most likely to benefit from HDL mimetic therapy. PMID- 28567352 TI - Endovascular versus surgical treatment for acute limb ischemia: a systematic review and meta-analysis of clinical trials. AB - BACKGROUND: A number of small studies have suggested that outcomes following endovascular (ENDO) therapy are comparable to those following surgical (SURG) revascularization for patients presenting with acute limb ischemia (ALI). We sought to compare mortality, limb amputation and recurrent ischemia across both revascularization strategies. METHODS: A comprehensive database search of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) electronic databases from January 1990 through January 2016 was performed to identify studies of ENDO versus SURG for ALI. Two independent reviewers selected studies and extracted the data. Random-effects meta-analysis was used to pool results across studies. Heterogeneity of treatment effect among trials was assessed using the I2 statistics. The primary endpoints were mortality and limb amputation at 1 month, 6 and 12 months. Secondary endpoint was recurrent ischemia at one year. RESULTS: A total of 1,773 patients were included from six studies (five randomized prospective and one observational retrospective) comparing ENDO and SURG in the setting of ALI. The mean age was 67 years and 65% of patients were male. There were no differences in mortality between the two groups at 1 month [risk ratio (RR) for ENDO vs. SURG is 0.70; 95% confidence interval (CI), 0.33 to 1.50], 6 months (RR 1.12; CI, 0.78 to 1.61) or 12 months (RR 0.74; CI, 0.29 to 1.85). Similarly, there was no significant difference in amputation rates between ENDO and SURG at 1 month (RR 0.75; CI, 0.40 to 1.42), 6 months (RR 0.87; CI, 0.52 to 1.48) or 12 months (RR 0.81; CI, 0.55 to 1.18). When looking into secondary outcomes, recurrent ischemia was not different between the two groups (RR 1.12; CI, 0.75 to 1.67). CONCLUSIONS: In patients presenting with ALI (<2 weeks of duration), ENDO and SURG approaches have similar rates of short-term and 12 month mortality, limb amputation and recurrent ischemia. PMID- 28567353 TI - Differential efficacy profile of aldosterone receptor antagonists, depending on the type of chronic heart failure, whether with reduced or preserved left ventricular ejection fraction-results of a meta-analysis of randomized controlled trials. AB - BACKGROUND: Because of renin-angiotensin-aldosterone system (RAAS) activation, the patients with chronic heart failure (CHF) manifest increased ventricular stress, with impaired left ventricular function, and a slowing down in systemic venous drainage. More importantly, a reduction of the patient's life expectancy has been proven in the case of RAAS overstimulation. For these reasons, huge efforts have been made to obtain molecules able to efficaciously antagonize the RAAS overstimulation, such as aldosterone receptor antagonists (ARAs). These drugs have been shown to improve clinical outcomes in patients with heart failure with reduced left ventricular ejection fraction (HFREF), but not in those with preserved left ventricular ejection fraction (HFpEF). In order to study this topic more deeply, we carried out a meta-analysis of selective and nonselective ARAs in HFREF and HFpEF. METHODS: Only randomized controlled trials (RCTs) were incorporated in our meta-analysis. Studies were included if they satisfied the following criteria: experimental groups included patients with CHF treated with ARAs in addition to the conventional therapy; control groups included patients with CHF receiving conventional therapy without ARAs. Outcomes of interest were all-cause mortality, cardiovascular hospitalizations, hyperkalemia, or gynecomastia. RESULTS: Overall, 15 RCTs including a total of 15,671 patients were eligible for inclusion in the meta-analysis. ARA use in patients with heart failure was associated with a significant reduction in adverse outcomes. Indeed, a significant reduced odds of all-cause death among CHF patients treated with ARAs compared to controls was found [odds ratio (OR) =0.79; 95% CI: 0.73-0.87]. Subgroup analysis based on the heart failure (HF) type revealed a statistically significant benefit as regards all- cause death for patients with HFREF (OR =0.77; 95% confidence interval (CI): 0.69-0.84), but not for those with HFpEF (OR =0.91; 95% CI: 0.76-1.1). Furthermore reduced odds of CV hospitalizations was detected in the entire group of CHF patients under treatment with ARAs (OR =0.73; 95% CI: 0.61-0.89) as well as among HFREF patients treated with ARAs, compared to controls (OR =0.66; 95% CI: 0.51-0.85). Hyperkalemia was significantly more frequent with ARA use. Besides, ARA use was shown to be associated with the occurrence of gynecomastia. In particular, selective ARAs didn't induce significant amounts of gynecomastia compared to controls (OR =0.74; 95% CI: 0.43 1.27), while nonselective ARAs did (OR =8.22; 95% CI: 4.9-13.81). CONCLUSIONS: Based on this meta-analysis, ARAs should be systematically used in patients with HFREF, in whom these drugs proved to reduce all-cause mortality and hospitalizations from cardiac cause. Conversely, ARA usage in HFpEF patients is questionable since in this CHF setting no significant improvement in clinical endpoints has been demonstrated so far. New selective ARAs are devoid of the risk of gynecomastia, while are similar to nonselective ARAs with regard to the efficacy profile as well as to the risk of eliciting hyperkalemia. PMID- 28567354 TI - Aortic flow conditions predict ejection efficiency in the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE). AB - BACKGROUND: The Windkessel model of the cardiovascular system, both in its original wind-chamber and flow-pipe form, and in its electrical circuit analog has been used for over a century to modeled left ventricular ejection conditions. Using parameters obtained from aortic flow we formed a Flow Index that is proportional to the impedance of such a "circuit". We show that the impedance varies with ejection fraction (EF) in a manner characteristic of a resonant circuit with multiple resonance points, with each resonance point centrally located in a small range of EF values, i.e., corresponding to multiple contiguous EF bands. METHODS: Two target populations were used: (I) a development group comprising male and female subjects (n=112) undergoing cardiovascular magnetic resonance (CMR) imaging for a variety of cardiac conditions. The Flow Index was developed using aortic flow data and its relationship to left ventricular EF was shown. (II) An illustration group comprised of female subjects from the Women's Ischemia Syndrome Evaluation (WISE) (n=201) followed for 5 years for occurrence of major adverse cardiovascular events (MACE). Flow data was not available in this group but since the Flow Index was related to the EF we noted the MACE rate with respect to EF. RESULTS: The EFs of the development population covered a wide range (9%-76%) traversing six Flow Index resonance bands. Within each Flow Index resonance band the impedance varied from highly capacitive at the lower range of EF through minimal impedance at resonance, to highly inductive at the higher range of EF, which is characteristic of a resonant circuit. When transitioning from one EF band to a higher band, the Flow Index made a sudden transition from highly inductive to capacitive impedance modes. MACE occurred in 26 (13%) of the WISE (illustration) population. Distance in EF units (Deltacenter) from the central location between peaks of MACE activity was derived from EF data and was predictive of MACE rate with an area under the receiver operator curve of 0.73. Of special interest, Deltacenter was highly predictive of MACE in the sub-set of women with EF >60% (AUC 0.79) while EF was no more predictive than random chance (AUC 0.48). CONCLUSIONS: A Flow Index that describes impedance conditions of left ventricular ejection can be calculated using data obtained completely from the ascending aorta. The Flow Index exhibits a periodic variation with EF, and in a separate illustration population the occurrence of MACE was observed to exhibit a similar periodic variation with EF, even in cases of normal EF. PMID- 28567355 TI - Impact of heart rate on diagnostic accuracy of second generation 320-detector computed tomography coronary angiography. AB - OBJECTIVE: To assess the impact of elevated heart rate (HR) on the diagnostic accuracy and image quality of second-generation 320-detector computed tomography coronary angiography (320-CTCA). METHODS: Consecutive patients with suspected coronary disease referred for invasive coronary angiography (ICA) were prospectively recruited and underwent 320-CTCA. Pre-scan beta-blockers were administered if native HR>80 bpm and post-scan cohorts stratified by traditional (HR <=60 bpm) and elevated HR (61-80 bpm). A wider phase window was used for the elevated HR group (30-80%). 320-CTCA and ICA were analyzed by independent readers blinded to other data. Significant disease was defined as >=50% visual stenosis on ICA. Uninterpretable segments by 320-CTCA were considered to be significant on an intention-to-diagnose principle. Image quality was assessed by 5-point Likert score. RESULTS: Of 107 patients studied (1,662 segments), there was no significant difference in sensitivity, specificity, positive and negative predictive value between patients with HR <=60 bpm (n=55) vs. HR 61-80 bpm (n=52): 97%, 88%, 95%, 94% vs. 100%, 88%, 95%, 100%; Receiver operator characteristic-area under the curve 0.93 vs. 0.94, P=0.82). Overall per-patient diagnostic accuracy was 96% in both groups with no significant difference in interpretable segments (Likert >=2) or median radiation dose (2.4 mSv vs. 2.7 mSv, P=0.35). Only 4/1,662 (0.2%) segments were uninterpretable by motion artefact in the whole cohort. CONCLUSIONS: In patients with HR >60 and up to 80bpm, second generation 320-CTCA provides comparably adequate diagnostic accuracy to HR <=60 without significantly impacting upon overall segmental evaluability. PMID- 28567357 TI - Assessing observer variability: a user's guide. AB - Some form of the assessment of observer variability may be the most frequent statistical task in medical literature. Still, very little attempt is made to make the reported methods uniform and clear to the reader. This paper provides overview of various measures of observer variability, and a rationale of why using standard error of measurement (SEM) is preferable to other measures of observer variability. The supplemental file contains examples on how to design a proper repeatability and reproducibility assessment, determine appropriate sample size, and test for significance of its findings. PMID- 28567358 TI - Beyond landscape: development of a major healing garden. AB - Healthcare in China is expanding faster than anywhere else on the planet and the impact of multiple, mega-medical centers on their communities, their culture and their general way of life is substantial. Through the lens of a 5.5 million square foot hospital located in the Hunan Province of China, this article addresses the factors design teams must consider when integrating nature in to hospital design. The Fifth Xiangya Hospital, designed by Boston-based architecture firm Payette, features a major public park, which is fully integrated in to the hospital design. The public park serves as connective tissue for the medical complex, extending its role beyond that of a traditional healing garden and embraces a much deeper purpose for the overall hospital campus. PMID- 28567356 TI - Radial artery occlusion after transradial coronary catheterization. AB - The transradial approach (TRA) for coronary angiography and interventions is increasingly utilized around the world. Radial artery occlusion (RAO) is the most common significant complication after transradial catheterization, with incidence varying between 1% and 10%. Although RAO is rarely accompanied by hand ischemia, it is an important complication because it prohibits future transradial access and radial artery utilization as a conduit for coronary artery bypass grafting or arteriovenous fistula formation. In this review, we discuss factors predicting the occurrence of RAO, aspects of accurate and prompt recognition, methods that contribute to its prevention and possible treatment options. PMID- 28567359 TI - Non-surgical extraction of right atrial mass by AngioVac aspiration device under fluoroscopic and transesophageal echocardiographic guidance. AB - Right-sided cardiac masses are commonly encountered. We present a challenging case of a right atrial thrombus in a patient who had a high surgical risk for open removal. AngioVac aspiration device, under transesophageal echocardiography (TEE) and fluoroscopy guidance, was successfully used to remove the thrombus. The patient tolerated the procedure well and was discharged home. Our case confirms the safety and efficacy of this procedure for treatment of unwanted intracardiac and intravascular masses in patients who are not candidates for conventional therapies of surgery or thrombolytics. PMID- 28567360 TI - Successful percutaneous closure of an extremely large secundum atrial septal defect during pregnancy. AB - Atrial septal defects (ASDs) are one of the most of the most common acyanotic congenital heart lesions. Awareness of potential clinical presentations and complications during pregnancy is essential for those managing these patients. We report successful percutaneous closure of an extremely large secundum ASD, using the largest available percutaneous ASD closure device in a 27-year-old pregnant female. Large ASDs may have their initial clinical presentation and diagnosis during pregnancy. If indicated, percutaneous closure can be performed safely. Only a very small number of cases have previously reported this being performed safely during pregnancy. PMID- 28567362 TI - Prof. Mattia Glauber: 13 years minimally invasive heart surgery. PMID- 28567361 TI - Unexpected evolution of a non-stenotic lesion in the left main coronary artery of a patient with non-ST-segment elevation myocardial infarction. AB - A 72-year-old man was referred to our catheterization laboratory 48 hours after a non-ST-segment elevation myocardial infarction. His medical history included coronary artery disease (CAD) (percutaneous coronary intervention of the right coronary artery and chronic total occlusion of the circumflex artery), atrial fibrillation (AF), and chronic kidney disease. An electrocardiogram showed a pre existent left bundle-branch block and the patient's maximum cardiac troponin concentration was 8.64 ug/L (upper limit of normal: 0.003 ug/L). The coronary angiogram revealed an ulcerated plaque of the left main coronary artery (LMCA) and moderate stenosis of the left anterior descending (LAD) coronary artery. A non-interventional approach to treatment was chosen. One month later, a control angiography showed a giant distal aneurysm complicating the lesion; the fractional flow reserve (FFR) value in the LAD was 0.74. The heart team discussed the case and concluded that the aneurysm was inaccessible via surgery. To protect the LAD from possible covered stent thrombosis or restenosis, coronary artery bypass grafting of the LAD was performed prior to percutaneous coronary intervention (PCI). Five days later, we proceeded with percutaneous exclusion of the aneurysm. We combined coil embolization of three InterlockTM two-dimensional detachable coils with stenting of the LMCA, using a PK PapyrusTM covered stent. Effective angiographic exclusion was achieved. The patient was discharged on warfarin, aspirin, and clopidogrel for 1 month, followed by long-term aspirin and oral anticoagulation. A 6-month follow-up angiography demonstrated a completely sealed aneurysm and optical coherence tomography (OCT) confirmed the successful endothelialization of the covered stent. PMID- 28567363 TI - Ancient landscapes. PMID- 28567364 TI - Coronary revascularization strategies in patients with multivessel disease: is it all about diabetes? PMID- 28567365 TI - Mesenchymal stromal cells and ischemic heart disease: hitting the target? PMID- 28567366 TI - Bioresorbable scaffolds: should we stay simple or go complex? PMID- 28567367 TI - Rare isolated primary peritoneal hydatid cysts: A case report from Syria. AB - Hydatid disease caused by Echinococcus granulosus is endemic in many regions of the world. The major primary site for the disease in adults is the liver and the secondary site are the lungs. Secondary peritoneal cysts are relatively common and expected to occur after rupture of the primary hepatic hydatid cyst. Primary peritoneal hydatid cyst disease without any other organ involvement has been previously reported, and yet it is still considered rare even in endemic areas. A case of a large primary peritoneal hydatid multicystic lesion without other organ involvement in a 25-year-old girl seen at the gastrointestinal outpatient clinic in the University of Kalamoon Medical City is presented and discussed. The disease was very extensive but surgical intervention was refused due to the patient being a young unmarried female. The patient was treated and observed over a period of ten months. She responded very well to medical treatment with albendazole. The case emphasizes the importance of hydatid disease being included in the differential diagnosis of any cyst in the abdominal cavity for patients living or coming from an area of endemic hydatid disease even without liver or lung involvement. This also goes to show that it can respond to medical treatment, which becomes even more valuable in conditions where surgical intervention might not be an option. PMID- 28567368 TI - Mycobacterium canettii Infection of Adipose Tissues. AB - Adipose tissues were shown to host Mycobacterium tuberculosis which is persisting inside mature adipocytes. It remains unknown whether this holds true for Mycobacterium canettii, a rare representative of the M. tuberculosis complex responsible for lymphatic and pulmonary tuberculosis. Here, we infected primary murine white and brown pre-adipocytes and murine 3T3-L1 pre-adipocytes and mature adipocytes with M. canettii and M. tuberculosis as a positive control. Both mycobacteria were able to infect 18-22% of challenged primary murine pre adipocytes; and to replicate within these cells during a 7-day experiment with the intracellular inoculums being significantly higher in brown than in white pre adipocytes for M. canettii (p = 0.02) and M. tuberculosis (p = 0.03). Further in vitro infection of 3T3-L1 mature adipocytes yielded 9% of infected cells by M. canettii and 17% of infected cells by M. tuberculosis (p = 0.001). Interestingly, M. canettii replicated and accumulated intra-cytosolic lipid inclusions within mature adipocytes over a 12-day experiment; while M. tuberculosis stopped replicating at day 3 post-infection. These results indicate that brown pre adipocytes could be one of the potential targets for M. tuberculosis complex mycobacteria; and illustrate differential outcome of M. tuberculosis complex mycobacteria into adipose tissues. While white adipose tissue is an unlikely sanctuary for M. canettii, it is still an open question whether M. canettii and M. tuberculosis could persist in brown adipose tissues. PMID- 28567369 TI - Dynamic Changes of the Frequency of Classic and Inflammatory Monocytes Subsets and Natural Killer Cells in Chronic Hepatitis C Patients Treated by Direct-Acting Antiviral Agents. AB - OBJECTIVE: Up to now, little was known about the immunological changes of chronic hepatitis C (CHC) patients treated with direct-acting antiviral agents (DAAs); we try to explore the effect of DAAs on the frequency of monocytes, NK cells, and cytokines that promote their activation. METHODS: 15 treatment-naive CHC patients and 10 healthy controls were recruited. Patients were examined before DAAs therapy (0 w) and at week 4 (4 w) and week 12 (12 w) of therapy. Percentage of monocytes and NK cells of the peripheral blood was analyzed by flow cytometry. Serum cytokines IL-12, IL-18, CXCL10, CXCL11, sCD14, and sCD163 were measured by enzyme linked immunosorbent assay. RESULTS: The frequency of CD3-CD16+CD56+ NK cells and classic CD14++CD16- monocytes decreased, while CD14+CD16+ monocytes and cytokines IL-12, IL-18, CXCL10, CXCL11, sCD14, and sCD163 increased at 0 w compared to healthy controls. During DAAs treatment, the decreased NK cells and classic monocytes gradually increased to normal levels; the increased inflammatory monocytes and cytokines IL-12 and CXCL11 decreased to normal levels, but the increased cytokines IL-18, CXCL10, sCD14, and sCD163 still remained at high levels at 12 w though they decreased rapidly from 0 w. CONCLUSION: Our results showed that DAAs treatment attenuated the activation of monocytes and NK cells in CHC patients. Trial registration number is NCT03063723. PMID- 28567370 TI - Maintenance of Remission with Partial Enteral Nutrition Therapy in Pediatric Crohn's Disease: A Retrospective Study. AB - BACKGROUND: Partial enteral nutrition (PEN) may be helpful for the maintenance of remission in pediatric Crohn's disease patients. AIMS: To evaluate the efficacy of PEN treatment for preventing clinical relapse. METHODS: We retrospectively assessed 42 pediatric Crohn's disease patients who entered clinical remission on 4-12 weeks of exclusive enteral nutrition (EEN) and were maintained on PEN as a supplementary diet. We evaluated the efficacy of the treatment at different time points using the weighted Pediatric Crohn Disease Activity Index (wPCDAI), Physician Global Assessment, laboratory parameters, and growth of each patient. Additionally, we assessed the use of concomitant medications. RESULTS: The median length of remission with PEN was 6 (0-36) months. Patients' remission was maintained on PEN without concomitant medications for a median time of zero months (0-16). The mean body mass index in the PEN group increased from 18.1 to 18.8 after six months of PEN. The median wPCDAI decreased from 30 at diagnosis to 5.0 after EEN and increased to 7.5 after three months of PEN. Overall, the median wPCDAI decreased by 26.2. CONCLUSIONS: PEN treatment was partially effective in maintaining remission and was able to increase BMI and lower wPCDAI. Most patients required concomitant medication after PEN initiation. PMID- 28567371 TI - The Use of Finite Element Analyses to Design and Fabricate Three-Dimensional Scaffolds for Skeletal Tissue Engineering. AB - Computational modeling has been increasingly applied to the field of tissue engineering and regenerative medicine. Where in early days computational models were used to better understand the biomechanical requirements of targeted tissues to be regenerated, recently, more and more models are formulated to combine such biomechanical requirements with cell fate predictions to aid in the design of functional three-dimensional scaffolds. In this review, we highlight how computational modeling has been used to understand the mechanisms behind tissue formation and can be used for more rational and biomimetic scaffold-based tissue regeneration strategies. With a particular focus on musculoskeletal tissues, we discuss recent models attempting to predict cell activity in relation to specific mechanical and physical stimuli that can be applied to them through porous three dimensional scaffolds. In doing so, we review the most common scaffold fabrication methods, with a critical view on those technologies that offer better properties to be more easily combined with computational modeling. Finally, we discuss how modeling, and in particular finite element analysis, can be used to optimize the design of scaffolds for skeletal tissue regeneration. PMID- 28567374 TI - The history of time for capsule endoscopy. AB - Capsule endoscopy was conceived by inventive minds of good people. In the beginning there was a will to do something for medicine. The idea fomented after a discourse between the talented engineer with his physician friend. It took years to develop the concept. Then excellent engineers created de novo the necessary components to turn the capsule into a viable reality. The story is a tribute to human ingenuity. PMID- 28567373 TI - Complete Genome Sequences of Two Acetic Acid-Producing Acetobacter pasteurianus Strains (Subsp. ascendens LMG 1590T and Subsp. paradoxus LMG 1591T). PMID- 28567372 TI - Soluble Factors on Stage to Direct Mesenchymal Stem Cells Fate. AB - Mesenchymal stem cells (MSCs) are multipotent stromal cells that are identified by in vitro plastic adherence, colony-forming capacity, expression of a panel of surface molecules, and ability to differentiate at least toward osteogenic, adipogenic, and chondrogenic lineages. They also produce trophic factors with immunomodulatory, proangiogenic, and antiapoptotic functions influencing the behavior of neighboring cells. On the other hand, a reciprocal regulation takes place; in fact, MSCs can be isolated from several tissues, and depending on the original microenvironment and the range of stimuli received from there, they can display differences in their essential characteristics. Here, we focus mainly on the bone tissue and how soluble factors, such as growth factors, cytokines, and hormones, present in this microenvironment can orchestrate bone marrow-derived MSCs fate. We also briefly describe the alteration of MSCs behavior in pathological settings such as hematological cancer, bone metastasis, and bone marrow failure syndromes. Overall, the possibility to modulate MSCs plasticity makes them an attractive tool for diverse applications of tissue regeneration in cell therapy. Therefore, the comprehensive understanding of the microenvironment characteristics and components better suited to obtain a specific MSCs response can be extremely useful for clinical use. PMID- 28567375 TI - Video capsule colonoscopy in routine clinical practice. AB - BACKGROUND: Colon capsule endoscopy (CCE) offers direct mucosal visualisation without sedation or gas insufflation required in conventional colonoscopy (CC). However, evidence for the role of CCE as an adjunct or alternative to CC remains equivocal. In this observational cohort study, we report our experience of using CCE to investigate patients with suspected colon pathology at a tertiary referral centre. METHODS: From 2007-2015, consecutive patients requiring colonoscopy were recruited from a tertiary care centre in Malmo, Sweden. Data collected: patient demographics, indication for CCE, findings, bowel cleansing, colon transit time (CTT) and completeness of colon examination. RESULTS: Seventy-seven patients (57 F/20 F, median age 56 years) were included. The reason for CCE was previously incomplete or refused CC in 39 and 26 cases, and follow up of previous findings in 12 cases, respectively. The main clinical indications were gastrointestinal (GI) bleeding (n=28; 36%) and suspected inflammatory bowel disease (IBD) or follow-up of known IBD (n=23; 30%). CCE was complete in 58/77 (75%) patients. In 3 patients the colon was not reached; in the other 16, the capsule reached the rectum (n=4), sigmoid (n=6), descending colon (n=5) and transverse colon (n=1). Findings were: normal CCE (n=15; 19%) colonic diverticula (n=29; 38%), polyps (n=17; 22%), active IBD (n=12; 16%), haemorrhoids (n=8; 10%), colonic angioectasia (n=4; 5%) and cancer (n=1; 1%). Small-bowel findings were recorded in 8 (10%) patients. All patients tolerated bowel preparation and CCE well. Two patients with an ulcerated small-bowel stricture and cancer respectively experienced temporary capsule retention with spontaneous resolution. CONCLUSIONS: CCE is a well-tolerated alternative to CC, but requires technological improvement and optimisation of clinical practice to meet current reference standards. Although further technical development is required, CCE may complement or even replace CC for certain clinical indications. PMID- 28567376 TI - Long-term effects of video capsule endoscopy in the management of obscure gastrointestinal bleeding. AB - Obscure gastrointestinal bleeding (OGIB) accounts for approximately 5% of all gastrointestinal (GI) hemorrhages. It usually arises from a small bowel lesion beyond the reach of conventional endoscopy including esophagogastroduodenoscopy and colonoscopy. Video capsule endoscopy (VCE) revolutionized the evaluation of OGIB patients since it allows reliable and noninvasive visualization of the small bowel mucosal surface. Since 2001, VCE has evolved into an efficient technology integrated in clinical practice. It is the cornerstone in the algorithm of OGIB investigation given its high diagnostic yield, which compares favorably to that of double-balloon enteroscopy (DBE). In terms of outcomes, a positive index VCE examination usually correlates to a high re-bleeding rate, while a negative one provides adequate evidence of low re-bleeding risk, suggesting a wait and watch approach in this subset of patients. Additionally, a variety of factors has been acknowledged as significant predictors of re-bleeding episodes. While research data regarding immediate endoscopic findings have matured, data concerning the clinical utility of VCE in patients with OGIB on the long-term remain sparse. This manuscript reviews the current literature, aiming to highlight the role of VCE in the long-term management of OGIB. PMID- 28567377 TI - Coeliac disease and the videocapsule: what have we learned till now. AB - Celiac disease is diagnosed in part by finding areas of pathology in the small bowel (SB) mucosa. This can often be difficult because the pathologic alterations, including atrophy of the small intestinal villi, can often be sparse and subtle. Some of the quantitative methods for detecting and measuring the presence of villous atrophy from videocapsule endoscopy (VCE) images are presented and discussed. These methods consist of static features of measurement including texture, gray level, and presence and abundance of fissures contained within each acquired image. The methods also consist of dynamic measurements including spectral analysis, and determining motion from a sequence of endoscopic images as obtained from a VCE clip. Thus far, several methods have been found useful to characterize the SB mucosa of untreated celiac disease patients versus control patients lacking villous atrophy, which have revealed significant differences in texture, frequency, and motion on analysis of VCE. In untreated celiac patients undergoing endoscopy, there tends to be greater magnitude of changes and spatial differences in textural descriptors, longer periodic components, indicating slower periodic activity, and differences in feature location, suggesting alterations in motility at areas of pathology as compared to patients without villous atrophy. Improvements in the quantitative analysis of VCE imaging in celiac patients is important to detect pathology in suspected patients, so that biopsies can be obtained from pertinent regions of the small intestinal mucosa. Improvements are also necessary so that patients with celiac disease can be monitored to evaluate the progress of mucosal healing after onset of treatment. PMID- 28567378 TI - Capsule retention: prevention, diagnosis and management. AB - Capsule retention (CR) has been defined as capsule remaining in the digestive tract for a minimum of two weeks. CR occurs approximately in 2% of all patients undergoing small bowel capsule endoscopy (CE). Prompt diagnosis of CR is important, as it has relevant clinical implications. CR should be suspected in (I) all asymptomatic patients who do not report capsule excretion within 15 days from capsule ingestion; and (II) patients with obstructive or perforation-related symptoms in which the capsule has not been excreted, regardless of the time between the onset of symptoms and capsule ingestion. Abdominal plain X-ray is the preferred test to confirm CR. An abdominal CT scan should be performed, on individual basis, if knowledge of the precise location of the retained capsule is necessary or whenever clinically indicated. Since CR is usually asymptomatic, an initial watchful monitoring is suggested. In inflammatory bowel disease (IBD) patients, a short course of medical therapy may allow capsule excretion. Nevertheless, in long-term CR, some cases of capsule fragmentation, acute obstruction and perforation have been described. Therefore, retrieval of the retained capsule is recommended if asymptomatic CR lasts for long time. A safe capsule retrieval is usually performed by endoscopy, whereas surgery remains a viable alternative if the first is unsuccessful or when clinically indicated. Either Patency Capsule(r) (PC) or dedicated small bowel cross-sectional imaging techniques have been proposed to prevent CR. Both have pros and cons, but head-to head comparative studies are lacking. PMID- 28567379 TI - Colonic obstruction caused by video capsule entrapment in a metal stent. AB - Video capsule endoscopy (VCE) has become the method of choice for visualizing the small bowel mucosa and is generally considered to be a safe method. Although uncommon, the most feared complication of VCE is capsule retention that can potentially lead to life-threatening bowel obstruction. Herein, we present for the first time a case of capsule retention in a colonic stent. The patient had known Crohn's disease with colonic involvement and underwent an uneventful but incomplete small bowel VCE for assessment of disease activity and extension for optimizing medical treatment. Five months later, the patient presented with intestinal obstruction due to a Crohn's-stricture in the sigmoid colon, which was successfully decompressed with a self-expandable metal stent. Nonetheless, two days later the patient showed signs of bowel obstruction again and abdominal X ray showed that the capsule was trapped in the metal stent in the sigmoid colon. Subsequently, emergency surgery was performed and the patient fully recovered. Intestinal capsule retention necessitating interventional removal is rare. This report describes a unique case of capsule retention in a colonic metal stent and highlights the potential risk of performing capsule endoscopy examinations in patients with gastrointestinal stents. PMID- 28567380 TI - Capsule endoscopy in Portugal. PMID- 28567381 TI - Ultrasound capsule endoscopy: sounding out the future. AB - Video capsule endoscopy (VCE) has been of immense benefit in the diagnosis and management of gastrointestinal (GI) disorders since its introduction in 2001. However, it suffers from a number of well recognized deficiencies. Amongst these is the limited capability of white light imaging, which is restricted to analysis of the mucosal surface. Current capsule endoscopes are dependent on visual manifestation of disease and limited in regards to transmural imaging and detection of deeper pathology. Ultrasound capsule endoscopy (USCE) has the potential to overcome surface only imaging and provide transmural scans of the GI tract. The integration of high frequency microultrasound (uUS) into capsule endoscopy would allow high resolution transmural images and provide a means of both qualitative and quantitative assessment of the bowel wall. Quantitative ultrasound (QUS) can provide data in an objective and measurable manner, potentially reducing lengthy interpretation times by incorporation into an automated diagnostic process. The research described here is focused on the development of USCE and other complementary diagnostic and therapeutic modalities. Presently investigations have entered a preclinical phase with laboratory investigations running concurrently. PMID- 28567382 TI - Where do I see minimally invasive endoscopy in 2020: clock is ticking. AB - Since it was introduced 17 years ago, capsule endoscopy has become an important diagnostic tool for the small bowel. Three generations of the original small bowel capsule have been developed since (PillCam SB3, Medtronic, USA), and four competitors were introduced for the small bowel. A non-video patency capsule (Agile patency capsule, Medtronic, USA) was also developed, in order to confirm patency and thus avoid retention in the GI tract. Moreover, capsules viewing other organs of the body (esophagus, colon) as well as three different magnetic guided capsules that visualize the stomach as good as optical endoscopy (OE) have been developed. Over 2,000 articles looking at the efficacy of the small bowel capsule in different clinical situations were published since then. Studies are comparing capsule endoscopy versus other modalities in various indications, looking at preparations aiming to improve the diagnostic yield and at technical aspects. The present paper, describes the available capsules in the market and my biased future expectations. PMID- 28567383 TI - Deep brain stimulation for treatment-resistant depression: optimizing interventions while preserving valid trial design. PMID- 28567384 TI - Radiosensitization of cancer stem cells in glioblastoma by the simultaneous inhibition of parallel DNA damage response pathways. PMID- 28567385 TI - Pokemon GO: snake oil or miracle cure for physical inactivity? PMID- 28567386 TI - High prevalence of tobacco use and exposure to secondhand tobacco smoke among adolescents in low- and middle-income countries. PMID- 28567387 TI - Treatment of hypertensive emergencies. PMID- 28567388 TI - Yet another key learning point in the quest universal cartilage repair and restoration. PMID- 28567389 TI - Liberal or restrictive dilemma-that's a CLASSIC! PMID- 28567390 TI - Extracellular vesicle-mediated communication in host-parasite interactions: insight from Fasciola hepatica. PMID- 28567391 TI - Lobectomy: no port at all? PMID- 28567393 TI - The promise of an augmented reality game-Pokemon GO. PMID- 28567392 TI - Kinematically aligned total knee arthroplasty: alternative standardized technique? PMID- 28567394 TI - How to establish a successful ex vivo lung perfusion program. PMID- 28567395 TI - Exercise for cardiac health and regeneration: killing two birds with one stone. PMID- 28567396 TI - AURA 3: the last word on chemotherapy as a control arm in EGFR mutant NSCLC? PMID- 28567397 TI - Poor outcome reporting in medical research; building practice on spoilt grounds. PMID- 28567398 TI - Extracellular vesicles: important players in immune homeostasis. PMID- 28567399 TI - Bicruciate-retaining total knee arthroplasty, a promising technology, that's not quite there. PMID- 28567400 TI - Secondary endpoints: surrogate interest or supplementary table? PMID- 28567401 TI - Editorial on "Epidemiology of fracture nonunion in 18 human bones". PMID- 28567402 TI - Research focused on microRNAs: a link between myocardial remodeling and growth during pathological processes and physical exercises. PMID- 28567403 TI - Timing of lymphocyte trafficking is regulated by the circadian clock. PMID- 28567404 TI - Self-renewal capacity of semi-differentiated CD8+ T cells sustains long-term protective responses in chronic persistent infection. PMID- 28567406 TI - mHealth is now indexed in PubMed/PMC: a tremendous step forward. PMID- 28567405 TI - Applying a mobile survey tool for assessing lymphatic filariasis morbidity in Mtwara Municipal Council of Tanzania. AB - BACKGROUND: A number of methods have been used to estimate lymphatic filariasis (LF) morbidity, including: routine programmatic data, cluster random surveys and the "town crier" method. Currently, few accurate data exist on the global LF morbidity burden in Tanzania. We aimed to estimate prevalence of lymphedema and hydrocele in Mtwara Municipal Council using mobile phone based survey. METHODS: A cross-sectional survey was conducted among adults of Mtwara Municipal council with access to mobile phones. A sample size of at least 384 completed surveys was required to estimate prevalence of lymphedema (both males and females) and hydrocele (males only) morbidity of 50% within a 5% error margin given a 5% level of significance and 95% confidence level. Eligible mobile phone users received a short message text (SMS) requesting consent to participate in the survey. A total of 10 questions were administered via interactive SMS through the GeoPoll, a survey platform developed by Mobile Accord (www.geopoll.com). RESULTS: The survey was completed over a period of 4 days. A total of 8,759 surveys were sent to mobile phone subscribers of whom 1,330 (15.2%) opted-in to complete the survey. A total of 492 (37.0% of those opted-in, 384 male and 108 female) people completed the survey. Lymphedema and hydrocele signs were reported by 20.9% (95% CI, 17.4 24.8) and 20.6% (95% CI, 16.6-25.0) of respondents, respectively. Majority of hydrocele patients (59.5%) and 46.6% of lymphedema patients reported having sought treatment. The proportion of patients reporting similar symptoms among friends and relatives was 66.0% and 70.9% for lymphedema and hydrocele, respectively. CONCLUSIONS: The findings suggest that mobile phone based surveys are a practical approach of undertaking morbidity surveys. While further surveys are needed to verify the findings, this approach can be expected to encourage identification of lymphedema and hydrocele morbidity at community level and provide evidence where further morbidity surveys are warranted. PMID- 28567407 TI - Roshan's telemedicine: expanding the frontier of quality healthcare through mobile technology. AB - The article highlights the power of mobile technology in expanding access to quality healthcare by telling the story of the first successful operation by Afghan doctors to separate conjoined twins at The French Medical Institute for Mothers and Children (FMIC) in Kabul, Afghanistan's capital. Roshan, Afghanistan's leading telecommunications provider, set up the telemedicine link in 2007, connecting three hospitals in Kandahar, Bamiyan and Badakhshan Provinces to FMIC in Kabul, and all three to one of the best and most modern hospitals in the region: The Aga Khan University Hospital in Karachi, Pakistan. PMID- 28567408 TI - Evidence-based adaptation and scale-up of a mobile phone health information service. AB - BACKGROUND: The research base recommending the use of mobile phone interventions for health improvement is growing at a rapid pace. The use of mobile phones to deliver health behavior change and maintenance interventions in particular is gaining a robust evidence base across geographies, populations, and health topics. However, research on best practices for successfully scaling mHealth interventions is not keeping pace, despite the availability of frameworks for adapting and scaling health programs. METHODS: m4RH-Mobile for Reproductive Health-is an SMS, or text message-based, health information service that began in two countries and over a period of 7 years has been adapted and scaled to new population groups and new countries. Success can be attributed to following key principles for scaling up health programs, including continuous stakeholder engagement; ongoing monitoring, evaluation, and research including extensive content and usability testing with the target audience; strategic dissemination of results; and use of marketing and sustainability principles for social initiatives. This article investigates how these factors contributed to vertical, horizontal, and global scale-up of the m4RH program. RESULTS: Vertical scale of m4RH is demonstrated in Tanzania, where the early engagement of stakeholders including the Ministry of Health catalyzed expansion of m4RH content and national level program reach. Ongoing data collection has provided real-time data for decision-making, information about the user base, and peer-reviewed publications, yielding government endorsement and partner hand-off for sustainability of the m4RH platform. Horizontal scale-up and adaptation of m4RH has occurred through expansion to new populations in Rwanda, Uganda, and Tanzania, where best practices for design and implementation of mHealth programs were followed to ensure the platform meets the needs of target populations. m4RH also has been modified and packaged for global scale-up through licensing and toolkit development, research into new business/distribution models, and serving as the foundation for derivative NGO and quasi-governmental mHealth platforms. CONCLUSIONS: The m4RH platform provides an excellent case study of how to apply best practices to successfully scale up mobile phone interventions for health improvement. Applying principles of scale can inform the successful scale-up, sustainability, and potential impact of mHealth programs across health topics and settings. PMID- 28567409 TI - Predicting appointment misses in hospitals using data analytics. AB - BACKGROUND: There is growing attention over the last few years about non attendance in hospitals and its clinical and economic consequences. There have been several studies documenting the various aspects of non-attendance in hospitals. Project Predicting Appoint Misses (PAM) was started with the intention of being able to predict the type of patients that would not come for appointments after making bookings. METHODS: Historic hospital appointment data merged with "distance from hospital" variable was used to run Logistic Regression, Support Vector Machine and Recursive Partitioning to decide the contributing variables to missed appointments. RESULTS: Variables that are "class", "time", "demographics" related have an effect on the target variable, however, prediction models may not perform effectively due to very subtle influence on the target variable. Previously assumed major contributors like "age", "distance" did not have a major effect on the target variable. CONCLUSIONS: With the given data it will be very difficult to make any moderate/strong prediction of the Appointment misses. That being said with the help of the cut off we are able to capture all of the "appointment misses" in addition to also capturing the actualized appointments. PMID- 28567410 TI - Erratum to "Mobile phone use among female entertainment workers in Cambodia: an observation study". AB - [This corrects the article DOI: 10.21037/mhealth.2017.01.01.]. PMID- 28567411 TI - Mobile-based blended learning for capacity building of health providers in rural Afghanistan. AB - BACKGROUND: Mobile-based blended learning initiative was launched in November 2014 in Badakshan province of Afghanistan by Tech4Life Enterprises, Aga Khan Health Service, Afghanistan (AKHS, A), and the University of Calgary, Canada. The goal of this initiative was to improve knowledge of health providers related to four major mental health problems, namely depression, psychosis, post-traumatic stress disorder (PTSD) and drug abuse. METHODS: This paper presents the results of quasi-experimental study conducted in 4 intervention districts in Badakshan for improvement in the knowledge among health providers about depression. The results were compared with three control districts for the change in knowledge scores. RESULTS: Sixty-two health providers completed pre and post module questionnaires from case district, while 31 health providers did so from the control sites. Significant change was noticed in the case districts, where overall knowledge scores changed from 45% in pre-intervention test to 63% in post intervention test. Overall background knowledge of pre to post module test scores changed from 30% to 40%, knowledge of symptoms showed correct responses raised from 25% to 44%, knowledge related to causes of depression from overall districts showed change from 22% to 51%, and treatment knowledge of depression improved from 29% to 35%. Average gain in scores among cases was 16.06, compared to 6.8 in controls. CONCLUSIONS: The study confirms that a blended Learning approach with multiple learning techniques for health providers in Badakshan, Afghanistan, enhanced their knowledge and offers an effective solution to overcome challenges in continuing education. Further research is needed to confirm that the gains in knowledge reported here translate into better practice and improved mental health. PMID- 28567412 TI - mHealth for diabetes support: a systematic review of apps available on the Italian market. AB - mHealth is an expanding field of research and experimentation, concerned with the potentialities of mobile applications as tools to enhance patients' abilities in the management of chronic conditions. We present a systematic review of mHealth applications available on the Italian market and for the Italian speakers in order to assess their reported usability and functions. The review shows that there are rather few products on offer and the ones that are available display weak educational components, do not seem to be based on solid theoretical models of behavior change or decision making, and do not seem to be intended as devices to be integrated in the ecology of the doctor-patient relationship. PMID- 28567413 TI - HealtheBrain: an innovative smartphone application to improve cognitive function in older adults. AB - BACKGROUND: Exercise-based interventions have shown promise in slowing cognitive decline, however there is limited evidence for scalability. Our previous research has linked a novel visuospatial memory exercise intervention, incorporating patterned walking or square-stepping exercise (SSE) with significant improvements in executive function and memory among older adults with normal cognition as well as those with subjective cognitive complaints (SCC) and mild cognitive impairment (MCI). The aim of the current study was to determine the feasibility and utility of the HealtheBrain smartphone app to deliver SSE outside the laboratory among older adults with and without cognitive impairment. METHODS: Previous healthy research subjects with and without SCC or MCI, who had previous exposure to SSE, and who owned or had access to an iPhone of iPad, were recruited to download the HealtheBrain app and use it up to 3 weeks. There were no restrictions on the number of times subjects could use the app. A 15-question survey was developed to assess feasibility and utility of the HealtheBrain app and completed online following the brief exposure period. RESULTS: Of 135 people who were identified, 95 were contacted between September 2014 to August 2015, 27 downloaded the HealtheBrain app on their iPhone or iPad from the App Store and 19 completed the questionnaire. Subjects (n=19) were an average age of 68.3+/-5.4; 74% female and had 15.5+/-2.8 years of education (84% post-secondary education), a mean Mini Mental State examination score of 29.1 (SD 1.2) out of 30 and Montreal Cognitive Assessment score of 26.3 (SD 1.9) out of 30. Subjects used the HealtheBrain app 1 7 days per week, mostly at home. Of possible stages of progression, subjects mainly used the stage 1 and 2 beginner patterns. Subjects reported perceived and technical challenges registering horizontal step patterns associated with stage 2 and greater progression. Sixty percent found the app was easy to use or similar to what they experienced with SSE in the laboratory setting. Most said they would continue to use the HealtheBrain app and would recommend it to friends and family. CONCLUSIONS: The HealtheBrain app was feasible in providing SSE to older adults with the appropriate smartphone device outside the laboratory setting. Challenges were identified with perceived capture of higher levels of SSE stages that used horizontal step patterns. This as well as technical issues with horizontal step patterns will be addressed by newer GPS technology in current smartphone devices. Most subjects stated they would continue to use the HealtheBrain app and refer to their friends and family. We believe that our findings in a representative cohort support the HealtheBrain app as a scalable intervention to promote cognitive health in older adults. PMID- 28567414 TI - Barriers in adopting blended learning in a private university of Pakistan and East Africa: faculty members' perspective. AB - BACKGROUND: Education methods have undergone transformation over the centuries. Use of technology is the cornerstone for innovation in teaching methods. Hence, blended learning which includes face to face and online modalities is being increasingly explored as effective method for learning. This pilot study determines the perceptions of faculty members in a private international university on barriers influencing adoption of technology for teaching and learning. METHODS: A cross-sectional survey was conducted through a self-reported questionnaire using 'survey monkey'. The data was entered and analyzed using Statistical Package for the Social Sciences (SPSS version 20). Frequencies and proportions are reported. RESULTS: Findings indicated that 51.6% faculty members perceived the importance of integration of technology in their teaching. Around 54% of the participants recognized that they do possess the ability and accessibility to integrate information communication technology (ICT) in teaching and learning, but there is a need to hone the basic information technology (IT) skills to initiate technology driven teaching. Findings revealed that 55% faculty members acknowledged the constraint of not getting protective time to develop and deliver technology driven courses. Further, results showed that 45% faculty members perceived that their innovation efforts in terms of teaching as blended learning do not count towards their professional promotion or recognition, as usually priority is given to research over teaching innovation. The findings also indicated that 54.5% participants asserted that university lack mentorship in the field of blended learning. CONCLUSIONS: Therefore, study suggests that universities should provide adequate mentorship programmes for the faculty members in enhancing their skills of integrating technology in their teaching. PMID- 28567417 TI - Corrigendum to "Dual Inhibiting Senescence and Epithelial-to-Mesenchymal Transition by Erythropoietin Preserve Tubular Epithelial Cell Regeneration and Ameliorate Renal Fibrosis in Unilateral Ureteral Obstruction". AB - [This corrects the article DOI: 10.1155/2013/308130.]. PMID- 28567416 TI - Negative Correlation between miR-200c and Decorin Plays an Important Role in the Pathogenesis of Colorectal Carcinoma. AB - Aim. To demonstrate the regulatory role of miRNA in colorectal carcinoma (CRC) and reveal the transcript markers that may be associated with CRC clinical outcomes. Method. Herein, we analyzed both mRNA and miRNA gene expression profiles of 255 CRC tumor samples from The Cancer Genome Atlas project to reveal the regulatory association between miRNA and mRNA. Also, the potential role of gene coexpression network in CRC has been explored. Results. The negative correlation between miR-200c and DCN (Decorin) was calculated in CRC, indicating that DCN could be a potential target of miR-200c. Clinical features indicated that colon polyp history and overall survival were significantly related to the expression level of miR-200c. Three coexpression networks have been constructed, and genes involved in the networks are related to cell cycle, NOTCH, and mTOR signaling pathways. Conclusion. Our result provides a new insight into cancer related mRNA coexpression network in CRC research. PMID- 28567418 TI - A Cancer Gene Selection Algorithm Based on the K-S Test and CFS. AB - BACKGROUND: To address the challenging problem of selecting distinguished genes from cancer gene expression datasets, this paper presents a gene subset selection algorithm based on the Kolmogorov-Smirnov (K-S) test and correlation-based feature selection (CFS) principles. The algorithm selects distinguished genes first using the K-S test, and then, it uses CFS to select genes from those selected by the K-S test. RESULTS: We adopted support vector machines (SVM) as the classification tool and used the criteria of accuracy to evaluate the performance of the classifiers on the selected gene subsets. This approach compared the proposed gene subset selection algorithm with the K-S test, CFS, minimum-redundancy maximum-relevancy (mRMR), and ReliefF algorithms. The average experimental results of the aforementioned gene selection algorithms for 5 gene expression datasets demonstrate that, based on accuracy, the performance of the new K-S and CFS-based algorithm is better than those of the K-S test, CFS, mRMR, and ReliefF algorithms. CONCLUSIONS: The experimental results show that the K-S test-CFS gene selection algorithm is a very effective and promising approach compared to the K-S test, CFS, mRMR, and ReliefF algorithms. PMID- 28567419 TI - Shin'iseihaito (Xinyiqingfeitang) Suppresses the Biofilm Formation of Streptococcus pneumoniae In Vitro. AB - Streptococcus pneumoniae (S. pneumoniae) is the important pathogen that causes otolaryngeal diseases such as sinusitis. S. pneumoniae frequently forms the biofilm to prevent severe circumstances such as antimicrobial agents. Shin'iseihaito (xinyiqingfeitang) is a formula of Japanese traditional Kampo medicine that has 9 crude drugs and provides the medicinal usage for sinusitis. The objective of the present study is to reveal the mechanism of antibiofilm activity by Shin'iseihaito extract (SSHT). SSHT significantly inhibited the formation of biofilm from S. pneumoniae ATCC 49619 in dose- and time-dependent manners. SSHT also significantly suppressed the biofilm formation by other five different cps types of S. pneumoniae clinical isolates. We found that the extracts of 8 out of 9 components in Shin'iseihaito had the inhibitory effects of biofilm formation, and the extract of the root of Scutellaria baicalensis had the strongest effect among the ingredients of Shin'iseihaito. We found that the capsule of SSHT-treated S. pneumoniae was significantly thinner than that of the untreated group and that SSHT reduced the hydrophobicity of bacterial cell surface. Our results suggest that Shin'iseihaito may be a useful agent for the treatment of S. pneumoniae-induced sinusitis because of the inhibition of biofilm formation of S. pneumoniae. PMID- 28567415 TI - Neurodevelopmental Disorders and Environmental Toxicants: Epigenetics as an Underlying Mechanism. AB - The increasing prevalence of neurodevelopmental disorders, especially autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), calls for more research into the identification of etiologic and risk factors. The Developmental Origin of Health and Disease (DOHaD) hypothesizes that the environment during fetal and childhood development affects the risk for many chronic diseases in later stages of life, including neurodevelopmental disorders. Epigenetics, a term describing mechanisms that cause changes in the chromosome state without affecting DNA sequences, is suggested to be the underlying mechanism, according to the DOHaD hypothesis. Moreover, many neurodevelopmental disorders are also related to epigenetic abnormalities. Experimental and epidemiological studies suggest that exposure to prenatal environmental toxicants is associated with neurodevelopmental disorders. In addition, there is also evidence that environmental toxicants can result in epigenetic alterations, notably DNA methylation. In this review, we first focus on the relationship between neurodevelopmental disorders and environmental toxicants, in particular maternal smoking, plastic-derived chemicals (bisphenol A and phthalates), persistent organic pollutants, and heavy metals. We then review studies showing the epigenetic effects of those environmental factors in humans that may affect normal neurodevelopment. PMID- 28567420 TI - Prognostic Significance of Blood Transfusion in Newly Diagnosed Multiple Myeloma Patients without Autologous Hematopoietic Stem Cell Transplantation. AB - The aim of this study was to evaluate whether blood transfusions affect overall survival (OS) and progression-free survival (PFS) in newly diagnosed multiple myeloma (MM) patients without hematopoietic stem cell transplantation. A total of 181 patients were enrolled and divided into two groups: 68 patients in the transfused group and 113 patients in the nontransfused group. Statistical analyses showed that there were significant differences in ECOG scoring, Ig isotype, platelet (Plt) counts, hemoglobin (Hb) level, serum creatinine (Scr) level, and beta2-microglobulin (beta2-MG) level between the two groups. Univariate analyses showed that higher International Staging System staging, Plt counts < 100 * 109/L, Scr level >= 177 MUmol/L, serum beta2-MG >= 5.5 MUmol/L, serum calcium (Ca) >= 2.75 mmol/L, and thalidomide use were associated with both OS and PFS in MM patients. Age >= 60 was associated with OS and Ig isotype was associated with PFS in MM patients. Moreover, blood transfusion was associated with PFS but not OS in MM patients. Multivariate analyses showed that blood transfusion was not an independent factor for PFS in MM patients. Our preliminary results suggested that newly diagnosed MM patients may benefit from a liberal blood transfusion strategy, since blood transfusion is not an independent impact factor for survival. PMID- 28567422 TI - Risk Factors for the Mortality of Pneumocystis jirovecii Pneumonia in Non-HIV Patients Who Required Mechanical Ventilation: A Retrospective Case Series Study. AB - BACKGROUND: The risk factors for the mortality rate of Pneumocystis jirovecii pneumonia (PCP) who required mechanical ventilation (MV) remained unknown. METHODS: A retrospective chart review was performed of all PCP patients admitted to our intensive care unit and treated for acute hypoxemic respiratory failure to assess the risk factors for the high mortality. RESULTS: Twenty patients without human immunodeficiency virus infection required mechanical ventilation; 19 received noninvasive ventilation; and 11 were intubated. PEEP was incrementally increased and titrated to maintain FIO2 as low as possible. No mandatory ventilation was used. Sixteen patients (80%) survived. Pneumothorax developed in one patient with rheumatoid arthritis (RA). Median PEEP level in the first 5 days was 10.0 cmH2O and not associated with death. Multivariate analysis showed the association of incidence of interstitial lung disease and increase in serum KL-6 with 90-day mortality. CONCLUSIONS: We found MV strategies to prevent pneumothorax including liberal use of noninvasive ventilation, and PEEP titration and disuse of mandatory ventilation may improve mortality in this setting. Underlying disease of interstitial lung disease was a risk factor and KL-6 may be a useful predictor associated with mortality in patients with RA. These findings will need to be validated in larger studies. PMID- 28567421 TI - Effects of Diode Laser, Gaseous Ozone, and Medical Dressings on Enterococcus faecalis Biofilms in the Root Canal Ex Vivo. AB - The objective was to compare the antibacterial effects of adjunctive disinfection using diode laser and gaseous ozone compared to the medical dressings calcium hydroxide (Ca(OH)2) and chlorhexidine gel (CHX-Gel) on Enterococcus faecalis biofilms in human root canals ex vivo. Root canals of 180 human extracted teeth were infected by E. faecalis and divided into 3 main groups (G): G1, control; G2, instrumentation and irrigation using 0.9% NaCl; G3, instrumentation and irrigation using 1% NaOCl. In each main group, the following treatments were applied: gaseous ozone, diode laser, and medical dressings of Ca(OH)2 or CHX-Gel for 7 days (n = 15). Reduction of colony forming units (CFUs) inside the root canal of planktons and frequencies of adherent bacteria after treatment were calculated. Bacterial reduction was significantly affected by the irrigation protocol (p < 0.0005) and the disinfection method (p < 0.0005), and a significant interaction between both factors could be observed (p < 0.0005; ANOVA). In G3 (instrumentation using 1% NaOCl), no significant effect of disinfection methods could be demonstrated on planktonic bacteria (p = 0.062; ANOVA) and frequencies of adherent bacteria (p > 0.05; chi-square test). Instrumentation and irrigation using NaOCl combined with ozone or laser application resulted in comparable bacterial reduction on E. faecalis to the application of medical dressings. PMID- 28567423 TI - Protective Effects of Lemon Juice on Alcohol-Induced Liver Injury in Mice. AB - Chronic excessive alcohol consumption (more than 40-80 g/day for males and more than 20-40 g/day for females) could induce serious liver injury. In this study, effects of lemon juice on chronic alcohol-induced liver injury in mice were evaluated. The serum biochemical profiles and hepatic lipid peroxidation levels, triacylglycerol (TG) contents, antioxidant enzyme activities, and histopathological changes were examined for evaluating the hepatoprotective effects of lemon juice in mice. In addition, the in vitro antioxidant capacities of lemon juice were determined. The results showed that lemon juice significantly inhibited alcohol-induced increase of alanine transaminase (ALT), aspartate transaminase (AST), hepatic TG, and lipid peroxidation levels in a dose-dependent manner. Histopathological changes induced by alcohol were also remarkably improved by lemon juice treatment. These findings suggest that lemon juice has protective effects on alcohol-induced liver injury in mice. The protective effects might be related to the antioxidant capacity of lemon juice because lemon juice showed in vitro antioxidant capacity. PMID- 28567424 TI - Effect of Naringenin, Quercetin, and Sesamin on Xenobiotica-Metabolizing CYP1A and CYP3A in Mice Offspring after Maternal Exposure to Persistent Organic Pollutants. AB - The aim of the present study was to evaluate in vitro effects of dietary phytochemicals naringenin, quercetin, and sesamin on the activities of ethoxy- (EROD; CYP1A) and benzyloxy- (BROD; CYP3A) resorufin O-dealkylases after the exposure to the cocktail of persistent organic pollutants (POPs). CD-1 mice were exposed from weaning, through gestation and lactation to a defined mixture of POPs. Hepatic microsomes were prepared from their female offspring at postnatal day 42. Hepatic EROD and BROD activity were evaluated in the presence of quercetin, naringenin, and sesamin at nine concentrations from 5 to 100000 nM. EROD activity was strongly inhibited by quercetin with Ki values from 1.7 to 2.6 MUM. BROD activity was inhibited by quercetin with Ki values from 64.9 to 75.3 MUM and naringenin with Ki values from 39.3 to 45.8 MUM. The IC50 and Ki values did not differ between the groups of mice with different levels of POPs exposure in any of the experimental sets. Sesamin did not inhibit either EROD or BROD. We concluded that the interactions of quercetin and naringenin with CYP1A and CYP3A in mice liver were not affected by the levels of POPs exposure. PMID- 28567425 TI - The Effectiveness of Lifestyle Adaptation for the Prevention of Prediabetes in Adults: A Systematic Review. AB - Diabetes prevalence is increasing exceptionally worldwide and with this come associated healthcare costs. The primary outcome of this systematic review was to assess glycaemic control and incidence of Type 2 diabetes mellitus (T2DM) diagnosis after exercise and dietary intervention (measured with any validated scale). The secondary outcome assessed body mass index change, weight change, and physical exercise capacity after diet and exercise intervention (measured with any validated scale). 1,780 studies were identified from searching electronic databases. Relevant studies went through a selection process. The inclusion criteria for all studies were people with prediabetes diagnosed by either impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). Lifestyle adaptation reduced the incidence of diabetes development more than standard treatment. Furthermore, better glycaemic control, improved physical exercise capacity, and increased weight reduction were observed with lifestyle intervention over standard treatment. Finally, improvements over the long term deteriorated, highlighting problems with long-term adherence to lifestyle changes. Overall, cumulative incidence of diabetes is drastically reduced in the intervention groups compared to control groups (standard care). Furthermore, glycaemic control was improved in the short term, with many participants reverting to normoglycaemia. PMID- 28567426 TI - Treatment of Subacromial Impingement Syndrome: Platelet-Rich Plasma or Exercise Therapy? A Randomized Controlled Trial. AB - BACKGROUND: Subacromial impingement syndrome (SAIS) is the most common disorder of the shoulder. The evidence for the effectiveness of treatment options is inconclusive and limited. Therefore, there is a need for more evidence in this regard, particularly for long-term outcomes. HYPOTHESIS: Platelet-rich plasma (PRP) would be an effective method in treating subacromial impingement. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: This was a single-blinded randomized clinical trial with 1-, 3-, and 6-month follow-up. Sixty-two patients were randomly placed into 2 groups, receiving either PRP or exercise therapy. The outcome parameters were pain, shoulder range of motion (ROM), muscle force, functionality, and magnetic resonance imaging findings. RESULTS: Both treatment options significantly reduced pain and increased shoulder ROM compared with baseline measurements. Both treatments also significantly improved functionality. However, the treatment choices were not significantly effective in improving muscle force. Trend analysis revealed that in the first and third months, exercise therapy was superior to PRP in pain, shoulder flexion and abduction, and functionality. However, in the sixth month, only shoulder abduction and total Western Ontario Rotator Cuff score were significantly different between the 2 groups. CONCLUSION: Both PRP injection and exercise therapy were effective in reducing pain and disability in patients with SAIS, with exercise therapy proving more effective. PMID- 28567427 TI - Medial Collateral Ligament Reconstruction in Patients With Medial Knee Instability: A Systematic Review. AB - BACKGROUND: The medial collateral ligament (MCL) is the most frequently injured ligament of the knee, but it infrequently requires surgical treatment. Current literature on MCL reconstructions is sparse and offers mixed outcome measures. PURPOSE/HYPOTHESIS: The purpose of this study was to compare the outcomes of isolated MCL reconstruction and multiligamentous MCL reconstruction. Our hypothesis was that in selective patients, MCL reconstruction would significantly improve objective and subjective patient knee performance measures, those being baseline valgus laxity, range of motion, objective and subjective International Knee Documentation Committee (IKDC) scores, Tegner score, and Lysholm knee activity scores. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and utilizing 3 computer-based databases. Studies reporting clinical outcomes of patients undergoing MCL reconstruction due to chronic instability or injury with mean follow-up of at least 2 years and levels of evidence 1 to 4 were eligible for inclusion. All relevant subject demographics and study data were statistically analyzed using 2-sample and 2-proportion z tests. RESULTS: Ten studies involving 275 patients met our inclusion criteria. Of these patients, 46 underwent isolated MCL reconstruction while another 229 underwent reconstruction of the MCL in addition to a variety of concomitant reconstructions. Overall outcomes for all patients were significant for (1) reducing the medial opening of the knee (8.1 +/ 1.3 vs 1.4 +/- 1.0 mm; P < .001), (2) improving the patient's objective IKDC score (1.2% vs 88.4%; P < .001), (3) improving the patient's subjective IKDC score (49.8 +/- 6.9 vs 82.4 +/- 9.6; P < .001), and (4) improving the Lysholm knee activity score (69.3 +/- 5.9 vs 90.5 +/- 6.6; P < .001). No differences existed between concomitant reconstruction groupings except that postoperative Lysholm scores were better for MCL/anterior cruciate ligament reconstruction than MCL/posterior cruciate ligament reconstruction (94.3 +/- 4.5 vs 84.0 +/- 11.7; P < .001). Normal or nearly normal range of motion was obtained by 88% of all patients. CONCLUSION: The systematic review of 10 studies and 275 knees found that the reported patient outcomes after MCL reconstruction were significantly improved across all measures studied, with no significant difference in outcomes between concomitant reconstructions. PMID- 28567428 TI - ACL Roof Impingement Revisited: Does the Independent Femoral Drilling Technique Avoid Roof Impingement With Anteriorly Placed Tibial Tunnels? AB - BACKGROUND: Anatomic femoral tunnel placement for single-bundle anterior cruciate ligament (ACL) reconstruction is now well accepted. The ideal location for the tibial tunnel has not been studied extensively, although some biomechanical and clinical studies suggest that placement of the tibial tunnel in the anterior part of the ACL tibial attachment site may be desirable. However, the concern for intercondylar roof impingement has tempered enthusiasm for anterior tibial tunnel placement. PURPOSE: To compare the potential for intercondylar roof impingement of ACL grafts with anteriorly positioned tibial tunnels after either transtibial (TT) or independent femoral (IF) tunnel drilling. STUDY DESIGN: Controlled laboratory study. METHODS: Twelve fresh-frozen cadaver knees were randomized to either a TT or IF drilling technique. Tibial guide pins were drilled in the anterior third of the native ACL tibial attachment site after debridement. All efforts were made to drill the femoral tunnel anatomically in the center of the attachment site, and the surrogate ACL graft was visualized using 3-dimensional computed tomography. Reformatting was used to evaluate for roof impingement. Tunnel dimensions, knee flexion angles, and intra-articular sagittal graft angles were also measured. The Impingement Review Index (IRI) was used to evaluate for graft impingement. RESULTS: Two grafts (2/6, 33.3%) in the TT group impinged upon the intercondylar roof and demonstrated angular deformity (IRI type 1). No grafts in the IF group impinged, although 2 of 6 (66.7%) IF grafts touched the roof without deformation (IRI type 2). The presence or absence of impingement was not statistically significant. The mean sagittal tibial tunnel guide pin position prior to drilling was 27.6% of the sagittal diameter of the tibia (range, 22% 33.9%). However, computed tomography performed postdrilling detected substantial posterior enlargement in 2 TT specimens. A significant difference in the sagittal graft angle was noted between the 2 groups. TT grafts were more vertical, leading to angular convergence with the roof, whereas IF grafts were more horizontal and universally diverged from the roof. CONCLUSION: The IF technique had no specimens with roof impingement despite an anterior tibial tunnel position, likely due to a more horizontal graft trajectory and anatomic placement of the ACL femoral tunnel. Roof impingement remains a concern after TT ACL reconstruction in the setting of anterior tibial tunnel placement, although statistical significance was not found. Future clinical studies are planned to develop better recommendations for ACL tibial tunnel placement. CLINICAL RELEVANCE: Graft impingement due to excessively anterior tibial tunnel placement using a TT drilling technique has been previously demonstrated; however, this may not be a concern when using an IF tunnel drilling technique. There may also be biomechanical advantages to a more anterior tibial tunnel in IF tunnel ACL reconstruction. PMID- 28567429 TI - Are the Current Little League Pitching Guidelines Adequate? A Single-Season Prospective MRI Study. AB - BACKGROUND: Little League throwing guidelines have recently been implemented in an attempt to lessen the growing number of elbow injuries occurring in youth baseball players. HYPOTHESIS/PURPOSE: The purpose of this study was to examine pre- and postseason changes seen on magnetic resonance imaging (MRI) in youth baseball players' elbows in an attempt to identify risk factors for pain and MRI abnormalities, with a particular focus on the current Little League guidelines. We hypothesized that MRI abnormalities would be common in pitchers with high pitch counts and poor guideline compliance. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A prospective study of Little League players aged 10 to 13 years was performed. Players were recruited prior to the start of the season and underwent bilateral elbow MRI as well as a physical examination and completed a questionnaire addressing their playing history and arm pain. At the end of the season, a repeat MRI and physical examination were performed. MRIs were read by blinded radiologists. During the season, player statistics including innings played, pitch counts, and guideline compliance were recorded. Physical examination findings and player statistics were compared between subjects with and without MRI changes utilizing chi-square and analysis of variance techniques. RESULTS: Twenty-six players were enrolled. Despite 100% compliance with pitching guidelines, 12 players (48%) had abnormal MRI findings, and 28% experienced pain during the season. There was a significant difference in distal humeral physeal width measured pre- to postseason (1.54 vs 2.31 mm, P < .001). There was a significant loss of shoulder internal rotation during the season, averaging 11 degrees . While pitch counts, player position, and throwing curveballs/sliders were not significantly associated with changes seen on MRI, year-round play was associated with abnormalities (P < .05). Much lower compliance (<50%) was observed with nonenforced guidelines, including avoidance of single-sport specialization, year-round play, and throwing curveballs/sliders. CONCLUSION: Arm pain and MRI abnormalities of the medial elbow are common in Little League baseball players who comply with the Little League throwing guidelines, especially those playing year-round. PMID- 28567430 TI - Can Hepatitis C Virus Antigen Testing Replace Ribonucleic Acid Polymearse Chain Reaction Analysis for Detecting Hepatitis C Virus? A Systematic Review. AB - The complexity and cost of current diagnostics for hepatitis C virus (HCV) may act as a prevention to the scale-up of treatment in the developing world. Currently, ribonucleic acid (RNA)-polymerase chain reaction tests are the gold standard. However, there is potential for the use of simpler and cheaper antigen tests to confirm HCV infection in different clinical settings. We evaluated the sensitivity and specificity of antigen assays. This was compared with the reference-standard RNA assays. A subanalysis also assessed Architect core antigen test, which is the only commercially available antigen test on the market. In 24 datasets, evaluating HCV-antigen assays in 8136 samples, the percentage of HCV antigen positive, HCV-RNA negative was 0.57%. The percentage HCV-antigen negative, HCV-RNA positive was 3.52%. There is strong evidence that antigen detection performs as well as RNA-based assays for HCV management. The use of antigen tests could improve access to HCV care in underresourced healthcare settings. PMID- 28567431 TI - Rotavirus Vaccine Schedules and Vaccine Response Among Infants in Low- and Middle Income Countries: A Systematic Review. AB - BACKGROUND: Rotavirus vaccine schedules may impact vaccine response among children in low- and middle-income countries (LMICs). Our objective was to review the literature evaluating the effects of monovalent (RV1) or pentavalent rotavirus vaccines schedules on vaccine response. METHODS: We searched PubMed, Web of Science, Embase, and ClinicalTrials.gov for eligible trials conducted in LMICs comparing >=2 vaccine schedules and reporting immunologic response or efficacy. We calculated seroconversion proportion differences and geometric mean concentration (GMC) ratios with 95% confidence intervals. RESULTS: We abstracted data from 8 eligible trials of RV1. The point estimates for seroconversion proportions difference ranged from -0.25 to -0.09 for the 6/10-week schedule compared with 10/14. The range for the 6/10/14- compared with 10/14-week schedule was -0.02 to 0.10. Patterns were similar for GMC ratios and efficacy estimates. CONCLUSIONS: The commonly used 6/10-week RV1 schedule in LMICs may not be optimal. Further research on the effect of rotavirus schedules using clinical endpoints is essential. PMID- 28567432 TI - Effect of a Fusion Peptide by Covalent Conjugation of a Mitochondrial Cell Penetrating Peptide and a Glutathione Analog Peptide. AB - Previously, we designed and synthesized a library of mitochondrial antioxidative cell-penetrating peptides (mtCPPs) superior to the parent peptide, SS31, to protect mitochondria from oxidative damage. A library of antioxidative glutathione analogs called glutathione peptides (UPFs), exceptional in hydroxyl radical elimination compared with glutathione, were also designed and synthesized. Here, a follow-up study is described, investigating the effects of the most promising members from both libraries on reactive oxidative species scavenging ability. None of the peptides influenced cell viability at the concentrations used. Fluorescence microscopy studies showed that the fluorescein mtCPP1-UPF25 (mtgCPP) internalized into cells, and spectrofluorometric analysis determined the presence and extent of peptide into different cell compartments. mtgCPP has superior antioxidative activity compared with mtCPP1 and UPF25 against H2O2 insult, preventing ROS formation by 2- and 3-fold, respectively. Moreover, we neither observed effects on mitochondrial membrane potential nor production of ATP. These data indicate that mtgCPP is targeting mitochondria, protecting them from oxidative damage, while also being present in the cytosol. Our hypothesis is based on a synergistic effect resulting from the fused peptide. The mitochondrial peptide segment is targeting mitochondria, whereas the glutathione analog peptide segment is active in the cytosol, resulting in increased scavenging ability. PMID- 28567433 TI - Maggot debridement therapy for a patient with critical limb ischaemia and severe cardiac dysfunction: possibility of limb salvage. AB - Ischaemic skin ulcer occurred on the foot of a 73-year-old man who had a history of fulminant myocarditis with severe cardiac dysfunction. We attempted wound bed preparation by maggot debridement therapy and salvaged his limb. It can be one of the adjuvant treatment strategies for critical limb ischaemia. PMID- 28567434 TI - Trigger finger at wrist caused by degenerative changes of the flexor tendon sheath and carpal tunnel syndrome: a case report. AB - Trigger finger at wrist is a rare condition. Symptoms include finger triggering, snapping or catching at the wrist level. Carpal tunnel syndrome and median nerve compression neuropathy are almost always associated. We reported one case which was caused by degenerative changes of the flexor tendon sheath and carpal tunnel syndrome. PMID- 28567435 TI - Abnormal brain metabolism on FDG-PET/CT is a common early finding in autoimmune encephalitis. AB - OBJECTIVE: To compare the rate of abnormal brain metabolism by FDG-PET/CT to other paraclinical findings and to describe brain metabolism patterns in autoimmune encephalitis (AE). METHODS: A retrospective review of clinical data and initial dedicated brain FDG-PET/CT studies for neurology inpatients with AE, per consensus criteria, treated at a single tertiary center over 123 months. Z score maps of FDG-PET/CT were made using 3-dimensional stereotactic surface projections with comparison to age group-matched controls. Brain region mean Z scores with magnitudes >=2.00 were interpreted as significant. Comparisons were made to rates of abnormal initial brain MRI, abnormal initial EEG, and presence of intrathecal inflammation. RESULTS: Sixty-one patients with AE (32 seropositive) underwent brain FDG-PET/CT at median 4 weeks of symptoms (interquartile range [IQR] 9 weeks) and median 4 days from MRI (IQR 8.5 days). FDG-PET/CT was abnormal in 52 (85%) patients, with 42 (69%) demonstrating only hypometabolism. Isolated hypermetabolism was demonstrated in 2 (3%) patients. Both hypermetabolic and hypometabolic brain regions were noted in 8 (13%) patients. Nine (15%) patients had normal FDG-PET/CT studies. CSF inflammation was evident in 34/55 (62%) patients, whereas initial EEG (17/56, 30%) and MRI (23/57, 40%) were abnormal in fewer. Detection of 2 or more of these paraclinical findings was in weak agreement with abnormal brain FDG-PET/CT (kappa = 0.16, p = 0.02). CONCLUSIONS: FDG-PET/CT was more often abnormal than initial EEG, MRI, and CSF studies in neurology inpatients with AE, with brain region hypometabolism the most frequently observed. PMID- 28567436 TI - "No Alcohol Is Recommended, But . . .": Health Care Students' Attitudes About Alcohol Consumption During Pregnancy. AB - Canadian findings suggest that health care providers require further training and education to support their work preventing fetal alcohol spectrum disorder (FASD). However, the knowledge and training of health care students in relation to FASD remains largely unexplored. The purpose of this study was to understand the attitudes and beliefs of health care students about alcohol use during pregnancy. Twenty-one health care students participated in a scenario-based vignette about alcohol consumption during pregnancy. Although almost all students recognized that no alcohol consumption during pregnancy is the safest recommendation, many students recounted that this advice is not always conveyed during encounters with their pregnant patients. Three primary themes related to students' attitudes concerning alcohol use during pregnancy were identified. Health care professionals in training need further education about the risks of alcohol consumption during pregnancy and the potential health outcomes associated with prenatal alcohol exposure. PMID- 28567439 TI - "Here I am" and the Women's Dermatology Society. PMID- 28567437 TI - Incontinence and Nocturia in Older Adults After Hip Fracture: Analysis of a Secondary Outcome for a Parallel Group, Randomized Controlled Trial. AB - Objective: To test the effect of a follow-up clinic on urinary incontinence (UI) and nocturia among older adults with hip fracture. Method: Fifty-three older adults (>=65 years) 3 to 12 months following hip fracture were enrolled and randomized to receive usual care plus the intervention (B4), or usual care (UC) only. The B4 group received management by health professionals, with need-based referrals. UI, nocturia, and quality of life were measured with questionnaires at baseline, 6 months, and 12 months. Results: There were 48 participants included in this analysis, and at baseline, 44% of study participants self-reported UI. At final assessment, six out of 24 B4 participants and 12 out of 24 UC participants reported UI. Four out of five study participants reported nocturia at baseline; this did not decrease during the study. Discussion: Following hip fracture, many older adults report UI and most report nocturia. Health professionals should be aware of the high occurrence of urinary symptoms among older adults post hip fracture. PMID- 28567438 TI - In-depth immunophenotyping data of IL-6R on the human peripheral regulatory T cell (Treg) compartment. AB - We provide in this paper a detailed characterization of the human peripheral CD4+ CD127lowCD25+ regulatory T cell (Treg) compartment, with a particular emphasis in defining the population expressing higher levels of the IL-6 receptor (IL-6R). We provide a description of the phenotype of this population by assessing both the surface expression by flow cytometry as well as their transcriptional profile and functional features. In addition, we also present functional data describing the responsiveness of these subsets to IL-6 signalling in vitro and to IL-2 in vivo. The data presented in this paper support the research article "Human IL-6RhiTIGIT CD4+CD127lowCD25+ T cells display potent in vitro suppressive capacity and a distinct Th17 profile" (Ferreira RC et al., 2017; doi: 10.1016/j.clim.2017.03.002) [1]. PMID- 28567440 TI - Brazilian Morus nigra Attenuated Hyperglycemia, Dyslipidemia, and Prooxidant Status in Alloxan-Induced Diabetic Rats. AB - Morus nigra has been used popularly for several proposes, including diabetic. In an attempt to support medicinal value, the acute hypoglycemic, hypolipidemic, and antioxidant effects of the ethanolic extract of Morus nigra (EEMn 200 or 400 mg/kg b.w.) were evaluated in normal and alloxan-induced diabetic treated for 14 days. Serum biochemical and antioxidant analysis were performed at the end of experiment. Oral glucose tolerance test was performed at 10th and 15th days. Chromatographic analysis by HPLC-DAD of EEMn was performed. Insulin was used as positive control to glycemic metabolism as well as fenofibrate to lipid metabolism. EEMn (400 mg/kg/day) reduced fasting and postprandial glycaemia, improved oral glucose tolerance, and reduced lipolysis and proteolysis in diabetic rats. EEMn decreased the blood levels of total cholesterol and increased HDL level when compared to the diabetic control rats. At higher levels, EEMn reduced triglycerides and VLDL levels in diabetic rats. Also, EEMn reduced malondialdehyde and increased the reduced glutathione levels in liver of diabetic rats. Chromatographic analysis identified the presence of the flavonoids rutin, isoquercetin, and kaempferitrin. Acute EEMn treatment reduced hyperglycemia, improved oral glucose tolerance, and minimized dyslipidemia and oxidative stress leading to a reduction in atherogenic index in alloxan-induced diabetic rats. PMID- 28567441 TI - Versatility of Chitosan-Based Biomaterials and Their Use as Scaffolds for Tissue Regeneration. AB - Chitosan is a naturally occurring polysaccharide obtained from chitin, present in abundance in the exoskeletons of crustaceans and insects. It has aroused great interest as a biomaterial for tissue engineering on account of its biocompatibility and biodegradation and its affinity for biomolecules. A significant number of research groups have investigated the application of chitosan as scaffolds for tissue regeneration. However, there is a wide variability in terms of physicochemical characteristics of chitosan used in some studies and its combinations with other biomaterials, making it difficult to compare results and standardize its properties. The current systematic review of literature on the use of chitosan for tissue regeneration consisted of a study of 478 articles in the PubMed database, which resulted, after applying inclusion criteria, in the selection of 61 catalogued, critically analysed works. The results demonstrated the effectiveness of chitosan-based biomaterials in 93.4% of the studies reviewed, whether or not combined with cells and growth factors, in the regeneration of various types of tissues in animals. However, the absence of clinical studies in humans, the inadequate experimental designs, and the lack of information concerning chitosan's characteristics limit the reproducibility and relevance of studies and the clinical applicability of chitosan. PMID- 28567443 TI - Correction for Miyoshi-Akiyama et al., "Comparative Genome Analysis of Extended Spectrum-beta-Lactamase-Producing Escherichia coli Sequence Type 131 Strains from Nepal and Japan". AB - [This corrects the article DOI: 10.1128/mSphere.00289-16.]. PMID- 28567442 TI - Genomewide Mutational Diversity in Escherichia coli Population Evolving in Prolonged Stationary Phase. AB - Prolonged stationary phase is an approximation of natural environments presenting a range of stresses. Survival in prolonged stationary phase requires alternative metabolic pathways for survival. This study describes the repertoire of mutations accumulating in starving Escherichia coli populations in lysogeny broth. A wide range of mutations accumulates over the course of 1 month in stationary phase. Single nucleotide polymorphisms (SNPs) constitute 64% of all mutations. A majority of these mutations are nonsynonymous and are located at conserved loci. There is an increase in genetic diversity in the evolving populations over time. Computer simulations of evolution in stationary phase suggest that the maximum frequency of mutations observed in our experimental populations cannot be explained by neutral drift. Moreover, there is frequent genetic parallelism across populations, suggesting that these mutations are under positive selection. Finally, functional analysis of mutations suggests that regulatory mutations are frequent targets of selection. IMPORTANCE Prolonged stationary phase in bacteria, contrary to its name, is highly dynamic, with extreme nutrient limitation as a predominant stress. Stationary-phase cultures adapt by rapidly selecting a mutation(s) that confers a growth advantage in stationary phase (GASP). The phenotypic diversity of starving E. coli populations has been studied in detail; however, only a few mutations that accumulate in prolonged stationary phase have been described. This study documented the spectrum of mutations appearing in Escherichia coli during 28 days of prolonged starvation. The genetic diversity of the population increases over time in stationary phase to an extent that cannot be explained by random, neutral drift. This suggests that prolonged stationary phase offers a great model system to study adaptive evolution by natural selection. PMID- 28567444 TI - Toxoplasma gondii MAF1b Binds the Host Cell MIB Complex To Mediate Mitochondrial Association. AB - Many diverse intracellular pathogens, such as Legionella pneumophila, Chlamydia psittaci, Encephalitozoon sp., and Toxoplasma gondii, manipulate and relocate host cell organelles, including mitochondria. Toxoplasma tachyzoites use a secreted protein, mitochondrial association factor 1b (MAF1b), to drive the association between the host mitochondria and the membrane of the parasitophorous vacuole, in which the parasites grow. The identity of the host partner in this interaction, however, has not previously been identified. By exogenously expressing tagged MAF1b in mouse embryonic fibroblasts, we were able to isolate host cell proteins that specifically interact with MAF1b. We then verified these interactions in the MAF1b-expressing fibroblasts, as well as in the context of parasite infection in human fibroblasts and HeLa cells. The results show that a host cell mitochondrial complex, the mitochondrial intermembrane space bridging (MIB) complex, specifically interacts with MAF1b. We further demonstrate that a version of MAF1b that is deficient in host-mitochondrial association does not efficiently coprecipitate the MIB complex. Validation of the importance of the MAF1b-MIB interaction came from showing that knockdown of two MIB complex components, MIC60 and SAM50, substantially reduces mitochondrial association with the parasitophorous vacuole membrane. This interaction between a secreted membrane-integral parasite protein and a membrane-bound complex of a host organelle represents the first instance of organelle relocalization in which both the host and pathogen molecules are known and provides the foundation for more detailed biochemical studies. IMPORTANCE Parasites interact intimately with their hosts, and the interactions shape both parties. The common human parasite Toxoplasma gondii replicates exclusively in a vacuole in a host cell and alters its host cell's environment through secreted proteins. One of these secreted proteins, MAF1b, acts to concentrate mitochondria around the parasite's vacuole, and this relocalization alters the host immune response. Many other intracellular pathogens also recruit host mitochondria, but the identities of the partners that mediate this interaction have not previously been described in any infection. Here, we show that Toxoplasma MAF1b binds to the multifunctional MIB protein complex on the host mitochondria. Reducing the levels of the proteins in this mitochondrial complex reduces the close association of host cell mitochondria and the parasite's vacuole. This work provides new insight into a key host-pathogen interaction and identifies possible targets for future therapeutic intervention as well as a more molecular understanding of important biology. PMID- 28567445 TI - Unique Features of Aeromonas Plasmid pAC3 and Expression of the Plasmid-Mediated Quinolone Resistance Genes. AB - A highly fluoroquinolone-resistant isolate of Aeromonas species was isolated from a wastewater treatment plant and found to possess multiple resistance mechanisms, including mutations in gyrA and parC, efflux pumps, and plasmid-mediated quinolone resistance (PMQR) genes. Complete sequencing of the IncU-type plasmid, pAC3, present in the strain revealed a circular plasmid DNA 15,872 bp long containing two PMQR genes [qnrS2 and aac(6')-Ib-cr]. A mobile insertion cassette element containing the qnrS2 gene and a typical miniature inverted-repeat transposable element (MITE) structure was identified in the plasmid. The present study revealed that this MITE sequence appears in other Aeromonas species plasmids and chromosomes. Plasmid pAC3 was introduced into Escherichia coli, and its PMQR genes were expressed, resulting in the acquisition of resistance. Proteome analysis of the recipient E. coli strain harboring the plasmid revealed that aac(6')-Ib-cr expression was constitutive and that qnrS2 expression was dependent upon fluoroquinolone stress through regulation by regulator of sigma D (Rsd). To the best of our knowledge, this is the first report to characterize a novel MITE sequence upstream of the PMQR gene within a mobile insertion cassette, as well as the regulation of qnrS2 expression. Our results suggest that this mobile element may play an important role in qnrS2 dissemination. IMPORTANCE In the present study, plasmid pAC3 isolated from a highly fluoroquinolone-resistant isolate of Aeromonas species was sequenced and found to contain two fluoroquinolone resistance genes, aac(6')-Ib-cr and qnrS2. Comparative analyses of plasmid pAC3 and other Aeromonas sp. IncU-type plasmids revealed a mobile insertion cassette element with a unique structure containing a qnrS2 gene and a typical miniature inverted-repeat transposable element (MITE) structure. This study also revealed that this MITE sequence appears in other Aeromonas species plasmids and chromosomes. Our results also demonstrate that the fluoroquinolone dependent expression of qnrS2 is associated with rsd in E. coli DH5alpha harboring plasmid pAC3. Our findings suggest that the mobile element may play an important role in qnrS2 dissemination and that Aeromonas species constitute an important reservoir of fluoroquinolone resistance determinants in the environment. PMID- 28567446 TI - Meta-analysis To Define a Core Microbiota in the Swine Gut. AB - The swine gut microbiota encompasses a large and diverse population of bacteria that play a significant role in pig health. As such, a number of recent studies have utilized high-throughput sequencing of the 16S rRNA gene to characterize the composition and structure of the swine gut microbiota, often in response to dietary feed additives. It is important to determine which factors shape the composition of the gut microbiota among multiple studies and if certain bacteria are always present in the gut microbiota of swine, independently of study variables such as country of origin and experimental design. Therefore, we performed a meta-analysis using 20 publically available data sets from high throughput 16S rRNA gene sequence studies of the swine gut microbiota. Next to the "study" itself, the gastrointestinal (GI) tract section that was sampled had the greatest effect on the composition and structure of the swine gut microbiota (P = 0.0001). Technical variation among studies, particularly the 16S rRNA gene hypervariable region sequenced, also significantly affected the composition of the swine gut microbiota (P = 0.0001). Despite this, numerous commonalities were discovered. Among fecal samples, the genera Prevotella, Clostridium, Alloprevotella, and Ruminococcus and the RC9 gut group were found in 99% of all fecal samples. Additionally, Clostridium, Blautia, Lactobacillus, Prevotella, Ruminococcus, Roseburia, the RC9 gut group, and Subdoligranulum were shared by >90% of all GI samples, suggesting a so-called "core" microbiota for commercial swine worldwide. IMPORTANCE The results of this meta-analysis demonstrate that "study" and GI sample location are the most significant factors in shaping the swine gut microbiota. However, in comparisons of results from different studies, some biological factors may be obscured by technical variation among studies. Nonetheless, there are some bacterial taxa that appear to form a core microbiota within the swine GI tract regardless of country of origin, diet, age, or breed. Thus, these results provide the framework for future studies to manipulate the swine gut microbiota for potential health benefits. PMID- 28567447 TI - Comparative Genomic Analysis Reveals Habitat-Specific Genes and Regulatory Hubs within the Genus Novosphingobium. AB - Species belonging to the genus Novosphingobium are found in many different habitats and have been identified as metabolically versatile. Through comparative genomic analysis, we identified habitat-specific genes and regulatory hubs that could determine habitat selection for Novosphingobium spp. Genomes from 27 Novosphingobium strains isolated from diverse habitats such as rhizosphere soil, plant surfaces, heavily contaminated soils, and marine and freshwater environments were analyzed. Genome size and coding potential were widely variable, differing significantly between habitats. Phylogenetic relationships between strains were less likely to describe functional genotype similarity than the habitat from which they were isolated. In this study, strains (19 out of 27) with a recorded habitat of isolation, and at least 3 representative strains per habitat, comprised four ecological groups-rhizosphere, contaminated soil, marine, and freshwater. Sulfur acquisition and metabolism were the only core genomic traits to differ significantly in proportion between these ecological groups; for example, alkane sulfonate (ssuABCD) assimilation was found exclusively in all of the rhizospheric isolates. When we examined osmolytic regulation in Novosphingobium spp. through ectoine biosynthesis, which was assumed to be marine habitat specific, we found that it was also present in isolates from contaminated soil, suggesting its relevance beyond the marine system. Novosphingobium strains were also found to harbor a wide variety of mono- and dioxygenases, responsible for the metabolism of several aromatic compounds, suggesting their potential to act as degraders of a variety of xenobiotic compounds. Protein-protein interaction analysis revealed beta-barrel outer membrane proteins as habitat specific hubs in each of the four habitats-freshwater (Saro_1868), marine water (PP1Y_AT17644), rhizosphere (PMI02_00367), and soil (V474_17210). These outer membrane proteins could play a key role in habitat demarcation and extend our understanding of the metabolic versatility of the Novosphingobium species. IMPORTANCE This study highlights the significant role of a microorganism's genetic repertoire in structuring the similarity between Novosphingobium strains. The results suggest that the phylogenetic relationships were mostly influenced by metabolic trait enrichment, which is possibly governed by the microenvironment of each microbe's respective niche. Using core genome analysis, the enrichment of a certain set of genes specific to a particular habitat was determined, which provided insights on the influence of habitat on the distribution of metabolic traits in Novosphingobium strains. We also identified habitat-specific protein hubs, which suggested delineation of Novosphingobium strains based on their habitat. Examining the available genomes of ecologically diverse bacterial species and analyzing the habitat-specific genes are useful for understanding the distribution and evolution of functional and phylogenetic diversity in the genus Novosphingobium. PMID- 28567449 TI - Mirizzi syndrome: a new insight provided by a novel classification. AB - BACKGROUNDS/AIMS: Mirizzi syndrome (MS) is an uncommon complication of cholelithiasis. The aim of this study is to evaluate our 15-year experience in this challenging entity and to propose a new classification for this disease. METHODS: A retrospective study including patients diagnosed with Mirizzi syndrome and undergoing surgical procedures for Mirizzi syndrome between January 2000 and October 2015 was conducted. Data collected included clinical, surgical procedure, postoperative morbidity. Patients were evaluated according to the Csendes classification and the proposed system, in which patients were divided into three types and three subtypes. RESULTS: 28 patients were included for analysis. They accounted as the 0.5% of a total of 4853 cholecystectomies performed in the study period. There were 21 women and 7 men. Initial laparotomic approach was performed in 12 patients and in 16 patients laparoscopic procedures were attempted. The procedure was completed in only 6 patients, 5 presenting type I and 1 type II Mirizzi syndrome. Mean postoperative stay was 15+/-9 days. Postoperative morbidity rate was 28%. Postoperative mortality was none. CONCLUSIONS: Laparoscopic surgery for Mirizzi syndrome has been shown succesful only in early stages. A novel classification is proposed, based on the types of common bile duct injuries and in the presence cholecystoenteric fistula. PMID- 28567448 TI - Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome. AB - Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and systemic glucose dysregulation. However, the immunological factors supporting these processes are poorly understood. We found that the liver accumulates pathogenic CD8+ T cell subsets which control hepatic insulin sensitivity and gluconeogenesis during diet-induced obesity in mice. In a cohort of human patients, CD8+ T cells represent a dominant intrahepatic immune cell population which links to glucose dysregulation. Accumulation and activation of these cells are largely supported by type I interferon (IFN-I) responses in the liver. Livers from obese mice upregulate critical interferon regulatory factors (IRFs), interferon stimulatory genes (ISGs), and IFNalpha protein, while IFNalphaR1-/- mice, or CD8-specific IFNalphaR1-/- chimeric mice are protected from disease. IFNalphaR1 inhibitors improve metabolic parameters in mice, while CD8+ T cells and IFN-I responses correlate with NAFLD activity in human patients. Thus, IFN-I responses represent a central immunological axis that governs intrahepatic T cell pathogenicity during metabolic disease. PMID- 28567451 TI - Robotic-assisted right hepatectomy via anterior approach for intrahepatic cholangiocarcinoma. AB - Major hepatic resection, especially right hepatectomy, has been successfully performed by specialized hepatobiliary centers using the robotic platform with low morbidity, conversion rates and outcomes comparable to laparoscopic and open surgery. The authors report a case of robotic-assisted right hepatectomy done for intrahepatic cholangiocarcinoma using anterior approach, after right portal vein embolisation for future liver remnant volume enhancement. PMID- 28567450 TI - Central pancreatectomy: an oncologically safe option to treat metastases of other neoplasms of the mid-portion of the pancreas? AB - BACKGROUNDS/AIMS: Standard pancreatic resections are the current approach for patients with resectable, isolated pancreatic metastases of other neoplasms. However, the role of parenchyma-sparing pancreatectomies for such pathology is poorly investigated. The aim of the present study is to assess the oncological safety of central pancreatectomies for pancreatic metastases of other neoplasms. METHODS: A literature search was performed in order to identify patients with central pancreatectomies for pancreatic metastases of other neoplasms. The available data of the patients were extracted and analyzed. RESULTS: A total number of 16 patients were identified. Renal carcinoma was the primary origin for the largest number of these patients (11 patients - 69%). The mean overall survival time was 109 months, with 1-, 5- and 10-year survival rates of 100%, 84%, and 60%, respectively. CONCLUSIONS: Although not often performed, a central pancreatectomy appears to be an oncologically safe surgical procedure in select patients with pancreatic metastases of other neoplasms of the pancreatic body and isthmus. However, no definitive conclusions should be drawn, based on the data provided in the present study, due to the limited number and heterogeneity of the patients. PMID- 28567452 TI - Laparoscopic cholecystectomy in a case of situs inversus totalis: a review of technical challenges and adaptations. AB - Situs inversus totalis is a rare congenital condition, characterized by the transposition of the thoracic and abdominal viscera, resulting in a mirror image of normal anatomy. Even though situs inversus does not predispose to gall stones, a laparoscopic cholecystectomy, in a case of situs inversus, can prove to be a technically challenging procedure, especially for the right-handed surgeon. In this case report, we present an unusual case of cholelithiasis in a patient with situs inversus totalis. A laparoscopic cholecystectomy, which is considered the gold standard procedure for symptomatic gallstones, was performed. The technical challenges that were anticipated due to anatomical anomalies were managed by various preoperative and intraoperative modifications. Through this present case report, we concluded that a laparoscopic cholecystectomy is a feasible and safe procedure in patients with situs inversus totalis and can be precisely performed by a right-handed surgeon, with necessary adaptations. PMID- 28567453 TI - Hemobilia due to arteriobiliary fistula complicating ERCP for residual bile duct stone in a case of Mirizzi syndrome. AB - Hemobilia is a rare cause of upper gastrointestinal tract bleeding. Most cases are iatrogenic following medical interventions, most commonly liver biopsy and transhepatic cholangiography. We present a case of arteriobiliary fistula between the right hepatic artery and the common hepatic duct, in a case of Mirrizi syndrome, following endoscopic biliary stenting and presenting with hemobilia. The patient was treated by surgical disconnection of the fistula, ligation of the right hepatic artery, and bilioenteric anastomosis. PMID- 28567454 TI - Distal pancreatectomy with splenorenal shunt to preserve spleen in a cirrhotic patient. AB - At pancreatic ductal adenocarcinoma is an aggressive malignancy with a high recurrence rate. Due to its high potentials of local invasion and distant metastasis, surgical resection is the only means for possible long-term survival. Surgical treatment comprises a distal pancreatectomy with or without splenectomy. Surgery has been conventionally contraindicated for patients with cirrhosis and portal vein hepato-biliary hypertension. Splenorenal shunt was first described by Warren and colleagues, to prevent death from bleeding esophageal varices in a patient with a patent portal vein hypertension. A 55-year-old Caucasian woman presented with an incidental pancreatic tumor. In our case, the shunt was necessary to complete the corrective oncological surgery for pancreatic ductal adenocarcinoma. The main difficulty was the presence of portal hypertension due to liver cirrhosis Child A; moreover, preservation of the spleen was mandatory in this patient. We successfully performed a distal pancreatectomy without splenectomy through the help of splenorenal shunt to preserve venous circulation. PMID- 28567455 TI - Laparoscopic total pancreatectomy for multiple metastasis of renal cell carcinoma of the pancreas: a case report and literature review. AB - Advances in surgical techniques and laparoscopic instruments have resulted in the development of laparoscopic pancreatic surgery. Total pancreaticoduodenectomy is performed for treating benign and borderline pancreatic disease involving the whole pancreas. Here, we report a case of metastatic renal cell carcinoma in the pancreas, treated by laparoscopic pylorus-preserving total pancreaticoduodenectomy. A 59-year-old woman was diagnosed with metastatic renal cell carcinoma. Multiple metastatic lesions were found on routine follow-up. She had a history of radical video-assisted right-nephrectomy for renal cell carcinoma (conventional type, pT1) in November 2003, without any recurrence. However, in 2014, a routine health checkup revealed multiple enhancing lesions throughout the pancreas. Positron emission tomography showed a suspicious 4-cm lesion in her left thyroid. Laparoscopic pylorus-preserving total pancreaticoduodenectomy with splenectomy was performed, along with simultaneous left total thyroidectomy with central compartment node dissection for metastatic renal cell carcinomas. The total operation time was 441 min, with an estimated blood loss of 150 ml; no transfusion was administered. Her hospital stay was 12 days. The histopath report confirmed metastatic renal cell carcinoma in the pancreas and left thyroid. Based on literature reviews, we further tried to estimate the oncologic outcome of total pancreatectomy in multiple pancreatic metastasis of renal cell carcinoma. Laparoscopic pylorus-preserving total pancreaticoduodenectomy is feasible and safe, even in cases of metastatic renal cell carcinoma. PMID- 28567456 TI - Surgery for intractable pain in a patient with chronic pancreatitis complicated with biliary obstruction, portal vein stenosis and mesenteric venous collaterals. AB - Pancreatic head resection for chronic pancreatitis is a challenging procedure, in the presence of venous collaterals, cavernous transformation, extensive fibrosis or porto-mesenteric stenosis or thrombosis. We present a surgically treated patient for the intractable pain of chronic pancreatitis. Complications with biliary obstruction and portal vein stenosis/thrombosis resulted in cavernous transformation. A pancreaticoduodenectomy combined with portal vein resection was intended in a 51 year-old male, but the procedure was terminated due to the high risk associated with intraoperative bleeding. The surgical procedure was switched to a Frey procedure, wherein partial pancreatic head resection, drainage of the pancreatic canal and sufficient pain palliation, without an increased risk of intraoperative hemorrhage, was ensured. The procedure was successfully combined with bilio-enteric anastomosis. PMID- 28567457 TI - SIRT3-SOD2-ROS pathway is involved in linalool-induced glioma cell apoptotic death. AB - Glioma is the most prevalent type of adult primary brain tumor and chemotherapy of glioma was limited by drug-resistance. Linalool is an acyclic monoterpene alcohol possessing various pharmacological activities. The present study was conducted to evaluate the effect of linalool on glioma cell growth. The effect of linalool on cell viability in U87-MG cells was investigated and the results showed that linalool significantly reduced cell viability in a concentration- and time-dependent manner. In addition, exposure of the cells to linalool resulted in a concentration-dependent increase of TUNEL-stained cells, indicating the occurrence of apoptotic cell death. Linalool decreased mitochondrial oxygen consumption rate, increased the expression of Bax and Bak, reduced the expression of Bcl-2 and Bcl-xl, and increased the activities of caspase 3 and caspase 9, leading to increase of apoptosis. Linalool resulted in a concentration-dependent decrease of SOD activity but had no significant effect on mRNA and protein expression of SOD2. Moreover, linalool resulted in a significant increase of the expression of acetylated SOD2. The mRNA and protein expression of SIRT3 was significantly inhibited by linalool. Immunoblot analysis showed that there was an evident protein/protein interaction between SOD2 and SIRT3 under normal condition. Linalool treatment significantly decreased the interaction between SOD2 and SIRT3. Overexpression of SIRT3 significantly inhibited linalool-induced increase of mitochondrial ROS production and apoptotic cell death, and decrease of cell viability. In summary, the data demonstrated that linalool exhibited inhibitory effect on glioma cells through regulation of SIRT3-SOD2-ROS signaling. PMID- 28567458 TI - Encapsulation and solid state sequestration of gases by calix[6]arene-based molecular containers. AB - Two calix[6]arene-based molecular containers were synthesized in high yields. These containers can encapsulate small guests through a unique "rotating door" complexation process. The sequestration of greenhouse gases is clearly demonstrated. They can be stored in the solid state for long periods and released via dissolution of the inclusion complex. PMID- 28567460 TI - Ni and Cu-catalyzed one pot synthesis of unsymmetrical 1,3-di(hetero)aryl-1H indazoles from hydrazine, o-chloro (hetero)benzophenones, and (hetero)aryl bromides. AB - The nickel-catalyzed cyclization of in situ generated ortho-chlorobenzophenone hydrazone derivatives, to afford 3-(hetero)aryl-1H-indazoles, is documented for the first time. The product 1H-indazoles can be transformed subsequently in a one pot procedure into 1,3-di(hetero)aryl-1H-indazoles via copper-catalyzed N arylation with (hetero)aryl bromides. PMID- 28567459 TI - Identification of new DNA i-motif binding ligands through a fluorescent intercalator displacement assay. AB - i-Motifs are quadruplex DNA structures formed from sequences rich in cytosine and held together by intercalated, hemi-protonated cytosine-cytosine base pairs. These sequences are prevalent in gene promoter regions and may play a role in gene transcription. Targeting these structures with ligands could provide a novel way to target genetic disease but there are very few ligands which have been shown to interact with i-motif DNA. Fluorescent intercalator displacement (FID) assays are a simple way to screen ligands against DNA secondary structures. Here we characterise how thiazole orange interacts with i-motif DNA and assess its ability for use in a FID assay. Additionally, we report FID-based ligand screening using thiazole orange against the i-motif forming sequence from the human telomere to reveal new i-motif binding compounds which have the potential for further development. PMID- 28567461 TI - A greener and efficient access to substituted four- and six-membered sulfur bearing heterocycles. AB - The regioselective functionalization of four- and six-membered cyclic sulfones was investigated using a lithiation/electrophile trapping strategy. The protocol features an interesting eco-compatibility profile because of the use of 2-MeTHF as a solvent (more eco-friendly than other organic solvents) and n-hexyllithium as a lithiating agent safer than other alkyllithium compounds. Several derivatives were prepared with different stereochemistry and substitution patterns. A number of selected derivatives, spanning a range of 5 log P units, were characterized for their lipophilicity through RP-HPLC. A good linear correlation, with a slope close to 1.0, was observed between the experimentally determined RP-HPLC lipophilicity parameters (log k'w) and calculated log P (clog P) values, whereas a systematic difference in absolute values between the chromatographic parameters and in silico lipophilicity descriptors can be attributed mainly to silanophilic interactions between the H-bond acceptor SO2 group and free silanol groups on silica-based C18 columns, which results in increased retention times. PMID- 28567462 TI - Surface-induced assembly of sophorolipids. AB - The surface self-assembly properties of acidic sophorolipids, a bolaform microbial glycolipids with pH-responsive properties in solution, were studied based on the chemical nature of the support and pH of the solution. Sophorolipids generally form micelles in water but formation of morphologies like platelets and twisted fibers depending on pH have also been reported. The surface self-assembly was achieved using dip-coating on three different substrates namely gold, silicon(111) and TiO2 anatase. Deposition conditions (dip-coating withdrawal speed, relative humidity, temperature) were tested, and it was found that optimum self-assembly occurs at a withdrawal speed of 1 mm s-1, T of 25 degrees C and relative humidity of 25%. The local structure of the sophorolipid films was characterized by atomic force microscopy, while scanning electron microscopy was used to characterize the spatial homogeneity. We also attempted to correlate dispersive, electron donor and electron attractor surface energy components, using Good-van Oss's approach, and the behavior of sophorolipids. We found that when the surface energy is dominated by dispersive components, sophorolipids spontaneously assemble into entangled needles at all pH values (4, 6 and 11). However, when the surface energy is dominated by electronic components, pH has a strong influence on the surface self-assembly. We could discriminate three major organizations: homogeneous layer, isolated aggregates and a two-dimensional fibrillar network. PMID- 28567463 TI - Relaxation-encoded NMR experiments for mixture analysis: REST and beer. AB - A new family of NMR experiments for mixture analysis (Relaxation-Encoded Selective TOCSY, REST) allows the extraction of component subspectra from mixtures. It uses isotropic mixing to label whole spin systems with the relaxation times (e.g. T1, T2) of individual spins. PMID- 28567464 TI - A facile synthesis of sulfonylureas via water assisted preparation of carbamates. AB - A novel and simple approach to the synthesis of sulfonylureas has been reported. It involved the reaction of various amines with diphenyl carbonate to yield the corresponding carbamates, which subsequently reacted with different sulphonamides to produce different sulfonylureas in excellent yields. The first reaction of diphenyl carbonate with amines was carried out in aqueous : organic (H2O : THF, 90 : 10) medium at room temperature to produce carbamates that paved a straightforward route to sulfonylureas after reaction with sulfonamides. The above process avoided traditional multistep protocols and the use of hazardous, irritant, toxic and moisture sensitive reagents such as phosgene, isocyanates and/or chloroformates. PMID- 28567465 TI - Metal-free regioselective formation of C-N and C-O bonds with the utilization of diaryliodonium salts in water: facile synthesis of N-arylquinolones and aryloxyquinolines. AB - Regioselective construction of crucial C-N and C-O bonds leading to N arylquinolones and aryloxyquinolines has been accomplished by employing easily accessible diaryliodonium salts and quinolones in water under metal- and ligand free conditions. This operationally simple strategy is significant due to mild reaction conditions, high product yields, recyclability of released iodoarenes and scalability to the gram level. The practical utility of the developed protocol was proved by the arylation of medicinally important heterocycles like acridin-9(10H)-one, 3-methylquinoxalin-2(1H)-one and 1H-benzo[d]imidazol-2(3H) one. PMID- 28567466 TI - Application of primary halogenated hydrocarbons for the synthesis of 3-aryl and 3 alkyl indolizines. AB - Indolizine is an important heterocyclic compound with several interesting properties that make it suitable for numerous applications in many fields, such as biology, medicine and materials. However, the synthesis of 3-alkyl indolizines from bulky primary halogenated alkanes has not yet been reported. Herein, a transition-metal-free synthetic route to 3-aryl and 3-alkyl indolizines from electron-deficient alkenes, pyridines and primary halogenated hydrocarbons has been reported for the first time using a tandem reaction. The key step of this method is the oxidative dehydrogenative aromatization of a tetrahydroindolizine intermediate with 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) as the oxidant. The advantages of this protocol are its use of easily available and low-cost starting materials, the transition-metal-free conditions and its ready scalability. PMID- 28567467 TI - Endomorphin-1 analogs containing alpha-methyl-beta-amino acids exhibit potent analgesic activity after peripheral administration. AB - This study describes the design and synthesis of endomorphin-1 analogs containing C-terminal aromatic alpha-methyl-beta-amino acids and an N-terminal native tyrosine or 2,6-dimethyl-tyrosine. We show that, in comparison with the parent peptide, these analogs exhibit improved bioactivity and blood-brain barrier penetration after intravenous administration, and have a lower tendency to induce constipation and sedation than morphine. PMID- 28567473 TI - Body Contouring After Massive Weight Loss: A Personal Integrated Approach. AB - BACKGROUND: After massive weight loss, patients typically presented with skin redundancy, which causes enormous esthetic, physical, medical and psychological problems. The growing number of patients with these sequelae triggered an increase in the search for body contouring procedures, which in turn produced an important development in the post-bariatric reconstructive surgery. METHODS: The author describes the principles of a personal approach in post-bariatric reconstructive surgery. The concept is based on an integrative approach, attending to multiple anatomic segments in the same procedure, associated with multiple refinements of the surgical technique. A retrospective study was carried out, including all body contouring procedures in massive weight loss patients performed by the author between January 2009 and December 2013. RESULTS: The sample is comprised of 74 patients, in a total of 120 surgeries, of which 70% were performed on the pelvic girdle and 30% on the scapular girdle. The most common complication noted by the author was small wound dehiscence. In 2011, the author began performing Pollock's technique in abdominoplasty, with fixation stitches to the deep planes, and double-layer sutures, instead of single intra dermal suture. At the same time, he stopped using drains. Interestingly, the rate of complications, including hematoma, proved to be lower in this group of patients. DISCUSSION: The application of this integrated post-bariatric surgery concept enables multiple anatomic segment contouring in less surgical procedures, which in turn permits a more immediate final result, associated with lower hospitalization times and lower complication rates. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28567474 TI - Impending Facial Skin Necrosis and Ocular Involvement After Dermal Filler Injection: A Case Report. AB - Demand for non-surgical rejuvenating procedure is constantly increasing due to the aging population, increasing expense of aesthetics and beauty procedures, introduction of new applications and rising demand for noninvasive aesthetic procedures over surgical procedures. Skin necrosis is a rare but severe potential complication. It is caused by impediment of the blood supply to the skin area by compression and/or obstruction of the vessel with filler material, and/or direct injury to the vessel. We report the case of a young patient who presented an acute and severe complication after a dermal filler injection by an unlicensed therapist. High-dose corticosteroids i.v. therapy among others helped in the process of healing. Skin necrosis left the patient with a full thickness scar on the forehead region. Dermal fillers are to be considered safe only when handled by trained doctors. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28567475 TI - Interface Between Cosmetic and Migraine Surgery. AB - This article describes connections between migraine surgery and cosmetic surgery including technical overlap, benefits for patients, and why every plastic surgeon may consider screening cosmetic surgery patients for migraine headache (MH). Contemporary migraine surgery began by an observation made following forehead rejuvenation, and the connection has continued. The prevalence of MH among females in the USA is 26%, and females account for 91% of cosmetic surgery procedures and 81-91% of migraine surgery procedures, which suggests substantial overlap between both patient populations. At the same time, recent reports show an overall increase in cosmetic facial procedures. Surgical techniques between some of the most commonly performed facial surgeries and migraine surgery overlap, creating opportunity for consolidation. In particular, forehead lift, blepharoplasty, septo-rhinoplasty, and rhytidectomy can easily be part of the migraine surgery, depending on the migraine trigger sites. Patients could benefit from simultaneous improvement in MH symptoms and rejuvenation of the face. Simple tools such as the Migraine Headache Index could be used to screen cosmetic surgery patients for MH. Similarity between patient populations, demand for both facial and MH procedures, and technical overlap suggest great incentive for plastic surgeons to combine both. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28567476 TI - Malignization of a vestibular schwannoma 13 years after radiation therapy. AB - This article presents a case of malignant transformation of vestibular schwannoma 13 years after stereotactic radiation therapy, which lead to an acute life threatening condition. Although the observation is currently only based on case reports, an increasing number of these support the hypothesis that there is a relevant risk of malignant transformation in the long-term course of previously irradiated vestibular schwannomas. Therefore, long-term MRI follow-up should be considered. PMID- 28567477 TI - Thread lifting: a minimally invasive surgical technique for long-standing facial paralysis. AB - BACKGROUND: Chronic facial paralysis induces degenerative facial muscle changes on the involved side, thus, making the individual seem as older than their actual age. Furthermore, contralateral facial hypertrophy aggravates facial asymmetry. A thread-lifting procedure has been used widely for correction of a drooping or wrinkled face due to the aging process. In addition, botulinum toxin injection can be used to reduce facial hypertrophy. The aim of study was to evaluate the effectiveness of thread lifting with botulinum toxin injection for chronic facial paralysis. METHODS: A total 34 of patients with chronic facial paralysis were enrolled from March to October 2014. Thread lifting for elevating loose facial muscles on the ipsilateral side and botulinum toxin A for controlling the facial muscle hypertrophy on the contralateral side were conducted. Facial function was evaluated using the Sunnybrook grading system and dynamic facial asymmetry ratios 1 year after treatment. RESULTS: All 34 patients displayed improved facial symmetry and showed improvement in Sunnybrook scores (37.4 vs. 83.3) and dynamic facial asymmetry ratios (0.58 vs 0.92). Of the 34 patients, 28 (82.4%) reported being satisfied with treatment. CONCLUSION: The application of subdermal suspension with a reabsorbable thread in conjunction with botulinum toxin A to optimize facial rejuvenation of the contralateral side constitutes an effective and safe procedure for face lifting and rejuvenation of a drooping face as a result of long-lasting facial paralysis. PMID- 28567478 TI - betaIII-tubulin enhances efficacy of cabazitaxel as compared with docetaxel. AB - Cabazitaxel is a novel taxane approved for treatment of metastatic hormone refractory prostate cancer in patients pretreated with docetaxel. Cabazitaxel, docetaxel, and paclitaxel bind specifically to tubulin in microtubules, disrupting functions essential to tumor growth. High levels of betaIII-tubulin isotype expression are associated with tumor aggressivity and drug resistance. To understand cabazitaxel's increased efficacy, we examined binding of radio-labeled cabazitaxel and docetaxel to microtubules and the drugs' suppression of microtubule dynamic instability in vitro in microtubules assembled from purified bovine brain tubulin containing or devoid of betaIII-tubulin. We found that cabazitaxel suppresses microtubule dynamic instability significantly more potently in the presence of betaIII-tubulin than in its absence. In contrast, docetaxel showed no betaIII-tubulin-enhanced microtubule stabilization. We also asked if the selective potency of cabazitaxel on betaIII-tubulin-containing purified microtubules in vitro extends to cabazitaxel's effects in human tumor cells. Using MCF7 human breast adenocarcinoma cells, we found that cabazitaxel also suppressed microtubule shortening rates, shortening lengths, and dynamicity significantly more strongly in cells with normal levels of betaIII-tubulin than after 50% reduction of betaIII-tubulin expression by siRNA knockdown. Cabazitaxel also more strongly induced mitotic arrest in MCF7 cells with normal betaIII tubulin levels than after betaIII-tubulin reduction. In contrast, docetaxel had little or no betaIII-tubulin-dependent selective effect on microtubule dynamics or mitotic arrest. The selective potency of cabazitaxel on purified betaIII tubulin-containing microtubules and in cells expressing betaIII-tubulin suggests that cabazitaxel may be unusual among microtubule-targeted drugs in its superior anti-tumor efficacy in tumors overexpressing betaIII-tubulin. PMID- 28567481 TI - Analysis of sucrose-induced small RNAs in Streptococcus mutans in the presence of different sucrose concentrations. AB - Streptococcus mutans (S. mutans) is the major pathogen contributing to dental caries. Sucrose is an important carbohydrate source for S. mutans and is crucial for dental caries. Small RNAs (sRNAs) are key post-transcriptional regulators of stress adaptation and virulence in bacteria. Here, for the first time, we created three replicate RNA libraries exposed to either 1 or 5% sucrose. The expression levels of sRNAs and target genes (gtfB, gtfC, and spaP) related to virulence were assessed. In addition, some phenotypic traits were evaluated. We obtained 2125 sRNA candidates with at least 100 average reads in 1% sucrose or 5% sucrose. Of these candidates, 2 were upregulated and 20 were downregulated in 1% sucrose. Six of these 22 differentially expressed sRNAs were validated by qRT-PCR. The expression level of target gene gtfB was higher in 1% sucrose. The adherence ratio of S. mutans was higher in 1% sucrose than in 5% sucrose. The synthesis of water-insoluble glucans (WIGs) was significantly higher in 5% sucrose than in 1% sucrose. These data suggest that a series of sRNAs can be induced in response to sucrose, and that some sRNAs might be involved in the regulation of phenotypes, providing new insight into the prevention of caries. PMID- 28567480 TI - Soil bacterial community responses to revegetation of moving sand dune in semi arid grassland. AB - Grasslands in semi-arid Northern China are widely desertified, thus inducing the formation of a large area of moving sand lands. Revegetation of the sandy land is commonly adopted to restore degraded grasslands. The structure of the soil microbial community might dramatically change during degradation and recovery because microorganisms are one of the major drivers of ecological process through their interactions with plants and soil. Assuming that soil properties are the key determinants of the structure of soil bacterial community within the same soil type, whether the vegetation type causes the significant difference in the structure of soil bacterial community during revegetation and restoration of the degraded grasslands remains poorly understood. Our study aimed to (1) investigate the response of soil bacterial communities to the changes during vegetation degradation and recovery and (2) evaluate whether the soil bacterial communities under plantations return to their native state. We detected the shifts in diversities and compositions of the soil bacterial communities and the relative abundance of dominant bacterial taxa by using the high-throughput Illumina MiSeq sequencing technique in an area covered by 32-year-old Caragana microphylla, Artemisia halodendron, Hedysarum fruticosum, Pinus sylvestris var. mongolica, Populus simonii, and Salix gordejevii sand-fixing plantations and in the native community (NC) dominated by elm, and moving sandy dune (MS). We found that the obtained operational taxonomic units by 16S rRNA gene sequencing and diversity index in MS were all significantly lower than those in NC, and the number and composition of dominant genera were significantly different between NC and MS. Interestingly, the compositions of bacterial communities and the dominant genera in different sand-fixation plantations (C. microphylla, A. halodendron, H. fruticosum, P. sylvestris var. mongolica, P. simonii, and S. gordejevii) were all similar to those of the native soil of NC, suggesting that the plantation type and soil properties exhibit a minimal effect on the compositions of soil microbial communities within a continuous landscape. These results revealed that the structure of the soil bacterial community of degraded sandy grassland (even degenerated into a mobile sand dunes) in semi-arid region can be reversibly restored by planting indigenous shrub or semi-shrub plantation on human time scales. PMID- 28567482 TI - MALDI-TOF mass spectrometry for rapid differentiation of Tenacibaculum species pathogenic for fish. AB - Tenacibaculosis is a fish disease that limits the culture of a variety of marine fish species of commercial value in the world. The genus Tenacibaculum includes several species, and their discrimination is of clinical interest in order to improve the management of an outbreak of the disease. In this study, a novel proteomic approach based on matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF-MS) analysis was evaluated for the identification and differentiation of Tenacibaculum species. The peak mass lists derived from MALDI-TOF-MS analysis were examined for the detection of potential biomarkers, similarity and cluster analysis and principal component analysis (PCA). Culture media used for bacterial growth did not affect the mass fingerprints. Eight genus-specific peaks were found in all the Tenacibaculum species analysed. Moreover, at least one species-specific peak was found in the species Tenacibaculum maritimum, Tenacibaculum soleae, Tenacibaculum dicentrarchi, Tenacibaculum litoreum and Tenacibaculum ovolyticum. These peaks could serve as biomarkers for the rapid identification of these bacterial fish pathogens. The cluster and PCA clearly separated the species T. maritimum, T. soleae, T. dicentrarchi and T. ovolyticum in different clusters. However, species of Tenacibaculum discolor and Tenacibaculum gallaicum were difficult to distinguish based on their protein fingerprints. To our knowledge, this is the first study that deals with the characterization and determination of biomarkers of Tenacibaculum species by MALDI-TOF mass spectrometry. This approach proved to be an effective and reliable technique for the discrimination of the Tenacibaculum species; therefore, it could be integrated as a routine diagnostic tool in microbiological laboratories. PMID- 28567483 TI - [Gender Norms and Expertise : Constructions of Gender in Psychiatrists' Legal Opinions in Imperial Germany, 1871-1914]. AB - This article focuses on notions of gender in psychiatrists' expert opinions written for lawsuits during the German Empire, 1871-1914. Four different narratives concerning gender can be identified in these testimonies. On the one hand, the reports describe women and men who did not conform to the gender stereotypes of the time. The psychiatrists found the non-conformist defendants to be of unsound mind. On the other hand, women and men who did conform to the gender stereotypes were also described. In those cases, however, "feminine" women were certified insane, whereas "masculine" men were accused of simulating a mental disease in order to avoid punishment. These findings strengthen basic assumptions of Feminist Epistemology by showing that first, psychiatric ideas of accountability were closely linked to the norm of "masculine" men and second, a double standard was used in assessing the soundness of minds of women and men respectively. PMID- 28567479 TI - Sub1/PC4, a multifaceted factor: from transcription to genome stability. AB - Yeast Sub1 and human PC4, two DNA-binding proteins, were originally identified as transcriptional coactivators with a role during transcription preinitiation/initiation. Indeed, Sub1 is a PIC component, and both PC4 and Sub1 also influence the initiation-elongation transition. Moreover, in the specific case of Sub1, it has been clearly reported that it influences processes downstream during mRNA biogenesis, such as transcription elongation, splicing and termination, and even RNAPII phosphorylation/dephosphorylation. Although Sub1 mechanism of action has been mostly unknown up to date, thanks to the recent finding that Sub1 directly interacts with the RNAPII stalk domain, we can envision how it can modulate so many processes. In addition, Sub1 and PC4 participate in RNAPIII transcription as well, and much additional evidence indicates an evolutionarily conserved role for Sub1 and PC4 in the maintenance of genome stability. In this regard, the most novel function of Sub1 and PC4 has been related to the ability of these proteins to bind G-quadruplex DNA structures that may arise as a consequence of the transcription process. PMID- 28567484 TI - Measurement of liver and spleen interstitial volume in patients with systemic amyloid light-chain amyloidosis using equilibrium contrast CT. AB - OBJECTIVES: To investigate equilibrium contrast-enhanced CT (EQ-CT) measurement of extracellular volume fraction (ECV) in patients with systemic amyloid light chain (AL) amyloidosis, testing the hypothesis that ECV becomes elevated in the liver and spleen and ECV correlates with other estimates of organ amyloid burden. METHODS: 26 patients with AL amyloidosis underwent EQ-CT, and ECV was measured in the liver and spleen. Patients also underwent serum amyloid P (SAP) component scintigraphy with grading of liver and spleen involvement. Mann-Whitney U test was used to test for a difference between patients with amyloid deposition (SAP grade 1-3) and those without (SAP grade 0). Variation in ECV across SAP grades was assessed using the Kruskal-Wallis test and association between ECV and SAP grades with Spearman correlation. RESULTS: Mean ECV in the spleen and liver was significantly greater (p < 0.0005) in amyloidotic organs (SAP grade 1-3) [spleen, liver: 0.430, 0.375] compared with healthy tissues [spleen, liver: 0.304, 0.269]. ECV increased with increasing amyloid burden, showing positive correlation with SAP grade in both the liver (r = 0.758) and spleen (r = 0.867). CONCLUSION: In patients with systemic AL amyloidosis, EQ-CT can demonstrate increased spleen and liver ECV, which is associated with amyloid disease burden. PMID- 28567485 TI - Mucinous nonneoplastic cyst of the pancreas: CT and MRI appearances. AB - PURPOSE: The purpose of this retrospective study was to evaluate imaging features of mucinous nonneoplastic cyst (MNNC) of the pancreas. MATERIALS AND METHODS: Three (0.9%) patients with MNNC of the pancreas were found in 335 surgically resected pancreatic cystic lesions. Three MDCT and two MRI/MRCP studies were retrospectively reviewed. RESULTS: Three cases of MNNC were found in the pancreatic neck, body, and tail, respectively. All the three cases were multilocular without communication with the main pancreatic duct (MPD), although upstream MPD dilatation was seen in two of the three cases. The signal intensity of the cyst fluid was low on T1-weighted, high on T2-weighted, and low on diffusion-weighted images. Cyst wall was thin in two cases, and the remaining case with obstructive pancreatitis showed visible cyst wall enhancement. CONCLUSION: Imaging findings of MNNC of the pancreas were nonspecific without communication with the MPD. Cyst wall is typically thin without visible enhancement. PMID- 28567486 TI - Xenobiology: State-of-the-Art, Ethics, and Philosophy of New-to-Nature Organisms. AB - The basic chemical constitution of all living organisms in the context of carbon based chemistry consists of a limited number of small molecules and polymers. Until the twenty-first century, biology was mainly an analytical science and has now reached a point where it merges with engineering science, paving the way for synthetic biology. One of the objectives of synthetic biology is to try to change the chemical compositions of living cells, that is, to create an artificial biological diversity, which in turn fosters a new sub-field of synthetic biology, xenobiology. In particular, the genetic code in living systems is based on highly standardized chemistry composed of the same "letters" or nucleotides as informational polymers (DNA, RNA) and the 20 amino acids which serve as basic building blocks for proteins. The universality of the genetic code enables not only vertical gene transfer within the same species but also horizontal gene transfer across biological taxa, which require a high degree of standardization and interconnectivity. Although some minor alterations of the standard genetic code are found in nature (e.g., proteins containing non-conical amino acids exist in nature, and some organisms use alternated coding systems), all structurally deep chemistry changes within living systems are generally lethal, making the creation of artificial biological system an extremely difficult challenge.In this context, one of the great challenges for bioscience is the development of a strategy for expanding the standard basic chemical repertoire of living cells. Attempts to alter the meaning of the genetic information stored in DNA as an informational polymer by changing the chemistry of the polymer (i.e., xeno nucleic acids) or by changes in the genetic code have already yielded successful results. In the future this should enable the partial or full redirection of the biological information flow to generate "new" version(s) of the genetic code derived from the "old" biological world.In addition to the scientific challenges, the attempt to increase biochemical diversity also raises important ethical and philosophical issues. Although promotors of this branch of synthetic biology highlight the many potential applications to come (e.g., novel tools for diagnostics and fighting infection diseases), such developments could also bring risks affecting social, political, and other structures of nearly all societies. PMID- 28567487 TI - Synthetic Biology of Polyhydroxyalkanoates (PHA). AB - Microbial polyhydroxyalkanoates (PHA) are a family of biodegradable and biocompatible polyesters which have been extensively studied using synthetic biology and metabolic engineering methods for improving production and for widening its diversity. Synthetic biology has allowed PHA to become composition controllable random copolymers, homopolymers, and block copolymers. Recent developments showed that it is possible to establish a microbial platform for producing not only random copolymers with controllable monomers and their ratios but also structurally defined homopolymers and block copolymers. This was achieved by engineering the genome of Pseudomonas putida or Pseudomonas entomophiles to weaken the beta-oxidation and in situ fatty acid synthesis pathways, so that a fatty acid fed to the bacteria maintains its original chain length and structures when incorporated into the PHA chains. The engineered bacterium allows functional groups in a fatty acid to be introduced into PHA, forming functional PHA, which, upon grafting, generates endless PHA variety. Recombinant Escherichia coli also succeeded in producing efficiently poly(3 hydroxypropionate) or P3HP, the strongest member of PHA. Synthesis pathways of P3HP and its copolymer P3HB3HP of 3-hydroxybutyrate and 3-hydroxypropionate were assembled respectively to allow their synthesis from glucose. CRISPRi was also successfully used to manipulate simultaneously multiple genes and control metabolic flux in E. coli to obtain a series of copolymer P3HB4HB of 3 hydroxybutyrate (3HB) and 4-hydroxybutyrate (4HB). The bacterial shapes were successfully engineered for enhanced PHA accumulation. PMID- 28567488 TI - Early rebleeding of intracranial dural arteriovenous fistulas after an intracranial hemorrhage. AB - BACKGROUND: The aim of this study was to evaluate the clinical and angiographic characteristics of dural arteriovenous fistulas (DAVF) presenting with intracranial hemorrhage (ICH), with a focus on early rebleeding according to the initial hemorrhage type. METHOD: The clinical and radiologic features of 21 dAVFs that presented with intracranial hemorrhage were retrospectively reviewed. The hemorrhage type was classified as pure intraparenchymal hemorrhage (pIPH) and subarachnoid or subdural hemorrhage with IPH (non-pIPH). RESULTS: There were 13 patients with pIPH and 8 with non-pIPH. The median follow-up period was 30 months (range, 1-116 months), and the median interval from hemorrhage to treatment was 4 days (range, 0-72 days). Rebleeding occurred in 8 (38.1%) of 21 patients. Four (50%) of eight patients with non-pIPH suffered from early rebleeding within 3 days, while there was no early rebleeding in patients with pIPH. There was a significantly higher rate of early rebleeding in the non-pIPH group (p = 0.012). Angiographically, venous ectasia (p = 0.005) and direct cortical venous drainage (dCVD) (p = 0.008) showed a significantly higher proportion in the non-pIPH group than in the pIPH group. CONCLUSIONS: DAVFs with ICH is likely to rebleed after the first hemorrhage. Thus, early treatment can be needed in all DAVFs with ICH. In addition, DAVFs that presenting with non-pIPH and containing venous ectasia or dCVD on initial angiography may have a higher risk of early rebleeding. Therefore, cautious attention and urgent treatment are necessary for these patients. PMID- 28567489 TI - Discovery of two small circular ssDNA viruses associated with the whitefly Bemisia tabaci. AB - The complete genome sequences of two novel small circular DNA viruses isolated from sweet-potato whiteflies collected in central-West (AdDF) and Southeast (AdO) regions of Brazil were determined by Next Generation Sequencing (NGS), and confirmed by cloning and Sanger sequencing. The genomes are 2,199 and 2,211 nt long, respectively, encoding a putative coat protein (CP) and a replication associated protein (Rep) and showing a genomic organization typical of viruses from the family Genomoviridae. Phylogenetic analysis with deduced amino acid sequences of Rep indicates that the virus from AdO is closely related to other members of the genus Gemycircularvirus, while the virus from AdDF is distantly related to other genomovirus. It was thus classified in a putative new genus, for which the name "Gemybolavirus" is proposed. These new genomoviruses are tentatively named "Bemisia associated gemybolavirus AdDF", and "Bemisia associated gemycircularvirus AdO". PMID- 28567490 TI - Ventricular rate stabilization for treatment of recurrent VT. AB - A patient with ischaemic cardiomyopathy received a secondary prevention VVI implantable cardioverter-defibrillator (ICD) after an episode of sustained ventricular tachycardia (VT). Because of recurrent VTs transmitted via CareLink, medical therapy was optimized and VT ablation was performed. Subsequently, a fast VT with a typical short-long-short initiation developed. In addition, there was an increasing need for ventricular pacing due to sinus bradycardia. This new type of VT could be successfully dealt with by upgrading to DDD ICD and activating the Ventricular Rate Stabilization algorithm. PMID- 28567491 TI - Pathophysiology of ventricular tachyarrhythmias : From automaticity to reentry. AB - Ventricular arrhythmias are a heterogeneous group of arrhythmias and may arise in patients with cardiomyopathy or structurally normal hearts. The electrophysiologic mechanisms responsible for the initiation and maintenance of ventricular tachycardia include enhanced automaticity, triggered activity, and reentry. Differentiating between these three mechanisms can be challenging and usually requires an invasive electrophysiology study. Establishing the underlying mechanism in a particular patient is helpful to define the optimal therapeutic approach, including the selection of pharmacologic agents or delineation of an ablation strategy. PMID- 28567492 TI - In vitro modeling of unsaturated free fatty acid-mediated tissue impairments seen in acne lesions. AB - Acne vulgaris is a disease of pilosebaceous units with multifactorial pathogenesis, including hyperkeratinization, increased sebum secretion, and inflammation. Recently, it was suggested that acne subjects may have also impaired skin barrier. We hypothesized that excess unsaturated free fatty acids (UFFA) present in the sebum may cause barrier impairment associated with increased follicular stratum corneum (SC) thickening and inflammation seen in acne. Therefore, epidermal and sebaceous lipid profiles from acne and healthy subjects were analyzed and an in vitro epidermal tissue model was developed to validate this hypothesis. Significantly increased levels of free fatty acids (p < 0.05) were observed in skin lipids of human acne vs. healthy subjects. Exposure of human epidermal equivalents (HEEs) to the UFFA oleic acid (OA), also present in sebum, led to barrier impairment associated with increased SC lipid disorder, increased secretion of interleukin-1alpha (IL-1alpha), and excessive SC thickening. Furthermore, the expression of genes encoding for inflammatory cytokines and epidermal differentiation proteins was also increased both in acne lesions and in OA-treated HEEs. Taken together, these data are in agreement with the hypothesis that excess UFFAs in sebum of acne subjects may contribute to impaired skin barrier associated with the increased follicular SC thickness and inflammation seen in acne. Moreover, OA induces similar molecular and phenotypic changes in HEEs as those seen in acne lesions and suggests that an UFFA-treated epidermal tissue model can be used to study the UFFA-mediated pathways involved in the pathogenesis of inflammatory acne and for the development of appropriate therapies. PMID- 28567493 TI - Epidemiologic features of 348 children with hepatitis C virus infection over a 30 year period: a nationwide survey in Japan. AB - BACKGROUND: Although the epidemiology of hepatitis C virus (HCV) infection among children may be rapidly changing, few reports have characterized large nationwide cohorts of children with HCV infection. We, therefore, sought to clarify the epidemiology and natural history of HCV infection in Japanese children born over the last three decades. METHODS: Sixty-five pediatric centers retrospectively and prospectively recruited consecutive, otherwise-healthy HCV-infected children born during 1986 to 2015. RESULTS: Entry criteria were met by 348 children. Age at initial diagnosis of infection has decreased significantly in recent years. Cirrhosis and hepatocellular carcinoma were not identified. Prevalence of spontaneous clearance and of interferon treatment with/without ribavirin were 9 and 54%, respectively. Maternal transmission has increased significantly, representing over 99% of cases in the last decade. No transfusion-related cases have been seen after 1994. HCV genotype 2 has increased to become the most prevalent in Japanese children. Histopathology examination of liver specimens showed no or mild fibrosis in most children with chronic hepatitis C; none showed cirrhosis. CONCLUSIONS: This largest nationwide cohort study of Asian children with HCV infection spanned the last three decades. None of these Japanese children developed cirrhosis or hepatocellular carcinoma. Maternal transmission increased to account for 99% of cases during the last decade. Genotype 2 now is most prevalent in these children. Histopathologically, most children with chronic hepatitis C showed mild fibrosis or none. PMID- 28567495 TI - Integrated 18F-FDG PET/MRI compared to MRI alone for identification of local recurrences of soft tissue sarcomas: a comparison trial. AB - PURPOSE: To assess and compare the diagnostic accuracy of PET/MRI and MRI alone for the detection of local recurrences of soft tissue sarcomas (STS) after initial surgical resection of the primary tumors. MATERIAL AND METHODS: A total of 41 patients with clinically suspected tumor relapse of STS underwent an 18F FDG-PET/MRI examination for assessment of local recurrence. Two experienced physicians interpreted the MRI data and subsequently the PET/MRI datasets in two separate reading sessions and were instructed to identify potential local tumor recurrences. Additionally, the diagnostic confidence in each reading for the identification of malignant lesions was determined. A McNemar test was applied to test for differences of both ratings and a Wilcoxon signed-rank test was used to identify differences of the confidence levels. Histopathological verification and follow-up imaging were applied for standard of reference. RESULTS: Tumor relapse was present in 27/41 patients. Calculated sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy for the detection of local tumor recurrence was 82%, 86%, 92%, 71% and 83% for MRI, and 96%, 79%, 90%, 92% and 90% for PET/MRI (p > 0.05). Furthermore, PET/MRI showed significantly higher confidence levels (p < 0.05) for the determination of malignant lesions. CONCLUSION: Our results endorse 18F-FDG PET/MRI to be an excellent imaging method in the evaluation of recurrent STS after surgical excision, yielding superior tumor detection when compared to MRI alone. PMID- 28567496 TI - Manifestation of meibomian gland dysfunction in patients with Sjogren's syndrome, non-Sjogren's dry eye, and non-dry eye controls. AB - PURPOSE: To evaluate the manifestation of meibomian gland dysfunction in patients with Sjogren's syndrome (SS), non-Sjogren's syndrome dry eye (non-SS) patients, and non-dry eye controls. METHODS: We recruited 31 participants with SS dry eye, 30 participants with non-SS dry eye, and 35 healthy controls without dry eye symptoms. Noninvasive tear breakup time (NITBUT) and meibomian gland dropout score (meiboscore) were measured using the Oculus Keratograph 5 M. Meibomian gland expressibility and secretion quality were evaluated via slit lamp biomicroscopy. The correlation between measurements was analyzed. RESULTS: NITBUT was lower, and the meiboscore, meibomian gland expressibility, and secretion quality scores were significantly higher in the SS and non-SS groups than in the control group (p < 0.001). NITBUT was lower, and the meiboscore and meibomian gland expressibility were higher in the SS group than in the non-SS group. NITBUT correlated negatively with the meiboscore in both SS and non-SS groups and with meibomian gland expressibility in the SS group. A positive correlation was obtained between meiboscore and meibomian gland expressibility in both the SS and the non-SS groups. CONCLUSION: Patients in both SS and non-SS groups exhibited greater impairment in meibomian gland function than the non-dry eye controls. SS patients had more severe meibomian gland dysfunction with poorer mean meiboscore and meibomian gland expressibility than non-SS patients. PMID- 28567494 TI - Therapy assessment of bone metastatic disease in the era of 223radium. AB - PURPOSE: Defining an optimal imaging modality for assessment of therapy and the best time of evaluation are pivotal for ideal patient's management. METHODS: 223Ra (Xofigo(r), formerly Alpharadin) has been approved by the FDA and European Medicines Agency for treatment of metastatic castration-resistant prostate cancer with painful osseous involvement. RESULTS: PET/CT imaging using various radiotracers such as 18F-FDG, 18F-FCH, 68Ga-PSMA and 18F-NaF have been investigated to mitigate the limitations of conventional imaging modalities. Diagnostic radiotracers that have properties similar to a therapeutic radiotracer will precisely assess of the possibility and efficacy of a treatment; this is the theranostic concept. An example of a diagnostic test employed for selecting targeted therapy is the combined use of 18F-fluoride PET/CT for evaluation of possible therapy with 223Ra. CONCLUSION: This review examines the most recent publications related to this topic. PMID- 28567498 TI - Metabolic, behavioral, and locomotive effects of feeding in five cyprinids with different habitat preferences. AB - Fish generally perform routine swimming behaviors during food digestion; thus, changes in swimming performance and adjustments to spontaneous behavior resulting from digestion can have important ecological significance for wild fishes. The effects of feeding on metabolism, spontaneous activity, fast-start escape movement, and critical swimming speed (U crit) were investigated in five cyprinids with different habitat preferences, specifically the Chinese crucian carp (Carassius auratus), common carp (Cyprinus carpio), black carp (Mylopharyngodon piceus), Chinese bream (Parabramis pekinensis), and qingbo (Spinibarbus sinensis). Generally, species in still water exhibited increased feeding metabolism, whereas species in flowing water showed higher spontaneous activity and locomotion performance. Digestion had no significant effects on either spontaneous activity or fast-start escape movement in the five cyprinids. These results could be due to the small meal sizes (approximately 2% body mass) and active foraging modes of cyprinids. The changes in aerobic swimming performance due to feeding were more complex. No effect of digestion on U crit was observed in crucian carp (still water, high feeding metabolism, and low U crit), common carp (widely distributed, high feeding metabolism, and high U crit), and qingbo (flowing water, low feeding metabolism, and high U crit), but digestion resulted in a significant decrease in the U crit of Chinese bream (moderate feeding metabolism but high U crit) and black carp (moderate feeding metabolism and low U crit), suggesting no connection between postprandial U crit changes and feeding metabolism (or between U crit and preferred habitat). The maximum metabolic rate (MMR) of common carp and crucian carp increased after feeding, whereas the corresponding values for the other three cyprinids remained the same. The oxygen uptake capacity appears to meet the oxygen demand of both aerobic swimming and digestion in common carp and crucian carp, whereas qingbo sacrifices digestion for locomotion, and black carp and Chinese bream sacrifice locomotion for digestion under postprandial swimming conditions. The locomotion priority mode of qingbo is adaptive to its active foraging mode in the demanding swimming habitat of rapidly flowing water, whereas the high respiratory capacities of postprandial crucian carp and common carp and hence the maintenance of their aerobic swimming performances might be a by-product of natural selection for hypoxia tolerance rather than for swimming speed. PMID- 28567497 TI - Experimental Sepsis Severity Score Associated to Mortality and Bacterial Spreading is Related to Bacterial Load and Inflammatory Profile of Different Tissues. AB - Pneumonia-induced sepsis is responsible for about 50% of cases in the world. Patients who develop severe sepsis and septic shock present organ dysfunction and elevated plasma cytokine levels, which may lead to death. Clinical scores are important to evaluate the framework of septic patients and are used to predict the syndrome progress, prognostics, and mortality. The objective of the present study was to verify the applicability of a murine clinical score system to experimental sepsis (pneumonia-induced sepsis in male mice) and to correlate it with mortality and bacterial dissemination in different organs. Results demonstrated that animals which present higher clinical scores (>3) are more likely to die. Animals presenting high clinical scores exhibited transient bacteremia and displayed bacterial spreading to different organs such as heart, kidney, liver, and brain. There is a correlation between clinical score and bacterial dissemination and consequently greater risk of death. In addition, animals which showed bacterial dissemination in more than three organs and high clinical scores presented high levels of cytokines (TNF-alpha, MCP-1, IL-6, and IL-10) in plasma, lung, heart, liver, kidney, and brain. Therefore, our study suggests that (1) severity scores have predictive power in experimental models of sepsis and (2) high concentrations of tissue cytokines may contribute to localized inflammation and be one of the factors responsible for the systemic inflammatory syndrome of sepsis. PMID- 28567499 TI - Synergistic effects of temperature and humidity on the symptoms of COPD patients. AB - This panel study investigates how temperature, humidity, and their interaction affect chronic obstructive pulmonary disease (COPD) patients' self-reported symptoms. One hundred and six COPD patients from Shanghai, China, were enrolled, and age, smoking status, St. George Respiratory Questionnaire (SGRQ) score, and lung function index were recorded at baseline. The participants were asked to record their indoor temperature, humidity, and symptoms on diary cards between January 2011 and June 2012. Altogether, 82 patients finished the study. There was a significant interactive effect between temperature and humidity (p < 0.0001) on COPD patients. When the indoor humidity was low, moderate, and high, the indoor temperature ORs were 0.969 (95% CI 0.922 to 1.017), 0.977 (0.962 to 0.999), and 0.920 (95% CI 0.908 to 0.933), respectively. Low temperature was a risk factor for COPD patients, and high humidity enhanced its risk on COPD. The indoor temperature should be kept at least on average at 18.2 degrees C, while the humidity should be less than 70%. This study demonstrates that temperature and humidity were associated with COPD patients' symptoms, and high humidity would enhance the risk of COPD due to low temperature. PMID- 28567501 TI - Erratum to: Extrapyramidal symptoms after exposure to calcium channel blocker flunarizine or cinnarizine. PMID- 28567500 TI - Treatment of Sleep Dysfunction in Parkinson's Disease. AB - OPINION STATEMENT: Impaired sleep and alertness affect the majority of Parkinson's disease (PD) patients, negatively impacting safety and quality of life. The etiology of impaired sleep-wake cycle in PD is multifactorial and encompasses medication side effects, nocturnal PD motor symptoms, and presence of co-existent sleep and neuropsychiatric disorders. The primary neurodegenerative process of PD involves brain regions that regulate the sleep-wake cycle, such as brainstem and hypothalamic nuclei. Sleep disorders in PD include insomnia, REM sleep behavior disorder (RBD), sleep disordered breathing (SDB), restless legs syndrome (RLS), and circadian disruption. Despite its high prevalence in the PD population, there is a paucity of clinical studies that have investigated treatment of sleep dysfunction associated with PD. Therefore, we aim to review available evidence and outline treatment strategies for improvement of disorders of sleep and wakefulness in PD patients. Evidence supporting the efficacy of pharmacological and non-pharmacological treatment strategies in PD is limited. There is thus a great need but also opportunity for development of well-designed clinical trials for impaired sleep and alertness in PD. Providing education about sleep hygiene and strategies for its implementation represents the initial step in management. Prompt diagnosis and treatment of co-existent primary sleep and psychiatric disorders are critical, as this may significantly improve sleep and alertness. While the optimal treatment for insomnia in PD has not been established, available strategies include cognitive-behavioral therapy, medications with soporific properties, and light therapy. Safety measures, clonazepam, and melatonin are the mainstay of treatment for RBD. Continuous positive airway pressure is an effective treatment for SDB in PD. The treatment algorithm for RLS associated with PD mirrors that used for idiopathic RLS. Circadian disruption has emerged as an important etiology of impaired sleep-wake cycles in PD, and circadian-based interventions hold promise for novel treatment approaches. PMID- 28567502 TI - Application challenges of the new EU Clinical Trials Regulation. AB - PURPOSE: The purpose of this paper is to discuss the challenges of the upcoming policy change in the field of clinical drug trials due to the shift from the Clinical Trials Directive 2001/20/EC to the new Clinical Trials Regulation 536/2014, adopted in 2014. Although it is expected that the new EU Clinical Trials Regulation will increase Europe's competitiveness in clinical research, the paper argues that some measures to assure protection of research subjects should be taken before the Regulation comes into application in 2018. METHODS: The methods used in this paper are comparative analysis of legal documents and related academic papers. RESULTS: The new Regulation serves as an efficient means to harmonize the clinical drug trial evaluation procedures across the EU. However, its application also raises potential challenges regarding interests and safety of research subjects: first, due to the possibility of skipping the assessment and balancing of benefits and risks from the scope of ethical review and limiting such a review to only Part II issues of the assessment report; second, due to direct applicability of the Regulation's rather vague and too general requirements for investigator's qualifications which does not allow the assessors (ethics committees and (or) competent authorities) to introduce higher qualification requirements for the investigators conducting high-risk clinical drug trials in the national legislation. CONCLUSIONS: There is an urgent need to raise awareness and facilitate debate on potential application challenges of the new Regulation. PMID- 28567504 TI - A clinical example of extreme dose exposure for an implanted cardioverter defibrillator : Beyond the DEGRO guidelines. AB - INTRODUCTION: Considering that the number of malignant diseases in patients over 65 years of age is increasing, it often occurs that patients who carry a cardiac implanted electronic device must undergo radiotherapy. Ionizing radiation can disturb the function of the implantable cardioverter-defibrillator (ICD). As a result of this, an update of the DEGRO/DKG guidelines for radiotherapy of this patient group has been published. METHODS: We report the case of a patient with an ICD and T-lymphoblastic lymphoma with cardiac involvement, who received i.a. a total body irradiation with 8 Gy followed by a consolidating radiotherapy of the pericardium with 14 Gy as well as additional radiotherapy courses after consecutive recurrences. For the purposes of the treatment, the antitachyarrhythmia (ATA) therapy was deactivated and temporarily replaced through a life vest. RESULTS: According to the current DEGRO guidelines for irradiation of patients with cardiac implanted electronic devices, a categorization of the patient in the "high-risk" group was made. Furthermore, regular telemetric checks of the ICD device were performed before and after treatment. Despite unavailable declaration of the manufacturer regarding the cumulative tolerable dose and DEGRO recommendation for a cumulative dose <2 Gy, the aftercare was unproblematic and normal values were assessed for all relevant ICD parameters, despite a cumulative dose >10 Gy in the device. CONCLUSION: This case shows that if the cardiac implanted electronic devices are not directly irradiated und the energy used is reduced to 6 MV, irradiation-induced damage is less likely and can possibly be prevented. PMID- 28567505 TI - Perspectives on Medical Education Special Edition : Lessons learned from health professions education scholarship failures surprises. PMID- 28567503 TI - Planning benchmark study for SBRT of early stage NSCLC : Results of the DEGRO Working Group Stereotactic Radiotherapy. AB - PURPOSE: The aim was to evaluate stereotactic body radiation therapy (SBRT) treatment planning variability for early stage nonsmall cell lung cancer (NSCLC) with respect to the published guidelines of the Stereotactic Radiotherapy Working Group of the German Society for Radiation Oncology (DEGRO). MATERIALS AND METHODS: Planning computed tomography (CT) scan and the structure sets (planning target volume, PTV; organs at risk, OARs) of 3 patients with early stage NSCLC were sent to 22 radiotherapy departments with SBRT experience: each department was asked to prepare a treatment plan according to the DEGRO guidelines. The prescription dose was 3 fractions of 15 Gy to the 65% isodose. RESULTS: In all, 87 plans were generated: 36 used intensity-modulated arc therapy (IMAT), 21 used three-dimensional conformal radiation therapy (3DCRT), 6 used static field intensity-modulated radiation therapy (SF-IMRT), 9 used helical radiotherapy and 15 used robotic radiosurgery. PTV dose coverage and simultaneously kept OARs doses were within the clinical limits published in the DEGRO guidelines. However, mean PTV dose (mean 58.0 Gy, range 52.8-66.4 Gy) and dose conformity indices (mean 0.75, range 0.60-1.00) varied between institutions and techniques (p <= 0.02). OARs doses varied substantially between institutions, but appeared to be technique independent (p = 0.21). CONCLUSION: All studied treatment techniques are well suited for SBRT of early stage NSCLC according to the DEGRO guidelines. Homogenization of SBRT practice in Germany is possible through the guidelines; however, detailed treatment plan characteristics varied between techniques and institutions and further homogenization is warranted in future studies and recommendations. Optimized treatment planning should always follow the ALARA (as low as reasonably achievable) principle. PMID- 28567506 TI - Seasonal dynamics of nitrate and ammonium ion concentrations in soil solutions collected using MacroRhizon suction cups. AB - The aims of the study were to analyse the concentration of nitrate and ammonium ions in soil solutions obtained using MacroRhizon miniaturized composite suction cups under field conditions and to determine potential nitrogen leaching from soil fertilized with three types of fertilizers (standard urea, slow-release urea, and ammonium nitrate) at the doses of 90 and 180 kg ha-1, applied once or divided into two rates. During a 3-year growing experiment with sugar sorghum, the concentration of nitrate and ammonium ions in soil solutions was the highest with standard urea fertilization and the lowest in variants fertilized with slow release urea for most of the months of the growing season. Higher concentrations of both nitrogen forms were noted at the fertilizer dose of 180 kg ha-1. One-time fertilization, at both doses, resulted in higher nitrate concentrations in June and July, while dividing the dose into two rates resulted in higher nitrate concentrations between August and November. The highest potential for nitrate leaching during the growing season was in July. The tests confirmed that the miniaturized suction cups MacroRhizon are highly useful for routine monitoring the concentration of nitrate and ammonium ions in soil solutions under field conditions. PMID- 28567507 TI - [A standard data set for the evaluation of venous leg ulcers in selective contracts : National consensus]. AB - BACKGROUND: Selective agreements are becoming increasingly important in health care management. To date, no standard recommendations for the evaluation of selective contracts are available. OBJECTIVES: Against this background, a recommendation on the evaluation of selective contracts in patients with leg ulcers (LU) was developed and approved by the nationwide consensus conference. MATERIALS AND METHODS: Based on a systematic literature review and followed by a manual search through other possible evaluation indicators in the care of patients with LU, a Delphi-based consensus process was performed by various scientific societies, professional associations, insurances and supply networks. RESULTS: For the evaluation of efficiency and quality of care, a recommendation on the evaluation of selective agreements with patients with LU was consented in six meetings and in five multistage online surveys. In total, 44 evaluation indicators were identified in the quality subareas structure, process, and outcome. The outcome indicators are divided into clinical, patient-related, and cost-related indicators. CONCLUSIONS: The developed evaluation indicators represent the quality of care in patients with LU. The indicators can be applied individually, depending on the agreed contract-specific supply target. After implementation of this national standard, the comparability of selective agreements in the management of patients with LU can be ensured and consolidated. PMID- 28567508 TI - [Psoriasis capitis and seborrhoic eczema of scalp diseases]. AB - The scalp may be affected by various diseases with equally varying manifestations. Erythema and scaling is often accompanied by agonizing itch. Scalp psoriasis and seborrheic eczema represent the most frequent diseases, which can be differentiated into classical cases; however, overlap and similarities are seen. Sharply demarcated erythematosquamous plaques across the natural hairline in psoriasis are opposed to blurred dark-red erythema and yellowish, greasy scales in seborrheic eczema. Whereas with the latter diffuse alopecia may frequently be found, hair loss is rarely seen in psoriasis and may also be related to therapeutic agents. Treatment is based on acuity as well as extent of disease and individual life quality aspects of the patients. It is mainly based on topical corticosteroids, combined with vitamin D derivatives in psoriasis and antimycotic agents in seborrheic eczema. In severe cases and widespread psoriatic disease, systemic treatment may be necessary, including the classic agents methotrexate, fumarates and ciclosporin as well as biologicals. Systemic treatment of seborrheic eczema is rarely necessary and resides on corticosteroids, antimycotic agents and vitamin A derivatives. In addition, intensive counseling of patients on the necessity of consequent and long-term treatment as well as use of mild skin care products is mandatory. PMID- 28567509 TI - [Clinical and histological spectrum of palisaded granulomatous dermatitides : Granuloma annulare, necrobiosis lipoidica, rheumatoid nodules, and necrobiotic xanthogranuloma]. AB - The palisading granulomatous dermatitides comprise a group of different skin diseases with similar histomorphologic forms of granuloma in the skin. Histopathologically characteristic are areas in the reticular dermis and subcutaneous fat with degenerated bundles of collagen surrounded by histiocytes and multinucleate giant cells aligned in a palisade (necrobiotic granuloma). Within the center of palisaded granulomas, mucin or fibrin can be found. The skin diseases presenting histologically with palisading granuloma are granuloma annulare and necrobiosis lipoidica. Palisading granuloma may also be an expression of systemic disease in rheumatoid nodules and necrobiotic xanthogranuloma. Little is known about the pathogenesis. The clinical presentation of the diseases is variable. Therapy is challenging and may not be satisfying. PMID- 28567510 TI - [Atypical course of an apocrine sweat gland carcinoma of the axilla : A very rare malignant tumor and its interdisciplinary treatment]. AB - We report on an atypical clinical course of a patient with the very rare diagnosis of an apocrine sweat gland carcinoma with lymphatic metastasis, a single metachronous distant metastasis and a now reached survival time of more than 4 years and give a review about the current literature. Only a very small number of cases have been described. The recommendations for diagnostics and treatment of this tumor, therefore, are not based on prospective randomized studies but upon case reports and on new immunohistochemical and genetic markers. PMID- 28567511 TI - Trochleoplasty techniques provide good clinical results in patients with trochlear dysplasia. AB - PURPOSE: The aim of this systematic review is to compare the clinical outcomes of patients treated with different trochleoplasty procedures, the rate of complications and recurrence of patellar dislocation. METHODS: A systematic review of the literature was performed, in accord with the PRISMA guidelines. PubMed, MEDLINE, CINAHL, Cochrane, EMBASE and Google Scholar databases were comprehensively searched using the keyword combinations, "Dejour trochleoplasty", "Bereiter Trochleoplasty", "Albee Trochleoplasty", "Recession Trochleoplasty", "Trochlear Dysplasia", "Instability", "Adult", "Clinical Outcome" and "Surgery". RESULTS: Three-hundred and ninety-two knees in 371 patients were included. Bereiter U-shaped deepening trochleoplasty was the most commonly used technique for the treatment of trochlear dysplasia in the included studies with the lowest rate of recurrence and post-operative ROM deficiency. On the other hand, Dejour V shaped deepening trochleoplasty showed the highest mean post-operative value of Kujala score with 79.3 (SD 8.4) points. Statistical differences were found in terms of redislocation rate between Goutallier procedure and Bereiter trochleoplasty (p < 0.05) and in terms of post-operative osteoarthritis between Bereiter and Dejour procedures (p < 0.05). CONCLUSION: Bereiter trochleoplasty seems to be the most efficiency procedure in terms of post-operative patellar redislocation, post-operative osteoarthritis and ROM, but the highest mean post operative Kujala score is obtained by Dejour procedure. Therefore, none of the surgical techniques analysed highlighted a real superiority. Randomised clinical trials are needed to establish whether of available surgical technique is the best to treat patient with trochlear dysplasia. The clinical relevance of this paper is that the three most popular trochleoplasty techniques are associated with significantly improved stability and function, showing a relatively low rate of osteoarthritis and pain, and a moderate rate of complications. LEVEL OF EVIDENCE: Systematic review, Level IV. PMID- 28567512 TI - Total flavonoids of Desmodium styracifolium attenuates the formation of hydroxy-L proline-induced calcium oxalate urolithiasis in rats. AB - Desmosium styracifolium (D. styracifolium), which is considered as a Chinese herbal medicine, has been reported to treat the kidney stone diseases. However, the potential phytochemically active components and the underlying mechanisms associated with its efficacy in targeting urolithiasis remain to be elucidated. This study aims to investigate the anti-urolithiatic effect of total flavonoids of D. styracifolium (TFDS) on calcium oxalate (CaOx) renal stones in Sprague Dawley rats. Animal models of CaOx urolithiasis were established in male Sprague Dawley rats by adding 5% w/w hydroxy-L-proline (HLP) in regular rat chow. The TFDS orally at 100, 400 mg/kg, respectively, were administered along with HLP for 28 days. At the end of 28 days of treatment, urine and serum samples were collected for crystalluria determination and various biochemical analysis. Kidney tissues were isolated and processed for antioxidant parameters measurement and histopathological examinations. HLP-induced hyperoxaluria alone reliably caused CaOx nephrolithiasis in rats. We showed that TFDS significantly reduced crystalluria and CaOx crystal deposits in the kidney sections as compared to untreated HLP group. Also, TFDS was observed to decrease urinary oxalate excretion, alleviate the pro-acidosis condition, improve the impaired renal functions and renal epithelial cell injury. Moreover, TFDS protected against the oxidative stress changes via reducing MDA content, increasing CAT and GSH-Px activities in renal homogenate, as well as attenuating the expression of MCP-1, OPN and TGF-beta proteins. These results indicated that TFDS had beneficial effect on inhibition of CaOx formation in the rat kidney probably through a combination of antioxidant, anti-inflammatory, urine alkalinizing activities, and lowering the concentration of urinary stone-forming constituents. Thus, TFDS might have clinical implications in preventing oxidative renal cell injury and, ultimately, kidney stone formation. The data provide a rationale for the medicinal use of TFDS in nephrolithiasis and identify this agent as a potential source of new antiurolithic drugs. PMID- 28567514 TI - [Orbit : Part 2: Diseases of the globe and retrobulbar space]. AB - After the first part of the article focused on the anatomy of the orbit and the anatomical relations of the orbital cavity, the second part provides an overview of common diseases of the globe and the retrobulbar space. The main focus is to describe and analyze current imaging procedures and their respective advantages. In addition to inflammatory lesions, traumatic, neoplastic, and congenital entities are also described. PMID- 28567513 TI - Age-dependent insulin resistance in male mice with null deletion of the carcinoembryonic antigen-related cell adhesion molecule 2 gene. AB - AIMS/HYPOTHESIS: Cc2 -/- mice lacking the gene encoding the carcinoembryonic antigen-related cell adhesion molecule 2 (Cc2 [also known as Ceacam2]) exhibit hyperphagia that leads to obesity and insulin resistance. This starts at 2 months of age in female mice. Male mutants maintain normal body weight and insulin sensitivity until the last age previously examined (7-8 months), owing to increased sympathetic tone to white adipose tissue and energy expenditure. The current study investigates whether insulin resistance develops in mutant male mice at a later age and whether this is accompanied by changes in insulin homeostasis. METHODS: Insulin response was assessed by insulin and glucose tolerance tests. Energy balance was analysed by indirect calorimetry. RESULTS: Male Cc2 -/- mice developed overt metabolic abnormalities at about 9 months of age. These include elevated global fat mass, hyperinsulinaemia and insulin resistance (as determined by glucose and insulin intolerance, fed hyperglycaemia and decreased insulin signalling pathways). Pair-feeding experiments showed that insulin resistance resulted from hyperphagia. Indirect calorimetry demonstrated that older mutant male mice had compromised energy expenditure. Despite increased insulin secretion caused by Cc2 deletion, chronic hyperinsulinaemia did not develop in mutant male mice until about 9 months of age, at which point insulin clearance began to decline substantially. This was probably mediated by a marked decrease in hepatic CEACAM1 expression. CONCLUSIONS/INTERPRETATION: The data demonstrate that at about 9 months of age, Cc2 -/- male mice develop a reduction in energy expenditure and energy imbalance which, combined with a progressive decrease in CEACAM1-dependent hepatic insulin clearance, causes chronic hyperinsulinaemia and sustained age-dependent insulin resistance. This represents a novel mechanistic underpinning of age-related impairment of hepatic insulin clearance. PMID- 28567521 TI - Comprehensive evaluation of disease- and trait-specific enrichment for eight functional elements among GWAS-identified variants. AB - Genome-wide association study (GWAS)-identified variants are enriched for functional elements. However, we have limited knowledge of how functional enrichment may differ by disease/trait and tissue type. We tested a broad set of eight functional elements for enrichment among GWAS-identified SNPs (p < 5*10-8) from the NHGRI-EBI Catalog across seven disease/trait categories: cancer, cardiovascular disease, diabetes, autoimmune disease, psychiatric disease, neurological disease, and anthropometric traits. SNPs were annotated using HaploReg for the eight functional elements across any tissue: DNase sites, expression quantitative trait loci (eQTL), sequence conservation, enhancers, promoters, missense variants, sequence motifs, and protein binding sites. In addition, tissue-specific annotations were considered for brain vs. blood. Disease/trait SNPs were compared to a control set of 4809 SNPs matched to the GWAS SNPs (N = 1639) on allele frequency, gene density, distance to nearest gene, and linkage disequilibrium at ~3:1 ratio. Enrichment analyses were conducted using logistic regression, with Bonferroni correction. Overall, a significant enrichment was observed for all functional elements, except sequence motifs. Missense SNPs showed the strongest magnitude of enrichment. eQTLs were the only functional element significantly enriched across all diseases/traits. Magnitudes of enrichment were generally similar across diseases/traits, where enrichment was statistically significant. Blood vs. brain tissue effects on enrichment were dependent on disease/trait and functional element (e.g., cardiovascular disease: eQTLs P TissueDifference = 1.28 * 10-6 vs. enhancers P TissueDifference = 0.94). Identifying disease/trait-relevant functional elements and tissue types could provide new insight into the underlying biology, by guiding a priori GWAS analyses (e.g., brain enhancer elements for psychiatric disease) or facilitating post hoc interpretation. PMID- 28567522 TI - NG2 plays a role in neuroinflammation but is not expressed by immune cells. PMID- 28567524 TI - Patterns of Care and Survival for Elderly Acute Myeloid Leukemia-Challenges and Opportunities. AB - PURPOSE OF REVIEW: Acute myeloid leukemia (AML) is a disease of the elderly, with a median age of diagnosis in the sixth decade of life. Mortality has declined over the last few years, but this impact is apparent only in the young, fit AML population. Outcomes for the elderly remain poor, with less than 20% 5-year overall survival rates. Hence, there is an unmet need to identify treatment strategies to maximize benefit in this age group. RECENT FINDINGS: Elderly AML is a difficult entity to treat due to both disease and patient-related factors. Treatment of this group has a lot of inter-physician and inter-institutional variability. Several objective criteria to assess biological age, impact of co morbidities, and fitness have been published, which could be utilized to make management decisions. For old and unfit AML patients, a variety of novel therapeutic agents are currently being investigated. Objective analysis of biological age should include assessment of fitness, frailty, and co-morbidities in elderly AML. Future areas of research include development of an objective risk based approach and its validation in clinical trials, development of novel therapeutic agents, and improvement in supportive care measures. PMID- 28567523 TI - Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica. AB - Neuromyelitis optica spectrum disorder (herein called NMO) is an autoimmune inflammatory disease of the central nervous system in which immunoglobulin G antibodies against astrocyte water channel aquaporin-4 (AQP4-IgG) cause demyelination and neurological deficit. Injury to oligodendrocytes, which do not express AQP4, links the initiating pathogenic event of AQP4-IgG binding to astrocyte AQP4 to demyelination. Here, we report evidence for a complement 'bystander mechanism' to account for early oligodendrocyte injury in NMO in which activated, soluble complement proteins following AQP4-IgG binding to astrocyte AQP4 result in deposition of the complement membrane attack complex (MAC) on nearby oligodendrocytes. Primary cocultures of rat astrocytes and mature oligodendrocytes exposed to AQP4-IgG and complement showed early death of oligodendrocytes in close contact with astrocytes, which was not seen in pure oligodendrocyte cultures, in cocultures exposed to AQP4-IgG and C6-depleted serum, or when astrocytes were damaged by a complement-independent mechanism. Astrocyte-oligodendrocyte cocultures exposed to AQP4-IgG and complement showed prominent MAC deposition on oligodendrocytes in contact with astrocytes, whereas C1q, the initiating protein in the classical complement pathway, and C3d, a component of the alternative complement pathway, were deposited only on astrocytes. Early oligodendrocyte injury with MAC deposition was also found in rat brain following intracerebral injection of AQP4-IgG, complement and a fixable dead-cell stain. These results support a novel complement bystander mechanism for early oligodendrocyte injury and demyelination in NMO. PMID- 28567526 TI - Mathematical modelling and kinetic study for CD production catalysed by Toruzyme(r) and CGTase from Bacillus firmus strain 37. AB - A new mathematical model was developed for the kinetics of alpha-, beta- and gamma-cyclodextrin production, expanding an existing model that only included the production of beta- and gamma-cyclodextrins, because a detailed kinetic modelling of the reactions involved allows the manipulation of the process yields. The kinetic behaviour of the commercial enzyme Toruzyme(r) was studied with maltodextrin as substrate at different concentrations and for CGTase from Bacillus firmus strain 37 at a concentration of 100 g L-1. The mathematical model showed a proper fit to the experimental data, within the 24-h period studied, confirming that the considered hypotheses represent the kinetic behaviour of the enzymes in the reaction medium. The kinetic parameters generated by the model allowed reproducing previous observed qualitative tendencies as it can be seen that changing experimental conditions in the reaction process such as enzyme and substrate concentrations results in large changes in the enzyme kinetics and using high substrate concentrations does not guarantee the highest conversion rates due to enzyme inhibition and reverse reactions. In addition, this new mathematical model complements previous qualitative observations enabling the manipulation of the direct and reverse reactions catalysed by the enzyme by adjusting the reaction conditions, to target quantitative results of increased productivity and better efficiency in the production of a desired cyclodextrin. PMID- 28567525 TI - Forensic entomotoxicology revisited-towards professional standardisation of study designs. AB - Forensic entomotoxicology is the use of insects as evidence of whether a toxicant is present in an environment such as a corpse, river or landscape. The earliest overtly forensic study was published in 1977, and since then, at least 63 papers have been published, most of them focused on the detection of toxicants in insects or on effects of toxicants on diverse insect indicator taxa. A comprehensive review of the published literature revealed various inconsistencies between studies that could be addressed by introducing standard protocols for such studies. These protocols could include selecting widespread and common model organisms (such as Lucilia sericata, Calliphora vicina, Chrysomya megacephala and Dermestes maculatus) and model toxicants (e.g. morphine and amitriptyline) to build up comparative databases; developing a standard matrix for use as a feeding substrate; setting guidelines for statistically adequate sample sizes; and deploying more sophisticated analytical methods from the general field of toxicology. Future studies should then be aimed at refining standardised protocols to improve experimental results, and make these results more comparable between studies. PMID- 28567527 TI - 13C-assisted metabolomics analysis reveals the positive correlation between specific erythromycin production rate and intracellular propionyl-CoA pool size in Saccharopolyspora erythraea. AB - Metabolomics analysis is extremely essential to explore the metabolism characteristics of Saccharopolyspora erythraea. The lack of suitable methods for the determination of intracellular metabolites, however, hinders the application of metabolomics analysis for S. erythraea. Acyl-CoAs are important precursors of erythromycin; phosphorylated sugars are intermediate metabolites in EMP pathway or PPP pathway; organic acids are intermediate metabolites in TCA cycle. Reliable determination methods for intracellular acyl-CoAs, phosphorylated sugars, and organic acids of S. erythraea were designed and validated in this study. Using the optimized determination methods, the pool sizes of intracellular metabolites during an erythromycin fermentation process were precisely quantified by isotope dilution mass spectroscopy method. The quantification results showed that the specific erythromycin production rate was positively correlated with the pool sizes of propionyl-CoA as well as many other intracellular metabolites. The experiment under the condition without propanol, which is a precursor of propionyl-CoA and an important substrate in industrial erythromycin production process, also corroborated the correlation between specific erythromycin production rate and intracellular propionyl-CoA pool size. As far as we know, this is the first paper to conduct the metabolomics analysis of S. erythraea, which makes the metabolomics analysis of S. erythraea in the industrial erythromycin production process possible. PMID- 28567528 TI - Portal vein embolization in extended liver resection. AB - BACKGROUND: Liver resection of benign, primary, and metastatic tumors is challenging and places patients at risk of postoperative liver insufficiency. This risk is largely dependent on the volume and function of the future liver remnant (FLR). It is, therefore, critical that hepatobiliary surgeons are well versed in the measurement of liver volume and function, as well as various techniques for preoperative liver volume augmentation. PURPOSE: This comprehensive review of portal vein embolization (PVE) begins with an overview of FLR measurement and progresses to patient factors to consider when choosing PVE and assessment of hypertrophy. PVE techniques and complications are subsequently discussed. CONCLUSIONS: The absolute volume of FLR required to avoid postoperative liver insufficiency is dependent on the patient, disease, and anatomic factors. Rapid expansion of the FLR can be achieved with PVE of contralateral liver segments. Although multiple metrics have been used to correlate hypertrophy with postoperative outcomes after PVE, the kinetic growth rate (KGR) is the most reliable predictor of freedom from postoperative liver insufficiency. PVE is now considered a safe and effective procedure when performed at high-volume hepatobiliary centers. It is an effective tool that, by lowering the risk of liver failure, increases the number of patients who can undergo potential curative hepatectomy. PMID- 28567529 TI - Influence of a face-bow on oral health-related quality of life after changing the vertical dimension in the articulator: a randomized controlled trial. Part II. AB - OBJECTIVES: In a double-blind randomized controlled clinical trial, the impact of face-bow registration for remounting complete dentures (CDs) on oral health related quality of life (OHRQoL) was evaluated. MATERIALS AND METHODS: New CDs of 32 subjects were clinically remounted using intraoral pin registration. CDs were transferred into a semi-adjustable articulator corresponding to group #1: mean settings with Bonwill triangle and Balkwill angle, and group #2: arbitrary hinge axis with a face-bow registration. After occlusal adjustment, subjects were followed up after 3 (T1) and 84 (T2) days. The primary outcome was the change of OHRQoL by OHIP-G49, while as secondary outcome, mucosal alterations were evaluated over time. Mean values of OHIP-G49 total sum scores and OHIP-dimensions were calculated for baseline (T0) and days 3 (T1) and 84 (T2) after intervention. Based on bootstrapping methods (changes of total OHIP sum score) and the Wilcoxon test (changes of sum scores of OHIP dimensions), analyses of between-group differences were performed. RESULTS: Mean values (MV) of OHIP-G49 sum scores decreased in both groups from T0 (#1 48.56; #2 45.46) to T1 (#1 31.43 (p = 0.012); #2 43.20) and to T2 (#1 29.06; #2 29.40), which represents an improvement in OHRQoL. MV of OHIP-dimension sum scores decreased from T0 to T1 in both groups (#1 seven dimensions; #2 four dimensions); the decrease of sum scores was tested as not statistically significant (p > 0.05). CONCLUSIONS: From the patient's perspective, mean-value-based remounting methods are of value. The use of a face bow was not perceived as superior. CLINICAL RELEVANCE: From the patient's perspective, remounting of CDs will be positively perceived, irrespective of the use of a face-bow. PMID- 28567530 TI - Immediate definitive individualized abutments reduce peri-implant bone loss: a randomized controlled split-mouth study on 16 patients. AB - OBJECTIVES: This paper aims to observe peri-implant time-related vertical bone level and soft tissue changes with immediate, non-detached glass-ceramic (lithium disilicate) individualized abutments and dis-/reconnections. MATERIALS AND METHODS: Sixteen split-mouth patients received provisionalized immediate definitive individualized abutments (test T) versus dis-/reconnected individualized abutments (control C). In group T, digital impressions were made by using titanium bases (Conelog, Camlog), and individualized abutments (E.maxCAD) and temporary crowns (TelioCAD) were designed and milled (CerecMCXL). Lithium-disilicate abutments were crystallized and luted (Multilink Hybrid Abutment) to titanium bases. Non-occluding temporary crowns were connected to abutments. After 16 weeks, definitive digital restorations were delivered. In group C, 8 weeks were allowed after healing cap mounting for conventional impressions. Lithium-disilicate individualized abutments were produced, try-ins were performed by dis-/reconnections. Crowns were luted. Cone beam computed tomography (CBCT) images were obtained at restoration delivery, 12 months and 24 months. Pink esthetic scoring was made, plaque-gingival index measurements were done and statistical analyses (Shapiro-Wilk, Mann-Whitney U, Wilcoxon's, Spearman's rank, alpha = 0.05) were completed. RESULTS: No implant failures occurred. At 12 months, T (-0.1 +/- 0.14 mm) exhibited significantly reduced vertical bone loss only on the labial side than C (-0.24 +/- 0.13 mm) (p < 0.05). In T, all sides except distal presented reduced vertical bone loss at 24 months (p < 0.05). Vertical bone loss for all measurement sides in both C (-0.12 +/- 0.09 mm; -0.18 +/- 0.11 mm) and T (-0.17 +/- 0.11; -0.26 +/- 0.10 mm) was higher for 24 months than 12 months, respectively (p < 0.05). CONCLUSIONS: Reduced vertical bone loss was observed around implants with immediate definitive individualized abutments than abutments with repeated dis-/reconnections. CLINICAL RELEVANCE: Non-detached immediate definitive lithium-disilicate individualized abutments and provisionalization through digital technology resulted in successful clinical outcomes and can be routinely applied. PMID- 28567531 TI - Predicting fractures using trabecular patterns on panoramic radiographs. AB - OBJECTIVES: The observer score of the trabecular pattern on panoramic radiographs is known to be a strong predictor of bone fractures. The aim of this study was to enhance the predictive power of panoramic radiographs by means of texture analysis methods. MATERIAL AND METHODS: The study followed 304 postmenopausal women during 26 years. At the beginning of the study, panoramic radiographs were obtained. One observer assessed the trabecular pattern in the premolar region as dense, sparse, or alternating dense and sparse. In addition, on each radiograph, a region of interest was selected in the molar/premolar region and analyzed with texture analysis procedures. During 26 years of follow-up, 115 women suffered a fracture of the hip, spine, leg, or arm. Logistic regression was applied to test the predictive power of various variables with respect to fractures. RESULTS: Of all variables, the observer score of the trabecular pattern correlated strongest with the occurrence of fractures. By itself, the score yielded an ROC curve with an area of 0.80 under the curve. Combining the observer score with the texture analysis features increased the area under the ROC curve to 0.85. CONCLUSIONS: The trabecular pattern on panoramic radiographs provides a strong predictor of fractures, at least for postmenopausal women. The assessment by an observer combined with texture analysis procedures yields a predictive power that parallels best known predictions in literature. CLINICAL RELEVANCE: This study illustrates that panoramic radiographs are state of the art predictors of postcranial fractures. PMID- 28567532 TI - [Pilon fractures : Review of diagnostics and classification]. AB - Intraarticular fractures of the distal tibia (pilon fractures) are rare injuries and today they occur mostly in traffic accidents and falls from a great height. There are simple fractures in the context of low-energy traumas, as well as complex comminuted fractures in high-energy traumas. Besides the clinical examination, plain radiographs and computed tomographic scans are diagnostic prerequisites. The aim of the diagnostic process is to clearly identify and classify the fracture before appropriate treatment is initiated. The systems used to classify the displaced distal pilon fractures are supposed to ensure the three dimensional assessment of the fracture and provide high inter- and intra-observer agreement. In addition to the classification of Ruedi and Allgower, the classification of pilon fractures has been carried out using the AO classification. PMID- 28567533 TI - A meta-analysis of montelukast for recurrent wheeze in preschool children. AB - : There is conflicting evidence of the effectiveness of montelukast in preschool wheeze. A recent Cochrane review focused on its use in viral-induced wheeze; however, such subgroups are unlikely to exist in real life and change with time, recently highlighted in an international consensus report. We have therefore sought to investigate the effectiveness of montelukast in all children with preschool wheeze (viral-induced and multiple-trigger wheeze). The PubMed, Cochrane Library, Ovid Medline and Ovid EMBASE were screened for randomised controlled trials (RCTs), examining the efficacy of montelukast compared with placebo in children with the recurrent preschool wheeze. The primary endpoint examined was frequency of wheezing episodes. Five trials containing 3960 patients with a preschool wheezing disorder were analysed. Meta-analyses of studies of intermittent montelukast showed no benefit in preventing episodes of wheeze (mean difference (MD) 0.07, 95% confidence interval (CI) -0.14 to 0.29; mean for montelukast 2.68 vs placebo 2.54 (p = 0.5)), reducing unscheduled medical attendances (MD -0.13, 95% CI -0.33 to 0.07; mean for montelukast 1.62 vs placebo 1.78 (p = 0.21)) and reducing oral corticosteroids (MD -0.06, 95% CI -0.16 to 0.02; mean for montelukast 0.35 vs placebo 0.36 (p = 0.25)). The pooled results of the continuous regimen showed no significant difference in the number of wheezing episodes between the montelukast and placebo groups (MD -0.40, 95% CI 1.00 to 0.19; mean for montelukast 2.05 vs placebo 2.37 (p = 0.18)). CONCLUSIONS: This review highlights that the currently available evidence does not support the use of montelukast in preschool children with recurrent wheeze. We recommend further studies to investigate if a 'montelukast responder' phenotype exists, and how these can be easily identified in the clinical setting. What is Known: * Current guidelines recommend montelukast use in preschool children with recurrent wheeze. * A recent Cochrane review has found montelukast to be ineffective at reducing courses of oral corticosteroids for viral-induced wheeze. What is New: * This meta-analysis has examined all children with preschool wheeze and found that montelukast was not effective at preventing wheezing episodes or reducing unscheduled medical attendances. * A specific montelukast responder phenotype may exist, but such patients should be sought in larger multicentre RCTs. PMID- 28567534 TI - Serum YKL-40 levels may help distinguish exacerbation of post-infectious bronchiolitis obliterans from acute bronchiolitis in young children. AB - : Children with post-infectious bronchiolitis obliterans (PIBO) are frequently hospitalized with acute exacerbation, but clinical differentiation of PIBO exacerbation from acute bronchiolitis is often challenging, which may result in treatment delay and chronic lung function impairment. We aimed to examine whether serum YKL-40 and growth factors could be markers for PIBO exacerbation. Thirty seven children admitted with acute exacerbation of PIBO were enrolled and studied retrospectively. Diagnosis of PIBO was based on clinical history of acute respiratory infection followed by persistent airway obstruction and characteristic findings in high-resolution computed tomography. Serum levels of YKL-40, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-beta1, and platelet-derived growth factor (PDGF)-BB were measured on admission. The biomarkers were also examined in children admitted with acute bronchiolitis serving as positive controls (N = 30) and in age-matched controls (N = 20). Only YKL-40 levels were found to be significantly higher in PIBO patients with exacerbation compared with that in bronchiolitis patients and showed a positive correlation with the severity of disease before diagnosis of PIBO. CONCLUSION: Our results suggest that measuring serum YKL-40 levels might help distinguish exacerbation of PIBO from acute bronchiolitis in young children. What is Known: * The children with post-infectious BO (PIBO) usually have recurrent wheezing and need frequent hospitalization due to acute exacerbation during the first disease years. * Clinical differentiation of PIBO exacerbation from acute bronchiolitis in young children is often challenging, which may result in treatment delay and chronic lung function impairment. What is New: * Measuring serum YKL-40 levels might help distinguish exacerbation of PIBO from acute bronchiolitis in young children. PMID- 28567535 TI - Immune-mediated syndromes following intravenous bisphosphonate therapy. AB - OBJECTIVES: Intravenous (IV) infusion of aminobisphosphonates (ABP) induces cytokine release by peripheral blood Vgamma9delta2 T cells, resulting in an immediate short-term inflammatory response in up to 50% of patients. We evaluated possible long-term pro-inflammatory effects of IV ABP. METHODS: Retrospective case-series study from one rheumatology specialist's clinic. 2261 electronic charts were reviewed for administration of 'zoledronate' or different brand names of zoledronic acid, and relevant clinical data was retrieved for patients who had received the infusion. RESULTS: Thirteen patients had recieved zoledronate. In six, new-onset or exacerbation of a previous inflammatory/autoimmune disorder was diagnosed within 3 months following infusion. Of these, one patient developed new onset rheumatoid arthritis (RA), two polymyalgia rheumatica (PMR), two suffered a flare of Crohn's disease-related and aromatase inhibitor-induced arthralgias, and one patient acquired autoimmune hemophilia. Pre-existing malignancy and immediate inflammatory response following zoledronate were more frequent in patients experiencing new or worsening immunologic manifestations (3/6 vs. 0/7, and 5/6 vs. 2/7, respectively). CONCLUSIONS: Intravenous ABP may trigger induction of persistent autoimmune syndromes, especially when accompanied by an immediate adverse reaction or pre-existing malignancy. PMID- 28567536 TI - Higher milk intake increases fracture risk: confounding or true association? PMID- 28567537 TI - HIV-1-associated neurocognitive disorder: epidemiology, pathogenesis, diagnosis, and treatment. AB - The modern antiretroviral treatment of human immunodeficiency virus (HIV-1) infection has considerably lowered the incidence of opportunistic infections. With the exception of the most severe dementia manifestations, the incidence and prevalence of HIV-associated neurocognitive disorders (HAND) have not decreased, and HAND continues to be relevant in daily clinical practice. Now, HAND occurs in earlier stages of HIV infection, and the clinical course differs from that before the widespread use of combination antiretroviral treatment (cART). The predominant clinical feature is a subcortical dementia with deficits in the domains concentration, attention, and memory. Motor signs such as gait disturbance and impaired manual dexterity have become less prominent. Prior to the advent of cART, the cerebral dysfunction could at least partially be explained by the viral load and by virus-associated histopathological findings. In subjects where cART has led to undetectable or at least very low viral load, the pathogenic virus-brain interaction is less direct, and an array of poorly understood immunological and probably toxic phenomena are discussed. This paper gives an overview of the current concepts in the field of HAND and provides suggestions for the diagnostic and therapeutic management. PMID- 28567538 TI - Comparative effectiveness of eight antiepileptic drugs in adults with focal refractory epilepsy: the influence of age, gender, and the sequence in which drugs were introduced onto the market. AB - The first objective was to determine the long-term retention rate of eight antiepileptic drugs (AEDs) commonly used as adjunctive therapy in adults with focal refractory epilepsy. Second, we assessed the effects of age and gender on retention rates. Third, we examined if the retention rate could be influenced by the sequence in which the AEDs had entered the market. Patients with focal refractory epilepsy treated with any of the eight AEDs in Tampere University Hospital were identified retrospectively (N = 507). Retention rates were evaluated with the Kaplan-Meier method. Follow-up started at the first date of treatment and each individual was followed a maximum of 36 months. We calculated the following 3-year retention rates: lacosamide 77.1% (N = 137), lamotrigine 68.3% (N = 177), levetiracetam 66.7% (N = 319), clobazam 65.6% (N = 130), topiramate 61.6% (N = 178), zonisamide 60.4% (N = 103), pregabalin 54.6% (N = 127), and gabapentin 40.2% (N = 66). Lacosamide, levetiracetam, and clobazam were the most effective AEDs in the elderly. The retention rate for pregabalin was higher in males (65%) than females (51%) whereas females had higher retention rates for both topiramate (72 vs. 58%) and zonisamide (67 vs. 57%). The retention rate was influenced by the sequence in which these AEDs entered the market. We provide important information about practical aspects of these eight AEDs, revealing that there are differences in their effectiveness as adjunctive treatment for focal refractory epilepsy. Most importantly, the retention rate appears to be influenced by the sequence in which these AEDs were introduced onto the market. PMID- 28567539 TI - Retinal ganglion cell analysis in multiple sclerosis and optic neuritis: a systematic review and meta-analysis. AB - The aim of this study was to summarise existing findings regarding optical coherence tomography (OCT) measurements of ganglion cell layer (GCL) alterations in optic neuritis (ON) and multiple sclerosis (MS). Peer-reviewed studies published prior to April 2016 were searched using PubMed, EMBASE, Web of Science and Scopus. Studies were included if they measured GCL thickness using OCT in patients with either ON, MS or clinically isolated syndrome. For the meta analysis, we compared GCL thickness in MS patients with and without prior ON, to healthy controls. 42/252 studies were reviewed. In acute ON, studies showed significant thinning of the GCL within the first 5 weeks (n = 5), earlier than retinal nerve fibre layer (RNFL) thinning. GCL thinning at 1-2 months after acute ON predicted visual function at 6 months (n = 3). The meta-analysis showed that the thickness of the GCL was significantly reduced in MS patients both with and without previous ON compared to healthy controls. GCL thinning was associated with visual function in most studies (n = 10) and expanded disability status scale (EDSS) scores (n = 6). In acute ON, thinning of the GCL is measurable prior to RNFL thinning, and GCL thickness after 1-2 months may predict visual function after 6 months. Furthermore, GCL thinning occurs in MS both with and without prior ON, and may be associated with visual function and EDSS score. This suggests that the GCL is a promising biomarker, which may be used to examine in vivo neurodegeneration in ON and MS. PMID- 28567540 TI - Hearing loss in children with Fabry disease. AB - BACKGROUND: Hearing loss (HL) is a well-known feature of Fabry disease (FD). Its presence and characteristics have mainly been studied in adult patients, while only limited data are available on the presence and degree of HL in children with FD. This prompted us to study hearing sensitivity in pediatric FD patients. METHODS: All available audiograms of the Dutch and Norwegian children with FD were retrospectively collected. First, hearing sensitivity was determined by studying hearing thresholds at low, high, and ultra-high frequencies in children with FD and comparing them to zero dB HL, i.e., healthy children. In addition, the presence and type of slight/mild HL (defined as hearing thresholds at low frequencies of 25-40 dB HL) and moderate to severe HL (hearing thresholds >40 dB HL) at first visit were analyzed. If available, follow-up data were used to estimate the natural course of hearing sensitivity and HL in children with FD. RESULTS: One-hundred-thirteen audiograms of 47 children with FD (20 boys, median age at first audiogram 12.0 (range 5.1-18.0) years) were analyzed. At baseline, slight/mild or moderate to severe HL was present in three children (6.4%, 2 boys). Follow-up measurements showed that three additional children developed HL before the age of 18. Of these six children, five had sensorineural HL, most likely caused by FD. Compared to healthy children (zero dB HL), FD children showed increased hearing thresholds at all frequencies (p < 0.01), which was most prominent at ultra-high frequencies (>8 kHz). Hearing sensitivity at these ultra high frequencies deteriorated in a period of 5 years of follow-up. CONCLUSION: A minority of children with FD show slight/mild or moderate to severe HL, but their hearing thresholds are poorer than the reference values for normal-hearing children. Clinical trials in FD children should demonstrate whether HL can be prevented or reversed by early treatment and should specifically study ultra-high frequencies. PMID- 28567543 TI - Risk factors for recurrent carbapenem resistant Klebsiella pneumoniae bloodstream infection: a prospective cohort study. AB - To assess risk factors for recurrent carbapenem-resistant Klebsiella pneumoniae bloodstream-infection (CR-KP BSI), we performed a prospective observational cohort study of all consecutive adult patients cured of a CR-KP BSI at our hospital over a six-year period (June 2010 to June 2016). Maximum follow-up per patient was 180 days from the index blood cultures (BCs). Recurrent CR-KP BSI was defined as new evidence of positive BCs in patients with documented clinical response after completing a course of anti-CR-KP therapy. Univariate and multivariate cause-specific Cox proportional hazards analysis were performed. During the study period 249 patients were diagnosed with a CR-KP BSI, 193 were deemed as cured within 14 days after index BCs and were analysed. Recurrence occurred in 32/193 patients (16.6%) within a median of 35 (IQR 25-45) days after index BCs. All but one of the recurrences occurred within 60 days after the index BCs. Comparison of recurrent and non-recurrent cases showed significant differences for colistin use (84.4% vs. 62.2%, p = 0.01), meropenem-colistin tigecycline regimen (43.8% vs. 24.8%, p = 0.03) and length of therapy for the index BSI episode (median 18 vs. 14 days, p = 0.004). All-cause 180-day mortality (34.4% vs. 16.1%, p = 0.02) was higher in recurrent cases. In the multivariate analysis, the only independent variable was source control as a protective factor for recurrence. Recurrence is frequent among patients cured of a CR-KP BSI and is associated with higher long-term mortality. When feasible, source control is mandatory to avoid recurrence. The role of antibiotic treatment should be further investigated in large multicentre studies. PMID- 28567544 TI - Enhanced liver fibrosis test using ELISA assay accurately discriminates advanced stage of liver fibrosis as determined by transient elastography fibroscan in treatment naive chronic HCV patients. AB - Evaluation of liver fibrosis stage is crucial in the assessment of chronic HCV patients, regarding decision to start treatment and during follow-up. Our aim was to assess the validity of the enhanced liver fibrosis (ELF) score in discrimination of advanced stage of liver fibrosis in naive chronic HCV patients. We prospectively evaluated liver fibrosis stage in one hundred eighty-one naive chronic HCV Egyptian patients by transient elastography (TE)-FibroScan. Patients were categorized into mild to moderate fibrosis (<=F2) group and advanced fibrosis (>=F3) group. The ELF score components, hyaluronic acid (HA), amino terminal propeptide of type-III-procollagen (PIIINP) and tissue inhibitor of metalloproteinase type-1 (TIMP-1), were done using ELISA test. The mean values of ELF and its individual components significantly correlated with the hepatic fibrosis stage as measured by TE-FibroScan (P value 0.001). ELF cutoff value of 9.8 generated a sensitivity of 77.8%, specificity of 67.1%, area under the receiver operator characteristic curve (AUROC) of 0.76 with 95% confidence interval [CI] (0.68-0.83) for detecting advanced fibrosis (F >= 3). ELF panel is a good, reliable noninvasive test and showed comparable results to TE-FibroScan in detecting liver fibrosis stage in treatment naive chronic HCV patients. PMID- 28567541 TI - Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects. AB - Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics. PMID- 28567546 TI - Examining the Efficacy of Peer Network Interventions on the Social Interactions of High School Students with Autism Spectrum Disorder. AB - Developing positive peer relationships is important. Unfortunately, due to challenges in social communication and increased complexity of peer groups during adolescence, many secondary students with autism spectrum disorder (ASD) engage in limited positive social interactions with peers. This study examined the effects of a peer network intervention implemented with three high school students with ASD. A multiple-baseline across participants design was used to evaluate the intervention on initiations and responses to and from students with ASD. The impact on frequency of victimization of students with ASD was also explored. Results indicate peer networks are effective at increasing social interactions of secondary students with ASD and provide preliminary support for the use of peer networks to reduce rates of bullying victimization. PMID- 28567545 TI - Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer. AB - PURPOSE: Multiple aspects of the tumor microenvironment (TME) impact breast cancer, yet the genetic modifiers of the TME are largely unknown, including those that modify tumor vascular formation and function. METHODS: To discover host TME modifiers, we developed a system called the Consomic/Congenic Xenograft Model (CXM). In CXM, human breast cancer cells are orthotopically implanted into genetically engineered consomic xenograft host strains that are derived from two parental strains with different susceptibilities to breast cancer. Because the genetic backgrounds of the xenograft host strains differ, whereas the inoculated tumor cells are the same, any phenotypic variation is due to TME-specific modifier(s) on the substituted chromosome (consomic) or subchromosomal region (congenic). Here, we assessed TME modifiers of growth, angiogenesis, and vascular function of tumors implanted in the SSIL2Rgamma and SS.BN3IL2Rgamma CXM strains. RESULTS: Breast cancer xenografts implanted in SS.BN3IL2Rgamma (consomic) had significant tumor growth inhibition compared with SSIL2Rgamma (parental control), despite a paradoxical increase in the density of blood vessels in the SS.BN3IL2Rgamma tumors. We hypothesized that decreased growth of SS.BN3IL2Rgamma tumors might be due to nonproductive angiogenesis. To test this possibility, SSIL2Rgamma and SS.BN3IL2Rgamma tumor vascular function was examined by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), micro-computed tomography (micro-CT), and ex vivo analysis of primary blood endothelial cells, all of which revealed altered vascular function in SS.BN3IL2Rgamma tumors compared with SSIL2Rgamma. Gene expression analysis also showed a dysregulated vascular signaling network in SS.BN3IL2Rgamma tumors, among which DLL4 was differentially expressed and co-localized to a host TME modifier locus (Chr3: 95-131 Mb) that was identified by congenic mapping. CONCLUSIONS: Collectively, these data suggest that host genetic modifier(s) on RNO3 induce nonproductive angiogenesis that inhibits tumor growth through the DLL4 pathway. PMID- 28567547 TI - Breast MR imaging for the assessment of residual disease following initial surgery for breast cancer with positive margins. AB - OBJECTIVES: To determine the accuracy of post-operative MR in predicting residual disease in women with positive margins, emphasizing the size thresholds at which residual disease can be confidently identified. METHODS: This IRB-approved HIPAA compliant retrospective study included 175 patients with MR after positive margins following initial surgery for breast cancer. Two expert readers independently re-evaluated MR images for evidence of residual disease at the surgical cavity and multifocal/multicentric disease. All patients underwent definitive surgery and MR findings were correlated to histopathology. RESULTS: 139/175 (79.4%) patients had residual disease at surgery. Average overall sensitivity, specificity, PPV and NPV for residual disease at the surgical cavity were 73%, 72%, 91% and 45%, respectively. The readers identified 42/45 (93%, reader 1) and 43/45 (95%, reader 2) patients with residual invasive disease at the cavity of >=5 mm and 22/22 (100%, both readers) patients with disease >=10 mm. Average sensitivity, specificity, PPV and NPV for unknown multifocal/multicentric disease were 90%, 96%, 93% and 86%, respectively. CONCLUSIONS: Post-operative breast MR can accurately depict >=5-mm residual disease at the surgical cavity and unsuspected multifocal/multicentric disease. These findings have the potential to lead to more appropriate selection of second surgical procedures in women with positive margins. KEY POINTS: * Post-operative breast MRI accurately defines residual disease of >=5 mm. * Surgical cavity sensitivities were high for both invasive carcinoma and DCIS. * Post-surgical changes and very small residual disease (<5 mm) may overlap. * Post-operative breast MRI may help planning an accurate re-resection. PMID- 28567549 TI - Minimally invasive surgery for advanced gastric cancer: are we sure? PMID- 28567550 TI - HIV Prevalence, Knowledge, Attitudes, and Practices Among Polydrug Users in Brazil: A Biological Survey Using Respondent Driven Sampling. AB - Brazil has a concentrated HIV epidemic among key populations. In 2009, the Ministry of Health conducted a survey in 10 Brazilian cities aiming to estimate HIV prevalence, knowledge, and associated risk behaviors of polysubstance users (PSU). Using Respondent Driven Sampling (RDS), 3449 PSU were recruited, answered an Audio-Computer Self Assisted Interview (ACASI) and were tested for HIV and syphilis. Analyses were weighted by individual's social network size generated on RDSAT. Pooled HIV prevalence was 5.8% but varied across cities. Most PSU were male, non-white, without income, unemployed, with low levels of education. Overall, 12.0% used injectable drugs, 48.7% had sex with occasional partners and 46.4% engaged in commercial sex. A majority received free condoms (71.4%) but 76.7% exhibited inconsistent condom use. Findings can support policies aiming to improve health care and preventive interventions tailored to this population that remains at high risk of acquiring and transmitting HIV/STI in multiple scenarios. PMID- 28567542 TI - Current Perspective in the Discovery of Anti-aging Agents from Natural Products. AB - Aging is a process characterized by accumulating degenerative damages, resulting in the death of an organism ultimately. The main goal of aging research is to develop therapies that delay age-related diseases in human. Since signaling pathways in aging of Caenorhabditis elegans (C. elegans), fruit flies and mice are evolutionarily conserved, compounds extending lifespan of them by intervening pathways of aging may be useful in treating age-related diseases in human. Natural products have special resource advantage and with few side effect. Recently, many compounds or extracts from natural products slowing aging and extending lifespan have been reported. Here we summarized these compounds or extracts and their mechanisms in increasing longevity of C. elegans or other species, and the prospect in developing anti-aging medicine from natural products. PMID- 28567548 TI - The impact of image reconstruction settings on 18F-FDG PET radiomic features: multi-scanner phantom and patient studies. AB - OBJECTIVES: The purpose of this study was to investigate the robustness of different PET/CT image radiomic features over a wide range of different reconstruction settings. METHODS: Phantom and patient studies were conducted, including two PET/CT scanners. Different reconstruction algorithms and parameters including number of sub-iterations, number of subsets, full width at half maximum (FWHM) of Gaussian filter, scan time per bed position and matrix size were studied. Lesions were delineated and one hundred radiomic features were extracted. All radiomics features were categorized based on coefficient of variation (COV). RESULTS: Forty seven percent features showed COV <= 5% and 10% of which showed COV > 20%. All geometry based, 44% and 41% of intensity based and texture based features were found as robust respectively. In regard to matrix size, 56% and 6% of all features were found non-robust (COV > 20%) and robust (COV <= 5%) respectively. CONCLUSIONS: Variability and robustness of PET/CT image radiomics in advanced reconstruction settings is feature-dependent, and different settings have different effects on different features. Radiomic features with low COV can be considered as good candidates for reproducible tumour quantification in multi-center studies. KEY POINTS: * PET/CT image radiomics is a quantitative approach assessing different aspects of tumour uptake. * Radiomic features robustness is an important issue over different image reconstruction settings. * Variability and robustness of PET/CT image radiomics in advanced reconstruction settings is feature-dependent. * Robust radiomic features can be considered as good candidates for tumour quantification. PMID- 28567551 TI - Mutation analysis of TGFBI and KRT12 in a case of concomitant keratoconus and granular corneal dystrophy. AB - PURPOSE: This study is to summarize the concurrent keratoconus (KC) and granular corneal dystrophy (GCD) phenotype and identify the underlying genetic cause in a 23-year-old male patient. METHODS: A detailed family history and clinical data from the patient and his parents were collected by ophthalmologic examination. The candidate genes were captured and sequenced by targeted next-generation sequencing, and the results were confirmed by Sanger sequencing. RESULTS: The proband was clinically diagnosed as a case of concurrent KC and GCD, which is a very rare presentation. His father and grandmother were diagnosed as GCD in both eyes. There was no character of KC in his father's and grandmother's eyes. A heterozygous TGFBI mutation in exon 4 (c.370G > A) was identified in the proband, which was predicted to generate a missense mutation (p.R124H). The mutation also existed in his father and grandmother. A heterozygous KRT12 mutation in exon 8 (c.1456-1457ins GTA) was identified in the proband, which was predicted to generate an insert mutation and created a premature termination codon. The mutation did not exist in his father and grandmother. The two mutations did not exist in his mother and 200 unrelated normal controls. CONCLUSIONS: KC can co exist with GCD. The missense mutation (c.370G > A) in the TGFBI gene and insert mutation (c.1456-1457ins GAT) in the KRT12 gene were identified in a 23-year-old male patient with concurrent KC and GCD. PMID- 28567552 TI - Periodontitis deteriorates peripheral arterial disease in Japanese population via enhanced systemic inflammation. AB - Peripheral arterial disease (PAD) is a common manifestation of arterial stenosis of the extremity that reduces arterial flow. While patients with periodontitis are at a high risk of PAD, little causal information has been provided to date. To clarify the relationship, we conducted this cross-sectional study. The oral condition of patients with or without PAD, who attended Tokyo Medical and Dental University Hospital, was evaluated. Blood examinations and dental clinical measurements, including number of teeth, probing pocket depth (PPD), bleeding on probing (BOP) and clinical attachment level (CAL) were performed. Chi-square test was performed to compare gender, smoker rate, prevalence of DM, hypertension and dyslipidemia and edentulous rate. Wilcoxon test was used to compare bacterial counts and anti-bacterial antibodies and Student's t test was used to compare the other numerical values. The subjects were patients with (n = 34) or without (n = 956) PAD. We revealed that the PAD patients had more missing teeth (17.5 +/- 11.0), a higher rate of edentulism (18%), and higher serum inflammatory factor levels than non-PAD patients (10.9 +/- 8.7, 5%, respectively). On the other hand, there was no significant difference between hypertension, dyslipidemia, smoking status, HbA1c, bacterial antibody titers, and bacterial counts between the groups. In conclusion, we clarified that PAD patients had decreased tooth number and worsened oral and periodontal condition with enhanced systemic inflammation. PMID- 28567554 TI - Erratum to: Expression of CCR6 on B cells in systemic lupus erythematosus patients. PMID- 28567553 TI - Plasma levels of sRANKL and OPG are associated with atherogenic cytokines in patients with intermediate cardiovascular risk. AB - Osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) are regulators of bone remodeling, but are also considered to play important roles in coronary artery disease (CAD). This study evaluated potential associations of soluble (s) RANKL and OPG with atherosclerosis-relevant cytokines. Blood was collected from 414 individuals who presented to our hospital with intermediate likelihood for CAD for further examination. Plasma concentrations of total sRANKL, OPG, and 20 cytokines were measured using sandwich-type enzyme-linked immunoassays (ELISAs; OPG and sRANKL) and Luminex laser-based fluorescence analysis and correlated with each other. The plasma levels of interferon-gamma (IFN-gamma) and the T-helper cell 2 cytokines interleukin-4 (IL-4) and IL-13 showed a positive correlation with sRANKL. The association with sRANKL levels was negative for IFN-gamma-induced protein-10 (IP 10) and monocyte chemotactic protein-1 (MCP-1). The strongest independent association with sRANKL in multivariable analyses was found for IFN-gamma (positive) and IP-10 (negative), while IL-13 showed a positive and independent association with OPG plasma levels. OPG and sRANKL plasma levels correlate strongly and independently with specific circulating atherosclerosis-related cytokines in patients with intermediate cardiovascular risk. PMID- 28567555 TI - Toward electronic health recording: evaluation of electronic patient reported outcome measures (e-PROMs) system for remote monitoring of early systemic lupus patients. AB - The study aimed to assess the value of evaluation of electronic patient reported outcome measures (e-PROMs) in the assessment and management of SLE disease activity flares, its association with adherence to therapy as well as organ damage. A randomized, controlled crossover study was carried out over a 24-month duration. One hundred forty-seven SLE patients meeting the revised American College of Rheumatology (ACR) criteria were enrolled. Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was used to assess disease activity, whereas organ damage was scored using the Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index. In the first 12 months, the patients were assessed every 3 months. At 12 months, the patients were randomized into a cohort of 73 patients who continued their care in the same style and 74 patients who completed an online e-PROMs questionnaire on monthly basis for another 12-month period. The data captured were then retrospectively analyzed at the end of the 24-month study period. At the end of the first year of the study, the mean SLEDAI and SDI scores were 8.72 (6.1) and 1.9 (2.2). At the end of the second year, the mean SLEDAI and SDI scores in the e-PROMs cohort were 3.1 (2.6) and 1.2 (1.3), whereas in the control group, the scores were 7.63 (6.7) and 1.8 (2.3), respectively (p < 0.01). Adjusting for possible confounding variables, the number of flares, regardless of their severity, was associated with damage accrual (OR 2.03, 95% CI 1.34 to 2.83, p < 0.001). Adherence to therapy was significantly (p < 0.1) higher in the e-PROMs group. e-PROMs was equivalent to PROMs paper format and has a potential disease-modifying effect as it facilitated close monitoring of disease activity with an option of management escalation whenever indicated. PMID- 28567556 TI - Minimal disease activity in patients with psoriatic arthritis treated with ustekinumab: results from a 24-week real-world study. AB - Psoriatic arthritis (PsA) is a chronic inflammatory joint disease affecting around 40% of psoriasis patients. Minimal disease activity (MDA) criteria have been proposed to identify a state of low disease activity, one of the principal goals of treatment for psoriatic disease. This study investigated treatment with ustekinumab (UST) in the context of a real-world setting. Thirty-four PsA patients who had failure or inadequate response to conventional synthetic disease modifying antirheumatic drugs or to anti-tumour necrosis factor alpha were enrolled. Demographic and clinical features, MDA criteria, and the impact of psoriatic skin manifestations on patients' quality of life (QoL) using the dermatology life quality index (DLQI) questionnaire were evaluated at baseline and after 24-week treatment. Adverse events were recorded. At week 24, 70.5% of patients (n = 24) achieved MDA. A sub-analysis of dermatological indices of the MDA criteria showed that the psoriasis area severity index score was significantly improved and body surface area was significantly decreased at 24 weeks compared with that at baseline (both p < 0.001). For the rheumatologic indexes, tender joint count, swollen joint count, and tender entheseal points were all significantly improved at 24 weeks of therapy (all p < 0.01 vs. baseline). Mean DLQI value decreased approximately fourfold, and there were no safety concerns. The achievement of MDA as well as the significant improvement in DLQI and lack of adverse events in the context of a real-life setting shown here confirms the efficacy and safety of UST in PsA. PMID- 28567557 TI - C-reactive protein +1444CT (rs1130864) genetic polymorphism is associated with the susceptibility to systemic lupus erythematosus and C-reactive protein levels. AB - The T rare allele of +1444CT (rs1130864) polymorphism of C-reactive protein (CRP) has been associated with increased CRP levels in some inflammatory conditions, but its role on systemic lupus erythematosus (SLE) susceptibility and on CRP levels in SLE patients remains uncertain. The objective of the study was to evaluate the association between the rs1130864 CRP polymorphism with SLE susceptibility, disease activity, and CRP levels in SLE Brazilian patients. The study enrolled 176 SLE patients and 137 controls. SLE disease activity was assessed using the SLE Disease Activity Index (SLEDAI). The rs1130864 CRP polymorphism was determined using polymerase chain reaction and restriction fragment length polymorphism. SLE patients presented higher body mass index (p = 0.046) and CRP levels (p = 0.017) than controls. The genotype and allele frequencies of patients differed from controls [CC vs. CT = odds ratio (OR) 1.730, 95% confidence interval (CI) 1.068-2.803, p = 0.035; CC vs. TT = OR 3.667, 95% CI 1.410-9.533, p = 0.009; C vs. T = OR 1.883, 95% CI 1.299-2.728, p = 0.001)]. Patients carrying the T allele presented higher CRP levels (p = 0.009), were more frequent Caucasians (p = 0.018), and with no use of immunosuppressive treatment (p = 0.004) than those carrying the C allele. However, the SLEDAI and anti-double-stranded DNA positivity did not differ from those carrying T vs. C allele (p = 0.595 and p = 0.243, respectively). The rs1130864 CRP polymorphism was associated with SLE susceptibility and CRP levels, but not with disease activity, suggesting that this polymorphism may play a role in the pathophysiology of SLE through increasing the CRP that, probably, plays an inflammatory role in SLE pathophysiology. PMID- 28567558 TI - Exercise-mediated reactive oxygen species generation in athletes and in patients with chronic disease. PMID- 28567559 TI - Diagnosis of canine Echinococcus multilocularis infections by copro-DNA tests: comparison of DNA extraction techniques and evaluation of diagnostic deworming. AB - The use of copro-DNA detection methods for the diagnosis of canine Echinococcus multilocularis infection was evaluated with a focus on DNA extraction techniques: two commercial kits and a modified alkaline-sodium dodecyl sulfate (SDS) technique. Dog feces (0.2 g) mixed with a protoscolex or with 1 or 10 eggs of E. multilocularis were subjected to DNA detection following extraction by these methods. DNA was extracted from all protoscolex samples by all methods, but success for samples with eggs depended on extraction technique with the modified technique showing success on all samples. Following experimental infection of dogs, copro-DNA was successfully extracted from fecal samples (0.2 g) of dogs in the patent period by all methods. In the prepatent period, PCR testing of feces subsamples (0.2 g) extracted by each technique was positive at a rate of 79.6 94.4%. Extraction by the modified technique with fecal samples of over 1 g showed detection of copro-DNA in all samples in both the patent and prepatent periods, and it produced reproducible detection in the addition recovery test using feces from 72 different domestic dogs. As copro-DNA was detected for at least 1 day following deworming with administration of anthelmintic drugs in experimentally infected dogs, diagnostic deworming might be useful for clinical examination. Using the present detection method can provide quick and accurate diagnosis of canine E. multilocularis infection, which with prompt management and treatment of infected dogs can prevent pet owners from becoming infected and prevent echinococcosis from spreading into non-endemic areas. PMID- 28567561 TI - Measuring healthcare expenditure: different methods, different results. AB - BACKGROUND: Accurate information on healthcare expenditure is essential; however, a number of issues arise when healthcare expenditure is being measured. Traditionally healthcare expenditure data in Ireland have been limited, especially data that facilitate comparable analysis through time and across particular programmes or services. Recently however, a major development in Irish healthcare expenditure estimates was the publication of Irish healthcare current expenditure estimates for 2013 according to the international standard of the OECD System of Health Accounts (SHA). AIMS: The aim of the analysis presented in this paper is to examine how alternative methodologies for measuring healthcare can influence the estimate(s) of healthcare expenditure. METHODS: The methods and results (in terms of healthcare expenditure) of the Central Statistics Office (CSO) application of SHA methodology will be compared and contrasted with an alternative methodology for measuring healthcare expenditure developed by Wren et al. [1]. RESULTS: The two approaches to measuring healthcare expenditure in Ireland reached a very similar figure for total current healthcare expenditure in 2013. However, there were considerable disparities in the components of expenditure. CONCLUSIONS: There is no one absolute definition or estimate of healthcare expenditure, and different methodological approaches to estimating expenditure will likely yield different results. Therefore, care is required when assessing healthcare expenditure to ensure that there is a clear understanding about what is and is not included in the estimate. PMID- 28567560 TI - A study of the Immune Epitope Database for some fungi species using network topological indices. AB - In the last years, the encryption of system structure information with different network topological indices has been a very active field of research. In the present study, we assembled for the first time a complex network using data obtained from the Immune Epitope Database for fungi species, and we then considered the general topology, the node degree distribution, and the local structure of this network. We also calculated eight node centrality measures for the observed network and compared it with three theoretical models. In view of the results obtained, we may expect that the present approach can become a valuable tool to explore the complexity of this database, as well as for the storage, manipulation, comparison, and retrieval of information contained therein. PMID- 28567562 TI - Identification and comparative analysis of hepatitis B virus genotype D/E recombinants in Africa. AB - Globally, there are approximately 240 million people chronically infected with hepatitis B virus (HBV)-a major cause of hepatocellular carcinoma. Ten different HBV genotypes (A-J) have been identified with distinct geographic distributions. Novel variants generated by recombination between different HBV genotypes have been documented worldwide and represent an important element of genetic variability with possible clinical implications. Here, the complete genome sequence of an HBV genotype D/E recombinant from Ghana is reported. The full length sequence was obtained using rolling circle amplification followed by PCR and sequenced using next-generation sequencing (NGS). A consensus sequence was extracted from the NGS data and underwent phylogenetic analysis to determine genotype, as well as the recombination pattern. Subsequently, the sequence was compared to recombinants described previously in Africa. Based on MCMC phylogenetic analysis, SimPlot recombination analyses, and intragroup genetic distance, the isolate 007N full-length genome is unique compared to other reported D/E recombinants in Africa. PMID- 28567563 TI - ROS-IGTL-Bridge: an open network interface for image-guided therapy using the ROS environment. AB - PURPOSE: With the growing interest in advanced image-guidance for surgical robot systems, rapid integration and testing of robotic devices and medical image computing software are becoming essential in the research and development. Maximizing the use of existing engineering resources built on widely accepted platforms in different fields, such as robot operating system (ROS) in robotics and 3D Slicer in medical image computing could simplify these tasks. We propose a new open network bridge interface integrated in ROS to ensure seamless cross platform data sharing. METHODS: A ROS node named ROS-IGTL-Bridge was implemented. It establishes a TCP/IP network connection between the ROS environment and external medical image computing software using the OpenIGTLink protocol. The node exports ROS messages to the external software over the network and vice versa simultaneously, allowing seamless and transparent data sharing between the ROS-based devices and the medical image computing platforms. RESULTS: Performance tests demonstrated that the bridge could stream transforms, strings, points, and images at 30 fps in both directions successfully. The data transfer latency was <1.2 ms for transforms, strings and points, and 25.2 ms for color VGA images. A separate test also demonstrated that the bridge could achieve 900 fps for transforms. Additionally, the bridge was demonstrated in two representative systems: a mock image-guided surgical robot setup consisting of 3D slicer, and Lego Mindstorms with ROS as a prototyping and educational platform for IGT research; and the smart tissue autonomous robot surgical setup with 3D Slicer. CONCLUSION: The study demonstrated that the bridge enabled cross-platform data sharing between ROS and medical image computing software. This will allow rapid and seamless integration of advanced image-based planning/navigation offered by the medical image computing software such as 3D Slicer into ROS-based surgical robot systems. PMID- 28567565 TI - Promoting Limb Salvage through Multi-Disciplinary Care of the Diabetic Patient. AB - OPINION STATEMENT: Despite an explosion in the number of options available for helping diabetic patients heal wounds, major amputation remains a critical issue for these persons. Since diabetes prematurely ages tissues and no organ system is immune to its presence, it makes inherent sense that multi-disciplinary team approaches to these patients is necessary to make significant strides forward. Here, we present literature from the fields of podiatric surgery/medicine, vascular and plastic surgery and introduce the successes that a multi disciplinary limb salvage center can have on the lives and limbs of patients with diabetes. PMID- 28567566 TI - Letter from the New Editor in Chief. PMID- 28567567 TI - Translation, Adaptation, and Preliminary Validation of the Female Sexual Function Index into Spanish (Colombia). AB - The Female Sexual Function Index (FSFI) subjectively explores the dimensions of female sexual functioning. This research undertook to adapt and validate the FSFI to Spanish language in a Colombian sample. To this effect, this study was conducted in two steps, namely: (1) cultural adaptation of the scale with the collaboration of seven experts; and (2) preliminary validation of the scale in a sample of 925 participants. Reliability indices were appropriate in this sample, and external validity in relation to other measures showed significant relationships. Findings suggest that the FSFI is reliable and valid in Spanish for a Colombian population. Further research is needed to establish the test retest reliability and discriminant validity of this Spanish version. PMID- 28567564 TI - Changes in cardiac Na+/K+-ATPase expression and activity in female rats fed a high-fat diet. AB - The aim of this study was to investigate whether the presence of endogenous estradiol alters the effects of a high-fat (HF) diet on activity/expression of the cardiac Na+/K+-ATPase, via PI3K/IRS and RhoA/ROCK signalling cascades in female rats. For this study, female Wistar rats (8 weeks old, 150-200 g) were fed a standard diet or a HF diet (balanced diet for laboratory rats enriched with 42% fat) for 10 weeks. The results show that rats fed a HF diet exhibited a decrease in phosphorylation of the alpha1 subunit of Na+/K+-ATPase by 30% (p < 0.05), expression of total alpha1 subunit of Na+/K+-ATPase by 31% (p < 0.05), and association of IRS1 with p85 subunit of PI3K by 42% (p < 0.05), while the levels of cardiac RhoA and ROCK2 were significantly increased by 84% (p < 0.01) and 62% (p < 0.05), respectively. Our results suggest that a HF diet alters cardiac Na+/K+-ATPase expression via molecular mechanisms involving RhoA/ROCK and IRS 1/PI3K signalling in female rats. PMID- 28567568 TI - Toward a taxonomic model of attention in effortful listening. AB - In recent years, there has been increasing interest in studying listening effort. Research on listening effort intersects with the development of active theories of speech perception and contributes to the broader endeavor of understanding speech perception within the context of neuroscientific theories of perception, attention, and effort. Due to the multidisciplinary nature of the problem, researchers vary widely in their precise conceptualization of the catch-all term listening effort. Very recent consensus work stresses the relationship between listening effort and the allocation of cognitive resources, providing a conceptual link to current cognitive neuropsychological theories associating effort with the allocation of selective attention. By linking listening effort to attentional effort, we enable the application of a taxonomy of external and internal attention to the characterization of effortful listening. More specifically, we use a vectorial model to decompose the demand causing listening effort into its mutually orthogonal external and internal components and map the relationship between demanded and exerted effort by means of a resource-limiting term that can represent the influence of motivation as well as vigilance and arousal. Due to its quantitative nature and easy graphical interpretation, this model can be applied to a broad range of problems dealing with listening effort. As such, we conclude that the model provides a good starting point for further research on effortful listening within a more differentiated neuropsychological framework. PMID- 28567569 TI - On the role, ecology, phylogeny, and structure of dual-family immunophilins. AB - The novel class of dual-family immunophilins (henceforth abbreviated as DFI) represents naturally occurring chimera of classical FK506-binding protein (FKBP) and cyclophilin (CYN), connected by a flexible linker that may include a three unit tetratricopeptide (TPR) repeat. Here, I report a comprehensive analysis of all current DFI sequences and their host organisms. DFIs are of two kinds: CFBP (cyclosporin- and FK506-binding protein) and FCBP (FK506- and cyclosporin-binding protein), found in eukaryotes. The CFBP type occurs in select bacteria that are mostly extremophiles, such as psychrophilic, thermophilic, halophilic, and sulfur reducing. Essentially all DFI organisms are unicellular. I suggest that DFIs are specialized bifunctional chaperones that use their flexible interdomain linker to associate with large polypeptides or multisubunit megacomplexes to promote simultaneous folding or renaturation of two clients in proximity, essential in stressful and denaturing environments. Analysis of sequence homology and predicted 3D structures of the FKBP and CYN domains as well as the TPR linkers upheld the modular nature of the DFIs and revealed the uniqueness of their TPR domain. The CFBP and FCBP genes appear to have evolved in parallel pathways with no obvious single common ancestor. The occurrence of both types of DFI in multiple unrelated phylogenetic clades supported their selection in metabolic and environmental niche roles rather than a traditional taxonomic relationship. Nonetheless, organisms with these rare immunophilins may define an operational taxonomic unit (OTU) bound by the commonality of chaperone function. PMID- 28567572 TI - Minute ventilation to carbon dioxide production ratio is a simple and non invasive index of ventilatory inefficiency in mechanically ventilated patients: proof of concept. PMID- 28567571 TI - Atypical acute motor axonal neuropathy following alemtuzumab treatment in multiple sclerosis patient. PMID- 28567573 TI - Intercultural Understanding through Intergroup Dialogue between Japanese and Chinese University Students. AB - This study had two purposes: (1) to develop university classes in which students can participate in intercultural dialogue by exchanging letters focusing on a topic about everyday norms implicit in each culture, and (2) to examine how students develop their intercultural understanding through participating in these classes. Twenty-two Japanese and six Chinese university students (each group in their own country) participated in three class sessions. At the beginning of the first class, students were given a dialogue theme that focused on cultural differences. The selected theme was mobile phone use while riding on public transportation, as this practice is prohibited in Tokyo but not in Beijing. Students discussed their opinions in small groups, wrote questions to their counterparts in the other country, and then reflected on and discussed the answers received. Analysis of the Japanese students' written reflections showed that their understanding of different cultural values and beliefs changed from one based only on a Japanese cultural perspective to one that respected the relativity of cultural norms. The results suggested that the arousal of negative emotions when students are exposed to the perspectives of other cultures is closely related to their understanding of cultural relativity. PMID- 28567570 TI - beta-Adrenergic signaling, monoamine oxidase A and antioxidant defence in the myocardium of SHR and SHR-mtBN conplastic rat strains: the effect of chronic hypoxia. AB - The beta-adrenergic signaling pathways and antioxidant defence mechanisms play important roles in maintaining proper heart function. Here, we examined the effect of chronic normobaric hypoxia (CNH, 10% O2, 3 weeks) on myocardial beta adrenergic signaling and selected components of the antioxidant system in spontaneously hypertensive rats (SHR) and in a conplastic SHR-mtBN strain characterized by the selective replacement of the mitochondrial genome of SHR with that of the more ischemia-resistant Brown Norway strain. Our investigations revealed some intriguing differences between the two strains at the level of beta adrenergic receptors (beta-ARs), activity of adenylyl cyclase (AC) and monoamine oxidase A (MAO-A), as well as distinct changes after CNH exposure. The beta2 AR/beta1-AR ratio was significantly higher in SHR-mtBN than in SHR, apparently due to increased expression of beta2-ARs. Adaptation to hypoxia elevated beta2 ARs in SHR and decreased the total number of beta-ARs in SHR-mtBN. In parallel, the ability of isoprenaline to stimulate AC activity was found to be higher in SHR-mtBN than that in SHR. Interestingly, the activity of MAO-A was notably lower in SHR-mtBN than in SHR, and it was markedly elevated in both strains after exposure to hypoxia. In addition to that, CNH markedly enhanced the expression of catalase and aldehyde dehydrogenase-2 in both strains, and decreased the expression of Cu/Zn superoxide dismutase in SHR. Adaptation to CNH intensified oxidative stress to a similar extent in both strains and elevated the IL-10/TNF alpha ratio in SHR-mtBN only. These data indicate that alterations in the mitochondrial genome can result in peculiar changes in myocardial beta-adrenergic signaling, MAO-A activity and antioxidant defence and may, thus, affect the adaptive responses to hypoxia. PMID- 28567574 TI - Differences in Effectiveness and Use of Robotic Surgery in Patients Undergoing Minimally Invasive Colectomy. AB - BACKGROUND: We compared patient outcomes of robot-assisted surgery (RAS) and laparoscopic colectomy without robotic assistance for colon cancer or nonmalignant polyps, comparing all patients, obese versus nonobese patients, and male versus female patients. METHODS: We used the 2013-2015 American College of Surgeons National Surgical Quality Improvement Program data to examine a composite outcome score comprised of mortality, readmission, reoperation, wound infection, bleeding transfusion, and prolonged postoperative ileus. We used propensity scores to assess potential heterogeneous treatment effects of RAS by patient obesity and sex. RESULTS: In all, 17.1% of the 10,844 of patients received RAS. Males were slightly more likely to receive RAS. Obese patients were equally likely to receive RAS as nonobese patients. In comparison to nonRAS, RAS was associated with a 3.1% higher adverse composite outcome score. Mortality, reoperations, wound infections, sepsis, pulmonary embolisms, deep vein thrombosis, myocardial infarction, blood transfusions, and average length of hospitalization were similar in both groups. Conversion to open surgery was 10.1% lower in RAS versus nonRAS patients, but RAS patients were in the operating room an average of 52.4 min longer. We found no statistically significant differences (p > 0.05) by obesity status and gender. CONCLUSIONS: Worse patient outcomes and no differential improvement by sex or obesity suggest more cautious adoption of RAS. PMID- 28567575 TI - Analysis of the Cost Effectiveness of Laparoscopic Pancreatoduodenectomy. AB - OBJECTIVE: We sought to determine if laparoscopic pancreatoduodenectomy (LPD) is a cost-effective alternative to open pancreatoduodenectomy (OPD). METHODS: Hospital cost data, discharge disposition, readmission rates, and readmission costs from periampullary cancer patient cohorts of LPD and OPD were compared. The surgical cohorts over a 40-month period were clinically similar, consisting of 52 and 50 patients in the LPD and OPD groups, respectively. RESULTS: The total operating room costs were higher in the LPD group as compared to the OPD group (median US$12,290 vs US$11,299; P = 0.05) due to increased costs for laparoscopic equipment and regional nerve blocks (P <= 0.0001). Although hospital length of stay was shorter in the LPD group (median 7 vs 8 days; P = 0.025), the average hospital cost was not significantly decreased compared to the OPD group (median $28,496 vs $28,623). Surgery-related readmission rates and associated costs did not differ between groups. Compared to OPD patients, significantly more LPD patients were discharged directly home rather than to other healthcare facilities (88% vs 72%; P = 0.047). CONCLUSION: For the index hospitalization, the cost of LPD is equivalent to OPD. Total episode-of-care costs may favor LPD via reduced post-hospital needs for skilled nursing and rehabilitation. PMID- 28567576 TI - Effect of a trans fatty acid-enriched diet on mitochondrial, inflammatory, and oxidative stress parameters in the cortex and hippocampus of Wistar rats. AB - PURPOSE: Previously showed that dietary trans fatty acids (TFAs) may cause systemic inflammation and affect the central nervous system (CNS) in Wistar rats by increased levels of cytokines in the cerebrospinal fluid (CSF) and serum (Longhi et al. Eur J Nutr 56(3):1003-1016, 1). Here, we aimed to clarifying the impact of diets with different TFA concentrations on cerebral tissue, focusing on hippocampus and cortex and behavioral performance. METHODS: Wistar rats were fed either a normolipidic or a hyperlipidic diet for 90 days; diets had the same ingredients except for fat compositions, concentrations, and calories. We used lard in the cis fatty acid (CFA) group and PHSO in the TFA group. The intervention groups were as follows: (1) low lard (LL), (2) high lard (HL), (3) low partially hydrogenated soybean oil (LPHSO), and (4) high partially hydrogenated soybean oil (HPHSO). Mitochondrial parameters, tumor necrosis factor alpha (TNF-alpha), 2'7'-dichlorofluorescein (DCFH) levels in brain tissue, and open field task were analyzed. RESULTS: A worse brain tissue response was associated with oxidative stress in cortex and hippocampus as well as impaired inflammatory and mitochondrial parameters at both PHSO concentrations and there were alterations in the behavioral performance. In many analyses, there were no significant differences between the LPHSO and HPHSO diets. CONCLUSIONS: Partially hydrogenated soybean oil impaired cortical mitochondrial parameters and altered inflammatory and oxidative stress responses, and the hyperlipidic treatment caused locomotor and exploratory effects, but no differences on weight gain in all treatments. These findings suggest that quality is more important than the quantity of fat consumed in terms of CFA and TFA diets. PMID- 28567577 TI - Does the surgical approach influence the implant alignment in total hip arthroplasty? Comparative study between the direct anterior and the anterolateral approaches in the supine position. AB - PURPOSE: The purpose of this study was to clarify the difference in implant alignment between the direct anterior approach (DAA) and the anterolateral approach in the supine position (ALS). METHODS: A retrospective comparative study consisted of 215 consecutive primary total hip arthroplasties using tapered polished and straight cemented-stems via two different minimally invasive approaches (DAA group in 106 hips and ALS group in 109 hips). RESULTS: The cup radiographic anteversion angle was significantly lower in the ALS group than in the DAA group (12.9 degrees versus 16.9 degrees , p = 0.001). The frequency of the safe zone tended to be more favourable in the ALS group than in the DAA group (95% versus 87%, p = 0.052). Stem alignment in the sagittal plane was significantly better in the ALS group than in the DAA group (84% versus 71%, p = 0.022). CONCLUSIONS: Both cup and stem alignments were better in the ALS group than the DAA group. PMID- 28567578 TI - The efficacy and safety of multiple-dose intravenous tranexamic acid on blood loss following total knee arthroplasty: a randomized controlled trial. AB - PURPOSE: To assess the efficacy and safety of multiple-dose intravenous tranexamic acid (IV-TXA) on blood loss following total knee arthroplasty (TKA). METHODS: One hundred fifty nine patients received one bolus of IV-TXA before skin incision and two boluses three and six hours later (group A), or another bolus nine hours later (group B), or another two boluses nine and 12 hours later (group C). The primary outcomes were total blood loss (TBL), hidden blood loss (HBL), and maximum haemoglobin (Hb) drop. Other outcome measurements such as fibrinolysis parameters [fibrin(-ogen) degradation products (FDP), D-dimer], inflammatory factors [interleukin-6 (IL-6)], transfusion rate, range of motion (ROM), length of hospital stay (LOH), and complications were also recorded and compared. RESULTS: The mean TBL, HBL and maximum Hb drop in group C (p < 0.001, p < 0.001, p = 0.025) and group B (p = 0.025, p = 0.025, p = 0.044) were lower than those in group A. FDP and D-Dimer in group C was lower than in group A and B on post-operative day one. IL-6 in group A, B and C showed a downward tendency on post-operative days one and three (POD1 and POD3). Moreover, the ROM and LOH were better in group C. No episodes of transfusion or deep venous thrombosis (DVT) were detected in all groups. CONCLUSIONS: The 5-dose TXA regimen can further reduce the blood loss, diminish the maximum Hb drop, minimize inflammation, enhance mobility, and shorten LOS following TKA, without increasing the risk of complications. An additional dose could be requisite when fibrinolysis maintains after 5-dose regimen has already been performed. LEVEL OF EVIDENCE: I. PMID- 28567579 TI - Left atrial appendage volume as a new predictor of atrial fibrillation recurrence after catheter ablation. AB - PURPOSE: Recurrence of atrial fibrillation (AF) after catheter ablation is common, being clinically relevant to identify predictors of recurrence. The left atrial appendage (LAA) role as an AF trigger is scarcely explored. Our aim was to identify if LAA volume is an independent predictor of AF recurrence after catheter ablation. METHODS: We analysed 52 patients (aged 54 +/- 10 years, 58% male) with paroxysmal and persistent AF who underwent a first AF catheter ablation and had performed contrast-enhanced cardiac computed tomography (CT) prior to the procedure. RESULTS: The mean left atrial and LAA volumes measured by cardiac CT were 98.9 +/- 31.8 and 9.3 +/- 3.5 mL, respectively. All patients received successful pulmonary vein isolation and were followed up for 24 months. AF recurrence occurred in 17 patients (33%). LAA volume was significantly greater in patients with AF recurrence than in those without recurrence (11.3 +/- 2.9 vs. 8.2 +/- 3.4 mL; p = 0.002). Multivariable analysis using Cox regression revealed that LAA volume (hazard ratio 1.32; 95% confidence interval 1.12-1.55; p = 0.001) and persistent AF (hazard ratio 4.22; 95% confidence interval 1.48-12.07; p = 0.007) were independent predictors for AF recurrence. An LAA volume greater than 8.825 mL predicted AF recurrence with 94% sensitivity and 66% specificity. The Kaplan-Meier analysis showed a lower rate free from AF recurrence in the group with an LAA volume >8.825 mL (p < 0.001). CONCLUSIONS: Larger LAA volume was associated with AF recurrence after catheter ablation in patients with paroxysmal and persistent AF. PMID- 28567580 TI - Review of Experimental Modelling in Vascular Access for Hemodialysis. AB - This paper reviews applications of experimental modelling in vascular access for hemodialysis. Different techniques that are used in in-vitro experiments are bulk pressure and flow rate measurements, Laser Doppler Velocimetry and Vector Doppler Ultrasound point velocity measurements, and whole-field measurements such as Particle Image Velocimetry, Ultrasound Imaging Velocimetry, Colour Doppler Ultrasound, and Planar Laser Induced Fluorescence. Of these methods, the ultrasound techniques can also be used in-vivo, to provide realistic boundary conditions to in-vitro experiments or numerical simulations. In the reviewed work, experimental modelling is mainly used to support computational models, but also in some cases as a tool on its own. It is concluded that, to further advance the utility of computational modelling in vascular access research, a rigorous verification and validation procedure should be adopted. Experimental modelling can play an important role in both in-vitro validation, and the quantification of the accuracy, uncertainty, and reproducibility of in-vivo measurement methods. PMID- 28567581 TI - Temporary biventricular support with extracorporeal membrane oxygenation: a feasible therapeutic approach for cardiogenic shock with multiple organ failure. AB - Various strategies using a ventricular assist device (VAD) are applied to rescue Interagency Registry for Mechanically Assisted Circulatory Support profile 1 (Profile-1) patients. However, the optimal use of VAD in Profile-1 patients has not been completely elucidated. We retrospectively reviewed 23 Profile-1 patients [mean age 36.9 +/- 16.6 years, 14 males; 11 with non-ischemic cardiomyopathy (NICM), 9 with fulminant myocarditis (FM), 2 with ischemic cardiomyopathy (ICM), and 1 with peripartum cardiomyopathy (PPCM); 18 with pre-operative percutaneous extracorporeal membrane oxygenation (p-ECMO) support] who underwent VAD implantation from 2011 to 2015 at our institution. Nine initially received left VAD (LVAD) alone (NICM in 9, ICM in 2 with ICM, and FM in 1), one with NICM received biventricular VAD (BiVAD; n = 1), and 10 received LVAD combined with right ventricular support using an ECMO circuit (BiVAD-ECMO) (FM in 8, NICM in 1, and PPCM in 1). Paracorporeal VAD was used in all patients. ECMO was used for the patients with severe pulmonary edema, inflammation, anemia, and thrombopenia. The BiVAD patient died 1.4 months after VAD implantation. The overall survival was comparable between patients with BiVAD-ECMO and LVAD (2-year survival, 80.0 and 75.0%, respectively). Three VAD strategies were initially applied in Profile-1 patients. Among them, the BiVAD-ECMO strategy is a promising therapeutic option to rescue Profile-1 patients with multiple organ failure. PMID- 28567582 TI - Serum and Hair Zinc Levels in Patients with Endemic Osteochondropathy in China: A Meta-analysis. AB - A large number of studies have shown growing interest in the zinc (Zn) levels of serum and hair samples collected from patients with Kashin-Beck disease (KBD), an endemic chronic osteochondral disease. However, inconsistent conclusions regarding the serum and hair Zn levels have been made. The aim of this study is to assess and to explore the change in serum and hair Zn levels among KBD patients. Multiple databases, including PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Wanfang database and Technology of Chongqing (VIP), were carefully searched for available studies up to January 13, 2017 in this integrated analysis. Standard mean difference (SMD) with a 95% confidence interval (95% CI) was calculated using STATA 11.0. A total of 18 studies, involving 978 KBD cases and 1116 healthy controls, were collected in this analysis. Pooled analysis found the KBD patients had a higher hair Zn level and a lower serum Zn level than the healthy controls (hair Zn (MUg/g), SMD = 0.030, 95% CI = -0.315, 0.376; serum Zn (mg/L), SMD = -0.069, 95%CI = -0.924, 0.785). Meta regression method and sensitivity analysis were utilized to analyze the heterogeneity of data. Positive correlations were separately identified between hair Zn level in KBD patients (r = 0.4639, P = 0.032) and controls (r = 0.4743, P = 0.012) and the survey year. No evidence of publication bias was observed. The available results suggest that increased hair Zn level and decreased serum Zn level are commonly found in KBD patients; however, the role of Zn in the etiology and pathogenesis of KBD could not yet be confirmed. PMID- 28567583 TI - Protective Effects of Fragaria ananassa Extract Against Cadmium Chloride-Induced Acute Renal Toxicity in Rats. AB - For experiments of cadmium toxicity in animal models, cadmium (II) chloride is often used due to its solubility in water and its ability to produce high concentrations of cadmium at the target site. The present study was designed to investigate the potential inhibitory effect of the Fragaria ananassa fruit extract on cadmium (II) chloride-induced renal toxicity in rats. Tested animals were pretreated with the extract of F. ananassa and injected with cadmium (II) chloride (6.5-mg/kg body weight) for 5 days. Cadmium (II) chloride significantly increased kidney cadmium concentration, kidney weight, lipid peroxidation, and nitric oxide production. Plasma uric acid, urea, and creatinine levels also increased significantly, indicative of kidney dysfunction. These effects were accompanied by significantly decreased levels of nonenzymatic and enzymatic antioxidant molecules (i.e., glutathione content and the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase). Moreover, messenger RNA (mRNA) expression of the antiapoptotic protein, Bcl-2, and the antioxidant proteins, superoxide dismutase 2 and glutathione reductase, were downregulated markedly, whereas mRNA expression of tumor necrosis factor alpha was upregulated significantly in kidney tissues of cadmium-treated rats. Histology of kidney tissue demonstrated severe, adverse changes that reflected cadmium-induced tissue damage. Pretreatment of rats with the extract of F. ananassa ameliorated all aforementioned cadmium (II) chloride-induced changes. In conclusion, the present study showed acute renal toxicity in rats treated with cadmium (II) chloride. The study also revealed that pretreatment with the extract of F. ananassa could protect the kidney against cadmium (II) chloride-induced acute renal toxicity. PMID- 28567585 TI - Core curriculum illustration: ventriculitis as a complication of ventriculoperitoneal shunt-induced rectal perforation. AB - This is the 35th installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at: http://www.aseronline.org/curriculum/toc.htm . PMID- 28567584 TI - rs3851179 Polymorphism at 5' to the PICALM Gene is Associated with Alzheimer and Parkinson Diseases in Brazilian Population. AB - Alzheimer's (AD) and Parkinson's diseases (PD) share clinical and pathological features, suggesting that they could have common pathogenic mechanisms, as well as overlapping genetic modifiers. Here, we performed a case-control study in a Brazilian population to clarify whether the risk of AD and PD might be influenced by shared polymorphisms at PICALM (rs3851179), CR1 (rs6656401) and CLU (rs11136000) genes, which were previously identified as AD risk factors by genome wide association studies. For this purpose, 174 late-onset AD patients, 166 PD patients and 176 matched controls were genotyped using TaqMan(r) assays. The results revealed that there were significant differences in genotype and allele frequencies for the SNP PICALM rs3851179 between AD/PD cases and controls, but none for CR1 rs6656401 and CLU rs11136000 intronic polymorphisms. After stratification by APOE epsilon4 status, the protective effect of the PICALM rs3851179 A allele in AD cases remains evident only in APOE epsilon4 (-) carriers, suggesting that the APOE epsilon4 risky allele weakens its protective effect in the APOE epsilon4 (+) subgroup. More genetic studies using large-sized and well-defined matched samples of AD and PD patients from mixed populations as well as functional correlation analysis are urgently needed to clarify the role of rs3851179 in the AD/PD risk. An understanding of the contribution of rs3851179 to the development of AD and PD could provide new targets for the development of novel therapies. PMID- 28567587 TI - Estimating the annual frequency of synchronous brain metastasis in the United States 2010-2013: a population-based study. AB - Brain metastases (BM) are one of the most common types of brain tumors and are a relatively common event in the disease process for several high-incidence cancer types, including breast and lung cancers. Historically, information on metastases including BM have not been collected as part of national cancer registration in the US, but BM at time of primary cancer diagnosis (SBM), is now collected by the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) system. Using data from 18 SEER registries from 2010 to 2013, we assessed the frequency of SBM at time of primary diagnosis in the US by site, histology group, sex, race, age, and insurance status. There were 1,634,954 total primary cancer cases in SEER from 2010 to 2013, 1.7% of which presented with SBM. The cancer type with the highest proportion of SBM was lung cancer (10.8% of cases with SBM), followed by esophageal (1.5%), kidney (1.4%), and melanoma (1.2%). SBM varied by age, sex, race, and insurance status for most histologies. Our results reflect the high proportion of patients who are diagnosed with lung cancer at late stages and present with SBM, in contrast to other common cancers in the US where SBM is less common. Demographic variation in molecular subtype and risk behavior may influence variation in SBM. BM is a relatively common event in late stage cancer and cause significant morbidity and mortality, and assessment of accurate population-based data is critical to estimate total disease burden. PMID- 28567586 TI - Tumor-related neurocognitive dysfunction in patients with diffuse glioma: a systematic review of neurocognitive functioning prior to anti-tumor treatment. AB - Deficits in neurocognitive functioning (NCF) frequently occur in glioma patients. Both treatment and the tumor itself contribute to these deficits. Data about the role of the tumor are scarce, because NCF has mostly been studied postoperatively. We aimed to summarize data on pre-treatment NCF in glioma patients and to determine the overall and domain-specific prevalence of neurocognitive dysfunction. We searched PubMed and Embase according to PRISMA-P protocol for studies that evaluated pre-treatment NCF in glioma patients (1995 November 2016) and extracted information about NCF. We performed analysis of data for two main outcome measures; mean cognitive functioning of the study sample (at group level) and the percentage of impaired patients (at individual level). We included 23 studies. Most studies were small observational prospective cohort studies. In 11 (47.5%) studies, patient selection was based on tumor location. NCF was analyzed at the group level in 14 studies, of which 13 (92.9%) found decreased NCF at group level, compared to normative data or matched controls. The proportion of individuals with decreased NCF was reported in 15 studies. NCF was impaired (in any domain) in 62.6% of the individuals (median; interquartile range 31.0-79.0). Cognitive impairments were more common in patients with high-grade glioma than with low-grade glioma (OR 2.50; 95% CI 1.71-3.66). Cognitive impairment occurs in the majority of treatment-naive glioma patients, suggesting that neurocognitive dysfunction is related to the tumor. However, the literature about pre-treatment NCF in glioma patients is characterized by small-scale studies and strong heterogeneity in patient selection, resulting in high risk of bias. PMID- 28567588 TI - Immunotherapy and radiation in glioblastoma. AB - Radiation therapy plays a central role in the management of glioblastoma. Although primarily thought of as modality to provide local tumor control through DNA damage, the capacity of ionizing radiation to modulate tumor immune response has long been recognized. The recent emergence of clinically active immunotherapies offers exciting potential for harnessing the immune modulatory effects or radiation through combinatorial strategies designed to enhance clinical outcomes. In this Review, we provide background describing the unique immune environment within the central nervous system, how ionizing radiation may modulate the tumor immune response, preclinical and clinical data testing the combination of radiation and immune modulating agents, and highlight some of the current challenges in extending these findings clinically. PMID- 28567589 TI - Early tumor growth between initial resection and radiotherapy of glioblastoma: incidence and impact on clinical outcomes. AB - Early tumor growth, or increased contrast-enhancing tumor not related to evolving post-surgical injury, in the interval between surgical resection and initiation of radiotherapy has implications for treatment planning and clinical outcomes. In this study we evaluated the incidence of early tumor growth, correlated tumor growth with survival outcome measures, and assessed predictors of early tumor growth in glioblastoma. We reviewed the records of patients with newly-diagnosed glioblastoma who underwent surgical resection and chemoradiotherapy at our institution. Patients with preoperative, immediate postoperative, and preradiotherapy MRI were included. Conventional MRI and DWI features were assessed. The correlation between early tumor growth and extent of resection with survival was assessed with Kaplan-Meier analysis. Logistic regression was carried out to evaluate predictors of early tumor growth. Of 140 included patients, sixty seven cases (48%) had new or increased contrast enhancement attributed to early tumor growth. Median progression free survival (PFS) and overall survival (OS) were shorter in patients with early tumor growth compared to those without early tumor growth (p < 0.001 for both). Additionally, PFS and OS were longer in patients who underwent gross total resection of enhancing tumor (p = 0.016 and <0.001, respectively). Of the evaluated predictors of early growth, subtotal resection was most likely to result in early growth (p < 0.001). Imaging evidence of early tumor growth is often observed at preradiotherapy MRI and is associated with shorter survival. Gross total resection of contrast enhancing tumor decreases likelihood of early tumor growth. PMID- 28567590 TI - Evaluation of outcomes after stereotactic radiosurgery for pilocytic astrocytoma. AB - Pilocytic astrocytomas are rare intracranial gliomas that are typically treated with surgical extirpation. Our aim was to report the radiologic and clinical outcomes of patients treated with stereotactic radiosurgery (SRS) for pilocytic astrocytoma in the primary and salvage setting. Patients with pilocytic astrocytoma treated at a single institution with SRS from 1990 to 2015 were reviewed. Patient, disease, and treatment characteristics were collected and overall survival, local control, and toxicity were evaluated. Twenty-eight consecutive patients (12 females and 16 males) with a median age of 17.4 years at SRS were identified. Overall, 46% of patients were treated with SRS as part of the initial treatment course after biopsy or subtotal resection, and the remainder as a salvage therapy. The most common location was the cerebellum (28%) followed by brainstem and basal ganglia (21 and 18%, respectively). Four patients received prior external beam radiation therapy (14%). Median tumor volume was 1.84 cc (0.19-15.94 cc), and 39% had a cystic component at SRS. Prescription dose ranged from 4 to 20 Gy (median 16 Gy) to a median isodose line of 50% (range 30 100%). With a median follow-up of 5.2 years (0.3-17.1 years), all patients remained alive at last follow-up. Two patients demonstrated evidence of local radiographic progression at last follow-up (7%). No toxicity could be directly attributed to SRS. In this SRS series, durable tumor control was achieved in 93% of patients with pilocytic astrocytoma, although continued follow up will be important giving the natural history of this disease. As demonstrated, SRS is an appropriate technique in the primary and recurrent treatment of pilocytic astrocytoma that offers favorable disease control and infrequent clinical toxicity. PMID- 28567592 TI - Transcriptional profiling distinguishes inner and outer annulus fibrosus from nucleus pulposus in the bovine intervertebral disc. AB - BACKGROUND: Cells in the intervertebral disc have unique phenotypes and marker genes that separate the nucleus pulposus (NP), annulus fibrosus (AF) and articular cartilage (AC) have been identified. Recently, it was shown that phenotypic marker genes exhibit variable expression in humans. In this study, the bovine tail was used to determine the ability of marker genes to distinguish the outer and inner AF from NP tissue and isolated cells. METHODS: Bovine tail intervertebral discs from 13 donors were dissected and correct isolation of tissue was confirmed. mRNA was isolated directly from tissue or passage 0 monolayer cells and used for gene expression measurements (qPCR). Conventional marker genes (bAcan, bCol1a1, bCol2a1) and novel marker genes (bAdamts17, bBrachyury/T, bCD24, bCol5a1, bCol12a1, bFoxf1, bKrt19, bPax1, bSfrp2) were evaluated. RESULTS: As expected bAcan, bCol2a1 and bCol1a1 distinguished outer AF from NP tissue, while inner AF and NP could not be discriminated. The NP markers bT, bCd24 and bKrt19 were significantly higher expressed in NP than inner and outer AF tissue. bFoxF1 and bPax1 only distinguished IVD tissues from AC. The AF markers bAdamts17, bCol5a1, bCol12a1 and bSfrp2 were higher expressed in the outer AF compared with inner AF and NP tissue. Monolayer culturing strongly decreased bAcan, bCol2a1, bCD24 and bCol5a1 expression, while bCol1a1, bT, bKrt19 and bSfrp2 were not affected. CONCLUSION: The IVD phenotypic marker genes bT, bKrt19, bSfrp2 and bCol12a1 convincingly distinguished NP from outer AF in situ and in vitro. PMID- 28567591 TI - Ribosomal PCR assay of excised intervertebral discs from patients undergoing single-level primary lumbar microdiscectomy. AB - PURPOSE: To determine the presence of infectious microorganisms in the herniated discs of immunocompetent patients, using methodology that we hoped would be of higher sensitivity and specificity than has been reported in the past. Recent studies have demonstrated a significant rate of positive cultures for low virulent organisms in excised HNP samples (range 19-53%). These studies have served as the theoretical basis for a pilot trial, and then, a well done prospective randomized trial that demonstrated that systemic treatment with antibiotics may yield lasting improvements in a subset of patients with axial back pain. Whether the reported positive cultures in discectomy specimens represent true positives is as yet not proven, and critically important if underlying the basis of therapeutic approaches for chronic low back pain. METHODS: This consecutive case series from a single academic center included 44 patients with radiculopathy and MRI findings of lumbar HNP. Patients elected for lumbar microdiscectomy after failure of conservative management. All patients received primary surgery at a single spinal level in the absence of immune compromise. Excised disc material was analyzed with a real-time PCR assay targeting the 16S ribosomal RNA gene followed by amplicon sequencing. No concurrent cultures were performed. Inclusion criteria were as follows: sensory or motor symptoms in a single lumbar nerve distribution; positive physical examination findings including positive straight leg raise test, distributional weakness, and/or a diminished deep tendon reflexes; and magnetic resonance imaging of the lumbar spine positive for HNP in a distribution correlating with the radicular complaint. RESULTS: The PCR assay for the 16S rRNA sequence was negative in all 44 patients (100%). 95% CI 0-8%. CONCLUSIONS: Based on the data presented here, there does not appear to be a significant underlying rate of bacterial disc infection in immunocompetent patients presenting with radiculopathy from disc herniation. PMID- 28567594 TI - The Interaction of Contextual and Syntactic Information in the Processing of Turkish Anaphors. AB - In contrast with languages where anaphors can be classified into pronouns and reflexives, Turkish has a tripartite system that consists of the anaphors o, kendi, and kendisi. The syntactic literature on these anaphors has proposed that whereas o behaves like a pronoun and kendi behaves like a reflexive, kendisi has a more flexible behavior and it can function as both a pronoun and a reflexive. Using acceptability judgments and a self-paced reading task, we examined how Turkish anaphors are processed in isolated sentences and within larger discourse contexts. We manipulated contextual information by creating passages where the context favored a local, long-distance or extra-sentential referent prior to the appearance of the anaphor. We measured the effect of the context on participants' reading times and their end-of-trial coreference assignments. Our results suggest that contextual information affects the interpretive possibilities associated with an anaphor, but that the influence of context depends on the degree to which the anaphor is syntactically constrained. PMID- 28567593 TI - The Social Aptitudes Scale: looking at both "ends" of the social functioning dimension. AB - PURPOSE: Dimensional approaches are likely to advance understanding of human behaviors and emotions. Nevertheless, it is unclear whether instruments in psychiatry capture variability at the full spectrum of these dimensions. We aimed to investigate this issue for two scales assessing distinct aspects of social functioning: the Social Aptitudes Scale (SAS), a "bidirectional" scale constructed to investigate both "ends" of social functioning; and the social Child Behavior Checklist (CBCL-social), a "unidirectional" scale constructed to assess social problems. METHODS: We investigated 2512 children and adolescents aged 6-14. Item response theory was used to investigate on which range of the trait each scale captures information. We performed quantile regressions to investigate if correlations between SAS and CBCL-social vary within different levels of social aptitudes dimension and multiple logistic regressions to investigate associations with negative and positive clinical outcomes. RESULTS: SAS was able to provide information on the full range of social aptitudes, whereas CBCL-social provided information on subjects with high levels of social problems. Quantile regressions showed SAS and CBCL-social have higher correlations for subjects with low social aptitudes and non-significant correlations for subjects with high social aptitudes. Multiple logistic regressions showed that SAS was able to provide independent clinical predictions even after adjusting for CBCL-social scores. CONCLUSIONS: Our results provide further validity to SAS and exemplify the potential of "bidirectional" scales to dimensional assessment, allowing a better understanding of variations that occur in the population and providing information for children with typical and atypical development. PMID- 28567596 TI - Long Pulmonary Residence Time and Plasma Half-Life of Tiotropium: Implications for Pharmacokinetic Bioequivalence Studies. PMID- 28567595 TI - Do Alpha Thalassemia, Fetal Hemoglobin, and the UGT1A1 Polymorphism have an Influence on Serum Bilirubin Levels and Cholelithiasis in Patients with Sickle Cell Disease? AB - BACKGROUND: Increased destruction of erythrocytes in patients with sickle cell disease results in chronic hyperbilirubinemia and leads to the formation of gallstones. OBJECTIVES: The objective of this study was to determine the combined influence of alpha thalassemia, fetal hemoglobin, and the UGT1A1 polymorphism on serum bilirubin levels and cholelithiasis in patients with sickle cell disease. METHODS: We analyzed 72 patients treated in the outpatient hematology unit of the Clinical Hospital of Porto Alegre. The alpha thalassemia trait was determined by multiplex polymerase chain reaction and the polymorphisms of UGT1A1 by capillary electrophoresis with tagged primers. RESULTS: Total and indirect bilirubin levels differed significantly between genotypes TA7/TA7 and TA6/TA6 (p < 0.05). Bilirubin levels were influenced by the UGT1A1 polymorphism but not by alpha thalassemia and fetal hemoglobin. There was no association between cholelithiasis and any of the variables studied. CONCLUSION: These preliminary findings suggest that the UGT1A1 gene can influence serum bilirubin levels in sickle cell anemia and serve as a tool to differentiate an acute hemolytic condition from a pre existing condition of hyperbilirubinemia. PMID- 28567597 TI - Presence of pesticide residues on produce cultivated in Suriname. AB - Agricultural pesticides are widely used in Suriname, an upper middle-income Caribbean country located in South America. Suriname imported 1.8 million kg of agricultural pesticides in 2015. So far, however, national monitoring of pesticides in crops is absent. Reports from the Netherlands on imported Surinamese produce from 2010 to 2015 consistently showed that samples exceeded plant-specific pesticide maximum residue limits (MRLs) of the European Union (EU). Consumption of produce containing unsafe levels of pesticide residues can cause neurological disorders, and particularly, pregnant women and children may be vulnerable. This pilot study assessed the presence of pesticide residues in commonly consumed produce items cultivated in Suriname. Thirty-two insecticides (organophosphates, organochlorines, carbamates, and pyrethroids) and 12 fungicides were evaluated for their levels in nine types of produce. Pesticide residue levels exceeding MRLs in this study regarded cypermethrin (0.32 MUg/g) in tomatoes (USA MRL 0.20 MUg/g), lambda-cyhalothrin (1.08 MUg/g) in Chinese cabbage (USA MRL 0.40 MUg/g), endosulfan (0.07 MUg/g) in tannia (EU MRL 0.05 MUg/g), and lindane (0.02 and 0.03 MUg/g, respectively) in tannia (EU MRL 0.01 MUg/g). While only a few pesticide residues were detected in this small pilot study, these residues included two widely banned pesticides (endosulfan and lindane). There is a need to address environmental policy gaps. A more comprehensive sampling and analysis of produce from Suriname is warranted to better understand the scope of the problem. Preliminary assessments, using intake rate, hazard quotient, and level of concern showed that it is unlikely that daily consumption of tannia leads to adverse health effects. PMID- 28567598 TI - The interplay between phenotypic and ontogenetic plasticities can be assessed using reaction-diffusion models : The case of Pseudoplatystoma fishes. AB - Every morphological, behavioral, or even developmental character expression of living beings is coded in its genotype and is expressed in its phenotype. Nevertheless, the interplay between phenotypic and ontogenetic plasticities, that is, the capability to manifest trait variations, is a current field of research that needs morphometric, numerical, or even mathematical modeling investigations. In the present work, we are searching for a phenotypic index able to identify the underlying correlation among phenotypic, ontogenetic, and geographic distribution of the evolutionary development of species of the same genus. By studying the case of Pseudoplatystoma fishes, we use their skin patterns as an auxiliary trait that can be reproduced by means of a reaction diffusion (RD) model. From this model, we infer the phenotypic index in terms of one of the parameters appearing in the mathematical equations. To achieve this objective, we perform extensive numerical simulations and analysis of the model equations and link the parameter variations with different environmental and physicochemical conditions in which the individuals develop, and which may be regulated by the ontogenetic plasticity of the species. Our numerical study indicates that the patterns predicted by a set of reaction diffusion equations are not uniquely determined by the value of the parameters of the equation, but also depend on how the process is initiated and on the spatial distribution of values of these parameters. These factors are therefore significant, since they show that an individual's growth dynamics and apparent secondary transport processes, like advection, can be determinant for the alignment of motifs in a skin pattern. Our results allow us to discern the correlation between phenotypic, ontogenetic, and geographic distribution of the different species of Pseudoplatystoma fishes, thus indicating that RD models represent a useful taxonomic tool able to quantify evolutionary indexes. PMID- 28567599 TI - Ocular and oto-syphilis: not a thing of the past. PMID- 28567600 TI - Dabrafenib Therapy in 30 Patients with Melanoma Metastatic to the Brain: a Single centre Controlled Retrospective Study in Hungary. AB - Dabrafenib is a potent BRAF inhibitor, which showed intracranial tumor activity. The purpose of our retrospective analysis was to evaluate the efficacy of dabrafenib for patients with melanoma brain metastasis (BM). We studied 30 BRAF mutant melanoma patients with BM, who received dabrafenib after local control of the brain between 2014 and 2017. Eastern Cooperative Oncology Group Performance Status (ECOG) was 0-2. The control arm consisted of 204 melanoma patients from our institutional melanoma database with BM and ECOG 0-2 treated with local therapies and/or chemotherapy, between 2003 and 2015. We found the intracranial disease control rate (DCR) was 83% including four (13%) complete remissions (CR), nine (30%) partial remissions (PR) and twelve (40%) stable diseases (SD) in contrast to five (17%) progressive diseases (PD). With a median follow-up of 14 months, median progression-free survival (PFS) and overall survival (OS) were 5.5 months, and 8.8 months, respectively. If calculated from BM onset, the OS turned to be 11.8 months on the dabrafenib arm, while it was only 6.0 months in the control arm (HR = 0.45, p = 0.0014). Higher risk of progression was observed with increasing ECOG (HR =4.06, p = 0.00027) and if more than 2 extracranial organs were involved (HR = 3.4, p = 0.0077). Elevated lactate dehydrogenase (LDH) was non-significantly associated with worse clinical outcome. Remarkable intracranial activity of dabrafenib in real practice was confirmed by our analysis. PMID- 28567601 TI - Use of large-scale HRQoL datasets to generate individualised predictions and inform patients about the likely benefit of surgery. AB - PURPOSE: The English NHS has mandated the routine collection of health-related quality of life (HRQoL) data before and after surgery, giving prospective patient information about the likely benefit of surgery. Yet, the information is difficult to access and interpret because it is not presented in a lay-friendly format and does not reflect patients' individual circumstances. We set out a methodology to generate personalised information to help patients make informed decisions. METHODS: We used anonymised, pre- and postoperative EuroQol-5D-3L (EQ 5D) data for over 490,000 English NHS patients who underwent primary hip or knee replacement surgery or groin hernia repair between April 2009 and March 2016. We estimated linear regression models to relate changes in EQ-5D utility scores to patients' own assessment of the success of surgery, and calculated from that minimally important differences for health improvements/deteriorations. Classification tree analysis was used to develop algorithms that sort patients into homogeneous groups that best predict postoperative EQ-5D utility scores. RESULTS: Patients were classified into between 55 (hip replacement) to 60 (hernia repair) homogeneous groups. The classifications explained between 14 and 27% of variation in postoperative EQ-5D utility score. CONCLUSIONS: Patients are heterogeneous in their expected benefit from surgery, and decision aids should reflect this. Large administrative datasets on HRQoL can be used to generate the required individualised predictions to inform patients. PMID- 28567602 TI - The impact of older person's frailty on the care-related quality of life of their informal caregiver over time: results from the TOPICS-MDS project. AB - PURPOSE: To examine the impact of changes in an older person's frailty on the care-related quality of life of their informal caregiver. METHODS: Five research projects in the TOPICS-MDS database with data of both older person and informal caregiver at baseline and after 12 months follow-up were selected. Frailty was measured in five health domains (functional limitations, psychological well being, social functioning, health-related quality of life, self-rated health). Care-related quality of life was measured with the Care-Related Quality of Life instrument (CarerQoL-7D), containing two positive (fulfilment, perceived support) and five negative dimensions (relational problems, mental health problems, physical health problems, financial problems, problems combining informal care with daily activities). RESULTS: 660 older person/caregiver couples were included. Older persons were on average 79 (SD 6.9) years of age, and 61% was female. Caregivers were on average 65 (SD 12.6) years of age, and 68% was female. Results of the multivariable linear and logistic regression analyses showed that an increase in older person's frailty over time was related to a lower total care related quality of life of the caregiver, and to more mental and physical health problems, and problems with combining informal care with daily activities at follow-up. A change in the older person's psychological well-being was most important for the caregiver's care-related quality of life, compared to the other health domains. CONCLUSIONS: Health professionals observing decreasing psychological well-being of an older person and increasing hours of informal care provision should be aware of the considerable problems this may bring to their informal caregiver, and should tailor interventions to support informal caregivers according to their specific needs and problems. PMID- 28567603 TI - Nearly complete mitogenome of hairy sawfly, Corynis lateralis (Brulle, 1832) (Hymenoptera: Cimbicidae): rearrangements in the IQM and ARNS1EF gene clusters. AB - The Cimbicidae is a small family of the primitive and relatively less diverse suborder Symphyta (Hymenoptera). Here, nearly complete mitochondrial genome (mitogenome) of hairy sawfly, Corynis lateralis (Hymenoptera: Cimbicidae) was sequenced using next generation sequencing and comparatively analysed with the mitogenome of Trichiosoma anthracinum. The sequenced length of C. lateralis mitogenome was 14,899 bp with an A+T content of 80.60%. All protein coding genes (PCGs) are initiated by ATN codons and all are terminated with TAR or T- stop codon. All tRNA genes preferred usual anticodons. Compared with the inferred insect ancestral mitogenome, two tRNA rearrangements were observed in the IQM and ARNS1EF gene clusters, representing a new event not previously reported in Symphyta. An illicit priming of replication and/or intra/inter-mitochondrial recombination and TDRL seem to be responsible mechanisms for the rearrangement events in these gene clusters. Phylogenetic analyses confirmed the position of Corynis within Cimbicidae and recovered a relationship of Tenthredinoidea + (Cephoidea + Orussoidea) in Symphyta. PMID- 28567604 TI - Preparation of timing structure involves two independent sub-processes. AB - The current study examined the processes involved in the preparation of sequencing and timing initiation for multi-component responses. In two experiments, participants performed a reaction time (RT) task involving a three key-press sequence with either a simple (isochronous) or complex (non isochronous) timing structure. Conditions involved a precue that provided information about all features of the movement (simple RT), no features of the movement (choice RT), sequencing only, or timing structure only. When sequencing was precued, RT decreased significantly as compared to choice RT, indicative of advance preparation of sequencing. When timing was precued, RT decreased significantly compared to choice RT when the timing structure was simple, suggesting that some aspect of timing preparation can occur prior to the go stimulus. However, even when the timing structure was known in advance, RT was still affected by timing complexity, confirming that some aspect of timing preparation cannot occur until after the onset of the stimulus and thus occurs during the RT interval. To explain these findings, we propose a two-component model of preparation for the timing initiation structure in which timing selection occurs in advance but timing implementation must occur following the go signal. These results support and extend previous findings regarding the independence of the processes associated with response sequencing and timing initiation. PMID- 28567605 TI - Erratum to: One-stage immobilization of the microalga Porphyridium purpureum using a biocompatible silica precursor and study of the fluorescence of its pigments. PMID- 28567606 TI - Autonomy, Equality, and Teaching among Aka Foragers and Ngandu Farmers of the Congo Basin. AB - The significance of teaching to the evolution of human culture is under debate. We contribute to the discussion by using a quantitative, cross-cultural comparative approach to investigate the role of teaching in the lives of children in two small-scale societies: Aka foragers and Ngandu farmers of the Central African Republic. Focal follows with behavior coding were used to record social learning experiences of children aged 4 to 16 during daily life. "Teaching" was coded based on a functional definition from evolutionary biology. Frequencies, contexts, and subtypes of teaching as well as the identity of teachers were analyzed. Teaching was rare compared to observational learning, although both forms of social learning were negatively correlated with age. Children received teaching from a variety of individuals, and they also engaged in teaching. Several teaching types were observed, including instruction, negative feedback, and commands. Statistical differences in the distribution of teaching types and the identity of teachers corresponded with contrasting forager vs. farmer foundational cultural schema. For example, Aka children received less instruction, which empirically limits autonomous learning, and were as likely to receive instruction and negative feedback from other children as they were from adults. Commands, however, exhibited a different pattern suggesting a more complex role for this teaching type. Although consistent with claims that teaching is relatively rare in small-scale societies, this evidence supports the conclusion that teaching is a universal, early emerging cognitive ability in humans. However, culture (e.g., values for autonomy and egalitarianism) structures the nature of teaching. PMID- 28567608 TI - Individual difference in pectoralis major muscle thickness and its effect on single-stage breast reconstruction using a tissue expander. AB - BACKGROUND: In breast reconstruction using a tissue expander (TE), sufficient coverage of the TE with the pectoralis major (PM) muscle, particularly with a musculofascial flap, is highly important for avoiding postoperative complications. In patients in whom the PM is thin, intraoperative trauma often occurs, leading to troublesome repair. The present study aimed to investigate the usefulness of preoperative measurement of PM thickness in planning of breast reconstruction using a TE. METHODS: In this case-control study, we identified 68 patients (70 breasts) with mammary carcinoma treated with simple mastectomy and TE insertion from April 2014 to December 2016. We measured average PM thickness at two specific points, sternocostal PM distance on the long axis and sternocostal PM area preoperatively using magnetic resonance imaging. Then, we analyzed the difference in PM thickness among individuals and its relationship to intraoperative trauma to the PM or surgical difficulty creating a muscular pocket (delicate PM). RESULTS: Average PM thickness was significantly larger in younger patients (p = 0.046) and those with larger breasts (p < 0.01). In addition, average PM thickness on the affected side was significantly smaller in patients with delicate PM (12 breasts) (p < 0.01). PM thickness had a significant influence on delicate or firm PM (odds ratio 27.40; 95% confidence interval 2.01 372.00; p = 0.013). CONCLUSION: These findings demonstrate the usefulness of preoperative measurement of PM thickness in planning of breast reconstruction using a TE. Dissection should be performed more carefully in patients with average PM thickness less than 2.9 mm. PMID- 28567609 TI - Positive Margins After Resection of Metastatic Colorectal Cancer in the Liver: Back to the Drawing Board? PMID- 28567607 TI - Pancreatic neuroendocrine tumors in MEN1 disease: a mono-centric longitudinal and prognostic study. AB - PURPOSE: Multiple endocrine neoplasia type 1 (MEN1) is an inherited endocrine neoplastic syndrome associated with a greater risk of endocrine tumor development like pancreatic neuroendocrine tumors (p-NET), with different clinical characteristics from sporadic ones. This paper aims to compare clinical, hystological and morphological aspects of p-NET in patients affected from MEN1 (MEN1+) and not-affected ones (MEN1-). METHODS: We performed a retrospective observational study. Data was collected between December 2010 and December 2015, including patients with a histological diagnosis of p-NET and radiological imaging. We compared clinical, histological, radiological, and prognostic aspects of MEN+ p-NET with MEN-1 p-NET. RESULTS: Of the 45 patients enrolled, 13 MEN1+ and 21 MEN1- cases were analyzed. Frequency of not secreting p-NETs and insulin secreting p-NETs, histopathological grades and Ki67 expression were superimposable between MEN1+ and MEN1- patients. MEN1+ pNETs are more often multicentric compared to MEN1- pNETs. Frequency of liver and nodes metastatic spread was higher in MEN1- p-NET compared to MEN1+ p-NET. Analyzing p-NET according to the disease outcome, we found that recovered and stable p-NETs in MEN1+ patients, compared to MEN1- cases, are diagnosed at lower age (p = 0.04/p = 0.002) and that are more frequently multifocal lesions (p = 0.009/p = 0.002). CONCLUSIONS: In our study pNETs in MEN1+ and pNETs in MEN1- don't significantly differ for prognosis but only for clinical features. p-NET stage disease and prognosis can be positively influenced by early diagnosis and screening in index patients' first-degree relatives. PMID- 28567610 TI - Impact of interrupted cyclosporine treatment on the development of chronic nephrotoxicity in children with steroid-dependent nephrotic syndrome. PMID- 28567611 TI - Dysfunctional voiding: the importance of non-invasive urodynamics in diagnosis and treatment. AB - In Dysfunctional voiding, failure of the external sphincter-pelvic floor complex to relax during micturition results in bladder outflow obstruction with a spectrum of presentation from more benign lower urinary tract dysfunction including recurrent urinary tract infections, to significant upper tract pathology and end-stage renal failure. There is no underlying neurological or anatomical cause and the condition is postulated to be a largely learnt behavior. Diagnosis relies on non-invasive urodynamics and in particular uroflowmetry, plus or minus EMG, which is also used in biofeedback, the mainstay of treatment. The etiology, presentation, diagnosis, and treatment with particular emphasis on non invasive urodynamics are covered. PMID- 28567612 TI - Uncontrolled delivery of liquid volatile anaesthetic when using the anaesthetic conserving device. AB - During patient sedation with liquid volatile anaesthetic, some problems may occur through a process called auto-pumping, defined as an expansion of bubbles inside the syringe, which can lead to uncontrolled anaesthetic delivery. The study examined how the temperature of liquid volatile anaesthetics (sevoflurane and isoflurane) and the presence of gas bubbles in the syringe affect the occurrence of auto-pumping when using the anaesthetic conserving device (ACD, AnaConDaTM, Sedana Medical, Uppsala, Sweden). Four different circumstances for each volatile anaesthetic were tested with a bench study: volatile anaesthetic at room temperature or precooled with and without the presence of gas bubbles in the syringe. Liquid volatile anaesthetic was infused into the ACD via a syringe pump at a fixed rate and heated gradually until the temperature of the syringe surface reached 50 degrees C. A main-stream gas monitor was used to measure the expired fraction of volatile anaesthetic (FE vol%). The occurrence of auto-pumping was observed only in the subgroups containing gas bubbles, with both anaesthetics. In these subgroups, the values of the expired anaesthetic gas fraction increased dramatically with the expansion of gas bubbles in the syringe (DeltaFE ranged from +1.6 to 2.4 vol% for sevoflurane and +2.3 to 3.4 vol% for isoflurane). Furthermore, when the heat source was removed, a substantial decline in anaesthetic agent values below the baseline was observed with both anaesthetics. The presence of gas bubbles in the syringe, especially when exposed to a heat source, may provoke auto-pumping with uncontrolled excessive anaesthetic delivery. If auto-pumping is suspected, the syringe pump must be stopped and the ACD removed from the breathing circuit at once. PMID- 28567614 TI - A Synonymous Mutation at Bovine Alpha Vitronectin Domain of Integrin Host Receptor (ITGAV) Gene Effect the Susceptibility of Foot-and-Mouth Disease in Crossbred Cattle. AB - Integrins are one of the major biologically active proteins responsible for Foot and-mouth disease virus (FMDV)- host interaction. Out of various heterodimeric integrins discovered, alphaVbeta6 heterodimer serves as the chief receptor for FMDV host tropism. Earlier studies reported that, SNPs at beta 6 subunit (ITGB6) were associated with the occurrence of the diseases in cattle. In this study we report the association between a synonymous SNP (rs719257875) at bovine alpha vitronectin domain of integrin receptor (ITGAV) gene and FMD susceptibility in cattle. A strong significant association (P < 0.0001) of the genotypes with FMD susceptibility were obtained, where the CC genotypes play a major role in occurrence of FMD in crossbred cattle. PMID- 28567613 TI - Characterisation of a pucBA deletion mutant from Rhodopseudomonas palustris lacking all but the pucBAd genes. AB - Rhodopseudomonas palustris is a species of purple photosynthetic bacteria that has a multigene family of puc genes that encode the alpha and beta apoproteins, which form the LH2 complexes. A genetic dissection strategy has been adopted in order to try and understand which spectroscopic form of LH2 these different genes produce. This paper presents a characterisation of one of the deletion mutants generated in this program, the pucBAd only mutant. This mutant produces an unusual spectroscopic form of LH2 that only has a single large NIR absorption band at 800 nm. Spectroscopic and pigment analyses on this complex suggest that it has basically a similar overall structure as that of the wild-type HL LH2 complex. The mutant has the unique phenotype where the mutant LH2 complex is only produced when cells are grown at LL. At HL the mutant only produces the LH1-RC core complex. PMID- 28567615 TI - Obstructive Sleep Apnea and Chronic Kidney Disease. AB - Chronic kidney disease (CKD) often accompanies obstructive sleep apnea (OSA). A causative connection of the two disease entities is uncertain. However, eliminating OSA improves the prognosis of CKD patients. In the present study we examined a possible relationship between OSA and CKD, and whether there would be a mutual enhancing interaction in the severity of the two diseases. The study was of a retrospective nature and encompassed 382 patients over the period of 1 January 2014-30 June 2015. The OSA diagnosis was supported by a polysomnographic examination in 363 (95.0%) patients. Blood samples were taken for the determination of kidney function indices. The influence on OSA and CKD of comorbidities also was examined. We found a high probability of a simultaneous occurrence of OSA and CKD; with the odds ratio of 3.94 (95% CI 1.5-10.3%; p = 0.005). The 363 patients with OSA were stratified into 73 (20.1%) mild, 98 (27.0%) moderate, and 192 (52.9%) severe OSA cases according to the apnea hypopnea index. CKD was found in 43 (58.9%) patients with mild OSA, 73 (74.5%) with moderate OSA, and 137 (71.4%) with severe OSA. Most OSA patients also suffered from hypertension and obesity. For comparison, CKD was detected in 7 (36.8%) out of the 19 patients without OSA (p < 0.003). We conclude that CKD develops significantly more often in patients with OSA than in those without it, and CKD frequency increases with the severity of OSA. PMID- 28567616 TI - Chagas Disease Knowledge and Risk Behaviors of the Homeless Population in Houston, TX. AB - Chagas disease is a parasitic infection, caused by Trypanosoma cruzi, endemic in Latin America. Sylvatic T. cruzi-infected triatomine vectors are present in rural and urban areas in the southern USA and may transmit T. cruzi infection to at risk populations, such as homeless individuals. Our study aimed to evaluate Chagas disease knowledge and behaviors potentially associated with transmission risk of Chagas disease among Houston, Texas' homeless population by performing interviews with 212 homeless individuals. The majority of the 212 surveyed homeless individuals were male (79%), African-American (43%), American-born individuals (96%). About 30% of the individuals reported having seen triatomines in Houston, and 25% had evidence of blood-borne transmission risk (IV drug use and/or unregulated tattoos). The median total time homeless was significantly associated with recognition of the triatomine vector. Our survey responses indicate that the homeless populations may exhibit potential risks for Chagas disease, due to increased vector exposure, and participation in blood-borne pathogen risk behaviors. Our findings warrant additional research to quantify the prevalence of Chagas disease among homeless populations. PMID- 28567617 TI - Analysis of Fluorescence Quenching for Newly Synthesized Biologically Active 3(2H)-pyridazinone Derivative by Aniline. AB - Herein, we have studied the analysis of fluorescence quenching for newly synthesized biologically active 3(2H)-pyridazinone derivative 5-(5-bromo-2 hydroxy-phenyl)-2-phenyl-2H-pyridazin-3-one [BHP] by various concentrations of aniline using UV-Visible spectroscopy, fluorescence spectroscopy and time correlated single photon counting technique in five different solvents namely, methanol, ethanol, propan-2-ol, dimethylsulfoxide and ethyl acetate at room temperature. The fluorescence intensity of BHP molecule decrease with increasing in the aniline concentration and it is studied using the Stern-Volmer relation. The obtained Stern-Volmer plots were found to be linear in all the five solvents. The various parameters responsible for the fluorescence quenching such as quenching rate parameters (k q ), diffusion rate parameter (k d ) and the probability of quenching per encounter (p) were experimentally calculated in all five solvents. An activation energy of quenching (E a ) was calculated using the values of activation energy of diffusion (E d ) and p. It was found that the values of E a are greater than E d in all five solvents studied. Further, it is inferred that the fluorescence quenching reactions in BHP molecule are more significantly affected by activation energy processes. PMID- 28567619 TI - Malignant Duodenal GIST in a Patient with Situs Inversus Totalis-a Rare Association and Brief Review of Literature. PMID- 28567618 TI - Ganglion cell loss in early glaucoma, as assessed by photopic negative response, pattern electroretinogram, and spectral-domain optical coherence tomography. AB - PURPOSE: To evaluate discrimination ability of pattern electroretinography (PERG) and photopic negative response (PhNR) between early glaucoma and healthy controls, and their relationship with structural measurements using spectral domain optical coherence tomography (SD-OCT). METHODS: Cross-sectional study with 34 patients with ocular hypertension (n = 7), suspect glaucoma (n = 17), and early glaucoma (n = 10), plus 24 age-matched controls. The following parameters were analyzed: P50 and N95 amplitude of the PERG, PhNR amplitude and PhNR/b-wave ratio, peripapillary retinal and macular nerve fiber layer (NFL) thicknesses, and ganglion cell complex (GCC) thickness. Data from only one eye per individual were included in the statistical analysis. Descriptive statistics, ANOVA, receiver operating characteristics (ROC) curves, and correlation tests were used for analysis of the variables. RESULTS: PERG N95 and PhNR amplitudes were significantly reduced in suspect and early glaucoma eyes versus controls. Significant differences across ocular hypertensive, suspect, and early glaucoma eyes were found for macular NFL and GCC thickness, but not for any of the ERG parameters. The mean PhNR amplitude did not differ across these groups and was already reduced on average by 46% in ocular hypertensive and early glaucoma eyes and by 52% in suspect glaucoma eyes. The P50 and N95 amplitudes showed similar reduction in suspect and early glaucoma eyes on average by 15 and 26%, respectively. Of the ERG parameters, PhNR amplitude distinguished best between glaucoma and control groups, with an area under ROC curve of 0.90 for suspect glaucoma, and 0.86 for early glaucoma. PhNR/b-wave ratio showed strongest association in suspect glaucoma eyes with peripapillary retinal (r, 0.61) and macular NFL (r, 0.76) thicknesses. In eyes with early glaucoma, peripapillary retinal NFL thickness correlated best with PhNR amplitude (r, 0.71) and PERG P50 amplitude (r, 0.67). CONCLUSIONS: In eyes with suspect glaucoma, important decrease in PhNR amplitude is associated with small changes in peripapillary retinal and macular NFL thicknesses. These findings suggest that PhNR may be a useful and sensitive test in eyes with diagnostic dilemma, although further follow-up of such eyes is required for definitive confirmation. PMID- 28567620 TI - Endophytic fungal assemblage in Achyranthes aspera Linn. revealed by internal transcribed spacer region of nuclear ribosomal RNA genes. AB - Only scanty reports are available on endophytic fungal associations in Achyranthes aspera Linn. Hence in this study a total of 504 isolates belonging to ten different species of fungi were isolated from asymptomatic, surface sterilised segments of leaf, stem and root of A. aspera collected from different locations of Kerala, India. Among the isolates ascomycetes were most prevalent. Colonisation rate of fungal endophytes was high in leaf tissue (95%) followed by stem (77.75%) and root segments (33.33%). The most frequent and dominant coloniser of the host plant were Colletotrichum sp., which was isolated from all locations. Scanning electron microscopy demonstrated the presence of hyphae in the intra and intercellular spaces of the plant tissue. Morphological and phylogenetic analyses using internal transcribed spacer (ITS) sequences of nuclear rRNA genes showed that the fungi recovered belonged to the lineages of Sordariomycetes, Dothideomycetes, Eurotiomycetes and Tremellomycetes. A maximum likelihood tree revealed the relationship between the obtained sequence data and the closest sequences retrieved from the GenBank. PMID- 28567621 TI - Cost-effective screening and isolation of xylano-cellulolytic positive microbes from termite gut and termitarium. AB - In this study, screening and isolation of xylano-cellulolytic enzymes producing positive microbes from termitarium and termite gut microbiome were done using cost-effective agricultural wastes. The enrichment of xylano-cellulolytic microbes was done in three steps using wheat bran and waste paper. The qualitative screening of xylanase and cellulase producing micro-organisms was done on nutrient agar plates containing wheat bran and waste paper, respectively. Xylanase and cellulase positive colonies were analysed by observing the zone of substrate (wheat bran and waste paper) hydrolysis around the colonies. A total of 30 bacterial isolates were obtained from termite gut and termitarium, respectively. Xylan and cellulose degrading potential of the positive isolates was also quantitatively estimated using agro-wastes-based medium. All the bacterial isolates displayed cellulase and xylanase activities in the range of 0.45-6.80 and 51-380 IU/ml, respectively. This is the first report mentioning the isolation of xylano-cellulolytic microbes from termite gut and termitarium using very simple cost-effective methodology. PMID- 28567622 TI - Fungal pretreatment of sweet sorghum bagasse with supplements: improvement in lignin degradation, selectivity and enzymatic saccharification. AB - Sweet sorghum bagasse (SSB) from food processing and agricultural industry has attracted the attention for uses in production of biofuel, enzymes and other products. The alteration in lignocellulolytic enzymes by use of supplements in fungal pretreatment of SSB to achieve higher lignin degradation, selectivity value and enzymatic hydrolysis to fermentable sugar was studied. Fungal strain Coriolus versicolor was selected for pretreatment due to high ligninolytic and low cellulolytic enzyme production resulting in high lignin degradation and selectivity value. SSB was pretreated with supplements of veratryl alcohol, syringic acid, catechol, gallic acid, vanillin, guaiacol, CuSO4 and MnSO4. The best results were obtained with CuSO4, gallic acid and syringic acid supplements. CuSO4 increased the activities of laccase (4.9-fold) and polyphenol oxidase (1.9 fold); gallic acid increased laccase (3.5-fold) and manganese peroxidase (2.5 fold); and syringic acid increased laccase (5.6-fold), lignin peroxidase (13 fold) and arylalcohol oxidase (2.8-fold) resulting in enhanced lignin degradations and selectivity values than the control. Reduced cellulolytic enzyme activities resulted in high cellulose recovery. Enzymatic hydrolysis of pretreated SSB yielded higher sugar due to degradation of lignin and reduced the crystallinity of cellulose. The study showed that supplements could be used to improve the pretreatment process. The results were confirmed by scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy and thermogravimetric/differential thermogravimetric analysis of SSB. PMID- 28567623 TI - Molecular and functional characterization of myxobacteria isolated from soil in India. AB - This study reports the isolation of myxobacteria from soil collected from plains in north India. Based on the morphology and 16S rDNA sequence, the isolated myxobacteria were identified as Corallococcus sp., Pyxidicoccus sp., Myxococcus sp., Cystobacter sp. and Archangium sp. The myxobacteria were functionally characterized to assess their ability to produce antibacterial and anticancer metabolites. The isolates were found to be functionally versatile as they produced extracellular bioactive molecules that exhibited high frequency of activities against Bacillus cereus, Mycobacterium smegmatis, Enterobacter cloacae and Pseudomonas syringae. The strains also showed cytotoxic activity against the human cancer cell lines of liver, pancreas, prostrate, bone and cervix. These results indicate the importance of isolating diverse strains of myxobacteria from unexplored habitats to find novel bioactive compounds. Moreover, the bioactive molecules explored in this study are predominantly hydrophilic compounds, obviating the limitations of solubility-related aspect of drug discovery. PMID- 28567625 TI - Biodegradation of alpha-endosulfan via hydrolysis pathway by Stenotrophomonas maltophilia OG2. AB - Stenotrophomonas maltophilia OG2 was isolated from the intestine of cockroaches that was collected from a cow barn contaminated some pesticides belong to pyrethroid and organochlorine groups. OG2 was able to degrade alpha-endosulfan in non sulfur medium (NSM) as a sole sulfur source for growth within 10 days of incubation. The effects of some growth parameters on endosulfan biodegradation by OG2 was studied and found that the biodegradation was significantly affected by the endosulfan concentrations, pH and temperature. Experimental results obtained in different conditions show that the optimum concentration of alpha-endosulfan, pH and temperature were 100 mg/L, 8.0 and 30 degrees C, respectively. Under these conditions, the bacterium degraded 81.53% of the alpha-endosulfan after 10 days. The concentration of alpha-endosulfan and its metabolites was determined by HPLC. Endosulfan ether, endosulfan lactone and endosulfan diol were the main metabolites in culture, but did not produce toxic metabolite, endosulfan sulfate. These results suggested that S. maltophilia OG2 degrades alpha-endosulfan via a hydrolysis pathway. The present study indicates that strain OG2 may have potential use in the biodegradation of pesticides contaminated environments. PMID- 28567624 TI - Properties, environmental fate and biodegradation of carbazole. AB - The last two decades had witnessed extensive investigation on bacterial degradation of carbazole, an N-heterocyclic aromatic hydrocarbon. Specifically, previous studies have reported the primary importance of angular dioxygenation, a novel type of oxygenation reaction, which facilitates mineralization of carbazole to intermediates of the TCA cycle. Proteobacteria and Actinobacteria are the predominant bacterial phyla implicated in this novel mode of dioxygenation, while anthranilic acid and catechol are the signature metabolites. Several studies have elucidated the degradative genes involved, the diversity of the car gene clusters and the unique organization of the car gene clusters in marine carbazole degraders. However, there is paucity of information regarding the environmental fate as well as industrial and medical importance of carbazole and its derivatives. In this review, attempt is made to harness this information to present a comprehensive outlook that not only focuses on carbazole biodegradation pathways, but also on its environmental fate as well as medical and industrial importance of carbazole and its derivatives. PMID- 28567626 TI - Isolation, characterization and genetic diversity of NBS-LRR class disease resistant gene analogs in multiple virus resistant line of chilli (Capsicum annuum L.). AB - Viruses are serious threat to chilli crop production worldwide. Resistance screening against several viruses resulted in identifying a multiple virus resistant genotype 'IHR 2451'. Degenerate primers based on the conserved regions between P-Loop and GLPL of Resistance genes (R-genes) were used to amplify nucleotide binding sites (NBS)-encoding regions from genotype 'IHR 2451'. Alignment of deduced amino acid sequences and phylogenetic analyses of isolated sequences distinguished into two groups representing toll interleukin-1 receptor (TIR) and non-TIR, and different families within the group confirming the hypotheses that dicots have both the types of NBS-LRR genes. The alignment of deduced amino acid sequences revealed conservation of subdomains P-loop, RNBS-A, kinase2, RNBS-B, and GLPL. The distinctive five RGAs showing specific conserved motifs were subjected to BLASTp and indicated high homology at deduced amino acid level with R genes identified such as Pvr9 gene for potyvirus resistance, putative late blight resistance protein homolog R1B-23 and other disease resistance genes suggesting high correlation with resistance to different pathogens. These pepper RGAs could be regarded as candidate sequences of resistant genes for marker development. PMID- 28567627 TI - Endophytic Nocardiopsis sp. from Zingiber officinale with both antiphytopathogenic mechanisms and antibiofilm activity against clinical isolates. AB - Novel and potential antimicrobial compounds are essential to tackle the frequently emerging multidrug-resistant pathogens and also to develop environment friendly agricultural practices. In the current study, endophytic actinomycetes from rhizome of Zingiber officinale were explored in terms of its diversity and bioactive properties. Fourteen different organisms were isolated, identified and screened for activity against Pythium myriotylum and human clinical pathogens. Among these, Nocardiopsis sp. ZoA1 was found to have highest inhibition with excellent antibacterial effects compared to standard antibiotics. Remarkable antibiofilm property was also shown by the extract of ZoA1. Its antifungal activity against Pythium and other common phytopathogens was also found to be promising as confirmed by scanning electron microscopic analysis. By PCR-based sequence analysis of phz E gene, the organism was confirmed for the genetic basis of phenazine biosynthesis. Further GC-MS analysis of Nocardiopsis sp. revealed the presence of various compounds including Phenol, 2,4-bis (1,1-dimethylethyl) and trans cinnamic acid which can have significant role in the observed result. The current study is the first report on endophytic Nocardiopsis sp. from ginger with promising applications. In vivo treatment of Nocardiopsis sp. on ginger rhizome has revealed its inhibition towards the colonization of P. myriotylum which makes the study to have promises to manage the severe diseases in ginger like rhizome rot. PMID- 28567629 TI - Optimization of rhamnolipid production by Pseudomonas aeruginosa OG1 using waste frying oil and chicken feather peptone. AB - In the present study, production of rhamnolipid biosurfactant by Pseudomonas aeruginosa OG1 was statistically optimized by response surface methodology. Box Behnken design was applied to determine the optimal concentrations of 52, 9.2, and 4.5 g/L for carbon source (waste frying oil), nitrogen source (chicken feather peptone), and KH2PO4, respectively, in production medium. Under the optimized cultivation conditions, rhamnolipid production reached up to 13.31 g/L (with an emulsification activity of 80%), which is approximately twofold higher than the yield obtained from preliminary cultivations. Hence, rhamnolipid production, noteworthy in the literature, was achieved with the use of statistical optimization on inexpensive waste materials for the first time in the present study. PMID- 28567628 TI - Enzyme-mediated biodegradation of long-chain n-alkanes (C32 and C40) by thermophilic bacteria. AB - Removal of long-chain hydrocarbons and n-alkanes from oil-contaminated environments are mere important to reduce the ecological damages, while bio augmentation is a very promising technology that requires highly efficient microbes. In present study, the efficiency of pure isolates, i.e., Geobacillus thermoparaffinivorans IR2, Geobacillus stearothermophillus IR4 and Bacillus licheniformis MN6 and mixed consortium on degradation of long-chain n-alkanes C32 and C40 was investigated by batch cultivation test. Biodegradation efficiencies were found high for C32 by mixed consortium (90%) than pure strains, while the pure strains were better in degradation of C40 than mixed consortium (87%). In contrast, the maximum alkane hydroxylase activities (161 umol mg-1 protein) were recorded in mixed consortium system that had supplied with C40 as sole carbon source. Also, the alcohol dehydrogenase (71 umol mg-1 protein) and lipase activity (57 umol mg-1 protein) were found high. Along with the enzyme activities, the hydrophobicity natures of the bacterial strains were found to determine the degradation efficiency of the hydrocarbons. Thus, the study suggested that the hydrophobicity of the bacteria is a critical parameter to understand the biodegradation of n-alkanes. PMID- 28567630 TI - Hot springs of Indian Himalayas: potential sources of microbial diversity and thermostable hydrolytic enzymes. AB - Microbial communities in hot springs at high elevations have been extensively studied worldwide. In this sense, the Indian Himalaya regions is valuable ecosystems for providing both the extreme 'cold' and 'hot' sites for exploring microbial diversity. In the present study, a total of 140 thermophilic bacteria were isolated from 12 samples collected from Manikaran and Yumthang hot springs of Indian Himalayas. The bacterial isolates were studied for phylogenetic profiling, growth properties at varying conditions and potential sources of extracellular thermostable hydrolytic enzymes such as protease, amylase, xylanase and cellulase. Based on production of extracellular hydrolases, 51 isolates from Manikaran (28) and Yumthang thermal springs (23) were selected and identified using 16S rRNA gene sequencing which included 37 distinct species of 14 different genera namely Anoxybacillus, Bacillus, Brevibacillus, Brevundimonas, Burkholderia, Geobacillus, Paenibacillus, Planococcus, Pseudomonas, Rhodanobacter, Thermoactinomyces, Thermobacillus, Thermonema and Thiobacillus. Out of 51 hydrolase producing bacteria, 24 isolates showed stability at wide range of temperature and pH treatments. In present investigation, three thermotolerant bacteria namely, Thermobacillus sp NBM6, Paenibacillus ehimensis NBM24 and Paenibacillus popilliae NBM68 were found to produced cellulase-free xylanase. These potential extracellular thermostable hydrolytic enzymes producing thermophilic bacteria have a great commercial prospect in various industrial, medical and agriculture applications. PMID- 28567631 TI - Iron acquisition in maize (Zea mays L.) using Pseudomonas siderophore. AB - Siderophore facilitates iron availability in soil, but its assistance in iron transportation to different plant parts is not reported till date. Therefore, it is worthwhile to study the effect of siderophore produced by Pseudomonas for iron acquisition in the presence and absence of iron. To study these effects, two siderophore-producing Pseudomonas aeruginosa strains RSP5 and RSP8 were selected. RSP5 and RSP8 produced the highest and lowest amounts of siderophore, respectively. Iron (Fe) concentration of stem, leaf, seed, and shoot length, root length, cob length, and number of grains parameters were analysed. It was observed that the plants treated with RSP5 were sturdier and taller than RSP5 + Fe > RSP8 > RSP8 + Fe > Fe > Control plants. Iron content of RSP8 vs. RSP8 + Fe, RSP8 + Fe vs. Control, and RSP8 + Fe vs. RSP5 + Fe was significantly different (P < 0.01). Analysis of variance (ANOVA) proves that RSP5 was able to transport higher amount of iron to maize plant than other treatments. Increase in shoot length, root length, cob length, grain number and iron content of stem, and leaf and seed of maize plant inoculated with RSP5 suggests that the strain can be used as an inoculant for increasing iron transportation in maize plant. (Indian Patent Filed: 40163/DEL/2016). PMID- 28567632 TI - Analysis of toxic, antidiabetic and antioxidant potential of Bambusa balcooa Roxb. leaf extracts in alloxan-induced diabetic rats. AB - Bambusa balcooa (Poaceae) is native to India and has been used traditionally by the tribes of Northeast India to treat diabetes. The present investigation was aimed to evaluate the toxicity, anti-diabetic activity along with in vitro antioxidant activity of the leaf of B. balcooa in alloxan-induced diabetic rats and also identify active compounds by using HPLC. The acute toxicity test of aqueous extract of B. balcooa leaf revealed that the median lethal dose (LD50) of B. balcooa aqueous extract (BAQE) was 5.18 g/kg body weight in mice. Administration of BAQE at 100 and 200 mg/kg in alloxan-induced diabetic rats showed significant reduction in fasting blood glucose and glycated hemoglobin while plasma insulin level was elevated compared to diabetic control. Both the doses were effective when compared to diabetic glibenclamide rats. The BAQE treated diabetic rats showed significant increase in the endogenous antioxidant enzymes superoxide dismutase, glutathione peroxidase and decrease in malondialdehyde levels. HPLC analysis of BAQE showed the presence of rutin, gallic acid and beta sitosterol. Thus, it can be inferred from this study that BAQE possess antidiabetic and in vivo antioxidant activity. The overall activity might be possibly due to the presence of potential antioxidants. PMID- 28567633 TI - Technical insight on the requirements for CO2-saturated growth of microalgae in photobioreactors. AB - Microalgal cultures are usually sparged with CO2-enriched air to preclude CO2 limitation during photoautotrophic growth. However, the CO2 vol% specifically required at operating conditions to meet the carbon requirement of algal cells in photobioreactor is never determined and 1-10% v/v CO2-enriched air is arbitrarily used. A scheme is proposed and experimentally validated for Chlorella vulgaris that allows computing CO2-saturated growth feasible at given CO2 vol% and volumetric O2 mass-transfer coefficient (k L a)O. CO2 sufficiency in an experiment can be theoretically established to adjust conditions for CO2 saturated growth. The methodology completely eliminates the requirement of CO2 electrode for online estimation of dissolved CO2 to determine critical CO2 concentration (Ccrit), specific CO2 uptake rate (SCUR), and volumetric CO2 mass transfer coefficient (k L a)C required for the governing CO2 mass-transfer equation. Ccrit was estimated from specific O2 production rate (SOPR) measurements at different dissolved CO2 concentrations. SCUR was calculated from SOPR and photosynthetic quotient (PQ) determined from the balanced stoichiometric equation of growth. Effect of light attenuation and nutrient depletion on biomass estimate is also discussed. Furthermore, a simple design of photosynthetic activity measurement system was used, which minimizes light attenuation by hanging a low depth (ca. 10 mm) culture over the light source. PMID- 28567635 TI - In vitro regeneration of Drosera burmannii Vahl.: a carnivorous plant of north east India. AB - An efficient in vitro regeneration protocol has been developed from shoot tips of Drosera burmannii Vahl., a carnivorous plant of north-east India. Various plant growth regulators were used to study their efficacy in the induction of multiple shoots and roots. Of the various treatments, the maximum number of shoots (28.8 +/- 1.5) and roots (9.7 +/- 0.6) was observed in one-fourth strength standard medium (MS with 50 mg/l citric acid and 10 mg/l ascorbic acid) supplemented with 4 mg/l 6-benzylaminopurine (BAP) and 4 mg/l alpha-naphthalene acetic acid (NAA) followed by 26.8 +/- 1.4 shoots in one-fourth strength SM fortified with 4 mg/l kinetin (KN) and 4 mg/l NAA. The well-developed plantlets with shoots and roots were potted in small plastic glasses filled with a mixture of sand and farmyard manure (3:1); these plantlets when transferred to a glasshouse for hardening and acclimatization showed 90% survival. PMID- 28567634 TI - Production, purification and biochemical characterization of an exo polygalacturonase from Aspergillus niger MTCC 478 suitable for clarification of orange juice. AB - Polygalacturonases (PG) represent an important member of pectinases group of enzymes with immense industrial applications. A fungal strain Aspergillus niger MTCC478 was used for the production of polygalacturonase both under submerged and solid-state fermentation condition. Further its production was optimized under solid-state fermentation condition with media comprising of wheat bran and tea extract. Purification of an exo-PG was achieved by acetone precipitation (60-90%) and CM-cellulose column chromatography revealing 15.28-fold purification with a specific activity of 33.47 U/mg protein and 1.2% yield. A relative molecular mass of purified PG was approximately 124.0 kDa. The pH and temperature optimum was found to be 4 and 50 degrees C, respectively. The k cat and K m value for degradation of PGA by the purified enzyme was found to be 194 s-1 and 2.3 mg/mL, respectively. Cu2+ was found to enhance the PG activity while Ag+ completely inhibited the enzyme activity. The application of the purified PG in orange juice clarification was elucidated. PMID- 28567636 TI - Biosorption characteristic of Alcaligenes sp. BAPb.1 for removal of lead(II) from aqueous solution. AB - In this study, strain BAPb.1 was isolated from lead mining area and used as an adsorbent to remove lead(II) ions from aqueous solution. The physicochemical characteristics, heavy metal resistance and antibiotic sensitivity of strain BAPb.1 were investigated. Biosorption capacity was evaluated by batch biosorption experiments, and isothermal characteristics were discussed. Atomic force microscopy (AFM), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX) and Fourier transform infrared spectrometry (FTIR) were conducted to explore the mechanism for lead(II) adsorption. Based on morphological and physiological characteristics as well as the phylogenetic analysis of 16S rDNA sequences, strain BAPb.1 was identified as a member of the genus Alcaligenes. It exhibited high resistances to multiple heavy metals such as lead(II), copper(II), zinc(II), nickel(II) and chromium(VI), and to antibiotics such as kanamycin, ampicillin, streptomycin, chloramphenicol, and tetracycline. The optimum conditions for maximum biosorption rate of 85.2% and maximum capacity of 56.8 mg g-1 were found at pH of 5, adsorbent dosage of 1.5 g L-1 (dry weight), initial lead(II) concentration of 100 mg L-1, and contact time of 30 min at 30 degrees C. Biosorption isotherms were well fitted with Langmuir isotherm model. Mechanism analysis reveals that the lead(II) ions may exchange with sodium and potassium ions, and the hydroxyl, carbonyl and phosphate groups on the cell surface can chelate the lead(II) ions, therefore, surface adsorption play significant role in the biosorption process. PMID- 28567638 TI - Expression of Plant Receptor Kinases in E. coli. AB - Plant receptor kinases play diverse signaling roles in disease resistance and plant development. They represent a large plant gene family with over 600 members in Arabidopsis thaliana. While the functions of several members of the receptor kinase family have now been elucidated, a great proportion still remains uncharacterized. The structural and functional characterization of such plant receptor kinases may entail biochemical approaches that require access to purified protein, which can be made possible through heterologous protein expression. This chapter describes a strategy for expressing plant receptor kinases in E. coli, a bacterial host that has successfully been used to express and purify certain plant receptor kinase domains, some of which were subsequently used for biochemical assays. As full-length receptor-like kinases may be difficult to express, it is suggested to clone and express domains separately, after having identified domain borders using bioinformatics tools. A detailed cloning protocol is provided, as well as advice for testing expression efficiency and handling of expressed protein ending up in inclusion bodies. PMID- 28567637 TI - Comparison of HER2 amplification status among breast cancer subgroups offers new insights in pathways of breast cancer progression. AB - Although the prognostic and predictive significance of human epidermal growth factor receptor 2 (HER2) in invasive breast cancer is well established, its role in ductal carcinoma in situ (DCIS) remains unclear. Reports on combined evaluation of both HER2 protein expression and HER2 amplification status in pure DCIS and DCIS adjacent to invasive ductal carcinoma (i.e., admixed DCIS) are scarce. In this study, immunohistochemistry and fluorescence in situ hybridization (FISH) were used to assess HER2 status in 72 cases of pure DCIS, 73 cases of DCIS admixed with invasive ductal carcinoma (IDC), and 60 cases of pure IDC. HER2 copy number-based amplification was present in 49% of pure DCIS, 16% of admixed DCIS, 18% of admixed IDC, and 8% of pure IDC. Amplified pure DCIS with clusters of HER2 signals showed a significantly lower HER2 copy number than amplified admixed DCIS with clusters. Whereas pure DCIS and admixed DCIS presented significant differences, the in situ and invasive component of admixed tumors showed striking similarities regarding mean HER2 and chromosome 17 centromere (CEP17) copy number, grade, and estrogen and progesterone receptor expression. The discrepant prevalence of HER2 amplification among breast cancer subgroups indirectly suggests that HER2 may not play a crucial role in the transition of in situ to invasive breast cancer. The similarities in HER2 amplification status between the in situ and invasive component of admixed tumors hint at a common biological pathway for both components. Our data support the theory that pure DCIS, pure IDC, and admixed lesions have a common progenitor, but can progress as separate lineages. PMID- 28567639 TI - Expression of Plant Receptor Kinases in Yeast. AB - The budding yeast Saccharomyces cerevisiae is a useful system to express recombinant proteins and analyze protein-protein interaction. Membrane-spanning proteins like plant receptor kinases find their way to the plasma membrane when expressed in yeast and seem to retain their structure and function. Here, we describe a general yeast DNA transformation procedure based on lithium acetate, salmon sperm DNA, and polyethylene glycol used to express recombinant proteins. Yeast cells expressing plant receptor kinases can be used for in vivo and in vitro studies of receptor function. PMID- 28567640 TI - Expression of Plant Receptor Kinases in Tobacco BY-2 Cells. AB - Although more than 600 single-transmembrane receptor kinase genes have been found in the Arabidopsis genome, only a few of them have known physiological functions, and even fewer plant receptor kinases have known specific ligands. Ligand-binding analysis must be operated using the functionally expressed receptor form. However, the relative abundance of native receptor kinase molecules in the plasma membrane is often quite low. Here, we present a method for stable and functional expression of plant receptor kinases in tobacco BY-2 cells that allows preparation of microsomal fractions containing the receptor. This procedure provides a sufficient amount of receptor proteins while maintaining its ligand binding activities. PMID- 28567641 TI - Cell-Free Synthesis of Plant Receptor Kinases. AB - The wheat germ cell-free protein synthesis system has been used as a eukaryotic protein production system since it was first reported in 1964. Although initially the productivity of this system was not very high, it has now become one of the most versatile protein production systems, thanks to the enhancements made by several groups. In this chapter, we report a protein production method for plant receptor kinases using the wheat cell-free system. We describe a method for the preparation of a cell-free extract from wheat germ, the split-primer PCR method for preparation of transcription templates, and the bilayer cell-free protein synthesis method. PMID- 28567642 TI - Purification of Plant Receptor Kinases from Plant Plasma Membranes. AB - Receptor kinases play a central role in various biological processes, but due to their low abundance and highly hydrophobic and dynamic nature, only a few of them have been functionally characterized, and their partners and ligands remain unidentified. Receptor protein extraction and purification from plant tissues is one of the most challenging steps for the success of various biochemical analyses to characterize their function. Immunoprecipitation is a widely used and selective method for enriching or purifying a specific protein. Here we describe two different optimized protein purification protocols, batch and on-chip immunoprecipitation, which efficiently isolate plant membrane receptor kinases for functional analysis. PMID- 28567643 TI - Photoaffinity Labeling of Plant Receptor Kinases. AB - Defining the ligand-binding activity of receptors is important because the binding of ligands is the initial reaction in secreted ligand-dependent cell-to cell communication. Photoaffinity labeling is one of the most efficient biochemical techniques for detecting direct ligand-receptor interactions. Here, we describe photoaffinity labeling to visualize the direct interaction between peptide ligands and their receptors by using photoactivatable and radioactive peptide ligand derivatives. PMID- 28567644 TI - Quantitative Detection of Oxidative Burst upon Activation of Plant Receptor Kinases. AB - The oxidative burst or the production of reactive oxygen species (ROS) is a typical cellular response of both plants and animals to diverse abiotic and biotic stresses. Mainly, the (re-)active oxygen species include the superoxide anion (O2-), hydrogen peroxide (H2O2), and the hydroxyl radical (OH*). Here, we outline the detection of extracellularly produced ROS in plant leaf pieces using a chemiluminescence-based bioassay with the luminol L-012 as a substrate being oxidized in the presence of ROS. Since this type of assay is in use in many laboratories, e.g., as a readout for activation of plant receptor kinases, we include a discussion on the interpretation of results and points addressing problems with the buffers at suboptimal pH values that negatively influence the chemiluminescence production. PMID- 28567645 TI - Extraction and Curation of Gene Models for Plant Receptor Kinases for Phylogenetic Analysis. AB - Analysis of gene families and identification of homologous genes are important for phylogenetic analysis and for translating results from model to crop species. While numerous plant genomes have been sequenced and made available, the identification of gene models can be difficult, in particular for large gene families arranged in tandem repeats or encoding proteins with a variable number of internal repeats. Thus, correct annotation of plant receptor kinases (PRK) is a challenge. Here, we describe a workflow for the semi-manual extraction, annotation, and verification of genes from annotated gene models as well as from non-annotated DNA regions. This protocol allows the efficient identification of gene family member of PRK from most available plant genomes. PMID- 28567646 TI - In Silico Prediction of Ligand-Binding Sites of Plant Receptor Kinases Using Conservation Mapping. AB - Plasma membrane-bound plant receptor-like kinases (RLKs) can be categorized based on their ligand-binding extracellular domain. The largest group encompasses RLKs having ectodomains with leucine-rich repeats (LRRs). The LRR-RLKs can further be assigned to classes mainly based on the number of LRRs. Many of the receptors of the classes X and XI with more than 20 LRRs are activated by small secreted peptide ligands. To understand how peptide signaling works, it is of interest to identify the amino acids of the receptor that are directly involved in ligand interaction. Such residues have most likely been conserved over evolutionary time and can therefore be predicted to be conserved in receptor orthologues of different plant species. Here we present an in silico method to identify such residues. This involves a simplified method for identification of orthologues and a web-based program for identifying the most conserved amino acids aside from the leucines that structure the ectodomain. The method has been validated for the LRR RLKs HAESA (HAE) and PHYTOSULFOKINE RECEPTOR1 (PSKR1) for which conservation mapping results closely matched recent structure-based identification of ligand and co-receptor-interacting residues. PMID- 28567647 TI - Co-immunoprecipitation of Plant Receptor Kinases. AB - In order to comprehend the function of a particular protein, identification of the interacting protein partners is a useful approach. Co-immunoprecipitation (Co IP) is employed to test physical interactions between proteins. Specific antibodies or antibodies against tagged versions can be used to immunoprecipitate the proteins. In this chapter, we describe a method to carry out Co-IP using recombinant membrane proteins expressed in yeast microsomal fractions. PMID- 28567648 TI - Autophosphorylation Assays Using Plant Receptor Kinases Synthesized in Cell-Free Systems. AB - The wheat germ cell-free protein synthesis system has a significant advantage for high-throughput production of eukaryotic multidomain proteins in a folded state. In this chapter, we describe two kinds of methods for performing autophosphorylation assay of plant receptor kinases (PRKs) by using the wheat cell-free system. One is an in vitro kinase assay performed using biotin streptavidin affinity purification technology, and the other is a luminescence based high-throughput assay for autophosphorylation analysis. We anticipate that our cell-free-based methods might facilitate the characterization of plant PRKs. PMID- 28567649 TI - Investigation of Autophosphorylation Sites of Plant Receptor Kinases and Phosphorylation of Interacting Partners. AB - The optimal kinase activity of plant receptor-like kinases (RLKs) is often regulated by autophosphorylation of specific sites. Many of these phosphorylated residues then serve as recruiting sites for downstream interacting proteins. Therefore, identification of the phosphosites can be an important first step in delineating the signaling network. This chapter describes a protocol for identification of phosphorylated residues by mass spectrometry as well as a protocol to determine if an interacting partner can be phosphorylated in vitro. PMID- 28567650 TI - In Vitro Assessment of Guanylyl Cyclase Activity of Plant Receptor Kinases. AB - Cyclic nucleotides such as 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5' cyclic guanosine monophosphate (cGMP) are increasingly recognized as key signaling molecules in plants, and a growing number of plant mononucleotide cyclases, both adenylate cyclases (ACs) and guanylate cyclases (GCs), have been reported. Catalytically active cytosolic GC domains have been shown to be part of many plant receptor kinases and hence directly linked to plant signaling and downstream cellular responses. Here we detail, firstly, methods to identify and express essential functional GC domains of receptor kinases, and secondly, we describe mass spectrometric methods to quantify cGMP generated by recombinant GCs from receptor kinases in vitro. PMID- 28567651 TI - BiFC Assay to Detect Calmodulin Binding to Plant Receptor Kinases. AB - Plant receptor-like kinases (RLKs) are regulated at various levels including posttranscriptional modification and interaction with regulatory proteins. Calmodulin (CaM) is a calcium-sensing protein that was shown to bind to some RLKs such as the PHYTOSULFOKINE RECEPTOR1 (PSKR1). The CaM-binding site is embedded in subdomain VIa of the kinase domain. It is possible that many more of RLKs interact with CaM than previously described. To unequivocally confirm CaM binding, several methods exist. Bimolecular fluorescence complementation (BiFC) and pull-down assays have been successfully used to study CaM binding to PSKR1 and are described in this chapter (BiFC) and in Chapter 15 (pull down). The two methods are complementary. BiFC is useful to show localization and interaction of soluble as well as of membrane-bound proteins in planta. PMID- 28567653 TI - The Use of FRET/FLIM to Study Proteins Interacting with Plant Receptor Kinases. AB - The investigation of protein interactions in living plant tissue has become of increasing importance in recent years. A high spatial and temporal resolution for the observation of in vivo protein interaction is needed, e.g., in order to follow changes of plant receptor kinase interactions and complex formation over time. In vivo fluorescence or Forster resonance energy transfer (FRET) measurements allow for detailed analyses of interacting proteins in their natural environment at a subcellular level. Especially FRET-FLIM (fluorescence lifetime imaging microscopy) measurements provide an extremely powerful and reliable tool meeting the demands for investigating in vivo protein interaction quantitatively and with high precision. Here, we will describe in detail how to practically perform in vivo FRET measurements of receptor kinases in plants and discuss potential pitfalls and points of consideration. PMID- 28567652 TI - Pull-down Assay to Characterize Ca2+/Calmodulin Binding to Plant Receptor Kinases. AB - Plant receptor-like kinases (RLKs) are regulated by posttranscriptional modification and by interaction with regulatory proteins. A common modification of RLKs is (auto)phosphorylation, and a common regulatory protein is the calcium sensor calmodulin (CaM). We have developed protocols to detect the interaction of an RLK with CaM. The interaction with CaM was shown by bimolecular fluorescence complementation (BiFC) (see Chapter 14) and pull-down assay (this chapter). Both methods offer unique advantages. BiFC is useful in showing interaction of soluble as well as of membrane-bound proteins in planta. Pull-down assays are restricted to soluble proteins and provide in vitro data. The pull-down assay provides the advantage that proteins can be modified prior to binding and that experimental conditions such as the concentration of Ca2+ or other divalent cations can be controlled. This chapter provides a pull-down protocol to study RLK-CaM interaction with optional steps to investigate the impact of RLK phosphorylation or of Ca2+. PMID- 28567654 TI - Detection and Analyses of Endocytosis of Plant Receptor Kinases. AB - Genetic dissection has led to a sophisticated understanding of receptor kinases in plant development and responses to abiotic and biotic stresses. Fluorescence confocal microscopy is essential to identify the (sub)cellular locations of resting and signaling receptor kinases that trigger molecular events in plant cells upon ligand perception. In this regard, the internalization of plasma membrane-localized FLAGELLIN SENSING 2 (FLS2) into endosomes induced by its ligand flg22, a peptide derived from bacterial flagellin, is a model system for studying activation status-dependent and endosomal receptor kinase trafficking routes and can be used in screens to identify pathogen effectors that target these trafficking routes for virulence promotion. In this chapter we describe approaches of visualizing fluorescently tagged FLS2, including protocols for flg22-induced endocytosis, instrument parameters, and image analysis. These approaches can be easily adapted for other receptor kinases, using the fast transient expression system in Nicotiana benthamiana for microscopic inspection. PMID- 28567655 TI - The Evaluation and Office Management of Hemorrhoids for the Gastroenterologist. AB - PURPOSE OF REVIEW: Hemorrhoid disease is extremely common, and seldom requires surgical intervention. The vast majority of patients can be cared for in the office setting and by the gastroenterologist. This piece aims to summarize the epidemiology and pathophysiology of hemorrhoid disease, along with the proper evaluation and office-based treatment of these patients. RECENT FINDINGS: Most GI fellowship training programs spend little time on these topics, and the recommendation has been made to include anorectal care in the GI's "core curriculum." The use of the anoscope and a proper anorectal examination are keys to evaluating these patients, and the techniques available to treat these patients are described. Often overlooked in these patients are other anorectal issues that occur alongside hemorrhoidal issues very commonly-the most common being anal fissure. Comprehensive management of all of these issues will allow all but the most severely affected patients to avoid the expense and morbidity of surgical intervention. The anatomy, etiology, pathophysiology, diagnosis, and non surgical treatment of hemorrhoid disease are presented with the gastroenterologist in mind. PMID- 28567656 TI - Nasoduodenal tube placement: Are two views necessary to confirm position? AB - BACKGROUND: Nasoduodenal tube (NDT) placement is typically performed at the bedside and two-view abdominal radiographs are usually used to confirm tube position. Anecdotally, in most instances the lateral view is unnecessary and utilizes more than twice the radiation than an anteroposterior (AP) view alone. OBJECTIVE: We hypothesize that NDT location can be determined using only the AP view, with the NDT position determined on two views utilized as the gold standard. MATERIALS AND METHODS: A search was performed for all two- or three view abdominal radiographs from September 2012 to September 2013 with the phrase "ND tube" in the reason field of the requisition. These studies were independently reviewed by two radiologists and scored for anatomical tube position in three different scenarios: AP view alone, the lateral view alone, and both views together, with the latter serving as the gold standard. The anatomical scores were subsequently grouped to reflect clinically significant scenarios. Comparative analysis was performed with the original and clinically grouped scores. RESULTS: A total of 102 patients and 306 separate two-view exams were evaluated. Of the 102 patients, 55 had at least two separate exams. Across raters, concordances of AP and lateral scores relative to the gold standard assessment were 88% and 73% for anatomical scores, and 91.5% and 86.4% for clinically grouped data. Trend differences for fewer errors were found with the AP compared to the lateral view. There were statistically significant group differences with a greater number of false-negative errors in the lateral data set. No clear differences were found when comparing AP and lateral ratings for false-positive errors. Upon review of the common errors, we determined a few imaging findings on AP radiographs that can help assess the need for an additional lateral view. CONCLUSION: A single AP view is sufficient to determine the NDT position in most cases. Two views should be reserved for cases where the NDT position cannot be definitively assessed. Transitioning toward the single AP view to evaluate the NDT position could have immediate consequences for dose reduction. PMID- 28567657 TI - Special Issue Devoted to a New Field of Regenerative Medicine: Reproductive Tissue Engineering. PMID- 28567659 TI - Perspective. PMID- 28567658 TI - Left Ventricular Assist Devices: Challenges Toward Sustaining Long-Term Patient Care. AB - Over the last few decades, the left ventricular assist device (LVAD) technology has been tremendously improved transitioning from large and noisy paracorporeal volume displacement pumps to small implantable turbodynamic devices with only a single transcutaneous element, the driveline. Nevertheless, there remains a great demand for further improvements to meet the challenge of having a robust and safe device for long-term therapy. Here, we review the state of the art and highlight four key areas of needed improvement targeting long-term, sustainable LVAD function: (1) LVADs available today still have a high risk of thromboembolic and bleeding events that could be addressed by the rational fabrication of novel surface structures and endothelialization approaches aiming at improving the device hemocompatibility. (2) Novel, fluid dynamically optimized pump designs will further reduce blood damage. (3) Infection due to the paracorporeal driveline can be avoided with a transcutaneous energy transmission system that additionally allows for increased freedom of movement. (4) Finally, the lack of pump flow adaptation needs to be encountered with physiological control systems, working collaboratively with biocompatible sensor devices, targeting the adaptation of the LVAD flow to the perfusion requirements of the patient. The interdisciplinary Zurich Heart project investigates these technology gaps paving the way toward LVADs for long-term, sustainable therapy. PMID- 28567660 TI - Perspective. PMID- 28567661 TI - Perspective. PMID- 28567662 TI - Perspective. PMID- 28567663 TI - Perspective. PMID- 28567664 TI - QTL mapping and comparative genome analysis of agronomic traits including grain yield in winter rye. AB - KEY MESSAGE: Genetic diversity in elite rye germplasm as well as F 2:3 testcross design enables fast QTL mapping to approach genes controlling grain yield, grain weight, tiller number and heading date in rye hybrids. Winter rye (Secale cereale L.) is a multipurpose cereal crop closely related to wheat, which offers the opportunity for a sustainable production of food and feed and which continues to emerge as a renewable energy source for the production of bioethanol and biomethane. Rye contributes to increase agricultural crop species diversity particularly in Central and Eastern Europe. In contrast to other small grain cereals, knowledge on the genetic architecture of complex inherited, agronomic important traits is yet limited for the outbreeding rye. We have performed a QTL analysis based on a F2:3 design and testcross performance of 258 experimental hybrids in multi-environmental field trials. A genetic linkage map covering 964.9 cM based on SSR, conserved-orthologous set (COS), and mixed-phase dominant DArT markers allowed to describe 22 QTL with significant effects for grain yield, heading date, tiller number, and thousand grain weight across seven environments. Using rye COS markers, orthologous segments for these traits have been identified in the rice genome, which carry cloned and functionally characterized rice genes. The initial genome scan described here together with the existing knowledge on candidate genes provides the basis for subsequent analyses of the genetic and molecular mechanisms underlying agronomic important traits in rye. PMID- 28567665 TI - Severe hyperkalemia is rescued by low-potassium diet in renal betaENaC-deficient mice. AB - In adulthood, an induced nephron-specific deficiency of alphaENaC (Scnn1a) resulted in pseudohypoaldosteronism type 1 (PHA-1) with sodium loss, hyperkalemia, and metabolic acidosis that is rescued through high-sodium/low potassium (HNa+/LK+) diet. In the present study, we addressed whether renal betaENaC expression is required for sodium and potassium balance or can be compensated by remaining (alpha and gamma) ENaC subunits using adult nephron specific knockout (Scnn1bPax8/LC1) mice. Upon induction, these mice present a severe PHA-1 phenotype with weight loss, hyperkalemia, and dehydration, but unlike the Scnn1aPax8/LC1 mice without persistent salt wasting. This is followed by a marked downregulation of STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) and Na+/Cl- co-transporter (NCC) protein expression and activity. Most of the experimental Scnn1bPax8/LC1 mice survived with a HNa+/LK+ diet that partly normalized NCC phosphorylation, but not total NCC expression. Since salt loss was minor, we applied a standard-sodium/LK+ diet that efficiently rescued these mice resulting in normokalemia and normalization of NCC phosphorylation, but not total NCC expression. A further switch to LNa+/standard-K+ diet induced again a severe PHA-1-like phenotype, but with only transient salt wasting indicating that low-K+ intake is critical to decrease hyperkalemia in a NCC dependent manner. In conclusion, while the betaENaC subunit plays only a minor role in sodium balance, severe hyperkalemia results in downregulation of NCC expression and activity. Our data demonstrate the importance to primarily correct the hyperkalemia with a low-potassium diet that normalizes NCC activity. PMID- 28567667 TI - Adherence in the Cancer Care Setting: a Systematic Review of Patient Navigation to Traverse Barriers. AB - Patient navigation is an evidence-based intervention involving trained healthcare workers who assist patients in assessing and mitigating personal and environmental factors to promote healthy behaviors. The purpose of this research is to systematically assess the efficacy of patient navigation and similar programs to improve diagnosis and treatment of diseases affecting medically underserved populations. A systematic review was performed by searching PubMed, MEDLINE, PsychINFO, and CINAHL to identify potential studies. Eligible studies were those containing original peer-reviewed research reports in English on patient navigation, community health workers, vulnerable and underserved populations, and healthcare disparity. Specific outcomes regarding patient navigator including the effect of the intervention on definitive diagnosis and effect on initiation of treatment were extracted from each study. The search produced 1428 articles, and 16 were included for review. All studies involved patient navigation in the field of oncology in underserved populations. Timing of initial contact with a patient navigator after diagnostic or screening testing is correlated to the effectiveness of the navigator intervention. The majority of the studies reported significantly shorter time intervals to diagnosis and to treatment with patient navigation. Patient navigation expedites oncologic diagnosis and treatment of patients in underserved populations. This intervention is more efficacious when utilized shortly after screening or diagnostic testing. PMID- 28567666 TI - Serum Protein-Based Profiles as Novel Biomarkers for the Diagnosis of Alzheimer's Disease. AB - As a multi-stage disorder, Alzheimer's disease (AD) is quickly becoming one of the most prevalent neurodegenerative diseases worldwide. Thus, a non-invasive, serum-based diagnostic platform is eagerly awaited. The goal of this study was to identify a serum-based biomarker panel using a predictive protein-based algorithm that is able to confidently distinguish AD patients from control subjects. One hundred and fifty-six patients with AD and the same number of gender- and age matched control participants with standardized clinical assessments and neuroimaging measures were evaluated. Serum proteins of interest were quantified using a magnetic bead-based immunofluorescent assay, and a total of 33 analytes were examined. All of the subjects were then randomized into a training set containing 70% of the total samples and a validation set containing 30%, with each containing an equal number of AD and normal samples. Logistic regression and random forest analyses were then applied to develop a desirable algorithm for AD detection. The random forest method was found to generate a more robust predictive model than the logistic regression analysis. Furthermore, an eight protein-based algorithm was found to be the most robust with a sensitivity of 97.7%, specificity of 88.6%, and AUC of 99%. Our study developed a novel eight protein biomarker panel that can be used to distinguish AD and control multi source candidates regardless of age. It is hoped that these results provide further insight into the applicability of serum-based screening methods and contribute to the development of lower-cost, less invasive methods for diagnosing AD and monitoring progression. PMID- 28567669 TI - Cerebral oxygenation during cortical activation: the differential influence of three exercise training modalities. A randomized controlled trial. AB - PURPOSE: To determine if a cerebral oxygenation response during cortical activation is influenced by exercise training mode. METHODS: Sixty-seven individuals (55-75 years old) volunteered for this 16-week intervention study. Participants were randomized into a resistance training (RT) group (n = 22), high intensity interval training (HIIT) group (n = 13), moderate continuous training (MCT) group (n = 13) and a control (CON) group (n = 19). Near-infrared spectroscopy was used to measure cerebral oxygenation during the Stroop task. A submaximal Bruce treadmill test was used to measure changes in walking endurance. RESULTS: The GROUP * TIME interaction for reaction time on the naming and executive Stroop conditions were not significant (P > 0.05). At post-test, the CON group showed increased brain activation, with significantly higher relative oxy-haemoglobin (O2Hb) values during the naming Stroop condition compared to pre test (P = 0.03), while their increased relative O2Hb on the complex condition showed a distinct trend toward significance (P = 0.09). MCT and HIIT participants exhibited decreased brain activation during the Stroop task, with MCT showing a significant increase in relative deoxy-haemoglobin (HHb) compared to pre-test during the naming and executive Stroop conditions (P < 0.05). The HIIT group improved significantly in walking endurance (P = 0.04). CONCLUSION: Sixteen weeks of exercise training resulted in more efficient cerebral oxygenation during cortical activation compared to a no-exercise control group. Furthermore, HIIT and MCT were superior to RT for task-efficient cerebral oxygenation and improved oxygen utilization during cortical activation in older individuals. PMID- 28567668 TI - The impact of acute high-intensity interval exercise on biomarkers of cardiovascular health in type 2 diabetes. AB - PURPOSE: High-intensity interval training (HIIT) interventions improve cardiovascular health, yet the acute effects on circulating and functional biomarkers of cardiovascular function are unclear in individuals with type 2 diabetes (T2D). To explore this, we conducted two investigations to examine the acute response to HIIT in individuals with T2D. METHODS: Study 1 measured blood pressure, endothelial-dependent dilation, circulating measures of endothelial activation, and troponin T, 30 min and 2 h after HIIT (7 * 1-min intervals) in T2D (n = 8) and age-matched normoglycemic controls (CTL; n = 8). Study 2 assessed circulating measures of endothelial activation and troponin T, 30 min, and 24 h after HIIT (10 * 1-min intervals) in ten previously trained T2D men. RESULTS: In study 1, markers of endothelial function and activation within the first 2 h after HIIT did not differ from baseline between T2D and CTL participants, except at 30 min after HIIT for glucose, which was reduced more in T2D than CTL (by -0.8 +/- 1.2 mmol/L, p = 0.04), and VCAM-1, which was reduced more 30 min after HIIT in CTL compared to T2D (by -187 +/- 221 ng/mL, p = 0.05). Study 2 saw no significant difference in any circulating markers of endothelial activation and troponin T, 30 min, and 24 h after HIIT in trained T2D males. CONCLUSION: Exploratory findings from these two studies suggest that acute HIIT does not substantially alter circulating and functional markers of cardio(vascular) health in individuals with T2D who are unaccustomed (study 1) and accustomed to HIIT (study 2). PMID- 28567670 TI - Severity of Hypertension Correlates with Risk of Thromboembolic Stroke. AB - Hypertension plays a significant role in the development of atrial fibrillation (AF) and its complications. The coexistence of the two diseases increases the risk of thromboembolism events. Although CHADS2 and CHA2DS2-VASc scores have been used in the evaluation of the thromboembolism events in AF patients, the different levels of the blood pressure are not appropriately recognized. In this study, the 970 AF patients were divided into three groups according to the severity of hypertension. The CHADS2 and CHA2DS2-VASc scores in the patients of grade 3 hypertension were significantly higher than those of the patients with grade 1 and 2 hypertension, respectively (P < 0.05). Both the CHADS2 and CHA2DS2 VASc scores were positively related to the severity of hypertension (P < 0.001). Our data demonstrated that three grades for hypertensive subjects with AF significantly improved antithrombotic risk stratification in addition to current clinical risk stratification models, such as CHADS2 and CHA2DS2-VASc scores. PMID- 28567671 TI - Downregulation of the Complement Cascade In Vitro, in Mice and in Patients with Cardiovascular Disease by the BET Protein Inhibitor Apabetalone (RVX-208). AB - Apabetalone (RVX-208) is an epigenetic regulator developed to treat cardiovascular disease (CVD) that targets BET proteins. Through transcriptional regulation RVX-208 modulates pathways that underlie CVD including reverse cholesterol transport, vascular inflammation, coagulation, and complement. Using transcriptomics and proteomics we show that complement is one of the top pathways downregulated by RVX-208 in primary human hepatocytes (PHH) and in plasma from CVD patients. RVX-208 reduces basal and cytokine-driven expression of complement factors in PHH and in chimeric mice with humanized livers. Plasma proteomics of CVD patients shows that RVX-208 decreases complement proteins and regulators, including complement activators SAP and CRP. Circulating activated fragments C5a, C3b, and C5b-C6 are reduced by 51, 32, and 10%, respectively, indicating decreased activity of complement in patients. As complement components are linked to CVD and metabolic syndrome, including major acute cardiac events, modulating their levels and activity by RVX-208 may alleviate risks associated with these diseases. PMID- 28567672 TI - Bioprocess engineering to produce 9-(nonanoyloxy) nonanoic acid by a recombinant Corynebacterium glutamicum-based biocatalyst. AB - Here, Corynebacterium glutamicum ATCC13032 expressing Baeyer-Villiger monooxygenase from Pseudomonas putida KT2440 was designed to produce 9 (nonanoyloxy) nonanoic acid from 10-ketostearic acid. Diverse parameters including cultivation and reaction temperatures, type of detergent, and pH were found to improve biotransformation efficiency. The optimal temperature of cultivation for the production of 9-(nonanoyloxy) nonanoic acid from 10 ketostearic acid using whole cells of recombinant C. glutamicum was 15 degrees C, but the reaction temperature was optimal at 30 degrees C. Enhanced conversion efficiency was obtained by supplying 0.05 g/L of Tween 80 at pH 7.5. Under these optimal conditions, recombinant C. glutamicum produced 0.28 mM of 9-(nonanoyloxy) nonanoic acid with a 75.6% (mol/mol) conversion yield in 2 h. This is the first report on the biotransformation of 10-ketostearic acid to 9-(nonanoyloxy) nonanoic acid with a recombinant whole-cell C. glutamicum-based biocatalyst and the results demonstrate the feasibility of using C. glutamicum as a whole-cell biocatalyst. PMID- 28567673 TI - Diesel reformulation using bio-derived propanol to control toxic emissions from a light-duty agricultural diesel engine. AB - In the Indian agricultural sector, millions of diesel-driven pump-sets were used for irrigation purposes. These engines produce carcinogenic diesel particulates, toxic nitrogen oxides (NOx), and carbon monoxide (CO) emissions which threaten the livelihood of large population of farmers in India. The present study investigates the use of n-propanol, a less-explored high carbon bio-alcohol that can be produced by sustainable pathways from industrial and crop wastes that has an attractive opportunity for powering stationary diesel engines meant for irrigation and rural electrification. This study evaluates the use of n-propanol addition in fossil diesel by up to 30% by vol. and concurrently reports the effects of exhaust gas recirculation (EGR) on emissions of an agricultural DI diesel engine. Three blends PR10, PR20, and PR30 were prepared by mixing 10, 20, and 30% by vol. of n-propanol with fossil diesel. Results when compared to baseline diesel case indicated that smoke density reduced with increasing n propanol fraction in the blends. PR10, PR20, and PR30 reduced smoke density by 13.33, 33.33, and 60%, respectively. NOx emissions increased with increasing n propanol fraction in the blends. Later, three EGR rates (10, 20, and 30%) were employed. At any particular EGR rate, smoke density remained lower with increasing n-propanol content in the blends under increasing EGR rates. NOx reduced gradually with EGR. At 30% EGR, the blends PR10, PR20, and PR30 reduced NOx emissions by 43.04, 37.98, and 34.86%, respectively when compared to baseline diesel. CO emissions remained low but hydrocarbon (HC) emissions were high for n propanol/diesel blends under EGR. Study confirmed that n-propanol could be used by up to 30% by vol. with diesel and the blends delivered lower soot density, NOx, and CO emissions under EGR. PMID- 28567674 TI - Electro-Fenton oxidation of para-aminosalicylic acid: degradation kinetics and mineralization pathway using Pt/carbon-felt and BDD/carbon-felt cells. AB - Degradation of a widely used antibiotic, the para-aminosalicylic acid (PAS), and mineralization of its aqueous solution was investigated by electro-Fenton process using Pt/carbon-felt and boron-doped diamond (BDD)/carbon-felt cells with applied currents in the range of 50-1000 mA. This process produces the highly oxidizing species, the hydroxyl radical (*OH), which is mainly responsible for the oxidative degradation of PAS. An absolute rate constant of 4.17 * 109 M-1 s-1 for the oxidation of PAS by ?OH was determined from the competition kinetics method. Degradation rate of PAS increased with current reaching an optimal value of 500 mA with complete disappearance of 0.1 mM PAS at 7 min using Pt/carbon-felt cell. The optimum degradation rate was reached at 300 mA for BDD/carbon-felt. The latter cell was found more efficient in total organic carbon (TOC) removal where a complete mineralization was achieved within 240 min. A multi-step mineralization process was observed with the formation of a number of aromatic intermediates, short-chain carboxylic acids, and inorganic ions. Eight aromatic intermediate products were identified using both LC-Q-ToF-MS and GC-MS techniques. These products were the result of hydroxylation of PAS followed by multiple additions of hydroxyl radicals to form polyhydroxylated derivatives. HPLC and GC/MS analyses demonstrated that extended oxidation of these intermediate products conducted to the formation of various short-chain carboxylic acids. Prolonged electrolysis resulted in a complete mineralization of PAS with the evolution of inorganic ions such as NO3- and NH4+. Based on the identified intermediates, carboxylic acids and inorganic ions, a plausible mineralization pathway is also deduced. The remarkably high degree of mineralization (100%) achieved by the present EF process highlights the potential application of this technique to the complete removal of salicylic acid-based pharmaceuticals from contaminated water. PMID- 28567675 TI - Impact of metal stress on the production of secondary metabolites in Pteris vittata L. and associated rhizosphere bacterial communities. AB - Plants adapt to metal stress by modifying their metabolism including the production of secondary metabolites in plant tissues. Such changes may impact the diversity and functions of plant associated microbial communities. Our study aimed to evaluate the influence of metals on the secondary metabolism of plants and the indirect impact on rhizosphere bacterial communities. We then compared the secondary metabolites of the hyperaccumulator Pteris vittata L. collected from a contaminated mining site to a non-contaminated site in Vietnam and identified the discriminant metabolites. Our data showed a significant increase in chlorogenic acid derivatives and A-type procyanidin in plant roots at the contaminated site. We hypothesized that the intensive production of these compounds could be part of the antioxidant defense mechanism in response to metals. In parallel, the structure and diversity of bulk soil and rhizosphere communities was studied using high-throughput sequencing. The results showed strong differences in bacterial composition, characterized by the dominance of Proteobacteria and Nitrospira in the contaminated bulk soil, and the enrichment of some potential human pathogens, i.e., Acinetobacter, Mycobacterium, and Cupriavidus in P. vittata's rhizosphere at the mining site. Overall, metal pollution modified the production of P. vittata secondary metabolites and altered the diversity and structure of bacterial communities. Further investigations are needed to understand whether the plant recruits specific bacteria to adapt to metal stress. PMID- 28567677 TI - Illumina sequencing-based analysis of a microbial community enriched under anaerobic methane oxidation condition coupled to denitrification revealed coexistence of aerobic and anaerobic methanotrophs. AB - Methane is produced in anaerobic environments, such as reactors used to treat wastewaters, and can be consumed by methanotrophs. The composition and structure of a microbial community enriched from anaerobic sewage sludge under methane oxidation condition coupled to denitrification were investigated. Denaturing gradient gel electrophoresis (DGGE) analysis retrieved sequences of Methylocaldum and Chloroflexi. Deep sequencing analysis revealed a complex community that changed over time and was affected by methane concentration. Methylocaldum (8.2%), Methylosinus (2.3%), Methylomonas (0.02%), Methylacidiphilales (0.45%), Nitrospirales (0.18%), and Methanosarcinales (0.3%) were detected. Despite denitrifying conditions provided, Nitrospirales and Methanosarcinales, known to perform anaerobic methane oxidation coupled to denitrification (DAMO) process, were in very low abundance. Results demonstrated that aerobic and anaerobic methanotrophs coexisted in the reactor together with heterotrophic microorganisms, suggesting that a diverse microbial community was important to sustain methanotrophic activity. The methanogenic sludge was a good inoculum to enrich methanotrophs, and cultivation conditions play a selective role in determining community composition. PMID- 28567678 TI - Removal of hexavalent chromium upon interaction with biochar under acidic conditions: mechanistic insights and application. AB - Chromium pollution of soil and water is a serious environmental concern due to potential carcinogenicity of hexavalent chromium [Cr(VI)] when ingested. Eucalyptus bark biochar (EBB), a carbonaceous black porous material obtained by pyrolysis of biomass at 500 degrees C under oxygen-free atmosphere, was used to investigate the removal of aqueous Cr(VI) upon interaction with the EBB, the dominant Cr(VI) removal mechanism(s), and the applicability to treat Cr(VI) contaminated wastewater. Batch experiments showed complete removal of aqueous Cr(VI) at pH 1-2; sorption was negligible at pH 1, but ~55% of total Cr was sorbed onto the EBB surface at pH 2. Detailed investigations on unreacted and reacted EBB through Fourier transform infrared spectroscopy and X-ray photoelectron spectrometry (XPS) indicate that the carboxylic groups in biochar played a dominant role in Cr(VI) sorption, whereas the phenolic groups were responsible for Cr(VI) reduction. The predominance of sorption-reduction mechanism was confirmed by XPS studies that indicated ~82% as Cr(III) and ~18% as Cr(VI) sorbed on the EBB surface. Significantly, Cr(VI) reduction was also facilitated by dissolved organic matter (DOM) extracted from biochar. This reduction was enhanced by the presence of biochar. Overall, the removal of Cr(VI) in the presence of biochar was affected by sorption due to electrostatic attraction, sorption-reduction mediated by surface organic complexes, and aqueous reduction by DOM. Relative dominance of the aqueous reduction mechanism depended on a critical biochar dosage for a given electrolyte pH and initial Cr(VI) concentration. The low-cost EBB developed here successfully removed all Cr(VI) in chrome tanning acidic wastewater and Cr(VI)-contaminated groundwater after pH adjustment, highlighting its potential applicability in effective Cr(VI) remediation. PMID- 28567676 TI - Occurrence of phthalates in aquatic environment and their removal during wastewater treatment processes: a review. AB - Phthalates are plasticizers and are concerned environmental endocrine-disrupting compounds. Due to their extensive usage in plastic manufacturing and personal care products as well as the potential to leach out from these products, phthalates have been detected in various aquatic environments including drinking water, groundwater, surface water, and wastewater. The primary source of their environmental occurrence is the discharge of phthalate-laden wastewater and sludge. This review focuses on recent knowledge on the occurrence of phthalate in different aquatic environments and their fate in conventional and advanced wastewater treatment processes. This review also summarizes recent advances in biological removal and degradation mechanisms of phthalates, identifies knowledge gaps, and suggests future research directions. PMID- 28567679 TI - Androgens, oestrogens, and progesterone concentrations in wastewater purification processes measured with capillary electrophoresis. AB - A novel analytical-scale concept to improve reliability of detection and analysis of natural and processed wastewater samples from a purification plant was developed. A sequential sample clean-up system of polymer-based octadecyl and silane-based quaternary amine sorbents were used for concentrating human based steroid hormones and their metabolites and detecting them by UV absorption with capillary electrophoresis (CE). The water samples were collected from influent and effluent processes of the water purification plant in Helsinki, Finland.The CE methods were partial-filling micellar electrokinetic chromatography and capillary zone electrophoresis. The analysis times and method concentration levels were optimized with eight steroids at the range of 0.5-10 mg/L. Since in CE the detectable quantities were higher than the existing amounts in the process waters, the real samples needed matrix removal combined with steroid enrichment. After 20,000-fold concentration testosterone-glucoside, androstenedione, progesterone, and estradiol-glucoside could be determined in the process water samples. The amounts of individual steroids in influent and effluent waters were 0-429 and 0-207 ng/L, respectively. Correspondently, their total amounts were 735 and 212 ng/L with excellent in day and inter-day repeatability. The RSD values were less than 1, 9.7, and 19% in repeated analyses, calculated from 60 analyses during 24 h, and from 130 analyses during 15 months, respectively. The steroid removal in purification process was 65% on average. The solid particles separated in three steps during the water clean-up concept contained 9.8-45 ng/g steroids in combined dry precipitates. PMID- 28567680 TI - Determination of a new index of sexual maturity (ISM) in zebra mussel using flow cytometry: interest in ecotoxicology. AB - The global dynamic spread of chemical contamination through the aquatic environment calls for the development of biomarkers of interest. Reproduction is a key element to be considered because it is related to the sustainability of species. Spermatogenesis is a complex process that leads to the formation of mature germ cells, whose steps and impairments need to be finely described in ecotoxicological analyses. The physiological process has been commonly described by histological analyses of gonads in different taxa. In the present paper, we describe the development of a novel technique to characterize spermatogenesis based on the analysis of the DNA content of germ cells by flow cytometry, using a DNA-intercalating agent. This new biomarker, referred to as an index of sexual maturity, proved relevant to describe the seasonal reproductive cycle of the zebra mussel, Dreissena polymorpha (Pallas, 1771), used as a sentinel species in the biomonitoring of continental waters and sensitive to highlight the reprotoxicity of carbamazepine (an anti-epileptic pharmaceutical) tested under ecosystemic conditions (mesocosms). PMID- 28567681 TI - Study on the removal of hormones from domestic wastewaters with lab-scale constructed wetlands with different substrates and flow directions. AB - Eight wastewater samples from a university campus were analysed between May and July of 2014 to determine the concentration of 14 natural and synthetic steroid hormones. An on-line solid-phase extraction combined with ultra-high performance liquid chromatography coupled with mass spectrometry (on-line SPE-UHPLC-MS/MS) was used as extraction, pre-concentration and detection method. In the samples studied, three oestrogens (17beta-estradiol, estrone and estriol), two androgens (boldenone and testosterone), three progestogens (norgestrel, progesterone and norethisterone) and one glucocorticoid (prednisone) were detected. The removal of hormones was studied in primary and secondary constructed wetland mesocosms. The porous media of the primary constructed wetlands were palm tree mulch. These reactors were used to study the effect of water flow, i.e. horizontal (HF1) vs vertical (VF1). The latter was more efficient in the removal of 17beta-estradiol (HF1: 30%, VF1: 50%), estrone (HF1: 63%, VF1: 85%), estriol (100% both), testosterone (HF1: 45%, VF1: 73%), boldenone (HF1:-77%, VF1: 100%) and progesterone (HF1: 84%, VF1: 99%). The effluent of HF1 was used as influent of three secondary constructed wetland mesocosms: two double-stage vertical flow constructed wetlands, one with gravel (VF2gravel) and one with palm mulch (VF2mulch), and a mineral-based, horizontal flow constructed wetland (HFmineral). VF2mulch was the most efficient of the secondary reactors, since it achieved the complete removal of the hormones studied with the exception of 17beta-estradiol. The significantly better removal of BOD and ammonia attained by VF2mulch suggests that the better aeration of mulch favoured the more efficient removal of hormones. PMID- 28567682 TI - Nitrate removal from drinking water with a focus on biological methods: a review. AB - This article summarizes several developed and industrial technologies for nitrate removal from drinking water, including physicochemical and biological techniques, with a focus on autotrophic nitrate removal. Approaches are primarily classified into separation-based and elimination-based methods according to the fate of the nitrate in water treatment. Biological denitrification as a cost-effective and promising method of biological nitrate elimination is reviewed in terms of its removal process, applicability, efficiency, and associated disadvantages. The various pathways during biological nitrate removal, including assimilatory and dissimilatory nitrate reduction, are also explained. A comparative study was carried out to provide a better understanding of the advantages and disadvantages of autotrophic and heterotrophic denitrification. Sulfur-based and hydrogen-based denitrifications, which are the most common autotrophic processes of nitrate removal, are reviewed with the aim of presenting the salient features of hydrogenotrophic denitrification along with some drawbacks of the technology and research areas in which it could be used but currently is not. The application of algae-based water treatment is also introduced as a nature-inspired approach that may broaden future horizons of nitrate removal technology. PMID- 28567683 TI - The biological response chain to pollution: a case study from the "Italian Triangle of Death" assessed with the liverwort Lunularia cruciata. AB - The liverwort Lunularia cruciata, known for being a species tolerant to pollution able to colonize urban areas, was collected in the town of Acerra (South Italy) to investigate the biological effects of air pollution in one of the three vertices of the so-called Italian Triangle of Death. The ultrastructural damages observed by transmission electron microscopy in specimens collected in Acerra were compared with samples collected in the city center of Naples and in a small rural site far from sources of air pollution (Riccia, Molise, Southern Italy). The biological response chain to air pollution was investigated considering vitality, photosynthetic efficiency, heat shock protein 70 (Hsp70) induction and gene expression levels, and chlorophyll degradation and related ultrastructural alterations. Particularly, a significant increment in Hsp70 expression and occurrence, and modifications in the chloroplasts' ultrastructure can be strictly related to the environmental pollution conditions in the three sites. The results could be interpreted in relation to the use of these parameters as biomarkers for environmental pollution. PMID- 28567684 TI - Possible maternal offloading of metals in the plasma, uterine and capsule fluid of pregnant ragged-tooth sharks (Carcharias taurus) on the east coast of South Africa. AB - We studied the possible metal offloading onto the progeny of three pregnant female ragged-tooth sharks (Carcharias taurus) (C. taurus). The presences of five metals, i.e. aluminium (Al), arsenic (As), cadmium (Cd), lead (Pb) and selenium (Se) were validated by mass spectrometry in the maternal plasma as well as the intracapsular and uterine fluids (UF) in which embryos develop. Metals were ranked in a decreasing concentration as follows: Plasma: As > Al > Se > Pb > Cd; ICF: As > Se > Al > Cd > Pb and UF: As > Se > Al > Cd > Pb. As was present in the highest concentration in all three sharks. Al, Pb and Cd were found to be the highest within the plasma, while concentrations of Se were similar in all three fluids. These results indicate that C. taurus embryos are exposed to metals during early development, but the impact of this exposure remains unknown. To the best of our knowledge, this is the first investigation to confirm the presence of metals in the fluids that surround the developing C. taurus embryos, a species that is already listed as vulnerable. PMID- 28567685 TI - Genotoxicity in adult residents in mineral coal region-a cross-sectional study. AB - The present study assessed the DNA damage in environmentally exposed volunteers living in seven municipalities in an industrial coal region, through the use of the comet assay with blood cells and the micronucleus test with buccal cells. Blood and buccal smears were collected from 320 male volunteers living in seven cities inserted in a coal region. They were ages of 18 and 50 years and also completed a questionnaire intended to identify factors associated with DNA damage through a Poisson regression analysis. The comet assay detected significant differences in DNA damage in volunteers from different municipalities, and neighboring cities (Pedras Altas, Acegua, and Hulha Negra) had a higher level of DNA damage in relation to control city. Some of the risk factors associated with identified DNA lesions included residence time and life habits. On the other hand, the micronucleus test did not identify differences between the cities studied, but the regression analysis identified risk factors such as age and life habits (consumption of mate tea and low carbohydrates diet). We conclude that there are differences in the DNA damage of volunteers from different cities of the carboniferous region, but the presence of micronuclei in the oral mucosa does not differ between the same cities. Furthermore, we alert that some related factors may increase the risk of genotoxicity, such as residence location and time, and living and food habits. Finally, we suggest the need for continuous biomonitoring of the population, as well as for investing in health promotion in these vulnerable populations. PMID- 28567686 TI - Tobacco Rattle Virus-Based Silencing of Enoyl-CoA Reductase Gene and Its Role in Resistance Against Cotton Wilt Disease. AB - A Tobacco rattle virus (TRV)-based virus-induced gene silencing assay was employed as a reverse genetic approach to study gene function in cotton (Gossypium hirsutum). This approach was used to investigate the function of the Enoyl-CoA reductase (GhECR) gene in pathogen defense. Amino acid sequence alignment of Arabidopsis ECR with homologous sequence from G. hirsutum, G. arboreum, G. herbaceum and G. barbadense showed that ECRs are highly conserved among these species. TRV-based silencing of GhECR gene in G. hirsutum induced a cell death/necrotic lesion-like phenotype. Reverse transcription polymerase chain reaction (RT-PCR) and real-time quantitative PCR showed reduced GhECR mRNA levels in TRV inoculated plants. Three isolates of Verticillium dahliae (V. dahliae) and Fusarium oxysporum f. sp. vasinfectum (FOV) were used to infect GhECR-silenced plants. Out of 6 races of 2 pathogens, down regulation of GhECR gene resulted in reduced resistance. This is the first report showing that cotton GhECR gene is involved in resistance to different strains of V. dahliae and FOV. PMID- 28567687 TI - Integrated Method for Purification and Single-Particle Characterization of Lentiviral Vector Systems by Size Exclusion Chromatography and Tunable Resistive Pulse Sensing. AB - Elements derived from lentiviral particles such as viral vectors or virus-like particles are commonly used for biotechnological and biomedical applications, for example in mammalian protein expression, gene delivery or therapy, and vaccine development. Preparations of high purity are necessary in most cases, especially for clinical applications. For purification, a wide range of methods are available, from density gradient centrifugation to affinity chromatography. In this study we have employed size exclusion columns specifically designed for the easy purification of extracellular vesicles including exosomes. In addition to viral marker protein and total protein analysis, a well-established single particle characterization technology, termed tunable resistive pulse sensing, was employed to analyze fractions of highest particle load and purity and characterize the preparations by size and surface charge/electrophoretic mobility. With this study, we propose an integrated platform combining size exclusion chromatography and tunable resistive pulse sensing for monitoring production and purification of viral particles. PMID- 28567688 TI - Effects of upper-airway stimulation on sleep architecture in patients with obstructive sleep apnea. AB - PURPOSE: Selective upper-airway stimulation (UAS) is a novel therapy for patients with obstructive sleep apnea (OSA). The aim of this study was to compare changes in sleep architecture during the diagnostic polysomnography and the post implantation polysomnography in UAS in patients with OSA. METHODS: Twenty-six patients who received a UAS device (Inspire Medical Systems) were included. Treatment outcome was evaluated 2 and 3 months after surgery. Data collection included demographics, body mass index (BMI), apnea hypopnea index (AHI), oxygen saturation and desaturation index (ODI), Epworth sleepiness score (ESS), arousal parameter, and sleep patterns. RESULTS: The mean age was 60.2 years, 25 patients were male, 1 patient was female. Mean BMI was 29.0 kg/m2. The mean pre implantation AHI of 33.9/h could be reduced to 9.1/h at 2 months post implantation (p < 0.001). The amount of time spent in N1-sleep could be reduced from 23.2% at baseline to 16.0% at month 3 post-implantation. The amount of time spent in N2- and N3-sleep did not change during the observation period. A significant increase of the amount of REM sleep at month 2 (15.7%) compared to baseline (9.5%; p = 0.010) could be observed. A reduction of the number of arousals and the arousal index could be observed. CONCLUSION: In conclusion, significant changes in sleep architecture of patients with OSA and sufficient treatment with UAS could be observed. A reduction of the amount of time spent in N1-sleep could be caused by treatment with UAS and the rebound of REM sleep, observed for the first time in a study on UAS, is also a potential marker of the efficacy of UAS on sleep architecture. TRIAL REGISTRATION: NCT02293746. PMID- 28567689 TI - Response to "is sedation administration strategy and analysis during drug-induced sedation endoscopy objective and systematic?" PMID- 28567690 TI - Intervention for CPAP adherence in OSAS: a choice to patient or technique? PMID- 28567691 TI - Autologous adipose tissue-derived stem cells for the treatment of complex perianal fistulas not associated with Crohn's disease: a phase II clinical trial for safety and efficacy. AB - PURPOSE: Injection of adipose tissue-derived stem cells (ASCs) is a novel method for the treatment of complex perianal fistulas. We aimed to evaluate the safety and efficacy of ASCs in the treatment of complex anal fistulas not associated with Crohn's disease. METHODS: A phase II clinical trial was performed comparing two different doses of ASCs (group 1: 1 * 107 cells/mL and group 2: 2 * 107 cells/mL). Eligible patients were administered an amount of ASCs proportional to the length of the fistula by injection into the submucosal layer surrounding the internal opening and inside of the fistula tract. ASCs at twice the initial concentration were administered if complete closure was not achieved within 8 weeks. The efficacy endpoint was the complete closure of fistulas 8 weeks after injection. Patients demonstrating complete closure at week 8 were subjected to follow-up for 6 months. RESULTS: Fifteen patients were injected with ASCs; thirteen completed the study. Complete closure was observed in 69.2% (9/13) of patients at 8 weeks. Three of five patients in group 1, and six of eight in group 2 displayed complete closure; no significant differences were observed between the groups. Six of nine patients who showed complete closure participated in additional follow-up; five (83.3%) showed persistent response at 6 months. No grade 3 or 4 adverse events (AEs) were observed; observed AEs were not related to ASC treatment. CONCLUSION: ASCs might be a good option for the treatment of complex perianal fistulas are not healed by conventional operative procedures. PMID- 28567692 TI - Bioelectrical impedance vector analysis in patients with irritable bowel syndrome on a low FODMAP diet: a pilot study. AB - BACKGROUND: The aim of this study was to determine the effects of a low fermentable oligo-, di- and monosaccharides and polyols (FODMAP) diet on the nutritional status and body composition, abdominal symptoms, quality of life, anxiety/depression and sleep quality of patients with irritable bowel syndrome (IBS). METHODS: Consecutive patients were given a low FODMAP diet for 8 weeks. At baseline and after 8 weeks, blood tests were taken to evaluate nutritional status and a bioelectrical impedance analysis was performed to assess body composition. Anthropometric data, IBS Symptom Severity Score, results of a bowel habits questionnaire, Bristol Stool Chart classification, SF36, Hamilton Depression Anxiety Scale outcome and Pittsburgh Sleep Quality Index were also recorded. During the 8-week diet period, the patients were phoned periodically by the nutritionist to verify their compliance. RESULTS: Twenty-six IBS patients with a mean age of 46.2 +/- 13.8 years were studied. After 8 weeks, there were no abnormalities in anthropometric data, bioelectrical impedance parameters and blood tests. The patients' IBS Symptom Severity Score improved (305.2 +/- 84.1 vs 156.3 +/- 106.4; p < 0.0001), as did bowel habits, Bristol Stool Chart classification, quality of life and HADS anxiety score, whereas sleeping quality and depression were unchanged. The degree of relief from symptoms and satisfaction with the diet was high. CONCLUSIONS: A low FODMAP diet improved IBS symptoms without effects on nutritional status and body composition. PMID- 28567693 TI - Per oral endoscopic pyloromyotomy for refractory gastroparesis: initial results from a single institution. AB - INTRODUCTION: Gastroparesis is a debilitating disease characterized by delayed gastric emptying in the absence of mechanical obstruction. A new intramural technique, per oral endoscopic pyloromyotomy (POP), has been proposed as an alternative to surgical pyloroplasty for the management of medical refractory gastroparesis. Herein, we detail the short-term results of POP at our institution. METHODS: POP was first performed at our institution in January 2016. All patients undergoing POP for management of gastroparesis from January 2016 through January 2017 were prospectively followed. All patients underwent a 4-h, non-extrapolated gastric emptying scintigraphy study and were asked to rate their symptoms using the Gastroparesis Cardinal Symptom Index (GCSI) at their pre procedure visit and at 3 months post-procedure. RESULTS: A total of 47 patients underwent POP during the defined study period. Twenty-seven (57.4%) patients had idiopathic gastroparesis, 12 (25.6%) had diabetic gastroparesis, and eight (17.0%) had post-surgical gastroparesis. Forty-one (87.2%) patients had at least one previous intervention (i.e., enteral feeding tube, gastric pacer, botox injection) for their gastroparesis symptoms. All patients had evidence of gastroparesis on pre-procedure gastric emptying studies. The average length of hospital stay was 1 day. One patient died within 30-days of their index procedure which was unrelated to the procedure itself. The average pre-procedure percentage of retained food at 4 h was 37% compared to an average post-procedure percentage of 20% (p < 0.03). The average pre-procedure GCSI score was 4.6 compared to an average post-procedure GCSI of 3.3 (p < 0.001). CONCLUSIONS: POP is a safe and feasible endoscopic intervention for medical refractory gastroparesis. Additional follow-up is required to determine the long-term success of this approach in alleviating gastroparesis symptoms. PMID- 28567694 TI - A novel surgery technique: non-visual dissection for establishing the operating space during total endoscopic thyroidectomy. AB - BACKGROUND: Patients and surgeons are typically satisfied with the cosmetic results of total endoscopic thyroidectomy using the complete areola approach. However, the disadvantages of this approach include an excessive free flap and a longer operative time. METHODS: A retrospective analysis was conducted in 72 patients (64 women and 8 men) with a benign thyroid nodule who underwent non unvisual dissection to establish the operating space for endoscopic surgery. RESULTS: The time needed to create the operating space in the chest was 6.43 +/- 0.94 min. The time for the overall operating space was 15.35 +/- 1.52 min. The overall surgical time was 96.54 +/- 19.32 min. The flap area in the chest was 30.25 +/- 3.42 cm2. CONCLUSIONS: Application of non-visual dissection shorten the time to create operating space and the overall surgical time, and markedly reduced the flap area. Our non-unvisual dissection technique for establishing the operating space is different from any previous techniques. PMID- 28567695 TI - Endoscopic submucosal dissection for laterally spreading tumors involving the appendiceal orifice. AB - BACKGROUND: Since the endoscopic resection of laterally spreading tumors (LSTs) involving the appendiceal orifice remains technically difficult, such lesions are usually treated by surgical resection. However, with recent advances in endoscopic devices, endoscopic submucosal dissection (ESD) has become feasible and may be safely performed even for lesions involving the appendiceal orifice. Therefore, in order to assess the validity of endoscopic treatment for such lesions, we retrospectively evaluated the safety and efficacy of ESD. METHODS: A total of 30 patients with LSTs extending to within 10 mm of the appendiceal orifice (Group AO) and 122 patients with cecal LSTs located away from the appendiceal orifice (Group C) who were treated between December 2011 and September 2015 were retrospectively enrolled in the present study. The indications for ESD were determined by the preoperative endoscopic diagnosis made on the basis of Kudo's pit pattern classification. Based on these preoperative endoscopic diagnoses, 8 of the 30 enrolled patients underwent surgical resection as the initial treatment, because the tumor showed deep invasion beyond the orifice and/or a VN pit pattern was visible. The treatment outcomes (en bloc R0 resection rates, tumor size, procedure time, and complication rates) were compared between the two groups. RESULTS: The sensitivity and specificity for the cancer diagnosis were 81.8 and 94.7%, respectively. There was no significant difference in the en bloc R0 resection rate between Group AO and Group C (90.9 vs. 95.9%, P = 0.23). Furthermore, there were also no differences in the mean tumor size (30.0 +/- 20.8 vs. 34.9 +/- 14.5 mm, P = 0.17) or mean OR time (55.0 +/- 39.2 vs. 58.9 +/- 48.2 min P = 0.72) between the two groups. One case from Group AO (4.5%) was complicated by a perforation, which was successfully managed endoscopically. CONCLUSIONS: Although proficiency in endoscopic techniques is required, our results indicate that LSTs involving the appendiceal orifice can be successfully treated by ESD. PMID- 28567696 TI - Blunted stress reactivity in chronic cannabis users. AB - RATIONALE: One of the most commonly cited reasons for chronic cannabis use is to cope with stress. Consistent with this, cannabis users have shown reduced emotional arousal and dampened stress reactivity in response to negative imagery. OBJECTIVES: To our knowledge, the present study represents the first to examine the effects of an acute stress manipulation on subjective stress and salivary cortisol in chronic cannabis users compared to non-users. METHODS: Forty cannabis users and 42 non-users were randomly assigned to complete either the stress or no stress conditions of the Maastricht Acute Stress Test (MAST). The stress condition of the MAST manipulates both physiological (placing hand in ice bath) and psychosocial stress (performing math under conditions of social evaluation). Participants gave baseline subjective stress ratings before, during, and after the stress manipulation. Cortisol was measured from saliva samples obtained before and after the stress manipulation. Further, cannabis cravings and symptoms of withdrawal were measured. RESULTS: Subjective stress ratings and cortisol levels were significantly higher in non-users in the stress condition relative to non-users in the no stress condition. In contrast, cannabis users demonstrated blunted stress reactivity; specifically, they showed no increase in cortisol and a significantly smaller increase in subjective stress ratings. The stress manipulation had no impact on cannabis users' self-reported cravings or withdrawal symptoms. CONCLUSION: Chronic cannabis use is associated with blunted stress reactivity. Future research is needed to determine whether this helps to confer resiliency or vulnerability to stress-related psychopathology as well as the mechanisms underlying this effect. PMID- 28567700 TI - Different impact of aortic regurgitation assessed by aortic root angiography after transcatheter aortic valve implantation according to baseline left ventricular ejection fraction and N-terminal pro-B-type natriuretic peptide. AB - Transcatheter aortic valve implantation (TAVI) is an alternative therapeutic option for severe aortic stenosis. Aortic regurgitation (AR) is commonly observed after TAVI and increases the mortality rate. We hypothesized that the influence of significant AR, defined as that more severe than mild AR, on survival rate after TAVI might differ according to the baseline left ventricular ejection fraction (LVEF) and N-terminal pro-B-type natriuretic peptide (NT-pro BNP) level. We categorized 856 patients who underwent transfemoral TAVI into 2 groups according to their baseline LVEF (<40 and >=40%) and NT-pro BNP levels (<=5000 and >5000 pg/mL). Significant AR was observed in 92 patients (11%). Among patients with significant AR, the proportion of patients with CoreValve/EvolutR implantation was higher than that of patients with SAPIEN XT/3 implantation. Kaplan-Meier curves and the log-rank test showed that significant AR was not associated with 1-year mortality in patients with LVEF >=40% and those with NT pro BNP level <=5000 pg/mL. On the other hand, it was significantly associated with a higher 1-year mortality in patients with LVEF <40% (p = 0.003) and those with NT-pro BNP level >5000 pg/mL (p = 0.011). Similarly, multivariate Cox regression analysis showed that the presence of AR was significantly associated with a higher 1-year mortality in patients with LVEF <40% [p = 0.005, hazard ratio (HR) = 3.626] and NT-pro BNP level >5000 pg/mL (p = 0.004, HR = 3.221). However, AR was not significantly associated with a higher 1-year mortality in patients with LVEF >=40% and NT-pro BNP level <=5000 pg/mL. Thus, the impact of significant AR on mortality after TAVI seems to be considerable in patients with reduced LVEF or high NT-pro BNP levels, but not those with preserved LVEF or low NT-pro BNP levels, suggesting that the influence of AR differs depending on the baseline LVEF and NT-pro BNP level. PMID- 28567697 TI - Dopaminergic mechanisms in memory consolidation and antidepressant reversal of a chronic mild stress-induced cognitive impairment'. AB - Cognitive deficits in depression can be modelled using the novel object recognition (NOR) test, performance in which is impaired by chronic mild stress (CMS). We aimed to examine the involvement of mesocorticolimbic DA terminal regions, and to establish the substrate for CMS-induced impairment of NOR and its reversal by chronic antidepressant treatment. In experiments 1 and 2, we examined the effect of infusions into medial PFC, dorsal hippocampus (HPC), and nucleus accumbens (NAc) shell of D1 and D2 antagonists and D3 agonist, which were predicted to impair NOR with a short (1 h) delay, and of D1 and D2 agonists and D3 antagonist, which were predicted to facilitate NOR with a long (24 h) delay. Using optimal doses identified in experiment 2, in experiments 3 and 4, we examined effects on drug-stimulated NOR of CMS and chronic treatment with venlafaxine (VFX) or risperidone (RSP). We found a wide involvement of DA systems in memory for NOR: D1 receptors in PFC, HPC, and NAc; D3 receptors in PFC and HPC; and D2 receptors in PFC. CMS impaired D2- and D3-mediated effects in PFC and HPC; antidepressants rescued those effects in PFC but not HPC. The involvement of DA in NOR is multifaceted, but the effects of CMS and antidepressants are more discrete, involving D2 and D3 receptors in PFC specifically. While raising many difficult questions, these results suggest that the D2 and D3 receptors in the medial PFC may be an important substrate for cognitive deficits in depression and their remediation. PMID- 28567698 TI - Incidence and risk factors of acute akathisia in 493 individuals with first episode non-affective psychosis: a 6-week randomised study of antipsychotic treatment. AB - INTRODUCTION: Acute akathisia is a neuropsychiatric syndrome with a negative effect on illness outcome. Its incidence in patients treated with antipsychotics has shown to be highly variable across studies. OBJECTIVES: Our goals were to investigate prevalence, risk factors for the development of acute akathisia, and differences in incidence between antipsychotics in a sample of 493 first episode non-affective psychosis patients. METHODS: This is a pooled analysis of three prospective, randomized, flexible-dose, and open-label clinical trials. Patients were randomized assigned to different arms of treatment (haloperidol, quetiapine, olanzapine, ziprasidone, risperidone, or aripiprazole). Akathisia was determined using the Barnes Akathisia Scale at 6 weeks after antipsychotic initialization. Univariate analyses were performed to identify demographic, biochemical, substance use, clinical, and treatment-related predictors of acute akathisia. Considering these results, a predictive model based of a subsample of 132 patients was constructed with akathisia as the dependent variable. RESULTS: The overall incidence of akathisia was 19.5%. No differences in demographic, biochemical, substance use, and clinical variables were found. Significant incidence differences between antipsychotics were observed (Chi 2 = 68.21, p = 0.000): haloperidol (57%), risperidone (20%), aripiprazole (18.2%), ziprasidone (17.2%), olanzapine (3.6%), and quetiapine (3.5%). The predictive model showed that the type of antipsychotic (OR = 21.3, p = 0.000), need for hospitalization (OR = 2.6, p = 0.05), and BPRS total score at baseline (OR = 1.05, p = 0.03) may help to predict akathisia emergence. CONCLUSIONS: Among second generation antipsychotics, only olanzapine and quetiapine should be considered as akathisia sparing drugs. The type of antipsychotic, having been hospitalized, and a more severe symptomatology at intake seem to predict the development of acute akathisia. PMID- 28567699 TI - Effects of nalfurafine on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone: modeling an abuse-deterrent opioid analgesic in rats. AB - RATIONALE: Strategies to reduce the misuse of mu opioid agonists are critically needed. Previous work has shown that kappa opioid agonists can diminish the abuse related effects and augment the antinociceptive effects of mu agonists. However, use of traditional kappa agonists is limited by their dysphoric side effects. OBJECTIVES: The current study examined the effects of nalfurafine, a clinically available atypical kappa agonist, on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone in male rats. METHODS: To determine oxycodone/nalfurafine mixture proportions to be examined intravenously across procedures, a progressive ratio (PR) self-administration procedure compared the reinforcing effects of oxycodone (56 MUg/kg/inj) available alone or as a mixture with co-administered nalfurafine (0.32, 1, or 3.2 MUg/kg/inj), corresponding to oxycodone/nalfurafine proportions of 175:1, 56:1, and 18:1, respectively. Next, PR and thermal antinociception dose-effect functions were each determined for oxycodone, nalfurafine, and the same oxycodone/nalfurafine mixture proportions. Finally, the respiratory-depressant effects of equi antinociceptive doses of oxycodone, nalfurafine, and the mixtures were compared. RESULTS: Nalfurafine decreased the reinforcing effects of oxycodone, and the 18:1 mixture did not function as a reinforcer. Oxycodone and nalfurafine each produced dose-dependent antinociception, and the mixtures produced additive antinociception. In addition, antinociceptive doses of the 56:1 and 18:1 mixtures did not produce respiratory depression. CONCLUSIONS: These results suggest that nalfurafine may augment the thermal antinociceptive effects while reducing the reinforcing and respiratory-depressant effects of oxycodone. PMID- 28567701 TI - Towards Microcapsules with Improved Barrier Properties. AB - Microencapsulation is the generic term for numerous technologies, which are often used when the release rate of an active substance in a medium has to be controlled and/or contact between the active substance and the medium has to be prevented. This is achieved by wrapping the tiny particles or droplets of the active substance (capsule core) with a thin layer, or membrane, of another material (capsule shell). The permeability of the membrane determines whether, how fast and under which conditions the active material will be released and/or the components of the medium will enter the inner part of the capsule. Insofar as application is concerned, premature release of an active substance from microcapsules during storage is a very common problem. Prevention of diffusion of an active component or components of the outer medium through the capsule membrane is a complex challenge, which so far cannot be considered as solved. This review briefly covers the theoretical aspects of release kinetics from microcapsules and discusses how such parameters as capsule average size, capsule shell thickness as well as the chemical composition of active material and medium can influence the release profiles. All theoretical considerations are based on the dissolution-diffusion mechanism classically used for the explanation of diffusion trough flat membranes/films. In the second part of the manuscript it is discussed, which strategies have been used for the improvement of the barrier properties of microcapsules up to date and to which extent those strategies were successful. PMID- 28567702 TI - Cardiovascular morbidity and long term mortality associated with in hospital small increases of serum creatinine. AB - BACKGROUND: The cardiovascular risk associated with an increase in serum creatinine below the acute kidney injury (AKI) threshold, during hospitalization, has not been studied in depth. We assessed patients' features and outcomes associated with these changes. METHODS: Retrospective cohort study of 12,493 consecutive patients admitted to hospital throughout 12 months. We investigated the patients who had a small creatinine increase (SISCr) between 1.2 and <1.5 times the admission value, and tested the association of creatinine changes with the prevalence of cardiovascular disease (CVD). In a follow-up study, we assessed the all-cause mortality and its relationship with SISCr. RESULTS: Among patients with two or more creatinine measurements, 14.9% showed a SISCr. Older age, female gender and higher estimated glomerular filtration rate (eGFR) at admission were characteristics of these patients. The prevalence of CVD was 14.6% in patients with SISCr vs. 10.7% in those with stable creatinine (p < 0.001). SISCr was detected in 36, 26.6 and 18.9% of chronic heart failure (CHF), chronic ischemic heart disease (CIHD) and acute myocardial infarction (AMI) patients, respectively. The follow-up was 26.7 +/- 10.6 months with 770 all-cause deaths. Serum creatinine increase above 20% was associated with a significant higher mortality compared to changes below 20%, adjusted hazard (HR) ratio 1.577 (p < 0.001). A higher risk was found associated with creatinine increases >1.5 times the baseline: HR 1.704 (p < 0.001). CONCLUSIONS: In hospitalized patients, increases in serum creatinine below the AKI threshold are associated with CHF, CIHD and long-term mortality. PMID- 28567703 TI - Alcohol Intake and Risk of Breast Cancer by Histologic Subtype and Estrogen Receptor Status Among Women Aged 55 to 74 Years. AB - Previous studies suggest that alcohol consumption and risk of breast cancer may differ by histologic subtype and hormone receptor status, though results are not entirely consistent. In this population-based case-control study, we evaluated the association between alcohol consumption and risk of invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and invasive ductal-lobular carcinoma (IDLC) overall and by estrogen receptor (ER) status, among women aged 55-74 years of age. Using polytomous regression, associations between current alcohol consumption, overall and by type of alcohol, and breast cancer risk were evaluated in 891 controls and 905 IDC, 567 ILC, and 489 IDLC cases. Current alcohol use was moderately associated with risk of ILC (odds ratio = 1.25, 95% confidence interval 0.99, 1.58) with a positive dose-response relationship based on average number of drinks per week consumed (P trend = 0.0005). When further stratified by ER status, alcohol use was positively associated with risk of ER+ ILC (P trend = 0.002) and ER+ IDC (P trend = 0.02), but inversely associated with risk of ER-IDC (P trend = 0.01). No association between alcohol and risk of IDLC tumors was observed. While the link between alcohol consumption and breast cancer risk is well established, our results suggest that the increased risk associated with alcohol is largely limited to ER+ ILC and ER+ IDC. Thus, avoiding or moderating alcohol consumption may be one way that women can lower their risks of these forms of breast cancer. PMID- 28567704 TI - Fission yeast Ctf1, a cleavage and polyadenylation factor subunit is required for the maintenance of genomic integrity. AB - Accurate segregation of chromosome during mitosis requires the coordinated action of several cell cycle checkpoints that monitor replication of the genome and the attachment of sister chromatids to the mitotic spindle apparatus. Here we have characterized the fission yeast Ctf1, an ortholog of S. cerevisiae Rna15 in the maintenance of genomic integrity. The ctf1 is nonessential for the cell survival and its deletion strain exhibit cold sensitivity. The ctf1 deleted cells exhibit genetic interaction with spindle checkpoint protein Mad2 and Bub1. The deletion of ctf1 gene affects the chromosomal attachment to the mitotic spindle leading to the accumulation of Bub1-GFP foci. Ctf1 localizes to the nucleus and physically interacts with Rna14, a cleavage and polyadenylation factor. PMID- 28567705 TI - Diagnostic value of Doppler echocardiography for identifying hemodynamic significant pulmonary valve regurgitation in tetralogy of Fallot: comparison with cardiac MRI. AB - Quantification of pulmonary regurgitation (PR) is essential in the management of patients with repaired tetralogy of Fallot (TOF). We sought to evaluate the accuracy of first-line Doppler echocardiography in comparison with cardiac magnetic resonance imaging (MRI) to identify hemodynamic significant PR. Paired cardiac MRI and echocardiographic studies (n = 97) in patients with repaired TOF were retrospectively analyzed. Pressure half time (PHT) and pulmonary regurgitation index (PRi) were measured using continuous wave Doppler. The ratio of the color flow Doppler regurgitation jet width to pulmonary valve (PV) annulus (jet/annulus ratio) and diastolic to systolic time velocity integral (DSTVI; pulsed wave Doppler) were assessed. Accuracy of echocardiographic measurements was tested to identify significant PR as determined by phase-contrast MRI (PR fraction [PRF] >= 20%). Mean PRF was 29.4 +/- 15.7%. PHT < 100 ms had a sensitivity of 93%, specificity 75%, positive predictive value (PPV) 92% and negative predictive value (NPV) 78% for identifying significant PR (C-statistic 0.82). PRi < 0.77 had sensitivity and specificity of 66% and 54%, respectively (C statistic 0.63). Jet/annulus ratio >=1/3 had sensitivity 96%, specificity 75%, PPV 92% and NPV 82% (C-statistic 0.87). DSTVI had sensitivity 84%, specificity 33%, PPV 84% and NPV 40%, (C-statistic 0.56). Combined jet/annulus ratio >=1/3 and PHT < 100 ms was highly accurate in identifying PRF >= 20%, with sensitivity 97% and specificity 100%. PHT and jet/annulus ratio on Doppler echocardiography, especially when combined, are highly accurate in identifying significant PR and therefore seem useful in the follow-up of patients with repaired TOF. PMID- 28567706 TI - The effect of strut thickness on shear stress distribution in a preclinical model. PMID- 28567707 TI - Anaerobic digestion of amine-oxide-based surfactants: biodegradation kinetics and inhibitory effects. AB - Recently, anaerobic degradation has become a prevalent alternative for the treatment of wastewater and activated sludge. Consequently, the anaerobic biodegradability of recalcitrant compounds such as some surfactants require a thorough study to avoid their presence in the environment. In this work, the anaerobic biodegradation of amine-oxide-based surfactants, which are toxic to several organisms, was studied by measuring of the biogas production in digested sludge. Three amine-oxide-based surfactants with structural differences in their hydrophobic alkyl chain were tested: Lauramine oxide (AO-R12), Myristamine oxide (AO-R14) and Cocamidopropylamine oxide (AO-cocoamido). Results show that AO-R12 and AO-R14 inhibit biogas production, inhibition percentages were around 90%. AO cocoamido did not cause inhibition and it was biodegraded until reaching a percentage of 60.8%. Otherwise, we fitted the production of biogas to two kinetic models, to a pseudo first-order model and to a logistic model. Production of biogas during the anaerobic biodegradation of AO-cocoamido was pretty good adjusted to the logistics model. Kinetic parameters were also determined. This modelling is useful to predict their behaviour in wastewater treatment plants and under anaerobic conditions in the environment. PMID- 28567708 TI - Clinical value of fluorine-18alpha-methyltyrosine PET in patients with gliomas: comparison with fluorine-18 fluorodeoxyglucose PET. AB - BACKGROUND: We investigated the relationship between metabolic activity and histological features of gliomas using fluorine-18alpha-methyltyrosine (18F-FAMT) positron emission tomography (PET) compared with fluorine-18 fluorodeoxyglucose (18F-FDG) PET in 38 consecutive glioma patients. The tumor to normal brain ratios (T/N ratios) were calculated, and the relationships between T/N ratio and World Health Organization tumor grade or MIB-1 labeling index were evaluated. The diagnostic values of T/N ratios were assessed using receiver operating characteristic (ROC) curve analyses to differentiate between high-grade gliomas (HGGs) and low-grade gliomas (LGGs). RESULTS: Median T/N ratio of 18F-FAMT PET was 2.85, 4.65, and 4.09 for grade II, III, and IV gliomas, respectively, with significant differences between HGGs and LGGs (p = 0.006). Both T/N ratio (p = 0.016) and maximum standardized uptake value (p = 0.033) of 18F-FDG PET showed significant differences between HGGs and LGGs. ROC analysis yielded an optimal cut-off of 3.37 for the T/N ratio of 18F-FAMT PET to differentiate between HGGs and LGGs (sensitivity 81%, specificity 67%, accuracy 76%, area under the ROC curve 0.776). Positive predictive value was 84%, and negative predictive value was 62%. T/N ratio of 18F-FAMT PET was not correlated with MIB-1 labeling index in all gliomas, whereas T/N ratio of 18F-FDG PET was positively correlated (r s = 0.400, p = 0.013). Significant positive correlation was observed between T/N ratios of 18F-FDG and 18F-FAMT (r s = 0.454, p = 0.004), but median T/N ratio of 18F-FAMT PET was significantly higher than that of 18F-FDG PET in all grades of glioma. CONCLUSIONS: The T/N ratio of 18F-FAMT uptake has high positive predictive value for detection of HGGs. 18F-FAMT PET had higher T/N ratio, with better tumor-normal brain contrast, compared to 18F-FDG PET in both LGGs and HGGs. Therefore, 18F-FAMT is a useful radiotracer for the preoperative visualization of gliomas. PMID- 28567709 TI - Renal cell cancers: unveiling the hereditary ones and saving lives-a tailored diagnostic approach. AB - The prevalence of RCC in Europe is 2-3% and increasing every year. Hereditary predisposition is found in 5-8% of all RCC cases. Hereditary syndromes associated with RCC include: Von Hippel-Lindau, hereditary papillary renal cell carcinoma, Birt-Hogg-Dube', hereditary leiomyomatosis, succinate dehydrogenase's deficiency, tuberous sclerosis complex and Cowden's syndrome. These syndromes are related to specific genetic mutations. So far the European Association of Urology and American Urological Association have not established guidelines for referral of patients with RCC for germline mutation screening. The scope of this article is to review which clinical manifestations should direct clinicians' thinking towards hereditary kidney carcinomas and therefore suggest which patients could benefit from genetic testing. PMID- 28567710 TI - The preoperative cardiology consultation: indications and risk modification. AB - BACKGROUND: The cardiologist is regularly consulted preoperatively by anaesthesiologists. However, insights into the efficiency and usefulness of these consultations are unclear. METHODS: This is a retrospective study of 24,174 preoperatively screened patients >=18 years scheduled for elective non-cardiac surgery, which resulted in 273 (1%) referrals to the cardiologist for further preoperative evaluation. Medical charts were reviewed for patient characteristics, main reason for referring, requested diagnostic tests, interventions, adjustment in medical therapy, 30-day mortality and major adverse cardiac events. RESULTS: The most common reason for consultation was the evaluation of a cardiac murmur (95 patients, 35%). In 167 (61%) patients, no change in therapy was initiated by the cardiologist. Six consultations (2%) led to invasive interventions (electrical cardioversion, percutaneous coronary intervention or coronary artery bypass surgery). On average, consultation delayed clearance for surgery by two weeks. CONCLUSION: In most patients referred to the cardiologist after being screened at an outpatient anaesthesiology clinic, echocardiography is performed for ruling out specific conditions and to be sure that no further improvement can be made in the patient's health. In the majority, no change in therapy was initiated by the cardiologist. A more careful consideration about the potential benefits of consulting must be made for every patient. PMID- 28567712 TI - Cellular fluid shear stress on implant surfaces-establishment of a novel experimental set up. AB - BACKGROUND: Mechanostimuli of different cells can affect a wide array of cellular and inter-cellular biological processes responsible for dental implant healing. The purpose of this in vitro study was to establish a new test model to create a reproducible flow-induced fluid shear stress (FSS) of osteoblast cells on implant surfaces. METHODS: As FSS effects on osteoblasts are detectable at 10 dyn/cm2, a custom-made flow chamber was created. Computer-aided verification of circulation processes was performed. In order to verify FSS effects, cells were analysed via light and fluorescence microscopy. RESULTS: Utilising computer-aided simulations, the underside of the upper plate was considered to have optimal conditions for cell culturing. At this site, a flow-induced orientation of osteoblast cell clusters and an altered cell morphology with cellular elongation and alteration of actin fibres in the fluid flow direction was detected. CONCLUSIONS: FSS simulation using this novel flow chamber might mimic the peri-implant situation in the phase of loaded implant healing. With this FSS flow chamber, osteoblast cells' sensitivity to FSS was verified in the form of morphological changes and cell re-clustering towards the direction of the flow. Different shear forces can be created simultaneously in a single experiment. PMID- 28567711 TI - The Case for Diabetes Population Health Improvement: Evidence-Based Programming for Population Outcomes in Diabetes. AB - PURPOSE OF REVIEW: The goal of this review is to describe diabetes within a population health improvement framework and to review the evidence for a diabetes population health continuum of intervention approaches, including diabetes prevention and chronic and acute diabetes management, to improve clinical and economic outcomes. RECENT FINDINGS: Recent studies have shown that compared to usual care, lifestyle interventions in prediabetes lower diabetes risk at the population-level and that group-based programs have low incremental medial cost effectiveness ratio for health systems. Effective outpatient interventions that improve diabetes control and process outcomes are multi-level, targeting the patient, provider, and healthcare system simultaneously and integrate community health workers as a liaison between the patient and community-based healthcare resources. A multi-faceted approach to diabetes management is also effective in the inpatient setting. Interventions shown to promote safe and effective glycemic control and use of evidence-based glucose management practices include provider reminder and clinical decision support systems, automated computer order entry, provider education, and organizational change. Future studies should examine the cost-effectiveness of multi-faceted outpatient and inpatient diabetes management programs to determine the best financial models for incorporating them into diabetes population health strategies. PMID- 28567713 TI - Serial reconstruction of order and serial recall in verbal short-term memory. AB - We carried out a series of experiments on verbal short-term memory for lists of words. In the first experiment, participants were tested via immediate serial recall, and word frequency and list set size were manipulated. With closed lists, the same set of items was repeatedly sampled, and with open lists, no item was presented more than once. In serial recall, effects of word frequency and set size were found. When a serial reconstruction-of-order task was used, in a second experiment, robust effects of word frequency emerged, but set size failed to show an effect. The effects of word frequency in order reconstruction were further examined in two final experiments. The data from these experiments revealed that the effects of word frequency are robust and apparently are not exclusively indicative of output processes. In light of these findings, we propose a multiple mechanisms account in which word frequency can influence both retrieval and preretrieval processes. PMID- 28567715 TI - MDMX is a prognostic factor for non-small cell lung cancer and regulates its sensitivity to cisplatin. AB - PURPOSE: Chemoradiotherapy is the standard treatment modality for advanced non small cell lung cancer (NSCLC). However, drug and radiation resistance remain major factors influencing its clinical outcome. The purpose of this study was to evaluate whether MDMX can affect the chemosensitivity and clinical outcome of NSCLC. METHODS: Quantitative real-time PCR (qRT-PCR) was performed to assess MDMX mRNA expression levels in 105 primary NSCLC tissues, its corresponding non cancerous tissues and two NSCLC-derived cell lines (A549 and SK-MES-1). In addition, immunohistochemistry was carried out to detect MDMX protein expression in the primary NSCLC tissues. The MDMX expression levels were correlated with clinicopathological and survival features. The effects of MDMX expression knockdown on NSCLC cell proliferation and chemosensitivity were evaluated using MTT, flow cytometry and soft agar colony assays. RESULTS: We found that the mRNA expression level of MDMX in NSCLC tissues was significantly higher than that in its corresponding non-tumorous tissues. High MDMX expression was found to be related to poor tumor cell differentiation, advanced TNM stages and the occurrence of lymph node metastases. Patients with a high MDMX expression level exhibited a lower overall survival rate than those with a low expression level. Multivariate analysis showed that a high MDMX protein expression level may serve as an independent prognostic factor for NSCLC patients. In addition, we found that MDMX expression knockdown combined with cisplatin treatment in vitro significantly increased apoptosis and decreased soft agar colony formation in NSCLC-derived cells. CONCLUSIONS: Our data indicate that MDMX expression may serve as an independent unfavorable prognostic factor for NSCLC patient outcome, which in turn may at least partly be due to the ability of the MDMX protein to regulate the proliferative capacity and chemosensitivity of NSCLC cells. PMID- 28567716 TI - Bariatric surgery influences beta-cell turnover in non obese rats. AB - BACKGROUND: The aim of this study was to investigate the relation between the different bariatric surgeries and pancreatic beta-cell turnover. MATERIAL AND METHODS: We used healthy adult male Wistar rats to undergo the different techniques. Three surgical techniques were developed (malabsorptive, Sleeve gastrectomy and Roux-Y Gastric Bypass-), together with two control groups (Sham and fasting control). Pancreatic beta-cell mass was measured, as well as apoptosis, proliferation and neogenesis related to cellular turnover. Otherwise, we measured the functional issues to elucidate the physiological role that these surgical techniques trigger in the carbohydrate metabolism (e.g. food intake, weight gain, intraperitoneal glucose tolerance test, and basal glycaemia). Results included the differences in phenotypes of the rat after the surgery. The rats did not show important differences in glycaemic parameters between the surgical groups. The beta-cell mass presented modifications related with proliferation processes. A significant increase of beta-cell mass in the malabsorptive technique was reported. On the other hand, the peripheral resistance to insulin tended to be reduced in rats which underwent malabsorptive and mixed techniques. CONCLUSION: This work showed an increase in beta-cell mass after the resection of an important portion of small bowel. The Roux-Y Gastric Bypass produced a non-significant increase in beta-cell mass. We considered that these implications of surgery over the endocrine pancreas must be one of the mechanisms related to the improvement of type 2 Diabetes mellitus following bariatric surgery. PMID- 28567714 TI - Epidemiology of hip fracture and the development of FRAX in Ukraine. AB - : A country-specific FRAX model has been developed for the Ukraine to replace the Austrian model hitherto used. Comparison of the Austrian and Ukrainian models indicated that the former markedly overestimated fracture probability whilst correctly stratifying risk. INTRODUCTION: FRAX has been used to estimate osteoporotic fracture risk since 2009. Rather than using a surrogate model, the Austrian version of FRAX was adopted for clinical practice. Since then, data have become available on hip fracture incidence in the Ukraine. METHODS: The incidence of hip fracture was computed from three regional estimates and used to construct a country-specific FRAX model for the Ukraine. The model characteristics were compared with those of the Austrian FRAX model, previously used in Ukraine by using all combinations of six risk factors and eight values of BMD (total number of combinations =512). RESULTS: The relationship between the probabilities of a major fracture derived from the two versions of FRAX indicated a close correlation between the two estimates (r > 0.95). The Ukrainian version, however, gave markedly lower probabilities than the Austrian model at all ages. For a major osteoporotic fracture, the median probability was lower by 25% at age 50 years and the difference increased with age. At the age of 60, 70 and 80 years, the median value was lower by 30, 53 and 65%, respectively. Similar findings were observed for men and for hip fracture. CONCLUSION: The Ukrainian FRAX model should enhance accuracy of determining fracture probability among the Ukrainian population and help to guide decisions about treatment. The study also indicates that the use of surrogate FRAX models or models from other countries, whilst correctly stratifying risk, may markedly over or underestimate the absolute fracture probability. PMID- 28567718 TI - SPATIAL RELATIONSHIPS BETWEEN STAMINATE AND PISTILLATE PLANTS OF DIOECIOUS TROPICAL FOREST TREES. PMID- 28567719 TI - MALE RARITY OR NOVELTY, FEMALE CHOICE BEHAVIOR, AND SEXUAL SELECTION IN THE GUPPY, POECILIA RETICULATA PETERS (PISCES: POECILIIDAE). PMID- 28567717 TI - ZP1609/danegaptide and mitochondrial connexin hemichannels: a harbinger for peptide drug design. AB - LINKED ARTICLES: This article is a Commentary on Boengler K, Bulic M, Schreckenberg R, Schluter K-D, Schulz R (2017). The gap junction modifier ZP1609 decreases cardiomyocyte hypercontracture following ischaemia/reperfusion independent from mitochondrial connexin 43. Br J Pharmacol 174: 2060-2073. https://doi.org/10.1111/bph.13804. PMID- 28567720 TI - CHROMOSOMAL DIVERGENCE AND SPECIATION IN TWO FAMILIES OF NORTH AMERICAN FISHES. PMID- 28567721 TI - ELECTROPHORETIC ANALYSIS OF EVOLUTIONARY RELATIONSHIPS IN TETRAHYMENA. PMID- 28567722 TI - OBSERVATIONAL LEARNING OF BABOONS AND AVOIDANCE OF MIMICS: EXPLORATORY TESTS. PMID- 28567723 TI - POLLEN-OVULE RATIOS: A CONSERVATIVE INDICATOR OF BREEDING SYSTEMS IN FLOWERING PLANTS. PMID- 28567725 TI - ANELOSIMUS STUDIOSUS (ARANEAE: THERIDIIDAE) AND THE EVOLUTION OF QUASISOCIALITY IN THERIDIID SPIDERS. PMID- 28567724 TI - THE REPRODUCTIVE BIOLOGY OF CUPANIA GUATEMALENSIS RADLK. (SAPINDACEAE). PMID- 28567726 TI - A GENERAL MODEL TO ACCOUNT FOR ENZYME VARIATION IN NATURAL POPULATIONS. III. MULTIPLE ALLELES. PMID- 28567727 TI - POPULATION SIZE FLUCTUATIONS IN THE EVOLUTION OF EXPERIMENTAL CULTURES OF DROSOPHILA SUBOBSCURA. PMID- 28567728 TI - GENETIC HOMOGENEITY AND SPECIATION IN THE PARTHENOGENETIC LIZARDS CNEMIDOPHORUS VELOX AND C. NEOMEXICANUS: EVIDENCE FROM INTRASPECIFIC HISTOCOMPATIBILITY. PMID- 28567729 TI - ALLOZYME, SI GENE, CYTOLOGICAL, AND MORPHOLOGICAL POLYMORPHISMS IN A POPULATION OF OENOTHERA BIENNIS. PMID- 28567730 TI - CRYPTIC SELF-INCOMPATIBILITY IN AMSINCKIA GRANDIFLORA. PMID- 28567731 TI - AN EXPERIMENTAL STUDY OF GROUP SELECTION. PMID- 28567732 TI - THE SIGNIFICANCE OF LACTATION IN THE EVOLUTION OF MAMMALS. PMID- 28567733 TI - LIFE HISTORY STRATEGY AND EVOLUTIONARY HISTORY OF TRIBOLIUM FLOUR BEETLES. PMID- 28567734 TI - GENETIC DIVERGENCE IN CLOSELY RELATED SIBLING SPECIES DROSOPHILA PSEUDOOBSCURA, DROSOPHILA PERSIMILIS AND DROSOPHILA MIRANDA. PMID- 28567735 TI - GENETIC VARIATION AND REPRODUCTIVE ISOLATION IN PARTULA. PMID- 28567736 TI - VARIATION IN AGONISTIC BEHAVIOR BETWEEN POPULATIONS OF THE STOMATOPOD, HAPTOSQUILLA GLYPTOCERCUS. PMID- 28567737 TI - HOST-PARASITE RESEMBLANCE IN AUSTRALIAN MISTLETOES: THE CASE FOR CRYPTIC MIMICRY. PMID- 28567738 TI - FIGHTING BEHAVIOR OF MUNTJAC AND THE EVOLUTION OF ANTLERS. PMID- 28567739 TI - LEK BEHAVIOR IN DROSOPHILA (HIRTODROSOPHILA) POLYPORI MALLOCH-AN AUSTRALIAN RAINFOREST SPECIES. PMID- 28567740 TI - TEMPORAL VARIATION IN THE RELATIONSHIP BETWEEN SIZE, NUMBERS, AND AN ALLELE FREQUENCY IN A POPULATION OF MYTILUS EDULIS. PMID- 28567741 TI - REPLY TO "SEXUAL DIMORPHISM IN SKATES (RAJIDAE)". PMID- 28567742 TI - Transient ischemic attack and ischemic stroke patients with or without prior stroke. AB - OBJECTIVES: A history of stroke is common in patients with transient ischemic attack (TIA) and ischemic stroke (IS), but there are few reports characterizing this group of patients. We aimed to compare characteristics, risk factors, and secondary preventive treatment in patients with TIA or IS with vs without a history of stroke. METHODS: Hospital-based data on TIA and IS events, registered from July 2011 to June 2013, were obtained from the Swedish Stroke Register (Riksstroke). Previous stroke was not specified as hemorrhagic or ischemic. RESULTS: A history of stroke was present in 19.3% (2892/15012) of TIA and 24.6% (10853/44169) of IS patients. Patients with prior stroke were older, more often male, and more likely to have atrial fibrillation (AF) (TIA: 27.4% vs 16.4%; IS: 36.1% vs 28.0%), hypertension (TIA: 77.5% vs 56.4%; IS: 74.2% vs 59.0%), and diabetes mellitus (TIA: 22.2% vs 14.2%; IS: 26.3% vs 19.5%) compared with those without (all differences P<.0001). At discharge, patients with prior stroke were more often treated with antihypertensive drugs than those without, whereas proportions treated with statins were similar in both groups. Patients with AF and prior stroke were less often treated with oral anticoagulant (OAC) medication than those without prior stroke. CONCLUSIONS: Both in TIA and IS, vascular risk factors were more common in patients with a history of stroke compared with those without. In contrast to other secondary preventive medications, OAC treatment in the presence of AF was underutilized in patients with a history of stroke. PMID- 28567744 TI - EVOLUTION OF SPERM SHORTAGE IN A SELFING HERMAPHRODITE. PMID- 28567743 TI - The use of selective progestin receptor modulators (SPRMs) and more specifically ulipristal acetate in the practice of gynaecology. AB - This review discusses the development of selective progestin receptor modulators (SPRMs) for use in women's health and specifically the use of ulipristal acetate (UPA) as emergency contraception (EC) and as a treatment for symptomatic fibroids in women who want to preserve their fertility or avoid a hysterectomy. As an EC, UPA 30 mg should be recommended for women, within 102 h of unprotected intercourse. As a treatment of fibroids, UPA (5 mg daily dose) should be administered for periods of three months as a pre-surgical strategy, reducing bleeding and fibroid size and facilitating surgery. A proportion of these patients may even avoid surgery. Future developments will demonstrate whether UPA can be used for other indications such as endometriosis and breast cancer prevention or treatment. PMID- 28567745 TI - ARE TRIOECY AND SEXUAL LABILITY IN ATRIPLEX CANESCENS GENETICALLY BASED?: EVIDENCE FROM CLONAL STUDIES. AB - Prior studies have alternatively considered floral phenotypes in Atriplex canescens as trioecious (having three sexual genders) and/or dioecious and having a "leaky genetical switch." Clones transplanted from three populations and grown in common gardens reveal the existence of two distinctly different genetic controls regulating gender expression. In some clones gender is fixed as male (staminate) or female (pistillate), while in other clones gender varies, ranging from a mixture of male and female ramets to simultaneous hermaphrodites with various proportions of male and female flowers. For clones which vary their sex expression, variation occurs within irrigation treatments, between treatments and over time, as a consequence of the combined effects of genotype plus environment. The magnitude of sex change is also a product of the interaction of genetics and environment. Some clones have been repeatedly examined for 20 years. PMID- 28567746 TI - THE RELATIVE IMPORTANCE OF INBREEDING AND MATERNAL SEX IN DETERMINING PROGENY FITNESS IN SIDALCEA OREGANA SSP. SPICATA, A GYNODIOECIOUS PLANT. AB - Gynodioecious plant populations contain both hermaphrodite and female individuals. For females to be maintained they must compensate for their loss of reproductive fitness through pollen. Females may achieve compensation by producing more and/or higher quality seeds than hermaphrodites. In this study, I investigated the independent and interactive effects of maternal sexual identity and inbreeding level on fitness of the progeny of hermaphrodites and females of Sidalcea oregana ssp.spicata. Seeds produced by selling hermaphrodites and by outcrossing or sib-crossing hermaphrodites and females, were planted in the field and greenhouse. Maternal-sex effects were substantial at the juvenile stages of the life cycle; seeds of females germinated in higher proportions and produced seedlings that grew significantly faster. Inbreeding effects were manifested primarily at the adult stage of the life cycle. Outcrossed plants were significantly larger and produced more flowers per plant than sib-crossed and selfed plants growing in the greenhouse. Progeny of hermaphrodites and females appeared to respond similarly to sib-matings. The maternal-sex effects observed in Sidalcea may have been related to cytoplasmically inherited factors and could be a driving force in the maintenance of females. Inbreeding depression could play a role in determining the fitness of both sex morphs, if females experience biparental inbreeding in the field. Frequent inbreeding of hermaphrodites may not be necessary to explain the maintenance of gynodioecy in this species. PMID- 28567747 TI - COMPARISON OF QUANTITATIVE GENETIC PARAMETERS: REPLY TO COWLEY AND ATCHLEY. PMID- 28567748 TI - PHENOTYPIC PLASTICITY IN CHRYSOPERLA: GENETIC VARIATION IN THE SENSORY MECHANISM AND IN CORRELATED REPRODUCTIVE TRAITS. AB - A genetically variable sensory mechanism provides phenotypic plasticity in the seasonal cycle of the Chrysoperla carnea species-complex of green lacewings. The mechanism functions as a switch during the pupal and early imaginal stages to determine aestival reproduction versus aestival dormancy, and it has two major components: (1) response to photoperiod and (2) response to a stimulus(i) associated with the prey of the larvae. Ultimately, the switch is based on the response to photoperiod-an all-or-nothing trait whose variation (long-day reproduction versus a short-day/long-day requirement for reproduction) is determined by alleles at two unlinked autosomal loci. In eastern North America, variation in this component of the switch differentiates two reproductively isolated "species" that are sympatric throughout the region: Chrysoperla carnea, in which both loci are homozygous for the dominant alleles that determine long day, spring and summer reproduction and thus multivoltinism, and C. downesi, which has a very high incidence of the recessive alleles for the short-day/long day requirement, and thus univoltine spring breeding. In contrast, geographical populations in western North America harbor variable amounts of within-and among family genetic variation for the photoperiodic responses and also for the switch's second component-adult responsiveness to the prey of the larvae. The geographic pattern of genetic variation in the two components of the switch indicates that it is a highly integrated adaptation to environmental heterogeneity. Expression of among-family variation in the prey component of the switch is highly dependent on photoperiodic conditions and genotype (it requires a constant long daylength and the recessive short-day/long-day genotype). Thus, we infer that responsiveness to prey evolved as a modifier of the photoperiodic trait. The switch has a significant negative effect on a major determinant of fitness; it lengthens the preoviposition period in nondiapausing reproductives. This negative effect may result in temporal variation in the direction of selection, which helps maintain genetic variability in the switch mechanisms of western populations. Also, the photoperiodic and prey components of the switch are positively correlated with fecundity in nondiapausing reproductives; however, the strong influence of environmental factors-presence or absence of prey-leaves open the question whether the correlated effects on fecundity are expressed in nature. PMID- 28567749 TI - MORPHOLOGICAL EVOLUTION IN MUROID RODENTS II. CRANIOMETRIC FACTOR DIVERGENCE IN SEVEN NEOTROPICAL GENERA, WITH EXPERIMENTAL RESULTS FROM ZYGODONTOMYS. AB - First principal components extracted from covariance matrices of log-transformed craniodental measurements closely approximate general size factors within field collected samples representing 14 species in seven Neotropical muroid genera; because these samples are mixed-cross-sectional, scores are age-correlated and coefficients reflect postweaning growth allometries. Compared between congeners, sample first principal component coefficients are very similar, an observation that implies a nearly parallel orientation of ontogenetic trajectories in log measurement space. On the assumption that a common general size factor (estimated as the first principal component of the pooled-within covariance matrix) accounts for most of the observed measurement covariance within samples, size-adjusted differences between congeneric species were estimated variable-by-variable in separate analyses of covariance; these differences reflect developmental adjustments of craniodental morphology that precede the measured interval of postweaning ontogeny. Vectors of size-adjusted difference coefficients are not similar from genus to genus, and a diversity of causal mechanisms is probably responsible. Analyses of captive-bred samples from two "species" of Zygodontomys provide prima facie evidence that size-adjusted differences estimated from field collected samples have a genetic basis. Postweaning growth allometries in the muroid head skeleton may be conserved due to the biomechanical constraints of masticatory function; the apparent evolutionary plasticity of earlier ontogenetic adjustments may reflect the absence of such constraints in the fetus or suckling pup. The relevance of these results for current theories concerning the developmental genetics of mammalian morphometric evolution is discussed. PMID- 28567750 TI - PREMATING ISOLATION IS DETERMINED BY LARVAL SUBSTRATES IN CACTOPHILIC DROSOPHILA MOJAVENSIS. PMID- 28567751 TI - EDITORIAL ON PUBLISHING PAPERS IN EVOLUTION. PMID- 28567752 TI - TEMPERATURE DETERMINATION OF MALE OUTCROSSING ABILITY IN A SIMULTANEOUS HERMAPHRODITE. AB - Phally, a genital dimorphism found in some species of self-compatible simultaneous hermaphrodites, presents an opportunity to examine factors maintaining outcrossing within an animal species in the presence of recombination. Both aphallics and euphallics can self-fertilize but only euphallics develop a functional penis and prostate allowing them to donate sperm. Previous studies of phally in the gastropod Bulinus truncatus (Mollusca: Pulmonata) suggest that phally may be under direct genetic control in some populations and strongly influenced by environmental factors in others. Experiments reported here identify temperature as a cue affecting phally determination in two populations of B. truncatus. In both populations, a higher proportion of euphallics was produced at low temperature (22 +/- 1 degrees C) than at high temperature (30 +/- 1 degrees C). Temperatures experienced by parents did not affect the proportion of euphallics they produced. Instead, phally was sensitive to temperature during the egg stage postoviposition and during the hatchling stage; the relative influence of temperature before and after hatching varied between populations. The total number of hatchlings reaching maturity at high and low temperature did not differ, but at low temperature, snails took longer to hatch and mature, and had lower survivorship. Just as studies of environmental sex determination have shed light on selective pressures influencing sex ratio evolution, we suggest that temperature-sensitive phally determination may shed light on the selective pressures maintaining outcrossing in B. truncatus. PMID- 28567753 TI - OPTIMUM BROOD SIZE: TESTS OF ALTERNATIVE HYPOTHESES. AB - The most productive litter size (five) was not as common as expected in a free living population of white-footed mice. I evaluated four competing hypotheses that can explain this pattern. Reproductive costs and annual variation in recruitment appear to be insufficient explanations for the empirical distribution of litter size. Optimal investment of reproductive resources that vary among parents is supported by some tests, but not by all. The abundance of litters less than the apparent optimum is at least partially explained by asymmetric survival in large litters (the cliff-edge hypothesis). Hypotheses that explain the empirical distribution of brood size are not mutually exclusive. Several mechanisms can act alone, or interact, to create an average brood size less than that which appears to produce the greatest number of descendants. PMID- 28567754 TI - COMPARISON OF QUANTITATIVE GENETIC PARAMETERS. PMID- 28567755 TI - SEXUAL SELECTION AND FITNESS VARIATION IN A POPULATION OF SMALLMOUTH BASS, MICROPTERUS DOLOMIEUI (PISCES: CENTRARCHIDAE). AB - Monogamy is often presumed to constrain mating variance and restrict the action of sexual selection. We examined the reproductive patterns of a monogamous population of smallmouth bass (Micropterus dolomieui), and attempted to identify sources of within-season fitness variation among females and known-age males. Many males did not acquire a nest site, and many territorial males were unsuccessful in acquiring a mate. The likelihood that territorial males mated depended on several aspects of nest sites. Mated males of age three were larger than the average size of age-three males in the population. The mean sizes of age four and age-five mated males were not different from the average of same-age males in the population. Thus, selection resulting from the acquisition of a mate favored large size among only age-three males. Timing of nest construction and breeding among territorial males was negatively related to male size and did not depend on male age after taking male size into account. Indirect evidence (numbers of eggs deposited in nests) suggests that the timing of spawning among females was also negatively related to female size. Fertility selection favored early reproduction within the season by males of all ages, but large male size was favored among only age-four males. The combined early breeding of fecund females and female mate choice of large males may explain the positive correlation between the size of age-four males and the number of eggs acquired. Despite large differences of female fecundity, however, the variance of relative mate number contributed about two times more than the variance of relative fertility among females to the total variance of relative fitness within each sex. PMID- 28567756 TI - THE DETECTION OF GAMETIC DISEQUILIBRIUM BETWEEN ALLOZYME LOCI IN NATURAL POPULATIONS OF DROSOPHILA. AB - The capacity of the usual tests (chi-square and related tests) to detect gametic disequilibrium between allozyme loci in natural populations of Drosophila has been investigated. We analyzed a large collection of previously reported gametic samples from natural populations involving a variety of loosely linked allozyme loci located along the O chromosome of Drosophila subobscura and the second chromosome of D. melanogaster. It is found that the statistical power of the individual tests to detect the sample disequilibria between allozyme loci is remarkably low, being the average (over pairs of loci) of power estimates close to 0.20 in both species. Moreover, the average minimum disequilibrium (D'min ) that would be required to reject (90% probability) the hypothesis of gametic equilibrium is higher than 0.50 given the observed degree of polymorphism and sample sizes used. This means that statistically significant associations between allozyme loci would rarely be detected by single-sample tests even when much disequilibrium is present in natural populations of Drosophila. However, an alternative approach based on the analysis of disquilibrium for large sets of gametic samples, combining probabilities from single independent tests and assessing significance by a bootstrap procedure, reveals that most of the locus pairs within segment I and II of the O chromosome of D. subobscura and left arm of the second chromosome of D. melanogaster present significant nonrandom associations. Within these chromosomal sections, the observed average absolute value of disquilibrium (D') between loci is around 0.25 (under the more conservative estimation). Also, a positive relationship between the magnitude of disequilibrium and linkage was detected. These findings suggest that weak or moderate values of disequilibrium between loosely linked allozyme loci are more frequent in natural populations of Drosophila than is currently believed. PMID- 28567757 TI - BALANCING SELECTION IN A DESERT STREAM-DWELLING FISH, POECILIOPSIS MONACHA. AB - The desert stream-dwelling fish Poeciliopsis monacha is exposed to extreme seasonal and spatial variation in physical stresses. We examined four diallelic gene loci (Ldh-1, Idh-2, Pgd, and Ck-A) in P. monacha and tested whether genotypes were associated with differential survival of individuals exposed to acute stress. For each locus, the common allele was associated with higher survival during heat and hypoxic stress, whereas the alternate allele was associated with higher survival during cold stress. In most cases, survival of heterozygotes was intermediate and they exhibited less variance in survival than corresponding homozygotes. Identification of substantial linkage disequilibrium in these fish confounds our ability to discern whether the allozymes are the direct targets of selection, or if they just mark chromosomal regions that contain the true modifiers of survival. Nevertheless, the present results clearly identified balancing processes that can serve to stabilize genetic polymorphism in this species. PMID- 28567758 TI - VARIABLE SELECTION ON EUROSTA'S GALL SIZE, I: THE EXTENT AND NATURE OF VARIATION IN PHENOTYPIC SELECTION. AB - Natural fluctuations in environmental conditions are likely to induce variation in the intensity or direction of natural selection. A long-term study of the insect, Eurosta solidaginins Fitch (Diptera; Tephritidae), which induces stem galls on the perennial herb Solidago altissima (Asteraceae) was performed to explore the patterns of variation in phenotypic selection. The intensity of selection imposed by parasitoids and predators on gallmaking larvae, for gall size, was measured across 16 populations over the course of 4 generations, for a total of 64 population-generations. Directional selection was quantified by i, the selection intensity, and variance selection by j', a measure of the intensity of selection on phenotypic variance. Size-dependent attack by parasitoids caused upward directional selection (mean ip = 0.42; SE = 0.023), while size-dependent bird attack favored larvae that induced smaller galls (mean ib = -0.07; SE = 0.013. The mean net directional selection intensity was 0.35 (SE = 0.030), which indicates that insects inducing larger galls are generally favored by selection. The opposing patterns of size-dependent attack resulted in stabilizing selection in half the population generations, with an overall average. j' of -0.11 (SE = 0.078). The magnitude of directional selection was strongly influenced by the population mean gall size and weakly by the optimal gall size. The intensity of variance selection was strongly influenced by the shape of the fitness function, with sigmoidal and Gaussian-like shapes causing greater depletion of phenotypic variance. PMID- 28567759 TI - COMPARATIVE ONTOGENY OF A WILD CUCURBIT AND ITS DERIVED CULTIVAR. AB - Most previous studies of evolutionary modification of form in plants have focused primarily on individual organs or flowers. Few have investigated the role of evolutionary changes in timing or position at the level of whole plant ontogeny. This study compares ontogenies of the primary shoots of two subspecies of Cucurbita argyrosperma, one a cultivar and the other its wild progenitor. Differences in flowering times between these subspecies suggested that the cultivar may have evolved from the wild subspecies via heterochronic processes leading to paedomorphosis. Analyses showed that both subspecies are similar in vegetative architecture and rates of leaf production. Earlier flowering in the cultivar, both in terms of position and absolute time, appears to have arisen through progenesis. Initial observations of leaf blade morphology led to the hypothesis that paedomorphosis and gigantism also may have been involved in the evolution of leaf blade shape in the cultivar: all leaves of the cultivar are larger and visually similar in shape to early leaves of the wild subspecies. However, quantitative analysis revealed that leaves of the cultivar are neither geometrically, nor solely allometrically larger versions of early leaves of the progenitor. Leaf shape in the cultivar exhibits novel features as well as effects of allometry shared with the progenitor, hence a simple hypothesis of paedomorphic evolution of leaf shape is not supported. PMID- 28567760 TI - MORPHOLOGICAL VARIABILITY AND ENZYME HETEROZYGOSITY: INDIVIDUAL AND POPULATION LEVEL CORRELATIONS. PMID- 28567761 TI - EFFECTS OF PARENTAGE AND SIZE OF THE POLLEN LOAD ON PROGENY PERFORMANCE IN CAMPANULA AMERICANA. AB - To examine the effects of maternal and paternal parentage and the size of the pollen load on seed size and weight and on progeny performance we conducted a controlled crossing experiment using a natural population of Campanula americana. We found that seed size was positively correlated with early seedling performance for all but one of traits we measured (days to emergence), but was not significantly correlated with any of the later vegetative measures or reproductive output. We detected significant effects due to the maternal parent for the vegetative traits days to emergence, days to first leaf, and final plant height, as well as total seed weight, and mean seed weight per fruit. Significant paternal effects were found for all of the seedling traits except number of leaves after vernalization. The progeny from fruits receiving high pollen loads significantly outperformed the progeny from fruits receiving low pollen loads for the traits days to first and second leaf, numbers of leaves after vernalization, and days to first flower. These results not only demonstrate the importance of parentage and seed weight on progeny performance, but also indicate that variations in the size of the pollen load may be important in seedling establishment in natural populations. PMID- 28567762 TI - HETEROMORPHISM FOR A HIGHLY REPEATED SEQUENCE IN THE NEW ZEALAND FROG LEIOPELMA HOCHSTETTERI. AB - A satellite DNA sequence, Lhl, was cloned from the New Zealand endemic frog Leiopelma hochstetteri. Large tandem arrays of Lh1 were localized by in situ hybridization to the long arm of a small telocentric autosome in some individuals, but these arrays were absent from other individuals. Lh1 is also present in varying amounts on some supernumerary chromosomes in some individuals. Heteromorphism for the presence of Lh1 exists in two populations that have been separated by a sea channel since the end of the Pleistocene, indicating that the heteromorphism either has arisen repeatedly or has persisted for at least 10,000 years. Individuals lacking Lh1 thus appear to be at no significant selective disadvantage. The variation in Lh1 copy number probably results from its interstitial chromosomal location, which exposes it to more frequent unequal crossovers than the pericentromeric or telocentric locations of most satellite DNA. Lh1 may be parasitic or simply inert junk, but in either case it may be deleted or dispersed throughout the rest of the genome through unequal crossing over. PMID- 28567763 TI - THE THIRD PHASE OF WRIGHT'S SHIFTING-BALANCE: A SIMPLE ANALYSIS OF THE EXTREME CASE. PMID- 28567764 TI - SEXUAL DIMORPHISM, MATING SYSTEM AND BODY SIZE IN NEW WORLD BLACKBIRDS (ICTERINAE). AB - Although sexual selection is widely accepted as a primary functional cause of sexual size dimorphism in birds and mammals, results from some comparative studies have cast doubt on this conclusion. Chief among these contradictory results is the widespread association between body size and size dimorphism-large species tend to be more dimorphic than small species. This correlation is not directly predicted by the normal sexual selection scenario, and many hypotheses have been advanced to explain it. This paper reviews these hypotheses and evaluates them using data for the New World blackbirds (Icterinae). In this avian subfamily, (1) body size correlates with the intensity of sexual selection (as measured by mean harem size), and (2) size does not correlate with dimorphism if the effects of mating system are removed. Similar results are obtained when controlling for the confounding influence of phylogeny. Further, body size and mating system are associated with nesting dispersion. These results strongly argue that sexual dimorphism is a product of sexual selection in this subfamily, and suggest that either: (1) large body size itself, or the ecology of large species, promotes the development of coloniality and a polygynous mating system; or (2) polygyny and/or coloniality lead to the evolution of large size in both males and females. None of the other hypotheses examined predict an association between size and mating system, and all predict that size will correlate with dimorphism after the effects of mating system are removed. Thus, none of the other hypotheses seem applicable in this case. These results are compared to those obtained for other avian and mammalian taxa. Difficulties of analysis present in previous studies are discussed. I argue that it is inappropriate to assume that associations between a trait and body size or phylogeny are evidence of nonadaptive evolutionary "constraints." PMID- 28567765 TI - GENETIC AND MORPHOMETRIC DIVERGENCE IN ANCESTRAL EUROPEAN AND DESCENDENT NEW ZEALAND POPULATIONS OF CHAFFINCHES (FRINGILLA COELEBS). AB - Descendent populations of chaffinches (Fringilla coelebs) introduced to New Zealand about 120 years ago were compared with "ancestral" populations in northern Europe and with those in a broader region of Europe (including Iberia) using protein electrophoresis at 42 loci and 12 skeletal measurements. The New Zealand populations exhibit very small scale differentiation in genetics (Fst = 0.040) and morphometrics, and the haphazard pattern of among-population variation does not align with environmental variation nor is it predicted by the geographic proximity of populations. Thus random drift is implicated in the differentiation among the descendent populations. The New Zealand chaffinches have diverged only slightly in morphometrics from an extant population in southern England, and constant heritability rate tests suggest that random drift alone could account for this small shift. In sharp contrast, the European populations are subdivided genetically (Fst = 0.222) and morphometrically, and this subdivision coincides with the Pyrenees mountains between Iberia and northern Europe which act as a barrier to gene flow between these regions. Iberian populations have smaller skulls and longer wings on average than northern European populations and are characterized by high frequencies of alternative common alleles at Ada and Np. Within both the Iberian and northern European regions, however, populations are effectively panmictic in protein-encoding genes, indicating that homogenizing gene flow is apparently extensive enough to prevent among-population differentiation in allozymes by drift. Variation in body size as represented by PC I is related to environmental productivity across Europe, unlike in New Zealand. These observations jointly suggest that longer term adaptive differentiation via selection for optimal body size has evolved in Europe. Because multilocus evolution is expected to proceed slowly in populations subject to the opposing forces of selection and homogenizing gene flow, I argue that local adaptation within "ancestral" populations in northern Europe may still be evolving. PMID- 28567766 TI - SPATIAL AND TEMPORAL VARIATION IN SELECTION ON CORRELATED LIFE-HISTORY TRAITS AND PLANT SIZE IN CHAMAECRISTA FASCICULATA. AB - Intraspecific studies of selection on multiple traits of a plant's life history provide insight as to how the composite life history of an organism evolves. Current understanding of selection on plant life-history traits is deficient in three important areas: 1) the effects of selection through correlated traits, 2) the effects of selection on a trait throughout the plant's lifetime, and 3) spatial and temporal variation in selection on plant life-history traits among populations and years. This study documents spatial and temporal variation in selection on three life-history and two morphological traits for two natural populations of Chamaecrista fasciculata, a native summer annual. Life-history and morphological traits (date of seedling emergence, size at establishment, size prior to reproduction, date of initial flowering, and date of initial fruit maturation) varied significantly between sites and/or years. Selection on traits varied either spatially, between sites and among transects within one site, or temporally, between years. In addition, life-history traits were phenotypically correlated among themselves and with morphological traits; correlations were generally constant over time and space. Indirect selection caused changes in means and variances in traits not under direct selection, but which were correlated with traits under selection. Selection on date of emergence varied in direction and magnitude among different life-cycle stages, while selection on other traits varied only in magnitude among life stages of the plant. This study documents the complexity of the selective process and the importance of considering multiple life stages and traits when studying the evolution of life history traits. PMID- 28567767 TI - PATTERNS IN TREE BALANCE AMONG CLADISTIC, PHENETIC, AND RANDOMLY GENERATED PHYLOGENETIC TREES. AB - I examine patterns in tree balance for a sample of 208 cladograms and phenograms from the recent literature. I provide an expression for expected imbalance under a simple, uniform-rate random speciation model, and I estimate variances by simulation for the same model. Imbalance decreases with tree size (number of included taxa) in both theoretical and literature trees. In contrast to previous suggestions, I find cladistic trees to be no more imbalanced than phenetic trees when confounding variables are appropriately controlled. The degree of imbalance found in literature trees is inconsistent with the uniform-rate speciation model; this is most likely a result of variability in speciation and extinction rates among real lineages. The existence of such variation is a necessary (but not sufficient) condition for the operation of the macroevolutionary processes of species sorting and species selection. PMID- 28567768 TI - SEX CHROMOSOMES, HETEROCHROMATIN, AND RETROTRANSPOSON ACCUMULATION IN DEER MICE. PMID- 28567769 TI - SEX RATIO SELECTION AND THE EVOLUTION OF ENVIRONMENTAL SEX DETERMINATION IN LABORATORY POPULATIONS OF MENIDIA MENIDIA. AB - What happens when a population with environmental sex determination (ESD) experiences a change to an extreme environment that causes a highly unbalanced sex ratio? Theory predicts that frequency-dependent selection would increase the proportion of the minority sex and decrease the level of ESD in subsequent generations. We empirically modeled this process by maintaining five laboratory populations of a fish with temperature-dependent sex determination (the Atlantic silverside, Menidia menidia) in extreme constant temperature environments that caused highly skewed sex ratios to occur initially. Increases in the minority sex consistently occurred from one generation to the next across all five populations, first establishing and then maintaining a balanced sex ratio until termination of the experiment at 8 to 10 generations. The extent to which the level of ESD changed as balanced sex ratios evolved, however, was not consistent. Two populations that experienced high temperatures each generation displayed a loss of ESD, and in one of these ESD was virtually eliminated. This suggests that temperature-insensitive, sex-determining genes were being selected. In populations maintained in low temperature environments, however, the level of ESD did not decline. Instead, the response of sex ratio to temperature was adjusted upward or downward, perhaps by selection of sex-determining genes sensitive to higher (or lower) temperatures. The two different outcomes at low versus high temperatures occurred independent of the geographic origin of the founding population. Our results demonstrate that ESD is capable of evolving in response to selection. PMID- 28567770 TI - EFFECTIVE POPULATION SIZE AND GENETIC DRIFT IN TRISTYLOUS EICHHORNIA PANICULATA (PONTEDERIACEAE). AB - Populations of the tristylous, annual Eichhornia paniculata are markedly differentiated with respect to frequency of mating types. This variation is associated with evolutionary changes in mating system, from predominant outcrossing to high self-fertilization. To assess the potential influence of genetic drift acting on this variation, we estimated effective population size in 10 populations from northeastern Brazil using genetic and demographic methods. Effective size (Ne ) was inferred from temporal changes in allele frequency at two to eight isozyme loci and also calculated using five demographic variables: 1) the number of flowering individuals (N); 2) temporal fluctuations in N; 3) variance in flower number; 4) frequency of mating types; and 5) selfing rate. Average Ne based on isozyme data was 15.8, range 3.4-70.6, and represented a fraction (mean Ne /N = 0.106) of the census number of individuals (mean N = 762.8; range: 30.5-5,040). Temporal variation in N and variance in flower number each reduced Ne to about a half of N whereas mating type frequencies and selfing rate caused only small reductions in Ne relative to N. All estimates of Ne based on demographic variables were considerably larger than those obtained from genetic data. The two kinds of estimates were in general agreement, however, when all demographic variables were combined into a single measure. Monte Carlo simulations indicated that effective size must be fewer than about 40 for drift to overcome the frequency-dependent selection that maintains the polymorphism for mating type. Applying the average Ne /N value to 167 populations censused in northeastern Brazil indicated that 72% had effective sizes below this number. This suggests that genetic drift is likely to play a dominant role in natural populations of E. paniculata. PMID- 28567771 TI - A NOTE ON THE INBREEDING EFFECTIVE POPULATION SIZE. PMID- 28567772 TI - SELFISH LARVAE: DEVELOPMENT AND THE EVOLUTION OF PARASITIC BEHAVIOR IN THE HYMENOPTERA. AB - Queens of hymenopteran social parasites manipulate the workers of other social species into raising their offspring. However, nonconspecific brood care may also allow the parasite larvae to control their own development to a greater extent than possible in nonparasitic species. An evolutionary consequence of this may be the loss of the parasite's worker caste if the larvae can increase their fitness by developing into sexuals rather than workers. We argue that this loss is particularly likely in species in which there is little inclusive fitness benefit in working. Retention of a worker caste correlates with characteristics that increase the fitness of working relative to becoming a sexual, such as worker production of males, high intracolony relatedness, and seasonal environments where the hosts of potential parasite queens are not always available. Further evidence strongly suggests that when the worker caste is evolutionarily lost in perennial species like ants, it disappears rapidly and through a reduction in caste threshold and queen size, so that parasite larvae become queens with less food than required to produce host workers. This evolutionary process, however, appears to lower overall population fitness, resulting in workerless parasite species having small populations and being geographically restricted. Conversely, in annual species like bees and wasps, workerless social parasitism evolves with no size reduction in queens, which is consistent with an expected lower level of queen/offspring conflict. PMID- 28567773 TI - SPECIES ISOLATION, GENITAL MECHANICS, AND THE EVOLUTION OF SPECIES-SPECIFIC GENITALIA IN THREE SPECIES OF MACRODACTYLUS BEETLES (COLEOPTERA, SCARABEIDAE, MELOLONTHINAE). AB - The question asked was why male genitalic structures have diverged in three syntopic species of Macrodactylus beetles. Four hypotheses were evaluated: 1. The ways in which male genitalia mesh with internal female structures indicate that selection for species isolation via mechanical exclusion ("lock and key") is unlikely to explain the genitalic differences. 2. The specific mate recognition hypothesis also clearly fails to explain genitalic differences due to the implausibility of postulated environmental effects on genitalia, and lack of postulated coevolution of male and female morphologies. 3. Selection for species isolation via differences in genitalic stimulation (sensory lock and key) is unlikely due to relatively infrequent cross-specific pair formation and intromission in the field, and "excessive" numbers of species-specific genitalic structures and male courtship behavior patterns which nevertheless occasionally fail. It also fails to explain the frequent failure of intraspecific copulations to result in sperm transfer. This hypothesis cannot, however, be rejected as confidently as the previous hypotheses. 4. Conditions under which sexual selection by cryptic female choice could take place are common. Females frequently exercise their ability to prevent sperm transfer by conspecific males even after intromission has occurred, and females generally mate repeatedly, probably with different males. Males behave as if cryptic female choice is occurring, courting assiduously while their genitalia are within the female. Sexual selection by female choice could thus contribute to the divergence in genitalic structures. PMID- 28567774 TI - GYNOGENETIC REPRODUCTION IN HYBRID MOLE SALAMANDERS (GENUS AMBYSTOMA). AB - Ambystoma platineum, a unisexual clonal triploid taxon of mole salamander, originated by hybridization between the Mendelian species A. jeffersonianum and A. laterale. Studies of lampbrush chromosomes indicated that A. platineum reproduces gynogenetically, that is, sperm from a sexual host species is required to activate egg development but makes no genetic contribution to the developing embryo. Nevertheless, electrophoretic diversity in populations of some hybrid Ambystoma suggested continual in situ recreation of unisexual hybrids and bidirectional gene exchange between the parental species and the hybrids. A. platineum usually lives with, and is sexually dependent on, one of its parental species, A. jeffersonianum. In central Indiana, however, A. platineum populations have shifted their host dependency to A. texanum. Such A. texanum-dependent populations of A. platineum provide an almost ideal system for studying reproductive mode in A. platineum, because both replacement of a jeffersonianum or laterale genome of A. platineum by a texanum genome, and movement of genes from A. platineum to the host species, A. texanum, would be readily detected by electrophoretic markers. Our samples of A. texanum provided no evidence for the transfer of jeffersonianum or laterale genes into A. texanum. Similarly, among 32 A. platineum sampled from six localities in east-central Illinois and central Indiana, we find no texanum alleles, and thus no evidence for genome replacement. The one diploid hybrid individual contained only a jeffersonianum and a laterale genome; because of the absence of either parental species from these populations, this hybrid could only have come from a diploid ovum produced by A. platineum. Both morphometric and electrophoretic results for the two tetraploid individuals indicate that they resulted from fertilization of triploid oocytes of A. platineum by sperm of A. texanum. Because genome replacement in A. texanum dependent populations of A. platineum is irreversible, the persistence of A. platineum in A. texanum-dependent populations demonstrates conclusively that the major mode of reproduction in A. platineum populations is clonal: A. platineum produces mainly triploid eggs that develop gynogenetically. PMID- 28567775 TI - ALGAE CONTAINING CHLOROPHYLLS a + c ARE PARAPHYLETIC: MOLECULAR EVOLUTIONARY ANALYSIS OF THE CHROMOPHYTA. AB - Sequence comparisons of small subunit ribosomal RNA coding regions from 12 chlorophylls a + c-containing algae were used to infer phylogenetic relationships within the Chromophyta. Three chromophyte lines of descent, delineated by the Bacillariophyceae, the Phaeophyceae/Xanthophyceae, and the Chrysophyceae/Eustigmatophyceae/Synurophyceae are members of a complex evolutionary assemblage, which also includes representatives of the Oomycota ("lower" fungi). Maximum parsimony and distance matrix methods demonstrate a common evolutionary history for these lineages but their relative branching order could not be determined. Other algal species with chlorophylls a + c, including dinoflagellates and prymnesiophytes, are not members of this complex assemblage. Dinoflagellates are specifically related to apicomplexans and ciliates, and the prymnesiophyte, Emiliania huxleyi, represents an independent photosynthetic lineage that separated from other eukaryotes during the nearly simultaneous divergence of plants, animals, fungi, and a number of other protist lineages. The small subunit rRNA phylogenies of chromophytes/oomycetes were compared to those derived from comparisons of ultrastructural characters. Only tubular, tripartite mastigonemes (flagellar hairs) characterized all studied taxa of chromophytes/oomycetes as a monophyletic assemblage. PMID- 28567776 TI - Patient-reported outcomes (PROs) in chronic urticaria. AB - Chronic urticaria is an itching skin disease which persists for more than 6 weeks. Chronic urticaria has great impact on the daily life of the patient, and the fluctuating nature of the symptoms complicates the monitoring and treatment of the disease. Currently, there are no reliable biomarkers to identify and measure disease activity in chronic spontaneous urticaria. Consequently, use of patient-reported outcomes (PROs) is crucial when evaluating and monitoring different aspects of chronic urticaria such as disease activity/severity, disease control, and quality of life. We present an overview of seven different PROs used in chronic urticaria and highlight their strengths, limitations, and use in clinical practice and research. PMID- 28567777 TI - POPULATION CAGE EXPERIMENTS WITH A VERTEBRATE: THE TEMPORAL DEMOGRAPHY AND CYTONUCLEAR GENETICS OF HYBRIDIZATION IN GAMBUSIA FISHES. AB - The dynamics of mitochondrial and multilocus nuclear genotypic frequencies were monitored for 2 yr in experimental populations established with equal numbers of two poeciliid fishes (Gambusia affinis and Gambusia holbrooki) that hybridize naturally in the southeastern United States. In replicated "small-pool" populations (experiment I), 1018 sampled individuals at six time periods revealed an initial flush of hybridization, followed by a rapid decline in frequencies of G. affinis nuclear and mitochondrial alleles over 64 wk. Decay of gametic and cytonuclear disequilibria differed from expectations under random mating as well as under a model of assortative mating involving empirically estimated mating propensities. In two replicate "large-pond" populations (experiment II), 841 sampled individuals across four reproductive cohorts revealed lower initial frequencies of F1 hybrids than in experiment I, but again G. holbrooki alleles achieved high frequencies over four generations (72 wk). Thus, evolution within experimental Gambusia hybrid populations can be extremely rapid, resulting in consistent loss of G. affinis nuclear and cytoplasmic alleles. Concordance in results between experiments and across genetic markers suggests strong directional selection favoring G. holbrooki genotypes. Results are interpreted in light of previous reports of genotype-specific differences in life-history traits, reproductive ecology, patterns of recruitment, and size-specific mortality, and in the context of patterns of introgression previously studied indirectly from spatial observations on cytonuclear genotypes in natural Gambusia populations. PMID- 28567778 TI - ERNST MAYR AND THE ORIGIN OF SPECIES. PMID- 28567779 TI - FITNESS COSTS OF RESISTANCE TO BACILLUS THURINGIENSIS IN THE DIAMONDBACK MOTH (PLUTELLA XYLOSTELLA). PMID- 28567780 TI - INDIRECT SELECTION OF STIGMA POSITION IN IPOMOPSIS AGGREGATA VIA A GENETICALLY CORRELATED TRAIT. AB - Experimental manipulation of a trait can be used to distinguish direct selection from selection of correlated traits and to identify mechanisms of selection. Here we use experiments to investigate phenotypic selection of stigma position in angiosperm flowers. In natural populations of the subalpine herb Ipomopsis aggregata, plants with more strongly exserted stigmas receive more pollen per flower, indicating selection favoring stigma exsertion during the pollination stage of the life cycle. We pose four hypotheses for this association, two involving direct selection on stigma position and two involving indirect selection of a correlated floral trait. The first three hypotheses were tested using hand pollinations that mimicked natural hummingbird visitation, and by presenting captive hummingbirds with a series of flowers that differed in stigma and anther positions, sex ratio, and presence of anthers. In these experiments, pollen deposition either was independent of stigma exsertion or was highest on inserted stigmas, suggesting direct selection against exserted stigmas. In natural populations, however, stigma exsertion is highly correlated with time spent by the protandrous flowers in the pistillate phase. When we manipulated the latter trait in the field, pollen deposition increased with duration of exposure to hummingbirds, indicating indirect selection for stigma exsertion. Stigma exsertion and time spent in the pistillate phase are genetically and phenotypically correlated, as shown by a quantitative genetic experiment conducted in the field with paternal half sibships. Our results suggest that the evolution of stigma position can be driven by selection of a genetically correlated trait. PMID- 28567781 TI - DISCIPLINING EVOLUTIONARY BIOLOGY: ERNST MAYR AND THE FOUNDING OF THE SOCIETY FOR THE STUDY OF EVOLUTION AND EVOLUTION (1939-1950). PMID- 28567782 TI - GENETIC VARIATION FOR FEMALE MATE DISCRIMINATION IN DROSOPHILA MELANOGASTER. AB - Comparisons between the Canton-S and Tai-Y strains of Drosophila melanogaster (both wild type) revealed variation in female mate discrimination based on chemical courtship signals present as hydrocarbons on the male cuticle. Mating tests indicated that 7-tricosene, which is the primary hydrocarbon on the Canton S male cuticle but is nearly absent from Tai-Y, was a significant component of the signal. The discrimination was asymmetrical in that Canton-S females clearly distinguished between the two types of males in no-choice tests, but Tai-Y females did not. F1 females expressed an intermediate ability to discriminate, and female progeny of backcrosses expressed a mating phenotype very similar to that of the parental strain to which the backcross was made. Analysis of independent effects from the X and both major autosomes indicated that the discrimination is controlled by gene(s) on chromosome 3. PMID- 28567783 TI - CHROMOSOMAL REPATTERNING AND LINKAGE GROUP CONSERVATION IN MOSQUITO KARYOTYPIC EVOLUTION. AB - Chromosome number and morphology in mosquitoes is remarkably uniform: virtually all mosquitoes have a diploid chromosome number of six (2N = 6), and their chromosomes are invariably metacentric or submetacentric. Numerical changes obviously have not been important in mosquito chromosomal evolution, and because of the morphological similarity of their chromosomes, it appears that structural changes have played little or no role in mosquito karyotypic evolution. The goal of the present study was to identify the types and relative numbers of chromosomal changes in mosquito evolution and to extend the comparison where possible to the higher diptera. To do this, we compared the enzyme linkage maps of six species of Aedes to each other and to enzyme maps of seven other mosquito species and to Drosophila melanogaster. Our results indicate that Aedes chromosomes have been modified by inversions, most which were paracentric, and by translocations, most which were Robertsonian. Intrageneric comparison of Aedes enzyme maps also revealed groups of linked enzyme loci whose integrity has been maintained throughout Aedes evolution (conserved linkages/syntenies). Intergeneric comparisons of Aedes enzyme maps with those of species in the genera Culex, Anopheles, and Toxorhynchites disclosed conserved associations of enzyme loci between mosquito genera. These findings lead us to postulate that the ancestral mosquito karyotype consisted of six chromosomal elements which, other than being combined in different ways in various mosquito groups, have remained essentially intact during mosquito evolution. Furthermore, the identification of groups of linked enzyme loci common to mosquitoes and to D. melanogaster indicates that linkage group conservation may characterize the karyotypic evolution of all dipteran insects. PMID- 28567784 TI - RATE LIMITS FOR MISPAIRING AND COMPENSATORY CHANGE: THE MITOCHONDRIAL RIBOSOMAL DNA OF ANTELOPES. PMID- 28567785 TI - THE SCALING OF PLANT AND ANIMAL BODY MASS, LENGTH, AND DIAMETER. AB - The interspecific scaling exponents of body mass M and diameter D with respect to length L were determined to evaluate the predictions of three scaling hypotheses (geometric, stress, and elastic similitude). The relation between M and L was determined for data from a total of 133 aquatic and terrestrial species (66 plant and 67 animal species); the relation between D and L was determined independently for a total of 753 aquatic and terrestrial species (667 plant and 86 animal species). Organisms were crudely classified as to their geometry (spheres, spheroids, cylinders) and shape (defined as the body slenderness factor, L/D) to examine whether geometry and shape evinced size-dependent variations. Regression indicated M = 1.29L2.95 (r2 = 0.91, N = 133; alphaRMA = 3.09 +/- 0.088). The stress and elastic similitude (which respectively predict alphaRMA = 5 and alphaRMA = 4) were rejected; geometric similitude was not (alphaRMA = 3). For animals and plants, alphaRMA = 2.81 +/- 0.061 (r2 = 0.98), and alphaRMA = 2.95 +/ 0.093 (r2 = 0.94), respectively. For aquatics and terrestrial organisms, alphaRMA = 2.82 +/-0.134 (r2 = 0.97, N = 36), and alphaRMA = 3.08 +/-0.111 (r2 = 0.89, N = 97), respectively. These results were interpreted to support the hypothesis of geometric similitude. For the pooled plant and animals data, D = 0.05L1.00 (r2 = 0.95; alphaRMA = 1.03 +/- 0.009), which was compatible with the hypothesis of geometric similitude. For plants, D = 0.05L1.06 (r2 = 0.95; alphaRMA = 1.09). For animals, D = 0.29L0.98 (r2 = 0.95; alphaRMA = 1.01 +/- 0.025). Also, for aquatics, alphaRMA = 0.951 +/- 0.151, whereas for terrestrial plants and animals, alphaRMA = 1.03 +/- 0.089. Although the scaling exponent for D differed among individual groupings of animals and plants, the results of regression analyses were interpreted to indicate that, on the average, body diameter scaled isometrically with respect to length as predicted by geometric similitude. For the pooled data set, organic shape varied over 3 orders of magnitude; L varied over 9 orders of magnitude reflecting 22 orders of magnitude of M. In terms of body geometry and the absolute numbers of species in the total data set: spherical shaped species (L = D) < unassigned species < prolate spheroidal species < cylindrical (squat < slender) species. The largest organisms in the data set were slender (L/D > 20) cylindrical plants; the smallest organisms were spherical plants and animals. Although not subject to statistical inference, these data were interpreted to indicate that organic shape and geometry evince size-dependent variations. These variations as well as size dependent changes in bulk density are hypothesized to account for the scaling exponents of M and D determined for individual plant and animal clades and grades. PMID- 28567786 TI - THE GEOGRAPHY OF MITOCHONDRIAL DNA VARIATION, POPULATION STRUCTURE, HYBRIDIZATION, AND SPECIES LIMITS IN THE FOX SPARROW (PASSERELLA ILIACA). AB - Geographic variation in mitochondrial DNA (mtDNA) restriction sites was studied in the fox sparrow (Passerella iliaca). Seventy-eight haplotypes were found. Haplotypes fall into four phylogeographic groups that correspond to groups defined by plumage characters. The geographic distribution of these four groups does not appear congruent with mtDNA patterns in other vertebrates. Within each group, there is little geographic variation in mtDNA restriction sites, although there is geographic variation in plumage coloration and body size. The evolution of mtDNA diversity in fox sparrows seems best explained by vicariant events rather than isolation by distance. The mtDNA evidence suggests that Passerella megarhyncha and Passerella schistacea, two nonsister taxa that occur in western North America, have independently undergone bottlenecks. Hybridization is limited between all pairs of taxa except P. megarhyncha and P. schistacea, where mtDNA evidence suggests a narrow contact zone along the interface of the Great Basin and Sierra Nevada/Cascades. Morphometric characters intergrade over a broader area, suggesting that different processes are responsible for the two gradients. The occurrence of limited backcrossing among taxa suggests that cytoplasmic nuclear incompatibility is lacking. The number of biological species would range from one to four, depending on the degree of hybridization tolerated. The mtDNA and plumage characters suggest four phylogenetic species: P. iliaca, P. megarhyncha, P. unalaschcensis, and P. schistacea. PMID- 28567787 TI - THE EVOLUTION OF REPRODUCTIVE EFFORT IN SQUAMATE REPTILES: COSTS, TRADE-OFFS, AND ASSUMPTIONS RECONSIDERED. AB - We evaluated Shine and Schwarzkopf's (SS) model of the evolution of reproductive effort (RE) in squamate reptiles. They suggested that fecundity trade-offs were unimportant in the evolution of RE in most squamate reptiles and that only survival trade-offs needed to be considered. However, we show that by assuming no variation in offspring size exists, and that adult mortality is episodic, the results of the SS model are not general. By extension, we argue that conclusions drawn about factors important in the evolution of RE in squamate reptiles are premature. Using a modified version of the SS model, we demonstrate that variation in the form of trade-offs relating offspring size and survival substantially affect relationships among clutch size, relative clutch mass, and lifetime reproductive success. We also demonstrate that the way in which adult mortality is simulated drastically affects conclusions about the potential fecundity trade-offs experienced by populations of squamate reptiles. Finally, we suggest that a complete understanding of the evolution of RE will come from theory that incorporates trade-offs between offspring size and quality, as well as other system-specific constraints on the allocation of energy to growth, maintenance, storage, and reproduction. PMID- 28567788 TI - GENETIC ANALYSIS OF A RARE AND A WIDESPREAD SPECIES OF ECHINACEA (ASTERACEAE). PMID- 28567789 TI - ERNST MAYR AND EVOLUTIONARY BIOLOGY. PMID- 28567791 TI - AMELIORATION OF THE DELETERIOUS PLEIOTROPIC EFFECTS OF AN ADAPTIVE MUTATION IN BACILLUS SUBTILIS. AB - The deleterious pleiotropic effects of an adaptive mutation may be ameliorated by one of two modes of evolution: (1) by replacement, in which an adaptive mutation with harmful pleiotropic effects is replaced by one that confers an equal benefit but at less cost; or (2) by compensatory evolution, in which natural selection favors modifiers at other loci that compensate for the deleterious effects of the mutant allele. In this study, we have measured the potential of these two modes of evolution to ameliorate the deleterious pleiotropic effects of resistance to the antibiotic rifampicin in the soil bacterium Bacillus subtilis. One approach was to measure the fitness cost of a series of spontaneous rifampicin-resistance mutations from each of several strains. The potential for amelioration by the replacement mode was estimated by the variation in fitness cost among the mutants of a single strain. Another approach was to introduce a series of different rifampicin-resistance alleles into a diversity of strains, and to measure the fitness cost of rifampicin resistance for each allele-by-strain combination. The potential for amelioration by the replacement mode was estimated by the variation in fitness costs among rifampicin-resistance alleles; the potential for compensatory evolution was estimated by variation in the fitness cost of rifampicin resistance among strains. This study has shown that the cost of rifampicin resistance may be ameliorated by both the compensatory and replacement modes. PMID- 28567792 TI - ERNST MAYR, THE ORNITHOLOGIST. PMID- 28567793 TI - USING PHYLOGENIES TO TEST HYPOTHESES OF ADAPTATION: A CRITIQUE OF SOME CURRENT PROPOSALS. PMID- 28567794 TI - ERNST MAYR AND THE CENTRALITY OF SPECIES. PMID- 28567795 TI - A SIMULATION OF WRIGHT'S SHIFTING-BALANCE PROCESS: MIGRATION AND THE THREE PHASES. AB - Wright partitioned the shifting-balance process into three phases. Phase one is the shift of a deme within a population to the domain of a higher adaptive peak from that of the historical peak. Phase two is mass selection within a deme towards that higher peak. Phase three is the conversion of additional demes to the higher peak. The migration rate between demes is critical for the existence of phases one and three. Phase one requires small effective population sizes, hence low migration rates. Phase three is optimal under high migration rates that spread the most-fit genotype from deme to deme. Thus, a population-wide peak shift requires intermediate levels of migration. By altering the rates of phases one and three, migration affects the predominant direction of mass selection within a population. This study examines the degree to which migration, through its effects on phases one and three, determines the probability of a simulated population arriving at its genotypic optimum after 12,000 generations. These simulations reveal that there is a range of migration rates for which an entire population might be expected to shift to a higher peak. Below m = 0.001 peak shifts occur frequently (phases I and II) but are not successfully exported out of subpopulations (phase III), and above 0.01 peak shifts within demes (phase I and II), required to initiate phase III, become increasingly uncommon. Because it is unlikely that real populations will have uniform migration rates from generation to generation, the probable effects of varying migration rates on broadening the range of conditions producing peak shifts are discussed. PMID- 28567796 TI - SOME PERSONAL RECOLLECTIONS OF ERNST MAYR. PMID- 28567797 TI - HISTORICAL BIOGEOGRAPHY AND CONTEMPORARY PATTERNS OF MITOCHONDRIAL DNA VARIATION IN WHITE-TAILED DEER FROM THE SOUTHEASTERN UNITED STATES. AB - Mitochondrial DNA (mtDNA) was used to characterize patterns of geographic variation among white-tailed deer (Odocoileus virginianus) populations in the southeastern United States. Fifteen restriction enzymes were employed to survey and map 99 restriction sites in 142 deer from 18 localities in five southeastern states. Phylogenetic analysis revealed three primary groups of haplotypes: (1) southern Florida and the Florida Keys, (2) the remainder of peninsular Florida northward to South Carolina, and (3) the Florida panhandle westward to Mississippi. Geographical heterogeneity in haplotype frequencies suggests that stochastic lineage sorting or isolation by distance are not important determinates of mtDNA differentiation among deer populations. The pattern of mtDNA variation in white-tailed deer is concordant spatially with those observed in unrelated taxa suggesting the common influence of historical biogeographic events. The data (1) support previous hypotheses that relate contemporary patterns of intraspecific phylogeography in northern Florida to the physiogeographic history of the region; and (2) suggest that genetic differentiation in southern Florida may be attributable to episodes of Pleistocene dispersal. Despite potentially high vagility and human intervention, ecological and demographic characteristics of deer have effectively preserved the historical pattern of intraspecific mtDNA differentiation. PMID- 28567798 TI - Management for intussusception in children. AB - BACKGROUND: Intussusception is a common abdominal emergency in children with significant morbidity. Prompt diagnosis and management reduces associated risks and the need for surgical intervention. Despite widespread agreement on the use of contrast enema as opposed to surgery for initial management in most cases, debate persists on the appropriate contrast medium, imaging modality, pharmacological adjuvant, and protocol for delayed repeat enema, and on the best approach for surgical management for intussusception in children. OBJECTIVES: To assess the safety and effectiveness of non-surgical and surgical approaches in the management of intussusception in children. SEARCH METHODS: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library; Ovid MEDLINE (1950 to September 2016); Ovid Embase (1974 to September 2016); Science Citation Index Expanded (via Web of Science) (1900 to September 2016); and BIOSIS Previews (1969 to September 2016).We examined the reference lists of all eligible trials to identify additional studies. To locate unpublished studies, we contacted content experts, searched the World Health Organization International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov (September 2016), and explored proceedings from meetings of the British Association of Paedatric Surgeons (BAPS), the American Soceity of Pediatric Surgery, and the World Congress of Pediatric Surgery. SELECTION CRITERIA: We included all randomised controlled trials comparing contrast media, imaging modalities, pharmacological adjuvants, protocols for delayed repeat enema, and/or surgical approaches for the management of intussusception in children. We applied no language, publication date, or publication status restrictions. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted study selection and data extraction and assessed risk of bias using a standardised form. We resolved disagreements by consensus with a third review author when necessary. We reported dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs). We analysed data on an intention-to-treat basis and evaluated the overall quality of evidence supporting the outcomes by using GRADE criteria. MAIN RESULTS: We included six randomised controlled trials (RCTs) with a total of 822 participants. Two trials compared liquid enema reduction plus glucagon versus liquid enema alone. One trial compared liquid enema plus dexamethasone versus liquid enema alone. Another trial compared air enema plus dexamethasone versus air enema alone, and two trials compared use of liquid enema versus air enema. We identified three ongoing trials.We judged all included trials to be at risk of bias owing to omissions in reported methods. We judged five of six trials as having high risk of bias in at least one domain. Therefore, the quality of the evidence (GRADE) for outcomes was low. Interventions and data presentation varied greatly across trials; therefore meta-analysis was not possible for most review outcomes. Enema plus glucagon versus enema alone It is uncertain whether use of glucagon improves the rate of successful reduction of intussusception when compared with enema alone (reported in two trials, 218 participants; RR 1.09, 95% CI 0.94 to 1.26;low quality of evidence). No trials in this comparison reported on the number of children with bowel perforation(s) nor on the number of children with recurrent intussusception. Enema plus dexamethasone versus enema alone Use of the adjunct, dexamethasone, may be beneficial in reducing intussusception recurrence with liquid or air enema (two trials, 299 participants; RR 0.14, 95% CI 0.03 to 0.60; low quality of evidence). This equates to a number needed to treat for an additional beneficial outcome of 13 (95% CI 8 to 37). It is uncertain whether use of the adjunct, dexamethasone, improves the rate of successful reduction of intussusception when compared with enema alone (reported in two trials, 356 participants; RR 1.01, 95% CI 0.92 to 1.10;low quality of evidence). Air enema versus liquid enema Air enema may be more successful than liquid enema for reducing intussusception (two trials, 199 participants; RR 1.28, 95% CI 1.10 to 1.49; low quality of evidence). This equates to a number needed to treat for an additional beneficial outcome of 6 (95% CI 4 to 19). No trials in this comparison reported on the number of children with bowel perforation(s) or on the number of children with recurrent intussusception nor any intraoperative complications, such as bowel perforation, or other adverse effects. Only one trial reported postoperative complications, but owing to the method of reporting used, a quantitative analysis was not possible. We identified no studies that exclusively evaluated surgical interventions for management of intussusception. AUTHORS' CONCLUSIONS: This review identified a small number of trials that assessed a variety of interventions. All included trials provided evidence of low quality and were subject to serious concerns about imprecision, high risk of bias, or both. Air enema may be superior to liquid enema for successfully reducing intussusception in children; however, this finding is based on a few studies including small numbers of participants. Dexamethasone as an adjuvant may be more effective in reducing intussusception recurrence rates following air enema or liquid enema, but these results are also based on a few studies of small numbers of participants. This review highlights several points that need to be addressed in future studies, including reducing the risk of bias and including relevant outcomes. Specifically, surgical trials are lacking, and future research is needed to address this evidence gap. PMID- 28567800 TI - WHY SHOULD LEK-BREEDERS BE MONOMORPHIC? AB - Approximately one-quarter of all lek-breeding bird species are sexually monomorphic. Understanding the significance, if any, of this exception to the usual correlation between sexual selection and dimorphism requires detailed data on the mating systems of both monomorphic and dimorphic species. The capuchinbird (Perissocephalus tricolor) is a sexually monomorphic, lek-breeding member of the cotinga family. I studied the social and sexual behavior of this species, and compared it with the Guianan cock-of-the-rock (Rupicola rupicola), a dimorphic, lekking member of the same family. Male-male competition in capuchinbirds involved direct contests for dominance, rather than territorial displays as in classic lek species. In each year, one dominant individual was able to control the most desired display site on the 8-male lek, and was the only male that copulated. In contrast to dimorphic lek birds, female as well as male capuchinbirds engaged in frequent and intense aggression at the lek, and both males and females engaged in sexual mimicry. I suggest that plumage monomorphism in lek birds has evolved as a result of social competition affecting both sexes. This hypothesis accounts for the exaggerated plumage characters shared by males and females in capuchinbirds and a number of other monomorphic lek birds. The evolution of plumage can best be analyzed as an arms race, in which the balance of selective forces acting on each sex can produce a variety of equilibrium states, ranging from sexual indistinguishability to extreme dimorphism. PMID- 28567801 TI - THE EVOLUTION OF FEMALE BODY SIZE IN RED-WINGED BLACKBIRDS: THE EFFECTS OF TIMING OF BREEDING, SOCIAL COMPETITION, AND REPRODUCTIVE ENERGETICS. AB - We examined opposing selective forces on female body size in the sexually dimorphic red-winged blackbird: social competition favoring larger females, and energetic advantages favoring smaller females. Downhower proposed that selection might drive female birds to be smaller than the optimum for survival, if smaller females were able to exceed their energetic requirements for self-maintenance earlier in the season and therefore breed earlier. Since in most birds the earliest breeders fledge the most young, this could favor the evolution of smaller female size, and therefore contribute to the magnitude of sexual size dimorphism in these birds. We tested this hypothesis in 1987 and 1988 by comparing the size and breeding date of female red-winged blackbirds. Consistent with our preditions, early-nesting females had much higher nesting success, but contrary to prediction, larger females bred earlier. We then examined the effects of female size on competition. If large females have an advantage in social competition, and if competition influences breeding date and reproductive success, then larger females might breed earlier. Primary females, the first females to arrive and nest on a territory, were more aggressive than lower ranked females; more aggressive females settled on better territories and laid earlier than less aggressive females; and larger females were more aggressive. Social competition between females may therefore favor large females. Finally, we tested the prediction that selection favoring large females might be limited by energetic constraints on large females. We found that large females had less fat than small females during breeding, and that the levels of fat that females of a given size carried affected breeding date and egg size. Therefore, social competition may favor large females, but reproductive energetics favoring smaller females may constrain selection for large female body size. PMID- 28567799 TI - COX-2-selective inhibitors celecoxib and deracoxib modulate transient receptor potential vanilloid 3 channels. AB - BACKGROUND AND PURPOSE: The transient receptor potential vanilloid 3 (TRPV3) channel is a heat-sensitive ion channel, which is predominantly expressed in keratinocytes. TRPV3 channels are involved in numerous physiological and pathophysiological processes within the skin, including cutaneous nociception, temperature sensation and development of itch. The role of TRPV3 channels in such processes is poorly understood; therefore, the establishment of selective modulators of TRPV3 channels is highly desirable. EXPERIMENTAL APPROACH: Novel TRPV3-modulating compounds were identified using fluorometric intracellular Ca2+ assays and further evaluated with electrophysiological techniques. KEY RESULTS: TRPV3 activity, elicited by 2-aminoethoxydiphenyl borate (2-APB), was efficaciously enhanced by deracoxib and celecoxib, two COX-2-selective inhibitors. They exerted their potentiating effect via a direct interaction with TRPV3 as evident from excised inside-out recordings. Structurally-related COX-2 inhibitors affected TRPV3 channel gating to a much lesser degree. Similar results were obtained in HEK293 cells stably expressing cyan fluorescent protein-tagged mouse TRPV3 channels and in a mouse keratinocyte cell line, endogenously expressing TRPV3. The effects of celecoxib and deracoxib on TRPV3 were dependent on the stimulus used to activate TRPV3. While 2-APB and heat-activated TRPV3 channels were potentiated by celecoxib, carvacrol-activated channels were inhibited by celecoxib. CONCLUSIONS AND IMPLICATIONS: We identified a new class of drugs that modulate TRPV3 channels. The most potent compound celecoxib is an approved analgesic and anti-inflammatory drug, which is currently being investigated for its topical application in the treatment of skin cancer. As TRPV3 is highly expressed in skin, celecoxib might affect TRPV3 activity in vivo when used at high local concentrations. PMID- 28567802 TI - INTERSEXES IN A SHRIMP: A POSSIBLE DISADVANTAGE OF ENVIRONMENTAL SEX DETERMINATION. PMID- 28567803 TI - COLONIZATION OF AMERICA BY DROSOPHILA SUBOBSCURA: LETHAL GENES AND THE PROBLEM OF THE O5 INVERSION. AB - In this work, the process of colonization of North and South America by the species Drosophila subobscura has been studied by analyzing the variability of lethal genes. The genetic structures of a Palearctic natural central population (Bordils, Spain) and a colonizer population from America (Gilroy, California) have been compared. The frequencies of lethal chromosomes and their allelism are 29.007% and 0.0069 in the first population and 14.414% and 0.0526 in the American population. A founder effect is detected after the computation of some population parameters (Ne , h, he and the lethal load). Furthermore, the allelism of lethal chromosomes has revealed a strong association between a lethal gene and the O5 inversion both in Gilroy and in the population of Puerto Montt (Chile). The interpopulation allelism shows that the O5 arrangement from the USA and Chile is the same, confirming that the colonizing processes of North and South America are correlated. The O5 arrangement can also be useful as a genetic marker to trace the origin of the colonization. The frequency of the O5 arrangement in the original population of the colonization could be used to estimate the number of colonizers. This population is still unknown, but taking the extreme values of the frequency of the O5 inversion in natural Palearctic populations (1-15%), the number of colonizers could vary between 9 and 149 individuals. PMID- 28567804 TI - QUANTITATIVE GENETICS OF SIZE, SHAPE, LIFE-HISTORY, AND FRUIT CHARACTERISTICS OF THE SEED HETEROMORPHIC COMPOSITE HETEROSPERMA PINNATUM. II. CORRELATION STRUCTURE. AB - We have investigated phenotypic, environmental, within-population broad-sense genetic correlations and among-population genetic correlations for 17 traits in six populations of Heterosperma pinnatum Cav. (Compositae) grown in the greenhouse. The within-population genetic, environmental, and phenotypic correlations were somewhat similar while the among-population genetic correlations showed little correspondence to these. The different correlation matrices were compared to a hypothesis matrix, which predicted higher correlations for groups of functionally and developmentally related traits. The groups were seed and head traits, size and shape traits, and life history traits, with subgroups predicted to have still higher correlations. The phenotypic and environmental matrices corresponded well to the hypothesis matrix, the within population broad-sense genetic matrix showed weaker, though still significant, correspondence, and the among-population genetic correlations showed no correspondence. Genetic correlations did not differ significantly among populations, though the power of these comparisons was low. Some particular genetic correlations are discussed as possible examples of adaptive correlations (e.g., a negative correlation between dispersal and dormancy) and as examples of developmental or physiological constraints including life-history tradeoffs. PMID- 28567805 TI - THE PLEIOTROPY THEORY FOR POLYMORPHISM OF DISEASE RESISTANCE GENES IN PLANTS. PMID- 28567806 TI - HYBRID BREAKDOWN IN DEVELOPMENTAL TIME IN THE COPEPOD TIGRIOPUS CALIFORNICUS. AB - Laboratory crosses were carried out among three genetically differentiated Los Angeles populations (all located within approximately 15 km) and one San Diego population (approximately 150 km away) of the intertidal copepod Tigriopus californicus. Despite high levels of allozyme differentiation, all crosses produced viable F1 progeny. Most F1 progeny had shorter developmental times and reduced variance in developmental times compared to the parental populations. Only one pair of populations failed to produce viable F2 progeny; when the central Los Angeles population (AB) was crossed to the San Diego (SD) population, most larvae died during the late naupliar stages. Developmental times in the F2 generation of the other Los Angeles * San Diego crosses were typically 40% longer than developmental times of the parental populations. Among the Los Angeles populations, only one cross (and not its reciprocal) showed a similarly large increase in developmental time. Variance in F2 developmental times was greater than the parental variance in 5 of 10 crosses. These results are discussed with regard to the evolution of coadapted gene complexes and population differentiation in T. californicus. PMID- 28567807 TI - VARIATION IN DEVELOPMENTAL CONSTRAINTS IN SIGMODON. AB - Developmental constraints can be interpreted as factors of developmental origin responsible for covariation among measured variables. Several hypotheses have been proposed to link the possession of such constraints to subsequent evolution. Using confirmatory factor analysis, we compare developmental factors across selected taxa of cotton rats, genus Sigmodon. Three factors explain well the covariation among orofacial measurements: (1) responses to body size variation, (1) coordinated growth of traits of the occluding-tooth complex, and (3) responses to musculoskeletal interactions. Sigmodon taxa share these factors, but differ in the variance-covariance matrix of factors, and the unique variances of individual traits. Patterns of covariation among measurements of the neurocranial complex reflect responses to body size variation, and perhaps also responses to fetal brain growth. While there are no significant differences across taxa in factorpattern, variance-covariance matrix of factors, or unique variance of measured neurocranial variables, the neurocranium is only weakly constrained. We doubt that even the relatively stronger developmental constraints on the orofacial complex would prevent evolutionary divergence because differences in the variances and covariances of factors, and in levels of unique variance of individual traits can provide different opportunities for selection to act in different Sigmodon taxa. PMID- 28567808 TI - THE ROLE OF ENVIRONMENTAL SELECTION IN INTRASPECIFIC DIVERGENCE OF MATE RECOGNITION SIGNALS IN THE CRICKET FROG, ACRIS CREPITANS. PMID- 28567809 TI - GENETIC CORRELATIONS AMONG TRAITS DETERMINING MIGRATORY TENDENCY IN THE SAND CRICKET, GRYLLUS FIRMUS. AB - Migration by flight is an important component of the life cycles of most insects. The probability that a given insect will migrate by flight is influenced by many factors, most notably the presence or absence of fully-developed wings and functional flight musculature. Considerable variation has also been reported in the flight propensity of fully-winged individuals with functional flight musculature. We test the hypothesis that these components of migratory tendency are genetically correlated in a wing-dimorhic cricket, Gryllus firmus. Flight propensity and condition of the dorsal longitudinal flight muscles (DLM) are examined in fully-winged (LW) crickets from lines selected for increasing and for decreasing %LW, as well as from unselected control lines. Increased %LW is found to be associated with increased flight propensity among individuals with intact DLM, and with retention of functional DLM. The opposite is true for lines selected for decreased %LW. These results indicate both phenotypic and genetic correlations among behavioral, physiological, and morphological traits determining migratory tendency. We propose that these correlations may result from the multifunctional role of juvenile hormone, which has been reported to influence wing development, flight muscle development and degeneration, and flight propensity. Finally, we discuss the potential influence of genetic correlations for migratory traits on the evolution and maintenance of migratory polymorphisms in insects. PMID- 28567810 TI - HYBRID BREAKDOWN IN PHYSIOLOGICAL RESPONSE: A MECHANISTIC APPROACH. AB - Data comparing the physiological response to hyperosmotic stress in individual copepods (Tigriopus californicus) from natural populations and laboratory hybrids are presented. While individuals from two genetically differentiated natural populations and F1 interpopulation hybrids showed only minor differences in patterns of free amino acid (FAA) accumulation during hyperosmotic stress, patterns of FAA synthesis were highly variable among the F2 hybrids. Isofemale lines initiated from later hybrid generations (F7 -F10 ) exhibited substantial inter-line variance in FAA accumulation. This increased variance in physiological response appears unrelated to allozyme polymorphisms at two loci encoding FAA metabolizing enzymes and appears to result from other, unidentified polymorphisms in the proline synthetic pathway. PMID- 28567811 TI - MUTATION LOAD AND THE SURVIVAL OF SMALL POPULATIONS. AB - Previous attempts to model the joint action of selection and mutation in finite populations have treated population size as being independent of the mutation load. However, the accumulation of deleterious mutations is expected to cause a gradual reduction in population size. Consequently, in small populations random genetic drift will progressively overpower selection making it easier to fix future mutations. This synergistic interaction, which we refer to as a mutational melt-down, ultimately leads to population extinction. For many conditions, the coefficient of variation of extinction time is less than 0.1, and for species that reproduce by binary fission, the expected extinction time is quite insensitive to population carrying capacity. These results are consistent with observations that many cultures of ciliated protozoans and vertebrate fibroblasts have characteristic extinction times. The model also predicts that clonal lineages are unlikely to survive more than 104 to 105 generations, which is consistent with existing data on parthenogenetic animals. Contrary to the usual view that Muller's ratchet does more damage when selection is weak, we show that the mean extinction time declines as mutations become more deleterious. Although very small sexual populations, such as self-fertilized lines, are subject to mutational meltdowns, recombination effectively eliminates the process when the effective population size exceeds a dozen or so. The concept of the effective mutation load is developed, and several procedures for estimating it are described. It is shown that this load can be reduced substantially when mutational effects are highly variable. PMID- 28567812 TI - RESOURCE INFLUENCED SEX ROLES OF ZAPROCHILINE TETTIGONIIDS (ORTHOPTERA: TETTIGONIIDAE). AB - Male tettigoniids donate nutrients to females at mating in the form of a spermatophylax. Male-donated nutrients function as paternal investment leading to a reversal in the sex roles of males and females. Reversal in the behavioral sex roles of a zaphrochiline tettigoniid was found to be directly related to the current availability of food resources in the environment. When resource availability was low, females were less fecund and males had lower and more variable accessory gland weights (the spermatophylax producing gland) than when resource availability was high. When resources were scarce, larger individuals had a reproductive advantage having more eggs or heavier accessory glands. All individuals were equally fecund or had equal accessory gland weights when resources were plentiful. During low resource availability males that had a spermatophylax to offer were choosy of their mates, and females were competitive. When resources were plentiful, males were less discriminative and females showed signs of discrimination. There was evidence that female sexual motivation decreased when environmental resources were plentiful (as indicated by mating frequency) and that only females of low nutritional status continued to mate. When resources were scarce, females achieved fecundities equivalent to those achieved during high resource availability through spermatophylax consumption. These data support the hypothesis that females continue to mate to compensate for low resource availability and that male parental investment may be important only in poor quality habitats. When resources are plentiful females do not need to remate. Thus resource availability may directly influence the number of sexually active males and females (operational sex ratio) and the form of sexual selection. PMID- 28567813 TI - PARENTAL QUALITY AND SELECTION ON EGG SIZE IN THE MAGELLANIC PENGUIN. AB - We examined the relative contributions of egg size and parental quality to hatching success, fledging success, and chick growth in the Magellanic penguin (Spheniscus magellanicus) be exchanging clutches between nests to reduce the covariation between egg and parental factors. Among control nests, fledging success increased slightly with egg size. However, the effect of egg size independently of parental quality was limited to an influence on chick mass and size for the first 10 days post-hatching. In contrast, attributes of the parents influenced nesting success and chick size at fledging, independently of the egg size actually raised. We suggest that the common occurrence of a positive phenotypic correlation between egg size and fledging success is due to two factors: (1) adults laying large eggs tend to be of higher quality; and (2) to the extent that egg size does influence early survival independently of parental quality, the effect on survival is due to a maternal effect on egg composition rather than an inherent effect of egg size. PMID- 28567814 TI - FLUCTUATING SELECTION AND RESPONSE IN A POPULATION OF FRESHWATER COPEPODS. AB - The timing of springtime production of diapausing eggs by a population of the freshwater copepod, Diaptomus sanguineus, has been shown previously to be consistent with avoidance of seasonally intense fish predation. Natural selection acting on the timing of diapause fluctuates between years depending upon the population density of fish. Here we show that, in the field, the mean timing of diapause shifts between years in response to fluctuations in selection. Diapause is earlier in years following high predator density, and is later in years following low predator density. Although selection intensity in individual years may be large, the mean intensity over the decade of fluctuating selection investigated here is close to zero. Photoperiod sensitivity of the diapausetiming trait is heritable in the laboratory. The combination of fluctuating selection and multi-generation storage of genotypes as diapausing eggs in lake sediments may contribute to the maintenance of the genetic variation that permits the rapid selection response seen in the field. PMID- 28567815 TI - SOME POPULATION GENETIC CONSEQUENCES OF COLONY FORMATION AND EXTINCTION: GENETIC CORRELATIONS WITHIN FOUNDING GROUPS. AB - Extinction and recolonization in an island model affects genetic differentiation among subpopulations through a combination of sampling and mixing. We investigate the balance of these forces in a general model of population founding that predicts first the genetic variance among new groups and then the effect of these new groups on the total genetic variance among all populations. We allow for a broad range of types of mixing at the time of colonization and demonstrate the significant effects on differentiation from the probability of common origin of gametes (phi). We further demonstrate that kin-structured founding and inbreeding within populations can have a significant effect on the genetic variance among groups and use these results to make predictions about lineal fission and fusion of populations. These results show that population structure is critically affected by non-equilibrium dynamics and that the properties of new populations, especially founding number, probability of common origin, and kin structure, are vital in our understanding of genetic variation. PMID- 28567817 TI - ALLOZYME FREQUENCIES IN A LINEAR SERIES OF SONG DIALECT POPULATIONS. PMID- 28567816 TI - Technologies in pediatric vascular access: have we improved success rate in peripheral vein cannulation? PMID- 28567818 TI - Society Meetings. PMID- 28567820 TI - ON HETEROZYGOSITY AND THE EFFECTIVE SIZE OF POPULATIONS SUBJECT TO SIZE CHANGES. PMID- 28567819 TI - BODY SHAPE METRICS AND ORGANISMAL EVOLUTION. PMID- 28567821 TI - AN EXPERIMENTAL STUDY OF EVOLUTION IN HETEROGENEOUS ENVIRONMENTS: PHENOLOGICAL ADAPTATION BY A BRUCHID BEETLE. PMID- 28567822 TI - INTRASEXUAL SELECTION AND THE SEGREGATION OF POLLEN AND STIGMAS IN HERMAPHRODITE PLANTS, EXEMPLIFIED BY WAHLENBERGIA ALBOMARGINATA (CAMPANULACEAE). PMID- 28567823 TI - HEAT EXCHANGE AND ENDOTHERMY IN PROTODONATA. PMID- 28567824 TI - THE GENETIC BASIS OF ALTITUDINAL VARIATION IN THE WOOD FROG RANA SYLVATICA. I. AN EXPERIMENTAL ANALYSIS OF LIFE HISTORY TRAITS. PMID- 28567825 TI - PARENTAL INVESTMENT PER OFFSPRING BY A SPECIALIST BEE: DOES IT CHANGE SEASONALLY? PMID- 28567826 TI - HETERODICHOGAMY IN WALNUTS: INHERITANCE AND STABLE RATIOS. PMID- 28567827 TI - ORIGIN OF THERMAL ADAPTATIONS IN NORTHERN VERSUS SOUTHERN POPULATIONS OF A UNISEXUAL HYBRID FISH. PMID- 28567829 TI - WHY ASYMMETRIC MATING PREFERENCES MAY NOT SHOW THE DIRECTION OF EVOLUTION. PMID- 28567828 TI - GROUP SELECTION: MIGRATION AND THE DIFFERENTIATION OF SMALL POPULATIONS. PMID- 28567830 TI - EVOLUTIONARY GENETICS OF BIRDS. VI. A REEXAMINATION OF PROTEIN DIVERGENCE USING VARIED ELECTROPHORETIC CONDITIONS. PMID- 28567831 TI - DISCONTINUOUS DNA VARIATION IN THE EVOLUTION OF PLANT SPECIES: THE GENUS LATHYRUS. PMID- 28567832 TI - PARENTAL BEHAVIOR IN LAPWINGS (CHARADRIIDAE) AND ITS RELATIONSHIPS WITH CLUTCH SIZES AND MATING SYSTEMS. PMID- 28567833 TI - A STUDY OF REACTION NORMS IN NATURAL POPULATIONS OF DROSOPHILA PSEUDOOBSCURA. PMID- 28567834 TI - BEHAVIORAL CHARACTERS FOR THE HIGHER CLASSIFICATION OF ORB-WEAVING SPIDERS. PMID- 28567835 TI - SURVIVAL OF DISTASTEFUL INSECTS AFTER BEING ATTACKED BY NAIVE BIRDS: A REAPPRAISAL OF THE THEORY OF APOSEMATIC COLORATION EVOLVING THROUGH INDIVIDUAL SELECTION. PMID- 28567837 TI - ONTOGENY OF A MACROEVOLUTIONARY PHENOTYPE: THE EXTERNAL CHEEK POUCHES OF GEOMYOID RODENTS. PMID- 28567836 TI - GENETIC DIFFERENTIATION AMONG ANCESTRAL AND INTRODUCED POPULATIONS OF THE EURASIAN TREE SPARROW (PASSER MONTANUS). AB - We compared genetic variation in three introduced North American populations of Passer montanus with an ancestral German population, a native Swedish population, and an introduced Australian population. The North American P. montanus were less variable genetically than the ancestral German birds, presumably a result of the founding event. The genetic structure of all six populations of P. montanus can be explained in terms of interaction among mutation, genetic drift, effective population size, and unknown selective factors. Cluster analyses and an ordination of distance measures derived from electrophoretic data generally showed relationships in phenetic space among populations consistent with the magnitude of their geographic separation. An exception occurred with the Swedish population, which was closer in the ordination to a North American population than to the geographically neighboring German population. This seemingly anomolous juxtaposition was attributed to the relative abundance of alleles present in the Swedish birds. Populations of P. montanus seem to have diverged in a manner similar to that seen in conspecific disjunct populations, i.e., at present showing no trenchant indication of genetic speciation. PMID- 28567838 TI - ENVIRONMENTAL EFFECTS ON REMATING IN DROSOPHILA MELANOGASTER. AB - The effects of density and food on remating were investigated using Drosophila melanogaster. The frequency of remating was unaffected by density for some combinations of fly strains but was reduced at low relative densities for other combinations. Until females had used most of their stored sperm, remating was less likely when food was absent or contact with food was prevented. Food availability had little effect on the incidence of remating once stored sperm were depleted and had no effect on initial virgin mating frequency. This study indicates that environmental factors can have a substantial direct influence on the frequency of remating in populations of Drosophila melanogaster. PMID- 28567839 TI - THE COST OF HEAVY-METAL TOLERANCE: AN EXAMPLE. PMID- 28567840 TI - DISEQUILIBRIUM BETWEEN DISEASE-RESISTANCE VARIANTS AND ALLOZYME LOCI IN AN ANNUAL LEGUME. AB - Polymorphism existed at 58% of the enzyme loci examined (11/19) in one population of the highly self-pollinated annual legume Amphicarpaea bracteata. Due to extreme gametic disequilibrium among loci, genetic variation in this population was structured into a small number of multilocus genotypes. Over 97% of the plants sampled could be grouped into two classes (biotypes "A" and "B"), each consisting of a few highly similar genotypes. The two classes had mutually exclusive sets of alleles at nine loci. These classes differed sharply in their disease resistance toward one isolate of the specialist fungal pathogen Synchytrium decipiens from their native habitat. All biotype A plants were strongly susceptible, and all biotype B plants were resistant. When plants of both biotypes were exposed to this pathogen in a greenhouse, the resistant biotype (B) exhibited a significantly higher growth rate. The strong association between plant disease-resistance phenotypes and allozyme variants implies that pathogen attack could be a major selective agent influencing the evolution of neutral or near-neutral alleles at enzyme loci in this plant. PMID- 28567841 TI - LONG-TERM CORRELATED RESPONSE, INTERPOPULATION COVARIATION, AND INTERSPECIFIC ALLOMETRY. AB - A model of long-term correlated evolution of multiple quantitative characters is analyzed, which partitions selection into two components: one stabilizing and the other directional. The model assumes that the stabilizing component is less variable than the directional component among populations. The major result is that, within a population, the responses of characters to selection in the short term differ qualitatively from those in the long term. In the short term, the responses depend on genetic correlations between characters, but in the long term they are only determined by the fitness functions of stabilizing and directional selection, independent of genetic and phenotypic correlations. Treating the stabilizing component as a constant and assuming the directional component to vary among populations, I present formulas for the interpopulation covariation and interspecific allometry, which are functions of the intensity matrix of stabilizing selection. Particular attention is paid to the relationship between intra- and interpopulation correlations. PMID- 28567842 TI - GENETIC ORGANIZATION AND EVOLUTIONARY HISTORY IN TWO NORTH AMERICAN SPECIES OF CIRSIUM. AB - Relationships involving progenitor and derivative species pairs have been documented for a number of plant taxa. In this study, we used starch-gel electrophoresis to examine the probable relationship between Cirsium pitcheri, an endemic thistle restricted to the shorelines of the Great Lakes, and Cirsium canescens, a closely related species of the central Great Plains (U.S.A.). The species shared the same enzyme loci but differed greatly in levels of genetic diversity. C. pitcheri was genetically much less variable than its congener, with fewer polymorphic loci and significantly lower heterozygosity. The genetic variation in C. pitcheri represents a depauperate subset of the alleles present in C. canescens, consistent with the hypothesis that the two species represent a progenitor-derivative species pair. We suggest that C. pitcheri migrated into newly created dune habitats in the Great Lakes region near the end of the Wisconsin glaciation and that its low genetic variability results from repeated and probably prolonged population bottlenecks which accompanied its movement. PMID- 28567843 TI - FEMALE STRATEGY DURING MATE CHOICE: THRESHOLD ASSESSMENT. PMID- 28567844 TI - ANTAGONISTIC PLEIOTROPY: AN INTERSPECIFIC DROSOPHILA COMPARISON. AB - Wild-type flies of 12 Drosophila species and semispecies were examined to determine whether correlation patterns between early- and late-life fitness characters predicted for individuals within a population by the antagonistic pleiotropy hypothesis are reflected in comparisons of related species and semispecies that are known to differ in lifespan. Our goal was to determine whether the hypothesis is relevant to the evolution of life-history differences beyond the population level. Two fitness traits, egg production and percentage mating success, were observed at three ages: onset of reproductive age, one week later, and one month later. Age-dependent patterns of these traits do not consistently conform to predictions of the hypothesis. Species or semispecies that show reproductive vitality early in life need not be short-lived, and long lifespan need not be accompanied by a cost in early reproductive vitality, as measured by mating success and egg production. The two fitness traits can show different age-dependent patterns in the same species or semispecies. Potential explanations for the frequent inconsistency of the data with predictions of the hypothesis are discussed. Results support the idea that the hypothesis is only relevant to the evolution of life-history differences among individuals in the same breeding population confronted by the same environmental constraints. PMID- 28567845 TI - SEXUAL ALLOCATION STRATEGY IN WIND-POLLINATED PLANTS. PMID- 28567846 TI - A MOLECULAR REEXAMINATION OF INTROGRESSION BETWEEN HELIANTHUS ANNUUS AND H. BOLANDERI (COMPOSITAE). AB - Heiser (1949) hypothesized that a weedy race of Helianthus bolanderi had originated by the introgression of genes from H. annum into a serpentine race of H. bolanderi. Although Heiser's investigation of these species is frequently cited as one of the best examples of introgression in plants, definitive evidence of gene exchange is lacking (Heiser, 1973). To determine whether the weedy race of H. bolanderi actually originated via introgression, we analyzed allozyme, chloroplast-DNA (cpDNA), and nuclear-ribosomal-DNA (rDNA) variation. Evidence from enzyme electrophoresis did not support the proposed introgressive origin of weedy H. bolanderi. We detected a total of 37 low-frequency alleles distinguishing the serpentine race of H. bolanderi from H. annuus. Weedy H. bolanderi possessed only four of the 37 marker alleles. Further analysis demonstrated that serpentine H. bolanderi combined seven of the 35 alleles distinguishing H. annuus from weedy H. bolanderi, indicating that serpentine H. bolanderi shares three more marker alleles with H. annuus than does weedy H. bolanderi. These results are similar to expectations for race divergence from a single common ancestor and suggest that, if introgression occurred, the majority of marker alleles were rapidly lost following the initial hybridization event. Even more compelling evidence opposing Heiser's (1949) hypothesis, however, was from restriction-fragment analysis of cpDNA and nuclear rDNA. We detected a total of 17 cpDNA and five rDNA restriction-site mutations among the 19 populations examined. No parallel or back mutations were observed in phylogenetic trees constructed using either cpDNA or rDNA mutations, and both phylogenies were completely congruent regarding the alignment of all three taxa. In addition, the weedy race of H. bolanderi possessed a unique cpDNA, which was outside the range of variation observed among populations of either of the presumed parental species. Mean sequence divergences between the cpDNAs of weedy H. bolanderi and those of serpentine H. bolanderi and H. annuus were 0.30% and 0.35%, respectively. These estimates are comparable to sequence-divergence values observed between closely related species in other plant groups. Given the lack of parallel or convergent mutations in the cpDNA and rDNA phylogenetic trees, the complete congruence of these trees with flavonoid- and allozyme-variation patterns, and the presence of a unique and divergent chloroplast genome in the weedy race of H. bolanderi, we suggest that the weedy race of H. bolanderi was not derived recently through introgression, as hypothesized, but is relatively ancient in origin. PMID- 28567847 TI - THE CONSEQUENCES OF BROOD SIZE FOR BREEDING BLUE TITS. III. MEASURING THE COST OF REPRODUCTION: SURVIVAL, FUTURE FECUNDITY, AND DIFFERENTIAL DISPERSAL. AB - To determine how the cost of reproduction varies with brood size, a population of blue tits (Parus caeruleus) breeding in Wytham Wood, England, was manipulated over a three year period. Two hundred sixteen pairs were randomly assigned 3, 6, 9, 12, or 15 nestlings; nestlings were exchanged soon after hatching. Survival of adult females (as measured by the proportion recaptured in the following winter and/or spring) declined significantly with increasing brood size in two out of three years; there was significant year-to-year variation in the relationship of recapture rate to brood size. Mean female recapture rates (averaged over the three years) declined in a linear fashion (P < 0.01). There was no significant linear or curvilinear relationship between male-recapture rate and brood size in any of the three years nor was there a significant linear or curvilinear relationship for the data averaged over the three years. Nevertheless, recapture proportions for males differed significantly with respect to brood size (chi2 test, P < 0.05). The possibility that experimental brood size influences subsequent dispersal (and therefore biases measures of survival based on recapture rates to differing degrees) was examined by comparing distances moved by breeding adults from one year to the next. There was no relationship between brood size and dispersal distance within the study area for either sex, except that females given broods of three were significantly more likely to move more than 300 m than were those given broods of 6-15 young. Both males and females showed evidence of a cost with respect to future fecundity: as brood size increased, the number of surviving offspring produced in the following year decreased from 1.5-1.6 (for adults that had reared 3-6 young) to 0.4 (for those that had reared 15 young). The relationship of future reproductive success to experimental brood size did not differ among years or between the sexes. The number of eggs laid and number of young hatched in year n + 1 did not differ significantly with respect to brood size in year n; rather, differences in future fecundity reflected differences in the survival prospects of young reared in year n + 1. PMID- 28567848 TI - FURTHER SIMULATION STUDIES ON EVOLUTION BY GENE DUPLICATION. AB - In order to understand the origin of multigene families, Monte Carlo simulations were performed to see how a genetic system evolves under unequal crossing-over, mutation, random genetic drift and natural selection, starting from a single gene copy. Both haploid and diploid models were examined. Beneficial, neutral, and detrimental mutations were incorporated, and "positive" selection favors those chromosomes (haploid) or individuals (diploid) with more beneficial mutations than others. The same model for haploids was previously investigated with special reference to the evolution of gene organization, and the ratio of the numbers of beneficial genes to pseudogenes was found to be a rough indicator of the relative strengths of positive and negative (against deleterious alleles) natural selection (Ohta, 1987b). In the present paper, the evolution of gene organization and of sequence divergence among genes in the multigene family is examined. It is shown that positive selection accelerates the accumulation of arrays containing different beneficial mutations, but that total divergence including both neutral and beneficial mutations is not very sensitive to positive selection, under this model. The proportion of beneficial mutations in the total mutations accumulated is a better indicator of positive selection than is the total divergence. It is pointed out that various observed examples in which amino-acid substitutions are accelerated, as compared with synonymous substitutions in duplicated genes (Li, 1985), may reflect the effect of selection similar to the present scheme. The diploid model is shown to be more efficient for accumulating beneficial mutations in duplicated genes than the haploid one, and the relevance of this finding to the advantage of sexual reproduction is discussed. PMID- 28567849 TI - EVOLUTION OF GREGARIOUSNESS IN APOSEMATIC BUTTERFLY LARVAE: A PHYLOGENETIC ANALYSIS. AB - Gregariousness ought to be disadvantageous for palatable organisms that live exposed and are relatively immobile and small in comparison to potential predators. Therefore, the idea that unpalatability generally evolves before egg clustering/larval gregariousness in butterflies was tested. Aposematic coloration in the larva was used as the criterion of unpalatability (it is argued that Batesian mimicry is rare in butterfly larvae), and the relative order of evolution of aposematism and gregariousness was inferred through phylogenetic analysis. Here, existing phylogenies were used, and the analysis was based on an assumption of a minimum number of evolutionary changes (parsimony). A total of 23 cases of independent evolution of gregariousness and 12 cases of independent evolution of aposematic coloration were found. In five cases, gregariousness evolved in cryptic species, the palatability of which is unknown. For lineages in which both unpalatability, as evidenced by aposematic coloration, and gregariousness were found and the two evolutionary events could be separated, unpalatability always preceded gregariousness: five cases of independent evolution of warning coloration were followed by a total of 15 cases of independent evolution of gregariousness. In no lineage did gregariousness evolve before warning coloration. It is thus concluded that unpalatability is an important predisposing factor for the evolution of egg clustering and larval gregariousness in butterflies. Insofar as kin selection is related to larval gregariousness, this study indicates that kin selection is of minor importance for the evolution of both unpalatability and warning coloration. PMID- 28567850 TI - POPULATION DIFFERENTIATION AND THE TRANSMISSION OF DENSITY EFFECTS BETWEEN GENERATIONS. PMID- 28567851 TI - STURM UND DRANG AND THE EVOLUTIONARY SYNTHESIS. PMID- 28567852 TI - GENETIC BASIS OF ACTIVITY METABOLISM. I. INHERITANCE OF SPEED, STAMINA, AND ANTIPREDATOR DISPLAYS IN THE GARTER SNAKE THAMNOPHIS SIRTALIS. AB - Recent conceptual advances in physiological ecology emphasize the potential selective importance of whole-animal performance. Empirical studies of locomotor performance in reptiles have revealed surprising amounts of individual variation in speed and stamina. The present study is the first in a series examining the genetic basis of variation in locomotor performance, activity metabolism, and associated behaviors in garter snakes. Maximal sprint crawling speed, treadmill endurance, and antipredator displays (Arnold and Bennett, 1984; exhibited as snakes reached exhaustion on the treadmill) were measured for approximately six offspring (presumed to be full siblings) from each of 46 wild-caught gravid garter snakes (Thamnophis sirtalis). Each character was measured on two days; all were individually repeatable. Correlations of these characters with body mass, snout-vent length, age at testing, litter size, dam mass, and dam snout-vent length were removed by computing residuals from multiple-regression equations. These residuals were used in subsequent genetic analyses. Approximate coefficients of variation of residuals were 17% for speed, 48% for endurance, and 31% for antipredator displays. Broad-sense heritabilities were significant for all characters: speed h2 = 0.58; stamina h2 = 0.70; antipredator display h2 = 0.42. All three residual characters showed positive and statistically significant phenotypic correlations (r = 0.19-0.36). Genetic correlations (estimated and tested by restricted maximum likelihood) among residuals were positive and highly significant between speed and endurance (0.58), but nonsignificant between speed and antipredator display (0.43), and between endurance and antipredator display (0.26). All environmental correlations were nonsignificant. These data suggest that, contrary to expectations based on previous physiological studies, there may be no necessary evolutionary trade-off between speed and stamina in these animals. This tentative conclusion will have important implications for future theoretical studies of the evolution of locomotor performance and associated antipredator behaviors. PMID- 28567853 TI - ISOZYME VARIABILITY IN TRYPANOSOMA CRUZI, THE AGENT OF CHAGAS' DISEASE: GENETICAL, TAXONOMICAL, AND EPIDEMIOLOGICAL SIGNIFICANCE. AB - A genetic interpretation of the zymograms of 524 Trypanosoma cruzi stocks from various hosts and representing a broad geographical range (United States to Southern Brazil) reveals high genetic variability (only one monomorphic locus out of 15) and suggests that this parasite has a diploid structure. The data do not give any indication of Mendelian sexuality, although many opportunities are present for genetic exchange between extremely different genotypes. The population structure of T. cruzi appears to be multiclonal and complex. The natural clones evidenced by isozyme analysis are numerous (43 different ones are recorded among 121 stocks assayed at 15 gene loci) and exhibit a large range of genotypes, in a nonhierarchical structure; it is not possible to cluster them into a few strictly delimited groups which could represent natural taxa. The available data suggest that the genetic variability of T. cruzi reflects the long separate evolution of multiple clones. It is suggested that long clonal evolution may explain the present biological and medical variability of the causative agent of Chagas' disease. PMID- 28567854 TI - DEVELOPMENTAL BUFFERING AS A MECHANISM FOR STASIS: EVIDENCE FROM THE PULMONATE THEBA PISANA. PMID- 28567855 TI - ASYMMETRICAL DEVELOPMENTAL PLASTICITY IN AN INTERTIDAL SNAIL. AB - Field and laboratory experiments were used to investigate the variation and phenotypic plasticity in the adhesive abilities of the intertidal snail Nucella lapillus between high- and low-wave-energy environments. Whelks from an exposed coast produced a larger pedal surface area and were more resistant to dislodgement than were similar-sized individuals from a protected shore. Tenacity (g/cm2 ) was similar between individuals from exposed and protected shores, indicating that variation in resisting dislodgement was solely a function of pedal surface area. Whelks from exposed and protected shores did not differ in pedal surface area as they emerged from egg capsules or when reared in the laboratory under uniform conditions, suggesting that variation between populations does not represent genetic differentiation. Individuals from high-and low-wave-energy environments reared intertidally produced a larger pedal surface area than did those reared in the laboratory. The extent to which pedal surface area increased corresponded to the intensity of wave action. These findings suggest that pedal surface area is a highly plastic character modulated or induced by the water turbulence accompanying breaking waves. A reciprocal transplant experiment confirmed this notion but revealed an asymmetry in the plasticity. Snails from the protected site transplanted to an exposed shore formed a much larger pedal surface area than did controls reared on the protected shore. In contrast, whelks from a wave-swept shore transplanted to a protected shore differed little from their controls reared on the exposed shore. The asymmetric response parallels a possible asymmetry in the risks of acclimating to a temporally unpredictable environmental cue, such as wave action. PMID- 28567857 TI - DEMONSTRATION OF CRYPTIC INCOMPATIBILITY IN DISTYLOUS AMSINCKIA DOUGLASIANA. AB - Hand pollinations experiments with distylous Amsinckia douglasiana A. DC. (Boraginaceae) revealed that legitimate (intermorph) crosses produce more seed than self-pollinations and that self-pollinations yield more seed than illegitimate (intramorph) crosses. We tested the occurrence of cryptic incompatibility in both style-length morphs by pollinating them with a mixture of legitimate and illegitimate pollen, each homozygous for a different electrophoretically distinguishable allele of phosphoglucose isomerase. The success of intramorph pollen was greatly reduced in mixture; only about 4% of the offspring of both pins and thrums were sired by illegitimate pollen. One pin and one thrum had sufficiently high seed set that the results cannot be attributed to selective abortion of embryos. In those individuals, discrimination against illegitimate pollen must have occurred on the stigma or in the style. Based on our findings, it appears that illegitimate matings are rare in natural populations. The progeny of legitimate crosses was biased toward pins, which suggests some regulation of morph ratios independent of the style-length locus. Prezygotic discrimination against the thrum genotype or selective abortion of embryos with the thrum genotype are both possible, but selective mortality of seedlings with the thrum genotype cannot be ruled out for some families. PMID- 28567858 TI - Optimization of Interphase Intervals to Enhance the Evoked Muscular Responses of Transcutaneous Neuromuscular Electrical Stimulation. AB - Neuromuscular electrical stimulation (NMES) is a widely used technique for clinical diagnostic, treatment, and research. Normally, it applies charge balanced biphasic pulses, which several publications have reported to be less efficient than monophasic pulses. A good alternative is the use of interphase intervals (IPI) on biphasic pulses that allows to achieve similar responses than those evoked by monophasic stimulation. This study analyzes the enhancing mechanism of the IPI and provides guidelines on how to optimize the IPI in order to reduce secondary effects such as the electrode corrosion. The tibial nerve was excited by NMES biphasic pulses with different IPI durations and polarities. Then, the elicited responses were recorded on the soleus muscle via electromyography. When cathodic-first pulses were applied, the responses increased proportionally to the IPI until the duration of 250 us, where the increase saturated at 30% of the original amplitude. The responses evoked during anodic-first were 6% to 30% smaller than those evoked during cathodic-first pulses and continuously increased until the IPI duration of 2500 us, where the responses reached an increase of around 30%. The results suggest that when a cathodic-first pulse is used, the IPI could be optimized (based on the setup geometry) to allow the action potentials to travel out of the hyperpolarization zone induced by the anodic phase. When anodic-first stimuli are applied, the IPI duration allows the fiber to recover from an apparent insensitive state induced by the anodic phase. The use of IPI is a viable option to improve the efficiency of actual stimulation systems, since only small modifications are required to significantly reduce the electrical charge required and boost the stimulation efficiency. PMID- 28567860 TI - Earliest evidence of bitumen from Homo sp. teeth is from El Sidron. PMID- 28567859 TI - Therapeutic targeting of chemoresistant and recurrent glioblastoma stem cells with a proapoptotic variant of oncolytic herpes simplex virus. AB - Temozolomide (TMZ) chemotherapy, in combination with maximal safe resection and radiotherapy, is the current standard of care for patients with glioblastoma (GBM). Despite this multimodal approach, GBM inevitably relapses primarily due to resistance to chemo-radiotherapy, and effective treatment is not available for recurrent disease. In this study we identified TMZ resistant patient-derived primary and previously treated recurrent GBM stem cells (GSC), and investigated the therapeutic activity of a pro-apoptotic variant of oHSV (oHSV-TRAIL) in vitro and in vivo. We show that oHSV-TRAIL modulates cell survival and MAP Kinase proliferation signaling pathways as well as DNA damage response pathways in both primary and recurrent TMZ-resistant GSC. Utilizing real time in vivo imaging and correlative immunohistochemistry, we show that oHSV-TRAIL potently inhibits tumor growth and extends survival of mice bearing TMZ-insensitive recurrent intracerebral GSC tumors via robust and selective induction of apoptosis-mediated death in tumor cells, resulting in cures in 40% of the treated mice. In comparison, the anti-tumor effects in a primary chemoresistant GSC GBM model exhibiting a highly invasive phenotype were significant but less prominent. This work thus demonstrates the ability of oHSV-TRAIL to overcome the therapeutic resistance and recurrence of GBM, and provides a basis for its testing in a GBM clinical trial. PMID- 28567862 TI - GENETICS OF BRASSICA CAMPESTRIS. 1. GENETIC CONSTRAINTS ON EVOLUTION OF LIFE HISTORY CHARACTERS. AB - Energy allocation arguments suggest a possible tradeoff between timing and magnitude of reproduction: plants that postpone reproduction may accumulate greater resources and consequently produce more offspring. However, early reproduction may be favored when adult mortality is high. Tradeoffs among life history characters may be a consequence of constraints imposed by genetic and environmental covariation among traits. In this paper we examine the genetic basis of the relationship between timing and magnitude of reproduction in an annual plant, Brassica campestris, by selecting to change flowering date and plant size in each of four directions (early and large, late and large, early and small, or late and small). There is a strong positive relationship between flowering date and flowering height. The response to selection was greatest along the axis of positive genetic covariation. Populations may evolve to become early flowering and small or late flowering and tall, but there is little response for the alternative combinations of characters. In this instance, the constraints imposed by quantitative genetics are in striking accord with predictions that might be made on physiological, energetic, or ecological grounds. PMID- 28567861 TI - THE GENETIC STRUCTURE OF THE HYBRID ZONE BETWEEN THE FIRE-BELLIED TOADS BOMBINA BOMBINA AND B. VARIEGATA: COMPARISONS BETWEEN TRANSECTS AND BETWEEN LOCI. AB - We compare the pattern of morphological and electrophoretic variation in the hybrid zone between Bombina bombina and B. variegata across two transects: one near Cracow and one 200 km away, near Przemysl in southeastern Poland. Morphological variation across the Przemysl transect had been surveyed more than 50 years ago; though we found a significant shift at one site, there is no evidence for gross movement over this period. Morphological and electrophoretic changes coincide, and the average shape of the clines is the same across both transects. At the center, most of the change in frequency of six diagnostic allozymes occurs within w = 6.05 km (2-unit support limits 5.56-6.54 km). These steep gradients are generated not by selection on the allozymes themselves, but by associations with other loci: though these markers are unlinked, they are in strong linkage disequilibrium with each other [R = D/?pquv = 0.22 (0.15-0.29) at the center]. Disequilibria are broken up as alleles diffuse away from the zone and flow into the new genetic background. The net barrier to the flow of genes from bombina into variegata, which is generated by these disequilibria, is B = 51 (22-81) km. The fitness of hybrids must be substantially reduced to produce such a barrier [WH /WP = 0.58 (0.54-0.68)], and this selection must be spread over many loci [N = 55 (26-88)]. Alleles introgress significantly less far than would be expected from the age of the zone and the estimated dispersal rate [sigma = 0.99 (0.82-1.14) km gen.1/2 ]: this implies selection of se = 0.37 (0.15-0.58)% on the enzymes themselves. There is weak but significant linkage disequilibrium well away from the center of the zone; this, together with the presence of parental and F1 genotypes, suggests some long-range migration. However, such migration is not likely to cause significant introgression. PMID- 28567863 TI - LIFETIME DATA AND THE MEASUREMENT OF SELECTION. PMID- 28567864 TI - MATING PROPENSITY AND COURTSHIP BEHAVIOR IN SERIALLY BOTTLENECKED LINES OF THE HOUSEFLY. AB - The efficacy of bottlenecks to stimulate divergence in courtship behavior and consequent premating isolation was tested by serial founder-flush episodes of three sizes (one, four, or 16 pairs) on a population of houseflies established in the laboratory from a single field population. After the fifth founder-flush episode, intraline and interline crosses were performed to detect divergence in mating propensities and patterns of assortative mating. Videotapings of intraline courtships for the bottleneck lines and the control were evaluated for changes in courtship repertoire. All bottleneck lines showed significant divergence from the control in male and/or female mating propensity and in courtship behavior. Divergence from the control was bidirectional for both male and female mating propensities as well as for courtship element utilization. Out of 15 tests for assortative mating between bottleneck lines and between bottleneck lines and the control, only two cases of positive assortative mating and one case of negative assortative mating were detected. Because some bottleneck lines showed increased courtship element utilization and because decreased courtship utilization in some bottleneck lines was related to higher male mating success, the mechanisms behind the Kaneshiro model (which is based upon ancestral females discriminating against bottleneck males that had "lost" courtship elements) were not supported in general. A partitioning effect of the bottlenecks upon the intrinsic variation in the ancestral population for courtship pattern appeared to explain a large component of the directions of divergence from the control. Still, the pattern of divergence of some bottleneck lines apparently was not constrained by the intercorrelation structure of courtship behaviors detected in the control. Because previous studies showed that the bottleneck lines had rebounded from inbreeding depression to fitness levels of the control, this study documents nondebilitating differentiation in the courtship repertoire that can account for divergent mating propensities and premating isolation. PMID- 28567865 TI - ESTIMATION OF SINGLE GENERATION MIGRATION DISTANCES FROM GEOGRAPHIC VARIATION IN ANIMAL MITOCHONDRIAL DNA. AB - A new approach is introduced for the analysis of dispersal from the geographic distributions of mtDNA lineages. The method is based on the expected spatial distributions of lineages arising under a multigeneration random walk process. Unlike previous methods based on the predicted equilibria between genetic drift and gene flow, this approach is appropriate for non-equilibrium conditions, and yields an estimate of dispersal distance rather than dispersal rate. The theoretical basis for this method is examined, and an analysis of mtDNA restriction site data for Peromyscus maniculatus is presented as an example of how this approach can be applied to empirical data. PMID- 28567866 TI - COMPARISONS OF OBSERVED PHYLOGENETIC TOPOLOGIES WITH NULL EXPECTATIONS AMONG THREE MONOPHYLETIC LINEAGES. AB - Three null models have been proposed to predict the relative frequencies of topologies of phylogenetic trees. One null model assumes each distinguishable n member tree is equally likely (proportional-to-distinguishable-arrangements model). A second model assumes that each topological type is equally likely (equiprobable model). A third model assumes that the probability of each topological type is determined by random speciation (Markov model). We sampled published phylogenetic trees from three major groups of organisms: division Angiospermae, class Insecta, and superclass Tetrapoda. Our sampling was more restricted than previous studies and was designed to test whether observed topological frequencies were distinguishable from those predicted by the three null models. The pattern of evolution reflected in five-member phylogenetic trees is different from predictions of the equiprobable and Markov model but is indistinguishable from the proportional-to-distinguishable-arrangements model. This indicates that 1) speciation (and/or extinction) is not equally likely among all taxa, even for small phylogenies; or 2) systematists' attempts at reconstructing small phylogenies are, on average, indistinguishable from those expected if they had merely selected a tree at random from the pool of all possible trees. The topology frequencies were not different among the three groups of organisms, suggesting that factors shaping patterns of speciation and extinction are consistent among major taxonomic groups. PMID- 28567867 TI - SEXUAL CANNIBALISM, SIZE DIMORPHISM, AND COURTSHIP BEHAVIOR IN ORB-WEAVING SPIDERS (ARANEIDAE). PMID- 28567868 TI - ASSOCIATION BETWEEN QUANTITATIVE TRAITS AND ALLOZYME HETEROZYGOSITY IN A TETRASOMIC SPECIES: DACTYLIS GLOMERATA. AB - Tetraploid individuals of orchardgrass (Dactylis glomerata L. subsp. hispanica Roth.) sampled from a natural population were used to evaluate the correlation between both single and multilocus heterozygosity at 7 enzyme loci, and several quantitative traits (plant size at time of collection, leaf weight, and panicle number in experimental trials). Four hundred and forty-eight plants were studied at the 7 loci and 288 of these individuals were scored for an additional eighth locus. Five genotype classes (monogenic, simplex, and duplex digenic, trigenic, and tetragenic) were distinguished according to their heterozygosity level. Multilocus heterozygosity showed a significant positive correlation with both leaf and panicle yield in experimental conditions, but not with original plant size, which was found to be markedly influenced by environmental microheterogeneity. Multilocus heterozygosity, estimated from both the number of heterozygous loci and the number of distinct alleles per locus, had a significant influence on plant performance. Individual locus effects were positive and significant at two loci (GOT1 and PX1). Panicle number increased regularly with heterozygosity level (from monogenics to tetragenics) at the GOT1 locus, as did leaf weight and panicle number at the PX1 locus. Such variation would be predicted by overdominance at these loci or at linked loci. Significant relationships between leaf yield and heterozygosity level at the GOT1 locus distinguished the homozygotes from the heterozygotes (of any class) and was thus more consistent with inbreeding effects. No significant differences were observed among the five genotype classes for any quantitative trait at the six remaining loci. At both the GOT1 and PX1 loci, heterozygosity had a significant independent effect on leaf weight and panicle number even when the correlation between these traits was removed by analysis of covariance. PMID- 28567869 TI - APOSEMATISM AND SYNERGISTIC SELECTION IN MARINE GASTROPODS. PMID- 28567871 TI - GENE FLOW IN CHAMAECRISTA FASCICULATA (LEGUMINOSAE) II. GENE ESTABLISHMENT. AB - The role of gene establishment in gene flow was investigated in a population of the annual legume Chamaecrista fasciculata by determining the effect of interparent distance on progeny fitness throughout the entire life history. A decelerating gain in progeny fitness with increasing interparent distance was observed. Selfed progeny suffered a 2-fold fitness disadvantage compared to progeny derived from mating events between individuals in the same neighborhood. Progeny derived from within neighborhood crosses had lower fitness than progeny from crosses between neighborhoods. Coupling the effect of interparent distance on gene establishment with information on gene dispersal resulted in a considerable increase in estimated gene flow. However, gene flow was still limited, as the average neighborhood area corresponded to a circle with radius of approximately 3.0 m. Yearly fluctuations in population size and variation in reproductive output lowered the estimate of Ne below the census estimate to approximately 100 individuals. The role of a seed bank in increasing the estimate of Ne was found to be insignificant. It is likely that genetic drift plays a major role in determining the distribution of genetic variation in this population. PMID- 28567870 TI - FACULTATIVE SEX ALLOCATION BIASING BY WORKERS IN SOCIAL HYMENOPTERA. AB - A single-locus two-allele model is analyzed to determine the invasion conditions for facultative biasing of colony sex allocation by hymenopteran workers in response to queen mating frequency, for a situation in which colonies have a single queen mated to one or two males. Facultative biasing of sex allocation towards increased male production in double mated colonies and increased female production in single mated colonies can both invade when the population sex allocation ratio is at the worker optimum. However, when the population sex allocation ratio is more male biased than the worker optimum, plausibly due to mixed queen and worker control, it is likely that only increased female allocation in colonies perceived by the workers to have single mated queens can invade. In this case, the frequency of mistakes made by workers in assessing queen mating frequency is an important constraint on the invasion of facultative male biasing in colonies perceived to have a double mated queen. When the population sex allocation ratio is not between the optima for workers in single and double mated colonies, plausibly due to strong queen control, then facultative biasing cannot invade. In this situation, workers in all colonies should attempt to bias allocation towards increased females. Worker male production in queenright colonies (provided not all males are worker-derived), unequal sperm use by double mated queens, and the amount of facultative biasing, do not alter these results. PMID- 28567872 TI - THE GEOGRAPHY OF MITOCHONDRIAL DNA VARIATION IN TWO SYMPATRIC SPARROWS. AB - Geographic variation in mitochondrial DNA (mtDNA) restriction sites was studied in samples of two sympatric passerine birds, fox (Passerella iliaca) and song (Melospiza melodia) sparrows, collected at the same sites in the western United States. Different levels of variation and differentiation were observed in each species. In 46 fox sparrows taken at nine sites, five clones were observed, partitioned into two distinct east-west groups that meet at the Great Basin Sierra Nevada interface; percent nucleotide divergence was 0.86 between groups and 0.08 within groups. An additional 43 individuals were examined using at least one of seven diagnostic endonucleases, and all supported the east-west groupings. Considering common mtDNA haplotypes as alleles, an FST of 0.50 was computed, which is an order of magnitude greater than that computed from allozyme comparisons (0.019); mtDNA analyses suggest little intergroup gene exchange. Compared to allozymic variation, analysis of mtDNA revealed a greater degree of population structuring and greater consistency with broad patterns of morphological variation. Fifteen clones were observed in 27 song sparrows taken at seven of the same sites at which fox sparrows were sampled; the percent nucleotide divergence averaged 0.27. There was no detectable geographic pattern to the variation, and no evidence of an east-west division as in the fox sparrow. However, the mosaic nature of mtDNA variation in song sparrows suggests limited gene exchange. Considering the 15 clones as alleles yielded an Fst of 0.24, which is reduced to 0.039 when corrected for sampling error. In spite of occupying the same geographic area, mtDNA analyses showed that the two species (or at least their mtDNA gene genealogies) have had different evolutionary histories. PMID- 28567873 TI - CAN ONE PREDICT THE EVOLUTION OF QUANTITATIVE CHARACTERS WITHOUT GENETICS? PMID- 28567874 TI - THE EVOLUTION OF APOSEMATISM IN MARINE GASTROPODS. PMID- 28567875 TI - CONSEQUENCES OF FLORAL VARIATION FOR MALE AND FEMALE REPRODUCTION IN EXPERIMENTAL POPULATIONS OF WILD RADISH, RAPHANUS SATIVUS L. AB - We documented effects of floral variation on seed paternity and maternal fecundity in a series of small experimental populations of wild radish, R. sativus. Each population was composed of two competing pollen donor groups with contrasting floral morphologies and several designated maternal plants. Progeny testing with electrophoretic markers allowed us to measure paternal success. Realized fecundity by each maternal plant and the fraction of those seeds attributable to each pollen donor group were used as outcome variables in path analysis to explore relationships between floral characters (petal size, pollen grain number per flower, and modal pollen grain size), pollinator visitation patterns, and reproductive success. A wide range of pollinator taxa visited the experimental populations, and patterns of discrimination appeared to vary among them. The impact of visitation on male and female reproduction also varied among taxa; visits of small native bees significantly increased paternal success, while those of honey bees reduced male fitness. Only visits by large native bees had discernible effects on recipient fecundity, and, overall, fecundity was not limited by visitation. Maternal plants bearing large-petalled flowers produced fewer flowers during the experiment, reducing their total seed production. In these small populations, postpollination processes (at least in part, compatibility) significantly influenced male and female reproductive success. Variation in pollinator pools occurring on both spatial and temporal scales may act to preserve genetic variation for floral traits in this species. PMID- 28567876 TI - GENE FLOW IN CHAMAECRISTA FASCICULATA (LEGUMINOSAE) I. GENE DISPERSAL. AB - Both pollen and seed dispersal components of gene flow were examined in the annual plant Chamaecrista fasciculata (Leguminosae) and quantified in terms of Wright's neighborhood area. Pollen dispersal was estimated by measuring pollinator flight movement throughout the flowering season and the contribution of pollen carryover to pollen dispersal was determined by comparing pollinator flight movement with dispersal of electrophoretic markers in an experimental transect. Phenological effects on the probability of fruit set were measured to determine whether pollinations should be weighted differentially across the flowering season. The outcrossing rate, a major determinant of the role of pollen dispersal in gene flow, was estimated from electrophoretic analysis of progeny arrays and by measuring the proportion of nongeitonogamous pollinator flight movements. Seed dispersal was measured in a prairie habitat and in experimental plots without surrounding vegetation. Seed dispersal was small in comparison to pollen dispersal in both environments. Fruit set was low at the beginning and end of the flowering season, periods when flower density is low and pollinator flight distances are large. Although the outcrossing rate was high (t = 80%) and pollen carryover substantial, pollen dispersal was limited. Averaged over 4 years, neighborhood area, based on both seed and pollen dispersal, was 17.6 m2 , and corresponds to a circle of radius 2.4 m. The observed limited gene dispersal suggests the population of C. fasciculata is genetically subdivided into small breeding units of related individuals. PMID- 28567877 TI - HETEROZYGOSITY IN THE HAPLODIPLOID THYSANOPTERA. PMID- 28567878 TI - SPERM COMPETITION AND THE EVOLUTION OF NONFERTILIZING SPERM IN MAMMALS. AB - Nonfertilizing sperm with special morphologies have long been known to exist in invertebrates. Until recently, abnormal sperm in mammals were considered errors in production. Now, however, Baker and Bellis (1988, 1989) have proposed that mammalian sperm, like some invertebrate sperm, are polymorphic and adapted to a variety of nonfertilizing roles in sperm competition, including prevention of passage of sperm inseminated by another male. More specifically, their "kamikaze" sperm hypothesis proposes that deformed mammalian sperm are adapted to facilitate the formation and functioning of copulatory plugs (Baker and Bellis, 1988). Here I argue that most, maybe all, mammals are unlikely to produce nonfertilizing sperm. First, mammals might not be able to afford to evolve nonfertilizing sperm, given that a) fertilization is often unlikely despite the huge numbers of sperm produced; b) production of larger numbers of sperm is constrained, presumably because of metabolic costs, evidence for which includes the fact that in species in which sperm morphology and anatomy of the female reproductive tract increase the probability of fertilization, the numbers of sperm produced is lower than in others; and c) selection appears to act against the production of deformed sperm. Second, some of the evidence advanced for the existence of nonfertilizing sperm does not in fact support the idea. Third, accessory gland secretions are sufficient on their own to coagulate semen and produce fully functioning plugs; thus the male that used accessory gland secretions would be at a clear advantage over the male that diluted his fertilizing sperm with "kamikaze" sperm; and indeed, current evidence indicates selection on accessory glands, not sperm morphology, to enhance coagulation of semen. Fourth, predictions made on the basis of the "kamikaze" sperm hypothesis are not supported by quantitative comparisons of data from polyandrous and monandrous primates (i.e., those in which several males mate with a fertile female, and therefore in which sperm competition should be operating, and those in which only one male mates). Although sperm competition is almost certainly more intense in polyandrous genera than in monandrous genera (as indicated by, e.g., more frequent copulations and the production of more sperm per ejaculate from larger spermatogenic organs), polyandrous genera do not produce a greater proportion of deformed (i.e., nonfertilizing) sperm than do monandrous genera, or even necessarily a greater number of deformed sperm; nor a greater variety of sperm sizes-indeed they might produce fewer; nor fewer motile sperm (as might be expected if sperm are selected to stay behind and compete with sperm from subsequent males); and nor larger sperm (as might be expected if sperm are produced for functions other than to reach the egg). In sum, currently available evidence suggests that the function of all mammalian sperm is to fertilize, and that sperm competition in mammals occurs through scramble competition, not contest competition. PMID- 28567879 TI - A PRELIMINARY TEST OF THE ADAPTIVE SIGNIFICANCE OF ENVIRONMENTAL SEX DETERMINATION IN REPTILES. PMID- 28567880 TI - DIVERGENCE OF MEIOTIC DRIVE-SUPPRESSION SYSTEMS AS AN EXPLANATION FOR SEX-BIASED HYBRID STERILITY AND INVIABILITY. AB - Two empirical generalizations about speciation remain unexplained: the tendency of the heterogametic sex to be sterile or inviable in F1 hybrids (Haldane's rule), and the tendency of the X chromosome to harbor the genetic elements that cause this sex bias in hybrid fitness. I suggest that divergence of meiotic drive systems on the sex chromosomes can explain these observations. The theory follows from two simple facts. First, sex chromosomes are particularly susceptible to the forces of meiotic drive. Second, divergence of meiotic drive systems can cause hybrid sterility and in viability. The main objection to the theory is that meiotic drive is apparently rare, whereas the observed pattern of hybrid fitness is widespread. I answer this objection by showing that divergence of meiotic drive systems can explain the two generalizations even if large departures from Mendelian segregation are rarely observed. PMID- 28567881 TI - THE GENETIC BASIS OF LIFE-HISTORY CHARACTERS IN A POLYCHAETE EXHIBITING PLANKTOTROPHY AND LECITHOTROPHY. AB - The polychaete Streblospio benedicti is unusual in that several field populations consist of individuals that exhibit either planktotrophic or lecithotrophic larval development. Planktotrophy in this species involves production of many small ova that develop into feeding larvae with a two- to three-week planktonic period. Lecithotrophy involves production of fewer, larger ova that develop into nonfeeding larvae that are brooded longer and have a brief planktonic stage. Reciprocal matings were performed to investigate genetic variance components and the correlation structure of life-history traits associated with planktotrophy and lecithotrophy. Our objective was to better understand persistence of this developmental dichotomy in Streblospio benedicti, and among marine invertebrates in general. Substantial additive genetic variation (75-98% of total) was detected for the following characters at first reproduction: female length; position of the first gametogenic setiger and first brood pouch; ovum diameter; three traits related to fecundity (numbers of ova per ovary, larvae per brood pouch, and larvae per brood); median larval planktonic period and the presence of larval swimming setae; but not for total number of brood pouches; larval length; larval feeding; and larval survivorship. Based on the unusual geographic distribution of development modes in this species, we hypothesize that the developmental traits have evolved in allopatry and have only recently come into contact in North Carolina. The high additive contribution to variance observed for many traits may be inflated due to (a) nonrandom breeding in nature, and (b) examination of only one component of an age-structured population at one time. Nuclear interaction variance and maternal variance accounted for 84% of the total variation in larval survivorship. This observation supports other empirical studies and theoretical predictions that nonadditive components of variance will increase in importance in individual traits that are most closely tied to fitness. A network of life history trait correlations was observed that defines distinct planktotrophic and lecithotrophic trait complexes. Negative genetic correlations were present between fecundity and egg size, between fecundity and position of the first gametes, and between larval survivorship and median planktonic period. Positive genetic correlations were detected between fecundity and female size at first reproduction and between planktonic period and the presence of swimming setae. Intergenerational product-moment correlations were negative for larval length and fecundity, planktonic period and egg size, female size and larval survivorship, and fecundity and larval survivorship. If the genetic correlation structure observed in the laboratory persists in the field, it may constrain responses of individual characters to directional selection, and indirectly perpetuate the dichotomies associated with planktotrophy and lecithotrophy. PMID- 28567882 TI - ASYMMETRICAL MATING PATTERNS BETWEEN GEOGRAPHIC STRAINS OF DROSOPHILA MERCATORUM: A TEST OF THE KANESHIRO HYPOTHESIS. PMID- 28567883 TI - EXTINCTION DUE TO EVOLUTION OF A COMPETITOR. AB - When Drosophila simulans and Drosophila funebris were cultured together in population cages over many generations, there was a prolonged period of apparently stable coexistence followed by a rapid exclusion of D. funebris. As both species maintained large population sizes in monocultures it follows that the extinctions of D. funebris in the mixed-species cultures must have been caused by D. simulans. The time to extinction of D. funebris ranged from 26 weeks in one cage, to between 40 and 48 weeks in the other five. To test the idea that an evolutionary increase in competitive ability of D. simulans had occurred during the course of its interaction with D. funebris, a single-generation experiment was set up. In this experiment the interspecific competitive ability of a population of D. simulans that had been in competition with D. funebris for 44 weeks was compared to that of a stock population that had had no previous contact with D. funebris. In this experiment both stock and precompeted populations of D. simulans increased the egg-to-adult development time of D. funebris. However, precompeted D. simulans caused a significantly greater increase in the development time of D. funebris than did stock D. simulans. Thus D. simulans had evolved an increase in competitive ability as a result of its interaction with D. funebris. Development time is important because in the population cages the resource bottles-in which the larvae reside-were replaced every three weeks. An increase in development time of D. funebris in the multigeneration experiment similar to that observed in the single-generation experiment would lead to a rapid decrease in adult population size, resulting in the extinction of this species, as was observed to happen. PMID- 28567884 TI - SEXUAL PREFERENCE FOR FEMALES REARED ON CACTUS MEDIA BY DROSOPHILA PEGASA MALES. PMID- 28567885 TI - IN SEARCH OF HOMOPLASTIC TENDENCIES: STATISTICAL INFERENCE OF TOPOLOGICAL PATTERNS IN HOMOPLASY. AB - The "tendency" for homoplasy to appear in closely related taxa has been widely discussed but rarely quantified. This paper proposes statistical tests that examine the topological distribution of homoplasy within characters in phylogenies. They test whether character changes are localized (confined to some subtree), or clustered (occur in proximity to each other), relative to two null models of character evolution. Null Model I assumes that the observed number of character changes are dispersed randomly among the internodes of the tree, whereas Model II weights the probability that an internode contains a change by the length of that internode-estimated by the total number of character changes along that internode. Localization is measured by the largest furthest-neighbor distance between changes, clustering by the mean nearest neighbor distance. Distances are measured either by the number of intervening branches or the number of intervening character changes. Analyses of four cladistic data sets from the literature reveal very few characters that exhibit significant levels of clustering or localization-no more than would be expected by chance. In every data set a majority of characters exhibited at least weak tendencies, but in only one data set was there a significant excess of such characters. The present findings do not provide compelling evidence for the existence of "tendencies" in homoplasy, at least among characters used to reconstruct phylogenies. They should be sought elsewhere, in cladistic analyses of larger scope, probably among a class of characters defined a priori on a structural or functional basis. PMID- 28567886 TI - CLINAL VARIATION IN EASTERN POPULATIONS OF THE WATERSTRIDER AQUARIUS REMIGIS: GRADUAL INTERGRADATION OR DISCONTINUITY? PMID- 28567887 TI - CRITERIA OF FEMALE MATE CHOICE IN DROSOPHILA LITTORALIS, D. MONTANA, AND D. EZOANA. AB - We examined sexual selection by Drosophila littoralis, D. montana, and D. ezoana females on male courtship sounds to determine whether the females use absolute or relative criteria when choosing their mates. Behavior of the females was observed, when they were courted by a single male producing normal sounds, or by a single wing-manipulated male producing abnormal sounds; and when they were courted by one or both of these males in a choice situation. The females usually accepted short-winged (but not wingless) males producing abnormal sounds, if they had no alternatives. However, if they heard the sound produced by a normal male, they rejected the deficient male. Drosophila littoralis and D. ezoana females selected between two wing-manipulated males with different wing areas. Our results suggest that the females choose their mates on the basis of relative criteria if the signals emitted by the courting males are within the range of acceptable cues. PMID- 28567888 TI - EVOLUTION OF PELVIC REDUCTION IN THREESPINE STICKLEBACK FISH: A TEST OF COMPETING HYPOTHESES. AB - Reimchen hypothesized that pelvic reduction in threespine stickleback is favored by an absence of piscivorous fishes and the resulting increase in predation by insects, but Giles hypothesized that the predation regime is unimportant and that a low dissolved calcium concentration favors evolution of pelvic reduction. Substantial pelvic reduction in threespine stickleback sampled from 179 lakes around Cook Inlet, Alaska is strongly associated both with an absence of predatory fishes and a low calcium concentration. However, the association of pelvic reduction with low calcium concentration appears to be contingent on the absence of predatory fishes. These results emphasize the importance of interactions between seemingly unrelated environmental variables for selection of a single trait. However, these results also conflict with some observations elsewhere and do not rule out the possibility that other environmental factors are important for selection for pelvic reduction in threespine stickleback. PMID- 28567889 TI - ON THE RELATIONSHIP BETWEEN QUANTITATIVE GENETIC AND ESS MODELS. PMID- 28567890 TI - EVIDENCE FOR MULTIPLE ORIGINS AND SYMPATRIC DIVERGENCE OF TROPHIC ECOTYPES OF SMELT (OSMERUS) IN NORTHEASTERN NORTH AMERICA. AB - The rainbow smelt, Osmerus mordax (Mitchill), is an osmerid fish that exhibits extensive life-history diversity throughout watersheds of northeastern North America. There are both ***sea-run (anadromous) and lake-resident (lacustrine) populations and the latter have diversified further into "dwarf-" and "normal sized" life-history types. Anadromous and lacustrine smelt may inhabit the same watershed and there are several instances where dwarf and normal populations reside within the same lake. We assayed variation among smelt for morphological traits linked to feeding performance in fishes to see if trophic ecology might promote life-history diversity in Osmerus. We also examined mitochondrial DNA (mtDNA) restriction site variation among forms to assess their evolutionary interrelationships. Dwarf smelt had significantly more gill rakers, larger eyes, but shorter upper jaws than normal lake and anadromous smelt. The populations clustered into two trophic "morphotypes"; an anadromous/normal lake group of populations and a group consisting only of dwarf smelt. The mtDNAs of 444 smelt from 16 populations were digested with 12 restriction enzymes revealing 93 composite mtDNA genotypes that clustered (UPGMA) into two major phylogenetic groups differing by 0.78% in sequence. Both genetic groups were present in dwarf and normal smelt as well as in anadromous fish. Further, geographic proximity, rather than trophic morphotype, appeared to be the major determinant of genetic affinities among populations. In two lakes, however, dwarf and normal smelt populations had significantly different mtDNA genotype frequency distributions indicating that the forms are reproductively isolated within both lakes. A clustering analysis of population affinities suggested that the divergence of sympatric dwarf and normal populations had occurred independently in the two lakes. We concluded (1) that trophic ecology is an important factor promoting differentiation in smelt life histories; (2) that smelt ecotypes are polyphyletic and there have been multiple, independent divergences of Osmerus life-history types throughout northeastern North America; and (3) that the biological and mtDNA differences between coexisting dwarf and normal lake smelt argue strongly that their genetic isolation may have developed sympatrically. PMID- 28567891 TI - EXPERIMENTAL EVIDENCE FOR INTERSPECIFIC FEMALE MIMICRY IN SYMPATRIC FICEDULA FLYCATCHERS. PMID- 28567892 TI - EVOLUTIONARY CHANGE IN THE MORPHOLOGICAL COMPLEXITY OF THE MAMMALIAN VERTEBRAL COLUMN. AB - The notion that morphological complexity increases in evolution is widely accepted in biology and paleontology. Several possible explanations have been offered for this trend, among them the suggestion that it has an active forcing mechanism, such as natural selection or the second law of thermodynamics. No such mechanism has yet been empirically demonstrated, but testing is possible: if a forcing mechanism has operated, the expectation is that complexity would have increased in evolutionary lineages more frequently than it decreased. However, a quantitative analysis of changes in the complexity of the vertebral column in a random sample of mammalian lineages reveals a nearly equal number of increases and decreases. This finding raises the possibility that no forcing mechanism exists, or at least that it may not be as powerful or pervasive as has been assumed. The finding also highlights the need for more empirical tests. PMID- 28567893 TI - GENETICS OF HOST-CACTUS RESPONSE AND LIFE-HISTORY EVOLUTION AMONG ANCESTRAL AND DERIVED POPULATIONS OF CACTOPHILIC DROSOPHILA MOJAVENSIS. AB - The extent of host-specific genetic variation for two life-history traits, egg to adult developmental time and viability, and one morphological trait closely tied to fitness, adult thorax size, was exposed by employing a nested half-sib/full sib breeding design with Baja and mainland populations of Drosophila mojavensis recently extracted from nature. This study was motivated by the presence of substantial variation in life histories among populations of D. mojavensis that use the fermenting tissues of particular species of columnar cacti for feeding and breeding in the Sonoran Desert. Full-sib progeny from all sire-dam crosses were split into cultures of agria cactus, Stenocereus gummosus, and organ pipe cactus, S. thurberi, to examine patterns of genotype-by-environment interaction for these fitness components. Baja flies expressed shorter egg-to-adult developmental times, higher viabilities, and smaller body sizes than mainland flies consistent with previous studies. Significant sire and dam components of variance were exposed for developmental time and thorax size. Genotype-by environment interactions were significant at the level of dams for developmental time and nearly significant for viability (P = 0.09). Narrow- and broad-sense heritabilities were influenced by host cactus, sex, and population. No strong pattern of genetic correlation emerged among fitness components suggesting that host-range expansion has not been accompanied by formation of coadapted life histories, yet the ability to estimate genetic correlations and their standard errors was compromised by the unbalanced nature of the data set. Genetic correlations in performance across cacti were slightly positive, evidence for ecological generalism among populations explaining the observed pattern of multiple host cactus use within the species range of D. mojavensis. PMID- 28567894 TI - GENETIC CONSTRAINTS AND THE PHYLOGENY OF INSECT-PLANT ASSOCIATIONS: RESPONSES OF OPHRAELLA COMMUNA (COLEOPTERA: CHRYSOMELIDAE) TO HOST PLANTS OF ITS CONGENERS. AB - We ask whether patterns of genetic variation in a phytophagous insect's responses to potential host plants shed light on the phylogenetic history of host association. Ophraella communa feeds chiefly, and in eastern North America exclusively, on Ambrosia (Asteraceae: Ambrosiinae). Using mostly half-sib breeding designs, we screened for genetic variation in feeding responses to and larval survival on its own host and on seven other plants that are hosts (or, on one case, closely related to the host) of other species of Ophraella. We found evidence for genetic variation in feeding responses to five of the seven test plants, other than the natural host. We found no evidence of genetic variation in feeding responses to two plant species, nor in capacity for larval survival on six. These results imply constraints on the availability of genetic variation; however, little evidence for constraints in the form of negative genetic correlations was found. These results are interpreted in the context of a provisional phylogeny of, and a history of host shifts within, the genus. Ophraella communa does not present evidence of genetic variation in its ability to feed and/or survive on Solidago, even though it is probably descended from a lineage that fed on Solidago or related plants, possibly as recently as 1.9 million years ago. Genetic variation in performance on this plant may have been lost. Based on evidence for genetic variation and on mean performance, by far the greatest potentiality for adaptation to a congener's host was evinced in responses to Iva frutescens, which not only is related and chemically similar to Ambrosia, but also is the host of a closely related species of Ophraella that may have been derived from an Ambrosia-associated ancestor. Genetic variation in O. communa's capacity to feed and/or survive on its congeners' hosts is less evident for plants that do not represent historically realized host shifts (with one exception) than for those that may (but see Note Added in Proof). The results offer some support for the hypothesis that the evolution of host shifts has been guided in part by constrained genetic variation. PMID- 28567895 TI - GENETIC HETEROGENEITY INCREASES VIABILITY IN COMPETING GROUPS OF DROSOPHILA HYDEI. PMID- 28567896 TI - QUANTITATIVE GENETICS OF RESPONSE TO COMPETITORS IN NEMOPHILA MENZIESII: A GREENHOUSE STUDY. AB - To determine the potential for adaptation to a local biotic environment, we examined the magnitude and nature of genetic variation in response to neighboring plants within a natural population of the native California annual, Nemophila menziesii. A total of 22 plants from a natural population were crossed in three reciprocal factorials. The progeny were grown in a greenhouse in nine treatments that varied in conspecific density and in the density of a naturally co-occurring grass species, Bromus diandrus. Increasing the density of each species significantly reduced individual survival, fruit number, and dry weight. Among survivors, we found small to moderate heritability of dry weight within treatments. Additive genetic correlations (rA ) of dry weight between competitive regimes were generally large and positive. In no case were they significantly different from 1, as expected under the null hypothesis that the relative performance of the genotypes under consideration is the same in all environments. On the basis of these results, we cannot conclude that the structure of genetic covariation within this population would promote genetic differentiation in response to locally varying conditions of density of these two species. Aspects of the experiment that may have compromised our ability to detect rA differing from 1 are discussed. PMID- 28567897 TI - POWERED FLIGHT IN ARCHAEOPTERYX: RESPONSE TO SPEAKMAN. PMID- 28567898 TI - GENE FLOW, REFUGIA, AND EVOLUTION OF GEOGRAPHIC VARIATION IN THE SONG SPARROW (MELOSPIZA MELODIA). AB - We surveyed mtDNA restriction-site variation in song sparrows taken from across their continental range. Despite marked geographic variation in size and plumage color, mtDNA variation was not geographically structured. Subspecies were not identifiable by mtDNA analysis. We suggest that postglaciation dispersal scattered mtDNA haplotypes across the continent, explaining the lack of mtDNA geographic patterns. Evolution of size and plumage coloration has probably proceeded faster than mtDNA evolution, leading to the well-structured continental pattern of morphological variation. We suggest that the nonordered geographic distribution of haplotypes reflects the recency of population establishment following completion of range expansion. Dispersal distance was estimated from the mtDNA data at 6.1 km per generation, an order of magnitude greater than that (0.3 km) estimated from demographic data. Island samples were not especially different from continental ones. Rooting the haplotype cladogram with a putative primitive haplotype identified Newfoundland and the Queen Charlotte Islands as potential sites of recent refugia. We question whether study of geographic variation in song sparrows leads to insights concerning speciation. PMID- 28567899 TI - ESTIMATION OF GENE FLOW FROM F-STATISTICS. AB - We present theory clarifying the general behavior of FST -based and GST -based estimators of gene flow, and confirm these predictions with simulations. In particular, we use the correlation of genes within groups within populations to define an estimator. The theoretical value of the correlation doe not depend on the number of groups in a population, and properties of the estimated correlation do not depend on the number of groups sampled or the number of individuals sampled per group. This invariance is in contrast to properties of GST . For a complete census of a population, bias and variance considerations would suggest the use of the GST -based estimator of gene flow, but lack of knowledge of population size or group number in practice suggests preference be given to the correlation-based estimator. We acknowledge that these estimators require that several conditions of a population-genetic model be met, since they do not make use of direct observations on the flow of genes. Our results differ from some of those based on simulation in a series of recent papers by M. Slatkin. PMID- 28567900 TI - THE INCREASED POTENTIAL FOR SELECTION OF THE LAC OPERON OF ESCHERICHIA COLI. AB - The fitness effects of six lac operons from natural isolates of Escherichia coli were determined in chemostats, in a test of the idea that selective differences among natural alleles are greater in novel conditions than in the prevailing environment, resulting in a greater genetic variance in fitness in novel conditions. Fitnesses were determined in the common milk sugar lactose, the natural substrate of the lac operon, and in three rare beta-galactosides, lactulose, galactosyl-arabinose, and methyl-galactopyranoside, that are novel for E. coli. Significantly greater fitness differences were observed among the lac alleles in each of the novel beta-galactosides than in lactose. An alternative explanation of the experimental findings is discussed. General evolutionary causes and consequences of selection potentials are discussed, and an outline of the work necessary to further elucidate the physiological basis of the observed potential for selection of the lac operon of E. coli is presented. PMID- 28567901 TI - DOES INCREASED MORTALITY FAVOR THE EVOLUTION OF MORE RAPID SENESCENCE? AB - It is widely believed (following the 1957 hypothesis of G. C. Williams) that greater rates of "extrinsic" (age- and condition-independent) mortality favor more rapid senescence. However, a recent analysis of mammalian life tables failed to find a significant correlation between minimum adult mortality rate and the rate of senescence. This article presents a simple theoretical analysis of how extrinsic mortality should affect the rate of senescence (i.e., the rate at which probability of mortality increases with age) under different evolutionary and population dynamical assumptions. If population dynamics are density independent, extrinsic mortality should not alter the senescence rate favored by natural selection. If population growth is density dependent and populations are stable, the effect of extrinsic mortality depends on the age specificity of the density dependence and on whether survival or reproduction (or both) are functions of density. It is possible that higher extrinsic mortality will increase the rate of senescence at all ages, decrease the rate at all ages, or increase it at some ages while decreasing it at others. Williams's hypothesis is most likely to be supported when density dependence acts primarily on fertility and does not differentially decrease the fertilities of older individuals. Patterns contrary to Williams's prediction are possible when density dependence acts primarily on the survival or fertility of later ages or when most variation in mortality rates is due to variation in nonextrinsic mortality. PMID- 28567902 TI - PATTERNS OF SELECTION ON PHYTOPHAGE RESISTANCE IN IPOMOEA PURPUREA. PMID- 28567903 TI - SURVIVAL OF HYBRIDS IN A MOSAIC HYBRID ZONE. AB - The ground crickets Allonemobius fasciatus and A. socius meet in a mosaic hybrid zone that stretches from New Jersey at least as far west as Illinois. Within mixed populations from the contact zone, "pure" species individuals predominate. To determine whether hybrids are less viable than pure-species individuals, and to assess whether the high proportion of pure-species individuals in mixed populations results from hybrid inviability, we performed a cohort analysis. In this study, five mixed populations from the hybrid zone were each sampled three to five times from the fall of 1986 to the spring of 1988. Individuals were assigned to one of three categories based on their genotypes: A. socius (individuals harboring only alleles unique to A. socius), hybrid (individuals with alleles unique to both species), and A. fasciatus (individuals harboring only alleles unique to A. fasciatus). This sampling and measurement scheme permitted monitoring of the proportion of hybrid individuals in a population over time. The results were fairly consistent. The relative survival of A. socius was greater than the relative survival of members of the other two groups in four of the five populations. The relative viability of A. fasciatus was greater than that of hybrids in one population, approximately equal to that of hybrids in two populations, and less than that of hybrids in two populations. These results not only shed light on an important component of fitness, viability from hatching to adulthood, but they demonstrate that loss of hybrid individuals during the course of the field season will not explain deviations from random mating expectations present in mixed populations in late summer. The deviations must be due to assortative mating or to a reproductive barrier operating prior to egg hatch. PMID- 28567904 TI - CONTRIBUTION OF CRYPTIC INCOMPATIBILITY TO THE MATING SYSTEM OF EICHHORNIA PANICULA TA (PONTEDERIACEAE). AB - Tristylous populations of the annual aquatic Eichhornia paniculata have high levels of outcrossing and intermorph mating despite being fully self- and intramorph compatible. Experimental studies of pollen germination, ***pollen-tube growth, and pollinations with mixtures of genetically marked pollen were used to determine whether postpollination processes contribute to the observed mating patterns. Differences in pollen germination were small and did not contribute to differences in pollen siring ability. The fraction of pollen tubes first entering the ovary, however, was greater for legitimate outcross pollen than for either of the other two pollen types (self or outcross illegitimate pollen) in all recipient morphs. Moreover, legitimate pollen had higher siring success when in competition with illegitimate pollen types (self or outcross) in each recipient style morph. The ranking of pollen performance for different pollen-style combinations was the same for both the pollen-tube growth and marker-gene experiments indicating that differences in pollen-tube growth rate are the principal cause of differences in pollen siring ability. Cryptic incompatibility in E. paniculata may represent a weak heteromorphic incompatibility system because the observed patterns of pollen-tube growth parallel pollen-tube growth and seed-set patterns that occur in related species with strong trimorphic incompatibility. The ability to produce mostly outcrossed progeny when pollinators are abundant, but to reliably produce seed under a variety of environmental and demographic conditions may be favored in E. paniculata because of its colonizing life history and occurrence in ephemeral habitats. Cryptic incompatibility may be more likely to occur in species subject to wide fluctuations in population size and levels of pollinator service. PMID- 28567905 TI - HOMOGENEITY OF THE GENETIC VARIANCE-COVARIANCE MATRIX FOR ANTIPREDATOR TRAITS IN TWO NATURAL POPULATIONS OF THE GARTER SNAKE THAMNOPHIS ORDINOIDES. AB - Quantitative genetic models of evolution rely on the genetic variance-covariance matrix to predict the phenotypic response to selection. Both prospective and retrospective studies of phenotypic evolution across generations rely on assumptions about the constancy of patterns of genetic covariance through time. In the absence of robust theoretical predictions about the stability of genetic covariances, this assumption must be tested with empirical comparisons of genetic parameters among populations and species. Genetic variance-covariance matrices were estimated for a suite of antipredator traits in two populations of the northwestern garter snake, Thamnophis ordinoides. The characters studied include color pattern and antipredator behaviors that interact to facilitate escape from predators. Significant heritabilities for all traits were detected in both populations. Genetic correlations and covariances were found among behaviors in both populations and between color pattern and behavior in one of the populations. Phenotypic means differed among populations, but pairwise comparisons revealed no heterogeneity of genetic parameters between the populations. The structure of the genetic variance-covariance matrix has apparently not changed significantly during the divergence of these two populations. PMID- 28567906 TI - INCREASED HERITABLE VARIATION FOLLOWING POPULATION BOTTLENECKS: THE ROLE OF DOMINANCE. PMID- 28567907 TI - EFFECTS OF DIFFERENT LEVELS OF INBREEDING ON FITNESS COMPONENTS IN MIMULUS GUTTATUS. AB - Recent theoretical work has shown that there can be selection favoring the maintenance of sexual reproduction and the evolution of increased recombination when deleterious mutations at different loci interact synergistically, such that the logarithm of fitness declines at a greater than linear rate with the number of harmful mutations per genome. The purpose of this experimental study was to determine whether synergism exists for genes affecting fitness components in two partially selfing populations of the monkey flower Mimulus guttatus. For each wild population, a large randomly mated base population was constructed and many independent lines, inbred to differing degrees, were extracted from this base population. Lines with expected inbreeding coefficients of 0, 0.25, 0.5, and 0.75 were raised simultaneously in the greenhouse and were scored for germination, flowering, flower production, and pollen viability. All fitness traits except germination success declined with increased inbreeding, but in spite of the substantial inbreeding depression found in this study, relatively little evidence of synergistic epistasis was found. The only trait that showed evidence of synergism was pollen viability. These results indicate that synergism is not strong for the fitness components measured in this study. The evidence for synergism from other published studies is also reviewed. PMID- 28567908 TI - A TEST OF THE "GENERAL-PURPOSE" GENOTYPE HYPOTHESIS: DIFFERENTIAL TOLERANCE TO THERMAL AND SALINITY STRESS AMONG DAPHNIA CLONES. PMID- 28567909 TI - THE GENETICS OF AN ISOLATING MECHANISM BETWEEN TWO SIBLING SPECIES OF DROSOPHILA. AB - Matings between Drosophila simulans females and males of the sibling species D. mauritiana are of abnormally short duration. These rapid matings interrupt the transfer of sperm, leading to substantial reproductive isolation in interspecific as compared to intraspecific copulations. Genetic analysis of this behavior shows that it is influenced much more by the male than the female genotype, with genes from D. simulans being dominant. In males, shortened copulation is caused by interspecific divergence at a minimum of three loci, with one gene on each of the major chromosomes. This is an underestimate of the true number of loci affecting the trait, which could be much larger. The two autosomes have the largest effect, whereas that of the X chromosome is much smaller. The genetic architecture of copulation duration and the larger effect of male than female genotype suggest that females can detect and discriminate against differences in male genitalia. PMID- 28567910 TI - DIFFERENTIAL SUCCESS OF POLLEN DONORS IN A SELF-COMPATIBLE LILY. AB - If pollen donors are equally effective at siring seeds, the presence of equal proportions of pollen from two pollen donors on a stigma will lead to equal proportions of seeds sired by each pollen donor. Variation in germination rates, pollen-tube growth, and embryo viability may cause one donor to sire more seed than another. We looked for differential donor success in the field by simultaneously applying equal amounts of pollen from two pollen donors. We simultaneously applied equal amounts of self and outcross pollen to receptive stigmas and simultaneously applied pollen from two donors at different physical distances from the recipient. Following simultaneous application of self and outcross pollen, significantly more of the seeds were sired by outcross pollen donors. Seed set following simultaneous application of two outcross donors was also nonrandom. Pollen donors from 100 m were more likely to sire seeds when competing with pollen from plants nearby (1 m). To determine whether pollen-tube growth rates were responsible for these patterns of paternity, we varied the timing of deposition of outcross pollen allowing self pollen tubes a head start on the stigma. Outcross pollen was applied 3 or 24 h after self pollen. In spite of this time delay, the majority of the seeds were again sired by outcross pollen. There was no significant difference in the amount of seeds sired by self pollen between the two delay treatments. This result suggests that mechanisms operating after ovule fertilization may contribute to the discordance between the proportions of the pollen present and the proportions of seeds sired. PMID- 28567911 TI - ERRATA. PMID- 28567913 TI - COSTLY POLLEN IN MAIZE. PMID- 28567912 TI - A LIFE-HISTORY BASED STUDY OF POPULATION GENETIC STRUCTURE: SEED BANK TO ADULTS IN PLANTAGO LANCEOLATA. AB - We explored the extent to which the soil seed bank differed genetically and spatially in comparison to two actively growing stages in a natural population of Plantago lanceolata. All seed-bank seeds, seedlings, and adults of P. lanceolata within eight subunits in a larger population were mapped, subjected to starch gel electrophoresis, and allozyme analysis in 1988. Gel electrophoresis was also used to estimate the mating system in two years, 1986 and 1988. The spatial distributions of seeds, seedlings, and adults were highly coincident. Allele frequencies of the dormant seeds differed significantly from those of the adults for four of the five polymorphic loci. In addition, a comparison of the genotype frequencies of the three life-history stages indicated that the seed bank had an excess of homozygotes. Homozygosity, relative to Hardy-Weinberg expectations, decreased during the life cycle (for seed bank, seedlings, and adults respectively: Fit = 0.19, 0.09, 0.01; Fis = 0.14, 0.04, -0.12). Spatial genetic differentiation increased sixfold during the life cycle: (for seed bank, seedling and adults: Fs1 *** = 0.02, 0.05, 0.12). The apparent selfing rate was 0.01 in 1986 and 0.09 in 1988. These selfing rates are not large enough to account for the elevated homozygosity of the seed bank. Inbreeding depression, overdominance for fitness, and a "temporal Wahlund's effect" are discussed as possible mechanisms that could generate high homozygosity in the seed bank, relative to later life-history stages. In Plantago lanceolata, the influence of the mating system and the "genetic memory" of the seed bank are obscured by the time plants reach the reproductive stage. PMID- 28567914 TI - Bedside identification of patients at risk for PVC-induced cardiomyopathy: Is ECG useful? AB - BACKGROUND: Premature ventricular complexes (PVCs) are an underrecognized cause of cardiomyopathy. Standard 12-lead electrocardiogram (ECG) has potential to direct attention toward at-risk patients. METHODS: We performed a single-center, retrospective chart review of 1,240 patients who completed ECG and Holter monitoring at Oregon Health and Science University Hospital between January 1, 2011 and December 31, 2013 to investigate the relationship of PVC frequency on ECG with burden on Holter. Primary outcome measures included PVC quantity on ECG, mean PVC quantity on Holter, and percentage of total beats on Holter recorded as PVCs. High PVC burden was defined as >=10% of total beats. RESULTS: Weighted mean percentages of total beats on Holter monitor recorded as PVCs were calculated for 0, 1, 2, and >=3 PVCs on ECG and found to be 1.4% (n = 1,128), 3.5% (n = 32), 4.3% (n = 25), and 16.6% (n = 55), respectively, which represent statistically significant differences (P < 0.001). The positive predictive value of at least three PVCs on ECG for >=10% PVC Holter burden was 58%. Negative predictive value for 0 PVCs on ECG was 98%. The sensitivity and specificity of ECG to identify high PVC burden on Holter was 72% and 93.6%, respectively, when utilizing a positive ECG result as one PVC or more, and 44% and 98.9%, respectively, with >=3 PVCs on ECG. The positive likelihood ratio corresponding to >=3 PVCs on ECG was 40. CONCLUSION: These findings demonstrate that the number of PVCs on ECG can be utilized for quick bedside estimation of high PVC burden. PMID- 28567915 TI - COMPARATIVE MORPHOMETRIC ADAPTATION OF THE HOUSEFLY AND THE FACE FLY IN THE UNITED STATES. PMID- 28567916 TI - THE TAILSPOT POLYMORPHISM OF XIPHOPHORUS (PISCES: POECILIIDAE). PMID- 28567917 TI - EDITOR'S NOTE: CORRECTIONS AND CLARIFICATIONS FOR LACTATE DEHYDROGENASE ISOZYMES IN TELEOSTS (TOLEDO AND RIBEIRO, VOL. 32:212-216). PMID- 28567918 TI - DOMINANCE, SURVIVAL, AND ENZYME POLYMORPHISM IN DARK-EYED JUNCOS, JUNCO HYEMALIS. PMID- 28567920 TI - LABORATORY SYNTHESIS OF A PSEUDOGAMOUS TRIPLOID "SPECIES" OF THE GENUS MUELLERIANELLA (HOMOPTERA, DELPHACIDAE). PMID- 28567919 TI - GENETIC DIFFERENTIATION IN TWO MEMBERS OF THE DROSOPHILA ATHABASCA COMPLEX. PMID- 28567922 TI - RELATIVE BRAIN SIZE AND FEEDING STRATEGIES IN THE CHIROPTERA. PMID- 28567923 TI - EFFECTIVE POPULATION SIZE AND INTERDEMIC MIGRATION RATES IN A METAPOPULATION OF THE RED-SPOTTED NEWT, NOTOPHTHALMUS VIRIDESCENS (RAFINESQUE). PMID- 28567924 TI - THE HANDICAP PRINCIPLE IN SEXUAL SELECTION. PMID- 28567925 TI - AN ANALYSIS OF GENETIC STRUCTURE IN THE MONARCH BUTTERFLY, DANAUS PLEXIPPUS L. PMID- 28567926 TI - FREQUENCY-DEPENDENT SELECTION: WHAT IS THE PROBLEM? PMID- 28567927 TI - NOTICE CHANGES IN JOURNAL POLICIES. PMID- 28567928 TI - TEMPORAL PATTERNS OF ALLOZYMIC VARIATION IN FLUCTUATING POPULATIONS OF MICROTUS OCHROGASTER. PMID- 28567929 TI - BIOLOGY OF ECOLOGICALLY MARGINAL POPULATIONS OF ANTHOXANTHUM ODORATUM. I. PHENETICS AND DYNAMICS. PMID- 28567930 TI - THERMOREGULATORY ADAPTATIONS ALLOWING ECOLOGICAL RANGE EXPANSION BY THE PIERID BUTTERFLY, NATHALIS IOLE BOISDUVAL. PMID- 28567931 TI - PROGRESSIVE VACATING OF ADAPTIVE TYPES DURING THE PHANEROZOIC. PMID- 28567933 TI - SEX RATIOS IN TROPICAL FOREST TREES. PMID- 28567934 TI - MODIFIERS AND "SEX RATIO" IN DROSOPHILA PSEUDOOBSCURA. PMID- 28567935 TI - FEMALE CHOICE AND THE MATING STRUCTURE OF A NATURAL POPULATION OF THE SOLDIER BEETLE, CHAULIOGNATHUS PENNSYLVANICUS. PMID- 28567936 TI - THE EVOLUTION AND LOSS OF FEEDING LARVAL STAGES OF MARINE INVERTEBRATES. PMID- 28567939 TI - SELECTION FOR AMYLASE ALLOZYMES IN D. MELANOGASTER: A WORD OF CAUTION. PMID- 28567938 TI - SONG DIALECTS AS BARRIERS TO DISPERSAL IN WHITE-CROWNED SPARROWS, ZONOTRICHIA LEUCOPHRYS NUTTALLI. PMID- 28567940 TI - PRIMATE SKELETAL ALLOMETRY AND HOMINOID EVOLUTION. PMID- 28567941 TI - THE EVOLUTION OF MATING STRATEGIES IN BULLFROGS, RANA CATESBEIANA. PMID- 28567942 TI - DEVELOPMENTAL STABILITY IN SPECIES HYBRID AND BACKCROSS PROGENIES OF DROSOPHILA. PMID- 28567943 TI - REPLY TO SHIELDS ON AVIAN WINTER PLUMAGE VARIABILITY. PMID- 28567944 TI - ANALYSIS OF A NARROW HYBRID ZONE BETWEEN TWO SPECIES OF PSEUDOPHRYNE (ANURA: LEPTODACTYLIDAE) IN SOUTH-EASTERN AUSTRALIA. PMID- 28567945 TI - GENETIC VARIATION AMONG TYPHA POPULATIONS OF THE SOUTHEASTERN UNITED STATES. PMID- 28567946 TI - ETHOLOGICAL ISOLATION AND PHYLOGENY IN THE GRIMSHAWI SPECIES COMPLEX OF HAWAIIAN DROSOPHILA. PMID- 28567947 TI - COURTSHIP AND MATING SOUNDS IN SPECIES OF THE DROSOPHILA AFFINIS SUBGROUP. PMID- 28567948 TI - THE FOUNDER-FLUSH SPECIATION THEORY: AN EXPERIMENTAL APPROACH. PMID- 28567949 TI - THE EVOLUTION OF PARENTAL CARE IN BIRDS. PMID- 28567950 TI - GENETIC VARIABILITY IN THE KENTUCKY CAVE BEETLE NEAPHAENOPS TELLKAMPFII (COLEOPTERA: CARABIDAE). PMID- 28567951 TI - EVOLUTION IN HAWAIIAN DROSOPHILIDAE. III. THE MICROCHROMOSOME AND HETEROCHROMATIN OF DROSOPHILA. PMID- 28567952 TI - INTRA-POPULATION DIFFERENTIATION IN ANNUAL PLANTS. II. ELECTROPHORETIC VARIATION IN VERONICA PEREGRINA. PMID- 28567953 TI - GENETIC DIFFERENTIATION, ALBUMIN EVOLUTION, AND THEIR BIOGEOGRAPHIC IMPLICATIONS IN PLETHODONTID SALAMANDERS OF CALIFORNIA AND SOUTHERN EUROPE. PMID- 28567954 TI - THE GENETICS OF SPECIATION IN THE RODENT GENUS PEROMYSCUS. PMID- 28567955 TI - EXPERIMENTAL HYBRIDIZATION BETWEEN THE NYMPHALID BUTTERFLIES PHYCIODES THAROS AND P. CAMPESTRIS MONTANA. PMID- 28567956 TI - RESOURCE PREDICTABILITY AND NICHE BREADTH IN THE DROSOPHILA QUINARIA SPECIES GROUP. PMID- 28567957 TI - GENETIC DIFFERENTIATION WITHOUT ISOLATION IN THE AMERICAN EEL, ANGUILLA ROSTRATA. II. TEMPORAL STABILITY OF GEOGRAPHIC PATTERNS. PMID- 28567958 TI - REPRODUCTIVE COMPENSATION IN TRIBOLIUM CASTANEUM. PMID- 28567959 TI - ALLOMETRY AND JUMPING IN FROGS: HELPING THE TWAIN TO MEET. PMID- 28567960 TI - SPERM COMPETITION, MALE FITNESS, AND REPEATED MATING BY FEMALE DROSOPHILA MELANOGASTER. PMID- 28567961 TI - WHY ARE PISTILLATE INFLORESCENCES OF SIMAROUBA GLAUCA EATEN LESS THAN STAMINATE INFLORESCENCES? PMID- 28567962 TI - ECOLOGICAL AND EVOLUTIONARY RELATIONSHIPS AMONG DIPLOID AND TRIPLOID UNISEXUAL FISHES ASSOCIATED WITH THE BISEXUAL SPECIES, POECILIOPSIS LUCIDA (CYPRINODONTIFORMES: POECILIIDAE). PMID- 28567963 TI - RESOURCE PARTITIONING IN PASSION VINE BUTTERFLIES. PMID- 28567964 TI - CHROMOSOMAL EVOLUTION AND THE MODE OF SPECIATION IN THREE SPECIES OF PEROMYSCUS. PMID- 28567965 TI - NOTICE CHANGES IN JOURNAL POLICIES. PMID- 28567966 TI - Autoimmune neutropenia of childhood secondary to other autoimmune disorders: Data from the Italian neutropenia registry. PMID- 28567968 TI - Sudden Death by Spontaneous Epiglottic Hematoma Secondary to High Blood Levels of Warfarin. AB - A 67-year-old man was found dead, at his home. On external examination, we found a voluminous purplish black ecchymosis of the anterior neck area. On internal examination, we found a voluminous epiglottis hematoma completely obstructing the upper airway. It was associated with other sites of intra-abdominal hemorrhage. Toxicological studies revealed the presence of warfarin at a concentration of 8.4 mg/L in peripheral blood, which supposes an INR well above 4.5. To conclude, we supposed death was due to asphyxia secondary to a spontaneous epiglottic hematoma caused by a high blood concentration of warfarin. Hemorrhage in the epiglottis is very rare. To our knowledge, our patient is the only case of "sudden death" reported with spontaneous epiglottic hematoma due to high blood concentration of warfarin. In forensic practice, an anterior neck ecchymosis, without trauma, may suggest hemorrhage into soft airway tissues. Pathology findings make it possible to exclude exogenous trauma. PMID- 28567970 TI - ORIGIN AND SUBSTITUTION OF B CHROMOSOMES IN THE GRASSHOPPER EYPREPOCNEMIS PLORANS. PMID- 28567969 TI - HOST EFFECTS ON FERTILITY AND REPRODUCTIVE SUCCESS OF DENDROCTONUS PONDEROSAE HOPKINS (COLEOPTERA: SCOLYTIDAE). AB - Mountain pine beetles from lodgepole and limber pine in western Canada were crossbred. We compared data about reproductive success and fecundity of parents as well as development, mortality, and fertility of their progeny to determine whether there was reproductive isolation among beetle populations in these hosts. Three factors, directly or indirectly related to the host, influenced reproductive performance of parents (reproductive success, egg gallery length, fecundity, and number of eggs laid per centimeter of gallery) as well as the mortality, dry weight, and fat content of the progeny: (1) the host species in which progeny were reared, (2) the host species in which the female parent was reared, and (3) whether both parents originated from the same or different host species. Limber pine appears to be a better host for Dendroctonus ponderosae reproduction and survival than lodgepole pine. Nonetheless, beetles reared from lodgepole and limber pine can reproduce in either host and will mate with each other. Progeny of all crosses were fertile. Thus, there is no apparent barrier to prevent beetles from the two host species from interbreeding in the field. PMID- 28567967 TI - Evaluation of genetic variants in association with colorectal cancer risk and survival in Asians. AB - Genome-wide association studies (GWAS) have identified over 40 genetic loci associated with colorectal cancer (CRC) risk. The association of single nucleotide polymorphisms (SNPs) at these loci with CRC risk and survival has not been adequately evaluated in East Asians. GWAS-identified CRC risk variants were used to construct weighted genetic risk scores (GRSs). We evaluated these GRSs in association with CRC risk in 3,303 CRC cases and 3,553 controls using logistic regression models. Associations with overall and CRC-specific survival were assessed in 731 CRC patients using Cox regression models. The association between the GRSs (overall and Asian-specific) and CRC risk was approximately twofold (highest vs. lowest quintile), and the shape of the dose-response was linear (ptrend = 1.24 * 10-13 and 3.02 * 10-14 for overall GRS and Asian-specific GRS, respectively). The association of the GRS with CRC risk was stronger among those with a family history of CRC (pinteraction = 0.007). Asian-specific GRS using previously reported survival SNPs increased risk for mortality and the shape of the dose-response was linear for CRC-specific and all-cause mortality (ptrend = 0.01 and 0.006, respectively). Furthermore, the minor alleles of rs6983267 and rs1957636 were associated with worse CRC-specific and overall survival. We show that GRSs constructed using GWAS-identified common variants are strongly associated with CRC risk in Asians. We confirm previous findings for the possible association between some SNPs with survival, and provide evidence for two additional CRC risk variants that may be related to CRC survival. PMID- 28567971 TI - SEXUAL SELECTION THROUGH FEMALE CHOICE IN LAWES' PAROTIA, A LEK-MATING BIRD OF PARADISE. AB - We studied sexual selection in Lawes' Parotia, a lek-mating bird of paradise, during 1981-1983 in Papua New Guinea. There was a high variance in mating success among males, with fewer than half of the individuals mating in any one year. This variance was independent of male-male interactions and disruptions. A role of female choice in sexual selection was suggested by the patterns of female visitation to courts and statistical correlations across males between phenotypic traits and mating success. Females repeatedly visited most males in their home ranges and began visiting males up to six weeks before mating. In one or more years, six aspects of male behavior and one morphological variable were positively correlated with mating success, but the probability values were not significant using a simultaneous inference test. Calculation of combined probability values across all three years revealed that one aspect of male display behavior, the probability of display, positively and significantly influenced mating status. The probability of display was also significantly correlated with relative mating success among males. Females showed strong fidelity to mates, both within and between seasons. Display sites of male Lawes' Parotia are variably dispersed, but mating success did not differ for grouped and solitary males. These data confirm an important role of female choice in sexual selection in birds of paradise but also suggest that female choice may be unrelated to the process of lek-initiation in this species. PMID- 28567972 TI - TETRODOTOXIN RESISTANCE IN GARTER SNAKES: AN EVOLUTIONARY RESPONSE OF PREDATORS TO DANGEROUS PREY. AB - The use of the "arms race" analogy as a conceptualization of evolutionary predator-prey interactions has been criticized because of the lack of evidence that predators can and do adapt to increased antipredator ability of prey. We present evidence that the garter snake Thamnophis sirtalis has evolved resistance to tetrodotoxin (TTX) in response to the toxicity of the newt Taricha granulosa on which the snake feeds. A bioassay (locomotor performance before and after injection of TTX) was used to obtain repeated measures of resistance for individual snakes. We studied interpopulation and interspecific variation by comparing resistance in Thamnophis sirtalis from populations occurring sympatrically and allopatrically with Taricha granulosa, and in Thamnophis ordinoides (which does not feed on the newt) occurring sympatrically with Taricha granulosa. We also examined intrapopulation variation in TTX resistance using snakes from a population known to feed on Taricha granulosa. Resistance differed significantly among individuals and litters; repeatability and heritability estimates of the assay were significantly different from zero, demonstrating the potential for response to selection. The population of Thamnophis sirtalis that occurs with Taricha granulosa exhibited levels of resistance much greater than either of the other groups. These results suggest that the predator-prey arms race analogy may be applicable to this system. PMID- 28567973 TI - A PHYLOGENETIC ANALYSIS OF CHARACTER DISPLACEMENT IN CARIBBEAN ANOLIS LIZARDS. AB - Twenty-seven islands in the Lesser Antilles contain either one or two species of Anolis lizards. On nine of the ten two-species islands, the species differ substantially in size; 16 of the 17 one-species islands harbor an intermediate sized species. Two processes could produce such a pattern: size adjustment (or character displacement), in which similar-sized species evolve in different directions in sympatry; and size assortment, in which only different-sized species can successfully colonize the same island together. Previous analyses implicitly have assumed that size is evolutionarily plastic and determined solely by recent ecological conditions, and consequently have tested the hypothesis that character displacement has occurred on each of the ten two-species islands. Other studies have focused only on size assortment. By analyzing such patterns in a phylogenetic context, I explicitly consider historical effects and can distinguish between size adjustment and size assortment. Using a minimum evolution algorithm, I assess evidence for size adjustment by partitioning changes in size along branches of the phylogenetic tree. Size evolution appears rare (a minimum of 4-7 instances of substantial size evolution). In the northern (but not the southern) Lesser Antilles, size change was significantly greater when a descendant taxon occurred on a two-species island and its hypothetical ancestor occurred on a one-species island, thus supporting the size adjustment hypothesis, though size adjustment might have occurred only once. The relative rarity of size evolution suggests that size assortment might be responsible for nonrandom patterns. In both the northern and southern Lesser Antilles, a null model of no size assortment is convincingly rejected. Closely related taxa, however, are usually similar in size, and hybridization between species has been reported. Consequently, similar-sized species might not coexist because they interbreed and coalesce into one gene pool. A null model that only allows species from different "clades" to co-occur is rejected for the northern Lesser Antilles, but is ambiguous with regard to the southern Lesser Antilles. Thus, competitive exclusion is probably responsible for the pattern of size assortment in the northern Lesser Antilles; both competitive exclusion and interbreeding of closely related species of similar size might be responsible for the patterns evident in the southern Lesser Antilles. PMID- 28567974 TI - ECOLOGICAL AND EVOLUTIONARY STABILITY OF SPERM-DEPENDENT PARTHENOGENESIS: EFFECTS OF PARTIAL NICHE OVERLAP BETWEEN SEXUAL AND ASEXUAL FEMALES. AB - Pseudogamous females reproduce parthenogenetically but require sperm. We analyze a density- and frequency-dependent model for the ecological and evolutionary stability of bisexual populations exposed to invasion by pseudogamous clones. In particular, we examine the effects of partial niche overlap and asymmetric competition between sexual and asexual forms. The model predicts that for a variety of relative fitness values for asexual females, pseudogamous forms can successfully invade bisexual populations. The probability of successful invasion increases as niche overlap decreases. Furthermore, invaded populations are often likely to be stable; for the parameter values analyzed, only combinations of nearly complete niche overlap and high asexual fitness will lead to extinction. Even such combinations will be stable under pronounced asymmetric competition. Asymmetric competition does not, however, affect the invadability of bisexual populations. The model predicts that stable populations cannot have more than three or four females per male; populations with more biased sex ratios are expected to be unstable. We analyze available sex ratio data for pseudogamous insects, fish, and salamanders, and find significant changes in roughly one-half of the asexual-dominated populations, but in only one sexual-dominated population. This analysis includes previously unpublished data on population sex ratios in a pseudogamous bark beetle, Ips acuminatus. Some asexual-dominated populations have far more than four females per male, contrary to predictions of the model. PMID- 28567975 TI - REGIONAL, LOCAL AND MICROGEOGRAPHIC ALLELE FREQUENCY VARIATION BETWEEN APPLE AND HAWTHORN POPULATIONS OF RHAGOLETIS POMONELLA IN WESTERN MICHIGAN. AB - In the preceding study (Feder et al., 1990), we report that paired apple and hawthorn infesting populations of Rhagoletis pomonella are genetically differentiated for six allozymes. Here, we show that patterns of intra- and inter host allele frequency variation seen for these six loci across the eastern United States are consistent on a more fine grained spatial scale in western Michigan. Malic enzyme, Aconitase-2, Mannose phosphate isomerase, and Hydroxyacid dehydrogenase all displayed significant linear relationships with latitude among five "regional" hawthorn populations sampled along a north-south transect between the cities of Cadillac and Portage, Michigan. Clines were not as evident among "regional" apple populations in western Michigan, although allele frequencies for Malic enzyme100 , Mannose phosphate isomerase100 and Aconitase-295 varied with latitude among six "local" apple populations within a 60 km2 area near the town of Grant. Significant allele frequency differences were observed between hawthorn and apple populations at all "regional" and "local" collecting sites analyzed in the study (a total of 20 different apple and hawthorn populations). As was the case in the geographic survey of the eastern United States, the magnitude and pattern of inter-host frequency differences at "regional" and "local" sites were a function of latitude. Host related genetic differentiation was consistent on a "microgeographic" scale as well. Allele frequencies for Malic enzyme100 and Aconitase-295 were significantly higher over a four-year period (1984 to 1987) for flies sampled from individual hawthorn trees (N = 6) than apple trees (N = 7) within an old field (0.09-km2 area) located near Grant. The fine level of genetic subdivision between hawthorn and apple populations of R. pomonella in western Michigan substantiates the existence of host associated polymorphism in the fly and supports a sympatric mode of divergence for the "apple race". PMID- 28567976 TI - HABITAT SELECTION AS AN EVOLUTIONARY GAME. AB - Under habitat selection, mobile foragers may not only possess behavioral flexibility that allows them to utilize habitats selectively or opportunistically, but they may also possess heritable traits that influence their performance within each habitat. A game theoretic model is developed that investigates this evolutionary dimension of habitat selection. The model follows that of Rosenzweig (1987b) and considers a patchy environment containing two distinct habitat types. Behaviorally, foragers may be selective or opportunistic; morphologically, foragers possess traits that represent a trade-off between performance in the two habitat types. Depending on the environment's structure, one of three types of communities emerges as the ESS: (1) a single generalist species that behaves opportunistically, (2) two species that are extreme specialists on habitat 1 and 2, respectively; behaviorally, these species are selective on their respective habitat types, and (3) one generalist species that behaves opportunistically and one specialist species that behaves selectively on its preferred habitat. Community (1) emerges when habitat selection is costly, community (2) emerges when habitat selection is cost-free, and community (3) emerges when the relative abundances or productivities of the two habitat types are lopsided. PMID- 28567977 TI - MECHANISMS OF FEMALE CHOICE IN RED JUNGLE FOWL. AB - We examined mate preference behavior in red jungle fowl, Gallus gallus, to determine if the mechanism of mate preference used by females was relative or absolute. Under a relative model, females compare males and prefer the one with the most exaggerated form of secondary sex character, regardless of where the proffered males lie along the population distribution of the trait. Under an absolute or threshold model, females have a threshold for the character, above which they will exert a preference and below which they will not. Female red jungle fowl preferred roosters with longer combs and redder irises, but this preference was exerted only when hens mated quickly; females mating slowly mated at random. The threshold model was supported in two ways: i) chosen males from the fast-mating group had larger combs than chosen males in the slow-mating group; ii) when the same female was presented with two pairs of males in two different trials, one large-combed pair and one small-combed pair, hens mated significantly more slowly, and often refused to mate, when only short-combed roosters were available. Hens thus alter their behavior depending on the males they see, and they may not exert a preference at all if both males fall below the threshold. Further corroborating evidence comes from a set of mate choice trials using underdeveloped roosters, in which males had small combs and females mated slowly or did not mate. The method of choice used by females could affect the speed with which correlations develop between the genes for male traits and genes for female preferences. Sexual selection for good genes may be more consistent with an absolute than a relative method of female choice. PMID- 28567978 TI - GENETIC COMPONENTS OF VARIATION IN ENERGY STORAGE IN DROSOPHILA MELANOGASTER. AB - One approach to examining the underlying genetic structure of the variation in a continuous phenotype is to measure a set of possibly mechanistically related traits and determine the quantitative genetic aspects of their transmission. In this study the quantities of stored triacylglycerol and glycogen were measured along with the activities of 10 enzymes in related metabolic pathways in a set of 1,157 half-sib families of Drosophila melanogaster. The families were structured with each male being mated to 10 females and two offspring were scored from each female. Parents and offspring were scored for the phenotypes, and the components of variance (additive, dominance, and environmental) were estimated in three ways, including analysis of variance on offspring alone, parent-offspring regression, and maximum likelihood methods. While there were differences among the estimates made by the three methods, a consistent result was that substantial additive genetic variation was detected for all the traits. Consistent with models for the quantitative genetics of enzyme kinetics, the genetic variances of global properties were largely additive. Previous studies with extracted chromosome lines had indicated several significant genetic correlations among these characters, and much of the correlation was attributable to additive effects. The results imply that there is substantial opportunity for natural or artificial selection to act on quantities of stored lipid and carbohydrate, and that the response to selection is likely to be in part mediated by changes in the kinetics of the enzymes targeted in this study. PMID- 28567979 TI - A METHOD FOR TESTING THE CORRELATED EVOLUTION OF TWO BINARY CHARACTERS: ARE GAINS OR LOSSES CONCENTRATED ON CERTAIN BRANCHES OF A PHYLOGENETIC TREE? AB - A method is presented for assessing whether changes in a binary character are more concentrated than expected by chance on certain branches of a phylogenetic tree. It can be used to test for correlated evolution of two characters by asking whether changes in the first character are significantly concentrated on those branches on which the second character has a specified state. Thus, one could test whether this specified state is associated with, and thus might enable or select, gains or losses in the first character. The probability of achieving a concentration as or more extreme than that observed under the null hypotheses that changes are distributed randomly on the cladogram is obtained by calculating (a) the number of ways that n gains and m losses can be distributed on the cladogram and (b) the number of ways that p gains q losses can be distributed on the branches of interest given n gains and m losses in the cladogram overall. Summing (b) for appropriate p and q then dividing by (a) yields the desired probability. Simulations suggest that biases resulting from errors in parsimony reconstructions of ancestral states are not extreme. PMID- 28567980 TI - STATISTICAL TESTS OF PHENOGRAMS BASED ON GENETIC DISTANCES. AB - Methods used for estimating the confidence levels of UPGMA-type phenograms based on molecular-genetic data are examined. The methods based on internodal variances or on bootstrapping over characters are compared by simulating a three-species phylogeny with a trifurcation. The bootstrap method seems slightly better in this comparison. Weighting of OTU's when constructing the phenogram is also examined. A method that weights each OTU according to the estimated independent evolutionary information, a modified WPGMA, appears slightly better than UPGMA in estimating the branching points and branch lengths. The methods are applied to the data on restriction sites in eight Hawaiian Drosophila species. The significance of the clusters among them differ from those reported earlier. PMID- 28567981 TI - QUANTITATIVE VARIATION IN FINITE PARTHENOGENETIC POPULATIONS: WHAT STOPS MULLER'S RATCHET IN THE ABSENCE OF RECOMBINATION? AB - Finite parthenogenetic populations with high genomic mutation rates accumulate deleterious mutations if back mutations are rare. This mechanism, known as Muller's ratchet, can explain the rarity of parthenogenetic species among so called higher organisms. However, estimates of genomic mutation rates for deleterious alleles and their average effect in the diploid condition in Drosophila suggest that Muller's ratchet should eliminate parthenogenetic insect populations within several hundred generations, provided all mutations are unconditionally deleterious. This fact is inconsistent with the existence of obligatory parthenogenetic insect species. In this paper an analysis of the extent to which compensatory mutations can counter Muller's ratchet is presented. Compensatory mutations are defined as all mutations that compensate for the phenotypic effects of a deleterious mutation. In the case of quantitative traits under stabilizing selection, the rate of compensatory mutations is easily predicted. It is shown that there is a strong analogy between the Muller's ratchet model of Felsenstein (1974) and the quantitative genetic model considered here, except for the frequency of compensatory mutations. If the intensity of stabilizing selection is too small or the mutation rate too high, the optimal genotype becomes extinct and the population mean drifts from the optimum but still reaches a stationary distribution. This distance is essentially the same as predicted for sexually reproducing populations under the same circumstances. Hence, at least in the short run, compensatory mutations for quantitative characters are as effective as recombination in halting the decline of mean fitness otherwise caused by Muller's ratchet. However, it is questionable whether compensatory mutations can prevent Muller's ratchet in the long run because there might be a limit to the capacity of the genome to provide compensatory mutations without eliminating deleterious mutations at least during occasional episodes of sex. PMID- 28567982 TI - INSECT PHENOLOGY MEDIATED BY HOST-PLANT WATER RELATIONS. AB - Water relations of host plants modify Enchenopa binotata life histories by mediating the termination of egg dormancy, thereby promoting synchronization of egg hatch. Dormant eggs must undergo dehydration and subsequent hydration to begin development. Dehydration of eggs is brought about in the field by declining water levels in branches during the fall and by prolonged cold. Hydration of eggs occurs when sap begins to rise in early spring. Since the ascent of sap occurs at different times in the six species of Enchenopa host plants, the phenology of egg hatch and adult maturation are allochronic. Shifts to novel host plants differing in phenology promote asynchrony of Enchenopa life histories among host-plant species. Thus, the host plant acts as an extrinsic disruptive factor that may promote genetic divergence and temporal reproductive isolation in Enchenopa. PMID- 28567983 TI - OPTIMIZATION MODELS, QUANTITATIVE GENETICS, AND MUTATION. AB - The process of selection on a multivariate set of characters subject to functional constraints is considered from the points of view of both evolutionary optimization theory and quantitative genetics. Special attention is given to life history characteristics. It is shown that, under suitable conditions (including weak selection), useful approximate formulas for the relations between the functional constraints and the additive genetic variance-covariance matrix can be derived. These can be used to show that the conditions for equilibrium under selection according to the two different approaches are approximately equivalent. Although large negative genetic correlations are to be expected between some pairs of life-history traits in populations at equilibrium under selection, in general some small negative genetic correlations and some positive genetic correlations will also be present. Thus, the observation of a positive genetic correlation between a pair of life-history traits does not necessarily refute the possibility of trade-offs among a multivariate set of traits that contains the pair in question. The relation between the pattern of functional constraints and the genetic correlations is often complex, and little insight into the former can be derived from the latter. The effects of mutations that lower the overall efficiency of resource utilization, thereby creating a positive component to the genetic covariances among life-history traits, are also considered for a specific model. Although such mutations can have a substantial effect on the form of the life history, extreme conditions seem to be needed for them to produce a large effect on the pattern of genetic correlations in a random-mating population. They can, however, cause the appearance of positive correlations following inbreeding, due to the exposure of deleterious recessive or partially recessive mutations. The analysis also suggests that the population means of individual components of a constrained multivariate system may often equilibrate at values that are far from the optima that would be attained if they were selected in isolation from the other members of the system. PMID- 28567984 TI - CORRELATED RESPONSE IN THE DEVELOPMENTAL CHOREOGRAPHIES OF THE MOUSE MANDIBLE TO SELECTION FOR BODY COMPOSITION. AB - The correlated response to 13 generations of selection for percent fatness and leanness is investigated in 11 mandible traits in mice. Five selection lines are examined including high fat (HF), low fat (LF), high lean (HL), low lean (LL) and a randomly selected control strain (RC. The ontogenetic patterns of growth in the RC strain serve as a model to evaluate the developmental consequences of directional selection. Selection has systematically altered the patterns of mandible growth in selection lines relative to the control strain. Further, selection has significantly altered the age-specific phenotypic covariance among these traits. In the HF strain, growth in the mandible is completed by 12 weeks of age for most traits. In other selected strains, notably LF and LL, there is a significant growth spurt that occurs between 12 and 15 weeks of age. Changes in the patterns of mandibular growth produce significant differences among strains in the final form of the mandible. Because of the changes in the patterns of growth, the differences among strains are themselves shown to vary at different postnatal ages. The phenotypically similar strains, i.e., HF and LL or LF and HL, show different but correlated patterns of divergence. Multivariate statistical analyses suggest that the temporal strain differences in these traits are multidimensional. PMID- 28567985 TI - HOST-PLANT-INDUCED ASSORTATIVE MATING IN ENCHENOPA TREEHOPPERS. AB - The hypothesis tested here is whether extrinsic host-plant-induced life-history timing and mating biology promote assortative mating along host-plant lines. In the arboreal, univoltine Enchenopa treehopper system, host plants mediate the timing and synchronization of egg hatch. The result is a uniform age structure with a restricted mating window during which females mate once. Enchenopa on host plants that differ in phenology have asynchronous life histories and mating windows, suggesting that temporal differences may promote assortative mating. To test this hypothesis, egg hatch of Enchenopa from the same host-plant species was manipulated to produce continuous adult age-classes. Under experimental conditions with no spatial barriers, mating occurred between individuals similar in age. The mechanism promoting this assortative mating is differential mortality in males and females, such that few males are still alive when females in successive age-classes mate. Such host-plant-induced assortative mating is viewed as an effective mechanism to protect the integrity of gene pools from migrants, permitting selection for host-plant-adapted genotypes and speciation. PMID- 28567986 TI - THE MATING SYSTEM GENETICALLY AFFECTS OFFSPRING PERFORMANCE IN WOODHOUSE'S TOAD (BUFO WOODHOUSEI). AB - To determine if the nonrandom, non-resource-based mating system of Bufo woodhousei affects tadpole performance, I performed a series of controlled matings and reared the tadpoles to metamorphosis in the laboratory and field. I asked whether differences in paternal identity, mating status, or body size were related to differences in tadpole mass, larval period duration, metamorphic mass, or survival of offspring. Although both laboratory and field rearings indicated that male and female parentage affected most offspring traits, no correspondence existed between either laboratory and field metamorphic mass or laboratory and field survival of offspring sired by the same male. The lack of correspondence between sire breeding values in the laboratory and field for two of three traits raises doubts as to the validity of drawing conclusions concerning how evolution might be expected to work from laboratory studies. Paternal effects were more pronounced in the field than in the laboratory, despite what is usually presumed to be a greater amount of environmental variation in the field. In the laboratory neither sire body size nor mating status affected any trait, but in the field larger males produced offspring that were 10% heavier at transformation than offspring sired by small males. This predictable relationship between sire phenotype (body size) and offspring performance means that nonrandom mating based on male body size could have a directional effect on offspring performance. Because larger males mate disproportionately often in this population (Woodward, 1982a; Mitchell, unpubl.), the mating system may exert a directional effect on metamorphic body size. PMID- 28567987 TI - MULTIVARIATE PHENOTYPIC DIFFERENTIATION AMONG BOTTLENECK LINES OF THE HOUSEFLY. AB - Multivariate phenotypic differentiation in eight morphometric traits was examined in bottleneck lines of the housefly initiated with one, four, or 16 pairs of flies from a natural outbred population. Differentiation was assessed using a Mahalanobis' distance metric in units of additive genetic variance and covariance estimated from the ancestral population (i.e., generalized genetic distance). This distance metric was partitioned into contributions of size and shape to total distance. Bottleneck lines of all sizes diverged significantly from the ancestral line, but the direction of these shifts differed among the lines of different initial founding size. Those populations founded with single pairs diverged from the ancestral line mostly in shape; the 16-pair lines differentiated almost entirely in size, and the four-pair lines were intermediate in the relative contribution of shape to differentiation from the control. Bottlenecks serve to alter the genetic relationships among traits within the derived populations and in doing so could promote speciation by permitting differentiation of the populations along evolutionary trajectories less accessible to the base population. PMID- 28567988 TI - THE GEOGRAPHIC PATTERN OF GENETIC DIFFERENTIATION BETWEEN HOST ASSOCIATED POPULATIONS OF RHAGOLETIS POMONELLA (DIPTERA: TEPHRITIDAE) IN THE EASTERN UNITED STATES AND CANADA. AB - True fruit flies in the Rhagoletis pomonella sibling species group are at the center of a long-standing debate concerning modes of speciation. The allopatric separation of populations is widely thought to be a prerequisite for speciation in sexually reproducing animals. However, speciation in the R. pomonella group appears to have occurred sympatrically as a consequence of these flies shifting and adapting to new host plants. The sympatric shift of R. pomonella from its native host hawthorn to introduced domestic apple, which occurred approximately 150 years ago, provides a test of whether host specialization is sufficient to allow populations to differentiate in the absence of geographic barriers to gene flow. We report the results of a geographic study of allozyme variation for hawthorn and apple infesting populations of R. pomonella across the eastern United States and Canada. Six loci consistently show significant allele frequency differences at paired apple and hawthorn sites. These six loci map to three different regions of the genome, and linkage disequilibrium exists between non allelic genes within each of these regions. Allele frequencies for five of the six loci displaying host associated differences also co-vary significantly with latitude. Inter-host divergence is, therefore, superimposed on north-south clinal patterns of intra-host variation such that the magnitude of genetic divergence between hawthorn and apple flies is a function of latitude. The findings suggest that partially reproductively isolated "host races" can evolve in sympatry as a consequence of R. pomonella infesting new host plants. Host recognition and host associated developmental traits are discussed as important factors differentiating apple and hawthorn flies. PMID- 28567990 TI - GENE INTERACTION AFFECTS THE ADDITIVE GENETIC VARIANCE IN SUBDIVIDED POPULATIONS WITH MIGRATION AND EXTINCTION. AB - We investigated the effect of nonadditive genetic variance on the amount of additive genetic variance within local populations in an infinite-allele, infinite-island model with migration, extinction, and recolonization, using two locus descent measures. For an island model with extinction, one- and two-locus descent measures are expressed in a matrix form that allows equilibrium solutions to be calculated similar to previous work on Wright's F-statistics. In a subdivided population, the additive genetic variation within a local deme depends on the dominance and epistatic genetic variation in the species. Moreover, to a good approximation, the amount of additive variance within a deme is a simple function of Fst , which is twice the demic fraction of genic variance. At equilibrium, it is equal to (1 - Fst ) VA plus 4 Fst (1 - Fst ) VA*A , where VA and VA*A are the additive and additive * additive epistatic variances at the level of the species, respectively, plus a contribution from the dominance variance and other terms including dominance. Paradoxically, with nonadditive genetic effects, drift on average increases the amount of additive genetic variance within populations, whereas migration decreases the equilibrium amount. In the presence of nonadditive genetic effects, measurements of additive genetic variance in natural populations must be taken at the proper spatial scale with respect to natural selection, or they will provide an inaccurate description of evolutionary potential both within local populations and within the species as a whole. PMID- 28567989 TI - The novel synthetic microneurotrophin BNN27 protects mature oligodendrocytes against cuprizone-induced death, through the NGF receptor TrkA. AB - BNN27, a member of a chemical library of C17-spiroepoxy derivatives of the neurosteroid DHEA, has been shown to regulate neuronal survival through its selective interaction with NGF receptors (TrkA and p75NTR ), but its role on glial populations has not been studied. Here, we present evidence that BNN27 provides trophic action (rescue from apoptosis), in a TrkA-dependent manner, to mature oligodendrocytes when they are challenged with the cuprizone toxin in culture. BNN27 treatment also increases oligodendrocyte maturation and diminishes microglia activation in vitro. The effect of BNN27 in the cuprizone mouse model of demyelination in vivo has also been investigated. In this model, that does not directly involve the adaptive immune system, BNN27 can protect from demyelination without affecting the remyelinating process. BNN27 preserves mature oligodendrocyte during demyelination, while reducing microgliosis and astrogliosis. Our findings suggest that BNN27 may serve as a lead molecule to develop neurotrophin-like blood-brain barrier (BBB)-permeable protective agents of oligodendrocyte populations and myelin, with potential applications in the treatment of demyelinating disorders. PMID- 28567991 TI - HALDANE'S RULE IS SIGNIFICANT. PMID- 28567992 TI - BEHAVIORAL EVIDENCE FOR HOST-RACE FORMATION IN EUROSTA SOLIDAGINIS. AB - We report behavioral evidence that Eurosta solidaginis, a stem-galling tephritid fly, has formed host races on its two goldenrod hosts, Solidago altissima and S. gigantea. Previous work has shown that flies from each host plant differ electrophoretically at the level of host races. The two host-associated populations were truly sympatric and were frequently found on host plants of the two species growing interdigitated with each other. Each host-associated population demonstrated a strong preference for ovipuncturing its own host. The S. gigantea-associated population emerged 10 to 14 d earlier than the S. altissima-associated population, contributing to the reproductive isolation between populations. Partial reproductive isolation is also maintained by a preference for mating on the host from which the fly emerged. The populations meet the criteria established for host races, suggesting that they may be in an intermediate stage of sympatric speciation. PMID- 28567994 TI - MULLER'S RATCHET AND MUTATIONAL MELTDOWNS. AB - We extend our earlier work on the role of deleterious mutations in the extinction of obligately asexual populations. First, we develop analytical models for mutation accumulation that obviate the need for time-consuming computer simulations in certain ranges of the parameter space. When the number of mutations entering the population each generation is fairly high, the number of mutations per individual and the mean time to extinction can be predicted using classical approaches in quantitative genetics. However, when the mutation rate is very low, a fixation-probability approach is quite effective. Second, we show that an intermediate selection coefficient (s) minimizes the time to extinction. The critical value of s can be quite low, and we discuss the evolutionary implications of this, showing that increased sensitivity to mutation and loss of capacity for DNA repair can be selectively advantageous in asexual organisms. Finally, we consider the consequences of the mutational meltdown for the extinction of mitochondrial lineages in sexual species. PMID- 28567993 TI - HETEROCHRONY AND ALLOMETRY: LESSONS FROM THE WATER STRIDER GENUS LIMNOPORUS. AB - Heterochrony and allometry both deal with evolutionary modifications of ontogenies. Although data about both morphology and age are required to identify heterochronic processes, age data are not needed to study allometry. Using a simple graphical model, we show that allometric patterns cannot be used to infer the underlying heterochronic processes. We present a case study of the water strider genus Limnoporus Stal (Heteroptera: Gerridae) to illuminate the distinct roles that allometry and heterochrony play in integrated studies of the evolution of form. Multivariate analyses reveal several evolutionary modifications of growth trajectories (changes in direction, lateral transposition, and ontogenetic scaling), which are fairly consistent with the hypothesized phylogeny of the genus. Because there is no positive correlation between instar durations and size increments, size cannot be used as a proxy for age data in studies of heterochrony. In fact, a measure of overall size itself shows a remarkable variety of heterochronic changes among the six species. Mixtures of several heterochronic processes predominate over the more unitary reflections of "pure" processes. Heterochronic changes in different branches of the phylogeny, apparently independent of size scaling, suggest considerable potential for adaptive evolution. "Local" differentiation of ontogenetic traits within small clades may be at least as important as "global" evolutionary trends in large clades and will often be missed in "global" analyses. PMID- 28567995 TI - THE EVOLUTION OF GAMETIC INCOMPATIBILITY IN NEOTROPICAL ECHINOMETRA: A REPLY TO MCCLARY. PMID- 28567996 TI - THE SIGNIFICANCE OF GENETIC EROSION IN THE PROCESS OF EXTINCTION. IV. INBREEDING DEPRESSION AND HETEROSIS EFFECTS CAUSED BY SELFING AND OUTCROSSING IN SCABIOSA COLUMBARIA. AB - The effects of self-fertilization, within-population crosses (WPC) and between population crosses (BPC) on progeny fitness were investigated in the greenhouse for Scabiosa columbaria populations of varying size. Plants grown from field collected seeds were hand pollinated to produce selfed, WPC, and BPC progeny. The performance of these progenies was examined throughout the entire life cycle. The different pollination treatments did not significantly affect germination, seedling-to-adult survival, flowering percentage and the number of flower heads. But severe inbreeding depression was demonstrated for biomass production, root development, adult survival, and seed set. Additionally, multiplicative fitness functions were calculated to compare relative fitnesses for progeny. On average, WPC progeny showed a more than 4-fold, and BPC progeny an almost 10-fold, advantage over selfed progeny, indicating that S. columbaria is highly susceptible to inbreeding. No clear relationship was found between population size and level of inbreeding depression, suggesting that the genetic load has not yet been reduced substantially in the small populations. A significant positive correlation was found between plant dry weight and total fitness. In two out of six populations, the differences between the effects of the pollination treatments on dry weight increased significantly when seedlings were grown under competitive conditions. This result is interpreted as an enhancement of inbreeding depression under these conditions. It is argued that improvement of the genetic exchange between populations may lower the probability of population extinction. PMID- 28567997 TI - ABSENCE OF POLLEN DISCOUNTING IN A GENOTYPE OF IPOMOEA PURPUREA EXHIBITING INCREASED SELFING. AB - Throughout southeastern North America, the annual morning glory Ipomoea purpurea exhibits a polymorphism at a locus that influences the intensity of floral pigmentation. Previous studies have shown that when rare, the homozygous white genotype has a greater selfing rate than the homozygous dark genotype. In the absence of pollen discounting (a reduction in transmission of pollen to other plants by genotypes that exhibit increased selfing) and inbreeding depression, this increased selfing rate should favor the white allele. Experiments reported here confirm that the white genotype has elevated selfing rates when rare but indicate pollen discounting is not associated with elevated selfing. Rather, white genotypes contribute more pollen to the outcross pollen pool. The disparity between genotypes in both selfing rates and success at pollen contribution to other plants disappears at intermediate to high frequencies of the white allele. Pollinator movements are consistent with the pattern of selfing. These results suggest that elevated selfing and enhanced success at pollen donation contribute to maintenance of the white allele in natural populations of morning glories. PMID- 28567998 TI - COLOR-PATTERN VARIATION IN LAKE ERIE WATER SNAKES: PREDICTION AND MEASUREMENT OF NATURAL SELECTION. AB - A classic example of natural selection, that of color-pattern variation in Lake Erie island populations of water snakes, was reexamined to overcome shortcomings resulting from classification of snakes into discrete color-pattern categories and use of cross-sectional data. Four continuously varying color-pattern components (DB, the number of dorsal blotches; LB, the number of lateral blotches; ROWS, the height of lateral blotches measured in scale rows; and VEXT, the extent of ventral pigmentation) were analyzed. Patterns of natural selection were predicted from the relationship between color-pattern scores and independent measures of relative crypsis. Tests for natural selection were carried out using longitudinal data on neonate to juvenile-aged snakes and cross-sectional data on juvenile to adult-aged snakes. As predicted, the form of selection differed between younger and older age classes of snakes: selection resulted in a reduction in DB and LB among neonate and juvenile snakes but had little influence on color-pattern components in older snakes. The correspondence between observed patterns of natural selection and predictions based on the relationship between color-pattern scores and relative crypsis supports the hypothesis that differential predation by visual predators on younger age classes of snakes is the mechanism of selection. Gene flow from mainland populations or the initial lack of an allele necessary for reduced pattern may explain why selection has not resulted in greater differentiation between island and mainland populations. PMID- 28567999 TI - PEAK SHIFTS AND POLYMORPHISM DURING PHASE THREE OF WRIGHT'S SHIFTING-BALANCE PROCESS. AB - The third phase of Wright's shifting-balance theory involves the export of adaptive gene combinations from one subpopulation to another. Previous results have demonstrated that this can occur at very low migration rates, but it has been argued that this simply reflects the ability of migration to overcome selection and fix any (even deleterious) alleles. Here, previous analyses are extended by concentrating on the critical balance between forward and reverse migration rates that still allows phase III to proceed. It is shown that selective advantage, dominance, recombination rate, and the number of loci all affect the ability of a genotype to invade and become fixed in a new subpopulation, but it is unlikely that phase III will occur in the absence of differential migration unless the invading genotype consists of a few dominant loci with a large selection advantage, spreading into a few populations of lower fitness. Therefore, as was envisioned by Wright, differential migration from more to less fit populations will be necessary for phase III to occur under most circumstances. PMID- 28568000 TI - SEX-RATIO MANIPULATION BY THE PARASITOID WASP MUSCIDIFURAX RAPTOR IN RESPONSE TO HOST SIZE. PMID- 28568001 TI - REACTION NORMS OF MORPHOLOGICAL AND LIFE-HISTORY TRAITS TO LIGHT AVAILABILITY IN IMPATIENS CAPENSIS. AB - For plants, light availability is an important environmental factor that varies both within and between populations. Although the existence of sun and shade "ecotypes" is controversial, it is often assumed that trade-offs may exist between performance in sun and in shade. This study therefore investigated variation in reaction norms to light availability within and between two neighboring natural populations of the annual Impatiens capensis, one in full sun and the other in a forest understory. Seedlings were collected randomly from both populations and grown to maturity in a greenhouse under two light conditions: full light and 18% of full light. Selfed full-sib seed families were collected from plants from both populations grown in both parental light environments. To characterize family reaction norms, seedlings from each family were divided into the same two light treatments and individuals were scored for a variety of morphological and life-history traits. The maternal light environment had little impact on progeny reaction norms. However, the two study populations differed both qualitatively and quantitatively in plastic response to light availability (indicated by significant population x environment interactions in mixed-model ANCOVA). Much of this difference was attributable to population differences in light sensitivity of axillary meristem allocation patterns, which produced concurrent differences in reaction norms for a suite of developmentally linked traits. Within each population, different sets of traits displayed significant variation in plasticity (indicated by significant family x environment interactions). Thus, the genetic potential for evolutionary response to selection in heterogeneous light environments may differ dramatically between neighboring plant populations. Between-environment genetic correlations were largely positive in the woods population and positive or nonsignificant in the sun population; there was no evidence for performance trade-offs across environments or sun or shade "specialist" genotypes within either population. There was little evidence that population differences represented adaptive differentiation for sun or shade; rather, the results suggested the hypothesis of differential selection on patterns of meristem allocation caused by population differences in timing of mortality and intensity of competition. PMID- 28568002 TI - GENETIC CORRELATION BETWEEN A FEMALE MATING PREFERENCE AND THE PREFERRED MALE CHARACTER IN SEAWEED FLIES (COELOPA FRIGIDA). AB - The mating preferences of female seaweed flies Coelopa frigida were determined by observing their acceptance or rejection of males of known size. The inversion karyotype of both males and females was also determined. Females exhibited a preference to mate with large males, and evidence is presented that a genetic correlation exists between the female preference and the preferred trait. Females carrying the inversion karyotype associated with large male size showed a strong preference for large males; females carrying the inversion associated with small male size also exhibited a preference for large males, but it was significantly less strong. This finding suggests that a Fisherian process may be operating. PMID- 28568003 TI - POLLINATORS DISCRIMINATE AMONG FLORAL HEIGHTS OF A SEXUALLY DECEPTIVE ORCHID: IMPLICATIONS FOR SELECTION. AB - Pollinators have influenced the evolution of many morphological floral traits, although few studies have shown that pollinators have influenced plant height. Chiloglottis trilabra is one of many Australian orchids that deceive and attract male pollinators by mimicking the sex pheromones and morphology of females insects. Orchids in this genus have unusually short flowers whose peduncle elongates dramatically after pollination to approximately twice the original height. In a series of choice experiments in the field, we show that pollinators of C. trilabra strongly discriminate among floral heights, preferring flowers presented at 15 cm-20 cm over flowers presented at lower and higher positions (ranging from 2 cm-100 cm). Our results suggested pollinators have the potential to mediate stabilizing selection for floral height when pollination is limiting. However, the natural height range of the orchid (mean = 10 cm, range 5 cm-15 cm) was lower than the experimentally determined optimum for visitation frequency. This difference may indicate that pollinator-mediated selection does not occur in this species, perhaps because seed set is not sufficiently limited. Alternatively, other life-history factors may counteract pollinator-mediated selection, yielding an evolutionary compromise in height. PMID- 28568004 TI - ADAPTIVE GENETIC VARIATION IN GROWTH AND DEVELOPMENT OF TADPOLES OF THE HYBRIDOGENETIC RANA ESCULENTA COMPLEX. AB - The distribution and proportion of the sexual species Rana lessonae to the hemiclonal hybrid R. esculenta among natural habitats suggests that these anurans may differ in adaptive abilities. I used a half-sib design to partition phenotypic and quantitative genetic variation in tadpole responses at two food levels into causal variance components. Rana lessonae displays strong phenotypic variation across food levels. Growth rate is strictly determined by environmental factors and includes weak maternal effects. Larval period and body size at metamorphosis both contain moderate levels of additive genetic variance. The sire x food interactions and the lack of environmental correlations indicate that adaptive phenotypic plasticity is present in both of these traits. In contrast, R. esculenta displays less phenotypic variation across food levels, especially for larval period. Variation in body size at metamorphosis is underlain by genetic variation as shown by high levels of additive genetic variance, yet growth rate and larval period are not. Significant environmental correlations between larval period at high food level and growth, larval period, and body size at low food, indicate phenotypic plasticity is absent. A positive phenotypic correlation between body size at metamorphosis and larval period for R. lessonae at both food levels suggests a trade-off between growing large and metamorphosing quickly to escape predation or pond drying. The lack of a similar correlation for R. esculenta at the high food level suggests it may be less constrained. Different levels of adaptive genetic variation among larval traits suggest that the sexual species and the hybridogenetic hemiclone differ in their abilities to cope with temporally and spatially heterogeneous environments. PMID- 28568005 TI - EVOLUTION OF HOST-PARASITE DIVERSITY. AB - Hosts and parasites often have extensive genetic diversity for resistance and virulence (host range). Qualitative diversity occurs when the success of attack is an all-or-nothing response that varies according to the genotypes of the host and parasite. Quantitative diversity occurs when the success of attack is a graded response that depends on additive genetic variation in the host and parasite. Community diversity occurs when parasites vary in the success with which they can attack different host species, leading to a mixture of specialists and generalists. I developed a series of models that classify components of host parasite interactions according to whether they cause stabilizing or disruptive selection for resistance and virulence. Stabilizing selection reduces diversity by favoring a single optimal phenotype. Disruptive selection creates diversity by favoring a mixture of widely separated phenotypes. The evolution of maximal resistance and virulence are opposed by one of three forces: metabolic costs, frequency dependence, or negative genetic correlations among beneficial traits. The models predict that qualitatively inherited resistance and virulence traits typically cause greater diversity than quantitatively inherited traits. However, each natural system is composed of many stabilizing factors that reduce diversity and disruptive factors that promote diversity. I advocate a style of modeling in which families of related assumptions are compared by their equilibrium properties, and general conclusions from equilibrium properties are tested by complete dynamical analysis. The comparison among models highlights the need for empirical studies that compare levels of diversity among related host-parasite systems. PMID- 28568006 TI - BRIEF COMMUNICATIONS: COUNTING GENES IN MODELS OF BIPARENTAL INBREEDING. PMID- 28568007 TI - LABORATORY EXPERIMENTS ON SPECIATION: WHAT HAVE WE LEARNED IN 40 YEARS? AB - We integrate experimental studies attempting to duplicate all or part of the speciation process under controlled laboratory conditions and ask what general conclusions can be made concerning the major models of speciation. Strong support is found for the evolution of reproductive isolation via pleiotropy and/or genetic hitchhiking with or without allopatry. Little or no support is found for the bottleneck and reinforcement models of speciation. We conclude that the role of geographical separation in generating allopatry (i.e., zero gene flow induced by spatial isolation) has been overemphasized in the past, whereas its role in generating diminished gene flow in combination with strong, discontinuous, and multifarious divergent selection, has been largely unappreciated. PMID- 28568008 TI - MORPHOLOGICAL DIFFERENTIATION AND GENETIC COHESIVENESS OVER A MICROENVIRONMENTAL GRADIENT IN THE MARINE SNAIL LITTORINA SAXATILIS. AB - The marine gastropod Littorina saxatilis has different ecotypes in shores only a few meters apart. This has both taxonomic and evolutionary implications. Here we report on an extreme type of within-shore dimorphism in shell characters. In the wave-exposed rocky shores in northwestern Spain, we found one form of L. saxatilis in the upper-level barnacle zone. It had a white, ridged shell, with black bands in the grooves. Another form confined to the lower-shore mussel belt had a smooth shell that was either white and tessellated or darkly colored. These two forms cooccured in a narrow midshore zone together with individuals that had combined characters, but were present in low frequencies (11%-29%). We used principal-component analysis of metric shell characters to study variation in shell size and shape. We found that the upper-shore form was larger than the lower-shore form. We also found small but significant differences in shell shape. Experiments in a common laboratory environment suggested the differences in shell ornamentation and color are inherited, but the individuals did not develop the morph-specific characters until a shell height of about 3 mm. The occurrence of mainly two distinct forms may suggest the presence of two species that hybridize. An analysis of five polymorphic enzyme loci in populations of snails from three geographically separated sites indicated, however, that there was no positive correlation between morphological distances and genetic distances among populations on a geographic scale (tens of kilometers). Thus, we rejected the hypothesis of two species. However, on a microgeographic scale (meters), genetic differentiation between groups with the same form was less than differentiation between forms. This indicated a partial barrier to gene flow between the two forms, and preliminary mate choice data suggested this was caused by nonrandom mating in the midshore zone of overlap. PMID- 28568009 TI - HALDANE'S COINCIDENCE: A REPLY TO BROOKFIELD. PMID- 28568010 TI - MODE OF SWARMING IN RELATION TO REPRODUCTIVE ISOLATION IN MAYFLIES. AB - Mayfly males swarm, that is they fly in a fixed pattern by a specific object, the swarm marker. Females orientate to the same markers. Leptophlebia marginata mayflies were observed to orientate to two kinds of objects in a single locality in central Finland: to trees and to horizontal pale objects on the ground; when dispersed or moved to the other type of marker, they returned to their former orientation. Tree swarming is by far the most common mode of swarming, but some horizontally orientating populations were found. Sympatric populations are genetically and morphologically distinct, whereas other populations appear to have some gene flow between the swarming types. The tree-swarming mode appears to be primitive and the horizontal mode derived; wind rather than predation is the factor favoring swarming close to the ground. Swarming constitutes an effective mechanism of premating isolation in mayflies. PMID- 28568011 TI - ALLOCATION TO ATTRACTIVE STRUCTURES IN ANIMAL-POLLINATED FLOWERS. AB - An optimal allocation model was developed for the evolutionarily stable size of attractive structures of flowers (ESA) in animal-pollinated plants. It was assumed that a plant can change the sizes of attractive and sexual structures of a flower and the size and the number of flowers. In the absence of constraints on flower size, the ESA should not depend on the frequency of self-fertilization or the sexuality of plants. However, with constraints on flower size, the ESA decreases with increasing self-fertilization, except in special cases, and it is possible that males have a larger or a smaller ESA than females. Thus, differences in self-fertilization and sexuality alone cannot explain the differences in allocation among nondomesticated plants. In addition, attractive structures can contribute more to male or female function depending on the cost of gamete production, pollination efficiency for pollen and ovules, and pollinator availability. PMID- 28568012 TI - MORPHOLOGICAL EVOLUTION OF THE SCAPULA IN TREE SQUIRRELS, CHIPMUNKS, AND GROUND SQUIRRELS (SCIURIDAE): AN ANALYSIS USING THIN-PLATE SPLINES. AB - The mammalian scapula, like many bones, is a single structural element that serves as an attachment site for several muscles. The goal of this study was to determine whether the scapula evolves as an integrated unit, or as a collection of distinct parts. Shape differences among the scapulae of tree squirrels, chipmunks, and ground squirrels were described using thin-plate spline analysis. This technique produces a geometric description of shape differences that can be decomposed into a series of components ranging in scale from features that span the entire form to features that are highly localized. Shape differences among tree squirrel scapulae were found only in large-scale features, indicating spatially integrated shape change. Chipmunks and ground squirrels differ from tree squirrels in several features, but shared differences reflecting divergence of their common ancestor were found only in the small-scale features. Divergence of ground squirrels from the common ancestor involved some large-scale changes but was dominated by small-scale changes. Divergence of chipmunks was dominated by large-scale changes. Thus, the scapula evolved as an integrated unit during some transitions but as a collection of distinct parts during others. These results suggest that evolutionary patterns of the postcranial skeleton may be as complex as the patterns that have been described for skulls and feeding mechanisms. PMID- 28568013 TI - A multicenter review of ablation in the aortic cusps in young people. AB - BACKGROUND: Ablation within the aortic cusp is safe and effective in adults. There are little data on aortic cusp ablation in the pediatric literature. We investigated the safety and efficacy of aortic cusp ablation in young patients. METHODS: A retrospective, descriptive study of aortic cusp ablation in five pediatric electrophysiology centers from 2008 to 2014 was performed. All patients <21 years of age who underwent ablation in the aortic cusps were included. Factors analyzed included patient demographics, procedural details, outcomes, and complications. RESULTS: Thirteen patients met inclusion criteria (median age 16 years [range 10-20.5] and median body surface area 1.58 m2 [range 1.12-2.33]). Substrates for ablation included: nine premature ventricular contractions or sustained ventricular tachycardia (69%), two concealed anteroseptal accessory pathways (APs) (15%), one Wolff-Parkinson-White with an anteroseptal AP (8%), and one ectopic atrial tachycardia (8%). Three-dimensional electroanatomic mapping in combination with fluoroscopy was used in 12/13 (92%) patients. Standard 4-mm-tip radiofrequency (RF) current was used in 11/13 (85%) and low-power irrigated-tip RF in 2/13 (15%). Angiography was used in 13/13 and intracardiac echocardiography was additionally utilized in 3/13 (23%). Ablation locations included: eight noncoronary (62%), three left (23%), and two right (15%) cusps. Ablation was acutely successful in all patients. At median follow-up of 20 months, there was one recurrence of PVCs (8%). There were no ablation-related complications and no valvular injuries observed. CONCLUSION: Arrhythmias originating from the coronary cusps in this series were successfully and safely ablated in young people without injury to the coronary arteries or the aortic valve. PMID- 28568015 TI - INCREASED NUMBER OF ALLELES FOUND IN HYBRID POPULATIONS DUE TO INTRAGENIC RECOMBINATION. PMID- 28568014 TI - Interdependence of ICD rates in paired quantum dots on geometry. AB - Using state-of-the-art antisymmetrized multiconfiguration time-dependent Hartree (MCTDH) electron dynamics calculations we study the interdependence of the intermolecular Coulombic decay (ICD) process on the geometric parameters of a doubly-charged paired quantum dot (PQD) model system in the framework of the effective mass approximation (EMA). We find that ICD displays a maximum rate for a certain geometry of the electron-emitting quantum dot, which is simultaneously dependent on both the distance between the quantum dots as well as the photon absorbing quantum dot's geometry. The rate maximum is shown to be caused by the competing effects of polarization of electron density and Coulomb repulsion. The ICD rate-maximized PQD geometry in GaAs QDs yields a decay time of 102.39 ps. It is given by two vertically-aligned cylindrical QDs with radii of 14.42 nm separated by 86.62 nm. The photon absorbing QD then has a height of 46.59 nm and the electron emitting QD a height of 16.33 nm. (c) 2017 Wiley Periodicals, Inc. PMID- 28568016 TI - COMPETITION BETWEEN HIGH AND LOW MUTATING STRAINS OF ESCHERICHIA COLI. PMID- 28568017 TI - Society Meetings. PMID- 28568019 TI - Society Meetings. PMID- 28568018 TI - COMPARATIVE ASSESSMENT OF MODES OF REPRODUCTIVE ISOLATION AMONG FOUR SPECIES OF LEOPARD FROGS (RANA PIPIENS COMPLEX). PMID- 28568020 TI - SEXUAL SELECTION AND SEXUAL DIMORPHISM IN MOTTLED SCULPINS. PMID- 28568021 TI - SEX RATIO EVOLUTION UNDER LOCAL MATE COMPETITION IN A PARASITIC WASP. PMID- 28568022 TI - Letter to the Editor. PMID- 28568023 TI - CHROMOSOME EVOLUTION IN THE IGUANID LIZARD SCELOPORUS GRAMMICUS. II. ALLOZYME VARIATION. PMID- 28568024 TI - COUMARINS AND CATERPILLARS: A CASE FOR COEVOLUTION. PMID- 28568025 TI - MACROGEOGRAPHIC VARIATION IN LITTER SIZE IN ANTECHINUS (MARSUPIALIA: DASYURIDAE). PMID- 28568026 TI - TESTING THE CONSTANT-RATE NEUTRAL ALLELE MODEL WITH PROTEIN SEQUENCE DATA. PMID- 28568027 TI - CHROMOSOME EVOLUTION IN THE IGUANID LIZARD SCELOPORUS GRAMMICUS. I. CHROMOSOME POLYMORPHISMS. PMID- 28568028 TI - HOST RANGE EVOLUTION: THE SHIFT FROM NATIVE LEGUME HOSTS TO ALFALFA BY THE BUTTERFLY, COLIAS PHILODICE ERIPHYLE. PMID- 28568029 TI - EXTENSIVE GENETIC VARIATION IN MITOCHONDRIAL DNA'S AMONG GEOGRAPHIC POPULATIONS OF THE DEER MOUSE, PEROMYSCUS MANICULATUS. PMID- 28568030 TI - KINETIC AND ELECTROPHORETIC DIFFERENTIATION OF LACTATE DEHYDROGENASES OF TELEOST SPECIES-PAIRS FROM THE ATLANTIC AND PACIFIC COASTS OF PANAMA. PMID- 28568031 TI - RESOURCE PARTITIONING AMONG GENOTYPES OF DROSOPHILA PSEUDOOBSCURA. PMID- 28568032 TI - GENE DIVERSITY AND GENETIC STRUCTURE IN A NARROW ENDEMIC, TORREY PINE (PINUS TORREYANA PARRY EX CARR.). PMID- 28568033 TI - THE KLUGE-KERFOOT PHENOMENON-A STATISTICAL ARTIFACT. PMID- 28568034 TI - MORPHOLOGICAL DIFFERENTIATION IN WING VENATION AMONG BROODS OF 13- AND 17-YEAR PERIODICAL CICADAS. PMID- 28568035 TI - MACROEVOLUTION AND THE FOSSIL RECORD. PMID- 28568036 TI - POPULATION DIFFERENTIATION IN EUPHYDRYAS EDITHA BUTTERFLIES: LARVAL ADAPTATION TO DIFFERENT HOSTS. PMID- 28568037 TI - MATING SYSTEM VARIATION IN FESTUCA MICROSTACHYS. PMID- 28568038 TI - SYMPATRIC GENETIC DIVERGENCE IN THE LEAF-MINING INSECT LIRIOMYZA BRASSICAE (DIPTERA: AGROMYZIDAE). PMID- 28568039 TI - ON THE FALLACY OF CONSTANT EXTINCTION RATES. PMID- 28568040 TI - EVOLUTION AND BIFURCATION OF DEVELOPMENTAL PROGRAMS. PMID- 28568042 TI - CHARACTER CHANGE, SPECIATION, AND THE HIGHER TAXA. PMID- 28568041 TI - ENVIRONMENTAL CHANGE AND THE EVOLUTIONARY HISTORY OF THE PERIWINKLE (LITTORINA LITTOREA) IN NORTH AMERICA. PMID- 28568043 TI - LABORATORY HYBRIDIZATION BETWEEN SEMI-INCOMPATIBLE RACES OF THE ARRHENOTOKOUS SPIDER MITE TETRANYCHUS URTICAE KOCH (ACARI: TETRANYCHIDAE). PMID- 28568044 TI - GENETIC DISTANCE IN THE SIBLING SPECIES DROSOPHILA MELANOGASTER, DROSOPHILA SIMULANS AND DROSOPHILA MAURITIANA. PMID- 28568046 TI - MACROEVOLUTION: PATTERN AND PROCESS INTRODUCTION AND BACKGROUND. PMID- 28568045 TI - XO FEMALES IN THE VARYING LEMMING, DICROSTONYX TORQUATUS: REPRODUCTIVE PERFORMANCE AND ITS EVOLUTIONARY SIGNIFICANCE. PMID- 28568047 TI - A NARROW HYBRID ZONE BETWEEN CLOSELY RELATED CRICKET SPECIES. PMID- 28568048 TI - PROMOTION OF GENE FLOW BY TRANSIENT INDIVIDUALS IN AN OTHERWISE SEDENTARY POPULATION OF BOX TURTLES (TERRAPENE CAROLINA TRIUNGUIS). PMID- 28568049 TI - A NEO-DARWINIAN COMMENTARY ON MACROEVOLUTION. PMID- 28568050 TI - PHENOTYPIC, GENETIC, AND ENVIRONMENTAL MORPHOLOGICAL INTEGRATION IN THE CRANIUM. PMID- 28568051 TI - DIPLOID-TETRAPLOID-DIHAPLOID CYCLES AND THE EVOLUTION OF PANICUM MAXIMUM JACQ. PMID- 28568052 TI - SEX RATIOS IN THE EASTERN BLUEBIRD. PMID- 28568054 TI - CYTOGENETICS OF THE PARTHENOGENETIC GRASSHOPPER WARRAMABA (FORMERLY MORABA) VIRGO AND ITS BISEXUAL RELATIVES. V. INTERACTION OF W. VIRGO AND A BISEXUAL SPECIES IN GEOGRAPHIC CONTACT. PMID- 28568055 TI - COMPETITIVE HIERARCHIES IN LABORATORY DROSOPHILA. PMID- 28568053 TI - Low vitamin B12 increases risk of gastric cancer: A prospective study of one carbon metabolism nutrients and risk of upper gastrointestinal tract cancer. AB - Previous studies have found associations between one-carbon metabolism nutrients and risk of several cancers, but little is known regarding upper gastrointestinal tract (UGI) cancer. We analyzed prediagnostic serum concentrations of several one carbon metabolism nutrients (vitamin B12, folate, vitamin B6, riboflavin and homocysteine) in a nested case-control study within the Alpha-Tocopherol, Beta Carotene Cancer Prevention (ATBC) Study of male smokers, which was undertaken in Finland between 1985 and 1988. We conducted a nested case-control study including 127 noncardia gastric adenocarcinoma (NCGA), 41 esophagogastric junctional adenocarcinoma and 60 esophageal squamous cell carcinoma incident cases identified within ATBC. Controls were matched to cases on age, date of serum collection and follow-up time. One-carbon nutrient concentrations were measured in fasting serum samples collected at baseline (up to 17 years prior to cancer diagnosis). Odds ratios and 95% confidence intervals (CI) were calculated using conditional logistic regression. Lower prediagnostic vitamin B12 concentrations at baseline were associated with a 5.8-fold increased risk of NCGA (95% CI = 2.7 12.6 for lowest compared to highest quartile, p-trend <0.001). This association remained in participants who developed cancer more than 10 years after blood collection, and after restricting the analysis to participants with clinically normal serum vitamin B12 (>300 pmol/L). In contrast, pepsinogen I, a known serologic marker of gastric atrophy, was not associated with NCGA in this population. As vitamin B12 absorption requires intact gastric mucosa to produce acid and intrinsic factor, our findings suggest vitamin B12 as a possible serologic marker for the atrophic gastritis that precedes NCGA, one more strongly associated with subsequent NCGA than pepsinogen. PMID- 28568057 TI - EVOLUTION OF THE STING APPARATUS IN THE MYRMICINE ANTS. PMID- 28568056 TI - BIOCHEMICAL AND CYTOLOGICAL DIFFERENTIATION AMONG CICHLID FISHES OF THE SEA OF GALILEE. PMID- 28568058 TI - SELF-FERTILIZATION: ADVANTAGEOUS OR DELETERIOUS? PMID- 28568059 TI - GENETIC VARIATION IN HAWAIIAN DROSOPHILA. V. CHROMOSOMAL AND ALLOZYMIC DIVERSITY IN DROSOPHILA SILVESTRIS AND ITS HOMOSEQUENTIAL SPECIES. PMID- 28568060 TI - A GEOGRAPHICAL ANALYSIS OF QUANTITATIVE MORPHOLOGICAL VARIATION IN THE GRASSHOPPER ARPHIA CONSPERSA. PMID- 28568061 TI - THE RELATION OF GENETIC STRUCTURE TO ENVIRONMENTAL STRUCTURE: GAMMARUS MINUS IN A KARST AREA. PMID- 28568062 TI - REPRODUCTIVE CHARACTER DISPLACEMENT IN CALOPTERYX (ODONATA: CALOPTERYGIDAE). PMID- 28568063 TI - EFFECTIVE DEME SIZES DURING LONG-TERM EVOLUTION ESTIMATED FROM RATES OF CHROMOSOMAL REARRANGEMENT. PMID- 28568064 TI - FLORAL DISPLAY IN PHLOX AND GERANIUM: ADAPTIVE ASPECTS. PMID- 28568065 TI - BEHAVIORAL AND BIOCHEMICAL EVIDENCE FOR SPECIES DISTINCTIVENESS IN THE FIDDLER CRABS, UCA SPECIOSA AND U. SPINIZARPA. PMID- 28568067 TI - MOMENTARILY EXCESSIVE CONSTRUCTION AS THE BASIS FOR PROTOADAPTATION. PMID- 28568068 TI - CLONAL DIVERSITY IN THE UNISEXUAL FISH POECILIOPSIS MONACHA-LUCIDA : A TISSUE GRAFT ANALYSIS. PMID- 28568066 TI - STUDIES ON FOOD SIZE AS A SELECTION PRESSURE ON BODY SIZE. I. EFFECTS OF FOOD SIZE ON FITNESS OF TWO SIZE STRAINS OF ACHETA DOMESTICUS L. PMID- 28568069 TI - MATING PATTERNS AND SPECIATION IN THE FAIRY SHRIMP GENUS STREPTOCEPHALUS. PMID- 28568070 TI - Society for the Study of Evolution. PMID- 28568071 TI - EVOLUTIONARY IMPLICATIONS OF CHROMOSOMAL HOMOLOGY IN FOUR GENERA OF STENODERMINE BATS (PHYLLOSTOMATIDAE: CHIROPTERA). PMID- 28568072 TI - POPULATION STRUCTURE OF FRESHWATER FISHES I. GENETIC VARIATION OF BLUEGILL (LEPOMIS MACROCHIRUS) POPULATIONS IN MAN-MADE RESERVOIRS. PMID- 28568073 TI - RESISTANCE OF THE SIBLING SPECIES DROSOPHILA MELANOGASTER AND DROSOPHILA SIMULANS TO HIGH TEMPERATURES IN RELATION TO HUMIDITY: EVOLUTIONARY IMPLICATIONS. PMID- 28568074 TI - EVOLUTIONARY ASPECTS OF PARENTAL CARE IN THE COMMON GRACKLE, QUISCALUS QUISCULA L. PMID- 28568075 TI - THE DROSOPHILA OF SOUTHERN CALIFORNIA. I. COLONIZATION AFTER A FIRE. PMID- 28568076 TI - A Statistical Method for Reassociating Human Tali and Calcanei from a Commingled Context. AB - In a commingled context, assessing that a talus and a calcaneus correspond to the same individual could become a primary step for accurately sorting human remains. For this purpose, the lengths and widths of the trochlea, posterior calcaneal articular surface, and posterior talar articular surface were measured in 197 individuals (105 males, 92 females) from the Athens Collection. A total of 12 highly accurate equations for reassociating tali and calcanei were developed, using simple and multiple linear regression analysis and they were found to be suitable for sorting commingled human remains. Bilateral asymmetry and sex did not have an effect on the accuracy of the method. PMID- 28568077 TI - Letter to the editor: Reply to Hardy & Buckley: Earliest evidence of bitumen from Homo sp. teeth is from El Sidro'n. PMID- 28568078 TI - PRE-ADAPTATION OF YORKSHIRE FOG, HOLCUS LANATUS L. (POACEAE) TO ARSENATE TOLERANCE. PMID- 28568079 TI - ATTERNS AND LEVELS OF POLLEN-MEDIATED GENE FLOW IN LATHYRUS LATIFOLIUS. AB - While gene flow can be an important force in evolution, few direct measures are available in the plant literature. Descriptions of gene movement within populations are more common, but have primarily involved crop species and artificially constructed populations. In this study, fractional paternity procedures were used to examine patterns of pollen movement over two years within two sites of Lathyrus latifolius, a bumblebee-pollinated, self-compatible perennial legume. Study sites consisted of 15 to 23 semi-discrete flowering patches that contained 1 to 29 distinct genotypes. Distributions of gene movement distances within the study sites differed significantly from that expected under random mating. Mean gene movement was 14 m. On average, 17.6% (range = 0-52%) of matings occurred within a flowering patch. Outcrossing rates, estimated from paternity analysis, ranged from 0.87 to 0.90 across sites and years. Significant heterogeneity occurred among maternal individuals with respect to outcrossing and immigration rates, indicating that mating patterns were idiosyncratic to each plant. Apparent rates of pollen flow into the sites ranged from 5 to 15%, while estimates of total pollen flow into sites ranged from 16 to 46%. Significant increases in immigration rates between years were associated with decreases in the density of flowering plants. PMID- 28568080 TI - REVERSIBILITY IN EVOLUTION: A MAXIMUM LIKELIHOOD APPROACH TO CHARACTER GAIN/LOSS BIAS IN PHYLOGENIES. AB - Statistical methods are used to test the hypothesis that rate of gain is equal to rate of loss for a single character on a cladogram. Ancestral character states are used as input for maximum likelihood (ML) rate estimation. Two markovian models of character evolution are considered: one has equality of rate across branches; the other permits variation in rate according to predetermined weights for branches. ML estimates are derived for both models, and their properties in large and small trees are investigated. Bias and error are significant in small trees. Error is greatest for characters in which rate of gain is low, and is greater for the loss estimate than for the gain estimate. Likelihood ratio (LR) tests of the null hypothesis of equality of gain/loss rate are derived, and their properties investigated. The distribution of -2 log LR is close to chi2 with 1 df with as few as 32 taxa. However, the power of the test is low unless the character is evolving rapidly. Methods for increasing power are examined, including selection of rapidly evolving subsets of characters, and pooling across characters. A goodness of fit test is presented to determine if pooling is justified. An example using published restriction site data on the Asteraceae demonstrates significant deviation from the null model in the direction predicted on the basis of the molecular biology of restriction enzyme site recognition, but only for one large subset of the data in which pooling is warranted. PMID- 28568081 TI - THE "GENERAL VIGOR" PROBLEM: CAN ANTAGONISTIC PLEIOTROPY BE DETECTED WHEN GENETIC COVARIANCES ARE POSITIVE? PMID- 28568082 TI - THE DEVELOPMENTAL ROLE OF THE EXTRACELLULAR MATRIX SUGGESTS A MONOPHYLETIC ORIGIN OF THE KINGDOM ANIMALIA. AB - The fundamental events of early development are similar in all animals, including sponges. Recent developments in the molecular biology of the extracellular matrix strongly suggest that the molecular mechanisms behind these events are also similar among all animals. I propose that the complex (collagen, proteoglycan, adhesive glycoprotein, and integrin) system that mediates cell motility and transitions between epithelial and motile cell types is central to multicellularity in animals. I further propose that the extracellular matrix is a deep rooted homology that unites the kingdom Animalia into a monophyletic group of multicellular organisms. PMID- 28568083 TI - HERITABILITY OF HOST PLANT RESISTANCE TO HERBIVORY CHANGES WITH GALLMIDGE DENSITY DURING AN OUTBREAK ON WILLOW. PMID- 28568084 TI - EVOLUTIONARY ADAPTATION TO TEMPERATURE II. THERMAL NICHES OF EXPERIMENTAL LINES OF ESCHERICHIA COLI. AB - Groups of replicated lines of the bacterium Escherichia coli were propagated for 2,000 generations at constant 32, 37, or 42 degrees C, or in an environment that alternated between 32 and 42 degrees C. Here, we examine the performance of each group across a temperature range of 12-44 degrees C measuring the temperatures over which each line can maintain itself in serial dilution culture (the thermal niche). Thermal niche was not affected by selection history: average lower and upper limits remained about 19 and 42 degrees C for all groups. In addition, no significant differences among groups were observed in rate of extinction at more extreme temperatures. Within the thermal niche, we measured the mean fitness of the evolved groups relative to their common ancestor. Increases in mean fitness were temperature specific, with the largest increase for each group occurring near its selected temperature. Thus, the temperature at which mean fitness relative to the ancestor was greatest (the thermal optimum) diverged by about 10 degrees C for the groups selected at constant 32 degrees C versus constant 42 degrees C. Tradeoffs in relative fitness (decrements relative to the ancestor elsewhere within the thermal niche) did not necessarily accompany fitness improvements, although tradeoffs were observed for a few of the lines. We conclude that adaptation in this system was quite temperature specific, but substantial divergence among groups in thermal optima had little effect on the limits of their thermal niches and did not necessarily involve tradeoffs in fitness at other temperatures. PMID- 28568085 TI - THE USEFULNESS OF BEHAVIOR FOR PHYLOGENY ESTIMATION: LEVELS OF HOMOPLASY IN BEHAVIORAL AND MORPHOLOGICAL CHARACTERS. AB - It is widely believed that behavior is more evolutionarily labile and/or more difficult to characterize than morphology, and thus that behavioral characters are not as useful as morphological characters for estimating phylogenetic relationships. To examine the relative utility of behavior and morphology for estimating phylogeny, we compared levels of homoplasy for morphological and behavioral characters that have been used in systematic studies. In an analysis of 22 data sets that contained both morphological and behavioral characters we found no significant difference between mean consistency indices (CIs, which measure homoplasy) within data sets for the two types of characters. In a second analysis we compared overall CIs for 8 data sets comprised entirely of behavioral characters with overall CIs for 32 morphological data sets and found no significant difference between the two types of data sets. For both analyses, 95% confidence limits on the difference between the two types of characters indicate that, even if given the benefit of the doubt, morphological characters could not have substantially higher mean CIs than behavioral characters. These results do not support the idea that behavioral characters are less useful than morphological characters for the estimation of phylogeny. PMID- 28568086 TI - QUANTITATIVE GENETICS OF SIZE AND PHENOLOGY OF LIFE-HISTORY TRAITS IN CHAMAECRISTA FASCICULATA. AB - Despite numerous adaptive scenarios concerning the evolution of plant life history phenologies few studies have examined the heritable basis for and genetic correlations among these phenologies. Documentation of genetic variation for and covariation among reproductive phenologies is important because it is this variation/covariation that will determine the potential for response to evolutionary forces. To address this problem, I conducted a breeding experiment to determine narrow-sense heritabilities for and genetic correlations among the phenologies of life-history events and plant size in Chamaecristafasciculata, a temperate summer annual plant species. Paternal families showed no evidence of heritable variation for two estimates of plant size, six measures of reproductive phenology or two fitness components. Similarly, paternal estimates of genetic correlations among these traits were low or zero. In contrast, maternal estimates of heritability suggested the influence of maternal parent on one estimate of plant size and four phenological traits. Likewise, maternal effects influenced maternal estimates of genetic correlations. These maternal effects can arise from three sources: endosperm nuclear, cytoplasmic genetic and/or maternal phenotypic. The degree to which the phenology of one life-history trait acts as a constraint on the evolution of other phenological traits depends on the source of the maternal influence in this species. PMID- 28568087 TI - DIFFERENTIAL AVOIDANCE OF CORAL SNAKE BANDED PATTERNS BY FREE-RANGING AVIAN PREDATORS IN COSTA RICA. AB - Empirical studies of mimicry have rarely been conducted under natural conditions. Field investigations of some lepidopteran systems have provided a bridge between experiments examining artificial situations and the mimicry process in nature, but these systems do not include all types of mimicry. The presence of dangerous or deadly models is thought to alter the usual rules for mimicry complexes. In particular, a deadly model is expected to protect a wide variety of mimics. Avoidance of different types of mimics should vary according to how closely they resemble the model. Coral snake mimicry complexes in the neotropics may provide natural systems in which these ideas can be examined, but there is no direct evidence that the patterns of venomous coral snakes or potential mimics are avoided in the wild. Plasticine replicas of snakes were used to assess the frequency of avian predation attempts as a function of color pattern. Avian predators left identifiable marks on the replicas, the position of which indicated that replicas were perceived as potentially dangerous prey items by birds. The number of attacks on unmarked brown replicas was greater than that on tricolor coral snake banded replicas. This result was true whether replicas were placed on natural or plain white backgrounds, suggesting that coral snake banded patterns function aposematically. In a separate experiment, replicas representing all six patterns of proposed coral mimics at the study site were attacked less often than unmarked brown replicas. Within these six banded patterns, some were attacked significantly more often than others. This study provides direct field evidence that coral snake banded patterns are avoided by free-ranging avian predators and supports theoretical predictions about mimicry systems involving deadly models. PMID- 28568088 TI - A MODEL OF INDUCIBLE DEFENSE. PMID- 28568089 TI - ORIGINS OF GENOTYPIC VARIATION IN NORTH AMERICAN DANDELIONS INFERRED FROM RIBOSOMAL DNA AND CHLOROPLAST DNA RESTRICTION ENZYME ANALYSIS. AB - Restriction enzyme analysis of ribosomal DNA (rDNA) and chloroplast DNA (cpDNA) is used to assess the relative contribution of hybridization and mutation as sources of genotypic variation in weedy asexual dandelions, with focus on the dandelion flora of North America. Of 318 North American dandelions surveyed, 145 rDNA-cpDNA clones are detected. The combined rDNA-cpDNA genotypes show that most of the polymorphic rDNA and cpDNA restriction sites or lengths in these plants are also present in weedy asexual dandelions collected from natural populations in Europe and in asexual and diploid taxa (microspecies) chosen to represent diverse Eurasian members of the genus. However, of 222 combined rDNA-cpDNA genotypes found in 427 asexual plants surveyed, only 9 genotypes are found in both North American and Eurasian dandelions. Two rDNA and three cpDNA characters are unique to individual plants in North America and are consistent with mutational origins of genotypic variation in asexual lineages. But the array of genotypic diversity, characterized by different combinations of the rDNA and cpDNA characters, show that multiple hybridization events are a more important source of genotypic variation than mutation in the asexual polyploids. The rDNA and cpDNA data also indicate polyphyletic origin of several asexual Taraxacum taxa. PMID- 28568090 TI - PEAK SHIFTS PRODUCED BY CORRELATED RESPONSE TO SELECTION. AB - Traits may evolve both as a consequence of direct selection and also as a correlated response to selection on other traits. While correlated response may be important for both the production of evolutionary novelty and in the build-up of complex characters, its potential role in peak shifts has been neglected empirically and theoretically. We use a quantitative genetic model to investigate the conditions under which a character, Y, which has two alternative optima, can be dragged from one optimum to the other as a correlated response to selection on a second character, X. High genetic correlations between the two characters make the transition, or peak shift, easier, as does weak selection tending to restore Y to the optimum from which it is being dragged. When selection on Y is very weak, the conditions for a peak shift depend only on the location of the new optimum for X and are independent of the strength of selection moving it there. Thus, if the "adaptive valley" for Y is very shallow, little reduction in mean fitness is needed to produce a shift. If the selection acts strongly to keep Y at its current optimum, very intense directional selection on X, associated with a dramatic drop in mean fitness, is required for a peak shift. When strong selection is required, the conditions for peak shifts driven by correlated response might occur rarely, but still with sufficient frequency on a geological timescale to be evolutionarily important. PMID- 28568091 TI - EXAMINATION OF POPULATION STRUCTURE IN RED-COCKADED WOODPECKERS USING DNA PROFILES. AB - The degree to which DNA similarity is related to kinship and population structure in natural populations was investigated for a small population of cooperatively breeding Red-cockaded Woodpeckers (Picoides borealis) in the western Piedmont region of South Carolina. An independent pedigree was established from records of color-banded individuals. Results of DNA profiles were then examined relative to this pedigree. DNA similarity among unrelated woodpeckers averaged 0.55 +/- 0.01 (SE). The mean number of DNA bands scored and similarity did not significantly differ between founders and the current population. Examination of parentage in 10 families indicated that multiple paternity did not occur when band by band comparisons or similarity values were compared among parents, helpers, and offspring. Thus, Red-cockaded Woodpeckers were monogamous in this population. DNA similarity among all individuals ranged from 0.32-0.78. Distribution of these similarity values by kinship resulted in some overlap with other kin values. Therefore, specific similarity values could not be assigned a kinship value without knowledge of the pedigree. However, least-squares linear regression indicated that similarity was significantly related to kinship (P < 0.05). These results indicate that use of DNA profiles may be important in quantifying population structure, however, they must be used in conjunction with a known pedigree before any assessment of kinship among individuals is made. Band by band comparisons remain a viable technique for examination of parentage when all putative parents have been sampled. PMID- 28568092 TI - THE EFFECTS OF HOST-PLANT GENOTYPE, HYBRIDIZATION, AND ENVIRONMENT ON GALL-APHID ATTACK AND SURVIVAL IN COTTONWOOD: THE IMPORTANCE OF GENETIC STUDIES AND THE UTILITY OF RFLPS. AB - Using restriction fragment length polymorphisms (RFLPs) we show how host-plant genotype and hybridization in cotton wood, Populus sp., affects the attack and survival of the gall-forming aphid, Pemphigus betae. Fremont cottonwoods, hybrid ***F1's and backcross ***1's were found to be highly resistant, while backcross 2's, 3's, 4's and pure narrowleafs ranged from highly resistant to highly susceptible with only a few trees being highly resistant. Results from our genetic analysis also suggest that resistance is likely polygenic, not the result of single gene resistance. In addition, genetic analysis showed that studies based upon leaf morphology alone give an inaccurate assessment of host-plant genotype ***and the extent of hybridization, altering previous views of the relationship between plant hybridization and pest attack. Previous studies assumed that narrowleafs were more resistant than backcross genotypes based upon comparisons of overall levels of resistance between the hybrid zone and the "pure" narrowleaf zone. Results from RFLP analyses, however, show that there are no significant differences in the levels of resistance between backcross genotypes (BC2's-4's) and pure narrowleafs. Furthermore, results show that the "pure" narrowleaf zone is in fact a mixture of pure and backcross genotypes, extending the zone of introgression previously reported. Experiments in combination with RFLP analyses suggest that resistance traits are differentially expressed along an environmental gradient partially explaining the previously reported differences in resistance between these two regions. In light of our results it is clear that genetic studies will be necessary to discern the true relationship between hybridization and pest resistance. Until such studies are widely conducted generalizations regarding the effects of hybridization on the structure and dynamics of pest populations will be premature at best. PMID- 28568093 TI - DIRECT AND INDIRECT ESTIMATES OF NEIGHBORHOOD AND EFFECTIVE POPULATION SIZE IN A TROPICAL PALM, ASTROCARYUM MEXICANUM. AB - To estimate the relative importance of genetic drift, the effective population size ***(Ne ) can be used. Here we present estimates of the effective population size and related measures in Astrocaryum mexicanum, a tropical palm from Los Tuxtlas rain forest, Veracruz, Mexico. Seed and pollen dispersal were measured. Seeds are primarily dispersed by gravity and secondarily dispersed by small mammals. Mean primary and secondary dispersal distances for seeds were found to be small (0.78 m and 2.35 m, respectively). A. mexicanum is beetle pollinated and pollen movements were measured by different methods: a) using fluorescent dyes, b) as the minimum distance between active female and male inflorescences, and c) using rare allozyme alleles as genetic markers. All three estimates of pollen dispersal were similar, with a mean of approximately 20 m. Using the seed and pollen dispersal data, the genetic neighborhood area (A) was estimated to be 2,551 m2 . To obtain the effective population size, three different overlapping generation methods were used to estimate an effective density with demographic data from six permanent plots. The effective density ranged from 0.040 to 0.351 individuals per m2 . The product of effective density and neighborhood area yields a direct estimate of the neighborhood effective population size (Nb ). Nb ranged from 102 to 895 individuals. Indirect estimates of population size and migration rate (Nm) were obtained using Fst for five different allozymic loci for both adults and seeds. We obtained a range of Nm from 1.2 to 19.7 in adults and a range of Nm from 4.0 to 82.6 for seeds. We discuss possible causes of the smaller indirect estimates of Nm relative to the direct and compare our estimates with values from other plant populations. Gene dispersal distances, neighborhood size, and effective population size in A. mexicanum are relatively high, suggesting that natural selection, rather than genetic drift, may play a dominant role in patterning the genetic variation in this tropical palm. PMID- 28568094 TI - RESPONSES AND CORRELATED RESPONSES TO ARTIFICIAL SELECTION ON THORAX LENGTH IN DROSOPHILA MELANOGASTER. AB - Two sets of four replicate lines of Drosophila melanogaster were selected for large and small thorax with controls. F, progeny of crosses between the selected lines within each size category showed (a) a reduction in preadult viability in large lines relative to control and small lines when they were cultured at medium or high density in competition with a standard mutant marked competitor stock, and (b) an increase in larval development time in large lines relative to control and small lines. Natural selection for increased body size in adults may therefore be opposed by adverse effects on larval viability. The results are discussed in terms of the developmental mechanisms probably responsible for the change in body size. The preadult survival of the large and control lines was measured at three different temperatures, and there was no evidence for a significant interaction between size and temperature. The observed evolutionary increase in body size in response to reduced temperature in Drosophila must therefore involve either different genes from those subject to selection for size at a single temperature, or a fitness component other than preadult survival. There was no significant asymmetry in response to selection, and thorax length showed heterosis in crosses between the selected lines. PMID- 28568095 TI - PHENOTYPIC PLASTICITY IN BODY SIZES AND SEXUAL SIZE DIMORPHISM IN EUROPEAN GRASS SNAKES. PMID- 28568096 TI - OUTCROSSING RATE AND INBREEDING DEPRESSION IN TWO ANNUAL MONOECIOUS HERBS, BEGONIA HIRSUTA AND B. SEMIOVATA. AB - Most models of mating-system evolution predict inbreeding depression to be low in inbred populations due to the purging of deleterious recessive alleles. This paper presents estimates of outcrossing rates and inbreeding depression for two highly selfing, monoecious annuals Begonia hirsuta and B. semiovata. Outcrossing rates were estimated using isozyme polymorphisms, and the magnitude of inbreeding depression was quantified by growing progeny in the greenhouse produced through controlled selfing and outcrossing. The estimated single-locus outcrossing rate was 0.03 +/- 0.01 (SE) for B. hirsuta and 0.05 +/- 0.02 for B. semiovata. In both species, the seed production of selfed flowers was on average 12% lower than that of outcrossed flowers (B. hirsuta P = 0.07, B. semiovata P < 0.05, mixed model ANOVAs). There was no significant effect of crosstype on germination rate or survival, but selfed offspring had a lower dry mass than outcrossed offspring 18 weeks after planting in both species (on average 18% lower in B. hirsuta and 31% lower in B. semiovata). Plants that were the products of selfing began flowering later than plants produced through outcrossing in B. semiovata, but not in B. hirsuta. The effects of crosstype on seed production (B. semiovata), days to first flower and offspring dry mass (both species) varied among maternal parents, as indicated by significant crosstype x maternal parent interactions for these characters. Both species showed significant inbreeding depression for total fitness (estimated as the product of seed production, germination rate, survival and dry mass at 18 weeks). In B. hirsuta, the average total inbreeding depression was 22% (range -57%-98%; N = 23 maternal parents), and in B. semiovata, it was 42% (-11%-84%; N = 21). This study demonstrates that highly selfing populations can harbor substantial inbreeding depression. Our findings are consistent with the hypothesis that a high mutation rate to mildly deleterious alleles contributes to the maintenance of inbreeding depression in selfing populations. PMID- 28568097 TI - ISOLATION BY DISTANCE IN EQUILIBRIUM AND NON-EQUILIBRIUM POPULATIONS. AB - It is shown that for allele frequency data a useful measure of the extent of gene flow between a pair of populations is M?=(1/FST-1)/4, which is the estimated level of gene flow in an island model at equilibrium. For DNA sequence data, the same formula can be used if FST is replaced by NST . In a population with restricted dispersal, analytic theory shows that there is a simple relationship between M and geographic distance in both equilibrium and non-equilibrium populations and that this relationship is approximately independent of mutation rate when the mutation rate is small. Simulation results show that with reasonable sample sizes, isolation by distance can indeed be detected and that, at least in some cases, non-equilibrium patterns can be distinguished. This approach to analyzing isolation by distance is used for two allozyme data sets, one from gulls and one from pocket gophers. PMID- 28568098 TI - FLIGHT CAPABILITIES IN ARCHAEOPTERYX. PMID- 28568099 TI - DIRECTIONAL AND STABILIZING DENSITY-DEPENDENT NATURAL SELECTION FOR PUPATION HEIGHT IN DROSOPHILA MELANOGASTER. AB - Six populations of Drosophila melanogaster have been kept at extreme population densities, three high and three low, for 175 generations. Larvae from the high density populations pupate 50%-100% higher than larvae from the low density populations. At high larval test densities there is both a directional and a stabilizing component to selection, with viabilities ranging from 0.14 to 0.992, depending on the choice of pupation site. The directional component is stronger on the populations which have evolved at low densities, while the stabilizing component is stronger on the populations which have evolved at high densities. There is no indication that the evolution of this trait, in response to density, has altered its phenotypic plasticity. PMID- 28568100 TI - PHYLOGENY AND THE REVERSIBILITY OF PARASITISM. PMID- 28568101 TI - ADAPTIVE SIGNIFICANCE OF IPOMOPSIS AGGREGATA NECTAR PRODUCTION: OBSERVATION AND EXPERIMENT IN THE FIELD. AB - Production of floral nectar is generally thought to be an adaptation that increases plant fitness by altering pollinator behavior, and therefore pollination success. To test this hypothesis, I investigated the effects of floral nectar production rate on pollination success of the hermaphroditic plant Ipomopsis aggregata (Polemoniaceae). Success through male function (estimated by the export of fluorescent dyes) was significantly greater for plants with naturally high nectar production rates than for nearby plants with low nectar production rates, whereas success through female function (receipt of fluorescent dye) was unrelated to nectar production rate. Experimental addition of artificial nectar also produced a significant increase in male function success and no increase in several estimates of female function success. Observations confirmed that hummingbirds probed a larger proportion of flowers on plants that received supplemental nectar, as they do in response to natural variation in nectar production. The concordance of results across these observational and experimental studies indicates that nectar production acts primarily to increase pollination success through male function for this species. PMID- 28568103 TI - LARVAL DISPERSAL AND LOCAL ADAPTATION IN ACORN BARNACLES. PMID- 28568102 TI - SPECIATION IN NORTH AMERICAN CHICKADEES: I. PATTERNS OF mtDNA GENETIC DIVERGENCE. AB - We surveyed mitochondrial DNA haplotype divergence within and between populations of six species of North American chickadees (Parus, Subgenus Poecile) with the following results. (1) Genotype diversities (range 0.3 to 0.7) and low nucleotide diversities (range 3 to 27 * 10-4 ) within populations were typical of known vertebrates. (2) The two widespread, northern species (atricapillus and hudsonicus) exhibit little mtDNA genetic differentiation throughout their previously glaciated continental distributions, most likely because of recent, postglacial range expansions. (3) Newfoundland populations of atricapillus and maritime province (Newfoundland plus Nova Scotia) populations of hudsonicus have distinct mtDNA haplotypes which differ from continental haplotypes by single restriction site changes. (4) Haplotypes of the southeastern U.S. species P. carolinensis divide into eastern and western sets which have diverged by three percent. This heretofore unrecognized, divided population structure may correspond to the Tombigbee River/ Mobile Bay disjunction known in some other vertebrate taxa. (5) Allopatric populations of the southwestern species sclateri and gambeli exhibit divergences of one and three percent respectively. (6) Prevailing interspecific divergence distances of three to seven percent suggest speciation early in the Pleistocene rather than during late (e.g., Wisconsin) glaciations. (7) Phylogenetic analyses suggest that North American taxa include two clades, hudsonicus-rufescens-sclateri versus carolinensis-atricapillus gambeli and that carolinensis and atricapillus are not sister species. PMID- 28568104 TI - PATTERNS OF RUST INFECTION AS A FUNCTION OF HOST GENETIC DIVERSITY AND HOST DENSITY IN NATURAL POPULATIONS OF THE APOMICTIC CRUCIFER, ARABIS HOLBOELLII. AB - It is often assumed that genetic diversity contributes to reduced disease incidence in natural plant populations. However, little is known about the genetic structure of natural populations affected by disease. Here I present data from three apomictic (asexual) populations of Arabis holboellii infected by the rusts Puccinia monoica and P. thlaspeos. An average of 300 host individuals per population were genotyped (using seven variable allozyme loci) and scored for disease presence. Arabis holboellii populations are genetically diverse; the number of clones detected per population ranged from 6 to 27. There was substantial variation in frequency of host clones within and among sites, and significant variation among clones in susceptibility to the different rusts. Contrary to predictions based on frequency-dependent selection theory there was not a consistent positive relationship between clone frequency and disease incidence within any of the populations (Spearman's r = -0.096, P > 0.5). In addition, clonally diverse populations did not necessarily have decreased disease incidence. The population with the lowest overall (both pathogens combined) disease incidence (7.5 +/- 1.9%) had the smallest number of clones (6), the lowest spatial variability, and the highest Arabis density. By comparison, another population had 22 clones, high spatial variability, low Arabis density and significantly more disease overall (16.8 +/- 2.7%). Although this study does not eliminate the possibility of frequency-dependent pathogen attack in these populations, the results suggest that it is likely to be weak or intermittent. PMID- 28568105 TI - ADAPTIVE RADIATION AND THE TOPOLOGY OF LARGE PHYLOGENIES. AB - The idea that some organisms possess adaptive features that make them more likely to speciate and/or less likely to go extinct than closely related groups, suggests that large phylogenetic trees should be unbalanced (more species should occur in the group possessing the adaptive features than in the sister group lacking such features). Several methods have been used to document this type of adaptive radiation. One problem with these attempts is that evolutionary biologists may overlook balanced phylogenies while focusing on a few impressively unbalanced ones. To overcome this potential bias, we sampled published large phylogenies without regard to tree shape. These were used to test whether or not such trees are consistently unbalanced. We used recently developed null models to demonstrate that the shapes of large phylogenetic trees: 1) are similar among angiosperms, insects, and tetrapods; 2) differ from those expected due to random selection of a phylogeny from the pool of all trees of similar size; and 3) are significantly more unbalanced than expected if species diverge at random, therefore, conforming to one prediction of adaptive radiation. This represents an important first step in documenting whether adaptive radiation has been a general feature of evolution. PMID- 28568106 TI - A PRODUCT OF DISCRIMINATIVE LEARNING MAY LEAD TO FEMALE PREFERENCES FOR ELABORATE MALES. PMID- 28568107 TI - A QUANTITATIVE GENETIC ANALYSIS OF OVIPOSITION PREFERENCE AND LARVAL PERFORMANCE ON TWO HOSTS IN THE BRUCHID BEETLE, CALLOSOBRUCHUS MACULATUS. AB - The presence of positive genetic correlations between oviposition or feeding preference for hosts, and performance on those hosts, is of fundamental importance to models of host race formation, sympatric speciation, and the maintenance of genetic variation within phytophagous insect populations. In this paper, I estimate the amount of genetic variation in oviposition preference and larval performance present in two California populations of a cosmopolitan pest of stored legumes, Callosobruchus maculatus (Bruchidae: Coleoptera), and examine whether positive genetic correlations exist between preference and performance. High levels of genetic variation in both preference and performance were detected in one population (Bay Area population, h2 = 0.73 for oviposition preference), but not in another population (Davis population). A second estimate of the amount of genetic variation for oviposition preference in the Bay Area population, after three generations of laboratory rearing, supports the hypothesis that the absence of significantly nonzero heritabilities in the Davis population is probably due to the three generations of laboratory rearing prior to the start of the experiment. No positive genetic correlations were detected between preference and any performance character measured. Data are also presented on the genetic correlations between performance on azuki (Vigna angularis) and cowpea (Vigna unguiculata). Genetic correlations were found to be positive for all characters in both populations of C. maculatus (range 0.132 to 0.542). PMID- 28568108 TI - HOST PREFERENCE AND ALLOZYME DIFFERENTIATION IN SHOOT GALLING SAWFLY, EUURA ATRA. PMID- 28568109 TI - DEVELOPMENTAL SELECTION IN RESPONSE TO ENVIRONMENTAL CONDITIONS OF THE MATERNAL PARENT IN MIMULUS GUTTATUS. AB - Copper tolerance is expressed in the diploid sporophyte as well as the microgametophyte of Mimulus guttatus. Previous studies, based on reproductive output, suggested that selection for copper tolerance could occur within the pistil. The objective of this study was to determine if selection within the pistil can increase sporophytic tolerance to copper and to determine whether this selection occurs pre- or postzygotically. Mixtures of pollen from copper tolerant or sensitive sources or from plants heterozygous for tolerance to copper were applied at two intensities to plants cloned and grown in control or copper supplemented solutions. The proportion of copper tolerant progeny showed a small, 7%, but significant increase when pollen recipients were grown with added copper. Comparisons of the numbers of tolerant progeny, as well as various components of reproduction, following light and heavy pollinations suggested that microgametophytic selection was unlikely to account for this increase. However, the 8 to 10% decrease in the seed/zygote ratio, compared to control values, was sufficient to account for the difference in proportion of copper tolerant progeny from control and copper treated plants. Thus, it appeared likely that selection for copper tolerance could occur within the pistil, and that much of this selection occurred postzygotically through the early failure of developing seeds. PMID- 28568110 TI - PLASTIC RELATIONSHIPS BETWEEN REPRODUCTIVE AND VEGETATIVE MASS IN SOLIDAGO ALTISSIMA. AB - To test several predictions of a model of linear, size-dependent reproductive output in plants, we analyzed the relationship between shoot vegetative (v) and reproductive (r) mass in five experiments on Solidago altissima from an invading population in Switzerland. There was large environmentally-induced and genetic variation in r and v. A large amount of variation in r could be explained by variation in v, using the simple linear model. There was a minimum size for sexual reproduction, and above this size, shoots devoted a relatively constant proportion (about one third) of their biomass to reproductive structures. We detected significant genetic variation for both the minimum size and the slope of the r-v relationship, but there was no evidence for an hypothesized trade-off between minimum size and slope. There was significant genotype-environment interaction for the slope of the r-v relationship. There were also developmental effects on the r-v relationship: plants grown from seeds behaved differently than those of the same genotype grown from rhizomes. PMID- 28568111 TI - A follow-up on desiderosmia (olfactory craving), a novel symptom associated with iron deficiency anemia. PMID- 28568112 TI - Factors associated with early extubation after superior cavopulmonary connection: analysis from single ventricle reconstruction trial. AB - BACKGROUND: To evaluate the landscape of early extubation, and identify factors associated with early extubation (<= 24 h) after superior cavopulmonary connection (stage 2 operation) among children with single ventricle anatomy. METHODS: Patients undergoing stage 2 operation after Norwood operation from the Pediatric Heart Network Single Ventricle Reconstruction (SVR) trial public-use dataset were included. Elastic net regularized logistic regression models were fitted to evaluate the factors associated with early extubation after stage 2 operation. RESULTS: In total, 390 patients from 15 North American centers qualified for inclusion. Of these, 42 patients (10.8%) were extubated in operating room, 151 patients (38.7%) were extubated outside the operating room within the first 24 h after stage 2 operation, and the remaining 197 patients (50.5%) required mechanical ventilation for > 24 h. In adjusted models, factors associated with early extubation after stage 2 operation were elective timing of stage 2 operation, lower incidence of post-Norwood complications, shorter CPB duration for stage 2 operation, and no cardiac catheterization after Stage 2 operation. We also performed multiple other alternative analyses to identify factors associated with early extubation that demonstrated same associations as the primary model. The mean hospital length of stay after Stage 2 operation was 20% shorter among patients with early extubation. CONCLUSIONS: Data from this large multicenter study demonstrate that approximately one-half of the patients undergoing operation for superior cavopulmonary connection are extubated within 24 h after heart operation. Furthermore, early extubation is associated with shorter hospital length of stay. PMID- 28568114 TI - CONVERGENCE OF ECOLOGICAL PROCESSES BETWEEN INDEPENDENTLY EVOLVED COMPETITIVE DOMINANTS: A TUNICATE-MUSSEL COMPARISON. PMID- 28568115 TI - AN ESTIMATE OF THE RELATIVE OPPORTUNITIES FOR NATURAL AND SEXUAL SELECTION IN A POPULATION OF MILKWEED BEETLES. PMID- 28568113 TI - Can mobile phone technology support a rapid sharing of information on novel psychoactive substances among health and other professionals internationally? AB - BACKGROUND: The diffusion of novel psychoactive substances (NPSs), combined with the ability of the Internet to act as an online marketplace, has led to unprecedented challenges for governments, health agencies, and substance misuse services. Despite increasing research, there is a paucity of reliable information available to professionals working in the field. The paper will present the pilot results of the first mobile application (SMAIL) for rapid information sharing on NPSs among health professionals. METHODS: The development of SMAIL was divided into 2 parts: (a) the creation of the application for registered users, enabling them to send an SMS or email with the name or "street name" of an NPS and receive within seconds emails or SMS with the information, when available and (b) the development of a database to support the incoming requests. RESULTS: One hundred twenty-two professionals based in 22 countries used the service over the pilot period of 16 months (from May 2012 to September 2013). Five hundred fifty-seven enquires were made. Users received rapid information on NPSs, and 61% of them rated the service as excellent. CONCLUSIONS: This is the right time to use mobile phone technologies for rapid information sharing and prevention activities on NPSs. PMID- 28568116 TI - ON THE RELATIONSHIP BETWEEN AVERAGE COPULATION DURATION AND INSEMINATION REACTION IN THE GENUS DROSOPHILA. PMID- 28568117 TI - SELF-INCOMPATIBILITY IN CENTRAL AMERICAN HELICONIA. PMID- 28568118 TI - CHEMICAL EVOLUTION AND CHEMOSYSTEMATICS OF THE DUFOUR'S GLAND SECRETIONS OF THE LACTONE-PRODUCING BEES (HYMENOPTERA: COLLETIDAE, HALICTIDAE, AND OXAEIDAE). PMID- 28568119 TI - EVOLUTION OF AN ALL-FEMALE FISH, MENIDIA CLARKHUBBSI (ATHERINIDAE). PMID- 28568120 TI - A COADAPTED TROPHIC NICHE IN TWO SPECIES OF CRUSTACEA (ISOPODA): ASELLUS AQUATICUS (L.) AND PROASELLUS COXALIS DOLFF. PMID- 28568121 TI - GENIC VARIATION AND DIFFERENTIATION OF REMNANT NATURAL POPULATIONS OF THE DESERT PUPFISH, CYPRINODON MACULARIUS. PMID- 28568122 TI - POLYMORPHISM OF ALCOHOL DEHYDROGENASE (ADH) IN A WINERY CELLAR POPULATION OF DROSOPHILA MELANOGASTER: GENE FREQUENCY ASSOCIATION WITH TEMPERATURE AND GENOTYPIC DIFFERENCES IN PROGENY PRODUCTION. PMID- 28568123 TI - GENETIC AND ENVIRONMENTAL COMPONENTS OF CLUTCH SIZE VARIANCE IN A WILD POPULATION OF LESSER SNOW GEESE (ANSER CAERULESCENS CAERULESCENS). PMID- 28568124 TI - CONTRASTING GENE FLOW PATTERNS AND GENETIC SUBDIVISION IN ADJACENT POPULATIONS OF CUCUMIS SATIVUS (CUCURBITACEAE). PMID- 28568125 TI - CLONAL DIVERSITY AND EVOLUTIONARY DYNAMICS IN A DIPLOID-TRIPLOID BREEDING COMPLEX OF UNISEXUAL FISHES (POECILIA). PMID- 28568126 TI - Erratum. PMID- 28568127 TI - MULTIPLE MATING AND FEMALE FITNESS IN DROSOPHILA PSEUDOOBSCURA. PMID- 28568128 TI - MALE FERTILITY AND ANISOPLETHIC POPULATION STRUCTURE IN TRISTYLOUS PONTEDERIA CORDATA (PONTEDERIACEAE). PMID- 28568129 TI - REDUCTION OF GENE FLOW DUE TO THE PARTIAL STERILITY OF HETEROZYGOTES FOR A CHROMOSOME MUTATION. I. STUDIES ON A "NEUTRAL" GENE NOT LINKED TO THE CHROMOSOME MUTATION IN A TWO POPULATION MODEL. PMID- 28568130 TI - PATTERN AND CHANCE IN THE STRUCTURE OF MODEL AND NATURAL COMMUNITIES. PMID- 28568131 TI - INTERSPECIFIC VARIATION IN THE SIZE OF THE NUTRIENT INVESTMENT MADE BY MALE BUTTERFLIES DURING COPULATION. PMID- 28568132 TI - UNORTHODOXIES IN THE FIRST FORMULATION OF NATURAL SELECTION. PMID- 28568133 TI - GENETIC DISTANCE AND EVOLUTIONARY RELATIONSHIPS IN THE DROSOPHILA OBSCURA GROUP. PMID- 28568134 TI - Lysyl oxidase-mediated VEGF-induced differentiation and angiogenesis in human dental pulp cells. AB - AIM: To investigate the effects of recombinant human vascular endothelial growth factor (rhVEGF) on odontoblastic differentiation, in vitro angiogenesis, and expression and activity of lysyl oxidase (LOX) in human dental pulp cells (HDPCs), compared with rhFGF-2. To identify the underlying molecular mechanisms, the study focused on whether LOX was responsible for the actions of rhVEGF. METHODOLOGY: Recombinant human vascular endothelial growth factor (rhVEGF) was constructed using the pBAD-HisA plasmid in Escherichia coli. HDPCs were treated with 1-50 MUg mL-1 rhVEGF for 14 days. Alkaline phosphatase (ALP) activity was measured, and the formation of calcified nodules was assessed using alizarin red staining after the induction of odontogenic differentiation of HDPCs. The expression level of the odontogenic differentiation markers was detected by reverse transcription polymerase chain reaction. Signal pathways were assessed by Western blot and immunocytochemistry. The data were analysed by anova with Bonferroni's test (alpha = 0.05). RESULTS: Recombinant human vascular endothelial growth factor significantly increased cell growth (P < 0.05), ALP activity (P < 0.05) and mineralization nodule formation and upregulated the mRNA expression levels of the osteogenic/odontogenic markers that were lower with rhFGF-2. rhVEGF significantly increased amine oxidase activity (P < 0.05) and upregulated LOX and LOXL mRNA expression in HDPCs. Additionally, rhVEGF dose-dependently upregulated angiogenic gene mRNAs and capillary tube formation to a greater degree than rhFGF 2. Inhibition of LOX using beta-aminopropionitrile (BAPN) and LOX or LOXL gene silencing by RNA interference attenuated rhVEGF-induced growth, ALP activity, mineralization, the expression of marker mRNAs and in vitro angiogenesis. Furthermore, treatment with rhVEGF resulted in phosphorylation of Akt, ERK, JNK and p38, and activation of NF-kappaB, which was inhibited by LOX or LOXL silencing and BAPN. CONCLUSION: Recombinant human vascular endothelial growth factor promoted cell growth, odontogenic potential and in vitro angiogenesis via modulation of LOX expression. These results support the concept that rhVEGF may offer therapeutic benefits in regenerative endodontics. PMID- 28568136 TI - MHC VARIATION IN THE ENDANGERED GILA TOPMINNOW. AB - Sequence variation at a major histocompatibility complex (MHC) gene, assumed to be involved in parasite and pathogen resistance, was examined in the endangered Gila topminnow (Poeciliopis o. occidentalis), from the four watersheds where they remain in the United States. This is the first estimate of variation in MHC genes in natural populations of an endangered species. The population that has experienced the most bottlenecks historically was monomorphic for MHC variation. Another population, which earlier had been found to be the only population polymorphic for allozymes, had five MHC alleles, four different from those found in the other populations. Overall, nine different alleles were found. The four populations were highly divergent at MHC with four of the six population pairs not sharing any alleles. However, the magnitude of differentiation between populations on the amino-acid level varied fivefold for the populations that shared no alleles. Using single-stranded conformational polymorphism (SSCP), these alleles segregated consistently with Mendelian expectations in families. Because of the high genetic differentiation between these populations for a potentially adaptive gene, we recommend that the four watersheds be examined further for separate conservation and management. PMID- 28568135 TI - EVIDENCE OF A BIOGEOGRAPHIC BREAK BETWEEN POPULATIONS OF A HIGH DISPERSAL STARFISH: CONGRUENT REGIONS WITHIN THE INDO-WEST PACIFIC DEFINED BY COLOR MORPHS, mtDNA, AND ALLOZYME DATA. AB - Both mtDNA variation and allozyme data demonstrate that geographic groupings of different color morphs of the starfish Linckia laevigata are congruent with a genetic discontinuity between the Indian and Pacific Oceans. Populations of L. laevigata sampled from Thailand and South Africa, where an orange color morph predominates, were surveyed using seven polymorphic enzyme loci and restriction fragment analysis of a portion of the mtDNA including the control region. Both allozyme and DNA data demonstrated that these populations were significantly genetically differentiated from each other and to a greater degree from 23 populations throughout the West Pacific Ocean, where a blue color morph is predominant. The genetic structure observed in L. laevigata is consistent with traditional ideas of a biogeographic boundary between the Indian and Pacific Oceans except that populations several hundreds kilometers off the coast of north Western Australia (Indian Ocean) were genetically similar to and had the same color morphs as Pacific populations. It is suggested that gene flow may have continued (possibly at a reduced rate) between these offshore reefs in Western Australia and the West Pacific during Pleistocene falls in sea level, but at the same time gene flow was restricted between these Western Australian populations and those in both Thailand and South Africa, possibly by upwellings. The molecular data in this study suggest that vicariant events have played an important role in shaping the broadscale genetic structure of L. laevigata. Additionally, greater genetic structure was observed among Indian Ocean populations than among Pacific Ocean populations, probably because there are fewer reefs and island archipelagos in the Indian Ocean than in the Pacific, and because present-day surface ocean currents do not facilitate long-distance dispersal. PMID- 28568137 TI - POLYMORPHISM REGENERATION FOR A NEUTRALIZED SELFISH B CHROMOSOME. AB - Long-run evolution of B chromosomes is mainly made up by an evolutionary arms race between these selfish genetic elements and the standard genome. The suppression of B drive is one of the clearest expressions of genome defense against B chromosomes. After drive neutralization, the B is condemned to extinction unless a new variant showing drive can emerge and replace it. This paper reports the first empirical evidence for the substitution of a neutralized B variant by a new selfish B variant. Such a polymorphism regeneration has recently taken place in a natural population of the grasshopper Eyprepocnemis plorans. PMID- 28568138 TI - MATE AVAILABILITY AND FECUNDITY SELECTION IN MULTI-ALLELIC SELF-INCOMPATIBILITY SYSTEMS IN PLANTS. AB - We investigate mate availability in different models of multiallelic self incompatibility systems in mutation-selection-drift balance in finite populations. Substantial differences among self-incompatibility systems occur in average mate availability, and in variances of mate availability among individual plants. These differences are most pronounced in small populations in which low mate availability may reduce seed set in some types of sporophytic self incompatibility. In cases where the pollination system causes a restriction in the number of pollen genotypes available to an individual plant, the fecundity of that plant depends on the availability of compatible pollen, which is determined by its genotype at the incompatibility locus. This leads to an additional component of selection acting on self-incompatibility systems, which we term "fecundity selection." Fecundity selection increases the number of alleles maintained in finite populations and increases mate availability in small populations. The strength of fecundity selection is dependent on the type of self incompatibility. In some cases, fecundity selection markedly alters the equilibrium dynamics of self-incompatibility alleles. We discuss the population genetic consequences of mate availability and fecundity selection in the contexts of conservation management of self-incompatible plant species and experimental investigations on self-incompatibility in natural populations. PMID- 28568139 TI - DISENTANGLING THE EFFECTS OF MATING PROPENSITY AND MATING CHOICE IN DROSOPHILA. AB - Incipient sexual isolation between genotypes, lines, or populations of the same species is commonly measured in Drosophila by choice tests. Results of these tests are known to be influenced, in an undetermined manner, by the mating propensity of competitors and by discriminatory factors during courtship. We have approached the problem by measuring male and female propensities in separate, independent tests, and by examining whether these estimates could explain the results of the choice tests. First, male and female choice tests were used to measure sexual isolation between populations of Drosophila melanogaster and between populations of D. simulans. Significant deviations from random mating occurred in 31 out of 48 tests, in agreement with the propensity values of the tested genotypes. We conclude that mating propensity instead of discrimination is directly involved in the estimation of sexual isolation in our populations, and advise against the application of male and female choice tests to assess intraspecific isolation without a proper knowledge of the mating propensities of competing individuals. Second, multiple choice tests were used to assess isolation between D. melanogaster populations. In examining the dynamics of matings throughout the test, we show that if competing individuals differ in mating propensities and tests are long enough to allow most matings to happen, a spurious sexual isolation can appear. We recommend that multiple choice tests be terminated once 50 percent of matings had been observed. PMID- 28568140 TI - HABITAT PREFERENCE IN THE BOMBINA HYBRID ZONE IN CROATIA. AB - This paper demonstrates the effect of habitat heterogeneity and a habitat preference on the genetic structure of a hybrid zone between the toads Bombina bombina and B. variegata (Anura: Discoglossidae); 1613 toads from 85 sites across a transect near Pescenica, Croatia, were scored for five unlinked diagnostic allozyme markers. These were found to be largely concordant. Aside from minor systematic deviations, there was little variance in allele frequency among loci within sites. Yet the allele frequencies did not follow a smooth cline, but formed a mosaic in the center, such that neighboring sites could differ markedly in their enzyme score. A detailed ecological survey revealed a correlation between this pattern and habitat. In keeping with the typical breeding sites of the parental taxa, B. bombina-like hybrids were found more often in ponds, whereas B. variegata-like hybrids were more common in puddles. In addition, there was significant heterozygote deficit (FIS ) and strong linkage disequilibrium (R), both of which were stronger on the B. bombina side of the transect, and stronger in puddles than ponds. Mark-recapture data showed: (1) that the animals disperse beyond the scale of the habitat pattern; (2) frequent turn-over of individuals within sites; and (3) nonrandom movement between two sites of different habitat type. We conclude that an active habitat preference must contribute to the observed association between marker alleles and habitat. As a consequence, there is incomplete mixing of the two gene pools, which could explain the high level of FIS and R. The asymmetry in these parameters may reflect asymmetry in the preference or in the distribution of habitats across the zone. We discuss the implications of habitat preference for the dynamics of hybrid zones. PMID- 28568141 TI - DIRECT AND INDIRECT ESTIMATES OF SEED VERSUS POLLEN MOVEMENT WITHIN A POPULATION OF PONDEROSA PINE. AB - We examined the spatial distribution of maternally inherited mitochondrial DNA and paternally inherited chloroplast DNA polymorphisms in a permanently marked stand of ponderosa pine (Pinus ponderosa Laws). Movement of maternally inherited mtDNA occurs only via seed dispersal, and mtDNA haplotypes showed significant patch structure. Moreover, individuals within patches identified by mtDNA haplotypes were related approximately as half-sibs based upon analysis of allozyme genotypes. Thus, seed dispersal is limited within the population, and creates matrilineal clusters in space. By contrast, paternally inherited cpDNA is dispersed by movement of both seed and pollen. Chloroplast DNA polymorphisms showed no evidence of patch structure, but rather a weak (and nonsignificant) trend toward hyperdispersion, suggesting nearly unlimited movement of pollen among trees within this stand. Two of the trees had unique allozyme alleles, which were used to directly measure pollen movement away from those trees. Marked pollen was as likely to disperse across the population as it was to fertilize near neighbors. PMID- 28568142 TI - CALLING SONGS OF FIELD CRICKETS (TELEOGRYLLUS OCEANICUS) WITH AND WITHOUT PHONOTACTIC PARASITOID INFECTION. AB - The field cricket Teleogryllus oceanicus has been introduced to Hawaii, where it is parasitized by an acoustically orienting parasitoid fly, Ormia ochracea. Previous work showed that call parameters from parasitized populations differ from those in unparasitized populations in a direction expected if selection by flies is occurring. Here we examined songs of males collected in the field and compare calling song characters of crickets later found to harbor parasitoid larvae with those of males free of parasitoids. The two groups differ significantly in several song characteristics, particularly the trill-like long chirp given at the beginning of each song. Males with longer long chirps containing shorter interpulse intervals are more likely to be parasitized, suggesting that the flies find such males more attractive. Depending on the traits females prefer, sexual selection may oppose natural selection in altering T. oceanicus song in parasitized populations. PMID- 28568143 TI - GENETIC VARIATION AND POLYMORPHISM IN THE INDUCIBLE SPINES OF A MARINE BRYOZOAN. AB - Of particular value in understanding the evolution of genotypes with broad phenotypic ranges (phenotypic plasticity) are the few examples of organisms with adaptive plasticity, such as those that develop a defensive morphology in response to cues from predators. We know little about the heritability of inducible defensive characters or the range of phenotypes available for selection to act on in the field. Membranipora membranacea is a colonial marine bryozoan that produces spines within two days of exposure to waterborne predator extracts. Surveys done in 1993 and 1995 showed that the population at Friday Harbor Labs, Washington, was polymorphic for inducible spine type and was composed of a constitutively spined type that produced spines in the absence of a predator stimulus, an unspined phenotype that did not produce spines irrespective of a stimulus, and an inducibly spined phenotype that would produce spines if exposed to the appropriate cue. In 1995, the frequencies of these types were determined through a laboratory common-garden experiment; 178 colonies were cultured from metamorphosis through approximately 30 days and then exposed to the cue. The inducible type was the dominant, comprising 80.3% of the population. The constitutive type made up 6.2% of the population, and the remaining 13.4 % was the unspined type. The frequency of the three types was similar to a preliminary trial of the experiment run in 1993. Experiments also showed that the lengths of the spines of the inducible type varied continuously among genotypes. To assess causes of variation in the inducible spine response and its clonal heritability, 16 clones were subdivided and grown in a common environment and exposed to a single dosage of spine inducing substance (SIS). Spine length showed high clonal heritability. The range of colony responses from a single environment varied from relatively unresponsive to highly responsive colonies with a very low threshold of response. Norms of reaction were quantified for spine lengths of inducible genotypes originating from two field environments by testing them in a concentration series of SIS. Both spine length and spine type varied with concentration of inducer. Within a clone, colonies were more likely to produce membranous spines than corner spines at higher concentrations. At low concentrations, only straight spines were produced. This study showed that populations of M. membranacea at Friday Harbor are a mix of inducible, nonspined and constitutively spined individuals. Even the inducible individuals showed high heritable variation in the length of spine activated, suggesting that there is considerable scope for the evolution of this character. A norm-of-reaction experiment further showed that the type of spine produced, membranous or corner, varied with the concentration of the cue. Factors maintaining the polymorphism and the broad range of genotypes could include high costs of defending the spined types coupled with a shifting biotic regime. PMID- 28568144 TI - SPECIES-WIDE POPULATION STRUCTURE IN A SOUTHEASTERN U.S. FRESHWATER FISH, HETERANDRIA FORMOSA: GENE FLOW AND BIOGEOGRAPHY. AB - The phylogeography of the freshwater fish fauna of the southeastern United States has almost achieved paradigm status in evolutionary biology (Avise 1992), and the major geographic features responsible for shaping species distributions are well characterized. Nevertheless, variation among species in distributions of allele or haplotype frequencies suggests that species-specific processes (e.g., migration) may also play a role in establishing those distributions. There has also been relatively little investigation into how population structure may differ among subregions in the Southeast, for example, on the Florida peninsula versus the U.S. mainland to the northwest and/or northeast. The geology of the peninsula is such that both physical and biotic fluctuations may have been (and still be) particularly important in establishing the population structure of freshwater taxa. This possibility leads to two interesting questions in population genetics. (1) Does gene flow in freshwater species of the region better approximate a one- or two-dimensional pattern? (2) Are populations on the peninsula farther from migration-genetic drift equilibrium than their counterparts on the mainland? These questions were addressed by examining the population strucuture of a livebearing fish, Heterandria formosa; several features of the biology of the species make it particularly likely that recent gene flow has been important in its evolution. I surveyed electrophoretic variation in 34 populations distributed throughout the species range. The phylogeographic patterns observed are in general concordance with those found in other species, although with some differences. A two-dimensional hypothesis of gene flow on the Florida peninsula better explains the data than does a one dimensional one. There is no evidence that populations on the peninsula are farther from migration-drift equilibrium than those to the northwest. Populations in the northeast have lower genetic diversity than those to the south and west and show no isolation by distance; those results are consistent with a recent range expansion into the northeast, although smaller historical effective population sizes could also explain the pattern. PMID- 28568145 TI - INTERSPECIFIC LABORATORY COMPETITION OF THE RECENTLY SYMPATRIC SPECIES DROSOPHILA SUBOBSCURA AND DROSOPHILA PSEUDOOBSCURA. AB - -Drosophila subobscura and D. pseudoobscura are closely related species coexisting on the West Coast of North America, which was recently colonized by D. subobscura. In competition experiments with overlapping generations, D. subobscura is eliminated by D. pseudoobscura in a few generations at all four temperatures and two initial frequencies tested. Yet in one-species cultures, D. subobscura thrives at all experimental conditions. Single-generation competition experiments reveal lower survivorship and productivity of D. subobscura at all temperatures and frequencies. Productivity per female is dependent on the initial frequencies: greater for D. subobscura as its initial frequency becomes higher, but lower for D. pseudoobscura as its frequency becomes higher. Strains of D. subobscura from three disparate geographic origins yield similar results. PMID- 28568146 TI - INTERACTION-INDEPENDENT SEXUAL SELECTION AND THE MECHANISMS OF SEXUAL SELECTION. AB - Darwin identified explicitly two types of sexual selection, male contests (combat and displays) and female choice, and he devoted the overwhelming majority of his examples to traits that influence the outcome of these interactions. Subsequent treatments of sexual selection have emphasized the importance of intra- and intersexual interactions as sources of sexual selection. However, many traits that are important determinants of mating success influence mating success without necessarily affecting the outcome of intra- and intersexual interactions. Here, I argue that traits can be subject to sexual selection even if they do not affect the outcome of intra- and intersexual interactions. I distinguish two types of sexual selection, interaction-independent and interaction-dependent selection, based on whether variance in mating success is the result of trait dependent outcomes of interactions between conspecifics. I then use this distinction to construct a framework for classifying types of sexual selection that unifies and expands previously proposed frameworks. Finally, I outline several implications that the concept of interaction-independent sexual selection has for the general theory of sexual selection. PMID- 28568147 TI - MITOCHONDRIAL PHYLOGEOGRAPHY OF THE LAND SNAIL ALBINARIA IN CRETE: LONG-TERM GEOLOGICAL AND SHORT-TERM VICARIANCE EFFECTS. AB - The land snail genus Albinaria exhibits an extreme degree of morphological differentiation in Greece, especially in the island of Crete. Twenty-six representatives of 17 nominal species and a suspected hybrid were examined by sequence analysis of a PCR-amplified mitochondrial DNA fragment of the large rRNA subunit gene. Maximum parsimony and neighbor-joining phylogenetic analyses demonstrate a complex pattern of speciation and differentiation and suggest that Albinaria species from Crete belong to at least three distinct monophyletic groups, which, however, are not monophyletic with reference to the genus as a whole. There is considerable variation of genetic distance within and among "species" and groups. The revealed phylogenetic relations do not correlate well with current taxonomy, but exhibit biogeographical coherence. Certain small- and large-scale vicariance events can be traced, although dispersal and parapatric speciation may also be present. Our analysis suggests that there was an early and rapid differentiation of Albinaria groups across the whole of the range followed by local speciation events within confined geographical areas. PMID- 28568148 TI - A COMPARATIVE ANALYSIS OF THE ECOLOGICAL SIGNIFICANCE OF MAXIMAL LOCOMOTOR PERFORMANCE IN CARIBBEAN ANOLIS LIZARDS. AB - We examined the sprinting and jumping capabilities of eight West Indian Anolis species during three natural activities (escape from a predator, feeding, and undisturbed activity). We then compared these field data with maximal performance under optimal laboratory conditions to answer three questions: (1) Has maximal (i.e., laboratory) sprinting and jumping performance coevolved with field performance among species? (2) What proportion of their maximum capabilities do anoles sprint and jump in different ecological contexts? (3) Does a relationship exist between maximal sprinting and jumping ability and the proportion of maximal performance used in these contexts? Among species, maximal speed is tightly positively correlated with sprinting performance during both feeding and escape in the field. Sprinting speed during escape closely matches maximal sprinting ability (i.e., about 90% of maximum performance). By contrast, sprinting performance during undisturbed activity is markedly lower (about 32% of maximum) than maximal sprinting performance. Sprinting ability during feeding is intermediate (about 71% of maximum) between field escape and field undisturbed activity. In contrast to sprinting ability, jumping ability is always substantially less than maximum (about 40% of maximum during feeding and undisturbed activity). A negative relationship exists among species between maximal speed and the proportion to which species sprint to their maximal abilities during field escape. PMID- 28568149 TI - FITNESS CONSEQUENCES OF MATERNAL AND NONMATERNAL COMPONENTS OF INBREEDING IN THE GYNODIOECIOUS PHACELIA DUBIA. AB - I assessed the relationship between the level of inbreeding, F, and fitness, and the effects of nonmaternal and maternal components of inbreeding on fitness in Phacelia dubia. I conducted two generations of controlled crosses and tested the performance of the F2 progeny in field and artificial conditions covering the whole life cycle. Inbreeding significantly decreased the individual contribution of seeds to the next generation in the field, but this decrease apparently is not enough to explain the maintenance of gynodioecy. The inbred progeny contributes significantly to the population genetic structure of P. dubia. Fitness estimates and fitness components tended to decrease, usually monotonically, with F. However, nonmonotonic relationships were found in male fitness components and, in some families, in fitness estimates, seed production per fruit, and establishment. Most of the inbreeding depression takes place at the level of seed establishment in the field, but, in artificial conditions the effects of inbreeding were similar at fecundity and establishment. I studied maternal and nonmaternal components of inbreeding by testing the effects of the relatedness of maternal grandparents and parents on the performance of the progeny. Both components affected fitness. Inbreeding depression was conditioned by the level of inbreeding of the maternal plant, but this interaction varied at different fitness components. Also, the magnitude and even the direction of the relationship between fitness and F changed as a result of the combined effects of maternal and nonmaternal components of inbreeding. Such interactions can render convex or concave fitness functions, giving in the latter case the appearance of a false purging. Maternal effects of inbreeding can result from several processes: maternal investment perhaps with serial adjustments during seed development, purging of recessive deleterious genes, and nucleocytoplasmic interactions. These results illustrate the importance of maternal effects of inbreeding, and the complex effects of inbreeding on fitness. A full understanding of the fitness consequences of inbreeding and, therefore, their potential implications in the evolution of breeding systems, should take into account male and female components as well as transgenerational effects in the context of the particular environment in which fitness is evaluated. PMID- 28568150 TI - PHYLOGENY OF THE TRIBE CERATAPHIDINI (HOMOPTERA) AND THE EVOLUTION OF THE HORNED SOLDIER APHIDS. AB - The horned soldier aphids of the Cerataphidini, unlike most social insects that reside in nests, live on the open surface of plants. The lack of a nest and other obvious ecological correlates makes it unclear why secondary-host soldiers might have evolved. Here I present a molecular phylogenetic analysis of 32 species of the Cerataphidini, including 10 species from the genera Ceratovacuna and Pseudoregma that produce horned soldiers. The phylogeny suggests that horned soldiers evolved once and were lost once or twice. Most horned soldiers are a morphologically specialized caste and two species that have unspecialized soldiers are independently derived from species with specialized castes. The genus Ceratovacuna appears to have undergone a relatively rapid radiation. Mapping secondary-host plants and geographic ranges onto the phylogeny suggests that bamboos were the ancestral secondary-host plants and that the Asian tropics and subtropics were the ancestral geographic regions for the genera Astegopteryx, Ceratoglyphina, Ceratovacuna Chaitoregma, and Pseudoregma and possibly for the entire tribe. There is evidence for vicariant events that separate the tropical and subtropical lineages in all of the major lineages of the tribe and for dispersal of some lineages. Based on these results, I present hypotheses for the causes and consequences of horned-soldier evolution. PMID- 28568151 TI - THE GENETIC STRUCTURE OF A GYNODIOECIOUS PLANT: NUCLEAR AND CYTOPLASMIC GENES. AB - Sex expression in gynodioecious plants is often determined by an interaction between biparentally and maternally inherited genes. Their relative rates of gene flow should be considered when modeling the evolution of the sex ratio in structured populations. In order to understand patterns of gene flow in Silene vulgaris, a gynodioecious plant, genetic structure was estimated from biparentally inherited genetic markers (allozymes) and a maternally inherited marker (chloroplast DNA) using Wright's Fst . Based on data from 16 local populations, chloroplast DNA showed considerably more genetic structure than did allozymes (Fst values of 0.62 and 0.22, respectively). This suggests that the rate of gene flow is about three times greater for nuclear genes. PMID- 28568152 TI - INHERITANCE OF ENVIRONMENTAL VARIATION IN BODY SIZE: SUPERPARASITISM OF SEEDS AFFECTS PROGENY AND GRANDPROGENY BODY SIZE VIA A NONGENETIC MATERNAL EFFECT. AB - Maternal effects provide the most common mechanism by which environmental variation in one generation affects the phenotype of individuals in subsequent generations. In egg-laying animals, however, we typically observe that maternal effects can have large influences on early growth (egg size and early development), but these effects gradually disappear and become undetectable by the time progeny mature due to developmental plasticity in progeny. We describe a system in which an environmentally induced reduction in body size is inherited by progeny via a nongenetic maternal effect. The seed beetle, Callosobruchus maculatus, completes development inside a discrete resource package (a seed) selected by its mother. Due to superparasitism in response to low host availability, progeny frequently develop at high densities, resulting in intense larval competition and pupation at a smaller body size. Females reared at higher density (and thus emerging smaller) lay smaller eggs than females reared at lower density. Progeny from these smaller eggs mature at a smaller size than progeny reared from the larger eggs laid by females reared at lower density. Crosses between high and low density lines demonstrated that treatment differences in body size are maternally inherited, confirming that the inheritance of body size variation in part involves an environmentally based maternal effect. PMID- 28568153 TI - SPERM PRODUCTION AND STERILITY IN HYBRIDS BETWEEN TWO SUBSPECIES OF DROSOPHILA PSEUDOOBSCURA. AB - Subspecies of Drosophila pseudoobscura, one occurring in the United States and the other in Bogota, Columbia, exhibit Haldane's Rule in one direction of the cross. Additionally, D. pseudoobscura produces two sperm types: short, sterile sperm and long, fertile, sperm. Here I examine the relationship between the production of short and long sperm and hybrid sterility. Fertile and sterile hybrid males produce a greater proportion of short sperm compared to parental males with sterile hybrids producing mainly short, immotile sperm. Sperm transfer and storage patterns were similar between fertile hybrid and parental strains; and unexpectedly, short, immotile sperm from sterile hybrids were stored. These findings raise the question of whether different genetic mechanisms disrupt both sperm heteromorphic production and sperm motility and whether this indicates that females exert some control over sperm storage. PMID- 28568154 TI - PERSPECTIVE: CHASE-AWAY SEXUAL SELECTION: ANTAGONISTIC SEDUCTION VERSUS RESISTANCE. AB - A model of sexual selection that leads to the evolution of exaggerated male display characters that is based on antagonistic coevolution between the sexes is described. The model is motivated by three lines of research: intersexual conflict with respect to mating, sensory exploitation, and the evolution of female resistance, as opposed to preference, for male display traits. The model generates unique predictions that permit its operation to be distinguished from other established models of sexual selection. One striking prediction is that females will frequently win the coevolutionary arms race with males, leaving them encumbered with costly ornaments that have little value except that their absence understimulates females. Examples from the literature suggest that the model may have broad application in nature. The chase-away model is a special case of the more general phenomenon of Interlocus Contest Evolution (ICE). PMID- 28568155 TI - REDUCED MALE ALLOCATION IN THE PARTHENOGENETIC HERMAPHRODITE DUGESIA POLYCHROA. AB - Parthenogenetic lineages that arise in a hermaphroditic, sexual population will inherit the male function from their sexual progenitors. Natural selection then acts to reduce male allocation of the parthenogens, freeing resources presumably for the female function. Depending on age and the available genetic variation, one therefore expects to find reduced male allocation in naturally occurring parthenogenetic lineages. We investigated the allocation to sperm production in the hermaphroditic flatworm Dugesia polychroa in three lakes containing a sexual (S), a (pseudogamous) parthenogenetic (P), and a mixed sexual-parthenogenetic population (M). Parthenogenetic lineages from M were assumed to be relatively young due to recurrent origins from the coexisting sexuals, whereas those from P were assumed to be older on biogeographical grounds. As predicted, we found drastically reduced sperm production in parthenogens compared to sexuals, even in the parthenogenetic lineages from M, which may be younger. M parthenogens did not have more testes, but produced more sperm than individuals from the purely parthenogenetic population (P). However, the latter result could not be reproduced with laboratory-raised animals and therefore may be a consequence of different ecological conditions in the different lakes, for example, differences in mating rates. To study the behavioral component of male allocation, copulation frequencies were recorded for sexuals from M and for parthenogens from P. Compared to the drastic reduction in sperm production, copulation frequency was less reduced in parthenogens. This may be a consequence of allosperm limitation in pseudogamous parthenogenetic populations. PMID- 28568156 TI - BODY SIZE, NATURAL SELECTION, AND SPECIATION IN STICKLEBACKS. AB - There is little evidence from nature that divergent natural selection is crucial to speciation. However, divergent selection is implicated if traits conferring adaptation to alternative environments also form the basis of reproductive isolation. We tested the importance of body size differences to premating isolation between two sympatric sticklebacks. The species differ greatly in size, and several lines of evidence indicate that this difference is an adaptation to alternative foraging habitats. Strong assortative mating was evident in laboratory trials, but a few hybridization events occurred. Probability of interspecific mating was strongly correlated with body size: interspecific spawning occurred only between the largest individuals of the smaller species and the smallest individuals of the larger species. Probability of spawning between similar-sized individuals from different species was comparable to spawning rates within species. Disruption of mating between individuals from different species can be traced to increased levels of male aggression and decreased levels of male courtship as size differences increased between paired individuals. Interspecific mate preferences in sympatric sticklebacks appears to be dominated by body size, implicating natural selection in the origin of species. PMID- 28568157 TI - HYBRID FITNESS IN THE LOUISIANA IRISES: ANALYSIS OF PARENTAL AND F1 PERFORMANCE. AB - The assumption of hybrid inferiority is central to the two models most widely applied to the prediction of hybrid zone evolution. Both the tension zone and mosaic models assume that natural selection acts against hybrids regardless of the environment in which they occur. To test this assumption, we investigated components of fitness in Iris fulva, I. hexagona and their reciprocal F1 hybrids under greenhouse conditions. The four cross types were compared on the basis of seed germination, vegetative and clonal growth, and sexual reproduction. In all cases, the hybrids performed as well as, or significantly better than, both of their parents. These results suggest that F1 hybrids between I. fulva and I. hexagona are at least as fit as their parents. The results of this study are therefore inconsistent with the assumptions of both the tension zone and mosaic models of hybrid zone evolution. PMID- 28568158 TI - ANTAGONISTIC PLEIOTROPIC EFFECT OF SECOND-CHROMOSOME INVERSIONS ON BODY SIZE AND EARLY LIFE-HISTORY TRAITS IN DROSOPHILA BUZZATII. AB - A simple way to think of evolutionary trade-offs is to suppose genetic effects of opposed direction that give rise to antagonistic pleiotropy. Maintenance of additive genetic variability for fitness related characters, in association with negative correlations between these characters, may result. In the cactophilic species Drosophila buzzatii, there is evidence that second-chromosome polymorphic inversions affect size-related traits. Because a trade-off between body size and larval developmental time has been reported in Drosophila, we study here whether or not these inversions also affect larva-adult viability and developmental time. In particular, we expect that polymorphic inversions make a statistically significant contribution to the genetic correlation between body size (as measured by thorax length) and larval developmental time. This contribution is expected to be in the direction predicted by the trade-off, namely, those flies whose karyotypes cause them to be genetically larger should also have a longer developmental time than flies with other karyotypes. Using two different experimental approaches, a statistically significant contribution of the second chromosome inversions to the phenotypic variances of body size and developmental time in D. buzzatii was found. Further, these inversions make a positive contribution to the total genetic correlation between the traits, as expected by the suggested trade-off. The data do not provide evidence as to whether the genetic correlation is due to antagonistic pleiotropic gene action or to gametic disequilibrium of linked genes that affect one or both traits. The results do suggest, however, a possible explanation for the maintenance of inversion polymorphism in this species. PMID- 28568159 TI - DESIGNING EXPERIMENTS TO MAXIMIZE THE POWER OF DETECTING CORRELATIONS. AB - Studies investigating correlations among traits are increasingly common in evolutionary biology. By providing power calculations, minimum sample sizes, and standard errors of correlation coefficients in a variety of contexts, this note provides guidelines to insure that nonzero correlations will not be erroneously dismissed as nonsignificant in properly designed experiements. Forty individuals is often sufficient for reasonable estimation of correlation coefficients, although 100 or more individuals may be nexessary if a large number of traits are involved or comparisons are to be made among the coefficients. PMID- 28568160 TI - RECENT BOOKS IN PRINT. PMID- 28568161 TI - MOLECULAR AND REPRODUCTIVE CHARACTERIZATION OF SIBLING SPECIES IN THE EUROPEAN EARWIG (FORFICULA AURICULARIA). AB - The European earwig (Forficula auricularia) was formerly thought to present a mosaic of populations differing in their reproductive biology. We show that it is comprised of two as yet unrecognized sibling species. The molecular divergence between the two species, for a 627-bp amplified fragment overlapping the COI and COII mitochondrial loci, is six times larger than intraspecific variation. A species with two clutches a year lives predominantly in lowland and oceanic European habitats. A species with one clutch a year-except in the Mediterranean area where it has two clutches-lives predominantly in highland and continental European habitats. They both invaded North America during the 20th century, respectively, from the west and the east coasts, with no apparent mixing of their populations. The two species can occur in sympatry in Europe and are reproductively isolated by nearly complete failure to produce F1 hybrids. PMID- 28568162 TI - ASYMMETRIC INTROGRESSION OF MITOCHONDRIAL DNA AMONG EUROPEAN POPULATIONS OF BLUE MUSSELS (MYTILUS SPP.). AB - -Mytilus edulis and M. galloprovincialis are two blue mussel species that coexist in western Europe. Previously, we reported that M. galloprovincialis populations contain female and male haplotypes that are fixed in M. edulis populations as well as unique haplotypes. This study assesses whether paraphyly for these species is due to introgression or incomplete lineage extinction. The lineage extinction hypothesis predicts that the shared mtDNA haplotypes in M. galloprovincialis will be significantly diverged from those in M. edulis and form distinct sequence clades. In contrast, the introgression hypothesis proposes that M. edulis haplotypes have only recently been introduced into M. galloprovincialis through hybridization with relatively little divergence accumulating between the shared RFLP haplotypes. We examined 80 mtl6S gene sequences for both the maternal and paternal mtDNA lineages from mussels sampled from various European populations and found strong support for the introgression hypothesis. In addition, we found that M. edulis mtDNA haplotypes appear to be introgressing into mussel populations in the Baltic Sea, which have predominantly M. trossulus nuclear genotypes, indicating that introgressive hybridization is prevalent among European mussel populations. PMID- 28568163 TI - REINFORCEMENT OF STICKLEBACK MATE PREFERENCES: SYMPATRY BREEDS CONTEMPT. AB - Detailed studies of reproductive isolation and how it varies among populations can provide valuable insight into the mechanisms of speciation. Here we investigate how the strength of premating isolation varies between sympatric and allopatric populations of threespine sticklebacks to test a prediction of the hypothesis of reinforcement: that interspecific mate discrimination should be stronger in sympatry than in allopatry. In conducting such tests, it is important to control for ecological character displacement between sympatric species because ecological character divergence may strengthen prezygotic isolation as a by-product. We control for ecological character displacement by comparing mate preferences of females from a sympatric population (benthics) with mate preferences of females from two allopatric populations that most closely resemble the sympatric benthic females in ecology and morphology. No-choice mating trials indicate that sympatric benthic females mate less readily with heterospecific (limnetic) than conspecific (benthic) males, whereas two different populations of allopatric females resembling benthics show no such discrimination. These differences demonstrate reproductive character displacement of benthic female mate choice. Previous studies have established that hybridization between sympatric species occurred in the past in the wild and that hybrid offspring have lower fitness than either parental species, thus providing conditions under which natural selection would favor individuals that do not hybridize. Results are therefore consistent with the hypothesis that female mate preferences have evolved as a response to reduced hybrid fitness (reinforcement), although direct effects of sympatry or a biased extinction process could also produce the pattern. Males of the other sympatric species (limnetics) showed a preference for smaller females, in contrast to the inferred ancestral preference for larger females, suggesting reproductive character displacement of limnetic male mate preferences as well. PMID- 28568164 TI - AGE AND MOVEMENT OF A HYBRID ZONE: IMPLICATIONS FOR DISPERSAL DISTANCE IN POCKET GOPHERS AND THEIR CHEWING LICE. AB - Historical flood records for the Rio Grande Valley of New Mexico suggest that a pocket gopher (Thomomys bottae) hybrid zone previously thought to be 10,000 years old may actually be closer to 50 years old. Measured zone width (defined genetically) is consistent with the hypothesis of recent contact, if we assume a reasonable dispersal distance of approximately 400 m/year for pocket gophers. A five-year study of movement of the contact zone between the two species of chewing lice that parasitize these pocket gophers also is consistent with the hypothesis of recent origin of the zone. PMID- 28568165 TI - FREQUENCY-DEPENDENT FITNESS IN SILENE VULGARIS, A GYNODIOECIOUS PLANT. AB - In gynodioecious plants the selective processes that determine the relative number of female and hermaphroditic individuals are often frequency dependent. Frequency-dependent fitness can occur in the two sexes through a variety of mechanisms, especially given pollen limitation and inbreeding depression when hermaphrodites are rare. Frequency dependence in several components of the fitness of female and hermaphroditic Silene vulgaris was tested in experiments in which the relative numbers of the two sexes was varied among 12 artificial populations. In females, the proportion of flowers that set fruit covaried positively among populations with the frequency of hermaphrodites in two separate experiments, whereas the number of flowers/plant covaried negatively in one case. In hermaphrodites, the number of seeds/fruit covaried positively with the frequency of hermaphrodites, whereas the fitness of hermaphrodites estimated through pollen transfer covaried negatively. The results are discussed as they relate to the selective maintenance of gynodioecy in S. vulgaris and in light of a recent model of the effect of population structure on selection in gynodioecious systems. PMID- 28568166 TI - HERITABLE VARIATION FOR FECUNDITY IN FIELD-COLLECTED DROSOPHILA MELANOGASTER AND THEIR OFFSPRING REARED UNDER DIFFERENT ENVIRONMENTAL TEMPERATURES. AB - Heritable variation for fitness components is normally measured under favorable laboratory conditions, but organisms in the field experience variable conditions that are often stressful and may affect the expression of heritable variation. We examined heritable variation for early fecundity in three samples of Drosophila melanogaster from the field. Flies were obtained from a rotting fruit pile in summer, autumn, and spring, and progeny were reared under laboratory conditions. Field parents were tested for fecundity at 14 degrees C or 28 degrees C depending on ambient temperatures. Wing/thorax length ratios measured on flies from the spring collection suggested that flies had developed at around 20 degrees C. Progeny were reared and tested at 14 degrees C, 25 degrees C, and 28 degrees C. In the summer collection, parent-offspring regression coefficients were high and significant, compared to nonsignificant values obtained in two of three autumn comparisons. In the spring collection, parent-offspring regressions were negative regardless of testing temperature, suggesting that field females with a high fecundity produced offspring with low scores. Comparisons of F1 and F2 laboratory generations indicated intermediate heritabilities for fecundity in the laboratory. The lower bound heritability estimate for fecundity in field individuals was 37% in summer and 59% in autumn. Estimates of field heritability and evolvability for wing length measured in the spring collection were lower than in the laboratory. The results indicate that heritabilities and additive genetic variances for fecundity can be high in field-reared flies, but that results may vary between field collections. PMID- 28568167 TI - INBREEDING AND ITS FITNESS EFFECTS IN AN INSULAR POPULATION OF SONG SPARROWS (MELOSPIZA MELODIA). AB - Inbreeding depression is thought to be a major factor affecting the evolution of mating systems and dispersal. While there is ample evidence for inbreeding depression in captivity, it has rarely been documented in natural populations. In this study, I examine data from a long-term demographic study of an insular population of song sparrows (Melospiza melodia) and present evidence for inbreeding depression. Forty-four percent of all matings on Mandarte Island, British Columbia, were among known relatives. Offspring of a full-sib mating (f = 0.25) experienced a reduction in annual survival rate of 17.5% on average. Over their lifetime, females with f = 0.25 produced 48% fewer young that reached independence from parental care. In contrast, male lifetime reproductive success was not affected by inbreeding. Reduced female lifetime reproductive success was mostly due to reduced hatching rates of the eggs of inbred females. Relatedness among the parents did not affect their reproductive success. Using data on survival from egg stage to breeding age, I estimated the average song sparrow egg on Mandarte Island to carry a minimum of 5.38 lethal equivalents (the number of deleterious genes whose cumulative effect is equivalent to one lethal); 2.88 of these lethal equivalents were expressed from egg stage to independence of parental care. This estimate is higher than most estimates reported for laboratory populations and lower than those reported for zoo populations. Hence, the costs of inbreeding in this population were substantial and slightly above those expected from laboratory studies. Variability in estimates of lethal equivalents among years showed that costs of inbreeding were not constant across years. PMID- 28568168 TI - EVIDENCE FROM THE FOSSIL RECORD OF AN ANTIPREDATORY EXAPTATION: CONCHIOLIN LAYERS IN CORBULID BIVALVES. AB - Conchiolin layers, organic-rich laminae, are characteristic of the shells of corbulid bivalves. The retention of these layers, despite their high metabolic cost, throughout the evolutionary history of Corbulidae has prompted the proposal of several adaptive scenarios to explain the origin and maintenance of these layers. The most widely held hypothesis contends that conchiolin layers are an adaptation for inhibiting drilling by predatory naticid gastropods. However, others suggest that the layers are adaptations to retard shell dissolution in waters undersaturated with calcium carbonate or to increase shell strength in the face of durophagous (shell crushing) predators. In this paper, experiments using recent Corbula (Varicorbula) gibba (Olivi) and observations of corbulids' present natural habitat demonstrate the current utility of conchiolin layers for all three functions: retardation of shell dissolution in waters undersaturated in calcium carbonate, increase of mechanical shell strength, and inhibition of drilling by predatory naticid gastropods. Earlier analyses of the extensive history of naticid predator-corbulid prey interactions suggested that conchiolin layers were an adaptation, a feature that promotes fitness and was built by selection for its current role, for deterring naticid predators. Not only are naticid drillholes widespread in fossil and recent corbulid shells, but an unusually large number of incomplete drillholes terminate unsuccessfully at conchiolin layers. In addition, a phylogenetic analysis of the origin of conchiolin layers and its function to deter naticid predators is consistent with a hypothesis of adaptation for this function. However, this hypothesis is rejected by an examination of fossil Jurassic Corbulomima. These oldest corbulids contained conchiolin layers before the evolution of naticid drilling during the Early Cretaceous. Therefore, conchiolin layers appear to be an exaptation, characters evolved for other usages and later "coopted" for their current role, for defense against drilling predators. The layers may in fact be an adaptation to resist durophagous predation. PMID- 28568170 TI - Diagnostic accuracy, work-up, and outcomes of pregnancies with clubfoot detected by prenatal sonography. AB - OBJECTIVE: To assess diagnostic accuracy, related findings, and outcomes of fetuses with clubfoot. METHODS: Sonographic characteristics, pregnancy work-up, and postnatal outcomes were evaluated in 109 fetuses with clubfoot. RESULTS: Among 40 320 prenatal ultrasound anomaly scans, clubfoot was diagnosed in 150 (0.37%). Analysis included 108 pregnancies (72%) with 109 fetuses. Bilateral clubfoot was diagnosed in 51/109 (46.7%) fetuses and unilateral in 58/109 (53.2%). Clubfoot was diagnosed as an isolated anomaly in 76/109 (69.7%) and complex in 33/109 (30.2%). Amniocentesis or chorionic villus sampling in 48/109 (44%) yielded 6 (12.5%) with abnormalities (5.5% of the entire cohort). Diagnosis was confirmed in 65/91 (71.4%) liveborn infants. In singletons, 7/63 (11.1%) cases considered isolated on ultrasound had additional anomalies postpartum and 8/14 (57.1%) complex cases were verified after birth. Sonographic diagnosis of clubfoot was verified postpartum in more singletons than twins (p = 0.05). Bilateral clubfoot was verified postpartum more often than unilateral [29/33 (87.9%) vs. 29/44 (65.9%), respectively; p = 0.03]. Bilateral clubfoot resulted in additional prenatal testing without increased likelihood of finding additional anomalies and was associated with more surgical interventions postnatally. CONCLUSIONS: Prenatal ultrasound diagnosis of clubfoot is more accurate in singletons with bilateral findings. Bilateral findings do not increase the likelihood of additional anomalies. Karyotyping should be considered even with isolated clubfoot. (c) 2017 John Wiley & Sons, Ltd. PMID- 28568169 TI - Effect of Dexamethasone and Fluticasone on Airway Hyperresponsiveness in Horses With Inflammatory Airway Disease. AB - BACKGROUND: Airway hyperresponsiveness (AWHR), expressed as hypersensitivity (PC75 RL ) or hyperreactivity (slope of the histamine dose-response curve), is a feature of inflammatory airway disease (IAD) or mild equine asthma in horses. Glucocorticoids are used empirically to treat IAD. OBJECTIVES: To determine whether dexamethasone (DEX) (0.05 mg/kg IM q24h) and inhaled fluticasone (FLUT) (3,000 MUg q12h) administered by inhalation are effective in decreasing AWHR, lung inflammation, and clinical signs in horses with IAD. METHODS: A randomized crossover study design was used. Eight horses with IAD were assigned to a treatment group with either DEX or FLUT. Measured outcomes included lung mechanics during bronchoprovocative challenges, bronchoalveolar lavage fluid (BALF) cytology, and scoring of clinical signs during exercise. RESULTS: Dexamethasone and FLUT abolished the increase in RL by 75% at any histamine bronchoprovocative dose in all horses after the first week of treatment. However, after 2 weeks of FLUT treatment, 1 horse redeveloped hypersensitivity. There was a significant decrease in the number of lymphocytes after treatment with both DEX and FLUT (P = .039 for both) but no significant differences in other BALF cell types or total cell counts (P > .05). There was no difference in the scoring of the clinical signs during each treatment and washout period (P > .05). CONCLUSIONS AND CLINICAL IMPORTANCE: Both DEX and FLUT treatments significantly inhibit airway hypersensitivity and hyperreactivity in horses with IAD. There are no significant effects on the clinical signs or the number of inflammatory cells (except lymphocytes) in BALF. The treatments have no residual effect 3 weeks after discontinuation. PMID- 28568171 TI - THE EVOLUTION AND BREAKDOWN OF TRISTYLY. PMID- 28568172 TI - A COMMENT ON VEGETATIVE AND SEED REPRODUCTION IN PLANTS. PMID- 28568173 TI - GENETIC DISTINCTNESS OF SYMPATRIC FORMS OF AEDES AEGYPTI IN EAST AFRICA. PMID- 28568174 TI - HETEROZYGOSITY AND DEVELOPMENTAL STABILITY: ANOTHER LOOK. PMID- 28568175 TI - RELATEDNESS IN THE POLYGYNOUS ANT MYRMECIA PILOSULA. PMID- 28568176 TI - NEW STATISTICAL METHODS FOR ALLOMETRY WITH APPLICATION TO FLORIDA RED-WINGED BLACKBIRDS. PMID- 28568177 TI - GENETICS OF SPECIATION IN LAKE WHITEFISHES IN THE ALLEGASH BASIN. PMID- 28568178 TI - ONCE AGAIN, WHY 300 SPECIES OF HAWAIIAN DROSOPHILA? PMID- 28568179 TI - BATESIAN MIMICRY: FIELD DEMONSTRATION OF THE SURVIVAL VALUE OF PIPEVINE SWALLOWTAIL AND MONARCH COLOR PATTERNS. PMID- 28568180 TI - PARENTAL MANIPULATION, KIN SELECTION, AND THE EVOLUTION OF ALTRUISM. PMID- 28568181 TI - 'PROTOVIPERS" AND THE EVOLUTION OF SNAKE FANGS. PMID- 28568182 TI - AVERAGE FITNESS OF POPULATIONS OF DROSOPHILA MELANOGASTER AS ESTIMATED USING COMPOUND-AUTOSOME STRAINS. PMID- 28568183 TI - CONVERGENT EVOLUTION BETWEEN PHYLA: A TEST CASE OF MIMICRY BETWEEN CADDISFLY LARVAE (HELICOPSYCHE BOREALIS) AND AQUATIC SNAILS (PHYSA INTEGRA). PMID- 28568184 TI - EVOLUTION OF THE RICHNESS-AREA CORRELATION FOR CYNIPID GALL WASPS ON OAK TREES: A COMPARISON OF TWO GEOGRAPHIC AREAS. PMID- 28568185 TI - POPULATION GENETICS OF MEXICAN DROSOPHILA VI. CYTOGENETIC ASPECTS OF THE INVERSION POLYMORPHISM IN DROSOPHILA PSEUDOOBSCURA. PMID- 28568186 TI - CYTOGENETICS AND EVOLUTION OF SIMULIUM ORNATIPES SKUSE (DIPTERA: SIMULIIDAE). III. GEOGRAPHIC VARIATION OF CHROMOSOMAL POLYMORPHISMS AND SPECIES DIVERGENCE. PMID- 28568187 TI - THE ADAPTIVE DEMOGRAPHY OF FOUR FRESHWATER PULMONATE SNAILS. PMID- 28568188 TI - GENETIC CAPACITY FOR ADAPTATION TO COLD RESISTANCE AT DIFFERENT DEVELOPMENTAL STAGES OF DROSOPHILA MELANOGASTER. PMID- 28568189 TI - SPECIES-AREA RELATIONS OF BIRDS ON SMALL ISLANDS IN A MINNESOTA LAKE. PMID- 28568190 TI - THE EVOLUTIONARY BREAKDOWN OF TRISTYLY IN EICHHORNIA CRASSIPES (MART.) SOLMS (WATER HYACINTH). PMID- 28568191 TI - ESTIMATION OF AVERAGE FITNESS OF POPULATIONS OF DROSOPHILA MELANOGASTER AND THE EVOLUTION OF FITNESS IN EXPERIMENTAL POPULATIONS. PMID- 28568192 TI - REPLY TO W. G. ABRAHAMSON. PMID- 28568193 TI - CYTOGENETICS AND EVOLUTION OF SIMULIUM ORNATIPES SKUSE (DIPTERA: SIMULIIDAE). II. TEMPORAL VARIATION IN CHROMOSOMAL POLYMORPHISMS AND HOMOSEQUENTIAL SIBLING SPECIES. PMID- 28568194 TI - QUANTITATIVE GENETIC ANALYSIS OF MULTIVARIATE EVOLUTION, APPLIED TO BRAIN:BODY SIZE ALLOMETRY. PMID- 28568195 TI - ALDEHYDE OXIDASE ALLOZYMES, INVERSIONS AND DDT RESISTANCE IN SOME LABORATORY POPULATIONS OF DROSOPHILA MELANOGASTER. PMID- 28568196 TI - HERITABILITY OF SOME MORPHOLOGICAL CHARACTERS IN A SONG SPARROW POPULATION. PMID- 28568197 TI - PHENOTYPIC PLASTICITY IN THE SAILFIN MOLLY, POECILIA LATIPINNA (PISCES: POECILIIDAE). I. FIELD EXPERIMENTS. AB - Sailfin mollies (Poecilia latipinna) display marked interdemic variation in body size. We employed "common-garden" experiments in field enclosures to explore the potential role of environmental factors in determining the interdemic phenotypic variation in growth rate, age at maturity, and size at maturity. The largest single, consistent source of variation for all traits was family identity within populations. Environmental effects acted predominantly through family x environment interactions. There was little evidence for any intrinsic variation among populations once family heterogeneity had been accounted for. In general, when statistically significant differences existed, fish raised in a saltwater pond grew faster than their broodmates raised in a freshwater pond. Both males and females tended to mature at a smaller size and later in the freshwater pond than in the saltwater pond. The effects of the environmental conditions differed among the three years in which we performed these studies. In only one year was there a substantial difference between fish raised under the two environmental conditions. These results indicate that direct environmental effects are not strong enough to account for the differences in body size among natural populations and that intrinsic differences among natural populations are due to different frequency distributions of genotypes that are present in all populations. PMID- 28568198 TI - GENETIC STRUCTURE OF NORWAY SPRUCE (PICEA ABIES): CONCORDANCE OF MORPHOLOGICAL AND ALLOZYMIC VARIATION. AB - This study describes the population structure of Norway spruce (Picea abies) as revealed by protein polymorphisms and morphological variation. Electrophoretically detectable genetic variability was examined at 22 protein loci in 70 populations from the natural range of the species in Europe. Like other conifers, Norway spruce exhibits a relatively large amount of genetic variability and little differentiation among populations. Sixteen polymorphic loci (73%) segregate for a total of 51 alleles, and average heterozygosity per population is 0.115. Approximately 5% of the total genetic diversity is explained by differences between populations (GST = 0.052), and Nei's standard genetic distance is less than 0.04 in all cases. We suggest that the population structure largely reflects relatively recent historical events related to the last glaciation and that Norway spruce is still in a process of adaptation and differentiation. There is a clear geographic pattern in the variation of allele frequencies. A major part of the allelefrequency variation can be accounted for by a few synthetic variables (principal components), and 80% of the variation of the first principal component is "explained" by latitude and longitude. The central European populations are consistently depauperate of genetic variability, most likely as an effect of severe restrictions of population size during the last glaciation. The pattern of differentiation at protein loci is very similar to that observed for seven morphological traits examined. This similarity suggests that the same evolutionary forces have acted upon both sets of characters. PMID- 28568199 TI - DYNAMICS OF P-M HYBRID DYSGENESIS IN P-TRANSFORMED LINES OF DROSOPHILA SIMULANS. AB - An autonomous P element from Drosophila melanogaster was introduced by microinjection into the germ line of its sibling species, Drosophila simulans. The invasion kinetics of P elements was studied in seven independent lines over 60 generations, using gel blotting, in situ hybridization, and dysgenic crosses. Some of the main phenotypic and molecular characteristics of P-M hybrid dysgenesis were observed, i.e., gonadal dysgenesis (GD sterility), chromosome rearrangements, and the occurrence of degenerate P elements. At least four lines reached a steady state with complete or nearly complete P-element regulation but with a moderate number of P elements (10-24 per haploid genome) and P activity (10-35% GD sterility). This failure to obtain strong P strains in D. simulans could be due to experimental conditions, a host-dependent component of P transposition, or more severe selection against the deleterious effects of this transposon. PMID- 28568200 TI - EVOLUTIONARY NOVELTY AND ATAVISM IN THE SEMIONOTUS COMPLEX: RELAXED SELECTION DURING COLONIZATION OF AN EXPANDING LAKE. AB - Fishes of the genus Semionotus diversified in the rift lakes of eastern North America during the Mesozoic (Newark Supergroup). Like the well-known cichlid fishes of the African great lakes, diverse complexes of semionotids were apparently endemic to a number of different lakes. Semionotid fishes show considerable morphological diversity in body shape and in a modified row of scales termed "dorsal ridge scales." A number of distinct dorsal-ridge-scale patterns characterize groups of species from the Newark Supergroup. Interestingly, about 5.5% of individuals examined have anomalous scales mixed in with otherwise stereotypic dorsal-ridge-scale patterns. In this study, I take advantage of nearly annual stratigraphic resolution to determine whether dorsal ridge-scale anomalies are concentrated stratigraphically in the early phase of lake formation and colonization by semionotids. More than 1,700 specimens of semionotid fish were collected from a single lake deposit (cycle P4), representing approximately 21,000 years, in the Early-Jurassic Towaco Formation of the Newark Basin. Dorsal-ridge-scale anomalies are significantly more frequent in older than in younger lake sediments, which I interpret as being the result of relaxed selection during the early colonization of the lake. Anomalous variation parallels variation in dorsal ridge scales between species-groups. Some anomalies are atavisms, while others are unique or foreshadow future evolutionary events. One type of anomaly is incorporated into the dorsal-ridge-scale series of two new species that gave rise to a radiation in a subsequent lake filling the same topographic basin. Because both novelties and atavisms occur in the dorsal-ridge scale series of single individuals, I argue that the disruptions of the same "developmental program" produced both atavistic and novel traits. PMID- 28568201 TI - LACK OF SIGNIFICANT ASSOCIATIONS BETWEEN ALLOZYME HETEROZYGOSITY AND PHENOTYPIC TRAITS IN THE LAND SNAIL CERION. PMID- 28568202 TI - SEX-RATIO VARIATION IN THE GYNODIOECIOUS SHRUB HEBE STRICTISSIMA (SCROPHULARIACEAE). AB - The frequency of females was determined for eight populations of the gynodioecious shrub, Hebe strictissima (Scrophulariaceae) and related to plant vigor among populations, as indicated by the average number of leaves per shoot. The purpose was to test the idea that females should be more prevalent in relatively poor sites where plant vigor is low. This hypothesis was based on sex ratio theory, coupled with the idea that fruit-set in the polleniferous morph (i.e., in "males") is more dependent on vigor than it is in females. I found that, within populations, females produced significantly more fruit than males and that plant vigor did not differ significantly between the sexes. Fruit-set on males was positively and significantly correlated with the number of leaves per shoot within plants, among plants within populations, and among populations. No such correlations were found for females. The greater plasticity of the males altered the relative seed fitnesses of the two morphs among the eight populations, resulting in a negative correlation between female frequency and average plant vigor. I suggest, in general, that such plasticity may be an important factor in sex-ratio variation among populations and that it should be incorporated into models of sex-ratio evolution. PMID- 28568203 TI - ALTERNATIVE FORMULATIONS OF THE MIXED-MODEL ANOVA APPLIED TO QUANTITATIVE GENETICS. PMID- 28568204 TI - MITOCHONDRIAL-DNA RESTRICTION-SITE POLYMORPHISMS IN THE TELEOST FUNDULUS HETEROCLITUS SUPPORT SECONDARY INTERGRADATION. AB - Fundulus heteroclitus is a highly polymorphic fish distributed along the Atlantic coast of North America. Several loci show directional changes in gene frequency with latitude (i.e., clines). Such directional changes have classically been described by two general models: primary and secondary intergradation. Previously, it has not been possible to distinguish between these models for Fundulus heteroclitus on the basis of allelic isozymes or morphological data. However, recent analysis of mitochondrial-DNA (mtDNA) restriction electromorphs helps resolve this issue. Mitochondrial-DNA samples from 48 individuals representing four populations were digested with 17 restriction endonucleases. After electrophoresis, the sizes of the mtDNA fragments were used to analyze the phylogenetic relatedness of fish collected over most of the species range. The analysis clearly identified two major races within the species: a northern and a southern form. The distribution of the mtDNA electromorphs, combined with zoogeographical changes in allelic isozymes and in eggs and adult morphologies (published elsewhere), makes the secondary-intergradation hypothesis most compelling. PMID- 28568205 TI - THE DARWIN-FISHER THEORY OF SEXUAL SELECTION IN MONOGAMOUS BIRDS. AB - Males of monogamous birds often show secondary sexual traits that are conspicuous but considerably less extreme than those of polygynous species. We develop a quantitative-genetic model for the joint evolution of a male secondary sexual trait, a female mating preference, and female breeding date, following a theory proposed by Darwin and Fisher. Good nutritional condition is postulated to cause females to breed early and to have high fecundity. The most-preferred males are mated by early-breeding females and receive a sexual-selection advantage from those females' greater reproductive success. Results show that conspicuous male traits that decrease survival can evolve but suggest that the extent of maladaptive evolution is greatly limited relative to what is possible in a polygynous mating system for two reasons. First, in the absence of direct fitness effects of mate choice on the female, the equilibria for the male trait and female preference form a curve whose shape shows that the maximum possible strength of sexual selection on males (and hence the potential for maladaptive evolution) is constrained. Under certain conditions, a segment of the equilibrium curve may become unstable, leading to two alternative stable states for the male trait. Second, male parental care will often favor the evolution of mating preferences for less conspicuous males. We also find that sexual selection can appear in the absence of the nutritional effects emphasized by Darwin and Fisher. A review of the literature suggests that the assumptions of the Darwin-Fisher mechanism may often be met in monogamous birds and that other mechanisms may often reinforce it by producing additional components of sexual selection. PMID- 28568206 TI - ENZYME HETEROZYGOSITY, GROWTH RATE, AND VIABILITY IN MYTILUS EDULIS: ANOTHER LOOK. PMID- 28568207 TI - EVIDENCE FOR POLLINATION ECOTYPES IN THE YELLOW-FRINGED ORCHID, PLATANTHERA CILIARIS. AB - Platanthera ciliaris is a butterfly-pollinated, terrestrial orchid with a loose terminal raceme of 10-50 orange flowers, characterized by a long nectariferous spur. In the southeastern United States, P. ciliaris occurs in the Appalachian mountains and coastal-plain physiographic provinces, but it is found rarely in the intervening Piedmont. In 1983 and 1984, detailed observations of two populations within these disjunct areas revealed that the butterfly species that serve as the primary pollinators differ sharply. In the mountains, Papilio troilus (spicebush swallowtail) was the most frequent and effective visitor, whereas in the coastal plain, P. palamedes (palamedes swallowtail) was the predominant pollinator. Proboscis lengths of P. troilus (mean = 23.3 mm) were significantly shorter than those of P. palamedes (mean = 28.7 mm). Floral characters, most notably spur length, also differed significantly between mountain (mean = 23.8 mm) and coastal-plain (mean = 25.6 mm) plants. In both 1983 and 1984, levels of pollinator service, as assessed by rates of removal and insertion of pollinia, were higher in the mountains (0.81 and 0.86) than in the coastal plain (0.63 and 0.67). In addition, fruit-set was significantly greater in mountain (83.9% in 1983, 86.5% in 1984) than in coastal-plain (63.8% in 1983, 65.5% in 1984) populations. We hypothesize that selection pressure exerted through pollinator proboscis lengths has resulted in pollination ecotypes of P. ciliaris. The short-spurred mountain plants appear to be in equilibrium with their short-tongued butterfly pollinators, receiving high levels of effective pollination and achieving high levels of fruit-set. Coastal-plain plants produce flowers with longer spurs which, nevertheless, are shorter than optimal for insuring that very long-tongued butterflies make contact with their pollinia. Thus, effective pollinator service and fruit-set are reduced. Correlation analyses in 1984 showed a positive relationship between spur length and fruit-set only in the coastal plain. The presence of long-tongued nectar thieves in the coastal plain may also contribute to lower effective pollinator service and fruit set. Results of reciprocal-transplant studies attempting to determine the genetic basis of floral characters, including spur length, were inconclusive but suggest that differences between mountain and coastal-plain plants are not due solely to phenotypic plasticity. PMID- 28568208 TI - CLINES OF CHROMOSOMAL ARRANGEMENTS OF DROSOPHILA SUBOBSCURA IN SOUTH AMERICA EVOLVE CLOSER TO OLD WORLD PATTERNS. PMID- 28568209 TI - BIOCHEMICAL GENETICS OF FUNDULUS HETEROCLITUS (L.). VI. GEOGRAPHICAL VARIATION IN THE GENE FREQUENCIES OF 15 LOCI. AB - Geographic variation in the gene frequencies corresponding to 15 polymorphic enzymes were studied in the common killifish Fundulus heteroclitus. Aat-A, Est-B, Fum-A, H6pdh-A, Mpi-A and Pgm-B showed clinal variation in allelic frequencies along the Atlantic coast of North America, while Aat-B, Ap-A, and the EST-C phenotypes did not. The clinal allelic variation of six previously examined loci (Ldh-B, Mdh-A, Gpi-B, Idh-A, Pgm-A, and 6-Pgdh-A) was extended to locations farther north. Gene diversity was lowest in the cold waters of northern latitudes and highest in the warmer waters of southern latitudes. The variety of clinal shapes and widths suggests that selection has affected the allelic distributions for at least some of these loci. This hypothesis is discussed with regard to the range contractions and extensions caused by the glacial advances and retreats during the Pleistocene. PMID- 28568210 TI - THE EFFECT OF SOFT SELECTION ON THE VARIABILITY OF A QUANTITATIVE TRAIT. AB - The equilibrium phenotypic variance (sigma^2) of a normally distributed quantitative character P under soft selection is studied. This character is assumed to undergo Gaussian stabilizing selection W(p, x) = exp[-(p - x)2 /2w2 ]. The environmentally determined optimum (x) is a normal variable with variance s2 . A stable equilibrium with sigma^2=S2-w2 is found, so that sigma^2 increases both with increasing environmental heterogeneity and with increasing local intensity of stabilizing selection. It is shown that both genetic and environmental components of the variance are selected until this equilibrium is reached. Habitat selection, supposed to be normal (with variance H2 ) around the optimum, also increases the sigma^2 value. Nevertheless, relatively intense local stabilizing selection (w < s) and accurate habitat choice (H < s) are required for the initial spread and the evolutionary stability of this habitat selection. PMID- 28568211 TI - GENOTYPIC VARIATION IN LEAF DAMAGE IN PIPER ARIEIANUM (PIPERACEAE) BY A MULTISPECIES ASSEMBLAGE OF HERBIVORES. AB - The shrub Piper arieianum (Piperaceae) has a diverse herbivore fauna (95 species total) in Costa Rican rain forest. The effect of plant genotype on leaf damage by individual herbivore species and total leaf area removed was studied in P. arieianum through a cloning experiment. Damage patterns were measured over 3.5 years for two plots, four genotypes per plot, in the understory of lowland rain forest. In both plots, there were significant differences among genotypes in total leaf area missing throughout the study period. Rankings of genotypes based on overall damage remained constant over time in plot 1 but changed in plot 2. Certain individual herbivore species caused significantly higher damage in some genotypes than in others; the change in genotype rankings in plot 2 was associated with increased damage to particular genotypes by specific herbivore groups. The genotype most heavily damaged by a given insect species varied depending on the herbivore species; thus, resistance to one herbivore species did not necessarily confer resistance against all species. Those herbivore species causing the greatest proportion of damage for a given plant changed over time. Because total damage resulted from the summation of losses to individual herbivore species, whether an individual plant lost more leaf area than its neighbors depended on the relative abundance of the herbivore species at any one time. Finally, for a portion of the study period in each plot, more heavily damaged clones grew less than lesser damaged clones. Together with previous reports that naturally growing plants differ significantly in damage and that these differences are sufficient to cause fitness differences, the results presented here suggest that the herbivores of P. arieianum represent a selective force for changes in resistance but that this selective force changes both in intensity and quality over time. PMID- 28568212 TI - HETEROZYGOSITY AND GROWTH IN MARINE BIVALVES: RESPONSE TO KOEHN'S REMARKS. PMID- 28568213 TI - HISTORICAL BIOGEOGRAPHY IN NORTH AMERICAN ARID REGIONS: AN APPROACH USING MITOCHONDRIAL-DNA PHYLOGENY IN GRASSHOPPER MICE (GENUS ONYCHOMYS). AB - Restriction-endonuclease-site variation of mitochondrial DNA (mtDNA) was used to investigate patterns of geographic and phylogenetic divergence within the rodent genus Onychomys. Onychomys has occupied arid habitats in the western North American deserts, shrub-steppes, and grasslands since the late Tertiary. A phylogenetic analysis of the total mtDNA restriction-site variation throughout the range of Onychomys suggests that the distribution of this genus has been affected by the same Quaternary pluvial-interpluvial climatic fluctuations that have resulted in the periodic fragmentation of arid habitats in western North America. Onychomys mtDNA haplotypes define at least five discrete geographical subsets, suggesting that there are five areas of endemism for biota restricted to arid and semiarid habitats in North America. The mtDNA-haplotype phylogeny can be used to infer an hypothesis of historical relationships among the five areas of endemism as follows: ([{(Wyoming Basin + Interior Plains + Colorado Plateaus) + (Columbia Basin + Great Basin)} + Gulf Coastal Plain] + Chihuahuan) + Western Deserts. The results of this study point to the potential use of mtDNA-haplotype phylogenies to reconstruct historical biogeographic events in Quaternary time. The utility of mtDNA variation depends in part on the ecology and distribution of the species being examined. Therefore, our hypothesized area cladogram can be tested by investigating regional relationships in other western North American taxa with distributions similar to Onychomys. PMID- 28568214 TI - PHENOTYPIC PLASTICITY IN THE SAILFIN MOLLY, POECILIA LATIPINNA (PISCES: POECILIIDAE). II. LABORATORY EXPERIMENT. AB - Field studies indicate that the influence of environmental factors on growth rate and size and age at maturity in sailfin mollies (Poecilia latipinna) is inconsistent over time and suggest that the marked interdemic variation in male body size in this species is the result of genetic variation. However, the role of specific environmental factors in generating phenotypic variation must be studied under controlled conditions unattainable in nature. We raised newborn sailfin mollies from four populations in laboratory aquaria under all possible combinations of two temperatures, three salinities, and two food levels to examine explicitly the influence of these environmental factors. Males were much less susceptible than females to temperature variation and were generally less plastic than females in terms of all three traits. Members of both sexes matured at larger sizes and at later ages in less saline and in cooler environments. Food levels were not sufficiently different to affect the traits we studied. The effects of temperature and salinity were not synergistic. Males from different populations exhibited different average ages and sizes at maturity, but females did not. The magnitudes of the effects we found were not substantial enough to account for the consistent interdemic differences in male and female body size that have been observed previously. Our results also indicate that no single environmental factor is solely responsible for the environmental effects observed in field experiments on growth and development. These studies, together with other work, indicate that the strongest sources of interdemic variation are genetic differences in males and differences in postmaturation growth and survivorship in females. PMID- 28568215 TI - BIOLOGICAL AND HISTORICAL FACTORS INFLUENCING GENETIC DIVERSITY IN THE SCUTELLARIA ANGUSTIFOLIA COMPLEX (LABIATAE). AB - Studies of genetic diversity at isozyme loci were used to examine the phylogenetic distribution of several frequently reported population-genetic parameters in a putatively monophyletic group of plant species, the Scutellaria angustifolia complex. The influence of taxon-specific differences in habitat preference, breeding system, degree of endemism, and phylogenetic relatedness was examined. Many characters of reproductive morphology traditionally used in phylogenetic inference vary with breeding system. To the extent that reproductive systems are conservative markers of phylogenetic relationships, one would expect the distribution of genetic variation to be similar in closely related taxa. Results showed that closely related taxa may exhibit very different genetic diversity statistics and that distantly related taxa may exhibit very similar genetic-diversity statistics. This suggests that complex patterns of evolution of breeding systems and morphological characters have occurred in the ten taxa included in the Scutellaria angustifolia complex. Similarity in habitat is not associated with similarity in genetic diversity in this group of species. PMID- 28568216 TI - PATTERNS OF QUANTITATIVE VARIATION IN LEPIDOPTERAN WING MORPHOLOGY: THE CONVERGENT GROUPS HELICONIINAE AND ITHOMIINAE (PAPILIONOIDEA: NYMPHALIDAE). AB - Wing morphology has historically been a major focus in taxonomic and evolutionary studies of lepidopterans. However, general patterns of quantitative variation and diversification in wing sizes and shapes and the factors underlying them have been unexplored. A morphometric study of wing variation in the convergent heliconine and ithomine butterflies reveals remarkable similarities, both in their morphologies at a given size and in their patterns of allometry and variability. The groups differ primarily in the relative lengths of inner and outer forewing margins, with larger species being more similar across groups than smaller ones. Allometric size-scaling variation accounts for more than 90% of the total morphological variation in the two groups and thus seems to be the major determinant of wing shape. Forewings and hind wings are isometric in size (area) with respect to one another; however, wing shape within and among groups is significantly allometric, resulting in considerable shape differences between small and large species. A strong trend of increasing variability from anterior to posterior along the wings is consistent with hypotheses of aerodynamic constraint. Wings and bodies represent classical morphological "character suites" in that size and shape variation are more tightly correlated within suites than among them. Such complexes argue against the overriding importance of aerodynamic factors, such as wing load and muscle development, in constraining gross morphology. PMID- 28568217 TI - HETEROZYGOSITY AND GROWTH IN MARINE BIVALVES: COMMENTS ON THE PAPER BY ZOUROS, ROMERO-DOREY, AND MALLET (1988). PMID- 28568218 TI - Integrating renal nutrition guidelines into daily family life: a qualitative exploration. AB - BACKGROUND: Renal dietary compliance is challenging for individuals with chronic renal disease. Advice may change depending on renal function and medical treatment. Although patients seek support from family members with these changes, no literature exists with respect to how family members experience the offering of this support. The present study aimed to describe and interpret this lived experience of family members. METHODOLOGY: Phenomenological qualitative semi structured interviews were conducted with 12 adult family members via telephone (transcribed verbatim). Framework analysis and the qualitative software nvivo, version 10 (QSR International Pty Ltd, Melbourne, VIC, Australia) were used. Participants commented on the themes for accuracy of experience representation. RESULTS: Four major themes emerged: (i) intrusion of the renal diet; (ii) dealing with the recommendations of a renal diet; (iii) seeking a new identity; and (iv) transition of family dynamics. Perceived conflicting advice intruded into family life. Children in the family resulted in more complex nutritional decisions. Continuing a diet to avoid perceived family and wider social judgement was not an option. Balance between nurturing the family as a whole and the necessity of attending to the specific needs of one individual with renal disease was challenging. Transition to a new identity included family members being drawn to scientifically guided understandings of nutrition and a medicalisation of daily food requirements, which included low prioritisation of children's nutritional needs. CONCLUSION: Family members who cooked found the integration of renal nutrition guidelines challenging, with children presenting further challenges. The present study highlights the need to offer practical and psychological support to families who are coping with end-stage renal failure and renal nutritional guidelines. PMID- 28568219 TI - Neurodevelopmental outcome of isolated ventriculomegaly: a prospective cohort study. AB - OBJECTIVE: Data regarding the neurodevelopmental outcome of children diagnosed in utero with isolated ventriculomegaly (IVM) are limited and principally founded on ultrasound-based studies. Here, we endeavored to assess the outcome of such cases in a large-scale, magnetic resonance imaging (MRI)-based study. METHODS: We conducted a study on 133 cases of IVM with a documented fetal brain MRI scan. Children were assessed at ages 18 to 36 months by using the Vineland Adaptive Behavior Scales (VABS). RESULTS: Vineland Adaptive Behavior Scales scores were within normal range. There was no significant difference between VABS score in symmetric versus asymmetric IVM (101.7 vs. 101.6, respectively; p = 0.94), and the VABS score of mild IVM was comparable with that of moderate IVM (101.8 vs. 101; p = 0.8). Only five cases (3.8%) were found to have an abnormal score (<85). There was no significant difference in the rate of abnormal scores between mild and moderate IVM (2.8% vs. 8.3%, respectively; p = 0.22). CONCLUSION: In cases of isolated ventriculomegaly, a normal neurodevelopmental outcome is to be expected; moreover, the outcome does not appear to be affected by the severity or asymmetry of the ventriculomegaly. Thus, following a meticulous workup, patients can be given reassuring counseling regarding the child's prognosis. (c) 2017 John Wiley & Sons, Ltd. PMID- 28568220 TI - THE ROLES OF POLYEMBRYONY AND EMBRYO VIABILITY IN THE GENETIC SYSTEM OF CONIFERS. PMID- 28568221 TI - A CONDITION FOR GROUP SELECTION TO PREVAIL OVER COUNTERACTING INDIVIDUAL SELECTION. PMID- 28568223 TI - GENETIC INTERACTIONS AT A CONTACT ZONE OF URODERMA BILOBATUM (CHIROPTERA: PHYLLOSTOMIDAE). PMID- 28568222 TI - EXPERIMENTAL ECOLOGICAL GENETICS IN PLANTAGO. VII. REPRODUCTIVE EFFORT IN POPULATIONS OF P. LANCEOLATA L. PMID- 28568224 TI - THE CICHLID FISH OF CUATRO CIENEGAS, MEXICO: DIRECT EVIDENCE OF CONSPECIFICITY AMONG DISTINCT TROPHIC MORPHS. PMID- 28568225 TI - FIRST MALE SPERM PRIORITY IN THE BOWL AND DOILY SPIDER, FRONTINELLA PYRAMITELA (WALCKENAER). PMID- 28568226 TI - EVOLUTION OF THE SEED PLANTS AND INCLUSIVE FITNESS OF PLANT TISSUES. PMID- 28568227 TI - A THEORETICAL ANALYSIS OF THE EFFECTS OF SEX CHROMOSOME ANEUPLOIDY ON X AND Y CHROMOSOME MEIOTIC DRIVE. PMID- 28568228 TI - EVOLUTIONARY HISTORY OF DROSOPHILA BUZZATII. II. HOW MUCH HAS CHROMOSOMAL POLYMORPHISM CHANGED IN COLONIZATION? PMID- 28568229 TI - NICHE SHIFTS AND COMPETITION IN DARWIN'S FINCHES: GEOSPIZA CONIROSTRIS AND CONGENERS. PMID- 28568230 TI - HETEROZYGOSITY AND DEVELOPMENTAL STABILITY UNDER SEXUAL AND ASEXUAL BREEDING SYSTEMS. PMID- 28568231 TI - NEOTENIC EVOLUTION OF DELPHINIUM NUDICAULE (RANUNCULACEAE): A HUMMINGBIRD POLLINATED LARKSPUR. PMID- 28568232 TI - POPULATION SYNCHRONY IN MAYFLIES: A PREDATOR SATIATION HYPOTHESIS. PMID- 28568233 TI - WHEN DOES OUTCROSSING OCCUR IN A MASS-FLOWERING PLANT? PMID- 28568234 TI - A MULTIVARIATE STATISTICAL ANALYSIS OF DIRECT AND CORRELATED RESPONSE TO SELECTION IN THE RAT. PMID- 28568235 TI - ADAPTATION OF GRAY SQUIRREL BEHAVIOR TO AUTUMN GERMINATION BY WHITE OAK ACORNS. PMID- 28568236 TI - ENVIRONMENTAL AND GENETIC DETERMINANTS OF CLEISTOGAMY IN A NATURAL POPULATION OF THE GRASS DANTHONIA SPICATA. PMID- 28568237 TI - PATTERNS OF SEED DISPERSAL AND POPULATION DIFFERENTIATION IN MIMULUS GUTTATUS. PMID- 28568238 TI - THE STRUCTURE OF THE HYBRID ZONE IN URODERMA BILOBATUM (CHIROPTERA: PHYLLOSTOMATIDAE). PMID- 28568239 TI - SEA URCHIN DNA SEQUENCE VARIATION AND REDUCED INTERSPECIES DIFFERENCES OF THE LESS VARIABLE DNA SEQUENCES. PMID- 28568240 TI - SYNCHRONY IN THE LESSER SNOW GOOSE (ANSER CAERULESCENS CAERULESCENS). II. THE ADAPTIVE VALUE OF REPRODUCTIVE SYNCHRONY. PMID- 28568241 TI - Team structure, skill mix and clinical outcomes. AB - The majority of presentations to Australian EDs are for semi-urgent and non urgent complaints in the older adult. For these patient's treatment and care is typically delivered by loosely organised teams of professionals. While substantial research has examined the clearly defined, hierarchical team structures used during resuscitation events, little is known about the composition and functioning of teams involved in non-urgent patient care in ED. Investigation of these team dynamics can identify personal and professional factors involved in the delivery of this care and enable the design of teams that enhance patient outcomes. PMID- 28568242 TI - History cleans up messes: The impact of time in driving divergence and introgression in a tropical suture zone. AB - Contact zones provide an excellent arena in which to address questions about how genomic divergence evolves during lineage divergence. They allow us to both infer patterns of genomic divergence in allopatric populations isolated from introgression and to characterize patterns of introgression after lineages meet. Thusly motivated, we analyze genome-wide introgression data from four contact zones in three genera of lizards endemic to the Australian Wet Tropics. These contact zones all formed between morphologically cryptic lineage-pairs within morphologically defined species, and the lineage-pairs meeting in the contact zones diverged anywhere from 3.1 to 5.8 million years ago. By characterizing patterns of molecular divergence across an average of 11K genes and fitting geographic clines to an average of 7.5K variants, we characterize how patterns of genomic differentiation and introgression change through time. Across this range of divergences, we find that genome-wide differentiation increases but becomes no less heterogeneous. In contrast, we find that introgression heterogeneity decreases dramatically, suggesting that time helps isolated genomes "congeal." Thus, this work emphasizes the pivotal role that history plays in driving lineage divergence. PMID- 28568243 TI - Rethinking the starch digestion hypothesis for AMY1 copy number variation in humans. AB - Alpha-amylase exists across taxonomic kingdoms with a deep evolutionary history of gene duplications that resulted in several alpha-amylase paralogs. Copy number variation (CNV) in the salivary alpha-amylase gene (AMY1) exists in many taxa, but among primates, humans appear to have higher average AMY1 copies than nonhuman primates. Additionally, AMY1 CNV in humans has been associated with starch content of diets, and one known function of alpha-amylase is its involvement in starch digestion. Thus high AMY1 CNV is considered to result from selection favoring more efficient starch digestion in the Homo lineage. Here, we present several lines of evidence that challenge the hypothesis that increased AMY1 CNV is an adaptation to starch consumption. We observe that alpha- amylase plays a very limited role in starch digestion, with additional steps required for starch digestion and glucose metabolism. Specifically, we note that alpha-amylase hydrolysis only produces a minute amount of free glucose with further enzymatic digestion and glucose absorption being rate-limiting steps for glucose availability. Indeed alpha-amylase is nonessential for starch digestion since sucrase-isomaltase and maltase-glucoamylase can hydrolyze whole starch granules while releasing glucose. While higher AMY1 CN and CNV among human populations may result from natural selection, existing evidence does not support starch digestion as the major selective force. We report that in humans alpha-amylase is expressed in several other tissues where it may have potential roles of evolutionary significance. PMID- 28568245 TI - Quality Metrics and Systems Transformation: Are We Advancing Alcohol and Drug Screening in Primary Care? AB - OBJECTIVE: To examine the influence of Oregon's coordinated care organizations (CCOs) and pay-for-performance incentive model on completion of screening and brief intervention (SBI) and utilization of substance use disorder (SUD) treatment services. DATA SOURCES/STUDY SETTING: Secondary analysis of Medicaid encounter data from 2012 to 2015 and semiannual qualitative interviews with stakeholders in CCOs. STUDY DESIGN: Longitudinal mixed-methods design with simultaneous data collection with equal importance. DATA COLLECTION/EXTRACTION METHODS: Qualitative interviews were recorded, transcribed, and coded in ATLAS.ti. Quantitative data included Medicaid encounters 30 months prior to CCO implementation, a 6-month transition period, and 30 months following CCO implementation. Data were aggregated by half-year with analyses restricted to Medicaid recipients 18-64 years of age enrolled in a CCO, not eligible for Medicare coverage or Medicaid expansion. PRINCIPAL FINDINGS: Quantitative analysis documented a significant increase in SBI rates coinciding with CCO implementation (0.1 to 4.6 percent). Completed SBI was not associated with increased initiation in treatment for SUD diagnoses. Qualitative analysis highlighted importance of aligning incentives, workflow redesign, and leadership to facilitate statewide SBI. CONCLUSIONS: Results provide modest support for use of a performance metric to expand SBI in primary care. Future research should examine health reform efforts that increase initiation and engagement in SUD treatment. PMID- 28568244 TI - The prognostic significance of polyclonal bone marrow plasma cells in patients with relapsing multiple myeloma. AB - Prior studies have revealed that the presence of increasing number of polyclonal plasma cells (pPCs) in the bone marrow (BM) are associated with better outcomes in newly diagnosed multiple myeloma (MM) patients. This effect has not been studied in patients with MM at the time of disease relapse. We determined the prognostic value of depletion of pPCs in the BM by 7-color multiparameter flow cytometry in a series of 174 relapsing MM patients. The time to next therapy (TTNT) in those with <5% pPCs was 9.4 months versus 13.9 months in those with >=5% pPCs (P = .0091). The median overall survival (OS) in those with <5% pPCs was 21.4 months, while the median OS was not reached in those patients with >=5% pPCs (P = .019). Of the 109 patients with standard risk cytogenetics, the median OS of those with <5% pPCs was 28.4 months, while the median OS was not reached in those with >=5% pPCs (P = .033). As such, <5% pPCs in the BM appears to have prognostic utility in identifying a subset of relapsing MM patients, even with standard-risk cytogenetics, who have a particularly adverse outcome. PMID- 28568247 TI - BREEDING COMPETITION IN A PACIFIC SALMON (COHO: ONCORHYNCHUS KISUTCH): MEASURES OF NATURAL AND SEXUAL SELECTION. AB - In the breeding system of Pacific salmon, females compete for oviposition territories, and males compete to fertilize eggs. The natural selection in females and sexual selection in males likely has been responsible for their elaborate breeding morphologies and the dimorphism between the sexes. We quantified direct-selection intensities during breeding on mature coho salmon (Oncorhynchus kisutch), measured for seven phenotypic characters, including three secondary sexual characters. Wild and sea-ranched hatchery coho were used to enhance the range of phenotypes over which selection could be examined. The fish were allowed to breed in experimental arenas where we could quantify components of breeding success as well as estimate overall breeding success. We found that without competition, natural selection acts only on female body size for increased egg production; there is no detectable selection on males for the phenotypic distribution we used. Under competition, the opportunity for selection increased sixfold among females. Natural selection favored female body size and caudal-peduncle (tail) depth. Increased body size meant increased egg production and access to nesting territories. The caudal peduncle, used in burst swimming and nest digging, influenced both successful egg deposition and nest survival. Increasing density increased competition among females, though it did not significantly intensify natural selection on their characters. In males, competition increased the opportunity for selection 52-fold, which was nine times greater than for females. Sexual selection favored male body size and hooked snout length, both characters directly influencing male access to spawning opportunities. Selection on male body size was also affected significantly by breeding density. The ability of large males to control access to spawning females decreased at higher densities reflecting an increase in the operational sex ratio. Further, the relative success of small males, which could sneak access to spawning females, appeared to increase as that of intermediate-sized males decreased. Such disruptive selection may be responsible for the evolution of alternative reproductive tactics in salmon. PMID- 28568248 TI - A MULTILEVEL APPROACH TO THE SIGNIFICANCE OF GENETIC VARIATION IN ALCOHOL DEHYDROGENASE OF DROSOPHILA. AB - Prior studies showed that differences in alcohol dehydrogenase (ADH) activity across genotypes of Drosophila are decisive for the outcome of selection by ethanol. In the present paper, the effect on ADH activity and egg-to-adult survival of combinations of ethanol, propan-2-ol, and acetone in naturally occurring concentrations is examined. Propan-2-ol is converted into acetone by ADH in vitro. Acetone is considered a competitive inhibitor of ethanol for the ADH enzymes. The melanogaster-ADH-S allozyme is two times more sensitive towards inhibition by acetone than either simulans-ADH or melanogaster-ADH-F. The physiological implications of these in vitro differences for larvae were studied in short-term in vivo and long-term exposure experiments. No major differences in acetone accumulation or fitness parameters were found between the strains in response to ecologically relevant concentrations of acetone or propan-2-ol. Ethanol, however, strongly decreased egg-to-pupal survival in both Drosophila simulans strains and increased developmental time in four out of the five strains tested. Therefore, under physiological conditions only ethanol was shown to act as a selective agent on the ADH polymorphism during egg-to-pupa development in Drosophila. PMID- 28568246 TI - Total sleep time as a predictor of suicidal behaviour. AB - Insomnia symptoms are a known predictor of suicide; however, less is known about the relationship between hypersomnia and suicide, and how total sleep time may better account for suicidal ideation compared with subjective reports of insomnia symptoms. In the present secondary data analysis, a squared term confirmed the importance of both short and long total sleep time on suicidal behaviour. Total sleep time had a significant positive direct effect on suicidal behaviour (b = 0.20, SE = 0.08, P < 0.05), significant negative direct effects on insomnia symptoms (b = -1.67, SE = 0.13, P < 0.0001) and on depressive symptoms (b = 1.76, SE = 0.29, P < 0.0001). Depression had a significant positive effect on suicidal behaviour (b = 0.17, SE = 0.01, P < 0.0001), and significantly mediated the relationship between total sleep time and suicidal behaviour, but insomnia symptoms did not. Total sleep time squared had a significant positive relationship with suicidal behaviour (b = 0.02, SE = 0.01, P < 0.05), significant negative direct effects on insomnia symptoms (b = -0.12, SE = 0.01, P < 0.0001) and on depressive symptoms (b = -0.12, SE = 0.02, P < 0.0001). Depression had a significant positive effect on suicidal behaviour (b = 0.17, SE = 0.01, P < 0.0001), and significantly mediated the relationship between total sleep time and suicidal behaviour. These results suggest the importance of assessing for total sleep time in clinical settings with regard to suicide risk. PMID- 28568249 TI - HETEROZYGOTE DEFICIENCIES UNDER LEVENE'S POPULATION SUBDIVISION STRUCTURE. PMID- 28568250 TI - TEMPORAL VARIATION IN POPULATIONS OF THE MARINE ISOPOD EXCIROLANA: HOW STABLE ARE GENE FREQUENCIES AND MORPHOLOGY? AB - Excirolana braziliensis is a dioecious marine isopod that lives in the high intertidal zone on both sides of tropical America. It lacks a dispersal phase and displays a remarkable degree of genetic divergence even between localities less than 1 km apart. Nine populations of this nominal species from both sides of the Isthmus of Panama and one population of the closely allied species, Excirolana chamensis, from the eastern Pacific were studied for 2 yr for allozymic temporal variation in 13 loci and for 3 to 4 yr for morphological variation in nine characters. The genetic and morphological constitution of 9 out of 10 populations remained stable. Allele frequencies at two loci and overall morphology in a tenth beach occupied by E. braziliensis changed drastically and significantly between 1986 and 1988. The change in gene frequency is too great to explain by genetic drift occurring during a maximum of 14 generations regardless of assumed effective population size; drift is also unlikely to have caused observed changes in morphology. Selective survival of a previously rare genotype is more plausible but still not probable. The most credible explanation is that the resident population at this locality became extinct and that the beach was recolonized by immigrants from another locality. Such infrequent episodes of extinction and recolonization from a single source may account for the large amount of genetic divergence between local populations of E. braziliensis. However, the low probability of large temporal genetic change even in a species such as this, in which gene flow between local demes is limited and generation time is short, suggests that a single sample through time is usually adequate for reconstructing the genetic history of populations. PMID- 28568251 TI - GENETIC VARIABILITY, QUEEN NUMBER, AND POLYANDRY IN SOCIAL HYMENOPTERA. AB - Several hypotheses have been put forward to explain the adaptive significance of interspecific variation in mating frequencies by eusocial hymenopteran queens. Four of these hypotheses assert that polyandry is advantageous to queens because of the resultant increase in genetic variability within colonies (referred to as the "GV" hypotheses). Here we compare the frequency of polyandry between monogynous (single-queen) and polygynous (multiple-queen) ant species to test the hypotheses that (1) multiple mating functions primarily to increase intracolonial genetic variability, and (2) mating has costs (such as increased energetic losses or risk of predation or venereal disease). If one of the GV hypotheses is true and mating is costly, the frequency of polyandry should be lower in polygynous species (in which the presence of multiple queens results in low relatedness among workers) than in monogynous species. As predicted by the GV hypotheses, polyandry is less common among polygynous than among monogynous species. Furthermore, it seems that the causal relationship underlying this association is that the number of matings by queens depends on the number of queens present in the colony (rather than the number of queens being influenced by the number of matings), which also supports the GV hypotheses together with the assumption that mating has costs. PMID- 28568252 TI - QUANTITATIVE GENETICS OF SEQUENTIAL LIFE-HISTORY AND JUVENILE TRAITS IN THE PARTIALLY SELFING PERENNIAL, AQUILEGIA CAERULEA. AB - We determined the genetic basis of several traits related to overall fitness of Aquilegia caerulea, a perennial herb of the Rocky Mountains in western North America. To obtain measures of heritability relevant to the evolutionary potential of wild populations, we performed full and partial diallel crosses and studied progeny performance in the field. Based on a joint analysis of two designs with a total of 18 parents and 102 crosses, we detected significant maternal variance for seed mass and emergence time, but this component was negligible for later-expressed traits. Low heritability and evidence that maternal effects on seed mass are largely environmental suggest that in this population there is little evolutionary potential for change in seed mass under conditions experienced during the study. Seed mass varied depending on particular combinations of parents and cross direction. Such an interaction can have several different biological interpretations, including that particular maternal parents selectively provision embryos sired by particular pollen genotypes. Width of the first true leaf after 4 wk of growth and leaf size of juvenile plants at years one and two were significantly heritable and positively genetically correlated. Juvenile survival exhibited significant dominance variance, as expected from evidence of inbreeding depression in this trait. In contrast, for other traits that exhibit inbreeding depression in this population (seed mass and third-year leaf size), dominance variance was negligible. PMID- 28568253 TI - ERRATUM. PMID- 28568254 TI - GEOGRAPHIC DISTRIBUTION OF MITOCHONDRIAL DNA VARIANTS AND THE HISTORICAL BIOGEOGRAPHY OF THE SPOTTED SALAMANDER, AMBYSTOMA MACULATUM. AB - I analyzed geographic partitioning of mitochondrial DNA (mtDNA) restriction-site variants in the spotted salamander, Ambystoma maculatum. Two highly divergent and geographically separate genetic lineages were identified that differed by a minimum of 19 restriction sites (6% sequence divergence). One of the lineages has a disjunct distribution with very closely related haplotypes occurring in Missouri, Arkansas, North Carolina, and Virginia. The other lineage is found in Michigan, Illinois, and Alabama. The geographic separation of highly divergent mtDNA haplotypes, a pattern that was predicted based on the sedentary nature of these salamanders, is evidence for long-term barriers to gene flow. In contrast, the large-scale disjunction of very similar haplotypes suggests recent, long distance gene flow and does not match the phylogeographic expectation for a small terrestrial vertebrate. I explain this potential contradiction in the level of importance assigned to gene flow by a scenario in which historical barriers to gene flow account for the two divergent mtDNA assemblages, but stochastic sorting of ancestral polymorphism is responsible for the large-scale geographic disjunction. Ten of 16 populations collected in the Ozark Highlands were fixed for the same haplotype. I attribute this lack of detectable variation to recent colonization of this area, a hypothesis that is supported by paleoecological data and demonstrates the potential benefits of combining data from paleobotany, geology, and other disciplines to reconstruct the historical biogeography of a species. PMID- 28568255 TI - ALCOHOL TOLERANCE, ADH ACTIVITY, AND ECOLOGICAL NICHE OF DROSOPHILA SPECIES. AB - In vitro alcohol dehydrogenase (ADH) activity was measured in adults of species belonging to Drosophila and to the related genus Zaprionus. Data were analyzed according to the known breeding sites and the level of ethanol tolerance of these species. Alcohol dehydrogenase activity was assayed with both ethanol (E) and isopropanol (I). Our results show a very broad range of activities among the 71 species investigated, the ratio of the highest value observed (D. melanogaster) to the lowest (D. pruinosa) being 65:1. A general positive correlation was found between the level of ADH activity and the capacity to detoxify ethanol. Nevertheless, many species show exceptions to this rule. Contrary to a logical expectation, adaptation to high alcoholic resources, which has been a recurrent evolutionary event, was not mediated by a more efficient use of ethanol, that is, an increase of the E/I ratio. This ratio seems to be quite variable according to the phylogeny and is especially low in the subgenus Sophophora as well as in Zaprionus. Alcohol tolerance clearly is related to the larval habitat of the species and shows that adaptation to alcoholic resources has been a major evolutionary challenge in drosophilids. This adaptation is not related to phylogeny, having occurred independently several times during the evolution of the group. Finally, it should be borne in mind that, besides metabolization and detoxification, other physiological processes such as nervous-system tolerance or ethanol excretion may be involved in ethanol tolerance, and such functions also should be investigated. Environmental ethanol, which is certainly a major ecological parameter for many drosophilids, has selected a diversity of physiological adaptations, all related to the Adh locus, but presumably much more complicated than was previously believed. PMID- 28568256 TI - EVOLUTIONARY AND HISTORICAL ANALYSIS OF PROTEIN VARIATION IN THE BLOTCHED FORMS OF SALAMANDERS OF THE ENSATINA COMPLEX (AMPHIBIA: PLETHODONTIDAE). AB - Geographic variation in 23 to 29 protein-encoding genetic loci was examined in 48 populations of the Ensatina complex, a "ring species" distributed around the Central Valley of California. The samples span two critical links in the chain of morphologically distinct units: the transition from the unblotched to blotched color pattern types in the vicinity of Lassen Peak, northeastern California, and a geographic gap in the range of the complex in the San Gabriel Mountains, southern California. A general pattern of isolation by distance with a regular buildup of genetic distance correlated with increases in geographic distance characterizes the populations studied, with the exception of a little differentiated group of populations in the northern Sierra Nevada; this region is postulated to be a zone of genetic reticulation characterized by relatively high gene flow. An adaptively significant color pattern is thought to have spread into the northern Sierra Nevada from the south, but protein variants have been introduced both from the north and the south. Genetic distances across the San Gabriel Mountain gap match expectations from the pattern of buildup of genetic distance as a function of geographic distance elsewhere in the complex. A phylogenetic analysis of the protein data supports the reticulation hypothesis; whereas the southernmost populations currently do constitute a monophyletic assemblage, an "extinction experiment" demonstrates that the distinction could be the result of the recent extinction of populations in a present gap in our sampling. The Ensatina complex appears to be a dynamic entity representing several stages in the evolution of species. It is a ring species, and whereas various taxonomic arrangements are possible, no taxonomic changes are proposed. PMID- 28568257 TI - MATING PATTERN AND FITNESS-COMPONENT ANALYSIS ASSOCIATED WITH INVERSION POLYMORPHISM IN A NATURAL POPULATION OF DROSOPHILA BUZZATII. AB - Direct studies of mating success or mating pattern associated with Mendelian factors rarely have been carried out in nature. From the samples taken for the standard analyses of selection components, it is not usually possible to obtain the mating table, and only directional selection for male mating success can be detected. Both processes, mating pattern and differential mating probability, together with other fitness components, have been investigated for the inversion polymorphism of a natural population of the cactophilic species Drosophila buzzatii. Two independent samples of adult flies were collected: nonmating or single individuals (base population) and mating pairs (mating population). All individuals were karyotyped for the second and fourth chromosomes. A sequence of models with increasing simplicity was fitted to the data to test null hypotheses of no selection and random union of gametes and karyotypes. The main results were (1) no deviations from random mating were found; (2) differential mating probability was nonsignificant in both sexes; (3) inversion and karyotypic frequencies did not differ between sexes; and (4) karyotypic frequencies did not depart from Hardy-Weinberg expectations. These results are discussed in light of complementary evidence showing the need for interpreting with caution no-effect hypotheses such as the ones tested here. The use of complementary selective tests in these studies is suggested. PMID- 28568258 TI - SOME EVOLUTIONARY POSSIBILITIES FOR A MICROBE THAT CAUSES INCOMPATIBILITY IN ITS HOST. PMID- 28568259 TI - GENETIC AND MORPHOLOGICAL DIVERGENCE AMONG MORPHOTYPES OF THE ISOPOD EXCIROLANA ON THE TWO SIDES OF THE ISTHMUS OF PANAMA. AB - Excirolana braziliensis is a dioecious marine isopod that lives in the high intertidal zone of sandy beaches on both sides of Central and South America. It possesses no larval stage and has only limited means of adult dispersal. Indirect estimates of gene flow have indicated that populations from each beach exchange less than one propagule per generation. Multivariate morphometrics have discovered three morphs of this species in Panama, two of them closely related and found on opposite sides of Central America ("C morph" in the Caribbean and "C' morph" in the eastern Pacific), the third found predominantly in the eastern Pacific ("P morph"). Though the P and C' morphs are seldom found on the same beach, they have overlapping latitudinal ranges in the eastern Pacific. A related species, Excirolana chamensis, has been described from the Pacific coast of Panama. Each beach contains populations that remain morphologically and genetically stable, but a single drastic change in both isozymes and morphology has been documented. We studied isozymes and multivariate morphology of 10 populations of E. braziliensis and of one population of E. chamensis. Our objective was to assess the degree of genetic and morphological variation, the correlation of divergence on these two levels of integration, the phylogenetic relationships between morphs, and the possible contributions of low vagility, low gene flow, and occasional extinction and recolonization to the genetic structuring of populations. Genetic distance between the P morph, on one hand, and the other two morphotypes of E. braziliensis, on the other, was as high as the distance between E. braziliensis and E. chamensis. Several lines of evidence agree that E. chamensis and the P morph had diverged from other morphs of E. braziliensis before the rise of the Panama Isthmus separated the C and C' forms, and that the P morph constitutes a different species. A high degree of genetic differentiation also exists between populations of the same morph. On the isozyme level, every population can be differentiated from every other on the basis of at least one diagnostically different locus, regardless of geographical distance or morphological affiliation. Morphological and genetic distances between populations are highly correlated. However, despite the high degree of local variation, evolution of E. braziliensis as a whole has not been particularly rapid; divergence between the C and C' morphs isolated for 3 million yr by the Isthmus of Panama is not high by the standard of within-morph differentiation or by comparison with other organisms similarly separated. Alleles that are common in one population may be absent from another of the same morph, yet they appear in a different morph in a separate ocean. The high degree of local differentiation, the exclusive occupation of a beach by one genotype with rare arrival of foreign individuals that cannot interbreed freely with the residents, the genetic stability of populations with infrequent complete replacement by another genetic population, and the sharing by morphs of polymorphisms that are not shared by local populations, all suggest a mode of evolution concentrated in rare episodes of extinction and recolonization, possibly coupled with exceptional events of gene flow that help preserve ancestral variability in both oceans. PMID- 28568260 TI - POLYPHYLY OF THE BLACKBIRD GENUS AGELAIUS AND THE IMPORTANCE OF ASSUMPTIONS OF MONOPHYLY IN COMPARATIVE STUDIES. AB - A phylogeny for Agelaius blackbirds was constructed using sequence data from an 890 base-pair (bp) region of the mitochondrial cytochrome-b gene in nine species of Agelaius and a single species from all but 1 of the 28 described blackbird genera and subgenera. The genus was found to be polyphyletic with the South American members of Agelaius more closely related to other South American blackbird genera. Application of bootstrap and jackknife manipulations supports this conclusion. That this relatively well-known genus is polyphyletic represents a warning to those attempting to construct phylogenies without first demonstrating monophyly of the ingroup. The conclusion that Agelaius is polyphyletic necessitates (1) the reinterpretation of previous studies that assumed monophyly and (2) the initiation of a variety of new comparative behavioral and ecological studies suggested by this finding. PMID- 28568261 TI - EFFECTS OF SERIAL INBREEDING ON FITNESS COMPONENTS IN IMPATIENS CAPENSIS. AB - Studies of inbreeding depression in wild plants customarily compare the fitness of outcrossed progeny to progeny derived from one generation of self-pollination. We compare levels of inbreeding depression in a greenhouse in two populations of jewelweed using progeny derived from random outcrosses, one generation of self pollination, and three generations of selling. The progeny have expected inbreeding coefficients of, respectively, 0, 0.5, and 0.875. Seedling survivorship declined linearly with the level of inbreeding in both populations. Inbreeding also increased the variability of emergence date. Maternal family membership affected early seedling performance and often interacted significantly with the level of inbreeding. In contrast, path analyses reveal that inbreeding had both negative linear and positive quadratic direct effects on seed and final plant weight, causing the highly inbred progeny to outperform progeny derived from one generation of selfing. These results suggest either the rapid purging of deleterious alleles or diminishing epistasis among the loci affecting these characters. It is not clear why the loci affecting survival responded differently. PMID- 28568262 TI - MORPHOLOGICAL VERSUS GENETIC MARKERS IN CLASSIFYING HYBRID PLANTS. PMID- 28568263 TI - THE DUAL ROLE OF SELECTION AND EVOLUTIONARY HISTORY AS REFLECTED IN GENETIC CORRELATIONS. AB - The patterns of genetic correlations between a series of eye and antenna characters were compared among two sets of spring-dwelling and cave-dwelling populations of Gammarus minus. The two sets of populations originate from different drainages and represent two separate invasions of cave habitats from surface-dwelling populations. Matrix correlations, using permutation tests, indicated significant correlations both between populations in the same basin and from the same habitat. The technique of biplot, which allows for the simultaneous consideration of relationships between different genetic correlations and different populations, was used to further analyze the correlation structure. A rank-3 biplot indicated that spring and cave populations were largely differentiated by eye-antennal correlations, whereas basins were differentiated by both eye-antennal and antennal-antennal correlations. Eye-antennal correlations, which are likely to be subject to selection, were most similar within habitats, which are likely to have similar selective regimes. PMID- 28568264 TI - VARIABLE SELECTION ON EUROSTA'S GALL SIZE. II. A PATH ANALYSIS OF THE ECOLOGICAL FACTORS BEHIND SELECTION. AB - We examined phenotypic selection exerted by natural enemies on the gall-making fly Eurosta solidaginis in an extensive field study of 16 populations, spanning four generations. Gall-makers that induce small galls are vulnerable to the attack of Eurytoma gigantea. This imposes upward directional selection on gall size. Insectivorous birds, predominantly the downy woodpecker, are more likely to attack larvae that induce large galls than small ones, and this imposes downward directional selection. We used path analysis to explore the relative contributions of these natural enemies to the net directional selection on gall size. The path models further examined several ecological factors that influence selection intensity through their effects on parasitoid and bird attack rates. Net directional selection varied more strongly with E. gigantea attack than bird attack. Competitive interactions among birds and the three parasitoid species, including E. gigantea, were evidenced by low winter bird attack rates in fields where a high proportion of galls contained the overwintering parasitoids. Eurytoma gigantea attack was heavier in fields where mean gall size was small and bird attack heavier in fields where mean gall size was large. Neither birds nor E. gigantea showed simple density-dependent attack. Data suggested a form of frequency-dependent attack by birds but not by E. gigantea. PMID- 28568265 TI - ASSORTATIVE MATING AND THE ADAPTIVE LANDSCAPE. AB - The ability of a population to shift from one adaptive peak to another was examined for a two-locus model with different degrees of assortative mating, selection, and linkage. As expected, if the proportion of the population that mates assortatively increases, so does its ability to shift to a new peak. Assortative mating affects this process by allowing the mean fitness of a population to increase monotonically as it passes through intermediate gene frequencies on the way to a new, higher, homozygotic peak. Similarly, if the height of the new peak increases or selection against intermediates becomes less severe, the population becomes more likely to shift to a new peak. Close linkage also helps the shift to a new adaptive peak and acts similarly to assortative mating, but it is not necessary for such a shift as was previously thought. When a population shifts to a new peak, the number of generations required is significantly less than that needed to return to the original peak when that happens. The short period of time required may be an explanation for rapid changes in the geological record. Under extremely high degrees of assortative mating, the shift takes longer, presumably because of the difficulty of breaking up less favored allelic combinations. PMID- 28568266 TI - SPECIATION BY POLYPLOIDY IN TREEFROGS: MULTIPLE ORIGINS OF THE TETRAPLOID, HYLA VERSICOLOR. AB - Speciation by polyploidy is rare in animals, yet, in vertebrates, there is a disproportionate concentration of polyploid species in anuran amphibians. Sequences from the cytochrome b gene of the mitochondrial DNA (mtDNA) were used to determine phylogenetic relationships among 37 populations of the diploid tetraploid species pair of gray treefrogs, Hyla chrysoscelis and Hyla versicolor. The diploid species, H. chrysoscelis, consists of an eastern and a western lineage that have 2.3% sequence divergence between them. The tetraploid species, H. versicolor, had at least three separate, independent origins. Two of the tetraploid lineages are more closely related to one or the other of the diploid lineages (0.18%-1.4% sequence divergence) than they are to each other (1.9%-3.4% sequence divergence). The maternal ancestor of the third tetraploid lineage is unknown. The phylogenetic relationships between the two species and among lineages within each species support the hypothesis of multiple origins of the tetraploid lineages. PMID- 28568267 TI - PHYLOGENIES WITHOUT FOSSILS. AB - Phylogenies that are reconstructed without fossil material often contain approximate dates for lineage splitting. For example, particular nodes on molecular phylogenies may be dated by known geographic events that caused lineages to split, thereby calibrating a molecular clock that is used to date other nodes. On the one hand, such phylogenies contain no information about lineages that have become extinct. On the other hand, they do provide a potentially useful testing ground for ideas about evolutionary processes. Here we first ask what such reconstructed phylogenies should be expected to look like under a birth-death process in which the birth and death parameters of lineages remain constant through time. We show that it is possible to estimate both the birth and death rates of lineages from the reconstructed phylogenies, even though they contain no explicit information about extinct lineages. We also show how such phylogenies can reveal mass extinctions and how their characteristic footprint can be distinguished from similar ones produced by density-dependent cladogenesis. PMID- 28568268 TI - SEXUAL SIZE DIMORPHISM AND EGG-SIZE ALLOMETRY IN BIRDS. AB - We tested the hypothesis that egg size should evolve in sexually dimorphic birds to reduce costs associated with more rapid growth by nestlings of the larger sex. Consistent with this hypothesis, we found that in species in which males were larger, females laid proportionately larger eggs as sexual size dimorphism increased. However, this result was also consistent with the hypothesis that egg size varied allometrically with both male and female body size. Furthermore we found that in species in which females were larger, relative egg size decreased as size dimorphism increased, which is consistent with the "allometry hypothesis" but not the "cost-reduction hypothesis. That male body size contributes to the allometric relationship between egg size and body size suggests that the basis for the allometric relationship is not wholly a mechanical one stemming from the physical requirements of developing, transporting, and laying an egg of a particular size. Rather, the relationship seems likely to be tied more directly to body size itself the tact that male body size influences a female trait suggests that egg size-body size relationships otter some scope for investigating the basis for allometric relationships in general. PMID- 28568269 TI - THE RELATIONSHIP BETWEEN INBREEDING DEPRESSION AND PRIOR INBREEDING AMONG POPULATIONS OF FOUR MIMULUS TAXA. AB - When recessive mutations are the primary cause of inbreeding depression, a negative relationship between the levels of prior inbreeding and inbreeding depression is expected. We tested this prediction using 15 populations chosen a priori to represent a wide range of prior inbreeding among four closely related taxa of the Mimulus guttatus species complex. Artificially selfed and outcrossed progeny were grown under controlled growth-chamber conditions, and inbreeding depression was estimated for each population as one minus the ratio of the fitness of selfed to outcrossed progeny. Estimates of inbreeding depression varied from 0% to 68% among populations. Inbreeding coefficients, estimated from electrophoretic assay of field-collected progenies, ranged from 0.02 to 0.76. All five fitness traits displayed a negative association between inbreeding depression and the inbreeding coefficient, but only height showed a statistically significant correlation. Inbreeding depression was also not correlated with the level of genetic variability. In addition, populations with similar levels of prior inbreeding showed significant differences of inbreeding depression, whereas populations with different levels of prior inbreeding showed similar inbreeding depression. Within populations, inbreeding depression did not differ between progeny selfed one versus two generations. Our results are weakly consistent with the recessive mutation model of inbreeding depression, but suggest that additional factors, including genotype-by-environment interaction and complex modes of inheritance, may influence the expression of inbreeding depression. PMID- 28568270 TI - THE EVOLUTION OF UNPALATABILITY AND WARNING COLORATION IN SOFT-BODIED MARINE INVERTEBRATES. PMID- 28568271 TI - POPULATION STRUCTURE AND LEVELS OF GENE FLOW IN THE MEDITERRANEAN LAND SNAIL ALBINARIA CORRUGATA (PULMONATA: CLAUSILIIDAE). AB - The amount of gene flow among local populations partly determines the relative importance of genetic drift and natural selection in the differentiation of such populations. Land snails, because of their limited powers for dispersal, may be particularly likely to show such differentiation. In this study, we directly estimate gene flow in Albinaria corrugata, a sedentary, rock-dwelling gastropod from Crete, by mark-recapture studies. In the same area, 23 samples were taken and studied electrophoretically for six polymorphic enzyme loci. The field studies indicate that the population structure corresponds closely to the stepping-stone model: demes are present on limestone boulders that are a few meters apart, and dispersal takes place mainly between adjacent demes. Average deme size (N) is estimated at 29 breeding individuals and the proportion of migrants per generation at 0.195 (Nm = 5.7). We find no reason to assume long distance dispersal, apart from dispersal along occasional stretches of suitable habitat. Genetic subdivision of the population, as derived from FST values, corresponds to the direct estimate only at the lowest spatial level (distance between sample sites < 10 m), where values for Nm of 5.4 and 17.6 were obtained. In contrast, at the larger spatial scales, FST values give gene-flow estimates that are incompatible with the expected amount of gene flow at these scales. We explain these discrepancies by arguing that gene flow is in fact extremely limited, making correct estimates of Nm from FST impossible at the larger spatial scales. In view of these low levels of gene flow, it is concluded that both genetic drift and natural selection may play important roles in the genetic differentiation of this species, even at the lowest spatial scales. PMID- 28568272 TI - EVIDENCE FOR WIDESPREAD COURTSHIP DURING COPULATION IN 131 SPECIES OF INSECTS AND SPIDERS, AND IMPLICATIONS FOR CRYPTIC FEMALE CHOICE. AB - Male courtship behavior is generally thought to function prior to copulation, as an inducement to the female to allow the male to copulate with her; this study indicates however, that male courtship during and following copulation ("copulatory courtship") is common in insects and spiders (81% of 131 species in 102 genera and 49 families, mostly Coleoptera, Hemiptera, Diptera, and Araneioidea). Copulatory courtship is apparently evolutionarily labile, as expected if it is under sexual selection; intrageneric variation occurred in all 17 genera in which more than one species was observed. In 81% of 94 species with copulatory courtship, the male abandoned the female soon after copulation ended; thus, copulatory courtship appears not to function generally to induce acceptance of further copulatory attempts. The most likely explanation for copulatory courtship is that it represents attempts by males to influence cryptic female choice. This suggests that an aspect of sexual selection by female choice not considered by Darwin may be more important than previously appreciated and that the common practice in evolutionary studies of measuring male reproductive success by counting numbers of copulations may sometimes be misleading because of cryptic female choice during and after copulation. PMID- 28568273 TI - THE EVOLUTION OF MATE PREFERENCES FOR MULTIPLE SEXUAL ORNAMENTS. AB - Males of many species use multiple sexual ornaments in their courtship display. We investigate the evolution of female sexual preferences for more than a single male trait by the handicap process. The handicap process assumes that ornaments are indicators of male quality, and a female benefits from mate choice by her offspring inheriting "good genes" that increase survival chances. A new handicap model is developed that allows equilibria to be given in terms of selection pressures, independent of genetic parameters. Multiple sexual preferences evolve if the overall cost of choice is not greatly increased by a female using additional male traits in her assessment of potential mates. However, only a single preference is evolutionarily stable if assessment of additional male traits greatly increases the overall cost of choice (more than expected by combining the cost of each preference independently). Any single preference can evolve, the outcome being determined by initial conditions. The evolution of one preference effectively blocks the evolution of others, even for traits that are better indicators of male quality. Comparison is made with sexual selection caused by Fisher's runaway process in which male traits are purely attractive characters. This shows that sexual preferences for multiple Fisher traits are likely to evolve alongside preference for a single handicap trait that indicates male quality. This is a general difference in the evolutionary outcome of these two causes of sexual selection. PMID- 28568275 TI - SEXUAL SELECTION IN THE BARN SWALLOW (HIRUNDO RUSTICA). IV. PATTERNS OF FLUCTUATING ASYMMETRY AND SELECTION AGAINST ASYMMETRY. AB - The patterns of variation in fluctuating asymmetry were studied in four morphological characters of the barn swallow Hirundo rustica. The level of absolute and relative asymmetry was larger in the secondary sexual character "outer tail length" than in three nonsexual morphological traits (wing, central tail, and tarsus length). The extent of individual asymmetry in outer tail length was negatively correlated with tail-ornament size, whereas the relationship between asymmetry of all other morphological characters and their size was flat or U-shaped. Asymmetry in outer tail length was unrelated to asymmetry in other morphological characters, whereas asymmetries in the length of wing, central tail, and tarsus were positively correlated. Male bam swallows exhibited larger asymmetry in outer tail length than females. Asymmetry of most morphological traits exhibited intermediate repeatabilities between years, with the exception of male and female outer tail length, which were highly repeatable. Tail asymmetry of offspring weakly, though significantly, resembled that of their parents. Asymmetry in wing and outer tail length was also significantly related to several fitness components. Male barn swallows that acquired a mate were less asymmetric in wing and outer tail length than unmated males. Females with more asymmetrical tails laid eggs significantly later. Annual reproductive success was unrelated to fluctuating asymmetry. Male barn swallows that survived were less asymmetric in wing and outer tail length than nonsurvivors, whereas female survivors were less asymmetric in outer tail length than nonsurvivors. These results suggest that levels of fluctuating asymmetry in barn swallows are associated with differences in fitness. PMID- 28568274 TI - CHROMOSOMAL VERSUS MITOCHONDRIAL DNA EVOLUTION: TRACKING THE EVOLUTIONARY HISTORY OF THE SOUTHWESTERN EUROPEAN POPULATIONS OF THE SOREX ARANEUS GROUP (MAMMALIA, INSECTIVORA). AB - The shrews of the Sorex araneus group have undergone a spectacular chromosome evolution. The karyotype of Sorex granarius is generally considered ancestral to those of Sorex coronatus and S. araneus. However, a sequence of 777 base pairs of the cytochrome b gene of the mitochondrial DNA (mtDNA) produces a quite different picture: S. granarius is closely related to the populations of S. araneus from the Pyrenees and from the northwestern Alps, whereas S. coronatus and S. araneus from Italy and the southern Alps represent two well-separated lineages. It is suggested that mtDNA and chromosomal evolution are in this case largely independant processes. Whereas mtDNA haplotypes are closely linked to the geographical history of the populations, chromosomal mutations were probably transmitted from one population to another. Available data suggest that the impressive chromosome polymorphism of this group is quite a recent phenomenon. PMID- 28568277 TI - IS DECREASED FREQUENCY OF MATING AMONG CONSPECIFICS A COST OF SYMPATRY IN SALAMANDERS? PMID- 28568276 TI - GENETIC CONSEQUENCES OF SEED DISPERSAL IN THREE SYMPATRIC FOREST HERBS. I. HIERARCHICAL POPULATION-GENETIC STRUCTURE. AB - To examine the effects of seed dispersal on spatial genetic structure, we compare three sympatric species of forest herbs in the family Apiaceae whose fruits differ widely in morphological adaptations for animal-attached dispersal. Cryptotaenia canadensis has smooth fruits that are gravity dispersed, whereas Osmorhiza claytonii and Sanicula odorata fruits have appendages that facilitate their attachment to animals. The relative seed-dispersal ability among species, measured as their ability to remain attached to mammal fur, is ranked Sanicula > Osmorhiza > Cryptotaenia. We use a nested hierarchical sampling design to analyze genetic structure at spatial scales ranging from a few meters to hundreds of kilometers. Genetic differentiation among population subdivisions, estimated by average genetic distance and hierarchical F-statistics, has an inverse relationship with dispersal ability such that Cryptotaenia > Osmorhiza > Sanicula. In each species, genetic differentiation increases with distance among population subdivisions. Stochastic variation in gene flow, arising from seed dispersal by attachment to animals, may partly explain the weak relationship between pairwise spatial and genetic distance among populations and heterogeneity in estimates of single locus F-statistics. A hierarchical island model of gene flow is invoked to describe the effects of seed dispersal on population genetic structure. Seed dispersal is the predominant factor affecting variation in gene flow among these ecologically similar, taxonomically related species. PMID- 28568278 TI - HYBRIDIZATION OF SYMPATRIC PATIRIELLA SPECIES (ECHINODERMATA: ASTEROIDEA) IN NEW SOUTH WALES. AB - Three species of the asteroid genus Patiriella occur sympatrically in New South Wales and the possibility for hybridization among them was examined through a series of cross-fertilization experiments. Patiriella calcar and P. gunnii are morphologically distinct as adults but indistinguishable as larvae. Patiriella exigua is morphologically distinct in both its adult and larval morphologies. The gametes of P. calcar and P. gunnii were reciprocally compatible: laboratory crosses between these species produced viable hybrid juveniles. In crosses between female P. calcar and male P. gunnii, most of the juveniles metamorphosed with an arm number intermediate between that of the parents, whereas crosses between female P. gunnii and male P. calcar produced juveniles with an arm number more similar to the maternal phenotype. Heterospecific crosses with P. exigua resulted in low fertilization rates, and viable hybrids were not produced. This species appears capable of self-fertilization. Because hybrids between P. calcar and P. gunnii were viable, neither gametic incompatibility nor hybrid inviability appears to ensure reproductive isolation between these species. Ecological or habitat segregation and temporal separation in breeding may isolate these species in the field. The results demonstrate that if gamete surface recognition molecules are involved in fertilization of P. calcar and P. gunnii, then they are not strongly species specific, at least at the sperm concentrations used in this study. Reproductive isolation between these species has evolved despite their gametic compatibility. In contrast, P. exigua is isolated from its congeners because of gametic incompatibility and several features characteristic of its reproduction and development. The implications of these findings for reproductive isolation and speciation of Patiriella and for the evolution of reproductive isolation in free-spawning marine organisms are discussed. PMID- 28568279 TI - A POSTINSEMINATION BARRIER TO FERTILIZATION ISOLATES TWO CLOSELY RELATED GROUND CRICKETS. AB - Postinsemination barriers to fertilization generally have been ignored by biologists interested in the origin and nature of reproductive isolation among closely related terrestrial animals. Yet evidence presented in this paper indicates that such a barrier bears primary responsibility for the reproductive isolation between the ground crickets Allonemobius fasciatus and Allonemobius socius. Postinsemination barriers to fertilization may isolate many other terrestrial animals as well, but the design of most laboratory hybridization experiments precludes the detection of these barriers. PMID- 28568280 TI - CROSSING-DISTANCE EFFECTS IN DELPHINIUM NELSONII: OUTBREEDING AND INBREEDING DEPRESSION IN PROGENY FITNESS. AB - Depending on its genetic causes, outbreeding depression in quantitative characters may occur first in the free-living F1 generation produced by a wide cross. In 1981-1985, we generated F1 progenies by hand-pollinating larkspurs (Delphinium nelsonii) with pollen from 1-m, 3-m, 10-m, or 30-m distances. From the spatial genetic structure indicated by previous electrophoretic and reciprocal transplantation studies, we estimate that these crosses range from being inbred (f ~ 0.06) to outbred. We planted 594 seeds from 66 maternal sibships under natural conditions. As of 1992, there was strong evidence for both inbreeding depression and outbreeding depression. Progeny from intermediate crossing distances grew approximately twice as large as more inbred or outbred progeny in the first 5 yr after planting (P = 0.013, repeated measures ANOVA), and survived almost 1 yr longer on average (contrast of 3-m and 10-m treatments versus 1 m and 30 m; P = 0.028, ANOVA). Twenty maternal sibships produced flowering individuals; only four and two of these represented 1-m and 30-m crossing distances, respectively (P = 0.021, G-test). The cumulative fitness of intermediate distance sibships averaged about twice that of 1-m sibships, and five to eight times that of 30-m sibships (P = 0.017, ANOVA). Thus, even though progeny of 1-m crosses were inbred to a degree only about one-eighth that of selling, inbreeding depression approximated 50%, and outbreeding depression equaled or exceeded 50% for all fitness components. PMID- 28568281 TI - GLOBAL SURVEY OF MITOCHONDRIAL DNA SEQUENCES IN THE THREESPINE STICKLEBACK: EVIDENCE FOR RECENT MIGRATIONS. AB - Phylogenetic analyses of mitochondrial DNA (mtDNA) sequences were used to assess the matriarchal genetic structure of the threespine stickleback, Gasterosteus aculeatus. A 747 base-pair (bp) fragment of the cytochrome b was sequenced from 36 individuals collected from 25 localities in Europe, North America, and Japan. Two major divergent clades were revealed: one widespread in Japan but with representatives in some Alaskan and British Columbian lakes and the other common in Europe and North America. A simple diagnostic test using the polymerase chain reaction (PCR) and a restriction enzyme was used to assay additional individuals, confirming the absence of the Japanese clade in the Atlantic basin. Geographic distribution of mtDNA variation suggests (1) a recent origin of the Atlantic populations, and (2) support for previous hypotheses about the existence of Pleistocene refugia for freshwater fishes in Alaska and British Columbia. Silent substitution rates were used to date the colonization of the Atlantic at 90,000 to 260,000 yr before present, which conflicts with earlier dates implied by the fossil record. The recent replacement of Atlantic mitochondrial lineages suggested by our data may be explained by severe reduction or extinction of northern Atlantic populations during the Pleistocene, followed by a recent reinvasion from the Pacific. With a global perspective of the distribution of genetic variation as a framework, meaningful comparisons at a smaller geographical scale will now be possible. PMID- 28568282 TI - SPERM DISPLACEMENT WITHOUT SPERM TRANSFER IN DROSOPHILA MELANOGASTER. AB - In this paper we show that when Drosophila melanogaster females are mated twice, the semen of the second male causes a reduction of the effective number of resident sperm from the previous mating. This is demonstrated by two different kinds of experiments. In one set of experiments, mated females were remated to two different kinds of sterile males, one with normal semen and the other with deficient semen. The effect on the resident sperm was determined from the number of remaining progeny after mating to the sterile male, with the result that the normal semen reduced the amount of resident sperm in comparison with matings to the males with deficient semen. The second set of experiments employed interrupted matings. These experiments were based on the observation that semen is delivered before sperm during the first 5 min of copulation. The second matings were interrupted instantly, 2 min, and 4 min after the initiation of copulation. Compared to the instant interruptions, the two later interruptions had the effect of reducing the amount of resident sperm. The results of these two experiments clearly indicate that a sperm-incapacitation process plays a role in the well-documented phenomenon of sperm displacement (last-male advantage) in this species. Such a process could play a role in sperm displacement in the many cases where the mechanism is unknown. PMID- 28568283 TI - The lungs of Polypterus senegalus and Erpetoichthys calabaricus: Insights into the structure and functional distribution of the pulmonary epithelial cells. AB - The present article is a comparative, structural study of the lung of Polypterus senegalus and Erpetoichthys calabaricus, two species representative of the two genera that constitute the Polypteriformes. The lung of the two species is an asymmetric, bi-lobed organ that arises from a slit-like opening in the ventral side of the pharynx. The wall is organized into layers, being thicker in P. senegalus. The inner epithelium contains ciliated and non-ciliated bands. The latter constitute the respiratory surface and are wider in E. calabaricus. The air-blood barrier is thin and uniform in P. senegalus and thicker and irregular in E. calabaricus. In the two species, the ciliated areas contain ciliated cells, mucous cells and cells with lamellar bodies. Additionally, P. senegalus contains polymorphous granular cells (PGCs) and neuroendocrine cells (NECs) while E. calabaricus lacks PGCs but shows granular leukocytes and a different type of NEC. Interestingly, ciliated cells and secretory cells show a dual morphology in E. calabaricus indicating the presence of cellular subtypes and suggesting more complex secretory activity. Also in E. calabaricus, cilia show a novel doublet membrane interaction that may control the displacement of the microtubule doublets. The subepithelium is a connective layer that appears thicker in P. senegalus and contains, in the two species, fibroblasts and granulocytes. The outer layer contains bundles of richly innervated striated muscle. This layer is likely involved in the control of lung motion. In the two species, smooth muscle cells constitute a limiting layer between the subepithelium and the striated muscle compartment. The role of this layer is unclear. PMID- 28568284 TI - When It Comes to Older Adults, Language Matters: Journal of the American Geriatrics Society Adopts Modified American Medical Association Style. PMID- 28568285 TI - Claviform aspergillus-related vegetation in the left ventricle of a patient with systemic lupus erythematosus. AB - A 38-year-old woman was diagnosed with systemic lupus erythematosus and received immunosuppressive therapy. After 6 months of treatment, workup for low-grade fever yielded elevated enzyme-linked immunosorbent assay titers for Aspergillus antigen in serum and ascites, leading to the diagnosis of disseminated aspergillosis. Transthoracic echocardiography revealed a claviform vegetation attached to the left ventricular anterior septum. Two days after the start of antifungal Amphotericin-B therapy, the patient suffered from several neurologic disorders. A second transthoracic echocardiography revealed that the vegetation decreased in size. Two weeks later, the vegetation increased again. Combination therapy of Amphotericin-B and Voriconazole was initiated, and the vegetation eventually disappeared completely. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:231-232, 2018. PMID- 28568287 TI - EVIDENCE FOR A MOSAIC HYBRID ZONE IN THE GRASS SHRIMP PALAEMONETES KADIAKENSIS (PALAEMONIDAE) AS REVEALED BY MULTIPLE GENETIC MARKERS. AB - Molecular techniques provide powerful tools for studying the geographic structure of hybrid zones and the dynamics of gene exchange between incipient species. We examined allozyme variation at five loci (PGM, GPI, MDH-1, MDH-2, and LDH) for 27 populations of Palaemonetes kadiakensis from the central, coastal, and eastern regions of Texas. Central Texas populations of P. kadiakensis exhibited highly significant linkage disequilibrium and departures from Hardy-Weinberg genotype proportions. In populations with linkage disequilibrium, allelic differences at GPI defined two types of P. kadiakensis, designated A and B. Both types existed in central Texas with little or no evidence of interbreeding, whereas the populations from all other localities showed complete introgression of type B alleles into the type A gene pool. We also examined ribosomal DNA (rDNA) and mitochondrial DNA (mtDNA) variation in a subset of populations, chosen to cover a range of geographic locations and levels of linkage disequilibrium. Two groups of mtDNA haplotypes and two restriction fragment patterns for the rDNA corresponded to allozyme type A and B individuals in populations exhibiting linkage disequilibrium. In populations with ongoing hybridization, all hybrid animals (N= 15) exhibited type A mtDNA. Exhibition of type A mtDNA indicated that type A females had mated successfully with type B males, but type B females had not mated successfully with type A males. Genotype distributions suggest reduced reproduction by hybrid offspring in central Texas populations. These patterns are consistent with a mosaic model of hybrid zone dynamics. PMID- 28568286 TI - RNASET2, GPR174, and PTPN22 gene polymorphisms are related to the risk of liver damage associated with the hyperthyroidism in patients with Graves' disease. AB - OBJECTIVES: This study was designed to unveil the association of GPR174 rs3827440, PTPN22 rs3789604, and RNASET2 rs9355610 with the onset of liver damage (LD) among the Graves' disease (GD) patients. METHODS: A total of 120 GD patients were divided into the none-LD and LD groups. Several indicators were detected for assessing liver functions, and genotypes of single nucleotide polymorphisms (SNPs) were identified. Logistic regression was introduced for investigating the relationship between risk SNPs and LD-associated hyperthyroidism in GD patients. RESULTS: Significant differences were identified between LD and none-LD groups regarding genotype distributions of rs3827440, rs3789604, and rs9355610. Results from logistic regression indicted that among the GD patients, C carriers of PTPN22 rs3789604 were associated with a higher risk of LD-associated hyperthyroidism, while C carriers of rs3827440 (GPR174) and G carriers of rs9355610 (RNASET2) were associated with a reduced risk of LD-associated hyperthyroidism. CONCLUSIONS: The C allele of rs3789604 (PTPN22) was a significant risk factor for LD-associated hyperthyroidism in GD patients, whereas C allele of GPR174 rs3827440 and G allele of RNASET2 rs9355610 appeared to be a protective factor for this disease. PMID- 28568288 TI - SENESCENCE IN NATURAL POPULATIONS OF MAMMALS: A REANALYSIS. PMID- 28568289 TI - MITOCHONDRIAL DNA VARIATION WITHIN AND BETWEEN SPECIES OF THE PAPILIO MACHAON GROUP OF SWALLOWTAIL BUTTERFLIES. AB - Species limits and phylogenetic relationships in the Papilio machaon species group are potentially confounded by a complex pattern of Pleistocene range fragmentation, hybridization, and ecological race formation. Mitochondrial DNA (mtDNA) restriction-site analysis has been used to define genetic affinities and genetic population structure within this species group. The distribution of mtDNA haplotypes generally confirms prior phylogenetic hypotheses and species delineations, but there is poor correspondence between ecological races and mtDNA haplotypes. The amount and distribution of mtDNA sequence variation within species vary among species, reflecting differences in current patterns of gene flow and/or historical population structure. In spite of wing pattern characters that ally them with P. polyxenes, both P. joanae and P. brevicauda have mtDNA that is closely related to that of P. machaon. We suggest that P. joanae and P. brevicauda are of hybrid origin. PMID- 28568290 TI - PHENOTYPIC AND GENETIC EFFECTS OF HYBRIDIZATION IN DARWIN'S FINCHES. AB - Morphological consequences of hybridization were studied in a group of three interbreeding species of Darwin's finches on the small Galapagos island of Daphne Major in the inclusive years 1976 to 1992. Geospiza fortis bred with G. scandens and G. fuliginosa. Although interbreeding was always rare (< 5%), sufficient samples of measurements of hybrids and backcrosses were accumulated for analysis. Five beak and body dimensions and mass were measured, and from these two synthetic (principal-component) traits were constructed. All traits were heritable in two of the interbreeding species (G. fuliginosa were too rare to be analyzed) and in the combined samples of F, hybrids and backcrosses to G. fortis. In agreement with expectations from a model of polygenic inheritance, hybrid and backcross classes were generally phenotypically intermediate between the breeding groups that had produced them. Hybridization increased additive genetic and environmental variances, increased heritabilities to a moderate extent, and generally strengthened phenotypic and genetic correlations. New additive genetic variance introduced by hybridization is estimated to be two to three orders of magnitude greater than that introduced by mutation. Enhanced variation facilitates directional evolutionary change, subject to constraints arising from genetic correlations between characters. The Darwin's finch data suggest that these constraints become stronger when species with similar proportions hybridize, but some become weaker when the interbreeding species have different allometries. This latter effect of hybridization, together with an enhancement of genetic variation, facilitates evolutionary change in a new direction. PMID- 28568291 TI - THE SIGNIFICANCE OF OUTCROSSING IN AN INTIMATE PLANT-HERBIVORE RELATIONSHIP. II. DOES OUTCROSSING POSE A PROBLEM FOR THRIPS ADAPTED TO THE HOST-PLANT CLONE? AB - The thrips herbivore Apterothrips apteris reproduces both sexually and parthenogenetically and exhibits fine-scale local adaptation to individual phenotypes of its host plant, Erigeron glaucus. We ask whether we can disrupt the ability of thrips to use progeny of their "home"-plant clone by outcrossing females with males from other plant clones. We compare the performance of sexually produced thrips to that of parthenogenetically produced thrips on plant progeny of the home clone. Because we use thrips from plant clones experiencing both high and low infestations by thrips, we also ask whether the relative performance of "sexuals" versus "parthenogens" differs with the infestation level of the home clone. Plant progeny of 10 E. glaucus clones were either the product of selfing or of outcrossing with the other 9 clones. We have shown in previous work that selfing preserved the parental phenotype with respect to attack by thrips. Because of this result, we predicted that parthenogens should fare better than sexuals on the selfed progeny of the home-plant clone. Our results, however, showed the contrary: sexuals outperformed parthenogens on these selfed plants. We also found that plant characters appear to influence thrips performance more than the mating system of thrips. We found no evidence for outbreeding depression in this system. PMID- 28568293 TI - DIFFERENCES BETWEEN LARVAL AND ADULT DROSOPHILA IN METABOLIC DEGRADATION OF ETHANOL. PMID- 28568292 TI - QUANTITATIVE GENETICS OF BRYOZOAN PHENOTYPIC EVOLUTION. II. ANALYSIS OF SELECTION AND RANDOM CHANGE IN FOSSIL SPECIES USING RECONSTRUCTED GENETIC PARAMETERS. AB - The roles of natural selection and random genetic change in the punctuated phenotypic evolution of eight Miocene-Pliocene tropical American species of the cheilostome bryozoan Metrarabdotos are analyzed by quantitative genetic methods. Trait heritabilities and genetic covariances reconstructed by partitioning within and among-colony phenotypic variance are similar to those previously obtained for living species of the cheilostome Stylopoma using breeding data. The hypothesis that differences in skeletal morphology between species of Metrarabdotos are entirely due to mutation and genetic drift cannot be rejected for reasonable rates of mutation maintained for periods brief enough to account for the geologically abrupt appearances of these species in the fossil record. Except for one pair of species, separated by the largest morphologic distance, directional selection acting alone would require unrealistically high rates of selective mortality to be maintained for these periods. Thus, directional selection is not strongly implicated in the divergence of Metrarabdotos species. Within species, rates of net phenotypic change are slow enough to require stabilizing selection, but mask large, relatively rapid fluctuations, all of which, however, can be attributed to chance departures from the mean phenotype by mutation and genetic drift, rather than to tracking environmental fluctuation by directional selection. The results are consistent with genetic models involving shifts between multiple adaptive peaks on which phenotypes remain more or less static through long-term stabilizing selection. Regardless of the degree to which directional selection may be involved in peak shifts, phenotypic differentiation is thus related to processes different than the pervasive stabilizing selection acting within species. PMID- 28568294 TI - EVOLUTIONARY SHIFTS IN THE SPECTRAL PROPERTIES OF SPIDER SILKS. AB - We measured the reflectance properties of unpigmented silks spun by a systematic array of primitive (Deinopoidea) and derived (Araneoidea) aerial, web-spinning spiders, as well as silks spun by Araneomorphae and Mygalomorphae spiders that do not spin aerial webs. Our data show that all of the primitive aerial web spinners produce catching silks with a spectral peak in the ultraviolet (UV), and cladistic analysis suggests that high UV reflection is the primitive character state for silk spectral properties. In contrast, all of the derived aerial web spinners produce silks that are spectrally flat or characterized by reduced reflectance in the UV. Correlated with the evolution of these catching silks is a 37-fold increase in species number and apparent habitat expansion. This suggests that the unique silk proteins spun by the araneoids have been important to their ecological and evolutionary diversity. PMID- 28568295 TI - THE SIGNIFICANCE OF OUTCROSSING IN AN INTIMATE PLANT-HERBIVORE RELATIONSHIP. I. DOES OUTCROSSING PROVIDE AN ESCAPE FROM HERBIVORES ADAPTED TO THE PARENT PLANT? AB - Sexual reproduction may be advantageous for hosts that are preyed on or parasitized by enemies that are highly adapted to them. Sexual reproduction can create rare genotypes that may escape predation by virtue of rarity and can create variable progeny that may escape predation if enemies are specialized to only one genotype of host. Populations of the herbivorous thrips, Apterothrips apteris, have been shown to be adapted to individual Erigeron glaucus clones. Here, we show that thrips adapted to the parental clone could better use plant progeny of the "home" clone produced through selfing than progeny derived from selfing of other clones. Thus, despite recombination, progeny produced by selfing presented a resource that was similar to the parental phenotype with respect to use by adapted thrips. We also show that E. glaucus susceptibility to thrips has a genetic basis and then ask whether outcrossing provides a means for E. glaucus clones to escape attack by adapted thrips. When we compared the success of thrips on progeny produced by selfing or outcrossing of the home clone, we found that the merits or disadvantages associated with outcrossing were dependent on the susceptibility to infestation of the parental clones. Selfing by clones characterized by low infestations of thrips appeared to preserve resistant genotypes; all outcrossed progeny had, on average, higher infestation levels than selfed progeny. In contrast, outcrossed progeny of clones characterized by high infestations of thrips had either the same thrips density as progeny from selfing, when the pollen donor was a highly infested clone, or lower density, when the pollen donor was a low infestation clone. The advantages of outcrossing were caused by the alleles contributed to progeny rather than to progeny variability or rarity. PMID- 28568296 TI - A POPULATION MEMETICS APPROACH TO CULTURAL EVOLUTION IN CHAFFINCH SONG: DIFFERENTIATION AMONG POPULATIONS. AB - We investigated cultural evolution in populations of common chaffinches (Fringilla coelebs) in the Atlantic islands (Azores, Madeira, and Canaries) and neighboring continental regions (Morocco and Iberia) by employing a population memetic approach. To quantify differentiation, we used the concept of a song meme, defined as a single syllable or a series of linked syllables capable of being transmitted. The levels of cultural differentiation are higher among the Canaries populations than among the Azorean ones, even though the islands are on average closer to each other geographically. This is likely the result of reduced levels of migration, lower population sizes, and bottlenecks (possibly during the colonization of these populations) in the Canaries; all these factors produce a smaller effective population size and therefore accentuate the effects of differentiation by random drift. Significant levels of among-population differentiation in the Azores, in spite of substantial levels of migration, attest to the differentiating effects of high mutation rates of memes, which allow the accumulation of new mutants in different populations before migration can disperse them throughout the entire region. PMID- 28568297 TI - A PROBLEM WITH THE ESTIMATE OF SELF-FERTILIZATION DEPRESSION IN THE HERMAPHRODITE FRESHWATER SNAIL BULINUS TRUNCATUS: THE EFFECT OF GROUPING. PMID- 28568298 TI - DNA EVOLUTION AND COLONIZATION SEQUENCE OF ISLAND LIZARDS IN RELATION TO GEOLOGICAL HISTORY: MTDNA RFLP, CYTOCHROME B, CYTOCHROME OXIDASE, 12S RRNA SEQUENCE, AND NUCLEAR RAPD ANALYSIS. AB - A novel source of nuclear DNA information from random amplified polymorphisms (RAPD) and a wide-range mitochondrial DNA information (cytochrome b, cytochrome oxidase, and 12s rRNA sequence, RFLP from 4-base and 6-base recognition endonucleases) are used to reconstruct the population phylogeny of the western Canary Island lizard, Gallotia galloti, which, for geological reasons, has been subject to dispersal but not vicariance. Interpretation of DNA phylogenies in terms of colonization sequence indicates that G. galloti arose in Tenerife and dispersed westward in two independent pathways: north from north Tenerife to La Palma, and south from south Tenerife to Gomera to Hierro. The direction and timing of colonization by DNA divergence is entirely compatible with geological time and sequence of island origin. PMID- 28568299 TI - GENETICS OF PHYSIOLOGICAL DIFFERENTIATION WITHIN THE MARINE MUSSEL GENUS MYTILUS. AB - Two divergent taxa in the marine mussel genus Mytilus are largely isolated geographically and are routinely exposed to distinctly different thermal environments. We tested the hypothesis that the two taxa are physiologically differentiated with respect to temperature and examined the evolved adaptations allowing one of the taxa to exploit habitats where warm-temperate conditions prevail for prolonged periods. We first analyzed the physiological response to high temperature of mussels collected from a hybrid population containing members of both pure taxa, F, hybrids, and a variety of introgressed genotypes. The experimental temperature of 23 degrees C was chosen to be permissive to the taxon that occurs in warm-temperate regions (Mytilus galloprovincialis) and restrictive to the cold-water taxon (Mytilus edulis). The results show that the two taxa are physiologically differentiated. Under the experimental conditions, M. galloprovincialis exhibited a threefold higher feeding rate and a slightly elevated metabolic rate compared with M. edulis. These differences did not result in a significant difference in net energy balance between the two taxa, probably because of an interaction between physiological response and food availability. However, M. galloprovincialis grew significantly faster in the field, indicating that the physiological differences observed in the laboratory also occur in nature. Numerous introgressed genotypes provided the opportunity to test for cosegregation between the physiological differences and four highly differentiated genetic markers. Two of the markers (esterase and octopine dehydrogenase) cosegregate with variation in feeding rate and shell growth and explained most of the physiological differences observed between taxa. A strong concordance existed between these two loci, suggesting that they may be linked and may mark segregation of the same linkage group. The results suggest that the physiological differentiation between these taxa may be controlled by a few genes (perhaps only one) each with large effect. PMID- 28568300 TI - POPULATION GENETIC STRUCTURE OF CECROPIA OBTUSIFOLIA, A TROPICAL PIONEER TREE SPECIES. AB - Theoretical analyses of the genetic organization of pioneer species have postulated two very different scenarios. Some models have predicted that such species would show strong population substructuring, whereas other models have suggested that extinction and recolonization can augment gene flow and reduce interpopulation differentiation. We tested these alternative scenarios by analyzing the genetic structure of eight loci from populations of the pioneer dioecious tree, Cecropia obtusifolia, in the tropical rain forest region of Los Tuxtlas, Mexico. The populations studied exhibit low overall FST values, no clear pattern of isolation by distance, and high estimates of gene flow. These results suggest either that the species is not at a genetic equilibrium under present levels of gene flow with populations derived from each other in the recent past, or that pollen and seed dispersal in this species occur over long distances (up to more than 100 km). Mating among relatives appears higher than expected by chance based on significantly positive fixation indices (F) and FIS values at some loci. However, no direct evidence for biparental inbreeding was found. The multilocus and single-locus outcrossing rates for C. obtusifolia were estimated at tm = 0.974 (SE = 0.024) and ts = 0.980 (SE = 0.035), respectively. These are not significantly different from 1, and the difference, tm - ts = - 0.006 (SE = 0.018), is not significantly different from 0. These estimates, however, could be biased because in all enzymes, except PGM-1, we found statistically significant departures from the mixed-mating model used to estimate them. Two rare alleles were found only in seeds collected from the soil, and the greatest number of different alleles were found also in soil seeds. It is hypothesized that the seed bank may play an important role in the genetic buffering of C. obtusifolia. Significantly positive or negative fixation indices in adults at some loci and significantly different heterozygosities among different life stages (from seeds to adults) suggest the action of selection at some loci. PMID- 28568301 TI - HISTORICAL EXAMINATION OF DELAYED PLUMAGE MATURATION IN THE SHOREBIRDS (AVES: CHARADRIIFORMES). AB - Delayed plumage maturation refers to the presence of nonadultlike immature plumages (juvenal plumage excluded). It is usually considered the result of selection for distinctive first-winter or first-summer appearance. In the present study, evolution of delayed plumage maturation is examined in the shorebirds: the sandpipers, plovers, gulls, and their allies. Nine plumage-maturation characters were identified, and their states were superimposed onto topologies generated during two recent investigations of shorebird relationships (Sibley and Ahlquist; revised Strauch). The characters were then optimized so as to assign character states to interior nodes of the trees in the most parsimonious way. Reconstructions of character evolution on six of the shortest revised Strauch trees were ambiguous with respect to delayed plumage maturation in the hypothetical ancestral shorebird. If plumage maturation was not delayed in the shorebird ancestor, optimization indicated that delay appeared when nonadultlike juvenal feathers were acquired. In contrast, on the single Sibley and Ahlquist tree, absence of delayed plumage maturation in the shorebird ancestor was indicated unambiguously, with three evolutionary novelties (nonadultlike juvenal feathers, seasonal plumage change, and a reduced first-spring molt) implicated in its acquisition. Optimization indicated that delayed plumage maturation in shorebirds can be explained plausibly without invoking selection for distinctive first-winter or first-summer appearance. Two of the novel conditions generating delayed plumage maturation (modified juvenal feathers and seasonal plumage change) did so only because they were acquired in a taxon possessing restricted first-year molts, which are primitive. Given these observations, it seems simplest to explain the delay in plumage maturation as an incidental consequence of the phylogenetic inertia of shorebird molts. The third novelty that generates delayed plumage maturation, a reduced first-spring molt, may have been acquired to reduce molt-associated energetic demands in young birds. PMID- 28568302 TI - MODES OF SPECIATION IN BIRDS: A TEST OF LYNCH'S METHOD. PMID- 28568303 TI - TURBINATES IN THERAPSIDS: EVIDENCE FOR LATE PERMIAN ORIGINS OF MAMMALIAN ENDOTHERMY. AB - The structure and function of the nasal conchae of extant reptiles, birds, and mammals are reviewed, and the relationships to endothermy of the mammalian elements are examined. Reptilian conchae are relatively simple, recurved structures, which bear primarily sensory (olfactory) epithelium. Conversely, the conchae, or turbinates, of birds and mammals are considerably more extensive and complex, and bear, in addition, nonsensory (respiratory) epithelium. Of the mammalian turbinates, only the exclusively respiratory maxilloturbinal has a clear functional relationship with endothermy, as it reduces desiccation associated with rapid and continuous pulmonary ventilation. The other mammalian turbinates principally retain the primitive, olfactory function of the nasal conchae. The maxilloturbinates are the first reliable morphological indicator of endothermy that can be used in the fossil record. In fossil mammals and mammallike reptiles, the presence and function of turbinates are most readily revealed by the ridges by which they attach to the walls of the nasal cavity. Ridges for olfactory turbinals are located posterodorsally, away from the main flow of respiratory air, whereas those of the respiratory maxilloturbinals are situated in the anterolateral portion of the nasal passage, directly in the path of respired air. The maxilloturbinal is also characterized by its proximity to the opening of the nasolacrimal canal. Posterodorsal ridges, for olfactory turbinals, have long been recognized in many mammallike reptiles, including early forms such as pelycosaurs. However, ridges for respiratory turbinals have not been identified previously in this group. In this paper, the presence of anterolateral ridges, which most likely supported respiratory turbinals, is reported in the primitive therocephalian Glanosuchus and in several cynodonts. The presence of respiratory turbinals in these advanced mammallike reptiles suggests that the evolution of "mammalian" oxygen consumption rates may have begun as early as the Late Permian and developed in parallel in therocephalians and cynodonts. Full mammalian endothermy may have taken as much as 40 to 50 million yr to develop. PMID- 28568304 TI - CLINES FOR HYBRID DYSFUNCTION IN A GRASSHOPPER HYBRID ZONE. AB - Two subspecies of the grasshopper Chorthippus parallelus meet in the Pyrenees forming a hybrid zone several kilometers wide. Crosses between the two pure taxa result in sterile male offspring and normal females (i.e., Haldane's rule applies). However, no such dysfunction has been detected in hybrid males collected through the center of the hybrid zone. By assessing the level of dysfunction in the offspring of reciprocal crosses, it was possible to map clines for the genes responsible for dysfunction through the zone. This analysis shows that there is no abrupt transition between incompatible genomes in the field. Crosses were also made between females collected from a transect spanning the hybrid zone and pure males of both subspecies. This reveals noncoincident clines for dysfunction near the center of the hybrid zone such that the dysfunction expressed in the offspring of these crosses is less than expected from simple models. More complex models involving interaction among genes must be invoked. Also, the possibility exists that since the postglacial contact of these two grasshopper taxa, hybrid dysfunction has become ameliorated by the evolution of modifiers. This hybrid zone is thought to be a tension zone, maintained by a balance between selection against hybrid genotypes and dispersal into the zone center. The lessening of hybrid disadvantage over time through the breakdown of epistatic interactions by recombination or through modification could account for the general lack of dysfunction in field collected hybrids today. PMID- 28568305 TI - EVOLUTION OF PARASITISM AMONG CLOSELY RELATED SPECIES: PHYLOGENETIC RELATIONSHIPS AND THE ORIGIN OF INQUILINISM IN GALL WASPS (HYMENOPTERA, CYNIPIDAE). AB - A new term, agastoparasitism, is proposed for parasitism among closely related species. Cynipid inquilines are typical agastoparasites. They cannot induce galls; instead their larvae live inside the galls formed by other cynipids. As in many other groups of agastoparasites, there are two competing hypotheses for the evolutionary origin of cynipid inquilines: either they arose from one of their cynipid hosts, and later radiated to exploit other gall-inducing cynipids (monophyletic origin), or they arose repeatedly, each inquiline from its host (polyphyletic origin). These hypotheses for the origin of cynipid inquilines were tested by a phylogenetic analysis of representative species of cynipid gall inducers and inquilines based on adult morphological characters. The analysis supported the monophyly of the inquilines and indicated an origin from gall inducers related to the genus Diastrophus, one of the current host groups. To examine whether the result of the analysis was influenced by convergent similarities among inquilines because of their similar mode of life, all putative apomorphies shared by some or all of the inquilines but not occurring in any of the gall inducers were removed. Despite this, the phylogenetic conclusions essentially remained the same, that is, the support for inquiline monophyly was not caused by convergent evolution. Based on these results, adaptive aspects of the evolutionary origin and maintenance of cynipid inquilinism are discussed, as well as general patterns in the evolution of agastoparasitism. PMID- 28568306 TI - EVOLUTIONARY ECOLOGY OF DATURA STRAMONIUM L. IN CENTRAL MEXICO: NATURAL SELECTION FOR RESISTANCE TO HERBIVOROUS INSECTS. AB - It has been assumed that herbivores constitute a selective agent for the evolution of plant resistance. However, few studies have tested this hypothesis. In this study, we look at the annual weed Datura stramonium for evidence of current natural selection for resistance to herbivorous insects. Paternal half sib families obtained through controlled crosses were exposed to herbivores under natural conditions. The plants were damaged by two folivorous insects: the tobacco flea beetle Epitrix parvula and the grasshopper Sphenarium purpurascens. Selection was estimated using a multiple-regression analysis of plant size and of damage by the two herbivores on plant fitness measured as fruit production for both individual phenotypes and family breeding values (genetic analysis). Directional phenotypic selection was detected for both larger plant size and lower resistance to the flea beetles, whereas stabilizing phenotypic selection was revealed for resistance to S. purpurascens. However, performing the same analyses on the breeding values of the characters revealed directional and stabilizing selection only for plant size. Thus, no agreement existed between the results of the two types of analyses, nor was there any detectable potential for genetic change in the studied population because of selection on herbivore resistance. The narrow-sense heritability of every trait studied was small (all <0.1) and not different from zero. The potential for evolutionary response to natural selection for higher resistance to herbivores in the studied population of D. stramonium is probably limited by lack of genetic variation. Natural selection acts on phenotypes, and the detection of phenotypic selection on resistance to herbivores confirms their ecological importance in determining plant fitness. However, evolutionary inferences based solely on phenotypic selection analyses must be interpreted with caution. PMID- 28568307 TI - GENETIC SIMILARITY BETWEEN PARENTS PREDICTS HATCHING FAILURE: NONINCESTUOUS INBREEDING IN THE GREAT REED WARBLER? AB - The DNA-fingerprinting technique was used to find the true pedigrees and to detect the overall genetic similarity between mates of great reed warblers (Acrocephalus arundinaceus) at an isolated breeding site in Sweden. The study covered 4 yr preceded by 3 yr when almost all adults and nestlings in the study area had been banded. DNA fingerprinting revealed that the putative father had sired 97% of the young (N = 455). The mate's genetic similarity, revealed as the proportion of bands shared in restriction fragment length polymorphism (RFLP) patterns, was high compared with other species of wild birds. Also, band sharing was higher between mates native to the area than between pairs in which the female was experimentally introduced from a distant breeding site. Hatching success of eggs was negatively correlated with the degree of genetic similarity between the mates, whereas pedigree data, up to the level of great-grandparents, clearly demonstrated an absence of close inbreeding. These are the first data showing a significant fitness cost associated with the choice of a mate that has high genetic similarity, even if it is not a close kin. This cost might be caused by generalized negative consequences of genomewide inbreeding in the present study, possibly accentuated by recent population bottlenecks. PMID- 28568308 TI - ON THE EVOLUTIONARY CONSEQUENCES OF SEXUAL IMPRINTING. AB - The idea that sexual imprinting may generate sexual selection and possibly lead to speciation has been much discussed in the ethological literature. Here the feasibility of three such hypotheses is investigated using mathematical models of sexual selection in which mating preferences are acquired through imprinting and hence dependent upon the parental phenotypes. The principal findings are the following. (1) Sexual imprinting reduces the likelihood of novel adaptive traits spreading through a population, except in some circumstances in which there is heterozygote advantage. (2) Asymmetrical mating preferences, acquired through imprinting, can generate sexual selection for traits that impair survival. (3) The conditions under which sexual imprinting will maintain a genetic polymorphism in a population are fairly restricted. (4) Sexual imprinting can act as a barrier to gene flow minimizing the impact of migration and preserving and accentuating genetic differences between populations. The findings suggest that sexual imprinting may be of considerable evolutionary significance. PMID- 28568309 TI - Effect of soybean husk supplementation on the fecal fermentation metabolites and microbiota of dogs. AB - In vitro fermentation and in vivo feeding experiments were conducted to characterize the effects of soybean (Glycine max) husk on the fecal fermentation metabolites and microbiota of dogs. An in vitro fermentation study using feces from three Toy Poodle dogs (6.5 +/- 3.5 months in age and 2.9 +/- 0.4 kg in body weight) revealed that the fecal inoculum was able to ferment soybean husk (supplemented at 0.01 g/mL culture) and increased levels of short chain fatty acids (SCFA) and Bifidobacterium, irrespective of pre-digestion of the husk by pepsin and pancreatin. In a feeding experiment, four Shiba dogs (7-48 months in age and 7.5 +/- 1.7 kg in body weight) fed a commercial diet supplemented with 5.6% soybean husk showed an increase in SCFA, such as acetate and butyrate, and lactate, and a decrease in indole and skatole in the feces compared to those fed a 5.6% cellulose diet. Real-time PCR assay showed that soybean husk supplementation stimulated the growth of lactobacilli, Clostridium cluster IV including Faecalibacterium prausnitzii, Clostridium cluster XIVa, Bacteroides Prevotella-Porphyromonas group but inhibited the growth of Clostridium cluster XI. Both in vitro and in vivo experiments indicated that soybean husk supplementation improves gastrointestinal health through optimization of beneficial organic acid production and increase of beneficial bacteria. Therefore, soybean husk is suggested to be applicable as a functional fiber in the formulation of canine diets. PMID- 28568310 TI - Pharmacokinetics of intravenous clindamycin phosphate in captive Bennett's wallabies (Macropus rufogriseus). AB - This study was designed to investigate the pharmacokinetics of clindamycin, a lincosamide antibiotic, in Bennett's wallabies. The pharmacokinetic properties of a single intravenous (IV) dose of clindamycin were determined in six wallabies. A single 20-min IV infusion of 20 mg/kg of clindamycin was administered, followed by blood collection prior to, and up to 12 hr after clindamycin administration. Plasma clindamycin concentrations were determined by high-pressure liquid chromatography (HPLC) with ultraviolet (UV) detection. Pharmacokinetic variables were calculated using a two-compartment model with first order elimination which best fit the data. The mean volume of distribution at steady-state, distribution half-life, and elimination half-life were 898.25 ml/kg, 0.16 hr, 1.79 hr, respectively. No adverse effects were noted after IV administration. PMID- 28568311 TI - Defining the clinical relevance of red blood cell autoantibodies by Monocyte Monolayer Assay. AB - BACKGROUND: The Monocyte Monolayer Assay (MMA) is an in vitro simulation of red blood cell (RBC) alloantibody behavior. It has been classically applied to predict the risks of post-transfusion hemolytic reactions when transfusing incompatible RBC units. Quantifying erythrophagocytosis by MMA may be an interesting option for situations where there is doubt whether a RBC autoantibody is mediating significant hemolysis. Here, we present three situations involving RBC autoantibodies in which the MMA was decisive for clarifying the diagnosis and choosing the best clinical treatment. CASE REPORT: Case 1. Pregnant patient with severely anemic fetus exhibited warm autoantibody without signs of hemolysis. MMA revealed 30% of monocyte index (MI) highlighting that fetal hemolysis was caused by maternal autoantibody. Prednisone was prescribed with fetal clinical improvement. Cases 2 and 3. Two patients with the diagnosis of mixed auto-immune hemolytic anemia and poor response to corticosteroids were evaluated using MMA. The resulting MI was less than 10% in both cases, suggesting that the cold agglutinin rather than the warm auto-IgG was responsible for overt hemolysis. Treatment with rituximab was begun, with good clinical response. CONCLUSION: MMA can be used to evaluate the ability of RBC autoantibodies to mediate overt hemolysis. It can be especially useful to determine the role played by cold and warm auto-antibodies in mixed auto-immune hemolytic disease, helping to define the best treatment option. PMID- 28568313 TI - ANOVA and the variance homogeneity assumption: Exploring a better gatekeeper. AB - Valid use of the traditional independent samples ANOVA procedure requires that the population variances are equal. Previous research has investigated whether variance homogeneity tests, such as Levene's test, are satisfactory as gatekeepers for identifying when to use or not to use the ANOVA procedure. This research focuses on a novel homogeneity of variance test that incorporates an equivalence testing approach. Instead of testing the null hypothesis that the variances are equal against an alternative hypothesis that the variances are not equal, the equivalence-based test evaluates the null hypothesis that the difference in the variances falls outside or on the border of a predetermined interval against an alternative hypothesis that the difference in the variances falls within the predetermined interval. Thus, with the equivalence-based procedure, the alternative hypothesis is aligned with the research hypothesis (variance equality). A simulation study demonstrated that the equivalence-based test of population variance homogeneity is a better gatekeeper for the ANOVA than traditional homogeneity of variance tests. PMID- 28568312 TI - Autoimmune comorbidity in achalasia patients. AB - BACKGROUND AND AIM: Idiopathic achalasia is a rare esophageal motor disorder. The disease state manifests local and systemic inflammation, and it appears that an autoimmune component and specific autoantibodies participate in the pathogenesis. The study aims to determine the prevalence of autoimmune and chronic inflammatory diseases in patients with achalasia and compare the results with those from patients with gastroesophageal reflux disease (GERD). METHODS: It was a cross sectional and included 114 patients with idiopathic achalasia and 114 age-matched and sex-matched control patients with GERD. Data on the presence of autoimmune and inflammatory diseases, the time of presentation, and any family history of autoimmune disease were obtained from the hospital's medical records. RESULTS: Seventy three (64%) were female patients (mean age: 42.3 +/- 15.5; median disease duration: 12 months). We identified the presence of autoimmune disease in 19 patients with achalasia (16.7%), hypothyroidism was the main diagnosis, and it was present in 52.6% of patients compared with 4.2% in controls. Thirteen of the 19 achalasia patients (68.4%) with autoimmune disease had history of familial autoimmunity. We identified 11 achalasia (9.6%) and 5 GERD patients (4.16%) with an inflammatory condition. Compared with the GERD, the achalasia group was 3.8 times more likely to have an autoimmune disease (95% CI: 1.47-9.83), 3.0 times more likely to have thyroidopathies (95% CI: 1.00-9.03), and 3.02 times more likely to suffer from any chronic inflammatory disease (95% CI: 1.65-6.20). CONCLUSIONS: The non-negligible number of patients with autoimmune diseases identified among the patients with idiopathic achalasia supports the hypothesis that achalasia has an autoimmune component. PMID- 28568314 TI - Greater circadian disadvantage during evening games for the National Basketball Association (NBA), National Hockey League (NHL) and National Football League (NFL) teams travelling westward. AB - We investigated the effects of a circadian disadvantage (i.e. playing in a different time zone) on the winning percentages in three major sport leagues in North America: the National Basketball Association, the National Hockey League and the National Football League. We reviewed 5 years of regular season games in the National Basketball Association, National Hockey League and National Football League, and noted the winning percentage of the visiting team depending on the direction of travel (west, east, and same time zone) and game time (day and evening games). T-tests and analysis of variance were performed to evaluate the effects of the circadian disadvantage, its direction, the number of time zones travelled, and the game time on winning percentages in each major league. The results showed an association between the winning percentages and the number of time zones traveled for the away evening games, with a clear disadvantage for the teams travelling westward. There was a significant difference in the teams' winning percentages depending on the travelling direction in the National Basketball Association (F2,5908 = 16.12, P < 0.0001) and the National Hockey League (F2,5639 = 4.48, P = 0.011), and a trend was found in the National Football League (F2,1279 = 2.86, P = 0.058). The effect of the circadian disadvantage transcends the type of sport and needs to be addressed for greater equity among the western and eastern teams in professional sports. These results also highlight the importance of circadian rhythms in sport performance and athletic competitions. PMID- 28568315 TI - Relationships between the genes expressed in the mesenteric adipose tissue of beef cattle and feed intake and gain. AB - Mesenteric fat, a depot within the visceral fat, accumulates in cattle during maturation and finishing and may be a potential source of production inefficiency. The aim of this study was to determine whether the genes expressed in the mesenteric fat of steers were associated with body weight gain and feed intake. Sixteen steers chosen by their rank of distance from the bivariate mean for gain and feed intake were used for this study. Mesenteric fat was obtained and evaluated for differences in gene expression. A total of 1831 genes were identified as differentially expressed among steers with variation in feed intake and gain. Many of these genes were involved with metabolic processes such as proteolysis, transcription and translation. In addition, the Gene Ontology annotations including transport and localization were both over-represented among the differentially expressed genes. Pathway analysis was also performed on the differentially expressed genes. The superoxide radical degradation pathway was identified as over-represented based on the differential expression of the genes GPX7, SOD2 and TYRP1, suggesting a potential role for oxidative stress or inflammatory pathways among low gain-high intake animals. GPX7 and SOD2 were in lower transcript abundance, and TYRP1 was higher in transcript abundance among the low gain-high feed intake animals. The retinoate biosynthesis pathway was also enriched due to the differential expression of the genes AKR1C3, ALDH8A1, RDH8, RDH13 and SDR9C7. These genes were all more highly expressed in the low gain-high intake animals. The glycerol degradation and granzyme A signaling pathways were both associated with gain. Three glycerol kinase genes and the GZMA gene were differentially expressed among high vs. low gain animals. Mesenteric fat is a metabolically active tissue, and in this study, genes involved in proteolysis, transcription, translation, transport immune function, glycerol degradation and oxidative stress were differentially expressed among beef steers with variation in body weight gain and feed intake. PMID- 28568317 TI - Two FMR1 premutation cases without nuclear inclusions. PMID- 28568318 TI - A New Electron-Rich Unit for Polymer Electron Acceptors: 4,4-Difluoro-4H cyclopenta[2,1-b:3,4-b']dithiophene. AB - We report 4,4-difluoro-4H-cyclopenta[2,1-b:3,4-b']dithiophene (fCDT) as a new electron-rich unit to design polymer electron acceptors. Owing to the fluoro substitutes, fCDT unit exhibits downshifted LUMO energy level, diminished steric hindrance effect and strong intermolecular interaction. The resulting polymer electron acceptor exhibits low-lying LUMO energy level and high electron mobility, as well as good all-polymer solar cell device performance. PMID- 28568316 TI - Influence of diabetes on plasma pharmacokinetics and brain bioavailability of grape polyphenols and their phase II metabolites in the Zucker diabetic fatty rat. AB - SCOPE: The effect of diabetes on the pharmacokinetics, bioavailability and brain distribution of grape polyphenols and select metabolites was studied in the Zucker diabetic fatty (ZDF) rat model. METHODS AND RESULTS: (ZDF) rats and their lean controls (LN) were dosed with a Standardized Grape Polyphenol (SGP) Mixture consisting of grape seed extract, Concord grape juice and resveratrol (RES) by oral gavage for 10 days. An 8-h pharmacokinetic study was performed. After 24 h, a second dose of SGP was administered and 1 h later animals were sacrificed and brain tissue was harvested. Plasma, urine, and brain tissue were analyzed for grape polyphenols. ZDF rats exhibited significantly diminished Cmax for all catechin, epicatechin, quercetin and resveratrol conjugated metabolites. Bioavailability was significantly lower in ZDF rats for methylated flavan-3-ol, RES, and quercetin metabolites. Significantly lower levels of metabolites of RES, quercetin, and flavan-3-ols were found in brains of ZDF rats. There was no significant difference between ZDF and LN in anthocyanins in plasma and no anthocyanins were detectable in brain extracts. ZDF rats showed significantly higher urinary excretion for all polyphenols. CONCLUSION: Diabetes may alter the overall bioavailability of some polyphenols in plasma and brain in part due to higher urinary clearance. PMID- 28568319 TI - Narcolepsy with cataplexy and pregnancy: a case-control study. AB - This was a retrospective case-control study in 25 patients with narcolepsy with cataplexy and 75 women in the control group. Patients completed the questionnaire by Maurovich-Horvat et al. (J. Sleep Res., 2013, 22: 496-512). We personally interviewed 25 patients with narcolepsy with cataplexy using the administered questionnaire regarding conception, pregnancy, delivery, perinatal and breastfeeding periods. Patients with narcolepsy with cataplexy reported 59 pregnancies versus 164 in the control group. In 16 cases (27.1%), a disease before pregnancy was present compared with eight cases (4.9%) in the control group (P < 0.001); among them, extrinsic asthma was reported 11 times in the narcolepsy with cataplexy group (P < 0.005). Patients with narcolepsy with cataplexy more often had a single pregnancy compared with controls (P < 0.05). Gestational diabetes was more frequent in patients with narcolepsy with cataplexy (P < 0.05). Induced deliveries were higher in controls (P < 0.009). No differences were found between the groups in terms of duration of pregnancies and complications during and after delivery, as during the puerperium. Neonates from patients had heavier birth weight (P < 0.015). The breastfeeding period was longer in patients (P < 0.01). Modafinil and methylphenidate were the drugs administered in six pregnancies. No significant differences in depression during pregnancy and during puerperium were found between patients and controls. This is the first case-control study in women with narcolepsy with cataplexy related to pregnancy, delivery, childbirth and puerperium. Data suggest that patients have pregnancy outcomes similar to controls. The prevalence of gestational diabetes was higher in women with narcolepsy with cataplexy. Caesarean sections, complications during delivery and normal perinatal period for infants were similar in both groups. Breastfeeding was longer in patients. PMID- 28568320 TI - CONSPECIFIC SPERM PRECEDENCE IS AN EFFECTIVE BARRIER TO HYBRIDIZATION BETWEEN CLOSELY RELATED SPECIES. AB - Conspecific sperm precedence is widespread in animals, appears to evolve rapidly, and is thought to have the potential to prevent hybridization between closely related species. However, to date no study has tested the isolating potential of such a barrier in mixed populations of two taxa under conditions in which other potential barriers to gene flow are controlled for or are prevented from operating. We tested the isolating potential of conspecific sperm precedence in the ground crickets Allonemobius fasciatus and A. socius in population cage experiments in which the frequency of the two species was varied. Despite the observation of abundant interspecific matings, the proportions of hybrid progeny were low and differed statistically from the proportions expected in the absence of conspecific sperm precedence. The results demonstrate that conspecific sperm precedence can severely limit gene flow between closely related species, even when one species is less abundant than the other. PMID- 28568322 TI - THE COADAPTATION OF PARENTAL AND OFFSPRING CHARACTERS. AB - Parents often have important influences on their offspring's traits and/or fitness (i.e., maternal or paternal effects). When offspring fitness is determined by the joint influences of offspring and parental traits, selection may favor particular combinations that generate high offspring fitness. We show that this epistasis for fitness between the parental and offspring genotypes can result in the evolution of their joint distribution, generating genetic correlations between the parental and offspring characters. This phenomenon can be viewed as a coadaptive process in which offspring genotypes evolve to function with the parentally provided environment and, in turn, the genes for this environment become associated with specific offspring genes adapted to it. To illustrate this point, we present two scenarios in which selection on offspring alone alters the correlation between a maternal and an offspring character. We use a quantitative genetic maternal effect model combined with a simple quadratic model of fitness to examine changes in the linkage disequilibrium between the maternal and offspring genotypes. In the first scenario, stabilizing selection on a maternally affected offspring character results in a genetic correlation that is opposite in sign to the maternal effect. In the second scenario, directional selection on an offspring trait that shows a nonadditive maternal effect can result in selection for positive covariances between the traits. This form of selection also results in increased genetic variation in maternal and offspring characters, and may, in the extreme case, promote host-race formation or speciation. This model provides a possible evolutionary explanation for the ubiquity of large genetic correlations between maternal and offspring traits, and suggests that this pattern of coinheritance may reflect functional relationships between these characters (i.e., functional integration). PMID- 28568321 TI - SELECTION FOR KNOCKDOWN RESISTANCE TO HEAT IN DROSOPHILA MELANOGASTER AT HIGH AND LOW LARVAL DENSITIES. AB - Responses to short-term selection for knockdown resistance to heat (37 degrees C) in Drosophila melanogaster reared under stressful (high larval density) and nonstressful (low larval density) conditions were compared. No difference in selection response between density treatments was found. A test of heat resistance (39 degrees C) after pretreatment (37 degrees C) did not reveal an increase in survival for selected lines as compared to controls. Flies reared at high density had higher knockdown resistance throughout the experiment. Resistance to heat was not associated with body size. PMID- 28568323 TI - INDIRECT METHODS TO ESTIMATE GENE FLOW IN CAVE AND SURFACE POPULATIONS OF ANDRONISCUS DENTIGER (ISOPODA: ONISCIDEA). AB - We estimateci gene flow among several populations of the troglophilic woodlouse Androniscus dentiger from central Italy using allozyme data. Estimates of gene flow were obtained from GST , theta, and the private alleles method, after being tested whether the assumption of the population genetic model and the assumption of neutrality of alleles had been met. Hierarchical analysis of gene flow has been used to investigate the geographic scale at which gene exchange can actually occur. Results showed that, independent of the methods, no ongoing gene flow can be detected among populations, even among geographically proximate ones. Genetic drift is likely the main agent shaping the pattern of genetic divergence among these populations. Patterns of past and ongoing gene flow were considered, as surface populations have become genetically isolated more recently than cave populations. In general, all three methods to estimate gene flow provided Nm estimates of the same magnitude. PMID- 28568324 TI - GENE FLOW AND INEFFECTIVE ANTIPREDATOR BEHAVIOR IN A STREAM-BREEDING SALAMANDER. AB - Predators often feed on prey that show ineffective antipredator behavior. Gene flow among populations may constrain evolution of effective antipredator ability in larvae of the streamside salamander, Ambystoma barbouri, a species that occupies distinctly different habitats with conflicting selection pressures. Some streams are ephemeral, where larvae should be active to feed and reach metamorphosis before stream drying. In contrast, other streams are more permanent and contain pools with predatory fish, where larvae should remain inactive to avoid fish predation. Feeding rates and predator escape behavior were assayed for laboratory-reared larvae from 15 populations. Larval survival was also compared among populations in artificial streams with natural predators. Five populations represented streams subjected to fish predation along a gradient of genetic and geographic isolation from populations without fish; the remaining 10 populations were ephemeral and without fish. Individuals from populations with fish had significantly stronger behavioral responses to fish (i.e., decreased feeding rate associated with the presence of fish and increased escape response) than individuals from fishless populations. Larvae from populations containing fish that were more isolated from fishless populations showed stronger antipredator responses than less isolated populations. Further, larvae from more isolated populations survived longer in the predation experiment, indicating that the behaviors measured were related with survival. These results suggest that gene flow between populations with conflicting selection pressures limits local adaptation in some salamander populations with fish. While previous studies have typically focused on the role of gene flow in pairs of populations, the results of this study suggest that gene flow is acting to swamp local adaptation across several populations. PMID- 28568326 TI - STABILIZING SELECTION AND VARIANCE IN FIG WASP SEX RATIOS. AB - Theory predicts that the phenotypic variance observed in a trait subject to stabilizing selection should be negatively correlated with the trait's impact on fitness. However, this relationship has rarely been tested directly. The offspring sex ratios produced by pollinating fig wasp foundresses upon entrance to a fruit and oviposition alone (single foundress sex ratios) are subject to stabilizing selection because too many males reduce the total number of dispersing females and too few males will result in unmated females or complete loss of the brood. Furthermore, we argue that the impact on fitness of, and therefore the intensity of stabilizing intensity on, single foundress sex ratios are correlated to how frequently a species produces single foundress broods in nature. Specifically, the intensity of stabilizing selection will be greater in species that encounter single foundress broods more frequently, both because the trait is expressed more often and because fitness shows a greater sensitivity to variation (narrower fitness profile) when that trait is expressed. Across 16 species of Panamanian pollinating fig wasps, the phenotypic variance in single foundress sex ratios was negatively correlated with the frequency with which that species encounters single foundress broods in nature. In addition, a formal comparative analysis based upon a molecular phylogeny of the wasps gave results that were the same as when species were used as independent data points. PMID- 28568325 TI - SEED MORPHOMETRICS AND ADAPTIVE GEOGRAPHIC DIFFERENTIATION. AB - Adaptive geographic differentiation is documented for seed morphology of 36 populations of Heterosperma pinnatum Cav. (Asteraceae), a seed heteromorphic annual plant in the central highlands of Mexico. Achenes (single-seeded fruits) vary continuously within heads but are classified by shape and position as central, intermediate, or peripheral morphs and as having adhesive awns or not. Here we quantify shape as a principal component score contrasting log length and width of achenes. Heads and their variation among populations are described in terms of maximum, minimum, and range of shape scores; the number of achenes per head; quantitative indices of the abruptness of shape shift; where in the head the most abrupt change in shape occurs; and what achene shapes have awns. First and second principal components of these descriptors summarize 86% of among population variation in achene and head morphology and correlate strongly with percent central achenes per head (%C) and percent of achenes with awns (%A), respectively. Awns are associated with greater dispersibility and achene shape is correlated with speed of dormancy loss. We hypothesized that dispersal morphology would be associated with vegetation attributes indicative of population ephemerality and that dormancy morphology would be associated with precipitation patterns during the early germination season. Morphological distance matrices were calculated using Euclidean distances among populations in %A and %C. Geographic distances among populations were calculated, as were genetic distances based on isozyme frequencies from 29 bands of six enzymes. Vegetation was classified as open or closed and early spring (germination season) and summer precipitation means were determined for each site. Closed vegetation was assumed to provide only ephemeral habitats for H. pinnatum. Partial matrix correlations between morphology and environment controlled for geographic but not genetic distance among sites, since the latter was not significantly correlated with either morphology or geography. A significant relationship was found between %A and closed vegetation, lower spring, and higher summer precipitation. %C was only correlated with lower spring precipitation. Independence of isozyme and morphological traits is interpreted in terms of selection on the latter but not the former. PMID- 28568327 TI - THE MAINTENANCE OF SEX BY PARASITISM AND MUTATION ACCUMULATION UNDER EPISTATIC FITNESS FUNCTIONS. AB - The mutation accumulation hypothesis predicts that sex functions to reduce the population mutational load, while the Red Queen hypothesis holds that sex is adaptive as a defense against coevolving pathogens. We used computer simulations to examine the combined and separate effects of selection against deleterious mutations and host-parasite coevolution on the spread of a clone into an outcrossing sexual population. The results suggest that the two processes operating simultaneously may select for sex independent of the exact shape of the function that maps mutation number onto host fitness. PMID- 28568328 TI - THE RELATIONSHIP BETWEEN CROSS SUCCESS AND SPATIAL PROXIMITY OF EUCALYPTUS GLOBULUS SSP. GLOBULUS PARENTS. AB - The genetic structure of Eucalyptus globulus forest was examined using progeny vigor as an indirect measure of parental relatedness. Seven trees were crossed with pollen from trees: 0 m (seifing); 21 m (nearest flowering neighbors), 250 m, 500 m, 1 km, 10 km, and 100 km away from the female. Only selfing depressed seed set. Growth of the 21 m progenies was intermediate to selfing and the longer distance pollinations, suggesting tight family clusters occur due to limited seed dispersal. Under this structure biparental inbreeding may be common, however, the cumulative impact of inbreeding seems negligible as relatedness did not appear to decline with distance between mates beyond 50 m. PMID- 28568329 TI - ONE SIZE FITS ALL? RELATIONSHIPS BETWEEN THE SIZE AND DEGREE OF VARIATION IN GENITALIA AND OTHER BODY PARTS IN TWENTY SPECIES OF INSECTS AND SPIDERS. AB - Hypotheses regarding the function of elaborate male genitalia were tested in a sample of insects and spiders by comparing their allometric values (slopes in log log regressions on indicators of body size) with those of other body parts. Male genitalia consistently had lower slopes than other body parts. Perhaps as a consequence of this pattern, genitalic size also tended, though less consistently, to have lower coefficients of variation than did the size of other body parts. The morphological details of coupling between males and females in several species clearly indicated that selection favoring mechanical fit is not responsible for these trends. Sexual selection on male courtship structures that are brought into contact with females in precise ways may favor relatively low allometric values, in contrast to the high values seen in the other sexually selected characters (usually visual display devices) that have been studied previously, because a female's own size will influence her perception of the contact courtship devices of a male. PMID- 28568330 TI - TESTING MODELS OF MIGRATION AND ISOLATION AMONG POPULATIONS OF CHINOOK SALMON (ONCORHYNCHUS TSCHAWYTSCHA). AB - The chinook salmon (Oncorhynchus tschawytscha) is a behaviorally, morphologically, and ecologically variable species distributed over a large geographic range. Although previous genetic surveys have revealed considerable genetic differences among populations with different life history types and from different major river drainages, it is not clear to what degree these genetically distinct populations are connected by low levels of gene flow. The work described in this paper addresses this question by surveying DNA restriction site variation at six nuclear genes from nine populations encompassing most of the species's North American range, and then attempting to fit the patterns of variation observed at these genes to five different evolutionary models using computer simulations of the coalescent process. Two commonly used constant population size models, one hypothesizing no migration among populations and one hypothesizing equal rates of migration among populations, were found to be statistically inconsistent with the observed patterns of variation. The other three models, which involved either recent divergence among populations coupled with large changes in populations size, unequal migration rates among populations, or selection, were all found to be consistent with the observed patterns of variation. Assuming selective neutrality, these results suggest that either the populations have all descended from a common ancestral population within the last ~50,000 years and have all suffered large declines in effective population size since that time, or that they have a more ancient divergence time but are connected by low levels of gene flow. These conclusions rest on the assumption of selective neutrality. With the methods employed, it was not possible to simultaneously test hypotheses of both selective neutrality and population structure. PMID- 28568331 TI - SPATIAL SCALE OF GENETIC STRUCTURE AND AN INDIRECT ESTIMATE OF GENE FLOW IN EELGRASS, ZOSTERA MARINA. AB - In this study, the first investigation of population structure in an aquatic angiosperm, I show that populations of a marine angiosperm (eelgrass, Zostera marina) are genetically differentiated at a number of spatial scales. I find also that there is no correspondence between geographic and genetic distances separating subpopulations, an increasingly common result in spatially stratified studies of genetic structure in marine invertebrates. F-statistics, calculated for two years from electrophoretic variation at five polymorphic allozyme loci, indicate significant genetic differentiation among sampling quadrats within each of two bays (theta = 0.064-0.208), between tide zones within a bay (theta = 0.025 0.157) and between bays (theta = 0.079). Spatial autocorrelation analysis was used to explore genetic differentiation at smaller spatial scales; estimated patch sizes (within which genetic individuals are randomly associated) indicated no appeciable genetic structure at scales less than 20 m * 20 m. Calculated values of F-statistics were a function of the spatial scale from which samples were drawn: increasing the size of the "subpopulation" included in calculation of fixation indices for the same "total" sample resulted in an increase in the magnitude of f (e.g., from 0.092 to 0.181) and a decrease in theta (e.g., from 0.186 to 0.025). On the basis of the best estimate of the spatial scale of subpopulations, the effective number of migrants per generation (Ne m) ranges from 1.1 to 2.8. Genetic consequences of the disturbance regime in the eelgrass habitat sampled were extreme variation between years in the allele richness and proportion of heterozygotes in a sample and a positive relationship between the extinction probability of patches and the genetic variance among them. The changes in F-statistics as a function of sampling scale and the observation that theta among sampled quadrats was positively associated with the probability of extinction among quadrats indicated that indirect estimates of gene flow (Ne m) calculated from theta should be cautiously interpreted in populations that may not yet be in drift-migration equilibrium. PMID- 28568332 TI - EVOLUTION OF DIFFERENT GALL TYPES IN WILLOW-FEEDING SAWFLIES (HYMENOPTERA: TENTHREDINIDAE). AB - The sawflies that feed on the plant family Salicaceae can be divided into eight informal groups based on larval feeding habit or gall type: (1) species with free living larvae; (2) leaf folders; (3) leaf blade gallers; (4) apical leaf gallers; (5) basal leaf gallers; (6) midrib and petiole gallers; (7) stem gallers; and (8) bud gallers. It has been proposed that the galling habit evolved from free-living larvae via leaf folders, and that the different gall types evolved gradually in the sequence mentioned above. Thus, the galling site would have "wandered" from the leaf margin toward the stem as a result of gradual changes in oviposition site preference. Allozyme data from eight informative loci were used to reconstruct the phylogeny of 18 representative sawfly species. The results suggest that indeed leaf folders seem to be a basal group; leaf blade gallers evolved independently of the other true gallers; apical and basal leaf gallers are not the ancestors of petiole and bud gallers, but they may share a common galling ancestor; bud gallers evolved from midrib/petiole gallers; and stem gallers are polyphyletic. The cause for the observed wandering of the galling site could be intraspecific competition due to a possible "nutrient shading effect" of galls situated closer to the host plant's main vascular system. PMID- 28568333 TI - CENTROMERIC INCOMPATIBILITIES IN THE HYBRID ZONE BETWEEN HOUSE MOUSE SUBSPECIES FROM DENMARK: EVIDENCE FROM PATTERNS OF NOR ACTIVITY. AB - The introgression pattern of centromeric nucleolar organizer regions (NORs) was studied in house mice from the hybrid zone between Mus musculus musculus and Mus musculus domesticus in Denmark. In this region, the two subspecies are chromosomally differentiated: M. m domesticus carries three pairs of Robertsonian (Rb) fusion chromosomes (2n = 34), while M. m. musculus exhibits the ancestral karyotype of 2n = 40 acrocentric chromosomes. A previous chromosomal analysis showed that the Rb clines were staggered and nonconcordant, and that the Rb fusions did not introgress into the M. m. musculus genome due to incompatibilities involving only the centromeric regions. In the present study, the distribution of a centromeric NOR cluster located on an acrocentric chromosome not involved in the Rb fusions (chromosome 11; NOR11 ) was investigated to determine if the observed centromeric incompatibilities were limited to the chromosomal rearrangements or were related to centromeric differentiation between the subspecies. The cytogenetic study by silver staining documented the activity pattern of the five major NOR-bearing chromosome pairs (12, 15, 16, 18, and 19) common to both subspecies and confirmed presence of NOR11 in M. m. musculus and absence in M. m. domesticus. The NOR11 activity pattern showed a very narrow and off-centered clinal transition. An in situ hybridization analysis with rDNA probes indicated that the decrease in frequency of activity of NOR11 through the hybrid zone was related to absence of ribosomal genes in this cluster and not to transcription repression due to competitive or dominance interactions. The center of the NOR11 cline was significantly different from that of the consensus allozymic markers, but coincided with that of the steepest Rb cline. Several arguments support the view that the selective processes involved in maintaining the NOR11 cline are related to the centromeric region of these chromosomes. These include: (1) the similarity in shape and position of the Rb and NOR11 clines; (2) the absence of activity dysfunction involving NOR11 ; and (3) the tight linkage between NORs and centromeres in house mice. This study indicates that the centromeric segments of acrocentric chromosomes not involved in chromosomal rearrangements show incompatibilities similar to those evidenced by the Rb fusions. These centromeric incompatibilities are thus more likely related to centromeric origin and subspecific differentiation (domesticus vs. musculus) than to centromeric rearrangement (Rb vs. non-Rb). In this case, it may be predicted that the selective processes maintaining the chromosomal clines are distributed over many, if not all, the centromeres and may combine . to limit the gene flow between M. m. domesticus and M. m. musculus. PMID- 28568335 TI - TESTING ADAPTIVE RADIATION AND KEY INNOVATION HYPOTHESES IN SPIDERS. AB - We combine statistical and phylogenetic approaches to test the hypothesis that adaptive radiation and key innovation have contributed to the diversity of the order Araneae. The number of unbalanced araneid clades (those whose species numbers differ by 90% or more) exceeds the number predicted by a null Markovian model. The current phylogeny of spider families contains 74 bifurcating nodes, of which 31 are unbalanced. As this is significantly more than the 14.8 expected unbalanced nodes, some of the diversity within the Araneae can be attributed to some deterministic cause (e.g., adaptive radiation). One of the more highly unbalanced (97%) bifurcations divides the orb-weaving spiders into the Deinopoidea and the larger Araneoidea. A simple statistical model shows that the inequality in diversity between the Deinopoidea and the Araneoidea is significant, and that it is associated with the replacement of primitive cribellar capture thread by viscous adhesive thread and a change from a horizontal to a vertical orb-web orientation. These changes improve an orb-web's ability to intercept and retain prey and expand the adaptive zone that orb weaving spiders can occupy and are, therefore, considered to be "key innovations." PMID- 28568334 TI - POPULATION STRUCTURE OF A CLONAL GORGONIAN CORAL: THE INTERPLAY BETWEEN CLONAL REPRODUCTION AND DISTURBANCE. AB - Clonality is a common feature of plants and benthic marine organisms. In some cases clonal propagation results in a modest increase in population density, while in other cases dense populations may be generated by the propagation of only a few clones. We analyzed the population structure of the clonal gorgonian Plexaura kuna across several reef habitats with a range of disturbance regimes in the San Blas Islands, Panama, and the Florida Keys, U.S.A. Using multilocus DNA fingerprinting to distinguish clones, we estimated that clones ranged in size from single individuals to 500 colonies. The number of genotypes identified on nine reefs ranged from three to 25. Population density and clonal structure varied markedly among reefs with GO :GE ranging from 0.03 to 1.00. On some reefs vegetative reproduction transformed P. kuna from a rare species to the numerically most abundant gorgonian. The effect of clonal propagation on P. kuna population structure was dependent on interactions between fragmentation and the reef environment (disturbance regime, substratum). We present a generalized model relating population structure of clonal species to disturbance and the mode of vegetative propagation. Disturbance promotes colony propagation and skews the size-frequency distribution of clones among P. kuna and many species that propagate via fragmentation. Propagation of these species is promoted by disturbance (disturbance sensitive), and they tend to have clones that are dispersed across local sites. Species that fragment and have dispersed clones, have high genotypic diversity in habitats with low levels of disturbance. Genotypic diversity then decreases at intermediate disturbance and increases again at the highest disturbance levels. Clonal species that do not rely on disturbance for vegetative propagation (disturbance insensitive) generally do not disperse and form aggregated clones. Among these taxa disturbance has a greater affect on individual survival than on propagation. Genotypic diversity is directly related to the level of disturbance until very high levels of disturbance, at which time genotypic diversity declines. PMID- 28568336 TI - COVARIATION OF DEFENSIVE TRAITS IN TIGER BEETLES (GENUS CICINDELA): A PHYLOGENETIC APPROACH USING mtDNA. AB - Inferences about the evolution of defensive strategies in tiger beetles (genus Cicindela) have been contentious, largely due to the lack of a phylogenetic hypothesis for the group. We used a dataset that includes measures of chemical defense, habitat association, and body coloration for a representative sample of North American Cicindela (Pearson et al. 1988) to reassess, within a phylogenetic context, the problem of covariation in defensive strategies. We reconstructed a phylogenetic hypothesis from mtDNA for a total of 44 Cicindela and seven outgroup taxa using 1896 base pairs from three segments of the mitochondrial genome. Characters involved in predator deterrence and escape were optimized onto this phylogeny. Although most taxa producing large amounts of benzaldehyde fall into two monophyletic clades, numerous changes in the level of benzaldehyde secretion across the genus suggest that this parameter is poorly conserved phylogenetically. In contrast to previous studies, we also found little support for correlated character changes in benzaldehyde secretion and habitat type, a presumed indicator of the selective regime. Aposematic coloration of the abdomen was restricted to a single monophyletic group of taxa producing large amounts of benzaldehyde. Bright iridescent coloration, implicated in predator evasion during flight, was only loosely correlated with the phylogenetic affinities of taxa and appears to be part of a defensive strategy not usually acting in combination with chemical defenses. Our study of character covariation clarifies earlier analyses of the adaptive significance of benzaldehyde defense, which were inconclusive without a phylogenetic hypothesis. PMID- 28568338 TI - MORTALITY PLATEAUS AND THE EVOLUTION OF SENESCENCE: WHY ARE OLD-AGE MORTALITY RATES SO LOW? AB - Age-specific mortality rates level off far below 100% at advanced ages in experimental populations of Drosophila melanogaster and other organisms. This observation is inconsistent with the equilibrium predictions of both the antagonistic pleiotropy and mutation accumulation models of senescence, which, under a wide variety of assumptions, predict a "wall" of mortality rates near 100% at postreproductive ages. Previous models of age-specific mortality patterns are discussed in light of recent demographic data concerning late-age mortality deceleration and age-specific properties of new mutations. The most recent theory (Mueller and Rose 1996) argues that existing evolutionary models can easily and robustly explain the demographic data. Here we discuss the sensitivity of that analysis to different types of mutational effects, and demonstrate that its conclusion is very sensitive to assumptions about mutations. A legitimate resolution of evolutionary theory and demographic data will require experimental observations on the age-specificity of mutational effects for new mutations and the degree to which mortality rates in adjacent ages are constrained to be similar (positive pleiotropy), as well as consideration of redundancy and heterogeneity models from demographic theory. PMID- 28568337 TI - TRADEOFF BETWEEN HORIZONTAL AND VERTICAL MODES OF TRANSMISSION IN BACTERIAL PLASMIDS. AB - It has been hypothesized that there is a fundamental conflict between horizontal (infectious) and vertical (intergenerational) modes of parasite transmission. Activities of a parasite that increase its rate of infectious transmission are presumed to reduce its host's fitness. This reduction in host fitness impedes vertical transmission of the parasite and causes a tradeoff between horizontal and vertical transmission. Given this tradeoff, and assuming no multiple infections (no within-host competition among parasites), a simple model predicts that the density of uninfected hosts in the environment should determine the optimum balance between modes of parasite transmission. When susceptible hosts are abundant, selection should favor increased rates of horizontal transfer, even at the expense of reduced vertical transmission. Conversely, when hosts are rare, selection should favor increased vertical transmission even at the expense of lower horizontal transfer. We tested the tradeoff hypothesis and these evolutionary predictions using conjugative plasmids and the bacteria that they infect. Plasmids were allowed to evolve for 500 generations in environments with different densities of susceptible hosts. The plasmid's rate of horizontal transfer by conjugation increased at the expense of host fitness, indicating a tradeoff between horizontal and vertical transmission. Also, reductions in conjugation rate repeatedly coincided with the loss of a particular plasmid encoded antibiotic resistance gene. However, susceptible host density had no significant effect on the evolution of horizontal versus vertical modes of plasmid transmission. We consider several possible explanations for the failure to observe such an effect. PMID- 28568339 TI - VIRULENCE OF MIXED-CLONE AND SINGLE-CLONE INFECTIONS OF THE RODENT MALARIA PLASMODIUM CHABAUDI. AB - Most evolutionary models treat virulence as an unavoidable consequence of microparasite replication and have predicted that in mixed-genotype infections, natural selection should favor higher levels of virulence than is optimal in genetically uniform infections. Increased virulence may evolve as a genetically fixed strategy, appropriate for the frequency of mixed infections in the population, or may occur as a conditional response to mixed infection, that is, a facultative strategy. Here we test whether facultative alterations in replication rates in the presence of competing genotypes occur and generate greater virulence. An important alternative, not currently incorporated in models of the evolution of virulence, is that host responses mounted against genetically diverse parasites may be more costly or less effective than those against genetically uniform parasites. If so, mixed clone infections will be more virulent for a given parasite replication rate. Two groups of mice were infected with one of two clones of Plasmodium chabaudi parasites, and three groups of mice were infected with 1:9, 5:5, or 9:1 mixtures of the same two clones. Virulence was assessed by monitoring mouse body weight and red blood cell density. Transmission stage densities were significantly higher in mixed- than in single clone infections. Within treatment groups, transmission stage production increased with the virulence of the infection, a phenotypic correlation consistent with the genetic correlation assumed by much of the theoretical work on the evolution of virulence. Consistent with theoretical predictions of facultative alterations in virulence, we found that mice infected with both parasite clones lost more weight and had on average lower blood counts than those infected with single-clone infections. However, there was no consistent evidence of the mechanism invoked by evolutionary models that predict this effect. Replication rates and parasite densities were not always higher in ***mixed-clone infections, and for a given replication rate or parasite density, mixed-clone infections were still more virulent. Instead, prolonged anemia and increased transmission may have occured because genetically diverse infections are less rapidly cleared by hosts. Differences in maximum weight loss occured even when there were comparable parasite densities in mixed- and single-clone infections. We suggest that mounting an immune response against more that one parasite genotype is more costly for hosts, which therefore suffer higher virulence. PMID- 28568340 TI - THE GENETICS OF PHENOTYPIC PLASTICITY. VIII. THE COST OF PLASTICITY IN DAPHNIA PULEX. AB - In a heterogeneous world, the optimal strategy for an individual is to continually change its phenotype to match the optimal type. However, in the real world, organisms do not behave in this fashion. One potential reason why is that phenotypic plasticity is costly. We measured production and maintenance costs of plasticity in the freshwater crustacean Daphnia pulex (Cladocera: Crustacea) in response to the presence of chemical signals from a predator, the insect Chaoborus americanus. We looked at three changes in juvenile body size and shape: body length, body depth, and tailspine length. Fitness costs were measured as changes in adult growth and fecundity, and summarized as the intrinsic rate of increase (r) for individuals reared in the presence or absence of Chaoborus extract. The cost of plasticity was measured as a multiple regression of mean clone fitness against trait and trait plasticity. We found scant evidence for either production or maintenance costs of plasticity. We also failed to find direct costs of these juvenile structures, which is surprising, as others have found such costs. We attribute the lack of measurable direct or plasticity costs to a decrease in metabolic rates in the presence of the Chaoborus extract. This decrease in metabolic rate may have compensated for any cost increases. We call for more extensive measures of the costs of plasticity, especially under natural conditions, and the incorporation of costs into evolutionary models. PMID- 28568341 TI - ESTIMATING THE MATING BEHAVIOR OF A PAIR OF HYBRIDIZING HELICONIUS SPECIES IN THE WILD. AB - Premating isolation between incipient species is rarely studied in nature, even though mating tests in captivity may give an inaccurate picture of natural hybridization. We studied premating barriers between the warningly colored butterflies Heliconius erato and H. himera (Lepidoptera) in a narrow contact zone in Ecuador, where hybrids are found at low frequency. Eggs obtained from wild mated females, supplemented with eggs and young larvae collected from the wild, were reared to adulthood. Adult color patterns of these progeny were then used to infer how their parents must have mated. Likelihood was used to estimate both the frequencies of potential parental genotypes from adult phenotypes collected in the wild, and the degree of assortative mating from the inferred parents. The frequencies of parental genotypes varied across the hybrid zone, but our statistical method allowed estimates of hybrid deficit and assortative mating to be integrated across all sites sampled. The best estimate of the frequency of F1 and backcross hybrid adults in the center of the hybrid zone was 10%, with support limits (7.1%, 13.0%; support limits are asymptotically equivalent to 95% confidence limits). Mating was highly assortative: in the center of the hybrid zone the cross-mating probability between H. erato and H. himera was only 5% (0.3%, 21.4%). Wild hybrids themselves mated with both pure forms, and the probabilities that they mated in any direction were not significantly lower than those among conspecifics. These results are consistent with earlier laboratory studies on mate choice, and suggest that selection against hybrids must be strong to prevent formation of a hybrid swarm. Unfortunately, the wide support limits on mating behavior precluded a measure of the strength of selection from these data alone. Our statistical approach provides a useful general method for estimating mate choice in the wild. PMID- 28568342 TI - GENETIC DETERMINANTS OF PROTANDRIC SEX IN THE PACIFIC OYSTER, CRASSOSTREA GIGAS THUNBERG. AB - A unique feature of sex in Crassostrea oysters is the coexistence of protandric sex change, dioecy, and hermaphroditism. To determine whether such a system is genetically controlled, we analyzed sex ratios in 86 pair-mated families of the Pacific oyster, Crassostrea gigas Thunberg. The overall female ratios of one-, two-, and three-year-old oysters were 37%, 55%, and 75%, respectively, suggesting that a significant proportion of oysters matured first as males and changed to females in later years. Detailed analysis of sex ratios in factorial and nested crosses revealed significant paternal effects, which corresponded to two types of sires. No major maternal effects on sex were observed. Major genetic control of sex was further indicated by the distribution of family sex ratios in two to four apparently discreet groups. These and other data from the literature are compatible with a single-locus model of primary sex determination with a dominant male allele (M) and a protandric female allele (F), so that MF are true males and FF are protandric females that are capable of sex change. The rate of sex change of FF individuals may be influenced by secondary genes and/or environmental factors. Strong maternal and weak paternal effects on sexual maturation or time of spawning were also suggested. PMID- 28568343 TI - THE EVOLUTION OF HOST-PLANT USE AND SEQUESTRATION IN THE LEAF BEETLE GENUS PHRATORA (COLEOPTERA: CHRYSOMELIDAE). AB - Leaf beetles in the genus Phratora differ in host plant use and in the chemical composition of their larval defensive secretion. Most species specialize on either poplars or willows (family Salicaceae), but two species feed on birch (family Betulaceae). Phratora vitellinae utilizes salicylates from the host plant to produce its larval secretion, which contains salicylaldehyde, while other Phratora species produce an autogenous secretion. To reconstruct the evolutionary history of host plant use and the larval secretion chemistry in this genus, we sequenced 1383 base pairs of the mt cytochrome oxidase I gene for six European and one North American Phratora species and three outgroup taxa. Bootstrap values of the complete nucleotide sequence were 99-100% for six of eight nodes in the maximum parsimony tree. They were 71% and 77% for the two other nodes. The maximum parsimony tree and the maximum likelihood tree based on nucleotide sequence showed the same relationships as a maximum parsimony tree based on the amino acid sequence. Beetle phylogeny overlapped broadly with host plant taxonomy and chemistry, and it revealed historical constraints influencing host plant use. However, there was one host shift from the willow family (Salicaceae) to the birch family (Betulaceae). The use of host plant phenol glycosides for the larval defensive secretion evolved along the lineage that led to P. vitellinae. Phratora vitellinae feeds on the taxonomically widest range of host plants, which are characterized by moderate to high levels of salicylates. The results support the hypothesis that the use of salicylates for the larval secretion evolved twice independently in chrysomeline leaf beetles. PMID- 28568344 TI - QUANTITATIVE GENETIC ESTIMATES OF MORPHOMETRIC VARIATION IN WILD-CAUGHT AND LABORATORY-REARED HOUSEFLIES. AB - Quantitative genetic estimates of morphometric traits in the housefly, Musca domestica L, were made on parents captured in the wild or reared in the laboratory. Phenotypic variation of morphometric traits declined within the laboratory, but as the additive genetic component of variation also declined, there was no net change in ***narrow-sense heritabilities of these traits across environments. Additive genetic variances were inflated only when wild-caught females were used as parents, suggesting that a maternal effect was present. PMID- 28568345 TI - EVOLUTIONARY DYNAMICS OF FITNESS RECOVERY FROM THE DEBILITATING EFFECTS OF MULLER'S RATCHET. AB - The great adaptability shown by RNA viruses is a consequence of their high mutation rates. The evolution of fitness in a severely debilitated, clonal population of the nonsegmented ribovirus vesicular stomatitis virus (VSV) has been compared under five different demographic regimes, ranging from severe serial bottleneck passages (one virion) to large population passages (105 virions or more) under similar environmental conditions (cell culture type and temperature). No matter how small the bottleneck, the fitness of the evolved populations was always higher than the fitness of the starting population; this result is clearly different from that previously reported for viruses with higher fitness. The reattainment of fitness under a regime of serial population passages showed two main characteristics: (1) the rate of adaptation was higher during early passages; and (2) a maximum fitness value was reached after a large number of passages. The maximum fitness reached by this initially debilitated clone was similar to the fitness of wild-type virus. The practical implications of these findings in the design of vaccines using attenuated viruses are also discussed. PMID- 28568346 TI - EVOLUTION OF RESISTANCE IN CULEX PIPIENS: ALLELE REPLACEMENT AND CHANGING ENVIRONMENT. AB - Fixation of adaptive mutations in populations is often constrained by pleiotropic fitness costs. The evolutionary pathways that compensate such fitness disadvantages are either the occurrence of modifier genes or replacement of the adaptive allele by less costly ones. In this context, 23 years of evolution of insecticide resistance genes in the mosquito Culex pipiens from southern France are analyzed. The aim of this study is to answer the following points. Is there a fitness cost associated with these resistance genes in natural populations? Does evolution proceed through allele replacement or through selection of modifiers? And finally, how do environmental changes affect the evolution of resistance genes? Samples from the same transect, crossing the boundary between an insecticide-treated and a nontreated area, are analyzed. Clinal analyses indicate a variable fitness cost among the resistance genes and show that allele replacement has been the primary mechanism of resistance evolution in this area. It is also shown that replacement was probably due to environmental changes corresponding to modification in pesticide-treatment intensity. PMID- 28568347 TI - EVOLUTIONARY ASSOCIATIONS OF BROOD PARASITIC FINCHES (VIDUA) AND THEIR HOST SPECIES: ANALYSES OF MITOCHONDRIAL DNA RESTRICTION SITES. AB - The species-specific associations of the African brood parasitic finches Vidua with their estrildid finch host species may have originated by cospeciation with the host species or by later colonizations of new hosts. Predictions of these alternative models were tested in two species groups of brood parasites (indigobirds, paradise whydahs) and their hosts. Phylogenetic analyses suggested that the brood parasites and their hosts did not speciate in parallel. The parasitic indigobirds share mitochondrial haplotypes with each other, and species limits in both indigobirds and paradise whydahs do not correspond with their gene trees. Different parasite species within a region are more closely related to each other than any is to parasites that are associated with its same host species in other regions of Africa. There is little genetic difference between parasite species Di,j < 0.001 in the indigobirds, Di,j = 0.01 in the whydahs). Genetic distances Di,j between the parasite species are less than the genetic distances between their corresponding host species in all parasite-host comparisons, and average only 7.2% as large in the indigobirds as in their hosts and 42% as large in the paradise whydahs as in their hosts. A phylogenetic model that allows ancestral haplotype polymorphisms to be retained in descendant species was compared to a constraint model of species monophyly requiring all but the one ancestral haplotype to be independently derived within each species. The constraint model increases the length of the indigobird tree by 50% over that of the model of retained ancestral polymorphisms; the difference is statistically significant. Both phylogenetic and distance analyses indicate that the brood parasites have become associated with their host species through host switches and independent colonizations of the hosts, rather than through parallel cospeciation with them. The molecular genetic results are supported by recent discoveries of additional host species that are associated with the indigobirds in the field and by variation in the species-specific song behaviors of the brood parasites. PMID- 28568348 TI - ERRATUM. PMID- 28568349 TI - THE RELATIVE IMPORTANCE OF HISTORICAL EVENTS AND GENE FLOW ON THE POPULATION STRUCTURE OF A MEDITERRANEAN RAGWORT, SENECIO GALLICUS (ASTERACEAE). AB - Comparisons of cytoplasmic and nuclear diversity within and among natural plant populations have the potential to distinguish the relative influences of seed and pollen dispersal on contemporary gene flow, or alternatively, may permit inferences of the colonization history of a species via seed. We examined patterns of cpDNA and allozyme variation in Senecio gallicus, a diploid, annual plant that occurs in both coastal and ruderal inland areas of the Iberian Peninsula and southern France. The species appears to have a strong propensity for long-distance seed dispersal. Five cpDNA haplotypes were found by RFLP analysis among a sample of 111 individuals derived from 11 populations. Differences in haplotype frequencies across populations were most evident with respect to a dramatic increase in the frequency of a derived haplotype from coastal to inland localities. The level of cpDNA differentiation among populations within the inland group (theta0 = 0.07) was significantly less than that seen within the coastal group (theta0 = 0.41). In contrast, for allozymes, no significant difference in population structure was evident between collections from coastal and inland habitats. At the rangewide geographic scale, there was only a very weak association between inferred levels of gene flow and geographic distance for cpDNA, and no such association was found for allozymes. It appears that while seed movement in the species might be sufficiently great to disturb the pattern of isolation by distance for cpDNA, it cannot fully account for the nearly randomized spatial structure at polymorphic allozyme loci. It is suggested that isolation of populations in Atlantic-Mediterranean coastal refugia during previous glacial maxima, and the effects of subsequent colonization events in inland areas, have had an important effect on molding the present genetic structure of the species. PMID- 28568350 TI - BUTTERFLIES AND PLANTS: A PHYLOGENETIC STUDY. AB - A database on host plant records from 437 ingroup taxa has been used to test a number of hypotheses on the interaction between butterflies and their host plants using phylogenetic methods (simple character optimization, concentrated changes test, and independent contrasts test). The butterfly phylogeny was assembled from various sources and host plant clades were identified according to Chase et al.'s rbcL-based phylogeny. The ancestral host plant appears to be associated within a highly derived rosid clade, including the family Fabaceae. As fossil data suggest that this clade is older than the butterflies, they must have colonized already diversified plants. Previous studies also suggest that the patterns of association in most insect-plant interactions are more shaped by host shifts, through colonization and specialization, than by cospeciation. Consequently, we have focused explicitly on the mechanisms behind host shifts. Our results confirm, in the light of new phylogenetic evidence, the pattern reported by Ehrlich and Raven that related butterflies feed on related plants. We show that host shifts have generally been more common between closely related plants than between more distantly related plants. This finding, together with the possibility of a higher tendency of recolonizing ancestral hosts, helps to explain the apparent large-scale conservation in the patterns of association between insects and their host plants, patterns which at the same time are more flexible on a more detailed level. Plant growth form was an even more conservative aspect of the interaction between butterflies and their host plants than plant phylogeny. However, this is largely explained by a higher probability of colonizations and host shifts while feeding on trees than on other growth forms. PMID- 28568351 TI - ADAPTATION TO COMPETITION BY NEW MUTATION IN CLONES OF ALEXANDRIUM MINUTUM. AB - We describe two competition experiments between clones of the dinoflagellate Alexandrium minutum. In the first experiment, two clones originating from a single haploid cell competed until one of the clones was almost driven to extinction. In the second experiment, these two clones were allowed to compete with the original populations, which were previously kept as cysts. The results indicate that an improvement of the competitive ability in both clones has occurred during the history of competition. This adaptation to competition must be attributed to selection acting on the new genetic variation that has arisen by mutation. PMID- 28568352 TI - Plica neuropathica (matting hair) in an autistic patient. PMID- 28568354 TI - FREQUENCY-DEPENDENT MATING? PMID- 28568353 TI - Prevention of complications in glycogen storage disease type Ia with optimization of metabolic control. AB - Prior to 1971, type Ia glycogen storage disease was marked by life-threatening hypoglycemia, lactic acidosis, severe failure to thrive, and developmental delay. With the introduction of continuous feeds in the 1970s and cornstarch in the 1980s, the prognosis improved, but complications almost universally developed. Changes in the management of type Ia glycogen storage disease have resulted in improved metabolic control, and this manuscript reviews the increasing evidence that complications can be delayed or prevented with optimal metabolic control as previously was seen in diabetes. PMID- 28568355 TI - GENETIC CHANGES AT THE TRANSFERRIN LOCUS IN THE RED-BACKED VOLE (CLETHRIONOMYS GAPPERI). PMID- 28568356 TI - THE MATING SYSTEM OF THE TERRESTRIAL SLUG DEROCERAS LAEVE. PMID- 28568357 TI - SEXUAL SELECTION AND COMMUNICATION IN A NEOTROPICAL FROG, PHYSALAEMUS PUSTULOSUS. PMID- 28568359 TI - Society Meetings. PMID- 28568358 TI - DETERMINANTS OF MULTIPLE HOST USE BY A PHYTOPHAGOUS INSECT POPULATION. PMID- 28568360 TI - GENETIC VARIABILITY WITHIN AND AMONG POPULATIONS OF THE BLACK-TAILED PRAIRIE DOG. PMID- 28568361 TI - TESTING THE FEMALE MIMICRY HYPOTHESIS OF DELAYED PLUMAGE MATURATION: A COMMENT ON PROCTER-GRAY AND HOLMES. PMID- 28568362 TI - HYBRID INVIABILITY AND PREDOMINANT SURVIVAL OF MATING TYPE MINUS PROGENY IN LABORATORY CROSSES BETWEEN TWO CLOSELY RELATED MATING GROUPS OF CLOSTERIUM EHRENBERGII. PMID- 28568363 TI - GRASSHOPPER MANDIBLES AND THE NICHE VARIATION HYPOTHESIS. PMID- 28568364 TI - RELATIVE FITNESSES OF SELFED AND OUTCROSSED PROGENY IN GILIA ACHILLEIFOLIA (POLEMONIACEAE). PMID- 28568365 TI - A STEEP CLINE IN PINUS MURICATA. PMID- 28568366 TI - PROBLEMS IN THE USE OF GENETIC SIMILARITY TO SHOW RELATEDNESS. PMID- 28568367 TI - BARRIERS TO GENE EXCHANGE BETWEEN CLOSELY RELATED CRICKET SPECIES. I. LABORATORY HYBRIDIZATION STUDIES. PMID- 28568368 TI - ECOLOGICAL GENETICS OF DAPHNIA PULEX. PMID- 28568369 TI - INFLUENCES OF GENETIC VARIABILITY AND MATERNAL FACTORS ON FETAL GROWTH IN WHITE TAILED DEER. PMID- 28568370 TI - Society Meetings. PMID- 28568371 TI - PATTERNS AND LEVELS OF GENETIC VARIATION IN GREAT BASIN BRISTLECONE PINE, PINUS LONGAEVA. PMID- 28568372 TI - DIFFERENCES BETWEEN GENERATIONS IN THE SEX RATIO OF ACULEATE HYMENOPTERA. PMID- 28568373 TI - PHYLOGENETIC INFERENCE FROM RESTRICTION ENDONUCLEASE CLEAVAGE SITE MAPS WITH PARTICULAR REFERENCE TO THE EVOLUTION OF HUMANS AND THE APES. PMID- 28568374 TI - HIGH LEVELS OF PHENOTYPIC VARIABILITY OF METAL AND TEMPERATURE TOLERANCE IN PARAMECIUM. PMID- 28568375 TI - GENETIC EVIDENCE OF OUTBREEDING IN THE BLACK-TAILED PRAIRIE DOG (CYNOMYS LUDOVICIANUS). PMID- 28568376 TI - ENAMEL-LIKE ANTIGENS IN HAGFISH: POSSIBLE EVOLUTIONARY SIGNIFICANCE. PMID- 28568377 TI - One in two cancer patients is significantly distressed: Prevalence and indicators of distress. AB - OBJECTIVE: Psychological distress is common in cancer patients, and awareness of its indicators is essential. We aimed to assess the prevalence of psychological distress and to identify problems indicative of high distress. METHODS: We used the distress thermometer (DT) and its 34-item problem list to measure psychological distress in 3724 cancer patients (mean age 58 years; 57% women) across major tumor entities, enrolled in an epidemiological multicenter study. To identify distress-related problems, we conducted monothetic analyses. RESULTS: We found high levels of psychological distress (DT >= 5) in 52% of patients. The most prevalent problems were fatigue (56%), sleep problems (51%), and problems getting around (47%). Sadness, fatigue, and sleep problems were most strongly associated with the presence of other problems. High distress was present in 81.4% of patients reporting all 3 of these problems (DT M = 6.4). When analyzing only the subset of physical problems, fatigue, problems getting around, and indigestion showed the strongest association with the remaining problems and 76.3% of patients with all 3 problems were highly distressed (DT M = 6.1). CONCLUSIONS: Our results show a high prevalence of psychological distress in cancer patients, as well as a set of problems that indicate the likely presence of other problems and high distress and can help clinicians identify distressed patients even if no routine distress screening is available. PMID- 28568378 TI - Cytotoxic Properties of the Stem Bark of Citrus reticulata Blanco (Rutaceae). AB - The bioassay-guided fractionation of the n-hexane extract of Citrus reticulata Blanco (Rutaceae) stem bark yielded scoparone (1), xanthyletin (2), lupeol (3), beta-amyrin (4), stigmasterol (5), beta-sitosterol (6) and palmitic acid. The structures of these compounds were determined by comprehensive spectroscopic analyses, i.e., 1D and 2D NMR and EI-MS, and by comparison with the reported data. Extracts, fractions and isolated compounds 1-6 were assessed for cytotoxicity by the 3-(4,5-dimethylthiazol-2-yl)-2,5-dphenyltetrazolium bromide (MTT) assay against three human cancer cell lines, i.e., human lung adenocarcinoma cell line A549, human breast adenocarcinoma cell line MCF7 and human Caucasian prostate adenocarcinoma cell line PC3. Significant activity of the n-hexane and the dichloromethane extracts was observed against the breast cancer cell line MCF7 with IC50 s of 45.6 and 54.7 MUg/mL, respectively. Moreover, the 70% ethyl acetate in n-hexane chromatographic fraction showed significant activity displaying IC50 values of 53.0, 52.4 and 49.1 MUg/mL against the cancer cell lines A549, MCF7 and PC3, respectively. Encouragingly, an IC50 of 510.0 MUg/mL against the human normal prostate cell line PNT2 indicated very low toxicity and hence favourable selectivity indices for the 70% ethyl acetate in n hexane fraction in the range of 9.6-10.4 towards cell lines A549, MCF7 and PC3. Because compounds isolated from the above fraction only delivered IC50 values in the range of 18.2-96.3, 9.2-34.1 and 7.5-97.2 MUg/mL against A549, MCF7 and PC3 cell lines, respectively, synergistic action between compounds is suggested. Bioassay results valorize the anticancer effectivity of the stem bark of this plant in Cameroonian pharmacopoeia. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28568380 TI - CHLOROPLAST-DNA VARIATION AND MULTIPLE ORIGINS OF AUTOPOLYPLOIDY IN HEUCHERA MICRANTHA (SAXIFRAGACEAE). PMID- 28568379 TI - Ketoacidosis at onset of type 1 diabetes is a predictor of long-term glycemic control. AB - BACKGROUND: Few studies have evaluated the impact of diabetic ketoacidosis (DKA) at diabetes onset on long-term glycemic control in patients with type 1 diabetes (T1D). OBJECTIVE: We aimed to determine any differences in long-term glycemic control between children/adolescents with T1D presenting with DKA at diabetes onset and those without. METHODS: This retrospective study comprised 335 patients diagnosed with T1D from September 2007 to December 2012, among which 132 (39.4%) presented with DKA. Variables compared between patients with DKA at onset and those without: yearly hemoglobin A1c (HbA1c) levels, daily insulin dose, yearly rates of severe hypoglycemia and DKA, percent of patients achieving target HbA1c levels. RESULTS: After the first year of diabetes, the mean daily insulin dose and HbA1c level were significantly higher in the group with DKA at onset (0.74 +/ 0.26 vs 0.69 +/- 0.27 units/kg/d, P = .049, and 7.85 +/- 1.13% vs 7.49 +/- 0.94%, P = .01, respectively), despite similarity of therapy (multiple daily injections or continuous subcutaneous insulin infusion), with a similar but not statistically significant trend subsequently. Mean HbA1c since onset was significantly higher in the DKA group (8.08 +/- 0.95% vs 7.86 +/- 0.95%, P = .025). A significantly higher percentage of patients in the group without DKA at onset achieved a mean level of HbA1c since onset within glycemic targets (32% vs 20.5%, P = .02). In the DKA group, the frequency of subsequent DKA episodes per diabetes years was significantly higher (P = .042). CONCLUSIONS: DKA at diagnosis was associated with less favorable long-term glycemic control as assessed by HbA1c and the rate of DKA episodes. T1D patients presenting with DKA may therefore need stricter treatment and tight follow-up. PMID- 28568381 TI - THE EVOLUTION OF RESISTANCE TO HERBIVORY IN IPOMOEA PURPUREA. II. NATURAL SELECTION BY INSECTS AND COSTS OF RESISTANCE. AB - An important component of the process of coevolution between plants and their insect herbivores is the imposition of selection on plants by insects. Although such selection has been inferred from indirect evidence, little direct evidence for it exists. One goal of this study was to seek direct evidence by determining, for a single plant-herbivore system, whether insect herbivores impose selection on their host plants. A second goal was to determine whether costs are associated with genotypes that confer resistance to herbivores, as has been commonly postulated. The annual morning glory, Ipomoea purpurea, exhibits genetic variation in resistance to four different types of insects. For three of these types, most of the genetic variation is additive. Removal of insect herbivores increased the number of seeds produced by I. purpurea by 20% and eliminated additive genetic variation for seed number (fitness). This result implies that herbivores impose selection on some trait(s) of their host plants. Coupled with selection for decreased damage by corn earworms, as revealed by a negative additive genetic covariance between damage and fitness, this result suggests that insect herbivores impose selection on resistance to corn earworms in I. purpurea. Two types of cost of resistance to herbivores were sought in I. purpurea: 1) internal trade-offs in allocation of resources and 2) ecological trade-offs between resistances to different insects. No costs of either type were detected. This result suggests that cost-benefit arguments that attempt to predict the evolution of levels of resistance to herbivores are not applicable to I. purpurea. PMID- 28568382 TI - CONFIDENCE LIMITS ON THE MAXIMUM-LIKELIHOOD ESTIMATE OF THE HOMINOID TREE FROM MITOCHONDRIAL-DNA SEQUENCES. PMID- 28568383 TI - REPRODUCTIVE ISOLATION AND INTROGRESSION BETWEEN NOTROPIS CORNUTUS AND NOTROPIS CHRYSOCEPHALUS (FAMILY CYPRINIDAE): COMPARISON OF MORPHOLOGY, ALLOZYMES, AND MITOCHONDRIAL DNA. AB - Hybrid zones in fluvial fishes may be heterogeneous from drainage to drainage. The comparison of data from morphology, allozymes, and mitochondrial DNA (mtDNA) indicates variability in the causes and degree of restriction of gene flow between Notropis cornutus and Notropis chrysocephalus. Allozyme marker loci show frequency-dependent introgression; i.e., the rarer species, whichever it is at a particular locality, tends to exhibit a higher proportion of introgressed alleles. Unlike allozymes, introgression of mtDNA haplotypes varies geographically. In westward-flowing Michigan drainages, N. cornutus mtDNA haplotypes are more common in F1 hybrids and backcrosses, independent of parental frequencies. In eastward-flowing Michigan drainages, N. chrysocephalus mtDNA is more common in F1 hybrids and backcrosses; this pattern may be due to local ecological effects or frequency-dependent introgression. Morphological data alone are not sufficient to distinguish all classes of hybrids. The lack of concordance of morphological, allozymic, and mtDNA introgression patterns implies operation of one or two factors: 1) geographically variable patterns of selection against different hybrid and backcross combinations or 2) genetic differences between Michigan populations inhabiting eastward- and westward-flowing drainage systems accumulated during historical isolation. PMID- 28568384 TI - THE EVOLUTION OF RESISTANCE TO HERBIVORY IN IPOMOEA PURPUREA. I. ATTEMPTS TO DETECT SELECTION. AB - In this study, we looked for evidence of directional or stabilizing/disruptive selection on plant size and on the level of damage (resistance) caused by four types of herbivores in the annual morning glory Ipomoea purpurea. Selection was estimated by standard phenotypic regression analysis and by regression on breeding values. The phenotypic regression analysis revealed directional selection for all five characters (i.e., plant size and resistance to four types of herbivores) and indicated that plant size and resistance to corn-earworm damage were subject to stabilizing selection. By contrast, the analysis using breeding values revealed directional selection only for plant size and resistance to corn earworms, while none of the characters examined indicated stabilizing or disruptive selection. These results suggest that intermediate levels of damage in I. purpurea are, in general, not maintained by stabilizing selection. Rather, they may reflect either 1) a transient state that exists while directional selection pushes the population toward complete resistance (or, in one case, total absence of resistance) or 2) the evolution of susceptibility to damage by genetic drift. PMID- 28568385 TI - COMBINATORICS AND VARIETY OF MATING-TYPE SYSTEMS. PMID- 28568386 TI - MASS-MORTALITY LAYERS OF FOSSIL STICKLEBACK FISH: CATASTROPHIC KILLS OF POLYMORPHIC SCHOOLS. AB - Stickleback fish (Gasterosteus doryssus) from late middle-Miocene lacustrine deposits of the Truckee Formation in west-central Nevada are abundant and well preserved. They occasionally occur in unusually high densities on single annual laminations (varves) in "mass-mortality layers." We demonstrate that stickleback mass-mortality layers consist of members of schools and may be used as population samples. Comparison of stickleback mass-mortality samples to time-averaged samples, which accumulated over hundreds or thousands of years in the same deposit, indicates that, for some purposes, the time-averaged samples are acceptable surrogates for instantaneous population samples from the G. doryssus lineage. Mass-mortality and time-averaged samples are similar for variation of pelvic structure and dorsal-spine number, but associations between states of different characters may be weaker in mass-mortality samples than in time averaged samples. Thus, character variances in time-averaged samples of G. doryssus are comparable to those of living populations, but character correlations are suspect. Character variances and correlations in time-averaged fossil samples must be evaluated on a case-by-case basis and interpreted with caution. PMID- 28568387 TI - EVIDENCE FOR SELECTION ON SENSORY STRUCTURES IN A CAVE POPULATION OF GAMMARUS MINUS (AMPHIPODA). PMID- 28568388 TI - A DEVELOPMENTAL CONSTRAINT IN CERION, WITH COMMENTS ON THE DEFINITION AND INTERPRETATION OF CONSTRAINT IN EVOLUTION. AB - Since orthodox evolutionary theory is functionalist, constraints attain their most important positive meaning as channels of change imposed by historical and formal determinants, rather than by immediate natural selection. Since ontogeny is the usual locus of expression for these determinants, developmental constraint is an appropriate, general term. A particular developmental constraint in Cerion, most variable of West Indian land snails, stands out for two reasons: 1) it is simply and inexorably defined as a consequence both of formal principles (coiling of tube about axis) and of historical contingencies in Cerion's invariant allometry of growth; 2) it is pervasive in its influence, underlying major patterns of variation in every Cerion study I have ever undertaken. I refer to this pattern as the "jigsaw constraint." When whorls are large and final size is limited, adult shells must grow fewer whorls. In Cerion, this obvious fact is promoted from trivial to important because complex allometries impose a substantial set of further consequences for form upon this basic trade-off of whorl size and whorl number. I show that this complex of consequences dominates patterns of natural variation in Cerion at all levels (among shells within samples, between samples in the geographic variation of single species, and between species in multitaxon faunas). It also sets patterns of hybridization between taxa. This paper is primarily a compendium of such examples. It is designed to illustrate the importance of this constraint by the fundamental criterion of relative frequency. PMID- 28568389 TI - VARIABLE SELECTION ALONG A SUCCESSIONAL GRADIENT. AB - Patterns of selection were measured in populations of the perennial grass Danthonia spicata from a successional gradient in northern lower Michigan for a five-year period. Phenotypic variation was found both within and among populations for morphological, reproductive, and life-history traits. Two fitness components were measured: fecundity (total number of spikelets produced) and mortality (number of years an individual lived). Multiple-regression analysis of relative reproductive effort (percentage of culms that flowered), culm length, and leaf length against fitness showed substantial variation in the magnitude and direction of selection among the populations and among the fitness components. When three other reproductive traits were added to the analysis, there were no qualitative changes in estimates of directional selection coefficients, but there were pronounced changes in estimates of stabilizing/disruptive selection components. Patterns of selection were concordant with previously measured genetic changes in reproductive effort along the successional gradient but not concordant with genetic changes in culm length and leaf length. These same patterns were found in comparisons of Michigan and North Carolina populations. PMID- 28568390 TI - AN EXAMPLE OF NONEQUILIBRIUM PROCESSES: GYNODIOECY OF THYMUS VULGARIS L. IN BURNED HABITATS. PMID- 28568391 TI - MIGRATION PATTERNS AND THE DEVELOPMENT OF MULTILOCUS ASSOCIATIONS IN A SELFING ANNUAL, TRITICUM DICOCCOIDES. AB - Migration patterns in wild emmer wheat, Triticum dicoccoides, were inferred from single-locus and multilocus genetic distributions based primarily on expectations derived from single-locus and multilocus cline theory. Populations from five collections displayed a large amount of multilocus structuring, as indicated by high values of gametic-phase disequilibrium between pairs of loci and by high values of multilocus associations. Analyses of the distributions of individual alleles, however, indicated that alleles had apparent independent centers of origin and that at least some independent dispersal within regions occupied by ecotypes or races of wild emmer had occurred. The distribution of the degrees of multilocus association suggests that there has been a net migration of the northern or Qazrin race south and west into the pocket occupied by the Yehudiyya race. The results suggest that ecotypic differentiation may be independent and may antedate electrophoretically determined differentiation in these populations. There is no convincing evidence that the multilocus associations represent coadapted complexes; rather they appear to involve associations of mutant alleles that have been accentuated and preserved by low recombination rates and gene-flow barriers within previously differentiated ecotypes. PMID- 28568392 TI - DENTAL DEVELOPMENT AS A MEASURE OF LIFE HISTORY IN PRIMATES. PMID- 28568393 TI - THE EVOLUTION OF SELECTIVE AGGRESSION CONDITIONED ON ALLORECOGNITION SPECIFICITY. AB - Many sessile cnidarians deploy specialized structures while competing aggressively for living space. The initiation of aggression is often contingent on the relatedness of the interacting contestants; clonemates and close kin generally behave passively toward one another, whereas more distant relatives generally behave aggressively. Behavioral specificity of this sort requires that there be 1) an allorecognition system that can discriminate among subtle differences in cell-surface determinants and 2) a highly polymorphic genetic system that provides specific labels of relatedness (haplotypes or allotypes). The evoutionary models analyzed in this paper show that a population of individuals that behave aggressively only against haplotypically distinct individuals (discriminating phenotypes) will not be evolutionarily stable in the face of either unconditionally aggressive or unconditionally nonaggressive phenotypes. Furthermore, even if the discriminating trait were somehow fixed, the rare recognition alleles necessary to confer allotypic specificity could not become established through natural selection. Thus, allotypic specificity is unlikely to be maintained by individual selection acting directly through aggressive behavior. Other selective mechanisms might account for the evolution of allorecognition specificity. Allotypic polymorphism could be maintained by pleiotropic mechanisms in which rare alleles are favored by natural selection acting either on gametic incompatibility, pathogen resistance, or somatic fusion, rather than aggressive behavior per se. However, these mechanisms do not explain the maintenance of selective aggression based on allotypic differences. Alternatively, if aggressive members of a clone indirectly enhance the reproductive output or survival of the entire clone (or close relatives), then kin selection acting directly through aggressive behavior could favor allorecognition specificity. Choosing among these alternatives will require the development of more sophisticated theory and empirical analyses of the costs and benefits of aggression. PMID- 28568394 TI - MITOCHONDRIAL-DNA AND ALLOZYME DIVERGENCE PATTERNS ARE CORRELATED AMONG ISLAND DEER MICE. PMID- 28568395 TI - DISEASE IMPACT AND LOCAL GENETIC DIVERSITY IN THE CLONAL PLANT PODOPHYLLUM PELTATUM. AB - Genotypic diversity is restricted within local colonies of mayapple (Podophyllum peltatum), due to extensive asexual reproduction. Transplant experiments were used to examine whether disease impact from a specialist fungal pathogen (Puccinia podophylli) was affected by the local frequency of host genotypes within colonies. In each of six large mayapple colonies, I measured infection intensity on 1) ramets replanted in their native colony (which were thus surrounded mostly by identical genotypes) and 2) transplants from two foreign colonies (surrounded by different genotypes). Disease incidence during the pathogen's first generation did not vary significantly between native (11% infected) and foreign host genotypes (6% infected). In the pathogen's second generation, significant variation in infection intensity occurred among ramets from different source populations. However, at five of the six transplant sites, mean infection intensity was higher on some nonnative plants (locally rare host genotypes) than on natives (locally common host genotypes). In this system, pathogen attack does not act in a frequency-dependent manner to promote local genetic diversity among hosts. PMID- 28568396 TI - DISPERSAL OF ERYTHRONIUM GRANDIFLORUM POLLEN BY BUMBLEBEES: IMPLICATIONS FOR GENE FLOW AND REPRODUCTIVE SUCCESS. PMID- 28568397 TI - KIN RECOGNITION IN ANIMALS. PMID- 28568398 TI - GENETIC CONSEQUENCES OF AUTOPOLYPLOIDY IN TOLMIEA (SAXIFRAGACEAE). AB - Although there is an extensive literature on the genetic attributes of allopolyploids, very little information is available regarding the genetic consequences of autopolyploidy in natural populations. We therefore addressed the major predicted genetic consequences of autopolyploidy using diploid and tetraploid populations of Tolmiea menziesii. Individual autotetraploid plants frequently maintain three or four alleles at single loci: 39% of the 678 tetraploid plants exhibited three or four alleles for at least one locus. Heterozygosity was also significantly higher in autotetraploid populations than in diploid populations: H degrees = 0.070 and 0.237 in diploid and tetraploid Tolmiea, respectively. Most of the genetic diversity in T. menziesii is maintained within populations (ratio of gene diversity within populations to mean total genetic diversity = 0.636). The total genetic diversity due to differentiation between the two cytotypes is only 0.055. Such a low degree of differentiation between cytotypes would be expected between a diploid and its autotetraploid derivative. Most diploid and all tetraploid populations examined are in genetic equilibrium. Diploid and tetraploid Tolmiea share three or four alleles at six of eight polymorphic loci. This suggests that either autotetraploid Tolmiea was formed via crossing of genetically different diploids (perhaps via a triploid intermediate) or autopolyploidy occurred more than once in separate individual plants, followed by later crossing of autotetraploids. PMID- 28568399 TI - SMALL SAMPLE SIZE DOES DECREASE THE STABILITY OF DENDROGRAMS CALCULATED FROM ALLOZYME-FREQUENCY DATA. PMID- 28568400 TI - THE EVOLUTION OF MATERNAL CHARACTERS. AB - We develop quantitative-genetic models for the evolution of multiple traits under maternal inheritance, in which traits are transmitted through non-Mendelian as well as Mendelian mechanisms, and maternal selection, in which the fitness of offspring depends on their mother's phenotype as well as their own. Maternal inheritance results in time lags in the evolutionary response to selection. These cause a population to evolve for an indefinite number of generations after selection ceases and make the rate and direction of evolution change even when the strength of selection and parameters of inheritance remain constant. The rate and direction of evolution depend on the inheritance of traits that are not under selection, unlike under classical Mendelian inheritance. The models confirm earlier findings that the response to selection can be larger or smaller than what is possible with simple Mendelian inheritance, and even in a direction opposite to what selection favors. Maternal selection, in which a mother's phenotype influences her offspring's fitness, is frequency-dependent and can cause a population to evolve maladaptively away from a fitness peak, regardless of whether traits are transmitted by Mendelian or maternal inheritance. Maternal selection differs from other forms of selection in that its force depends not only on the fitness function but also on the phenotypic resemblance of parents and offspring. PMID- 28568401 TI - GENOTYPIC AND ENVIRONMENTAL COMPONENTS OF VARIATION IN GROWTH AND REPRODUCTION OF FISH HEMICLONES (POECILIOPSIS: POECILIIDAE). AB - The frozen-niche-variation model was proposed to account for the coexistence of genetically related clones in naturally occurring unisexual populations. This model is based on two assumptions: 1) ecologically different clones have multiple independent origins from sexual ancestors; and 2) the population of sexual ancestors contains genetic variability for ecologically relevant traits. To test these assumptions, we produced 14 new "hemiclones" (nonrecombining haploid genotypes) of fish (Poeciliopsis: Poeciliidae). Our ability to synthesize many new hemiclones demonstrates the feasibility of multiple independent origins of nonrecombining genotypes. A substantial proportion (10-50%) of the phenotypic variation among hemiclones in size at birth, juvenile growth rate, and fecundity had a genetic basis. Thus, we conclude that multiple origins can give rise to an assemblage of genetically distinct hemiclones, each with a unique combination of life-history traits. Additionally, a comparative analysis of two natural hemiclones revealed that the synthetic strains represent a broad field of variation from which natural hemiclones can be selected. PMID- 28568402 TI - SPECIES RICHNESS WITHIN FAMILIES OF FLOWERING PLANTS. AB - Variation in species and genus richness among families of flowering plants was examined with respect to four classification variables: geographical distribution, growth form, pollination mode, and dispersal mode. Previous studies have estimated rates of species proliferation from age and contemporary diversity. Here we found that the earliest appearances in the fossil record are correlated with contemporary familial species richness, abundance in the fossil record, and the independent variables considered in this analysis. Thus, we believe that the fossil record does not provide reasonable estimates of the ages of families and that the rate of species proliferation cannot be calculated from such data without bias. Accordingly, our subsequent analyses were based on contemporary species richness of families. Although the classification variables were interrelated, each made largely independent contributions to familial species richness. Cosmopolitan families were 5.6 times more species-rich than strictly tropical families and 35 times more species-rich than strictly temperate families. Families including both herbaceous and woody growth forms were 5.7 and 14 times more species-rich than families with either growth form alone. Although animal pollination was significantly associated with elevated familial species richness, the effect was statistically weak. The most prominent effect was that families with both abiotic and biotic dispersal had more than 10 times as many species as families with either dispersal mode alone. Our analyses also revealed that families having both dispersal modes were more likely to have several growth forms, suggesting that evolutionary flexibility of morphology may be generalized over diverse aspects of life history. These results do not support the idea that pollination and dispersal by animals were primarily responsible for the tremendous proliferation of angiosperm species, either by producing population structures conducive to speciation or by applying selection for diversification. Instead, the importance of varied dispersal mode, growth form, and climate zone in predicting high familial species richness suggests that a capacity to diversify morphologically and physiologically may have been primarily responsible for high rates of species proliferation in the flowering plants. PMID- 28568403 TI - DIFFERENTIAL COSTS OF A SECONDARY SEXUAL CHARACTER: AN EXPERIMENTAL TEST OF THE HANDICAP PRINCIPLE. AB - The evolution of reliable signaling can be explained by the handicap principle, which assumes that (1) the cost of a signal guarantees its reliability, and (2) cheating is prevented because the cost of a unit of display is greater for low quality than for high-quality individuals. A test of these two assumptions was performed using manipulations of the length of the outermost tail feathers of male barn swallows Hirundo rustica, a trait currently subject to a directional female mate preference. We found that survival decreased with tail elongation and increased with tail shortening of males, supporting the assumption that the secondary sexual character is costly. Naturally long-tailed males were better able to survive with an elongated tail, whereas naturally short-tailed males improved their survival following tail shortening. This observation supports the second assumption of a differential cost of a signal. One mechanism imposing differential costs on sexually signaling barn swallows is foraging. Males with elongated tails captured smaller, less profitable Diptera, whereas males with shortened tails captured large, profitable prey items. The conditions for reliable sexual signaling by the tail ornament of male barn swallows are thus fulfilled. PMID- 28568404 TI - EVOLUTION OF INCOMPATIBILITY-INDUCING MICROBES AND THEIR HOSTS. AB - In many insect species, males infected with microbes related to Wolbachia pipientis are "incompatible" with uninfected females. Crosses between infected males and uninfected females produce significantly fewer adult progeny than the other three possible crosses. The incompatibility-inducing microbes are usually maternally transmitted. Thus, incompatibility tends to confer a reproductive advantage on infected females in polymorphic populations, allowing these infections to spread. This paper analyzes selection on parasite and host genes that affect such incompatibility systems. Selection among parasite variants does not act directly on the level of incompatibility with uninfected females. In fact, selection favors rare parasite variants that increase the production of infected progeny by infected mothers, even if these variants reduce incompatibility with uninfected females. However, productivity-reducing parasites that cause partial incompatibility with hosts harboring alternative variants can be favored once they become sufficiently abundant locally. Thus, they may spread spatially by a process analogous to the spread of underdominant chromosome rearrangements. The dynamics of modifier alleles in the host are more difficult to predict, because such alleles will occur in both infected and uninfected individuals. Nevertheless, the relative fecundity of infected females compared to uninfected females, the efficiency of maternal transmission and the mutual compatibility of infected individuals all tend to increase under within population selection on both host and parasite genes. In addition, selection on host genes favors increased compatibility between infected males and uninfected females. Although vertical transmission tends to harmonize host and parasite evolution, competition among parasite variants will tend to maintain incompatibility. PMID- 28568405 TI - A COMPARISON OF TWO STICKLEBACKS. AB - We present results of an experiment designed to address fundamental issues in the ecology and evolution of plastic trophic morphology: (1) Is observed plasticity adaptive? (2) How much interspecific morphological variation is the result of plasticity? (3) Have different selective regimes resulted in the evolution of different degrees of plasticity? (4) Is genetic variation for phenotypic plasticity present in contemporary populations? We raised fish from two recently diverged species of freshwater threespine sticklebacks on two different diets representative of the natural prey of the two species. Both species exhibited morphological plasticity in an adaptive direction: each species more closely resembled the other when raised on the latter's diet. Dietreversal reduced the natural morphological gap between these two species, -1% to 58%, depending on the trait. One species is known to have a more variable diet in the wild than the other species, and we found that it also exhibited the greater amount of morphological plasticity. Given that the two species have recently diverged, this result is compelling evidence that diet variability is important in the evolution of plastic trophic morphology. Finally, by using a full-sib experimental design, we demonstrated that genetic variation for morphological plasticity exists in contemporary populations, thus confirming that plasticity has evolutionary potential. PMID- 28568406 TI - VIRULENCE. AB - Why do parasites harm their hosts? Intuition suggests that parasites should evolve to be benign whenever the host is needed for transmission. Yet a growing theoretical literature offers several models to explain why natural selection may favor virulent parasites over avirulent ones. This perspective first organizes these models into a simple framework and then evaluates the empirical evidence for and against the models. There is relatively scant evidence to support any of the models rigorously, and indeed, there are only a few unequivocal observations of virulence actually evolving in parasite populations. These shortcomings are surmountable, however, and empirical models of host-parasite interactions have been developed for many kinds of pathogens so that the relevant data could be acquired in the near future. PMID- 28568407 TI - THE DISTRIBUTION AND ORIGIN OF GENES FOR RACE-SPECIFIC RESISTANCE TO MELAMPSORA LINI IN LINUM MARGINALE. AB - The genetic basis of resistance in wild flax (Linum marginale) to its host specific pathogen Melampsora lini was investigated in seven lines collected from a single population growing at Kiandra, New South Wales and in an additional ten lines collected more widely across southeastern Australia. All lines showed different phenotypic patterns of resistance and susceptibility. Genetic analyses indicated the presence of single dominant genes for race-specific resistance in all but one of these lines. That particular line appeared to carry two linked dominant genes for resistance. Intercrosses between lines in each of these groups of L. marginale detected substantially more linkage between the resistance genes in the Kiandra population sample than between those in the broader geographic collection. This result is interpreted to indicate a possible mechanism whereby resistance genes are generated in natural populations. PMID- 28568408 TI - POLYMORPHISM OF BACTERIAL RESTRICTION-MODIFICATION SYSTEMS: THE ADVANTAGE OF DIVERSITY. AB - Bacterial restriction-modification systems provide defense against foreign DNA by using a self versus nonself recognition mechanism. A great diversity of recognition motifs is maintained in natural populations. Circumstantial evidence suggests that defense against bacteriophage viruses favors this diversity. (1) Bacterial restriction enzymes can destroy invading phage DNA. (2) Phage DNA can mimic the host's self-recognition mechanism. The ability of the virus to pose as a mimic favors diversification of the host's recognition motif. Other observations suggest that restriction modification (RM) does not provide any significant defensive advantages in mature communities. PMID- 28568409 TI - PHYLOGENETIC ANALYSIS OF THE EVOLUTION OF ALTERNATIVE SOCIAL BEHAVIOR IN THE MANAKINS (AVES: PIPRIDAE). AB - Phylogenetic analyses of lekking, lek spatial organization, and cooperative and coordinated lek display in the manakins (Aves: Pipridae) demonstrate that variation in social behavior in the group has a strong, phylogenetic component. Two of the three classes of social behavior examined also show significant phylogenetic constraints. Current adaptive plasticity models are insufficient to explain the phylogenetic variation in these behaviors in the manakins. These findings support the conclusion that vertebrate reproductive social behavior has an evolutionary history, and that it is not determined solely by adaptive individual plasticity to current conditions. The evolution of social behavior, particularly through sexual selection, can have historical consequences that can limit subsequent behavioral adaptation. PMID- 28568410 TI - MODELING BRAIN EVOLUTION FROM BEHAVIOR: A PERMUTATIONAL REGRESSION APPROACH. AB - This paper has two complementary purposes: first, to present a method to perform multiple regression on distance matrices, with permutation testing appropriate for path-length matrices representing evolutionary trees, and then, to apply this method to study the joint evolution of brain, behavior and other characteristics in marsupials. To understand the computation method, consider that the dependent matrix is unfolded as a vector y; similarly, consider X to be a table containing the independent matrices, also unfolded as vectors. A multiple regression is computed to express y as a function of X. The parameters of this regression (R2 and partial regression coefficients) are tested by permutations, as follows. When the dependent matrix variable y represents a simple distance or similarity matrix, permutations are performed in the same manner as the Mantel permutational test. When it is an ultrametric matrix representing a dendrogram, we use the double-permutation method (Lapointe and Legendre 1990, 1991). When it is a path length matrix representing an additive tree (cladogram), we use the triple permutation method (Lapointe and Legendre 1992). The independent matrix variables in X are kept fixed with respect to one another during the permutations. Selection of predictors can be accomplished by forward selection, backward elimination, or a stepwise procedure. A phylogenetic tree, derived from marsupial brain morphology data (28 species), is compared to trees depicting the evolution of diet, sociability, locomotion, and habitat in these animals, as well as their taxonomy and geographical relationships. A model is derived in which brain evolution can be predicted from taxonomy, diet, sociability and locomotion (R2 = 0.75). A new tree, derived from the "predicted" data, shows a lot of similarity to the brain evolution tree. The meaning of the taxonomy, diet, sociability, and locomotion predictors are discussed and conclusions are drawn about the evolution of brain and behavior in marsupials. PMID- 28568411 TI - DEVELOPMENTAL NOISE, PHENOTYPIC PLASTICITY, AND ALLOZYME HETEROZYGOSITY IN DAPHNIA. AB - Previous theories and studies have postulated negative correlations between allozyme heterozygosity and developmental noise and between heterozygosity and phenotypic plasticity. We examined these relationships for morphological and life history traits of Daphnia magna in four independent experiments using two different Moscow populations and one German population. Clones were raised under a range of food levels or individual densities. Heterozygosity was scored at five allozyme loci in two experiments and at three loci in two others. Relative differences in developmental noise among clones with different heterozygosity levels were estimated as the pooled residual variation from an analysis of variation that removed the effects of macroenvironment, clones, and their interaction. Plasticity was measured as the amount of macroenvironmental variation plus genotype-by-environment interaction variation. We found a positive correlation between developmental noise and heterozygosity, although this correlation varied among traits and experiments. This result contradicts most previous claims about these relationships. In contrast, we found that phenotypic plasticity and heterozygosity were negatively correlated for some traits. Developmental noise and phenotypic plasticity were correlated for only two traits in two different experiments. This trait-specific relationship is in concordance with previous studies. Our results could not be explained by effects of developmental time, a previously hypothesized mechanism. We propose several explanations for our results and the disparate results of others that do not require that heterozygosity be the actual cause of variation in developmental noise. PMID- 28568412 TI - THE EVOLUTION OF CARBON ALLOCATION TO PLANT SECONDARY METABOLITES: A GENETIC ANALYSIS OF COST IN DIPLACUS AURANTIACUS. AB - Diplacus aurantiacus contains large amounts of a leaf phenolic resin, an important deterrent to a leaf-eating caterpillar, Euphydryas chalcedona. The resin can also retard water loss during drought. Furthermore, the leaf resin content differs among plants and populations. This study investigates the existence of heritable variation (h2 ) in resin production and tests for a genetic correlation (rG ) between carbon allocation to secondary metabolites and growth rate, as well as with three other vegetative traits. Nine dam and 10 sire plants were chosen randomly at a field site and used to generate 78 full-sib families (19 half-sib families) by crossing all males to all females in a factorial design. Heritability was estimated in two ways, and genetic correlations were estimated by three methods. We found: (1) the heritability of resin production estimated by the regression of offspring on sires was significantly greater than zero (hs2=0.32, P<0.01); (2) the maternal variance in resin content was significantly greater than zero (21.3% of total phenotypic variance); (3) significant negative genetic correlation between resin content and growth rate was observed from two of three methods and was consistent with the phenotypic correlation; and (4) the cost of resin could be assessed quantitatively. The genetic cost of 1 mg in resin is equivalent to 25 mg of dry shoot-biomass growth, but the phenotypic cost is only 2.1 mg. This study indicates that carbon allocation to these secondary metabolites may respond to natural selection, and the phenotypic cost of resin production has a genetic basis in D. aurantiacus. This trade-off suggests that once selection occurs, increased phenolic resin production may result in decreased growth, or vice versa. PMID- 28568413 TI - RISK OF POPULATION EXTINCTION FROM FIXATION OF NEW DELETERIOUS MUTATIONS. AB - The fixation of new deleterious mutations is analyzed for a randomly mating population of constant size with no environmental or demographic stochasticity. Mildly deleterious mutations are far more important in causing loss of fitness and eventual extinction than are lethal and semilethal mutations in populations with effective sizes, Ne , larger than a few individuals. If all mildly deleterious mutations have the same selection coefficient, s against heterozygotes and 2s against homozygotes, the mean time to extinction, t-, is asymptotically proportional to e4Nes/Ne for 4Ne s > 1. Nearly neutral mutations pose the greatest risk of extinction for stable populations, because the magnitude of selection coefficient that minimizes t- is about s = 0.4/Ne . The influence of variance in selection coefficients among mutations is analyzed assuming a gamma distribution of s, with mean s- and variance sigmas2. The mean time to extinction increases with variance in selection coefficients if s- is near s, but can decrease greatly if s- is much larger than s. For a given coefficient of variation of s, c=sigmas/s-, the mean time to extinction is asymptotically proportional to Ne1+1/c2 for 4Nes->1. When s is exponentially distributed, (c = 1) t- is asymptotically proportional to Ne2. These results in conjunction with data on the rate and magnitude of mildly deleterious mutations in Drosophila melanogaster indicate that even moderately large populations, with effective sizes on the order of Ne = 103 , may incur a substantial risk of extinction from the fixation of new mutations. PMID- 28568414 TI - GENOTYPE-BY-ENVIRONMENT INTERACTIONS FOR FITNESS OF ERIGERON ANNUUS SHOW FINE SCALE SELECTIVE HETEROGENEITY. AB - The results of natural selection depend critically on whether variation in fitness is finegrained or coarse-grained with respect to dispersal, but little is known of the spatial scale of fitness variation in natural populations. For most evolutionary questions, environmental heterogeneity must be defined by reversals in the relative fitness of genotypes; absolute fitness may vary, but if genotypes respond in parallel then selection is uniform. Thus, measurements of genotype-by environment (G * E) interactions for fitness are necessary to understand patterns of variation in natural selection. PMID- 28568415 TI - EVIDENCE THAT THE MAGNITUDE OF THE TRADE-OFF IN A DICHOTOMOUS TRAIT IS FREQUENCY DEPENDENT. AB - Many traits, such as wing dimorphism, paedomorphosis, and cyclomorphosis vary dichotomously. Such dimorphisms are maintained in part because of a trade-off between components of fitness: for example, in insects, the flightless morph cannot migrate but has a greater fecundity than the flight-capable morph. Several recent theoretical studies have analyzed the evolution of dichotomous traits, assuming that each morph can be characterized by a discrete syndrome of characters. Consideration of the genetic basis of dimorphism suggests that this assumption is incorrect. In this paper, I report a test of this assumption using the wing-dimorphic sand cricket, Gryllus firmus. It is predicted that, rather than remaining constant, the fecundity of macropterous (long-winged, flight capable) females will decrease as the proportion of macropterous females in the population or family increases. This prediction is supported by fecundity data from lines selected for high and low proportions of macroptery and by sib analysis. Thus, models that seek to predict the evolution of dichotomous traits should take into account the likelihood that values of components of fitness, such as fecundity, may be related to their frequencies in the population. PMID- 28568416 TI - A QUANTITATIVE-GENETIC MODEL FOR SELECTION ON DEVELOPMENTAL NOISE. AB - We propose a simple model for analyzing the effects of microenvironmental variation in quantitative genetics. Our model assumes that the sensitivity of the phenotype to fluctuations in microenvironment has a genetic basis and allows for genetic correlation between trait value and microenvironmental sensitivity. We analyze the effects of short-term stabilizing and directional selection on the genotypic and microenvironmental components of phenotypic variance. Our model predicts that stabilizing selection on a quantitative trait increases developmental canalization. We show that stabilizing selection can result in an increase in the heritability. Our findings may provide an explanation for the results of selection experiments in which artificial stabilizing selection did not change the heritability coefficient or increased it. PMID- 28568417 TI - GENETIC STRUCTURE AND DIVERSITY WITHIN LOCAL POPULATIONS OF BACILLUS MYCOIDES. AB - Sixty strains of Bacillus mycoides were isolated from each of two sites and characterized by their responses to standard metabolic tests used in bacterial taxonomy, by multilocus enzyme electrophoresis (MLEE), and by restriction fragment-length polymorphism (RFLP) analysis of Southern blots probed with both a conserved DNA fragment derived from a Salmonella typhimurium ribosomal cistron and with two cosmid probes derived from B. mycoides ATCC strain 6463. Both MLEE and RFLP analyses indicated that the collection contained two genetically distinct sets of strains (I and II); one of these sets was further differentiated genetically by the same analyses (IIA and IIB). Standard taxonomic analysis did not distinguish these sets of strains; biochemical test profiles were similar for all isolates. The genetic distance between groups I and II is as great as that observed for recognized species of bacteria. It is proposed that these groups are sibling species having a common evolutionary descent and that their metabolic phenotype has been conserved, whereas their DNA and protein sequences have diverged. No strong evidence of geographic differentiation between strains from the two sites appeared in either genetic or phenetic characters. PMID- 28568418 TI - EFFECTS OF MATERNAL AND PATERNAL ENVIRONMENT AND GENOTYPE ON OFFSPRING PHENOTYPE IN SOLIDAGO ALTISSIMA L. AB - To predict the possible evolutionary response of a plant species to a new environment, it is necessary to separate genetic from environmental sources of phenotypic variation. In a case study of the invader Solidago altissima, the influences of several kinds of parental effects and of direct inheritance and environment on offspring phenotype were separated. Fifteen genotypes were crossed in three 5 * 5 diallels excluding selfs. Clonal replicates of the parental genotypes were grown in two environments such that each diallel could be made with maternal/paternal plants from sand/sand, sand/soil, soil/sand, and soil/soil. In a first experiment (1989) offspring were raised in the experimental garden and in a second experiment (1990) in the glasshouse. Parent plants growing in sand invested less biomass in inflorescences but produced larger seeds than parent plants growing in soil. In the garden experiment, phenotypic variation among offspring was greatly influenced by environmental heterogeneity. Direct genetic variation (within diallels) was found only for leaf characters and total leaf mass. Germination probability and early seedling mass were significantly affected by phenotypic differences among maternal plants because of genotype (genetic maternal effects) and soil environment (general environmental maternal effects). Seeds from maternal plants in sand germinated better and produced bigger seedlings than seeds from maternal plants in soil. They also grew taller with time, probably because competition accentuated the initial differences. Height growth and stem mass at harvest (an integrated account of individual growth history) of offspring varied significantly among crosses within parental combinations (specific environmental maternal effects). In the glasshouse experiment, the influence of environmental heterogeneity and competition could be kept low. Except for early characters, the influence of direct genetic variation was large but again leaf characters (= basic module morphology) seemed to be under stricter genetic control than did size characters. Genetic maternal effects, general environmental maternal effects, and specific environmental maternal effects dominated in early characters. The maternal effects were exerted both via seed mass and directly on characters of young offspring. Persistent effects of the general paternal environment (general environmental paternal effects) were found for leaf length and stem and leaf mass at harvest. They were opposite in direction to the general environmental maternal effects, that is the same genotypes produced "better mothers" in sand but "better fathers" in soil. The general environmental paternal effects must have been due to differences in pollen quality, resulting from pollen selection within the male parent or leading to pre- or postzygotic selection within the female parent. The ranking of crosses according to mean offspring phenotypes was different in the two experiments, suggesting strong interaction of the observed effects with the environment. The correlation structure among characters changed less between experiments than did the pattern of variation of single characters, but under the competitive conditions in the garden plant height seemed to be more directly related to fitness than in the glasshouse. Reduced competition could also explain why maternal effects were less persistent in the glasshouse than in the garden experiment. Evolution via selection of maternal effects would be possible in the study population because these effects are in part due to genetic differences among parents. PMID- 28568419 TI - SPECIATION BY REINFORCEMENT OF PREMATING ISOLATION. AB - The generation of premating isolation given partial or complete postzygotic isolation between populations is termed reinforcement or, in the case of complete isolation, reproductive character displacement. In this study we use computer simulations and a multilocus genetic model to reevaluate the theory of reinforcement. We consider the evolution of female preferences for a male secondary sexual trait. If the populations differ in mean female preference, there is direct selection on the preference for further divergence, which may be augmented by a correlated response to sexual selection on males. Two factors prevent divergence. First, if postzygotic isolation is not complete, gene flow can prevent divergence and lead to a hybrid swarm. This is the usual outcome whenever the average number of breeding adult offspring produced by a hybrid mating is sufficient to replace the parents. Second, one or the other population may become extinct because of the large number of hybrid matings it is involved in. The likelihood of extinction is lowered if population growth rates are high, if hybrids are inviable rather than infertile, or under some conditions when allopatric populations provide immigrants into the contact zone. Provided hybrid fitness is sufficiently low, there is a wide range of genetic and ecological conditions under which reinforcement rather easily occurs, and also a range under which it may occur because of stochastic effects on both the inheritance parameters and the population sizes. PMID- 28568420 TI - THE EVOLUTION OF DISTYLY: POLLEN TRANSFER IN ARTIFICIAL FLOWERS. AB - A recent model by Lloyd and Webb derives conditions necessary for the evolution of distyly based on pollen-transfer probabilities between ancestral morphs and invading mutants. We used bumblebees visiting artificial flowers to measure the parameters of the model. Our findings supported the first evolutionary step proposed by the model, establishment of a stigma-height polymorphism. Conditions for the subsequent establishment of an anther-height polymorphism were not satisfied by pollen-transfer patterns alone. Because conditions for the first step are considered more onerous, however, and because the second stage depends on inbreeding depression as well as pollen-transfer patterns, we interpret our results as supporting the plausibility of the Lloyd-Webb model. Video images of bees visiting glass-sided artificial flowers demonstrate a mechanism for disassortative pollination between the ancestral and mutant morph. In general, pollen-transfer probabilities were negatively correlated with the height difference between anthers of the donor and stigma of the recipient. Style length affects bee feeding posture in such a way that disassortative pollination could feasibly occur in the absence of an anther-height polymorphism. PMID- 28568421 TI - THE EFFECT OF ENVIRONMENTAL VARIABILITY ON THE HERITABILITIES OF TRAITS OF A FIELD CRICKET. AB - The presence of heritable variation in traits is a prerequisite for evolution. The great majority of heritability (h2 ) estimates are performed under laboratory conditions that are characterized by low levels of environmental variability. Very little is known about the effect of environmental variability on the estimation of components of quantitative variation, although theoretical extrapolations from lab studies have been attempted. Here we investigate the effects of environmental heterogeneity on variance component estimation using full-sib families of Gryllus pennsylvanicus split between a homogeneous laboratory environment and a more variable field environment. Although large standard errors prevent demonstration of statistically significant differences among h2 of traits measured in the two environments for all but one trait, the values of h2 are, on average, lower in the variable field environment, with a mean reduction of 19%. Developmental time is an exception, exhibiting high levels of additive variance in the field, leading to a higher value of h2 in the variable environment. Underlying the lower field h2 estimates are greater components of environmental variance as expected, as well as lower components of genetic variance. In this study, there is no evidence that the increase in the environmental component of variance in the field is any more important in the reduction of h2 than is the decrease in the additive genetic component. The implications of the relative changes in the two components of variance are discussed. PMID- 28568422 TI - FEMALE-BIASED SEX RATIOS IN A FACULTATIVELY SOCIAL BEE AND THEIR IMPLICATIONS FOR SOCIAL EVOLUTION. AB - Montane populations of the Australian allodapine bee, Exoneura bicolor, are characterized by high levels of cooperative nesting and strongly female-biased sex ratios. A conspecific population from heathland shows much lower levels of cooperative nesting and lower levels of female bias. In both habitats, sex-ratio bias is greatest in the smallest brood sizes and becomes successively less biased in larger broods. Parity is approached in the largest heathland colonies, but not for any brood-size category in montane areas. Adult intracolony relatedness is moderately high for colonies in both reused and newly founded nests in the montane habitat, but probably low or zero for newly founded nests in heathland. Colony efficiency, measured as the number of brood per adult, increases with colony size in both habitats, suggesting that cooperation between females increases mean female fitness. It is argued that patterns of sex allocation are consistent with nonlinear fitness-return models, in which the mean reproductive value of daughters increases with the number of daughters produced in a brood. Such increases probably arise from a number of social interactions, including cooperative brood defense, increased task efficiency, and lower per capita costs in nest construction. The term "local fitness enhancement" is introduced here to describe these effects collectively. The female-biased ratios should lower selective thresholds for sib-directed altruism, at least in the earlier stages of colony development. It is argued that local fitness enhancement facilitates eusociality in allodapine bees and could also play a role in other haplodiploid taxa, provided cooperative nesting largely involves sisters, colony efficiency increases with colony size, and optimal colony sizes are only achieved after two or more generations after founding. PMID- 28568423 TI - THE EFFECTS OF HOST GENOTYPE AND SPATIAL DISTRIBUTION ON TREMATODE PARASITISM IN A BIVALVE POPULATION. AB - A basic assumption underlying models of host-parasite coevolution is the existence of additive genetic variation among hosts for resistance to parasites. However, estimates of additive genetic variation are lacking for natural populations of invertebrates. Testing this assumption is especially important in view of current models that suggest parasites may be responsible for the evolution of sex, such as the Red Queen hypothesis. This hypothesis suggests that the twofold reproductive disadvantage of sex relative to parthenogenesis can be overcome by the more rapid production of rare genotypes resistant to parasites. Here I present evidence of significant levels of additive genetic variance in parasite resistance for an invertebrate host-parasite system in nature. Using families of the bivalve mollusc, Transennella tantilla, cultured in the laboratory, then exposed to parasites in the field, I quantified heritable variation in parasite resistance under natural conditions. The spatial distribution of outplanted hosts was also varied to determine environmental contributions to levels of parasite infection and to estimate potential interactions of host genotype with environment. The results show moderate but significant levels of heritability for resistance to parasites (h2 = 0.36). The spatial distribution of hosts also significantly influenced parasite prevalence such that increased host aggregation resulted in decreased levels of parasite infection. Family mean correlations across environments were positive, indicating no genotype-environment interaction. Therefore, these results provide support for important assumptions underlying coevolutionary models of host-parasite systems. PMID- 28568424 TI - ON THE MEASUREMENT OF INBREEDING DEPRESSION. PMID- 28568425 TI - FITNESS SENSITIVITY AND THE CANALIZATION OF LIFE-HISTORY TRAITS. AB - Canalization is an abstract term that describes unknown developmental mechanisms that reduce phenotypic variation. A trait can be canalized against environmental perturbations (e.g., changes in temperature or nutrient quality), or genetic perturbations (e.g., mutations or recombination); this paper is about genetic canalization. Stabilizing selection should improve the canalization of traits, and the degree of canalization should be positively correlated with the traits' impact on fitness. Experiments testing this idea should measure the canalization of a series of traits whose impact on fitness is known or can be inferred, exclude differences among traits in the number of loci and alleles segregating as an explanation for the pattern of variability found, and distinguish between canalization against genetic and environmental variation. These conditions were met by three experiments within which the variation of fitness components among Drosophila melanogaster lines was measured and among which the genetic contribution to the variation among lines was clearly different. The canalization of the traits increased with their impact on fitness and did not depend on the degree of genetic differences among lines. That the flies used had been transformed by a P-element insert suggests that canalization was also effective against novel genetic variation. The results reported here cannot be explained by the classical hypothesis of reduction in the number of loci segregating for traits with greater impact on fitness and confirm that traits with greater impact on fitness are more strongly canalized. This pattern of canalization reveals an underappreciated role for development in microevolution. There is differential genetic canalization of fitness components in D. melanogaster. PMID- 28568426 TI - POLLEN DISCOUNTING AND THE SPREAD OF A SELFING VARIANT IN TRISTYLOUS EICHHORNIA PANICULATA: EVIDENCE FROM EXPERIMENTAL POPULATIONS. AB - Floral traits that increase self-fertilization are expected to spread unless countered by the effects of inbreeding depression, pollen discounting (reduced outcross pollen success by individuals with increased rates of self fertilization), or both. Few studies have attempted to measure pollen discounting because to do so requires estimating the male outcrossing success of plants that differ in selfing rate. In natural populations of tristylous Eichhornia paniculata, selfing variants of the mid-styled morph are usually absent from populations containing all three style morphs but often predominate in nontrimorphic populations. We used experimental garden populations of genetically marked plants to investigate whether the effects of population morph structure on relative gamete transmission by unmodified (M) and selfing variants (M') of the mid-styled morph could explain their observed distribution. Transmission through ovules and self and outcross pollen by plants of the M and M' morphs were compared under trimorphic, dimorphic (S morph absent), and monomorphic (L and S morphs absent) population structures. Neither population structure nor floral morphology affected female reproductive success, but both had strong effects on the relative transmission of male gametes. The frequency of self-fertilization in the M' morph was consistently higher than that of the M morph under all morph structures, and the frequency of self-fertilization by both morphs increased as morph diversity of experimental populations declined. In trimorphic populations, total transmission by the M and M' morphs did not differ. The small, nonsignificant increase in selfing by the M' relative to the M morph was balanced by decreased outcross siring success, particularly on the S morph. In populations lacking the S morph, male gamete transmission by the M' morph was approximately 1.5 times greater than that by the M morph because of both increased selfing and increased success through outcross pollen donation. Therefore, gamete transmission strongly favored the M' morph only in the absence of the S morph, a result consistent with the distribution of the M' morph in nature. This study indicates that floral traits that alter the selfing rate can have large and context-dependent influences on outcross pollen donation. PMID- 28568428 TI - EVOLUTION OF TEMPERATE FRUIT/BIRD INTERACTIONS: PHENOLOGICAL STRATEGIES. PMID- 28568427 TI - Left ventricular ejection fraction of < 20%: Too bad for MitraClip(c) ? AB - OBJECTIVES: This study sought to investigate whether the percutaneous mitral regurgitation (MR) reduction with the MitraClip(r) system in end-stage heart failure patients with a left ventricular ejection fraction (LVEF) of <20% also effects beneficial outcome or whether the underlying myogenic problem is leading and therefore of prognostic relevance. BACKROUND: The interventional treatment of functional mitral regurgitation (FMR) with the MitraClip(r) system could improve the clinical and hemodynamic outcome in patients with severely impaired left ventricular function. MATERIALS AND METHODS: Between 2011 and 2016, a total of 147 patients with FMR were treated with MitraClip(r) at our institution. The cohort was divided into two groups: LVEF >= 20% (N = 126) and <20% (N = 21). Follow-up assessments included exercise capacity, 6-min walk test, probrain natriuretic peptide-measurement (ProBNP), echocardiography and right heart catheterization. Only three patients with an LVEF >= 20% and one patient with an LVEF < 20% were lost for follow-up. RESULTS: In the vast majority of patients, a reduction from severe to mild MR was demonstrated with no difference between both groups (P = 0.422). At follow-up, both subgroups experienced similar improvements in exercise capacity and hemodynamics. Patients with an LVEF < 20% were on average 5.8 years younger, while mortality rates were comparable in both groups (P = 0.760). CONCLUSION: By careful selection, even patients in the end stage of advanced LV dysfunction as the result of the underlying myogenic problem and the additional harmful effects of the high volume loading due to the FMR can exhibit significant clinical and hemodynamic improvement after MitraClip(c) therapy. PMID- 28568429 TI - GENETIC VARIATION AND HOST PLANT RELATIONS IN A PARTHENOGENETIC MOTH. PMID- 28568430 TI - ELEVATIONAL GRADIENTS IN ADULT SEX RATIOS AND SEXUAL DIFFERENTIATION IN VEGETATIVE GROWTH RATES OF POPULUS TREMULOIDES MICHX. PMID- 28568431 TI - GENETIC DIVERSITY AND ENVIRONMENTAL ASSOCIATIONS OF WILD BARLEY, HORDEUM SPONTANEUM, IN ISRAEL. PMID- 28568432 TI - EVOLUTION OF COLOR PATTERN AND PUBESCENCE CHARACTERISTICS IN MALE BUMBLEBEES: AUTOMIMICRY VS. THERMOREGULATION. PMID- 28568433 TI - SELECTION FOR SEROTINY IN LODGEPOLE PINE: MATHEMATICAL ANALYSIS OF THE MODEL OF PERRY AND LOTAN. PMID- 28568434 TI - TESTS OF COMMUNITY-WIDE CHARACTER DISPLACEMENT AGAINST NULL HYPOTHESES. PMID- 28568435 TI - CHARACTER VARIABILITY AND EVOLUTIONARY RATE IN MENIDIA. PMID- 28568436 TI - MONOTERPENE VARIATION IN PONDEROSA PINE XYLEM RESIN RELATED TO WESTERN PINE BEETLE PREDATION. PMID- 28568437 TI - NATURAL SELECTION RESISTING INBREEDING DEPRESSION IN CAPTIVE WILD HOUSEMICE (MUS MUSCULUS). PMID- 28568438 TI - EVIDENCE FOR ECOLOGICAL CHARACTER DISPLACEMENT IN WESTERN AMERICAN CATOSTOMID FISHES. PMID- 28568439 TI - EVOLUTION OF PAEDOMORPHOSIS IN SALAMANDERS OF THE GENUS GYRINOPHILUS. PMID- 28568440 TI - RAPID HOST RANGE EVOLUTION IN A POPULATION OF THE PHYTOPHAGOUS MITE TETRANYCHUS URTICAE KOCH. PMID- 28568441 TI - HETEROSIS AND INTERCLONAL VARIATION IN THERMAL TOLERANCE IN UNISEXUAL FISHES. PMID- 28568442 TI - HYBRID ZONES IN THOMOMYS BOTTAE POCKET GOPHERS: GENETIC, PHENETIC, AND ECOLOGIC CONCORDANCE PATTERNS. PMID- 28568443 TI - ECTOTHERMY AND THE SUCCESS OF DINOSAURS. PMID- 28568444 TI - CHANGE IN EDITORIAL POLICY. PMID- 28568446 TI - EVOLUTION IN PERIPHERAL ISOLATED POPULATIONS: CARPODACUS FINCHES ON THE CALIFORNIA ISLANDS. PMID- 28568445 TI - SEXUAL DIMORPHISM IN BRACHIONUS PLICATILIS (ROTIFERA): EVOLUTIONARY AND ADAPTIVE SIGNIFICANCE. PMID- 28568447 TI - A MODEL OF FIRE SELECTION FOR SEROTINY IN LODGEPOLE PINE. PMID- 28568448 TI - GENETIC VARIANCE, FITNESS, AND HOMEOSTASIS IN VARYING ENVIRONMENTS: AN EXPERIMENTAL CHECK OF THE THEORY. PMID- 28568449 TI - DOES ASYMMETRICAL MATING PREFERENCE SHOW THE DIRECTION OF EVOLUTION? PMID- 28568451 TI - ANNOUNCEMENT OF THE THEODOSIUS DOBZHANSKY PRIZE. PMID- 28568450 TI - INTRASPECIFIC LITTER SIZE VARIATION IN MICROTUS CALIFORNICUS II. VARIATION BETWEEN POPULATIONS. PMID- 28568452 TI - DETERMINATION OF THE TIME OF DAY AT WHICH DIURNAL MOTHS PAINTED TO RESEMBLE BUTTERFLIES ARE ATTACKED BY BIRDS. PMID- 28568453 TI - CLOSELY LINKED ALPHA-CHAIN HEMOGLOBIN LOCI IN PEROMYSCUS AND OTHER ANIMALS: SPECULATIONS ON THE EVOLUTION OF DUPLICATE LOCI. PMID- 28568454 TI - CONSIDERATION OF MULLER'S RATCHET MECHANISM THROUGH STUDIES OF GENETIC LINKAGE AND GENOMIC COMPATIBILITIES IN CLONALLY REPRODUCING POECILIOPSIS. PMID- 28568455 TI - BELTSVILLE SYMPOSIUM IN AGRICULTURAL RESEARCH VI. PMID- 28568456 TI - EVOLUTION OF MATING PREFERENCES. PMID- 28568457 TI - ROLE OF POLLINATORS IN THE EVOLUTION OF DIOECY FROM DISTYLY. PMID- 28568458 TI - GENETIC VARIATION AND POPULATION DIFFERENTIATION IN THE RHYTIDOPONERA IMPRESSA GROUP, A SPECIES COMPLEX OF PONERINE ANTS (HYMENOPTERA: FORMICIDAE). PMID- 28568459 TI - EVOLUTIONARY MONOGRAPHS. PMID- 28568460 TI - CORRELATIONS OF ALLOZYMIC VARIATION WITH HABITAT PARAMETERS USING THE GRASS SHRIMP, PALAEMONETES PUGIO. PMID- 28568461 TI - GENETIC COMPONENTS OF SIZE AND SHAPE. I. DYNAMICS OF COMPONENTS OF PHENOTYPIC VARIABILITY AND COVARIABILITY DURING ONTOGENY IN THE LABORATORY RAT. PMID- 28568462 TI - POPULATION BIOLOGY OF CHAMAELIRIUM LUTEUM, A DIOECIOUS LILY. I. SPATIAL DISTRIBUTIONS OF MALES AND FEMALES. PMID- 28568463 TI - THE ROLE OF VENOM DELIVERY STRATEGIES IN SNAKE EVOLUTION. PMID- 28568464 TI - POLYMORPHISM FOR BREEDING COLORS IN GASTEROSTEUS ACULEATUS II. REPRODUCTIVE SUCCESS AS A RESULT OF CONVERGENCE FOR THREAT DISPLAY. PMID- 28568465 TI - EXPERIMENTAL CONFIRMATION OF HERITABLE MORPHOLOGICAL VARIATION IN A NATURAL POPULATION OF SONG SPARROWS. PMID- 28568467 TI - GEOLOGIC FACTORS AND THE EVOLUTION OF PLANTS. PMID- 28568466 TI - NON-LINEAR MACROMOLECULAR EVOLUTION AND THE MOLECULAR CLOCK. PMID- 28568468 TI - Society for the Study of Evolution and American Society of Naturalists. PMID- 28568469 TI - r- AND K-SELECTION IN DROSOPHILA PSEUDOOBSCURA. PMID- 28568470 TI - GENETIC VARIATION AND DIFFERENTIATION IN SCANDINAVIAN MOOSE (ALCES ALCES): ARE LARGE MAMMALS MONOMORPHIC? PMID- 28568471 TI - SEED PRODUCTION AND POLLEN VECTORS IN SEVERAL NECTARLESS PLANTS. PMID- 28568472 TI - BATESIAN AND MULLERIAN MIMICRY: SEMANTIC AND SUBSTANTIVE DIFFERENCES OF OPINION. PMID- 28568473 TI - Facial skin photo-aging and development of hyperpigmented spots from children to middle-aged Japanese woman. AB - BACKGROUND/PURPOSE: Facial skin hyperpigmention caused by chronic sun exposure is a major skin complaint, however, its characteristics and influential factors are still limitedly known. METHODS: A cross-sectional survey in healthy Japanese women aged from 6 to 62 years (n=169) was conducted using a facial image analyzer VISIATM for knowing onset age of hyperpigmented spot formation, its chronological changes, and influence of environmental factors. RESULTS: UV Pigmented Spot (PS) Score was positively correlated with age (R=.487, P=.000). Hyperpigmented spots appeared first around 18 years old in most subjects, and PS score remarkably increased at 20s then gradually increased by ages. The subjects with Skin Type I, one of the three grades of Japanese Skin Type (JST), whose melanin formation is genetically lower, showed higher PS score. A woman aged 31 years was subjected a weekly VISIA measurement for 2 years, and found no changes in the number, place, size and intensity of the pigment spots in this duration. CONCLUSION: Hyperpigmented spots developed in women over 20 years of age due to chronic sun exposure without sun protection during childhood and adolescent and it was stable afterwards, whose intensity was influenced by age and skin type. PMID- 28568474 TI - The biomechanical effect of tunnel placement on ACL graft forces in double-bundle ACL reconstruction - A 3D computational simulation. AB - BACKGROUND: The posterolateral (PL) graft experiences a high failure rate in anterior cruciate ligament double-bundle (DB) reconstruction. It is hypothesized that tunnel positions could dramatically affect the graft forces. METHODS: A validated computational model was used to simulate DB reconstruction with various femoral PL tunnel locations (8-11 mm center-center tunnel spacing). Graft fixation was simulated at both 0 degrees and 30 degrees . Knee biomechanics were examined with the knee under a 134 N anterior load and 400 N quadriceps load at 0 degrees , 30 degrees , 60 degrees , and 90 degrees of flexion. Graft forces, tibial translation, and tibial rotation were calculated. RESULTS: PL graft forces at full extension increased with increasing tunnel spacing under both fixation settings, but the knee kinematics was not dramatically affected. CONCLUSION: Small changes in the femoral PL tunnel position could result in large changes in graft forces, implying that precise PL tunnel position is an important factor in a successful DB reconstruction. PMID- 28568475 TI - Factors Associated With Functional Capacity in Hemodialysis Patients. AB - Hemodialysis patients have a marked decrease in functional capacity when compared to healthy individuals. We evaluated the factors associated with functional capacity in hemodialysis patients. A total of 102 hemodialysis patients were evaluated. The patients were submitted to a 6-min walk test, peripheral muscle strength tests, and an evaluation of quality of life, anxiety, and depression. The laboratory data were measured. The 6-min walk test distance correlated significantly with age, educational level, hemoglobin, creatinine, number of comorbidities, peripheral muscle strength, and some domains of SF-36 quality of life questionnaire and depression (P < 0.05). Multiple linear regression showed that educational level, hemoglobin, peripheral muscle strength, and depression significantly affected the 6-min walk test distance (P < 0.05). The multiple correlation coefficient was 0.74, and the squared multiple correlation coefficient adjusted was 0.52. In conclusion, functional capacity was significantly associated with educational level, hemoglobin, peripheral muscle strength, and depression in hemodialysis patients. PMID- 28568476 TI - Reversal of response to artificial selection on body size in a wild passerine. AB - A general assumption in quantitative genetics is the existence of an intermediate phenotype with higher mean individual fitness in the average environment than more extreme phenotypes. Here, we investigate the evolvability and presence of such a phenotype in wild bird populations from an eleven-year experiment with four years of artificial selection for long and short tarsus length, a proxy for body size. The experiment resulted in strong selection in the imposed directions. However, artificial selection was counteracted by reduced production of recruits in offspring of artificially selected parents. This resulted in weak natural selection against extreme trait values. Significant responses to artificial selection were observed at both the phenotypic and genetic level, followed by a significant return toward preexperimental means. During artificial selection, the annual observed phenotypic response closely followed the predicted response from quantitative genetic theory (ryears = 0.96, rcohorts = 0.56). The rapid return to preexperimental means was induced by three interacting mechanisms: selection for an intermediate phenotype, immigration, and recombination between selected and unselected individuals. The results of this study demonstrates the evolvability of phenotypes and that selection may favor an intermediate phenotype in wild populations. PMID- 28568477 TI - Two-Stage Residual Inclusion Estimation in Health Services Research and Health Economics. AB - OBJECTIVES: Empirical analyses in health services research and health economics often require implementation of nonlinear models whose regressors include one or more endogenous variables-regressors that are correlated with the unobserved random component of the model. In such cases, implementation of conventional regression methods that ignore endogeneity will likely produce results that are biased and not causally interpretable. Terza et al. (2008) discuss a relatively simple estimation method that avoids endogeneity bias and is applicable in a wide variety of nonlinear regression contexts. They call this method two-stage residual inclusion (2SRI). In the present paper, I offer a 2SRI how-to guide for practitioners and a step-by-step protocol that can be implemented with any of the popular statistical or econometric software packages. STUDY DESIGN: We introduce the protocol and its Stata implementation in the context of a real data example. Implementation of 2SRI for a very broad class of nonlinear models is then discussed. Additional examples are given. EMPIRICAL APPLICATION: We analyze cigarette smoking as a determinant of infant birthweight using data from Mullahy (1997). CONCLUSION: It is hoped that the discussion will serve as a practical guide to implementation of the 2SRI protocol for applied researchers. PMID- 28568478 TI - Behavioural changes in patients with intellectual disability treated with perampanel. AB - OBJECTIVES: The aim of this cross-sectional retrospective study was to assess the tolerability and efficacy of perampanel in patients with drug-resistant epilepsy who also suffered from intellectual disability (ID). PATIENTS AND METHODS: We used an industry-independent, non-interventional retrospective evaluation based on standardized, daily seizure records. Twenty-seven patients with ID and drug resistant epilepsy were started on perampanel between September 2012 and November 2015 after a 3-month observation period without perampanel treatment. Perampanel was given at a maximum dosage of 4-12 mg daily. Evaluation was carried out after 6, 12 and 24 months, including calculation of the retention rate. Mean seizure frequency was compared between the 3-month baseline period and subsequent 3-month treatment periods. The Clinical Global Impression scale was applied to assess qualitative changes in seizure severity, and the Aggressive Behaviour Scale (ABS) gave further insights into challenging behaviour. RESULTS: Perampanel was efficacious and well tolerated in five of 25 patients. In 18 patients, perampanel treatment was stopped, mainly because of adverse events (n=6), lack of efficacy (n=3) or both (n=9). Behavioural changes were documented in 15 of 27 patients, with aggressive behaviour being the commonest effect; we observed ataxia (n=6) and sedation (n=8) in further patients. The ABS showed worsening of aggressive behaviour in six patients. CONCLUSIONS: Perampanel was well tolerated and efficacious in one-fifth of our patients. We observed challenging behaviour, ataxia and sedation in a relevant number of patients with ID under perampanel treatment. Further studies are warranted to explore the tolerability of perampanel in patients with ID. PMID- 28568479 TI - Erratum. PMID- 28568480 TI - Identifying influential individuals on intensive care units: using cluster analysis to explore culture. AB - AIM: The objective of this paper is to identify attribute patterns of influential individuals in intensive care units using unsupervised cluster analysis. BACKGROUND: Despite the acknowledgement that culture of an organisation is critical to improving patient safety, specific methods to shift culture have not been explicitly identified. METHODS: A social network analysis survey was conducted and an unsupervised cluster analysis was used. RESULTS: A total of 100 surveys were gathered. Unsupervised cluster analysis was used to group individuals with similar dimensions highlighting three general genres of influencers: well-rounded, knowledge and relational. CONCLUSIONS: Culture is created locally by individual influencers. Cluster analysis is an effective way to identify common characteristics among members of an intensive care unit team that are noted as highly influential by their peers. To change culture, identifying and then integrating the influencers in intervention development and dissemination may create more sustainable and effective culture change. Additional studies are ongoing to test the effectiveness of utilising these influencers to disseminate patient safety interventions. IMPLICATIONS FOR NURSING MANAGEMENT: This study offers an approach that can be helpful in both identifying and understanding influential team members and may be an important aspect of developing methods to change organisational culture. PMID- 28568481 TI - Participant evaluation of an inpatient occupational therapy groups programme in brain injury rehabilitation. AB - BACKGROUND/AIM: Therapy groups are commonly used in brain injury rehabilitation yet patient perceptions of participation in groups are largely uninvestigated. This paper describes the occupational therapy groups programme at an inpatient brain injury rehabilitation unit and presents an evaluation from the patient's perspective. METHODS: Participants were in patients with traumatic brain injury who participated in the groups programme and completed a customised self-report questionnaire measuring perceptions about and satisfaction with four occupational therapy groups. Data were analysed descriptively and comparisons made between groups with a functional focus (meal preparation and community access) and an impairment focus (cognitive and upper limb) using Z scores. RESULTS: Thirty-five participants (30 males, five females) completed a total of 83 questionnaires. Over 90% of responses agreed or strongly agreed that working with others was enjoyable, that the groups provided feedback and individualised treatment, and were useful for them. There were no significant differences in perceptions about the functional and impairment-focussed groups. An illustrative case example of participation in the groups programme is presented. CONCLUSIONS: Overall, consumer feedback on different aspects of the occupational therapy groups programme in brain injury rehabilitation was positive. Further in-depth investigation of patient perceptions of groups including processes that facilitate or challenge participation is warranted. PMID- 28568482 TI - Diffusion-limited PBPK model for predicting pulmonary pharmacokinetics of florfenicol in pig. AB - For most bacterial lung infections, the concentration of unbound antimicrobial agent in lung interstitial fluid has been thought to be responsible for antimicrobial efficacy. In this study, a diffusion-limited physiologically based pharmacokinetic (PBPK) model was developed to predict the pulmonary pharmacokinetics of florfenicol (FF) in pigs. The model included separate compartments corresponding to blood, diffusion-limited lung, flow-limited muscle, liver, and kidney and an extra compartment representing the remaining carcass. The absorption rate constant and renal and hepatic clearance of FF were determined in vivo. Other parameters were taken from the literature or optimized based on existing pharmacokinetic data. All mathematical operations during the development of the model were performed using acslXtreme version 3.0.2.1 (Aegis Technologies Group, Inc., Huntsville, AL, USA). The model accurately predicted the concentration-time courses of FF in lung interstitial fluid, serum, and plasma following different dosing schedules, except at the dose of 15 mg/kg. When compared with the tissue residue data, the model generally underestimated the FF concentration at the injection site, whereas it gave good predictions of FF concentrations in lung, liver, and kidney at early time points. The model predictions provide a scientific basis for the dosage regimen design of FF. PMID- 28568484 TI - NATURAL SELECTION RESULTING FROM FEMALE BREEDING COMPETITION IN A PACIFIC SALMON (COHO: ONCORHYNCHUS KISUTCH). AB - We studied breeding competition among wild female coho salmon (Oncorhynchus kisutch) and quantified natural selection acting on two important female characters: body size and kype size (a secondary sexual character used for fighting). We found that body size contributed to adult female fitness in three ways, through 1) an increased initial biomass of egg production, 2) the ability to acquire a high-quality territory for egg development, and 3) success in nest defense. These factors together resulted in as much as a 23-fold fitness advantage to the largest females in the population. The initial investment into egg production accounted for 50-60% of the measured intensity of natural selection on female body size. The effective investment into egg production (after female competition for territories) accounted for 40-50% of natural selection on female body size. Therefore, success in breeding competition is about as important as egg production in the current evolution of female body size. This is contrary to the expectation based on most fisheries literature. The size of a female's kype was also important to female reproductive success, although its contribution could not be separated from that of body size in our study. The strong natural selection that we have found for female competitive ability is presumably the basis for the evolution of female parental care in salmonids. PMID- 28568485 TI - ACACIA MANGIUM: A TROPICAL FOREST TREE OF THE COASTAL LOWLANDS WITH LOW GENETIC DIVERSITY. PMID- 28568483 TI - Allogeneic hematopoietic cell transplantation in morphologic leukemia-free aplastic state. PMID- 28568486 TI - FLIGHTLESSNESS IN GREBES (AVES, PODICIPEDIDAE): ITS INDEPENDENT EVOLUTION IN THREE GENERA. AB - The morphological bases of flightlessness in three genera of grebes were studied using 790 study skins, 322 skeletons, myological data from 40 anatomical specimens studied by Sanders (1967), and ancillary data on wing-loadings. Three species, Rollandia microptera, Podilymbus gigas, and Podiceps taczanowskii, are considered to be flightless; each is endemic to a high-altitude, neotropical lake or lake system. Compared to their flighted (capable of flight) sister-species, the three flightless species shared several broadly convergent characters: larger body mass and skeletal dimensions (exclusive of the sternal carina), reductions in relative lengths of wing, tail, and primary remiges, and reduction in the relative size of breast muscles. Rollandia microptera exhibited the greatest morphological differences from its flighted sister-species; these differences were comparable to intergeneric morphometric differences in magnitude and involved a tripling of body mass, a modal loss of one primary remex in each wing, absolute reduction of the sternal carina, flattening of proximal wing elements, a large morphometric shift in skeletal dimensions, an increase in the scapulocoracoid angle, and six qualitative differences in the pectoral musculature. Morphological differences between Podilymbus gigas and its flighted congener were comparatively minor; flightlessness in this species, if genuine, evidently results from an allometric increase in size combined with a large decrease in relative bulk of breast musculature and shift of alar muscle mass. Podiceps taczanowskii was intermediate in degree of anatomical difference from its flighted relatives, but was unique in its slight reduction in absolute length of the wings and decrease in absolute widths of the skeletal wing elements. Multivariate differences in external characters associated with flightlessness were strongly convergent in the three genera, but multivariate differences in skeletal proportions differed substantially among genera in detail. An estimate of wing-loading indicated that Podilymbus gigas and, especially, Podiceps taczanowskii may be only "flight-impaired" rather than flightless. Relative wing lengths and conformation of sterna in Rollandia microptera and Podiceps taczanowskii indicate that morphological changes associated with flightlessness are paedomorphic; intraspecific allometry in Rollandia indicates that the underlying ontogenetic change may involve a delay in the start of pectoral-alar development (postdisplacement). Flightlessness in grebes, a family typified by moderately heavy wing-loadings and relatively small pectoral muscles, is related in all three instances to the year-round residency afforded by large lakes at low latitudes. The primary selective advantages of morphological changes leading to flightlessness probably are related to the thermodynamic advantages of increased body sizes, feeding specialization associated with enlargement of the bill, and reduction of intraspecific niche overlap through increased sexual dimorphism; the changes are also possibly related to economy of pectoral-alar development. PMID- 28568487 TI - GENETICS OF STERILITY IN HYBRIDS BETWEEN TWO SUBSPECIES OF DROSOPHILA. AB - Hybrids between D. pseudoobscura bogotana and D. pseudoobscura pseudoobscura are fertile except for males produced in one of the two reciprocal crosses. As there is no premating isolation between these subspecies, nonreciprocal male sterility represents the first step in speciation. Genetic analysis reveals two causes of hybrid F1 sterility: a maternal effect and incompatibilities between chromosomes within males. The maternal effect appears to play the greatest role in hybrid sterility. The X chromosome has the largest effect on fertility of any chromosome, a ubiquitous result in analyses of hybrid sterility and inviability in Drosophila. This effect is entirely attributable to a region comprising less than 30% of the X chromosome. These results are compared to those from a similar study of D. pseudoobscura-D. persimilis hybrids, an older and more reproductively isolated species pair in the same lineage. Such comparisons may allow one to identify the genetic changes characterizing the early versus late stages of speciation. PMID- 28568488 TI - MITOCHONDRIAL-DNA VARIATION IN THE CRESTED NEWT SUPERSPECIES: LIMITED CYTOPLASMIC GENE FLOW AMONG SPECIES. AB - The crested newt has a widespread European distribution and encompasses four taxa recently elevated to full species: Triturus cristatus, T. carnifex, T. dobrogicus, and T. karelini. These are distinct on morphological, chromosomal, and isozymic grounds and have fairly sharp transition zones. A widespread survey (12 countries, 49 geographic sites, 210 individuals) of mtDNA variation (20-27 restriction enzyme sites mapped per individual) was made in order to 1) correlate mtDNA variation with morphological features defining the species, 2) determine the degree of differentiation within and among species, and 3) detect any introgression among species. The mtDNAs of these species were clearly differentiated (d = 3.9-7.1%). Additionally, geographic structuring was observed within T. carnifex and T. karelini, each displaying two divergent mitochondrial genome types (d = 3.5% and 4.7%, respectively). The other two (more northerly distributed) species were genetically homogeneous over most (T. cristatus) or all (T. dobrogicus) of their ranges. In the case of T. cristatus, one may infer bottlenecking as a result of Pleistocene glaciation events. This may also apply in part to T. dobrogicus, but high population connectedness and gene flow in this lowland river species may alone be sufficient for homogenization of mtDNA. Patterns of mtDNA variation were largely concordant with morphology; some interspecific mitochondrial gene flow was observed, but only close to or in the transition zones. Analyses of mapped restriction-site data by UPGMA and parsimony methods (using the closely related T. marmoratus as an outgroup) produce very similar dendrograms. The levels of divergence found concur with the systematics of the group, but the differentiation within T. carnifex and T. karelini is notable. PMID- 28568489 TI - QUANTITATIVE GENETICS OF SIZE, SHAPE, LIFE-HISTORY, AND FRUIT CHARACTERISTICS OF THE SEED-HETEROMORPHIC COMPOSITE HETEROSPERMA PINNATUM. I. VARIATION WITHIN AND AMONG POPULATIONS. AB - We document phenotypic and genetic variation within and among populations of the seed heteromorphic species Heterosperma pinnatum Cav. (Compositae) in the production of seed morphs and in a variety of life-history and morphological characteristics that might be correlated with seed and head traits. Each trait is found to have significant genetic variance in most or, usually, all populations. Significant among-population genetic variation exists for all traits except number of achenes per head and seedling shape, although some traits have much less genetic variation among than within populations. Number and percentage of intermediate achenes per head, total number of achenes per head, and lengths of central and peripheral achenes had little among-population genetic variation compared to within-population variation. Most traits had slightly less genetic variation among than within populations; however, some traits (percentage of central achenes, length of awns, date that the first flowering head opened, date that the first fruiting head opened, and death date) had more among-population genetic variation. The proportions of achene morphs produced had high broad-sense heritabilities and high among-population genetic variance, except in the case of intermediate achenes. All phenological variables had high among-population genetic variation. Within-population heritabilities were high for dates of first flowering head and fruiting head but low for death date and reproductive interval. Family and population means measured in the greenhouse for traits having high broad-sense heritability or among-population genetic variance were closely correlated with field means for the corresponding families or populations. The amounts of phenotypic variation were similar for traits that were measured in both the field and the greenhouse. These lines of evidence suggest that greenhouse results provide reasonable estimates of genetic variation in the field for this species. Numerous studies have reported variation in the proportion of seed morphs for different heteromorphic-seeded species and have discussed adaptive scenarios for the evolution of seed proportions; however, our investigation is one of only a few that have documented the amount of phenotypic and genetic variation within and among populations. PMID- 28568490 TI - SIMILAR GEOGRAPHIC VARIATION AT THE LAP LOCUS IN THE MUSSELS MYTILUS TROSSULUS AND M. EDULIS. PMID- 28568491 TI - A PATH-ANALYTIC MODEL FOR THE MEASUREMENT OF SELECTION ON MORPHOLOGY. AB - This paper describes a path model for the analysis of phenotypic selection upon continuous morphological characters. The path-analysis model assumes that selection occurs on unmeasured general size and shape allometry factors that summarize linear relations among sets of ontogenetically, phylogenetically, or functionally related traits. An unmeasured factor for general size is considered the only aspect of morphometric covariance matrices for which there is an a priori biological explanation. Consequently, selection coefficients are derived for each measured character by holding constant only a general size factor, rather than by using multiple regression to adjust for the full covariance matrix. Fitness is treated as an unmeasured factor with loadings, representing directional selection coefficients, computed as the covariances of the size adjusted characters with the measured fitness indicator. The magnitudes and signs of the selection coefficients, combined with biological insight, may suggest hypotheses of selection on one or more shape allometry factors. Hypotheses of selection on general size and shape allometry factors are evaluated through cycles of measurement, analysis, and experimentation, designed to refine the path diagram depicting the covariances among the measured characters, the measured indicator of fitness, and unmeasured factors for morphology and fitness. The path analysis and multiple-regression models were applied to data from remeasurement of Lande and Arnold's (1983) pentatomid bugs and to Bumpus's (1899) data on house sparrows. The path analysis suggested the hypothesis that variation in bug survivorship was an expression of directional selection on wing loading. Bumpus's data are consistent with a hypothesis of stabilizing selection on general size in females and directional selection for small wing size relative to body size in males. PMID- 28568492 TI - THE GENETICS AND EVOLUTION OF CANNIBALISM IN FLOUR BEETLES (GENUS TRIBOLIUM). AB - Cannibalism plays a major role in population regulation in Tribolium confusum, accounting for up to tenfold differences in population size between different genetic strains. I characterized the within- and between-strain genetic variation for cannibalism using standard quantitative-genetic methods. The four laboratory strains studied have similar birth and death rates but differ in their strain specific cannibalistic tendencies. The cannibalism rates of the strains were stable for more than 60 generations of laboratory husbandry. I found considerable genetic variation for cannibalism within each strain. A genetic analysis of the between-strain differences in each of three types of cannibalism (larvae eating eggs, adults eating eggs, and adults eating pupae) showed that all three cannibalism pathways are autosomally inherited and exhibit minor degrees of dominance. Adult cannibalism of eggs and larval cannibalism of eggs appear to be genetically correlated. The differences between the "high" and "low" cannibalism strains appear to be polygenic for two kinds of cannibalism, larvae eating eggs and adults eating pupae. However, strain differences in adult cannibalism of eggs may be due to only two loci. The stability of the between-strain differences for more than 60 generations, the additive nature of inheritance, and the demonstration of considerable within-strain genetic variation suggest that cannibalism may be selectively neutral or under stabilizing selection with many adaptive peaks. PMID- 28568493 TI - PHYLOGEOGRAPHIC PATTERNS IN MITOCHONDRIAL DNA OF THE DESERT TORTOISE (XEROBATES AGASSIZI), AND EVOLUTIONARY RELATIONSHIPS AMONG THE NORTH AMERICAN GOPHER TORTOISES. AB - Restriction-fragment polymorphisms in mitochondrial DNA (mtDNA) were used to evaluate population-genetic structure in the desert tortoise Xerobates agassizi and to clarify evolutionary affinities among species of the gopher tortoise complex. Fourteen informative endonucleases were employed to assay mtDNAs from 56 X. agassizi representing 22 locations throughout the species' range. The mtDNA genotypes observed were readily partitioned into three major phylogenetic assemblages, each with striking geographic orientation. Overall, the X. agassizi mtDNA genotypes typify a common phylogeographic pattern, in which broad genetic uniformity of populations is interrupted by geographic features that presumably have functioned as dispersal barriers. The geologic history of the Colorado River area, which includes extensive marine incursions, may account for the marked mtDNA divergence between eastern and western X. agassizi assemblages. In mtDNA comparisons among the four species of the gopher tortoise complex, both UPGMA and Wagner parsimony analysis strongly support the recognition of two distinct species groups previously suggested by traditional systematic approaches. Furthermore, the mtDNA data identify the eastern X. agassizi assemblage as the probable inceptive lineage of X. berlandieri. Results from both intra- and interspecific comparisons illustrate how clues to historical events may be present in the geographic structure of mtDNA phylogenies. PMID- 28568494 TI - GERMINATION SCHEDULES OF POLLEN GRAINS: IMPLICATIONS FOR POLLEN SELECTION. PMID- 28568495 TI - ARTIFICIAL SELECTION FOR PAEDOMORPHOSIS IN THE SALAMANDER AMBYSTOMA TALPOIDEUM. AB - Heterochronic ontogenetic mechanisms such as paedomorphosis are potentially important mechanisms of both microevolutionary and macroevolutionary change. The salamander Ambystoma talpoideum is facultatively paedomorphic. Expression of paedomorphosis in this species varies among local natural populations. Two breeding lines, one from a population associated with a temporary pond where metamorphosis to a terrestrial adult always occurs, another from a population associated with a nearly permanent pond where paedomorphosis is common, were selected artificially for paedomorphosis over four generations. The F5 generation of each breeding line was reared in a "common garden" field experiment under two drying regimes to simulate the larval environment in a temporary and in a permanent pond. There was a significantly different response to the drying regimes and to the artificial selection in the two lines. A significant population * selection interaction indicated that the two populations responded differently to artificial selection for paedomorphosis. The presence of heritable genetic variation suggests that evolution and divergence among populations of salamanders is possible with intense natural selection over short periods of ecological time. PMID- 28568496 TI - A REEVALUATION OF CHROMOSOMAL VARIATION IN POPULATIONS OF PEROMYSCUS MANICULATUS ALONG AN ELEVATIONAL GRADIENT. PMID- 28568497 TI - PHYLOGENETIC HYPOTHESES UNDER THE ASSUMPTION OF NEUTRAL QUANTITATIVE-GENETIC VARIATION. AB - There are many situations in which the only available characters for reconstructing phylogenies are morphological. Those traits that are subject only to the forces of mutation and random genetic drift can be used to obtain unbiased estimates of phylogenetic relationships. However, the accurate recovery of a phylogeny from information on neutral characters requires the procurement of data for a large number of independent traits, individuals, and populations. Phylogenetic trees fit to data from more than five species will almost always contain topological errors, even with very large data sets. The population genetic consequences of the neutral model are reviewed, and some statistical methods for testing whether the diversification of a phylogeny is compatible with such a model are outlined. The theory is then applied to a very large data set on cranial morphology in modern man. The results are consistent with the hypothesis that interracial differences in human skull dimensions are a simple consequence of random drift and mutation. PMID- 28568498 TI - FILIAL CANNIBALISM IN THE CORTEZ DAMSELFISH STEGASTES RECTIFRAENUM. AB - Male cortez damselfish, Stegastes rectifraenum, in a central Gulf of California population, ate a large percentage (28.3%) of the clutches they received. This high rate of filial cannibalism permitted the testing of several predictions concerning the types of clutches that should be preferentially eaten and the mating tactics females should employ to reduce cannibalism rates. Males ate clutches that were smaller than average and that were at early stages of development. Experimentally reduced clutches were consumed at higher rates than controls. When multiple clutches were present, males preferentially ate the younger, smaller clutches. Females were more likely to deposit eggs with males who were caring for other early-stage eggs and to avoid males with late-stage eggs. This pattern was accentuated in females that deposited smaller clutches. These results provide evidence that filial cannibalism represents an adaptive response to clutches that do not provide adequate benefits to warrant the costs of parental care. PMID- 28568499 TI - RIBOSOMAL-DNA, MITOCHONDRIAL-DNA, CHROMOSOMAL, AND ALLOZYMIC STUDIES ON A CONTACT ZONE IN THE POCKET GOPHER, GEOMYS. AB - We studied 75 individuals of the Plains pocket gopher, Geomys bursarius, from eastern New Mexico, where the subspecies major and knoxjonesi hybridize. Each individual was examined for chromosome number, ribosomal DNA, mitochondrial DNA, and three protein systems for which reference parental populations were fixed for alternative alleles. Twenty individuals were indistinguishable from parental major, 14 individuals were indistinguishable from parental knoxjonesi, and 41 individuals had genotypes composed of combinations of character states that distinguish the two parental types. The parental types appear to represent discrete genetic entities that have restricted introgression across a narrow hybrid zone (width approximately 3 km, using the 20/80 criterion). Parental types overlap in geographic distribution near the center of the zone, and changes in mitochondrial DNA and the five nuclear markers are concordant across the zone. It is probable that there is premating isolation between knoxjonesi males and major females. The frequencies of individuals with certain genotypic combinations within our sample imply differential reproductive success of certain genotypes. We propose that F1 's and highly heterozygous males are sterile and that hybrid females are less fertile than parental females. These postmating factors, along with premating isolation for one of the reciprocal crosses, probably account for the restriction of gene flow across the contact zone. The structure of the zone can be explained by the "dynamic equilibrium" model. PMID- 28568500 TI - FUNCTIONAL DIOECY AND ANDROMONOECY IN SOLANUM. AB - Field and laboratory studies of 19 diclinous species endemic to Australia help to clarify the nature and evolution of andromonoecy, androdioecy, and dioecy in the genus Solanum. Ten species are andromonoecious; typically these species bear inflorescences with a single, large basal hermaphroditic flower and 12-60 distal, smaller staminate flowers. We suggest that the andromonoecious condition was derived from hermaphroditic-flowered ancestors in part by hemisterilization of flowers but largely by addition of staminate flowers. The resultant larger inflorescences are hypothesized to serve both to attract and to entrain pollinators, yielding more or higher-quality seed set in hermaphroditic flowers and/or greater dispersion of pollen from staminate flowers. We suggest that andromonoecy may also serve to reduce selling. Nine other species are morphologically androdioecious but functionally dioecious. In these species, staminate flowers, like those of the andromonoecious species, bear anthers with copious tricolporate pollen and a highly reduced gynoecium. The morphologically hermaphroditic flowers are functionally pistillate and borne singly in inflorescences, and they bear anthers with inaperturate pollen. The inaperturate pollen, although viable, never germinates and is hypothesized to be retained in pistillate flowers as a reward to pollinators in the nectarless Solanum flowers. All other species of Solanum studied with pollen dimorphism in which one pollen morph is inaperturate are also best treated as functionally dioecious. We conclude that there is no evidence for androdioecy in Solanum. A review of other families suggests that there is little support for this unusual breeding system in any other angiosperm group either. Preliminary analyses suggest that andromonoecy and dioecy are polyphyletic in Solanum. Furthermore, dioecy is as likely to have arisen from hermaphroditic as from andromonoecious ancestors. PMID- 28568501 TI - ANALYZING TABLES OF STATISTICAL TESTS. PMID- 28568502 TI - EVOLUTION OF ADULT FEMALE LIFE HISTORY AND MORPHOLOGY IN A PACIFIC SALMON (COHO: ONCORHYNCHUS KISUTCH). AB - Female competition on the spawning grounds can generate strong natural selection on female coho salmon (Oncorhynchus kisutch). We examined the morphology and investment into egg production of 13 wild and five hatchery populations. For each population, the degrees of breeding competition and migration arduousness were quantified. The results support the importance of breeding competition in the evolution of female morphology and life history. Female secondary sexual characters, including body coloration and length of kype (an extension of the upper jaw used for fighting), increase significantly with degree of breeding competition among populations. In contrast, egg size and female investment into egg production tend to decrease as competition increases, probably as a result of life-history trade-offs. The difficulty of migration to the spawning grounds also molds female morphology and life history. Salmon become more streamlined with increasing migration arduousness, and the biomass of eggs produced appears to decline. In hatcheries, where breeding competition is relaxed, characters associated with breeding competition and spawning performance are reduced. In contrast, egg size is increased. These results indicate that the morphology and life history of adult female salmon respond evolutionarily to local selection pressures, including both the biotic demands of breeding competition and the abiotic demands of migration. PMID- 28568503 TI - THE DECLINE OF AN ADAPTATION IN THE ABSENCE OF A PRESUMED SELECTION PRESSURE. AB - The colonial nesting Village Weaver (Ploceus cucullatus) lays eggs that vary in ground color and pattern, but individual females lay similar eggs each time. Tests on captive African stocks have shown that females reject eggs of other cohorts if such eggs are sufficiently different. The Village Weaver may have evolved rejection behavior and variable eggs in response to cuckoo parasitism in Africa. The Village Weaver was introduced into Hispaniola from Africa as early as the 18th century. Before the arrival of the Shiny Cowbird (Molothrus bonariensis) in the early 1970's, there were no brood parasites on Hispaniola. Furthermore, in an experimental parasitism study, Hispaniolan Village Weavers accepted both dummy eggs and dissimilar Village Weaver eggs. The Village Weaver may have decreased the egg-rejection behavior in the absence of the selective pressure of brood parasitism. Now Hispaniolan populations of the Village Weaver are parasitized by the Shiny Cowbird, which lays eggs dissimilar to those of the weaver. Brood parasitism by the Shiny Cowbird exerts a detrimental impact on the Village Weaver by reducing nest success and productivity. PMID- 28568504 TI - NATURAL HYBRIDIZATION BETWEEN THE SYMPATRIC HAWAIIAN SPECIES DROSOPHILA SILVESTRIS AND DROSOPHILA HETERONEURA. AB - Two newly formed, morphologically distinct species of Drosophila from the island of Hawaii have been found to form fertile hybrids in two areas of sympatry. Both F1 and backcross hybrids have been recognized in nature; in one case, the hybridization events extended over three years. Original hybridizations involved one or more D. silvestris females mating with D. heteroneura males. Female F1 hybrids from this cross have participated in backcrosses to D. silvestris. In any one locality, less than 2% hybrids have been found in nature. A hybrid swarm was not formed; selection appears to favor a strict maintenence of morphologies characteristic of the separate species. This result is attributed to pervasive sexual selection, which serves to preserve the syndromes of sexual characteristics that arose during past allopatric divergence. Populations of D. silvestris both within and outside the present range of D. heteroneura often display heritable variation in color patterns involving the abdomen, pleurae, legs, and wings. Genes effecting variation in these characters may be derived from genes involved in a past introgression from D. heteroneura. Independent evidence for past hybridization between these species comes from study of mitochondrial DNA. Although the inferred direction of the cross is the opposite of that observed in the recent case described here, both reciprocal crosses have been obtained experimentally in the laboratory. Accordingly, we suggest that these species may have been open to hybridization since their first sympatic encounters following their inception in allopatry. That they remain as strictly recognizable morphological entities is due both to their current partial allopatry and to the action of sexual selection in maintaining two separate major modes of efficient reproduction. There is no reason to invoke specific reinforcing selection that has imposed reproductive isolation. PMID- 28568505 TI - BOLA-DRB3 gene polymorphisms influence bovine leukaemia virus infection levels in Holstein and Holstein * Jersey crossbreed dairy cattle. AB - Bovine leukemia virus (BLV) infections, causing persistent lymphocytosis and lethal lymphosarcoma in cattle, have reached high endemicity on dairy farms. We observed extensive inter-individual variation in the level of infection (LI) by assessing differences in proviral load in peripheral blood. This phenotypic variation appears to be determined by host genetics variants, especially those located in the BoLA-DRB3 MHCII molecule. We performed an association study using sequencing-based typed BOLA-DRB3 alleles from over 800 Holstein and Holstein * Jersey cows considering LI in vivo and accounting for filial relationships. The DBR3*0902 allele was associated with a low level of infection (LLI) (<1% of circulating infected B-cells), whereas the DRB3*1001 and DRB3*1201 alleles were related to a high level of infection (HLI). We found evidence that 13 polymorphic positions located in the pockets of the peptide-binding cleft of the BOLA-DRB3 alleles were associated with LI. DRB3*0902 had unique haplotypes for each of the pockets: Ser13 -Glu70 -Arg71 -Glu74 (pocket 4), Ser11 -Ser30 (pocket 6), Glu28 Trp61 -Arg71 (pocket 7) and Asn37 -Asp57 (pocket 9), and all of them were significantly associated with LLI. Conversely, Lys13 -Arg70 -Ala71 -Ala74 and Ser13 -Arg70 -Ala71 -Ala74 , corresponding to the DRB3*1001 and *1201 alleles respectively, were associated with HLI. We showed that the specific amino acid pattern in the DRB3*0902 peptide-binding cleft may be related to the set point of a very low proviral load level in adult cows. Moreover, we identified two BOLA DRB3 alleles associated with a HLI, which is compatible with a highly contagious profile. PMID- 28568506 TI - PBB3 imaging in Parkinsonian disorders: Evidence for binding to tau and other proteins. AB - BACKGROUND AND OBJECTIVES: To study selective regional binding for tau pathology in vivo, using PET with [11 C]PBB3 in PSP patients, and other conditions not typically associated with tauopathy. METHODS: Dynamic PET scans were obtained for 70 minutes after the bolus injection of [11 C]PBB3 in 5 PSP subjects, 1 subject with DCTN1 mutation and PSP phenotype, 3 asymptomatic SNCA duplication carriers, 1 MSA subject, and 6 healthy controls of similar age. Tissue reference Logan analysis was applied to each region of interest using a cerebellar white matter reference region. RESULTS: In comparison to the control group, PSP subjects showed specific uptake of [11 C]PBB3 in putamen, midbrain, GP, and SN. Longer disease duration and more advanced clinical severity were generally associated with higher tracer retention. A DCTN1/PSP phenotype case showed increased binding in putamen, parietal lobe, and GP. In SNCA duplication carriers, there was a significant increase of [11 C] PBB3 binding in GP, putamen, thalamus, ventral striatum, SN, and pedunculopontine nucleus. The MSA case showed increased binding in frontal lobe, GP, midbrain, parietal lobe, putamen, temporal lobe, SN, thalamus, and ventral striatum. CONCLUSIONS: All PSP patients showed increased retention of the tracer in the basal ganglia, as expected. Binding was also present in asymptomatic SNCA duplication carriers and in an MSA case, which are not typically associated with pathological tau deposition. This suggests the possibility that [11 C]PBB3 binds to alpha-synuclein. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28568508 TI - Cytotoxicity and genotoxicity of nanosilver in stable GADD45alpha promoter-driven luciferase reporter HepG2 and A549 cells. AB - OBJECTIVES: The intense commercial application of silver nanoparticles (AgNPs) has been raising concerns about their potential adverse health effects to human. This study aimed to explore the potency of AgNPs to induce GADD45alpha gene, an important stress sensor, and its relationships with the cytotoxicity and genotoxicity elicited by AgNPs. METHODS: Two established HepG2 and A549 cell lines containing the GADD45alpha promoter-driven luciferase reporter were treated with increasing concentrations of AgNPs for 48 hours. After the treatment, transcriptional activation of GADD45alpha indicated by luciferase activity, cell viability, cell cycle arrest, and levels of genotoxicity were determined. The uptake and intracellular localization of AgNPs, cellular Ag doses as well as Ag+ release were also detected. RESULTS: AgNPs could activate GADD45alpha gene at the transcriptional level as demonstrated by the dose-dependent increases in luciferase activity in both the reporter cells. The relative luciferase activity was greater than 12* the control level in HepG2-luciferase cells at the highest concentration tested where the cell viability decreased to 17.0% of the control. These results was generally in accordance with the positive responses in cytotoxicity, cell cycle arrest of Sub G1 and G2/M phase, Olive tail moment, micronuclei frequency, and the cellular Ag content. CONCLUSIONS: The cytotoxicity and genotoxicity of AgNPs seems to occur mainly via particles uptake and the subsequent liberation of ions inside the cells. And furthermore, the GADD45alpha promoter-driven luciferase reporter cells, especially the HepG2-luciferase cells, could provide a new and valuable tool for predicting nanomaterials genotoxicity in humans. PMID- 28568510 TI - PROBLEMS WITH NULL MODELS IN THE STUDY OF PHYLOGENETIC RADIATION. PMID- 28568507 TI - Biomarkers of oxidatively induced DNA damage in dreissenid mussels: A genotoxicity assessment tool for the Laurentian Great Lakes. AB - Activities of fast growing human population are altering freshwater ecosystems, endangering their inhabitants and public health. Organic and trace compounds have a high potential for adverse impacts on aquatic organisms in some Great Lakes tributaries. Toxic compounds in tissues of organisms living in contaminated environments change their metabolism and alter cellular components. We measured oxidatively induced DNA damage in the soft tissues of dreissenid mussels to check on the possible contaminant-induced impact on their DNA. The animals were obtained from archived samples of the National Oceanic and Atmospheric Administration (NOAA) Mussel Watch Program. Mussels were collected from the harbor of Ashtabula River in Ohio, and a reference area located at the Lake Erie shore. Using gas chromatography-tandem mass spectrometry with isotope dilution, we identified and quantified numerous oxidatively modified DNA bases and 8,5' cyclopurine-2'-deoxynucleosides. We found significant differences in the concentrations of these potentially mutagenic and/or lethal lesions in the DNA of mussels from the harbor as compared to the animals collected at the reference site. These results align NOAA's data showing that elevated concentrations of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and heavy metals were found in mussels within the harbor as compared to mussels collected in the reference site. The measured DNA lesions can be used as biomarkers for identifying DNA damage in mussels from polluted and reference sites. Such biomarkers are needed to identify the bioeffects of contaminants in affected organisms, as well as whether remedial actions have proven successful in reducing observed toxic effects. PMID- 28568509 TI - Investigation and treatment for iron deficiency in heart failure: the unmet need in Lower and Middle Income Countries. AB - Frank iron deficiency has been associated with a wide range of cardiac and pulmonary abnormalities including non-ischaemic cardiomyopathy. Iron deficiency anaemia and isolated iron deficiency are well-defined adverse prognostic factors in non-ischaemic cardiac failure. Furthermore, iron-deficient patients in chronic heart failure with a serum ferritin of <100 MUg/l or <300 MUg/l with reduced transferrin saturation of <20%, who were given intravenous iron showed improved clinical outcomes. Iron deficiency with or without anaemia affects over a quarter of the world's population, but the impact of iron deficiency in heart failure and the effective management of iron deficiency in heart failure in Lower and Middle Income Countries (LMICs) is not well described. Heart failure in African cohorts occurs at a younger age than in North America and Europe and is more likely to be due to hypertension. Recent studies suggest that iron deficiency anaemia, which is very common in heart failure patients in Africa, and iron deficiency are independently associated with a poor prognosis in heart failure. Preliminary data suggest that iron deficiency in patients with heart failure can be treated with oral iron, with significant beneficial effects on haematological and physiological variables. Cost may prohibit the use of intravenous iron on a large scale in LMICs and optimal regimes to treat iron deficiency in heart failure patients with oral iron therapy remain to be defined. PMID- 28568511 TI - A SIMULATION STUDY OF MULTILOCUS CLINES. AB - Fisher's method of junctions is used to investigate the degree of association between selected alleles in a cline, in the limit where there is divergence between very many genes. A computer model is used to simulate one of a pair of infinite demes that exchange individuals each generation. Selection is on haploids; it is additive and is equivalent to heterozygote disadvantage. Recombination is uniform over a single chromosome. A "critical value" of selection exists at equilibrium, below which loci act independently and above which they act in association (Barton 1983). Starting with secondary contact, simulation results contrast markedly with the equilibrium solution. The "critical value" is not apparent in the simulated clines, even after many generations. Rather, loci remain associated to some extent under all degrees of selection. The simulation is consistent with the equilibrium analysis in all other respects, and therefore indicates that under weak selection the approach to equilibrium is very slow. This is borne out by further numerical calculations. The slow approach to equilibrium enables us to estimate the time since contact between two demes under idealized conditions. Extending this work toward natural hybrid zones is discussed. PMID- 28568512 TI - EVOLUTION AND CLASSIFICATION OF INSECT FLIGHT KINEMATICS. AB - Classification of the main types of insect in-flight kinematics is proposed here, based on comparative data of wing movement during flapping flight. By comparing the described kinematic patterns with the results of studies of the vortex-wake structures of flying insects, these patterns can be explained as adaptations for overcoming the negative effects of mutual deceleration of fore- and hind wing starting vortex bubbles, which take place in insects with the most primitive type of wing kinematics. The aerodynamic efficiency of the flying system can be decreased if natural selection favors behavioral patterns that involve suboptimal wing kinematics. PMID- 28568513 TI - PARASITES, SEX, AND EARLY REPRODUCTION IN A MIXED POPULATION OF FRESHWATER SNAILS. PMID- 28568514 TI - RECOMBINATION AND MIGRATION RATES IN NATURAL POPULATIONS OF BACILLUS SUBTILIS AND BACILLUS MOJAVENSIS. AB - We have investigated the rates of recombination and migration in native populations of two closely related, naturally competent Bacillus species. Native soil isolates of Bacillus subtilis and Bacillus mojavensis were obtained from three continents and, within North America, from populations at a range of geographical distances from one another. The rate of recombination within populations of each species was estimated from restriction-site data for three genes. Recombination was shown to occur within each species at about the same rate as neutral mutation, whatever the geographical scale or phylogenetic scale over which strains were sampled. The rate of migration between populations was estimated by a cladistic analysis and was shown to be high (i.e., Nm > 1), even among populations on different continents. The level of migration within each species is sufficient to prevent neutral geographical divergence within species. PMID- 28568515 TI - VARIATION IN SPECIES DIVERSITY AND SHELL SHAPE IN HAWAIIAN LAND SNAILS: IN SITU SPECIATION AND ECOLOGICAL RELATIONSHIPS. AB - The native land-snail fauna of the Hawaiian islands was investigated from a combined perspective of ecological and historical, vicariant, and dispersalist biogeography. There were more than 750 described, valid species; almost all were endemic to the archipelago, many to single islands. Path analysis showed that island area, per se, had the strongest influence on numbers of species. Island altitude and number of plant communities, both strongly related to area and both dimensions of habitat diversity, also had major influences. The influence of island age was complex. A direct effect, older islands having more species, was more than counterbalanced by the strong indirect effects of age on area and altitude: older islands are smaller and lower, and smaller, lower islands had fewer species. Distance of an island from a source of colonization was of minor importance. Species richness thus appears to be related almost exclusively to evolutionary radiation in situ and not to an equilibrium between immigration and extinction. Islands need not be extremely isolated for evolutionary radiation to be more important than immigration/extinction dynamics in determining species richness, but isolation is a relative term dependent on the dispersal abilities of the organisms in question. Numbers of recorded species were also strongly correlated with collecting effort on each island, a result that stands as a warning to others involved in such studies. Numbers of species in different families were not evenly distributed across islands. Notably, Kauai had more amastrids and helicinids and fewer achatinellids than predicted; Oahu had more amastrids but fewer pupillids and succineids than predicted; Hawaii exhibited the opposite pattern from Oahu. These patterns may partly reflect the vagaries of collecting/describing effort, but some may be due to the combined effects of historical factors and competitive exclusion. The distribution of shell height/diameter was bimodal with a distinct absence of more or less equidimensional species, a general pattern seen in other faunas. Among the pulmonates, tall species predominated, suggesting a relative lack of opportunity for globular/flat species. Notably, amastrids occurred in both modes, evidence that, at least in part, ecological not taxonomic factors underlie the bimodality. The proportions of tall and globular/flat species did not vary among islands. Prosobranchs were mostly low-spired but generally less flat than the pulmonates in the low-spired mode. The islands were probably colonized originally by small taxa. Large, tall shells are found only on Kauai and Niihau, the oldest of the main islands, suggesting that opportunities for such species are probably available on other islands. PMID- 28568516 TI - VARIATION IN GENOTYPE FREQUENCIES DURING THE LIFE HISTORY OF THE BIVALVE, DREISSENA POLYMORPHA. PMID- 28568517 TI - EVOLUTION OF BRASSICA RAPA L. (CRUCIFERAE) POPULATIONS IN INTRA- AND INTERSPECIFIC COMPETITION. AB - Populations of Brassica rapa were grown for three generations in each of two environments: intraspecific competition, with four surrounding Brassica rapa neighbors per pot, and interspecific competition, with two Raphanus sativus neighbors per pot. In each environment, the largest (by flower number) 10% of the plants were outcrossed and provided seeds for the next generation. As a control, a randomly chosen 10% of the plants in each environment were outcrossed to produce seed for the next generation. Each of these four treatments, the selected lines in intra- and interspecific competition and the corresponding control lines, was maintained for three generations. After a single generation of growth in a common, no-competition environment, replicate plants from each treatment were grown with no competition and with intra- and interspecific competition for determination of growth responses. After two generations of selection, flower number in the intraspecific-selection line had increased by more than 50% over that in the control line and by more than 19% over that under interspecific selection. After a common-environment generation, plants from the intraspecific selection line were shown to have significantly faster growth in height and flower number as seedlings. Plants in the interspecific-selection line showed similar but nonsignificant trends. No differences in seed mass, emergence time, or photosynthetic rate were found between control and selected lines in either intra- or interspecific competition. Some differences between control and selected lines were noted in biomass allocation related to differences in phenology. The results demonstrate that performance in competitive environments can evolve through changes in plant development but that rates of evolution will differ in intra- and interspecific competition. PMID- 28568519 TI - MEASURING THE EFFECTS OF PAIRING SUCCESS, EXTRA-PAIR COPULATIONS AND MATE QUALITY ON THE OPPORTUNITY FOR SEXUAL SELECTION. AB - Sexual selection can act through variation in the number of social mates obtained, variation in mate quality, or variation in success at obtaining extra pair fertilizations. Because within-pair fertilizations (WPF) and extra-pair fertilizations (EPF) are alternate routes of reproduction, they are additive, rather than multiplicative, components of fitness. We present a method for partitioning total variance in reproductive success (a measure of the opportunity for selection) when fitness components are both additive and multiplicative and use it to partition the variance into components that correspond to each mechanism of sexual selection. Computer simulations show that extra-pair fertilizations can either increase or decrease total variance, depending on the covariance between within-pair and extra-pair success. Simulations also suggest that for socially monogamous species, extra-pair fertilizations have a greater effect than variation in mate quality or pairing status on the opportunity for selection. Application of our model to data gathered for a population of red winged blackbirds (Agelaius phoeniceus) indicates that most of the variance in male reproductive success was attributable to within-pair sources of variance. Nevertheless, extra-pair copulations increased the opportunity for selection because males varied both in the proportion of their social young that they sired and in the number of extra-pair mates that they obtained. Furthermore, large and positive covariances existed between the number of extra-pair mates a male obtained and both social pairing success and within-pair paternity, indicating that, in this population, males preferred as social mates also were preferred as extra-pair mates. PMID- 28568518 TI - PERSPECTIVE: DARWIN, PROGRESS, AND ECONOMIC PRINCIPLES. AB - Darwin's concept of progress was an economic one, with the accumulation of adaptations having a strong analogy to technological innovations. This interpretation makes it easier to understand his differences with Lamarck and others whose views he considered metaphysically objectionable. It also clarifies his relationship to Malthus and such features of his theory as the episodic nature of evolutionary change. His position is consistent with modern theories of biotic invasions and long-term evolutionary trends. It also accords well with current efforts to produce a synthesis between biology and economics. PMID- 28568520 TI - CHANGES IN GENETIC VARIANCES AND COVARIANCES: G WHIZ! PMID- 28568521 TI - MUTATIONAL MELTDOWNS IN SEXUAL POPULATIONS. AB - Although it is widely acknowledged that the gradual accumulation of mildly deleterious mutations is an important source of extinction for asexual populations, it is generally assumed that this process is of little relevance to sexual species. Here we present results, based on computer simulations and supported by analytical approximations, that indicate that mutation accumulation in small, random-mating monoecious populations can lead to mean extinction times less than a few hundred to a few thousand generations. Unlike the situation in obligate asexuals in which the mean time to extinction (te ) increases more slowly than linearly with the population carrying capacity (K), te increases approximately exponentially with K in outcrossing sexual populations. The mean time to extinction for obligately selfing populations is shown to be equivalent to that for asexual populations of the same size, but with half the mutation rate and twice the mutational effect; this suggests that obligate selfing, like obligate asexuality, is inviable as a long-term reproductive strategy. Under all mating systems, the mean time to extinction increases relatively slowly with the logarithm of fecundity, and mutations with intermediate effects (similar to those observed empirically) cause the greatest risk of extinction. Because our analyses ignore sources of demographic and environmental stochasticity, which have synergistic effects that exacerbate the accumulation of deleterious mutations, our results should yield liberal upper bounds to the mean time to extinction caused by mutational degradation. Thus, deleterious mutation accumulation cannot be ruled out generally as a significant source of extinction vulnerability in small sexual populations or as a selective force influencing mating-system evolution. PMID- 28568522 TI - INCIPIENT REPRODUCTIVE ISOLATION BETWEEN TWO SYMPATRIC MORPHS OF THE INTERTIDAL SNAIL LITTORINA SAXATILIS. AB - The study of speciation in recent populations is essentially a study of the evolution of reproductive isolation mechanisms between sub-groups of a species. Prezygotic isolation can be of central importance to models of speciation, either being a consequence of reinforcement of assortative mating in hybrid zones, or a pleiotropic effect of morphological or behavioral adaptation to different environments. To suggest speciation by reinforcement between incipient species one must at least know that gene flow occurs, or have recently occurred, and that assortative mating has been established in the hybrid zone. In Galician populations of the marine snail Littorina saxatilis, two main morphs appear on the same shores, one on the upper-shore barnacle belt and the other in the lower shore mussel belt. The two morphs overlap in distribution in the midshore where hybrids are found together with pure forms. Allozyme variation indicates that the two parental morphs share a common gene pool, although within shores, gene flow between morphs is less than gene flow within morphs. In this study, we observed mating behavior in the field, and we found that mating was not random in midshore sites, with a deficiency of heterotypic pairs. Habitat selection, assortative mating, and possibly sexual selection among females contributed to the partial reproductive isolation between the pure morphs. Sizes of mates were often positively correlated, in particular, in the upper shore, indicating size assortative mating too. However, this seemed to be a consequence of nonrandom microdistributions of snails of different sizes. Because we also argue that the hybrid zone is of primary rather than secondary origin, this seems to be an example of sympatric reproductive isolation, either established by means of reinforcement or as a by-product to divergent selection acting on other characters. PMID- 28568523 TI - AN EXACT TEST FOR POPULATION DIFFERENTIATION. PMID- 28568524 TI - SEX-RATIO BIAS WITH ASYMMETRIC EXCHANGE OF POLLEN BETWEEN DEMES. AB - In a patch of hermaphroditic plants, with a low level of pollen migration between patches, a prevailing wind creates a gradient, within the patch, in the strength of local competition among pollen for reproductive success. This leads to a sex ratio gradient, with a male (pollen) bias in downwind individuals, which can be quite strong even for large patches. The effect can be understood as follows: downwind individuals have relatively low reproductive value and respond by putting more resources into the gamete (pollen) with the best long-range (extra patch) reproductive success. PMID- 28568525 TI - NATURAL SELECTION ON QUANTITATIVE TRAITS IN THE BOMBINA HYBRID ZONE. AB - Observations on the means, variances, and covariances of quantitative traits across hybrid zones can give information similar to that from Mendelian markers. In addition, they can identify particular traits through which the cline is maintained. We describe a survey of six traits across the hybrid zone between Bombina bombina and Bombina variegata (Amphibia: Discoglossidae) near Pescenica in Croatia. We obtained laboratory measuments of the belly pattern, skin thickness, mating call, skeletal form, egg size, and the developmental time of tadpoles. Although offspring from hybrid populations showed no evidence of reduced viability, a third of the F1 families failed completely, irrespective of the direction of the cross. All traits differed significantly between the taxa. Clines in belly pattern, skin thickness, mating call, and skeletal form were closely concordant with clines in four diagnostic enzyme loci. However, the cline in developmental time was displaced towards bombina, and the cline in egg size was displaced towards variegata. This discordance could be because the traits are not inherited additively or because they are subject to different selection pressures. We favor the latter explanation in the case of developmental time. We show that moderate selection acting directly on a trait suffices to shift its position; rather stronger selection is needed to change its width appreciably. Within hybrid populations, there are significant associations among quantitative traits, and between traits and enzymes. Phenotypic variances also increase in hybrid populations. These observations can be explained by linkage disequilibria among the underlying loci. However, the average magnitude of the covariance between traits is about half that expected from the linkage disequilibria between enzyme loci. The discrepancy is not readily explained by nonadditive gene action. This puzzle is now unresolved and calls for further investigation. PMID- 28568526 TI - COMPARATIVE METHODS AT THE SPECIES LEVEL: GEOGRAPHIC VARIATION IN MORPHOLOGY AND GROUP SIZE IN GREY-CROWNED BABBLERS (POMATOSTOMUS TEMPORALIS). AB - We show that a new comparative method that sheds light on evolutionary trends among species may also illuminate trends within species. This finding comes from a phylogenetic autocorrelation analysis of morphological traits among individuals sampled from ten populations of a cooperatively breeding songbird, the Grey crowned Babbler (Pomatostomus temporalis). Highly variable mitochondrial DNA (mtDNA) sequences from both the eastern (Pomatostomus temporalis temporalis) and western (Pomatostomus temporalis rubeculus) lineages were used to define genetic distances among 120 individuals and to estimate correlations among individuals in wing length, tarsus length, and body weight via an intraspecific weighting matrix. The autoregressive model effectively removed intraspecific correlations for all three morphological variables, and the proportion of the total phenotypic variance due to genealogical relationships varied from 0.68 (weight) to 0.23 (tarsus). The analysis revealed correlations among the specific components of traits, in which none were previously detected (type-I error) and diminished correlations that appeared strong when phylogeny was ignored. Group size was the only trait for which the autoregressive model failed to remove intraspecific correlations, a result likely due to the plasticity, convergence, and clinal variation in this trait in both the eastern and western lineages. The autocorrelation analysis weakened significant negative correlations between group size and total values for wing length and body weight, but the interpretation of this result depends on the adaptive significance ascribed to the "phylogenetic component" of trait values removed by the analysis. Comparative methods employing distance matrices are one useful way of summarizing the pattern of nonhierarchical relationships among conspecific individuals ("tokogenetic" relationships, sensu Hennig). PMID- 28568527 TI - NUCLEOTYPIC EFFECT IN HOMEOTHERMS: BODY-MASS-CORRECTED BASAL METABOLIC RATE OF MAMMALS IS RELATED TO GENOME SIZE. AB - The body-mass-corrected rate of basal metabolism in mammals is found to be negatively correlated with genome size, which is possibly linked to average cell size. The correlation, already significant at the species level (rsp = -0.61, P < 0.0002), gradually strengthens as mean values for higher taxonomic levels (genera, families, and orders) are substituted in place of the species points (rgen = -0.65, P < 0.0002; rfam = -0.71, P < 0.0004; rord = -0.81, P < 0.008). This finding suggests that a sizeable part of the mammalian (above 25% of human) genome can be used for evolutionary adjustment of metabolic rate resulting from nucleotypic effect independently of body size. The total variance of mammalian genome-size values is found to be divided into two parts: within genera (43%) and taxonomic levels higher than order (57%), with no tangible variance being added between these taxonomic levels; whereas the body-mass-corrected rate of basal metabolism varies mainly at family (42%) and order (53%) levels. The only order for which there seems to be a necessary minimum of data for intraorder analysis (rodents) shows a not statistically significant correlation at the species level (rsp = -0.47; P < 0.09), significant at the genus level (rgen = -0.74; P < 0.04), and very high at the family level (rfam = -0.98; P < 0.03). The concept of ultimate (distant) characters consolidation is proposed. In birds, with average genome sizes 40% of those of mammals, and similarly narrower ranges both of genome sizes and of body-mass-corrected metabolic rates, the correlation was not significant. PMID- 28568528 TI - OPTIMALITY THEORY, GOMPERTZ' LAW, AND THE DISPOSABLE SOMA THEORY OF SENESCENCE. AB - The "disposable soma" theory for the evolution of senescence suggests that senescence arises from an optimal balancing of resources between reproduction and somatic repair. Dynamic programming models are constructed and analyzed to determine the optimal relationship between reproduction, diversion of resources from repair, and added senescent mortality. Of particular interest is the relationship between the repair-reproduction trade-off and the form of the mortality-rate-versus-age curve predicted. The models analyzed in the greatest detail assume that the relationship between reproduction and added senescent mortality does not change with age. These suggest that mortality should increase at an increasing rate with age, but may approach a linear rate as mortality becomes very high. General results are derived for the shape of the mortality curves early and late in the senescing part of the life span, and mortality curves for specific trade-off functions are illustrated. An exponential increase in death rate with age (Gompertz' Law) corresponds to only one of many possible relationships between reproduction and aging. The "Law" is unlikely to hold generally if the disposable soma theory accounts for a large fraction of the observed senescent increase in mortality with age. However, support for the generality of Gompertz' Law is weak, and other theories have not produced an evolutionary explanation for the law. The disposable soma theory is consistent with some of the exceptions to Gompertz' Law that have been observed. PMID- 28568529 TI - EVOLUTION AND POPULATION STRUCTURE OF AFRICANIZED HONEY BEES IN BRAZIL: EVIDENCE FROM SPATIAL ANALYSIS OF MORPHOMETRIC DATA. AB - In recent years, studies based on isoenzymatic patterns of geographic variation have revealed that what is usually called the Africanized honey bee does not constitute a single population. Instead, several local populations exist with various degrees of admixture with European honey bees. In this paper, we evaluated new data on morphometric patterns of Africanized honey bees collected at 42 localities in Brazil, using univariate and multivariate (canonical) trend surface and spatial autocorrelation analyses. The clinal patterns of variation found for genetically independent characters (wing size characters and some wing venation angles) are concordant with previous studies of malate dehydrogenase (MDH) allelic frequencies and support the hypothesis that larger honey bees in southern and southeastern Brazil originated by racial admixture in the initial phases of African honey bee colonization. Geographic variation patterns of Africanized honey bee populations reflect a demic diffusion process in which European genes were gradually lost because of the higher fitness of the African gene pool in Neotropical environmental conditions. PMID- 28568530 TI - CYTOPLASMIC INCOMPATIBILITY: WHY IS IT SEXUALLY ASYMMETRIC? PMID- 28568531 TI - GENETICAL POPULATION STRUCTURE IN PLANTS: GENE FLOW BETWEEN DIPLOID SEXUAL AND TRIPLOID ASEXUAL DANDELIONS (TARAXACUM SECTION RUDERALIA). AB - Levels and distribution of genetic variation were studied in central and western European populations of Taraxacum section Ruderalia containing differing mixtures of sexual diploid and asexual triploid plants. All sexual populations were panmictic with their variation partitioned mainly among populations. Genotypic diversity in triploid samples was very high with few clones widespread and many clones restricted to one or a few populations. Extensive amounts of gene (pollen) flow between the diploid and triploid components of a population were inferred from the following data: (1) the two ploidy levels share all major allozyme polymorphisms; (2) the intrapopulational homogeneity in genic variation between diploids and triploids contrasts strongly with the geographic differentiation at each ploidy level separately; (3) population-unique alleles simultaneously occur at the two ploidy levels; (4) not only sexuals but also asexuals generally simulate Hardy-Weinberg expectations. Most likely, intrapopulational gene exchange occurs bidirectionally by mechanisms such as reductional pollen meiosis in apomictic plants, facultative apomixis, and formation of unreduced gametes in sexuals. Thus, diploid and triploid Taraxacum section Ruderalia are less genetically isolated than has previously been supposed and probably form a cohesive evolutionary unit with the level at which gene pools are shared differing by population. PMID- 28568532 TI - ORIGIN AND RECENT ENDEMIC DIVERGENCE OF A CASPIAN MYSIS SPECIES FLOCK WITH AFFINITIES TO THE "GLACIAL RELICT" CRUSTACEANS IN BOREAL LAKES. AB - Aspects of the evolution of intralacustrine species flocks and of the origin of the Arctic or "glacial-relict" zoogeographical element in Eurasian inland waters were elucidated in an allozyme study of the crustacean genus Mysis. This element, of supposedly northern marine ancestry, is represented by vicarious taxa in the deeper parts of the Caspian Sea (an enclosed ancient basin) and in young boreal lakes. The three endemic Caspian Mysis species studied are very close genetically (Nei's D = 0.06), which suggests a recent intrabasin radiation and rapid morphological divergence. This is in contrast to the pattern in postglacial Holarctic boreal lakes, where the Mysis relicta group is represented by a set of morphologically uniform but probably much older sibling species (D = 0.3-0.6). The results provide a parallel to those on the recent diversification of some fish species flocks in ancient freshwater lakes. The situation is, however, unusual in that the Caspian sympatric Mysis flock is pelagic, and conditions promoting speciation through allopatric isolation or spatial segregation by trophic substrate specialization seem implausible. The monophyletic Caspian Mysis clade shows a relatively strong divergence from both the northern lacustrine and the Arctic marine congeners (D = 0.6-1.0); the phylogenetic branching order of these three zoogeographical groups is not conclusively resolved. The results contradict the prevailing hypothesis of a recent Pleistocene origin of the Caspian Arctic element by invasion from Eastern European continental proglacial lakes that drained south to the Caspian basin during the glacial maxima and served as refugia for the boreal lacustrine taxa. PMID- 28568533 TI - DIFFERENTIAL ALLOCATION AND SEXUAL ORNAMENTATION. PMID- 28568534 TI - EVOLUTION OF BASAL METABOLIC RATE AND ORGAN MASSES IN LABORATORY MICE. AB - Animal species of similar body mass vary widely in basal metabolic rate (BMR). A central problem of evolutionary physiology concerns the anatomical/physiological origin and functional significance of that variation. It has been hypothesized that such interspecific differences in wild animals evolved adaptively from differences in relative sizes of metabolically active organs. In order to minimize confounding phenotypic effects and maximize relevant genetic variation, we tested for intraspecific correlations between body-mass-corrected BMR and masses of four organs (heart, kidney, liver, and small intestine) among six inbred strains of mice. We found significant differences between strains in BMR and in masses of all four organs. Strains with exceptionally high (or low) BMR tended to have disproportionately large (or small) organs. The mass of each organ was correlated with the masses of each of the other three organs. Variation in organ masses accounted for 52% of the observed variation in BMR, of which 42% represented between-strain variation, and 10% represented within-strain variation. This conclusion is supported by published measurements of metabolic rates of tissue slices from the four organs. The correlation between BMR and intestine or heart mass arose exclusively from differences between strains, while the correlation between BMR and liver or kidney mass also appeared in comparing individual mice within the same strain. Thus, even though the masses of the four examined organs account for no more than 17% of total body mass, their high metabolic activities or correlated factors account for much of the variation in BMR among mice. We suggest that large masses of metabolically active organs are subject to natural selection through evolutionary trade-offs. On the one hand, they make possible high-energy budgets (advantageous under some conditions), but on the other hand they are energetically expensive to maintain. PMID- 28568535 TI - REPLY TO CUNNINGHAM. PMID- 28568536 TI - EFFECTIVE POPULATION SIZE IN A CONTINUOUSLY DISTRIBUTED POPULATION. AB - An individual-based simulation model was created to examine genetic variability, time until fixation and spatial genetic structure in a continuously distributed population. Previous mathematical models for continuously distributed populations have the difficulty that the assumption of independent reproduction and independent dispersal of offspring cause clumped spatial distribution and thus violate an assumption of random spatial distribution. In this study, this problem is avoided by considering the dispersal behavior of offspring. The simulation results showed that the inbreeding effective population size estimated by the rate of decrease of heterozygosity during the first 15 generations corresponds to the neighborhood size calculated by the standard deviation of the dispersal distance (sigmaT ). This inbreeding effective population size does not greatly change with the area of simulation when the densities and sigmaT are the same. However, the inbreeding effective population size estimated by heterozygosity using the first 500 generations is larger than the neighborhood size calculated by the dispersal distance and increases with the area of simulation with the same densities. The variance effective population size, estimated by time until fixation of alleles, increases with dispersal distance (sigmaT ) and with the area of simulation given the same densities. The inbreeding effective population size and variance effective population size were smaller than the actual population size unless sigmaT is sufficiently large (2 sigmaT > approximate L/2, where L is a side of the simulation square). PMID- 28568537 TI - MAINTENANCE OF ECOLOGICALLY SIGNIFICANT GENETIC VARIATION IN THE TIGER SWALLOWTAIL BUTTERFLY THROUGH DIFFERENTIAL SELECTION AND GENE FLOW. AB - Differential selection in a heterogeneous environment is thought to promote the maintenance of ecologically significant genetic variation. Variation is maintained when selection is counterbalanced by the homogenizing effects of gene flow and random mating. In this study, we examine the relative importance of differential selection and gene flow in maintaining genetic variation in Papilio glaucus. Differential selection on traits contributing to successful use of host plants (oviposition preference and larval performance) was assessed by comparing the responses of southern Ohio, north central Georgia, and southern Florida populations of P. glaucus to three hosts: Liriodendron tulipifera, Magnolia virginiana, and Prunus serotina. Gene flow among populations was estimated using allozyme frequencies from nine polymorphic loci. Significant genetic differentiation was observed among populations for both oviposition preference and larval performance. This differentiation was interpreted to be the result of selection acting on Florida P. glaucus for enhanced use of Magnolia, the prevalent host in Florida. In contrast, no evidence of population differentiation was revealed by allozyme frequencies. FST -values were very small and Nm, an estimate of the relative strengths of gene flow and genetic drift, was large, indicating that genetic exchange among P. glaucus populations is relatively unrestricted. The contrasting patterns of spatial differentiation for host-use traits and lack of differentiation for electrophoretically detectable variation implies that differential selection among populations will be counterbalanced by gene flow, thereby maintaining genetic variation for host-use traits. PMID- 28568538 TI - EFFECT OF REARING ENVIRONMENT ON CALLING-SONG PLASTICITY IN THE STRIPED GROUND CRICKET. PMID- 28568539 TI - Erratum. PMID- 28568540 TI - RESPONSE TO NATURAL ENVIRONMENTAL HETEROGENEITY: MATERNAL EFFECTS AND SELECTION ON LIFE-HISTORY CHARACTERS AND PLASTICITIES IN MIMULUS GUTTATUS. AB - Recent studies in plant populations have found that environmental heterogeneity and phenotypic selection vary at local spatial scales. In this study, I ask if there is evolutionary change in response to environmental heterogeneity and, if so, whether the response occurs for characters or character plasticities. I used vegetative clones of Mimulus guttatus to create replicate populations of 75 genotypes. These populations were planted into the natural habitat where they differed in mean growth, flowering phenology, and life span. This phenotypic variation was used to define selective environments. There was variation in fitness (flower production) among genotypes across all planting sites and in genotype response to the selective environment. Offspring from each site were grown in the greenhouse in two water treatments. Because each population initially had the same genetic composition, variation in the progeny between selective environments reveals either evolutionary change in response to environmental heterogeneity or environmental maternal effects. Plants from experimental sites that flowered earlier, had shorter life spans and were less productive, produced offspring that had more flowers, on average, and were less plastic in vegetative allocation than offspring of longer-lived plants from high productivity areas. However, environmental maternal effects masked phenotypic differences in flower production. Therefore, although there was evidence of genetic differentiation in both life-history characters and their plasticities in response to small-scale environmental heterogeneity, environmental maternal effects may slow evolutionary change. Response to local-scale selective regimes suggests that environmental heterogeneity and local variation in phenotypic selection may act to maintain genetic variation. PMID- 28568541 TI - RETRODISPLACEMENT OF THE ORAL AND ANAL OPENINGS IN DENDRASTERID SAND DOLLARS. AB - In regular echinoids, the mouth opening (or peristome) and the anal opening (or periproct) are located centrally. In irregular echinoids, the peristome tends to shift toward the anterior end of the test, whereas the periproct typically shifts toward the posterior end. This produces an anatomically polarized morphology, which is consistent with functional expectations. In the dendrasterid sand dollars, however, the peristome and periproct have been displaced in the "wrong" directions; the peristome has shifted posteriorly, whereas the periproct has shifted anteriorly. These movements, which run counter to functional expectations, may be termed "retrodisplacements." This study presents a new model for the development of the oral surface in dendrasterids. The model assumes that the "Dendraster pattern" of development (which occurs in dendrasterids) was derived from the older "Echinarachnius pattern" (which occurs in other northern Pacific sand dollars). The Echinarachnius pattern includes two successive phases of asymmetric growth: the first phase favors anterior growth, whereas the second phase favors posterior growth. These two phases are normally balanced, and at maturity, the test appears to be symmetrical. But if the second phase of unequal growth were suppressed through a heterochronic change in development, the effects on test development would be profound. On the aboral surface, the predicted effects include posterior displacement of the apical system. On the oral surface, the predicted effects include retrodisplacement of the peristome and periproct, as well as conspicuous changes in ambulacral and interambulacral development. In fact, all of the predicted effects are characteristic features of dendrasterids. The model assumes that the oral and aboral surfaces could be simultaneously affected by the same developmental processes. This assumption is supported by empirical evidence: in dendrasterids, there is a strong correlation between the displacement of the apical system (on the aboral surface) and the displacement of the peristome (on the oral surface). The displacement of the apical system (known as "apical eccentricity") is regarded as a valuable adaptation, because it facilitates suspension feeding. But if oral and aboral development are linked, then selective pressure for apical eccentricity would simultaneously produce new oral characters as well. Thus, the retrodisplacement of the peristome and periproct in dendrasterids may be related to developmental constraints. These unusual characters may have little or no functional significance. PMID- 28568542 TI - THE DIFFERENTIAL-ALLOCATION HYPOTHESIS: DOES THE EVIDENCE SUPPORT IT? PMID- 28568543 TI - MOLECULAR ANALYSIS OF THE ALLELES OF ALCOHOL DEHYDROGENASE ALONG A CLINE IN DROSOPHILA MELANOGASTER. I. MAINE, NORTH CAROLINA, AND FLORIDA. AB - Clinal variation in natural populations is often assumed to be due to the operation of natural selection. However, for many clines there exist plausible neutralist explanations which suggest that aspects of population structure maintain differences among subpopulations for particular traits. We used a restriction-mapping technique to investigate the contributions of population subdivision and selection to the maintenance of the allozyme polymorphism at the alcohol dehydrogenase (Adh) locus of Drosophila melanogaster. Digestions of genomic DNAs from 270 lines of flies by seven enzymes reveal 15-20% of all possible nucleotide substitutions and virtually all of the insertion/deletion variation in a 2.7-kilobase region containing the Adh structural locus. Analysis of large samples from each of three populations along the east coast of the United States provides evidence of founder effects in the most northerly population. Although there are signs of population differentiation among the samples, similarities between two of the populations indicate that migration among populations is extensive and strengthen the argument that natural selection plays a role in maintaining the cline. PMID- 28568544 TI - EVOLUTION OFFICE STAFF, 1988. PMID- 28568545 TI - MOLECULAR GENETIC-DISTANCE ESTIMATES AMONG THE URSIDAE AS INDICATED BY ONE- AND TWO-DIMENSIONAL PROTEIN ELECTROPHORESIS. AB - Evolutionary relationships among eight species of Ursidae (including the giant panda) relative to two Procyonidae species (raccoon and red panda) were estimated based on the extent of electrophoretic variation of 289 radiolabelled fibroblast proteins resolved by two-dimensional gel electrophoresis and among 44 isozyme loci resolved by one-dimensional electrophoresis. Allelic differences among these species were converted to genetic distances, and phenetic trees were constructed. In addition, the electrophoretic data were coded as unit characters, and minimum length trees were derived based on the Wagner method using maximum parsimony. Regardless of the tree-building method employed, the data sets agreed on the following branching sequence: between 22.4 and 32.3 million years (MY) ago, the ancestors of the procyonids and the ursids split into two lineages. Within 10 MY, the red panda split from the line that led to the raccoon. An ancestor of the giant panda split from the ursid line 18-22 MY ago, and the South American spectacled bear split from the line leading to ursine bears 10.5-15.0 MY B.P. A group of six closely related ursine bears (brown bear, polar bear, Asiatic black bear, Malayan sun bear, American black bear, and sloth bear) diverged from a common ancestor during the past 4-8 MY. Much of this ursine radiation was not resolved by our results, with the exception of a recent (2-3 MY B.P.) divergence of brown bear and polar bear. The topological concordance of the data sets from one- and two-dimensional electrophoresis supports the usefulness of these procedures for evolutionary inference and provides additional precision to the reconstruction of divergence nodes of this carnivore group. PMID- 28568546 TI - LOSS OF NUPTIAL COLOR IN THREESPINE STICKLEBACKS (GASTEROSTEUS ACULEATUS). AB - Loss of conspicuous nuptial color in Gasterosteus aculeatus (threespine stickleback) has been reported from several localities in western North America and is ascribed to increased rates of predation or to convergent threat displays. I have examined 66 populations of G. aculeatus from the Queen Charlotte Archipelago and found extensive variation in the expression of red nuptial color. Males in 31 of the populations lack red throats, while males in five populations have major expression of red nuptial color. I test two hypotheses for nuptial color loss: that the loss results from increased predation rates and that it involves differences in water spectra (relative transmission at 400 nm). Results, which are consistent with the second hypothesis, show that the greatest expression of red pigment occurs in habitats with the highest water clarity, while loss of red nuptial color is generally found in heavily stained waters. There is no correlation between nuptial-color loss and presence or absence of vertebrate predators. Two new hypotheses for these associations are proposed: signal-masking in spectrally restricted habitats and carotenoid deficiencies in the diet. Previous studies of red nuptial color and its loss in Gasterosteus merit additional attention, given the associations with underwater spectra. PMID- 28568547 TI - MEASUREMENTS OF SELECTION IN A HERMAPHRODITIC PLANT: VARIATION IN MALE AND FEMALE POLLINATION SUCCESS. AB - I measured phenotypic selection of floral traits through both male and female functions of the hermaphroditic flowers of Ipomopsis aggregata (Pursh) V. Grant subsp. aggregata (Polemoniaceae). Fluorescent powdered dyes were used to track movement of pollen by hummingbirds and to measure pollen delivery to individual plants as well as pollen receipt. A phenotypic selection analysis revealed that selection due to male-male competition during pollination was capable of delaying flowering date and widening corolla tubes by 0.22 and 0.24 standard-deviation units, respectively, in a single generation. Several floral traits were highly correlated with each other. Multivariate selection analysis suggested that selection through male function directly favored late flowering as well as a sexual expression characterized by a short pistillate phase and long corollas. Selection intensities through male and female functions were of similar overall magnitude during the pollination stage of the life cycle, but different traits were favored, and selection sometimes acted in opposing directions. In 1985, selection through female function favored increased time spent in the pistillate phase and exserted stigmas (unlike selection through male function). As a result, individual plants varied greatly in functional gender. Plants that had exserted stigmas and narrow corollas and that spent a disproportionately long time in the pistillate phase achieved greater pollination success as females, while plants with the opposite traits achieved greater success as males. Moreover, female pollination success tended to increase, and male pollination success to decrease, with time spent in the pistillate phase, supporting a critical assumption of sex allocation theory. Selection in the populations studied fluctuated from year to year and was highly sex-specific. PMID- 28568548 TI - REVERSE SEX-RATIO ADJUSTMENT IN AN APPARENTLY OUTBREEDING WASP, BRACON HEBETOR. PMID- 28568549 TI - DENSITY-DEPENDENT EVOLUTION OF LIFE-HISTORY TRAITS IN DROSOPHILA MELANOGASTER. AB - Populations of Drosophila melanogaster were maintained for 36 generations in r- and K-selected environments in order to test the life-history predictions of theories on density-dependent selection. In the r-selection environment, populations were reduced to low densities by density-independent adult mortality, whereas populations in the K-selection environment were maintained at their carrying capacity. Some of the experimental results support the predictions or r- and K-selection theory; relative to the r-selected populations, the K-selected populations evolved an increased larval-to-adult viability, larger body size, and longer development time at high larval densities. Mueller and Ayala (1981) found that K-selected populations also have a higher rate of population growth at high densities. Other predictions of the thoery are contradicted by the lack of differences between the r and K populations in adult longevity and fecundity and a slower rate of development for r-selected individuals at low densities. The differences between selected populations in larval survivorship, larval-to-adult development time, and adult body size are strongly dependent on larval density, and there is a significant interaction between populations and larval density for each trait. This manifests an inadequacy of the theory on r- and K-selection, which does not take into account such interactions between genotypes and environments. We describe mechanisms that may explain the evolution of preadult life-history traits in our experiment and discuss the need for changes in theories of density-dependent selection. PMID- 28568551 TI - EVOLUTIONARY INFERENCES FROM A COMPARISON OF COCKROACH NUCLEAR DNA AND DNA FROM THEIR FAT-BODY AND EGG ENDOSYMBIONTS. AB - DNA was isolated from muscle tissue and from concentrations of the egg and fat body endosymbionts of the cockroaches Periplaneta americana, Blatta orientalis, Blaberus giganteus, Gromphadorhina portentosa, Leucophaea maderae, Cryptocercus punctulatus, and Nyctibora lutzi. Denatured DNA from each was immobilized on nitrocellulose membranes and reassociated with labeled probe DNAs from egg endosymbionts and muscle nuclei of B. orientalis. The DNAs were compared by extent of binding and by the thermal melting profiles of the DNA duplexes. The DNAs from the endosymbionts in the eggs and fat body in both P. americana and B. orientalis were shown to be virtually identical, confirming that transovarial transmission of the bacteria does take place. The thermal stabilities of the heteroduplexes formed with the probe DNA from egg endosymbionts of B. orientalis differed from the homologous duplexes by only 1 degrees -11 degrees C, indicating a close relationship among the endosymbiont strains. The heteroduplexes of the nuclear DNAs differ from the homologous duplexes by 2 degrees -7 degrees C. Compared with known systems in bacterial and Drosophila species, these results indicate similar base-pair mismatches for host and endosymbiont DNAs. From these correlations, we deduce that the endosymbionts have probably been associated with their host cockroaches since before the latter speciated. PMID- 28568552 TI - ECOLOGICAL GENETICS OF A MOSAIC HYBRID ZONE: MITOCHONDRIAL, NUCLEAR, AND REPRODUCTIVE DIFFERENTIATION OF CRICKETS BY SOIL TYPE. AB - We investigated the effects that habitat variation has on the structure and dynamics of a hybrid zone between two closely related crickets in Connecticut. A collecting protocol was developed in which crickets were sampled from characteristic habitats on either side of the hybrid zone and from two distinct habitat types within the zone. Presumptive pure Gryllus pennsylvanicus were sampled from fields in northwestern Connecticut and represent "inland" populations. "Pure" Gryllus firmus were sampled from beaches along the coast and represent the "coastal" populations. Crickets from within the hybrid zone were sampled from two different soil types: the "loam" populations from loamy soils and the "sand" populations from sandy soils. Moreover, an attempt was made to identify closely adjacent sand and loam localities to determine the scale of habitat variation and its possible effects on hybrid-zone structure. In general, there was little variation in morphological traits or in allozyme and mtDNA genotype frequencies among localities from within each of the four habitat types. Between each of the closely situated sand and loam localities within the hybrid zone, however, there were very significant differences in each of these sets of markers. In addition, crickets from hybrid-zone populations were tested for reproductive isolation. The asymmetric outcome of hybrid crosses that exists across the zone (Harrison, 1983) also exists on a finer ecological scale within the zone. Thus, this hybrid zone is a mosaic of strikingly differentiated populations. The dynamics of hybrid zones with mosaic structures are discussed in contrast to the traditional clinal models. The data are also discussed in light of the semipermeable nature of species boundaries. The extent to which a species boundary is permeable varies not only from one genetic marker to the next, but also with the ecological and geographic context of species interaction. PMID- 28568553 TI - TEMPORAL VARIATION IN SELECTION ON A FLORAL CHARACTER. PMID- 28568554 TI - PATTERNS OF SPECIATION IN DROSOPHILA. AB - To investigate the time course of speciation, we gathered literature data on 119 pairs of closely related Drosophila species with known genetic distances, mating discrimination, strength of hybrid sterility and inviability, and geographic ranges. Because genetic distance is correlated with divergence time, these data provide a cross-section of taxa at different stages of speciation. Mating discrimination and the sterility or inviability of hybrids increase gradually with time. Hybrid sterility and inviability evolve at similar rates. Among allopatric species, mating discrimination and postzygotic isolation evolve at comparable rates, but among sympatric species strong mating discrimination appears well before severe sterility or inviability. This suggests that prezygotic reproductive isolation may be reinforced when allopatric taxa become sympatric. Analysis of the evolution of postzygotic isolation shows that recently diverged taxa usually produce sterile or inviable male but not female hybrids. Moreover, there is a large temporal gap between the evolution of male-limited and female hybrid sterility or inviability. This gap, which is predicted by recent theories about the genetics of speciation, explains the overwhelming preponderance of hybridizations yielding male-limited hybrid sterility or inviability (Haldane's rule). PMID- 28568555 TI - ESTIMATING RELATEDNESS USING GENETIC MARKERS. AB - A new method is described for estimating genetic relatedness from genetic markers such as protein polymorphisms. It is based on Grafen's (1985) relatedness coefficient and is most easily interpreted in terms of identity by descent rather than as a genetic regression. It has several advantages over methods currently in use: it eliminates a downward bias for small sample sizes; it improves estimation of relatedness for subsets of population samples; and it allows estimation of relatedness for a single group or for a single pair of individuals. Individual estimates of relatedness tend to be highly variable but, in aggregate, can still be very useful as data for nonparametric tests. Such tests allow testing for differences in relatedness between two samples or for correlating individual relatedness values with another variable. PMID- 28568556 TI - STRONG NATURAL SELECTION IN A WARNING-COLOR HYBRID ZONE. AB - Frequency-dependent selection on warning color can maintain narrow hybrid zones between unpalatable prey taxa. To measure such selection, we transferred marked Heliconius erato (Lepidoptera: Nymphalidae) in both directions across a 10-km wide hybrid zone between Peruvian races differing in color pattern. These experimental H. erato were released at four sites, along with control H. erato of the phenotype native to each site. Survival of experimental butterflies was significantly lower than that of controls at two sites and overall. Most selection, measured as differences in survival, occurred soon after release. Selection against foreign morphs was 52% (confidence limits: 25-71 %) and was probably due to bird attacks on unusual warning-color morphs (more than 10% of the recaptures had beak marks). Since only three major loci determine the color pattern differences, this suggests an average selection coefficient of 0.17 per locus, sufficient to maintain the narrow clines in H. erato. PMID- 28568557 TI - INTERSPECIFIC HYBRIDS OF DROSOPHILA HETERONEURA AND D. SILVESTRIS I. COURTSHIP SUCCESS. AB - Drosophila heteroneura and D. silvestris are well-defined, sympatric species of the planitibia subgroup of Hawaiian Drosophila. D. silvestris can be subdivided into two allopatric morphotypes that differ in the number of bristle rows on the front tibia (two rows versus three rows). We measured courtship success of intraspecific and interspecific hybrids as the proportion of females inseminated during a two-week period with a single sib male. Proportions were arcsin transformed so that the values were asymptotically normal in distribution, and tests of homogeneity and of mean differences were performed. Of key importance is the discovery of genetic variation for the proportion of inseminated females within both D. heteroneura and D. silvestris. The interspecific crosses and the D. silvestris intraspecific crosses also provide evidence for a coadapted gene complex with some dominance or heterosis. This coadapted gene complex correlates with the morphotypes of these flies, rather than with the D. heteroneura/D. silvestris contrasts per se. This observation stresses the importance of recognizing both behavioral and morphological components of the mate-recognition system. The incompatible coadaptation that separates the two-row from the three row forms also supports recent molecular studies which indicate that the three row form split from the two-row form prior to the split between D. heteroneura and two-row D. silvestris. The observations of intraspecific variability and coadaptation support the predictions of a genetic-transilience model which explains the origin of a new mate-recognition system in terms of sexual selection in the context of a founder-flush event. PMID- 28568558 TI - THE EVOLUTION OF PHENOTYPIC VARIANCE WITH ITEROPARITY. PMID- 28568559 TI - THE MAINTENANCE OF SEX BY GROUP SELECTION. AB - The traditional group-selection model for the maintenance of sex is based upon the assumption that the long-term evolutionary benefits of sexual reproduction result in asexual lineages having a higher extinction rate than sexual species. This model is reexamined, as is a related model that incorporates the possibility that sexual and asexual lines differ in their speciation rates. In these models, the long-term advantage of sex is opposed by a strong short-term disadvantage arising from the twofold reproductive cost of producing males. It is shown that once some sexual lines become established, then group selection can act to maintain sex despite its short-term disadvantage. The short-term disadvantage is included in the model by assuming that, if asexual individuals arise by mutation within a previously completely sexual species, then the asexuals quickly displace their sexual conspecifics and the species is transformed to asexuality. The probability of this event is given by the transition rate, us . If the value of us varies between lineages, then one of the effects of group selection is to favor groups (i.e., species) with the lowest values of us . This occurs because lines that do convert to asexuality (because of a high us ) are doomed to a high rate of extinction, and in the long term only those that do not convert to asexuality (because of a low us ) survive. The net result of group selection is that sex is maintained because of its lower extinction rate (or higher speciation rate) and because asexual mutants only rarely arise. PMID- 28568560 TI - INTERSEXUAL COMPARISON OF MIMETIC PROTECTION IN THE BLACK SWALLOWTAIL BUTTERFLY, PAPILIO POLYXENES: EXPERIMENTS WITH CAPTIVE BLUE JAY PREDATORS. AB - The black swallowtail butterfly (Papilio polyxenes asterius Stoll), is commonly assumed to exhibit female-limited Batesian mimicry of the aposematic pipevine swallowtail (Battus philenor [L.]), since the dorsal wing surfaces of P. polyxenes females, but not males, resemble those of the model. However, the ventral wing surface is monomorphic and closely resembles that of the model in both sexes. Thus both sexes of P. polyxenes should benefit from mimicry during periods of ventral surface exposure, such as during overnight roosting and other times of high predatory risk. Eight blue jays (Cyanocitta cristata L.) were offered ventrally and dorsally exposed butterfly prey items in an outdoor aviary. Model-conditioned birds refused male and female P. polyxenes equally when the butterflies were presented ventrally. However, significantly more males than females were attacked when the dimorphic dorsum was visible. Both sexes are thus similarly protected when the ventral wing surface is displayed during roosting. The high degree of bird-to-bird variability in response to P. polyxenes mimics suggests that there is a spectrum in ability or willingness of predators to discriminate among mimics of varying similarity to the model. Sexual dimorphism of the dorsal surface of P. polyxenes wings may reflect sexual selection favoring males that are recognizable as satisfactory mates or intrasexual competitors. PMID- 28568561 TI - PHYLOGENETIC RELATIONSHIPS AND MOLECULAR VARIABILITY WITHIN AND AMONG SIX CHROMOSOME RACES OF SCELOPORUS GRAMMICUS (SAURIA, IGUANIDAE), BASED ON NUCLEAR AND MITOCHONDRIAL MARKERS. AB - Selected populations of Sceloporus grammicus from central Mexico were karyotyped and screened for variability at the protein, ribosomal-DNA, and mitochondrial-DNA levels. Molecular markers were used to construct phylogenies of the chromosome races, which were then qualitatively evaluated for congruence with each other and with the original chromosomal phytogeny proposed by Hall (1973). Between-cytotype protein divergence generally was low, and few allozyme markers were fixed between cytotypes. Hence, these data were combined with the rDNA restriction-site data for phylogeny reconstruction. This combined nuclear data set provided a phylogenetic hypothesis that, with one exception, is reasonably congruent with that based on standard karyotypes. Similar results were obtained from mtDNA restriction-site data, although there are some discrepancies, and trees based on both DNA data sets are complicated by evidence for historical and/or ongoing hybridization. An unexpectedly rapid rate of rDNA divergence is demonstrated relative to the degree of allozyme divergence, suggesting that restriction-site variation in rDNA has systematic utility at lower taxonomic levels. PMID- 28568562 TI - THE IMPACT OF A FLOWER-COLOR POLYMORPHISM ON MATING PATTERNS IN EXPERIMENTAL POPULATIONS OF WILD RADISH (RAPHANUS RAPHANISTRUM L.). AB - We conducted field experiments to determine how a naturally occurring petal-color polymorphism influences mating patterns in wild radish (Raphanus raphanistrum). The polymorphism is controlled at a single genetic locus, with white petal color being completely dominant to yellow. In experimental populations with equal numbers of yellow- and white-flowered homozygous individuals, insect visitors strongly discriminated against white flowers. Pieris rapae, the most frequent pollinator, was almost 50% more likely to visit yellow than white flowers. Maternal fecundity did not differ between the morphs and was not significantly influenced by a plant's compatibility with potential donors, suggesting that seed production was not limited by receipt of compatible pollen. In contrast, the yellow-flowered morph sired approximately 75% of all seeds produced during the study. This paternity proportion was consistently greater than that expected on the basis of postpollination compatibility measures and was indistinguishable from that expected on the basis of pollinator-visitation frequency. We conclude that the male-fitness advantage of the yellow morph resulted from enhanced pollen export due to the greater attractiveness of its flowers to insect pollinators. With color morphs evenly distributed in experimental arrays, insects did not move assortatively on the basis of petal color, and we found no evidence for assortative pollen flow due to the floral polymorphism. Once postpollination compatibility relationships within populations were taken into account, paternal success of yellow donors did not differ between yellow- and white-flowered maternal plants. PMID- 28568563 TI - LABORATORY EVOLUTION OF EPICUTICULAR HYDROCARBON COMPOSITION AND CUTICULAR PERMEABILITY IN DROSOPHILA PSEUDOOBSCURA: EFFECTS ON SEXUAL DIMORPHISM AND THERMAL-ACCLIMATION ABILITY. PMID- 28568564 TI - Long-term clinical results of bioresorbable absorb scaffolds using the PSP technique in patients with and without diabetes. AB - OBJECTIVES: We evaluated clinical results up to 36 months after implantation of Absorb BVS using PSP-technique and compared the outcome of patients with and without diabetes mellitus. BACKGROUND: Absorb II demonstrated that interventional treatment of coronary artery disease with bioresorbable vascular scaffolds (BVS) without proper PSP-technique (pre-dilation, proper sizing, and post-dilation) is associated with an increased thrombotic risk, even in simple lesions. METHODS: In this prospective study 319 patients with 420 lesions were enrolled and treated with the Absorb BVS. Pre-dilation was mandatory and post-dilation with a high pressure balloon was performed in patients with a scaffold length >12 mm. Patients were clinically followed up to 3 years. Primary outcome measure was the device-oriented endpoint (DoCE) defined as cardiac death, myocardial infarction not clearly related to a non-target vessel and target lesion revascularization. RESULTS: DoCE was 5.0%, 7.1%, and 10.0% after 12, 24, and 36 months for the total population. Rate of scaffold thrombosis was 0.5%, 0.8%, and 1.4% after 12, 24, and 36 months. Rate of DoCE was higher in the diabetic subgroup with 9.1%, 12.6%, and 12.9% after 12, 24, and 36 months compared with 4.0% (P = 0.13), 5.6% (P = 0.05), and 9.9% (P = 0.20) in patients without diabetes mellitus. CONCLUSIONS: Patients treated with the Absorb BVS using the PSP-technique show good results up to 3 years with a low rate of scaffold thrombosis. Patients suffering from diabetes mellitus have an increased rate of DoCE compared with non-diabetic patients. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov_NCT02162056. PMID- 28568565 TI - Inhibition of Th1 and Th17 Cells by Medicinal Plants and Their Derivatives: A Systematic Review. AB - Searching for new natural drugs that are capable of targeting Th1 and Th17 may lead to development of more effective treatments for inflammatory and autoimmune diseases. Most of the natural drugs can be derived from plants that are used in traditional medicine and folk medicine. The aim of this systematic review is to identify and introduce plants or plant derivatives that are effective on inflammatory diseases by inhibiting Th1 and Th17 responses. To achieve this purpose, the search terms herb, herbal medicine, herbal drug, medicinal plant, phytochemical, traditional Chinese medicine, Ayurvedic medicine, natural compound, inflammation, inflammatory diseases, Th1, Th17, T helper 1 or T helper 17 were used separately in Title/Keywords/Abstract in Web of Science and PubMed databases. In articles investigating the effect of the medicinal plants and their derivatives in inhibiting Th1 and Th17 cells, the effects of eight extracts of the medicinal plants, 21 plant-based compounds and some of their derivatives, and eight drugs derived from the medicinal plants' compounds in inhibiting Th1 and Th17 cells were reviewed. The results showed that medicinal plants and their derivates are able to suppress Th17 and Th1 T cell functions as well as cytokine secretion and differentiation. The results can be used to produce herbal drugs that suppress Th, especially Th17, responses. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28568566 TI - Quantitative Modeling and Simulation in PMDA: A Japanese Regulatory Perspective. AB - In Japan in October 2016, the Pharmaceuticals and Medical Devices Agency (PMDA) began to receive electronic data in new drug applications (NDAs). These electronic data are useful to conduct regulatory assessment of sponsors' submissions and contribute to the PMDA's research. In this article, we summarize the number of submissions of quantitative modeling and simulation (M&S) documents in NDAs in Japan, and we describe our current thinking and activities about quantitative M&S in PMDA. PMID- 28568567 TI - INTRASPECIFIC PHYLOGEOGRAPHY OF NORTH AMERICAN HIGHLAND FISHES: A TEST OF THE PLEISTOCENE VICARIANCE HYPOTHESIS. AB - The highland fish fauna of eastern North America consists of Appalachian and Ozark centers of endemism separated by the intervening Glacial Till Plains. Clades within these areas are more closely related phylogenetically to each other than to clades occurring in the intervening formerly glaciated region, suggesting that the Pleistocene glaciations fragmented a widespread highland region and its associated fauna. Alternatively, it is possible that these faunal assemblages predate the glaciations or that recent dispersals may have been more important than vicariance in determining faunal compositions. We examined the relationships among mitochondrial DNA (mtDNA) haplotypes within five clades of highland fishes, each with a distribution suggestive of a Pleistocene vicariance event. Darters of the subgenera Litocara and Odontopholis have distributions and mtDNA relationships that are consistent with the Pleistocene integration and burial of the Teays-Mahomet valley, a major drainage of the early Pleistocene. The distribution and mtDNA relationships among subspecies of Erimystax dissimilis are not consistent with Pleistocene vicariance, but relationships among Appalachian haplotypes are consistent with the late Pleistocene integration of the modern Ohio River system. Both Cottus carolinae and the Fundulus catenatus species group have representatives in the Mobile basin consistent with pre-Pleistocene divergences. Three haplotype clusters were found in C. carolinae, corresponding to the Appalachian, Ozark, and upper Kanawha River populations. However, Appalachian and Ozark F. catenatus populations are paraphyletic with respect to each other. This, coupled with a relatively low degree of sequence divergence, suggests that no long-term barriers to gene flow exist for C. carolinae and F. catenatus. These three distinct phylogeographic patterns indicate that Pleistocene vicariance is not the only explanation for the Appalachian-Ozark distribution of highland fish communities. PMID- 28568568 TI - GENETIC EVIDENCE FOR LONG TERM PERSISTENCE OF MARINE INVERTEBRATE POPULATIONS IN AN EPHEMERAL ENVIRONMENT. PMID- 28568569 TI - QUANTITATIVE GENETIC VARIANCE MAINTAINED BY FLUCTUATING SELECTION WITH OVERLAPPING GENERATIONS: VARIANCE COMPONENTS AND COVARIANCES. AB - The quantitative genetic variance-covariance that can be maintained in a random environment is studied, assuming overlapping generations and Gaussian stabilizing selection with a fluctuating optimum. The phenotype of an individual is assumed to be determined by additive contributions from each locus on paternal and maternal gametes (i.e., no epistasis and no dominance). Recurrent mutation is ignored, but linkage between loci is arbitrary. The genotype distribution in the evolutionarily stable population is generically discrete: only a finite number of polymorphic alleles with distinctly different effects are maintained, even though we allow a continuum of alleles with arbitrary phenotypic contributions to invade. Fluctuating selection maintains nonzero genetic variance in the evolutionarily stable population if the environmental heterogeneity is larger than a certain threshold. Explicit asymptotic expressions for the standing variance-covariance components are derived for the population near the threshold, or for large generational overlap, as a function of environmental variability and genetic parameters (i.e., number of loci, recombination rate, etc.), using the fact that the genotype distribution is discrete. Above the threshold, the population maintains considerable genetic variance in the form of positive linkage disequilibrium and positive gamete covariance (Hardy-Weinberg disequilibrium) as well as allelic variance. The relative proportion of these disequilibrium variances in the total genetic variance increases with the environmental variability. PMID- 28568570 TI - GENETICS OF SEXUAL ISOLATION AND COURTSHIP DYSFUNCTION IN MALE HYBRIDS OF DROSOPHILA PSEUDOOBSCURA AND DROSOPHILA PERSIMILIS. AB - Despite the importance of sexual isolation to speciation, few studies have analyzed the genetic basis of interspecific mating discrimination, particularly using hybrid males. In this study, I investigated the genetic basis of sexual isolation using male hybrids of Drosophila pseudoobscura and D. persimilis. Hybrid male mating success was caused by interactions between the X-chromosome and autosomes (or Y-chromosome), and different arms of the X-chromosome contributed to mating success with females of each species. Further, although there was an X-chromosome component to mating success, its magnitude was not disproportionately large when compared with the proportion of the genome contained on this chromosome. Some hybrid males courted with an anomalously low intensity, so I simultaneously mapped the genetic basis of this "courtship dysfunction." The courtship dysfunction was caused by an interaction between the left arm of the X-chromosome in D. persimilis with the autosomes or Y-chromosome from D. pseudoobscura. Anomalous courtship behavior in interspecific hybrids can obscure the conclusions of studies of the genetics of sexual isolation, so courtship intensity should be evaluated in all such investigations. PMID- 28568571 TI - THE EVOLUTION OF SPERM SIZE IN BIRDS. AB - Sperm size varies enormously among species, but the reasons for this variation remain obscure. Since it has been suggested that swimming velocity increases with sperm length, earlier studies proposed longer (and therefore faster) sperm are advantageous under conditions of intense sperm competition. Nonetheless, previous work has been equivocal, perhaps because the intensity of sperm competition was measured indirectly. DNA profiling now provides a more direct measure of the number of offspring sired by extrapair males, and thus a more direct method of assessing the potential for sperm competition. Using a sample of 21 species of passerine birds for which DNA profiling data were available, we found a positive relation between sperm length and the degree of extrapair paternity. A path analysis, however, revealed that this relationship arises only indirectly through the positive relationship between the rate of extrapair paternity and length of sperm storage tubules (SSTs) in the female. As sperm length is correlated positively with SST length, an increase in the intensity of sperm competition leads to an increase in sperm length only through its effect on SST length. Why females vary SST length with the intensity of sperm competition is not clear, but one possibility is that it increases female control over how sperm are used in fertilization. Males, in turn, may respond on an evolutionary time scale to changes in SST size by increasing sperm length to prevent displacement from rival sperm. Previous theoretical analyses predicting that sperm size should decrease as sperm competition becomes more intense were not supported by our findings. We suggest that future models of sperm-size evolution consider not only the role of sperm competition, but also how female control and manipulation of ejaculates after insemination selects for different sperm morphologies. PMID- 28568572 TI - EVOLUTION OF GYNODIOECY AND MAINTENANCE OF FEMALES: THE ROLE OF INBREEDING DEPRESSION, OUTCROSSING RATES, AND RESOURCE ALLOCATION IN SCHIEDEA ADAMANTIS (CARYOPHYLLACEAE). AB - Levels of inbreeding depression, outcrossing rates, and phenotypic patterns of resource allocation were studied to examine their relative importance in the maintenance of high numbers of females in gynodioecious Schiedea adamantis (Caryophyllaceae), an endemic Hawaiian shrub found in a single population on Diamond Head Crater, Oahu. In studies of inbreeding depression in two greenhouse environments, families of hermaphrodites exhibited significant inbreeding depression (delta = 0.60), based on a multiplicative fitness function using seeds per capsule, germination, survival, and the inflorescence biomass of progeny. Differences between inbred and outcrossed progeny were smallest at the early stage of seeds per capsule and more pronounced at the later stages of survival and inflorescence production. These results are consistent with inbreeding depression caused by many mutations of small effect. Using allozyme analyses, the inbreeding coefficient of adult plants in the field was not significantly different from zero, implying that delta in nature may be equal to one. The single locus estimate of the outcrossing rate for hermaphrodites was 0.50 based on progeny that survived to flowering; corrected for the disproportionate loss before flowering of progeny from selfing, the adjusted outcrossing rate at the zygote stage was 0.32, suggesting that considerable selfing occurs in hermaphrodites. Females were totally outcrossed. When females and hermaphrodites were compared for reproductive output in the field, females produced over twice as many seeds per plant as hermaphrodites, primarily because females had far more capsules per inflorescence than hermaphrodites. Females had greater mass per seed than hermaphrodites in the field, either because of greater provisioning or reduced inbreeding depression. There was no significant differential mortality with respect to sex over a seven year period. The higher number of seeds per plant of females, combined with substantial inbreeding depression and relatively high selfing rates for hermaphrodites, are probably responsible for the maintenance of females in this population. The predicted frequency of females based on data for seed production, the adjusted selfing rate, and inbreeding depression is 42%, remarkably close to the observed frequency of 39%. High levels of inbreeding depression suggest that considerable quantitative genetic variation is present for traits affecting fitness in this population, despite low allozyme variability and a presumed founder effect. PMID- 28568573 TI - SPONTANEOUS MUTATIONAL GENOTYPE-ENVIRONMENT INTERACTION FOR FITNESS-RELATED TRAITS IN DROSOPHILA MELANOGASTER. AB - Spontaneous mutations were allowed to accumulate for 104-161 generations in 113 176 inbred lines, independently maintained by a single brother-sister mating per generation, all of them derived from a completely homozygous population of Drosophila melanogaster. In each of two to three consecutive generations, all lines were scored for fecundity, egg-to-pupa and pupa-to-adult viabilities, both in the standard laboratory culture medium (ST) and in three harsh media differing from the former by a single factor: higher temperature (HT), higher NaCl concentration (HSC), or a much reduced concentration of nutrients (D). Relative to the standard medium, productivity (fecundity * viability) decreased by 25% (HT), 66% (HSC), and 80% (D). In each medium, mutational variances of those traits and mutational covariances between all possible pairs were calculated from the between-line divergence (codivergence). Mutational correlations between character states in different media were also obtained. Because we used inbred lines, those estimates were mainly due to the accumulation of mildly detrimental mutations, deleterious mutations of large effect being underrepresented. For all traits, mutational heritabilities ranged from 1.41 * 10-4 to 11.24 * 10-4 , and did not increase with intensified environmental harshness. Mutational correlations between character states in different media were usually not large (average absolute value 0.31), reflecting a high degree of environmental specificity of the mutations involved. In our results, mutations quasi-neutral in ST conditions and mildly detrimental in more stressful media were not, as a class, important. Mutational correlations between fecundity and egg-to-pupa viability were small and positive in all media. Those involving pupa-to-adult viability were positive in HT, nonsignificant in HSC, and negative in ST and D, showing how the genetic covariance structure of quantitative traits in populations may change in variable environments. PMID- 28568574 TI - SINGLE LOCUS CLINES. PMID- 28568575 TI - ERRATA. PMID- 28568576 TI - A TIME COMMITMENT HYPOTHESIS FOR SIZE-DEPENDENT GENDER ALLOCATION. PMID- 28568577 TI - GENE DISPERSAL AND SPATIAL GENETIC STRUCTURE. AB - Spatial autocorrelation statistics have been studied in theoretical population genetic models and widely used in experimental studies of spatial structure in many plant and animal populations. However, the statistical properties of spatial autocorrelation statistics have remained uncharacterized. Little is known about how values of spatial autocorrelation statistics in population samples depend on the level of dispersal and scheme of sampling. In this paper, we characterize the statistical properties of join-count spatial autocorrelation statistics for population genetic surveys under various conditions of dispersal and sampling. The results indicate generally high statistical power. These results can provide a method to estimate gene dispersal based on standing spatial patterns of genetic variation observed within populations. PMID- 28568578 TI - IS THE PRODUCTION OF MULTIPLE SPERM TYPES ADAPTIVE? AB - Males of many species concurrently produce more than one sperm type, now called sperm heteromorphism. In the Drosophila obscura group, all species examined to date produce multiple sperm types that differ in sperm length. Short sperm types in at least three obscura group species do not participate in fertilization, leading to questions regarding the adaptive value of sperm heteromorphism. The common and pervasive inheritance of this trait in the obscura group, however, may indicate that sperm heteromorphism is phylogenetically constrained and therefore does not reflect an adaptive response to selection pressures. I measured interspecific variation in sperm length and determined the number of sperm types produced in 10 obscura group species. I subsequently tested if interspecific variation in sperm length is significantly associated with phylogeny by using an autoregressive comparative method. All obscura group species examined produce two visually distinct sperm lengths, short and long. Phylogenetic autoregression analyses indicated that 22% of the interspecific variation in long sperm is related to phylogeny, whereas short sperm are not significantly correlated with phylogeny. These results suggest different selection pressures on the two sperm length types; long sperm have evolved in response to fertilization demands and short sperm have been decoupled from these requirements. PMID- 28568579 TI - BODY SIZE AND SEXUAL SIZE DIMORPHISM IN MARINE IGUANAS FLUCTUATE AS A RESULT OF OPPOSING NATURAL AND SEXUAL SELECTION: AN ISLAND COMPARISON. AB - Body size is often assumed to represent the outcome of conflicting selection pressures of natural and sexual selection. Marine iguana (Amblyrhynchus cristatus) populations in the Galapagos exhibit 10-fold differences in body mass between island populations. There is also strong sexual size dimorphism, with males being about twice as heavy as females. To understand the evolutionary processes shaping body size in marine iguanas, we analyzed the selection differentials on body size in two island populations (max. male mass 900 g in Genovesa, 3500 g in Santa Fe). Factors that usually confound any evolutionary analysis of body sizes-predation, interspecific food competition, reproductive role division-are ruled out for marine iguanas. We show that, above hatchlings, mortality rates increased with body size in both sexes to the same extent. This effect was independent of individual age. The largest animals (males) of each island were the first to die once environmental conditions deteriorated (e.g., during El Ninos). This sex-biased mortality was the result of sexual size dimorphism, but at the same time caused sexual size dimorphism to fluctuate. Mortality differed between seasons (selection differentials as low as -1.4) and acted on different absolute body sizes between islands. Both males and females did not cease growth when an optimal body size for survival was reached, as demonstrated by the fact that individual adult body size phenotypically increased in each population under favorable environmental conditions beyond naturally selected limits. But why did marine iguanas grow "too large" for survival? Due to lek mating, sexual selection constantly favored large body size in males (selection differentials up to +0.77). Females only need to reach a body size sufficient to produce surviving offspring. Thereafter, large body size of females was less favored by fertility selection than large size in males. Resulting from these different selection pressures on male and female size, sexual size dimorphism was mechanistically caused by the fact that females matured at an earlier age and size than males, whereafter they constantly allocated resources into eggs, which slowed growth. The observed allometric increase in sexual size dimorphism is explained by the fact that the difference between these selective processes becomes larger as energy abundance in the environment increases. Because body size is generally highly heritable, these selective processes are expected to lead to genetic differences in body size between islands. We propose a common-garden experiment to determine the influence of genetic factors and phenotypic reaction norms of final body size. PMID- 28568580 TI - PREDATION BY FREE-RANGING BIRDS ON PARTIAL CORAL SNAKE MIMICS: THE IMPORTANCE OF RING WIDTH AND COLOR. PMID- 28568581 TI - NEGATIVE FREQUENCY-DEPENDENT SELECTION BY POLLINATORS ON ARTIFICIAL FLOWERS WITHOUT REWARDS. AB - Many species of nonmodel deceptively pollinated orchids are polymorphic for corolla color. These species are pollinated by naive insects searching for nectar, and are not mimics. It has been suggested that the foraging behavior of insect pollinators during the avoidance learning process results in these stable corolla color polymorphisms; for this to occur pollinators must induce negative frequency-dependent selection on corolla color. Therefore the hypothesis that pollinator behavior results in a preference for rare color morphs of deceptive species was tested experimentally. Bumblebees (Bombus terrestris) foraged in the laboratory on arrays of artificial flowers with different corolla color morphs. Morphs were varied in frequency, and bumblebee preferences were recorded on arrays where morphs did and did not contain sucrose solution rewards. Bumblebees preferred the most common color morph when flowers contained sucrose solution rewards, but overvisited rare morphs when sampling flowers that contained no rewards. Bumblebees also tended to move between unlike color morphs when these were unrewarding, suggesting that a probabilistic sampling strategy was adopted. Thus experiments demonstrated that pollinator behavior could result in a selective advantage for rare color morphs of plant species that are pollinated by deception without mimicry, which would induce negative frequency-dependent selection on corolla color. The observed pollinator behavior could allow stable corolla color polymorphisms to be maintained by selection in nonmodel deceptively pollinated species. PMID- 28568582 TI - ADAPTATION AND SPECIALIZATION IN A TWO-RESOURCE ENVIRONMENT IN DROSOPHILA SPECIES. AB - We assayed two components of performance (development time and survivorship), on food medium with and without ethanol, in laboratory populations of Drosophila simulans and D. melanogaster for which ethanol-medium was a novel food resource. These assays were done before and after 12 generations of rearing in either one (regular medium only) or two-resource (regular medium and ethanol medium) environments. Initially, D. simulans was highly susceptible to ethanol, whereas D. melanogaster was relatively unaffected. After 12 generations in the two resource environment, D. simulans showed significantly improved mean performance on ethanol medium; mean performance of D. melanogaster did not significantly change. Variation among families for both traits was higher on ethanol medium in D. simulans. Variation in D. melanogaster was not significantly affected by ethanol level, suggesting that resource quality was more important than novelty per se. In both species, the least variation was seen in populations after 12 generations in the two-resource environment. For development time in D. simulans, the decrease in variation was largely due to reduced variation within families, suggesting the evolution of canalization. Development time on the two media was not negatively correlated. In D. simulans, correlations measured before and after the experiment were not heterogeneous, suggesting that trade-offs in performance did not block diet expansion. In D. melanogaster, correlations became significantly less positive after 12 generations in the two-resource environment, supporting the view that correlations between performance on different resources may become less positive over time through selection. PMID- 28568583 TI - DO BLACK-TAILED PRAIRIE DOGS MINIMIZE INBREEDING? AB - Considerable controversy surrounds the importance of inbreeding in natural populations. The rate of natural inbreeding and the influences of behavioral mechanisms that serve to promote or minimize inbreeding (e.g., philopatry vs. dispersal) are poorly understood. We studied inbreeding and social structuring of a population of black-tailed prairie dogs (Cynomys ludovicianus) to assess the influence of dispersal and mating behavior on patterns of genetic variation. We examined 15 years of data on prairie dogs, including survival and reproduction, social behavior, pedigrees, and allozyme alleles. Pedigrees revealed mean inbreeding coefficients (F) of 1-2%. A breeding-group model that incorporated details of prairie dog behavior and demography was used to estimate values of fixation indices (F-statistics). Model predictions were consistent with the minimization of inbreeding within breeding groups ("coteries," asymptotic FIL = 0.18) and random mating within the subpopulation ("colony," asymptotic FIS = 0.00). Estimates from pedigrees (mean FIL = -0.23, mean FIS = 0.00) and allozyme data (mean FIL = -0.21, mean FIS = -0.01) were consistent with predictions of the model. The breeding-group model, pedigrees, and allozyme data showed remarkably congruent results, and indicated strong genetic structuring within the colony (FLS = 0.16, 0.19, and 0.17, respectively). We concluded that although inbreeding occurred in the colony, the rate of inbreeding was strongly minimized at the level of breeding groups, but not at the subpopulation level. The behavioral mechanisms most important to the minimization of inbreeding appeared to be patterns of male-biased dispersal of both subadults and adults, associated with strong philopatry of females. Incest avoidance also occurred, associated with recognition of close kin via direct social learning within the breeding groups. PMID- 28568584 TI - RECENT BOOKS IN PRINT. PMID- 28568585 TI - MODELS OF RETICULATE EVOLUTION IN THE CORAL GENUS ACROPORA BASED ON CHROMOSOME NUMBERS: PARALLELS WITH PLANTS. AB - Somatic chromosome number was determined for 22 species of the scleractinian coral genus Acropora, three species of Montipora, and one species of Fungia, using colchicine-treated cells of externally developing embryos. Most had 28 chromosomes, except for six species of Acropora, which had somatic numbers of 24, 30, 30, 42, 48, and 54. Two models that invoke a combination of polyploidy and aneuploidy are presented to account for the observed intrageneric variation in somatic chromosome number. The ability to propagate clones through vegetative fragmentation plus the opportunities for hybridization during multispecies spawning events may have contributed to the development of polyploidy and rapid, sympatric speciation in the uniquely speciose coral genus Acropora. PMID- 28568586 TI - PERSPECTIVE: A CRITIQUE OF SEWALL WRIGHT'S SHIFTING BALANCE THEORY OF EVOLUTION. AB - We evaluate Sewall Wright's three-phase "shifting balance" theory of evolution, examining both the theoretical issues and the relevant data from nature and the laboratory. We conclude that while phases I and II of Wright's theory (the movement of populations from one "adaptive peak" to another via drift and selection) can occur under some conditions, genetic drift is often unnecessary for movement between peaks. Phase III of the shifting balance, in which adaptations spread from particular populations to the entire species, faces two major theoretical obstacles: (1) unlike adaptations favored by simple directional selection, adaptations whose fixation requires some genetic drift are often prevented from spreading by barriers to gene flow; and (2) it is difficult to assemble complex adaptations whose constituent parts arise via peak shifts in different demes. Our review of the data from nature shows that although there is some evidence for individual phases of the shifting balance process, there are few empirical observations explained better by Wright's three-phase mechanism than by simple mass selection. Similarly, artificial selection experiments fail to show that selection in subdivided populations produces greater response than does mass selection in large populations. The complexity of the shifting balance process and the difficulty of establishing that adaptive valleys have been crossed by genetic drift make it impossible to test Wright's claim that adaptations commonly originate by this process. In view of these problems, it seems unreasonable to consider the shifting balance process as an important explanation for the evolution of adaptations. PMID- 28568587 TI - CONTRASTING PATTERNS OF HERITABLE GEOGRAPHIC VARIATION IN SHELL MORPHOLOGY AND GROWTH POTENTIAL IN THE MARINE GASTROPOD BEMBICIUM VITTATUM: EVIDENCE FROM FIELD EXPERIMENTS. AB - Similar phenotypes do not always imply similar genotypes. In species distributed over a broad latitudinal range, geographical variation in morphological and life history traits may reflect very different relations between genotypic and environmental effects on these traits. Patterns of selection among latitudinally separated sites may minimize phenotypic differences in life-history traits but promote phenotypic differences in form. Thus, for example, latitudinal variation in temperature often leads to genetically based metabolic differences that minimize differences in growth rate among populations at different latitudes (countergradient variation). However, variation in habitat experienced by the same populations may promote genetically based differences in shell form (cogradient variation). Few attempts have been made to assess simultaneously such mosaic effects of natural selection on the genetic basis of variation in both morphological and life-history traits among geographically separated populations. I quantified the extent to which widely separated populations of the rocky shore marine gastropod Bembicium vittatum exhibited genetic differences in shell shape, shell pattern, and growth rate. Bembicium vittatum occurs naturally at only three widely separated locations on the Western Australian coast. Individuals were transplanted from all three locations to a latitudinally intermediate site, where they were released in different pairwise combinations and allowed to reproduce. F1 offspring from crosses between same- or different-source parents were identified using allozyme markers. When grown in a common environment, offspring from same-source parents exhibited similar differences in shell shape and pattern, but dramatic differences in growth rates, compared to native populations. Genetic variation therefore exists for all three traits. Growth rates in the common environment were positively correlated with latitude of the source population, confirming the existence of countergradient variation for growth associated with metabolic compensation. In addition, for both shell shape and growth rate, hybrids exhibited phenotypes roughly midway between the same source parents, suggesting that genetic differences have a large additive component. In contrast, when one parent had pigmented spots, the offspring also had spots, suggesting a strong dominance component to the genetic basis of shell pattern. Genetic differences therefore yield different morphological phenotypes but similar life-history phenotypes, among latitudinally distant populations, and confirm a pattern of mosaic evolution in B. vittatum. PMID- 28568588 TI - DISPERSAL AND EVOLUTION OF THE PACIFIC BASIN GEKKONID LIZARDS GEHYRA OCEANICA AND GEHYRA MUTILATA. AB - The Pacific island geckos Gehyra mutilata and Gehyra oceanica were studied on several Pacific Basin archipelagos to determine the degree that their distributions have been modified by humans (as commensals), through the analysis of protein variation using starch gel electrophoresis. Gehyra mutilata is an anthropophilic species that is widespread in the Pacific Basin and Southeast Asia. No protein variation was found in the Pacific Basin and southern Asia, although there were fixed allelic differences between populations of southern Asia and those further north. These results suggest possible recent human-aided transport across the Pacific from a population that experienced a genetic bottleneck in southern Asia. Gehyra oceanica, based on protein variation, consists of two natural groups in the Pacific, a northern (Micronesian) form and a southern (Melanesian and Polynesian) form. The northern form has very similar gene frequencies across its range in Micronesia. The southern form has its greatest allelic diversity in the south-central Pacific. F-statistics for G. oceanica in the south fall within the range of values in the literature for mainland Australian species of Gehyra that are not human commensals and for other island lizards that have been considered as natural dispersers. These values are consistent with the hypothesis that G. oceanica was naturally dispersed across the Pacific, prior to the arrival of humans and that the equatorial currents are a barrier to natural, north-south gene flow/dispersal in Pacific Basin lizards. However, human-aided dispersal within the northern and southern regions cannot be ruled out. By comparing the ecology of these two species, G. oceanica has the adaptations necessary for natural oversea dispersal, whereas G. mutilata has an ecology consistent with human-mediated dispersal, in support of the conclusions from the genetic data. PMID- 28568589 TI - THE ECOLOGY OF BODY SIZE IN A SEED BEETLE, STATOR LIMBATUS: PERSISTENCE OF ENVIRONMENTAL VARIATION ACROSS GENERATIONS? PMID- 28568590 TI - FREQUENCY-DEPENDENT SEED PRODUCTION AND HYBRIDIZATION RATES: IMPLICATIONS FOR GENE FLOW BETWEEN LOCALLY ADAPTED PLANT POPULATIONS. AB - Gene flow between genetically distinct plant populations can have significant evolutionary consequences. It can increase genetic diversity, create novel gene combinations, and transfer adaptations from one population to another. This study addresses the roles of frequency-dependent selection and mating system in gene exchange between two subspecies of Gilia capitata (Polemoniaceae). Long-distance migrants are likely to be rare in new habitats, and the importance of immigrant frequency to fitness, gene exchange, and ultimately introgression, has not been explored. To test for the importance of frequency in migration, a field experiment was conducted in which artificial populations (arrays) composed of different mixtures of the two subspecies were placed in the home habitats of both. Female function (seed production) and a portion of male function (hybridization rate) were compared for the two subspecies to assess the potential for gene exchange and introgression between them. Individual fitness (through both hybridization and seed production) for the inland subspecies varied with its frequency as an immigrant at the coastal site. Rare immigrants produced fewer seeds and fathered fewer hybrid offspring. In contrast, both forms of reproductive function were frequency independent for the coastal subspecies when it was an immigrant at the inland site. Seed production was high and insensitive to frequency, and immigrants from the coast never successfully fertilized the inland subspecies' seeds. To control for the effects of frequency-dependent pollinator behavior in the field, hand crosses were performed in the greenhouse using a range of pollen mixtures. The greenhouse experiment demonstrated that cross-fertilization is possible in only one direction, that cross-pollination in the other direction is only partially successful, and that pollen from the coastal subspecies has a strong negative effect on seed production by the inland subspecies. Experimental pollen supplementation in the field verified both the unilateral incompatibility and the negative effect of coastal pollen on inland plant seed production observed in the greenhouse. Contrasts between field array and greenhouse results suggest that pollinator behavior and other ecological factors act to exaggerate reproductive barriers between the two subspecies. In this system, immigrant frequency interacts with reproductive biology and pollinator ecology to enhance gene flow between the populations in one direction, while restricting gene establishment and introgression in the other direction. PMID- 28568591 TI - PHYLOGENETIC EXAMINATION OF FEMALE INCORPORATION OF EJACULATE IN DROSOPHILA. AB - Males of some invertebrate species transfer large ejaculates, and many of the substances contained therein are incorporated by females into their somatic and ovarian tissues. These incorporated substances are expected to be energetically costly for males to produce, but benefit males by enhancing their fertilization success and/or the viability of their offspring. A better understanding of the evolution and maintenance of this important reproductive strategy should come from phylogenetic examination. We therefore quantified the extent of ejaculate incorporation by females of 34 species of Drosophila. Substantive amounts of male derived proteins were more frequently detected in female somatic tissue than in ovarian tissue. Substantive ejaculate incorporation by females was found to have arisen numerous times across the phylogeny and tended to be lineage specific in expression. The extent to which evolution of a nutritive function of the ejaculate may have been influenced by phylogenetic history in the genus Drosophila is discussed. Macroevolutionary relationships between the amount of ejaculate incorporated by females and other features of species' reproductive and life-history biology, including body size, sperm length, the formation of an insemination reaction in females, and sex-specific ages of reproductive maturity, also were examined after controlling for phylogenetic effects. PMID- 28568592 TI - A SEARCH FOR QUANTITATIVE TRAIT LOCI AFFECTING ASYMMETRY OF MANDIBULAR CHARACTERS IN MICE. AB - An interval mapping procedure was used to search for and describe the effects of any quantitative trait loci (QTLs) for directional asymmetry (DA) and fluctuating asymmetry (FA) of 10 bilateral mandible characters in house mice. It was hypothesized that more QTLs would be found for DA than for FA, but that any discovered for FA should tend to exhibit dominance. All mandible characters were triply measured and 76 microsatellite markers were scored in an average of 471 mice from the F2 intercross of the Large (LG/J) and Small (SM/J) inbred strains. A total of 16 QTLs significantly affected DA in nine of the 10 mandible characters, and this was more than the 9.5 expected by chance alone. These QTLs were found on seven of the 19 chromosomes, often at or near locations of QTLs affecting the mean of the two sides for various dimensions on the mandible. It was concluded that there is genetical variability for DA in these characters, although its level was low (4.4% of the total variation in this particular F2 population). Eleven QTLs were detected for FA, suggesting that there is very little genetic variability for FA, at least as seen in the mandible characters in this particular F2 population. As hypothesized, however, these QTLs did tend to exhibit dominance. PMID- 28568594 TI - A RECENT HOST RANGE EXPANSION IN JUNONIA COENIA HUBNER (NYMPHALIDAE): OVIPOSITION PREFERENCE, SURVIVAL, GROWTH, AND CHEMICAL DEFENSE. AB - This paper reports on an investigation of two populations of Junonia coenia, the buckeye butterfly, one that feeds on the species' typical host plant (Plantago lanceolata) and one that utilizes a novel host plant (Kickxia elatine). I examined these populations for local adaptive responses in terms of oviposition behavior, growth, and chemical defense, on both P. lanceolata and K. elatine. In addition, I examined the genetic architecture underlying these traits using a full-sib quantitative genetic analysis. I found that a significant majority of females prefer the host plant species found at their collection sites in oviposition tests, but that there is no evidence that they are locally adapted in growth performance, as measured by fifth-instar and pupal weights and development times. Neither are there correlations between oviposition preferences of females and the growth performance or levels of chemical defense of their offspring. The two populations studied do, however, show specialization in terms of the levels of chemical defense they sequester from their host plants. I argue that these results indicate that natural enemies are the normal barriers to host range expansion in this oligophagous herbivore because a breakdown in those barriers results in genetic changes that enhance resistance to predation. This is despite the fact that adaptive responses in physiology are unlikely to be limited by a lack of genetic variability; the genetic architecture among traits would be conducive to specialization in growth performance; and there are costs to chemical defense in this species. All these conditions would tend to argue that J. coenia harbors considerable potential for coevolutionary interactions with its chemically defended hosts, but this potential is not realized, probably because natural selection on diet breadth by natural enemies is much stronger than selection from host plants in this system. PMID- 28568593 TI - HOW DISCRETE ARE OAK SPECIES? INSIGHTS FROM A HYBRID ZONE BETWEEN QUERCUS GRISEA AND QUERCUS GAMBELII. AB - The white oaks Quercus gambelii and Q. grisea overlap in distribution in New Mexico and Arizona. Within the region of overlap, there are numerous instances of contact between the two taxa. In some areas of contact morphologically, intermediate trees are common, whereas in others, morphologically intermediate trees are rare or absent. We describe a set of RAPD markers that distinguish between the two species and use these markers to examine patterns of gene exchange in an area of contact in the San Mateo Mountains of New Mexico. The markers are highly coincident with morphology and confirm that hybridization between the two species takes place. Despite the occurrence of hybrids, both species remain distinct, even in areas of sympatry, and marker exchange appears to be limited. PMID- 28568595 TI - GENETIC STRUCTURE OF GIANT CLAM (TRIDACNA MAXIMA) POPULATIONS IN THE WEST PACIFIC IS NOT CONSISTENT WITH DISPERSAL BY PRESENT-DAY OCEAN CURRENTS. AB - The Pacific marine biota, particularly species with long planktonic larval stages, are thought to disperse widely throughout the Pacific via ocean currents. The little genetic data available to date has supported this view in that little or no significant regional differentiation of populations has been found over large geographical distances. However, recent data from giant clams has demonstrated not only significant regional differentiation of populations, but routes of gene flow that run perpendicular to the main present-day ocean currents. Extensive surveys of genetic variation at eight polymorphic loci in 19 populations of the giant clam Tridacna maxima, sampled throughout the West and Central Pacific, confirmed that the patterns of variation seen so far in T. gigas were not unique to that species, and may reflect a fundamental genetic structuring of shallow-water marine taxa. Populations of T. maxima within highly connected reef systems like the Great Barrier Reef were panmictic (average FST < 0.003), but highly significant genetic differences between reef groups on different archipelagos (average FST = 0.084) and between West and Central Pacific regions (average FST = 0.156) were found. Inferred gene flow was high (Ne m usually > 5) between the Philippines and the Great Barrier Reef, between the Philippines and Melanesia (the Solomon Islands and Fiji), and between the Philippines and the Central Pacific island groups (Marshall Islands, Kiribati, Tuvalu and Cook Islands). Gene flow was low between these three sets of island chains (Ne m < 2). These routes of gene flow are perpendicular to present-day ocean currents. It is suggested that the spatial patterns of gene frequencies reflect past episodes of dispersal at times of lower sea levels which have not been erased by subsequent dispersal by present-day circulation. The patterns are consistent with extensive dispersal of marine species in the Pacific, and with traditional views of dispersal from the Indo-Malay region. However, they demonstrate that dispersal along present-day ocean surface currents cannot be assumed, that other mechanisms may operate today or that major dispersal events are intermittent (perhaps separated by several thousands of years), and that the nature and timing of dispersal of Pacific marine species is more complex than has been thought. PMID- 28568596 TI - ECOLOGICAL ORIGIN OF MORPHOLOGICAL DIVERSITY: A STUDY OF ALTERNATIVE TROPHIC PHENOTYPES IN LARVAL SALAMANDERS. AB - The role of ecological factors in promoting morphological diversity within and among species is an area of debate among evolutionary biologists. Using morphological differences between sympatric species as evidence that competition promotes divergence (e.g., character displacement), has, in particular, drawn harsh criticism because morphological differences may have evolved during allopatry. In contrast to species, alternative phenotypes within a species have a common phylogenetic history, so differences between phenotypes are likely to result from ecological conditions experienced in sympatry. Using cannibal and typical larval phenotypes of the Arizona tiger salamander, Ambystoma tigrinum nebulosum, we tested two predictions of the hypothesis that resource competition promotes morphological divergence: (1) larval phenotypes should reduce competition by using different resources; and (2) the advantage to developing the alternative, cannibal phenotype should be highest when competition among typical larvae is most intense. We used field surveys and a field experiment to test these predictions. The two larval phenotypes used different resources, especially when competition was intense. The advantage to individual larvae of becoming cannibals was highest when competition for resources among typical larvae was high. These results support the hypothesis that resource competition can promote morphological divergence. PMID- 28568597 TI - ONTOGENY OF SUBTLE SKELETAL ASYMMETRIES IN INDIVIDUAL LARVAE OF THE SAND DOLLAR DENDRASTER EXCENTRICUS. PMID- 28568598 TI - REINFORCEMENT: A NEW PERSPECTIVE ON AN OLD CONTROVERSY. AB - A critical component of the reinforcement model, incomplete postzygotic reproductive isolation, has been overlooked in the many selection experiments designed to test this model. Many field observations are consistent with the reinforcement model, but theoretical work predicts that reinforcement should only work when nearly complete postzygotic reproductive isolation has developed. The experiments described here used four levels of postzygotic reproductive isolation: complete, strong, moderate, and none. A significant decrease in heterotypic matings occurred over 25 generations in the complete postzygotic reproductive isolation treatment. No evidence for reinforcement was found in any of the other treatments using incomplete postzygotic reproductive isolation. PMID- 28568599 TI - QUANTITATIVE GENETIC ANALYSIS OF DIVERGENCE IN MALE SECONDARY SEXUAL TRAITS BETWEEN DROSOPHILA SIMULANS AND DROSOPHILA MAURITIANA. AB - The sibling species Drosophila simulans and D. mauritiana differ significantly in a number of male secondary sexual traits, providing an ideal system for genetic analysis of interspecific morphological divergence. In the experiment reported here, F1 hybrids from a cross of two inbred lines were backcrossed in both directions and about 200 flies from each backcross were scored for several traits (bristle numbers and cuticle areas), as well as 18 markers distributed throughout the genome. Each trait was analyzed by composite interval mapping to identify quantitative trait loci (QTL) and estimate their effects. For each trait, from one to eight loci were detected, with more divergent traits showing evidence for greater numbers of QTL. Estimates of additive effects varied widely, with a range of 0.4 to 4.1 environmental standard deviation units and an average of 2.2 units. There was substantial evidence for nonadditive effects, since the magnitude of estimates often differed significantly between the two backcrosses. The sign of the estimated effect differed among QTL for bristle traits, but not for cuticle area traits, suggesting that these two types of trait may have undergone different types of selection. Finally, several similarities were found between different traits in the estimated positions of QTL, suggesting that pleiotropy and/or linkage of QTL may have been important in the evolution of these traits. PMID- 28568600 TI - HISTORICAL DEMOGRAPHY AND PRESENT DAY POPULATION STRUCTURE OF THE GREENFINCH, CARDUEUS CHLORIS-AN ANALYSIS OF mtDNA CONTROL-REGION SEQUENCES. AB - Genetic variability within and among 10 geographically distinct populations of Greenfinches (Carduelis chloris) was assayed by directly sequencing a 637 BP part of the mtDNA control region from 194 individuals. Thirteen variable positions defined 18 haplotypes with a maximum sequence divergence of 0.8%. Haplotype (h = 0.28-0.77) and nucleotide (pi = 0.058-0.17%) diversities within populations were low, and decreased with increasing latitude (h:rs = -0.81; pi: rs = -0.89). The distribution of pairwise nucleotide differences fit better with expectations of a "sudden expansion" than of an "equilibrium" model, and the estimates of long term effective population sizes were considerably lower than current census estimates, especially in northern European samples. Selection is an unlikely cause of observed patterns because the distribution of variability conformed to expectations of neutral infinite alleles model and haplotype diversity across populations was positively correlated with heterozygosity (HE ) in nuclear genes (rs = 0.74, P < 0.05). Hence, a recent bottleneck, followed by serial bottlenecking during the process of post-Pleistocene recolonization of northern Europe, together with recent population expansion provide a plausible explanation for the low genetic diversity in the north. Genetic distances among populations showed a clear pattern of isolation-by-distance, and 14% of the haplotypic variation was among populations, the rest being distributed among individuals within populations. In accordance with allozyme and morphological data, a hierarchical analysis of nucleotide diversity recognized southern European populations as distinct from northern European ones. However, the magnitude of divergence in mtDNA, allozymes and morphology were highly dissimilar (morphology > mtDNA > allozymes). PMID- 28568601 TI - THE EFFECT OF INBREEDING IN DIPLOID AND TETRAPLOID POPULATIONS OF EPILOBIUM ANGUSTIFOLIUM (ONAGRACEAE): IMPLICATIONS FOR THE GENETIC BASIS OF INBREEDING DEPRESSION. AB - The partial dominance model for the evolution of inbreeding depression predicts that tetraploids should exhibit less inbreeding depression than their diploid progenitors. We tested this prediction by comparing the magnitude of inbreeding depression in tetraploid and diploid populations of the herbaceous perennial Epilobium angustifolium (Onagraceae). Inbreeding depression was estimated in the greenhouse for three tetraploid and two diploid populations at four life stages. The mating system of a tetraploid population was estimated and compared to a previous estimate for diploids. Tetraploids showed less inbreeding depression than diploids at all life history stages, and these differences were significant for seed-set and cumulative fitness, but not for germination, survival, or plant dry mass at nine weeks. This result suggests that the genetic basis of inbreeding depression may differ among life stages. The primary selfing rate of the tetraploid population was r = 0.43, which is nearly identical to that of a diploid population (r = 0.45), indicating that differences in inbreeding depression between diploids and tetraploids are probably not due to differences in the mating system. Cumulative inbreeding depression, calculated from the four life history stages, was significantly higher for diploids (x-=0.95) than for tetraploids (x-=0.67), supporting the partial dominance model of inbreeding depression. PMID- 28568602 TI - ALLOZYMIC DIFFERENTIATION IN RESPONSE TO LABORATORY DEMOGRAPHIC SELECTION OF DROSOPHILA MELANOGASTER. AB - Drosophila melanogaster populations that exhibit constrasting life histories as a result of laboratory selection were compared at several potentially relevant enzyme loci. Selection regimes included postponed reproduction, accelerated development, and intermediate generation time. Each selection regime was represented by fivefold replicated populations maintained for between 50 and 500 generations. For each population, allele frequencies were calculated from frequencies of electrophoretically distinguishable allozymes of alcohol dehydrogenase, alpha-glycerol-3-phosphate dehydrogenase, phosphoglucomutase, and CuZn-superoxide dismutase. Based on allozyme frequency changes consistent across replicate populations, two of the studied loci responded to both selection for postponed reproduction and selection for accelerated development. The responses to contrasting selection regimes were in opposing directions, suggesting antagonistic pleiotropy. PMID- 28568603 TI - FREQUENCY-DEPENDENT SELECTION IN A MAMMALIAN RNA VIRUS. PMID- 28568604 TI - Estimation of tissue and crevicular fluid oxidative stress marker in premenopausal, perimenopausal and postmenopausal women with chronic periodontitis. AB - OBJECTIVES: The aim of this study was to estimate tissue and gingival crevicular fluid (GCF) levels of the oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8 OHdG) in premenopausal, perimenopausal and postmenopausal women with chronic periodontitis. BACKGROUND: Oxidative stress has been implicated in the etiopathogenesis of periodontitis and menopause induces oxidative stress. MATERIALS AND METHODS: According to Stages of Reproductive Aging Workshop (STRAW) criteria, women diagnosed with periodontitis were subdivided into three groups of 31 participants each 1. Premenopausal 2. Perimenopausal and 3. Postmenopausal. GCF and gingival tissue samples were collected from sites with maximum probing depth. Tissue DNA was extracted from the gingival sample and 8-OHdG in the extracted DNA, and GCF samples were measured using ELISA. RESULTS: There was a highly significant difference in the overall GCF 8-OHdG levels among the three groups with the pairwise difference being highly significant between the premenopausal-postmenopausal groups and perimenopausal-postmenopausal groups. However, no overall significant differences in tissue 8-OHdG levels were found among the three groups. Pairwise, highly significant differences were found between the premenopausal-postmenopausal groups and perimenopausal-postmenopausal groups for tissue 8-OHdG levels. No significant correlations were found between various measure of periodontal disease and GCF/tissue 8-OHdG levels among all the groups. CONCLUSION: Premenopausal-postmenopausal and perimenopausal postmenopausal transition resulted in significant increase in tissue and GCF 8 OHdG levels. However, no association was found between stages of reproductive ageing and tissue levels of 8-OHdG. PMID- 28568605 TI - Vascular beds maintain pancreatic tumour explants for ex vivo drug screening. AB - Our understanding of cancer progression or response to therapies would benefit from benchtop, tissue-level assays that preserve the biology and anatomy of human tumours ex vivo. We present a methodology for maintaining patient tumour samples ex vivo for the purpose of drug testing in a clinical setting. The harvested tumour biopsy, excised from mice or patients, is integrated into a support tissue that includes stroma and vasculature. This support tissue preserves tumour histoarchitecture and relevant expression profiles, and tumour tissues cultured using this system display different sensitivities to chemotherapeutics compared with tumour explants with no supporting tissue. The methodology is more rapid than patient-derived xenograft models, easy to implement, and amenable to high throughput assays, making it an attractive tool for in vitro drug screening or for the guidance of patient-specific chemotherapies. PMID- 28568607 TI - Differential item functioning in the Unified Dyskinesia Rating Scale (UDysRS). AB - OBJECTIVE: Test if differential item functioning due to gender, age, race/ethnicity, or education impacts Unified Dyskinesia Rating Scale scores. BACKGROUND: Testing rating scales for differential item functioning is a core validation step. If differential item functioning exists, interpretation of item scores must consider secondary influences on dyskinesia ratings. METHODS: Using Unified Dyskinesia Rating Scale translation databases (N = 3,132), we tested uniform and nonuniform differential item functioning. We required confirmation by two independent methods and considered differential item functioning pertinent if McFadden pseudo R2 magnitude statistics exceeded negligible ratings. RESULTS: No age, race/ethnicity, or education nonuniform differential item functioning was identified. Gender nonuniform differential item functioning occurred for 2 items, both with negligible magnitude. Gender, race, and education uniform differential item functioning was observed for multiple items, all with negligible magnitude. CONCLUSIONS: The Unified Dyskinesia Rating Scale items effectively capture dyskinesia severity without pertinent gender, age, race/ ethnicity, or education influence. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28568606 TI - Coupling of excitation to Ca2+ release is modulated by dysferlin. AB - KEY POINTS: Dysferlin, the protein missing in limb girdle muscular dystrophy 2B and Miyoshi myopathy, concentrates in transverse tubules of skeletal muscle, where it stabilizes voltage-induced Ca2+ transients against loss after osmotic shock injury (OSI). Local expression of dysferlin in dysferlin-null myofibres increases transient amplitude to control levels and protects them from loss after OSI. Inhibitors of ryanodine receptors (RyR1) and L-type Ca2+ channels protect voltage-induced Ca2+ transients from loss; thus both proteins play a role in injury in dysferlin's absence. Effects of Ca2+ -free medium and S107, which inhibits SR Ca2+ leak, suggest the SR as the primary source of Ca2+ responsible for the loss of the Ca2+ transient upon injury. Ca2+ waves were induced by OSI and suppressed by exogenous dysferlin. We conclude that dysferlin prevents injury induced SR Ca2+ leak. ABSTRACT: Dysferlin concentrates in the transverse tubules of skeletal muscle and stabilizes Ca2+ transients when muscle fibres are subjected to osmotic shock injury (OSI). We show here that voltage-induced Ca2+ transients elicited in dysferlin-null A/J myofibres were smaller than control A/WySnJ fibres. Regional expression of Venus-dysferlin chimeras in A/J fibres restored the full amplitude of the Ca2+ transients and protected against OSI. We also show that drugs that target ryanodine receptors (RyR1: dantrolene, tetracaine, S107) and L-type Ca2+ channels (LTCCs: nifedipine, verapamil, diltiazem) prevented the decrease in Ca2+ transients in A/J fibres following OSI. Diltiazem specifically increased transients by ~20% in uninjured A/J fibres, restoring them to control values. The fact that both RyR1s and LTCCs were involved in OSI-induced damage suggests that damage is mediated by increased Ca2+ leak from the sarcoplasmic reticulum (SR) through the RyR1. Congruent with this, injured A/J fibres produced Ca2+ sparks and Ca2+ waves. S107 (a stabilizer of RyR1-FK506 binding protein coupling that reduces Ca2+ leak) or local expression of Venus-dysferlin prevented OSI-induced Ca2+ waves. Our data suggest that dysferlin modulates SR Ca2+ release in skeletal muscle, and that in its absence OSI causes increased RyR1-mediated Ca2+ leak from the SR into the cytoplasm. PMID- 28568609 TI - Two minuses can make a plus: waterlogging and elevated CO2 interactions in sweet cherry (Prunus avium) cultivars. AB - The increase in the ambient concentration of CO2 and other greenhouse gases is producing climate events that can compromise crop survival. However, high CO2 concentrations are sometimes able to mitigate certain stresses such as salinity or drought. In this experiment, the effects of waterlogging and CO2 are studied in combination to elucidate the eventual response in sweet cherry trees. For this purpose, four sweet cherry cultivars ('Burlat', 'Cashmere', 'Lapins and 'New Star') were grafted on a typically hypoxia-tolerant rootstock (Mariana 2624) and submitted to waterlogging for 7 days at either ambient CO2 concentration (400 umol mol-1 ) or at elevated CO2 (800 umol mol-1 ). Waterlogging affected plants drastically, by decreasing photosynthesis, stomatal conductance, transpiration, chlorophyll fluorescence and growth. It also brought about the accumulation of proline, chloride and sulfate. Nonetheless, raising the CO2 supply not only mitigated all these effects but also induced the accumulation of soluble sugars and starch in the leaf. Therefore, sweet cherry plants submitted to waterlogging were able to overcome this stress when grown in a CO2 -enriched environment. PMID- 28568608 TI - Next-day residual effects of flibanserin on simulated driving performance in premenopausal women. AB - OBJECTIVE: The objective of this study was to determine the next-day residual effects of acute and steady-state nighttime dosing of flibanserin on simulated driving performance and cognitive function in healthy premenopausal women. METHODS: In this randomized, double-blind, placebo-controlled, four-way crossover study, 72 subjects were treated with either acute oral doses of placebo, zopiclone 7.5 mg (positive control) or flibanserin 100 mg at bedtime (indicated therapeutic dose), or after chronic nightly oral doses of flibanserin 100 mg for 1 week followed by a single bedtime dose of flibanserin 200 mg (supratherapeutic dose). Simulated driving assessments were conducted 9 hr after dosing and cognitive function tests were administered immediately before or during the driving assessment. RESULTS: Zopiclone increased standard deviation of lateral position (>=3.1 cm; p < .0001) relative to placebo and impaired other parameters previously shown to be sensitive to sedation. No impairment was detected for flibanserin at either dose relative to placebo. Flibanserin 200 mg was similar to the 100-mg dose on cognitive testing and driving performance even though commonly reported adverse events for flibanserin were predictably increased at the higher dose. CONCLUSIONS: At both therapeutic and supratherapeutic doses, flibanserin did not impair next-day driving performance and cognitive function compared to placebo. PMID- 28568610 TI - GENERALISTS, SPECIALISTS, AND THE EVOLUTION OF PHENOTYPIC PLASTICITY IN SYMPATRIC POPULATIONS OF DISTINCT SPECIES. AB - The evolution of phenotypic plasticity is studied in a model with two reproductively isolated "species" in a coarse-grained environment, consisting of two types of habitats. A quantitative genetic model for selection was constructed, in which habitats differ in the optimal value for a focal trait, and with random dispersal among habitats. The main interest was to study the effects of different selection regimes. Three cases were investigated: (1) without any limits to plasticity; (2) without genetic variation for plasticity; and (3) with a fitness cost for phenotypically plastic reactions. In almost all cases a generalist strategy to exploit both habitats emerged. Without any limits to plasticity, optimal adaptive reactions evolved. Without any genetic variation for plasticity, a compromise strategy with an intermediate, fixed phenotype evolved, whereas in the presence of costs a plastic compromise between the demands of the habitats and the costs associated with plasticity was found. Specialization and phenotypic differentiation was only found when selection within habitats was severe and optimal phenotypes for different habitats were widely different. Under soft selection (local regulation of population numbers in each habitat) the specialists coexisted; under hard selection (global regulation of population numbers) one specialist outcompeted the other. The prevalent evolutionary outcome of compromises rather than specialization implies that costs or constraints are not necessarily detectable as local adaptation in transplantation or translocation experiments. PMID- 28568611 TI - THE EFFECT OF INFLORESCENCE SIZE ON MALE FITNESS: EXPERIMENTAL TESTS IN THE ANDROMONOECIOUS LILY, ZIGADENUS PANICULATUS. AB - We studied the relationship between inflorescence size and male fitness in the andromonoecious lily Zigadenus paniculatus, using experimentally manipulated inflorescences to eliminate possible correlations between flower number, resource availability, and other floral traits. Allozyme markers were used to determine the siring success of large versus small plants in 14 arrays of plants, each array containing five large and five small plants. The inflorescence size of small plants was held constant both within and among arrays; the size of large plants was held constant within an array but was varied among arrays. Large plants sired more than half the seeds in 12 of the 14 arrays, and significantly more than half in six of these 12. However, in eight of the arrays, large plants sired significantly fewer seeds than expected on the basis of their size advantage. Furthermore, there was no significant relationship between relative size and relative siring success in comparisons among arrays. A maximum likelihood model estimated that 28% of seeds were sired by imported pollen, with 95% confidence limits of 13% and 50%. Within these limits, high import rates tended to mask the relative success of large plants in several arrays. These results suggest that the evolution of inflorescence size in Z. paniculatus is at least partly driven by selection for increased male success, assuming genetic variation for flower number. However, the data also support a growing body of evidence that estimates of male fitness in plants can be highly variable. We discuss the sources of this variability and the possible effects of inflorescence design on the relationship between inflorescence size and fitness. PMID- 28568612 TI - DIFFERENTIAL SURVIVAL OF SEXUAL AND ASEXUAL POECILIOPSIS DURING ENVIRONMENTAL STRESS. AB - According to the Frozen Niche-Variation model, coexisting clones of an asexual species can freeze and faithfully replicate ecologically relevant genetic variability that segregates in the sexual ancestors. The present experiments with fish of the genus Poeciliopsis provide further evidence in support of this model. Sexual and clonal forms of Poeciliopsis live in the desert streams of Sonora, Mexico, and are exposed to environmental extremes ranging from flash floods to hot, desiccating, residual pools. We examined coexisting members of the monacha complex to see whether the fish types differed with respect to survival during stress and swimming endurance in an artificial flume. The two coexisting clones of the triploid gynogenetic fish P. 2 monacha-lucida differed dramatically: clone MML/II had the best survival during heat and cold stress and the worst survival during hypoxic stress, whereas clone MML/I had the best survival during hypoxic stress and the worst during heat stress. Poeciliopsis monacha, the sexual species with which these clones coexist, had intermediate survival during heat and hypoxic stress and very poor swimming endurance in the flume. The physiological differences seen in this study are consistent with the Frozen Niche-Variation model and provide some insights into environmental factors that affect the distribution and abundance of these fish. PMID- 28568613 TI - INBREEDING DEPRESSION UNDER JOINT SELFING, OUTCROSSING, AND ASEXUALITY. AB - Partial asexual reproduction was introduced into a model of inbreeding depression due to nearly recessive lethal mutations in a partially selfing population. The frequencies of asexuality, selfing, and outcrossing were either constant or occurred in cycles of a single sexual generation followed by one or more asexual generations. We found that increasing the degree of asexuality generally increases the inbreeding depression maintained in an equilibrium population with a given selfing rate. This is due to the increase in the number of mutations relative to sexual generations during which selfing-induced purging of mutations may take place. For very high genomic mutation rates, sufficient to produce a threshold rate of self-fertilization for purging recessive lethal mutations, asexuality can have the opposite effect, decreasing equilibrium inbreeding depression, because of an increase in the efficiency of selection against mutations in heterozygotes with asexuality. PMID- 28568614 TI - THE INFLUENCE OF SELF-FERTILIZATION AND POPULATION DYNAMICS ON THE GENETIC STRUCTURE OF SUBDIVIDED POPULATIONS: A CASE STUDY USING MICROSATELLITE MARKERS IN THE FRESHWATER SNAIL BULINUS TRUNCATUS. AB - The distribution of neutral genetic variability within and among sets of populations results from the combined actions of genetic drift, migration, extinction and recolonization processes, mutation, and the mating system. We here analyzed these factors in 38 populations of the hermaphroditic snail Bulinus truncatus. The sampling area covered a large part of the species range. The variability was analyzed using four polymorphic microsatellite loci. A very large number of alleles (up to 55) was found at the level of the whole study. Observed heterozygote deficiencies within populations are consistent with very high selfing rates, generally above 0.80, in all populations. These should depress the variability within populations, because of low effective size, genetic hitchhiking, and background selection, whatever the model of mutation assumed. However, that some populations exhibit much more variability than others suggests that historical demographic processes (e.g., population size variation, bottlenecks, or founding events) may play a significant role. A hierarchical analysis of the distribution of the variability across populations indicates a strong pattern of isolation by distance, whatever the geographical scale considered. Our analysis also illustrates how the mutation rate may affect population differentiation, as different mutation rates result in different levels of homoplasy at microsatellite loci. The effects of both genetic drift and gene flow vary with the temporal and spatial scales considered in B. truncatus populations. PMID- 28568615 TI - EXAMINING TWO STANDARD ASSUMPTIONS OF ANCESTRAL RECONSTRUCTIONS: REPEATED LOSS OF DICHROMATISM IN DABBLING DUCKS (ANATINI). AB - Although phylogenetic reconstruction of ancestral character states is becoming an increasingly common technique for studying evolution, few researchers have assessed the reliability of these reconstructions. Here I test for congruence between a phylogenetic reconstruction and a widely accepted scenario based on independent lines of evidence. I used Livezey's (1991) phylogeny to reconstruct ancestral states of plumage dichromatism in dabbling ducks (Anatini). Character state mapping reconstructs monochromatic ancestors for the genus Anas as well as most of its main clades. This reconstruction differs strongly from the widely accepted scenario of speciation and plumage evolution in the group (e.g., Delacour and Mayr 1945; Sibley 1957). This incongruence may occur because two standard assumptions of character state reconstruction are probably not met in this case. Violating either of these two assumptions would be a source of error sufficient to create misleading reconstructions. The first assumption that probably does not apply to ducks is that terminal taxa, in this case species, are monophyletic. Many of the widespread dichromatic species of ducks may be paraphyletic and ancestral to isolated monochromatic species. Three lines of evidence support this scenario: population-level phylogenies, biogeography, and vestigial plumage patterns. The second assumption that probably does not apply to duck plumage color is that gains and losses of character states are equally likely. Four lines of evidence suggest that dichromatic plumage might be lost more easily than gained: weak female preferences for bright male plumage, biases toward the loss of sexually dichromatic characters, biases toward the loss of complex characters, and repeated loss of dichromatism in other groups of birds. These seven lines of evidence support the accepted scenario that widespread dichromatic species repeatedly budded off isolated monochromatic species. Drift and genetic biases probably caused the easy loss of dichromatism in ducks and other birds during peripatric speciation. In order to recover the accepted scenario using Livezey's tree, losses of dichromatism must be five times more likely than gains. The results of this study caution against the uncritical use of unordered parsimony as the sole criterion for inferring ancestral states. Detailed population-level sampling is needed and altered transformation weighting may be warranted in ducks and in many other groups and character types with similar attributes. PMID- 28568616 TI - STABILIZING SELECTION AND THE COMPARATIVE ANALYSIS OF ADAPTATION. AB - Comparative studies tend to differ from optimality and functionality studies in how they treat adaptation. While the comparative approach focuses on the origin and change of traits, optimality studies assume that adaptations are maintained at an optimum by stabilizing selection. This paper presents a model of adaptive evolution on a macroevolutionary time scale that includes the maintenance of traits at adaptive optima by stabilizing selection as the dominant evolutionary force. Interspecific variation is treated as variation in the position of adaptive optima. The model illustrates how phylogenetic constraints not only lead to correlations between phylogenetically related species, but also to imperfect adaptations. From this model, a statistical comparative method is derived that can be used to estimate the effect of a selective factor on adaptive optima in a way that would be consistent with an optimality study of adaptation to this factor. The method is illustrated with an analysis of dental evolution in fossil horses. The use of comparative methods to study evolutionary trends is also discussed. PMID- 28568617 TI - VARIATION IN SEED CHARACTERS IN NEMOPHILA MENZIESII: EVIDENCE OF A GENETIC BASIS FOR MATERNAL EFFECT. AB - A growing body of evidence indicates that phenotypic selection on juvenile traits of both plants and animals may be considerable. Because juvenile traits are typically subject to maternal effects and often have low heritabilities, adaptive responses to natural selection on these traits may seem unlikely. To determine the potential for evolutionary response to selection on juvenile traits of Nemophila menziesii (Hydrophyllaceae), we conducted two quantitative genetic studies. A reciprocal factorial cross, involving 16 parents and 1960 progeny, demonstrated a significant maternal component of variance in seed mass and additive genetic component of variance in germination time. This experiment also suggested that interaction between parents, though small, provides highly significant contributions to the variance of both traits. Such a parental interaction could arise by diverse mechanisms, including dependence of nuclear gene expression on cytoplasmic genotype, but the design of this experiment could not distinguish this from other possible causes, such as effects on progeny phenotype of interaction between the environmental conditions of both parents. The second experiment, spanning three generations with over 11,000 observations, was designed for investigation of the additive genetic variance in maternal effect, assessment of paternal effects, as well as further partitioning of the parental interaction identified in the reciprocal factorial experiment. It yielded no consistent evidence of paternal effects on seed mass, nor of parental interactions. Our inference of such interaction effects from the first experiment was evidently an artifact of failing to account for the substantial variance among fruits within crosses. The maternal effect was found to have a large additive genetic component, accounting for at least 20% of the variation in individual seed mass. This result suggests that there is appreciable potential for response to selection on seed mass through evolution of the maternal effect. We discuss aspects that may nevertheless limit response to individual selection on seed mass, including trade-offs between the size of individual seeds and germination time and between the number of seeds a maternal plant can mature and their mean size. PMID- 28568618 TI - THE PONTIA DAPLIDICE-ED USA HYBRID ZONE IN NORTHWESTERN ITALY. AB - The pierid butterflies Pontia daplidice and P. edusa, parapatrically distributed in southern Europe, have very similar morphologies and life histories, but show fixed differences at four allozyme markers. We sampled these allozymes in a 28 population transect north of Genoa in Italy, through the hybrid zone where these taxa meet. We used the numerical techniques developed for hybrid zone analysis to study the patterns of genetic differentiation and their underlying evolutionary causes. The hybrid zone is characterized by a very short and steep central region, flanked by broad tails of introgression extended up to 100 km in either direction. From mean two-locus disequilibium of D = 0.148 (maximum-likelihood two unit support limits 0.139-0.153), and after accounting for minor differences in the center locations of the single-locus clines, which act to bias the dispersal estimate, we estimated a dispersal rate of sigma = 4.4 (3.7-5.5) km/gen1/2 . The effective selection needed to maintain the steep central portion is strong, 0.47 < s* < 0.64, when combined over potential intrinsic (genetic background) and extrinsic (ecological) sources of selection. The clines in allozyme loci showed variation that was significantly different between the most divergent shapes, and the differences are attributable to different degrees of introgression on the edusa side of the zone. The average selection acting on individual allozyme loci was high at s***e ? 1.5%, but because of the narrowness of the central region of the cline, we suspect that this estimate is somewhat biased by selection on loci closely linked to the allozyme markers. A common question for taxa that show fixed allozyme differences in parapatry is whether or not they are genetically isolated. A fairly general measure of genetic isolation across hybrid zones is the time, T, that it takes a neutral allele to cross the hybrid zone and recombine into the opposite genetic background, given by T = (beta/sigma)2 , where beta is the barrier strength of the hybrid zone. Genetic isolation in the Pontia zone is weak, with T ? 25 generations for most allozyme markers. By this measure, populations of daplidice and edusa on opposite sides of the hybrid zone share more identical-by-descent alleles than do populations of phenotypically pure daplidice in, say, France and Morocco. Accordingly, we think it best for systematists to consider edusa as a well-marked subspecies of P. daplidice. PMID- 28568619 TI - SELECTION FOR NATIVE CHARACTERS IN HYBRIDS BETWEEN TWO LOCALLY ADAPTED PLANT SUBSPECIES. AB - Gene exchange between locally adapted plant populations can have significant evolutionary consequences, including changes in genetic diversity, introduction of adaptive or maladaptive traits, disruptive of coadaptive gene complexes, and the creation of new ecotypes or even species. The potential for introgression between divergent populations will depend on the strength of selection against nonnative characters. Morphologically variable F2 hybrids of two Gilia capitata subspecies were used to evaluate the strength of phenotypic selection and the response to selection in the home habitats of each subspecies. At both sites, traits diagnostic of the subspecies were subject to significant phenotypic selection, probably mediated by direct selection on unmeasured correlated characters. Phenotypic selection favored native morphologies in all but a single case; leaf shape of one subspecies was favored in both habitats. The strength of selection varied between sites, with one site selecting more strongly against nonnative characters. Offspring of the F2 hybrids showed a significant evolutionary response to selection when grown in a common environment. Evolution was in the direction of similarity with the subspecies native to the site where selection was imposed. This result reveals that native character states are adaptive and suggests that selection will maintain native morphologies even after a substantial influx of genes from an ecologically and morphologically distinct, and locally adapted subspecies. PMID- 28568620 TI - MATERNAL ANCESTRY OF THE RUTILUS ALBURNOIDES COMPLEX (TELEOSTEI, CYPRINIDAE) AS DETERMINED BY ANALYSIS OF CYTOCHROME b SEQUENCES. AB - Cytochrome b (cyt b) sequences from specimens of the Rutilus alburnoides unisexual complex and five bisexual species were compared to examine hypotheses regarding the origin and maternal ancestry of this complex. Phylogenetic analysis revealed a monophyletic relationship among unisexuals and Leuciscus pyrenaicus, clearly identifying this species as the maternal ancestor. Considerable mtDNA diversity exists among R. alburnoides populations, with many localities exhibiting unique haplotypes. The topology recovered from analysis of cyt b variation among populations suggested that R. alburnoides is polyphyletically derived from their sympatric L. pyrenaicus populations, indicating that unisexual lineages have been generated through multiple hybridization events. Although much less abundant, R. alburnoides is present outside the range of L. pyrenaicus, suggesting that it may have dispersed from the Tejo drainage into the northern basins. In this region, Leuciscus carolitertii is most likely the sexual host for the unisexual complex. PMID- 28568621 TI - SIZE-DEPENDENT ASYMMETRY: FLUCTUATING ASYMMETRY VERSUS ANTISYMMETRY AND ITS RELEVANCE TO CONDITION-DEPENDENT SIGNALING. AB - Fluctuating asymmetry (FA) has received much recent attention in studies of the evolution of sexual signaling systems. Tests apparently showing that symmetry decreases as individual condition decreases have bolstered the view that FA plays a significant role in the evolution of sexual signals. However, a closer inspection of several examples of bilateral variation as a function of trait size (a correlate of condition) suggests a different pattern of variation. Rather than FA, these traits suggest a pattern of size-dependent antisymmetry (a bimodal frequency distribution of R - L). We introduce some quantitative methods to test for condition- or size-dependent FA. Our analyses reject pure FA for four of the five published datasets involving signals (the fifth is equivocal), but confirm the presence of size-dependent FA in one nonsignaling trait. In the studies not conforming to FA, the data appear to fit more closely a pattern of antisymmetry in individuals with smaller signaling traits. Our results thus suggest that current discussions and conclusions about the role of FA in the evolution of signaling systems should be reconsidered. More specifically, we note that condition-dependent antisymmetry offers a more reliable indicator than condition dependent FA. We caution, however, that additional work will be needed to determine whether the pattern is general and not an artifact. Our method of analysis could usefully be applied to studies of other continuous factors expected to be correlated with asymmetries, including heterozygosity, inbreeding, and environmental stress. Finally, we suggest that antisymmetry may have commonly been mistaken for FA in a variety of cases dealing with a variety of problems. PMID- 28568622 TI - SPECIATION AND POPULATION GENETIC STRUCTURE IN TROPICAL PACIFIC SEA URCHINS. AB - Unlike populations of many terrestrial species, marine populations often are not separated by obvious, permanent barriers to gene flow. When species have high dispersal potential and few barriers to gene flow, allopatric divergence is slow. Nevertheless, many marine species are of recent origin, even in taxa with high dispersal potential. To understand the relationship between genetic structure and recent species formation in high dispersal taxa, we examined population genetic structure among four species of sea urchins in the tropical Indo-West Pacific that have speciated within the past one to three million years. Despite high potential for gene flow, mtDNA sequence variation among 200 individuals of four species in the urchin genus Echinometra shows a signal of strong geographic effects. These effects include (1) substantial population heterogeneity; (2) lower genetic variation in peripheral populations; and (3) isolation by distance. These geographic patterns are especially strong across scales of 5000-10,000 km, and are weaker over scales of 2500-5000 km. As a result, strong geographic patterns would not have been readily visible except over the wide expanse of the tropical Pacific. Surface currents in the Pacific do not explain patterns of gene flow any better than do patterns of simple spatial proximity. Finally, populations of each species tend to group into large mtDNA regions with similar mtDNA haplotypes, but these regional boundaries are not concordant in different species. These results show that all four species have accumulated mtDNA differences over similar spatial and temporal scales but that the precise geographic pattern of genetic differentiation varies for each species. These geographic patterns appear much less deterministic than in other well-known coastal marine systems and may be driven by chance and historical accident. PMID- 28568623 TI - TESTING FOR UNEQUAL AMOUNTS OF EVOLUTION IN A CONTINUOUS CHARACTER ON DIFFERENT BRANCHES OF A PHYLOGENETIC TREE USING LINEAR AND SQUARED-CHANGE PARSIMONY: AN EXAMPLE USING LESSER ANTILLEAN ANOLIS LIZARDS. AB - Although a large body of work investigating tests of correlated evolution of two continuous characters exists, hypotheses such as character displacement are really tests of whether substantial evolutionary change has occurred on a particular branch or branches of the phylogenetic tree. In this study, we present a methodology for testing such a hypothesis using ancestral character state reconstruction and simulation. Furthermore, we suggest how to investigate the robustness of the hypothesis test by varying the reconstruction methods or simulation parameters. As a case study, we tested a hypothesis of character displacement in body size of Caribbean Anolis lizards. We compared squared change, weighted squared-change, and linear parsimony reconstruction methods, gradual Brownian motion and speciational models of evolution, and several resolution methods for linear parsimony. We used ancestor reconstruction methods to infer the amount of body size evolution, and tested whether evolutionary change in body size was greater on branches of the phylogenetic tree in which a transition from occupying a single-species island to a two-species island occurred. Simulations were used to generate null distributions of reconstructed body size change. The hypothesis of character displacement was tested using Wilcoxon Rank-Sums. When tested against simulated null distributions, all of the reconstruction methods resulted in more significant P-values than when standard statistical tables were used. These results confirm that P-values for tests using ancestor reconstruction methods should be assessed via simulation rather than from standard statistical tables. Linear parsimony can produce an infinite number of most parsimonious reconstructions in continuous characters. We present an example of assessing the robustness of our statistical test by exploring the sample space of possible resolutions. We compare ACCTRAN and DELTRAN resolutions of ambiguous character reconstructions in linear parsimony to the most and least conservative resolutions for our particular hypothesis. PMID- 28568624 TI - EXPERIMENTAL MANIPULATION OF PUTATIVE SELECTIVE AGENTS PROVIDES EVIDENCE FOR THE ROLE OF NATURAL ENEMIES IN THE EVOLUTION OF PLANT DEFENSE. AB - Although biologists have long assumed that plant resistance characters evolved under selection exerted by such natural enemies as herbivores and pathogens, experimental evidence for this assumption is sparse. We present evidence that natural enemies exert selection on particular plant resistance characters. Specifically, we demonstrate that elimination of natural enemies from an experimental field population of Arabidopsis thaliana alters the pattern of selection on genetic variation in two characters that have been shown to reduce herbivore damage in the field: total glucosinolate concentration and trichome density. The change in pattern of selection reveals that natural enemies imposed selection favoring increased glucosinolate concentration and increased trichome density, and thus, supports one of the major assumptions of the coevolution hypothesis. We also demonstrate that a pattern of stabilizing selection on glucosinolate concentration results from a balance between the costs and benefits associated with increasing levels of this resistance character. This result provides direct confirmation of the appropriateness of cost-benefit models for characterizing the evolution of plant defenses. PMID- 28568626 TI - COMPARATIVE PATTERNS OF CRANIOFACIAL DEVELOPMENT IN EUTHERIAN AND METATHERIAN MAMMALS. AB - The sequence of differentiation of major elements of the skeletal, muscular and nervous systems of the head is examined in developmental series of five eutherian (placental) and four metatherian (marsupial) mammals. The analysis identifies the elements that are conserved across the Theria, those that are unique to the Metatheria and to the Eutheria, and those that are variable. It is shown that although there are slight shifts in the sequence of development within the somatic tissues of the head, the primary difference between marsupial and placental mammals involves the timing and rate of differentiation of structures of the central nervous system (CNS) relative to a specific subset of structures of the cranial skeleton and musculature. In eutherians, CNS morphogenesis is well underway before the somatic tissues of the head begin differentiation. In metatherians, CNS development is delayed considerably and certain elements of the skeletal and muscular systems are advanced. It is concluded that the developmental differences between marsupial and placental mammals are best explained by the interaction of several processes including neurogenesis as a potential rate-limiting step, the developmental requirements of somatic elements, and the extremely short period of organogenesis of marsupial mammals. Several other issues, including the way that these data may be applied to determine the primitive therian developmental condition, and the use of comparative developmental data to address basic questions on morphogenetic processes, are discussed. PMID- 28568625 TI - HYBRIDIZATION STUDIES ON THE HOST RACES OF EUROSTA SOLIDAGINIS: IMPLICATIONS FOR SYMPATRIC SPECIATION. AB - We studied the inheritance of survival ability in host-associated populations of the tephritid fly, Eurosta solidaginis, to test predictions of sympatric speciation models. Eurosta solidaginis induces galls on two species of goldenrod, Solidago altissima and S. gigantea. The host-associated populations have been hypothesized to be host races that originated in sympatry (Craig et al. 1993). We found evidence for disruptive selection for host use, which is a critical assumption of sympatric speciation models. Each host race had higher survival rates on their host plant than on the alternative host. F1 and backcross hybrids also had lower survival rates than the pure host-race flies on their host plant. Since assortative mating occurs due to host-plant preference (Craig et al. 1993) this would select for divergence in host preference. Low hybrid survival could have been due to strong genetic incompatibilities of the populations or due to host adaptation by each population. Strong genetic incompatibilities would result in poor survival on all host plants, while host adaptation could result in low overall survival with high hybrid survival on some host plants with particularly "benign" environments. High survival of F1 , F2 , and backcross hybrids on some plant genotypes in some years supported the host adaptation hypothesis. F1 flies mated and oviposited normally and produced viable F2 and backcross hybrids indicating gene flow is possible between the host races. A few flies developed and emerged on the alternative host plant. This demonstrates that genes necessary to utilize the alternative host exist in both host races. This could have facilitated the origin of one of the populations via a host shift from the ancestral host. The inheritance of survival ability appears to be an autosomal trait. We did not find evidence that survival ability was maternally influenced or sex linked. PMID- 28568627 TI - SIGNIFICANT ROLE FOR HISTORICAL EFFECTS IN THE EVOLUTION OF REPRODUCTIVE ISOLATION: EVIDENCE FROM PATTERNS OF INTROGRESSION BETWEEN THE CYPRINID FISHES, LUXILUS CORNUTUS AND LUXILUS CHRYSOCEPHALUS. AB - Samples of Luxilus cornutus, Luxilus chrysocephalus, and their hybrids were collected along hypothesized routes of dispersal from Pleistocene refugia to examine the significance of geographic variation in patterns of introgression between these species. Patterns of allozyme and mitochondrial DNA (mtDNA) variation were generally consistent with those from previous studies. Tests of Hardy-Weinberg equilibrium revealed significant deficiencies of heterozygotes in all samples, indicating some form of reproductive isolation. Mitochondrial DNAs of each species were not equally represented in F1 hybrids; however, this bias was eliminated when the two largest samples were excluded from the analysis. Backcross hybrids exhibited biased mtDNA introgression, as samples from Lake Erie (eastern) and Lake Michigan (western) drainages showed significant excesses of mtDNAs from L. chrysocephalus and L. cornutus, respectively, relative to frequencies of diagnostic allozyme markers. The extent and direction of allozyme and mtDNA introgression was quantified by calculating isolation index values from morphologically "pure" individuals of each species from each locality. Analysis of variance of these measures identified limited introgression of allozyme variants with no geographic pattern, but significant differences in direction of mtDNA introgression between drainages (i.e., postglacial dispersal route). Association between patterns of mtDNA introgression and dispersal route across the latitudinal width of the contact zone is best explained by genetic divergence during past isolation of ancestral populations from these drainages. These results identify a significant role for historical effects in the evolution of reproductive isolation and the process of speciation. PMID- 28568629 TI - UNPREDICTABILITY OF CORRELATED RESPONSE TO SELECTION: LINKAGE AND INITIAL FREQUENCY ALSO MATTER. AB - In a recent paper, Gromko (1995) showed using computer simulations that pleiotropy and sampling interact to generate variation in correlated response to selection. His simulations demonstrated that different combinations of pleiotropic effects could lead to the same genetic correlation value, yet, as long as the population size and correlation value were large enough, result in significantly different variance of correlated responses after 10 generations of selection. We extended those results using Alan Roberston's "reparameterization" of selection processes in finite populations. As for direct selection response, a satisfactory description of the correlated response and its variability can be expressed in terms of Nih, t/N, and NL, where N is the effective population size, i is the selection intensity in standard units, h2 is the heritability of the selected and correlated traits, t is the number of generations, and L is the length of the chromosome in map units. For a given number of loci, there exits an Nih threshold under which differences between pleiotropic systems will not be detected. For values of Nih above this threshold, the higher Nih is the smaller t/N needs to be for significant differences in correlated responses between pleiotropic systems to be observed. A large number of loci or tight linkage increases the unpredictability of the correlated response, but if Nih is large enough, it does not absolutely prevent significant differences between pleiotropic systems to occur. On the other hand, a small initial allele frequency of the favorable allele would tend to cancel the differences between pleiotropic systems, even for large values of Nih and t/N. Finally, epistasis decreases the overall variability of the correlated response, but generally preserves the difference between pleiotropic systems. Thus, Gromko's conclusions on the unpredictability of correlated response due to variable pleiotropy seem fairly robust, at least in the long term. PMID- 28568628 TI - ADVANTAGES OF MULTIPLE MATINGS TO FEMALES: A TEST OF THE INFERTILITY HYPOTHESIS USING LIZARDS. PMID- 28568630 TI - TEST OF INTERACTION BETWEEN GENETIC MARKERS THAT AFFECT FITNESS IN ASPERGILLUS NIGER. AB - In this paper we study whether and how a number of arbitrarily chosen marker mutations interact in their effect on fitness, which is relevant for our understanding of the evolution of sex. If epistasis is synergistic, the main function of sex may be to facilitate selection against deleterious mutations. We use strains of the filamentous fungus Aspergillus niger with variable combinations of marker mutations that have been obtained by isolating segregants from a diploid between a wild-type strain and a related strain carrying a marker mutation on each of its eight chromosomes. The marker mutations include five auxotrophic and two resistance mutations. As a measure of fitness the mycelium growth rate on supplemented medium has been used. The results suggest that the marker mutations have independent effects on fitness, and hence they do not support the deterministic mutation hypothesis of the evolution of sex. The apparent linear relationship between mutation number and log fitness is the result of interactions of opposite type (i.e., synergistic and antagonistic) that cancel each other's effect. However, due to an isolation bias caused by the fact that not all possible strains with many mutations could be isolated, the results may be relatively biased towards an antagonistic relationship between mutation number and log fitness. PMID- 28568631 TI - POLYGYNANDRY IN THE DUSKY PIPEFISH SYNGNATHUS FLORIDAE REVEALED BY MICROSATELLITE DNA MARKERS. AB - In the dusky pipefish Syngnathus floridae, like other species in the family Syngnathidae, 'pregnant' males provide all post-zygotic care. Male pregnancy has interesting implications for sexual selection theory and the evolution of mating systems. Here, we employ microsatellite markers to describe the genetic mating system of S. floridae, compare the outcome with a previous report of genetic polyandry for the Gulf pipefish S. scovelli, and consider possible associations between the mating system and degree of sexual dimorphism in these species. Twenty-two pregnant male dusky pipefish from one locale in the northern Gulf of Mexico were analyzed genetically, together with subsamples of 42 embryos from each male's brood pouch. Adult females also were assayed. The genotypes observed in these samples document that cuckoldry by males did not occur; males often receive eggs from multiple females during the course of a pregnancy (six males had one mate each, 13 had two mates, and three had three mates); embryos from different females are segregated spatially within a male's brood pouch; and a female's clutch of eggs often is divided among more than one male. Thus, the genetic mating system of the dusky pipefish is best described as polygynandrous. The genetic results for S. floridae and S. scovelli are consistent with a simple model of sexual selection which predicts that for sex role-reversed organisms, species with greater degrees of sexual dimorphism are more highly polyandrous. PMID- 28568632 TI - GENETIC EFFECTS OF GERMINATION TIMING AND ENVIRONMENT: AN EXPERIMENTAL INVESTIGATION. AB - Seeds of many species do not germinate immediately after dispersal, but instead may remain indefinitely in a dormant but viable state. Although it is well established that seeds often exhibit diversified patterns of dormancy and germination, the causes and consequences of this variation remain poorly understood. In this study, we investigate the extent to which seed genotypes of the desert mustard Lesquerella fendleri differentially germinate and establish under experimental conditions in a greenhouse. We used a two-way factorial design to compare genotypes of Lesquerella plants derived from seeds that germinated and established at different times and under different soil water regimes. Overall allozyme allele frequencies of Lesquerella plants varied significantly with both germination time and initial soil water availability. Single-locus heterozygosity analyses revealed that seeds sown into initially low water conditions produced plants that were significantly more heterozygous than plants derived from seeds experiencing constantly high water conditions, but heterozygosity did not differ significantly among plants originating from early- and late-germinating seeds. This is the first study to experimentally demonstrate that germination timing and environment can significantly affect the genetic structure of emerging plant populations. The study suggests that germination and survival behavior may (1) play an important role in generating and maintaining the genetic structure of natural plant populations and (2) set the stage for subsequent evolution. PMID- 28568633 TI - EXPERIMENTAL EVOLUTION OF ACCELERATED DEVELOPMENT IN DROSOPHILA. 1. DEVELOPMENTAL SPEED AND LARVAL SURVIVAL. AB - Developmental time is a trait of great relevance to fitness in all organisms. In holometabolous species that occupy ephemeral habitat, like Drosophila melanogaster, the impact of developmental time upon fitness is further exaggerated. We explored the trade-offs surrounding developmental time by selecting 10 independent populations from two distantly related selection treatments (CB1-5 and CO1-5 ) for faster development. After 125 generations, the resulting accelerated populations (ACB1-5 and ACO1-5 ) displayed net selection responses for development time of -33.4 hours (or 15%) for ACB and -38.6 hours (or 17%) for ACO. Since most of the change in egg-to-adult developmental time was accounted for by changes in larval duration, the "accelerated" larvae were estimated to develop 25-30% faster than their control/ancestor populations. The responses of ACB and ACO lines were remarkably parallel, despite being founded from populations evolved independently for more than 300 generations. On average, these "A" populations developed from egg to adult in less than eight days and produced fertile eggs less than 24 hours after emerging. Accelerated populations showed no change in larval feeding rate, but a reduction in pupation height, the latter being a trait relating to larval energetic expenditure in wandering prior to pupation. This experiment demonstrates the existence of a negative evolutionary correlation between preadult developmental time and viability, as accelerated populations experienced a severe cost in preadult survivorship. In the final assay generation, viability of accelerated treatments had declined by more than 10%, on average. A diallel cross demonstrated that the loss of viability in the ACO lines was not due to inbreeding depression. These results suggest the existence of a rapid development syndrome, in which the fitness benefits of fast development are balanced by fitness costs resulting from reduced preadult survivorship, marginal larval storage of metabolites, and reduced adult size. PMID- 28568634 TI - GENE EFFECTS ON A QUANTITATIVE TRAIT: TWO-LOCUS EPISTATIC EFFECTS MEASURED AT MICROSATELLITE MARKERS AND AT ESTIMATED QTL. AB - Most evolutionarily and agriculturally important traits are affected by many genes (quantitative trait loci, or QTL) of relatively small effect. Usually the genetics of these traits are examined by indirect statistical analysis of the covariance among relatives, rather than by direct analyses. We use new analytical and molecular techniques to examine nonadditive interactions of microsatellite markers and estimated QTL that influence adult body weight in mice. Offspring of a cross between a large inbred mouse strain (LG/J) and a small inbred strain (SM/J) were intercrossed to form a segregating F2 generation. Using 76 microsatellite markers and 19 estimated QTL, we estimate gene-level epistasis and population-level epistasis for body weight at 10 weeks for 534 F2 mice. Significant epistasis was found for large numbers of the two locus comparisons using both markers and previously detected QTL. There are many genes segregating for adult body weight in this cross and many of these genes appear to interact epistatically. The discovery of potentially extensive epistasis has important implications for evolutionary models. PMID- 28568635 TI - MUTATION AND EXTINCTION: THE ROLE OF VARIABLE MUTATIONAL EFFECTS, SYNERGISTIC EPISTASIS, BENEFICIAL MUTATIONS, AND DEGREE OF OUTCROSSING. AB - Recent theoretical studies have illustrated the potential role of spontaneous deleterious mutation as a cause of extinction in small populations. However, these studies have not addressed several genetic issues, which can in principle have a substantial influence on the risk of extinction. These include the presence of synergistic epistasis, which can reduce the rate of mutation accumulation by progressively magnifying the selective effects of mutations, and the occurrence of beneficial mutations, which can offset the effects of previous deleterious mutations. In stochastic simulations of small populations (effective sizes on the order of 100 or less), we show that both synergistic epistasis and the rate of beneficial mutation must be unrealistically high to substantially reduce the risk of extinction due to random fixation of deleterious mutations. However, in analytical calculations based on diffusion theory, we show that in large, outcrossing populations (effective sizes greater than a few hundred), very low levels of beneficial mutation are sufficient to prevent mutational decay. Further simulation results indicate that in populations small enough to be highly vulnerable to mutational decay, variance in deleterious mutational effects reduces the risk of extinction, assuming that the mean deleterious mutational effect is on the order of a few percent or less. We also examine the magnitude of outcrossing that is necessary to liberate a predominantly selfing population from the threat of long-term mutational deterioration. The critical amount of outcrossing appears to be greater than is common in near-obligately selfing plant species, supporting the contention that such species are generally doomed to extinction via random drift of new mutations. Our results support the hypothesis that a long-term effective population size in the neighborhood of a few hundred individuals defines an approximate threshold, below which outcrossing populations are vulnerable to extinction via fixation of deleterious mutations, and above which immunity is acquired. PMID- 28568636 TI - EFFECTS OF POLLEN QUANTITY ON PROGENY VIGOR: EVIDENCE FROM THE DESERT MUSTARD LESQUERELLA FENDLERI. PMID- 28568637 TI - CORRELATED RATES OF MOLECULAR AND MORPHOLOGICAL EVOLUTION. AB - Since Zuckerkandl and Pauling (1962, 1965) proposed the molecular clock, many studies seem to have supported their prediction that rates of molecular and morphological evolution generally will be decoupled. Most of these studies were aimed at taxa in which rates of morphological evolution were thought to vary greatly a priori. For the current survey eight diverse taxa were systematically chosen from published studies without regard to prior expectations about rates. Two approaches showed that rates of molecular and morphological evolution may usually be coupled. First, correlations in the total number of changes accumulated in terminal taxa suggest that some mechanism alters the rates of both morphological and molecular evolution in concert. Second, node-density effects were removed statistically, and average corrected base-to-tip totals were compared among sister clades. Across all taxa 50 of 72 of these corrected contrasts support the hypothesis that rates of molecular and morphological evolution are correlated; this finding is highly significant by a binomial test. Furthermore, there were positive correlations between inferred molecular and morphological branch lengths in seven of eight cases, which is also significant. These branch length correlations are consistent with the rate correlations, and suggest that amounts of molecular and morphological evolution often are correlated also. This study supports the assumptions of several phylogenetic methods, and highlights a need for new inquiries into many aspects of both molecular and morphological evolution. PMID- 28568638 TI - GENETICS OF RESISTANCE OF SALIX SERICEA TO A DIVERSE COMMUNITY OF HERBIVORES. AB - We measured resistance of Salix sericea, the silky willow, to a diverse assemblage of 12 herbivores. We investigated the potential for multispecies coevolution among these herbivores by measuring genetic correlations between pairs of herbivores interacting within the component community. After measuring herbivore attack on half-sib families of potted S. sericea during three years, we found significant narrow-sense heritabilities of resistance to Phyllonorycter salicifoliella and Phyllocnistis sp. in 1991. Thus, there is the potential for selection on resistance to these two herbivores. Despite the many significant phenotypic correlations between herbivore abundances within a year, most genetic correlations between herbivore abundances within a year were not significant. The genetic and phenotypic correlation structure varied from year to year in this three-year study. Thus, it appears that there is the potential for evolution of resistance to the two herbivores for which we found significant heritabilities, but multispecies coevolution seems unlikely. PMID- 28568639 TI - PHYLOGEOGRAPHY OF THE SARDINES (SARDINOPS SPP.): ASSESSING BIOGEOGRAPHIC MODELS AND POPULATION HISTORIES IN TEMPERATE UPWELLING ZONES. AB - Sardines (Sardinops spp.) occupy temperate upwelling zones in the coastal regions of the Indian and Pacific Oceans, including locations in Japan, California, Chile, Australia, and South Africa. East and West Pacific populations are separated by vast expanses of open ocean, and northern and southern hemisphere populations are separated by tropical waters which are lethal to sardines. The relative importance of these barriers has been the focus of a longstanding debate between vicariance and dispersal schools in biogeography. Comparisons of a 500 bp fragment of the mitochondrial (mt) DNA control region reveal strong geographic structuring of mtDNA lineages but shallow divergence both within and between regional populations. Regional populations are related to one another in a stepping-stone pattern, the apparent result of a series of Pleistocene dispersal events around the continental margins of the Indian-Pacific Basin. These mtDNA data, combined with an electrophoretic survey of variability at 34 nuclear loci (Grant and Leslie 1996), indicate that the five regional forms of Sardinops (considered separate taxa by most authorities) probably diverged within 500,000 years BP, a much shorter timeframe than predicted by vicariance models based on plate tectonics. High mtDNA haplotype diversity, coupled with an excess of rare alleles in the protein electrophoretic dataset, may indicate exponential growth from a small ancestral population. The mtDNA and allozyme data are concordant with climate records and fossil evidence in portraying regional populations as recent, unstable, and ephemeral. Regional populations of sardines have probably been extinguished and recolonized over short evolutionary timescales in response to changes in climate and the oceanography of coastal upwelling zones. PMID- 28568640 TI - RECENT BOOKS IN PRINT. PMID- 28568641 TI - ANTHER-SMUT DISEASE IN SILENE DIOICA: VARIATION IN SUSCEPTIBILITY AMONG GENOTYPES AND POPULATIONS, AND PATTERNS OF DISEASE WITHIN POPULATIONS. AB - In an archipelago in northern Sweden, populations of the perennial, dioecious, and insect-pollinated herb Silene dioica are commonly infected by the sterilising anther-smut fungus Microbotryum violaceum. The results from transplantation and inoculation experiments in this study show that variation between populations in the incidence of disease may partly be due to variation in resistance among populations. In the transplantation experiment in which plants were naturally exposed to the fungus, disease levels varied greatly among transplants from three healthy populations when transplanted to three diseased populations in the archipelago. Clear genotypic differences in susceptibility among 25 replicated genotypes of the host plants were found when inoculated manually with two different isolates. Susceptibility varied between 0-90%, but the two isolates used did not differ in inoculation success. The results also suggest a geographical structuring in resistance of the host and virulence of the fungus. First, disease levels among experimental plants from two of the disease-free populations of S. dioica (originating from inner and outer archipelago, respectively), were high when transplanted to a diseased population nearby, but low when transplanted far away. Second, regardless of origin, plants from all healthy populations became diseased in the diseased experimental populations located in the middle part of the archipelago. Due to isostatic land upheaval in the studied archipelago, there is a vertical age-axis within islands such that the highest point on an island is the oldest. Since this may affect the demography of the host, disease spread, and the dynamics of disease, spatial patterns in adult and seedling densities, and disease and spore deposition along the age-axis were studied within three diseased populations. A low incidence of disease was found in the young, low and old, high parts of the populations and a high incidence in the vertical, middle parts of the populations. The higher disease incidence in the middle part compared with the lower part of the population may reflect less disturbance and an increased probability of disease with age. PMID- 28568642 TI - THE EFFECT OF TEMPERATURE ON BODY SIZE AND FECUNDITY IN FEMALE DROSOPHILA MELANOGASTER: EVIDENCE FOR ADAPTIVE PLASTICITY. AB - The reaction norm linking rearing temperature and size in Drosophila melanogaster results in progressively larger flies as the temperature is lowered from 30 degrees C to 18 degrees C, but it has remained unclear whether this phenotypic plasticity is part of an adaptive response to temperature. We found that female D. melanogaster reared to adulthood at 18 degrees C versus 25 degrees C showed a 12% increase in dry weight. Measurements of the fecundity of these two types of fly showed that the size change had no effect on lifetime fecundity, regardless of the adult test temperature. Thus the phenotypic plasticity breaks the usual positive correlation between body size and fecundity. However, at a given temperature, early fecundity (defined as productivity for days 5 through 12 after eclosion at 25 degrees C and days 7 through 17 at 18 degrees C) was highest when the rearing and test temperatures were the same. The early fecundity advantage due to rearing at the test temperature was 25% at 18 degrees C and 16% at 25 degrees C, a result consistent with the overall phenotypic response to temperature being adaptive. This conclusion is further supported by the finding that the temperature treatments resulted in a trade-off between early fecundity and longevity, a trade-off that parallels the known genetic correlation. Another parallel is that both the temperature-induced and genetic effects are independent of total fecundity. By contrast, within the temperature treatments, the phenotypic correlation between early fecundity and longevity was positive, illustrating the danger of assuming that phenotypic and genetic correlations are similar, or even of the same sign. PMID- 28568643 TI - NORTH AMERICAN BLACK BEAR mtDNA PHYLOGEOGRAPHY: IMPLICATIONS FOR MORPHOLOGY AND THE HAIDA GWAII GLACIAL REFUGIUM CONTROVERSY. AB - The controversial role of Haida Gwaii (Queen Charlotte Islands) as a biological refugium on the northwestern coast of North America has been widely discussed for more than fifty years. The presence of morphologically divergent subspecies on Haida Gwaii is one of the major lines of evidence suggesting this archipelago's role as a refugium during the Wisconsin. However, since morphological distinction can be derived postglacially as well as in extended isolation, such evidence is ambiguous. To examine this question, we did a phylogenetic analysis of cytochrome b sequences (719 bp) of black bear (Ursus americanus), one of the distinctive endemics of Haida Gwaii, and compared these with conspecifics from across North America, focusing primarily on the northwestern coast. We found that the Haida Gwaii bear are indistinguishable from coastal bear of British Columbia and Vancouver Island, but are highly distinct from continental bear. Coastal and continental bears differ by 24 synapomorphies and an average sequence divergence of 3.6%. The coastal mitochondrial lineage occurs in each of the three recognized coastal subspecies suggesting that the morphological characteristics differentiating these taxa may be postglacially derived. The data are consistent with recent suggestions that a glacial refugium existed on the now submerged continental shelf connecting Haida Gwaii, Vancouver Island, and the coastal fringe of mainland British Columbia. This refugium would have been an additional source for postglacial recolonization of northwestern North America. PMID- 28568644 TI - INTERACTING PHENOTYPES AND THE EVOLUTIONARY PROCESS: I. DIRECT AND INDIRECT GENETIC EFFECTS OF SOCIAL INTERACTIONS. AB - Interacting phenotypes are traits whose expression is affected by interactions with conspecifics. Commonly-studied interacting phenotypes include aggression, courtship, and communication. More extreme examples of interacting phenotypes traits that exist exclusively as a product of interactions-include social dominance, intraspecific competitive ability, and mating systems. We adopt a quantitative genetic approach to assess genetic influences on interacting phenotypes. We partition genetic and environmental effects so that traits in conspecifics that influence the expression of interacting phenotypes are a component of the environment. When the trait having the effect is heritable, the environmental influence arising from the interaction has a genetic basis and can be incorporated as an indirect genetic effect. However, because it has a genetic basis, this environmental component can evolve. Therefore, to consider the evolution of interacting phenotypes we simultaneously consider changes in the direct genetic contributions to a trait (as a standard quantitative genetic approach would evaluate) as well as changes in the environmental (indirect genetic) contribution to the phenotype. We then explore the ramifications of this model of inheritance on the evolution of interacting phenotypes. The relative rate of evolution in interacting phenotypes can be quite different from that predicted by a standard quantitative genetic analysis. Phenotypic evolution is greatly enhanced or inhibited depending on the nature of the direct and indirect genetic effects. Further, unlike most models of phenotypic evolution, a lack of variation in direct genetic effects does not preclude evolution if there is genetic variance in the indirect genetic contributions. The available empirical evidence regarding the evolution of behavior expressed in interactions, although limited, supports the predictions of our model. PMID- 28568645 TI - GENETIC FINGERPRINT-INFERRED POPULATION SUBDIVISION AND SPATIAL GENETIC TESTS FOR ISOLATION BY DISTANCE AND ADAPTATION IN THE COASTAL PLANT LIMONIUM CAROLINIANUM. AB - This paper examines two wild populations of Limonium carolinianum for population genetic subdivision and spatial patterns of genetic variation in an attempt to simultaneously test for both the action of local adaptation to tidal gradients and isolation by distance (IBD). A VNTR (variable number of tandem repeats) genetic "fingerprinting" marker was used to infer relatedness among mapped plants in two populations. Band sharing within and between populations estimated F'ST , an approximate measure of FST . Regression models were used to analyze the relationship between band sharing and spatial separation in tidal elevation and horizontal distance, as well as the relationship of fecundity differences with band sharing and spatial distance. Populations differed in band size frequency distributions and mean number of bands per profile and, therefore, likely differed in effective population size. F'ST was estimated at 0.0678 and was significantly greater than F'ST among randomly constructed subpopulations. Band sharing decreased 0.13% per meter in one population but showed no significant relation to distance in the other. In the population with significant IBD band sharing increased with increasingly different tidal elevation, contrary to an adaptive hypothesis, possibly due to directional gene flow or drift. Deme sizes were approximately 25 meters and greater than 100 meters, spanning larger areas than the entire environmental gradient. Fecundity differences were not associated with spatial parameters or band sharing. Unequal potential maternal fecundity measured as variance in number of seeds per maternal family was a significant source of genetic sampling variance. The VNTR marker employed is capable of detecting adaptation as identity by descent in ecological time and is an appropriate method for estimating the net evolutionary fate of polygenic traits. The results show that the net balance between selection along an environmental gradient and the effects of IBD and unequal maternal fecundity favor genetic differentiation by random processes in populations of Limonium. PMID- 28568646 TI - Genetic diversity of Syrian Arabian horses. AB - Although Arabian horses have been bred in strains for centuries and pedigrees have been recorded in studbooks, to date, little is known about the genetic diversity within and between these strains. In this study, we tested if the three main strains of Syrian Arabian horses descend from three founders as suggested by the studbook. We examined 48 horses representing Saglawi (n = 18), Kahlawi (n = 16) and Hamdani (n = 14) strains using the Equine SNP70K BeadChip. For comparison, an additional 24 Arabian horses from the USA and three Przewalski's horses as an out group were added. Observed heterozygosis (Ho ) ranged between 0.30 and 0.32, expected heterozygosity (He ) between 0.30 and 0.31 and inbreeding coefficients (Fis ) between -0.02 and -0.05, indicating high genetic diversity within Syrian strains. Likewise, the genetic differentiation between the three Syrian strains was very low (Fst < 0.05). Hierarchical clustering showed a clear distinction between Arabian and Przewalski's horses. Among Arabian horses, we found three clusters containing either horses from the USA or horses from Syria or horses from Syria and the USA together. Individuals from the same Syrian Arabian horse strain were spread across different sub-clusters. When analyzing Syrian Arabian horses alone, the best population differentiation was found with three distinct clusters. In contrast to expectations from the studbook, these clusters did not coincide with strain affiliation. Although this finding supports the hypothesis of three founders, the genetic information is not consistent with the currently used strain designation system. The information can be used to reconsider the current breeding practice. Beyond that, Syrian Arabian horses are an important reservoir for genetic diversity. PMID- 28568647 TI - Standardized Passiflora incarnata L. Extract Reverts the Analgesia Induced by Alcohol Withdrawal in Rats. AB - Passiflora incarnata L. (Passifloraceae) has been traditionally used for treatment of anxiety, insomnia, drug addiction, mild infections, and pain. The aim of this study was to investigate the effect of a commercial extract of P. incarnata in the analgesia induced by alcohol withdrawal syndrome in rats. In addition, brain-derived neurotrophic factor and interleukin-10 levels were evaluated in prefrontal cortex, brainstem, and hippocampus. Male adult rats received by oral gavage: (1: water group) water for 19 days, 1 day interval and water (8 days); (2: P. incarnata group) water for 19 days, 1 day interval and P. incarnata 200 mg/kg (8 days); (3: alcohol withdrawal group) alcohol for 19 days, 1 day interval and water (8 days); and (4: P. incarnata in alcohol withdrawal) alcohol for 19 days, 1 day interval and P. incarnata 200 mg/kg (8 days). The tail flick and hot plate tests were used as nociceptive response measures. Confirming previous study of our group, it was showed that alcohol-treated groups presented an increase in the nociceptive thresholds after alcohol withdrawal, which was reverted by P. incarnata, measured by the hot plate test. Besides, alcohol treatment increased brain-derived neurotrophic factor and interleukin-10 levels in prefrontal cortex, which was not reverted by P. incarnata. Considering these results, the P. incarnata treatment might be a potential therapy in the alcohol withdrawal syndrome. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28568649 TI - Psychosis and identity: Alteration or loss? AB - The onset of psychotic disorders often brings major changes to an individual, which, for some, are never fully reversed and remain a dominant force. Despite such changes, the individual still experiences themselves as a continuous person and must find some way to assimilate these shifts into their self-concept. From a philosophical perspective, the various models of continuing identity all depend upon some notion of fundamental stability, which seems a poor fit for the trajectory associated with psychotic disorders. This article will explore, in more depth, how the transitions that accompany psychotic disorders present a challenge to conventional and philosophical notions of selfhood. If we are not simply to judge psychotic disorders as bringing about a loss of selfhood, we will need an alternative model of identity to use in this context. PMID- 28568648 TI - Influence of sex on the number of circulating endothelial microparticles and microRNA expression in middle-aged adults. AB - NEW FINDINGS: What is the central question of this study? Are there sex-related differences in the number of circulating endothelial microparticles (EMPs) and microparticle microRNA expression in middle-aged adult humans? What is the main finding and its importance? Although the numbers of circulating endothelial microparticles do not differ between middle-aged men and women, there are sex related differences in the expression of miR-125a in activation-derived EMPs and miR-34a in apoptosis-derived EMPs. Differences in circulating endothelial microparticle microRNA content may provide new insight into the sex-related disparity in the risk and prevalence of vascular disease in middle-aged adults. The aims of this study were to determine: (i) whether circulating concentrations of endothelial microparticles (EMPs) differ in middle-aged men compared with women; and (ii) whether there are sex-related differences in microRNA expression in EMPs. Peripheral blood was collected from 30 sedentary adults: 15 men (56 +/- 6 years old) and 15 women (56 +/- 5 years old). Endothelial microparticles were defined by markers of activation (CD62e+ ) or apoptosis (CD31+ /CD42b- ) by flow cytometry. Expression of microRNA (miR-34a, 92a, 125a and 126) in activation- and apoptosis-derived EMPs was measured by RT-PCR. Circulating activation- (33 +/- 31 versus 39 +/- 35 microparticles MUl-1 ) and apoptosis-derived EMPs (49 +/- 54 versus 42 +/- 43 microparticles MUl-1 ) were not significantly different between men and women. Expression of miR-125a (2.23 +/- 2.01 versus 6.95 +/- 3.99 a.u.) was lower (~215%; P < 0.05) in activation-derived EMPs, whereas expression of miR 34a (1.17 +/- 1.43 versus 0.38 +/- 0.35 a.u.) was higher (~210%; P < 0.05) in apoptosis-derived EMPs from men compared with women. Expression of microRNA in circulating EMPs may provide new insight into sex-related differences in cardiovascular disease. PMID- 28568650 TI - Robotic proctectomy for rectal cancer: analysis of 71 patients from a single institution. AB - BACKGROUND: Despite increasing use of robotic surgery for rectal cancer, few series have been published from the practice of generalizable US surgeons. METHODS: A retrospective chart review was performed for 71 consecutive patients who underwent robotic low anterior resection (LAR) or abdominoperineal resection (APR) for rectal adenocarcinoma between 2010 and 2014. RESULTS: 46 LARs (65%) and 25 APRs (35%) were identified. Median procedure time was 219 minutes (IQR 184 275) and mean blood loss 164.9 cc (SD 155.9 cc). Radial margin was negative in 70/71 (99%) patients. Total mesorectal excision integrity was complete/near complete in 38/39 (97%) of graded specimens. A mean of 16.8 (SD+/- 8.9) lymph nodes were retrieved. At median follow-up of 21.9 months, there were no local recurrences. CONCLUSIONS: Robotic proctectomy for rectal cancer was introduced into typical colorectal surgery practice by a single surgeon, with a low conversion rate, low complication rate, and satisfactory oncologic outcomes. PMID- 28568652 TI - RELATIVE CLUTCH MASS AND BODY SHAPE IN LIZARDS AND SNAKES: IS REPRODUCTIVE INVESTMENT CONSTRAINED OR OPTIMIZED? PMID- 28568651 TI - Red blood cells for transfusion in patients with sepsis: respective roles of unit age and exposure to recipient plasma. AB - BACKGROUND: Red blood cell (RBC) storage in blood banks is not exempt from cellular injury. Alterations not observed on RBCs freshly isolated from units can rapidly appear in circulation. The transfusion of old blood units, even if this is a controversial issue, could therefore have adverse effects on the recipient. We wanted to determine the respective effects of storage duration and recipient plasma on RBCs for transfusion into patients with severe sepsis. STUDY DESIGN AND METHODS: Eleven stored RBC units were sampled at various time points, approximately Days 3 to 8 (referred to as fresh RBCs) and Days 38 to 42 (old RBCs) and tested in coincubation experiments with plasma obtained from 13 patients with severe sepsis and 17 healthy donors as controls. RBCs were tested after 24 or 48 hours at 37 degrees C for the detection of senescence markers (phosphatidylserine exposure, calcium influx, and reactive oxygen species detection and decrease in size) with or without exposure to plasma. RESULTS: We confirmed that a 42-day refrigerated storage of RBCs alone (without any incubation in plasma) had no significant effect on RBCs and no senescence marker detected. By contrast, ex vivo exposure to plasma samples altered both fresh and old RBCs, with a much larger effect for old RBCs, regardless of the plasma used (sepsis vs. control). CONCLUSION: We show that the main factor affecting the senescence of RBCs for transfusion into patients with severe sepsis is the age of the stored units rather than the clinical status of the recipient. PMID- 28568653 TI - OUTBREEDING DEPRESSION IN A SELFING ANNUAL. PMID- 28568654 TI - PHYLOGENETIC ESTIMATION OF PLASMID EXCHANGE IN BACTERIA. AB - The existence of differential horizontal gene transfer may be assessed by comparing the phylogenetic trees derived from two different genes. We use this concept to estimate quantitatively the amount of plasmid exchange that has occurred in a bacterial population. By means of computer simulations we studied the effect of gene transfer on the topological distortion between two phylogenetic trees: one obtained from an euchromosomal gene and another from a plasmid-borne sequence, which may be subjected to horizontal transfer. The basic assumptions of our simulations were (a) that plasmid exchange had occurred recently (after the last population split); and (b) that either the amount of chromosomal horizontal exchange was negligible or that it was only a fraction of the amount of plasmid exchange in which case we will be estimating relative amounts of plasmid transfer. We found that the topological difference between two such trees is a function of the number of plasmid exchange events that have occurred. It can be explained by a logistic model that relates the average distortion index between two trees (dT ) to the number of transfer events (x). The behavior remains the same under different conditions that were tested (symmetry of the topology, number of taxa in the tree, effect of reconstruction errors, mutation after plasmid transfer). We have also tried our method on empirical data from the literature and estimated the amount of gene transfer that may have occurred among Sym plasmids in agricultural field populations of Rhizobium leguminosarum biovar phaseoli. We found that between 15.77 to 29.98% of all genetic types in these populations have been either the source or the target of a plasmid transfer event. When the comparisons were made among trees derived exclusively from plasmid probes this value dropped to 2.00%. Phylogenetic trees derived from symbiotic and nonsymbiotic sequences were also used to infer the number of gene transfer events among 11 isolates from R. galegae. The estimated number of transfer events of symbiotic sequences was 10.515 (although we do not know out of how many genetic types). We concluded that intraspecific transfer of symbiotic sequences is widespread in these two species of the genus Rhizobium. PMID- 28568655 TI - ON GENETIC SEGREGATION AND THE EVOLUTION OF SEX. AB - It has recently been argued that because the genetic load borne by an asexual species resulting from segregation, relative to a comparable sexual population, is greater than two, sex can overcome its twofold disadvantage and succeed. We evaluate some of the assumptions underlying this argument and discuss alternative assumptions. Further, we simulate the dynamics of competition between sexual and asexual types. We find that for populations of size 100 and 500 the advantages of segregation do not outweigh the cost of producing males. We conclude that, at least for small populations, drift and the cost of sex govern the evolution of sexuality, not selection or segregation. We believe, however, that if sexual and asexual populations were isolated for a sufficiently long period, segregation might impart a fitness advantage upon sexuals that could compensate for the cost of sex and allow sexuals to outcompete asexuals upon their reunion. PMID- 28568657 TI - PLUMAGE COLOR IS A CONDITION-DEPENDENT SEXUAL TRAIT IN MALE PIED FLYCATCHERS. PMID- 28568656 TI - EFFECTS OF CROSS AND SELF-FERTILIZATION ON PROGENY FITNESS IN LOBELIA CARDINALIS AND L. SIPHILITICA. AB - Inbreeding depression, or the decreased fitness of progeny derived from self fertilization as compared to outcrossing, is thought to be the most general factor affecting the evolution of self-fertilization in plants. Nevertheless, data on inbreeding depression in fitness characters are almost nonexistent for perennials observed in their natural environments. In this study I measured inbreeding depression in both survival and fertility in two sympatric, short lived, perennial herbs: hummingbird-pollinated Lobelia cardinalis (two populations) and bumblebee-pollinated L. siphilitica (one population). Crosses were performed by hand in the field, and seedlings germinated in the greenhouse. Levels of inbreeding depression were determined for one year in the greenhouse and for two to three years for seedlings transplanted back to the natural environment. Fertility was measured as flower number, which is highly correlated with seed production under natural conditions in these populations. Inbreeding depression was assessed in three ways: 1) survival and fertility within the different age intervals; 2) cumulative survival from the seed stage through each age interval; and 3) net fertility, or the expected fertility of a seed at different ages. Net fertility is a comprehensive measure of fitness combining survival and flower number. In all three populations, selfing had nonsignificant effects on the number and size of seeds. Lobelia siphilitica and one population of L. cardinalis exhibited significant levels of inbreeding depression between seed maturation and germination, excluding the consideration of possible differences in dormancy or longterm viability in the soil. There was no inbreeding depression in subsequent survival in the greenhouse in any population. In the field, significant survival differences between selfed and outcrossed progeny occurred only in two years and in only one population of L. cardinalis. For both survival and fertility there was little evidence for the expected differences among families in inbreeding depression. Compared to survival, inbreeding depression in fertility (flower number) tended to be much higher. By first-year flower production, the combined effects on survival and flower number caused inbreeding depression in net fertility to reach 54%, 34% and 71% for L. siphilitica and the two populations of L. cardinalis. By the end of the second year of flowering in the field, inbreeding depression in net fertility was 53% for L. siphilitica and 54% for one population of L. cardinalis. For the other population of L. cardinalis, these values were 76% through the second year of flowering and 83% through the third year. Such high levels of inbreeding depression should strongly influence selection on those characters affecting self fertilization rates in these two species. PMID- 28568658 TI - TEMPORAL FLUCTUATIONS IN DEMOGRAPHIC PARAMETERS AND THE GENETIC VARIANCE AMONG POPULATIONS. AB - Contrary to assumptions commonly made in the study of population genetics, the demographic properties of many populations are not always constant. Important characteristics of populations such as migration rate and population size may vary in time and space. Moreover, local populations often come and go; the rate of extinction and the properties of colonization may also vary. In this paper, the approach to equilibrium following a disturbance in the genetic variance among populations is described. The rate of migration is shown to be critical in determining the extent to which extinction and recolonization affects genetic differentiation. Perturbations and variations through time and space in demographic parameters such as population size and migration rate are shown to be important in determining the partitioning of genetic variance. Equations are given to predict the average through time of genetic differentiation among populations in the event of a single disturbance or in constant fluctuations in the pertinent demographic parameters. In general, these fluctuations increase the FST of a species. Spatial demographic variation affects FST much more than temporal variation. These demographic properties make some species unsuitable for the empirical analysis of migration with indirect genetic measures. Demographic instability may play a large role in the evolution of genetic variation. PMID- 28568659 TI - USING PHYLOGENETIC TREES TO STUDY SPECIATION AND EXTINCTION. AB - One tool in the study of the forces that determine species diversity is the null, or simple, model. The fit of predictions to observations, good or bad, leads to a useful paradigm or to knowledge of forces not accounted for, respectively. It is shown how simple models of speciation and extinction lead directly to predictions of the structure of phylogenetic trees. These predictions include both essential attributes of phylogenetic trees: lengths, in the form of internode distances; and topology, in the form of internode links. These models also lead directly to statistical tests which can be used to compare predictions with phylogenetic trees that are estimated from data. Two different models and eight data sets are considered. A model without species extinction consistently yielded predictions closer to observations than did a model that included extinction. It is proposed that it may be useful to think of the diversification of recently formed monophyletic groups as a random speciation process without extinction. PMID- 28568660 TI - SMALL POPULATION GENETIC VARIABILITY AT LOCI UNDER STABILIZING SELECTION. AB - Genetic variability at a locus under stabilizing selection in a finite population is investigated using analytic methods and computer simulations. Three measures are examined: the number of alleles k, heterozygosity H, and additive genetic variance Vg. A nearly-neutral theory results. The composite parameter S = NVM /Vs (where N is the population size, VM the variance of new mutant allelic effects and Vs the weakness of stabilizing selection) figures prominently in the results. The equilibrium heterozygosity is similar to that of strictly neutral theory, H = 4NMUc / (1 + 4NMUc ), except that MUc = MUe=MU/1+cS where c is about 0.5. Simulations corroborate Vg=4MUVs1+1/S except for very low N. Genetic variability attains similar equilibrium values at both a "lone" locus and at an "embedded" locus. This agrees with my earlier work concerning molecular clock rates. These results modify the neutralist interpretation of data concerning genetic variability and genetic distances between populations. Low H values are proportional not to N but to N. This may explain the narrow observed range of H among species. Heterozygosities need not be highly correlated to genetic variances. Genetic variances are not highly dependent on population size except in very small populations which are difficult to sample without bias because the smallest populations go extinct the fastest. Nearly neutral evolution will not be easily distinguished from strictly neutral theory under the Hudson-Kreitman Aguade inter-/intraspecific variation ratio test, since a similar effective mutation rate holds for genetic distances and D = 2MUc t, where MUe=MU/1+S. As with strictly neutral theory, comparisons across loci should show D and H to be positively correlated because of the shared MUc . But unlike neutral theory, for a given locus, comparisons across species should show D and H to be negatively correlated. There is no obvious threshold of population size below which genetic variability inevitably declines. Extinction depends on both genetic variation and natural selection. Neither theory nor observation presently indicates the measure of genetic variability (k, H, VG or other) that best indicates vulnerability of a small population to extinction. PMID- 28568661 TI - POLLEN COMPETITION AND PATERNAL SUCCESS IN DOUGLAS-FIR. PMID- 28568662 TI - CAENOGENESIS, DEVELOPMENTAL VARIABILITY, AND EVOLUTION IN THE CARPUS AND TARSUS OF THE MARBLED NEWT TRITURUS MARMORATUS. AB - In this paper, after a comparative analysis of the development of Triturus marmoratus, we explore the existence of caenogenetic events and their ontogenetic and phylogenetic consequences. The adult morphology of the Triturus marmoratus limb, in terms of number and spatial arrangement of skeletal elements, agrees with the general pattern of urodeles. The congruence in the typical pattern of adult morphology does not hint at the striking differences in embryonic development. These differences can be summarized as follows: 1) Presence of a "central axis" that develops in a distal-to-proximal direction. It originates in the basale commune giving rise to the centrale and the intermedium. Thus, there is no postaxial branching as found in Ambystoma mexicanum. 2) Again, unlike in Ambystoma mexicanum, we find a postaxial structure composed of the ulnare (fibulare)-distal carpal (tarsal) 4-metacarpal (metatarsal) 4 which is independent of the "digital arch." 3) The (forelimb) digits, in particular, digits 1, 2, and 3, undergo disproportionate elongation. For example, the second digit, composed of a thin continuous, cartilaginous rod, becomes longer than the rest of the limb. Our study of the patterns of embryonic connectivity suggests the coexistence of three directions of growth and morphogenesis in the development of the Triturus marmoratus limb. 1) A proximo-distal one that gives rise to the preaxial axis, "primary axis," and individual digits. 2) An anterio posterior axis of development that gives rise to the "digital arch" and determines the number of digits. 3) A disto-proximal central axis that originates in the basale commune and sequentially generates the centrale and the intermedium. We speculate that heterochronic interspecific variation in the time of onset of limb bud formation is related to the degree of precocious digital elongation. Selection for long extremities in early larval stages, associated with functional demands for locomotion and balancing, may be the cause for the above listed changes in developmental pattern. Thus, the reported system is an example of how selection during ontogeny can result in the evolution of the developmental process. PMID- 28568663 TI - THE PENNSYLVANIAN-PERMIAN VEGETATIONAL TRANSITION: A TERRESTRIAL ANALOGUE TO THE ONSHORE-OFFSHORE HYPOTHESIS. AB - An analysis of 68 floras from the Pennsylvanian and Early Permian of Euramerica reveals distinct patterns of environmental distribution. Wetland assemblages are the most commonly encountered floras from the Early and Middle Pennsylvanian. Floras from drier habitats characterize the Permian. Both wetland and dry-site floras occur in the Late Pennsylvanian, but floristic overlap is minimal, which implies strong environmental controls on the distributions of the component species. Drier habitats appear to be the sites of first appearance of orders that become prominent during the Late Permian and Mesozoic. Higher taxa originated in physically heterogeneous, drier habitats, which were geographically marginal throughout most of the Pennsylvanian. They then moved into the lowlands during periods of climatic drying in the Permian, replacing older wetland vegetation. This pattern is analogous to the marine onshore-offshore pattern of origination and migration. The derivation of Mesozoic wetland clades from the Permian dry lowland vegetation completes the parallel. The similarities of the marine and terrestrial patterns suggest that the combination of evolutionary opportunity, created by physical heterogeneity of the environment, and migrational opportunity, created by changing extrinsic conditions, may be underlying factors that transcend the specifics of organism and environment. PMID- 28568664 TI - VARIATION IN MATING CALL ACROSS THE HYBRID ZONE BETWEEN THE FIRE-BELLIED TOADS BOMBINA BOMBINA AND B. VARIEGATA. AB - Three components of mating call (pulse duration, cycle length, and fundamental frequency) were measured and six diagnostic enzyme loci scored across the hybrid zone between the toads Bombina bombina and B. variegata. All three call components differ significantly, but only cycle length is diagnostic. The clines in call coincide with those for enzymes, and have similar widths. This suggests that there is no strong selection on any of these characters. There are significant correlations between electrophoretic markers and call components, but these are no stronger than would be expected if the electrophoretic loci and the genes causing mating call were neutral. The selection differential on the call is no greater than 6% of the difference in mean cycle length between the two taxa. There is a substantial increase in the variance of cycle length in the center of the zone, suggesting that a small number of loci are involved (~ three). Recombination between these loci will hinder the evolution of reinforcement and may partly be responsible for the lack of premating isolation between B. bombina and B. variegata. PMID- 28568665 TI - GENETIC CORRELATIONS AMONG MORPHOMETRIC TRAITS AND RATES OF GROWTH AND DIFFERENTIATION IN THE GREEN TREE FROG, HYLA CINEREA. AB - It is often proposed that the morphometric shape of animals often evolves as a correlated response to selection on life-history traits such as whole-body growth and differentiation rates. However, there exists little empirical information on whether selection on rates of growth or differentiation in animals could generate correlated response in morphometric shape beyond that owing to the correlation between these rates and body size. In this study genetic correlations were estimated among growth rate, differentiation rate, and body-size-adjusted head width in the green tree frog, Hyla cinerea. Head width was adjusted for size by using the residuals from log-log regressions of head width on snout-vent length. Size-adjusted head width at metamorphosis was positively genetically correlated with larval period length. Thus, size-independent shape might evolve as a correlated response to selection on a larval life-history trait. Larval growth rate was not significantly genetically correlated with size-adjusted head width. An additional morphometric trait, size-adjusted tibiofibula length, had a nonnormal distribution of breeding values, and so was not included in the analysis of genetic correlations (offspring from one sire had unusually short legs). This result is interesting because, although using genetic covariance matrices to predict long-term multivariate response to selection depends on the assumption that all loci follow a multivariate Gaussian distribution of allelic effects, few data are available on the distribution of breeding values for traits in wild populations. Size at metamorphosis was positively genetically correlated with larval period and larval growth rate. Quickly growing larvae that delay metamorphosis therefore emerge at a large size. The genetic correlation between larval growth rate and juvenile (postmetamorphic) growth rate was near zero. Growth rate may therefore be an example of a fitness-related trait that is free to evolve in one stage of a complex life cycle without pleiotropic constraints on the same trait expressed in the other stage. PMID- 28568666 TI - THE MEASUREMENT OF SELECTION ON QUANTITATIVE TRAITS: BIASES DUE TO ENVIRONMENTAL COVARIANCES BETWEEN TRAITS AND FITNESS. AB - The use of regression techniques for estimating the direction and magnitude of selection from measurements on phenotypes has become widespread in field studies. A potential problem with these techniques is that environmental correlations between fitness and the traits examined may produce biased estimates of selection gradients. This report demonstrates that the phenotypic covariance between fitness and a trait, used as an estimate of the selection differential in estimating selection gradients, has two components: a component induced by selection itself and a component due to the effect of environmental factors on fitness. The second component is shown to be responsible for biases in estimates of selection gradients. The use of regressions involving genotypic and breeding values instead of phenotypic values can yield estimates of selection gradients that are not biased by environmental covariances. Statistical methods for estimating the coefficients of such regressions, and for testing for biases in regressions involving phenotypic values, are described. PMID- 28568667 TI - THE GENETIC BASIS OF DEVELOPMENTAL STABILITY IN APIS MELLIFERA: HETEROZYGOSITY VERSUS GENIC BALANCE. AB - The genetic basis for developmental stability in the haplo-diploid honeybee Apis mellifera was determined by comparing the level of asymmetry between diploid females and haploid males both among and within inbreeding levels. There was no significant relationship between the level of inbreeding and the level of fluctuating asymmetry for both females and males. It is therefore argued that the general level of genomic heterozygosity is not an important factor for the determination and maintenance of developmental stability in this system, but rather that the balance of genes within chromosomes plays the major role. The observation that males were generally more asymmetric than females suggests that developmental stability in females may also be influenced by additional factors such as gene dosage, sex-limited genes or cytoplasmic elements. PMID- 28568668 TI - A COMMENT ON PLEISTOCENE POPULATION BOTTLENECKS IN PERIODICAL CICADAS (HOMOPTERA: CICADIDAE: MAGICICADA SPP.). PMID- 28568669 TI - PERFORMANCE OF TADPOLES FROM THE HYBRIDOGENETIC RANA ESCULENTA COMPLEX: INTERACTIONS WITH POND DRYING AND INTERSPECIFIC COMPETITION. AB - The performance of three genotypes (LL, LR, RR) of tadpoles resulting from the hybrid mating system of Rana lessonae (phenotype L, genotype LL) and Rana esculenta (phenotype E, genotype LR) was determined in artificial ponds. The effects of interspecific competition and pond drying on growth, development, and survival of tadpoles were used to measure the performance of genotypes and the relative fitness of offspring. Among the three genotypes, tadpoles from the homogametic mating RR had the lowest survival, growth, and development under all environmental conditions. Body size of the LL and LR genotype tadpoles at metamorphosis was reduced by competition and pond drying. Days to metamorphosis were also higher for the LL and LR genotype tadpoles in competition ponds. The proportion of individuals metamorphosing of each genotype was differentially lowered by competition and pond drying. The LL genotype produced more metamorphs than the LR genotype in the constant water level ponds, but the LR genotype produced more in drying ponds. In competition ponds, the LR genotype produced more metamorphs than the LL genotype, but the LL genotype produced more metamorphs in ponds without competition. The RR genotype produced no metamorphs in any of the experimental environments. Increased performance of LR offspring from the heterogametic mating, in harsh conditions, and reduced performance of RR offspring from the homogametic mating, even under favorable conditions, relative to the parental genotype (LL) suggests that the population dynamics of this hybridogenetic system is strongly dependent on mate choice in mixed populations and the subsequent pond environment females select for oviposition and larval development. PMID- 28568670 TI - CHROMOSOMAL POLYMORPHISM IN ISOFEMALE LINES AND CAGE POPULATIONS OF DROSOPHILA MELANOGASTER. AB - Drosophila melanogaster populations in nature usually carry inversion polymorphisms. When they were transferred to and maintained in the laboratory as large cage populations, frequencies of polymorphic inversions were drastically decreased and finally eliminated. This "cage effect" was observed irrespective of the geographical origin of the population or the initial frequency of each inversion. The decrease and elimination of inversions in the cage was not overcome by changing conditions such as medium, temperature, or the number of isofemale lines (40-600) introduced. On the other hand, in the sets of isofemale lines derived from the same geographical origins as the cage populations, each of which was maintained as a small vial population, the inversion frequencies, though decreased from the initial frequencies, were kept at significantly high levels. The cage populations initiated with one or two isofemale lines also maintained the inversion polymorphisms that were as high as vial populations. PMID- 28568671 TI - THE SOCIETY FOR THE STUDY OF EVOLUTION CONSTITUTION AND BYLAWS. PMID- 28568672 TI - REPRODUCTIVE ISOLATION IN RHABDITIDAE (NEMATODA: SECERNENTEA); MECHANISMS THAT ISOLATE SIX SPECIES OF THREE GENERA. AB - We have attempted interspecific hybridizations among six species of rhabditid nematodes: Caenorhabditis elegans, Caenorhabditis briggsae, Caenorhabditis remanei, Caenorhabditis sp. v, Rhabditis sp., and Pelodera teres. Copulation was observed in all crosses between Caenorhabditis species; however, none resulted in the generation of stable hybrid populations. No copulation was observed in crosses between Caenorhabditis males and Rhabditis or Pelodera females, even when congeneric females were present, suggesting that Caenorhabditis males are able to selectively recognize congeneric females by a short-range stimulus. All pairwise combinations of Caenorhabditis species were isolated to some degree by gametic mechanisms; 7 of 12 combinations were cross infertile and 5 of 12 were cross fertile but had low brood sizes. In cross-fertile combinations, most hybrid embryos were inviable and arrested prior to gastrulation. Only in crosses of C. briggsae males to C. sp. v females did any hybrids survive embryogenesis. Most of these C. briggsae/C. sp. v hybrids arrested during larval development, and the few that reached adulthood invariably were female. These results are consistent with the presence of at least two lethal factors in the C. briggsae-C. sp. v combination: a maternal lethal factor in the cytoplasm of C. briggsae and a recessive lethal factor on the X chromosome of C. sp. v. PMID- 28568673 TI - VARIATION IN ALCOHOL DEHYDROGENASE ACTIVITY AND FLOOD TOLERANCE IN WHITE CLOVER, TRIFOLIUM REPENS. AB - Flooding results in induction of anaerobic metabolism in many higher plants. As an important component of anaerobic energy production, alcohol dehydrogenase (ADH) activity increases markedly in response to flooding in white clover, Trifolium repens. Significant inter-individual variation in flood-induced ADH activity exists in natural populations of T. repens. The genetic basis of this variation was analyzed by offspring-midparent regression of data from 75 greenhouse reared families; the estimated heritability of flood-induced ADH activity was 0.55 (+/-0.13). Genetic variation in flood-induced ADH activity has pronounced effects on physiological response and flood tolerance in this species. ADH activity is positively correlated with the rate of ethanol production, indicating that observed in vitro activity differences are manifested in in vivo physiological function. T. repens plants with higher ADH activities during flooding have greater flood tolerance (measured as growth rate when flooded/unflooded growth rate). Variation in ADH activity during flooding accounts for more than 79% of the variance in flood tolerance. On the basis of a limited field survey of populations occupying three sites differing in exposure to flooding conditions, individuals from site C, the most frequently flooded site, expressed significantly higher average ADH activity when flooded than individuals from site A, a site with no history of flooding. Since ADH activity levels are not correlated with electrophoretic mobility variation in T. repens, this work supports previous suggestions that regulatory variation in enzyme activity may play a central role in biochemical adaptations to environmental stress. PMID- 28568674 TI - GENETIC VARIATION IN THE SEXUAL REPRODUCTION RATE WITHIN A POPULATION OF A CYCLIC PARTHENOGEN, DAPHNIA MAGNA. PMID- 28568675 TI - CORRELATED RESPONSES IN LIFE-HISTORY TRAITS TO ARTIFICIAL SELECTION FOR BODY WEIGHT IN DROSOPHILA MELANOGASTER. AB - Drosophila melanogaster that had been successfully selected on rich and poor larval medium for increased and decreased fresh weight at eclosion were tested on an intermediate medium for correlated responses in longevity, fertility, and hatchability. Larger flies laid more eggs early in life and lived shorter lives than smaller flies, which not only lived longer but also laid more eggs later in life. This supports the notion of a mortality cost of reproduction in Drosophila. The total number of eggs laid per lifetime did not differ between the two groups. The percentage of offspring hatched started at normal levels (about 50% of eggs laid), then declined rapidly in large flies. In small flies, hatchability started at a lower level early in life (40-65%), but declined less rapidly, and later in life was higher than the hatchability of eggs laid by larger flies. PMID- 28568676 TI - SKEWED PRIMARY SEX RATIO IN THE SOLITARY SPIDER PITYOHYPHANTES PHRYGIANUS. PMID- 28568677 TI - TIME OF ORIGIN AND BIOGEOGRAPHICAL HISTORY OF SPECIALIZED RELATIONSHIPS BETWEEN NORTHERN MARINE PLANTS AND HERBIVOROUS MOLLUSCS. AB - A survey of cool-temperate North Pacific and North Atlantic marine plants and herbivorous molluscs and their descendants was undertaken to determine the time of origin and the biogeographical history of specialized host-guest relationships between plants and herbivores. Of 12 such associations, 6 (50%) were established no earlier than the Pliocene. These six associations resulted from the invasion of either the plant (three cases) or the herbivore (three cases) from geographical regions other than the one in which the association was forged. These results are contrary to the widely held view that specialized ("coevolved") relationships tend to be ancient, and highlight the importance of biotic interchange as a biogeographical process influencing the opportunity for trophic specialization. PMID- 28568678 TI - HYBRIDOGENESIS AND ANDROGENESIS IN THE STICK-INSECT BACILLUS ROSSIUS-GRANDII BENAZZII (INSECTA, PHASMATODEA). AB - In northwestern Sicily interspecific hybrid females between Bacillus rossius and B. grandii benazzii (Insecta, Phasmatodea) are sympatric with facultatively parthenogenetic demes of the former and bisexual populations of the latter. Preliminary observations suggested that hybrid females are maintained by hybridogenetic reproduction, not by current F1 hybrid production nor through parthenogenesis. Being hybridogens, a complex of hemiclonal lineages, we informally refer to them as B. rossius-grandii benazzii, according to Schultz's proposal. In this study B. rossius-g. benazzii females were crossed with males of B. g. benazzii, B. g. grandii, B. g. maretimi, and B. rossius. Allozyme analysis of the progeny showed that the great majority of them were actually produced by hybridogenesis with a hemiclonal inheritance of the maternal B. rossius genotype (Brm ) and actual syngamy with a sperm from the fathering male, so that Brm -gbp , Brm -ggp , Brm -gmp , and Brm -rp offspring were obtained in the respective crosses. All-paternal progeny (androgenetics) were also produced (Bgbp gbp , Bgmp gmp , Brp rp ) and two gynogenetic descendants were observed. Cytological investigations on virgin eggs that failed to hatch revealed in most of them a haploid-diploid blocked blastoderm; this rudimentary parthenogenesis appears to be an important prerequisite for further evolution of this hybridogen. Reproductive modes of descendants were also analyzed; although Brm -gp hybrids are still able to reproduce by hybridogenesis, a progressive disruption of the hybridogenetic-androgenetic system takes place in synthetic B. rossius (Brm -rp , Brp rp ) and abundant thelytokous parthenogenetic offspring are obtained from females of androgenetic origin. The evolutionary role of these hybridogens appears to be linked to their shift towards parthenogenesis; this has apparently occurred in the southeastern Sicilian hybrid B. whitei (=B. rossius/g. grandii), which exhibits both hybridogenesis and parthenogenesis. PMID- 28568679 TI - THE EFFECTS OF SELECTION IN THE GAMETOPHYTE STAGE ON MUTATIONAL LOAD. AB - We have studied a multilocus selection model of a plant population in which mutations to deleterious alleles occur that may affect not only the diploid sporophyte stage, but also the haploid pollen stage before zygote formation. We investigated the reduction in inbreeding depression (as measured in the sporophyte) caused by the lowering of mutant allele frequencies due to selection in the pollen. This is important for a full understanding of the role of inbreeding depression in the maintenance of outcrossing in seed plants. We also studied the theoretically expected relationship between the pollen fitnesses of different pollen donor genotypes and the fitnesses of the diploid progeny that they sire. This relationship can be compared with the results of experiments in which pollen was subjected to selection, and improved progeny quality was observed. We found that on the mutational load model there is, as expected intuitively, a positive covariance between the pollen and zygote fitnesses, but that it is likely to be small. Subjecting pollen to an episode of strong selection is usually expected to increase sporophyte fitness only slightly. PMID- 28568680 TI - Mucositis Secondary to Chlamydia pneumoniae Infection: Expanding the Mycoplasma pneumoniae-Induced Rash and Mucositis Concept. AB - The term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) was recently proposed to identify the mucocutaneous condition secondary to M. pneumoniae infection that had historically been regarded among the more confusing pathologies of erythema multiforme and Stevens-Johnson syndrome. Based on a number of previous reports, these syndromes require differentiation since they have different prognoses and specific treatment requirements. We report a case of oral and genital erosions that strongly resembled MIRM without rash but were found to be secondary to a Chlamydia pneumoniae infection. After a thorough review of the literature on this subject, we propose that C. pneumoniae should also be considered a potential causative agent of MIRM and that this term should be amended to include C. pneumoniae infection. PMID- 28568682 TI - EVOLUTION UNDER INTERSPECIFIC COMPETITION: FIELD EXPERIMENTS ON TERRESTRIAL SALAMANDERS. PMID- 28568683 TI - SELECTION FOR COMPETITIVE ABILITY: NEGATIVE RESULTS IN DROSOPHILA. PMID- 28568681 TI - Asthma, bones and corticosteroids: Are inhaled corticosteroids associated with fractures in children with asthma? AB - AIM: The prevalence of asthma worldwide among older children varies between 10 and 20%. One of the most effective therapies to treat asthma and prevent exacerbations is inhaled corticosteroids (ICSs). Systemic corticosteroids are known to decrease bone mineral density and increase the risk of fractures among children, but little is known about the effect of ICSs on fracture risk in children with asthma. The aim of this study was to investigate the fracture rates in children with asthma using ICSs. METHODS: A survey on fracture history and risk, bone health and asthma was administered by a researcher to children aged 6 18 years attending a tertiary care children's hospital in Melbourne, Australia over a 6-month period. Fracture risks were compared in children on low or high dose ICS with those not on any ICS and non-asthmatics. RESULTS: A total of 216 healthy control participants were compared with 211 children with asthma - 22% (n = 46) on low dose ICS therapy, 44% (n = 94) on high dose ICS and 34% (n = 71) not on any ICS. There was no difference in the incidence of fractures between children with asthma (24.6% n = 53) and healthy controls (24% n = 51) (chi2 = 0.132; P = 0.717). There were no differences in fracture incidence in the sub groups of children with asthma (P = 0.695). CONCLUSION: ICS use was not associated with fracture risk in children with asthma. PMID- 28568684 TI - EVOLUTION OF CLONAL DIVERSITY IN THE PARTHENOGENETIC FLY LONCHOPTERA DUBIA. PMID- 28568685 TI - MECHANISMS OF FIXATION AND ACCUMULATION OF CENTRIC FUSIONS IN NATURAL POPULATIONS OF MUS MUSCULUS L. I. KARYOLOGICAL ANALYSIS OF A HYBRID ZONE BETWEEN TWO POPULATIONS IN THE CENTRAL APENNINES. PMID- 28568686 TI - UNPALATABILITY AS A DEFENSE STRATEGY OF EUPHYDRYAS PHAETON (LEPIDOPTERA: NYMPHALIDAE). PMID- 28568687 TI - EFFECTS OF COLD CLIMATE ON THE EVOLUTION OF PINNIPED BREEDING SYSTEMS. PMID- 28568688 TI - SEXUAL ISOLATION AMONG POPULATIONS OF DROSOPHILA MOJAVENSIS: RESPONSE TO PRESSURE FROM A RELATED SPECIES. PMID- 28568690 TI - Erratum. PMID- 28568689 TI - MATE CHOICE IN HYLOBITTACUS APICALIS (INSECTA: MECOPTERA) AND ITS RELATION TO SOME MODELS OF FEMALE CHOICE. PMID- 28568691 TI - ALTERED COMPETITION BETWEEN TWO REPRODUCTIVELY ISOLATED STRAINS OF DROSOPHILA MELANOGASTER. PMID- 28568692 TI - ON CASTE RATIOS IN ANT COLONIES: POPULATION RESPONSES TO CHANGING ENVIRONMENTS. PMID- 28568693 TI - EVOLUTION OF FLORAL DISPLAY IN THE ORCHID BRASSAVOLA NODOSA. PMID- 28568694 TI - WHEN IS IT COEVOLUTION? PMID- 28568695 TI - LOCAL POPULATION SIZE AS A DETERMINANT OF MATING SYSTEM AND SEXUAL COMPOSITION IN TWO TROPICAL MARINE FISHES (THALASSOMA SPP.). PMID- 28568696 TI - THE QUESTION OF SYNCHRONY OR "TEMPORAL SYMPATRY" IN MIMICRY. PMID- 28568697 TI - SEXUAL ISOLATION, SPECIATION AND THE DIRECTION OF EVOLUTION. PMID- 28568698 TI - GEOGRAPHIC VARIATION IN THE MILKFISH CHANOS CHANOS. I. BIOCHEMICAL EVIDENCE. PMID- 28568699 TI - MASS-FLOWERING OF A TROPICAL SHRUB (HYBANTHUS PRUNIFOLIUS): INFLUENCE ON POLLINATOR ATTRACTION AND MOVEMENT. PMID- 28568700 TI - SELECTION FOR AMYLASE ALLOZYMES IN DROSOPHILA MELANOGASTER: A REPLY. PMID- 28568701 TI - Joint Meeting of The Society for the Study of Evolution and American Society of Naturalists Tucson, Arizona June 29-July 2, 1980. PMID- 28568702 TI - THE NATURE OF VARIATION IN LIFE HISTORY CHARACTERS OF DYSDERCUS BIMACULATUS (HETEROPTERA: PYRRHOCORIDAE), A COLONIZING SPECIES. PMID- 28568703 TI - MIMICRY OF MALE BY FEMALE FLOWERS AND INTRASEXUAL COMPETITION FOR POLLINATORS IN JACARATIA DOLICHAULA (D. SMITH) WOODSON (CARICACEAE). PMID- 28568704 TI - HETEROZYGOTE ADVANTAGE AT THE FRUIT WING LOCUS IN PLECTRITIS CONGESTA (VALERIANACEAE). PMID- 28568705 TI - Hair analysis for the detection of drug use-is there potential for evasion? AB - BACKGROUND: Hair analysis for illicit substances is widely used to detect chronic drug consumption or abstention from drugs. Testees are increasingly seeking ways to avoid detection by using a variety of untested adulterant products (e.g., shampoos, cleansers) widely sold online. This study aims to investigate adulteration of hair samples and to assess effectiveness of such methods. METHODS: The literature on hair test evasion was searched for on PubMed or MEDLINE, Psycinfo, and Google Scholar. Given the sparse nature of peer-reviewed data on this subject, results were integrated with a qualitative assessment of online sources, including user-orientated information or commercial websites, drug fora and "chat rooms". Over four million web sources were identified in a Google search by using "beat hair drug test" and the first 86 were monitored on regular basis and considered for further analysis. RESULTS: Attempts to influence hair test results are widespread. Various "shampoos," and "cleansers" among other products, were found for sale, which claim to remove analytes. Often advertised with aggressive marketing strategies, which include discounts, testimonials, and unsupported claims of efficacy. However, these products may pose serious health hazards and are also potentially toxic. In addition, many anecdotal reports suggest that Novel Psychoactive Substances are also consumed as an evasion technique, as these are not easily detectable via standard drug test. Recent changes on Novel Psychoactive Substances legislations such as New Psychoactive Bill in the UK might further challenge the testing process. CONCLUSION: Further research is needed by way of chemical analysis and trial of the adulterant products sold online and their effects as well as the development of more sophisticated hair testing techniques. PMID- 28568706 TI - Examining Maternal Psychopathology, Family Functioning and Coping Skills in Childhood Obesity: A Case-Control Study. AB - The shared family environment is an important risk factor in the development of childhood obesity. This study aims to examine differences in maternal psychopathology, family functioning, expressed emotion and coping skills between families of a child with obesity and those with a normal-weight child. This case control study consisted of 50 mothers with a child (age 8-12 years) with obesity (p >= 97) and a control group of 50 mothers of a child with normal weight (p < 85), matched for age, sex and socio-economic status. Compared with families with normal-weight children, those with children with obesity showed significant differences in levels of trait anxiety, criticism and over-protectiveness, and maladaptive coping skills. Structural equation modelling revealed that the mothers' psychopathology predicted children's body mass index (BMI) z-scores through expressed emotion and maladaptive coping scores. There were significant direct and indirect relations among maternal BMI, psychopathology, expressed emotion and coping, which all together explained 26.5% of variance of children's BMI z-scores. Considering this relation between maternal variables and child weight status, childhood obesity intervention programs may benefit from targeting maternal BMI, psychopathology, expressed emotion and coping skills. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28568707 TI - Hemispheric language organization after congenital left brain lesions: A comparison between functional transcranial Doppler and functional MRI. AB - This study investigated whether functional transcranial Doppler ultrasound (fTCD) is a suitable tool for studying hemispheric lateralization of language in patients with pre-perinatal left hemisphere (LH) lesions and right hemiparesis. Eighteen left-hemisphere-damaged children and young adults and 18 healthy controls were assessed by fTCD and fMRI to evaluate hemispheric activation during two language tasks: a fTCD animation description task and a fMRI covert rhyme generation task. Lateralization indices (LIs), measured by the two methods, differed significantly between the two groups, for a clear LH dominance in healthy participants and a prevalent activation of right hemisphere in more than 80% of brain-damaged patients. Distribution of participants in terms of left, right, and bilateral lateralization was highly concordant between fTCD and fMRI values. Moreover, right hemisphere language dominance in patients with left hemispheric lesions was significantly associated with severity of cortical and subcortical damage in LH. This study suggests that fTCD is an easily applicable tool that might be a valid alternative to fMRI for large-scale studies of patients with congenital brain lesions. PMID- 28568709 TI - ASYMMETRIC COMPETITION IN MIXED POPULATIONS OF TADPOLES OF THE HYBRIDOGENETIC: RANA ESCULENTA COMPLEX. AB - Hybridogenetic Rana esculenta tadpoles display tolerance to extreme environmental conditions and fit criteria of the "general-purpose" genotype. A trade-off between generality and competitive ability is assumed to occur in asexual species, but the evidence remains unclear. The purpose of my experiment was to test the competitive ability of hemiclonal hybrid Rana esculenta tadpoles relative to the parental species Rana lessonae. Mixed and single genotype populations of R. esculenta and R. lessonae tadpoles were reared at three densities in artificial ponds. Survival of R. esculenta was higher than for R. lessonae tadpoles, but did not differ among densities. Body size at metamorphosis was the same between genotypes, but decreased with increasing density. Larval period was not affected by density, but R. esculenta tended to metamorphose earlier than R. lessonae. Percentage of individuals metamorphosing was higher for R. esculenta at both medium and high densities, but the same as R. lessonae at the low density. The difference in survival, body size, and larval period between tadpoles reared in single and mixed genotype populations was unaffected by genotype or density. The difference in the percentage of metamorphs, however, was strongly affected. The percentage of hybrids metamorphosing was 9% above the responses of single genotype populations at the highest density. Conversely, the percentage of R. lessonae metamorphosing was 12% below the responses of single genotype populations at the same density. Hybrid success in this experiment further supports the criterion of a "general-purpose" genotype without assumptions of reduced competitive ability. PMID- 28568710 TI - UNIDIRECTIONAL CYTOPLASMIC INCOMPATIBILITY IN THE MOSQUITO, AEDES ALBOPICTUS. PMID- 28568711 TI - SEXUAL SELECTION IN THE BARN SWALLOW HIRUNDO RUSTICA. III. FEMALE TAIL ORNAMENTS. AB - Male secondary sexual characters are often expressed in females, and the maintenance of the character in females can be due to either direct selection on females favoring the maintenance of the trait, or a correlated response to selection in males. Here I report on determinants of and phenotypic selection on tail length of female barn swallows Hirundo rustica. The homologous trait in males is under strong directional sexual selection. Female tail length was positively associated with several reproductive parameters including total seasonal reproductive success, even when controlling for year and age effects. A change in female tail length from one year to another was often associated with a change in the reproductive parameters correlated with absolute tail length. There was little evidence for an association between female tail length and the duration of the incubation period (only females incubate) and absolute and relative female provisioning rates of offspring, and subsequent size of offspring. Tail length of female barn swallows was positively correlated with that of their mates. Female tail length was a heritable trait as determined from regression of the tail trait of offspring on that of their mother and their father, and there was a positive genetic correlation between the tail trait in males and females. In conclusion, female tail length reliably reflects female reproductive potential, and the trait appears to be under directional selection, which may result in an evolutionary response to selection because of the heritability of the tail trait. PMID- 28568708 TI - Prognostic value of Notch receptors in postsurgical patients with hepatitis B virus-related hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and a major cause of cancer involved death worldwide. Prognosis remains poor because of high recurrence rates and lack of effective relapse prevention strategies. Notch pathway plays an important role in tumor progression and metastasis, and it is associated with the prognosis of cancer. A total of 465 hepatitis B virus (HBV) related HCC patients who underwent surgery were enrolled. Single nucleotide polymorphisms (SNP) of Notch pathway receptors were genotyped using Sanger DNA sequencing. Kaplan-Meier curves and the Cox proportional hazards regression model were adopted to analyze the association of polymorphisms and mRNA expression with clinical and pathological features, respectively. Four SNPs (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) were significantly associated with overall survival (OS) (P = 0.023, P = 0.042, P = 0.028, and P = 0.001 respectively). Patients carrying the AA genotype in rs1043996 and TT/TC genotypes in rs422951 and rs520692 significantly decreased risks of death, compared to those carrying the AG/GG genotype in rs1043996 and CC genotype in rs422951 and rs520692, respectively. Patients carrying the TT genotype in rs3830041 showed poorer OS, compared with those carrying the TC/CC genotype. A haplotype block (rs422951 was in strong LD with rs520692, r2 = 0.843) was identified in Notch4. Notch3 mRNA expression significantly increased in tumor tissue, compared with nontumor normal tissue (P < 0.0001). Moreover, higher expression of Notch3 was associated with poorer OS (HR = 2.11, 95% CI = 1.32-3.37, P = 0.002) and shorter recurrence time of HBV-related HCC (HR = 1.96, 95% CI = 1.31-2.93, P = 0.001). Our findings collectively indicate that Notch receptors variants (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) are independent predictive targets for OS in HBV-related HCC patients. Notch3 expression is a potential prognostic biomarker of OS and recurrence-free survival (RFS) prediction in HBV related HCC patients following surgical treatment. PMID- 28568712 TI - QUANTITATIVE GENETICS OF SHELL FORM OF AN INTERTIDAL SNAIL: CONSTRAINTS ON SHORT TERM RESPONSE TO SELECTION. AB - We investigated the genetic and environmental determinants of shell form in an intertidal snail (Prosobranchia: Littorina sp.) to identify constraints on the short-term response to selection. Our quantitative genetic parameters were estimated from a half-sib experimental design using 288 broods of snails. Each brood was divided into two treatments differing in snail population density, and therefore in grazing area per snail. Differences in population density induced marked differences in shell form. Snails in the low density treatment grew faster and had lighter shells with narrower whorls and narrower apertures than their siblings at high density. Despite this environmental plasticity in shell shape we found significant additive genetic variance for components of shell shape. We discuss two mechanisms that may maintain additive genetic variance for shell shape in intertidal snail populations: migration between environments with different selective pressures and migration between environments with different mean growth rates. We also estimated a genetic variance-covariance matrix for shell form traits and used the matrix to identify constraints on the short-term response to selection. We predict the rate of response to selection for predator resistant morphology such as would occur upon invasion of predatory crabs. The large negative genetic correlation between relative spire height and shell weight would facilitate simultaneous selection for a lower spire and a heavier shell, both of which would increase resistance to predatory crabs. PMID- 28568713 TI - SEXUAL SELECTION FOR INCREASED MALE COURTSHIP AND ACOUSTIC SIGNALS AND AGAINST LARGE MALE SIZE AT SHARP-TAILED GROUSE LEKS. PMID- 28568714 TI - THE ACCURACY OF PHYLOGENETIC ESTIMATION USING THE NEIGHBOR-JOINING METHOD. AB - We studied the factors affecting the accuracy of the neighbor-joining (NJ) method for estimating phylogenies by simulating character change under different evolutionary models applied to twenty different 8-OTU tree topologies that varied widely with respect to tree imbalance and stemminess. The models incorporated three evolutionary rates-constant, varying among lineages, varying among characters-and three evolutionary contexts concerning patterns of character change relative to speciation events-phyletic, speciational, and punctuational. All combinations of the rate and context models were studied. In addition, three different absolute rates of change were investigated. To measure the accuracy, the strict consensus index was computed between the estimated tree and the tree topology along which the data had been generated. The results were analyzed by analysis of variance and compared to a previous study that evaluated UPGMA clustering and maximum parsimony (MP) as phylogenetic estimation techniques. We found evolutionary context and tree imbalance to be the most important factors affecting the accuracy of the NJ method. NJ was more accurate than UPGMA or MP in terms of the average strict consensus index over all treatments. However, no one method was more accurate than the other two for all combinations of treatments. Higher absolute rate of change generally resulted in higher accuracy for all three methods. PMID- 28568715 TI - SPECIES RECOGNITION AND SEXUAL SELECTION AS A UNITARY PROBLEM IN ANIMAL COMMUNICATION. AB - We investigated patterns of mating call preference and mating call recognition by examining phonotaxis of female tungara frogs, Physalaemus pustulosus, in response to conspecific and heterospecific calls. There are four results: females always prefer conspecific calls; most heterospecific calls do not elicit phonotaxis; some heterospecific calls do elicit phonotaxis and thus are effective mate recognition signals; and females prefer conspecific calls to which a component of a heterospecific call has been added to a normal conspecific call. We use these data to illustrate how concepts of species recognition and sexual selection can be understood in a unitary framework by comparing the distribution of signal traits to female preference functions. PMID- 28568716 TI - INBREEDING DEPRESSION IN TWO MIMULUS TAXA MEASURED BY MULTIGENERATIONAL CHANGES IN THE INBREEDING COEFFICIENT. AB - In mixed-mating plant populations, one can estimate the relative fitness of selfed progeny w by measuring the inbreeding coefficient F and selfing rate s of adults of one generation, together with F of adults in the following generation (after selection). In the first application of this multigenerational method, we estimated F and s for adults over three consecutive generations in adjacent populations of two annual Mimulus taxa: the outbreeding M. guttatus and the inbreeding M. platycalyx. This gave estimates of w for the last two generations. Although average multilocus selfing rates were high in both taxa (0.63 in M. guttatus; 0.84 in M. platycalyx), the relative fitness of selfed progeny averaged only 0.19 in M. guttatus and 0.32 in M. platycalyx. An alternative estimator for w that incorporates biparental inbreeding gave even lower estimates of w. These values are significantly below the 0.5 threshold thought to favor selfing, and show that partially selfing populations can harbor substantial genetic load. In accordance with the purging hypothesis, the more highly selfing M. platycalyx showed marginally lower inbreeding depression than M. guttatus in both years (P = 0.08). Inbreeding depression and selfing rates also varied among years in concert among taxa. Several sources of bias are discussed, but computer simulations indicate it is unlikely that w is biased downwards by linkage of marker loci to load loci. PMID- 28568717 TI - SYNERGISTIC SELECTION OF UNPALATABILITY IN PLANTS. PMID- 28568718 TI - ARE WARNING COLORS HANDICAPS? AB - The handicap theory, in which the cost of waste guarantees honest advertising, is being used increasingly in solutions to the problems of biological signal evolution. However, it is usually applied to systems which are insufficiently understood to allow testing against alternative theories. In particular, the ability of the handicap theory to explain the design of signals has never been properly tested. We test its ability to explain signal design features in an unusually well studied area of biological signalling: warning coloration and mimicry. Since a full handicap model proves immediately unrealistic, we modify the model to incorporate realistic assumptions about predator learning. Using this model we explicitly compare the handicap theory with a purely "conventional" signalling model and with a null model. Predictions relating to three key design features (conspicuousness, pattern similarity, and Batesian mimicry) are compared, and tested against available data. Although many predictions remain to be tested adequately, we conclude that: (i) conspicuousness is most plausibly explained by the conventional signalling theory that ascribes the function of conspicuous coloration to signal efficacy rather than waste; (ii) pattern similarity, within and between species, is unlikely to be the result of the need to produce similar degrees of conspicuousness, as predicted by the handicap theory, but is plausibly explained as the result of pattern generalization amongst discriminating predators, as predicted by the conventional signalling theory; and (iii) Batesian mimicry is predicted by the conventional signalling theory, but not the handicap theory. Therefore the handicap theory fails to provide an adequate explanation of the main design features of at least one major signalling system. PMID- 28568719 TI - PHAGE-MEDIATED SELECTION AND THE EVOLUTION AND MAINTENANCE OF RESTRICTION MODIFICATION. AB - Restriction-modification (R-M) was discovered because it provides bacteria with immunity to phage infection. But, is phage-mediated selection the sole mechanism responsible for the evolution and maintenance of these ubiquitous and multiply evolved systems? In an effort to answer this question, we have performed experiments with laboratory populations of E. coli and phage and computer simulations. We consider two ecological situations whereby phage-mediated selection could favor R-M immunity; i) when bacteria with a novel R-M system invade communities of phage-sensitive bacteria in which there are one or more species of phage, and ii) when bacteria colonize bacterial-free habitats in which phage are present. The results of our experiments indicate that in established communities of bacteria and phage, the advantage R-M provides an invading population of bacteria is ephemeral. Within short order, mutants resistant (refractory) to the phage evolve in the dominant population and subsequently in the invading population. The outcome of competition then depends on the relative fitness of the resistant states of these bacterial clones, rather than R-M. As a consequence of sequential selection for independent mutants, this rapid evolution of resistance occurs even when two and three species of phage are present. While in our experiments resistance also evolved when bacteria colonized new habitats in which phage were present, a novel R-M system greatly augmented the likelihood of their becoming established. We interpret the results of this study as support for the hypothesis that the latter, colonization selection, may play an important role in the evolution and maintenance of restriction-modification. However, we also see these results and other observations we discuss as questioning whether protection against phage is the unique biological role of restriction modification. PMID- 28568720 TI - THE MOLECULAR CLOCK AND THE RELATIONSHIP BETWEEN POPULATION SIZE AND GENERATION TIME. PMID- 28568721 TI - EVOLUTION OF SOCIAL BEHAVIOR IN A RESOURCE-RICH, STRUCTURED ENVIRONMENT: SELECTION EXPERIMENTS WITH MEDAKA (ORYZIAS LATIPES). AB - Schooling and aggression in fish are known to be partially inherited traits. Their genetic relationship to growth rate and to each other is, however, not fully understood. In this study we present evidence that schooling, social tolerance, and agonistic behavior in medaka (Oryzias latipes) are altered as an indirect result of selection on growth in two environments that differed in the intensity of social interactions required to obtain access to food. In the high interaction environment food was provided to excess inside a floating cork ring, which limited access to the food and allowed fish to attempt to monopolize it. In the low interaction environment the same amount of food was spread over the container's surface. After two generations of selection on growth the correlation of agonistic behavior and mean growth of broods was negative in the line selected for fast growth, when selection took place in a high interaction environment, but not when it took place in a low interaction environment. School cohesion was higher in the lines selected for fast growth than in those selected for slow growth when selection and rearing environments were both the same, either high or low interaction, but not when they were different. The correlation of social tolerance with growth was significantly more positive in the line selected for fast growth than in that selected for slow growth, but only when selection took place under high social interaction. It appears from these experiments that when resources are aggregated, but unlimited in quantity, competition favors individuals that avoid wasting time and energy on unnecessary and ultimately futile attempts to monopolize food and that also exhibit higher tolerance of nearby conspecifics. The results are interpreted in terms of a hypothesized stimulus-response threshold level for agonistic responses to conspecifics. We suggest that this threshold, which is altered by selection on growth, could provide a common causal (genetic) link between growth and the observed aspects of social behavior. By combining the probabilities from the separate behavioral experiments to obtain an overall significance of our hypothesis we conclude that the probability of no change in threshold is in fact low (P < 0.01). PMID- 28568722 TI - HYBRID ZONE DYNAMICS ARE INFLUENCED BY GENOTYPE-SPECIFIC VARIATION IN LIFE HISTORY TRAITS: EXPERIMENTAL EVIDENCE FROM HYBRIDIZING GAMBUSIA SPECIES. AB - Results from two experiments are presented that contrast differences in life history traits and population dynamics between two species of live bearing fishes (Gambusia affinis and G. holbrooki) that hybridize across portions of the southeastern United States. Progeny from parental holbrooki and holbrooki-affinis F1 crosses exhibited larger lengths at birth, at 15 days, and matured earlier, and at larger size than did progeny from parental affinis and affinis-holbrooki F1 crosses. Comparisons of experimental populations of affinis, holbrooki, and mixed (affinis + holbrooki) species composition followed over two years revealed that affinis populations consistently exhibited smaller population size, lower carrying capacity, lower recruitment, and larger over-winter mortality than did holbrooki or mixed populations. Evidence for density-dependent reductions in fecundity and concomitant increases in juvenile mortality rates were observed in all populations, but were most pronounced for affinis populations. Genotype specific differences in life-history traits appear to confer differential advantage to offspring of parental holbrooki origin and F, progeny of holbrooki maternal parentage given the resource availability and the age structure and densities experienced during these experiments. Results have direct implications regarding the rate and direction of evolution within hybrid zones formed by these two species. PMID- 28568723 TI - PATTERNS OF PHENOTYPIC AND GENETIC CORRELATIONS AMONG MORPHOLOGICAL AND LIFE HISTORY TRAITS IN WILD RADISH, RAPHANUS RAPHANISTRUM. PMID- 28568724 TI - THE SKELETON SPACE: A FINITE SET OF ORGANIC DESIGNS. AB - The structures of animal skeletons converge repeatedly on a limited number of architectural designs that can be constructed by growing organisms and that are functionally viable, although often not optimal. Properties of materials, construction rules that determine patterns of development, and physical constraints exerted by the requirements of function suggest that organic structure must necessarily approach these recurrent elements of design. A set of potential designs for the elements of animal skeletons is derived in terms of geometric and construction rules and the properties of materials. Skeletons of actual living and extinct organisms are matched with the possibilities defined within this theoretical morphospace. This provides a metric of skeletal complexity and of the extent to which various groups of animals have been able to exploit the range of possibilities of organic structure. These analyses show that the most evolutionarily advanced animals within a given phylum do not have the most complex skeletons; that arthropods are less morphologically diverse than vertebrates and molluscs; that the physical constraints of life on land and in the air substantially limit the variety of skeletal structures suitable for life in these environments; and that overall the range of possible skeletal designs has been very fully exploited by living and extinct organisms. These results strongly support the hypothesis that the essential elements of organic design are inherent in the material properties of the universe. The organizational properties of animal skeletons suggest that their design elements are fixed point attractors, structures that we characterize as topological attractors that evolution cannot avoid. PMID- 28568725 TI - LABORATORY EVOLUTION OF LONGEVITY AND REPRODUCTIVE FITNESS COMPONENTS IN MALE FRUIT FLIES: MATING ABILITY. AB - Populations of Drosophila melanogaster that had been selected for divergent rates of senescence were compared with respect to age-specific male mating ability. The competitive mating ability of males from populations with delayed senescence was inferior to that of males from populations with higher rates of senescence when males were young. This relationship was reversed when males were older. For noncompetitive mating ability and for recovery of fertility after an exhaustive mating bout, there was no difference between populations with different rates of senescence when males were young. However when males were older, flies from populations selected for delayed senescence again had superior mating ability. Thus, rates of male reproductive senescence can be altered in predictable ways by natural selection. The results for the competitive mating tests are consistent with the hypothesis that antagonistic gene action between early- and late-life fitness components influences the evolution of senescence in these populations. PMID- 28568726 TI - ENVIRONMENTAL AND GENETIC MATERNAL EFFECTS ON SEED CHARACTERS IN NEMOPHILA MENZIESII. AB - Nuclear genetic, maternal genetic and maternal environmental effects on seed characters were estimated in the California native annual plant Nemophila menziesii using two greenhouse crosses. In one cross, according to a nested mating design, the narrow sense heritability of seed weight was small (3.9%). A subset of full-sib progenies produced in this cross was grown singly and in competition with the introduced grass Bromus diandrus. In a second cross, these plants were used as mothers (dams) and were each mated to the same three sires. Seeds produced by mothers competing with B. diandrus showed a significant reduction in weight, increase in time to germination, and increase in the incidence of dormancy, when compared to seeds from mothers grown singly. Significant sire components were found for time to germination and incidence of dormancy. Maternal genetic variation for seed weight was largely expressed as maternal genotype by maternal environment interaction, and showed no significant maternal genetic main effect. Time to germination and dormant fraction showed a relatively large maternal genetic effect. Evolution of seed characters in N. menziesii is more likely to occur via indirect response to selection among maternal plants than among the seeds themselves. Maternal genotype by maternal environment interaction could potentially contribute to the maintenance of maternal genetic variation in seed weight, but this does not appear likely for dormancy. PMID- 28568727 TI - FURTHER EVIDENCE AGAINST MEIOTIC-DRIVE MODELS OF HYBRID STERILITY. PMID- 28568728 TI - EVOLUTIONARY EFFECTS OF SELECTION ON AGE AT REPRODUCTION IN LARVAL AND ADULT: DROSOPHILA MELANOGASTER. AB - Two sets of three replicate lines of Drosophila melanogaster were artificially selected by reproduction at either a 'young' or an 'old' age. The pure lines, the hybrids between the lines within a selection regimen and the base stock from which the lines were derived were compared for longevity, early and late fertility, development time, larval viability and adult thorax length. Comparison of hybrid with pure lines showed some evidence for inbreeding depression in the lines from both selection regimes. Comparison of hybrid lines with the base stock did not provide evidence for any trade-off in either males or females between early fertility on the one hand and late life fertility and longevity on the other. Nor was there any clear evidence of a trade-off between pre-adult and adult fitness components. There was evidence of inadvertent selection for rapid development in both selection regimens, especially in the females of the 'young' lines, and this complicated the interpretation of the responses and correlated responses to selection. An improvement in adult performance in the 'old' line males relative to the base stock appeared to be attributable to reversal of mutation accumulation. Comparison of the hybrid 'young' and 'old' lines with the base stock did not support the idea that the superior longevity and late life fertility of the 'old' lines relative to the 'young' lines could be accounted for by the effects of mutation accumulation in the 'young' lines. The results point to the need to compare selected lines with their base stock when deducing responses and correlated responses to selection and to avoid unintentional selection. In this type of experiment, larval density should be standardized during selection, and adults should not be under pressure for rapid maturation. PMID- 28568729 TI - GENETIC VARIATION AND COVARIATION FOR CHARACTERISTICS ASSOCIATED WITH CADMIUM TOLERANCE IN NATURAL POPULATIONS OF THE SPRINGTAIL ORCHESELLA CINCTA (L.). AB - Heavy metals can be strong and stable directional selective agents for metal exposed populations. Genetic variation for the metal-tolerance characteristic "cadmium excretion efficiency" was studied in populations of the collembolan Orchesella cincta from a reference- and a metal-contaminated forest soil. Previously it has been shown that "excretion efficiency" influences tolerance through midgut-mediated immobilization and excretion of toxic metal ions, and that an increased mean excretion efficiency is present in animals inhabiting metal-contaminated litter. In the present research, offspring-parent regressions showed that additive genetic variation for cadmium excretion efficiency was present in the population from the reference site. The heritability estimate was 0.33. In the natural population exposed to heavy metals from an industrial source, additive genetic variation was not significantly different from zero. Differences in the heritability between the reference and the exposed population were not significant. Genetic variation for cadmium excretion efficiency allows for a response to selection in the reference population. Such a response has probably occurred in the metal-exposed population. Half-sib analysis with animals from the reference population was used to estimate genetic variation and maternal effects for excretion efficiency, relative growth rate and molting frequency, and to determine genetic correlations between these characteristics. Additive genetic variation was demonstrated for all three characteristics, heritability estimates were 0.48, 0.75 and 0.46, respectively. Maternal effects were low for excretion efficiency and molting frequency, but may be present for relative growth rate. Phenotypic and genetic correlations among these characteristics were positive. The environmental correlation between relative growth rate and molting frequency was positive, others were negative. Direct selection for any of the characteristics, or genetic correlations between tolerance characteristics and growth characteristics, or both may have caused the responses previously observed in field populations. PMID- 28568730 TI - NEPOTISM IN A SOLITARY WASP AS REVEALED BY DNA FINGERPRINTING. PMID- 28568731 TI - MACROEVOLUTIONARY PATTERNS OF MORPHOLOGICAL DIVERSIFICATION AMONG PARASITIC FLATWORMS (PLATYHELMINTHES: CERCOMERIA). AB - Patterns of parasite morphological diversification were investigated using a morphological data base for the parasitic platyhelminths comprising 1,459 characters analyzed using phylogenetic systematic methods. Only 10.8% of the 1,882 character transformations are losses, casting doubt on views that parasites are secondarily simplified and exhibit degenerate evolution. Chi-squared analysis indicates that character loss in the Digenea and Monogenea occurs in proportion to total change and is disproportionately lower within the Eucestoda. In the Digenea fewer female characters and more male characters have been lost than expected by the total number of characters in that group, and more male and more nonreproductive characters have been lost in proportion to their distribution across groups. In the Monogenea fewer nonreproductive and more larval characters have been lost than expected within the group, and female character loss is high relative to other groups. In the Eucestoda fewer female and more larval characters have been lost than expected within the group, whereas loss of male and nonreproductive character is low, and loss of larval characters is high, compared to the other groups. Patterns of character loss result partially from characters that show repeated (homoplasious) loss in different groups. High consistency index and low homoplasy slope ratio values indicate that the parasitic platyhelminths show unusually low levels of homoplasy, casting doubt on views that parasite morphology is unusually adaptively plastic. Homoplasy within the monogeneans occurs in proportion to overall character change, is slightly higher than expected in the digeneans, and is much lower than expected within the eucestodes. Homoplasy occurs less often than expected in larval characters, and more often than expected in nonreproductive characters in the Digenea. Monogeneans show more homoplasy than expected for larval characters both within and among groups. Eucestodes show fewer homoplasious male and nonreproductive, and more homoplasious larval, characters than expected within the group, and higher homoplasy in larval characters and lower homoplasy in female and nonreproductive characters among groups. PMID- 28568732 TI - INBREEDING DEPRESSION IN HYDROPHYLLUM APPENDICULATUM: ROLE OF MATERNAL EFFECTS, CROWDING, AND PARENTAL MATING HISTORY. AB - This paper examines several aspects of the expression of inbreeding depression in an outcrossing, obligately biennial plant, Hydrophyllum appendiculatum (Hydrophyllaceae). The amount of inbreeding depression detected was small during the first year of life but increased with age and had significant effects on adult size and reproductive traits. The lack of significant inbreeding depression during early growth is likely due to the overriding influence of maternal environmental effects on seed size and seedling growth. However, as maternal effects decreased with age, the seedling's own genotype became a more important determinant of its fate. To examine whether the expression of inbreeding depression was sensitive to ecological conditions, selfed and outcrossed seedlings were grown alone or with other H. appendiculatum seedlings. No inbreeding depression was detected in the plants grown alone. In contrast, under competitive conditions, outcrossed seedlings were significantly larger than selfed seedlings by the end of the first growing season. To address whether parental mating history influences the amount of inbreeding depression expressed, I examined the consequences of two successive generations of selfing on seed set and seed weight. The amount of inbreeding depression increased following the second generation of selfing. In the first generation, seed set and seed weight differed by less than 5% between selfed and outcrossed progeny. However, both traits were 15% greater for outcrossed plants after two generations. These results indicate that the alleles responsible for the reductions in these traits were not purged and suggest the action of multiple loci with deleterious effects. PMID- 28568733 TI - THE EFFECT OF BIRTH DATE ON FITNESS OF FEMALE DWARF PERCH, MICROMETRUS MINIMUS (PERCIFORMES: EMBIOTOCIDAE). AB - Lifetime reproductive success may vary considerably with birth date. I measured phenotypic selection on female birth date in a viviparous teleost fish (Embiotocidae: Micrometrus minimus) by sampling birth-date cohorts over time in Tomales Bay, California. Four episodes of selection were measured: survival from birth to first reproduction, reproductive success in the first breeding season, survival to second reproduction, and reproductive success in the second season. Birth date had a significant impact on fitness in the first two episodes. Early born females were more successful in their first breeding season than late born females (directional selection on birth date), but early born females were less likely to survive the period between birth and first reproduction, relative to females born in the middle of the season (stabilizing selection on birth date). The final two episodes of selection had no detectable effect on birth date. Because of the relationship between birth date and survival in the first year, overall selection on female birth date was stabilizing. PMID- 28568734 TI - MITOCHONDRIAL DNA IN GASTEROSTEUS AND PLEISTOCENE GLACIAL REFUGIUM ON THE QUEEN CHARLOTTE ISLANDS, BRITISH COLUMBIA. PMID- 28568735 TI - FOUNDER-FLUSH SPECIATION IN DROSOPHILA PSEUDOOBSCURA: A LARGE-SCALE EXPERIMENT. AB - A founder-flush-crash model of speciation has been proposed that may particularly apply to island and other colonizations. Previous laboratory experiments testing the model have given inconsistent results. We have conducted a large experiment with Drosophila pseudoobscura designed to meet the essential postulates of the model and to separately test some of the postulates. Forty-five experimental and 12 control populations have been studied during seven successive founder-flush crash cycles, or about 50 generations. Sexual isolation tests yield significantly positive assortative mating in a few tests between pairs of experimental populations. Populations with fewer founders (N = 1 or 3) yield more significant instances of assortative mating than those with more founders (n = 5, 7, or 9), and this difference becomes statistically significant for pooled data. Only one of 15 population pairs tested three times (generations 25, 32, and 46) shows positive assortative mating in all three tests. No significant assortative mating occurs between control populations, including highly inbred ones. We conclude that although founder events may occasionally lead to the evolution of assortative mating and hence to speciation, our results do not support the claim that the founder-flush-crash model identifies conditions very likely to result in speciation events. PMID- 28568736 TI - PHENOTYPIC CORRELATION STRUCTURE AMONG ELEMENTS OF THE COLOR PATTERN IN PRECIS COENIA (LEPIDOPTERA: NYMPHALIDAE). AB - The component parts of butterfly wing patterns are arranged in sets of serially homologous pattern elements, repeated from wing cell to wing cell. Measurements were made on the sizes and positions of these elements on two successive, independent, sets of specimens in order to elucidate the phenotypic correlation structure among pattern elements. That portion of the correlation between measures due to overall size variation was accounted for through two alternate methods: multiple regression on two vein length measures, which represent wing size, and a Wright-style factor analysis. The sizes of pattern elements belonging to a homologous series were found to be significantly correlated whereas those of non-homologous elements varied independently. The degree of correlation among homologs varied, and, in the case of eyespot sizes, appeared to be inversely related to the degree of their morphological divergence. Although not correlated in size, the positions of non-homologous elements that lie within the same wing cell are moderately correlated. The results support current developmental models for the ontogeny of butterfly color pattern. PMID- 28568737 TI - AN APPLICATION OF THE NEUTRAL MODEL TO THE EVOLUTION OF TAIL LENGTH IN THE GENUS EUPLECTES (AVES, PLOCEIDAE). PMID- 28568738 TI - VARIATION IN ENVIRONMENTAL AND GENOTYPIC SEX-DETERMINING MECHANISMS ACROSS A LATITUDINAL GRADIENT IN THE FISH, MENIDIA MENIDIA. AB - Models of environmental sex determination (ESD) usually assume that genetic influences on sex are polygenic, but the validity of this (or any other) form of genotype-environment interaction is virtually unknown. In the Atlantic silverside, Menidia menidia, sex is determined by an interaction between temperature and genotype and the response of sex ratio to temperature differs among populations from different latitudes. We examined the genetic basis of this pattern by measuring among family variation in the proportion of females, F/(F + M), within and among high (21 degrees C) and low (15 degrees C) temperatures for two populations: one from Nova Scotia (NS) where the level of ESD is low, and another from South Carolina (SC) where the level of ESD is high. In NS fish, temperature had a significant influence on sex ratio in only 1 of 23 families. The distribution of the fraction of females within temperatures for families from NS was highly heterogeneous and tended to fall into distinct classes (0.0, 0.25, 0.5, 1.0) like that expected from Mendelian segregation of a major sex factor(s). In contrast, temperature had a highly significant influence on sex ratio in all SC families examined (N = 24). Family sex ratios within temperatures were highly heterogeneous and, at least at 15 degrees C, did not conform to simple Mendelian ratios. At 21 degrees C, the proportion of females in most SC families was near zero and so the underlying sex tendencies of different families could not be discerned. Based on a previous study, mid-latitude fish appear to have an intermediate form of sex determination: simple Mendelian sex-ratio patterns exist and there is a moderate thermal influence on sex ratio in most but not all families. We suggest that sex determination in M. menidia is controlled by an interaction between major genetic factors, polygenic factors, and temperature and that the relative importance of each component differs with latitude. High latitude populations appear to have evolved a major sex-determining factor(s) that overrides the effect of temperature, and this factor(s) is lacking in low latitude populations. PMID- 28568739 TI - MATERNAL INHERITANCE OF CONDITION AND CLUTCH SIZE IN THE COLLARED FLYCATCHER. AB - Maternal effects may strongly influence evolutionary response to natural selection but they have been little studied in the wild. We use a novel combination of experimental and statistical methods to estimate maternal effects on condition and clutch size in the collared flycatcher, where we define "condition" to be the nongenetic component of clutch size. We found evidence of two maternal effects. The first (m) was the negative effect of mother's clutch size on daughter's condition, when mother's condition was held constant. The second (M) was the positive effect of mother's condition on daughter's condition, when mother clutch size was held constant. These two effects oppose one another because mothers in good condition also lay many eggs. The maternal effects were large: Experimentally adding an egg to a mother's nest reduced clutch sizes of her daughters by 1/4 egg (i.e., m = -0.25). Measured degree of resemblance between mother and daughter clutch sizes yielded M = 0.43. The results weakly support the presence of heritable genetic variation in clutch size: additive genetic variance/total phenotypic variance = 0.33. This estimate was highly variable probably because, as we show, mother-daughter resemblance may depend hardly at all on the amount of genetic variance when maternal effects are present. Daughter-mother regression (a standard method for estimating heritability) is consequently a poor guide to the amount of genetic variance in clutch size. Our results emphasize the value of combining field experiments with observations for studying inheritance. PMID- 28568740 TI - Dynamics of binary mixtures of an ionic liquid and ethanol by NMR. AB - A study of molecular dynamics of the ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoro-methylsulphonyl)imide ([Emim][Tf2N]) in solution with deuterated ethanol at different molar concentration and temperatures is presented. The study was performed using 1 H and 2 H nuclear magnetic relaxation and 2 H 1D spectroscopy. The temperature dependence of the spin-lattice relaxation time T1 of the cations allows the evaluation of the activation energies of the rotational degree of freedom of these molecules. The viscosity in the binary system increases with the concentration of ionic liquid. However, the activation energy in the cation molecules decreases when the concentration of the ionic liquid increases, indicating that the rotational dynamics is facilitated. This behavior is explained from the fact that the presence of the ionic liquid in the system disrupts the degree of intermediate range order expected in the alcohol system. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28568741 TI - Birth Defects: Etiology, screening, and detection. PMID- 28568742 TI - Chromosome copy number variants in fetuses with syndromic malformations. AB - Chromosome copy number variants (CNVs; gains and losses of DNA sequences >1 kb) are wide-spread throughout the genome of healthy individuals. Laboratory studies show that a subset of CNVs are pathogenic, and not only can be responsible for the pathogenesis of major birth defects and cancer, but are also associated with neurodevelopmental disorders at birth. The characteristics of the pathogenic microdeletions and microduplications are important for both clinical implications and genetic counselling regarding test selection for prenatal screening and diagnosis. Unfortunately, our knowledge of the phenotypic effects of most CNV is still minimal, leading to the classification of many CNVs as "genomic imbalances of unknown clinical significance". Microdeletions and microduplications can occur in all pregnancies and the spectrum of pathogenic CNVs in fetuses with syndromic malformations is not well studied. This review summarizes our current understanding of CNVs, the common detection methods, and the characteristics of pathogenic CNVs identified in fetuses with syndromic malformations. Birth Defects Research 109:725-733, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28568743 TI - Interventions for treatment and/or prevention of alcohol hangover: Systematic review. AB - OBJECTIVE: To evaluate new research conducted over the past few years (2009-2016) assessing the effectiveness of potentially curative and/or preventive methods of alcohol hangover. METHODS: Data were retrieved by a 4-stage systematic search process. A search of the online Pubmed and Scopus databases were performed, using a combination of keywords: "Alcohol," "Ethanol," and "C2 H5 OH," in combination with the terms "Hangover," "Treatment," and "Prevention." The search comprised studies listed between January 1, 2009 and June 30, 2016. Findings were synthesized using a systematic approach. Quantitative analysis was not done because of the heterogeneity of the included studies. RESULTS: Six controlled human studies were identified (placebo controlled-3, controlled studies with a comparator intervention-3). Of the interventions, the use of polysaccharide rich extract of Acanthopanax senticosus, red ginseng antihangover drink, Korean pear juice, KSS formula, and the After-Effect(c) were associated with a significant improvement of hangover symptoms (p < .05). The highest improvement was observed for the following symptoms: tiredness, nausea/vomiting, and stomachache. None of the methods were effective for all the symptoms. CONCLUSION: The available evidence suggests that several products are capable of significantly improving some, but not all, of the symptoms related to alcohol hangover. Therefore, further research is necessary to develop clinically effective hangover treatments. PMID- 28568744 TI - Structured risk assessment for reduction of multiple risk outcomes in a secure mental health setting: Use of the START. AB - BACKGROUND: Structured risk assessment is commonly used in secure settings to aid prediction and prevention of risky behaviours; the expected benefits have rarely been investigated. AIMS: The aim of the study is to determine whether adverse outcomes (physical and verbal aggression, self-harm, victimisation, self-neglect, unauthorised leave and substance abuse) reduced after patients were assessed with the Short-term Assessment of Risk and Treatability (START). METHODS: In a naturalistic study, anonymised demographic and clinical information was collected from 50 male patients. Data included START assessment and frequency of target behaviour for 3 months before and after first assessment. Chi-square and linear mixed models analyses were used to determine whether there was any change in the behaviours of interest. RESULTS: There were no significant changes in physical or verbal aggression over time, although a tendency towards fewer incidents was apparent. Other adverse behaviours were very infrequent at baseline, precluding adequate analysis. CONCLUSIONS: In this small sample, START did not achieve its primary purpose of significant reduction in adverse behaviours. Although our sample size was informed by a power calculation, we may have over-estimated the size of anticipated change. Further, the 3-month comparison periods before and after the assessment follow-up period were rather short. Accordingly, we recommend more research on the value of this tool in practice rather than discontinuing its use. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28568745 TI - Effect of resin infiltration on the color and microhardness of bleached white spot lesions in bovine enamel (an in vitro study). AB - OBJECTIVES: The aim of this study was to investigate both the effect of resin infiltration on the color and microhardness of white spot lesions (WSLs) that treated with bleaching and to analyze the penetration of the infiltrant. MATERIALS AND METHODS: In each of 135 bovine enamel specimens, WSLs were produced. The samples were then randomly divided into three groups (n = 45): group I, bleached; group II, resin-infiltrated; group III, bleached and resin infiltrated. The specimens were subjected to a pH-cycling regime for four weeks. The color and microhardness were measured at the baseline, after production of WSLs, after the treatments. The color alteration (DeltaE*) and the percentage of surface microhardness recovery (SMHR) were calculated. The penetration of the infiltrant was evaluated by scanning electron microscopy. Results were analyzed with analysis of variance, Shapiro-Wilk, Tukey's, Kruskal-Wallis and Conover-Dunn tests (P = .05). RESULTS: The SMHR% in resin infiltration groups was significantly higher than that of the bleached group only (P < .05). Bleaching treatment prior to resin infiltration produced no significant change in the microhardness (P > .05). Using a bleaching treatment prior to resin infiltration produced significant color alteration (P < .05). The penetration of the resin infiltrant was deepest in-group II. CONCLUSIONS: The resin infiltration enhanced the microhardness of the WSLs regardless of whether or not a bleaching treatment was used. Using a bleaching treatment before resin infiltration resulted in color alteration, and it was also found to negatively influence the penetration of the infiltrant. PMID- 28568746 TI - DEVELOPMENTAL QUANTITATIVE GENETICS AND THE EVOLUTION OF ONTOGENIES. AB - A model is presented which permits integration of developmental information into genetic discussions about evolutionary change in morphology. Development of a trait is described in terms of an ontogenetic trajectory whose properties are defined by a small number of parameters. Some evolutionary aspects of development are examined from the perspective of this quantitative genetic model. Particular attention is given to the developmental origin of pleiotropic effects, developmental constraints, heterochrony, and the growth and morphogenesis of complex morphologies. The role of genetic maternal effects in mammalian development is briefly examined, particularly as it relates to selection on developmental traits. PMID- 28568747 TI - THE POTENTIAL ROLE OF HYPERCARBIA IN THE TRANSITION FROM WATER-BREATHING TO AIR BREATHING IN VERTEBRATES. PMID- 28568749 TI - REPEATABILITY AND HERITABILITY OF CLUTCH SIZE IN LESSER SNOW GEESE. PMID- 28568748 TI - LIMITED DISPERSAL AND PROXIMITY-DEPENDENT MATING SUCCESS IN THE COLONIAL ASCIDIAN BOTRYLLUS SCHLOSSERI. AB - Although the propagules of many sessile organisms have the capacity to disperse over large distances, dispersal is often spatially restricted. In this paper, I document, using a combination of mark/recapture techniques and histocompatibility assays, dispersal distance of the planktonic larvae of the sessile, colonial sea squirt Botryllus schlosseri. Both of these methods indicate that most larvae remain within a meter of their birthplace. Such limited dispersal should lead to increased matings among relatives, and the potential for inbreeding depression. However, the success of: 1) fertilization, 2) embryogenesis, and 3) larval metamorphosis all decrease as distance between mated colonies increases. The spatial scale over which this decrease in mating success occurs is concordant with the estimates of dispersal distance based on the larval mark/recapture data and histocompatibility assays. Taken together, these results imply that inbreeding depression is not a necessary consequence of limited dispersal and consanguineous matings in B. schlosseri. PMID- 28568750 TI - HOLDING ON BY THEIR HOOKS: ANCHORS FOR WORMS. AB - We examined the hooked setae of a dominant group of tube-dwellers, the polychaete annelids, and found a pattern of setation that is predictable by tube type, exclusive of worm taxon or orientation; we also demonstrated the mechanical significance of these hooked setae. When tube-dwelling worms belonging to different lineages are pressurized, they resist differentially as a function of the direction in which hooks face. The results are consistent with the hypothesis that hooks are used primarily to resist removal of worms from their tubes, are polyphyletic in origin, and are active agents of resistance. PMID- 28568751 TI - GENETIC VARIATION AND COVARIATION IN RESPONSES TO HOST PLANTS BY ALSOPHILA POMETARIA (LEPIDOPTERA: GEOMETRIDAE). AB - Progeny of uncommon parthenogenetic genotypes of the polyphagous geometric Alsophila pometaria were reared on four host plant species representing the same genus, different confamilial genera, and different families. On the supposition that uncommon asexual genotypes have arisen recently from the sympatric sexual population, they may be viewed as a representation of variation in the sexual population that has been captured by parthenogenesis. In both the laboratory and the field, significant effects of genotype, host, and their interaction were found for survival. Live weight displayed significant effects of genotype, host, and genotype x host interaction in the laboratory, and significant main effects in the field. The broad heritability of live weight within hosts was significantly greater than zero in all cases, ranging from 0.18 to 0.33. Heritability values in the field were similar to those in the laboratory. Genetic correlations between weight attained on pairs of host plants, calculated from uncorrected family means, were all positive and many were statistically significant. When the data were corrected for differences in generalized vigor by taking the deviations from genotype means on a standard host plant, one of nine genetic correlations was significant and positive, and one was significant and negative. Within their limits of precision, these data suggest that genetic factors enhancing performance on one host do not generally have strong antagonistic pleiotropic effects on performance on the other hosts in this population. The relevance of these observations to the evolution of resource specialization in general and host specialization by phytophagous insects in particular is discussed. The common assumption that trade-offs in efficiency of utilization cause the evolution of specialized resource use requires more empirical evidence than seems to exist. PMID- 28568752 TI - REPEATED GEOGRAPHIC VARIATION AT THREE ENZYME LOCI IN THE AMPHIPOD PLATORCHESTIA PLATENSIS. PMID- 28568753 TI - PARENTAL EFFECTS ON SEED DEVELOPMENT AND SEED YIELD IN RAPHANUS RAPHANISTRUM: IMPLICATIONS FOR NATURAL AND SEXUAL SELECTION. AB - The possibility that sexual selection operates in angiosperms to effect evolutionary change in polygenic traits affecting male reproductive success requires that there is additive genetic variance for these traits. I applied a half-sib breeding design to individuals of the annual, hermaphroditic angiosperm, wild radish (Raphanus raphanistrum: Brassicaceae), to estimate paternal genetic effects on, or, when possible, the narrow-sense heritability of several quantitative traits influencing male reproductive success. In spite of significant differences among pollen donors with respect to in vitro pollen tube growth rates, I detected no significant additive genetic variance in male performance with respect to the proportion of ovules fertilized, early ovule growth, the number of seeds per fruit, or mean individual seed weight per fruit. In all cases, differences among maternal plants in these traits far exceeded differences among pollen donors. Abortion rates of pollinated flowers and fertilized ovules also differed more among individuals as maternal plants than as pollen donors, suggesting strong maternal control over these processes. Significant maternal phenotypic effects in the absence of paternal genetic or phenotypic effects on reproductive traits may be due to maternal environmental effects, to non-nuclear or non-additive maternal genetic effects, or to additive genetic variance in maternal control over offspring development, independent of offspring genotype. While I could not distinguish among these alternatives, it is clear that, in wild radish, the opportunity for natural or sexual selection to effect change in seed weight or seed number per fruit appears to be greater through differences in female performance than through differences in male performance. PMID- 28568754 TI - A MODEL OF KIN-STRUCTURED MIGRATION. AB - When individuals disperse from one local group to another, they often do so in the company of relatives. This is known as "kin-structured migration," and its effect on genetic population structure is investigated here. It is shown that when migration is kin-structured, the ratio of between- to within-group variance is increased by a quantity that can be estimated either from behavioral or genetic data. Theoretical results indicate that kin-structured migration should be most important in populations with high mobility, and analysis of data for humans and lions suggests the kin-structured migration may have a substantial effect on genetic population structure in both species. Its effect seems to be small in a population of pine voles. PMID- 28568755 TI - GEOGRAPHIC VARIATION WITHIN AN ISLAND: UNIVARIATE AND MULTIVARIATE CONTOURING OF SCALATION, SIZE, AND SHAPE OF THE LIZARD GALLOTIA GALLOTI. AB - Microgeographic variation of the vegetarian lizard Gallotia galloti within the island of Tenerife is described using univariate analysis, correlation, multiple group principal component analysis, canonical analysis, transects, and contours. The size varies locally in a mosaic pattern while head shape shows a WNW-ESE cline in the south. The scalation (scale and femoral pore counts) has two facets to its geographic variation, both of which are incongruent with the primary variation in the size and shape. The scalation shows categorical variation (stepped cline) between northern and southern populations and also a strong clinal relationship with altitude. The possible causes of this variation are considered and adaptation to current ecological conditions appears to be implicated for at least the altitudinal variation, although the pertinent factors are not obvious. It is apparent that vertebrate populations distributed across small islands do not necessarily offer the advantage of a discrete homogeneous unit for evolutionary studies but can offer the opportunity for studying microgeographic variation. PMID- 28568756 TI - EVOLUTION OF PHENOTYPIC VARIANCE. AB - A cornerstone of evolutionary theory is that the phenotypic variance of a population may be partitioned into genetic and environmental (nonheritable) components. The traditional motivation for this distinction is that the rate of evolution under natural selection depends on the (relative) magnitudes of certain genetic components of variance. The components of variation are also interesting from another perspective, as illustrated here. Phenotypic variation may be selectively maintained in a population according to its components: selection may favor the maintenance of only the environmental components, only the genetic components, or be indifferent to the composition of the variance. Even when selection is shown to favor phenotypic variation regardless of its components, the possibility exists that environmental variance will evolve to displace the genetic components or vice versa. Environmental and genetic factors may thus compete to produce a given selected level of phenotypic variance. A test of some of these models is provided from the example of seed dormancy: the prediction that variation in seed germination time should be purely environmental is supported by the demonstration of low heritability of germination time in the two available studies. PMID- 28568758 TI - MACRO- AND MICROGEOGRAPHIC STRUCTURE OF A SPATIALLY SUBDIVIDED BEETLE SPECIES IN NATURE. AB - Spatial subdivision of species can affect their population structure by allowing processes such as limited dispersal, spatial heterogeneity in selective pressures, small population sizes, and random events to operate. By studying species restricted to islands or "island" habitats, one can attempt to determine which of these factors have affected the current structure of the population. Collops georgianus (Coleoptera: Melyridae), a beetle species endemic to the "island" habitat of granitic rock outcrops, was chosen to see how its spatially subdivided distribution has affected its genetic structure. Its genetic structure was examined on both a macrogeographic and a microgeographic level using protein electrophoresis. Macrogeographically, 12 populations throughout its range were sampled. The discontinuous distribution of outcrops, and thus populations, throughout its range, has determined the connectivity of the populations. Significant variation in allele frequencies and substructuring (FST = 0.192) was found throughout the range, but there was no spatial autocorrelation. Microgeographically, in the central part of the range, where outcrops are denser and more continuously distributed in space, there was evidence of isolation by distance. Very little variation in allele frequencies was found, but a low but significant level of substructuring occurred among the populations. Comparison of disjunct and continuous populations microgeographically revealed no effect of disjunct distributions, although a significant effect of distance was detected. Effective population size variation among populations and between years, compounded with the effects of local extinctions, suggest that random processes such as drift and founder effects are important determinants of the population's genetic structure. PMID- 28568757 TI - VARIATION AND EVOLUTION OF BREEDING SYSTEMS IN THE TURNERA ULMIFOLIA L. COMPLEX (TURNERACEAE). AB - The evolutionary and functional relationships among breeding systems and floral morphology were investigated in the Turnera ulmifolia complex. Predictions of a model of breeding system evolution among distylous and homostylous varieties were tested. Chromosome counts of 73 accessions revealed an association between breeding system and chromosome number. Diploid and tetraploid populations of five taxonomic varieties are distylous and self-incompatible, whereas hexaploid populations of three varieties are homostylous and self-compatible. The latter occur at different margins of the geographical range of the complex. Crossing studies and analyses of pollen and ovule fertility in F1 's revealed that the three homostylous varieties are intersterile. To test the prediction that, homostylous varieties are long homostyles that have originated by crossing over within the distyly supergene, a crossing program was undertaken among distylous and homostylous plants. Residual incompatibility was observed in styles and pollen of each homostylous variety with patterns consistent with predictions of the cross-over model. The intersterility of hexaploid varieties suggests that long homostyly has arisen on at least three occasions in the complex by recombination within the supergene controlling distyly. Deviation from expected compatibility behavior occurs in populations of var. angustifolia that have the longest styles. These phenotypes displayed the greatest separation between anthers and stigmas (herkogamy) and set little seed in crosses with long- or short-styled plants. This suggests that they are derived from long homostyles with shorter length styles. It is proposed that selection for increased outcrossing has favored the evolution of herkogamy in long homostyles. Estimates of outcrossing rate in a distylous population using allozyme markers confirmed that dimorphic incompatibility enforces complete outcrossing. Significant genetic variation for floral traits likely to influence the mating system, such as stigma anther separation, occurs within and among homostylous populations of var. angustifolia on Jamaica. Estimates of the mating system of families from a population with varying degrees of stigma-anther separation, using five isozyme loci, were heterogeneous and ranged from t = 0.04-0.79. Families exhibiting the largest mean stigma-anther separation have higher outcrossing rates than those with little separation. PMID- 28568759 TI - COLOR PATTERN POLYMORPHISM IN THE LAKE ERIE WATER SNAKE, NERODIA SIPEDON INSULARUM. AB - Populations of the water snake, Nerodia sipedon, on islands in western Lake Erie are polymorphic for color pattern. These populations include banded, intermediate, and unbanded morphs while surrounding mainland populations consist solely of the banded morph. The hypothesis that this polymorphism is maintained by strong selection and migration pressures is widely accepted. Unbanded morphs are apparently more cryptic along island shorelines while banded morphs are more cryptic on the mainland. Migration of banded morphs from the mainland explains their persistence in island populations. Data collected in a capture-mark recapture program on six islands provide no evidence of differential selection among morphs; morph frequencies do not differ among age classes, between once captured and multiply-captured snakes, or between scarred and unscarred snakes. Furthermore, herring gulls, the most common snake predators in the island area, appear to detect banded and unbanded model snakes with equal ease. High site fidelity of water snakes and the distribution of morphs among islands suggest that migration from the mainland is not common. However, islands close to each other are similar in morph frequency, and water snakes have colonized islands elsewhere in the Great Lakes, indicating that some migration does occur. Recently, the frequency of banded morphs has increased in island populations while adult population sizes have declined. This increase in banded morphs is interpreted as reflecting an increased impact of migration from the mainland into these reduced populations. One scenario for the evolution and maintenance of this polymorphism is that selection was important in establishing unbanded morphs in island populations as they became isolated from the mainland. As populations declined to their present size, the impact of migration from the mainland increased and is now swamping the effect of selection. Further declines in island population size may result in fixation of the banded morph. PMID- 28568760 TI - VARIATIONS IN CUTICULAR HYDROCARBONS AMONG THE EIGHT SPECIES OF THE DROSOPHILA MELANOGASTER SUBGROUP. AB - In addition to protecting against desiccation, some of the hydrocarbons of the waxy cuticle have previously been shown to be mating pheromones in Drosophila melanogaster and D. simulans. Therefore, cuticular hydrocarbons were compared among the eight species in the D. melanogaster subgroup. For the two cosmopolitan species and several geographic strains that were studied, all males are quite similar with very abundant monoenes. The major compound in most cases is 7 tricosene. Only three exceptions were found: D. sechellia, and the Afrotropical strains of D. melanogaster and D. simulans. A significant sexual dimorphism exists in three species: D. melanogaster, D. erecta, and D. sechellia. Greater variation was observed in females than in males. D. erecta is singular in the production of long-chain molecules (31-33 carbons). Only three species (D. melanogaster, D. erecta, and D. sechellia) produce diene in significant amounts. Such products, especially 7,11-heptacosadiene, are known to act as aphrodisiacs for D. melanogaster males. In the five other species, females show only quantitative differences from males, generally with 7-tricosene as the most abundant compound. This compound is an aphrodisiac for D. simulans males. Some species such as D. yakuba, D. teissieri, D. orena, D. mauritiana, and the Seychelles strain of D. simulans are almost identical in the chemical composition of cuticular hydrocarbons. In contrast, important variations are observed between geographic populations of D. melanogaster and D. simulans. PMID- 28568761 TI - HETEROZYGOSITY AND DEVELOPMENTAL STABILITY UNDER INBREEDING AND CROSSBREEDING IN PINUS ATTENUATA. AB - The relationship between stability of annual trunk growth and heterozygosity at 24 polymorphic isozyme loci was studied in 10-year-old trees of knobcone pine (Pinus attenuata Lemm.) that were the products of contrasting systems of mating, self-, and interpopulation cross-pollination. Heterozygosity and variability of trunk growth were strongly related only when inbreds and crossbreds were compared; the crossbreds showed greater residual variability on an absolute scale, and greater responsiveness to climate on both absolute and relative scales. Within the inbreds there was no evidence of a relationship between heterozygosity and variability. Within the crossbreds, only one trait, a measure of relative trunk growth rate, showed a relationship with heterozygosity, and indicated greater variability of the more heterozygous trees. These results, and others in the literature, suggest that the relationship of heterozygosity to homeostasis for fitness components is neither simple nor monotonic; it varies between scales of measurement, genetic backgrounds, and environments. PMID- 28568762 TI - SIMILARITIES IN SECTIONAL DELIMITATION IN TRIPSACUM AND ZEA (GRAMINEAE). PMID- 28568763 TI - A MULTISPECIES APPROACH TO THE ANALYSIS OF GENE FLOW IN MARINE SHORE FISHES. AB - Ten species of marine shore fishes with a wide range of life-history strategies were collected from four areas in southern California, U.S.A., and Baja California, Mexico, and examined for patterns of genetic differentiation. Multilocus D and FST values (based on 32-42 presumptive gene loci in each species) were both negatively correlated with estimated dispersal capability. These results were robust to variations in the number and type of loci used in the analysis and are compatible with the hypothesis that levels of genetic differentiation in these shore fishes are determined primarily by gene flow and genetic drift. There is no a priori reason to expect the observed correlation to result from natural selection or historical factors. The findings thus suggest that populations of these shore fishes are in at least a quasi-equilibrium with respect to migration, mutation, and genetic drift. Present data were also used to compare estimates of mNe obtained by three different methods. Estimates based on FST values calculated by the methods of Nei and Chesser (FST(N) ) and Weir and Cockerham (FST(W) ) were highly correlated, but FST(N) <= FST(W) for every species, leading to generally higher mNe estimates for Nei and Chesser's method. Estimates of mNe based on the frequency of private alleles (Slatkin, 1985a) were not as strongly correlated with dispersal capability as were FST and D values. A low incidence of private alleles in many species may be responsible for this relatively weak correlation and may limit the general usefulness of Slatkin's method. In spite of their sensitivity to natural selection, FST and D may be better indicators of relative gene flow levels for high gene flow species. PMID- 28568764 TI - RIBOSOMAL DNA IN RANA. PMID- 28568765 TI - POPULATION SUBDIVISION FOR RIBOSOMAL DNA REPEAT VARIANTS IN CLEMATIS FREMONTII. PMID- 28568766 TI - BIOCHEMICAL PHENOTYPIC AND GENETIC STUDIES OF TWO INTRODUCED FIRE ANTS AND THEIR HYBRID (HYMENOPTERA: FORMICIDAE). AB - Two introduced fire ants, Solenopsis invicta and S. richteri, and their hybrid were studied using phenotypic markers from gas chromatographic analysis of hydrocarbons and venom alkaloids, as well as genetic markers from enzyme electrophoresis. Both methods show that extensive gene introgression is occurring over a distance of at least 120 km at the contact zone between the two forms in eastern Mississippi. Genetic analyses suggest that the hybrid population does not depart dramatically from panmixia. Also, recombinant genotypes predominate in the hybrid zone, indicating that F1 hybrids are viable. Allele frequency clines through the hybrid zone are apparent for four polymorphic loci. Data sets generated by the chromatographic and electrophoretic methods are highly concordant in that they differentiate completely between the two forms and agree in designating colonies from the contact zone as hybrid or parental in a high proportion (90%) of cases. The two methods can serve as complementary tools for studying closely related but genetically distinct populations in this, and perhaps other, groups of insects. PMID- 28568767 TI - Self-reported Mental Health Issues Among Arrestees in the Paris, France Area. AB - We studied (May-September 2014) all arrestees who reported mental health issues during the medical examination performed by a forensic physician for the assessment of fitness for detention. Among 4814 arrestees, 420 (9%) reported a current mental health issue. The suspected crimes among arrestees reporting a current mental health issue were more often related to violent behaviors (physical assault, 23% vs. 16%, p < 0.001, sexual assault, 3% vs. 1%, p = 0.01) and less often drug offenses (18% vs. 29%, p < 0.001). Among arrestees reporting mental health issues, 80% reported psychiatric or psychological care, of whom 33% reported previous mental health care. Decisions of unfitness for detention were more frequent among arrestees reporting mental health issues than in other detainees (3% vs. 1%, p < 0.001). The high proportion of patients with interrupted mental health care among those reporting mental disorders suggests that the medical examination during custody could be a significant opportunity to restore psychiatric care. PMID- 28568768 TI - Corrigendum. PMID- 28568769 TI - Indomethacin on extra-cranial cerebral arterial vasomotion: beyond cyclooxygenase prostaglandin inhibition. PMID- 28568770 TI - Reply from Vienna E. Brunt, Matthew J. Howard, Michael A. Francisco, Brett R. Ely and Christopher T. Minson. PMID- 28568771 TI - Short-term heat therapy: sufficient stimulus for structural vascular adaptations? PMID- 28568772 TI - Reply from Ryan L. Hoiland and Philip N. Ainslie. PMID- 28568773 TI - Cost-effective and rapid lysis of Saccharomyces cerevisiae cells for quantitative western blot analysis of proteins, including phosphorylated eIF2alpha. AB - The common method for liberating proteins from Saccharomyces cerevisiae cells involves mechanical cell disruption using glass beads and buffer containing inhibitors (protease, phosphatase and/or kinase inhibitors), followed by centrifugation to remove cell debris. This procedure requires the use of costly inhibitors and is laborious, in particular when many samples need to be processed. Also, enzymatic reactions can still occur during harvesting and cell breakage. As a result low-abundance and labile proteins may be degraded, and enzymes such as kinases and phosphatases may still modify proteins during and after cell lysis. We believe that our rapid sample preparation method helps overcome the above issues and offers the following advantages: (a) it is cost effective, as no inhibitors and breaking buffer are needed; (b) cell breakage is fast (about 15 min) since it only involves a few steps; (c) the use of formaldehyde inactivates endogenous proteases prior to cell lysis, dramatically reducing the risk of protein degradation; (d) centrifugation steps only occur prior to cell lysis, circumventing the problem of losing protein complexes, in particular if cells were treated with formaldehyde intended to stabilize and capture large protein complexes; and (e) since formaldehyde has the potential to instantly terminate protein activity, this method also allows the study of enzymes in live cells, i.e. in their true physiological environment, such as the short-term effect of a drug on enzyme activity. Taken together, the rapid sample preparation procedure provides a more accurate snapshot of the cell's protein content at the time of harvesting. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28568776 TI - HYBRIDIZATION FREQUENCY IS NEGATIVELY CORRELATED WITH DIVERGENCE TIME OF MITOCHONDRIAL DNA HAPLOTYPES IN A SEA STAR (LEPTASTERIAS SPP.) SPECIES COMPLEX. PMID- 28568774 TI - Atrial premature beat on wide QRS tachycardia with LBBB morphology. What is the mechanism? PMID- 28568775 TI - Ion Pairing and Co-facial Stacking Drive High-Fidelity Bisulfate Assembly with Cyanostar Macrocyclic Hosts. AB - Hydroxyanions pair up inside CH H-bonding cyanostar macrocycles against Coulombic repulsions and solvation forces acting to separate them. The driving forces responsible for assembly of bisulfate (HSO4- ) dimers are unclear. We investigated them using solvent quality to tune the contributing forces and we take advantage of characteristic NMR signatures to follow the species distributions. We show that apolar solvents enhance ion pairing to stabilize formation of a 2:2:2 complex composed of pi-stacked cyanostars encapsulating the [HSO4 ???HSO4 ]2- dimer and endcapped by tetrabutylammonium cations. Without cations engaged, a third macrocycle can be recruited with the aid of solvophobic forces in more polar solvents. The third macrocycle generates a more potent electropositive pocket in which to stabilize the anti-electrostatic anion dimer as a 3:2 assembly. We also see unprecedented evidence for a water molecule bound to the complex in the acetonitrile solution. In methanol, OH H-bonding leads to formation of 2:1 complexes by bisulfate solvation inside the macrocycles inhibiting anion dimers. Knowledge of the driving forces for stabilization (strong OH???O H-bonding, CH H-bonding, ion pairs, pi-stacking) competing with destabilization (Coulomb repulsion, solvation) allows high-fidelity selection of the assemblies. Thermodynamic stabilization of hydroxyanion dimers also demonstrates the ability to use macrocycles to control ion speciation and stoichiometry of the overall assemblies. PMID- 28568777 TI - NUCLEOTYPIC EFFECT IN HOMEOTHERMS: BODY-MASS INDEPENDENT RESTING METABOLIC RATE OF PASSERINE BIRDS IS RELATED TO GENOME SIZE. AB - The resting metabolic rate of passerines is shown to be negatively correlated with genome size when body mass is held constant (r = -0.75, P < 0.01). This finding extends previous conclusion for mammals to this bird order. The result holds when higher taxonomic levels are used instead of the species (for genera, r = -0.76, P < 0.03; for families, r = -0.991, P < 0.01) as well as when the independent contrasts derived from the resolved phylogeny are used instead of the taxa (r = -0.73, P < 0.02), with the evolutionarily older contrasts being more strongly correlated (for the contrasts older than 30 million yr, r = -0.998, P < 0.002). The concept of evolutionary characters consolidation (ECC), previously formulated for mammals, is tested with special reference to the error fraction in the total character variance. In this test, the ECC for the nucleotypic effect cannot be proven for mammals as a whole class, but it holds for the two separate orders tested, rodents and passerine birds. An upper taxonomic limit for the ECC is suggested. PMID- 28568778 TI - THE EFFECT OF INBREEDING ON PHENOTYPIC VARIANCE IN THE RED FLOUR BEETLE TRIBOLIUM CASTANEUM. PMID- 28568779 TI - NARROW HYBRID ZONE BETWEEN TWO SUBSPECIES OF BIG SAGEBRUSH (ARTEMISIA TRIDENTATA: ASTERACEAE). IV. RECIPROCAL TRANSPLANT EXPERIMENTS. AB - Does endogenous or exogenous selection stabilize the big sagebrush (Artemisia tridentata) hybrid zone? After two years of study, our reciprocal transplant experiments showed significant genotype by environment interactions for a number of fitness components, including germination, growth, and reproduction. Hybrids were the most fit within the hybrid garden. In the parental gardens, the native parental taxon was more fit than either the alien parental or hybrids. These results are consistent with the bounded hybrid superiority model, which assumes exogenous selection, but are clearly at odds with the dynamic equilibrium model, which assumes endogenous selection and universal hybrid unfitness. PMID- 28568781 TI - RECENT BOOKS IN PRINT. PMID- 28568780 TI - A COMPARISON OF TWO MODELS FOR ESTIMATING PHYLOGENETIC EFFECT ON TRAIT VARIATION. PMID- 28568782 TI - GENETIC MODELS OF ADAPTATION AND GENE FLOW IN PERIPHERAL POPULATIONS. AB - We investigate the interplay between gene flow and adaptation in peripheral populations of a widespread species. Models are developed for the evolution of a quantitative trait under clinally varying selection in a species whose density decreases from the center of the range to its periphery. Two major results emerge. First, gene flow from populations at the range center can be a strong force that inhibits peripheral populations from evolving to their local ecological optima. As a result, peripheral populations experience persistent directional selection. Second, response to local selection pressures can cause rapid and substantial evolution when a peripheral population is isolated from gene flow. The amount of evolutionary change depends on gene flow, selection, the ecological gradient, and the trait's heritability. Rapid divergence can also occur between the two halves of a formerly continuous population that is divided by a vicariant event. A general conclusion is that disruption of gene flow can cause evolutionary divergence, perhaps leading to speciation, in the absence of contributions from random genetic drift. PMID- 28568783 TI - EFFECTS OF EGG SIZE ON POSTLARVAL PERFORMANCE: EXPERIMENTAL EVIDENCE FROM A SEA URCHIN. AB - Many life-history and developmental studies of marine invertebrates assume that eggs of species with nonfeeding larvae are large because they provide materials for rapid development. Using the sea urchin Heliocidaris erythrogramma which has 400 MUm eggs and nonfeeding larvae, we removed an acellular, lipid-rich component from the blastula equivalent to ca. 40% of the egg volume and ca. 50% of the organic mass. Experimentally manipulated, reduced-lipid larvae survived well, developed in the usual time (3.5 d), and high percentages of the original numbers metamorphosed into anatomically normal juveniles. Control juveniles were larger at metamorphosis, grew more, and survived longer than siblings that lacked this lipid-rich material. Moderate increases in egg size in species with nonfeeding larvae may enhance postlarval performance significantly and therefore may reflect selection on early juvenile traits. The contrasts of our results and comparable experiments with feeding larvae suggests that egg size may play fundamentally different roles in species with feeding and nonfeeding larvae. The accommodation of materials reserved for the juvenile stage should be considered among hypotheses on evolutionary modification of developmental patterns. PMID- 28568784 TI - FIVE GENERATIONS OF ENFORCED SELFING AND OUTCROSSING IN MIMULUS GUTTATUS: INBREEDING DEPRESSION VARIATION AT THE POPULATION AND FAMILY LEVEL. AB - The focus of this study was to examine the consequences of five sequential generations of enforced selfing and outcrossing in two annual populations of the mixed-mating Mimulus guttatus. Our primary goal was to determine whether purging of deleterious recessive alleles occurs uniformly between populations and among families, and thus gain insights into the mode of gene action (dominance, overdominance, and/or epistasis) governing the expression of inbreeding depression at both the population and family levels across the life cycle. PMID- 28568785 TI - WOLBACHIA INFECTION IN DROSOPHILA SIMULANS: DOES THE FEMALE HOST BEAR A PHYSIOLOGICAL COST? AB - Fitness traits of three Drosophila simulans strains infected by endocellular bacteria belonging to the genus Wolbachia have been compared with those of replicate stocks previously cured from the infection by an antibiotic treatment. The traits measured were development time, egg-to-adult viability, egg hatch, productivity, fecundity, and the number of functional ovarioles. Individuals of the first strain were bi-infected by two Wolbachia variants, wHa and wNo. The second strain was infected by wHa, the third one by wNo. The Wolbachia studied here cause cytoplasmic incompatibility (CI), a high embryonic mortality (70% to > 90%) when an infected male is crossed with an uninfected female. Three generations after antibiotic treatment, we observed in all strains a significant drop in productivity in the cured stocks. This drop was not due to antibiotic toxicity and was associated with the loss of the Wolbachia. However the effect had disappeared in two of the three strains five generations after treatment, and could not be found in the third strain in a third measurement carried out 14 generations after treatment. The temporary nature of the productivity difference indicates that Wolbachia do not enhance productivity in infected strains. On the other hand, in all traits measured, our results show the absence of any negative effects of the Wolbachia on their host. This could be explained when considering Wolbachia evolution, as maternally transmitted parasites bear a strong selective pressure not to harm their female host. However, CI would allow the bacteria to be maintained even when harming the female. The apparent absence of deleterious effects caused by these Wolbachia might result from a trade-off, where a relatively low bacteria density would advantage the Wolbachia by suppressing any deleterious effects on the female host, at the cost of a weaker maternal transmission rate of the infection. PMID- 28568786 TI - A PHYLOGENETIC ANALYSIS OF BODY SIZE EVOLUTION AND BIOGEOGRAPHY IN CHUCKWALLAS (SAUROMALUS) AND OTHER IGUANINES. AB - The evolution of body size was reconstructed in chuckwallas (genus Sauromalus), large herbivorous lizards of southwest North America, using a phylogeny derived from sequence variation in the mitochondrial cytochrome b gene. The body mass of two endemic island species (S. hispidus and S. varius) is typically fivefold larger than mainland species. We tested the hypothesis that large body size has evolved on these islands in response to local ecological conditions against the alternative hypothesis that large size is simply retained from large iguanine ancestors. The most parsimonious tree topology depicts the insular gigantic Sauromalus as monophyletic, having diverged from a common ancestor on the Baja California peninsula after the radiation of smaller bodied clades. In a robustness analysis of this topology, we found general support for this tree over alternative topologies representing minimum evolution hypotheses that imply large body size is retained from large iguanine ancestors. The most parsimonious reconstruction of body size evolution implies a change from large to small size after the Sauromalus ancestor diverged from Iguana, and one reversal back to large size within Sauromalus. The large size increase in the gigantic clade contrasts with evolutionary stasis of small body size (for an iguanine) in mainland populations. The gigantic species show 3-4% total sequence divergence from S. obesus populations on the nearby Baja California peninsula, and mainland populations of S. obesus obesus show similar levels of divergence from each other. An analysis of character transitions and comparative behavior implicates predation, and its relaxation on isolated islands, as a strong selective force in Sauromalus. Patterns of genetic differentiation in Sauromalus and biogeographic implications are discussed. PMID- 28568787 TI - MATING BEHAVIOR IN DROSOPHILA MELANOGASTER SELECTED FOR ALTERED LONGEVITY. PMID- 28568788 TI - POPULATION STRUCTURE ALONG A STEEP ENVIRONMENTAL GRADIENT: CONSEQUENCES OF FLOWERING TIME AND HABITAT VARIATION IN THE SNOW BUTTERCUP, RANUNCULUS ADONEUS. AB - Few studies have determined how gene flow and selection interact to generate population genetic structure in heterogeneous environments. One way to identify the potential role played by natural selection is to compare patterns of spatial genetic structure between different life cycle stages and among microenvironments. We examined patterns of spatial structure in a population of the snow buttercup (Ranunculus adoneus), using both adult plants and newly emerged seedlings. The study population spans a steep environmental gradient caused by gradual melting of snow within a permanent snowbed. Early-melting sites are characterized by denser vegetation, more fertile soils, and a longer growing season than late-melting sites tens of meters away. The flowering time of R. adoneus is controlled entirely by time of snowmelt, so the contiguous population is phenologically substructured into a series of successively flowering cohorts, reducing the opportunity for direct pollen transfer between early- and late melting sites. For four highly polymorphic enzyme loci in this tetraploid species, there was subtle, but statistically significant, genetic differentiation between early, middle, and late-melting cohorts; adults usually showed greater differentiation among snowmelt zones than did seedlings. At two loci in adults and one locus in seedlings, homozygotes were more common than predicted at Hardy Weinberg equilibrium, even when assuming maximum levels of double reduction during meiosis. This pattern suggests the occurrence of self-fertilization and/or population substructure. To determine how spatial isolation and phenological separation each contribute to genetic substructure, we used bivariate regression models to predict the numbers of allele differences between randomly paired individuals as a function of meters separation in space and days separation in flowering time. For newly emerged seedlings, we found that spatial separation was positively associated with genetic difference, but that the additional contribution of phenological separation to genetic difference was not significant. This implies that seeds and/or pollen move effectively across the snowmelt gradient, despite differences in flowering time. As was true for seedlings, spatial separation between paired adults contributed to greater genetic difference, but for a given spatial separation, the genetic difference between adult plants was reduced by phenological separation. This result implies that postemergence selection is favoring at least some seeds that migrate across the snowmelt gradient. Directional gene flow across the snowmelt gradient probably results from a genetic source-sink interaction, that is, the colonization of ecologically marginal late-melting sites by high quality seeds produced by the larger subpopulation in early-melting sites. Effective gene flow from high to low quality microenvironments is likely to impede adaptation to late melting locations. PMID- 28568789 TI - HETEROCHRONY WITHIN SPECIES: CRANIOFACIAL GROWTH IN GIANT, STANDARD, AND DWARF RABBITS. AB - Change in developmental timing is one source of heritable variation upon which selection can act. However, the amount of variation possible in ontogenetic trajectories is often unknown. We used three different-sized conspecific breeds of domestic rabbits to investigate the extent of variation in growth trajectories of craniofacial morphology. The growth and adult morphology of several structures (one soft tissue and 15 skeletal) were quantified and analyzed. We took two views of radiographs at close time intervals throughout ontogeny, from one week of age through adult size. Measurements from the radiographs were analyzed using a Gompertz growth model. Between-breed differences in model parameters were tested using one-way ANOVA. Few significant differences existed between the white and giant rabbits, but several differences were found between the white and dwarf breeds. Similarly, comparisons of adult morphology showed that white and giant rabbits are the same shape, while dwarf rabbits have shorter and broader snouts than white rabbits. The variation in size among breeds appeared to be due to differences in the length of time spent growing at rates near the maximum growth rate. While no one parameter of this model quantifies this pattern, differences in duration of maximum growth rate can be seen in the first derivative of the growth trajectory. Small changes in the model's parameters that measure rate and timing of growth have large morphological consequences, indicating that heterochronic changes are important sources of variation. PMID- 28568790 TI - THE MAINTENANCE OF GYNODIOECY AND ANDRODIOECY IN A METAPOPULATION. AB - Males and females are at a selective disadvantage relative to hermaphrodites (cosexuals) in species with a colonizing habit, as only cosexuals are able to establish new colonies on their own. The implications of this disadvantage are assessed by means of a computer model of metapopulation dynamics, in which individual colonies are established through different rates of immigration and suffer different rates of local extinction. Results are given for simulations of an island model, a stepping-stone model, and for a partial analysis of the island model with simplifying assumptions. It is shown that: (1) unisexual frequencies in a metapopulation can be reasonably approximated by a linear function of the logarithm of the ratio of the immigration rate to the colony extinction rate; (2) metapopulation dynamics favor the maintenance of females (gynodioecy) over males (androdioecy) with cosexuals when they would otherwise be equally likely in a panmictic situation; (3) the way in which extinction and immigration rates affect unisexual frequencies at metapopulation equilibrium interacts with whether sterility is determined by a dominant or a recessive allele; and (4) unisexual frequencies are affected in a qualitatively similar way by the dynamics of a metapopulation when cosexuals are self-incompatible to when they are self compatible, although only in the former case are high frequencies of unisexuals maintained when extinction and colonization rates approach the threshold at which the metapopulation goes extinct. These results are discussed with reference to existing data from species with nuclear male or female sterility. PMID- 28568791 TI - SEX ALLOCATION AND MALE FITNESS GAIN IN A COLONIAL, HERMAPHRODITIC MARINE INVERTEBRATE. AB - While simultaneous hermaphroditism occurs in most animal phyla, theories for its adaptive significance remain untested. Sex allocation theory predicts that combined sexes are favored in sedentary and sessile organisms because localized gamete dispersal and local mate competition (LMC) among gametes promote decelerating fitness "gain curves" that relate male investment to reproductive success. Under this LMC model, males fertilize all locally available eggs at low sperm output, additional output leads to proportionally fewer fertilizations, and combined sexes with female-biased sex allocation are favored. Decelerating male gain curves have been found in hermaphroditic flowering plants, but the present paper reports the first analysis in an animal. The colonial hermaphroditic bryozoan Celleporella hyalina forms unisexual male and female zooids that can be counted to estimate absolute and relative gender allocations. I placed "sperm donor" colonies-each with different numbers of male zooids, and each homozygous for diagnostic allozyme alleles-among target maternal colonies on field mating arrays, and estimated donor fertilization success by scoring allozyme markers in target-colony progeny. Fertilization success increased with numbers of donor male zooids, but linear and not decelerating curves fit the data best. Mean sex allocation was not female biased, consistent with nondecelerating male gain. Sperm donors, moreover, did not monopolize matings as expected under high LMC, but rather shared paternity with rival colonies. Hence localized water-borne gamete dispersal alone may not yield decelerating male gain and favor the maintenance of hermaphroditism; relaxed sperm competition in low density populations might also be required. In free-spawning marine organisms, males cannot control access to fertilizations, intense sperm competition may be commonplace, and high male sex allocation may be selected to enhance siring success under competition. PMID- 28568792 TI - LONG-TONGUED FLY POLLINATION AND EVOLUTION OF FLORAL SPUR LENGTH IN THE DISA DRACONIS COMPLEX (ORCHIDACEAE). AB - Field studies in South Africa showed that floral spur length in the Disa draconis complex (Orchidaceae) varies enormously between populations in the southern mountains (means = 32-38 mm), lowland sandplain (mean = 48 mm), and northern mountains (means = 57-72 mm). We tested the hypothesis that divergence in spur length has resulted from selection exerted through pollinator proboscis length. Short-spurred plants in several southern mountain populations, as well as long spurred plants in one northern mountain population, were pollinated by a horsefly, Philoliche rostrata (Tabanidae), with a proboscis length that varied from 22 to 35 mm among sites. Long-spurred plants on the sandplain were pollinated by the tanglewing fly, Moegistorynchus longirostris (Nemestrinidae), which has a very long proboscis (mean = 57 mm). Selection apparently favors long spurs in sandplain plants, as artificial shortening of spurs resulted in a significant decline in pollen receipt and fruit set, although pollinaria removal was not significantly affected. Fruit set in the study populations was limited by pollen availability, which further suggests that selection on spur length occurs mainly through the female component of reproductive success. PMID- 28568793 TI - NATURAL VARIATION IN THE EXPRESSION OF THE HEAT-SHOCK PROTEIN HSP70 IN A POPULATION OF DROSOPHILA MELANOGASTER AND ITS CORRELATION WITH TOLERANCE OF ECOLOGICALLY RELEVANT THERMAL STRESS. AB - Although Hsp70, the principal inducible heat-shock protein of Drosophila melanogaster, has received intense scrutiny in laboratory strains, its variation within natural populations and the consequences of such variation for thermotolerance are unknown. We have characterized variation in first-instar larvae of 20 isofemale lines isolated from a single natural population of D. melanogaster, in which larvae are prone to thermal stress in nature. Hsp70 expression varied more than twofold among lines after induction by exposure to 36 degrees C for one hour, with an estimated proportion of the variation due to genetic differences of 0.24 +/- 0.08. Thermotolerance with and without a Hsp70 inducing pretreatment, survival at 25 degrees C, and developmental time also varied significantly. As expected, expression of Hsp70 correlated positively with larval thermotolerance. By contrast, lines in which larval survival was high in the absence of heat stress showed lower than average Hsp70 expression and lower than average inducible thermotolerance. This conditional performance suggests an evolutionary trade-off between thermotolerance and the ability to produce higher concentrations of Hsp70, and survival in a benign environment. PMID- 28568794 TI - MULTIPLE MODES OF SPECIATION INVOLVED IN THE PARALLEL EVOLUTION OF SYMPATRIC MORPHOTYPES OF LAKE WHITEFISH (COREGONUS CLUPEAFORMIS, SALMONIDAE). AB - We performed a phylogenetic analysis of mtDNA variation among seven sympatric pairs of dwarf and normal morphotypes of whitefish from northern Quebec and the St. John River drainage to address three questions relevant to understanding their radiation. Are all sympatric pairs reproductively isolated? Do phylogenetic analyses confirm that sympatric whitefish morphotypes found in eastern North America represent the outcome of polyphyletic evolutionary events? If so, did all sympatric pairs from the St. John River drainage originate from the same scenario of allopatric divergence and secondary contact? The hypothesis of genetic differentiation was supported for all sympatric pairs from the St. John River drainage, whereas lack of mtDNA diversity precluded any test of reproductive isolation for northern Quebec populations. Patterns of mtDNA variation confirmed that dwarf and normal morphotypes evolved in parallel among independent, yet closely related, lineages, thus providing indirect evidence for the role of natural selection in promoting phenotypic radiation in whitefish. Patterns of mtDNA diversity among sympatric pairs of the St. John River indicated a complex picture of whitefish evolution that implied sympatric divergence and multiple allopatric divergence/secondary contact events on a small geographic scale. These results suggests that ecological opportunities, namely trophic niche availability, may promote population divergence in whitefish. PMID- 28568795 TI - "PATTERNS OF SPECIATION IN DROSOPHILA" REVISITED. PMID- 28568796 TI - A CONTACT ZONE WITH NONCOINCIDENT CLINES FOR SEX-SPECIFIC MARKERS IN THE FIELD VOLE (MICROTUS AGRESTIS). AB - A field vole (Microtus agrestis) population characterized by unique mitochondrial DNA (mtDNA) and Y chromosome markers occurs in southwest Sweden. A contact zone between this Lund (Lu) population and a standard (St) population was examined with two sex-specific genetic markers. The field vole mtDNA and Y chromosome clines display a remarkable lack of coincidence, rarely observed in contact zones. The cline width for both markers is about 50 km, but the two clines are displaced from each other: the mtDNA cline is found in the central part of the study area, whereas the cline for the Y chromosome is located in the eastern part. Thus, the absolute width of the Lu-St zone spans about 95-110 km. As a result of the cline shift, all male hybrids carry the Lu-Y chromosome and St-type mtDNA. The other possible male hybrid class is lacking. The distinct noncoincidence of the mtDNA and Y chromosome clines is most likely explained by selection against male hybrids with the St-Y chromosome and Lu-mtDNA. It is possible that incompatibilities between the maternal genome of Lu-type animals and the paternal genome of St-type individuals exist. However, alternative explanations based on neutrality or selective advantage cannot be totally dismissed. PMID- 28568797 TI - TRANSMISSION RATES AND HIV VIRULENCE: COMMENTS TO MASSAD. PMID- 28568798 TI - SEXUAL SELECTION, SPACE, AND SPECIATION. AB - A Fisherian model of sexual selection is combined with a diffusion model of mate dispersal to investigate the evolution of assortative mating in a sympatric population. Females mate with one of two types of polygynous males according to a male's display of one of two sex-limited, autosomal traits; these male traits may be associated with differential phenotypic mortalities. Through a Fisherian runaway process, female preferences and male traits can become associated in linkage disequilibrium, leading to patterns of assortative mating. Dispersing males, whose rate of movement is dependent on mating success, carry female preference genes with them, and displaced males thereby produce daughters with preference genes for their respective traits in locally higher than average frequencies. The reduced diffusion of the more preferred males permits the success of other male types in adjacent areas. Thus, mating-success dependent diffusion, when coupled with the rapid divergence in phenotypes possible under the Fisher process, can lead to the coexistence of two female preferences and two male traits in sympatry. We argue that many existing approaches to sympatric speciation fail to explain observed male polymorphisms because they exclude explicit spatial structure from their speciation models. PMID- 28568799 TI - CONTRIBUTIONS OF SEXUAL AND ASEXUAL REPRODUCTION TO POPULATION STRUCTURE IN THE CLONAL SOFT CORAL, ALCYONIUM RUDYI. AB - Numerous studies of population structure in sessile clonal marine invertebrates have demonstrated low genotypic diversity and nonequilibrium genotype frequencies within local populations that are monopolized by relatively few, highly replicated genets. All of the species studied to date produce planktonic sexual propagules capable of dispersing long distances; despite local genotypic disequilibria, populations are often panmictic over large geographic areas. The population structure paradigm these species represent may not be typical of the majority of clonal invertebrate groups, however, which are believed to produce highly philopatric sexual propagules. I used allozyme variation to examine the population structure of the temperate soft coral, Alcyonium rudyi, a typical clonal species whose sexually produced larvae and asexually produced ramets both have very low dispersal capabilities. Like other clonal plants and invertebrates, the local population dynamics of A. rudyi are dominated by asexual reproduction, and recruitment of new sexually produced genets occurs infrequently. As expected from its philopatric larval stage, estimates of genetic differentiation among populations of A. rudyi were highly significant at all spatial scales examined (mean theta = 0.300 among 20 populations spanning a 1100-km range), suggesting that genetic exchange seldom occurs among populations separated by as little as a few hundred meters. Mapping of multilocus allozyme genotypes within a dense aggregation of A. rudyi ramets confirmed that dispersal of asexual propagules is also very limited: members of the same genet usually remain within < 50 cm of one another on the same rock surface. Unlike most previously studied clonal invertebrates, populations of A. rudyi do not appear to be dominated by a few widespread genets: estimates of genotypic diversity (Go ) within 20 geographically distinct populations did not differ from expectations for outcrossing, sexual populations. Despite theoretical suggestions that philopatric dispersal combined with typically small effective population sizes should promote inbreeding in clonal species, inbreeding does not appear to contribute significantly to the population structure of A. rudyi. Genet genotype frequencies conformed to Hardy-Weinberg expectations in all populations, and inbreeding coefficients (f) were close to zero. In general, the population structure of A. rudyi did not differ significantly from that observed among outcrossing sexual species with philopatric larval dispersal. Age estimates suggest, however, that genets of A. rudyi live for many decades. Genet longevity may promote high genotypic diversity within A. rudyi populations and may be the most important evolutionary consequence of clonal reproduction in this species and the many others that share its dispersal characteristics. PMID- 28568800 TI - LIMITED SEED DISPERSAL AND GENETIC STRUCTURE IN LIFE STAGES OF CECROPIA OBTUSIFOLIA. PMID- 28568801 TI - EVOLUTIONARY ADAPTATION TO TEMPERATURE. VI. PHENOTYPIC ACCLIMATION AND ITS EVOLUTION IN ESCHERICHIA COLI. AB - Acclimation refers to reversible, nongenetic changes in phenotype that are induced by specific environmental conditions. Acclimation is generally assumed to improve function in the environment that induces it (the beneficial acclimation hypothesis). In this study, we experimentally tested this assumption by measuring relative fitness of the bacterium Escherichia coli acclimated to different thermal environments. The beneficial acclimation hypothesis predicts that bacteria acclimated to the temperature of competition should have greater fitness than do bacteria acclimated to any other temperature. The benefit predicted by the hypothesis was found in only seven of 12 comparisons; in the other comparisons, either no statistically demonstrable benefit was observed or a detrimental effect of acclimation was demonstrated. For example, in a lineage evolutionarily adapted to 37 degrees C, bacteria acclimated to 37 degrees C have a higher fitness at 32 degrees C than do bacteria acclimated to 32 degrees C, a result exactly contrary to prediction; acclimation to 27 degrees C or 40 degrees C prior to competition at those temperatures confers no benefit over 37 degrees C acclimated forms. Consequently, the beneficial acclimation hypothesis must be rejected as a general prediction of the inevitable result of phenotypic adjustments associated with new environments. However, the hypothesis is supported in many instances when the acclimation and competition temperatures coincide with the historical temperature at which the bacterial populations have evolved. For example, when the evolutionary temperature of the population was 37 degrees C, bacteria acclimated to 37 degrees C had superior fitness at 37 degrees C to those acclimated to 32 degrees C; similarly, bacteria evolutionarily adapted to 32 degrees C had a higher fitness during competition at 32 degrees C than they did when acclimated to 37 degrees C. The more surprising results are that when the bacteria are acclimated to their historical evolutionary temperature, they are frequently competitively superior even at other temperatures. For example, bacteria that have evolved at either 20 degrees C or 32 degrees C and are acclimated to their respective evolutionary temperatures have a greater fitness at 37 degrees C than when they are acclimated to 37 degrees C. Thus, acclimation to evolutionary temperature may, as a correlated consequence, enhance performance not only in the evolutionary environment, but also in a variety of other thermal environments. PMID- 28568802 TI - THE SYMMETRY OF CORRELATED SELECTION RESPONSES IN ADAPTIVE EVOLUTION: AN EXPERIMENTAL STUDY USING DROSOPHILA. AB - The relationship between the processes of density-dependent and age-specific selection has been investigated by examining a common phenotype, urea resistance, which has apparently evolved in response to each of these selection mechanisms. Twenty populations that have experienced differing levels of age-specific selection show differences in egg-to-adult viability in environments with high levels of urea. Among this group of populations, it appears that resistance to urea is correlated with longevity, but not development time. Ten populations kept at extreme larval densities for many generations also show responses to urea: those kept at high larval densities appear to be most resistant to urea. However, these populations show no differences in adult longevity. An additional five populations were selected directly for urea resistance by adding this compound to the larval food environment. Again, there was a strong response to this artificial selection, with urea resistance increasing dramatically, but these populations showed no response in adult longevity or resistance to crowding when compared to five control populations. There is clearly no simple relationship between longevity and larval urea resistance. It may be that age-specific and density-dependent selection induce similar changes in this phenotype, but do so through different genetic and physiological pathways. We suggest that these data are not consistent with the view of constant and symmetric genetic variance covariance matrices. These data support a more prominent role for observations of evolutionary trajectories rather than static measurements of genetic components of variance. PMID- 28568803 TI - EXTINCTION-RECOLONIZATION DYNAMICS IN THE MYCOPHAGOUS BEETLE PHALACRUS SUBSTRIATUS. AB - The population structure of the mycophagous beetle Phalacrus substriatus is characterized by many small, local populations interconnected by migration over a small spatial scale (10 * 75 m2 ). Each local P. substriatus population has a relatively short expected persistence time, but persistence of the species occurs due to a balance between frequent local extinctions and recolonizations. This nonequilibrium population structure can have profound effects on how the genetic variation is structured between and within populations. Theoretical models have stated that the genetic differentiation among local populations will be enhanced relative to an island model at equilibrium if the number of colonizers is less than approximately twice the number of migrants among local populations. To study these effects, a set of 50 local P. substriatus populations were surveyed over a four-year period to record any naturally occurring extinctions and recolonizations. The per population colonization and extinction rate were 0.237 and 0.275, respectively. Mark-recapture techniques were used to estimate a number of demographic parameters: local population size (N = 11.1), migration rate (m?=0.366), number of colonizers (k = 4.0), and the probability of common origin of colonizers (phi = 0.5). The theoretically predicted level of differentiation among local populations (measured as Wright's FST ) was 0.070. Genetic data obtained from an electrophoretic survey of seven polymorphic loci gave an estimated degree of differentiation of 0.077. There was thus a good agreement between the empirical results and the theoretical predictions. Young populations (theta?young=0.090) had significantly higher levels of differentiation than old, more established populations (theta?old=0.059). The extinction-recolonization dynamics resulted in an overall increase in the genetic differentiation among local populations by c. 40%. The global effective population size was also reduced by c. 55%. The results give clear evidence to how nonequilibrium processes shape the genetic structure of populations. PMID- 28568804 TI - SELF-FERTILIZATION WITHOUT GENOMIC OR POPULATION STRUCTURING IN A PARASITIC TAPEWORM. PMID- 28568805 TI - EVOLUTION OF AVIAN COOPERATIVE BREEDING: COMPARATIVE TESTS OF THE NEST PREDATION HYPOTHESIS. AB - Comparative analyses carried out on two different phylogenies of cooperatively and noncooperatively breeding Australian passerine birds (parvorder Corvida) were unable to detect a significant difference in nest predation rates after controlling for body mass and risk of predation due to location of the nest (nest safety). Nest predation rates, however, decrease as nest safety and body mass increase. We suggest that cooperative breeding does not bring about a current net change in rates of nest predation among Australian passerines. Species breeding cooperatively may have developed antipredator strategies that produce results similar to those adopted by noncooperatively breeding species. The function of cooperative breeding may lie outside of antipredator strategies. PMID- 28568806 TI - A CLADISTIC ANALYSIS OF PHEROMONE EVOLUTION IN IPS BARK BEETLES (COLEOPTERA: SCOLYTIDAE). PMID- 28568807 TI - POSTDISPERSAL SELECTION FOLLOWING MIXED MATING IN EUCALYPTUS REGNANS. AB - Eucalyptus regnans is a mass flowering, tall forest tree of southeastern Australia with a mixed mating system. A field trial containing randomized single tree plots of self, outcross, and naturally open-pollinated (OP) progenies of 13 parents from two natural populations was surveyed over 15 yr. Inbreeding depression in survival at 15 years was 67% for selfs, one of the highest levels reported for a tree species, and differed little between populations. OP progenies were intermediate and the difference in fitness among the three cross types indicated that at planting, 59% were derived from outcrossing. However, with selection against the inbred progenies, this increased to 83% by 15 yr of age. Most selection against selfs occurred after four years, coincident with canopy closure and the apparent onset of intense competition. PMID- 28568808 TI - NATURAL SELECTION ON GENETICALLY CORRELATED PHENOLOGICAL CHARACTERS IN LYTHRUM SALICARIA L. (LYTHRACEAE). PMID- 28568809 TI - THE EFFECT OF DELAYED POPULATION GROWTH ON THE GENETIC DIFFERENTIATION OF LOCAL POPULATIONS SUBJECT TO FREQUENT EXTINCTIONS AND RECOLONIZATIONS. AB - I investigated the effects of delayed population growth on the genetic differentiation among populations subjected to local extinction and recolonization, for two different migration functions; (1) a constant migration rate, and (2) a constant number of migrants. A delayed period of population growth reduces the size of the newly founded populations for one or several generations. Whether this increases differentiation among local populations depends on the actual pattern of migration. With a constant migration rate, fewer migrants move into small populations than into large, thus providing ample opportunity for drift to act within a population. A prolonged period of population growth thus makes the conditions for enhanced differentiation between local populations less restrictive and also inflates the actual levels of differentiation. The effect depends on the relative magnitudes of ke , the effective number of colonizers and k, the actual number of colonizers. When there is a constant number of migrants into a population per generation, migration into small populations is increased. This increase of migration in small populations counteracts the effects of genetic drift due to small population size. It increases the rate by which populations approach equilibrium, as small populations are swamped by migrants from larger populations closer to genetic equilibrium, and overall levels of differentiation are thus reduced. I also discuss situations for which the results of this paper are relevant. PMID- 28568810 TI - ECOLOGICAL HISTORY AND EVOLUTION IN A NOVEL ENVIRONMENT: HABITAT HETEROGENEITY AND INSECT ADAPTATION TO A NEW HOST PLANT. AB - Environmental heterogeneity has often been implicated in the maintenance of genetic variation. However, previous research has not considered how environmental heterogeneity might affect the rate of adaptation to a novel environment. In this study, I used an insect-plant system to test the hypothesis that heterogeneous environments maintain more genetic variation in fitness components in a novel environment than do uniform environments. To manipulate recent ecological history, replicate populations of the dipteran leafminer Liriomyza trifolii were maintained for 20 generations in one of three treatments: a heterogeneous environment that contained five species of host plant, and two uniform environments that contained either a susceptible chrysanthemum or tomato. The hypothesis that greater genetic variance for survivorship and developmental time on a new host plant (a leafminer-resistant chrysanthemum) would be maintained in the heterogeneous treatment relative to the uniform environments was then tested with a sib-analysis and a natural selection experiment. Populations from the heterogeneous host plant treatment had no greater genetic variance in either larval survivorship or developmental time on the new host than did populations from either of the other treatments. Moreover, the rate of adaptation to the new host did not differ between the ecological history treatments, although the populations from the uniform chrysanthemum treatment had higher mean survivorship throughout the selection experiment. The estimates of the heritability of larval survivorship from the sib-analysis and selection experiment were quite similar. These results imply that ecologically realistic levels of environmental heterogeneity will not necessarily maintain more genetic variance than uniform environments when traits expressed in a particular novel environment are considered. PMID- 28568811 TI - SELECTION ON A FLORAL COLOR POLYMORPHISM IN THE TALL MORNING GLORY (IPOMOEA PURPUREA): TRANSMISSION SUCCESS OF THE ALLELES THROUGH POLLEN. AB - The W locus, a codominant locus influencing floral pigment intensity in the tall morning glory, Ipomoea purpurea, is polymorphic throughout the southeastern United States. Previous studies suggest that this polymorphism is actively maintained by balancing selection, and that increased selfing accompanied by lack of pollen discounting ("Fisher effect") may act to protect the white allele when it is rare. Processes that act to protect the dark allele and thus stabilize the polymorphism in conjunction with the Fisher effect have not been previously detected. The goal of this study was to determine whether any of three such processes might operate in I. purpurea. Estimates of breeding system parameters in a large experimental population in which the white allele was in higher than normal frequency (0.5) provided little evidence that either dark- or light flowered plants were more successful as pollen parents than white-flowered plants. In addition, no evidence was found for a transmission bias favoring the dark allele in the ovules produced by light heterozygotes. In contrast, a strong transmission bias favoring the dark allele in pollen of heterozygotes was observed. A simple model using parameter estimates derived from this and previous studies indicates that a balance between the Fisher effect and biased transmission in heterozygote pollen could account for many properties of the polymorphism. PMID- 28568812 TI - Second-order cooperation: Cooperative offspring as a living public good arising from second-order selection on non-cooperative individuals. AB - Switching rate between cooperating and non-cooperating genotypes is a crucial social evolution factor, often neglected by game theory-inspired theoretical and experimental frameworks. We show that the evolution of alleles increasing the mutation or phenotypic switching rates toward cooperation is in itself a social dilemma. Although cooperative offspring are often unlikely to reproduce, due to high cost of cooperation, they can be seen both as a living public good and a part of the extended parental phenotype. The competition between individuals that generate cooperators and ones that do not is often more relevant than the competition between cooperators and non-cooperators. The dilemma of second-order cooperation we describe relates directly to eusociality, but can be also interpreted as a division of labor or a soma-germline distinction. The results of our simulations shine a new light on what Darwin had already termed a "special difficulty" of evolutionary theory and describe a novel type of cooperation dynamics. PMID- 28568814 TI - THE ORIGIN OF AN ORGAN: PHYLOGENETIC ANALYSIS OF EVOLUTIONARY INNOVATION IN THE DIGESTIVE TRACT OF FLIES (INSECTA: DIPTERA). AB - The cardia, a prominent digestive tract organ consisting of several specialized cell types, occurs throughout the "higher" or muscoid flies, division Schizophora of order Diptera. Phylogenetic analysis of cellular organization in 65 insect species from 36 families indicates that this organ originated within the order Diptera from ancestrally undifferentiated tissues. "Lower" flies, suborder "Nematocera," display little or no epithelial cell specialization at the corresponding site. Scorpionflies of the outgroup order Mecoptera are similarly unspecialized. Intermediate levels of cellular specialization occur in Tabanomorpha, Asilomorpha and Aschiza, dipteran taxa that diverge between "Nematocera" and Schizophora. The distribution of epithelial characteristics suggests that the cardia evolved through a sequence of simple tissue transformations, combining changes in epithelial configuration with local differentiation of cell structure and function. The evolution of locally specialized cell types implies the emergence of structural genes and regulatory mechanisms through the modification of an ancestral genome that had not supported such extensive differentiation. Comparison of localized gene expression in Drosophila melanogaster with that in other fly species having greater or lesser degrees of cell specialization may provide a practical model system for studying specific patterns of mutation associated with such evolutionary innovation. PMID- 28568813 TI - A Population Dose-Response Model for Inhaled Technosphere Insulin Administered to Healthy Subjects. AB - Technosphere insulin (TI), an inhaled insulin with a fast onset of action, provides a novel option for the control of prandial glucose. A euglycemic glucose clamp study was performed to compare the effects of TI and regular human insulin (RHI) on the induced glucose infusion rate (GIR) in healthy volunteers. Generation of a dose-response relationship between insulin dose and effect (expressed as AUC of GIR) was not possible from the clinical data directly. The GIR recording time was too short to capture the full effect and higher doses were not tested. Thus, a pharmacokinetic-GIR model was developed to simulate GIR for a sufficient time window of 20 h and for higher doses. A dose-response model was then generated from the simulated GIR profiles. The resulting model provides an ED50 for TI that is 5-fold higher than for RHI, a ratio that can be used as conversion factor for equivalent doses of RHI and TI. PMID- 28568815 TI - GENETIC CONSEQUENCES OF PASSIVE DISPERSAL IN POND-DWELLING COPEPODS. AB - Pond-dwelling copepods have colonized habitats throughout North America after glaciers have receded. Most species are passively transported via resting eggs into new habitats. Colonists originating in a glacial refugium could lose some of the ancestral genetic diversity when they establish new populations and the attenuation may be substantial in populations far removed from the refugium due to multiple founder events. Genetic variation was measured in Heterocope septentrionalis from 27 populations at arctic sites near potential refugia and those more recently deglaciated to determine the effects of postglacial dispersal on patterns of genetic relatedness and diversity. Some populations were more distant, genetically, from others within the same site than those from other more distant sites. Eleven polymorphic enzyme loci were significantly more variable (F [1,294 df] = 5.94, P < 0.025) among individuals from populations near the Alaskan refuge than those at the eastern limit of their distribution. Because populations are typically extremely large and stable this loss of genetic diversity is attributed primarily to repeated founder events during colonization. This result suggests profound genetic changes may occur on a continental scale in passively dispersed copepods due to founder events alone. Their potential for divergence and speciation is greater than currently recognized. PMID- 28568816 TI - GENETIC COVARIANCE OF FITNESS CORRELATES: WHAT GENETIC CORRELATIONS ARE MADE OF AND WHY IT MATTERS. AB - The genetic variance-covariance matrix, G, is determined in part by functional architecture, the pathways by which variation in genotype influences phenotype. I develop a simple architectural model for G for two traits under directional selection constrained by their dependence on a common limiting resource. I assume that genetic variance is maintained by mutation-selection balance. The relative numbers of loci that play a role in acquiring versus allocating a limiting resource play a crucial role in determining genetic covariance. If many loci are involved in acquiring a resource, genetic covariance may be either negative or positive at equilibrium, depending on the fitness function and the input of mutational variance. The form of G does not necessarily reveal the constraint on resource acquisition inherent in the system, and therefore studies estimating G do not test for the existence of life-history tradeoffs. Characters may evolve in patterns that are unpredictable from G. Experiments are suggested that would indicate if this model could explain observations of positive genetic covariance. PMID- 28568817 TI - IS SINGLE-GENE SPECIATION POSSIBLE? PMID- 28568818 TI - POPULATION AND DEVELOPMENTAL VARIATION IN THE FEATHER TIP. AB - Variation among adults reflects variation in basic developmental processes, such as cell division rate. Partitioning the variation into its developmental components would be a major step in understanding evolutionary constraints, but is far from being achieved for any character. In this paper, we examine population variation in the feather tip, a useful structure to study because the history of development is recorded in the adult form. Our goal is to document the variability, and provide a developmentally based explanation for the level of variation observed. Using feathers collected from chicks of a small warbler, we partition population variation into variation attributed to accidents of development (through a consideration of fluctuating asymmetry), and among- and within-family components. Population variation in the earliest formed part of the feather is high (the coefficient of variation is c. 30%); population variation in later formed parts of the feather is lower. The among-individual and developmental noise components are both reduced in later formed parts, but there are differences in the way the two components are associated among the feather parts. The early and later formed parts are highly integrated at the among individual level (correlations ~ 1.0) but not at the developmental noise level (correlations ~ 0.5). This suggests that at least two basic developmental processes are involved in determining the length of the various feather parts. We review feather development and pattern formation models to demonstrate that at least two developmental processes are indeed involved in feather growth. We show how these processes could interact to achieve the relative invariance in the later formed parts of the feather. PMID- 28568819 TI - SPATIAL DISTRIBUTION OF A PRIMITIVELY SOCIAL BEE: DOES GENETIC POPULATION STRUCTURE FACILITATE ALTRUISM? AB - Exoneura bicolor is a univoltine, facultatively social bee exhibiting a solitary/quasisocial/semisocial colony polymorphism (Schwarz, 1986, 1987). Intracolony relatedness in semisocial colonies has been previously estimated at 0.49 +/- 0.06 (Schwarz, 1987), although the crucial relatedness between altruists and the brood that they rear will be about half this value. This value is unlikely to be increased by the preferential rearing of only close relatives (Schwarz, 1988a) and no known morphological specializations preclude workers from reproducing in this species. Hamilton (1972, 1975) suggested that relatedness may be increased through population subdivision, if this leads to significant inbreeding and increased between-colony genetic variance. The same process may also operate at higher levels of population structure (e.g., Wade, 1978). Population structure and intracolony relatedness in E. bicolor were investigated in seven localities in southern Victoria, Australia, to determine if inbreeding at any level of population structure was contributing to relatedness between altruists and beneficiaries within these colonies. Population structure was described using hierarchical F-statistics and an identity by descent measure, developed by Queller and Goodnight (1989), was used to estimate intracolony relatedness. It was found that inbreeding was not contributing to between-group genetic variance, at any level, in a consistent manner across localities. Therefore relatedness, considered in isolation, does not seem sufficient to account for the presence of worker behavior. It is suggested that large benefits for group living may be responsible for maintaining altruistic behavior, in part, in this species. Significant heterogeneity among localities for all F-statistics estimated in our analysis was found and this may be attributable to stochastic elements such as cofounding behavior and the low percentage of males in the brood. The possible consequences of such heterogeneity in population structure for the maintenance of altruism in E. bicolor are discussed. PMID- 28568820 TI - CYTOPLASMIC EFFECTS ON COMPONENTS OF FITNESS IN TOBACCO CYBRIDS. PMID- 28568821 TI - LIMITS TO REPRODUCTIVE SUCCESS IN A PARTIALLY SELF-INCOMPATIBLE HERB: FECUNDITY DEPRESSION AT SERIAL LIFE-CYCLE STAGES. AB - Like many angiosperms, Crinum erubescens is partially self-compatible, producing fewer seeds upon selfing than after outcrossing. In this paper we test the relative magnitude of the prefertilization and postfertilization effects of self incompatibility, inbreeding depression, or both in a natural population of this hermaphroditic tropical herb. We characterize prefertilization effects by examining pollen tube growth, while postfertilization effects are characterized by examination of embryo abortion and seed maturation. Statistical methods are developed to test the magnitude of these effects from one life-cycle stage to the next. We find that although pollen performance in selfed flowers is lower than that in outcrossed flowers, pollen performance is low overall. Postfertilization effects attributable to inbreeding depression account for a larger proportion of the reduction in fecundity in selfed compared to outcrossed flowers. Among naturally pollinated plants, despite ample pollen deposition, the numbers of fruits and seeds set are intermediate to selfed and outcrossed treatments. PMID- 28568822 TI - THE GENETIC INTERPRETATION OF INBREEDING DEPRESSION AND OUTBREEDING DEPRESSION. AB - Inbreeding with close relatives and outbreeding with members of distant populations can both result in deleterious shifts in the means of fitness-related characters, most likely for very different reasons. Such processes often occur simultaneously and have important implications for the evolution of mating systems, dispersal strategies, and speciation. They are also relevant to the design of breeding strategies for captive populations of endangered species. A general expression is presented for the expected phenotype of an individual under the joint influence of inbreeding and crossbreeding. This expression is a simple function of the inbreeding coefficient, of source and hybridity indices of crossbreeding, and of specific forms of gene action. Application of the model may be of use in identifying the mechanistic bases for a number of evolutionary phenomena such as the shift from outbreeding enhancement to outbreeding depression that occurs with population divergence. PMID- 28568823 TI - A MOLECULAR REEXAMINATION OF DIPLOID HYBRID SPECIATION OF SOLANUM RAPHANIFOLIUM. PMID- 28568824 TI - THE PROBABILITY OF FIXATION OF A NEW KARYOTYPE IN A CONTINUOUS POPULATION. AB - We investigate the probability of fixation of a chromosome rearrangement in a subdivided population, concentrating on the limit where migration is so large relative to selection (m ? s) that the population can be thought of as being continuously distributed. We study two demes, and one- and two-dimensional populations. For two demes, the probability of fixation in the limit of high migration approximates that of a population with twice the size of a single deme: migration therefore greatly reduces the fixation probability. However, this behavior does not extend to a large array of demes. Then, the fixation probability depends primarily on neighborhood size (Nb), and may be appreciable even with strong selection and free gene flow (~exp(-B ~ Nb?s) in one dimension, ~exp(-B ~ Nb) in two dimensions). Our results are close to those for the more tractable case of a polygenic character under disruptive selection. PMID- 28568825 TI - THE ECOLOGY AND GENETICS OF FITNESS IN CHLAMYDOMONAS III. GENOTYPE-BY-ENVIRONMENT INTERACTION WITHIN STRAINS. AB - The fitness of genotypes created by crossing strains of Chlamydomonas reinhardtii was measured in axenic pure culture in a set of chemically defined environments. There was substantial and highly significant genotype-by-environment interaction, with genetic correlations between environments averaging only about +0.1 for both r and K. Higher-order interactions with combinations of environmental factors appeared to be no less important than simple interactions with single factors. The importance of genotype-by-environment interaction increased with the number of environmental factors manipulated. The linear reaction norms of genotypic score on environmental mean score varied substantially among genotypes and often intersected. There was also some evidence that nonallelic genetic interactions were present, and varied among environments. The genetic correlation of r with K also varied among environments, being significantly negative in some but not in others. These results are similar in all important respects to those previously obtained with different species, and suggest that genotype-by-environment interaction is important at all genetic scales. It is argued that they provide empirical support for a general theory of diversity, the "Tangled Bank," based on the different response of genotypes to the range of conditions found in heterogeneous natural environments. PMID- 28568826 TI - A TEST OF THE LOW MARGINAL VARIANCE (LMV) THEORY, IN LEPTOSPERMUM SCOPARIUM (MYRTACEAE). PMID- 28568828 TI - EVOLUTION, PHYLOGENY, SEXUAL DIMORPHISM AND MATING SYSTEM IN THE GRACKLES (QUISCALUS SPP.: ICTERINAE). AB - According to theory, two consequences of sexual selection are sexual dimorphism in size and secondary sexual characteristics, due to either intra- or intersexual selection. In this paper I suggest three criteria for the test of an evolutionary hypothesis involving quantitative morphological characters. First, the postulated change must be shown to have occurred in evolutionary time. Second, this change must be positively correlated with a change in the proposed selective agent. Third, given two taxa with different degrees of sexual size dimorphism and different mating system, the possible influence of drift must be rejected. If the hypothesis is not rejected by these three criteria, then we still have no proof of causality, but we can at least be more confident about its plausibility. This is applied to the particular hypothesis that sexual dimorphism in the Boat-tailed and Great-tailed grackles (Quiscalus spp; Icterinae; Aves) is caused by the highly polygynous mating system in these species. In relation to an outgroup, both species have increased disproportionately in male tarsus and tail size, creating an increased sexual dimorphism. This has cooccurred with the evolution of their particular mating system. However, the variance among species in male tarsus size can be accounted for by drift, and need not be a result of selection for increased size. In contrast, the variance among species in male tail size was much larger than expected under a null model of drift, indicating directional selection for long tails. The variance in female tail size was not larger than expected by drift, whereas the variance in female tarsus size was in fact lower than expected by drift, indicating stabilizing selection. The data are consistent with the hypothesis with regard to tail size, but not with regard to body size. PMID- 28568827 TI - EVOLVED ENVIRONMENT-DEPENDENT EXPRESSION OF DETOXICATION ENZYME ACTIVITY IN DROSOPHILA MELANOGASTER. PMID- 28568829 TI - THERMAL SENSITIVITY OF DROSOPHILA MELANOGASTER RESPONDS RAPIDLY TO LABORATORY NATURAL SELECTION. PMID- 28568830 TI - THE IMPACT OF ELECTROPHORETIC GENOTYPE ON LIFE HISTORY TRAITS IN PINUS TAEDA. AB - Reports of positive associations between allozymic heterozygosity and measures of fitness are routine, but it has not been possible to distinguish between the two preeminent explanations of the phenomenon, dominance and overdominance. We tested several of the assumptions of these hypotheses in our study of the relationship between electrophoretic genotype and three life history traits in loblolly pines (Pinus taeda L.). Traits examined included the survival and growth of selfed and outcrossed progeny of 45 maternal trees, and maternal fecundity, measured as the number of surviving progeny per mother tree. Inbreeding depression was severe; the relative fitness of the selfed progeny was only 8% that of the outcrossed progeny. We found a heterozygote fecundity advantage, which should have resulted in an excess of rare alleles in the progeny. Instead, there was evidence of severe survival selection against rare alleles in both heterozygous and homozygous forms. The deficit of rare alleles averaged 69 and 50% in the selfed and outcrossed progeny, respectively. The one allele in the sample that we should have suspected of being maintained by overdominance (a PGI2 mid-frequency allele) appeared to be overdominant for outcrossed height growth and probably for fecundity as well. Multiple-locus genotype explained very little of the variation in growth, however, and rather than seeing evidence for overdominance as a force in maintaining most of the observed polymorphism, we were left to explain, in the face of the severe survival selection, why the rare alleles were present at all. Projection of the stand into the future through computer simulation showed how balancing selection acting on differential growth, fecundity, and mortality among genotypes could, over the life of the stand, account for the maintenance of the rare alleles in the population. PMID- 28568831 TI - COEVOLUTION IN BACTERIAL-PLASMID POPULATIONS. AB - Evolutionary changes are described in plasmid-containing strains isolated after approximately 800 generations of growth in glucose-limited chemostat culture. The reproductive fitness increased dramatically over this period. Genetic changes associated with the increases in fitness were localized to both the bacterial and the plasmid chromosomes. In addition, some of the genetic changes on the bacterial and the plasmid chromosomes interact to minimize the deleterious effect of the plasmid. Thus, the changes observed may be considered coevolutionary. Reductions in the deleterious effects of the plasmid were shown to be associated with a decrease in plasmid copy number and an increase in the rate of segregational loss of the plasmid. PMID- 28568832 TI - TRANSFER OF EJACULATE AND INCORPORATION OF MALE-DERIVED SUBSTANCES BY FEMALES IN THE NANNOPTERA SPECIES GROUP (DIPTERA: DROSOPHILIDAE). PMID- 28568833 TI - THE EVOLUTION OF COPULATION IN WATER MITES: A COMPARATIVE TEST FOR NONREVERSING CHARACTERS. AB - Although copulation is a widespread behavior with multiple origins, hypotheses about selective forces behind its evolution have not been tested by the comparative method. Because copulation has arisen many times in the water mites (Acari: Parasitengona), they are good subjects for a comparative study of copulation. I determined that copulation evolved 91 times in the 343 extant genera. There was no evidence of reversals to noncopulation; therefore, Ridley's (1983) contingency-table comparative test was not appropriate. I designed a comparative test for instances in which there is no loss of the derived trait of interest. This test determines whether independent evolutions of a trait cooccur with a predictor more often than expected by chance. Two hypotheses were tested: 1) that copulation would be selected for in running-water habitats because of disruption of pheromonal communication; 2) that copulation would be selected for in swimming mites because females are less likely to contact spermatophores deposited on a substrate. Independent evolutions of copulation among running water mites were not more frequent than expected by chance (P > 0.4), but there were more evolutions of copulation than expected among swimming mites (P < 0.005). Endoparasitism, secondary loss of swimming hairs, production of spermatophore fields, courtship, and benthivorous habits may explain why some mites copulate but do not swim while others swim but do not copulate. PMID- 28568834 TI - MORPHOLOGY AND BEHAVIOR OF CRABS AND GASTROPODS FROM LAKE TANGANYIKA, AFRICA: IMPLICATIONS FOR LACUSTRINE PREDATOR-PREY COEVOLUTION. AB - The shells of most lacustrine gastropods are typically small, weakly calcified, and modestly ornamented to unornamented. Similarly, most lacustrine crabs are usually small detritivores with weak chelae. A number of invertebrate taxa in Lake Tanganyika, however, deviate from these generalities. This study explores a predator-prey coevolution model as an explanation for the large, heavily calcified, and ornate gastropods and the robust, durophagous crabs of Lake Tanganyika. The endemic thiarid and viviparid gastropods from Lake Tanganyika have significantly thicker shells and higher frequencies of terminal apertural lip thickening than closely related cosmopolitan taxa from outside the lake. Tanganyikan gastropods also display considerably higher incidence of shell repair, following nonlethal shell damage, than cosmopolitan taxa of the same families. There is a strong positive correlation between gastropod apertural lip thickness and shell repair frequency among all the gastropod species analyzed. The endemic Tanganyikan potamonautid crab Platytelphusa armata (a molluscivore) possesses larger, more robust crushing chelae than other African potamonautid or potamonid crabs. In contrast with the cosmopolitan African crabs, the Tanganyikan crabs display molariform, rather than serrate dentition on their crushing chelipeds. In shell-crushing experiments, the Tanganyikan gastropod shells were an order of magnitude stronger than typical lacustrine gastropod shells, many well within the range of tropical marine gastropod shell strengths. Predation experiments with the endemic gastropods Spekia, Neothauma, Lavigeria spp., Paramelania spp. and the crab Platytelphusa armata showed that increased size, apertural lip thickness or shell sculpture reduced the successful predation rate of P. armata. Crabs with large chelae have a greater ratio of successful: unsuccessful attacks than crabs with small chelae. Among cases of successful predation, crabs with large chelae employed predation methods that required less time and energy (such as crushing the shell in the cheliped) than the methods employed by crabs with small chelae (such as peeling the shell from the aperture or the spire). The morphological, shell-crushing, and aquarium experiment data, considered in concert, provide strong support for the idea that the endemic gastropods and crabs of Lake Tanganyika have coevolved over the past 7 million years. PMID- 28568835 TI - FLEXURAL STIFFNESS ALLOMETRIES OF ANGIOSPERM AND FERN PETIOLES AND RACHISES: EVIDENCE FOR BIOMECHANICAL CONVERGENCE. AB - Evidence for convergence in biomechanical and anatomical features of leaves (elastic modulus E, second moment of area I, taper of petioles, the longitudinal distribution of petiolar and laminar weight, and volumes of tissues) is presented based on a survey of 22 species (distributed among dicots, monocots, and ferns). In general, regardless of taxonomic affinity, petioles were found to be mechanically constructed in one of two ways: Type I petioles-as cantilevered, end loaded beams with relatively uniform flexural stiffness (EI) (simple and palmate leaves); and Type II petioles-as tapered cantilevered beams whose static loadings (biomass) and EI increase basipetally (pinnate leaves). In general, collenchyma and sclerenchyma were found to be peripherally located in transections through Type I and II petioles, respectively. Statistical analyses within each species and among species with either type of petiole indicated that EI ~ k1 Lp2.98 and EI ~ k2 Lp2.05 for Type I and II petioles, respectively, where k1 and k2 are dimensional constants and Lp is petiolar length. The data are interpreted to indicate that Type I and II petioles mechanically operate to deal with static loadings in two distinct ways, such that Type II petioles function in an analogous manner to branches supporting separate leaves (leaflets). The convergence in mechanical "designs" among taxonomically distinct lineages (angiosperms and ferns) is interpreted as evidence for selection on mechanical attributes of load supporting structures (petioles). PMID- 28568836 TI - MUTATIONS DO NOT ACCUMULATE IN ASEXUAL ISOLATES CAPABLE OF GROWTH AND EXTINCTION MULLER'S RATCHET RE-EXAMINED. AB - The rarity of exclusively asexual species is often attributed to Muller's Ratchet. This supposes that because asexual populations cannot recreate individuals with fewer mutations than the currently least-loaded line, mutations will accumulate in such isolates. However, because the computer models that corroborate this theory have assumed isolate immortality, it is possible that mutations will accumulate only if there is "soft" selection acting on relative, rather than absolute, fitness. Here we, therefore, describe several models in which 200 asexual organisms randomly selected from an infinite population in genetic equilibrium under "hard" selection (acting through absolute fitness), were followed for 100 generations. When there were no limits to the fluctuations in population size, the deterministic distribution of mutations per individual was maintained for 100 (as well as for 200) generations. If population growth was limited by a proportional decrease in fertility of the whole isolate, then the isolates tended to become extinct. The rate of extinction was inversely related to maximum isolate size. When resource limitation at maximum population size had an extra deleterious effect on mutants, then isolates shed the mutant classes. Mutations accumulated (ad inifinitum) in immortal isolates whose population numbers were kept constant by proportionately increasing or decreasing each class's size whenever isolate size ? 200. Muller's Ratchet, therefore, operates only when mutations affect the outcome of intraspecific contests, but not the organisms' intrinsic ability to survive in the ecosystem. PMID- 28568837 TI - EGG COMPETITION IN A SEX-ROLE REVERSED PIPEFISH: SUBDOMINANT FEMALES TRADE REPRODUCTION FOR GROWTH. PMID- 28568838 TI - PHYLOGENETIC ANALYSES OF THE CORRELATED EVOLUTION OF CONTINUOUS CHARACTERS: A SIMULATION STUDY. AB - We use computer simulation to compare the statistical properties of several methods that have been proposed for estimating the evolutionary correlation between two continuous traits, and define alternative evolutionary correlations that may be of interest. We focus on Felsenstein's (1985) method and some variations of it and on several "minimum evolution" methods (of which the procedure of Huey and Bennett [1987] is a special case), as compared with a nonphylogenetic correlation. The last, a simple correlation of trait values across the tips of a phylogeny, virtually always yields inflated Type I error rates, relatively low power, and relatively poor estimates of evolutionary correlations. We therefore cannot recommend its use. In contrast, Felsenstein's (1985) method yields acceptable significance tests, high power, and good estimates of what we term the input correlation and the standardized realized evolutionary correlation, given complete phylogenetic information and knowledge of the rate and mode of character change (e.g., gradual and proportional to time ["Brownian motion"] or punctuational, with change only at speciation events). Inaccurate branch length information may affect any method adversely, but only rarely does it cause Felsenstein's (1985) method to perform worse than do the others tested. Other proposed methods generally yield inflated Type I error rates and have lower power. However, certain minimum evolution methods (although not the specific procedure used by Huey and Bennett [1987]) often provide more accurate estimates of what we term the unstandardized realized evolutionary correlation, and their use is recommended when estimation of this correlation is desired. We also demonstrate how correct Type I error rates can be obtained for any method by reference to an empirical null distribution derived from computer simulations, and provide practical suggestions on choosing an analytical method, based both on the evolutionary correlation of interest and on the availability of branch lengths and knowledge of the model of evolutionary change appropriate for the characters being analyzed. Computer programs that implement the various methods and that will simulate (correlated) character evolution along a known phylogeny are available from the authors on request. These programs can be used to test the effectiveness of any new methods that might be proposed, and to check the generality of our conclusions with regard to other phylogenies. PMID- 28568839 TI - MOLECULAR EVIDENCE FOR HOMOPLOID RETICULATE EVOLUTION AMONG AUSTRALIAN SPECIES OF GOSSYPIUM. AB - Interspecific hybridization and introgression are important evolutionary processes in plants, but their full significance with respect to speciation at the diploid level remains unresolved. In this study, molecular markers from the plastid and nuclear genomes were used to document an unusual evolutionary history of Gossypium bickii Prokh. (Malvaceae). This species is one of three morphologically similar Australian cottons (along with G. austrate F. Muell. and G. nelsonii Fryx.) in section Hibiscoidea. In contrast to expectations based on previous morphological data, cladistic analysis of maternally inherited cpDNA restriction site mutations unites G. bickii with G. sturtianum J. H. Willis, a morphologically distant species in a different taxonomic section (Sturtia). Few restriction site mutations distinguish the plastomes of G. bickii and G. sturtianum, but these two cpDNAs are differentiated from those of G. australe and G. nelsonii by a minimum of 33 mutations (out of 640 sites scored). These two highly distinct clades are not supported by phylogenetic analyses of allozyme markers (from 58 populations) and restriction site mutations in nuclear ribosomal DNAs. Rather, phylogenies based on 83 nuclear markers indicate that G. bickii shares a more recent common ancestor with G. australe and G. nelsonii than it does with G. sturtianum. We suggest that the striking discrepancy between independent molecular phylogenies from two different genomes indicates a biphyletic ancestry of G. bickii. Our preferred hypothesis involves an ancient hybridization, in which G. sturtianum, or a similar species, served as the maternal parent with a paternal donor from the lineage leading to G. australe and G. nelsonii. Because we detected no G. sturtianum nuclear genes in G. bickii, we suggest that the nuclear genomic contribution of the maternal parent was subsequently eliminated from the hybrid or its descendent maternal lineage. Several possible mechanisms of cytoplasm transfer are suggested, including repeated backcrossing of the hybrid, as female, into the paternal donor lineage, selection against recombinant nuclear genomes and a form of apomixis known as semigamy. This example, and several others in Gossypium as well as other genera, attest to the evolutionary possibility of interspecific cytoplasmic transfer, and perhaps the origin of diploid species via reticulate speciation. In addition, this study offers an example of natural cytoplasmic introgression without long term survival of nuclear genes from the maternal progenitor. PMID- 28568841 TI - Thin, High-Flux, Self-Standing, Graphene Oxide Membranes for Efficient Hydrogen Separation from Gas Mixtures. AB - The preparation and gas-separation performance of self-standing, high-flux, graphene oxide (GO) membranes is reported. Defect-free, 15-20 MUm thick, mechanically stable, unsupported GO membranes exhibited outstanding gas separation performance towards H2 /CO2 that far exceeded the corresponding 2008 Robeson upper bound. Remarkable separation efficiency of GO membranes for H2 and bulky C3 or C4 hydrocarbons was achieved with high flux and good selectivity at the same time. On the contrary, N2 and CH4 molecules, with larger kinetic diameter and simultaneously lower molecular weight, relative to that of CO2 , remained far from the corresponding H2 /N2 or H2 /CH4 upper bounds. Pore size distribution analysis revealed that the most abundant pores in GO material were those with an effective pore diameter of 4 nm; therefore, gas transport is not exclusively governed by size sieving and/or Knudsen diffusion, but in the case of CO2 was supplemented by specific interactions through 1) hydrogen bonding with carboxyl or hydroxyl functional groups and 2) the quadrupole moment. The self standing GO membranes presented herein demonstrate a promising route towards the large-scale fabrication of high-flux, hydrogen-selective gas membranes intended for the separation of H2 /CO2 or H2 /alkanes. PMID- 28568840 TI - Characterization of a deletion in the Hsp70 cluster in the bovine reference genome. AB - The 70 kilodalton heat shock proteins (Hsp70) are highly conserved molecular chaperones which have a crucial role in the stress response of the cell. In mammals, the Hsp70 proteins are encoded by a cluster of three genes: HSPA1A, HSPA1B and HSPA1L. In bovines, this cluster is located on chromosome 23 downstream of the major histocompatibility complex (BoLA). We detected inconsistencies in the location of markers on the Hsp70 genes reported in the literature that pointed to a potential deletion in the bovine reference genome UMD 3.1.1. An in silico analysis of the bovine genomic region of the Hsp70 cluster, using available information from public databases, confirmed the existence of a deletion of 11.1-kb spanning the HSPA1B gene and the intergenic region between HSPA1B and HSPA1A. Although we originally considered this an assembly error, it is most likely a particular condition of L1 Dominette 01449, the cow sequenced in the Bovine Genome Project. Moreover, we suggest a new classification of bovine Hsp70 sequences reported in NCBI and a reassignment of the location of SNPs from dbSNP that map to the deletion on BTA23. We also compared the location of selected transcription factor binding sites on the promoters of HSPA1A and HSPA1B. The results generated in the present work could be helpful to refine the reference genome of an important livestock species and also to understand the role and the regulation of the bovine Hsp70 genes. PMID- 28568842 TI - Cardiac tamponade in myelofibrosis: A Mayo clinic series of nine consecutive cases. PMID- 28568843 TI - Is there additional value attached to health gains at the end of life? A revisit. AB - Researchers have in recent years sought to establish whether the general public value treatment at the end of life (EOL) more highly than other treatments. Results are mixed, with social preferences most often exhibiting lack of preferences for EOL treatments. This null result may be driven by the often applied study design, where respondents are to choose between treatments targeting patients with varying fixed life expectancies. When remaining life is certain and salient, a rule-of-rescue sentiment may drive preferences across all scenarios. This study presents a different design, where the comparator is a preventive intervention. We study preferences from both an individual and social perspective and find no preference for an EOL premium. PMID- 28568844 TI - Effect of sampling on BACE-1 ligands binding free energy predictions via MM-PBSA calculations. AB - The BACE-1 enzyme is a prime target to find a cure to Alzheimer's disease. In this article, we used the MM-PBSA approach to compute the binding free energies of 46 reported ligands to this enzyme. After showing that the most probable protonation state of the catalytic dyad is mono-protonated (on ASP32), we performed a thorough analysis of the parameters influencing the sampling of the conformational space (in total, more than 35 MUs of simulations were performed). We show that ten simulations of 2 ns gives better results than one of 50 ns. We also investigated the influence of the protein force field, the water model, the periodic boundary conditions artifacts (box size), as well as the ionic strength. Amber03 with TIP3P, a minimal distance of 1.0 nm between the protein and the box edges and a ionic strength of I = 0.2 M provides the optimal correlation with experiments. Overall, when using these parameters, a Pearson correlation coefficient of R = 0.84 (R2 = 0.71) is obtained for the 46 ligands, spanning eight orders of magnitude of Kd (from 0.017 nm to 2000 MUM, i.e., from -14.7 to 3.7 kcal/mol), with a ligand size from 22 to 136 atoms (from 138 to 937 g/mol). After a two-parameter fit of the binding affinities for 12 of the ligands, an error of RMSD = 1.7 kcal/mol was obtained for the remaining ligands. (c) 2017 Wiley Periodicals, Inc. PMID- 28568846 TI - ADDENDUM. PMID- 28568845 TI - THE POLYTYPIC SPECIES REVISITED: GENETIC DIFFERENTIATION AND MOLECULAR PHYLOGENETICS OF THE TIGER SALAMANDER AMBYSTOMA TIGRINUM (AMPHIBIA: CAUDATA) COMPLEX. AB - We present a phylogenetic analysis of the Ambystoma tigrinum complex, based on approximately 840 base pairs of mitochondrial-DNA sequence from the rapidly evolving D-loop and an adjacent intron. Our samples include populations of the continentally distributed species, A. tigrinum, plus all described species of Mexican ambystomatids. Sequence divergence is low, ranging from 0-8.5%, and most phylogenetic groupings are weakly supported statistically. We identified eight reasonably well-defined clades from the United States and Mexico, with the geographically isolated A. californiense from California as the probable sister group to the remaining taxa. Our sequence data are not capable of resolving the relationships among these clades, although the pattern of transitional-site evolution suggests that these eight lineages diverged during a period of rapid cladogenesis. We roughly calibrate a molecular clock and identify a few lineages that significantly deviate from the slow, baseline rate of 0.5-0.75% per million years. Our data also suggest that species boundaries for several U.S. and Mexican species need to be altered and that the concept of a continentally distributed, polytypic tiger salamander is not valid. PMID- 28568847 TI - GENETIC CONSTRAINTS ON LIFE-HISTORY EVOLUTION: QUANTITATIVE-TRAIT LOCI INFLUENCING GROWTH AND FLOWERING IN ARABIDOPSIS THALIANA. AB - We have mapped genes causing life-history trade-offs, and they behave as predicted by ecological theory. Energetic and quantitative-genetic models suggest a trade-off between age and size at first reproduction. Natural selection favored plants that flower early and attain large size at first reproduction. Response to selection was opposed by a genetic trade-off between these two components of fitness. Two quantitative-trait loci (QTLs) influencing flowering time were mapped in a recombinant inbred population of Arabidopsis. These QTLs also influenced size at first reproduction, but did not affect growth rate (resource acquisition). Substitutions of small chromosomal segments, which may represent allelic differences at flowering time loci, caused genetic trade-offs between life-history components. One QTL explained 22% of the genetic variation in flowering time. It is within a few centiMorgans (cM) of the gigantea (GI) locus, and may be allelic with GI. Sixteen percent of the genetic variation was explained by another QTL, FDR1, near 18 cM on chromosome II, which does not correspond to any previously identified flowering-time locus. These life-history genes regulate patterns of resource allocation and life-history trade-offs in this population. PMID- 28568848 TI - NESTMATE RELATEDNESS IN A COMMUNAL BEE, PERDITA TEXANA (HYMENOPTERA: ANDRENIDAE), BASED ON DNA FINGERPRINTING. AB - Perdita texana is a facultatively communal bee species with up to 28 females per nest. We used multilocus DNA fingerprinting to test the hypothesis that nestmates are more closely related to each other than are nonnestmates. The mean band sharing proportion among pairwise nestmate comparisons did not differ significantly from the mean among nonnestmate comparisons [P = 0.787 (df = 484)]. Although mean band sharing proportions did not differ among nestmates and nonnestmates, some nestmates show very high band sharing proportions (in excess of the upper 95% confidence limit for the nonnestmate mean). These individuals almost certainly are related, probably as half-sib sisters, however, they comprise a very small percentage of the nestmate populations. Our results indicate that kin selection is unlikely to play an important role in the evolution and maintenance of communal nesting. Communal societies most likely arise because of the mutualistic benefits of cooperative nesting, including accelerated nest founding and improved nest defense. PMID- 28568849 TI - PHENOTYPIC PLASTICITY IN AN INTERTIDAL SNAIL: THE ROLE OF A COMMON CRAB PREDATOR. PMID- 28568850 TI - FERTILITY SELECTION ON A DISCRETE FLORAL POLYMORPHISM IN CLARKIA (ONAGRACEAE). AB - This study investigated fertility selection on a flower petal pigmentation polymorphism in Clarkia gracilis ssp. sonomensis. Natural populations are typically composed of nearly 100% spotted-petal plants, although rare populations contain a majority of unspotted plants. I compared fitness values for the two morphs using a simple fertility model to estimate selection for experimental arrays of plants placed into existing populations of different phenotypic frequencies. Both male and female reproductive success were estimated as well as the pattern of mating among phenotypes. Although the separate fitness components varied from no differences to a strong advantage for spotted plants, for every situation the selection calculations predicted an increase in the frequency of the spotted allele. Pollinator behavior and postpollination mechanisms may be responsible for the fitness differences. The apparent inability of the unspotted allele to spread though most natural populations is consistent with its selective disadvantage in this study. PMID- 28568851 TI - EVOLUTIONARY LOSS OF LARVAL FEEDING: DEVELOPMENT, FORM AND FUNCTION IN A FACULTATIVELY FEEDING LARVA, BRISASTER LATIFRONS. AB - Species with large eggs and nonfeeding larvae have evolved many times from ancestors with smaller eggs and feeding larvae in numerous groups of aquatic invertebrates and amphibians. This change in reproductive allocation and larval form is often accompanied by dramatic changes in development. Little is known of this transformation because the intermediate form (a facultatively feeding larva) is rare. Knowledge of facultatively feeding larvae may help explain the conditions under which nonfeeding larvae evolve. Two hypotheses concerning the evolutionary loss of larval feeding are as follows: (1) large eggs evolve before modifications in larval development, and (2) the intermediate form (facultatively feeding larva) is evolutionarily short-lived. I show that larvae of a heart urchin, Brisaster latifrons, are capable of feeding but do not require food to complete larval development. Food for larvae appears to have little effect on larval growth and development. The development, form, and suspension feeding mechanism of these larvae are similar to those of obligate-feeding larvae of other echinoids. Feeding rates of Brisaster larvae are similar to cooccurring, obligate-feeding echinoid larvae but are low relative to the large size of Brisaster larvae. The comparison shows that in Brisaster large egg size, independence from larval food, and relatively low feeding rate have evolved before the heterochronies and modified developmental mechanisms common in nonfeeding echinoid larvae. If it is general, the result suggests that hypotheses concerning the origin of nonfeeding larval development should be based on ecological factors that affect natural selection for large eggs, rather than on the evolution of heterochronies and developmental novelties in particular clades. I also discuss alternative hypotheses concerning the evolutionary persistence of facultative larval feeding as a reproductive strategy. These hypotheses could be tested against a phylogenetic hypothesis. PMID- 28568852 TI - GLOBAL MITOCHONDRIAL DNA PHYLOGEOGRAPHY OF HOLARCTIC BREEDING DUNLINS (CALIDRIS ALPINA). AB - Comparison of mitochondrial DNA (mtDNA) control-region sequences of 155 dunlins from 15 breeding populations confirmed the existence of five major phylogeographic groups in the circumpolar breeding range of this migratory shorebird species. Time estimates of the origin of groups, based on sequence divergences and a molecular clock for birds, suggest a scenario of repeated fragmentation of populations in isolated tundra refugia during the late Pleistocene. The distribution of about three-quarters of all detected molecular variance between phylogeographic groups attests to the strongly subdivided genetic population structure in dunlins that is being maintained by natal philopatry. Each mtDNA phylogeographic group can be related to a morphometrically defined subspecies, but several other recognized subspecies are not supported by monophyletic mtDNA lineages within their purported ranges. More detailed analysis of several European populations reveals low amounts of gene flow and the partitioning of a substantial fraction of molecular variance between them. This ongoing evolution of population-genetic structuring within the European phylogeographic group most likely started with the last retreat of the ice sheets some 10,000 years ago. Dunlins thus provide one of the clearest examples of the linkage between historical and contemporary components of mtDNA phylogeographic structuring in birds. PMID- 28568853 TI - GEOGRAPHICAL VARIATION IN THE INBREEDING DEPRESSION OF SCOTS PINE. AB - The magnitude of inbreeding depression caused by recessive mutations in a population is dependent on the mutation rate and on the intensity of selection against the mutations. We studied geographical differences in the level of early inbreeding depression of Scots pine in a common garden experiment. The mean abortion rate of experimentally self-pollinated seeds was significantly lower (75.4%) among trees that originated from northern populations (66-69 degrees N) than among trees from more southern (60-62 degrees N) populations (86.5%). Thus, the number of embryonic lethal equivalents was lower in the northern populations (4.5) than in the southern ones (6.9). The outcrossing rate at the mature seed stage was slightly lower in the northern populations (average 0.93) than in the southern one (0.99). The estimated selfing rate at the zygote stage varied from 0 0.28 in the populations. The reduction in the magnitude of inbreeding depression in the north may have been caused by increased levels of self-fertilization in the northern populations. The proportion of self-fertilized seedlings and adults was very small in all populations (F ~ 0), indicating high inbreeding depression also in later life stages. The high level of inbreeding depression in the partially selfing Scots pine can be explained by mutation-selection balance only if the mutation rate is high. PMID- 28568854 TI - SEQUENTIAL RADIATIONS AND PATTERNS OF SPECIATION IN THE HAWAIIAN CRICKET GENUS LAUPALA INFERRED FROM DNA SEQUENCES. AB - The tremendous diversity of endemic Hawaiian crickets is thought to have originated primarily through intraisland radiations, in contrast to an interisland mode of diversification in the native Hawaiian Drosophila. The Hawaiian cricket genus Laupala (family Gryllidae) is one of several native genera of flightless crickets found in rain-forest habitat across the Hawaiian archipelago. I examined the phylogenetic relationships among mitochondrial DNA (mtDNA) sequences sampled from 17 species of Laupala, including the 12S ribosomal RNA (rRNA), transfer RNA (RNA)val and 16S rRNA regions. The distribution of mtDNA variants suggests that species within Laupala are endemic to single islands. The phylogenetic estimate produced from both maximum likelihood and maximum parsimony supports the hypothesis that speciation in Laupala occurred mainly within islands. The inferred biogeographical history suggests that diversification in Laupala began on Kauai, the oldest rain-forested Hawaiian island. Subsequently, colonization to younger islands in the archipelago resulted in a radiation of considerable phylogenetic diversity. Phylogenetic patterns in mtDNA are not congruent with prior systematic or taxonomic hypotheses. Hypotheses that may explain the conflict between the phylogenetic patterns of mtDNA variation and the species taxonomy are discussed. PMID- 28568855 TI - RESOURCE-ASSOCIATED POPULATION SUBDIVISION IN A SYMBIOTIC CORAL-REEF SHRIMP. AB - The importance of sympatric speciation remains controversial. An empirical observation frequently offered in its support is the occurrence of sister taxa living in sympatry but using different resources. To examine the possibility of sympatric differentiation in producing such cases, I measured genetic, behavioral, and demographic differentiation between populations of the tropical sponge-dwelling shrimp Synalpheus brooksi occupying two alternate host species on three reefs in Caribbean Panama. This species belongs to an apparently monophyletic group of >= 30 species of mostly obligate, host-specific sponge dwellers, many of which occur in sympatry. Demographic data demonstrated the potential for disruptive selection imposed by the two host species: shrimp demes from the sponge Agelas clathrodes were consistently denser, poorer in mature females, more heavily parasitized by branchial bopyrid isopods, and less parasitized by thoracic isopods, than conspecific shrimp from the sponge Spheciospongia vesparium. Laboratory assays demonstrated divergence in host preference: shrimp on all three reefs tended to choose their native sponge species more often than did conspecific shrimp from the other host. Because S. brooksi mates within the host, this habitat selection should foster assortative mating by host species. A hierarchical survey of protein-electrophoretic variation also supported host-mediated divergence, revealing the following: (1) shrimp from the two hosts are conspecific, as evidenced by absence of fixed allelic differences at any of nine allozyme loci scored; (2) strong genetic subdivision among populations of this philopatric shrimp on reefs separated by 1 3 km; and (3) significant host-associated genetic differentiation within two of the three reefs. Finally, intersexual aggression (a proxy for mating incompatibility) between shrimp from different host species was significantly elevated on the one reef where host-associated genetic differences were strongest, demonstrating concordance between genetic and behavioral estimates of divergence. Adjacent reefs appear to be semi-independent sites of host-associated differentiation, as evidenced by differences in the degree of host-associated behavioral and genetic differentiation, and in the specific loci involved, on different reefs. In philopatric organisms with highly subdivided populations, such as S. brooksi, resource-associated differentiation can occur independently in different populations, thus providing multiple "experiments" in differentiation and resulting in a mosaic pattern of polymorphism as reflected by neutral genetic markers. Several freshwater fishes, an amphipod, and a snail similarly show independent but remarkably convergent patterns of resource associated divergence in different conspecific populations, often in the absence of obvious spatial barriers. In each case, substantial differentiation has occurred in the face of continuing gene flow. PMID- 28568856 TI - MOLECULAR GENETIC EVIDENCE FOR PARALLEL LIFE-HISTORY EVOLUTION WITHIN A PACIFIC SALMON (SOCKEYE SALMON AND KOKANEE, ONCORHYNCHUS NERKA). AB - The Pacific salmon Oncorhynchus nerka typically occurs as a sea-run form (sockeye salmon) or may reside permanently in lakes (kokanee) thoughout its native North Pacific. We tested whether such geographically extensive ecotypic variation resulted from parallel evolutionary divergence thoughout the North Pacific or whether the two forms are monophyletic groups by examining allelic variation between sockeye salmon and kokanee at two minisatellite DNA repeat loci and in mitochondrial DNA (mtDNA) Bgl II restriction sites. Our examination of over 750 fish from 24 populations, ranging from Kamchatka to the Columbia River, identified two major genetic groups of North Pacific O. nerka: a "northwestern" group consisting of fish from Kamchatka, western Alaska, and northwestern British Columbia, and a "southern" group consisting of sockeye salmon and kokanee populations from the Fraser and Columbia River systems. Maximum-likelihood analysis accompanied by bootstrapping provided strong support for these two genetic groups of O. nerka; the populations did not cluster by migratory form, but genetic affinities were organized more strongly by geographic proximity. The two major genetic groups resolved in our study probably stem from historical isolation and dispersal of O. nerka from two major Wisconsinan glacial refugia in the North Pacific. There were significant minisatellite DNA allele frequency differences between sockeye salmon and kokanee populations from different parts of the same watershed, between populations spawning in different tributaries of the same lake, and also between sympatric populations spawning in the same stream at the same time. MtDNA Bgl II restriction site variation was significant between sockeye salmon and kokanee spawning in different parts of the same major watershed but not between forms spawning in closer degrees of reproductive sympatry. Patterns of genetic affinity and allele sharing suggested that kokanee have arisen from sea-run sockeye salmon several times independently in the North Pacific. We conclude that sockeye salmon and kokanee are para- and polyphyletic, respectively, and that the present geographic distribution of the ecotypes results from parallel evolutionary origins of kokanee from sockeye (divergences between them) thoughout the North Pacific. PMID- 28568857 TI - ERRATUM. PMID- 28568858 TI - THE EFFECT OF A VARIABLE ENVIRONMENT ON THE GENETIC CORRELATION STRUCTURE IN A FIELD CRICKET. AB - The evolutionary trajectory of a trait depends not only on the presence of genetic variation, but also on the pattern of genetic correlations (rg ) among traits. Genetic correlations are most easily measured under homogeneous, controlled laboratory conditions, whereas natural populations typically experience a higher degree of environmental variability. The effect of environmental variability on genetic correlations in the cricket, Gryllus pennsylvanicus, was studied by measuring genetic correlations within and between two environments differing in levels of environmental heterogeneity. Within environment rg among morphological traits measured in the homogeneous laboratory environment were found to be reliable predictors of rg measured in the experimental field environment. Laboratory measures of rg involving life-history traits, though, were not found to reflect the same correlations measured in the heterogeneous environment. A significant negative genetic correlation between fecundity and developmental time was found in the field environment, yet was not detectable when measured in the laboratory. Phenotypic correlations may be obtained much more easily than genetic correlations, but their usefulness in evolutionary inference depends on the pattern of similarity between the two correlations. A comparison of genetic and phenotypic correlations revealed a close match between the two measures for morphological traits, but revealed only broad similarities when considering life-history traits. Male-female genetic correlations between morphological traits were high (all rg > 0.73) and were consistently higher in the field environment than in the laboratory. The genetic correlations between the sexes in developmental time followed the same trend, but the male-female genetic correlation of gonad weights was low in both environments. Across-environment correlations were found to be strong for morphological traits and for gonad weight, whereas the genetic expression of developmental time was found to be dependent on the environment in which the crickets were raised. PMID- 28568859 TI - HERITABILITY OF WING LENGTH IN NATURE FOR THE MILKWEED BUG, ONCOPELTUS FASCIATUS. PMID- 28568860 TI - EVOLUTION OF THE MAGNITUDE AND TIMING OF INBREEDING DEPRESSION IN PLANTS. AB - Estimates of inbreeding depression obtained from the literature were used to evaluate the association between inbreeding depression and the degree of self fertilization in natural plant populations. Theoretical models predict that the magnitude of inbreeding depression will decrease with inbreeding as deleterious recessive alleles are expressed and purged through selection. If selection acts differentially among life history stages and deleterious effects are uncorrelated among stages, then the timing of inbreeding depression may also evolve with inbreeding. Estimates of cumulative inbreeding depression and stage-specific inbreeding depression (four stages: seed production of parent, germination, juvenile survival, and growth/reproduction) were compiled for 79 populations (using means of replicates, N = 62) comprising 54 species from 23 families of vascular plants. Where available, data on the mating system also were collected and used as a measure of inbreeding history. A significant negative correlation was found between cumulative inbreeding depression and the primary selfing rate for the combined sample of angiosperms (N = 35) and gymnosperms (N = 9); the correlation was significant for angiosperms but not gymnosperms examined separately. The average inbreeding depression in predominantly selfing species (delta = 0.23) was significantly less (43%) than that in predominantly outcrossing species (delta = 0.53). These results support the theoretical prediction that selfing reduces the magnitude of inbreeding depression. Most self fertilizing species expressed the majority of their inbreeding depression late in the life cycle, at the stage of growth/reproduction (14 of 18 species), whereas outcrossing species expressed much of their inbreeding depression either early, at seed production (17 of 40 species), or late (19 species). For species with four life stages examined, selfing and outcrossing species differed in the magnitude of inbreeding depression at the stage of seed production (selfing delta = 0.05, N = 11; outcrossing delta = 0.32, N = 31), germination (selfing delta = 0.02, outcrossing delta = 0.12), and survival to reproduction (selfing delta = 0.04, outcrossing delta = 0.15), but not at growth and reproduction (selfing delta = 0.21, outcrossing delta = 0.27); inbreeding depression in selfers relative to outcrossers increased from early to late life stages. These results support the hypothesis that most early acting inbreeding depression is due to recessive lethals and can be purged through inbreeding, whereas much of the late acting inbreeding depression is due to weakly deleterious mutations and is very difficult to purge, even under extreme inbreeding. PMID- 28568861 TI - SHORT-TERM EVOLUTION IN THE SIZE AND SHAPE OF PEA APHIDS. AB - Phenotypic evolution in contemporary populations can generally be witnessed only when novel selective forces produce rapid evolution. Examples of conditions that have led to rapid evolution include drastic environmental change, invasion of a new predator, or a host-range expansion. In cyclical parthenogens, however, yearly cycles of phenotypic evolution may occur due to the loss of adaptation during recombination in the sexual phase (genetic slippage), permitting an opportunity to observe adaptive evolutionary change in contemporary populations that are not necessarily subject to new patterns of natural selection. In insect herbivores, comparative studies suggest that morphological features that aid individuals in remaining on the plant or exploiting it as a food source are likely targets for selection. Here, we estimated the genetic variability of morphological traits in a cyclical parthenogen, the pea aphid (Acyrthosiphon pisum), to determine the potential for their evolution and we tested the hypothesis that size and/or shape evolves by clonal selection during one season of parthenogenetic reproduction. Genetic variation in a set of morphological traits was estimated using laboratory-reared descendents of clones collected from a single alfalfa field in May 1988 and April 1989 (henceforth, the "early" collections). In both years, there was significant clonal heritability early in the season both for overall morphology and for several individual aspects of size and shape. Because the course of short-term evolutionary change in the multivariate phenotype is a function of patterns of genetic covariance among characters, genetic correlations between size and 12 shape variables were also estimated for these early collections. A comparison between the mean phenotype of each early collection and that of a corresponding "late" collection made from the same field seven to eight clonal generations later in the same years revealed qualitatively similar changes in the average multivariate morphological phenotypes between the time periods in both years, although the difference was only significant for the 1989 samples. The pattern of genetic correlations that we estimated early in the 1989 season between overall size and various shape variables suggests that the observed short-term evolutionary changes in shape could have been due to natural selection acting only to increase overall size. We tested this hypothesis by estimating selection on size using a separate data set in which both demographic and morphological variables were measured on individuals reared under field conditions. Highly significant regressions of individual relative fitness on size were found for two major fitness components. Thus, it is likely that the evolutionary change in morphology that we observed is attributable to natural selection, possibly acting primarily through body size. A shift back to smaller size between the late 1988 and early 1989 collections from the same field suggests that either a cost of recombination or opposing selective forces during overwintering may produce persistent yearly cycles of morphological evolution in this cyclically parthenogenetic species. PMID- 28568862 TI - COMPARATIVE PHYLOGEOGRAPHY IN NORTH AMERICAN BIRDS. AB - Modern molecular methods yield descriptions of the phylogenetic deployment of genetic variation within species, or phylogeography. A developing field is the comparison of geographic patterns of genetic variation in codistributed species, or comparative phylogeography. One determines whether species that currently share the same broad area exhibit congruent phylogeographic patterns, which would indicate that they were historically codistributed and differentiated in response to same geological or environmental events. I reviewed studies of mitochondrial DNA (mtDNA) variation in five codistributed, widespread species of North American birds. In addition to phylogeographic patterns, data were available on levels of genetic variation, gene flow, and evolutionary distance from common ancestors (an index of a species' relative age) for each species, all important factors involved in geographic differentiation. Two species, Canada goose (Branta canadensis) and fox sparrow (Passerella iliaca), exhibited incongruent phylogeographic patterns of mtDNA variation, whereas three other codistributed species, the song sparrow (Melospiza melodia), chipping sparrow (Spizella passerina), and red-winged blackbird (Agelaius phoeniceus), lacked geographically structured mtDNA patterns. Thus, the first two species have had demonstrably different histories, whereas the histories of the latter three are speculative. However, the three species without geographic variation in mtDNA exhibit shallow mtDNA haplotype trees, which are consistent with recent population expansion. Thus, lack of geographic variation in mtDNA is likely due to these three species arriving relatively recently at their current distributions, and after historical isolating events produced genetic divisions in the fox sparrow and Canada goose. Within the geographically uniform species, or parts thereof, dispersal seems a likely homogenizing factor; no consistent explanations emerged from consideration of levels of genetic variation. Lack of congruent phylogeographic patterns suggests that currently codistributed species have not had a long history of co association. These results and comparison of other North American species for which less extensive mtDNA surveys are available, reveal that the North American avifauna is probably a composite of species with different histories. PMID- 28568863 TI - THE RESPONSE TO DIFFERING SELECTION ON PLANT PHYSIOLOGICAL TRAITS: EVIDENCE FOR LOCAL ADAPTATION. AB - Understanding adaptive evolution to differing environments requires studies of genetic variances, of natural selection, and of the genetic differentiation between populations. Plant physiological traits such as leaf size and water-use efficiency (the ratio of carbon gained per water lost) have been suggested by physiological plant ecologists to be important in local adaptation to environments differing in water availability. In this study, I raised families of Cakile edentula var lacustris derived from a wet-site population and a dry-site population in a common greenhouse environment to determine the degree of genetic differentiation between the two populations and the genetic architecture of the traits. The dry-site population had significantly smaller leaf size and significantly greater water-use efficiency than the wet-site population. I used a retrospective selection analysis to compare long-term selection inferred from these results to measures of phenotypic selection from a field experiment. Both direct measures in the field and the retrospective selection gradients were consistent with the hypothesis that greater water-use efficiency and smaller leaves were adaptive in drier environments. Though the correlation between population means for water-use efficiency and leaf size was negative, the genetic correlation within populations between water-use efficiency and leaf size was positive and thus would be expected to constrain the evolutionary response to selection. PMID- 28568864 TI - GENETICS OF MIMICRY IN THE TIGER SWALLOWTAIL BUTTERFLIES, PAPILIO GLAUCUS AND P. CANADENSIS (LEPIDOPTERA: PAPILIONIDAE). AB - The tiger swallowtail butterfly, Papilio glaucus, exhibits a female-limited polymorphism for Batesian mimicry; the Canadian tiger swallowtail, Papilio canadensis, lacks the mimetic (dark) form entirely. The species hybridize to a limited extent where their ranges overlap. Field collections and censuses indicate that mimetic females occur throughout the range of P. glaucus but at lowest frequencies in populations at the latitudinal edges of its geographic range such as the southernmost part of Florida and along the entire northern edge of its distribution from Massachusetts to Minnesota. Frequencies of mimetic females have remained relatively stable over time. Inheritance of the mimetic form is controlled primarily by two interacting sex-linked loci. The typical matrilineal pattern of inheritance in P. glaucus can be explained by polymorphism at a Y-linked locus, b. Analysis of P. glaucus * P. canadensis crosses has also revealed an X-linked locus, s, which controls the expression of the mimetic phenotype. The P. canadensis allele, scan , suppresses the mimetic phenotype in hybrid and backcross females. Results from more than 12 yr of rearing tiger swallowtails, including interspecies hybrids, indicate that the absence of mimetic P. canadensis females is due to both a high frequency of the "suppressing" allele scan and low frequency of the black-pigment-determining b + allele. The frequency of scan (or other suppressing alleles of s) in P. glaucus populations outside the hybrid zone is low. Some males heterozygous at the s locus and some suppressed mimetic females occur within the hybrid zone. A simple genetic model predicts the frequency of daughters that differ in phenotype from their mothers. PMID- 28568865 TI - MORPHOMETRICS AND CLADISTICS: MEASURING PHYLOGENY IN THE SEA URCHIN ECHINOCARDIUM. AB - A phylogenetic approach to the study of evolutionary patterns is based on taxic homologies (synapomorphies). In contrast, the recognition of evolutionary processes (namely heterochronies) involves analysis of the entire morphology. Recent developments in geometric morphometry permit analysis of morphological similarities grounded in operational homologies. Such morphometric techniques are explored (1) at the level of evolutionary processes, and (2) as a complement in exploration of phylogenetic relationships. To examplify this, we perform a two part study of the ontogeny and phylogeny of the spatangoid sea urchin Echinocardium. First, a phylogenetic analysis of ten Recent species in the genus is performed on 18 informative characters of the test. Second, morphological divergences among the species are analyzed using procrustean (superimposition) methods based on 49 homologous points. An additive distance tree is built from a matrix of morphometric distances among adult specimens. This tree is fully congruent with the phyletic results. Ontogenetic processes are explored by inserting ontogenetic series into the analysis. A distance tree including the juvenile stages shows that the general evolutionary trend of the genus is peramorphic, but species-to-species comparisons attest that no general clinal trend exists. Our analysis emphasizes the importance of morphometric approaches in evolutionary studies (1) for the understanding of heterochronies; (2) to trace the morphological implications of phylogenetic patterns; and (3) to estimate the impact of homoplasies. PMID- 28568866 TI - ALLOZYME DIVERSITY AND GENETIC IDENTITY IN SCHIEDEA AND ALSINIDENDRON (CARYOPHYLLACEAE: ALSINOIDEAE) IN THE HAWAIIAN ISLANDS. AB - Genetic diversity of allozymes, genetic identity based on allozyme variability, and phylogenetic relationships were studied with respect to breeding system diversity, population size, and island age in 20 of the 29 species of Schiedea and Alsinidendron (Caryophyllaceae: Alsinoideae), a monophyletic lineage endemic to the Hawaiian Islands. Average levels of genetic variability in Schiedea and Alsinidendron were comparable to or higher than those found in other Hawaiian lineages for which equivalent data are available [Bidens, Tetramolopium, and the silversword alliance (Asteraceae: Madiinae)] and similar to average values for species of dicots. Allozyme variability was strongly dependent on breeding system, which varies widely in the Hawaiian Alsinoideae. Species with autogamous breeding systems showed very low variability, measured as the number of alleles per locus, percent polymorphic loci, and mean heterozygosity per locus. Outcrossing hermaphroditic and dimorphic species (those with gynodioecious, subdioecious, and dioecious breeding systems) showed significantly higher genetic variability. Small population size was associated with lower values for all measures of genetic variability. Nearly half of the species occurring in small populations are also autogamous; thus, both factors may have influenced levels of genetic variability in these species. Founder effect was apparent in one species (Schiedea adamantis), which occurs in a single large population, has a gynodioecious breeding system but a very low genetic variability. Island age appeared to have little effect on genetic variability. Slightly lower values of genetic variability for species occurring on Kaua'i and O'ahu result primarily from the occurrence of autogamous Alsinidendron species on those islands. Values for Nei's genetic identity for different species pairs were 0.201-0.942, a far greater range than in Bidens, the silversword alliance, and Tetramolopium. Using UPGMA clustering, there was only moderate support for relationships detected through cladistic analysis. Nei's unbiased genetic identity (I) was greatest among species with outcrossing breeding systems, which for the most part clustered together. Nei's genetic identities for self-fertilizing species were low, indicating that these species are less similar to one another and to outcrossing species, regardless of their affinities based on cladistic analysis. Parsimony analysis of allele frequency data supported two clades also found in phylogenetic analyses using morphological and molecular data. Clades recognized in parsimony analysis of allele frequencies were those lineages containing selfing species, indicating that conditions favoring fixation of alleles occurred in ancestral species. In contrast, maintenance of high genetic diversity in outcrossing species interferes with recognition of phylogenetic relationships using allozyme variability. PMID- 28568867 TI - THE EVOLUTION OF OVIPARITY WITH EGG GUARDING AND VIVIPARITY IN LIZARDS AND SNAKES: A PHYLOGENETIC ANALYSIS. AB - This paper investigates the evolution of viviparity and of egg guarding in lizards and snakes in which three modes of reproduction can be described: oviparity without egg guarding, oviparity with egg guarding, and viviparity. All possible transitions of reproductive modes were detected in each taxon using Maddison's method. We then tested two specific hypotheses. First, egg guarding can be regarded as an alternative to viviparity. A relatively frequent association of egg guarding and viviparous species in the same taxon may be due to similar environmental conditions or species characteristics leading to two different solutions. Second, egg guarding may facilitate the evolution of viviparity. This hypothesis is supported by the high frequency of viviparous species in taxa containing egg guarding species and by a tendency for prolonged uterine retention of eggs in brooding squamates. Our analyses demonstrate that the first hypothesis is the best supported. Egg guarding and viviparity most often evolved independently. If a major benefit of egg guarding is the repulsion of potential predators, size is one of the most obvious morphological characters that should be correlated with the evolution of reproductive modes. The two reproductive traits were correlated to a reduction in body size for viviparous species and an increase in body size for egg guarding species. This could partly explain why the evolution of these reproductive modes seems almost antagonist. PMID- 28568868 TI - ON THE ASSIGNMENT OF FITNESS VALUES IN STATISTICAL ANALYSES OF SELECTION. PMID- 28568870 TI - A TRADE-OFF FOR HOST PLANT UTILIZATION IN THE BLACK BEAN APHID, APHIS FABAE. AB - Many studies on insect herbivores have sought to find trade-offs between utilization of alternate host plants, both to understand the prevalence of specialization and to appreciate the likelihood of sympatric speciation due to disruptive selection. To date, few studies have found trade-offs. Seventy-seven clones of the black bean aphid, Aphis fabae, were collected from field sites in East Anglia, U.K., over an area of about 10,000 km2 . These clones exhibit a trade-off in fitness between two alternative hosts, broad bean and nasturtium. This pattern is maintained in the F2 generation. The predominance of broad bean in the area, the fact that clones were only sampled from one of these two hosts, and the absence of "master-of-all-trades" genotypes after recombination all point to the importance of antagonistic pleiotropy rather than linkage disequilibrium in maintaining this trade-off. It is concluded that this population presents strong evidence for a fundamental trade-off for host utilization. PMID- 28568869 TI - PARENTAL EFFECTS ON PROGENY PHENOTYPE IN PLANTS: DISTINGUISHING GENETIC AND ENVIRONMENTAL CAUSES. AB - The experimental measurement of additive genetic variation in plant populations is complicated by the potential for non-Mendelian inheritance. Maternal influences on progeny phenotype resulting from the cytoplasmic inheritance of plastids or RNA transcripts and effects of the maternal environment have consequently been the focus of much research. To exclude or to control for these sources of variation, breeding designs (e.g., cross-factored, nested, or diallel) in which genetically unrelated pollen donors are mated to maternal genotypes have been adopted. Using these designs, some empirical studies have detected statistically significant differences among pollen donors in the mean performance of their pollen (the mature male gametophytes) or in the mean phenotype of their progeny. These statistical effects of pollen-donor identity on pollen performance or progeny phenotype have frequently been interpreted as evidence for additive genetic variance among pollen donors, although patrilineal cytoplasmic inheritance or effects of the paternal environment on pollen performance or gene expression are recognized as alternative explanations. We note that environment specific selection among developing gametophytes-in which the environment experienced by developing pollen grains (or ovules) provides a selective force causing the differential survival of gametophyte genotypes (analagous to meiotic drive)-is an additional process that may cause genetically based paternal (or maternal) effects on gametophyte performance. If genes selected during this process are expressed in the sporophyte (postfertilization), this process could also influence the phenotype of the diploid progeny. Here, we review the potential causes of statistically significant differences in mean phenotype among the gametophytes or progeny of maternal (seed-bearing) or paternal (pollen donating) parental plants. We suggest an experimental approach that permits the detection or elimination of selection among developing gametophytes as one such cause. Specifically, the replication of homozygous parental genotypes within and across environments allows the detection and measurement of paternal and maternal environmentally induced effects on gametophyte or offspring phenotype, while eliminating meiotic drive as a source of the phenotypic variation. PMID- 28568871 TI - COMPLEX COLONY STRUCTURE IN SOCIAL INSECTS: II. REPRODUCTION, QUEEN-WORKER CONFLICT, AND LEVELS OF SELECTION. AB - Differences in colony structure between two populations of the forest ant, Myrmica punctiventris, have had dramatic consequences on allocation to growth and reproduction. A population in Vermont, in which colonies have a single, once mated queen, shows no evidence of inbreeding or population subdivision and has allocated 25% of sexual reproduction to males in two consecutive years. In contrast, for a population in New York that is facultatively polygynous, we have evidence of microgeographic genetic structure and inbreeding, and the populationwide allocation ratio was extremely male-biased. Additionally, the Vermont population allocated much more energy to sexual reproduction than did the New York population. Detailed analysis of data from the Vermont population, within which colonies undergo a seasonal cycle of expansion to multiple nesting sites (polydomy), gave strong evidence of queen-worker conflict over male allocation and indicated that workers are winning that conflict. Finally, we used contextual analysis to find that fertility selection operates almost exclusively at the level of the individual nest rather than at the higher level of the multinest colony. PMID- 28568872 TI - PRESUMPTIVE RAPID SPECIATION AFTER A FOUNDER EVENT IN A LABORATORY POPULATION OF NEREIS: ALLOZYME ELECTROPHORETIC EVIDENCE DOES NOT SUPPORT THE HYPOTHESIS. PMID- 28568873 TI - DIFFERING SELECTION ON PLANT PHYSIOLOGICAL TRAITS IN RESPONSE TO ENVIRONMENTAL WATER AVAILABILITY: A TEST OF ADAPTIVE HYPOTHESES. AB - I used phenotypic selection analysis to test the prediction from functional and comparative studies of plants that smaller leaves and more efficient water use are adaptive in drier environments. I measured selection gradients on leaf size and instantaneous water-use efficiency (a measure of carbon gain per unit water loss) in experimental populations of Cakile edentula var. lacustris placed into wet and dry environments in the field. Linear and nonlinear selection differed significantly between the two environments as predicted. Water-use efficiency was selected to be higher, and leaf area was selected toward a small intermediate optimum, in the dry environment. There was also significant positive correlational selection on water-use efficiency and leaf size, suggesting that the optimum leaf size in the dry environment is greater for plants with higher water-use efficiency. In contrast, neither leaf size nor water-use efficiency were selected in the wet environment, though larger leaves resulted in greater vegetative biomass. Path analysis of the linear selection gradients found that water-use efficiency affected plant fitness primarily because it increased vegetative biomass, as suggested by the hypotheses about the function of physiological traits. These results were not only consistent with the functional hypotheses but also with the observed genetic differentiation in water-use efficiency and leaf size between wet and dry site populations. PMID- 28568874 TI - PARALLEL RACE FORMATION AND THE EVOLUTION OF MIMICRY IN HELICONIUS BUTTERFLIES: A PHYLOGENETIC HYPOTHESIS FROM MITOCHONDRIAL DNA SEQUENCES. AB - Mimicry has been a fundamental focus of research since the birth of evolutionary biology yet rarely has been studied from a phylogenetic perspective beyond the simple recognition that mimics are not similar due to common descent. The difficulty of finding characters to discern relationships among closely related and convergent taxa has challenged systematists for more than a century. The phenotypic diversity of wing pattens among mimetic Heliconius adds an additional twist to the problem, because single species contain more than a dozen radically different-looking geographical races even though the mimetic advantage is theoretically highest when all individuals within and between species appear the same. Mitochondrial DNA (mtDNA) offers an independent way to address these issues. In this study, Cytochrome Oxidase I and II sequences from multiple, parallel races of Heliconius erato and Heliconius melpomene are examined, to estimate intraspecific phylogeny and gauge sequence divergence and ages of clades among races within each species. Although phenotypes of sympatric races exhibit remarkable concordance between the two species, the mitochondrial cladograms show that the species have not shared a common evolutionary history. H. erato exhibits a basal split between trans- and cis-Andean groups of races, whereas H. melpomene originates in the Guiana Shield. Diverse races in either species appear to have evolved within the last 200,000 yr, and convergent phenotypes have evolved independently within as well as between species. These results contradict prior theories of the evolution of mimicry based on analysis of wing-pattern genetics. PMID- 28568875 TI - COMPUTER-SIMULATED SHELL SIZE AND SHAPE VARIATION IN THE CARIBBEAN LAND SNAIL GENUS CERION: A TEST OF GEOMETRICAL CONSTRAINTS. AB - A computer graphical model of gastropod shell form is used to test a hypothesis of geometric constraint proposed to explain the disjunct distribution of shell forms observed in Cerion, a species-rich and geometrically varied genus of terrestrial gastropods. The mapping of computer-simulated forms into a morphospace of Cerion shells produces a continuum of sizes and shapes. Therefore, the absence of particular shell forms is not explained by geometric constraints. Two proposed modes of shell morphogenesis at extreme ranges in size ("dwarfs" and "giants") previously were thought to be exclusive routes to the construction of high-spired ("smokestack") forms. The present study shows that there are, in fact, multiple routes of transformation. In addition, these routes are geometrically reversible and interconnect the members of the shell-form continuum. Thus, the possible pathways followed during the course of evolution within this genus cannot be determined until an adequate phylogenetic hypothesis has been proposed. PMID- 28568876 TI - CONDUCTING PHYLOGENETIC COMPARATIVE STUDIES WHEN THE PHYLOGENY IS NOT KNOWN. AB - A method is proposed to conduct phylogenetic analyses of comparative or interspecific data when the true phylogeny is not known. Standard models of speciation and/or extinction or other methods are used to generate a sample from the set of all possible phylogenies for the measured species. The comparative data are then analyzed on each of the possible trees to obtain a distribution of possible evolutionary statistics for these data. The mean of this distribution is proposed as a reasonable estimate of the true evolutionary statistic of interest. Ways of obtaining confidence intervals and of developing hypothesis tests for this mean statistic are also proposed. The method can be used with any comparative method or phylogenetic analysis technique when phylogenetic relationships among species are not known or when branch lengths for a phylogeny in units of expected character change (as required by most methods) are not available. Computer programs to conduct the analyses are available on request. PMID- 28568877 TI - POPULATION STRUCTURE AND MORPH-SPECIFIC FITNESS DIFFERENCES IN TRISTYLOUS LYTHRUM SALICARIA. AB - In tristylous plant populations, style-morph frequencies are governed by an interaction between frequency-dependent selection due to disassortative mating and stochastic processes. Provided that there are no inherent fitness differences among morphs, frequency-dependent selection should result in equal morph frequencies at equilibrium. Stochastic models indicate that the short-styled morph has the highest and the long-styled morph the lowest probability of being lost from local populations as a result of random processes. We surveyed the morph composition of 82 populations of the tristylous, self-incompatible herb Lythrum salicaria in two archipelagos, one in central and one in northern Sweden, located close to the range-margin of the species. To examine whether deviations from even morph frequencies can be explained by among-morph differences in reproductive success, we quantified flower and seed production in six and three populations in the northern and southern archipelago, respectively, and we recorded segregation ratios in offspring produced in six trimorphic populations in the northern area. Seed germination and offspring growth were studied in the greenhouse. Ninety percent of the populations in the southern archipelago (N = 31) and 69% of the populations in the northern archipelago (N = 35) were trimorphic; the remaining populations were dimorphic (only populations consisting of at least three flowering plants considered). Dimorphic populations were smaller than trimorphic populations, as predicted by stochastic models. There was a striking difference in the morph composition of L. salicaria populations between the two archipelagos. In the southern archipelago, there was a slight excess of the long-styled morph and a corresponding deficiency of the short styled morph. In contrast, the northern populations were characterized by a marked deficiency of the mid-styled morph: the average frequency of the mid styled morph in trimorphic populations was 0.21, and nine of eleven dimorphic populations lacked the mid-styled morph. In both archipelagos, the long-styled morph (the most common morph) produced about 20% fewer seeds per fruit than the other morphs. The long-styled morph also tended to produce fewer seeds per plant. A hand-pollination experiment performed in two of the northern populations indicated that seed production per flower was pollen-limited in the long-styled morph but not in the other two morphs. Seed germination and offspring size after 24 weeks of growth did not differ among morphs. The mid-styled morph tended to have a higher representation in the offspring than in the parental generation in all six trimorphic populations studied further indicating that the deficiency of the mid-styled morph in the northern archipelago does not represent an equilibrium. Taken together, the results do not support the hypothesis that morph specific differences in reproductive success can account for deviations from even morph frequencies in L. salicaria. It is suggested that among-morph differences in other components of fitness and historical factors may contribute to the current morph structure. PMID- 28568878 TI - POSTGLACIAL RANGE FLUCTUATION, GENETIC SUBDIVISION AND SPECIATION IN THE WESTERN NORTH AMERICAN SPOTTED FROG COMPLEX, RANA PRETIOSA. AB - The western North American complex of spotted frogs (Rana pretiosa) exhibits isolation-by-distance, genetic subdivision, and speciation in association with its extensive northward range shift in postglacial times. The southern relict populations of R. pretiosa species B existing at high altitudes or in desert springs have been subjected to restricted gene flow, high inbreeding, and bottlenecks to produce significant between-population genetic diversity. The more recently established northern populations, however, show genetic uniformity and isolation-by-distance, as estimated using Slatkin's (1993) statistic M. Middle latitude populations have higher heterozygosities than populations at either extreme. Fixed differences in allozyme variation separate 21 populations of species B from five populations of R. pretiosa species A found in southwest Washington State and the Cascades Mountains of Oregon. Morphological variation of 20 metric characters among 38 samples, examined using multiple discriminant function analysis, could partially resolve partitioning among populations but specimens from the vicinity of the type series of R. p. pretiosa could not be assigned to either species A or species B. Speciation in these frogs may not be correlated with morphological evolution since comparatively neutral allozyme changes may be established more rapidly than changes in morphology. PMID- 28568879 TI - THE ROLE OF GENETIC VARIATION IN ADAPTATION AND POPULATION PERSISTENCE IN A CHANGING ENVIRONMENT. PMID- 28568880 TI - EVOLUTIONARY ADAPTATION TO TEMPERATURE. IV. ADAPTATION OF ESCHERICHIA COLI AT A NICHE BOUNDARY. AB - Following an environmental change, the course of a population's adaptive evolution may be influenced by environmental factors, such as the degree of marginality of the new environment relative to the organism's potential range, and by genetic factors, including constraints that may have arisen during its past history. Experimental populations of bacteria were used to address these issues in the context of evolutionary adaptation to the thermal environment. Six replicate lines of Escherichia coli (20 degrees C group), founded from a common ancestor, were propagated for 2000 generations at 20 degrees C, a novel temperature that is very near the lower thermal limit at which it can maintain a stable population size in a daily serial transfer (100-fold dilution) regime. Four additional groups (32/20, 37/20, 42/20, and 32-42/20 degrees C groups) of six lines, each with 2000 generation selection histories at different temperatures (32, 37, 42, and daily alternation of 32 and 42 degrees C), were moved to the same 20 degrees C environment and propagated in parallel to ascertain whether selection histories influence the adaptive response in this novel environment. Adaptation was measured by improvement in fitness relative to the common ancestor in direct competition experiments conducted at 20 degrees C. All five groups showed improvement in relative fitness in this environment; the mean fitness of the 20 degrees C group after 2000 generations increased by about 8%. Selection history had no discernible effect on the rate or final magnitude of the fitness responses of the four groups with different histories after 2000 generations. The correlated fitness responses of the 20 degrees C group were measured across the entire thermal niche. There were significant tradeoffs in fitness at higher temperatures; for example, at 40 degrees C the average fitness of the 20 degrees C group was reduced by almost 20% relative to the common ancestor. We also observed a downward shift of 1-2 degrees C in both the upper and lower thermal niche limits for the 20 degrees C selected group. These observations are contrasted with previous observations of a markedly greater rate of adaptation to growth near the upper thermal limit (42 degrees C) and a lack of trade-off in fitness at lower temperatures for lines adapted to that high temperature. The evolutionary implications of this asymmetry are discussed. PMID- 28568881 TI - NONRANDOM GENOTYPIC ASSOCIATIONS IN A LEGUME-BRADYRHIZOBIUM MUTUALISM. AB - Genetically divergent lineages often coexist within populations of the annual legume Amphicarpaea bracteata. At one site dominated by two such lineages (termed biotypes "C" and "S"), isolates of root-nodule bacteria (Bradyrhizobium sp.) were sampled from both hosts and analyzed by enzyme electrophoresis. Symbiont populations on the two plant biotypes were highly distinct. Out of 15 bacterial multilocus genotypes detected (among 51 isolates analyzed), only one was shared in common by the two plant biotypes. Cluster analysis revealed three bacterial lineages (designated I, II, and III), with lineage I found exclusively on biotype C plants, and the two other lineages almost completely restricted to biotype S hosts. Laboratory inoculation tests indicated that lineage I bacteria were strictly specialized on biotype C hosts, forming few or no nodules on plants of the other host biotype. Bacterial lineages II and III were capable of forming nodules on both kinds of plants, but nodule numbers were often significantly higher on biotype S hosts. The nonrandom association between plant and bacterial lineages at this site implies that genetic diversity of hosts is an important factor in the maintenance of polymorphism within the symbiont population. PMID- 28568882 TI - COMPLEX COLONY STRUCTURE IN SOCIAL INSECTS: I. ECOLOGICAL DETERMINANTS AND GENETIC CONSEQUENCES. AB - For social insect species, intraspecific variation in colony social structure provides an opportunity to relate the evolution of social behavior to ecological factors. The species Myrmica punctiventris is a cavity-dwelling forest ant that exhibits very different colony structures in two populations in the northeastern United States. Combined data from seasonal censuses, allozyme electrophoresis, and worker hostility tests showed that a population of M. punctiventris in Vermont was strictly monogynous and seasonally polydomous. The same procedures showed that a population of M. punctiventris in New York was facultatively polygynous and predominantly monodomous. Genetic relatedness among colony-mates was not different from Hamilton's expected values in the Vermont population and was consistent with little exchange of ants between colonies and single-mating of queens. In contrast, relatedness was lower in New York, and examination of nest mate genotypes revealed exchange of ants between colonies, high rates of colony loss and replacement of queens, or multiple-mating of queens. The genetic structure of the Vermont population was consistent with no inbreeding, but in New York, the population genetic structure reflected microgeographic subdivision and inbreeding. Previous study of the ant communities at these sites implicates nest site limitation in New York as a primary constraint on social structure. PMID- 28568884 TI - DEVELOPMENTAL STABILITY IN LEAVES OF CLARKIA TEMBLORIENSIS (ONAGRACEAE) AS RELATED TO POPULATION OUTCROSSING RATES AND HETEROZYGOSITY. AB - Four natural populations of Clarkia tembloriensis, whose levels of heterozygosity and rates of outcrossing were previously found to be correlated, are examined for developmental instability in their leaves. From the northern end of the species range, we compare a predominantly selfing population (t = 0.26) with a more outcrossed population (t = 0.84), which is genetically similar. From the southern end of the range, we compare a highly selfing population (t = 0.03) with a more outcrossed population (t = 0.58). We measured developmental stability in the populations using two measures of within-plant variation in leaf length as well as calculations of fluctuating asymmetry (FA) for several leaf traits. Growth chamber experiments show that selfing populations are significantly more variable in leaf length than more outcrossed populations. Developmental instability can contribute to this difference in population-level variance. Plants from more homozygous populations tend to have greater within-plant variance over developmentally comparable nodes than plants from more heterozygous populations, but the difference is not significant. At the upper nodes of the plant, mature leaf length declines steadily with plant age, allowing for a regression of leaf length on node. On average, the plants from more homozygous populations showed higher variance about the regression (MSE) and lower R2 values, suggesting that the decline in leaf length with plant age is less stable in plants from selfing populations than in plants from outcrossing populations. Fluctuating asymmetry (FA) was calculated for four traits within single leaves at up to five nodes per plant. At the early nodes of the plant where leaf arrangement is opposite, FA was also calculated for the same traits between opposite leaves at a node. Fluctuating asymmetry is significantly greater in the southern selfing population than in the neighboring outcrossed population. Northern populations do not differ in FA. Fluctuating asymmetry can vary significantly between nodes. The FA values of different leaf traits were not correlated. We show that developmental stability can be measured in plants using FA and within-plant variance. Our data suggest that large differences in breeding system are associated with differences in stability, with more inbred populations being the least stable. PMID- 28568883 TI - TEMPORAL VARIATION IN MITOCHONDRIAL DNA HAPLOTYPE FREQUENCIES IN A BROWN TROUT (SALMO TRUTTA L.) POPULATION THAT SHOWS STABILITY IN NUCLEAR ALLELE FREQUENCIES. PMID- 28568885 TI - EVOLUTION OF BROAD AND SPECIFIC COMPETITIVE ABILITY IN NOVEL VERSUS FAMILIAR ENVIRONMENTS IN DROSOPHILA SPECIES. AB - We used nine pairs of competing Drosophila melanogaster and Drosophila simulans populations to test three hypotheses. (1) Weaker competitors undergo greater evolutionary increases in competitive ability, compared with stronger ones. (2) Increased competitive ability against a specific competitor population causes a correlated increase in competitive ability against other competitor populations. (3) In a novel environment, adaptation to the abiotic environment contributes more to competitive ability than adaptation to the competitor population. After 11 generations of competition, initially weaker competitor populations showed relatively greater increases in competitive ability. Broad and specific competitive abilities, the latter being specific to a particular competitor population, were positively correlated in both familiar and novel environments. Adaptation to the abiotic environment seemed to be a more important component of competitive ability in the novel environments. We conclude that in geographically structured species, biotic and abiotic factors affecting the evolution of competitive ability may interact to help create a mosaic of outcomes that can affect the evolutionary dynamics of the interaction over the range of the competing species. PMID- 28568886 TI - LOCOMOTOR MODULES AND THE EVOLUTION OF AVIAN FLIGHT. AB - The evolution of avian flight can be interpreted by analyzing the sequence of modifications of the primitive tetrapod locomotor system through time. Herein, we introduce the term "locomotor module" to identify anatomical subregions of the musculoskeletal system that are highly integrated and act as functional units during locomotion. The first tetrapods, which employed lateral undulations of the entire body and appendages, had one large locomotor module. Basal dinosaurs and theropods were bipedal and possessed a smaller locomotor module consisting of the hind limb and tail. Bird flight evolved as the superimposition of a second (aerial) locomotor capability onto the ancestral (terrestrial) theropod body plan. Although the origin of the wing module was the primary innovation, alterations in the terrestrial system were also significant. We propose that the primitive theropod locomotor module was functionally and anatomically subdivided into separate pelvic and caudal locomotor modules. This decoupling freed the tail to attain a new and intimate affiliation with the forelimb during flight, a configuration unique to birds. Thus, the evolution of flight can be viewed as the origin and novel association of locomotor modules. Differential elaboration of these modules in various lineages has produced the diverse locomotor abilities of modern birds. PMID- 28568887 TI - PERSPECTIVE: EVOLUTIONARY PATTERNS IN THE FOSSIL RECORD. AB - The study of large-scale evolutionary patterns in the fossil record has benefited from a diversity of approaches, including analysis of taxonomic data, ecology, geography, and morphology. Although genealogy is an important component of macroevolution, recent visions of phylogenetic analysis as replacing rather than supplementing other approaches are short-sighted. The ability of traditional Linnaean taxa to document evolutionary patterns is mainly an empirical rather than a theoretical issue, yet the use of these taxa has been dismissed without thorough evaluation of their empirical properties. Phylogenetic analysis can help compensate for some of the fossil record's imperfections. However, the shortcomings of the phylogenetic approach have not been adequately acknowledged, and we still lack a rigorous comparison between the phylogenetic approach and probabilistic approaches based on sampling theory. Important inferences about the history of life based on nongenealogical data have later been corroborated with genealogical and other analyses, suggesting that we risk an enormous loss of knowledge and understanding if we categorically dismiss nonphylogenetic data. PMID- 28568888 TI - RATES OF FLORAL EVOLUTION: ADAPTATION TO BUMBLEBEE POLLINATION IN AN ALPINE WILDFLOWER, POLEMONIUM VISCOSUM. AB - Animal pollinators are thought to shape floral evolution, yet the tempo of this process has seldom been measured. I used the prediction equation of quantitative genetics, R = h2 S, to predict the rate at which a change in pollinator abundance may have caused divergence in floral morphology of the alpine skypilot, Polemonium viscosum. A selection experiment determined the rate at which such divergence can actually proceed. Corolla flare in this species increases by 12% from populations pollinated by a wide assemblage of insect visitors to those pollinated only by bumblebees. To simulate the evolutionary process giving rise to this change, I used a pollinator selection experiment. Plants with broad flowers set significantly more seeds than plants with narrow flowers under bumblebee pollination but had equivalent fecundity when visited by other insects or hand-pollinated. Bumblebee-mediated selection for broad corolla flare intensified from 0.07 at seed set to 0.17 at progeny establishment. Maternal parent-offspring regression yielded a confidence interval of 0.22-1.00 for trait heritability. Given these parameter estimates, the prediction equation shows that broadly flared flowers of bumblebee-pollinated P. viscosum could have evolved from narrower ones in a single generation. This prediction is matched by an observed 9% increase in offspring corolla flare after a single bout of bumblebee mediated selection, relative to offspring of unselected controls. Findings show that plant populations can adapt rapidly to abrupt changes in pollinator assemblages. PMID- 28568889 TI - POLYGENIC INHERITANCE OF A BEHAVIORAL PHENOTYPE: INTERSPECIFIC GENETICS OF SONG IN THE HAWAIIAN CRICKET GENUS LAUPALA. AB - The Hawaiian cricket genus Laupala (family Gryllidae) is one of several native genera of flightless crickets found in rain-forest habitat across the Hawaiian archipelago. Species in this genus are morphologically quite similar, but the songs produced by adult males are acoustically distinct. I examined the nature of song variation found within Laupala paranigra and between Laupala kohalensis and L. paranigra, both endemic to the island of Hawaii. Variation within and among species was most notable in the temporal structure of the song, as quantified by the pulse rate. The variation in pulse rate present in natural populations of L. paranigra bred true through the F1 laboratory generation, suggesting that the intraspecific variation in this species has a genetic basis. Interspecific hybridizations between L. kohalensis and L. paranigra successfully produced F1 , F2 , and backcross generations. Hybrid F1 males from reciprocal crosses sang with significantly different pulse rates, implicating an X chromosomal contribution to the phenotypic difference between these species. Interspecific patterns of inheritance are most consistent with a type-I genetic architecture. Polygenic inheritance of the interspecific pulse-rate variation was observed, and approximately eight genetic factors were estimated to underlie the difference in pulse rate between L. kohalensis and L. paranigra. PMID- 28568890 TI - Myocardial Mass Contributes to the Discrepancy Between Anatomic Stenosis Severity Assessed by Intravascular Ultrasound and Fractional Flow Reserve in Intermediate Lesions of the Coronary Artery. AB - OBJECTIVES: The present study investigated the major contributors to the discrepancy between the minimal lumen area (MLA) and fractional flow reserve (FFR). BACKGROUND: There was considerable discrepancy between MLA or diameter stenosis (DS) and FFR. METHODS: We enrolled 744 patients with intermediate stenoses of the left anterior descending artery (LAD). Summed epicardial coronary artery length distal to the target stenosis was obtained from each longest view of the vessels on the coronary angiograms. Mismatching was defined as a lesion with FFR of >0.80 and MLA smaller than the best cut-off value (BCV) for predicting FFR of <=0.80. Reverse mismatching was defined as a lesion with FFR of <=0.80 and MLA larger than the BCV. RESULTS: Summed epicardial coronary artery length was longer at the lesions of proximal LAD than that of middle LAD (380 mm +/- 82 mm vs. 341 mm +/- 80 mm, P < 0.001). Reverse mismatching was found more frequently in the proximal than middle LAD (28.3% vs. 5.5%, P < 0.001). Independent predictors of FFR <= 0.80 were age, male, multi-vessel disease, proximal LAD lesion, MLA, DS, plaque burden at distal reference, lesion length and summed epicardial coronary artery length. Proximal LAD lesion was an independent predictor of reverse mismatching (hazard ratio 3.162, 1.858-5.382, P < 0.001). CONCLUSIONS: Myocardial mass subtended by a lesion is an important factor predicting FFR <=0.80 and discrepancy between FFR and MLA. Myocardial mass subtended by a lesion should be considered when determining the revascularization therapy by intravascular ultrasound parameters. (c) 2017 Wiley Periodicals, Inc. PMID- 28568891 TI - Oncolytic Maraba Virus MG1 as a Treatment for Sarcoma. AB - The poor prognosis of patients with advanced bone and soft-tissue sarcoma has not changed in the past several decades, highlighting the necessity for new therapeutic approaches. Immunotherapies, including oncolytic viral (OV) therapy, have shown great promise in a number of clinical trials for a variety of tumor types. However, the effective application of OV in treating sarcoma still remains to be demonstrated. Although few pre-clinical studies using distinct OVs have been performed and demonstrated therapeutic benefit in sarcoma models, a side-by side comparison of clinically relevant OV platforms has not been performed. Four clinically relevant OV platforms (Reovirus, Vaccinia virus, Herpes-simplex virus and Rhabdovirus) were screened for their ability to infect and kill human and canine sarcoma cell lines in vitro, and human sarcoma specimens ex vivo. In vivo treatment efficacy was tested in a murine model. The rhabdovirus MG1 demonstrated the highest potency in vitro. Ex vivo, MG1 productively infected more than 80% of human sarcoma tissues tested, and treatment in vivo led to a significant increase in long-lasting cures in sarcoma-bearing mice. Importantly, MG1 treatment induced the generation of memory immune response that provided protection against a subsequent tumor challenge. This study opens the door for the use of MG1-based oncolytic immunotherapy strategies as treatment for sarcoma or as a component of a combined therapy. PMID- 28568892 TI - Patch testing in patients with suspected cosmetic dermatitis: A retrospective study. AB - BACKGROUND: Growing use of cosmetics has led to an increase in the incidence of allergic contact dermatitis (ACD) to cosmetics. Patch testing helps to confirm allergy to cosmetics and pinpoint the exact offending allergens. AIMS AND OBJECTIVES: The study aimed to find the frequency of positive patch test reactions in cases with suspected ACD to cosmetics, and the common allergens responsible for it. METHODS: This is a retrospective record-based study of 58 patients, with suspected ACD to cosmetics, who had undergone patch testing with Indian standard series and Indian cosmetic and fragrance series from January 2013 to December 2015. RESULTS: The majority of patients (60.34%) belonged to the age group of 20-40 years. The most common site of involvement was face (94.8%) followed by neck (22.4%). The most commonly implicated cosmetics in history were soaps (53.4%), and face creams (24.1%). The most common allergens detected on patch testing were cetrimide (20.7%) and thimerosal (15.5%) followed by paraphenylenediamine (6.9%), and fragrance mix (5.2). Positive allergic reactions were obtained in 2.12% of the patches. CONCLUSION: Most common cosmetic products implicated for causing ACD were face creams, soaps, and hair dyes. The principal culprit allergens were cetrimide and thimerosal. PMID- 28568893 TI - TGF-beta signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes. AB - The electrogenic sodium bicarbonate cotransporter NBCe1 (SLC4A4) expressed in astrocytes regulates intracellular and extracellular pH. Here, we introduce transforming growth factor beta (TGF-beta) as a novel regulator of NBCe1 transcription and functional expression. Using hippocampal slices and primary hippocampal and cortical astrocyte cultures, we investigated regulation of NBCe1 and elucidated the underlying signaling pathways by RT-PCR, immunoblotting, immunofluorescence, intracellular H(+ ) recording using the H(+ ) -sensitive dye 2',7'-bis-(carboxyethyl)-5-(and-6)-carboxyfluorescein, mink lung epithelial cell (MLEC) assay, and chromatin immunoprecipitation. Activation of TGF-beta signaling significantly upregulated transcript, protein, and surface expression of NBCe1. These effects were TGF-beta receptor-mediated and suppressed following inhibition of JNK and Smad signaling. Moreover, 4-aminopyridine (4AP)-dependent NBCe1 regulation requires TGF-beta. TGF-beta increased the rate and amplitude of intracellular H+ changes upon challenging NBCe1 in wild-type astrocytes but not in cortical astrocytes from Slc4a4-deficient mice. A Smad4 binding sequence was identified in the NBCe1 promoter and Smad4 binding increased after activation of TGF-beta signaling. The data show for the first time that NBCe1 is a direct target of TGF-beta/Smad4 signaling. Through activation of the canonical pathway TGF-beta acts directly on NBCe1 by binding of Smad4 to the NBCe1 promoter and regulating its transcription, followed by increased protein expression and transport activity. PMID- 28568894 TI - Intravital investigation of rat mesenteric small artery tone and blood flow. AB - KEY POINTS: Substantial information on rat mesenteric small artery physiology and pharmacology based on in vitro experiments is available. Little is known about the relevance of this for artery function in vivo. We here present an intravital model where rat mesenteric small artery diameters are studied under isolated and controlled conditions in situ with simultaneous measurement of blood flow. The responses of the isolated arteries vary with the anaesthetic used, and they are quantitatively but not qualitatively different from the responses seen in vitro. ABSTRACT: Functional characteristics of rat mesenteric small arteries (internal diameter ~150-200 MUm) have been extensively studied in vitro using isometric and isobaric myographs. In vivo, precapillary arterioles (internal diameter < 50 MUm) have been studied, but only a few studies have investigated the function of mesenteric small arteries. We here present a novel approach for intravital studies of rat mesenteric small artery segments (~5 mm long) isolated in a chamber. The agonist-induced changes in arterial diameter and blood flow were studied using video imaging and laser speckle analysis in rats anaesthetized by isoflurane, pentobarbital, ketamine-xylazine, or by a combination of fentanyl, fluanison and midazolam (rodent mixture). The arteries had spontaneous tone. Noradrenaline added to the chamber constricted the artery in the chamber but not the downstream arteries in the intestinal wall. The constriction was smaller when rats were anaesthetized by rodent mixture in comparison with other anaesthetics, where responses were qualitatively similar to those reported in vitro. The contraction was associated with reduction of blood flow, but no flow reduction was seen in the downstream arteries in the intestinal wall. The magnitude of different endothelium-dependent relaxation pathways was dependent on the anaesthesia. Vasomotion was present under all forms of anaesthesia with characteristics similar to in vitro. We have established an intravital method for studying the tone and flow in rat mesenteric arteries. The reactivity of the arteries was qualitatively similar to the responses previously obtained under in vitro conditions, but the choice of anaesthetic affects the magnitude of responses. PMID- 28568895 TI - Developmentally-faithful and effective human erythropoiesis in immunodeficient and Kit mutant mice. AB - Immunodeficient mouse models have been valuable for studies of human hematopoiesis, but high-fidelity recapitulation of erythropoiesis in most xenograft recipients remains elusive. Recently developed immunodeficient and Kit mutant mice, however, have provided a suitable background to achieve higher-level human erythropoiesis after long-term hematopoietic engraftment. While there has been some characterization of human erythropoiesis in these models, a comprehensive analysis from various human developmental stages has not yet been reported. Here, we have utilized cell surface phenotypes, morphologic analyses, and molecular studies to fully characterize human erythropoiesis from multiple developmental stages in immunodeficient and Kit mutant mouse models following long-term hematopoietic stem and progenitor cell engraftment. We show that human erythropoiesis in such models demonstrates complete maturation and enucleation, as well as developmentally appropriate globin gene expression. These results provide a framework for future studies to utilize this model system for interrogating disorders affecting human erythropoiesis and for developing improved therapeutic approaches. PMID- 28568896 TI - An autopsied case of MV2K + C-type sporadic Creutzfeldt-Jakob disease presenting with widespread cerebral cortical involvement and Kuru plaques. AB - MV2-type sporadic Creutzfeldt-Jakob disease (sCJD), which was previously called "Kuru-plaque variant", was gradually revealed to have a wide spectrum and has been classified into three pathological subtypes: MV2K, MV2C and MV2K + C. We herein describe the detailed clinical findings and neuropathologic observations from an autopsied MV2K + C-type Japanese sCJD case with widespread cerebral cortical pathology and Kuru plaques. In the early stages of the disease, the patient exhibited gait disturbance with ataxia and dysarthria as well as gradual appearance of cognitive dysfunction. Diffusion-weighted images (DWI) on MRI revealed extensive cerebral cortical hyperintensity. Pathologic investigation revealed extensive spongiform change in the cerebral cortex, particularly in the deeper layers. Vacuole size varied, and some were confluent. Prion protein (PrP) immunostaining revealed extensive PrP deposition in the cerebral cortex, basal ganglia, thalamus, cerebellum, brainstem and spinal cord. In the cerebral cortex, synaptic-type, Kuru plaque-like, and coarse plaque-type PrP depositions were mainly observed, along with some perivacuolar-type PrP depositions. Kuru plaques and coarse plaque-type PrP depositions also were observed in the cerebellar cortex. PrP gene analysis revealed no mutations, and polymorphic codon 129 exhibited Met/Val heterozygosity. Western blot analysis revealed a mixture of intermediate-type PrPSc and type 2 PrPSc . Based on previous reports regarding MV2-type sCJD and the clinicopathologic findings of the present case, we speculated that it may be possible to clinically distinguish each MV2 subtype. Clinical presentation of the MV2K + C subtype includes predominant cerebral cortical involvement signs with ataxia and DWI hyperintensity of the cerebral cortex on MRI. PMID- 28568897 TI - Balloon cells in metastatic melanoma. PMID- 28568898 TI - Conventional and Novel Spinal Stimulation Algorithms: Hypothetical Mechanisms of Action and Comments on Outcomes. AB - OBJECTIVE: Spinal cord stimulation (SCS) emerged as a direct clinical spin-off from the Gate Control Theory from 1965. Over the last decade, several new modes of SCS have appeared. This review discusses these novel techniques and their hypothetical mechanisms of action. MATERIAL AND METHODS: A recent literature search on SCS coupled with the most recent data from poster presentations and congress lectures have been used to illustrate new hypothetical ways of modulating pain. RESULTS: Several physiological and neurochemical mechanisms for conventional paresthetic SCS have been described in detail. However, much less is known about the novel SCS modes of action. One new algorithm utilizes very high frequencies (up to 10 kHz) intended for direct stimulation of dorsal horns at the T9-T10 level to treat both low back pain and leg pain. Another technique uses bursts of impulses with a high internal frequency delivered to the dorsal spinal cord with a frequency of 40 Hz. Both of these therapies intend to be subparesthetic and effective both for neuropathic and nociceptive pain components. During the last few years, more moderate changes in SCS parameters have been tried in order to increase the amount of electric charge passed from the lead to the neural tissue. This strategy, called "high density SCS," utilizes frequencies up to 1200 Hz or long pulse widths. CONCLUSIONS: The present SCS therapies have developed beyond the Gate Control Concept. New hypotheses about mechanisms of action are presented and some improved results are discussed. PMID- 28568900 TI - An overview of the security of cardiac implantable electronic devices. PMID- 28568899 TI - Winding back Wnt signalling: potential therapeutic targets for treating gastric cancers. AB - : Gastric cancer persists as a frequent and deadly disease that claims over 700 000 lives annually. Gastric cancer is a multifactorial disease that is genetically, cytologically and architecturally more heterogeneous than other gastrointestinal cancers, making it therapeutically challenging. As such, and largely attributed to late-stage diagnosis, gastric cancer patients show only partial response to standard chemo and targeted molecular therapies, highlighting an urgent need to develop new targeted therapies for this disease. Wnt signalling has a well-documented history in the genesis of many cancers and is, therefore, an attractive therapeutic target. As such, drug discovery has focused on developing inhibitors that target multiple nodes of the Wnt signalling cascade, some of which have progressed to clinical trials. The collective efforts of patient genomic profiling has uncovered genetic lesions to multiple components of the Wnt pathway in gastric cancer patients, which strongly suggest that Wnt targeted therapies could offer therapeutic benefits for gastric cancer patients. These data have been supported by studies in mouse models of gastric cancer, which identify Wnt signalling as a driver of gastric tumourigenesis. Here, we review the current literature regarding Wnt signalling in gastric cancer and highlight the suitability of each class of Wnt inhibitor as a potential treatment for gastric cancer patients, in relation to the type of Wnt deregulation observed. LINKED ARTICLES: This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc. PMID- 28568901 TI - The replicative lifespan-extending deletion of SGF73 results in altered ribosomal gene expression in yeast. AB - Sgf73, a core component of SAGA, is the yeast orthologue of ataxin-7, which undergoes CAG-polyglutamine repeat expansion leading to the human neurodegenerative disease spinocerebellar ataxia type 7 (SCA7). Deletion of SGF73 dramatically extends replicative lifespan (RLS) in yeast. To further define the basis for Sgf73-mediated RLS extension, we performed ChIP-Seq, identified 388 unique genomic regions occupied by Sgf73, and noted enrichment in promoters of ribosomal protein (RP)-encoding genes. Of 388 Sgf73 binding sites, 33 correspond to 5' regions of genes implicated in RLS extension, including 20 genes encoding RPs. Furthermore, half of Sgf73-occupied, RLS-linked RP genes displayed significantly reduced expression in sgf73Delta mutants, and double null strains lacking SGF73 and a Sgf73-regulated, RLS-linked RP gene exhibited no further increase in replicative lifespan. We also found that sgf73Delta mutants display altered acetylation of Ifh1, an important regulator of RP gene transcription. These findings implicate altered ribosomal protein expression in sgf73Delta yeast RLS and highlight altered acetylation as a pathway of relevance for SCA7 neurodegeneration. PMID- 28568902 TI - Managing consequences of climate-driven species redistribution requires integration of ecology, conservation and social science. AB - Climate change is driving a pervasive global redistribution of the planet's species. Species redistribution poses new questions for the study of ecosystems, conservation science and human societies that require a coordinated and integrated approach. Here we review recent progress, key gaps and strategic directions in this nascent research area, emphasising emerging themes in species redistribution biology, the importance of understanding underlying drivers and the need to anticipate novel outcomes of changes in species ranges. We highlight that species redistribution has manifest implications across multiple temporal and spatial scales and from genes to ecosystems. Understanding range shifts from ecological, physiological, genetic and biogeographical perspectives is essential for informing changing paradigms in conservation science and for designing conservation strategies that incorporate changing population connectivity and advance adaptation to climate change. Species redistributions present challenges for human well-being, environmental management and sustainable development. By synthesising recent approaches, theories and tools, our review establishes an interdisciplinary foundation for the development of future research on species redistribution. Specifically, we demonstrate how ecological, conservation and social research on species redistribution can best be achieved by working across disciplinary boundaries to develop and implement solutions to climate change challenges. Future studies should therefore integrate existing and complementary scientific frameworks while incorporating social science and human-centred approaches. Finally, we emphasise that the best science will not be useful unless more scientists engage with managers, policy makers and the public to develop responsible and socially acceptable options for the global challenges arising from species redistributions. PMID- 28568904 TI - Mitochondrial DNA analysis of ancient sheep from Altai. AB - A comparative analysis of the genetic diversity of ancient and modern sheep can shed light on the origin of these animals and their distribution as well as help to evaluate the role of humans at each formation stage of different sheep breeds. Here we isolated ancient DNA and performed sequencing of the mitochondrial DNA D loop from 17 sheep bone remains (~4000-1000 years old) found in the archaeological complexes in the south of Altai (Western Siberia). The length of the sequences obtained ranged between 318 and 586 bp. The haplotype diversity and nucleotide diversity were 0.801 +/- 0.081 and 0.0096 +/- 0.0014 respectively. The average number of nucleotide differences was ~3.1. Nucleotide sequence analysis revealed that 15 specimens were nested within previously described A,B,C,D and E lineages and that two specimens had a basal position relative to the rest of the analyzed samples. A relatively high diversity of sheep haplotypes, including the presence of two basal haplotypes, indicates that the Altai region may have been a transport route of human migration. Further ancient DNA analysis of other specimens and deeper genome sequencing of samples with novel haplotypes is needed to better understand the demographic history of sheep in Southern Siberia. PMID- 28568903 TI - Multidisciplinary assessment of PFO with substantial right-to-left shunting and medium-term follow-up after PFO device closure: A single-center experience. AB - OBJECTIVES: To describe the multidisciplinary assessment of patent foramen ovale (PFO) with substantial right-to-left shunting (RLS) and medium-term follow-up after PFO closure for stroke or transient ischemic attack (TIA). BACKGROUND: PFO closure is a therapeutic option to prevent recurrent ischemic event in patients with cryptogenic stroke and TIA. The apparent lack of benefit seen in previous studies was in part due to the inclusion of patients with alternate mechanisms of stroke/TIA. However, the long-term follow-up results of RESPECT trial confirmed that PFO closure could reduce the recurrence rate of stroke compared to medical therapy. The obvious difference between RESPECT and the other studies is that RESPECT recruited more relevant patients with substantial RLS. METHODS: From May 2013 to October 2015, all subjects diagnosed as cryptogenic stroke or TIA with substantial RLS who underwent PFO closure at our institution were included. All patients underwent multidisciplinary assessment to exclude stroke/TIA with definite etiology. Baseline characteristics, clinical manifestations, procedural, and follow-up data were reviewed. RESULTS: A total of 219 consecutive patients with substantial RLS undergoing PFO closure were identified. There were no procedure-related deaths, strokes, or TIA. Mean follow-up was 2.0 +/- 0.7 years. Early residual shunting was visible in 9 patients (4.1%); however, during follow up, only 3 patients (1.4%) had residual RLS detected by contrast transthoracic echocardiography (cTTE). The annual risk of recurrent ischemic stroke or TIA was 0.457%. CONCLUSIONS: PFO closure can be performed safely and effectively in patients with cryptogenic stroke or TIA. In selected patients with substantial RLS, following appropriate multidisciplinary assessment, excellent results with low incidence of recurrent events may be achieved. PMID- 28568905 TI - TMEM230: How does it fit in the etiology and pathogenesis of Parkinson's disease? AB - Mutations in the transmembrane protein 230 (TMEM230) gene were recently identified in a large Canadian pedigree and 7 smaller Chinese families, nominating TMEM230 as the third gene causing a Mendelian form of late onset Parkinson's disease (PD) with typical Lewy-body pathology (after synuclein alpha (SNCA) and leucine rich repeat kinase 2 (LRRK2)). The protein encoded by TMEM230 remains largely uncharacterized, but initial evidence points to roles in the trafficking of recycling vesicles, retromers, and endosomes, suggesting intriguing links to the pathways targeted by other PD-causing genes. The focus on family-based studies is gaining new momentum in the next-generation sequencing era, for the discovery of further, high-penetrance (medically relevant) genetic variants in PD. However, at this junction, important aspects of the TMEM230 story remain unclear, such as the prevalence of these mutations in the Chinese and other populations of the world, the penetrance of the mutations, and even their mode of inheritance. The first replication studies among Chinese and White PD patients have been largely negative. Furthermore, much more work remains ahead to elucidate the mechanisms by which these mutations might lead to neuronal cell death, alpha-synuclein pathology, and parkinsonism. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28568906 TI - Effect of iron supplementation in children with breath holding spells. AB - AIM: The aim of this study was to analyse the effect of iron supplementation in children with breath holding spells, irrespective of their iron status and study the factors associated with the response. METHODS: This was a prospective interventional study. Study population comprised of patients aged 6-36 months, attending a paediatric outpatient department with recurrent episodes (more than three in last 4 weeks) of breath holding spells. Children with loss of consciousness or convulsive movements associated with breath holding spells were considered as severe. After baseline investigations, all enrolled patients were given elemental iron at the dose of 3 mg/kg/day as a single daily dose. Four weekly follow-ups were done until 3 months after initiation of the intervention. At 12 weeks, investigations were repeated and outcome assessed for remission or decrease in severity of breath holding episodes. RESULTS: A total of 100 children with breath holding spells received iron supplementation. Almost 73% of children showed complete response, with another 23% showing greater than 50% reduction in frequency. Frequency of spells at diagnosis and intolerance to oral iron were significantly associated with poor response to iron supplementation. Other factors such as age at onset, age at presentation, severity of spells, anaemia and serum iron parameters had no significant association with the response. Of the 27 children without iron deficiency (serum ferritin >= 30 ug/L), 77.7% responded completely to iron supplementation, similar to the iron-deficient group. CONCLUSIONS: Iron supplementation is effective in the management of breath holding spells. Non-anaemic and iron-replete children with breath holding spells also respond well to iron supplementation. PMID- 28568907 TI - Anticipated next-day demand affects the magnitude of the cortisol awakening response, but not subjective or objective sleep. AB - Whilst the association between sleep and stress is well established, few studies have examined the effects of an anticipated stressor upon sleep and relevant physiological markers. The aim of the present study was to examine whether an anticipated stressor in the form of next-day demand affects subjective and objective sleep, and multiple indices of the cortisol awakening response. Subjective and objective sleep and the cortisol awakening response were measured over three consecutive nights in 40 healthy adults in a sleep laboratory. During their second night, participants were informed that they would either be required to complete a series of demanding cognitive tasks, in a competition format, during the next day (anticipation condition; n = 22), or were given no instruction (sedentary condition; n = 18). Sleep was measured subjectively using sleep diaries, objectively using polysomnography, and saliva was measured at awakening, +15, +30, +45 and +60 min each morning, from which cortisol awakening response measurement indices were derived: awakening cortisol levels, the mean increase in cortisol levels and total cortisol secretion. There were no between group differences in subjective or objective sleep in the night preceding the anticipated demand; however, compared with the sedentary condition, those in the anticipation group displayed a larger mean increase in cortisol levels, representing the cortisol awakening response magnitude, on the morning of the anticipated demand. Overall, the results suggest that whilst anticipated stress affected the subsequent cortisol awakening response, subjective and objective sleep remained undisturbed. It is possible that the timing of an anticipated stressor, rather than its expected duration, may influence subsequent sleep disruption. PMID- 28568909 TI - A Guide for the Design of Functional Polyaromatic Organophosphorus Materials. AB - The impact of integrating six-membered phosphorus heterocycles into a poly(hetero)aromatic materials is investigated. Mechanistic studies reveal the key synthetic requirements to embed the latter phosphorus heterocycles in polyaromatic molecules. DFT calculations indicate that introducing six-membered phosphorus rings into pi-extended molecules induces a particular electron distribution over the pi-extended system. Electrochemical investigations confirm that inserting six-membered phosphacycles into polyaromatics triggers ambipolar redox behavior. Steady-state spectroscopy reveals that fusing pyrroles with phosphorus-containing polyaromatic molecules induces fluorescence quantum yields as high as 0.8, whereas transient absorption spectroscopy demonstrates that fusing thiophenes promote the formation of non-emissive triplet-excited states. As a whole, the optoelectronic properties of fused phosphorus-containing materials give rise to promising performances in photoelectrochemical cells. Moreover, X-ray analyses confirm that the 3D arrangement in the solid state of polyaromatic systems containing six-membered phosphorus rings can be tailored through post-functionalization of the phosphorus center. Altogether, this investigation sets the bedrock for the design of a new generation of highly functional polyaromatic organophosphorus materials, keeping control over their electrochemical properties, fluorescence features, photo-induced excited states, and 3D molecular arrangement. PMID- 28568908 TI - A magnetic resonance imaging study of gastric motor function in patients with dyspepsia associated with Ehlers-Danlos Syndrome-Hypermobility Type: A feasibility study. AB - BACKGROUND: The clinical use of Magnetic Resonance Imaging (MRI) for investigating gastric motor function in dyspepsia is limited, largely due to protocol complexity, cost and limited availability. In this study, we explore the feasibility of a sub 60-minute protocol using a water challenge to assess gastric emptying, motility and accommodation in a cohort of Ehlers-Danlos Syndrome Hypermobility type (EDS-HT) patients presenting with dyspepsia. METHODS: Nine EDS HT patients (mean age 33, range: 26-50 all female) with a history of dyspepsia were recruited together with nine-matched controls. Subjects fasted for 6 hours prior to MRI. A baseline anatomical and motility scan was performed after which the subjects ingested 300 mL water. The anatomical and motility scans were then repeated every 10 minutes to a total of 60 minutes. Gastric emptying time, motility, and accommodation were calculated based on the observations of two observers for each EDS-HT subject and compared to their matched control using paired statistics. KEY RESULTS: Median motility increase following the water challenge was lower in EDS-HT subjects (11%, range: 0%-22%) compared to controls (22%, range: 13%-56%), P=.03. Median gastric emptying time was non-significantly decreased in EDS-HT subjects (12.5 minutes, range: 6-27) compared to controls (20 minutes, range: 7-30), P=.15. Accommodation was non-significantly reduced in EDS HT subjects (56% increase, range: 32%-78%) compared to healthy controls (67% increase, range: 52%-78%), P=.19. CONCLUSIONS & INFERENCES: This study demonstrates the feasibility of a water challenge MRI protocol to evaluate gastric physiology in the clinical setting. Motility differences between EDS-HT and controls are worthy of further investigation. PMID- 28568911 TI - Dream emotions: a comparison of home dream reports with laboratory early and late REM dream reports. AB - The aim of this study was to compare the emotional content of dream reports collected at home upon morning awakenings with those collected in the laboratory upon early and late rapid eye movement (REM) sleep awakenings. Eighteen adults (11 women, seven men; mean age = 25.89 +/- 4.85) wrote down their home dreams every morning immediately upon awakening during a 7-day period. Participants also spent two non-consecutive nights in the sleep laboratory where they were awoken 5 min into each continuous REM sleep stage, upon which they gave a verbal dream report. The content of a total of 151 home and 120 laboratory dream reports was analysed by two blind judges using the modified Differential Emotions Scale. It was found that: (1) home dream reports were more emotional than laboratory early REM dream reports, but not more emotional than laboratory late REM dream reports; (2) home dream reports contained a higher density of emotions than laboratory (early or late REM) dream reports; and (3) home dream reports were more negative than laboratory dream reports, but differences between home and early REM reports were larger than those between home and late REM reports. The results suggest that differences between home and laboratory dream reports in overall emotionality may be due to the time of night effect. Whether differences in the density of emotions and negative emotionality are due to sleep environment or due to different reporting procedures and time spent in a sleep stage, respectively, remains to be determined in future studies. PMID- 28568912 TI - TRANSMISSION RATES AND THE EVOLUTION OF HIV VIRULENCE. PMID- 28568910 TI - Sex differences in parent-reported executive functioning and adaptive behavior in children and young adults with autism spectrum disorder. AB - This study is the largest to date examining executive function and adaptive skills in females with autism spectrum disorder (ASD). Its primary aim was to utilize parent ratings of real-world executive functioning and adaptive behavior to better understand whether females with ASD differ from males with ASD in these areas of everyday functioning. We compared 79 females with ASD to 158 males with ASD (ages 7-18) who were statistically matched on age, IQ, and level of ADHD or ASD traits. All participants were assessed using the Behavior Rating Inventory of Executive Function (BRIEF) and a subset (56 females and 130 males) also received the Vineland Adaptive Behavior Scales (VABS). Females were rated by parents as having greater problems with executive function on the BRIEF. Parents also rated females as exhibiting more difficulties than males on the Daily Living Skills domain of the VABS. There was a correlation between increased global EF difficulty and decreased adaptive ability in both males and females. Our results indicate relative weaknesses for females compared to males diagnosed with ASD on executive function and daily living skills. These differences occur in the absence of sex differences in our sample in age, IQ, clinician ratings of core ASD symptomatology, parent ratings of ADHD symptoms, and parent-reported social and communication adaptive skills on the VABS. These findings indicate specific liabilities in real world EF and daily living skills for females with ASD and have important implications for targeting their treatments. Autism Res 2017, 10: 1653-1662. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 28568913 TI - MORPHOMETRIC DIFFERENTIATION IN SERIALLY BOTTLENECKED POPULATIONS OF THE HOUSEFLY. PMID- 28568914 TI - COSTS AND BENEFITS OF A PREDATOR-INDUCED POLYPHENISM IN THE GRAY TREEFROG HYLA CHRYSOSCELIS. AB - The phenotypes of gray treefrog (Hyla chrysoscelis) tadpoles vary depending on whether predators are present in the pond. Tadpoles reared in ponds with predatory dragonfly larvae are relatively inactive compared with tadpoles in predator-free ponds, and have relatively large, brightly colored tailfins with dark spots along the margins. Models for the evolution of plasticity predict that induced phenotypes such as this should confer high fitness relative to the typical phenotype when in the presence of predators, but should be costly when the predator is absent. Our study tested for the predicted fitness trade-off in H. chrysoscelis by first rearing tadpoles in mesocosms under conditions that induce the alternate phenotypes, and then comparing the performance of both phenotypes in both environments. We generated the two phenotypes by rearing tadpoles in 600-liter outdoor artificial ponds that contained either two caged dragonflies (Anax junius) or an empty cage. Tadpoles from the two environments showed significantly different behavior, tail shape, and tail color within two weeks of exposure. We compared the growth and survival of both phenotypes over four weeks in ponds where there was no actual risk of predation. Under these conditions, both phenotypes grew at the same rate, but the predator-induced phenotype had significantly lower survival than the typical phenotype, indicating that induced tadpoles suffered greater mortality from causes other than odonate predation. We tested the susceptibility of both phenotypes to predation by exposing them to dragonflies in 24-h predation trials. The predator-induced phenotype showed a significant survival advantage in these trials. These results confirm that the predator-induced phenotype in H. chrysoscelis larvae is associated with fitness costs and benefits that explain why the defensive phenotype is induced rather than constitutive. PMID- 28568915 TI - INTRASEXUAL SELECTION CONSTRAINS THE EVOLUTION OF THE DORSAL COLOR PATTERN OF MALE BLACK SWALLOWTAIL BUTTERFLIES, PAPILIO POLYXENES. AB - Males of the eastern black swallowtail (Papilio polyxenes asterius Stoll) with typical coloration were more successful in intrasexual competition for mating territories than were males altered to have female-like mimetic coloration. Sibling males were matched for wingspan and emergence date and released as pairs, one with its pattern altered and one a control that was marked but with unaltered appearance. Significantly fewer altered males were resighted one or more days after release compared with control males (33% vs. 76%, 1990; 46% vs. 83%, 1993). Altered males were less able to establish and maintain themselves in preferred territories. The inability of released, altered males to establish a territory appears related to significantly longer male-male encounters. Encounters involving at least one participant with altered appearance averaged 66 s compared with 24 s if neither male was altered. However, altering the coloration of P. polyxenes males that already had established themselves in a territory had little effect. After courtships of similar duration (~ 40 s), released virgin females were equally likely to mate with either altered or control males. This suggests that male-male intrasexual selection is of greater importance than female mate choice in maintaining a non-mimetic dorsal coloration in male P. polyxenes. PMID- 28568916 TI - THE GENETIC BASIS OF DIFFERENCES IN GROWTH AND BEHAVIOR OF SPECIALIST AND GENERALIST HERBIVORE SPECIES: SELECTION ON HYBRIDS OF HELIOTHIS VIRESCENS AND HELIOTHIS SUBFLEXA (LEPIDOPTERA). AB - Two species of moths and their hybrids were studied to determine the genetic basis of host range. One species, Heliothis virescens (HV), has a broad host range and is an agricultural pest on cotton (Malvaceae), soybean (Fabaceae), and tobacco (Solanaceae). The other species, Heliothis subflexa (HS), has a narrow host range, feeding on plants in the genus Physalis (Solanaceae). Experiments were done to determine whether the abilities to feed on cotton, soybean, and tobacco were each under separate genetic control in HV (genetically uncorrelated) or whether feeding on all three hosts was genetically correlated. By repeatedly backcrossing hybrids to HS while selecting for high larval survival and weight on soybean, loci conferring the ability to feed on soybean were moved from HV into the genetic background of the specialist, HS. After six generations of selection on soybean we tested the selected line on soybean, cotton, Physalis, and tobacco to determine if ability to feed on soybean was correlated with feeding ability on these other hosts. We found no evidence to support the hypothesis that feeding on all three hosts was correlated and controlled by a single locus. Compared to HS, the survival and weight of the selected line were significantly higher on soybean, similar on tobacco and Physalis, and slightly, but not significantly, higher on cotton. We also conducted a behavioral choice test to determine if larval preference for soybean was correlated with preference for other hosts. The selected line larvae had higher preference for soybean and cotton than HS. Preference for tobacco was equal in the selected line and in HS. These results support the trends seen in survival and growth tests where performances on soybean and cotton appeared partially correlated and performances on soybean and tobacco were uncorrelated. In conclusion, the generalist, HV, did not have a single set of loci that governed feeding on soybean, cotton and tobacco. It is likely that some of the loci governing performance and preference for soybean also contributed to performance and preference for cotton and that the soybean loci examined did not interact negatively to lower performance and preference for Physalis, the specialist's host. This approach can be applied more widely to address evolutionary questions about host range and other ecological traits. PMID- 28568917 TI - THE RECONSTRUCTION OF ANCESTRAL CHARACTER STATES. AB - The problem of error in the phylogenetic reconstruction of ancestral character states is explored by developing the model of Frumhoff and Reeve (1994). Information about the evolutionary rate of change within a character is inferred from the distribution of its character states on a known phylogeny, and this information is used to impose confidence limits on the error associated with ancestral state inference. Ancestral state inference is found to be remarkably robust under the model assumptions for a wide range of parameter values; however, the probability of error increases when the number of species within a clade is small and/or state-transition probabilities are strongly skewed in favor of the non-ancestral state. The rationale for expecting such a skew, a hypothesis of parallelism, is shown to rely on assumptions of low rates of change in at least two phylogenetically inherited characters: the tendency to occupy a particular ecological niche and the tendency to respond in a particular way to selection. A means for judging the relative likelihoods of parallelism vs. straightforward homology as explanations for a given character-state distribution is suggested. General problems with the model are discussed, as are methods for making it more realistic. PMID- 28568918 TI - PLEIOTROPIC EFFECTS OF FLOWER-COLOR INTENSITY ON HERBIVORE PERFORMANCE ON IPOMOEA PURPUREA. PMID- 28568919 TI - INTRASPECIFIC VARIATION IN SEX ALLOCATION IN A SIMULTANEOUS HERMAPHRODITE: THE EFFECT OF INDIVIDUAL SIZE. AB - Within a population of simultaneous hermaphrodites, individuals may vary in both their current reproductive investment (biomass invested in gonads) and in how they allocate that investment between male and female function. In the chalk bass, Serranus tortugarum, estimates of both reproductive allocation and reproductive success as a male and a female can be made for individuals of different sizes. As individuals increase in size, their investment in gamete production increases, and there is a shift in allocation to a stronger female bias. Spawning frequency as a female in pair spawnings and as a male in both pair spawning and streaking (an alternative mating tactic) does not vary with individual size. As a result, larger individuals should release more sperm or eggs per spawn. Size-assortative pair spawning in this species leads to larger individuals having higher potential returns in total male reproductive success than smaller individuals, which should lead to increases in absolute levels of sperm production in larger individuals when individuals compete for fertilizations through sperm competition. However, smaller individuals contribute a smaller proportion of the sperm released in spawns with multiple spawners and thus are under more intense sperm competition than larger individuals, which should select for increases in male allocation in smaller individuals, all else equal. A local-mate-competition (LMC) model predicts that these factors select for increasing absolute male and female investment with individual size but a relative shift to more female-biased allocation as individual size increases. These predictions are supported by gonadal data. The predictions of average male allocation from the quantitative LMC model were 21.6% and 25.7%, whereas the collections averaged 21.3%. This close agreement of both the mean male allocation and its relative shift with individual size between model and data support the hypothesis that size-specific shifts in sex allocation in this species represent an adaptive response to patterns of mating success and sperm competition. PMID- 28568920 TI - COMPLEX TRADE-OFFS AND THE EVOLUTION OF STARVATION RESISTANCE IN DROSOPHILA MELANOGASTER. AB - The measurement of trade-offs may be complicated when selection exploits multiple avenues of adaptation or multiple life-cycle stages. We surveyed 10 populations of Drosophila melanogaster selected for increased resistance to starvation for 60 generations, their paired controls, and their mutual ancestors (a total of 30 outbred populations) for evidence of physiological and life-history trade-offs that span life-cycle stages. The directly selected lines showed an impressive response to starvation selection, with mature adult females resisting starvation death 4-6 times longer than unselected controls or ancestors-up to a maximum of almost 20 days. Starvation-selected flies are already 80% more resistant to starvation death than their controls immediately upon eclosion, suggesting that a significant portion of their selection response was owing to preadult growth and acquisition of metabolites relevant to the stress. These same lines exhibited significantly longer development and lower viability in the larval and pupal stages. Weight and lipid measurements on one of the starvation-selected treatments (SB1-5 ), its control populations (CB1-5 ), and their ancestor populations (B1-5 ) revealed three important findings. First, starvation resistance and lipid content were linearly correlated; second, larval lipid acquisition played a major role in the evolution of adult starvation resistance; finally, increased larval growth rate and lipid acquisition had a fitness cost exacted in reduced viability and slower development. This study implicates multiple life-cycle stages in the response to selection for the stress resistance of only one stage. Our starvation-selected populations illustrate a case that may be common in nature. Patterns of genetic correlation may prove misleading unless multiple pleiotropic interconnections are resolved. PMID- 28568921 TI - INBREEDING DEPRESSION IN FOUR POPULATIONS OF COLLINSIA HETEROPHYLLA NUTT (SCROPHULARIACEAE). AB - The effects of one and two generations of inbreeding were studied in plants from four natural populations of the annual plant, Collinsia heterophylla, using inbred and outcrossed plants generated by hand pollinations to create expected inbreeding coefficients ranging from 0-0.75. The selfing rates of the populations were estimated using allozyme markers to range from 0.37-0.69. Inbreeding depression was mild, ranging from 5-40%, but significant effects were detected for characters measured at all stages of the life cycle. Fitness components declined significantly with the inbreeding coefficient, and regression of fitness characters on inbreeding coefficients gave no evidence of any strongly synergistic effects attributable to the different genetic factors that contribute to decline in fitness under inbreeding. The magnitude of inbreeding depression did not clearly decrease with the populations' levels of inbreeding. This is not surprising because the selfing rates are similar enough that it is unlikely that the populations have been characterized for long periods of time by these different inbreeding levels. PMID- 28568922 TI - ON THE EVOLUTION OF PHENOTYPIC PLASTICITY IN A SPATIALLY HETEROGENEOUS ENVIRONMENT. AB - A genetic model for the dynamics of a quantitative trait is analyzed in terms of gene frequencies, linkage disequilibria, and environmental effects on the trait. In a randomly mating population, at each generation progeny move to niches where they are subject to weak Gaussian selection on the trait, with different fitness levels in the different niches. Initially, the variability of the trait is due to additive loci with heterozygous homeostasis. The evolution of plasticity is then described in terms of the invasion of the population by genetic modifiers that may epistatically affect the trait, its optimum in each niche, the strengths of selection, and other parameters characteristic of the niches. We show that the evolution of trait means within niches depends on the overall evolution in the whole system, and in general, optimum phenotypic values are not attained. The reaction norm and genotype-environment interaction may evolve even if the only effects of the modifier are on individual rates of dispersal, or on fitness effects resulting from the different environments in the different niches; this evolution does not require that the modifier affect parameters that influence the values of the trait. It is conjectured that in the least frequently reached niches with low fitness levels, the deviations from the trait optima should be larger than those in more commonly experienced and less stringent niches. Our analysis makes explicit the different contribution of between- and within-niche effects on the evolutionary dynamics of phenotypic plasticity in heterogeneous environments. PMID- 28568923 TI - INDEPENDENT EVOLUTION OF TERRESTRIALITY IN ATLANTIC TRUNCATELLID GASTROPODS. AB - Phylogenetic analysis of truncatellid gastropods using comparative anatomy and ribosomal RNA sequences shows that terrestrial truncatellids likely evolved three times independently in the Caribbean. The terrestrial subfamily Geomelaniinae, characterized in part by pallial fertilization and uniquely derived features of radula and protoconch, occurs in the Greater Antilles and Cayman Islands. Truncatellinae, with renopericardial fertilization, has several widespread amphibious species and two terrestrial species restricted to Trinidad and Barbados. The species in Barbados may be the most recent animal species to evolve full terrestriality; Barbados emerged above sea level only about one million years ago. By the mid-Cenozoic, truncatellids had traits enabling them to colonize land in appropriate tectonic settings. Parallel trends in character evolution occurred in the terrestrial lineages. In older terrestrial radiations, transitional character states would likely be lost, potentially allowing parallelism to confound phylogenetic analysis of morphological characters. PMID- 28568924 TI - EFFECTS ON FITNESS COMPONENTS OF P-ELEMENT INSERTS IN DROSOPHILA MELANOGASTER: ANALYSIS OF TRADE-OFFS. AB - We analyzed the trade-offs between fitness components detected in four experiments in which traits were manipulated by inserting small (control) and large (treatment) P-elements into the Drosophila melanogaster genome. Treatment effects and the interactions of treatment with temperature, experiment, and line were caused by the greater length and different positions of the treatment insert. In inbred flies, the treatment decreased early and total fecundity. Whether it increased the lifespan of mated females depended upon adult density. Analysis of line-by-treatment-by-temperature interactions revealed hidden trade offs that would have been missed by other methods. They included a significant trade-off between lifespan and early fecundity. At 25 degrees C high early fecundity was associated with decreased reproductive rates and increased mortality rates 10-15 days later and persisting throughout life, but not at 29.5 degrees C. Correlations with Gompertz coefficients suggested that flies that were heavier at eclosion also aged more slowly and that flies that aged more slowly had higher fecundity late in life at 25 degrees C. The results support the view that lifespan trades off with fecundity and that late fecundity trades off with rate of aging in fruitflies. Genetic engineering is an independent method for the analysis of trade-offs that complements selection experiments. PMID- 28568925 TI - ERRATUM. PMID- 28568926 TI - POPULATION GENETICS, DIPLOID MALES, AND LIMITS TO SOCIAL EVOLUTION OF EUGLOSSINE BEES. PMID- 28568927 TI - LIFE-HISTORY ADAPTATION AND REPRODUCTIVE ISOLATION IN A GRASSHOPPER HYBRID ZONE. AB - Patterns of life-history adaptation and reproductive isolation were investigated in the acridid grasshoppers Melanoplus sanguinipes and M. devastator, which hybridize along an altitudinal gradient in the Sierra Nevada of California. Melanoplus sanguinipes females crossed with M. devastator males produced eggs that were approximately half as viable as eggs from other crosses. Diminished viability was not attributable either to infection by Wolbachia pipientis or to failure of sperm transfer. When offered an opportunity to choose a mate, females from all populations discriminated against males of the other species, whereas in no-choice tests measuring copulation duration only females from the tails of the clines showed preferences. Melanoplus sanguinipes, found at high elevations where the growing season is short, exhibited faster egg hatch, faster larval development, smaller adult body sizes, and smaller clutch sizes than M. devastator. Melanoplus devastator, from California's Central Valley, endured a hot and dry summer in a reproductive diapause that was absent in M. sanguinipes. Clines in reproductive diapause and clutch size coincided with the region of reproductive incompatibility. Development time, body size, and hatch time also changed across the hybrid zone, but the regions of largest transitions in these traits were either difficult to locate using the limited populations studied here or were not coincident with the zone's center. A method is described for combining ecological and phylogenetic analyses to address the unknown issue of whether life-history divergence has conributed to reproductive isolation in this system. PMID- 28568928 TI - WHY ARE THERE SO MANY SPECIES OF BROODING ANTARCTIC ECHINOIDS? AB - Marine invertebrates display a great variety of life-history traits and reproductive strategies. In echinoids, four patterns of larval development are generally recognized: planktotrophy, pelagic lecithotrophy, bottom dwelling, and brood protecting. Each broad type of free and protected development is found in all the oceans, but comparisons of the principal reproductive modes between different geographic regions have shown that they are not equally distributed. Frequency of pelagic development (planktotrophic and lecithotrophic) decreases from equator to Antarctic, where brood protecting becomes dominant. Numerous theories have been proposed to explain the richness of nonpelagic development in most marine invertebrates within the Southern Ocean. These theories can be grouped into three categories: (1) larval survival, where selection acts on larval; (2) energy allocation; and (3) dispersal. All of them consider the adaptative significance of brood protecting as the key to the success of this strategy in the Antarctic. However, the adaptative significance of brooding and the evolutionary success of this strategy in the Antarctic must be considered as two separate questions. To consider the problem at an evolutionary level, we have examined the consequences of different reproductive strategies on the genetic structure of species and on the long-term evolution of the clade. We examine this problem in the case of echinoids, a clade particularly well suited to addressing this question. In echinoids, the reduction of larval-stage duration is associated with a decrease in gene flow and consequently in the geographical scale of genetic differentiation. This allows us to reconsider the high-speciation-rate model, which leads to an increase in the number of low-dispersal species (isolation by distance). This model, previously tested by means of fossils is not satisfactory in living echinoids. Thus, the model is rebuilt with the addition of differential extinction rate between planktotrophic and brooding species in relation with the climatic history of the Antarctic. PMID- 28568929 TI - EVOLUTIONARY ADAPTATION TO TEMPERATURE. V. ADAPTIVE MECHANISMS AND CORRELATED RESPONSES IN EXPERIMENTAL LINES OF ESCHERICHIA COLI. AB - We previously demonstrated temperature-specific genetic adaptation in experimental lines of Escherichia coli. Six initially identical populations were propagated for 2000 generations under each of five regimes: constant 20 degrees C, 32 degrees C, 37 degrees C, and 42 degrees C, and a daily switch between 32 degrees C and 42 degrees C. Glucose was the sole carbon source in all cases. Here, we examine the physiological bases of adaptation to determine whether the same mechanisms evolved among the replicate lines within each thermal regime and across different regimes. Specifically, we investigate whether changes in glucose transport may account for the temperature-specific adaptation. We compared each line's direct response of fitness to glucose with its correlated response to maltose; glucose and maltose enter the cell by different pathways, but their catabolism is identical. Except for lines maintained at the ancestral temperature (37 degrees C), almost all derived lines had significantly different fitnesses (relative to their common ancestor) in glucose and maltose, supporting the hypothesis that adaptation involved changes in glucose transport. An alternative explanation, that maltose transport decayed by genetic drift, appears unlikely for reasons that are discussed. Although most lines showed evidence of temperature-specific adaptation in glucose transport, several different mechanisms may underlie these improvements, as indicated by heterogeneity in correlated responses (across temperatures and substrates) among replicate lines adapted to the same regime. This heterogeneity provides a latent pool of genetic variation for responding to environmental change. PMID- 28568930 TI - PATERNAL MITOCHONDRIAL DNA DIFFERENTIATION FAR EXCEEDS MATERNAL MITOCHONDRIAL DNA AND ALLOZYME DIFFERENTIATION IN THE FRESHWATER MUSSEL, ANODONTA GRANDIS GRANDIS. PMID- 28568931 TI - GENETIC EVIDENCE FOR REPRODUCTIVE ISOLATION AND MULTIPLE ORIGINS OF SYMPATRIC TROPHIC ECOTYPES OF WHITEFISH (COREGONUS). AB - We assessed variation in mitochondrial DNA (mtDNA) by restriction fragment length polymorphism (RFLP) analysis and in nuclear genes by allozyme analysis among sympatric pairs of limnetic and benthic ecotypes of whitefish (Coregonus) coexisting in three lakes of southern Yukon to address three evolutionary questions regarding their origins. Are sympatric low and high gill-raker count ecotypes genetically differentiated? Are they issued from monophyletic or polyphyletic evolutionary events? If they are polyphyletic in origins, did they originate from multiple allopatric speciation events or intralacustrine radiation? Our results corroborated previous genetic and ecological studies of these ecotypes, indicating that they represent genetically distinct reproductive units, and therefore refuting the hypothesis of phenotypic polymorphism within a single population. However, the amount of gene flow between ecotypes varied among lakes, correlating with the extent of morphological differentiation and the potential for premating reproductive isolation. The results indicated a polyphyletic origin of ecotypes whereby each of them have been expressed independently more than once. In the two lakes of Squanga Creek drainage, the existence of sympatric pairs was best explained by the secondary contact of two monophyletic whitefish groups that evolved in allopatry during the last glaciation events. In Dezadeash L. of Alsek R. drainage, our results could not verify either sympatric or allopatric (or microallopatric) origin of ecotypes. Regardless of the mode of speciation involved in their origins, these sympatric whitefish populations provided further evidence that Pleistocene glaciation events created conditions favoring rapid divergence and phenotypic differentiation among northern freshwater fishes. PMID- 28568932 TI - SEXUAL SELECTION, VIABILITY SELECTION, AND DEVELOPMENTAL STABILITY IN THE DOMESTIC FLY MUSCA DOMESTICA. AB - Associations between developmental stability, sexual selection, and viability selection were studied in the domestic fly Musca domestica (Diptera, Muscidae). Developmental stability of the wings and tibia of flies of both sexes, measured in terms of their level of fluctuating asymmetry, was positively associated with mating success in free ranging populations and in sexual selection experiments. Mated individuals may have obtained indirect fitness benefits from sexual selection of two different kinds. First, the entomopathogenic fungus Enthomophthora muscae (Zygomycetes, Entomophthorales) infects and kills adult domestic flies, and flies dead from fungus infections had more asymmetric wings than flies dead for other reasons. Experimental deposition of fungus spores on uninfected flies demonstrated that flies with asymmetric wings were more susceptible to fungus infections than flies with symmetric wings. Second, domestic flies were frequently eaten by insectivorous barn swallows Hirundo rustica, and flies depredated by birds had more asymmetric wings and tibia than surviving flies. PMID- 28568933 TI - PARENTAL EFFECTS IN PLANTAGO LANCEOLATA L. I.: A GROWTH CHAMBER EXPERIMENT TO EXAMINE PRE- AND POSTZYGOTIC TEMPERATURE EFFECTS. AB - In spite of the potential evolutionary importance of parental effects, many aspects of these effects remain inadequately explained. This paper explores both their causes and potential consequences for the evolution of life-history traits in plants. In a growth chamber experiment, I manipulated the pre- and postzygotic temperatures of both parents of controlled crosses of Plantago lanceolata. All offspring traits were affected by parental temperature. On average, low parental temperature increased seed weight, reduced germination and offspring growth rate, and accelerated onset of reproduction by 7%, 50%, 5%, and 47%, respectively, when compared to the effects of high parental temperature. Both pre- and postzygotic parental temperatures (i.e., prior to fertilization vs. during fertilization and seed set, respectively) influenced offspring traits but not always in the same direction. In all cases, however, the postzygotic effect was stronger. The prezygotic effects were more often transmitted paternally than maternally. Growth and onset of reproduction were influenced both directly by parental temperature as well as indirectly via the effects of parental temperature on seed weight and germination. Significant interactions between parental genotypes and prezygotic temperature treatment (G * E interactions) show that genotypes differ in their intergenerational responses to temperature with respect to germination and growth. The data suggest that temperature is involved in both genetically based and environmentally induced parental effects and that parental temperature may accelerate the rate of evolutionary change in flowering time in natural populations of P. lanceolata. The environmentally induced temperature effects, as mediated through G * (prezygotic) E interactions are not likely to affect the rate or direction of evolutionary change in the traits examined because postzygotic temperature effects greatly exceed prezygotic effects. PMID- 28568934 TI - QUANTITATIVE GENETICS AND POPULATION DYNAMICS. AB - This study examines the dynamics of a competition and a host-parasite model in which the interactions are determined by quantitative characters. Both models are extensions of one-dimensional difference equations that can exhibit complicated dynamics. Compared to these basic models, the phenotypic variability given by the quantitative characters reduces the size of the density fluctuations in asexual populations. With sexual reproduction, which is described by modeling the genetics of the quantitative character explicitly with many haploid loci that determine the character additively, this reduction in fitness variance is magnified. Moreover, quantitative genetics can induce simple dynamics. For example, the sexual population can have a two-cycle when the asexual system is chaotic. This paper discusses the consequences for the evolution of sex. The higher mean growth rate implied by the lower fitness variance in sexual populations is an advantage that can overcome a twofold intrinsic growth rate of asexuals. The advantage is bigger when the asexual population contains only a subset of the phenotypes present in the sexual population, which conforms with the tangled bank theory for the evolution of sex and shows that tangled bank effects also occur in host-parasite systems. The results suggest that explicitly describing the genetics of a quantitative character leads to more flexible models than the usual assumption of normal character distributions, and therefore to a better understanding of the character's impact on population dynamics. PMID- 28568935 TI - SHELL MICROSTRUCTURE OF GASTROPODS FROM LAKE TANGANYIKA, AFRICA: ADAPTATION, CONVERGENT EVOLUTION, AND ESCALATION. AB - Gastropod shells from Lake Tanganyika, with their heavy calcification, coarse noded ribbing, spines, apertural lip thickening and repair scars, resemble marine shells more closely than they resemble other lacustrine shells. This convergence between Tanganyikan and marine gastropod shells, however, is not just superficial. Scanning electron microscope (SEM) studies reveal that the Tanganyikan shells are primarily layers of crossed-lamellar crystal architecture (that is, needle-like aragonite crystals arranged into laths that are packed into sheets such that the aragonite needles of adjacent laths are never parallel). The number of crossed-lamellar layers can vary from one to four between different Tanganyikan gastropod species. In species with two or more crossed-lamellar layers, the orientation of the lamellae is offset by approximately 90 degrees between the different layers. The number of crossed-lamellar layers in the shell wall is positively correlated with shell strength and with predation resistance. Three and four crossed-lamellar layers in the shell wall evolved several times independently within the endemic thiarid gastropod radiation in Lake Tanganyika. Repeated origins of three and four crossed-lamellar layers suggest that they may be specific adaptations by Tanganyikan gastropods to strengthen their shells as a defense against shell-crushing predators. PMID- 28568936 TI - SELECTION AND THE "SEX-RATIO" POLYMORPHISM IN NATURAL POPULATIONS OF DROSOPHILA PSEUDOOBSCURA. AB - "Sex-ratio" (SR) is a naturally occurring X-linked meiotic drive system, where the SR-X chromosome is transmitted to nearly all progeny of SR males. It occurs at frequencies of up to 25% in some populations of Drosophila pseudoobscura. Because of the twofold drive advantage, SR should rapidly fix in populations, causing the extinction of the species, unless opposed by strong selection. I examine several of the adult components of fitness, including the frequencies of all genotypic mating combinations, fertilities, and fecundities of flies from two populations in southeastern Arizona. Significant reduction of fecundity of SR/SR females was observed in the Tucson population. No evidence was found for either lower fertility or reduced mating success of SR males, relative to standard males. Most selection opposing SR appears to be operating at the larval stages in nature. PMID- 28568937 TI - EXPERIMENTAL EVIDENCE FOR THE GENETIC-TRANSILIENCE MODEL OF SPECIATION. PMID- 28568938 TI - MOLECULAR EVIDENCE FOR KIN GROUPS IN THE ABSENCE OF LARGE-SCALE GENETIC DIFFERENTIATION IN A MIGRATORY BIRD. PMID- 28568939 TI - EVOLUTIONARY PATTERNS OF ALTERED BEHAVIOR AND SUSCEPTIBILITY IN PARASITIZED HOSTS. AB - Adaptation is the usual context for interpreting parasite-host interactions. For example, altered host behavior is often interpreted as a parasite adaptation, because in some cases it enhances parasite transmission. Resistance to parasites also has obvious adaptive value for hosts. However, it is difficult to evaluate the adaptive significance of host-parasite interactions without considering the historical context in which these traits have evolved and if they can be predicted by host (or parasite) phylogeny. We examined the influence of host phylogeny on patterns of altered behavior and resistance to parasitism in a cockroach-acanthocephalan system. A consensus cladogram for cockroach subfamilies was produced from the morphological data of McKittrick. We used this cladogram to predict patterns of altered host behavior in seven cockroach host species. Each species was experimentally infected with a single species of acanthocephalan, Moniliformis moniliformis, a parasite that is transmitted when cockroaches are eaten by rodent final hosts. Activity patterns, substrate choices, and responses to light were measured for control and infected animals. These data were recoded into a behavioral matrix of discrete characters. We determined the most parsimonious distribution of the behavioral characters on the tree obtained from McKittrick's data. We then measured the concordance between the behavioral data and the cockroach cladogram with the consistency index (CI). We compared the observed CI to the expected value based on a randomization of observed character states. For three different models of evolutionary character change, there was no evidence of strong concordance (significantly large CI) between altered host behavior and host relationships. Parsimony analysis of the interior nodes of the phylogenetic reconstruction suggested that unaltered behavior was the ancestral state for most host behaviors. We also compared host phylogeny to a data set on the susceptibility of 29 cockroach species to infection with M. moniliformis. At the species level, there was a significant concordance between susceptibility and host phylogeny. This pattern was consistent with the finding that susceptibility of species varied significantly among different subfamilies. However, at the subfamily level, susceptibility was not strongly concordant with phylogeny. We predict that, given enough time, resistance should be lost in subfamilies that are currently resistant to parasitism. In spite of the potential importance of phylogeny in the evolution of behavior and susceptibility, we found little evidence for phylogenetic effects in this system. We conclude that changes in the behavioral responses of hosts to parasites and, to a lesser extent, changes in susceptibility are more frequent than cockroach speciation events in different cockroach lineages. This finding strengthens the assertion that at least some of the altered behaviors are adaptive for host and/or parasite. PMID- 28568940 TI - PERSPECTIVE METAZOAN COMPLEXITY AND EVOLUTION: IS THERE A TREND? AB - The notion that complexity increases in evolution is widely accepted, but the best-known evidence is highly impressionistic. Here I propose a scheme for understanding complexity that provides a conceptual basis for objective measurement. The scheme also shows complexity to be a broad term covering four independent types. For each type, I describe some of the measures that have been devised and review the evidence for trends in the maximum and mean. In metazoans as a whole, there is good evidence only for an early-Phanerozoic trend, and only in one type of complexity. For each of the other types, some trends have been documented, but only in a small number of metazoan subgroups. PMID- 28568941 TI - MULTIVARIATE PATTERNS OF GENETIC DIFFERENTIATION SUPPORT COMPLEX COLONIZATION SCHEMES IN BUFO MARINUS POPULATIONS. PMID- 28568942 TI - ADAPTIVE RADIATION OF DAY-GECKOS (PHELSUMA) IN THE SEYCHELLES ARCHIPELAGO: A PHYLOGENETIC ANALYSIS. AB - A phylogenetic analysis using characters derived from mitochondrial DNA was used to show that the species of Phelsuma in the Seychelles Islands represent a single, monophyletic lineage that has diversified as a result of both historical and ecological factors. In the distant past, the Seychelles archipelago was physically invaded by a single species of Phesluma. Separate eustatic sea level changes likely led first to allopatric speciation and then to the secondary contact of these sister species. Differences in the relative timing of the secondary contact between island groups resulted in P. sundbergi evolving an intermediate body size in the group of islands associated with Mahe and a large body size, while sympatric with P. astriata, in the group of islands associated with Praslin. Ecological information was used to support the conclusion that the actual evolutionary mechanism for the body size shift was a response to frequency dependent natural selection of P. sundbergi in single-species and two-species competitive regimes. PMID- 28568943 TI - PHYLOGENY AND EVOLUTION OF PARTHENOGENETIC WEEVILS OF THE ARAMIGUS TESSELLATUS SPECIES COMPLEX (COLEOPTERA: CURCULIONIDAE: NAUPACTINI): EVIDENCE FROM MITOCHONDRIAL DNA SEQUENCES. AB - Molecular-phylogenetic studies of parthenogenetic animals have been a valuable recent addition to the literature on the evolutionary biology of sex. By illuminating the origins and ages of parthenogenetic lineages, such studies can help to define the temporal scale at which selection acts against parthenogenetic lineages, as well as provide an essential framework for further study. Although parthenogenetic weevils have played an important role in cytogenetic and protein electrophoretic studies of parthenogenesis, they have not previously been subjects of DNA-based molecular-phylogenetic study. A mitochondrial DNA study of Aramigus tessellatus, a species complex of weevils native to South America, indentified 12 distinct (1-9% divergent) maternal lineages, of which 2 represent sexual populations, while at least 9 represent parthenogenetic lineages. These lineages partially correspond to lineages previously recognized by morphological differences. Phylogenetic analysis found 14 most parsimonious trees, according to which parthenogenesis appears to have arisen 3-7 times. There is a monophyletic group of lineages (the "brown clade"), having up to 4.5% sequence divergence within it, which may be primitively parthenogenetic and over 2 million years old. PMID- 28568944 TI - ESTIMATION OF GENETIC NEIGHBORHOOD PARAMETERS FROM POLLEN AND SEED DISPERSAL IN THE MARINE ANGIOSPERM ZOSTERA MARINA L. AB - The relative importance of random genetic drift and local adaptation in causing population substructuring in plant species remains an important empirical question. Here I estimate the effective size of the genetic neighborhood, Nb , as a means of evaluating the likely role of genetic drift in creating genetic differentiation within a population of a marine plant, Zostera marina L. (eelgrass). Calculations of effective neighborhood size are based on field estimates of pollen and seed-dispersal distributions, an electrophoretic estimate of the mating system using open-pollinated progeny arrays, and determination of the effective density of reproductive individuals in the population. Neighborhood area calculated from the parent-offspring dispersal variances was equal to Na = 524 m2 ; variance in the seed-dispersal distribution contributes more than twice as much as variance in pollen dispersal to Na . Including an outcrossing rate slightly different from random, estimated neighborhood size for Z. marina is Nb = 6255. This estimate is one of the largest reported for plants or animals and indicates that genetic drift in small neighborhoods is highly unlikely to cause genetic substructuring in the study population. High gene-flow levels provided by the marine environment appear to prevent genetic isolation by distance among eelgrass patches, but the importance of drift through founder events in this population characterized by high patch turnover cannot be discounted and is the subject of ongoing study. PMID- 28568945 TI - THE USE OF DNA DIVERGENCE TO HELP DETERMINE THE CORRELATES OF EVOLUTION OF MORPHOLOGICAL CHARACTERS. AB - Even though, from Darwin onwards, interisland evolution has been a cornerstone of evolutionary theory it has not been possible to determine to what extent this geographic variation reflects the phylogeny (e.g., pattern of island colonization) or ecogenetic adaptation to different ecological conditions on each island. Using the morphology of western Canary Island lacertids (Gallotia galloti) as an example, a procedure is explored that gives a preliminary answer to this problem when there are a limited number of islands. The phylogenetic component (represented by patristic distances derived from 1005 mitochondrial DNA [mtDNA] base pairs) can be separated from two potential ecogenetic factors (environmental richness and climate) by partial Mantel tests. This reveals that, although these components interact, some characters are correlated primarily to biodiversity/paucity (e.g., size), others are correlated to wet and lush environments (e.g., dorsal pattern), and others are correlated primarily to the phylogeny (e.g., sexual leg markings). The former two correlations may be due to ecogenetic adaptation to current ecological conditions, wheras the latter reflects historical processes. PMID- 28568947 TI - MITOCHONDRIAL DNA PHYLOGEOGRAPHY OF HOST RACES OF THE GOLDENROD BALL GALLMAKER, EUROSTA SOLIDAGINIS (DIPTERA: TEPHRITIDAE). AB - We determined the phylogenetic relationships and geographic distribution of mitochondrial haplotypes of two host races of the tephritid fly Eurosta solidaginis, a gallmaker that attacks species of goldenrod (Solidago). We performed a preliminary survey by sequencing 492 bp from the 3' ends of the mitochondrial cytochrome oxidase I and II subunits from a single individual from eight S. gigantea- and 10 S. altissima-associated populations across their range in eastern North America and from two outgroup species, Eurosta comma (two populations) and E. cribrata. Eurosta solidaginis haplotypes fell into two groups ("E" and "W" clades), which differed by four substitutions, one of which occurred within the recognition site of the DdeI restriction enzyme. We used the presence or absence of the restriction site to survey a total of 11 S. gigantea (20 individuals) and 20 S. altissima (43 individuals) host-race populations. All gigantea-fly haplotypes regardless of geographic origin carried the E-clade haplotype, whereas altissima-fly haplotypes were geographically partitioned. Altissima flies east of Michigan were of haplotype E, whereas those west of Michigan were of haplotype W, with mixed populations found in lower Michigan. These patterns confirm an earlier allozyme survey that suggested that S. altissima is the ancestral host for the gallmaker, but also suggest that the gigantea fly populations were derived from eastern U.S. altissima fly populations. The data support the conclusions of behavioral and ecological studies indicating that the shift to the derived host was facilitated by escape from natural enemies. PMID- 28568946 TI - CHARACTER DISCRIMINATORY POWER, CHARACTER-SET CONGRUENCE, AND THE CLASSIFICATION OF INDIVIDUALS FROM HYBRID ZONES: AN EXAMPLE USING STONE CRABS (MENIPPE). AB - Many investigators categorize individuals from hybrid zones to facilitate comparisons among genotypic classes (e.g., parental, F1 , backcross) for comparative studies in which components of fitness or geographic variation are being analyzed. Frequently, multiple character sets representing genetically independent traits are used to classify these individuals and various methodologies are employed to combine the classifications obtained from the different character sets. We adapted the principles of total evidence and taxonomic congruence (two formalized approaches used by systematists in formulating phylogenetic hypotheses) to address the problem of discriminating hybridizing species and classifying individuals from hybrid zones. As our model, we used two morphological (coloration and morphometric) and two molecular (allozyme and mitochondrial DNA restriction-fragment-length polymorphism) character sets that differentiate two stone crab species (Menippe adina and M. mercenaria). Using principal-components analysis, we determined that combining character sets and eliminating characters or character sets that did not have large eigenvector coefficients for the principal component that best separated the two species yielded the highest level of discrimination between species and allowed us to classify a broad range of morpho-genotypes as hybrids. For the stone crabs, three diagnostic allozyme loci and five diagnostic coloration characters best separated the species. The two character sets were not completely congruent, but they agreed in their classification of 50% of the individuals from the hybrid zone and rarely strongly disagreed in their classifications. Classification discrepancies between the two character sets probably represent variation between traits in interspecific gene flow rather than intraspecific, ecologically mediated variation. Our results support the assertions of previous investigators who espoused the benefits associated with using multiple character sets to classify individuals from hybrid zones and demonstrate that, if character sets are reasonably congruent and numerically balanced, combining diagnostic characters from multiple character sets (a total-evidence approach) can enhance discriminatory power between species and facilitate the assignment of hybrid-zone individuals to genotypic classes. On the contrary, classifying hybrid-zone individuals using character sets separately (a taxonomic-congruence approach) provides the opportunity to compare levels of introgression between species and to assess reasons for discordance among the data sets. PMID- 28568948 TI - MATING SYSTEM AND ASYMMETRIC HYBRIDIZATION IN A MIXED STAND OF EUROPEAN OAKS. AB - The sessile (Quercus petraea [Matt.] Liebl.) and pedunculate (Quercus robur L.) oaks are two closely related species having a wide sympatric distribution over Europe. Under natural conditions, they frequently form mixed forests, where hybridization is suspected to occur. In this paper, two different approaches have been applied to the study of the mating system and the interspecific gene flow in a mixed stand formed by the two species. The mating systems of both species have been studied separately by means of the mixed-mating model. The relative contribution of the parental species to the progenies have been estimated with two different methods. The first uses the admixture model. The second is an extension of the mixed-mating model and subdivides the outcrossing rate into intra- and interspecific components. The two species were almost completely outcrossing. This high level of outcrossing and interspecific gene flow could play an important role in the maintenance of the genetic diversity in these long lived forest tree species. The contribution of the sessile oak to the pedunculate oak progenies varied from 17% to 48%. In contrast, ovules of sessile oak trees appear to be preferentially fertilized by other extreme sessile genotypes. We suggest that interspecific and directional gene flow was responsible for such patterns. Pedunculate oak is considered as a pioneer species and is progressively replaced by sessile oak. Our present findings add a further genetic component to this succession scheme, suggesting that unidirectional gene flow reinforces succession between the two species. PMID- 28568949 TI - DIFFERENT PATHWAYS IN ARTHROPOD POSTEMBRYONIC DEVELOPMENT. AB - To investigate the consequences of canalization and plasticity in arthropod developmental pathways, we developed a model that predicts eight possible combinations among three larval developmental parameters. From the descriptions of insect and spider postembryonic development, it is apparent that not all aspects of juvenile development are plastic and that species differ in which traits are plastic. Most strikingly, only four of the possible eight combinations of canalized and plastic parameters have been found in nature. Using this model, we show that the identity of the canalized developmental parameters and the degree of genetic variation in the value at which a given parameter is fixed have important implications for the ecology and evolution of complex life cycles. PMID- 28568950 TI - OPTIMAL SAMPLING DESIGN FOR STUDIES OF GENE FLOW FROM A POINT SOURCE USING MARKER GENES OR MARKED INDIVIDUALS. PMID- 28568951 TI - POSTMATING ISOLATION ANALYSIS IN FOUNDER-FLUSH EXPERIMENTAL POPULATIONS OF DROSOPHILA PSEUDOOBSCURA. PMID- 28568952 TI - THE PARADOX OF THE PHYLOGENY: CHARACTER DISPLACEMENT OF ANALYSES OF BODY SIZE IN ISLAND ANOLIS. AB - The evolution of body size in Anolis lizards of the Lesser Antilles Islands has been the subject of intensive, if divisive, study. Early research by Schoener revealed a regularity in the number of Anolis species that coexisted on islands and the difference in body size between coexisting congeners in the Northern Lesser Antilles. This consistent pattern of body size was suggested to be the result of competitive character displacement. Two recent studies critically evaluated this hypothesis by incorporating information about the phylogenetic relationships of insular Anolis. Roughgarden and Pacala suggested that the patterns of body-size differences in the Northern Lesser Antilles could be explained as a cyclical phenomenon that they labeled a taxon cycle. However, Losos supported the character-displacement hypothesis ("size adjustment"). The conflict between these two studies is important because both investigations were based on the same phylogenetic hypothesis. We investigated body-size evolution in Lesser Antilles Anolis to resolve the differences in the conclusions of these studies. Our new analysis supported the taxon-cycle hypothesis but nevertheless failed to reject the character-displacement hypothesis. We argue that this curious scenario is largely a function of the method by which phylogenetic information is incorporated in comparative analyses. Different comparative analyses may lead to dramatic differences in results and ambiguity in the conclusions to be drawn. We suggest that ecologists and evolutionary biologists specifically consider the underlying assumptions and models of character evolution inherent to each of the phylogenetically based analytical methods now available. PMID- 28568953 TI - INBREEDING: ITS EFFECT ON RESPONSE TO SELECTION FOR PUPAL WEIGHT AND THE HERITABLE VARIANCE IN FITNESS IN THE FLOUR BEETLE, TRIBOLIUM CASTANEUM. AB - We report our studies of the effect of inbreeding on the response to selection for increased pupal weight in the flour beetle, Tribolium castaneum. We also report the effects of inbreeding and selection for pupal weight on the heritable variation in fitness and fitness components. We created replicate and independent inbred lines with F-values of 0.00, 0.375, and 0.672, by 0, 2, and 5 generations, respectively, of brother-sister mating of adult beetles from an outbred stock population. Subsequently, we imposed artificial within-family selection for increased pupal weight in each of 15 inbred lines for eight generations; each line had its own paired, unselected control. We compared the response to selection across the three levels of inbreeding with theoretical expectation, and investigated the effects of inbreeding and selection on fitness variation among families within all 30 selected and control lines. Among-line variation in pupal weight increased with increased inbreeding prior to selection but diminished with directional selection. Inbreeding reduced the realized heritability of pupal weight concordant with quantitative predictions of additive theory. Mean fitness, measured in several ways, declined with inbreeding and declined further with selection. In contrast, the genetic variation for fitness in the inbred and selected lines lines equalled or exceeded that of the outbred controls. Our results suggest that inbreeding and selection may affect traits in different ways depending on the relative amounts of additive and nonadditive genetic variation. PMID- 28568954 TI - EVOLUTION OF UNISEXUALITY IN THE HAWAIIAN FLORA: A TEST OF MICROEVOLUTIONARY THEORY. AB - The evolution of separate sexes as a means of avoiding self-fertilization requires the controversial coexistence of large inbreeding depression and high selfing rate in the ancestral hermaphrodite population. Fitness components of adult females and hermaphrodites in nature, of their open-pollinated progeny, and of experimental selfs and outcrosses onto hermaphrodites were compared in endemic Hawaiian Bidens sandvicensis, all of whose known populations are gynodioecious, consisting of a mixture of females and hermaphrodites. Multilocus selfing rates of hermaphrodites were also estimated, and sex morph ratio monitored over four seasons in three populations of B. sandvicensis and one population of gynodioecious B. cervicata. Total mean inbreeding depression in seed set (in the glasshouse), germination rate (in an open-air nursery on Kauai), and first year survivorship and fecundity in the field were estimated as 0.94 (SE 0.04), and occurred primarily in drought months. Lower survivorship and fecundity of selfs were partially explained by their consistently smaller size. Open-pollinated seed of females had significantly lower germination rate, proportion flowering, and fecundity than outcrossed progeny of hermaphrodites, suggesting moderate biparental inbreeding in females and a lack of any non-outcrossing advantage to progeny of females. In all fitness components, open-pollinated progeny of hermaphrodites were inferior to those of females and to outcrosses, and in most components were superior to selfs. Total performance of open-pollinated progeny of females relative to those of hermaphrodites was calculated as 2.3 (SE = 0.4), but since inflorescences of females also set 20% to 50% more seed than those of hermaphrodites, their total relative ovule success was estimated as 3.2 (SE = 0.5). If inheritance of male sterility is nuclear, this superiority is sufficient to maintain females in frequencies over 20% in populations, whose actual frequencies ranged from 14% to 33%. In four populations, selfing rates of hermaphrodites, assayed in seedlings, were 0.50, 0.45, 0.25, and 0.30, but since substantial inbreeding depression occurred prior to germination, the mean selfing rate of hermaphrodite ovules exceeded 0.57. Female frequencies were significantly higher in the two populations with higher hermaphrodite selfing rate. These results suggest that inbreeding depression can exert a profound influence on the mating system of self-compatible plants on Hawaii and perhaps other oceanic islands, and can be sufficiently strong to electively favor the elimination of the male function. PMID- 28568955 TI - SOCIAL SELECTION AND THE EVOLUTION OF ANIMAL SIGNALS. AB - Social selection is presented here as a parallel theory to sexual selection and is defined as a selective force that occurs when individuals change their own social behaviors, responding to signals sent by conspecifics in a way to influence the other individuals' fitness. I analyze the joint evolution of a social signal and behavioral responsiveness to the signal by a quantitative genetic model. The equilibria of average phenotypes maintained by a balance of social selection and natural selection and their stability are examined for two alternative assumptions on behavioral responsiveness, neutral and adaptive. When behavioral responsiveness is neutral on fitness, a rapid evolution by runaway selection occurs only with enough genetic covariance between the signal and responsiveness. The condition for rapid evolution also depends on natural selection and the number of interacting individuals. When signals convey some information on signalers (e.g., fighting ability), behavioral responsiveness is adaptive such that a receiver's fitness is also influenced by the signal. Here there is a single point of equilibrium. The equilibrium point and its stability do not depend on the genetic correlation. The condition needed for evolution is that the signal is beneficial for receivers, which results from reliability of the signal. Frequency-dependent selection on responsiveness has almost no influence on the equilibrium and the rate of evolution. PMID- 28568956 TI - MODE OF SEXUAL SELECTION DETERMINED BY RESOURCE ABUNDANCE IN TWO SAND GOBY POPULATIONS. AB - We used field observations and experiments to show that sexual selection in two populations of sand gobies, Pomatoschistus minutus (Pisces, Gobiidae), was affected by differences in resource availability. Male sand gobies rely on empty mussel shells for nest building and spawning. The two populations differed considerably in nest-site abundance and sexual-selection regimes. In one population nest sites were scarce, leading to stronger male-male competition over nests, a higher nest site colonization rate and reduced potential for female choice compared with the other population that had a surplus of nests. In the high-competition population, males were larger than females, perhaps as a response to selection, whereas the other population was not sexually size dimorphic. The results from the field were confirmed in a pool experiment that demonstrated the effect of nest abundance on nest occupancy and male reproductive success. Larger males were more successful in obtaining nest sites in both high and low nest availability treatments. Larger males were also favored by females as mating partners, but only in the treatment with surplus nest sites. Nest shortage was associated with an increased potential for intrasexual selection (measured as the coefficient of variation), whereas the potential for intersexual selection was increased when nests were common. In conclusion, nest-site abundance can influence the relative contribution of intrasexual competition and mate choice in a population. Hence, resource availability can contribute to within-species variation in mating patterns. PMID- 28568957 TI - ADAPTATION TO FERMENTING RESOURCES IN DROSOPHILA MELANOGASTER: ETHANOL AND ACETIC ACID TOLERANCES SHARE A COMMON GENETIC BASIS. AB - Ethanol and acetic acid tolerances were compared in a French, highly tolerant population, and in a Congolese, very sensitive population. For both tolerances, chromosome substitutions demonstrated a major effect on chromosome 3, a lesser effect on chromosome 2, and no effect on chromosome 1, except in interactions. Directional selection experiments led to significant increases of tolerance to both toxics. Of greater interest, a strong correlated response was observed in each line: increased ethanol tolerance was accompanied by higher acetic acid tolerance and vice versa. A high genetic correlation (average value r = 0.77) was found between the two traits. These data suggest that alcohol dehydrogenase (ADH) activity does not play a major role in explaining the physiological differences known between Afrotropical and European populations. The metabolic flux permitting the detoxification of ethanol and acetic acid seems to be mainly controlled by acetyl-coA synthetase (ACS) at least in adult flies. Acetic acid adaptation could be as important as ethanol adaptation in the ecology of Drosophila melanogaster and other Drosophila species. PMID- 28568958 TI - RESPONSE TO SELECTION ON AUTOGAMY IN PHLOX. AB - Two cycles of artificial selection were performed to increase autogamous fruiting in two wild populations of the self-incompatible Phlox drummondii, to decrease autogamous fruiting in two wild populations of the self-compatible Phlox cuspidata, and to both increase and decrease autogamous fruiting in a cultivar of P. drummondii which is pseudo-self-compatible. The breeding systems were determined to be genetically quite flexible, independent of inbreeding depression and other genetic phenomena which could hinder a breeding system shift. This is especially true for increasing autogamy. Self-pollen-pistil compatibility seems to be the single character affected by selection. Based on the continuous variation in both autogamy and self-compatibility, we suggest that the change has been due to genes which modify the self-incompatibility reaction rather than to the simple segregation of alleles at the S-locus. PMID- 28568959 TI - FECAL METHANOGENS AND VERTEBRATE EVOLUTION. AB - It has been assumed that the feeding habits of vertebrates predispose the variety of intestinal differentiations and the composition of the microbial biota living in their intestinal tracts. Consequently, the presence of methanogenic bacteria in the various differentiations of the large intestine and the foregut of herbivorous vertebrates had been attributed primarily to the existence of anaerobic habitats and the availability of carbon dioxide and hydrogen originating from the fermentative microbial digestion of plant-based diets. However, Australian ratites, many murids, and several New World primates lack methanogens, despite their intestinal differentiations and their vegetarian feeding habits. Crocodiles, giant snakes, aardvarks, and ant-eaters on the other hand release significant amounts of methane. A determination of methane emissions by 253 vertebrate species confirmed that competence for intestinal methanogenic bacteria is shared by related species and higher taxa, irrespective of different feeding habits. In "methanogenic" branches of the evolutionary tree, a variety of differentiations of the large intestine evolved and, in some cases, differentiations of the foregut. In contrast, the lack of competence for methanogens in chiropterans/insectivores and carnivores apparently has precluded the evolution of specialized fermenting differentiations of the digestive tract. Our observations reveal that the presence of intestinal methanogenic bacteria is under phylogenetic rather than dietary control: competence for intestinal methanogenic bacteria is a plesiomorphic (primitive-shared) character among reptiles, birds, and mammals. This competence for methanogenic bacteria has been crucial for the evolution of the amniotes. PMID- 28568960 TI - FEMALE CONTROL OF SPERM TRANSFER AND INTRASPECIFIC VARIATION IN SPERM PRECEDENCE: ANTECEDENTS TO THE EVOLUTION OF A COURTSHIP FOOD GIFT. AB - Manipulation of ejaculates is believed to be an important avenue of female choice throughout the animal kingdom, but evidence of its importance to sexual selection remains scarce. In crickets, such manipulation is manifest in the premature removal of the externally attached spermatophore, which may afford females an important means of postcopulatory mate choice. We tested the hypothesis that premature spermatophore removal contributes significantly to intraspecific variation in sperm precedence by (1) experimentally manipulating spermatophore attachment durations of competing male Gryllodes sigillatus and (2) employing protein electrophoresis to determine the paternity of doubly mated females. The relative spermatophore attachment durations of competing males had a significant influence on male paternity, but the pattern of sperm precedence deviated significantly from the predictions of an ideal lottery. Instead, paternity data and morphological evidence accorded best with a model of partial sperm displacement derived here. Our model is similar to a displacement model of Parker et al. in that sperm of the second male mixes instantaneously with that of the first throughout the displacement process, but the novel feature of our model is that the number of sperm displaced is only a fraction of the number of sperm transferred by the second male. Regardless of the underlying mechanism, female G. sigillatus can clearly alter the paternity of their offspring through their spermatophore-removal behavior, and employ such cryptic choice in favoring larger males and those providing larger courtship food gifts. We discuss how female control of sperm transfer and intraspecific variation in sperm precedence may be important precursors to the evolution of gift giving in insects. PMID- 28568962 TI - Rhetoric versus reality: The role of research in deconstructing concepts of caring. AB - Our aim was to employ a critical analytic lens to explicate the role of nursing research in supporting the notion of caring realities. To do this, we used case exemplars to illustrate the infusion of such discourses. The first exemplar examines the fundamental concept of caring: using Florence Nightingale's Notes on Nursing, the case study surfaces caring as originally grounded in ritualized practice and subsequently describes its transmutation, via competing discourses, to a more holistic concept. It is argued that in the many and varied attempts to define the dynamic concept of care, caring has now become paradoxically, a more fragmented concept despite attempts to render it more holistic and inclusive. In the second exemplar, one of the authors draws on her personal experience of the gap between theory and practice, so pronounced that it pushed the author to revisit the concept of evidence-based practice and nursing education. In our third and final exemplar, we refer to the absence of knowledge and practice generated through natural enquiry and curiosity, an absence which has led to production of corporate led rhetoric. Drawing together the central arguments of the three exemplars, we reflect on the influential role of nursing research in enabling the deconstruction of taken for granted assumptions such as caring, evidence-based practice and empowerment; assumptions which have been generated by discourses riddled with confusion and alienation from the reality of practice and the natural spirit of professional enquiry. PMID- 28568963 TI - Retraction: 'Mathematical relationships and their consequences between rat pulse waveform parameters and blood pressure during decreasing NO bioavailability'. PMID- 28568961 TI - Improved respiratory self-navigation for 3D radial acquisitions through the use of a pencil-beam 2D-T2 -prep for free-breathing, whole-heart coronary MRA. AB - PURPOSE: In respiratory self-navigation (SN), signal from static structures, such as the chest wall, may complicate motion detection or introduce post-correction artefacts. Suppressing signal from superfluous tissues may therefore improve image quality. We thus test the hypothesis that SN whole-heart coronary magnetic resonance angiography (MRA) will benefit from an outer-volume suppressing 2D-T2 Prep and present both phantom and in vivo results. METHODS: A 2D-T2 -Prep and a conventional T2 -Prep were used prior to a free-breathing 3D-radial SN sequence. Both techniques were compared by imaging a home-built moving cardiac phantom and by performing coronary MRA in nine healthy volunteers. Reconstructions were performed using both a reference-based and a reference-independent approach to motion tracking, along with several coil combinations. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were compared, along with vessel sharpness (VS). RESULTS: In phantoms, using the 2D-T2 -Prep increased SNR by 16% to 53% and mean VS by 8%; improved motion tracking precision was also achieved. In volunteers, SNR increased by an average of 29% to 33% in the blood pool and by 15% to 25% in the myocardium, depending on the choice of reconstruction coils and algorithm, and VS increased by 34%. CONCLUSION: A 2D-T2 -Prep significantly improves image quality in both phantoms and volunteers when performing SN coronary MRA. Magn Reson Med 79:1293-1303, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28568965 TI - Switchable Access to Different Spirocyclopentane Oxindoles by N-Heterocyclic Carbene Catalyzed Reactions of Isatin-Derived Enals and N-Sulfonyl Ketimines. AB - A novel NHC-catalyzed annulation protocol for the asymmetric synthesis of biologically important beta-lactam fused spirocyclopentane oxindoles with four contiguous stereocenters, including two quaternary carbon centers, was developed. Alternatively, spirocyclopentane oxindoles containing an enaminone moiety can be achieved using the same starting materials, isatin-derived enals, and N-sulfonyl ketimines, in the presence of a slightly different NHC catalytic system. This switchable annulation strategy enables the selective assembly of both heterocyclic scaffolds with good yields and excellent enantioselectivities for a broad range of substrates. PMID- 28568964 TI - Angiotensin II and skeletal muscle abnormalities. PMID- 28568966 TI - Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment. AB - Genetically caused neurological disorders of the central nervous system (CNS) are usually orphan diseases with poor or even fatal clinical outcome and few or no treatments that will improve longevity or at least quality of life. Neuroinflammation is common to many of these disorders, despite the fact that a plethora of distinct mutations and molecular changes underlie the disorders. In this article, data from corresponding animal models are analyzed to define the roles of innate and adaptive inflammation as modifiers and amplifiers of disease. We describe both common and distinct patterns of neuroinflammation in genetically mediated CNS disorders and discuss the contrasting mechanisms that lead to adverse versus neuroprotective effects. Moreover, we identify the juxtaparanode as a neuroanatomical compartment commonly associated with inflammatory cells and ongoing axonopathic changes, in models of diverse diseases. The identification of key immunological effector pathways that amplify neuropathic features should lead to realistic possibilities for translatable therapeutic interventions using existing immunomodulators. Moreover, evidence emerges that neuroinflammation is not only able to modify primary neural damage-related symptoms but also may lead to unexpected clinical outcomes such as neuropsychiatric syndromes. PMID- 28568967 TI - Globalisation and national trends in nutrition and health: A grouped fixed effects approach to intercountry heterogeneity. AB - Using a panel dataset of 70 countries spanning 42 years (1970-2011), we investigate the distinct effects of social globalisation and trade openness on national trends in markers of diet quality (supplies of animal proteins, free fats and sugar, average body mass index, and diabetes prevalence). Our key methodological contribution is the application of a grouped fixed-effects estimator, which extends linear fixed-effects models. The grouped fixed-effects estimator partitions our sample into distinct groups of countries in order to control for time-varying unobserved heterogeneity that follows a group-specific pattern. We find that increasing social globalisation has a significant impact on the supplies of animal protein and sugar available for human consumption, as well as on mean body mass index. Specific components of social globalisation such as information flows (via television and the Internet) drive these results. Trade openness has no effect on dietary outcomes or health. These findings suggest that the social and cultural aspects of globalisation should receive greater attention in research on the nutrition transition. PMID- 28568969 TI - Clinical significance of anti-HLA antibodies associated with ventricular assist device use in pediatric patients: A United Network for Organ Sharing database analysis. AB - While VAD use in pediatric patients has previously been associated with anti-HLA antibody production, the clinical significance of these antibodies is unclear. We investigated the clinical impact of anti-HLA antibodies associated with VAD use in a large cohort of pediatric HTx recipients. From 2004 to 2011, pediatric cardiomyopathy patients post-HTx (N=1288) with pre-HTx PRA levels were identified from the United Network for Organ Sharing database. PRA levels were compared between VAD patients and those with no history of MCS. Incidence of rejection and overall survival were compared between VAD and non-MCS groups after stratification by PRA and age. VAD recipients were more likely to produce anti HLA antibodies than non-MCS patients (25.5% vs 10.5% had PRA>10%, P<.0001). Sensitized VAD patients (PRA>10%) had a higher incidence of rejection within 15 months of HTx compared to sensitized non-MCS patients (57.1% vs 35.9%, P=.02). There was no intergroup difference in 15-month mortality. Among pediatric cardiomyopathy patients supported with a VAD, the presence of anti-HLA antibodies prior to HTx is associated with an increased risk of rejection. The mechanism of the association between VAD-associated antibodies and early rejection is unclear and warrants further investigation. PMID- 28568968 TI - Effect of known history of heart disease on survival outcomes after out-of hospital cardiac arrests. AB - OBJECTIVE: We aimed to investigate the effect of known heart disease on post-out of-hospital cardiac arrest (OHCA) survival outcomes, and its association with factors influencing survival. METHODS: This was an observational, retrospective study involving an OHCA database from seven Asian countries in 2009-2012. Heart disease was defined as a documented diagnosis of coronary artery disease or congenital heart disease. Patients with non-traumatic arrests for whom resuscitation was attempted and with known medical histories were included. Differences in demographics, arrest characteristics and survival between patients with and without known heart disease were analysed. Multivariate logistic regression was performed to identify factors influencing survival to discharge. RESULTS: Of 19 044 eligible patients, 5687 had known heart disease. They were older (77 vs 72 years) and had more comorbidities like diabetes (40.9 vs 21.8%), hypertension (60.6 vs 36.0%) and previous stroke (15.2 vs 10.1%). However, they were not more likely to receive bystander cardiopulmonary resuscitation (P = 0.205) or automated external defibrillation (P = 0.980). On univariate analysis, known heart disease was associated with increased survival (unadjusted odds ratio 1.16, 95% confidence interval 1.03-1.30). However, on multivariate analysis, heart disease predicted poorer survival (adjusted odds ratio 0.76, 95% confidence interval 0.58-1.00). Other factors influencing survival corresponded with previous reports. CONCLUSIONS: Known heart disease independently predicted poorer post-OHCA survival. This study may provide information to guide future prospective studies specifically looking at family education for patients with heart disease and the effect on OHCA outcomes. PMID- 28568970 TI - The changing trends and profile of pneumocystosis mortality in the United States, 1999-2014. AB - Pneumocystosis (PCP) mortality in the U.S. has received less attention in recent years. This study describes recent trends in mortality and the estimated burden of PCP in the U.S., using the national multiple cause of death data during 1999 2014. PCP mortality rates were calculated for age, sex, race and year. Demographic differences were presented for decedents with and without a human immunodeficiency virus (HIV) co-diagnosis. Matched odds ratios (MOR) were generated to describe associations between non-HIV conditions and PCP mortality. In total, 11 512 PCP deaths occurred during 1999-2014. Annual age-adjusted PCP mortality decreased over this time period, from 0.479 to 0.154 per 100 000 population (1999 vs 2014 respectively). Over two-thirds of decedents were male and Blacks had the highest mortality as compared to Whites. HIV co-diagnosis accounted for 48% of all PCP deaths in 2014 vs 71% in 1999. Comorbid conditions such as connective tissue disorders (MOR=12.29; 95% confidence interval=[10.26, 14.71]) were associated with a PCP diagnosis. Productivity losses amounted to >$12 billion during the study period. Although widespread use of antiretroviral therapy and PCP prophylaxis for HIV infection likely contributed to the overall decline in PCP deaths during 1999-2014, a continual need exists to prevent and treat this fungal disease in immune-compromised populations that are not infected with HIV. PMID- 28568971 TI - Longitudinal Bi-directional Effects of Disordered Eating, Depression and Anxiety. AB - OBJECTIVE: The present study aims to explore the potentially longitudinal bi directional effects of disordered eating (DE) symptoms with depression and anxiety. METHOD: Participants were 189 (49.5% male) adolescents from Melbourne, Australia. DE, depressive and anxiety symptoms were assessed at approximately 15, 16.5 and 18.5 years of age. RESULTS: Analysis of longitudinal bi-directional effects assessed via cross-lagged models indicated that DE symptoms of eating and shape/weight concerns were risk factors for anxiety. Results also showed that depression was a risk factor for eating concerns. CONCLUSION: Our findings provide preliminary evidence that preventative measures designed to target concerns about eating and shape/weight might be most efficacious in reducing the transmission of effects between symptoms of DE, depression and anxiety. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28568972 TI - Fetal cerebral magnetic resonance imaging, neurosonography and the brave new world of fetal medicine. PMID- 28568973 TI - Substance P/dexamethasone-encapsulated PLGA scaffold fabricated using supercritical fluid process for calvarial bone regeneration. AB - Poly(lactic-co-glycolic acid) (PLGA) scaffolds encapsulated with substance P (SP) and dexamethasone (Dex) by the supercritical CO2 foaming method were fabricated to treat calvarial bone. We compared the release profiles of SP and Dex according to the incorporation methods using encapsulation or dipping. Ninety percent of the SP or Dex molecules in the scaffolds prepared by the encapsulating method were released by day 14 or day 6, respectively. In vivo real-time assays for human mesenchymal stem cell (hMSC) tracking were performed to confirm the MSC recruitment abilities of the scaffolds. The results showed that the optical intensity of the SP-encapsulated group was 2.59 times higher than that of the phosphate-buffered saline group and 1.3 times higher than that of the SP-dipping group. Furthermore, we compared the angiogenesis activity of the scaffolds. In the SP-encapsulated group, 72.9 +/- 2.6% of the vessels showed matured features by 1 week, and it increased to 82.0 +/- 4.6% after 4 weeks. We implanted the scaffolds into rat calvarial defects. After 24 weeks, SP- and Dex-encapsulated scaffolds showed 67.1% and 26.2% higher bone formation than those of the Dex encapsulated group and SP-encapsulated group, respectively, and they formed 36.1% more bone volume compared with the SP- and Dex-dipped scaffolds. Consequently, the results of this study suggest that SP- and Dex-encapsulated scaffolds made by the supercritical CO2 foaming method could be a good treatment modality to treat critical bone defects without cell transplantation by recruiting autologous stem cells and forming new bone tissues. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28568974 TI - Randomised non-inferiority trial: 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis. AB - BACKGROUND: High concentration mesalazine formulations are more convenient than conventional low concentration formulations for the treatment of ulcerative colitis (UC). AIM: To compare the efficacy and safety of 1600 mg and 400 mg tablet mesalazine formulations. METHODS: Patients with mild-to-moderate active UC (Mayo Clinic Score >5; N=817) were randomised to 3.2 g of oral mesalazine, administered as two 1600 mg tablets once, or four 400 mg tablets twice daily. We hypothesised that treatment with the 1600 mg tablet was non-inferior (within a 10% margin) to the 400 mg tablet for induction of clinical and endoscopic remission at week 8. Open-label treatment with the 1600 mg tablet continued for 26-30 weeks based on induction response. Predictors of treatment response were also explored. RESULTS: At week 8, remission occurred in 22.4% and 24.6% of patients receiving the 1600 mg and 400 mg tablets, respectively (absolute difference -2.2%, 95% CI: -8.1% to 3.8%, non-inferiority P=.005). Endoscopic and histopathologic disease activity, leucocyte concentration and age were significantly associated with clinical remission (P=.022, .042, .014 and .023, respectively). At week 38, 43.9% (296/675) of patients who continued treatment with the 1600 mg formulation were in remission, including 70.3% (142/202) of patients who received a reduced dose of mesalazine (1.6 g/d). The overall incidence of serious adverse events was low. CONCLUSIONS: Induction therapy with 3.2 mg mesalazine using two 1600 mg tablets once-daily was statistically and clinically non-inferior to a twice-daily regimen using four 400 mg tablets (NCT01903252). PMID- 28568975 TI - Stable isotopes of carbon and nitrogen as markers of dietary variation among sociocultural subgroups of Inuit in Greenland. AB - OBJECTIVES: We assessed the use of stable isotopes of carbon and nitrogen as biomarkers for traditional versus store-bought food among the Inuit. Furthermore, we compared the isotope patterns among sociocultural population groups. METHODS: As a part of a country-wide health survey in Greenland during 2005-2010, we analyzed the isotope composition of toenails from 1025 adult Inuit and meat of common species hunted for food. Information on diet and sociocultural variables was collected by interviews. RESULTS: Weighted by sex and place of residence to the total population of Inuit in Greenland, the average delta13 C value in toenails was -20.20/00 and the delta15 N value was 12.00/00 which are higher than in a general Danish omnivorous population. Both isotopes were significantly associated with other biomarkers of marine food and with results of a Food Frequency Questionnaire (FFQ). The percentage of marine food in the diet was estimated at 21% from the mean delta13 C value, 25% from the mean delta15 N value, and 23% from the FFQ. CONCLUSION: Nail samples for analysis of stable isotopes of carbon and nitrogen were convenient to collect during a large population health survey among the Inuit. Isotope enrichment levels showed statistically significant associations with other biomarkers for consumption of marine food and with results of an FFQ and were used to estimate the percentage of marine food in the diet. Isotope levels were significantly associated with a novel score of sociocultural transition. PMID- 28568976 TI - Percutaneous obliteration of left ventricular cavity to eliminate aortic regurgitation and presumed coronary steal in an infant with hypoplastic left heart syndrome. AB - The phenomenon of coronary steal is well known in the setting of HLHS (Hypoplastic Left Heart Syndrome) early after the Classical Norwood Operation. We report a rare case of an infant with HLHS [Severe Aortic Stenosis (AS), Mitral Stenosis (MS) and small Left Ventricle (LV)], who developed aortic regurgitation and presumed coronary steal late after the Sano Modification of the Norwood Procedure. Coronary steal developed secondary to progressive aortic and mitral regurgitation and resulted in poor right ventricular function and severe tricuspid regurgitation. We describe a novel interventional approach for obliteration of the LV cavity by using hydrogel coils. LV obliteration eliminated the presumed steal and resulted in improvement in ventricular function, tricuspid regurgitation and clinical course. PMID- 28568978 TI - SEX RATIO VARIATION IN A PARASITIC WASP I. REACTION NORMS. AB - To understand genetic and phenotypic constraints on the sex ratio in a parasitic wasp that attacks fly pupae, I carried out a laboratory study of sex ratio variability in five strains of Muscidifurax raptor (Hymenoptera: Pteromalidae). I manipulated the environment through combinations of temperature and day length, and the numbers of females that attack a group of hosts. The change of phenotype in each strain over the range of environmental conditions describes the norm of each reaction for that strain, and measures how a strain responds to environmental variation to create phenotypic variability. Sex ratio in parasitic wasps is a complex trait that has several components-the numbers of eggs laid by an ovipositing wasp and the fraction of eggs that are fertilized (female). Further, sex ratio may be influenced by a female's reaction to other females exploiting the same hosts (superparasitism). I found no strain-environment interactions in either sex ratio or fecundity when I varied environmental conditions. Although strains differed in sex ratio and fecundity, all strains produced a more female-biased sex ratio and had higher fecundity when temperature and day length increased. Sex ratio and fecundity were phenotypically correlated, and strains with greater fecundity also produced a more female-biased sex ratio. All strains facultatively shifted sex ratio toward a higher fraction of males with increasing female density, despite apparent differences in superparasitism among strains. Males and females survived equally during development, so that mortality differences among strains and across environments could not account for sex ratio variability. This study indicates that sex ratio variability among strains is constrained by the correlation between sex ratio and fecundity, and that strains display similar facultative shifts in sex ratio as female density increases because sex ratio shifts are insensitive to differing levels of superparasitism. PMID- 28568977 TI - Reproductive performance and expression of imprinted genes in somatic cell cloned boars. AB - To assess the performance of boars derived by somatic cell cloning, we analyzed various aspects of their reproductive characteristics and the expression of two imprinted genes. Cloned boars (cloned Duroc * Jinhua) were analyzed for birth weight, growth rate, age at first ejaculation, semen characteristics and fertility, in comparison with naturally bred control boars of the same strain. The expression of imprinted genes was analyzed using the microsatellite marker SWC9 for the paternally expressed gene insulin-like growth factor -2 (IGF2) and with single nucleotide polymorphisms (SNPs) for the gene maternally expressed 3 (MEG3). The cloned boars had high production of semen and were nearly equal in level of fertility to conventional pigs; they showed similar characteristics as naturally bred boars of the same strains. The expression of IGF2 was partially disturbed, but this disturbed expression was not linked to a change in developmental fate or reproductive performance. These results indicate that use of cloned boars could be highly effective for proliferation of pigs with desirable characteristics, preservation of genetic resources and risk reduction against epidemic diseases, such as foot-and-mouth disease, through storage of somatic cells as a precautionary measure for use in regenerating pig populations after a future pandemic. PMID- 28568979 TI - THE EVOLUTION OF CLUTCH SIZE: A REPLY TO WOOTTON, YOUNG, AND WINKLER. PMID- 28568980 TI - POPULATION GENETICS OF A PARASITIC CHROMOSOME: EXPERIMENTAL ANALYSIS OF PSR IN SUBDIVIDED POPULATIONS. AB - Nasonia vitripennis is a parasitoid wasp that harbors several non-Mendelian sex ratio distorters. These include MSR (Maternal Sex Ratio), a cytoplasmic element that causes nearly all-female families, and PSR (Paternal Sex Ratio), a supernumerary chromosome that causes all-male families. As in other hymenoptera, N. vitripennis has haplodiploid sex determination. Normally, unfertilized (haploid) eggs develop into males and fertilized (diploid) eggs develop into females. The PSR chromosome violates this normal pattern; it is inherited through sperm, but then causes destruction of the paternal chromosomes (except itself), thus converting diploid fertilized eggs (normally females) into haploid eggs that develop into PSR-bearing males. PSR is an extreme example of "parasitic" or "selfish" DNA. Because N. vitripennis has a highly subdivided population structure in nature, population-level selection may be important in determining the dynamics of PSR in natural populations. A theoretical analysis shows that subdivided population structure reduces PSR frequency, whereas high fertilization proportion (such as produced by the MSR element) increases PSR frequency. Population experiments using two deme sizes (3- and 12-foundress groups) and strains producing two fertilization proportions [wild-type (LabII)-57-67% female, and MSR (MI)-90-93% female] confirm these predictions. PSR achieved frequencies over 0.90 in 12-foundress group MSR populations in contrast to 0.20-0.40 in wild type 12-foundress populations. PSR was selected against in wild-type populations composed of three-foundress groups. In MSR populations with three-foundress groups, presence of PSR selected against the MSR cytoplasmic element, eventually leading to low frequencies of both PSR and MSR. Complicated dynamics may occur when these two sex-ratio distorters are both present in highly subdivided populations. The existence of PSR in natural populations may depend on the presence of MSR. Results indicate that population subdivision could be important in determining the frequency of sex ratio distorters in N. vitripennis. PMID- 28568981 TI - POLYPHENISM IN SPADEFOOT TOAD TADPOLES AS A LOCALLY ADJUSTED EVOLUTIONARILY STABLE STRATEGY. AB - I examined the evolutionary factors maintaining two environmentally induced morphs in ponds of variable duration. Larvae of New Mexico spadefoot toads (Scaphiopus multiplicatus) often occur in the same pond as a large, rapidly developing carnivorous morph and as a smaller, more slowly developing omnivorous morph. Previous studies revealed that carnivores can be induced by feeding tadpoles live fairy shrimp and that morph determination is reversible. Field and laboratory experiments indicated that the ability of an individual to become a carnivore or an omnivore is maintained evolutionarily as a response to variability in pond longevity and food abundance. Carnivores survived better in highly ephemeral artificial ponds, because they developed faster. Omnivores survived better in longer-duration artificial ponds, because their larger fat reserves enhanced postmetamorphic survival. The two morphs also occupy different trophic niches. Experimental manipulations of morph frequency in ponds of intermediate duration revealed that increased competition for food among individuals of the more common morph made the rarer form more successful. Morph frequency within each pond was stabilized at an equilibrium by frequency dependent morph reversal, which reflected frequency-dependent natural selection on size at metamorphosis: larger metamorphs had higher survival, and individuals reared at a frequency above the pond's equilibrium frequency were smaller at metamorphosis than were individuals of that morph reared at a frequency below the pond's equilibrium. Because neighboring ponds often differed in pond longevity and food abundance, each pond possessed a unique equilibrium morph frequency. This implies that morph determination in Scaphiopus is a locally adjusted evolutionarily stable strategy (ESS). PMID- 28568982 TI - SEXUAL COMPETITION AMONG BROTHERS MAY INFLUENCE OFFSPRING SEX RATIO IN SNAKES. PMID- 28568983 TI - RESOURCE COMPENSATION AND THE EVOLUTION OF GYNODIOECY IN PHACELIA LINEARIS (HYDROPHYLLACEAE). AB - Gynodioecy is a dimorphic breeding system in which hermaphrodite and female individuals coexist in populations. Theoretical models have shown that if nuclear genes control sex expression, then gynodioecy can evolve only when females have large advantages in one or more fitness components. These female advantages must be large enough that females' expected lifetime production of viable seeds is more than twice that of hermaphrodites. Previous studies have found that cytoplasmic inheritance and/or a large offspring-vigor advantage of females (caused by hermaphrodite self-pollination and inbreeding depression of selfed seeds) account for this breeding system's evolution. This paper reports studies of gynodioecy in Phacelia linearis, an insect-pollinated annual plant in which gender inheritance appears to be nuclear. Twenty-six P. linearis populations surveyed in northern Utah, USA, contain a majority of perfect-flowered hermaphrodites, but most (22) also contain male-sterile individuals (females), at frequencies of up to 0.16. The hermaphrodite selfing rate is low (0.00-0.20 in four populations). Maternal gender does not consistently affect components of offspring vigor, such as seed size, germination rate, seedling survivorship, and vegetative size. Plants of the two genders do not differ in number of seeds per fruit or mean seed mass. Females produce significantly more fruits and seeds than hermaphrodites in natural populations. The ratio of the mean lifetime seed production of females to the mean lifetime seed production of hermaphrodites ranged from 1.31 to 2.52 in six natural populations. Females have greater shoot biomass than hermaphrodites and produce more seeds at any given shoot biomass than hermaphrodites, suggesting that their seed-production advantage arises from gender-specific patterns of resource allocation to growth and reproduction. The gender difference in plant size varies across environments and across genetic backgrounds. In this species nuclear gynodioecy appears to be evolutionarily stable mainly because of resource compensation by females, without a large outcrossing advantage of females. PMID- 28568984 TI - APPARENT SELECTIVE NEUTRALITY OF MITOCHONDRIAL DNA SIZE VARIATION: A TEST IN THE DEEP-SEA SCALLOP PLACOPECTEN MAGELLANICUS. AB - Animal mitochondrial DNA (mtDNA) is believed to have evolved under intense selection for economy of the size of the molecule. Among scallop species mtDNA size may vary by a factor of two and among conspecific individuals by as much as 25%. We have examined the possibility that large mtDNA size differences may be associated with fitness in the deep sea scallop Placopecten magellanicus by comparing shell lengths of individuals with different copy numbers of a large mtDNA repeated sequence. Among juvenile cohorts of same age, shell length is known to be a good index of overall fitness in marine bivalves and it is shown here to be affected by differences in nuclear genotype, expressed as the degree of enzyme heterozygosity. We have observed no correlation between shell length and mtDNA length and interpreted this to mean that variation in the size of animal mtDNA is effectively neutral to the forces of natural selection acting on the individual. This type of mtDNA variation must, therefore, be explained in terms of biases in the molecular mechanisms causing expansion or contraction of the molecule, differential replication rates of mtDNA molecules of different size, and the stochastic assortment of mtDNA size classes among individuals. PMID- 28568985 TI - GLUCOSEPHOSPHATE ISOMERASE AND FITNESS: EFFECTS OF TEMPERATURE ON GENOTYPE DEPENDENT MORTALITY AND ENZYME ACTIVITY IN TWO SPECIES OF THE GENUS GAMMARUS (CRUSTACEA: AMPHIPODA). PMID- 28568986 TI - GAMETE COMPATIBILITY OR INCOMPATIBILITY? A COMMENT ON LESSIOS AND CUNNINGHAM (1990). PMID- 28568987 TI - DIVERGENT AMBULATORY AND GROOMING BEHAVIOR IN SERIALLY BOTTLENECKED LINES OF THE HOUSEFLY. AB - The extent of genome-wide restructuring predicted in bottleneck models of speciation is addressed in assays of non-reproductive behavior in lines of the housefly. After five serial founder-flush cycles of one of three sizes (1, 4, or 16 pairs), each bottleneck line showed significant differentiation from the outbred control in ambulatory levels and grooming sequences in videotaped records of precopulatory activity. Only one line (4-pair) showed overall lethargy which was associated to inbreeding depression in egg-to-adult viability, thus exemplifying a case of probable extinction due to bottlenecks. The two most hyperactive lines (1- and 16-pair) showed very similar directions of differentiation from the control in locomotor activity and grooming behavior, as well as in mating behavior evaluated from a separate study. This high congruence suggested that directional selection toward the phenotypic optima of the ancestor operated on the bottleneck populations and that a 10-fold difference in theoretical inbreeding coefficients did not affect the magnitude of response. The remaining two bottleneck lines showed some independence from these general trajectories, their divergence along minor axes of ancestral intercorrelation structure possibly being more important to the formation of new species. Significant perturbations of the thresholds for execution of grooming and locomotor movements suggested increased evolutionary potential for ritualization (i.e., sexual selection for adoption of non-reproductive behavior into courtship repertoire) due to bottlenecks. PMID- 28568988 TI - THE EFFECT OF SERPENTINE ON THE POPULATION STRUCTURE OF SILENE DIOICA (CARYOPHYLLACEAE). AB - Serpentine soils are rich in heavy metals and have a distinctive flora. Silene dioica is a member of the Scandinavian serpentine plant community but is also widespread outside serpentine soils. To study the population genetic consequences of serpentine stress and the origin and evolution of serpentine populations we analyzed the isozyme genetic structure of S. dioica. Seventeen populations located in the mountains of Vasterbotten and Jamtland, central Sweden, were investigated by starch gel enzyme electrophoresis. About one half of the populations grow in serpentine soils and the rest on adjacent non-serpentine sites. Analyses of allele frequencies show that both serpentine and non serpentine populations in the northern part of the studied area (Vasterbotten) are genetically similar. Evidently serpentine does not exert strong selection acting upon isozyme loci. In the south (Jamtland), however, the serpentine populations exhibit genetic differentiation. This allozyme divergence is probably not due to direct selection but rather represents the effects of isolation and genetic drift. The results suggest that S. dioica has colonized serpentine repeatedly and that the tolerant populations have a multiple origin. PMID- 28568989 TI - POPULATION GENETIC CONSEQUENCES OF DEVELOPMENTAL EVOLUTION IN SEA URCHINS (GENUS HELIOCIDARIS). AB - Within the sea urchin genus Heliocidaris, changes in early embryonic and larval development have resulted in dramatic differences in the length of time larvae spend in the plankton before settling. The larvae of one species, H. tuberculata, spend several weeks feeding in the plankton before settling and metamorphosing into juveniles. The other species, H. erythrogramma, has modified this extended planktonic larval stage and develops into a juvenile within 3-4 days after fertilization. We used restriction site polymorphisms in mitochondrial DNA to examine the population genetic consequences of these developmental changes. Ten restriction enzymes were used to assay the mitochondrial genome of 29 individuals from 2 localities for H. tuberculata and 62 individuals from 5 localities for H. erythrogramma. Within H. tuberculata, 11 mitochondrial genotypes were identified. A GST analysis showed high levels of genetic exchange between populations separated by 1,000 kilometers of open ocean. In contrast, in H. erythrogramma, 13 mitochondrial genotypes differing by up to 2.33% were geographically partitioned over spatial scales ranging from 800 to 3,400 kilometers. Between distant localities, there was complete mitochondrial lineage sorting and large sequence divergence between resulting clades. Over much smaller spatial scales (< 1,000 km), genetic differentiation was due to the differential sorting of very similar genotypes. This pattern of mitochondrial variation suggests that these population differences have arisen recently and may reflect the historical interplay between the restricted dispersal capabilities of H. erythrogramma and the climatic and geological changes associated with Pleistocene Ice Ages. PMID- 28568990 TI - MITOCHONDRIAL DNA SEQUENCE VARIATION AMONG NATURAL POPULATIONS OF THE TRINIDAD GUPPY, POECILIA RETICULATA. AB - Guppies were sampled from eight populations representing four river drainage basins in northern Trinidad, and from one population on the nearby island of Tobago. For each individual, a 465 base pair (bp) segment of the control region of the mitochondrial genome was sequenced. The resulting DNA sequences were subjected to sequence divergence calculations and the populations were linked by maximum parsimony analysis to determine their phylogenetic relationships. Mitochondrial DNA (mtDNA) sequence variation was found both within and between river drainages, correlated with the geographic features of northern Trinidad. The variation observed exists primarily between drainages, particularly between the Oropuche drainage and all other Trinidad drainages examined. Estimates of time of divergence between guppy populations of different drainages, based on mtDNA sequence variation, ranged from 100,000 to 200,000 for the most recently separated populations and from 600,000 to 1.2 million years between the Oropuche populations and all others examined. Examination of fish from northeastern South America will be required to determine whether these populations differentiated in their present locations or were the result of separate invasions of Trinidad from different Venezuelan sources. However, genetic isolation of these populations appears to predate the current physical separation of the island of Trinidad from the Venezuelan mainland. PMID- 28568991 TI - COLONIZATION OF AMERICA BY DROSOPHILA SUBOBSCURA: ANALYSIS OF THE O5 INVERSIONS FROM EUROPE AND AMERICA AND THEIR IMPLICATIONS FOR THE COLONIZING PROCESS. PMID- 28568992 TI - APHID DISTRIBUTION AND THE EVOLUTION OF GOLDENROD RESISTANCE. AB - Although there is considerable evidence indicating that herbivory is detrimental to plant fitness, some recent studies of the evolution of plant resistance have concluded that insects do not impose selection on their host plants. A previously untested assumption that underlies most studies of the evolution of plant resistance is that insect distribution patterns are controlled directly by the effects of plant genotype on insect preference and performance. The experiments described here explicitly tested this assumption using the specialist herbivore Uroleucon tissoti (Homoptera: Aphididae) and its host plant Solidago altissima (Asteraceae). Measures of aphid preference and performance were used to predict aphid distribution patterns, and then the predicted distribution patterns were compared with the natural distribution pattern. Although goldenrod genotype had a strong effect on aphid distribution, aphid distribution was not controlled directly by the effect of goldenrod genotype on aphid preference and performance. Instead, a second experiment demonstrated that aphid and spittlebug (Philaenus spumarius and Lepyronia quadrangularis Homoptera: Cercopidae) distribution is controlled largely by genetic variation for resistance to a suite of "branch causing" herbivores. These herbivores induce branching and aphids and spittlebugs are more abundant on branched plants than unbranched plants. These results indicate that any natural selection imposed by aphids and spittlebugs on goldenrod will depend on the presence or absence of branch-causing herbivores. Thus, selection for plant resistance may depend as much on the assemblage of insect species present as on the identity of each individual species. PMID- 28568993 TI - THE GENETIC BASIS OF SEXUAL ISOLATION BETWEEN DROSOPHILA MELANOGASTER AND D. SIMULANS. AB - The genetic analysis of sexual isolation between the closely-related species Drosophila melanogaster and Drosophila simulans involved two experiments with no choice tests. The efficiency of sexual isolation was measured by the frequency of courtship initiation and interspecific mating. We first surveyed the variation in sexual isolation between D. melanogaster strains and D. simulans strains of different geographic origin. Then, to investigate variation in sexual isolation within strains, we made F1 diallel sets of reciprocal crosses within strains of D. melanogaster and D. simulans. The F1 diallel progeny of one sex were paired with the opposite sex of the other species. The first experiment showed significant differences in the frequency of interspecific mating between geographic strains. There were more matings between D. simulans females and D. melanogaster males than between D. melanogaster females and D. simulans males. The second experiment uncovered that the male genotypes in the D. melanogaster diallel significantly differed in interspecific mating frequency, but not in courtship initiation frequency. The female genotypes in the D. simulans diallel were not significantly different in courtship initiation and interspecific mating frequency. Genetic analysis reveals that in D. melanogaster males sexual isolation was not affected by either maternal cytoplasmic effects, sex-linked effects, or epistatic interaction. The main genetic components were directional dominance and overdominance. The F1 males achieved more matings with D. simulans females than the inbred males. The genetic architecture of sexual isolation in D. melanogaster males argues for a history of weak or no selection for lower interspecific mating propensity. The behavioral causes of variation in sexual isolation between the two species are discussed. PMID- 28568994 TI - SEXUAL SELECTION AND BUTTERFLY DESIGN-A COMPARATIVE STUDY. AB - Temperate butterflies of 44 species were examined to determine if their mating system (perching and patrolling) affected flight design. To control for spurious effects due to ancestry, 25 of these species were assigned to eight contrasts within which a change in mating system had occurred. In perching species sexual selection was predicted to favor traits associated with high acceleration ability and speed, while in patrolling species traits associated with flight endurance were predicted. In conformance with these expectations males of perching species had larger thorax/body mass ratios, higher wing loadings, and higher aspect ratios than patrolling species. The male mating system affected females in the same direction in the same variables as males. This could be explained by a genetic correlation with males. When removing the covariance between the sexes, only male design was explained by the mating system. The mating system was also associated with different degrees of sexual dimorphism in wing size. This supported the hypothesis that male design was affected by the mating system. PMID- 28568995 TI - CORRELATIONAL SELECTION FOR COLOR PATTERN AND ANTIPREDATOR BEHAVIOR IN THE GARTER SNAKE THAMNOPHIS ORDINOIDES. AB - Correlational selection favors combinations of traits and is a key element of many models of phenotypic and genetic evolution. Multiple regression techniques for measuring selection allow for the direct estimation of correlational selection gradients, yet few studies in natural populations have investigated this process. Color patterns and antipredator behaviors of snakes are thought to function interactively in predator escape and therefore may be subject to correlational selection. To investigate this hypothesis, I studied the survivorship of juvenile garter snakes, Thamnophis ordinoides, as a function of a suite of escape behaviors and color pattern. The only natural selection detected favored opposite combinations of stripedness of the color pattern and the tendency to perform during escape evasive behaviors called reversals. This selection presumably results from optical illusions created by moving patterns and their effects on visually foraging predators. Analysis of the bivariate selection surface shows that pure correlational selection can be thought of as a series of linear selection functions on one trait whose slopes depend on the value of the second trait. Alternatively, viewing the selection surface along its major axes reveals stabilizing and disruptive components of correlational selection. It is further shown that correlational selection alone can promote genetic variance and covariance within a generation. This phenomenon may be partially responsible for the extreme variation in color pattern and the genetic covariance between color pattern and behavior observed in natural populations of T. ordinoides. PMID- 28568996 TI - VOCAL DIALECTS AND THE STRUCTURE OF GEOGRAPHIC VARIATION IN MORPHOLOGICAL AND ALLOZYMIC CHARACTERS IN THE RUFOUS-COLLARED SPARROW, ZONOTRICHIA CAPENSIS. AB - The geographical patterns of variation shown at 20 allozyme and non-enzymatic protein-coding loci, in 8 external, and in 12 skeletal morphological characters in the rufous-collared sparrow, Zonotrichia capensis, were analyzed in order to test the local (genetic) adaptation hypothesis regarding the origin and maintenance of vocal dialects in birds. Approximately 20 males were collected from each of four sites within each of six different dialect zones. There was significant variability in both external and skeletal morphology among all 24 sites and among dialect groups. Average Wright's corrected fixation coefficient (FST ) was 0.118, indicating significant genetic differentiation among all sites, regardless of dialect. Hierarchical F statistics indicated that only 50% of among site variability was due to a dialect effect. Puna dialect sites were highly differentiated from all other sites with respect to both morphology (external and skeletal measures) and allozyme frequencies. Heterogeneity at the PGM-1 locus among puna scrub sites was the major cause of the high average FST across all sites, and within the puna scrub dialect. Average genetic differentiation among non-puna sites (FST = 0.018) was similar to differentiation among sites within each of the five non-puna dialect groups (mean FST = 0.0132 +/- 0.0069). Hierarchical F statistics indicated that none of the among-site differentiation in this subset of samples was due to a dialect effect. These observations are not consistent with the local adaptation hypothesis. All significant genetic heterogeneity occurred among sites in mountainous habitats, and we suggest that topography and patchiness of habitat may have been major factors involved in population differentiation, rather than vocal dialects. PMID- 28568997 TI - TEMPORAL STABILITY OF THIRD-CHROMOSOME INVERSION FREQUENCIES IN DROSOPHILA PERSIMILIS AND D. PSEUDOOBSCURA. PMID- 28568998 TI - BIOGEOGRAPHY OF NEW WORLD TAIGA-DWELLING MICROTUS (MAMMALIA: ARVICOLIDAE): A HYPOTHESIS TEST THAT ACCOUNTS FOR PHYLOGENETIC UNCERTAINTY. AB - If we adopt a statistical approach to systematics and recognize that phylogenies are estimated with error, then we can begin to explore statistically justified methods for testing a variety of comparative hypotheses, including those concerning the evolution of life-history characters and biogeography. In this paper I examine two biogeographic hypotheses concerning the rodent genus Microtus. Like many comparative hypotheses, these can be phrased so that each predicts the existence of a particular monophyletic group. Neither of the predicted groups appear on the single best phylogeny as determined by both Dollo parsimony and maximum likelihood analysis of restriction site maps of mitochondrial DNA. Simulation studies, however, suggest that often the best phylogeny from a single data set has only a low probability of being exactly correct. We must also examine those trees that, while not the single best supported tree, are not rejected by the data. If we find the best phylogeny for which a hypothesis is satisfied, then likelihood methods can be used to test whether that phylogeny is significantly worse then the best tree overall. If that tree can be rejected, then so can the hypothesis. Computational constraints limit the use of likelihood methods for searching among topologies, so parsimony is used as a data exploratory tool. One of the predicted groups cannot be rejected, even though the most parsimonious tree which includes that group requires 11 more steps than does the most parsimonious tree. PMID- 28568999 TI - RESTRICTED MIGRATION AND THE EVOLUTION OF ALTRUISM. AB - A suggestion that limited migration, i.e., population viscosity, should favor the evolution of altruism has been challenged by recent kin selection models explicitly incorporating restricted migration. It is demonstrated that these models compound two distinct elements of population structure, spatial-genotypic variation and density regulation. These two characteristics are often determined by distinct biological processes. While they may be linked under certain circumstances, this is not invariably true. A simple modification of the migration system employed in these studies decouples migration and population regulation thus favoring inter-group selection. At least in some cases, restricted migration will facilitate the evolution of altruism. PMID- 28569000 TI - GENETICS OF PHYSIOLOGICAL AND BEHAVIORAL RESISTANCE TO HOST FURANOCOUMARINS IN THE PARSNIP WEBWORM. AB - Depressaria pastinacella, the parsnip webworm, feeds almost exclusively on the flowers and fruits of Pastinaca sativa, the wild parsnip. Resistance to webworms in wild parsnip populations is largely attributable to genetically based variation in furanocoumarin chemistry; by differentially reducing fruit set among chemical phenotypes, parsnip webworms may act as selective agents on wild parsnip populations. To determine whether wild parsnip chemistry can act as a selective agent on webworm populations, it is necessary to establish that resistance mechanisms in the webworm to furanocoumarins are genetically based. In this study, we estimated the amount of genetic variation in behavioral and physiological responses of webworms to parsnip furanocoumarins. Virtually no variation was found among webworm families for feeding preferences for diets varying as much as fourfold in furanocoumarin content. Nor was significant variation found for mean furanocoumarin intake over the assay period, except in one case, in which maternal effects may account for differences among families. In contrast, substantial familial variation existed for cytochrome P450-mediated metabolism of bergapten and xanthotoxin, two host furanocoumarins. The presence of additive genetic variation in metabolism, and the absence of such variation in discriminative feeding behavior, suggests that adaptation to changes in furanocoumarin chemistry, resulting either from changes in the distribution of chemical phenotypes in parsnip populations or from shifts to new chemically different host plants, is likely to be facilitated by physiological rather than behavioral means. PMID- 28569001 TI - SEX RATIO VARIATION IN A PARASITIC WASP II. DIALLEL CROSS. AB - Sex ratio has been studied from many theoretical and empirical perspectives, but a general assumption in sex ratio research is that changes in sex ratio occur because of selection on sex ratio itself. I carried out a quantitative genetic experiment-a diallel cross among three strains-on a parasitic wasp, Muscidifurax raptor (Hymenoptera: Pteromalidae), to measure genetic variation for sex ratio. I also tested whether sex ratio may change as a consequence of selection on other life-history traits by estimating genetic covariances between sex ratio, fecundity, longevity, and development time. Most of the variation among strains could be accounted for by a maternal effect, likely caused by a microsporidian parasite that was transmitted through the West Germany (WG) strain. Genetic variation was small by comparison, but almost all traits were affected by dominance. The only significant additive genetic effect was for fecundity early in life. Upon crossing, all traits displayed heterosis: more female-biased sex ratio, greater fecundity, longer life, and faster development time. All life history traits were correlated phenotypically, but the correlations were mainly the result of decreased performance in crosses with the WG strain that carried the microsporidian parasite. Dominance genetic correlations were also found between sex ratio, fecundity, and longevity. How the correlation between sex ratio and other life-history traits would affect sex ratio evolution depends upon the frequencies of sex-ratio genotypes within a population as well as the signs of the correlations, because sex ratio is under frequency-dependent selection whereas other traits are generally under directional selection. Although the results from crosses among laboratory populations should be approached with caution, the inbreeding depression (the difference between inbred and outcrossed progeny) found in M. raptor implies that the evolution of a female-biased sex ratio could be affected by selection for inbreeding avoidance. PMID- 28569002 TI - A NOTE ON HALDANE'S RULE: HYBRID INVIABILITY VERSUS HYBRID STERILITY. PMID- 28569003 TI - ORGANIZATION OF PREDATOR-PREY COMMUNITIES AS AN EVOLUTIONARY GAME. AB - We consider a simple predator-prey model of coevolution. By allowing coevolution both within and between trophic levels the model breaks the traditional dichotomy between coevolution among competitors and coevolution between a prey and its predator. By allowing the diversity of prey and predator species to emerge as a property of the evolutionarily stable strategies (ESS), the model breaks another constraint of most approaches to coevolution that consider as fixed the number of coevolving species. The number of species comprising the ESS is influenced by a parameter that determines the predator's niche breadth. Depending upon the parameter's value the ESS may contain: 1) one prey and one predator species, 2) two prey and one predator, 3) two prey and two predators, 4) three prey and two predators, 5) three prey and three predators, etc. Evolutionarily, these different ESSs all emerge from the same model. Ecologically, however, these ESSs result in very different patterns of community organization. In some communities the predator species are ecologically keystone in that their removal results in extinctions among the prey species. In others, the removal of a predator species has no significant impact on the prey community. These varied ecological roles for the predator species contrasts sharply with the essential evolutionary role of the predators in promoting prey species diversity. The ghost of predation past in which a predator's insignificant ecological role obscures its essential evolutionary role may be a frequent property of communities of predator and prey. PMID- 28569004 TI - SEXUAL SELECTION AND MALE CHARACTERISTICS IN THE BLUEHEAD WRASSE, THALASSOMA BIFASCIATUM: MATING SITE ACQUISITION, MATING SITE DEFENSE, AND FEMALE CHOICE. AB - Through a series of replacement experiments with the bluehead wrasse, Thalassoma bifasciatum, we have identified male morphological characteristics that appear to be under phenotypic sexual selection. We were particularly interested in whether the various sources of sexual selection (male-male competition for unoccupied mating sites, defense of mating sites against small males, and female choice of males) were (1) independently associated with different phenotypic characteristics; (2) jointly affected the same characteristic in the same way; or (3) jointly affected the same characteristic in an antagonistic fashion. We replaced the resident large, brightly colored Terminal Phase (TP) males on a reef with the same number of TP males from other reefs. When transplanted, these males contest with each other to take over mating sites. The transplanted group of males were then scored for three components of fitness: (1) the quality of the site obtained through competition with other large males; (2) the male's ability to defend arriving females from small intruding males; and (3) changes in female visits to the site once the new male takes over. The first and second components are part of intrasexual selection; the third represents intersexual selection. We measured the opportunity for selection by partitioning variance in mating success, and measured the direct effects of sexual selection by estimating the covariance between morphology and fitness components. Opportunities for selection: Because females generally remain faithful to particular mating sites, most (54%) of the explainable variation in male mating success is due to the acquisition of a particular mating territory, which is the outcome of competition among TP males. There was less variation in mating success due to shifts in site use by females and defense of females against the intrusions of smaller males, but all components were significant. Effects of selection: Success in male-male competition among TP males, estimated by the quality of the territory acquired, was positively associated with body length and the relative length of the pectoral fin. Success in territorial defense against small males was primarily related to body length, with lesser contributions from body depth and the area of a white band on the flank. Contribution to fitness through female choice of males was positively associated with white band area. In the two instances where a character was associated with two fitness components, the direction of selection was the same. While body length was positively associated with winning intrasexual contests, it was not correlated to any behavioral measures of aggression. Similarly, the white band associated with attractiveness was not correlated with any aspect of courtship or aggression. Parasite load was uncorrelated with other morphological characters, and did not appear to affect any aspect of sexual selection. There was no evidence for stabilizing selection or significant additional contributions from second-order effects to the fitness surfaces. Fitness functions calculated using cubic splines were generally linear except for body length, which appeared sigmoid in its effect on site acquisition ability; this same feature tended to plateau in its effect on site defense. Analyses of the interactions of selection gradients with reef or experiment indicated that the effect of particular male characters on estimates of fitness was generally homogeneous in both time and space. PMID- 28569005 TI - ADAPTIVE SEASONAL VARIATION IN GRASSHOPPER OFFSPRING SIZE. PMID- 28569006 TI - HYBRIDS AND PHYLOGENETIC SYSTEMATICS II. THE IMPACT OF HYBRIDS ON CLADISTIC ANALYSIS. AB - I examined three aspects of the cladistic treatment of a set of 17 F1 hybrids of known parental origin: (1) impact of hybrids on consistency index (CI) and number of most parsimonious trees (Trees), (2) placement of hybrids in cladograms, and (3) impact of hybrids on hypotheses of relationship among species. The hybrids were added singly and in randomly selected sets of two to five to a data set composed of Central American species of Aphelandra (including the parents of all hybrids). Compared to analyses with the same number of OTUs all of which were species, the analyses with hybrids yielded results with significantly higher CI. There was no difference in Trees between analyses with hybrids versus species. There was thus no evidence that hybrids would appear to be more problematic for cladistic methods than species. Accordingly, hybrids will not be readily identifiable as taxa that cause marked change in these indices. About % of the hybrids were placed as the cladistically basal members of the lineage that included the most apomorphic parent. Relatively apomorphic hybrids were placed proximate to the most derived parent (ca. 13% of hybrids). Other placements occurred more rarely. The most frequent placements of hybrids thus did not distinguish them from normal intermediate or apomorphic taxa. When analyses with hybrids yielded multiple most parsimonious trees, these were no more different from each other than were the equally parsimonious trees that resulted from analyses with species. Most analyses with one or two hybrids resulted in minor or no change in topology. When hybrids caused topological change, they frequently caused rearrangements of weakly supported portions of the cladogram that did not include their parents. When they disrupted the cladistic placement of their parents, they often caused their parents to change positions, with at least one topology bringing the parental lineages into closer proximity with the hybrid placed between them. Hybrids between parents from the two main lineages of the group caused total cladistic restructuring. In fact, the degree of relationship between a hybrid's parents (measured by both cladistic and patristic distance) was strongly correlated with CI (negatively) and with the degree of disturbance to cladistic relationships (positively). Thus, hybrids between distantly related parents resulted in cladograms with low CI and major topological changes. This study suggests that hybrids are unlikely to cause breakdown of cladistic structure unless they are between distantly related parents. However, these results also indicate that cladistics may not be specially useful in distinguishing hybrids from normal taxa. The applicability of these results to other kinds of hybrids is examined and the likely cladistic treatment of hybrids using other sources of data is discussed. PMID- 28569007 TI - HOW SEDENTARY ARE GREYWING FRANCOLINS (FRANCOLINUS AFRICANUS)? AB - Phasianids are considered to be sedentary birds with limited dispersal so that populations may be expected to show genetic isolation by distance. To test this, we examined genetic variability in 618 greywing francolins (Francolinus africanus) at 24 localities over a 1,500 km2 area. We subdivided the samples to measure genetic population structure among localities separated by 6-60 km, and among coveys separated by 0.1-6 km. Thirteen of 30 (43%) allozyme loci were polymorphic, and heterozygosity ranged from 5.3 to 8.5% over 24 localities and averaged 7.0%, a value much larger than that found for other phasianids. Significant allele-frequency heterogeneity was detected among localities and among coveys at several localities for several loci. Mantel's test, however, showed that there was no correlation between geographical distance and the allele frequency difference between localities for all but one allele. Although spatial autocorrelation was detected with Moran's I and Geary's c for two alleles, the geographical patterns of I in correlograms of 18 independent alleles showed a "crazy-quilt" pattern of allele-frequency patches. This shows that the isolation by-distance model of subpopulation structure is inappropriate for these birds. Individuals, therefore, appear to disperse far beyond neighboring populations. "Private-allele" and FST estimates of migration under the island model were 8-9 individuals between localities of each generation. Allele-frequency heterogeneity, large amounts of gene flow, and the general lack of spatial autocorrelation imply that the small, socially-structured populations of greywing are subject to high rates of turnover, founder effects, and random drift. PMID- 28569008 TI - ON THE DIFFERENCE BETWEEN MEAN AND OPTIMUM OF QUANTITATIVE CHARACTERS UNDER SELECTION. PMID- 28569009 TI - Myeloid sarcoma identified on liquid-based cervical cytology samples: A report of two cases. AB - The purpose of the Papanicolaou (Pap) smear is to detect primary squamous lesions of the uterine cervix. Although most successful at detection of squamous lesions, the Pap may also detect metastatic carcinomas, sarcomas, and melanomas. We report two rare cases of myeloid sarcoma (MS) of the uterine cervix identified on screening Pap smears with concurrent confirmatory cervical biopsies. The purpose of our study is to identify and report cytologic features of MS on Pap smears utilizing a liquid-based ThinPrep method, which has not been previously documented in literature. Two Pap smears were identified from the pathology laboratory information system, both with positive cervical biopsy findings of MS. Both women, age 40 and 39, presented with ureteral obstruction, hydronephrosis, and past medical histories significant for acute myeloid leukemia (AML). On imaging, cervical masses were identified, and subsequent work-up with Pap smears and biopsies were performed. Cytologic examination of the ThinPrep Pap smears were negative for squamous intraepithelial lesion. Atypical hematologic cells were seen in the background with irregular nuclear contours, increased nuclear to cytoplasmic ratios, variably prominent nucleoli, and variable amounts of agranular cytoplasm. The biopsy confirmed these findings to represent MS. MS is defined as a tumor mass of myeloblasts or immature myeloid cells occurring in an extramedullary site. This rarely involves the female genital tract, about 50 reported cases. Although very rare, MSs in the setting of a history of AML are able to be identified on liquid-based ThinPrep smears. PMID- 28569010 TI - Interpersonal discrimination and markers of adiposity in longitudinal studies: a systematic review. AB - While the impact of interpersonal discrimination on mental health is well established, its effects on physical health outcomes have not been fully elucidated. This study systematically reviewed the literature on the prospective association between interpersonal discrimination and markers of adiposity. Medline, Web of Science, Scopus, PsycInfo, SciELO, LILACS, Google Scholar, Capes/Brazil and ProQuest databases were used to retrieve relevant information in November 2016. The results from the 10 studies that met the inclusion criteria support an association between interpersonal self-reported discrimination and the outcomes. In general, the most consistent findings were for weight and body mass index (BMI) among women, i.e. high levels of self-reported discrimination were related to increased weight and BMI. Waist circumference (WC) showed a similar pattern of association with discrimination, in a positive direction, but an inverted U-shaped association was also found. Despite a few inverse associations between discrimination and markers of adiposity, none of the associations were statistically significant. Overall, markers of adiposity were consistently associated with discrimination, mainly through direct and nonlinear associations. This review provides evidence that self-reported discrimination can play an important role in weight, BMI and WC changes. PMID- 28569011 TI - InSourcerer: a high-throughput method to search for unknown metabolite modifications by mass spectrometry. AB - RATIONALE: Using mass spectrometry, the analysis of known metabolite structures has become feasible in a systematic high-throughput fashion. Nevertheless, the identification of previously unknown structures remains challenging, partially because many unidentified variants originate from known molecules that underwent unexpected modifications. Here, we present a method for the discovery of unknown metabolite modifications and conjugate metabolite isoforms in a high-throughput fashion. METHODS: The method is based on user-controlled in-source fragmentation which is used to induce loss of weakly bound modifications. This is followed by the comparison of product ions from in-source fragmentation and collision-induced dissociation (CID). Diagonal MS2 -MS3 matching allows the detection of unknown metabolite modifications, as well as substructure similarities. As the method relies heavily on the advantages of in-source fragmentation and its ability to 'magically' elucidate unknown modification, we have named it inSourcerer as a portmanteau of in-source and sorcerer. RESULTS: The method was evaluated using a set of 15 different cytokinin standards. Product ions from in-source fragmentation and CID were compared. Hierarchical clustering revealed that good matches are due to the presence of common substructures. Plant leaf extract, spiked with a mix of all 15 standards, was used to demonstrate the method's ability to detect these standards in a complex mixture, as well as confidently identify compounds already present in the plant material. CONCLUSIONS: Here we present a method that incorporates a classic liquid chromatography/mass spectrometry (LC/MS) workflow with fragmentation models and computational algorithms. The assumptions upon which the concept of the method was built were shown to be valid and the method showed that in-source fragmentation can be used to pinpoint structural similarities and indicate the occurrence of a modification. PMID- 28569012 TI - INBREEDING DEPRESSION WITH HETEROZYGOTE ADVANTAGE AND ITS EFFECT ON SELECTION FOR MODIFIERS CHANGING THE OUTCROSSING RATE. AB - The equilibrium level of inbreeding depression in populations with different selfing rates is studied for models with symmetrical or asymmetrical heterozygous advantage at several loci with partial linkage. As for the case of a single locus, the inbreeding depression caused by loci with heterozygous advantage can be higher for partially selfing populations than for complete outcrossing. The spread of modifier alleles at another locus that affects the selfing rate is studied. The stability of outcrossing populations to invasion by alleles that give increased selfing is found to depend on levels of inbreeding depression being greater than one-half, in accordance with earlier models that assumed a fixed level of inbreeding depression. However, in partially selfing populations the spread of such alleles can be checked by smaller levels of inbreeding depression than one-half, so that they do not always spread to fixation. This is interpreted as being due to associations between the genotypes at the modifier locus and the selected loci, together with increasing inbreeding depression as selfing increases, and does not occur if the inbreeding depression is due to mutation-selection balance. PMID- 28569013 TI - INDIVIDUAL SEX RATIO ADJUSTMENT IN RESPONSE TO THE OPERATIONAL SEX RATIO IN THE SOUTHERN GREEN STINKBUG. AB - Females of the southern green stinkbug, Nezara viridula (Hemiptera: Pentatomidae), initiating copulation in a female-biased environment produced relatively more sons than females initiating copulation in a male-biased environment. Although families suffering greater mortality yielded more sons, the difference in offspring sex ratio between treatments was not due to differential mortality by sex since the distribution of family size did not vary between treatments. Female condition, indexed by female size and size of the first egg mass laid, did not vary between treatments and, therefore, apparently did not contribute to the results. Thus, it appears that the stinkbug is capable of facultative sex ratio adjustment in response to the operational sex ratio, increasing the production of sons when males are rare. In nature, overlapping generations and female-biased operational sex ratios may occur; conditions under which selection for sex ratio adjustment is most intense. PMID- 28569014 TI - EFFECTS OF A HAEMATOPHAGOUS MITE ON THE BARN SWALLOW (HIRUNDO RUSTICA): A TEST OF THE HAMILTON AND ZUK HYPOTHESIS. AB - I tested three assumptions of the Hamilton and Zuk hypothesis (1982), which suggests that the extravagant male plumage of many bird species allows females to choose mates that are resistant to the parasites exploiting the host population at a given time. By choosing such males as mates, females will rear offspring carrying the genes for resistance. I tested three necessary conditions for the Hamilton and Zuk model: (1) whether parasites affect the fitness of their hosts; (2) whether there is heritable variation in parasite resistance, and (3) whether the expression of the sexual ornament varies with parasite burden. The haematophagous mite Ornithonyssus bursa (Macronyssidae, Gamasida) sucks blood from their Barn Swallow (Hirundo rustica) hosts. Experimental manipulation of mite loads and partial cross-fostering experiments on Barn Swallows, where half of the nestlings in the brood were exchanged with nestlings from another nest, shows that parasite burdens and origin, but not rearing conditions, of Bam Swallow nestlings, affected their adult tarsus length and maximum body weight shortly before fledging. Mite loads of adult Barn Swallows at spring arrival were more similar to mite loads of their own offspring, whether reared in their own or in foster nests inoculated with mites, than to loads of foster offspring. Parent Barn Swallows with long tail ornaments had offspring with smaller mite loads in the partial cross-fostering experiments. The amount of increase in male tail ornaments from one year to another was negatively related to experimentally manipulated mite loads of Barn Swallow nests during the preceding breeding season. In conclusion, the three assumptions of the hypothesis were supported by the experimental tests. PMID- 28569015 TI - GAMETIC INCOMPATIBILITY BETWEEN SPECIES OF THE SEA URCHIN ECHINOMETRA ON THE TWO SIDES OF THE ISTHMUS OF PANAMA. AB - The Pliocene rise of the Central American Isthmus has resulted in numerous "geminate pairs," i.e., closely related species, one on each coast. Such species pairs can provide information on the evolution of isolating mechanisms in allopatry and on the relationship between genetic divergence and reproductive isolation in populations separated at a known time. The sea urchin genus Echinometra has one species, E. vanbrunti, in the eastern Pacific, and two, E. lucunter and E. viridis, in the Caribbean. E. viridis is morphologically distinct from the other two species, leading to the conclusion that E. lucunter and E. vanbrunti constitute a geminate pair. Allozyme data, on the other hand, place the speciation event of the two currently sympatric species after the rise of the Isthmus. We report fertilization experiments between the gametes of the three species performed to determine degree of reproductive isolation. Crosses between E. viridis and E. vanbrunti produce rates of fertilization almost equal to those manifested in homogamic crosses. Sperm of E. lucunter can fertilize eggs of the other two species, but few of its eggs permit fertilization by heterospecific sperm. Contrary to the predictions of the "speciation by reinforcement" hypothesis, degree of incompatibility between the allopatric E. lucunter and E. vanbrunti is higher than between the sympatric E. lucunter and E. viridis. Despite the incomplete and unidirectional nature of their gametic isolation, E. lucunter and E. viridis maintain their genetic integrities. Consideration of the likely phylogenetic relationships between the three species suggests that incompatibility of E. lucunter eggs with heterospecific sperm has evolved in the last 3.5 million years, after the rise of the Isthmus. There is no correlation between genetic divergence and strength of reproductive isolation, either within Echinometra, or among the geminate species pairs of echinoids that have been studied to date. Because recognition between echinoid gametes depends on the chemical compositions of a sperm protein and an egg glycoprotein, the appearance of gametic isolation would require only the fixation of a few mutations in each population on either side of a geographic barrier and could be independent of any other kind of genetic divergence. Thus, in animals with external fertilization, speciation need not be accompanied by major genomic reorganization. PMID- 28569016 TI - DIFFERING LEVELS OF AMONG-POPULATION DIVERGENCE IN THE MITOCHONDRIAL DNA OF PERIODICAL CICADAS RELATED TO HISTORICAL BIOGEOGRAPHY. AB - Mitochondrial DNA (mtDNA) haplotypes were determined for 118 individuals of 13 and 17-year periodical cicadas (genus Magicicada) collected from 16 localities throughout the Midwest and eastern United States. Two distinct mtDNA lineages, identified as A and B, differ by 2.5% based on analysis of fragment patterns and restriction maps. Observed levels of mtDNA diversity within each lineage are low compared to estimates for other taxa. The two lineages are regionally segregated, with the boundary line occurring at a latitude of approximately 33 degrees North. The levels of mtDNA diversity and population genetic structure differ within the two lineages. There is a remarkably low level of mean mtDNA divergence and no genetic structure in lineage A, whereas lineage B exhibits an order of magnitude higher level of mtDNA diversity and significant genetic structure among sampled populations. The low level of mtDNA diversity in cicadas may be attributed to (1) a population bottleneck that most likely occurred during the Pleistocene, (2) recent colonization following the retreat of the glaciers and the expansion of deciduous forests, and/or (3) high among-family reproductive variance (as a consequence of large population size, high fecundity, aggregative behavior of adults, and clumping of eggs). The difference in mtDNA diversity and population genetic structure between the lineages suggests that they experienced different biogeographic histories; we relate this to Pleistocene changes. PMID- 28569017 TI - NATURAL SELECTION ON BILL CHARACTERS IN THE TWO BILL MORPHS OF THE AFRICAN FINCH PYRENESTES OSTRINUS. AB - Evidence for natural selection on seven bill and body characters is examined in the two bill morphs of the African estrildid finch Pyrenestes ostrinus. Two regression methods are used in examining natural selection in association with survivorship: a parametric (Lande and Arnold, 1983) and a non-parametric (Schluter, 1988) method. Selection was estimated in adult males, females and juveniles over a four-year period in a population in south-central Cameroon. Selection was common among groups but patterns differed and depended on the method used in detecting selection. The non-parametric method revealed evidence for disruptive selection occurring on bill width and is explained within the context of known feeding efficiencies and the hardness of important seeds in finch diets. Directional selection was common on bill characters in all groups, but infrequent on other characters. There was no evidence of selection on generalized size or shape characters. Selection on bill characters was common across groups despite low annual variation in rainfall. This contrasts with studies of Galapagos finches in which selection is frequently associated with dramatic changes in food supply caused by high variance in annual rainfall. Patterns of selection on bill traits in P. ostrinus also differ from those in song sparrows and Galapagos finches by exhibiting evidence for natural selection on all bill dimensions. PMID- 28569018 TI - GENETIC DIVERGENCE IN PERIPHERALLY ISOLATED POPULATIONS OF CHAFFINCHES IN THE ATLANTIC ISLANDS. AB - Peripherally isolated populations of common chaffinches (Fringilla coelebs) in the Canaries, Madeira, and Azores were compared genetically with their putative ancestral stock in Iberia and Morocco, and with a population of blue chaffinches (F. teydea) from Tenerife, using protein electrophoresis of 42 loci. The continental populations are only weakly differentiated genetically (FST = 0.092), despite distinctive subspecific differences in plumage and morphometrics between Iberia and Morocco populations. Estimated levels of gene flow among continental populations are high enough to account for their relative genetic homogeneity, and it is unlikely that homogenizing selection is operating to mimic the effects of gene flow. In contrast, the Atlantic island populations are well differentiated genetically (FST = 0.321), and have diverged considerably from their continental conspecifics. The development of significant genetic differentiation within the Canaries but not the Azores likely results from smaller population sizes, very restricted gene flow, and enhanced random drift in the former populations. There is no convincing evidence in support of stronger directional selection acting on genotypes or phenotypes to reduce within population variability in Canaries populations as proposed by Grant (1979), although other tenets of his model of island evolution are supported by our analysis. Although genetic variability is reduced in four of the Canaries populations, only the Hierro population appears to have encountered a severe bottleneck. Yet it has not differentiated markedly from the La Palma population to which it is subspecifically allied. We conclude that gradual divergence in isolated populations of small to moderate size is the most plausible explanation for the evolution of intraspecific and interspecific diversity in Atlantic island chaffinches. PMID- 28569019 TI - FREQUENCY-DEPENDENT SELECTION IN DROSOPHILA: ESTIMATION OF NET FITNESS IN PSEUDOHAPLOID POPULATIONS. AB - There is much evidence that the viability of Drosophila larvae depends on the genotypes of other larvae with which they develop. There is, however, little evidence concerning frequency dependence of net fitness. This report documents variation in net fitness among male D. melanogaster from 17 lines studied in 49 discrete-generation populations. The experimental design, which uses attached-X females, eliminates effects of dominance, heterosis, recombination, genetic background, and selection in females. Selection operates only on patroclinously inherited X-chromosomes in males, causing frequency dynamics to mimic those of haploid populations. Analysis of one-generation transitions shows a general pattern of frequency dependence of net fitnesses. Analysis of multigeneration trajectories suggests frequency dependence in 12 populations, but trajectories tend to be heterogeneous among replicates. For a deterministic model in which fitness w(p) is a function of allelic frequency (p), oscillatory dynamics can occur where |dw(p)/dp| > w(p) (Curtsinger, 1984a). The derivative measures the strength of frequency-dependent selection, and divides models into two categories: dynamically "well-behaved" and "complex." For the pooled data, this criterion is violated in about half of the frequency space, though several factors probably cause strength to be overestimated. The strength criterion is a useful predictor of evolutionary dynamics: observed oscillations tend to occur most often where frequency dependence is strong, and less often where it is weak. PMID- 28569020 TI - FISHER'S SEX RATIO THEORY MAY EXPLAIN HATCHING PATTERNS IN BIRDS. AB - I present the hypothesis that asynchronous hatching is a means of ensuring an equal degree of parental investment in the progeny of each sex in altricial species of birds that are sexually dimorphic in size. In a comparative analysis of bird species of Africa and the Western Palearctic, I find a positive relationship between hatching asynchrony and sexual size dimorphism, in support of the hypothesis. The relation is significant for species in which males are larger than females, and in species in which females are larger than males. In addition, it holds even if allometric effects of body size are controlled for. No such relationship is found in species with self-feeding young. Alternative hypotheses to explain asynchronous hatching in altricial birds are discussed. The results of the comparative study are also consistent with some of these hypotheses. For instance, asynchronous hatching may be a mechanism used by parents of dimorphic species to deal with unpredictable primary sex ratios; it may be a way of avoiding simultaneous peak food demands by the young; or it may be a way of advancing the time of hatching so that the division of labor between the parents is optimized. PMID- 28569021 TI - PLOIDY AND EVOLUTION BY SEXUAL SELECTION: A COMPARISON OF HAPLOID AND DIPLOID FEMALE CHOICE MODELS NEAR FIXATION EQUILIBRIA. AB - We compare the stability properties of haploid and diploid models of Fisherian sexual selection (with male contribution limited to sperm) by examining both models at equilibria for which a male trait is fixed or absent. Haploid and diploid two locus diallelic models share the property that the stability of such fixation equilibria is determined by the relationship between the harmonic mean of relative preference values for the common male trait, weighted by the frequency of the preferences, and the relative viability associated with the common male trait. When diploid females with heterozygotic-based preferences express preference strengths intermediate between homozygote-based preferences, then boundary equilibria of haploid and diploid models share many stability properties. However, even with intermediate heterozygote preferences, haploid and diploid models do differ: (1) for a particular frequency of the preference allele, both fixation boundaries can be stable for the diploid model, and (2) with over- or underdominance at the preference locus (a possibility precluded in the haploid model), a fixation boundary in the diploid model may show two switches in its stability state for increasing frequencies of one of the preference alleles. These differences are due not just to the impossibility of dominance in haploid models, but also to the larger number of diploid genotypes. PMID- 28569022 TI - THE EVOLUTIONARY HISTORY OF PARTHENOGENETIC CNEMIDOPHORUS LEMNISCATUS (SAURIA: TEIIDAE). II. MATERNAL ORIGIN AND AGE INFERRED FROM MITOCHONDRIAL DNA ANALYSES. AB - Restriction endonuclease analyses were performed on mitochondrial DNAs (mtDNAs) representing unisexual parthenogenetic (cytotypes A, B, and C) and bisexual (cytotypes D and E) populations of Amazonian lizards presently regarded as Cnemidophorus lemniscatus. The results of mtDNA cleavage map comparisons among these C. lemniscatus indicated that (1) there was no cleavage site variation among the unisexuals, (2) mtDNAs from the bisexual cytotypes D and E differed in sequence from one another by about 13%, and (3) mtDNAs from cytotypes A-C differed from those of cytotype D by about 5% and from those of cytotype E by about 13%. Higher resolution restriction fragment size comparisons confirmed the high degree of similarity among the unisexual mtDNAs, but identified 12 cleavage site variants among the 13 cytotype D mtDNAs examined. Both cladistic and phenetic (UPGMA) analyses of the data indicate that the unisexual and cytotype D mtDNAs form a single clade, suggesting that a female of cytotype D was the maternal progenitor of the unisexuals. The similarity among the unisexual mtDNAs and the variability among those of cytotype D suggest that the three unisexual cytotypes arose recently from a common maternal lineage. The mtDNA variability observed among cytotype D individuals has a strong geographic component, suggesting that the unisexuals arose from one or a few geographically proximal populations. The mtDNA comparisons also support the conclusion, based on allozyme comparisons (Sites et al., 1990, this issue), that cytotypes D and E, although presently allocated to C. lemniscatus, are separate species. PMID- 28569023 TI - CLONAL INHERITANCE OF A DIPLOID NUCLEAR GENOME BY A HYBRID FRESHWATER MINNOW (PHOXINUS EOS-NEOGAEUS, PISCES: CYPRINIDAE). AB - Hybrids between the minnows Phoxinus eos and Phoxinus neogaeus coexist with a population of P. eos in East Inlet Pond, Coos Co., New Hampshire. Chromosome counts and flow cytometric analysis of erythrocyte DNA indicate that these hybrids include diploids, triploids, and diploid-triploid mosaics. The mosaics have both diploid and triploid cells in their bodies, even within the same tissues. All three hybrid types are heterozygous at seven putative loci for which P. eos and P. neogaeus are fixed for different allozymes, indicating that the hybrids carry one eos and one neogaeus haploid genome. The diploid hybrids are therefore P. eos-neogaeus, whereas the triploids and mosaics are derived from P. eos-neogaeus but have an extra eos or neogaeus genome in all or some of their cells. Diploid, triploid, and mosaic hybrids accept tissue grafts from diploid hybrids, indicating that all individuals carry the identical eos-neogaeus diploid genome. Thus, one P. eos-neogaeus clone exists at East Inlet Pond. Grafts among the triploids and mosaics or from these individuals to diploid hybrids are rejected, indicating that the third genome is different in each triploid and mosaic individual. In this study, diploid and mosaic hybrids, carrying the clonal eos-neogaeus genome, were bred in the laboratory with males of P. eos or P. neogaeus. Both diploid and mosaic hybrids produced diploid, triploid, and mosaic offspring, revealing the source of the three hybrid types present at East Inlet Pond. These offspring accepted grafts from P. eos-neogaeus individuals, indicating that they all had inherited the identical eos-neogaeus genome. Most grafts among triploid and mosaic progeny, or from these individuals to their diploid broodmates, were rejected, indicating that the third genome was different in each triploid and mosaic (as was observed in the wild hybrids) and was contributed by sperm from males of P. eos or P. neogaeus. Diploid progeny are produced if sperm serves only to stimulate embryogenesis; triploid or mosaic progeny are produced if the sperm genome is incorporated. Although based on a mode of reproduction that by definition results in a genetically identical community of individuals, i.e., gynogenesis, reproduction in hybrid Phoxinus results in a variety of genetically distinct individuals by the incorporation of sperm into approximately 50% of the diploid ova produced. PMID- 28569024 TI - MEASURING SELECTION ON REACTION NORMS: AN EXPLORATION OF THE EUROSTA-SOLIDAGO SYSTEM. AB - The sensitivity of genotypic expression to the environment can be depicted as the reaction norm, which is defined as the array of phenotypes produced by a single genotype over a range of environments. We studied selection on reaction norms of the gall-inducing insect Eurosta solidaginis (Diptera; Tephritidae), which attacks tall goldenrod Solidago altissima (Compositae). Gall size was treated as a component of insect phenotype and attributes of the host plant as environmental influences on gall development. Genetic differences in the response of gall size to plant lag time (the number of days before a plant responds to the gall maker) were examined. Reaction norms for full-sib families of flies were quantified as linear functions; the elevation of the function denoted gall size produced by the family averaged across all plants, and the function's slope denoted family sensitivity to lag time. Expected fitness of each family was regressed over reaction norm elevation and slope to yield selection gradients on these reaction norm parameters. Directional selection on gall size averaged across environments is four times stronger than selection on sensitivity. Yet, genetic variation for sensitivity contributes more than twice as much to gall phenotypic variance as family mean gall size. Our results suggest that selection on environmental sensitivity will be weak for populations restricted to a narrow segment of an environmental gradient, but strong for broadly distributed species. PMID- 28569025 TI - SPATIAL RELATIONSHIP AND GENE FLOW PATHS BETWEEN POPULATIONS OF THE ALPINE SNAIL ARIANTA ARBUSTORUM (PULMONATA: HELICIDAE). AB - The alpine snail Arianta arbustorum (Pulmonata, Helicidae) was sampled along an 8 km contour line in the Swiss Alps orthogonal to well-known altitudinal clines in life history and shell traits. The allele frequencies and the morphs of 16 populations were compared with habitats. Two hypotheses about the recolonization of the mountain slopes after the last glaciation were tested against the present population structure. The allele frequencies are best explained by the spatial structure whereas the morphs are better explained by the habitats. The genotypic distances point to a historical explanation by recolonization processes, the phenotypical dissimilarities to a selectionistic interpretation of the present distribution of the populations. The following conclusions are from the study of the spatial relationship and the gene flow paths for A. arbustorum at Mount Martegnas: (1) Streams are the main gene flow paths; gene flow is low, allowing differentiation of local populations. (2) Morphs and habitats are correlated, but the interpretation has to be made carefully. The spatial dependence of habitats has to be included into the analysis of selection. (3) The random assumption for gene flow of A. arbustorum is not a spatial isolation-by-distance model, but a functional isolation-by-distance model, assuming gene flow over the drainage system. PMID- 28569026 TI - MITOCHONDRIAL GENE TREES AND THE EVOLUTIONARY RELATIONSHIP OF MALLARD AND BLACK DUCKS. AB - We assayed restriction site differences in mitochondrial DNA (mtDNA) within and among allopatric populations of the Mallard (Anas platyrhynchos) and the American Black Duck (A. rubripes). The observed mtDNA clones grouped into two phylogenetically distinct arrays that we estimate differ by about 0.8% in nucleotide sequence. Genotypes in one clonal array were present in both species, while genotypes in the other array were seen only in Mallards. In terms of the mtDNA "gene tree," the assayed Mallards exhibit a paraphyletic relationship with respect to Black Ducks, meaning that genealogical separations among some extant haplotypes in the Mallard predate the species separation. Evidence is advanced that this pattern probably resulted from demographically based processes of lineage sorting, rather than recent, secondary introgressive hybridization. However, haplotype frequencies were most similar among conspecific populations, so the Mallard and Black Ducks cluster separately in terms of a population phenogram. The results provide a clear example of the distinction between a gene tree and a population tree, and of the distinction between data analyses that view individuals versus populations as operational taxonomic units (OTUs). Overall, the mtDNA data indicate an extremely close evolutionary relationship between Mallards and Black Ducks, and in conjunction with the geographic distributions suggest that the Black Duck is a recent evolutionary derivative of a more broadly distributed Mallard-Black ancestor. PMID- 28569027 TI - THE INCIDENCE AND EFFECTS OF HYBRIDIZATION BETWEEN CULTIVATED RICE AND ITS RELATED WEED RED RICE (ORYZA SATIVA L.). AB - The objectives of this study were (1) to determine if hybridization occurs naturally between cultivated rice and a closely related weed, red rice (both Oryza sativa L.) and (2) to determine the incidence of hybridization and possible convergence of red rice with cultivated rice. Both morphological and electrophoretic characters were used to confirm the existence of hybrids. A total of 12,000 seeds were collected from red rice plants from fields of six different rice cultivars and sown in a common garden. Hybrids were generally taller and had longer, wider flag leaves than either red rice or cultivated rice. In addition, hybrids produced more tillers than red rice. Overall, hybrids were vegetatively robust plants, demonstrating heterosis and expressing morphological characteristics of both parents. That these plants were hybrids was confirmed by the existence of electrophoretic banding patterns common to both synthetic and natural hybrids. The incidence of hybridization was estimated as the percentage of hybrids found in red rice populations while morphological characteristics were used to test for convergence. Percentage hybridization ranged from 1% in the Lemont cultivar to 52% in the Nortai variety. The greater number of hybrids found in the Nortai variety was attributed to a later flowering time of this variety and the overlap of its flowering time with that of the F1 hybrids. F1 hybrids were observed to flower later than either red rice or the early season varieties of cultivated rice. Thus, early season varieties have a temporal separation in flowering time from the F1 hybrids that prevents back crossing. Unlike the other hybrids that were vegetatively robust, Nortai hybrids were less robust and more similar to the cultivar. These results suggest that later season cultivars may have a higher incidence of hybridization and introgression with red rice and that this may lead to morphological convergence of the weed toward the crop. Convergents were observed in the Nortai variety. Hybridization between cultivated and red rice has the potential to increase the adaptability of red rice populations by promoting genetic diversity. PMID- 28569028 TI - WHY PARSIMONY? PMID- 28569029 TI - THE EVOLUTIONARY HISTORY OF PARTHENOGENETIC CNEMIDOPHORUS LEMNISCATUS (SAURIA, TEIIDAE). I. EVIDENCE FOR A HYBRID ORIGIN. AB - Chromosomes and allozymes were studied from chromosomally distinct unisexual (races B and C) and bisexual (races D and E) populations of the teiid lizard Cnemidophorus lemniscatus, and from selected outgroup taxa (C. murinus, C. nigricolor, Ameiva ameiva, and A. auberi). Karyotyping confirmed the racial identity of individuals and showed that the chromosomal composition of populations at specific localities has remained the same for 20 years. All individuals of both unisexual populations were heterozygous for a pericentric inversion that distinguishes D and E bisexuals. Also, the unisexuals were all heterozygous for 8 of 11 protein loci for which D and E were fixed or nearly fixed for different alleles. Most of these alleles represent derived states relative to the other Cnemidophorus and Ameiva analyzed, and the fixed heterozygote condition at these nine markers provides unequivocal support for the hypothesis that the unisexual C. lemniscatus arose by hybridization between ancestors genetically similar to extant D and E populations. At the remaining three loci for which D and E show fixed differences, the unisexuals were homozygous rather than heterozygous. This suggests that either (1) allozymes have been lost by mutations to null, silent, or convergent mobility states, (2) ancestral genotypes were similar to but not identical with the extant D and E races, and/or (3) limited recombination may occur between unisexual genomes. Allozyme-based genetic distances between D and E were large, suggesting that bisexual races D and E are genetically isolated; each race should be accorded full species status. This conclusion is supported by the absence of any clear biochemical evidence for their monophyly with respect to the other Cnemidophorus examined. Cladistic analyses of 17 phylogenetically informative loci revealed two equally parsimonious shortest trees, one supporting monophyly and the other paraphyly of the C. lemniscatus complex. Further testing of the monophyly of C. lemniscatus requires additional data. With the present study, the evidence that all parthenogenetic Cnemidophorus are of hybrid origin is complete. PMID- 28569030 TI - GENOTYPE DIVERSITY AND SELECTION IN ASEXUAL BRINE SHRIMP (ARTEMIA). AB - An obligately asexual population of Artemia parthenogenetica at Salin de Giraud, France consists of numerous clones that are genetically and ecologically divergent. The clones are distributed in a nonrandom fashion among eight ponds of highly variable environments. A total of 63 allozymically unique genotypes were identified, with significant differences in numerous fitness traits found among a sample subset of clones. The frequencies of four alleles, as well as the percentage of loci polymorphic, were significantly correlated with salinity. Genotypes face rapid selection along salinity gradients in the field and this selection is reproducible in the lab. mtDNA analysis suggests that obligate asexuality in this population is of monophyletic origin. PMID- 28569031 TI - THE COST OF MERISTEM LIMITATION IN POLYGONUM ARENASTRUM: NEGATIVE GENETIC CORRELATIONS BETWEEN FECUNDITY AND GROWTH. AB - Growth and reproduction in higher plants depend on meristems, which have three developmental fates. A meristem can become reproductive, but doing so terminates its activity, it can differentiate vegetatively, or it can remain quiescent for extended periods. The first two fates are mutually exclusive, and only the second leads to the production of additional meristems for subsequent growth and reproduction. In Polygonum arenastrum (frequently referred to as P. aviculare in North American Floras), an annual species lacking quiescent meristems, a quantitative genetic analysis of inbred full-sibling families revealed genetic variation in the developmental pattern of axillary meristem commitment to vegetative growth versus reproduction. Developmental variation resulted in family differences in the age of first reproduction, in age-specific fecundity and growth, and in final plant size and reproductive output. Furthermore, there were strong negative genetic correlations between age-specific growth and fecundity. Early commitment of meristems to reproduction favors high early fecundity, but reduces the number of meristems available for vegetative differentiation, and leads to lowered growth rates and fecundity later in life, when meristems are limiting. Conversely, meristem commitment to vegetative growth early in life results in low early fecundity but high late fecundity and growth. Meristem limitation, like resource limitation, is a proximate mechanism that generates trade-offs between life history traits. Differences between meristem limitation and resource limitation are discussed. Meristem limitation leads automatically to a senescent life history because of the determinate fate of reproductive meristems. Developmental characters were also found to be genetically correlated with metamer characters (leaf size, internode length) and seed size in this selfing species. The pattern of correlation is suggestive of selection for particular suites of life history and morphological characters. PMID- 28569032 TI - DIFFERENT SPATIAL SCALES OF ADAPTATION IN THE CLIMBING BEHAVIOR OF PEROMYSCUS MANICULATUS: GEOGRAPHIC VARIATION, NATURAL SELECTION, AND GENE FLOW. AB - Patterns of geographic variation in tree-climbing ability of Peromyscus maniculatus were used to examine the influence of spatial variation in natural selection and gene flow on the genetic divergence of climbing behavior among populations. Offspring of adults of two subspecies sampled from 10 localities in montane conifer forest, conifer woodland, and desert scrub/grassland habitats were raised in the laboratory and tested to determine their tree-climbing ability (the maximum diameter artificial rod that a mouse could climb). Comparisons of mean rod-climbing scores revealed that individuals of P. m. rufinus sampled from montane conifer forest and conifer woodland in Arizona were better climbers than P. m. sonoriensis sampled from conifer woodland and desert habitats in Nevada. This result was consistent with the hypothesis that natural selection has produced large-scale adaptation in climbing behavior. However, the climbing ability of P. m. sonoriensis sampled from conifer woodland habitats on isolated mountaintops in Nevada has not evolved in response to natural selection to the degree expected. In addition, populations sampled from desert grassland habitat, adjacent to woodland P. m. rufinus in Arizona, have climbing abilities that are not significantly different from conifer woodland populations. These observations indicate that local adaptation was constrained. An estimate of the heritability of climbing ability (h2 = 0.352 +/- 0.077) indicates that lack of a response to selection was not due to the absence of additive genetic variation. In addition, regressions of interpopulation differences on the degree of geographic isolation between pairs of populations do not support the hypothesis that gene flow between habitats has constrained evolution. Instead, a combination of historical events and insufficient time to respond to selection appears to have influenced geographic variation and the spatial scale of adaptation in climbing ability. PMID- 28569033 TI - EVOLUTIONARY ANALYSIS OF THE LARGE SUBUNIT OF CARBOXYLASE (rbcL) NUCLEOTIDE SEQUENCE AMONG THE GRASSES (GRAMINEAE). AB - The full nucleotide sequences of the chloroplast encoded large subunit of ribulose-1,5-bisphosphate carboxylase (rbcL) are available for nine grass species and partial sequence data for one species. Relative rate tests of the "molecular clock" hypothesis suggest that rbcL evolved more rapidly in the lineage leading to Zea than in those leading to the other species. The estimated overall substitution rate for rbcL among these grasses is about 5 times 10-10 substitutions per site per year, or about one-half the synonymous rate. The nine full sequences were analyzed by the UPGMA, Wagner parsimony, maximum likelihood, and Fitch-Margoliash methods. The latter three methods produced trees with the same topology. This topology largely agrees with current taxonomic evidence regarding the relationships among these grasses. UPGMA produced a topology that conflicts more substantially with available taxonomic evidence. Statistical comparison of the three alternative topologies for the subfamilies Panicoideae, Pooideae and Bambusoideae failed to support one of these topologies over the others, reflecting the taxonomic ambiguities surrounding the relationships among these taxa. Phylogenetic analyses based on the partial sequences of all 10 species gave conflicting results with regard to the relationship between Hordeum and Triticum, both members of the tribe Triticeae. This indicates that rbcL sequences contain too little information to resolve relationships among genera within this tribe. Overall, the results suggest that rbcL sequence data can provide some new information concerning grass phylogeny, but that the amount of available data from this gene is too small to differentiate statistically among alternative topologies for the grasses. Conflicting results from parsimony, maximum likelihood, and Fitch-Margoliash methods proved useful in exploring the validity of assumptions underlying these methods. PMID- 28569034 TI - DO CONSTANT ENVIRONMENTS PROMOTE COMPLEXITY OF FORM?: THE DISTRIBUTION OF BRYOZOAN POLYMORPHISM AS A TEST OF HYPOTHESES. AB - The distribution of cheilostome bryozoans on the Caribbean reefs of Panama was surveyed to test the hypothesis that physically constant environments favor increased morphologic complexity, expressed as the number of zooid types within a colony. The proportion of species within defined grades of complexity did not vary significantly with locality, depth, or substratum. Some differences were found in grade-specific ecological success, measured by colony abundance and spatial cover, but these were not consistently related to habitat type. There was no inverse correlation between morphologic complexity and range of distribution: morphologically specialized cheilostomes were not more stenotopic than generalized forms. Patterns of distribution and total space occupation indicate a sensitivity to local habitat conditions, but relative success of species was not correlated with level of polymorphism. In a bryozoan fauna from Florida, the frequency of polymorphic species was weakly associated with constancy of habitat. In estuaries, polymorphic cheilostomes are almost absent at salinities below 180/00, but this pattern is strongly confounded taxonomically. All species tolerant of low salinities are encrusting anascans; within this group, polymorphism does not decrease significantly with declining salinity. Bryozoan faunas from different biogeographic zones may vary in frequency of avicularian polymorphism, but not along a simple latitudinal cline. These large-scale comparisons may be strongly biased historically and taxonomically. The distribution of cheilostome polymorphism on a local and geographic scale provides no evidence for a causal relationship between habitat constancy and morphologic specialization at the zooidal level. This is in striking contrast to the strong habitat dependence of colony form, which suggests that selective processes may operate differently at the zooidal and colonial levels. PMID- 28569035 TI - INTRASPECIFIC VARIATION IN ANT SEX RATIOS AND THE TRIVERS-HARE HYPOTHESIS. AB - We consider worker-controlled sex investments in eusocial Hymenoptera (ants in particular) and assume that relatedness asymmetry is variable among colonies and that workers are able to assess the relatedness asymmetry in their own colony. We predict that such "assessing" workers should maximize their inclusive fitness by specializing in the production of the sex to which they are relatively most related, i.e., colonies whose workers have a relatedness asymmetry below the population average should specialize in males, whereas colonies whose workers have a higher than average relatedness asymmetry should specialize in making females. Our argument yields the expectation that colony sex ratios will be bimodally distributed in ant populations where relatedness asymmetry is variable owing to multiple mating, worker reproduction, and/or polygyny. No such bimodality is expected, however, in ant species where relatedness asymmetry is known to be constant, or in cases where relatedness asymmetry is supposed to be irrelevant due to allospecific brood rearing under queen control, as in the slave making ants. Comparative data on colony sex ratios in ants are reviewed to test the predictions. The data partly support our contentions, but are as yet insufficient to be considered as decisive evidence. PMID- 28569036 TI - "KIN RECOGNITION" AMONG SPADEFOOT TOAD TADPOLES: A SIDE-EFFECT OF HABITAT SELECTION? AB - Many animals modify their behavior toward unfamiliar conspecifics as a function of their genetic relatedness. A fundamental problem of any kin recognition study is determining what is being recognized and why. For anuran tadpoles, the predominant view is that associating with relatives is kin-selected because these relatives may thereby accrue benefits through increased growth or predation avoidance. An alternative view is that kin associations are simply a side-effect of habitat selection and thus do not represent attempts to identify kin per se. In the laboratory, spadefoot toad tadpoles (Scaphiopus multiplicatus) preferentially associated with unfamiliar siblings over unfamiliar nonsiblings, as do other anurans. However, same age tadpoles also were more likely to orient toward unfamiliar nonsiblings reared on the same food (familiar food) than toward unfamiliar siblings that were reared on unfamiliar food. These results, together with the results of previous tadpole kin recognition studies, suggest that tadpoles orient toward cues learned early in ontogeny, regardless of the cues' source. Tadpoles that preferentially associated with cues learned from their environment at birth would tend to be philopatric. Censuses of 14 natural ponds revealed that tadpole density remained greatest near oviposition sites until four days before metamorphosis. Tadpole philopatry may be advantageous: tadpoles restricted to their natal site had greater growth and survivorship than did their siblings restricted to randomly selected sites elsewhere within the same pond. Thus kin affiliative tendency observed in the laboratory in this and perhaps other species of anurans may be a byproduct of habitat selection. Since kin discrimination in animals is most commonly assayed as orientation toward kin, it follows that many examples of "kin recognition" may not represent true attempts to identify kin as such, but rather may reflect some other recognition system that is under entirely different selective pressures. PMID- 28569037 TI - GENETIC DIFFERENTIATION AMONG CHEWING LOUSE POPULATIONS (MALLOPHAGA: TRICHODECTIDAE) IN A POCKET GOPHER CONTACT ZONE (RODENTIA: GEOMYIDAE). AB - Genetic variation among populations of chewing lice (Geomydoecus actuosi) was examined in relation to chromosomal and electrophoretic variation among populations of their hosts (Thomomys bottae) at a contact zone. Louse demes were characterized by low levels of genetic heterozygosity (H = 0.039) that may result from founder effects during primary infestation of hosts, compounded by seasonal reductions in louse population size. Louse populations sampled from different hosts showed high levels of genetic structuring both within and among host localities. Microgeographic differentiation of louse populations is high (mean FST = 0.092) suggesting that properties of this host-parasite system promote differentiation of louse populations living on different individual hosts. Among population differentiation in lice (FST = 0.240) was similar to that measured among host populations (FST = 0.236), suggesting a close association between gene flow in pocket gophers and gene flow in their lice. PMID- 28569038 TI - RESTRICTION FRAGMENT ANALYSIS OF PINE PHYLOGENY. AB - We used restriction fragment analysis of chloroplast, nuclear, and mitochondrial DNA to study phylogeny in the genus Pinus. Total genomic DNA of 18 to 19 pine species that spanned 14 of the 15 subsections in the genus was cut with 8 restriction enzymes, blotted, and then probed with up to 17 cloned DNA fragments which were mostly from the chloroplast genome of Douglas-fir (Pseudotsuga menziesii [Mirb.] Franco). A total of 116 shared characters, the majority representing single point mutations, were subjected to Wagner and Dollo parsimony analyses, coupled with bootstrapping and construction of consensus trees. The hard (subgenus Pinus) and soft pines (subgenus Strobus) were distinct. The soft pines in section Parrya, represented by P. longaeva, edulis, monophylla, and gerardiana, were the group closest to the hypothesized root of the genus. They were also more diverse and more closely related to the hard pines than were their descendents in section Strobus, represented by P. koraiensis, albicaulis, griffithii, and lambertiana, all of which were remarkably similar. Except for a strong clade involving P. canariensis and pinea (section Ternatae), the hard pines were weakly differentiated. The high similarity within the most speciose groups of pines (sections Strobus and Pinus) suggests that the bulk of the genus radiated relatively recently. In contrast to a recent classification, P. leiophylla was not associated with section Ternatae; instead, it appears to belong in section Pinus, and showed a high similarity to P. taeda of subsection Australes. Subsection Oocarpae, represented by P. oocarpa and radiata, appears to be a natural group, and is related to subsection Contortae, represented by P. contorta. More extensive restriction fragment studies will yield many new insights into evolution in the genus. Other methods, however, such as DNA sequencing or fine structure analysis of restriction site mutations, are likely to be necessary for rooting pine phylogenies with respect to other coniferous genera, and for estimating divergence times. PMID- 28569039 TI - VARIATION IN POLLEN SIZE, FERTILIZATION ABILITY, AND POSTFERTILIZATION SIRING ABILITY IN ERYTHRONIUM GRANDIFLORUM. AB - The mean volume of pollen grains and total pollen production varied both within and among plants of Erythronium grandiflorum. The second flowers of two-flowered plants tended to produce smaller and fewer grains than first flowers, but there was no overall relationship between mean pollen grain size and production per flower. I evaluated the effects of pollen size differences within and among plants on two components of male reproductive success: pollen tube growth and postfertilization siring ability. Pollen tubes grown in media were longer for second flowers, but were not correlated with the mean size of pollen grains, suggesting that (1) internal resource content of pollen (i.e., carbohydrates plus lipids) was not associated with the hydrated size of pollen, and that (2) pollen from second flowers contained more resources. I analyzed the growth rate and the fertilization ability of pollen growing in styles. Growth rate differed among donors and recipients, but no effects of pollen or donor characters (i.e., pollen production, grain size, and flower position) were detected. In single donor pollinations, pollen size was negatively correlated with fertilization ability across donors, and positively correlated with postfertilization siring ability of donors. A second experiment used pairs of donors; within-plant differences in pollen size and flower position had effects similar to the single donor experiment on fertilization ability, but among-plant differences were not significant. The results corroborate earlier experiments that suggest that the growth of pollen tubes in the style is probably controlled by the recipient, since donor characters had minimal effects on pollen fertilization ability. Postfertilization siring ability was not affected by within-plant differences in mean grain size and production. For among-donor differences, the number of seeds set for each donor was positively correlated with the mean grain volume, and when a donor producing large pollen fertilized ovules in an ovary, there was increased seed abortion for seeds in the same ovary sired by a second donor. In addition, the total number of seeds produced by a fruit was decreased when both donors had large pollen, apparently due to increased postfertilization abortion. Postfertilization processes appear to be influenced by paternal differences that are expressed through competition among developing seeds for maternal resources. PMID- 28569040 TI - Protective effects of Ziziphora tenuior extract against chlorpyrifos induced liver and lung toxicity in rat: Mechanistic approaches in subchronic study. AB - Chlorpyrifos (CPF) is one of the most widely used organophosphorus, which has spurred renewed interest. This study was conducted to investigate the protective effect of ziziphora tenuior extract against CPF-induced liver and lung toxicity. This study conducted 8-week rat sub-chronic toxicity study and then the effect of ziziphora tenuior extract in 3 different doses (40, 80, 160 mg/kg) was determined. We administrated maximum tolerated dose of CPF (6.75 mg/kg) by gavage for 8 weeks (5 times in week) to male rats. Rats were sacrificed 24 h after last dose and the biochemical analysis, which confirms involvement of oxidative stress in the pathogenesis of CPF toxicity in liver including increased in lipid peroxidation, protein carbonyl content, and ROS formation, glutathione depletion, decreased of antioxidant effect via frap oxidation and cytochrome c expulsion. In addition, pathological lesions confirm the dysfunction of the organs (liver and lung). In addition, using of ziziphora extract as an antioxidant is resulted in amelioration of oxidative stress marker in liver and lung damage. In conclusion, the current study revealed that CPF toxicity is related to oxidative stress and induction of cell death signaling and cotreatment with ziziphora extract is recommended in the routine therapy for the protection against CPF induced liver and lung tissue damage. PMID- 28569043 TI - Lanthanum-Based Compounds: Electronic Band-Gap-Dependent Electrocatalytic Materials for Oxygen Reduction Reaction. AB - The electronic energy level of lanthanum compounds plays an important role in the oxygen reduction reaction (ORR) electrocatalytic process. In this work, three lanthanum compounds, LaOHCO3 , La2 O2 CO3 , and La2 O3 , have been synthesized through an in situ urea hydrolysis method, followed by annealing at different temperatures. Among these lanthanum compounds, the layer-structured La2 O2 CO3 has the smallest band gap and moderate values of the conduction band (CB) and valence band (VB). Electrochemical measurements in 0.1 m KOH solution have shown that, compared with the other catalysts, La2 O2 CO3 exhibits the best electrocatalytic activity with the lowest H2 O2 production and highest durability for ORR, which proves the close correlation between electronic energy level and electrocatalytic ORR activity. During the ORR process over La2 O2 CO3 , some covalent electrons from the VB are first excited to the CB and then transfer to the unoccupied pi*2p orbitals of an active oxygen molecule, leading to strengthened oxygen adsorption and promotion of the reduction of oxygen. Moreover, La2 O2 CO3 has an ability to chemically disproportionate hydrogen peroxide (to give HO2- ), and the produced HO2- at the energy level of O2 /HO2- can undergo prompt chemical disproportionation into O2 and OH- . The O2 generated at this stage is adsorbed on the catalyst surface, which can be utilized for further oxygen reduction. PMID- 28569041 TI - Predictive value of TLR7 polymorphism for cetuximab-based chemotherapy in patients with metastatic colorectal cancer. AB - The TLR7 and TLR9 signalings are implicated in the regulation of the immune system through type-I interferon induction. Preclinical studies have demonstrated the immunomodulatory and antitumor effects of TLR7 and TLR9 agonists in combination with cetuximab. We tested the hypothesis that genetic variations in TLR7 and TLR9 and their downstream molecules IRF5 and IRF7 were associated with outcomes in metastatic colorectal cancer (mCRC) patients receiving cetuximab based chemotherapy. Six single nucleotide polymorphisms (SNPs) in TLR7, TLR9, IRF5 and IRF7 were tested for the association with RR, PFS, and OS in KRAS-wild type mCRC patients. Patients treated with FOLFIRI + cetuximab or FOLFIRI + bevacizumab in the FIRE-3 trial served as a discovery set (FIRE3-Cet, n = 244) or a control set (FIRE3-Bev, n = 246), respectively. Patients treated with FOLFOX or SOX + cetuximab in the JACCRO-CC05/06 trial served as a validation set (JACCRO, n = 76). Genomic DNA isolated from tumor tissue samples was analyzed by PCR-based direct sequencing. In the discovery cohort, patients with the TLR7 rs3853839 G/G variant showed a trend toward longer PFS than those with any C variants (median 10.0 vs. 11.8 months, HR 1.39, p = 0.092). This preliminary association was confirmed in the validation cohort, and those with the G/G genotype showed a PFS benefit compared with others (univariate: 9.1 vs. 11.6 months, HR 2.04, p = 0.005, multivariate: HR 2.02, 95% CI: 1.14-3.55, p = 0.015). This association was not observed in the control cohort. Our findings suggest that TLR7 rs3853839 predicts the outcome of cetuximab-based chemotherapy in mCRC patients. PMID- 28569042 TI - Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients. AB - We sought to describe the exposure-response relationship of necitumumab efficacy in squamous non-small cell lung cancer patients and evaluate intrinsic and extrinsic patient descriptors that may guide dosing. SQUIRE was a phase III study comparing necitumumab in combination with gemcitabine and cisplatin vs. gemcitabine and cisplatin alone in 1,014 patients. An integrated model for tumor size dynamics and overall survival was developed, where reduction in tumor size results in a decrease in survival hazard. The change in tumor size was characterized using linear growth and first-order shrinkage. Overall survival was described using a combination of a Weibull function and Gompertz function for the hazard, with dynamic tumor size being a predictor for the hazard. Although body weight resulted in higher clearance and lower exposure, simulations showed that an 800 mg flat dose provided optimal response regardless of body weight. PMID- 28569044 TI - Anxiety disorders, gender nonconformity, bullying and self-esteem in sexual minority adolescents: prospective birth cohort study. AB - BACKGROUND: Sexual minority adolescents (i.e. youth not exclusively heterosexual) report more anxiety than heterosexual youth on symptom questionnaires but no research has used standardised diagnostic tools to investigate anxiety disorder risk. This study uses a UK birth cohort to investigate the risk of anxiety disorders in sexual minority and heterosexual youth using a computerised structured clinical interview and explores the influence of gender nonconformity, bullying and self-esteem. METHODS: Participants were 4,564 adolescents (2,567 girls and 1,996 boys) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Logistic regression analyses were performed to investigate the association between sexual orientation at 15.5 years and the presence of an anxiety disorder at 17.5 years. Covariates including maternal occupation, ethnicity, mother-reported childhood gender nonconformity at 30, 42 and 57 months, child-reported gender nonconformity at 8 years, child-reported bullying between 12 and 16 years and self-esteem at 17.5 years were added sequentially to regression models. RESULTS: Sexual minority adolescents (i.e. those not exclusively heterosexual) had higher early childhood gender nonconformity (CGN), lower self-esteem and reported more bullying than adolescents identifying as 100% heterosexual. Minority sexual orientation at 15.5 years was associated with increased risk of an anxiety disorder at 17.5 years for girls (OR 2.55, CI 1.85 3.52) and boys (OR 2.48, CI 1.40-4.39). Adjusting for ethnicity, maternal occupation, mother-reported and child-reported CGN had minimal impact on this association. Adjusting for bullying between 12 and 16 years and self-esteem at 17.5 years reduced the strength of the associations, although the overall association remained significant for both sexes (girls OR 2.14 and boys OR 1.93). CONCLUSIONS: Sexual minority youth are at increased risk of anxiety disorders relative to heterosexual youth at 17.5 years. Bullying between 12-16 years and lower self-esteem may contribute to this risk. PMID- 28569046 TI - Training Improves Vibrotactile Spatial Acuity and Intensity Discrimination on the Lower Back Using Coin Motors. AB - Tactile vision substitution devices are assistive technologies for the blind that redirect visual information to the tactile sense. They typically include a tactile display that conveys visual information to the skin. Two important parameters that determine the maximum information bandwidth of tactile displays are the spatial acuity of the skin, and the ability of the user to discriminate between stimulus intensities. These two parameters were investigated by determining the two-point discrimination (TPD) threshold and the just-noticeable intensity difference (JND) using coin motors on the lower back. Coin motors are eccentric rotating-mass motors that are affordable, energy-efficient, and easy to implement. The lower back was chosen because it is a discreet place to wear assistive technology. It is generally available for use, as it is usually not critically involved in activities of daily living. Rehabilitation with sensory substitution devices often requires training by professional occupational therapists, because the user needs to extract visual information from sparse information presented through an alternative channel such as the skin. In this study they determined whether short, automated training sessions of 5 min each could improve the TPD threshold and JND. It was found that 10 min of computer assisted training improved the vibrotactile TPD threshold on the lower back by 36%, and that 18 min of training improved the just-noticeable intensity difference (JND) by 44%. It was concluded that short, automated training sessions could provide a fast and inexpensive means to improve people's basic spatial acuity and intensity discrimination skills with coin motors. PMID- 28569045 TI - A novel EWS-CREB3L3 gene fusion in a mesenteric sclerosing epithelioid fibrosarcoma. AB - Sclerosing epithelioid fibrosarcoma (SEF) is a rare, malignant fibroblastic neoplasm, morphologically composed of cords, nests or sheets of monotonous epithelioid cells within a collagenous matrix. It has been recently characterized by recurrent pathogenic EWS-CREB3L1/2 or FUS-CREB3L2 fusions and common MUC4 protein expression by immunohistochemistry. Typically SEF occur in middle-aged adults and rarely have been reported within the abdominal cavity. Here we report an 18-year-old man with intraabdominal tumor and multiple disseminated liver metastases, presenting pure SEF histologic and immunophenotypic features. Fluorescence in situ hybridization analysis showed unbalanced rearrangement of Ewing sarcoma breakpoint region 1 (EWSR1) gene. Genomic profiling by array CGH, followed by RT-PCR and sequencing analysis, revealed a previously not reported EWSR1 translocation partner, cAMP-responsive element-binding protein 3-like 3 (CREB3L3). The novel EWSR1-CREB3L3 fusion further extends the range of fusion types involving EWSR1 that are characteristic for SEF. PMID- 28569048 TI - Astrocyte-mediated synapse remodeling in the pathological brain. AB - Astrocytes, a major type of glia, reciprocally influence synaptic transmission and connectivity, forming the "tripartite synapses". Astrocytic metabotropic glutamate receptor (mGluR)-mediated Ca2+ waves and release of gliotransmitters or synaptogenic molecules mediate this neuron-glia interaction in the developing brain, but this signaling has been challenged for adult brain. However, cumulative evidence has suggested that mature astrocytes exhibit re-awakening of such immature phenotype in the pathological adult brain. This phenotypic change in astrocytes in response to injury may induce neural circuit and synapse plasticity. In this review article, we summarize astrocyte-mediated synapse remodeling during physiological development, discuss re-emergence of immature astrocytic signaling in adult pathological brain, and finally highlight its contribution to significant modification of synaptic connections correlating with functional progress of brain pathology. PMID- 28569047 TI - Transformation in pretreatment manifestations of Gaucher disease type 1 during two decades of alglucerase/imiglucerase enzyme replacement therapy in the International Collaborative Gaucher Group (ICGG) Gaucher Registry. AB - This study tests the hypothesis that the prevalence of severe clinical manifestations in Gaucher disease type 1 (GD1) patients at the time of treatment initiation has changed since alglucerase/imiglucerase enzyme replacement therapy (ERT) was approved in the United States (US) in 1991. US alglucerase/imiglucerase treated GD1 patients from the International Collaborative Gaucher Group Gaucher Registry clinicaltrials.gov NCT00358943 were stratified by age at ERT initiation (<18, 18 to <50, >=50 years), era of ERT initiation (1991-1995, 1996-2000, 2001 2005, 2006-2009), and splenectomy status pre-ERT. Prevalence of splenectomy decreased dramatically across the eras among all age groups. Bone manifestations were more prevalent in splenectomized patients than non-splenectomized patients in all age groups. Prevalence of bone manifestations differed across eras in certain age groups: non-splenectomized patients had a lower prevalence of ischemic bone events (pediatric patients) and bone crisis (pediatric patients and adults 18 to <50 years) in later eras; splenectomized adult (18 to <50 years) patients had a lower prevalence of ischemic bone events and bone crisis in later eras. Over two decades after the introduction of ERT, the prevalence of splenectomy and associated skeletal complications has declined dramatically. Concomitantly, the interval between diagnosis and initiation of ERT has decreased, most strikingly in pediatric patients who have the most severe disease. Together, these findings suggest that since the introduction of alglucerase/imiglucerase ERT, optimal standard of care has become established in the US to prevent destructive complications of GD1. PMID- 28569050 TI - Serum miR-146a, miR-155, and miR-210 as potential markers of Graves' disease. AB - BACKGROUND: Previous studies have demonstrated that dysfunctional regulatory T cells (Tregs) may be associated with Graves' disease (GD). In this study, we evaluated four serum Treg-associated miRNAs (miR-210, miR-182, miR-155, and miR 146a) expressions and assessed the potential of serum miRNAs as biomarkers of GD. METHODS: Foxp3 and serum miRNAs expressions both in GD patients and healthy controls were measured by RT-PCR. RESULTS: Serum miR-210 in GD patients was significantly higher than that of healthy controls (2.64-fold, P<.001); in contrast, miR-155 and miR-146a were lower (P<.001 and P=.008). No significant difference was found in miR-182. ROC curve analysis indicated that miR-210, miR 155, and miR-146a with the area under ROC (AUC) of 0.803 (70.0% sensitivity and 83.1% specificity), 0.796 (76.3% sensitivity and 76.9% specificity), and 0.736 (68.8% sensitivity and 73.8% specificity), respectively, could differentiate GD patients from healthy controls. Combination of three miRNAs yielded an AUC of 0.976 (91.3% sensitivity and 93.8% specificity) with 92.41% diagnostic efficiency. In addition, serum miR-210 and miR-155 in GD were associated with the extent of goiter. Three miRNAs levels were different by gender. Besides, serum miR-210 was positively correlated with free thyroxine (FT4) and thyrotrophin receptor antibody (TRAb) level. CONCLUSION: The serum levels of miR-210, miR-155, and miR-146a may be potential new markers for the diagnosis of GD and play important roles in GD pathogenesis. PMID- 28569051 TI - The chances that an emergency physician will demonstrate three abdominal aortic aneurysms by ultrasound in the emergency department for credentialing: A statistician's view. AB - The Australasian College for Emergency Medicine requires 15 proctored examinations of the aorta for credentialing in ultrasonography for abdominal aortic aneurysm (AAA). Furthermore, at least three examinations need to be positive for an aneurysm. In the ED where AAA presentations are sporadic, what are the chances that an emergency physician (EP) will have the opportunity to demonstrate three AAAs in the next 12 months? The probability of an event occurring within a given time-frame can be modelled by the Poisson distribution. Central to the Poisson distribution is the infrequency of the event such as encountering an AAA in the ED. An EP working 30 clinical hours/week in our tertiary-referral hospital ED can be expected to encounter 15.6 (3.6 symptomatic + 12 asymptomatic) AAA in the next 12 months. The probability of seeing three or more cases during this time is 99.9%. Assuming a proctor can be found for half the cases, the probability of an EP performing proctored ultrasound examinations in at least three AAAs is 98%. This probability drops to 89% if a proctor can be found for only one-third of cases. For an EP to be almost 100% certain of meeting the credentialing requirements, he/she would need almost 10 proctored ultrasound cases of AAA to be available within his/her shifts during the year. The Poisson distribution has enabled us to model the probability of encountering a given number of AAA in the ED. Analysis such as this may help rationalise the numbers needed for credentialing. PMID- 28569053 TI - Pathology of balloon-expandable transcatheter aortic valves. AB - BACKGROUND: The Placement of AoRtic TraNscathetER Valves trials (PARTNER) showed favorable safety and efficacy versus medical or surgical therapy in inoperable, high, and intermediate surgical risk patients with severe aortic stenosis. However, the biological responses to transcatheter aortic valves have not been well characterized. OBJECTIVES: The aim of this study was to perform pathologic assessment of Edwards SAPIEN transcatheter aortic valves removed either at autopsy or surgically during the PARTNER I and II clinical trials. METHODS: Explanted valves and frame were evaluated for pathologic responses including extent of thrombus, inflammation, neointima, and leaflet degeneration/calcification according to semiquantitative grading by implant duration (<=30 days; 31-90 days; >90 days). RESULTS: A total of 22 cases (median age 82.0 years, 45% men) were included, with a duration of implantation that ranged from 0 to 1739 days (median duration 16.5 days [interquartile range, 2.8 68.3]). Valve thrombosis resulting in severe aortic stenosis was observed in one case. Moderate leaflet thrombus was seen in 14% of cases (n = 3) and all were asymptomatic. Calcification was seen in two valves: one with severe leaflet calcification had severe aortic stenosis requiring surgical replacement, while the other showed early calcification. Mild structural leaflet changes were exclusively seen in valve implants >90 days. Valve inflammation and thrombus formation was mild in majority of the cases. CONCLUSIONS: Overall, our study demonstrates moderate thrombus formation in 14% and calcification in only 2 valves, >=4 years duration. In this short-duration study, acceptable durability and biocompatibility of the Edwards SAPIEN transcatheter valve system was demonstrated; however, further studies are required to confirm the significance and application of our findings. PMID- 28569054 TI - Flexible, Low-Power Thin-Film Transistors Made of Vapor-Phase Synthesized High-k, Ultrathin Polymer Gate Dielectrics. AB - A series of high-k, ultrathin copolymer gate dielectrics were synthesized from 2 cyanoethyl acrylate (CEA) and di(ethylene glycol) divinyl ether (DEGDVE) monomers by a free radical polymerization via a one-step, vapor-phase, initiated chemical vapor deposition (iCVD) method. The chemical composition of the copolymers was systematically optimized by tuning the input ratio of the vaporized CEA and DEGDVE monomers to achieve a high dielectric constant (k) as well as excellent dielectric strength. Interestingly, DEGDVE was nonhomopolymerizable but it was able to form a copolymer with other kinds of monomers. Utilizing this interesting property of the DEGDVE cross-linker, the dielectric constant of the copolymer film could be maximized with minimum incorporation of the cross-linker moiety. To our knowledge, this is the first report on the synthesis of a cyanide-containing polymer in the vapor phase, where a high-purity polymer film with a maximized dielectric constant was achieved. The dielectric film with the optimized composition showed a dielectric constant greater than 6 and extremely low leakage current densities (<3 * 10-8 A/cm2 in the range of +/-2 MV/cm), with a thickness of only 20 nm, which is an outstanding thickness for down-scalable cyanide polymer dielectrics. With this high-k dielectric layer, organic thin-film transistors (OTFTs) and oxide TFTs were fabricated, which showed hysteresis-free transfer characteristics with an operating voltage of less than 3 V. Furthermore, the flexible OTFTs retained their low gate leakage current and ideal TFT characteristics even under 2% applied tensile strain, which makes them some of the most flexible OTFTs reported to date. We believe that these ultrathin, high-k organic dielectric films with excellent mechanical flexibility will play a crucial role in future soft electronics. PMID- 28569052 TI - Serum YKL-40 is a reliable biomarker for pulmonary alveolar proteinosis. AB - BACKGROUND AND OBJECTIVE: Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by alveolar filling. YKL-40, a chitinase-like protein produced by macrophages and epithelial cells, is increased in patients with interstitial lung diseases. We aimed to evaluate the role of YKL-40 as a biomarker for PAP. METHODS: A total of 34 patients with autoimmune PAP and 50 healthy controls were studied. YKL-40 was measured by ELISA in serum and bronchoalveolar lavage fluid (BALF). Chitinase coding gene polymorphisms (CHI3L1-329 and -131) were detected by PCR and pyrosequencing. Correlations between serum YKL-40 levels and disease outcome were analysed. RESULTS: Baseline serum and BALF levels of YKL-40 were higher in PAP patients than in controls (286 +/- 27 ng/mL vs 42 +/- 4 ng/mL, P < 0.0001; 323 +/- 36 ng/mL vs 3 +/- 1 ng/mL, P < 0.0001, respectively). Serum YKL 40 levels correlated with diffusing capacity of the lung for carbon monoxide (DLCO ) at baseline (P = 0.002) and over time (P < 0.0001). Patients with disease progression had higher baseline serum YKL-40 levels than those who remained stable or improved (P < 0.0001). A baseline cut-off level of 300 ng/mL was predictive of disease progression (HR (hazard ratio): 7.875, P = 0.001). The presence of the G allele was associated with higher serum and BALF levels of YKL 40. CONCLUSION: YKL-40 is elevated in serum and BALF of PAP patients, and may be of clinical utility to predict outcome in PAP. PMID- 28569055 TI - Solution NMR Provides New Insight into Lipid-Protein Interaction. PMID- 28569056 TI - Correction to Metabolite Profiling of a Zinc-Accumulating Rice Mutant. PMID- 28569057 TI - Synthesis of Cu-Nanoparticle Hydrogel with Self-Healing and Photothermal Properties. AB - Copper (Cu) nanoparticles possess unusual electrical, thermal, and optical properties. However, applications of these materials are often limited by their tendency to oxidize. We prepared Cu nanoparticles by a simple polyol method, with a good control over the particle size. The reaction required no inert atmosphere or surfactant agents. The as-prepared Cu nanoparticles showed good resistance to oxidation in solution. These Cu nanoparticles were then incorporated into a biocompatible polysaccharide hydrogel, which further stabilized the nanoparticles. The hybrid hydrogel exhibited a rapid self-healing ability. Because of the excellent photothermal conversion properties of the embedded Cu nanoparticles, the hybrid hydrogel showed rapid temperature elevation under laser irradiation. The hybrid hydrogel showed limited cytotoxicity; however, under laser irradiation the hydrogel displayed antibacterial properties owing to the heating effects. This study demonstrates that our hybrid hydrogel may have applications in biomedical fields and photothermal therapy. PMID- 28569058 TI - Recovery of the Pristine Surface of Black Phosphorus by Water Rinsing and Its Device Application. AB - Black phosphorus (BP) has attracted significant attention due to its excellent optical and electrical properties. However, the rapid degradation of BP under ambient air limits further research on its properties and implementation in various fields. This degrading behavior lowers the performance of BP-based devices and can even result in a complete failure when exposed to air for an extended period of time. In our research, the degraded surface with "bubbles" was recovered to its pristine state by rinsing with deionized water and following with post-treatments. The formation of bubbles and their optical, morphological, and electrical effects were systematically investigated by fabricating BP field effect transistors (FETs) in conjunction with micro-Raman spectroscopy and atomic force microscopy. Water rinsing of the degraded BP flakes also allowed us to thin BP flakes down because phosphorus atoms are consumed while forming bubbles. Therefore, recovery of the pristine surface not only results in a smoother and thinner morphology but also improves device performances. After the rinsing process, field-effect mobility of the BP FET was maintained, whereas a significant enhancement in the switching behaviors was achieved in conclusion. The capability of reversing the inevitable degradation that occurs once exposed to ambient conditions can open up new opportunities for further applications of BP that was limited due to its instability. PMID- 28569059 TI - Decarbonylative Cyanation of Amides by Palladium Catalysis. AB - Transition-metal-catalyzed cyanation of aryl halides is a process of significant importance in the preparation pharmaceuticals, organic materials and agrochemicals. Here, we demonstrate a palladium-catalyzed decarbonylative cyanation of amides by highly selective carbon-nitrogen bond cleavage for the synthesis of a wide range of aryl nitriles. The utility of this technology is demonstrated by the synthesis of isotopically labeled aryl nitriles and orthogonal cross-coupling reactions of bench-stable amides to establish cross coupling synthons with opposite polarity. PMID- 28569060 TI - Methylenecyclopropane Ring Formation/Opening Cascade for the Synthesis of Indolizines. AB - A unique strategy toward the synthesis of polysubstituted indolizines has been developed. When 2-pyridinyl-2-(2'-bromoallyl)-1-carboxylates were treated with Cs2CO3, the starting material went through a methylenecyclopropane ring formation/opening cascade, and the corresponding indolizines were obtained in moderate to good yield as a single regioisomer. PMID- 28569061 TI - Structure-Based Design of Scaffolds Targeting PDE10A by INPHARMA-NMR. AB - Phosphodiesterases (PDE) hydrolyze both cyclic AMP and GMP (cAMP/cGMP) and are responsible for the regulation of their levels in a multitude of cellular functions. PDE10A is expressed in the brain and is a validated target for both schizophrenia and Huntington disease. Here, we address the identification of novel chemical scaffolds that may bind PDE10A via structure-based drug design. For this task, we use INPHARMA, an NMR-based method that measures protein mediated interligand NOEs between pairs of weakly, competitively binding ligands. INPHARMA is applied to a combination of four chemically diverse PDE10A binding fragments, with the aim of merging their pharmacophoric features into a larger, tighter binding molecule. All four ligands bind the PDE10A cAMP binding domain with affinity in the micromolar range. The application of INPHARMA to identify the correct docking poses of these ligands is challenging due to the nature of the binding pocket and the high content of water-mediated intermolecular contacts. Nevertheless, ensemble docking in the presence of conserved water molecules generates docking poses that are in agreement with all sets of INPHARMA data. These poses are used to build a pharmacophore model with which we search the ZINC database. PMID- 28569062 TI - Scalable Device for Automated Microbial Electroporation in a Digital Microfluidic Platform. AB - Electrowetting-on-dielectric (EWD) digital microfluidic laboratory-on-a-chip platforms demonstrate excellent performance in automating labor-intensive protocols. When coupled with an on-chip electroporation capability, these systems hold promise for streamlining cumbersome processes such as multiplex automated genome engineering (MAGE). We integrated a single Ti:Au electroporation electrode into an otherwise standard parallel-plate EWD geometry to enable high-efficiency transformation of Escherichia coli with reporter plasmid DNA in a 200 nL droplet. Test devices exhibited robust operation with more than 10 transformation experiments performed per device without cross-contamination or failure. Despite intrinsic electric-field nonuniformity present in the EP/EWD device, the peak on chip transformation efficiency was measured to be 8.6 +/- 1.0 * 108 cfu.MUg-1 for an average applied electric field strength of 2.25 +/- 0.50 kV.mm-1. Cell survival and transformation fractions at this electroporation pulse strength were found to be 1.5 +/- 0.3 and 2.3 +/- 0.1%, respectively. Our work expands the EWD toolkit to include on-chip microbial electroporation and opens the possibility of scaling advanced genome engineering methods, like MAGE, into the submicroliter regime. PMID- 28569063 TI - Facile Phase Control of Multivalent Vanadium Oxide Thin Films (V2O5 and VO2) by Atomic Layer Deposition and Postdeposition Annealing. AB - Atomic layer deposition was adopted to deposit VOx thin films using vanadyl tri isopropoxide {VO[O(C3H7)]3, VTIP} and water (H2O) at 135 degrees C. The self limiting and purge-time-dependent growth behaviors were studied by ex situ ellipsometry to determine the saturated growth conditions for atomic-layer deposited VOx. The as-deposited films were found to be amorphous. The structural, chemical, and optical properties of the crystalline thin films with controlled phase formation were investigated after postdeposition annealing at various atmospheres and temperatures. Reducing and oxidizing atmospheres enabled the formation of pure VO2 and V2O5 phases, respectively. The possible band structures of the crystalline VO2 and V2O5 thin films were established. Furthermore, an electrochemical response and a voltage-induced insulator-to-metal transition in the vertical metal-vanadium oxide-metal device structure were observed for V2O5 and VO2 films, respectively. PMID- 28569064 TI - Full-Spectral Fine-Tuning Visible Emissions from Cation Hybrid Cs1-mFAmPbX3 (X = Cl, Br, and I, 0 <= m <= 1) Quantum Dots. AB - Full-color visible emissions are particularly crucial for applications in displays and lightings. In this work, we developed a facile room-temperature ligand-assisted supersaturated recrystallization synthesis of monodisperse, cubic structure Cs1-mFAmPbX3 (X = Cl, Br, and I or their mixtures Cl/Br and Br/I, 0 <= m <= 1) hybrid perovskite quantum dots (QDs). Impressively, cation substitution of Cs+ by FA+ was beneficial in finely tuning the band gap and in exciton recombination kinetics, improving the structural stability, and raising the absolute quantum yields up to 85%. With further assistance of anion replacement, full-spectral visible emissions in the wavelength range of 450-750 nm; narrow full width at half-maxima, and a wide color gamut, encompassing 130% of National Television System Committee television color standard, were achieved. Finally, Cs1-mFAmPbX3-polymer films retaining multicolor luminescence are prepared and a prototype white light-emitting diode device was constructed using green Cs0.1FA0.9PbBr3 and red Cs0.1FA0.9Br1.5I1.5 QDs as color converters, certainly suggesting their potential applications in the optoelectronics field. PMID- 28569065 TI - Co7Fe3 and Co7Fe3@SiO2 Nanospheres with Tunable Diameters for High-Performance Electromagnetic Wave Absorption. AB - Ferromagnetic metal/alloy nanoparticles have attracted extensive interest for electromagnetic wave-absorbing applications. However, ferromagnetic nanoparticles are prone to oxidization and producing eddy currents, leading to the deterioration of electromagnetic properties. In this work, a simple and scalable liquid-phase reduction method was employed to synthesize uniform Co7Fe3 nanospheres with diameters ranging from 350 to 650 nm for high-performance microwave absorption application. Co7Fe3@SiO2 core-shell nanospheres with SiO2 shell thicknesses of 30 nm were then fabricated via a modified Stober method. When tested as microwave absorbers, bare Co7Fe3 nanospheres with a diameter of 350 nm have a maximum reflection loss (RL) of 78.4 dB and an effective absorption with RL > 10 dB from 10 to 16.7 GHz at a small thickness of 1.59 mm. Co7Fe3@SiO2 nanospheres showed a significantly enhanced microwave absorption capability for an effective absorption bandwidth and a shift toward a lower frequency, which is ascribed to the protection of the SiO2 shell from direct contact among Co7Fe3 nanospheres, as well as improved crystallinity and decreased defects upon annealing. This work illustrates a simple and effective method to fabricate Co7Fe3 and Co7Fe3@SiO2 nanospheres as promising microwave absorbers, and the design concept can also be extended to other ferromagnetic alloy particles. PMID- 28569066 TI - Iron-Catalyzed Oxidative C-H Functionalization of Internal Olefins for the Synthesis of Tetrasubstituted Furans. AB - Tetrasubstituted furans were efficiently synthesized from Fe(OAc)2-catalyzed C H/C-H cross-dehydrogenative-coupling (CDC) reactions of activated carbonyl methylenes with S,S-functionalized internal olefins, that is, alpha-oxo ketene dithioacetals and analogues, under oxidative conditions. beta-Ketoesters, 1,3 dicarbonyls, beta-keto nitrile, and amide derivatives were used as the coupling partners. The resultant alkylthio- and carbonyl-functionalized furans could be further transformed to diverse arylated furan derivatives and furan-fused N heterocycles, respectively. The control experiments have revealed a radical reaction pathway. PMID- 28569067 TI - Comparative Proteomic Analysis of Posterior Silk Glands of Wild and Domesticated Silkworms Reveals Functional Evolution during Domestication. AB - The wild silkworm Bombyx mandarina was domesticated to produce silk in China approximately 5000 years ago. Silk production is greatly improved in the domesticated silkworm B. mori, but the molecular basis of the functional evolution of silk gland remains elusive. We performed shotgun proteomics with label-free quantification analysis and identified 1012 and 822 proteins from the posterior silk glands (PSGs) of wild silkworms on the third and fifth days of the fifth instar, respectively, with 128 of these differentially expressed. Bioinformatics analysis revealed that, with the development of the PSG, the up regulated proteins were mainly involved in the ribosome pathway, similar to what we previously reported for B. mori. Additionally, we screened 50 proteins with differential expression between wild and domesticated silkworms that might be involved in domestication at the two stages. Interestingly, the up-regulated proteins in domesticated compared to wild silkworms were enriched in the ribosome pathway, which is closely related to cell size and translation capacity. Together, these results suggest that functional evolution of the PSG during domestication was driven by reinforcing the advantageous pathways to increase the synthesis efficiency of silk proteins in each cell and thereby improve silk yield. PMID- 28569068 TI - Genetic Characterization of Periphyton Communities Associated with Selenium Bioconcentration and Trophic Transfer in a Simple Food Chain. AB - A major source of uncertainty in predicting selenium (Se) distribution in aquatic food webs lies in the enrichment factor (EF), the ratio of Se bioconcentration in primary producers and microorganisms relative to the concentration of Se in the surrounding water. It has been well demonstrated that EFs can vary dramatically among individual algal taxa, but data are lacking regarding the influence of periphyton community composition on EFs for a given geochemical form of Se. Therefore, the goals of this study were first to assess whether different periphyton communities could be established in aquaria with the same starting inoculum using different light and nutrient regimes, and second, to determine if the periphyton assemblage composition influences the uptake of waterborne Se (as selenite) and subsequent Se transfer to a model macroinvertebrate primary consumer. Periphyton biofilms were grown in aquaria containing filtered pond water (from Saskatoon, SK) spiked with approximately 20 MUg Se/L (mean measured concentration 21.0 +/- 1.2 MUg Se/L), added as selenite. Five different light and nutrient regimes were applied to the aquaria (three replicates per treatment) to influence biofilm community development. After 6 weeks of biofilm maturation, 40 to 80 immature cultured snails (Stagnicola elodes) were added to each aquarium. The bacterial and algal members of the periphyton community were characterized by targeted metagenomic analyses before and after addition of snails to ensure the snails themselves did not significantly alter the biofilm community. Samples were collected for Se analysis of water, periphyton, and whole-body snail. The nutrient and light treatments resulted in substantially different compositions of the periphytic biofilms, with each being relatively consistent across replicates and throughout the study. Although the aqueous concentration of dissolved Se administered to treatments was constant, uptake by the different periphytic biofilms differed significantly. Both the low-light (61.8 +/- 12.1 MUg Se/g d.w.) and high-light (30.5 +/- 4.7 MUg Se/g d.w.) biofilms, which were found to have high proportions of cyanobacteria, contained statistically higher concentrations of Se relative to the other treatments. Furthermore, the concentration of Se in bulk periphyton was predictive of Se bioaccumulation in grazing snails but as an inverse relationship, opposite to expectations. The trophic transfer factor was inversely correlated with periphyton enrichment factor (r = -0.841). A number of different bacterial and algal taxa were correlated (either positively or negatively) with Se accumulation in periphyton biofilm and snails. Recent advancements in genetic methods make it possible to conduct detailed characterization of periphyton assemblages and begin to understand the influence that periphyton composition has on Se biodynamics in aquatic systems. PMID- 28569069 TI - Surgical Management of Percutaneous Transfemoral Access to Minimize Vascular Complications Related to Transcatheter Aortic Valve' Implantation. AB - Transcatheter aortic valve implantation (TAVI) is associated with substantial rates of vascular complications. The aim of our study is to describe the surgical management of percutaneous transfemoral access by a vascular surgeon and to report the 30-day postoperative vascular complications and mortality. Perioperative procedures to manage the femoral access site were recorded retrospectively from 220 consecutive patients who underwent TAVI. Postoperative vascular complications related to the main access were categorized according to the Valve Academic Research Consortium 2 classification. Perioperative procedures related to vascular access were performed for 56 (25.4%) patients: 6 patients required open surgical repair, 48 patients underwent endovascular stenting, and 2 patients had both procedures. The all-cause mortality was 3.6%, but no death related to a vascular complication was reported during the 30-day postoperative follow-up period. Ten (4.5%) patients developed postoperative hematomas; 2 (0.9%) of them were retroperitoneal and led to major bleeding requiring an unplanned surgical intervention. Our study underlines the utility of a multidisciplinary approach to manage the percutaneous access in TAVI for managing postoperative vascular complications. PMID- 28569071 TI - A Good Idea May Not Be Good Enough: Stakeholder Buy In to QuitConnect, a National Smokers' Registry. AB - PURPOSE: To examine interest and concerns among those who fund and operate state run smoking cessation helplines (quitlines) about the concept of creating a centralized smokers' registry that could be used to reengage smokers after they receive initial quitline support services. DESIGN: We conducted 3, hour-long focus groups with stakeholders, covering the perceived benefits and barriers to creating a smokers' registry. SETTING: The focus groups were conducted via telephone. PARTICIPANTS: Three groups participated: quitline service providers (n = 14), quitline funders (n = 9), and national quitline partners (n = 8). METHOD: Data collection: Focus groups were recorded, transcribed, and coded for major relevant themes. Analysis Strategies: We used a grounded theory approach. RESULTS: Stakeholders were generally positive about the concept of a centralized smokers' registry (ie, QuitConnect), especially with its potential to link relapsed smokers to ongoing research studies designed to help smokers achieve abstinence from tobacco. However, stakeholders expressed concern about QuitConnect duplicating services already offered by state quitlines. CONCLUSION: Despite a common goal, many state quitline stakeholders had strong reservations about the creation of a centralized smokers' registry unless they could see clear evidence that the registry added value and was not duplicative of their existing services. PMID- 28569072 TI - The role of oral methotrexate as a steroid sparing agent in refractory eosinophilic asthma. AB - The use of oral methotrexate for refractory eosinophilic asthma in a tertiary asthma referral centre, Glenfield Hospital, Leicester, was evaluated between January 2006 and December 2014. The patients ( n = 61) were carefully phenotyped at baseline with markers of airway inflammation. In addition, a structured oral methotrexate proforma was utilized to evaluate response to therapy and adverse events. Oral steroid withdrawal was attempted 3 months after commencing treatment. Several outcomes were evaluated at 12 months, including both efficacy and adverse effects; 15% ( n = 9/61) responded by achieving a decrease in daily oral corticosteroid dose (mean 8.43 (+/-8.76) mg), although we were unable to identify factors that predicted a treatment response. There were no other significant changes in any other clinical outcome measures. There was a high rate of adverse events (19/61 (31%)), primarily gastrointestinal/hepatitis. Our findings support the use of biological agents in preference to using oral methotrexate as a steroid sparing agent at the first instance. In the event of failure of these agents, oral methotrexate remains a therapeutic option, which can be considered in highly specialist severe asthma centres. PMID- 28569073 TI - Can self-efficacy ameliorate interrole conflict among employed family caregivers? A moderated mediation approach. AB - OBJECTIVES: This study examined the moderation effect of different dimensions of self-efficacy on the way in which various types of interrole conflict mediate between caregiving demands and the mental health of employed family caregivers. METHOD: Using a moderated mediation approach, we examined the moderation effect of self-efficacy on interrole conflict's mediation between caregiving demands and mental health (psychological strain and quality of life) in a sample of Japanese employed family caregivers who regularly provide care at home (263 males aged 53.14 +/- 8.28 years and 116 females aged 47.92 +/- 9.77 years). RESULTS: Increased self-efficacy in managing dementia and in self-care were correlated with lower caregiving demands and better mental health among family caregivers. Self-efficacy in managing dementia was also positively correlated with increased interrole conflict. Increased caregiving demands were related to higher psychological strain in those with higher (+1SD), but not lower (-SD) self efficacy in managing dementia. CONCLUSION: Self-efficacy does not play a protective role in managing the effect of caregiving demands on interrole conflict. It also does not appear to protect against any indirect effects of caregiving demands on the mental health of employed family caregivers. PMID- 28569074 TI - The platelet-to-lymphocyte ratio as a predictor of patient outcomes in ovarian cancer: a meta-analysis. AB - OBJECTIVES: The platelet-to-lymphocyte ratio (PLR) is a predictive clinical biomarker for different cancers. However, the results of several studies investigating the association between the PLR and the prognosis of ovarian cancer have been inconclusive. Therefore, there is a need to conduct a meta-analysis to estimate the prognostic value of the PLR in ovarian cancer. METHODS: We searched the EMBASE, Medline, PubMed, and Web of Science databases to identify clinical studies that had evaluated the association between the PLR and ovarian cancer prognosis. Outcomes evaluated included overall survival (OS) and progression-free survival (PFS). We also analyzed PLR differences between malignant ovarian masses and the controls. RESULTS: Twelve relevant studies that comprised 2340 patients were selected for the meta-analysis. The results revealed that elevated PLR was significantly associated with poor OS (hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.05-2.56, p < 0.01) and PFS (HR 1.61, 95% CI 1.03-2.51, p < 0.01). The PLRs in malignant cases were higher than in controls (mean difference = 63.57, 95% CI 39.47-87.66, p < 0.00001). CONCLUSION: An elevated PLR is associated with poor prognosis in patients with ovarian cancer. The PLR could be employed as a prognostic marker in patients with ovarian cancer. PMID- 28569075 TI - On the Link Between Emotionally Driven Impulsivity and Aggression: Evidence From a Validation Study on the Dutch UPPS-P. AB - The UPPS-P seems to be a promising instrument for measuring different domains of impulsivity in forensic psychiatric patients. Validation studies of the instrument however, have been conducted only in student groups. In this validation study, three groups completed the Dutch UPPS-P: healthy student ( N = 94) and community ( N = 134) samples and a forensic psychiatric sample ( N = 73). The five-factor structure reported previously could only be substantiated in a confirmatory factor analysis over the combined groups but not in the subsamples. Subgroup sample sizes might be too small to allow such complex analyses. Internal consistency, as assessed by Cronbach's alpha, was high on most subscale and sample combinations. In explaining aggression, especially the initial subscale negative urgency (NU) was related to elevated scores on self-reported aggression in the healthy samples (student and community). The current study is the second study that found a relationship between self-reported NU and aggression highlighting the importance of addressing this behavioural domain in aggression management therapy. PMID- 28569076 TI - Clinical Impact of Blood Glucose Monitoring Accuracy: An In-Silico Study. AB - BACKGROUND: Patients with diabetes rely on blood glucose (BG) monitoring devices to manage their condition. As some self-monitoring devices are becoming more and more accurate, it becomes critical to understand the relationship between system accuracy and clinical outcomes, and the potential benefits of analytical accuracy. METHODS: We conducted a 30-day in-silico study in type 1 diabetes mellitus (T1DM) patients using continuous subcutaneous insulin infusion (CSII) therapy and a variety of BG meters, using the FDA-approved University of Virginia (UVA)/Padova Type 1 Simulator. We used simulated meter models derived from the published characteristics of 43 commercial meters. By controlling random events in each parallel run, we isolated the differences in clinical performance that are directly associated with the meter characteristics. RESULTS: A meter's systematic bias has a significant and inverse effect on HbA1c ( P < .01), while also affecting the number of severe hypoglycemia events. On the other hand, error, defined as the fraction of measurements beyond 5% of the true value, is a predictor of severe hypoglycemia events ( P < .01), but in the absence of bias has a nonsignificant effect on average glycemia (HbA1c). Both bias and error have significant effects on total daily insulin (TDI) and the number of necessary glucose measurements per day ( P < .01). Furthermore, these relationships can be accurately modeled using linear regression on meter bias and error. CONCLUSIONS: Two components of meter accuracy, bias and error, clearly affect clinical outcomes. While error has little effect on HbA1c, it tends to increase episodes of severe hypoglycemia. Meter bias has significant effects on all considered metrics: a positive systemic bias will reduce HbA1c, but increase the number of severe hypoglycemia attacks, TDI use, and number of fingersticks per day. PMID- 28569077 TI - Diabetes and Prediabetes Classification Using Glycemic Variability Indices From Continuous Glucose Monitoring Data. AB - BACKGROUND: Tens of glycemic variability (GV) indices are available in the literature to characterize the dynamic properties of glucose concentration profiles from continuous glucose monitoring (CGM) sensors. However, how to exploit the plethora of GV indices for classifying subjects is still controversial. For instance, the basic problem of using GV indices to automatically determine if the subject is healthy rather than affected by impaired glucose tolerance (IGT) or type 2 diabetes (T2D), is still unaddressed. Here, we analyzed the feasibility of using CGM-based GV indices to distinguish healthy from IGT&T2D and IGT from T2D subjects by means of a machine-learning approach. METHODS: The data set consists of 102 subjects belonging to three different classes: 34 healthy, 39 IGT, and 29 T2D subjects. Each subject was monitored for a few days by a CGM sensor that produced a glucose profile from which we extracted 25 GV indices. We used a two-step binary logistic regression model to classify subjects. The first step distinguishes healthy subjects from IGT&T2D, the second step classifies subjects into either IGT or T2D. RESULTS: Healthy subjects are distinguished from subjects with diabetes (IGT&T2D) with 91.4% accuracy. Subjects are further subdivided into IGT or T2D classes with 79.5% accuracy. Globally, the classification into the three classes shows 86.6% accuracy. CONCLUSIONS: Even with a basic classification strategy, CGM-based GV indices show good accuracy in classifying healthy and subjects with diabetes. The classification into IGT or T2D seems, not surprisingly, more critical, but results encourage further investigation of the present research. PMID- 28569079 TI - Effect of a high phosphorus diet on indicators of renal health in cats. AB - Objectives High phosphorus intake may further impair renal health in cats with chronic kidney disease (CKD). The hypothesis that a high phosphorus (HP) diet might be nephrotoxic for healthy animals was tested in cats, a species with a high incidence of naturally occurring CKD. Methods Thirteen healthy adult cats were fed a phosphorus excess diet (about five times maintenance requirements), and this HP group was compared with cats on a balanced control diet (CON). The trial lasted for 29 days (10 days of faeces and urine collection). Endogenous creatinine clearance was determined towards the end of the trial. Fresh urine was tested for glucose and proteins. Results Glucosuria and microalbuminuria were observed exclusively in the HP group in 9/13 cats. Creatinine clearance was significantly decreased after feeding HP. In the HP group phosphorus was highly available (apparent digestibility around 60%). Renal phosphorus excretion was significantly increased in the HP group (115 mg/kg body weight/d vs 16 mg/kg body weight/d in the CON group). Conclusions and relevance The intake of a diet with an excessive content of highly available phosphorus may have adverse effects on parameters of kidney function in healthy cats. PMID- 28569078 TI - Palonosetron compared with ondansetron in pediatric cancer patients: multicycle analysis of a randomized Phase III study. AB - AIM: To investigate across multiple cycles the efficacy and safety of palonosetron in the prevention of chemotherapy-induced nausea and vomiting in pediatric cancer patients receiving highly or moderately emetogenic chemotherapy (HEC/MEC). PATIENTS & METHODS: Patients were randomly assigned to 10, 20 MUg/kg palonosetron or 3 * 150 MUg/kg ondansetron for up to four cycles of HEC/MEC. RESULTS: In all on-study chemotherapy cycles, complete response rates were higher in patients in the 20 MUg/kg palonosetron group than the ondansetron group. Treatment-emergent adverse events were comparable between the palonosetron 20 MUg/kg and ondansetron groups. CONCLUSION: Over four cycles of HEC/MEC, 20 MUg/kg palonosetron was an efficacious and safe treatment for the prevention of chemotherapy-induced nausea and vomiting in pediatric cancer patients. PMID- 28569080 TI - Comparison of carbohydrate content between grain-containing and grain-free dry cat diets and between reported and calculated carbohydrate values. AB - Objectives The aim of this study was to compare the carbohydrate content of grain containing and grain-free dry cat diets and compare major protein and carbohydrate sources of these diets. Methods This was a cross-sectional study of 77 randomly selected dry cat diets (42 grain-containing, 35 grain-free). Reported carbohydrate values were compared between grain-containing and grain-free cat diets. A subset of 25% of diets from each category (grain-containing and grain free) was analyzed and nitrogen-free extract was calculated as an estimate of carbohydrate content. These calculated values were compared with reported values from the manufacturer. Animal- and plant-sourced ingredients were also compared between grain-containing and grain-free diets. Results Mean reported carbohydrate content of the grain-free diets (n = 35) was lower than the grain-containing diets (n = 41; 64 +/- 16 vs 86 +/- 22 g/1000 kcal; P <0.001). Reported carbohydrate values were higher than analyzed nitrogen-free extract (n = 20; 79 +/- 30 vs 73 +/- 27 g/1000 kcal; P = 0.024). Poultry ( P = 0.009) and soy (P = 0.007) were less common in grain-free diets than in diets containing grain. The alternative carbohydrate sources of chickpeas, lentils, peas, potato, sweet potato and cassava/tapioca were more common ( P <0.05) in grain-free diets than in diets containing grain. Conclusions and relevance This sample of grain-free diets had lower mean reported carbohydrate content than grain-containing diets, but there was considerable overlap between groups and individual diets' carbohydrate/nitrogen-free extract content varied widely. PMID- 28569081 TI - Owner perceptions of their cat's quality of life when treated with a modified University of Wisconsin-Madison protocol for lymphoma. AB - Objectives The objectives of this study were to assess owner perceptions of their cat's quality of life during treatment for lymphoma with a doxorubicin-containing multi-agent chemotherapy protocol, whether various health-related parameters correlated with quality of life scores, and to assess owner satisfaction with the protocol. Methods A postal questionnaire was sent to the owners of 33 treated cats. Owners retrospectively assessed their cat's quality of life using a Likert scale (1-10) before lymphoma was diagnosed, at diagnosis and during chemotherapy. Owners assigned scores to various health-related parameters previously reported to affect quality of life at the three time points, and correlations with quality of life scores were sought. Owners were asked to rate the importance of these health-related parameters. Satisfaction with the protocol was investigated. Results Twenty questionnaires were completed (61% response rate). The median quality of life score before diagnosis (10, range 5-10) was higher than at diagnosis (3, range 1-9) ( P <0.05). The median quality of life score during chemotherapy (7, range 3-9) was lower than before diagnosis ( P <0.05) and higher than at diagnosis, but this was not statistically significant. Quality of life scores did not correlate with individual health-related parameter scores consistently; however, quality of life scores did correlate with appetite scores during chemotherapy. Appetite, vomiting and diarrhoea were parameters perceived as important in affecting quality of life. Most owners (75%) were happy they had treated their cat. Conclusions and relevance The quality of life scores observed were comparable to a previous study using cyclophosphamide, vincristine and prednisolone, employing the same scoring system. Although quality of life scores during chemotherapy were not significantly improved at diagnosis, owner satisfaction with the protocol was high. The factors perceived by owners to determine quality of life in their pets may be different to those previously conjectured, but appetite during chemotherapy remains important. PMID- 28569082 TI - Child Maltreatment Trauma, Posttraumatic Stress Disorder, and Cortisol Levels in Women: A Literature Review. AB - BACKGROUND: Studies of the relationship between cortisol and posttraumatic stress disorder (PTSD) have had inconsistent results. Gender, trauma type, and age at trauma exposure may explain the inconsistencies. OBJECTIVE: The objective of the review was to examine cortisol levels in relation to PTSD in women with a history of child maltreatment trauma. DESIGN: A review of literature found 13 articles eligible for inclusion. RESULTS: Despite limiting focus to the relatively homogeneous population, the patterns of associations between PTSD and cortisol levels were still inconsistent. CONCLUSIONS: The reasons for the inconsistencies likely include highly varied methods across studies, small convenience samples, and unmeasured neuroendocrine hormones that may be stronger predictors of PTSD. The review does not point to a clear bio-behavioral target for psychiatric nursing intervention. It is important to continue to address the developmental and clinical stress response aspects of child maltreatment trauma-related PTSD without assuming that these stress responses are hypothalamic-pituitary-adrenal axis driven. PMID- 28569084 TI - The Correlates of Quality of Life Among Jordanian Patients With Schizophrenia. AB - BACKGROUND: Addressing the quality of life (QOL) of patients with schizophrenia is of special importance in the Arab world, where little knowledge is available about their well-being, and most of them experience stigma and living in poverty. AIMS: The purpose of this study was to examine the association of sociodemographic characteristics, severity of depressive symptoms, and various aspects of public stigma against mental illness, with QOL among Jordanian patients with schizophrenia. METHOD: In this descriptive correlational study, 160 Jordanian outpatients diagnosed with schizophrenia completed measures of demographic characteristics, perceived public stigma against mental illness, severity of depression, and QOL. RESULTS: Participants had poor QOL. Age, marital status, relapse, education level, stigma against mental illness, and severity of depression were significantly associated with QOL among Jordanian patients with schizophrenia. Data analysis revealed that the severity of depression accounted for an additional 27% of the variance above and beyond the 36.7% accounted for by age of the participants and perceived public stigma against mental illness. CONCLUSIONS: Health care professionals should develop culturally competent nursing practice considering the specific factors associated with QOL among Arab patients with schizophrenia. PMID- 28569083 TI - Magnetic fields exposure from high-voltage power lines and risk of amyotrophic lateral sclerosis in two Italian populations. AB - The aetiology of amyotrophic lateral sclerosis (ALS), a rare and extremely severe neurodegenerative disease, has been associated with magnetic fields exposure. However, evidence for such a relation in the general population is weak, although the previous null results might also be due to exposure misclassification, or a relationship might exist only for selected subgroups. To test such a hypothesis we carried out a population-based case-control study in two Northern and Southern Italy regions, including 703 ALS cases newly diagnosed from 1998 to 2011 and 2737 controls randomly selected from the residents in the study provinces. Overall, we found that a residence near high-voltage power lines, within the corridors yielding a magnetic fields of >=0.1 MUT, was not associated with an excess disease risk, nor did we identify a dose-response relationship after splitting the exposed corridor according to the 0.1, 0.2 and 0.4 MUT cut-points of exposure. These results were confirmed taking into account age at onset, period of diagnosis, sex, geographical area, and length of exposure. Overall, despite the residual possibility of unmeasured confounding or small susceptible subgroups not identified in our study, these results appear to confirm that the exposure to magnetic fields from power lines occurring in the general population is not associated with increased ALS risk. PMID- 28569085 TI - Acrylamide-derived cytotoxic, anti-proliferative, and apoptotic effects on A549 cells. AB - BACKGROUND: Acrylamide is a very common compound even reaching up to our daily foods. It has been studied in a wealth of cell lines on which it proved to have various toxic effects. Among these cell lines, human lung adenocarcinoma cell line (A549) is one of that on which acrylamide's toxicity has not been studied well yet. AIM: We intended to determine the half maximal inhibitory concentration (IC50) dose of acrylamide and to investigate its cytotoxic, anti-proliferative and apoptotic effects on A549 cells. METHODS: We determined the IC50 dose by 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Then, the mode of cell death was evaluated by flow cytometry using Annexin-V fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. Next, we performed transmission electron microscopy (TEM) and confocal microscopy analyses for morphological alterations and apoptotic indices. RESULTS: According to the MTT assay results, A549 cell viability decreases proportionally with increasing acrylamide concentrations and IC50 for A549 was 4.6 mM for 24 h. Annexin-V FITC/PI assay results indicated that acrylamide induces apoptosis in 64% of the A549 cells. TEM and confocal microscopy analyses showed nuclear condensations, fragmentations, cytoskeleton laceration, and membrane blebbing, which are morphological characteristics of apoptosis. CONCLUSION: Our research suggests that acrylamide causes cytotoxic, anti-proliferative, and apoptotic effects on A549 cells at 4.6 mM IC50 dose in 24 h. PMID- 28569086 TI - Estimation of the physiological mechanical conditioning in vascular tissue engineering by a predictive fluid-structure interaction approach. AB - The in vitro replication of physiological mechanical conditioning through bioreactors plays a crucial role in the development of functional Small-Caliber Tissue-Engineered Blood Vessels. An in silico scaffold-specific model under pulsatile perfusion provided by a bioreactor was implemented using a fluid structure interaction (FSI) approach for viscoelastic tubular scaffolds (e.g. decellularized swine arteries, DSA). Results of working pressures, circumferential deformations, and wall shear stress on DSA fell within the desired physiological range and indicated the ability of this model to correctly predict the mechanical conditioning acting on the cells-scaffold system. Consequently, the FSI model allowed us to a priori define the stimulation pattern, driving in vitro physiological maturation of scaffolds, especially with viscoelastic properties. PMID- 28569087 TI - Mexicanolide-type limonoids from the seeds of Swietenia macrophylla. AB - Three new mexicanolide-type limonoids, 3-O-propionylproceranolide (1), 6-O acetylswietenin B (2), and 6-deoxyswietemahonin A (3), together with 15 known limonoids, were isolated from the seeds of Swietenia macrophylla (Meliaceae). The structures of those new compounds were established by extensive analysis of MS, 1D, and 2D NMR spectral data. PMID- 28569088 TI - Thoughts and Considerations of Women With Bipolar Disorder About Family Planning and Pregnancy: A Qualitative Study. AB - BACKGROUND: Women with bipolar disorder have an increased risk of relapse during pregnancy and the postpartum period, and they often express broad concerns about family planning. OBJECTIVE: To explore the thoughts and considerations of women of childbearing age with bipolar disorder, about family planning and pregnancy. DESIGN: A qualitative study was conducted: 15 women with bipolar I disorder were individually interviewed. Content analysis was applied. RESULTS: Women worried about heritability of bipolar disorder, medication issues, and risk of relapse during pregnancy. They mentioned their fear to be incompetent as a mother during future mood episodes. Support of partner, family/friends, and professionals was mentioned as essential. CONCLUSIONS: Family planning is an essential topic in the treatment of every woman with bipolar disorder of childbearing age. These women expect early consultation with professionals for support, and specific information about heritability of the illness and use of medication during and after pregnancy. PMID- 28569089 TI - Professionals' Awareness of Sexual Abuse in Late Life: An Exploratory Survey. AB - BACKGROUND: The sexual abuse phenomenon is considered taboo. It has been discussed, to date, mainly in relation to children and young women, with insufficient attention to sexual abuse in a late-life context. OBJECTIVES: The aim of this survey was to explore professionals' awareness of elder sexual abuse (ESA). DESIGN: The survey was conducted among 161 Jewish and Arab professionals from health care and social services, who worked with older adults in Israel. RESULTS: Of the entire sample, 70 professionals (only 43%) reported encountering at least one to three cases of ESA. A total of 98% of the victims were women, and the primary offender was the spouse (75%). In most cases (70%), the victim reported the abuse, which was mainly sexual assault (64%). All participants (100%) noted taking action. CONCLUSION: This exploratory survey indicates that professionals are partially aware of the existence of and the need to address the ESA phenomenon. PMID- 28569091 TI - Teachers' Perceptions of Preschool Children's Psychomotor Development in Spain. AB - This study analyzed the psychomotor profiles of preschool stage students and to determine how these data agreed with the students' teachers' subjective assessment. We also correlated these data with other variables such as age, gender, and family influence. A total of 211 children aged 3 to 6 years, in the second cycle of preschool from 30 classes of 10 schools in Spain participated. Additionally, 30 preschool teachers from these classes participated. Study results revealed serious teacher misperceptions regarding their students' psychomotor development, with low agreement rates between students and teachers in the motor dimension and slight agreement rates in communicative, cognitive, and social areas. The reasons for and implications of these misperceptions are discussed. PMID- 28569090 TI - Insulin differentially affects the distribution kinetics of amyloid beta 40 and 42 in plasma and brain. AB - Impaired brain clearance of amyloid-beta peptides (Abeta) 40 and 42 across the blood-brain barrier (BBB) is believed to be one of the pathways responsible for Alzheimer's disease (AD) pathogenesis. Hyperinsulinemia prevalent in type II diabetes was shown to damage cerebral vasculature and increase Abeta accumulation in AD brain. However, there is no clarity on how aberrations in peripheral insulin levels affect Abeta accumulation in the brain. This study describes, for the first time, an intricate relation between plasma insulin and Abeta transport at the BBB. Upon peripheral insulin administration in wild-type mice: the plasma clearance of Abeta40 increased, but Abeta42 clearance reduced; the plasma-to brain influx of Abeta40 increased, and that of Abeta42 reduced; and the clearance of intracerebrally injected Abeta40 decreased, whereas Abeta42 clearance increased. In hCMEC/D3 monolayers (in vitro BBB model) exposed to insulin, the luminal uptake and luminal-to-abluminal permeability of Abeta40 increased and that of Abeta42 reduced; the abluminal-to-luminal permeability of Abeta40 decreased, whereas Abeta42 permeability increased. Moreover, Abeta cellular trafficking machinery was altered. In summary, Abeta40 and Abeta42 demonstrated distinct distribution kinetics in plasma and brain compartments, and insulin differentially modulated their distribution. Cerebrovascular disease and metabolic disorders may disrupt this intricate homeostasis and aggravate AD pathology. PMID- 28569092 TI - Willingness to express emotion depends upon perceiving partner care. AB - Two studies document that people are more willing to express emotions that reveal vulnerabilities to partners when they perceive those partners to be more communally responsive to them. In Study 1, participants rated the communal strength they thought various partners felt toward them and their own willingness to express happiness, sadness and anxiety to each partner. Individuals who generally perceive high communal strength from their partners were also generally most willing to express emotion to partners. Independently, participants were more willing to express emotion to particular partners whom they perceived felt more communal strength toward them. In Study 2, members of romantic couples independently reported their own felt communal strength toward one another, perceptions of their partners' felt communal strength toward them, and willingness to express emotions (happiness, sadness, anxiety, disgust, anger, hurt and guilt) to each other. The communal strength partners reported feeling toward the participants predicted the participants' willingness to express emotion to those partners. This link was mediated by participants' perceptions of the partner's communal strength toward them which, itself, was a joint function of accurate perceptions of the communal strength partners had reported feeling toward them and projections of their own felt communal strength for their partners onto those partners. PMID- 28569093 TI - Mindfulness in Anorexia Nervosa: An Integrated Review of the Literature. AB - BACKGROUND: Anorexia nervosa is a serious psychiatric illness with limited evidenced-based treatment options. Mindfulness appears useful in many conditions, but few studies focus on its use in individuals with anorexia nervosa. OBJECTIVE: To examine and summarize studies of mindfulness in individuals with anorexia nervosa and identify areas for future research. DESIGN: An integrated review was conducted by searching health care computerized databases. RESULTS: Results were mixed among the eight studies that met inclusion criteria. Multimodal mindfulness based therapies appear effective, while brief interventions may be equally useful or result in greater anxiety compared to distraction. Qualitative data support that some participants feel mindfulness is challenging but beneficial. CONCLUSION: Mindfulness as a concurrent part of therapy and/or when routinely practiced may be more clinically useful than single-episode mindful eating interventions. Due to the complexity of the concept of mindfulness and limited existing data, additional research is needed. PMID- 28569094 TI - C18-Diterpenoid alkaloids from Delphinium anthriscifolium var. majus. AB - Five new C18-diterpenoid alkaloids, anthriscifoltines C-G (1-5), along with four known diterpenoid alkaloids anthriscifolcines C-F (6-9), were isolated from the extract of Delphinium anthriscifolium var. majus. Their structures were elucidated by extensive spectroscopic analyses (including 1D-, 2D-NMR, and HR-ESI MS). Compounds 1-5 were also evaluated for their cytotoxic activity against MCF 7, HepG2, and H460 human cancer cell lines. PMID- 28569095 TI - Review of Use of Standardized Patients in Psychiatric Nursing Education. AB - BACKGROUND: Simulations using standardized patients (SPs) are increasingly used to teach and assess competencies in psychiatric/mental health (PMH) nursing education. To advance the field, it is important to identify current knowledge, practice, and evidence. OBJECTIVE: To determine the current knowledge, evidence, and practice of using SPs in PMH nursing education by conducting an integrative review of the empirical research on the use of SPs in PMH nursing education, and by providing a supplementary descriptive review of non-research articles on PMH simulations using SPs. DESIGN: A comprehensive search using electronic databases was conducted to identify both research and simulation description papers meeting inclusion criteria. The research literature was reviewed using an integrative review approach and a simple descriptive review of the non-research simulation literature was also conducted. RESULTS: Six research studies and 18 simulation description articles were included in the review. Although there are several PMH SP simulation descriptions in the literature, and anecdotal indications that they are a valuable educational tool, there is insufficient research evidence regarding their effectiveness as a method in psychiatric nursing education due to few published studies and methodological limitations of existing studies. CONCLUSIONS: Well-designed research studies are needed to develop an evidence base for this promising and increasingly employed teaching method. PMID- 28569096 TI - Hispanics' Retirement Transitions and Differences by Nativity. AB - OBJECTIVE: This study examines differences in retirement decisions between older Hispanics and non-Hispanics, with a special focus on the role of nativity. METHODS: We use 1998-2012 waves of the Health and Retirement Study. We estimate survival models of retirement and compare retirement transitions for U.S.-born Hispanics, foreign-born Hispanics, non-Hispanic Whites, and non-Hispanic Blacks. RESULTS: Foreign-born Hispanics retire significantly later than other racial and ethnic groups. Controlling for personal characteristics, their risk of retirement is 39% lower compared with non-Hispanic Whites. Retirement transitions do not differ significantly between U.S.-born Hispanics and non-Hispanic Whites. DISCUSSION: Difference in retirement timing between U.S.- and foreign-born Hispanics may partly be due to lower incomes and wealth accumulation of foreign born Hispanics. Workforce development initiatives, policy initiatives promoting retirement savings, and Social Security reforms could improve future retirement security for older Hispanics, and make retirement a viable option for more foreign-born Hispanics. PMID- 28569098 TI - A Handbook for Teaching and Learning in Higher Education. Enhancing Academic Practice. PMID- 28569097 TI - Testing the convergent and discriminant validity of the Systemic Therapy Inventory of Change Initial scales. AB - OBJECTIVE: The Systemic Therapy Inventory of Change (STIC(r)) is the first multi systemic and multi-dimensional measurement and feedback system designed for assessment in family, couple, and individual functioning. Patients fill out the STIC Initial before the first session to identify treatment targets and provide starting values for subsequent assessments of trajectories of change. This study tested the construct validity of five of the six STIC Initial scales. METHODS: We administered both the STIC Initial and a set of validity measures to a relatively large sample of patients. Convergent and discriminant validity were tested using both an examination of observed correlations and confirmatory factor analysis (CFA). RESULTS: The correlations among the observed measures showed that the convergent validity coefficients were generally large, whereas the discriminant validity coefficients were moderate to small. Similarly, CFAs suggested that the STIC total scales and subscales are good indicators of the factors they were intended to measure and that the STIC total scales and subscales are weakly related to the factors they were intended to not measure. CONCLUSION: The results supported the convergent and discriminant validity of the five scales of the STIC Initial. Clinical or methodological significance of this article: The clinical significance of this article is that it demonstrates that the STIC Initial should be useful for identifying treatment targets including both which systems, in addition to the facets within each system, that require targeting. The methodological significance is twofold. First, the use of CFA for testing convergent and discriminant validity is still relatively rare. Second, we demonstrated how to use CFA for a more stringent test of discriminant validity compared with the original approach described by Cole ( 1987 ). PMID- 28569099 TI - Craniofacial Dysfunction and Pain: Manual Therapy, Assessment and Management. PMID- 28569100 TI - Problem Based Learning: Case Studies, Experience and Practice. PMID- 28569101 TI - Core Clinical Skills for OSCEs in Medicine. PMID- 28569102 TI - "An ex-vivo assessment of resin modified glass ionomer cement in relation to bonding technique: C. J. Larmour and D. R. Stirrups". PMID- 28569104 TI - Systematized orthodontic treatment mechanics. PMID- 28569103 TI - Structured abstracts of clinical trials. PMID- 28569105 TI - Orthodontics and Dentofacial Orthopedics. PMID- 28569106 TI - A Practical Guide for Medical Teachers. PMID- 28569107 TI - Universities and Students. A Guide to Rights, Responsibilities and Practical Remedies. PMID- 28569108 TI - Reviews & Abstracts. PMID- 28569110 TI - Commentaries on scientific papers published in this edition. PMID- 28569112 TI - Let's Talk About Depression in the Asia Pacific Region. PMID- 28569111 TI - The Association of Workplace Exposures on Quality of Life in Small and Medium Enterprises Workers: A Cross-Sectional Study in Four ASEAN Countries. AB - Quality of life is associated with several factors, including personal living styles and working conditions. This article aims to investigate the factors associated with quality of life among small and medium enterprises (SME) workers in 4 countries of the Association of Southeast Asian Nations (ASEAN), namely Malaysia, Indonesia, Thailand, and Vietnam. A total of 2014 workers from food and textile industries were asked to answer a questionnaire about their sociodemographic characteristics, working environment and conditions, and quality of life. Results from showed that lifestyle (ie, alcohol intake and exercising), working characteristics (ie, shift work, working hours, and working days) and workplace conditions were associated with SME workers' quality of life (ie, physical, psychological, social, and environmental domain). Among the 16 types of workplace conditions, "sitting on the chair" and "slippery floor" most affect their quality of life . It is important for these variables to be taken into account in promoting workers' well-being and quality of life. PMID- 28569113 TI - Antimicrobial Resistance Control Strategies: A Coordinated Research Initiative Experience in the Asia Pacific Region. AB - The objective was to gather information on the status of antimicrobial surveillance in the Asia Pacific region and suggest control strategies. Twenty one economies of the Asia Pacific region participated in this initiative. A survey was conducted on antimicrobial use and surveillance throughout the region. A workshop was carried out to create awareness about the issue and discuss the implementation of control strategies. Based on the survey results and workshop conclusions, it can be established that there is better understanding of the implications of antimicrobial resistance in the human medicine area. Only few economies take actions to control antimicrobial resistance on a veterinary/agricultural level. To confront antimicrobial resistance, it is critical to raise awareness; cooperation between all countries is needed to apply international standards, to be able to have harmonized public policies. Countries must align and improve their systems for surveillance and monitoring of antimicrobial resistance in human, animals, and the environment. PMID- 28569114 TI - Dynamic Changes in the Bivariable Distribution of Urinary Iodine Concentration and Thyroid Volume in Children Aged 8 to 10 Years in China. AB - National iodine-deficiency disorder surveillance surveys were conducted in 1999, 2005, and 2011 in China. Probability-proportional-to-size sampling technique was used to select sampling units. The mean of thyroid volume (Tvol) in the 100 to 199 ug/L UIC (urinary iodine concentration) group was significantly lower than that in the 200 to 299 ug/L UIC group in 2011 ( P < .05). The status in the 100 to 199 ug/L versus >=300 ug/L and 200 to 299 ug/L versus >=300 ug/L groups in 1999, and 100 to 199 ug/L versus >=300 ug/L group in 2011 were the same ( P < .05). The mean Tvol in the <100 ug/L UIC group was significantly higher than that in the 100 to 199 ug/L UIC group in 1999 ( P < .05). Both insufficient and excess iodine may be associated with an increase in Tvol, and adequate iodine intake should be defined as median UIC 100 to 299 ug/L. PMID- 28569115 TI - Associations Between Bicycling for Transportation and Cardiometabolic Risk Factors Among Minneapolis-Saint Paul Area Commuters: A Cross-Sectional Study in Working-Age Adults. AB - PURPOSE: This study describes the association between frequency of bicycling for active transportation and modifiable cardiometabolic risk factors in the Minneapolis-Saint Paul (MSP) metropolitan area. DESIGN: We conducted an online survey from a convenience sample of likely bicycle commuters. SETTING: Participants were e-mailed invitations including a link to the online survey. PARTICIPANTS: Participants (n = 1450, 15.6% response rate) were residents of the 7-county MSP metropolitan area aged 20 to 64 years. MEASURES: Participants reported frequency of commute and destination cycling from April to September and October to March, prevalent cardiometabolic risk factors, and demographic covariates. ANALYSIS: We performed logistic regressions for associations between average weekly transportation bicycling and self-reported prevalent obesity, high blood pressure, high cholesterol, low high-density lipoprotein cholesterol, and high triglycerides. We used Poisson regression for the count of cardiometabolic risk factors. All models were adjusted for age, sex, race, smoking, alcohol consumption, and other physical activity, with random intercepts by zip code. RESULTS: Self-reported bicycling frequency is associated with significantly lower odds of prevalent obesity, hypertension, and high triglycerides. Three bicycling trips per week is associated with 20% fewer (95% confidence interval: 12%-28%) cardiometabolic risk factors. CONCLUSION: Bicycling frequency is inversely associated with cardiometabolic risk factors. These results provide empirical support for the promotion of active transportation as public health policy. PMID- 28569116 TI - Patient and health care professional perspectives on using telehealth to deliver pulmonary rehabilitation. AB - The objective of this study was to identify the necessary features of pulmonary telerehabilitation (P-TR) from the perspectives of individuals living with chronic lung disease and health care professionals (HCPs) who deliver pulmonary rehabilitation (PR). Focus groups were carried out with patients ( n = 26) and HCPs ( n = 26) to elicit and explore their opinions about the critical elements of in-person PR and ideas for how these elements could be supported using technology. A questionnaire was used to assess technology use, PR experience, and general health status. Four key elements of PR were identified as critical to P TR: the social aspect of PR; communicating with HCPs for education and support; using biosensors for monitoring and promoting self-knowledge; and the evolution of support with progress over time. A range of technology-enabled devices and programs were suggested as means to recreate aspects of these integral elements. Consultations with patients and HCPs suggest that users are interested in technology and want to ensure it recreates the important aspects of PR. Patients and HCPs identified similar key elements for P-TR. The opinions and suggestions of patients and HCPs should be the driving force of innovation if P-TR is to succeed in improving health outcomes. PMID- 28569117 TI - Testicular ultrasensitive Doppler preliminary experience: a feasibility study. AB - Background Ultrasensitive Doppler is a novel non-invasive ultrasound (US) Doppler technique that improves sensitivity and resolution for the detection of slow flow. Purpose To investigate the feasibility of ultrasensitive Doppler (USD) for testicular disease diagnosis, using both qualitative and quantitative results. Material and Methods This prospective study was conducted in 160 successive men referred for scrotal US including B-mode and conventional Color-Doppler. A new USD sequence and algorithm dedicated to academic research were implemented into the US system. The quality criterion for a successful examination was the detection of well delineated intratesticular vessels. Qualitative USD results were described in terms of tumor vascular architecture and flow intensity for different pathologies for 41 patients. The testicular vascularization (TV), defined as a vessel's surface ratio, was quantified using customized MATLAB(r) software and compared in azoospermic and normal patients. Results USD was acquired successfully in 153/160 patients (95.6%). The tumor vascular architecture differed depending on the nature of the tumors. Leydig cell tumors exhibited mostly circumferential vascularization, while germ cell tumors exhibited straight vessels through the tumors, or anarchic vascular maps. USD improved the diagnostic performance of testicular Doppler US in a case of incomplete spermatic cord torsion and acute epididymitis. The reproducibility of TV measurements established an interclass correlation of 0.801. Non-Klinefelter syndrome non-obstructive azoospermia patients exhibited a lower TV compared to normal patients, to Klinefelter syndrome, and to obstructive azoospermia patients ( P < 0.002, P < 0.005, and P < 0.05, respectively). Conclusion Testicular USD can become a promising technique for improving US diagnosis of tumors, acute scrotum, and for determining infertility status. PMID- 28569118 TI - Analysis of Nonstationary Time Series for Biological Rhythms Research. AB - This article is part of a Journal of Biological Rhythms series exploring analysis and statistics topics relevant to researchers in biological rhythms and sleep research. The goal is to provide an overview of the most common issues that arise in the analysis and interpretation of data in these fields. In this article on time series analysis for biological rhythms, we describe some methods for assessing the rhythmic properties of time series, including tests of whether a time series is indeed rhythmic. Because biological rhythms can exhibit significant fluctuations in their period, phase, and amplitude, their analysis may require methods appropriate for nonstationary time series, such as wavelet transforms, which can measure how these rhythmic parameters change over time. We illustrate these methods using simulated and real time series. PMID- 28569119 TI - Skin Temperature Rhythms in Humans Respond to Changes in the Timing of Sleep and Light. AB - Body temperature is known to vary with circadian phase and to be influenced by factors that can mask its circadian expression. We wanted to test whether skin temperature rhythms were sensitive to an abrupt shift of the sleep schedule and to the resetting effects of light. Nineteen healthy subjects spent 6 days in time isolation and underwent a simulated night-shift procedure. They were assigned to either a control group ( n = 10) or bright light group ( n = 9) and measurements were taken under a baseline day-oriented schedule and during the 4th cycle of a night-oriented schedule. In the bright light group, participants were exposed to a 3-cycle 8-h exposure of ~6,500 lux at night, while the control group remained in dim light conditions (~3 lux). Skin temperature was recorded in 10 and 4 participants from the control and bright light groups, respectively. We found significant circadian rhythms of plasma melatonin, core body temperature (CBT), and skin temperature at baseline for both groups ( p < 0.001 for all). Rhythms of melatonin, CBT, and skin temperature following night shifts were significantly phase delayed by about 7 to 9 h ( p < 0.05) in response to bright light at night, whereas there was no shift in the control group. In addition, we found that at bedtime melatonin does not consistently increase before the increase in distal skin temperature and subsequent decrease in CBT, in contrast to what has been previously reported. The present study shows that, in constant posture conditions, skin temperature rhythms have an evoked component sensitive to abrupt changes in the timing of sleep. They also comprise an endogenous component that is sensitive to the resetting effects of bright light exposure. These results have applications for the determination of circadian phase, as skin temperature is less intrusive than rectal temperature recordings. PMID- 28569120 TI - Burning mouth syndrome. AB - Objective To review the clinical entity of primary burning mouth syndrome (BMS), its pathophysiological mechanisms, accurate new diagnostic methods and evidence based treatment options, and to describe novel lines for future research regarding aetiology, pathophysiology, and new therapeutic strategies. Description Primary BMS is a chronic neuropathic intraoral pain condition that despite typical symptoms lacks clear clinical signs of neuropathic involvement. With advanced diagnostic methods, such as quantitative sensory testing of small somatosensory and taste afferents, neurophysiological recordings of the trigeminal system, and peripheral nerve blocks, most BMS patients can be classified into the peripheral or central type of neuropathic pain. These two types differ regarding pathophysiological mechanisms, efficacy of available treatments, and psychiatric comorbidity. The two types may overlap in individual patients. BMS is most frequent in postmenopausal women, with general population prevalence of around 1%. Treatment of BMS is difficult; best evidence exists for efficacy of topical and systemic clonazepam. Hormonal substitution, dopaminergic medications, and therapeutic non-invasive neuromodulation may provide efficient mechanism-based treatments for BMS in the future. Conclusion We present a novel comprehensive hypothesis of primary BMS, gathering the hormonal, neuropathic, and genetic factors presumably required in the genesis of the condition. This will aid in future research on pathophysiology and risk factors of BMS, and boost treatment trials taking into account individual mechanism profiles and subgroup clusters. PMID- 28569121 TI - Military Lesbian, Gay, Bisexual, and Transgender (LGBT) Awareness Training for Health Care Providers Within the Military Health System [Formula: see text]. AB - BACKGROUND AND SIGNIFICANCE: Lesbian, gay, bisexual, and transgender (LGBT) individuals serving within the U.S. military and their beneficiaries have unique health care requirements. Department of Defense Directive 1304.26 "Don't Ask, Don't Tell" created a barrier for service members to speak candidly with their health care providers, which left specific health care needs unaddressed. There are no standardized cultural education programs to assist Military Health System (MHS) health care providers in delivering care to LGBT patients and their beneficiaries. PURPOSE: The purpose of this project was to develop, implement, and evaluate the effectiveness of an LGBT educational program for health care providers within the MHS to increase cultural awareness in caring for this special population. METHOD: This multisite educational program was conducted at Travis Air Force Base and Joint Base Lewis-McChord from November 15, 2014, to January 30, 2015. A 15-question multiple-choice questionnaire was developed based on the education program and was administered before and after the education program. A total of 51 individuals completed the program. RESULTS: Overall posttest scores improved compared to pretest scores. CONCLUSION: This program was designed to begin the process of educating health care providers about the unique health care issues of military LGBT Service Members and their beneficiaries. This program was the first to address the disparities in LGBT health care needs within the Department of Defense. It also provided a platform for facilitating open communication among providers regarding LGBT population health needs in the military. PMID- 28569122 TI - Rationale and design of combination of an immune modulator Fingolimod with Alteplase bridging with Mechanical Thrombectomy in Acute Ischemic Stroke (FAMTAIS) trial. AB - Rationale In acute ischemic stroke patients with large vessel occlusion, although reperfusion within 6 h after stroke onset using combined intravenous alteplase and mechanical thrombectomy (bridging therapy) can improve functional outcome, still approximately 50% patients suffer disability which may result from reperfusion injury. Proof-of-concept clinical trials have indicated that the sphingosine-1-phosphate receptor modulator fingolimod may be efficacious in attenuating brain inflammation and improving clinical outcomes in acute ischemic stroke patients as a single therapy beyond 4.5 h of disease onset, or in combination with alteplase within 4.5 h of disease onset. Aim To assess whether the treatment of fingolimod combined with bridging therapy in large vessel occlusion acute ischemic stroke patients is effective and safe. Design and sample size estimates Fingolimod with Alteplase bridging with Mechanical Thrombectomy in Acute Ischemic Stroke (FAMTAIS) study is a randomized, open-label, multiple central trial. This study includes 98 patients with anterior circulation large vessel occlusion acute ischemic stroke who are eligible for bridging therapy, providing 80% power to reject the null hypothesis that, combined with fingolimod, the bridging therapy has an at least 15% higher penumbra tissue salvage index than receiving bridging therapy alone. Study outcomes The primary outcome is the penumbra tissue salvage index. Key secondary outcomes focus on: infarct growth and extent of clinical improvement from day 1 to day 7, frequency of parenchymal hemorrhage at day 1. Discussion If the hypothesis of FAMTAIS is confirmed, combination of fingolimod with bridging therapy is effective in attenuating reperfusion injury in patients with large vessel occlusion treated with 6 h of stroke onset. PMID- 28569123 TI - Diffusion-weighted imaging or computerized tomography perfusion assessment with clinical mismatch in the triage of wake up and late presenting strokes undergoing neurointervention with Trevo (DAWN) trial methods. AB - Rationale Efficacy of mechanical thrombectomy for acute stroke due to large vessel occlusion initiated beyond 6 h of time last seen well has not been demonstrated in randomized trials. Aim To establish whether subjects considered to have substantial areas of salvageable brain based on age-adjusted clinical core mismatch who can undergo endovascular treatment within 6-24 h from time last seen well (TLSW) have better outcomes at three months compared to subjects treated with standard medical therapy alone. Age-adjusted clinical core mismatch is defined by age (<=80 or >80 years), baseline National Institutes of Health Stroke Scale (NIHSS) (10-20 or >=21), and core size (0-20 cm3 in subjects older than 80 and, in subjects younger than 80, 0-30 cm3 with NIHSS 10-20 and 31-50 cm3 with NIHSS >=21). Design Prospective, randomized, multicenter, Bayesian adaptive enrichment, open label trial with blinded endpoint assessment. For the purpose of enrolment, ischemic core size will be evaluated by CT perfusion or magnetic resonance imaging-diffusion-weighted imaging measured by automated software (RAPID). Procedures Subjects with acute ischemic stroke due to computed tomography angiography- or magnetic resonance angiogram-proven arterial occlusion of the intracranial internal carotid and/or proximal middle cerebral artery (M1) with age-adjusted clinical core mismatch in whom treatment can be initiated between 6 and 24 h from TSLW are randomized in a 1:1 ratio to receive mechanical embolectomy with the Trevo device or medical management alone. Sequential interim analyses allowing adaptation of enrolment criteria or stopping new enrolment for futility or predicted success will occur in every 50 randomized patients starting at 150 to a maximum of 500 patients. Study outcomes The primary endpoint is the modified Rankin Scale score at 90 days. The primary safety outcome is stroke related mortality at 90 days. Analysis The primary endpoint, expressed as a utility-weighted modified Rankin Scale score is analyzed using a Bayesian posterior probability with adjustment for ischemic core size. For regulatory reasons, a nested co-primary endpoint analysis was added consisting of the proportion of subjects with modified Rankin Scale 0-2 between the active and control groups also analyzed using a Bayesian model. PMID- 28569124 TI - Low bone mineral density is associated with breast cancer in postmenopausal women: a case-control study. AB - OBJECTIVE: To evaluate risk factors for low bone mineral density (BMD) in postmenopausal breast cancer survivors compared with postmenopausal women without breast cancer (controls). METHOD: In this study, 112 breast cancer survivors were compared to 224 women (controls). Inclusion criteria were amenorrhea >=12 months, age 45-75 years, treated for breast cancer, and metastasis-free for at least 5 years. The control group consisted of women without breast cancer, matched by age and menopause status (in a proportion of 1: 2 as sample calculation). The risk factors for low BMD (osteopenia/osteoporosis) were assessed by interview. BMD was measured by dual-energy X-ray absorptiometry in the lumbar spine (L1-L4) and femoral neck. Logistic regression models (odds ratio, OR) were used to identify factors associated with low BMD. RESULTS: The mean (standard deviation) age of breast cancer survivors was 61.3 (9.7) years, with a mean follow-up of 10.2 (3.9) years. These women had a higher incidence of osteopenia (45.1%) and osteoporosis (22.3%) in the femoral neck than controls (39.3% and 9.0%, respectively) (p = 0.0005). Lumbar spine BMD did not differ between groups (p = 0.332). Univariate analysis adjusted for age and time since menopause revealed that chemotherapy (OR 6.90; 95% confidence interval (CI) 5.57-9.77) was associated with a higher risk of low BMD. Contrarily, regular physical exercise (OR 0.24; 95% CI 0.06-0.98) and a body mass index >=30 kg/m2 (OR 0.09; 95% CI 0.02-0.37) reduced the risk among breast cancer survivors. CONCLUSION: Postmenopausal breast cancer survivors had a higher incidence of osteopenia and osteoporosis in the femoral neck than women without breast cancer. A history of chemotherapy was a risk factor for low BMD, whereas regular physical activity and high body mass index reduced the risk among breast cancer survivors. PMID- 28569125 TI - Genetic Variability of Phyllosticta ampelicida, the Agent of Black Rot Disease of Grapevine. AB - Phyllosticta ampelicida causes black rot disease of Vitis spp. Genetic homogeneity of pathogen populations was investigated by analyzing the number of haplotypes present in infected samples from Europe and America. The fungus was identified from an analysis of the internal transcribed spacer (ITS)1-ITS2 region, and partial sequences of beta-tubulin and calmodulin genes. The analysis of nuclear microsatellites applied to strains from Vitis spp. confirmed the existence of a high degree of genetic variability in the fungal populations, revealed four subpopulations, and showed that strains from America are distinct from the European ones. Furthermore, the results obtained by landscape genetics showed that there were different introductions of the pathogen in the main vine areas of Europe, confirming what was observed in the first reports of the disease. The genetic variability of the fungus revealed by this study confirms the ability to generate new haplotypes by sexual reproduction. The difference found between the European populations and the American one confirms that the pathogen originated from America. PMID- 28569126 TI - Isothermal Amplification and Lateral-Flow Assay for Detecting Crown-Gall-Causing Agrobacterium spp. AB - Agrobacterium is a genus of soilborne gram-negative bacteria. Members carrying oncogenic plasmids can cause crown gall disease, which has significant economic costs, especially for the orchard and nursery industries. Early and rapid detection of pathogenic Agrobacterium spp. is key to the management of crown gall disease. To this end, we designed oligonucleotide primers and probes to target virD2 for use in a molecular diagnostic tool that relies on isothermal amplification and lateral-flow-based detection. The oligonucleotide tools were tested in the assay and evaluated for detection limit and specificity in detecting alleles of virD2. One set of primers that successfully amplified virD2 when used with an isothermal recombinase was selected. Both tested probes had detection limits in picogram amounts of DNA. Probe 1 could detect all tested pathogenic isolates that represented most of the diversity of virD2. Finally, the coupling of lateral-flow detection to the use of these oligonucleotide primers in isothermal amplification helped to reduce the onerousness of the process, and alleviated reliance on specialized tools necessary for molecular diagnostics. The assay is an advancement for the rapid molecular detection of pathogenic Agrobacterium spp. PMID- 28569127 TI - A Retrospective Study of Patient Factors That Indicate Provider Nonadherence to an Institutional Clostridium difficile Treatment Guideline. AB - BACKGROUND: Clostridium difficile infection (CDI) is treated most often with metronidazole or vancomycin. Both have been effective in treatment of mild to moderate infection. In more severe cases, vancomycin may be more effective. OBJECTIVES: The primary objectives were to quantify the severity of CDI and to describe overall adherence to the institutional CDI guideline. Secondary objectives were to assess factors associated with adherence to the guidelines. METHODS: Retrospective analysis of the electronic medical record was used to evaluate adherence to institutional guidelines. Data collected included demographics and other factors potentially contributing to adherence: Charlson comorbidity index, severity of infection, recurrence, intensive care unit (ICU) admission, infectious diseases (ID) consult, total duration and number of antibiotics, alternative therapies, and acid suppression. Descriptive statistics and bivariate analyses were used to describe and compare factors associated with guideline adherence; multivariate logistic regression assessed independent predictors of adherence. RESULTS: A total of 387 patients met the inclusion criteria. CDI severity was 55.8% mild/moderate cases, 42.4% severe, 0.5% fulminant, and 1.3% prophylaxis. Overall, institutional guideline adherence was 51.9%. In bivariate analyses, 5 factors were associated with nonadherence to guidelines: older age, ICU admission, duration of antibiotics, mild/moderate and severe infection (all P < .05). In the logistic regression model, severe infection ( P < .001) and longer duration of antibiotics ( P < .05) were independently associated with guideline nonadherence. CONCLUSION: In this study, 42.4% of the patients met criteria for severe infection. Providers for patients with severe infection and longer duration of antibiotic therapy were less likely to adhere to the institutional guideline. PMID- 28569128 TI - Development of a Student-Led Ambulatory Medication Reconciliation Program at an Academic Institution. AB - OBJECTIVES: To integrate fourth-year student pharmacists on advanced pharmacy practice experience (APPE) rotations within several different ambulatory clinics to perform medication reconciliations and enhance interdisciplinary practice. METHODS: The study design was a descriptive, prospective multisite study among a variety of ambulatory care outpatient clinics. Student pharmacists were partnered with physicians to conduct medication reconciliations during clinic visits for 4 hours per week, with data collection from January 2016 to September 2016. This program originated from physician requests for additional pharmacy involvement and led to the development of a successful implementation strategy to involve student pharmacists in the medication reconciliation process. RESULTS: Student pharmacists identified 537 medication discrepancies among 491 patients, including commission of medications (36%), documentation of previously omitted medications (27%), and incomplete patient allergy information (11%). Students spent an average of 10 minutes on each encounter. CONCLUSION: Documentation from this innovative program suggests improvement in medication reconciliation and enhanced patient care with limited time required of student pharmacists. A similar program could be developed and utilized at other clinical sites. PMID- 28569129 TI - Early Versus Late Initiation of Renal Replacement Therapy in Critically Ill Patients: Systematic Review and Meta-Analysis. AB - OBJECTIVE: Early initiation of renal replacement therapy (RRT) effect on survival and renal recovery of critically ill patients is still uncertain. We aimed to systematically review current evidence comparing outcomes of early versus late initiation of RRT in critically ill patients. METHODS: We searched the Medline (via Pubmed), LILACS, Science Direct, and CENTRAL databases from inception until November 2016 for randomized clinical trials (RCTs) or observational studies comparing early versus late initiation of RRT in critically ill patients. The primary outcome was mortality. Duration of mechanical ventilation, intensive care unit (ICU) length of stay (LOS), hospital LOS, and renal function recovery were secondary outcomes. Meta-analysis and trial sequential analysis (TSA) were used for the primary outcome. RESULTS: Sixty-two studies were retrieved and analyzed, including 11 RCTs. There was no difference in mortality between early and late initiation of RRT among RCTs (odds ratio [OR] = 0.78; 95% confidence interval [CI]: 0.52-1.19; I2 = 63.1%). Trial sequential analysis of mortality across all RCTs achieved futility boundaries at both 1% and 5% type I error rates, although a subgroup analysis of studies including only acute kidney injury patients was not conclusive. There was also no difference in time on mechanical ventilation, ICU and hospital LOS, or renal recovery among studies. Early initiation of RRT was associated with reduced mortality among prospective (OR = 0.69; 95% CI: 0.49 0.96; I2 = 85.9%) and retrospective (OR = 0.61; 95% CI: 0.41-0.92; I2 = 90.9%) observational studies, both with substantial heterogeneity. However, subgroup analysis excluding low-quality observational studies did not achieve statistical significance. CONCLUSION: Pooled analysis of randomized trials indicates early initiation of RRT is not associated with lower mortality rates. The potential benefit of reduced mortality associated with early initiation of RRT was limited to low-quality observational studies. PMID- 28569130 TI - Meta-Analysis of Electroacupuncture in Cardiac Anesthesia and Intensive Care. AB - BACKGROUND: Acupuncture treatment has been employed in China for over 2500 years and it is used worldwide as analgesia in acute and chronic pain. Acupuncture is also used in general anesthesia (GA). The aim of this systematic review and meta analysis was to assess the efficacy of electroacupuncture (EA) in addition to GA in patients undergoing cardiac surgery. METHODS: We searched 3 databases (Pubmed, Cochrane Library, and Web of Science-from 1965 until January 31, 2017) for randomized controlled trials (RCTs) including patients undergoing cardiac surgery and receiving GA alone or GA + EA. As primary outcomes, we investigated the association between GA + EA approach and the dosage of intraoperative anesthetic drugs administered, the duration of mechanical ventilation (MV), the postoperative dose of vasoactive drugs, the length of intensive care unit (ICU) and hospital stay, and the levels of troponin I and cytokines. RESULTS: The initial search yielded 477 citations, but only 7 prospective RCTs enrolling a total of 321 patients were included. The use of GA + EA reduced the dosage of intraoperative anesthetic drugs ( P < .05), leading to shorter MV time ( P < .01) and ICU stay ( P < .05) as well as reduced postoperative dose of vasoactive drugs ( P < .001). In addition, significantly lower levels of troponin I ( P < .01) and tumor necrosis factor alpha ( P < .01) were observed. CONCLUSION: The complementary use of EA for open-heart surgery reduces the duration of MV and ICU stay, blunts the inflammatory response, and might have protective effects on the heart. Our findings stimulate future RCT to provide definitive recommendations. PMID- 28569131 TI - Safety of Phenylephrine Infusion Through Peripheral Intravenous Catheter in the Neurological Intensive Care Unit. AB - OBJECTIVE: The traditional approach for infusing vasopressors is to insert central venous catheters, which is associated with several complications. Phenylephrine is a commonly used vasopressor in the neurologic intensive care unit (neuro ICU), and due to its modest potency, the risk of local tissue injury from extravasation may be overestimated. The purpose of this study was to evaluate the safety of phenylephrine infusion through peripheral intravenous catheter (PIV) in the neuro ICU. PATIENTS AND METHODS: Retrospective review of all consecutive adults admitted to the neuro ICU receiving phenylephrine infusion via PIV at a tertiary academic medical center from September 2012 to November 2015. RESULTS: Two hundred seventy-seven patients with a mean age of 65 years (standard deviation [SD]: +/-15) were included in the final analysis. The most common indications for phenylephrine use were hemodynamic augmentation (40%) and postoperative hypotension (32%). The most common location of PIV-infusing phenylephrine was proximal upper extremity (50%). The most common PIV gauge was 20 (41%). The mean maximum dose of phenylephrine was 79 MUg/min (SD: +/-53, range: 5-200) or 1.04 MUg/kg/min (SD: +/-0.74, range: 0.07-3.49) and was continued for a mean duration of 19 hours (SD: +/-18, range: 1-129). Nine (3%) total episodes of PIV infiltration were noted, none requiring intervention for significant tissue injury or limb ischemia. CONCLUSION: Infusion of phenylephrine through PIV is safe when used in moderate doses for a short time and can be considered in lieu of placing a central line solely for this purpose. PMID- 28569132 TI - A Pilot Study of the Use of Dexmedetomidine for the Control of Delirium by Reducing the Serum Concentrations of Brain-Derived Neurotrophic Factor, Neuron Specific Enolase, and S100B in Polytrauma Patients. AB - BACKGROUND: Delirium is very common among patients with polytrauma, although no suitable means exist to feasibly reduce the incidence and duration of delirium in these patients. Recent reports have suggested that continuous intravenous (IV) infusions of dexmedetomidine, rather than benzodiazepine, be administered for sedation to reduce the duration of delirium in this population. However, serum neuron-specific enolase (NSE), S100 calcium binding protein B (S100B), and brain derived neurotrophic factor (BDNF) levels have not yet been investigated in polytrauma patients who received sedation with dexmedetomidine rather than other conventional sedatives. The aim of this study was to assess the association of blood BDNF, NSE, and S100B with the occurrence of delirium among polytrauma patients who had been sedated with dexmedetomidine. MATERIALS AND METHODS: Consecutive patients were randomly assigned to 1 of 2 treatment study groups, namely the "dexmedetomidine group" or the "common group." This case-control study included 18 patients with delirium and 34 matched controls in a 63-bed general intensive care unit (ICU). Blood samples were collected from all patients upon ICU admission, on the day when delirium was diagnosed, and on days 3 and 5 following diagnosis. The serum levels of S100B, BDNF, and NSE were determined by enzyme-linked immunosorbent assay. The sedation levels and delirium were assessed using the Richmond Agitation and Sedation Scale and the Confusion Assessment Method for the ICU. RESULTS: The median BDNF, NSE, and S100B concentrations were significantly lower in the dexmedetomidine group than in the common group on the day when delirium was diagnosed and on the third day after delirium was diagnosed. The rate of delirium was significantly lower in the dexmedetomidine group than in the common group. There were clear differences in the BDNF, NSE, and S100B levels between the 2 groups on the fifth day after delirium was diagnosed. CONCLUSIONS: Our randomized controlled study suggests that the sedation of polytrauma patients with dexmedetomidine could help reduce the serum BDNF, S100B, and NSE levels, which appear to be associated with the occurrence of delirium in the dexmedetomidine group. PMID- 28569133 TI - Defining the ABC of gene essentiality in streptococci. AB - BACKGROUND: Utilising next generation sequencing to interrogate saturated bacterial mutant libraries provides unprecedented information for the assignment of genome-wide gene essentiality. Exposure of saturated mutant libraries to specific conditions and subsequent sequencing can be exploited to uncover gene essentiality relevant to the condition. Here we present a barcoded transposon directed insertion-site sequencing (TraDIS) system to define an essential gene list for Streptococcus equi subsp. equi, the causative agent of strangles in horses, for the first time. The gene essentiality data for this group C Streptococcus was compared to that of group A and B streptococci. RESULTS: Six barcoded variants of pGh9:ISS1 were designed and used to generate mutant libraries containing between 33,000-66,000 unique mutants. TraDIS was performed on DNA extracted from each library and data were analysed separately and as a combined master pool. Gene essentiality determined that 19.5% of the S. equi genome was essential. Gene essentialities were compared to those of group A and group B streptococci, identifying concordances of 90.2% and 89.4%, respectively and an overall concordance of 83.7% between the three species. CONCLUSIONS: The use of barcoded pGh9:ISS1 to generate mutant libraries provides a highly useful tool for the assignment of gene function in S. equi and other streptococci. The shared essential gene set of group A, B and C streptococci provides further evidence of the close genetic relationships between these important pathogenic bacteria. Therefore, the ABC of gene essentiality reported here provides a solid foundation towards reporting the functional genome of streptococci. PMID- 28569134 TI - Incidence and outcome of severe ante-partum hemorrhage at the Teaching Hospital Yalgado Ouedraogo in Burkina Faso. AB - BACKGROUND: Hemorrhage is the main cause of maternal death during pregnancy. This study aims to evaluate incidence and outcomes of Severe Ante Partum Hemorrhage (SAPH) during the third trimester of pregnancy prior to delivery. METHODS: Analytical cross-sectional study with prospective data collection during 12 months in Yalgado Ouedraogo Hospital, Ouagadougou, Burkina Faso. In this context SAPH is specifically referring to Ante Partum Hemorrhage (APH) and Intra Partum Hemorrhage (IPH) in the 3rd trimester. Postpartum Hemorrhage (PPH) was not included. RESULTS: During our study 7,469 women were admitted in obstetrics and 122 cases of SAPH were recorded. SAPH represented 1.6% (n = 122) of hospitalizations causes and 14.5% (n = 1083) of hemorrhages during pregnancy. Mean age was 27.8 +/- 6.9 years, mean parity 2.8 +/- 1.3 and mean duration of pregnancy was 37 Weeks Amenorrhea (WA). Evacuation from other facilities was the main mode of admission (91.8%, n = 112) and blood transfusion was the essence of resuscitation. Complications were observed in 80.3% (n = 98). During the study, 118 maternal deaths were reported of which 15.6% (n = 19) related to SAPH. Among SAPH cases who died (n = 19) majority (n = 16) had severe anemia (n = 16; 82.6%, p = 0.004). Ten women (8.19%) were admitted in Intensive Care Unit (ICU). Fifteen premature births (12.3%) and 22 perinatal deaths (18.1%) were recorded. Evacuation (p = 0.04), critical clinical condition during admission (p = 0.004), and Uterine Rupture (UR) (p = 0.002) were associated with poor outcome. The Retroplacental Hemorrhage (RPH) (40.9%) was the most common cause of fetal death (p = 0.005) and was associated with High Blood Pressure (HBP) and pre-eclampsia. CONCLUSION: APH is a complication associated with significant maternal and fetal morbidity and mortality. PMID- 28569135 TI - Intervene: a tool for intersection and visualization of multiple gene or genomic region sets. AB - BACKGROUND: A common task for scientists relies on comparing lists of genes or genomic regions derived from high-throughput sequencing experiments. While several tools exist to intersect and visualize sets of genes, similar tools dedicated to the visualization of genomic region sets are currently limited. RESULTS: To address this gap, we have developed the Intervene tool, which provides an easy and automated interface for the effective intersection and visualization of genomic region or list sets, thus facilitating their analysis and interpretation. Intervene contains three modules: venn to generate Venn diagrams of up to six sets, upset to generate UpSet plots of multiple sets, and pairwise to compute and visualize intersections of multiple sets as clustered heat maps. Intervene, and its interactive web ShinyApp companion, generate publication-quality figures for the interpretation of genomic region and list sets. CONCLUSIONS: Intervene and its web application companion provide an easy command line and an interactive web interface to compute intersections of multiple genomic and list sets. They have the capacity to plot intersections using easy-to-interpret visual approaches. Intervene is developed and designed to meet the needs of both computer scientists and biologists. The source code is freely available at https://bitbucket.org/CBGR/intervene , with the web application available at https://asntech.shinyapps.io/intervene . PMID- 28569136 TI - Molecular differences in susceptibility of the kidney to sepsis-induced kidney injury. AB - BACKGROUND: Septic acute kidney injury affects 40-50% of all septic patients. Molecular differences between septic patients with and without acute kidney injury (AKI) are only poorly understood. Here, we investigated gene expression changes that differentiated the subjects who developed septic AKI from those who did not and coupled this approach with traditional parameters of renal physiology. METHODS: In 15 anesthetized, mechanically ventilated and instrumented pigs, progressive sepsis was induced either by peritonitis or by continuous intravenous infusion of Pseudomonas aeruginosa. Animals received standard intensive care including goal-directed hemodynamic management. Analyses were performed on kidneys from sham operated animals, septic pigs without AKI, and pigs with septic AKI. Before, and at 12, 18 and 22 h of progressive sepsis, systemic and renal hemodynamics, cortex microcirculation and plasma IL-6 and TNF alpha were measured. At 22 h whole kidney expression of pre-selected genes was analyzed by quantitative Real Time PCR. RESULTS: Animals with septic AKI had systemic hemodynamic phenotype (normo- or hyperdynamic) comparable with non-AKI subjects, but demonstrated higher plasma levels of cytokines, an increase in renal vascular resistance and early fall in cortical microcirculatory blood flow. The genes whose expression discriminated septic AKI from non-AKI included Toll like receptor 4 (up-regulated 2.7-fold, P = 0.04); Cyclooxygenase-2 (up-regulated 14.6-fold, P = 0.01), Angiotensin II Receptor (up-regulated 8.1-fold, P = 0.01), Caspase 3 (up-regulated 5.1-fold, P = 0.02), Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha (down-regulated 2-fold, P = 0.02). CONCLUSIONS: In this preliminary experimental study, kidney gene expression was profoundly different in animals that developed septic AKI as opposed to septic animals that did not. The biological functions of the genes differentially expressed support a role of inflammatory overstimulation coupled with metabolic and apoptotic molecular responses in early septic AKI. Cyclooxygenase-2 and angiotensin type 2 receptor-dependent downstream mechanisms appear fruitful targets for future mechanistic research. PMID- 28569137 TI - Optimal timing of cholecystectomy after percutaneous gallbladder drainage for severe cholecystitis. AB - BACKGROUND: The Tokyo guideline for acute cholecystitis recommended percutaneous transhepatic gallbladder drainage followed by cholecystectomy for severe acute cholecystitis, but the optimal timing for the subsequent cholecystectomy remains controversial. METHODS: Sixty-seven patients who underwent either laparoscopic or open cholecystectomy after percutaneous transhepatic gallbladder drainage for severe acute cholecystitis were enrolled and divided into difficult cholecystectomy (group A) and non-difficult cholecystectomy (group B). Patients who had one of these conditions were placed in group A: 1) conversion from laparoscopic to open cholecystectomy; 2) subtotal cholecystectomy and/or mucoclasis; 3) necrotizing cholecystitis or pericholecystic abscess formation; 4) tight adhesions around the gallbladder neck; and 5) unsuccessfully treated using PTGBD. Preoperative characteristics and postoperative outcomes were analyzed. RESULTS: The interval between percutaneous transhepatic gallbladder drainage and cholecystectomy in Group B was longer than that in Group A (631 h vs. 325 h; p = 0.031). Postoperative complications occurred more frequently when the interval was less than 216 h compared to when it was more than 216 h (35.7 vs. 7.6%; p = 0.006). CONCLUSIONS: Cholecystectomy for severe acute cholecystitis was technically difficult when performed within 216 h after percutaneous transhepatic gallbladder drainage. PMID- 28569139 TI - Genomic prediction in early selection stages using multi-year data in a hybrid rye breeding program. AB - BACKGROUND: The use of multiple genetic backgrounds across years is appealing for genomic prediction (GP) because past years' data provide valuable information on marker effects. Nonetheless, single-year GP models are less complex and computationally less demanding than multi-year GP models. In devising a suitable analysis strategy for multi-year data, we may exploit the fact that even if there is no replication of genotypes across years, there is plenty of replication at the level of marker loci. Our principal aim was to evaluate different GP approaches to simultaneously model genotype-by-year (GY) effects and breeding values using multi-year data in terms of predictive ability. The models were evaluated under different scenarios reflecting common practice in plant breeding programs, such as different degrees of relatedness between training and validation sets, and using a selected fraction of genotypes in the training set. We used empirical grain yield data of a rye hybrid breeding program. A detailed description of the prediction approaches highlighting the use of kinship for modeling GY is presented. RESULTS: Using the kinship to model GY was advantageous in particular for datasets disconnected across years. On average, predictive abilities were 5% higher for models using kinship to model GY over models without kinship. We confirmed that using data from multiple selection stages provides valuable GY information and helps increasing predictive ability. This increase is on average 30% higher when the predicted genotypes are closely related with the genotypes in the training set. A selection of top-yielding genotypes together with the use of kinship to model GY improves the predictive ability in datasets composed of single years of several selection cycles. CONCLUSIONS: Our results clearly demonstrate that the use of multi-year data and appropriate modeling is beneficial for GP because it allows dissecting GY effects from genomic estimated breeding values. The model choice, as well as ensuring that the predicted candidates are sufficiently related to the genotypes in the training set, are crucial. PMID- 28569138 TI - Identification of candidate genes for fiber length quantitative trait loci through RNA-Seq and linkage and physical mapping in cotton. AB - BACKGROUND: Cotton (Gossypium spp.) fibers are single-celled elongated trichomes, the molecular aspects of genetic variation in fiber length (FL) among genotypes are currently unknown. In this study, two backcross inbred lines (BILs), i.e., NMGA-062 ("Long") and NMGA-105 ("Short") with 32.1 vs. 27.2 mm in FL, respectively, were chosen to perform RNA-Seq on developing fibers at 10 days post anthesis (DPA). The two BILs differed in 4 quantitative trait loci (QTL) for FL and were developed from backcrosses between G. hirsutum as the recurrent parent and G. barbadense. RESULTS: In total, 51.7 and 54.3 million reads were obtained and assembled to 49,508 and 49,448 transcripts in the two genotypes, respectively. Of 1 551 differentially expressed genes (DEGs) between the two BILs, 678 were up-regulated and 873 down-regulated in "Long"; and 703 SNPs were identified in 339 DEGs. Further physical mapping showed that 8 DEGs were co localized with the 4 FL QTL identified in the BIL population containing the two BILs. Four SNP markers in 3 DEGs that showed significant correlations with FL were developed. Among the three candidate genes encoding for proline-rich protein, D-cysteine desulfhydrase, and thaumatin-like protein, a SNP of thaumatin like protein gene showed consistent correlations with FL across all testing environments. CONCLUSIONS: This study represents one of the first investigations of positional candidate gene approach of QTL in cotton in integrating transcriptome and SNP identification based on RNA-Seq with linkage and physical mapping of QTL and genes, which will facilitate eventual cloning and identification of genes responsible for FL QTL. The candidate genes may serve as the foundation for further in-depth studies of the molecular mechanism of natural variation in fiber elongation. PMID- 28569140 TI - An evaluation of copy number variation detection tools for cancer using whole exome sequencing data. AB - BACKGROUND: Recently copy number variation (CNV) has gained considerable interest as a type of genomic/genetic variation that plays an important role in disease susceptibility. Advances in sequencing technology have created an opportunity for detecting CNVs more accurately. Recently whole exome sequencing (WES) has become primary strategy for sequencing patient samples and study their genomics aberrations. However, compared to whole genome sequencing, WES introduces more biases and noise that make CNV detection very challenging. Additionally, tumors' complexity makes the detection of cancer specific CNVs even more difficult. Although many CNV detection tools have been developed since introducing NGS data, there are few tools for somatic CNV detection for WES data in cancer. RESULTS: In this study, we evaluated the performance of the most recent and commonly used CNV detection tools for WES data in cancer to address their limitations and provide guidelines for developing new ones. We focused on the tools that have been designed or have the ability to detect cancer somatic aberrations. We compared the performance of the tools in terms of sensitivity and false discovery rate (FDR) using real data and simulated data. Comparative analysis of the results of the tools showed that there is a low consensus among the tools in calling CNVs. Using real data, tools show moderate sensitivity (~50% - ~80%), fair specificity (~70% - ~94%) and poor FDRs (~27% - ~60%). Also, using simulated data we observed that increasing the coverage more than 10* in exonic regions does not improve the detection power of the tools significantly. CONCLUSIONS: The limited performance of the current CNV detection tools for WES data in cancer indicates the need for developing more efficient and precise CNV detection methods. Due to the complexity of tumors and high level of noise and biases in WES data, employing advanced novel segmentation, normalization and de-noising techniques that are designed specifically for cancer data is necessary. Also, CNV detection development suffers from the lack of a gold standard for performance evaluation. Finally, developing tools with user-friendly user interfaces and visualization features can enhance CNV studies for a broader range of users. PMID- 28569141 TI - Disease burden and antimicrobial resistance of invasive group B streptococcus among infants in China: a protocol for a national prospective observational study. AB - BACKGROUND: Group B Streptococcus (GBS) is a cause of neonatal sepsis, pneumonia, and meningitis that can lead to neurological sequelae in infants less than 3 months of age. The GBS disease burden is not known in China, therefore it cannot receive major attention. The main objectives of this study are the evaluation of the incidence of neonatal GBS infection, GBS case-fatality ratio, its serotypes and genotypes, bacterial resistance, clinical treatment and outcomes in China. METHODS: We are conducting a nation-wide, population-based, multi-center, prospective, observational cohort study in China from May 2016 to December 2017. Eighteen large urban tertiary care hospitals from 16 provinces were selected that cover the eastern, southern, western, northern and central regions of China. Meanwhile, we retrospectively collected data and GBS strains from January 2015 to April 2016 from selected hospitals. The incidence rate per 1000 live births will be defined as the total number of confirmed GBS cases born in the selected hospitals divided by the number of live births in the hospitals during the study period. All GBS cases detected in selected hospitals will be used to calculate the case-fatality ratio and for the typing analysis. GBS isolates will be serotyped using the Strep-B-Latex(r) rapid latex agglutination test for serotyping of Group B streptococci. Multi-locus sequence typing (MLST) will be performed by sequencing the internal fragments of seven house-keeping genes. Antimicrobial susceptibility will be tested per interpretive standards established by the Clinical and Laboratory Standards Institute. The presence of the common resistance genes ermA, ermB, mefA, tetI, tetO and tetM will be tested by PCR. DISCUSSION: We are conducting the first national study to estimate the invasive GBS disease burden and antimicrobial resistance of GBS among infants in China. Study findings will provide important evidence for improving clinical practice to ensure timely diagnosis of GBS disease and decisions for preventive measures. Surveillance of antimicrobial resistance will promote the rational use of antimicrobials. TRIAL REGISTRATION: The study was retrospectively registered at http://clinicaltrials.gov on June 13, 2016. It was granted a registration number of "NCT02812576". PMID- 28569142 TI - Bacterial vaginosis, human papilloma virus and herpes viridae do not predict vaginal HIV RNA shedding in women living with HIV in Denmark. AB - BACKGROUND: Bacterial vaginosis (BV) has been found to be associated with HIV acquisition and transmission. This is suggested to be due to higher HIV RNA levels in cervicovaginal fluids in women living with HIV (WLWH) with BV, as bacteria associated with BV may induce viral replication and shedding in the genital tract despite undetectable HIV RNA plasma viral load. We examined the prevalence and diagnostic predictors of BV and HIV-1 RNA vaginal shedding in women living with HIV (WLWH) in Denmark, taking into account the presence of human papillomavirus (HPV) and herpes viridae. METHODS: WLWH between 18-51 years were recruited from six Departments of Infectious Diseases in Denmark during enrolment in the SHADE cohort; a prospective cohort study of WLWH attending regular outpatient care. BV was diagnosed by microscopy of vaginal swabs and PCR was used for detection of BV-associated bacteria, HPV, herpes viridae, and vaginal HIV viral load. RESULTS: Median age of the 150 included women was 41 years; ethnicity was predominantly White (35%) or Black (47%). The majority (96%) was on ART and had undetectable (85%) plasma HIV RNA (<40 copies/mL). BV was diagnosed in 32%. Overall, 11% had detectable vaginal HIV RNA. Both before and after adjustment for BV, age, ethnicity, plasma HIV RNA, CD4 cell count, herpes viridae and HPV, we found no significant predictors of HIV RNA vaginal shedding. CONCLUSION: In well-treated WLWH, BV, herpes viridae or HPV do not predict vaginal HIV RNA shedding. This implies that HIV shedding does not seem to be increased by BV. PMID- 28569143 TI - Spondylodiscitis in a healthy 12-year-old girl with Extraintestinal pathogenic Escherichia coli (ExPEC) bacteraemia. AB - BACKGROUND: Escherichia coli (E. coli) is rarely implicated in bone or joint infections in children. CASE PRESENTATION: We discuss the case of a healthy 12 year-old girl with an E. coli bacteraemia and a T11-T12 spondylodiscitis revealed by magnetic resonance imaging. The strain harboured serogroup O1:K1 and virulence factors common to highly virulent extra intestinal pathogenic E. coli (ExPEC). Immunological work-up was normal. CONCLUSION: The identification of E. coli in a spondylodiscitis should lead to the search for immunosuppression of the host and virulence factors of the strain, particularly those of ExPEC. PMID- 28569144 TI - The incidence, risk factors and in-hospital mortality of acute kidney injury in patients after abdominal aortic aneurysm repair surgery. AB - BACKGROUND: Acute kidney injury (AKI) is a severe complication associated with abdominal aortic aneurysm (AAA) repair. In this study, we evaluated the incidence, risk factors and in-hospital mortality of AKI in patients after the AAA repair surgery. METHODS: A total of 314 Chinese AAA patients who underwent endovascular aneurysm repair (EVAR) or open aneurysm repair (OPEN) were enrolled in this study. AKI was diagnosed according to the 2012 KDIGO criteria. Logistic regression modeling was used to explore risk factors of AKI, while risk factors associated with in-hospital mortality in AKI patients were investigated using Cox proportional hazards model and Kaplan-Meier analysis, respectively. Multicollinearity analysis was performed to identify the collinearity between the variables before logistic regression analysis and Cox proportional hazards analysis. RESULTS: Among 314 patients, 94 (29.9%) developed AKI after AAA repair surgery. Severity of AKI and ruptured AAA were independently associated with an increase in in-hospital mortality in AKI patients after AAA repair. Kaplan-Meier analysis identified severity of AKI as being negatively associated with hospital survival in AKI patients. Risk factors associated with AKI included cardiovascular disease (OR 3.169, 95% confidence interval (CI) 1.538 to 6.527, P = 0.002), decreased eGFR (OR 0.965, 95%CI 0.954 to 0.977, P < 0.001), ruptured AAA (OR 2.717, 95%CI 1.320 to 5.592, P = 0.007), renal artery involvement (OR 2.903, 95%CI 1.219 to 6.912, P = 0.016) and OPEN (OR 2.094, 95%CI 1.048 to 4.183, P = 0.036). Further subgroup analysis identified OPEN as an important risk factor of AKI in ruptured AAA patients but not in ruptured AAA patients. The incidence of AKI was significantly lower in EVAR than in OPEN (27.1% vs. 42.8%) and, similarly lower in nonruptured AAA than in ruptured AAA (26.2% vs. 48.1%). CONCLUSION: One-third of AAA patients developed AKI after repair surgery. Severity of AKI was associated with reduced survival rate in AAA patients who developed postoperative AKI. Decreased preoperative creatinine clearance, cardiovascular disease, ruptured AAA and OPEN were independent risk factors for postoperative AKI in all 314 AAA patients. Although a lower rate of incident AKI was observed in EVAR compared with OPEN, subgroup analysis of ruptured AAA versus nonruptured AAA showed that EVAR was an independent protective factor for AKI only in ruptured AAA patients but not in nonruptured AAA patients. PMID- 28569145 TI - Spatial-temporal distribution of genotyped tuberculosis cases in a county with active transmission. AB - BACKGROUND: Harris County, Texas is the third most populous county in the United States and consistently has tuberculosis rates above the national average. Understanding jurisdictional epidemiologic characteristics for the most common Mycobacterium tuberculosis genotyped clusters is needed for tuberculosis prevention programs. Our objective is to describe the demographic, laboratory, clinical, temporal and geospatial characteristics for the most common Mycobacterium tuberculosis GENType clusters in Harris County from 2009 to 2015. METHODS: We analyzed data from the Centers for Disease Control and Prevention (CDC) Tuberculosis Genotyping Information Management System (TB GIMS). Chi-square analyses were used to determine associations between selected clusters and specific characteristics of interest. Geographical Information System (GIS) point density and hot spot maps were generated and analyzed with ArcGIS 10.4. RESULTS: In Harris County from 2009 to 2015, 1655 of 1705 (97.1%) culture positive tuberculosis cases were genotyped and assigned a GENType, and 1058 different GENTypes were identified. The analyzed genotype clusters represent 14.1% (233/1655) of all genotyped cases: G00010 (n = 118), G00014 (n = 38), G00769 (n = 33), G01521 (n = 26), and G08964 (n = 18). Male gender (p = 0.002), ethnicity (p < 0.001), homelessness (p < 0.001), excessive alcohol use (p = 0.002), and U.S. birth (p = 0.004) were associated with the 5 GENTypes. Hot and cold spots were identified as geographic areas having high and low TB incidence. CONCLUSIONS: Of more than 1000 distinct GENTypes identified in Harris County, there were 5 common Mycobacterium tuberculosis GENType clusters seen from 2009 to 2015. The common genotypes were observed primarily in U.S.-born populations despite the large foreign-born population residing in Harris County. GENType was significant distributed spatially and temporally in Harris County in the analyzed time period indicating that there may be outbreaks caused by transmission. PMID- 28569146 TI - Clinicopathological features and surgical outcomes of neuroendocrine tumors of ampulla of Vater. AB - BACKGROUND: The study aims to investigate the clinicopathological features and surgical outcomes of neuroendocrine tumors of ampulla of Vater (NETAoVs) patients who underwent pancreaticoduodenectomy. METHODS: From January 2007 to December 2014, 45 patients underwent pancreaticoduodenectomy for malignant disease of the ampulla of Vater in our institution. Of those, 5 patients were diagnosed as neuroendocrine tumors. The data included age, sex, presenting symptoms, preoperative imaging, preoperative type of biopsy results, type of operation, pathologic findings and survival status. RESULTS: The patient's mean age was 55.2 +/- 9.7 years. Endoscopic ultrasound guided biopsy was performed in 4 patients and gastroduodenoscopic biopsy was performed in one patient. All showed neuroendocrine tumor without mitosis. Mean tumor size was 1.9 +/- 0.56 cm (range, 1.2-2.0 cm). Lymph node metastases were detected in two patients. All patients were synaptophysin-positive. Median periods of follow-up were 45 months (range, 43-78 months). Recurrence after operation occurred in two patients. 4 patients were alive at the last follow-up. CONCLUSIONS: Radical resection for NETAoVs can provide the information of status of lymph node metastasis after surgery. However, correlation between lymph node metastasis and overall survival is uncertain to date. PMID- 28569147 TI - Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor. AB - BACKGROUND: Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results. RESULTS: Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC50 of 36 MUM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC50 of 2.1 MUM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5. CONCLUSION: We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds. PMID- 28569148 TI - Diagnostic accuracy and usefulness of the Genotype MTBDRplus assay in diagnosing multidrug-resistant tuberculosis in Cameroon? a cross-sectional study. AB - BACKGROUND: Drug-resistant tuberculosis, especially multidrug-resistant tuberculosis (MDR-TB), is a major public health problem. Effective management of MDR-TB relies on accurate and rapid diagnosis. In this study, we assessed the diagnostic accuracy of the Genotype MTBDRplus assay in diagnosing MDR-TB in Cameroon, and then discuss on its utility within the diagnostic algorithm for MDR TB. METHODS: In this cross-sectional study, 225 isolates of Mycobacterium tuberculosis cultured from sputum samples collected from new and previously treated pulmonary tuberculosis patients in Cameroon were used to determine the accuracy of the Genotype MTBDRplus assay. We compared the results of the Genotype MTBDRplus assay with those from the automated liquid culture BACTEC MGIT 960 SIRE system for sensitivity, specificity, and degree of agreement. The pattern of mutations associated with resistance to RIF and INH were also analyzed. RESULTS: The Genotype MTBDRplus assay correctly identified Rifampicin (RIF) resistance in 48/49 isolates (sensitivity, 98% [CI, 89%-100%]), Isoniazid (INH) resistance in 55/60 isolates (sensitivity 92% [CI, 82%-96%]), and MDR-TB in 46/49 (sensitivity, 94% [CI, 83%-98%]). The specificity for the detection of RIF-resistant and MDR-TB cases was 100% (CI, 98%-100%), while that of INH resistance was 99% (CI, 97% 100%). The agreement between the two tests for the detection of MDR-TB was very good (Kappa = 0.96 [CI, 0.92-1.00]). Among the 3 missed MDR-TB cases, the Genotype MTBDRplus assay classified two samples as RIF-monoresistant and one as INH monoresistant. The most frequent mutations detected by the Genotype MTBDRplus assay was the rpoB S531 L MUT3 41/49 (84%) in RIF-resistant isolates, and the KatG S315 T1 (MUT1) 35/55 (64%) and inhA C15T (MUT1) 20/55 (36%) mutations in INH resistant isolates. CONCLUSION: The Genotype MTBDRplus assay had good accuracy and could be used for the diagnosis of MDR-TB in Cameroon. For routine MDR-TB diagnosis, this assay could be used for Mycobacterium tuberculosis cultures containing contaminants, to complement culture-based drug susceptibility testing or to determine drug resistant mutations. PMID- 28569150 TI - Heterologous expression of pikromycin biosynthetic gene cluster using Streptomyces artificial chromosome system. AB - BACKGROUND: Heterologous expression of biosynthetic gene clusters of natural microbial products has become an essential strategy for titer improvement and pathway engineering of various potentially-valuable natural products. A Streptomyces artificial chromosomal conjugation vector, pSBAC, was previously successfully applied for precise cloning and tandem integration of a large polyketide tautomycetin (TMC) biosynthetic gene cluster (Nah et al. in Microb Cell Fact 14(1):1, 2015), implying that this strategy could be employed to develop a custom overexpression scheme of natural product pathway clusters present in actinomycetes. RESULTS: To validate the pSBAC system as a generally applicable heterologous overexpression system for a large-sized polyketide biosynthetic gene cluster in Streptomyces, another model polyketide compound, the pikromycin biosynthetic gene cluster, was preciously cloned and heterologously expressed using the pSBAC system. A unique HindIII restriction site was precisely inserted at one of the border regions of the pikromycin biosynthetic gene cluster within the chromosome of Streptomyces venezuelae, followed by site-specific recombination of pSBAC into the flanking region of the pikromycin gene cluster. Unlike the previous cloning process, one HindIII site integration step was skipped through pSBAC modification. pPik001, a pSBAC containing the pikromycin biosynthetic gene cluster, was directly introduced into two heterologous hosts, Streptomyces lividans and Streptomyces coelicolor, resulting in the production of 10-deoxymethynolide, a major pikromycin derivative. When two entire pikromycin biosynthetic gene clusters were tandemly introduced into the S. lividans chromosome, overproduction of 10-deoxymethynolide and the presence of pikromycin, which was previously not detected, were both confirmed. Moreover, comparative qRT PCR results confirmed that the transcription of pikromycin biosynthetic genes was significantly upregulated in S. lividans containing tandem clusters of pikromycin biosynthetic gene clusters. CONCLUSIONS: The 60 kb pikromycin biosynthetic gene cluster was isolated in a single integration pSBAC vector. Introduction of the pikromycin biosynthetic gene cluster into the pikromycin non-producing strains resulted in higher pikromycin production. The utility of the pSBAC system as a precise cloning tool for large-sized biosynthetic gene clusters was verified through heterologous expression of the pikromycin biosynthetic gene cluster. Moreover, this pSBAC-driven heterologous expression strategy was confirmed to be an ideal approach for production of low and inconsistent natural products such as pikromycin in S. venezuelae, implying that this strategy could be employed for development of a custom overexpression scheme of natural product biosynthetic gene clusters in actinomycetes. PMID- 28569149 TI - Psychometric properties of the mammography self-efficacy and fear of breast cancer scales in Iranian women. AB - BACKGROUND: Research investigating mammography screening has often reported low mammography self-efficacy and breast cancer fear contribute to underutilization of mammography. This study aimed to examine the reliability and validity of Champion's Mammography Self-efficacy Scale (CMSS) and Champion's Breast Cancer Fear Scale (CBCFS) in a sample of Iranian women. METHODS: The adapted instruments were administered to a community sample of 482 women aged 40 years or older. They inhibited in Sanandaj, Iran. Cronbach's alpha coefficients, item-total, and test retest correlations were used to assess the reliability of the scales. Confirmatory factor analysis was applied to assess construct validity. RESULTS: The alpha coefficients for the Farsi 14-item CMSS and 8-item BCFS were .87 and.95, respectively. In terms of the CMSS confirmatory factor analysis, the proportion of x 2/df was 2.4, Comparative Fit Index (CFI) = 0.93, Tucker Lewis Index (TLI) = 0.96 providing a strong fit to the data induced by two-factor model. With regard to CBCFS, x 2/df was 86.33, CFI =0.99, and TLI =0.99 supporting one-factor model. CONCLUSION: The CMSS and CBCFS exhibited strong initial psychometric properties; therefore, they are recommended to understand women's breast cancer screening behaviors better. PMID- 28569151 TI - Reliability, feasibility, and validity of the quality of interactions schedule (QuIS) in acute hospital care: an observational study. AB - BACKGROUND: Research into relational care in hospitals will be facilitated by a focus on staff-patient interactions. The Quality of Interactions Schedule (QuIS) uses independent observers to measure the number of staff-patient interactions within a healthcare context, and to rate these interactions as 'positive social'; 'positive care'; 'neutral'; 'negative protective'; or 'negative restrictive'. QuIS was developed as a research instrument in long term care settings and has since been used for quality improvement in acute care. Prior to this study, its use had not been standardised, and reliability and validity in acute care had not been established. METHODS: In 2014 and 2015 a three - phase study was undertaken to develop and test protocols for the use of QuIS across three acute wards within one NHS trust in England. The phases were: (1) A pilot of 16 h observation which developed implementation strategies for QuIS in this context; (2) training two observers and undertaking 16 h of paired observation to inform the development of training protocols; (3) training four nurses and two lay volunteers according to a finalised protocol followed by 36 h of paired observations to test inter-rater agreement. Additionally, patients were asked to rate interactions and to complete a shortened version of the Patient Evaluation of Emotional Care during Hospitalisation (PEECH) questionnaire. RESULTS: Protocols were developed for the use of QuIS in acute care. Patients experienced an average of 6.7 interactions/patient/h (n = 447 interactions). There was close agreement between observers in relation to the number of interactions observed (Intraclass correlation coefficient (ICC) = 0.97) and moderate to substantial agreement on the quality of interactions (absolute agreement 73%, kappa 0.53 to 0.62 depending on weighting scheme). There was 79% agreement (weighted kappa 0.40: P < 0.001; indicating fair agreement) between patients and observers over whether interactions were positive, negative or neutral. CONCLUSIONS: Observers using clear QuIS protocols can achieve levels of agreement that are acceptable for the use of QuIS as a research instrument. There is fair agreement between observers and patients' rating of interactions. Further research is needed to explore the relationship between QuIS measures and reported patient experience. PMID- 28569152 TI - Reliability and screening ability of the StarT Back screening tool in patients with low back pain in physiotherapy practice, a cohort study. AB - BACKGROUND: Low back pain (LBP) is the most common reported musculoskeletal disorder, with large prevalence numbers and high costs. Focus on early identification of patients at risk of developing chronic LBP has increased. The Keele Start Back Tool (SBT) is a questionnaire aiming at screening prognostic indicators in LBP patients, categorizing patients into risk-groups and guide treatment. The aim of this study was to explore the Norwegian version of the SBT with regard to reliability of the SBT-scoring and the screening ability in LBP patients in primary care physiotherapy. METHODS: LBP patients answered a package of questionnaires twice, with 1-3 days in between, containing SBT, Hannover functional ability questionnaire, pain intensity questions and demographics. The relative and absolute reliability of SBT was calculated using intraclass correlation coefficient (ICC) and the smallest detectable change respectively. Independent sample t-tests were used for group comparisons. RESULTS: Fifty-two patients with LBP. Mean age (SD) was 45 (12) years and 62% were female. The ICC (95% CI) for SBT total score and psychosocial subscore was 0.89 (0.82, 0.94) and 0.82 (0.70, 0.90) respectively. None of the participants were allocated to the high risk group. The medium risk group reported significantly more pain last week and more activity limitations than the low risk group at both test and retest (0.001 <= p <= 0.003), whereas no significant difference between the groups was found on pain now (0.05 <= p <= 0.16). CONCLUSIONS: The Norwegian version of the SBT was reliable and the screening ability was good as the subgrouping of patients into risk-groups reflected the severity of their back problems. The SBT may be an applicable and useful tool in physiotherapy practice. PMID- 28569153 TI - Aberrant monocyte responses predict and characterize dengue virus infection in individuals with severe disease. AB - BACKGROUND: Currently, several assays can diagnose acute dengue infection. However, none of these assays can predict the severity of the disease. Biomarkers that predicts the likelihood that a dengue patient will develop a severe form of the disease could permit more efficient patient triage and allows better supportive care for the individual in need, especially during dengue outbreaks. METHODS: We measured 20 plasma markers i.e. IFN-gamma, IL-10, granzyme-B, CX3CL1, IP-10, RANTES, CXCL8, CXCL6, VCAM, ICAM, VEGF, HGF, sCD25, IL-18, LBP, sCD14, sCD163, MIF, MCP-1 and MIP-1beta in 141 dengue patients in over 230 specimens and correlate the levels of these plasma markers with the development of dengue without warning signs (DWS-), dengue with warning signs (DWS+) and severe dengue (SD). RESULTS: Our results show that the elevation of plasma levels of IL-18 at both febrile and defervescence phase was significantly associated with DWS+ and SD; whilst increase of sCD14 and LBP at febrile phase were associated with severity of dengue disease. By using receiver operating characteristic (ROC) analysis, the IL-18, LBP and sCD14 were significantly predicted the development of more severe form of dengue disease (DWS+/SD) (AUC = 0.768, P < 0.0001; AUC = 0.819, P < 0.0001 and AUC = 0.647, P = 0.014 respectively). Furthermore, we also found that the levels of VEGF were directly correlated and sCD14 was inversely correlated with platelet count, suggesting that the endothelial activation and microbial translocation may played a role in pathogenesis of dengue disease. CONCLUSIONS: Given that the elevation IL-18, LBP and sCD14 among patients with severe form of dengue disease, our findings suggest a pathogenic role for an aberrant inflammasome and monocyte activation in the development of severe form of dengue disease. PMID- 28569154 TI - Evaluation of the knowledge and attitude of pharmacists about the national malaria control policy in southern Benin. AB - BACKGROUND: The national strategy against malaria in an endemic country should involve all the health stakeholders. In Benin, the private sector is rarely present in the activities of the National Malaria Control Programme (NMCP), and its surveillance system does not cover private sector outlets that are a non negligible part of the healthcare system. OBJECTIVE: The aim of this study was to describe the drug delivery practices within private pharmacies of Cotonou and Porto-Novo and the awareness of medicine providers concerning the national policy of malaria treatment. METHODS: A survey was performed among pharmacy staff members responsible for dispensing medicines and providing advice to patients within pharmacies of Cotonou and Porto-Novo. Dispensing/pharmacy assistants ('dispensators') from 82 pharmacies in Cotonou and 19 in Porto-Novo were surveyed. Data entry was performed using Epidata 3.1 software and data analysis was carried out using SPSS software version 21.1. Chi square test was used to compare proportions. A significance threshold of 0.05 was defined for the p value. RESULTS: 46% of providers did not know the artemisinin-based combination therapy recommended by the NMCP for treating uncomplicated malaria. 58.7% were not able to recognize the gravity signs of malaria. 89.8% of dispensators were used to deliver an anti-malarial upon patient request, without prior biological confirmation as requested by the NMCP policy. CONCLUSIONS: Dispensing practices within the studied pharmacies from Cotonou and Porto-Novo were not in adequacy with the NMCP guidelines for uncomplicated malaria, which is a striking weakness in the training of drug providers on key elements of the guidelines for managing malaria. The NMCP needs to help dispensator from private pharmacies sector to standardize drug delivery practices according to its guidelines. PMID- 28569155 TI - The effects of different velogenic NDV infections on the chicken bursa of Fabricius. AB - BACKGROUND: Virulent Newcastle disease virus (NDV) was reported to cause rapid depletion of chicken bursa of Fabricius. Severe pathological condition of the organ is commonly associated with high levels of virus replication, intense inflammatory response and also the degree of apoptosis. In this study, the responses of chicken bursa of Fabricius infected with two different strains of velogenic NDV, namely AF2240 and IBS002, were investigated by observing cell population changes, oxidative stress, viral replication and cytokine expression in the organ. Subsequently, apoptosis of enriched bursal IgM+ cells was determined to help us elucidate possible host pathogen relationships between the chicken bursa of Fabricius and NDV infection. RESULTS: The depletion of IgM+ cells and infiltration of macrophages were observed to be higher in bursa infected with AF2240 as compared to IBS002. In line with the increment of the macrophage population, higher nitric oxide (NO) and malondialdehyde (MDA) contents which indicated higher oxidative stress were also detected in bursa infected with NDV AF2240. In addition, higher pro-inflammatory cytokines and chemokine gene expression such as chicken CXCLi2, IL-18 and IFN-gamma were observed in AF2240 infected bursa. Depletion of IgM+ cells was further confirmed with increased cell death and apoptosis of the cells in AF2240 infected bursa as compared to IBS002. However, it was found that the viral load for NDV strain IBS002 was comparatively higher than AF2240 although the magnitude of the pro- inflammatory cytokines expression and cell apoptosis was lower than AF2240. CONCLUSION: The results of our study demonstrated that infection of NDV strains AF2240 and IBS002 caused apoptosis in bursa IgM+ cells and its severity was associated with increased expression of pro-inflammatory cytokines/chemokine, macrophage infiltration and oxidative stress as the infection duration was prolonged. However, of the two viruses, we observed that NDV AF2240 induced a greater magnitude of apoptosis in chicken bursa IgM+ cells in comparison to IBS002. This might be due to the high level of oxidative stress and inflammatory cytokines/chemokine as well as lower IL10 expression which subsequently led to a high rate of apoptosis in the chicken bursa of Fabricius although the detected viral load of AF2240 was lower than IBS002. PMID- 28569156 TI - How Chinese clinicians face ethical and social challenges in fecal microbiota transplantation: a questionnaire study. AB - BACKGROUND: Fecal microbiota transplantation (FMT) is reportedly the most effective therapy for relapsing Clostridium Difficile infection (CDI) and a potential therapeutic option for many diseases. It also poses important ethical concerns. This study is an attempt to assess clinicians' perception and attitudes towards ethical and social challenges raised by fecal microbiota transplantation. METHODS: A questionnaire was developed which consisted of 20 items: four items covered general aspects, nine were about ethical aspects such as informed consent and privacy issues, four concerned social and regulatory issues, and three were about an FMT bank. This was distributed to participants at the Second China gastroenterology and FMT conference in May 2015. Basic descriptive statistical analyses and simple comparative statistical tests were performed. RESULTS: Nearly three quarters of the 100 respondents were gastro-enterologist physicians. 89% of all respondents believed FMT is a promising treatment modality for some diseases and 88% of whom chose clinical efficacy as the primary reason for recommending FMT. High expectation from patients and pressure on clinicians (33%) was reported as the most frequent reasons for not recommending FMT. The clinicians who had less familiarity with FMT reported significantly more worry related to the dignity and psychological impact of FMT compared to those who have high familiarity with FMT (51.6% vs 27.8%, p = 0.021).More than half of the respondents (56.1%) were concerned about the commercialization of FMT, although almost one in five respondents did not see this as a problem. CONCLUSIONS: We found most respondents have positive attitudes towards FMT but low awareness of published evidence. Informed consent for vulnerable patients, privacy and protection of donors were perceived as the most challenging ethical aspects of FMT. This study identified areas of limited knowledge and ways of addressing ethical issues and indicates the need to devise the education and training for clinicians on FMT. PMID- 28569157 TI - Effects of sesamin on chondroitin sulfate proteoglycan synthesis induced by interleukin-1beta in human chondrocytes. AB - BACKGROUND: Numerous studies have reported on the health benefits of sesamin, a major lignin found in sesame (S. indicum) seeds. Recently, sesamin was shown to have the ability to promote chondroitin sulfate proteoglycan synthesis in normal human chondrocytes. This study assesses the anti-inflammatory effect of sesamin on proteoglycans production in 3D chondrocyte cultures. METHODS: To evaluate the effects of sesamin on IL-1beta-treated human articular chondrocytes (HAC) pellets, the pellets were pre-treated with IL-1beta then cultured in the presence of various concentrations of sesamin for 21 days. During that period, the expression of IL-1beta, glycosaminoglycans (GAGs) content and Chondroitin sulfate proteoglycans (CSPGs) synthesis genes (ACAN, XT-1, XT-2, CHSY1 and ChPF) was measured. The GAGs accumulation in the extracellular matrix was determined on day 21 by histological analysis. RESULTS: There was clear evidence that sesamin upregulated expression of all the CSPGs synthesis genes, in contrast to the down regulation of IL-1beta expression both in genes and in protein levels. The level of release and matrix accumulation of GAGs in IL-1beta pre-treated HAC pellets in the presence of sesamin was recovered. These results correlate with the histological examination which showed that sesamin enhanced matrix CSPGs accumulation. CONCLUSIONS: Sesamin enhances CSPGs synthesis, suppresses IL-1beta expression and ameliorates IL-1beta induced inflammation in human chondrocytes. Sesamin could have therapeutic benefits for treating inflammation in osteoarthritis. PMID- 28569158 TI - Leptin differentially regulates chondrogenesis in mouse vertebral and tibial growth plates. AB - BACKGROUND: Leptin plays an important role in mediating chondrogenesis of limb growth plate. Previous studies suggest that bone structures and development of spine and limb are different. The expression of Ob-Rb, the gene that encodes leptin receptors, is vertebral and appendicular region-specific, suggesting the regulation of leptin on VGP and TGP chondrogenesis may be very different. The aim of the present study was to investigate the differential regulation of leptin on the chondrogenesis of vertebral growth plate (VGP) and tibial growth plate (TGP). METHODS: We compared the VGP and TGP from wild type (C57BL/6) and leptin deficient (ob/ob) mice. We then generated primary cultures of TGP and VGP chondrocytes. By treating the primary cells with different concentrations of leptin in vitro, we analyzed proliferation and apoptosis of the primary chondrocytes from TGP and VGP. We further measured expression of chondrogenic related genes in these cells that had been incubated with different doses of leptin. RESULTS: Leptin-deficient mice of 8-week-old had shorter tibial and longer vertebral lengths than the wide type mice. Disturbed columnar structure was observed for TGP but not for VGP. In primary chondrocyte cultures, leptin inhibited VGP chondrocyte proliferation but promoted their apoptosis. Collagen IIA and aggrecan mRNA, and the protein levels of proliferation- and chondrogenesis-related markers, including PCNA, Sox9, and Smad4, were downregulated by leptin in a dose-dependent manner. In contrast, leptin stimulated the proliferation and chondrogenic differentiation of TGP chondrocytes at physiological levels (i.e., 10 and 50 ng/mL) but not at high levels (i.e., 100 and 1000 ng/mL). CONCLUSION: Leptin exerts a stimulatory effect on the proliferation and chondrogenic differentiation of the long bone growth plate but an inhibitory effect on the spine growth plate. The ongoing study will shed light on the regulatory mechanisms of leptin in bone development and metabolism. PMID- 28569160 TI - Erratum to: Disability, support and long-term social care of an elderly Spanish population, 2008-2009: an epidemiologic analysis. PMID- 28569159 TI - Fast and robust single PCR for Plasmodium sporozoite detection in mosquitoes using the cytochrome oxidase I gene. AB - BACKGROUND: Molecular tools for detecting malaria-infected mosquitoes with improved practicality, sensitivity and specificity, and high-throughput are required. A common PCR technique used to detect mosquitoes infected with Plasmodium spp. is a nested PCR assay based on the 18s-rRNA gene. However, this technique has several technical limitations, is laborious and time consuming. METHODS: In this study, a PCR-based on the Plasmodium cytochrome oxidase I (COX I) gene was compared with the 18s-rRNA nested PCR using serial dilutions (330 0.0012 pg) of DNA from Plasmodium vivax, Plasmodium falciparum and Plasmodium knowlesi and with DNA from 48 positive and negative Kenyan mosquitoes (previously detected by using both ELISA and PCR). This assay for Plasmodium spp. DNA detection using the fast COX-I PCR assay was then performed individually on 2122 field collected mosquitoes (from the Solomon Islands) in which DNA was extracted from head and thorax. RESULTS: The fast COX-I PCR assay took 1 h to run and consistently detected as low as to 0.043 pg of parasite DNA (equivalent to two parasites) in a single PCR, while analyses with the 18s-rRNA nested PCR required 4 h to complete with a consistent detection threshold of 1.5 pg of DNA. Both assays produced concordant results when applied to the 48 Kenyan control samples with known Plasmodium spp. infection status. The fast COX-I PCR identified 23/2122 Plasmodium-infected mosquitoes from the Solomon Islands. CONCLUSIONS: This new COX-I PCR adapted for a single PCR reaction is a faster, simpler, cheaper, more sensitive technique amenable to high-throughput analyses for Plasmodium DNA detection in mosquitoes and is comparable to the 18s-rRNA nested PCR. The improved sensitivity seen with the fast COX-I PCR will improve the accuracy of mosquito infection rate determination. PMID- 28569161 TI - Basal cell carcinoma: 10-year experience with electrochemotherapy. AB - BACKGROUND: Electrochemotherapy (ECT), by combining manageable cytotoxic agents with short electric pulses, represents an effective palliative skin-directed therapy. The accumulated evidence indicates that ECT stands out as a safe and well-tolerated alternative treatment for patients with multiple or large basal cell carcinoma (BCC), who are not suitable for conventional treatments. However, long-term data and shared indications are lacking. METHODS: In this observational study, we retrospectively analyzed 84 prospectively collected patients with multiple, recurrent or locally advanced BCC who were not candidate for standard therapies and received bleomycin-based ECT according to the European Standard Operative Procedures of ECT, from 2006 to 2016. RESULTS: Disease extent was local, locally advanced and metastatic in 40 (48%), 41 (49%) and 3 (3%), respectively. Forty-four (52%) individuals had multiple BCCs. Grade 3 skin toxicity after ECT was observed in 6% of cases. Clearance rate was 50% (95% CI 39 61%). Primary presentation (p = 0.004), tumor size <3 cm (p < 0.001), well defined borders (p = 0.021), absence of tumor ulceration (p = 0.001), non aggressive BCC histology (p = 0.046) and age <=69 years were associated with higher complete response rate. In patients with local BCC, the clearance rate was 72.5 and 85% after one or two ECT cycles, respectively. In the laBCC group, 32 patients (78%) achieved an objective response. Five-year recurrence rate for local and laBCC was 20 and 38%, respectively (p <= 0.001). CONCLUSIONS: One or two ECT cycles with bleomycin may be a valuable palliative treatment in well selected patients with multiple BCCs and favorable tumor features. Validation of predictive factors will be imperative to match patients with optimal ECT treatment modalities. Management of laBCC with ECT warrants further investigation. Trial registration ISRCTN14633165 Registered 24 March 2017 (retrospectively registered). PMID- 28569162 TI - Psychometric properties of the original and short versions of the Falls Efficacy Scale-International (FES-I) in people with Parkinson's disease. AB - BACKGROUND: Fear of falling is common in people with Parkinson's disease (PD) and is associated with an increased risk for future falls, activity limitations and a reduced quality of life. The Falls Efficacy Scale-International (FES-I) assesses fear of falling conceptualized as concerns about falling. The original FES-I has good psychometric properties in people with PD, but whether this applies also for the short version of FES-I remains to be shown. The aim of the present study was to evaluate the psychometric properties of the short FES-I and to compare these with the original FES-I in the same sample of people with PD. The investigated psychometric properties included known groups validity, data completeness, scaling assumptions, targeting and reliability. METHODS: A postal survey, which included the original, full-length FES-I, was distributed to 174 people with PD. Responders received a second survey after two weeks. From these data, short FES-I total scores were calculated by extracting the items that are included in the short version of the scale. RESULTS: Median age and PD duration of the 101 responders (43% women) were 73 and 5 years, respectively. The original as well as the short FES-I scores were able to discriminate (p < 0.001) between groups with and without fear of falling, activity avoidance, falls, near falls, and with various self-rated PD severity, respectively. Both versions of FES-I had a high level of data completeness (0.7 to 0.9% missing item responses). Scaling assumptions were acceptable for the original as well as the short FES-I. While the short FES-I had 19% floor effect, the original version was better targeted. Both versions were reliable and obtained high values for internal consistency (Cronbach's alpha >0.8) and test-retest reliability (Intraclass Correlation Coefficient > 0.9). CONCLUSIONS: Both the original and short FES-I revealed generally good psychometric properties in people with PD, although the original scale was better targeted. Due to the higher floor effect in the short FES-I, the present findings favors using the original, full-length FES-I in longitudinal follow-ups, intervention studies and clinical practice when addressing concerns about falling. PMID- 28569163 TI - Validity of the Nurses' health study physical activity questionnaire in estimating physical activity in adults with rheumatoid arthritis. AB - BACKGROUND: Patients with rheumatoid arthritis (RA) demonstrate reduced aerobic capacity, excess cardiovascular risk, mobility limitations and are less physically active than their healthy peers. Physical activity may decrease RA disease activity through its anti-inflammatory effects and psychological and health benefits. To successfully manage RA symptoms and reduce cardiovascular risks associated with RA through increased physical activity (PA), accurate physical activity assessments are critical. Accelerometry is an objective physical activity measure, but not widely used. Validity of the Nurses' Health Study physical activity questionnaire II (NHSPAQ) has not been determined for estimation of physical activity in RA. This study examined NHSPAQ validity in adults with RA compared to accelerometry-based metabolic equivalents determined (METs) and results of performance tests. We hypothesized NHSPAQ scores would correlate moderately (0.4-0.5) with accelerometer physical activity estimates. METHODS: Thirty-five adults with RA (mean age [SD] 62 (Williams et. al, Health Qual Life Outcomes 10:28, 2012) years, 28 females (80%) recruited from a hospital based clinic registry participated in a one-week accelerometry trial. Medical data was compiled. Participants completed the NHSPAQ, a self-paced 20-m walk test, and modified timed step test. Participants wore an accelerometer for 7 consecutive days, then completed a physical activity log and another NHSPAQ. Metabolic equivalents (METs) were derived from NHSPAQ and accelerometers using standardized formulas. NHSPAQ METs were correlated with accelerometer METs and data from performance measures. RESULTS: Average disease duration was 21 years (SD = 11), 63% patients took biologics. The average weekly METs reported were 29 (SD = 33) and accelerometer METs were 33 (SD = 22). NHSPAQ METs correlated moderately with accelerometer-derived METs (r = 0.48 95% CI (0.15-0.70). Self reported PA correlated moderately with Step Test performance (r = 0.50 95% CI (0.18-0.72). CONCLUSION: Patients with RA exhibit low physical activity levels. General fitness measures were moderately correlated with physical activity levels. A moderate significant correlation existed between NHSPAQ and accelerometry METs. These preliminary data suggest the NHSPAQ may be useful to describe physical activity levels in this population. PMID- 28569164 TI - Omega-3 fatty acids, phenolic compounds and antioxidant characteristics of chia oil supplemented margarine. AB - BACKGROUND: Chia (Salvia hispanica L.) is known as power house of omega fatty acids which has great health benefits. It contains up to 78% linolenic acid (omega-3) and 18% linoleic acid (omega-6), which could be a great source of omega 3 fatty acids for functional foods. Therefore, in this study, margarines were prepared with supplementation of different concentrations of chia oil to enhance omega-3 fatty acids, antioxidant characteristics and oxidative stability of the product. METHODS: Margarines were formulated from non-hydrogenated palm oil, palm kernel and butter. Margarines were supplemented with 5, 10, 15 and 20% chia oil (T1, T2, T3 and T4), respectively. Margarine without any addition of chia oil was kept as control. Margarine samples were stored at 5 degrees C for a period of 90 days. Physico-chemical (fat, moisture, refractive index, melting point, solid fat index, fatty acids profile, total phenolic contents, DPPH free radical scavenging activity, free fatty acids and peroxide value) and sensory characteristics were studied at the interval of 45 days. RESULTS: The melting point of T1, T2, T3 and T4 developed in current investigation were 34.2, 33.8, 33.1 and 32.5 degrees C, respectively. The solid fat index of control, T1, T2, T3 and T4 were 47.21, 22.71, 20.33, 18.12 and 16.58%, respectively. The alpha-linolenic acid contents in T1, T2, T3 and T4 were found 2.92, 5.85, 9.22, 12.29%, respectively. The concentration of eicosanoic acid in T2, T3 and T4 was 1.82, 3.52, 6.43 and 9.81%, respectively. The content of docosahexanoic acid in T2, T3 and T4 was present 1.26, 2.64, 3.49 and 5.19%, respectively. The omega-3 fatty acids were not detected in the control sample. Total phenolic contents of control, T1, T2, T3 and T4 samples were 0.27, 2.22, 4.15, 7.23 and 11.42 mg GAE/mL, respectively. DPPH free radical scavenging activity for control, T1, T2, T3 and T4 was noted 65.8, 5.37, 17.82, 24.95, 45.42 and 62.8%, respectively. Chlorogenic acid, caffeic acid, quercetin, phenolic glycoside k and phenolic glycoside Q in T3 were present 0.78, 0.73, 1.82, 4.12 and 4.49 mg/mL, respectively. After 90 days of storage period, free fatty acids and peroxide value of all the treatments were less than 0.2 (% and MeqO2/kg). Sensory characteristics of treatments were not different from the control. CONCLUSION: Margarines supplemented with chia oil showed enhanced level of omega-3 fatty acids and antioxidant characteristics. These results suggest that chia oil can be used for formulation of margarine with increased level of omega-3 fatty acids and acceptable sensory characteristics. PMID- 28569165 TI - Getting off on the wrong foot? How community groups in Zimbabwe position themselves for partnerships with external agencies in the HIV response. AB - BACKGROUND: Partnerships are core to global public health responses. The HIV field embraces partnership working, with growing attention given to the benefits of involving community groups in the HIV response. However, little has been done to unpack the social psychological foundation of partnership working between well resourced organisations and community groups, and how community representations of partnerships and power asymmetries shape the formation of partnerships for global health. We draw on a psychosocial theory of partnerships to examine community group members' understanding of self and other as they position themselves for partnerships with non-governmental organisations. METHODS: This mixed qualitative methods study was conducted in the Matobo district of Matabeleland South province in Zimbabwe. The study draws on the perspectives of 90 community group members (29 men and 61 women) who participated in a total of 19 individual in-depth interviews and 9 focus group discussions (n = 71). The participants represented an array of different community groups and different levels of experience of working with NGOs. Verbatim transcripts were imported into Atlas.Ti for thematic indexing and analysis. RESULTS: Group members felt they played a central role in the HIV response. Accepting there is a limit to what they can do in isolation, they actively sought to position themselves as potential partners for NGOs. Partnerships with NGOs were said to enable community groups to respond more effectively as well as boost their motivation and morale. However, group members were also acutely aware of how they should act and perform if they were to qualify for a partnership. They spoke about how they had to adopt various strategies to become attractive partners and 'supportable' - including being active and obedient. CONCLUSIONS: Many community groups in Zimbabwe recognise their role in the HIV response and actively navigate representational systems of self and other to showcase themselves as capable actors. While this commitment is admirable, the dynamics that govern this process reflect knowledge encounters and power asymmetries that are conditioned by the aid architecture, undermining aspiring efforts for more equitable partnerships from the get-go. PMID- 28569166 TI - Influence of change of tunnel axis angle on tunnel length during double-bundle ACL reconstruction via the transportal technique. AB - BACKGROUND: Commercially available flexible reamer and curved guide systems allow a certain degree of control over intra-articular tunnel orientation, therefore allows a wide range of intra-osseous femoral tunnel orientations, contrary to the femoral tunneling technique using a straight guide pin, which are determined by knee flexion angle. We sought to find the clinical relevance of intra-osseous femoral tunnel orientations in the respect of tunnel length. To evaluate the relationship between the tunnel axis angle in three orthogonal planes and tunnel length in the anteromedial (AM) and posterolateral (PL) femoral tunnels in patients who underwent anatomic double-bundle anterior cruciate ligament reconstruction (DB-ACLR) using the transportal (TP) technique with a 42o curved guide. METHODS: A total of 40 patients who underwent primary DB-ACLR with the TP technique using a curved guide were evaluated retrospectively. The tunnel axis angle in three orthogonal planes were evaluated on a three-dimensional surface model constructed using an axial computed tomography scan obtained after reconstruction. Then, correlations with tunnel length were analyzed. RESULTS: In the AM tunnel, tunnel axis angles in the coronal (beta = 0.0252, p = 0.022) and sagittal (beta = 0.0168, p = 0.029) plane showed significant correlations with tunnel length, while the axial plane did not (p = 0.493) (adjusted R2 = 0.801). In the PL tunnel, only tunnel axis angles in the axial plane (beta = 0.0262, p = 0.008) showed a significant relationship with tunnel length (adjusted R2 = 0.700). CONCLUSION: Drilling at a higher angle in the coronal and sagittal planes in AM tunnels and at a higher angle in the axial plane in PL tunnels decreases the incidence of short femoral tunnels. PMID- 28569167 TI - Increased serum concentrations of IL-1 beta, IL-21 and Th17 cells in overweight patients with rheumatoid arthritis. AB - BACKGROUNDS: Obesity is associated with worse disease activity and drug responses in patients with rheumatoid arthritis (RA). However, the immunological mechanisms responsible for the relationship between RA and obesity have not yet been clarified in detail. This study aimed to elucidate the immunological mechanisms contributing to the pathogenesis of RA in overweight patients. METHODS: The frequencies of CD4+ T cell, B cell and monocyte subsets were analyzed in RA (n = 81) and healthy donors (n = 99) by flow cytometry, and were compared between three groups (body mass index (BMI) <20, >=20 to 25, >25). Serum cytokines were measured using multiplex ELISA. Gene expression was analyzed by quantitative PCR. Clinical information was extracted from medical records. RESULTS: The frequencies of T helper (Th)17 (CD4+CD45RA-CXCR5-CXCR3-CCR6+) cells and plasmablasts (PB) were significantly increased in patients with RA with BMI >25. Significant correlation was observed between BMI and Th17 cells in patients with RA. No significant differences in cell frequencies between the three BMI groups were observed in the healthy donors. Serum interleukin (IL)-1beta and IL-21 significantly correlated with BMI in RA patients. Gene expression patterns in Th17 cells from overweight patients with RA showed the characteristics of pathogenic Th17 cells. CONCLUSIONS: Quantitative and qualitative changes in Th17 cells were characteristic in overweight patients with RA. PMID- 28569168 TI - Construct design, production, and characterization of Plasmodium falciparum 48/45 R0.6C subunit protein produced in Lactococcus lactis as candidate vaccine. AB - BACKGROUND: The sexual stages of Plasmodium falciparum are responsible for the spread of the parasite in malaria endemic areas. The cysteine-rich Pfs48/45 protein, exposed on the surface of sexual stages, is one of the most advanced antigens for inclusion into a vaccine that will block transmission. However, clinical Pfs48/45 sub-unit vaccine development has been hampered by the inability to produce high yields of recombinant protein as the native structure is required for the induction of functional transmission-blocking (TB) antibodies. We have investigated a downstream purification process of a sub-unit (R0.6C) fragment representing the C-terminal 6-Cys domain of Pfs48/45 (6C) genetically fused to the R0 region (R0) of asexual stage Glutamate Rich Protein expressed in Lactococcus lactis. RESULTS: A series of R0.6C fusion proteins containing features, which aim to increase expression levels or to facilitate protein purification, were evaluated at small scale. None of these modifications affected the overall yield of recombinant protein. Consequently, R0.6C with a C-terminal his tag was used for upstream and downstream process development. A simple work flow was developed consisting of batch fermentation followed by two purification steps. As such, the recombinant protein was purified to homogeneity. The composition of the final product was verified by HPLC, mass spectrometry, SDS PAGE and Western blotting with conformation dependent antibodies against Pfs48/45. The recombinant protein induced high levels of functional TB antibodies in rats. CONCLUSIONS: The established production and purification process of the R0.6C fusion protein provide a strong basis for further clinical development of this candidate transmission blocking malaria vaccine. PMID- 28569169 TI - High-biologically effective dose palliative radiotherapy for a tumor thrombus might improve the long-term prognosis of hepatocellular carcinoma: a retrospective study. AB - BACKGROUND: This study aimed to highlight the type of tumor thrombus and identify the prognostic factors influencing the long-term survival outcomes in patients with hepatocellular carcinoma (HCC) having a tumor thrombus. A tumor thrombus in HCC is associated with poor prognosis. METHODS: Eighty patients diagnosed with HCC having a tumor thrombus between May 2006 and April 2014 were enrolled in this study. Age, gender, clinical characteristics, laboratory findings, Child-Pugh classification, performance status (ECOG), types of tumor thrombi, radiotherapy method, biologically effective dose (BED), and primary treatment method were analyzed to identify the prognostic factors associated with the overall survival (OS) rates. Statistical analyses were performed using SPSS version 19.0. RESULTS: The median follow-up duration was 24 months (range 6-90). The 1-, 3-, and 5-year OS rates of the patients were 77.6%, 37.6%, and 18.8%, respectively. On univariate analysis, gender, radiotherapy method, BED, types of tumor thrombi, Child-Pugh classification, ECOG, and total bilirubin were associated with OS (P < 0.001, P = 0.001, P = 0.016, P = 0.003, P < 0.001, P < 0.001, P = 0.039, respectively). The prognostic factors for OS in multi-variate analyses were gender (P < 0.001), BED (P = 0.044), Child Pugh classification (P = 0.020), performance status (ECOG) (P = 0.004), and types of tumor thrombi (P = 0.001). The median OS for the high-BED group was better than that for the low-BED groups (42 months vs. 19 months, P = 0.016). CONCLUSIONS: Gender, BED, performance status (ECOG), Child-Pugh classification, and types of tumor thrombi seemed to affect OS, and a stepwise decrease in survival was observed with the types of tumor thrombi ranging from I to IV. High-BED palliative radiotherapy might improve the long-term outcomes for patients with HCC having a tumor thrombus. PMID- 28569170 TI - The developmental regulator PKL is required to maintain correct DNA methylation patterns at RNA-directed DNA methylation loci. AB - BACKGROUND: The chromodomain helicase DNA-binding family of ATP-dependent chromatin remodeling factors play essential roles during eukaryote growth and development. They are recruited by specific transcription factors and regulate the expression of developmentally important genes. Here, we describe an unexpected role in non-coding RNA-directed DNA methylation in Arabidopsis thaliana. RESULTS: Through forward genetic screens we identified PKL, a gene required for developmental regulation in plants, as a factor promoting transcriptional silencing at the transgenic RD29A promoter. Mutation of PKL results in DNA methylation changes at more than half of the loci that are targeted by RNA-directed DNA methylation (RdDM). A small number of transposable elements and genes had reduced DNA methylation correlated with derepression in the pkl mutant, though for the majority, decreases in DNA methylation are not sufficient to cause release of silencing. The changes in DNA methylation in the pkl mutant are positively correlated with changes in 24-nt siRNA levels. In addition, PKL is required for the accumulation of Pol V-dependent transcripts and for the positioning of Pol V-stabilized nucleosomes at several tested loci, indicating that RNA polymerase V-related functions are impaired in the pkl mutant. CONCLUSIONS: PKL is required for transcriptional silencing and has significant effects on RdDM in plants. The changes in DNA methylation in the pkl mutant are correlated with changes in the non-coding RNAs produced by Pol IV and Pol V. We propose that at RdDM target regions, PKL may be required to create a chromatin environment that influences non-coding RNA production, DNA methylation, and transcriptional silencing. PMID- 28569172 TI - Results of the Schirmer tear test performed with open and closed eyes in clinically normal horses. AB - BACKGROUND: The Schirmer tear test (STT) is widely used in both human and veterinary ophthalmology. Two types of STTs have been developed: STT I and SST II. The STT I measures the basal and reflex tear production and is the most widely used STT. However, several factors influence the STT results such as the person performing the test and the location of the strip placement within the conjunctival sac. The aim of this study was to measure the basal and reflex tear production (STT I) in clinically normal horses with open versus closed eyes. RESULTS: Forty clinically healthy horses without any ocular diseases were included. On day 1, the STT I was first performed on all the horses with the eyes open followed by an STT I with closed eyes performed 30 min later. On day 2, all horses had their eyes closed during the first STT and the eyes open during the second test performed 30 min later. The mean value of the STTs performed on open eye was significantly less than the STT performed on closed eye on both days of examination. CONCLUSION: This study showed a small but statistically significant difference between STT values obtained with open versus closed eyes in clinically normal horses. PMID- 28569171 TI - Oral mucosal lesions in teenagers: a cross-sectional study. AB - BACKGROUND: Adolescence is a period of transition to adulthood. Little is known about oral mucosal lesions (OMLs) in teenagers, in which the emergence of new habits, unfamiliar to children, could affect the type of lesions. The aim of this study was to evaluate the distribution of oral mucosal lesions (OMLs) in a wide sample of adolescents. METHODS: A retrospective cross-sectional study was carried out examining all medical records of adolescents (aged 13-18 years) treated at the Dental Clinic of the University of Brescia (Italy) in the period from 2008 to 2014. Cases with OMLs were selected. Data regarding age, gender, type of OML, bad habits, systemic chronic diseases were collected. RESULTS: A total of 6.374 medical records (mean age 15.2 + -1.7 years) were examined. We found 1544 cases (31.7%) of oral mucosal lesions; 36 different types of mucosal alterations were detected and the most frequent were: aphthous ulcers (18%), traumatic ulcerations (14.3%), herpes simplex virus (11%), geographic tongue (9.6%), candidiasis (5.5%), and morsicatio buccarum (4.7%). Papilloma virus lesions (1.7%), piercing related lesions (4%), multiform erythema (0.13%), oral lichen planus (0.13%) and granular cell tumour (0.06%) were also diagnosed. CONCLUSIONS: The prevalence of OMLs in adolescents are different from those in children and, in some conditions, it could increase with age. PMID- 28569173 TI - ApoE isoforms differentially regulates cleavage and secretion of BDNF. AB - Apolipoprotein E4 (ApoE4) is a major genetic risk factor for sporadic or late onset Alzheimer's disease (AD). Brain-derived neurotrophic factor (BDNF) is decreased by 3 to 4-fold in the brains of AD patients at autopsy. ApoE4 mice also have reduced BDNF levels. However, there have been no reports relating the different ApoE isoforms or AD to differential regulation of BDNF. Here we report that in the hippocampal regions of AD patients both prepro-BDNF and pro-BDNF expression showed a 40 and 60% decrease respectively compared to that expression in the hippocampi of age-matched control patients. We further report that ApoE isoforms differentially regulate maturation and secretion of BDNF from primary human astrocytes. After 24 h, ApoE3 treated astrocytes secreted 1.75- fold higher pro-BDNF than ApoE2-treated astrocytes, and ApoE2-treated astrocytes secreted 3 fold more mature-BDNF (m-BDNF) than ApoE3-treated astrocytes. In contrast, ApoE4 treated cells secreted negligible amounts of m-BDNF or pro-BDNF. ApoE2 increased the level of intracellular pre-pro BDNF by 19.04 +/- 6.68%, while ApoE4 reduced the pre-pro BDNF by 21.61 +/- 5.9% compared to untreated cells. Similar results were also seen in ApoE2, ApoE3 or ApoE4 treated cells at 4 h. Together, these results indicate that an ApoE2 or ApoE3 mediated positive regulation of BDNF may be protective while ApoE4 related defects in BDNF processing could lead to AD pathophysiology. These interactions of the ApoE isoforms with BDNF may help explain the increased risk of AD associated with the ApoE4 isoform. PMID- 28569174 TI - Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus. AB - BACKGROUND: In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm), one of the most pathogenic parasites of ruminants. METHODS: In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus. RESULTS: Amongst the 55 compounds, we identified two compounds (designated a-15 and a-17) that reproducibly inhibit xL3 motility as well as L4 motility and development, with IC50 values ranging between ~3.4 and 55.6 MUM. We studied the effect of these two 'hit' compounds on mitochondrial function by measuring oxygen consumption. This assessment showed that xL3s exposed to each of these compounds consumed significantly less oxygen and had less mitochondrial activity than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. CONCLUSIONS: The present findings provide a sound basis for future work, aimed at identifying the targets of compounds a-15 and a-17 and establishing the modes of action of these chemicals in H. contortus. PMID- 28569175 TI - Effects of sublethal exposure to metofluthrin on the fitness of Aedes aegypti in a domestic setting in Cairns, Queensland. AB - BACKGROUND: Metofluthrin is highly effective at reducing biting activity in Aedes aegypti. Its efficacy lies in the rapid onset of confusion, knockdown, and subsequent kill of a mosquito. In the field, there are a variety of scenarios that might result in sublethal exposure to metofluthrin, including mosquitoes that are active at the margins of the chemical's lethal range, brief exposure as mosquitoes fly in and out of treated spaces or decreasing efficacy of the emanators with time. Sublethal effects are key elements of insecticide exposure and selection. METHODS: The metofluthrin dose for each treatment group of male and female Ae. aegypti was controlled using exposure time intervals to a 10% active ingredient (AI) metofluthrin emanator. Room size and distance from the emanator for all groups was maintained at 3 m. In bioassay cages, male Ae. aegypti were exposed at 0, 5, 10, 20, 30 and 40-min intervals. Females were exposed in bioassay cages at 0, 10, 20, 30, 40 and 60-min intervals. Mortality rates and fecundity were observed between the exposure time groups for both sexes. RESULTS: Female Ae. aegypti exposed for 60 min had a significantly higher mortality rate (50%), after a 24-h recovery period, than other exposure times, 10, 20, 30 and 40 min (P < 0.001). An overall difference in fecundity was not observed in females between treatments. A significant effect on male mortality was only observed at 40 min exposure times, three meters from the 10% AI emanator [Formula: see text]. Males that survived metofluthrin exposure were as likely to produce viable eggs with an unexposed female as males that had not been exposed (P > 0.05). CONCLUSION: Regardless of sex, if a mosquito survived exposure, it would be as biologically successful as its unexposed counterpart. Portability of the metofluthrin emanator and delayed knockdown effects create opportunities for sublethal exposure and potential pyrethroid resistance development in Ae. aegypti, and should be taken into consideration in recommendations for field application of this product, including minimum exposure periods and a prescribed number of emanators per room based on volume. PMID- 28569177 TI - Serological and molecular detection of spotted fever group Rickettsia in a group of pet dogs from Luanda, Angola. AB - BACKGROUND: Infections with tick-borne rickettsiae can cause diseases well known in humans but still not so well characterized in dogs. Susceptibility to infection depends on the virulence of Rickettsia spp. and only a few of them have been described to cause disease in dogs. The aim of this study was to investigate the exposure to Rickettsia spp. among a group of pet dogs from Luanda, Angola. RESULTS: Out of 103 dogs included in the study, 62 (60.2%) were infested with ticks. Plasma specimens tested for serology by an immunofluorescence assay (IFA) revealed that six (5.8%) dogs had detectable immunoglobulin G (IgG) antibodies to spotted fever group Rickettsia (SFGR), with endpoint titers of 64 for two dogs, 128 for three dogs and 1024 for one dog. From the seropositive group of dogs, five (83%) of them were males, with their age ranging from 1 to 8 years old. Among the seropositive dogs, four (66.7%) were parasitized with ticks and no breed (or cross) was found to be associated with specific antibodies. Rickettsia spp. DNA was detected by nested-polymerase chain reaction (PCR) in two (1.9%) dogs that were found to be seronegative. CONCLUSIONS: Seroprevalence and molecular detection of Rickettsia spp. infection in this group of pet dogs from Luanda is low compared with other studies performed in the same type of hosts in other areas. Although many dogs were parasitized with ticks, a low prevalence of Rickettsia spp. could be related with the hypothesis of a low rickettsial prevalence in the infesting ticks. This study provides evidence that dogs in Luanda are exposed to Rickettsia spp., but further studies are needed to better characterize the bacterial infections in dogs and in their ectoparasites. PMID- 28569178 TI - Prediction of response to remission induction therapy by gene expression profiling of peripheral blood in Japanese patients with microscopic polyangiitis. AB - BACKGROUND: Microscopic polyangiitis (MPA), which is classified as an anti neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis, is one of the most frequent primary vasculitides in Japan. We earlier nominated 16 genes (IRF7, IFIT1, IFIT5, OASL, CLC, GBP-1, PSMB9, HERC5, CCR1, CD36, MS4A4A, BIRC4BP, PLSCR1, DEFA1/DEFA3, DEFA4, and COL9A2) as predictors of response to remission induction therapy against MPA. The aim of this study is to determine the accuracy of prediction using these 16 predictors. METHODS: Thirty-nine MPA patients were selected randomly and retrospectively from the Japanese nationwide RemIT-JAV-RPGN cohort and enrolled in this study. Remission induction therapy was conducted according to the Guidelines of Treatment for ANCA-Associated Vasculitis published by the Ministry of Health, Labour, and Welfare of Japan. Response to remission induction therapy was predicted by profiling the altered expressions of the 16 predictors between the period before and 1 week after the beginning of treatment. Remission is defined as the absence of clinical manifestations of active vasculitis (Birmingham Vasculitis Activity Score 2003: 0 or 1 point). Persistent remission for 18 months is regarded as a "good response," whereas no remission or relapse after remission is regarded as a "poor response." RESULTS: "Poor" and "good" responses were predicted in 7 and 32 patients, respectively. Five out of 7 patients with "poor" prediction and 1 out of 32 patients with "good" prediction experienced relapse after remission. One out of 7 patients with "poor" prediction was not conducted to remission. Accordingly, the sensitivity and specificity to predict poor response was 85.7% (6/7) and 96.9% (31/32), respectively. CONCLUSIONS: Response to remission induction therapy can be predicted by monitoring the altered expressions of the 16 predictors in the peripheral blood at an early point of treatment in MPA patients. PMID- 28569176 TI - Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis. AB - An increasing number of studies show how changes in intracellular metabolic pathways alter tumor and immune cell function. However, little information about metabolic changes in other cell types, including synovial fibroblasts, is available. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) are the most common cell type at the pannus-cartilage junction and contribute to joint destruction through their production of cytokines, chemokines, and matrix degrading molecules and by migrating and invading joint cartilage. In this review, we show that these cells differ from healthy synovial fibroblasts, not only in their marker expression, proto-oncogene expression, or their epigenetic changes, but also in their intracellular metabolism. These metabolic changes must occur due to the stressful microenvironment of inflamed tissues, where concentrations of crucial nutrients such as glucose, glutamine, and oxygen are spatially and temporally heterogeneous. In addition, these metabolic changes will increase metabolite exchange between fibroblast and other synovial cells, which can potentially be activated. Glucose and phospholipid metabolism as well as bioactive lipids, including sphingosine-1-phosphate and lysophosphatidic acid, among others, are involved in FLS activation. These metabolic changes likely contribute to FLS involvement in aspects of immune response initiation or abnormal immune responses and strongly contribute to joint destruction. PMID- 28569179 TI - Immunolocation and enzyme activity analysis of Cryptosporidium parvum enolase. AB - BACKGROUND: Enolase is an essential multifunctional glycolytic enzyme that is involved in many biological processes of apicomplexan protozoa, such as adhesion and invasion. However, the characteristics of enolase in Cryptosporidium parvum, including the location on the oocyst and the enzyme activity, remain unclear. METHODS: The C. parvum enolase gene (cpeno) was amplified by RT-PCR and sequenced. The deduced amino acid sequence was analysed by bioinformatics software. The gene was expressed in Escherichia coli BL21 (DE3) and purified recombinant protein was used for enzyme activity analysis, binding experiments and antibody preparation. The localisation of enolase on oocysts was examined via immunofluorescence techniques. RESULTS: A 1,350 bp DNA sequence was amplified from cDNA taken from C. parvum oocysts. The deduced amino acids sequence of C. parvum enolase (CpEno) had 82.1% homology with Cryptosporidium muris enolase, and 54.7-68.0% homology with others selected species. Western blot analysis indicated that recombinant C. parvum enolase (rCpEno) could be recognised by C. parvum infected cattle sera. Immunolocalization testing showed that CpEno was found to locate mainly on the surface of oocysts. The enzyme activity was 33.5 U/mg, and the Michaelis constant (K m ) was 0.571 mM/l. Kinetic measurements revealed that the most suitable pH value was 7.0-7.5, and there were only minor effects on the activity of rCpEno with a change in the reaction temperature. The enzyme activity decreased when the Ca2+, K+, Mg2+ and Na+ concentrations of the reaction solution increased. The binding assays demonstrated that rCpEno could bind to human plasminogen. CONCLUSION: This study is the first report of immunolocation, binding activity and enzyme characteristics of CpEno. The results of this study suggest that the surface-associated CpEno not only functions as a glycolytic enzyme but may also participate in attachment and invasion process of the parasite. PMID- 28569180 TI - Rotational restriction of nascent peptides as an essential element of co translational protein folding: possible molecular players and structural consequences. AB - BACKGROUND: A basic tenet of protein science is that all information about the spatial structure of proteins is present in their sequences. Nonetheless, many proteins fail to attain native structure upon experimental denaturation and refolding in vitro, raising the question of the specific role of cellular machinery in protein folding in vivo. Recently, we hypothesized that energy dependent twisting of the protein backbone is an unappreciated essential factor guiding the protein folding process in vivo. Torque force may be applied by the ribosome co-translationally, and when accompanied by simultaneous restriction of the rotational mobility of the distal part of the growing chain, the resulting tension in the protein backbone would facilitate the formation of local secondary structure and direct the folding process. RESULTS: Our model of the early stages of protein folding in vivo postulates that the free motion of both terminal regions of the protein during its synthesis and maturation is restricted. The long-known but unexplained phenomenon of statistical overrepresentation of protein termini on the surfaces of the protein structures may be an indication of the backbone twist-based folding mechanism; sustained maintenance of a twist requires that both ends of the protein chain are anchored in space, and if the ends are released only after the majority of folding is complete, they are much more likely to remain on the surface of the molecule. We identified the molecular components that are likely to play a role in the twisting of the nascent protein chain and in the anchoring of its N-terminus. The twist may be induced at the C terminus of the nascent polypeptide by the peptidyltransferase center of the ribosome. Several ribosome-associated proteins, including the trigger factor in bacteria and the nascent polypeptide-associated complex in archaea and eukaryotes, may restrict the rotational mobility of the N-proximal regions of the peptides. CONCLUSIONS: Many experimental observations are consistent with the hypothesis of co-translational twisting of the protein backbone. Several molecular players in this hypothetical mechanism of protein folding can be suggested. In addition, the new view of protein folding in vivo opens the possibility of novel potential drug targets to combat human protein folding diseases. REVIEWERS: This article was reviewed by Lakshminarayan Iyer and Istvan Simon. PMID- 28569181 TI - The cost of severe haemophilia in Europe: the CHESS study. AB - BACKGROUND: Severe haemophilia is associated with major psychological and economic burden for patients, caregivers, and the wider health care system. This burden has been quantified and documented for a number of European countries in recent years. However, few studies have taken a standardised methodology across multiple countries simultaneously, and sought to amalgamate all three levels of burden for severe disease. The overall aim of the 'Cost of Haemophilia in Europe: a Socioeconomic Survey' (CHESS) study was to capture the annualised economic and psychosocial burden of severe haemophilia in five European countries. A cross section of haemophilia specialists (surveyed between January and April 2015) provided demographic and clinical information and 12-month ambulatory and secondary care activity for patients via an online survey. In turn, patients provided corresponding direct and indirect non-medical cost information, including work loss and out-of-pocket expenses, as well as information on quality of life and adherence. The direct and indirect costs for the patient sample were calculated and extrapolated to population level. RESULTS: Clinical reports for a total of 1,285 patients were received. Five hundred and fifty-two patients (43% of the sample) provided information on indirect costs and health-related quality of life via the PSC. The total annual cost of severe haemophilia across the five countries for 2014 was estimated at EUR 1.4 billion, or just under EUR 200,000 per patient. The highest per-patient costs were in Germany (mean EUR 319,024) and the lowest were in the United Kingdom (mean EUR 129,365), with a study average of EUR 199,541. As expected, consumption of clotting factor replacement therapy represented the vast majority of costs (up to 99%). Indirect costs are driven by patient and caregiver work loss. CONCLUSIONS: The results of the CHESS study reflect previous research findings suggesting that costs of factor replacement therapy account for the vast majority of the cost burden in severe haemophilia. However, the importance of the indirect impact of haemophilia on the patient and family should not be overlooked. The CHESS study highlights the benefits of observational study methodologies in capturing a 'snapshot' of information for patients with rare diseases. PMID- 28569182 TI - A pharmacogenetic signature of high response to Copaxone in late-phase clinical trial cohorts of multiple sclerosis. AB - BACKGROUND: Copaxone is an efficacious and safe therapy that has demonstrated clinical benefit for over two decades in patients with relapsing forms of multiple sclerosis (MS). On an individual level, patients show variability in their response to Copaxone, with some achieving significantly higher response levels. The involvement of genes (e.g., HLA-DRB1*1501) with high inter-individual variability in Copaxone's mechanism of action (MoA) suggests the potential contribution of genetics to treatment response. This study aimed to identify genetic variants associated with Copaxone response in patient cohorts from late phase clinical trials. METHODS: Single nucleotide polymorphisms (SNPs) associated with high and low levels of response to Copaxone were identified using genome wide SNP data in a discovery cohort of 580 patients from two phase III clinical trials of Copaxone. Multivariable Bayesian modeling on the resulting SNPs in an expanded discovery cohort with 1171 patients identified a multi-SNP signature of Copaxone response. This signature was examined in 941 Copaxone-treated MS patients from seven independent late-phase trials of Copaxone and assessed for specificity to Copaxone in 310 Avonex-treated and 311 placebo-treated patients, also from late-phase trials. RESULTS: A four-SNP signature consisting of rs80191572 (in UVRAG), rs28724893 (in HLA-DQB2), rs1789084 (in MBP), and rs139890339 (in ZAK(CDCA7)) was identified as significantly associated with Copaxone response. Copaxone-treated signature-positive patients had a greater reduction in annualized relapse rate (ARR) compared to signature-negative patients in both discovery and independent cohorts, an effect not observed in Avonex-treated patients. Additionally, signature-positive placebo-treated cohorts did not show a reduction in ARR, demonstrating the predictive as opposed to prognostic nature of the signature. A 10% subset of patients, delineated by the signature, showed marked improvements across multiple clinical parameters, including ARR, MRI measures, and higher proportion with no evidence of disease activity (NEDA). CONCLUSIONS: This study is the largest pharmacogenetic study in MS reported to date. Gene regions underlying the four-SNP signature have been linked with pathways associated with either Copaxone's MoA or the pathophysiology of MS. The pronounced association of the four-SNP signature with clinical improvements in a ~10% subset of the MS patient population demonstrates the complex interplay of immune mechanisms and the individualized nature of response to Copaxone. PMID- 28569183 TI - The work experience of a patient affected by Williams Syndrome: a pilot project at the Bambino Gesu Children's Hospital. AB - A new approach has been designed at the Bambino Gesu Children's Hospital in Rome aimed at increasing empowerment in Williams Syndrome individuals through tutor assisted work activities. Williams Syndrome is characterized by a combination of distinguishing physical traits, congenital anomalies, intellectual disabilities, and a specific developmental profile.This manuscript describes the case of a Williams Syndrome patient.There are only few papers in the scientific literature describing interventions targeting improvement in the quality of life of adult Williams Syndrome individuals. Therefore, this experience may prove useful to several patients, their families, and the experts helping them.We described an example of intervention aimed at guiding and facilitating a Williams Syndrome patient within a work environment, taking into consideration the peaks and valleys of these individuals' specific abilities.Based on our results, we also stressed the need to promote a set of projects and initiatives aimed at enhancing as much as possible self-sufficiency and psycho-affective balance in Williams Syndrome individuals, in order to protect their dignity and self-esteem. PMID- 28569184 TI - Large schwannoma of the femur - a common tumor at an unusual site: a case report and review of the literature. AB - BACKGROUND: Schwannomas are benign nerve sheath tumors and are most frequently encountered as soft tissue tumors of peripheral nerves of the head and neck or the extensor extremities. Osseous involvement is very uncommon with fewer than 200 cases described in the world literature, the majority of which arise in the skull (including mandible), vertebrae, and sacrum. Long bone involvement is highly unusual and of the approximately 20 cases described thus far, only five have been documented to arise in the femur. We describe an unusually large schwannoma of the femur which was discovered incidentally and was diagnosed only after biopsy, given the rarity of this tumor at that particular site. Following prophylactic internal fixation and bone grafting, our patient remains well and disease-free, 2.5 years later. CASE PRESENTATION: A 56-year-old Sri Lankan woman was discovered to have a large lytic lesion in her lower femur on routine X-ray following a fall. A history and physical examination, along with selective imaging and tissue sampling, were necessary to arrive at the diagnosis of schwannoma of the femur. The clinical presentation, radiology, pathology, and surgical management are discussed and contrasted with the other five cases documented in the literature. The tumor was successfully treated with evacuation through a lateral surgical approach and internal fixation. She remains well and disease-free 2.5 years later. CONCLUSIONS: We present the case of an unusually large lytic lesion found incidentally in the femur of a 56-year-old woman, which was subsequently diagnosed to be a schwannoma on biopsy. Its exceptional rarity in long bones makes it less likely to be considered in an initial differential diagnosis, and we stress the importance of tissue biopsy for diagnosis. PMID- 28569185 TI - The impact of poverty on dog ownership and access to canine rabies vaccination: results from a knowledge, attitudes and practices survey, Uganda 2013. AB - BACKGROUND: Rabies is a neglected disease despite being responsible for more human deaths than any other zoonosis. A lack of adequate human and dog surveillance, resulting in low prioritization, is often blamed for this paradox. Estimation methods are often employed to describe the rabies burden when surveillance data are not available, however these figures are rarely based on country-specific data. METHODS: In 2013 a knowledge, attitudes, and practices survey was conducted in Uganda to understand dog population, rabies vaccination, and human rabies risk factors and improve in-country and regional rabies burden estimates. Poisson and multi-level logistic regression techniques were conducted to estimate the total dog population and vaccination coverage. RESULTS: Twenty four villages were selected, of which 798 households completed the survey, representing 4 375 people. Dog owning households represented 12.9% of the population, for which 175 dogs were owned (25 people per dog). A history of vaccination was reported in 55.6% of owned dogs. Poverty and human population density highly correlated with dog ownership, and when accounted for in multi level regression models, the human to dog ratio fell to 47:1 and the estimated national canine-rabies vaccination coverage fell to 36.1%. This study estimates there are 729 486 owned dogs in Uganda (95% CI: 719 919 - 739 053). Ten percent of survey respondents provided care to dogs they did not own, however unowned dog populations were not enumerated in this estimate. 89.8% of Uganda's human population was estimated to reside in a community that can support enzootic canine rabies transmission. CONCLUSIONS: This study is the first to comprehensively evaluate the effect of poverty on dog ownership in Africa. These results indicate that describing a dog population may not be as simple as applying a human: dog ratio, and factors such as poverty are likely to heavily influence dog ownership and vaccination coverage. These modelled estimates should be confirmed through further field studies, however, if validated, canine rabies elimination through mass vaccination may not be as difficult as previously considered in Uganda. Data derived from this study should be considered to improve models for estimating the in-country and regional rabies burden. PMID- 28569186 TI - Patterns of regional recurrence in papillary thyroid cancer patients with lateral neck metastases undergoing neck dissection. AB - BACKGROUND: Practice variability exists for the extent of neck dissection undertaken for papillary thyroid carcinoma (PTC) metastatic to the lateral neck nodes, with disagreement over routine level V dissection. METHODS: We performed a retrospective medical record review of PTC patients with lateral neck nodal metastases treated at University Health Network from 2000 to 2012. Predictive factors for regional neck recurrence, including extent of initial neck dissection, were analyzed using Cox regression. RESULTS: Out of 204 neck dissections in 178 patients, 110 (54%) underwent selective and 94 (46%) had comprehensive dissection including level Vb. Mean follow-up was 6.3 years (SD). Significant predictors of regional failure were the total number of suspicious nodes on preoperative imaging (p = 0.029), largest positive node on initial neck dissection (p < 0.01), and whether patients received adjuvant radiotherapy (p = 0.028). The 5-year ipsilateral regional recurrence rate was 8 and 9% with selective and comprehensive dissection, respectively (p = 0.89). CONCLUSION: The extent of neck dissection did not predict the probability of regional recurrence in PTC patients presenting with lateral neck metastases. PMID- 28569188 TI - Clustering and correlates of screen-time and eating behaviours among young adolescents. AB - BACKGROUND: Screen-time and eating behaviours are associated in adolescents, but few studies have examined the clustering of these health behaviours in this age group. The identification of clustered health behaviours, and influences on adolescents' clustered health behaviours, at the time when they are most likely to become habitual, is important for intervention design. The purpose of this study was to assess the prevalence and clustering of health behaviours in adolescents, and examine the sociodemographic, individual, behavioural, and home social and physical environmental correlates of clustered health behaviours. METHODS: Adolescents aged 11-12 years (n = 527, 48% boys) completed a questionnaire during class-time which assessed screen-time (ST), fruit and vegetable (FV), and energy-dense (ED) snack consumption using a Food Frequency Questionnaire. Health behaviours were categorised into high and low frequencies based on recommendations for FV and ST and median splits for ED snacks. Adolescents reported on their habits, self-efficacy, eating at the television (TV), eating and watching TV together with parents, restrictive parenting practices, and the availability and accessibility of foods within the home. Behavioural clustering was assessed using an observed over expected ratio (O/E). Correlates of clustered behaviours were examined using multivariate multinomial logistic regression. RESULTS: Approximately 70% reported having two or three health risk behaviours. Overall, O/E ratios were close to 1, which indicates clustering. The three risk behaviour combination of low FV, high ED, and high ST occurred more frequently than expected (O/E ratio = 1.06 95% CI 1.01, 1.15. Individual, behavioural, and social and physical home environmental correlates were differentially associated with behavioural clusters. Correlates consistently associated with clusters included eating ED snacks while watching TV, eating at the TV with parents, and the availability and accessibility of ED snack foods within the home. CONCLUSIONS: There is a high prevalence of screen time and unhealthy eating, and screen time is coupled with unhealthy dietary behaviours. Strategies and policies are required that simultaneously address reductions in screen time and changes to habitual dietary patterns, such as TV snacking and snack availability and accessibility. These may require a combination of individual, social and environmental changes alongside conscious and more automatic (nudging) strategies. PMID- 28569187 TI - The effects of acute renal denervation on kidney perfusion and metabolism in experimental septic shock. AB - BACKGROUND: Perfusion deficits likely play an important role in the development of renal dysfunction in sepsis. Renal denervation may improve kidney perfusion and metabolism. METHODS: We randomized 14 female sheep to undergo bilateral surgical renal denervation (n = 7) or sham procedure (n = 7) prior to induction of sepsis. Renal blood flow (RBF) was measured with a pre-calibrated flowprobe. Laser Doppler probes were implanted to measure cortical and medullary perfusion. Cortical glucose, lactate and pyruvate levels were measured using the microdialysis technique. Creatinine clearance was determined. Sepsis was induced by peritonitis and fluid resuscitation was provided to avoid hypovolemia. RESULTS: RBF and cortical perfusion were higher in the denervated group during the first 6 h after induction of sepsis (P < 0.001 and P < 0.05, respectively), while medullary perfusion decreased similarly in both groups. After hypotension developed, RBF decreased to similar levels in both groups. Cortical pyruvate and lactate levels were lower in the denervated animals (P < 0.001 and P < 0.001, respectively). There were no differences between groups in creatinine clearance, urine output or time to oliguria. CONCLUSION: Denervation thus caused an early increase in RBF that was distributed towards the kidney cortex. Although associated with an attenuation of early cortical metabolic alterations, denervation failed to prevent the deterioration in renal function. PMID- 28569189 TI - Experimental infections of mosquitoes with severe fever with thrombocytopenia syndrome virus. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a newly identified emerging infectious disease, which is caused by a novel bunyavirus (termed SFTSV) in Asia. Although mosquitoes have not been identified as the primary vectors, as revealed by epidemiological surveys, their role in transmitting this SFTSV as a suspicious vector has not been validated. FINDINGS: In this study, we conducted experimental infections of mosquitoes with SFTSV to examine the role of mosquitoes in the transmission of the virus. We did not detect viral replication in Culex pipiens pallens, Aedes aegyptis and Anopheles sinensis as revealed by qRT-PCR assay. In addition, we failed to isolate SFTSV from the Vero cells cultured with suspensions of SFTSV-infected mosquitoes. CONCLUSION: The results of the present study demonstrate little possibility that mosquitoes act as vectors for the emerging pathogen SFTSV. PMID- 28569190 TI - Single-cell mRNA profiling reveals transcriptional heterogeneity among pancreatic circulating tumour cells. AB - BACKGROUND: Single-cell mRNA profiling of circulating tumour cells may contribute to a better understanding of the biology of these cells and their role in the metastatic process. In addition, such analyses may reveal new knowledge about the mechanisms underlying chemotherapy resistance and tumour progression in patients with cancer. METHODS: Single circulating tumour cells were isolated from patients with locally advanced or metastatic pancreatic cancer with immuno-magnetic depletion and immuno-fluorescence microscopy. mRNA expression was analysed with single-cell multiplex RT-qPCR. Hierarchical clustering and principal component analysis were performed to identify expression patterns. RESULTS: Circulating tumour cells were detected in 33 of 56 (59%) examined blood samples. Single-cell mRNA profiling of intact isolated circulating tumour cells revealed both epithelial-like and mesenchymal-like subpopulations, which were distinct from leucocytes. The profiled circulating tumour cells also expressed elevated levels of stem cell markers, and the extracellular matrix protein, SPARC. The expression of SPARC might correspond to an epithelial-mesenchymal transition in pancreatic circulating tumour cells. CONCLUSION: The analysis of single pancreatic circulating tumour cells identified distinct subpopulations and revealed elevated expression of transcripts relevant to the dissemination of circulating tumour cells to distant organ sites. PMID- 28569191 TI - The strategic framework of tuberculosis control and prevention in the elderly: a scoping review towards End TB targets. AB - With the rapid pace of population ageing, tuberculosis (TB) in the elderly increasingly becomes a public health challenge. Despite the increasing burden and high risks for TB in the elderly, targeted strategy has not been well understood and evaluated. We undertook a scoping review to identify current TB strategies, research and policy gaps in the elderly and summarized the results within a strategic framework towards End TB targets. Databases of Embase, MEDLINE, Global health and EBM reviews were searched for original studies, review articles, and policy papers published in English between January 1990 and December 2015. Articles examining TB strategy, program, guideline or intervention in the elderly from public health perspective were included.Nineteen articles met the inclusion criteria. Most of them were qualitative studies, issued in high- and middle income countries and after 2000. To break the chain of TB transmission and reactivation in the elderly, infection control, interventions of avoiding delay in diagnosis and containment are essential for preventing transmission, especially in elderly institutions and aged immigrants; screening of latent TB infection and preventive therapy had effective impacts on reducing the risk of reactivation and should be used less reluctantly in older people; optimizing early case-finding with a high index of suspicion, systematic screening for prioritized high-risk groups, initial empirical and adequate follow-up treatment with close monitoring and evaluation, as well as enhanced programmatic management are fundamental pillars for active TB elimination. Evaluation of TB epidemiology, risk factors, impacts and cost-effectiveness of interventions, adopting accurate and rapid diagnostic tools, shorter and less toxic preventive therapy, are critical issues for developing strategy in the elderly towards End TB targets.TB control strategies in the elderly were comprehensively mapped in a causal link pathway. The framework and principals identified in this study will help to evaluate and improve current program, develop targeted strategy, as well as raise more discussions on the research priority settings and policy transitions. Given the scarceness of policy and evaluated interventions, as well as the unawareness of shifting TB epidemiology and strategy especially in developing countries, the increasing need of a ready TB program for the elderly warrants further research. PMID- 28569192 TI - The Binding Sites of miR-619-5p in the mRNAs of Human and Orthologous Genes. AB - BACKGROUND: Normally, one miRNA interacts with the mRNA of one gene. However, there are miRNAs that can bind to many mRNAs, and one mRNA can be the target of many miRNAs. This significantly complicates the study of the properties of miRNAs and their diagnostic and medical applications. RESULTS: The search of 2,750 human microRNAs (miRNAs) binding sites in 12,175 mRNAs of human genes using the MirTarget program has been completed. For the binding sites of the miR-619-5p the hybridization free energy of the bonds was equal to 100% of the maximum potential free energy. The mRNAs of 201 human genes have complete complementary binding sites of miR-619-5p in the 3'UTR (214 sites), CDS (3 sites), and 5'UTR (4 sites). The mRNAs of CATAD1, ICA1L, GK5, POLH, and PRR11 genes have six miR-619-5p binding sites, and the mRNAs of OPA3 and CYP20A1 genes have eight and ten binding sites, respectively. All of these miR-619-5p binding sites are located in the 3'UTRs. The miR-619-5p binding site in the 5'UTR of mRNA of human USP29 gene is found in the mRNAs of orthologous genes of primates. Binding sites of miR-619-5p in the coding regions of mRNAs of C8H8orf44, C8orf44, and ISY1 genes encode the WLMPVIP oligopeptide, which is present in the orthologous proteins. Binding sites of miR-619-5p in the mRNAs of transcription factor genes ZNF429 and ZNF429 encode the AHACNP oligopeptide in another reading frame. Binding sites of miR-619-5p in the 3'UTRs of all human target genes are also present in the 3'UTRs of orthologous genes of mammals. The completely complementary binding sites for miR 619-5p are conservative in the orthologous mammalian genes. CONCLUSIONS: The majority of miR-619-5p binding sites are located in the 3'UTRs but some genes have miRNA binding sites in the 5'UTRs of mRNAs. Several genes have binding sites for miRNAs in the CDSs that are read in different open reading frames. Identical nucleotide sequences of binding sites encode different amino acids in different proteins. The binding sites of miR-619-5p in 3'UTRs, 5'UTRs and CDSs are conservative in the orthologous mammalian genes. PMID- 28569193 TI - Health care utilization in patients with gout: a prospective multicenter cohort study. AB - BACKGROUND: All published studies of health care utilization in gout have been cross-sectional to date, and most used a patient-reported diagnosis of gout. Our objective was to assess health care utilization and its predictors in patients with physician-confirmed gout in a prospective cohort study. METHODS: In a multi center prospective cohort study of U.S. veterans with rheumatologist-confirmed gout (N = 186; two centers), we assessed patient self-reported overall and gout specific health care utilization with the Gout Assessment Questionnaire (GAQ) every 3-months for a 9-month period. Comparisons were made using the student's t test or the chi-square, Wilcoxon rank sum test or Fisher exact test, as appropriate. Mixed effects Poisson regression was used to assess potential correlates of gout-related health care utilization. RESULTS: Mean age was 64.6 years, 98% were men, 13% Hispanic or Latino, 32% were African-American, 6% did not graduate high school, mean serum urate was 8.3 and mean Deyo-Charlson score was 3.1. During the past year, mean gout-related visits were as follows: rheumatologist, 1.5; primary care physician, 2 visits; >=1 inpatient visits, 7%; >=1 ER visits, 26%; and urgent care/walk-in visit, 33%. In longitudinal analyses, African-American race and gout flares in the last 3 months were associated with significantly higher rate ratio of gout-related outpatient visits. African American race and lack of college education were associated with significantly higher rate ratio for gout-related urgent visits and overnight stays. CONCLUSIONS: African-American race and recent gout flares were associated with higher outpatient utilization and African-American race and no college education with higher urgent or inpatient utilization. Future studies should examine whether modifiable predictors of utilization can be targeted to reduce healthcare utilization in patients with gout. PMID- 28569195 TI - How parents perceive screen viewing in their 5-6 year old child within the context of their own screen viewing time: a mixed-methods study. AB - BACKGROUND: Few studies have examined parental perceptions of their child's screen-viewing (SV) within the context of parental SV time. This study qualitatively examined parents' perceptions of their 5-6-year-old child's SV within the context of their own quantitatively measured SV. METHODS: A mixed methods design employed semi-structured telephone interviews, demographic and SV questionnaires, objectively-measured physical activity and sedentary time. Deductive content analysis was used to explore parents' perceptions of, and concerns about, their child's SV, and management of their child's SV. Comparisons were made between parent-child dyads reporting low (<2-h per day) versus high SV time. RESULTS: Fifty-three parents were interviewed (94.3% mothers), with 52 interviews analysed. Fifteen parent-child dyads (28.8%) exceeded the 2-h SV threshold on both weekdays and weekend days; 5 parent-child dyads (9.6%) did not exceed this threshold. The remaining 32 dyads reported a combination of parent or child exceeding/not exceeding the SV threshold on either weekdays or weekend days. Three main themes distinguished the 15 parent-child dyads exceeding the SV threshold from the 5 dyads that did not: 1) parents' personal SV-related views and behaviours; 2) the family SV environment; and 3) setting SV rules and limits. Parents in the dyads not exceeding the SV threshold prioritized and engaged with their children in non-SV behaviours for relaxation, set limits around their own and their child's SV-related behaviours, and described an environment supportive of physical activity. Parents in the dyads exceeding the SV threshold were more likely to prioritise SV as a shared family activity, and described a less structured SV environment with minimal rule setting, influenced their child's need for relaxation time. CONCLUSIONS: The majority of parents in this study who exceeded the SV threshold expressed minimal concern and a relaxed approach to managing SV for themselves and their child(ren), suggesting a need to raise awareness amongst these parents about the time they spend engaging in SV. Parents may understand their SV-related parenting practices more clearly if they are encouraged to examine their own SV behaviours. Designing interventions aimed to create environments that are less supportive of SV, with more structured approaches to SV parenting strategies are warranted. PMID- 28569194 TI - Severe child form of primary hyperoxaluria type 2 - a case report revealing consequence of GRHPR deficiency on metabolism. AB - BACKGROUND: Primary hyperoxaluria type 2 is a rare monogenic disorder inherited in an autosomal recessive pattern. It results from the absence of the enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR). As a consequence of deficient enzyme activity, excessive amounts of oxalate and L-glycerate are excreted in the urine, and are a source for the formation of calcium oxalate stones that result in recurrent nephrolithiasis and less frequently nephrocalcinosis. CASE PRESENTATION: We report a case of a 10-month-old patient diagnosed with urolithiasis. Screening of inborn errors of metabolism, including the performance of GC/MS urine organic acid profiling and HPLC amino acid profiling, showed abnormalities, which suggested deficiency of GRHPR enzyme. Additional metabolic disturbances observed in the patient led us to seek other genetic determinants and the elucidation of these findings. Besides the elevated excretion of 3-OH-butyrate, adipic acid, which are typical marks of ketosis, other metabolites such as 3-aminoisobutyric acid, 3-hydroxyisobutyric acid, 3 hydroxypropionic acid and 2-ethyl-3-hydroxypropionic acids were observed in increased amounts in the urine. Direct sequencing of the GRHPR gene revealed novel mutation, described for the first time in this article c.454dup (p.Thr152Asnfs*39) in homozygous form. The frequent nucleotide variants were found in AGXT2 gene. CONCLUSIONS: The study presents metabolomic and molecular genetic findings in a patient with PH2. Mutation analysis broadens the allelic spectrum of the GRHPR gene to include a novel c.454dup mutation that causes the truncation of the GRHPR protein and loss of its two functional domains. We also evaluated whether nucleotide variants in the AGXT2 gene could influence the biochemical profile in PH2 and the overproduction of metabolites, especially in ketosis. We suppose that some metabolomic changes might be explained by the inhibition of the MMSADH enzyme by metabolites that increase as a consequence of GRHPR and AGXT2 enzyme deficiency. Several facts support an assumption that catabolic conditions in our patient could worsen the degree of hyperoxaluria and glyceric aciduria as a consequence of the elevated production of free amino acids and their intermediary products. PMID- 28569196 TI - Mathematical models for devising the optimal Ebola virus disease eradication. AB - BACKGROUND: The 2014-2015 epidemic of Ebola virus disease (EVD) in West Africa defines an unprecedented health threat for human. METHODS: We construct a mathematical model to devise the optimal Ebola virus disease eradication plan. We used mathematical model to investigate the numerical spread of Ebola and eradication pathways, further fit our model against the real total cases data and calculated infection rate as 1.754. RESULTS: With incorporating hospital isolation and application of medication in our model and analyzing their effect on resisting the spread, we demonstrate the second peak of 10,029 total cases in 23 days, and expect to eradicate EVD in 285 days. Using the regional spread of EVD with our transmission model analysis, we analyzed the numbers of new infections through four important transmission paths including household, community, hospital and unsafe funeral. CONCLUSIONS: Based on the result of the model, we find out the key paths in different situations and propose our suggestion to control regional transmission. We fully considers Ebola characteristics, economic and time optimization, dynamic factors and local condition constraints, and to make our plan realistic, sensible and feasible. PMID- 28569198 TI - Determination of reference values and frequency of occurrence of patella alta in German shepherd dogs: a retrospective study. AB - BACKGROUND: Patella alta and patella baja are important conditions underlying a predisposition to many joint diseases, including patellar luxation and patellar chondromalacia of the articular cartilage. The frequencies of patella alta and patella baja have not yet been determined. The objectives of this study were to determine the frequency of patella alta and to determine reference values to the position of the vertical patella according to two modified techniques of the Insall-Salvati method in a group of 65 German shepherd dogs (115 stifle joints). RESULTS: The upper limits of reference values for the normal vertical position of the patella were 1.79 and 2.13, depending on the method of measurement. A high prevalence of patella alta was observed in the group of German shepherd dogs. A correlation was demonstrated between the classification of dogs' joints in the patella alta group and the multiplied risk of canine hip dysplasia (CHD) through the estimation of odds ratios. CONCLUSIONS: Dogs with patella alta were healthy dogs that did not exhibit orthopaedic problems in the stifle joints. The results revealed that the risk of CHD is twice as high in dogs with higher patellar ligament length to patella length ratio. PMID- 28569197 TI - An objective nodal staging system for breast cancer patients undergoing neoadjuvant systemic treatment. AB - BACKGROUND: In this study, we aimed to develop an objective staging system to determine the degree of nodal metastasis in breast cancer patients undergoing neoadjuvant systemic treatment (NST). METHODS: We reviewed the pretreatment computed tomography (CT) images of 392 breast cancer patients who received NST. The association between the patterns of the enlarged regional lymph nodes and treatment outcome was analyzed. RESULTS: In the development cohort of 260 patients, 88 (33.8%) patients experienced tumor recurrence and had a significantly higher number of enlarged lymph nodes on the pretreatment CT compared to patients with no recurrence. When patients were classified according to the numbers and locations of enlarged lymph nodes on pretreatment CT, the number of lymph nodes larger than 1 cm was most significantly associated with tumor recurrence. The accuracy of the CT-based nodal staging system was validated in an independent cohort of 132 patients. The presence of the enlarged supraclavicular nodes was associated with worse outcome, but the effect seemed to originate from the accompanied extensive axillary nodal burden. The prognostic effect of the objectively measured axillary nodal metastasis was more pronounced in hormone receptor-negative tumors. CONCLUSIONS: We have developed and validated an objective method of nodal staging in breast cancer patients who undergo NST based on the number of enlarged axillary lymph nodes. Our system can improve the current subjective approach, which uses physical examination alone. PMID- 28569200 TI - Faecal transplantation for the treatment of Clostridium difficile infection in a marmoset. AB - BACKGROUND: The common marmoset has been used as an experimental animal for various purposes. Because its average weight ranges from 250 to 500 g, weight loss quickly becomes critical for sick animals. Therefore, effective and non stressful treatment for chronic diseases, including diarrhoea, is essential. CASE PRESENTATION: We report a case in which faecal microbiota transplantation (FMT) led to immediate recovery from chronic and recurrent diarrhoea caused by Clostridium difficile infection. A male common marmoset experienced chronic diarrhoea after antibiotic treatments. The animal experienced severe weight loss, and a faecal sample was confirmed to be C. difficile-positive but was negative for protozoa. Metronidazole was partially effective at the first administration but not after the recurrence of the clinical signs. Then, oral FMT was administered to the subject by feeding fresh faeces from healthy individuals mixed with the marmoset's usual food. We monitored the faeces by categorization into four groups: normal, loose, diarrhoea, and watery. After the first day of FMT treatment, the marmoset underwent a remarkable recovery from diarrhoea, and after the fourth day of treatment, a test for C. difficile was negative. The clinical signs did not recur. The marmoset recovered from sinusitis and bilateral dacryocystitis, which also did not recur, as a by-product of the improvement in its general health caused by the cessation of diarrhoea after the FMT. CONCLUSION: This is the first reported case of successful treatment of a marmoset using oral FMT. As seen in human patients, FMT was effective for the treatment of recurrent C. difficile infection in a captive marmoset. PMID- 28569199 TI - Shikonin-induced necroptosis is enhanced by the inhibition of autophagy in non small cell lung cancer cells. AB - BACKGROUND: Shikonin, a natural naphthoquinone pigment purified from Lithospermum erythrorhizon, induces necroptosis in various cancer types, but the mechanisms underlying the anticancer activity of shikonin in lung cancer are not fully understood. This study was designed to clarify whether shikonin causes necroptosis in non-small cell lung cancer (NSCLC) cells and to investigate the mechanism of action. METHODS: Multiplex and caspase 8 assays were used to analyze effect of shikonin on A549 cells. Cytometry with annexin V/PI staining and MTT assays were used to analyze the mode of cell death. Western blotting was used to determine the effect of shikonin-induced necroptosis and autophagy. Xenograft and orthotopic models with A549 cells were used to evaluate the anti-tumor effect of shikonin in vivo. RESULTS: Most of the cell death induced by shikonin could be rescued by the specific necroptosis inhibitor necrostatin-1, but not by the general caspase inhibitor Z-VAD-FMK. Tumor growth was significantly lower in animals treated with shikonin than in the control group. Shikonin also increased RIP1 protein expression in tumor tissues. Autophagy inhibitors, including methyladenine (3-MA), ATG5 siRNA, and bafilomycin A, enhanced shikonin-induced necroptosis, whereas RIP1 siRNA had no effect on the apoptotic potential of shikonin. CONCLUSIONS: Our data indicated that shikonin treatment induced necroptosis and autophagy in NSCLC cells. In addition, the inhibition of shikonin induced autophagy enhanced necroptosis, suggesting that shikonin could be a novel therapeutic strategy against NSCLC. PMID- 28569201 TI - A propensity matched analysis of outcomes and long term survival in stented versus stentless valves. AB - BACKGROUND: To compare the perioperative and long term survival after aortic valve replacement using stentless versus stented valves in a large cohort of patients grouped using propensity score matching. METHODS: From 1991 to 2012, 4,563 patients underwent aortic valve replacement with stentless and stented valves at our institution. Propensity score matching identified 444 pairs using 13 independent variables: incidence of operation, smoking status, renal failure, hypertension, diabetes, peripheral vascular disease, cerebrovascular disease, chronic lung disease, ejection fraction, gender, age, valve status, and use of coronary artery bypass graft. Data were collected from our Society of Thoracic Surgeons database and the Social Security Death Index. Groups were compared using univariate and Kaplan-Meier analysis. RESULTS: The two groups demonstrated no significant differences for the 13 matching variables and the majority of 30-day outcomes (p > 0.05). The stented valve group showed a higher incidence of postoperative bleeding (3.6% vs 1.1%, p = 0.015), but a lower incidence of stroke (0.9% vs. 2.9%, p = 0.028). One, five, and 10-year survival was 95.0, 80.7, and 52.8% for stented and 93.2, 80.5, and 51.3% for stentless valves. Overall survival did not differ significantly between the two groups (p = 0.641). CONCLUSIONS: Stentless and stented valves had identical 30-day outcomes except for a higher postoperative incidence of bleeding and a lower incidence of stroke in the stented group. There was no significant difference in long term survival between valve types. Both valves may be used for aortic valve replacement with low morbidity and excellent long term survival. PMID- 28569202 TI - A health partnership to reduce neonatal mortality in four hospitals in Rwanda. AB - BACKGROUND: A health partnership to improve hospital based neonatal care in Rwanda to reduce neonatal mortality was requested by the Rwandan Ministry of Health. Although many health system improvements have been made, there is a severe shortage of health professionals with neonatal training. METHODS: Following a needs assessment, a health partnership grant for 2 years was obtained. A team of volunteer neonatologists and paediatricians, neonatal nurses, lactation consultants and technicians with experience in Rwanda or low-income countries was assembled. A neonatal training program was provided in four hospitals (the 2 University hospitals and 2 district hospitals), which focused on nutrition, provision of basic respiratory support with nasal CPAP (Continuous Positive Airway Pressure), enhanced record keeping, thermoregulation, vital signs monitoring and infection control. To identify if care delivery improved, audits of nutritional support, CPAP use and its complications, and documentation in newly developed neonatal medical records were conducted. Mortality data of neonatal admissions was obtained. RESULTS: Intensive neonatal training was provided on 27 short-term visits by 10 specialist health professionals. In addition, a paediatric doctor spent 3 months and two spent 6 months each providing training. A total of 472 training days was conducted in the neonatal units. For nutritional support, significant improvements were demonstrated in reduction in time to initiation of enteral feeds and to achieve full milk feeds, in reduction in maximum postnatal weight loss, but not in days for regaining birth weight. Respiratory support with bubble CPAP was applied to 365 infants in the first 18 months. There were no significant technical problems, but tissue damage, usually transient, to the nose and face was recorded in 13%. New medical records improved documentation by doctors, but nursing staff were reluctant to use them. Mortality for University teaching hospital admissions was reduced from 23.6% in the 18 months before the project to 21.7%. For the two district hospitals, mortality reduced from 10% to 8.1%. A major barrier to training and improved care was low number of nurses working on neonatal units and staff turnover. CONCLUSION: This health partnership delivered an intensive program of capacity building by volunteer specialists. Improved care and documentation were demonstrated. CPAP was successfully introduced. Mortality was reduced. This format can be adapted for further training and improvement programs to improve the quality of facility-based care. PMID- 28569203 TI - Neurobehavioral changes in mice offspring exposed to green tea during fetal and early postnatal development. AB - BACKGROUND: Green tea extract (GTE) has various health promoting effects on animals and humans. However, the effects of perinatal exposure to GTE on the behavioral aspects of offspring have not been elucidated thus far. GTE was provided for pregnant female mice at concentrations of either 20 or 50 g/L, beginning the day of conception until the third week after delivery, postnatal day 22 (PD 22). Mice pups were subjected to behavioral testing to assess sensory motor reflexes, locomotion, anxiety, and learning on various postnatal days. RESULTS: Perinatal exposure to GTE resulted in a significant reduction in body weight, as well as earlier body hair appearance and opening of the eyes. Sensory motor reflexes exhibited faster responses and significant stimulatory effects in pups exposed to GTE. During the adolescent period, male and female offspring exhibited increased locomotor activity (on PD 22), reduced anxiety and fear (on PD 25), and enhanced memory and learning abilities (on PD 30), all in both GTE treated groups. All blood counts (RBCs, WBCs, Hb, and platelets), and glucose, cholesterol, triglyceride, and low density lipoprotein concentrations were significantly lower in the GTE-treated pups; however, there was no effect on high density lipoprotein levels. CONCLUSION: Our data provide evidence that the high dose of GTE (50 g/L) had higher anxiolytic properties and positive effects on locomotor activities and sensory motor reflexes, as well as learning and memory of the offspring than the low dose of GTE (20 g/L). PMID- 28569205 TI - Association between blood pressure and Alzheimer disease measured up to 27 years prior to diagnosis: the HUNT Study. AB - BACKGROUND: A lot of attention has been paid to the relationship of blood pressure and dementia because epidemiological research has reported conflicting evidence. Observational data has shown that midlife hypertension is a risk factor for cognitive decline and dementia later in life, whereas there is evidence that low blood pressure is predictive in later life. The aim of the present study was to examine the association between dementia and blood pressure measured up to 27 years (mean 17.6 years) prior to ascertainment. METHODS: In Nord-Trondelag County, Norway, incident dementia data were collected during 1995-2011, and the diagnoses were validated by a panel of experts in the field. By using the subjects' personal identification numbers, the dementia data were linked to data from the Nord-Trondelag Health Study (the HUNT Study), a large, population-based health study performed in 1984-1986 (HUNT 1) and 1995-1997 (HUNT 2). A total of 24,638 participants of the HUNT Study were included in the present study, 579 of whom were diagnosed with Alzheimer disease, mixed Alzheimer/vascular dementia, or vascular dementia. Multiple logistic regression analyses were conducted to analyze the association between dementia and blood pressure data from HUNT 1 and HUNT 2. RESULTS: Over the age of 60 years, consistent inverse associations were observed between systolic blood pressure and all-cause dementia, mixed Alzheimer/vascular dementia, and Alzheimer disease, but not with vascular dementia, when adjusting for age, sex, education, and other relevant covariates. This was observed for systolic blood pressure in both HUNT 1 and HUNT 2, regardless of antihypertensive medication use. There was an adverse association between systolic blood pressure, pulse pressure, and Alzheimer disease in individuals treated with antihypertensive medication under the age of 60 years. CONCLUSIONS: Our data are in line with those in previous studies demonstrating an inverse association between dementia and systolic blood pressure in individuals over the age of 60 years. We cannot exclude a survival effect, however. Among middle-aged subjects (<60 years), elevated systolic blood pressure and pulse pressure were associated with eventual Alzheimer disease in individuals who reported using antihypertensive medication. PMID- 28569204 TI - TGFbeta1-induced SMAD2/3 and SMAD1/5 phosphorylation are both ALK5-kinase dependent in primary chondrocytes and mediated by TAK1 kinase activity. AB - BACKGROUND: Dysregulated transforming growth factor beta (TGFbeta) signaling is implicated in osteoarthritis development, making normalizing TGFbeta signaling a possible therapy. Theoretically, this can be achieved with small molecule inhibitors specifically targeting the various TGFbeta receptors and downstream mediators. In this study we explore in primary chondrocytes the use of small molecule inhibitors to target TGFbeta-induced pSmad1/5/9-, pSmad2/3- and TGFbeta activated kinase 1 (TAK1)-dependent signaling. METHOD: Primary bovine chondrocytes and explants were isolated from metacarpophalangeal joints. To modulate TGFbeta signaling the activin receptor-like kinase (ALK)1/2/3/6 inhibitor LDN-193189, the ALK4/5/7 inhibitor SB-505124 and the TAK1 inhibitor (5Z)-7-Oxozeaenol were used. pSmad1/5 and pSmad2 were measured using western blot analysis and TGFbeta1-induced gene expression was measured using quantitative real time PCR (qPCR). RESULTS: In chondrocytes, TGFbeta1 strongly induced both pSmad1/5 and pSmad2. Remarkably, LDN-193189 did not inhibit TGFbeta-induced pSmad1/5. In contrast, SB-505124 did inhibit both TGFbeta-induced Smad2 and Smad1/5 phosphorylation. Furthermore, (5Z)-7-Oxozeaenol also profoundly inhibited TGFbeta-induced pSmad2 and pSmad1/5. Importantly, both SB-505124 and (5Z)-7 Oxozeaenol did not significantly inhibit constitutively active ALK1, making an off-target effect unlikely. Additionally, LDN-193189 was able to potently inhibit BMP2/7/9-induced pSmad1/5, showing its functionality. On gene expression, LDN 193189 did not affect TGFbeta1-induced regulation, whereas both SB-505124 and (5Z)-7-Oxozeaenol did. Similar results were obtained in cartilage explants, although pSmad1/5 was not strongly induced by addition of TGFbeta1. CONCLUSION: Our data suggest that ALK5 kinase activity plays a central role in both TGFbeta induced Smad1/5 and Smad2/3 phosphorylation, making it difficult to separate both pathways with the use of currently available small molecule inhibitors. Furthermore, our data regarding (5Z)-7-Oxozeaenol suggest that TAK1 facilitates Smad-dependent signaling. PMID- 28569206 TI - Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845. AB - BACKGROUND: In study TMC647055HPC2001, a 3-direct-acting-antiviral (DAA) regimen combining NS3/4A protease inhibitor simeprevir (SMV), non-nucleoside NS5B inhibitor TMC647055/ritonavir (RTV) and NS5A inhibitor JNJ-56914845 resulted in high sustained virologic response 12 weeks after actual end of treatment (SVR12) in chronic hepatitis C virus (HCV) genotype 1-infected patients. SVR12 rates were generally lower in the 2-DAA regimen SMV + TMC647055/RTV with or without ribavirin. The objective of this study was to identify and characterise pre existing and emerging resistance-associated variants (RAVs) in patients enrolled in study TMC647055HPC2001. METHODS: HCV population sequencing analyses were performed on baseline isolates from all patients (n = 90) and post-baseline isolates from patients with virologic failure (n = 22). In addition, deep sequencing and phenotypic analyses were performed on selected baseline and post baseline isolates. RESULTS: The majority of patients with virologic failure had emerging RAVs to all study drugs at the time of failure: in all 22 patients SMV RAVs emerged at NS3 positions 80, 155, 156 and/or 168, consistent with the known SMV resistance profile. Emerging TMC647055 RAVs at NS5B position 495 were detected in the majority of patients (16/22), and all 5 patients who failed the 3 DAA regimen had emerging JNJ-56914845 RAVs at NS5A positions 30 and/or 31. While at the end of study emerging SMV and TMC647055 RAVs were no longer observed by population sequencing in 40% (8/20) and 62.5% (10/16) of patients with follow-up data available, respectively, emerging JNJ-56914845 RAVs were still detected in all (5/5) patients. CONCLUSIONS: Virologic failure in the 2- and 3-DAA combinations was, in the majority of patients, associated with the emergence of RAVs to all study drugs. While emerging SMV and TMC647055 RAVs became undetectable during follow-up, JNJ-56914845 RAVs in NS5A were still observed at end of study. TRIAL REGISTRATION NUMBER: NCT01724086 (date of registration: September 26, 2012). PMID- 28569207 TI - Seed-effect modeling improves the consistency of genome-wide loss-of-function screens and identifies synthetic lethal vulnerabilities in cancer cells. AB - BACKGROUND: Genome-wide loss-of-function profiling is widely used for systematic identification of genetic dependencies in cancer cells; however, the poor reproducibility of RNA interference (RNAi) screens has been a major concern due to frequent off-target effects. Currently, a detailed understanding of the key factors contributing to the sub-optimal consistency is still a lacking, especially on how to improve the reliability of future RNAi screens by controlling for factors that determine their off-target propensity. METHODS: We performed a systematic, quantitative analysis of the consistency between two genome-wide shRNA screens conducted on a compendium of cancer cell lines, and also compared several gene summarization methods for inferring gene essentiality from shRNA level data. We then devised novel concepts of seed essentiality and shRNA family, based on seed region sequences of shRNAs, to study in-depth the contribution of seed-mediated off-target effects to the consistency of the two screens. We further investigated two seed-sequence properties, seed pairing stability, and target abundance in terms of their capability to minimize the off target effects in post-screening data analysis. Finally, we applied this novel methodology to identify genetic interactions and synthetic lethal partners of cancer drivers, and confirmed differential essentiality phenotypes by detailed CRISPR/Cas9 experiments. RESULTS: Using the novel concepts of seed essentiality and shRNA family, we demonstrate how genome-wide loss-of-function profiling of a common set of cancer cell lines can be actually made fairly reproducible when considering seed-mediated off-target effects. Importantly, by excluding shRNAs having higher propensity for off-target effects, based on their seed-sequence properties, one can remove noise from the genome-wide shRNA datasets. As a translational application case, we demonstrate enhanced reproducibility of genetic interaction partners of common cancer drivers, as well as identify novel synthetic lethal partners of a major oncogenic driver, PIK3CA, supported by a complementary CRISPR/Cas9 experiment. CONCLUSIONS: We provide practical guidelines for improved design and analysis of genome-wide loss-of-function profiling and demonstrate how this novel strategy can be applied towards improved mapping of genetic dependencies of cancer cells to aid development of targeted anticancer treatments. PMID- 28569208 TI - Development of a health education intervention strategy using an implementation research method to control taeniasis and cysticercosis in Burkina Faso. AB - BACKGROUND: Taeniasis and cysticercosis are two diseases caused by Taenia solium, a parasite transmitted between humans and pigs, leading to considerable economic loss and disabilities. Transmission of the parasite is linked to environmental and behavioural factors such as inadequate sanitation and hygiene, poor pig management, and consumption of infected pork. This study used implementation research method to design a health education intervention strategy for reducing T. solium infections in Burkina Faso, a country endemic for the parasite. METHODS: Eighteen group discussions were conducted with 8-18 participants each in three villages. In addition, structured interviews were conducted among 4 777 participants and 2 244 pig owners, who were selected through cluster random sampling in 60 villages of three provinces of Burkina Faso. Both approaches assessed knowledge and practices related to T. solium. The information obtained was used to develop a community-adapted health education intervention strategy to control taeniasis and cysticercosis in Burkina Faso. RESULTS: The group discussions revealed that participants had a poor quality of life due to the diseases as well as inadequate access to latrines, safe water, and healthcare services. In addition, it was found that pig production was an important economic activity, especially for women. Furthermore, financial and knowledge constraints were important limitations to improved pig management and latrine construction. The survey data also showed that open defecation and drinking unboiled water were common behaviours, enhanced by a lack of knowledge regarding the transmission of the parasite, perceived financial barriers to the implementation of control measures, lack of public sensitization, as well as a lack of self-efficacy towards control of the parasite. Nevertheless, the perceived financial benefits of controlling porcine cysticercosis could be emphasized by an education program that discourages open defecation and encourages drinking safe water. The final intervention strategy included a Participatory Hygiene and Sanitation Transformation (PHAST) approach, as well as a 52-min film and an accompanying comic booklet. CONCLUSIONS: The main problem in the study communities regarding the transmission of T. solium cysticercosis is the random disposal of human faeces, which can be contaminated with parasite eggs. Prevention of open defecation requires the building of latrines, which can be quite problematic in economically challenged settings. Providing the community with the skills to construct durable latrines using low-cost locally available materials would likely help to resolve this problem. Further studies are required to implement and evaluate the T. solium control strategy developed in this study. PMID- 28569209 TI - In-vivo monitoring of anti-folate therapy in arthritic rats using [18F]fluoro-PEG folate and positron emission tomography. AB - BACKGROUND: Folate receptor beta (FRbeta) is involved in facilitating cellular uptake of folates and anti-folates (such as methotrexate (MTX)). In rheumatoid arthritis, FRbeta is expressed on synovial macrophages and recently has been explored as a biomarker for imaging in arthritic rats using the folate-based positron emission tomography (PET) tracer [18F]fluoro-PEG-folate. The purpose of this study was to examine whether this folate tracer can also be used to monitor therapeutic efficacy of MTX in arthritic rats. METHODS: Arthritic rats received either no treatment or MTX therapy (1 mg/kg, either 2* or 4*). Healthy rats did not receive any arthritic induction or therapy. [18F]fluoro-PEG-folate PET-CT scans (60 min) were performed before and after MTX therapy. Following PET, the ex vivo tissue distribution of radioactivity was determined in excised knees and multiple tissues. Synovial macrophage infiltration in knee sections was quantified by immunohistochemistry using ED1 and ED2 antibodies. RESULTS: PET scans clearly visualized increased uptake of [18F]fluoro-PEG-folate in arthritic knees compared with contralateral knees. Significantly lower standard uptake values (1.5-fold, p < 0.01) were observed in arthritic knees of both MTX-treated groups after therapy, approximating the levels seen in healthy rats. Consistently, ex-vivo tissue distribution demonstrated a 2-4-fold lower tracer uptake in the arthritic knee of 2* and 4* MTX-treated rats, respectively, compared with control rats. These results were corroborated with significantly reduced (2-4-fold, p < 0.01) ED1-positive and ED2-positive synovial macrophages in arthritic knees of the MTX-treated rats compared with those of the control rats. CONCLUSION: This study in arthritic rats underscores the potential and usefulness of [18F]fluoro-PEG-folate PET as a therapeutic monitoring tool of MTX therapy and potentially other anti-folate treatment of arthritis. PMID- 28569210 TI - Bacteriophage-prokaryote dynamics and interaction within anaerobic digestion processes across time and space. AB - BACKGROUND: Bacteriophage-prokaryote dynamics and interaction are believed to be important in governing microbiome composition and ecosystem functions, yet our limited knowledge of the spatial and temporal variation in phage and prokaryotic community compositions precludes accurate assessment of their roles and impacts. Anaerobic digesters are ideal model systems to examine phage-host interaction, owing to easy access, stable operation, nutrient-rich environment, and consequently enormous numbers of phages and prokaryotic cells. RESULTS: Equipped with high-throughput, cutting-edge environmental genomics techniques, we examined phage and prokaryotic community composition of four anaerobic digesters in full scale wastewater treatment plants across China. Despite the relatively stable process performance in biogas production, phage and prokaryotic groups fluctuated monthly over a year of study period, showing significant correlations between those two groups at the alpha- and beta-diversity levels. Strikingly, phages explained 40.6% of total variations of the prokaryotic community composition, much higher than the explanatory power by abiotic factors (14.5%). Consequently, phages were significantly (P < 0.010) linked to parameters related to process performance including biogas production and volatile solid concentrations. Association network analyses showed phage-prokaryote pairs were shallowly conserved since they were detected only within small viral clades. CONCLUSIONS: Those results collectively demonstrate phages as a major biotic factor in controlling prokaryotic composition and process performance. Therefore, phages may play a larger role in shaping prokaryotic community dynamics and process performance of anaerobic digesters than currently appreciated. PMID- 28569211 TI - Exosomal amyloid A and lymphatic vessel endothelial hyaluronic acid receptor-1 proteins are associated with disease activity in rheumatoid arthritis. AB - BACKGROUND: Exosomes are thought to play an important role in exchanging information between cells. The proteins and lipids in exosomes play roles in mediating inflammatory and autoimmune diseases. The aim of this study was to identify exosomal candidate proteins that are related to other inflammatory parameters in rheumatoid arthritis (RA). METHODS: The study population consisted of 60 patients with RA: 30 in the clinical remission (CR) group with a Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) <=2.6 and 30 in the non-clinical remission (non-CR) group with a DAS28-ESR >2.6. Preparation of exosomes from patient serum samples was performed with the ExoQuick kit, and protein identification/quantification was performed using tandem mass tag labeling/mass spectrometry and an enzyme-linked immunosorbent assay. Comparisons between groups were made using Student's t test or the Mann Whitney U test, as appropriate. Spearman's correlation coefficients (rho) were calculated. RESULTS: We identified six candidate proteins. Exosomal levels of amyloid A (AA) and lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE 1) differed between the CR and non-CR groups. Both serum and exosomal AA levels were higher in the non-CR group than in the CR group (p = 0.001). Significant positive correlations were found between exosomal AA and C-reactive protein (CRP) as well as between serum AA and CRP (rho = 0.614, p = 0.001, and rho = 0.624, p = 0.001, respectively). Although serum levels of LYVE-1 did not differ between the non-CR and CR groups, exosomal levels of LYVE-1 were lower in the non-CR group than in the CR group (p = 0.01). We identified positive correlations between serum/exosomal LYVE-1 and CRP only in the non-CR group (serum rho = 0.376, p = 0.04; exosome rho = 0.545, p = 0.002). CONCLUSIONS: Exosomal LYVE-1 shows potential for use as an additional marker of disease activity in patients with RA, and exosomes may carry other useful markers for RA. PMID- 28569212 TI - The prevalence of ACPA is lower in rheumatoid arthritis patients with an older age of onset but the composition of the ACPA response appears identical. AB - BACKGROUND: Rheumatoid arthritis (RA) consists of two syndromes, one autoantibody positive and one autoantibody-negative. Existing data on the relation between age of onset and prevalence of autoantibodies were conflicting. Therefore this multicohort study assessed the age of onset in relation to the presence of autoantibodies. The association with characteristics of the anti-citrullinated protein antibodies (ACPA) response was also explored. METHODS: The 1987 criteria positive RA patients included in the Leiden EAC, BARFOT, ESPOIR, Umea and Lund cohorts (n = 3321) were studied at presentation for age of onset and the presence of ACPA, rheumatoid factor (RF) and anti-carbamylated protein (anti-CarP) antibodies. Logistic regression analyses were performed; effect sizes were summarized in inverse-weighted meta-analyses. Within ACPA-positive RA, ACPA level was studied in all cohorts; ACPA isotypes, ACPA fine specificity and ACPA avidity index and clinical characteristics were studied in the Leiden EAC. RESULTS: From the age of 50 onward, the proportion of ACPA-negative RA patients increased with age in the five cohorts. Similar observations were made for RF and anti-CarP. The composition of the ACPA response did not change with increasing age of onset with respect to titer, isotype distribution, fine specificity and avidity index. With increasing age of onset, RA patients smoked less often, had higher acute phase reactants and more often had a sub(acute) symptom onset. CONCLUSIONS: Data of five cohorts revealed that with older age of onset ACPA-negative RA is more frequent than ACPA-positive RA, while characteristics of ACPA-positive RA as judged by the composition of the ACPA response appeared not age dependent. Further biologic studies are needed to characterize the pathogenesis of ACPA negative polyarthritis at older age and to promote personalized treatment decisions in ACPA-negative patients in daily practice. PMID- 28569213 TI - Is early intervention using Mansoura-VV uterine compression sutures an effective procedure in the management of primary atonic postpartum hemorrhage? : a prospective study. AB - BACKGROUND: Postpartum hemorrhage is the leading cause of maternal death, uterine atony accounts for 75-90% of primary postpartum hemorrhage. The efficacy of the Uterine compression suture in the treatment of atonic postpartum hemorrhage is time-tested and can be said to be almost established.The aim of this study was to assess the role of the Mansoura-VV uterine compression suture as an early intervention in the management of primary atonic postpartum hemorrhage. METHODS: This prospective observational study included 108 women with primary atonic PPH over a period of 44 months. Uterine atony was diagnosed when the uterus was soft and failed to respond to ordinary ecbolics. Early intervention by Mansoura-VV uterine compression sutures was carried out within 15 min of the second dose of ecobolics and before progressing to any further surgical procedure. RESULTS: Following the Mansoura-VV uterine compression sutures, uterine bleeding was controlled in all except one patient (107/108 cases; 99.07%) who required additional bilateral uterine vessels ligation. Another case (0.93%) was subjected to re-laparotomy due to intraperitoneal hemorrhage. Packed RBC transfusion was needed in 10 cases (9.25%). Admission to ICU was needed in 9 cases (8.33%) because of associated medical conditions. One week following the procedure, 1 case (0.93%) was diagnosed with haematometra. CONCLUSION: Early intervention in cases of primary atonic PPH using the Mansoura-VV uterine compression sutures is an easy, rapid and effective method in controlling PPH in low resource settings. TRIAL REGISTRATION: The study was registered at clinicaltrial.gov , Identifiers: NCT03117647 "retrospectively registererd" registered at April 7, 2017. PMID- 28569214 TI - Decreased cardiac mortality with nicorandil in patients with ischemic heart failure. AB - BACKGROUND: Effective treatments in heart failure (HF) patients with ischemic etiology have not been fully established. Nicorandil, combination of nitrate component and sarcolemmal adenosine triphosphate-sensitive potassium channel opener, is a potent vasodilator of coronary and peripheral vessels and has been used as an antianginal agent. Therefore, we examined impacts of nicorandil on cardiac mortality in ischemic HF patients. METHODS: Consecutive 334 HF patients with ischemic etiology were retrospectively registered and divided into 2 groups based on oral administration of nicorandil: nicorandil group (n = 116) and non nicorandil group (n = 218). We retrospectively examined cardiac mortality. RESULTS: In the Kaplan-Meier analysis (mean follow-up period 963 days), cardiac mortality was significantly lower in the nicorandil group than in the non nicorandil group (11.2% vs. 19.7%, P = 0.032). In the Cox proportional hazard analysis, usage of nicorandil was a suppressor of cardiac mortality (hazard ratio 0.512, 95% confidence interval 0.275-0.953, P = 0.035), and this result was consistent in several subgroup analyses, such as left ventricular ejection fraction, percutaneous coronary intervention, coronary artery bypass graft, diabetes, beta-blockers, and statins. CONCLUSION: Nicorandil is potentially effective for reducing mortality in patients with ischemic heart failure. TRIAL REGISTRATION: This was a retrospective study. PMID- 28569215 TI - Diagnosis of Swine Toxoplasmosis by PCR and Genotyping of Toxoplasma gondii from pigs in Henan, Central China. AB - BACKGROUND: Toxoplasma gondii, a widely prevalent protozoan parasite, causes serious toxoplasmosis infections in humans and other animals. Among livestock, pigs are susceptible to T. gondii infection. Despite Henan being one of the biggest pig-raising provinces in China, little information exists on the epidemiology of toxoplasmosis in this location. Therefore, we molecularly characterized DNA samples from pigs in Henan. A total of 1647 samples, including 952 from dead piglets, 478 from seriously sick fattening pigs and 217 from abortion sows, were collected from different animal hospitals or pig farms from 10 different cities in Henan (2006-2008). Each pig corresponded to a separate pig farm. DNA was extracted from 3 to 5 g of the most severely affected pig tissue (liver, spleen, lung, hilar lymph nodes and amniotic fluid) after postmortem examination. The presence of the T. gondii B1 gene was detected using nested polymerase chain reactions (PCR). Genotyping was performed directly on DNA from the PCR-positive tissue samples using 11 PCR restriction fragment length polymorphism markers (SAG1, 5'- and 3'-SAG2, alternative SAG2, SAG3, BTUB, GRA6, L358, PK1, c22-8, c29-2, and Apico). RESULTS: Of all samples, thirty-four were positive for the T. gondii B1 gene (2.06%, 95% CI: 1.86%-2.26%) from four cities, including 31 from NanYang city, one (PgXY 1) from Xinyang City, one (PgZZ 1) from Zhengzhou City and one (PgZK1) from Zhoukou City. The prevalence was found to be highest in piglets than in fattening pigs and sows. And the difference was statistically significant (P<0.01). The following 32 samples were genotyped with complete data: 13 hilar lymph node tissue samples, seven liver tissue samples, seven lung tissue samples, four spleen tissue samples, and one amniotic fluid sample. Only one genotype, belonging to ToxoDB Genotype #9, was identified. CONCLUSIONS: This is the first large-scale survey molecularly characterizing T. gondii from pigs in Henan. The results of the present study revealed that T. gondii infection is present in swine in Henan and is a potential source of foodborne toxoplasmosis in the investigated areas. Implementation of effective control measures for T. gondii to reduce the chance of zoonotic toxoplasmosis spreading from pig farms may be warranted. The results show that the ToxoDB #9 genotype may be the dominant T. gondii lineage in mainland China. These findings strengthen the limited Chinese T. gondii epidemiology database. PMID- 28569216 TI - Potent and reversible lentiviral vector restriction in murine induced pluripotent stem cells. AB - BACKGROUND: Retroviral vectors are derived from wild-type retroviruses, can be used to study retrovirus-host interactions and are effective tools in gene and cell therapy. However, numerous cell types are resistant or less permissive to retrovirus infection due to the presence of active defense mechanisms, or the absence of important cellular host co-factors. In contrast to multipotent stem cells, pluripotent stem cells (PSC) have potential to differentiate into all three germ layers. Much remains to be elucidated in the field of anti-viral immunity in stem cells, especially in PSC. RESULTS: In this study, we report that transduction with HIV-1-based, lentiviral vectors (LV) is impaired in murine PSC. Analyses of early retroviral events in induced pluripotent stem cells (iPSC) revealed that the restriction is independent of envelope choice and does not affect reverse transcription, but perturbs nuclear entry and proviral integration. Proteasomal inhibition by MG132 could not circumvent the restriction. However, prevention of cyclophilin A (CypA) binding to the HIV-1 capsid via use of either a CypA inhibitor (cyclosporine A) or CypA-independent capsid mutants improved transduction. In addition, application of higher vector doses also increased transduction. Our data revealed a CypA mediated restriction in iPSC, which was acquired during reprogramming, associated with pluripotency and relieved upon subsequent differentiation. CONCLUSIONS: We showed that murine PSC and iPSC are less susceptible to LV. The block observed in iPSC was CypA dependent and resulted in reduced nuclear entry of viral DNA and proviral integration. Our study helps to improve transduction of murine pluripotent cells with HIV-1-based vectors and contributes to our understanding of retrovirus-host interactions in PSC. PMID- 28569218 TI - A knowledge-based framework for the discovery of cancer-predisposing variants using large-scale sequencing breast cancer data. AB - BACKGROUND: The landscape of cancer-predisposing genes has been extensively investigated in the last 30 years with various methodologies ranging from candidate gene to genome-wide association studies. However, sequencing data are still poorly exploited in cancer predisposition studies due to the lack of statistical power when comparing millions of variants at once. METHOD: To overcome these power limitations, we propose a knowledge-based framework founded on the characteristics of known cancer-predisposing variants and genes. Under our framework, we took advantage of a combination of previously generated datasets of sequencing experiments to identify novel breast cancer-predisposing variants, comparing the normal genomes of 673 breast cancer patients of European origin against 27,173 controls matched by ethnicity. RESULTS: We detected several expected variants on known breast cancer-predisposing genes, like BRCA1 and BRCA2, and 11 variants on genes associated with other cancer types, like RET and AKT1. Furthermore, we detected 183 variants that overlap with somatic mutations in cancer and 41 variants associated with 38 possible loss-of-function genes, including PIK3CB and KMT2C. Finally, we found a set of 19 variants that are potentially pathogenic, negatively correlate with age at onset, and have never been associated with breast cancer. CONCLUSIONS: In this study, we demonstrate the usefulness of a genomic-driven approach nested in a classic case-control study to prioritize cancer-predisposing variants. In addition, we provide a resource containing variants that may affect susceptibility to breast cancer. PMID- 28569217 TI - Platelets, diabetes and myocardial ischemia/reperfusion injury. AB - Mechanisms underlying the pathogenesis of ischemia/reperfusion injury are particularly complex, multifactorial and highly interconnected. A complex and entangled interaction is also emerging between platelet function, antiplatelet drugs, coronary diseases and ischemia/reperfusion injury, especially in diabetic conditions. Here we briefly summarize features of antiplatelet therapy in type 2 diabetes (T2DM). We also treat the influence of T2DM on ischemia/reperfusion injury and how anti-platelet therapies affect post-ischemic myocardial damage through pleiotropic properties not related to their anti-aggregating effects. miRNA-based signature associated with T2DM and its cardiovascular disease complications are also briefly considered. Influence of anti-platelet therapies and different effects of healthy and diabetic platelets on ischemia/reperfusion injury need to be further clarified in order to enhance patient benefits from antiplatelet therapy and revascularization. Here we provide insight on the difficulty to reduce the cardiovascular risk in diabetic patients and report novel information on the cardioprotective role of widely used anti-aggregant drugs. PMID- 28569219 TI - HDL cholesterol efflux capacity in rheumatoid arthritis patients: contributing factors and relationship with subclinical atherosclerosis. AB - BACKGROUND: Lipid profiles appear to be altered in rheumatoid arthritis (RA) patients because of disease activity and inflammation. Cholesterol efflux capacity (CEC), which is the ability of high-density lipoprotein cholesterol to accept cholesterol from macrophages, has been linked not only to cardiovascular events in the general population but also to being impaired in patients with RA. The aim of this study was to establish whether CEC is related to subclinical carotid atherosclerosis in patients with RA. METHODS: We conducted a cross sectional study that encompassed 401 individuals, including 178 patients with RA and 223 sex-matched control subjects. CEC, using an in vitro assay, lipoprotein serum concentrations, and standard lipid profile, was assessed in patients and control subjects. Carotid intima-media thickness (CIMT) and carotid plaques were assessed in patients with RA. A multivariable analysis was performed to evaluate the relationship of CEC with RA-related data, lipid profile, and subclinical carotid atherosclerosis. RESULTS: Mean (SD) CEC was not significantly different between patients with RA (18.9 +/- 9.0%) and control subjects (16.9 +/- 10.4%) (p = 0.11). Patients with RA with low (beta coefficient -5.2 [-10.0 to 0.3]%, p = 0.039) and moderate disease activity (beta coefficient -4.6 [-8.5 to 0.7]%, p = 0.020) were associated with lower levels of CEC than patients in remission. Although no association with CIMT was found, higher CEC was independently associated with a lower risk for the presence of carotid plaque in patients with RA (odds ratio 0.94 [95% CI 0.89-0.98], p = 0.015). CONCLUSIONS: CEC is independently associated with carotid plaque in patients with RA. PMID- 28569220 TI - BRCA promoter methylation in sporadic versus BRCA germline mutation-related breast cancers. AB - BACKGROUND: In breast cancer, BRCA promoter hypermethylation and BRCA germline mutations are said to occur together rarely, but this property has not yet been translated into a clinical test. Our aim in this study was to investigate the diagnostic value of BRCA1/2 methylation in distinguishing breast carcinomas of BRCA1 and BRCA2 germline mutation carriers from sporadic breast carcinomas using a recently developed BRCA methylation assay based on methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). METHODS: MS-MLPAs were performed to assess BRCA1 and BRCA2 methylation in breast carcinoma tissues from 39 BRCA1 and 33 BRCA2 germline mutation carriers, 80 patients with sporadic breast cancer, and normal breast tissues from 5 BRCA1 and 4 BRCA2 mutation carriers and 5 nonmutation carriers. RESULTS: Methylation frequencies varied considerably between CpG sites across the BRCA1 and BRCA2 promoters. Some CpG sites were methylated more frequently in BRCA1/2-related than in sporadic carcinomas, whereas other CpG sites were methylated more frequently in sporadic carcinomas, with large variances in sensitivity and specificity as a consequence. CONCLUSIONS: The diagnostic value of BRCA promoter methylation analysis in distinguishing BRCA1/2-related from sporadic breast carcinomas seems to be considerably dependent on the targeted CpG sites. These findings are important for adequate use of BRCA methylation analysis as a prescreening tool for BRCA germline genetic testing or to identify BRCAness patients who may benefit from targeted therapies such as poly(adenosine diphosphate-ribose) polymerase inhibitors. PMID- 28569221 TI - A four-part working bibliography of neuroethics: Part 4 - Ethical issues in clinical and social applications of neuroscience. AB - BACKGROUND: As a discipline, neuroethics addresses a range of questions and issues generated by basic neuroscientific research (inclusive of studies of putative neurobiological processes involved in moral and ethical cognition and behavior), and its use and meanings in the clinical and social spheres. Here, we present Part 4 of a four-part bibliography of the neuroethics literature focusing on clinical and social applications of neuroscience, to include: the treatment enhancement discourse; issues arising in neurology, psychiatry, and pain care; neuroethics education and training; neuroethics and the law; neuroethics and policy and political issues; international neuroethics; and discourses addressing "trans-" and "post-" humanity. METHODS: To complete a systematic survey of the literature, 19 databases and 4 individual open-access journals were employed. Searches were conducted using the indexing language of the U.S. National Library of Medicine (NLM). A Python code was used to eliminate duplications in the final bibliography. RESULTS: When taken with Parts 1-3, this bibliography aims to provide a listing of international peerreviewed papers, books, and book chapters published from 2002 through 2016. While seeking to be as comprehensive as possible, it may be that some works were inadvertently and unintentionally not included. We therefore invite commentary from the field to afford completeness and contribute to this bibliography as a participatory work-in-progress. PMID- 28569223 TI - Influenza vaccination in patients with suspected egg allergy. AB - Egg allergy is not necessarily a contraindication to influenza vaccination. For patients with suspected egg allergy, if the clinician determines benefits to outweigh risks, cautionary measures are available that can enhance safe vaccine administration. Batch to batch variability of egg content in extant influenza vaccines necessitates an informed and cautious approach to vaccination of an egg allergic individual. Although patients with egg allergy are likely to develop egg tolerance by late childhood, tolerance to ingestion of "baked egg" products may not predict tolerance to "native egg" proteins present in the influenza vaccine. Even in cases where the skin test to the vaccine is positive, vaccination may still be cautiously administered, if necessary, in a graded dose protocol. PMID- 28569222 TI - Is the current ASAS expert definition of a positive family history useful in identifying axial spondyloarthritis? Results from the SPACE and DESIR cohorts. AB - BACKGROUND: The Assessment of SpondyloArthritis international Society (ASAS) definition of a positive family history (PFH) of spondyloarthritis (SpA) includes the following diseases in first- or second-degree relatives: ankylosing spondylitis (AS), acute anterior uveitis (AAU), reactive arthritis (ReA), inflammatory bowel disease (IBD), and psoriasis. However, it is not known if a PFH for each of these diseases contributes to making a diagnosis of axSpA, sacroiliitis on imaging, or fulfilling the ASAS criteria in patients presenting with chronic back pain (CBP). Therefore, the aim of this study was to assess which SpA diseases in family members are associated with human leukocyte antigen B27 (HLA-B27) and axial spondyloarthritis (axSpA) in CBP patients. METHODS: CBP patients suspected of axSpA from the SPACE (n = 438) and the DESIR (n = 647) cohort were asked about the presence of SpA diseases in first- or second-degree relatives (AS, AAU, ReA, IBD, and psoriasis). The associations between a PFH and HLA-B27, sacroiliitis on imaging (magnetic resonance imaging (MRI) or radiographs), axSpA diagnosis, and ASAS classification in CBP patients were assessed. RESULTS: In the SPACE and the DESIR cohort, a PFH of AS (odds ratio (OR) 5.9 (95% confidence interval (CI) 3.5-9.9), and OR 3.3 (95% CI 2.1-5.2)) and a PFH of AAU (OR 9.8 (95% CI 3.3-28.9) and OR 21.6 (95% CI 2.9-160.1)) were significantly associated with presence of HLA-B27. Furthermore, in both cohorts a PFH of AS and a PFH of AAU were positively associated with fulfilment of the ASAS criteria, but not with sacroiliitis on imaging. In SPACE but not in DESIR a PFH of AAU was positively associated with axSpA diagnosis. In both cohorts a PFH of ReA, IBD, or psoriasis was not positively associated with HLA-B27 positivity, sacroiliitis on imaging, axSpA diagnosis, or meeting the ASAS criteria for axSpA. CONCLUSIONS: In our cohorts, a PFH of AS or AAU is useful for case-finding of axSpA as this is correlated with HLA-B27 carriership. However, as a PFH of ReA, IBD, or psoriasis does not contribute to identifying axSpA in CBP patients, these data suggest that the widely used ASAS definition of a PFH of SpA should be updated. TRIAL REGISTRATION: Trial registration number, NCT01648907 . Registered on 20 July 2012. PMID- 28569224 TI - A call for papers. PMID- 28569225 TI - Mometasone furoate improves nasal and ocular symptoms of seasonal allergic rhinitis in adolescents. PMID- 28569226 TI - The status of asthma control in the U.S. adult population. PMID- 28569227 TI - Efficacy and safety of azelastine 0.15% nasal spray and azelastine 0.10% nasal spray in patients with seasonal allergic rhinitis. PMID- 28569228 TI - Contemporary assessment of the disease burden of sinusitis. PMID- 28569229 TI - Nasal polyp cell populations and fungal-specific peripheral blood lymphocyte proliferation in allergic fungal sinusitis. PMID- 28569230 TI - Characterization of bacterial and fungal biofilms in chronic rhinosinusitis. PMID- 28569231 TI - Adsorption Kinetics of 137Cs+/90Sr2+ on Ca-Bentonite. AB - 137Cs+/90Sr2+ adsorption kinetics on natural Ca-bentonite under the impact of different adsorption conditions was examined in detail. The results indicate that natural Ca-bentonite shows a strong adsorption capacity for Cs+/Sr2+. The adsorption reached at equilibrium after 2 hours for Cs+. Cs+/Sr2+removal efficiency reaches the highest when the pH value is 5 to 8 and increases with the increase of Ca-bentonite adding amount. Cs+ removal efficiency increases with the increase of Cs+ initial concentration, while Sr2+ removal efficiency slightly varies around 70%. The adsorption of Cs+/Sr2+ by Ca-bentonite follows the pseudo second-order model and is controlled by chemical adsorption. Meanwhile, the results of intraparticle diffusion modelling indicate that intraparticle diffusion is a kinetics controlling step, besides surface adsorption and liquid film diffusion. PMID- 28569232 TI - Dynamics of Phosphorus Content in the Water-Sediment Interface of Wetlands in a Mid-Temperature Steppe. AB - In order to reveal dynamics changes in phosphorus release from the sediments of wetlands in a mid-temperature steppe without external phosphorus input, the relationship between phosphorus content in the overlying water, sediment, and interstitial water was studied using the variables control method. The results showed that, during the incubation period, the content of total phosphorus in the overlying water and the content of total phosphorus in interstitial water both presented in the order of August > September > July. Furthermore, the correlation relationships between phosphorus content in the overlying water, total phosphorus in the interstitial water, and the ratios of sediment Olsen-P to total phosphorus in the interstitial water, indicated that Olsen-P might be a kind of release form of phosphorus - from the sediment to the overlying water of the wetlands in Hulunbeier steppe, without external phosphorus input. PMID- 28569233 TI - Balloon catheter sinuplasty in young children. AB - BACKGROUND: Balloon catheter sinuplasty (BCS) for chronic rhinosinusitis (CRS) was found to be successful in adults. The safety and feasibility of BCS in children has been recently established. The purpose of this study was to study the outcome of this technology in CRS in children. METHODS: A prospective, multicenter, nonrandomized evaluation was performed on patients with CRS. Thirty two children between the ages of 2 and 11 years were enrolled. Safety was assessed by rate of adverse events. Effectiveness was assessed using the Sino Nasal (SN)-5 quality-of-life questionnaire for children with CRS at 52 weeks follow-up. RESULTS: Thirty-two children were enrolled of which 24 completed their 52 weeks follow-up. No adverse events were reported because of the procedure. SN 5 score improved from a mean of 4.9 at baseline to a mean of 2.95 at 52 weeks (p < 0.0001). Twelve (50%) children had a significant improvement of their SN-5 (> 1.5), 7 (29%) had moderate improvement (>-1.0 and <-1.5), 2 (8%) had mild improvement (>-0.5 and <-1.0), 1 (4%) remained the same, and 2 (8%) had worsening scores. CONCLUSION: Balloon catheter dilation of the sinus ostia in children was safe and a significant number showed improvement of their SN-5 at 1 year follow up. Additional studies comparing balloon sinuplasty to other modalities of treatment in children are needed to determine its efficacy in the treatment of CRS in children. PMID- 28569234 TI - House-dust mite nasal provocation: A diagnostic tool in perennial rhinitis. AB - BACKGROUND: In perennial allergic rhinitis (PAR), the skin-prick test (SPT) is a good diagnostic tool to identify the specific allergens. A nasal provocation test (NPT) is used to identify allergens and to confirm the diagnosis. The aim of this study was to determine the optimal cutoff values of symptom and peak nasal inspiratory flow (PNIF) changes after dust-mite NPT for predicting PAR. We also studied the relationship of the changes of symptoms in NPT and the wheal size of SPT. METHODS: One hundred five patients with perennial rhinitis underwent the NPT to Dermatophagoides pteronyssinus and the SPT. The NPT was assessed by changes in symptoms and PNIF. The optimal cutoff values of the symptoms score and PNIF changes after the NPT for predicting the SPT were determined using a receiver operating characteristic (ROC) curve. The relationship of the wheal sizes of SPT and the changes from the NPT were analyzed. RESULTS: Forty-eight patients had a positive SPT to D. pteronyssinus, of whom 33 patients had a positive NPT by increases of the symptom score. Twenty patients had a positive NPT by decreases of PNIF. The area under the ROC curve was 0.85 for symptom score changes and it was 0.612 for PNIF changes. There was a significant correlation between the wheal size of the SPT and symptom changes in the NPT. CONCLUSION: Nasal provocation is a valuable test to confirm the diagnosis of D. pteronyssinus allergy, especially when the wheal from the SPT is small. The symptom change after the house-dust mite NPT is better than the PNIF change for predicting the PAR. PMID- 28569235 TI - A comparison of intranasal corticosteroid, leukotriene receptor antagonist, and topical antihistamine in reducing symptoms of perennial allergic rhinitis as assessed through the Rhinitis Severity Score. AB - Rhinitis symptom complex consists of rhinorrhea, congestion, itchy mucosa, itchy eyes, and sneezing. Available medications vary in their benefit for each of these symptoms. It was the purpose of this article to compare symptom reduction with three different classes of medications. Montelukast, azelastine, and budesonide were compared to determine the effect on individual, as well as total, symptom scores using the Rhinitis Severity Score (RSS). All three medications were compared with placebo and showed efficacy in prior studies using Balaam's crossover design. The inclusion and exclusion criteria and all procedures were identical for all three studies. In analyzing the data from the RSS questionnaire, we used the procedure PROC MIXED in SAS specific for Balaam's crossover design (SAS Institute, Inc., Cary, NC). Although all three medications were effective compared with placebo, montelukast had the greatest effect of the three medications on reduction of ocular itching and throat and palate itching. Azelastine's effect was greater than budesonide and montelukast for reduction of rhinorrhea. Systemic medication, montelukast, as expected, provided better relief for symptoms distant from the nasal cavity, and the antihistamine, azelastine, reduced rhinorrhea, more than either montelukast or budesonide. PMID- 28569236 TI - Evaluation of olopatadine hydrochloride nasal spray, 0.6%, used in combination with an intranasal corticosteroid in seasonal allergic rhinitis. AB - The combination of intranasal antihistamines and intranasal corticosteroids results in superior relief of seasonal allergic rhinitis (SAR) symptoms compared with monotherapy. This study was designed to evaluate the safety and efficacy of olopatadine hydrochloride nasal spray, 0.6% (OLO), administered in combination with fluticasone nasal spray, 50 micrograms (FNS), relative to azelastine nasal spray, 0.1% (AZE), administered in combination with FNS in the treatment of SAR. This was a multicenter, double-blind, randomized, parallel-group comparison of OLO + FNS versus AZE + FNS administered for 14 days to patients >=12 years of age with histories of SAR. Efficacy assessments recorded by patients in a daily diary included nasal symptom scores. Safety was evaluated based on adverse events (AEs). Pretreatment values for reflective total nasal symptoms scores (rTNSS) were similar for both treatment groups. The mean (SD) 2-week average rTNSS was 4.28 (2.63) for OLO + FNS and 4.15 (2.63) for AZE + FNS; these scores were not statistically different between treatment groups. No significant differences (p > 0.05) between OLO + FNS and AZE + FNS were observed for the average 2-week percent changes from baseline in rTNSS or in the individual nasal symptoms (nasal congestion, rhinorrhea, itchy nose, and sneezing). Compared with baseline, both groups had statistically significant improvement in rTNSS (p < 0.05). No serious AEs were reported in either group during the study period. Overall, 19 AEs were reported in the OLO + FNS group and 29 AEs were reported in the AZE + FNS group. OLO, when administered adjunctively with FNS, is effective, safe, and well tolerated in patients with SAR. PMID- 28569237 TI - Pharmaceutical and Endocrine Disruptor Compounds in Surface and Wastewater in San Marcos, Texas. AB - Water resource recovery facilities (WRRFs) and hospitals are major point sources of pharmaceuticals and endocrine disrupting compounds (EDCs) in aquatic environments. This study investigated the removal efficiencies of 23 known or suspected EDCs through the San Marcos WRRF to determine which treatment process was the most effective at removal. Results from samples collected at the hospital indicate that the hospital discharge is contributing to the concentration of these compounds in the San Marcos wastewater collection system (0.05-140 MUg/L concentrations). The most frequently detected compounds in the WRRF influent included acetaminophen, nonylphenol, caffeine, benzophenone, N,N-diethyl-m toluamide (DEET), bisphenol A (BPA), and triclosan. Comparison of influent and effluent concentrations showed that the San Marcos WRRF is effectively removing (>92%) of these compounds, with the exception of carbamazepine and tris(2 chloroethyl) phosphate (TCEP). These preliminary results will be used to guide future improvements within the WRRF. PMID- 28569238 TI - Analyzing breath samples of hypoglycemic events in type 1 diabetes patients: towards developing an alternative to diabetes alert dogs. AB - Diabetes is a disease that involves dysregulation of metabolic processes. Patients with type 1 diabetes (T1D) require insulin injections and measured food intake to maintain clinical stability, manually tracking their results by measuring blood glucose levels. Low blood glucose levels, hypoglycemia, can be extremely dangerous and can result in seizures, coma, or even death. Canines trained as diabetes alert dogs (DADs) have demonstrated the ability to detect hypoglycemia from breath, which led us to hypothesize that hypoglycemia, a metabolic dysregulation leading to low blood glucose levels, could be identified through analyzing volatile organic compounds (VOCs) contained within breath. We hoped to replicate the canines' detection ability and success by analytically using gas chromatography/mass spectrometry of VOCs in 128 breath samples collected from 52 youths with T1D at two different diabetes camps. We used different tests for significance including Ranksum, Student's T-test, and difference between means, and found a subset of 56 traces of potential metabolites. Principle component and linear discriminant analysis (LDA) confirmed a hypoglycemic signature likely resides within this group. Supervised machine learning combined with LDA narrowed the list of likely components to seven. The technique of leave one out cross validation demonstrated the model thus developed has a sensitivity of 91% (95% confidence interval (CI) [57.1, 94.7]) and a specificity of 84% (95% CI [73.0, 92.7]) at identifying hypoglycemia. Confidence intervals were obtained by bootstrapping. These results demonstrate that it is possible to differentiate breath samples obtained during hypoglycemic events from all other breath samples by analytical means and could lead to developing a simple analytical monitoring device as an alternative to using DADs. PMID- 28569239 TI - Environmental noise spectroscopy with qubits subjected to dynamical decoupling. AB - A qubit subjected to pure dephasing due to classical Gaussian noise can be turned into a spectrometer of this noise by utilizing its readout under properly chosen dynamical decoupling (DD) sequences to reconstruct the power spectral density of the noise. We review the theory behind this DD-based noise spectroscopy technique, paying special attention to issues that arise when the environmental noise is non-Gaussian and/or it has truly quantum properties. While we focus on the theoretical basis of the method, we connect the discussed concepts with specific experiments, and provide an overview of environmental noise models relevant for solid-state based qubits, including quantum-dot based spin qubits, superconducting qubits, and NV centers in diamond. PMID- 28569240 TI - Substrate independent approach for synthesis of graphene platelet networks. AB - Graphene platelet networks (GPNs) comprised of randomly oriented graphene flakes two to three atomic layers thick are synthesized using a novel plasma-based approach. The approach uses a substrate capable of withstanding synthesis temperatures around 800 degrees C, but is fully independent of the substrate material. The synthesis occurs directly on the substrate surface without the necessity of any additional steps. GPNs were synthesized on various substrate materials including silicon (Si), thermally oxidized Si (SiO2), molybdenum (Mo), nickel (Ni) and copper (Cu), nickel-chromium (NiCr) alloy and alumina ceramics (Al2O3). The mismatch between the atomic structures of sp2 honeycomb carbon networks and the substrate material is fully eliminated shortly after the synthesis initiation, namely when about 100 nm thick deposits are formed on the substrate. GPN structures synthesized on a substrate at a temperature of about 800 degrees C are significantly more porous in comparison to the much denser packed amorphous carbon deposits synthesized at lower temperatures. The method proposed here can potentially revolutionize the area of electrochemical energy storage by offering a single-step direct approach for the manufacture of graphene based electrodes for non-Faradaic supercapacitors. Mass production can be achieved using this method if a roll-to-roll system is utilized. PMID- 28569241 TI - Atrial fibrillation detection on compressed sensed ECG. AB - OBJECTIVE: Compressive sensing (CS) approaches to electrocardiogram (ECG) analysis provide efficient methods for real time encoding of cardiac activity. In doing so, it is important to assess the downstream effect of the compression on any signal processing and classification algorithms. CS is particularly suitable for low power wearable devices, thanks to its low-complex digital or hardware implementation that directly acquires a compressed version of the signal through random projections. In this work, we evaluate the impact of CS compression on atrial fibrillation (AF) detection accuracy. APPROACH: We compare schemes with data reconstruction based on wavelet and Gaussian models, followed by a P&T-based identification of beat-to-beat (RR) intervals on the MIT-BIH atrial fibrillation database. A state-of-the-art AF detector is applied to the RR time series and the accuracy of the AF detector is then evaluated under different levels of compression. We also consider a new beat detection procedure which operates directly in the compressed domain, avoiding costly signal reconstruction procedures. MAIN RESULTS: We demonstrate that for compression ratios up to 30[Formula: see text] the AF detector applied to RR intervals derived from the compressed signal exhibits results comparable to those achieved when employing a standard QRS detector on the raw uncompressed signals, and exhibits only a 2% accuracy drop at a compression ratio of 60%. We also show that the Gaussian-based reconstruction approach is superior in terms of AF detection accuracy, with a negligible drop in performance at a compression ratio ?75%, compared to a wavelet approach, which exhibited a significant drop in accuracy at a compression ratio ?65%. SIGNIFICANCE: The results suggest that CS should be considered as a plausible methodology for both efficient real time ECG compression (at moderate compression rates) and for offline analysis (at high compression rates). PMID- 28569242 TI - 13C isotopic abundances in natural nutrients: a newly formulated test meal for non-invasive diagnosis of type 2 diabetes. AB - A new method to replace commercially prepared 13C-labelled glucose with naturally available 13C-enriched substrates could result in promotion of the clinical applicability of the isotopic breath test for detection of type 2 diabetes (T2D). Variation of the carbon-13 isotope in human breath depends on the 13C enrichment in the diet taken by subjects. Here, we formulated a new test meal comprising naturally available 13C-enriched foods and subsequently administered it to non diabetic control (NDC) subjects and those with T2D. We found that the new test meal-derived 13C enrichment of breath CO2 was significantly lower in T2D compared with NDC. Furthermore, from our observations T2D exhibited higher isotopic enrichment of oxygen-18 (18O) in breath CO2 compared with NDC following ingestion of the new meal. We determined the optimal diagnostic cut-off values of 13C (i.e. delta 13C0/00 = 7.50/00) and 18O (i.e. delta 18O0/00 = 3.50/00) isotopes in breath CO2 for precise classification of T2D and NDC. Our new method involving the administration of naturally 13C-abundant nutrients showed a typical diagnostic sensitivity and specificity of about 95%, suggesting a valid and potentially robust global method devoid of any synthetically manufactured commercial 13C-enriched glucose which thus may serve as an alternative diagnostic tool for routine clinical applications. PMID- 28569244 TI - Capacitance-voltage characteristics of sub-nanometric Al2O3 / TiO2 laminates: dielectric and interface charge densities. AB - Advanced amorphous sub-nanometric laminates based on TiO2 and Al2O3 were deposited by atomic layer deposition at low temperature. Low densities of 'slow' and 'fast' interface states are achieved with values of 3.96 . 1010 cm-2 and 4.85 . 10-9 eV-1 cm-2, respectively, by using a 40 nm laminate constituted of 0.7 nm TiO2 and 0.8 nm Al2O3. The sub-nanometric laminate shows a low hysteresis width of 20 mV due to the low oxide charge density of about 3.72 . 1011 cm-2. Interestingly, such properties are required for stable and reliable performance of MOS capacitors and transistor operation. Thus, decreasing the individual layer thickness to the sub-nanometric range and combining two dielectric materials with oppositely charged defects may play a major role in the electrical response, highly promising for the application in future micro and nano-electronics applications. PMID- 28569243 TI - Cell sheet based bioink for 3D bioprinting applications. AB - In this research, a novel development of bioink from cell sheets is presented for scaffold free bioprinting applications. Poly(N-isopropylacrylamide) (PNIPAAm) coated surfaces were first prepared by using initiated chemical vapor deposition method. Cell-sheets were then grown on these thermoresponsive pNIPAAm coated surfaces and easily detached without disturbing delicate cell-extracellular matrix (ECM) and cell-cell interactions. The detached cells sheets were used to prepare cell sheet based bioink and bioprinted to form various shapes. The results showed that the prepared cell-sheet based bioink shows an increase in the structural integrity compare to cell-aggregates suggesting that the cell sheet aggregates preserved interconnected ECM proteins. The viability of cell sheet based aggregates was also compared to single cell aggregates at three different time points in a seven-day period after printing. The developed cell-sheet based bioink has several advantages in terms of shape fidelity, reproducibility and automated deposition for bioprinting applications. The results also demonstrated that the bioprinted constructs secreted collagen type I which is a strong indication of starting ECM deposition. Moreover, the immunostaining results showed that the fibronectin in cell sheets was preserved during and after the preparation process of bioink. PMID- 28569246 TI - Inactivation of RAD52 and HDF1 DNA repair genes leads to premature chronological aging and cellular instability. AB - The present study aims to investigate the role of radiation sensitive 52 (RAD52) and high-affinity DNA binding factor 1 (HDF1) DNA repair genes on the life span of budding yeasts during chronological aging. Wild type (wt) and rad52, hdf1, and rad52 hdf1 mutant Saccharomyces cerevisiae strains were used. Chronological aging and survival assays were studied by clonogenic assay and drop test. DNA damage was analyzed by electrophoresis after phenol extraction. Mutant analysis, colony forming units and the index of respiratory competence were studied by growing on dextrose and glycerol plates as a carbon source. Rad52 and rad52 hdf1 mutants showed a gradual decrease in surviving fraction in relation to wt and hdf1 mutant during aging. Genomic DNA was spontaneously more degraded during aging, mainly in rad52 mutants. This strain showed an increased percentage of revertant colonies. Moreover, all mutants showed a decrease in the index of respiratory competence during aging. The inactivation of RAD52 leads to premature chronological aging with an increase in DNA degradation and mutation frequency. In addition, RAD52 and HDF1 contribute to maintain the metabolic state, in a different way, during chronological aging. The results obtained could have important implications in the chronobiology of aging. PMID- 28569245 TI - Genetic diagnosis of a Chinese multiple endocrine neoplasia type 2A family through whole genome sequencing. AB - Approximately 98% of patients with multiple endocrine neoplasia type 2A (MEN 2A) have an identifiable RET mutation. Prophylactic or early total thyroidectomy or pheochromocytoma/parathyroid removal in patients can be preventative or curative and has become standard management. The general strategy for RET screening on family members at risk is to sequence the most commonly affected exons and, if negative, to extend sequencing to additional exons. However, different families with MEN 2A due to the same RET mutation often have significant variability in the clinical exhibition of disease and aggressiveness of the MTC, which implies additional genetic loci exsit beyond RET coding region. Whole genome sequencing (WGS) greatly expands the breadth of screening from genes associated with a particular disease to the whole genome and, potentially, all the information that the genome contains about diseases or traits. This is presumably due to additive effect of disease modifying factors. In this study, we performed WGS on a typical Chinese MEN 2A proband and identified the pathogenic RET p.C634R mutation. We also identified several neutral variants within RET and pheochromocytoma-related genes. Moreover, we found several interesting structural variants including genetic deletions (RSPO1, OVCH2 and AP3S1, etc.) and fusion transcripts (FSIP1 BAZ2A, etc.). PMID- 28569247 TI - Cytoplasmic tail of coronavirus spike protein has intracellular targeting signals. AB - Intracellular trafficking and localization studies of spike protein from SARS and OC43 showed that SARS spike protein is localized in the ER or ERGIC compartment and OC43 spike protein is predominantly localized in the lysosome. Differential localization can be explained by signal sequence. The sequence alignment using Clustal W shows that the signal sequence present at the cytoplasmic tail plays an important role in spike protein localization. A unique GYQEL motif is identified at the cytoplasmic terminal of OC43 spike protein which helps in localization in the lysosome, and a novel KLHYT motif is identified in the cytoplasmic tail of SARS spike protein which helps in ER or ERGIC localization. This study sheds some light on the role of cytoplasmic tail of spike protein in cell-to-cell fusion, coronavirus host cell fusion and subsequent pathogenicity. PMID- 28569248 TI - Effect of foliar application of salicylic acid, hydrogen peroxide and a xyloglucan oligosaccharide on capsiate content and gene expression associatedwith capsinoids synthesis in Capsicum annuum L. AB - Capsinoids are non-pungent analogues of capsaicinoids in pepper (Capsicum spp). The absence of pungency, in addition to their biological activities similar to that of capsaicinoids such as anti-inflammatory, antimicrobial, and antioxidant properties, makes capsinoids an excellent option for increasing use in human and animal nutrition, as well as health and pharmaceutical industries. There are only few sources of pepper producing capsinoids, and one of them (accession 509-45-1), Capsicum annuum L., is a potential source for increasing capsinoids content using strategies as controlled elicitation during plant production in the greenhouse. In this research we evaluated the effect of weekly and one-day-before-harvest foliar applications of hydrogen peroxide, salicylic acid and a xyloglucan oligosaccharide on the concentration of capsiate in fruits of this pepper accession, as well as the gene expression of phenylalanine ammonia-lyase (pal), putative aminotransferase (pamt), capsaicin synthase (at3) and beta-keto acyl synthase (kas). Results showed that the two tested concentrations of H2O2 significantly increased capsiate content and gene expression associated with capsaicinoids (pamt, at3 and kas) and the phenylpropanoids (pal) pathways. Plant yield was not affected using this induction strategy. Our results indicated that the pre-harvest and weekly application of hydrogen peroxide and xyloglucan oligosaccharide improved production of capsiate in C. annuum L. PMID- 28569249 TI - Estrogen is essential but not sufficient to induce endometriosis. AB - Endometriosis is a common gynaecological disorder of unknown aetiology. Among the several factors, estrogen has been implicated as a causative factor in endometriosis. In the present study using mouse model, we assessed the role of estrogen in the initial implantation and growth of endometrium in ectopic locations. Uterine tissues from green fluorescent protein (GFP) mice were transplanted in to the peritoneum of wild type mice in presence and absence of estrogen. As compared to untreated controls, the implantation of uterine tissue at ectopic locations was higher when estrogen was administered to both host and donor animals. However, this effect was not sustained as lesions regressed within 14 days of treatment. Irrespective of the treatment, peritoneal adipose was the most preferred site of lesion establishment. The lesions did not have typical features of the endometriosis (presence of glands and stroma) even after estrogen treatment and the ectopic tissue underwent regression by apoptosis irrespective of treatment. Since estrogen promotes implantation of endometrial tissue to ectopic locations but failure of these ectopic lesions to grow and sustain even in high estrogenic environment we propose that estrogen is necessary but not sufficient to sustain endometriosis. PMID- 28569250 TI - Interleukin 8 in progression of hormone-dependent early breast cancer. PMID- 28569251 TI - Long-term dietary restriction up-regulates activity and expression of renal arginase II in aging mice. AB - Arginase II is a mitochondrial enzyme that catalyses the hydrolysis of L-arginine into urea and ornithine. It is present in other extra-hepatic tissues that lack urea cycle. Therefore, it is plausible that arginase II has a physiological role other than urea cycle which includes polyamine, proline, glutamate synthesis and regulation of nitric oxide production. The high expression of arginase II in kidney, among extrahepatic tissues, might have an important role associated with kidney functions. The present study is aimed to determine the age-associated alteration in the activity and expression of arginase II in the kidney of mice of different ages. The effect of dietary restriction to modulate the agedependent changes of arginase II was also studied. Results showed that renal arginase II activity declines significantly with the progression of age (p less than 0.01 and p less than 0.001 in 6- and 18-month-old mice, respectively as compared to 2 month old mice) and is due to the reduction in its protein as well as the mRNA level (p less than 0.001 in both 6- and 18-month-old mice as compared to 2-month old mice). Long-term dietary restriction for three months has significantly up regulated arginase II activity and expression level in both 2- and 18-month-old mice (p less than 0.01 and p less than 0.001, respectively as compared to AL group). These findings clearly indicate that the reducing level of arginase II during aging might have an impact on the declining renal functions. This age dependent down-regulation of arginase II in the kidney can be attenuated by dietary restriction which may help in the maintenance of such functions. PMID- 28569252 TI - Somatic PI3K activity regulates transition to the spermatocyte stages in Drosophila testis. AB - Spermatogenesis, involving multiple transit amplification divisions and meiosis, occurs within an enclosure formed by two somatic cells. As the cohort of germline cells divide and grow, the surface areas of the somatic cells expand maintaining a tight encapsulation throughout the developmental period. Correlation between the somatic cell growth and germline development is unclear. Here, we report standardization of a quantitative assay developed for estimating the somatic roles of target molecules on germline division and differentiation in Drosophila testis. Using the assay, we studied the somatic roles of phosphatidylinositol-3 kinase (PI3K). It revealed that the expression of PI3KDN is likely to facilitate the early germline development at all stages, and an increase in the somatic PI3K activity during the early stages delays the transition to spermatocyte stage. Together, these results suggest that somatic cell growth plays an important role in regulating the rate of germline development. PMID- 28569253 TI - Enhanced delivery of biodegradable mPEG-PLGA-PLL nanoparticles loading Cy3 labelled PDGF-BB siRNA by UTMD to rat retina. AB - We investigated the efficacy and safety of ultrasound (US)-targeted microbubble (MB) destruction (UTMD)-enhanced delivery of monomethoxypoly(ethylene glycol) poly(lactic-co-glycolic acid)-poly-L-lysine (mPEG-PLGA-PLL) nanoparticles (NPs) loading Cy3-labelled platelet-derived growth factor BB (PDGF-BB) siRNA to rat retina in vivo. Eighty Wistar rats were divided into five groups (G). The right eyes, respectively, received an intravitreal injection as follows: normal saline (NS) (G1), NPs and NS (G2), NPs and MBs (G3), NPs and NS (G4) and NPs and MBs (G5). In G4 and G5, the eyes were exposed to US for 5 mins. Twenty-four hours after transfection, the uptake and distribution of Cy3-labelled siRNA in rat retina were observed by fluorescent microscope. The percentage of Cy3- labelled siRNA-positive cells was evaluated by flow cytometer. The levels of PDGF-BB mRNA in retinal pigment epithelium (RPE) cells and secreted PDGF-BB proteins were also measured. Hematoxylin and eosin staining and frozen sections were used to observe tissue damage. Our results showed that the number of Cy3-labelled siRNApositive cells in G5 was significantly higher than those of the other groups (P less than 0.05 for all comparisons). The maximum efficiency of siRNA uptake in neural retina was 18.22 +/_ 1.67%. In G4 and G5, a small number of Cy3- labelled siRNA positive cells were also detected in the pigmented cell layer of the retina. NPs loading siRNA delivered with UTMD could more effectively down-regulate the mRNA and protein expression of PDGF-BB than NPs plus US (P=0.014 and P=0.007, respectively). Histology showed no evident tissue damage after UTMDmediated NPs loading siRNA transfection. UTMD could be used safely to enhance the delivery of mPEG-PLGAPLL NPs loading siRNA into rat retina. PMID- 28569255 TI - An evaluation of the status of living collections for plant, environmental, and microbial research. AB - While living collections are critical for biological research, support for these foundational infrastructure elements is inconsistent, which makes quality control, regulatory compliance, and reproducibility difficult. In recent years, the Ecological Society of America has hosted several National Science Foundation sponsored workshops to explore and enhance the sustainability of biological research infrastructure. At the same time, the United States Culture Collection Network has brought together managers of living collections to foster collaboration and information exchange within a specific living collections community. To assess the sustainability of collections, a survey was distributed to collection scientists whose responses provide a benchmark for evaluating the resiliency of these collections. Among the key observations were that plant collections have larger staffing requirements and that living microbe collections were the most vulnerable to retirements or other disruptions. Many higher plant and vertebrate collections have institutional support and several have endowments. Other collections depend on competitive grant support in an era of intense competition for these resources. Opportunities for synergy among living collections depend upon complementing the natural strong engagement with the research communities that depend on these collections with enhanced information sharing, communication, and collective action to keep them sustainable for the future. External efforts by funding agencies and publishers could reinforce the advantages of having professional management of research resources across every discipline. PMID- 28569254 TI - Maternal high-fat diet during pregnancy and lactation affects hepatic lipid metabolism in early life of offspring rat. AB - We investigated whether maternal over-nutrition during pregnancy and lactation affects the offspring's lipid metabolism at weaning by assessing liver lipid metabolic gene expressions and analysing its mechanisms on the development of metabolic abnormalities. Female Sprague-Dawley rats were fed with standard chow diet (CON) or high-fat diet (HFD) for 8 weeks, and then continued feeding during gestation and lactation. The offspring whose dams were fed with HFD had a lower birth weight but an increased body weight with impaired glucose tolerance, higher serum cholesterol, and hepatic steatosis at weaning. Microarray analyses showed that there were 120 genes differently expressed between the two groups. We further verified the results by qRT-PCR. Significant increase of the lipogenesis (Me1, Scd1) gene expression was found in HFD (P less than 0.05), and up-regulated expression of genes (PPAR-alpha, Cpt1 alpha, Ehhadh) involved in beta-oxidation was also observed (P less than 0.05), but the Acsl3 gene was down-regulated (P less than 0.05). Maternal over-nutrition could not only primarily induce lipogenesis, but also promote lipolysis through an oxidation pathway as compensation, eventually leading to an increased body weight, impaired glucose tolerance, elevated serum cholesterol and hepatic steatosis at weaning. This finding may provide some evidence for a healthy maternal diet in order to reduce the risk of metabolic diseases in the early life of the offspring. PMID- 28569258 TI - Corrigendum: Intravenous administration of lidocaine directly acts on spinal dorsal horn and produces analgesic effect: An in vivo patch-clamp analysis. AB - This corrects the article DOI: 10.1038/srep26253. PMID- 28569257 TI - Current status and future prospect of FSHD region gene 1. AB - FSHD region gene 1 (FRG1), as the name suggests, is the primary candidate gene for fascioscapulohumeral muscular dystrophy disease. It seemingly affects muscle physiology in normal individuals but in FSHD, where it is found to be highly upregulated, might be involved in disruption of face, scapula and humeral skeletal muscle. Literature on FRG1, reviewed from 1996 to 2016, reveals that it is primarily associated with muscle development and maintenance. Approximately 75% of FSHD patients also show vascular abnormalities indicating that FRG1 might have some part to play in these abnormalities. Research involving vasculature in X. laevis larvae shows that FRG1 positively affects normal vasculature. Few of the well-established angiogenic regulators seem to get affected by abnormal expression level of FRG1. Its primary localization in sub nuclear structures like Cajal bodies and nuclear speckles indicates regulation of the above-mentioned factors by transcriptional and post-transcriptional machineries, but in-depth studies need to be done to conclude a clear statement. In this review, we have attempted to present all the work done on FRG1, all the lacunas which need to be unraveled, and hypothesized a model for our readers to get an insight into its molecular mechanism. PMID- 28569256 TI - Regulation of dynamin family proteins by post-translational modifications. AB - Dynamin superfamily proteins comprising classical dynamins and related proteins are membrane remodelling agents involved in several biological processes such as endocytosis, maintenance of organelle morphology and viral resistance. These large GTPases couple GTP hydrolysis with membrane alterations such as fission, fusion or tubulation by undergoing repeated cycles of self-assembly/disassembly. The functions of these proteins are regulated by various post-translational modifications that affect their GTPase activity, multimerization or membrane association. Recently, several reports have demonstrated variety of such modifications providing a better understanding of the mechanisms by which dynamin proteins influence cellular responses to physiological and environmental cues. In this review, we discuss major post-translational modifications along with their roles in the mechanism of dynamin functions and implications in various cellular processes. PMID- 28569259 TI - Revealing complete complex KIR haplotypes phased by long-read sequencing technology. AB - The killer cell immunoglobulin-like receptor (KIR) region of human chromosome 19 contains up to 16 genes for natural killer (NK) cell receptors that recognize human leukocyte antigen (HLA)/peptide complexes and other ligands. The KIR proteins fulfill functional roles in infections, pregnancy, autoimmune diseases and transplantation. However, their characterization remains a constant challenge. Not only are the genes highly homologous due to their recent evolution by tandem duplications, but the region is structurally dynamic due to frequent transposon-mediated recombination. A sequencing approach that precisely captures the complexity of KIR haplotypes for functional annotation is desirable. We present a unique approach to haplotype the KIR loci using single-molecule, real time (SMRT) sequencing. Using this method, we have-for the first time comprehensively sequenced and phased sixteen KIR haplotypes from eight individuals without imputation. The information revealed four novel haplotype structures, a novel gene-fusion allele, novel and confirmed insertion/deletion events, a homozygous individual, and overall diversity for the structural haplotypes and their alleles. These KIR haplotypes augment our existing knowledge by providing high-quality references, evolutionary informers, and source material for imputation. The haplotype sequences and gene annotations provide alternative loci for the KIR region in the human genome reference GrCh38.p8. PMID- 28569262 TI - Osteoarthritis: Nerve ablation - a new treatment for OA pain? PMID- 28569260 TI - Association of left ventricular structural and functional abnormalities with aortic and brachial blood pressure variability in hypertensive patients: the SAFAR study. AB - Both brachial blood pressure (BP) level and its variability (BPV) significantly associate with left ventricular (LV) structure and function. Recent studies indicate that aortic BP is superior to brachial BP in the association with LV abnormalities. However, it remains unknown whether aortic BPV better associate with LV structural and functional abnormalities. We therefore aimed to investigate and compare aortic versus brachial BPV, in terms of the identification of LV abnormalities. Two hundred and three participants who underwent echocardiography were included in this study. Twenty-four-hour aortic and brachial ambulatory BP was measured simultaneously by a validated BP monitor (Mobil-O-Graph, Stolberg, Germany) and BPV was calculated with validated formulae. LV mass and LV diastolic dysfunction (LVDD) were evaluated by echocardiography. The prevalence of LV hypertrophy (LVH) and LVDD increased significantly with BPV indices (P?0.04) in trend tests. After adjustment to potential confounders, only aortic average real variability (ARV), but not brachial ARV or weighted s.d. (wSD, neither aortic nor brachial) significantly associated with LV mass index (P=0.02). Similar results were observed in logistic regression. After adjustment, only aortic ARV significantly associated with LVH (odds ratio (OR) and 95% confidence interval (CI): 2.28 (1.08, 4.82)). As for LVDD, neither the brachial nor the aortic 24-hour wSD, but the aortic and brachial ARV, associated with LVDD significantly, with OR=2.28 (95% CI: (1.03, 5.02)) and OR=2.36 (95% CI: (1.10, 5.05)), respectively. In summary, aortic BPV, especially aortic ARV, seems to be superior to brachial BPV in the association of LV structural and functional abnormalities. PMID- 28569264 TI - Experimental arthritis: FLIPping the switch on macrophages. PMID- 28569261 TI - Optogenetic neuronal stimulation of the lateral cerebellar nucleus promotes persistent functional recovery after stroke. AB - Stroke induces network-wide changes in the brain, affecting the excitability in both nearby and remotely connected regions. Brain stimulation is a promising neurorestorative technique that has been shown to improve stroke recovery by altering neuronal activity of the target area. However, it is unclear whether the beneficial effect of stimulation is a result of neuronal or non-neuronal activation, as existing stimulation techniques nonspecifically activate/inhibit all cell types (neurons, glia, endothelial cells, oligodendrocytes) in the stimulated area. Furthermore, which brain circuit is efficacious for brain stimulation is unknown. Here we use the optogenetics approach to selectively stimulate neurons in the lateral cerebellar nucleus (LCN), a deep cerebellar nucleus that sends major excitatory output to multiple motor and sensory areas in the forebrain. Repeated LCN stimulations resulted in a robust and persistent recovery on the rotating beam test, even after cessation of stimulations for 2 weeks. Furthermore, western blot analysis demonstrated that LCN stimulations significantly increased the axonal growth protein GAP43 in the ipsilesional somatosensory cortex. Our results demonstrate that pan-neuronal stimulations of the LCN is sufficient to promote robust and persistent recovery after stroke, and thus is a promising target for brain stimulation. PMID- 28569265 TI - Spondyloarthropathies: Gut-bone crosstalk in HLA-B27 rats. PMID- 28569266 TI - Pharmacotherapy: Biosimilar switching - "To set a form upon desired change". PMID- 28569263 TI - The genetics revolution in rheumatology: large scale genomic arrays and genetic mapping. AB - Susceptibility to rheumatic diseases, such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, juvenile idiopathic arthritis and psoriatic arthritis, includes a large genetic component. Understanding how an individual's genetic background influences disease onset and outcome can lead to a better understanding of disease biology, improved diagnosis and treatment, and, ultimately, to disease prevention or cure. The past decade has seen great progress in the identification of genetic variants that influence the risk of rheumatic diseases. The challenging task of unravelling the function of these variants is ongoing. In this Review, the major insights from genetic studies, gained from advances in technology, bioinformatics and study design, are discussed in the context of rheumatic disease. In addition, pivotal genetic studies in the main rheumatic diseases are highlighted, with insights into how these studies have changed the way we view these conditions in terms of disease overlap, pathways of disease and potential new therapeutic targets. Finally, the limitations of genetic studies, gaps in our knowledge and ways in which current genetic knowledge can be fully translated into clinical benefit are examined. PMID- 28569268 TI - Dyslipidaemia: Is CETP inhibition a viable therapeutic strategy? PMID- 28569267 TI - Biologics registers in RA: methodological aspects, current role and future applications. AB - The beginning of the 21st century saw a biopharmaceutical revolution in the treatment of inflammatory rheumatic diseases, particularly rheumatoid arthritis. The fast-evolving use of biologic therapies highlighted the need to develop registers at national and international levels with the aim of collecting long term data on patient outcomes. Over the past 15 years, many biologics registers have contributed a wealth of data and provided robust and reliable evidence on the use, effectiveness and safety of these therapies. The unavoidable challenges posed by the continuous introduction of new therapies, particularly with regard to understanding their long-term safety, highlights the importance of learning from experience with established biologic therapies. In this Perspectives article, the role of biologics registers in bridging the evidence gap between efficacy in clinical trials and real-world effectiveness is discussed, with a focus on methodological aspects of registers, their unique features and challenges and their role going forward. PMID- 28569270 TI - Heart failure: HF-induced diaphragmatic atrophy and weakness. PMID- 28569271 TI - Heart failure: BRD4 inhibition slows HF progression. PMID- 28569272 TI - Gastric adenocarcinoma. AB - Gastric cancers, with gastric adenocarcinoma (GAC) as the most common histological type, impose a considerable global health burden. Although the screening strategies for early detection have been shown to be successful in Japan and South Korea, they are either not implemented or not feasible in most of the world, leading to late diagnosis in most patients. Helicobacter pylori infection contributes to the development of many endemic GACs, and pre-emptive eradication or early treatment of this bacterial infection might provide effective primary prevention. GACs are phenotypically and genotypically heterogeneous. Localized (clinical stage I) GAC is best treated either endoscopically or with limited surgical resection, but clinical stage II or stage III tumours require multidisciplinary adjunctive approaches in addition to surgery. Although GAC is highly treatable in its early stages, advanced (clinical stage IV) GAC has a median survival of just ~9-10 months. However, detailed molecular and immune profiling of GAC is yielding promise; early studies with immune checkpoint inhibitors suggest that GAC is amenable to immune modulation. Molecular studies have yielded a vast quantity of new information for potential exploitation. Nevertheless, advances against GACs have lagged compared with other tumours of similar incidence, and more research is necessary to overcome the obstacles to prolong survival. PMID- 28569269 TI - Mendelian randomization in cardiometabolic disease: challenges in evaluating causality. AB - Mendelian randomization (MR) is a burgeoning field that involves the use of genetic variants to assess causal relationships between exposures and outcomes. MR studies can be straightforward; for example, genetic variants within or near the encoding locus that is associated with protein concentrations can help to assess their causal role in disease. However, a more complex relationship between the genetic variants and an exposure can make findings from MR more difficult to interpret. In this Review, we describe some of these challenges in interpreting MR analyses, including those from studies using genetic variants to assess causality of multiple traits (such as branched-chain amino acids and risk of diabetes mellitus); studies describing pleiotropic variants (for example, C reactive protein and its contribution to coronary heart disease); and those investigating variants that disrupt normal function of an exposure (for example, HDL cholesterol or IL-6 and coronary heart disease). Furthermore, MR studies on variants that encode enzymes responsible for the metabolism of an exposure (such as alcohol) are discussed, in addition to those assessing the effects of variants on time-dependent exposures (extracellular superoxide dismutase), cumulative exposures (LDL cholesterol), and overlapping exposures (triglycerides and non-HDL cholesterol). We elaborate on the molecular features of each relationship, and provide explanations for the likely causal associations. In doing so, we hope to contribute towards more reliable evaluations of MR findings. PMID- 28569273 TI - Turning predator into prey - the problem of predatory journals. PMID- 28569274 TI - The state of medical training: refocusing our narrative. PMID- 28569275 TI - A critique of the National Clinical Strategy for Scotland. PMID- 28569276 TI - The case for using an evolutionary professional protocol for improving care: act local, think global. PMID- 28569277 TI - Clinical Stroke prevention in atrial fibrillation. AB - Oral anticoagulation therapy has reduced the risk of ischaemic stroke and improved the outcomes for patients with atrial fibrillation considerably. The emergence of the non-vitamin K oral anticoagulants as alternatives to vitamin K antagonists has significantly changed the practice of stroke prevention in atrial fibrillation. As the main complication with antithrombotic therapy is bleeding, physicians should always balance the risk of ischaemic stroke against intracranial haemorrhage and intervene where appropriate to reduce both risks. Individual approach is often mandatory due to heterogeneity of the risks and patient preferences. The purpose of this review is to summarise the current knowledge of the oral anticoagulation therapy in atrial fibrillation patients and guide physicians with the management of anticoagulants based on data from clinical trials and systematic reviews. PMID- 28569278 TI - Governance and oversight of researcher access to electronic health data: the role of the Independent Scientific Advisory Committee for MHRA database research, 2006 2015. AB - In order to promote understanding of UK governance and assurance relating to electronic health records research, we present and discuss the role of the Independent Scientific Advisory Committee (ISAC) for MHRA database research in evaluating protocols proposing the use of the Clinical Practice Research Datalink. We describe the development of the Committee's activities between 2006 and 2015, alongside growth in data linkage and wider national electronic health records programmes, including the application and assessment processes, and our approach to undertaking this work. Our model can provide independence, challenge and support to data providers such as the Clinical Practice Research Datalink database which has been used for well over 1,000 medical research projects. ISAC's role in scientific oversight ensures feasible and scientifically acceptable plans are in place, while having both lay and professional membership addresses governance issues in order to protect the integrity of the database and ensure that public confidence is maintained. PMID- 28569279 TI - Safety and efficacy of self-expandable metal stents for obstructive proximal and distal large bowel cancer. AB - Self-expandable metal stents are often used to treat obstructive large bowel cancers. This study assessed the safety and efficacy of colonic stent insertion carried out in a district general hospital. Methods A retrospective review was carried out between 1 January 2007 and 28 February 2014 to identify patients who underwent stent insertion for malignant colorectal obstruction. Results Seventy five patients (median age 75.2 years, 70.6% male) with primary colorectal cancer underwent stent insertion - 53 underwent semi-elective self-expanded metal stent insertion (for subacute bowel obstruction) and 22 had emergency stent inserted (for acute bowel obstruction). The majority (88%) had self-expanded metal stents inserted for palliation. Technical and clinical success rates were 98.7% and 91.2%, respectively. One patient had stent-related perforation; there was no procedure-related mortality. Conclusion This study shows that self-expanded metal stent insertion in malignant colorectal obstruction is safe and effective and can be successfully delivered in a district general hospital with high technical and clinical success rates. PMID- 28569280 TI - Respiratory dysfunction in Parkinson's disease. AB - Respiratory dysfunction has been associated with Parkinson's disease since it was first described in 1817. The respiratory symptoms observed in Parkinson's disease patients vary greatly. Most patients remain asymptomatic, whereas others present with acute shortness of breath and even stridor. In August 2016, an electronic literature search was conducted using PubMed and Google Scholar. Results were screened and studies reporting on respiratory dysfunction associated with Parkinson's disease were included. Respiratory dysfunction is due to a combination of factors including restrictive changes, upper airway obstruction, abnormal ventilatory drive and response to medications. Much debate surrounds the mechanism underlying respiratory dysfunction in Parkinson's disease, its prevalence and the effect of levodopa on respiration. It is clear from this review that larger studies, comparing patients of similar disease duration and severity using the same pulmonary function parameters, are required to provide a better understanding of the pathophysiology underlying respiratory dysfunction in Parkinson's disease. PMID- 28569281 TI - A qualitative study of determinants of patient behaviour leading to an infection related hospital admission. AB - Objectives To describe and understand the determinants of patients' behaviours surrounding admission to hospital for an acute infective episode Method Patients admitted to the infection or acute medicine admission units of a major Scottish teaching hospital and commenced on antibiotic therapy after admission were included. Semi-structured face-to-face interviews were conducted using a pre piloted interview schedule guide that focused on gathering information about patient behaviours and experiences prior to admission to hospital with an acute infection. Interviews were audio-recorded, transcribed verbatim and analysed using the Framework Approach. Emerging themes were matched to the Theoretical Domains Framework of behavioural determinants. Results Twenty-one patients consented to participate and 18 transcripts were suitable for analysis. The most common infections were those of the skin, soft tissue and respiratory tract. From the patients' perspectives, behavioural determinants that appeared to impact their admission to hospital were principally their knowledge, beliefs of consequences, the environmental context and resources (mainly out-of-hours services), social influences and their own emotions. Determinants such as knowledge of the signs and symptoms, beliefs of consequences and environmental context were facilitators of health seeking behaviours. The main barriers were a lack of awareness of consequences of infection potentially leading to delayed admission impacting infection severity, stay in secondary care and resource utilisation. Conclusions This study has shown that any initial patient-centred intervention that is proposed to change patient behaviour needs to be based on behavioural determinants emerging in this research. The intervention may include aspects such as patient education on resources available out-of-hours and ways to access the healthcare system, education on recognising signs of infection leading to prompter treatment and positive reinforcement for patients who present with recurrences of infection. PMID- 28569282 TI - Do not attempt cardiopulmonary resuscitation decisions: joint guidance. AB - Since its introduction in the 1960s as a treatment to restart the heart after sudden cardiac arrest from a heart attack, attempts at cardiopulmonary resuscitation have become more common in other clinical situations. Cardiopulmonary resuscitation can be a lifesaving treatment, with the likelihood of recovery varying greatly depending on individual circumstances; however, overall, the proportion of people who survive following cardiopulmonary resuscitation is relatively low. Anticipatory decisions were recognised as being the best way of ensuring that cardiopulmonary resuscitation was not attempted against individuals' wishes. Since 2001, the British Medical Association, Resuscitation Council (UK) and Royal College of Nursing have published professional guidance on decisions relating to cardiopulmonary resuscitation. The latest version of this guidance was published in June 2016. This paper summarises the key legal and ethical principles that should inform all cardiopulmonary resuscitation decisions, with particular emphasis on the recent changes in law and policy. PMID- 28569283 TI - Isolated mediastinal lymphadenopathy - performance of EBUS-TBNA in clinical practice. AB - Background Isolated mediastinal lymphadenopathy is an increasingly common finding as a result of the increasing use of cross-sectional thoracic imaging. We investigated the performance of endobronchial ultrasoundguided transbronchial needle-aspiration (EBUS-TBNA) in establishing a pathological diagnosis in patients with isolated mediastinal lymphadenopathy. Methods We retrospectively analysed all consecutive EBUS-TBNA examinations performed over a 4-year period at a single tertiary referral centre. Final diagnoses were made using pathology reports, correlated with clinical features and the results of any other investigations. Results In total, 126 EBUS-TBNA examinations were performed to investigate isolated mediastinal lymphadenopathy. A positive pathological diagnosis was made following EBUSTBNA in 54 cases (43%). When the results of further investigations and variable radiological follow up were included, the final sensitivity of EBUS-TBNA for making a diagnosis in isolated mediastinal lymphadenopathy was 80% (95% CI 69%-89%). Conclusions This study confirms that EBUS-TBNA has acceptable sensitivity for detecting both benign and malignant pathologies underlying isolated mediastinal lymphadenopathy. PMID- 28569284 TI - Acute pulmonary oedema: not always cardiogenic. AB - A patient presented with fulminant pulmonary oedema and required acute intubation and ventilation. There was no history of a prior cardiac disorder. As he was weaned from sedation, following stabilisation of his pulmonary status, neurological signs suggestive of brainstem dysfunction became apparent. Investigations showed infarcts in the posterior cerebral circulation secondary to a vertebral artery dissection. Neurogenic pulmonary oedema needs to be considered in any patient with fulminant pulmonary oedema without overt evidence or history of cardiac disease. PMID- 28569285 TI - A promising new scoring system to detect and predict delirium in the acute clinical setting. PMID- 28569286 TI - Autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis. PMID- 28569287 TI - Effect of a national focused course on academic medicine for UK candidates applying for a Clinical Academic Programme. AB - Background Academic medicine is crucial for healthcare advancement. However, recruitment of junior doctors into academia remains an area of concern globally. In the UK, a national integrated clinical academic pathway was developed to address these issues, with the Academic Foundation Programme as the 'first opportunity for research'. We aimed to evaluate whether a focused course on academic medicine could enhance knowledge, confidence and preparedness of candidates wishing to apply for an academic programme. Methods UK medical students attended a national course conducted by current UK Academic Foundation Programme doctors that comprised lectures on academic medicine and various aspects of the Academic Foundation Programme. An online questionnaire-based cross sectional study was conducted with participants rating measures including knowledge, preparedness and confidence related to Academic Foundation Programme applications. Outcomes were measured using Likert scales (1=low; 5=high). Results In total, 103 out of 155 attendees from 11 different UK medical schools responded to the survey (66% response rate). Pre and post-course data showed increase in participants' knowledge (median score 2 vs 4, p < 0.0001), understanding of the application process (median score 2 vs 4, p < 0.0001), confidence (median score 2 vs 4, p < 0.0001) and preparedness (median score 2 vs 4, p < 0.0001) in applying for the Academic Foundation Programme. Conclusion To our knowledge this is the first study in the available literature that demonstrates a focused course on academic medicine may enhance UK medical students' knowledge, confidence and preparedness in applying for a clinical academic programme. Further research will ascertain whether such courses can augment trainee numbers undertaking and remaining within academic medicine. PMID- 28569288 TI - Being the 'med reg': an exploration of junior doctors' perceptions of the medical registrar role. AB - The role of the medical registrar is challenging and acknowledged as being a disincentive to a career in medicine for some junior doctors. We set out to build a broader understanding of the role through exploration of Foundation Doctors' and Core Medical Trainees' perceptions of the role. Data, gathered from focus groups, were analysed using a framework approach. Six key themes were identified, which were grouped under the headings 'perceptions of the medical registrar role' and 'transition into the role'. Our work builds on existing literature to inform a deeper understanding of how junior doctors perceive the medical registrar role. In light of our findings we offer suggestions on possible training initiatives to tackle the issues identified. We also highlight positive perceptions of the role and emphasise the key ambassadorial role that current medical registrars have in relation to attracting tomorrow's medical registrars to the specialty. PMID- 28569289 TI - What happens to the heart in chronic kidney disease? AB - Cardiovascular disease is common in patients with chronic kidney disease. The increased risk of cardiovascular disease seen in this population is attributable to both traditional and novel vascular risk factors. Risk of sudden cardiac or arrhythmogenic death is greatly exaggerated in chronic kidney disease, particularly in patients with end stage renal disease where the risk is roughly 20 times that of the general population. The reasons for this increased risk are not entirely understood and while atherosclerosis is accelerated in the presence of chronic kidney disease, premature myocardial infarction does not solely account for the excess risk. Recent work demonstrates that the structure and function of the heart starts to alter early in chronic kidney disease, independent of other risk factors. The implications of cardiac remodelling and hypertrophy may predispose chronic kidney disease patients to heart failure, arrhythmia and myocardial ischaemia. Further research is needed to minimise cardiovascular risk associated with structural and functional heart disease associated with chronic kidney disease. PMID- 28569290 TI - Novel combined management approaches to patients with diabetes, chronic kidney disease and cardiovascular disease. AB - Most patients we care for today suffer from more than one chronic disease, and multimorbidity is a rapidly growing challenge. Concomitant cardiovascular disease, renal dysfunction and diabetes represent a large proportion of all patients in cardiology, nephrology and diabetology. These entities commonly overlap due to their negative effects on vascular function and an accelerated atherosclerosis progression. At the same time, a progressive subspecialisation has caused the cardiologist to treat 'only' the heart, nephrologists 'only' the kidneys and endocrinologists' 'only' diabetes. Studies and guidelines follow the same pattern. This often requires patients to visit specialists for each field, with a risk of both under-diagnosis and under-treatment. From the patient's perspective, there is a great need for coordination and facilitation of the care, not only to reduce disease progression but also to improve quality of life. Person-centred integrated clinics for patients with cardiovascular disease, renal dysfunction and diabetes are a promising approach for complex chronic disease management. PMID- 28569291 TI - Misadventure in Muirhouse. HIV infection: a modern plague and persisting public health problem. AB - This story is of particular interest and importance to Edinburgh and Scottish medicine. It describes the events in one general medical practice in Edinburgh, the Muirhouse Medical Group, and their impact and relationship to the AIDS pandemic. For many, the origin of HIV in the UK is now history. Since the introduction of HIV/AIDS into the intravenous illegal drug using community, much has changed but problems remain that should concern policy makers and clinicians. Reflections on the recent history of the HIV epidemic among drug users in the UK provide important insights into risks for current policy making and the potentially problematic direction that policy has taken. Rather than starting from a pragmatic baseline of harm minimisation, with its low cost, high impact, prevention approach, the emphasis, and consequently the resources, has been on a model of recovery which fails to acknowledge the fragile control maintained by early intervention and supporting treatments. In 2015, the re-emergence of HIV in a vulnerable inner city population of people who inject drugs highlighted a policy failure. An ongoing epidemic could and should have been prevented, as should several other recent epidemics of other viral or bacterial infections in urban populations in Scotland. The story of HIV is full of controversy, denial, prejudice and stigma. At all levels across the world from national presidents, governments and public opinion, progress has been impeded by these problems. People using drugs have an additional set of problems: criminality, poverty and marginalisation from education and the supports of main stream society. These continue to hamper efforts to improve lives and prevent disease. PMID- 28569292 TI - From The House with the Green Shutters to Our Lady of Perpetual Succour: the portrayal of alcohol in the modern Scottish novel. AB - In modern Scottish literature alcohol is a recurrent subject; this paper examines the different ways it is portrayed with particular emphasis on the novel. It has been seen as the resort of the weak-minded and the cause of personal degradation. It has been portrayed as a response to and a symptom of social disintegration. It has been depicted as leading to delirium and psychosis. On a positive note it has been hailed as a source of inspiration and as a means of celebration. It has helped some troubled characters find the road to redemption. Along the way we encounter various literary stereotypes of the drinker, while the pub forms the backdrop to much of the action. PMID- 28569293 TI - Rhubarb (Rheum species): the role of Edinburgh in its cultivation and development. AB - Rhubarb was grown and used throughout China for thousands of years. It then found its way to St Petersburg where the Romanovs developed a flourishing trade in the plant to the rest of Europe. James Mounsey, a physician to the Tsar, brought back seeds from Russia to Scotland at considerable risk to himself. He passed some of the seeds to Alexander Dick and John Hope. Both these physicians then grew rhubarb at Prestonfield and the Botanic Garden (both in Edinburgh), respectively. Eventually rhubarb, in the form of Gregory's powder, became a common and popular medicine throughout the UK. PMID- 28569294 TI - The medical consultation in historical perspective. Reflections on talking and touching PMID- 28569295 TI - Solution plasma synthesis of a boron-carbon-nitrogen catalyst with a controllable bond structure. AB - Synthesis of boron-carbon-nitrogen (BCN) nanocarbon with a controllable bond structure for enhanced oxygen reduction reaction (ORR) activity and durability was performed using a new method of discharge in organic solution mixtures named the 'Solution Plasma Process'. Using selected precursors a new strategy for the simultaneous synthesis of nanocarbon co-doped with heteroatoms was found. The synergistic effect of N and B in an uncoupling bond state improved the formation of new active sites for the ORR performance by changing the electronic structure of the base carbon. Meanwhile, when B and N are bonded together, the BCN catalyst contributes to a reduced ORR activity by forming a balanced electronic structure in carbon. The BCN nanocarbon with an uncoupling bond state exhibits an enhanced ORR activity under alkaline conditions, with an onset potential of -0.25 V versus -0.31 V for B/N coupling and 3.43 transferred electrons during the ORR. Although the ORR activity of the B/N uncoupling nanocarbon was not as good as the typical Pt/C, the durability of this synthesized material (15.1% current decrease after 20 000 s of operation) was significantly better than that of the Pt/C catalyst (61.5% current drop under the same conditions). After the durability test, the increase of the chemical states containing oxygen was higher for Pt/C than B/N uncoupling. PMID- 28569296 TI - Gold-catalyzed diastereoselective domino dearomatization/ipso-cyclization/aza Michael sequence: a facile access to diverse fused azaspiro tetracyclic scaffolds. AB - A facile and diversity-oriented access to complex tetracyclic benzo[e]pyrrolo[2,3 c]indole-2,4,7(5H)-triones through a post-Ugi gold(i)-catalyzed domino dearomatization/ipso-cyclization/aza-Michael sequence is elaborated. This process furnishes tetracyclic scaffolds in good yields from readily available precursors with unique diastereoselectivity. PMID- 28569297 TI - Direct N-acylation of sulfoximines with carboxylic acids catalyzed by the B3NO2 heterocycle. AB - In contrast to recent significant progress in the development of catalytic methodologies for nitrogen acylations, syntheses of N-acyl sulfoximines have been slow to evolve, and still largely rely on the use of stoichiometric amounts of activating reagents. Here we describe the direct acylation of the nitrogen atom in sulfoximines with carboxylic acids promoted by a heterocyclic catalyst featuring the B3NO2 ring system. The protocol used was found to be operationally simple and to tolerate a wide range of functional groups, furnishing the N acylated sulfoximines in good yield. The multiboron catalyst tamed previously intractable nitrogen nucleophiles, allowing for the short synthesis of a factor Xa inhibitor by catalyzing two consecutive nitrogen acylations in the same pot. PMID- 28569298 TI - Nickel-catalyzed hydrocarboxylation of ynamides with CO2 and H2O: observation of unexpected regioselectivity. AB - We describe the nickel-catalyzed hydrocarboxylation of ynamides with CO2 and H2O to afford a variety of alpha-amino-alpha,beta-unsaturated esters with high regioselectivities. The selective alpha-carboxylation of ynamides with this catalytic protocol is unexpected in view of the electronic bias of ynamides and is in sharp contrast to our previous study in which a stoichiometric amount of Ni(0) was used to form a beta-carboxylated product exclusively. We revealed that this unexpected C-C bond formation was induced by the combination of Zn and MgBr2. PMID- 28569299 TI - Tiny changes in local order identify the cluster formation threshold in model fluids with competing interactions. AB - We use Monte Carlo simulations to carry out a thorough analysis of structural correlations arising in a relatively dense fluid of rigid spherical particles with prototype competing interactions (short-range attractive and long-range repulsive two-Yukawa model). As the attraction strength increases, we show that the local density of the fluid displays a tiny reversal of trend within specific ranges of interparticle distances, whereupon it decreases first and increases afterwards, passing through a local minimum. Particles involved in this trend display, accordingly, distinct behaviours: for a sufficiently weak attraction, they seem to contribute to the long-wave oscillations typically heralding the formation of patterns in such fluids; for a stronger attraction, after the reversal of the local density has occurred, they form an outer shell of neighbours stabilizing the existing aggregation seeds. Following the increment of attraction, precisely in correspondence of the local density reversal, the local peak developed in the structure factor at small wavevectors markedly rises, signalling-in agreement with recent structural criteria-the onset of a clustered state. A detailed cluster analysis of microscopic configurations fully validates this picture. PMID- 28569301 TI - Interacting nanoscale magnetic superatom cluster arrays in molybdenum oxide bronzes. AB - In this study, we examine several reduced ternary molybdates in the family of yellow rare earth molybdenum bronzes produced by electrochemical synthesis with composition LnMo16O44. These compounds contain an array of electrically isolated but magnetically interacting multi-atom clusters with composition Mo8O36. These arrayed superatom clusters support a single hole shared among the eight molybdenum atoms in the unit, corresponding to a net spin moment of 1MUB, and exhibit magnetic exchange between the units via the MoO4 tetrahedra (containing Mo6+ ions) and the LnO8 cubes (containing Ln3+ ions). The findings presented here expand on the physics of the unusual collective properties of multi-atom clusters and extend the discussion of such assemblages to the rich structural chemistry of molybdenum bronzes. PMID- 28569300 TI - Opportunities for natural products in 21st century antibiotic discovery. AB - Natural products and their derivatives are mainstays of our antibiotic drugs, but they are increasingly in peril. The combination of widespread multidrug resistance in once susceptible bacterial pathogens, disenchantment with natural products as sources of new drugs, lack of success using synthetic compounds and target-based discovery methods, along with shifting economic and regulatory issues, conspire to move investment in research and development away from the antibiotics arena. The result is a growing crisis in antibiotic drug discovery that threatens modern medicine. 21st century natural product research is perfectly positioned to fill the antibiotic discovery gap and bring new drug candidates to the clinic. Innovations in genomics and techniques to explore new sources of antimicrobial chemical matter are revealing new chemistry. Increasing appreciation of the value of narrow-spectrum drugs and re-examination of once discarded chemical scaffolds coupled with synthetic biology methods to generate new compounds and improve yields offer new strategies to revitalize once moribund natural product programs. The increasing awareness that the combination of antibiotics with adjuvants, non-antibiotic compounds that overcome resistance and enhance drug activity, can rescue older chemical scaffolds, and concepts such as blocking pathogen virulence present orthogonal strategies to traditional antibiotics. In all these areas, natural products offer chemical matter, shaped by natural selection, that is privileged in this therapeutic area. Natural product research is poised to regain prominence in delivering new drugs to solve the antibiotic crisis. PMID- 28569302 TI - Fano resonances in the photoinduced H-atom elimination dynamics in the pisigma* states of pyrrole. AB - Fano resonances are predicted to be prominent features of the pisigma* photochemistry of pyrrole. The Fano interference leads to distorted absorption bands and internally hot photofragments. The interference, studied using high level ab initio theory and quantum mechanics, is supported by two distinct dynamical scenarios controlled by two exit channel conical intersections between the pisigma* states and the ground electronic state X[combining tilde]. For the lowest state 1A2(pisigma*), the coupling at the conical intersection is weak, and the interfering dissociation pathways are diabatic; for the higher lying 1B1(pisigma*) state, the coupling at the conical intersection is strong, and the interfering dissociation pathways are adiabatic. Both scenarios persist with increasing number of degrees of freedom included in the dynamic modelling. They are expected to be operative in the pisigma* photochemistry of a broad class of model UV biochromophores. PMID- 28569304 TI - Interfacial charge transfer in functionalized multi-walled carbon nanotube@TiO2 nanofibres. AB - A new insight into photoinduced charge transfer processes across carbon nanotube@TiO2 interfaces has been gained based on experimental details from transient absorption spectroscopy. We show that photoinduced, interfacial hole transfer to carboxylic acid-functionalized multiwalled carbon nanotubes (oxMWCNTs) from TiO2 results in hole-doped oxMWCNTs and reduced TiO2. The latter is inferred from femto- and nanosecond transient absorption spectroscopy performed with oxMWCNT@TiO2 dispersions and complemented with investigations using methyl viologen and N,N,N',N'-tetramethyl-p-phenylenediamine as an electron scavenger and a hole scavenger, respectively. The results of ultraviolet photoemission spectroscopy (UPS) of the compounds corroborate the findings, highlighting the strong coupling between oxMWCNTs and TiO2 in these hybrids. PMID- 28569306 TI - Effects of temperature, concentration, and isomer on the hydration structure in monosaccharide solutions. AB - Water-monosaccharide coupled interactions are essential for the function, stability, and dynamics of all glycans. Using molecular dynamics simulations, we investigated the effects of temperature, concentration, and monosaccharide isomer on the hydration structure and water dynamics in the hydration shell of monosaccharides in solution. We found that perturbations of the hydrogen-bond (H bond) network in the first hydration shell around each monosaccharide molecule can be separated into two regions: one rich in water molecules with donor H-bonds (in the 2.4-2.8 A region) and the other rich in water molecules with abundant acceptor H-bonds (in the 2.8-3.3 A region). Moreover, we investigated the dependencies of clustering and conversion of the conformers of the monosaccharides on temperature and concentration. Increasing the concentration enhances monosaccharide clustering in all the monosaccharide solutions, while cluster formation does not depend on temperature. In the clusters, some water molecules in the hydration shell are replaced with monosaccharide oxygen atoms, which contributes to the shrinkage of the hydration shell with increasing monosaccharide concentration. The monosaccharides basically adopt one of two conformers, the stable chair or the unstable boat conformer. We revealed that the hydration structures of the boat and chair conformers were dramatically different. As the temperature increases, the content of the chair conformer decreases. Thus, the conversion of conformers strongly affects the hydration structure around the monosaccharide. These results are critical to understand the important roles of the hydration structure in glycan solutions. PMID- 28569307 TI - Photodynamics of Zr-based MOFs: effect of explosive nitroaromatics. AB - The present work describes the spectroscopic and photodynamics of two different Zr mixed-linkers MOFs (Zr-NDC/Tz and Zr-NDC/CN) and their interaction with nitroaromatics. Both MOFs exhibit comparable spectroscopic behaviours, with a broad emission band mainly due to the naphthalene excimers within their three dimensional structure. Flash photolysis experiments show a slow radiative electron-hole (e--h+) recombination, reflected as a large negative absorption band. The interaction with the selected nitroaromatic compounds produces a static fluorescence quenching of Zr-NDC/Tz. Interestingly, the addition of trinitrophenol (TNP) induces the formation of a charge-transfer complex, helped by intermolecular H-bonds formation, as shown by the steady-state and ps-time resolved emission experiments. Remarkably, the (e--h+) recombination is strongly affected due to the inhibition of the ligand-to-cluster charge transfer process within the MOF. The quenching constants for the nitroaromatics lacking -OH groups are in the order of 102 M-1, while it is two orders of magnitude higher for the TNP (1.8 * 104 M-1). Both MOFs are highly selective toward TNP. We also demonstrate the possibility to recycle these MOFs without significant loses in their ability to detect TNP. Our findings give the clues to understand the fluorescence quenching mechanism of new Zr-based MOFs in presence of explosive like molecules, opening the way to improve these nanomaterials as highly selective sensor of nitroaromatics. PMID- 28569310 TI - Aryne triggered [2,3]-sigmatropic rearrangement of allyl and propargyl thioethers. AB - An efficient protocol for [2,3]-sigmatropic rearrangement of allyl and propargyl thioethers is reported. The key sulfonium ylide intermediate is in situ formed via S-arylation of arynes. This transition metal-free method allows for ready access to a wide array of functionalized thioether derivatives in good to excellent yields. PMID- 28569312 TI - Insights into the mechanism of electrocatalysis of the oxygen reduction reaction by a porphyrinic metal organic framework. AB - Metal Organic Frameworks (MOFs) have been recently proposed as promising electrocatalysts, yet the exact nature of the mechanisms in play has not been addressed in depth. By comparing the electrocatalytic activity of a MOF for the oxygen reduction reaction (ORR) and the corresponding molecular building units through electrochemical techniques, here, we investigate the nature of the catalytic sites, their redox states and the electron transfer pathways. PMID- 28569313 TI - Coordination coupling enhanced two-photon absorption of a ZnS-based microhybrid for two-photon microscopy imaging in HepG2. AB - Coordination coupling induced self-assembly of ZnS microparticles was performed with the help of a pi-conjugated sulphur-terminal Zn(ii) complex ZnS2L (L = N hexyl-3-{2-[4-2,2':6',2''-terpyridin-4'-yl-phenyl]ethenyl}-carbazole). The interactions between ZnS and ZnS2L components at the interface, which were analyzed by far-IR and XPS, resulted in a tunable single-photon excited fluorescence and an enhanced nonlinear optical response, including a two-photon absorption cross section and a two-photon excited fluorescence. Such an enhancement in nonlinear optical properties was triggered by the coordination coupling effect between terminal S atoms of ZnS2L and naked Zn2+ ions at the surface of ZnS particles. Thus, the novel hybrid system displayed a unique two photon excited fluorescence to facilitate promising two-photon microscopy imaging of HepG2 cells upon NIR light illumination at 840 nm. The hybrid shows a stronger ability to enter the cells than free ZnS2L. PMID- 28569315 TI - Enhancing the sensing specificity of a MoS2 nanosheet-based FRET aptasensor using a surface blocking strategy. AB - Aptamer-based biosensing, which uses short, single-stranded nucleic acid segments to bind to a target, can be advantageous over antibody-based diagnostics due to the ease of synthesis and high stability of aptamers. However, the development of most aptamer-based sensors (aptasensors) is still in its initial stages and many factors affecting their performance have not been studied in great detail. Here, we enhance the sensing specificity of a fluorescence resonance energy transfer (FRET)-based MoS2 nanosheet aptasensor in detecting the malarial biomarker Plasmodium lactate dehydrogenase (pLDH). In this sensing scheme, the presence of target is signaled by an increase in fluorescence when fluorescently-labeled aptamers bind to pLDH and release from a quenching material. Interestingly, unlike most of the reported literature on aptasensors, we observe that non-target proteins also cause a considerable increase in the detected fluorescence. This may be due to the nonspecific adsorption of proteins onto the fluorescence quencher, leading to the displacement of aptamers from the quencher surface. To reduce this nonspecific association and to enhance the sensor specificity, we propose the application of a surface blocking agent to the quenching material. Importantly, we demonstrate that the sensing specificity of the MoS2 nanosheet based aptasensor towards target pLDH biomolecules can be significantly enhanced through surface passivation, thus contributing to the development of highly selective and robust point-of-care malaria diagnostics. PMID- 28569317 TI - Origin of cooperativity in hydrogen bonding. AB - The origin of non-additivity in hydrogen bonds (H-bonds), usually termed as H bond cooperativity, is investigated in H-bonded linear chains. It is shown that H bond cooperativity originates solely from classical electrostatics. The latter is corroborated by comparing the H-bond cooperativity in infinitely-long H-bonded hydrogen cyanide, 4-pyridone and formamide chains, assessed using density functional theory (DFT), against the strengthening of the dipole-dipole interaction upon the formation of an infinite chain of effective point-dipoles. It is found that the magnitude of these effective point-dipoles is a consequence of mutual polarization and additional effects beyond a polarizable point-dipole model. Nevertheless, the effective point-dipoles are fully determined once a single H-bond is formed, indicating that quantum effects involved in H-bonding are circumscribed to nearest-neighbor interactions only; i.e. in a linear chain of H-bonds, quantum effects do not contribute to the H-bond non-additivity. This finding is verified by estimating cooperativity along the dissociation path of H bonds in the infinite chains, using two empirical parameters that account for polarizability, together with DFT association energies and molecular dipoles of solely monomers and dimers. PMID- 28569318 TI - Thermosensitive polymer controlled morphogenesis and phase discrimination of calcium carbonate. AB - Homogeneous aragonite flowers with controlled surface structures can be synthesized by using a thermosensitive polymer, i.e. poly (ethylene glycol) poly(N-isopropyl acrylamide)-poly(acrylamido methyl propane sulfonate) (PEG PNIPAM-PAMPS), as a crystal growth modifier in the mineralization of calcium carbonate. PMID- 28569319 TI - Employing shells to eliminate concentration quenching in photonic upconversion nanostructure. AB - It is generally accepted that a lanthanide ions based upconversion material follows an activator low doping strategy (normally <3 mol%), because of the restriction of the harmful concentration quenching effect. Here, we demonstrate that this limitation can be broken in nanostructures. Simply by using an inert shell coating strategy, the concentration quenching effect for the activator (Er3+) could be eliminated and highly efficient upconversion luminescence realized in the activator fully doped nanostructure, e.g. NaErF4@NaYF4. More importantly, this novel nanostructure achieves some long-cherished desires, such as multiple-band co-excitation (~800 nm, ~980 nm and ~1530 nm) and monochromic red emission. Proof-of-concept experiments are presented of the potential benefit of this structure in solar cells and anti-counterfeiting. This nanostructure offers new possibilities in realizing high upconversion emission and novel functionalities of lanthanide based nanomaterials. PMID- 28569320 TI - A chimeric design of heterospin 2p-3d, 2p-4f, and 2p-3d-4f complexes using a novel family of paramagnetic dissymmetric compartmental ligands. AB - End-off bicompartmental ligands bearing a nitronyl-nitroxide arm have been designed for synthesizing various heterospin molecular systems. These ligands can selectively interact with 3d and 4f metal ions, leading to 2p-4f, 2p-3d, and 2p 3d-4f complexes. The magnetic properties of the 2p-4f and 2p-3d-4f complexes have been investigated and rationalized by theoretical calculations. PMID- 28569321 TI - Achieving biosensing at attomolar concentrations of cardiac troponin T in human biofluids by developing a label-free nanoplasmonic analytical assay. AB - Acute myocardial infarction (heart attack) is the fifth leading cause of death in the United States (Dariush et al., Circulation, 2015, 131, e29-e322). This highlights the need for early, rapid, and sensitive detection of its occurrence and severity through assaying cardiac biomarkers in human fluids. Herein we report chip-based fabrication of the first label-free, nanoplasmonic biosensor to assay cardiac troponin T (cTnT) in human biofluids (plasma, serum, and urine) with high specificity. The sensing mechanism is based on the adsorption model that measures the localized surface plasmon resonance (LSPR) wavelength shift of anti-cTnT functionalized gold triangular nanoprisms (Au TNPs) induced by a change of their local dielectric environment upon binding of cTnT. We demonstrate that controlled manipulation of the sensing volume and decay length of Au TNPs together with an appropriate surface functionalization and immobilization of anti cTnT onto TNPs allows us to achieve a limit of detection (LOD) of our cTnT assay at attomolar concentration (~15 aM) in human plasma. This LOD is at least 50-fold more sensitive than that of other label-free techniques. Furthermore, we demonstrate excellent sensitivity of our sensors in human serum and urine. Importantly, our chip-based fabrication strategy is extremely reproducible. We believe our powerful analytical tool for detection of cTnT directly in human biofluids using this highly reproducible, label-free LSPR sensor will have great potential for early diagnosis of heart attack and thus increase patients' survival rate. PMID- 28569323 TI - Investigation of a new "N2S2O2" chelating agent with high Po(iv) affinity. AB - A water-soluble "N2S2O2" complexing agent was designed for polonium(iv) decorporation. The bifunctional ligand showed outstanding Po(iv) complexing abilities, with a conditional stability constant three orders of magnitude higher than the reference ligand BAL. PMID- 28569322 TI - Total synthesis of agalloside, isolated from Aquilaria agallocha, by the 5-O glycosylation of flavan. AB - Agalloside (1) is a neural stem cell differentiation activator isolated from Aquilaria agallocha by our group using Hes1 immobilized beads. We conducted the first total synthesis of agalloside (1) via the 5-O-glycosylation of flavan 25 using glycosyl fluoride 20 in the presence of BF3.Et2O. Subsequent oxidation with DDQ to flavanone 2 and deprotection successively provided agalloside (1). This synthetic strategy holds promise for use in the synthesis of 5-O-glycosylated flavonoids. The synthesized agalloside (1) accelerated neural stem cell differentiation, which is a result comparable to that for the naturally occurring compound 1. PMID- 28569325 TI - Correction: Introducing dip pen nanolithography as a tool for controlling stem cell behaviour: unlocking the potential of the next generation of smart materials in regenerative medicine. AB - Correction for 'Introducing dip pen nanolithography as a tool for controlling stem cell behaviour: unlocking the potential of the next generation of smart materials in regenerative medicine' by Judith M. Curran et al., Lab Chip, 2010, 10, 1662-1670. PMID- 28569326 TI - Kinetics of the electrochemically-assisted deposition of sol-gel films. AB - Electrochemically-assisted deposition is now becoming a widespread method for preparing sol-gel films. It is based on the electrochemical generation of OH- ions, which can then catalyze the sol-gel condensation reactions. It has a key advantage of selectively facilitating the film deposition on electrochemically active surfaces while not affecting the stability of the bulk precursor solution. Experimental studies have clearly shown that the thickness of the electrochemically-assisted deposited films is influenced by the deposition parameters such as the potential and time. However, there is still a lack of quantitative description of the kinetics of film growth due to the complexity of the process. In this preliminary study, we derived quantitative analytical expressions for describing the kinetics associated with the growth of sol-gel films generated by electrochemically assisted deposition. Both heterogeneous and homogeneous condensation reactions were considered. The key strategy was to simplify the process by separating the electrochemical step of generating OH- ions with the condensation steps of film formation under approximation. Furthermore, numerical simulation was carried out to examine the validity and any errors in the analytical expressions in the cases when the required approximations were not fulfilled. The analytical expressions could well explain the trends observed in the experimental studies and could also be used for fitting the experimental results from the literature. This study provides a deeper understanding of the mechanism and quantitative guidance for manipulating electrochemically-assisted deposition processes at a large scale in industry. It may also be referred to in regard to other indirect electrodeposition systems in which the deposition is not an electrochemical step but is instead driven by electrochemically-generated catalysts. PMID- 28569328 TI - An EGFRvIII targeted dual-modal gold nanoprobe for imaging-guided brain tumor surgery. AB - Surgery is a mainstay to treat malignant brain tumors. However, due to the infiltrative nature of these tumors, it is a great challenge for surgeons to accurately identify and excise all the tumor foci. EGFRvIII, a variant of epidermal growth factor receptor (EGFR), is found in 20% of glioblastoma cases, which is the brain tumor with the highest malignancy. In this study, we developed an EGFRvIII-targeted nanoprobe to guide glioblastoma surgery by pre-operatively defining the tumor boundary via magnetic resonance imaging (MRI) and intra operatively guiding resection by surface-enhanced resonance Raman scattering (SERRS) imaging. In vivo MRI studies show that this nanoprobe delineates an orthotopic EGFRvIII+ U87MG glioblastoma xenograft with a higher target to background ratio than the control nanoprobe without targeting specificity. With the assistance of a handheld Raman scanner, this nanoprobe successfully guided EGFRvIII+ glioblastoma resection by tracking its characteristic SERRS signal peaks. Ex vivo Raman microscopy and histological images verified that this nanoprobe precisely demarcated the glioblastoma boundary and no residual neoplastic foci were observed in the tumor bed. This dual-modal nanoprobe not only precisely guided glioblastoma resection, but also overcame the brain shift induced false-positive signal by real-timely co-registering pre-operative and intra-operative images. This nanoprobe is promising for the improvement in diagnostic accuracy and surgical outcome of EGFRvIII+ glioblastoma. PMID- 28569330 TI - Porous organic cage membranes for water desalination: a simulation exploration. AB - Porous organic cages (POCs) have emerged as a new class of porous materials and received considerable interest for their potential applications. Herein we report the first proof-of-concept simulation study on POC membranes for water desalination. Five [4+6] POCs (CC1, CC2, CC3, CC16, and CC17) are considered with similar crystal structures, but different periphery groups and pore morphologies. CC1 is found to be impermeable to water due to disconnected pores. With an interconnected tetrahedral pore network, CC3 and CC16 have an intermediate water permeability of 1-5 * 10-7 kg m (m2 h bar)-1. CC2 and CC17 contain straight pores and a widely open pore network, respectively, thus exhibit a high water permeability of 2-3 * 10-6 kg m (m2 h bar)-1; nevertheless, salt rejection in CC17 is only 89%. Among the five POC membranes, CC2 is the best for water desalination with performance superior to other membranes reported in the literature. The membrane flexibility is revealed to have a weak effect on water permeation. To provide further microscopic understanding, the permeation duration, diffusion and hydrogen bonding of water in the POC membranes are quantitatively analyzed. From this simulation study, the key factors governing water permeation in the POC membranes are unraveled and CC2 is identified to be an interesting candidate for water desalination. PMID- 28569331 TI - Isolated alkali cation complexes of the antibiotic ionophore nonactin: correlation with crystalline structures. AB - The antibiotic activity of nonactin is sustained by its ability to transport K+ across lipophilic phases, e.g., the cell membranes. Such a feature can be traced back to a specific ionophoric behavior and to a balanced hydrophobicity modulated by the formation of a cation complex. In this study, the dominant conformations and coordination arrangements in the alkali cation complexes (Na+, K+, Cs+) of nonactin are characterized by means of action vibrational spectroscopy and quantum chemical computations. The low energy conformers of the complexes comprise compact inclusion structures, in which the cation interacts with a varying number of oxygen atoms of the carbonyl and oxolane ring groups of the nonactin macrocycle. The spectroscopy experiments indicate that the three alkali complexes explored are formed in a S4 conformation. This is in contrast with previous crystallography studies, which concluded that the symmetry of the most stable conformer of the complex changes qualitatively with the cation size, from C2 for Na+ to S4 for K+ and Cs+. Computations with different hybrid density functionals lead to contradictory predictions that appear to be quite sensitive to the modelling of the long range interactions in the coordination arrangements. The stabilization of the nonactin-Na+ complex in the C2 or S4 forms emerges as a subtle feature that may be tuned with an appropriate control of the environmental conditions, and constitutes a challenging benchmark to confront novel computational methods for supramolecular systems. PMID- 28569332 TI - Mixed Cu(i)/Au(i) coordination polymers as reversible turn-on vapoluminescent sensors for volatile thioethers. AB - Vapour-phase thioethers play an important role in a wide number of fields, including plant biology, chemical weapon disposal, and brewing but few sensor materials are known. The emissive coordination polymer Cu1/2Au1/2CN does not react with vapour phase dimethyl sulphide (DMS) or diethyl sulphide (DES) despite the independent synthesis of emissive [Cu1/2Au1/2CN]2(DMS) and [Cu1/2Au1/2CN]2(DES) from their constituent components in solution. However, the doped Cu2/3Au1/3CN rapidly reacts in the solid state with both of these vapour phase thioethers reversibly, with a change in emission from 380/560 nm to 460 nm (DMS) or 420 nm (DES), illustrating that doping the inactive parent Cu1/2Au1/2CN with Cu(i) generates an active sensor material. This response can be thermally cycled with little to no loss in functionality. [Cu1/2Au1/2CN]2(DMS), [Cu2/3Au1/3CN]2(DMS), and [Cu2/3Au1/3CN]2(DES) were structurally characterized as 3-D network structures supported by aurophilic interactions. PMID- 28569333 TI - Photo-controlled cell-specific metabolic labeling of RNA. AB - Elucidating gene expression programs within a cell-specific manner is a grand challenge for biologists. Harder still is the ability to have kinetic control over such experiments. Metabolic labeling with bioorthogonally-functionalized metabolic intermediates provides a means to profile RNA expression in a cell specific manner, but there is still a lack of kinetic resolution. Herein we present the synthesis and evaluation of photocaged metabolic uracil intermediates. We compare the photo-decaging properties and demonstrate their utility in metabolic labeling experiments in a cell-specific manner. We anticipate that our approach will have far-reaching impact as it provides control over tagging of nascent RNA. PMID- 28569334 TI - Knowledge, Attitudes and Practices of Agricultural Workers towards Tetanus Vaccine: a Field Report. AB - BACKGROUND: Agricultural Workers are both more exposed to tetanus and at higher risk to be inadequately immunized than other usual recipients of the same vaccine. STUDY DESIGN: Our cross-sectional questionnaire-based study aimed to evaluate tetanus vaccination status, knowledge, attitudes and practices in Agricultural Workers in North-Eastern Italy. METHODS: Bivariate and multivariate logistic regression analyses were used to identify, from individual and work related characteristics, factors significantly associated with appropriate vaccination status. RESULTS: Among 707 participants, 58.4% had an up-to-date immunization status. In 33.1%, last booster was performed by an Emergency Department. The main reason for inadequate immunization was having forgotten the recommended periodic booster (146/707; 20.7%). Attitude towards tetanus vaccination was somehow favourable in 79.5% of participants, and 72.7% correctly identified tetanus vaccination as mandatory for Agricultural Workers. A lower degree of false beliefs and better knowledge of official recommendations were significant predictors of vaccine propensity. The main predictor for an appropriate vaccination status was interaction with a healthcare provider, in general (adjusted Odds Ratio, adjOR 2.516 95%CI 1.707-3.710), and specifically regarding vaccine counseling, (adjOR 6.275 3.184-12.367 and adjOR 9.739 95%CI 3.933-24.111 for general practitioners and occupational physicians, respectively). CONCLUSIONS: Our study enlightens the key role of healthcare providers in recalling and promoting vaccination policies, as well in increasing the general awareness of Agricultural Workers regarding vaccines and official recommendations. PMID- 28569335 TI - Assessment of coverage and analysis of the determinants of adherence to influenza vaccination in the general practitioners of Taranto. AB - BACKGROUND: In Italy, the general practitioner (GP) is the operations manager of the campaigns regarding influenza immunization. He/she identifies people eligible for vaccination among the clients, invites them actively and administers the vaccine. The GPs are directly in contact with the target population that should be vaccinated and their opinion about the flu vaccine may ultimately influence the decision of the patient to accept or not the vaccination. This study aims to assess levels of immunization for influenza vaccination among GPs and factors influencing their adherence to the vaccinations recommended for GPs in the province of Taranto (Apulia region, Southern Italy). METHODS: We conducted a cross-sectional study among 471 general practitioners working in the province of Taranto during the February-March period of 2016. We emailed all GPs a self administered web-based standardized questionnaire. The questionnaire analyzed the self-reported flu vaccination coverage, knowledge, perception and positions of the GPs with regard to the forecasted vaccinations of the in-risk categories among their patients. RESULTS: A total of 229 (48.6%) GPs participated in the survey. In the 2015/2016 influenza season, the vaccination coverage among the interviewed GPs was 76.4% (n = 175). A patient number >= 900 increased the likelihood to have been vaccinated in the 2015/2016 season (OR = 3.3; P < 0.01). Overall only 79.9% prefers to use the adjuvated vaccines on patients > 64 and the 58% of GPs who chose not to get vaccinated considers influenza as a non-risk pathology for a healthy subject. CONCLUSIONS: The coverage achieved among the Taranto's ASL GPs during the 2015/16 season reaches the minimum threshold set by the Minister, but they could implement their knowledge and their participation in relation to the anti-influenza vaccine in order to discard all the wrong or clearly unfounded common beliefs. The best strategy in order to optimize the governance system seems to be the empowerment of primary care physicians, to be fulfilled through actions shared with the Public Healthcare Services based on training, communication and projects supporting vaccine coverage. PMID- 28569336 TI - Molecular epidemiology and characteristics of 16 cases with Stenotrophomonas maltophilia bacteraemia in pediatric Intensive Care Units. AB - BACKGROUND: Recently, Stenotrophomonas maltophilia has increasingly been reported as an important nosocomial opportunistic pathogen. Limited therapeutic options of S. maltophilia infections demand early identification and knowledge about the probable risk factors for controlling its spread. STUDY DESIGN: The present study aimed to investigate the risk factors and trend of antibiotic susceptibility, along with genetic analysis in bacteraemia cases at pediatric intensive care units (PICUs). METHODS: A total of 16 S. maltophilia isolates were obtained, during 4 months from August to November 2015, from blood cultures of patients admitted to PICUs at Nemazee teaching hospital, Shiraz, Iran. S. maltophilia isolates were identified by conventional tests and confirmed by specific PCR primers. Minimum inhibitory concentrations (MICs) were determined by the MIC strip test as described by the Clinical and Laboratory Standards Institute's (CLSI) recommendation. The genetic relatedness among the isolates was assessed by ERIC-PCR. RESULTS: All isolates of S. maltophilia were susceptible to ciprofloxacin, co-trimoxazole and colistin, and only 1 (6.2%) isolate was resistant against ceftazidime. The MIC50/MIC90 of ciprofloxacin, trimethoprim/sulfamethoxazole, colistin and ceftazidime was 0.25/0.38 mg/mL, 0.125/0.19 mg/mL, 0.25/0.38 mg/mL, and 2/4 mg/mL, respectively. Genotypic analysis of ERIC-PCR results revealed two distinct types of pattern. Interestingly, the only ceftazidime resistant isolate showed different patterns with other isolates. CONCLUSIONS: Our findings indicated the importance of routine surveillance in infection control, since early detection of pathogens prevented the spread of nosocomial infections and granted effectiveness to care practices. Moreover, the results suggest that the routine drug of choice for S. maltophilia was mostly active against clinical isolates in our region. PMID- 28569337 TI - The assessment of the complexity of care through the clinical nursing information system in clinical practice: a study protocol. AB - BACKGROUND: The costs of nursing staff amounts to approximately 50% of the total budget of the health workforce and accounts for 20% to 30% of the total costs incurred by the health care companies. The goal of the study, by analyzing the complexity of care, is to provide a quantification of the assistance delivered, through the assessment of the technical aspects of the welfare activities according to the variable of time. Data from these activities flow into the clinical nursing information system Professional Assessment Instrument - PAI - which is used at the health facility involved in this study. This instrument allows nurses to document the nursing process in electronic format by using a standardized nursing language (nursing diagnoses, nursing interventions and nursing outcomes). METHODS: The design of the study is observational. The participants will be patients that are hospitalized in the cardiology departments, the intensive care units for cardiac and thoracic surgery, pulmonary medicine and medical oncology of the "A.Gemelli" hospital in Rome, Italy. The observers who will carry out the surveys will be students of the nursing degree course and the coordinators of the respective wards. The times recorded for each health care activity will be correlated with variables that are defined in the literature as the indicators of the complexity of care. The research protocol was approved by the Ethics Committee of the "A. Gemelli" Hospital in June 2015. RESULTS: In terms of results, this study aims to verify the reliability of the Professional Assessment Instrument tool as a system for the classification and measurement of nursing care which includes the entire care process, taking into account all of the variables deemed crucial to the nursing care effort. CONCLUSIONS: This study will provide a tool for the assessment of the complexity of care, with the goal of improving the quality of care for the patients and of interacting with the health administration system for the management of resources. PMID- 28569338 TI - Clinical characteristics of juvenile idiopathic arthritis in an area of central Italy: a population-based study. AB - BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and an important cause of short and long-term disability. In a recent systematic review of population based studies, the epidemiology of JIA is variable worldwide with incidence rates ranging between 1.6 and 23.0/100,000, and prevalence rates between 3.8 and 400.0/100,000. We investigate the incidence and describe the characteristics of juvenile idiopathic arthritis in the pediatric population of the central Italy, in the period 2000 2009. METHODS: A retrospective study was conducted in the Marche region to identify patients with a diagnosis of juvenile idiopathic arthritis according to ILAR criteria, between January 1, 2000 and December 31, 2009. JIA was classified according to the ILAR criteria, that is, arthritis of unknown etiology that persisted for > 6 weeks with onset before the age of 16 years. The pooled global ascertainment of cases was estimated by capture-recapture methods and two independent information sources of ascertainment of new cases of JIA were considered. RESULTS: We studied 151 patients (56 males, 37.1% and 95 females, 62.9%) meeting the ILAR criteria of juvenile idiopathic arthritis. Mean age at presentation was 6.8 +/- 3.7 years for males and 6.0 +/- 4.0 years for females (p=0.22). The overall incidence rate was 6.34 per 100,000/year (C.I. 6.26-7.35) and the total incidence rate increase from 2000-2009 was 8.16%. Oligoarthritis was the most common onset type (n=98, 65.0%) with 62.5% of ANA-positive patients in at least two determinations. CONCLUSIONS: Our results indicate that juvenile idiopathic arthritis incidence rates in Italy are comparable to previous data from southern Europe, with a higher frequency of oligoarthritis. To the best of our knowledge, this is the first population-based epidemiological study carried out in Italy focusing on the incidence of juvenile idiopathic arthritis. PMID- 28569339 TI - High Resolution Melting as a rapid, reliable, accurate and cost-effective emerging tool for genotyping pathogenic bacteria and enhancing molecular epidemiological surveillance: a comprehensive review of the literature. AB - INTRODUCTION: Rapid, reliable and accurate molecular typing methods are essential for outbreaks detection and infectious diseases control, for monitoring the evolution and dynamics of microbial populations, and for effective epidemiological surveillance. The introduction of a novel method based on the analysis of melting temperature of amplified products, known as High Resolution Melting (HRM) since 2002, has found applications in epidemiological studies, either for identification of bacterial species or molecular typing, as well as an extensive and increasing use in many research fields. HRM method is based on the use of saturating third generation dyes, advanced real-time PCR platforms, and bioinformatics tools. OBJECTIVE: To describe, by a comphrehensive review of the literature, the use, application and usefulness of HRM for the genotyping of bacterial pathogens in the context of epidemiological surveillance and public health. MATERIAL AND METHODS: A literature search was carried out during July August 2016, by consulting the biomedical databases PubMed/Medline, Scopus, EMBASE, and ISI Web of Science without limits. The search strategy was performed according to the following keywords: high resolution melting analysis and bacteria and genotyping or molecular typing. All the articles evaluating the application of HRM for bacterial pathogen genotyping were selected and reviewed, taking into account the objective of each study, the rationale explaining the use of this technology, and the main results obtained in comparison with gold standards and/or alternative methods, when available. RESULTS: HRM method was extensively used for molecular typing of both Gram-positive and Gram-negative bacterial pathogens, representing a versatile genetic tool: a) to evaluate genetic diversity and subtype at species/subspecies level, based also on allele discrimination/identification and mutation screening; b) to recognize phylogenetic groupings (lineage, sublineage, subgroups); c) to identify antimicrobial resistance; d) to detect and screen for mutations related to drug resistance; e) to discriminate gene isoforms. HRM method showed, in almost all instances, excellent typeability and discriminatory power, with high concordance of typing results obtained with gold standards or comparable methods. Conversely, for the evaluation of genetic determinants associated to antibiotic-resistance or for screening of associated mutations in key gene fragments, the sensitivity and specificity was not optimal, because the targeted amplicons did not encompass all the crucial mutations. CONCLUSIONS: Despite the recent introduction of sequencing based methods, the HRM method deserves consideration in research fields of infectious diseases, being characterized by low cost, rapidity, flexibility and versatility. However, there are some limitations to HRM assays development, which should be carefully considered. The most common application of HRM for bacterial typing is related to Single Nucleotide Polymorphism (SNP)-based genotyping with the analysis of gene fragments within the multilocus sequence typing (MLST) loci, following an approach termed mini-MLST or Minim typing. Although the resolving power is not totally correspondent to MLST, the Simpson's Index of Diversity provided by HRM method typically >0.95. Furthermore, the cost of this approach is less than MLST, enabling low cost surveillance and rapid response for outbreak control. Hence, the potential of HRM technology can strongly facilitate routine research and diagnostics in the epidemiological studies, as well as advance and streamline the genetic characterization of bacterial pathogens. PMID- 28569340 TI - Adoption of TSH Reflex algorithm in an Italian clinical laboratory. AB - BACKGROUND: TSH Reflex is an automated diagnostic algorithm which follows the rule "If ... then", in which the initial determination of TSH is followed by the determination of fT4, and possibly of fT3, if TSH is not within the reference limits. The aim of our study was to evaluate the results of the introduction and implementation of the test "TSH Reflex", which started in late 2013 in the hospital of Grosseto, comparing the requests of thyroid hormones for external patients, in 2012, 2014 and 2015. METHODS: In our study we analyzed the number of thyroid tests prescribed in 2012, 2014 and 2015 and we calculated the increase in prescription of "TSH Reflex" from 2014 to 2015; the prescriptive appropriateness, after the introduction of the "TSH Reflex", through the ratios TSH/FT4, TSH/FT3 and the ratio "TSH Reflex"/TSH. Finally we calculated the total spending for the reagents in 2012, 2014 and 2015 and the consequent savings in euros (the costs of the reagents did not change during that time). RESULTS: Requests for TSH decreased by 4.6% in 2014, compared to 2012 and by 5.4% in 2015 compared to 2014, with a 9.8% reduction in 2015 compared to 2012. The requests for FT4 decreased by 11.5%, comparing 2014 with 2012, by 5.3% comparing 2015 with 2014, with a 16.2% reduction in 2015 compared to 2012. The requests for FT3 decreased by 13.3% in 2014 compared to 2012 and by 8.4% in 2015 compared to 2014, with a 20.6% reduction in 2015 compared to 2012. The appropriateness, evaluated the indicator TSH/FT4, increased by 7.6%, comparing 2014 with 2012, and remained unchanged in 2015. In 2012 71,134 euros were spent, 63,998 euros in 2014, 60,055 euros in 2015, resulting in a saving of ? 11,079 in 2015 compared to 2012. The spending for "TSH Reflex" should be subtracted (1,964 Euros in 2015) from the previous savings. CONCLUSIONS: The improvement of the efficiency and the prescriptive appropriateness was better in 2014, the first year of implementation of the "TSH Reflex". The overall assessment suggests that the 2014 results are attributable to the letters that general practitioners received in December 2013, with a temporary increase of the use of the test. We need further analyses with the same indicators in order to assess the possibility of additional improvements in the future. PMID- 28569341 TI - Health inequalities and inadequate housing: the case of exceptions to hygienic requirements for dwellings in Italy. AB - In the past decades, Italian hygienic requirements for dwellings have been modified by multiple derogations. Aim of the present work is to analyse the derogations introduced at a national, regional, and local level. The most important derogations were related to the habitable use of semi-basements and garrets, and building restoration. The paper also describes the regulations regarding indemnity for infringement of building abuses. The authors underline the need for more uniformity and clarity in the determination of health standards of dwellings, as well as for a simplification of the existing legislation. PMID- 28569342 TI - May the gross domestic product growth be a valid indicator of decent work? PMID- 28569343 TI - Tertiary prevention in athletes' diseases: new challenges for the clinical medicine and the public health. PMID- 28569345 TI - Vascular targeted photodynamic therapy with TOOKAD(r) Soluble (WST11) in localized prostate cancer: efficiency of automatic pre-treatment planning. AB - Vascular targeted photodynamic therapy (VTP) with WST11 is a novel non-thermal focal treatment for localized prostate cancer that has shown favorable and early efficacy results in previously published studies. In this work, we investigate the efficiency of automatic dosimetric treatment planning. An action model established in a previous study was used in an image-guided optimization scheme to define the personalized optimal light dose for each patient. The calculated light dose is expressed as the number of optical cylindrical fibers to be used, their positions according to an external insertion grid, and the lengths of their diffuser parts. Evaluation of the method was carried out on data collected from 17 patients enrolled in two multi-centric clinical trials. The protocol consisted of comparing the method-simulated necrosis to the result observed on day 7 MR enhanced images. The method performances showed that the final result can be estimated with an accuracy of 10%, corresponding to a margin of 3 mm. In addition, this process was compatible with clinical conditions in terms of calculation times. The overall process took less than 10 min. Different aspects of the VTP procedure were already defined and optimized. Personalized treatment planning definition remained as an issue needing further investigation. The method proposed herein completes the standardization of VTP and opens new pathways for the clinical development of the technique. PMID- 28569344 TI - Radiofrequency treatment induces fibroblast growth factor 2 expression and subsequently promotes neocollagenesis and neoangiogenesis in the skin tissue. AB - Radiofrequency (RF) treatment appears to be involved in production of new collagen fibrils and the improvement of existing collagen structures; however, the molecular bases of the effect of non-invasive RF on the skin tissue have not been fully elucidated. This study reports the effects of RF associated or not with hydrolyzed collagen (HC) in the skin tissue. Wistar rats were randomly divided into four groups, according to the treatment received: control group (G1, n = 5), no treatment; subjects in group G2 (n = 5) were treated with HC; and capacitive RF was applied to the back of each subject in G3 (n = 5) and RF associated with HC in G4 (n = 5). Biopsies were taken 30 days after treatment and then were histologically processed and studied for inflammatory cell counting, collagen content, and morphometry. In addition, FGF2, CD105, and COX-2 expression was assessed by immunohistochemical staining. The most relevant changes were the increase in cellularity and accumulation of intercellular substance in RF-treated animals (G3 and G4). The greatest dermis thickness rate was observed in G4, followed by G3 and G2 (p < 0.05). RF-treated skins (G3 and G4) exhibited a significant overexpression of FGF2 (p < 0.0001) and increased microvessel density (p < 0.0001) in comparison with G1 and G2. Moreover, the amount of COX-2 was significantly higher (p < 0.0001) in dermis of RF-treated areas compared to G1 and G2, and demonstrated differences in G3 (RF) compared to G4 (RF + HC) (p < 0.0001). Our results suggests that RF treatment associated or not with HC induces FGF2 overexpression, promotes neoangiogenesis and modulates the COX-2 expression, subsequently promotes neocollagenesis, and increased thickness rate of dermis. PMID- 28569346 TI - Relations and dependencies between morphological characters. AB - In biological classification, a character is a property of a taxon that can distinguish it from other taxa. Characters are not independent, and the relations between characters can arise from structural constraints, developmental pathways or functional constraints. That has lead to famous controversies in the history of biology. In addition, a character as a tool of data analysis has some subjective aspects. In this contribution, I develop algebraic and geometric schemes to address these issues in a mathematical framework. PMID- 28569347 TI - Clinical parameters associated with anti-programmed death-1 (PD-1) inhibitors induced tumor response in melanoma patients. AB - Background The identification of the melanoma patients sensitive to anti-PD-1 inhibitors, nivolumab or pembrolizumab, is a major therapeutic challenge and an urgent need. We hypothesized that the natural history of the disease might partly reflect the immune state of the patients. Methods We analyzed our cohort of melanoma patients treated with anti-PD-1 from August 2014 to January 2016 in our institution. Objective response was defined as a complete or partial response according to v1.1 RECIST criteria. Results Among 63 metastatic melanoma patients, the overall response rate was 43%. Median time from diagnosis to anti-PD-1 initiation was longer among responders than non-responders (64 months vs. 35 months, p = 0.02). The response rate was 10% in patients starting anti-PD-1 within 1 year, 35% after 1 to 5 years and 63% after 5 years. Performance status (PS) 0 was also associated with enhanced tumor response: 70% of responders were PS 0 vs. 36% of non-responders (p = 0.04). PS 0, normal LDH levels and wild-type BRAF status were significant predictors of progression free survival. Conclusion A long time lapse from diagnosis to anti-PD-1 initiation and PS 0 are associated with higher sensitivity to anti-PD-1 in melanoma patients. These two clinical features might reflect a potentially intact immune system of the host. PMID- 28569349 TI - Real-time PCR quantification of arbuscular mycorrhizal fungi: does the use of nuclear or mitochondrial markers make a difference? AB - Root colonization by arbuscular mycorrhizal fungi (AMF) can be quantified by different approaches. We compared two approaches that enable discrimination of specific AMF taxa and are therefore emerging as alternative to most commonly performed microscopic quantification of AMF in roots: quantitative real-time PCR (qPCR) using markers in nuclear ribosomal DNA (nrDNA) and mitochondrial ribosomal DNA (mtDNA). In a greenhouse experiment, Medicago truncatula was inoculated with four isolates belonging to different AMF species (Rhizophagus irregularis, Claroideoglomus claroideum, Gigaspora margarita and Funneliformis mosseae). The AMF were quantified in the root samples by qPCR targeted to both markers, microscopy and contents of AMF-specific phospholipid fatty acids (PLFA). Copy numbers of nrDNA and mtDNA were closely related within all isolates; however, the slopes and intercepts of the linear relationships significantly differed among the isolates. Across all isolates, a large proportion of variance in nrDNA copy numbers was explained by root colonization intensity or contents of AMF-specific PLFA, while variance in mtDNA copy numbers was mainly explained by differences among AMF isolates. We propose that the encountered inter-isolate differences in the ratios of mtDNA and nrDNA copy numbers reflect different physiological states of the isolates. Our results suggest that nrDNA is a more suitable marker region than mtDNA for the quantification of multiple AMF taxa as its copy numbers are better related to fungal biomass across taxa than are copy numbers of mtDNA. PMID- 28569348 TI - Black Tar Heroin Skin Popping as a Cause of Wound Botulism. AB - BACKGROUND: Botulism is a rare potentially fatal and treatable disorder caused by a bacteria-produced toxin that affects the presynaptic synaptic membrane resulting in a characteristic neuromuscular dysfunction. It is caused by either the ingestion of the toxin or the bacteria, inhalation, or wound infection. We present our observations with a descriptive case series of wound botulism secondary to black tar heroin (BTH) injection. METHODS: We report a retrospective single-center case series of 15 consecutive cases of wound botulism presenting to University Medical Center of El Paso. Medical records where reviewed to obtain demographic information, clinical presentation, treatment, and outcome. RESULTS: We identified fifteen patients with mean age of 47 years: twelve men, and three women. All had administered BTH through skin popping and had abscesses in the administration areas. By history, the most common symptoms were dysphagia (66%), proximal muscle weakness of upper and lower extremity (60%), neck flexor muscle weakness (33%), ophthalmoplegia (53%), bilateral ptosis (46%), dysarthria (53%), double vision (40%), blurred vision (33%), and dry mouth (20%). During the examination, the most common features noted were: proximal muscle weakness of upper and lower extremities (73%), ophthalmoplegia (53%), ptosis (46%). In patients with documented wound botulism, the pupils were reactive in 46%. All patients required mechanical ventilation and were treated with the trivalent antitoxin. Eleven patients (73.3%) were discharged home, two were transferred to a skill nursing facility, and two were transferred to long-term acute care facility. CONCLUSION: In our patients, BTH injection, involving the action of injecting under the skin acetylated morphine derivatives (mostly 6 monoacetylmorphine and 3-monoacetylmorphine), was associated with the development of botulism. The availability of BTH at the US-Mexican border is not surprising since it is frequently produced in Latin America. Its association with the development of botulism should be recognized early to allow a prompt diagnosis and treatment with the antitoxin. A clinical feature worth noting is the presence of normal pupillary light reflex in nearly half of patients. Therefore, the presence of a normal pupillary response does not exclude the presence of wound botulism. PMID- 28569350 TI - Cost-effectiveness of posaconazole tablets versus fluconazole as prophylaxis for invasive fungal diseases in patients with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: The cost-effectiveness of posaconazole oral suspension versus fluconazole capsules for the prophylaxis of invasive fungal diseases (IFDs) in immunosuppressed allogeneic hematopoietic stem cell transplantation (HSCT) recipients has already been proven. Now, a new solid oral tablet formulation for posaconazole has been developed with improved bioavailability, allowing a reduced daily dosage that can be taken independently of food intake. However, the efficacy of this new formulation should be evaluated since it is associated with a higher cost than the posaconazole oral suspension. OBJECTIVES: To evaluate the cost-effectiveness of solid oral tablets of posaconazole versus fluconazole capsules for the prophylaxis of IFDs in allogeneic HSCT recipients with graft versus-host disease (GVHD) in Spain. METHODOLOGY: A mathematical model comparing the efficacy and costs of posaconazole versus fluconazole was adapted to the Spanish National Healthcare System. Clinical data were obtained from the pivotal clinical trial of posaconazole oral suspension for allogeneic HSCT recipients, while pharmacological costs and use of resources were obtained from national sources. Deterministic and probabilistic sensitivity analyses (PSA), as well as two alternative scenarios, were run to evaluate the robustness of the results under varying input values. RESULTS: Posaconazole tablets reduced the number of IFD events and enhanced overall survival, while maintaining a controlled budget. When compared to fluconazole, it was found to be a cost-effective alternative, with an incremental cost-effectiveness ratio of ?13,193/life years gained. The PSA showed that posaconazole remained cost-effective in 74.6% of the cases, while alternatives scenarios yielded similar results as the base case. CONCLUSIONS: Posaconazole tablets are a cost-effective alternative to fluconazole and may show better results than the oral suspension formulation. PMID- 28569351 TI - Valuing EQ-5D-5L health states 'in context' using a discrete choice experiment. AB - BACKGROUND: In health state valuation studies, health states are typically presented as a series of sentences, each describing a health dimension and severity 'level'. Differences in the severity levels can be subtle, and confusion about which is 'worse' can lead to logically inconsistent valuation data. A solution could be to mimic the way patients self-report health, where the ordinal structure of levels is clear. We develop and test the feasibility of presenting EQ-5D-5L health states in the 'context' of the entire EQ-5D-5L descriptive system. METHODS: An online two-arm discrete choice experiment was conducted in the UK (n = 993). Respondents were randomly allocated to a control (standard presentation) or 'context' arm. Each respondent completed 16 paired comparison tasks and feedback questions about the tasks. Differences across arms were assessed using regression analyses. RESULTS: Presenting health states 'in context' can significantly reduce the selection of logically dominated health states, particularly for labels 'severe' and 'extreme' (chi2 = 46.02, p < 0.001). Preferences differ significantly between arms (likelihood ratio statistic = 42.00, p < 0.05). Comparing conditional logit modeling results, coefficients are ordered as expected for both arms, but the magnitude of decrements between levels is larger for the context arm. CONCLUSIONS: Health state presentation is a key consideration in the design of valuation studies. Presenting health states 'in context' affects valuation data and reduces logical inconsistencies. Our results could have implications for other valuation tasks such as time trade-off, and for the valuation of other preference-based measures. PMID- 28569355 TI - Comparative physiology of vocal musculature in two odontocetes, the bottlenose dolphin (Tursiops truncatus) and the harbor porpoise (Phocoena phocoena). AB - The mechanism by which odontocetes produce sound is unique among mammals. To gain insight into the physiological properties that support sound production in toothed whales, we examined myoglobin content ([Mb]), non-bicarbonate buffering capacity (beta), fiber-type profiles, and myosin heavy chain expression of vocal musculature in two odontocetes: the bottlenose dolphin (Tursiops truncatus; n = 4) and the harbor porpoise (Phocoena phocoena; n = 5). Both species use the same anatomical structures to produce sound, but differ markedly in their vocal repertoires. Tursiops produce both broadband clicks and tonal whistles, while Phocoena only produce higher frequency clicks. Specific muscles examined in this study included: (1) the nasal musculature around the phonic lips on the right (RNM) and left (LNM) sides of the head, (2) the palatopharyngeal sphincter (PPS), which surrounds the larynx and aids in pressurizing cranial air spaces, and (3) the genioglossus complex (GGC), a group of muscles positioned ventrally within the head. Overall, vocal muscles had significantly lower [Mb] and beta than locomotor muscles from the same species. The PPS was predominately composed of small diameter slow-twitch fibers. Fiber-type and myosin heavy chain analyses revealed that the GGC was comprised largely of fast-twitch fibers (Tursiops: 88.6%, Phocoena: 79.7%) and had the highest beta of all vocal muscles. Notably, there was a significant difference in [Mb] between the RNM and LNM in Tursiops, but not Phocoena. Our results reveal shared physiological characteristics of individual vocal muscles across species that enhance our understanding of key functional roles, as well as species-specific differences which appear to reflect differences in vocal capacities. PMID- 28569356 TI - Effects of Laparoscopic Sleeve Gastrectomy on Parathyroid Hormone, Vitamin D, Calcium, Phosphorus, and Albumin Levels. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) reduces obesity-related co morbidities, such as diabetes, hypertension, and hyperlipidemia. Endocrinological abnormalities may occur as undesired side effects. Most centers routinely prescribe folic acid, cyanocobalamin (vitB12), and protein replacement in the postoperative period, but 25-OH-vitamin-D3 (vitD) and intact parathyroid hormone (iPTH) levels are not routinely followed up. The aim of this study was to identify the effects of LSG on iPTH, vitD, calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and albumin levels. METHODS: Data of morbidly obese patients who underwent LSG between January and December 2014 were studied in this prospectively designed study. Serum levels of iPTH, vitD, Ca, P, folic acid, vitB12, ALP, and albumin were measured preoperatively and postoperatively at the 3rd, 6th, and 12th months. RESULTS: In total, 119 patients were analyzed. All patients had normal iPTH, vitD, Ca, P, folic acid, vitB12, ALP, and albumin values preoperatively, and 31.6% had received vitD supplementation during their nutritionist observation time before surgery. At the 3rd, 6th, and 12th postoperative months, 21 (17.6%), 17 (17.3%), and 1 (0.8%) patients, respectively, had increased iPTH and ALP and decreased vitD levels. A total of 39 (32.7%) patients needed high-dose vitD treatment during a 1 year follow-up. Approximately 37.5% of the patients who received vitD supplementation preoperatively needed vitD supplementation postoperatively. Hospital records of 101 of 119 patients who underwent LSG could be screened to determine their vitD supplementation requirements previously ordered by their nutritionist for a 1 year period before LSG. Thirty-two (31.6%) of the 101 patients had received vitD supplementation during the 1-year period preoperatively. CONCLUSIONS: Although serum levels of iPTH, vitD, Ca, P, vitB12, ALP, and albumin may be normal preoperatively, severe vitD insufficiency requiring high-dose vitD replacement may develop in morbidly obese patients postoperatively. Instead of iPTH and vitD, which are expensive to measure, ALP serum level, which is correlated with iPTH levels, can be a good indicator to monitor calcium metabolism. PMID- 28569357 TI - Complications Following the Mini/One Anastomosis Gastric Bypass (MGB/OAGB): a Multi-institutional Survey on 2678 Patients with a Mid-term (5 Years) Follow-up. AB - BACKGROUND: In recent years, several articles have reported considerable results with the Mini/One Anastomosis Gastric Bypass (MGB/OAGB) in terms of both weight loss and resolution of comorbidities. Despite those positive reports, some controversies still limit the widespread acceptance of this procedure. Therefore, a multicenter retrospective study, with the aim to investigate complications following this procedure, has been designed. PATIENTS AND METHODS: To report the complications rate following the MGB/OAGB and their management, and to assess the role of this approach in determining eventual complications related especially to the loop reconstruction, in the early and late postoperative periods, the clinical records of 2678 patients who underwent MGB/OAGB between 2006 and 2015 have been studied. RESULTS: Intraoperative and early complications rates were 0.5 and 3.1%, respectively. Follow-up at 5 years was 62.6%. Late complications rate was 10.1%. A statistical correlation was found for perioperative bleeding both with operative time (p < 0.001) or a learning curve of less than 50 cases (p < 0.001). A statistical correlation was found for postoperative duodenal-gastro esophageal reflux (DGER) with a preexisting gastro-esophageal-reflux disease (GERD) or with a gastric pouch shorter than 9 cm, (p < 0.001 and p = 0.001), respectively. An excessive weight loss correlated with a biliopancreatic limb longer than 250 cm (p < 0.001). CONCLUSIONS: Our results confirm MGB/OAGB to be a reliable bariatric procedure. According to other large and long-term published series, MGB/OAGB seems to compare very favorably, in terms of complication rate, with two mainstream procedures as standard Roux-en-Y gastric bypass (RYGBP) and laparoscopic sleeve gastrectomy (LSG). PMID- 28569358 TI - Revision Procedures After Failed Adjustable Gastric Banding: Comparison of Efficacy and Safety. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) was one of the commonly performed bariatric operations; however, it carries a high revision rate. The aim of the present study was to report the long-term outcomes of LAGB and compare the outcomes between the different revision procedures. METHODS: All patients who underwent LAGB in a large bariatric center in Asia between May 2002 and April 2011 were included. Interval between primary LAGB to the revision operation, the reason and type of revision surgery were identified and analyzed. RESULTS: A total of 275 consecutive patients were included. All of the procedures were completed laparoscopically with no major complications. The percentage of excess weight loss (%EWL) at 10-year follow-up was 45%. In this study, 53 patients (19.3%) had revision surgery, including with 26 single anastomosis (mini ) gastric bypass (R-LSAGB) (49%), 17 sleeve gastrectomy (R-LSG) (32.1%), 9 Roux en-Y gastric bypass (R-LRYGB) (17%), and 1 other procedure (1.9%). A major complication occurred in 6 patients (11.3%). All of the follow-up patients with revision surgeries had %EWL > 50% at the 2-year follow-up. R-LSAGB patients achieved better weight loss than those who underwent R-LSG and R-LRYGB (p = 0.001). CONCLUSIONS: The long-term result for weight loss after LAGB is unsatisfactory. The revision of failed LAGB to other bariatric surgeries is safe and can be performed in one stage with a low complication rate. Patients who underwent R-LSAGB had better weight loss results than the R-LSG or R-LRYGB patients. PMID- 28569360 TI - Response to Letter to the Editor: Successful Management of Laparoscopic Sleeve Gastrectomy Leak with Negative Pressure Therapy. PMID- 28569359 TI - Early Effects of Sleeve Gastrectomy on Obesity-Related Cytokines and Bile Acid Metabolism in Morbidly Obese Japanese Patients. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has wide-ranging positive effects on adipocytokine metabolism, bile acid profile, and chronic low-grade inflammation related to obesity. However, the early temporal changes in these markers following LSG have not been well investigated. This study aimed to evaluate the early effects of LSG on adipocytokines, bile acid profile, and inflammatory markers. METHODS: This was a nonrandomized prospective study examining morbidly obese Japanese patients undergoing LSG. Serial measurements of leptin, adiponectin, bile acids, fibroblast growth factor (FGF)-19, and inflammatory markers were performed preoperatively and 1 and 6 months after LSG. RESULTS: The study included ten patients (five females) with a mean age of 48.8 years and BMI 40.9 kg/m2. At baseline, 90% of the patients had T2DM, 70% had dyslipidemia, and 90% had hypertension. Patients lost 5.1 kg/m2 BMI at 1 month and 10.1 kg/m2 BMI at 6 months. The leptin levels sharply decreased, and FGF-19 increased significantly as early as 1 month postoperatively. Adiponectin levels showed an increasing trend at 1 month and a significant increase at 6 months. A significant decrease in high-sensitivity CRP and plasminogen activator inhibitor 1 was observed at 6 months. No significant changes were observed in interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, serum amyloid A protein, or monocyte chemotactic protein-1 throughout the study. CONCLUSIONS: LSG improved the secretion of adipocytokines, increased FGF-19 secretion soon after surgery, and slowly ameliorated inflammation related to obesity through significant weight loss. PMID- 28569362 TI - Can ARFI elastography be used to differentiate parathyroid from thyroid lesions? AB - OBJECTIVES: To assess if elasticity score (ES) and shear wave velocity (SWV) measurement obtained using ARFI elastography can differentiate between parathyroid lesions and thyroid nodules. MATERIALS AND METHODS: ARFI elastography was performed on patients with primary hyperparathyroidism or solid thyroid nodules who were being considered for surgery using virtual touch quantification and virtual touch imaging (VTI) software. Only patients with surgical histopathology (47 parathyroid lesions, 38 benign thyroid nodules and 55 malignant thyroid nodules) were included for final analysis. SWV and ES of the parathyroid and thyroid nodules were compared and their ability to differentiate between parathyroid and thyroid was analyzed using receiver operating characteristic curve analysis. RESULTS: There were 39 solitary adenomas, 2 double adenomas and 4 parathyroid hyperplasias with mean size of 19.6 +/- 9.7 mm in 44 patients (21 male, 23 females) with primary hyperparathyroidism. The mean SWV of the parathyroid lesion (1.6 +/- 0.78 m/s) was significantly different from benign (2.11 +/- 0.8 m/s) and malignant (4.3 +/- 2.71 m/s) thyroid nodules, p < 0.05; so was the ES, Chi square = 51.6, p < 0.001. The majority of parathyroid lesions (n = 37, 78.7%) had ES of 2 with speckled (n = 42, 89.3%) appearance, and none showed ES of 4. The diagnostic performance of speckled appearance on VTI, elasticity score and SWV measurements was 0.901, 0.724 and 0.797, respectively, to differentiate between parathyroid and thyroid lesions. CONCLUSIONS: Parathyroid lesions are softer than thyroid nodules. A shear wave velocity of 1.72 m/s can differentiate between parathyroid lesions and thyroid nodules. PMID- 28569361 TI - Hypertrophic Scars: Are Vitamins and Inflammatory Biomarkers Related with the Pathophysiology of Wound Healing? AB - BACKGROUND: Hypertrophic scars are a consequence of wound healing. OBJECTIVE: The objective of the present study is to evaluate vitamin D and inflammatory biomarker plasma levels during wound healing. METHODS: A prospective study was performed in patients (n = 63) submitted to body contouring surgery. Blood samples were collected before (t 0) and 5 days after surgery (t 5). Blood cell count, protein inflammatory biomarkers, and circulating plasma levels of 25(OH)D, vitamin A and vitamin E were quantified. Six months after surgery, scars were evaluated and classified as normal or hypertrophic. RESULTS: At the end of the study, 73% of the patients developed a normal scar (control group, n = 46) and 27% of the patients presented hypertrophic scars (HT group, n = 17). The patients in the HT group presented higher eosinophil (0.145 * 109 /L vs. 0.104 * 109 /L, p = 0.028) and basophil count (0.031 * 109 /L vs. 0.22 * 109 /L, p = 0.049) and C reactive protein levels (6.12 mg/L vs. 2.30 mg/L, p = 0.015) in t 0 than the patients in the control group. At t 5, the patients in the HT group showed a decrease in neutrophil (3.144 * 109/L vs. 4.03 * 109/L, p = 0.031) and an increase in basophil (0.024 * 109/L vs. 0.015 * 109/L, p = 0.005) and lymphocyte count (1.836 * 109 /L vs. 1.557 * 109/L; p = 0.028). Before surgery, vitamin D plasma levels were found to be decreased by almost 50% (23.52 ng/mL vs. 15.46 ng/mL, p = 0.031) in the patients who developed hypertrophic scars. Thirty-one percent of the patients submitted to bariatric surgery had more hypertrophic scars, versus 24% of the patients with no previous bariatric surgery. CONCLUSION: There is a different systemic inflammatory profile response in the patients during the formation of hypertrophic scars. Vitamin D plasma levels are marked reduced in these patients. Considering the powerful anti-inflammatory effect of vitamin D, these findings could be related. PMID- 28569363 TI - Glucagon-like peptide-1 receptor agonists and atrial fibrillation: a systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND: The pharmacological stimulation of GLP-1 receptors is associated with an increase in heart rate. A pooled analysis of patient-level data from phase III trials with albiglutide revealed a significant increase in the risk of atrial fibrillation. Aim of the present meta-analysis is to summarize all available evidence on the effects of individual GLP-1 receptor agonists (RA), and of the whole class, on the incidence of atrial fibrillation. METHODS: A Medline search for GLP-1 RA (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration >=12 weeks, enrolling patients with type 2 diabetes and comparing a GLP 1 RA with placebo or any other non-GLP-1 RA drug. RESULTS: Of the 113 trials fulfilling the inclusion criteria, 19 did not report information on atrial fibrillation, whereas 63 reported zero events in all treatment groups. In the remaining trials (enrolling 17,966 and 15,305 patients in GLP-1 RA and comparator arms, respectively, 55.3% women, with a mean age of 57.0 +/- 3.8 years), treatment with GLP-1 RA was not associated with a significant increase in the incidence of atrial fibrillation [Mantel-Haenszel OR (95% CI) 0.87 (0.71-1.05), p = 0.15]. CONCLUSIONS: In conclusion, available data suggest that GLP-1 RA is not associated with atrial fibrillation, with the only possible exception of albiglutide. Newly onset atrial fibrillation deserves to be investigated as an event of special interest in future trials with GLP-1 RA. PMID- 28569364 TI - Anti-thyroglobulin antibodies and risk of finding iodine avid metastases on post radioactive iodine ablation scan in low-risk thyroid cancer patients. PMID- 28569365 TI - Risk-adjusted procedure tailoring leads to uniformly low complication rates in ventral and incisional hernia repair: a propensity score analysis and internal validation of classification criteria. AB - BACKGROUND: The usual approach in hernia surgery is to select the ideal repair method independent of the patient's characteristics. In the present study, we change the approach to ask which technique is best for the individual patient's risk profile. For this, two criteria are important: does the patient need reconstruction of the abdominal wall? or does he or she need treatment of symptoms without being exposed to unnecessarily high perioperative risks? METHODS: In a heuristic selection procedure, 486 consecutive patients were classified according to their characteristics as low-risk or high-risk for postoperative complications. Low-risk patients preferentially underwent open abdominal wall reconstruction with mesh (MFR + mesh), high-risk patients mainly a bridging-mesh procedure, either by laparoscopic (Lap.-IPOM) or open approach (Open-IPOM). Primary outcome was the incidence of postoperative complications. Secondary outcome was the recurrence-free interval. The propensity score was used for covariate adjustment analyzing recurrence rate as well as postoperative complications using Cox regression and logistic regression, respectively. RESULTS: Comparison of all surgical procedures showed risk factors had no independent influence on occurrence of complications (p = 0.110). Hernial gap width was an independent factor for occurrence of complications (p = 0.002). Propensity score adjustment revealed Lap.-IPOM to have a significantly higher recurrence rate than MFR + mesh (HR 2.367, 95% CI 1.123-4.957, p = 0.024). Three or more risk factors were protective against recurrence (HR 0.454, 95% CI 0.221 0.924, p = 0.030). In the univariate Cox regression analysis for recurrence, age >50 years was a protective prognostic factor (HR 0.412, 95% CI 0.245-0.702, p = 0.002). CONCLUSIONS: The classification criteria applied were internally validated. The heuristic algorithm ensured that patients at high-risk of complications did not have a higher perioperative complication rate than patients at low-risk. PMID- 28569366 TI - The water avoidance stress induces bladder pain due to a prolonged alpha1A adrenoceptor stimulation. AB - Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) remains an elusive disease with the cause for the pain unclear. BPS/IC patients present increased sympathetic activity and high levels of urinary noradrenaline. At the experimental level, it has been shown that chronic adrenergic stimulation produces pain and bladder changes through an alpha 1A adrenoceptor mediated mechanism. Water avoidance stress (WAS) in rodents reproduces signs of nociception and bladder changes seen in BPS/IC patients. In this study, we explore the possible role of alpha 1A adrenoceptor in bladder pain and morphological changes. WAS was induced in a group of female Wistar rats. A separate WAS group received 0.2 mg/kg day silodosin (WAS + S). Lower abdominal pain was determined by performing sensitivity to Von Frey filaments. Bladder reflex activity was determined by cystometry in anaesthetised animals. Urine was collected for noradrenaline quantification by HPLC. Bladders were harvested and stained with Haematoxylin-eosin (to analyse urothelial morphology and to determine the disruption of surface umbrella cells) or with Toluidine Blue 0.1% to analyse mast cell infiltration. WAS increased urinary noradrenaline level and bladder frequency and decreased mechanical pain threshold, which was reversed by silodosin. WAS induced lymphocytic and mast cells infiltration in the mucosa and mild urothelial disruption, which was absent in WAS + S group. Alpha 1A adrenoceptor stimulation has an important role in the appearance of bladder pain in rats. Since BPS/IC patients present high levels of noradrenaline, alpha 1A stimulation may be an additional trigger for bladder dysfunction presented by these patients. Further studies will determine the clinical relevance of this finding in the treatment of BPS/IC patients. PMID- 28569367 TI - Resonance modulation, annihilation and generation of anti-resonance and anti phasonance in 3D neuronal systems: interplay of resonant and amplifying currents with slow dynamics. AB - Subthreshold (membrane potential) resonance and phasonance (preferred amplitude and zero-phase responses to oscillatory inputs) in single neurons arise from the interaction between positive and negative feedback effects provided by relatively fast amplifying currents and slower resonant currents. In 2D neuronal systems, amplifying currents are required to be slave to voltage (instantaneously fast) for these phenomena to occur. In higher dimensional systems, additional currents operating at various effective time scales may modulate and annihilate existing resonances and generate antiresonance (minimum amplitude response) and antiphasonance (zero-phase response with phase monotonic properties opposite to phasonance). We use mathematical modeling, numerical simulations and dynamical systems tools to investigate the mechanisms underlying these phenomena in 3D linear models, which are obtained as the linearization of biophysical (conductance-based) models. We characterize the parameter regimes for which the system exhibits the various types of behavior mentioned above in the rather general case in which the underlying 2D system exhibits resonance. We consider two cases: (i) the interplay of two resonant gating variables, and (ii) the interplay of one resonant and one amplifying gating variables. Increasing levels of an amplifying current cause (i) a response amplification if the amplifying current is faster than the resonant current, (ii) resonance and phasonance attenuation and annihilation if the amplifying and resonant currents have identical dynamics, and (iii) antiresonance and antiphasonance if the amplifying current is slower than the resonant current. We investigate the underlying mechanisms by extending the envelope-plane diagram approach developed in previous work (for 2D systems) to three dimensions to include the additional gating variable, and constructing the corresponding envelope curves in these envelope space diagrams. We find that antiresonance and antiphasonance emerge as the result of an asymptotic boundary layer problem in the frequency domain created by the different balances between the intrinsic time constants of the cell and the input frequency f as it changes. For large enough values of f the envelope curves are quasi-2D and the impedance profile decreases with the input frequency. In contrast, for f ? 1 the dynamics are quasi-1D and the impedance profile increases above the limiting value in the other regime. Antiresonance is created because the continuity of the solution requires the impedance profile to connect the portions belonging to the two regimes. If in doing so the phase profile crosses the zero value, then antiphasonance is also generated. PMID- 28569368 TI - Comparison of body mass index, waist circumference, and waist-height ratio in predicting functional outcome following ischemic stroke. AB - Although a positive association between body mass index (BMI) and stroke incidence has been reported, having a higher BMI is known to be advantageous in surviving and recovering from stroke. The association between adiposity and stroke incidence is more evident for measures of abdominal obesity than for general obesity. The aim of our study was to compare BMI, waist circumference, and waist-height ratio (WHR) as predictors of 3-month functional outcome in stroke patients. The BMI, waist circumference, and WHR of acute stroke patients were divided into sex-specific quartiles. A total of 605 female and 727 male patients were included. For BMI, male patients in the second quartile were more likely to have a favorable functional outcome compared with those in the lowest quartile (adjusted OR 1.64, 95% CI 1.02-2.62). For waist circumference (adjusted OR for top quartile vs. lowest quartile 1.79, 95% CI 1.14-2.82) and WHR (adjusted OR for second quartile vs. lowest quartile 1.99, 95% CI 1.22-3.25), male patients in the two top quartiles were more likely to have a favorable functional outcome compared with those in the respective lowest quartile. BMI and WHR showed similar relationships to a favorable functional outcome, with a favorable functional outcome occurring most often among male patients in the second quartiles. In women, however, obesity was not related to functional outcome. In conclusion, general obesity measured by BMI and abdominal obesity measured by WHR showed similar effects on the functional outcome after stroke in men. PMID- 28569369 TI - CORR Insights(r): What Injury Mechanism and Patterns of Ligament Status Are Associated With Isolated Coronoid, Isolated Radial Head, and Combined Fractures? PMID- 28569370 TI - Letter to Editor: Editorial: Appropriate Use? Guidelines on Arthroscopic Surgery for Degenerative Meniscus Tears Need Updating. PMID- 28569371 TI - Editorial: Giving at the Office. PMID- 28569373 TI - CORR Insights(r): What Demographic and Clinical Characteristics Correlate With Expectations With Trapeziometacarpal Arthritis? PMID- 28569372 TI - Venous Thromboembolism Prophylaxis After TKA: Aspirin, Warfarin, Enoxaparin, or Factor Xa Inhibitors? AB - BACKGROUND: There is considerable debate regarding the ideal agent for venous thromboembolism (VTE) prophylaxis after TKA. Numerous studies and meta-analyses have yet to provide a clear answer and often omit one or more of the commonly used agents such as aspirin, warfarin, enoxaparin, and factor Xa inhibitors. QUESTIONS/PURPOSES: Using a large database analysis, we asked: (1) What are the differences in VTE incidence in primary TKA after administration of aspirin, warfarin, enoxaparin, or factor Xa inhibitors? (2) What are the differences in bleeding risk among these four agents? (3) How has use of these agents changed with time? METHODS: We queried a combined Humana and Medicare database between 2007 and Quarter 1 of 2016, and identified all primary TKAs performed using ICD-9 and Current Procedural Terminology codes. All patients who had any form of antiplatelet or anticoagulation prescribed within 1 year before TKA were excluded from our study cohort. We then identified patients who had either aspirin, warfarin, enoxaparin, or factor Xa inhibitors prescribed within 2 weeks of primary TKA. Each cohort was matched by age and sex. Elixhauser comorbidities and Charlson Comorbidity Index for each group were calculated. We identified 1016 patients with aspirin, and age- and sex-matched 6096 patients with enoxaparin, 6096 patients with warfarin, and 5080 patients with factor Xa inhibitors. Using ICD-9 codes, with the understanding that patients at greater risk may have had more-attentive surveillance, the incidence of postoperative deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding-related complications (bleeding requiring surgical intervention, hemorrhage, hematoma, hemarthrosis), postoperative anemia, and transfusion were identified at 2 weeks, 30 days, 6 weeks, and 90 days postoperatively. A four-way chi-squared test was used to determine statistical significance. Utilization was calculated using compound annual growth rate. RESULTS: There was a difference in the incidence of DVT at 90 days (p < 0.01). Factor Xa inhibitors (2.9%) had the lowest incidence of DVT followed by aspirin (3.0%) and enoxaparin (3.5%), and warfarin (4.8%). There was a difference in the incidence of PE at 90 days (p < 0.01). Factor Xa inhibitors (0.9%) had the lowest incidence of PE followed by enoxaparin (1.1%), aspirin (1.2%), and warfarin (1.6%). There was a difference in the incidence of postoperative anemia at 90 days (p < 0.01). Aspirin (19%) had the lowest incidence of postoperative anemia followed by warfarin (22%), enoxaparin (23%), and factor Xa inhibitors (23%). There was a difference in the incidence of a blood transfusion at 90 days (p < 0.01). Aspirin (7%) had the lowest incidence of a blood transfusion followed by factor Xa inhibitors (9%), warfarin (12%), and enoxaparin (13%). There were no differences in bleeding-related complications (p = 0.81) between the groups. Aspirin use increased at a compound annual growth rate of 30%, enoxaparin at 3%, and factor Xa inhibitors at 43%, while warfarin use decreased at a compound annual growth rate of -3%. CONCLUSIONS: Factor Xa inhibitors had the highest growth in utilization during our study period, followed by aspirin, when compared with enoxaparin and warfarin. When selected for the right patient, factor Xa inhibitors provided improved VTE prophylaxis compared with enoxaparin and warfarin, with a lower rate of blood transfusion. Aspirin provided comparable VTE prophylaxis compared with factor Xa inhibitors with improved VTE prophylaxis compared with enoxaparin and warfarin with the lowest risk of bleeding. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28569374 TI - Quantitative pulsed CEST-MRI at a clinical 3T MRI system. AB - OBJECTIVES: The goal of this study was to quantify CEST related parameters such as chemical exchange rate and fractional concentration of exchanging protons at a clinical 3T scanner. For this purpose, two CEST quantification approaches-the AREX metric (for 'apparent exchange dependent relaxation'), and the AREX-based Omega-plot method were used. In addition, two different pulsed RF irradiation schemes, using Gaussian-shaped and spin-lock pulses, were compared. MATERIALS AND METHODS: Numerical simulations as well as MRI measurements in phantoms were performed. For simulations, the Bloch-McConnell equations were solved using a two pool exchange model. MR experiments were performed on a clinical 3T MRI scanner using a cylindrical phantom filled with creatine solution at different pH values and different concentrations. RESULTS: The validity of the Omega-plot method and the AREX approach using spin-lock preparation for determination of the quantitative CEST parameters was demonstrated. Especially promising results were achieved for the Omega-plot method when the spin-lock preparation was employed. CONCLUSION: Pulsed CEST at 3T could be used to quantify parameters such as exchange rate constants and concentrations of protons exchanging with free water. In the future this technique might be used to estimate the exchange rates and concentrations of biochemical substances in human tissues in vivo. PMID- 28569375 TI - Motion-compensated data decomposition algorithm to accelerate dynamic cardiac MRI. AB - OBJECTIVES: In dynamic cardiac magnetic resonance imaging (MRI), the spatiotemporal resolution is often limited by low imaging speed. Compressed sensing (CS) theory can be applied to improve imaging speed and spatiotemporal resolution. The combination of compressed sensing and low-rank matrix completion represents an attractive means to further increase imaging speed. By extending prior work, a Motion-Compensated Data Decomposition (MCDD) algorithm is proposed to improve the performance of CS for accelerated dynamic cardiac MRI. MATERIALS AND METHODS: The process of MCDD can be described as follows: first, we decompose the dynamic images into a low-rank (L) and a sparse component (S). The L component includes periodic motion in the background, since it is highly correlated among frames, and the S component corresponds to respiratory motion. A motion-estimation/motion-compensation (ME-MC) algorithm is then applied to the low-rank component to reconstruct a cardiac motion compensated dynamic cardiac MRI. RESULTS: With validations on the numerical phantom and in vivo cardiac MRI data, we demonstrate the utility of the proposed scheme in significantly improving compressed sensing reconstructions by minimizing motion artifacts. The proposed method achieves higher PSNR and lower MSE and HFEN for medium to high acceleration factors. CONCLUSION: The proposed method is observed to yield reconstructions with minimal spatiotemporal blurring and motion artifacts in comparison to the existing state-of-the-art methods. PMID- 28569376 TI - Sex, body mass index, and blood pressure are related to aortic characteristics in healthy, young adults using magnetic resonance vessel wall imaging: the AMBITYON study. AB - OBJECTIVES: More detailed evaluation of atherosclerosis and its key determinants in young individuals is warranted to improve knowledge on the pathophysiology of its development and progression. This study evaluated associations of magnetic resonance imaging (MRI)-derived aortic wall area, wall thickness, and pulse wave velocity (PWV) with cardiovascular risk factors in asymptomatic, young adults. MATERIALS AND METHODS: In 124 adults (age: 25-35 years) from the general population-based Atherosclerosis Monitoring and Biomarker Measurements in the Young study, demography, anthropometry, and blood samples were collected. The studied MRI-parameters were measured using a 3.0T MRI system. Relations between cardiovascular risk factors and aortic characteristics were assessed using multivariable linear regression analyses. RESULTS: Mean age was 31.8 years, 47.6% was male. Aortic wall area was positively associated with age [beta = 0.01, (95% confidence interval (CI) 2.00 * 10-3, 0.02), p = 0.01] and BMI [beta = 0.01, (0.01, 0.02), p = 0.003] and negatively associated with sex (reference: men) [beta = -0.06, (-0.11, -0.01), p = 0.02]. Natural logarithm transformed (ln) aortic wall thickness was positively associated with BMI [beta = 0.01, (1.00 * 10 3, 0.02), p = 0.02]. Ln aortic PWV was positively associated with 10 mmHg increment of SBP [beta = 0.06, (0.03, 0.09), p < 0.001] and DBP [beta = 0.06, (0.02, 0.09), p = 0.006]. No relations were observed for smoking and lipids. CONCLUSIONS: Already in early adulthood, aortic wall geometry and stiffness vary by age, sex, BMI, and blood pressure. PMID- 28569377 TI - Testing for Noonan syndrome after increased nuchal translucency. AB - OBJECTIVE: The aim of this study was to report the prevalence of Noonan syndrome (NS) in a cohort of fetuses that presented with increased nuchal translucency (NT) thickness in the first trimester of pregnancy. METHODS: This is a retrospective chart review. INCLUSION CRITERIA: (1) first trimester NT measurement >=3 mm, (2) normal karyotype by either a CVS or an amniocentesis procedure, and (3) prenatal molecular genetic testing for NS completed. Results with known pathogenic variants were considered positive, while those with variants of unknown clinical significance, or with no variants, were considered negative. RESULTS: A total of 804 fetuses had an NT measurement of >=3 mm, with a median NT thickness of 3.6 mm. Of these, 302 had karyotyping by CVS or amniocentesis, 200 (66.23%) with normal results. Of fetuses with a normal karyotype, 39 with a median NT thickness of 4.0 mm had a NS gene sequencing panel done, and 161 fetuses with a mean NT thickness of 4.3 mm were not tested for NS (p = 0.05). Of the 39 fetuses who were tested for NS, four (10.3%) had variants consistent with this diagnosis. CONCLUSION: In euploid fetuses, increased NT is associated with a 10% risk of NS. (c) 2017 John Wiley & Sons, Ltd. PMID- 28569379 TI - Use and Education of Point-of-Care Ultrasound in Pediatric Emergency Medicine in Saudi Arabia. AB - OBJECTIVES: Point-of-care ultrasound (US) is an emerging tool used by pediatric emergency physicians in the last decade. Currently in the Middle East, point-of care US use and education are at an early stage, with no designed curriculum or guidelines for its implementation in pediatric emergency medicine (EM). The objective of this article is to describe the clinical and educational uses of point-of-care US among certified pediatric EM physicians. METHODS: A 19-question survey was sent to all certified pediatric emergency physicians and fellows in pediatric emergency fellowships in Saudi Arabia in February 2016. Reminders were sent weekly for 4 weeks. RESULTS: The response rate was 84 of 88 (95%). Fifty-one of 84 (61%) reported using point-of-care US. Focused assessment with sonography for trauma was the most frequent use of point-of-care US (37%), followed by procedures (19%). The most common barrier for not using point-of-care US was limited training (86%). The most preferred tool for point-of-care US teaching was courses by EM physicians. Currently, there is no specific curriculum designed for pediatric EM in the Middle East. CONCLUSIONS: Despite the multiple applications of point-of-care US in pediatric EM, its use is still limited. Formal point-of care US training with bedside sessions and courses was the mort preferred method of education. A designed curriculum needs to be implemented in pediatric emergency fellowships in Saudi Arabia. PMID- 28569380 TI - The Role of Speaker Knowledge in Children's Pragmatic Inferences. AB - During communication, conversational partners should offer as much information as is required and relevant. For instance, the statement "Some Xs Y" is infelicitous if one knows that all Xs Y. Do children understand the link between speaker knowledge and utterance strength? In Experiment 1, 5-year-olds (N = 32) but not 4 year-olds (N = 32) reliably connected statements of different logical strength (e.g., "The girl colored all/some of the star") to observers who were fully or partially informed. Four-year-olds' performance improved when observer knowledge could be assessed more easily (Experiment 2a, N = 25) but remained the same in a nonlinguistic version of Experiment 1 that preserved the epistemic requirements of the original study (Experiment 2b, N = 26). These findings have implications for the development of early communicative abilities. PMID- 28569378 TI - Cyclosporine exacerbates ketamine toxicity in zebrafish: Mechanistic studies on drug-drug interaction. AB - Cyclosporine A (CsA) is an immunosuppressive drug commonly used in organ transplant patients to prevent allograft rejections. Ketamine is a pediatric anesthetic that noncompetitively inhibits the calcium-permeable N-methyl-d aspartic acid receptors. Adverse drug-drug interaction effects between ketamine and CsA have been reported in mammals and humans. However, the mechanism of such drug-drug interaction is unclear. We have previously reported adverse effects of combination drugs, such as verapamil/ketamine and shown the mechanism through intervention by other drugs in zebrafish embryos. Here, we show that ketamine and CsA in combination produce developmental toxicity even leading to lethality in zebrafish larvae when exposure began at 24 h post-fertilization (hpf), whereas CsA did not cause any toxicity on its own. We also demonstrate that acetyl l carnitine (ALCAR) completely reversed the adverse effects. Both ketamine and CsA are CYP3A4 substrates. Although ketamine and CsA independently altered the expression of the hepatic marker CYP3A65, a zebrafish ortholog of human CYP3A4, both drugs together induced further increase in CYP3A65 expression. In the presence of ALCAR, however, CYP3A65 expression was normalized. ALCAR has been shown to prevent ketamine toxicity in mammal and zebrafish. In conclusion, CsA exacerbated ketamine toxicity and ALCAR reversed the effects. These results, providing evidence for the first time on the reversal of the adverse effects of CsA/ketamine interaction by ALCAR, would prove useful in addressing potential occurrences of such toxicities in humans. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. PMID- 28569381 TI - LncRNA-TP53TG1 Participated in the Stress Response Under Glucose Deprivation in Glioma. AB - Gliomas are the most common brain tumors of the center nervous system. And long non-coding RNAs (lncRNAs) are non-protein coding transcripts, which have been considered as one type of gene expression regulator for cancer development. In this study, we investigated the role of lncRNA-TP53TG1 in response to glucose deprivation in human gliomas. The expression levels of TP53TG1 in glioma tissues and cells were analyzed by qRT-PCR. In addition, the influence of TP53TG1 on glucose metabolism related genes at the mRNA level during both high and low glucose treatment was detected by qRT-PCR. MTT, clonogenicity assays, and flow cytometry were performed to detect the cell proliferation and cell apoptosis. Furthermore, the migration of glioma cells was examined by Transwell assays. The expression of TP53TG1 was significantly higher in human glioma tissues or cell lines compared with normal brain tissue or NHA. Moreover, TP53TG1 and some tumor glucose metabolism related genes, such as GRP78, LDHA, and IDH1 were up-regulated significantly in U87 and LN18 cells under glucose deprivation. In addition, knockdown of TP53TG1 decreased cell proliferation and migration and down regulated GRP78 and IDH1 expression levels and up-regulated PKM2 levels in U87 cells under glucose deprivation. However, over-expression of TP53TG1 showed the opposite tendency. Moreover, the effects of TP53TG1 were more remarkable in low glucose than that in high glucose. Our data showed that TP53TG1 under glucose deprivation may promote cell proliferation and migration by influencing the expression of glucose metabolism related genes in glioma. J. Cell. Biochem. 118: 4897-4904, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28569382 TI - Reconstruction of a clinician training system in China-A successful "5 + 3" model from Shanghai. AB - To promote medical educational reforms and improve the quality of health care services in China, Shanghai has embarked on a pilot reform programme to combine 3 year graduate education with standardized residency training, which is called the 5 + 3 model and consists of 5 years of undergraduate studies plus 3 years of graduate studies integrated with standardized residency training. In the current review, we present the reconstruction and practice of the model in China. PMID- 28569384 TI - Parent and Peer Predictors of Change in Attachment Security From Adolescence to Adulthood. AB - Interview, self-report, peer report, and observational data were used to examine parent and peer relationship qualities as predictors of relative changes in attachment security in a community sample of adolescents followed from ages 14 to 24. Early maternal supportive behavior predicted relative increases in attachment security from adolescence to adulthood, whereas psychological control and interparental hostile conflict predicted relative decreases. Peer predictors of relative increases in security included collaborative and autonomous behaviors and lack of hostile interactions, with peer predictions growing stronger for relationships assessed at later ages. Overall, models accounted for sufficient variance as to suggest that attachment security across this period is well explained by a combination of stability plus theoretically predicted change linked to social relationship qualities. PMID- 28569385 TI - Engaging Indigenous families in a community-based Indigenous early childhood programme in British Columbia, Canada: A cultural safety perspective. AB - This article is part of a larger study that explored how an Indigenous early intervention programme in British Columbia (BC), Canada, known as the 'Aboriginal Infant Development Program' (AIDP), influenced family and children's health and well-being and was responsive to child health inequities. Postcolonial feminist and Indigenous feminist perspectives provided a critical analytical lens to this qualitative inquiry. The study was undertaken with AIDPs based in diverse community organisations located in off-reserve urban municipalities throughout the province of BC. From September 2013 to March 2014, in-depth, semi-structured interviews were undertaken with: Indigenous primary caregivers (n = 10), Indigenous Elders (n = 4), AIDP workers (n = 18) and administrative leaders (n = 3). The purpose of this article is to examine and analyse the findings that focus on how AIDP workers supported family and children's health and well-being by transforming their routine policies and practices in ways that fostered caregivers' active engagement in their programmes. Findings centre on three main themes: (i) overcoming mistrust; (ii) 'being willing to move a step forward' and (iii) resisting what's taken-for-granted. These inter-related themes are examined and discussed in relation to the concept of cultural safety. The findings have international relevancy for social and healthcare community-based programmes that are questioning how to engage with parents who may be hard to reach as a result of multi-faceted social and structural factors. PMID- 28569383 TI - Atrial fibrillation, cognition and dementia: A review. AB - Atrial fibrillation (AF) is one of the most common types of cardiac arrhythmia, particularly among older adults. AF confers a 5-fold risk for thromboembolic stroke as well as a 2-fold higher risk for congestive heart failure, morbidity, and mortality. Although stroke remains an important and impactful complication of AF, recent studies have shown that AF is independently associated with other neurological disorders, including cognitive impairment and dementia, even after adjusting for prior ischemic stroke. We performed a review of the published literature on the association between AF and cognitive status. Further, we reviewed studies investigating the underlying mechanisms for this association and/or reporting the impact of AF treatment on cognitive function. While most published studies demonstrate associations between AF and impaired cognition, no AF treatment has yet been associated with a reduced incidence of cognitive decline or dementia. PMID- 28569386 TI - Risk score to assess mortality risk in patients undergoing transvenous lead extraction. AB - AIMS: The main aim of this study was to assess 1-year mortality and its predictors in a cohort of patients who underwent transvenous lead extraction (TLE) procedure. METHODS: Retrospective analysis of clinical characteristics and 1-year follow-up of patients referred for a TLE procedure in a single, high volume center between June 2006 and October 2014 was performed. RESULTS: The studied population included 130 patients (82 males; mean age 64 +/- 15 years) implanted with pacemakers (74%), implantable cardioverter defibrillators (15%), or cardiac resynchronization therapy defibrillator (11%). Indications for the extraction included infective endocarditis (40.5%), pocket infection (18.5%), and lead fault or failure (41%). Total radiological success rate was 90% while clinical success rate was 93.5%. The cumulative 1-year mortality was 28%. Mortality was higher in a group of older patients (94.4% vs 68%, P = 0.001) and those with chronic kidney disease (33.3% vs 4.3 %, P = 0.0002) as well as in patients after removal of high voltage lead (88.9% vs 26.3%, P = 0.01). Higher mortality was also related to infection as an indication for TLE (37.2% vs 13.5%, P = 0.002). Following these findings a new risk score model named IKAR (I = infective indications; K = kidney dysfunction; A = age >= 56; R = removal of high voltage lead) was constructed. Patients with IKAR score >=3 points were characterized by 79% mortality as compared to 16% in those with a score 1-2 points. CONCLUSIONS: One-year mortality of patients undergoing TLE procedure can be predicted by using IKAR risk score. PMID- 28569388 TI - Longitudinal Associations Among Reading-Related Skills and Reading Comprehension: A Twin Study. AB - This study investigated the etiology of longitudinal relations among kindergarten prereading skills, first-grade word level reading skills, and seventh-grade reading comprehension in 265 monozygotic and 459 dizygotic twin pairs (Mage = 6.29 years in kindergarten) from the Florida Twin Project on Reading. Using a quadvariate Cholesky decomposition, results showed genetic, shared, and nonshared environmental overlap among prereading skills, word level reading skills, and reading comprehension. In addition, genetic and shared environmental overlap was indicated among word level reading skills and reading comprehension, outside the influence of prereading skills. After accounting for overlapping, there remained moderate genetic and nonshared environmental influence specific to reading comprehension. Implications for reading education are discussed. PMID- 28569387 TI - Synthesis and in vitro antioxidant activity study of some new piperazinyl flavone compounds. AB - Flavones exhibit a variety of beneficial effects and are well known for their medicinal importance in several diseases, including cardiovascular, neurodegenerative and cancer. The inclusion of the piperazine ring to the flavone backbone is an important strategy in drug discovery but only a few studies have synthesized piperazinyl flavone compounds to test their biological activity. While there is a major focus on the antioxidant properties of drugs in therapy of several diseases of inflammatory origin, we synthesized a series of the novel piperazinyl flavone analogues bearing the phenyl ring with different substituents. The analogues were evaluated for in vitro antioxidant activity against superoxide anion radical, hydroxyl radical, 2,2-diphenyl-1-picrylhydrazyl radical, and hydrogen peroxide scavenging properties. The total antioxidant status based on the absorbance of the 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulphonic acid) radical cation (ABTS+* ) and total antioxidant capacity using the Fe(III)-ferrozine complex were also monitored. The results of the above studies showed that the compounds synthesized were found possessed moderate radical scavenging potential, and that their interaction with reactive oxygen species is complex and depends on their structural conformation and the type of substituent R in the piperazine ring being attached. Best antiradical activity were found for the compounds with methoxy groups on the phenyl ring of substituent R, whereas the presence of methoxy or trifluoromethyl groups in substituent R resulted in higher ABTS+* and ion Fe(III) reduction. These compounds are promising molecules to be used for their antioxidant properties and may be regarded, after improvement of the antioxidant potential, to control diseases of free radical etiology. PMID- 28569389 TI - About the contrast of delta' precipitates in bulk Al-Cu-Li alloys in reflection mode with a field-emission scanning electron microscope at low accelerating voltage. AB - Characterising the impact of lithium additions in the precipitation sequence in Al-Li-Cu alloys is important to control the strengthening of the final material. Since now, transmission electron microscopy (TEM) at high beam voltage has been the technique of choice to monitor the size and spatial distribution of delta' precipitates (Al3 Li). Here we report on the imaging of the delta' phase in such alloys using backscattered electrons (BSE) and low accelerating voltage in a high resolution field-emission scanning electron microscope. By applying low-energy Ar+ ion milling to the surface after mechanical polishing (MP), the MP-induced corroded layers were efficiently removed and permitted the delta's to be visible with a limited impact on the observed microstructure. The resulting BSE contrast between the delta's and the Al matrix was compared with that obtained using Monte Carlo modelling. The artefacts possibly resulting from the sample preparation procedure were reviewed and discussed and permitted to confirm that these precipitates were effectively the metastable delta's. The method described in this report necessitates less intensive sample preparation than that required for TEM and provides a much larger field of view and an easily interpretable contrast compared to the transmission techniques. PMID- 28569390 TI - Do Children and Adolescents Have Different Types of Trauma Narratives and Does It Matter? Reliability and Face Validation for a Narrative Taxonomy. AB - The construction of trauma narratives is a major component of several psychotherapy approaches for trauma-related problems, but questions remain as to whether fully expressive narratives are necessary and whether it is detrimental to ask avoidant youths to tell their narratives repeatedly. Characteristics of trauma narratives during psychotherapy have not been examined in youths and this represents a salient gap in knowledge. This study aimed to begin filling this gap by identifying categories of trauma narratives and empirically validating them. Youths (N = 47) aged 7 to 18 years, who were involved in a randomized controlled trial, received cognitive behavioral therapy. Transcripts of all narrative exposure therapy sessions for each youth were rated. Four categories were identified and were named expressive, avoidant, fabricated, and undemonstrative. Interrater reliability for identifying these categories was good, and face validation of the categories was supported by statistically significant differences between categories on the number of data elements of the trauma events, negative emotion words, and positive emotion words. These promising findings indicate that different types of narrative styles can be reliably identified. There was strong evidence for reduction of posttraumatic stress symptoms in each of the categories (Cohen's d = 0.9 to 2.5). Favorable treatment outcomes for all categories suggest that more remembering is not always better and clients appeared to effectively deal with memories in different ways. PMID- 28569391 TI - Permanent His bundle pacing: Electrophysiological and echocardiographic observations from long-term follow-up. AB - BACKGROUND: Permanent His bundle pacing (HBP) is a physiological alternative to right ventricular pacing. It is not known whether HBP can cause His-Purkinje conduction (HPC) disease. The aim of our study is to assess His bundle capture and its effect on left ventricular (LV) function in long-term follow-up and to determine HPC at the time of pulse generator change (GC) in patients with chronic HBP. METHODS: HB electrograms were recorded from the pacing lead at implant and GC. HBP QRS duration (QRSd), His-ventricular (HV) intervals, and HB pacing thresholds at GC were compared with implant measurements. HPC was assessed by pacing at cycle lengths of 700 ms, 600 ms, and 500 ms at GC. LV internal diameters, ejection fraction (EF), and valve dysfunction at baseline were compared with echocardiography during follow-up. RESULTS: GC was performed in 20 patients (men 13; age 74 +/- 14 years) with HBP at 70 +/- 24 months postimplant. HV intervals remained unchanged from initial implant (44 +/- 4 ms vs 45 +/- 4 ms). During HBP at 700 ms, 600 ms, and 500 ms (n = 17), consistent 1:1 HPC was present. HBP QRSd remained unchanged during follow-up (117 +/- 20 ms vs 118 +/- 23 ms). HBP threshold at implant and GC was 1.9 +/- 1.1 V and 2.5 +/- 1.2 V @ 0.5 ms. Despite high pacing burden (77 +/- 13%), there was no significant change in LVEF (50 +/- 14% at implant) during follow-up (55 +/- 6%, P = 0.06). CONCLUSIONS: HBP does not appear to cause new HPC abnormalities and is associated with stable HBP QRSd during long-term follow-up. Despite high pacing burden, HBP did not result in deterioration of left ventricular systolic function or cause new valve dysfunction. PMID- 28569392 TI - MiR-133a-3p Inhibits Oral Squamous Cell Carcinoma (OSCC) Proliferation and Invasion by Suppressing COL1A1. AB - The aim of our study was to investigate the effects of miR-133a-3p on human oral squamous cell carcinoma (OSCC) cells by regulating gene COL1A1. OSCC tissues, adjacent tongue epithelial tissues, the immortalized oral epithelial cell line HIOEC, and OSCC cell lines (CAL-27, TCA-8113, SCC-4, SCC-9, and SCC-15) were used in this research. Quantitative real-time PCR (RT-qPCR) was employed to determine the expression of miR-133a-3p and COL1A1. Dual luciferase reporter gene assay and Western blot were applied to verify the binding relationship between miR-133a-3p and COL1A1. Functional assays were also conducted in this study, including CCK-8 assay, colony formation assay, flow cytometry analysis as well as Transwell assay. MiR-133a-3p was found low-expressed both in OSCC tissues and cells lines compared with normal tissues and cell line, respectively, whereas COL1A1 was just the opposite. The over-expression of miR-133a-3p or the down-regulation of COL1A1 suppressed the proliferation, invasion, and mitosis of OSCC cells, whereas simultaneous down-regulation of miR-133a-3p and up-regulation of COL1A1 led to no significant alteration of cell activities. MiR-133a-3p could inhibit the proliferation and migration of OSCC cells through directly targeting COL1A1 and reducing its expression. J. Cell. Biochem. 119: 338-346, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28569393 TI - Multidimensional latent trait linear mixed model: an application in clinical studies with multivariate longitudinal outcomes. AB - Multilevel item response theory (MLIRT) models have been widely used to analyze the multivariate longitudinal data of mixed types (e.g., categorical and continuous) in clinical studies. The MLIRT models often have unidimensional assumption, that is, the multiple outcomes are clinical manifestations of a univariate latent variable. However, the unidimensional assumption may be unrealistic because some diseases may be heterogeneous and characterized by multiple impaired domains with variable clinical symptoms and disease progressions. We relax this assumption and propose a multidimensional latent trait linear mixed model (MLTLMM) to allow multiple latent variables and within item multidimensionality (one outcome can be a manifestation of more than one latent variable). We conduct extensive simulation studies to assess the unidimensional MLIRT model and the proposed MLTLMM model. The simulation studies suggest that the MLTLMM model outperforms unidimensional model when the multivariate longitudinal outcomes are manifested by multiple latent variables. The proposed model is applied to two motivating studies of amyotrophic lateral sclerosis: a clinical trial of ceftriaxone and the Pooled Resource Open-Access ALS Clinical Trials database. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28569394 TI - Autopsy case of systemic EBV-positive T-cell lymphoma of childhood with marked hepatomegaly in a middle-aged man. PMID- 28569395 TI - Co-located welfare advice in general practice: A realist qualitative study. AB - General practitioners (GPs) engage with patients about a variety of social issues distinct from direct clinical work ("non-health" issues), such as health-related benefits and debt. Co-located welfare advice services could provide support to practices but have usually been considered in terms of patient rather than practice outcomes. We aimed to develop an initial programme theory for how the provision of co-located advice supports specific practice outcomes, and to identify salient barriers and enabling factors. Twenty-four semi-structured interviews with general practice staff, advice staff and service funders in two UK urban localities were conducted between January and July 2016. Data were thematically analysed and a modified Realist Evaluation approach informed the topic guide, thematic analysis and interpretation. Two outcomes are described linked to participant accounts of the impact of such non-health work on practices: reduction of GP consultations linked to non-health issues and reduced practice time spent on non-health issues. We found that individual responses and actions influencing service awareness were key facilitators to each of the practice outcomes, including proactive engagement, communication, regular reminders and feedback between advice staff, practice managers and funders. Facilitating implementation factors were: not limiting access to GP referral, and offering booked appointments and advice on a broader range of issues responsive to local need. Key barriers included pre-existing sociocultural and organisational rules and norms largely outside of the control of service implementers, which maintained perceptions of the GP as the "go-to-location". We conclude that co-location of welfare advice services alone is unlikely to enable positive outcomes for practices and suggest several factors amenable to intervention that could enhance the potential for co-location to meet desired objectives. PMID- 28569396 TI - miR-100 promotes the proliferation of spermatogonial stem cells via regulating Stat3. AB - Micro RNAs play important roles during mammalian spermatogenesis, but the function(s) of specific miRNAs remain largely unknown. Here, we report that miR 100 is predominantly expressed in undifferentiated murine spermatogonia, including spermatogonial stem cells (SSCs). We utilized a miRNA mimic and inhibitor to knock down and overexpress miR-100 in cultured SSCs, respectively, finding that the miR-100 promotes the proliferation of SSCs in vitro. Furthermore, signals promoting SSC maintenance induced, whereas retinoic acid repressed, expression of miR-100. Stat3 expression was modulated by miR-100, with increased transcript and protein abundance in the presence of the miR-100 inhibitor versus reduced protein levels following miR-100 overexpression. Stat3 silencing also mimicked the reduced SSC proliferation phenotype associated with elevated miR-100 levels. Importantly, Stat3 silencing rescued the anti proliferation capacity of miR-100 inhibitor on cultured SSCs. Given that the Stat3 3' untranslated region was not repressed by pre-miR-100 in a standard luciferase reporter assay, we suggest that miR-100 promotes SSC proliferation by indirect regulation of Stat3. PMID- 28569397 TI - Promoting continuity of care for homeless adults with unmet health needs: The role of brief interventions. AB - Promoting timely and continuous care for people experiencing homelessness has been a challenge in many jurisdictions, plagued by access barriers and service fragmentation. As part of a larger programme evaluation, this study used qualitative methods to examine the role of a brief interdisciplinary intervention in supporting continuity of care for this population in a large Canadian urban centre. The intervention provides time-limited case management, primary and psychiatric care, and peer accompaniment to homeless adults with unmet health needs discharged from hospital. Data were collected from 52 study participants between July 2013 and December 2014. Three focus groups were conducted with service providers and people with lived experience of homelessness, and 29 individual, semi-structured interviews were conducted with service users and other key informants. Transcripts were analysed using thematic analysis. Analysis was informed by existing frameworks for continuity of care, while remaining open to additional or unexpected findings. Findings suggest that brief interdisciplinary interventions can promote continuity of care by offering low barrier access, timely and responsive service provision, including timely connection to long-term services and supports, appropriate individualised services and effective co-ordination of services. Although brief interdisciplinary interventions were perceived to promote access, timeliness and co-ordination of care for this population with complex health and social needs, gaps in the local service delivery context can present persisting barriers to care comprehensiveness and continuity. PMID- 28569398 TI - Sodium MRI of T1 High Signal Intensity in the Dentate Nucleus due to Gadolinium Deposition in Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: Recently, several studies reported increased signal intensity (SI) of the dentate nucleus (DN) on unenhanced T1-weighted magnetic resonance imaging (MRI) as a possible consequence of multiple applications of gadolinium-based contrast agents. The aim of this study was to investigate with sodium (23 Na) MRI possible tissue abnormalities of the DN in multiple sclerosis (MS) patients. METHODS: Sodium and conventional MRI were performed on a clinical 3T scanner. Total sodium concentrations (TSCs) of the DN, as well as DN-to-pons and DN-to-cerebellum SI ratios on unenhanced T1-weighted MRI were calculated. RESULTS: A total of 18 subjects (6/18 normal controls, 12/18 MS patients [6/12 with T1 hyperintense DN]) were investigated. There was no significant difference of TSC values of the DN in MS patients with a T1-hyperintense DN (33.70 +/- 2.14 mM) compared to MS patients without those signal abnormalities (33.29 +/- 1.67 mM; P = .67) or to healthy controls (33.14 +/- 1.12; P = .32). CONCLUSIONS: Normal sodium signal in the T1-hyperintense DN in MS patients may point to relative tissue integrity despite gadolinium deposition in this area. PMID- 28569399 TI - School absence and its effect on school performance for children born with orofacial clefts. AB - BACKGROUND: School absence is associated with lower performance on standardized tests. Children born with orofacial clefts (OFC) are likely to have more absence than children without OFC; however, school absence for children with OFC has not been quantified. We aimed to describe school absence and its relationship with school performance for children with and without OFC. METHODS: Population-based record-linked cohort study of children (402 with OFC, 1789 without OFC) enrolled in schools in Western Australia, 2008 to 2012. We compared median school absence rates using Wilcoxon rank tests, and investigated the impact of school absence on standardized scores from reading, numeracy, and writing tests, using multivariable models fitted by generalized estimating equations. RESULTS: In Semester 1, at each primary school year level, children without OFC and children with cleft lip only or cleft palate only had similar median absence rates (approximately 1 week). Children with cleft lip and palate had significantly higher absence rates in Years 4 to 6 (between 1 and 2 weeks). During secondary school, median absence rates were higher (2 weeks) for all children, but not statistically different between children with and without OFC. Higher absence was significantly associated with lower standardized reading, numeracy, and writing scores. However, having a cleft of any type had little influence on the association between absence and test scores. CONCLUSION: School absence affected school performance for all children. Absence did not differentially disadvantage children born with OFC, suggesting current practices to identify and support children with OFC are minimizing effects of their absence on school performance. Birth Defects Research 109:1048-1056, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28569400 TI - Conducting research in clinical psychology practice: Barriers, facilitators, and recommendations. AB - OBJECTIVES: The combination of clinical psychologists' therapeutic expertise and research training means that they are in an ideal position to be conducting high quality research projects. However, despite these skills and the documented benefits of research to services and service users, research activity in practice remains low. This article aims to give an overview of the advantages of, and difficulties in conducting research in clinical practice. METHOD: We reviewed the relevant literature on barriers to research and reflected on our clinical and research experiences in a range of contexts to offer practical recommendations. RESULTS: We considered factors involved in the planning, sourcing support, implementation, and dissemination phases of research, and outline suggestions to improve the feasibility of research projects in post-qualification roles. CONCLUSIONS: We suggest that research leadership is particularly important within clinical psychology to ensure the profession's continued visibility and influence within health settings. PRACTITIONER POINTS: Clinical implications Emerging evidence suggests that clinical settings that foster research are associated with better patient outcomes. Suggestions to increase the feasibility of research projects in clinical settings are detailed. Limitations The present recommendations are drawn from the authors' practical experience and may need adaptation to individual practitioners' settings. This study does not attempt to assess the efficacy of the strategies suggested. PMID- 28569401 TI - Macrophage inhibitory cytokine-1/growth differentiation factor-15 as a predictor of colonic neoplasia. AB - BACKGROUND: Serum macrophage inhibitory cytokine-1 (MIC-1/GDF15) concentration has been associated with colonic adenomas and carcinoma. AIMS: To determine whether circulating MIC-1/GDF15 serum concentrations are higher in the presence of adenomas and whether the level decreases after excision. METHODS: Patients were recruited prospectively from a single centre and stratified into five groups: no polyps (NP); hyperplastic polyps (HP); sessile serrated ademona (SSA); adenomas (AP); and colorectal carcinoma (CRC). Blood samples were collected immediately before and 4 weeks after colonoscopy. MIC-1/GDF15 serum levels were quantified using ELISA. RESULTS: Participants (n=301) were stratified as: NP; n=116 (52%), HP; n=37 (12%), SSA; n=19 (7%), AP; n=68 (23%); and CRC; n=3 (1%). Patients were excluded from the study due to nondiagnostic pathology (n=9, 3%) and exclusion criteria (n=20, 6%). In the 272 remaining subjects (M=149; F=123), age (P=.005), history of colonic polyps (P=.003) and family history of colonic polyps (P=.002) were associated with presence of adenomas. Baseline median MIC 1/GDF15 serum levels increased significantly from NP 609 (460-797) pg/mL, HP 582 (466-852) pg/mL, SSA 561 (446-837) pg/mL to AP 723 (602-1122) pg/mL and CRC 1107 (897-1107) pg/mL; (P<.001). In the pre- and postpolypectomy paired adenoma samples median MIC-1/GDF15 reduced significantly from 722 (603-1164) pg/mL to 685 (561-944) pg/mL (P=.002). A ROC analysis for serum MIC-1/GDF15 to identify adenomatous polyps indicated an area under the curve of 0.71. CONCLUSIONS: Our data suggest that serum MIC-1/GDF15 has the diagnostic characteristics to increase the detection of colonic neoplasia and improve screening. PMID- 28569402 TI - LRWD1 Regulates Microtubule Nucleation and Proper Cell Cycle Progression in the Human Testicular Embryonic Carcinoma Cells. AB - Leucine-rich repeats and WD repeat domain containing protein 1 (LRWD1) is a testis-specific protein that mainly expressed in the sperm neck where centrosome is located. By using microarray analysis, LRWD1 is identified as a putative gene that involved in spermatogenesis. However, its role in human male germ cell development has not been extensively studied. When checking in the semen of patients with asthenozoospermia, teratozoospermia, and asthenoteratozoospermia, the level of LRWD1 in the sperm neck was significantly reduced with a defective neck or tail. When checking the sub-cellular localization of LRWD1 in the cells, we found that LRWD1 resided in the centrosome and its centrosomal residency was independent of microtubule transportation in NT2/D1, the human testicular embryonic carcinoma, cell line. Depletion of LRWD1 did not induce centrosome re duplication but inhibited microtubule nucleation. In addition, the G1 arrest were observed in LRWD1 deficient NT2/D1 cells. Upon LRWD1 depletion, the levels of cyclin E, A, and phosphorylated CDK2, were reduced. Overexpression of LRWD1 promoted cell proliferation in NT2/D1, HeLa, and 239T cell lines. In addition, we also observed that autophagy was activated in LRWD1 deficient cells and inhibition of autophagy by chloroquine or bafilomycin A1 promoted cell death when LRWD1 was depleted. Thus, we found a novel function of LRWD1 in controlling microtubule nucleation and cell cycle progression in the human testicular embryonic carcinoma cells. J. Cell. Biochem. 119: 314-326, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28569404 TI - Spectrofluorimetric determination of atenolol from human urine using high affinity molecularly imprinted solid-phase extraction sorbent. AB - This study presents a novel, sensitive and selective molecularly imprinted solid phase extraction (MISPE)-spectrofluorimetric method for the removal and determination of atenolol from human urine. Molecularly imprinted and non imprinted polymers were synthesized thermally using a radical chain polymerization technique and used as solid-phase extraction sorbents. Acrylic acid ethylene glycol dimethacrylate, dibenzoyl peroxide and dichloroethane were used as a functional monomer, cross-linker, initiator and porogen, respectively. The calibration curve was in the range of 0.10-2.0 MUg/ml for the developed method. Limit of detection and limit of quantification values were 0.032 and 0.099 MUg/ml, respectively. Owing to the selectivity of the MISPE technique and the sensitivity of spectrofluorimetry, trace levels of atenolol have been successfully determined from both organic and aqueous media. Relatively high imprinting factor (4.18) and recovery results (74.5-75.3%) were obtained. In addition, intra- and interday precision values were 0.38-1.03% and 0.47-2.05%, respectively, proving the precision of the proposed method. Thus, a selective, sensitive and simple MISPE-spectrofluorimetric method has been developed and applied to the direct determination of atenolol from human urine. PMID- 28569403 TI - Ultra-sensitive fluorescent sensor for intracellular miRNA based on enzyme-free signal amplification with carbon nitride nanosheet as a carrier. AB - A novel ultra-sensitive fluorescent sensor for monitoring microRNA (miRNA) in living cells was constructed by utilizing a hybridization chain reaction (HCR) as the signal amplification with a carbon nitride nanosheet (CNNS) as a carrier. The Cy5-labeled hairpin DNA could be adsorbed onto the surface of CNNS, resulting in fluorescence quenching of Cy5. When treated with complementary miRNA, the fluorescence was recovered because miRNA could efficiently trigger an HCR, which led to the release of the HCR products from the CNNS. This intracellular HCR strategy can be used for ultra-sensitive monitoring of intracellular miRNA. The main advantages of the proposed method are its simplicity, high sensitivity, high specificity and low toxicity for monitoring low-level biomarkers. PMID- 28569405 TI - Sex-Dependent, Osteoblast Stage-Specific Effects of Progesterone Receptor on Bone Acquisition. AB - The role of the progesterone receptor (PR) in the regulation of sexual dimorphism in bone has yet to be determined. Here we utilized genetic fate mapping and Western blotting to demonstrate age-dependent PR expression in the mouse femoral metaphysis and diaphysis. To define sex-dependent and osteoblast stage-specific effects of PR on bone acquisition, we selectively deleted PR at different stages of osteoblast differentiation. We found that when Prx1-Cre mice were crossed with PR floxed mice to generate a mesenchymal stem cell (MSC) conditional KO model (Prx1; PRcKO), the mutant mice developed greater trabecular bone volume with higher mineral apposition rate and bone formation. This may be explained by increased number of MSCs and greater osteogenic potential, particularly in males. Age-related trabecular bone loss was similar between the Prx1; PRcKO mice and their WT littermates in both sexes. Hormone deficiency during the period of rapid bone growth induced rapid trabecular bone loss in both the WT and the Prx1; PRcKO mice in both sexes. No differences in trabecular bone mass was observed when PR was deleted in mature osteoblasts using osteocalcin-Cre (Bglap-Cre). Also, there were no differences in cortical bone mass in all three PRcKO mice. In conclusion, PR inactivation in early osteoprogenitor cells but not in mature osteoblasts influenced trabecular bone accrual in a sex-dependent manner. PR deletion in osteoblast lineage cells did not affect cortical bone mass. (c) 2017 American Society for Bone and Mineral Research. PMID- 28569407 TI - Agreement Between an Automated Volume Breast Scanner and Handheld Ultrasound for Diagnostic Breast Examinations. AB - OBJECTIVES: To compare the agreement and interobserver variability of diagnostic handheld ultrasound (US) and a single volume on an automated breast volume scanner (ABVS) and to determine whether there was a significant difference if the ABVS was used by a sonographer or mammographic technologist. METHODS: Ninety patients scheduled for diagnostic US examinations were randomized to either handheld US or the ABVS first. The AVBS was randomized between a sonographer and a mammographic technologist performing the study. The studies were blinded, randomized, and read by 2 radiologists. The lesion with the highest Breast Imaging Reporting and Data System (BI-RADS) score was used in the analysis. Final diagnoses were made by core biopsy or follow-up for 2 years. Lesions included 9 malignant and 81 benign. RESULTS: The 90 patients had a mean age +/- SD of 53.1 +/- 16.3 years. The kappa value for agreement between the ABVS and handheld US was 0.831 (95% confidence interval, 0.744-0.925), whereas the global agreement for a 7-point BI-RADS score was 0.488 (0.372-0.560). The agreement between the ABVS and handheld US was nearly the same when the ABVS was used by a mammographic technologist (kappa = 0.858 [0.723-0.963]) or sonographer (kappa = 0.803 [0.596 1.000]; P = .47). The areas under the receiver operating characteristic curves for characterization by the ABVS were 0.91 (0.84-0.96) for reader 1 and 0.91 (0.83-0.96) for reader 2; those for handheld US were 0.91 (0.84-0.96) for reader 1 and 0.83 (0.74-0.90) for reader 2, with no statistical difference. The agreement based on pathologic images was kappa = 0.831 (0.718-0.944); for handheld US, kappa = 0.795 (0.623-0.967); and for the AVBS, kappa = 0.869 (0.725 1.000). CONCLUSIONS: Performing a single-view diagnostic ABVS examination has good agreement with a handheld diagnostic US workup. There is no difference if the ABVS is used by a sonographer or mammographic technologist. PMID- 28569406 TI - Meta-analysis of single-port versus conventional laparoscopic cholecystectomy comparing body image and cosmesis. AB - BACKGROUND: The purpose of this study was to evaluate improvements in cosmetic results and postoperative morbidity for single-incision laparoscopic cholecystectomy (SILC) in comparison with multiport laparoscopic cholecystectomy (MLC). METHODS: A literature search was undertaken for RCTs comparing SILC with MLC in adult patients with benign gallbladder disease. Primary outcomes were body image and cosmesis scores at different time points. Secondary outcomes included intraoperative and postoperative complications, postoperative pain and frequency of port-site hernia. RESULTS: Thirty-seven RCTs were included, with a total of 3051 patients. The body image score favoured SILC at all time points (short term: mean difference (MD) -2.09, P < 0.001; mid term: MD -1.33, P < 0.001), as did the cosmesis score (short term: MD 3.20, P < 0.001; mid term: MD 4.03, P < 0.001; long-term: MD 4.87, P = 0.05) and the wound satisfaction score (short term: MD 1.19, P = 0.03; mid term: MD 1.38, P < 0.001; long-term: MD 1.19, P = 0.02). Duration of operation was longer for SILC (MD 13.56 min; P < 0.001) and SILC required more additional ports (odds ratio (OR) 6.78; P < 0.001). Postoperative pain assessed by a visual analogue scale (VAS) was lower for SILC at 12 h after operation (MD in VAS score -0.80; P = 0.007). The incisional hernia rate was higher after SILC (OR 2.50, P = 0.03). All other outcomes were similar for both groups. CONCLUSION: SILC is associated with better outcomes in terms of cosmesis, body image and postoperative pain. The risk of incisional hernia is four times higher after SILC than after MLC. PMID- 28569408 TI - Aerobic exercise reduces hippocampal ERK and p38 activation and improves memory of middle-aged rats. AB - Aging is often accompanied by cognitive decline, memory impairment, and an increased susceptibility to neurodegenerative disorders. Although the physiological processes of aging are not fully understood, these age-related changes have been interpreted by means of various cellular and molecular theories. Among these theories, alterations in the intracellular signaling pathways associated with cell growth, proliferation, and survival have been highlighted. Based on these observations and on recent evidence showing the beneficial effects of exercise on cognitive function in the elderly, we investigated the cell signaling pathways in the hippocampal formation of middle aged rats (18 months old) submitted to treadmill exercise over 10 days. To do this, we evaluated the hippocampal activation of intracellular signaling proteins linked to cell growth, proliferation, and survival, such as Akt, mTOR, p70S6K, ERK, CREB, and p38. We also explored the cognitive performance (inhibitory avoidance) of middle-aged rats. It was found that physical exercise reduces ERK and p38 activation in the hippocampal formation of aged rats, when compared to the control group. The hippocampal activation and expression of Akt, mTOR, p70S6K, and CREB were not statistically different between the groups. It was also observed that aged rats from the exercise group exhibited better cognitive performance in the inhibitory avoidance task (aversive memory) than aged rats from the control group. Our results indicate that physical exercise reduces intracellular signaling pathways linked to inflammation and cell death (i.e., ERK and p38) and improves memory in middle-aged rats. PMID- 28569409 TI - There is an app for that! The current state of mobile applications (apps) for DSM 5 obsessive-compulsive disorder, posttraumatic stress disorder, anxiety and mood disorders. AB - Mental health apps are viewed as a promising modality to extend the reach of mental health care beyond the clinic. They do so by providing a means of assessment, tracking, and treatment through a smartphone. Given that nearly 2/3 of the American population owns a smartphone, mental health apps offer the possibility of overcoming treatment barriers such as geographic location or financial barriers. Unfortunately, the excitement surrounding mental health apps may be premature as the current supporting literature regarding their efficacy is limited. The app marketplace is littered with apps claiming to treat or assess symptoms, but even those created by reputable organizations or those incorporating components of evidence-based treatments have not yet been validated in terms of their efficacy. This review aims to provide a comprehensive review of the current state of the mental health app literature by examining published reports of apps designed for DSM-5 anxiety and mood disorders, OCD, and PTSD. The breadth of apps reviewed includes those oriented around assessment, symptom tracking, and treatment as well as "multipurpose" apps, which incorporate several of these components. This review will also present some of the most popular mental health apps which may have clinical utility and could be prescribed to clients. While we discuss many potential benefits of mental health apps, we focus on a number of issues that the current state of the app literature presents. Overall there is a significant disconnect between app developers, the scientific community and health care, leaving the utility of existing apps questionable. PMID- 28569410 TI - PD-1 and PD-L1 in neoplastic cells and the tumor microenvironment of Merkel cell carcinoma. AB - BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive neoplasm, which is often associated with Merkel cell polyomavirus (MCPyV). Programmed death-1 (PD-1) and its ligand PD-L1 are key players of the tumor microenvironment (TME). METHODS: Fourteen paraffin-embedded tissue samples of MCC were stratified by their MCPyV detection. Apart from PD-L1 and PD-1, the TME was further characterized for the expression of CD33, FOXP3 and MxA. RESULTS: We observed PD-1 in 2 of 12 tumors. PD-L1 expression by tumor cells was found in 7 of 8 MCPyV(+) samples and was detected particularly in the periphery. The tumor cells were surrounded by a shield of PD-L1/CD33 immune cells. Expression of PD-L1 by the tumor cells was higher in areas with a denser immune infiltrate. CD33(+) cells without direct tumor contact were PD-L1 negative. Only a low number of FOXP3(+) regulatory T cells was admixed. Tumor cells of MCPyV(-) samples were mostly PD-L1 negative. CONCLUSIONS: Our data demonstrate that PD-L1 expression occurs in tumor and immune cells, in areas in which they are close in contact. Interferon seems to play a role in this interaction. We postulate that PD-L1(+)/CD33(+) cells shield the tumor against attacking PD-1(+) immune cells. Therefore, next to anti-PD-1/PD L1 antibodies, blockade of CD33 seems to be a promising therapeutic approach. PMID- 28569411 TI - Regional and district peer effects in obesity: A UK panel data analysis. AB - Most research concerning the causes of obesity has focused on macroeconomic trends or individual-level determinants relating to socioeconomic status. There is now growing interest in the psychosocial determinants of obesity. Little research has been conducted into wide-scale peer effects and so the aim of this study was to determine whether regional and district peer effects determine individual-level obesity in the UK. Data from the British Household Panel Survey (for the years 2004 and 2006) were used to model individual-level BMI and probability of obesity as a function of regional and district BMI, controlling for a variety of other variables. Instrumental variable techniques were used to investigate simultaneity bias. We found no statistically significant regional peer effect in the UK. For men, we found that a 1 point increase in average district BMI increased individual BMI by 0.640 and probability of being obese by 1.9% points; for women, BMI increased by 0.230 and probability of being obese by 1.6% points. Men appear to be more susceptible to these effects than women. Peer effects at the district level may have played a significant role in the rise of obesity in the UK. Further research must aim to disentangle the two routes by which these processes are theorised to function. PMID- 28569412 TI - Programmed Site-Selective Palladium-Catalyzed Arylation of Thieno[3,2 b]thiophene. AB - Mono-, di-, tri-, and tetraarylated thieno[3,2-b]thiophenes were synthesized by direct site-selective Pd-catalyzed C-H activation reactions with various aryl bromides in the presence of a phosphine-free Pd(OAc)2 /KOAc catalyst system in N,N-dimethylacetamide (DMAc). The arylation of 2-arylthieno[3,2-b]thiophene took place at the C3 position if the 2-aryl substituents possessed electron withdrawing groups and at the C5 position if they were bulky and possessed electron-donating groups. PMID- 28569413 TI - Transcatheter aortic valve replacement: The year in review 2016. PMID- 28569414 TI - BSA-AuNPs@Tb-AMP metal-organic frameworks for ratiometric fluorescence detection of DPA and Hg2. AB - An easy and effective strategy for synthesizing a ratiometric fluorescent nanosensor has been demonstrated in this work. Novel fluorescent BSA-AuNPs@Tb-AMP (BSA, bovine serum albumin; AMP, adenosine 5'-monophosphate; AuNPs, Au nanoparticles) metal-organic framework (MOF) nanostructures were synthesized by encapsulating BSA-AuNPs into Tb-AMP MOFs for the detection of 2,6 pyridinedicarboxylic acid (DPA) and Hg2+ . DPA could strongly co-ordinate with Tb3+ to replace water molecules from the Tb3+ center and accordingly enhanced the fluorescence of Tb-AMP MOFs. The fluorescence of BSA-AuNPs at 405 nm remained constant. While the fluorescence of BSA-AuNPs at 635 nm was quenched after Hg2+ was added, the fluorescence of Tb-AMP MOFs remained constant. Accordingly, a ratiometric fluorescence nanosensor was constructed for detection of DPA and Hg2+ . The ratiometric nanosensor exhibited good selectivity to DPA over other substances. The F545 /F405 linearly increased with increase of DPA concentration in the range of 50 nM to 10 MUM with a detection limit as low as 17.4 nM. F635 /F405 increased linearly with increase of Hg2+ concentration ranging from 50 nM to 1 MUM with a detection limit as low as 20.9 nM. Additionally, the nanosensor could be successfully applied for the determination of DPA and Hg2+ in running water. PMID- 28569415 TI - Group of Quantum Bits Acting as a Bit Using a Single-Domain Ferromagnet of Uniaxial Magnetic Ions. AB - Read/write operations with individual quantum bits (i.e., qbits) are a challenging problem to solve in quantum computing. To alleviate this difficulty, we considered the possibility of using a group of qbits that act collectively as a bit (hereafter, a group bit or a gbit, in short). A promising candidate for a gbit is a single-domain ferromagnet (SDF) independent of its size, which can be prepared as a magnet of well-separated uniaxial magnetic ions (UMIs) at sites of no electric dipole moment with their uniaxial axes aligned along one common direction. When magnetized, the UMIs of such a magnet have a ferromagnetic (FM) arrangement and the resulting SDF becomes a gbit with its two opposite moment orientations representing the |0? and |1? states of a bit. We probed the requirements for such magnets and identified several 2H-perovskites as materials satisfying these requirements. PMID- 28569416 TI - Applying cultural safety beyond Indigenous contexts: Insights from health research with Amish and Low German Mennonites. AB - People who identify as members of religious communities, such as the Amish and Low German Mennonites, face challenges obtaining quality health care and engagement in research due in part to stereotypes that are conveyed through media and popular discourses. There is also a growing concern that even when these groups are engaged in research, the guiding frameworks of the research fail to consider the sociocultural or historical relations of power, further skewing power imbalances inherent in the research relationship. This paper aims at discussing the uses of cultural safety in the context of health research and knowledge translation with groups of people that are associated with a specific religion. Research with the Amish and Low German Mennonites is provided as examples to illustrate the use of cultural safety in this context. From these examples, we discuss how the use of cultural safety, grounded in critical theoretical perspectives, offers new insight into health research with populations that are traditionally labeled as minority, vulnerable, or marginalized, especially when a dominant characteristic is a unique religious perspective. PMID- 28569417 TI - Down-Regulation of AQP4 Expression via p38 MAPK Signaling in Temozolomide-Induced Glioma Cells Growth Inhibition and Invasion Impairment. AB - Glioma is the most common and lethal central nervous system tumors. Temozolomide (TMZ) is an effective drug for malignant glioma, however, the intracellular and molecular mechanisms behind this anti-cancer effect have yet to be fully understood. The aim of the present study was to determine whether TMZ inhibits proliferation, invasion of glioma cells in vitro and whether these effects can be mediated through modulation of aquaporin 4 (AQP4) and phosphorylation of the MAPK pathway. The viability of U87 and U251 human glioma cells was evaluated using MTT assay. The cell cycle distribution was detected with flow cytometry. Migration ability and invasion ability were tested by scratch assays and transwell assays, respectively. The levels of AQP4 and MAPK were measured using immunoblot analyses. Our results showed that TMZ inhibited proliferation, migration and invasion, and induced G2/M arrest in U87 and U251 glioma cell lines. These changes were associated with a decrease in the levels of AQP4 expression as well as activation phosphorylated level of p38. Treatment with a p38 chemical activator (anisomycin) resulted in similar effects as TMZ treatment on glioma cells. And p38 chemical inhibitor (SB203580) could block these effects in glioma treated with TMZ, suggesting a direct up-regulation of the p38 signaling pathway. Therefore, we identified that TMZ might have therapeutic potential for controlling proliferation, invasion of malignant glioma by inhibiting AQP4 expression through activation of p38 signal transduction pathway. J. Cell. Biochem. 118: 4905-4913, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28569418 TI - LncRNA LINC01512 Promotes the Progression and Enhances Oncogenic Ability of Lung Adenocarcinoma. AB - Previously, a significantly upregulated lncRNA, LINC01512, in lung adenocarcinoma (LAD) was obtained, while its biological function and molecular mechanisms were unclear. The expression level of LINC01512 was estimated by qPCR from 100 pairs of LAD and NT samples. The correlation of LINC01512 to clinical data of LAD patients was analyzed. LINC01512 was knocked down and overexpressed in SPCA-1 and A549 cell lines by lentivirus-mediated technology, and the oncological behavioral changes of SPCA-1 and A549 cells were observed, as well as, tumorigenicity in experimental nude mice. Compared to the adjacent tissues, LINC01512 was obviously upregulated in LAD. The expression level of LINC01512 was closely related to lymph node metastasis and tumor node metastasis (TNM) stage. Survival analysis showed that the survival time of high expression LINC01512 group was significantly shorter than the low-expression group in LAD. Knockdown or overexpression test unanimously confirmed that LINC01512 can increase the ability of cell migration, invasion, proliferation, colony formation, adhesion, and S phase and G2/M phase cells, whereas decrease the apoptosis and G0/G1 phase cells. Nude mice experiments confirmed that LINC01512 significantly enhanced the speed and weight of tumorigenicity. LINC01512 is an oncogenic lncRNA gene that promotes the progression and distinctly enhances the oncogenic ability in lung adenocarcinoma. J. Cell. Biochem. 118: 3102-3110, 2017. (c) 2017 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals Inc. PMID- 28569419 TI - Regulating drivers with epilepsy in Maryland: Results of the application of a United States consensus guideline. AB - OBJECTIVE: Driving regulations for people with seizures vary widely throughout the United States and the world. Maryland updated their guidelines in 2003 to reflect those of a U.S. consensus guideline requiring a minimum 3-month seizure free period as well as an individual risk assessment by a Medical Advisory Board (MAB). This retrospective study provides the first analysis of outcomes after the implementation of the consensus guidelines and an assessment of their predictive validity through longitudinal outcome data. METHODS: MAB reviews and licensing records for Maryland driver applicants with seizures between 2004 and 2005 were reviewed, during which 254 first-time applicants were processed. The initial licensing decisions were assessed and the subsequent seizure recurrence and crash rates over the following 7 years were evaluated. RESULTS: The MAB approved driving for 74.8% of initial applicants; most had been seizure-free for over 6 months. Approved drivers had a longer median seizure-free period (563 days) compared to those who were denied (104.5 days, p < 0.01), and 22.7% of approved drivers had seizures recur during monitoring over the next year, although none resulted in crashes or deaths. Of applicants initially denied (n = 50), 89.3% were eventually licensed. Treating physicians recommended driving for 84.4% of applicants rejected by the MAB. SIGNIFICANCE: Maryland's individualized system for assessing driving applicants with seizures resulted in a dynamic process of approvals and denials based on favorable and unfavorable risk factors and lengths of seizure freedom. Seizure recurrences were comparable to internationally accepted rates. Over the course of monitoring, most applicants were eventually licensed. Treating physicians recommended that nearly all their patient applicants be permitted to drive, which raises safety concerns for the 10 states that rely solely on physician recommendations. Further assessment is needed of the risk factors deemed favorable and unfavorable by the U.S. consensus guidelines. PMID- 28569420 TI - Rhodopsin T17M Mutant Inhibits Complement C3 Secretion in Retinal Pigment Epithelium via ROS Induced Downregulation of TWIST1. AB - Rhodopsin mutations cause autosomal dominant form of retinitis pigmentosa (RP). T17M rhodopsin predisposes cells to endoplasmic reticulum stress induced apoptosis. However, the pathogenic role of T17M rhodopsin in RP is not completely understood. Complement C3 has a protective role in RP pathogenesis. This study aimed to investigate whether T17M rhodopsin regulates C3 secretion in retinal pigment epithelium. The human retinal pigment epithelial cell line (ARPE-19) was engineered to overexpress wide-type (WT) and T17M rhodopsin. Gene expression was detected by RT-PCR and Western blot analysis. C3 secretion was detected by ELISA. The overexpression of T17M rhodopsin significantly induced ROS and reduced C3 secretion and transcription in ARPE-19 cells, but ROS scavengers could partially rescue reduced C3 secretion and transcription. Mechanistically, we found that ROS suppressed transcription factor TWIST1 which is responsible for activated transcription of C3. In conclusion, our data provide the first evidence that T17M rhodopsin mutant disrupts C3 secretion via the induction of ROS and the suppression of TWIST1. These findings reveal novel insight into the pathogenic role of mutant rhodopsin in RP. J. Cell. Biochem. 118: 4914-4920, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28569421 TI - Autonomic nervous system modulation and clinical outcome after pulmonary vein isolation using the second-generation cryoballoon. AB - BACKGROUND: The intrinsic cardiac autonomic nervous system (ANS) plays a significant role in atrial fibrillation (AF) mechanisms. This study evaluated the incidence and impact of intraprocedural vagal reactions and ANS modulation by pulmonary vein isolation (PVI) using second-generation cryoballoons on outcomes. METHODS: One hundred three paroxysmal AF patients underwent PVI with one 28-mm second-generation balloon. The median follow-up was 15.0 (12.0-18.0) months. ANS modulation was defined as a >20% cycle length decrease on 3-minute resting electrocardiograms at 1, 3, 6, and 12 months postindex procedure relative to baseline if sinus rhythm was maintained. RESULTS: Marked sinus arrests/bradycardia and atrioventricular block (intraprocedural vagal reaction) occurred in 14 and 2 patients, and all sinus arrest/bradycardia occurred in 44 patients with left superior pulmonary veins (PVs) targeted before right PVs. ANS modulation was identified in 66 of 95 (69.5%) patients, and it persisted 12-month postprocedure in 36 (37.9%) patients. Additional beta-blocker administration was required in 9 patients for sinus tachycardia. ANS modulation was similarly observed in patients with and without intraprocedural vagal reactions (P = 0.443). Forty-eight (46.6%) patients experienced early recurrences, and the single procedure success at 12 months was 72.7%. Neither intraprocedural vagal reactions nor ANS modulation predicted AF freedom within or after the blanking period. Thirty-three patients underwent second procedures, and reconnections were detected in 39 of 130 (30.0%) PVs among 23 (69.7%) patients. The incidence of reconnections was similar in patients with and without ANS modulation. CONCLUSIONS: Increased heart rate persisted in 37.9% of patients even at 12-month post-second-generation cryoballoon PVI. Neither intraprocedural vagal reactions nor increased heart rate predicted a single procedure clinical outcome. PMID- 28569422 TI - Role of contact force-guided radiofrequency catheter ablation for treatment of atrial fibrillation: A systematic review and meta-analysis. AB - INTRODUCTION: CF-sensing catheter emerged as a novel ablation technology and was increasingly used in clinical practice. Nonetheless, available evidence of efficacy and safety comparison between CF-guided RF catheter ablation and non-CF guided ablation for treatment of AF was still lacking. METHODS AND RESULTS: Twenty-two eligible studies were included after systematic review through the MEDLINE, Google Scholar, the Cochrane Library and PubMed databases. AF/atrial tachycardia-free survival was markedly improved in CF-guided catheter ablation compared with non-CF-guided ablation at a median 12-month follow-up (RR: 1.12, 95% CI: 1.06-1.19, P = 0.000, fixed). Notably, CF-guided catheter ablation presented a robust survival benefit for treatment of paroxysmal AF (RR: 1.10, 95% CI: 1.03-1.18, P = 0.005, fixed), but not persistent AF (RR: 1.07, 95% CI: 0.89 1.28, P = 0.466, fixed). Moreover, procedure time (WMD: -23.87, 95% CI: -33.83 to -13.91, P = 0.000, random), fluoroscopy time (WMD: -7.78, 95% CI: -13.93 to 1.63, P = 0.013, random) and RF time (WMD: -3.98, 95% CI: -7.78 to -0.17, P = 0.040, random) were significantly reduced in CF-guided catheter ablation. The incidence of procedure-related complications did not differ between these two technologies (RR: 0.83, 95% CI: 0.59 to 1.16, P = 0.271, fixed). CONCLUSION: CF guided RF catheter ablation was associated with a significant AF/atrial tachycardia-free survival benefit compared with non-CF-guided ablation in patients with paroxysmal AF rather than persistent AF. In addition, CF-guided ablation strategy also reduced the procedure time, fluoroscopy time, as well as RF time despite no distinct effect on the alleviation of procedure-related complications. PMID- 28569424 TI - Single-incision percutaneous pericardial ICD lead placement in a piglet model. AB - INTRODUCTION: Our group has demonstrated the feasibility of percutaneous pericardial ICD lead placement in a piglet model utilizing direct visualization from a lateral thoracoscopic approach. Development of a novel delivery tool that incorporates visualization allows for the procedure to be performed with a 1 cm subxiphoid incision. METHODS AND RESULTS: A 1 cm incision is made in the subxiphoid area and a novel self-anchoring delivery tool is inserted. A rigid thoracoscope and needle are inserted into two crossed working channels of the tool. After needle visualization, pericardial needle access, followed by sheath access is obtained. A modified side-biting ICD lead is inserted and fixated to the ventricular epicardial surface. The lead is connected to an ICD generator and lead testing followed by defibrillation threshold testing (DFT) is performed. Single-incision ICD lead placement was performed in 6 piglets without acute complications. Median time from subxiphoid incision to DFT testing was 64 minutes; median time from thoracoscope insertion to lead fixation was 16.5 minutes (range 9-30). All had adequate ventricular sensing and pacing at implant and underwent successful defibrillation (range 3-5 J). Survival period ranged from 1 to 16 weeks. Two piglets had survival periods of 12 and 16 weeks with mean weight gain of 7 kg; both had successful repeat DFT at 10 J. All survival animals had stable lead impedances and R-wave amplitudes throughout the survival period. CONCLUSION: Percutaneous pericardial placement of an ICD lead using our novel access tool can be safely performed through a 1 cm incision without complications. PMID- 28569423 TI - Probing Human Telomeric DNA and RNA Topology and Ligand Binding in a Cellular Model by Using Responsive Fluorescent Nucleoside Probes. AB - The development of biophysical systems that enable an understanding of the structure and ligand-binding properties of G-quadruplex (GQ)-forming nucleic acid sequences in cells or models that mimic the cellular environment would be highly beneficial in advancing GQ-directed therapeutic strategies. Herein, the establishment of a biophysical platform to investigate the structure and recognition properties of human telomeric (H-Telo) DNA and RNA repeats in a cell like confined environment by using conformation-sensitive fluorescent nucleoside probes and a widely used cellular model, bis(2-ethylhexyl) sodium sulfosuccinate reverse micelles (RMs), is described. The 2'-deoxy and ribonucleoside probes, composed of a 5-benzofuran uracil base analogue, faithfully report the aqueous micellar core through changes in their fluorescence properties. The nucleoside probes incorporated into different loops of H-Telo DNA and RNA oligonucleotide repeats are minimally perturbing and photophysically signal the formation of respective GQ structures in both aqueous buffer and RMs. Furthermore, these sensors enable a direct comparison of the binding affinity of a ligand to H-Telo DNA and RNA GQ structures in the bulk and confined environment of RMs. These results demonstrate that this combination of a GQ nucleoside probe and easy-to handle RMs could provide new opportunities to study and devise screening compatible assays in a cell-like environment to discover GQ binders of clinical potential. PMID- 28569425 TI - Pituitary gamma-aminobutyric acid receptor stimulation by carnitine may be a new strategy for antipsychotic-induced hyperprolactinemia. PMID- 28569427 TI - Corrigendum: Preparation of Vinyl Arenes by Nickel-Catalyzed Reductive Coupling of Aryl Halides with Vinyl Bromides. PMID- 28569426 TI - Structure and expression of sulfatase and sulfatase modifying factor genes in the diamondback moth, Plutella xylostella. AB - The diamondback moth, Plutella xylostella (L.), uses sulfatases (SULF) to counteract the glucosinolate-myrosinase defensive system that cruciferous plants have evolved to deter insect feeding. Sulfatase activity is regulated by post translational modification of a cysteine residue by sulfatase modifying factor 1 (SUMF1). We identified 12 SULF genes (PxylSulfs) and two SUMF1 genes (PxylSumf1s) in the P. xylostella genome. Phylogenetic analysis of SULFs and SUMFs from P. xylostella, Bombyx mori, Manduca sexta, Heliconius melpomene, Danaus plexippus, Drosophila melanogaster, Tetranychus urticae and Homo sapiens showed that the SULFs were clustered into five groups, and the SUMFs could be divided into two groups. Profiling of the expression of PxylSulfs and PxylSumfs by RNA-seq and by quantitative real-time polymerase chain reaction showed that two glucosinolate sulfatase genes (GSS), PxylSulf2 and PxylSulf3, were primarily expressed in the midgut of 3rd- and 4th-instar larvae. Moreover, expression of sulfatases PxylSulf2, PxylSulf3 and PxylSulf4 were correlated with expression of the sulfatases modifying factor PxylSumf1a. The findings from this study provide new insights into the structure and expression of SUMF1 and PxylSulf genes that are considered to be key factors for the evolutionary success of P. xylostella as a specialist herbivore of cruciferous plants. PMID- 28569428 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 24/2017. PMID- 28569429 TI - CarbORev-5901: The First Carborane-Based Inhibitor of the 5-Lipoxygenase Pathway. AB - The progression of cancer is accelerated by increased proliferation, angiogenesis, and inflammation. These processes are mediated by leukotrienes. Several cancer cell lines overexpress 5-lipoxygenase, an enzyme that converts arachidonic acid into leukotrienes. An early inhibitor of the 5-lipoxygenase pathway is Rev-5901, which, however, lacks in in vivo efficacy, as it is rapidly metabolized. We investigated the introduction of carboranes as highly hydrophobic and metabolically stable pharmacophores into lipoxygenase inhibitors. Carboranes are icosahedral boron clusters that are remarkably stable and used to increase the metabolic stability of unstable pharmaceutics without changing their biological activity. By introduction of meta-carborane into Rev-5901, the first carborane-based inhibitor of the 5-lipoxygenase pathway was obtained. We report the synthesis and inhibitory and cytotoxic behavior of these compounds toward several melanoma and colon cancer cell lines and their related anticancer mechanisms. PMID- 28569430 TI - MiR-377 Regulates Inflammation and Angiogenesis in Rats After Cerebral Ischemic Injury. AB - Ischemic stroke is the leading cause of disabilities worldwide. MicroRNA-377 (miR 377) plays important roles in ischemic injury. The present study focused on the mechanisms of miR-377 in protecting ischemic brain injury in rats. Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in rats. Primary rat microglial cells and brain microvascular endothelial cells (BMECs) were exposed to oxygen-glucose deprivation (OGD). The concentrations of cytokines (TNF alpha, IL-1beta, IL-6, IFN-gamma, TGF-beta, MMP2, COX2, and iNOS) in the culture medium were measured by specific ELISA. Tube formation assay was for the in vitro study of angiogenesis. Luciferase reporter assay was performed to confirm whether VEGF and EGR2 were direct targets of miR-377. The MCAO rats were intracerebroventricular (ICV) injection of miR-377 inhibitor to assess its protective effects in vivo. MiR-377 levels were decreased in the rat brain tissues at 1, 3, and 7 d after MCAO. Both microglia cells and BMECs under OGD showed markedly lower expression levels of miR-377 while higher expression levels of EGR2 and VEGF compared to those under normoxia conditions. Knockdown of miR 377 inhibited microglial activation and the release of pro-inflammatory cytokines after OGD. Suppression of miR-377 promoted the capillary-like tube formation and cell proliferation and migration of BMECs. The anti-inflammation effect of EGR2 and the angiogenesis effect of VEGF were regulated by miR-377 after OGD. Inhibition of miR-377 decreased cerebral infarct volume and suppressed cerebral inflammation but promoted angiogenesis in MCAO rats. Knockdown of miR-377 lessened the ischemic brain injury through promoting angiogenesis and suppressing cerebral inflammation. J. Cell. Biochem. 119: 327-337, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28569431 TI - Providing support to surrogate decision-makers for people living with dementia: Healthcare professional, organisational and community responsibilities. AB - The prevalence of dementia will continue to increase with the ageing of the population. Many people living with dementia will reach a stage where surrogate decision-makers-mostly family carers-will need to make a range of decisions on their behalf. The aim of this study was to learn from surrogate decision-makers how they can be most effectively supported in this role. The study employed a qualitative design using semi-structured face-to-face or telephone interviews with a purposive sample of 34 surrogate decision-makers of people living with dementia. Transcripts of participant interviews were reviewed using a thematic approach to analysis. Four main themes were identified from this analysis: needing greater community awareness of dementia and its impact; intervening early in cognitive decline; relying on health professionals for ongoing support; and seeking and using support from wherever is relevant for each person. Based on this analysis and a review of the literature, we propose a wholistic set of recommendations for the support of surrogate decision-makers. Healthcare professionals need to help family carers understand the likely trajectory of dementia, including the significance of surrogate decision-making. They can support the person living with dementia and their surrogates to undertake advance care planning and they can act as empathic guides during this process. Health and community care organisations need to provide a "key worker" model wherever possible so that the person living with dementia and their surrogate decision maker do not have to seek support from multiple staff members or organisations. Carer support programmes can routinely include information and resources about surrogate decision-making. Community and government organisations can help people prepare for the possibility of becoming surrogate decision-makers by promoting a greater public awareness and understanding of both dementia and advance care planning. PMID- 28569432 TI - Plasma folate levels and associated factors in women planning to become pregnant in a population with high prevalence of neural tube defects. AB - BACKGROUND: Optimal blood folate levels of women before pregnancy are critical to the prevention of neural tube defects (NTDs). However, few studies have focused on blood folate levels of women planning to become pregnant. The aims of this study were to assess plasma folate levels in women who planned to become pregnant in a population with high prevalence of NTDs, to identify factors associated with plasma folate levels, and to evaluate the risk of NTDs at the population level. METHODS: A total of 2065 women were enrolled at the time of premarital health check-up in two rural counties in northern China from November 2009 to December 2012. Fasting venous blood samples were collected and plasma folate concentrations were measured by microbiological method. RESULTS: The overall median of plasma folate was 10.5 nmol/L. 50% of the women had a plasma folate level below 10.5 nmol/L, a cutoff for megaloblastic anemia, and 88% below 18 nmol/L, a proposed optimal plasma folate level for the prevention of NTDs. Folic acid supplementation was the only factor to be associated with plasma folate concentrations, but only 1.9% of the women reported having taken folic acid supplements. A population risk of 29.3 NTD cases per 10,000 births was predicted. CONCLUSION: Women who planned to become pregnant had very low plasma folate in the population. Folic acid supplementation was the only factor to be associated with a high plasma folate concentration. High NTD risk would remain if women would get pregnant without having taken folic acid supplements. Birth Defects Research 109:1039-1047, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28569433 TI - Ascochlorin Suppresses MMP-2-Mediated Migration and Invasion by Targeting FAK and JAK-STAT Signaling Cascades. AB - Human glioblastomas express higher levels of matrix metalloprotease-2 (MMP-2) than low-grade brain tumors and normal brain tissues. Ascochlorin (ASC) has anti metastatic, anti-angiogenic, and synergistic effect in various types of cancer cells. However, it remains unknown whether ASC can affect cell migration and invasion in malignant human glioma cells. In this study, we found that ASC indeed inhibits cell migration and invasion in U373MG and A172. ASC significantly suppresses the MMP-2 gelatinolytic activity and expression in U373MG and A172. To determine the molecular mechanism by which ASC suppressed cell migration and invasion, we investigated whether ASC could modulate metastasis via focal adhesion kinase (FAK) and janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, a potential drug target. ASC strongly inhibits the phosphorylation of FAK, and treatment with a FAK inhibitor significantly suppresses cancer cell migration in the presence of ASC. In addition, ASC significantly decreased phosphorylation of JAK2/STAT3, cancer cell migration and nuclear translocation of STAT3. Taken together, these results suggest that ASC inhibits cell migration and invasion by blocking FAK and JAK/STAT signaling, resulting in reduced MMP-2 activity. J. Cell. Biochem. 119: 300-313, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28569434 TI - A colorimetric and fluorogenic probe for bisulfite using benzopyrylium as the recognition unit. AB - A coumarin-benzopyrylium (CB) platform has been developed for the colorimetric and fluorogenic detection of bisulfite. The proposed probe utilizes coumarin as the fluorophore and positively charged benzopyrylium as the reaction site. The method employs the nucleophilic addition of bisulfite to the benzopyrylium moiety of CB to inactivate the electron-deficient oxonium ion. The driving force for photo-induced electron transfer is considerably diminished, thereby promoting the emission intensity of the coumarin fluorophore. The fluorescence intensity at 510 nm is linear with bisulfite concentration over a range of 0.2-7.5 MUM with a detection limit of 42 nM (3delta). CB shows a rapid response (within 30 s) and high selectivity and sensitivity for bisulfite. Preliminary studies show that CB has great potential for bisulfite detection in real samples and in living cells. PMID- 28569435 TI - The new kids on the block of arrhythmogenic disorders: Short QT syndrome and early repolarization. AB - Short QT syndrome (SQTS) is one of the rarest inheritable cardiac channelopathies, characterized by an accelerated cardiac repolarization, which is also the substrate for the development of life-threatening ventricular arrhythmias. Up to this date, fewer than 200 SQTS cases have been reported in the literature worldwide. Patients with SQTS may experience a cardiac arrest as early as in the neonatal period or as late as 80 years old. The cumulative probability of experiencing a cardiac arrest by the fifth decade of life approaches 40%, highlighting the importance of early recognition and management. SQTS is an autosomal dominant disease with five identified causative genes, including three that encode for potassium channels (KCNH2, KCNQ1, and KCNJ2) and two that encode for subunits of the L-type calcium channels (CACNA1C and CACNB2). The term "early repolarization" (ER) has long been used to refer to a heterogeneous group of specific QRS-T junction patterns that are commonly found on the electrocardiograms of young healthy subjects. In the last decade, it has been suggested that in some individuals, the presence of ER may be associated with an increased risk of sudden cardiac death, and thus the term "early repolarization syndrome" (ERS) has progressively entered into use. Up to this point, however, whether ER constitutes a true primary arrhythmic disorder or whether it is simply a predisposing substrate that facilitates arrhythmias in the presence of other triggers remains an unresolved issue. In this review paper, we aim to integrate the current literature on SQTS and ERS. For each, we will describe the key steps that first led to the identification of the syndrome before moving into a discussion of our current understanding of each entity, including the epidemiology, genetics, diagnosis, clinical manifestations, and management. PMID- 28569436 TI - Sociodemographic, physical, mental and social factors in the cessation of breastfeeding before 6 months: a systematic review. AB - BACKGROUND: The World Health Organization recommends exclusive breastfeeding as the main source of nutrition for infants during their first 6 months of life. However, despite this well-known recommendation, not all mothers breastfeed, whether partly or fully, during this time. OBJECTIVE: The aim of this systematic literature review was to compile evidence regarding sociodemographic, physical, mental and social factors that influence breastfeeding mothers to stop breastfeeding before the infant reaches 6 months. SEARCH METHOD: A systematic search was conducted in four databases. SELECTION CRITERIA: Studies with quantitative research were included. DATA COLLECTION AND ANALYSIS: Totally, 186 abstracts were read, 83 seemed relevant but 18 were found to be duplicates. Finally, 27 articles met the inclusion criteria and were included. The quality assessment was carried out with a quality assessment template from the Swedish Council on Technology and Assessment, and the grading of the result was carried out according to GRADE. RESULTS: The association of breastfeeding cessation between the mother's young age, low level of education, return to work within 12 week postpartum, caesarean birth and inadequate milk supply was found to have a low level of evidence. The link found between depressions among the mothers with the cessation of breastfeeding was found to have a very low level of evidence. CONCLUSIONS: Sociodemographic factors appeared to have caused cessation of breastfeeding in some of the included articles. The preventive work should focus on how to improve the knowledge of healthcare professionals and targeted interventions must address mothers who are at risk of ceasing breastfeeding before the recommended time. PMID- 28569437 TI - Tumor Necrosis Factor-Alpha: Role in Development of Insulin Resistance and Pathogenesis of Type 2 Diabetes Mellitus. AB - Pathogenesis of type 2 diabetes mellitus (T2DM) and development of insulin resistance are characterized by multi-stimuli factors notably glucolipotoxicity, generation of reactive oxygen species (ROS), epigenetic factors, activation of various transcriptional mediated pathways along with the augmented levels of various pro-inflammatory cytokines. Among the various pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) is one the most important pro inflammatory mediator that is critically involved in the development of insulin resistance and pathogenesis of T2DM. TNF-alpha is mainly produced in adipocytes and/or peripheral tissues, and induces tissue-specific inflammation through the involvement of generation of ROS and activation of various transcriptional mediated pathways. The raised level of TNF-alpha induces insulin resistance in adipocytes and peripheral tissues by impairing the insulin signaling through serine phosphorylation that leads to the development of T2DM. Anti-TNF-alpha treatment strategies have been developed to reduce the incidence of insulin resistance and development of T2DM. In this article, we have briefly described how TNF-alpha plays crucial role to induce insulin resistance and pathogenesis of T2DM. To block the inflammatory responses by blocking TNF-alpha and TNF-alpha signaling may be an effective strategy for the treatment of insulin resistance and T2DM. J. Cell. Biochem. 119: 105-110, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28569438 TI - Enzymatic, urease-mediated mineralization of gellan gum hydrogel with calcium carbonate, magnesium-enriched calcium carbonate and magnesium carbonate for bone regeneration applications. AB - Mineralization of hydrogel biomaterials is considered desirable to improve their suitability as materials for bone regeneration. Calcium carbonate (CaCO3 ) has been successfully applied as a bone regeneration material, but hydrogel-CaCO3 composites have received less attention. Magnesium (Mg) has been used as a component of calcium phosphate biomaterials to stimulate bone-forming cell adhesion and proliferation and bone regeneration in vivo, but its effect as a component of carbonate-based biomaterials remains uninvestigated. In the present study, gellan gum (GG) hydrogels were mineralized enzymatically with CaCO3 , Mg enriched CaCO3 and magnesium carbonate to generate composite biomaterials for bone regeneration. Hydrogels loaded with the enzyme urease were mineralized by incubation in mineralization media containing urea and different ratios of calcium and magnesium ions. Increasing the magnesium concentration decreased mineral crystallinity. At low magnesium concentrations calcite was formed, while at higher concentrations magnesian calcite was formed. Hydromagnesite (Mg5 (CO3 )4 (OH)2 .4H2 O) formed at high magnesium concentration in the absence of calcium. The amount of mineral formed and compressive strength decreased with increasing magnesium concentration in the mineralization medium. The calcium:magnesium elemental ratio in the mineral formed was higher than in the respective mineralization media. Mineralization of hydrogels with calcite or magnesian calcite promoted adhesion and growth of osteoblast-like cells. Hydrogels mineralized with hydromagnesite displayed higher cytotoxicity. In conclusion, enzymatic mineralization of GG hydrogels with CaCO3 in the form of calcite successfully reinforced hydrogels and promoted osteoblast-like cell adhesion and growth, but magnesium enrichment had no definitive positive effect. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28569439 TI - Vanadium Chloroperoxidases: The Missing Link in the Formation of Chlorinated Compounds and Chloroform in the Terrestrial Environment? AB - It is well established that the majority of chlorinated organic substances found in the terrestrial environment are produced naturally. The presence of these compounds in soils is not limited to a single ecosystem. Natural chlorination is also a widespread phenomenon in grasslands and agricultural soils typical for unforested areas. These chlorinated compounds are formed from chlorination of natural organic matter consisting of very complex chemical structures, such as lignin. Chlorination of several lignin model compounds results in the intermediate formation of trichloroacetyl-containing compounds, which are also found in soils. These decay, in general, through a haloform-type reaction mechanism to CHCl3 . Upon release into the atmosphere, CHCl3 will produce chlorine radicals through photolysis, which will, in turn, lead to natural depletion of ozone. There is evidence that fungal chloroperoxidases able to produce HOCl are involved in the chlorination of natural organic matter. The objective of this review is to clarify the role and source of the various chloroperoxidases involved in the natural formation of CHCl3 . PMID- 28569440 TI - Small reentry in a mega coronary sinus: Anatomical and high-density activation mapping. PMID- 28569441 TI - Ultrafast Light-Driven Substrate Expulsion from the Active Site of a Photoswitchable Catalyst. AB - The photoswitchable piperidine general base catalyst is a prototype structure for light control of catalysis. Its azobenzene moiety moves sterically shielding groups to either protect or expose the active site, thereby changing the basicity and hydrogen-bonding affinity of the compound. The reversible switching dynamics of the catalyst is probed in the infrared spectral range by monitoring hydrogen bond (HB) formation between its active site and methanol (MeOH) as HB donor. Steady-state infrared (IR) and ultrafast IR and UV/Vis spectroscopies are used to uncover ultrafast expulsion of MeOH from the active site within a few picoseconds. Thus, the force generated by the azobenzene moiety even in the final phase of its isomerization is sufficient to break a strong HB within 3 ps and to shut down access to the active site. PMID- 28569442 TI - First derivative emission spectrofluorimetric method for the determination of LCZ696, a newly approved FDA supramolecular complex of valsartan and sacubitril in tablets. AB - LCZ696 (sacubitril/valsartan, EntrestoTM) is a therapy lately approved by United States Food and Drug Administration (US FDA) as a heart failure therapy. It is claimed to decrease the mortality rate and hospitalization for patients with chronic heart failure. This study is considered as the first report to investigate the fluorimetric behavior of sacubitril in addition to pursuing all the different conditions that may affect its fluorescence. Various conditions were studied, for example studying the effects of organized media, solvents and pH, which may affect the fluorescence behavior of sacubitril. For the simultaneous determination of the newly approved supramolecular complex of valsartan (VAL) and sacubitril (SAC) in their tablets, a sensitive and simple first derivative spectrofluorimetric method was developed. The method involved the measurement of native fluorescence at 416 nm and 314 nm (lambdaex 249 nm) for VAL and SAC, respectively. The first (D1) derivative technique was applied to the emission data to resolve a partial overlap that appeared in their emission spectra. The proposed method was successfully applied for the assay of the two drugs in their supramolecular complex LCZ696 with no interference from common pharmaceutical additives. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines were followed in order to validate the proposed method. PMID- 28569443 TI - Europium Oxybromide Catalysts for Efficient Bromine Looping in Natural Gas Valorization. AB - The industrialization of bromine-mediated natural gas upgrading is contingent on the ability to fully recycle hydrogen bromide (HBr), which is the end form of the halogen after the activation and coupling of the alkanes. Europium oxybromide (EuOBr) is introduced as a unique catalytic material to close the bromine loop via HBr oxidation, permitting low-temperature operation and long lifetimes with a stoichiometric feed (O2 :HBr=0.25)-conditions at which any catalyst reported to date severely deactivates because of excessive bromination. Besides, EuOBr exhibits unparalleled selectivity to methyl bromide in methane oxybromination, which is an alternative route for bromine looping. This novel active phase is finely dispersed on appropriate carriers and scaled up to technical extrudates, enhancing the utilization of the europium phase while preserving the performance. This catalytic system paves the way for sustainable valorization of stranded natural gas via bromine chemistry. PMID- 28569445 TI - Can Cleansing Regimens Effectively Eliminate Saliva Contamination from Lithium Disilicate Ceramic Surface? AB - This study evaluated the effect of cleaning protocols on the bond strength of resin cement to glass-ceramic. Ceramic specimens (N=120, n=12 per group) were etched with hydrofluoric acid and rinsed with water. After saliva contamination, specimens were cleaned as follows: water, 37% H3PO4, cleaning-paste (Ivoclean), or isopropanol. Non-contaminated specimens acted as the control. Resin cement was bonded to the specimens, and tested either after 24 h or x5000 thermocycling. Both the cleaning method (p=0.001) and the storage conditions (p=0.005) significantly affected the bond strength results. In dry conditions, the groups PA and IV showed no significant difference, being also similar to the non-saliva contaminated control group (p?0.05). In dry conditions, no significant difference was observed between the mean DW and IS being significantly lower than those of other groups (p?0.05). Except for the group IV, thermocycling decreased the results significantly in all groups (p?0.05). Predominantly mixed failure type was observed in both dry and aged conditions. SEM micrographs of ceramic surfaces after cleaning agents showed no major differences but on the specimens from the IV group, small, rounded-zirconia particles were observed. In case of saliva contamination of acid-etched glass-ceramics, mechanical cleaning can restore adhesion to the baseline situation. PMID- 28569444 TI - Multiple Adhesive Layering Influence on Dentin Bonding and Permeability. AB - The aim was to evaluate the effect of the number of layers on the microtensile bond strength (MUTBS), permeability and nanoleakage of an etch-and-rinse adhesive (Adper Single Bond 2). Different numbers of layers (1, 2 and 4) were applied on dentin susbstrate. Specimens were obtained and tested for MUTBS. Stick-shaped samples were analysed by scanning electron microscope, to observe silver nitrate penetration. One-way ANOVA and Tukey tests were applied (alpha=0.05) for MUTBS values. The fracture mode was evaluated under a stereomicroscope and a scanning electron microscope (SEM). Groups with two and four layers of bond showed higher MUTBS to dentin and they also showed lower adhesive permeability than ONE layer. The silver nitrate uptake occurred in the hybrid layer in practically all groups. Fracture occurred predominantly at the mixed interface. The authors recommend the application of more than one layer of Adper Single Bond 2, because a single layer showed lower MUTBS and higher permeability values. PMID- 28569446 TI - The Effect of Lithium Disilicate Opacity on Polymerization of a Dual-Cured Resin Cement. AB - The aim of this study was to evaluate the influence of different levels of opacity of the lithium disilicate framework upon polymerization of dual-cured resin cement. Four ceramic discs were used, one for each opacity framework covered by their respective ceramic veneering, and a cement group without a ceramic cover. The degree of conversion for each resin cement was estimated using the Knoop microhardness test. The group with the highest opacity showed the lowest hardness score at baseline. The study concluded that the opacity level of lithium disilicate framework could influence the degree of polymerization of a dual-cured resin cement. PMID- 28569447 TI - Marginal Accuracy and Internal Fit of Dental Copings Fabricated by Modern Additive and Subtractive Digital Technologies. AB - The margins of copings for crowns and retainers of fixed partial dentures affect the progress of microleakage and dental caries. Failures occur due to altered fit which is also influenced by the method of fabrication. An in-vitro study was conducted to determine among the cast base metal, copy milled zirconia, computer aided designing computer aided machining/manufacturing zirconia and direct metal laser sintered copings which showed best marginal accuracy and internal fit. Forty extracted maxillary premolars were mounted on an acrylic model and reduced occlusally using a milling machine up to a final tooth height of 4 mm from the cementoenamel junction. Axial reduction was accomplished on a surveyor and a chamfer finish line was given. The impressions and dies were made for fabrication of copings which were luted on the prepared teeth under standardized loading, embedded in self-cure acrylic resin, sectioned and observed using scanning electron microscope for internal gap and marginal accuracy. The copings fabricated using direct metal laser sintering technique exhibited best marginal accuracy and internal fit. Comparison of mean between the four groups by ANOVA and post-hoc Tukey HSD tests showed a statistically significant difference between all the groups (p?0.05). It was concluded that the copings fabricated using direct metal laser sintering technique exhibited best marginal accuracy and internal fit. Additive digital technologies such as direct metal laser sintering could be cost-effective for the clinician, minimize failures related to fit and increase longevity of teeth and prostheses. PMID- 28569448 TI - Outcomes of Immediate Function Implant Prosthetic Restorations with Mechanical Complications: A Retrospective Clinical Study with 5 Years of Follow-Up. AB - Mechanical complications may have a significant impact on the outcome of implant supported restorations; however, few studies address the topic. This study investigated the outcomes of implant supported restorations with mechanical complications. A total of 378 patients with 378 restorations supported by 1283 implants were included. Results demonstrated a prosthetic and implant cumulative survival rate at 5 years of 99.7% and 95.7%, respectively. Maxillary implants were a determinant for implant failure (hazard ratio= 6.7), while a reduced risk was registered for single tooth restorations (hazard ratio= 0.1) after adjusting for other variables of interest. PMID- 28569449 TI - A randomised controlled trial of a nanofilled composite at three years: Did selective enamel etching have an effect? AB - General dental practice is increasingly being recognised as the ideal situation for the conduct of clinical trials into the longevity of restorations. The aim of this study was to investigate the survival of 75 nanofilled resin composite restorations placed in an assortment of cavities using a self-etch dentine bonding agent, in five UK dental practices by members of the UK-based practice based research group, the PREP Panel, with half of the restorations receiving a selective enamel etch and the other half being placed using a self-etching approach. The results indicated good performance of the restorations examined, with no failures being identified and excellent surface characteristics, in terms of colour stability, minimal surface roughness and optimal anatomic form. Selective enamel etching tended to produce less marginal discolouration, although these results were not statistically significant. PMID- 28569450 TI - A Cross-Sectional Survey on Reasons for Initial Placement and Replacement of Single Crowns. AB - This cross-sectional survey investigated the reasons for placement and replacement of single crowns, the type of materials selected for initial placement and evaluated their longevity. Information was collected over 19 months period using a questionnaire focusing on the principal reasons for the placement and replacement of crowns, selected material type and the age of the crowns at the time of replacement. A total of 842 single crowns were evaluated in 476 patients. Of the 842 crowns, 472 (56%) were initial placements and 370 (44%) replacements. The main reason for placement of first single crowns was related to endodontic problems (26.5%). Metal-ceramic was indicated significantly more frequent (88.9%; p?0.01) than other materials for the placement and replacement of single crowns. The median age of the replaced crowns was 6 years. PMID- 28569452 TI - Zirconia-Reinforced Lithium Silicate Ceramic - A 2-Year Follow-up of a Clinical Experience with Anterior Crowns. AB - The aim of this manuscript is to describe 2-year follow-up of a clinical experience with a zirconia-reinforced lithium silicate ceramic for an anterior rehabilitation with single metal-free crowns. The maxillary-central incisor teeth crowns were made by zirconium-reinforced lithium silicate and covered with porcelain were obtained with a digital impression with the intra-oral scanner of the CEREC system as a basis for virtual design, as well as a laminate for the left lateral maxillary incisor, based on a "double scanning" technique. Lithium silicate material seems to be a safe and satisfactory alternative for anterior crowns' rehabilitation. PMID- 28569451 TI - Treatment Outcomes and Assessment of Oral Health Related Quality of Life in Treated Hypodontia Patients. AB - OBJECTIVES: 1. Assess treatment outcomes and oral health related quality of lifeM (OHRQoL) of hypodontia patients after completing dental treatment at the Eastman Dental Hospital and compare it with British public norms. 2. Assess factors which have an association with patients' reported OHRQoL. METHODS: Hypodontia patients who finished their treatment completed a 16-item questionnaire (UK oral health related quality-of-life measure), a list of four questions about their satisfaction with treatment received and a clinical assessment using modified USPHS criteria. RESULTS: The sample included 52 participants; median age 28 years (range 16 - 61 years). All participants had completed treatment for at least 6 months (range 6-60 months). Clinical assessment revealed 4 of the participants had complications requiring treatment. The OHRQoL mean scores of the sample were statistically significantly higher than the mean scores of the British public norms for most age groups (P?0.05). Factors which revealed association with OHRQoL scores were: gender (P=.047) and satisfaction with dental aesthetics (P=.006). CONCLUSIONS: Hypodontia patients following treatment reported higher OHRQoL average scores compared to the British population. Higher OHRQoL scores were related to patients' satisfaction with dental aesthetics after treatment. Females tended to report higher OHRQoL scores than males. PMID- 28569453 TI - Stratification of prosthetic complications by manufacturer in implant-supported restorations with a 5 years' follow-up: systematic review of the literature. AB - INTRODUCTION: Prosthetic complications on implant-supported restorations have been documented in several papers published in the literature. Several manufacturers are present on the market but results are often cumulated and may thus be misleading. The objective of the present review is to assess the prosthetic complications of implant-supported restorations with particular interest of the results obtained with prostheses from different manufacturers. EVIDENCE ACQUISITION: A manual search of Medline/PubMed was carried out up to June 2016, yielding a total of 6832 articles, which were narrowed down to 1450, then 347 abstracts to include 55 papers after full text reading. Papers with at least 5 years of follow-up reporting on prosthetic complications of single and fixed partial prosthesis were included. Prosthetic complications were divided into mechanical and technical complications, and reported in a table. EVIDENCE SYNTHESIS: Overall 14.4% of prosthetic complication was found for a total of 6623 restorations followed for an average of 7.4 years (range 5-16 years). Results where then sorted and compared. Single crowns were affected by 1.4% of mechanical complications and 10.9% of technical complications after a mean of 7.4 years. Fixed partial prosthesis were affected by 2.5% of mechanical complications and 18% of technical complications. Screw-retained and cemented restorations were calculated to have a 5 years rate of complications of 21.2% and 9.3%, respectively, which demonstrated a statistically difference with fisher exact test with P<0.1. Only 3 manufacturers presented more than 10 articles and were directly compared with Fisher's exact test with P<0.1. The incidence of overall complications was estimated to be after 5 years of 11.2%, 10.8% and 13.8% for Straumann, Nobel, and Astratech, respectively, but dividing results in mechanical and technical complications, gave different results. Straumann was estimated to have less mechanical complications after 5 years in respect to Nobel and Astratech, but the three were similar for technical complications. CONCLUSIONS: although studies present very different material and methods and do not report all data, some conclusions can be made. The difference between mechanical complications lead the authors to suppose that there might be a difference in results obtained by different implant abutment connections. It is also noticed that all papers were published by expert clinicians and universities research centers that apply rigid surgical and prosthetic protocols and use original abutments. PMID- 28569454 TI - Antibiotic treatment to prevent postextraction complications: a monocentric, randomized clinical trial. Preliminary outcomes. AB - BACKGROUND: Tooth extraction is a very common procedure in oral surgery. Despite this, very little information is available in the literature as to the antibiotic management of the patient. The aim of this study is to evaluate whether the antibiotic prophylaxis could be beneficial in preventing postextraction local complications and whether the use of a probiotic could help reduce the antibiotic gastro-intestinal side effects. METHODS: One hundred eleven patients meeting the inclusion criteria were initially included in this randomized clinical trial and randomly allocated to one of the three experimental groups according to a computer-generated randomization list. Patients allocated to the group 1 were given amoxicillin+clavulanic acid (2 g/day for 6 days), patients allocated to the group 2 received antibiotic + probiotic (Bifidobacterium longum+lactoferrin) and patients allocated to the group 3 received no antibiotic therapy after the extraction. To evaluate post-extractive complications, controls were performed at days 7, 14 and 21 after the extraction. RESULTS: At T1 pain at the surgical site was present in the 48%, 30% and 71.4% of the patients belonging respectively to the antibiotic alone group, to the antibiotic+probiotic group and to the control group. The mean Numeric Rating Score (NRS) score was 1.56+/-1.91, 1.08+/-1.93, 2.02+/-2.27 respectively (P=0.0498). Two patients belonging to the control group experienced dry socket. In addition, 9 patients (33.3%) in the antibiotic-alone group and 1 patient (2.7%) in the antibiotic+probiotic group reported intestinal distension (P=0.0012), 7 days after surgery. Finally, diarrhea was recorded in 5 patients of the antibiotic alone group (18.5%), on the other hand, no patients of the antibiotic+probiotic group and the control group reported diarrhea. CONCLUSIONS: Postextractive complications observed in each group have been mild and fast to resolve. The antibiotic administration showed a decrease in pain suffered by patients but a higher incidence of gastrointestinal side effects, such as abdominal distension and diarrhea, which seemed to be relieved by the concomitant use of the probiotic. PMID- 28569455 TI - Nordic walking and specific strength training for neck- and shoulder pain in office workers: a pilot-study. AB - BACKGROUND: More than half of all adults have experienced neck pain during the last six months. Studies have demonstrated reduced pain in the neck-and shoulder region after specific strength training of the affected muscles, but specific endurance training of neck and shoulder muscles has not been properly examined. AIM: To examine the impact of Nordic walking (NW) compared to specific strength training (ST) and a non-training control group (Con) on self-reported neck-and shoulder pain among office workers. DESIGN: Randomized intervention trial with a stratified control group. SETTINGS: University research laboratory. POPULATION: Thirty-four female office workers with neck- and shoulder pain. METHODS: The participants were allocated to NW, ST or Con. Pain intensity (0-100 mm Visual Analog Scale), isometric abduction strength and a Six-Minute Walk Test (6MWT) were assessed pre, post and 10 weeks postintervention. Both training groups attended the training programs twice per week for ten weeks (30 minutes per session). RESULTS: Both training groups demonstrated a similar (P=0.421-0.802), but significant reduction in pain intensity (P=0.014-0.018). Between post-test and the 10 weeks postintervention test, similar pain intensity was observed in the NW (P=0.932) while the ST demonstrated an increase (P=0.136). Throughout the testing period, no difference in pain was observed for the Con (P=0.724-1.000) or between the Con and the training groups (P=0.421-0.802). No changes in strength and 6MWT were observed between or within the groups (P=0.184-0.870). CONCLUSIONS: Both NW and ST reduced pain for office workers with low neck-and shoulder pain and appear to be useful exercise modalities for this group. CLINICAL REHABILITATION IMPACT: Both interventions reduced pain, but larger randomized studies should verify these findings. PMID- 28569456 TI - ICF-OB: a multidisciplinary questionnaire based on the International Classification of Functioning, Disability and Health to address disability in obesity. PMID- 28569458 TI - Inflammation. PMID- 28569457 TI - Advances in radioguided surgery in oncology. AB - The sentinel lymph node (SLN) biopsy is probably the most well-known radioguided technique in surgical oncology. Today SLN biopsy reduces the morbidity associated with lymphadenectomy and increases the identification rate of occult lymphatic metastases by offering the pathologist the lymph nodes with the highest probability of containing metastatic cells. These advantages may result in a change in clinical management both in melanoma and breast cancer patients. The SLN evaluation by pathology currently implies tumor burden stratification for further prognostic information. The concept of SLN biopsy includes pre-surgical lymphoscintigraphy as a "roadmap" to guide the surgeon toward the SLNs and to localize unpredictable lymphatic drainage patterns. In addition to planar images, SPECT/CT improves SLN detection, especially in sites closer to the injection site, providing anatomic landmarks which are helpful in localizing SLNs in difficult to interpret studies. The use of intraoperative imaging devices allows a better surgical approach and SLN localization. Several studies report the value of such devices for excision of additional sentinel nodes and for monitoring the whole procedure. The combination of preoperative imaging and radioguided localization constitutes the basis for a whole spectrum of basic and advanced nuclear medicine procedures, which recently have been encompassed under the term "guided intraoperative scintigraphic tumor targeting" (GOSTT). Excepting SLN biopsy, GOSTT includes procedures based on the detection of target lesions with visible uptake of tumor-seeking radiotracers on SPECT/CT or PET/CT enabling their subsequent radioguided excisional biopsy for diagnostic of therapeutic purposes. The incorporation of new PET-tracers into nuclear medicine has reinforced this field delineating new strategies for radioguided excision. In cases with insufficient lesion uptake after systemic radiotracer administration, intralesional injection of a tracer without migration may enable subsequent excision of the targeted tissue. This approach has been helpful in non-palpable breast cancer and in solitary pulmonary nodules. The introduction of allied technologies like fluorescence constitutes a recent advance aimed to refine the search for SLNs and tracer-avid lesions in the operation theatre in combination with radioguidance. PMID- 28569460 TI - Antibiotics and Chemotherapy in Surgery. PMID- 28569459 TI - Natural Resistance to Infection. PMID- 28569462 TI - ? PMID- 28569461 TI - Progress in Surgery of the Pancreas Since 1945. PMID- 28569463 TI - Portal Hypertension. PMID- 28569464 TI - Some Aspects of the Repair Process in Mammals. PMID- 28569465 TI - ? PMID- 28569466 TI - ? PMID- 28569468 TI - New Concepts in Burn Physiology and Burn Treatment. PMID- 28569467 TI - ? PMID- 28569469 TI - Current Concepts and Controversies on Traumatic Shock. PMID- 28569471 TI - University Hospitals of Today and Tomorrow. PMID- 28569470 TI - ? PMID- 28569472 TI - ? PMID- 28569473 TI - ? PMID- 28569474 TI - University Surgery in America 1782-1962. PMID- 28569475 TI - ? PMID- 28569476 TI - University Surgery in Sweden. PMID- 28569477 TI - ? PMID- 28569478 TI - ? PMID- 28569482 TI - Liver Surgery. PMID- 28569483 TI - Thoracic Transposition of the Spleen and Spleno-pneumorrhaphy in Portal Hypertension Experimental Studies in Dogs. PMID- 28569485 TI - Introduction. PMID- 28569484 TI - Fat Embolism. PMID- 28569486 TI - First to Third Week. PMID- 28569487 TI - Fourth Week. PMID- 28569489 TI - Sixth Week. PMID- 28569488 TI - Fifth Week. PMID- 28569490 TI - Seventh Week. PMID- 28569491 TI - Eighth Week. PMID- 28569492 TI - Third Month. PMID- 28569493 TI - Fourth Month. PMID- 28569494 TI - Fifth Month. PMID- 28569495 TI - Sixth Month. PMID- 28569497 TI - Eighth Month. PMID- 28569496 TI - Seventh Month. PMID- 28569498 TI - Ninth Month. PMID- 28569499 TI - Birth and after Birth. PMID- 28569501 TI - Protonated MIL-125-NH2: Remarkable Adsorbent for the Removal of Quinoline and Indole from Liquid Fuel. AB - The removal of nitrogen-containing compounds (NCCs) from fossil fuels prior to combustion is currently of particular importance, and so we investigated an adsorptive method using metal-organic frameworks (MOFs) for the removal of indole (IND) and quinoline (QUI), which are two of the main NCCs present in fossil fuels. We herein employed an amino (-NH2)-functionalized MIL-125 (MIL-125-NH2) MOF, which was further modified by protonation (P-MIL-125-NH2). These modified MOFs exhibited extraordinary performance in the adsorption of both IND (as representative neutral NCC) and QUI (as representative basic NCC). These MOFs were one of the most efficient adsorbents for the removal of NCCs. For example, P MIL-125-NH2 showed the highest adsorption capacity for QUI among ever reported adsorbent. The improved adsorption of IND was explained by H-bonding and cation pi interactions for MIL-125-NH2 and P-MIL-125-NH2, respectively, while the mechanisms for QUI were H-bonding and acid-base interactions, respectively. This is a rare phenomenon for a single material (especially not with very high porosity) to exhibit such remarkable performances in the adsorption of both basic QUI and neutral IND. The adsorption results obtained using regenerated MIL-125 NH2 and P-MIL-125-NH2 also showed that these materials can be used several times without any severe degradation. PMID- 28569500 TI - Extreme Dynamics in the BamA beta-Barrel Seam. AB - BamA is an essential component of the beta-barrel assembly machine (BAM) that is responsible for insertion and folding of beta-barrel outer membrane proteins (OMPs) in Gram-negative bacteria. BamA is an OMP itself, and its beta-barrel transmembrane domain is thought to catalyze OMP insertion and folding, although the molecular mechanism remains poorly understood. Crystal structures of BamA and complementary molecular dynamics simulations have shown that its beta-barrel seam (the interface between the first and last barrel strands) is destabilized. This has led to mechanistic models in which the BamA barrel seam functions as a lateral gate that opens and successively accepts beta-hairpins from a nascent OMP such that a nascent barrel can bud from BamA. Consistent with this model, disulfide locking of the BamA barrel seam is lethal in Escherichia coli. Here we show that disulfide locking of the BamA barrel has no effect on its ability to catalyze folding of a model OMP into liposomes. However, disulfide trapping experiments indicate that the BamA barrel is highly dynamic in the liposome membranes, with the beta-strands at the barrel seam undergoing "register sliding" by more than 14 A both up and down the membrane. Remarkably, these extreme dynamics were also observed in the BamA barrel in the context of the native E. coli outer membrane. These results are consistent with a model in which the BamA barrel dynamics induce defects in the outer membrane that facilitate insertion of nascent OMPs. PMID- 28569502 TI - Prevention of Bacterial Colonization on Catheters by a One-Step Coating Process Involving an Antibiofouling Polymer in Water. AB - As reports of multidrug resistant pathogens have increased, patients with implanted medical catheters increasingly need alternative solutions to antibiotic treatments. As most catheter-related infections are directly associated with biofilm formation on the catheter surface, which, once formed, is difficult to eliminate, a promising approach to biofilm prevention involves inhibiting the initial adhesion of bacteria to the surface. In this study, we report an amphiphilic, antifouling polymer, poly(DMA-mPEGMA-AA) that can facilely coat the surfaces of commercially available catheter materials in water and prevent bacterial adhesion to and subsequent colonization of the surface, giving rise to an antibiofilm surface. The antifouling coating layer was formed simply by dipping a model substrate (polystyrene, PET, PDMS, or silicon-based urinary catheter) in water containing poly(DMA-mPEGMA-AA), followed by characterization by X-ray photoelectron spectroscopy (XPS). The antibacterial adhesion properties of the polymer-coated surface were assessed for Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) growth under static (incubation in the presence of a bacterial suspension) and dynamic (bacteria suspended in a solution under flow) conditions. Regardless of the conditions, the polymer-coated surface displayed significantly reduced attachment of the bacteria (antiadhesion effect > ~8-fold) compared to the bare noncoated substrates. Treatment of the implanted catheters with S. aureus in vivo further confirmed that the polymer-coated silicon urinary catheters could significantly reduce bacterial adhesion and biofilm formation in a bacterial infection animal model. Furthermore, the polymer-coated catheters did not induce hemolysis and were resistant to the adhesion of blood-circulating cells, indicative of high biocompatibility. Collectively, the present amphiphilic antifouling polymer is potentially useful as a coating platform that renders existing medical devices resistant to biofilm formation. PMID- 28569503 TI - Interpenetrated Networks between Graphitic Carbon Infilling and Ultrafine TiO2 Nanocrystals with Patterned Macroporous Structure for High-Performance Lithium Ion Batteries. AB - Interpenetrated networks between graphitic carbon infilling and ultrafine TiO2 nanocrystals with patterned macropores (100-200 nm) were successfully synthesized. Polypyrrole layer was conformably coated on the primary TiO2 nanoparticles (~8 nm) by a photosensitive reaction and was then transformed into carbon infilling in the interparticle mesopores of the TiO2 nanoparticles. Compared to the carbon/graphene supported TiO2 nanoparticles or carbon coated TiO2 nanostructures, the carbon infilling would provide a conductive medium and buffer layer for volume expansion of the encapsulated TiO2 nanoparticles, thus enhancing conductivity and cycle stability of the C-TiO2 anode materials for lithium ion batteries (LIBs). In addition, the macropores with diameters of 100 200 nm in the C-TiO2 anode and the mesopores in carbon infilling could improve electrolyte transportation in the electrodes and shorten the lithium ion diffusion length. The C-TiO2 electrode can provide a large capacity of 192.8 mA h g-1 after 100 cycles at 200 mA g-1, which is higher than those of the pure macroporous TiO2 electrode (144.8 mA h g-1), C-TiO2 composite electrode without macroporous structure (128 mA h g-1), and most of the TiO2 based electrodes in the literature. Importantly, the C-TiO2 electrode exhibits a high rate performance and still delivers a high capacity of ~140 mA h g-1 after 1000 cycles at 1000 mA g-1 (~5.88 C), suggesting good lithium storage properties of the macroporous C-TiO2 composites with high capacity, cycle stability, and rate capability. This work would be instructive for designing hierarchical porous TiO2 based anodes for high-performance LIBs. PMID- 28569505 TI - Copper(I) Complexes of a Flexible Bis-phospholane Ligand: Route to Paddle-Wheel- and Box-Type Macrocycles. AB - Two bis-phospholane copper(I) metallamacrocycles were selectively synthesized starting from the same two building blocks, namely, ligand 1 and [Cu(NCCH3)4]BF4. Reaction conditions (ligand:metal (L:M) ratio and dilution) can be tuned to obtain either a paddle-wheel- (2, L:M = 3:2) or box-type complex (3, L:M = 8:4). Their structures were unequivocally determined by X-ray crystallography. The solution 31P{1H} NMR spectrum of complex 2 consists of a broad signal, as is common for such complexes, whereas complex 3 shows splitting of the 31P{1H} NMR signal into a pseudoquartet due to 63,65Cu-31P coupling, a rare occurrence exhibited only by highly symmetrical copper(I) phosphine complexes. PMID- 28569506 TI - Tunable Luminescent Heterometallic Zn2Ln2 Edge-Defective Molecular Cubane with Stimuli-Responsive Properties. AB - Heterometallic Zn2Ln2 [Ln = Gd (1), Eu (2), Tb (3), Dy (4)] discrete molecules with edge-defective cubane structure are assembled from a multifunctional fluorescent conjugate ligand and LnIII/ZnII mixed-metal ions; they exhibit the tunable luminescence, including ligand-based yellow-green light emission for 1 and 4 and lanthanide-center emission for 2 and 3. The multiple stimuli-responsive photoluminescences were investigated to show a two-step thermal-responsive luminescence increase in the intensity upon cooling and piezochromic luminescence. PMID- 28569504 TI - pH-Switchability and Second-Order Nonlinear Optical Properties of Monocyclopentadienylruthenium(II)/iron(II) Tetrazoles/Tetrazolates: Synthesis, Characterization, and Time-Dependent Density Functional Theory Calculations. AB - Tetrazole/tetrazolate monocyclopentadienyliron(II) and ruthenium(II) compounds of general formulas [(eta5-C5H5)M(dppe)(N4(H)CC6H4NO2)][PF6]/[(eta5 C5H5)M(dppe)(N4CC6H4NO2)] were investigated for their pH-switching second-order nonlinear optical (SONLO) properties. Compounds [(eta5-C5H5)M(dppe)(N4CC6H4NO2)] (M = Fe, Ru) and compound [(eta5-C5H5)Ru(dppe)(N4(H)CC6H4NO2)][PF6] were fully characterized by (1H-, 13C-, 31P-) NMR, cyclic voltammetry, and elemental analysis, and compounds [(eta5-C5H5)Fe(dppe)(N4CC6H4NO2)] and [(eta5 C5H5)Ru(dppe)(N4(H)CC6H4NO2)][PF6] were further characterized by single-crystal X ray diffraction; the synthesis of [(eta5-C5H5)Fe(dppe)(N4(H)CC6H4NO2)][PF6] was unsuccessful. Time-dependent density functional theory calculations were performed using PBE0 and CAM-B3LYP functionals to evaluate the first hyperpolarizability (betatot) of the tetrazole/tetrazolate complexes and for a detailed analysis of the experimental data. Both functionals predict (i) high first hyperpolarizabilities for the tetrazolate complexes [(eta5 C5H5)M(dppe)(N4CC6H4NO2)], with betatot[Ru] ~ 1.2betatot[Fe], and (ii) a 3-fold reduction in betatot[Ru] upon protonation, in complex [(eta5 C5H5)Ru(dppe)(N4(H)CC6H4NO2)]+, forecasting [(eta5 C5H5)Ru(dppe)(N4CC6H4NO2)]/[(eta5-C5H5)Ru(dppe)(N4(H)CC6H4NO2)]+ complexes as on/off, pH-switchable SONLO forms. PMID- 28569507 TI - The Role of Ligand Steric Bulk in New Monovalent Aluminum Compounds. AB - The tetrameric Al(I) cyclopentadienyl compound Al4Cp*4 (Cp* = C5Me5) is a prototypical low-valence Al compound, with delocalized bonding between four Al(I) atoms and eta5 ligands bound to the cluster exterior. The synthesis of new [AlR]4 (R = C5Me4Pr, C5Me4iPr) tetramers is presented. Though these systems failed to crystallize, comparison of variable-temperature 27Al NMR data with density functional theory (DFT) calculations indicate that these are Al4R4 tetramers analogous to Al4Cp*4 but with increased ligand steric bulk. NMR, DFT, and Atoms in Molecules analyses show that these clusters are enthalpically more stable as tetramers than the Cp* variant, due in part to noncovalent interactions across the bulkier ligand groups. Thermochemistry calculations for the low-valence metal interactions were found to be extremely sensitive to the DFT methodology used; the M06-2X functional with a cc-pVTZ basis set is shown to provide very accurate values for the enthalpy of tetramerization and 27Al NMR shifts. This computational method is then used to predict geometrical structures, noncovalent ligand interactions, and monomer/tetramer equilibrium in solution for a series of Al(I) cyclopentadienyl compounds of varying steric bulk. PMID- 28569508 TI - Tailoring Metalloporphyrin Frameworks for an Efficient Carbon Dioxide Electroreduction: Selectively Stabilizing Key Intermediates with H-Bonding Pockets. AB - The electrocatalytic reduction of carbon dioxide (CO2ER) is a great challenge within the field of energy and environmental research. Competing reactions, including hydrogen evolution reactions (HER) and surface oxidation, limit the conversion of CO2ER at low overpotentials. This is because these competing reactions produce intermediates (adsorbed H and OH) with chemical bonds similar to those formed in CO2ER (adsorbed COOH and OCHO). Here, we report the adsorption free energies of CO2ER and competitive intermediates within H-bonding functionalized metalloporphyrin frameworks using first-principles calculations. The functionalized frameworks shift the scaling relation of adsorption free energies to favor the CO2ER intermediates rather than the HER. Inspired by molecular catalysts, we proposed and studied H-bonding interfaces that specifically stabilize the target intermediates of the CO2ER. The selective H bonding stabilization reduced the limiting potential for CO2ER by up to 0.2-0.3 V. Our results agree with previous experiments that found that cobalt- and iron based metalloporphyrins exhibited the most promising catalytic activity in CO2-to CO reduction, with small potential barriers for the adsorbed COOH intermediate. In addition, embedding the functionalized metalloporphyrin moieties in a rigid framework structure acted to enhance the CO2ER selectivity by preventing the porphyrin from stacking and keeping H-bonding interfaces in close proximity to only CO2ER intermediates. Improved selectivity to the desired CO2ER was achieved through three steps: first by systematically screening for metal centers, second by creating an ideal H-bonding environment, and finally by using a rigid macrocycle ring structure. PMID- 28569509 TI - Correction to "Do Cyclodextrins Aggregate in Water? Insights from NMR Experiments". PMID- 28569510 TI - In Situ Electrodeposited Synthesis of Electrochemiluminescent Ag Nanoclusters as Signal Probe for Ultrasensitive Detection of Cyclin-D1 from Cancer Cells. AB - Metal nanoclusters (NCs) as a new type of electrochemiluminescence (ECL) nanomaterials have attracted great attention, but their applications are limited due to relatively low luminescent efficiency and a complex preparation process. Herein, an ultrasensitive ECL biosensor for the detection of Cyclin-D1 (CCND1) was designed by utilizing in situ electrogenerated silver nanoclusters (AgNCs) as ECL emitters and Fe3O4-CeO2 nanocomposites as a coreaction accelerator. The ECL luminous efficiency of AgNCs on the electrode could be significantly enhanced with the use of the Fe3O4-CeO2 for accelerating the reduction of S2O82- to generate the strong oxidizing intermediate radical SO4*-. As a result, the assay for CCND1 detection achieved excellent sensitivity with a linear range from 50 fg/mL to 50 ng/mL and limit of detection down to 28 fg/mL. Impressively, the efficiency of Traditional Chinese Medicines (TCM), sophorae, toward MCF-7 cells was successfully investigated due to the overexpression of CCND1 in relation to the growth and metastasis of MCF-7 human breast cancer cells. In general, the proposed strategy provided an effective method for anticancer drug screening and expanded the application of metal NCs in ultrasensitive biodetection. PMID- 28569511 TI - New Insight of Water-Splitting Photocatalyst: H2O2-Resistance Poisoning and Photothermal Deactivation in Sub-micrometer CoO Octahedrons. AB - Hydrogen production by photocatalytic overall water-splitting represents an ideal pathway for clean energy harvesting, for which developing high-efficiency catalysts has been the central scientific topic. Nanosized CoO with high solar-to hydrogen efficiency (5%) is one of the most promising catalyst candidates. However, poor understanding of this photocatalyst leaves the key issue of rapid deactivation unclear and severely hinders its wide application. Here, we report a sub-micrometer CoO octahedron photocatalyst with high overall-water-splitting activity and outstanding ability of H2O2-resistance poisoning. We show that the deactivation of CoO catalyst originates from the unintended thermoinduced oxidation of CoO during photocatalysis, with coexistence of oxygen and water. We then demonstrate that introduction of graphene, as a heat conductor, largely enhanced the photocatalytic activity and stability of the CoO. Our work not only provides a new insight of CoO for photocatalytic water splitting but also demonstrates a new concept for photocatalyst design. PMID- 28569512 TI - Medical and non-medical costs of Parkinson disease - comparison of Europe, USA, Asia an Australia. AB - At present different kinds of dementia impose a significant economic burden on the whole societies. Parkinsons disease is the second most common type of dementia. The purpose of this study is to analyze the costs of people suffering from Parkinsons disease in the context of public expenditure needs for the affected people. Firstly, the treatment costs and care in the selected European countries are analyzed, and secondly, these data are compared with the data from other countries and continents. The focus is not only on the developed economies where the issue of costs and PD already causes significant expenditure from public budgets, but also on the developing economies. The methods applied in this study include a method of literature search of available sources describing the costs of PD and a qualitative comparative analysis method. The findings show that the data from the European countries range between 1,949 ? and 12,054 ?. Comparable data are in the USA at 17,064 ?, in Australia at 7,020 ? and in Asia they range between 649 ? and 9,544 ?. These values are certainly connected not only with the available data, but also with the level and possibilities of healthcare services in these countries. In addition, GDP for these continents and countries was specified and the cost ratio of patient with respect to GHD per capita was described. This calculation provides an orientation relative indicator about the economic burden with respect to the countrys development. The results indicate that the most significant issues are diseases and treatment in the European countries in which their highest incidence is expected in future.Key words: Parkinsons disease costs health care analysis. PMID- 28569513 TI - Gas chromatography - mass spectrometry studies of the component composition of carboxylic acids of the rhizomes of Iris medwedewii and Iris carthaliniae (Iridaceae). AB - The composition of carboxylic acids of the rhizomes of Iris carthaliniae and Iris medwedewii by the gas chromatography - mass spectrometry method has been studied for the first time. The total content of carboxylic acids for I. carthaliniae was 1.34%, including (%) - 0.65 fatty; 0.36 mono-, di- and tri-carboxylic; 0.33 phenol carboxylic acids. The yield of carboxylic acids for I. medwedewii was 1.58%, including (%) - 0.73 fatty; 0.38 mono-, di- and tri-carboxylic; 0.47 phenol carboxylic acids. The dominant fatty acids in the rhizomes of I. carthaliniae were myristic acid (25%), palmitic acid (14.41%), stearic acid (10.51%) and linoleic acid (6.05%). Besides, levulinic acid (15.84%) and oxalic acid (4.42%) prevailed among organic acids, while ferulic acid (2.43%), citric acid (1.88%) and malic acid (3.62%) prevailed among the hydroxy acids. The fatty acids palmitic acid (6.51%), linoleic acid (8.38%), oleic acid (3.87%) and capric acid (3.21%) were found in the rhizomes of I. medwedewii, and also, levulinic (29.39%), malonic (1.45%), succinic (1.72%) acids prevailed among the organic acids and citric (25.37%), malic (3.30%) and ferulic (2.42%) acids in the rhizomes of I. medwedewii prevailed among the hydroxy acids.Key words: Iris carthaliniae Iris medwedewii rhizomes carboxylic acids GC-MS analysis. PMID- 28569515 TI - Self-emulsifying drug delivery system (SEDDS) of Ibuprofen: formulation, in vitro and in vivo evaluation. AB - The goal of the present study was to develop a self-emulsifying drug delivery system for the oral poorly water-soluble drug ibuprofen and to evaluate its oral bioavailability. Phase diagrams were constructed to determine the phase behaviour of the microemulsions and to compare the efficiency of various surfactant-oil mixtures. The SEDDS formulations of ibuprofen were prepared from a mixture of Labrafil M2125, Cremophor RH40, and Plurol oleique. The prepared emulsions were characterized for in vitro and in vivo behaviour. A FTIR study confirmed there is no interaction between the drug and excipients. DSC studies showed that the drug is in a solubilised form in the self-emulsifying formulations. The formulations were evaluated for thermodynamic stability, dispersibility, refractive index, viscosity and cloud point. Formulations showed a negative charge on globules which indicates their stability. The optimized formulation produced a microemulsion with a globule size of 177.5 nm. The in vitro release profile of the optimized formulation was significantly higher than that of the marketed formulation and pure drug. The anti-inflammatory activity of the optimized formulation was significantly higher than that of the marketed formulation and pure drug. The AUC and Cmax values after oral administration were higher for the ibuprofen SEDDS in comparison with the marketed product. These results suggest that SEDDS of Ibuprofen can be a useful tool to increase the bioavailability and an alternative to enhance the bioavailability of poorly soluble drugs.Key words: ibuprofen self-emulsifying system phase diagram zeta potential, anti-inflammatory activity. PMID- 28569514 TI - Cytotoxic, anti-cancer, and anti-microbial effects of different extracts obtained from Artemisia rupestris. AB - Artemisia rupestris is a part of traditional Kazakh folk medicine. Extracts obtained from this plant are used to treat various diseases, including cancer. This study evaluates the anti-microbial, cytotoxic, and anti-cancer effects of different extracts of the plant. Different extraction techniques were used and the resultant activities were compared. Extracts of A. rupestris were prepared from the flowers plus the leaves and from the stems. The antimicrobial activity against Candida albicans and Staphylococcus aureus was quantified. Cell lines L1210 and THP-1 were used to evaluate the cytotoxic potential of these extracts in vitro. The anti-cancer effect was tested using L1210-induced tumorgenesis in mouse model. The aqueous extract of stems was the most active against C. albicans, whereas the methanolic extract of flowers plus leaves especially inhibited the growth of S. aureus. The aqueous extracts were found to be non cytotoxic for both cell lines, whereas the lipophilic extracts showed cytotoxic effects. The extract obtained from flowers plus leaves was more cytotoxic than that from stems. The tested extracts showed no anti-cancer potential. The results obtained testify to the relatively safe consumption of aqueous extracts of A. rupestris, but lipophilic extracts showed toxic effects and their consumption should be considered more carefully.Key words: L1210 cell line THP-1 cell line microwave-assisted extraction ultrasonic-assisted extraction Candida albicans Staphylococcus aureus. PMID- 28569516 TI - [The fate of Jewish pharmacists from the Czech Lands during the holocaust]. AB - The authors describe the lives of several Jewish pharmacists and their families who lived and worked in the Czech Lands during the years 1918-1945. Their stories represented a typical mosaic, which corresponds to the fate of the Jewish community in the Czech Lands during World War II - all lost their property and the majority of them were murdered or lost their immediate families. Only a few of them succeeded to survive thanks to early emigration. Some of them lived until the liberation of the concentration camp Theresienstadt, too.Key words: Jews pharmacy shoah concentration camp Auschwitz. PMID- 28569517 TI - Quantifying the structure of free association networks across the life span. AB - We investigate how the mental lexicon changes over the life span using free association data from over 8,000 individuals, ranging from 10 to 84 years of age, with more than 400 cue words per age group. Using network analysis, with words as nodes and edges defined by the strength of shared associations, we find that associative networks evolve in a nonlinear (U-shaped) fashion over the life span. During early life, the network converges and becomes increasingly structured, with reductions in average path length, entropy, clustering coefficient, and small world index. Into late life, the pattern reverses but shows clear differences from early life. The pattern is independent of the increasing number of word types produced per cue across the life span, consistent with a network encoding an increasing number of relations between words as individuals age. Lifetime variability is dominantly driven by associative change in the least well connected words. (PsycINFO Database Record PMID- 28569518 TI - Outcomes of psychological therapies for prisoners with mental health problems: A systematic review and meta-analysis. AB - OBJECTIVE: Prisoners worldwide have substantial mental health needs, but the efficacy of psychological therapy in prisons is unknown. We aimed to systematically review psychological therapies with mental health outcomes in prisoners and qualitatively summarize difficulties in conducting randomized clinical trials (RCTs). METHOD: We systematically identified RCTs of psychological therapies with mental health outcomes in prisoners (37 studies). Effect sizes were calculated and meta-analyzed. Eligible studies were assessed for quality. Subgroup and metaregression analyses were conducted to examine sources of between-study heterogeneity. Thematic analysis reviewed difficulties in conducting prison RCTs. RESULTS: In 37 identified studies, psychological therapies showed a medium effect size (0.50, 95% CI [0.34, 0.66]) with high levels of heterogeneity with the most evidence for CBT and mindfulness-based trials. Studies that used no treatment (0.77, 95% CI [0.50, 1.03]) or waitlist controls (0.71, 95% CI [0.43, 1.00]) had larger effect sizes than those that had treatment-as-usual or other psychological therapies as controls (0.21, 95% CI [0.01, 0.41]). Effects were not sustained on follow-up at 3 and 6 months. No differences were found between group and individual therapy, or different treatment types. The use of a fidelity measure was associated with lower effect sizes. Qualitative analysis identified difficulties with follow-up and institutional constraints on scheduling and implementation of trials. CONCLUSIONS: CBT and mindfulness-based therapies are modestly effective in prisoners for depression and anxiety outcomes. In prisons with existing psychological therapies, more evidence is required before additional therapies can be recommended. (PsycINFO Database Record PMID- 28569520 TI - Rapid response to intensive treatment for bulimia nervosa and purging disorder: A randomized controlled trial of a CBT intervention to facilitate early behavior change. AB - OBJECTIVE: Rapid response to cognitive behavior therapy (CBT) for eating disorders (i.e., rapid and substantial change to key eating disorder behaviors in the initial weeks of treatment) robustly predicts good outcome at end-of treatment and in follow up. The objective of this study was to determine whether rapid response to day hospital (DH) eating disorder treatment could be facilitated using a brief adjunctive CBT intervention focused on early change. METHOD: 44 women (average age 27.3 [8.4]; 75% White, 6.3% Black, 6.9% Asian) were randomly assigned to 1 of 2 4-session adjunctive interventions: CBT focused on early change, or motivational interviewing (MI). DH was administered as usual. Outcomes included binge/purge frequency, Eating Disorder Examination Questionnaire and Difficulties in Emotion Regulation Scale. Intent-to-treat analyses were used. RESULTS: The CBT group had a higher rate of rapid response (95.7%) compared to MI (71.4%; p = .04, V = .33). Those who received CBT also had fewer binge/purge episodes (p = .02) in the first 4 weeks of DH. By end-of-DH, CBT participants made greater improvements on overvaluation of weight and shape (p = .008), and emotion regulation (ps < .008). Across conditions, there were no significant baseline differences between rapid and nonrapid responders (ps > .05). CONCLUSIONS: The results of this study demonstrate that rapid response can be clinically facilitated using a CBT intervention that explicitly encourages early change. This provides the foundation for future research investigating whether enhancing rates of rapid response using such an intervention results in improved longer term outcomes. (PsycINFO Database Record PMID- 28569521 TI - How dispositional social risk-seeking promotes trusting strangers: Evidence based on brain potentials and neural oscillations. AB - Trust is a risky social decision because betrayal may occur. It's not clear how individual differences in social risk-seeking propensity modulate brain processes of trusting strangers. We examined event-related potentials and time-frequency power to investigate this question while 40 participants played the one-shot trust game. Twenty high social risk-seekers (HSR) and 20 low social risk-seekers (LSR) made trusting or distrusting decisions regarding unknown trustees while their electroencephalogram activity was recorded. At the decision-making stage, HSR participants exhibited a larger N2 and increased beta power following distrusting decisions than trusting decisions, suggesting greater cognitive control exerted to distrust. By contrast, no such N2 and beta differences were found for LSR participants. At the outcome evaluation stage, LSR participants exhibited a more negative-going difference wave between loss feedback-related negativity (FRN) and gain FRN (dFRN) and increased theta power (following losses compared to gains) than did HSR participants, indicating enhanced risk sensitivity of LSR people. Our findings provide insights into the mechanism by which social risk-taking facilitates trusting strangers. The results also shed light on the temporal course of brain activity involved in trust decision-making and outcome evaluation, as well as how individual differences modulate brain dynamics of trusting strangers. (PsycINFO Database Record PMID- 28569519 TI - Concurrent varenicline and prolonged exposure for patients with nicotine dependence and PTSD: A randomized controlled trial. AB - BACKGROUND: Prevalence of smoking among individuals with posttraumatic stress disorder (PTSD) is disproportionately high, and PTSD is associated with especially poor response to smoking cessation treatment. OBJECTIVE: The current study examined whether integrating treatments for smoking cessation (varenicline plus smoking cessation counseling; VARCC) and PTSD (prolonged exposure therapy; PE) enhances smoking outcomes among smokers diagnosed with PTSD. METHOD: 142 adults with nicotine dependence (ND) and PTSD were randomized to a treatment program consisting of varenicline, smoking cessation counseling, and PE (VARCC + PE) or to VARCC only. Seven-day point prevalence abstinence (PPA) at posttreatment (3-months postquit day) and follow-up (6-months postquit day), verified by serum cotinine levels and exhaled carbon monoxide, was the primary smoking outcome. Psychological outcomes were PTSD and depression severity. Mixed effects models included baseline PTSD severity as a moderator of treatment condition effects. RESULTS: Overall, VARCC + PE participants did not show greater PPA than VARCC participants. However, treatment effects were moderated by baseline PTSD severity. For participants with moderate and high PTSD severity, VARCC + PE led to significantly higher PPA than VARCC alone (ps<.05). No differences between treatment conditions emerged for participants with low baseline PTSD severity. Participants who received PE showed significantly greater reduction of PTSD and depression symptoms than those who did not receive PE. CONCLUSIONS: Integrating psychological treatment for PTSD and smoking cessation treatment enhances smoking cessation for participants with moderate or severe PTSD symptom severity, but does not enhance smoking cessation for participants with low baseline PTSD severity. (PsycINFO Database Record PMID- 28569522 TI - Exercise motivation and nonspecific back pain: A comparison of patients and nonpatients. AB - OBJECTIVE: Motivation is a key variable to consider during exercise or exercise therapy of individuals with back pain. Based on organismic integration theory, this study aims to improve the understanding of exercise motivation in patients and nonpatients by evaluating the relationships between typical motivational profiles and personal characteristics, therapy parameters and pain related variables. METHOD: One hundred nine women and 145 men with back pain (mean age 33.3 years; 31.9% currently under the care of a physician) involved in some kind of exercise for current nonspecific back pain voluntarily participated in this study. An adapted version of the Behavioral Regulation in Sport Questionnaire was used to measure exercise motivation. Furthermore, data on pain, disability status, level of sport activity, body concept, and the type of treatment or exercise were gathered. RESULTS: Autonomous forms of regulation were most prevalent among subjects. Of 4 motivational profiles found, 2 showed a positive pattern (29.1% highly motivated individuals, 21.7% autonomously convinced individuals), and 2 showed a more negative pattern (19.7% controlled convinced individuals, 29.5% less motivated individuals). Relationships between profiles and age, body concept, involvement in sport competition, and type of exercise were found. CONCLUSIONS: The different motivational profiles respectively reveal specific practical relevance. In particular, the controlled convinced pattern is supposed to be more maladaptive than all other profiles. The insights provided by this study supports the development of motivation-oriented treatments based on the assessment of individuals' motivational profiles. (PsycINFO Database Record PMID- 28569523 TI - Mastery motivation and executive functions as predictors of adaptive behavior in adolescents and young adults with cerebral palsy or myelomeningocele. AB - PURPOSE/OBJECTIVE: To examine mastery motivation and executive functions or behaviors as predictors of adaptive behavior in adolescents and young adults with congenital neurodevelopmental conditions. METHOD: Participants were 2 groups of adolescents and young adults, ages 13-29, including 43 with cerebral palsy and 36 with myelomeningocele living with a parent or caregiver. Participants completed measures of mastery motivation, executive functions or behaviors, and a measure of adaptive behavior. RESULTS: Group differences in mastery motivation, executive functions and executive behaviors, and adaptive behavior profiles were not significant. Mastery motivation, executive functions, and executive behaviors explained a significant portion of variance in adaptive behavior. CONCLUSIONS: Findings highlight the importance of assessing and addressing motivational and executive needs in developing interventions to promote independence. Findings also suggest the need for more comprehensive assessment of adaptive behaviors that include the ability to self-direct others in the completion of tasks necessary for successful daily functioning. (PsycINFO Database Record PMID- 28569524 TI - Mentalizing as a mechanism of change in the treatment of patients with borderline personality disorder: A parallel process growth modeling approach. AB - Although a number of effective psychotherapeutic treatments have been developed for borderline personality disorder (BPD), little is known about the mechanisms of change explaining the effects of these treatments. There is increasing evidence that impairments in mentalizing or reflective functioning-the capacity to reflect on the internal mental states of the self and others-are a central feature of BPD. To date, no study has directly investigated the core assumption of the mentalization-based approach to BPD, that changes in this capacity are associated with treatment outcome in BPD patients. This study is the first to directly investigate this assumption in a sample of 175 patients with BPD who received long-term hospitalization-based psychodynamic treatment. Using a parallel process growth modeling approach, this study investigated whether (a) treatment was related to changes in mentalizing capacity as measured with the Reflective Functioning Questionnaire; (b) these changes could be explained by pretreatment levels of mentalizing and/or symptomatic distress; and (c) changes in mentalizing capacity over time were associated with symptomatic improvement. Mentalizing and symptomatic distress were assessed at admission, 12 and 24 weeks into treatment, and at discharge. Results showed that treatment was associated with significant decreases in mentalizing impairments (i.e., uncertainty about mental states) and symptomatic distress. Pretreatment levels of mentalizing and symptomatic distress did not predict these changes. However, improvements in mentalizing were strongly associated with the rate of decrease in symptomatic distress over time (r = .89). These findings suggest that increases in mentalizing may indeed in part explain therapeutic change in the treatment of BPD, but more research is needed to further substantiate these conclusions. (PsycINFO Database Record PMID- 28569525 TI - Web-based alcohol intervention for veterans: PTSD, combat exposure, and alcohol outcomes. AB - OBJECTIVE: The purpose of the current study was to evaluate the relationship between baseline levels of posttraumatic stress disorder (PTSD), combat exposure, and alcohol outcomes in a sample of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans using a web-based self-management intervention (VetChange) for problem drinking. METHOD: The current study focuses on 523 veterans who participated in a larger randomized clinical trial. Analyses in the current study include (a) multivariable linear regression models to assess the relationship between PTSD, combat exposure, and alcohol variables at baseline, and (b) general linear models accounting for correlated data within subjects to analyze change over time for alcohol outcomes as a function of baseline PTSD symptoms, combat exposure, and covariates. RESULTS: There was a positive association between PTSD symptom severity and alcohol use and alcohol problem severity at baseline. However, participants with higher baseline PTSD symptoms demonstrated a significantly greater reduction in alcohol use during the intervention and a greater reduction in alcohol problems from baseline to 3-month follow-up. Combat exposure severity was positively associated with alcohol problems at baseline. However, veterans with higher exposure demonstrated a greater reduction in average weekly drinking between end of intervention and follow-up, and otherwise showed changes similar to participants with lower exposure. CONCLUSIONS: Higher levels of baseline PTSD symptoms and combat exposure severity did not prevent OEF/OIF veterans from achieving positive alcohol outcomes through participation in a self-management web intervention for problem drinking. (PsycINFO Database Record PMID- 28569526 TI - Noisy preferences in risky choice: A cautionary note. AB - We examine the effects of multiple sources of noise in risky decision making. Noise in the parameters that characterize an individual's preferences can combine with noise in the response process to distort observed choice proportions. Thus, underlying preferences that conform to expected value maximization can appear to show systematic risk aversion or risk seeking. Similarly, core preferences that are consistent with expected utility theory, when perturbed by such noise, can appear to display nonlinear probability weighting. For this reason, modal choices cannot be used simplistically to infer underlying preferences. Quantitative model fits that do not allow for both sorts of noise can lead to wrong conclusions. (PsycINFO Database Record PMID- 28569527 TI - Pseudocontingencies and choice behavior in probabilistic environments with context-dependent outcomes. AB - Pseudocontingencies are inferences about correlations in the environment that are formed on the basis of statistical regularities like skewed base rates or varying base rates across environmental contexts. Previous research has demonstrated that pseudocontingencies provide a pervasive mechanism of inductive inference in numerous social judgment tasks (Fiedler, Freytag, & Meiser, 2009). The present research extended the analysis of pseudocontingencies from social judgment to actual choice behavior in a decision scenario of personal relevance. In 4 experiments, participants were first exposed to a learning environment in which choice options were presented together with positive or negative outcomes. The base rates of options and outcomes were skewed and varied across different contexts. After the learning phase, participants chose between options on the basis of the previously learned outcome probabilities and were rewarded in accordance with their individual performance. The results revealed that participants inferred a pseudocontingency between options and outcomes and followed the pseudocontingency in their decision behavior (Experiments 1-4). The observed pseudocontingency was stronger in a context with predominantly positive outcomes and replicated with different learning distributions. Pseudocontingency effects were related to interindividual differences in risk aversion and moderated by ease of base rate learning (Experiment 2) and processing time (Experiment 4), whereas the salience of rare events with extreme outcomes did not affect choice behavior (Experiment 3). The findings underline the role of pseudocontingencies in choice behavior as a subjectively cogent tool for decision making in complex probabilistic environments. (PsycINFO Database Record PMID- 28569528 TI - Context influences on the relationship between views of aging and subjective age: The moderating role of culture and domain of functioning. AB - Subjective age has been shown to reliably predict a variety of psychological and physical health outcomes, yet our understanding of its determinants is still quite limited. Using data from the Aging as Future project, the authors examined the degree to which views of aging influence subjective age and how this influence varies across cultures and domains of everyday functioning. Using data from 1,877 adults aged from 30 to 95 years of age collected in China, Germany, and the United States, they assessed how general attitudes about aging and perceptions of oneself as an older adult influenced subjective age estimates in 8 different domains of functioning. More positive attitudes about aging were associated with older subjective ages, whereas more positive views of self in old age were associated with younger subjective age. It is hypothesized that these effects are reflective of social-comparison processes and self-protective mechanisms. These influences varied considerably over contexts, with views of aging having a greater impact in domains associated with stronger negative stereotypes of aging (e.g., health) compared to those with more positive ones (e.g., family). Culture also moderated the impact of aging views in terms of the strength of prediction, direction of effect, and age of greatest influence, presumably due to cultural differences in the salience and strength of aging related belief systems across contexts. The results illustrate the contextual sensitivity of subjective age and highlight the role played by an individual's views of old age-both in general and regarding oneself-in determining their own experience of aging. (PsycINFO Database Record PMID- 28569529 TI - Age differences in coupling of intraindividual variability in mnemonic strategies and practice-related associative recall improvements. AB - The importance of encoding strategies for associative recall is well established, but there have been no studies of aging and intraindividual variability (IAV) in strategy use during extended practice. We observed strategy use and cued-recall test performance over 101 days of practice in 101 younger adults (M = 25.6 years) and 103 older adults (M = 71.3 years) sandwiched by a pretest and posttest battery including an associative recall test. Each practice session included 2 lists of 12 number-noun paired-associate (PA) items (e.g., 23-DOGS), presented for brief exposures titrated to maintain below-ceiling performance throughout practice. Participants reported strategy use (e.g., rote repetition, imagery) after each test. Substantial IAV in strategy use was detected that was coupled with performance; lists studied with normatively effective strategies (e.g., imagery) generated higher PA recall than lists studied with less effective strategies (e.g., rote repetition). In comparison to younger adults, older adults' practice (a) relied more on repetition and less on effective strategies, (b) showed lower levels of IAV in effective strategy use, and (c) had lower within-person strategy-recall coupling, especially late in practice. Individual differences in pretest-posttest gains in PA recall were predicted by average level of effective strategy use in young adults but by strategy-recall coupling in older adults. Results are consistent with the hypothesis that experiencing variability in strategic outcomes during practice helps hone the effectiveness of strategic encoding behavior, and that older adults' reduced degree of pretest posttest gains is influenced by lower likelihood of using and optimizing effective strategies through practice. (PsycINFO Database Record PMID- 28569530 TI - Network analysis for the visualization and analysis of qualitative data. AB - We present a novel manner in which to visualize the coding of qualitative data that enables representation and analysis of connections between codes using graph theory and network analysis. Network graphs are created from codes applied to a transcript or audio file using the code names and their chronological location. The resulting network is a representation of the coding data that characterizes the interrelations of codes. This approach enables quantification of qualitative codes using network analysis and facilitates examination of associations of network indices with other quantitative variables using common statistical procedures. Here, as a proof of concept, we applied this method to a set of interview transcripts that had been coded in 2 different ways and the resultant network graphs were examined. The creation of network graphs allows researchers an opportunity to view and share their qualitative data in an innovative way that may provide new insights and enhance transparency of the analytical process by which they reach their conclusions. (PsycINFO Database Record PMID- 28569531 TI - Social-cognitive factors of long-term physical exercise 7 years after orthopedic treatment. AB - OBJECTIVE: Although it has been confirmed that physical exercise improves orthopedic conditions, many individuals fail to maintain a regular exercise regimen after being discharged from medical rehabilitation. The present study examines the role of intention, social support, self-determination, planning, and self-efficacy in facilitating strength and endurance training. DESIGN: In a 7 year observational study, intention, received social support and self determination were assessed at baseline, self-efficacy and planning at 6-month follow-up, and physical exercise at 1-year, 3-year, and 7-year follow-up. Study participants were recruited from an orthopedic rehabilitation center, N = 641 participated in the survey at baseline, n = 495 at 6-month follow-up, n = 373 at 1-year follow-up, n = 330 at 3-year follow-up, and n = 191at 7-year follow-up. Path analyses were applied to investigate whether personal and social resources contribute to long-term physical activity. RESULTS: Self-determination and planning mediated the link from intention and from social support to physical exercise at 1-, 3- and 7-year follow-ups. Self-efficacy facilitated planning and bridged the intention-behavior relationship in the domain of strength training after 1 year. An inverse direct relationship between social support and strength training was also found for all follow-ups. CONCLUSIONS: Findings indicate that intention, received social support and self-determination act as crucial resources in the long-term management of exercise. Planning can bridge the intention-behavior gap on a long-term basis. Behavior change interventions should replenish personal and social resources to empower individuals to maintain a healthy lifestyle (PsycINFO Database Record PMID- 28569532 TI - College-age adults' religiosity, family functioning and values, and willingness to provide care for a relative with a chronic health condition. AB - PURPOSE/OBJECTIVE: The population of adults age 65 and older is increasing at a faster rate than the rest of the U.S. POPULATION: As such, older adults, particularly those with chronic health conditions and disabilities, will require informal care from today's college-age adults. At present, there is no research examining factors predicting college-age individuals' willingness to provide care for a family member with a chronic condition. The purpose of this study was to examine the pattern of associations among college-age adults' religiosity, family functioning, family values, and willingness to provide care for a family member with a chronic health condition. Research Method/Design: A sample of 330 undergraduate students from a major public research university completed an online survey with measures assessing these constructs. Four different structural equation models were tested. RESULTS: The fourth model revealed good fit indices and was therefore retained. This model found that religiosity and family values were positively and uniquely associated with willingness to provide care. Family functioning yielded a significant indirect effect through family values. CONCLUSIONS/IMPLICATIONS: The current study findings suggest religiosity, family functioning, and family values play a role in willingness to provide care, and thus, future researchers should target these constructs for intervention-based studies. (PsycINFO Database Record PMID- 28569533 TI - Evaluation of a concentric biopsychosocial model of well-being in persons with spinal cord injuries. AB - OBJECTIVE: The objective of this study was to evaluate a concentric biopsychosocial model of well-being in individuals with spinal cord injuries (SCI). METHOD: Adults (N = 235) with SCI participated in this study. A cross sectional design with hierarchical regression and Andrew Hayes' (2013) PROCESS mediation analysis procedure was used to evaluate the model. RESULTS: Each step of the hierarchical regression on life satisfaction, in which biological variables were entered first, social variables were entered second, and psychological variables were entered third, was significant. Examining the standardized partial coefficients, pain, interpersonal self-efficacy, social support, hope-agency, and self-esteem were all significantly associated with life satisfaction, controlling for variables in each outward ring of the concentric model. Four serial mediational analyses were also conducted in which the social and psychological variables significantly partially mediated the relationship between pain and life satisfaction. CONCLUSIONS: The results provide support for a concentric biopsychosocial model of well-being in persons with SCI. Rehabilitation interventions should focus on augmenting biopsychosocial factors to allow for maximum improvement in well-being outcomes in individuals with SCI. (PsycINFO Database Record PMID- 28569534 TI - Family caregivers' opinions about interaction with the environment in consciousness disorders. AB - OBJECTIVES: To assess family caregivers' opinions about level of interaction with the environment in their relatives with disorders of consciousness (DOCs) and to explore psychological features of caregivers whose opinions diverge from clinicians' diagnosis. METHOD: Forty-five family caregivers of 38 DOC inpatients without communication abilities answered 2 questions assessing their opinion about level of interaction with the environment in their relatives. Self-report questionnaires were used to evaluate caregivers' depression, anxiety, psychophysiological disturbances, prolonged grief disorder, coping strategies, quality of perceived needs and social support. RESULTS: Fifteen caregivers (5 relatives of patients in vegetative state and 10 of patients in minimally conscious state) considered their relatives able to communicate, in contrast with clinical diagnosis. These caregivers had significantly higher depressive symptoms, and higher worries about possible death of their relatives with respect to the remaining caregivers. CONCLUSIONS: Caregivers of DOC patients detected some interaction with the environment in their relatives more often than care professionals. This is likely related to caregivers' beliefs and expectations, but is also based on observations closer and longer than those possible for physicians. These considerations are important to build a therapeutic alliance with caregivers and to involve them in the diagnostic process and rehabilitative program. (PsycINFO Database Record PMID- 28569535 TI - A review of the use and psychometric properties of the Cognistat/Neurobehavioral Cognitive Status Examination in adults post-cerebrovascular accident. AB - This Rehabilitation Measures Database summary provides a review of the psychometric properties of the Cognistat/Neurobehavioral Cognitive Status Examination in individuals with cognitive impairment. A full review of the Cognistat/Neurobehavioral Cognitive Status Examination as well as reviews of over 300 other instruments can be found at www.rehabmeasures.org. (PsycINFO Database Record PMID- 28569536 TI - Health-related quality of life trajectories during predialysis care and associated illness perceptions. AB - OBJECTIVE: To identify health-related quality of life (HRQOL) trajectories during 18 months of predialysis care and associated patient characteristics and illness perceptions. METHOD: 396 incident predialysis patients participating in the prospective PREdialysis PAtient REcord-2 study completed every 6 months the 36 item Short Form Health Survey (i.e., mental and physical HRQOL) and Revised Illness Perception Questionnaire. HRQOL trajectories were examined using latent class growth models, and associated baseline factors were identified using logistic regression. Analyses for illness perceptions were adjusted for demographic and clinical characteristics. RESULTS: Three physical HRQOL trajectories (low-stable [34.1% of the sample], medium-declining [32.5%], and high-increasing [33.4%]) and two mental HRQOL trajectories (low-stable [38.7%] and high-stable [61.3%]) were identified. Increased odds for a low-stable physical HRQOL trajectory were detected in older patients (Odds ratio [OR] = 1.04), patients with cardiovascular disease (OR = 2.1) and patients who believed to a lesser extent they can personally control their disease (ORadj = 0.88). Increased odds for both a low-stable physical and mental HRQOL trajectory were detected in patients who believed to a higher extent that their disease is cyclical, has negative consequences, causes negative feelings, and in patients who believed to a lesser extent they understand their disease (ORadj ranged between 0.84 and 1.36). Additionally, patients who attributed more symptoms to their disease had increased odds for a medium-declining (ORadj = 1.21) and low stable physical HRQOL trajectory (ORadj = 1.50). CONCLUSIONS: Older age and cardiovascular disease are markers for unfavorable physical HRQOL trajectories, and stronger negative illness perceptions are markers for unfavorable physical and mental HRQOL trajectories. Targeting negative illness perceptions could possibly optimize HRQOL during predialysis care. (PsycINFO Database Record PMID- 28569538 TI - Suppression and expression as distinct emotion-regulation processes in daily interactions: Longitudinal and meta-analyses. AB - Emotional suppression and expression both occur frequently in daily social interactions, yet research examining these emotion regulation processes simultaneously in naturalistic contexts remains limited. Although theory and research tend to reflect an implicit assumption that suppression and expression represent opposite sides of the same construct, they are likely to occur independently and exert different influences on intrapersonal and interpersonal experiences. In 4 experience-sampling and longitudinal studies, we assessed the personal and interpersonal consequences of daily emotional suppression and expression within romantic and close relationships. Mixed-model analyses revealed that suppression and expression consistently predicted independent and distinct outcomes across the studies. When individuals suppressed their emotions, they experienced more intrapersonal costs such as greater depressed mood, greater fatigue, lower self-esteem, and lower life satisfaction. Interpersonally, they also felt less acceptance from others, more distancing by others, and less relationship satisfaction. Greater suppression in daily life also predicted increases in depressive symptoms and reductions in relationship satisfaction 3 months later. In contrast, when individuals were more emotionally expressive during daily interactions, they experienced interpersonal benefits such as greater acceptance from others, greater relatedness and relationship satisfaction, and less distancing by others. Greater emotional expression in daily life also predicted increases in self-esteem and relationship satisfaction across time. Meta-analyses of the 4 studies confirmed the reliability and significance of these relationships; |r's| = .12-.33. These studies demonstrate that suppression and expression are distinct processes used to manage emotions within social relationships and operate differently in shaping personal well being and relationship functioning. (PsycINFO Database Record PMID- 28569537 TI - Variation in the serotonin transporter polymorphism (5-HTTLPR) and inertia of negative and positive emotions in daily life. AB - An important element of understanding the genotype-phenotype link in psychiatric disorders lies in identifying the psychological mechanisms through which genetic variation impacts mental health. Here we examined whether emotional inertia, the tendency for a person's emotions to carry over from 1 moment to the next and a prospective predictor of the development of depression, is associated with a known genetic risk factor for emotional dysregulation, a polymorphism in the serotonin transporter gene (5-HTTLPR). Two hundred thirty-six adolescents recorded their positive and negative emotions in daily life 9 times a day for 6 consecutive days using smartphones, completed a depression questionnaire, and were genotyped for the 5-HTTLPR polymorphism. Carriers of the short 5-HTTLPR were characterized by higher inertia for negative emotions, even after controlling for depressive symptoms. These findings suggest a possible psychological pathway how the serotonin transporter gene contributes to risk for depression. (PsycINFO Database Record PMID- 28569539 TI - Distracting tracking: Interactions between negative emotion and attentional load in multiple-object tracking. AB - Stimuli that attract exogenous attention have been shown to interfere with behavioral performance on various tasks. In the present study, participants performed multiple-object tracking (MOT) in conditions where either neutral or negatively valenced images were flashed at fixation. Results reveal a significant impairment of tracking accuracy in the emotional MOT conditions compared to the neutral conditions specifically at the highest level of task difficulty. These findings suggest that emotional distraction is most detrimental when maximal endogenous attentional engagement is required. This interaction between emotional distraction and attentional load is inconsistent with existing models of emotional distraction. (PsycINFO Database Record PMID- 28569540 TI - Vicarious learning and reduction of fear in children via adult and child models. AB - Children can learn to fear stimuli vicariously, by observing adults' or peers' responses to them. Given that much of school-age children's time is typically spent with their peers, it is important to establish whether fear learning from peers is as effective or robust as learning from adults, and also whether peers can be successful positive models for reducing fear. During a vicarious fear learning procedure, children (6 to 10 years; N = 60) were shown images of novel animals together with images of adult or peer faces expressing fear. Later they saw their fear-paired animal again together with positive emotional adult or peer faces. Children's fear beliefs and avoidance for the animals increased following vicarious fear learning and decreased following positive vicarious counterconditioning. There was little evidence of differences in learning from adults and peers, demonstrating that for this age group peer models are effective models for both fear acquisition and reduction. (PsycINFO Database Record PMID- 28569541 TI - "Embodiment as procedures: Physical cleansing changes goal priming effects": Correction to Dong and Lee (2017). AB - Reports an error in "Embodiment as procedures: Physical cleansing changes goal priming effects" by Ping Dong and Spike W. S. Lee (Journal of Experimental Psychology: General, 2017[Apr], Vol 146[4], 592-605). In the article, the following F-value and p-values in the Results section of Experiment 3 were set incorrectly: The p-value p=.925 should be p=.922. The F- and p-values F(1, 201)=.011, p=.916 should be F(1, 201) .014, p= .906. (The following abstract of the original article appeared in record 2017-14922-010.) Physical cleansing reduces the influence of numerous psychological experiences, such as guilt from immoral behavior, dissonance from free choice, and good/bad luck from winning/losing. How do these domain-general effects occur? We propose an integrative account of cleansing as an embodied procedure of psychological separation. By separating physical traces from a physical target object (e.g., detaching dirt from hands), cleansing serves as the embodied grounding for the separation of psychological traces from a psychological target object (e.g., dissociating prior experience from the present self). This account predicts that cleansing reduces the accessibility of psychological traces and their consequences for judgments and behaviors. Testing these in the context of goal priming, we find that wiping one's hands (vs. not) decreases the mental accessibility (Experiment 1), behavioral expression (Experiment 2), and judged importance (Experiments 3-4) of previously primed goals (e.g., achievement, saving, fitness). But if a goal is primed after cleansing, its importance gets amplified instead (Experiment 3). Based on the logic of moderation-of-process, an alternative manipulation that psychologically separates a primed goal from the present self produces the same effects, but critically, the effects vanish once people wipe their hands clean (Experiment 4), consistent with the notion that cleansing functions as an embodied procedure of psychological separation. These findings have implications for the flexibility of goal pursuit. More broadly, our procedural perspective generates novel predictions about the scope and mechanisms of cleansing effects and may help integrate embodied and related phenomena. (PsycINFO Database Record PMID- 28569542 TI - "Racial bias in mock juror decision-making: A meta-analytic review of defendant treatment": Correction to Mitchell et al. (2005). AB - Reports an error in "Racial Bias in Mock Juror Decision-Making: A Meta-Analytic Review of Defendant Treatment" by Tara L. Mitchell, Ryann M. Haw, Jeffrey E. Pfeifer and Christian A. Meissner (Law and Human Behavior, 2005[Dec], Vol 29[6], 621-637). In the article, all of the numbers in Appendix A were correct, but the signs were reversed for z' in a number of studies, which are listed. Also, in Appendix B, some values were incorrect, some signs were reversed, and some values were missing. The corrected appendix is included. (The following abstract of the original article appeared in record 2006-00971-001.) Common wisdom seems to suggest that racial bias, defined as disparate treatment of minority defendants, exists in jury decision-making, with Black defendants being treated more harshly by jurors than White defendants. The empirical research, however, is inconsistent -some studies show racial bias while others do not. Two previous meta-analyses have found conflicting results regarding the existence of racial bias in juror decision-making (Mazzella & Feingold, 1994, Journal of Applied Social Psychology, 24, 1315-1344; Sweeney & Haney, 1992, Behavioral Sciences and the Law, 10, 179 195). This research takes a meta-analytic approach to further investigate the inconsistencies within the empirical literature on racial bias in juror decision making by defining racial bias as disparate treatment of racial out-groups (rather than focusing upon the minority group alone). Our results suggest that a small, yet significant, effect of racial bias in decision-making is present across studies, but that the effect becomes more pronounced when certain moderators are considered. The state of the research will be discussed in light of these findings. (PsycINFO Database Record PMID- 28569543 TI - The Effects of Attractiveness and Source Expertise on Online Health Sites. AB - The surface characteristics (presentational or design elements) of online content have been the focus of a growing body of credibility literature in recent decades. However, since the online health information communities such as WebMD do not provide any design options when writing comments on the original post, how the simplistic presentational of comments (e.g., spacing, bullet-points, labeling, and line breaks) can affect web users' responses was examined. Our study found that minimal variations in the presentation of online contents can influence assessments of their credibility and behavioral intentions. In addition, the current study revealed interaction effects between surface characteristics and source expertise. Other findings and implications are discussed. PMID- 28569545 TI - Interview with Alexander Cohen. AB - Ander Cohen speaks to Adam Price-Evans, Commissioning Editor of Future Cardiology: Alexander (Ander) Cohen MBBS (Hons), MSc, MD, FRACP is a vascular physician and epidemiologist at Guy's and St Thomas' Hospital, King's College (London, UK). He graduated with honors in medicine and honors in surgery from the University of Melbourne, Australia, and became a fellow of the Royal Australasian College of Physicians in 1990. He was awarded an MSc in Epidemiology from the London School of Hygiene and Tropical Medicine, University of London in 1991 with a thesis on the metabolic syndrome in South-Asian populations. In 1998, he was awarded an MD with a thesis on the epidemiology of venous thromboembolism and thromboprophylaxis. In addition to his clinical work, he is involved in designing, managing and analyzing clinical trials from Phase I to IV. He is the Chairman and a member of many international steering committees for multicenter trials, epidemiological and pharmacoeconomic studies, and was previously the Director of Clinical Research and an Epidemiologist in Thrombosis Research at King's College Hospital. PMID- 28569544 TI - Novel reading index for identifying disordered reading skill development: A preliminary study. AB - Children with ADHD are at high risk of developing a Reading Disability (RD), although the reasons remain unclear. ADHD-associated impairments, including processing speed, can complicate clinical evaluation for a co-occurring RD diagnosis. We propose a novel metric to (a) assess reading development and (b) provide an alternative method to classifying readers that may aid investigations for etiologies of RD in ADHD. Specifically, as both phonological decoding and word recognition skills are important precursors of reading fluency, we propose a new quantitative method comparing these skills after accounting for variations in perception, motor response, or processing speeds. Forty boys (14 control, 15 ADHD, 11 ADHD/ + RD) completed a lexical decision task testing decoding and another assessing word recognition. Response time data was modeled using a Drift Diffusion approach to estimate the underlying reading skills. Using these reading skill estimates, we calculated a novel Reading Tendency Index and classified participants into three reading groups (Decoders, Balanced Readers, and Sight Readers). The reading and cognitive performance of these groups were consistent with theoretical predictions and subsequently provided external validity for the novel Reading Tendency Index classification. Our findings demonstrate a potential classification tool for readers based on individual's developed, reading tendencies. PMID- 28569546 TI - What should the blood pressure be in patients with a prior ischemic stroke or a transient ischemic attack? PMID- 28569547 TI - Phylodynamic Analysis Revealed That Epidemic of CRF07_BC Strain in Men Who Have Sex with Men Drove Its Second Spreading Wave in China. AB - CRF07_BC was originally formed in Yunnan province of China in 1980s and spread quickly in injecting drug users (IDUs). In recent years, it has been introduced into men who have sex with men (MSM) and become the most dominant strain in China. In this study, we performed a comprehensively phylodynamic analysis of CRF07_BC sequences from China. All CRF07_BC sequences identified in China were retrieved from database. More sequences obtained in our laboratory were added to make the dataset more representative. A maximum-likelihood (ML) tree was constructed with PhyML3.0. Maximum clade credibility (MCC) tree and effective population size were predicted by using Markov Chains Monte Carlo sampling method with Beast software. A total of 610 CRF07_BC sequences coving 1,473 bp of the gag gene (from 817 to 2,289 according to HXB2 calculator) were included into the dataset. Three epidemic clusters were identified; two clusters comprised sequences from IDUs, while one cluster mainly contained sequences from MSMs. The time of the most recent common ancestor of clusters that composed of sequences from MSMs was estimated to be in 2000. Two rapid spreading waves of effective population size of CRF07_BC infections were identified in the skyline plot. The second wave coincided with the expanding of MSM cluster. The results indicated that the control of CRF07_BC infections in MSMs would help to decrease its epidemic in China. PMID- 28569548 TI - Collective occupation in public spaces and the construction of the social fabric: L'occupation collective dans les espaces publics et la construction du tissu social. AB - BACKGROUND: Contemporary research is expanding understandings of occupation beyond that of the individual's doing, including the shared and social nature of occupation. The concept of collective occupation has been introduced to capture this broader understanding. PURPOSE: This study aimed to explicate the concept of occupation in a Greek town. METHOD: Ethnographic methodology was used and primary data were collected through observation, participation, and informal interviews. Analysis involved a hermeneutic process to develop a narrative of occupation in the town, including action, setting, and plots. FINDINGS: Occupation, a dynamic and multidimensional process, served to maintain the self, family, and social fabric and balance between and within them. Collective occupation maintained the social fabric through three forms: informal daily encounters in public spaces, organization and associations, and celebration and commemoration. IMPLICATIONS: Occupational therapists may consider engaging with the potential power of such collective occupation when working toward social change to enable just and inclusive societies. PMID- 28569549 TI - The efficacy of a video-based marker-less tracking system for gait analysis. AB - Most clinical gait analyses are conducted using motion capture systems which track retro-reflective markers that are placed on key landmarks of the participants. An alternative to a three-dimensional (3D) motion capture, marker based, optical camera system may be a marker-less video-based tracking system. The aim of our study was to investigate the efficacy of the use of a marker-less tracking system in the calculation of 3D joint angles for possible use in clinical gait analysis. Ten participants walked and jogged on a treadmill and their kinematic data were captured with a marker and marker-less tracking system simultaneously. The hip, knee and ankle angles in the frontal, sagittal and transverse planes were computed. Root Mean Square differences (RMSdiff) between corresponding angles for each participant's support phase were calculated and averaged to derive the mean within-subject RMSdiff. These within-subject means were averaged to obtain the mean between-subject RMSdiff for the relevant joint angles in the two gait conditions (walking and jogging). The RMSdiff between the two tracking systems was less than 1 degrees for all rotations of the three joint angles of the hip and knee. However, there were slightly larger differences in the ankle joint angles. The results of this study suggest a potential application in gait analysis in clinical settings where observations of anatomical motions may provide meaningful feedback. PMID- 28569551 TI - Nanoparticle delivery of mitoprotective agents to target ischemic heart disease. PMID- 28569550 TI - Ultra-Deep Sequencing Analysis on HIV Drug-Resistance-Associated Mutations Among HIV-Infected Individuals: First Report from the Philippines. AB - A sharp increase in the number of people living with HIV has been documented in the Philippines. In response, the government has instituted antiretroviral therapy (ART) nationwide through HIV treatment hubs. However, no data presently exist on the status of ART drug-resistance-associated mutations (DRMs). In this study, we aim at analyzing DRM profiles in the Philippines and at providing comprehensive data on DRMs to guide treatment decisions and prevent viral failures. We conducted a cross-sectional study in 119 volunteers who tested positive for HIV from more than 8,000 participants screened for HIV across the nation through the 2013 Integrated HIV Behavioral and Serologic Surveillance (IHBSS) program. Amplicons were generated from plasma RNA by using primers designed to analyze diverse HIV-1 isolates targeting the reverse transcriptase region and sequenced on a 454 ultra-deep sequencing (UDS) platform to assess DRMs. DRMs were defined by using the Stanford HIV drug resistance database, and we found only 2 from 110 evaluable individuals with major HIV variants (>20% prevalence) that were highly resistant to the non-nucleoside reverse transcriptase inhibitor (NNRTI: efavirenz and nevirapine). However, a larger fraction of individuals harbored minority drug-resistant HIV variants (0.5%-20% prevalence) and they were highly resistant to NNRTI nevirapine (89/110), rilpivirine (5/110), and efavirenz (49/110). This study is the first report on the presence of HIV drug resistance in the Philippines and demonstrates the utility of UDS in assisting the detection of HIV minor variants. Monitoring for ART-DRMs will assist in improving HIV management strategies in curtailing the evolving epidemic in the Philippines. PMID- 28569552 TI - Cardiac troponins: Potential biomarkers for the detection of subclinical coronary artery disease in athletes participating in endurance sports. PMID- 28569554 TI - Non-steroidal anti-inflammatory drug related upper gastrointestinal bleeding: types of drug use and patient profiles in real clinical practice. AB - BACKGROUND: The best available evidence regarding non-steroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) bleeding comes from randomized controlled trials including patients who use NSAIDs to manage chronic rheumatic diseases; however, patients with varying background profiles commonly take NSAIDs for many other reasons, often without prescription, and such usage has not been well studied. OBJECTIVES AND METHODS: To define the characteristics of patients hospitalized for upper GI bleeding in clinical practice, we conducted a case control study among patients with endoscopy-proven major upper GI bleeding due to gastroduodenal peptic lesions and control subjects. We used adjusted logistic regression models to estimate bleeding risks. Data analysis was performed using SPSS 22.0. RESULTS: Our analysis included 3785 cases and 6540 controls, including 1270 cases (33.55%) and 834 controls (12.75%) reporting recent use (<30 days) of NSAIDs including high-dose acetylsalicylic acid (ASA). NSAID use was associated with increased risk of upper GI bleeding, with an adjusted relative risk of 4.86 (95% CI, 4.32-5.46). Acute musculoskeletal pain (36.1%), chronic osteoarthritis (13.5%), and headache (13.6%) were the most common reasons for NSAID use. Among cases, only 17.31% took NSAIDs and 6.38% took high dose ASA due to chronic osteoarthritis. Demographic characteristics significantly differed between subjects with chronic vs. acute musculoskeletal pain. Proton pump inhibitor use was significantly higher in patients who used NSAIDs due to chronic osteoarthritis compared to patients with acute musculoskeletal pain. NSAID (65.15%) or high-dose ASA use (65.83%) preceding upper GI bleeding was most often short-term. In over half of cases (63.62%), the upper GI bleeding event was not preceded by dyspeptic warning symptoms. CONCLUSIONS: The majority of patients hospitalized due to NSAID-related upper GI bleeding reported short-term NSAID use for reasons other than chronic rheumatic disease. These findings suggest that current prevention strategies may not reach a wide population of short-term NSAID users. PMID- 28569553 TI - Effects of combined exercise training and electromyostimulation treatments in chronic heart failure: A prospective multicentre study. AB - Background Exercise training as part of a comprehensive cardiac rehabilitation is recommended for patients with cardiac heart failure. It is a valuable method for the improvement of exercise tolerance. Some studies reported a similar improvement with quadricipital electrical myostimulation, but the effect of combined exercise training and electrical myostimulation in cardiac heart failure has not been yet evaluated in a large prospective multicentre study. Purpose The aim of this study was to determine whether the addition of low frequency electrical myostimulation to exercise training may improve exercise capacity and/or muscular strength in cardiac heart failure patients. Methods Ninety-one patients were included (mean age: 58 +/- 9 years; New York Heart Association II/III: 52/48%, left ventricular ejection fraction: 30 +/- 7%) in a prospective French study. The patients were randomised into two groups: 41 patients in exercise training and 50 in exercise training + electrical myostimulation. All patients underwent 20 exercise training sessions. In addition, in the exercise training + electrical myostimulation group, patients underwent 20 low frequency (10 Hz) quadricipital electrical myostimulation sessions. Each patient underwent a cardiopulmonary exercise test, a six-minute walk test, a muscular function evaluation and a quality of life questionnaire, before and at the end of the study. Results A significant improvement of exercise capacity (Delta peak oxygen uptake+15% in exercise training group and +14% in exercise training + electrical myostimulation group) and of quality of life was observed in both groups without statistically significant differences between the two groups. Mean creatine kinase level increased in the exercise training group whereas it remained stable in the combined group. Conclusions This prospective multicentre study shows that electrical myostimulation on top of exercise training does not demonstrate any significant additional improvement in exercise capacity in cardiac heart failure patients. PMID- 28569555 TI - Sleep and Mechanical Ventilation in Stable COPD Patients. AB - Respiratory work is physiologically increased during sleep and leads to severe alterations in COPD patients, especially by raising sleep hypoventilation. The diurnal impact of these nocturnal events may have been underestimated in COPD patients. Impaired sleep and the increase of respiratory work may be one of the major trigger of diurnal events like hypoventilation, exacerbation and even mortality. One of the most commonly used nocturnal treatments at the present time is noninvasive ventilation (NIV). However, there is an on-going debate concerning the indications and objectives of NIV in COPD patients. In most studies, NIV initiation and monitoring depend on diurnal tools like PaCO2, and the nocturnal efficacy of this treatment has not yet been adequately determined. In other respiratory diseases, sleep events have a predominant role in NIV therapy. Such nocturnal events drive NIV initiation and setting adaptation. Monitoring of sleep events is associated with an increase in health related to quality of life and a decrease in mortality. The monitoring may be the solution to solve the debate of NIV in COPD patients. This article reviews the impact of sleep in COPD patients and the value of long-term NIV. PMID- 28569556 TI - Guarana, a Highly Caffeinated Food, Presents in vitro Antitumor Activity in Colorectal and Breast Cancer Cell Lines by Inhibiting AKT/mTOR/S6K and MAPKs Pathways. AB - The mammalian target of rapamycin (mTOR) and mitogen-activated protein kinases (MAPKs) pathways are frequently upregulated in cancer. Some authors have reported that some antioxidant molecules could be potential inhibitors of these pathways. Therefore, we investigated the in vitro antitumor effect of guarana by inhibiting the AKT/mTOR/S6K and MAPKs pathways. Colorectal and breast cancer cell lineages, HT-29 and MCF-7 cells, respectively, were exposed to different guarana concentrations (0.1, 1, 10, and 100 ug/mL) as well as its main bioactive molecule, caffeine, in proportional concentrations to those found in the extract. Western blot, clonogenic assay, and growth curve were performed. Moreover, we investigated the potential cytotoxic effect of guarana in normal cells. The results revealed that guarana and caffeine inhibited some MAPKs proteins (p-p38 and p-HSP27) in MCF-7 cells. However, they did not affect this pathway in HT-29 cells. Furthermore, guarana inhibited mTORC1 (p-S6K) and mTORC2 (p-AKT) in MCF-7 cells, but only mTORC1 in HT-29 cells. Caffeine only inhibited the mTOR pathway in MCF-7 cells. Guarana decreased the colony formation and cell growth in MCF-7 and HT-29 cells. Guarana did not affect normal cells. In conclusion, guarana could be an important agent in antitumor pharmacologic therapies by inhibiting the mTOR and MAPKs pathways. PMID- 28569557 TI - Effects of acute blood pressure elevation on biochemical-metabolic parameters in individuals with hypertensive crisis. AB - Hypertensive crisis is a common clinical situation that presents a high rate of morbidity and mortality and it is characterized by symptomatic rise of blood pressure (BP), systolic (SBP) >= 180 mmHg and/or diastolic (DBP) >= 120 mmHg. It is classified as emergency (HE) or hypertensive urgency (HU). There is no description of laboratory findings in patients who present acute BP elevation. Thus, this study had the objective to assess the biochemical-metabolic parameters of patients with HC. We studied 74 normotensive individuals (NT), 74 controlled hypertensive patients (ContrHT), 50 subjects with HU, and 78 with HE for evaluating biochemical-metabolic parameters. HE occurs in older individuals and more frequently in those with known hypertension. More patients with HE had dyslipidemia than those with HU (58% vs. 38%). The diastolic BP and heart rate were higher in the HE group (120 mmHg and 87 bpm) compared to ContrHT (71 mmHg and 71 bpm; p < 0.0001) and NT groups (75 mmHg and 68 bpm; p < 0.0001). Glycemia was higher in HE vs. NT and ContrHT (p < 0.05). HDL cholesterol was lower in HE than NT (p = 0.0088). Potassium was lower in HE vs. NT, ContrHT and HU groups (p < 0.05). Creatinine was higher in the HC group vs. NT and ContrHT (p < 0.05). The GFR was significantly lower in HE group vs. HU, ContrHT and NT (p < 0.001). In conclusion, individuals with HC show biochemical alterations when compared to ContrHT and NT. Acute BP elevations are associated with hyperglycemia, dyslipidemia, and higher potassium and creatinine levels and lower renal function. Abbreviations BMI = body mass index BP = blood pressure CH = hypertensive crisis ContrHT = controlled hypertensive DBP = diastolic blood pressure GFR = glomerular filtration rate HbA1c = glycated hemoglobin HDLc = high density lipoprotein cholesterol HE = hypertensive emergency HPLC = high performance liquid chromatography HR = heart rate HU = hypertensive urgency JNC 7 = VII Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure LDLc = low-density lipoprotein cholesterol MDRD = Modification of Diet in Renal Disease NT = normotensive RASB = renin-angiotensin system blockers SBP = systolic blood pressure TC = total cholesterol TG = triglycerides. PMID- 28569560 TI - E- Only Section. PMID- 28569558 TI - Persistent Left Superior Vena Cava in Fetuses: An Autopsy Series. AB - OBJECTIVE: To review fetal autopsy reports with persistent left superior vena cava (PLSVC) and identify its associations. MATERIALS AND METHODS: Autopsy reports of all fetuses diagnosed with PLSVC in our center from January 2011 to December 2015 were reviewed. Fetuses less than 15 weeks gestational age along with autolyzed and damaged hearts were excluded from the study. The study group was compared with controls during this period. RESULTS: Prenatal ultrasound detection rate of PLSVC was 13.06%. All the cases had associated anomalies of which 96% had extra cardiac anomalies and 67% had intrinsic cardiac defects among which septal defects were most common (39.6%). Anomalies of cardiovascular, respiratory, genitourinary and musculoskeletal, hypoplastic thymus and single umbilical artery were significantly higher in the study group. CONCLUSION: This study emphasizes on the importance of improving the technical skill for imaging the three-vessel view as PLSVC seems to have significant associations. PMID- 28569561 TI - Vitamin B6 Intake and the Risk of Colorectal Cancer: A Meta-Analysis of Prospective Cohort Studies. AB - OBJECTIVES: We performed this meta-analysis to estimate the association between vitamin B6 intake and colorectal cancer risk. METHODS: Prospective cohort studies on vitamin B6 intake and colorectal cancer risk were identified by searching databases from the period of 1960 to 2016. Results from individual studies were synthetically combined using Stata 13.0 software. RESULTS: A total of 10 prospective cohort studies including 13 data sets were included in our meta analysis, containing 7,817 cases and 784,550 subjects. The combined relative risks (RR) of colorectal cancer for the highest vitamin B6 intake compared with the lowest vitamin B6 intake was 0.88 [95% confidence intervals (CIs): 0.77 1.02]. Dose-response meta-analysis based on five eligible studies showed that for each additional 3 and 5 mg of vitamin B6 intake, the risk would decrease by 11% (RR: 0.89, 95%CI: 0.81-0.98) and 17% (RR: 0.83, 95%CI: 0.71-0.97), respectively. Little evidence of publication bias was found. CONCLUSION: This meta-analysis provides evidence of a nonsignificant decrease in colorectal cancer risk associated with the high level of vitamin B6 intake, but the risk in dose response analysis is significant. However, the latter finding is based on a limited number of studies, which should be interpreted with caution. PMID- 28569562 TI - Low-grade bronchial mucoepidermoid carcinoma during pregnancy successfully treated by lobectomy. PMID- 28569563 TI - Impact of Early Enteral Nutrition on Nutritional and Immunological Outcomes of Gastric Cancer Patients Undergoing Gastrostomy: A Systematic Review and Meta Analysis. AB - OBJECTIVES: The present systematic review and meta-analysis study evaluated the impact of early enteral nutrition (EN) on postoperative nutritional and immunological outcomes of gastric cancer (GC) patients. METHOD: The databases of PubMed, Embase, Springer, and Cochrane library were searched till September 2016 to identify studies which evaluated the effects of EN compared with parenteral nutrition (PN) on postoperative immunological and nutritional status and hospitalization time in GC patients. Mean difference (MD) or standard mean difference (SMD) was calculated and I-square statistic test was used for heterogeneity analysis. RESULTS: The present systematic review and meta-analysis have consisted of seven trials, containing 835 GC patients. According to the result of meta-analysis, compared with PN, EN significantly resulted in more increase in the level of albumin [MD = 2.07 (0.49, 3.64)], prealbumin [MD = 9.41 (049, 33.55)], weight [MD = 1.52 (0.32, 2.72)], CD3+ [SMD = 1.96 (1.50, 2.43)], CD4+ [SMD = 2.45 (1.97, 2.93)], natural killers [MD = 5.80 (3.75, 7.85)], and also a decrease in the hospitalization time [MD=-2.39 (-2.74, -2.03)]. CONCLUSION: The results demonstrated that early administration of EN is more effective in improving postsurgical nutrition status and immune index in GC patients. So, based on these results, postoperative early administration of EN is recommended for GC patients where possible. PMID- 28569564 TI - Inhibition of the alpha-carbonic anhydrase from Vibrio cholerae with amides and sulfonamides incorporating imidazole moieties. AB - We discovered novel and selective sulfonamides/amides acting as inhibitors of the alpha-carbonic anhydrase (CA, EC 4.2.1.1) from the pathogenic bacterium Vibrio cholerae (VchCA). This Gram-negative bacterium is the causative agent of cholera and colonises the upper small intestine where sodium bicarbonate is present at a high concentration. The secondary sulfonamides and amides investigated here were potent, low nanomolar VchCA inhibitors whereas their inhibition of the human cytosolic isoforms CA I and II was in the micromolar range or higher. The molecules represent an interesting lead for antibacterial agents with a possibly new mechanism of action, although their CA inhibition mechanism is unknown for the moment. PMID- 28569565 TI - Prediction of preeclampsia in primigravida in late first trimester using serum placental growth factor alone and by combination model. AB - We investigated a placental growth factor alone and combined clinical (mean arterial pressure, MAP), biophysical (uterine artery pulsability index, PI) and biochemical (placental growth factor, PLGF) model for predicting preeclampsia in late first trimester. The inclusion criteria was primigravida (<40 years) attending their first hospital visit with singleton pregnancy at 11-14 weeks of gestation. Of the enrolled and followed 291 subjects, 35 (12%) later developed PE (5.8%)/GH (6.2%). An equal number of randomised women with normotensive non proteinuric course were considered as reference group. For preeclampsia, PLGF alone had detection rate of 40% and 51% with 5% and 10% FPR, respectively. On addition of MAP, the AUC improved to 0.937 for PE. Further, addition of mean PI slightly improved AUC to 0.965. This signifies that a model with all three markers had better prediction of preeclampsia rather than PLGF alone. Impact statement In view of high morbidity and mortality due to hypertensive disorders in pregnancy, there has been extensive research for developing markers to detect/screen the condition in early pregnancy. Several such markers have been tested in their individual capacities and in combination during early pregnancy. Most of these studies have originated from high income countries and focussed mainly on the second trimester of pregnancy. We investigated a placental growth factor alone and combined clinical (mean arterial pressure, MAP), biophysical (uterine artery pulsability index, PI) and biochemical (placental growth factor, PLGF) model for predicting preeclampsia in the first trimester in primigravida (<40 years). A nested case control model was used for our study. For preeclampsia, PLGF alone had detection rate of 40% and 51% with 5% and 10% FPR, respectively. On addition of MAP, the AUC improved to 0.937 for PE. Further, addition of mean PI slightly improved AUC to 0.965. The present study has been done in an Indian subcontinent setting (where maternal mortality related to preeclampsia are even higher) where very limited studies are available for the role of either PLGF or in combinations for prediction of preeclampsia. Our research pointed shows better predictability for PE when a combination of markers is used especially in low-risk nulligravida. These are easy, cheap and non invasive measurements that can be taken in all women at their first routine antenatal visit. PMID- 28569566 TI - Ocular biometry and determinants of refractive error in a founder population of European ancestry. AB - BACKGROUND: The prevalence of myopia is increasing worldwide. Previous studies have found a positive association between myopia, education, and near activities, while others have noted a negative association with outdoor exposure. This study reports refractive error and biometry in a founder population of European ancestry, the Hutterites, and discusses risk factors contributing to myopia. METHODS: Cross-sectional study, including complete eye exams with retinoscopy and biometry. RESULTS: 939 study participants, ages 6 to 89, were examined. Females were significantly more myopic than males (SE -0.87 +/- 2.07 and -0.40 +/- 1.49 in females and males, respectively, p < 0.0001). Males had significantly longer axial lengths. Females had steeper corneas. This is the first epidemiological report of refractive error among the Hutterites. DISCUSSION: As a genetically isolated population with a communal lifestyle, the Hutterites present a unique opportunity to study risk factors for myopia. Hutterite females are more myopic than males, a finding which has only been reported in a few other populations. Hutterite children complete compulsory education through the 8th grade, after which women and men assume gender-specific occupational tasks. Men often work outside on the farm, while women engage in more domestic activities inside. These occupational differences likely contribute to the increased myopia comparing females to males, and their uniform lifestyle reduces the impact of potential confounding factors, such as education and income. CONCLUSIONS: The Hutterites are more myopic than most other North American and European populations. Greater time spent doing near work and less time spent outdoors likely explain the increased myopia comparing females to males. PMID- 28569567 TI - Nomograms of the whole foetal adrenal gland and foetal zone at gestational age of 16-24 weeks. AB - The aim of this study was to create nomograms of the whole foetal adrenal gland and the foetal zone at 16-24 weeks of gestation in the Thai population, as well as to evaluate the relationships between the gestational age and the whole foetal adrenal gland and the foetal zone. Transabdominal measurement of the whole foetal adrenal gland and adrenal foetal zone were added to the routine biometric measurements at 16-24 weeks of gestation of singleton low-risk pregnancies. A total of 189 measurements were used for analysis. A linear correlation was observed between gestational age and the length, width and depth of the whole foetal adrenal gland at 16-24 weeks of gestation. A linear correlation was also found between gestational age and the length, width and depth of the foetal zone at 16-24 weeks of gestation. This study shows the linear growth of the foetal adrenal gland and foetal zone from 16-24 weeks of gestation. These reference values may be helpful in detecting abnormal growth of foetal adrenal gland or any abnormalities of the foetal adrenal gland. Impact Statement What is already known on this subject: Foetal adrenal glands play a pivotal role, mainly through steroidogenesis, in the regulation of the intrauterine homeostasis, and in foetal development and maturation. There is evidence to support that the foetus may be in control of the timing of its own birth by activating its hypothalamic pituitary-adrenal axis to increase the production of dehydroepiandrosterone sulphate to predominately induce the enlargement of the central foetal zone. What the results of this study add: This study shows the nomograms of the foetal adrenal gland and foetal zone from 16-24 weeks of gestation and the linear growth of the foetal adrenal gland and foetal zone from 16-24 weeks of gestation. What are the implications of these findings for clinical practice and/or further research:These reference values may be helpful in detecting abnormal growth of foetal adrenal gland or any abnormalities of the foetal adrenal gland. PMID- 28569568 TI - Performance of the classification criteria in patients with late-onset axial spondyloarthritis. AB - AIM: To evaluate the performance of four different classification criteria for spondyloarthritis (SpA) in patients with late-onset symptoms and to compare the clinical, laboratory and radiographic outcomes among the patients with symptoms before and after 45 years of age. PATIENTS AND METHODS: A total of 329 patients with SpA were enrolled in this prospective cohort. Patients with psoriatic arthritis, reactive arthritis, colitis associated arthritis and peripheral or undifferentiated SpA were excluded. The remaining individuals were divided into two groups based on their ages at the time of onset of symptoms: from 16 to 45 years of age (adult-onset, A-O) and after 45 years of age (late-onset, L-O). The clinical data were collected, including BASDAI, BASFI, BASMI, mSASSS, ASDAS, as were concomitant diseases and medications, efficacy and safety data. The performance of four SpA classification criteria, including modified New York, ESSG, Amor and ASAS, was evaluated in both groups. p value <.05 was considered as significant. RESULTS: Thirty-two patients (9.72%) had L-O axial SpA. Mean age of diagnosis and symptoms were 57.6 (8.0) years and 7.6 (5.1) years, respectively. L O patients had statistically worse functional impairment and higher disease activity. However, they had lower radiographic sacroiliac and spine damage (p < .001). CONCLUSION: Our data showed that almost 10% of the patients with SpA had late-onset of symptoms. Moreover, they had higher disease activity, worse physical function and lower spine radiographic damage than A-O SpA patients. Additionally, the ASAS classification criteria had the best performance and might be used in clinical practice. PMID- 28569569 TI - Nonsteroidal anti-inflammatory drugs and cardiovascular safety - translating pharmacological data into clinical readouts. AB - INTRODUCTION: The pharmacological management of pain includes the use of nonsteroidal anti-inflammatory drugs(NSAIDs). They comprise traditional(t) NSAIDs and selective cyclooxygenase(COX)-2 inhibitors (named coxibs). The analgesic and anti-inflammatory effects of NSAIDs are dependent on the extent and duration of COX-2 inhibition in the spinal cord and inflammatory sites. However, the simultaneous inhibition of COX-2 in the vasculature translates into a prothrombotic phenotype and promotes hypertension and heart failure. Areas covered: The results of the clinical pharmacology of coxibs and the most used tNSAIDs provide a mechanistic interpretation of the cardiovascular(CV) outcomes found in randomized clinical trials(RCTs), meta-analyses of RCTs and epidemiological studies. A critical analysis of the design and results of the PRECISION trial, which compared the CV risk of celecoxib, ibuprofen, and naproxen in high-risk CV patients, was performed. Expert opinion: tNSAIDs and coxibs may increase the chance of a heart attack or stroke. The reduction of the dose of NSAIDs may mitigate, but not avoid, the risk of CV adverse effects. The development of novel biomarkers which identify susceptibility phenotypes associated with increased risk of CV complications by COX-2 inhibition is an unmet clinical need that once filled will lead to personalized treatments with NSAIDs. PMID- 28569570 TI - Efficacy of peeling during different periods of the menstrual cycle on acne. AB - BACKGROUND AND DESIGN: The aim of this study was to investigate the efficacy of 50% glycolic acid peeling performed at different phases of menstruation on acne. MATERIALS AND METHODS: This study included 30 patients with mild-to-moderate acne. Those with regular menstrual cycles and no history or laboratory evidence of hormonal pathology, hirsutism were selected. Thirty patients were divided in three groups. The first group received peeling applications in the first 7 days of menstruation; the second group received the peel between 10 and 14 days; and the third group received the peel during the last 10 days of menstruation. RESULTS: The 30 female patients included in study. All patients' menstrual cycles were regular. All groups were homogenous in terms of initial acne severity scores. Acne severity scores decreased in all groups after 3 months of therapy; statistically significant differences were achieved only in the second group. DISCUSSION: The results of our study suggest that chemical peeling administered during ovulation provides the most significant benefit for acne lesions. Ovulation is the period when estrogen reaches its highest level. Estrogen decreases sebum production through different mechanisms. The beneficial effects of estrogen on acne and healing in combination with those of chemical peeling may cause synergistic therapeutic effects with pronounced results. PMID- 28569572 TI - Erratum: New Guidelines for the Treatment of Drug-Susceptible Tuberculosis from the American Thoracic Society, Centers for Disease Control and Prevention, and the Infectious Diseases Society of America: Now Comes the Hard Part. PMID- 28569571 TI - Curcumin inhibits oxidative stress-induced TRPM2 channel activation, calcium ion entry and apoptosis values in SH-SY5Y neuroblastoma cells: Involvement of transfection procedure. AB - Transient Receptor Potential (TRP) channels are mostly Ca2+ permeable cation channels. Transient Receptor Potential Melastatin-like 2 (TRPM2) is expressed in neurological tissues such as brain, dorsal root ganglia (DRG) neurons, hippocampus and also liver, heart and kidney. The SH-SY5Y cells are mostly used as a cellular model of neurodegenerative diseases, Alzheimer's and Parkinson's diseases. Curcumin, shows phenolic structure, synthesized by Curcuma longa L. (turmeric), has powerful non-enzymatically antioxidant effects compared with Vitamin E. Hence, we aimed to investigate that effects of curcumin on TRPM2 cation channel currents using the whole-cell Patch-Clamp method, Ca2+ signaling, apoptosis and cell viability (MTT) assays, reactive oxygen species (ROS) production, mitochondrial membrane potential levels, caspase 3 and caspase 9 activities in TRPM2 transfected SH-SY5Y neuroblastoma cells. For this aim, we designed four experimental groups named; control, curcumin, transfected and transfected + curcumin groups. Cytosolic free calcium concentrations were higher in transfected group compared with curcumin and transfected + curcumin group. Moreover, these data examined with whole-cell Patch-Clamp recordings of single cells in all groups. ROS levels were significantly higher in transfected group than in transfected + curcumin group. Apoptosis levels in transfected + curcumin group were lower than in transfected group. Procaspase 9 and procaspase 3 levels measured by western blotting and caspase 3 and caspase 9 levels by spectrophotometric methods show that TRPM2 transfected cells are more tended to apoptosis. In conclusion, curcumin strongly induces modulator effects on TRPM2 mediated Ca2+ influx caused by ROS and caspase 3 and 9 processes in SH-SY5Y neuroblastoma cells. PMID- 28569573 TI - Using Network Analysis to Understand Severe Asthma Phenotypes. PMID- 28569574 TI - Reply: The Genetic Diagnosis of Interstitial Lung Disease: A Need for an International Consensus. PMID- 28569576 TI - EnRAGEed Kidneys in Chronic Obstructive Pulmonary Disease? PMID- 28569575 TI - Airway Hyperresponsiveness Does Not Predict Morbidity in Children with Sickle Cell Anemia. PMID- 28569577 TI - Fletcher and Peto 40 Years On. A Tribute and Reflection. PMID- 28569578 TI - Integrative Medicine (Complementary and Alternative Medicine) for the Lungs. PMID- 28569579 TI - Hypotrophy versus Hypertrophy: It's Not Black or White with Gray Matter. PMID- 28569580 TI - Stress Testing the Respiratory System: Too Little or Too Much? PMID- 28569581 TI - Investigating the Pathogen Genomic Determinants of Tuberculosis Transmission. PMID- 28569583 TI - Lung Function Abnormalities in Smokers with Ischemic Heart Disease. PMID- 28569582 TI - Metagenomic Analysis Identified Human Rhinovirus B91 Infection in an Adult Suffering from Severe Pneumonia. PMID- 28569584 TI - Reply: Lung Function Abnormalities in Smokers with Ischemic Heart Disease. PMID- 28569585 TI - Continuity of Care for Complex Medical Patients: How Far Do We Go? PMID- 28569586 TI - Erratum: An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome. PMID- 28569587 TI - The Genetic Diagnosis of Interstitial Lung Disease: A Need for an International Consensus. PMID- 28569588 TI - Increasing relevance of sunfleck research. AB - Contemporary reviews of leaf responses to sunflecks indicate gymnosperms exhibit slower photosynthetic inductions times than angiosperms, but the gymnosperms were represented exclusively by conifers. I recently reported that the gymnosperm Cycas micronesica exhibited photosynthetic induction times in conformity with some of the most rapid angiosperms and opined that representatives from non conifer gymnosperms must be added to the published conifer database before gymnosperm-wide conclusions can be formulated. Guiding principles for this urgently needed research will maximize relevance and improve accuracy of conclusions. PMID- 28569589 TI - Cytokine signal suppressor (SOCS) 1-1478 CA/del gene polymorphism in Turkish patients with polycystic ovary syndrome. AB - Eighty-four subjects, premenopausal female patients (n = 42, mean (SD) age: 26.4 (4.2) years) diagnosed with polycystic ovary syndrome (PCOS) and age-matched healthy volunteers (n = 42, mean (SD) age: 27.6(3.4) years), were included in this study. Data on physical examination, anthropometric measurements and blood biochemistry analysis were recorded for each subject along with analysis for SOCS1-1478 CA/del polymorphism by polymerase chain reaction-restriction fragment length polymorphism. The relation of SOCS1-1478 CA/del polymorphism to PCOS status and insulin resistance was analysed via logistic regression analysis. Mean (SD) levels for BMI (28.5(6.5) vs.22.5 (4.9) kg/m2, p < .001), HOMA-IR (3.1(1.8) vs.1.5 (1.0), p < .001), LDL-cholesterol (115.9(32.7) vs.100.7 (27.3)mg/dL, p = .03) and triglyceride (113.8(64.9) vs.83.3(36.3)mg/dL, p = .017) were significantly higher in patients. Groups were similar in terms of SOCS1-1478 CA/del polymorphism. No significant relation of this polymorphism was noted to PCOS and HOMA-IR. Our findings revealed no difference between groups in terms of the rate of SOCS1-1478 CA/del polymorphism, and no significant relation of this polymorphism to insulin resistance and PCOS status. Impact statement Polycystic ovary syndrome (PCOS), the most common cause of anovulation and the most commonly encountered form of female endocrine disease. SOCS proteins have been suggested to play a fundamental role in the negative feedback regulation of the JAK-STAT pathway, which is the major signalling pathway involved in a wide range of physiologic and pathologic processes, including inflammatory diseases, malignancies and immune disorders. Pathways involving the induction of suppression of SOCS proteins were also shown likely to be involved in mediating cytokine-induced insulin resistance. The present study was designed to determine the frequency of SOCS1-1478 CA/del gene polymorphism in patients with PCOS in relation to healthy controls and insulin resistance. Our findings revealed significantly higher rates of insulin resistance, obesity and dyslipidaemia in Turkish patients with PCOS compared with age-matched healthy controls, while no difference between study groups in terms of the rate of SOCS1-1478 CA/del polymorphism along with no significant relation of SOCS1-1478 CA/del polymorphism to insulin resistance and PCOS status. Future larger scale studies with the application of standardised diagnostic methods and criteria, and of state-of-the art modern techniques including genomics, proteomics and pharmacogenetics would provide better understanding of the association between PCOS and genomic variants. PMID- 28569590 TI - Pharmacokinetic comparison of two buprenorphine formulations after buccal administration in healthy male cats. AB - Objectives The objective of this study was to compare the pharmacokinetics of compounded and commercially available aqueous formulations of buprenorphine after a single buccal dose to healthy cats and to evaluate the concentrations of a compounded buprenorphine solution over 21 days when stored at room temperature (RT; 22-24 degrees C) with exposure to light or when refrigerated at 4 degrees C while protected from light. Methods Six young healthy male cats were administered single buccal doses of compounded and commercially available formulations of buprenorphine (0.03 mg/kg) using a randomized, blinded, two-period crossover design. Blood samples were obtained over a 24 h period and plasma buprenorphine concentrations were determined using ultra-high-pressure liquid chromatography with mass spectrometry detection. Three batches of the compounded formulation were stored at RT or 4 degrees C and aliquots were evaluated over 21 days for buprenorphine concentration using high-performance liquid chromatography with fluorescence detection. Results Plasma concentrations of buprenorphine were above the limit of quantification up to 6 h in some cats and up to 3 h in all cats. The area under the curve was significantly less for the compounded formulation ( P = 0.004). A significant difference was not detected between formulations for time to maximum concentration ( P = 0.11), maximum concentration ( P = 0.06), half life ( P = 0.88) and mean residence time ( P = 0.57). Buprenorphine concentration in the compounded formulation was not affected by storage condition or time and remained between 90% and 110% of the target concentration at all time points. Conclusions and relevance A buprenorphine solution prepared from sublingual tablets is absorbed after buccal administration in healthy cats. The extent of absorption is significantly less than that of the commercially available formulation. The compounded solution maintains an acceptable buprenorphine concentration for at least 21 days when stored at RT or refrigerated. PMID- 28569593 TI - FAM13A, A Fatty Acid Oxidation Switch in Mitochondria. Friend or Foe in Chronic Obstructive Pulmonary Disease Pathogenesis? PMID- 28569591 TI - Influence of the loop size and nucleotide composition on AgoshRNA biogenesis and activity. AB - Short hairpin RNAs (shRNAs) are widely used for gene silencing by the RNA interference (RNAi) mechanism. The shRNA precursor is processed by the Dicer enzyme into active small interfering RNAs (siRNAs) that subsequently target a complementary mRNA for cleavage by the Argonaute 2 (Ago2) complex. Recent evidence indicates that shRNAs with a relatively short basepaired stem bypass Dicer and are instead processed by Ago2. We termed these molecules AgoshRNAs as both processing and silencing steps are mediated by Ago2 and proposed rules for the design of effective AgoshRNA molecules. Active and non-cytotoxic AgoshRNAs against HIV-1 RNA were generated, but their silencing activity was generally reduced compared with the matching shRNAs. Thus, further optimization of the AgoshRNA design is needed. In this study, we evaluated the importance of the single-stranded loop, in particular its size and nucleotide sequence, in AgoshRNA mediated silencing. We document that the pyrimidine/purine content is important for AgoshRNA-mediated silencing activity. PMID- 28569594 TI - A New Step in the Marathon of Understanding Chronic Rejection after Lung Transplantation. PMID- 28569595 TI - Roles for Myoepithelial Cells in the Formation and Maintenance of Submucosal Glands. PMID- 28569596 TI - Vitamin D in Host Defense: Implications for Future Research. PMID- 28569598 TI - Associations Between Nutritional Parameters and Clinicopathologic Factors in Patients with Gastric Cancer: A Comprehensive Study. AB - The aim of this study was to assess and analyze the nutritional status of gastric cancer (GC) patients. The analysis included 207 patients with GC treated in a large center of oncology. Patients were divided into two groups according to the cutoff value of the mean prognostic nutritional index (PNI): those with a PNI < 52.78 and those with a PNI >= 52.78. The higher PNI was associated with lower age and higher total protein and hemoglobin levels (P < 0.01). The total lymphocyte count (P = 0.02), albumin, total protein and PNI (P < 0.01) were significantly higher in stable-weight patients and lower in the group with weight loss > 10% (P = 0.000031). Body mass index (BMI) after disease recognition, albumin and total protein (0.003) levels, total lymphocyte count, and PNI were significantly lower in patients with nutritional risk. Significantly lower BMI before disease and BMI after disease recognition were noted in smoking patients. Significantly higher total lymphocyte count was observed in smoking patients (P < 0.01). Significantly lower PNI was noted in tumors with lymph node metastasis (N+). G3 tumors were associated with the lowest total lymphocyte count (P = 0.01). Assessment of nutritional status using PNI calculation should be the standard management of patients with GC before treatment. PMID- 28569597 TI - Endothelial Glycocalyx Repair: Building a Wall to Protect the Lung during Sepsis. PMID- 28569599 TI - The Tridimensional Structure of Sociosexuality: Spanish Validation of the Revised Sociosexual Orientation Inventory. AB - Casual sex has become a common experience for many university students. Therefore, it is necessary to have instruments and studies that analyze youth's orientation toward sociosexuality. The SOI-R assesses sociosexual behavior, attitudes toward sociosexuality, and the desire for relationships without commitment with just nine items. The goal of this study was to validate the Spanish version of the SOI-R, to improve the scale, and to contribute evidence of the utility of the Sociosexual Desire subscale. Participants were 839 heterosexual university students of both sexes, aged between 18 and 26, who completed a battery of online questionnaires. The internal structure of the SOI-R revealed the three proposed theoretical dimensions, with medium to low relationships between factors. The instrument has measurement invariance with regards to sex and age. The Spanish version of the SOI-R had adequate levels of reliability. The modification of the first item of the scale is suggested, as well as the relevance of assessing sociosexual desire as an independent construct. The relation between sociosexuality and other sociodemographic and psychosocial variables was also analyzed. The discussion highlights the need for research to determine youth's sociosexual orientation and patterns of casual sex. PMID- 28569600 TI - The associations among co-morbidity, cardiac geometries and mechanics in hospitalized heart failure with or without preserved ejection fraction. AB - BACKGROUND: The associations among chronic health conditions, ventricular geometric alterations or cardiac contractile mechanics in different phenotypes heart failure (HF) remain largely unexplored. METHODS: We studied 438 consecutive hospitalized patients (mean age: 64.9 +/- 16.6 years, 52.5% female) with or without clinical evidence of HF. We examined the associations among clinical co morbidities, LV geometries and systolic mechanics in terms of global myocardial strains. RESULTS: Increasing clinical co-morbidities was associated with greater LV mass, worse longitudinal deformations and higher proportion of admission with HF diagnosis, which was more pronounced in HFpEF (from 6.4% to 40.7%, X2 < 0.001). The independent association between co-morbidity burden and longitudinal functional decay remained unchanged after adjusting for age and sex for all admissions and in HFpEF (Coef: 0.82 & 0.71, SE: 0.13 & 0.21, both p<=0.001). By using co-morbidity scores, the area under receiver operating characteristic curves (AUROC) in identifying HFpEF was 0.71 (95% CI: 0.65 to 0.77), 0.64 (95% CI: 0.58 to 0.71) for HFrEF and 0.72 for both (95% CI: 0.67 to 0.77). Co morbidity burden superimposed on LV mass index and LV filling pressure (E/E') further expanded the AUROC significantly in diagnosing both types HF (c statistics from 0.73 to 0.81, p for DeltaAUROC: 0.0012). CONCLUSION: Chronic health conditions in the admission population were associated with unfavorable cardiac remodeling, impair cardiac contractile mechanics and further added significantly incremental value in HF diagnosis. Our data suggested the potentiality for better cardiac function by controlling baseline co-morbidities in hospitalized HF patients, especially HFpEF. ABBREVIATIONS: CAD: coronary artery disease; CKD: chronic kidney disease; DT: deceleration time; eGFR: Estimated glomerular filtration rate; HF: heart failure; IVRT: iso-volumic relaxation time; LV: left ventricular; LVEF: left ventricular ejection fraction; RWT: relative wall thickness; TDI: Tissue Doppler imaging. PMID- 28569601 TI - Prevalence of Fatigue and Associated Factors in a Spinal Cord Injury Population: Data from an Internet-Based and Face-to-Face Surveys. AB - Fatigue has a profound impact on patients with spinal cord injury (SCI), but only limited treatments are available. The aim of this study was to determine the prevalence of fatigue in SCI and its association with clinical and demographic factors. We used an internet-based survey and a face-to-face interview to estimate the prevalence of fatigue in a SCI population. Fatigue was measured using the Fatigue Severity Scale (FSS). Clinically significant fatigue was defined as FSS scores greater than or equal to four. A total of 253 participants with SCI were included in the study. Clinically significant fatigue was present in one third of our sample. There was no relationship between fatigue and injury level or completeness. We found significant correlations between depression, pain, and level of injury. The relation of fatigue with completeness of injury and spasticity is less clear. Moreover, the online survey and the standard face to-face interview showed similar results concerning fatigue evaluation. Several factors may contribute to fatigue, however. Future studies should be conducted to clarify which are the most relevant ones and, if possible, to determine which factors are modifiable. PMID- 28569602 TI - Factors Associated With Risky Alcohol Consumption Among Male Street Laborers in Urban Vietnam. AB - BACKGROUND: Alcohol consumption is of global concern. However, drinking patterns and associated factors remain under-investigated, especially among low socioeconomic groups such as street laborers. OBJECTIVE: Using the social cognitive model as a framework for the study we aimed to identify factors associated with risky alcohol consumption. METHODS: In a cross-sectional study using structured questionnaires, 450 male street laborers searching for casual works in Hanoi, Vietnam were interviewed. A logistic regression was applied in order to detect predictors of risky alcohol drinking. RESULTS: During the last month, 45% of the participants reported daily consumption while the other 55% consumed weekly or less. Among the drinkers (416 out of 450, 92%), 27% were identified as high-risk drinkers who reported more than 14 standard drinks per week, while only 8% were lifetime abstainers. The multivariable logistic regression showed that older age, higher income were positively associated with a higher likelihood of drinking alcohol, while high school level negatively. The environmental predictor was the higher level of peer connection. The association between drinking and risky behavior was found positive with regards to the number of sexual partners. CONCLUSIONS: The study suggests that male street laborers are vulnerable to health risks. Decision makers should note that a significant proportion of this target group exceeds the guidelines for alcohol use and this should be included in future interventions or further research. A multisectoral approach together with an important strategy of education is needed to control alcohol use. PMID- 28569603 TI - Clinical accuracy of point-of-care urine culture in general practice. AB - OBJECTIVE: To assess the clinical accuracy (sensitivity (SEN), specificity (SPE), positive predictive value and negative predictive value) of two point-of-care (POC) urine culture tests for the identification of urinary tract infection (UTI) in general practice. DESIGN: Prospective diagnostic accuracy study comparing two index tests (FlexicultTM SSI-Urinary Kit or ID FlexicultTM) with a reference standard (urine culture performed in the microbiological department). SETTING: General practice in the Copenhagen area patients. Adult female patients consulting their general practitioner with suspected uncomplicated, symptomatic UTI. MAIN OUTCOME MEASURES: (1) Overall accuracy of POC urine culture in general practice. (2) Individual accuracy of each of the two POC tests in this study. (3) Accuracy of POC urine culture in general practice with enterococci excluded, since enterococci are known to multiply in boric acid used for transportation for the reference standard. (4) Accuracy based on expert reading of photographs of POC urine cultures performed in general practice. Standard culture performed in the microbiological department was used as reference standard for all four measures. RESULTS: Twenty general practices recruited 341 patients with suspected uncomplicated UTI. The overall agreement between index test and reference was 0.76 (CI: 0.71-0.80), SEN 0.88 (CI: 0.83-0.92) and SPE 0.55 (CI: 0.46-0.64). The two POC tests produced similar results individually. Overall agreement with enterococci excluded was 0.82 (0.77-0.86) and agreement between expert readings of photographs and reference results was 0.81 (CI: 0.76-0.85). CONCLUSIONS: POC culture used in general practice has high SEN but low SPE. Low SPE could be due to both misinterpretation in general practice and an imperfect reference standard. Registration number: ClinicalTrials.gov NCT02323087. PMID- 28569604 TI - Adaptation and implementation of family-based treatment enhanced with dialectical behavior therapy skills for anorexia nervosa in community-based specialist clinics. AB - Although family-based therapy (FBT) is a well-established treatment for anorexia nervosa, its implementation and effectiveness in clinical settings has been neglected. A group of seven therapists at a community-based eating disorders clinic were trained in skills-enhanced FBT and provided treatment to 11 youth with anorexia nervosa. Family-based skills training, which borrowed heavily from dialectical behavior therapy, was introduced in four additional sessions and then integrated throughout the remainder of FBT. FBT was perceived as appropriate and acceptable by all participants. Therapists reported high treatment fidelity. There was a large improvement in weight and moderate improvement in caregiver reported eating disorder psychopathology but no clinically significant change by youth report. This study provides preliminary data on the implementation and effectiveness of FBT in the community. PMID- 28569605 TI - Dying Is Unexpectedly Positive. AB - In people's imagination, dying seems dreadful; however, these perceptions may not reflect reality. In two studies, we compared the affective experience of people facing imminent death with that of people imagining imminent death. Study 1 revealed that blog posts of near-death patients with cancer and amyotrophic lateral sclerosis were more positive and less negative than the simulated blog posts of nonpatients-and also that the patients' blog posts became more positive as death neared. Study 2 revealed that the last words of death-row inmates were more positive and less negative than the simulated last words of noninmates-and also that these last words were less negative than poetry written by death-row inmates. Together, these results suggest that the experience of dying-even because of terminal illness or execution-may be more pleasant than one imagines. PMID- 28569606 TI - Spatial surrogate for domestic combustion's air emissions: A case study from Silesian Metropolis, Poland. AB - : The aim of this study is improving currently applied methodology for spatial disaggregation, as well as mapping air emission inventories by taking into account the auxiliary spatial data on population density. District heating infrastructure occurring in more populated areas changes distinctly the spatial distribution of estimated air emission; however, it does not change the initial estimate. That means the total, disaggregated value is constant. Considered sources of domestic combustion are located in the central part of the Silesian Metropolis, in the southern part of Poland. A large part of this area is strongly urbanized and supplied with heat (hot water) from the district heating system. Data on population density help to determine the area within which the dwellers use heat energy and hot water supplied by the heating infrastructure, apart from heating with small domestic boilers and stoves. This causes the domestic combustion's emission impact within the distinguished area to be significantly lower in comparison to the official guidelines on air emission inventories. The important differences in spatial air emissions distributions calculated using a top-down approach are found for strongly urbanized areas supplied partly with heat and hot water from the district heating network. This fact should be taken into account when preparing detailed, high-resolution emission inventories for air regional and local quality modeling. IMPLICATIONS: The spatial issues connected with elaboration of the high-resolution emission inventories are presented for the example of the populated area of the Silesian Metropolis (Poland). Spatial distribution of the population density is used to determine the area supplied with heat and hot water from the district heating system. It changes distinctly the spatial distribution of the air emission from small residential combustion sources. PMID- 28569607 TI - Validation of TICS for detection of dementia and mild cognitive impairment among individuals characterized by low levels of education or illiteracy: a population based study in rural Greece. AB - OBJECTIVE: The efficacy of the most widely used tests for dementia screening is limited in populations characterized by low levels of education. This study aimed to validate the face-to-face administered Telephone Interview for Cognitive Status (TICS) for detection of dementia and mild cognitive impairment (MCI) in a population-based sample of community dwelling individuals characterized by low levels of education or illiteracy in rural Greece. METHODS: The translated Greek version of TICS was administered through face-to-face interview in 133 elderly residents of Velestino of low educational level (<12 years). We assessed its internal consistency and test-retest reliability, its correlation with sociodemographic parameters, and its discriminant ability for cognitive impairment and dementia, as defined by a brief neurological evaluation, including assessment of cognitive status and level of independence. RESULTS: TICS was characterized by adequate internal consistency (Cronbach's alpha: .72) and very high test-retest reliability (intra-class correlation coefficient: .93); it was positively correlated with age and educational years. MCI and dementia were diagnosed in 18 and 10.5% of the population, respectively. Its discriminant ability for detection of dementia was high (Area under the curve, AUC: .85), with a sensitivity and specificity of 86 and 82%, respectively, at a cut-off point of 24/25. TICS did not perform well in differentiating MCI from cognitively normal individuals though (AUC: .67). CONCLUSION: The directly administered TICS questionnaire provides an easily applicable and brief option for detection of dementia in populations of low educational level and might be useful in the context of both clinical and research purposes. PMID- 28569608 TI - Visceral Adipose Tissue Volume and the Occurrence of Colorectal Adenoma in Follow up Colonoscopy for Screening and Surveillance. AB - Whether obesity accelerates adenoma recurrence is not yet clear; therefore, we analyzed the risk factors for adenoma occurrence at follow-up colonoscopy, with a focus on visceral adiposity. In total, 1516 subjects underwent index colonoscopy, computed tomography, and questionnaire assessment from February to May 2008; 539 subjects underwent follow-up colonoscopy at the National Cancer Center at least 6 mo after the index colonoscopy. The relationships between the presence of adenoma at follow-up colonoscopy and anthropometric obesity measurements, including body mass index (BMI), waist circumference (WC), visceral adipose tissue (VAT) volume, and subcutaneous adipose tissue (SAT) volume, were analyzed. 188 (34.9%) had adenomatous polyps at follow-up colonoscopy. Multivariate analysis revealed that VAT volume >= 1000 cm3 and BMI >= 30 kg/m2 were related to the presence of adenoma at follow-up colonoscopy (VAT volume 1000-1500 cm3: odds ratio [OR] = 2.13(95% confidence interval, CI = 1.06-4.26), P = 0.034; VAT volume >= 1000 cm3: OR = 2.24(95% CI = 1.03-4.88), P = 0.043; BMI >= 30 kg/m2: OR = 4.22(95% CI = 1.12-15.93), P = 0.034). In contrast, BMI 25-29.9 kg/m2, SAT volume, and WC were not associated with the presence of adenoma at follow-up colonoscopy. In conclusion, excess VAT can contribute to the development and growth of new colorectal adenomas, and is a better predictor of colorectal adenoma occurrence at follow-up colonoscopy than BMI, WC, and SAT volume. PMID- 28569609 TI - Progress in acetylcholinesterase reactivators and in the treatment of organophosphorus intoxication: a patent review (2006-2016). AB - INTRODUCTION: organophosphorus compounds act as irreversible inhibitors of the vital enzyme acetylcholinesterase (AChE). this leads in the accumulation of acetylcholine (ACh) leading to cholinergic crisis and death. The main therapeutic approach is based on immediate administration of an ache reactivator as an antidote enabling recovery of the ache function. Areas covered: This review covers the development of AChE reactivators in order to introduce a new efficient drug that will overcome significant failures of common antidotes. Further options together with methods of detection are also discussed in order to assure a complete insight into the treatment of intoxication. Expert opinion: Since organophosphates belong to the most toxic chemical warfare agents, efficient antidotes are a matter of importance. The solution of how to limit the basic drawbacks of clinically used reactivators remained a spotlight for many researches worldwide. Recent strategies of the treatment of OP exposure bring us new possibilities which may overcome classic antidotes. The importance of detection of OP also has to be taken into consideration. Especially, with the fast spreading toxic effect when death can occur within minutes. PMID- 28569610 TI - The Stability of Retrospective Child Sexual Abuse Reports and its Association With Problem Avoidance. AB - Due to reliability problems, use of retrospective measurement to assess child sexual abuse has long concerned researchers. Possible psychosocial causes of these reliability issues-including problem avoidance-have not been thoroughly studied. We tested the reliability of retrospective child sexual abuse measurement in a nationally representative sample of 12,438 adults over two periods (2001-2002, 2007-2008), assessed sex differences in reliability, and examined whether reliability depends on problem avoidance tendencies. Nearly three-fourths of child sexual abuse cases in the former wave were not again reported, and two-thirds of child sexual abuse cases in the latter wave were not previously reported. Females were more likely to report CSA later if reported previously (OR = 5.11). Participants who reported child sexual abuse in the former wave but not the latter were more avoidant than consistent reporters (3.13 versus 2.77). Our findings suggest that females may report child sexual abuse more consistently. Furthermore, inconsistent reporting may indicate problem avoidance. Suggestions for researchers and practitioners are discussed. PMID- 28569611 TI - Parental marital satisfaction in a family-based partial hospitalization program. AB - In family-based treatment, parents are initially put in charge of the weight restoration process, requiring parents to work closely together to help their child recover, possibly putting a strain on the marital relationship. The purpose of the current study was to examine marital satisfaction in families before and after treatment in a family-based program and to determine whether marital satisfaction is related to patient outcome. Parents of 53 adolescent patients participated in the study. Almost half of mothers and a third of fathers reported a decrease in marital satisfaction over the course of treatment. Descriptive analyses revealed that patients whose parents reported a decrease in marital satisfaction scored worse on a measure of eating disorder psychopathology. Further research is needed to determine the direction of causality. PMID- 28569612 TI - Prospective study of serum uric acid levels and stroke in a Chinese hypertensive cohort. AB - Our aim was to investigate the association between serum uric acid (SUA) levels and the risk of first stroke in a Chinese population of hypertensive patients. This prospective study enrolled 20,577 hypertensive participants who without a history of stroke, and was conducted from May 2008 to August 2013 in Anqing and Lianyungang (China). A total of 632 (3.1%) first stroke events (510 ischemic events, 120 hemorrhagic events and 2 unspecified stroke events) were identified during a mean 4.5-year follow-up period. The risk of first stroke was not significantly associated with the increased SUA levels; this conclusion was also found after adjustment for gender and age. However, a statistically significant decreased risk of hemorrhagic stroke for the second SUA quartile (Q2) compared to the first quartile (Q1) (HR 0.56, 95%CI: 0.32-0.97, P = 0.037) was found. In addition, when grouped by tertiles of diastolic blood pressure (DBP), the results showed that high SUA lowered the risk of total stroke in participants in the third SUA quartile (Q3) (HR 0.69, 95%CI: 0.49-0.96, P = 0.028) and fourth SUA quartile (Q4) (HR 0.70, 95%CI: 0.50-0.99, P = 0.043) as compared with that in the first quartile (Q1). To sum up, no significant evidence in present study indicates that increased SUA levels are predictive of first stroke in a Chinese population of hypertensive patients. PMID- 28569613 TI - The role of bone marrow microenvironment in platelet production and their implications for the treatment of thrombocytopenic diseases. AB - OBJECTIVES: Impaired platelet production has been found to be an important pathological mechanism of thrombocytopenia in many diseases. Platelet generation is a complex process that mainly occurs in the bone marrow, and thus is closely regulated by the bone marrow microenvironment. This review attempts to summarize the most current knowledge referring the role of bone marrow microenvironment in the regulation of platelet production. METHODS: The effects of multiple microenvironment ingredients in regulating megakaryopoiesis and thrombocytopoiesis have been discussed. Abnormalities of these components in thrombocytopenic diseases are also described. DISCUSSIONS: Thrombocytopenia is a common clinical manifestation of a variety of diseases. The functional importance of platelets has driven the developments of a broad range of studies. Platelet generation mainly occurs within the bone marrow, where the cells, soluble factors, and extracellular matrix proteins collaboratively form a complex regulatory network, directing megakaryocytic proliferation and differentiation. Alteration in any part of the regulating network may result in defective platelet formation, and eventually lead to thrombocytopenia. A variety of thrombocytopenic diseases have been found to be related with the disregulated bone marrow microenvironment. Identification of the variations of these niche ingredients in certain diseases has facilitated the developments of multiple therapeutic regimes. Further studies that can combine these niche factors with their downstream regulatory factors will be beneficial for developing more effective therapies. CONCLUSIONS: Further definition of the role of bone marrow microenvironment in platelet generation may deepen our understanding of the underlying mechanisms as well as provide new therapeutic targets for thrombocytopenic diseases. PMID- 28569614 TI - Stability of Blood Eosinophil Count in Patients with COPD in the UK Clinical Practice Research Datalink. AB - Blood eosinophil counts may be predictive of corticosteroid response in chronic obstructive pulmonary disease (COPD) patients. However, little is known about measurement stability, which is important for understanding the utility of blood eosinophil counts as a potential biomarker. We evaluated the stability of blood eosinophil counts over 1 year in a population-based cohort of patients with COPD in primary care. Patients were aged >= 40 years with forced expiratory volume in 1 second/forced vital capacity < 0.7 and >= 1 blood eosinophil measurement taken during a period of stable disease within 6 months of a COPD diagnosis code recorded between January 1, 2010 and December 31, 2012. Generalized linear mixed models were fitted to log-transformed data to estimate the between-(s2between) and within-patient (s2within) variance in eosinophil count; an intra-class correlation coefficient Ri was calculated (s2between/[s2between + s2within]). A sensitivity analysis was performed from which patients who were prescribed systemic corticosteroids or antibiotics at any time during follow-up were excluded. All models were adjusted for age, gender, smoking status, and asthma history. Overall, 27,557 patients were included in the full cohort (51.5% male, mean age [standard deviation] 71.1 [10.6] years) and 54% of patients had >= 2 eosinophil measurements (median 2 [interquartile range 1]) during follow-up. For the full cohort, Ri = 0.64, and in the sensitivity analysis subgroup, Ri = 0.70, mainly due to a decrease in s2within. For patients with COPD in primary care, eosinophil measurements demonstrated reasonable repeatability over 1 year, which increased after exclusion of patients who were prescribed systemic corticosteroids or antibiotics. PMID- 28569616 TI - Doctor-Related Medication Safety Incidents on a Specialist Palliative Medicine Inpatient Unit: A Retrospective Analysis of Three Years of Voluntary Reporting. AB - Patients receiving palliative care and those at the end of life are known to be susceptible to medical errors. Errors related to medications are the most avoidable cause of patient harm. This retrospective study examined reported anonymized medication safety incidents, related to physician errors, assessed by the risk committee in a specialist palliative care unit over a 3-year time period. The aim of the study was to describe medication errors, with specific attention paid to what type of errors occurred and when these errors happened. Of the 218 reported medication safety incidents 28% (n = 62) were related to doctor prescribing. The data showed that there was a wide variation per year in the numbers of reported medication safety incidents. Medication prescribing errors were the most common error, followed by medication omissions. Medication safety incidents are at least in part dependent on staff reporting. Fostering a culture of openness that is blame free is crucial to medication error reporting. Formal reporting may help to increase patient safety and forms an essential element in the clinical governance and risk management of an institution. PMID- 28569615 TI - Assessment of relationships between novel inflammatory markers and presence and severity of preeclampsia: Epicardial fat thickness, pentraxin-3, and neutrophil to-lymphocyte ratio. AB - OBJECTIVE: The aim of this study was to evaluate the relation of three new inflammatory markers with presence and severity of preeclampsia and to compare the predictive values of all markers for presence of this setting. METHODS: In this study, a total of 100 consecutive pregnants with a diagnosis of preeclampsia and 40 healthy pregnants between October 2014 and April 2015 were included. Epicardial fat tissue was calculated by two-dimensional transthoracic echocardiography, and pentraxin-3 and neutrophil-to-lymphocyte ratio were measured by using an enzyme-linked immunosorbent assay method and routine blood count analysis, respectively. RESULTS: Epicardial fat thickness (p < 0.001), pentraxin-3 (p < 0.001), and neutrophil-to-lymphocyte ratio (p < 0.001) were found to be significantly increased in the preeclampsia as compared to the healthy pregnants. Furthermore, epicardial fat thickness (p = 0.002), pentraxin-3 (p < 0.001), and neutrophil-to-lymphocyte ratio (p < 0.001) were significantly elevated in the severe preeclampsia compared to mild preeclampsia. In the multivariate analysis, epicardial fat thickness (p = 0.013), pentraxin-3 (p = 0.04), and neutrophil-to-lymphocyte ratio (p < 0.001) were found as significant independent predictors of presence of preeclampsia after adjusting for other risk factors. CONCLUSION: Epicardial fat thickness, neutrophil-to-lymphocyte ratio, and pentraxin-3 are important markers that provide an additional information beyond that provided by conventional methods in predicting presence and severity of preeclampsia. PMID- 28569617 TI - Multimodal partial volume correction: Application to [11C]PIB PET/MRI myelin imaging in multiple sclerosis. AB - The [11C]PIB PET tracer, originally developed for amyloid imaging, has been recently repurposed to quantify demyelination and remyelination in multiple sclerosis (MS). Myelin PET imaging, however, is limited by its low resolution that deteriorates the quantification accuracy of white matter (WM) lesions. Here, we introduce a novel partial volume correction (PVC) method called Multiresolution-Multimodal Resolution-Recovery (MM-RR), which uses the wavelet transform and a synergistic statistical model to exploit MRI structural images to improve the resolution of [11C]PIB PET myelin imaging. MM-RR performance was tested on a phantom acquisition and in a dataset comprising [11C]PIB PET and MR T1- and T2-weighted images of 8 healthy controls and 20 MS patients. For the control group, the MM-RR PET images showed an average increase of 5.7% in WM uptake while the grey-matter (GM) uptake remained constant, resulting in +31% WM/GM contrast. Furthermore, MM-RR PET binding maps correlated significantly with the mRNA expressions of the most represented proteins in the myelin sheath (R2 = 0.57 +/- 0.09). In the patient group, MM-RR PET images showed sharper lesion contours and significant improvement in normal-appearing tissue/WM-lesion contrast compared to standard PET (contrast improvement > +40%). These results were consistent with MM-RR performances in phantom experiments. PMID- 28569619 TI - Effects of point massage of liver and stomach channel combined with pith and trotter soup on postpartum lactation start time. AB - Delay in lactation initiation causes maternal anxiety and subsequent adverse impact on maternal exclusive breast feeding. It is important to explore a safe and convenient way to promote lactation initiation. The feasibility of point massage of liver and stomach channel combined with pith and trotter soup on prevention of delayed lactation initiation was investigated in the present study. 320 women were enrolled and randomly divided into four groups, control group (80 women), point massage group (80 women), pith and trotter soup group (80 women), and massage + soup group (80 women) to compare the lactation initiation time. We found that women in point massage group, pith and trotter soup group and massage + soup group had earlier initiation of lactation compared with control group. Women in massage + soup group had the earliest initiation time of lactation. There were significant differences between massage + soup group and pith and trotter soup group. But, there were no significant differences between massage + soup group and massage group. We conclude that point massage of the liver and stomach channel is easy to operate and has the preventive effect on delayed lactation initiation. Impact statement What is already known on this subject: Initiation of lactation is a critical period in postpartum milk secretion. Delays in lactation initiation lead to maternal anxiety and have an adverse impact on maternal exclusive breastfeeding. Sucking frequently by babies and mammary massage might be effective but insufficient for delayed lactation initiation. What the results of this study add: We found in the present study that lactation initiation is significantly earlier in women receiving routine nursing combined with point massage of liver and stomach channel, or pith trotters soup, or massage of liver and stomach channel with pith and trotters soup than in a control group receiving routine nursing. These three methods are all effective, while the most effective method is point massage combined with pith trotter soup. There was no maternal drug allergy, postpartum bleeding or other adverse reactions noted in all women. What the implications are of these findings for clinical practice and/or further research: The present study suggested that the application of point massage in clinic might be useful for preventing lack of milk postpartum by delayed lactation initiation and improving the exclusive breastfeeding rate. Further research might explore that molecular mechanism of lactation promotion by point massage using blood samples or animal models. PMID- 28569618 TI - Effects of chronic exposure to triclosan on reproductive and thyroid endpoints in the adult Wistar female rat. AB - Triclosan (TCS), an antibacterial, has been shown to be an endocrine disruptor in the rat. Previously, subchronic TCS treatment to female rats was found to advance puberty and potentiate the effect of ethinyl estradiol (EE) on uterine growth when EE and TCS were co-administered prior to weaning. In the pubertal study, a decrease in serum thyroxine (T4) concentrations with no significant change in serum thyroid-stimulating hormone (TSH) was also observed. The purpose of the present study was to further characterize the influence of TCS on the reproductive and thyroid axes of the female rat using a chronic exposure regimen. Female Wistar rats were exposed by oral gavage to vehicle control, EE (1 MUg/kg), or TCS (2.35, 4.69, 9.375 or 37.5 mg/kg) for 8 months and estrous cyclicity monitored. Although a divergent pattern of reproductive senescence appeared to emerge from 5 to 11 months of age between controls and EE-treated females, no significant difference in cyclicity was noted between TCS-treated and control females. A higher % control females displayed persistent diestrus (PD) by the end of the study, whereas animals administered with positive control (EE) were predominately persistent estrus (PE). Thyroxine concentration was significantly decreased in TCS-administered 9.375 and 37.5 mg/kg groups, with no marked effects on TSH levels, thyroid tissue weight, or histology. Results demonstrate that a long-term exposure to TCS did not significantly alter estrous cyclicity or timing of reproductive senescence in females but suppressed T4 levels at a lower dose than previously observed. PMID- 28569620 TI - Indoor air quality in preschools (3- to 5-year-old children) in the Northeast of Portugal during spring-summer season: pollutants and comfort parameters. AB - Indoor air quality at schools (elementary, primary) has been the subject of many studies; however, there are still relative few data regarding preschool (3- to 5 year-old children) environments. This investigation determined the concentrations of particulate matter (PM)2.5, total volatile organic compounds (TVOC), formaldehyde, carbon monoxide (CO), and ozone (O3) as well as the levels of carbon dioxide (CO2), temperature, and relative humidity (RH) in the indoor and outdoor air of two preschools situated in different geographical regions of Portugal. The indoor concentrations of TVOC, CO, O3, and CO2 were predominantly higher at the end of school day compared to early morning periods. The TVOC and CO2 concentrations were higher indoors than outdoors suggesting predominantly an indoor origin. Outdoor air infiltrations were the major contributing source of CO and O3 to indoor air in both preschools. The concentrations of all pollutants were within the limits defined by national regulations and international organizations, except for TVOC that exceeded 8-12-fold higher than the recommendation of 0.2 mg/m3 proposed by European Commission. The levels of CO2 were below the protective guideline of 2250 mg/m3 (Portuguese legislation); however, the observed ranges exceeded the Portuguese margin of tolerance (2925 mg/m3) at the end of school days, indicating the impact of occupancy rates particularly at one of the preschools. Regarding comfort parameters, temperature exerted a significant influence on O3 concentrations, while RH values were significantly correlated with TVOC levels in indoor air of preschools, particularly during the late afternoon periods. PMID- 28569622 TI - Homophobic Bullying and Cyberbullying: Study of a Silenced Problem. AB - Bullying and cyberbullying have been studied extensively. In lesbian, gay, bisexual, and questioning (LGBQ) students, these phenomena seem to be overrepresented so that, although they share some common elements, homophobic bullying and cyberbullying could be considered as specific phenomena. This study analyzed homophobic bullying and cyberbullying, with the participation of 533 Spanish secondary school students aged from 12 to 20 (M = 14.9, SD = 1.7). The results showed that students identified as non-heterosexual experienced a higher level of being targeted with bullying and cyberbullying, almost one half of them declaring that they had been victimized and more than 20% cybervictimized. Many stated they had suffered both kinds of harassment. In addition, the prevalence of all kinds of bullying was higher among non-heterosexual students. Regression analyses showed that sexual orientation could be considered a risk factor for suffering these aggressions. We discuss results in relation to previous research and look at their practical implications. PMID- 28569621 TI - Attachment orientations and psychological adjustment of parents of children with cancer: A matched-group comparison. AB - OBJECTIVE: To investigate the impact of childhood cancer on parents' adult attachment, social support, marital adjustment, anxiety, and depression. METHODS: 30 parents of children with childhood cancer and 30 matched controls completed the following questionnaires: Experiences in Close Relationships-Revised, Dyadic Adjustment Scale-4, Multidimensional Scale of Perceived Social Support, State Trait Anxiety Inventory - form Y, and Beck Depression Inventory. RESULTS: Parents of children with childhood cancer had a significantly lower dyadic adjustment than controls, and higher levels of insecure-avoidant attachment, state anxiety, and depression. CONCLUSION: It is important for health-care personnel to take into account these parents' propensity to show increased levels of avoidant attachment during children's treatment to foster effective communication and supportive relationships between clinicians, pediatric patients, and parents. PMID- 28569623 TI - Increased total DNA damage and oxidative stress in brain are associated with decreased longevity in high sucrose diet fed WNIN/Gr-Ob obese rats. AB - BACKGROUND: Obesity and Type 2 Diabetes (T2D) are chronic nutrient-related disorders that occur together and pose a grave burden to society. They are among the most common causes of ageing and death. Obesity and T2D per se accelerate ageing albeit the underlying mechanisms are unclear yet. Also, it is not clear whether or not superimposing T2D on obesity accelerates ageing. Present study validated the hypothesis, 'super-imposing T2D on obesity accelerates ageing' in WNIN/Gr-Ob, the impaired glucose tolerant, obese rat as the model and evaluated probable underlying mechanisms. OBJECTIVES: To estimate the survival analysis of WNIN/Gr-Ob rats induced with T2D. To determine the extent of DNA damage and oxidative stress in the brain, the master controller of the body, in WNIN/Gr-Ob rats with/without high sucrose induced T2D/aggravation of insulin resistance (IR) after 3 and 6 months of feeding. METHODS: T2D was induced/IR was aggravated by feeding high sucrose diet (HSD) to 9-10 weeks old, male WNIN/Gr-Ob rats. Survival percentage was determined statistically by Kaplan-Meier estimator. Neuronal DNA damage was quantified by the Comet assay while the oxidative stress and antioxidant status were evaluated from the levels of malonaldialdehyde, reduced glutathione, and superoxide dismutase (SOD) activity. RESULTS AND DISCUSSION: HSD feeding decreased longevity of WNIN/Gr-Ob rats and was associated with significantly higher total neuronal DNA damage after three months of feeding but not later. In line with this was the increased neuronal oxidative stress (lipid peroxidation) and decreased antioxidant status (reduced glutathione and SOD activity) in HSD than Starch-based diet (SBD) fed rats. The results suggest that HSD feeding decreased the longevity of WNIN/Gr-Ob obese rats probably by increasing oxidative stress and aggravating IR, a condition that precedes T2D. PMID- 28569624 TI - Effectiveness of Parenteral Glutamine on Methotrexate-induced Oral Mucositis in Children with Acute Lymphoblastic Leukemia. AB - High-dose methotrexate (HDMTX) is important for children with acute lymphoblastic leukemia (ALL). There is no effective treatment for patients with oral mucositis, which is a major side effect associated with HDMTX. Here, we reviewed the medical records of patients younger than 18 yr with newly diagnosed ALL in our hospitals from 2002 to 2013. According to the nationwide protocol (TPOG-ALL-2002), each patient received four courses of HDMTX (2.5 or 5 g/m2) during consolidation therapy. HDMTX courses with glutamine therapy were as the glutamine group, and intravenous glutamine (0.4 g/kg/day) was started within 48 h after the initiation of HDMTX for 3 consecutive days. HDMTX courses without glutamine were as the control group. A total of 347 HDMTX courses were administrated in the 96 children with ALL during the study period. The incidence of oral mucositis was significantly lower in the glutamine group than in the control group (3.8% vs. 17.6%; P = 0.004). In the glutamine group, no patients suffered from severe oral mucositis. No severe adverse effects associated with glutamine administration were noted. Accordingly, parenteral glutamine appears to be feasible and safe to prevent oral mucositis in patients receiving HDMTX. PMID- 28569625 TI - Sexual Preferences and Partnerships of Transgender Persons Mid- or Post Transition. AB - The process of gender transition has varying effects on various aspects of sexuality. The purpose of this study was to investigate the effects of transitioning on transgender persons' sexual preferences and partnerships. Data were collected through an anonymous online survey. Questions focused on timing of gender transition in relation to change in sexual preference. Transgender individuals have a variety of sexual partners, predominantly cisgender, and may change sexual preference when they transition. Transitioning can be associated with having no primary sexual partner, despite past sexual partnerships. Length of time between identifying as transgender and starting the transition might be associated with changing sexual partner preference, particularly in transgender women. The emerging trends of sexual partnerships and changing sexual preferences related to the transition in this study warrant further investigation. These data provide more understanding of the relationship between transitioning and sexual preferences and partnerships. PMID- 28569626 TI - What Is Your Diagnosis? PMID- 28569628 TI - Pathology in Practice. PMID- 28569629 TI - ECG of the Month. PMID- 28569630 TI - A case-control study developing a model for predicting risk factors for high SeM specific antibody titers after natural outbreaks of Streptococcus equi subsp equi infection in horses. AB - OBJECTIVE To develop a risk prediction model for factors associated with an SeM specific antibody titer >= 3,200 in horses after naturally occurring outbreaks of Streptococcus equi subsp equi infection and to validate this model. DESIGN Case control study. ANIMALS 245 horses: 57 horses involved in strangles outbreaks (case horses) and 188 healthy horses (control horses). PROCEDURES Serum samples were obtained from the 57 cases over a 27.5-month period after the start of outbreaks; serum samples were obtained once from the 188 controls. A Bayesian mixed-effects logistic regression model was used to assess potential risk factors associated with an antibody titer >= 3,200 in the case horses. A cutoff probability for an SeM-specific titer >= 3,200 was determined, and the model was externally validated in the control horses. Only variables with a 95% credibility interval that did not overlap with a value of 1 were considered significant. RESULTS 9 of 57 (6%) case horses had at least 1 titer >= 3,200, and 7 of 188 (3.7%) of control horses had a titer >= 3,200. The following variables were found to be significantly associated with a titer >= 3,200 in cases: farm size > 20 horses (OR, 0.11), history of clinically evident disease (OR, 7.92), and male sex (OR, 0.11). The model had 100% sensitivity but only 24% specificity when applied to the 188 control horses (area under the receiver operating characteristic curve = 0.62.) CONCLUSIONS AND CLINICAL RELEVANCE Although the Bayesian mixed-effects logistic regression model developed in this study did not perform well, it may prove useful as an initial screening tool prior to vaccination. We suggest that SeM-specific antibody titer be measured prior to vaccination when our model predicts a titer >= 3,200. PMID- 28569631 TI - Evaluation of pyramid training as a method to increase diagnostic sampling capacity during an emergency veterinary response to a swine disease outbreak. AB - OBJECTIVE To develop and evaluate a pyramid training method for teaching techniques for collection of diagnostic samples from swine. DESIGN Experimental trial. SAMPLE 45 veterinary students. PROCEDURES Participants went through a preinstruction assessment to determine their familiarity with the equipment needed and techniques used to collect samples of blood, nasal secretions, feces, and oral fluid from pigs. Participants were then shown a series of videos illustrating the correct equipment and techniques for collecting samples and were provided hands-on pyramid-based instruction wherein a single swine veterinarian trained 2 or 3 participants on each of the techniques and each of those participants, in turn, trained additional participants. Additional assessments were performed after the instruction was completed. RESULTS Following the instruction phase, percentages of participants able to collect adequate samples of blood, nasal secretions, feces, and oral fluid increased, as did scores on a written quiz assessing participants' ability to identify the correct equipment, positioning, and procedures for collection of samples. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the pyramid training method may be a feasible way to rapidly increase diagnostic sampling capacity during an emergency veterinary response to a swine disease outbreak. PMID- 28569632 TI - Diagnostic Imaging in Veterinary Dental Practice. PMID- 28569633 TI - Pathology in Practice. PMID- 28569634 TI - Open reduction and cranial bone plate fixation of fractures involving the distal aspect of the radius and ulna in miniature- and toy-breed dogs: 102 cases (2008 2015). AB - OBJECTIVE To determine outcomes and complication rates of open reduction and cranial bone plate fixation of fractures involving the distal aspect of the radius and ulna in miniature- and toy-breed dogs. DESIGN Retrospective case series. ANIMALS 102 miniature- and toy-breed dogs (105 fractures) weighing <= 7 kg (15.4 lb) that had undergone open reduction and cranial bone plate fixation of a fracture involving the distal aspect of the radius and ulna from 2008 through 2015. PROCEDURES Medical records were reviewed and information extracted regarding dog and fracture characteristics, surgical variables, and follow-up examination data (including postoperative complications). Postoperative radiographs were examined for distal fragment size, implant placement, apposition, alignment, and healing stage. A long-term follow-up questionnaire was completed by telephone interview with dog owners at least 6 months after surgery. RESULTS Mean length of the distal bone fragment in all fractures was 19.2 mm, with a mean distal-to-total radial length ratio of 0.21. At last follow-up examination (typically 6 weeks after surgery), 97 (95%) dogs had no signs of lameness; minor lameness was identified in 5 (5%) dogs. Complications developed in 26 (25%) fractures (23 [22%] minor and 3 [3%] major complications). Sixty eight of 71 (96%) owners rated the overall and long-term outcome as excellent and 3 (4%) as good; 68 of 71 (96%) dogs reportedly had no signs of residual lameness. CONCLUSIONS AND CLINICAL RELEVANCE Open reduction and cranial bone plate fixation for the treatment of radius-ulna fractures in miniature- and toy-breed dogs provided an excellent outcome with a low complication rate. PMID- 28569637 TI - What Is Your Neurologic Diagnosis? PMID- 28569638 TI - Anesthesia Case of the Month. PMID- 28569635 TI - Thyrotoxicosis induced by excessive 3,5,3'-triiodothyronine in a dog. AB - CASE DESCRIPTION A 7-year-old castrated male Havanese was evaluated at a veterinary teaching hospital because of a 12-week history of hyperactivity, aggression, and progressive weight loss despite a healthy appetite. CLINICAL FINDINGS Tachycardia was the only remarkable finding during physical examination. Serum 3,5,3'-triiodothyronine (T3) and free T3 concentrations were markedly increased, and thyroxine (T4), free T4, and thyroid-stimulating hormone concentrations were at or decreased from the respective reference ranges. Thyroid scintigraphy revealed suppressed uptake of sodium pertechnetate Tc 99m by the thyroid gland but no ectopic thyroid tissue, which was indicative of thyrotoxicosis induced by an exogenous source of T3. TREATMENT AND OUTCOME The dog was hospitalized for 24 hours, and its diet was changed, after which the clinical signs rapidly resolved and serum T3 and free T3 concentrations returned to within the respective reference ranges. This raised suspicion of an exogenous source of T3 in the dog's home environment. Analysis of the commercial beef-based canned food the dog was being fed revealed a high concentration of T3 (1.39 MUg/g) and an iodine (82.44 MUg/g) concentration that exceeded industry recommendations. No other source of T3 was identified in the dog's environment. CLINICAL RELEVANCE To our knowledge, this is the first report of clinical thyrotoxicosis in a dog induced by exogenous T3, although the source of exogenous T3 was not identified. This case highlights the importance of measuring serum T3 and thyroid-stimulating hormone concentrations in addition to T4 and free T4 concentrations when there is incongruity between clinical findings and thyroid function test results. PMID- 28569640 TI - Prevalence of serum antibody titers against canine distemper virus and canine parvovirus in dogs hospitalized in an intensive care unit. AB - OBJECTIVE To determine the prevalence of dogs hospitalized in an intensive care unit (ICU) with serum antibody titers against canine distemper virus (CDV) and canine parvovirus (CPV). DESIGN Prospective observational study. ANIMALS 80 dogs. PROCEDURES Dogs hospitalized in an ICU for > 12 hours between February 1 and June 1, 2015, that had at least 0.25 mL of serum left over from diagnostic testing were eligible for study inclusion. Dogs with serum antibody titers > 1:32 (as determined by serum neutralization) and > 1:80 (as determined by hemagglutination inhibition) were considered seropositive for CDV and CPV, respectively. The date of last vaccination was obtained from the medical record of each dog. RESULTS Of the 80 dogs, 40 (50%) and 65 (81%) dogs were seropositive for CDV and CPV, respectively. Of the 40 dogs that were seronegative for CDV, 27 had been vaccinated against CDV within 3 years prior to testing. Of the 15 dogs that were seronegative for CPV, 3 had been vaccinated against CPV within 3 years prior to testing. Ten dogs were seronegative for both CDV and CPV. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated the prevalence of dogs hospitalized in an ICU that were seropositive for CDV and CPV was lower than expected given the high vaccination rate reported for dogs. Although the antibody titer necessary to prevent disease caused by CDV or CPV in critically ill dogs is unknown, adherence to infectious disease control guidelines is warranted when CDV- or CPV-infected dogs are treated in an ICU. PMID- 28569641 TI - Letters to the Editor. PMID- 28569642 TI - Effects of colonization of a bacterial endophyte, Azospirillum sp. B510, on disease resistance in tomato. AB - A plant growth-promoting bacteria, Azospirillum sp. B510, isolated from rice, can enhance growth and yield and induce disease resistance against various types of diseases in rice. Because little is known about the interaction between other plant species and this strain, we have investigated the effect of its colonization on disease resistance in tomato plants. Treatment with this strain by soil-drenching method established endophytic colonization in root tissues in tomato plant. The endophytic colonization with this strain-induced disease resistance in tomato plant against bacterial leaf spot caused by Pseudomonas syringae pv. tomato and gray mold caused by Botrytis cinerea. In Azospirillum treated plants, neither the accumulation of SA nor the expression of defense related genes was observed. These indicate that endophytic colonization with Azospirillum sp. B510 is able to activate the innate immune system also in tomato, which does not seem to be systemic acquired resistance. PMID- 28569643 TI - The HOOK region of beta subunits controls gating of voltage-gated Ca2+ channels by electrostatically interacting with plasma membrane. AB - Recently, we showed that the HOOK region of the beta2 subunit electrostatically interacts with the plasma membrane and regulates the current inactivation and phosphatidylinositol 4,5-bisphosphate (PIP2) sensitivity of voltage-gated Ca2+ (CaV) 2.2 channels. Here, we report that voltage-dependent gating and current density of the CaV2.2 channels are also regulated by the HOOK region of the beta2 subunit. The HOOK region can be divided into 3 domains: S (polyserine), A (polyacidic), and B (polybasic). We found that the A domain shifted the voltage dependent inactivation and activation of CaV2.2 channels to more hyperpolarized and depolarized voltages, respectively, whereas the B domain evoked these responses in the opposite directions. In addition, the A domain decreased the current density of the CaV2.2 channels, while the B domain increased it. Together, our data demonstrate that the flexible HOOK region of the beta2 subunit plays an important role in determining the overall CaV channel gating properties. PMID- 28569644 TI - Microwave-assisted facile fabrication of porous poly (glycerol sebacate) scaffolds. AB - The biodegradable elastomeric polyester poly(glycerol sebacate) (PGS) was developed for soft-tissue engineering. It has been used in various research applications such as wound healing, cartilage tissue engineering, and vascular grafting due to its biocompatibility and elastomeric properties. However conventional PGS manufacture is generally limited by the laborious reaction conditions needed for curing which requires elevated reaction temperatures, high vacuum and multi-day reaction times. In this study, we developed a microwave irradiation methodology to fabricate PGS scaffolds under milder conditions with curing times that are 8 times faster than conventional methods. In particular, we determined microwave reaction temperatures and times for maximum crosslinking of PGS elastomers, demonstrating that PGS is fully crosslinked using gradual heating up to 160 degrees C for 3 h. Porosity and mechanical properties of these microwave-cured PGS elastomers were shown to be similar to PGS elastomers fabricated by the conventional polycondensation method (150 degrees C under 30 Torr for 24 h). To move one step closer to clinical application, we also examined the biocompatibility of microwave-cured PGS using in vitro cell viability assays with primary baboon arterial smooth muscle cells (SMCs). These combined results show microwave curing of PGS is a viable alternative to conventional curing. PMID- 28569646 TI - Mapping Exposure to Multi-Pollutants Using Environmental Biomonitors-A Multi Exposure Index. AB - Atmosphere is a major pathway for transport and deposition of pollutants in the environment. In industrial areas, organic compounds are released or formed as by products, such as polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F's). Inorganic chemical elements, including lead and arsenic, are also part of the pollutants mixture, and even in low concentrations may potentially be toxic and carcinogenic. However, assessing the spatial pattern of their deposition is difficult due to high spatial and temporal heterogeneity. Lichens have been used as biomonitors of atmospheric deposition, because these organisms encompass greater spatial detail than air monitoring stations and provide an integration of overall pollution. Based upon the ability of lichens to concentrate pollutants such as PCDD/F and chemical elements, the main objectives of this study were to develop a new semi-quantitative multi-pollutant toxicity exposure index (TEQ like), derived from risk estimates, in an attempt to correlate several atmospheric pollutants to human exposure levels. The actual pollutant concentrations were measured in the environment, from biomonitors (organisms that integrate multi-pollutants), enabling interpolation and mapping of contaminant deposition within the region. Thus, the TEQ-like index provides a spatial representation not from absolute accumulation of the different pollutants, but from the accumulation weighted by their relative risk. The assessment of environmental human exposure to multi-pollutants through atmospheric deposition may be applied to industries to improve mitigation processes or to health stakeholders to target populations for a comprehensive risk assessment, epidemiological studies, and health recommendations. PMID- 28569647 TI - Matching Message Design and Depressed Cognition: An Exploration of Attention Patterns for Gain- and Loss-Framed Depression Help-Seeking Messages. AB - Although disproportionally affected by depression, most depressed college students do not seek the help they need. Research has recently uncovered the potential negative effects of depression help-seeking messages if depressed cognition is not considered in the health message design process. It is unclear if depression determines whether and how individuals pay attention to gain- and loss-framed depression help-seeking messages-a mechanism that has significant implications for the strategic planning of health communication interventions. In order to enable the effective matching of message design and audience features, this study investigated attention patterns for gain (n = 75)- and loss (n = 78) framed depression help-seeking messages using eye-tracking technology and self report measures. The results confirmed that depression is a characteristic of risk avoidance and negative cognition. Depressed participants tended to pay more attention to disease information that was placed in a loss-framed rather than a gain-framed depression help-seeking message. Using negative message framing strategies for health messages seeking to educate about depression symptoms might therefore be a useful persuasive strategy-particularly when disseminated to vulnerable populations affected by depression. Furthermore, the present study emphasizes the effective use of eye-tracking technology in communication research. PMID- 28569645 TI - In vivo evidence of oxidative stress in brains of patients with progressive multiple sclerosis. AB - BACKGROUND: The oxidative stress hypothesis links neurodegeneration in the later, progressive stages of multiple sclerosis (MS) to the loss of a major brain antioxidant, glutathione (GSH). OBJECTIVE: We measured GSH concentrations among major MS subtypes and examined the relationships with other indices of disease status including physical disability and magnetic resonance imaging (MRI) measures. METHODS: GSH mapping was performed on the fronto-parietal region of patients with relapsing-remitting multiple sclerosis (RRMS, n = 21), primary progressive multiple sclerosis (PPMS, n = 20), secondary progressive multiple sclerosis (SPMS, n = 20), and controls ( n = 28) using GSH chemical shift imaging. Between-group comparisons were performed on all variables (GSH, T2 lesion, atrophy, Expanded Disability Status Scale (EDSS)). RESULTS: Patients with MS had substantially lower GSH concentrations than controls, and GSH was lower in progressive MS (PPMS and SPMS) compared with RRMS. GSH concentrations were not significantly different between PPMS and SPMS, or between RRMS and controls. Brain atrophy was significant in both RRMS and progressive MS compared with controls. CONCLUSION: Markedly lower GSH in progressive MS than RRMS indicates more prominent involvement of oxidative stress in the progressive stage of MS than the inflammatory stage. The association between GSH and brain atrophy suggests the important role of oxidative stress contributing to neurodegeneration in progressive MS, as suggested in other neurodegenerative diseases. PMID- 28569648 TI - Edutainment as a Strategy for Parental Discussion With Israeli Children: The Potential of a Children's Play in Preventing Sexual Abuse. AB - Edutainment is a communication strategy to influence attitudes and behaviors through the use of the media. Through the children's play "Yael Learns to Take Care of Her Body," designed for joint viewing by children aged 5-8 and their parents, sexual abuse is raised. This qualitative study findings indicate that parents from low socioeconomic subgroups from the secular sector reported that their awareness had been raised by viewing the play and that they received tools for holding a conversation. Conversely, parents from high socioeconomic subgroups in the secular sector and parents from the national-religious sector were more ambivalent regarding the play's effectiveness. In order to make the conversation meaningful, the play has to tailor different messages to different audiences. A single program is not enough but should be part of a series of customized intervention programs for different subpopulations and separate programs for parents and children accompanied by professionals. PMID- 28569649 TI - Antibiotic prescribing for acute respiratory tract infections in Norwegian primary care out-of-hours service. AB - PURPOSE: To examine factors correlating with antibiotic prescribing for acute respiratory tract infections (ARTIs) in Norwegian primary care out-of-hours service. MATERIALS AND METHODS: Retrospective data analysis for the year 2014 in two out-of-hours primary care units located in the towns of Hamar and Tonsberg in Norway, analysing type and frequency of different antibiotics prescribed by 117 medical doctors for ARTIs, and factors correlating with these. RESULTS: The 117 doctors in two out-of-hours units diagnosed 6757 cases of ARTIs. 2310 (34.2%) of these resulted in an antibiotic prescription, where of 1615 (69.9%) were penicillin V (PcV). Tonsillitis and sinusitis were the two ARTI diagnoses with the highest antibiotic prescription rate. The antibiotic prescription rate increased successively with increasing activity level, measured as shorter median duration of consultations per session, from 28.7% (reference) in the least busy quintile of sessions to 36.6% (OR: 1.38 (95% CI =1.06-1.80)) in the busiest quintile of sessions. Prescribing of broad-spectrum antibiotics was not correlated with median duration of consultations per session. Female doctors had an OR of 0.61 (0.40-0.92) of a broad-spectrum antibiotic prescription compared to their male colleagues. CONCLUSIONS: Antibiotic prescribing for ARTIs in the primary care out-of-hours services investigated is at the same level as in Norwegian general practice, but with a higher prescription rate of PcV. Antibiotic prescribing increases on busy sessions, measured as median duration of consultations per session. The work frame in primary care out-of-hours service might influence the quality of clinical decisions. PMID- 28569650 TI - High Betrayal Child Sexual Abuse and Hallucinations: A Test of an Indirect Effect of Dissociation. AB - Though hallucinations traditionally have been conceptualized as a central feature of psychosis, some hallucinations may be dissociative, with dissociation potentially contributing to hallucinations. Childhood trauma has been linked with dissociation and hallucinations. Betrayal trauma theory distinguishes abusive experiences based on closeness to the perpetrator. In the current study, we examined the indirect effect of dissociation on the relationship between high betrayal child sexual abuse (perpetrated by a close other) and hallucinations. Participants (N = 192) from a northwestern university in the United States completed self-report measures online assessing history of high betrayal child sexual abuse and current dissociation and hallucinations. Bootstrapping analyses indicated a significant indirect effect of high betrayal child sexual abuse on hallucinations through dissociation, 95% Confidence Interval (.16, .66). Through betrayal trauma theory, this study provides a non-pathologizing framework for understanding how dissociation and hallucinations may develop as natural reactions to the harm inherent in child sexual abuse perpetrated by a close other. These findings have clinical implications for relational models of healing for trauma survivors who are distressed by dissociation and hallucinations. PMID- 28569651 TI - "How We Stay Together Without Going Crazy:" Reconstruction of Reality Among Women of Mixed-Orientation Relationships. AB - Until recently, the literature that addressed the phenomenon of mixed-orientation relationships, in which the female partner is straight and the male partner is non-straight, has focused mainly on the men's perspective. Most of the studies have employed a pessimistic tone, underscoring the obstacles faced by each of the partners. This study was designed to understand how women of mixed-orientation relationships construct their reality within such a relationship, focusing on elements that assist them in maintaining those relationships. Based on the phenomenological paradigm, in-depth interviews with eight women in mixed orientation relationships were conducted. The findings indicate that in order to adapt to their newly constructed reality, women reframe various individual, marital, and social aspects in their lives. Those reframing processes constituted a point of departure to developing a conceptual model, which outlines the journey to reality reconstruction among women in mixed-orientation relationships. PMID- 28569653 TI - Physiological responses and lipid storage of the coral Lophelia pertusa at varying food density. AB - Despite the importance of the cold-water coral Lophelia pertusa to deep-sea reef ecosystem functioning, current knowledge of key physiological responses to available food resources is scarce. Scenarios with varying food density may help to understand how corals deal with seasonal variations in the dark ocean and might be used to study consequences of anthropogenic activities potentially affecting food availability. Thus, the physiological responses of L. pertusa to varying food (Artemia salina nauplii) concentration, ranging from 20% to 300% of carbon equivalent turned over by basal coral respiration, were investigated. A starvation group was also included. Measurements of respiration, growth, mucus production, and energy reserves (storage fatty acids) were performed at several time intervals over 26 weeks. In general, data showed a stronger effect of experimental time on measured responses, but no significant influence of food density treatment. In starved corals, respiration rate declined to 52% of initial respiration, while skeleton growth rate was maintained at the same rate as Artemia-fed corals throughout the investigation. Mucus production measured as the sum of dissolved organic carbon (DOC) and particulate organic carbon (POC) was also similar across food treatments, but POC production exceeded that of DOC at the highest food density. No marked effect was observed on storage fatty acids. These results confirm that L. pertusa is highly resilient to environmental conditions with suboptimal food densities over a time scale of months. Regulation of several physiological processes, including respiration and mucus production, possibly in combination with an opportunistic feeding strategy, contributed to this tolerance to maintain viable corals. Thus, it appears that L. pertusa is well adapted to life in the deep sea. PMID- 28569652 TI - Something New about Something Old: A 10-Year Follow-Up on Classical and New Psychoactive Tryptamines and Results of Analysis. AB - New psychoactive tryptamines may be a public health risk since they intend to mimic the hallucinogenic effects of regulated psychoactive drugs. Few studies describe uses and clinical effects of unregulated new psychoactive tryptamines. This study aims (1) to explore the presence of tryptamines classified as NPS among the substances delivered for analysis to a harm-reduction organization; (2) to describe the substances found in the samples after analysis; and (3) to compare analytical results of regulated vs. non-regulated tryptamines. Samples delivered and analyzed by gas chromatography-mass spectrometry from 2006 to 2015 were included. A descriptive study of results was conducted. From 25,296 samples that were delivered, 436 were tryptamines; from these 232 (53.21%) were non regulated. The most delivered non-regulated tryptamine was 4-AcO-DMT. A search of the PubMed database in July 2016 revealed that no studies in humans have ever been carried out with 4-AcO-DMT. Unregulated tryptamines likely contained one unadulterated substance (p <= 0.001). The number of samples submitted which contained tryptamines increased during the course of the study, with significant differences in client expectations vs. analysis results between the controlled and uncontrolled groups. There is a need for further research in order to prevent the potential health risks associated with their use. PMID- 28569654 TI - "Unexpected and Distressing": Understanding and Improving the Experience of Transferring Palliative Care Inpatients to Residential Care. AB - The survival of patients with advanced cancer, coupled with the increased presence of end-stage chronic illnesses in an aging population, is leading to a demand in palliative care. Due to the ongoing need for acute-pain and symptom control in hospice/palliative care units, few are able to offer long-stay admission for those whose symptoms have stabilized. When a patient no longer requires specialist palliative care services, transfer from an inpatient palliative care facility may then be necessary. A core component of the role of palliative-care social workers involves working with patients and their families/carers when the care pathway shifts and the option of residential aged care facility (RACF) needs to be considered. This research explored several issues, including the impact of this transition on the patient and their families and on the interdisciplinary health care team treating the patient. An investigation was undertaken to identify concerns and barriers regarding the transition from hospice care to RACF and opportunities were highlighted to improve clinical practice in this area. A tripartite approach was adopted conducting face-to-face interviews with patients, their families/carers, and health care professionals. Members of the interdisciplinary team were interviewed and social workers working in similar inpatient palliative-care facilities undertook telephone interviews to gauge their experiences. A thematic analysis discerned a number of themes highlighting the impact of this transition on key stakeholders and incorporated recommendations to improve or best manage this process. The research has highlighted the difficulties that patients/families encounter in this transition, as well as the emphases of protecting the integrity of the patient and family. This is achieved by holding open and ongoing dialogue, particularly through family meetings and working in collaboration with the patient, the family, and the team. Understanding the experience and impact of this transition on key stakeholders is helpful in building up a knowledge base and to ensure a more effective relationship occurs. This research incorporated the voices of terminally ill patients, families, and members of the health care team in order to understand their views and recommendations for best managing the transition from a hospice/inpatient palliative-care facility to a RACF. This enables their input to have some real impetus in clinical practice and service delivery. PMID- 28569656 TI - Leveraging Technology for Innovation. PMID- 28569657 TI - Consultation: A Key Component of Case Studies? PMID- 28569655 TI - Sustained (S)-roscovitine delivery promotes neuroprotection associated with functional recovery and decrease in brain edema in a randomized blind focal cerebral ischemia study. AB - Stroke is a devastating disorder that significantly contributes to death, disability and healthcare costs. In ischemic stroke, the only current acute therapy is recanalization, but the narrow therapeutic window less than 6 h limits its application. The current challenge is to prevent late cell death, with concomitant therapy targeting the ischemic cascade to widen the therapeutic window. Among potential neuroprotective drugs, cyclin-dependent kinase inhibitors such as (S)-roscovitine are of particular relevance. We previously showed that (S)-roscovitine crossed the blood-brain barrier and was neuroprotective in a dose dependent manner in two models of middle cerebral artery occlusion (MCAo). According to the Stroke Therapy Academic Industry Roundtable guidelines, the pharmacokinetics of (S)-roscovitine and the optimal mode of delivery and therapeutic dose in rats were investigated. Combination of intravenous (IV) and continuous sub-cutaneous (SC) infusion led to early and sustained delivery of (S) roscovitine. Furthermore, in a randomized blind study on a transient MCAo rat model, we showed that this mode of delivery reduced both infarct and edema volume and was beneficial to neurological outcome. Within the framework of preclinical studies for stroke therapy development, we here provide data to improve translation of pre-clinical studies into successful clinical human trials. PMID- 28569658 TI - Long-Term Care: Safe Drug Handling of Oral Chemotherapy. AB - Many oral chemotherapy agents have been approved over the last 15 years and are displacing or augmenting parenteral chemotherapy. As 8,000 Baby Boomers turn 65 years of age every day, more elders will migrate to long-term care and assisted living facilities, and consultant pharmacists may need to manage chemotherapy for the first time. Though many therapeutic classes of oral drugs are hazardous, the majority of oral chemotherapy agents are hazardous by virtue of their mechanisms of action. Previous hazardous drug-handling recommendations from the Occupational Safety and Health Administration, the National Institute of Occupational Safety and Health, the American Society of Health-System Pharmacists, the American Society of Clinical Oncology, the Hematology/Oncology Pharmacy Association, and the Oncology Nursing Society have matured into new standards from the United States Pharmacopeial Convention (USP), Chapter <800>, "Hazardous Drugs-Handling in Health Care Settings." These standards provide a comprehensive approach for safe drug handling across all health care settings and underscore the need for consultant pharmacist involvement in nursing and assisted living facilities. PMID- 28569659 TI - Highlights from the 2016 Annual Meeting. PMID- 28569660 TI - Use of Telemedicine to Enhance Pharmacist Services in the Nursing Facility. AB - OBJECTIVE: To conduct a systematic literature review to determine what telemedicine services are provided by pharmacists and the impact of these services in the nursing facility setting. DATA SOURCES: MEDLINE(r), Scopus(r), and Embase(r) databases. STUDY SELECTION: The terms "telemedicine" or "telehealth" were combined by "and" with the terms "pharmacist" or "pharmacy" to identify pharmacists' use of telemedicine. Also, "telepharmacy" was added as a search term. The initial search yielded 322 results. These abstracts were reviewed by two individuals independently, for selection of articles that discussed telemedicine and involvement of a pharmacist, either as the primary user of the service or as part of an interprofessional health care team. Those abstracts discussing the pharmacist service for purpose of dispensing or product preparation were excluded. DATA EXTRACTION: A description of pharmacists' services provided and the impact on resident care. DATA SYNTHESIS: Only three manuscripts met inclusion criteria. One was a narrative proposition of the benefits of using telemedicine by senior care pharmacists. Two published original research studies indirectly assessed the pharmacists' use of telemedicine in the nursing facility through an anticoagulation program and an osteoporosis management service. Both services demonstrated improvement in patient care. CONCLUSION: There is a general paucity of practice-related research to demonstrate potential benefits of pharmacists' services incorporating telemedicine. Telemedicine may be a resource-efficient approach to enhance pharmacist services in the nursing facility and improve resident care. PMID- 28569661 TI - Incorporation of Herbal Supplements into a Pharmacogenomic Medication Therapy Management Practice. AB - Personalized medicine, including direct-to-consumer (DTC) testing, is becoming a more common patient-centered approach to pharmacotherapy. However, DTC testing companies may not provide adequate information and follow-up to patients after genetic testing is done. This article is the first report describing a medication therapy management pharmacotherapy service that specializes in pharmacogenomic counseling, specifically geared toward identifying implications of dietary and herbal supplements. A pharmacist provides a comprehensive review of pharmacokinetic and pharmacodynamic consequences of a patient's herbal substances, and counseling is provided on subsequent drug therapy effects. If properly implemented, offering a pharmacogenomic medication therapy management service that specializes in the use of herbal supplements provides patients with education on the safe use of these substances based on their genetic factors. PMID- 28569662 TI - Sliding-Scale Insulin Use in Long-Term Care: An Updated Perspective. AB - Diabetes affects approximately 26% of individuals oldeR THAN 65 years of age in the United States and up to 33% of patients in long-term care facilities. The most commonly prescribed insulin therapy for patients in long-term care is sliding-scale insulin (SSI): the use of finger-stick blood glucose testing to assess the need for insulin administration based on current blood glucose levels. SSI has been on the Beers Criteria of Potentially Inappropriate Medications since 2012. However, its sole use for long-term treatment is specifically not recommended by the American Diabetes Association and other stakeholders in diabetes management. This review discusses recent updates to several published guidelines, including Centers for Medicare & Medicaid Services, the Beers criteria, the American Medical Directors Association, and the American Diabetes Association regarding the use of SSI-only insulin regimens for elderly patients in long-term care. PMID- 28569663 TI - Do Restrictions on Antipsychotic Use Differ Between Medicare Part D Stand-Alone Versus Medicare Advantage Plans? AB - OBJECTIVE: The objective of this study was to describe the type of restrictions and differences among antipsychotic users enrolled in Medicare Part D Stand-Alone (PDPs) and Advantage (MAPDs) prescription drug plans. METHODS: This retrospective study used data from Chronic Condition Data Warehouse, comprising a random 5% sample of the Medicare population in 2008. This study used bivariate analyses and multivariate logistical regression models to study differences in formulary restrictions on antipsychotic use between PDP and MAPD enrollees, adjusting for enrollee characteristics. Dependent variables included type of restriction and antipsychotic therapeutic class. The study sample was restricted to continuous Part D enrollees (N = 1,346,978) stratified by plan type, MAPDs (N = 435,591), and PDPs (N = 911,387). RESULTS: According to the bivariate analysis, antipsychotic users enrolled in PDPs were more likely to encounter restrictions (39.8%), compared with those in MAPDs (30.3%). In the multivariate analyses, antipsychotic users in MAPDs were less likely to face any restriction (odds ratio [OR] = 0.75, 95% confidence interval [CI] 0.72-0.78). Furthermore, atypical antipsychotic users in MAPDs were less likely to face any restriction (OR = 0.76, 95% CI 0.73-0.79), while first-generation antipsychotic users in MAPDs were more likely to face any restriction (OR = 1.87, 95% CI 1.32-2.65). Low-income subsidy (LIS) beneficiaries using any antipsychotic were much more likely to face restrictions compared with non-LIS beneficiaries. CONCLUSION: PDP enrollees prescribed antipsychotics were more likely to face formulary restrictions, as opposed to those in MAPDs. LIS beneficiaries enrolled in PDPs faced much higher risk of restricted access to this "protected" drug class. PMID- 28569664 TI - The Importance of Early Grassroots on Policy. PMID- 28569667 TI - Piezoelectric effects in boron nitride nanotubes predicted by the atomistic finite element method and molecular mechanics. AB - We calculate the tensile and shear moduli of a series of boron nitride nanotubes and their piezoelectric response to applied loads. We compare in detail results from a simple molecular mechanics (MM) potential, the universal force field, with those from the atomistic finite element method (AFEM) using both Euler-Bernoulli and Timoshenko beam formulations. The MM energy minimisations are much more successful than those using the AFEM, and we analyse the failure of the latter approach both qualitatively and quantitatively. PMID- 28569665 TI - A vitamin-B2-sensing mechanism that regulates gut protease activity to impact animal's food behavior and growth. AB - To survive challenging environments, animals acquired the ability to evaluate food quality in the intestine and respond to nutrient deficiencies with changes in food-response behavior, metabolism and development. However, the regulatory mechanisms underlying intestinal sensing of specific nutrients, especially micronutrients such as vitamins, and the connections to downstream physiological responses in animals remain underexplored. We have established a system to analyze the intestinal response to vitamin B2 (VB2) deficiency in Caenorhabditis elegans, and demonstrated that VB2 level critically impacts food uptake and foraging behavior by regulating specific protease gene expression and intestinal protease activity. We show that this impact is mediated by TORC1 signaling through reading the FAD-dependent ATP level. Thus, our study in live animals uncovers a VB2-sensing/response pathway that regulates food-uptake, a mechanism by which a common signaling pathway translates a specific nutrient signal into physiological activities, and the importance of gut microbiota in supplying micronutrients to animals. PMID- 28569668 TI - Achieving independent control of core diameter and carbon shell thickness in Pd-C core-shell nanoparticles by gas phase synthesis. AB - Pd-C core-shell nanoparticles with independently controllable core size and shell thickness are grown by gas phase synthesis. First, the core size is selected by electrical mobility values of charged particles, and second, the shell thickness is controlled by the concentration of carbon precursor gas. The carbon shell grows by adsorption of carbon precursor gas molecules on the surface of nanoparticles, followed by sintering. The presence of a carbon shell on Pd nanoparticles is potentially important in hydrogen-related applications operating at high temperatures or in catalytic reactions in acidic/aqueous environments. PMID- 28569666 TI - Substrate transport and anion permeation proceed through distinct pathways in glutamate transporters. AB - Advances in structure-function analyses and computational biology have enabled a deeper understanding of how excitatory amino acid transporters (EAATs) mediate chloride permeation and substrate transport. However, the mechanism of structural coupling between these functions remains to be established. Using a combination of molecular modeling, substituted cysteine accessibility, electrophysiology and glutamate uptake assays, we identified a chloride-channeling conformer, iChS, transiently accessible as EAAT1 reconfigures from substrate/ion-loaded into a substrate-releasing conformer. Opening of the anion permeation path in this iChS is controlled by the elevator-like movement of the substrate-binding core, along with its wall that simultaneously lines the anion permeation path (global); and repacking of a cluster of hydrophobic residues near the extracellular vestibule (local). Moreover, our results demonstrate that stabilization of iChS by chemical modifications favors anion channeling at the expense of substrate transport, suggesting a mutually exclusive regulation mediated by the movement of the flexible wall lining the two regions. PMID- 28569669 TI - Scaling up liquid state machines to predict over address events from dynamic vision sensors. AB - Short-term visual prediction is important both in biology and robotics. It allows us to anticipate upcoming states of the environment and therefore plan more efficiently. In theoretical neuroscience, liquid state machines have been proposed as a biologically inspired method to perform asynchronous prediction without a model. However, they have so far only been demonstrated in simulation or small scale pre-processed camera images. In this paper, we use a liquid state machine to predict over the whole [Formula: see text] event stream provided by a real dynamic vision sensor (DVS, or silicon retina). Thanks to the event-based nature of the DVS, the liquid is constantly fed with data when an object is in motion, fully embracing the asynchronicity of spiking neural networks. We propose a smooth continuous representation of the event stream for the short-term visual prediction task. Moreover, compared to previous works (2002 Neural Comput. 2525 282-93 and Burgsteiner H et al 2007 Appl. Intell. 26 99-109), we scale the input dimensionality that the liquid operates on by two order of magnitudes. We also expose the current limits of our method by running experiments in a challenging environment where multiple objects are in motion. This paper is a step towards integrating biologically inspired algorithms derived in theoretical neuroscience to real world robotic setups. We believe that liquid state machines could complement current prediction algorithms used in robotics, especially when dealing with asynchronous sensors. PMID- 28569670 TI - Construction of cell-containing, anisotropic, three-dimensional collagen fibril scaffolds using external vibration and their influence on smooth muscle cell phenotype modulation. AB - Numerous methods have been developed for preparing guiding channels/tracks to promote the alignment of highly oriented cell types. However, these manufacture methods cannot fabricate interconnected guiding channels within three-dimensional (3D) scaffolds. Providing a suitable architectural scaffold for cell attachment could lead cells to more rapidly display a desired phenotype and perform their unique functions. Previously, we developed a simple device composed of a pneumatic membrane that can generate a tunable vibration frequency to apply physical stimulation for fabricating a 3D aligned collagen fibril matrix with the characteristic D-period structure in one step. In the present study, we aimed to evaluate the cellular responses of thoracic aortic smooth muscle cells (A7r5) incorporated during the fabrication of 3D-aligned collagen fibrils with D-periods and compared these cells with those incorporated in a 3D, randomly distributed collagen matrix and in a two-dimensional (2D) aligned substrate after up to 10 days of culture. The results consistently demonstrated that A7r5 cells cultured within the 3D and 2D anisotropic matrices were aligned. Cells cultured in the 3D aligned scaffolds exhibited a higher proliferation rate as well as higher F-actin and smoothelin expression levels compared with cells cultured in 3D randomly distributed scaffolds. Together, these results indicate that a 3D-reconstituted, anisotropic collagen matrix fabricated by our process provides synergistic effects of tension stimulation and matrix stiffness on encapsulated cells and can direct A7r5 cells to transform from a synthetic phenotype into a contractile state. PMID- 28569671 TI - Degradable magnesium implant-associated infections by bacterial biofilms induce robust localized and systemic inflammatory reactions in a mouse model. AB - Biomaterial-associated Pseudomonas aeruginosa biofilm infections constitute a cascade of host immune reactions ultimately leading to implant failure. Due to the lack of relevant in vivo biofilm models, the majority of the studies report host immune responses to free-living or planktonic bacteria, while bacteria in clinical situations live more frequently as biofilm communities than as single cells. The present study investigated host immune responses to biomaterial associated P. aeruginosa biofilms in a clinically relevant mouse model. Previously, we reported metallic magnesium, a prospective biodegradable implant, to be permissive for bacterial biofilm in vivo even though it exhibits antibacterial properties in vitro. Therefore, magnesium was employed as biomaterial to investigate in vivo biofilm formation and associated host immune responses by using two P. aeruginosa strains and two mouse strains. P. aeruginosa formed biofilm on subcutaneously implanted magnesium disks. Non-invasive in vivo imaging indicated transient inflammatory responses at control sites, whereas robust prolonged interferon-beta (IFN-beta) expression was observed from biofilm in a transgenic animal reporter. Furthermore, immunohistology and electron microscopic results showed that bacterial biofilms were located in 2D immediately on the implant surface and at a short distance in the adjacent tissue. These biofilms were surrounded by inflammatory cells (mainly polymorphonuclear cells) compared to the controls. Interestingly, even though the number of live bacteria in various organs remained below detectable levels, splenomegaly indicated systemic inflammatory processes. Overall, these findings confirmed the resistance of biofilm infections in vivo to potentially antibacterial properties of magnesium degradation products. In vivo imaging and histology indicated the induction of both local and systemic host inflammatory responses to P. aeruginosa biofilms. Even though the innate host immune defenses could not eliminate the local infection for up to two weeks, there was no apparent systemic bacteremia and all the animals investigated survived the infection. PMID- 28569673 TI - "Unmasked to a Positive Triumph": Women With HIV Share the Benefits of Showing Their Faces Through Photovoice. PMID- 28569672 TI - Implementing a Community-Driven Research Partnership: The Backyard Initiative Community Health Survey Methods and Approach. PMID- 28569675 TI - "Unmasked to a Positive Triumph": Women With HIV Share the Benefits of Showing Their Faces Through Photovoice. AB - BACKGROUND: The human immunodeficiency virus (HIV) and AIDS continue to affect the quality of life for minority and low-income women at alarming rates. As a result, research studies that collaborate with women with HIV are increasing with the intent of identifying ways to improve their outcomes. OBJECTIVES: This article identifies the effects on women with HIV who chose to show their faces in photographs taken to express their personal experiences. METHODS: In multiple community-based participatory research (CBPR) studies, researchers collaborated with participants to identify personal experiences of women with HIV using photovoice. During the data analysis of photographs, discussions, and interviews, the women with HIV shared the importance of showing their faces. This article presents the common themes to explain why some of the women desired to or actually chose to show their faces in the photographs. RESULTS: Of the 35 women with HIV who collaborated, 14 chose to show their self-portraits. Reasons for showing their faces varied and included to express self-pride, to reduce stigma by fighting stereotypes, to get help for their HIV, to help or educate others, and to show progression from sickness to health. The most prominent themes in the analysis were to (1) reveal the "real" face of HIV/AIDS, (2) share self-portraits as an act of resistance, and (3) help other women living with HIV. CONCLUSIONS: Photovoice is valuable and beneficial for participants. The women with HIV demonstrated strength and power as they explained reasons for showing their faces and revealing their selfies. PMID- 28569674 TI - Implementing a Community-Driven Research Partnership: The Backyard Initiative Community Health Survey Methods and Approach. AB - BACKGROUND: In community-based participatory research (CBPR), issues such as creating a setting where community members drive decisions and creating culturally relevant processes remain largely underachieved. The Backyard Initiative (BYI) provided the setting for implementing a community-centered collaborative research process. The BYI is a partnership between Allina Health, the Cultural Wellness Center (CWC), and community residents to improve health. OBJECTIVES: To describe the unique community-centered method used in the 2013 BYI Community Health Survey (CHS) as a viable approach for collecting meaningful and valid health related data. With this approach, the community operates as the agent of change rather than the target. METHODS: At the core was the BYI assessment team, which brought together conventional researchers and community members to collaboratively design, implement, analyze, interpret, and disseminate the CHS results. Focusing on the CHS, this structure and process permitted and facilitated important and difficult discussions about approach, content and outcomes of the research. RESULTS: We held seven sessions (239 participants). Participants were 37% African American/African and 34% Native American, 65% female, and 72% spoke English at home. Achievement of our recruitment goals, participation of groups typically underrepresented in research, and positive community feedback were indications that the BYI approach to survey research was successful. CONCLUSIONS: The BYI CHS community-centered methods built trust among research partners and participants, engaged populations often underrepresented in research, and collected meaningful data. Our success indicates that it is possible to co-design and implement a lengthy survey to inform future research and community activities. PMID- 28569676 TI - The State as Community in Community-Based Participatory Research. AB - BACKGROUND: Community-based participatory research (CBPR) typically defines communities by geography, ethnicity, shared health needs, or some combination. OBJECTIVES: We describe a CBPR project aiming to engage diverse minority and underserved communities throughout Michigan in deliberations about health research priorities. METHODS: A steering committee (SC) with 15 members from minority and underserved communities and 4 members from research organizations led the project, with the help of regional advisory groups (RAGs) formed at the SC's request. Evaluation of the SC used questionnaires, focused group discussion, and review of SC meetings to describe engagement, partnership, and communication. LESSONS LEARNED: An academic-community partnership with a diverse, dispersed, and broadly defined community found value in RAGs, dedicated academic staff, face-to face meetings, varied communication modalities, capacity building tailored to varying levels of CBPR experience, and ongoing evaluation. CONCLUSIONS: A geographically and culturally diverse partnership presents challenges and opportunities in representativeness, relationship building, capacity building, and communication. PMID- 28569677 TI - SMART (Student Media-based Asthma Research Team): Engaging Adolescents to Understand Asthma in Their Communities. AB - BACKGROUND: Asthma rates in Chicago exceed national averages and disproportionately affect minority adolescents. We collaborated with students in a neighborhood with high asthma prevalence to better understand community factors impacting asthma. OBJECTIVES: To evaluate the impact of our Student Media-based Asthma Research Team (SMART) program on student, parent, and student-peer outcomes related to asthma. METHODS: Students with asthma (n = 11), their parents (n = 9), and student-peers (n = 91) participated in a school-based asthma intervention grounded in community-based participatory research (CBPR) principles and completed multiple pre-/post-intervention questionnaires. RESULTS: After the program, participants significantly increased (p < 0.05) asthma-related quality of life (QOL), asthma control, emotional support, and empowerment. Parents significantly increased their QOL and student-peers showed significant improvements in asthma knowledge. CONCLUSIONS: This novel intervention-which used participatory media as a vehicle through which children learn about their own asthma and share their findings with parents and peers-was successful in engaging adolescents to improve asthma management and community support. PMID- 28569678 TI - Performing the Peace: Using Playback Theatre in the Strengthening of Police Community Relations. AB - BACKGROUND: Police-community relations have catapulted onto the national stage after several high-profile instances of alleged police brutality. Blame and hostility can be barriers to positive police-community relations. Playback is a form of audience-inspired, improvisational theater designed to promote connectivity and empathy through storytelling. OBJECTIVES: We tested the feasibility and acceptability of an arts-based intervention, bringing together police officers and formerly incarcerated individuals from the same community in Memphis, Tennessee. METHODS: We collected pre/post quantitative data from five police officers and five ex-offenders who took part in the intervention, as well as qualitative data to provide contextual information. RESULTS: The project was feasible and acceptable to participants. Participants showed gains in their ability to make meaning of stressful life experiences. The officers and ex offenders showed parallel gains in their increased positive attitudes toward the other group. CONCLUSIONS: This study demonstrates that creating contexts of safety and understanding necessary to address relational problems is both feasible and acceptable to law enforcement and ex-offenders. PMID- 28569679 TI - Strategic Partnerships for Change in an Environmental Justice Community: The ENRRICH Study. AB - BACKGROUND: San Bernardino, California, is home to the San Bernardino Railyard (SBR), a major commerce hub with high associated air-pollution, identified as an environmental justice (EJ) issue by local community and air quality agencies. Alarmingly, one elementary school is located only a few hundred yards from SBR. METHODS: The school, university researchers, and a local community-based organization (CBO) established a partnership to assess potential adverse health impacts in the children and develop interventions and mitigation plans. RESULTS: Study results comparing target school with a demographically matched school verified community concerns finding significantly poorer respiratory health in children attending school near the railyard. Partners are working with local and state collaboratives, the school board, and funding agencies to address the resulting needs of children through education, mitigation, and prevention in an environment where necessary systems changes involving the railyard are elusive. CONCLUSIONS: This paper shares lessons learned in moving toward change when addressing an EJ community's health challenges. PMID- 28569680 TI - A Co-Learning Model for Community-Engaged Program Evaluation. AB - OBJECTIVES: The development, implementation, and assessment of a masters-level program evaluation course designed to train future and current leaders of community-based organizations (CBOs) is described. BACKGROUND: In addition to sending students "out" into the community, staff from local community organizations were invited "in" to the classroom to take the course alongside students. Community partners selected a specific evaluation need within their organization that teams could address. The "final" for the course involved creating a comprehensive evaluation plan for each organization to implement. METHODS: Student course evaluations and semistructured interviews with community partners were conducted and analyzed to assess how course goals were met.Results/Lessons Learned: The course goals were met, the partnering experience was highly valued, and insightful improvements were suggested. CONCLUSIONS: This program evaluation course provides an innovative, effective, flexible, and replicable partnership practice model that builds student skills and community capacity in evaluation research. PMID- 28569681 TI - Lessons Learned From Implementing Health Coaching in The Heart Healthy Lenoir Hypertension Study. AB - BACKGROUND: Health coaching is increasingly important in patient-centered medical homes. OBJECTIVES: Describe formative evaluation results and lessons learned from implementing health coaching to improve hypertension self-management in rural primary care. METHODS: A hypertension collaborative was formed consisting of six primary care sites. Twelve monthly health coaching phone calls were attempted for 487 participants with hypertension. LESSONS LEARNED: Participant engagement was challenging; 58% remained engaged, missing fewer than three consecutive calls. Multivariate analyses revealed that older age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01-1.05), African American race (O,R 1.73; 95% CI, 1.15-2.60), greater number of comorbidities (OR, 1.17; 95% CI, 1.05-1.30) and receiving coaching closer to enrollment (OR, 5.03; 95% CI, 2.53-9.99) were correlated independently with engagement. Participants reported the coaching valuable; 96% would recommend health coaching to others. CONCLUSIONS: Health coaching in hypertension care can be successful strategy for engaging more vulnerable groups. A more tailored approach may improve engagement with counseling. PMID- 28569682 TI - Engaging Study Participants in Research Dissemination at a Center for Population Health and Health Disparities. AB - BACKGROUND: Research dissemination is a priority for The Partnership for Understanding and Eliminating Disparate Outcomes (PUEDO) for Latinas, a Center for Population Health and Health Disparities located at the Fred Hutchinson Cancer Research Center (FHCRC). OBJECTIVES: We aimed to identify types of PUEDO research findings our participants wanted and why, dissemination audiences beyond PUEDO participants, and strategies to communicate diverse findings about breast cancer and breast cancer disparities. METHODS: Five focus groups with PUEDO study participants (N = 25) were transcribed for qualitative content analysis (average participants per focus group, 5; range, 2-11). RESULTS: Participants reported wanting to learn aggregate and personal results and were influenced by their life experiences, their experiences as study participants, and the relevance they believed specific results would have for their lives. Women advocated for broad dissemination and inclusive communication using a simple paper-based strategy that would be accessible to diverse audiences (e.g., study participants, policymakers, recent immigrants). CONCLUSIONS: Focus groups informed PUEDO's dissemination strategy, which concentrates on study participants and the regional Latino community. This approach to dissemination should maximize information uptake and community benefit. PMID- 28569683 TI - Lessons Learned From a Partnership to Evaluate a School Food Program. AB - BACKGROUND: In 2013, leadership at a Boston school approached academic investigators for help with assessing their new school food program. METHODS: The community-academic partnership implemented a two-phase community-based participatory research (CBPR) assessment. The qualitative phase involved key stakeholder focus groups. The quantitative assessment involved height/weight measurement and dietary recalls at the beginning and end of the year. RESULTS: The qualitative assessment revealed low stakeholder engagement in the food program and resulted in substantive changes. In the quantitative phase, the partnership terminated the study after recruitment goals were not met. LESSONS LEARNED: The quantitative assessment faced administrative hurdles to conducting school-based research and obtaining institutional review board (IRB) approval of CBPR projects, low recruitment, and diminished partnership strength. The constant effort to sustain partnerships, IRB processes mal adapted for CBPR, and training needs for community investigators are challenges and opportunities for success. CONCLUSIONS: CBPR can be useful for school-based research, but key process changes could increase its effectiveness. PMID- 28569686 TI - The Evolution of an Innovative Community-Engaged Health Navigator Program to Address Social Determinants of Health. AB - BACKGROUND: Health navigators and other types of community health workers (CHWs) have become recognized as essential components of quality care, and key for addressing health disparities owing to the complex health care services landscape presents almost insurmountable challenges for vulnerable individuals. Bernalillo County, New Mexico, has high rates of uninsurance, poverty, and food insecurity. OBJECTIVES: The design of the Pathways to a Healthy Bernalillo County Program (BP) has evolved innovations that are unique in terms of program stability and security, expansive reach, and community capacity across six domains: sustainable public mechanism for program funding, involvement of community organizations in designing the program, expanded focus to address the broader social determinants of health with targeted outreach, an integrated, community-based implementation structure, an outcomes-based payment structure, and using an adaptive program design that actively incorporates navigators in the process. METHODS: In 2008, the Pathways to a Healthy Bernalillo County Program (BP), located in the Albuquerque metropolitan area in central New Mexico, was established to provide navigation and support for the most vulnerable county residents. BP is funded through a 1% carve out of county mill levy funds. RESULTS: The pathways model is an outcome-based approach for health and social services coordination that uses culturally competent CHW as "navigators" trained to connect at-risk individuals to needed health and social services. CONCLUSIONS: One of the important innovations of the pathways approach is a shift in focus from merely providing discrete services to confirming healthy outcomes for the individual patient. PMID- 28569684 TI - A Community-Based Participatory Research Guided Model for the Dissemination of Evidence-Based Interventions. AB - BACKGROUND: Dissemination is a principle within community-based participatory research (CBPR); however, published research focuses on the dissemination of findings from CBPR projects but less on dissemination of interventions developed through CBPR approaches. To disseminate an evidence-based lifestyle intervention tailored for Native Hawaiians and other Pacific Islanders, the PILI 'Ohana Project (POP), an 11-year CBPR initiative, developed an innovative dissemination model. OBJECTIVES: The community-to-community mentoring (CCM) model described in this paper extends the application of CBPR values and principles used in intervention development to intervention dissemination. METHODS: The CCM model combines a CBPR orientation with the diffusion of innovation theory, the social cognitive theory, and key concepts from community organizing and community building to address the multilevel factors that influence uptake of an evidence based intervention (EBI). Grounding the model in CBPR principles provides benefits for intervention dissemination and integrates a focus on community benefits and capacity building. CONCLUSIONS: By establishing co-equal, mutually beneficial relationships at the core of the CCM model, opportunities are created for building critical consciousness, community capacity, and social capital. More research is needed to determine the effectiveness of this model of intervention dissemination which may enhance diffusion of CBPR interventions and empower communities in the process. PMID- 28569688 TI - Engineering Philosophy: Theories of Technology, German Idealism, and Social Order in High-Industrial Germany. AB - During the so-called "Second Industrial Revolution," engineers were constituting themselves as a new social and professional group, and found themselves in often fierce competition with existing elites-the military, the nobility, and educated bourgeois mandarins-whose roots went back to medieval and early modern pre industrial social orders. During that same time, engineers also discovered the discipline of philosophy: as a means to express their intellectual and social agendas, and to theorize technology and its relationship to art, history, culture, philosophy, and the state. This article analyzes engineers' own philosophical writings about technology as well as the institutions in which they composed them in 1910s and 1920s Germany. It emphasizes engineers' contributions to well-known discourses founded by canonical philosophers, the role of preindustrial economies and their imagination in such philosophies, and the role of both the history and the philosophy of technology in engineers' desire for upward social mobility. PMID- 28569689 TI - The Text in the Machine: American Copyright Law and the Many Natures of Software, 1974-1978. AB - This article is a case study in the history of software copyright in the United States from 1974 to 1978. It focuses on the work of a group called the National Commission on New Technological Uses of Copyrighted Works. CONTU, as this group was known, faced the problem of choosing which ontology of software-by which I mean a conception of the nature of software as an invention-should serve as the conceptual underpinning for the law of software copyright. In particular, the commissioners needed to decide whether computer programs are texts, machines, means to communicate with machines, or many of these things at once. CONTU's history shows how the discursive emergence of software as a new technology has been shaped by the convergence of commercial interests, the transmission of technical knowledge to lay audiences, and idiosyncratic views on the nature of information technology and human creativity. PMID- 28569690 TI - Droughts and Dragons: Geography, Rainfall, and Eighteenth-Century London's Water Systems. AB - By the end of the eighteenth century the majority of households in London received a piped water supply. This article examines the geographical, technological, and environmental challenges that London's private water companies faced as they created and expanded the large technological networks necessary to provide the growing city's water supply. It identifies geography and drought as the main drivers of innovation in London's water supply neworks, and argues that the main impediment to expansion for the majority of the water companies was overcoming the differences in elevation between their intake points and customer bases, with major improvements often made as a result of water shortages. The timing and the success or failure of a company's technological improvements proved pivotal in the subsequent development of the water market. PMID- 28569691 TI - From Natural Monopoly to Public Utility: Technological Determinism and the Political Economy of Infrastructure in Progressive-Era America. AB - In present-day debates regarding telecommunication policy, one frequently hears the terms natural monopoly and public utility. This article investigates the origins of these ideas, finding that Richard T. Ely-a celebrated American economist of the late nineteenth century-embedded in the term "natural monopoly" a narrative of technological determinism. By arguing that certain services had monopolizing tendencies hardwired into them, Ely argued for their regulation. Ely's theory of natural monopoly formed the basis of Wisconsin's 1907 public utilities law, which served as a model for many other states' regulatory policies. The modern notion of public utility thus carries with it the technological determinism of Ely's natural monopoly idea. By tracing the lineage of these two terms, this article recaptures the influence that activists and progressive politicians exercised over the formation of large technological systems during the Second Industrial Revolution. PMID- 28569692 TI - Detente from the Air: Monitoring Air Pollution during the Cold War. AB - During the period of detente in the 1970s, a Norwegian proposal to construct an air pollution monitoring network for the European continent resulted in the first concrete collaboration between the communist and capitalist blocs after the 1975 Helsinki Accords. Known as the "European-wide monitoring programme" or EMEP, the network earned considerable praise from diplomats for facilitating cooperation across the Iron Curtain. Yet as this article argues, EMEP was strongly influenced by the politics of detente and the constraints of the Cold War even as it helped to decrease tensions. Concerns about national security and sharing data with the enemy shaped both the construction of the monitoring network and the modeling of pollution transport. The article also proposes that environmental monitoring systems like EMEP reveal the ways in which observational technologies can affect conceptions of the natural world and the role of science in public policy. PMID- 28569693 TI - Proximal Design: Users as Designers of Mobility in the Russian North. AB - By examining mobility in remote Arctic areas, we analyze how challenging environmental conditions, while affecting technology performance, evoke people's creativity and efforts as technology users. Based on historical materials and ethnographic observations of user inventiveness in the transport sector in the Russian North, we define and document a phenomenon of "proximal design" in three different modes: the proximal complementation of "distant design" machines (trucks and military equipment) to ascertain their reliability; the emergence of a new type of homemade all-terrain vehicle called a "karakat," made from salvaged parts to specialize in times and locations where other vehicles turn unreliable; and the traditional craft of sledge-making by nomadic reindeer herders of the Yamal area, where even materials are proximally collected and shaped. Our main argument is that continuous tuning, modification, and redesign of technology carried out by immediate users in situ make it possible for humans and machines to function in extreme settings and that this can lead also to emergence of enduring design principles. We outline key characteristics of proximal design such as constraining environment, inventiveness by necessity, flexible construction, personalization and symbolic meaning, and social embeddedness of making/maintaining practices. PMID- 28569694 TI - The Concave Faces of the Great Pyramid: An Explanation. AB - A construction methodology proposed by the author in 2003 to explain how the Great Pyramid was built suggested that workers used the angled faces of the pyramid as surfaces on which to transport block and sledge assemblies. This methodology however would leave few material traces behind making it more difficult to conclusively prove. This article argues that the known concavity of the outer packing blocks of the Great Pyramid provides meangingful archaeological evidence to add weight to the author's proposed construction methodology. PMID- 28569695 TI - STEP Matters: Historiographical Considerations. AB - In this introduction, we revisit major discussions around historical themes and historiographical issues that took place during the fifteen-year life of STEP (Science and Technology at the European Periphery). We will attempt to draw the profile of STEP, and put forth some concrete proposals as to its prospects of collaboration with other groups and societies. We also elaborate on the rationale behind the selection of topics presented in this issue, analyse questions posed and challenges faced, and offer some historiographical comments on the potential of the STEP perspective in the context of international scholarship. PMID- 28569696 TI - Beyond Fixed Geographies: Moving Localities and the Making of Knowledge. AB - In recent historiography the notion of circulation serves as a basis for weaving together global narratives of the history of science. However, the emphasis placed by such narratives on the impact of European science should not overshadow the fact that the making of knowledge in Europe is a dynamic and multi-layered process that cannot be reduced to simple models of knowledge circulation among fixed localities. In order to develop this perspective, the authors introduce the notion of "moving localities," as a means to depict the mutually transformative encounters that shaped the notion of European science and technology. PMID- 28569697 TI - Education and Textbooks. AB - Education and textbooks have traditionally been standard objects of research in the history of science, technology, and medicine. However, they have often remained marginal in the formulation of large historiographical questions. In the last decades, the work of some historians of science has challenged this state of affairs. STEP has promoted a distinctive focus on education and textbooks, compared to other scholarship cultures such as the Anglo-American. This essay reviews its work in this field and stresses the potential of education and textbooks to produce interdisciplinary research in local, national, and international perspective. PMID- 28569698 TI - Experts and Peripheries: Ongoing Research and Future Challenges. AB - Based on existing research on Spain and Greece, the essay is focused upon the activity of experts in criminal courts and advisory committees. Following the experts in these settings, we offer examples of their roles in governing techno sciences in societies of the European periphery. We highlight the tensions between the creative powers of localities and the movement of expert knowledge in a world marked by striking inequalities concerning economic, political and academic power. We claim that a comparative study of these movements will be refine the historical understanding of experts and expertise. PMID- 28569699 TI - Popularization of Science, Technology, and Medicine in the "Periphery": A Step Further? AB - Based on the research that has been carried out within STEP, this essay suggests an integrative approach for the study of science, technology and medicine popularization in the European periphery during the nineteenth and early twentieth century. Such an approach can be a privileged tool not only for examining the complex processes of institutionalization and specialization of STM in peripheral countries, but also for exploring the interplay of STM in the making of modernity, since popularization seemed to have deep political implications in the implementation of modernization programs and the construction of national and professional identities in the European periphery. PMID- 28569700 TI - How to Write an Urban History of STM on the "Periphery". AB - Within the STEP research agenda there has never been an explicit focus on the city as a central place for knowledge production. Scholars of the urban history of science tend to concentrate on the metropolis and have not looked in any systematic way at the scientific culture in "peripheral" urban contexts. To fill this gap, this essay proposes to focus on: (1) the role of science, technology and medicine in everyday life and the experiences of the citizens; (2) the plurality of the often conflicting notions of urban modernity; (3) the complex networks of interurban connections between the "peripheries." PMID- 28569701 TI - Technology and Nation: Learning from the Periphery. AB - This essay explores the role of technology in building nations as material and cultural artifacts from two peripheral perspectives. First, it brings to the fore what we call epistemic peripheries in the history of technology, be they objects or actors usually neglected when studying the interplay between technology and the nation. Second, it deals with geographic peripheries by focusing on connections, networks, and circulation processes far beyond linear and static core-periphery relations. We claim that one cannot properly understand how technological national identities were created if national boundaries are taken as strict analytical frameworks. In this sense, the essay advocates a transnational history with a wider empirical focus. PMID- 28569702 TI - Volume 57 (2016). PMID- 28569703 TI - Scholars versus Practitioners?: Anchor Proof Testing and the Birth of a Mixed Culture in Eighteenth-Century France. AB - In line with studies that question the conventional dichotomies between "head" and "hand," this article analyzes the emergence of a mixed naval culture, between science and technology, during the French Enlightenment. The case at issue is that of the circuitous development of an anchor proof testing protocol, an important method in the competition for maritime supremacy used at least until the first third of the nineteenth century. The story begins in the dockyard of Brest with a humble boatswain, and continues with the dissemination of his experiments thanks to prominent figures of the Naval Academy of Brest and of the Royal Academy of Sciences of Paris. The article suggests that if the findings of the latter were rather inconclusive, nevertheless, over time, a collaboration between practitioners and scientists did eventually generate a regular protocol for testing anchors. PMID- 28569704 TI - She Wears the Pants: The Reform Dress as Technology in Nineteenth-Century America. AB - This article examines the American dress-reform movement, detailing the ways in which reformers conceptualized clothing as a social and bodily technology. In the mid-nineteenth century, women began making and wearing the "reform dress"-a costume consisting of pants and shortened, lightweight skirts-as an alternative to burdensome feminine fashions. When ridiculed in public for wearing overtly masculine garments, dress reformers insisted their clothing was healthful, functional, and natural. This article discusses women's use of medical science and technical knowledge in their rejection of fashion, promotion of sexual equality, and efforts to change mainstream clothing practices. When approached from a technological perspective, the reform dress reveals broader tensions in an industrializing American society, such as changing gender relations and new understandings of the relationship between humans and technology. PMID- 28569705 TI - What's in a Pipe?: NATO's Confrontation on the 1962 Large-Diameter Pipe Embargo. AB - By the late 1950s, the Soviet Union had acquired a strong position as a world oil exporter, thanks to major discoveries in the Ural-Volga area. In order to transport their oil to strategic areas within the Union and to Europe, the Soviets devised a project to build a colossal pipeline system. This plan caused anxiety at NATO since Russian oil could be wielded as a weapon to weaken the West both militarily and economically. In order to complete the system, however, the Soviets needed large-diameter steel pipes and equipment, which they had to import from the West. Thus in 1961 the U.S. delegation at NATO proposed a comprehensive embargo of large-diameter pipes in order to delay the system's construction. I argue that the definition of what oil pipes were as technological artifacts, as well as their final content, was ultimately shaped by the NATO debate on this U.S. proposition. PMID- 28569706 TI - Naked Gene Salmon: Debating Fish, Genes, and the Politics of Science in the "Age of Publics". AB - This article follows what was supposed to become a new salmon for the aquaculture industry on its travels through Norwegian society during the 1980s. This is a history of a new animal technology that was born out of the biotechnology hype of the 1980s. The article takes Edmund Russell's claim that the tools of historians of technology can be utilized for investigating animals as technologies as a point of departure. However, instead of investigating the construction of the fish, the article focuses on how the new creature was integrated into society through controversy. PMID- 28569707 TI - Know-How in Postwar Business and Law. AB - In the mid-twentieth century, businesses around the world began to see technical know-how as one of the most important assets they could possess. While their exact definitions of know-how varied (usually centering on employees' tacit knowledge; accumulated, minor innovations rather than just patentable inventions; and tailoring to local conditions), the rapidly growing perception that it was invaluable led to widespread know-how licensing. As businesses embraced it, legal scholars and business lawyers during the 1950s through the 1970s scrambled to clarify legal bases for intellectual property protections for know-how. In the 1970s Supreme Court decisions undermined this effort, and a consortium of legal organizations turned instead to lobbying for statutory protection for the related, narrower category of "trade secrets." Despite the rise and relative decline of know-how in American business and law, interest in the term spread to other languages and legal systems, and the repercussions of these shifting understandings of technology transfer remain with us today. PMID- 28569708 TI - Introduction: Searching for the Historical Roots of 11 March 2011. AB - Debates about preserving traces of disaster for historical commemoration have emerged amid the processes of recovery and healing from the 2011 Great Tohoku Earthquake, tsunami, and nuclear power plant disasters. Prompted by the tensions that underlie decisions about the value of maintaining damaged artifacts and structures for public memorialization, this essay introduces the forum "Japan Before Disaster Studies," which encourages a reconsideration of "disaster heritage" as something that also maintains an active awareness of the roles of technology and science in the depths of Japan's disaster histories. Reconstructing these roots of disaster histories should enrich a more accessible understanding of the actors, institutions, policies, and discourses connected to various disaster contexts. PMID- 28569709 TI - Remembering Future Risk: Considering Technologies of the Archive for Discussion of Tohoku's Seismological Past after 2011. AB - In Japan, calls for the discovery, preservation, and translation of old documents that mention past earthquakes only intensified after the earthquake, tsunami, and nuclear disaster of March 2011. A closer look at the original record and archival processes that have gone into the historical account of the earthquake and tsunami of 9 July 869 reveals the ways in which the "memory" of the Jogan tsunami depends as much on modern seismic archaeology and educational institutions as ancient documents. Historical risk assessment, therefore, must draw on both old and new technologies of the archive. PMID- 28569710 TI - Reverse Flow: The Role of Built Environments in Shaping Disaster. AB - In contrast to approaches that examine the impacts of human-built efforts to ameliorate calamitous natural events, this essay argues that a wide array of large structures shape the outcomes of these events. Further, significant human artifacts can succeed in their function vis-a-vis one set of natural events, but can have unanticipated, even reverse effects when natural forces exceed planned expectations. Risk assessments do not normally consider such side effects, suffering from an agnotological narrowing of focus. The historian's emphasis on temporal contextualization and contingency has important implications for policy and assessment of risk. PMID- 28569711 TI - Reorganization, Deregulation, and Liberalization: Postwar Development of the Japanese Electric Power Industry and Its Change after 11 March 2011. AB - The reform of Japan's electric power industry after the Fukushima nuclear accident is, despite public expectations for the shutdown or reduction of nuclear power, placing more emphasis on liberalizing the industry. This essay tries to show that the present reform is a revival of the government's liberalization plan that emerged in the mid-1990s and was aborted around 2003 since the power companies hinted that further deregulation might discourage them from following the government's nuclear policy. The Fukushima accident changed the balance of power-political, not electric-between them and allowed the government to implement its long-cherished reform plan. PMID- 28569713 TI - Awards. PMID- 28569712 TI - Reconstructing the Linear No-Threshold Model in Japan: A Historical Perspective on the Technics of Evaluating Radiation Exposure. AB - The 2011 nuclear power plant disaster and subsequent medical surveys of citizens in Fukushima Prefecture have helped reopen questions about competing models' effects of long-term, low-dose radiation exposure on human health. A reconstruction of how Japanese scientists studied low-dose effects of radiation in the years following the 1954 Castle Bravo detonation can deepen understandings as to why questions about the reliability of such risk analysis tools persist. Greater attention to the hopes associated with local research contributions to building international safety standards can begin to shed historical light upon how different technics of evaluating radiation effects have allowed scientists to envision either uncertain or certain futures in Japan with respect to radiation. PMID- 28569714 TI - The Singapore Meeting, 22-26 June 2016. PMID- 28569715 TI - Forty-third Symposium of the International Committee for the History of Technology: "Technology, Innovation, and Sustainability: Historical and Contemporary Narratives," Porto, Portugal, 26-30 July 2016. PMID- 28569716 TI - In Memoriam Richard Selzer (1928-2016). PMID- 28569717 TI - Introduction: Pathological Reading. PMID- 28569718 TI - Two Kinds of "Literary Poison": Diseases of the Learned and Overstimulating Novels in Georgian Britain. AB - This article will analyze the complex relationship between two separate traditions of anxiety about the medical impact of reading. On the one hand there was the older concept of the diseases of the learned (Gelehrtenkrankheiten), associated with crabbed, often impecunious academics. This is a tradition that went back centuries and drew on the six non-naturals of Galenic medicine. On the other hand there was fear that the sentimental novel-reading habits of the leisured elite were overstimulating their nerves, a model that was based primarily on the newer medicine of stimulation associated with physicians such as Cullen, Whytt, Tissot, and Brown. This article will examine how these two models of pathological reading came together during the late eighteenth and early nineteenth centuries, and what they show about the role of the imagination, luxury, gender, and sexuality. PMID- 28569719 TI - Toxic Texts and Reading Remedies: Literary Medicine in Eighteenth-Century Print Cultures. AB - Today the idea of reading for health is perhaps most commonly associated with the term bibliotherapy. This seemingly new practice might be considered a significant shift of public and professional medical attitudes when compared with historical interpretations of the impact of reading on individuals' health. Much historiography concerning the reception of popular literature in eighteenth century print culture has focused on the belief that readers of fiction, most often women, were at risk of corrupting their own minds and bodies through their reading choices. Yet, although popular, this view was not exclusively subscribed to by either medical practitioners or the wider public. This article reveals perspectives that warned against and celebrated the effects of reading on human health during the eighteenth century. Unlike what we see from much contemporary scholarship there is, in fact, a range of evidence which demonstrates that eighteenth-century medical practitioners were already engaging with the concept of reading as a therapeutic activity. PMID- 28569721 TI - Leaky Bodies, Bawdy Books: Gonorrhea and Reading in Eighteenth-Century Britain. AB - In eighteenth-century Britain, reading lewd books was understood to exacerbate gonorrhea. That pathology corresponded to a specific physiological model, which historians describe as the leaky male body. This article demonstrates how the connection between reading and gonorrhea correlated to three phenomena: 1) the neuro-sexual economy of bodily fluids; 2) the effects of reading on the sensible mind and body; and 3) the crossover of erotic and medical literatures. Aware of the physiological power of imagination, authors intentionally wrote to elicit strong physiological and sexual responses in readers. Concerns about the pathological and moral consequences of reading provocative material similarly informed criticisms of both the outright pornographic and the ostensibly medical. Partly in response to such criticisms, medical authors developed a more careful, decorous, and objective tone for writing about sexual topics. Ultimately, the culture of sensibility receded, as did anxieties about involuntary leaks of bodily fluids caused by reading. PMID- 28569720 TI - The Medical Dangers of Literary Genius. AB - This essay examines three key texts by William Buchan, Isaac D'Israeli, and Richard Robert Madden, which demonstrate the emergence of the newly conceived idea of literary genius in the Romantic period. It considers the role of a new genre, the "medical biography," in the development of this phenomenon. While the mental precariousness of the Romantic genius has been much commented upon, this essay concentrates instead on the bodily or physical aspects of genius, which is itself figured as a disease. The study and writing involved in publication are viewed as stimulants that can be addictive, ruining the health and wellbeing of authors and even leading to their early deaths. PMID- 28569722 TI - The Visceral Novel Reader and Novelized Medicine in Georgian Britain. AB - The article introduces "the visceral novel reader" as a diachronic, context sensitive mode of novelistic reception, in which fact and fiction overlap cognitively: the mental rehearsal of the activity of seeing, hearing, smelling, tasting, and touching while reading novels and, vice versa, the mental rehearsal of novels in the act of perceiving the real world. Located at the intersection of literature, medicine and science, "the visceral novel reader" enhances our understanding of the role that novels played in the dialectic construction of erudition in English. In Georgian Britain, reading practices became a testing ground for the professionalization of physicians, natural philosophers, and men of letters. While it was in the professionals' common interest to implement protocols that taught readers to separate body from mind, and fact from fiction, novels came to stand for "debased" (visceral) reading. Novels inverted these notions by means of medicalization (regimentation, somatization, and individuation) and contributed to the professional stratification of medicine and literature. PMID- 28569723 TI - French Hoffmania: Theophile Gautier's "Onuphrius" (1833) and the Critique of the Etiology of Pathological Reading. AB - "Of unknown cause"- in the conclusion of the eponymous tale written by Theophile Gautier in 1833, it is not clear what exactly the protagonist Onuphrius dies of after his infatuation with E. T. A. Hoffmann drove him mad. Thus, the reference to the possibility of "Hoffmania" is both highly medicalized, as Hoffmann appears as a case study of the sick author, while all its causes and mechanisms are left unexplored. With this suppression of the etiology of pathological reading, Gautier separates himself from both the tradition of literary discourses on pathological reading and from the new etiology of mental disorders. This allows him to expound the premises of his theory of "art for art's sake," as it echoes the paradox this theory is based upon, which contends that art is free and independent, yet its effects are deeply felt on the subject's body, in a way that must remain unclear. PMID- 28569724 TI - Werther Goes Viral: Suicidal Contagion, Anti-Vaccination, and Infectious Sympathy. AB - The fear that suicidality could spread through textual contagion-that textually represented suicide could enter the reader's mind and cause self-destruction-took hold long before Emile Durkheim theorized it in the Victorian period. This article argues that the fear of suicidal contagion and the horror of vaccination, both of which raged in Britain in the long eighteenth century, were linked to ideas about sympathy and the importation of the Other into the Self. With reference to the psychoanalytic notions of extimite and etrangerete; the eighteenth-century medical theories of William Rowley and Edward Jenner; the philosophy of "sympathy," as adumbrated in the work of John Locke, Adam Smith, David Hume and Edmund Burke; and two key novels of sensibility (Jean-Jacques Rousseau's Julie and Johann Wolfgang von Goethe's The Sorrows of Young Werther), this article examines the root of a belief that exists even today: that, in a suicidal process, the invading Other could become the Self and, Trojan horse style, destroy it from the inside. PMID- 28569725 TI - Radical Contagion and Healthy Literature in Blackwood's Edinburgh Magazine. AB - During the late eighteenth and early nineteenth centuries, the revolution in France served as a catalyst for heavily allegorical political rhetoric, and the idea that radical politics were contagious became commonplace in conservative writing and oratory. This political contagion is described by Blackwood's as raging through the ranks of the rural poor as late as 1830. Confronted by this threat, Blackwood's promoted itself alternatively as a stimulant or as a cure for the metaphorical poison or infection that radical publications were seen to be spreading amongst the poor. Blackwood's also strove to maintain the political health of its readership by identifying healthy literature for its readers and the lower order. This article analyzes Blackwood's Edinburgh Magazine's application of the vocabulary of disease and contagion to radical politics and publications, and considers questions of taste, class, and Britishness in discussions of healthy reading habits. PMID- 28569726 TI - The Lazy Reader: Labor, Books, and Disease in Nineteenth-Century Germany. AB - Looking at nineteenth-century Germany, this article investigates the origin of the idea that fiction causes disease, among both the bourgeoisie and the working class. I argue that the socially constructed notions of reading addiction, which were consistent with medical concepts at that time, touched the bourgeois virtues of industriousness and health. However, little has been written about the transfer of the bourgeois attitudes towards reading to the German working class. The study of workers' autobiographies shows that social circumstances and the emulation of bourgeois values and attitudes resulted in appropriating the concept of lazy readers in the working class. The paper follows the paths from the early nineteenth century accusation of readers to the working class's perception of novels causing disease around 1900. PMID- 28569727 TI - The Discourse on Dangerous Reading in Nineteenth-Century Latvia. AB - During the nineteenth century, Latvian society experienced significant social and cultural changes due to a transition from agrarian to modern society and the emergence of a Latvian national culture. Reading, previously a mostly religious and practical activity, took new forms among the Latvian middle class and steadily began to be depicted as a dangerous pastime. In this essay, we have explored the connection between social change and pathological reading by turning attention to the rhetoric of the dangerous reading discourse, representations of effects of reading in the press, and the condemnation of female reading. PMID- 28569728 TI - Reading Disorders: Pro-Eating Disorder Rhetoric and Anorexia Life-Writing. AB - This article explores the relationship between eating disorders and reading behaviors, arguing that there is a meaningful difference in a minority of readers' approach to and understanding of anorexia life-writing, and of literary texts more broadly. To illuminate this distinction, this article begins by considering the reported deleterious influence of Marya Hornbacher's anorexia memoir, Wasted, elaborating the ways Hornbacher offers a positive presentation of anorexia nervosa that may, intentionally or not, induce certain readers to "try it" themselves. This is followed by an exploration of how Hornbacher's own reading praxis is implicated in a discursive feedback loop around anorexia narratives. It concludes with a discussion of disordered reading attitudes in relation to the emergence of the "pro-anorexia" phenomenon. PMID- 28569731 TI - ?????? ??????. AB - L'dor vador, transliterated from the Hebrew above, is an ancient concept in Judaic scripture meaning "from generation to generation," which is now generally interpreted to mean that we have a responsibility to pass on teachings to future generations. It has been 5 years that I have been at the helm of the Duke-UNC Editorial Board of the Journal of Clinical Investigation and have had the privilege of publishing scientific knowledge that will be passed on to generations of future scientists. Now, with the selection of Dr. Gordon Tomaselli as the next editor in chief, I pass on the editorial duties for the JCI to him and his team at Johns Hopkins. PMID- 28569730 TI - Inflammasomes and IL-1 biology in the pathogenesis of allograft dysfunction. AB - Inflammasomes are high-molecular-weight cytosolic complexes that mediate the activation of caspases. There are many inflammasomes, and each is influenced by a unique pattern-recognition receptor response. Two signals are typically involved in the inflammasome pathways. Signal one involves recognition of pathogen associated molecular patterns (PAMPs), such as LPS or other colonizing/invading microbes, that interact with TLRs, which induce the downstream production of pro IL-1beta. This is followed by signal two, which involves recognition of PAMPs or damage-associated molecular patterns (DAMPs), such as uric acid or ATP, via NLRP3, which leads to caspase-1-dependent cleavage of pro-IL-1beta to active IL 1beta and pyroptosis. Ultimately, these two signals cause the release of multiple proinflammatory cytokines. Both PAMPs and DAMPs can be liberated by early insults to the allograft, including ischemia/reperfusion injury, infections, and rejection. The consequence of inflammasome activation and IL-1 expression is the upregulation of adhesion molecules and chemokines, which leads to allograft neutrophil sequestration, mononuclear phagocyte recruitment, and T cell activation, all of which are key steps in the continuum from allograft insult to chronic allograft dysfunction. PMID- 28569733 TI - Twenty fascinating conversations. PMID- 28569734 TI - Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. PMID- 28569735 TI - Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice. PMID- 28569732 TI - Inflammatory osteolysis: a conspiracy against bone. AB - There are many causes of inflammatory osteolysis, but regardless of etiology and cellular contexts, the osteoclast is the bone-degrading cell. Thus, the impact of inflammatory cytokines on osteoclast formation and function was among the most important discoveries advancing the treatment of focal osteolysis, leading to development of therapeutic agents that either directly block the bone-resorptive cell or do so indirectly via cytokine arrest. Despite these advances, a substantial number of patients with inflammatory arthritis remain resistant to current therapies, and even effective anti-inflammatory drugs frequently do not repair damaged bone. Thus, insights into events such as those impacted by inflammasomes, which signal through cytokine-dependent and -independent mechanisms, are needed to optimize treatment of inflammatory osteolysis. PMID- 28569737 TI - Nursing Care Management: Influence on Bundled Payments: Erratum. PMID- 28569736 TI - Orthopaedic Nurses-Pioneers in Care Management: Erratum. PMID- 28569738 TI - Implementation of a Pediatric Orthopaedic Bundle to Reduce Surgical Site Infections: Erratum. PMID- 28569740 TI - Do the Data Support Manometric Subclassifications for Ineffective Esophageal Motility? PMID- 28569739 TI - Endoscopic-Guided Measurement of Mucosal Admittance can Discriminate Gastroesophageal Reflux Disease from Functional Heartburn. AB - OBJECTIVES: A novel catheter that can measure mucosal admittance (MA), the inverse of impedance, was developed recently. In this pilot study, we aimed to clarify the usefulness of measuring MA for diagnosing gastroesophageal reflux disease (GERD). METHODS: We conducted two prospective studies. In the first study, esophageal MA was evaluated in 120 participants (24 with erosive esophagitis, 82 with heartburn but non-erosive esophagitis, and 14 healthy volunteers) and compared with the endoscopic findings. In the second study, multichannel intraluminal impedance combined with pH (MII-pH) tests was conducted followed by an MA measurement in 33 patients with non-erosive esophagitis and proton pump inhibitor (PPI)-refractory heartburn. Based on the MII-pH test results, patients were divided into GERD or functional heartburn (FH). MA was compared between the GERD and FH groups and also compared with the baseline impedance (BI) and acid exposure time (AET). RESULTS: Median MA at the distal esophagus was significantly higher in patients with erosive esophagitis compared with that in patients with non-erosive esophagitis and healthy volunteers (46.8, 13.1 and 6.5, respectively, P<0.01). In patients with PPI-refractory heartburn, the median MA at the distal esophagus was significantly higher in patients with GERD than those with FH (19.3 vs. 7.2, P<0.05). There was a negative correlation between MA and BI, and a positive correlation between MA and AET at the distal esophagus (r=-0.46 and r=0.53, P<0.05). CONCLUSIONS: Real-time measurement of MA is useful to distinguish GERD from non-GERD. PMID- 28569741 TI - Detection of Zak phases and topological invariants in a chiral quantum walk of twisted photons. AB - Topological insulators are fascinating states of matter exhibiting protected edge states and robust quantized features in their bulk. Here we propose and validate experimentally a method to detect topological properties in the bulk of one dimensional chiral systems. We first introduce the mean chiral displacement, an observable that rapidly approaches a value proportional to the Zak phase during the free evolution of the system. Then we measure the Zak phase in a photonic quantum walk of twisted photons, by observing the mean chiral displacement in its bulk. Next, we measure the Zak phase in an alternative, inequivalent timeframe and combine the two windings to characterize the full phase diagram of this Floquet system. Finally, we prove the robustness of the measure by introducing dynamical disorder in the system. This detection method is extremely general and readily applicable to all present one-dimensional platforms simulating static or Floquet chiral systems. PMID- 28569742 TI - Quantum test of the equivalence principle for atoms in coherent superposition of internal energy states. AB - The Einstein equivalence principle (EEP) has a central role in the understanding of gravity and space-time. In its weak form, or weak equivalence principle (WEP), it directly implies equivalence between inertial and gravitational mass. Verifying this principle in a regime where the relevant properties of the test body must be described by quantum theory has profound implications. Here we report on a novel WEP test for atoms: a Bragg atom interferometer in a gravity gradiometer configuration compares the free fall of rubidium atoms prepared in two hyperfine states and in their coherent superposition. The use of the superposition state allows testing genuine quantum aspects of EEP with no classical analogue, which have remained completely unexplored so far. In addition, we measure the Eotvos ratio of atoms in two hyperfine levels with relative uncertainty in the low 10-9, improving previous results by almost two orders of magnitude. PMID- 28569743 TI - Sources of discordance among germ-line variant classifications in ClinVar. AB - PurposeClinVar is increasingly used as a resource for both genetic variant interpretation and clinical practice. However, controversies exist regarding the consistency of classifications in ClinVar, and questions remain about how best to use these data. Our study systematically examined ClinVar to identify common sources of discordance and thus inform ongoing practices.MethodsWe analyzed variants that had multiple classifications in ClinVar, excluding benign polymorphisms. Classifications were categorized by potential actionability and pathogenicity. Consensus interpretations were calculated for each variant, and the properties of the discordant outlier classifications were summarized.ResultsOur study included 74,065 classifications of 27,224 unique variants in 1,713 genes. We found that (i) concordance rates differed among clinical areas and variant types; (ii) clinical testing methods had much higher concordance than basic literature curation and research efforts; (iii) older classifications had greater discordance than newer ones; and (iv) low-penetrance variants had particularly high discordance.ConclusionRecent variant classifications from clinical testing laboratories have high overall concordance in many (but not all) clinical areas. ClinVar can be a reliable resource supporting variant interpretation, quality assessment, and clinical practice when factors uncovered in this study are taken into account. Ongoing improvements to ClinVar may make it easier to use, particularly for nonexpert users. PMID- 28569745 TI - The microprotein Minion controls cell fusion and muscle formation. AB - Although recent evidence has pointed to the existence of small open reading frame (smORF)-encoded microproteins in mammals, their function remains to be determined. Skeletal muscle development requires fusion of mononuclear progenitors to form multinucleated myotubes, a critical but poorly understood process. Here we report the identification of Minion (microprotein inducer of fusion), a smORF encoding an essential skeletal muscle specific microprotein. Myogenic progenitors lacking Minion differentiate normally but fail to form syncytial myotubes, and Minion-deficient mice die perinatally and demonstrate a marked reduction in fused muscle fibres. The fusogenic activity of Minion is conserved in the human orthologue, and co-expression of Minion and the transmembrane protein Myomaker is sufficient to induce cellular fusion accompanied by rapid cytoskeletal rearrangement, even in non-muscle cells. These findings establish Minion as a novel microprotein required for muscle development, and define a two-component programme for the induction of mammalian cell fusion. Moreover, these data also significantly expand the known functions of smORF-encoded microproteins. PMID- 28569744 TI - Delivery room interventions to prevent bronchopulmonary dysplasia in extremely preterm infants. AB - Bronchopulmonary dysplasia (BPD) is the most common chronic respiratory complication of preterm birth. Preterm infants are at risk for acute lung injury immediately after birth, which predisposes to BPD. In this article, we review the current evidence for interventions applied during neonatal transition (delivery room and first postnatal hours of life) to prevent BPD in extremely preterm infants: continuous positive airway pressure (CPAP), sustained lung inflation, supplemental oxygen use during neonatal resuscitation, and surfactant therapy including less-invasive surfactant administration. Preterm infants should be stabilized with CPAP in the delivery room, reserving invasive mechanical ventilation for infants who fail non-invasive respiratory support. For infants who require endotracheal intubation and mechanical ventilation soon after birth, surfactant should be given early (<2 h of life). We recommend prudent titration of supplemental oxygen in the delivery room to achieve targeted oxygen saturations. Promising interventions that may further reduce BPD, such as sustained inflation and non-invasive surfactant administration, are currently under investigation. PMID- 28569746 TI - Ants regulate colony spatial organization using multiple chemical road-signs. AB - Communication provides the basis for social life. In ant colonies, the prevalence of local, often chemically mediated, interactions introduces strong links between communication networks and the spatial distribution of ants. It is, however, unknown how ants identify and maintain nest chambers with distinct functions. Here, we combine individual tracking, chemical analysis and machine learning to decipher the chemical signatures present on multiple nest surfaces. We present evidence for several distinct chemical 'road-signs' that guide the ants' movements within the dark nest. These chemical signatures can be used to classify nest chambers with different functional roles. Using behavioural manipulations, we demonstrate that at least three of these chemical signatures are functionally meaningful and allow ants from different task groups to identify their specific nest destinations, thus facilitating colony coordination and stabilization. The use of multiple chemicals that assist spatiotemporal guidance, segregation and pattern formation is abundant in multi-cellular organisms. Here, we provide a rare example for the use of these principles in the ant colony. PMID- 28569749 TI - One-Year stable perovskite solar cells by 2D/3D interface engineering. AB - Despite the impressive photovoltaic performances with power conversion efficiency beyond 22%, perovskite solar cells are poorly stable under operation, failing by far the market requirements. Various technological approaches have been proposed to overcome the instability problem, which, while delivering appreciable incremental improvements, are still far from a market-proof solution. Here we show one-year stable perovskite devices by engineering an ultra-stable 2D/3D (HOOC(CH2)4NH3)2PbI4/CH3NH3PbI3 perovskite junction. The 2D/3D forms an exceptional gradually-organized multi-dimensional interface that yields up to 12.9% efficiency in a carbon-based architecture, and 14.6% in standard mesoporous solar cells. To demonstrate the up-scale potential of our technology, we fabricate 10 * 10 cm2 solar modules by a fully printable industrial-scale process, delivering 11.2% efficiency stable for >10,000 h with zero loss in performances measured under controlled standard conditions. This innovative stable and low-cost architecture will enable the timely commercialization of perovskite solar cells. PMID- 28569747 TI - Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth. AB - Intense infiltration of tumour-associated macrophages (TAMs) facilitates malignant growth of glioblastoma (GBM), but the underlying mechanisms remain undefined. Herein, we report that TAMs secrete abundant pleiotrophin (PTN) to stimulate glioma stem cells (GSCs) through its receptor PTPRZ1 thus promoting GBM malignant growth through PTN-PTPRZ1 paracrine signalling. PTN expression correlates with infiltration of CD11b+/CD163+ TAMs and poor prognosis of GBM patients. Co-implantation of M2-like macrophages (MLCs) promoted GSC-driven tumour growth, but silencing PTN expression in MLCs mitigated their pro tumorigenic activity. The PTN receptor PTPRZ1 is preferentially expressed in GSCs and also predicts GBM poor prognosis. Disrupting PTPRZ1 abrogated GSC maintenance and tumorigenic potential. Moreover, blocking the PTN-PTPRZ1 signalling by shRNA or anti-PTPRZ1 antibody potently suppressed GBM tumour growth and prolonged animal survival. Our study uncovered a critical molecular crosstalk between TAMs and GSCs through the PTN-PTPRZ1 paracrine signalling to support GBM malignant growth, indicating that targeting this signalling axis may have therapeutic potential. PMID- 28569748 TI - The critical role of SENP1-mediated GATA2 deSUMOylation in promoting endothelial activation in graft arteriosclerosis. AB - Data from clinical research and our previous study have suggested the potential involvement of SENP1, the major protease of post-translational SUMOylation, in cardiovascular disorders. Here, we investigate the role of SENP1-mediated SUMOylation in graft arteriosclerosis (GA), the major cause of allograft failure. We observe an endothelial-specific induction of SENP1 and GATA2 in clinical graft rejection specimens that show endothelial activation-mediated vascular remodelling. In mouse aorta transplantation GA models, endothelial-specific SENP1 knockout grafts demonstrate limited neointima formation with attenuated leukocyte recruitment, resulting from diminished induction of adhesion molecules in the graft endothelium due to increased GATA2 SUMOylation. Mechanistically, inflammation-induced SENP1 promotes the deSUMOylation of GATA2 and IkappaBalpha in endothelial cells, resulting in increased GATA2 stability, promoter-binding capability and NF-kappaB activity, which leads to augmented endothelial activation and inflammation. Therefore, upon inflammation, endothelial SENP1 mediated SUMOylation drives GA by regulating the synergistic effect of GATA2 and NF-kappaB and consequent endothelial dysfunction. PMID- 28569750 TI - Evidence for a palaeo-subglacial lake on the Antarctic continental shelf. AB - Subglacial lakes are widespread beneath the Antarctic Ice Sheet but their control on ice-sheet dynamics and their ability to harbour life remain poorly characterized. Here we present evidence for a palaeo-subglacial lake on the Antarctic continental shelf. A distinct sediment facies recovered from a bedrock basin in Pine Island Bay indicates deposition within a low-energy lake environment. Diffusive-advection modelling demonstrates that low chloride concentrations in the pore water of the corresponding sediments can only be explained by initial deposition of this facies in a freshwater setting. These observations indicate that an active subglacial meltwater network, similar to that observed beneath the extant ice sheet, was also active during the last glacial period. It also provides a new framework for refining the exploration of these unique environments. PMID- 28569751 TI - Simple and scalable growth of AgCl nanorods by plasma-assisted strain relaxation on flexible polymer substrates. AB - Implementing nanostructures on plastic film is indispensable for highly efficient flexible optoelectronic devices. However, due to the thermal and chemical fragility of plastic, nanostructuring approaches are limited to indirect transfer with low throughput. Here, we fabricate single-crystal AgCl nanorods by using a Cl2 plasma on Ag-coated polyimide. Cl radicals react with Ag to form AgCl nanorods. The AgCl is subjected to compressive strain at its interface with the Ag film because of the larger lattice constant of AgCl compared to Ag. To minimize strain energy, the AgCl nanorods grow in the [200] direction. The epitaxial relationship between AgCl (200) and Ag (111) induces a strain, which leads to a strain gradient at the periphery of AgCl nanorods. The gradient causes a strain-induced diffusion of Ag atoms to accelerate the nanorod growth. Nanorods grown for 45 s exhibit superior haze up to 100% and luminance of optical device increased by up to 33%. PMID- 28569752 TI - Direct and simultaneous observation of ultrafast electron and hole dynamics in germanium. AB - Understanding excited carrier dynamics in semiconductors is crucial for the development of photovoltaics and efficient photonic devices. However, overlapping spectral features in optical pump-probe spectroscopy often render assignments of separate electron and hole carrier dynamics ambiguous. Here, ultrafast electron and hole dynamics in germanium nanocrystalline thin films are directly and simultaneously observed by ultrafast transient absorption spectroscopy in the extreme ultraviolet at the germanium M4,5 edge. We decompose the spectra into contributions of electronic state blocking and photo-induced band shifts at a carrier density of 8 * 1020 cm-3. Separate electron and hole relaxation times are observed as a function of hot carrier energies. A first-order electron and hole decay of ~1 ps suggests a Shockley-Read-Hall recombination mechanism. The simultaneous observation of electrons and holes with extreme ultraviolet transient absorption spectroscopy paves the way for investigating few- to sub femtosecond dynamics of both holes and electrons in complex semiconductor materials and across junctions. PMID- 28569753 TI - Ultrafast terahertz snapshots of excitonic Rydberg states and electronic coherence in an organometal halide perovskite. AB - How photoexcitations evolve into Coulomb-bound electron and hole pairs, called excitons, and unbound charge carriers is a key cross-cutting issue in photovoltaics and optoelectronics. Until now, the initial quantum dynamics following photoexcitation remains elusive in the hybrid perovskite system. Here we reveal excitonic Rydberg states with distinct formation pathways by observing the multiple resonant, internal quantum transitions using ultrafast terahertz quasi-particle transport. Nonequilibrium emergent states evolve with a complex co existence of excitons, carriers and phonons, where a delayed buildup of excitons under on- and off-resonant pumping conditions allows us to distinguish between the loss of electronic coherence and hot state cooling processes. The nearly ~1 ps dephasing time, efficient electron scattering with discrete terahertz phonons and intermediate binding energy of ~13.5 meV in perovskites are distinct from conventional photovoltaic semiconductors. In addition to providing implications for coherent energy conversion, these are potentially relevant to the development of light-harvesting and electron-transport devices. PMID- 28569754 TI - Broad-spectrum kinetic resolution of alcohols enabled by Cu-H-catalysed dehydrogenative coupling with hydrosilanes. AB - The enantioselective silylation of racemic alcohols, where one enantiomer reacts faster than the other, is an alternative approach to established enzymatic and non-enzymatic acylation techniques. The existing art is either limited to structurally biased alcohols or requires elaborate catalysts. Simple substrates, such as benzylic and allylic alcohols, with no coordinating functionality in the proximity of the hydroxy group have been challenging in these kinetic resolutions. We report here the identification of a broadly applicable chiral catalyst for the enantioselective dehydrogenative coupling of alcohols and hydrosilanes with both the chiral ligand and the hydrosilane being commercially available. The efficiency of kinetic resolutions is characterized by the selectivity factor, that is, the ratio of the reaction rates of the fast-reacting over the slow-reacting enantiomer. The selectivity factors achieved with the new method are good for acyclic benzylic alcohols (<=170) and high for synthetically usefully cyclic benzylic (<=40.1) and allylic alcohols (<=159). PMID- 28569755 TI - Myomerger induces fusion of non-fusogenic cells and is required for skeletal muscle development. AB - Despite the importance of cell fusion for mammalian development and physiology, the factors critical for this process remain to be fully defined, which has severely limited our ability to reconstitute cell fusion. Myomaker (Tmem8c) is a muscle-specific protein required for myoblast fusion. Expression of myomaker in fibroblasts drives their fusion with myoblasts, but not with other myomaker expressing fibroblasts, highlighting the requirement of additional myoblast derived factors for fusion. Here we show that Gm7325, which we name myomerger, induces the fusion of myomaker-expressing fibroblasts. Thus, myomaker and myomerger together confer fusogenic activity to otherwise non-fusogenic cells. Myomerger is skeletal muscle-specific and genetic deletion in mice results in a paucity of muscle fibres demonstrating its requirement for normal muscle formation. Myomerger deficient myocytes differentiate and harbour organized sarcomeres but are fusion-incompetent. Our findings identify myomerger as a fundamental myoblast fusion protein and establish a system that begins to reconstitute mammalian cell fusion. PMID- 28569756 TI - Neuronal population coding of perceived and memorized visual features in the lateral prefrontal cortex. AB - The primate lateral prefrontal cortex (LPFC) encodes visual stimulus features while they are perceived and while they are maintained in working memory. However, it remains unclear whether perceived and memorized features are encoded by the same or different neurons and population activity patterns. Here we record LPFC neuronal activity while monkeys perceive the motion direction of a stimulus that remains visually available, or memorize the direction if the stimulus disappears. We find neurons with a wide variety of combinations of coding strength for perceived and memorized directions: some neurons encode both to similar degrees while others preferentially or exclusively encode either one. Reading out the combined activity of all neurons, a machine-learning algorithm reliably decode the motion direction and determine whether it is perceived or memorized. Our results indicate that a functionally diverse population of LPFC neurons provides a substrate for discriminating between perceptual and mnemonic representations of visual features. PMID- 28569757 TI - Fetal and postnatal metal dysregulation in autism. AB - Genetic and environmental factors contribute to the etiologies of autism spectrum disorder (ASD), but evidence of specific environmental exposures and susceptibility windows is limited. Here we study monozygotic and dizygotic twins discordant for ASD to test whether fetal and postnatal metal dysregulation increases ASD risk. Using validated tooth-matrix biomarkers, we estimate pre- and post-natal exposure profiles of essential and toxic elements. Significant divergences are apparent in metal uptake between ASD cases and their control siblings, but only during discrete developmental periods. Cases have reduced uptake of essential elements manganese and zinc, and higher uptake of the neurotoxin lead. Manganese and lead are also correlated with ASD severity and autistic traits. Our study suggests that metal toxicant uptake and essential element deficiency during specific developmental windows increases ASD risk and severity, supporting the hypothesis of systemic elemental dysregulation in ASD. Independent replication in population-based studies is needed to extend these findings. PMID- 28569758 TI - Polymorphism in a high-entropy alloy. AB - Polymorphism, which describes the occurrence of different lattice structures in a crystalline material, is a critical phenomenon in materials science and condensed matter physics. Recently, configuration disorder was compositionally engineered into single lattices, leading to the discovery of high-entropy alloys and high entropy oxides. For these novel entropy-stabilized forms of crystalline matter with extremely high structural stability, is polymorphism still possible? Here by employing in situ high-pressure synchrotron radiation X-ray diffraction, we reveal a polymorphic transition from face-centred-cubic (fcc) structure to hexagonal-close-packing (hcp) structure in the prototype CoCrFeMnNi high-entropy alloy. The transition is irreversible, and our in situ high-temperature synchrotron radiation X-ray diffraction experiments at different pressures of the retained hcp high-entropy alloy reveal that the fcc phase is a stable polymorph at high temperatures, while the hcp structure is more thermodynamically favourable at lower temperatures. As pressure is increased, the critical temperature for the hcp-to-fcc transformation also rises. PMID- 28569759 TI - Biogenic non-crystalline U(IV) revealed as major component in uranium ore deposits. AB - Historically, it is believed that crystalline uraninite, produced via the abiotic reduction of hexavalent uranium (U(VI)) is the dominant reduced U species formed in low-temperature uranium roll-front ore deposits. Here we show that non crystalline U(IV) generated through biologically mediated U(VI) reduction is the predominant U(IV) species in an undisturbed U roll-front ore deposit in Wyoming, USA. Characterization of U species revealed that the majority (~58-89%) of U is bound as U(IV) to C-containing organic functional groups or inorganic carbonate, while uraninite and U(VI) represent only minor components. The uranium deposit exhibited mostly 238U-enriched isotope signatures, consistent with largely biotic reduction of U(VI) to U(IV). This finding implies that biogenic processes are more important to uranium ore genesis than previously understood. The predominance of a relatively labile form of U(IV) also provides an opportunity for a more economical and environmentally benign mining process, as well as the design of more effective post-mining restoration strategies and human health-risk assessment. PMID- 28569761 TI - Chemically induced mouse models of acute and chronic intestinal inflammation. AB - Inflammatory bowel diseases (IBDs) result in diarrhea and abdominal pain with further potential complications such as tissue fibrosis and stenosis. Animal models help in understanding the immunopathogenesis of IBDs and in the design of novel therapeutic concepts. Here we present an updated version of a protocol we published in 2007 for key models of acute and chronic forms of colitis induced by 2,4,6-trinitro-benzene sulfonic acid (TNBS), oxazolone and dextran sulfate sodium (DSS). This protocol update describes an adaptation of the existing protocol that modifies the technique. This protocol has been used to generate improved mouse models that better reflect the nature of IBDs in humans. In TNBS and oxazolone colitis models, topical administration of hapten reagents results in T-cell mediated immunity against haptenized proteins and luminal antigens. By contrast, to generate DSS colitis models, mice orally receive DSS, causing death of epithelial cells, compromising barrier function and causing subsequent inflammation. The analysis of the acute colitis models can be performed within 1 2 weeks, whereas that of the chronic models may take 2-4 months. The strengths of the acute models are that they are based on the analysis of short-lasting barrier alterations, innate immune effects and flares. The advantages of the chronic models are that they may offer better insight into adaptive immunity and complications such as neoplasia and tissue fibrosis. The protocol requires basic skills in laboratory animal research. PMID- 28569760 TI - Strength of Neisseria meningitidis binding to endothelial cells requires highly ordered CD147/beta2-adrenoceptor clusters assembled by alpha-actinin-4. AB - Neisseria meningitidis (meningococcus) is an invasive bacterial pathogen that colonizes human vessels, causing thrombotic lesions and meningitis. Establishment of tight interactions with endothelial cells is crucial for meningococci to resist haemodynamic forces. Two endothelial receptors, CD147 and the beta2 adrenergic receptor (beta2AR), are sequentially engaged by meningococci to adhere and promote signalling events leading to vascular colonization, but their spatiotemporal coordination is unknown. Here we report that CD147 and beta2AR form constitutive hetero-oligomeric complexes. The scaffolding protein alpha actinin-4 directly binds to the cytosolic tail of CD147 and governs the assembly of CD147-beta2AR complexes in highly ordered clusters at bacterial adhesion sites. This multimolecular assembly process increases the binding strength of meningococci to endothelial cells under shear stress, and creates molecular platforms for the elongation of membrane protrusions surrounding adherent bacteria. Thus, the specific organization of cellular receptors has major impacts on host-pathogen interaction. PMID- 28569764 TI - The sands of time run faster near the end. AB - Grains exiting an underwater silo exhibit an unexpected surge in discharge rate as they empty. This contrasts with the constant flow rate of dry granular hoppers and the decreasing flow rate of pure liquids. Here we find that this surge depends on hopper diameter and happens also in air. The surge can be turned off by fixing the rate of fluid flow through the granular packing. With no flow control, dye injected on top of the packing gets drawn into the grains. We conclude that the surge is caused by a self-generated pumping of fluid through the packing. The effect is modelled via a driving pressure set by the exit speed of the grains. This highlights a surprising and unrecognized role that interstitial fluid plays in setting the discharge rate, and perhaps in controlling clog formation, for granular hoppers whether in air or under water. PMID- 28569763 TI - Integrating macromolecular X-ray diffraction data with the graphical user interface iMosflm. AB - X-ray crystallography is the predominant source of structural information for biological macromolecules, providing fundamental insights into biological function. The availability of robust and user-friendly software to process the collected X-ray diffraction images makes the technique accessible to a wider range of scientists. iMosflm/MOSFLM (http://www.mrc-lmb.cam.ac.uk/harry/imosflm) is a software package designed to achieve this goal. The graphical user interface (GUI) version of MOSFLM (called iMosflm) is designed to guide inexperienced users through the steps of data integration, while retaining powerful features for more experienced users. Images from almost all commercially available X-ray detectors can be handled using this software. Although the program uses only 2D profile fitting, it can readily integrate data collected in the 'fine phi-slicing' mode (in which the rotation angle per image is less than the crystal mosaic spread by a factor of at least 2), which is commonly used with modern very fast readout detectors. The GUI provides real-time feedback on the success of the indexing step and the progress of data processing. This feedback includes the ability to monitor detector and crystal parameter refinement and to display the average spot shape in different regions of the detector. Data scaling and merging tasks can be initiated directly from the interface. Using this protocol, a data set of 360 images with ~2,000 reflections per image can be processed in ~4 min. PMID- 28569762 TI - Quantitative proteomics: challenges and opportunities in basic and applied research. AB - In this Perspective, we discuss developments in mass-spectrometry-based proteomic technology over the past decade from the viewpoint of our laboratory. We also reflect on existing challenges and limitations, and explore the current and future roles of quantitative proteomics in molecular systems biology, clinical research and personalized medicine. PMID- 28569765 TI - Corrigendum: Small genomic insertions form enhancers that misregulate oncogenes. AB - This corrects the article DOI: 10.1038/ncomms14385. PMID- 28569766 TI - Experimental discrimination of ion stopping models near the Bragg peak in highly ionized matter. AB - The energy deposition of ions in dense plasmas is a key process in inertial confinement fusion that determines the alpha-particle heating expected to trigger a burn wave in the hydrogen pellet and resulting in high thermonuclear gain. However, measurements of ion stopping in plasmas are scarce and mostly restricted to high ion velocities where theory agrees with the data. Here, we report experimental data at low projectile velocities near the Bragg peak, where the stopping force reaches its maximum. This parameter range features the largest theoretical uncertainties and conclusive data are missing until today. The precision of our measurements, combined with a reliable knowledge of the plasma parameters, allows to disprove several standard models for the stopping power for beam velocities typically encountered in inertial fusion. On the other hand, our data support theories that include a detailed treatment of strong ion-electron collisions. PMID- 28569767 TI - Large spin accumulation and crystallographic dependence of spin transport in single crystal gallium nitride nanowires. AB - Semiconductor spintronics is an alternative to conventional electronics that offers devices with high performance, low power and multiple functionality. Although a large number of devices with mesoscopic dimensions have been successfully demonstrated at low temperatures for decades, room-temperature operation still needs to go further. Here we study spin injection in single crystal gallium nitride nanowires and report robust spin accumulation at room temperature with enhanced spin injection polarization of 9%. A large Overhauser coupling between the electron spin accumulation and the lattice nuclei is observed. Finally, our single-crystal gallium nitride samples have a trigonal cross-section defined by the (001), () and () planes. Using the Hanle effect, we show that the spin accumulation is significantly different for injection across the (001) and () (or ()) planes. This provides a technique for increasing room temperature spin injection in mesoscopic systems. PMID- 28569768 TI - Cancer nanobiotechnolgy. PMID- 28569769 TI - Tracing the oxygen isotope composition of the upper Earth's atmosphere using cosmic spherules. AB - Molten I-type cosmic spherules formed by heating, oxidation and melting of extraterrestrial Fe,Ni metal alloys. The entire oxygen in these spherules sources from the atmosphere. Therefore, I-type cosmic spherules are suitable tracers for the isotopic composition of the upper atmosphere at altitudes between 80 and 115 km. Here we present data on I-type cosmic spherules collected in Antarctica. Their composition is compared with the composition of tropospheric O2. Our data suggest that the Earth's atmospheric O2 is isotopically homogenous up to the thermosphere. This makes fossil I-type micrometeorites ideal proxies for ancient atmospheric CO2 levels. PMID- 28569770 TI - Interferon-gamma derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity. AB - Interferon gamma (IFNgamma) is a key moderator of cell-mediated immunity with diverse, mainly pro-inflammatory actions on immunocytes and target tissue. Recent studies have shown it may enhance anti-tumor and antiviral effects of CD8 T cells. Here we investigate the mechanisms by which IFNgamma mediates CD8 T-cell cytotoxic function. We show that in vivo, antigen-specific CD8 T cells that produce INFgamma are necessary to effect rejection of skin grafts expressing OVA as a transgene in keratinocytes. The ability of CD8 T cells to produce IFNgamma enhanced their ability to migrate to the site of antigen-presenting skin cells. By in vivo imaging, we show that CTL motility, particularly speed, during graft rejection was enhanced by locally available IFNgamma. We then used a reductionist two-cell model of CTL effectors and keratinocyte targets to investigate the effects of locally available (paracrine) and CTL-producing (autocrine) IFNgamma on the motility behavior and killing ability of the CTL. Using live-cell imaging by prolonged time-lapse microscopy of primary effector CD8 T cells and antigen expressing primary keratinocyte targets, we show that CD8 T-cell cytotoxic function and motility is enhanced by locally available IFNgamma. Conversely, deprivation of either autocrine or paracrine IFNgamma, or blockade of IFNgamma signaling to CTL markedly reduced their cytotoxic function, their kinematics, and effector cell survival. We conclude that in vitro and in vivo, autocrine production of IFNgamma by CTL enhances their motility and promotes killing of primary target keratinocytes. The absolute need for local IFNgamma to enable cytotoxic CD8 T-cell function is of significance for immunotherapy for chronic viral infection and for cancer. PMID- 28569771 TI - MiR-125b regulates proliferation and apoptosis of nasopharyngeal carcinoma by targeting A20/NF-kappaB signaling pathway. AB - MiR-125b is aberrantly expressed and has a role in the various types of tumors. However, the role and mechanism of miR-125b in nasopharyngeal carcinoma (NPC) are unclear. In this study, we investigated the role and mechanism of miR-125b in NPC. We observed that miR-125b was significantly upregulated in the NPC tissues relative to normal nasopharyngeal mucosa (NNM), and its increment was correlated with poor patient survival, and was an independent predictor for reduced patient survival; miR-125b promoted NPC cell proliferation and inhibited NPC cell apoptosis; in a mouse model, administration of miR-125b antagomir significantly reduced the growth of NPC xenograft tumors. Mechanistically, we confirmed that A20 was a direct target of miR-125b, and found that activation of nuclear factor kappaB (NF-kappaB) signaling pathway by A20 mediated miR-125b-promoting NPC cell proliferation and -inhibiting NPC cell apoptosis. With a combination of loss-of function and gain-of-function approaches, we further showed that A20 inhibited NPC cell proliferation, induced NPC cell apoptosis, and reduced the growth of NPC xenograft tumors. Moreover, A20 was significantly downregulated, whereas p p65(RelA) was significantly upregulated in the NPC tissues relative to normal nasopharyngeal mucosa, and miR-125b level was negatively associated with A20 level, whereas positively associated with p-p65 level. Our data demonstrate that miR-125b regulates NPC cell proliferation and apoptosis by targeting A20/NF kappaB signaling pathway, and miR-125b acts as oncogene, whereas A20 functions as tumor suppressor in NPC, highlighting the therapeutic potential of miR 125b/A20/NF-kappaB signaling axis in the NPC. PMID- 28569772 TI - Deficiency of pigment epithelium-derived factor in nasopharyngeal carcinoma cells triggers the epithelial-mesenchymal transition and metastasis. AB - Distant metastasis is the primary cause of nasopharyngeal carcinoma (NPC) treatment failure while epithelial-mesenchymal transition (EMT) is the critical process of NPC invasion and metastasis. However, tumor-suppressor genes involved in the EMT and metastasis of NPC have not been explored clearly compared with the oncogenes. In the present study, the expression of pigment epithelium-derived factor (PEDF), a potent endogenous antitumor factor, was diminished in human NPC tissues and associated with clinicopathological and EMT features. The knockdown of PEDF induced EMT in lower metastatic NPC cell lines and overexpression of PEDF restored epithelial phenotype in higher metastatic NPC cell lines with typical EMT. The inhibition of PEDF mediated NPC cell spontaneous metastasis in vivo. LRP6/GSK3beta/beta-catenin signal pathway rather than AKT/GSK3beta pathway was involved in the effects of PEDF on EMT. The expression of PEDF was directly downregulated by elevated miR-320c in NPC. In conclusion, our findings indicate for the first time that PEDF functions as tumor-suppressor gene in the occurrence of EMT and metastasis in NPC. PEDF could serve as a promising candidate for NPC diagnosis, prognosis and treatment. PMID- 28569773 TI - In vitro expansion impaired the stemness of early passage mesenchymal stem cells for treatment of cartilage defects. AB - In vitro cultured autologous mesenchymal stem cells (MSCs) within passage 5 have been approved for clinical application in stem cell-based treatment of cartilage defects. However, their chondrogenic potential has not yet been questioned or verified. In this study, the chondrogenic potential of bone marrow MSCs at passage 3 (P3 BMSCs) was investigated both in cartilage repair and in vitro, with freshly isolated bone marrow mononuclear cells (BMMNCs) as controls. The results showed that P3 BMSCs were inferior to BMMNCs not only in their chondrogenic differentiation ability but also as candidates for long-term repair of cartilage defects. Compared with BMMNCs, P3 BMSCs presented a decay in telomerase activity and a change in chromosomal morphology with potential anomalous karyotypes, indicating senescence. In addition, interindividual variability in P3 BMSCs is much higher than in BMMNCs, demonstrating genomic instability. Interestingly, remarkable downregulation in cell cycle, DNA replication and mismatch repair (MMR) pathways as well as in multiple genes associated with telomerase activity and chromosomal stability were found in P3 BMSCs. This result indicates that telomerase and chromosome anomalies might originate from expansion, leading to impaired stemness and pluripotency of stem cells. In vitro culture and expansion are not recommended for cell-based therapy, and fresh BMMNCs are the first choice. PMID- 28569775 TI - Promoting tumorigenesis in nasopharyngeal carcinoma, NEDD8 serves as a potential theranostic target. AB - Nasopharyngeal carcinoma (NPC), is one of the most common human malignancies in south China, it has the highest recurrence rate and treatment resistance. The underlying molecular mechanisms of NPC relapse and treatment tolerance are not fully understood. In this study, the effects of NEDD8 and NEDD8-activating enzyme inhibitor (MLN4924) on NPC were studied both in vitro and in vivo. Immunohistochemical staining of 197 NPC tissues revealed an elevated NEDD8 expression as an unfavorable independent factor in overall survival and disease free survival rates. NEDD8 expression was positively correlated with a high risk of death and positivity of lymph node metastasis. Depleted NEDD8 expression by shRNA and inhibited by specific inhibitor MLN4924 dramatically suppressed cell proliferation, cell apoptosis, cell cycle arrest, while ectopic NEDD8 exhibited opposing effects. NEDD8 affected cancer stem cell phenotypes of NPC as assessed in vitro using the cell number of side population (SP) by flow cytometry analysis, colony formation assay, sphere formation assay, and tumor initiation ability in vivo. Downregulation of NEDD8 enhanced the susceptibility of NPC cells to cisplatin and radiation. Moreover, we found that MLN4924 suppressed c-Jun degradation in human NPC cells. Taken together, this report revealed that NEDD8 may act as a novel prognostic marker and MLN4924 may serve as a promising therapeutic target for patients with NPC. PMID- 28569774 TI - RGD-modified oncolytic adenovirus-harboring shPKM2 exhibits a potent cytotoxic effect in pancreatic cancer via autophagy inhibition and apoptosis promotion. AB - The M2 isoform of pyruvate kinase (PKM2) is a key driver of glycolysis in cancer cells and has critical 'non-metabolic' functions in some cancers; however, the role of PKM2 in pancreatic cancer remains unclear. The aim of the current study was to elucidate the role of PKM2 in pancreatic cancer progression and the potential of PKM2 as a therapeutic target. In this study, we observed that PKM2 is highly expressed in patients with pancreatic cancer and is correlated to survival. Elevated PKM2 expression promoted cell proliferation, migration and tumor formation. The inhibition of cell growth by silencing PKM2 is caused by impairment of the autophagy process. To test the potential effects of downregulating PKM2 as a clinical therapy, we constructed an RGD-modified oncolytic adenovirus containing shPKM2 (OAd.R.shPKM2) to knock down PKM2 in pancreatic cancer cells. Cells transduced with OAd.R.shPKM2 exhibited decreased cell viability, and, in a PANC-1 xenograft model, intratumoral injection of OAd.R.shPKM2 resulted in reduced tumor growth. Furthermore, OAd.R.shPKM2 induced apoptosis and impaired autophagy in PANC-1 cells. Our results suggested that targeting PKM2 with an oncolytic adenovirus produced a strong antitumor effect, and that this strategy could broaden the therapeutic options for treating pancreatic cancer. PMID- 28569776 TI - HIV integrase inhibitor, Elvitegravir, impairs RAG functions and inhibits V(D)J recombination. AB - Integrase inhibitors are a class of antiretroviral drugs used for the treatment of AIDS that target HIV integrase, an enzyme responsible for integration of viral cDNA into host genome. RAG1, a critical enzyme involved in V(D)J recombination exhibits structural similarity to HIV integrase. We find that two integrase inhibitors, Raltegravir and Elvitegravir, interfered with the physiological functions of RAGs such as binding, cleavage and hairpin formation at the recombination signal sequence (RSS), though the effect of Raltegravir was limited. Circular dichroism studies demonstrated a distinct change in the secondary structure of RAG1 central domain (RAG1 shares DDE motif amino acids with integrases), and when incubated with Elvitegravir, an equilibrium dissociation constant (Kd) of 32.53+/-2.9 MUM was determined by Biolayer interferometry, leading to inhibition of its binding to DNA. Besides, using extrachromosomal assays, we show that Elvitegravir inhibited both coding and signal joint formation in pre-B cells. Importantly, treatment with Elvitegravir resulted in significant reduction of mature B lymphocytes in 70% of mice studied. Thus, our study suggests a potential risk associated with the use of Elvitegravir as an antiretroviral drug, considering the evolutionary and structural similarities between HIV integrase and RAGs. PMID- 28569777 TI - The novel hypoxia-inducible factor-1alpha inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth. AB - HIF-1 is associated with poor prognoses and therapeutic resistance in cancer patients. We previously developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, a clinical candidate for cancer therapy. We also reported that IDF-1174 inhibited HSP70 chaperone activity and suppressed accumulation of HIF-1alpha. In this study, IDF-11774 inhibited the accumulation of HIF-1alpha in vitro and in vivo in colorectal carcinoma HCT116 cells under hypoxic conditions. Moreover, IDF-11774 treatment suppressed angiogenesis of cancer cells by reducing the expression of HIF-1 target genes, reduced glucose uptake, thereby sensitizing cells to growth under low glucose conditions, and decreased the extracellular acidification rate (ECAR) and oxygen consumption rate of cancer cells. Metabolic profiling of IDF-11774-treated cells revealed low levels of NAD+, NADP+, and lactate, as well as of intermediates in glycolysis and the tricarboxylic acid cycle. In addition, we observed elevated AMP and diminished ATP levels, resulting in a high AMP/ATP ratio. The level of AMP-activated protein kinase phosphorylation also increased, leading to inhibition of mTOR signaling in treated cells. In vivo xenograft assays demonstrated that IDF-11774 exhibited substantial anticancer efficacy in mouse models containing KRAS, PTEN, or VHL mutations, which often occur in malignant cancers. Collectively, our data indicate that IDF-11774 suppressed hypoxia-induced HIF-1alpha accumulation and repressed tumor growth by targeting energy production-related cancer metabolism. PMID- 28569780 TI - MicroRNA-195 prevents dendritic degeneration and neuron death in rats following chronic brain hypoperfusion. AB - Impaired synaptic plasticity and neuron loss are hallmarks of Alzheimer's disease and vascular dementia. Here, we found that chronic brain hypoperfusion (CBH) by bilateral common carotid artery occlusion (2VO) decreased the total length, numbers and crossings of dendrites and caused neuron death in rat hippocampi and cortices. It also led to increase in N-terminal beta-amyloid precursor protein (N APP) and death receptor-6 (DR6) protein levels and in the activation of caspase-3 and caspase-6. Further study showed that DR6 protein was downregulated by miR-195 overexpression, upregulated by miR-195 inhibition, and unchanged by binding-site mutation and miR-masks. Knockdown of endogenous miR-195 by lentiviral vector mediated overexpression of its antisense molecule (lenti-pre-AMO-miR-195) decreased the total length, numbers and crossings of dendrites and neuron death, upregulated N-APP and DR6 levels, and elevated cleaved caspase-3 and caspase-6 levels. Overexpression of miR-195 using lenti-pre-miR-195 prevented these changes triggered by 2VO. We conclude that miR-195 is involved in CBH-induced dendritic degeneration and neuron death through activation of the N-APP/DR6/caspase pathway. PMID- 28569778 TI - Single-cell time-lapse imaging of intracellular O2 in response to metabolic inhibition and mitochondrial cytochrome-c release. AB - The detection of intracellular molecular oxygen (O2) levels is important for understanding cell physiology, cell death, and drug effects, and has recently been improved with the development of oxygen-sensitive probes that are compatible with live cell time-lapse microscopy. We here provide a protocol for the use of the nanoparticle probe MitoImage-MM2 to monitor intracellular oxygen levels by confocal microscopy under baseline conditions, in response to mitochondrial toxins, and following mitochondrial cytochrome-c release. We demonstrate that the MitoImage-MM2 probe, which embeds Pt(II)-5,10,15,20-tetrakis-(2,3,4,5,6 pentafluorophenyl)-porphyrin as oxygen sensor and poly(9,9-dioctylfluorene) as an O2-independent component, enables quantitative, ratiometric time-lapse imaging of intracellular O2. Multiplexing with tetra-methyl-rhodamine-methyl ester in HeLa cervical cancer cells showed significant increases in intracellular O2 accompanied by strong mitochondrial depolarization when respiratory chain complexes III or IV were inhibited by Antimycin A or sodium azide, respectively, and when cells were maintained at 'physiological' tissue O2 levels (5% O2). Multiplexing also allowed us to monitor intracellular O2 during the apoptotic signaling process of mitochondrial outer membrane permeabilization in HeLa expressing cytochrome-c-eGFP, and demonstrated that mitochondria post cytochrome c release are able to retain their capacity to respire at physiological O2 despite a decrease in mitochondrial membrane potential. PMID- 28569779 TI - Long noncoding RNA UCA1 induced by SP1 promotes cell proliferation via recruiting EZH2 and activating AKT pathway in gastric cancer. AB - Long noncoding RNA UCA1 has emerged as a novel regulator in cancer initiation and progression of various cancers. However, function and underlying mechanism of UCA1 in the progression of gastric cancer (GC) remain unclear. In the present study, we report that UCA1 expressed highly in GC tissues and GC cells, which was partly induced by SP1. UCA1 promoted GC cell proliferation and G1/S transition in vitro and in vivo. Moreover, UCA1 exerted its function through interacting with EZH2, promoting direct interaction with cyclin D1 promoter to activate the translation of cyclin D1. Furthermore, AKT/GSK-3B/cyclin D1 axis was activated to upregulate cyclin D1 due to overexpression of UCA1. In addition, EZH2 and phosphorylated AKT induced by UCA1 could impact each other to form a positive feedback to promote cyclin D1 expression. This study demonstrated that UCA1 as a critical regulator involved in GC proliferation and cell cycle progression by promoting cyclin D1 expression, which indicates that it may be clinically a potential therapeutic target in GC. PMID- 28569782 TI - The putative tumor suppressor microRNA-30a-5p modulates clear cell renal cell carcinoma aggressiveness through repression of ZEB2. AB - Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, can easily invade local tissues and metastasize, and is resistant to currently available treatments. Recent studies profiling microRNA expression in ccRCC have suggested miR-30a-5p may be deregulated in these cancer cells. To determine its role and mechanism of action in ccRCC, miR-30-5p expression levels were quantified and functions were analyzed using in vitro and in vivo experiments and bioinformatics. A decrease in miR-30a-5p expression was frequently noted in ccRCC cells and tissues. Importantly, low miR-30a-5p levels were significantly associated with a poor ccRCC patient prognosis. Stable overexpression of miR-30a-5p in 769-P cells was sufficient to prevent cellular proliferation and invasion in vitro and in vivo. Upon further examination, it was found that miR-30a-5p directly targeted the 3'-UTR of ZEB2 and suppressed ccRCC cell epithelial-mesenchymal transition. In addition, miR-30a-5p may be downregulated by the long non-coding RNA DLEU2. Taken together, these data reveal an important role for miR-30a-5p in the regulation of ccRCC proliferation and invasion, and indicate the potential for miR-30a-5p in applications furthering ccRCC prognostics and therapeutics. PMID- 28569783 TI - Damage-induced neuronal endopeptidase (DINE) enhances axonal regeneration potential of retinal ganglion cells after optic nerve injury. AB - Damage-induced neuronal endopeptidase (DINE)/endothelin-converting enzyme-like 1 (ECEL1) is a membrane-bound metalloprotease that we identified as a nerve regeneration-associated molecule. The expression of DINE is upregulated in response to nerve injury in both the peripheral and central nervous systems, while its transcription is regulated by the activating transcription factor 3 (ATF3), a potent hub-transcription factor for nerve regeneration. Despite its unique hallmark of injury-induced upregulation, the physiological relevance of DINE in injured neurons has been unclear. In this study, we have demonstrated that the expression of DINE is upregulated in injured retinal ganglion cells (RGCs) in a coordinated manner with that of ATF3 after optic nerve injury, whereas DINE and ATF3 are not observed in any normal retinal cells. Recently, we have generated a mature DINE-deficient (KOTg) mouse, in which exogenous DINE is overexpressed specifically in embryonic motor neurons to avoid aberrant arborization of motor nerves and lethality after birth that occurs in the conventional DINE KO mouse. The DINE KOTg mice did not show any difference in retinal structure and the projection to brain from that of wild-type (wild type) mice under normal conditions. However, injured RGCs of DINE KOTg mice failed to regenerate even after the zymosan treatment, which is a well-known regeneration promoting reagent. Furthermore, a DINE KOTg mouse crossed with a Atf3:BAC Tg mouse, in which green fluorescent protein (GFP) is visualized specifically in injured RGCs and optic nerves, has verified that DINE deficiency leads to regeneration failure. These findings suggest that injury-induced DINE is a crucial endopeptidase for injured RGCs to promote axonal regeneration after optic nerve injury. Thus, a DINE-mediated proteolytic mechanism would provide us with a new therapeutic strategy for nerve regeneration. PMID- 28569781 TI - Mitochondrial AKAP1 supports mTOR pathway and tumor growth. AB - Mitochondria are the powerhouses of energy production and the sites where metabolic pathway and survival signals integrate and focus, promoting adaptive responses to hormone stimulation and nutrient availability. Increasing evidence suggests that mitochondrial bioenergetics, metabolism and signaling are linked to tumorigenesis. AKAP1 scaffolding protein integrates cAMP and src signaling on mitochondria, regulating organelle biogenesis, oxidative metabolism and cell survival. Here, we provide evidence that AKAP1 is a transcriptional target of Myc and supports the growth of cancer cells. We identify Sestrin2, a leucine sensor and inhibitor of the mammalian target of rapamycin (mTOR), as a novel component of the complex assembled by AKAP1 on mitochondria. Downregulation of AKAP1 impaired mTOR pathway and inhibited glioblastoma growth. Both effects were reversed by concomitant depletion of AKAP1 and sestrin2. High levels of AKAP1 were found in a wide variety of high-grade cancer tissues. In lung cancer, AKAP1 expression correlates with high levels of Myc, mTOR phosphorylation and reduced patient survival. Collectively, these data disclose a previously unrecognized role of AKAP1 in mTOR pathway regulation and cancer growth. AKAP1/mTOR signal integration on mitochondria may provide a new target for cancer therapy. PMID- 28569784 TI - Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition. AB - Histone deacetylase 3 (HDAC3) has an oncogenic role in apoptosis and contributes to the proliferation of cancer cells. MI192 is a novel HDAC3-specific inhibitor that displays antitumor activity in many cancer cell lines. However, the role of HDAC3 and the antitumor activity of its inhibitor MI192 are not known in cholangiocarcinoma (CCA). The present study aims to identify the target of MI192 in CCA as well as evaluate its therapeutic efficacy. CCK8 and colony formation assays showed that HDAC3 overexpression promotes proliferation in CCA cell lines. HDAC3 knockdown or treatment with MI192 decreased CCA cell growth and increased caspase-dependent apoptosis, while apoptosis was partially rescued by HDAC3 overexpression. We demonstrated that MI192 can inhibit the deacetylation activity of HDAC3 and its downstream targets in vitro, and MI192 inhibited xenograft tumor growth in vivo. Immunochemistry showed that HDAC3 was upregulated in CCA tissues compared with adjacent normal tissues, and this was correlated with reduced patient survival. Taken together, these results demonstrate for the first time that MI192 targets HDAC3 and induces apoptosis in human CCA cells. MI192 therefore shows the potential as a new drug candidate for CCA therapy. PMID- 28569785 TI - Cytoprotective effect of neuropeptides on cancer stem cells: vasoactive intestinal peptide-induced antiapoptotic signaling. AB - Cancer stem cells (CSCs) are increasingly considered to be responsible for tumor initiation, metastasis and drug resistance. The drug resistance mechanisms activated in CSCs have not been thoroughly investigated. Although neuropeptides such as vasoactive intestinal peptide (VIP) can promote tumor growth and activate antiapoptotic signaling in differentiated cancer cells, it is not known whether they can activate antiapoptotic mechanisms in CSCs. The objectives of this study are to unravel the cytoprotective effects of neuropeptides and identify antiapoptotic mechanisms activated by neuropeptides in response to anticancer drug treatment in CSCs. We enriched and purified CSCs (CD44+/high/CD24-/low or CD133+ population) from breast and prostate cancer cell lines, and demonstrated their stemness phenotype. Of the several neuropeptides tested, only VIP could protect CSCs from drug-induced apoptosis. A functional correlation was found between drug-induced apoptosis and dephosphorylation of proapoptotic Bcl2 family protein BAD. Similarly, VIP-induced cytoprotection correlated with BAD phosphorylation at Ser112 in CSCs. Using pharmacological inhibitors and dominant negative proteins, we showed that VIP-induced cytoprotection and BAD phosphorylation are mediated via both Ras/MAPK and PKA pathways in CSCs of prostate cancer LNCaP and C4-2 cells, but only PKA signaling was involved in CSCs of DUVIPR (DU145 prostate cancer cells ectopically expressing VIP receptor) and breast cancer MCF7 cells. As each of these pathways partially control BAD phosphorylation at Ser112, both have to be inhibited to block the cytoprotective effects of VIP. Furthermore, VIP is unable to protect CSCs that express phosphorylation-deficient mutant-BAD, suggesting that BAD phosphorylation is essential. Thus, antiapoptotic signaling by VIP could be one of the drug resistance mechanisms by which CSCs escape from anticancer therapies. Our findings suggest the potential usefulness of VIP receptor inhibition to eliminate CSCs, and that targeting BAD might be an attractive strategy for development of novel therapeutics. PMID- 28569786 TI - Brg1-mediated Nrf2/HO-1 pathway activation alleviates hepatic ischemia reperfusion injury. AB - Cytoprotective gene heme oxygenase 1 (HO-1) could be induced by nuclear factor E2 related factor 2 (Nrf2) nuclear translocation. The purpose of this study was to determine the role of Brahma-related gene 1 (Brg1), a catalytic subunit of SWI2/SNF2-like chromatin remodeling complexes, in Nrf2/HO-1 pathway activation during hepatic ischemia-reperfusion (HIR). Our results showed that hepatic Brg1 was inhibited during early HIR while Brg1 overexpression reduced oxidative injury in CMV-Brg1 mice subjected to HIR. Moreover, promoter-driven luciferase assay showed that overexpression of Brg1 by adenovirus transfection in AML12 cells selectively enhanced HO-1 gene expression after hypoxia/reoxygenation (H/R) treatment but did not affect the other Nrf2 target gene NQO1. Furthermore, inhibition of HO-1 by the selective HO-1 inhibitor zinc protoporphyria could partly reverse the hepatic protective effects of Brg1 overexpression while HO-1 Adv attenuated AML12 cells H/R damage. Further, chromatin immunoprecipitation analysis revealed that Brg1 overexpression, which could significantly increase the recruitment of Brg1 protein to HO-1 but not NQO1 promoter, was recruited by Nrf2 to the HO-1 regulatory regions in AML12 hepatocytes subjected to H/R. In conclusion, our results demonstrated that restoration of Brg1 during reperfusion could enhance Nrf2-mediated inducible expression of HO-1 during HIR to effectively increase antioxidant ability to combat against hepatocytes damage. PMID- 28569788 TI - Disease-linked connexin26 S17F promotes volar skin abnormalities and mild wound healing defects in mice. AB - Several mutant mice have been generated to model connexin (Cx)-linked skin diseases; however, the role of connexins in skin maintenance and during wound healing remains to be fully elucidated. Here we generated a novel, viable, and fertile mouse (Cx26CK14-S17F/+) with the keratitis-ichthyosis-deafness mutant (Cx26S17F) driven by the cytokeratin 14 promoter. This mutant mouse mirrors several Cx26-linked human skin pathologies suggesting that the etiology of Cx26 linked skin disease indeed stems from epidermal expression of the Cx26 mutant. Cx26CK14-S17F/+ foot pad epidermis formed severe palmoplantar keratoderma, which expressed elevated levels of Cx26 and filaggrin. Primary keratinocytes isolated from Cx26CK14-S17F/+ neonates exhibited reduced gap junctional intercellular communication and migration. Furthermore, Cx26CK14-S17F/+ mouse skin wound closure was normal but repaired epidermis appeared hyperplastic with elevated expression of cytokeratin 6. Taken together, we suggest that the Cx26S17F mutant disturbs keratinocyte differentiation and epidermal remodeling following wound closure. We further posit that Cx26 contributes to epidermal homeostasis by regulating keratinocyte differentiation, and that mice harboring a disease-linked Cx26 mutant display epidermal abnormalities yet retain most wound healing properties. PMID- 28569787 TI - Inflammatory mediator ultra-low-molecular-weight hyaluronan triggers necrosis of B-precursor leukemia cells with high surface CD44 expression. AB - Acute lymphoblastic leukemia (ALL) with mixed lineage leukemia (MLL) gene rearrangements (MLL+ALL) has a dismal prognosis and is characterized by high surface CD44 expression. Known that CD44 has the specific binding sites for a natural ligand hyaluronan (HA), we investigated biological effects of HA with different molecular sizes on MLL+ALL cell lines, and found that the addition of ultra-low-molecular-weight (ULMW)-HA strongly suppressed their thymidine uptakes. The MLL+ALL cell line lacking surface CD44 expression established by genome editing showed no suppression of thymidine uptake. Surface CD44-high B-precursor ALL cell lines other than MLL+, but not T-ALL cell lines, were also suppressed in their thymidine uptakes. The inhibition of thymidine uptakes was because of induction of cell death, but dead cells lacked features of apoptosis on cytospin smears and flow cytometric analysis. The cell death was neither blocked by pan caspase inhibitor nor autophagy inhibitor, but was completely blocked by necrosis inhibitor necrostatin-1. Necrotic cell death was further supported by a marked release of a high-mobility protein group B1 and morphological changes on transmission electron microscopy. Elevation of intracellular reactive oxygen species production suggested a role for inducing this necrotic cell death. ULMW HA-triggered cell death was similarly demonstrated in surface CD44-high primary B precursor leukemia cells. Assuming that ULMW-HA is abundantly secreted at the site of infection and inflammation, this study sheds light on understanding the mechanism of a transient inflammation-associated remission of leukemia. Further, the CD44-targeting may become an effective approach in future for the treatment of refractory B-precursor ALL by its capability of predominantly eradicating CD44 high leukemia-initiating cells. PMID- 28569789 TI - Knockdown of miR-128a induces Lin28a expression and reverts myeloid differentiation blockage in acute myeloid leukemia. AB - Lin28A is a highly conserved RNA-binding protein that concurs to control the balance between stemness and differentiation in several tissue lineages. Here, we report the role of miR-128a/Lin28A axis in blocking cell differentiation in acute myeloid leukemia (AML), a genetically heterogeneous disease characterized by abnormally controlled proliferation of myeloid progenitor cells accompanied by partial or total inability to undergo terminal differentiation. First, we found Lin28A underexpressed in blast cells from AML patients and AML cell lines as compared with CD34+ normal precursors. In vitro transfection of Lin28A in NPM1 mutated OCI-AML3 cell line significantly triggered cell-cycle arrest and myeloid differentiation, with increased expression of macrophage associate genes (EGR2, ZFP36 and ANXA1). Furthermore, miR-128a, a negative regulator of Lin28A, was found overexpressed in AML cells compared with normal precursors, especially in acute promyelocytic leukemia (APL) and in 'AML with maturation' (according to 2016 WHO classification of myeloid neoplasms and acute leukemia). Its forced overexpression by lentiviral infection in OCI-AML3 downregulated Lin28A with ensuing repression of macrophage-oriented differentiation. Finally, knockdown of miR-128a in OCI-AML3 and in APL/AML leukemic cells (by transfection and lentiviral infection, respectively) induced myeloid cell differentiation and increased expression of Lin28A, EGR2, ZFP36 and ANXA1, reverting myeloid differentiation blockage. In conclusion, our findings revealed a new mechanism for AML differentiation blockage, suggesting new strategies for AML therapy based upon miR-128a inhibition. PMID- 28569790 TI - Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death. AB - Drug resistance is a major problem in cancer therapy. A growing body of evidence demonstrates that the tumor microenvironment, including cancer-associated fibroblasts (CAFs), can modulate drug sensitivity in tumor cells. We examined the effect of primary human CAFs on p53 induction and cell viability in prostate cancer cells on treatment with chemotherapeutic drugs. Co-culture with prostate CAFs or CAF-conditioned medium attenuated DNA damage and the p53 response to chemotherapeutic drugs and enhanced prostate cancer cell survival. CAF conditioned medium inhibited the accumulation of doxorubicin, but not taxol, in prostate cancer cells in a manner that was associated with increased cancer cell glutathione levels. A low molecular weight fraction (<3 kDa) of CAF-conditioned medium had the same effect. CAF-conditioned medium also inhibited induction of reactive oxygen species (ROS) in both doxorubicin- and taxol-treated cancer cells. Our findings suggest that CAFs can enhance drug resistance in cancer cells by inhibiting drug accumulation and counteracting drug-induced oxidative stress. This protective mechanism may represent a novel therapeutic target in cancer. PMID- 28569791 TI - E2F1 induces TINCR transcriptional activity and accelerates gastric cancer progression via activation of TINCR/STAU1/CDKN2B signaling axis. AB - Recent evidence indicates that E2F1 transcription factor have pivotal roles in the regulation of cellular processes, and is found to be dysregulated in a variety of cancers. Long non-coding RNAs (lncRNAs) are also reported to exert important effect on tumorigenesis. E2F1 is aberrantly expressed in gastric cancer (GC), and biology functions of E2F1 in GC are controversial. The biological characteristics of E2F1 and correlation between E2F1 and lncRNAs in GC remain to be found. In this study, integrated analysis revealed that E2F1 expression was significantly increased in GC cases and its expression was positively correlated with the poor pathologic stage, large tumor size and poor prognosis. Forced E2F1 expression promotes proliferation, whereas loss of E2F1 function decreased cell proliferation by blocking of cell cycle in GC cells. Mechanistic analyses indicated that E2F1 accelerates GC growth partly through induces TINCR transcription. TINCR could bind to STAU1 (staufen1) protein, and influence CDKN2B mRNA stability and expression, thereby affecting the proliferation of GC cells. Together, our findings suggest that E2F1/TINCR/STAU1/CDKN2B signaling axis contributes to the oncogenic potential of GC and may constitute a potential therapeutic target in this disease. PMID- 28569793 TI - Oocyte-specific deletion of furin leads to female infertility by causing early secondary follicle arrest in mice. AB - The process of follicular development involves communications between oocyte and surrounding granulosa cells. FURIN is a member of the family of proprotein convertases that is involved in the activation of a large number of zymogens and proproteins by cleavage at its recognition motif. To investigate the functions of FURIN in female fertility, furinflox/flox (furfl/fl) mice were crossed with Zp3 Cre mice and Gdf9-Cre, respectively, to achieve oocyte-specific disruption of FURIN. Here we report for the first time that FURIN is dispensable for primordial follicle maintenance and activation but important for early secondary follicular development, as ablation of FURIN in oocytes caused failure of follicle development beyond the type 4 and/or 5a follicles in mutant mice, resulting in increased number of early secondary follicles and the severely decreased number of mature follicles, thus anovulation and infertility. We also found that the developmental arrest of early secondary follicles might be rooted in the loss of the mature form of ADAMTS1 (85-kDa prodomain truncated) and compromised proliferation of granulosa cells in mutant mice. Taken together, our data highlight the importance of FURIN in follicle development beyond the early secondary follicle stage and indicate that compromised FURIN function leads to follicular dysplasia and female infertility in mice. PMID- 28569792 TI - Loss of epidermal AP1 transcription factor function reduces filaggrin level, alters chemokine expression and produces an ichthyosis-related phenotype. AB - AP1 transcription factors are important controllers of epidermal differentiation. Multiple family members are expressed in the epidermis in a differentiation dependent manner, where they function to regulate gene expression. To study the role of AP1 factor signaling, TAM67 (dominant-negative c-jun) was inducibly expressed in the suprabasal epidermis. The TAM67-positive epidermis displays keratinocyte hyperproliferation, hyperkeratosis and parakeratosis, delayed differentiation, extensive subdermal vasodilation, nuclear loricrin localization, tail and digit pseudoainhum and reduced filaggrin level. These changes are associated with increased levels of IFNgamma, CCL3, CCL5, CXCL9, CXCL10, and CXCL11 (Th1-associated chemokines), and CCL1, CCL2, CCL5 and CCL11 (Th2 associated chemokines) in the epidermis and serum. S100A8 and S100A9 protein levels are also markedly elevated. These changes in epidermal chemokine level are associated with increased levels of the corresponding chemokine mRNA. The largest increases were observed for CXCL9, CXCL10, CXCL11, and S100A8 and S100A9. To assess the role of CXCL9, CXCL10, CXCL11, which bind to CXCR3, on phenotype development, we expressed TAM67 in CXCR3 knockout mice. Using a similar strategy, we examine the role of S100A8 and S100A9. Surprisingly, loss of CXCR3 or S100A8/A9 did not attenuate phenotype development. These studies suggest that interfering with epidermal AP1 factor signaling initiates a loss of barrier function leading to enhanced epidermal chemokine production, but that CXCR3 and S100A8/A9 do not mediate the phenotypic response. PMID- 28569794 TI - P7C3 inhibits GSK3beta activation to protect dopaminergic neurons against neurotoxin-induced cell death in vitro and in vivo. AB - Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. Although its pathogenesis remains unclear, mitochondrial dysfunction plays a vital role in the pathology of PD. P7C3, an aminopropyl carbazole, possesses a significant neuroprotective ability in several neurodegenerative disorders, including PD. Here, we showed that P7C3 stabilized mitochondrial membrane potential, reduced reactive oxygen species production, and inhibited cytochrome c release in MES23.5 cells (a dopaminergic (DA) cell line) exposed to 1-methyl-4 phenylpyridinium (MPP+). In MES23.5 cells, P7C3 inhibited glycogen synthase kinase-3 beta (GSK3beta) activation induced by MPP+. P7C3 also inhibited p53 activity and repressed Bax upregulation to protect cells from MPP+ toxicity. In addition, the activation of p53 was significantly attenuated with the inhibition of GSK3beta activity by P7C3. Furthermore, P7C3 blocked GSK3beta and p53 activation in the midbrain, and prevented DA neuronal loss in the substantia nigra in 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine mice. Thus, our study demonstrates that P7C3 protects DA neurons from neurotoxin-induced cell death by repressing the GSK3beta-p53-Bax pathway both in vitro and in vivo, thus providing a theoretical basis for P7C3 in the potential clinical treatment of PD. PMID- 28569796 TI - Future threats to biodiversity and pathways to their prevention. AB - Tens of thousands of species are threatened with extinction as a result of human activities. Here we explore how the extinction risks of terrestrial mammals and birds might change in the next 50 years. Future population growth and economic development are forecasted to impose unprecedented levels of extinction risk on many more species worldwide, especially the large mammals of tropical Africa, Asia and South America. Yet these threats are not inevitable. Proactive international efforts to increase crop yields, minimize land clearing and habitat fragmentation, and protect natural lands could increase food security in developing nations and preserve much of Earth's remaining biodiversity. PMID- 28569797 TI - Speciation gradients and the distribution of biodiversity. AB - Global patterns of biodiversity are influenced by spatial and environmental variations in the rate at which new species form. We relate variations in speciation rates to six key patterns of biodiversity worldwide, including the species-area relationship, latitudinal gradients in species and genetic diversity, and between-habitat differences in species richness. Although they sometimes mirror biodiversity patterns, recent rates of speciation, at the tip of the tree of life, are often highest where species richness is low. Speciation gradients therefore shape, but are also shaped by, biodiversity gradients and are often more useful for predicting future patterns of biodiversity than for interpreting the past. PMID- 28569798 TI - Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity. AB - Microorganisms are often studied as populations but the behaviour of single, individual cells can have important consequences. For example, tuberculosis, caused by the bacterial pathogen Mycobacterium tuberculosis, requires months of antibiotic therapy even though the bulk of the bacterial population dies rapidly. Shorter courses lead to high rates of relapse because subpopulations of bacilli can survive despite being genetically identical to those that are easily killed. In fact, mycobacteria create variability each time a cell divides, producing daughter cells with different sizes and growth rates. The mechanism(s) that underlie this high-frequency variation and how variability relates to survival of the population are unknown. Here we show that mycobacteria actively create heterogeneity. Using a fluorescent reporter and a fluorescence-activated cell sorting (FACS)-based transposon screen, we find that deletion of lamA, a gene of previously unknown function, decreases heterogeneity in the population by decreasing asymmetric polar growth. LamA has no known homologues in other organisms, but is highly conserved across mycobacterial species. We find that LamA is a member of the mycobacterial division complex (the 'divisome'). It inhibits growth at nascent new poles, creating asymmetry in polar growth. The kinetics of killing individual cells that lack lamA are more uniform and more rapid with rifampicin and drugs that target the cell wall. Our results show that mycobacteria encode a non-conserved protein that controls the pattern of cell growth, resulting in a population that is both heterogeneous and better able to survive antibiotic pressure. PMID- 28569795 TI - Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units. AB - Cystatin C (CYS C, Cst3) is an endogenous cysteine protease inhibitor that plays neuroprotective roles in neurodegenerative diseases. We aimed to explore the association of CYS C with Parkinson's disease (PD) models and investigate its involvement in the role of neurovascular units (NVUs) in PD neuro-pathogenesis. We used A53T alpha-synuclein (SNCA) transgenic mice and 6-hydroxydopamine lesioned DAergic PC12 cells as experimental PD models to investigate the mechanisms behind this association. The injections of CYS C were administered to the right substantia nigra (SN) of A53T SNCA transgenic mice to measure the effects of CYS C in transgenic A53T SNCA mice. To explore the angiogenesis in vivo and in vitro, we used the chick embryo chorioallantoic membrane (CAM) assay and tube formation (TF) assay. We found that CYS C has a neuroprotective effect in this in vivo PD model. We observed increased VEGF, NURR1 and autophagy markers LC3B and decreased SNCA and apoptosis marker cleaved CASP3 in different brain regions of CYS C-treated A53T SNCA transgenic mice. In vitro, we observed that CYS C-induced VEGF, a secreted protein, attenuated 6-OHDA-lesioned DAergic PC12 cell degeneration by regulating p-PKC-alpha/p-ERK1/2-Nurr1 signaling and inducing autophagy. VEGF-mediated angiogenesis was markedly enhanced in the conditioned media of 6-OHDA-lesioned PC12 cells with CYS C-overexpression, whereas blockage of autophagy in CYS C-overexpressing PC12 cells significantly downregulated VEGF expression and the associated angiogenesis. Our data indicate that CYS C displays dual neuronal-vascular functions, promoting PC12 cell survival and angiogenesis via regulating the level of secreted VEGF in NVUs. Our study provides evidence that may aid in the development of an alternative approach for the treatment of PD through modulation of CYS C-mediated neuronal-vascular pathways. PMID- 28569800 TI - Biodiversity. PMID- 28569799 TI - Femtosecond response of polyatomic molecules to ultra-intense hard X-rays. AB - X-ray free-electron lasers enable the investigation of the structure and dynamics of diverse systems, including atoms, molecules, nanocrystals and single bioparticles, under extreme conditions. Many imaging applications that target biological systems and complex materials use hard X-ray pulses with extremely high peak intensities (exceeding 1020 watts per square centimetre). However, fundamental investigations have focused mainly on the individual response of atoms and small molecules using soft X-rays with much lower intensities. Studies with intense X-ray pulses have shown that irradiated atoms reach a very high degree of ionization, owing to multiphoton absorption, which in a heteronuclear molecular system occurs predominantly locally on a heavy atom (provided that the absorption cross-section of the heavy atom is considerably larger than those of its neighbours) and is followed by efficient redistribution of the induced charge. In serial femtosecond crystallography of biological objects-an application of X-ray free-electron lasers that greatly enhances our ability to determine protein structure-the ionization of heavy atoms increases the local radiation damage that is seen in the diffraction patterns of these objects and has been suggested as a way of phasing the diffraction data. On the basis of experiments using either soft or less-intense hard X-rays, it is thought that the induced charge and associated radiation damage of atoms in polyatomic molecules can be inferred from the charge that is induced in an isolated atom under otherwise comparable irradiation conditions. Here we show that the femtosecond response of small polyatomic molecules that contain one heavy atom to ultra intense (with intensities approaching 1020 watts per square centimetre), hard (with photon energies of 8.3 kiloelectronvolts) X-ray pulses is qualitatively different: our experimental and modelling results establish that, under these conditions, the ionization of a molecule is considerably enhanced compared to that of an individual heavy atom with the same absorption cross-section. This enhancement is driven by ultrafast charge transfer within the molecule, which refills the core holes that are created in the heavy atom, providing further targets for inner-shell ionization and resulting in the emission of more than 50 electrons during the X-ray pulse. Our results demonstrate that efficient modelling of X-ray-driven processes in complex systems at ultrahigh intensities is feasible. PMID- 28569802 TI - Ageing: Rejuvenation study stirs old memories. PMID- 28569801 TI - Coral reefs in the Anthropocene. AB - Coral reefs support immense biodiversity and provide important ecosystem services to many millions of people. Yet reefs are degrading rapidly in response to numerous anthropogenic drivers. In the coming centuries, reefs will run the gauntlet of climate change, and rising temperatures will transform them into new configurations, unlike anything observed previously by humans. Returning reefs to past configurations is no longer an option. Instead, the global challenge is to steer reefs through the Anthropocene era in a way that maintains their biological functions. Successful navigation of this transition will require radical changes in the science, management and governance of coral reefs. PMID- 28569804 TI - Biomedical research: Premature lambs grown in a bag. PMID- 28569803 TI - Genomics: Sunflowers sequenced. PMID- 28569805 TI - Atmospheric science: The self-cleansing ability of prehistoric air. PMID- 28569807 TI - Upgrading protected areas to conserve wild biodiversity. AB - International agreements mandate the expansion of Earth's protected-area network as a bulwark against the continued extinction of wild populations, species, and ecosystems. Yet many protected areas are underfunded, poorly managed, and ecologically damaged; the conundrum is how to increase their coverage and effectiveness simultaneously. Innovative restoration and rewilding programmes in Costa Rica's Area de Conservacion Guanacaste and Mozambique's Parque Nacional da Gorongosa highlight how degraded ecosystems can be rehabilitated, expanded, and woven into the cultural fabric of human societies. Worldwide, enormous potential for biodiversity conservation can be realized by upgrading existing nature reserves while harmonizing them with the needs and aspirations of their constituencies. PMID- 28569808 TI - Data management: Stable identifiers for collection specimens. PMID- 28569809 TI - Retractions: Stamp out fake peer review. PMID- 28569810 TI - Condensed-matter physics: Functional materials at the flick of a switch. PMID- 28569812 TI - Unsung heroes: Value coordinating roles in research. PMID- 28569813 TI - Beyond pairwise mechanisms of species coexistence in complex communities. AB - The tremendous diversity of species in ecological communities has motivated a century of research into the mechanisms that maintain biodiversity. However, much of this work examines the coexistence of just pairs of competitors. This approach ignores those mechanisms of coexistence that emerge only in diverse competitive networks. Despite the potential for these mechanisms to create conditions under which the loss of one competitor triggers the loss of others, we lack the knowledge needed to judge their importance for coexistence in nature. Progress requires borrowing insight from the study of multitrophic interaction networks, and coupling empirical data to models of competition. PMID- 28569811 TI - Linking the influence and dependence of people on biodiversity across scales. AB - Biodiversity enhances many of nature's benefits to people, including the regulation of climate and the production of wood in forests, livestock forage in grasslands and fish in aquatic ecosystems. Yet people are now driving the sixth mass extinction event in Earth's history. Human dependence and influence on biodiversity have mainly been studied separately and at contrasting scales of space and time, but new multiscale knowledge is beginning to link these relationships. Biodiversity loss substantially diminishes several ecosystem services by altering ecosystem functioning and stability, especially at the large temporal and spatial scales that are most relevant for policy and conservation. PMID- 28569816 TI - Microbiology: Diversity breeds tolerance. PMID- 28569818 TI - Electric-field control of tri-state phase transformation with a selective dual ion switch. AB - Materials can be transformed from one crystalline phase to another by using an electric field to control ion transfer, in a process that can be harnessed in applications such as batteries, smart windows and fuel cells. Increasing the number of transferrable ion species and of accessible crystalline phases could in principle greatly enrich material functionality. However, studies have so far focused mainly on the evolution and control of single ionic species (for example, oxygen, hydrogen or lithium ions). Here we describe the reversible and non volatile electric-field control of dual-ion (oxygen and hydrogen) phase transformations, with associated electrochromic and magnetoelectric effects. We show that controlling the insertion and extraction of oxygen and hydrogen ions independently of each other can direct reversible phase transformations among three different material phases: the perovskite SrCoO3-delta (ref. 12), the brownmillerite SrCoO2.5 (ref. 13), and a hitherto-unexplored phase, HSrCoO2.5. By analysing the distinct optical absorption properties of these phases, we demonstrate selective manipulation of spectral transparency in the visible-light and infrared regions, revealing a dual-band electrochromic effect that could see application in smart windows. Moreover, the starkly different magnetic and electric properties of the three phases-HSrCoO2.5 is a weakly ferromagnetic insulator, SrCoO3-delta is a ferromagnetic metal, and SrCoO2.5 is an antiferromagnetic insulator-enable an unusual form of magnetoelectric coupling, allowing electric-field control of three different magnetic ground states. These findings open up opportunities for the electric-field control of multistate phase transformations with rich functionalities. PMID- 28569821 TI - LHC fires up, Google bot retires and Jupiter up close. PMID- 28569820 TI - Training: Lure young surgeons on to research tracks. PMID- 28569822 TI - Correction. PMID- 28569823 TI - Announcement: Towards greater reproducibility for life-sciences research in Nature. PMID- 28569824 TI - UK election: science spending pledges overshadowed by Brexit. PMID- 28569825 TI - Biodiversity moves beyond counting species. PMID- 28569826 TI - Govern land as a global commons. PMID- 28569827 TI - Keep shouting to save science. PMID- 28569828 TI - Why function is catching on in conservation. PMID- 28569829 TI - Trump budget would slash science programmes across government. PMID- 28569830 TI - Crowd-based peer review can be good and fast. PMID- 28569831 TI - Trials of embryonic stem cells to launch in China. PMID- 28569832 TI - Mummy DNA unravels ancient Egyptians' ancestry. PMID- 28569833 TI - Taxonomy anarchy hampers conservation. PMID- 28569834 TI - Neutron stars set to open their heavy hearts. PMID- 28569835 TI - Software simplified. PMID- 28569836 TI - Single-cell entropy for accurate estimation of differentiation potency from a cell's transcriptome. AB - The ability to quantify differentiation potential of single cells is a task of critical importance. Here we demonstrate, using over 7,000 single-cell RNA-Seq profiles, that differentiation potency of a single cell can be approximated by computing the signalling promiscuity, or entropy, of a cell's transcriptome in the context of an interaction network, without the need for feature selection. We show that signalling entropy provides a more accurate and robust potency estimate than other entropy-based measures, driven in part by a subtle positive correlation between the transcriptome and connectome. Signalling entropy identifies known cell subpopulations of varying potency and drug resistant cancer stem-cell phenotypes, including those derived from circulating tumour cells. It further reveals that expression heterogeneity within single-cell populations is regulated. In summary, signalling entropy allows in silico estimation of the differentiation potency and plasticity of single cells and bulk samples, providing a means to identify normal and cancer stem-cell phenotypes. PMID- 28569837 TI - A robot for high yield electrophysiology and morphology of single neurons in vivo. AB - Single-cell characterization and perturbation of neurons provides knowledge critical to addressing fundamental neuroscience questions including the structure function relationship and neuronal cell-type classification. Here we report a robot for efficiently performing in vivo single-cell experiments in deep brain tissues optically difficult to access. This robot automates blind (non-visually guided) single-cell electroporation (SCE) and extracellular electrophysiology, and can be used to characterize neuronal morphological and physiological properties of, and/or manipulate genetic/chemical contents via delivering extraneous materials (for example, genes) into single neurons in vivo. Tested in the mouse brain, our robot successfully reveals the full morphology of single infragranular neurons recorded in multiple neocortical regions, as well as deep brain structures such as hippocampal CA3, with high efficiency. Our robot thus can greatly facilitate the study of in vivo full morphology and electrophysiology of single neurons in the brain. PMID- 28569838 TI - USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response. AB - BRCA1 regulates multiple cellular pathways that maintain genomic stability including cell cycle checkpoints, DNA repair, protein ubiquitination, chromatin remodelling, transcriptional regulation and apoptosis. Receptor-associated protein 80 (RAP80) helps recruit BRCA1 to double-strand breaks (DSBs) through the scaffold protein CCDC98 (Abraxas) and facilitates DNA damage response (DDR). However, the regulation of RAP80-BRCA1 complex is still unclear. Here we report that a deubiquitinase, USP13, regulates DDR by targeting RAP80. Mechanistically, USP13 is phosphorylated by ATM following DNA damage which, in turn, facilitates its DSB localization. USP13, in turn, deubiquitinates RAP80 and promotes RAP80 recruitment and proper DDR. Depleting or inhibiting USP13 sensitizes ovarian cancer cells to cisplatin and PARP inhibitor (olaparib) while overexpression of USP13 renders ovarian cancer cells resistant to chemotherapy. Overall, we identify USP13 as a regulator of DNA repair and reveal a model in which a phosphorylation-deubiquitination axis dynamically regulates RAP80-BRCA1 complex foci formation and function. PMID- 28569839 TI - Multicentennial record of Labrador Sea primary productivity and sea-ice variability archived in coralline algal barium. AB - Accelerated warming and melting of Arctic sea-ice has been associated with significant increases in phytoplankton productivity in recent years. Here, utilizing a multiproxy approach, we reconstruct an annually resolved record of Labrador Sea productivity related to sea-ice variability in Labrador, Canada that extends well into the Little Ice Age (LIA; 1646 AD). Barium-to-calcium ratios (Ba/Ca) and carbon isotopes (delta13C) measured in long-lived coralline algae demonstrate significant correlations to both observational and proxy records of sea-ice variability, and show persistent patterns of co-variability broadly consistent with the timing and phasing of the Atlantic Multidecadal Oscillation (AMO). Results indicate reduced productivity in the Subarctic Northwest Atlantic associated with AMO cool phases during the LIA, followed by a step-wise increase from 1910 to present levels-unprecedented in the last 363 years. Increasing phytoplankton productivity is expected to fundamentally alter marine ecosystems as warming and freshening is projected to intensify over the coming century. PMID- 28569840 TI - Thermal annihilation of photo-induced radicals following dynamic nuclear polarization to produce transportable frozen hyperpolarized 13C-substrates. AB - Hyperpolarization via dynamic nuclear polarization (DNP) is pivotal for boosting magnetic resonance imaging (MRI) sensitivity and dissolution DNP can be used to perform in vivo real-time 13C MRI. The type of applications is however limited by the relatively fast decay time of the hyperpolarized spin state together with the constraint of having to polarize the 13C spins in a dedicated apparatus nearby but separated from the MRI magnet. We herein demonstrate that by polarizing 13C with photo-induced radicals, which can be subsequently annihilated using a thermalization process that maintains the sample temperature below its melting point, hyperpolarized 13C-substrates can be extracted from the DNP apparatus in the solid form, while maintaining the enhanced 13C polarization. The melting procedure necessary to transform the frozen solid into an injectable solution containing the hyperpolarized 13C-substrates can therefore be performed ex situ, up to several hours after extraction and storage of the polarized solid. PMID- 28569843 TI - 5.6 W monolithic fiber laser at 3.55 MUm. AB - We report, to the best of our knowledge, the first monolithic erbium-doped fluorozirconate fiber laser bounded by two fiber Bragg gratings (FBGs) operating at 3.55 MUm. Its output power and total optical efficiency are 5.6 W and 26.4% respectively, the highest ever achieved at this wavelength from a fiber laser. The monolithic design of the cavity also increases its stability and prevents fiber tip damage which has limited prior demonstrations to a maximum output power of 1.5 W. This Letter also studies the performances of the laser cavity for various output FBG reflectivities and presents numerical modeling results exhibiting remarkable agreement with experimental results. PMID- 28569841 TI - Myosin Va molecular motors manoeuvre liposome cargo through suspended actin filament intersections in vitro. AB - Intracellular cargo transport relies on myosin Va molecular motor ensembles to travel along the cell's three-dimensional (3D) highway of actin filaments. At actin filament intersections, the intersecting filament is a structural barrier to and an alternate track for directed cargo transport. Here we use 3D super resolution fluorescence imaging to determine the directional outcome (that is, continues straight, turns or terminates) for an ~10 motor ensemble transporting a 350 nm lipid-bound cargo that encounters a suspended 3D actin filament intersection in vitro. Motor-cargo complexes that interact with the intersecting filament go straight through the intersection 62% of the time, nearly twice that for turning. To explain this, we develop an in silico model, supported by optical trapping data, suggesting that the motors' diffusive movements on the vesicle surface and the extent of their engagement with the two intersecting actin tracks biases the motor-cargo complex on average to go straight through the intersection. PMID- 28569842 TI - Giant barocaloric effect in the ferroic organic-inorganic hybrid [TPrA][Mn(dca)3] perovskite under easily accessible pressures. AB - The fast growing family of organic-inorganic hybrid compounds has recently been attracting increased attention owing to the remarkable functional properties (magnetic, multiferroic, optoelectronic, photovoltaic) displayed by some of its members. Here we show that these compounds can also have great potential in the until now unexplored field of solid-state cooling by presenting giant barocaloric effects near room temperature already under easily accessible pressures in the hybrid perovskite [TPrA][Mn(dca)3] (TPrA: tetrapropylammonium, dca: dicyanamide). Moreover, we propose that this will not be an isolated example for such an extraordinary behaviour as many other organic-inorganic hybrids (metal-organic frameworks and coordination polymers) exhibit the basic ingredients to display large caloric effects which can be very sensitive to pressure and other external stimuli. These findings open up new horizons and great opportunities for both organic-inorganic hybrids and for solid-state cooling technologies. PMID- 28569844 TI - 4.2 PW, 20 fs Ti:sapphire laser at 0.1 Hz. AB - We demonstrated the generation of 4.2 PW laser pulses at 0.1 Hz from a chirped pulse amplification Ti:sapphire laser. The cross-polarized wave generation and the optical parametric chirped-pulse amplification stages were installed for the prevention of the gain narrowing and for the compensation of the spectral narrowing in the amplifiers, obtaining the spectral width of amplified laser pulses of 84 nm (FWHM), and enhancing the temporal contrast. The amplified laser pulses of 112 J after the final booster amplifier were compressed to the pulses with 83 J at 19.4 fs with a shot-to-shot energy stability of 1.5% (RMS). This 4.2 PW laser will be a workhorse for exploring high field science. PMID- 28569845 TI - Combining phase images measured in the radio frequency and the optical frequency ranges. AB - Phase images measured in the radio frequency (RF) and optical frequency (OF) ranges, whose difference was about 4*105, were combined on the basis of a pattern matching method. RF phase imaging was implemented with an optical frequency-comb femtosecond laser and a single-pixel camera to measure a meter order depth object with micrometer-order accuracy. OF phase imaging was implemented with an optical interferometer using a low-coherence femtosecond laser pulse to measure the profile with nanometer-order accuracy and high spatial resolution. Combining the images obtained from both phase measurement systems enabled profilometry of a large depth object with high lateral and axial resolutions. PMID- 28569846 TI - Mid-infrared sensing of molecular vibrational modes with tunable graphene plasmons. AB - We study the tunable plasmons based on a graphene integrated gold grating structure to sense the vibrational modes of nanometric molecules. The greatly enhanced light-matter interaction and the broadband tunability of the localized graphene plasmonic resonance enable accurate label-free identification of the molecular vibrational modes at subwavelength scale. Our results may accelerate the further development of novel cost-effective biosensors with superior molecular chemical fingerprint sensitivity in an active graphene plasmonic device. PMID- 28569847 TI - Heart diffraction. AB - A theoretical study of the plane-wave diffraction by a heart-like sharp-edge aperture corresponding to the involute of a circle is proposed here. Through the recently developed paraxial boundary diffraction wave theory, expressed via the language of catastrophe optics, the presence of pseudo-nondiffracting regions within the three-dimensional spatial intensity distribution of the diffracted wavefield is intuitively explained and quantitatively characterized. The results of some old, beautiful, but nearly forgotten, diffraction experiments have also been reconsidered from such a peculiar and rather unorthodox perspective. PMID- 28569848 TI - Higher-order mode suppression in twisted single-ring hollow-core photonic crystal fibers. AB - A hollow-core single-ring photonic crystal fiber (SR-PCF) consists of a ring of capillaries arranged around a central hollow core. Spinning the preform during drawing introduces a continuous helical twist, offering a novel means of controlling the modal properties of hollow-core SR-PCF. For example, twisting geometrically increases the effective axial propagation constant of the LP01-like modes of the capillaries, providing a means of optimizing the suppression of HOMs, which occurs when the LP11-like core mode phase-matches to the LP01-like modes of the surrounding capillaries. (In a straight fiber, optimum suppression occurs for a capillary-to-core diameter ratio d/D=0.682.) Twisting also introduces circular birefringence (to be studied in a future Letter) and has a remarkable effect on the transverse intensity profiles of the higher-order core modes, forcing the two-lobed LP11 like mode in the untwisted fiber to become three-fold symmetric in the twisted case. These phenomena are explored by means of extensive numerical modeling, an analytical model, and a series of experiments. Prism-assisted side-coupling is used to measure the losses, refractive indices, and near-field patterns of individual fiber modes in both the straight and twisted cases. PMID- 28569849 TI - Graphene-coated nanowires with a drop-shaped cross section for 10 nm confinement and 1 mm propagation. AB - Strong confinement and long-range propagation of electromagnetic energy are longed for when designing efficient miniaturized photonic devices. Here, a graphene-coated nanowire with a drop-shaped cross section is proposed for guiding graphene surface plasmon polaritons to demonstrate an extremely long propagation length (1 mm) with ultra-strong mode confinement (10 nm), which results from the distinctive mode field distribution caused by both the top and bottom arcs of the waveguide. The combination of nanoconcentration and long-range propagation makes the waveguide very useful in nanophotonics, bio-photonics, and highly integrated photonic circuits. PMID- 28569850 TI - Tunable time-resolved tick-tock pulsed digital holographic microscopy for ultrafast events. AB - This study presents a time-resolved imaging technique for detecting ultrafast events in the sample with tunable tick-tock pulses in common-path digital holographic microscopy. The tick-tock pulses are generated from the same single femtosecond pulse source and manipulated through a spatial-multiplexing encoding/decoding scheme with two complementary binary codes for digital hologram recording and reconstruction. The spatial-multiplexing encoding/decoding scheme with compressive sensing on the Fresnel digital hologram is used to recover missing data and achieve high-fidelity wavefront reconstruction. The elapsed time of tick-tock pulses can be adjusted by changing the optical path difference between the pulse pair arms for dynamic observation at various timescales. The proposed method is applied to explore the ultrafast physical phenomenon by quantitative phase imaging with a stopwatch-like tunable timescale ranging from nanoseconds to femtoseconds. PMID- 28569852 TI - Micro-sized tunable liquid crystal optical filters. AB - Liquid crystal arrayed microcavities (LCAM) is a new technology for ultra-narrow optical filtering (FWHM ~0.1 nm) that uses picoliter volume Fabry-Perot-type optical cavities filled with liquid crystal for tuning. LCAMs are sub-nm spectral resolution filters, which utilize well-established laser writing, thin film deposition, and wafer manufacturing techniques. These filters are compact, robust, and inexpensive. Compact, high-resolution optical filters have applications, including biomedical imaging, chemical detection, and environmental monitoring. Here, we describe the LCAM design and initial performance metrics. PMID- 28569851 TI - Contribution of angle-dependent light penetration to electric-field enhancement at nodules in optical coatings. AB - The influence of angle-dependent light penetration on electric-field intensity (EFI) enhancement at nodules was investigated in this Letter. An experiment consisting of 3D finite-difference time-domain simulations was conducted on two types of polarizers that prevent light penetration at a low and a high incident angular range (IAR). The EFI at the focal point region is six times lower, and the laser damage resistance is three times higher in the polarizer blocking light penetration in a high IAR. These results reveal for the first time, to the best of our knowledge, that light penetration at a high IAR, rather than at a low IAR, contributes to EFI enhancement at the focal region of the nodules. Our findings may provide useful guidance in selecting optimal designs to suppress EFI enhancement at nodules in multilayer coatings. PMID- 28569853 TI - Focusing subwavelength grating coupler for mid-infrared suspended membrane germanium waveguides. AB - We present a focusing subwavelength grating (SWG) for efficient coupling of mid infrared (mid-IR) light into suspended membrane Ge photonic integrated circuits (PICs) that enable mid-IR applications in the entire fingerprint region. By virtue of their wide spectral transparency window and air-cladding device configuration, the suspended membrane Ge PICs are expected to be effective for mid-IR applications over the spectral region covering from 2 to 15 MUm. Specifically, we demonstrate the maximum coupling efficiency of -11 dB with a 1 dB bandwidth of ~58 nm at the SWG's center wavelength of 2.37 MUm. Our focusing SWG is expected to advance the development of on-chip long-wavelength mid-IR applications such as biochemical sensing, thermal imaging, and nonlinear optics in the fingerprint region. PMID- 28569854 TI - Tunable 7-12 MUm picosecond optical parametric amplifier based on a LiInSe2 mid-infrared crystal. AB - Mid-infrared (MIR) nonlinear optical crystals of LiInSe2 (LISe) were grown by a modified Bridgman technique on a (001)-seed. A 7-12 MUm widely tunable picosecond (ps) MIR optical parametric amplifier (OPA) based on a LISe crystal was demonstrated for the first time, to the best of our knowledge. The MIR OPA was pumped by a 30 ps 1064 nm Nd:YAG laser and injected by a KTiOPO4 (KTP)-based widely tunable near-infrared seed. The idler operating at 7.5 MUm with the highest pulse energy of 170 MUJ was obtained under a pump energy of 14 mJ. The corresponding energy conversion efficiency is ~1.21%, and the photon conversion efficiency is 8.6%. The output energies were measured to be ~121 MUJ at 7 MUm and ~21 MUJ at 12 MUm. PMID- 28569855 TI - Temporally versatile polarization entanglement from Bragg reflection waveguides. AB - Bragg reflection waveguides emitting broadband parametric downconversion (PDC) have been proven to be well suited for the on-chip generation of polarization entanglement in a straightforward fashion [Sci. Rep.3, 2314 (2013)SRWSDA2045 232210.1038/srep02314]. Here, we investigate how the properties of the created states can be modified by controlling the relative temporal delay between the pair of photons created via PDC. Our results offer an easily accessible approach for changing the coherence of the polarization entanglement, in other words, to tune the phase of the off-diagonal elements of the density matrix. Furthermore, we provide valuable insight into the engineering of these states directly at the source. PMID- 28569856 TI - Magnetic annihilation of the dark mode in a strongly coupled bright-dark terahertz metamaterial. AB - Dark mode in metamaterials has become a vital component in determining the merit of the Fano type of interference in the system. Its strength dictates the enhancement and suppression in the amplitude and Q-factors of resulting resonance features. In this work, we experimentally probe the effect of strong near-field coupling on the strength of the dark mode in a concentrically aligned bright resonator and a dark split ring resonator (SRR) system exhibiting the classical analog of the electromagnetically induced transparency effect. An enhanced strong magnetic field between the bright-dark resonators destructively interferes with the inherent magnetic field of the dark mode to completely annihilate its effect in the coupled system. Moreover, the observed annihilation effect in the dark mode has a direct consequence on the disappearance of the SRR effect in the proposed system, wherein under the strong magnetic interactions, the LC resonance feature of the split ring resonator becomes invisible to the incident terahertz wave. PMID- 28569857 TI - Editorial: Serving the Optics and Photonics Community for 40 Years. AB - Editor-in-Chief Xi-Cheng Zhang celebrates Optics Letters' 40th anniversary by discussing the Journal's success and clarifying an editorial policy that balances the Journal's high standards with the fulfillment of its mission to support the greater optics and photonics community. PMID- 28569858 TI - Quasi-phase-matched multispectral Kerr frequency comb. AB - We study a new type of Kerr frequency comb where the momentum conservation law is fulfilled by azimuthal modulation of the waveguide dispersion. The concept can expand the parametric range in which a Kerr frequency comb is obtained. In a good agreement with the theoretical analysis, we demonstrate a multispectral Kerr frequency comb covering important fiber-optic communication bands. Comb coherence and absence of a sub-comb offset are confirmed by continuous-wave heterodyne beat note and amplitude noise spectra measurements. The device can be used for achieving broadband optical frequency synthesizers and high-capacity coherent communication. PMID- 28569859 TI - Fiber-ring laser-based intracavity photoacoustic spectroscopy for trace gas sensing. AB - We demonstrated a novel trace gas sensing method based on fiber-ring laser intracavity photoacoustic spectroscopy. This spectroscopic technique is a merging of photoacoustic spectroscopy (PAS) with a fiber-ring cavity for sensitive and all-fiber gas detection. A transmission-type PAS gas cell (resonant frequency f0=2.68 kHz) was placed inside the fiber-ring laser to fully utilize the intracavity laser power. The PAS signal was excited by modulating the laser wavelength at f0/2 using a custom-made fiber Bragg grating-based modulator. We used this spectroscopic technique to detect acetylene (C2H2) at 1531.6 nm as a proof of principle. With a low Q factor (4.9) of the PAS cell, our sensor achieved a good linear response (R2=0.996) to C2H2 concentration and a minimum detection limit of 390 ppbv at 2-s response time. PMID- 28569860 TI - Narrowband terahertz generation with chirped-and-delayed laser pulses in periodically poled lithium niobate. AB - We generate narrowband terahertz (THz) radiation in periodically poled lithium niobate (PPLN) crystals using two chirped-and-delayed driver pulses from a high energy Ti:sapphire laser. The generated frequency is determined by the phase matching condition in the PPLN and influences the temporal delay of the two pulses for efficient terahertz generation. We achieve internal conversion efficiencies up to 0.13% as well as a record multicycle THz energy of 40 MUJ at 0.544 THz in a cryogenically cooled PPLN. PMID- 28569861 TI - Optical path difference microscopy with a Shack-Hartmann wavefront sensor. AB - In this Letter, we show that a Shack-Hartmann wavefront sensor can be used for the quantitative measurement of the specimen optical path difference (OPD) in an ordinary incoherent optical microscope, if the spatial coherence of the illumination light in the plane of the specimen is larger than the microscope resolution. To satisfy this condition, the illumination numerical aperture should be smaller than the numerical aperture of the imaging lens. This principle has been successfully applied to build a high-resolution reference-free instrument for the characterization of the OPD of micro-optical components and microscopic biological samples. PMID- 28569862 TI - Kerr frequency combs and triangular spectra. AB - Nonlinear externally driven optical cavities are known to generate periodic patterns. They grow from the linearly unstable background states due to modulation instability. These periodic solutions are also known as Kerr frequency combs, which have a variety of applications in metrology. The stationary state of periodic wave trains can be explained theoretically only in weakly nonlinear regimes near the onset of the instability using the order parameter description. However, in both weakly and strongly nonlinear dissipative regimes, only numerical solutions can be found. No analytic solutions are known so far except for the homogeneous continuous wave solution. Here, we derive an analytical expression for the intracavity fully nonlinear dissipative periodic wave train profiles that provides good agreement with the results of numerical simulations. Our approach is based on empirical knowledge of the triangular shape of the frequency comb spectrum. PMID- 28569863 TI - Hybrid single-mode laser based on graphene Bragg gratings on silicon. AB - We exploit distributed optoelectronic properties enabled by graphene Bragg gratings (GBGs) to realize a hybrid single-mode laser on silicon. This hybrid laser achieves single-mode, continuous-wave operation at 1540 nm with a remarkable side-mode suppression ratio of 48 dB, benefitting from the coupling of the GBGs. These results suggest that graphene thin films can be used as an essential and cost-saving component for hybrid photonic integration on silicon. PMID- 28569864 TI - Polarization dynamics induced by parallel optical injection in a single-mode VCSEL. AB - We report an experimental study of the polarization nonlinear dynamics in a 1550 nm single-mode vertical-cavity surface-emitting laser (VCSEL) subject to parallel optical injection. Experimentally measured stability maps identifying regions of different nonlinear dynamics for various values of bias current are reported. We show that VCSELs with more than a 35 dB polarization mode suppression ratio can have rich nonlinear dynamics in both linear polarizations, including periodic and chaotic behaviors appearing simultaneously in both polarization modes. PMID- 28569865 TI - Silicon waveguide polarization rotator sampled Bragg grating. AB - In this Letter, we demonstrate, to the best of our knowledge, the first experimental results of sampled Bragg grating with polarization rotator function. Silicon waveguide is used. Multiple polarization-independent reflection wavelength peaks were obtained. PMID- 28569866 TI - Absolute noninvasive measurement of CO2 mole fraction emitted by E. coli and S. aureus using calibration-free 2f WMS applied to a 2004 nm VCSEL. AB - We report the first demonstration, to the best of our knowledge, of accurate real time noninvasive measurement of the absolute cumulative mole fraction of metabolic carbon dioxide emitted by Escherichia coli and Staphylococcus aureus over a period of several hours of their life cycles using a recently developed calibration-free wavelength modulation spectroscopy technique. A 1 mW vertical cavity surface-emitting laser is used to interrogate a single rotational vibrational absorption line of carbon dioxide at 2003.5 nm. The measurements are immune to laser intensity fluctuations and variable optical coupling that is inevitable in such free-space coupled experiments that run over 10-18 h. The cumulative carbon dioxide mole fraction follows the characteristic modified Gompertz model that is typical of bacterial growth in batch cultures. The characteristic growth parameters are extracted from this curve. The technique can be readily extended to study multiple volatile organic compounds that bacteria are known to emit. PMID- 28569867 TI - Optical biopsy approach to basal cell carcinoma and melanoma based on all optically integrated photoacoustic and optical coherence tomography. AB - Basal cell carcinoma (BCC) and melanoma (MM), with the highest morbidity and mortality, respectively, are considered as two skin cancers of concern in dermatology. Histological studies have demonstrated that vascular patterns and collagenous stroma serve as key parameters for BCC and MM classification. In this Letter, we sought to identify BCC and MM based on the dual parameters of vascular patterns and scattering structures provided by all-optically integrated photoacoustic and optical coherence tomography (AOPA/OCT). The imaging capability of the AOPA/OCT was verified by the mimic phantoms. Furthermore, in vivo characterization of vasculatures and tissue structures from BCC and MM mice were successfully achieved with high resolution. Results prove the feasibility of AOPA/OCT as a novel method to dedicate to the in vivo biopsy of skin cancers which shows new insights into the study of skin diseases in early stages. PMID- 28569869 TI - Optimal Mueller matrix estimation in the presence of additive and Poisson noise for any number of illumination and analysis states. AB - We investigate the optimal strategies for estimating the Mueller matrix with arbitrary numbers of illumination and analysis states, in the presence of signal independent additive noise or signal-dependent Poisson shot noise. We demonstrate that the architectures that minimize and equalize the estimation variances for both types of noise sources are based on spherical designs of order 2 or 3, and we provide closed-form expressions of the estimation precision obtained with these optimal measurement strategies. The obtained results are important to design Mueller polarimeters in practice and assess their fundamental limits in terms of estimation precision. PMID- 28569868 TI - Frequency comb generation in SNAP bottle resonators. AB - We develop a theory of optical frequency comb generation in ultra-compact surface nanoscale axial photonic (SNAP) bottle microresonators, employing the nonlinear interaction of whispering gallery modes which are confined along an optical fiber with nanoscale radius variation. We predict that a SNAP microresonator with a radius of a few micrometers can generate a frequency comb with an ultra-fine sub gigahertz spectral spacing, which would require traditional ring resonators of centimeter radius. We identify regimes of stable or quasi-periodic comb dynamics due to soliton excitation, and show that special engineering of the SNAP radius profile can be used to compensate for nonlinearity-induced dispersion. PMID- 28569870 TI - Electro-optical effects of high aspect ratio P3HT nanofibers colloid in polymer micro-fluid cells. AB - This Letter reports the electro-optical (EO) effect of Poly(3-hexylthiophene-2,5 diyl) (P3HT) nanofibers colloid in a polymer micro-fluidic EO cell. P3HT nanofibers are high aspect ratio semiconducting nanostructures, and can be collectively aligned by an external alternating electric field. Optical transmission modulated by the electric field is a manifestation of the electro optical effect due to high inner crystallinity of P3HT nanofibers. According to our results, the degree of alignment reaches a maximum at 0.6 V/MUm of electric field strength, implying a big polarizability value due to geometry and electrical properties of P3HT nanofibers. We believe that one-dimensional crystalline organic nanostructures have a large potential in EO devices due to their significant anisotropy, wide variety of properties, low actuation voltages, and opportunity to be tailored via adjustment of the fabrication process. PMID- 28569871 TI - Temperature-independent optical transition with sub-nanometer linewidth in thermally diffused Gadolinium in GaN. AB - We have demonstrated temperature-independent optical transitions from thermally diffused Gd in GaN. The emission wavelength is sub-bandgap with respect to GaN. The origin of photon generation is identified as atomic transitions in Gd hosted in the weak interaction field of GaN. The emission linewidth remains sub nanometer (0.1-0.6 nm) from 19 to 300 K for all the optical pumping intensities. The shift in wavelength with temperature and optical pumping is negligible (~0.8 nm) for the entire temperature window. The output intensity is found to scale linearly with the pumping power. The magnetic, electrical, and physical characterizations indicate that Gd acts as an electron trap in GaN. Transient absorption spectroscopy discovers a major nonradiative parallel path for carrier leaking. The observed characteristics may find potential applications in narrow linewidth optical sources. PMID- 28569872 TI - Transverse Anderson localization of surface plasmon polaritons. AB - We investigate the effect of disorder on the propagation of surface plasmon polaritons in arrays of evanescently coupled dielectric loaded surface plasmon polariton waveguides. Diagonal disorder is implemented by randomly varying the heights of the waveguides. Real-space as well as momentum-space images of the surface plasmon polariton intensity distribution in the waveguide arrays are recorded by leakage radiation microscopy. In real space, increasing disorder results in a transverse localization of surface plasmon polaritons. In the momentum distribution, we observe for the first time a disorder-induced transition from a continuous band to a set of discrete modes. PMID- 28569873 TI - Single-shot chemical detection and identification with compressed hyperspectral Raman imaging. AB - Raman imaging is a powerful method to identify and detect chemicals, but the long acquisition time required for full spectroscopic Raman images limits many practical applications. Compressive sensing and compressed ultrafast photography have recently demonstrated the acquisition of multi-dimensional data sets with single-shot detection. In this Letter, we demonstrate the utilization of compressed sensing for single-shot compressed Raman imaging. In particular, we use this technique to demonstrate the identification of two similarly white substances in one image via the recovered two-dimensional array of Raman spectra. This technique can be further extended by coupling the compressed sensing apparatus with a microscope for compressed hyperspectral imaging microscopy. PMID- 28569874 TI - Demonstration of intradyne BPSK optical free-space transmission in representative atmospheric turbulence conditions for geostationary uplink channel. AB - Binary phase-shift keying optical transmission in the C-band with coherent intradyne reception is demonstrated over a long-range (10.45 km) link through the atmosphere. The link emulates representative channel conditions for geostationary optical feeder uplinks in satellite communications. The digital signal processing used in recovering the transmitted data and the performed measurements are described. Finally, the bit error rate results for 10 Gbit/s, 20 Gbit/s, and 30 Gbit/s of the outdoor experiments are presented and compared with back-to-back measurements and theory. PMID- 28569875 TI - Vectorial extreme events in VCSEL polarization dynamics. AB - We report on the occurrence of extreme events (EEs) in the polarization dynamics of vertical cavity surface emitting lasers with optical feedback. We have identified two types of EEs based on numerical simulations: vectorial and scalar events corresponding, respectively, to the emission of a high-power pulse in both linear polarizations simultaneously and in single linear polarization. We show that these two types of events follow the typical statistics of rogue waves. Finally, we observe that an emission in both polarizations leads to a larger generation rate of EEs with a saturation over a wide range of feedback strength by comparison to a single-polarization mode emission. PMID- 28569876 TI - Optical modulation based on tunable light absorption and amplification in metasurfaces coupled with gain medium. AB - While previous tunable metasurfaces were based mainly on tuning of dielectric permittivity or losses in associated tunable elements, here we propose gain assisted tunable metasurfaces as optical modulators with high ON-OFF ratio. They consist of a dye-doped film placed within metal-insulator-metal (MIM) cavities. Plasmonic modes with enhanced electric field significantly enhance both absorption and emission of light by dye molecules. As a result, it is possible to achieve the perfect absorption in MIM cavities with zero reflection, as well as to compensate losses thus achieving unit reflection. As a result, the achievable ON/OFF ratio is more than 100. PMID- 28569878 TI - Generation of unipolar half-cycle pulses via unusual reflection of a single-cycle pulse from an optically thin metallic or dielectric layer. AB - We propose a strikingly simple method to form approximately unipolar half-cycle optical pulses via reflection of a single-cycle optical pulse from a thin flat metallic or dielectric layer. Unipolar pulses in reflection arise due to specifics of one-dimensional pulse propagation. Namely, we show that the field emitted by the layer is proportional to the velocity of the oscillating charges in the medium, instead of their acceleration. Besides, the oscillation velocity of the charges can be forced to keep a constant sign throughout the pulse duration. That is, reflection of ultrashort pulses from broad-area layers with nanometer-scale thickness can be very different from the common reflection in the case of longer pulses and thicker layers. This suggests a possibility of unusual transformations of few-cycle light pulses in completely linear optical systems. PMID- 28569877 TI - Interferometric time-domain ptychography for ultrafast pulse characterization. AB - A novel pulse characterization method is presented, favorably combining interferometric frequency-resolved optical gating (FROG) and time-domain ptychography. This new variant is named ptychographic-interferometric frequency resolved optical gating (piFROG). The measurement device is simple, bearing similarity to standard second-harmonic FROG, yet with a collinear beam geometry and an added bandpass filter in one of the correlator arms. The collinear beam geometry allows tight focusing and circumvents possible geometrical distortion effects of noncollinear methods, making piFROG especially suitable for the characterization of unamplified few-cycle pulses. Moreover, the direction-of-time ambiguity afflicting most second-order FROG variants is eliminated. Possible group delay dispersion of pulses leads to a characteristic tilt in the piFROG traces, allowing the detection of uncompensated dispersion without a retrieval. Using nanojoule, three-cycle pulses at 800 nm, the piFROG method is tested, and the results are compared with spectral phase interferometry for direct electric field reconstruction measurements. Measured pulse durations agree within a fraction of a femtosecond. As a further test, the piFROG measurements are repeated with added group delay dispersion, and found to accurately reproduce the dispersion computed with Sellmeier equations. PMID- 28569879 TI - Nanosecond difference-frequency generation in orientation-patterned gallium phosphide. AB - We report a tunable, single-pass, pulsed nanosecond difference-frequency generation (DFG) source based on the new semiconductor nonlinear material, orientation-patterned gallium phosphide (OP-GaP). The DFG source is realized by mixing the output signal of a nanosecond OPO tunable over 1723-1827 nm with the input pump pulses of the same OPO at 1064 nm in an OP-GaP crystal, resulting in tunable generation over 233 nm in the mid-infrared from 2548 to 2781 nm. Using a 40-mm-long crystal, we have produced ~14 mW of average DFG output power at 2719 nm for a pump power of 5 W and signal power of 1 W at 80 kHz repetition rate. To the best of our knowledge, this is the first single-pass nanosecond DFG source based on OP-GaP. The DFG output beam has a TEM00 spatial mode profile and exhibits passive power stability better than 1.7% rms over 1.4 h at 2774 nm, compared to 1.6% and 0.1% rms for the signal and pump, respectively. The OP-GaP crystal is recorded to have a temperature acceptance bandwidth of 17.7 degrees C. PMID- 28569880 TI - Characterization of optical frequency transfer over 154 km of aerial fiber. AB - We present measurements of the frequency transfer stability and analysis of the noise characteristics of an optical signal propagating over aerial suspended fiber links up to 153.6 km in length. The measured frequency transfer stability over these links is on the order of 10-11 at an integration time of 1 s dropping to 10-12 for integration times longer than 100 s. We show that wind-loading of the cable spans is the dominant source of short-timescale noise on the fiber links. We also report an attempt to stabilize the optical frequency transfer over these aerial links. PMID- 28569881 TI - High-energy pulse stacking via regenerative pulse-burst amplification. AB - Here we present a coherent pulse stacking approach for upscaling the energy of a solid-state femtosecond chirped pulse amplifier. We demonstrate pulse splitting into four replicas, amplification in a burst-mode regenerative Yb:CaF2 amplifier, designed to overcome intracavity optical damage by colliding pulse replicas, and coherent combining into a single millijoule level pulse. The thresholds of pulse-burst-induced damage of optical elements are experimentally investigated. The scheme allows achieving an enhancement factor of 2.62 using a single-stage stacker cavity and, potentially, much higher enhancement factors using cascaded stacking. PMID- 28569882 TI - Polynomials of Gaussians and vortex-Gaussian beams as complete, transversely confined bases. AB - A novel type of discrete basis for paraxial beams is proposed, consisting of monomial vortices times polynomials of Gaussians in the radial variable. These bases have the distinctive property that the effective size of their elements is roughly independent of element order, meaning that the optimal scaling for expanding a localized field does not depend significantly on truncation order. This behavior contrasts with that of bases composed of polynomials times Gaussians, such as Hermite-Gauss and Laguerre-Gauss modes, where the scaling changes roughly as the inverse square root of the truncation order. PMID- 28569883 TI - BDK-doped core microstructured PMMA optical fiber for effective Bragg grating photo-inscription. AB - An endlessly single-mode doped microstructured poly(methyl methacrylate) (PMMA) optical fiber is produced for effective fiber Bragg grating (FBG) photo inscription by means of a 400 nm femtosecond pulsed laser and the phase mask technique. The fiber presents a uniform benzyl dimethyl ketal (BDK) distribution in its core without drastic loss increase. It was produced using the selected center hole doping technique, and the BDK dopant acts as a photoinitiator. In this Letter, we report a rapidly growing process of the grating reflection band. For an 11 mW mean laser power, the FBG reflectivity reaches 83% in only 40 s. PMID- 28569884 TI - Silicon PAM-4 optical modulator driven by two binary electrical signals with different peak-to-peak voltages. AB - We demonstrate a silicon PAM-4 optical modulator, which is based on a symmetric Mach-Zehnder interferometer. Two uncorrelated binary electrical signals with different peak-to-peak voltages are applied to the phase shifters of the silicon optical modulator. Accordingly, two different phase shifts are generated in the two arms. After the permutation, there are totally four phase differences between the two arms and the output optical power has four levels. The device can work at 32 Gbaud in the wavelength range from 1525 to 1565 nm, which is promising for the next-generation high-speed silicon optical link. PMID- 28569885 TI - Experimental study on the statistic characteristics of a 3x3 RF MIMO channel over a single conventional multimode fiber. AB - Based on the observed random fluctuation phenomenon of speckle pattern across multimode fiber (MMF) facet and received optical power distribution across three output ports, we experimentally investigate the statistic characteristics of a 3*3 radio frequency multiple-input multiple-output (MIMO) channel enabled by mode division multiplexing in a conventional 50 um MMF using non-mode-selective three dimensional waveguide photonic lanterns as mode multiplexer and demultiplexer. The impacts of mode coupling on the MIMO channel coefficients, channel matrix, and channel capacity have been analyzed over different fiber lengths. The results indicate that spatial multiplexing benefits from the greater fiber length with stronger mode coupling, despite a higher optical loss. PMID- 28569886 TI - Enhanced self-mixing interferometry based on volume Bragg gratings and laser diodes emitting at 405-nm wavelengths. AB - Self-mixing interferometry (SMI) represents a robust, self-aligned technique for metrology applications. Recently, it has been shown that the detection of the frequency-modulated (FM) signal enhances the conventional SMI signal based on the amplitude modulation. Here, an all-optical, simple and effective alternative approach to detect the FM self-mixing signal is presented. We demonstrate the enhanced self-mixing approach using a laser diode emitting at 405 nm and a volume Bragg grating (VBG) to map frequency to intensity modulations for further optical detection. Our approach overcomes the spectral range limitation of the edge filtering approach based on molecular absorption filters, since the VBGs can be fabricated at any spectral range. PMID- 28569887 TI - Compact coupling scheme to achieve the synchronously dual self-mode-locked operation with a 35.2 THz optical beating. AB - A synchronously dual self-mode-locked (SML) operation at 946 and 1064 nm is experimentally accomplished by using a compact coupling scheme to obtain the optical beating frequency up to 35.2 THz. The SML emissions at 946 and 1064 nm are established by a monolithic Nd:YAG cavity and a Nd:YVO4 crystal in a flat-flat cavity, respectively. Two gain media are butt adjoined to be longitudinally pumped by a single laser diode. The monolithic Nd:YAG crystal is used not only as the 946 nm laser cavity, but also as the output coupler of the Nd:YVO4 1064 nm laser. More importantly, the output surface of the monolithic Nd:YAG laser is coated to generate the optical feedback for the synchronization of the dual SML operation. At a pump power of 10.7 W, the output powers at 1064 and 946 nm can simultaneously reach 1.5 W by controlling the focal position of the pump waist. PMID- 28569888 TI - Narrow-linewidth carbon nanotube emission in silicon hollow-core photonic crystal cavity. AB - Polymer-sorted semiconducting single-walled carbon nanotubes (SWNTs) provide room temperature emission at near-infrared wavelengths, with potential for large volume production of high-quality solutions and wafer-scale deposition. These features make SWNTs a very attractive material for the realization of on-chip light sources. Coupling SWNT into optical microcavities could enhance and guide their emission, while enabling spectral selection by cavity resonance engineering. This could allow the realization of bright, narrowband sources. Here, we report the first demonstration of coupling SWNTs into the resonant modes of Si hollow-core photonic crystal cavities. We exploit the strong evanescent field in these resonators to interact with SWNT emission, coupling it into an integrated access waveguide. Based on this concept, we demonstrate narrowband SWNT emission resonantly coupled into a Si bus waveguide with a full width at half-maximum of 0.34 nm and an off-resonance rejection exceeding 5 dB. PMID- 28569889 TI - Soliton-plasma nonlinear dynamics in mid-IR gas-filled hollow-core fibers. AB - We investigate numerically soliton-plasma interaction in a noble-gas-filled silica hollow-core anti-resonant fiber pumped in the mid-IR at 3.0 MUm. We observe multiple soliton self-compression stages due to distinct stages where either the self-focusing or the self-defocusing nonlinearity dominates. Specifically, the parameters may be tuned so the competing plasma self-defocusing nonlinearity only dominates over the Kerr self-focusing nonlinearity around the soliton self-compression stage, where the increasing peak intensity on the leading pulse edge initiates a competing self-defocusing plasma nonlinearity acting nonlocally on the trailing edge, effectively preventing soliton formation there. As the plasma switches off after the self-compression stage, self-focusing dominates again, initiating another soliton self-compression stage in the trailing edge. This process is accompanied by supercontinuum generation spanning 1-4 MUm. We find that the spectral coherence drops as the secondary compression stage is initiated. PMID- 28569890 TI - Light-induced self-written waveguide fabrication using 1550 nm laser light. AB - Light-induced self-written (LISW) optical waveguides were fabricated for the first time, to the best of our knowledge, using a photopolymerizable resin system formed by 1550 nm pulse laser light. A two-photon absorption (TPA) chromophore with a TPA cross section of several hundred Goeppert-Mayer (GM) at 1550 nm was used. Furthermore, the optical interconnection between a single-mode fiber and a fiber Bragg grating was demonstrated by the present technique, using one-way irradiation of 1550 nm laser light through the single-mode fiber. The LISW waveguide formation using 1550 nm laser light offers a new and promising alternative route for optical interconnection in silicon photonics technology. PMID- 28569891 TI - Temperature dependence mitigation in stationary Fourier-transform on-chip spectrometers. AB - We present two techniques for mitigating the effects of temperature drifts in waveguide spatial heterodyne Fourier-transform on-chip spectrometers. In high resolution devices, large optical path length differences result in an increased sensitivity to temperature variations and impose stringent requirements on the thermal stabilization system. In order to overcome this limitation, here we experimentally demonstrate two new temperature mitigation techniques based on a temperature-sensitive calibration and phase error correction. The spectrometer chip under analysis comprises an array of 32 Mach-Zehnder interferometers fabricated on a silicon-on-insulator platform. The optical path delays are implemented as microphotonic spirals of linearly increasing length up to 3.779 cm, yielding a spectral resolution of 17 pm. We demonstrate that the degradation in retrieved spectra caused by temperature drift is effectively eliminated by temperature-sensitive calibration and phase error correction. PMID- 28569892 TI - Facile solvent-free fabrication of nitric oxide (NO)-releasing coatings for prevention of biofilm formation. AB - We describe a simple and solvent-free method to generate nitric oxide (NO) releasing coatings by incorporating diazeniumdiolate (NONOate) into allylamine or diallylamine plasma polymer coatings. The resulting coatings demonstrate continuous release of NO for over 48 hours and are effective at reducing the adhesion and biofilm formation of medically-relevant Gram-negative and Gram positive opportunistic pathogens. PMID- 28569893 TI - Single-component white-light emission via intramolecular electronic conjugation truncation with perylenemonoimide. AB - Solvent specific intramolecular electronic communication truncated optical behaviour, and white light emission with a CIE chromaticity index of (0.33, 0.33) using only a single component via non-covalent nano-assembly of alkyne phenanthrene conjugated perylenemonoimide (PMIAP) are demonstrated. PMID- 28569894 TI - Reliable nanometre-range distance distributions from 5-pulse double electron electron resonance. AB - Double electron electron resonance (DEER) enables determination of distance distributions in the nanometre range. A recently introduced 5-pulse version of this experiment prolongs the electron spin coherence lifetime and thus provides improved sensitivity or an extended distance range, but suffers from artefacts due to partial excitation and excitation band overlap. In particular, the partial excitation artefact is hard to eliminate experimentally at frequencies where DEER is most sensitive or on spectrometers that provide only monochromatic pulses. Here, a data post-processing method is introduced that removes the partial excitation artefact without relying on previous knowledge of its amplitude and without sensitivity loss. The method is based on acquisition of two traces with shifted positions of the artefact and computation of the artefact shape from the difference of the two traces. Artefact removal was successfully tested both on simulated and experimental data. It was found to be stable for a variety of distance distributions and down to low signal-to-noise ratios in the presence of moderate background decay. The artefact correction method also performs well in the regime of rather strong partial excitation artefacts that is usually encountered with rectangular monochromatic pump pulses on widely available commercial spectrometers. PMID- 28569895 TI - Quantification of f-element covalency through analysis of the electron density: insights from simulation. AB - The electronic structure of f-element compounds is complex due to a combination of relativistic effects, strong electron correlation and weak crystal field environments. However, a quantitative understanding of bonding in these compounds is becoming increasingly technologically relevant. Recently, bonding interpretations based on analyses of the physically observable electronic density have gained popularity and, in this Feature Article, the utility of such density based approaches is demonstrated. Application of Bader's Quantum Theory of Atoms in Molecules (QTAIM) is shown to elucidate many properties including bonding trends, orbital overlap and energy degeneracy-driven covalency, oxidation state identification and bond stability, demonstrating the increasingly important role that simulation and analysis play in the area of f-element bond characterisation. PMID- 28569896 TI - Designing polymer nanocomposites with a semi-interpenetrating or interpenetrating network structure: toward enhanced mechanical properties. AB - Using short polymer chains and through molecular dynamics simulation, we designed a well-dispersed nanoparticle (NP) network, which was then incorporated with the polymer matrix. First, we examined the effects of the dual-end grafted chains flexibility and density on the spatial distribution of this particular polymer nanocomposites system. By changing the interaction strength between the matrix polymer chains and the dual-end grafted chains in the semi-interpenetrating network system (NP network), we analyzed the interpenetration state between the linear polymer matrix and the NP network via calculating the total interfacial interaction energy. Moreover, the uniaxial tensile stress-strain and orientation behavior influenced by the interaction strength between the matrix polymer and the grafted chains were investigated for both the semi-interpenetrating network system and the interpenetrating network system (NP network and matrix network). Furthermore, for the interpenetrating network system, we modulated the integrity of the NP network ranging from 0% to 100%, corresponding to the gradual transition of the dispersion morphology of the NPs from the aggregation state to the uniform dispersion state, to examine the effect of the NP network on the tensile mechanical behavior. In particular, by simulating the dynamic shear process in the semi-interpenetrating network system, the composites were found to exhibit a lower non-linear behavior (the famous Payne effect), a higher storage modulus, and a lower tangent loss at large strain amplitude with increasing NP network integrity. In general, our results could provide a new approach for the design of high-performance polymer nanocomposites by taking advantage of the semi interpenetrating or interpenetrating network reinforcing structure. PMID- 28569897 TI - Reconfigurable opto-thermoelectric printing of colloidal particles. AB - We have developed a new optical technique - opto-thermoelectric printing - to print colloidal particles with reconfigurable patterns on substrates via light controlled thermoelectric fields. PMID- 28569898 TI - Pillar[n]arene-based supramolecular organic frameworks with high hydrocarbon storage and selectivity. AB - We report the high hydrocarbon storage capacity and adsorption selectivity of two low-density pillar[n]arene-based SOFs. Our study would open new perspectives in the development of pillar[n]arene-based SOFs and study of their great potential in gas-storage and gas-separation applications. PMID- 28569899 TI - Palladium-catalyzed benzofuran and indole synthesis by multiple C-H functionalizations. AB - Heterocyclic compounds are commonly found in the core structures of several pharmaceuticals, natural products, and agrochemicals, thus spurring intensive research for conducting their synthesis in a mild and simpler way. Over the years, a host of different strategies has been introduced in an effort to synthesize these heterocyles. In this context, significant attention has been gained by methodologies that ensure both step as well as atom efficiency. Synthesis of heterocyclic moieties via multiple C-H activations was found to fulfill these expectations besides guaranteeing the use of starting materials that are easily procurable. This review is focused on the current development in the field of benzofuran and indole synthesis using multiple C-H functionalization strategies. PMID- 28569900 TI - Bis(trialkylsilyl) peroxides as alkylating agents in the copper-catalyzed selective mono-N-alkylation of primary amides. AB - The copper-catalyzed selective mono-N-alkylation of primary amides with bis(trialkylsilyl) peroxides as alkylating agents was reported. The results of a mechanistic study suggest that this reaction should proceed via a free radical process that includes the generation of alkyl radicals from bis(trialkylsilyl) peroxides. PMID- 28569902 TI - pH-Driven self-sorting in a four component host-guest system. AB - A four component host-guest system comprising beta-cyclodextrin (beta-CD), cucurbit[7]uril (CB7) and two chalcone guests was demonstrated to undergo pH triggered self-sorting in aqueous solution. This phenomenon arises from the contrasting complexation induced pKa shifts displayed by these guests after complexation with CB7. PMID- 28569901 TI - Rates and equilibrium constants of the ligand-induced conformational transition of an HCN ion channel protein domain determined by DEER spectroscopy. AB - Ligand binding can induce significant conformational changes in proteins. The mechanism of this process couples equilibria associated with the ligand binding event and the conformational change. Here we show that by combining the application of W-band double electron-electron resonance (DEER) spectroscopy with microfluidic rapid freeze quench (MURFQ) it is possible to resolve these processes and obtain both equilibrium constants and reaction rates. We studied the conformational transition of the nitroxide labeled, isolated carboxy-terminal cyclic-nucleotide binding domain (CNBD) of the HCN2 ion channel upon binding of the ligand 3',5'-cyclic adenosine monophosphate (cAMP). Using model-based global analysis, the time-resolved data of the MURFQ DEER experiments directly provide fractional populations of the open and closed conformations as a function of time. We modeled the ligand-induced conformational change in the protein using a four-state model: apo/open (AO), apo/closed (AC), bound/open (BO), bound/closed (BC). These species interconvert according to AC + L ? AO + L ? BO ? BC. By analyzing the concentration dependence of the relative contributions of the closed and open conformations at equilibrium, we estimated the equilibrium constants for the two conformational equilibria and the open-state ligand dissociation constant. Analysis of the time-resolved MURFQ DEER data gave estimates for the intrinsic rates of ligand binding and unbinding as well as the rates of the conformational change. This demonstrates that DEER can quantitatively resolve both the thermodynamics and the kinetics of ligand binding and the associated conformational change. PMID- 28569903 TI - The role of acid-base equilibria in formal hydrogen transfer reactions: tryptophan radical repair by uric acid as a paradigmatic case. AB - The results presented in this work demonstrate the high complexity of chemical reactions involving species with multiple acid-base equilibria. For the case study investigated here, it was necessary to consider two radical species for tryptophan (Trp(-H) and Trp+) and three fractions for uric acid (H3Ur, H2Ur- and HUr2-) in order to properly reproduce the experimental results. At pH = 7.4, two main reaction mechanisms were identified: proton-electron sequential transfer (PEST) and sequential proton gain-electron transfer (SPGET). Combined, they account for more than 99% of the overall reaction, despite the fact that they involve minor species, i.e., H3Ur and Trp+, respectively. The excellent agreement between the calculated overall rate constant and the experimental value seems to support this proposal. In addition, if only the dominant species at pH = 7.4 (H2Ur- and Trp(-H)) were considered, there would be a large discrepancy with the experimental value (about 4 orders of magnitude), which also supports the finding that the key species in this case are not the most abundant ones. The influence of the pH on the kinetics of the investigated reaction was explored. It was found that the maximum repairing ability of uric acid does not occur at physiological pH, but at a more acidic pH (pH = 5.0). PMID- 28569904 TI - The first synthesis of Bi self-doped Bi2MoO6-Bi2Mo3O12 composites and their excellent photocatalytic performance for selective oxidation of aromatic alkanes under visible light irradiation. AB - We report the synthesis of Bi self-doped Bi2MoO6-Bi2Mo3O12 composites with heterostructures by a one-step method using Bi3.64Mo0.36O6.55 as precursor. Among them, Bi2.1MoO6-Bi2.1Mo3O12 shows excellent selectivity as well as recyclability in the oxidation of aromatic alkanes to aldehydes under visible light irradiation. PMID- 28569905 TI - Theoretical perspectives on the structure, electronic, and optical properties of titanosilicates Li2M4[(TiO)Si4O12] (M = K+, Rb+). AB - It is still a challenge to design and synthesize high performance broader ultraviolet non-linear optical (NLO) materials. Two new transition-metal silicates have recently attracted a lot of attention due to their strong phase matched second harmonic generation (SHG) responses (about 4.5 times higher than KDP). However, the electronic and optical properties underlying the high performance of these materials and consequently, the possibility of designing more efficient silicates for NLO applications are not presently clear. In this study, the geometrical structure and bonding character, electronic structure and optical properties of Li2M4[(TiO)Si4O12] (M = K+, Rb+) crystals have been systematically determined based on the density functional theory. Satisfactory agreement between the experimental and theoretical results indicates that the method and conditions used herein are favorable. A detailed analysis of the precise electronic structure and dipole moments of the two compounds suggests that it is the strong covalent character between Ti(Si) and O and the same orientation alignment of the dipole moment vector of the constituent asymmetric [TiO5]6- square pyramid anion units that result in the large SHG responses for the two compounds. In addition, the unavailable linear and non-linear optical experimental parameters, including dielectric function, optical absorption and birefringence, and all the components of the SHG coefficients are reported for the first time. This investigation unravels the structure-property relationships of titanosilicates and may be significant in terms of providing an efficient strategy towards designing more potential and competitive NLO materials. PMID- 28569906 TI - Development of a kit-like radiofluorinated biomolecule leading to a controlled self-assembly of 18F nanoparticles for a smart PET imaging application. AB - A kit-like 18F-fluorination method has been successfully applied to prepare an activatable probe 1 with good radiochemical yield and high specific activity. The probe has good in vitro stability and favorable cell membrane permeability. A controlled condensation reaction was initiated, and self-assembly into nanoparticles occurred when the probe was in a reducing environment. Positron emission tomography (PET) imaging of the biothiol level in living subjects was conveniently and precisely realized using this probe. The present study may provide a new platform for the development of "smart" PET tracers for tumor imaging. PMID- 28569907 TI - Rovibrational quantum dynamical computations for deuterated isotopologues of the methane-water dimer. AB - Rovibrational states of four dimers formed by the light and the heavy isotopologues of the methane and water molecules are computed using a potential energy surface taken from the literature. The general rovibrational energy-level pattern characteristic to all systems studied is analyzed employing two models of a dimer: the rigidly rotating complex and the coupled system of two rigidly rotating monomers. The rigid-rotor model highlights the presence of rovibrational sequences corresponding to formally negative rotational excitation energies, which is explained in terms of the coupled-rotors picture. PMID- 28569908 TI - Correction: Supramolecular influence on cis-trans isomerization probed by ion mobility spectrometry. AB - Correction for 'Supramolecular influence on cis-trans isomerization probed by ion mobility spectrometry' by Izabella Czerwinska et al., Phys. Chem. Chem. Phys., 2016, 18, 32331-32336. PMID- 28569909 TI - Direct folding simulation of helical proteins using an effective polarizable bond force field. AB - We report a direct folding study of seven helical proteins (, Trpcage, , C34, N36, , ) ranging from 17 to 53 amino acids through standard molecular dynamics simulations using a recently developed polarizable force field-Effective Polarizable Bond (EPB) method. The backbone RMSDs, radius of gyrations, native contacts and native helix content are in good agreement with the experimental results. Cluster analysis has also verified that these folded structures with the highest population are in good agreement with their corresponding native structures for these proteins. In addition, the free energy landscape of seven proteins in the two dimensional space comprised of RMSD and radius of gyration proved that these folded structures are indeed of the lowest energy conformations. However, when the corresponding simulations were performed using the standard (nonpolarizable) AMBER force fields, no stable folded structures were observed for these proteins. Comparison of the simulation results based on a polarizable EPB force field and a nonpolarizable AMBER force field clearly demonstrates the importance of polarization in the folding of stable helical structures. PMID- 28569911 TI - A rational catalyst design of CO oxidation using the bonding contribution equation. AB - A rational design of heterogeneous catalysts is an important yet challenging task. We show how the bonding contribution equation, a quantitative relation between the surface structure and adsorption energy, can be utilized for a rational catalyst design. Dozens of catalysts were efficiently designed, and full DFT calculations demonstrate that they possess excellent activities. PMID- 28569912 TI - Active sites on graphene-based materials as metal-free catalysts. AB - Graphenes and related materials have attracted growing interest as metal-free catalysts. The present review is focused on describing the active sites that have been proposed to be responsible for the catalytic activity observed for such systems. It will be shown that diverse defects and chemical functionalities on the graphene layers can catalyze reactions, including oxygenated functional groups, carbon vacancies and holes, edge effects, and the presence of dopant elements. Besides discrete active sites, the catalytic activity arising from the collective properties of graphenes as materials by adsorbing substrates and reagents and activating them by charge transfer is also commented. The review has an introductory general section summarizing the general methodologies that have been used to support the proposed structure of the active sites, including theoretical calculations, comparison of the catalytic activity of graphene samples with different compositions, the use of organic molecules as models of the active centers, and selective masking of functional groups. The review is concluded with our view on future developments in the field. PMID- 28569917 TI - Photoinduced excitation and charge transfer processes of organic dyes with siloxane anchoring groups: a combined spectroscopic and computational study. AB - Dye-sensitized solar cells (DSSCs) have attracted significant interest in the last few years as effective low-cost devices for solar energy conversion. We have analyzed the excited state dynamics of several organic dyes bearing both cyanoacrylic acid and siloxane anchoring groups. The spectroscopic properties of the dyes have been studied both in solution and when adsorbed on a TiO2 film using stationary and time-resolved techniques, probing the sub-picosecond to nanosecond time interval. The comparison between the spectra registered in solution and on the solid substrate evidences different pathways for energy and electron relaxation. The transient spectra of the TiO2-adsorbed dyes show the appearance of a long wavelength excited state absorption band, attributed to the cationic dye species, which is absent in the spectra measured in solution. Furthermore, the kinetic traces of the samples adsorbed on the TiO2 film show a long decay component not present in solution which constitutes indirect evidence of electron transfer between the dye and the semiconductor. The interpretation of the experimental results has been supported by theoretical DFT calculations of the excited state energies and by the analysis of molecular orbitals of the analyzed dye molecules. PMID- 28569910 TI - Cations induce shape remodeling of negatively charged phospholipid membranes. AB - The divalent cation Ca2+ is a key component in many cell signaling and membrane trafficking pathways. Ca2+ signal transduction commonly occurs through interaction with protein partners. However, in this study we show a novel mechanism by which Ca2+ may impact membrane structure. We find an asymmetric concentration of Ca2+ across the membrane triggers deformation of membranes containing negatively charged lipids such as phosphatidylserine (PS) and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). Membrane invaginations in vesicles were observed forming away from the leaflet with higher Ca2+ concentration, showing that Ca2+ induces negative curvature. We hypothesize that the negative curvature is produced by Ca2+-induced clustering of PS and PI(4,5)P2. In support of this notion, we find that Ca2+-induced membrane deformation is stronger for membranes containing PI(4,5)P2, which is known to more readily cluster in the presence of Ca2+. The observed Ca2+-induced membrane deformation is strongly influenced by Na+ ions. A high symmetric [Na+] across the membrane reduces Ca2+ binding by electrostatic shielding, inhibiting Ca2+-induced membrane deformation. An asymmetric [Na+] across the membrane, however, can either oppose or support Ca2+-induced deformation, depending on the direction of the gradient in [Na+]. At a sufficiently high asymmetric Na+ concentration it can impact membrane structure in the absence of Ca2+. We propose that Ca2+ works in concert with curvature generating proteins to modulate membrane curvature and shape transitions. This novel structural impact of Ca2+ could be important for Ca2+-dependent cellular processes that involve the creation of membrane curvature, including exocytosis, invadopodia, and cell motility. PMID- 28569918 TI - The Rashba effect and indirect electron-hole recombination in hybrid organic inorganic perovskites. AB - Slow electron-hole recombination, characterized by the bimolecular coefficient k2 in hybrid organic-inorganic perovskites (HOIPs), is a key to their outstanding photovoltaic performance. The measured k2 in HOIPs strongly deviates from k2 ? T 3/2 (T is the temperature) in typical direct-gap semiconductors. Here we show that the observed temperature dependence can be quantitatively accounted for by phonon-assisted recombination of electrons and holes located at the band extrema, which become indirect due to the Rashba effect. Polar optical phonons are most effective in facilitating this indirect recombination. The variation in k2 in HOIPs among different studies in the literature can be attributed to different Rashba strengths in their samples. Our results indicate that the confluence of the Rashba effect and polar coupling transform HOIPs into a unique indirect semiconductor that can accommodate both strong optical absorption and slow carrier dynamics. PMID- 28569919 TI - Elevated plasma TFPI activity causes attenuated TF-dependent thrombin generation in early onset preeclampsia. AB - Early onset preeclampsia (EOP) is a pregnancy-specific proinflammatory disorder that is characterised by competing thrombotic and bleeding risks. It was the aim of this study to characterise thrombin generation, a major determinant of thrombotic and bleeding risk, in order to better understand the haemostatic balance in patients with EOP. Patients with EOP were recruited at the Rotunda Hospital, Dublin. Twenty-six cases of EOP were recruited over a 21-month period, out of 15,299 deliveries at the Rotunda. Blood samples were collected into sodium citrate plus corn trypsin inhibitor anticoagulated vacutainers, platelet-poor plasma was prepared, and calibrated automated thrombography was used to assess thrombin generation. Results were compared to age and sex-matched non-pregnant controls (n=13) and age- and gestation-matched pregnant controls (n=20). The rate and extent of thrombin generation triggered by low-dose tissue factor (TF) was significantly reduced in patients with EOP compared to pregnant controls, most significantly in cases of severe EOP. EOP patients displayed a trend towards an increased response to endogenous activated protein C and thrombomodulin relative to pregnant controls. Plasma tissue factor pathway inhibitor (TFPI) activity was increased in EOP patients. Inhibition of TFPI abolished the attenuation of thrombin generation stimulated by low-dose TF. In conclusion, patients with EOP are characterised by an attenuated coagulation response characterised by reduced thrombin generation stimulated by low-dose TF and elevated plasma TFPI activity. These changes in coagulation may modulate thrombotic risk and bleeding risk in patients with EOP. PMID- 28569920 TI - Recombinant GPVI-Fc added to single or dual antiplatelet therapy in vitro prevents plaque-induced platelet thrombus formation. AB - The efficiency of current dual antiplatelet therapy might be further improved by its combination with a glycoprotein (GP) VI-targeting strategy without increasing bleeding. GPVI-Fc, a recombinant dimeric fusion protein binding to plaque collagen and concealing binding sites for platelet GPVI, acts as a lesion-focused antiplatelet drug, and does not increase bleeding in vivo. We investigated, whether GPVI-Fc added in vitro on top of acetylsalicylic acid (ASA), the P2Y12 antagonist ticagrelor, and the fibrinogen receptor antagonist abciximab alone or in combination would increase inhibition of platelet activation by atherosclerotic plaque. Under static conditions, GPVI-Fc inhibited plaque-induced platelet aggregation by 53 %, and increased platelet inhibition by ASA (51 %) and ticagrelor (64 %) to 66 % and 80 %, respectively. Under arterial flow, GPVI-Fc inhibited plaque-induced platelet aggregation by 57 %, and significantly increased platelet inhibition by ASA (28 %) and ticagrelor (47 %) to about 81 % each. The triple combination of GPVI-Fc, ASA and ticagrelor achieved almost complete inhibition of plaque-induced platelet aggregation (93 %). GPVI-Fc alone or in combination with ASA or ticagrelor did not increase closure time measured by the platelet function analyzer (PFA)-200. GPVI-Fc added on top of abciximab, a clinically used anti-fibrinogen receptor antibody which blocks platelet aggregation, strongly inhibited total (81 %) and stable (89 %) platelet adhesion. We conclude that GPVI-Fc added on top of single or dual antiplatelet therapy with ASA and/or a P2Y12 antagonist is likely to improve anti-atherothrombotic protection without increasing bleeding risk. In contrast, the strong inhibition of platelet adhesion by GPVI-Fc in combination with GPIIb/IIIa inhibitors could be harmful. PMID- 28569921 TI - Microvesicles in vascular homeostasis and diseases. Position Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology. AB - Microvesicles are members of the family of extracellular vesicles shed from the plasma membrane of activated or apoptotic cells. Microvesicles were initially characterised by their pro-coagulant activity and described as "microparticles". There is mounting evidence revealing a role for microvesicles in intercellular communication, with particular relevance to hemostasis and vascular biology. Coupled with this, the potential of microvesicles as meaningful biomarkers is under intense investigation. This Position Paper will summarise the current knowledge on the mechanisms of formation and composition of microvesicles of endothelial, platelet, red blood cell and leukocyte origin. This paper will also review and discuss the different methods used for their analysis and quantification, will underline the potential biological roles of these vesicles with respect to vascular homeostasis and thrombosis and define important themes for future research. PMID- 28569922 TI - Thrombin is a selective inducer of heparanase release from platelets and granulocytes via protease-activated receptor-1. AB - Heparanase, known to be involved in angiogenesis and metastasis, was shown to form a complex with tissue factor (TF) and to enhance the generation of factor Xa. Platelets and granulocytes contain abundant amounts of heparanase that may enhance the coagulation system upon discharge. It was the aim of this study to identify the inducer and pathway of heparanase release from these cells. Platelets and granulocytes were purified from pooled normal plasma and were incubated with ATP, ADP, epinephrine, collagen, ristocetin, arachidonic acid, serotonin, LPS and thrombin. Heparanase levels were assessed by ELISA, heparanase procoagulant activity assay and western blot analysis. The effects of selective protease-activated receptor (PAR)-1 and 2 inhibitors and PAR-1 and 4 activators were studied. An in-house synthesised inhibitory peptide to heparanase was used to evaluate platelet heparanase involvement in activation of the coagulation system. Heparanase was released from platelets only by thrombin induction while other inducers exerted no such effect. The heparanase level in a platelet was found to be 40 % higher than in a granulocyte. Heparanase released from platelets or granulocytes increased factor Xa generation by three-fold. PAR-1 activation via ERK intracellular pathway was found to induce heparanase release. In conclusion, heparanase is selectively released from platelets and granulocytes by thrombin interacting with PAR-1. Heparanase derived from platelets and granulocytes is involved in activation of the extrinsic coagulation pathway. The present study implies on a potential anticoagulant effect, in addition to anti platelet effect, of the new clinically studied PAR-1 inhibitors. PMID- 28569923 TI - Interplay between elevated cellular fibronectin and plasma fibrin clot properties in type 2 diabetes. AB - Type 2 diabetes is associated with faster formation of poorly lysable, denser fibrin clots and elevated cellular fibronectin (cFn), a marker of vascular injury. We investigated whether cFn affects clot properties in type 2 diabetes. In 200 consecutive patients with type 2 diabetes and 100 control subjects matched for age and sex, we determined plasma cFn along with clot formation and degradation using turbidimetric and permeability assays. Diabetic patients had elevated cFn (median, 3.99 [interquartile range, 2.87-4.81] ug/ml]), increased clot density (MaxAbsC) and prolonged lysis time (LysT) compared with those without type 2 diabetes (all p<0.01). Diabetic patients with documented cardiovascular disease (CVD, n=127, 63.5 %) had increased cFn (4.53 [3.68-4.95] ug/ml), decreased clot permeability (Ks) and increased MaxAbsC compared with those without CVD (all p<0.001). Diabetic patients with cFn in the top quartile (>4.81 ug/ml) were two times more likely to have CVD compared with those in the lowest quartile (odds ratio 1.80, 95 % confidence interval 1.41-2.46, p<0.001). No differences in cFn were observed in relation to microvascular complications. After adjustment for potential confounders, cFn accounted for 10.2 % of variance in Ks, 18.2 % of variance in clot density and 10.2 % of variance in AUC in diabetic patients. This study shows that elevated cFn is associated with unfavourably modified clot properties in type 2 diabetes, especially with concomitant CVD, which indicates novel links between vascular injury and prothrombotic alterations in diabetes. Coagulation, cellular fibronectin, type 2 diabetes, cardiovascular disease. PMID- 28569925 TI - Research on Primary Care: a necessity and a challenge to health professionals. PMID- 28569924 TI - Is a normal computed tomography pulmonary angiography safe to rule out acute pulmonary embolism in patients with a likely clinical probability? A patient level meta-analysis. AB - A normal computed tomography pulmonary angiography (CTPA) remains a controversial criterion for ruling out acute pulmonary embolism (PE) in patients with a likely clinical probability. We set out to determine the risk of VTE and fatal PE after a normal CTPA in this patient category and compare these risk to those after a normal pulmonary angiogram of 1.7 % (95 %CI 1.0-2.7 %) and 0.3 % (95 %CI 0.02-0.7 %). A patient-level meta-analysis from 4 prospective diagnostic management studies that sequentially applied the Wells rule, D-dimer tests and CTPA to consecutive patients with clinically suspected acute PE. The primary outcome was the 3-month VTE incidence after a normal CTPA. A total of 6,148 patients were included with an overall PE prevalence of 24 %. The 3-month VTE incidence in all 4,421 patients in whom PE was excluded at baseline was 1.2 % (95 %CI 0.48-2.6) and the risk of fatal PE was 0.11 % (95 %CI 0.02-0.70). In patients with a likely clinical probability the 3-month incidences of VTE and fatal PE were 2.0 % (95 %CI 1.0-4.1 %) and 0.48 % (95 %CI 0.20-1.1 %) after a normal CTPA. The 3-month incidence of VTE was 6.3 % (95 %CI 3.0-12) in patients with a Wells rule >6 points. In conclusion, this study suggests that a normal CTPA may be considered as a valid diagnostic criterion to rule out PE in the majority of patients with a likely clinical probability, although the risk of VTE is higher in subgroups such as patients with a Wells rule >6 points for which a closer follow-up should be considered. PMID- 28569926 TI - Spirituality and Religiosity in Elderly Adults with Chronic Disease. AB - OBJECTIVE: This work sought to explore the relationship between spirituality and religiosity in elderly adults with chronic disease. METHODS: This was a cross sectional cohort study with a representative sample of 229 elderly adults with chronic disease registered in 12 life centers in the city of Cartagena. Reed's Spiritual Perspective and Francis' Religiosity scales were applied. RESULTS: Mean age was 74.4 years, 62.9% were women, and the most frequent occupations were: unemployed (45.9%) and housewives (44.5%); the religion most practiced was Catholicism (81.2%). Levels of spirituality and religiosity were high, showing a moderate and direct correlation (r = 0.57). CONCLUSION: A directly proportional relationship exists between spirituality and religiosity in elderly adults with chronic disease. PMID- 28569927 TI - Attitudes toward consumer involvement in mental health services: a cross sectional survey of Indian medical and nursing undergraduates. AB - OBJECTIVE: To understand the views of medical and nursing undergraduates regarding consumer involvement in mental health services. METHODS: A descriptive cross sectional survey was conducted in Bangalore, South India, among medical (n=155) and nursing (n=116) undergraduates using self-reported the Mental Health Consumer Participation Questionnaire of Happell et al. ''Mental health consumer'' or ''consumer'' is defined as a person who is currently using mental health services as either an in-patient or out-patient. RESULTS: The overall mean score on Mental Health Consumer Participation Questionnaire (54.1+/-6.7) implies that 64% of the participants hold positive attitudes towards consumer involvement in mental health services. Medical students possessed more positive attitudes than nursing in: consumer capacity (p<0.001), consumer as staff (p< 0.001) and overall score on mental health consumer participation questionnaire (t=6.892, p<0.001). CONCLUSION: The findings suggest that majority of the participants hold positive attitudes towards mental health consumer involvement in health care services. However, additional research is urgently required from developing countries to understand the effectiveness of involving mental health consumers in academic programs at undergraduate level. PMID- 28569929 TI - Gender subordination in the vulnerability of women to domestic violence. AB - OBJECTIVE: To create and validate an instrument that identifies women's vulnerability to domestic violence through gender subordination indicators in the family. METHODS: An instrument consisting on 61 phrases was created, that indicates gender subordination in the family. After the assessment from ten judges, 34 phrases were validated. The approved version was administered to 321 health service users of Sao Jose dos Pinhais (Estado de Parana, Brasil), along with the validated Portuguese version of the Abuse Assessment Screen (AAS) (for purposes of separating the sample group - the ''YES'' group was composed of women who have suffered violence and the ''NO'' group consisted of women who had not suffered violence). Data were transferred into the Statistical Package for the Social Sciences (SPSS) software, version 22, and quantitatively analyzed using exploratory and factor analysis, and tests for internal consistency. RESULTS: After analysis (Kaiser-Meyer-Olkin (KMO) statistics, Monte Carlo Principal Components Analysis (PCA, and diagram segmentation), two factors were identified: F1 - consisting of phrases related to home maintenance and family structure; F2 - phrases intrinsic to the couple's relationship. For the statements that reinforce gender subordination, the mean of the factors were higher for the group that answered YES to one of the violence identifying issues. CONCLUSIONS: The created instrument was able to identify women who were vulnerable to domestic violence using gender subordination indicators. This could be an important tool for nurses and other professionals in multidisciplinary teams, in order to organize and plan actions to prevent violence against women. PMID- 28569928 TI - Expectations and satisfaction of pregnant women: unveiling prenatal care in primary care. AB - OBJECTIVE: To analyze the perception of primiparous women about prenatal care in Basic Health Units in a municipality in southern Brazil. METHODS: This is a qualitative research from the perspective of Social Representation Theory, from the following question: How has been the pre-natal care for you? Eighteen pregnant women were interviewed. RESULTS: The analysis resulted in three categories: Expectation representation about prenatal care; Rescuing the care offered in prenatal consultation; Unveiling the (dis) satisfaction with prenatal consultation. The prenatal care was apprehended as an essential moment for safe pregnancy, although centered on the doctor's figure and guarantee access to early laboratory and imaging tests. On the other hand, dissatisfaction was revealed from the reception at the entrance to the health unit to the consultations access, although some statements suggest timely satisfaction. CONCLUSION: Prenatal care did not meet the specific expectations of the study group and unveiled that the nurse did not supply it, as a member of the multidisciplinary team. The organization of the nursing work process in primary care, related to prenatal care, needs to be revisited to promote the effectiveness of its actions. PMID- 28569930 TI - Male and female condoms: What do women of a subnormal agglomerate know. AB - OBJECTIVE: Evaluate the knowledge about male and female condoms among women living in subnormal agglomerate and identify sources of information and appropriate care to use. METHODS: Household survey, descriptive, transversal and quantitative study with 300 women over 18 of Joao Pessoa, Paraiba, Brasil, who began their sexual life. The systematic sampling plan for data collection was used. The interview form included sociodemographic questions and gazed relevant aspects of the use of condoms as a preventive measure of sexually transmitted infections and AIDS. RESULTS: TV and healthcare professionals were the main sources of information. The participants knew more often the male condom features compared to women. The care most often mentioned by women as the use of male and female condoms were related to the validity, form of openness and conditions of packaging and storage of condoms. The largest number of care focused on measures taken in the pre-sexual moment. Moreover, care was nonspecific on the female condom. CONCLUSION: The participating women have inadequate knowledge on female and male condoms. It is necessary that the nursing seek health education strategies for improving knowledge about relevant information about male and female condoms. PMID- 28569931 TI - Caregiver role strain: bi-national study of content validation. AB - OBJECTIVE: To estimate content validity of the diagnosis Caregiver Role Strain. METHODS: Content validation of the defining characteristics according to Fehring's model was undertaken by 6 Colombian nurses and 9 Brazilian counterparts. The relevance of each defining characteristic for the diagnosis was assessed using 5-point Likert type scale. The Mann-Whitney test was used to estimate differences in assessing the relevance of defining characteristics between Brazilian and Colombian nurses. RESULTS: From 36 defining characteristics, 22 were identified as major, 13 as secondary and one as irrelevant (rash). The content validity index(sum of weighted averages divided by the total number of defining characteristics) was 0.79, considered adequate. CONCLUSION: Most of the defining characteristics were considered relevant to the nursing diagnosis Caregiver Role Strain. These findings reflect consensus among specialists from two different countries in relation to the relevance of the defining characteristics for this diagnosis. PMID- 28569932 TI - Interdisciplinary debate in the teaching-learning process on bioethics: academic health experiences. AB - OBJECTIVE: The study aimed to understand the health of student experiences to participate in interdisciplinary discussions in bioethics and know the contributions of interdisciplinary methodological resource for the teaching learning process at graduation. METHODS: Descriptive study of qualitative approach in a public higher education institution of Divinopolis, Minas Gerais, Brazil. RESULTS: Three categories of analysis were identified: ''active methodologies in the training of a professional critic,'' ''interdisciplinary debate as facilitator reflection of bioethics'' and ''feelings and attitudes caused by the interdisciplinary debate.'' Discussion. There was a lack of approach of bioethical contents in the health curriculum, and the adoption of active methodologies provides a better reflection in bioethics, but that requires changing paradigms of teachers and educational institutions. PMID- 28569933 TI - Use of digital applications in the medicament calculation education for nursing. AB - OBJECTIVE: To evaluate the influence of the use of digital applications in medicament calculation education for nursing students. METHODS: An experimental study was developed with a sample of 100 nursing students, who were divided randomly into two groups (use of the Calculation Medicines - CalcMed application available free on the Internet, n=50) and control (conventional method of the calculator use and pre-math skills, n=50). Both groups were assessed before and after the application of the teaching strategy through a test with ten specific questions of medicament calculations. RESULTS: The study group showed a mean score of 8.14 versus an average of 5.02 in the control group. The average time of test execution was faster in the study group compared to the control group (15.7 versus 38.9 minutes). CONCLUSION: The strategy of using this application positively influences learning and enables greater security in the implementation of medicament calculations. PMID- 28569934 TI - Association between risk factors for hypertension and the Nursing Diagnosis overweight in adolescents. AB - OBJECTIVE: To identify associations between the risk factors for hypertension and the nursing diagnosis of overweight in adolescents. METHODS: Cross-sectional study conducted in 2013 with 347 teenagers attending schools in Natal, Rio Grande do Norte, Brazil, who answered a form about the socioeconomic profile, physical activity, eating habits and family history of disease and who underwent physical examination. For analytical analysis, two groups were formed: students with the Nursing Diagnosis overweight (n=100) and students without this diagnosis (n=247). RESULTS: the risk factors for hypertension associated with the Nursing Diagnosis were: abdominal obesity (OR=40.0), food intake rich in sugar and fat (OR=40.0), family history of hypertension (OR=6.9), obesity and diabetes (OR=2.0), abnormal systolic and diastolic blood pressure (OR=5.5). CONCLUSION: the risk factors for hypertension that presented association with the Nursing Diagnosis overweight were abdominal obesity, eating habits, family history of diseases and abnormal blood pressure. These findings may contribute to prevent hypertension in adolescents, in that it directs the gaze of nurses to develop effective measures to address these risk factors. PMID- 28569935 TI - Impact of educational group strategy to improve clinical and glycemic parameters in individuals with diabetes and hypertension. AB - OBJECTIVE: To evaluate the impact of an educational group strategy to improve clinical and glycemic parameters in individuals with diabetes and hypertension. METHODS: This descriptive prospective study included 172 individuals living in Sao Jose do Rio Preto-SP, Brazil, who were enrolled in a well-integrated educational group called HIPERDIA (Record System for Follow-up of Hypertensive and Diabetic Individuals) coordinated by a qualified multidisciplinary team. We analyzed sociodemographic, anthropometric, clinical, and laboratory data. Data were collected in the first, fifth, and eighth meeting of the educational group. RESULTS: A total of 68.6% of patients were women, 85.4% were white, 64.0% had an incomplete basic education, 47.7% were retired, 79.7% had been diagnosed with diabetes for 6 or more years, 9.9% were smokers, and 9.9% used alcohol. Individuals' diastolic blood pressure decreased between the fifth and eighth meeting (p<0.05). Between the first and fifth meeting, both fasting glucose levels (p<0.05) and glycated hemoglobin decreased; the latter continue to drop at the fifth and eighth meetings (p<0.001). Anthropometric parameters remained unchanged. CONCLUSION: The results suggest that an educational group strategy is favorable for controlling diabetes mellitus and hypertension. PMID- 28569936 TI - Depressive symptoms in patients with coronary artery disease. AB - OBJECTIVE: To assess the presence of depressive symptoms in patients with coronary artery disease in the preoperative period for coronary artery bypass surgery (CABG) in Aracaju, Sergipe, Brazil. METHODS: A cross-sectional study with 63 hospitalized patients prior to CABG. Two instruments were used for data collection; one for the sociodemographic and clinical characteristics, and the other to evaluate the presence of depressive symptoms, Beck Depression Inventory (BDI). RESULTS: The mean age was 58 years; most were male (60.3%); with a partner (81%) low educational level (71.4% attended school through elementary school). Among the patients, 36.5% were classified with dysphoria, and 25.4% had some degree of depression (6.3% mild, 17.5% moderate, and 1.6% severe). The group of patients with lower educational level presented higher depressive symptoms. CONCLUSION: Six of every ten patients with coronary artery disease showed dysphoria or some degree of depression. The results of this study can support the planning of nursing care for patients before and after CABG, as well as the development of public health policies to ensure complete, quality care for these patients, understanding depression as a variable that can interfere with recovery after cardiac surgery. PMID- 28569937 TI - Nursing care in postwar Madrid. AB - OBJECTIVE: To describe the work of the Salus Infirmorum Sisterhood in caring for the most underprivileged individuals from the postwar outskirts of Madrid, through the voluntary service of the nurses who were part of that Institution. METHODS: A historical study based on the analysis of primary sources from the Sisterhood's archives. RESULTS: Salus Infirmorum once relied on more than 100 volunteer nurses who treated over 425-thousand people in 21 parish dispensaries located within the neediest neighborhoods of Madrid, providing both preventative and curative medical care. Nurses were offered adequate training in exchange for the care provided. CONCLUSION: Salus Infirmorum took healthcare to the streets of Madrid, treating patients in improvised medical clinics set up in parishes or in the patient's own home, as the situation required, in addition to training women who otherwise would not have had access to it. PMID- 28569938 TI - Depression in pregnancy. Prevalence and associated factors. AB - OBJECTIVE: To evaluate the occurrence of depression during pregnancy and its associated factors. METHODS: Epidemiological, quantitative, descriptive and cross sectional study, conducted from January to May 2013 with 209 pregnant women in the city of Alfenas, State of South Minas Gerais, Brazil. The Hospital Anxiety and Depression Scale (HASD) of Zigmond y Snaith and a form for characterization of participants were used for data collection. RESULTS: Depression was present in 14.8% of the pregnant women and was more frequent during the second trimester of pregnancy. Depression during pregnancy was significantly associated with number of births, number of children, ranking as the number of pregnancies, family support, amount of cigarettes smoked per day, consumption of alcohol, use of daily medications, history of mental disorder, presence of striking events in the last 12 months and history of domestic violence. CONCLUSION: The evaluation of depression showed that this disorder is common during pregnancy, and the risk is higher among primigravidae women, women who use alcohol, use daily medications, have history of mental disorder, have experienced a striking event in the last 12 months and who have suffered domestic violence. Knowledge of the factors associated with occurrence of depression allows early adoption of interventions to monitor the mental health of women throughout pregnancy, preventing this and other disorders. PMID- 28569939 TI - Educational software and improvement of first grade school students' knowledge about prevention of overweight and obesity. AB - OBJECTIVE: To evaluate the effects of educational software to improve first grade school students' knowledge about prevention of overweight and obesity. METHODS: This non-controlled trial with a before-and-after evaluation was carried out in an school located in the municipality of Divinopolis (Brazil) among 71 students aged 6 to 10 years. The educational software about prevention of overweight and obesity was designed and then validated. The educational intervention comprised the use of the software. Before and after of the intervention we applied a questionnaire based on the Ten Steps to Healthy Eating for Children, proposed by the Brazilian Ministry of Health. RESULTS: Comparing the times before and after application of the educational software, we observed statistically significant differences in proportion of questions answered correctly by first grade school students, mainly concerning daily eating of healthy and unhealthy food, adequate preparation of food and importance of exercise. CONCLUSION: This study highlights the importance of educational actions using software to build knowledge of first grade school students about prevention of overweight and obesity. PMID- 28569940 TI - Uncertainty Associated to Parents of Preterm Infants Hospitalized in Neonatal Intensive Care Units. AB - OBJECTIVE: This work sought to determine the factors associated to uncertainty in parents of preterm newborns hospitalized in neonatal intensive care units (NICU). METHODS: This was a cross-sectional analytic study with 117 parents (79 mothers and 38 fathers) of preterm newborns hospitalized in three NICUs of Cartagena (Colombia). Sociodemographic information was included; the biophysical profile of the preterm infant (PTI) and the results from the Mishel Uncertainty in Illness Scale. RESULTS: A high level of uncertainty was found in 49.3% of the mothers and 52.6% of the fathers. The OR lower limits the variables of the parents that were associated to uncertainty were: OR = 2.5 not having a partner and OR = 2.3 having secondary education, plan OR = 2.8 belonging to socioeconomic levels 1 and 2. In the PTI variables, the following were related to uncertainty: weight <1500 gr and mechanical ventilation care, with lower limits of the OR of 1.9 and 1.3, respectively. CONCLUSION: Nurses must incorporate in the care plan the evaluation and intervention of uncertainty in fathers and mothers of PTIs hospitalized in NICU. PMID- 28569941 TI - Representations by Caregivers, Teachers, and Children on Food, Nutrition, Health, and School Breakfast Contributions for the "ESNUT" Nutritional Stabilization Program. AB - OBJECTIVE: This work sought to determine the social representations conferred by caregivers, teachers, and children to food, health, and nutrition and the school breakfast program for children from three to seven years of age in the city of San Luis Potosi, San Luis Potosi, Mexico, through identifying a) knowledge and practices and b) meanings attributed on health and nutrition of children from three to seven years of age and on the school breakfast program. METHODS: This was a qualitative health study. The sample included 33 mothers, 3 grandmothers, 1 father, 30 children from 3 to 7 years of age, and 8 teachers who signed an informed consent. The data were collected through a semi-structured interview and treated through content analysis modality thematic analysis. RESULTS: The analysis yielded the categories: knowledge on food, the health-feeding relation, customs and practices of the child's feeding, and meanings of the school breakfast program. CONCLUSION: On the reflection on the representations of the different players included in the school breakfast program, elements become manifest that would support an educational intervention by nursing, which would have to be based on the family as the central figure to provide good nutrition and teach good habits. PMID- 28569943 TI - Social representations of nurses about professional autonomy and the use of technologies in the care of patients with wounds. AB - OBJECTIVE: To identify the social representations by nurses about professional autonomy in the care of patients with wounds and analyze their interfaces with the constant incorporation of technologies in this care. METHODS: This is a qualitative research, outlined from the Theory and method of social representations in its procedural approach and performed with 31 nurses. The interviews were submitted to thematic content analysis software NVivo instrumentalized by 10. RESULTS: The representational content on autonomy is linked mainly to the level of knowledge, power of decision, vocational training and institutional factors. The subjects are positioned favorably to the incorporation of care technologies in professional practice, which involves elements such as cost-effective structure, training, and other resources. CONCLUSION: It is concluded that autonomy is configured as a prerequisite for the full use of technology and technology is configured as a facilitator for nurses to become more autonomous. PMID- 28569942 TI - Risk factors associated with treatment abandonment by overweight or obese children and adolescents. AB - OBJECTIVE: To evaluate the risk factors associated with treatment abandonment by overweight or obese children and adolescents. METHODS: A cross-sectional study, conducted in 2011, at the Childhood Obesity Center, in Campina Grande, Brazil, with the records of 208 children and adolescents, between three and 18 years of age, divided into two groups: Group I included those who abandoned treatment, and Group II included those who did not abandon treatment. RESULTS: Non-adherence was significantly associated with higher income (OR=5.8), high maternal education (OR=2.4), white skin color (OR=2.9), and obesity (OR=3.6). CONCLUSION: Despite the new academic-care approach, the non-adherence to treatment rate was high, and was associated with sociodemographic and nutritional factors. PMID- 28569944 TI - Breastfeeding Education: disagreement of meanings. AB - OBJECTIVE: This work sought to analyze how educational processes have been developed for breastfeeding in a health institution, starting from the meanings mothers, families, and health staff construct thereon. METHODS: This was qualitative research of ethnographic approach, which included observations during the group educational activities of the programs, focal groups, and interviews of mothers, their families, and the health staff of a hospital unit in the city of Medellin, Colombia. The analysis was guided by the constant comparison method. RESULTS: The categories emerging from the data were: 1) breast milk is an ideal food. 2) The mothers' experiences influence upon the breastfeeding practice. 3) Family beliefs sometimes operate as cultural barriers. 4) Disagreements are revealed in the educational process. CONCLUSION: The way educational processes have taken place for breastfeeding reveals a break expressed by the scarce interaction between the meanings professionals have constructed on the topic and those the mothers and their families give to the experience of breastfeeding. PMID- 28569945 TI - The Faculty of Nursing. 65 years preparing professionals to care for life. PMID- 28569946 TI - Reproductive calendar of the Zenu and Embera indigenous peoples of the Eyabida and Chamibida subgroups from Antioquia (Colombia). AB - OBJECTIVE: This work sought to compare the reproductive calendar of the Zenu and Embera ethnicities of the Eyabida and Chamibida subgroups in Antioquia, Colombia from 2011 to 2013. METHODOLOGY: This was a sociodemographic study of purposive sampling through the reproductive history technique, conducted with 165 indigenous women older than 10 years of age. RESULTS: The reproductive calendar is characterized by an age of menarche between 12 and 13 years for both ethnicities; entry to union with a partner occurs 30 months and more in all groups; the first pregnancy 7.9 months after the entry to union with a partner for the Eyabida, 14.0 months for the Chamibida, and 11.3 months for the Zenu; the first delivery happens at 15 years of age among the Zenu, at 16 and 17 for the Eyabida and Chamibida, respectively. The use of Western contraceptive methods is highlighted in the ethnicities. CONCLUSION: For the ethnicities studied, early ages of onset of reproductive life are noted, along with the fastness of the divergent pattern conserved since the late 1990s for the Chamibida and the growing use of contraceptive methods to limit the number of children. PMID- 28569947 TI - Care management in nursing within emergency care units. AB - OBJECTIVE: Understand the conditions involved in the management of nursing care in emergency care units. METHODOLOGY: Qualitative research using the methodological framework of the Grounded Theory. Data collection occurred from September 2011 to June 2012 through semi-structured interviews with 20 participants of the two emergency care units in the city of Florianopolis, Brazil. RESULTS: Hindering factors to care management are: lack of experience and knowledge of professionals in emergency services; inadequate number of professionals; work overload of emergency care units in the urgent care network; difficulty in implementing nursing care systematization, and need for team meetings. Facilitating factors are: teamwork; importance of professionals; and confidence of the nursing technicians in the presence of the nurse. CONCLUSION: Whereas the hindering factors in care management are related to the organizational aspects of the emergency care units in the urgency care network, the facilitating ones include specific aspects of teamwork. PMID- 28569948 TI - Risk factors for prostate cancer, and motivational and hindering aspects in conducting preventive practices. AB - OBJECTIVE: Identify risk factors for Prostate Cancer (PC), preventive practices, and hindering and motivating factors for disease prevention among workers of a public university. METHODOLOGY: A descriptive study, conducted with 92 workers who answered a self-administered questionnaire on the variables related to sociodemographic characteristics and clinical risk factors, sources of information about PC, practices related to prevention, and information on the hindering and motivating factors for prevention of the disease. RESULTS: Most (95.0%) participants had one or more risk factors for PC; 68.5% underwent completion of the prostate-specific antigen (PSA) test annually at the request of the university; 50.0% of participants never performed the digital rectal examination (DRE); the main source of information was the media (64.1%); the main complicating factor for realization of the yearly preventive screening test was the lack of request for examination by their doctor; and the main motivating reason was recognition of the severity of the disease. CONCLUSION: Most participants had risk factors for the disease, do not perform the DRE, presented difficulties in carrying out prevention, and revealed they do not receive information about the disease from healthcare professionals, which could in turn lead to an erroneous understanding, resulting in hindering factors for practices to prevent PC. Thus, health care managers and multidisciplinary teams should engage in preventive health care for men in order to initiate preventive practices, and clarify any doubts about the disease. PMID- 28569949 TI - Relationship between risk stratification, mortality and length of stay in a Emergency Hospital. AB - OBJECTIVE: To evaluate the relationship between risk stratification, mortality and hospital length of stay in emergency medical services. METHODOLOGY: A prospective cohort study that used the information in the ALERTO database of the HOSPUB to know the evolution of patients classified by nurses using the Manchester Risk Classification Triage System in the emergency medical services, of the Belo Horizonte Municipal Hospital - MG, Brazil. RESULTS: 147,167 patients were analyzed, 5.9% were female. The most common risk classification was yellow (47.4%), followed by green (36.5%), orange (14.2%), blue (1.3%) and red (0.6%). The mean length of stay was less than one day in 95.4% of patients who were discharged from the hospital. Thirty percent of the patients classified as red, 2% of those classified as orange, and 0.3% of those classified as yellow died. There was direct a relationship between the severity of patient classification and the length of hospital stay. CONCLUSION: The risk classification system used by nurses in the hospital was a good predictor of death and hospital length of stay for patients admitted to the emergency medical services. PMID- 28569950 TI - Assessment of an educational intervention based on constructivism in nursing students from a Mexican public university. AB - OBJECTIVE: This work sought to evaluate the effect of an educational intervention centered on the analysis of clinical cases to inquire on conceptual learning in students on the theme of nursing care of women with complicated puerperium. METHODOLOGY: This was a quasi-experimental study with before and after evaluation. Two groups of students participated from the eighth semester of the nursing program, which professionalized individuals who were already nursing technicians: the study group (n = 33) was taught the theme of nursing care to women with complicated puerperium with the case analysis technique and the control group (n = 27) received traditional teaching. A self-applied question here was used related to the thematic unit, which included three clinical cases and the resolution of a total of 37 questions related to set cases. This questionnaire was the same applied before and after the intervention. RESULTS: The pre-intervention mean score was similar in both groups (26 during the study and 27 during the intervention). Upon completing the educational intervention, the post-intervention scores were equal in both groups (27 points). The intra group analysis showed that in the study group the intervention produced a slight change in conceptual learning, which was statistically significant. During the post-hoc analysis differences in scores were found in students who worked in hospitals with tier three level of care. CONCLUSION: Educational intervention favored conceptual learning slightly in the study group. It is necessary to explore other intervening variables that propitiate this learning in the program. PMID- 28569951 TI - Maternity perception by pregnant women living with HIV. AB - OBJECTIVE: Identify the perceptions of pregnant women living with HIV about motherhood and understand the expectations and feelings experienced by these women. METHODOLOGY: Study with descriptive design and qualitative approach, carried out with 10 pregnant women living with HIV who attend the prenatal service of a university hospital in Rio de Janeiro, Brazil. The participants answered a semi-structured interview. Data were analyzed using the content analysis technique. RESULTS: Pregnant women in their descriptions revealed that motherhood gives them different perspectives on the present and future. They see it as a good thing, a responsibility to care for the child, and consider bearing a child to be a gift. CONCLUSION: For pregnant women living with HIV, motherhood is a positive experience in their lives. Nurses must be sensitive to the needs of this group and aware of their role in health care and preventing any possible complications that may affect the mother and her baby. PMID- 28569952 TI - Validation of an instrument to assess the homecare competency of the family caregiver of a person with chronic disease. AB - OBJECTIVE: This work sought to develop, validate, and determine the reliability of an instrument on Competency in Homecare of the family caregiver of an individual with chronic disease. METHODOLOGY: The test validation study was carried out in the following phases: 1) literature review; 2) analysis of results of programs to help family caregivers in Latin America; 3) exploration of the classification of nursing results (NOC) related to the family caregiver and discharge; 4) proposal of an instrument of care competence; and 5) psychometric tests: apparent validity with 25 family caregivers of individuals with chronic disease and six experts in the area; construct validity and reliability through internal consistency with 311 family caregivers of chronic patients. RESULTS: The instrument on homecare competency of the family caregiver of an individual with chronic disease (CUIDAR, for the term in Spanish) has 60 items that inquire on six categories: knowledge, uniqueness, instrumentation, enjoyment of life, anticipation and relationships, and social interaction. The apparent validity evidences clarity, coherence, sufficiency, and relevance of the scale. With the factor analysis six components were obtained through the Varimax rotation in which most of the items are associated according to the categories proposed. The reliability (internal consistency) reported a Cronbach's alpha of 0.96. CONCLUSION: The Homecare Competency instrument permits assessing the capacity of a family caregiver to care for an individual with chronic disease, proving valid and reliable for the Colombian context. PMID- 28569953 TI - Knowledge of supplemental folic acid during pregnancy. AB - OBJECTIVE: To identify the use of folic acid during pregnancy, as well as the new mothers' knowledge about folic acid. METHODOLOGY: Quantitative, descriptive exploratory, and prospective study. A total of 198 mothers were interviewed in the pediatric outpatient service of Hospital de Base Sao Jose do Rio Preto, Brazil. They have taken their children for neonatal screening and formally consented to participating in the study. The research project was approved by the Research Ethics Committee (350,287). A specific instrument was used for data collection. The data were entered into an appropriate spreadsheet and later statistically analyzed. Pearson's chi-squared test, p <0.15, was used. RESULTS: On average, the interviewed mothers were 25 years old and received less than two minimum wages. Most had prenatal in the first quartile and a mean of seven appointments, starting the use of folic acid from the 7th to the 9th week of gestational age. However, when asked about the importance of folic acid and its action, almost the majority was not able to answer. CONCLUSION: Although daily acid supplementation is recommended in prenatal care, this study found that consumption is inadequate, contributing to the increased risk of fetal malformation. Healthcare professionals, especially nurses, should develop educational activities for women about the use of folic acid in the pre-gestation period and in the first pregnancy trimester. PMID- 28569954 TI - Coping with the diagnosis and hospitalization of a child with childhood cancer. AB - OBJECTIVE: Find out how family members cope with hospitalization due to the diagnosis of childhood cancer. METHODOLOGY: This is a descriptive-exploratory design study with qualitative data analyses, undertaken in the Support Center for Childhood Cancer in Salvador, Bahia, Brazil. 10 members of the families of children with cancer underwent a semi-structured interview as a resource to collect empirical data. Data were submitted to thematic content analysis. Two categories emerged: "family coping with diagnosis" and "family coping with hospitalization." RESULTS: It was observed that family members suffer deeply and cope with the diagnosis of cancer in different manners. In addition, psychological stress has a cumulative impact on long periods of hospitalization and occurs in the presence of sadness, anxiety, suffering due to the invasive procedures the children are submitted to, fear and uncertainties related to prognosis. CONCLUSION: The diagnosis of cancer and hospitalization process causes severe impact on family dynamics. A competent nurse must be aware and sensitive to minimize this suffering by listening carefully and providing humanized and comprehensive care to children and their families. PMID- 28569955 TI - Patient satisfaction with nursing care in an emergency service. AB - OBJECTIVE: To analyze patient satisfaction with nursing care received at a hospital emergency service. METHODOLOGY: This is a quantitative, descriptive, cross-sectional study. The sample was composed by 250 patients over 18 years old who used an emergency service in the south region of Brazil. Data were collected using an identification form and the Patient Satisfaction Instrument. RESULTS: Results point to a good level of satisfaction of patients with the nursing care received, with the greatest mean found in the technical-professional care domain. Satisfaction was significantly associated with the room where the patient was and correlated to age, education and the length of stay in the service. CONCLUSION: It was concluded that patients have good level of satisfaction with the care provided by nurses in emergency service. PMID- 28569956 TI - The transition of palliative care from the hospital to the home: a narrative review of experiences of patients and family caretakers. AB - OBJECTIVE: This work sought to identify, analyze, and synthesize the qualitative studies published on the experiences of patients and family caretakers during the transition of palliative care from the hospital to the home. METHODOLOGY: A narrative review was conducted on the PubMed, Cochrane Central, ScienceDirect, Ovid Nursing, CINALH, Scielo, and Bireme databases, from 2000 to 2014. RESULTS: After the analysis and comparison of the data, the results were grouped into six themes: (1) the dyad and its knowledge regarding the diagnosis and prognosis; (2) emotions experienced by the family caretaker and the patient during discharge; (3) effective communication among those involved with the care; (4) education for the care of the person at home; (5) continuous support to the dyad at home, and (6) care overload: social support for the family caretaker. CONCLUSION: Patients and relatives in palliative care experience a broad range of needs during the transition process from the hospital to the home, which are often not covered by healthcare professionals. This review evidences the need to research further on the experiences of these families, especially during the stage prior to the transfer to the domicile. PMID- 28569957 TI - Maternal care at home for children with special needs. AB - OBJECTIVE: To identify the feasibility of home care and difficulties of mothers who deliver this care for children with special health needs (CRIANES) and to analyze the role of nurses as facilitators of this care. METHODS: This descriptive study with a qualitative approach included ten mothers of CRIANES who completed a semi-structured interview at a teaching hospital in the municipality of Rio de Janeiro, Brazil. Data were analyzed using a thematic analysis. RESULTS: Participants pointed out as difficulties the accessibility of treatment facilities and the presence of complex disease. The administration of medicines was classified as both easy and difficult. Features that made home care feasible were help of the child and preparation of nurses in the hospital context for home care. Maternal love helped mothers to overcome difficulties. CONCLUSION: Encouragement from the nursing team for centered family care is needed. In addition, mothers should be better prepared for the transition from hospital to home. The health network needs to be reorganized with inclusion of CRIANES in the primary care network in order to reduce the dependency of this population on hospitals and to help broaden the social network for CRIANES. PMID- 28569958 TI - Education for the unified health system: what do good professors do from the perspective of students? AB - OBJECTIVE: to analyze the educational practices for the Unified Health System performed by good professors, from the perspective of nursing, medical and odontology students, based on the Shulman's concepts of knowledge of educational ends, purposes, values and their historical and philosophical grounds, at a university in southern Brazil. METHODS: A qualitative study with an exploratory and analytical approach in which the participants were graduating students, interviewed with the aid of vignettes, between October of 2011 and January of 2012. Data were analyzed based on thematic analysis. RESULTS: it was observed that good professors educate for the Unified Health System through the promotion of teamwork, interdisciplinary practices, good communication, leadership exercises, and promotion of a student's desire to be an agent of change for the sake of improvement and guaranteeing the right to health. CONCLUSION: the students attribute to professors the responsibility for the performance of these practices. Despite their consistency with the Brazilian curriculum guidelines, the professors that perform them are seen as a minority. PMID- 28569959 TI - Nursing Diagnosis of overweight and related factors in adolescents. AB - OBJECTIVE: The objective of the study was to compare the related factors to the nursing diagnosis (ND) of overweight in adolescents with and without overweight. METHODOLOGY: Transversal study conducted in 2013 with 347 adolescents that attended public schools in Natal, Rio Grande do Norte, Brazil, answered a questionnaire and had anthroprometric evaluation. The subjects were divided into two groups, the group without ND (n=247) and the group with ND (n=100). RESULTS: The prevalence of adolescents with ND overweight was 28.8%. The groups presented an unsatisfactory frequency of physical activity and a low consumption of healthy foods. The group with the ND overweight showed greater chance of consuming sweets and fried foods. The group with ND overweight had higher frequency of history family of illnesses. CONCLUSION: The prevalence of the ND overweight among adolescents in the public schools of Natal constitute a relevant nutritional deviance and the associated factors diet and family history disease are an alert for nursing in activities of prevention and follow-up for this population. PMID- 28569960 TI - Knowledge and attitudes of undergraduate nursing students toward dementia: An Indian perspective. AB - OBJECTIVE: This work evaluated nursing students' knowledge and attitudes toward individuals with Alzheimer's disease and dementia. METHODOLOGY: This was a transversal, descriptive study carried out with a randomly selected group of nursing students (N = 122) from Bangalore, India, in 2013. The study used the Alzheimer's Disease Knowledge scale (30 questions with true-false options) and the Attitude toward Alzheimer's Disease and Related Dementias scale (20 questions scored with seven Likert-type options; the higher the score, the better the attitude). RESULTS: The findings revealed that 56% of the questions were answered correctly and the average attitude score was 95 +/- 1.5. A negative correlation was observed between age and knowledge of dementia (r = -0.323; p < 0.001). CONCLUSION: The participants have inadequate knowledge of dementia. However, they have positive attitudes towards patients with dementia, giving way to improving their knowledge related to this disease. Thereby, there is urgent need to enhance the undergraduate study plan with respect to the content of this theme and strengthen the attitudes of comprehensive care to individuals with dementia. PMID- 28569961 TI - Quality of life of caregivers of octogenarians: a study using the WHOQOL-BREF. AB - OBJECTIVE: To evaluate the quality of life of octogenarians and to identify the domains related to quality of life and health. METHODOLOGY: A cross-sectional, quantitative study conducted in 2010 in the Family Health Units of Campina Grande/PB, Brazil. The study sample consisted of 52 subjects that met the eligibility criteria of: 18 years or older, being a lay caregiver of octogenarians, and having no apparent cognitive problem. A questionnaire containing a sociodemographic section and the WHOQOL-BREF that is composed of two questions about the perceptions of quality of life and health, and 24 on the physical, psychological, social relationships and environmental domains. The Cronbach's-alpha test and the logical regression analysis of the data were conducted using SPSS. The project was approved by the Research Committee of the Center for Development and Higher Education (CAAE no0490.0.133.000-08). RESULTS: The Cronbach's alpha was 0.72, attesting to the reliability of the instrument used. The domain scores were: environmental (59.43), psychological (59.01), social relationships (46.77) and physical (43.86), whose values indicate dissatisfaction of subjects with regard to aspects related to quality of life. The environmental domain was correlated with quality of life (p=0.014) and the physical domain with perceptions of health (p=0.019); the daily safety and pain aspects had the highest correlations with quality of life (p=0.001). CONCLUSION: The perception of the caregivers regarding quality of life was not good. The environmental and physical domains had the highest correlations with quality of life and health. PMID- 28569962 TI - Revealing the relationship of couples facing prophylaxis of vertical transmission of HIV. AB - OBJECTIVE: To reveal the behavior of couples who face prophylaxis of vertical transmission of HIV. METHODOLOGY: This study, based on Heidegger's theory of phenomenology, included 14 participants (7 couples), who received prophylaxis against HIV vertical transmission. The study was conducted from February 2011 to December 2012 in a prenatal outpatient and child care unit at a hospital in the countryside of Rio Grande do Sul, Brazil. RESULTS: Given the possibility of infection and of having a child, the couples revealed the existential movement of staying together to face the situation. The couple learn to take care of themselves in order to be able to care for and become involved with the baby. In this relationship, they teach themselves how to be a family. CONCLUSION: The inclusion of men in women's health care process, with both serving as a unit, makes it possible to develop assistance in the context of considering the family as being a participant in care. PMID- 28569963 TI - Families' concerns about the care of children with technology-dependent special health care needs. AB - OBJECTIVE: To identify concerns of family members of Children with Special Health Care Needs (CSHCN) as far as care related to using technology, and to discuss nurses' performance in the face of these concerns. METHODOLOGY: Qualitative descriptive research, developed through February and March 2014, through semi structured interviews with six family members, caregivers of technology-dependent CSHCN who are followed at a University Hospital in Rio de Janeiro. The setting chosen was the family members' home. Data were submitted to content analysis. RESULTS: Concerns were distributed in a timeframe, divided between those occurring the moment the family members received the information about the technological device needed, then those which arose while accompanying the child during hospitalization, and finally those that remained after the hospital discharge. CONCLUSION: The family needs information and support from nurses, because different concerns emerge throughout the treatment and accompaniment of a technology-dependent child. PMID- 28569964 TI - Women's primary care nursing in situations of gender violence. AB - OBJECTIVE: Identify the actions conducted by primary health care nurses for women in situations of domestic violence. METHODOLOGY: Exploratory-descriptive study with a qualitative approach. Participants were 17 nurses who worked in the Basic Health Unit in a city in the interior of Rio Grande do Sul, Brazil. The data was collected through semi-structured interviews and the information processing was performed using the interview content analysis technique. RESULTS: By acting in a context of the violence, the nurses describe some elements and strategies they use that allow recognition and action to combat violence, namely: acceptance and empathy, establishing a bond of trust between the professional and the woman, dialogue, and intent listening. The limitations mentioned by participants were: lack of professional training to address the situation, feeling of unpreparedness, lack of time for the workload, the professional's difficulty in recognizing and dealing with violence given its complexity, low efficiency of the service network, and the sense of professional impotence against the gravity and complexity involved in violence. CONCLUSION: The participants are not adequately prepared to care for women in situations of domestic violence. It is necessary that this issue be addressed in the training of nursing professionals. PMID- 28569965 TI - Hospitalized child and teenager with chronic diseases: feelings about death. AB - OBJECTIVE: Analyze the feelings of hospitalized children and adolescents with chronic diseases towards death. METHODOLOGY: Qualitative research, with four children and one teenager with chronic diseases, aged between 11 and 13 years old, who were admitted at a teaching hospital in Brazil, in the period from January to March 2009. In-depth interviews were carried out using a ludic material for therapeutic purposes, named ''As a guest in the hospital". The empirical material was submitted to thematic analysis. RESULTS: Two mains meanings were obtained: Feelings of hospitalized children and adolescents with chronic diseases dealing with the death of the other; and children and adolescents with chronic diseases and the fear of their own deaths. Hospitalization makes children and adolescents come across the death of other sick people, arousing feelings of sadness, consternation, anxiety, making the fear of their own death become a threat. CONCLUSION: The health team needs to be attentive to the feelings of hospitalized children and adolescents facing death so that they can get the demands, minimizing fears and anguish. PMID- 28569966 TI - The father's decision making in home birth. AB - OBJECTIVE: This work sought to inquire on the father's role on the decision making regarding home birth from the perspective of both partners. METHODOLOGY: The design was ethnographic of qualitative nature, conducted in the province of Alicante, Spain. A total of 11 couples participated voluntarily in the study. To gather the data, the following techniques were used: two life stories, five narrations, and in-depth interviews of all the study participants. The data obtained were analyzed with the ATLAS-ti v6.2 software. RESULTS: Four fundamental categories were obtained: father's attitude, role performed, influencing factors, and perception of the woman. Theproposal to carry out the delivery at home tends to be made by the woman, but its decision is made jointly. This decision is influenced by different factors, like: good evolution of the pregnancy, accompaniment by a professional, and the couple's beliefs on the delivery. The fathers consider they must be respectful of the woman's decision and accompany them during the whole process; the women are comforted by their unconditional support and accompaniment, considering it essential. CONCLUSION: The father's role is fundamental in the planned decision of having a home birth; a decision discussed and mediated by the couple in which their fears and beliefs are determinant in their decision. The woman has her partner's support to implement her decision. PMID- 28569967 TI - Publication among academic staff and students: an analysis from the ethical perspective. AB - This article analyzes, from the ethical perspective, the authorship of particles carried out among students and professors and their potential conflicts. After the literature review, it has been found that the Vancouver criteria that should be fulfilled for the attribution of authorship of an article are not popularly known by students and academic staff. Many problems are posed in this area, among which the following are highlighted: ghost writer, honorary author, and incorrect assignment in the order authors should appear. The professor-student relationship brings with it implicit risks that could lead to conflict, against which it is the academician who should be cautious to curtail any ethical fault when assigning the authors. The measures recommended to avoid conflicts of authorship among students and academic staff are: early assignment of the authors, reflection among academicians, education to students/academic staff, and external control conducted by journal editors. Conclusion is that lack of awareness of the criteria of authorship by academicians and students is the principal problem in the attribution of authorships. It is indispensable to improve this knowledge and look after the application of said criteria in practice. PMID- 28569968 TI - Research and Nursing Education changes to care for the environment. PMID- 28569969 TI - Homeless children: Experiences and meanings of the environments they construct. AB - OBJECTIVE: This work sought to learn of the experiences of homeless children and understand the meanings they give to environments they construct within these spaces. The study took place in Medellin, Colombia in 2015. METHODS: Ours was a qualitative research with ethnographic approach. Non-structured interviews and observations were conducted; a field diary was kept. RESULTS: The street, although a space of public use, is converted by children into their private space; they carry in it almost all their activities and construct two big environments: that of the street that attracts and educates and that of the work that is transitory because it is performed to survive. These children dream with an ideal environment that allows them to live quietly. CONCLUSION: Children convert the street into a private place where they carry out their daily practices: socializing, working, sleeping, having fun, and relaxing, that is, a place of social construction. PMID- 28569970 TI - The meaning of humanized nursing care for those participating in it: Importance of efforts of nurses and healthcare institutions. AB - OBJECTIVE: This study sought to understand this study sought to understand the meaning of the experience of humanized nursing care from the perspective of patients, relatives, and nurses. METHODS: This was an interpretative phenomenological study that included 16 adult participants and which was based on in-depth interviews to gather the information and on the procedures proposed by Cohen, Kahn, and Steeves to analyze the information. RESULTS: Efforts by healthcare institutions and nurses are key elements to advance from impersonal care toward humanized care because these will permit revising and eliminating the barriers present in the current exercise of caring. The results highlight the importance of the effort for humanized behavior from nurses, given that because they are human beings their behavior in the relationship with patients is not always have that connotation. CONCLUSION: Humanized care is not only supported on the human condition of nurses or on the institutional intentions, but on attitudes and on a disposition focused on the patient's wellbeing. Additionally, tensions in nursing care are solved through humanizing efforts. PMID- 28569971 TI - Needs of Parents in Caring for Their Children in a Pediatric Intensive Care Unit. AB - OBJECTIVE: This work sought to describe the needs of parents to participate in caring for their children hospitalized in a pediatric intensive care unit (PICU). METHODS: This is a qualitative study based on the ethno-nursing research method proposed by Leininger. For data collection and analysis, in-depth open interviews were used, along with field notes and enabler guidelines proposed by Leininger: stranger-friend, observation, participation, reflexion, and the Sunrise model. Parents of children hospitalized in a PICU in the city of Tunja (Boyaca, Colombia) participated between February 2012 and October 2013. RESULTS: The needs of parents to care for their children were described in the following themes: clear and timely communication, familiarization with technology, the value of the family, favoring the parent-children interaction during visits, and valuing and respecting generic (folk) knowledge. CONCLUSION: The study provides knowledge, from the cultural perspective of parents with children hospitalized in PICU, as input to plan and develop care actions with them, according to their own needs. PMID- 28569972 TI - Nursing outcome "Severity of infection": conceptual definitions for indicators related to respiratory problems. AB - OBJECTIVE: Build conceptual definitions for some indicators of the nursing outcome Infection Severity in the Nursing Outcomes Classification (NOC) related to respiratory problems, based on scientific evidence of signs and symptoms of infection in adults. METHODS: Integrative literature review with search in the databases PubMed, CINAHL, LILACS and SCOPUS. Studies whose full texts were available, published in Spanish, Portuguese or English, using the descriptors infection severity, nursing outcomes classification NOC, respiratory infections and respiratory signs and symptoms. RESULTS: Nine publications were analyzed that supported the elaboration of the conceptual definitions for eight indicators of the Nursing Outcome Infection Severity: purulent drainage, fever, chilling, unstable temperature, pain, colonization of drainage cultivation, white blood cell count elevation and white blood cell count drop. CONCLUSION: This study contributed to understand the terms used in the nursing outcome Infection Severity, in order to improve and facilitate the use of the NOC, as it enhances the conceptual clarity of the selected indicators with a view to producing better scientific evidence.Objetivo.Construir definicoes conceituais para alguns indicadores do resultado de enfermagem Gravidade de Infeccao da Nursing Outcomes Classification (NOC) relacionados aos problemas respiratorios, a partir de evidencias cientificas sobre sinais e sintomas de infeccao em pessoas adultas. Metodos. Revisao integrativa da literatura com busca nas bases de dados PubMed, CINAHL, LILACS e SCOPUS. Foram incluidos estudos com textos na integra, publicados em espanhol, portugues ou ingles, usando os descritores gravidade da infeccao, classificacao dos resultados de enfermagem da NOC, infeccoes respiratorias, e sinais e sintomas respiratorios. Resultados. Analisaram-se nove publicacoes que embasaram a elaboracao das definicoes conceituais de oitos indicadores do Resultado de Enfermagem Gravidade de Infeccao: expectoracao purulenta, febre, hipotermia, instabilidade da temperatura, dor, colonizacao em cultura de expectoracao, elevacao na contagem das celulas brancas e depressao na contagem das celulas brancas. Conclusao. O estudo contribuiu para a compreensao dos termos utilizados no resultado enfermagem Gravidade de Infeccao, de modo a aperfeicoar e facilitar o uso da NOC, a medida que apresenta refinamento do ponto de vista conceitual dos indicadores selecionados, de modo a produzir melhores evidencias cientificas. PMID- 28569973 TI - New demands for primary health care in Brazil: palliative care. AB - OBJECTIVE: Assess the need for incorporation of palliative care in primary health care (PHC) through the characterization of users eligible for this type of care, enrolled in a program for devices dispensing. METHODS: Descriptive study of case series conducted in 14 health units in Sao Paulo (Brazil) in 2012. It was included medical records of those enrolled in a program for users with urinary and fecal incontinence, and it was applied Karnofsky Performance Scale Index (KPS) to identify the indication of palliative care. RESULTS: 141 of the 160 selected medical records had KPS information. Most cases (98.3%, 138/141) had performance below 70% and, therefore, patients were eligible for palliative care. The most frequent pathologies was related to chronic degenerative diseases (46.3%), followed by disorders related to quality of care during pregnancy and childbirth (24.38%). CONCLUSION: It is necessary to include palliative care in PHC in order to provide comprehensive, shared and humanized care to patients who need this. PMID- 28569974 TI - Barriers to prevention of cervical cancer in the city of Porto Velho, Rondonia, Brazil. AB - OBJECTIVE: Identify the related factors with the no adhesion of women in preventive practices of cervical cancer (CC), in a coverage area of a Family Health Team in the city of Porto Velho (Rondonia, Brazil). METHODS: Descriptive, cross-sectional study held in 2013. It was applied a questionnaire containing questions related to the health belief model (HBM) of the instrument "Champion's Health Belief Model Scale", validated and culturally adapted to Brazil, to 286 women. RESULTS: 87.7% of women state that they have been submitted to prevention of CC; Regarding the parameters of the HBM, it was found that 74.5% of the women had low scores for the perception of susceptibility to the disease; equal percentage of women had an moderate perception of severity; 52.8% have an moderate perception of the benefits gained from the examination of prevention; and 51.4% have moderate perception of barriers to perform the same test. CONCLUSION: the process involving the prevention of CC involves the supply of services and availability of skilled professionals. However, the adoption of preventive behavior depends not only on external factors, but also own subjective factors to women. PMID- 28569975 TI - Functional social support in family caregivers of elderly adults with severe dependence. AB - OBJECTIVE: This work sought to determine functional social support in family caregivers of severely dependent elderly adults and its relationship with sociodemographic characteristics. METHODS: This was a cross-sectional study. The Duke-UNC-11 Functional Social Support questionnaire was applied to 67 family caregivers from Family Healthcare Centers in Valdivia (Chile) in 2012. RESULTS: Family caregivers perceived low levels of affective social support (49.3%) and of trust (98.5%); considering insufficient the information and advice they receive related, principally, to the scarce number of people who help, they need to establish communication to share their feelings and problems derived from the task of caring. These caregivers recognize the support from community healthcare centers. Functional social support is correlated to the following variables: number of people who live in the home, years of study, age of the caregiver, and number of people who help; with this last variable predicting the level of social support in its two dimensions. CONCLUSION: Family caregivers of severely dependent elderly adults perceive a level of functional social support, especially in the dimension of trust. Community nurses must increase the number of home visits, evaluate the needs for social support perceived in caregivers, and teach coping strategies to mitigate problems that emerge in this work. PMID- 28569976 TI - Validation of an instrument to measure tutor performance in promoting self directed learning by using confirmatory factor analysis. AB - OBJECTIVE: This work sought to validate and propose an instrument to measure the performance of tutors in promoting self-directed learning in students involved in processes of problem-based learning. METHODS: Confirmatory factor analysis (CFA) was applied to validate the instrument composed of 60 items and six factors (self assessment of learning gaps within the United Nations specific context: self assessment, reflexion, critical thinking, administration of information, group skills), using a sample of 207 students from a total of 279, which comprise the student population of the Faculty of Nursing at Universidad de Colima in Mexico. (2007). RESULTS: The CFA results demonstrated that the instrument is acceptable to measure performance of tutors in promoting self-directed learning, given that all the indicators, variances, covariances, and thresholds are statistically significant. CONCLUSION: The instrument permits obtaining students' opinions on how much professors contribute for them to develop each of the 60 skills described in the scale. Lastly, the results could report if professors are placing more emphasis in some areas than in other areas they should address during the problem-based learning (PBL) process, or if definitely their actions are removed from the premises of PBL, information that will be useful for school management in decision making on the direction of teaching as a whole. PMID- 28569977 TI - Body and Corporality in adolescents and young adults with spinal cord injury. AB - OBJECTIVE: To describe the meaning given by adolescents and young adults to the changes in their bodies and corporality after a spinal cord injury. METHODS: Qualitative study based on symbolic interactionism in which 12 adolescents and young adults, who had suffered spinal cord injury 6 months or more before, participated. The information was recollected through a series of in-depth interviews and field journals. The guidelines proposed by Corbin and Strauss were followed for the process of codification and categorization of the data. RESULTS: Four categories were identified that describe the meanings given by participants to the changes in their bodies and corporality: Transformation of self-image, living with contradictions in the relationships with others, withstanding the burden of a disability and adapting to the new conditions. CONCLUSION: The results allow for the comprehension of the meanings that are given by the people who have suffered a spinal cord lesion to their situation. This will in turn open the possibility of offering these people a better individual nursing care that focuses more on the particular needs, so that both they and their families can be helped on their way to adaptation to the new situation. PMID- 28569978 TI - Lifestyles of nursing students from a Colombian public university. AB - OBJECTIVE: To assess the lifestyles of nursing students from a Colombian public university. METHODS: A cross-sectional study was conducted in 2014. 380 students answered by self-reporting the adapted version in Spanish of FANTASTIC Lifestyles Assessment Questionnaire of Wilson and Ciliska. RESULTS: Lifestyles were poor in 9.2%, fair in 31.3%, good in 53.7%, and excellent in only 5.8% of the participants. Statistically-significant differences of the total mean score were not found when comparing with gender, age group, and course year, but were detected in two domains by gender: a) physical activity (higher score in men) and b) cigarette smoking (higher score in women). CONCLUSION: An important proportion of our nursing students has inadequate lifestyles, which means deferred risks for the development of chronic diseases. Universities should promote the training of the future professionals in nursing with knowledge and skills aimed at healthy lifestyles. PMID- 28569979 TI - Strategies for neonatal developmental care and family-centered neonatal care. AB - OBJECTIVE: To evaluate neonatal developmental care and family-centered care in a neonatal unit. METHODS: Participatory action research with a purposive sample of health personnel and parents of hospitalized newborn in a Neonatal Unit in Valle del Cauca, Colombia. Five focal groups were conducted with seven mothers and 40 professionals of the unit team, and additionally, 24 non-participant observations were conducted about neonatal developmental care and family-centered care. Three strategies for promotion were implemented for both approaches and subsequently, results were evaluated in terms of practices that take place during neonatal care, after the intervention. A quantitative analysis with descriptive statistics and a qualitative content analysis were done to process the data. Three strategies were implemented: continuing education for professionals, allocation of materials for the positioning of the babies and an informative video for the parents about how the unit operates. RESULTS: The focus groups and the initial observation showed the necessity to enhance knowledge and practices of the personnel regarding neonatal developmental care and family-centered care. CONCLUSION: The promotion of neonatal developmental care and family-centered care generated positive changes in care practices of the professionals in the neonatal unit, through the use of education strategies, communication and the provision of positioning materials. PMID- 28569980 TI - Classification tree for the assessment of sedentary lifestyle among hypertensive. AB - OBJECTIVE: To develop a classification tree of clinical indicators for the correct prediction of the nursing diagnosis "Sedentary lifestyle" (SL) in people with high blood pressure (HTN). METHODS: A cross-sectional study conducted in an outpatient care center specializing in high blood pressure and Mellitus diabetes located in northeastern Brazil. The sample consisted of 285 people between 19 and 59 years old diagnosed with high blood pressure and was applied an interview and physical examination, obtaining socio-demographic information, related factors and signs and symptoms that made the defining characteristics for the diagnosis under study. The tree was generated using the CHAID algorithm (Chi-square Automatic Interaction Detection). RESULTS: The construction of the decision tree allowed establishing the interactions between clinical indicators that facilitate a probabilistic analysis of multiple situations allowing quantify the probability of an individual presenting a sedentary lifestyle. The tree included the clinical indicator Choose daily routine without exercise as the first node. People with this indicator showed a probability of 0.88 of presenting the SL. The second node was composed of the indicator Does not perform physical activity during leisure, with 0.99 probability of presenting the SL with these two indicators. The predictive capacity of the tree was established at 69.5%. CONCLUSION: Decision trees help nurses who care HTN people in decision-making in assessing the characteristics that increase the probability of SL nursing diagnosis, optimizing the time for diagnostic inference. PMID- 28569981 TI - Construction and validation of a virtual learning object on intestinal elimination stoma. AB - OBJECTIVE: To construct and validate a virtual learning object (VLO) on intestinal elimination stoma. METHODS: Applied, descriptive and quantitative study. In 2014, eight stoma therapists and eight experts in computer science took part of the research. The VLO included four steps: i) planning, ii) construction of VLO and changes of content; iii) development of dynamic, and iv) conclusion and analysis. The VLO was inserted into the Moodle virtual learning environment. The ergonomic and pedagogical validation of the VLO was performed. RESULTS: The experts appreciated the VLO satisfactorily, and scored it between good and full agreement. CONCLUSION: The VLO on intestinal elimination stoma is a tool that can be implemented at undergraduate programs in nursing and continuing education programs for nurses in clinical practice, contributing significantly to improve the theoretical skills necessary for the care of ostomized people safely, with quality and enabling self-care. PMID- 28569982 TI - Relationship between wellness and sociodemographic characteristics of caregivers of people with cancer. AB - OBJECTIVE: To investigate the association between wellness and sociodemographic characteristics of caregivers of people with cancer. METHODS: This was a cross sectional study conducted in Maringa, Parana, Brazil, with 96 caregivers. Data were collected between July 2011 and February 2012. A global wellness assessment scale was used to measure wellness and data on sociodemographic characteristics were gathered using a complementary form. RESULTS: The characteristics associated with reduced wellness among caregivers of people with cancer were: being separated, being a mother, having a higher education degree, being employed, being the sole caregiver, having a family income of up to one minimum wage and presenting health problems. CONCLUSION: Some demographic characteristics are associated with loss of wellness among these caregivers. Nurses must take this information into account when formulating strategies to improve the wellness of caregivers, considering their context. PMID- 28569983 TI - Patient education among nurses: bringing evidence into clinical applicability in Iran. AB - OBJECTIVE: The aim of this study was to present a comprehensive review of the literatures describing barriers and facilitators of patient education (PE) perceived by Iranian nurses in order to explain clinical applicability of patient education. METHODS: Review of the literature was undertaken using the international databases including PubMed/Medline, Scopus, ScienceDirect, as well as Google Scholar. Also, Persian electronic databases such as Magiran, SID and IranMedex were searched. Electronic databases were searched up from conception to September 2014 using search terms: "patient education", " patients education", "patient teaching", "patient training", "nurse", " nurses", " nursing", " and "Iran". Only studies were included that were related to barriers and facilitators of PE among Iranian nurses. RESULTS: Twenty-seven studies were included. The main influential barriers were categorized into three major areas: 1) Nurse-related factors: nursing shortage 2) Administration-related factors: unsupportive organizational culture, and 3) Patient-related factors: low compliance. The most perceived facilitators were recognized as "increasing, selecting and training special nurses for providing PE" and "providing PE courses for nurses and appropriate facilities for PE". CONCLUSION: Iranian nurses encounter barriers in PE, and the most frequently encountered barriers were related to administration factors. These findings have implications for administrators and managers in health settings. In order to promote PE among nurses, administrators should create a supportive environment and use effective strategies to smooth the progress of PE by nurses in their practice in order to ensure optimal outcomes for patients. PMID- 28569984 TI - Reporting of violence against children and adolescents in a protective institution in southern Brazil. AB - OBJECTIVE: This study aimed to analyze the reports of violence against children and adolescents in the period between January 2009 and May 2014 in a municipality protection institution of Rio Grande, RS. METHODS: This is a descriptive and documentary study with a quantitative approach that analyzed 800 medical records of Specialized Reference Center for Social Assistance (CREAS), from the development of a research instrument containing the study variables. RESULTS: The results show that 44.5% of the notifications sent to the protection of organs were carried out by family members and evidence of physical signs was the reason that triggered them (34%). The dismissing by abandonment of families is very present in the institution (36.9%), which possibly supports the maintenance of the cycle of violence. CONCLUSION: The results of this study show that although there were improvements regarding the notification by the family, the number of notifications made by the health and education sectors are still reduced, thereby increasing the need for more effective and articulated actions in these sectors. PMID- 28569986 TI - Correlation of quality of life with knowledge and attitude of diabetic elderly. AB - OBJECTIVE: To describe the quality of life (QL), knowledge and attitude of the elderly with diabetes mellitus (DM) and to correlate the QL with the knowledge and the attitude of the elderly. METHOD: It is a cross-sectional study of household inquiry type and developed with 296 elderly with DM. The used instruments were: World Health Organization Quality of Life Bref (WHOQOL-BREF), World Health Organization Quality of Life Old (WHOQOL-OLD), Diabetes Knowledge Scale Questionnaire (DKN-A) and Diabetes Attitudes Questionnaire (ATT-19). RESULTS: The female were predominant (68.2%), aged from 70 - 79 years old (43.9%), married or living with a partner (41.6%), living with their children (43.2%), with income of one minimum wage (52.4%), had 4 - 7 years of education (32.8%), on diet use and oral hypoglycemic (68.6%) and less than five years diagnosis (29.1%). The greater the knowledge and the attitude the higher QL scores in physical, psychological, social relationships and environment domains; and facets of sensory works, autonomy, and intimacy. CONCLUSION: Educational activities need to be worked improving the knowledge and attitude of the elderly about the DM. PMID- 28569985 TI - Analysis of YouTube videos about urinary catheterization technique of male delay. AB - OBJECTIVE: To analyze the execution of urinary catheterization technique of male delay in YouTube videos. METHODS: This is an exploratory research with a quantitative approach, performed using the YouTube sharing site. The search of the videos was conducted in September 2014, using the controlled descriptor "urinary catheterization". RESULTS: 32 videos were analyzed, none were in accordance with the standards established in the literature; among the main errors highlight the absence of hand washing (78.1%), the absence of the medical recording (71.8%), the absence of cleaning and drying of the patient at the end of the procedure (71.8%), the incorrect technique during antisepsis (62.5%) and the absence of gloves changes (59.3%). CONCLUSION: Although the YouTube sharing video site is currently a widespread tool, there is an absence of videos that reproduce the technique according to what is recommended in the literature. PMID- 28569987 TI - The bond as a soft technology in the daily routine of the Family Health Strategy: perception of the user. AB - OBJECTIVE: This study aimed to analyze the production of a bond between users and health care professionals in a Family Health Unit (FHU). METHODS: This was a qualitative, descriptive study, with 33 hypertensive and/or diabetic users. Interviews were transcribed, analyzed and data were compared to the literature. RESULTS: The users who have been accessing the FHU for years stated that the bond with professionals has grown weak, it is a fragile bond. When it does exist, it is directed toward some professionals in the team. A disruption in the bond was also mentioned in some situations, owing to individual issues. Establishment of a bond between the user and the health care professionals in the reference FHU consists of a soft technology. Therefore, it impacts quality of health care and the prevention and management of chronic diseases. CONCLUSION: Establishment of a bond is essential for health care professionals to become references for the users of health care services. PMID- 28569988 TI - Which factors influence women in the decision to breastfeed? AB - OBJECTIVE: Identify the factors that influence women in the decision to breastfeed. METHODS: Integrative review. Information was gathered from original articles, case studies, theoretical studies, consensus and systematic reviews published between 2007-2013 in Spanish, Portuguese and English and recovered in the databases MEDLINE and LILACS. The descriptors used in this study were: breastfeeding, maternal behavior, risk factors, lactation and newborn. RESULTS: Were included 30 articles, grouped into five categories. Factors influencing the decision of the breastfeeding woman are a convergence of breastfeeding's advantages, benefits and justifications, family, social and professional support, sociodemographic and clinical characteristics of women, personal experience and family tradition and personal choice. CONCLUSION: The decision to breastfeed by women is influenced by a convergence of factors. It is essential the role of nursing to encourage women in the decision to initiate and maintain breastfeeding her child. PMID- 28569989 TI - Stressful situations and factors in students of nursing in clinical practice. AB - OBJECTIVE: To assess the risk factors for stress in undergraduate students of nursing in clinical practice in a public university in the Northeast region of Brazil. METHODS: Cross-sectional descriptive study with 116 students from the fifth to the ninth period. The bilingual KEZKAK questionnaire, validated for Portuguese, was used. Stress was considered to be present when the score was equal or superior to 2. RESULTS: The students with stress in clinical practice were 18 to 22 years old (2.82 +/- 0.98), women (2.81 +/- 0.96), married (2.80 +/- 0.97), and who were permanent contracted employees (2.74 +/- 0.94). The factors which were most associated with stress were: Lack of competence (2.99 +/- 0.88); Impotence and uncertainty (2.98 +/- 0.85); and Patients seeking a closer relationship (2.93 +/- 1.01). The students of the sixth period were the most vulnerable to stress (2.85+/-0.96). CONCLUSION: The studies showed the main risk factors for stress among students of nursing in their clinical practice. These results could be used in the development of strategies seeking to reduce stress in this context as well as to contribute to promoting mental health. PMID- 28569990 TI - Prospective, randomized, multicenter, controlled trial (TRIATHRON 1) on a new antithrombogenic hydrophilic dialysis membrane. AB - INTRODUCTION: Hemodialysis treatment requires anticoagulation to prevent thrombosis of the dialyzer. The Hydrolink(r) (NV series; Toray) has been designed to reduce thrombotic complications by increasing membrane hydrophilic properties. Previous studies have confirmed reduced platelet activation, improved removal of beta2-microglobulin and excellent small-solute removal. METHODS: We designed a prospective, multi-centered, randomized clinical study to compare the antithrombogenic effects (platelet count) of NV dialyzers versus conventional treatment. To compare the possibility of performing heparin-free dialysis, we carried out progressive heparin reduction tests. Patients with an average platelet count lower than 170,000 cells/mm3 using standard high flux membranes in the 6 months prior to the study were enrolled and randomized. Patients were either dialyzed for 6 months without changing the previous membrane (control group) or treated with the Hydrolink(r) membrane (NV group). After the third week, the heparin reduction test was conducted for 5 weeks in order to assess the minimum amount of anticoagulant needed to safely perform a 4-hour dialysis treatment. Performance and safety were evaluated measuring platelet count and activation, middle-molecule removal rate and nutritional status. RESULTS: We found no significant difference in platelet count, platelet activation factors beta-thromboglobulin and platelet factor 4 (PF-4), between the groups. More patients in the study group reached heparin-free dialysis without clotting events during the heparin reduction test. The NV dialyzers displayed anti-thrombogenic effects as compared to conventional dialyzers. CONCLUSIONS: The NV dialyzer series is safe with no adverse events reported. Further studies are required to understand the mechanisms of anti-thrombogenic effects. PMID- 28569991 TI - The role of 5-lipoxygenase in Aggregatibacter actinomycetemcomitans-induced alveolar bone loss. AB - AIM: Leukotrienes (LTs) are pro-inflammatory lipid mediators formed by the enzyme 5-lipoxygenase (5-LO). The involvement of 5-LO metabolites in periodontal disease (PD) is not well defined. This study aimed to assess the role of 5-LO in experimental PD induced by Aggregatibacter actinomycetemcomitans (Aa). MATERIAL AND METHODS: In vivo experiments were carried out using SV129 wild-type (WT) and 5-LO-deficient (5lo-/- ) mice inoculated with Aa. Osteoclasts were stimulated in vitro with AaLPS in the presence or not of selective inhibitors of the 5-LO pathway, or LTB4 or platelet-activating factor (PAF), as PAF has already been shown to increase osteoclast activity. RESULTS: In 5lo-/- mice, there were no loss of alveolar bone and less TRAP-positive osteoclasts in periodontal tissues, after Aa inoculation, despite local production of TNF-alpha and IL-6. The differentiation and activity of osteoclasts stimulated with AaLPS were diminished in the presence of BLT1 antagonist or 5-LO inhibitor, but not in the presence of cysteinyl leukotriene receptor antagonist. The osteoclast differentiation induced by PAF was impaired by the BLT1 antagonism. CONCLUSION: In conclusion, LTB4 but not CysLTs is important for Aa-induced alveolar bone loss. Overall, LTB4 affects osteoclast differentiation and activity and is a key intermediate of PAF-induced osteoclastogenesis. PMID- 28569992 TI - Technical Note: Detective quantum efficiency simulation of a-Se imaging detectors using ARTEMIS. AB - PURPOSE: This work studies the detective quantum efficiency (DQE) of a-Se-based solid state x-ray detectors for medical imaging applications using ARTEMIS, a Monte Carlo simulation tool for modeling x-ray photon, electron and charged carrier transport in semiconductors with the presence of applied electric field. METHODS: ARTEMIS is used to model the signal formation process in a-Se. The simulation model includes x-ray photon and high-energy electron interactions, and detailed electron-hole pair transport with applied detector bias taking into account drift, diffusion, Coulomb interactions, recombination and trapping. For experimental validation, the DQE performance of prototype a-Se detectors is measured following IEC Testing Standard 62220-1-3. RESULTS: Comparison of simulated and experimental DQE results show reasonable agreement for RQA beam qualities. Experimental validation demonstrated within 5% percentage difference between simulation and experimental DQE results for spatial frequency above 0.25 cycles/mm using uniform applied electric field for RQA beam qualities (RQA5, RQA7 and RQA9). Results include two different prototype detectors with thicknesses of 240 MUm and 1 mm. CONCLUSIONS: ARTEMIS can be used to model the DQE of a-Se detectors as a function of x-ray energy, detector thickness, and spatial frequency. The ARTEMIS model can be used to improve understanding of the physics of x-ray interactions in a-Se and in optimization studies for the development of novel medical imaging applications. PMID- 28569993 TI - A pretrained neural network shows similar diagnostic accuracy to medical students in categorizing dermatoscopic images after comparable training conditions. PMID- 28569995 TI - Lymphomatoid papulosis associated with chronic lymphocytic leukaemia/small lymphocytic lymphoma: three cases. PMID- 28569994 TI - Physiologically Based Pharmacokinetic Modeling for Predicting the Effect of Intrinsic and Extrinsic Factors on Darunavir or Lopinavir Exposure Coadministered With Ritonavir. AB - Management of comorbidities and medications is complex in HIV-1-infected patients. The overall objective of this project was to develop separate physiologically based pharmacokinetic (PBPK) substrate models for the protease inhibitors darunavir and lopinavir. These protease inhibitors are used in the treatment of HIV infection. Both darunavir and lopinavir are coadministered with another medication that inhibits cytochrome (CYP) 3A. The current project focused on PBPK modeling for darunavir and lopinavir coadministered with ritonavir. Darunavir and lopinavir PBPK models that accounted for ritonavir CYP3A inhibition effects (linked PBPK models) were developed. The linked PBPK models were then used to predict the effect on darunavir or lopinavir exposure from CYP modulators. In the next step, the predicted effect of hepatic impairment was evaluated. Additional exploratory analyses predicted CYP3A inhibition effects on darunavir or lopinavir exposure in simulated hepatically impaired subjects. The linked PBPK models reasonably predicted darunavir or lopinavir exposure based on simulations with CYP inhibitors or inducers. Exploratory simulations using the linked darunavir or lopinavir PBPK models indicated CYP3A inhibition may further increase darunavir or lopinavir exposure in patients with hepatic impairment. PMID- 28569996 TI - Technical Note: Validation of two methods to determine contact area between breast and compression paddle in mammography. AB - PURPOSE: To assess the accuracy of two methods of determining the contact area between the compression paddle and the breast in mammography. An accurate method to determine the contact area is essential to accurately calculate the average compression pressure applied by the paddle. METHODS: For a set of 300 breast compressions, we measured the contact areas between breast and paddle, both capacitively using a transparent foil with indium-tin-oxide (ITO) coating attached to the paddle, and retrospectively from the obtained mammograms using image processing software (Volpara Enterprise, algorithm version 1.5.2). A gold standard was obtained from video images of the compressed breast. During each compression, the breast was illuminated from the sides in order to create a dark shadow on the video image where the breast was in contact with the compression paddle. We manually segmented the shadows captured at the time of x-ray exposure and measured their areas. RESULTS: We found a strong correlation between the manual segmentations and the capacitive measurements [r = 0.989, 95% CI (0.987, 0.992)] and between the manual segmentations and the image processing software [r = 0.978, 95% CI (0.972, 0.982)]. Bland-Altman analysis showed a bias of -0.0038 dm2 for the capacitive measurement (SD 0.0658, 95% limits of agreement [-0.1329, 0.1252]) and -0.0035 dm2 for the image processing software [SD 0.0962, 95% limits of agreement (-0.1921, 0.1850)]. CONCLUSIONS: The size of the contact area between the paddle and the breast can be determined accurately and precisely, both in real-time using the capacitive method, and retrospectively using image processing software. This result is beneficial for scientific research, data analysis and quality control systems that depend on one of these two methods for determining the average pressure on the breast during mammographic compression. PMID- 28569997 TI - Impact of spot charge inaccuracies in IMPT treatments. AB - BACKGROUND: Spot charge is one parameter of pencil-beam scanning dose delivery system whose accuracy is typically high but whose required value has not been investigated. In this work we quantify the dose impact of spot charge inaccuracies on the dose distribution in patients. Knowing the effect of charge errors is relevant for conventional proton machines, as well as for new generation proton machines, where ensuring accurate charge may be challenging. METHODS: Through perturbation of spot charge in treatment plans for seven patients and a phantom, we evaluated the dose impact of absolute (up to 5* 106 protons) and relative (up to 30%) charge errors. We investigated the dependence on beam width by studying scenarios with small, medium and large beam sizes. Treatment plan statistics included the Gamma passing rate, dose-volume-histograms and dose differences. RESULTS: The allowable absolute charge error for small spot plans was about 2* 106 protons. Larger limits would be allowed if larger spots were used. For relative errors, the maximum allowable error size for small, medium and large spots was about 13%, 8% and 6% for small, medium and large spots, respectively. CONCLUSIONS: Dose distributions turned out to be surprisingly robust against random spot charge perturbation. Our study suggests that ensuring spot charge errors as small as 1-2% as is commonly aimed at in conventional proton therapy machines, is clinically not strictly needed. PMID- 28569998 TI - Recurrent deep vein thrombosis with a protein S Tokushima mutation. PMID- 28569999 TI - Second generation stationary digital breast tomosynthesis system with faster scan time and wider angular span. AB - PURPOSE: The aim of this study was to characterize a new generation stationary digital breast tomosynthesis system with higher tube flux and increased angular span over a first generation system. METHODS: The linear CNT x-ray source was designed, built, and evaluated to determine its performance parameters. The second generation system was then constructed using the CNT x-ray source and a Hologic gantry. Upon construction, test objects and phantoms were used to characterize system resolution as measured by the modulation transfer function (MTF), and artifact spread function (ASF). RESULTS: The results indicated that the linear CNT x-ray source was capable of stable operation at a tube potential of 49 kVp, and measured focal spot sizes showed source-to-source consistency with a nominal focal spot size of 1.1 mm. After construction, the second generation (Gen 2) system exhibited entrance surface air kerma rates two times greater the previous s-DBT system. System in-plane resolution as measured by the MTF is 7.7 cycles/mm, compared to 6.7 cycles/mm for the Gen 1 system. As expected, an increase in the z-axis depth resolution was observed, with a decrease in the ASF from 4.30 mm to 2.35 mm moving from the Gen 1 system to the Gen 2 system as result of an increased angular span. CONCLUSIONS: The results indicate that the Gen 2 stationary digital breast tomosynthesis system, which has a larger angular span, increased entrance surface air kerma, and faster image acquisition time over the Gen 1 s-DBT system, results in higher resolution images. With the detector operating at full resolution, the Gen 2 s-DBT system can achieve an in plane resolution of 7.7 cycles per mm, which is better than the current commercial DBT systems today, and may potentially result in better patient diagnosis. PMID- 28570000 TI - Morphological and molecular characterization of actinic lentigos reveals alterations of the dermal extracellular matrix. AB - BACKGROUND: Actinic lentigos (AL) are benign hyperpigmented skin lesions associated with photoageing. Despite their high prevalence, biological mechanisms driving their formation remain unclear. OBJECTIVES: To provide new insights about the physiopathology of AL through a comprehensive description of their histological and molecular features. METHODS: Quantitative analysis of dermoscopic images was used to select AL containing elongated patterns, predicted to display a highly deformed dermal-epidermal junction (DEJ), on the back of the hands of 15 Caucasian women. Biopsies from lesional and adjacent nonlesional (NL) areas were processed for histological analysis or gene expression profiling. RESULTS: Histological staining confirmed a drastic deformation of the DEJ in AL, with deep epidermal invaginations into the dermis. Although the melanin content was significantly higher in AL compared with NL epidermis, the distribution of melanocytes along the DEJ was unchanged. Transcriptomic analysis revealed a signature of 529 genes differently expressed in AL vs. NL skin. Alteration of epidermal homeostasis was confirmed by the dysregulation of keratinocyte proliferation and differentiation markers. Surprisingly, canonical genes involved in melanogenesis were not significantly modulated in AL. A striking finding was the overexpression of a large group of genes involved in dermal extracellular matrix organization and remodelling. Dermal alterations were confirmed by immunolabellings on AL and NL sections. CONCLUSIONS: Drastic disorganization of the cutaneous structure in AL is accompanied by a specific molecular signature revealing alterations in both epidermal and dermal compartments. In particular, our results suggest that local modifications of the dermal extracellular matrix might contribute to hyperpigmentation in AL. PMID- 28570001 TI - A clinically validated prediction method for facial soft-tissue changes following double-jaw surgery. AB - PURPOSE: It is clinically important to accurately predict facial soft-tissue changes prior to orthognathic surgery. However, the current simulation methods are problematic, especially in anatomic regions of clinical significance, e.g., the nose, lips, and chin. We developed a new 3-stage finite element method (FEM) approach that incorporates realistic tissue sliding to improve such prediction. METHODS: In Stage One, soft-tissue change was simulated, using FEM with patient specific mesh models generated from our previously developed eFace template. Postoperative bone movement was applied on the patient mesh model with standard FEM boundary conditions. In Stage Two, the simulation was improved by implementing sliding effects between gum tissue and teeth using a nodal force constraint scheme. In Stage Three, the result of the tissue sliding effect was further enhanced by reassigning the soft-tissue-bone mapping and boundary conditions using nodal spatial constraint. Finally, our methods have been quantitatively and qualitatively validated using 40 retrospectively evaluated patient cases by comparing it to the traditional FEM method and the FEM with sliding effect, using a nodal force constraint method. RESULTS: The results showed that our method was better than the other two methods. Using our method, the quantitative distance errors between predicted and actual patient surfaces for the entire face and any subregions thereof were below 1.5 mm. The overall soft-tissue change prediction was accurate to within 1.1 +/- 0.3 mm, with the accuracy around the upper and lower lip regions of 1.2 +/- 0.7 mm and 1.5 +/- 0.7 mm, respectively. The results of qualitative evaluation completed by clinical experts showed an improvement of 46% in acceptance rate compared to the traditional FEM simulation. More than 80% of the result of our approach was considered acceptable in comparison with 55% and 50% following the other two methods. CONCLUSION: The FEM simulation method with improved sliding effect showed significant accuracy improvement in the whole face and the clinically significant regions (i.e., nose and lips) in comparison with the other published FEM methods, with or without sliding effect using a nodal force constraint. The qualitative validation also proved the clinical feasibility of the developed approach. PMID- 28570002 TI - Role of poly(ADP-ribose) polymerase activation in the pathogenesis of periodontitis in diabetes. AB - AIM: The aetiology of progressive periodontitis in diabetes has not yet been elucidated. We previously demonstrated that nitrosative stress is increased in diabetic rats with periodontitis. Nitrosative stress induces poly(ADP-ribose) polymerase (PARP) activation. Here, we demonstrated the involvement of PARP activation in diabetic periodontitis and detailed the therapeutic effects of PARP inhibitor. MATERIALS AND METHODS: Experimental periodontitis was induced by placing a nylon thread ligature. Half of the normal and diabetic rats received the PARP inhibitor, 1,5-isoquinolinediol, for 2 weeks. Gingival PARP activation was detected by immunostaining for poly(ADP-ribose). Periodontitis was evaluated by gingival inflammatory cell infiltration, inflammatory gene expressions and micro-CT analyses. RESULTS: Although both periodontitis and the presence of diabetes increased PARP activation in the gingiva, diabetic rats with periodontitis had the highest activation of PARP. Diabetic rats with periodontitis also showed significant increases in monocyte/macrophage invasion into the gingiva, inflammatory gene expressions, nitrotyrosine-positive cells in the gingiva and alveolar bone loss, all of which were suppressed by treatment with the PARP inhibitor. CONCLUSIONS: These results indicate the involvement of PARP activation in the pathogenesis and aggravation of periodontal disease in diabetes and suggest the therapeutic potential of PARP inhibition for treating periodontal disease, especially in patients with diabetes. PMID- 28570003 TI - Age of onset of disease in subjects with severe periodontitis: A 9- to 34-year retrospective study. AB - AIM: The aim was to retrospectively assess the age of onset of disease in a group of patients, 30-45 years of age, diagnosed with severe, generalised periodontitis. MATERIAL & METHODS: Seventy-four patients agreed to be part of the study. Patient files and radiographs of 42 patients were retrieved from >80 private and public dental clinics. Interproximal sites in radiographs presenting with identifiable cement-enamel junction (CEJ) and alveolar bone crest (BC) were analysed. The distance between CEJ and BC was measured, and two thresholds were used; >=3 mm and >=5 mm. The lowest patient age at which a radiographic examination revealed a CEJ-BC distance of >=3 mm (F3) and >=5 mm (F5) at any site was recorded. Similarly, the highest patient age at which a radiographic examination revealed absence of sites with CEJ-BC >=3 mm (L0) was assessed. RESULTS: Complete sets of radiographs including periods prior to periodontal breakdown (L0) and disease stages F3, F5 and at recruitment were retrieved in 19 patients. Onset of disease, that is, the interval between L0 and F3, occurred on the average between 22.3 and 28.1 years of age and sites exhibiting severe bone loss (F5) were detected at the age of about 32.4 years. CONCLUSION: Severe, generalised periodontitis in 30- to 45-year-old subjects of the current sample commenced mainly between 22 and 28 years of age. PMID- 28570004 TI - ERRATA. PMID- 28570006 TI - Primary conjunctival myxoma: case series and review of the literature. AB - AIMS: Myxomas are benign soft tissue tumours resembling primitive mesenchyme. They rarely involve ocular structures, and have been recognized in the conjunctiva, eyelids, cornea, and orbit. The aim of this study was to investigate the clinicopathological features of seven patients with primary conjunctival myxoma seen at Dr Luis Sanchez Bulnes Hospital, an ophthalmological referral centre in Mexico City. METHODS AND RESULTS: We reviewed the clinical, histochemical and immunohistochemical studies of patients with documented myxoma of the conjunctiva diagnosed in our hospital. Seven conjunctival myxomas were retrieved from 5923 conjunctival biopsies (0.1%). The mean age of patients was 40 years, with a range of 27-51 years. Females were more frequently affected, and none of our patients had systemic disease. The left eye was involved in five cases, and most of the lesions were located in the bulbar conjunctiva. Histopathological examination revealed a benign tumour composed of spindle-shaped and stellate-shaped cells immersed within an abundant mucinous matrix with sparse vessels and reticulin fibres. Immunohistochemistry demonstrated positivity for vimentin and negativity for smooth muscle actin, SOX10 and GLUT1 in myxoma cells of all cases. S100 was found to be positive in four cases, and muscle-specific actin in three cases. CONCLUSIONS: Conjunctival myxomas are uncommon tumours. For accurate diagnosis, histopathological examination is mandatory. The treatment of choice is surgical removal, and the prognosis is excellent. PMID- 28570007 TI - Atypical intraductal proliferation and intraductal carcinoma of the prostate on core needle biopsy: a comparative clinicopathological and molecular study with a proposal to expand the morphological spectrum of intraductal carcinoma. AB - AIMS: Atypical intraductal proliferation (AIP) of the prostate is histologically worse than high-grade prostate intraepithelial neoplasia, but lacks the diagnostic criteria of intraductal carcinoma of the prostate (IDC-P). The aim of this study was to compare the clinicopathological and molecular characteristics (ERG overexpression and PTEN loss) of AIP and IDC-P in core needle biopsies. METHODS AND RESULTS: One hundred and six [84 (5.6%) of 1480 consecutive and 22 retrospectively collected] cases met the criteria: AIP only (2.4%), IDC-P only (1.3%), and IDC-P coexisting with AIP (2%). Invasive adenocarcinoma [prostate adenocarcinoma (PCa)] was present in 96% and 97% cases of AIP and IDC-P, respectively. The mean number of glands/focus and the largest gland diameter for AIP and IDC-P were 7.6 (range, 2-27) and 11.7 (range, 1-51), and 0.59 mm (range, 0.2-1.1 mm) and 0.75 mm (range, 0.2-1.8 mm), respectively. For AIP, loose cribriform architecture was the most common (93%) morphology. IDC-P-associated PCa had more aggressive pathology, including the highest combined Gleason score (GS), high-grade GS >= 4 + 3, and largest percentage involvement of core by PCa and percentage positive cores, than AIP-associated PCa (P < 0.05). Within the AIP group, ERG status and PTEN status were similar to those of adjacent PCa in 97% and 88% of cases, respectively. Within the IDC-P group, ERG status and PTEN status were similar among IDC-P, AIP and PCa in 96% and 91% of cases, respectively. PTEN loss was frequently heterogeneous in PCa, and localized adjacent to AIP or IDC-P. CONCLUSIONS: AIP represents a lower-grade morphological spectrum of IDC-P, associated with intermediate-risk PCa. Patients with only AIP need an immediate repeat biopsy to rule out clinically significant PCa. PMID- 28570008 TI - A comparison of p53 and WT1 immunohistochemical expression patterns in tubo ovarian high-grade serous carcinoma before and after neoadjuvant chemotherapy. AB - AIMS: The treatment of patients with tubo-ovarian high-grade serous carcinoma (HGSC) is increasingly based on diagnosis on small biopsy samples, and the first surgical sample is often taken post-chemotherapy. p53 and WT1 are important diagnostic markers for HGSC. The effect of neoadjuvant chemotherapy on p53 and WT1 expression has not been widely studied. We aimed to compare p53 and WT1 expression in paired pre-chemotherapy and post-chemotherapy samples of HGSC. METHODS AND RESULTS: Immunohistochemistry (IHC) was carried out for p53 and WT1 on paired omental HGSC samples pre-chemotherapy and post-chemotherapy. p53 IHC was recorded as normal (wild-type) or abnormal (mutation-type), and was further classified as overexpression, complete absence, or cytoplasmic. WT1 IHC was classified as positive or negative. A subset of cases were further assessed for the extent of nuclear immunoreactivity of WT1 by use of the H-score. Fifty-seven paired samples were stained with p53. Fifty-six of 57 (98%) cases showed mutation type p53 staining. Pre-chemotherapy and post-chemotherapy IHC results were concordant in 55 of 57 (96%) cases. For WT1, pre-chemotherapy and post chemotherapy IHC results were concordant in 56 of 58 (97%) cases. In 23 paired WT1 cases, the mean post-treatment H-score decreased from 227 [range 20-298, standard deviation (SD) 64] to 151 (range 0-288, SD 78) (P = 0.0008). CONCLUSIONS: Immunohistochemical expression of p53 (abnormal/mutation-type pattern) and WT1 in HGSC is almost universal and is largely concordant before and after chemotherapy. This finding underscores the reliability of these diagnostic markers in small samples and in surgical samples following neoadjuvant chemotherapy, with very few exceptions. A novel finding was the significant diminution in intensity of WT1 staining following chemotherapy. PMID- 28570009 TI - Mucinous cystic neoplasms of the liver and pancreas: relationship between KRAS driver mutations and disease progression. AB - AIMS: To compare the oncogenic mutation status among mucinous cystic neoplasms (MCNs) of different histological grades and between liver and pancreatic MCNs. METHODS AND RESULTS: KRAS, GNAS, RNF43 and PIK3CA were sequenced in 25 surgical cases of hepatopancreatic MCN. Molecular features were correlated with clinicopathological and immunohistochemical findings. KRAS mutations were identified in five cases (20%), whereas GNAS, RNF43 and PIK3CA were wild-type in all cases. KRAS mutations were uncommon in cases of low-grade dysplasia (1/20, 5%), whereas KRAS was mutated in all cases of higher grades, except for one liver MCN with intermediate-grade dysplasia (4/5, 80%; P = 0.002). This genetic alteration was slightly more frequent in the pancreas than in the liver [4/17 (24%) versus 1/8 (13%), P = not significant]. KRAS-mutated MCNs more commonly had a multilocular cystic appearance (P = 0.040) and expression of mucin (MUC) 1 (P = 0.040), MUC2 (P = 0.016) and MUC5AC (P = 0.015) than KRAS-wild-type tumours. In cases of KRAS-mutated MCNs with intermediate-grade or high-grade dysplasia, identical mutations were also detected in areas of adjacent low-grade dysplasia. CONCLUSIONS: KRAS mutations appear to be major driver genetic alterations in both liver and pancreatic MCNs. As identical KRAS mutations were present in low-grade and higher-grade areas in individual cases, KRAS mutations occurring in low-grade MCNs may lead to tumour progression. Thus, preoperative KRAS testing may contribute to estimations of malignant potential. The lower incidence of KRAS mutations in liver MCNs may also explain why the risk of malignant transformation in liver MCNs is lower than that in pancreatic MCNs. PMID- 28570010 TI - Targeting microtubules in axonal re- and degeneration (Commentary on Li et al. ()). PMID- 28570012 TI - Vancomycin-Dependent Response in Live Drug-Resistant Bacteria by Metabolic Labeling. AB - The surge in drug-resistant bacterial infections threatens to overburden healthcare systems worldwide. Bacterial cell walls are essential to bacteria, thus making them unique targets for the development of antibiotics. We describe a cellular reporter to directly monitor the phenotypic switch in drug-resistant bacteria with temporal resolution. Vancomycin-resistant enterococci (VRE) escape the bactericidal action of vancomycin by chemically modifying their cell-wall precursors. A synthetic cell-wall analogue was developed to hijack the biosynthetic rewiring of drug-resistant cells in response to antibiotics. Our study provides the first in vivo VanX reporter agent that responds to cell-wall alteration in drug-resistant bacteria. Cellular reporters that reveal mechanisms related to antibiotic resistance can potentially have a significant impact on the fundamental understanding of cellular adaption to antibiotics. PMID- 28570011 TI - Effect of transcervical arterial ligation on the severity of postoperative hemorrhage after transoral robotic surgery. AB - BACKGROUND: The value of transcervical arterial ligation during transoral robotic surgery (TORS) as a measure to decrease postoperative bleeding incidence or severity is unclear. METHODS: A retrospective single institution study was performed to identify risk factors for hemorrhage after TORS for oropharyngeal squamous cell carcinoma (SCC). RESULTS: Overall, 13.2% of patients (35/265) experience postoperative hemorrhage. T classification, perioperative use of anticoagulants, surgeon experience >50 cases, and tumor subsite were not predictors of postoperative hemorrhage. Of this cohort, 28% underwent prophylactic arterial ligation. The overall incidence of bleeding was not significantly decreased in patients who underwent arterial ligation (12.1% vs 13.6%; p = .84). However, arterial ligation significantly reduced the incidence of major and severe bleeding events (1.3% vs 7.8%; p = .04). Radiation before TORS was a risk factor for major and severe postoperative hemorrhage (p < .02). CONCLUSION: Transcervical arterial ligation during TORS may reduce the severity of postoperative hemorrhagic events. (c) 2017 Wiley Periodicals, Inc. Head Neck 39: 1510-1515, 2017. PMID- 28570013 TI - Toll-like receptor 2 antagonists identified through virtual screening and experimental validation. AB - Toll-like receptor 2 (TLR2) antagonists are key therapeutic targets because they inhibit several inflammatory diseases caused by surplus TLR2 activation. In this study, we identified two novel nonpeptide TLR2 antagonists, C11 and C13, through pharmacophore-based virtual screening. At 10 MUm, the level of interleukin (IL)-8 inhibition by C13 and C11 in human embryonic kidney TLR2 overexpressing cells was comparable to the commercially available TLR2 inhibitor CU-CPT22. In addition, C11 and C13 acted in mouse macrophage-like RAW 264.7 cells as TLR2-specific inhibitors and did not suppress the tumor necrosis factor-alpha induction by TLR3 and TLR4 activators. Moreover, the two identified compounds bound directly to the human recombinant TLR2 ectodomain, during surface plasmon resonance analysis, and did not affect cell viability in a 3-(4,5-dimethylthiazol-2-yl)-5(3 carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium assay. In total, two virtually screened molecules, C11 and C13, were experimentally proven to be effective as TLR2 antagonists, and thus will provide new insights into the structure of TLR2 antagonists, and pave the way for the development of TLR2 targeted drug molecules. PMID- 28570015 TI - Genomewide patterns of variation in genetic diversity are shared among populations, species and higher-order taxa. AB - Genomewide screens of genetic variation within and between populations can reveal signatures of selection implicated in adaptation and speciation. Genomic regions with low genetic diversity and elevated differentiation reflective of locally reduced effective population sizes (Ne ) are candidates for barrier loci contributing to population divergence. Yet, such candidate genomic regions need not arise as a result of selection promoting adaptation or advancing reproductive isolation. Linked selection unrelated to lineage-specific adaptation or population divergence can generate comparable signatures. It is challenging to distinguish between these processes, particularly when diverging populations share ancestral genetic variation. In this study, we took a comparative approach using population assemblages from distant clades assessing genomic parallelism of variation in Ne . Utilizing population-level polymorphism data from 444 resequenced genomes of three avian clades spanning 50 million years of evolution, we tested whether population genetic summary statistics reflecting genomewide variation in Ne would covary among populations within clades, and importantly, also among clades where lineage sorting has been completed. All statistics including population-scaled recombination rate (rho), nucleotide diversity (pi) and measures of genetic differentiation between populations (FST , PBS, dxy ) were significantly correlated across all phylogenetic distances. Moreover, genomic regions with elevated levels of genetic differentiation were associated with inferred pericentromeric and subtelomeric regions. The phylogenetic stability of diversity landscapes and stable association with genomic features support a role of linked selection not necessarily associated with adaptation and speciation in shaping patterns of genomewide heterogeneity in genetic diversity. PMID- 28570014 TI - Metronomic treatment in immunocompetent preclinical GL261 glioblastoma: effects of cyclophosphamide and temozolomide. AB - Glioblastoma (GBM) causes poor survival in patients even when applying aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment, but resistance always ensues. In previous years, efforts have focused on new therapeutic regimens with conventional drugs to activate immune responses that may enhance tumor regression and prevent regrowth, for example the "metronomic" approaches. In metronomic scheduling studies, cyclophosphamide (CPA) in GL261 GBM growing subcutaneously in C57BL/6 mice was shown not only to activate antitumor CD8+ T-cell response, but also to induce long-term specific T cell tumor memory. Accordingly, we have evaluated whether metronomic CPA or TMZ administration could increase survival in orthotopic GL261 in C57BL/6 mice, an immunocompetent model. Longitudinal in vivo studies with CPA (140 mg/kg) or TMZ (range 140-240 mg/kg) metronomic administration (every 6 days) were performed in tumor-bearing mice. Tumor evolution was monitored at 7 T with MRI (T2 -weighted, diffusion-weighted imaging) and MRSI-based nosological images of response to therapy. Obtained results demonstrated that both treatments resulted in increased survival (38.6 +/- 21.0 days, n = 30) compared with control (19.4 +/- 2.4 days, n = 18). Best results were obtained with 140 mg/kg TMZ (treated, 44.9 +/- 29.0 days, n = 12, versus control, 19.3 +/- 2.3 days, n = 12), achieving a longer survival rate than previous group work using three cycles of TMZ therapy at 60 mg/kg (33.9 +/- 11.7 days, n = 38). Additional interesting findings were, first, clear edema appearance during chemotherapeutic treatment, second, the ability to apply the semi-supervised source analysis previously developed in our group for non-invasive TMZ therapy response monitoring to detect CPA-induced response, and third, the necropsy findings in mice cured from GBM after high TMZ cumulative dosage (980-1400 mg/kg), which demonstrated lymphoma incidence. In summary, every 6 day administration schedule of TMZ or CPA improves survival in orthotopic GL261 GBM with respect to controls or non-metronomic therapy, in partial agreement with previous work on subcutaneous GL261. PMID- 28570016 TI - Divergent taxonomic and functional responses of microbial communities to field simulation of aeolian soil erosion and deposition. AB - Aeolian soil erosion and deposition have worldwide impacts on agriculture, air quality and public health. However, ecosystem responses to soil erosion and deposition remain largely unclear in regard to microorganisms, which are the crucial drivers of biogeochemical cycles. Using integrated metagenomics technologies, we analysed microbial communities subjected to simulated soil erosion and deposition in a semiarid grassland of Inner Mongolia, China. As expected, soil total organic carbon and plant coverage were decreased by soil erosion, and soil dissolved organic carbon (DOC) was increased by soil deposition, demonstrating that field simulation was reliable. Soil microbial communities were altered (p < .039) by both soil erosion and deposition, with dramatic increase in Cyanobacteria related to increased stability in soil aggregates. amyA genes encoding alpha-amylases were specifically increased (p = .01) by soil deposition and positively correlated (p = .02) to DOC, which likely explained changes in DOC. Surprisingly, most of microbial functional genes associated with carbon, nitrogen, phosphorus and potassium cycling were decreased or unaltered by both erosion and deposition, probably arising from acceleration of organic matter mineralization. These divergent responses support the necessity to include microbial components in evaluating ecological consequences. Furthermore, Mantel tests showed strong, significant correlations between soil nutrients and functional structure but not taxonomic structure, demonstrating close relevance of microbial function traits to nutrient cycling. PMID- 28570017 TI - User Authorization at the Molecular Scale. AB - Electronic user authorization systems help us maintain our privacy in many aspects of everyday life. However, the increasing difficulty to secure access and/or information digitally has inspired chemists to devise alternative, molecular approaches, in which users are identified by chemical means. The potential advantages of using molecular user authentication systems over conventional electronic devices are their versatility and unusual operating principles, which complicate replicating and, consequently, breaking into molecular security devices. Their molecular scale is another unique property that enables hiding such systems and, consequently, applying steganography as an additional layer of protection. Although the area of molecular-based user authorization is still in its infancy, the development of various molecular keypad locks and, more recently, a password-protected molecular cryptographic machine, indicate the possibility of protecting information at the molecular scale. PMID- 28570018 TI - Surface-Modified Gold Nanoparticles Possessing Two-Channel Responsive EuIII /TbIII Cyclen Complexes as Luminescent Logic Gate Mimics. AB - The development of material-supported molecular logic gate mimics (MGLMs) for contained application and device fabrication has become of increasing interest. Herein, we present the formation of ~5 nm gold nanoparticles (AuNPs) that have been surface-modified (via a thiol linkage) with heptadentate cyclen-based complexes of europium and terbium for sensing applications using delayed lanthanide luminescence and as integrated logic gate mimics within competitive media. PMID- 28570019 TI - Clinical assessment of cryoballoon ablation in cases with atrial fibrillation and a left common pulmonary vein. AB - INTRODUCTION: Pulmonary vein isolation (PVI) using a cryoballoon (CB) is a useful tool for treating atrial fibrillation (AF); however, the clinical efficacy of the CB has never been fully investigated in patients with a left common pulmonary vein (LCPV). METHODS AND RESULTS: Three hundred twenty-four consecutive paroxysmal AF patients underwent PVI with a CB. Three-dimensional computed tomography was performed in all patients before the ablation. The clinical outcomes of the AF ablation between patients with (Group A) and without an LCPV (Group B) were compared. An LCPV was observed in 27 (8%) patients. There were no significant differences in the procedure time (149 +/- 45 min vs. 143 +/- 40 min, respectively; P = 0.42) and percentage needing touch up ablation between the 2 groups (26% vs. 20%, respectively; P = 0.45). At a mean follow-up of 454 +/- 195 days, 282 of 324 (87%) patients were free from any atrial tachyarrhythmias (ATs) after a single procedure. Twenty out of 27 (74%) Group A patients and 262 of 297 (88%) Group B patients were free from ATs (15-month Kaplan-Meier event free rate estimates, 77% and 89%, respectively; P = 0.02). A multivariate analysis identified the presence of an LCPV and the left atrial diameter as reliable predictors of recurrent ATs. CONCLUSIONS: The long-term clinical outcomes of ablation of AF with the CB was worse in patients with an LCPV than in those without. The presence of an LCPV and the LA size seemed to be reliable predictors of a worse outcome. PMID- 28570021 TI - Crack abuse-induced recalcitrant ulcers. PMID- 28570020 TI - Coordination-Driven Folding in Multi-ZnII -Porphyrin Arrays Constructed on a Pillar[5]arene Scaffold. AB - Pillar[5]arene derivatives bearing peripheral porphyrin subunits have been efficiently prepared from a deca-azide pillar[5]arene building block (17) and ZnII -porphyrin derivatives bearing a terminal alkyne function (9 and 16). For the resulting deca-ZnII -porphyrin arrays (18 and 20), variable temperature NMR studies revealed an intramolecular complexation of the peripheral ZnII -porphyrin moieties by 1,2,3-triazole subunits. As a result, the molecules adopt a folded conformation. This was further confirmed by UV/Vis spectroscopy and cyclic voltammetry. In addition, we have also demonstrated that the coordination-driven unfolding of 18 and 20 can be controlled by an external chemical stimulus. Specifically, addition of an imidazole derivative (22) to solution of 18 or 20 breaks the intramolecular coordination at the origin of the folding. The resulting molecular motions triggered by the addition of the imidazole ligand mimic the blooming of a flower. PMID- 28570022 TI - Slow antegrade excitation and delayed retrograde activation through an "inexcitable zone": A basis for arrhythmia formation in infarcted myocardium ex vivo. AB - INTRODUCTION: The electrophysiologic mechanism for rate-dependent PVBs associated with double potentials (DPs) was investigated in infarcted canine hearts using bipolar and intracellular microelectrode recordings. METHODS AND RESULTS: Dogs exhibiting rate-related ventricular ectopic beats (coupling interval, 390 +/- 54 milliseconds) during sinus rhythm or atrial pacing were studied 4-5 days (N = 63) or 25 days (N = 16) following anterior descending coronary artery ligation. Sites of DP and rate-dependent arrhythmia formation were identified in vivo using bipolar recordings for subsequent ex vivo studies. Rate-dependent conduction delays with increasing duration isoelectric intervals representing very slow conduction were observed at sites of DP formation, frequently provoking both manifest and concealed reentry (non-stimulated beats) over a narrow range of paced cycle lengths. Both slow antegrade and retrograde activation across an inexcitable gap (reflection) were integral components of extrasystole formation. Retrograde reflection to a region of very slow conduction (mid-potential) during antegrade activation was routinely observed at 4-5 days (42 of 63 preparations, 67%) and 25 days (22 of 26 preparations, 85%) postcoronary artery ligation. Reflection and premature re-activation of the proximal site was then observed in 6 of 63 (9%), and 3 of 26 preparations (12%). CONCLUSION: The present experiments demonstrate DP formation and rate-dependent constant-coupled late epicardial premature beats in infarcted dog hearts. Microelectrode recordings at DP sites demonstrating prolonged isoelectric intervals display very slow conduction preceding distal activation and "reentrant" re-activation of more proximal sites, representing reflection as an arrhythmia mechanism in ischemically injured epicardium during subacute myocardial infarction. PMID- 28570024 TI - Direct and indirect effects of attention and visual function on gait impairment in Parkinson's disease: influence of task and turning (Commentary on Stuart et al. (2017)). PMID- 28570023 TI - Strength, toughness, and reliability of a porous glass/biopolymer composite scaffold. AB - Development of bioactive glass and ceramic scaffolds intended for the reconstruction of large segmental bone defects remains a challenge for materials science due to the complexities involved in clinical implantation, bone-implant reaction, implant degradation and the multiple loading modes the implants subjected to. A comprehensive evaluation of the mechanical properties of inorganic scaffolds and exploration of new ways to toughen brittle constructs are critical prior to their successful application in loaded sites. A simple and widely adopted approach involves the coating of an inorganic scaffold with a polymeric material. In this work, a systematic evaluation of the influence of a biopolymer, polycaprolactone (PCL), coating on the mechanical performance of bioactive glass scaffolds was carried out. Results from this work indicate that a biopolymer PCL coating was more effective in increasing the compressive strength and reliability of the glass scaffold under compression, but less effective in improving its flexural strength or fracture toughness. This is the first report that reveals the limited successfulness of a polymer coating in improving the toughness of strong scaffolds, suggesting that new and novel ways of toughening inorganic scaffolds should be future research directions for scaffolds applied in loaded sites. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1209-1217, 2018. PMID- 28570025 TI - Unraveling the Nature of Sites Active toward Hydrogen Peroxide Reduction in Fe-N C Catalysts. AB - Fe-N-C catalysts with high O2 reduction performance are crucial for displacing Pt in low-temperature fuel cells. However, insufficient understanding of which reaction steps are catalyzed by what sites limits their progress. The nature of sites were investigated that are active toward H2 O2 reduction, a key intermediate during indirect O2 reduction and a source of deactivation in fuel cells. Catalysts comprising different relative contents of FeNx Cy moieties and Fe particles encapsulated in N-doped carbon layers (0-100 %) show that both types of sites are active, although moderately, toward H2 O2 reduction. In contrast, N doped carbons free of Fe and Fe particles exposed to the electrolyte are inactive. When catalyzing the ORR, FeNx Cy moieties are more selective than Fe particles encapsulated in N-doped carbon. These novel insights offer rational approaches for more selective and therefore more durable Fe-N-C catalysts. PMID- 28570026 TI - Purpuric macules and plaques in a patient with myasthenia gravis. PMID- 28570027 TI - Structure-Activity Relationship Studies on 6,7-Dimethoxy-2-phenethyl-1,2,3,4 tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers. AB - A series of derivatives were synthesized and studied with the aim to investigate the structure-activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar. Then, different aryl-substituted amides were inserted, and to explore the effects of varying the amide function, the corresponding isosteric ester derivatives and some alkylamine analogues were synthesized. The new compounds were studied to evaluate their P-gp interaction profile and selectivity toward the two other ABC transporters, multidrug-resistance associated protein-1 (MRP-1) and breast cancer resistance protein (BCRP). Investigation of the chemical stability of the amide and ester derivatives toward spontaneous or enzymatic hydrolysis showed that these compounds were stable in phosphate-buffered saline and human plasma. This study allowed us to evaluate the selectivity of the three series on the three efflux pumps and to propose the structural requirements that define the P-gp interaction profile. We identified two P-gp substrates, a P-gp inhibitor, and three ester derivatives that were active on BCRP, which opens a new scenario in the development of ligands active toward this pump. PMID- 28570029 TI - Plasticity contributes to a fine-scale depth gradient in sticklebacks' visual system. AB - The light environment influences an animal's ability to forage, evade predators, and find mates, and consequently is known to drive local adaptation of visual systems. However, the light environment may also vary over fine spatial scales at which genetic adaptation is difficult. For instance, in aquatic systems, the available wavelengths of light change over a few metres depth. Do animals plastically adjust their visual system to such small-scale environmental light variation? Here, we show that in three-spine stickleback (Gasterosteus aculeatus), opsin gene expression (an important determinant of colour vision) changes over a 2-m vertical gradient in nest depth. By experimentally altering the light environment using light filters to cover enclosures in a lake, we found that opsin expression can be adjusted on a short time frame (weeks) in response to the local light environment. This is to our knowledge the smallest spatial scale on which visual adjustments through opsin expression have been recorded in a natural setting along a continuously changing light environment. PMID- 28570030 TI - Swearing and verbal aggression in China: A call to action. PMID- 28570028 TI - Transthyretin stability is critical in assisting beta amyloid clearance- Relevance of transthyretin stabilization in Alzheimer's disease. AB - BACKGROUND: The absence of transthyretin (TTR) in AD mice decreases brain Abeta clearance and reduces the low-density lipoprotein receptor-related protein 1 (LRP1). It is possible that neuroprotection by TTR is dependent on its tetramer structural stability, as studies using TTR mutants showed that unstable L55P TTR has low affinity for Abeta, and TTR tetrameric stabilizers such as iododiflunisal ameliorate AD features in vivo. METHODS: We firstly investigated TTR folding status in human plasma measuring the resistance to urea denaturation. The importance of TTR stability on Abeta internalization was studied in human cerebral microvascular endothelial (hCMEC/D3) and hepatoma cells (HepG2), by flow cytometry. To investigate the fate of Abeta at the blood-brain barrier, Abeta efflux from hCMEC/D3 cells seeded on transwells was measured using ELISA. Further, to assess Abeta colocalization with lysosomes, Lysotracker was used. Moreover, levels of LRP1 were assessed in the liver and plasma of mice with different TTR backgrounds or treated with iododiflunisal. RESULTS: We showed that TTR stability is decreased in AD and that WT TTR and drug-stabilized L55P TTR are able to increase uptake of Abeta. Furthermore, measurement of Abeta efflux showed that stable or stabilized TTR increased Abeta efflux from the basolateral to the apical side. Moreover, HepG2 cells incubated with Abeta in the presence of WT TTR, but not L55P TTR, showed an increased number of lysosomes. Further, in the presence of WT TTR, Abeta peptide colocalized with lysosomes, indicating that only stable TTR assists Abeta internalization, leading to its degradation. Finally, we demonstrated that only stable TTR can increase LRP1 levels. CONCLUSION: TTR stabilization exerts a positive effect on Abeta clearance and LRP1 levels, suggesting that TTR protective role in AD is dependent on its stability. These results provide relevant information for the design of TTR-based therapeutic strategies for AD. PMID- 28570031 TI - Evolution of sociality in spiders leads to depleted genomic diversity at both population and species levels. AB - Across several animal taxa, the evolution of sociality involves a suite of characteristics, a "social syndrome," that includes cooperative breeding, reproductive skew, primary female-biased sex ratio, and the transition from outcrossing to inbreeding mating system, factors that are expected to reduce effective population size (Ne). This social syndrome may be favoured by short term benefits but come with long-term costs, because the reduction in Ne amplifies loss of genetic diversity by genetic drift, ultimately restricting the potential of populations to respond to environmental change. To investigate the consequences of this social life form on genetic diversity, we used a comparative RAD-sequencing approach to estimate genomewide diversity in spider species that differ in level of sociality, reproductive skew and mating system. We analysed multiple populations of three independent sister-species pairs of social inbreeding and subsocial outcrossing Stegodyphus spiders, and a subsocial outgroup. Heterozygosity and within-population diversity were sixfold to 10-fold lower in social compared to subsocial species, and demographic modelling revealed a tenfold reduction in Ne of social populations. Species-wide genetic diversity depends on population divergence and the viability of genetic lineages. Population genomic patterns were consistent with high lineage turnover, which homogenizes the genetic structure that builds up between inbreeding populations, ultimately depleting genetic diversity at the species level. Indeed, species-wide genetic diversity of social species was 5-8 times lower than that of subsocial species. The repeated evolution of species with this social syndrome is associated with severe loss of genomewide diversity, likely to limit their evolutionary potential. PMID- 28570032 TI - Free-breathing pediatric chest MRI: Performance of self-navigated golden-angle ordered conical ultrashort echo time acquisition. AB - PURPOSE: To assess the feasibility and performance of conical k-space trajectory free-breathing ultrashort echo time (UTE) chest magnetic resonance imaging (MRI) versus four-dimensional (4D) flow and effects of 50% data subsampling and soft gated motion correction. MATERIALS AND METHODS: Thirty-two consecutive children who underwent both 4D flow and UTE ferumoxytol-enhanced chest MR (mean age: 5.4 years, range: 6 days to 15.7 years) in one 3T exam were recruited. From UTE k space data, three image sets were reconstructed: 1) one with all data, 2) one using the first 50% of data, and 3) a final set with soft-gating motion correction, leveraging the signal magnitude immediately after each excitation. Two radiologists in blinded fashion independently scored image quality of anatomical landmarks on a 5-point scale. Ratings were compared using Wilcoxon rank-sum, Wilcoxon signed-ranks, and Kruskal-Wallis tests. Interobserver agreement was assessed with the intraclass correlation coefficient (ICC). RESULTS: For fully sampled UTE, mean scores for all structures were >=4 (good excellent). Full UTE surpassed 4D flow for lungs and airways (P < 0.001), with similar pulmonary artery (PA) quality (P = 0.62). 50% subsampling only slightly degraded all landmarks (P < 0.001), as did motion correction. Subsegmental PA visualization was possible in >93% scans for all techniques (P = 0.27). Interobserver agreement was excellent for combined scores (ICC = 0.83). CONCLUSION: High-quality free-breathing conical UTE chest MR is feasible, surpassing 4D flow for lungs and airways, with equivalent PA visualization. Data subsampling only mildly degraded images, favoring lesser scan times. Soft-gating motion correction overall did not improve image quality. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:200-209. PMID- 28570034 TI - Risk factors for vertical transmission of hepatitis E virus infection. AB - Hepatitis E virus (HEV) infection can be vertically transmitted, but the factors that transmit the disease to foetuses are still unclear. We studied a total of 144 pregnant women with HEV infection. Cord blood and newborn samples were taken for analysis. Nutritional factors were evaluated on the basis of anthropometric parameters and biochemical factors, and HEV viral load was quantified by real time PCR. Sequencing of HEV-positive samples was performed. Approximately 14.63% (6/41) of pregnant patients with acute liver failure (ALF) died before delivery. Vertical transmission was observed in 46.09% (59/128) of HEV-IgM-positive mothers. Approximately 23.80% (10/42) of newborns in the acute viral hepatitis group and 29.41% (5/17) in the ALF group were positive for HEV-RNA. No significant difference was observed in the occurrence of vertical transmission in HEV groups. Viral load was found to be a significant predictor for vertical transmission of HEV infection adjusted with haemoglobin and folate in derivation cohort group. Incorporating these variables, a new score predicting vertical transmission of HEV was derived. Using these significant predictors, the probability for vertical transmission of HEV was well stratified in the validation group (P>.05). In conclusion, viral load was associated with vertical transmission of HEV infection. A valid prediction score model was generated that was verified in a validation cohort group. PMID- 28570037 TI - Families with Young Children in California: Findings from the California Health Interview Survey, 2011-2014, by Geography and Home Language. AB - Using data from the California Health Interview Survey (CHIS) for the years 2011 2014, this report presents findings on families with children ages 0-5 years. It breaks down differences between urban, suburban, and rural families, and it highlights the characteristics of families who speak a language other than English in the home. As more than half of families with young children in California speak a language other than English in the home, the characteristics of dual language households are highlighted. In 1998, California passed the California Children and Families Act to improve development for children from the prenatal stage to five years of age. One goal of this ongoing commitment is to expand our understanding of the social and physical environments that can impact a child's well-being and school readiness. PMID- 28570033 TI - Quantitative MRI and spectroscopy of bone marrow. AB - : Bone marrow is one of the largest organs in the human body, enclosing adipocytes, hematopoietic stem cells, which are responsible for blood cell production, and mesenchymal stem cells, which are responsible for the production of adipocytes and bone cells. Magnetic resonance imaging (MRI) is the ideal imaging modality to monitor bone marrow changes in healthy and pathological states, thanks to its inherent rich soft-tissue contrast. Quantitative bone marrow MRI and magnetic resonance spectroscopy (MRS) techniques have been also developed in order to quantify changes in bone marrow water-fat composition, cellularity and perfusion in different pathologies, and to assist in understanding the role of bone marrow in the pathophysiology of systemic diseases (e.g. osteoporosis). The present review summarizes a large selection of studies published until March 2017 in proton-based quantitative MRI and MRS of bone marrow. Some basic knowledge about bone marrow anatomy and physiology is first reviewed. The most important technical aspects of quantitative MR methods measuring bone marrow water-fat composition, fatty acid composition, perfusion, and diffusion are then described. Finally, previous MR studies are reviewed on the application of quantitative MR techniques in both healthy aging and diseased bone marrow affected by osteoporosis, fractures, metabolic diseases, multiple myeloma, and bone metastases. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:332-353. PMID- 28570038 TI - Molecular detecting of piroplasms in feeding and questing Ixodes ricinus ticks AB - The purpose of this study was to detect piroplasms, which are pathogens of veterinary and zoonotic importance in ticks, that were collected from ponies and field vegetation and to determine the role of Shetland ponies as potential reservoir hosts for piroplasms. A total of 1737 feeding and 371 questing Ixodes ricinus collected from horses or vegetation were tested for the presence of Babesia and Theileria DNA. Piroplasm 18S rRNA gene amplification was conducted, and the obtained amplicons were sequenced. Babesia DNA was detected in only three ticks (one tick collected from a pony and two collected from vegetation), and all of the obtained sequences had 100% similarity to B. divergens. Theileria DNA was not present in the examined ticks. Thus, the above results indicate that ponies are probably not essential hosts for the detected species of piroplasms. Piroplasm species typical for horses (Babesia caballi and Theileria equi) were not detected because I. ricinus is not their vector. The low infection rate of I. ricinus with B. divergens shows that the disease risk for the local horse population and people associated with pony horses is low, but it demonstrates their possible role as a source of human infection in northern Poland. PMID- 28570035 TI - Metabolic rewiring in mutant Kras lung cancer. AB - Lung cancer is the leading cause of cancer-related death worldwide, reflecting an unfortunate combination of very high prevalence and low survival rates, as most cases are diagnosed at advanced stages when treatment efficacy is limited. Lung cancer comprises several disease groups with non small cell lung cancer (NSCLC) accounting for ~ 85% of cases and lung adenocarcinoma being its most frequent histological subtype. Mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) affect ~ 30% of lung adenocarcinomas but unlike other commonly altered proteins (EGFR and ALK, affected in ~ 14% and 7% of cases respectively), mutant KRAS remains untargetable. Therapeutic strategies that rely instead on the inhibition of mutant KRAS functional output or the targeting of mutant KRAS cellular dependencies (i.e. synthetic lethality) are an appealing alternative approach. Recent studies focused on the metabolic properties of mutant KRAS lung tumours have uncovered unique metabolic features that can potentially be exploited therapeutically. We review these findings here with a particular focus on in vivo, physiologic, mutant KRAS activity. PMID- 28570039 TI - Salt-Responsive Bilayer Hydrogels with Pseudo-Double-Network Structure Actuated by Polyelectrolyte and Antipolyelectrolyte Effects. AB - Development of stimuli-responsive, shape-transformable materials is fundamentally and practically important for smart actuators. Herein, we design and synthesize a bilayer hydrogel by assembling a polycationic (polyMETAC/HEAA) layer with polyelectrolyte effect and a polyzwitterionic (polyVBIPS) layer with antipolyelectrolyte effect together. The bilayer hydrogels adopt a pseudo-double network structure, and both polyelectrolyte and polyzwitterionic layers have salt responsive swelling and shrinkage properties, but in a completely opposite way. The resulting polyMETAC/HEAA-polyVBIPS bilayer hydrogels exhibit bidirectional bending in response to salt solutions, salt concentrations, and counterion types. Such bidirectional bending of this bilayer hydrogel is fully reversible and triggered between salt solution and pure water multiple times. The bending orientation and degree of the bilayer hydrogel is driven by the opposite volume changes between the volume shrinking (swelling) of polyMETAC/HEAA layer and the volume swelling (shrinking) of polyVBIPS layer. Such cooperative, not competitive, salt-responsive swelling-shrinking properties of the two layers are contributed to by the polyelectrolyte and antipolyelectrolyte effects from the respective layers. Moreover, an eight-arm gripper made of this bilayer hydrogel is fabricated and demonstrates its ability to grasp an object in salt solution and release the object in water. This work provides a new shape-regulated, stimuli-responsive asymmetric hydrogel for actuator-based applications. PMID- 28570040 TI - Self-Assembly of Mesoscopic Peptide Surfactant Fibrils Investigated by STORM Super-Resolution Fluorescence Microscopy. AB - Super-resolution fluorescence microscopy, specifically stochastic reconstruction microscopy (STORM), and atomic force microscopy (AFM) were used to image the self assembly processes of the peptide surfactant I3K. The peptide surfactants self assembled into giant helical fibrils with diameters between 5 and 10 nm with significant helical twisting. The resolution of the STORM images was 30 nm, calculated using the Fourier ring correlation method. STORM compares favorably with AFM for the calculation of contour lengths (~6 MUm) and persistence lengths (10.1 +/- 1.2 MUm) due to its increased field of view (50 MUm), and its ability to image bulk morphologies away from surfaces under ambient solution conditions. Two-color STORM experiments were performed to investigate the dynamic process of self-assembly after mixing of two separately labeled samples, and the results revealed the formation of long nanofibers via end-to-end connections of short ones. No evidence was found for significant monomer exchange between the samples, and the self-assembled structures were very stable and long-lived. PMID- 28570041 TI - Prussian Blue Analogue with Fast Kinetics Through Electronic Coupling for Sodium Ion Batteries. AB - Alternative battery systems based on the chemistry of sodium are being considered to offer sustainability and cost-effectiveness. Herein, a simple and new method is demonstrated to enable nickel hexacyanoferrate (NiHCF) Prussian blue analogues (PBA) nanocrystals to be an excellent host for sodium ion storage by functionalization with redox guest molecule. The method is achieved by using NiHCF PBA powders infiltrated with the 7,7,8,8-tetracyanoquinododimethane (TCNQ) solution. Experimental and ab initio calculations results suggest that TCNQ molecule bridging with Fe atoms in NiHCF Prussian blue analogue leads to electronic coupling between TCNQ molecules and NiHCF open-framework, which functions as an electrical highway for electron motion and conductivity enhancement. Combining the merits including high electronic conductivity, open framework structure, nanocrystal, and interconnected mesopores, the NiHCF/TCNQ shows high specific capacity, fast kinetics and good cycling stability, delivering a high specific capacity of 35 mAh g-1 after 2000 cycles, corresponding a capacity loss of 0.035% decay per cycle. PMID- 28570042 TI - Anchoring Iodine to N-Doped Hollow Carbon Fold-Hemisphere: Toward a Fast and Stable Cathode for Rechargeable Lithium-Iodine Batteries. AB - Rechargeable lithium-iodine batteries with abundant raw materials and low cost are promising electrochemical energy storage systems. Herein, we demonstrate that anchoring iodine to N-doped hollow carbon fold-hemisphere (N-FHS) is highly efficient to overcome slow kinetics and low stability of iodine cathode in lithium-iodine batteries. For the first time, significant effects of carbon framework architecture on the lithium storage performance of iodine cathode are studied in detail. Notably, the fold-hemisphere (N-FHS) is more effective than the similar architectures, such as hollow sphere (N-S) or hemisphere (N-HS), in modifying slow ion transport capability and fast structure deterioration. The superior property of iodine@N-FHS is associated with its highly porous structure and strong interconnection to iodine. The iodine deterioration mechanism in lithium-iodine battery is analyzed, and the deterioration processes of iodine in different carbon frameworks during cycling are investigated. This work opens a new avenue to solve the key problems in lithium-iodine batteries, allowing it an important candidate for energy storage. PMID- 28570043 TI - Fabrication of Polymeric Micelles with Aggregation-Induced Emission and Forster Resonance Energy Transfer for Anticancer Drug Delivery. AB - With the aim of obtaining effective cancer therapy with simultaneous cellular imaging, dynamic drug-release monitoring, and chemotherapeutic treatment, a polymeric micelle with aggregation-induced emission (AIE) imaging and a Forster resonance energy transfer (FRET) effect was fabricated as the drug carrier. An amphiphilic conjugate of 1H-pyrrole-1-propanoicacid (MAL)-poly(ethylene glycol) (PEG)-Tripp-bearing AIE molecules were synthesized and self-assembled into micelles to load the anticancer drug doxorubicin (DOX). Spherical DOX-loaded micelles with the mean size of 106 nm were obtained with good physiological stability (CMC, 12.5 MUg/mL), high drug-loading capacity (10.4%), and encapsulation efficiency (86%). The cellular uptake behavior of DOX-loaded MAL PEG-Tripp micelles was visible for high-quality intracellular imaging due to the AIE property. The delivery of DOX from the drug-loaded micelles was dynamic monitored by the FRET effect between the DOX and MAL-PEG-Tripp. Both in vitro (IC50, 2.36 MUg/mL) and in vivo anticancer activity tests revealed that the DOX loaded MAL-PEG-Tripp micelles exhibited promising therapeutic efficacy to cancer with low systematic toxicity. In summary, this micelle provided an effective way to fabricate novel nanoplatform for intracellular imaging, drug-delivery tracing, and chemotherapy. PMID- 28570044 TI - Control Synthesis of Tubular Hyper-Cross-Linked Polymers for Highly Porous Carbon Nanotubes. AB - Porous carbon nanotubes (PCNTs) have attracted considerable attention due to their large specific surface areas and unique one-dimensional (1D) structures. However, most of the reported synthetic strategies for PCNTs are complex and expensive. Herein, we present a self-templated, surfactant-free strategy for the synthesis of high-quality PCNTs with high surface area by direct carbonization of 1D hyper-cross-linked polymer nanotubes. The precursors of the 1D hyper-cross linked polymer nanotubes were synthesized by FeCl3 catalyzed Friedel-Crafts alkylation of aromatic hydrocarbons with formaldehyde dimethyl acetal. It was found that the monomer concentration and mechanical agitation play crucial roles in the formation of the 1D tubular hyper-cross-linked polymer precursor. The tube size of the resulting PCNTs could be finely controlled by the aromatic monomers with different molecular sizes. The excellent electrochemical performances of the supercapacitors fabricated from the PCNTs demonstrate that these PCNTs are promising for the electrode materials of high-performance supercapacitors. This work highlights that the facile synthetic strategy for PCNTs would open up new avenues of porous carbon nanotube materials with promising applications. PMID- 28570045 TI - Characterization of DNA Binding by the Isolated N-Terminal Domain of Vaccinia Virus DNA Topoisomerase IB. AB - Vaccinia TopIB (vTopIB), a 314-amino acid eukaryal-type IB topoisomerase, recognizes and transesterifies at the DNA sequence 5'-(T/C)CCTT?, leading to the formation of a covalent DNA-(3'-phosphotyrosyl274)-enzyme intermediate in the supercoil relaxation reaction. The C-terminal segment of vTopIB (amino acids 81 314), which engages the DNA minor groove at the scissile phosphodiester, comprises an autonomous catalytic domain that retains cleavage specificity, albeit with a cleavage site affinity lower than that of the full-length enzyme. The N-terminal domain (amino acids 1-80) engages the major groove on the DNA face opposite the scissile phosphodiester. Whereas DNA contacts of the N-terminal domain have been implicated in the DNA site affinity of vTopIB, it was not known whether the N-terminal domain per se could bind DNA. Here, using isothermal titration calorimetry, we demonstrate the ability of the isolated N-terminal domain to bind a CCCTT-containing 24-mer duplex with an apparent affinity that is ~2.2-fold higher than that for an otherwise identical duplex in which the pentapyrimidine sequence is changed to ACGTG. Analyses of the interactions of the isolated N-terminal domain with duplex DNA via solution nuclear magnetic resonance methods are consistent with its DNA contacts observed in DNA-bound crystal structures of full-length vTopIB. The chemical shift perturbations and changes in hydrodynamic properties triggered by CCCTT DNA versus non-CCCTT DNA suggest differences in DNA binding dynamics. The importance of key N-terminal domain contacts in the context of full-length vTopIB is underscored by assessing the effects of double-alanine mutations on DNA transesterification and its sensitivity to ionic strength. PMID- 28570046 TI - Novel Green Luminescent and Phosphorescent Material: Semiconductive Nanoporous ZnMnO with Photon Confinement. AB - A novel green luminescent and phosphorescent material of semiconductive nanoporous ZnMnO was synthesized by the thermal nucleation of nanopores in the 20 period Zn0.93Mn0.07O/Zn0.65Mn0.35O multilayer structure. Nanoporous ZnMnO showed an n-type semiconducting property and exhibited an extremely strong green light emission in its luminescence and phosphorescence characteristics. This arises from the formation of the localized energy level (i.e., green emission band) within the energy band gap and the confinement of photons. The results suggest nanoporous ZnMnO to have a great potential for the new type of semiconducting green phosphors and semiconductor light-emitting diodes with lower thresholds, producing an efficient light emission. In-depth analyses on the structural, electrical, and optical properties are thoroughly examined, and the formation mechanism of nanoporous ZnMnO and the origin of the strong green light emission are discussed. PMID- 28570047 TI - Scaling Proteome-Wide Reactions of Activity-Based Probes. AB - Unified analysis of complex reactions of an activity-based probe with proteins in a proteome remains an unsolved challenge. We propose a power expression, rate = kobs[Probe]alpha, for scaling the progress of proteome-wide reactions and use the scaling factor (0 <= alpha <= 1) as an apparent, partial order with respect to the probe to measure the "enzyme-likeness" for a protein in reaction acceleration. Thus, alpha reports the intrinsic reactivity of the protein with the probe. When alpha = 0, the involved protein expedites the reaction to the maximal degree; when alpha = 1, the protein reacts with the probe via an unaccelerated, bimolecular reaction. The selectivity (beta) of the probe reacting with two proteins is calculated as a ratio of conversion factors (kobs values) for corresponding power equations. A combination of alpha and beta provides a tiered system for quantitatively assessing the probe efficacy; an ideal probe exhibits high reactivity with its protein targets (low in alpha) and is highly selective (high in beta) in forming the probe-protein adducts. The scaling analysis was demonstrated using proteome-wide reactions of HT-29 cell lysates with a model probe of threonine beta-lactone. PMID- 28570048 TI - Aerosol Mass Spectrometer for Simultaneous Detection of Polyaromatic Hydrocarbons and Inorganic Components from Individual Particles. AB - Online studies of single airborne particles represent a demanding challenge in aerosol chemistry. New technologies that help to unravel the role of ambient aerosols in earth climate and to assess local and specific health risks from air pollution are highly desired. Of particular relevance are polycyclic aromatic hydrocarbons (PAHs) from combustion processes that are associated with both acute and long-term health effects. Usually, online single particle analyses apply laser desorption/ionization (LDI) in a bipolar mass spectrometer, revealing elemental constituents and limited molecular information by detection of both positive and negative ions. Approaches for the detection of PAHs from single particles have been developed but the elemental information from LDI that allows particle classification and source apportionment is lost in that case. Here we present a novel laser desorption and ionization method delivering both the PAH profile and the inorganic composition from the same, individual particle. Test measurements demonstrate the technique's capability to reveal the single-particle PAH-distribution in aerosols (mixing state) and its assignment to specific pollution sources in a new and direct way. PMID- 28570049 TI - Titanium Sulfides as Intercalation-Type Cathode Materials for Rechargeable Aluminum Batteries. AB - We report the electrochemical intercalation-extraction of aluminum (Al) in the layered TiS2 and spinel-based cubic Cu0.31Ti2S4 as the potential cathode materials for rechargeable Al-ion batteries. The electrochemical characterizations demonstrate the feasibility of reversible Al intercalation in both titanium sulfides with layered TiS2 showing better properties. The crystallographic study sheds light on the possible Al intercalation sites in the titanium sulfides, while the results from galvanostatic intermittent titration indicate that the low Al3+ diffusion coefficients in the sulfide crystal structures are the primary obstacle to facile Al intercalation-extraction. PMID- 28570050 TI - Conductivity Optimization of Tysonite-type La1-xBaxF3-x Solid Electrolytes for Advanced Fluoride Ion Battery. AB - Use of lithium ion batteries is currently the method of choice when it comes to local stationary storage of electrical energy. In the search for an alternative system, fluoride ion batteries (FIBs) emerge as a candidate due to their high theoretical capacity, and no lithium is needed for its operation. To improve the cycling performance and lower the working temperature of a solid-state battery, one of the critical components is the electrolyte, which needs advanced performance. This paper aims at developing an electrolyte with enhanced ionic conductivity for fluoride ions, to be used in a FIB. Tysonite La1-xBaxF3-x (0 <= x <= 0.15) solid solutions were synthesized by a facile wet chemical method, and its ionic conductivity was analyzed using electrochemical impedance spectroscopy. A composition study shows that the conductivity reaches a maximum of 1.26 * 10-4 S.cm-1 at 60 degrees C for the La0.95Ba0.05F2.95 pellet sintered at 800 degrees C for 20 h, which is 1 order of magnitude higher than that for the as-prepared pellet and 2 times higher than the conductivity of sintered ball-milled batches. The reason for this dramatic increment is the more efficient decrement of grain boundary resistance upon sintering. Morphological, chemical, and structural characterizations of solid electrolytes were studied by X-ray diffraction, scanning electron microscopy , energy dispersive X-ray spectroscopy, physisorption by the Brunauer-Emmett-Teller method, and transmission electron microscopy. Electrochemical testing was carried out for the FIB cell using La0.95Ba0.05F2.95 as electrolyte due to its highest conductivity among the compositions, Ce as anode, and BiF3 as a cathode. The cycling performance was found to be considerably improved when compared to our earlier work, which used the ball-milled electrolyte. PMID- 28570051 TI - Cellulose Fibers Constructed Convenient Recyclable 3D Graphene-Formicary-like delta-Bi2O3 Aerogels for the Selective Capture of Iodide. AB - Radioiodine is highly radioactive and acutely toxic, which can be a serious health threat, and requires effective control. To fully utilize an adsorbent and reduce the overall production cost, successive recycling applications become necessary. Here, 3D formicary-like delta-Bi2O3 (FL-delta-Bi2O3) aerogel adsorbents were synthesized using a one-pot hydrothermal method. In this hybrid structure, abundant flowerlike delta-Bi2O3 (MR-delta-Bi2O3) microspheres were inlaid into the interconnected ant nest channel, forming a 3D hierarchical structure, which is applied as an efficient adsorbent with easy recovery for radioiodine removal. Notably, the FL-delta-Bi2O3 aerogel adsorbent exhibited a very high uptake capacity of 2.04 mmol/g by forming an insoluble Bi4I2O5 phase. Moreover, the FL-delta-Bi2O3 worked in a wide pH range of 4-10 and displayed fast uptake kinetics and excellent selectivity due to the 3D porous interconnected network and larger specific surface area. Importantly, the recycling process is easy, using only tweezers to directly move the 3D aerogel adsorbents from one reaction system to another. Therefore, the FL-delta-Bi2O3 aerogel may be a promising practical adsorbent for the selective capture of radioactive iodide. PMID- 28570052 TI - MoS2-Nanosheet-Assisted Coordination of Metal Ions with Porphyrin for Rapid Detection and Removal of Cadmium Ions in Aqueous Media. AB - Molybdenum disulfide (MoS2) is a two-dimensional (2D) graphene-like material that is gaining great attention because of its potential application in various fields. Here, we reported a self-assembled nanocomposite consisted of MoS2 nanosheets and 5,10,15,20-tetrakis(1-methyl-4-pyridinio)porphyrintetra(p toluenesulfonate) (TMPyP), named MoS2@TMPyP. This nanocomposite can be used as a sensing probe for low cost, rapid, selective detection of cadmium (Cd2+) ions. It is found that a new Soret band at 442 nm in UV-vis absorption spectra represented the coordination of Cd2+ ions into TMPyP of the MoS2@TMPyP. The coordination rates between TMPyP and Cd2+ ions is greatly accelerated from 72 h to 20 min with the assistance of MoS2, which is 200 times faster than in the absence of MoS2. The limit of detection (LOD) of the Cd2+ is as low as 7.2 * 10-8 mol/L. The binding behavior between the cationic TMPyP and MoS2 nanosheets was corroborated by molecular dynamics simulation and various control experiments. The results demonstrated that electrostatic interaction was the main force for driving TMPyP enriching around the MoS2 surface, resulting in an accelerated complexation of Cd2+ and TMPyP. Moreover, MoS2@TMPyP nanocomposite can also be used for removing of Cd2+ in water. The removal efficiency (RF) of the MoS2@TMPyP can reach to 91% for high concentrations of Cd2+. This work provides a new insight into detection and removal of Cd2+ ions in water. PMID- 28570053 TI - Correlative Analysis of Fluorescent Phytoalexins by Mass Spectrometry Imaging and Fluorescence Microscopy in Grapevine Leaves. AB - Plant response to their environment stresses is a complex mechanism involving secondary metabolites. Stilbene phytoalexins, namely resveratrol, pterostilbene, piceids and viniferins play a key role in grapevine (Vitis vinifera) leaf defense. Despite their well-established qualities, conventional analyses such as HPLC-DAD or LC-MS lose valuable information on metabolite localization during the extraction process. To overcome this issue, a correlative analysis combining mass spectroscopy imaging (MSI) and fluorescence imaging was developed to localize in situ stilbenes on the same stressed grapevine leaves. High-resolution images of the stilbene fluorescence provided by macroscopy were supplemented by specific distributions and structural information concerning resveratrol, pterostilbene, and piceids obtained by MSI. The two imaging techniques led to consistent and complementary data on the stilbene spatial distribution for the two stresses addressed: UV-C irradiation and infection by Plasmopara viticola. Results emphasize that grapevine leaves react differently depending on the stress. A rather uniform synthesis of stilbenes is induced after UV-C irradiation, whereas a more localized synthesis of stilbenes in stomata guard cells and cell walls is induced by P. viticola infection. Finally, this combined imaging approach could be extended to map phytoalexins of various plant tissues with resolution approaching the cellular level. PMID- 28570055 TI - Metamorphic Proteins: Emergence of Dual Protein Folds from One Primary Sequence. AB - Every amino acid exhibits a different propensity for distinct structural conformations. Hence, decoding how the primary amino acid sequence undergoes the transition to a defined secondary structure and its final three-dimensional fold is presently considered predictable with reasonable certainty. However, protein sequences that defy the first principles of secondary structure prediction (they attain two different folds) have recently been discovered. Such proteins, aptly named metamorphic proteins, decrease the conformational constraint by increasing flexibility in the secondary structure and thereby result in efficient functionality. In this review, we discuss the major factors driving the conformational switch related both to protein sequence and to structure using illustrative examples. We discuss the concept of an evolutionary transition in sequence and structure, the functional impact of the tertiary fold, and the pressure of intrinsic and external factors that give rise to metamorphic proteins. We mainly focus on the major components of protein architecture, namely, the alpha-helix and beta-sheet segments, which are involved in conformational switching within the same or highly similar sequences. These chameleonic sequences are widespread in both cytosolic and membrane proteins, and these folds are equally important for protein structure and function. We discuss the implications of metamorphic proteins and chameleonic peptide sequences in de novo peptide design. PMID- 28570056 TI - Intensity-Independent Noise Filtering in FT MS and FT MS/MS Spectra for Shotgun Lipidomics. AB - Shotgun lipidomics relies on the direct infusion of total lipid extracts into a high resolution tandem mass spectrometer. A single shotgun analysis produces several hundred of densely populated FT MS and FT MS/MS spectra, each of which might comprise thousands of peaks although a very small percentage of those belong to lipids. Eliminating noise by adjusting a minimal peak intensity threshold is biased and inefficient since lipid species and classes vary in their natural abundance and ionization capacity. We developed a method of peak intensity-independent noise filtering in shotgun FT MS and FT MS/MS spectra that capitalizes on a stable composition of the infused analyte leading to consistent time-independent detection of its bona fide components. Repetition rate filtering relies on a single quantitative measure of peaks detection reproducibility irrespectively of their absolute intensities, masses, or assumed elemental compositions. In comparative experiments, it removed more than 95% of signals detectable in shotgun spectra without compromising the accuracy and scope of lipid identification and quantification. It also accelerated spectra processing by 15-fold and increased the number of simultaneously processed spectra by ~500 fold hence eliminating the major bottleneck in high-throughput bottom-up shotgun lipidomics. PMID- 28570054 TI - Directing the Heterologous Production of Specific Cyanobacterial Toxin Variants. AB - Microcystins are globally the most commonly occurring freshwater cyanotoxins, causing acute poisoning and chronically inducing hepatocellular carcinoma. However, the detection and toxicological study of microcystins is hampered by the limited availability and high cost of pure toxin standards. Biosynthesis of microcystin variants in a fast-growing heterologous host offers a promising method of achieving reliable and economically viable alternative to isolating toxin from slow-growing cyanobacterial cultures. Here, we report the heterologous expression of recombinant microcystin synthetases in Escherichia coli to produce [d-Asp3]microcystin-LR and microcystin-LR. We assembled a 55 kb hybrid polyketide synthase/nonribosomal peptide synthetase gene cluster from Microcystis aeruginosa PCC 7806 using Red/ET recombineering and replaced the native promoters with an inducible PtetO promoter to yield microcystin titers superior to M. aeruginosa. The expression platform described herein can be tailored to heterologously produce a wide variety of microcystin variants, and potentially other cyanobacterial natural products of commercial relevance. PMID- 28570057 TI - Differences in the Oxylipid Profiles of Bovine Milk and Plasma at Different Stages of Lactation. AB - Mastitis is caused by a bacterial infection of the mammary gland, which reduces both milk quality and quantity produced for human consumption. The incidence and severity of bovine mastitis are greatest during the periparturient period that results from dysfunctional inflammatory responses and causes damage to milk synthesizing tissues. Oxylipids are potent fatty acid-derived mediators that control the onset and resolution of the inflammatory response. The purpose of this study was to investigate how oxylipid profiles change in bovine milk at different stages of the lactation cycle. Results showed significantly lower concentrations of both milk polyunsaturated fatty acid content and total oxylipid biosynthesis during early lactation when compared to mid- or late-lactation. The only oxylipid that was higher during early lactation was 20 hydroxyeicosatetraenoic acid (HETE), which is often associated with inflammatory based diseases. Milk oxylipid profiles during the different stages of lactation differed from plasma profiles. As such, plasma fatty acid and oxylipid concentrations are not a proxy for local changes in the mammary gland during the lactation cycle. PMID- 28570058 TI - Elucidating the Photoprotection Mechanism of Eumelanin Monomers. AB - Eumelanin, the functional polymer in human skin, forms a heterogeneous layered structure intrinsic to its broadband monotonic spectra. The inherent structural heterogeneity of eumelanin makes the photoprocesses very complex and diverse in nature. Due to this diversity, a complete mechanistic picture of these photoprocesses, essential to understanding the photoprotective properties, has been missing to date. In this study, we recreate the potential energy surfaces of the low-lying excited states of the multiple monomeric forms of eumelanin constituents that play a prominent role in either photoprotection or photodamage pathways. Our results indicate a diverse set of pathways for the photoexcited species to relax back to the ground state, that depends on the specific monomeric form. Furthermore, the excited state reaction channels show the scope of extensive interconversion between the different monomers and therefore, we propose that the heterogeneity of eumelanin is key to its photoprotection capability. PMID- 28570059 TI - The Hitchhiker's Guide to Flow Chemistry ?. AB - Flow chemistry involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask. Flow equipment provides chemists with unique control over reaction parameters enhancing reactivity or in some cases enabling new reactions. This relatively young technology has received a remarkable amount of attention in the past decade with many reports on what can be done in flow. Until recently, however, the question, "Should we do this in flow?" has merely been an afterthought. This review introduces readers to the basic principles and fundamentals of flow chemistry and critically discusses recent flow chemistry accounts. PMID- 28570060 TI - Evidence for the Importance of Atmospheric Nitrogen Deposition to Eutrophic Lake Dianchi, China. AB - Elevated atmospheric nitrogen (N) deposition has significantly influenced aquatic ecosystems, especially with regard to their N budgets and phytoplankton growth potentials. Compared to a considerable number of studies on oligotrophic lakes and oceanic waters, little evidence for the importance of N deposition has been generated for eutrophic lakes, even though emphasis has been placed on reducing external N inputs to control eutrophication in these lakes. Our high-resolution observations of atmospheric depositions and riverine inputs of biologically reactive N species into eutrophic Lake Dianchi (the sixth largest freshwater lake in China) shed new light onto the contribution of N deposition to total N loads. Annual N deposition accounted for 15.7% to 16.6% of total N loads under variable precipitation conditions, 2-fold higher than previous estimates (7.6%) for the Lake Dianchi. The proportion of N deposition to total N loads further increased to 27-48% in May and June when toxic blooms of the ubiquitous non-N2 fixing cyanobacteria Microcystis spp. are initiated and proliferate. Our observations reveal that reduced N (59%) contributes a greater amount than oxidized N to total N deposition, reaching 56-83% from late spring to summer. Progress toward mitigating eutrophication in Lake Dianchi and other bloom-impacted eutrophic lakes will be difficult without reductions in ammonia emissions and subsequent N deposition. PMID- 28570061 TI - Evidence for Anisotropic Electronic Coupling of Charge Transfer States in Weakly Interacting Organic Semiconductor Mixtures. AB - We present a comprehensive investigation of the charge-transfer (CT) effect in weakly interacting organic semiconductor mixtures. The donor-acceptor pair diindenoperylene (DIP) and N,N'-bis(2-ethylhexyl)-1,7-dicyanoperylene-3,4/9,10 bis(dicarboxyimide) (PDIR-CN2) has been chosen as a model system. A wide range of experimental methods was used in order to characterize the structural, optical, electronic, and device properties of the intermolecular interactions. By detailed analysis, we demonstrate that the partial CT in this weakly interacting mixture does not have a strong effect on the ground state and does not generate a hybrid orbital. We also find a strong CT transition in light absorption as well as in photo- and electroluminescence. By using different layer sequences and compositions, we are able to distinguish electronic coupling in-plane vs out-of plane and, thus, characterize the anisotropy of the CT state. Finally, we discuss the impact of CT exciton generation on charge-carrier transport and on the efficiency of photovoltaic devices. PMID- 28570062 TI - Impact of Photooxidation and Biodegradation on the Fate of Oil Spilled During the Deepwater Horizon Incident: Advanced Stages of Weathering. AB - While the biogeochemical forces influencing the weathering of spilled oil have been investigated for decades, the environmental fate and effects of "oxyhydrocarbons" in sand patties deposited on beaches are not well-known. We collected sand patties deposited in the swash zone on Gulf of Mexico beaches following the Deepwater Horizon oil spill. When sand patties were exposed to simulated sunlight, a larger concentration of dissolved organic carbon was leached into seawater than the corresponding dark controls. This result was consistent with the general ease of movement of seawater through the sand patties as shown with a 35SO42- radiotracer. Ultrahigh-resolution mass spectrometry, as well as optical measurements revealed that the chemical composition of dissolved organic matter (DOM) leached from the sand patties under dark and irradiated conditions were substantially different, but neither had a significant inhibitory influence on the endogenous rate of aerobic or anaerobic microbial respiratory activity. Rather, the dissolved organic photooxidation products stimulated significantly more microbial O2 consumption (113 +/- 4 MUM) than either the dark (78 +/- 2 MUM) controls or the endogenous (38 MUM +/- 4) forms of DOM. The changes in the DOM quality and quantity were consistent with biodegradation as an explanation for the differences. These results confirm that sand patties undergo a gradual dissolution of DOM in both the dark and in the light, but photooxidation accelerates the production of water-soluble polar organic compounds that are relatively more amenable to aerobic biodegradation. As such, these processes represent previously unrecognized advanced weathering stages that are important in the ultimate transformation of spilled crude oil. PMID- 28570064 TI - Tandem Reaction of Cationic Copolymerization and Concertedly Induced Hetero-Diels Alder Reaction Preparing Sequence-Regulated Polymers. AB - A unique tandem reaction of sequence-controlled cationic copolymerization and site-specific hetero-Diels-Alder (DA) reaction is demonstrated. In the controlled cationic copolymerization of furfural and 2-acetoxyethyl vinyl ether (AcOVE), only the furan ring adjacent to the propagating carbocation underwent the hetero DA reaction with the aldehyde moiety of another furfural molecule. A further and equally important feature of the copolymerization is that the obtained copolymers had unprecedented 2:(1 + 1)-type alternating structures of repeating sequences of two VE and one furfural units in the main chain and one furfural unit in the side chain. The specific DA reaction is attributed to the delocalization of the positive charge to the side furan ring. PMID- 28570063 TI - Tetra- and Heptametallic Ru(II),Rh(III) Supramolecular Hydrogen Production Photocatalysts. AB - Supramolecular mixed metal complexes combining the trimetallic chromophore [{(bpy)2Ru(dpp)}2Ru(dpp)]6+ (Ru3) with [Rh(bpy)Cl2]+ or [RhCl2]+ catalytic fragments to form [{(bpy)2Ru(dpp)}2Ru(dpp)RhCl2(bpy)](PF6)7 (Ru3Rh) or [{(bpy)2Ru(dpp)}2Ru(dpp)]2RhCl2(PF6)13 (Ru3RhRu3) (bpy = 2,2'-bipyridine and dpp = 2,3-bis(2-pyridyl)pyrazine) catalyze the photochemical reduction of protons to H2. This first example of a heptametallic Ru,Rh photocatalyst produces over 300 turnovers of H2 upon photolysis of a solution of acetonitrile, water, triflic acid, and N,N-dimethylaniline as an electron donor. In contrast, the tetrametallic Ru3Rh produces only 40 turnovers of H2 due to differences in the excited state properties and nature of the catalysts upon reduction as ascertained from electrochemical data, transient absorption spectroscopy, and flash-quench experiments. While the lowest unoccupied molecular orbital of Ru3Rh is localized on a bridging ligand, it is Rh-centered in Ru3RhRu3 facilitating electron collection at Rh in the excited state and reductively quenched state. The Ru -> Rh charge separated state of Ru3RhRu3 is endergonic with respect to the emissive Ru -> dpp 3MLCT excited and cannot be formed by static electron transfer quenching of the 3MLCT state. Instead, a mechanism of subnanosecond charge separation from high lying states is proposed. Multiple reductions of Ru3 and Ru3Rh using sodium amalgam were carried out to compare UV-vis absorption spectra of reduced species and to evaluate the stability of highly reduced complexes. The Ru3 and Ru3Rh can be reduced by 10 and 13 electrons, respectively, to final states with all bridging ligands doubly reduced and all bpy ligands singly reduced. PMID- 28570066 TI - Synthesis of Spirocyclic Amines by Using Dipolar Cycloadditions of Nitrones. AB - Aliphatic ketones containing a chloride and alkene were heated with hydroxylamine to promote cascade, tandem condensation to oximes, cyclization to nitrones, and 1,3-dipolar cycloaddition to tricyclic isoxazolidines as single stereoisomers. Single regioisomers were obtained when three atoms linked the ketone and dipolarophile to give five-membered rings but mixtures resulted with four atoms in the tether unless a terminal ester was located on the alkene. The N-O bond in the products could be reduced to give spirocyclic amines and diamines. PMID- 28570065 TI - Palladium-Catalyzed Cross-Coupling of Silyl Electrophiles with Alkylzinc Halides: A Silyl-Negishi Reaction. AB - We report the first example of a silyl-Negishi reaction between secondary zinc organometallics and silicon electrophiles. This palladium-catalyzed process provides direct access to alkyl silanes. The delicate balance of steric and electronic parameters of the employed DrewPhos ligand is paramount to suppressing isomerization and promoting efficient and selective cross-coupling. PMID- 28570068 TI - Solvent-Controlled Chemoselectivity in the Photolytic Release of Hydroxamic Acids and Carboxamides from Solid Support. AB - The synthetic utility and theoretical basis of a photolabile hydroxylamine-linker are presented. The developed protocols enable the efficient synthesis and chemoselective photolytic release of either hydroxamates or carboxamides from solid support. The bidetachable mode of the linker unit is uniquely dependent on the solvent. Hydroxamic acids are obtained by performing photolysis in protic solvents, whereas photolysis in aprotic solvents enables the selective release of carboxamides. PMID- 28570067 TI - Lead Optimization Generates CYP11B1 Inhibitors of Pyridylmethyl Isoxazole Type with Improved Pharmacological Profile for the Treatment of Cushing's Disease. AB - Cushing's disease, characterized by elevated plasma cortisol levels, can be controlled by inhibition of 11beta-hydroxylase (CYP11B1). The previously identified selective and potent CYP11B1 inhibitor 5-((5-methylpyridin-3 yl)methyl)-2-phenylpyridine Ref 7 (IC50= 2 nM) exhibited promutagenic potential as well as very low oral bioavailability in rats (F = 2%) and was therefore modified to overcome these drawbacks. Successful lead optimization resulted in similarly potent and selective 5-((5-methoxypyridin-3-yl)methyl)-3 phenylisoxazole 25 (IC50 = 2 nM, 14-fold selectivity over CYP11B2), exhibiting a superior pharmacological profile with no mutagenic potential. Furthermore, compound 25 inhibited rat CYP11B1 (IC50 = 2 MUM) and showed a high oral bioavailability (F = 50%) and sufficient plasma concentrations in rats, providing an excellent starting point for a proof-of-principle study. PMID- 28570070 TI - Divergent Asymmetric Total Synthesis of (+)-Vincadifformine, (-)-Quebrachamine, (+)-Aspidospermidine, (-)-Aspidospermine, (-)-Pyrifolidine, and Related Natural Products. AB - A uniformly strategic total synthesis of Aspidosperma alkaloids (+) vincadifformine, (-)-quebrachamine, (+)-aspidospermidine, (-)-aspidospermine, (-) pyrifolidine, and nine others from efficiently constructed tricyclic ketone 13 is reported. Highlights of these divergent and practical syntheses include (i) stereoselective intermolecular [4 + 2] cycloaddition to establish a C-E ring with one all-carbon quaternary stereocenter (C-5) and two bridged contiguous cis stereocenters (C-12 and C-19), (ii) a Pd/C-catalyzed hydrogenation/deprotection/amidation cascade process to assemble the D ring, and (iii) Fischer indolization to forge the A-B ring. PMID- 28570069 TI - Electrochemical Growth of Copper Hydroxy Double Salt Films and Their Conversion to Nanostructured p-Type CuO Photocathodes. AB - New electrochemical synthesis methods were developed to produce copper hydroxy double salt(Cu-HDS) films with four different intercalated anions (NO3-, SO42-, Cl-, and dodecyl sulfate (DS)) as pure crystalline films as deposited (Cu2NO3(OH)3, Cu4SO4(OH)6, Cu2Cl(OH)3, and Cu2DS(OH)3). These methods are based on p-benzoquinone reduction, which increases the local pH at the working electrode and triggers the precipitation of Cu2+ and appropriate anions as Cu-HDS films on the working electrode. The resulting Cu-HDS films could be converted to crystalline Cu(OH)2 and CuO films by immersing them in basic solutions. Because Cu-HDS films were composed of 2D crystals as a result of the atomic-level layered structure of HDS, the CuO films prepared from Cu-HDS films have unique low dimensional nanostructures, creating high surface areas that cannot be obtained by direct deposition of CuO, which has a 3D atomic-level crystal structure. The resulting nanostructures allowed the CuO films to facilitate electron-hole separation and demonstrate great promise for photocurrent generation when investigated as a photocathode for a water-splitting photoelectrochemical cell. Electrochemical synthesis of Cu-HDS films and their facile conversion to CuO films will provide new routes to tune the morphologies and properties of the CuO electrodes that may not be possible by other synthesis means. PMID- 28570071 TI - Inhibitory Effect of Adsorbed Water on the Transport of Methane in Carbon Nanotubes. AB - We investigate the transport diffusion of methane at 300 K and pressures of up to 15 bar in dry and wetted carbon nanotubes (CNTs) having diameters ranging from 0.95 to 2.034 nm using nonequilibrium molecular dynamics (NEMD) simulation. Because of their strong hydrogen bonding, preadsorbed water molecules transport in the form of clusters and block the diffusion of methane, reducing the Onsager coefficient of methane dramatically compared to that in dry CNTs. The reduction in the methane Onsager coefficient is greater in narrower CNTs or at higher water densities. Because the diameter of the water clusters is almost invariant with water density, the Onsager coefficient of water in the (10, 10) CNT increases linearly with water density. It is further found that whereas decreasing the CNT diameter from 2.034 to 0.95 nm enhances the Onsager coefficient of pure methane by about 1 order of magnitude, the Onsager coefficient of water is almost independent of the CNT diameter at a water density of 0.05 g/cm3. We propose a theoretical model for the strong dependency of methane diffusion in wetted CNTs on the Onsager coefficient of water, the preadsorbed water density, and the CNT diameter. The model predicts the Onsager coefficients of the methane/water mixture from the Onsager coefficients of the pure components. Our study provides a basic understanding of the coupled diffusion of immiscible components in nanochannels and will facilitate progress in gas storage and carbon capture as well as nanofiltration and biomedical and biotechnological applications. PMID- 28570072 TI - Friction between van der Waals Solids during Lattice Directed Sliding. AB - Nanometer-scale crystals of the two-dimensional oxide molybdenum trioxide (MoO3) were formed atop the transition metal dichalcogenides MoS2 and MoSe2. The MoO3 nanocrystals are partially commensurate with the dichalcogenide substrates, being aligned only along one of the substrate's crystallographic axes. These nanocrystals can be slid only along the aligned direction and maintain their alignment with the substrate during motion. Using an AFM probe to oscillate the nanocrystals, it was found that the lateral force required to move them increased linearly with nanocrystal area. The slope of this curve, the interfacial shear strength, was significantly lower than for macroscale systems. It also depended strongly on the duration and the velocity of sliding of the crystal, suggesting a thermal activation model for the system. Finally, it was found that lower commensuration between the nanocrystal and the substrate increased the interfacial shear, a trend opposite that predicted theoretically. PMID- 28570073 TI - Efficient and Stable Ternary Organic Solar Cells Based on Two Planar Nonfullerene Acceptors with Tunable Crystallinity and Phase Miscibility. AB - Planar perylene diimides (PDIs), when used as nonfullerene acceptors for organic photovoltaics, are constrained by their large pi-aggregation in solid state. To tackle this issue, another planar nonfullerene acceptor 3,9-bis(2-methylene-(3 (1,1-dicyanomethylene)-indanone)-5,5,11,11-tetrakis(4-hexylphenyl)-dithieno[2,3 d:2',3'-d']-s-indaceno[1,2-b:5,6-b']dithiophene (ITIC) with weak crystallinity and near-infrared light absorption is introduced into the PTB7-Th:PDI binary blend to fabricate efficient and stable ternary solar cells. We have finely tuned the PDI/ITIC weight ratio to investigate the influences of individual ITIC and PDI on the optical, electronic, and morphological properties of the PTB7 Th:ITIC:PDI ternary blend. Compared to the binary blend, complementary optical absorption is achieved in all ternary blends. More importantly, it is found that ITIC plays a critical role on largely suppressing the PDI aggregates in the PTB7 Th:PDI blend, while PDI aids to form an interpenetrating network morphology to facilitate charge transport in the PTB7-Th:ITIC blend. Consequently, when the PDI/ITIC ratio is 3:7 (w/w), the PTB7-Th:ITIC:PDI based inverted solar cells exhibit the highest power conversion efficiency of 8.64% due to their favorable out-of-plane pi-pi stacking, finest phase-separation morphology, and highest charge mobility. Remarkably, the optimal cells that are solution-processed in air show the promising efficiency of 7.09%, suggesting good ambient stability of such ternary solar cells. PMID- 28570074 TI - Rational Design of Wide Spectral-Responsive Heterostructures of Au Nanorod Coupled Ag3PO4 with Enhanced Photocatalytic Performance. AB - Noble metallic nanomaterials with surface plasmon resonance (SPR) effects and hot electron cell effects open new opportunities for designing efficient visible light-driven hybrid photocatalysts. In this work, we reported a broadband visible light responsive photocatalyst by incorporating Au nanorods (AuNRs) into Ag3PO4 nanostructures. The longitudinal plasma of AuNRs enabled AuNRs/Ag3PO4 heterostructures to harvest light energy up to 800 nm. The obtained AuNRs/Ag3PO4 hybrid exhibited enhanced photocatalytic efficiency toward the degradation of rhodamine B (RhB) under solar irradiation. Ag3PO4, RhB, and AuNRs played different roles according to the distinct optical properties of each individual component. The dominant photocatalytic process in the different light regions were divided as follows: direct excitation of Ag3PO4 for lambda >= 420 nm, RhB sensitization for lambda >= 550 nm, and SPR effect for lambda >= 600 nm. The relationship between the pathway of charge transfer and the photocatalytic activity of the AuNRs/Ag3PO4 heterostructures was investigated systematically, revealing the specific role of AuNRs in regulating the photocatalytic activity. This work presents an innovative strategy for determining the comprehensive function of the SPR effect in relevant semiconductor-based photocatalysis and functional nanodevices with a broadband light responses. PMID- 28570075 TI - Comparative Proteome Reveals Metabolic Changes during the Fruiting Process in Flammulina velutipes. AB - Understanding the molecular mechanisms regulating the fruiting process in macro fungi, especially industrially cultivated mushrooms, has long been a goal in mycological research. To gain insights into the events accompanying the transformation of mycelia into fruit-bodies in Flammulina velutipes, proteins expressed characteristically and abundantly at primordium and fruit-body stages were investigated by using the iTRAQ labeling technique. Among the 171 differentially expressed proteins, a total of 68 displayed up-regulated expression levels that were associated with 84 specific KEGG pathways. Some up regulated proteins, such as pyruvate carboxylase, aldehyde dehydrogenase, fatty acid synthase, aspartate aminotransferase, 2-cysteine peroxiredoxin, FDS protein, translation elongation factor 1-alpha, mitogen-activated protein kinases (MAPKs), and heat-shock protein 70 that are involved in carbohydrate metabolism, carotenoid formation, the TCA cycle, MAPK signaling pathway, and the biosynthesis of fatty acids and branched-chain amino acids, could serve as potential stage specific biomarkers to study the fruiting process in F. velutipes. Knowledge of the proteins might provide valuable evidence to better understand the molecular mechanisms of fruit-body initiation and development in basidiomycete fungi. Furthermore, this study also offers valuable evidence for yield improvement and quality control of super golden-needle mushroom in practice. PMID- 28570077 TI - Explicitly Correlated Orbital Optimized Contracted Pair Correlation Methods: A Short Overview. AB - Designing efficient algorithms to apply highly accurate pair correlation methods to large molecules of scientific interest has remained an important field of research for a long period of time. We present a new approach toward fast algorithms, which represents an interesting alternative and extension to currently existing methods. The presented new contraction scheme saves a significant amount of memory and can be easily combined with efficient linear scaling algorithms. Additionally, the extension to orbital optimization and explicitly correlated f12-theory is demonstrated to further improve accuracy and applicablility. PMID- 28570076 TI - Insight into the Complexity of the i-Motif and G-Quadruplex DNA Structures Formed in the KRAS Promoter and Subsequent Drug-Induced Gene Repression. AB - Activating KRAS mutations frequently occur in pancreatic, colorectal, and lung adenocarcinomas. While many attempts have been made to target oncogenic KRAS, no clinically useful therapies currently exist. Most efforts to target KRAS have focused on inhibiting the mutant protein; a less explored approach involves targeting KRAS at the transcriptional level. The promoter element of the KRAS gene contains a GC-rich nuclease hypersensitive site with three potential DNA secondary structure-forming regions. These are referred to as the Near-, Mid-, and Far-regions, on the basis of their proximity to the transcription start site. As a result of transcription-induced negative superhelicity, these regions can open up to form unique DNA secondary structures: G-quadruplexes on the G-rich strand and i-motifs on the C-rich strand. While the G-quadruplexes have been well characterized, the i-motifs have not been investigated as thoroughly. Here we show that the i-motif that forms in the C-rich Mid-region is the most stable and exists in a dynamic equilibrium with a hybrid i-motif/hairpin species and an unfolded hairpin species. The transcription factor heterogeneous nuclear ribonucleoprotein K (hnRNP K) was found to bind selectively to the i-motif species and to positively modulate KRAS transcription. Additionally, we identified a benzophenanthridine alkaloid that dissipates the hairpin species and destabilizes the interaction of hnRNP K with the Mid-region i-motif. This same compound stabilizes the three existing KRAS G-quadruplexes. The combined effect of the compound on the Mid-region i-motif and the G-quadruplexes leads to downregulation of KRAS gene expression. This dual i-motif/G-quadruplex interactive compound presents a new mechanism to modulate gene expression. PMID- 28570078 TI - Micellar Self-Assembly of Recombinant Resilin-/Elastin-Like Block Copolypeptides. AB - Reported here is the synthesis of perfectly sequence defined, monodisperse diblock copolypeptides of hydrophilic elastin-like and hydrophobic resilin-like polypeptide blocks and characterization of their self-assembly as a function of structural parameters by light scattering, cryo-TEM, and small-angle neutron scattering. A subset of these diblock copolypeptides exhibit lower critical solution temperature and upper critical solution temperature phase behavior and self-assemble into spherical or cylindrical micelles. Their morphologies are dictated by their chain length, degree of hydrophilicity, and hydrophilic weight fraction of the ELP block. We find that (1) independent of the length of the corona-forming ELP block there is a minimum threshold in the length of the RLP block below which self-assembly does not occur, but that once that threshold is crossed, (2) the RLP block length is a unique molecular parameter to independently tune self-assembly and (3) increasing the hydrophobicity of the corona-forming ELP drives a transition from spherical to cylindrical morphology. Unlike the self-assembly of purely ELP-based block copolymers, the self-assembly of RLP-ELPs can be understood by simple principles of polymer physics relating hydrophilic weight fraction and polymer-polymer and polymer-solvent interactions to micellar morphology, which is important as it provides a route for the de novo design of desired nanoscale morphologies from first principles. PMID- 28570079 TI - Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin. AB - Ciprofloxacin (CIP) is a poorly soluble drug that also displays poor permeability. Attempts to improve the solubility of this drug to date have largely focused on the formation of crystalline salts and metal complexes. The aim of this study was to prepare amorphous solid dispersions (ASDs) by ball milling CIP with various polymers. Following examination of their solid state characteristics and physical stability, the solubility advantage of these ASDs was studied, and their permeability was investigated via parallel artificial membrane permeability assay (PAMPA). Finally, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the ASDs were compared to those of CIP. It was discovered that acidic polymers, such as Eudragit L100, Eudragit L100-55, Carbopol, and HPMCAS, were necessary for the amorphization of CIP. In each case, the positively charged secondary amine of CIP was found to interact with carboxylate groups in the polymers, forming amorphous polymeric drug salts. Although the ASDs began to crystallize within days under accelerated stability conditions, they remained fully X-ray amorphous following exposure to 90% RH at 25 degrees C, and demonstrated higher than predicted glass transition temperatures. The solubility of CIP in water and simulated intestinal fluid was also increased by all of the ASDs studied. Unlike a number of other solubility enhancing formulations, the ASDs did not decrease the permeability of the drug. Similarly, no decrease in antibiotic efficacy was observed, and significant improvements in the MIC and MBC of CIP were obtained with ASDs containing HPMCAS-LG and HPMCAS-MG. Therefore, ASDs may be a viable alternative for formulating CIP with improved solubility, bioavailability, and antimicrobial activity. PMID- 28570080 TI - Access to Tetronic Acids via Silver-Catalyzed CO2 Incorporation into Conjugated Ynones. AB - Facile and versatile access to highly functionalized tetronic acids has been successfully achieved through the reaction of conjugated ynones with carbon dioxide. In the presence of a base, the enolates generated from the ynones capture CO2 via a carbon-carbon bond-forming reaction, accompanied by a 5-exo-dig cyclization reaction of the resulting carboxylate to the alkyne, activated by a silver catalyst. The present method should be applicable to the synthesis of a wide variety of tetronic acids. PMID- 28570081 TI - Iridium(III)-Catalyzed Synthesis of Benzimidazoles via C-H Activation and Amidation of Aniline Derivatives. AB - Ir(III)-catalyzed synthesis of benzimidazoles has been realized under redox neutral conditions by annulation of aniline derivatives with dioxazolones. The reaction proceeded via a C-H activation-amidation-cyclization pathway with a decent substrate scope. PMID- 28570082 TI - Management of the Nasopalatine Canal and Foramen Associated With Dental Implant Therapy. AB - In some patients, the contents of the nasopalatine canal must be removed to facilitate placement of a dental implant into the canal. Reasons to enucleate the canal in preparation for a bone graft or a dental implant include inadvertent perforation into the canal when creating an osteotomy for an implant, severe atrophy of the maxilla, and a large foramen that precludes placing an implant into the desired location along the bony ridge. The authors searched the dental literature for clinical reports in humans that addressed placement of dental implants into or adjacent to the nasopalatine canal. They found that the nasopalatine canal is usually around 10-mm long and 4-mm wide and slants from the horizontal plane at a 66-degree angle, and there is considerable variation regarding these measurements. Several clinical reports demonstrate that the canal can be enucleated and bone grafted before successful implant placement. It is also possible to place an implant into the canal at the time of surgery and this procedure may or may not be combined with an adjunctive bone graft. Numerous case reports indicate there is usually no permanent loss of sensation of the anterior palate when an implant is placed into the nasopalatine canal. The authors concluded that placing an implant into the nasopalatine canal is a viable procedure as part of a surgical and prosthetic treatment plan when there is a dearth of alternate sites for implant placement. In patients with severe atrophy of the maxilla, combination syndrome, or who have a large or malpositioned nasopalatine canal, the canal can be used as a site to place a dental implant to support a fixed or removable dental prosthesis. PMID- 28570083 TI - Bioactive Materials in Endodontics: An Evolving Component of Clinical Dentistry. AB - Achieving biocompatibility in a material requires an interdisciplinary approach that involves a sound knowledge of materials science, bioengineering, and biotechnology. The host microbial-material response is also critical. Endodontic treatment is a delicate procedure that must be planned and executed properly. Despite major advances in endodontic therapy in recent decades, clinicians are confronted with a complex root canal anatomy and a wide selection of endodontic filling materials that, in turn, may not be well tolerated by the periapical tissues and may evoke an immune reaction. This article discusses published reports of various bioactive materials that are used in endodontic therapy, including calcium hydroxide, mineral trioxide aggregate, a bioactive dentin substrate, calcium phosphate ceramics, and calcium phosphate cements. PMID- 28570084 TI - Compromised Hard- and Soft-Tissue Architecture: Immediate Implant Placement and Provisionalization in the Esthetic Zone. AB - Careful case selection is crucial for achieving short- and long-term success with immediate implant placement and provisionalization. Caution should be exercised for a tooth that presents with a compromised soft- and hard-tissue architecture. Nevertheless, a successful outcome can be achieved provided that the principles elucidated in the current literature are applied. The following report describes a case with a severely reduced but healthy periodontium around a tooth scheduled for extraction. Immediate implant placement and provisionalization utilizing the extracted tooth with simultaneous hard- and soft-tissue augmentation were performed in one surgical visit. This facilitated the restoration of a healthy peri-implant tissue complex and delivery of a functional and esthetic final implant-supported restoration. PMID- 28570085 TI - Use of Bloodborne Pathogens Exposure Control Plans in Private Dental Practices: Results and Clinical Implications of a National Survey. AB - Dental healthcare workers (DHWs) are at risk for occupational exposure to bloodborne pathogens (BBPs). The Occupational Safety and Health Administration Bloodborne Pathogens Standard requires employers to have a written exposure control plan (ECP) detailing methods and means to reduce and manage occupational BBP exposures. Because little information is available on whether ECPs are created and used, the National Institute for Occupational Safety and Health and the Organization for Safety, Asepsis and Prevention conducted an online survey to determine if dental practices had an ECP, whether present ECPs had the necessary components, and if impediments existed to prevent having an ECP in place. Respondents were primarily from nonfranchised practices (69%) and dentists who owned the practice (63%). Seventy-two percent of survey participants had an ECP, and 20% were unaware of any federal requirements for an ECP prior to the survey. Engineering controls were used by many practices, although the type varied. Fifteen percent of practices did not offer the hepatitis B vaccine for employees. The survey revealed many dental practices were unaware of or were lacking required elements of the ECP. Findings from this survey indicate DHWs would benefit from increased education regarding methods to prevent occupational exposures to BBPs. PMID- 28570086 TI - Today's Solutions for Edentulous Patients: Implants, Digital Dentures, and Streamlined Technologies. PMID- 28570087 TI - Viral hepatitis A, active component, U.S. Armed Forces, 2007-2016. AB - During 2007-2016, there were 237 incident diagnoses of acute hepatitis A, with an overall incidence rate of 1.88 cases per 100,000 person-years (p-yrs). Crude overall rates of hepatitis A were highest among service members in the youngest age group, those in healthcare occupations, and among Air Force and Navy members. Service members of "other" or unknown race/ethnicity and non-Hispanic black service members had higher overall incidence rates of hepatitis A, compared to their non-Hispanic white and Hispanic counterparts. Annual incidence rates of hepatitis A were relatively stable until 2012 when rates peaked at 2.94 per 100,000. Rates dipped to 1.41 per 100,000 p-yrs in 2015 and then increased to 2.22 per 100,000 p-yrs in 2016. During the 10-year period, annual rates among male service members were relatively stable. The low rates of acute hepatitis A among U.S. service members overall reflect the widespread use of the hepatitis A virus vaccine. PMID- 28570088 TI - Viral hepatitis B, active component, U.S. Armed Forces, 2007-2016. AB - During 2007-2016, there were 1,258 and 1,259 incident diagnoses of acute and chronic hepatitis B virus (HBV) infection, respectively. The overall incidence rates of diagnoses of acute and chronic hepatitis B were both 10.0 per 100,000 person-years (p-yrs). Overall crude incidence rates of acute hepatitis B were highest among females, Navy members, Asian/Pacific Islander and non-Hispanic black service members, those in healthcare occupations, recruits, and service members with no history of deployment. Overall incidence rates of chronic hepatitis B were highest among service members who were female; in the Navy or the Army; in healthcare occupations; and of non-recruit status. Asian/Pacific Islander service members, those of other/unknown race/ethnicity, and non-Hispanic black service members had overall rates of chronic hepatitis B that were more than 41, 11, and 10 times that of non-Hispanic white service members, respectively. Crude annual incidence rates of acute hepatitis B fluctuated between 7.7 per 100,000 p-yrs and 13.2 per 100,000 p-yrs during the surveillance period. Approximately one of 10 acute cases and close to one of five chronic cases had at least one HBV-related hospitalization. Rates of hospitalized cases of acute hepatitis B decreased over the 10-year period. PMID- 28570089 TI - Viral hepatitis C, active component, U.S. military service members and beneficiaries, 2008-2016. AB - Hepatitis C virus (HCV) infection remains an important concern for the Military Health System (MHS). This report updates numbers and incidence rates of HCV infection of U.S. military service members and MHS beneficiaries, incorporating a surveillance period before and after 2012 screening policy changes for military members. From 2008 to 2016, there were 342 and 1,491 incident cases of acute and chronic hepatitis C, respectively, among active component members of the U.S. Armed Forces; crude overall incidence rates during the period were 2.8 (acute) and 12.2 (chronic) cases per 100,000 person-years. Annual incidence rates of chronic hepatitis C decreased over the surveillance period; however, rates of acute hepatitis C remained steady. There were 141 acute and 587 chronic incident cases among reserve/guard service members, with annual counts of both acute and chronic cases decreasing over the surveillance period. In addition, there were 2,541 acute and 21,418 chronic cases among non-service member beneficiaries, with annual counts of acute and chronic cases also decreasing steadily over the surveillance period. Given recent pharmaceutical advances in treatment, screening and linkage to care are critical to improving health outcomes for those with HCV infection. PMID- 28570090 TI - Brief report: Tinea pedis, active component, U.S. Armed Forces, 2000-2016. PMID- 28570091 TI - Surveillance snapshot: Respiratory infections resulting in hospitalization, U.S. Air Force recruits, October 2010-February 2017. PMID- 28570092 TI - The Effect of Physical Exercise After a Concussion: A Systematic Review and Meta analysis. AB - BACKGROUND: Data evaluating the role of exercise in patients with a concussion are contradictory. Studies have reported improvement in the Post-Concussion Symptom Scale (PCSS) score, whereas others showed no effect on the PCSS score. PURPOSE: To conduct a systematic review and meta-analysis on the role of physical exercise on different outcomes in patients with a concussion. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A search of 5 databases from the earliest available date to September 30, 2016, and a hand search of a few articles were performed. Trial registries were reviewed, and authors of multiple studies were contacted to find additional published or unpublished studies. Randomized controlled trials (RCTs), cohort studies, and before and after (pre post) studies evaluating the effect of physical exercise, compared with control, in patients with a concussion or mild traumatic brain injury were included. RESULTS: The search generated 1096 studies. Of these, 14 studies (5 RCTs, 1 propensity score matching study, 3 cohort studies, and 5 before and after studies) met our inclusion criteria. Exercise significantly decreased the PCSS score (mean difference, -13.06; 95% CI, -16.57 to -9.55; P < .00001; I2 = 44%), percentage of patients with symptoms of a concussion (risk ratio, 0.74; 95% CI, 0.63 to 0.86; P = .0001; I2 = 0%), and days off work (17.7 days vs 32.2 days, respectively; P < .05) compared with control. Exercise improved the reaction time (standard mean difference, -0.43; 95% CI, -0.80 to -0.06; P = .02) component of the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) score without affecting the Balance Error Scoring System (BESS) score and neuropsychological parameters. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) scores were moderate for the PCSS, symptoms, ImPACT, BESS, and neuropsychological tests. CONCLUSION: Physical exercise appears to improve the PCSS score and symptoms in patients with a concussion. A high quality RCT evaluating different intensities of exercise at different time points, for different durations after a concussion, for different races/ethnicities, and for sex needs to be conducted to evaluate a clear effect of exercise in patients with a concussion. PMID- 28570093 TI - Predicting Future Hip Fractures on Routine Abdominal CT Using Opportunistic Osteoporosis Screening Measures: A Matched Case-Control Study. AB - OBJECTIVE: Hip fracture is a major consequence of low bone mineral density, which is treatable but underdiagnosed. The purpose of this case-control study is to determine whether lumbar vertebral trabecular attenuation, vertebral compression fractures, and femoral neck T scores readily derived from abdominopelvic CT scans obtained for various indications are associated with future hip fragility fracture. MATERIALS AND METHODS: A cohort of 204 patients with hip fracture (130 women and 74 men; mean age, 74.3 years) who had undergone abdominopelvic CT before fracture occurred (mean interval, 24.8 months) was compared with an age- and sex-matched control cohort without hip fracture. L1 trabecular attenuation, vertebral compression fractures of grades 2 and 3, and femoral neck T scores derived from asynchronous quantitative CT were recorded. The presence of one or more clinical risk factor for fracture was also recorded. Multivariate logistic regression models were used to determine the association of each measurement with the occurrence of hip fracture. RESULTS: The mean L1 trabecular attenuation value, the presence of one or more vertebral compression fracture, and CT-derived femoral neck T scores were all significantly different in patients with hip fracture versus control subjects (p < 0.01). Logistic regression models showed a significant association of all measurements with hip fracture outcome after adjustments were made for age, sex, and the presence of one or more clinical risk factor. L1 trabecular attenuation and CT-derived femoral neck T scores showed moderate accuracy in differentiating case and control patients (AUC, 0.70 and 0.78, respectively). CONCLUSION: L1 trabecular attenuation, CT-derived femoral neck T scores, and the presence of at least one vertebral compression fracture on CT are all associated with future hip fragility fracture in adults undergoing routine abdominopelvic CT for a variety of conditions. PMID- 28570094 TI - Femoral Torsion: Impact of Femur Position on CT and Stereoradiography Measurements. AB - OBJECTIVE: The purpose of this study is to evaluate stereoradiographic measurements of femoral torsion with different femoral positions, in comparison with CT measurements, with use of the current standard axial-slice technique. We hypothesize that CT measurements vary with femoral spatial positioning because of the resulting projection onto the CT plane, whereas stereoradiographic measurements, which are derived from a 3D reconstruction of the femur, remain constant. MATERIALS AND METHODS: Both in vitro and in vivo studies were conducted. CT and stereoradiographic examinations were performed using 30 dry femurs in the following six femoral positions: neutral position (with the femoral mechanical axis aligned with the longitudinal axis of the CT scanner or stereoradiography system), 10 degrees of abduction, 10 degrees of adduction, 5 degrees of flexion, 10 degrees of flexion, and 5 degrees of extension. The impact of femoral position on torsion measurement was assessed using paired t tests. In addition, 18 patients (mean [+/- SD] age, 42.3 +/- 19.9 years) who underwent both CT and stereoradiography examinations were retrospectively assessed. The correlation between femoral positioning and torsion measurement was determined using the Pearson correlation coefficient. RESULTS: Flexion and extension statistically significantly affected CT measurement of femoral torsion (p < 0.01) but not stereoradiography measurement (p > 0.21). A strong correlation existed between hip flexion and the difference between femoral torsion measured by CT and stereoradiography (r = -0.80). CONCLUSION: The accuracy of femoral torsion determined by axial CT depends on the position of the femur. Hip flexion significantly reduced the femoral torsion angle measured by CT. Conversely, the accuracy of stereoradiography was independent of femur positioning. Thus, stereoradiography is preferable to CT for accurate measurement of femoral torsion, while it also substantially reduces the radiation dose. PMID- 28570095 TI - Differentiating Transudative From Exudative Ascites Using Quantitative B-Mode Gray-Scale Ultrasound Histogram. AB - OBJECTIVE: The purpose of this article is to differentiate exudative from transudative ascites using B-mode gray-scale ultrasound histogram analysis. SUBJECTS AND METHODS: Sixty-two consecutive patients with ascites were prospectively studied from June 2014 through June 2015. All underwent ultrasound (US) and paracentesis in the radiology department. Five patients were excluded (three with hemorrhage and two with peritoneal carcinomatosis). The remaining 57 patients were divided into those with exudative and transudative ascites according to results of paracentesis. Electronically recorded US images were transferred to a workstation, and gray-scale histograms were generated. The ascites-to-rectus abdominis muscle echogenicity ratio (ARAER) was obtained from ascites adjacent to the rectus abdominis muscle. ROC curves were used to evaluate the sensitivity and specificity of this method in differentiating exudative from transudative ascites. RESULTS: ARAERs for exudative ascites were significantly higher than those for transudative ascites (p < 0.001). ROC was done to evaluate ARAERs for exudative ascites. The best cutoff value for ARAER histogram was 0.002. The sensitivity and specificity of ARAER were 87.5% and 79.2% (AUC = 0.843), respectively. CONCLUSION: ARAER is an easily applicable noninvasive quantitative sonographic method with high sensitivity and specificity in differentiating exudative from transudative ascites. PMID- 28570096 TI - Advanced MRI Techniques for the Ankle. AB - OBJECTIVE: The purposes of this article are to present a state-of-the-art routine protocol for MRI of the ankle, to provide problem-solving tools based on specific clinical indications, and to introduce principles for the implementation of ultrashort echo time MRI of the ankle, including morphologic and quantitative assessment. CONCLUSION: Ankle injury is common among both athletes and the general population, and MRI is the established noninvasive means of evaluation. The design of an ankle protocol depends on various factors. Higher magnetic field improves signal-to-noise ratio but increases metal artifact. Specialized imaging planes are useful but prolong acquisition times. MR neurography is useful, but metal reduction techniques are needed whenever a metal prosthesis is present. An ultrashort echo time sequence is a valuable tool for both structural and quantitative evaluation. PMID- 28570097 TI - CT Intensity Distribution Curve (Histogram) Analysis of Patients Undergoing Antiangiogenic Therapy for Metastatic Renal Cell Carcinoma. AB - OBJECTIVE: The purpose of this study was to evaluate the median versus mean attenuation obtained from histograms in the response assessment of renal cell carcinoma (RCC) target lesions in patients treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors. MATERIALS AND METHODS: Imaging findings of 19 patients with RCC and treated with a VEGFR tyrosine kinase inhibitor that included a baseline study and at least two follow-up studies were retrospectively analyzed. Histograms of target lesions were created from ROI measurements, and mean and median lesion attenuation were obtained. Shift of mean and median was used to classify response of lesions between baseline CT and the first follow-up examination according to the Choi criteria; morphology, attenuation, size, and structure (MASS) criteria; and the Response Evaluation Criteria in Solid Tumors (RECIST). RECIST classification of the last follow-up CT examination was considered the reference standard. RESULTS: Among the 19 patients (six women, 13 men; mean age, 60 +/- 8 [SD] years; body mass index, 24.5 +/- 4.6 kg/m2), three (16%) had evidence of disease progression; nine (47%), partial response; and seven (37%), stable disease. Temporal change in the shape of the histograms from or to gaussian occurred in 11 of the 19 (58%) lesions, which accounted for a significant difference between mean (64.3 +/- 38.5 HU) and median (71.0 +/- 36.5 HU) lesion attenuation (p < 0.001). According to the shift of median for outcome analysis, the number of properly classified lesions increased from 12 of 19 (63%) to 13 of 19 (68%) for the Choi criteria and from 14 of 19 (74%) to 15 of 19 (79%) for the MASS criteria. CONCLUSION: Mean and median attenuation of RCC target lesions differed significantly. Use of shift of median rather than shift of mean increased the number of accurate classifications of lesions at the first follow-up CT examination. PMID- 28570098 TI - Variation in Screening CT-Detected Nodule Volumetry as a Function of Size. AB - OBJECTIVE: The objective of this study is to evaluate measurement variability in volumetric assessment of pulmonary nodules on low-dose CT images with a view toward determining how this variability is influenced by nodule size. MATERIALS AND METHODS: A large CT screening database was reviewed to identify solid pulmonary nodules that had remained stable in size on the basis of findings from at least three scans obtained over a 2-year period. Two software packages (Lung VCAR and syngo.via) were used to assess the nodule volume on the two most recent CT scans, which were obtained at a slice thickness of 0.625 mm. The percentage of volume change was calculated for each nodule. The SD of the percentage of volume change was determined for nodules in each of the following nodule diameter size categories: less than 4 mm, 4-5 mm, 6-9 mm, and 10 mm or larger. The diameter was the mean of the length and width in the CT image that represented the largest cross-sectional area of the nodule. RESULTS: The 171 stable nodules that were identified in 117 CT screening participants (median age, 61 years) ranged in size from 2.2 to 18.7 mm. The time between acquisition of the first and last CT images ranged from 3.7 to 17.8 years (median, 11.5 years). For each of the four categories of diameter size (< 4, 4-5, 6-9, and >= 10 mm), the SD of the percentage of volume change was 20.4%, 17.7%, 14.6%, and 3.7%, with the use of Lung VCAR, and 59.5%, 24.3%, 9.1%, and 6.2%, with the use of syngo.via, respectively. The SD decreased with increasing nodule diameter, with the use of both software packages. CONCLUSION: Measurement variability decreased with increasing nodule diameter for both software packages and was different between the two software packages. PMID- 28570099 TI - Accuracy and Interobserver Agreement for Prostate Imaging Reporting and Data System, Version 2, for the Characterization of Lesions Identified on Multiparametric MRI of the Prostate. AB - OBJECTIVE: The objective of this study was to measure the accuracy and interobserver agreement of the Prostate Imaging Reporting and Data System, version 2 (PI-RADSv2), for the characterization of prostate lesions on multiparametric MRI. MATERIALS AND METHODS: This retrospective study included 170 men examined at a single institution between August 2014 and February 2015 on a 3 T MRI scanner. Study patients were found to have lesions concerning for prostate cancer that were targeted for MRI/transrectal ultrasound fusion biopsy. Two experienced readers independently assigned a PI-RADSv2 assessment category to the dominant lesion in each patient. The AUC was calculated to determine reader accuracy for the detection of clinically significant prostate cancer (Gleason score >= 3 + 4). The Cohen kappa statistic was used to quantify interobserver agreement. RESULTS: The prevalence of clinically significant prostate cancer was 0.36 (61/170 patients). The AUCs for readers 1 and 2 were 0.871 and 0.882, respectively. The AUCs were greater for peripheral zone lesions than for transition zone lesions. When a PI-RADSv2 assessment category >= 3 was considered positive, the agreement between readers was good overall (kappa = 0.63) and was fair for transition zone lesions (kappa = 0.53). When a PI-RADSv2 assessment category >= 4 was considered positive, the agreement was excellent overall (kappa = 0.91) and was excellent for both peripheral zone lesions (kappa = 0.91) and transition zone lesions (kappa = 0.87). CONCLUSION: Two experienced readers were able to accurately identify patients with clinically significant prostate cancer using PI-RADSv2 with good interobserver agreement overall. PMID- 28570102 TI - Cross-Sectional Imaging of Intrahepatic Cholangiocarcinoma: Development, Growth, Spread, and Prognosis. AB - OBJECTIVE: Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor that arises from the intrahepatic bile ducts. Although the pathologic and imaging features of ICC have been clearly identified, recent updates have addressed the pathologic classification and imaging features of ICC using new imaging techniques. First, a proposed new pathologic ICC subclassification includes perihilar large duct and peripheral small duct ICCs. Second, advanced MR-based imaging features of ICC, such as hepatobiliary phase imaging using hepatocytespecific contrast material and DWI, have recently been described. These imaging features are important when differentiating ICCs from hepatocellular carcinomas. Finally, some imaging features of ICC, such as prominent arterial enhancement or degree of delayed enhancement, exhibit potential as prognostic imaging biomarkers. CONCLUSION: Comprehensive and updated knowledge of ICC is necessary for accurate diagnosis and could facilitate prediction of clinical outcomes for patients with ICC. PMID- 28570100 TI - Serum Matrix Metalloproteinase-7, Respiratory Symptoms, and Mortality in Community-Dwelling Adults. MESA (Multi-Ethnic Study of Atherosclerosis). AB - RATIONALE: Matrix metalloproteinase-7 (MMP-7) has been implicated in interstitial lung disease pathobiology and proposed as a diagnostic and prognostic biomarker of idiopathic pulmonary fibrosis. OBJECTIVES: To test associations between serum MMP-7 and lung function, respiratory symptoms, interstitial lung abnormalities (ILA), and all-cause mortality in community-dwelling adults sampled without regard to respiratory symptoms or disease. METHODS: We measured serum MMP-7 in 1,227 participants in MESA (Multi-Ethnic Study of Atherosclerosis) at baseline. The 5-year outcome data were available for spirometry (n = 697), cough (n = 722), and dyspnea (n = 1,050). The 10-year outcome data were available for ILA (n = 561) and mortality (n = 1,227). We used linear, logistic, and Cox regression to control for potential confounders. MEASUREMENTS AND MAIN RESULTS: The mean (+/ SD) serum MMP-7 level was 4.3 (+/-2.5) ng/ml (range, 1.2-24.1 ng/ml). In adjusted models, each natural log unit increment in serum MMP-7 was associated with a 3.7% absolute decrement in FVC% (95% confidence interval [CI] = 0.9-6.6%), a 1.6-fold increased odds of exertional dyspnea (95% CI = 1.3-1.9), a 1.5-fold increased odds of ILAs (95% CI = 1.1-2.1), and a 2.2-fold increased all-cause mortality rate (95% CI = 1.9-2.5). The associations with ILA and mortality tended to be stronger among never-smokers (P values for interaction 0.06 and 0.01, respectively). CONCLUSIONS: Serum MMP-7 levels may be a quantitative biomarker of subclinical extracellular matrix remodeling in the lungs of community-dwelling adults, which may facilitate investigation of subclinical interstitial lung disease. PMID- 28570103 TI - Cavity Versus Ligand Shape Descriptors: Application to Urokinase Binding Pockets. AB - We analyzed 78 binding pockets of the human urokinase plasminogen activator (uPA) catalytic domain extracted from a data set of crystallized uPA-ligand complexes. These binding pockets were computed with an original geometric method that does NOT involve any arbitrary parameter, such as cutoff distances, angles, and so on. We measured the deviation from convexity of each pocket shape with the pocket convexity index (PCI). We defined a new pocket descriptor called distributional sphericity coefficient (DISC), which indicates to which extent the protein atoms of a given pocket lie on the surface of a sphere. The DISC values were computed with the freeware PCI. The pocket descriptors and their high correspondences with ligand descriptors are crucial for polypharmacology prediction. We found that the protein heavy atoms lining the urokinases binding pockets are either located on the surface of their convex hull or lie close to this surface. We also found that the radii of the urokinases binding pockets and the radii of their ligands are highly correlated (r = 0.9). PMID- 28570101 TI - MR Elastography Demonstrates Unique Regional Brain Stiffness Patterns in Dementias. AB - OBJECTIVE: The purpose of this study was to investigate age-corrected brain MR elastography (MRE) findings in four dementia cohorts (Alzheimer disease, dementia with Lewy bodies, frontotemporal dementia, and normal pressure hydrocephalus) and determine the potential use as a differentiating biomarker in dementia subtypes. SUBJECTS AND METHODS: Institutional review board approval and written informed consent were obtained to perform MRE on 84 subjects: 20 patients with normal pressure hydrocephalus, eight with Alzheimer disease, five with dementia with Lewy bodies, five with frontotemporal dementia, and 46 cognitively normal control subjects. Shear waves of 60-Hz vibration frequency were transmitted into the brain using a pillowlike passive driver, and brain stiffness was determined in eight different regions (cerebrum, frontal, occipital, parietal, temporal, deep gray matter-white matter, sensorimotor cortex, and cerebellum). All stiffness values were age-corrected and compared with control subjects. The Wilcoxon rank sum test and linear regression were used for statistical analysis. RESULTS: Regional stiffness patterns unique to each dementing disorder were observed. Patients with Alzheimer disease and frontotemporal dementia showed decreased cerebral stiffness (p = 0.001 and p = 0.002, respectively) with regional softening of the frontal and temporal lobes. Patients with Alzheimer disease additionally showed parietal lobe and sensorimotor region softening (p = 0.039 and p = 0.018, respectively). Patients with normal pressure hydrocephalus showed stiffening of the parietal, occipital, and sensorimotor regions (p = 0.007, p < 0.001, and p < 0.0001, respectively). Patients with dementia with Lewy bodies did not show significant stiffness changes in any of the regions. CONCLUSION: Quantitative MRE of changes in brain viscoelastic structure shows unique regional brain stiffness patterns between common dementia subtypes. PMID- 28570104 TI - Detection of Complexes in Biological Networks Through Diversified Dense Subgraph Mining. AB - Protein-protein interaction (PPI) networks, providing a comprehensive landscape of protein interaction patterns, enable us to explore biological processes and cellular components at multiple resolutions. For a biological process, a number of proteins need to work together to perform a job. Proteins densely interact with each other, forming large molecular machines or cellular building blocks. Identification of such densely interconnected clusters or protein complexes from PPI networks enables us to obtain a better understanding of the hierarchy and organization of biological processes and cellular components. However, most existing graph clustering algorithms on PPI networks often cannot effectively detect densely connected subgraphs and overlapped subgraphs. In this article, we formulate the problem of complex detection as diversified dense subgraph mining and introduce a novel approximation algorithm to efficiently enumerate putative protein complexes from biological networks. The key insight of our algorithm is that instead of enumerating all dense subgraphs, we only need to find a small diverse subset of subgraphs that cover as many proteins as possible. The problem is modeled as finding a diverse set of maximal dense subgraphs where we develop highly effective pruning techniques to guarantee efficiency. To scale up to large networks, we devise a divide-and-conquer approach to speed up the algorithm in a distributed manner. By comparing with existing clustering and dense subgraph based algorithms on several yeast and human PPI networks, we demonstrate that our method can detect more putative protein complexes and achieves better prediction accuracy. PMID- 28570105 TI - Understanding Consumer Interaction on Instagram: The Role of Satisfaction, Hedonism, and Content Characteristics. AB - The increasing relevance of Instagram and its growing adoption among top brands suggest an effort to better understand consumers' behaviors within this context. The purpose of this study is to examine the role of perceived hedonism and satisfaction in determining consumers' intentions to interact and their actual interaction behaviors (the number of likes, by tapping a heart icon, and comments) in a brand's official Instagram account. Also, we investigate the effect of consumer perceptions about the characteristics of the content generated in the account (perceived originality, quantity, and quality) on their perceived hedonism and satisfaction. Data were collected in two stages from 808 members of a fashion brand's official Instagram account. First, participants answered an online questionnaire to evaluate their perceptions, satisfaction, and interaction intentions. Second, 1 month later, we measure the number of likes and comments done by each participant in the brand's official Instagram account during that month. Using partial least squares to analyze the data, perceived hedonism is found to affect both satisfaction and the intention to interact in Instagram, which in turn influences actual behavior. Besides, perceived originality is the most relevant content characteristic to develop perceived hedonism. These findings offer managers a general vision of consumers' behaviors on Instagram, highlighting the importance of hedonism to create a satisfactory experience. PMID- 28570106 TI - Cause for optimism? PMID- 28570107 TI - Chronic oedema in the community: an overview. PMID- 28570108 TI - Time to make nursing the number one priority. PMID- 28570109 TI - Management of long-term conditions and dementia: The role of the Admiral Nurse. AB - As life expectancy increases so people often develop a range of conditions and disabilities in the years before death. Multimorbidity represents the most common 'disease pattern' found among the elderly and is characterised by complex interactions of co-existing diseases where a medical approach focused on a single disease does not suffice. People with dementia who also have other comorbidities do not always have their comorbid conditions managed as those without dementia which often lead to a high number of hospital admissions with longer lengths of stay and greater treatment costs. This case study presents the case management approach taken by Admiral Nursing in managing the complexities where there is comorbidity of a long-term condition and a diagnosis of dementia. By empowering the person and their carer with information and choices and through good case management and communication, people can be supported to live well and avoid inappropriate hospital admissions. PMID- 28570110 TI - The challenges of upskilling health care assistants in community nursing. AB - Community care is at the forefront of the National Health Service reforms. Role redistribution from registered nurses to health care assistants is growing. This paper examines the challenges of upskilling community health care assistants to undertake catheterisation for uncomplicated patients in the community. Social constructivist methods facilitated reflective practice. Challenges included fears around delegation, accountability and the responsibilities involved in supporting the development of health care assistants. Recommendations suggest that community health care assistants offer a valuable and much needed contribution to health care delivery and are enthusiastic to upskill in catheterisation. However, reluctance from community registered nurses around delegation delayed the process. Registered nurses will need to address these fears and engage in workforce planning to proactively influence role developments and safe practice. National guidance needs to be structured around clear pathways to support these valued participants in delivering health care. PMID- 28570111 TI - Diagnosis and management of cellulitis: a dermatology perspective. PMID- 28570112 TI - Physical exercise for those living with and beyond cancer: Changing perceptions in palliative caring. PMID- 28570113 TI - Giving evidence in court. AB - Appearing in court is becoming an almost routine part of a district nurse's role and the prospect of appearing in court or giving evidence at fitness to practice hearings remains a daunting one. The process is still largely adversarial and cross examination is a hostile experience that must be met with professionalism and gravitas. In this article Richard Griffith highlights the principles of effective evidence giving. PMID- 28570114 TI - Introducing community integrated nursing teams: How one Clinical Commissioning Group applied an evidence-based approach. AB - The present day collection of financial and demographic challenges confronted by health and social care mean that integrated services are undoubtedly essential to sustain adequate care. However, the impact of integrated care upon healthcare staff and patients as well as new ways of working will need to be demonstrated, with collaboration and engagement throughout any transition. This paper provides an overview of the evidence relating to the delivery of effective, integrated out of-hospital care, with a discussion of the literature. It also considers how one Clinical Commissioning Group has begun the process of integration with the focus on community nursing services for the provision of better care for patients with an evidence-based approach. PMID- 28570115 TI - Managing sepsis effectively with national early warning scores and screening tools. PMID- 28570117 TI - Effects of Chromium on Glucose Tolerance in Infants Receiving Parenteral Nutrition Therapy. AB - OBJECTIVES: Early hyperglycemia is prevalent in preterm infants receiving parenteral nutrition (PN) therapy. Chromium improves glucose tolerance by potentiating the action of insulin. Therefore, we hypothesized that supplementing PN with chromium would improve glucose tolerance and PN calorie delivery in infants during the first week of life. METHODS: We collected data on neonates receiving PN initiated at birth with chromium (0.2 mcg/kg/d) started either on days 5-7 (group A) vs day 1 (group B) on PN and compared glucose tolerance and PN calorie administration over the first week of life. RESULTS: For similar mean serum glucose concentrations between group A (n = 348) and B (n = 358) (107 +/- 48 vs 111 +/- 52 mg/dL, P = .3), infants in group B tolerated higher glucose infusion rates and received more PN calories during the first week of life: 8.4 +/- 2 vs 8 +/- 2 mg/kg/min (P < .001) and 74.8 +/- 23 vs 71.5 +/- 12 kcal/kg/d (P = .017), respectively. The difference in calories delivered was more pronounced among very low birth weight (VLBW) infants compared with infants >1500 g: 76.5 +/ 14 vs 72.4 +/- 11 kcal/kg/d (P = .009) and 73.8 +/- 27 vs 70.3 +/- 12 kcal/kg/d (P = .079), respectively. CONCLUSIONS: PN chromium supplementation resulted in better glucose tolerance and calorie delivery during the first week of life, especially in VLBW infants. This supports chromium's essential role in enhancing glucose tolerance during PN therapy in VLBW infants at risk for early hyperglycemia. PMID- 28570119 TI - Effect of Opioids and Benzodiazepines on Clinical Outcomes in Patients Receiving Palliative Care: An Exploratory Analysis. AB - BACKGROUND: Medications for symptom management in palliative care have associated, but poorly understood, harms. Drug-related harms have important clinical implications, may impact on patients' compliance and contribute to symptoms. OBJECTIVE: To explore the longitudinal relationship between oral morphine equivalent daily dose (MEDD) and oral diazepam equivalent daily dose (DEDD) with functional, cognitive, and symptom outcomes in patients receiving palliative care. DESIGN: Secondary longitudinal analysis of cancer decedents (n = 235) was carried out from a palliative care randomized controlled trial with multiple outcome measures. At each time point, MEDD and DEDD were calculated. Multilevel modeling was used to investigate independent associations between MEDD and DEDD, and cognitive and gastrointestinal symptoms, quality of life (QoL), performance status, and survival. SETTING/SUBJECTS: Participants were recruited from a specialist palliative care program in southern Adelaide, were expected to live >=48 hours, had pain in the previous 3 months, and a baseline Folstein Mini Mental Status Examination score >=25. RESULTS: Cognitive and gastrointestinal symptoms, performance status, and QoL worsened over time. In the adjusted multilevel analysis, statistically significant relationships remained between MEDD/DEDD and worsening performance status (p = 0.001), DEDD and gastrointestinal effects (p < 0.001), MEDD and QoL (p < 0.022). CONCLUSIONS: Commonly used palliative medications were associated with deteriorating performance status. The lack of association between MEDD with gastrointestinal or cognitive symptoms underlines that these associations are not inevitable with close attention. This analysis highlights the importance of including other medications as confounders when exploring medication-related harms. An understanding of the risk-benefit balance of medications is needed to maximize net benefits for patients. PMID- 28570118 TI - Distinct Genetic Diversity of Carbapenem-Resistant Acinetobacter baumannii from Colombian Hospitals. AB - The global success of multidrug-resistant Acinetobacter baumannii has been associated with the dissemination of a high-risk clone designated clonal complex (CC) 92B (Bartual scheme)/CC2P (Pasteur scheme), which is the most frequent genetic lineage in European, Asian, and North American carbapenem-resistant Acinetobacter isolates. In these isolates, carbapenem resistance is mainly mediated by beta-lactamases encoded by blaOXA-23-like, blaOXA-24-like, blaOXA-51 like, and/or blaOXA-58-like genes. In this study, we characterized the population genetics of 121 carbapenem-resistant A. baumannii complex isolates recovered from 14 hospitals in seven cities in Colombia (2008-2010). Multiplex PCR was used to detect blaOXA-23-like, blaOXA-24-like, blaOXA-51-like, and blaOXA-58-like genes. Molecular typing was performed using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). PCR showed that 118 (97.5%) of the isolates were positive for both blaOXA-23-like and blaOXA-51-like genes, and three other isolates were only positive for blaOXA-51-like. PFGE identified 18 different pulsotypes, while MLST identified 11 different sequence types (STs), seven of which had not been previously described in Acinetobacter. None of the STs found in this study was associated with CC92B/CC2P. The most widespread STs in our isolates belonged to ST636 and their single-locus variants ST121/ST124/ST634 (CC636B) followed by STs belonging to CC110B. Our observations suggest a wide distribution of diverse A. baumannii complex clones containing blaOXA-23-like in Colombian hospitals (especially CC636B and CC110B) that differ from the high-risk clones commonly found in other regions of the world, indicating a distinct molecular epidemiology of carbapenem-resistant Acinetobacter spp. in Colombia. PMID- 28570120 TI - Characterization of the coagulation profile in children with liver disease and extrahepatic portal vein obstruction or shunt. AB - INTRODUCTION: Chronic liver disease causes a disruption of procoagulant and anticoagulant factors, resulting in a fragile state, prone to increased rates of both bleeding and thrombosis. Currently, there is limited literature describing the changes observed in pediatric liver disease and extrahepatic portal vein obstruction or shunt. This study aimed to describe the changes that occur in children with chronic liver disease and extrahepatic portal vein obstruction or shunt. MATERIALS AND METHODS: We measured the concentration and activity of key procoagulant and anticoagulant factors in children with liver disease, children with extrahepatic portal vein obstruction or shunt, and healthy children. RESULTS: Children with severe liver disease had coagulopathic changes, including either decreased concentration or activity of factor II, factor V, and factor VII. Nineteen percent (8/42) of the cohort had significant bleeding. Thrombophilic changes were also observed, including decreased concentration or activity of protein C, protein S, and antithrombin and increased concentration and activity of factor VIII and Von Willebrand factor. Similar coagulation factor changes were observed in children with extrahepatic portal vein obstruction or shunt. There was a trend toward greater changes in coagulation factor activity compared to concentration. CONCLUSION: This study provides a detailed description of the changes in both the concentration and activity of coagulation factors in pediatric liver disease and extrahepatic portal vein obstruction or shunt. Interestingly, procoagulant and anticoagulant factors were deranged in portal vein obstruction or shunt to a similar degree as in liver disease. An improved understanding of the coagulation profile in the pediatric setting will contribute to the improved management of liver disease and extrahepatic portal obstruction or shunt. ABBREVIATIONS: PELD: pediatric end-stage liver disease score; MELD: model for end-stage liver disease score; ELISA: enzyme-linked immunosorbent assay; MCRI: Murdoch Childrens Research Institute; FII: factor II; FV: factor V; FVII: factor VII; FVIII: factor VIII; AT: antithrombin III; A2M: alpha-2 macroglobulin; vWF: Von Willebrand factor; PC: protein C; PS: protein S; ISTH BAT: International Society on Thrombosis and Haemostasis Bleeding Assessment Tool. PMID- 28570121 TI - Update in Chronic Obstructive Pulmonary Disease 2016. PMID- 28570122 TI - simUfish: An Interactive Application to Teach K-12 Students About Zebrafish Behavior. AB - As the zebrafish is rapidly becoming a species of choice in preclinical research, several efforts are being placed toward creating educational programs for K-12 students based on this promising model organism. However, as any other model organisms, the use of zebrafish in classroom settings requires additional experimental resources and poses ethical challenges related to animal use. To mitigate these factors, we have developed an application (app), simUfish, which implements a mathematical model of zebrafish behavior for generating multiple fish trajectories and animating their body undulations. simUfish is developed using a multiplatform game engine and is expected to promote the knowledge of zebrafish behavior to both K-12 students and the general public. Specifically, it demonstrates basic principles of fish individual and social behaviors, including environment interaction; fear response toward a predator; shoaling; and attraction toward a stimulus, which can be a food source or simply a finger placed on the touch screen. The effectiveness of the app as an accessible experimental tool for learning was tested in an outreach activity on middle school students from the New York City school system. The results from this activity show an immediate, tangible improvement of students' satisfaction and willingness to learn about key concepts on zebrafish behavior, accompanied by high level of interest in life sciences. PMID- 28570123 TI - Functional insights into the Magnaporthe oryzae class II myosin. PMID- 28570124 TI - Impact of the Prostate Imaging Reporting and Data System, Version 2, on MRI Diagnosis for Extracapsular Extension of Prostate Cancer. AB - OBJECTIVE: The purpose of this study is to validate the Prostate Imaging Reporting and Data System, version 2 (PI-RADSv2), in assessing extracapsular extension (ECE), compared with PI-RADS, version 1 (PI-RADSv1). MATERIALS AND METHODS: A total of 210 patients with clinically localized prostate cancer underwent MRI and radical prostatectomy. Two readers independently interpreted the MR images. In PI-RADSv1, 5-point ECE risk scoring was used. In PI-RADSv2, ECE criteria included morphologic features and a tumor-capsule contact length (CL) greater than 10 mm. The diagnostic performance of each PI-RADS version and the cutoff CL were evaluated. RESULTS: ECE was found in 56 patients (26.7%). In PI RADSv1, maximal accuracy was achieved with a risk score of 3 or greater. At this threshold, positive findings on PI-RADSv1 and PI-RADSv2 were identified in 21.0 34.3% and 49.0-51.4% of patients, respectively. Compared with PI-RADSv1, PI RADSv2 had higher negative predictive values (84.9-89.1% vs 96.3-97.1%, respectively; p = 0.003 and 0.021, for each reader). PI-RADSv1 and PI-RADSv2 had positive predictive values of 56.9-70.5% and 49.1-50.5%, respectively (p = 0.025 and 0.300, respectively). Interobserver kappa values for PI-RADSv1 and PI-RADSv2 were 0.511 and 0.781, respectively. The best cutoff CL was greater than 10 mm among patients without morphologic features of ECE. For patients positive for ECE on the basis of PI-RADSv2 but not PI-RADSv1, 73.3-74.1% of prostate cancer cases with a biopsy Gleason score of 7 or less and 35.7-44.4% of cases with a biopsy Gleason score of 8 or higher were overstaged. CONCLUSION: PI-RADSv2 reduces understaging and improves interobserver agreement in ECE assessment. However, overstaging is a concern, and the biopsy Gleason score may have a complementary role in reducing overstaging. PMID- 28570125 TI - High Omega-3 Polyunsaturated Fatty Acids in fat-1 Mice Reduce Inflammatory Pain. AB - Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs), such as alpha-linolenic and linoleic acids, are essential fatty acids in mammals, because they cannot be synthesized de novo. However, fat-1 transgenic mice can synthesize omega-3 PUFAs from omega-6 PUFAs without dietary supplementation of omega-3, leading to abundant omega-3 PUFA accumulation in various tissues. In this study, we used fat 1 transgenic mice to investigate the role of omega-3 PUFAs in response to inflammatory pain. A high omega-3 PUFA tissue content attenuated formalin-induced pain sensitivity, microglial activation, inducible nitric oxide synthase expression, and the phosphorylation of NR2B, a subunit of the N-methyl-d aspartate (NMDA) receptor. Our findings suggest that elevated omega-3 PUFA levels inhibit NMDA receptor activity in the spinal dorsal horn and modulate inflammatory pain transmission by regulating signal transmission at the spinal dorsal horn, leading to the attenuation of chemically induced inflammatory pain. PMID- 28570126 TI - Second and Third Metatarsophalangeal Plantar Plate Tears: Diagnostic Performance of Direct and Indirect MRI Features Using Surgical Findings as the Reference Standard. AB - OBJECTIVE: The objective of our study was to assess the diagnostic performance and associations of the direct and indirect MRI features of the metatarsophalangeal (MTP) joint that are thought to be related to tears of the plantar plate (PP) using surgical findings as the reference standard. MATERIALS AND METHODS: We retrospectively included 23 patients with symptomatic instability of lesser MTP joints who had undergone preoperative 1.5-T MRI and surgical assessment. The MRI examinations were independently assessed by two musculoskeletal radiologists. Using the surgical data as the reference standard, we calculated the sensitivity, specificity, and accuracy of each MRI feature in the detection of PP tears. Multivariate logistic regression analysis was performed to identify which MRI features were independently associated with PP tears. Interobserver reliability was assessed using kappa statistics. RESULTS: Forty-five lesser MTP joints were included. The presence of pericapsular fibrosis was highly sensitive (91.2%), specific (90.9%), and accurate (91.1%) for the diagnosis of PP tears. With a cutoff value of 0.275 cm, the PP-proximal phalanx distance had a sensitivity of 64.7%, specificity of 90.9%, and accuracy of 71.1% in diagnosing PP tears. CONCLUSION: In patients with clinical features indicating lesser MTP joint instability, some direct and indirect MRI features exhibited good to excellent diagnostic performance in detecting the presence of PP tears. PMID- 28570127 TI - JOURNAL CLUB: Benefit of Epinephrine Autoinjector for Treatment of Contrast Reactions: Comparison of Errors, Administration Times, and Provider Preferences. AB - OBJECTIVE: Given the rarity of contrast reactions in practice, most radiologists have little to no experience in their management, and errors are common. The purpose of this study was to compare treatment of a moderate-severity reaction with intramuscular epinephrine by either the traditional manual method of drawing up and delivering epinephrine with a needle and syringe or the use of an epinephrine autoinjector. SUBJECTS AND METHODS: All diagnostic radiologists at the study institution were requested to participate in an annual contrast reaction simulation program, which consisted of three simulation scenarios in a high-fidelity simulation laboratory. During the moderate-severity simulation scenario, the time to administer intramuscular epinephrine and any errors in administration were recorded. Groups were randomized to use an autoinjector device or manual delivery. All participants completed a survey assessing the experience with epinephrine and their comfort in treating contrast reactions using a traditional manual approach versus an epinephrine autoinjector. RESULTS: Among 189 participants in the contrast reaction simulation program, 76 participated in a moderate-severity reaction simulation two to five at a time in 25 sessions. Mean total time to administration was significantly longer for manual (108.8 seconds) than for autoinjector (38.7 seconds) delivery (p < 0.001). There were 11 errors in the manual group and one error in the autoinjector group (p = 0.005). Ninety-four percent of participants reported feeling very comfortable or comfortable with the autoinjector as opposed to 60% for manual delivery (p < 0.001). Overall, 96% of participants thought the autoinjector was easier to use. CONCLUSION: Use of an epinephrine autoinjector for treatment of contrast reactions was associated with a significantly greater degree of provider comfort, shorter time to administration, and fewer errors. PMID- 28570128 TI - Effect of a Biopsy Center on Adequacy Rates of Thyroid Nodule Fine-Needle Aspiration. AB - OBJECTIVE: The purpose of this study was to investigate the effect of a biopsy center-a dedicated space with a dedicated ultrasound machine and technologist, staffed daily by a radiologist responsible for performing ultrasound-guided procedures only-on the rate of non-diagnostic or unsatisfactory thyroid fine needle aspiration (FNA). MATERIALS AND METHODS: Three radiologists performed FNA on 1200 nodules in 998 patients between September 2010 and November 2015. We compared rates of nondiagnostic or unsatisfactory FNA before and after implementation of a biopsy center in September 2014 as part of a quality improvement initiative. Before the establishment of our biopsy center, ultrasound guided procedures were scheduled between diagnostic studies in the main ultrasound department and were performed by a radiologist responsible for both. Multivariate logistic regression analysis was performed to assess the effect of the biopsy center on the odds of obtaining an adequate sample. RESULTS: Rates of nondiagnostic or unsatisfactory FNA decreased significantly from 15.1% to 8.5% (p < 0.001) after implementation of the biopsy center. The odds of obtaining an adequate sample were higher in the biopsy center (odds ratio, 2.07; 95% CI, 1.43 3.01), even after adjusting for patient age, nodule size, the radiologist performing the procedure, and time over the study period. CONCLUSION: The implementation of a biopsy center was associated with significantly lower rates of nondiagnostic or unsatisfactory thyroid FNA, suggesting target rates of 10% or lower are achievable with quality improvement measures. PMID- 28570129 TI - Sexual Self-Schemas in the Real World: Investigating the Ecological Validity of Language-Based Markers of Childhood Sexual Abuse. AB - This is the first study to examine language use and sexual self-schemas in natural language data extracted from posts to a large online forum. Recently, two studies applied advanced text analysis techniques to examine differences in language use and sexual self-schemas between women with and without a history of childhood sexual abuse. The aim of the current study was to test the ecological validity of the differences in language use and sexual self-schema themes that emerged between these two groups of women in the laboratory. Archival natural language data were extracted from a social media website and analyzed using LIWC2015, a computerized text analysis program, and other word counting approaches. The differences in both language use and sexual self-schema themes that manifested in recent laboratory research were replicated and validated in the large online sample. To our knowledge, these results provide the first empirical examination of sexual cognitions as they occur in the real world. These results also suggest that natural language analysis of text extracted from social media sites may be a potentially viable precursor or alternative to laboratory measurement of sexual trauma phenomena, as well as clinical phenomena, more generally. PMID- 28570130 TI - An Integrative Computational Approach to Evaluate Genetic Markers for Chronic Lymphocytic Leukemia. AB - Recent studies reported hundreds of genes linked to chronic lymphocytic leukemia (CLL). However, many of these candidate genes were lack of replication and results were not always consistent. Here, we proposed a computational workflow to curate and evaluate CLL-related genes. The method integrates large-scale literature knowledge data, gene expression data, and related pathways/network information for quantitative marker evaluation. Pathway Enrichment, Sub-Network Enrichment, and Gene-Gene Interaction analysis were conducted to study the pathogenic profile of the candidate genes, with four metrics proposed and validated for each gene. By using our approach, a scalable CLL genetic database was developed including CLL-related genes, pathways, diseases and information of supporting references. The CLL case/control classification supported the effectiveness of the four proposed metrics, which successfully identified nine well-studied CLL genes (i.e., TNF, BCL2, TP53, VEGFA, P2RX7, AKT1, SYK, IL4, and MDM2) and highlighted two newly reported CLL genes (i.e., PDGFRA and CSF1R). The computational biology approach and the CLL database developed in this study provide a valuable resource that may facilitate the understanding of the genetic profile of CLL. PMID- 28570131 TI - Simplifying the management of venous leg ulcers: Choosing appropriate and acceptable compression therapy. PMID- 28570132 TI - Leg ulcers: time to benchmark? PMID- 28570133 TI - Biofilm-based wound care: the importance of debridement in biofilm treatment strategies. PMID- 28570134 TI - The sun, the potential for skin cancer, and the affect on wound healing. PMID- 28570135 TI - The Lindsay Leg Club Foundation update. PMID- 28570136 TI - More wounds, less time to treat them: 1717 nurses discuss the challenges in wound care in a series of study days. PMID- 28570138 TI - The use of prophylactic dressings in the prevention of pressure ulcers: a literature review. AB - Pressure ulcers pose a significant burden to both patients and health care resources. There are an increasing number of studies that have examined the use of prophylactic dressings, and their ability to redistribute pressure and protect the skin from shear and friction damage. This literature review examines six studies conducted on this controversial subject. Brindle and Wegelin ( 2012 ; Chaiken, 2012 ; Cubit et al, 2012 ; Santamaria et al, 2012) all examined the role of dressings to prevent pressure ulcers, and Call et al (2013a ; 2013b ), conducted in vitro research into the mode of dressings. Current research suggests that while further research is required, the use of prophylactic dressings have a place alongside standard measures, in helping to prevent pressure, shear and friction damage. PMID- 28570137 TI - Benefits of maggot debridement therapy on leg ulcers: a literature review. AB - Maggot debridement therapy (MDT) is an effective method for debriding wounds such as leg ulcers, supporting the concept of wound bed preparation ( Dumville et al, 2009 ; Soares et al, 2009 ; Mudge et al, 2014 ). New evidence is emerging to suggest that maggots might contribute to wound healing in other ways. For example, the reduction of biofilms and disinfection of wounds ( Van Der Plas et al, 2008 ; Brown et al, 2012 ; Pritchard and Brown, 2015 ) plus regulation of protease levels ( Chambers et al, 2003 ; Van Der Plas et al, 2009a ; Van Der Plas et al, 2009b ). This review will discuss research exploring new benefits of maggots in the management of individuals with chronic leg ulcers. PMID- 28570139 TI - Woundcare4Heroes celebrates its 5th anniversary. PMID- 28570140 TI - Does Conversion to Open of Laparoscopically Attempted Rectal Cancer Cases Affect Short- and Long-Term Outcomes? A Systematic Review and Meta-Analysis. AB - INTRODUCTION: Laparoscopy for rectal cancer is a challenge as it presents many technical difficulties and requires high level of expertise. That is the reason for the high conversion rate. Reports on outcomes of converted cases after laparoscopic rectal resection for cancer are conflicting. AIM: The present meta analysis compares short- and long-term outcomes between converted rectal cancer cases with both open and laparoscopically completed cases. METHOD: All studies reporting on outcomes separately for the converted cases were reviewed systematically. Main outcomes were intraoperative complications, procedure duration, short-term mortality and morbidity, length of stay, local recurrence, number of lymph nodes retrieved, and distant metastases. Quality assessment and data extraction were performed independently by 3 reviewers. RESULTS: Fourteen studies were eligible for analysis, including 10,845 patients. Overall conversion rate was 11.9%. Converted cases had significantly longer duration, hospital stay, and higher rates of wound infection compared with laparoscopic cases. All other outcomes had no difference. When compared with open cases, conversions displayed longer operative times, but there was no other significant difference in the short- or long-term outcomes. CONCLUSION: Converted cases seem to have some short term unfavorable outcomes. Further retrospective analysis of big registries will be helpful for further investigation of converted cases. PMID- 28570142 TI - An Efficient Approach to Explore and Discriminate Anomalous Regions in Bacterial Genomes Based on Maximum Entropy. AB - Recently, there has been an increase in the number of whole bacterial genomes sequenced, mainly due to the advancing of next-generation sequencing technologies. In face of this, there is a need to provide new analytical alternatives that can follow this advance. Given our current knowledge about the genomic plasticity of bacteria and that those genomic regions can uncover important features about this microorganism, our goal was to develop a fast methodology based on maximum entropy (ME) to guide the researcher to regions that could be prioritized during the analysis. This methodology was compared with other available methods. In addition, ME was applied to eight different bacterial genera. The methodology consists of two main steps: processing the nucleotide sequence and ME calculation. We applied ME to Xanthomonas axonopodis pv. citri 306 (XAC) and Xanthomonas campestris pv. campestris ATCC 33913 (XCC), both of which have their anomalous regions well documented. We then compared our results against those from Alien Hunter, HGT-DB, Islander, IslandPath, and SIGI-HMM. ME was shown to be superior in terms of efficiency and analysis duration. Besides, ME only needs the genome sequence in FASTA format as input. The proposed strategy based on ME is able to help in bacterial genome exploration. This is a simple and fast strategy for individual genomes in comparison with other available methods, without relying on previous annotation and alignments. This methodology can also be a new option in the early stages of analysis of newly sequenced bacterial genomes. PMID- 28570144 TI - Translational Animal Models in Orthopaedic Research. PMID- 28570143 TI - Zebrafish and the Cancer Moonshot. PMID- 28570141 TI - Management of ischemic coronary disease in patients receiving chemotherapy: an uncharted clinical challenge. AB - Acute coronary syndrome (ACS) coinciding with active malignancy presents a unique clinical challenge given intersecting pathophysiology and treatment-related effects. There is little established clinical guidance on management strategies, rendering most treatment approaches anecdotal. We present a case highlighting the complexity of managing a patient being treated for malignancy who concurrently suffers from ACS. We then review the literature on co-management of ACS and malignancy, including reports of specific cancer therapies associated with ACS, unique features of clinical presentation and optimal use of dual antiplatelet therapy to minimize risks of bleeding and thrombosis. We also describe gaps in current literature, challenges in systematically studying the clinical intersection of these disease processes and propose alternative methodologies for further research. PMID- 28570146 TI - Recombinant C1 Esterase Inhibitor Reduces Cytokine Storm in an Ex Vivo Whole Blood Model. AB - C1 esterase inhibitor (C1INH) is an abundant component of blood plasma (the average concentration is 250 mg/L); it is known to be involved in several biological processes, for instance, in the regulation of the coagulation system, adhesion of leukocytes on endothelial cells, and in the regulation of complement and kallikrein cascades. Lately, the role of C1INH in immunomodulation has gained considerable attention. We used an ex vivo whole blood model to examine the influence of C1INH and its mutated variants on the inflammatory cytokines interleukin (IL)-6, tumor necrosis factor-alpha (TNFalpha), and IL-1beta. The present study demonstrated for the first time that recombinant C1INH or its Seprin domain can downregulate bacterial endotoxin induced IL-6 release. We also observed that unstructured N-terminal domain of C1INH downregulates the release of IL-1beta and TNFalpha, but not IL-6. Our results suggest that C1INH may have therapeutic potential for treatment of inflammatory conditions. PMID- 28570147 TI - Estimating Arterial Partial Pressure of Carbon Dioxide in Ventilated Patients: How Valid Are Surrogate Measures? AB - The arterial partial pressure of carbon dioxide (PaCO2) is an important parameter in critically ill, mechanically ventilated patients. To limit invasive procedures or for more continuous monitoring of PaCO2, clinicians often rely on venous blood gases, capnography, or transcutaneous monitoring. Each of these has advantages and limitations. Central venous Pco2 allows accurate estimation of PaCO2, differing from it by an amount described by the Fick principle. As long as cardiac output is relatively normal, central venous Pco2 exceeds the arterial value by approximately 4 mm Hg. In contrast, peripheral venous Pco2 is a poor predictor of PaCO2, and we do not recommend using peripheral venous Pco2 in this manner. Capnography offers measurement of the end-tidal Pco2 (PetCO2), a value that is close to PaCO2 when the lung is healthy. It has the advantage of being noninvasive and continuously available. In mechanically ventilated patients with lung disease, however, PetCO2 often differs from PaCO2, sometimes by a large degree, often seriously underestimating the arterial value. Dependence of PetCO2 on alveolar dead space and ventilator expiratory time limits its value to predict PaCO2. When lung function or ventilator settings change, PetCO2 and PaCO2 can vary in different directions, producing further uncertainty. Transcutaneous Pco2 measurement has become practical and reliable. It is promising for judging steady state values for PaCO2 unless there is overt vasoconstriction of the skin. Moreover, it can be useful in conditions where capnography fails (high-frequency ventilation) or where arterial blood gas analysis is burdensome (clinic or home management of mechanical ventilation). PMID- 28570149 TI - Free Access to Costly Medical Resources: Provision of Extracorporeal Membrane Oxygenation for Profound Respiratory Failure in the French Health Care System. PMID- 28570150 TI - Stressing the Brain: The Immune System, Hypothalamic-Pituitary-Adrenal Axis, and Psychiatric Symptoms in Acute Respiratory Distress Syndrome Survivors. PMID- 28570152 TI - Shockingly Deficient: An Elderly Woman with Refractory Hypotension and Acidosis. PMID- 28570151 TI - A Tale of Two Hearts: Patients with Decompensated Right Heart Failure in the Intensive Care Unit. PMID- 28570153 TI - Managing Post-Pneumonectomy Tension Hydrothorax. PMID- 28570148 TI - An Official American Thoracic Society Workshop Report: Obesity and Metabolism. An Emerging Frontier in Lung Health and Disease. AB - The world is in the midst of an unprecedented epidemic of obesity. This epidemic has changed the presentation and etiology of common diseases. For example, steatohepatitis, directly attributable to obesity, is now the most common cause of cirrhosis in the United States. Type 2 diabetes is increasingly being diagnosed in children. Pulmonary researchers and clinicians are just beginning to appreciate the impact of obesity and altered metabolism on common pulmonary diseases. Obesity has recently been identified as a major risk factor for the development of asthma and for acute respiratory distress syndrome. Obesity is associated with profound changes in pulmonary physiology, the development of pulmonary hypertension, sleep-disordered breathing, and altered susceptibility to pulmonary infection. In short, obesity is leading to dramatic changes in lung health and disease. Simultaneously, the rapidly developing field of metabolism, including mitochondrial function, is shifting the paradigms by which the pathophysiology of many pulmonary diseases is understood. Altered metabolism can lead to profound changes in both innate and adaptive immunity, as well as the function of structural cells. To address this emerging field, a 3-day meeting on obesity, metabolism, and lung disease was convened in October 2015 to discuss recent findings, foster research initiatives, and ultimately guide clinical care. The major findings arising from this meeting are reported in this document. PMID- 28570154 TI - Cryobiopsy: A Work in Progress. PMID- 28570155 TI - Supplemental Oxygen for Patients with Interstitial Lung Disease: Managing Expectations. PMID- 28570156 TI - Refining the Burden of Idiopathic Pulmonary Fibrosis: The Cocktail Party Effect. PMID- 28570157 TI - Preserving Lung Function: The Holy Grail in Managing Cystic Fibrosis. PMID- 28570158 TI - Inhaled Corticosteroids and Systemic or Topical Antifungal Therapy: A Symmetry Analysis. PMID- 28570159 TI - Canon in Intensive Care Unit Utilization: The Importance of a Fine-Tuned Instrument. PMID- 28570160 TI - Acute Respiratory Distress Syndrome and Diffuse Alveolar Damage. New Insights on a Complex Relationship. AB - Acute respiratory distress syndrome (ARDS) is a major clinical problem with high morbidity and mortality. Diffuse alveolar damage (DAD) is considered the histological hallmark for the acute phase of ARDS. DAD is characterized by an acute phase with edema, hyaline membranes, and inflammation, followed by an organizing phase with alveolar septal fibrosis and type II pneumocyte hyperplasia. Given the difficulties in obtaining a biopsy in patients with ARDS, the presence of DAD is not required to make the diagnosis. However, biopsy and autopsy studies suggest that only one-half of patients who meet the clinical definition of ARDS also have DAD. The other half are found to have a group of heterogeneous disorders, including pneumonia. Importantly, the subgroup of patients with ARDS who also have DAD appears to have increased mortality. It is possible that the response of these patients to specific therapies targeting the molecular mechanisms of ARDS may differ from patients without DAD. Therefore, it may be important to develop noninvasive methods to identify DAD. A predictive model for DAD based on noninvasive measurements has been developed in an autopsy cohort but must be validated. It would be ideal to identify biomarkers or imaging techniques that help determine which patients with ARDS have DAD. We conclude that additional studies are needed to determine the effect of DAD on outcomes in ARDS, and whether noninvasive techniques to identify DAD should be developed with the goal of determining whether this population responds differently to specific therapies targeting the molecular mechanisms of ARDS. PMID- 28570162 TI - Sequential Bronchoscopic Cryobiopsy and Cryotherapy. PMID- 28570161 TI - A Phase II Clinical Trial of an Aromatase Inhibitor for Postmenopausal Women with Lymphangioleiomyomatosis. AB - RATIONALE: Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, suggesting an important role for estrogen in disease pathogenesis. OBJECTIVES: To assess the efficacy and safety of the aromatase inhibitor letrozole in the treatment of LAM. METHODS: Seventeen postmenopausal women with LAM were enrolled in this phase II trial and randomized to receive letrozole 2.5 mg daily (n = 9) or placebo (n = 8) for a period of 12 months. Five patients in each group were also taking sirolimus at baseline and remained on the drug throughout the treatment period. Lung function, exercise capacity, quality of life, and serum vascular endothelial growth factor D (VEGF D) were measured at baseline and at 3-month intervals. RESULTS: Fifteen patients completed the study. Two patients withdrew. There were no differences in adverse events in the letrozole and placebo groups. The target enrollment of 25 patients per arm was not met, so the efficacy of letrozole could not be assessed as planned. After adjusting for sirolimus use, we found that the rate of change in FEV1 for all subjects was -3 +/- 3 ml/mo (P = 0.4), and for serum VEGF-D, the rate of change was -0.024 +/- 0.009 pg/ml/mo (P = 0.015), showing a steeper decline in the letrozole group (-0.029 +/- 0.013; P = 0.025). All patients who were taking sirolimus had a reduction in VEGF-D levels from baseline to the last visit, compared with only half of the patients who were not taking sirolimus. In a post hoc analysis, eight matched letrozole-treated-placebo-treated pairs were constructed, six of which demonstrated better FEV1 improvement for the letrozole treated patients. CONCLUSIONS: Letrozole treatment appears to be safe and well tolerated in postmenopausal patients with LAM, including those taking sirolimus. Enrollment in this trial was compromised by the publication of an effective treatment (sirolimus) in the same month as the study opened, resulting in limited power to detect treatment effects. Post hoc matched pairs exploration studies provide tentative support for additional studies of letrozole in LAM. Considering the reduced rate of lung function decline in postmenopausal patients, future studies will likely require enhanced study designs, such as selective enrollment of those with prognostic biomarkers predictive of decline. Clinical trial registered with www.clinicaltrials.gov (NCT01353209). PMID- 28570164 TI - Reply to Letter to the Editor. PMID- 28570163 TI - Direct-Access Online Care for the Management of Atopic Dermatitis: A Randomized Clinical Trial Examining Patient Quality of Life. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic disease requiring regular follow up. To increase access to dermatological care, online management of AD is being studied. However, a critical knowledge gap exists in determining AD patients' quality of life in direct-to-patient online models. In this study, we examined quality of life in AD patients managed through a direct-access online model. MATERIALS AND METHODS: We randomized 156 patients to receiving care through a direct-access online platform or in person. Patients were seen for six visits over 12 months. At each visit, the patients completed Dermatology Life Quality Index/Children's Dermatology Life Quality Index (DLQI/CDLQI), and Short Form (SF 12). RESULTS: Between baseline and 12 months, the mean (standard deviation, SD) within-group difference in DLQI score in the online group was 4.1 (+/-2.3); for the in-person group, the within-group difference was 4.8 (+/-2.7). The mean (SD) within-group difference in CDLQI score in the online group was 4.7 (+/-2.8); for the in-person group, the within-group difference was 4.9 (+/-3.1). The mean (SD) within-group difference in physical component score (PCS) and mental component score (MCS) SF-12 scores in the online group was 6.5 (+/-3.8) and 8.6 (+/-4.3); for the in-person group, it was 6.8 (+/-3.2) and 9.1(+/-3.8), respectively. The difference in the change in DLQI, CDLQI, SF-12 PCS, and SF-12 MCS scores between the two groups was 0.72 (95% confidence interval [90% CI], -0.97 to 2.41), 0.23 (90% CI, -2.21 to 2.67), 0.34 (90% CI, -1.16 to 1.84), and 0.51 (90% CI, -1.11 to 2.13), respectively. All differences were contained within their equivalence margins. CONCLUSION: Adult and pediatric AD patients receiving direct-access online care had equivalent quality of life outcomes as those see in person. The direct-access online model has the potential to increase access to care for patients with chronic skin diseases. PMID- 28570165 TI - Response to Commentators on "What's Wrong With Enhancement?" PMID- 28570166 TI - Response to Commentators on "Will the 'Real Boy' Please Behave: Dosing Dilemmas for Parents of Boys with ADHD". PMID- 28570167 TI - Population Size and Site Fidelity of Fundulus heteroclitus in a Macrotidal Saltmarsh Creek. PMID- 28570168 TI - Interaction of Nitrogen Supply, Sea Level Rise, and Elevation on Species Form and Composition of Salt Marsh Plants. PMID- 28570169 TI - Dissolved Inorganic Nitrogen Flux and Mineralization in Waquoit Bay Sediments as Measured by Core Incubations. PMID- 28570171 TI - Temperature-Independent Period Immediately After Fertilization in Sea Urchin Eggs. AB - The experiments described here explore the regulation of the duration of cleavage cycles in sea urchin eggs. We measured the timing of early cleavages in individual fertilized eggs under various temperature conditions and applied methods of statistical analysis to the data obtained. At least for the first three cleavages, the temperature dependence of the cleavage intervals was nearly equal. In addition, we identified a temperature-independent period at the beginning of the first cleavage cycle. This period occurs immediately after fertilization and lasts for several minutes. Our results suggest that this interval of temperature independence is related to the process of egg activation. PMID- 28570170 TI - Effect of Methyl Farnesoate on Late Larval Development and Metamorphosis in the Prawn Macrobrachium rosenbergii (Decapoda, Palaemonidae): A Juvenoid-like Effect? AB - Methyl farnesoate (MF), the unepoxidated form of insect juvenile hormone III, was detected in larvae of the freshwater prawn Macrobrachium rosenbergii, which metamorphose to post-larvae following 11 larval stages. The possible role of MF as a morphogen was studied by administering the compound to M. rosenbergii larvae via an Artemia vector. Higher MF levels caused earlier retardation of late larval growth, and the highest dose retarded larval development. Furthermore, MF significantly affected the patterns of metamorphosis and the appearance of intermediate individuals exhibiting both larval and post-larval morphology and behavior. Three intermediate types were defined, two of which were found only at the MF-treated groups and one that was exclusive to the higher dose treatments. The relative abundance of intermediate specimens increased from 2% in the control to 32% in the high MF concentration, which suggests that MF has a juvenoid-like effect in this decapod crustacean. PMID- 28570172 TI - Body Polarity and Mineral Selectivity in the Demosponge Chondrosia reniformis. AB - The skeleton of the common Mediterranean demosponge Chondrosia reniformis lacks endogenous spicules; but exogenous siliceous material is selectively incorporated into its collagenous ectosome, strengthening this layer. Nevertheless, the settling of sponge buds during asexual reproduction necessitates an active incorporation of the calcareous substratum through the sponge lower ectosome. This fact suggests the presence of a polarity in the sponge, with the lower surface selecting primarily carbonates, and the upper surface selecting exclusively silicates and quartz. Our observations under experimental conditions showed that the strong selectivity of the upper ectosome is realized only when the sponge is fixed to the substratum; if detached, the sponge incorporates both quartz and carbonates. In laboratory experiments, the incapacity of both kinds of ectosome to regenerate into a new complete sponge suggests that this polarity arises early in ontogeny. PMID- 28570173 TI - Lead Concentration as an Indicator of Contamination History in Estuarine Sediments. PMID- 28570174 TI - Effect of Eelgrass (Zostera marina) Density on the Feeding Efficiency of Mummichog (Fundulus heteroclitus). PMID- 28570175 TI - Planktonic Feeding and Evolutionary Significance of the Lobate Body Plan Within the Ctenophora. PMID- 28570176 TI - Effects of Nitrogen Loading on Eelgrass Seed Coat Abundance, C to N Ratios, and delta15N in Sediments of Waquoit Bay. PMID- 28570177 TI - Calcium Regulatory Endomembranes of the Prophase Mitotic Apparatus of Sand Dollar Cells Contain Enzyme Activities That Produce Leukotriene B4 but Not 1,4,5 Inositol Trisphosphate. PMID- 28570178 TI - Structural Strengthening of Urchin Skeletons by Collagenous Sutural Ligaments. AB - Sea urchin skeletons are strengthened by flexible collagenous ligaments that bind together rigid calcite plates at sutures. Whole skeletons without ligaments (removed by bleaching) broke at lower apically applied forces than did intact, fresh skeletons. In addition, in three-point bending tests on excised plate combinations, sutural ligaments strengthened sutures but not plates. The degree of sutural strengthening by ligaments depended on sutural position; in tensile tests, ambital and adapical sutures were strengthened more than adoral sutures. Adapical sutures, which grow fastest, were also the loosest, suggesting that strengthening by ligaments is associated with growth. In fed, growing urchins, sutures overall were looser than in unfed urchins. Looseness was demonstrated visually and by vibration analysis: bleached skeletons of unfed urchins rang at characteristic frequencies, indicating that sound traveled across tightly fitting sutures; skeletons of fed urchins damped vibrations, indicating loss of vibrational energy across looser sutures. Furthermore, bleached skeletons of fed urchins broke at lower apically applied forces than bleached skeletons of unfed urchins, indicating that the sutures of fed urchins had been held together relatively loosely by sutural ligaments. Thus, the apparently rigid dome-like skeleton of urchins sometimes transforms into a flexible, jointed membrane as sutures loosen and become flexible during growth. PMID- 28570179 TI - Effect of Larval Swimming Duration on Growth and Reproduction of Bugula neritina (Bryozoa) Under Field Conditions. AB - A growing body of evidence indicates that even subtle events occurring during one portion of an animal's life cycle can have detrimental, and in some cases, lasting effects on later stages. Using a laboratory-field transplant design, postmetamorphic costs associated with the duration of larval swimming were investigated in the bryozoan Bugula neritina. Larvae were induced to metamorphose in the laboratory after swimming for either less than 1 h or between 23 and 24 h; colonies that developed from these two groups of larvae are referred to hereafter as "1-h colonies" and "24-h colonies," respectively. After completing metamorphosis, individuals were transplanted to the field, where rates of growth and reproduction were monitored. In a study of the interaction between colony orientation (up or down) and larval swimming duration, both factors significantly affected the number of autozooids produced. For example, 14 days after metamorphosis, 1-h colonies facing up were approximately 40% smaller than 1-h colonies facing down. In another study, the effects of larval swimming duration, orientation, and a neighboring conspecific colony on growth and reproduction were examined. In this experiment, proximity to a conspecific colony and orientation did not significantly affect growth or fecundity, whereas increased larval swimming duration significantly reduced both. For example, 14 days after metamorphosis, the 24-h colonies were 35% smaller than 1-h colonies. Furthermore, from the time metamorphosis was initiated, the onset of reproduction was delayed by about 1.5 days in 24-h colonies when compared to 1-h colonies; and a slight delay (ca. 1 day) was associated with proximity of a developing conspecific in 1 h and 24-h colonies. In addition, 17 days after metamorphosis, 24-h colonies had about half as many brood chambers (an index of fecundity) as 1-h colonies. Costs associated with increasing the larval swimming phase by only 24 h are significant in postmetamorphic individuals, and they clearly compromise colony fitness. PMID- 28570180 TI - Oocyte Maturation in Chaetopterus pergamentaceous Observed With Centrifuge Polarizing Microscope. PMID- 28570181 TI - Role of Mechanosensory Stimuli in Intraspecific Agonistic Encounters of the Snapping Shrimp (Alpheus heterochaelis). AB - Intraspecific agonistic encounters in snapping shrimp (Alpheus heterochaelis) were analyzed using single-frame video analysis. The pair of conspecifics in such an encounter are designated as the snapper, which emits a fast water jet by very rapid closure, or snap, of the large modified snapper claw, and the receiver, which is the target of the water jet. The behavior of both snapper and receiver was evaluated before, during, and after the snap. Interactions between two intact shrimp (experimental series I) were compared with those between an intact shrimp and a "deprived" opponent (one with mechanosensory occlusion produced by coating the setae on the snapper claw with clear lacquer) (experimental series II). The behavior of the receiver is significantly changed by the occlusion, but that of the snapper is not. Intact and deprived opponents usually face each other during snapping, which is often preceded by touching of frontal appendages. The mean duration of claw cocking before snapping is about 500 ms. More than 50% of all snaps (and especially initial snaps) are directed towards the opponent, the water jet usually hitting the snapper claw of the receiver from a mean distance of 0.9 cm. Male shrimp show longer cocking durations, keep a shorter distance, and hit their opponents more often than do females. Intact and deprived snappers usually retreat immediately after snapping, but intact receivers usually approach. In contrast, deprived receivers retreat in most cases and show significantly prolonged latencies compared to intact receivers. Thus, mechanoreceptors on the snapper claw of the receiver play a significant role in intraspecific agonistic encounters. PMID- 28570182 TI - Fluorescence Localization of Cytoskeletal Proteins in Fibrin-Trapped Cells. PMID- 28570183 TI - Efferent Mechanisms of Discharging Cnidae: II. A Nematocyst Release Response in the Sea Anemone Tentacle. AB - Feeding behavior in cnidarians is a sequence of coordinated responses beginning with nematocyst discharge. The nematocyst response produces prey capture by envenomating prey and attaching prey to the tentacle. The strength of attachment of discharged nematocysts to the tentacle is termed intrinsic adherence and is calculated from measurements of adhesive force. Following prey capture, the feeding response involves movement of the tentacles toward the mouth and mouth opening. For ingestion to occur, nematocysts attaching the prey to the tentacles must be released from the tentacle. A nematocyst release response has been proposed, but never documented nor measured. Our criterion for a nematocyst release response is that the intrinsic adherence of discharged nematocysts must decrease to zero. The unit of nematocyst discharge in sea anemone tentacles is the cnidocyte/ supporting cell complex (CSCC). The nematocyst response includes nematocysts discharged from Type C CSCCs by physical contact alone and nematocysts discharged from the more numerous Type B CSCCs that require both chemosensitization and physical contact. We identify two prey-derived substances, N-acetylneuraminic acid (NANA) and glycine, both of which chemosensitize nematocyst discharge from Type B CSCCs at low concentrations. At higher concentrations NANA stimulates the release response of Type Cs, and glycine stimulates the release response of Type Bs. PMID- 28570184 TI - Migratory Behavior of Ovigerous Blue Crabs Callinectes sapidus: Evidence for Selective Tidal-Stream Transport. AB - In the late summer and early fall, newly inseminated female blue crabs (Callinectes sapidus) leave low-salinity areas of estuaries and migrate seaward to spawn near the entrance. We tested the hypothesis that migration of female C. sapidus to spawning grounds is facilitated by selective tidal-stream transport (STST). We monitored the swimming direction of adult crabs from a stationary platform located about 1 km inside the entrance to the Newport River Estuary (Beaufort, North Carolina). Swimming activity near the surface occurred primarily at night and most crabs avoided swimming against tidal currents. Eighty-one percent of the crabs observed moving down-estuary toward the inlet during ebb tide were ovigerous females. Of the 36 gravid females captured traveling in ebb currents, 97% possessed dark egg masses containing late-stage embryos. Conversely, nearly all (98%) adult crabs observed traveling in flood currents lacked egg masses, and all the females captured while migrating up-estuary exhibited signs of recent spawning. These observations indicate that ovigerous blue crabs use ebb-tide transport to migrate seaward to spawn and flood-tide transport to reenter the estuary shortly after larval release. PMID- 28570186 TI - Distribution of Setae on the Homarus americanus Lateral Antennular Flagellum. PMID- 28570185 TI - A Little Shell to Live In: Evidence That the Fertilization Envelope Can Prevent Mechanically Induced Damage of the Developing Sea Urchin Embryo. PMID- 28570187 TI - Hydrodynamic Coupling of Lobster Antennule Motion to Oscillatory Water Flow. PMID- 28570188 TI - Juvenile Limulus polyphemus Generate Two Water Currents That Contact One Proven and One Putative Chemoreceptor Organ. PMID- 28570189 TI - The Biomechanics of Odorant Access to Aesthetascs in the Grass Shrimp, Palaemonetes vulgaris. PMID- 28570190 TI - In vivo and in vitro Growth of Nerve Parasite from Lophius americanus. PMID- 28570191 TI - Evidence for Multiple Spawning by Squids (Loligo pealei) in Captivity. PMID- 28570192 TI - Dependence of Herbivory on Autotrophic Nitrogen Content and on Net Primary Production Across Ecosystems. PMID- 28570193 TI - Preliminary Evaluation of Sedimentation Rates and Species Distribution in Plum Island Estuary, Massachusetts. PMID- 28570194 TI - Transport Pathways in the Neotropical Sponge Aplysina. AB - Strands of cells distinct from the rest of the tissue were found running lengthwise through the endosome of four species of the sponge Aplysina. Although the strands were more highly pigmented than the adjacent tissue and could be removed intact with forceps, ultra-structural studies revealed no obvious barrier separating the cells in the strands from the rest of the tissue. The strands consist of stretches of elongate cells tightly aligned along densely bundled collagen fibrils, and areas of other elongate cells that possess numerous filopodia. When sponges were fed fluorescent latex beads in situ, beads were taken up and transported specifically into the strands; eventually they were found at the tip of the sponge and further down the stalk, away from the site of feeding. Beads injected into endosomal strands were also transported upwards in the strands to the tip of the sponge. Video microscopy of cells in strands that had been exposed along a portion of their length showed no bulk movement of cells; but individual cells were seen moving in both directions along the strands at 0.025-0.04 {mu}m.s-1. The endosomal cell strands are suggestive of a primitive nutrient transport pathway in sponges. PMID- 28570195 TI - Metamorphic-Signal Transduction in Hydroides elegans (Polychaeta: Serpulidae) Is Not Mediated by a G Protein. AB - Evidence from larvae of hydrozoans, gastropods, and barnacles suggests that G protein-coupled receptors mediate induction of settlement and metamorphosis in response to environmental cues. We examined responses of larvae of the serpulid polychaete Hydroides elegans to neuropharmacological agents to determine if G protein-coupled receptors or their associated signal-transduction pathways regulated induction of metamorphosis by bacterial cues. Larvae of Hydroides elegans metamorphose rapidly and in high proportions when exposed to bacterial biofilms. Neither the G-protein activator Gpp[NH]p nor the inhibitor GDP-{beta}-S affected metamorphosis. Although the nonspecific phosphodiesterase inhibitors IBMX, theophylline, and papaverine induced larvae to metamorphose, RO-20-1724 (an inhibitor selective for cAMP-specific phosphodiesterase IV) and the cyclic nucleotide analogs db-cAMP and db-cGMP had no effect on metamorphosis. The adenylate cyclase activator forskolin inhibited responses of larvae to inductive bacterial biofilms. These apparently conflicting results may be due to side effects of IBMX, theophylline, papaverine, and forskolin on ion transport. The phorbol ester TPA, an activator of protein kinase C, also had no effect on larval metamorphosis. These experiments indicate that G protein-coupled receptors and signal transduction by the adenylate cyclase/cyclic AMP or phosphatidyl-inositol/ diacylglycerol/protein kinase C pathways are not components of the morphogenetic pathway that is directly responsible for processing metamorphic cues in H. elegans. PMID- 28570196 TI - Induction of Extra Claws on the Chelipeds of a Crayfish, Procambarus clarkii. AB - In a crayfish, Procambarus clarkii, growth of an extra claw was induced by making a V-shaped wound in the proximal end of the propodus of the second and third chelipeds. Two nerve bundles were damaged by the wounding. Some type of extra growth developed on the propodi of 13 of the damaged chelipeds: a pair of extra claws (2 chelipeds), a pair of extra dactyls (1 cheliped), a single extra dactyl (2 chelipeds), and a single slight projection (8 chelipeds). The extra claws and dactyls developed from the peripheral side of the propodus away from the wound site. One of a pair of extra dactyls and the single extra dactyls could be moved only slightly, either manually or by the crayfish. The other extra dactyls could be moved by the crayfish. Muscles were associated with each of the extra and primary claws. The muscles attached to the double extra claw or dactyl were innervated by nerve bundles that were branches from the primary thick nerve bundles. One possible explanation for these findings is that the severed nerve fibers in the thick nerve bundles regenerate, elongate into aberrant roots, and form extra claws or dactyls. PMID- 28570197 TI - Electrophysiology and Innervation of the Photosensitive Epistellar Body in the Lesser Octopus Eledone cirrhosa. AB - The innervation and responses to light of the cephalopod epistellar body were investigated in preparations isolated from the stellate ganglia of the lesser or northern octopus, Eledone cirrhosa. Extracellular generator potentials in response to flashes of light were recorded from these photosensitive vesicles, with the amplitude of the response being found to be dependent upon the intensity of the flash and the level of ambient illumination. Intracellular recordings from photoreceptor cells of the epistellar body showed that they had resting potentials of about -49 +/- 7 mV (mean +/- SD, n = 43) and were depolarized by flashes of white, but not red (>650 nm) light. The evoked depolarization consisted of a transient component, followed by a steady plateau in which the amplitude of the depolarization was well correlated with the log of the stimulus intensity. The evoked depolarizations induced action potentials in the photoreceptor cells, with the frequency of firing being well correlated with the stimulus intensity. The morphologies of individual photoreceptor cells were visualized by intracellular injections of the fluorescent dye Lucifer yellow, and the path of the epistellar nerve across the stellate ganglion, into the pallial nerve, toward the brain was traced using the lipophilic dye Di-I. This pathway was confirmed physiologically by recording light-evoked responses from the cut end of the pallial nerve. PMID- 28570198 TI - Physiological Progenesis in Cephalopod Molluscs. AB - The coleoid cephalopods (cuttlefish, squid and octopus) arose from their shelled ancestors during the late Devonian; they diversified in the Jurassic but did not radiate substantially until the Tertiary. Since then they have coevolved with the fish (1). Squid are less efficient energetically than fish (2) but have survived alongside them by evolving highly opportunistic reproductive and feeding strategies (3, 4) as well as rapid jetting and inking for escape and defense. Little is known about the life history strategies of the fossil forms, but the only surviving shelled cephalopods, the nautiluses, have relatively long life spans and are iteroparous; that is, in common with most members of other molluscan classes, they breed more than once during their lives. In contrast, all other living cephalopods are generally short lived (usually 1 year) and have monocyclic reproduction and a semelparous life history. The short-lived semelparous coleoids are typified by the mid-latitude ommastrephid squid which provide the basic model considered here. This family is relatively primitive and biologically well known. Its members are essentially monocyclic, but some species may spawn their eggs in batches (5, 6) although there is no evidence of this in laboratory spawnings (7). Most loliginid squid, at least in temperate seas, have a life cycle similar to that of the ommastrephids, despite having different spawning habits. A comparison of the lifetime energetics and growth pattern of benthic, iteroparous molluscs with those of the pelagic, semelparous ommastrephids shows that, although some squid may attain a length of 1 m or more, the allocation of their energy resource among growth components is essentially characteristic of the early life, especially the first year, of iteroparous forms. The life-time energy budget of these squid thus seems to have evolved by physiological progenesis, a process in which maturation is accelerated while other aspects of the physiology are more typical of the juvenile. PMID- 28570199 TI - D- and L-beta-Hydroxybutyrate Dehydrogenases and the Evolution of Ketone Body Metabolism in Gastropod Molluscs. AB - In vertebrate animals, ketone bodies, synthesized primarily from stored lipid, are important metabolic substrates (1). During starvation, ketone bodies, acetoacetate (Acac) and {beta}-hydroxybutyrate (BHB), are oxidized by some extrahepatic tissues at high rates, and thus perform the important function of sparing limited glycogen stores (1, 2). The enzyme {beta}-hydroxybutyrate dehydrogenase (BHBDH), which catalyzes the interconversion of the ketone bodies, is found in all mammals and most vertebrates, but is absent in most invertebrates (1, 3), including marine molluscs (4). The highest measured BHBDH activities in the animal kingdom, however, are found in the hearts of terrestrial gastropod molluscs (5, 6). We have recently demonstrated that, in tissues of the terrestrial gastropod Cepaea nemoralis, two unique and previously unknown isoforms of BHBDH occur (5). The isoforms differ from the well-characterized mitochondrial membrane-bound D-BHBDH found in all other animals (7) in that they are cytosolic, and one isoform is specific for the L-enantiomer of BHB. Here we identify patterns in the evolution of these enzyme isoforms in the Gastropoda. BHBDH activities, stereospecificity and subcellular compartmentalization were measured in gastropod species representing four major groups with freshwater and terrestrial representation: Neritomorpha (primitive gilled gastropods), Architaenioglossa (more advanced gilled gastropods), Basommatophora (freshwater pulmonates), and Stylommatophora (terrestrial pulmonates). Mapping of these data onto a phylogeny of the Gastropoda (8) indicates that cytosolic D- and L-BHBDH have arisen a single time, in an ancestral stylommatophoran. All gastropods of the order Stylommatophora possess this unique organization of ketone body metabolism, which has not been found elsewhere in the animal kingdom. PMID- 28570200 TI - Evolutionary Implications of FGF and Distal-Less Expressions During Proximal Distal Axis Formation in the Ampulla of a Direct-Developing Ascidian, Molgula pacifica. AB - The present results provide the first evidence of a fibroblast growth factor (FGF) family protein in a urochordate. Anti-FGF2 immunoreactive hemoblast cells were detected at day 3 of juvenile development in a direct-developing urochordate ascidian, Molgula pacifica. The detection of FGF in hemoblast cells coincided with the appearance of distal-less protein along the proximal-distal axis of growing ampullae. Ampullae are limb-like, fluid-filled ectodermal appendages that contain hemoblast cells and have holdfast, respiratory, and immunological functions (1). Given the evolutionary conservation of the genes encoding FGF (2) their receptors (2), and distal-less (3) the present results suggest that the formation of non-homologous ascidian appendages shares genetic elements in common with proximal-distal axis formation in arthropod limbs and vertebrate limbs (4,5). The possible evolutionary implications of these findings are discussed. PMID- 28570201 TI - Luciferase of the Scyphozoan Medusa Periphylla periphylla. AB - Two types of luciferase that catalyze the luminescent oxidation of coelenterazine were isolated from the marginal exumbrella epithelium (lappet) and the ovary of Periphylla periphylla; they were designated luciferase-L and luciferase-O, respectively. Luciferase-L (Mr 32,000), probably derived from highly specialized photocytes, was very resistant to heat, and its activity was little affected by boiling; but it was unstable in solutions of low ionic strength if bovine serum albumin was not included in the solvent. Luciferase-O (Mr 75,000) occurred in the eggs in association with particulate matter, and was solubilized and extracted with a buffer containing 2 M guanidine hydrochloride; the enzyme was highly stable in this strongly denaturing solvent. The intensities of the coelenterazine luminescence catalyzed by both luciferases were maximal at pH 7.8 and in the presence of about 1 M NaCl. The quantum yield of coelenterazine was estimated to be 0.14 with luciferase-L (emission max. at 465 nm) and 0.12 with luciferase-O (emission max. at 470 nm). The luminescence caused by both luciferases was strongly inhibited by Cu2+ and thiol compounds. PMID- 28570202 TI - Comparative Morphology of the Eyes of Postlarval Bresiliid Shrimps From the Region of Hydrothermal Vents. AB - The structure and ultrastructure of the eyes of postlarval vent shrimps provisionally designated 'Alvinocaris' and 'Chorocaris' are described. The eyes of the postlarval 'Alvinocaris' are cylindrical, borne on short stalks, and contain closely packed rhabdoms. The ommatidia lack dioptric apparatus and have rhabdoms extending almost to the cornea. The rhabdoms consist of orthogonal layers of microvilli typical of crustacean rhabdoms. The eyes of the 'Chorocaris' are similar, but the rhabdom layer extends back through the reduced eyestalks and covers some of the dorsal surface of the cephalothorax. The rhabdoms from both the anterior and the thoracic regions consist of layered microvilli. The eyes of a slightly smaller postlarval vent shrimp, termed 'Type A', differ. Although clearly related to the other vent shrimps, Type A has stalked eyes held at an angle to the head. The eye displays a gradient of ommatidial development, with the older ommatidia closely resembling those seen in the other postlarval types. Between the cornea and the rhabdom layer, the youngest ommatidia possess quadripartite crystalline cones similar to those seen in related families of caridean shrimps; these are absent in the more mature ommatidia. The external structure of the anterior and thoracic eyes of juvenile Rimicaris exoculata (after settlement at the vent site) is also described. Juveniles up to 9 mm in carapace length have anterior corneas similar to those seen in postlarvae, whereas in larger specimens the corneas are progressively replaced by an ocular plate. PMID- 28570203 TI - Nitric Oxide Function in an Echinoderm. AB - In vertebrates, nitric oxide (NO) is synthesized from L-arginine by NO synthase (NOS) and regulates relaxation of smooth muscle by activating the cyclic-GMP (cGMP) generating enzyme soluble guanylyl cyclase (SGC). Here we show that the NO cGMP pathway mediates relaxation of the cardiac stomach in the starfish Asterias rubens. The NO-donors hydroxylamine, S-nitrosoglutathione (SNOG) and S-nitroso-N acetylpenicillamine (SNAP) and the NOS substrate L-arginine cause relaxation of the cardiac stomach. The relaxing effect of SNAP is blocked by the SGC inhibitor 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and the relaxing effect of L arginine is inhibited by ODQ and the NOS inhibitor Nw-monomethyl-L-arginine (L NMMA). ODQ and methylene blue also cause contraction, which may be due to inhibition of the relaxing action of NO produced by cells in the cardiac stomach. These results suggest that NO is synthesized in the cardiac stomach and regulates relaxation by activating SGC. NO-cGMP-mediated relaxation of the cardiac stomach may be important during feeding in starfish where the relaxed stomach is everted through an oral opening and over the digestible parts of prey. The discovery of NO-cGMP-mediated relaxation in an echinoderm demonstrates that regulation of smooth muscle tone by this signaling pathway also occurs in animals other than vertebrates. PMID- 28570204 TI - Predation on Bivalve Veligers by Polychaete Larvae. AB - Polychaete larvae from several families are thought to be natural predators upon planktonic bivalve larvae. However, little direct evidence of interactions between these predators and prey is available. We conducted predator-prey experiments on laboratory roller tables for five putative predatory polychaete larvae, representing four families (metatroch-less larvae of the Polynoidae and metatrochophore larvae of the Spionidae, the Magelonidae, and the Phyllodocidae). D-hinge veliger larvae of the oyster Crassostrea gigas were offered as prey. Predation was monitored over a range of prey densities and in the presence and absence of background plankton. "Background plankton" are any naturally occurring plankton assemblages found in whole, unfiltered seawater at ambient concentrations. For all polychaete larvae examined, when natural C. gigas densities and background plankton were used, no predation was observed. Magelonids and phyllodocids did not consume any C. gigas larvae, regardless of conditions. Polynoid and spionid trochophores consumed C. gigas veligers at both the "natural" and unnaturally high prey densities in filtered seawater. The addition of background plankton eliminated the predation at all natural prey densities and significantly reduced the predation observed at high prey densities. PMID- 28570205 TI - Oyster Shell Protein and Atomic Force Microscopy of Oyster Shell Folia. AB - The organic layers within biominerals often are viewed as sheets that may function in part to limit and define the underlying crystal structure, as well as to promote formation of the next mineral layer. Some insights into the nature of the sheets were revealed by atomic force microscopy (AFM) of surfaces of freshly cleaved fragments of oyster shell folia. Visible in the micrographs were arrays of globular structures that resembled the globules seen in isolated oyster shell protein bound to calcite, mica, and glass. The results of chemical treatment showed that the foliar globules slowly dissolved in 5.25% NaOCl or 1 N NaOH, reacted with an antibody prepared against an isolated oyster shell protein, and were hydrolyzed by several proteolytic enzymes. These morphological and chemical observations suggested that protein was a significant component of the foliar globules. Although they might also have a significant mineral content, the foliar globules were not effective as nucleators of CaCO3 crystal formation at low levels of supersaturation in artificial seawater. Overall, the results suggested that molecules of oyster shell protein may agglomerate and combine with mineral to form a surface of complex topography that coats the calcite laths but exhibits no obvious correspondence to any specific crystallographic plane. PMID- 28570206 TI - Increased incidence of gonorrhoea and chlamydia in Greenland 1990-2012. AB - BACKGROUND: Since the 1970s, Greenland has presented the highest reported incidence rates of the sexually transmitted infections (STIs) gonorrhoea and chlamydia in the Arctic regions. OBJECTIVE: This study aims to describe sex- and age-specific incidence rates of gonorrhoea and chlamydia from 1990 to 2012 in Greenland, and to evaluate if changes in case definitions, diagnostic procedures and implementation of STI interventions during the period coincide with rate changes. DESIGN: Gonorrhoea and chlamydia cases were identified from the national STI surveillance. For 1990-2008, STI cases were identified from weekly notified aggregated data. For 2009-2012, cases were identified in person-identifiable national registers. We used log-linear Poisson regression to calculate incidence rates (IRs) and incidence rate ratios (IRRs) with 95% confidence intervals (95% CI). Analyses were stratified according to sex, age and calendar period. RESULTS: Gonorrhoea and chlamydia incidence rates have increased since 1995 to reach 2,555 per 100,000 person-years (PY) for gonorrhoea and 6,403 per 100,000 PY for chlamydia in 2012. From 2006 to 2012, the incidence rates among young adults aged 15-19 years were 8,187 and 22,515 per 100,000 PY for gonorrhoea and chlamydia, respectively. Changes in surveillance reporting did not seem to influence the incidence rates for either disease, whereas a change in diagnostic test coincided with an increased incidence of chlamydia. CONCLUSION: Overall, the incidence of chlamydia in Greenland increased during the study period, whereas the incidence of gonorrhoea decreased until 1995 but increased thereafter. Young adults aged 15 24 years were at highest risk of infection. The increase in incidence rates was independent of changes in case definitions, whereas an observed increase in chlamydia incidence in 2005 coincided with a change in diagnostic test. None of the STI interventions launched after 1995 seemed to coincide with decreasing national incidence rates. PMID- 28570208 TI - Evaluating Healthy Corner Stores: A Survey of Assessment Tools Used in the San Francisco Bay Area, 2016. AB - Stakeholders from healthy corner store programs in the San Francisco Bay Area convened in November 2015 to discuss the future of programmatic and collaborative efforts. This study's objective, to gather and synthesize the types of evaluation tools used in the 9-county region, was identified as one of several priorities. Tools were collected via an online survey in July 2016, and data were extracted for comparison, including data on the number and types of food items, nutritional standards, and store characteristics. Twenty-five evaluation tools were collected, and differences were found in nutritional standards, terminology, and use of validated measures. Discrepancies between evaluation tools should be reconciled to make robust regional comparisons. PMID- 28570207 TI - Improving access to specialists in remote communities: a cross-sectional study and cost analysis of the use of eConsult in Nunavut. AB - BACKGROUND: Residents of remote communities face inequities in access to specialists, excessive wait times, and poorly coordinated care. The Champlain BASETM (Building Access to Specialists through eConsultation) service facilitates asynchronous communication between primary care providers (PCP) and specialists. The service was extended to several PCPs in Nunavut in 2014. OBJECTIVE: To (1) describe the use of eConsult services in Nunavut, and (2) conduct a costing evaluation. DESIGN: A cross-sectional study and cost analysis of all eConsult cases submitted between August 2014 and April 2016. RESULTS: PCPs from Nunavut submitted 165 eConsult cases. The most popular specialties were dermatology (16%), cardiology (8%), endocrinology (7%), otolaryngology (7%), and obstetrics/gynaecology (7%). Specialists provided a response in a median of 0.9 days (IQR=0.3-3.0, range=0.01-15.02). In 35% of cases, PCPs were able to avoid the face-to-face specialist visits they had originally planned for their patients. Total savings associated with eConsult in Nunavut are estimated at $180,552.73 or $1,100.93 per eConsult. CONCLUSIONS: The eConsult service provided patients in Nunavut's remote communities with prompt access to specialist advice. The service's chief advantage in Canada's northern communities is its ability to offer electronic access to a breadth of specialties far greater than could be supported locally. Our findings suggest that a territory-wide adoption of eConsult would generate enormous savings. PMID- 28570210 TI - Surgical innovation is harder than it looks. PMID- 28570212 TI - Vascular control during laparoscopic kidney donation. AB - SUMMARY: Laparoscopic donor nephrectomy (LDN) is the gold standard for kidney donation. Recent literature has led to considerable debate regarding the safest route to provide vascular control during this procedure. The most common devices used for vascular control during LDN are staplers and surgical clips. Opinions regarding the safety of these devices vary, as both are prone to dysfunction. Certain clips have already been contraindicated for use on the donor artery owing to reports of catastrophic complications of falling off. Donor safety is paramount to the continued success of renal transplantation in Canada. A review of existing practice at each institution may be called for to ensure the safest standards possible are in place. An appendix to this commentary is available at canjsurg.ca. PMID- 28570209 TI - Contrasting Trends of Smoking Cessation Status: Insights From the Stages of Change Theory Using Repeat Data From the Global Adult Tobacco Survey, Thailand (2009 and 2011) and Turkey (2008 and 2012). AB - OBJECTIVE: The World Health Organization recommends that smokers be offered help to quit. A better understanding of smokers' interest in and commitment to quitting could guide tobacco control efforts. We assessed temporal differences in stages of change toward quitting among smokers in Thailand and Turkey. METHODS: Two waves (independent samples) of data from the Global Adult Tobacco Survey, a national household survey of adults aged 15 years or older, were assessed for Thailand (2009 and 2011) and Turkey (2008 and 2012). Current smokers were categorized into 3 stages of change based on their cessation status: precontemplation, contemplation, and preparation. Relative change in the proportion of smokers in each stage between waves 1 and 2 was computed for each country. RESULTS: Between waves, overall current tobacco smoking did not change in Thailand (23.7% to 24.0%) but declined in Turkey (31.2% to 27.1%; P < .001). Between 2009 and 2011, precontemplation increased among smokers in Thailand (76.1% to 85.4%; P < .001), whereas contemplation (17.6% to 12.0%; P < .001) and preparation (6.3% to 2.6%; P < .001) declined. Between 2008 and 2012, there were declines in precontemplation among smokers in Turkey (72.2% to 64.6%; P < .001), whereas there were increases in contemplation (21.2% to 26.9%; P = .008) and no significant change in preparation (6.5% to 8.5%; P = .097). CONCLUSION: Nearly two-thirds of smokers in Turkey and more than two-thirds in Thailand were in the precontemplation stage during the last survey wave assessed. The proportion of smokers in the preparation stage increased in Turkey but declined in Thailand. Identifying stages of cessation helps guide population-based targeted interventions to support smokers at varying stages of change toward quitting. PMID- 28570213 TI - The University of Toronto's lasting contribution to war surgery: how Maj. L. Bruce Robertson fundamentally transformed thinking toward blood transfusion during the First World War. AB - SUMMARY: During the Great War, Canadian military surgeons produced some of the greatest innovations to improve survival on the battlefield. Arguably, the most important was bringing blood transfusion practice close to the edge of the battlefield to resuscitate the many casualties dying of hemorrhagic shock. Dr. L. Bruce Robertson of the Canadian Army Medical Corps was the pioneering surgeon from the University of Toronto who was able to demonstrate the benefit of blood transfusions near the front line and counter the belief that saline was the resuscitation fluid of choice in military medicine. Robertson would go on to survive the Great War, but would be taken early in life by influenza. Despite his life and career being cut short, Robertson's work is still carried on today by many military medical organizations who strive to bring blood to the wounded in austere and dangerous settings. This article has an Appendix, available at canjsurg.ca. PMID- 28570214 TI - Comparison of outcomes of root replacement procedures and supracoronary techniques for surgical repair of acute aortic dissection. AB - BACKGROUND: Surgical approach to type A acute aortic dissection (AADA) is usually dictated by the presenting anatomy. We compared long-term outcomes of AADA repaired with a root replacement versus a supracoronary tube graft, regardless of the proximal extent of the intimal tear. METHODS: A single-centre, retrospective cohort of consecutive patients undergoing repair of AADA between December 1999 and March 2012 were stratified based on the proximal surgical procedure performed: supracoronary tube graft or root replacement. Imaging, chart reviews and clinical follow-ups were analyzed to identify the presenting anatomy and clinical outcomes. RESULTS: We included the cases of 75 patients in our analysis: 54 received a supracoronary tube graft and 21 received a root replacement. The proximal tear was identified below the sinotubular junction in all patients in the root group and in 61% of patients in the supracoronary group. We detected no differences between the groups for in-hospital mortality, length of stay, or complications. However, the root group had significantly increased renal failure (0% v. 9.5%, p = 0.018), cardiopulmonary bypass time (198.4 +/- 80.0 min v. 316.5 +/- 102.5 min, p < 0.001), cross-clamp time (91.6 +/- 34.9 min v. 191.3 +/- 52.8 min, p < 0.001), duration of surgery (457.5 +/- 129.9 min v. 611.6 +/- 197.8 min, p < 0.001), and platelet transfusions (8.1 +/- 7.6 v. 12.8 +/- 8.7 units, p = 0.021) than the supracoronary group. Long-term follow-up demonstrated a greater incidence of 2+ aortic regurgitation among patients in the supracoronary group than the root group (29.7% v. 0.0%, p = 0.006); however, there was no difference between the groups in symptoms or reoperation. CONCLUSION: In AADA, aortic root replacement involves a longer procedure with increased risk of early renal impairment. Long-term follow-up identified significantly more aortic regurgitation and root dilation in the supracoronary group than the root group, with a trend toward worse long-term survival. However, we found no difference between the groups in mortality, reoperation or New York Heart Association class. PMID- 28570215 TI - A comparison of revisional and primary bariatric surgery. AB - BACKGROUND: Revisional surgery is an important component of addressing weight regain and complications following primary bariatric surgery. Owing to provincial need and the complexity of this patient population, a specialized multidisciplinary revision clinic was developed. We sought to characterize patients who undergo revision surgery and compare their outcomes with primary bariatric surgery clinic data. METHODS: We completed a retrospective chart review of bariatric revision clinic patients compared with primary bariatric surgery patients from December 2009 to June 2014. RESULTS: We reviewed the charts of 2769 primary bariatric clinic patients, 886 of whom had bariatric surgery, and 534 revision bariatric clinic patients, 83 of whom had revision surgery. Fewer revision clinic patients underwent surgery than primary clinic patients (22% v. 32%). The mean preoperative body mass index (BMI) was 44.7 +/- 9.5 in revision patients compared with 45.7 +/- 7.6 in primary bariatric surgery patients. Most revision patients had a prior vertical banded gastroplasty (VBG; 48%) or a laparoscopic adjustable gastric band (LAGB; 24%). Bands were removed in 36% of all LAGB patients presenting to clinic. Of the 134 procedures performed in the revision clinic, 83 were bariatric weight loss surgeries, and 51 were band removals. Revision clinic patients experienced a significant decrease in BMI (from 44.7 +/- 9.5 to 33.8 +/- 7.5, p < 0.001); their BMI at 12-month follow-up was similar to that of primary clinic patients (34.5 +/- 7.0, p = 0.7). Complications were significantly more frequent in revision patients than primary patients (41% v. 15%, p < 0.001). CONCLUSION: A bariatric revision clinic manages a wide variety of complex patients distinct from those seen in a primary clinic. Operative candidates at the revision clinic are chosen based on favourable medical, anatomic and psychosocial factors, keeping in mind the resource constraints of a public health care system. PMID- 28570216 TI - Thirteen-year wear rate comparison of highly crosslinked and conventional polyethylene in total hip arthroplasty: long-term follow-up of a prospective randomized controlled trial. AB - BACKGROUND: The purpose of this study was to report the radiographic wear rates from a previous randomized controlled trial of first-generation highly crosslinked versus conventional polyethylene in total hip arthroplasty (THA) at a minimum of 13 years' follow-up. METHODS: Patients returned for radiographic imaging and radiostereometric analysis (RSA). Radiographs were reviewed for the presence of osteolysis or component loosening. Femoral head penetration (which includes both wear and creep) was measured using RSA. We compared Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), 12-Item Short Form Health Survey (SF-12) and Harris Hip Scores (HHS) with preoperative values. RESULTS: There was 1 revision in each group. There was no difference in WOMAC, SF-12, or HHS outcome scores between the highly crosslinked and conventional polyethylene groups (all p >= 0.13). Wear rate was lower with crosslinked polyethylene than conventional polyethylene (0.04 +/- 0.02 mm/year v. 0.08 +/- 0.03 mm/year, p = 0.007). CONCLUSION: First-generation crosslinked polyethylene demonstrates greater wear resistance than conventional polyethylene after 13 years of implantation. Crosslinked polyethylene continues to outperform conventional polyethylene into the second decade of implantation. PMID- 28570217 TI - In memoriam of Dr. Tom Starzl. PMID- 28570218 TI - Surgical mentorship in Canada in 2017. PMID- 28570223 TI - First Case Report of Aseptic Meningitis Induced by Adalimumab Administered for Treatment of Chronic Plaque Psoriasis. PMID- 28570224 TI - Component-Resolved Diagnosis of Dog Allergy. PMID- 28570219 TI - Experimental and observational studies find contrasting responses of soil nutrients to climate change. AB - Manipulative experiments and observations along environmental gradients, the two most common approaches to evaluate the impacts of climate change on nutrient cycling, are generally assumed to produce similar results, but this assumption has rarely been tested. We did so by conducting a meta-analysis and found that soil nutrients responded differentially to drivers of climate change depending on the approach considered. Soil carbon, nitrogen, and phosphorus concentrations generally decreased with water addition in manipulative experiments but increased with annual precipitation along environmental gradients. Different patterns were also observed between warming experiments and temperature gradients. Our findings provide evidence of inconsistent results and suggest that manipulative experiments may be better predictors of the causal impacts of short-term (months to years) climate change on soil nutrients but environmental gradients may provide better information for long-term correlations (centuries to millennia) between these nutrients and climatic features. Ecosystem models should consequently incorporate both experimental and observational data to properly assess the impacts of climate change on nutrient cycling. PMID- 28570226 TI - Pulmonary Embolism After Ceftriaxone-Induced Anaphylaxis. PMID- 28570225 TI - Identification of Novel JAK3 Mutations by Whole-Exome Sequencing in a Korean Boy With Severe Combined Immunodeficiency. PMID- 28570227 TI - Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Overlap Induced by Fexofenadine. PMID- 28570228 TI - Troponin as a Cause of Hypersensitivity to Barnacle. PMID- 28570230 TI - Kounis Syndrome: Is it Really a Takotsubo-Like Syndrome? PMID- 28570229 TI - Desensitization to Cyanocobalamin: Rush Protocol. PMID- 28570231 TI - A Minimum Difference Between 2 Syndromes. PMID- 28570232 TI - Training of Spanish Allergology Residents in Pediatric Allergology: A Survey of the Current Situation. PMID- 28570233 TI - Sex-Related Differences in Outcomes After Percutaneous Balloon Aortic Valvuloplasty. AB - OBJECTIVES: We aimed to evaluate sex-related differences in short-term and long term outcomes of patients undergoing balloon aortic valvuloplasty (BAV) for severe aortic stenosis (AS). METHODS: A total of 112 patients with severe AS underwent 114 BAV procedures as palliative procedure, bridge to definitive treatment, or before urgent non-cardiac surgery. Patients were followed for 24 months. RESULTS: Of the 112 patients, 70 (62.5%) were women. Women were older, and had a higher STS score and higher prevalence of chronic kidney disease and arterial hypertension. Indications for BAV did not differ by gender. Women had a higher risk of vascular complications than men (15.7% vs 0.0%; P=.01), but with a similar rate of major periprocedural complications (17.1% vs 9.5%; P=.40). Transcatheter aortic valve implantation (TAVI) was performed in 22.8% of women and 26.2% of men (P=.61) and surgical aortic valve replacement in 10% of women and 11.9% of men (P=.70). Women and men treated finally with TAVI/aortic valve replacement had lower mortality as compared with conservative treatment (P<.01). No difference in in-hospital and 24-month mortality between women and men was observed (11.4% vs 4.9% [P=.26]; 63.3% vs 39.0% [P=.22], respectively). In a multivariable Cox model, STS score above 9.8% (hazard ratio, 2.29; 95% confidence interval, 1.09-4.83; P=.03) was an independent predictor of all-cause death only in women. CONCLUSION: Despite the presence of sex-related differences in baseline and procedural characteristics as well as in the risk of vascular complications, no difference in major procedural complications and long-term mortality was confirmed for patients with severe AS undergoing BAV. PMID- 28570234 TI - Impact of the Occlusion Duration on the Performance of J-CTO Score in Predicting Failure of Percutaneous Coronary Intervention for Chronic Total Occlusion. AB - OBJECTIVES: The present study examined the association between Multicenter CTO Registry in Japan (J-CTO) score in predicting failure of percutaneous coronary intervention (PCI) correlating with the estimated duration of chronic total occlusion (CTO). BACKGROUND: The J-CTO score does not incorporate estimated duration of the occlusion. METHODS: This was an observational retrospective study that involved all consecutive procedures performed at a single tertiary-care cardiology center between January 2009 and December 2014. RESULTS: A total of 174 patients, median age 59.5 years (interquartile range [IQR], 53-65 years), undergoing CTO-PCI were included. The median estimated occlusion duration was 7.5 months (IQR, 4.0-12.0 months). The lesions were classified as easy (score = 0), intermediate (score = 1), difficult (score = 2), and very difficult (score >=3) in 51.1%, 33.9%, 9.2%, and 5.7% of the patients, respectively. Failure rate significantly increased with higher J-CTO score (7.9%, 20.3%, 50.0%, and 70.0% in groups with J-CTO scores of 0, 1, 2, and >=3, respectively; P<.001). There was no significant difference in success rate according to estimated duration of occlusion (P=.63). Indeed, J-CTO score predicted failure of CTO-PCI independently of the estimated occlusion duration (P=.24). Areas under receiver-operating characteristic curves were computed and it was observed that for each occlusion time period, the discriminatory capacity of the J-CTO score in predicting CTO-PCI failure was good, with a C-statistic >0.70. CONCLUSION: The estimated duration of occlusion had no influence on the J-CTO score performance in predicting failure of PCI in CTO lesions. The probability of failure was mainly determined by grade of lesion complexity. PMID- 28570235 TI - Five-Year Freedom From Target-Lesion Revascularization Using Excimer Laser Ablation Therapy in the Treatment of In-Stent Restenosis of Femoropopliteal Arteries. AB - BACKGROUND: Target-lesion revascularization (TLR) and loss of patency remain high following treatment of in-stent restenosis (ISR) of the femoropopliteal (FP) artery. Excimer laser atherectomy (ELA) is effective in reducing TLR and improves patency at 6-month and 1-year follow-up when compared with balloon angioplasty (PTA). The long-term sustainability of these early results is unknown. We present a retrospective analysis from our center on the 5-year outcomes of ELA in the treatment of ISR of the FP arteries. METHODS: Patients who underwent ELA for FP ISR from February 2005 to April 2010 at a single medical center were included. Demographics, angiographic and procedural variables were included. Major adverse events and 5-year TLR and target-vessel revascularization were obtained from medical records. Descriptive analysis was performed on all variables. Kaplan Meier survival curves for TLR were plotted censored for death among patients who died before the occurrence of a TLR. RESULTS: Forty consecutive patients (mean age, 67.2 +/- 9.0 years; 57.5% males) were included. Angiographic variables included: lesion length, 210.4 +/- 104.0 mm; lesion severity, 93.9 +/- 8.9%; and number of vessel runoffs, 1.7 +/- 1.0. All patients were treated with adjunctive PTA. Acute procedural success was achieved in 92.5% of vessels. Distal embolization requiring treatment was 2.5%. No unplanned amputation occurred. Total deaths occurred in 8/40 (20%). At 5-year follow-up, TLR occurred in 62.5% with the steepest decline in freedom from TLR occurred in the first year followed by a less decline in the subsequent 2 to 3 years. CONCLUSION: ELA for FP-ISR continues to show progressive increase in TLR up to 5-year follow-up, but mostly occurs in the first 3 years after index procedure. These data suggest that a minimum follow-up of 3 years is needed to determine stability of treatment of FP ISR with laser. PMID- 28570236 TI - Transcatheter Aortic Valve Replacement Versus Surgical Valve Replacement in Low Intermediate Surgical Risk Patients: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a viable alternative to surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis (SAS) who are at high risk for surgery. We sought to evaluate the outcomes of TAVR vs SAVR in low-intermediate risk patients with SAS. METHODS AND RESULTS: We performed random-effects meta-analysis of randomized controlled trials (RCTs) and propensity-matched observational studies comparing TAVR vs SAVR for low-intermediate risk patients. Five RCTs and 5 observational studies with a total of 6891 patients (3489 TAVR patients; 3402 SAVR patients) were included. Pooled data from RCTs showed no significant differences in all-cause mortality between TAVR and SAVR at 30 days (risk ratio [RR], 1.04; 95% confidence interval [CI], 0.73-1.47) and intermediate-term follow-up (RR, 0.86; 95% CI, 0.67-1.10). A trend toward decreased mortality was found with TAVR using the self-expandable vs balloon-expandable valves (RR, 0.77; 95% CI, 0.52-1.15 and RR, 1.91; 95% CI, 0.25 14.53, respectively) and transfemoral vs transthoracic approach (RR, 0.74; 95% CI, 0.55-1.01 and RR, 2.09; 95% CI, 0.40-11.03, respectively). Compared to SAVR, TAVR was associated with similar risks of stroke (RR, 0.91; 95% CI, 0.74-1.11) and myocardial infarction (RR, 1.00; 95% CI, 0.71-1.41). Furthermore, risks of major vascular complications, moderate-severe paravalvular regurgitation, and new permanent pacemaker implantation were higher with TAVR, whereas SAVR was associated with higher rates of acute kidney injury, atrial fibrillation, and major or life-threatening bleed. Finally, the above results from RCTs were consistent with pooled analyses of observational studies. CONCLUSION: TAVR appears to be a suitable alternative for patients with SAS who are at low intermediate risk for SAVR. PMID- 28570237 TI - Born From Risk: What Made TAVR Possible and the Future of a Transformational Technology. PMID- 28570238 TI - Transcatheter Aortic Valve Replacement for Perceval Sutureless Aortic Valve Failure. AB - As experience with Perceval aortic prosthesis and valve-in-valve TAVR grows, it will be crucial to meticulously document short- and long-term follow-up for establishment of real-world safety and durability of these new technologies. PMID- 28570240 TI - Retrograde Intervention of a Right Coronary Artery Chronic Total Occlusion Through an Ipsilateral Kugel's Artery Collateral. AB - Kugel described the arteria anastomotica auricularis magna. We describe a first case of chronic total occlusion of the right coronary artery that was successfully recanalized using the reverse controlled antegrade and retrograde subintimal tracking technique through the ipsilateral Kugel's artery collateral. PMID- 28570239 TI - Spontaneous Coronary Artery Dissection After Pregnancy as First Manifestation of a Vascular Ehlers-Danlos Syndrome. AB - We report the case of a myocardial infarction in the post-partum period due to a spontaneous coronary artery dissection. The role of intracoronary imaging was critical: OCT imaging led us to formulate the right diagnosis.OCT imaging revealed a multiple coronary artery dissection in the left main non-detectable on angiography and in the circumflex, with evidence of coronary hematoma in the circumflex and left anterior descending. Beside dissection, OCT showed evidence of a thrombus near the coronary tear in the left main. Our invasive OCT-based strategy proved to be non-harmful and gave an excellent clinical result in the clinical context of a spontaneous multivessel coronary dissection with left main involvement in a rare connective tissue disorder. PMID- 28570241 TI - Coronary CT Angiography for In-Stent Restenosis: Diagnosis and Therapeutic Planning. AB - A 64-year-old man presented with previous non-ST elevation myocardial infarction and cardiogenic shock. Due to hemodynamic instability, percutaneous coronary intervention (PCI) was performed with implantation of two everolimus-eluting stents by V-stenting technique to LM-LAD and LM-LCX. After 9 months without symptoms, he developed progressive angina. Non-selective LM coronary angiography was performed due to stents protrusion in the aortic root. A 128-slice dual source coronary CT angiography showed severe LM-LAD stent underexpansion with critical in-stent restenosis at the proximal third. Two days later, selective angiography and optical coherence tomography depicted stent underexpansion and confirmed the in-stent restenosis. This case is illustrative of the potential role of the complementary use of invasive and non-invasive imaging techniques. The coronary CT angiography was very useful to identify the severity and mechanism of restenosis, and thus guiding the PCI procedure in a case of especially difficult catheterization. PMID- 28570242 TI - Percutaneous Transaxillary Transcatheter Aortic Valve Replacement. AB - The axillary artery is an alternative, large-caliber vessel that can be utilized in the presence of hostile aortoiliac segments. It can accommodate sheaths up to 18 Fr and is infrequently affected by atherosclerosis. PMID- 28570243 TI - Hemodynamic Findings of Severe Subacute Aortic Regurgitation. AB - The hemodynamic features of subacute aortic regurgitation include equalization of the left ventricular pressure and the aortic pressure during diastole, a mildly increased pulse pressure, and systemic hypotension. These findings are distinct from the hemodynamics of chronic aortic regurgitation. PMID- 28570244 TI - Transcatheter Tricuspid Valve Replacement in Orthotopic Heart Transplant. AB - A patient with history of orthotopic heart transplant (OHT) followed by tricuspid valve replacement and two subsequent balloon valvuloplasties was offered transcatheter tricuspid valve replacement (TTVR) to avoid what would have been his fourth sternotomy. TTVR in patients with OHT can be a valuable approach to prevent further open-heart surgeries, which carry added morbidity and mortality. PMID- 28570245 TI - A Descriptive Study to Explore the Effect of Peristomal Skin Complications on Quality of Life of Adults With a Permanent Ostomy. AB - Approximately 1 million people are living with an ostomy, and 100 000 to 130 000 new ostomies are created each year. The exact incidence and prevalence of complications are unknown but have been reported to be as high as 70% and to affect quality of life (QoL). Using convenience sampling methods, a descriptive study was conducted to explore QoL scores and peristomal complications reported by adults with a permanent ostomy attending the 2009 United Ostomy Associations of America conference. Attendees who had a permanent ileostomy, colostomy, or urostomy; were at least 18 years of age; and able to read and speak English were invited to participate. Participants completed a paper/pen survey containing questions about demographics (age, gender, marital status), ostomy (time since and reason for surgery, ostomy type), and peristomal complication variables (number and type, who provided help, and satisfaction with treatment rated on a Likert-type scale from 0 [not satisfied] to 100 [completely satisfied]). QoL data were collected using the City of Hope-Quality of Life-Ostomy Questionnaire (COH QOL-OQ), which consists of 2 sections - Lifestyle Impact and Quality of Life Impact - and measures 4 QoL domains on a scale of 1 (lower) to 10 (higher) QoL. Descriptive statistics (means, standard deviation, frequencies, percentages) were used to describe the demographic, ostomy, and peristomal complication variables. Univariate analyses of covariance were used to investigate the relationships among QoL scores and peristomal complications, and the number of different complications was correlated with the QoL total score using hierarchical multiple regression analysis. Of the 230 eligible participants invited, 140 (the majority women [83, 59.3%], with an ileostomy [86, 61.4%], and a diagnosis of ulcerative colitis [55, 39.3%]) met inclusion criteria and completed the survey. The majority of participants were married both before (97, 69.3%) and after (88, 62.9%) surgery; the mean QoL score was 7.56 (SD 1.59). The mean number of complications was 0.83 (SD 1.03); approximately one third of participants experienced allergic contact dermatitis (43, 32.3%), and persons with irritant contact dermatitis reported significantly lower QoL total scores (mean 6.64 [SD 1.64], P = .02) than those without this complication (mean 7.77 [1.56]). Of those with complications, most saw an ostomy nurse (33, 47.8%), but many did not see anyone for help with their complications (24, 16.3%). Persons who sought help were generally satisfied with the help received (mean satisfaction score 77.94 +/ 24.71). In this study, allergic contact dermatitis was the most common peristomal complication reported. Irritant contact dermatitis negatively affected QoL, and almost half of the participants sought the help of an ostomy care nurse. The results of this study suggest patients may benefit from more education about peristomal complications and the reporting of appliance-related contact dermatitis. Studies examining the presence of peristomal skin complications and their influence on QoL, as well as availability of and access to follow-up care with qualified ostomy nurses, are needed. PMID- 28570246 TI - A Retrospective Study of the Impact of Pressure Ulcers on Survival in Elderly Persons With Chronic Diseases. AB - Medical advancements are extending the lives of persons with chronic diseases, increasing their risk for pressure ulcer (PU) development. A retrospective chart review of 192 patients (49.48% male, mean age 9.7 +/- 10.9 years) admitted to a skilled nursing department between 2008 and 2013 was performed to determine whether PUs and comorbidities, singly and combined, affect patient survival. Characteristics abstracted and assessed included sociodemographic factors (age, gender), diseases/comorbidities (eg, chronic renal failure, dementia, Parkinson's disease [PD], ischemic heart disease, and diabetes mellitus), persistent vegetative state (PVS), type and quantity of PUs (excluding Stage I and PUs that developed during the study), body mass index (BMI) <22, and laboratory data (serum albumin, total protein level, and hemoglobin [Hg] <10). Results were expressed as proportion or mean +/- standard deviation. All statistical tests were 2-sided. A P value <.05 was considered significant. Hazard ratios (HR) and statistical significance for survival by risk factors were calculated by the Cox proportional hazards model. Univariate survival models were fitted for all risk factors. Statistical and clinical considerations were used to choose a subset of significant factors to include in a multivariate survival model; all chosen factors were fitted at the first step of the univariate survival models. Age, gender, and BMI were included in the model due to their known clinical effects on survival and their influence on other prognostic factors. In assessing anemia and Hg, only anemia was included due to multicollinearity. From the chosen factors fitted at the first step, a backward elimination was used to successively remove nonsignificant factors until all factors were significant at the 0.10 level. Patients were followed from hospitalization date until death or censoring of study. Median survival time was 122 days (CI: 82-192 days). The median survival time of patients with PUs was 72 days. Every increase in the number of PUs increased mortality by 14% (P <.001, HR = 1.14, CI: 1.07-1.20). In univariate analysis, PUs, anemia, dementia, and PD were found to have a significant association with decreased survival (P = .0001, .003, .001, and .004, respectively). In multivariate analysis, significant risk factors for decreasing survival time were the presence of PUs (HR = 1.14, P = .0001) and dementia (HR = 1.585, P = .009). Anemia (HR = 1.345, P = .09) and PVS (HR = 0.51, P = .09) were determined not to be significant. Anemia was found to decrease survival time and PVS was found to increase survival time. When number of PUs was combined with anemia, advanced dementia, or BMI, the median survival decreased from 72 days to 52, 63, and 63 days, respectively. These findings suggest that PUs in this population are not an isolated health problem but are 1 indicator of systemic deterioration and decreased survival time. The significance of knowing the survival time of patients with PUs has clinical and ethical implications for the comprehensive treatment of elderly patients, particularly those with advanced dementia and other associated medical conditions. PMID- 28570247 TI - Cross-cultural Adaptation and Validation of the Stoma Quality of Life Questionnaire for Patients With a Colostomy or Ileostomy in Brazil: A Cross sectional Study. AB - Many studies examining the quality of life of stoma patients utilize questionnaires that have not been validated specifically for these patients in their native language. Owing to the large and increasing prevalence of intestinal stomas, a cross-sectional study was conducted among patients of a stoma patient health care service in Juiz de Fora, Brazil between September 2014 and August 2015 to validate the Stoma Quality of Life (Stoma-QoL) questionnaire in Portuguese (Brazilian variant). In addition, the effect of sociodemographic, clinical, and eating habit variables on the quality of life of people with a colostomy or ileostomy was assessed. Eating habit variables included eating comfort in the postoperative period, excluding foods for a period of time, fear of eating, and excluding foods that may cause odor, gas, diarrhea, and/or constipation. All patients with a colostomy or ileostomy served by 1 ostomy care center were invited to participate. Patients who were at least 18 years of age, provided signed informed consent, and had the physical and mental capacity to complete the questionnaire were eligible to participate. The sociodemographic, clinical history, eating behavior, and Stoma-QoL questionnaires were administered by trained researchers as part of patient nutritional care. A sample of 11 (10% of all study participants) also completed the 12-item Short Form Health Survey (SF-12), which includes a Mental Component Summary (MCS) and a Physical Component Summary (PCS), to establish convergent validity. All participant response data were collected using a standardized form developed for this study and stored in electronic files. The identities of patients were kept anonymous, and patients had the option to refuse to participate during the assessment. Data were analyzed descriptively; the Mann-Whitney and Kruskal-Wallis tests were used to analyze associations among the variables collected. Normal distribution of the Stoma-QoL total scores was assessed using the Kolmogorov-Smirnov test. Internal consistency was assessed as a whole using Cronbach's alpha, and agreement and reproducibility were determined using the intraclass correlation coefficient. Relationships between the Stoma-QoL and the SF-12 items were examined using the Pearson correlation coefficient. The majority of the 111 participants were men (57, 51.4%), most (94, 84.7%) were 50 years of age or older, 70 (63.1%) had a colostomy, and 41 (36.9%) had an ileostomy. Most stomas (79, 71.2%) were created to treat cancer of the colon and rectum. The mean overall Stoma-QoL score for study participants was 58.7 +/- SD 12.0 (range 32.0-78.0). The internal consistency of the translated Stoma-QoL was .87, demonstrating a high degree of reliability. The convergent validity of the Stoma-QoL with the SF-12 confirmed higher correlation among the items regarding emotional aspects, mental health, social aspects, and vitality, with a higher correlation with the MCS (r = .52; P = .02) and lower correlation between the PCS and the items that assess general health, functional capacity, physical aspects, and pain (r = .38; P = .04), although both were significant. A moderate and significant association was noted between the questionnaires. Women (P = .02) and patients who deprived themselves of food for a certain period of time had a lower quality of life (P = .05). Persons who excluded foods out of fear of repercussions also had significantly lower QoL scores (P <.001). Colostomy and ileostomy patients had a similar quality of life. This study confirms the Stoma-QoL is a valid research tool for colostomy and ileostomy patients in Brazil. Further studies are recommended in the field of food and nutrition to verify observed concerns related to the eating behavior of intestinal stoma patients and the relationship to their quality of life. PMID- 28570248 TI - The International Consolidated Venous Ulcer Guideline Update 2015: Process Improvement, Evidence Analysis, and Future Goals. AB - In 2015, members of the Association for the Advancement of Wound Care (AAWC), Wound Healing Society, and the Canadian Association for Enterostomal Therapy formed the International Consolidated Guidelines Taskforce to update the AAWC Venous Ulcer Guidelines to the collaborative, intersociety, endorsed International Consolidated Venous Ulcer Guideline. This "guideline of guidelines" integrates recommendations from all relevant, published evidence-based guidelines on venous ulcer care and prevention. The update process was conducted in accordance with the National Guideline Clearinghouse inclusion criteria and was informed by a systematic review of the evidence, with additional content validation of each venous ulcer management recommendation. Twenty-three (23) wound experts participated. Compared to the 2010 version of the guideline, A level recommendations increased from 62% to 77%, 31 recommendations were removed, and new recommendations included quality of life evaluations and surgical treatment options. Gaps in the evidence and needed areas for research include surgical, topical, and pharmaceutical interventions. Collaboration among societies and stakeholders and rigorous guideline development processes may expedite the implementation of evidence-based practices, fill in research gaps, and provide a powerful unified voice to regulatory and reimbursement agencies with the ultimate goal of improving outcomes for persons with a venous ulcer. PMID- 28570249 TI - Early Detection of Pressure Injury Using a Forensic Alternate Light Source. AB - OBJECTIVE: This study aimed to determine if an alternate light source (ALS) can be used to detect tissue trauma before visible manifestations of tissue injury are evident with the naked eye. MATERIALS AND METHODS: Ten participants were recruited and gave consent, and 7 completed the study. Researchers examined and photographed participants' heels in ambient light to establish baseline. A series of photographs using ALS and camera were taken as follows: violet wavelength at 415 nm to 445 nm with yellow lens; blue wavelength at 455 nm to 515 nm with orange lens; and green wavelength at 535 nm to 575 nm with red lens. Participants were examined weekly for 6 consecutive weeks to ascertain skin changes in ambient light and through the ALS. RESULTS: Overt tissue changes were noted when viewed with the ALS and camera compared with visual screens in ambient light. Descriptive statistics were calculated for all wavelengths. Two chi-square tests of independence were run to look for relationships between wavelength and the number of detected injuries (absorption). CONCLUSIONS: Participants presenting with nonblanching erythema in ambient light showed significant tissue absorption under ALS and camera, depicting the actual scope and magnitude of the tissue trauma. Participants with scars, areas of previous injury, and pigmentary changes also showed significant absorption at those sites. These combined findings indicate that ALS can detect tissue trauma and areas at risk not readily visible by the naked eye. This noninvasive tool could help identify patients in the early stages of tissue trauma as well as screen for sites of previous injury that are at risk for subsequent breakdown, saving significant health care dollars and improving outcomes and quality of life. PMID- 28570250 TI - Effect of Negative Pressure Wound Therapy With Instillation on Bioburden in Chronically Infected Wounds. AB - INTRODUCTION: Standard negative pressure wound therapy (NPWT) has been shown to help close wounds despite increasing planktonic bioburden. Both planktonic and biofilm critical colonization are associated with delayed wound healing; therefore, reducing microbial colonization is thought to aid wound healing. The use of NPWT with topical antimicrobial irrigation solution has previously shown reduction in quantitative planktonic bioburden when combined with sharp debridement in chronic wounds. OBJECTIVE: The goal of this study was to evaluate the effectiveness of NPWT with instillation (NPWTi) on biofilm of chronic wounds. MATERIALS AND METHODS: A prospective, randomized trial was conducted. Following sharp debridement, 20 patients with chronic wounds were randomized to 1 week of either NPWTi with 0.125% sodium hypochlorite solution (n = 10) or NPWT without instillation (n = 10). Serial wound biopsy was performed predebridement, postdebridement, and after 1 week of study therapy to test for quantitative nonplanktonic or biofilm-protected bacteria. RESULTS: As expected, there was no difference in change in wound size between the 2 groups at 1 week. The NPWTi group had a mean reduction in quantitative biofilm-protected bacteria of 48%, while the NPWT without instillation group had a mean increase of 14% (P < .05). DISCUSSION: Consistent with previous studies, this trial demonstrates that NPWTi with dilute sodium hypochlorite solution is effective at reducing nonplanktonic bioburden of chronically, critically colonized wounds. CONCLUSION: Therefore, based on this and previously published work, this therapy provides both planktonic and nonplanktonic bioburden reduction as well as NPWT benefits and may be a tool for the preparation of infected wound beds prior to definitive closure. PMID- 28570251 TI - Comparative Clinical Study of the Wound Healing Effects of a Novel Micropore Particle Technology: Effects on Wounds, Venous Leg Ulcers, and Diabetic Foot Ulcers AB - OBJECTIVE: The purpose of this study was to determine the wound healing effects of Acapsil, a white, odorless powder based on micropore particle technology (MPPT) (Willingsford Ltd, Southampton, UK) by comparing it to Gentaxane (Gentaksan, Borshchagovsky CCP, Kyiv, Ukraine) (polydimethylsiloxane powder with gentamicin antibiotic) and Ioddicerin (Farmak, Kyiv, Ukraine) (iodine with dimethyl sulfoxide [DMSO]). MATERIALS AND METHODS: The study included 266 patients with primarily trophic ulcers caused by pancreatic diabetes and venous insufficiency of the lower extremities, carbuncles, phlegmons, infected third- or fourth-degree heat burns, and infiltrations of postoperative wounds. The products were applied once daily to the wound until it was clean (ie, free from necrosis, pus, and fibrinogenous thickenings). RESULTS: The number of days (mean +/- standard deviation) to a clean wound was 3.0 +/- 0.9 for MPPT (n = 88) compared with 7.0 +/- 1.2 and 8.0 +/- 1.1 for Gentaxane (n = 90) and iodine/DMSO (n = 88), respectively. Thus, MPPT reduced the time to reach a clean wound by 57% and 62%, respectively. Products were used once daily until a clean wound was reached, which also reflects the number of applications. Days to onset of granulation for MPPT, Gentaxane, and iodine/DMSO were 4.5 +/- 0.8, 9.2 +/- 1.4, and 10.3 +/- 1.5 days, respectively; and days to onset of epithelialization were 7.8 +/- 1.1, 14.1 +/- 1.9, and 16.4 +/- 2.7 days, respectively. Subgroup analysis of patients with diabetic foot and venous leg ulcers found that each of these demonstrated the same pattern of healing as the overall study. The number of hospitalization days was 14.6 +/- 5.6 for MPPT, 21.0 +/- 10.7 for Gentaxane, and 24.0 +/- 7.9 for iodine/DMSO. Compared with Gentaxane, patients receiving MPPT had a 31% reduction in hospitalization duration and a 39% reduction compared with iodine/DMSO. CONCLUSION: These findings demonstrate that MPPT represents a valuable new approach to wound care. PMID- 28570252 TI - The Comparative Effectiveness of a Human Fibroblast Dermal Substitute versus a Dehydrated Human Amnion/Chorion Membrane Allograft for the Treatment of Diabetic Foot Ulcers in a Real-world Setting. AB - BACKGROUND: Impaired wound healing is associated with serious complications in patients with diabetes. Diabetic foot ulcers (DFUs) can lead to costly complications and an increased mortality rate. Standard treatments for DFUs often need to be augmented with adjunctive therapies designed to stimulate healing in recalcitrant wounds. OBJECTIVE: This analysis was conducted to evaluate the comparative effectiveness of a human broblast-derived dermal substitute (HFDS) and a dehydrated human amnion/chorion membrane allograft (dHACM) for the treatment of DFUs. MATERIALS AND METHODS: Using a wound care-specic electronic health record database, real-world outcomes from 122 patients with 122 DFUs receiving treatment in 2014 in 72 wound care facilities across the United States were evaluated. Key criteria for entry into the analysis included ulcer size >= 1 cm2 to < 25 cm2, ulcer duration <= 1 year, and ulcer area reduction <= 20% in the 14 days prior to the rst treatment. Key exclusion criteria included lack of follow-up visits and lack of baseline wound measurements. The frequency of wound closure by weeks 12 and 24, median time to wound closure, hazard ratio with 95% con dence interval, and P value were estimated from a Cox model with terms for treatment, baseline wound area, baseline wound duration, baseline wound depth, and wound location. RESULTS: The results show the incidence of wound closure for HFDS compared with dHACM was signicantly improved by weeks 12 (55% vs. 32%) and 24 (76% vs. 50%). The HFDS treatment signi cantly increased the probability of wound closure by 107%, with a median time to closure of 7.4 weeks (38%) less than that of dHACM treatment (P = .02). PMID- 28570253 TI - Review of Silicone Gel Sheeting and Silicone Gel for the Prevention of Hypertrophic Scars and Keloids. AB - BACKGROUND: Keloids and hypertrophic scars are fibroproliferative disorders of dermal tissue after skin injury. Many clinical control studies have reported evidence that silicone gel is effective in preventing and alleviating hypertrophic scarring. Whether silicone gel sheeting prevents hypertrophic scars or keloids requires clear evidence of its clinical effectiveness. OBJECTIVE: This review investigated the effectiveness of silicone gel and silicone gel sheeting for the prevention of hypertrophic or keloid scarring in patients with newly healed wounds. METHODS: The authors searched the MEDLINE, EMBASE, CINAHL, and CENTRAL databases (January 1, 1990 to September 24, 2014) for any randomized or quasi-randomized controlled trials or controlled clinical trials comparing silicone gel sheeting or silicone gel with a control group for prevention of hypertrophic scars or keloids. All collected trials were assessed for methodological quality, control group and treatment group, and number of participants developing hypertrophic scars and keloids. The authors calculated risk ratios (RR) from each trial for the development of abnormal scarring and combined these using random-effects model meta-analysis. Between-study heterogeneity was calculated by using the I2 statistic. RESULTS: Ten trials in 9 studies were pooled (random effect; I2 = 88%). There was a significant difference between the silicone gel sheeting group and the placebo group (RR 0.70; 95% confidence interval, 0.49-0.99; P = .04) in preventing the risk of hypertrophic scars. CONCLUSION: There was statistical significance in the effectiveness of silicone gel and silicone gel sheeting on the prevention of keloids or hypertrophic scars, especially in skin lesion wounds. However, most of the trials evaluating silicone gel sheeting or silicone gel as a prevention of hypertrophic scars and keloids had poor quality with high or uncertain risk of biases either in study design or in conduct. PMID- 28570255 TI - An Unusual Presentation of Deep Tissue Injury, Do We Really Understand It? A Case Report and Literature Review AB - Deep tissue injury (DTI) is an injury to the soft tissue under the skin due to pressure and is usually over boney prominence. This injury is commonly seen in bedridden patients in hospitals and nursing homes. Although many efforts were made to elucidate the precise mechanism and clinical presentation, the pathogenesis and the final clinical outcome are yet to be determined. Although the current agreed upon presentation describes DTI as purple- or maroon-colored skin with ulceration, presented herein is an unusual case where DTI presented with only erythema and induration over the sacrum and right gluteal area. PMID- 28570256 TI - The Vulva: An Uncommon Presentation of a Pressure Ulcer. AB - : Pressure ulcers may develop in different locations. Vulvar pressure ulcers can be easily misdiagnosed and, moreover, have been rarely reported in the literature. Surgical procedures that involve prolonged pressure on this area may trigger these lesions. CASE REPORT: The authors present a case of a vulvar pressure ulcer secondary to the use of a perineal post to provide countertraction during surgical repair of a hip fracture. Diagnosis was made after excluding other possible causes with anatomopathological and microbiological analysis. Wound care was based on relieving local pressure. CONCLUSION: Faced with the acute development of ulcers in the external genitals of women after this kind of surgical procedure, even with the use of padded posts, diagnosis of a pressure ulcer should be considered after excluding other possible causes. PMID- 28570257 TI - The Impact of Proximal Vessel Tortuosity on the Outcomes of Chronic Total Occlusion Percutaneous Coronary Intervention: Insights From a Contemporary Multicenter Registry. AB - INTRODUCTION: We examined the impact of proximal vessel tortuosity on the outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). METHODS: The baseline clinical and angiographic characteristics and procedural outcomes of 1618 consecutive CTO-PCIs performed between 2012 and 2016 at 14 United States centers in 1589 patients were reviewed. RESULTS: Mean patient age was 65.3 +/- 10.0 years and 85% were men. Moderate/severe proximal vessel tortuosity was present in 35.7% of target lesions. Compared with non-tortuous lesions, tortuous lesions had longer length (30 mm [interquartile range, 20-50 mm] vs 28 mm [interquartile range, 16-40 mm]; P<.001), more proximal cap ambiguity (36% vs 28%; P<.01), and more frequent utilization of the retrograde approach (52% vs 37%; P<.001). Moderate/severe proximal vessel tortuosity was associated with lower technical success rates (84.1% vs 91.3%; P<.001) and procedural success rates (82.3% vs 89.9%; P<.001), but similar incidence of major cardiac adverse events (3.0% vs 2.5%; P=.59). Moderate/severe tortuosity was associated with longer procedure time and fluoroscopy time, higher air kerma radiation dose, and larger contrast volume. CONCLUSION: In a contemporary multicenter registry, moderate/severe proximal vessel tortuosity was present in approximately one-third of target CTO lesions and was associated with more frequent use of the retrograde approach and lower success rates, but similar complication rates. PMID- 28570258 TI - Novel Method for Exchange of Impella Circulatory Assist Catheter: The "Trojan Horse" Technique. AB - Patients with an indwelling Impella may require escalation of hemodynamic support or exchange to another circulatory assistance platform. As such, preservation of vascular access is preferable in cases where anticoagulation cannot be discontinued or to facilitate exchange to an alternative catheter or closure device. Challenges exist in avoiding bleeding and loss of wire access in these situations. We describe a single-access "Trojan Horse" technique that minimizes bleeding while maintaining arterial access for rapid exchange of this percutaneous ventricular assist device. PMID- 28570259 TI - Propensity-Score Matched Comparison of the Cera PFO Occluder With the Amplatzer PFO Occluder for Percutaneous Closure of Patent Foramen Ovale Without Echocardiographic Guidance. AB - BACKGROUND: Percutaneous patent foramen ovale (PFO) closure has become a routine procedure and was proven to be safe and feasible. In a recently published pooled analysis of randomized trials, percutaneous PFO closure was shown to more effectively reduce recurrent stroke when compared with medical therapy in patients with cryptogenic strokes. However, procedural safety and closure rate are device dependent. METHODS: We performed a propensity-score matched comparison of 28 patients undergoing percutaneous PFO closure using the Cera PFO occluder (CPO) with 28 patients who received the Amplatzer PFO occluder (APO). The main endpoints were procedural complications and closure rate at 6 months verified by transesophageal echocardiography. RESULTS: The implantation procedure using the CPO was successful and without complications in all cases. After propensity-score matching, there was no significant difference between groups for the primary endpoint of residual shunt at 6 months (7% in the CPO group vs 4% in the APO group; log-rank test P=.15). CONCLUSIONS: With regard to procedural safety and closure rate at 6 months, the performance of the CPO is comparable with the APO in this small patient cohort. PMID- 28570261 TI - A general method for motion compensation in x-ray computed tomography. AB - Motion during data acquisition is a known source of error in medical tomography, resulting in blur artefacts in the regions that move. It is critical to reduce these artefacts in applications such as image-guided radiation therapy as a clearer image translates into a more accurate treatment and the sparing of healthy tissue close to a tumour site. Most research in 4D x-ray tomography involving the thorax relies on respiratory phase binning of the acquired data and reconstructing each of a set of images using the limited subset of data per phase. In this work, we demonstrate a motion-compensation method to reconstruct images from the complete dataset taken during breathing without recourse to phase binning or breath-hold techniques. As long as the motion is sufficiently well known, the new method can accurately reconstruct an image at any time during the acquisition time span. It can be applied to any iterative reconstruction algorithm. PMID- 28570260 TI - Comparison of Non-Contrast Cardiovascular Magnetic Resonance Imaging to Computed Tomography Angiography for Aortic Annular Sizing Before Transcatheter Aortic Valve Replacement. AB - BACKGROUND: Accurate measurement of aortic annulus is crucial before transcatheter aortic valve replacement (TAVR). Computed tomography (CT) angiography is the most commonly utilized method, but requires contrast administration. Cardiovascular magnetic resonance (CMR) imaging is a promising alternative modality to provide aortic annulus measurements. Few studies have compared the clinical feasibility and accuracy of non-contrast CMR to contrast enhanced computed tomography (CT) angiography in order to provide a non-contrast alternative to CT annular sizing. METHODS: Twenty-one consecutive patients (mean age, 85.7 +/- 5.2 years) with severe aortic stenosis (mean aortic valve area, 0.6 +/- 0.1 cm2) underwent pre-TAVR CT angiography and a non-contrast CMR at 1.5 T. CT measurements were performed during systole as the clinical non-invasive standard. CMR measurements were performed during systole and diastole and included three-dimensional (3D) and two-dimensional (2D) methods. Interobserver differences were assessed using intraclass correlation. We recorded scan time in each patient. RESULTS: The mean systolic annular area was not significantly different between CT and 3D-CMR (480.0 +/- 77.9 mm2 vs 479.4 +/- 66.2 mm2; P=.98) in systole. There was no clinically relevant systematic difference between area measurements [mean difference, 0.6 mm2; limits of agreement -38.2 mm2; 39.3 mm2] using Bland-Altman analyses. Interobserver correlation was excellent. The diagnostic systolic 3D-CMR annular sizing scan was achieved in 4.4 +/- 2.7 min. CONCLUSION: Non-contrast CMR protocol for the measurement of aortic annulus area is feasible and accurate. 3D-CMR could provide an alternative for annular sizing pre-TAVR assessment in patients who cannot undergo contrast-enhanced CT studies. PMID- 28570262 TI - Automatized spleen segmentation in non-contrast-enhanced MR volume data using subject-specific shape priors. AB - To develop the first fully automated 3D spleen segmentation framework derived from T1-weighted magnetic resonance (MR) imaging data and to verify its performance for spleen delineation and volumetry. This approach considers the issue of low contrast between spleen and adjacent tissue in non-contrast-enhanced MR images. Native T1-weighted MR volume data was performed on a 1.5 T MR system in an epidemiological study. We analyzed random subsamples of MR examinations without pathologies to develop and verify the spleen segmentation framework. The framework is modularized to include different kinds of prior knowledge into the segmentation pipeline. Classification by support vector machines differentiates between five different shape types in computed foreground probability maps and recognizes characteristic spleen regions in axial slices of MR volume data. A spleen-shape space generated by training produces subject-specific prior shape knowledge that is then incorporated into a final 3D level set segmentation method. Individually adapted shape-driven forces as well as image-driven forces resulting from refined foreground probability maps steer the level set successfully to the segment the spleen. The framework achieves promising segmentation results with mean Dice coefficients of nearly 0.91 and low volumetric mean errors of 6.3%. The presented spleen segmentation approach can delineate spleen tissue in native MR volume data. Several kinds of prior shape knowledge including subject-specific 3D prior shape knowledge can be used to guide segmentation processes achieving promising results. PMID- 28570263 TI - PET image reconstruction using multi-parametric anato-functional priors. AB - In this study, we investigate the application of multi-parametric anato functional (MR-PET) priors for the maximum a posteriori (MAP) reconstruction of brain PET data in order to address the limitations of the conventional anatomical priors in the presence of PET-MR mismatches. In addition to partial volume correction benefits, the suitability of these priors for reconstruction of low count PET data is also introduced and demonstrated, comparing to standard maximum likelihood (ML) reconstruction of high-count data. The conventional local Tikhonov and total variation (TV) priors and current state-of-the-art anatomical priors including the Kaipio, non-local Tikhonov prior with Bowsher and Gaussian similarity kernels are investigated and presented in a unified framework. The Gaussian kernels are calculated using both voxel- and patch-based feature vectors. To cope with PET and MR mismatches, the Bowsher and Gaussian priors are extended to multi-parametric priors. In addition, we propose a modified joint Burg entropy prior that by definition exploits all parametric information in the MAP reconstruction of PET data. The performance of the priors was extensively evaluated using 3D simulations and two clinical brain datasets of [18F]florbetaben and [18F]FDG radiotracers. For simulations, several anato functional mismatches were intentionally introduced between the PET and MR images, and furthermore, for the FDG clinical dataset, two PET-unique active tumours were embedded in the PET data. Our simulation results showed that the joint Burg entropy prior far outperformed the conventional anatomical priors in terms of preserving PET unique lesions, while still reconstructing functional boundaries with corresponding MR boundaries. In addition, the multi-parametric extension of the Gaussian and Bowsher priors led to enhanced preservation of edge and PET unique features and also an improved bias-variance performance. In agreement with the simulation results, the clinical results also showed that the Gaussian prior with voxel-based feature vectors, the Bowsher and the joint Burg entropy priors were the best performing priors. However, for the FDG dataset with simulated tumours, the TV and proposed priors were capable of preserving the PET unique tumours. Finally, an important outcome was the demonstration that the MAP reconstruction of a low-count FDG PET dataset using the proposed joint entropy prior can lead to comparable image quality to a conventional ML reconstruction with up to 5 times more counts. In conclusion, multi-parametric anato-functional priors provide a solution to address the pitfalls of the conventional priors and are therefore likely to increase the diagnostic confidence in MR-guided PET image reconstructions. PMID- 28570264 TI - Fast interactive segmentation of the pulmonary lobes from thoracic computed tomography data. AB - Automated lung lobe segmentation methods often fail for challenging and clinically relevant cases with incomplete fissures or substantial amounts of pathology. We present a fast and intuitive method to interactively correct a given lung lobe segmentation or to quickly create a lobe segmentation from scratch based on a lung mask. A given lobar boundary is converted into a mesh by principal component analysis of 3D lobar boundary markers to obtain a plane where nodes correspond to the position of the markers. An observer can modify the mesh by drawing on 2D slices in arbitrary orientations. After each drawing, the mesh is immediately adapted in a 3D region around the user interaction. For evaluation we participated in the international lung lobe segmentation challenge LObe and lung analysis 2011 (LOLA11). Two observers applied the method to correct a given lung lobe segmentation obtained by a fully automatic method for all 55 CT scans of LOLA11. On average observer 1/2 required 8 +/- 4/25 +/- 12 interactions per case and took 1:30 +/- 0:34/3:19 +/- 1:29 min. The average distances to the reference segmentation were improved from an initial 2.68 +/- 14.71 mm to 0.89 +/- 1.63/0.74 +/- 1.51 mm. In addition, one observer applied the proposed method to create a segmentation from scratch. This took 3:44 +/- 0:58 minutes on average per case, applying an average of 20 +/- 3 interactions to reach an average distance to the reference of 0.77 +/- 1.14 mm. Thus, both the interactive corrections and the creation of a segmentation from scratch were feasible in a short time with excellent results and only little interaction. Since the mesh adaptation is independent of image features, the method can successfully handle patients with severe pathologies, provided that the human operator is capable of correctly indicating the lobar boundaries. PMID- 28570266 TI - Integrin-Kindlin3 requirements for microglial motility in vivo are distinct from those for macrophages. AB - Microglia play a critical role in the development and homeostasis of the CNS. While mobilization of microglia is critical for a number of pathologies, understanding of the mechanisms of their migration in vivo is limited and often based on similarities to macrophages. Kindlin3 deficiency as well as Kindlin3 mutations of integrin-binding sites abolish both integrin inside-out and outside in signaling in microglia, thereby resulting in severe deficiencies in cell adhesion, polarization, and migration in vitro, which are similar to the defects observed in macrophages. In contrast, while Kindlin3 mutations impaired macrophage mobilization in vivo, they had no effect either on the population of microglia in the CNS during development or on mobilization of microglia and subsequent microgliosis in a model of multiple sclerosis. At the same time, acute microglial response to laser-induced injury was impaired by the lack of Kindlin3 integrin interactions. Based on 2-photon imaging of microglia in the brain, Kindlin3 is required for elongation of microglial processes toward the injury site and formation of phagosomes in response to brain injury. Thus, while Kindlin3 deficiency in human subjects is not expected to diminish the presence of microglia within CNS, it might delay the recovery process after injury, thereby exacerbating its complications. PMID- 28570265 TI - Identification and characterization of a supraclavicular brown adipose tissue in mice. AB - A fundamental challenge to our understanding of brown adipose tissue (BAT) is the lack of an animal model that faithfully represents human BAT. Such a model is essential for direct assessment of the function and therapeutic potential of BAT depots in humans. In human adults, most of the thermoactive BAT depots are located in the supraclavicular region of the neck, while mouse studies focus on depots located in the interscapular region of the torso. We recently discovered BAT depots that are located in a region analogous to that of human supraclavicular BAT (scBAT). Here, we report that the mouse scBAT depot has morphological characteristics of classical BAT, possesses the potential for high thermogenic activity, and expresses a gene signature that is similar to that of human scBAT. Taken together, our studies reveal a mouse BAT depot that represents human BAT and provides a unique tool for developing new translatable approaches for utilizing human scBAT. PMID- 28570267 TI - Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation. AB - Memory Th2 cell responses underlie the development and perpetuation of allergic diseases. Because these states result from immune dysregulation, established Th2 cell responses represent a significant challenge for conventional immunotherapies. New approaches that overcome the detrimental effects of immune dysregulation are required. We tested whether memory Th2 cell responses were silenced using a therapeutic approach where allergen expression in DCs is transferred to sensitized recipients using BM cells as a vector for therapeutic gene transfer. Development of allergen-specific Th2 responses and allergen induced airway inflammation was blocked by expression of allergen in DCs. Adoptive transfer studies showed that Th2 responses were inactivated by a combination of deletion and induction of T cell unresponsiveness. Transfer of BM encoding allergen expression targeted to DCs terminated, in an allergen-specific manner, Th2 responses in sensitized recipients. Importantly, when preexisting airway inflammation was present, there was effective silencing of Th2 cell responses, airway inflammation was alleviated, and airway hyperreactivity was reversed. The effectiveness of DC-targeted allergen expression to terminate established Th2 responses in sensitized animals indicates that exploiting cell intrinsic T cell tolerance pathways could lead to development of highly effective immunotherapies. PMID- 28570268 TI - Network analysis of the genomic basis of the placebo effect. AB - The placebo effect is a phenomenon in which patients who are given an inactive treatment (e.g., inert pill) show a perceived or actual improvement in a medical condition. Placebo effects in clinical trials have been investigated for many years especially because placebo treatments often serve as the control arm of randomized clinical trial designs. Recent observations suggest that placebo effects may be modified by genetics. This observation has given rise to the term "placebome," which refers to a group of genome-related mediators that affect an individual's response to placebo treatments. In this study, we conduct a network analysis of the placebome and identify a placebome module in the comprehensive human interactome using a seed-connector algorithm. The placebome module is significantly enriched with neurotransmitter signaling pathways and brain specific proteins. We validate the placebome module using a large cohort of the Women's Genome Health Study (WGHS) trial and demonstrate that the placebome module is significantly enriched with genes whose SNPs modify the outcome in the placebo arm of the trial. To gain insights into placebo effects in different diseases and drug treatments, we use a network proximity measure to examine the closeness of the placebome module to different disease modules and drug target modules. The results demonstrate that the network proximity of the placebome module to disease modules in the interactome significantly correlates with the strength of the placebo effect in the corresponding diseases. The proximity of the placebome module to molecular pathways affected by certain drug classes indicates the existence of placebo-drug interactions. This study is helpful for understanding the molecular mechanisms mediating the placebo response, and sets the stage for minimizing its effects in clinical trials and for developing therapeutic strategies that intentionally engage it. PMID- 28570270 TI - Molecular imaging of oxidized collagen quantifies pulmonary and hepatic fibrogenesis. AB - Fibrosis results from the dysregulation of tissue repair mechanisms affecting major organ systems, leading to chronic extracellular matrix buildup, and progressive, often fatal, organ failure. Current diagnosis relies on invasive biopsies. Noninvasive methods today cannot distinguish actively progressive fibrogenesis from stable scar, and thus are insensitive for monitoring disease activity or therapeutic responses. Collagen oxidation is a universal signature of active fibrogenesis that precedes collagen crosslinking. Biochemically targeting oxidized lysine residues formed by the action of lysyl oxidase on collagen with a small-molecule gadolinium chelate enables targeted molecular magnetic resonance imaging. This noninvasive direct biochemical elucidation of the fibrotic microenvironment specifically and robustly detected and staged pulmonary and hepatic fibrosis progression, and monitored therapeutic response in animal models. Furthermore, this paradigm is translatable and generally applicable to diverse fibroproliferative disorders. PMID- 28570269 TI - Zinc deficiency primes the lung for ventilator-induced injury. AB - Mechanical ventilation is necessary to support patients with acute lung injury, but also exacerbates injury through mechanical stress-activated signaling pathways. We show that stretch applied to cultured human cells, and to mouse lungs in vivo, induces robust expression of metallothionein, a potent antioxidant and cytoprotective molecule critical for cellular zinc homeostasis. Furthermore, genetic deficiency of murine metallothionein genes exacerbated lung injury caused by high tidal volume mechanical ventilation, identifying an adaptive role for these genes in limiting lung injury. Stretch induction of metallothionein required zinc and the zinc-binding transcription factor MTF1. We further show that mouse dietary zinc deficiency potentiates ventilator-induced lung injury, and that plasma zinc levels are significantly reduced in human patients who go on to develop acute respiratory distress syndrome (ARDS) compared with healthy and non-ARDS intensive care unit (ICU) controls, as well as with other ICU patients without ARDS. Taken together, our findings identify a potentially novel adaptive response of the lung to stretch and a critical role for zinc in defining the lung's tolerance for mechanical ventilation. These results demonstrate that failure of stretch-adaptive responses play an important role in exacerbating mechanical ventilator-induced lung injury, and identify zinc and metallothionein as targets for lung-protective interventions in patients requiring mechanical ventilation. PMID- 28570271 TI - Delayed decompression exacerbates ischemia-reperfusion injury in cervical compressive myelopathy. AB - Degenerative cervical myelopathy (DCM) is the most common progressive nontraumatic spinal cord injury. The most common recommended treatment is surgical decompression, although the optimal timing of intervention is an area of ongoing debate. The primary objective of this study was to assess whether a delay in decompression could influence the extent of ischemia-reperfusion injury and alter the trajectory of outcome in DCM. Using a DCM mouse model, we show that decompression acutely led to a 1.5- to 2-fold increase in levels of inflammatory cytokines within the spinal cord. Delayed decompression was associated with exacerbated reperfusion injury, astrogliosis, and poorer neurological recovery. Additionally, delayed decompression was associated with prolonged elevation of inflammatory cytokines and an exacerbated peripheral monocytic inflammatory response (P < 0.01 and 0.001). In contrast, early decompression led to resolution of reperfusion-mediated inflammation, neurological improvement, and reduced hyperalgesia. Similar findings were observed in subjects from the CSM AOSpine North America and International studies, where delayed decompressive surgery resulted in poorer neurological improvement compared with patients with an earlier intervention. Our data demonstrate that delayed surgical decompression for DCM exacerbates reperfusion injury and is associated with ongoing enhanced levels of cytokine expression, microglia activation, and astrogliosis, and paralleled with poorer neurological recovery. PMID- 28570273 TI - Myeloid-related protein-14 regulates deep vein thrombosis. AB - Using transcriptional profiling of platelets from patients presenting with acute myocardial infarction, we identified myeloid-related protein-14 (MRP-14, also known as S100A9) as an acute myocardial infarction gene and reported that platelet MRP-14 binding to platelet CD36 regulates arterial thrombosis. However, whether MRP-14 plays a role in venous thrombosis is unknown. We subjected WT and Mrp-14-deficient (Mrp-14-/-) mice to experimental models of deep vein thrombosis (DVT) by stasis ligation or partial flow restriction (stenosis) of the inferior vena cava. Thrombus weight in response to stasis ligation or stenosis was reduced significantly in Mrp-14-/- mice compared with WT mice. The adoptive transfer of WT neutrophils or platelets, or the infusion of recombinant MRP-8/14, into Mrp-14 /- mice rescued the venous thrombosis defect in Mrp-14-/- mice, indicating that neutrophil- and platelet-derived MRP-14 directly regulate venous thrombogenesis. Stimulation of neutrophils with MRP-14 induced neutrophil extracellular trap (NET) formation, and NETs were reduced in venous thrombi harvested from Mrp-14-/- mice and in Mrp-14-/- neutrophils stimulated with ionomycin. Given prior evidence that MRP-14 also regulates arterial thrombosis, but not hemostasis (i.e., reduced bleeding risk), MRP-14 appears to be a particularly attractive molecular target for treating thrombotic cardiovascular diseases, including myocardial infarction, stroke, and venous thromboembolism. PMID- 28570274 TI - Tristetraprolin expression by keratinocytes controls local and systemic inflammation. AB - Tristetraprolin (TTP, encoded by the Zfp36 gene) regulates the mRNA stability of several important cytokines. Due to the critical role of this RNA-binding protein in the control of inflammation, TTP deficiency leads to the spontaneous development of a complex inflammatory syndrome. So far, this phenotype has been largely attributed to dysregulated production of TNF and IL-23 by myeloid cells, such as macrophages or DCs. Here, we generated mice with conditional deletion of TTP in keratinocytes (Zfp36fl/flK14-Cre mice, referred to herein as Zfp36DeltaEP mice). Unlike DC-restricted (CD11c-Cre) or myeloid cell-restricted (LysM-Cre) TTP ablation, these mice developed exacerbated inflammation in the imiquimod-induced psoriasis model. Furthermore, Zfp36DeltaEP mice progressively developed a spontaneous pathology with systemic inflammation, psoriatic-like skin lesions, and dactylitis. Finally, we provide evidence that keratinocyte-derived TNF production drives these different pathological features. In summary, these findings expand current views on the initiation of psoriasis and related arthritis by revealing the keratinocyte-intrinsic role of TTP. PMID- 28570272 TI - Immunity against fungi. AB - Pathogenic fungi cause a wide range of syndromes in immune-competent and immune compromised individuals, with life-threatening disease primarily seen in humans with HIV/AIDS and in patients receiving immunosuppressive therapies for cancer, autoimmunity, and end-organ failure. The discovery that specific primary immune deficiencies manifest with fungal infections and the development of animal models of mucosal and invasive mycoses have facilitated insight into fungus-specific recognition, signaling, effector pathways, and adaptive immune responses. Progress in deciphering the molecular and cellular basis of immunity against fungi is guiding preclinical studies into vaccine and immune reconstitution strategies for vulnerable patient groups. Furthermore, recent work has begun to address the role of endogenous fungal communities in human health and disease. In this review, we summarize a contemporary understanding of protective immunity against fungi. PMID- 28570275 TI - Long-term culture of human liver tissue with advanced hepatic functions. AB - A major challenge for studying authentic liver cell function and cell replacement therapies is that primary human hepatocytes rapidly lose their advanced function in conventional, 2-dimensional culture platforms. Here, we describe the fabrication of 3-dimensional hexagonally arrayed lobular human liver tissues inspired by the liver's natural architecture. The engineered liver tissues exhibit key features of advanced differentiation, such as human-specific cytochrome P450-mediated drug metabolism and the ability to support efficient infection with patient-derived inoculums of hepatitis C virus. The tissues permit the assessment of antiviral agents and maintain their advanced functions for over 5 months in culture. This extended functionality enabled the prediction of a fatal human-specific hepatotoxicity caused by fialuridine (FIAU), which had escaped detection by preclinical models and short-term clinical studies. The results obtained with the engineered human liver tissue in this study provide proof-of-concept determination of human-specific drug metabolism, demonstrate the ability to support infection with human hepatitis virus derived from an infected patient and subsequent antiviral drug testing against said infection, and facilitate detection of human-specific drug hepatotoxicity associated with late onset liver failure. Looking forward, the scalability and biocompatibility of the scaffold are also ideal for future cell replacement therapeutic strategies. PMID- 28570276 TI - Macrophage infiltration and genetic landscape of undifferentiated uterine sarcomas. AB - Endometrial stromal tumors include translocation-associated low- and high-grade endometrial stromal sarcomas (ESS) and highly malignant undifferentiated uterine sarcomas (UUS). UUS is considered a poorly defined group of aggressive tumors and is often seen as a diagnosis of exclusion after ESS and leiomyosarcoma (LMS) have been ruled out. We performed a comprehensive analysis of gene expression, copy number variation, point mutations, and immune cell infiltrates in the largest series to date of all major types of uterine sarcomas to shed light on the biology of UUS and to identify potential novel therapeutic targets. We show that UUS tumors have a distinct molecular profile from LMS and ESS. Gene expression and immunohistochemical analyses revealed the presence of high numbers of tumor associated macrophages (TAMs) in UUS, which makes UUS patients suitable candidates for therapies targeting TAMs. Our results show a high genomic instability of UUS and downregulation of several TP53-mediated tumor suppressor genes, such as NDN, CDH11, and NDRG4. Moreover, we demonstrate that UUS carry somatic mutations in several oncogenes and tumor suppressor genes implicated in RAS/PI3K/AKT/mTOR, ERBB3, and Hedgehog signaling. PMID- 28570277 TI - Epithelial Gpr116 regulates pulmonary alveolar homeostasis via Gq/11 signaling. AB - Pulmonary function is dependent upon the precise regulation of alveolar surfactant. Alterations in pulmonary surfactant concentrations or function impair ventilation and cause tissue injury. Identification of the molecular pathways that sense and regulate endogenous alveolar surfactant concentrations, coupled with the ability to pharmacologically modulate them both positively and negatively, would be a major therapeutic advance for patients with acute and chronic lung diseases caused by disruption of surfactant homeostasis. The orphan adhesion GPCR GPR116 (also known as Adgrf5) is a critical regulator of alveolar surfactant concentrations. Here, we show that human and mouse GPR116 control surfactant secretion and reuptake in alveolar type II (AT2) cells by regulating guanine nucleotide-binding domain alpha q and 11 (Gq/11) signaling. Synthetic peptides derived from the ectodomain of GPR116 activated Gq/11-dependent inositol phosphate conversion, calcium mobilization, and cortical F-actin stabilization to inhibit surfactant secretion. AT2 cell-specific deletion of Gnaq and Gna11 phenocopied the accumulation of surfactant observed in Gpr116-/- mice. These data provide proof of concept that GPR116 is a plausible therapeutic target to modulate endogenous alveolar surfactant pools to treat pulmonary diseases associated with surfactant dysfunction. PMID- 28570280 TI - Battlefield Acupuncture: An Emerging Method for Easing Pain. PMID- 28570279 TI - Optimized multiplex immunofluorescence single-cell analysis reveals tuft cell heterogeneity. AB - Intestinal tuft cells are a rare, poorly understood cell type recently shown to be a critical mediator of type 2 immune response to helminth infection. Here, we present advances in segmentation algorithms and analytical tools for multiplex immunofluorescence (MxIF), a platform that enables iterative staining of over 60 antibodies on a single tissue section. These refinements have enabled a comprehensive analysis of tuft cell number, distribution, and protein expression profiles as a function of anatomical location and physiological perturbations. Based solely on DCLK1 immunoreactivity, tuft cell numbers were similar throughout the mouse small intestine and colon. However, multiple subsets of tuft cells were uncovered when protein coexpression signatures were examined, including two new intestinal tuft cell markers, Hopx and EGFR phosphotyrosine 1068. Furthermore, we identified dynamic changes in tuft cell number, composition, and protein expression associated with fasting and refeeding and after introduction of microbiota to germ-free mice. These studies provide a foundational framework for future studies of intestinal tuft cell regulation and demonstrate the utility of our improved MxIF computational methods and workflow for understanding cellular heterogeneity in complex tissues in normal and disease states. PMID- 28570281 TI - Response to the Letter to the Editor on "Ultrasound Anatomy of the Transverse Carpal Ligament". PMID- 28570278 TI - CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer. AB - T follicular helper cells (TFH cells) are important regulators of antigen specific B cell responses. The B cell chemoattractant CXCL13 has recently been linked with TFH cell infiltration and improved survival in human cancer. Although human TFH cells can produce CXCL13, their immune functions are currently unknown. This study presents data from human breast cancer, advocating a role for tumor infiltrating CXCL13-producing (CXCR5-) TFH cells, here named TFHX13 cells, in promoting local memory B cell differentiation. TFHX13 cells potentially trigger tertiary lymphoid structure formation and thereby generate germinal center B cell responses at the tumor site. Follicular DCs are not potent CXCL13 producers in breast tumor tissues. We used the TFH cell markers PD-1 and ICOS to identify distinct effector and regulatory CD4+ T cell subpopulations in breast tumors. TFHX13 cells are an important component of the PD-1hiICOSint effector subpopulation and coexpanded with PD-1intICOShiFOXP3hi Tregs. IL2 deprivation induces CXCL13 expression in vitro with a synergistic effect from TGFbeta1, providing insight into TFHX13 cell differentiation in response to Treg accumulation, similar to conventional TFH cell responses. Our data suggest that human TFHX13 cell differentiation may be a key factor in converting Treg-mediated immune suppression to de novo activation of adaptive antitumor humoral responses in the chronic inflammatory breast cancer microenvironment. PMID- 28570282 TI - Ultrasound Anatomy of the Transverse Carpal Ligament. PMID- 28570283 TI - Novel insights of microRNAs in the development of systemic lupus erythematosus. AB - PURPOSE OF REVIEW: To provide a brief overview of recent progress in microRNA biogenesis and homeostasis, its function in immune system and systemic lupus erythematosus (SLE), as well as successful microRNA-based therapy in vivo. RECENT FINDINGS: Stepwise microRNA biogenesis is elaborately regulated at multiple levels, ranging from transcription to ultimate function. Mature microRNAs have inhibitory effects on various biological molecules, which are crucial for stabilizing and normalizing differentiation and function of immune cells. Abnormality in microRNA expression contributes to dysfunction of lupus immune cells and resident cells in local tissues. Manipulation of dysregulated microRNAs in vivo through microRNA delivery or targeting microRNA might be promising for SLE treatment. SUMMARY: Recent advances highlight that microRNAs are important in immunity, lupus autoimmunity and as potential therapy target for SLE. PMID- 28570284 TI - Mathematical models of infection transmission in healthcare settings: recent advances from the use of network structured data. AB - PURPOSE OF REVIEW: Mathematical modeling approaches have brought important contributions to the study of pathogen spread in healthcare settings over the last 20 years. Here, we conduct a comprehensive systematic review of mathematical models of disease transmission in healthcare settings and assess the application of contact and patient transfer network data over time and their impact on our understanding of transmission dynamics of infections. RECENT FINDINGS: Recently, with the increasing availability of data on the structure of interindividual and interinstitution networks, models incorporating this type of information have been proposed, with the aim of providing more realistic predictions of disease transmission in healthcare settings. Models incorporating realistic data on individual or facility networks often remain limited to a few settings and a few pathogens (mostly methicillin-resistant Staphylococcus aureus). SUMMARY: To respond to the objectives of creating improved infection prevention and control measures and better understanding of healthcare-associated infections transmission dynamics, further innovations in data collection and parameter estimation in modeling is required. PMID- 28570285 TI - SymptomCare@Home: Developing an Integrated Symptom Monitoring and Management System for Outpatients Receiving Chemotherapy. AB - SymptomCare@Home, an integrated symptom monitoring and management system, was designed as part of randomized clinical trials to help patients with cancer who receive chemotherapy in ambulatory clinics and often experience significant symptoms at home. An iterative design process was informed by chronic disease management theory and features of assessment and clinical decision support systems used in other diseases. Key stakeholders participated in the design process: nurse scientists, clinical experts, bioinformatics experts, and computer programmers. Especially important was input from end users, patients, and nurse practitioners participating in a series of studies testing the system. The system includes both a patient and clinician interface and fully integrates two electronic subsystems: a telephone computer-linked interactive voice response system and a Web-based Decision Support-Symptom Management System. Key features include (1) daily symptom monitoring, (2) self-management coaching, (3) alerting, and (4) nurse practitioner follow-up. The nurse practitioner is distinctively positioned to provide assessment, education, support, and pharmacologic and nonpharmacologic interventions to intensify management of poorly controlled symptoms at home. SymptomCare@Home is a model for providing telehealth. The system facilitates using evidence-based guidelines as part of a comprehensive symptom management approach. The design process and system features can be applied to other diseases and conditions. PMID- 28570286 TI - Design and Implementation of the Intensive Care Unit Quality Management Registry: Monitoring Quality and Cost of an Adult Intensive Care Unit in a Greek State Hospital. AB - Intensive care electronic registries have been instrumental in quality measurement, improvement, and assurance of intensive care. In this article, the development and pilot implementation of the Intensive Care Unit Quality Management Registry are described, with a particular focus on monitoring the quality and operational cost in an adult ICU at a northern Greek state hospital. A relational database was developed for a hospital ICU so that qualitative and financial data are recorded for further analysis needed for planning quality care improvement and enhanced efficiency. Key features of this database registry were low development cost, user friendliness, maximum data security, and interoperability in existing hospital information systems. The database included patient demographics, nursing and medical parameters, and quality and performance indicators as established in many national registries worldwide. Cost recording was based on a mixed approach: at patient level ("bottom-up" method) and at department level ("top-down" method). During the pilot phase of the database operation, regular monitoring of quality and cost data revealed several fields of quality excellence, while indicating room for improvement for others. Parallel recording and trending of multiple parameters showed that the database can be utilized for optimum ICU quality and cost management and also for further research purposes by nurses, physicians, and administrators. PMID- 28570287 TI - Usual and unusual pitfalls of 18F-FDG-PET/CT in lymphoma after treatment: a pictorial review. AB - Fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) is now a standard of care in initial staging and treatment evaluation of lymphomas. It is also used in the interim evaluation in diffuse large B cell lymphoma and Hodgkin lymphoma. However, several pitfalls may occur during or after treatment, because of the nonspecificity of F-FDG for lymphoma disease and treatment as immunotherapy, thus possibly induces misinterpretation and wrong treatment decision. The aim of this pictorial review is to provide an illustrated tutorial of the most frequent pitfalls found on F-FDG-PET/CT during or after treatment. PMID- 28570288 TI - Myeloid-Derived Suppressor Cells Associated With Disease Progression in Primary HIV Infection: PD-L1 Blockade Attenuates Inhibition. AB - OBJECTIVE: Events occurring during the initial phase of human immunodeficiency virus (HIV) infection are intriguing because of their dramatic impact on the subsequent course of the disease. In particular, the relationship between myeloid derived suppressor cells (MDSCs) and HIV pathogenesis in primary infection remains unknown and the mechanism of MDSCs in HIV infection are incompletely defined. METHODS: The frequency of MDSC expression in patients with primary HIV infection (PHI) and chronic HIV infection was measured, and the association with disease progression was studied. Programmed death-ligand 1 (PD-L1) and galectin-9 (Gal-9) expression on MDSCs was measured and in vitro blocking experiments were performed to study the role of PD-L1 in MDSCs' inhibition. RESULTS: We found increased levels of HLA-DRCD14CD33CD11b granulocytic(G)-MDSCs in PHI individuals compared with normal controls, which correlated with viral loads and was negatively related to CD4 T-cell levels. When cocultured with purified G-MDSCs, both proliferation and interferon-gamma secretion by T cell receptor (TCR) stimulated CD8 T cells from HIV-infected patients were significantly inhibited. We also demonstrated that PD-L1, but not Gal-9, expression on HLA-DRCD14CD33CD11b cells increased during HIV infection. The suppressive activity of G-MDSCs from HIV-infected patients was attenuated by PD-L1 blockade. CONCLUSIONS: We found a significant increase in G-MDSCs in PHI patients that was related to disease progression and PD-L1 was used by MDSCs to inhibit CD8 T cells in HIV infection. Our data improve the understanding of HIV pathogenesis in PHI. PMID- 28570289 TI - Hydraulic Transcrestal Sinus Lift: Different Patterns of Elevation in Pig Sinuses. AB - PURPOSE: The aim of this study was to evaluate different patterns of sinus membrane elevation in pig jaws. MATERIALS AND METHODS: A total of 30 pig jaws (60 sinuses) were used for the present investigation. The hydraulic Crestal Approach Sinus kit was used to elevate sinus membrane, and different elevation patterns were recorded. RESULTS: There were 4 different scenarios of membrane separation patterns: center dome-shaped elevation, off-center dome-shaped elevation, horizontally spreading membrane elevation, and perforation. The incidence of each different type was 35.0% (n = 21) in center dome-shaped separation, 51.7% (n = 31) in off-center dome-shaped separation, 10.0% (n = 6) in horizontally spreading separation, and 3.3% (n = 2) in membrane perforation. CONCLUSION: Different patterns of membrane elevations are observed in pig sinuses and introduced in this study. The off-center dome-shaped elevation was the most common pattern followed by the center dome-shaped elevation and horizontally spreading elevation, respectively. PMID- 28570290 TI - Secondary data analysis: techniques for comparing interventions and their limitations. AB - PURPOSE OF REVIEW: Secondary data analysis has become increasingly common in health services research, specifically comparative effectiveness research. While a comprehensive study of the techniques and methods for secondary data analysis is a wide-ranging topic, we sought to perform a descriptive study of some key methodological issues related to secondary data analyses and to provide a basic summary of techniques to address them. RECENT FINDINGS: In this study, we first address common issues seen in analysis of secondary datasets, and limitations of datasets with respect to bias. We cover some strategies for handling missing or incomplete data and a basic summary of three statistical approaches that can be used to address the problem of bias. SUMMARY: While it is unrealistic for surgeon scientists to aspire to the depth of knowledge of professional statisticians or data scientists, it is important for researchers and clinicians reading to understand some of the common pitfalls and issues when using secondary data to investigate clinical questions. Ultimately, the choice of analytical technique and the particular data sets used should be dictated by the research question and hypothesis being tested. Transparency about data handling and statistical techniques are vital elements of secondary data analysis. PMID- 28570293 TI - Mother's Lived Experience During Repair of Long-Gap Esophageal Atresia: A Phenomenological Inquiry. AB - BACKGROUND: Infants born with long-gap esophageal atresia (LGEA) pose unique physiologic risks in the newborn period. Anatomic and physiologic anomalies require an extended hospitalization with procedural analgesia and sedation that impact the mother's experience of birth, maternal response, and nurturing of her infant. PURPOSE: The aim of this study was to understand the meaning of experiences that mothers of infants born with LGEA encounter in the neonatal intensive care unit while their infant undergoes esophageal repair. METHODS: A hermeneutical phenomenological design was used to guide this inquiry. Three mothers were interviewed on 3 separate occasions. The conversations were audio recorded and transcribed verbatim. The findings were analyzed using fundamental existential lifeworld themes. RESULTS: The essence that conceptualized the study was "making connections: day-by-day." Themes that emerged are (a) the many phases; (b) the long and winding road; (c) a new me, my purpose; and (d) our new community. IMPLICATIONS FOR PRACTICE: Nurses' knowledge and understanding of maternal experiences of having an infant with LGEA will enable for increased physical closeness, optimizing time spent together to learn their infant's unique personality. Creating partnerships with mothers can enhance our understanding of their perspectives, concerns, needs, and guide interventions. IMPLICATIONS FOR RESEARCH: Further exploration of family dynamics including fathers, siblings, and contextual factors may illuminate interventions to enhance relationships and communication that may influence developmental outcomes for families of infants with LGEA. PMID- 28570294 TI - Blind Intubation through Self-pressurized, Disposable Supraglottic Airway Laryngeal Intubation Masks: An International, Multicenter, Prospective Cohort Study. AB - BACKGROUND: Supraglottic airway devices commonly are used for securing the airway during general anesthesia. Occasionally, intubation with an endotracheal tube through a supraglottic airway is indicated. Reported success rates for blind intubation range from 15 to 97%. The authors thus investigated as their primary outcome the fraction of patients who could be intubated blindly with an Air-Qsp supraglottic airway device (Mercury Medical, USA). Second, the authors investigated the influence of muscle relaxation on air leakage pressure, predictors for failed blind intubation, and associated complications of using the supraglottic airway device. METHODS: The authors enrolled 1,000 adults having elective surgery with endotracheal intubation. After routine induction of general anesthesia, a supraglottic airway device was inserted and patients were ventilated intermittently. Air leak pressure was measured before and after full muscle relaxation. Up to two blind intubation attempts were performed. RESULTS: The supraglottic airway provided adequate ventilation and oxygenation in 99% of cases. Blind intubation succeeded in 78% of all patients (95% CI, 75 to 81%). However, the success rate was inconsistent among the three centers (P < 0.001): 80% (95% CI, 75 to 85%) at the Institute of Anesthesia and Pain Therapy, Kantonsspital Winterthur, Winterthur, Switzerland; 41% (95% CI, 29 to 53%) at the Department of Anesthesiology and Intensive Therapy, Medical University of Lodz, Lodz, Poland; and 84% (95% CI, 80 to 88%) at the Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland. Leak pressure before relaxation correlated reasonably well with air leak pressure after relaxation. CONCLUSIONS: The supraglottic airway device reliably provided a good airway and allowed blind intubation in nearly 80% of patients. It is thus a reasonable initial approach to airway control. Muscle relaxation can be used safely when unparalyzed leak pressure is adequate. PMID- 28570297 TI - Reinforcing effects of abused 'bath salts' constituents 3,4 methylenedioxypyrovalerone and alpha-pyrrolidinopentiophenone and their enantiomers. AB - Synthetic cathinones found in abused 'bath salts' preparations are chiral molecules. Racemic 3,4-methylenedioxypyrovalerone (MDPV) and alpha pyrrolidinopentiophenone (alpha-PVP) are two common constituents of these preparations that have been reported to be highly effective reinforcers; however, the relative contribution of each enantiomer toward these effects has not been determined. Thus, male Sprague-Dawley rats were trained to respond for racemic MDPV or alpha-PVP (n=9/drug), with full dose-response curves for the racemate and the S and R enantiomers of MDPV and alpha-PVP generated under a progressive ratio schedule of reinforcement. Racemic mixtures of both MDPV and alpha-PVP as well as each enantiomer maintained responding in a dose-dependent manner, with racemic MDPV and alpha-PVP being equipotent. The rank order of potency within each drug was S enantiomer>racemate ? R enantiomer. Although both enantiomers of alpha-PVP were as effective as racemic alpha-PVP, R-MDPV was a slightly less effective reinforcer than both S and racemic MDPV. The results of these studies provide clear evidence that both enantiomers of MDPV and alpha-PVP function as highly effective reinforcers and likely contribute toward the abuse-related effects of 'bath salts' preparations containing racemic MDPV and/or alpha-PVP. PMID- 28570296 TI - ADAMTS5 Deficiency Protects Mice From Chronic Tobacco Smoking-induced Intervertebral Disc Degeneration. AB - STUDY DESIGN: ADAMTS5-deficient and wild type (WT) mice were chronically exposed to tobacco smoke to investigate effects on intervertebral disc degeneration (IDD). OBJECTIVE: The aim of this study was to demonstrate a role for ADAMTS5 in mediating tobacco smoking-induced IDD. SUMMARY OF BACKGROUND DATA: We previously demonstrated that chronic tobacco smoking causes IDD in mice because, in part, of proteolytic destruction of disc aggrecan. However, it was unknown which matrix proteinase(s) drive these detrimental effects. METHODS: Three-month-old WT (C57BL/6) and ADAMTS5 mice were chronically exposed to tobacco smoke (four cigarettes/day, 5 day/week for 6 months). ADAMTS-mediated cleavage of disc aggrecan was analyzed by Western blot. Disc total glycosaminoglycan (GAG) content was assessed by dimethyl methylene blue assay and safranin O/fast green histology. Vertebral osteoporosity was measured by microcomputed tomography. Human nucleus pulposus (hNP) cell cultures were also exposed directly to tobacco smoke extract (TSE), a condensate containing the water-soluble compounds inhaled by smokers, to measure ADAMTS5 expression and ADAMTS-mediated cleavage of aggrecan. Activation of nuclear factor (NF)-kappaB, a family of transcription factors essential for modulating the cellular response to stress, was measured by immunofluorescence assay. RESULTS: Genetic depletion of ADAMTS5 prevented vertebral bone loss, substantially reduced loss of disc GAG content, and completely obviated ADAMTS-mediated proteolysis of disc aggrecan within its interglobular domain (IGD) in mice following exposure to tobacco smoke. hNP cell cultures exposed to TSE also resulted in upregulation of ADAMTS5 protein expression and a concomitant increase in ADAMTS-mediated cleavage within aggrecan IGD. Activation of NF-kappaB, known to be required for ADAMTS5 gene expression, was observed in both TSE-treated hNP cell cultures and disc tissue of tobacco smoke-exposed mice. CONCLUSION: The findings demonstrate that ADAMTS5 is the primary aggrecanase mediating smoking-induced disc aggrecanolysis and IDD. Mouse models of chronic tobacco smoking are important and useful for probing the mechanisms of disc aggrecan catabolism and IDD. LEVEL OF EVIDENCE: N/A. PMID- 28570298 TI - The effect of litter separation on methamphetamine-conditioned place preference in post-partum dams. AB - Methamphetamine (METH) abuse among women has recently increased to levels comparable to those observed in men. Although studies using animal models of addiction have begun to include more female subjects, examination of the effects of drugs of abuse on post-partum females is currently lacking. This is especially important in light of the significant hormonal and neurobiological changes that accompany pregnancy and rearing experiences. Furthermore, stress in a known factor in addiction vulnerability and the post-partum experience in the clinical population can be highly stressful. Here, we utilized the conditioned place preference paradigm to investigate the conditioned rewarding effects of METH either in virgin rats or in dams exposed to brief separation (15 min) or long separation (180 min) from the litter. We found that females in the brief separation group showed significantly greater METH conditioned place preference compared with both the long separation and virgin groups. No differences were found in locomotor activity during the conditioning sessions. These findings suggest that peripartum experience and brief litter separation may enhance the rewarding effects of METH. PMID- 28570299 TI - HLA-A*31: 01 and HLA-B*15:02 association with Stevens-Johnson syndrome and toxic epidermal necrolysis to carbamazepine in a multiethnic Malaysian population. AB - The majority of the carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis CBZ-SJS/TEN are associated with HLA-B*15:02 in Asian populations where this allele is common. In contrast, the association with HLA A*31:01 is only reported in Japanese and Europeans. This study aimed to further investigate the association with HLA-A*31:01 besides HLA-B*15:02 in a multiethnic Malaysian population. Twenty-eight CBZ-SJS/TEN cases and 227 CBZ-tolerant controls were recruited. Association was tested by comparing carrier frequencies of the alleles between cases and controls. Significant associations were detected between HLA-B*15:02 and CBZ-SJS/TEN in independent ethnic groups: Malays [P=2.00*10; odds ratio (OR): 49.0; 95% confidence interval (CI): 9.36-256.81], Chinese (P=0.0047; OR: 14.3; 95% CI: 2.38-86.03) and Indians (P=0.04; OR: 13.8; 95% CI: 1.51-124.99). Combined analysis of all ethnic groups showed a significant association with OR Cochran-Mantel-Haenszel (ORCMH) of 26.6 (95% CI: 12.80-55.25; PCMH=2.31*10). In Indians, HLA-A*31:01 was found to be associated significantly with CBZ-SJS/TEN (P=0.023; OR: 10.4; 95% CI: 1.64-65.79) and combined analyses of both variants, HLA-A*31:01 and HLA-B*15:02, increased the strength of the association (P=0.0068; OR: 14.3; 95% CI: 2.20-92.9). Besides HLA-B*15:02, our study found a new association between HLA-A*31:01 and CBZ-SJS/TEN in Indians. PMID- 28570300 TI - Impact of novel polymorphisms related to cytotoxicity of cytarabine in the induction treatment of acute myeloid leukemia. AB - Several novel single nucleotide polymorphisms (SNPs) involved in cytarabine cytotoxicity and related to clinical outcomes have been reported recently in a series of 232 pediatric patients with acute myeloid leukemia (AML). We report the first adult AML cohort in which the influence of these SNPs in cytarabine efficacy and toxicity was analyzed. Six of polymorphisms with clinical significance in the previous study [rs12036333, rs10758713, rs9883101, rs6550826, IRX2: rs2897047, mutated in colorectal cancers (MCC): rs7729269] were analyzed in a cohort of 225 adult patients at initial diagnosis of AML treated with an induction scheme of idarubicin plus cytarabine. The variant alleles of rs12036333 and rs10758713 confirmed the previous associations with lower survival rates. The minor alleles of rs9883101 and rs6550826 were also related to lower survival, in concordance with higher cytarabine-induced cytotoxicity observed in pediatric patients. However, discordant findings between AML adult and pediatric population were observed with IRX2 rs2897047, showing higher survival in heterozygous genotype carriers. The heterozygous genotype of MCC rs7729269 was associated with higher cytarabine-induced toxicities (renal, hepatic, lung, skin toxicities), whereas lower time to thrombocytopenia recovery was associated with the MCC rs7729269 minor allele. This study confirms the influence in survival rates of these polymorphisms in an adult AML population. Novel associations between MCC SNPs and cytarabine toxicities were reported and should be validated in prospective studies involving larger groups of patients. PMID- 28570302 TI - Ascending to descending aortic pulse pressure amplification in children. AB - INTRODUCTION: A peripheral pulse pressure (PP) is larger than a central PP (PP amplification). The phenomenon has been examined in adult, but not in children. METHODS: Fifty-four patients with a normal aorta were enrolled. The ascending and descending aorta pressure waveforms were recorded by a pressure sensor-mounted catheter. The difference of the PP, which was defined as the PP in the descending aorta minus that in the ascending aorta and the ratio of the PP, which was defined as the ratio of the descending to the ascending aortic PP, was examined as the index of the PP amplification. RESULTS: The patient's age was 6.2 +/- 3.0 years. The difference of the PP was 4.5 +/- 2.7 mmHg and had a significant positive relationship with the mean blood pressure (r = 0.46, P = 0.0005) and the age (r = 0.36, P = 0.009). The ratio of the PP was 1.14 +/- 0.08 and had a significant positive relationship with the mean blood pressure (r = 0.42, P = 0.002) and the age (r = 0.29, P = 0.04). CONCLUSION: The PP amplification is observed even in children. The degree of the PP amplification increases with age during childhood contrary to the relationship in adults. PMID- 28570301 TI - Clinical examination for diagnosing circulatory shock. AB - PURPOSE OF REVIEW: In the acute setting of circulatory shock, physicians largely depend on clinical examination and basic laboratory values. The daily use of clinical examination for diagnostic purposes contrasts sharp with the limited number of studies. We aim to provide an overview of the diagnostic accuracy of clinical examination in estimating circulatory shock reflected by an inadequate cardiac output (CO). RECENT FINDINGS: Recent studies showed poor correlations between CO and mottling, capillary refill time or central-to-peripheral temperature gradients in univariable analyses. The accuracy of physicians to perform an educated guess of CO based on clinical examination lies around 50% and the accuracy for recognizing a low CO is similar. Studies that used predefined clinical profiles composed of several clinical examination signs show more reliable estimations of CO with accuracies ranging from 81 up to 100%. SUMMARY: Single variables obtained by clinical examination should not be used when estimating CO. Physician's educated guesses of CO based on unstructured clinical examination are like the 'flip of a coin'. Structured clinical examination based on combined clinical signs shows the best accuracy. Future studies should focus on using a combination of signs in an unselected population, eventually to educate physicians in estimating CO by using predefined clinical profiles. PMID- 28570303 TI - Current Status of Fellowship Programs for Advanced Practice Registered Nurses in the Nurse Practitioner Role. AB - Students completing an advanced practice RN program for practice as a nurse practitioner may seek options for further advancement. Although postgraduate clinical fellowship programs exist, information about such programs is not readily available. This article offers a resource for faculty to assist graduate students in finding advanced practice RN nurse practitioner fellowship programs in the United States. PMID- 28570304 TI - Defining Roles and Expectations for Faculty, Nurses, and Students in a Dedicated Education Unit. AB - The dedicated education unit (DEU) model of clinical nursing education is an innovative, evidence-based model for creating a more effective learning environment. Although nursing programs have used this model for years, the literature provides minimal direction to assist faculty in transitioning from traditional clinical teaching to the DEU model. This article reports the development and evaluation of 2 resources to help all involved understand teaching roles and desired learning outcomes in the DEU model. PMID- 28570305 TI - Randomized, Crossover Study of Immersive Virtual Reality to Decrease Opioid Use During Painful Wound Care Procedures in Adults. AB - The objective of this study was to evaluate the effect of immersive virtual reality (IVR) distraction therapy during painful wound care procedures in adults on the amount of opioid medications required to manage pain. A convenience sample of consenting, adult inpatients requiring recurrent painful wound care procedures was studied. Using a within-subject, randomized controlled trial study design, 2 sequential wound procedures were compared, 1 with IVR distraction therapy and 1 without IVR. Total opioid medications administered before and during the wound procedures were recorded and pain and anxiety were rated before and after the 2 wound procedures. The IVR intervention included the wearing of virtual reality goggles and participation in an immersive, computer generated, interactive, 3 dimensional virtual world program. Data were analyzed with Student's t test and chi-square analysis, with P < 0.05 considered significant. A total of 18 patients were studied, with 12 completing both study wound procedures and 6 completing a single wound procedure. The amount of opioid administered before each of the 2 wound procedures was similar with and without IVR. Total opioid administration during the dressing procedures with IVR was significantly less than when no IVR was used, 17.9 +/- 6.0 and 29.2 +/- 4.5 mcg/kg fentanyl, respectively (t = -2.7; df = 14; P = 0.02). Two of 15 patients (11%) requested more than 1 opioid rescue dose with IVR and 9 of 15 patients (60%) requested more than 1 rescue dose without IVR. Seventy-five percentage of participants stated that they would want to use IVR with future dressing changes. Pain and anxiety scores were similar for the wound procedures with and without IVR (P > 0.05). IVR significantly reduced the amount of opioid medication administered during painful wound care procedures when IVR was used compared with no IVR. Since pain scores were similar before and after the wound procedures with IVR and without IVR, the 39% reduction in opioid medication during IVR supports its use as a pain distraction therapy during painful procedures. PMID- 28570306 TI - Analysis of Electrocardiograms Associated with Pediatric Electrical Burns. AB - The purpose of this study was to examine the utility of electrocardiograms (EKGs) for low-risk, low-voltage pediatric electrical burn victims. A retrospective chart review was conducted on 86 pediatric patients who presented to the children's hospital between 2000 and 2015 after sustaining electrical burns. Variables included source and estimated voltage, extent of injuries, length of stay, high risk factors, and EKG results. High risk factors included estimated voltage > 1000 V, lightning, tetany, symptoms, loss of consciousness, or seizures. Statistical analyses were conducted. Average age was 5 years. Of those who sustained burns, 84.5% (n = 71/84) had second-degree burns <= 1% TBSA or less. Eleven patients had high risk factors, 12.9% (n = 11/85) and most had length of stay < 3 days (91.8%; n = 78/85). Majority sustained burns from low voltage (< 300 V) household electrical outlets, cords, or light bulb sockets (90.4%; n = 75/83). Among patients with available EKGs, 12 had arrhythmias on initial EKG (i.e., low right atrial rhythm, t-wave inversions, sinus tachycardia, bundle branch block; 20.7%; n = 12/58). All were transient and nonfatal. The data suggest that low estimated voltage (< 300 V) electrical injuries were associated with negative EKGs; however, due to the low rate of arrhythmias, a Fisher's exact test did not show significance, P = 0.09 (P > 0.05). Preliminary data suggest that most pediatric electrical burns are due to low voltage (< 300 V) household sources. Few have high risk factors or arrhythmias that were transient and nonfatal. These data suggest that low-risk, asymptomatic, low-voltage pediatric electrical burns may not require an initial screening EKG. PMID- 28570307 TI - Early Mobilization in Lower Extremity Frostbite Injury: Preliminary Experience at a Single Burn Center. AB - Cold exposure that leads to frostbite puts patients at high risk for extremity amputations. Recent treatment advances, such as thrombolytic administration, have decreased amputation rates. However, little is known about patient outcomes with early mobilization of affected limbs. A retrospective review of 41 patients admitted for lower extremity frostbite was performed at an urban hospital burn unit. All patients received the institution's standard frostbite treatment protocol. The study group was allowed to bear weight within 72 hours, while the control group was immobilized beyond this time frame. No significant differences were found between groups when comparing total tissue loss, complications, or hospital length of stay. Previous treatment of frostbite at our institution involved strict avoidance of weight bearing to the affected extremity due to concern for repeat trauma and associated complications. Our findings show that patients who ambulated sooner had comparable outcomes to those immobilized for longer time periods. Larger studies would be useful to determine a standard time to mobilization in frostbite treatment protocols. PMID- 28570308 TI - Patient With Scald Burn of the Esophagus. AB - Burns of the esophagus are usually caused by chemical substances. In our report, we present a case of burn injury burn caused by swallowing boiling water under the influence of controlled substances. During the initial diagnostic procedures, a CT scan was performed. In contrast, in the later on performed gastroscopy, the computed tomography (CT scan) revealed intramural and free air. A conservative treatment was started including parenteral nutrition, application of a nasogastric tube, and administration of proton pump inhibitor (PPIs). We conclude that for diagnosing the extend of a burn of the esophagus, a CT scan should be performed in addition to endoscopic procedures. PMID- 28570309 TI - Admission Rapid Thrombelastography (rTEG(r)) Values Predict Resuscitation Volumes and Patient Outcomes After Thermal Injury. AB - In trauma, admission rapid thrombelastography (rTEG) has been shown to predict in hospital thromboembolic events, guide treatment of coagulopathy, and identify likely to require large volume resuscitations. We sought to evaluate the use of rTEG in describing the coagulation status of major burn patients at admission and assess whether rTEG values predicted resuscitation volumes and patient outcomes. This is a retrospective study of all patients admitted to our Burn intensive care unit between January 2010 and December 2012. We excluded those with < 15% TBSA burns, < 18 years of age, and with concomitant injuries requiring admission to the Trauma intensive care unit. Previously published and validated cut points for hypocoagulable (activated clotting time >= 128; k-time >= 2.5; angle <= 60; mA <= 55; LY30 >= 3%) and hypercoagulable (mA >= 65) rTEG values were used. Supra normal burn resuscitation was defined as >= 5.0 mL/kg/TBSA. Statistical analyses were conducted using STATA 13.1. Sixty-five patients met inclusion with a median age of 45 years, 74% male and 49% white. Median TBSA was 38% with 14% having third-degree burns. Sixty percentage of patients were hypercoagulable on admission, while 24% were hypocoagulable. rTEG values predicted increased 24-hour resuscitation volumes, as well as plasma and platelet transfusions (P < 0.05). Controlling for age, TBSA, and base deficit, admission rTEG >= 128 predicted a 5 fold increased likelihood of supra-normal resuscitation. In addition, an angle < 60 predicted in-hospital mortality. While the majority of severely burned patients arrive hypercoagulable, one-quarter are hypocoagulable and have increased resuscitation and transfusion requirements. Moreover, those with admission activated clotting time >= 128 are at 5-fold increased risk of supra normal resuscitation. PMID- 28570310 TI - Terminal Maturation of Orthochromatic Erythroblasts Is Impaired in Burn Patients. AB - Mechanisms of erythropoietin (Epo)-resistant anemia in burn patients are poorly understood. We have recently found that administering a nonselective beta 1,2 adrenergic blocker propranolol (PR) was effective in reversing myelo-erythroid commitment through MafB regulation and increase megakaryocyte erythrocyte progenitors in burn patients' peripheral blood mononuclear cell (PBMC)-derived ex vivo culture system. Having known that Epo-dependent proliferation of early erythroblasts is intact after burn injury, here we inquired whether or not Epo independent maturation stage of erythropoiesis is affected by burn injury and the relative role of PR on late-stage erythropoiesis. While majority of erythropoiesis occurs in the bone marrow, maturation into reticulocytes is crucial for their release into sinusoids to occupy the peripheral circulation for which enucleation is vital. peripheral blood mononuclear cells (PBMCs) from burn patients were extended beyond commitment and proliferation stages to late maturation stage in ex vivo culture to understand the role of PR in burn patients. Burn impedes late maturation of orthochromatic erythroblasts into reticulocytes by restricting the enucleation step. Late-stage erythropoiesis is impaired in burn patients irrespective of PR treatment. Further, substituting the microenvironment with control plasma (homologous) in place of autologous plasma rescues the conversion of orthochromatic erythroblasts to reticulocytes. Results show promise in formulating interventions to regulate late-stage erythropoiesis, which can be used in combination with PR to reduce the number of transfusions. PMID- 28570311 TI - The Importance of a Three-dimensional-Based Approach With Personalized Models for Accurately Assessing TBSA. AB - In this article, the relevance of a new three-dimensional computer-Based computer based framework with personalized 3D models for accurately assessing the TBSA is demonstrated through preliminary results and validation studies. First, a 3D rendering interface was developed for representation and calculation of TBSA. The personalized 3D models were built from anthropometric measurements using MakeHuman software. Fifteen paired models were randomly built with an equal BSA but a different morphology. The difference of local BSA, TBSA burned, and Parkland fluids between each paired models were observed to highlight the impact of morphology's variation on the TBSA. Finally, a preliminary validation study was made on 4 mannequins by 14 volunteers to assess the accuracy of the 3D models built with MakeHuman software and TBSA burned assessment with the proposed method. Small variations in the morphology impacted the TBSA assessment. Mannequin's 3D models built with MakeHuman software presented an absolute error of 3 +/- 2.2 % with no significant difference with their scans. The proposed approach allows for a better assessment of TBSA with a lower variability. No significant difference in the scores for expert and nonexpert conditions was observed. Personalized 3D model to the patient's morphology is suggested to overcome the difficulty of patients with specific morphologies such as obese and children. The proposed framework appears to be relevant for personalizing and accurately assessing TBSA and could reduce morbidity and mortality. PMID- 28570312 TI - Validation of the Ludwigshafen German Version of the Burn Specific Health Scale Brief. AB - The Burn Specific Health Scale-Brief (BSHS-B) is one of the most commonly used instruments to measure quality of life after burns. Our aim was to establish and to provide a German version of the BSHS-B for all German-speaking burn facilities. Translation and cross-cultural adaptation of the original English version into the German language was conducted. In a pilot study, 20 burn patients qualitatively validated the translated version concerning comprehensibility and content validity. The final version was then quantitatively validated by 364 patients who were treated in our burn center between 2011 and 2015. Internal consistency and test-retest reliability were assessed. Criterion validity was determined by correlating the subscales with relevant instruments (Short-Form Health Survey 36, Hospital Anxiety and Depression Scale, and Disabilities of the Arm, Shoulder and Hand Outcome Measure). The structure of the German version was investigated by principal component analysis. Confirmatory factor analysis was used to compare the structure with the original 9-factor structure and the second-order 3-factor structure. Qualitative testing revealed adequate comprehension and content validity. Cronbach's alphas ranged from alpha = 0.80 to alpha = 0.92. The test-retest reliability ranged from r = 0.72 to r = 0.97. The subscales correlated significantly with the measures of criterion validity (r = 0.30 to r = -0.77). The principal component analysis results showed a satisfactory overlap with the original data structure, except for the Affect and Sexuality domains, which were merged into 1 factor. The confirmatory factor analyses revealed the best model fit for the second-order 3-factor structure, excluding the Work domain. The Ludwigshafen German version of the BSHS-B shows good psychometric properties. It is well suited for clinical use, further research, and international comparison. PMID- 28570313 TI - The Cost of Burn Transfers: A Retrospective Review of 7 Years of Admissions to a Regional Burn Center. AB - The transport of thermally injured patients can involve significant costs; however, not all thermally injured patients necessitate transfer to a burn center. The purpose of this study was to review transfers to an American Burn Association-verified regional burn center to determine whether the transfers were necessary and the cost associated with unnecessary transfers. A retrospective chart review identified 707 patients transferred to an American Burn Association verified burn center with an acute burn injury during a 7-year period. For the purposes of this study, "unnecessary transfer" was defined as any patient admitted fewer than 7 days who did not undergo operative intervention. Transfer cost estimates were based on records from regional land paramedic and land and air medical transport services. In total, 27.3% of transfers were potentially "unnecessary transfers," with an associated cost of approximately $227,396.93 (18.9% of total transfer costs in study). Average unnecessary transfer cost varied by method of transport: land ambulance (n = 130) $285.72, helicopter (n = 27) $4,136.34, and airplane (n = 15) $4,908.67. The transfer of thermally injured patients is associated with significant cost. Unnecessary transfers represent an inefficient use of a limited resource in an already strained healthcare system. The findings of this study suggest that further initiatives should be explored to ensure the appropriate transfer of thermally injured patients. PMID- 28570314 TI - Negative Pressure Wound Therapy to the Dura. AB - Negative-pressure wound therapy is historically contraindicated in patients with osteomyelitis or exposed dura. The authors present a case of a complex reconstruction of an infected full thickness scalp burn, where negative-pressure wound therapy was successfully used over the dura. PMID- 28570315 TI - Assessment of Outreach by a Regional Burn Center: Could Referral Criteria Revision Help with Utilization of Resources? AB - The objectives of this study were to identify trends in preburn center care, assess needs for outreach and education efforts, and evaluate resource utilization with regard to referral criteria. We hypothesized that many transferred patients were discharged home after brief hospitalizations and without need for operation. Retrospective chart review was performed for all adult and pediatric transfers to our regional burn center from July 2012 to July 2014. Details of initial management including TBSA estimation, fluid resuscitation, and intubation status were recorded. Mode of transport, burn center length of stay, need for operation, and in-hospital mortality were analyzed. In two years, our burn center received 1004 referrals from other hospitals including 713 inpatient transfers. Within this group, 621 were included in the study. Among transferred patients, 476 (77%) had burns less than 10% TBSA, 69 (11%) had burns between 10-20% TBSA, and 76 (12%) had burns greater than 20% TBSA. Referring providers did not document TBSA for 261 (42%) of patients. Among patients with less than 10% TBSA burns, 196 (41%) received fluid boluses. Among patients with TBSA < 10%, 196 (41%) were sent home from the emergency department or discharged within 24 hours, and an additional 144 (30%) were discharged within 48 hours. Overall, 187 (30%) patients required an operation. In-hospital mortality rates were 1.5% for patients who arrived by ground transport, 14.9% for rotor wing transport, and 18.2% for fixed wing transport. Future education efforts should emphasize the importance of calculating TBSA to guide need for fluid resuscitation and restricting fluid boluses to patients that are hypotensive. Clarifying the American Burn Association burn center referral criteria to distinguish between immediate transfer vs outpatient referral may improve patient care and resource utilization. PMID- 28570316 TI - Severity of Inhalation Injury is Predictive of Alterations in Gas Exchange and Worsened Clinical Outcomes. AB - Inhalation injury (INH) is present in one third of large burn injuries and increases oxygenation and fluid resuscitation requirements, incidences of pulmonary complications, risk for multiple organ dysfunction syndrome (MODS), and overall mortality. Previous studies have demonstrated inconsistent correlation between bronchoscopic evaluation and clinical outcomes. The authors reviewed 161 patients admitted with a diagnosis of INH or underwent diagnostic bronchoscopy for suspected INH over a period of 8.5 years. One hundred one patients had concomitant burn injury and 60 had isolated INH. Seventeen patients had abbreviated injury score (AIS) 0, 81 patients had low-grade injury (AIS 1 and 2), and 63 patients had high-grade injury (AIS 3 and 4). Patients with high-grade INH had worse pulmonary dysfunction, worse oxygenation indices (P = 0.01) and plasma carboxyhemoglobin (COHgb; P < 0.01) on admission, increased fluid requirements (P < 0.01 at 24 hours; P = 0.04 at 48 hours), MODS (P = 0.04), pneumonia (P < 0.01), acute respiratory distress syndrome (P = 0.01 at 48 hours), fewer 28-day ventilator-free days (P < 0.01), greater ventilator dependence (P = 0.03), and longer length of stay (P < 0.01). Multivariate analyses demonstrated increased risk of MODS (P = 0.03), acute respiratory distress syndrome at 48 hours (P < 0.01), pneumonia (P = 0.01), prolonged ventilator dependence (P = 0.03), and a trend toward mortality (P = 0.08) with higher AIS groups. More severe INH correlates with early oxygenation impairments and is associated with more complicated hospitalization, fluid resuscitation requirements, and ventilation demands. Severe INH is associated with and predictive of increased morbidity and mortality. PMID- 28570321 TI - He Ain't Heavy, He's My Continuum Issue. PMID- 28570322 TI - Autoimmune Neurology of the Central Nervous System. AB - PURPOSE OF REVIEW: This article reviews the rapidly evolving spectrum of autoimmune neurologic disorders with a focus on those that involve the central nervous system, providing an understanding of how to approach the diagnostic workup of patients presenting with central nervous system symptoms or signs that could be immune mediated, either paraneoplastic or idiopathic, to guide therapeutic decision making. RECENT FINDINGS: The past decade has seen a dramatic increase in the discovery of novel neural antibodies and their targets. Many commercial laboratories can now test for these antibodies, which serve as diagnostic markers of diverse neurologic disorders that occur on an autoimmune basis. Some are highly specific for certain cancer types, and the neural antibody profiles may help direct the physician's cancer search. SUMMARY: The diagnosis of an autoimmune neurologic disorder is aided by the detection of an objective neurologic deficit (usually subacute in onset with a fluctuating course), the presence of a neural autoantibody, and improvement in the neurologic status after a course of immunotherapy. Neural autoantibodies should raise concern for a paraneoplastic etiology and may inform a targeted oncologic evaluation (eg, N methyl-D-aspartate [NMDA] receptor antibodies are associated with teratoma, antineuronal nuclear antibody type 1 [ANNA-1, or anti-Hu] are associated with small cell lung cancer). MRI, EEG, functional imaging, videotaped evaluations, and neuropsychological evaluations provide objective evidence of neurologic dysfunction by which the success of immunotherapy may be measured. Most treatment information emanates from retrospective case series and expert opinion. Nonetheless, early intervention may allow reversal of deficits in many patients and prevention of future disability. PMID- 28570317 TI - Safety of Nebulized Epinephrine in Smoke Inhalation Injury. AB - This pilot study was conducted to profile safety of nebulized racemic epinephrine when used as a therapy for smoke inhalation injury in severely burned children. We enrolled 16 patients who were 7 to 19 years of age ([mean +/- SD], 12 +/- 4 years) with burns covering more than 30% of the TBSA (55 +/- 17%) and smoke inhalation injury, as diagnosed by bronchoscopy at burn center admission. Patients were randomized to receive either standard of care (n = 8), which consisted of nebulized acetylcysteine, nebulized heparin, and nebulized albuterol, or to receive standard of care plus nebulized epinephrine (n = 8). Primary endpoints were death, chest pain, and adverse changes in cardiopulmonary hemodynamics (arrhythmia, arterial blood pressure, electrocardiographic [ST segment] changes, and peak inspiratory pressure). Additional endpoints included total days on ventilator, pulmonary function, and physiological cardiopulmonary measurements at intensive care unit discharge. No adverse events were observed during or after the nebulization of epinephrine, and no deaths were reported that were attributable to the administration of nebulized epinephrine. The groups did not significantly differ with regard to age, sex, burn size, days on ventilator, pulmonary function, or cardiopulmonary fitness. Results of this pilot trial indicate epinephrine to be safe when administered to pediatric burn patients with smoke inhalation injury. Current data warrant future efficacy studies with a greater number of patients. PMID- 28570323 TI - Neurologic Complications of Cardiac and Aortic Disease. AB - PURPOSE OF REVIEW: This article discusses neurologic complications that can arise from cardiac and aortic disease and dysfunction. RECENT FINDINGS: Advances in the care of patients with cardiac or aortic disease include the use of prolonged cardiac monitoring in cryptogenic stroke and the approval of the use of left atrial appendage closure devices for stroke prevention in patients with atrial fibrillation who are not candidates for anticoagulation. Continuing controversy surrounds patent foramen ovale closure, and new evidence indicates that cognitive impairment following coronary artery bypass grafting surgery may be less common than previously thought. SUMMARY: Dysfunction of the cardiovascular system can cause serious neurologic injury. In some cases, both the initial presenting symptom and the most serious damage done by cardiac or aortic dysfunction may be neurologic. Prompt recognition of the symptoms, combined with recent advances in both cardiology and neurology, may permit more accurate diagnoses, more effective treatment, and less injury to patients. PMID- 28570324 TI - Neurologic Complications of Lymphoma, Leukemia, and Paraproteinemias. AB - PURPOSE OF REVIEW: This article reviews the spectrum of neurologic complications associated with lymphoma, leukemia, and paraproteinemic disorders. While leptomeningeal metastasis is the most common complication of lymphoma and leukemia and peripheral neuropathy is the most common complication of paraproteinemic disorders, clinicians need to be familiar with the diverse neurologic complications of these disorders. RECENT FINDINGS: Lymphomatous nervous system involvement can be difficult to diagnose, especially when it is the presenting symptom. CSF cytology and flow cytometry, as well as the imaging pattern, assist in diagnosis. Neurologic complications are less common in Hodgkin lymphoma; however, some unique paraneoplastic syndromes are associated with Hodgkin lymphoma, including primary central nervous system angiitis, limbic encephalitis, and cerebellar degeneration. Recent reports suggest that anti metabotropic glutamate receptor 5 (mGluR5) antibodies are associated with limbic encephalitis and that anti-Tr antibodies are associated with cerebellar degeneration in Hodgkin lymphoma. Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome is often misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). A lambda protein, thrombocytosis, and elevated vascular endothelial growth factor (VEGF) can all be helpful clues in diagnosis. Early recognition is important, as the neuropathy responds to radiation therapy or chemotherapy. SUMMARY: Neurologic involvement can occur throughout the disease course in lymphoma and leukemia, including at presentation, with systemic progression, and at relapse. In paraproteinemias, the peripheral neuropathy phenotype, monoclonal protein type, and associated autonomic and systemic features aid in identification of an underlying plasma cell disorder. PMID- 28570325 TI - Rheumatology and Neurology. AB - PURPOSE OF REVIEW: This article reviews the various rheumatologic disorders that have neurologic complications and manifestations. RECENT FINDINGS: Recent advances have improved the understanding of the true epidemiology of many rheumatologic diseases and their complications. Many years of observation have clarified findings even in rarer disorders. Classification and diagnostic criteria have been updated and validated. As newer pharmacologic agents have become available, new information regarding efficacy and toxicity has emerged. SUMMARY: Rheumatologic disorders are common, as can be their neurologic complications. In many instances, these complications are treatable, but clinicians' understanding of the underlying disorder, its neurologic risks, and the risk of therapy is required. PMID- 28570326 TI - Renal Disease and Neurology. AB - PURPOSE OF REVIEW: Neurologic dysfunction is prevalent in patients with acute and chronic renal disease and may affect the central nervous system, peripheral nervous system, or both. Neurologic manifestations may result directly from the uremic state or as a consequence of renal replacement therapy. Early recognition of neurologic dysfunction may provide opportunities for intervention and reduced morbidity. RECENT FINDINGS: Advances in the understanding of neurologic complications of renal disease and its treatments have led to more widespread recognition and earlier identification of encephalopathy syndromes such as cefepime neurotoxicity and posterior reversible encephalopathy syndrome (PRES), dramatic reductions in the incidence of dialysis disequilibrium syndrome and dialysis dementia, and improved survival in disorders such as von Hippel-Lindau disease and thrombotic thrombocytopenic purpura. SUMMARY: This article summarizes the conditions that affect both the renal and the nervous systems, the effects of renal failure on the nervous system, and the neurologic complications of dialysis. PMID- 28570327 TI - Gastroenterology and Neurology. AB - PURPOSE OF REVIEW: Just as gastrointestinal dysfunction may develop in the setting of neurologic disease, neurologic dysfunction may become evident in the setting of gastrointestinal disease. This article describes the range of neurologic features that have been described in three primary gastrointestinal diseases: celiac disease and gluten-related disorders, inflammatory bowel disease, and Whipple disease. Particular emphasis is placed on the controversial and evolving clinical picture of neurologic dysfunction in disorders of gluten sensitivity. RECENT FINDINGS: Gluten-related disorders, including both the traditional autoimmune-based celiac disease and the more recently recognized nonautoimmune, nonallergic gluten sensitivity, have been the source of much attention in both medical and lay publications. The possible association between Crohn disease and neurologic disorders also is receiving attention. The recognition that, although Whipple disease is an exceedingly rare disorder, a surprising percentage of the population may be asymptomatic stool carriers of the causative organism makes it important to always be cognizant of the disorder. SUMMARY: The range of neurologic dysfunction in gastrointestinal diseases is broad and spans the spectrum from peripheral to central processes. Peripheral neuropathy, myopathy, myelopathy, cerebrovascular events, epilepsy, encephalopathy, and cerebellar dysfunction have all been described. Neurologists should be aware of the possibility that an underlying gastrointestinal disease process may be present in and responsible for the neurologic dysfunction that has prompted referral of an individual for evaluation. PMID- 28570328 TI - Liver Disease and Neurology. AB - PURPOSE OF REVIEW: Neurologists often encounter patients with acute and chronic liver disease and must be aware of how these diseases can affect the nervous system. This is particularly true when evaluating patients with alterations in cognition and level of consciousness. Wilson disease, while uncommon, is a treatable condition with many neurologic and psychiatric symptoms. Neurologic disorders associated with liver disease may affect not only the brain, but also the spinal cord and peripheral nervous system. This article reviews the association of liver disease and the nervous system and provides new information regarding diagnostic and therapeutic approaches to evaluating patients with liver diseases. RECENT FINDINGS: Early recognition of hepatic encephalopathy may be possible using a combination of clinical suspicion and various neuropsychological studies. Management of severe hepatic encephalopathy from acute liver failure is important to neurologists involved in neurocritical care. Next-generation genetic testing may aid in the diagnosis of patients suspected of having Wilson disease. The relationship of numerous neurologic findings from hepatocerebral degeneration and from viral hepatitis is more widely recognized. SUMMARY: It is important for neurologists to recognize the neurologic symptoms that may occur in patients with acute and chronic liver failure, Wilson disease, and viral hepatitis to inform prompt diagnostic and management decisions. PMID- 28570330 TI - Neurologic Complications of Transplantation. AB - PURPOSE OF REVIEW: This article describes the diagnosis and management of neurologic problems during hematopoietic cell and solid organ transplantation using time elapsed since transplantation as a guide to expected complications, including drug toxicities, infections, strokes, autoimmune phenomena, disease recurrence, and secondary neoplasms. RECENT FINDINGS: Growing clinical experience in the neurology of transplantation has led to appreciation of the diverse clinical and radiographic spectrum of calcineurin inhibitor-related posterior reversible encephalopathy syndrome (PRES) and progressive multifocal leukoencephalopathy. Novel autoimmune phenomena illustrate the delicate balance between adequate immunosuppression and necessary host inflammatory defenses that can lead to organ rejection. The spectrum of infectious complications has changed with the evolution of new conditioning regimens. SUMMARY: Neurologic problems remain an important source of morbidity and mortality, both in the immediate transplantation period and for years after the procedure. As perioperative management has reduced the incidence of acute infections, graft versus host disease, and organ rejection, problems of long-term survivors require neurologic input into multidisciplinary management of chronic neurologic conditions impacting quality of life. PMID- 28570331 TI - Nutrients and Neurology. AB - PURPOSE OF REVIEW: This article provides an update on the clinical presentation and management of neurologic disease related to key nutrient deficiencies. RECENT FINDINGS: Major advances have been made in understanding the pathway related to vitamin B12 absorption and distribution. It is now known that deficiencies of vitamin B12 and copper have similar neurologic manifestations. Bariatric surgery is a risk factor for both. Alcoholism is just one of the many causes of thiamine deficiency. Early neurologic complications following bariatric surgery are often due to thiamine deficiency. Encephalopathy in the setting of alcoholism that persists despite thiamine replacement should prompt consideration of niacin deficiency. Pyridoxine deficiency and toxicity both have neurologic sequelae. Vitamin D deficiency and the risk for multiple sclerosis has been an area of ongoing research. SUMMARY: Optimal functioning of the nervous system is dependent on a constant supply of certain vitamins and nutrients. This article discusses neurologic manifestations related to deficiency of these key nutrients. PMID- 28570329 TI - Endocrine Emergencies With Neurologic Manifestations. AB - PURPOSE OF REVIEW: This article provides an overview of endocrine emergencies with potentially devastating neurologic manifestations that may be fatal if left untreated. Pituitary apoplexy, adrenal crisis, myxedema coma, thyroid storm, acute hypercalcemia and hypocalcemia, hyperglycemic emergencies (diabetic ketoacidosis and hyperglycemic hyperosmolar state), and acute hypoglycemia are discussed, with an emphasis on identifying the signs and symptoms as well as diagnosing and managing these clinical entities. RECENT FINDINGS: To identify the optimal management of endocrine emergencies, using formal clinical diagnostic criteria and grading scales such as those recently proposed for pituitary apoplexy will be beneficial in future prospective studies. A 2015 prospective study in patients with adrenal insufficiency found a significant number of adrenal crisis-related deaths despite all study patients receiving standard care and being educated on crisis prevention strategies, highlighting that current prevention strategies and medical management remain suboptimal. SUMMARY: Early diagnosis and prompt treatment of endocrine emergencies are essential but remain challenging because of a lack of objective diagnostic tools. The optimal management is also unclear as prospective and randomized studies are lacking. Additional research is needed for these clinical syndromes that can be fatal despite intensive medical intervention. PMID- 28570332 TI - Environmental Neurologic Injuries. AB - PURPOSE OF REVIEW: This article discusses neurologic complications resulting from environmental injuries and the treatment modalities for these conditions. RECENT FINDINGS: Recent advances include improved management of altitude sickness. Relatively uncommon conditions, such as keraunoparalysis (lightning-induced paralysis) and high-pressure neurologic syndrome, are areas of ongoing study. SUMMARY: Environmental injuries may be associated with serious neurologic sequelae. This article reviews thermal and electrical injuries as well as injuries related to aviation, altitude, and diving. Recognition of signs and symptoms of such complex injuries and exposures will permit accurate diagnoses and improved outcomes. PMID- 28570333 TI - Response to Medical Errors. AB - Despite improvements in patient safety science over the past 15 years since the Institute of Medicine's publication of To Err Is Human, medical errors remain a major contributor to adverse patient outcomes and mortality. In the aftermath of a harmful medical error, providers often face dilemmas regarding how to best report and disclose errors. PMID- 28570334 TI - Safety Considerations During Transitions of Care From Inpatient to Outpatient Settings. AB - Hospital admissions are times of intense change. New medications are started, treatment regimens are modified, and care plans that will continue in the outpatient setting are initiated. After discharge, most patients receive care from different providers than those seen in the hospital. This situation will increase as inpatient-based practice patterns, such as neurohospitalist practices, become more prevalent. Communication failures during the transition from hospital to clinic increase the risk of adverse events. Providers must realize that successful transition can impact the patient's health as significantly as treatment of the admitting diagnosis. The transition should be carefully planned and standardized. This article discusses common pitfalls encountered during the transition period and highlights methods to improve patient care and safety. PMID- 28570339 TI - Patient Management Problem. PMID- 28570335 TI - Coding for Medication-related Poisoning and Adverse Effects. AB - Accurate coding is important for proper reimbursement and documentation of care provided. This article provides an overview of coding considerations for patient encounters associated with medication use, abuse, or poisoning. PMID- 28570340 TI - Patient Management Problem-Preferred Responses. PMID- 28570342 TI - The Perceval Sutureless Aortic Valve: Review of Outcomes, Complications, and Future Direction. AB - Surgical aortic valve replacement with a stented prosthesis has been the standard of care procedure for aortic stenosis. The Perceval (LivaNova, London, United Kingdom) is a sutureless aortic valve bioprosthesis currently implanted in more than 20,000 patients. The purpose of this article was to review the literature available after 9 years of clinical experience of the Perceval aortic valve. PubMED, Embase, and the Cochrane Library databases were searched. A meta-analysis of summary statistics from individual studies was conducted. A total of 333 studies were identified and 84 studies were included. Thirty-day mortality and 5 year survival ranged from 0% to 4.9% and 71.3% to 85.5%, respectively. Compared with stented prosthesis, pooled analysis demonstrated a statistically significant reduction in aortic cross-clamp and cardiopulmonary bypass times (minutes) with Perceval (38.6 vs 63.3 and 61.4 vs 84.9, P < 0.00001, respectively). Compared with transcatheter aortic valve implantation, pooled analysis demonstrated a statistically significant reduction with Perceval in paravalvular leakage (1.26% vs 14.31%) and early mortality (2.3% vs 6.9%). Favorable hemodynamics, acceptable valve durability, and ease of implantation in minimally invasive cases were reported as benefits. A trend toward increased rates of permanent pacemaker implantation and low postoperative platelet count were identified. Special use and off-label procedures described included bicuspid aortic valves, valve-in valve for homograft and stentless prosthesis failure, concomitant valvular procedures, porcelain aorta, and endocarditis. The Perceval valve has shown safe clinical and hemodynamic outcomes. Outcomes support its continued usage and potential expansion. PMID- 28570343 TI - Controlled attenuation parameter for diagnosing steatosis in bariatric surgery candidates with suspected nonalcoholic fatty liver disease. AB - INTRODUCTION: Steatosis in patients with nonalcoholic fatty liver disease (NAFLD) is often benign, but may progress to fibrosis. The accurate diagnosis of hepatic steatosis is therefore important for clinical decision-making and prognostic assessments. The controlled attenuation parameter (CAP), a noninvasive measurement obtained with Fibro-Scan, has been developed for liver steatosis assessment. CAP performs poorly in patients with high BMI. The XL probe was initially developed for measuring liver stiffness in overweight patients. We assessed the diagnostic value of CAP in candidates for bariatric surgery with suspected NAFLD examined with the XL probe. PATIENTS AND METHODS: For the retrospective group, raw ultrasonic radiofrequency signals were stored prospectively in the Fibro-Scan examination file for offline CAP calculation in 194 consecutive obese patients undergoing liver stiffness measurement in the 15 days before liver biopsy. For the prospective group, CAP was calculated automatically and prospectively from the XL probe in 123 obese patients. RESULTS: In the retrospective group, the diagnostic accuracy of CAP was satisfactory for differentiating S3 from S0-S1-S2 (0.79+/-0.03; 95% confidence interval: 0.71 0.84) and S3 from S0 (0.85+/-0.05; 95% confidence interval: 0.73-0.92). The Obuchowski measure demonstrated a very good discriminatory performance: 0.87+/ 0.02 in the retrospective group and 0.91+/-0.02 in the prospective group. CONCLUSION: CAP calculations from XL probe measurements efficiently detected severe steatosis in morbidly obese patients with suspected NAFLD. However, the cutoff values should now be confirmed in a larger prospective cohort. PMID- 28570344 TI - Pharmacotherapy of mast cell disorders. AB - PURPOSE OF REVIEW: Mast cell disorders (MCDs) comprise mastocytosis and disorders referred to as mast cell activation syndrome and are caused by abnormal accumulation and/or activation of mast cells in tissues. Clinical signs and symptoms are protean; therefore, finding suitable treatment options for individual patients entails a challenge for clinicians. The purpose of this manuscript is to review the literature on the available therapeutic interventions in patients with MCD. RECENT FINDINGS: Pharmacotherapy is mainly directed against the effects of mast cells and their mediators. The current recommendations are exclusively based on expert opinions due to the lack of controlled clinical trials. The targeted therapies aiming at blocking mutant KIT variants and/or downstream signaling pathways are currently being developed and may be considered in severely affected, therapy-refractory patients. SUMMARY: There is currently no method for predicting the best available approach to control symptoms in individual patients with MCD. Therefore, a stepwise, individual-based approach in pharmacotherapy options appears to be most successful strategy and is recommended in all patients. The core component of the treatment in most patients is to control symptoms caused by mast cell mediator release, whereas cytoreductive therapies are mainly reserved for patients with advanced/aggressive systemic mastocytosis. PMID- 28570345 TI - Reduction of pediatric pedestrian hazardous road conditions in a school drop-off zone using video review. AB - BACKGROUND: In 2012, 76,000 pedestrians were struck by motor vehicles. This resulted in 20% of all pediatric mortalities between the ages of 5 and 15. We hypothesize that children are exposed to increased risk as pedestrians to motor vehicle injury when arriving to school and that identification of these hazards would improve targeting of injury prevention efforts. METHODS: Within a county containing 355 public schools, we identified a primary school with 588 students located in an urban setting with concerns for a high-risk traffic environment. Field surveys observed traffic patterns and established an optimal surveillance period 30 minutes before school. Three observation periods, from two discreet and blinded locations, were conducted from January to March 2016. Videos were evaluated by two independent reviewers to identify and score quantifiable hazards. Three controlled observations were conducted on non-school days, followed by three post-intervention observations from October to December 2016. Comparison was made using Student's t test. Data was analyzed using SAS version 9.4 (SAS Institute Inc., Cary, NC). RESULTS: We identified nine safety hazards including double parking (29.3 +/- 5.5), dropping off in a bus stop (23.3 +/- 7.6), and jaywalking (9.3 +/- 3.1). Combining all hazards seen in each observation resulted in an overall hazard average of 83.0 +/- 3.6 events/period. Comparing control periods to school observation identified significantly increased hazard events on school days (p < 0.0001). Targeted safety intervention demonstrated a 26% reduction in hazard events (p < 0.0005). CONCLUSION: We identified the most common hazards associated with children arriving at a primary school in an urban setting, used our analysis to develop an intervention, and demonstrated the impact of our intervention. Our novel use of video review to identify hazards provides a metric against which the impact of pedestrian road safety interventions might be measured. LEVEL OF EVIDENCE: Epidemiological, level II; Therapeutic, level IV. PMID- 28570346 TI - Child welfare professionals' determination of when children's access or potential access to loaded firearms constitutes child neglect. AB - BACKGROUND: Pediatric deaths and injuries from access to firearms are a significant public health problem. No studies have examined how experts determine child neglect regarding firearm access in the home. Our study objectives were to identify factors that influenced pediatric experts' finding of firearm-related child neglect and to assess their attitudes toward child access prevention (CAP) laws. METHODS: A survey was distributed to the American Academy of Pediatrics Section on Child Abuse and Neglect members. Demographics, attitudes regarding CAP laws, and ages (up to 14 years old) at which experts deemed several scenarios as child neglect were determined. Scenarios tested potential versus actual loaded firearm access, presence or absence of a CAP law, and injury versus no injury when the firearm was accessed. RESULTS: One hundred ninety-three surveys were completed. Experts agreed (>95%) that CAP laws were important, even for children up to age 15 years. Although a high percentage considered potential access to a loaded firearm as child neglect, a CAP law significantly increased the percentage for each age. In addition, higher percentages of respondents from states with CAP laws than those without deemed potential access as child neglect for 12- and 14 year-olds. In contrast, if the child had accessed a loaded firearm, there were no significant differences in the high percentages that deemed the scenario as child neglect under any conditions, including with and without a CAP law. CONCLUSIONS: Although almost all child neglect experts considered potential and actual access to loaded firearms as child neglect, CAP laws increased the percentage for cases of potential access. Universal CAP laws may help ensure that determinations of child neglect are more consistent across states. The deterrent effect of potential child neglect findings may increase the number of parents securing firearms in ways that prevent child access and reduce firearm-related deaths and injuries. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 28570347 TI - Natural history of splenic vascular abnormalities after blunt injury: A Western Trauma Association multicenter trial. AB - BACKGROUND: Following blunt splenic injury, there is conflicting evidence regarding the natural history and appropriate management of patients with vascular injuries of the spleen such as pseudoaneurysms or blushes. The purpose of this study was to describe the current management and outcomes of patients with pseudoaneurysm or blush. METHODS: Data were collected on adult (aged >=18 years) patients with blunt splenic injury and a splenic vascular injury from 17 trauma centers. Demographic, physiologic, radiographic, and injury characteristics were gathered. Management and outcomes were collected. Univariate and multivariable analyses were used to determine factors associated with splenectomy. RESULTS: Two hundred patients with a vascular abnormality on computed tomography scan were enrolled. Of those, 14.5% were managed with early splenectomy. Of the remaining patients, 59% underwent angiography and embolization (ANGIO), and 26.5% were observed. Of those who underwent ANGIO, 5.9% had a repeat ANGIO, and 6.8% had splenectomy. Of those observed, 9.4% had a delayed ANGIO, and 7.6% underwent splenectomy. There were no statistically significant differences between those observed and those who underwent ANGIO. There were 111 computed tomography scans with splenic vascular injuries available for review by an expert trauma radiologist. The concordance between the original classification of the type of vascular abnormality and the expert radiologist's interpretation was 56.3%. Based on expert review, the presence of an actively bleeding vascular injury was associated with a 40.9% risk of splenectomy. This was significantly higher than those with a nonbleeding vascular injury. CONCLUSIONS: In this series, the vast majority of patients are managed with ANGIO and usually embolization, whereas splenectomy remains a rare event. However, patients with a bleeding vascular injury of the spleen are at high risk of nonoperative failure, no matter the strategy used for management. This group may warrant closer observation or an alternative management strategy. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 28570349 TI - Expert opinion: A spontaneous pneumoperitoneum following Klebsiella induced chronic granulomatous cholecystitis: Is the surgery warranted? PMID- 28570348 TI - Early infectious outcomes after addition of fluoroquinolone or aminoglycoside to posttrauma antibiotic prophylaxis in combat-related open fracture injuries. AB - BACKGROUND: We examined combat-related open extremity fracture infections as a function of whether posttrauma antimicrobial prophylaxis included expanded Gram negative (EGN) coverage. METHODS: Military personnel with open extremity fractures sustained in Iraq and Afghanistan (2009-2014) who transferred to participating hospitals in the United States were assessed. The analysis was restricted to patients with a U.S. hospitalization period of >=7 days. Prophylaxis was classified as narrow (e.g., IV cefazolin, clindamycin, and/or amoxicillin-clavulanate) or EGN, if the prophylactic regimen included fluoroquinolones and/or aminoglycosides. RESULTS: The study population included 1,044 patients, of which 585 (56%) and 459 (44%) received narrow and EGN coverage, respectively (p < 0.001). Skin and soft-tissue infections (SSTIs) were more common among patients who received narrow prophylaxis compared to EGN coverage (28% vs. 22%; p = 0.029), whereas osteomyelitis rates were comparable between regimens (8%). Similar findings were noted when endpoints were measured at 2 and 4 weeks postinjury. There was no significant difference related to length of hospitalization between narrow and EGN regimens (median: 34 and 32 days, respectively) or operating room visits (median: 5 and 4). A higher proportion of EGN coverage patients had Gram-negative organisms isolated that were not susceptible to fluoroquinolones and/or aminoglycosides (49% vs. 40%; p < 0.001). In a Cox proportional model, narrow prophylaxis was independently associated with an increased risk of extremity SSTIs (hazard ratio: 1.41; 95% confidence interval: 1.09-1.83). DISCUSSION: Despite seeing a small benefit with EGN coverage related to a reduction of SSTIs, it does not decrease the risk of osteomyelitis, and there seems to be a cost of increased antibiotic resistance associated with use. Overall, our findings support the current post-combat trauma antibiotic prophylaxis guidelines, which recommend the use of cefazolin or clindamycin with open fractures. LEVEL OF EVIDENCE: Prognostic/Epidemiological, Level II; Therapy, level IV. PMID- 28570350 TI - Impact of Critical Care Air Transport Team (CCATT) ventilator management on combat mortality. AB - BACKGROUND: Aeromedical evacuation platforms such as Critical Care Air Transport Teams (CCATTs) play a vital role in the transport and care of critically injured and ill patients in the combat theater. Mechanical ventilation is used to support patients with failing respiratory function and patients requiring high levels of sedation. Mechanical ventilation, if not managed appropriately, can worsen or cause lung injury and contribute to increased morbidity. The purpose of this study was to evaluate the impact of ARDSNet protocol compliance during aeromedical evacuation of ventilated combat injured patients. METHODS: We performed a retrospective chart review of combat injured patients transported by CCATTs from Afghanistan to Landstuhl Regional Medical Center (LRMC) in Germany between January 2007 and January 2012. After univariate analyses, we performed regression analyses to assess compliance and post-flight outcomes. Cox proportional hazard models were used to evaluate associations between the risk factor of non-compliance with increased number of ventilator, ICU, or hospital days. Nominal logistic regression models were performed to evaluate the association between non-compliance and mortality. RESULTS: Sixty-two percent (n = 669) of 1,086 patients required mechanical ventilation during transport. A total of 650 patients required volume-controlled mechanical ventilation and were included in the analysis. Of the 650 subjects, 62% (n = 400) were non-compliant per tidal volume and ARDSNet table recommendations. The groups were similar in all demographic variables, except the Non-compliant group had a higher Injury Severity Score compared to the Compliant group. Subjects in the Compliant group were less likely to have an incidence of acute respiratory distress, acute respiratory failure, and ventilator-associated pneumonia when combing the variables (2% vs. 7%, p < 0.0069). The Non-compliant group had an increased incidence of in-flight respiratory events, required more days on the ventilator and in the ICU, and had a higher mortality rate. CONCLUSIONS: Compliance with the ARDSNet guidelines was associated with a decrease in ventilator days, ICU days, and 30-day mortality. LEVEL OF EVIDENCE: Therapeutic/care management, level IV. PMID- 28570351 TI - Editor's Foreward: Proliferation versus prevention. PMID- 28570352 TI - From the Editor. PMID- 28570353 TI - Dramatic Changes in Health Care Professions in the Past 40 Years. AB - During the forty-year life of the Journal of Ambulatory Care Management, revolutionary transformations have occurred in the roles of existing health professions, as has the emergence of new categories of health professionals. This paper specifies the reasons for these dramatic changes, the new types of health care professions that have emerged, changes in existing professions, and suggestions of future directions. Many of these changes will be impacted by what occurs in Washington, DC in the debate over the Accountable Care Act. PMID- 28570354 TI - Commentry on "The Changing Medical Division of Labor". PMID- 28570355 TI - Transforming Health Care Systems: CHWs as the Glue in Multidisciplinary Teams. PMID- 28570356 TI - Commentary on "Evidence-Based Self-management Programs for Seniors and Other With Chronic Diseases": Patient Experience-Patient Health-Return on Investment. PMID- 28570357 TI - Commentary on "Changes in the Roles of Health Care Professionals in Primary Care in England's National Health Service". PMID- 28570358 TI - Commentary on "Community Health Workers and the Changing Workforce": No More Opportunities Lost. PMID- 28570359 TI - Changes in the Health Professions: A Commentary. AB - Increased life expectancy in the United States has been accompanied by a concomitant increase in the prevalence of chronic conditions in persons of all ages, especially older Americans. This necessitates new ways of organizing and conducting medical practice, and this affects the roles and interactions of health professionals. Physicians and other health professionals require appropriate training and more efficient workplaces to enhance their functioning and reduce burnout. Additional factors influencing the success of health professionals in further advancing the health and well-being of Americans are health information technology and ensuring that all have access to care. PMID- 28570360 TI - Atlanto-Axial Subluxation After Adenoidectomy. AB - Atlanto-axial subluxation is a rare but potentially serious complication after otolaryngological procedures. We are describing a case of a 4-year-old child who developed atlanto-axial subluxation of the cervical spine after adenoidectomy. Our patient underwent adenoidectomy and, 18 days later, presented to the emergency department with her neck tilted to the left in a cock-robin position and complaining of neck pain persisting since the surgery. A multiplanar 3 dimensional computed tomography was obtained and confirmed the diagnosis of an atlanto-axial subluxation (Fielding type 3). She was managed conservatively with the application of a cervical collar, anti-inflammatory medication, and manual reduction under anesthesia later in the course because of persistence of her symptoms. It is important to consider this diagnosis in any child who undergoes ENT surgical procedures complaining of neck pain subsequent to surgery or holding the head in a fixed position persistently after surgery. Early diagnosis is important to reduce the time between the onset of symptoms and reduction to reduce the risk or need for surgical intervention. PMID- 28570361 TI - Catecholaminergic Polymorphic Ventricular Tachycardia. AB - Catecholaminergic polymorphic ventricular tachycardia is a rare cause of exercise induced arrhythmia and sudden cardiac death in the pediatric patient. This arrhythmia is difficult to diagnose in the emergency department, given the range of presentations; thus, a familiarity with and high index of suspicion for this pathology are crucial. Furthermore, recognition of the characteristic electrocardiogram findings and knowledge of the management of the symptomatic patient are necessary, given the risk of arrhythmia recurrence and cardiac arrest. In this review, we discuss the presentation, differential diagnosis, and management of catecholaminergic polymorphic ventricular tachycardia for the emergency care provider. PMID- 28570363 TI - Point-of-Care Ultrasound Identification of a Psoas Abscess in a Child Presenting With Hip Pain. AB - This case-report describes a 4-year-old girl brought to the emergency department for the evaluation of limp and elevated inflammatory markers. The patient's history and physical examination did not reveal a clear source of pathology. Point-of-care ultrasound identified a right-sided psoas abscess that was confirmed with computed tomography scan. This case demonstrates the potential utility of point-of-care ultrasound in the diagnosis and management of patients presenting to the emergency department with symptoms concerning for pathology in the hip or lower abdomen. PMID- 28570364 TI - Backyard Pool Party: Not Your Typical Sunburn. PMID- 28570365 TI - Pediatric Emergency Medicine: Legal Briefs. PMID- 28570366 TI - ECGs in the ED. PMID- 28570367 TI - Antiretroviral dose optimization: the future of efavirenz 400 mg dosing. AB - PURPOSE OF REVIEW: Antiretroviral (ARV) therapy costs in low-income and middle income countries are major concerns, and lower doses of first-line treatment components, when possible, would save millions of dollars, which could be used to treat more people living with HIV. RECENT FINDINGS: The Encore-1 study, followed by a detailed pharmacokinetic analysis of efavirenz 400 versus 600 mg once daily, produced enough information for the most recent ARV treatment WHO guidelines to include efavirenz 400 mg among agents used for first-line treatment. However, data on efavirenz 400 mg plasma concentrations during pregnancy and when coadministered with rifampicin-containing antituberculosis (TB) treatment are not yet available as formal pharmacokinetic studies under these circumstances are ongoing. SUMMARY: Although efavirenz at a daily dose of 400 mg once daily in combination with tenofovir disoproxil fumarate and emtricitabine has shown noninferiority to the approved 600 mg once-daily dose, large global uptake has been delayed by the lack of data on drug exposure during pregnancy and anti-TB treatment. Knowledge on efavirenz 400 mg exposure in these scenarios will arise in mid-late 2017. PMID- 28570368 TI - Prioritizing the most needed formulations to accelerate paediatric antiretroviral therapy scale-up. AB - PURPOSE OF REVIEW: Initiatives are in place to reach super-fast targets by 2018 for paediatric patients living with HIV. However, these efforts are unlikely to be successful until better paediatric antiretrovirals and treatment strategies are available. This commentary reviews the specific features, challenges, and recent developments in paediatric HIV treatment to determine optimal regimen sequencing and use of available drug options. It also outlines a medium and long term vision for treatment optimization as endorsed by the paediatric antiretroviral drug optimization group. RECENT FINDINGS: Optimizing antiretroviral therapy (ART) is critical in the context of limited treatment options for children. A first-line dolutegravir-based regimen is the long-term goal for paediatric first-line ART across all age groups. Protease inhibitor based regimens are expected to continue to play a critical role for second and third-line treatment. New efforts are urgently needed to optimize treatment for children, ensuring access to existing drugs and speeding up development of newer and better formulations moving forward. SUMMARY: Over the last few years there have been a number of key developments in paediatric ART which offer the opportunity to reconsider the way ART is optimized for children. Additional evidence is needed to ensure optimal options are available from infancy through adulthood. PMID- 28570369 TI - Drug interactions and the role of pharmacokinetic trials in guiding choices in first-line HIV therapy in low-income and middle-income countries. AB - PURPOSE OF REVIEW: Low- and middle-income countries (LMICs) face specific challenges in the treatment of people living with HIV. Drug-drug interactions (DDIs) involving antiretrovirals (ARVs) are prevalent in all settings and have considerable potential to cause clinical harm to patients via toxicity or reduced efficacy of treatment. Differing comorbidities, endemic infections and traditional medicines may complicate ARV therapy (ART) in LMICs, which usually takes a public health approach in these settings, with fewer alternative regimens available. This review discusses the issues surrounding pharmacokinetic DDI studies and their application to ART in LMICs, with particular reference to first line ART regimens. RECENT FINDINGS: Pharmacokinetic studies with clinical endpoints are the gold standard for informing management of DDIs; however, data relevant to LMICs are sparse and of low quality. There is significant potential for clinically relevant DDIs between ARVs and antimalarials, antimycobacterials and drugs used in the treatment of neglected tropical diseases. SUMMARY: Many pharmacokinetic studies are difficult to interpret in LMICs due to differences in patient factors including weight, disease state and genetic polymorphisms. DDI studies relevant to LMICs may also be lacking due to the neglected nature of relevant comorbidities. The ARVs currently available as first-line ART in LMICs are among those with highest propensity for DDIs. PMID- 28570370 TI - Immunoassays for Measuring Serum Concentrations of Monoclonal Antibodies and Anti biopharmaceutical Antibodies in Patients. AB - Monoclonal antibodies (mAbs) may be used as biopharmaceuticals to treat various diseases, ranging from oncology to inflammatory and cardiovascular affections. Trustworthy analytical methods are necessary to study their pharmacokinetics, both during their development and in post-marketing studies. Because biopharmaceuticals are macromolecules, ligand-binding assays (both immunoassays and bioassays) are methods of choice to measure their concentrations. Immunoassays are based on the capture of biopharmaceuticals by their target, which may be a circulating or membrane antigen or by an antibody recognizing their structure. Bioassays measure the activity of the biopharmaceutical in a specific in vitro test. A number of techniques have been reported, but their limits of detection and quantification vary widely. Anti-drug antibodies (ADA) against biopharmaceuticals are often formed and sometimes interfere with clinical efficacy. Accurate and reliable detection of ADA is therefore necessary. Binding of ADA is dependent on affinity and avidity, which makes quantification challenging. In this review, we discuss the benefits and limitations of each method to determine mAb levels and carefully compare ADA assays. PMID- 28570371 TI - Prolongation of Biologic Dosing Intervals in Patients With Stable Psoriasis: A Feasibility Study. AB - BACKGROUND: Biologics are usually licensed according to the "one dose fits all" principle. It is therefore suspected that a significant number of patients with psoriasis are overtreated. However, evidence for successful dose reduction of biologics in psoriasis is scarce. The aim of this study was to investigate whether the dosing interval of 3 biologics, adalimumab, etanercept, or ustekinumab could be prolonged successfully in patients with plaque psoriasis. METHODS: In a prospective exploratory cohort study, 59 patients with psoriasis on maintenance treatment with adalimumab, etanercept, or ustekinumab were included. After a run-in period of 6 weeks, the dosing interval of the biologics was prolonged according to a predefined schedule. Our primary objective was to determine the proportion of patients who could maintain a successful prolongation of the per label dosing interval. Secondary objectives were to evaluate the predictive value of baseline serum trough concentrations for successful dosing interval prolongation and to explore the feasibility of dosing interval prolongations in off-label-treated patients. RESULTS: In the per label group, 7 out of 16 (44%) adalimumab patients, 5 out of 16 (31%) etanercept patients, and 2 out of 10 (20%) ustekinumab patients achieved a successful dosing interval prolongation. Baseline serum trough concentrations did not differ significantly between patients with successful dosing interval prolongation and failures. In the off-label group, prolongation in patients with already extended intervals was unsuccessful. For patients with shortened intervals, minor prolongation was successful in 3 out of 17 (17.6%) patients. CONCLUSIONS: Prolongation of the per label biologic dosing interval was feasible in approximately 30% of patients with psoriasis with stable minimal disease activity and can reduce costs in clinical practice. Baseline serum trough concentrations were not predictive for successful dosing interval prolongation. PMID- 28570372 TI - Exploring APN Students' Perceptions, Self-Confidence, and Satisfaction With Clinical Simulation. AB - The purpose of this study was to explore advanced practice students' perceptions, self-confidence, and satisfaction with clinical simulation as a learning tool. The simulation was part of a health assessment course with 69 students, 25 of whom had no RN experience. On average, students were undecided but trended toward agreement that each key simulation feature was present in the simulation. Students without experience were significantly less likely to feel supported during the simulation and to endorse the appropriateness of the selected problem for the simulation. Upon multiple regression analysis, only fidelity was significantly associated with self-confidence (p = .003). PMID- 28570373 TI - Effects of white noise on event-related potentials in somatosensory Go/No-go paradigms. AB - Exposure to auditory white noise has been shown to facilitate human cognitive function. This phenomenon is termed stochastic resonance, and a moderate amount of auditory noise has been suggested to benefit individuals in hypodopaminergic states. The present study investigated the effects of white noise on the N140 and P300 components of event-related potentials in somatosensory Go/No-go paradigms. A Go or No-go stimulus was presented to the second or fifth digit of the left hand, respectively, at the same probability. Participants performed somatosensory Go/No-go paradigms while hearing three different white noise levels (45, 55, and 65 dB conditions). The peak amplitudes of Go-P300 and No-go-P300 in ERP waveforms were significantly larger under 55 dB than 45 and 65 dB conditions. White noise did not affect the peak latency of N140 or P300, or the peak amplitude of N140. Behavioral data for the reaction time, SD of reaction time, and error rates showed the absence of an effect by white noise. This is the first event-related potential study to show that exposure to auditory white noise at 55 dB enhanced the amplitude of P300 during Go/No-go paradigms, reflecting changes in the neural activation of response execution and inhibition processing. PMID- 28570374 TI - What Can Be and What Cannot Be Accomplished With PET: Rectifying Ongoing Misconceptions. PMID- 28570375 TI - DCCN Welcomes Kelly A. Powers, PhD, RN, CNE, to 2017 Editorial Board. PMID- 28570376 TI - Research Use of Nurses Working in the Critical Care Units: Barriers and Facilitators. AB - BACKGROUND: There is a distinct gap between theory and practice with respect to research use in clinical practice, particularly in critical care units, that could be related to the presence of a number of barriers that hinder the use of research findings. AIMS: The aims of the study were to identify barriers and facilitators to research use as perceived by Jordanian nurses in critical care units and to examine the predictors of research use among those nurses. METHODS: The study used a cross-sectional, correlational design. The self-administered "Barriers Scale" was introduced to 200 registered critical care nurses, using the drop-and-collect technique, between October and November 2015. RESULTS: The results revealed that "nurse does not have time to read research at work" was the top ranked barrier that hinders research use (mean [SD], 3.45 [0.79]). The first 7 ranked barriers were related to the organizational subscale. Managerial support was the top perceived facilitator for research use. Only "attending special training courses in nursing research" was the significant predictor of research use and explained 59.1% of the variance in research use, t(190) = -3.93, P = .003. The most identified barriers toward research use revealed by the qualitative data include dominant routine nursing tasks, existence of gap between theory and practice, shortage of nursing staff, and public negative image about nursing profession. Participants suggested the importance of increasing organizational support and creating an organizational research culture to further promote research use in clinical nursing practice. CONCLUSIONS: Research use has not been widely implemented yet in Jordan because of various barriers. The organization-related barriers were the most influential. Factors hindering research use are multidimensional, and optimizing them should be a shared responsibility of nurse managers, researchers, clinicians, and academicians. Further initiatives are required to raise awareness of the importance of using evidence-based practice. PMID- 28570377 TI - Part I: The Effects of Music for the Symptom Management of Anxiety, Pain, and Insomnia in Critically Ill Patients: An Integrative Review of Current Literature. AB - Critical care environments are known for provoking anxiety, pain, and sleeplessness. Often, these symptoms are attributed to patients' underlying physiological conditions; life-sustaining or life-prolonging treatments such as ventilators, invasive procedures, tubes, and monitoring lines; and noise and the fast-paced technological nature of the critical care environment. This, in turn, possibly increases length of stay and morbidity and challenges the recovery and healing of critically ill patients. Complementary therapies can be used as adjunctive therapies alongside pharmacological interventions and modalities. One complementary therapy with promise in critical care for improving symptoms of anxiety, pain, and sleeplessness is music. A review of current literature from Ovid MEDLINE, Cumulative Index to Nursing and Allied Health Literature, and PubMed was conducted to examine the evidence for the use of this complementary therapy in critical care settings. This review presents the evidence on effectiveness of music for the symptom management of anxiety, pain, and insomnia in critically ill adult patients. The evidence from this review supports music in symptom management of pain, insomnia, and anxiety in critically ill patients. This review provides practice recommendations, generates dialog, and promotes future research. This review is part I of a 2-part series that focuses on evidence for use of music, aromatherapy and guided imagery for improving anxiety, pain, and sleeplessness of patients in critically ill patients. PMID- 28570379 TI - Promoting Evidence-Based Practice at a Primary Stroke Center: A Nurse Education Strategy. AB - BACKGROUND: Promoting a culture of evidence-based practice within a health care facility is a priority for health care leaders and nursing professionals; however, tangible methods to promote translation of evidence to bedside practice are lacking. OBJECTIVES: The purpose of this quality improvement project was to design and implement a nursing education intervention demonstrating to the bedside nurse how current evidence-based guidelines are used when creating standardized stroke order sets at a primary stroke center, thereby increasing confidence in the use of standardized order sets at the point of care and supporting evidence-based culture within the health care facility. METHODS: This educational intervention took place at a 286-bed community hospital certified by the Joint Commission as a primary stroke center. Bedside registered nurse (RN) staff from 4 units received a poster presentation linking the American Heart Association's and American Stroke Association's current evidence-based clinical practice guidelines to standardized stroke order sets and bedside nursing care. The 90-second oral poster presentation was delivered by a graduate nursing student during preshift huddle. The poster and supplemental materials remained in the unit break room for 1 week for RN viewing. After the pilot unit, a pdf of the poster was also delivered via an e-mail attachment to all RNs on the participating unit. A preintervention online survey measured nurses' self perceived likelihood of performing an ordered intervention based on whether they were confident the order was evidence based. The preintervention survey also measured nurses' self-reported confidence in their ability to explain how the standardized order sets are derived from current evidence. The postintervention online survey again measured nurses' self-reported confidence level. However, the postintervention survey was modified midway through data collection, allowing for the final 20 survey respondents to retrospectively rate their confidence before and after the educational intervention. This modification ensured that the responses for each individual participant in this group were matched. RESULTS: Registered nurses reported a significant increase in perceived confidence in ability to explain how standardized stroke order sets reflect current evidence after the intervention (n = 20, P < .001). This sample was matched for each individual respondent. No significant change was shown in unmatched group mean self-reported confidence ratings overall after the intervention or separately by unit for the progressive care unit, critical care unit, or intensive care unit (n = 89 preintervention, n = 43 postintervention). However, the emergency department demonstrated a significant increase in group mean perceived confidence scores (n = 20 preintervention, n = 11 postintervention, P = .020). Registered nurses reported a significantly higher self-perceived likelihood of performing an ordered nursing intervention when they were confident that the order was evidence based compared with if they were unsure the order was evidence based (n = 88, P < .001). DISCUSSION: This nurse education strategy increased RNs' confidence in ability to explain the path from evidence to bedside nursing care by demonstrating how evidence-based clinical practice guidelines provide current evidence used to create standardized order sets. Although further evaluation of the intervention's effectiveness is needed, this educational intervention has the potential for generalization to different types of standardized order sets to increase nurse confidence in utilization of evidence-based practice. PMID- 28570380 TI - Rigor or Reliability and Validity in Qualitative Research: Perspectives, Strategies, Reconceptualization, and Recommendations. AB - Issues are still raised even now in the 21st century by the persistent concern with achieving rigor in qualitative research. There is also a continuing debate about the analogous terms reliability and validity in naturalistic inquiries as opposed to quantitative investigations. This article presents the concept of rigor in qualitative research using a phenomenological study as an exemplar to further illustrate the process. Elaborating on epistemological and theoretical conceptualizations by Lincoln and Guba, strategies congruent with qualitative perspective for ensuring validity to establish the credibility of the study are described. A synthesis of the historical development of validity criteria evident in the literature during the years is explored. Recommendations are made for use of the term rigor instead of trustworthiness and the reconceptualization and renewed use of the concept of reliability and validity in qualitative research, that strategies for ensuring rigor must be built into the qualitative research process rather than evaluated only after the inquiry, and that qualitative researchers and students alike must be proactive and take responsibility in ensuring the rigor of a research study. The insights garnered here will move novice researchers and doctoral students to a better conceptual grasp of the complexity of reliability and validity and its ramifications for qualitative inquiry. PMID- 28570382 TI - Critical Care Nurses' Suggestions to Improve End-of-Life Care Obstacles: Minimal Change Over 17 Years. AB - BACKGROUND: Critical-care nurses (CCNs) provide end-of-life (EOL) care on a daily basis as 1 in 5 patients dies while in intensive care units. Critical-care nurses overcome many obstacles to perform quality EOL care for dying patients. OBJECTIVES: The purposes of this study were to collect CCNs' current suggestions for improving EOL care and determine if EOL care obstacles have changed by comparing results to data gathered in 1998. METHODS: A 72-item questionnaire regarding EOL care perceptions was mailed to a national, geographically dispersed, random sample of 2000 members of the American Association of Critical Care Nurses. One of 3 qualitative questions asked CCNs for suggestions to improve EOL care. Comparative obstacle size (quantitative) data were previously published. RESULTS: Of the 509 returned questionnaires, 322 (63.3%) had 385 written suggestions for improving EOL care. Major themes identified were ensuring characteristics of a good death, improving physician communication with patients and families, adjusting nurse-to-patient ratios to 1:1, recognizing and avoiding futile care, increasing EOL education, physicians who are present and "on the same page," not allowing families to override patients' wishes, and the need for more support staff. When compared with data gathered 17 years previously, major themes remained the same but in a few cases changed in order and possible causation. CONCLUSION: Critical-care nurses' suggestions were similar to those recommendations from 17 years ago. Although the order of importance changed minimally, the number of similar themes indicated that obstacles to providing EOL care to dying intensive care unit patients continue to exist over time. PMID- 28570383 TI - Validity of Cardiovascular Disease Event Ascertainment Using Linkage to UK Hospital Records. AB - BACKGROUND: Use of electronic health records for ascertainment of disease outcomes in large population-based studies holds much promise due to low costs, diminished study participant burden, and reduced selection bias. However, the validity of cardiovascular disease endpoints derived from electronic records is unclear. METHODS: Participants were 7860 study members of the UK Whitehall II cohort study. We compared cardiovascular disease ascertainment using linkage to the National Health Service's Hospital Episode Statistics database records (hereafter, "HES-ascertainment") against repeated biomedical examinations-our gold standard ascertainment method (Whitehall-ascertainment). Follow-up for both methods was from 1997 to 2013 for coronary heart disease and from 1997 to 2009 for stroke. RESULTS: We identified 950 prevalent or incident nonfatal coronary heart disease cases and 118 prevalent or incident nonfatal stroke cases using Whitehall-ascertainment. The corresponding figures for HES-ascertainment were 926 and 107. For coronary heart disease, the sensitivity of HES-ascertainment was 70%, positive predictive value 72%, specificity 96%, and the negative predictive value 96%. The pattern of results for stroke was similar. These statistics did not differ in analyses stratified by age, sex, baseline risk factor status, or after exclusion of prevalent cases. Estimates of risk factor-disease associations were similar between the two ascertainment methods. Including fatal cardiovascular disease in the outcomes improved the agreement between the methods. CONCLUSION: Our analyses support the validity of cardiovascular disease ascertainment using linkage to the UK Hospital Episode Statistics database records by showing agreement with high resolution disease data collected in the Whitehall II cohort. PMID- 28570384 TI - Team Logo Predicts Concussion Risk: Lessons in Protecting a Vulnerable Sports Community from Misconceived, but Highly Publicized Epidemiologic Research. AB - BACKGROUND: Observational research has linked altitude to concussion risk, but the physiologic and epidemiologic bases for this association remain questionable. METHODS: We performed a retrospective cohort study by analyzing four seasons of National Football League data from a widely used database (Concussion Watch) to determine if previous claims that altitude >=196 m reduced concussion risk were replicable and whether an arbitrary predictor variable (animal vs. non-animal team logo) was related to concussion risk. Relative risk (RR) and 95% confidence intervals (95% CIs) were computed. RESULTS: The previous association with altitude was reproduced for earlier seasons, but not replicable for recent seasons (RR = 0.92 [95% CI = 0.70, 1.22]). Across four combined seasons, "higher altitude" (RR = 0.78 [0.64, 0.96]) and animal logo (RR = 0.75 [0.63, 0.89]) were similarly associated with reduced concussion risk. CONCLUSIONS: Inconsistent epidemiologic effects, combined with weak physiologic rationale, suggest links between altitude and concussion are coincidental. Interdisciplinary critique of concussion research is necessary to ensure that marketing claims and clinical recommendations are scientifically justified.See video abstract at, http://links.lww.com/EDE/B234. PMID- 28570385 TI - Validation of Self-reported Diagnosis of Gestational Diabetes at 6-weeks Postpartum. AB - BACKGROUND: Self-report is often used in identifying gestational diabetes events in epidemiologic studies; however, validity data are limited, with little to no data on self-reported severity or treatment. METHODS: We aimed to assess the validity of self-reported gestational diabetes diagnosis and evaluate the accuracy of glucose diagnosis results and gestational diabetes treatment self reported at 6-week postpartum. Data were from 82 and 83 women with and without gestational diabetes, respectively, within the prospective National Institute Child Health and Human Development Fetal Growth Studies-Singletons (2009-2013). Medical record data were considered the gold standard. RESULTS: Sensitivity was 95% (95% confidence interval [CI] = 88, 98), and specificity was 100% (95% CI = 96, 100); four women with gestational diabetes incorrectly reported not having the disease, and none of the women without gestational diabetes reported having gestational diabetes. Sensitivity did not vary substantially across maternal characteristics including race/ethnicity. For women who attempted to recall their values (84/159 women), self-reported glucose challenge test results did not differ from the medical records (median difference: 0; interquartile range: 0-0 mg/dl). Medical records indicated that 42 (54%) of 78 women with confirmed gestational diabetes were treated by diet only and 33 (42%) were treated by medication. All 42 women with diet-treated gestational diabetes correctly reported having had diet and lifestyle modification, and 28 (85%) of 33 women with medication-treated gestational diabetes indicated postpartum that they had medication treatment. CONCLUSIONS: At 6-week postpartum, regardless of race/ethnicity or socioeconomic status, women accurately recalled whether they had gestational diabetes and, as applicable, their treatment method. PMID- 28570386 TI - Re: Seasonal Variation in Exposure to Endocrine-disrupting Chemicals. PMID- 28570387 TI - Douglas Wiebe, Winner of the 2017 Kenneth Rothman EPIDEMIOLOGY Prize. PMID- 28570389 TI - Interstitial granulomatous dermatitis during talimogen laherparepvec treatment. PMID- 28570388 TI - Effort-Reward Imbalance at Work and Incident Coronary Heart Disease: A Multicohort Study of 90,164 Individuals. AB - BACKGROUND: Epidemiologic evidence for work stress as a risk factor for coronary heart disease is mostly based on a single measure of stressful work known as job strain, a combination of high demands and low job control. We examined whether a complementary stress measure that assesses an imbalance between efforts spent at work and rewards received predicted coronary heart disease. METHODS: This multicohort study (the "IPD-Work" consortium) was based on harmonized individual level data from 11 European prospective cohort studies. Stressful work in 90,164 men and women without coronary heart disease at baseline was assessed by validated effort-reward imbalance and job strain questionnaires. We defined incident coronary heart disease as the first nonfatal myocardial infarction or coronary death. Study-specific estimates were pooled by random effects meta analysis. RESULTS: At baseline, 31.7% of study members reported effort-reward imbalance at work and 15.9% reported job strain. During a mean follow-up of 9.8 years, 1,078 coronary events were recorded. After adjustment for potential confounders, a hazard ratio of 1.16 (95% confidence interval, 1.00-1.35) was observed for effort-reward imbalance compared with no imbalance. The hazard ratio was 1.16 (1.01-1.34) for having either effort-reward imbalance or job strain and 1.41 (1.12-1.76) for having both these stressors compared to having neither effort-reward imbalance nor job strain. CONCLUSIONS: Individuals with effort reward imbalance at work have an increased risk of coronary heart disease, and this appears to be independent of job strain experienced. These findings support expanding focus beyond just job strain in future research on work stress. PMID- 28570390 TI - Lymph Node Metastasis With Both Components of Combined Cutaneous Squamous Cell Carcinoma/Merkel Cell (Neuroendocrine) Carcinoma. PMID- 28570391 TI - Spiradenocarcinoma: A Comprehensive Data Review. AB - INTRODUCTION: Spiradenocarcinomas (SCs) are rare and potentially aggressive skin adnexal tumors. Optimal treatment has not yet been established. Experiences with this carcinoma are mostly presented in case reports and few case series. OBJECTIVE: To generate to a synopsis of published data on SC with regard to diagnostic procedures, treatment, and outcome. RESULTS: Median patient age was 60 years and sex distribution was balanced. Tumor manifestations were evenly distributed within the sweat gland carrying skin. The most commonly reported symptom was accelerated growth of a longstanding indolent lesion, typically present for more than 2 years. Metastatic spread to the lung, bone, lymph nodes, liver, kidney, and breast has been documented. For staging computed tomography (CT) and positron emission tomography-CT are recommended, especially for detection of hematogenic metastases and lymph node involvement. Clear resection margins and tumor free regional lymph nodes reduce recurrence and carcinoma related death. Although low-grade SCs were reported over 3 times more often, high grade carcinomas show a greater likelihood for recurrence and lethal outcome. CONCLUSION: Suspicion of an SC should lead to performance of a magnetic resonance imaging for defining tumor extent, and a fludeoxyglucose positron emission tomography-CT for detection of metastases. Radical tumor excision and resection of tumor involved regional lymph nodes are essential for a curative approach. Histopathological evaluation should involve determination of tumor differentiation grade, because high-grade carcinomas seem to have a much more aggressive behavior. Excision of distant metastases has no therapeutic value. Follow-up needs to be carried out in short intervals with frequent imaging. PMID- 28570392 TI - Primary Cutaneous Small Cell Variant of Anaplastic Large Cell Lymphoma: A Case Series and Review of the Literature. AB - Primary cutaneous anaplastic large cell lymphoma (ALCL), similar to systemic ALCL, has as its histomorphologic hallmarks cohesive sheets of large lymphoid cells expressing CD30. Several morphologic variants of systemic ALCL have been reported, including the common (classic) type, lymphohistiocytic, and small cell variants. The small cell variant of ALCL is characterized by a predominant cytomorphology which is unexpected for ALCL, being in the context of a small- to medium-sized hyperchromatic atypical lymphocyte. Although well recognized in its systemic form including cases with secondary cutaneous involvement, it is less well characterized as a form of primary cutaneous ALCL. In this study, we collected 8 cases of primary cutaneous small cell variant of ALCL and examined their clinical, histologic, and phenotypic features. All patients were middle aged to older adult men; the youngest patient was a 46-year-old man with underlying hepatitis C. In one case, there was a history of lymphomatoid papulosis. In all patients, the disease was in the context of a local regional presentation. Patients were treated with complete excision and/or radiation except in one in whom chemotherapy was administered. In all but one patient, the cutaneous presentation was a regionally confined process; however, in 2 cases, recurrent disease occurred, and in 25% of cases, extracutaneous dissemination specifically to regional lymph nodes was observed. Although there was nodal involvement, there was no dissemination to bone marrow or peripheral blood; no patient has died because of disseminated lymphoma. In all cases, there was a predominance of small atypical hyperchromatic cells with a variable background of larger hallmark cells typical of ALCL. Epidermotropism was seen in half of the cases, and in one case, there was striking pseudoepitheliomatous hyperplasia. The smaller cells demonstrated CD30 positivity, and the neoplastic cells showed a CD4 positive phenotype with a variable expression of cytotoxic proteins in about half of the cases, whereas in the remaining cases, a double negative phenotype was observed. Epithelial membrane antigen expression was observed in the cases tested. In our literature review, similar demographics were observed with a comparable percent of cases with extracutaneous dissemination; one case manifested an aggressive clinical course eventuating in death. In summation, the small cell variant of primary cutaneous ALCL exhibits distinctive features clinically and histologically. While exhibiting an overall higher incidence of extracutaneous dissemination, the prognosis fairs better compared with other forms of cutaneous T-cell lymphoma associated with extracutaneous dissemination, an event that defines a harbinger of aggressive disease. PMID- 28570394 TI - Longitudinal changes of associations between the preproghrelin Leu72Met polymorphism with depression in Chinese Han adolescents after the Wenchuan earthquake. AB - AIM: The present study aimed to investigate longitudinal associations of preproghrelin Leu72Met with depression in Chinese Han adolescents after the Wenchuan earthquake in 2008. MATERIALS AND METHODS: A total of 709 volunteers were enrolled from a high school near the epicenter of the earthquake and 662, 643, and 510 students were finally included at 6, 12, and 18 months, respectively, after the earthquake. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). The genotypes were identified by PCR-restriction fragment length polymorphism analyses and verified by DNA sequencing. RESULTS: Females had a higher prevalence of depression than males at 6 months after the earthquake in 72Leu/Leu homozygotes (chi-test, P=0.007), but not in 72Met allele carriers. 72Met allele carriers had lower prevalence (chi-test, P=0.025) and BDI scores (Kruskal-Wallis test, P=0.034) than 72Leu/Leu homozygotes only among males at 18 months, but not at 6 or 12 months. The prevalence was consecutively decreased in male 72Met allele carriers (chi-test, P=0.010), but not in male 72Leu/Leu homozygotes, female 72Met allele carriers, or female 72Leu/Leu homozygotes during follow-up. Potential factors of depression prevalence and predictors of BDI scores were different between 72Leu/Leu homozygotes and 72Met allele carriers at different time points during follow-up. CONCLUSION: These results suggest that the 72Met allele of the preproghrelin Leu72Met polymorphism may be associated with rehabilitation of depression in male Chinese Han adolescents after the natural disaster. PMID- 28570396 TI - How to Achieve Facial Balance by Mandibular Contouring Ostectomy in Hemimandibular Hyperplasia. AB - Hemimandibular hyperplasia is a rare type of condylar hyperplasia which leads to facial asymmetry. Its surgical correction may be challenging since it usually requires complex mandibular osteotomies. Mandibular inferior border ostectomy is poorly described in the literature. The aim of this report is to present a new surgical technique guided by a customized surgical splint manufactured using computer-aided design/computer-aided manufacturing technology. Very good aesthetic results are achieved as it is very precise. PMID- 28570397 TI - Coexistence of Lymphoepithelial Carcinoma of the Parotid Gland and Submandibular Gland Pleomorphic Adenoma. AB - Lymphoepithelial carcinoma is a variant of undifferentiated carcinoma with characteristic dense lymphoid stroma in which nasopharynx is site of predilection. Racial and geographic association and Epstein-Barr virus positivity in endemic areas are other characteristics of this rare neoplasm. Lymphoepithelial carcinoma accounts for only 0.4% of malignant salivary gland tumors. The authors present a patient with Epstein-Barr virus positive lymphoepithelial carcinoma of the parotid gland in a nonendemic region. Besides this, synchronous pleomorphic adenoma in the contralateral submandibular gland caused a challenge in making initial therapeutic decision. PMID- 28570395 TI - Runs of homozygosity, copy number variation, and risk for depression and suicidal behavior in an Arab Bedouin kindred. AB - OBJECTIVES: Inbreeding increases the probability of homozygosity of deleterious alleles. Inbreeding and runs of homozygosity (ROH) are associated with an increased risk for disease phenotypes, including schizophrenia and other psychiatric disorders. The effects of inbreeding, ROH, homozygous deletions, and other copy number variations (CNVs) on risk for depression and suicide attempt (SA) were quantified in an Arab Bedouin Kindred. METHODS: We carried out genetic analyses of 439 individuals from an Arab kindred with high rates of depression and suicidal behavior. We obtained complete ascertainment of SAs and first-degree relatives of individuals who have attempted or died by suicide. RESULTS: We found extensive regions of ROH. On average, 5% of the genome is covered by ROH for these individuals, two-fold higher than ROH rates for individuals from populations of European ancestry. Inbreeding and total length of ROH were not associated with risk for depression or attempt. For CNVs, an increased number of duplications more than 500 kb was associated with an increased risk for attempt (odds ratio: 2.9; P=0.01; 95% confidence interval: 1.3-6.6). Although not significant after correction for multiple testing, the risk for SA appears to increase with copy number for a CNV on chromosome 9p24.1. This possibility is intriguing because the CNV covers GLDC, which encodes glycine dehydrogenase that binds to glycine, a co-agonist at N-methyl-D-aspartate glutamate receptors, and is involved in glutamatergic neurotransmission. CONCLUSION: Our findings add to the growing evidence of genetic risk factors that act pleiotropically to increase the risk for several neuropsychiatric disorders, including depression and SA, irrespective of ancestry. PMID- 28570398 TI - Patient With Cleft Maxillary Hypoplasia Who Underwent Distraction Osteogenesis and Conservative Therapies to Postoperative Velopharyngeal Insufficiency. AB - The authors performed distraction osteogenesis using The Maxillary Distractor System (SYNTHES) to maxillary hypoplasia patient with cleft lip palate, and consequently improved the aesthetic complexion of the patient. Velopharyngeal insufficiency developed after bone elongation; the authors improved the insufficiency with conservative therapies such as articulatory training using the bulb attached palatal lift prosthesis. The authors were successful and accepted postoperative speech outcome. PMID- 28570399 TI - Canine Eruption After Secondary Alveolar Bone Graft in Unilateral Cleft Lip and Palate Patients. AB - PURPOSE: The aim of this article is to analyze dental abnormalities in unilateral cleft lip and palate patients by focusing on the role of the secondary alveolar bone graft (SABG) surgery and its outcomes on canine eruption/inclusion. MATERIALS AND METHODS: A sample of 24 patients with unilateral cleft lip and palate were selected.Dental anomalies, canine eruption based on the existence of supernumeraries, agenesis elements, inclination of the major canine axis before and after surgery, distance from the occlusal plane before and after surgery, and sector classification were analyzed. RESULTS: Out of the 24 patients, 87.5% presented a canine spontaneously erupted in the dental arch while 12.5% needed surgical-orthodontic traction.There is also no proof that inclination of the canine significantly influenced the eruption before (P = 0.5889) and after (P = 0.4029) surgery. Also, there is no any correlation between the 2 sides (P = 0.1257).The SABG surgery showed a significant correlation with canine eruption (P = 0.009242); moreover, SABG shows a positive relationship with the radicular development of the canine (P = 0.005163).Lateral incisive (P = 0.8493) and second premolar agenesis (P = 1) are not statistically correlated with the eruption of the canine. This does not happen with supernumerary elements that are correlated with the surgical-orthodontic traction (P = 0.0004464). CONCLUSIONS: Agenesis does not play any role in the process of canine eruption while supernumeraries do. There is no relationship between the inclination and eruption of the canine.The SABG surgery has a key role because it contributes to create an appropriate support for the erupting canine, the nasal base and the anterior maxilla. PMID- 28570400 TI - Fibrin Tissue Sealant as an Adjunct to Cleft Palate Repair. AB - PURPOSE: Fibrin glue is a common tissue sealant used to promote hemostasis, adhere tissues, and accelerate healing. Cleft palate repair can be technically challenging, creating dead space between tissue planes, and can be prone to complications such as would dehiscence or bleeding. The purpose of this study is to assess the role of fibrin glue as an adjunct to cleft palate repair. The authors hypothesize a beneficial impact on complication rates, including bleeding, dehiscence, and fistula formation, among others. METHODS: Primary cleft palate repairs using fibrin glue were retrospectively analyzed. Demographic, intraoperative, perioperative, and postoperative data were combed for outcome variables. Complication rates were calculated in percentages and the results were compared to the published literature. Z-test statistics were performed for comparison. RESULTS: A total of 45 patients, 21 females and 24 males, who underwent primary cleft palate repair with fibrin glue between 2011 and 2014, had sufficient data to be reviewed. There were no instances of bleeding, dehiscence, airway obstruction, infection, oronasal fistula, or return to the operating room in any patients. One patient exhibited mild postoperative coughing and secretions that resolved with conservative measures. Another patient displayed postoperative seizure activity due to a pre-existing condition. All complication rates in our fibrin glue series were lower than those reported without the use of fibrin glue. Overall complication rates with fibrin sealant are significantly lower than overall complication rates without. CONCLUSION: Our data suggest that fibrin sealant is a beneficial adjunct to cleft palate repair. Its application is well tolerated and the complication profile in our cohort was much less than the reported rates. The results of this preliminary study should be vetted with a prospective analysis involving a control group. PMID- 28570401 TI - Asymmetry of Preoperative Incision Design Markings for Upper Blepharoplasty. AB - PURPOSE: To compare preoperative incision design markings between both eyelids in upper blepharoplasty. METHODS: This retrospective study examined 22 patients who underwent bilateral upper blepharoplasty surgery resulting from senile dermatochalasis and/or blepharoptosis. The initial preoperative incision design markings were drawn with the patient sitting upright. Then, with the patient in a supine position, preoperative design photographs were taken. The authors measured medial canthal excision angle, maximal lid excision height, maximal lid excision width, peak point angle, and peak point distance and compared measurements between both upper eyelids designs using Image J software. RESULTS: The mean medial canthal excision angle, maximal lid excision height, and maximal lid excision width for the right side (30.68 degrees +/- 10.16 degrees , 1.17 +/- 0.24 cm, and 0.72 +/- 0.19 cm) were significantly different from those for the left side (35.39 degrees +/- 13.82 degrees ; P < 0.001, 1.24 +/- 0.25 cm; P = 0.002, and 0.77 +/- 0.21 cm; P = 0.011). The mean peak point angle and peak point distance for the right side (15.67 degrees +/- 5.09 degrees , 2.41 degrees +/- 0.31 degrees ) were significantly different from those for the left side (18.11 degrees +/- 5.49 degrees ; P = 0.001, 2.22 +/- 0.28 cm; P = 0.001). CONCLUSIONS: In upper blepharoplasty, the preoperative incision marking design measurements of the left side were significantly greater than those of the right side. The symmetry can therefore be maximized by including the asymmetries in the preoperative design. PMID- 28570402 TI - Genetic Factors Involved in Mandibular Prognathism. AB - Mandibular prognathism is defined as an abnormal forward projection of the mandible beyond the standard relation to the cranial base and it is usually categorized as both a skeletal Class III pattern and Angle Class III malocclusion. The etiology of mandibular prognathism is still uncertain, with various genetic, epigenetic, and environmental factors possibly involved. However, many reports on its coexistence in both twins and segregation in families suggest the importance of genetic influences. A multifactorial and polygenic background with a threshold for expression or an autosomal dominant mode with incomplete penetrance and variable expressivity are the most probable inheritance patterns. Linkage analyses have, thus far, shown the statistical significance of such loci as 1p22.1, 1p22.3, 1p32.2, 1p36, 3q26.2, 4p16.1, 6q25, 11q22, 12pter-p12.3, 12q13.13, 12q23, 12q24.11, 14q24.3 to 31.2, and 19p13.2. The following appear among candidate genes: MATN1, EPB41, growth hormone receptor, COL2A1, COL1A1, MYO1H, DUSP6, ARHGAP21, ADAMTS1, FGF23, FGFR2, TBX5, ALPL, HSPG2, EVC, EVC2, the HoxC gene cluster, insulin-like growth factor 1, PLXNA2, SSX2IP, TGFB3, LTBP2, MMP13/CLG3, KRT7, and FBN3. On the other hand, MYH1, MYH2, MYH3, MYH7, MYH8, FOXO3, NFATC1, PTGS2, KAT6B, HDAC4, and RUNX2 expression is suspected to be involved in the epigenetic regulations behind the mandibular prognathism phenotype. PMID- 28570403 TI - Nasolabial Growth in Individuals With Unilateral Cleft Lip and Palate: A Preliminary Study of Longitudinal Observation Using Three-Dimensional Stereophotogrammetry. AB - There are limited numbers of studies comparing the preoperative and postoperative facial features of infants with unilateral cleft lip and palate (UCLP) using three-dimensional (3D) stereophotogrammetry. The authors attempted an anthropometric analysis of nasolabial asymmetry 1 year after primary lip repair using a handheld 3D imaging system. Five different nasolabial dimensions in 24 infants with UCLP were measured using 3D images captured during primary lip repair and again, 1 year after the repair. The nasal and upper-lip elements of the cleft side were significantly changed after primary lip repair, and nasolabial asymmetry was anthropometrically improved. This is a preliminary longitudinal observation of nasolabial growth in individuals with UCLP using 3D stereophotogrammetric technique. The authors would like to follow these children until adulthood, capturing 3D images at every intervention. PMID- 28570404 TI - Surrogate Outcome Measures for Corneal Neurotization in Infants and Children. AB - BACKGROUND: Corneal anesthesia is a rare and challenging condition, particularly in young children. The insensate cornea leads to abnormal epithelial cell metabolism and loss of trophic influences supplied by the corneal nerve fibers. This results in recurrent spontaneous epithelia erosion and eventual loss of sight. Corneal reinnervation is a definitive treatment option for neuropathic keratitis. The outcome measures in young children following corneal sensitization are different to adults as esthesiometry is unachievable. METHODS: The authors have undertaken corneal reinnervation in a young patient using a sural nerve graft. Surrogate measures suitable for pediatric patients were used for assessment of the outcome. RESULTS: Postoperatively there was evidence of improved corneal healing and function after 8 weeks. At 10 months postprocedure, the cornea was completely free of vascularization. CONCLUSION: Resensitization of the cornea using nerve grafts has previously been reported in older children and adults. This is the first time the procedure has been undertaken in a young child. Although the technique is still in its infancy with only 4 patients reported worldwide including our report, it seems to hold promise of improvement to this challenging cohort of patients. PMID- 28570406 TI - Coding Challenges in Craniofacial Surgery. PMID- 28570405 TI - Nasal Root Deviation in Unicoronal Craniosynostosis: A Craniometric Analysis of Early and Late Postoperative Outcomes. AB - PURPOSE: Current operative techniques for correcting unicoronal craniosynostosis (UCS) leave the nasal bones untouched, resulting in an unclear long-term impact on nasal root deviation. The purpose of this study is to quantify nasal root deviation in the preoperative and late postoperative setting in patients who have undergone conventional single-staged UCS correction. METHODS: The authors performed a retrospective, craniometric analysis of nasal root deviation comparing preoperative computed tomography scans, with those of the early, and late postoperative period. Three vectors were analyzed to measure nasal root deviation, one extending from the nasion to the rhinion (nasal bone vector), the second from the rhinion to the anterior nasal spine (nasal aperture vector), and the third from the nasion to the anterior nasal spine (nasal longitudinal vector). RESULTS: Twenty-five subjects were included in the study. Average ages at the time of preoperative, early, and late postoperative imaging were 0.6 +/- 0.3, 0.9 +/- 0.6, and 9.3 +/- 2.7 years, respectively. Improvement of angular deviation of both the nasal aperture vector and nasal longitudinal vector was observed. Mean angular deviation of the nasal aperture vector was 6.0 +/- 1.9 degrees preoperatively, 6.0 +/- 2.1 degrees early postoperatively (P = 0.952), and 2.4 +/- 2.1 in the late postoperative period (P = 0.013). Mean angular deviation of the nasal longitudinal vector was 5.7+2.0 degrees preoperatively, 5.8 +/- 2.3 degrees early postoperatively (P = 0.948), and 3.7 +/- 1.6 degrees in the late postoperative period (P = 0.019). CONCLUSION: Nasal root deviation decreased significantly only in the late postoperative period, lending credence to the notion that though UCS correction does not directly address nasal root deviation, this pathology improves significantly over time. PMID- 28570408 TI - Hidradenoma of the Chin. AB - Clear cell hidradenoma is a rare skin tumor in the head and neck. Clear cell hidradenoma of skin is an uncommon soft tissue tumor originating from the sweat glands. The authors report a case of clear cell hidradenoma developing in the chin in a 61-year-old woman, which occurred during the course of 8 months. The clinical and histologic findings of the tumor are documented. The lesion was totally removed by excision and revealed no evidence of recurrence. PMID- 28570407 TI - A Modified External Fixator System in Treatment of Mandibular Condylar Fractures. AB - The purpose of this study is to evaluate patient's outcomes after condylar fractures treated with the modified external fixation system from 2008 to 2012.A group of 58 patients with unilateral and bilateral fractures of mandibular condyle was admitted in the authors' study.The final sample included a total of 44 patients, 24 males (54.6%) and 20 females (45.4%).The remaining 14 (24%) patients were excluded because they did not fulfill all the criteria requested.After 12 months from surgery, the functional-clinical evaluation of mouth's maximum opening and mostly extent of lateral excursion and of protrusion showed the following results: 8% of the sample showed a maximum mouth opening <30 mm, 72% of the sample showed a maximum mouth opening between 30 and 40 mm, 20% of the sample showed a maximum mouth opening >40 mm lateral excursion (contralateral to fracture) and protrusion was respectively of 9.5 and 3.9 mm.Only 2 (4.5%) of the 44 evaluated patients reported headaches. 86.5% of the patients showed no postoperative temporomandibular joint dysfunction; 9% of them reported occasional clicking, while 4.5% reported recurrent disorders. The average satisfaction score of surgery outcome reported by patients was 94.5/100, and it ranged between 50/100 and 100/100. PMID- 28570409 TI - Microsurgical Decompression of Inferior Alveolar Nerve After Endodontic Treatment Complications. AB - Iatrogenic injury in oral surgery is the most frequent cause of sensory disturbance in the distribution of the inferior alveolar nerve (IAN) and mental nerve.Inferior alveolar nerve damage can occur during third molar extraction, implant location, orthognathic surgery, preprosthetic surgery, salivary gland surgery, local anesthetic injections or during the resection of benign or malignant tumors.Injuries to the IAN can be caused also by endodontic treatment of mandibular molars and premolars when filling material is forced into the tooth and mandibular canal.The sensory disturbances that could follow a damage of the IAN could be hypoesthesia, dysesthesia, hyperesthesia, anesthesia, and sometimes a painful anesthesia that strike ipsilateral lower lip, chin, and teeth. These can undermine life quality by affecting speech, chewing, and social interaction.Treatment of these complications is sometimes difficult and could consist in observation or in surgical decompression of the involved nerve to relieve the patient's symptoms and improve sensory recovery. The most debated points are the timing of intervention and the effective role of decompression in clinical outcome-improvement.The purpose of this article is to show authors' experience with 2 patients treated with microsurgical nerve decompression to remove endodontic material from the mandibular canal and providing also a comprehensive review of the literature. PMID- 28570410 TI - Nasal Soft Tissue Change Following Bimaxillary Orthognathic Surgery. AB - OBJECTIVE: The purpose of this study is to identify the correlation between maxillary movement and nasal soft tissue changes on three-dimensional reconstructed cone beam computed tomography (CBCT) images after Le Fort I osteotomy. MATERIALS AND METHODS: The authors also investigate the long-term change of alar base width (ABW) to determine the effect of cinch suture. The authors retrospectively studied 52 subjects (14 males and 38 females) who were treated by bimaxillary orthognathic surgery including Le Fort I osteotomy and mandibular ramus surgery. The landmarks and planes were established on three dimensional reconstructed CBCT images. The authors measured each parameters preoperatively, 1 month postoperatively, and 1 year postoperatively. RESULTS: There was no significant correlation between the horizontal movement of A-point and the widening of ABW (P < 0.038), nor was there a significant correlation between the vertical movement of A-point and the change of ABW (P < 0.61). There was no significant correlation between horizontal and vertical movement of anterior nasal spine and the widening of ABW, nor was there a significant correlation between the nasal tip length and the vector of maxillary movement. CONCLUSION: There was no significant correlation between the ABW widening and the vector of surgical maxillary movement. The effect and stability of the alar base cinch suture is difficult to determine and require further investigation. PMID- 28570413 TI - Professional Reimbursement by Medicaid for Cochlear Implants and Related Services. AB - HYPOTHESIS: Medicaid reimbursement rates for cochlear implants and related services fall short of the federal benchmark set by Medicare. BACKGROUND: The financial hardships of cochlear implant centers around the United States may be a repercussion of poor Medicaid reimbursement. In time, these reimbursement discrepancies could force additional Otolaryngologists and cochlear implant centers to not provide these crucial services due to financial limitations. METHODS: Based on Medicare (MCR) claims data, current procedural terminology (CPT) codes used for cochlear implantation and related services were selected. Medicaid (MCD) and Medicare (MCR) payment schemes were queried for the same services in 49 states and Washington, D.C. The difference in MCD and MCR payment in dollars and percent was determined and reimbursement per relative value of work (RVU) calculated. MCD reimbursement differences (by dollar amount and by percentage) were qualified as a shortfall or excess as compared with the MCR benchmark. RESULTS: Marked differences in MCD and MCR reimbursement exist for all cochlear implant related services, most commonly as a substantial shortfall. The MCD shortfall varied in amount between states and great variability in reimbursement exists within and between audiology, surgery, and speech services. Shortfalls and excesses were not consistent between procedures or states. CONCLUSIONS: The variation in MCD payment models reflects marked differences in the value of the same work provided, which in many cases is far less than federal benchmarks. These results question the fairness of the MCD reimbursement scheme in cochlear implantation with potential serious implications on access to care for this underserved patient population. PMID- 28570412 TI - Perceived Maternal Behavioral Control, Infant Behavior, and Milk Supply: A Qualitative Study. AB - OBJECTIVE: Disparities persist in breastfeeding exclusivity and duration despite increases in breastfeeding initiation. The objective of this study was to examine factors that influence maternal decision making surrounding infant feeding practices over time in a diverse inner-city population. METHODS: We conducted a prospective qualitative study with 20 mothers recruited from 2 urban primary care clinics. Participants completed open-ended interviews and demographic questionnaires in English or Spanish administered at approximately 2 weeks and 6 months postpartum. Transcripts were analyzed using a combined technique of inductive (data-driven) and deductive (theory-driven, based on the Theory of Planned Behavior) thematic analysis using 3 independent coders and iterative discussion to reach consensus. RESULTS: All women initiated breastfeeding, and 65% reported perceived insufficient milk (PIM). An association between PIM and behavioral control emerged as the overarching theme impacting early breastfeeding cessation and evolved over time. Early postpartum, PIM evoked maternal distress strong emotional responses to infant crying and need to control infant behaviors. Later, mothers accepted a perceived lack of control over milk supply with minimal distress or as a natural process. Decisions to stop breastfeeding occurred through an iterative process, informed by trials of various strategies and observations of subsequent changes in infant behavior, strongly influenced by competing psychosocial demands. CONCLUSION: Infant feeding decisions evolve over time and are influenced by perceptions of control over infant behavior and milk supply. Tailored anticipatory guidance is needed to provide time-sensitive strategies to cope with challenging infant behaviors and promote maternal agency over breastfeeding in low-income populations. PMID- 28570414 TI - Head Shadow and Binaural Squelch for Unilaterally Deaf Cochlear Implantees. AB - BACKGROUND: Cochlear implants (CIs) can improve speech-in-noise performance for listeners with unilateral sensorineural deafness. But these benefits are modest and in most cases are limited to head-shadow advantages, with little evidence of binaural squelch. HYPOTHESIS: The goal of the investigation was to determine whether CI listeners with normal hearing or moderate hearing loss in the contralateral ear would receive a larger head-shadow benefit for target speech and noise originating from opposite sides of the head, and whether listeners would experience binaural squelch in the free field in a test involving interfering talkers. METHODS: Eleven CI listeners performed a speech identification task in the presence of interfering noise or speech. Six listeners had single-sided deafness (normal or near-normal audiometric thresholds in the acoustic ear) and five had asymmetric hearing loss (hearing loss in the acoustic ear treated with a hearing aid). Listeners were tested with the acoustic ear only and bilaterally with the CI turned on. One set of conditions examined head-shadow effects with target speech and masking noise presented from azimuths of 0 or +/ 108 degrees. A second set of conditions examined binaural squelch, with target speech presented from the front and interfering talkers symmetrically placed on both sides. RESULTS: On average, the largest head-shadow benefit (5 dB) occurred when the target and masking noise were presented on opposite sides of the head. Listeners also showed an average of 2 dB of squelch, but only when the target speech was masked by interfering talkers of the same sex as the target. CONCLUSIONS: CIs provide listeners with unilateral deafness important benefits for speech perception in complex spatial environments, including a larger head shadow benefit when speech and noise originate on opposite sides of the head, and an improved ability to perceptually organize an auditory scene with multiple competing voices.The views expressed in this abstract are those of the authors and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or US Government. PMID- 28570416 TI - In Response to Letter to the Editor Entitled, "The Role of Radiation in Tympanojugular Paragangliomas Needs to be Re-evaluated". PMID- 28570415 TI - Inflammatory Pseudotumor of the Temporal Bone: A Case Series. AB - OBJECTIVE: Inflammatory pseudotumor of the temporal bone is a benign, idiopathic inflammatory process that is locally invasive and a cause of significant morbidity. This study reviews our experience with seven patients and is currently the largest series to date. STUDY DESIGN: Retrospective review from January 1, 2014 to January 1, 2016. SETTING: Single tertiary medical center. PATIENTS: There were five male and two female (n = 7) subjects with a diagnosis of temporal bone inflammatory pseudotumor. The mean age at presentation was 41 years old. The most common presenting symptoms were hearing loss (7/7) and headache (4/7). Four patients demonstrated an inflammatory aural polyp. Two patients experienced facial nerve paralysis. INTERVENTION(S): Seven patients underwent computed tomography and six underwent magnetic resonance imaging. Corticosteroids and antibiotics were the initial treatment of choice. Five patients also underwent surgery. As adjuvant therapy, two patients received Rituximab, one patient received radiation, and one received mycophenolate mofetil. MAIN OUTCOME MEASURE(S): Clinical courses were followed with focus on symptoms, disease recurrence, duration, and treatment. Mean follow-up was 17.8 months. RESULTS: The primary lesions demonstrated T2 hypo-intensity and enhancement as well as diffuse dural thickening on magnetic resonance imaging in five of six patients. Histopathology demonstrated chronic inflammation in the setting of hyalinized fibrosis (7/7). All the patients are currently symptomatically stable. CONCLUSION: Inflammatory pseudotumor of the temporal bone can cause devastating effects on neurological function and quality of life. Recognition of characteristic imaging and histopathology can expedite appropriate treatment. Patients may require chronic steroid therapy. Adjunctive therapy with radiation and immuno-modulation are currently being explored. PMID- 28570418 TI - Cochlear Implant Electrode Localization Using an Ultra-High Resolution Scan Mode on Conventional 64-Slice and New Generation 192-Slice Multi-Detector Computed Tomography. AB - HYPOTHESIS: A new generation 192-slice multi-detector computed tomography (MDCT) clinical scanner provides enhanced image quality and superior electrode localization over conventional MDCT. BACKGROUND: Currently, accurate and reliable cochlear implant electrode localization using conventional MDCT scanners remains elusive. METHODS: Eight fresh-frozen cadaveric temporal bones were implanted with full-length cochlear implant electrodes. Specimens were subsequently scanned with conventional 64-slice and new generation 192-slice MDCT scanners utilizing ultra high resolution modes. Additionally, all specimens were scanned with micro-CT to provide a reference criterion for electrode position. Images were reconstructed according to routine temporal bone clinical protocols. Three neuroradiologists, blinded to scanner type, reviewed images independently to assess resolution of individual electrodes, scalar localization, and severity of image artifact. RESULTS: Serving as the reference standard, micro-CT identified scalar crossover in one specimen; imaging of all remaining cochleae demonstrated complete scala tympani insertions. The 192-slice MDCT scanner exhibited improved resolution of individual electrodes (p < 0.01), superior scalar localization (p < 0.01), and reduced blooming artifact (p < 0.05), compared with conventional 64-slice MDCT. There was no significant difference between platforms when comparing streak or ring artifact. CONCLUSION: The new generation 192-slice MDCT scanner offers several notable advantages for cochlear implant imaging compared with conventional MDCT. This technology provides important feedback regarding electrode position and course, which may help in future optimization of surgical technique and electrode design. PMID- 28570417 TI - Vestibular Restoration and Adaptation in Vestibular Neuritis and Ramsay Hunt Syndrome With Vertigo. AB - OBJECTIVE: To evaluate vestibular restoration and the evolution of the compensatory saccades in acute severe inflammatory vestibular nerve paralysis, including vestibular neuritis and Ramsay Hunt syndrome with vertigo. STUDY DESIGN: Prospective. SETTING: Tertiary referral center. PATIENTS: Vestibular neuritis (n = 18) and Ramsay Hunt syndrome patients with vertigo (n = 13) were enrolled. INTERVENTION: After treatment with oral corticosteroids, patients were followed up for 6 months. MAIN OUTCOME MEASURES: Functional recovery of the facial nerve was scored according to the House-Brackman grading system. Caloric and video head impulse tests were performed in every patient at the time of enrolment. Subsequently, successive video head impulse test (vHIT) exploration was performed at the 1, 3, and 6-month follow-up. RESULTS: Eighteen patients with vestibular neuritis and 13 with Ramsay Hunt syndrome and associated vertigo were included. Vestibular function was significantly worse in patients with Ramsay Hunt syndrome than in those with vestibular neuritis. Similar compensatory saccades velocity and latency values were observed in both groups, in both the caloric and initial vHIT tests. Successive vHIT results showed a significantly higher vestibulo-ocular reflex gain recovery in vestibular neuritis patients than in Ramsay Hunt syndrome patients. A significantly faster reduction in the latency, velocity, and organization of the compensatory saccades was observed in neuritis than in Ramsay Hunt syndrome patients. CONCLUSIONS: In addition to the recovery of the vestibulo-ocular reflex, the reduction of latency, velocity and the organization of compensatory saccades play a role in vestibular compensation. PMID- 28570419 TI - Ultra-high-field (9.4 T) MRI Analysis of Contrast Agent Transport Across the Blood-Perilymph Barrier and Intrastrial Fluid-Blood Barrier in the Mouse Inner Ear. AB - HYPOTHESIS: Effective paramagnetic contrast agent for the penetration of the perilymphatic spaces of the scala tympani, scala vestibuli, and scala media of the mouse inner ear can be determined using intravenous injection of various gadolinium (Gd) complexes and ultra-high-field magnetic resonance imaging (MRI) at 9.4 Tesla. BACKGROUND: A number of contrast agents have been explored in experimental high-field MRI to determine the most effective Gd complex for ideal signal-to-noise ratio and maximal visualization of the in vivo mammalian inner ear in analyzing the temporal and spatial parameters involved in drug penetration of the blood-perilymph barrier and intrastrial fluid-blood barrier in the mouse model using MRI. METHODS: Gadoteric acid (Dotarem), Gadobutrol (Gadovist), Gadodiamide (Omniscan), Gadopent acid (Magnevist), and Mangafodipir (Teslascan) were administered intravenously using the tail vein of 60 Balb/C mice. High resolution T1 images of drug penetration were acquired with a horizontal 9.4 T Agilent magnet after intravenously injection. Signal intensity was used as a metric of temporal and spatial parameters of drug delivery and penetration of the perilymphatic and endolymphatic spaces. RESULTS: ANOVA analysis of the area under the curve of intensity enhancement in perilymph revealed a significant difference (p < 0.05) in the scalae uptake using different contrast agents (F (3,25) = 3.54, p = 0.029). The Gadoteric acid complex Dotarem was found to be the most effective Gd compound in terms of rapid, morphological enhancement for analysis of the temporal, and spatial distribution in the perilymphatic space of the inner ear. CONCLUSION: Gadoteric acid (Dotarem) demonstrated efficacy as a contrast agent for enhanced visualization of the perilymphatic spaces of the inner ear labyrinthine in the mouse, including the scala tympani and scala vestibuli of the cochlea, and the semicircular canals of the vestibular apparatus. These findings may inform the clinical application of Gd compounds in patients with inner ear fluid disorders and vertigo. PMID- 28570420 TI - Semicircular Canal Pressure Changes During High-intensity Acoustic Stimulation. AB - HYPOTHESIS: Acoustic stimulation generates measurable sound pressure levels in the semicircular canals. BACKGROUND: High-intensity acoustic stimuli can cause hearing loss and balance disruptions. To examine the propagation of acoustic stimuli to the vestibular end-organs, we simultaneously measured fluid pressure in the cochlea and semicircular canals during both air- and bone-conducted sound presentation. METHODS: Five full-cephalic human cadaveric heads were prepared bilaterally with a mastoidectomy and extended facial recess. Vestibular pressures were measured within the superior, lateral, and posterior semicircular canals, and referenced to intracochlear pressure within the scala vestibuli with fiber optic pressure probes. Pressures were measured concurrently with laser Doppler vibrometry measurements of stapes velocity during stimulation with both air- and bone-conduction. Stimuli were pure tones between 100 Hz and 14 kHz presented with custom closed-field loudspeakers for air-conducted sounds and via commercially available bone-anchored device for bone-conducted sounds. RESULTS: Pressures recorded in the superior, lateral, and posterior semicircular canals in response to sound stimulation were equal to or greater in magnitude than those recorded in the scala vestibuli (up to 20 dB higher). The pressure magnitudes varied across canals in a frequency-dependent manner. CONCLUSION: High sound pressure levels were recorded in the semicircular canals with sound stimulation, suggesting that similar acoustical energy is transmitted to the semicircular canals and the cochlea. Since these intralabyrinthine pressures exceed intracochlear pressure levels, our results suggest that the vestibular end-organs may also be at risk for injury during exposure to high-intensity acoustic stimuli known to cause trauma in the auditory system. PMID- 28570421 TI - Time for more creativity in health care management research and practice. PMID- 28570422 TI - STRONGER TEAM, BETTER CARE: BUILDING THE BIG PICTURE IN GASTROENTEROLOGY. PMID- 28570423 TI - Effectiveness of a Dietary Support Program Based on Behavior Analysis Approach for Patients With Crohn Disease. AB - The purpose of this study was to assess the effectiveness of a dietary support program for patients with Crohn disease based on behavior analysis and designed to maintain remission and improve satisfaction with meals. The core of the program consisted of self-monitoring by patients and evaluation by a healthcare professional. The 32-week program consisted of a 4-week baseline period, 20-week intervention period, and 8-week follow-up period. Participants filled out questionnaires measuring outcomes every 4 weeks, for a total of nine questionnaires per patient. Of the 13 patients who started the program, 11 completed the study. Of these, nine showed increased frequency of testing foods during the intervention period, with seven maintaining testing during the follow up period. No patient experienced a worsening of health conditions. Of the 11 patients who completed the program, seven reported increased satisfaction with meals. In conclusion, this program helped increase the frequency of testing foods in patients with Crohn disease, while maintaining health conditions and improving satisfaction with meals. PMID- 28570424 TI - Adherence to Hepatitis B Antiviral Therapy: A Qualitative Study. AB - Hepatitis B virus (HBV) antiviral therapies potentially suppress HBV viral load to an undetectable level reducing the risk of progressive liver disease and the development of HBV-related hepatocellular carcinoma. Adherence to antiviral therapies is imperative to achieve and maintain viral suppression. To date, there has been limited research on adherence to HBV therapies. Our study aimed to explore factors influencing adherence to antiviral therapy. A total of 29 participants consented to in-depth qualitative interviews at three outpatient clinics in Sydney, New South Wales, Australia. Interviews were digitally recorded and transcribed. Transcripts were initially classified as adherent or nonadherent and thematic analysis was used to identify dominant themes. Adherent behavior was reported by 59% (n = 17) of participants. Several themes influenced adherence including routine, fear of HBV-related disease progression, clinician-patient communication, treatment knowledge, and forgetfulness. To our knowledge, this is the first qualitative study to explore adherence to HBV antiviral therapy. An interplay of several dominant themes emerged from our data including fear of chronic HBV disease progression, clinician-patient communication, treatment knowledge, routine, and forgetfulness. Study findings have the potential to change nursing clinical practice, especially the way nurses and other clinicians target key HBV treatment messages and education, while monitoring adherence. PMID- 28570425 TI - THYROID HEMATOMA: AN UNUSUAL COMPLICATION OF UPPER GASTROINTESTINAL ENDOSCOPY. PMID- 28570426 TI - ACUTE MUCOSAL PERFORATION AFTER LAPAROSCOPIC HELLER MYOTOMY IN A CHILD. PMID- 28570427 TI - THIS I KNOW. PMID- 28570428 TI - Combined Detection of NUDT15 Variants Could Highly Predict Thiopurine-induced Leukopenia in Chinese Patients with Inflammatory Bowel Disease: A Multicenter Analysis. AB - BACKGROUND: NUDT15 c.415C>T was a novel genetic marker confirmed in our center for thiopurine-induced leukopenia in Chinese inflammatory bowel disease (IBD). For validation, a large cohort study is needed. Meanwhile, the newly discovered NUDT15 coding variants (c.36_37insGGAGTC and c.52 G>A) have not been studied in patients with IBD. We aimed to further confirm the influence of 3 NUDT15 variants (c.415C>T, c.36_37insGGAGTC, and c.52G>A) on thiopurine-induced leukopenia in Chinese patients with IBD. METHODS: Patients prescribed on thiopurines for at least 2 weeks were recruited from 4 tertiary hospitals. Clinical data were collected. NUDT15 genotypes were determined with polymerase chain reaction-RFLP and sequencing. The interactions between variants and leukopenia were analyzed. RESULTS: A total of 732 patients were included, 177 (24.3%) of whom developed leukopenia. There were strong associations of NUDT15 c.415C>T, c.36_37insGGAGTC, and c.52G>A with thiopurine-induced leukopenia (P = 1.81 * 10, P = 4.74 * 10 and P = 0.04, respectively), whereas there was no relevance for thiopurine S methyltransferase genotypes (P = 0.25). The predictive sensitivity of NUDT15 c.415C>T was 49.2%, whereas it increased to 55.4% when combined analysis with c.36_37insGGAGTC and c.52G>A. Notably, not only the homozygotes with NUDT15 c.415C>T but also the heterozygotes both carrying c.415C>T and c.52G>A developed early leukopenia. The median dosage for NUDT15 c.415C>T carriers was significantly lower than that for wild-type (P < 0.001). CONCLUSIONS: We confirmed that NUDT15 c.415C>T, c.36_37insGGAGTC, and c.52G>A variants were risk factors for thiopurine-induced leukopenia. Combined detection of the 3 variants could increase the predictive sensitivity of thiopurine-induced leukopenia and help to distinguish early leukopenia in heterozygote of c.415C>T in Chinese patients with IBD. Treatment monitoring by NUDT15 variants may be promising in individualized therapy. PMID- 28570429 TI - Incidence of and Predictors for Early Discontinuation of Biological Therapies in Veteran Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Biological therapies are effective for inducing and maintaining remission in inflammatory bowel disease (IBD), but patients often require changes in biological agents over the course of their illness. We sought to evaluate the rate of and reasons for discontinuing biological agents and to identify risk factors for their discontinuation. METHODS: We performed a retrospective cohort study across 4 VA hospital systems (Dallas, TX; Houston, TX; Ann Arbor, MI; Richmond, VA). Patients with IBD who were started on biological therapy between 1998 and 2015 were identified, and their medical records were reviewed to confirm the diagnosis of IBD and to collect study data. RESULTS: Of 1969 patients with IBD; 256 were treated with 346 courses of therapy. By 6 months after initiation of therapy, 82 (24%) had stopped the biological agent. Among patients starting their first biological agent, 21.5% had stopped by 6 months. Patients taking a concomitant thiopurine and those with ileocolonic disease or a nonpenetrating, nonstricturing phenotype were less likely to discontinue biological therapy, whereas those taking 5-ASA concomitantly were more likely to discontinue biological therapy. The most common reasons for discontinuation were primary nonresponse (40%) and adverse drug reactions (29%). CONCLUSIONS: In conclusion, in a large multicenter VA cohort, we found that 24% of patients who are prescribed a biological stop their treatment early, most commonly for primary nonresponse or for an adverse drug reaction. Consideration should be given to treating patients with a concomitant thiopurine if at all possible, as this reduces the likelihood of early discontinuation. PMID- 28570430 TI - Point Prevalence of Pediatric Inflammatory Bowel Disease in New Zealand in 2015: Initial Results from the PINZ Study. AB - BACKGROUND: The incidence of pediatric inflammatory bowel disease (IBD) around the world is increasing. However, there is a scarcity of data on the epidemiology of pediatric IBD in the Southern Hemisphere. This study aimed to document the point prevalence of pediatric IBD in New Zealand on June 30, 2015. METHODS: All patients in New Zealand, under 16 years of age, with a diagnosis of IBD on June 30, 2015 were identified. Demographic and disease phenotypic details were collected and entered into a secure database. Age-specific population data for New Zealand were obtained and national and regional prevalence rates were calculated. RESULTS: The point prevalence of pediatric IBD, Crohn's disease, ulcerative colitis, and inflammatory bowel disease unclassified in New Zealand on June 30, 2015 was (95% confidence intervals) 21.7 (18.9-24.8), 16.5 (14.0-19.2), 3.3 (2.2-4.6), and 1.9 (1.2-3.0) per 100,000 children, respectively. There was a striking disparity between the prevalence rates in the North and South Islands. CONCLUSIONS: The point prevalence of pediatric IBD in New Zealand represents the first-ever national, population-based prevalence rates of pediatric IBD published. Results from the Paediatric IBD in New Zealand (PINZ) study are also the first to show markedly higher prevalence rates of IBD in the southern part of a country compared with its northern counterpart. Ongoing prospective ascertainment of the incidence of pediatric IBD is required. PMID- 28570431 TI - Comparative Acceptability and Perceived Clinical Utility of Monitoring Tools: A Nationwide Survey of Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Objective control of intestinal inflammation during inflammatory bowel disease (IBD) is becoming the main driver for medical treatment. However, the monitoring tools-related burden remains poorly investigated. We aimed to evaluate their comparative acceptability and utility according to patients with IBD. METHODS: After a preliminary phase, the final questionnaire encompassing self-administered and physician questionnaires was prospectively and consecutively submitted to 916 patients with IBD from 20 public and private centers. Acceptability and utility visual analog scales (VAS) were expressed as median with interquartile range. RESULTS: Regarding the group of patients with Crohn's disease (n = 618), venipuncture (VAS = 9.3 [8.8-9.7]) and ultrasonography (VAS = 9.3 [8.7-9.7]) were the most acceptable tools (P < 0.0001, for each comparison), whereas rectosigmoidoscopy was the least acceptable tool (VAS = 4.4 [1.2-7.3]) (P < 0.0001, for each comparison). Wireless capsule endoscopy (VAS = 8.5 [5.2-9.3]), magnetic resonance enterocolonography (VAS = 8.0 [5.0-9.2]), and stools collection (VAS = 7.7 [4.6-9.3]) were more acceptable than colonoscopy (VAS = 6.7 [4.3-8.9]) (P < 0.0001, for each comparison). The acceptability was assessed in 298 patients with ulcerative colitis for venipuncture (VAS = 9.4 [8.8 9.7]), stools collection (VAS = 8.1 [5.7-9.4]), colonoscopy (VAS = 7.5 [4.7 9.2]), and rectosigmoidoscopy (VAS = 6.7 [2.8-9.1]); (P < 0.001 for each comparison). All monitoring tools were considered as highly useful by patients with IBD. Decreased acceptability was related to embarrassment for the collection/transport of stools (60.7%), bowel cleansing (76.3%) for colonoscopy, abdominal discomfort (51.3%) and rectal enema (36.6%) for rectosigmoidoscopy, bowel distension (48.3%) for magnetic resonance enterocolonography, and potential capsule retention (21.4%) for wireless capsule endoscopy. CONCLUSIONS: Among the IBD monitoring tools, endoscopy demonstrated the lowest acceptability supporting the development of alternative modalities. Patients' information and examination conditions should be improved to ensure proper monitoring adherence. PMID- 28570434 TI - The Prospective Association of the Diurnal Cortisol Rhythm With Sleep Duration and Perceived Sleeping Problems in Preschoolers: The Generation R Study. AB - OBJECTIVE: Cortisol, the end product of the hypothalamic-pituitary-adrenal axis, plays an important role in modulating sleep. Yet, studies investigating the association between diurnal cortisol rhythm and sleep patterns in young children are scarce. We tested the hypothesis that the diurnal cortisol rhythm is associated with shorter sleep duration and more sleep problems across early childhood. METHODS: This study was embedded in Generation R, a population-based cohort from fetal life onward. Parents collected saliva samples from their infant at five moments during day 1. In 322 infants aged 12 to 20 months, we determined the diurnal cortisol rhythm by calculating the area under the curve (AUC), the cortisol awakening response (CAR), and the diurnal slope. Sleep duration and sleep behavior were repeatedly assessed across ages of 14 months to 5 years. Generalized estimating equation models were used to assess related cortisol measures to sleep duration and sleep behavior. RESULTS: The diurnal cortisol slope and the CAR, but not the AUC, were associated with sleep duration across childhood. Children with flatter slopes and children with a more positive CAR were more likely to have shorter nighttime sleep duration (beta per nmol/L/h slope = -0.12, 95% confidence interval = -0.19 to -0.05, p = .001; beta per nmol/L CAR = -0.01, 95% confidence interval = -0.02 to 0.00, p = .04). Cortisol measures did not predict sleep problems. CONCLUSIONS: The present study suggests that a flatter diurnal cortisol slope and a more marked morning rise, which can indicate stress (or hypothalamic-pituitary-adrenal dysregulation), have a long term association with sleep regulation. PMID- 28570435 TI - INTERMEDIATE UVEITIS ASSOCIATED WITH PERIODIC FEVER, APHTHOUS STOMATITIS, PHARYNGITIS, AND CERVICAL ADENITIS SYNDROME. AB - BACKGROUND/PURPOSE: To report two novel cases of intermediate uveitis associated with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome. METHODS: Observational case reports and review of the literature. RESULTS: Both patients in this report had an established diagnosis of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome before the onset of ocular inflammation. Infectious and noninfectious systemic conditions known to be associated with intermediate uveitis were excluded. Intermediate uveitis was confirmed clinically in both patients by the presence of vitritis, snowballs, and peripheral snowbanks in the region of the pars plana. Both cases had a course characterized by recurrent inflammation; in which systemic steroid treatment, and in one case, immunomodulatory therapy was necessary. CONCLUSION: Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome is an auto-inflammatory fever disorder in childhood. Although other auto-inflammatory disorders such as, Blau syndrome, Muckle-Wells syndrome, and Behcets disease have been associated with various forms of uveitis, Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis has never been reported to be associated with any type of ocular inflammation. We describe for the first time, two cases of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome presenting with intermediate uveitis. PMID- 28570433 TI - Trauma and Autonomic Dysregulation: Episodic-Versus Systemic-Negative Affect Underlying Cardiovascular Risk in Posttraumatic Stress Disorder. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) has been linked to elevated heart rate (HR) and reduced heart rate variability (HRV) in cross-sectional research. Recent evidence suggests that this link may be driven by individual differences in autonomic arousal associated with momentary negative affect (NA). Using ecological momentary assessment (EMA) of NA and minute-to-minute HR/HRV monitoring, we examined whether NA-related HR/HRV mediated the association of PTSD symptom severity with 24-hour HRV and endothelial functioning. METHODS: One hundred ninety-seven young adults (18-39 years), 93 with PTSD, underwent 1 day of Holter monitoring while concurrently reporting NA levels via EMA. Two noninvasive measures of endothelial functioning-flow-mediated dilation and hyperemic flow were also collected. Multilevel modeling was used to assess the associations of momentary NA with HR and low- and high-frequency HRV during the 5-minute intervals after each EMA reading. Latent variable modeling was then used to determine whether individual differences in these associations mediated the association of PTSD symptom severity with 24-hour HRV, flow-mediated dilation, and hyperemic flow. RESULTS: PTSD symptom severity was positively associated with NA-related autonomic arousal (beta = .21, p < .001), which significantly mediated the association of PTSD symptom severity with 24-hour HRV and hyperemic flow, accounting for 62% and 34% of their associations, respectively, while overshadowing the influence of smoking, lifetime alcohol dependence, sleep duration, mean NA, and episodes of acute NA. CONCLUSIONS: Results suggest that NA related autonomic arousal is both a primary factor driving cardiovascular risk in PTSD and a potential point of intervention. PMID- 28570436 TI - Integration of Mobile Health Technology in the Treatment of Chronic Pain: A Critical Review. AB - This article provides a critical overview and best-evidence synthesis of the use of mobile health (mHealth) technology among persons with chronic pain and their health care providers and examines the future benefits and barriers of implementing mHealth technology in clinical care. We critically review articles about electronic pain diaries, pain assessment programs, text messaging, and smartphone pain apps for management of persons with pain. Also presented are findings on the utility of activity trackers and use of telehealth to deliver cognitive behavioral therapy. Finally, barriers, study gaps, and future challenges of incorporating mobile technology for chronic pain are discussed. Although the future of mHealth technology and telemedicine in clinical practice is promising, this critical review highlights the need for rigorous studies to establish an association of the use of mHealth technology with improved quality of life, functional autonomy, and decreased hospital use. PMID- 28570437 TI - Identification and Validation of Clinically Relevant Clusters of Severe Fatigue in Rheumatoid Arthritis. AB - OBJECTIVE: The considerable heterogeneity of rheumatoid arthritis (RA)-related fatigue is the greatest challenge to determining pathogenesis. The identification of homogenous subtypes of severe fatigue would inform the design and analysis of experiments seeking to characterize the likely numerous causal pathways that underpin the symptom. This study aimed to identify and validate such fatigue subtypes in patients with RA. METHODS: Data were obtained from patients recruited to the British Society for Rheumatology Biologics register for RA, as either receiving traditional disease-modifying antirheumatic drugs (DMARD cohort, n = 522) or commencing anti-tumor necrosis factor therapy (anti-TNF cohort, n = 3909). In those reporting severe fatigue (Short-Form 36 vitality <= 12.5), this cross-sectional analysis applied hierarchical clustering with weighted-average linkage identified clusters of pain, fatigue, mental health (all Short-Form 36), disability (Health Assessment Questionnaire), and inflammation (erythrocyte sedimentation rate) in the DMARD cohort. K-means clustering sought to validate the solution in the anti-TNF cohort. Clusters were characterized using a priori generated symptom definitions and between-cluster comparisons. RESULTS: Four severe fatigue clusters, labeled as basic (46%), affective (40%), inflammatory (4.5%), and global (8.9%) were identified in the DMARD cohort. All clusters had severe levels of pain and disability and were distinguished by the presence/absence of poor mental health and high inflammation. The same symptom clusters were present in the anti-TNF cohort, although the proportion of participants in each cluster differed (basic = 28.7%; affective = 30.2%; global = 24.1%; inflammatory = 16.9%). CONCLUSIONS: Among RA patients with severe fatigue, recruited to two diverse RA cohorts, clinically relevant clusters were identified and validated. These may provide the basis for future mechanistic studies and ultimately support a stratified approach to fatigue management. PMID- 28570438 TI - Surgically Induced Changes in Gut Microbiome and Hedonic Eating as Related to Weight Loss: Preliminary Findings in Obese Women Undergoing Bariatric Surgery. AB - OBJECTIVE: Weight loss surgery results in significant changes in the anatomy, function, and intraluminal environment of the gastrointestinal tract affecting the gut microbiome. Although bariatric surgery results in sustained weight loss, decreased appetite, and hedonic eating, it is unknown whether the surgery-induced alterations in gut microbiota play a role in the observed changes in hedonic eating. We explored the following hypotheses: (1) laparoscopic sleeve gastrectomy (LSG) results in changes in gut microbial composition; (2) alterations in gut microbiota are related to weight loss; (3) alterations in gut microbiome are associated with changes in appetite and hedonic eating. METHODS: Eight obese women underwent LSG. Their body mass index, body fat mass, food intake, hunger, hedonic eating scores, and stool samples were obtained at baseline and 1-month postsurgery. 16S ribosomal RNA gene sequencing was performed on stool samples. DESeq2 changes in microbial abundance. Multilevel-sparse partial least squares discriminant analysis was applied to genus-level abundance for discriminative microbial signatures. RESULTS: LSG resulted in significant reductions in body mass index, food intake, and hedonic eating. A microbial signature composed of five bacterial genera discriminated between pre- and postsurgery status. Several bacterial genera were significantly associated with weight loss (Bilophila, q = 3E-05; Faecalibacterium q = 4E-05), lower appetite (Enterococcus, q = 3E-05), and reduced hedonic eating (Akkermansia, q = .037) after surgery. CONCLUSIONS: In this preliminary analysis, changes in gut microbial abundance discriminated between pre- and postoperative status. Alterations in gut microbiome were significantly associated with weight loss and with reduced hedonic eating after surgery; however, a larger sample is needed to confirm these findings. PMID- 28570440 TI - Successful Reinnervation of the Diaphragm After Intercostal to Phrenic Nerve Neurotization in Patients With High Spinal Cord Injury. AB - OBJECTIVE: Our objective in this study was to extend diaphragmatic pacing therapy to include paraplegic patients with high cervical spinal cord injuries between C3 and C5. INTRODUCTION: Diaphragmatic pacing has been used in patients experiencing ventilator-dependent respiratory failure due to spinal cord injury as a means to reduce or eliminate the need for mechanical ventilation. However, this technique relies on intact phrenic nerve function. Recently, phrenic nerve reconstruction with intercostal nerve grafting has expanded the indications for diaphragmatic pacing. Our study aimed to evaluate early outcomes and efficacy of intercostal nerve transfer in diaphragmatic pacing. METHODS: Four ventilator-dependent patients with high cervical spinal cord injuries were selected for this study. Each patient demonstrated absence of phrenic nerve function via external neck stimulation and laparoscopic diaphragm mapping. Each patient underwent intercostal to phrenic nerve grafting with implantation of a phrenic nerve pacer. The patients were followed, and ventilator dependence was reassessed at 1 year postoperatively. RESULTS: Our primary outcome was measured by the amount of time our patients tolerated off the ventilator per day. We found that all 4 patients have tolerated paced breathing independent of mechanical ventilation, with 1 patient achieving 24 hours of tracheostomy collar. CONCLUSIONS: From this study, intercostal to phrenic nerve transfer seems to be a promising approach in reducing or eliminating ventilator support in patients with C3 to C5 high spinal cord injury. PMID- 28570439 TI - Cortisol Awakening Response as a Prospective Risk Factor for Depressive Symptoms in Women After Treatment for Breast Cancer. AB - OBJECTIVE: The aim of the study was to investigate hypothalamic-pituitary-adrenal axis (HPA axis) functioning as a neurobiological risk factor for depressive symptoms in an ongoing longitudinal, observational study of women undergoing treatment and recovery from breast cancer. Many women with breast cancer experience depressive symptoms that interfere with their treatment, recovery, and quality of life. Psychosocial risk factors for depression among patients with cancer and survivors have been identified, yet neurobiological risk factors in this population remain largely unexamined. METHODS: Women recently diagnosed with early-stage breast cancer (N = 135) were enrolled before starting neoadjuvant/adjuvant treatment (radiation, chemotherapy, endocrine therapy). At baseline, participants collected saliva samples to measure diurnal HPA axis functioning for 3 days: at waking, 30 minutes after waking, 8 hours after waking, and bedtime. Participants also completed a standardized measure of depressive symptoms (Center for Epidemiological Studies-Depression Scale) at baseline and 6 months after completion of primary treatment. Multivariate regression was used to predict continuous depressive symptoms at 6-month posttreatment from continuous depressive symptoms at baseline, cortisol awakening response (CAR), and other measures of diurnal HPA axis functioning. RESULTS: The magnitude of CAR predicted changes in depressive symptoms over time, such that women with a higher CAR showed a greater increase from baseline to 6-month posttreatment (b = 5.67, p = .023). Diurnal slope and total cortisol output were not associated with concurrent depressive symptoms or their change over time. CONCLUSIONS: Elevated CAR may be a neurobiological risk factor for increases in depressive symptoms in the months after breast cancer treatment and warrants further investigation. PMID- 28570442 TI - Localized Arm Volume Index: A New Method for Body Type-Corrected Evaluation of Localized Arm Lymphedematous Volume Change. AB - BACKGROUND: Volume measurement is a common evaluation for upper extremity lymphedema. However, volume comparison between different patients with different body types may be inappropriate, and it is difficult to evaluate localized limb volume change using arm volume. METHODS: Localized arm volumes (Vk, k = 1-5) and localized arm volume indices (LAVIk) at 5 points (1, upper arm; 2, elbow; 3, forearm; 4, wrist; 5, hand) of 106 arms of 53 examinees with no arm edema were calculated based on physical measurements (arm circumferences and lengths and body mass index [BMI]). Interrater and intrarater reliabilities of LAVIk were assessed, and Vk and LAVIk were compared between lower BMI (BMI, <22 kg/m) group and higher BMI (BMI, >=22 kg/m) group. RESULTS: Interrater and intrarater reliabilities of LAVIk were all high (all, r > 0.98). Between lower and higher BMI groups, significant differences were observed in all Vk (V1 [P = 6.8 * 10], V2 [P = 3.1 * 10], V3 [P = 1.1 * 10], V4 [P = 8.3 * 10], and V5 [P = 3.0 * 10]). Regarding localized arm volume index (LAVI) between groups, significant differences were seen in LAVI1 (P = 9.7 * 10) and LAVI5 (P = 1.2 * 10); there was no significant difference in LAVI2 (P = 0.60), LAVI3 (P = 0.61), or LAVI4 (P = 0.22). CONCLUSIONS: Localized arm volume index is a convenient and highly reproducible method for evaluation of localized arm volume change, which is less affected by body physique compared with arm volumetry. PMID- 28570441 TI - Significance of the Lateral Thoracic Artery in Pectoralis Major Musculocutaneous Flap Reconstruction: Quantitative Assessment of Blood Circulation Using Indocyanine Green Angiography. AB - Free tissue transfer is the preferred reconstruction option in most major head and neck reconstructions. The pectoralis major muscle musculocutaneous (PMMC) flap is commonly used in salvage of necrotic free flaps and is the first choice for patients who are not candidates for free flaps. The lateral thoracic artery (LTA), which is thought to contribute to blood perfusion of the inferior and lateral mammary area, is not preserved in a conventionally harvested PMMC flap. With regard to blood supply, it has been suggested that the LTA should be preserved, in addition to the pectoral branch of the thoracoacromial artery, when a skin island is designed in the lower chest to attain a pedicle length sufficient for head and neck reconstruction. However, an effect on hemodynamic improvement using the LTA has not been shown quantitatively. In this study, we examined 8 patients with oral cancer who underwent reconstruction procedures with a bipedicle PMMC flap that included the LTA, in addition to the thoracoacromial artery. Intraoperative indocyanine green angiography was performed to examine circulation to the PMMC flap with or without LTA clamping after harvesting. After image processing, data were analyzed using a new quantitative perfusion assessment system with parameters that we recently established for assessment of peripheral arterial disease of the lower limbs. All patients had good clinical courses with whole-flap survival, no vascular insufficiency of the skin island, and no fistula formation. Intraoperative indocyanine green angiography showed an increased inflow rate into the skin island in an LTA-declamped condition in all cases, implying that the preserved LTA increased the blood supply to skin islands in the pectoralis major muscle. We conclude that preserving the LTA in a PMMC flap can increase blood perfusion and stabilize the vascularity of the flap, making the reconstruction more effective and reliable than with use of a conventionally harvested flap. Therefore, it is worthwhile to preserve the LTA as a major contributor to a lateral and distal PMMC flap. PMID- 28570443 TI - Outcomes of Geriatric Burns Treated as Outpatients. AB - OBJECTIVE: Most literature about geriatric burns has focused on inpatient management; therefore, our study investigated the effects of burn characteristics and preexisting medical comorbidities on treatment outcomes for geriatric burn patients treated as outpatients. METHODS: A retrospective review was conducted for 391 patients over 65 years of age seen in the emergency department of Fukui Prefectural Hospital over a 10-year period. Charts were reviewed for age, sex, burn characteristics, burn mechanisms, preexisting medical comorbidities, and treatment outcomes. Multivariate regression analysis was used to examine the relationship between outcomes of outpatients and comorbidities, which were calculated by the Charlson comorbidity index. RESULTS: Seventy-three patients aged 65 years and older were treated as outpatients at Fukui Prefectural Hospital. The majority (80%) of these patients had burns on less than 5% of their total body surface area. Scald burns accounted for 63% of burn mechanisms, with burns to the lower extremities being the most frequent. The mean percentage of total burn surface area was 4% in the outpatient group and 28% for the inpatient group. The mean time to healing was 24.3 days in outpatients. Of the 73 outpatients, 17 (23%) showed delayed healing. Of these 17 patients, 3 patients experienced wound infection and 2 patients had documented hypertrophic scarring. Four patients ultimately underwent excision and grafting. The common preexisting medical comorbidities in the outpatient group were congestive heart failure and diabetic mellitus. There were no significant differences for medical comorbidities between outpatients and inpatients. The Charlson comorbidity index for outpatients with delayed healing was higher than that for those without delayed healing. The Charlson comorbidity index was associated with delayed healing of outpatients, but age or total burn surface area were not. CONCLUSIONS: The characteristics of geriatric burn outpatients were distinct from those of inpatients. The weighted sum of preexisting medical comorbidities may affect wound healing among geriatric burn outpatients. PMID- 28570444 TI - Mastering Lymphatic Microsurgery: A New Training Model in Living Tissue. AB - BACKGROUND: Advanced microsurgical techniques have emerged as a promising approach for the treatment of lymphedema, but achieving international standards is limited by a scarcity of adequate training models. The purpose of this report is to describe our in vivo porcine training model for microsurgery. STUDY DESIGN: Five female common-breed pigs (Sus scrofa domesticus) weighing 20 to 28 kg were placed under general anesthesia, and blue patent violet dye was injected to highlight lymphatic structures and prepare the pigs for anatomical exploration and microsurgery. The number and type of patent anastomoses achieved and lymph node flaps created and any anatomical differences between porcine and human vessels were noted, in light of evaluating the use of pigs as a training model for microsurgery in living tissue. RESULTS: Multiple lymphatic-venous anastomoses were created at the site of a single incision made at the subinguinal region, running medial and parallel to the saphenous vessels. Ten multiple lymphatic venous anastomoses were created in total, and all were demonstrated to be patent. Four lymph node flaps were prepared for lymph node transfer. The superficial lymphatic collector system in the caudal limb of the pig was identified and described with particular reference to the superficial, medial (dominant), and lateral branches along the saphenous vein and its accessory. CONCLUSIONS: The authors present a safe and adaptable in vivo experimental microsurgical porcine model that provides the opportunity to practice several advanced lymphatic microsurgical techniques in the same animal. The ideal lymph node transfer training model can be developed from this anatomical detail, giving the opportunity to use it for artery-to-artery anastomoses, vein-to-vein anastomoses, and lymphatic-to-lymphatic anastomoses. PMID- 28570445 TI - Characteristics, Management Techniques, and Outcomes of the Most Common Soft Tissue Hand Tumors: A Literature Review and Our Experience. AB - INTRODUCTION: Diagnosis of the hand's soft-tissue tumors is often difficult because of the different anatomic structures present in this region and yet clinicians must be able to distinguish typical benign entities from life threatening or limb-threatening malignant diseases. MATERIALS AND METHODS: At the Department of Plastic and Reconstructive Surgery at the University of Palermo, 629 patients with hand tumors were studied. Treatment was surgical for all of them; also radiotherapy and chemotherapy were necessary based on the histological diagnosis. CONCLUSIONS: Our retrospective study with a literature review aims to present the most commonly observed soft-tissue hand lesions, analyzing their causes, their objective and instrumental evaluation, and their treatments. PMID- 28570447 TI - The Prevalence of Congenital Heart Disease in Nonsyndromic Cleft Lip and/or Palate: A Systematic Review of the Literature. AB - BACKGROUND: Life-threatening anomalies, such as congenital heart disease (CHD) must be identified in patients with cleft lip and/or palate (CL/P) to minimize perioperative risk. Nevertheless, screening practices vary highly among cleft teams and programs, and little is known about the prevalence and clinical significance of CHD in nonsyndromic CL/P patients. Through a systematic literature review, this study examines the demographics and severity of CHD in the nonsyndromic CL/P population. The implications of concomitant CHD in providing safe and comprehensive cleft care both in the United States and abroad are discussed. METHODS: A systematic review of PubMed literature from 1980 to September 2015 was performed following PRISMA guidelines. Studies describing rates of CHD and severity of lesions specifically in nonsyndromic and all CL/P patients were included. Analysis of cumulative data was performed according to nonsyndromic status and cleft type. RESULTS: Twelve studies were found to meet inclusion criteria. Of the 4055 nonsyndromic CL/P patients who met inclusion criteria, 7.42% (n=301) had CHD, which was significantly greater than the general population (~1%; odds ratio [OR], 7.94; P<0.0001). Congenital heart disease was significantly more common in cleft palate (CP) (OR, 15.1), combined CL and palate (CL+P) (OR, 13.5), and CL (OR, 4.23) compared with the general population. Palatal clefts (CP and CL+P) had significantly increased odds of CHD compared with CL (OR, 3.58 and 3.19, respectively, both P<0.0001). The most common forms of CHD were atrial or ventricular septal defects (n=210, 74.2%), which typically do not require surgical intervention in the general population. Clinical significance of these CHD lesions in CL/P patients is not fully known. CONCLUSIONS: Cleft management programs aim to maximize the number of patients receiving care while maintaining patient safety. Appropriate evaluation of perioperative risk necessitates understanding the prevalence of CHD in CL/P patients and the severity of those lesions. Patients with CL/P, particularly patients with palatal clefts, have significantly higher odds of having CHD than the general population. Congenital heart disease is most likely to present as atrial or ventricular septal defects, which are lesions that are unlikely to impact safety during cleft repair surgery. PMID- 28570446 TI - Vascular Endothelial Growth Factor Induction of Muscle-Derived Stem Cells Enhances Vascular Phenotype While Preserving Myogenic Potential. AB - BACKGROUND: Previous work by our group and other laboratories have revealed that muscle-derived stem cells (MDSCs) may contain both myogenic and endothelial progenitors, making MDSCs a promising option for skeletal muscle regeneration. The purpose of this study was to investigate the impact of vascular endothelial growth factor (VEGF) induction on the vascular and myogenic potential of MDSCs. METHODS: Muscle-derived stem cells were isolated from 4- to 8-week-old C57BL/6J mice using a preplate technique and recombinant human VEGFa was used as the induction agent. Cellular proliferation and migration were assessed using serial imaging and wound healing assays, respectively. Myosin heavy chain staining was performed to assess MDSC myotube formation. Vascular potential of MDSCs was measured by expression of CD31 and in vitro capillary tube formation. RESULTS: Vascular endothelial growth factor stimulation led to a dose-dependent increase in MDSC proliferation (P < 0.05) and migration kinetics (P < 0.01). Control MDSCs had low levels of baseline expression of CD31, which was significantly upregulated by VEGF stimulation. Similarly, MDSCs demonstrated a basal capability for capillary tube formation, which was significantly increased after VEGF induction as evidenced by increased branches (5.91 +/- 0.58 vs 9.23 +/- 0.67, P < 0.01) and total tube length (11.73 +/- 0.97 vs 18.62 +/- 1.57 mm, P < 0.01). Additionally, the myogenic potential of MDSCs as measured by fusion index remained unchanged with increasing concentration of VEGF up to 250 ng/mL (P = 0.77). CONCLUSIONS: Vascular endothelial growth factor induction enhances MDSC proliferation, migration, and endothelial phenotypes without negatively impacting myogenic potential. These results suggest that VEGF stimulation may improve vascularization of MDSC-based strategies for skeletal muscle regeneration. PMID- 28570448 TI - Free Lateral Digital Flap for Reconstruction of the Fingers. AB - BACKGROUND: The region between the proximal interphalangeal (PIP) and the metacarpophalangeal (MP) creases has greater laxity than other regions in the fingers, allowing for primary closure of the donor site. We postulated if we could consistently locate perforators from the region between the PIP and the MP crease on the radial side of the middle and ring fingers, on which a scar would be less conspicuous than one on the radial side of the index finger, these regions would be ideal donor sites for digital reconstruction using very small flaps. METHODS: In 20 fingers (10 middle fingers and 10 ring fingers) from 5 volunteers, perforators from the radial proper digital artery were visualized between the PIP and the MP creases using ultrasonography. Based on this information, and to evaluate its feasibility, a free lateral digital flap was used for reconstruction of small digital defects in 3 cases. RESULTS: Of the 20 fingers, 19 had at least 1 digital artery perforator (DAP) arising from the radial proper digital artery between the PIP and MP creases. The average distance from the PIP crease to the DAP was 9.0 mm. The average diameter of the DAP was 0.37 mm. In all clinical cases, flaps survived completely with pleasing cosmesis. There were no donor site complications. CONCLUSIONS: With their consistent anatomy and relatively low donor site morbidity, free lateral digital flaps from the radial side of the middle or ring fingers may be a reliable option for reconstruction of the volar surface of the digits. PMID- 28570449 TI - Quality Measures in Breast Reconstruction: A Systematic Review. AB - BACKGROUND: The importance of providing quality care over quantity of care, and its positive effects on health care expenditure and health, has motivated a transition toward value-based payments. The Centers for Medicare and Medicaid Services and private payers are establishing programs linking financial incentives and penalties to adherence to quality measures. As payment models based on quality measures are transitioned into practice, it is beneficial to identify current quality measures that address breast reconstruction surgery as well as understand gaps to inform future quality measure development. METHODS: We performed a systematic review of quality measures for breast reconstruction surgery by searching quality measure databases, professional society clinical practice guidelines, and the literature. Measures were categorized as structure, process, or outcome according to the Donabedian domains of quality. RESULTS: We identified a total of 27 measures applicable to breast reconstruction: 5 candidate quality measures specifically for breast reconstruction surgery and 22 quality measures that relate broadly to surgery. Of the breast reconstruction candidate measures, 3 addressed processes and 2 addressed outcomes. Seventeen of the general quality measures were process measures and 5 were outcome measures. We did not identify any structural measures. CONCLUSIONS: Currently, an overrepresentation of process measures exists, which addresses breast reconstruction surgery. There is a limited number of candidate measures that specifically address breast reconstruction. Quality measure development efforts on underrepresented domains, such as structure and outcome, and stewarding the measure development process for candidate quality measures can ensure breast reconstruction surgery is appropriately evaluated in value-based payment models. PMID- 28570450 TI - The Impact of Physician Assistants on a Breast Reconstruction Practice: Outcomes and Cost Analysis. AB - BACKGROUND: Physician assistants (PAs) are commonly employed in plastic surgery. However, limited data exist on their impact, which may guide decisions regarding how best to integrate them into practice. METHODS: A review of the practices of 2 breast reconstructive surgeons was performed. A comparison was made between a 1 year period before to a 1-year period after the addition of a PA into practice. The practice model was a one-to-one pairing of a plastic surgeon and a PA. RESULTS: A total of 4141 clinic encounters and 1356 surgical cases were reviewed. After the addition of PAs, there was a significant increase in relative value units (1057 vs 1323 per month per surgeon, P < 0.001). Operative times were similar with and without PAs (P = 0.45). However, clinic encounter times for surgeons were shorter for all visit types when patients were first seen by a PA before the surgeon: global follow-up (P = 0.03), other follow-up (P = 0.002), consultation (P = 0.76), and preoperative (P = 0.02), translating to 9 additional patients seen per day. Charges (P = 0.001) and payments (P = 0.007) also increased, which offset the cost of using a PA. However, the financial contribution from PA involvement as first assistant in surgery was limited (5.2%). The peak effect of PAs was observed between the third and fourth quarters. CONCLUSIONS: In breast reconstruction, PAs primarily enhance the efficiency of plastic surgeons, particularly in the clinic, with downstream clinical and financial gains of an indirect nature for surgeons. PMID- 28570451 TI - The Cardioplastic Approach to the Treatment of Infected Aortic Grafts. AB - BACKGROUND: Aortic graft infection (AGI) is a rare complication following reconstructive aortic surgery, yet it represents a significant source of morbidity and mortality. There is no consensus regarding the optimal surgical management, due in part to the small cohorts of patient reports. Pedicled muscle or omental flap coverage of AGI has been shown to improve outcomes, making them a valuable consideration in the treatment algorithm. Thus, we aim to compile and evaluate cases of autologous vascularized tissue (AVT) in the treatment of infected aortic grafts, summarizing location specific trends, treatments, and outcomes. METHODS: A comprehensive review of peer-reviewed literature regarding the management of AGI was performed. Data collected included patient characteristics, original procedure, pathogen, infection location, tissue utilized, technique of tissue isolation and delivery, staging, outcome, length of follow-up, and level of evidence. RESULTS: Ninety-four cases of AGI managed with AVT transfer were identified. Infection of ascending aorta grafts accounted for 59% of cases, followed by a combination of ascending aorta and aortic arch (21%), the descending thoracic aorta (18%), and the thoracoabdominal aorta (2%). The infected graft was preserved in 81% of cases, followed by debridement and AVT coverage. The omentum was the most commonly applied flap (69%) for all divisions of the aorta followed by the pectoralis major (19%), the rectus abdominis (5%), and latissimus dorsi (4%). Mortality was limited, and the Powered by Editorial Manager and ProduXion Manager from Aries Systems Corporation overall survival was 93% (7 deaths), with a mean follow-up of 33.5 months. CONCLUSIONS: Autologous vascularized tissue coverage has proven to be a successful approach for treatment of infected aortic grafts. Although the incidence of AGI is rare, it represents an area of scarce evidence-based literature that warrants increased attention and surgical refinement. These results, which show a remarkably low infection-related mortality rate (3%), should encourage interdisciplinary collaboration with the plastic surgeon, cardiothoracic surgeon, and infectious disease specialists with the goal of improving outcomes in the treatment of infected aortic grafts. PMID- 28570452 TI - Comparison of V-Y Advancement Flap Versus Lotus Petal Flap for Plastic Reconstruction After Surgery in Case of Vulvar Malignancies: A Retrospective Single Center Experience. AB - Vulvoperineal defects after demolitive surgery for preneoplastic or malignant vulvar lesions require a reconstruction to restore good sexual functions and to offer a satisfactory cosmetic result. Several techniques of reconstruction have been described in the past, leading to a more conservative and localized treatment. This study retrospectively reviewed patients with primary or recurrent vulvar malignancies that had undergone vulvoperineal reconstruction between 2010 and 2016 using the V-Y advancement flap and the 2 variant of the lotus petal flap (LPF) in terms of surgical outcome and postoperative complications. Two hundred eighty-four (284) women were reviewed, 234 of them having undergone V-Y flap and 128, the LPF. Overall, postoperative complications occurred in 21.5% of patients including 21% (27/128) of the V-Y group and in 13% (14/106) of the LPF group. The 2 techniques are valid and feasible for vulvar reconstruction in case of moderate defects. No statistically significant differences in terms of complications were observed between the 2 groups overall (P = 0.588), or by comparing the primary (P = 0.202) or the recurrent setting (P = 0.281). Lotus petal flap, particularly the tunneled variant, was superior to V-Y advancement flap in terms of functional and cosmetic results in patients undergoing resection for primary vulvar malignancies. PMID- 28570453 TI - Anterolateral Thigh Flap for Reconstruction in Postburn Axillary Contractures. AB - BACKGROUND: Reconstruction of postburn axillary contractures is difficult and particularly challenging without healthy adjacent soft tissue for axillary scar resurfacing. In this case, a free soft-tissue transfer is among the best treatment options. Here, we describe our experience with free anterolateral thigh (ALT) flap for reconstruction in postburn axillary contractures. METHODS: We enrolled 10 patients with postburn axillary contractures from August 2003 to July 2015. They all underwent wide scar contracture release through a transverse incision from the anterior axillary fold to the posterior axillary fold. The ALT flap was subfascially raised. The huge soft tissue defect after scar release was resurfaced with the ALT flap. RESULTS: Eight male patients and 2 female patients (age, 16-64 years; mean, 46 years) were included. The mean total burn surface area, follow-up time, duration between injury onset and free-flap transfer surgery, and flap size were 48%, 27 months, 7.7 months, and 12 * 23 cm, respectively. The most common recipient vessels were the thoracodorsal artery and vein (77%). The mean improvement in the range of motion of shoulder abduction was 86 degrees (range, 60-130 degrees). The mean operative time was 7 hours. All flaps survived without reexploration or failure. All but 1 donor site was managed by split-thickness skin grafting. No infection, hematoma, or deaths were noted postoperatively. Transient brachial palsy was noted in a 16-year-old male patient postoperatively, with full recovery 3 months after. CONCLUSIONS: For postburn axillary contractures without healthy adjacent soft tissue for scar resurfacing, ALT flap reconstruction represents a suitable treatment option. It allows simultaneous surgery on both the donor and recipient sites, without the need to change the patient's position. Furthermore, the ALT flap provides sufficient soft tissue and blood flow for reconstruction, leading to satisfactory functional outcomes. PMID- 28570454 TI - Intramedullary Venous Drainage System for Distal Fingertip Replantations. AB - The number of venous anastomoses performed during fingertip replantation is one of the most important factors affecting the success of replantation. However, because vessel diameters decrease in the zone 1 level, vessel anastomoses, especially vein anastomoses, are technically difficult and, thus, cannot be performed in most cases. Alternative venous drainage methods are crucial when any reliable vein repair is not possible. In the literature, so many artery-only replantation techniques have been defined, such as arteriovenous anastomoses, forming an arteriovenous or venocutaneous fistula, manual milking and massage, puncturing, and external bleeding via a fishmouth incision and using a medical leech. It has been shown that, in distal fingertip replantations, the medullary cavity may also be a good way for venous return. In this study, we introduce an alternative intramedullary venous drainage system we developed to facilitate venous drainage in artery-only fingertip replantations. The results of 24 fingertip replantations distal to the nail fold by using this system are presented with a literature review. PMID- 28570455 TI - Anatomical Reconstruction of the Nasal Floor in Complete Unilateral Cleft Lip Repair. AB - BACKGROUND: Numerous methods exist for repairing unilateral cleft lips and mainly focus on cutaneous design to achieve sufficient rotation of the medial (M) cleft lip and produce a natural Cupid's bow and philtrum. However, precise nasal floor reconstruction has not been described in detail. This is the first study to introduce a technique for repairing complete unilateral cleft lips with a focus on nasal floor reconstruction. METHODS: In our technique, "Straight-Line Advanced Release Technique (StART)," the nasal floor is considered a 3-dimensional cuboid structure; the M mucosal and lateral (L) mucosal flaps constituted the posterior surface. The M flap became the roof of the orbicularis oris muscle sling and the posterior side of the nasal lining. The B flap met the L lip flap at the superior border of the M flap, and together they formed the roof and anterior surface. The B flap also formed a transitional zone connecting the columella and nasal floor. RESULTS: Seventy-two patients with complete unilateral cleft lip were treated from 2003 to 2015. The difference in the height of the nostril sills between the cleft and non-cleft sides was not significantly different from that in control patients (P = 0.472) 1 year postoperatively. Twenty operations for secondary deformities were performed: 8 for nose deformities not involving the nasal floor. The transverse scar at the alar base was concealed within the nostril. CONCLUSIONS: Nasal floor reconstruction is important in complete unilateral cleft lip repair. Our technique provides a naturally shaped, symmetrical nasal floor without conspicuous scarring. PMID- 28570456 TI - Significance of Objective Structured Clinical Examinations to Plastic Surgery Residency Training. AB - INTRODUCTION: Objective structured clinical examinations (OSCEs) have proven to be a powerful tool. They possess more than a 30-year track record in assessing the competency of medical students, residents, and fellows. Objective structured clinical examinations have been used successfully in a variety of medical specialties, including surgery. They have recently found their way into the subspecialty of plastic surgery. METHODS: This article uses a systematic review of the available literature on OSCEs and their recent use in plastic surgery. It incorporates survey results assessing program directors' views on the use of OSCEs. RESULTS: Approximately 40% of programs surveyed use OSCEs to assess the Accreditation Council for Graduate Medical Education core competencies. We found that 40% use OSCEs to evaluate specific plastic surgery milestones. Objective structured clinical examinations are usually performed annually. They cost anywhere between $100 and more than $1000 per resident. Four milestones giving residents the most difficulties on OSCEs were congenital anomalies, noncancer breast surgery, breast reconstruction, and practice-based learning and improvement. It was determined that challenges with milestones were due to lack of adequate general knowledge and surgical ward patient care, as well as deficits in professionalism and system-based problems. Programs were able to remediate weakness found by OSCEs using a variety of methods. CONCLUSIONS: Objective structured clinical examinations offer a unique tool to objectively assess the proficiency of residents in key areas of the Accreditation Council for Graduate Medical Education core competencies. In addition, they can be used to assess the specific milestones that plastic surgery residents must meet. This allows programs to identify and improve identified areas of weakness. PMID- 28570457 TI - Reviewing the Evidence to Guide Clinical Care: Proliferative Breast Lesions in Breast Reduction Specimens. AB - The number of reduction mammoplasties performed in the United States continues to increase annually. Given the high incidence of breast cancer in women, it is routine practice for breast tissue excised during routine breast reductions procedures to be sent for pathology review. During pathology assessment, occult malignancy and on-occasion proliferative breast lesions of unknown and/or variable malignancy may also be present. We provide a review of commonly diagnosed atypical proliferative breast lesions in breast reduction specimens and a guide to plastic surgeons for further management. PMID- 28570458 TI - Efficacy and Safety of the Babysitter Procedure With Different Percentages of Partial Neurectomy. AB - BACKGROUND: After 2 months of denervation, the number of motor units in the muscle decreases; after 6 months of denervation, muscle atrophy and weakness are irreversible and successful nerve reconstruction does not generally restore function. The babysitter procedure was reported to successfully avoid muscle atrophy. One study found that the babysitter procedure with a 40% neurectomy was most suitable; however, the amount of donor nerve that can be borrowed for the babysitter procedure in peripheral nerve injury is unknown. METHOD: One hundred adult female Sprague-Dawley rats were used in this study. The rats were randomly allocated to 5 groups (groups A-E; n = 20 each). The rats underwent different surgeries based on their grouping. At 6, 12, 18, and 24 weeks after surgery, 5 rats in each group were selected for electrophysiology and muscle force tests. These rats were then killed, and the gastrocnemius and tibialis anterior muscles were harvested for weight measurement and cross-sectional muscle measurement. RESULT: The results of the effects on the peroneal nerves and tibialis anterior muscles after the babysitter procedure with 40% and 80% neurectomies showed that the functional ability of the recipient nerves was maintained and the muscle was effectively prevented from atrophy, whereas the 20% neurectomy and end-to-side procedures showed relatively poor performance. The results of the effects on the tibial nerve and gastrocnemius muscles after the babysitter procedure with 20% and 40% neurectomies showed that there was little effect on the donor nerve. By contrast, 80% neurectomy strongly and negatively affected the donor nerve. CONCLUSIONS: Our results indicate that the babysitter procedure using a donor nerve with a partial neurectomy of 40% was the best choice for effectively treating peripheral (peroneal) nerve injury in rats. PMID- 28570459 TI - Alar Pinning in Rigid External Distraction for Midfacial Hypoplasia. AB - BACKGROUND: Distraction osteogenesis with a rigid external distractor is a widely accepted treatment for midfacial hypoplasia. In this study, the authors introduce the utilization of alar pinning with the external halo distractor for maxillary advancement, in place of an oral splint. METHODS: A retrospective chart review was conducted of 7 patients who successfully underwent distraction osteogenesis using the alar pinning technique. Midfacial hypoplasia was secondary to Crouzon syndrome (n = 4), Apert syndrome (n = 1), Pfeiffer syndrome (n = 1), or bacterial meningitis (n = 1). Three patients were managed with monobloc osteotomies, 2 with Le Fort III osteotomies, 1 with Le Fort III osteotomy and frontoorbital advancement, and 1 with Le Fort I osteotomy alone. Patient charts were analyzed for postoperative course and complications relating to the alar pins. RESULTS: Two patients had minor complications specifically related to the alar pins. One patient had concern for a mild skin infection at a pin site that resolved with oral antibiotics. The other patient had loosening of an alar pin, which did not require operative management. Retrospective chart review indicated that all patients were pleased with their results from the distraction, and no patients opted for further advancement. DISCUSSION: Utilization of alar pin sites for external distraction is a feasible and reasonable option for treatment of midfacial hypoplasia involving a Le Fort osteotomy or monobloc procedure. Fixation sites within the alar crease minimize the visibility of pin site scars and eliminate the need for a custom-made oral splint, which prevents usage of the upper dentition and frequently requires consulting a dentist or orthodontist for fabrication. CONCLUSIONS: Alar pinning with an external halo distraction system for management of midfacial hypoplasia has minimal complications and is an alternative to using a custom-made oral splint. PMID- 28570460 TI - Lesions Associated With Calcium Gluconate Extravasation: Presentation of 5 Clinical Cases and Analysis of Cases Published. AB - INTRODUCTION: Calcium gluconate extravasation is a process, which, while not common, occurs more frequently in neonatal intensive care units. The aim of this study is to present a number of cases of calcium gluconate extravasation, which have occurred in our hospital, and to carry out a review of those clinical cases published in the literature to obtain relevant epidemiological data. METHODS: Data were gathered on the medical histories of 5 patients who presented lesions secondary to calcium gluconate extravasation in our center. A review of the literature was also performed to include clinical cases of calcium gluconate extravasation already published. RESULTS: Data were collected on 60 cases published in 37 articles. Most patients (55%) were neonates. The average age of these neonates was 8 days. The commonest location of injuries was the back of the hand and wrist (42%). The 2 most frequent symptoms were the appearance of erythema (65%) and swelling/edema (48%) followed by the appearance of skin necrosis (47%), indurated skin (33%), and yellow-white plaques or papules (33%). Most cases are cured within a period of 3 to 6 months. Fifty percent of patients required surgery, and in 13% of cases, skin grafts were performed. The most frequent histological finding was the presence of calcium deposits. Other histological findings described were the presence of necrosis, lymphohistiocytic infiltrate, and granulomas. Most histological findings were located in the dermis. Most x-rays showing calcium deposits had been performed at 3 to 4 weeks. CONCLUSIONS: Calcium gluconate extravasation is a process, which, although infrequent, is associated with serious skin and soft-tissue lesions, mainly affecting infants. Further studies are needed to determine possible specific procedures to be carried out in these cases. PMID- 28570461 TI - Epineural Sheath Jacket as a New Surgical Technique for Neuroma Prevention in the Rat Sciatic Nerve Model. AB - BACKGROUND: Terminal neuromas resulting from severe nerve injuries and traumatic or surgical limb amputations can become a source of pain, and significantly impair patients' quality of life. Recently, the number of patients with peripheral nerve injuries increased due to modern war conflicts, natural disasters, and traffic accidents. This study investigated the efficacy of the epineural sheath jacket (ESJ) as a novel technique for neuroma prevention in the rat sciatic nerve model. METHODS: A 20-mm segment of the right sciatic nerve was excised in 18 Lewis rats, and the animals were divided into 3 experimental groups (n = 6/group): group I-control, nerve stump without protection; group II-muscle burying group, nerve stump buried in the muscle; group III-ESJ group, nerve stump protected by ESJ. The ESJ was created from the excised sciatic nerve and applied as a "cap" over the proximal nerve stump. The presence of neuropathic pain was assessed weekly by pinprick test and Tinel sign, up to 24 weeks postsurgery. At 24 weeks, assessments, such as macroscopic evaluation, retrograde neuronal labeling analysis, histomorphometry, and neural/connective tissue ratio were performed. RESULTS: Epineural sheath jacket significantly reduced neuroma formation, which was associated with decreased Tinel sign (16.7%, P < 0.05) response compared with the nerve stump control. Moreover, ESJ reduced axonal sprouting, bulb-shaped nerve ending formation and perineural adhesions, as confirmed by macroscopic evaluation. Histological evaluation confirmed that nerve stumps protected with the ESJ showed less fibrosis and presented well-organized axonal structure. Neural/connective tissue ratio and retrograde neuronal labeling analysis revealed significantly improved results in the ESJ group compared to the control nerve stump group (P = 0.032 and P = 0.042, respectively). CONCLUSIONS: The protective effect of the ESJ against neuroma formation was confirmed by behavioral and histological analyses, showing outcomes comparable to the muscle burying technique-the criterion standard of neuroma management. PMID- 28570462 TI - Visualization of Accessory Lymphatic Pathways in Secondary Upper Extremity Lymphedema Using Indocyanine Green Lymphography. AB - INTRODUCTION: The anatomical variations in accessory lymphatic pathways around the axillary region may work as a drainage route for excess lymphatic fluid accumulation in secondary upper extremity lymphedema. In this report, accessory lymphatic pathways extending to the shoulder, neck, and breast regions in secondary upper extremity lymphedema patients are shown using indocyanine green (ICG) lymphography. PATIENTS AND METHODS: Between January 2012 and May 2015, 30 limbs of 29 patients with upper extremity lymphedema after malignant tumor resection were evaluated. ICG lymphography was performed after chronic lymphedema formation. RESULTS: Of the 30 limbs, accessory lymphatic pathways were identified across the axillary region in 3 patients using ICG lymphography. In 2 of these 3 patients, accessory drainage lymphatics were connected to the cervical lymph nodes. In regard to the distribution of dermal backflow patterns, dermal backflow appeared in 26 patients-in the forearm in 26 patients and in the upper arm in 20 patients. CONCLUSIONS: Accessory lymphatic pathways are thought to be the drainage routes in the affected arm, which may prevent edema progression to the terminal stage. Variations in the lymphatic system are easily visualized using ICG lymphography. Understanding of accessory lymphatic routes in lymphedema patients may provide new insight for further understanding the pathophysiology of lymphedema. PMID- 28570463 TI - Does the Sequence of Tattooing and Nipple Reconstruction Affect Nipple Projection? AB - BACKGROUND: In nipple reconstruction, the maintenance of adequate projection is one of the most important and challenging aspects. However, no reports have evaluated whether tattooing after nipple reconstruction affects nipple projection. This study aimed to test our hypothesis that tattooing after reconstruction adversely affects nipple projection. METHOD: Between September 2001 and July 2009, 384 nipples were reconstructed using the modified top hat technique after breast reconstruction with a transverse rectus abdominis musculocutaneous flap. Of these, 320 were reconstructed before tattooing, and 64 were reconstructed after tattooing. Projection at 6 months and 1 year was compared with that measured immediately after the operation, and projection was compared between the nipples reconstructed after tattooing and those reconstructed before tattooing. RESULTS: After 6 months, the mean loss of projection was 52.5% in the tattoo-after group and 55.1% in the tattoo-before group. After 1 year, it was 59.2% in the tattoo-after group and 58.6% in the tattoo-before group. There were no significant differences between the groups regarding the sequence of the procedures. The additional tattoo and retattoo rate was 20% in the tattoo-before group and 1% in the tattoo-after group. CONCLUSIONS: These findings showed that the sequence of nipple reconstruction and tattooing had no significant effect on the projection of the reconstructed nipple. It is easier to tattoo homogeneously before nipple reconstruction because of the flat surface but more difficult to make a smooth areolar peripheral margin and circular areolar shape when reconstructing the nipple. The sequence of tattooing and nipple reconstruction can be determined according to esthetic and clinical considerations. PMID- 28570464 TI - Analysis of Mechanical Behavior of Dermal Fibroblasts Obtained From Various Anatomical Sites in Humans. AB - PURPOSE: Facial skin fibroblasts imposed with cyclic stretch at 10% magnitude display considerable mechanotransduction properties and biochemical reactions in our previous study. However, it is poorly understood how these shared traits are fully parallel to the common features across all fibroblasts derived from different skin-based anatomical regions in response to cyclic stretch stimulation. Thus, the purpose of this study was to evaluate the effects of various cyclic stretches on fibroblasts derived from multiple anatomical skin sites of human bodies, and the optimal stretch magnitude was defined based on the changes to cell mechanical behavior. METHODS: Fibroblasts from skin areas of the scalp, anterior chest, suprapubic, axilla, and planta were cultured and characterized in vitro. Cyclic stretch at 0%, 5%, 10%, 15%, and 20% magnitudes was imposed at a loading frequency of 0.1 Hz for 48 hours, and thereafter, the mechanical behavior and biochemical reaction of the dermal fibroblasts were analyzed. RESULTS: Dermal fibroblasts from various anatomical sites preconditioned with varying cyclic stretch led to an evident increase in the cell proliferation ability, the expression of integrin beta1 and p130 Crk-associated substrate messenger RNA and protein, and the productions of type I collagen and transforming growth factor beta1, most importantly in a strain magnitude dependent manner with the peak appearing in the range of 10% to 15% magnitude cyclic stretch. CONCLUSIONS: These findings may facilitate the subsequent studies on the conversion of normal skin fibroblasts into hypertrophic scar cells, which should be considered in an interpretation of the mechanisms of hypertrophic scarring and skin mechanics. PMID- 28570465 TI - Shared Medical Appointments for Adolescent Breast Reduction. AB - Adolescents with macromastia face serious physical, emotional, and social burdens because of their large breast size. Studies have shown that reduction mammoplasty results in improvement in physical symptoms and quality of life for these patients. Shared medical appointments (SMAs), defined as individual patient physician encounters that occur in a group setting, have been successfully applied to clinics for adult patients seeking breast reduction for this condition. We decided to apply the SMA model to our clinic for preoperative evaluation of adolescent patients with macromastia. The purpose of this article is to describe how our clinic implemented SMAs, evaluate changes in clinic efficiency, measure patient quality of life before surgery, and assess patient and provider satisfaction with the SMA model.From February to June 2016, our department instituted SMAs for preoperative evaluation of female adolescent patients with macromastia. We measured days from referral to appointment for 25 patients who attended SMAs and compared this with a retrospective cohort of 21 patients who attended traditional visits from 2013 to 2015.Clinic efficiency was measured in new patients per hour. During SMAs, we also administered the BREAST Q, Pediatric Quality of Life Inventory, and patient and provider satisfaction surveys. Mean days between referral and office visit was reduced from 75.3 with traditional visits to 40.3 with shared appointments, although this finding was not statistically significant (P = 0.69). New patients per hour increased from 1.33 with traditional visits to 3 with SMAs, without reducing time spent on education or with the surgeon. The mean preoperative BREAST-Q scores were less than 40 for the 4 tested domains, and the mean (SD) total Pediatric Quality of Life Inventory score was 56.7 (14.8). Patients and the provider reported high satisfaction with SMAs, and the provider wishes to continue using SMAs in the clinic.In conclusion, SMAs resulted in high patient and provider satisfaction and increased clinic efficiency, without sacrificing time spent on education or with the surgeon. Low quality-of-life scores demonstrate a need for these patients to be evaluated and treated for their condition. Measuring patient-reported outcomes with validated surveys and improving clinic efficiency without sacrificing patient care have the potential to increase value at our institution. PMID- 28570466 TI - Risk Factors for Urethrocutaneous Fistula Repair After Hypospadias Surgery: A Retrospective Study. AB - OBJECTIVES: We review our experience in urethrocutaneous fistula (UCF) repair after hypospadias surgery to investigate the risk factors for unsuccessful outcome. METHODS: Two hundred eleven patients had undergone UCF repair in our department from January 2005 to December 2015. This study included 185 patients who were followed up for more than 6 months. The age of patients, size, site and number of UCFs, number of UCF repairs, urethral complications other than UCF, and postoperative infection were included as potential risk factors. Binary logistic regression analysis was used for multivariate analysis. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated. Stratified analysis and assessment of additive interaction were performed to have a better understanding of the relation between the risk factors. RESULTS: Urethrocutaneous fistula repairs failed in 38 patients (20.5%) at first attempt. In the univariate analysis, size of UCFs (P = 0.012), times of UCF repair (P = 0.008), and postoperative infection (P = 0.044) were statistically related with the outcome of surgery. In the multivariate analysis, only the size of UCFs (P = 0.030; adjusted OR, 2.42; 95% CI, 1.09-5.36) and times of repair (P = 0.008; adjusted OR, 3.09; 95% CI, 1.35 7.07) were identified as risk factors for unsuccessful outcome. We had consistent results in the stratified analysis. No additive or multiplicative interaction between the 2 risk factors was found. CONCLUSIONS: Our study suggested that UCF repairs after hypospadias surgery were easier to fail if one of the UCFs was larger than 2 mm or it had been repaired repeatedly. But when both factors existed, the increase of the risk was not statistically significant. The age of patients, site and number of UCFs, complications other than UCF, and postoperative infection were not significantly related to the success rate of UCF repair. PMID- 28570470 TI - Advances in Aesthetic Therapies: Plasma-Rich Protein Procedure for the Treatment of Alopecia. AB - Predominance of aesthetic options is growing and evolving to include procedures that have traditionally been much more invasive and fiscally challenging for the average patient. It is not uncommon now for the Canadian consumers to begin to look for lesser invasive options that show results significant enough to improve their appearance but that may not fall under the traditional health care coverage. One area that is evolving quickly is the nonsurgical treatment of hair loss. This is not a new condition, but generally the methods of treatment are not under the current health coverage; therefore, consumers are paying out of pocket to reduce or replace their hair loss. Recently, more options have evolved, and utilizing platelet-rich plasma has become more prevalent as a method to support hair growth and prevent hair loss. PMID- 28570471 TI - Vaginal Health and Wellness: Vaginal Laser Therapy. PMID- 28570472 TI - A Recipe for Improved Nonsurgical Cosmetic Outcomes: Know Your Herbs and Spices. AB - The nonsurgical cosmetic arena continues to grow, with more people consistently seeking minimally invasive procedures for facial rejuvenation. However, although these prospective patients are not seeking surgical correction to obtain their results, there is still the potential for nonsurgical procedures to yield adverse events posttreatment. Patients often do not realize that their dietary regimens may affect their nonsurgical cosmetic outcomes. For example, many patients desiring these types of treatments are often found to be taking prescription medications, herbs, and spices on a daily basis that may have the capacity to potentiate adverse outcomes such as bleeding and/or bruising. For these reasons, it is important for clinicians to be inclusive while taking health histories and to properly educate their patients so that administered treatments have the best chance of yielding the desired results. The focus of this article is to provide health care providers information on many of the herbs and spices that have the potential to negatively impact nonsurgical cosmetic outcomes. PMID- 28570473 TI - Evaluating Long-Term Outcomes following Nipple-Sparing Mastectomy and Reconstruction in the Irradiated Breast. PMID- 28570474 TI - Acellular Dermal Matrix for the Treatment and Prevention of Implant-Associated Breast Deformities. PMID- 28570475 TI - How to Write a Journal Article for PSN. AB - Are you considering writing a journal article for Plastic Surgical Nursing? This official journal of the American Society of Plastic Surgical Nurses presents the latest advances in plastic and reconstructive surgical nursing practice. The journal features clinical articles covering a wide variety of surgical and nonsurgical procedures. Patient education techniques and research findings are also included, as well as articles discussing the ethical issues and trends in this expanding clinical nursing specialty. This is a perfect forum to share your knowledge with others in the plastic surgery field, resulting in improved patient care. The editorial board is established and available to assist you in the writing process. It is important to know that you do not have to be an academic scholar to write an article; instead, you have information that you would like to share. This article is intended to provide key points to follow to make sure that writing your article is a positive experience. PMID- 28570479 TI - Sensitization of C-fiber nociceptors in mice with sickle cell disease is decreased by local inhibition of anandamide hydrolysis. AB - Chronic pain and hyperalgesia, as well as pain resulting from episodes of vaso occlusion, are characteristic features of sickle cell disease (SCD) and are difficult to treat. Since there is growing evidence that increasing local levels of endocannabinoids can decrease hyperalgesia, we examined the effects of URB597, a fatty acid amide hydrolase (FAAH) inhibitor, which blocks the hydrolysis of the endogenous cannabinoid anandamide, on hyperalgesia and sensitization of cutaneous nociceptors in a humanized mouse model of SCD. Using homozygous HbSS-BERK sickle mice, we determined the effects of URB597 on mechanical hyperalgesia and on sensitization of C-fiber nociceptors in vivo. Intraplantar administration of URB597 (10 MUg in 10 MUL) decreased the frequency of withdrawal responses evoked by a von Frey monofilament (3.9 mN bending force) applied to the plantar hind paw. This was blocked by the CB1 receptor antagonist AM281 but not by the CB2 receptor antagonist AM630. Also, URB597 decreased hyperalgesia in HbSS-BERK/CB2R sickle mice, further confirming the role of CB1 receptors in the effects produced by URB597. Electrophysiological recordings were made from primary afferent fibers of the tibial nerve in anesthetized mice. The proportion of Adelta- and C-fiber nociceptors that exhibited spontaneous activity and responses of C-fibers to mechanical and thermal stimuli were greater in HbSS-BERK sickle mice as compared to control HbAA-BERK mice. Spontaneous activity and evoked responses of nociceptors were decreased by URB597 via CB1 receptors. It is suggested that enhanced endocannabinoid activity in the periphery may be beneficial in alleviating chronic pain associated with SCD. PMID- 28570481 TI - The relationship of sociodemographic and psychological variables with chronic pain variables in a low-income population. AB - Chronic pain is a pervasive condition that is complicated by economic, educational, and racial disparities. This study analyzes key factors associated with chronic pain within an understudied and underserved population. The sample is characterized by a triple disparity with respect to income, education/literacy, and racial barriers that substantially increase the vulnerability to the negative consequences of chronic pain. The study examined the pretreatment data of 290 participants enrolled in the Learning About My Pain trial, a randomized controlled comparative effectiveness trial of psychosocial interventions (B.E.T., Principal Investigator, Patient-Centered Outcomes Research Institute Contract No. 941; clinicaltrials.gov identifier NCT01967342) for chronic pain. Hierarchical multiple regression analyses evaluated the relationships among sociodemographic (sex, age, race, poverty status, literacy, and education level) and psychological (depressive symptoms and pain catastrophizing) variables and pain interference, pain severity, and disability. The indirect effects of depressive symptoms and pain catastrophizing on the sociodemographic and pain variables were investigated using bootstrap resampling. Reversed mediation models were also examined. Results suggested that the experience of chronic pain within this low-income sample is better accounted for by psychological factors than sex, age, race, poverty status, literacy, and education level. Depressive symptoms and pain catastrophizing mediated the relationships between age and pain variables, whereas pain catastrophizing mediated the effects of primary literacy and poverty status. Some reversed models were equivalent to the hypothesized models, suggesting the possibility of bidirectionality. Although cross-sectional findings cannot establish causality, our results highlight the critical role psychological factors play in individuals with chronic pain and multiple health disparities. PMID- 28570480 TI - Sequential analysis of child pain behavior and maternal responses: an observational study. AB - This laboratory-based study examined lagged associations between child pain behavior and maternal responses as a function of maternal catastrophizing (CAT). Mothers completed the parent version of the Pain Catastrophizing Scale. Children participated in a validated water ingestion procedure to induce abdominal discomfort with mothers present. Video recordings of their interactions were edited into 30-second segments and coded by 2 raters for presence of child pain behavior, maternal solicitousness, and nontask conversation. Kappa reliabilities ranged from 0.83 to 0.95. Maternal CAT was positively associated with child pain behavior and maternal solicitousness, P values <0.05. In lagged analyses, child pain behavior during a given segment (T) was positively associated with child pain behavior during the subsequent segment (T + 1), P <0.05. Maternal CAT moderated the association between (1) child pain behavior at T and maternal solicitousness at T + 1, and (2) solicitousness at T and child pain behavior at T + 1, P values <0.05. Mothers higher in CAT responded solicitously at T + 1 irrespective of their child's preceding pain behavior, and their children exhibited pain behavior at T + 1 irrespective of the mother's preceding solicitousness. Mothers lower in CAT were more likely to respond solicitously at T + 1 after child pain behavior, and their children were more likely to exhibit pain behavior at T + 1 after maternal solicitousness. These findings indicate that high CAT mothers and their children exhibit inflexible patterns of maternal solicitousness and child pain behavior, and that such families may benefit from interventions to decrease CAT and develop more adaptive responses. PMID- 28570483 TI - The Efficacy of Superior Inverted Internal Limiting Membrane Flap Technique for the Treatment of Full-Thickness Macular Hole. PMID- 28570484 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FEATURES OF CHOROIDAL NEOVASCULARIZATION ASSOCIATED WITH CHOROIDAL NEVUS. AB - PURPOSE: To describe the imaging features of choroidal neovascularization (CNV) associated with choroidal nevus using optical coherence tomography angiography (OCT-A) imaging. METHODS: Retrospective observational case series. Patients with CNV secondary to choroidal nevus underwent full imaging examination including fundus photography, fluorescein angiography, indocyanine green angiography, spectral domain OCT, and OCT-A. The OCT-A features were analyzed and correlated with conventional angiography findings and spectral domain OCT. RESULTS: There were 11 eyes from 11 patients (6 men and 5 women, mean age of 65 +/- 20.4 years) included in the analysis. Fluorescein angiography and indocyanine green angiography disclosed CNV in 90% and 83%, respectively. Optical coherence tomography angiography displayed CNV network in 11 eyes (100%) and the pattern was classified as "sea-fan" in 8 (73%) and "long filamentous linear vessels" in 3 (27%) eyes. Distinct from CNV, intrinsic vasculature within the nevus was observed in six eyes (55%), corresponding to those with chronic retinal pigment epithelium changes. CONCLUSION: Optical coherence tomography angiography is a useful imaging technique to disclose CNV associated with choroidal nevus. Despite the presence of intraretinal or subretinal fluid and hemorrhage, OCT-A revealed the CNV in all cases, results noninferior to indocyanine green angiography. This imaging modality can be useful for analysis of long-standing nevi with related exudation. PMID- 28570482 TI - Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation. AB - Metastatic bone pain is the single most common form of cancer pain and persists as a result of peripheral and central inflammatory, as well as neuropathic mechanisms. Here, we provide the first characterization of sphingolipid metabolism alterations in the spinal cord occurring during cancer-induced bone pain (CIBP). Following femoral arthrotomy and syngenic tumor implantation in mice, ceramides decreased with corresponding increases in sphingosine and the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P). Intriguingly, de novo sphingolipid biosynthesis was increased as shown by the elevations of dihydro-ceramides and dihydro-S1P. We next identified the S1P receptor subtype 1 (S1PR1) as a novel target for therapeutic intervention. Intrathecal or systemic administration of the competitive and functional S1PR1 antagonists, TASP0277308 and FTY720/Fingolimod, respectively, attenuated cancer-induced spontaneous flinching and guarding. Inhibiting CIBP by systemic delivery of FTY720 did not result in antinociceptive tolerance over 7 days. FTY720 administration enhanced IL-10 in the lumbar ipsilateral spinal cord of CIBP animals and intrathecal injection of an IL-10 neutralizing antibody mitigated the ability of systemic FTY720 to reverse CIBP. FTY720 treatment was not associated with alterations in bone metabolism in vivo. Studies here identify a novel mechanism to inhibit bone cancer pain by blocking the actions of the bioactive metabolites S1P and dihydro S1P in lumbar spinal cord induced by bone cancer and support potential fast-track clinical application of the FDA-approved drug, FTY720, as a therapeutic avenue for CIBP. PMID- 28570485 TI - RISK FACTORS FOR RECURRENCES OF CENTRAL SEROUS CHORIORETINOPATHY. AB - PURPOSE: To describe recurrence patterns and investigate candidate risk factors for recurrences of central serous chorioretinopathy. METHODS: In 46 patients with acute central serous chorioretinopathy and follow-up >12 months after first episode resolution, parameters influencing recurrences were retrospectively evaluated using a frailty Cox proportional hazard survival model. Covariates included baseline systemic findings: age, gender, corticosteroid use, stress, shift work, sleep disorder, depression, allergy, cardiovascular risk; baseline optical coherence tomography findings: subfoveal choroidal thickness, pigment epithelial detachment pattern (regular/bump/irregular), number of subretinal hyperreflective foci at leakage site; baseline angiographic findings: fluorescein leakage intensity (intense/moderate/subtle/absent), hyperpermeability pattern on indocyanine-green angiography (focal/multifocal); and episode-related findings: duration and treatment of previous episode. RESULTS: Twenty of 46 subjects (43%) presented >=1 recurrences during a mean follow-up of 29.9 +/- 9.5 months (range, 15-54 months). Follow-up duration did not differ between cases with or without recurrences (P = 0.3). Worse final visual acuity levels (logarithm of the minimal angle of resolution) were associated with a higher number of episodes during follow-up (P = 0.032, r = 0.28). In a univariate analysis, higher subfoveal choroidal thickness (P = 0.021), nonintense fluorescein leakage (= moderate/subtle/absent, P = 0.033), multiple subretinal hyperreflective foci (P = 0.026), and shift work (P < 0.0001) were significantly associated with recurrences, with a near-significant influence of irregular pigment epithelial detachment (P = 0.093). In a multivariate analysis, higher subfoveal choroidal thickness (P = 0.007), nonintense fluorescein leakage (P = 0.003) and shift work (P < 0.0001) remained significant and independent risk factors for recurrences. CONCLUSION: Multiple factors influence the risk of central serous chorioretinopathy recurrence. These findings may contribute to identify patients at higher risk, who could benefit from earlier or more intensive treatment. PMID- 28570486 TI - HANDHELD SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY IMAGING THROUGH THE UNDILATED PUPIL IN INFANTS BORN PRETERM OR WITH HYPOXIC INJURY OR HYDROCEPHALUS. AB - PURPOSE: The authors investigated feasibility of undilated handheld spectral domain optical coherence tomography (SDOCT) retinal imaging in preterm infants and children with neurologic abnormalities. METHODS: Under an institutional review board-approved protocol, the authors attempted handheld SDOCT imaging of the retina, choroid, and optic nerve in infants and young children without pupil dilation. Scans were analyzed for quality and successful capture of foveal, optic nerve, and retinal structural parameters and abnormalities. RESULTS: The authors obtained images through an undilated pupil of 11 infants/children over 28 eye imaging sessions, 27 at the bedside without sedation, and one under anesthesia. Infants had retinopathy of prematurity (n = 8), hypoxic ischemic encephalopathy (n = 2), or obstructive hydrocephalus (n = 1 child). Pupil sizes ranged from 1.0 mm to 3.5 mm. The authors captured fovea and optic nerve scans in 25/28 eye imaging sessions, with scans of adequate quality to discern prespecified foveal and optic nerve morphology, and of the 25 sessions, the choroidal-scleral junction was visible in all but 6 sessions. CONCLUSION: Undilated, handheld SDOCT imaging is a potential alternative method to evaluate the retina and optic nerve in patients with relative contraindication to pharmacological pupil dilation. This approach will enable the study of the eye-brain connection and ocular manifestations of neurologic diseases. PMID- 28570487 TI - Stopping the Resuscitation When Family Is Present: Teaching Ethical and Professional Challenges. PMID- 28570488 TI - Experience of Simulation-Based Training in a Developing Country. PMID- 28570489 TI - Possible Hormone Predictors Of Physical Performance In Adolescent Team Sport Athletes. AB - The research aim of this study was to determine possible hormone predictors of physical performance in adolescent team sport athletes. Saliva samples were collected immediately prior to performance testing sessions from 114 state squad athletes (77 male, 37 female) participating in either Australian football, basketball, hockey, or netball. Participants completed tests of aerobic and anaerobic capacity, agility, power and speed. Samples were collected over 22 months at quarterly, six-monthly and/or yearly intervals depending on the testing schedule of the athlete. Saliva was analysed for testosterone (T), cortisol (C), estradiol (E) and progesterone (P) levels. A strong negative correlation existed between multistage fitness test performance and T:E ratio (r=-0.76, p=0.01) in females not taking oral contraceptives and a strong positive correlation existed between repeat agility total time and estradiol levels (r=-0.71, p=0.001) in females taking oral contraceptives. In males, strong negative correlations were evident for individual changes in planned agility time and estradiol levels (r=0.87, p=0.02), and CMJ height and T:C (r=-0.88, p=0.01). In females taking oral contraceptives a strong positive correlation was noted between individual change in yo-yo intermittent recovery test performance and T:E (r=0.74, p=0.01) and a strong negative correlation was noted between 20m speed and T:P (r=0.73, p=0.01). In females not taking oral contraceptives a strong negative correlation was found between individual change in CMJ height and T:P (r=-0.72, p=0.02). The findings show that in adolescent team sport athletes the P:E, T:E and the T:P ratios are important predictors of performance in tests of physical capacity. The findings also indicate estradiol and progesterone have a predictive function in the physical performance of adolescent male team sport athletes. PMID- 28570490 TI - A Review of the Biomechanical Differences Between the High-Bar and Low-Bar Back Squat. AB - Glassbrook, DJ, Helms, ER, Brown, SR, and Storey, AG. A review of the biomechanical differences between the high-bar and low-bar back-squat. J Strength Cond Res 31(9): 2618-2634, 2017-The back-squat is a common exercise in strength and conditioning for a variety of sports. It is widely regarded as a fundamental movement to increase and measure lower-body and trunk function, as well as an effective injury rehabilitation exercise. There are typically 2 different bar positions used when performing the back-squat: the traditional "high-bar" back squat (HBBS) and the "low-bar" back-squat (LBBS). Different movement strategies are used to ensure that the center of mass remains in the base of support for balance during the execution of these lifts. These movement strategies manifest as differences in (a) joint angles, (b) vertical ground reaction forces, and (c) the activity of key muscles. This review showed that the HBBS is characterized by greater knee flexion, lesser hip flexion, a more upright torso, and a deeper squat. The LBBS is characterized by greater hip flexion and, therefore, a greater forward lean. However, there are limited differences in vertical ground reaction forces between the HBBS and LBBS. The LBBS can also be characterized by a greater muscle activity of the erector spinae, adductors, and gluteal muscles, whereas the HBBS can be characterized by greater quadriceps muscle activity. Practitioners seeking to develop the posterior-chain hip musculature (i.e., gluteal, hamstring, and erector muscle groups) may seek to use the LBBS. In comparison, those seeking to replicate movements with a more upright torso and contribution from the quadriceps may rather seek to use the HBBS in training. PMID- 28570491 TI - Effects of a 6-Week Upper Extremity Low-Volume, High Intensity Interval Training on Oxygen Uptake, Peak Power Output and Total Exercise Time. AB - The purpose of this study was to compare the effects of upper extremity (UE) high intensity interval training (HIIT) to UE continuous training (CT) when training at a similar intensity. 20 participants (mean age = 23 +/- 3 yrs) were randomly assigned to either a HIIT (n = 10) or CT (n = 10) group. Participants completed a graded exercise test utilizing arm cranking prior to and following 6 wks (2 sessions . wk-1) of UE training. During sessions, HIIT performed 10 repetitions of 60 s of work at 92.3 +/- 1.0% of the arm HRpeak (%aHRpeak) and 60 s of passive recovery (%aHRpeak = 73.0 +/- 4.0%) yielding an average training intensity of 82.6 +/- 1.5 %aHRpeak. CT exercised for 20 min. at an average intensity of 81.9 +/- 2.2 %aHRpeak. Following training HIIT showed greater improvement in V[Combining Dot Above]O2peak compared to CT (Delta = 4.1 ml . min-1 . kg-1, 95%CI: 1.3 - 6.9 ml . min-1 . kg-1, p = .007). Total exercise time during the post-test GXT was also improved as a result of HIIT (Delta = 1.4 min, 95%CI: 0.4 2.3 min, p = .008). Both groups improved peak power output, but no difference was observed between them (Delta = 3.3 W, 95%CI: -3.3 - 9.9 W, p = .305). For a similar time investment, HIIT appeared to improve cardiopulmonary capacity and exercise time to a greater extent than CT and may be a time-efficient alternative for those who incorporate UE aerobic activity into a training program. PMID- 28570492 TI - Estimation of peak muscle power from a countermovement vertical jump in children and adolescents. AB - Several equations to predict muscle power (MP) from vertical jump height (VJH) have been developed in adults. However, few have been derived in children. We therefore aimed to: 1) evaluate the validity of existing MP estimation equations from a vertical countermovement jump (CMJ) in children and adolescents, and 2) develop and validate a new MP estimation equation for use in children and adolescents. We measured peak MP (Watts) and VJH (cm) during a CMJ using a force platform in 249 children and adolescents (9-17 years; 119 boys). We compared actual (force platform) to predicted (twelve existing prediction equations) MP using repeated measures ANOVA and estimated bias using modified Bland-Altman plots. We developed a new prediction equation using stepwise linear regression, assessed predictive error using leave-one-out and ten-fold cross-validation and externally validated the equation in an independent sample (n=100). All existing prediction equations demonstrated some degree of bias, either systematic bias (mean differences ranging 178 W to 1377 W; 8%-64%), bias at the extremes or interactions with sex. Our new prediction equation estimates MP from VJH and body mass: Power (W) = 54.2*VJH(cm) + 34.4*body mass(kg) - 1520.4. With this new equation, there was no difference between actual and predicted MP (0%) and negligible differences (0.2-0.9%) in R and root mean square error between our observed and cross-validated sets. Actual and predicted MP were not different in our external validation (p=0.12). The new equation demonstrates excellent validity and can be used to predict MP from a CMJ in children and adolescents. PMID- 28570493 TI - Effects of intra-cyclic velocity variations on the drag exerted by different swimming parachutes. AB - Swimming parachutes are often used as a tool for resisted swimming training. However, little is known on their behavior in terms of exerted drag as a consequence of intra-cyclic velocity fluctuations. This study aimed to assess the drag provided by two swimming parachutes of different shape, also characterized by different volumes and cross-sectional areas, under conditions of velocity variations in the range of those occurring in swimming. A flat square shaped parachute (FLAT, cross-sectional area and volume: 400 cm; 0.12 l) and a truncated cone shaped parachute (CONE, 380 cm; 7.15 l) were passively towed: 1) at constant velocities ranging from 1.0 to 2.2 m/s, and 2) with velocity fluctuations from 10 to 40 % around a mean of 1.6 m/s. At constant velocities, FLAT showed 0.1 N (at 1.0 m/s) to 10.8 N (at 2.2 m/s) higher drag than CONE. For both parachutes, the average drag showed trivial differences between constant and any fluctuating velocity. Conversely, the maximum drag values were higher under conditions of velocity fluctuations than the respective values estimated under stationary instantaneous velocity, although this was observed in CONE only. These findings suggest that swimmers and coaches can select the parachute characteristics based on whether the focus is on increasing/decreasing the average drag or regulating the maximum resistance provided. PMID- 28570494 TI - Endurance Running Training Individually-Guided By Hrv In Untrained Women. AB - The aim of this study was to analyze the effects of HRV-guided training compared to a standardized prescription on i) time to complete 5-km running performance (t5km), ii) peak treadmill running speed (Vpeak) and its time limit (tlim at Vpeak), and iii) autonomic cardiac modulation (i.e., parasympathetic activity and recovery) in untrained women. Additionally, we correlated changes in t5km with changes in Vpeak, tlim at Vpeak and autonomic cardiac modulation. Thirty-six untrained women were divided into a HRV-guided training group (HRVG) and a control group (CG). The CG followed a pre-defined program, alternating moderate intensity continuous training (MICT) and high-intensity interval training (HIIT). The determination of MICT or HIIT was based on the pre-training HRV for HRVG. MICT was performed if HRV was < mean - 1 SD of previous measures. Otherwise, HIIT was prescribed. The t5km, Vpeak, tlim at Vpeak, parasympathetic activity (i.e., rMSSD) and parasympathetic reactivation (i.e., HRR) were measured before and after the training period. The t5km decreased to a greater magnitude in the HRVG (-17.5+/-5.6% vs. -14+/-4.7%; Effect Size (ES) between-group difference=moderate). rMSSD and tlim at Vpeak only improved in HRVG (+23.3+/ 27.8% and +23.6+/-31.9%, respectively). The HRVG experienced greater improvements in Vpeak and HRR (Vpeak: 10+/-7.3% vs. 8.2+/-4.7%; HRR: 19.1+/-28.1% vs. 12.6+/ 12.9%; ES between-group difference=small). Although HRVG performed less MICT than CG, the volume of MICT was negatively related to changes in t5km. Vpeak changes were highly correlated with t5km changes. The greater improvements in HRVG for t5km and autonomic modulation reinforce the potential application of this tool. PMID- 28570495 TI - Power profiles of competitive and non-competitive mountain bikers. AB - The performance of Olympic distance cross-country mountain bikers (XCO-MTB) is affected by constraints such as erosion of track surfaces and mass start congestion which can affect race results. Standardised laboratory assessments quantify inter-seasonal and intra-seasonal cycling potential through the assessment of multiple physiological capacities. Therefore, this study examined whether the power profile assessment could discriminate between competitive XCO MTB and non-competitive mountain bikers (NC-MTB). Secondly, it aimed to report normative power profile data for competitive XCO-MTB cyclists. Twenty-nine male participants were recruited across groups of XCO-MTB (n=14) and NC-MTB (n=15) mountain bikers. Each cyclist completed a power profile assessment that consisted of increasing duration maximal efforts (6, 15, 30, 60, 240 and 600 s) that were interspersed by longer rest periods (174, 225, 330, 480 and 600 s) between efforts. Normative power outputs were established for XCO-MTB cyclists ranging between 13.8 +/- 1.5 W.kg (5 s effort) to 4.1 +/- 0.6 W.kg (600 s effort). No differences in absolute peak power or cadence were identified between groups across any effort length (p>0.05). However, the XCO-MTB cyclists produced greater mean power outputs relative to body mass than the NC-MTB during the 60 s (6.9 +/- 0.8 vs 6.4 +/- 0.6 W.kg; p=0.002), 240 s (4.7 +/- 0.7 vs 3.8 +/- 0.4 W.kg; p<0.001) and 600 s (4.1 +/- 0.6 vs 3.4 +/- 0.3 W.kg; p<0.001) efforts. The power profile assessment is a useful discriminative assessment tool for XCO-MTB and highlights the importance of aerobic power for XCO-MTB performance. PMID- 28570496 TI - The Effect of Training Load Distribution on Aerobic Fitness Measures in Hurling Players. AB - The aim of the current investigation was to quantify the training intensity distribution of hurling players and their association to changes in aerobic fitness measures within hurling players. Thirty hurling players (n = 30; age 25.5 +/- 3.2 years; height 178.9 +/- 3.2 cm; body mass 78.5 30 +/- 4.5 kg) were observed during the pre-championship training period (12 weeks). Aerobic fitness measures (VO2max), peak treadmill velocity (PVT; km.h) and heart rates (HR) at 2 and 4 mmol.L blood-lactate concentrations, Yo-Yo intermittent recovery test performance (Yo-YoIR1) were assessed pre and post the training period. Training intensities were categorized using 3 individualised HR zones based on the following criteria: low intensity (<= HR 2 mmol.L), moderate intensity (between HR 2 and 4 mmol.L), and high intensity (>=HR 4 mmol.L). Analysis of 1025 individual training sessions showed that players spent 58.1 +/- 2.5%, 24.3 +/- 2.9% and 17.6 +/- 1.3% of time in the low, moderate and high intensity zones. The training time spent at high intensity (Zone 3) showed moderate to large associations with improvements in S2 (r = 0.80; p = 0.04) and S4 (r = 0.58; p = 0.03). Similar trends were observed for time spent in high intensity and improvements in VO2max (r = 0.77; p = 0.001) and Yo-YoIR1 performance (r = 0.65; p = 0.05). Hurling players have been shown to spend the majority of training time in low (<= HR 2 mmol.L) to moderate intensity (between HR 2 and 4 mmol.L) training. However, only the time spent at high intensity (>= 90% of maximal HR) was related to changes in aerobic fitness. These results support the usefulness of the quantification of aerobic training load using HR. The study also supports the efficacy of spending elements of training time within the high intensity zone in order to increase hurling player's aerobic fitness characteristics. PMID- 28570497 TI - A Time-Out Before Every ECT Procedure. PMID- 28570498 TI - Factors Associated With Global Variability in Electroconvulsive Therapy Utilization. AB - OBJECTIVES: The aims of this study were to investigate the social and economic factors that contribute to global variability in electroconvulsive therapy (ECT) utilization and to contrast these to the factors associated with antidepressant medication rates. METHODS: Rates of ECT and antidepressant utilization across nations and data on health, social, and economic indices were obtained from multiple international organizations including the World Health Organization and the Organization for Economic Co-operation and Development, as well as from the published literature. To assess whether relationships exist between selected indices and each of the outcome measures, a correlational analysis was conducted using Pearson correlation coefficients. Those that were significant at a level of P < 0.05 in the correlation analysis were selected for entry into the multivariate analyses. Selected predictor variables were entered into a stepwise multiple regression models for ECT and antidepressant utilization rates separately. RESULTS: A stepwise multiple regression analysis indicated that government expenditure on mental health was the only significant contributor to the model, explaining 34.2% of global variation in ECT use worldwide. Human Development Index was the only variable found to be significantly correlated with global antidepressant utilization, accounting for 71% of the variation in global antidepressant utilization. CONCLUSIONS: These findings suggest that across the globe ECT but not antidepressant medication utilization is associated with the degree to which a nation financially invests in mental health care for its citizens. PMID- 28570499 TI - Stable Remission of Multiple Chemical Sensitivity Syndrome and Major Depression With Citalopram and 1-Month Deep Transcranial Magnetic Stimulation: A Case Report. PMID- 28570500 TI - Concurrent Electroconvulsive Therapy and Bupropion Treatment. AB - BACKGROUND: Bupropion is associated with a dose-dependent increased risk of seizures. Use of concomitant bupropion and electroconvulsive therapy (ECT) remains controversial because of an increased risk of prolonged seizures. This is the first systematic evaluation of the effect of bupropion on ECT. METHODS: A case group (n = 119), patients treated with concomitant ECT and bupropion, was compared with an age and gender frequency-matched control group (n = 261), treated with only ECT. Electroconvulsive therapy treatment data including seizure length, number of treatments, and concurrent medications were extracted. Longitudinal mixed models examined ECT versus ECT + bupropion group differences over the course of treatments measured by seizure duration (electroencephalogram [EEG] and motor). Multivariable models examined the total number of treatments and first and last seizure duration. All models considered group differences with ECT treatment measures adjusted for age, gender, benzodiazepine treatment, lead placement, and setting. RESULTS: Electroconvulsive therapy treatment with bupropion led to shorter motor seizure duration (0.047) and EEG seizure duration (P = 0.001). The number of ECT treatments (7.3 vs 7.0 treatments; P = 0.23), respectively, or the probability of a prolonged seizure (P = 0.15) was not significantly different. Benzodiazepine use was significantly more common in control subjects (P = 0.01). LIMITATIONS: This is a retrospective analysis limited in part by unavailable variables (seizure threshold, nature of EEG and motor seizure monitoring, type of ECT device, dosing and formulation of bupropion, and duration of the current depressive illness). CONCLUSIONS: This study revealed a significantly shorter duration in seizure length with ECT + concomitant bupropion, but not in the number of required treatments in those treated compared with ECT without bupropion. There remains a critical need to reevaluate the efficacy of concomitant use of psychotropic medications + ECT. PMID- 28570502 TI - QuickStats: Age-Adjusted Rate* of Motor Vehicle Traffic Deaths,? by Urbanization of County of ResidenceS - 2005 and 2015. AB - The overall age-adjusted rate of motor vehicle traffic deaths in the United States decreased 25% from 14.6 deaths per 100,000 population in 2005 to 10.9 in 2015. During this period, the rate declined in each of the county groupings, with the largest decline of 26% in the large fringe metropolitan and micropolitan counties and the smallest decline of 20% in rural counties. For both years, the rates for motor vehicle traffic deaths were higher in nonmetropolitan areas than in metropolitan areas. In 2015, the age-adjusted rate in rural counties was nearly three times the rate for large central metropolitan counties (23.0 compared with 7.9 per 100,000). PMID- 28570501 TI - Estrogen Receptor Mediates the Radiosensitivity of Triple-Negative Breast Cancer Cells. AB - BACKGROUND This study aimed to evaluate differences in the radiosensitivities of triple-negative breast cancer (TNBC) and luminal-type breast cancer cells and to investigate the effects of estrogen receptor (ER) expression on the biological behaviors of the cells. MATERIAL AND METHODS Colony-forming assays were performed to detect differences in radiosensitivities in breast cancer cell lines. Gene transfection technology was used to introduce the expression of ERalpha in TNBC cells to compare the difference in radiosensitivity between the TNBC cells and ERalpha transfected cells. CCK-8 assays were used to observe changes in the proliferation of TNBC cells after ERalpha transfection. Immunofluorescence was used to detect the number of gammaH2AX foci in nuclei. Flow cytometry was used to detect changes in cell cycle distribution and apoptosis. Western blotting was used to detect changes in autophagy-associated proteins. RESULTS The radioresistance of the TNBC cell line MDA-MB-231 (231 cells) was greater than that of ERalpha-positive luminal-type breast cancer cell line MCF-7. Moreover, 231 cell proliferation and radioresistance decreased after ERalpha transfection. Interestingly, ERalpha-transfected 231 cells showed increased double-stranded breaks and delayed repair compared with 231 cells, and ERalpha-transfected 231 cells showed increased G2/M phase arrest and apoptosis after irradiation compared with those in 231 cells. ERalpha transfection in 231 cells reduced autophagy related protein expression, suggesting that autophagy activity decreased in 231 ER-positive cells after irradiation. CONCLUSIONS TNBC cells were more resistant to radiation than luminal-type breast cancer cells. ERalpha expression may have major roles in modulating breast cancer cell radiosensitivity. PMID- 28570503 TI - Notes from the Field: Veillonella Misidentified as Francisella tularensis - Idaho, 2016. PMID- 28570504 TI - Amanita phalloides Mushroom Poisonings - Northern California, December 2016. AB - Amanita phalloides, colloquially known as the "death cap," belongs to the Phalloideae section of the Amanita family of mushrooms and is responsible for most deaths following ingestion of foraged mushrooms worldwide (1). On November 28, 2016, members of the Bay Area Mycological Society notified personnel at the California Poison Control System (CPCS) of an unusually large A. phalloides bloom in the greater San Francisco Bay Area, coincident with the abundant rainfall and recent warm weather. Five days later, CPCS received notification of the first human A. phalloides poisoning of the season. Over the following 2 weeks, CPCS was notified of an additional 13 cases of hepatotoxicity resulting from A. phalloides ingestion. In the past few years before this outbreak, CPCS received reports of only a few mushroom poisoning cases per year. A summary of 14 reported cases is presented here. Data extracted from patient medical charts revealed a pattern of delayed gastrointestinal manifestations of intoxication leading to dehydration and hepatotoxicity. Three patients received liver transplants and all but one recovered completely. The morbidity and potential lethality associated with A. phalloides ingestion are serious public health concerns and warrant medical provider education and dissemination of information cautioning against consuming foraged wild mushrooms. PMID- 28570505 TI - Notice to Readers: Special Podcast: "Defining Moments in MMWR History - E. coli O157:H7". AB - MMWR has released a special podcast that highlights the leading role that MMWR played in reporting on the deadly multistate Escherichia coli O157:H7 foodborne outbreak of 1993. "Defining Moments in MMWR History - E. coli O157:H7" features an interview with Dr. Beth Bell conducted by MMWR Editor-in-Chief Dr. Sonja Rasmussen. Dr. Bell, who served as director of the National Center for Emerging and Zoonotic Infectious Diseases (NCEZID) from 2010 to 2017 and as an Epidemic Intelligence Service Officer during 1992-1994, was one of the first public health responders on the scene for this landmark public health emergency. PMID- 28570506 TI - Strategies for Preventing HIV Infection Among HIV-Uninfected Women Attempting Conception with HIV-Infected Men - United States. AB - By the end of 2014, a total of 955,081 persons in the United States (299.5 per 100,000 population) had received a diagnosis of human immunodeficiency virus type 1 (HIV-1) infection (1). The annual estimated number of HIV infections and incidence rate in the United States decreased from 2010 to 2014, and the survival rate has increased over time (1). Effective highly active antiretroviral therapy (HAART) is helping persons with HIV to live longer, healthier lives. Many of these persons, including an unknown percentage in discordant relationships (i.e., one partner is HIV-infected, and the other is HIV-uninfected), might wish to have their own biologic children. When the female partner is HIV-infected and the male partner is not, a discordant couple can undergo autologous sperm intrauterine inseminations to achieve conception without placing the man at risk for infection. However, for HIV-discordant couples in which the man is HIV-infected and the woman is not, strategies to minimize the risk for sexual transmission are needed. In 1988, CDC recommended against insemination with semen from HIV infected men (2). Since 1988, new information has emerged regarding prevention of HIV transmission in HIV-discordant couples. This report reviews laboratory and epidemiologic information regarding the prevention of HIV transmission for HIV discordant couples, in which the male is HIV-infected and the female is HIV uninfected, who would like to attempt conception. PMID- 28570508 TI - En Face Preparation of Mouse Blood Vessels. AB - Sections of paraffin embedded tissues are routinely used for studying tissue histology and histopathology. However, it is difficult to determine what the three-dimensional tissue morphology is from such sections. In addition, the sections of tissues examined may not contain the region within the tissue that is necessary for the purpose of the ongoing study. This latter limitation hinders histopathological studies of blood vessels since vascular lesions develop in a focalized manner. This requires a method that enables us to survey a wide area of the blood vessel wall, from its surface to deeper regions. A whole mount en face preparation of blood vessels fulfills this requirement. In this article, we will demonstrate how to make en face preparations of the mouse aorta and carotid artery and to immunofluorescently stain them for confocal microscopy and other types of fluorescence-based imaging. PMID- 28570507 TI - Trends in Prevalence of Advanced HIV Disease at Antiretroviral Therapy Enrollment - 10 Countries, 2004-2015. AB - Monitoring prevalence of advanced human immunodeficiency virus (HIV) disease (i.e., CD4+ T-cell count <200 cells/MUL) among persons starting antiretroviral therapy (ART) is important to understand ART program outcomes, inform HIV prevention strategy, and forecast need for adjunctive therapies.*,?,S To assess trends in prevalence of advanced disease at ART initiation in 10 high-burden countries during 2004-2015, records of 694,138 ART enrollees aged >=15 years from 797 ART facilities were analyzed. Availability of national electronic medical record systems allowed up-to-date evaluation of trends in Haiti (2004-2015), Mozambique (2004-2014), and Namibia (2004-2012), where prevalence of advanced disease at ART initiation declined from 75% to 34% (p<0.001), 73% to 37% (p<0.001), and 80% to 41% (p<0.001), respectively. Significant declines in prevalence of advanced disease during 2004-2011 were observed in Nigeria, Swaziland, Uganda, Vietnam, and Zimbabwe. The encouraging declines in prevalence of advanced disease at ART enrollment are likely due to scale-up of testing and treatment services and ART-eligibility guidelines encouraging earlier ART initiation. However, in 2015, approximately a third of new ART patients still initiated ART with advanced HIV disease. To reduce prevalence of advanced disease at ART initiation, adoption of World Health Organization (WHO)-recommended "treat all" guidelines and strategies to facilitate earlier HIV testing and treatment are needed to reduce HIV-related mortality and HIV incidence. PMID- 28570509 TI - Mapping RNA-RNA Interactions Globally Using Biotinylated Psoralen. AB - Knowing how RNAs interact with themselves and with others is key to understanding RNA based gene regulation in the cell. While examples of RNA-RNA interactions such as microRNA-mRNA interactions have been shown to regulate gene expression, the full extent to which RNA interactions occur in the cell is still unknown. Previous methods to study RNA interactions have primarily focused on subsets of RNAs that are interacting with a particular protein or RNA species. Here, we detail a method named Sequencing of Psoralen crosslinked, Ligated, and Selected Hybrids (SPLASH) that allows genome-wide capture of RNA interactions in vivo in an unbiased manner. SPLASH utilizes in vivo crosslinking, proximity ligation, and high throughput sequencing to identify intramolecular and intermolecular RNA base pairing partners globally. SPLASH can be applied to different organisms including bacteria, yeast and human cells, as well as diverse cellular conditions to facilitate the understanding of the dynamics of RNA organization under diverse cellular contexts. The entire experimental SPLASH protocol takes about 5 days to complete and the computational workflow takes about 7 days to complete. PMID- 28570510 TI - Simultaneous Isolation of High Quality Cardiomyocytes, Endothelial Cells, and Fibroblasts from an Adult Rat Heart. AB - The rat is an important animal model used in cardiovascular research, and rat cardiac cells are used routinely for in vitro analysis of the molecular mechanisms of cardiovascular disease progression such as cardiac hypertrophy, fibrosis, and atherosclerosis. Although several attempts with variable success have been made to develop immortalized cell lines from the cardiovascular system to understand these cellular mechanisms, primary cells offer a more natural and close to in vivo environment for such studies. Therefore, different laboratories working on a particular cell type have developed protocols to isolate individual types of rat cardiac cells of interest. A protocol that allows the isolation of more than one cell type, however, is missing. Here an optimized protocol is described that allows the isolation of high-quality major cardiac cell types (cardiomyocytes, endothelial cells, and fibroblasts) from a single preparation and enables their use for cellular analyses. This permits the most efficient use of available resources, which may save time and reduce research costs. PMID- 28570512 TI - Atomic Force Microscopy Investigations of DNA Lesion Recognition in Nucleotide Excision Repair. AB - AFM imaging is a powerful technique for the study of protein-DNA interactions. This single molecule method allows the simultaneous resolution of different molecules and molecular assemblies in a heterogeneous sample. In the particular context of DNA interacting protein systems, different protein complex forms and their corresponding binding positions on target sites containing DNA fragments can thus be distinguished. Here, an application of AFM to the study of DNA lesion recognition in the prokaryotic and eukaryotic nucleotide excision DNA repair (NER) systems is presented. The procedures of DNA and protein sample preparations are described and experimental as well as analytical details of the experiments are provided. The data allow important conclusions on the strategies by which target site verification may be achieved by the NER proteins. Interestingly, they indicate different approaches of lesion recognition and identification for the eukaryotic NER system, depending on the type of lesion. Furthermore, distinct structural properties of the two different helicases involved in prokaryotic and eukaryotic NER result in and explain the different strategies observed for these two systems. Importantly, these experimental and analytical approaches can be applied not only to the study of DNA repair but also very similarly to other DNA interacting protein systems such as those involved in replication or transcription processes. PMID- 28570511 TI - Ovine Lumbar Intervertebral Disc Degeneration Model Utilizing a Lateral Retroperitoneal Drill Bit Injury. AB - Intervertebral disc degeneration is a significant contributor to the development of back pain and the leading cause of disability worldwide. Numerous animal models of intervertebral disc degeneration have been developed. The ideal animal model should closely mimic the human intervertebral disc with regard to morphology, biomechanical properties and the absence of notochordal cells. The sheep lumbar intervertebral disc model fulfils these criteria. We present an ovine model of intervertebral disc degeneration utilizing a drill bit injury through a lateral retroperitoneal approach. The lateral approach significantly reduces the incision and potential morbidity associated with the traditional anterior approach to the ovine spine. Utilization of a drill-bit method of injury affords the ability to produce a consistent and reproducible injury, of precise dimensions, that initiates a consistent degree of intervertebral disc degeneration. The focal nature of the annular and nucleus pulposus defect more closely mimics the clinical condition of focal intervertebral disc herniation. Sheep recover rapidly following this procedure and are typically mobile and eating within the hour. Intervertebral disc degeneration ensues and sheep undergo necropsy and subsequent analysis at periods from eight weeks. We believe that the drill bit injury model of intervertebral disc degeneration offers advantages over more conventional annular injury models. PMID- 28570513 TI - Oligopeptide Competition Assay for Phosphorylation Site Determination. AB - Protein phosphorylation at specific sites determines its conformation and interaction with other molecules. Thus, protein phosphorylation affects biological functions and characteristics of the cell. Currently, the most common method for discovering phosphorylation sites is by liquid chromatography/mass spectrometry (LC/MS) analysis, a rapid and sensitive method. However, relatively labile phosphate moieties are often released from phosphopeptides during the fragmentation step, which often yields false-negative signals. In such cases, a traditional in vitro kinase assay using site-directed mutants would be more accurate, but this method is laborious and time-consuming. Therefore, an alternative method using peptide competition may be advantageous. The consensus recognition motif of 5' adenosine monophosphate-activated protein kinase (AMPK) has been established1 and was validated using a positional scanning peptide library assay2. Thus, AMPK phosphorylation sites for a novel substrate could be predicted and confirmed by the peptide competition assays. In this report, we describe the detailed steps and procedures for the in vitro oligopeptide competing kinase assay by illustrating AMPK-mediated nuclear factor erythroid 2 related factor 2 (Nrf2) phosphorylation. To authenticate the phosphorylation site, we carried out a sequential in vitro kinase assay using a site-specific mutant. Overall, the peptide competition assay provides a method to screen multiple potential phosphorylation sites and to identify sites for validation by the phosphorylation site mutants. PMID- 28570514 TI - Single-cell RNA-Seq of Defined Subsets of Retinal Ganglion Cells. AB - The discovery of cell type-specific markers can provide insight into cellular function and the origins of cellular heterogeneity. With a recent push for the improved understanding of neuronal diversity, it is important to identify genes whose expression defines various subpopulations of cells. The retina serves as an excellent model for the study of central nervous system diversity, as it is composed of multiple major cell types. The study of each major class of cells has yielded genetic markers that facilitate the identification of these populations. However, multiple subtypes of cells exist within each of these major retinal cell classes, and few of these subtypes have known genetic markers, although many have been characterized by morphology or function. A knowledge of genetic markers for individual retinal subtypes would allow for the study and mapping of brain targets related to specific visual functions and may also lend insight into the gene networks that maintain cellular diversity. Current avenues used to identify the genetic markers of subtypes possess drawbacks, such as the classification of cell types following sequencing. This presents a challenge for data analysis and requires rigorous validation methods to ensure that clusters contain cells of the same function. We propose a technique for identifying the morphology and functionality of a cell prior to isolation and sequencing, which will allow for the easier identification of subtype-specific markers. This technique may be extended to non-neuronal cell types, as well as to rare populations of cells with minor variations. This protocol yields excellent-quality data, as many of the libraries have provided read depths greater than 20 million reads for single cells. This methodology overcomes many of the hurdles presented by Single-cell RNA-Seq and may be suitable for researchers aiming to profile cell types in a straightforward and highly efficient manner. PMID- 28570515 TI - High-resolution Single Particle Analysis from Electron Cryo-microscopy Images Using SPHIRE. AB - SPHIRE (SPARX for High-Resolution Electron Microscopy) is a novel open-source, user-friendly software suite for the semi-automated processing of single particle electron cryo-microscopy (cryo-EM) data. The protocol presented here describes in detail how to obtain a near-atomic resolution structure starting from cryo-EM micrograph movies by guiding users through all steps of the single particle structure determination pipeline. These steps are controlled from the new SPHIRE graphical user interface and require minimum user intervention. Using this protocol, a 3.5 A structure of TcdA1, a Tc toxin complex from Photorhabdus luminescens, was derived from only 9500 single particles. This streamlined approach will help novice users without extensive processing experience and a priori structural information, to obtain noise-free and unbiased atomic models of their purified macromolecular complexes in their native state. PMID- 28570517 TI - Micro/Nano-scale Strain Distribution Measurement from Sampling Moire Fringes. AB - This work describes the measurement procedure and principles of a sampling moire technique for full-field micro/nano-scale deformation measurements. The developed technique can be performed in two ways: using the reconstructed multiplication moire method or the spatial phase-shifting sampling moire method. When the specimen grid pitch is around 2 pixels, 2-pixel sampling moire fringes are generated to reconstruct a multiplication moire pattern for a deformation measurement. Both the displacement and strain sensitivities are twice as high as in the traditional scanning moire method in the same wide field of view. When the specimen grid pitch is around or greater than 3 pixels, multi-pixel sampling moire fringes are generated, and a spatial phase-shifting technique is combined for a full-field deformation measurement. The strain measurement accuracy is significantly improved, and automatic batch measurement is easily achievable. Both methods can measure the two-dimensional (2D) strain distributions from a single-shot grid image without rotating the specimen or scanning lines, as in traditional moire techniques. As examples, the 2D displacement and strain distributions, including the shear strains of two carbon fiber-reinforced plastic specimens, were measured in three-point bending tests. The proposed technique is expected to play an important role in the non-destructive quantitative evaluations of mechanical properties, crack occurrences, and residual stresses of a variety of materials. PMID- 28570516 TI - Fiber Connections of the Supplementary Motor Area Revisited: Methodology of Fiber Dissection, DTI, and Three Dimensional Documentation. AB - The purpose of this study is to show the methodology for the examination of the white matter connections of the supplementary motor area (SMA) complex (pre-SMA and SMA proper) using a combination of fiber dissection techniques on cadaveric specimens and magnetic resonance (MR) tractography. The protocol will also describe the procedure for a white matter dissection of a human brain, diffusion tensor tractography imaging, and three-dimensional documentation. The fiber dissections on human brains and the 3D documentation were performed at the University of Minnesota, Microsurgery and Neuroanatomy Laboratory, Department of Neurosurgery. Five postmortem human brain specimens and two whole heads were prepared in accordance with Klingler's method. Brain hemispheres were dissected step by step from lateral to medial and medial to lateral under an operating microscope, and 3D images were captured at every stage. All dissection results were supported by diffusion tensor imaging. Investigations on the connections in line with Meynert's fiber tract classification, including association fibers (short, superior longitudinal fasciculus I and frontal aslant tracts), projection fibers (corticospinal, claustrocortical, cingulum, and frontostriatal tracts), and commissural fibers (callosal fibers) were also conducted. PMID- 28570518 TI - High Precision FRET at Single-molecule Level for Biomolecule Structure Determination. AB - A protocol on how to perform high-precision interdye distance measurements using Forster resonance energy transfer (FRET) at the single-molecule level in multiparameter fluorescence detection (MFD) mode is presented here. MFD maximizes the usage of all "dimensions" of fluorescence to reduce photophysical and experimental artifacts and allows for the measurement of interdye distance with an accuracy up to ~1 A in rigid biomolecules. This method was used to identify three conformational states of the ligand-binding domain of the N-methyl-D aspartate (NMDA) receptor to explain the activation of the receptor upon ligand binding. When comparing the known crystallographic structures with experimental measurements, they agreed within less than 3 A for more dynamic biomolecules. Gathering a set of distance restraints that covers the entire dimensionality of the biomolecules would make it possible to provide a structural model of dynamic biomolecules. PMID- 28570520 TI - Measuring Protein Binding to F-actin by Co-sedimentation. AB - Filamentous actin (F-actin) organization within cells is regulated by a large number of actin-binding proteins that control actin nucleation, growth, cross linking and/or disassembly. This protocol describes a technique - the actin co sedimentation, or pelleting, assay - to determine whether a protein or protein domain binds F-actin and to measure the affinity of the interaction (i.e., the dissociation equilibrium constant). In this technique, a protein of interest is first incubated with F-actin in solution. Then, differential centrifugation is used to sediment the actin filaments, and the pelleted material is analyzed by SDS-PAGE. If the protein of interest binds F-actin, it will co-sediment with the actin filaments. The products of the binding reaction (i.e., F-actin and the protein of interest) can be quantified to determine the affinity of the interaction. The actin pelleting assay is a straightforward technique for determining if a protein of interest binds F-actin and for assessing how changes to that protein, such as ligand binding, affect its interaction with F-actin. PMID- 28570519 TI - Whole-cell Patch-clamp Recordings for Electrophysiological Determination of Ion Selectivity in Channelrhodopsins. AB - Over the past decade, channelrhodopsins became indispensable in neuroscientific research where they are used as tools to non-invasively manipulate electrical processes in target cells. In this context, ion selectivity of a channelrhodopsin is of particular importance. This article describes the investigation of chloride selectivity for a recently identified anion-conducting channelrhodopsin of Proteomonas sulcata via electrophysiological patch-clamp recordings on HEK293 cells. The experimental procedure for measuring light-gated photocurrents demands a fast switchable - ideally monochromatic - light source coupled into the microscope of an otherwise conventional patch-clamp setup. Preparative procedures prior to the experiment are outlined involving preparation of buffered solutions, considerations on liquid junction potentials, seeding and transfection of cells, and pulling of patch pipettes. The actual recording of current-voltage relations to determine the reversal potentials for different chloride concentrations takes place 24 h to 48 h after transfection. Finally, electrophysiological data are analyzed with respect to theoretical considerations of chloride conduction. PMID- 28570521 TI - Histological Analyses of Acute Alcoholic Liver Injury in Zebrafish. AB - Alcoholic Liver Disease (ALD) refers to damage to the liver due to acute or chronic alcohol abuse. It is among the leading causes of alcohol-related morbidity and mortality and affects more than 2 million people in the United States. A better understanding of the cellular and molecular mechanisms underlying alcohol-induced liver injury is crucial for developing effective treatment for ALD. Zebrafish larvae exhibit hepatic steatosis and fibrogenesis after just 24 h of exposure to 2% ethanol, making them useful for the study of acute alcoholic liver injury. This work describes the procedure for acute ethanol treatment in zebrafish larvae and shows that it causes steatosis and swelling of the hepatic blood vessels. A detailed protocol for Hematoxylin and Eosin (H&E) staining that is optimized for the histological analysis of the zebrafish larval liver, is also described. H&E staining has several unique advantages over immunofluorescence, as it marks all liver cells and extracellular components simultaneously and can readily detect hepatic injury, such as steatosis and fibrosis. Given the increasing usage of zebrafish in modeling toxin and virus induced liver injury, as well as inherited liver diseases, this protocol serves as a reference for the histological analyses performed in all these studies. PMID- 28570522 TI - fMRI Mapping of Brain Activity Associated with the Vocal Production of Consonant and Dissonant Intervals. AB - The neural correlates of consonance and dissonance perception have been widely studied, but not the neural correlates of consonance and dissonance production. The most straightforward manner of musical production is singing, but, from an imaging perspective, it still presents more challenges than listening because it involves motor activity. The accurate singing of musical intervals requires integration between auditory feedback processing and vocal motor control in order to correctly produce each note. This protocol presents a method that permits the monitoring of neural activations associated with the vocal production of consonant and dissonant intervals. Four musical intervals, two consonant and two dissonant, are used as stimuli, both for an auditory discrimination test and a task that involves first listening to and then reproducing given intervals. Participants, all female vocal students at the conservatory level, were studied using functional Magnetic Resonance Imaging (fMRI) during the performance of the singing task, with the listening task serving as a control condition. In this manner, the activity of both the motor and auditory systems was observed, and a measure of vocal accuracy during the singing task was also obtained. Thus, the protocol can also be used to track activations associated with singing different types of intervals or with singing the required notes more accurately. The results indicate that singing dissonant intervals requires greater participation of the neural mechanisms responsible for the integration of external feedback from the auditory and sensorimotor systems than does singing consonant intervals. PMID- 28570524 TI - Comparing the Effects of Electronic Cigarette Vapor and Cigarette Smoke in a Novel In Vivo Exposure System. AB - Electronic cigarettes (E-cigarettes) are being widely used, and growing in popularity. It is estimated that more than 9 million adults use them regularly. The potential adverse health effects of electronic cigarette vapor (E-vapor) exposure are poorly defined. While several animal models of E-vapor exposure have been developed, few models expose rodents to clinically relevant quantities of nicotine and make direct comparisons to cigarette smoke within the same exposure system. Here, we present a method for constructing and operating an E-vapor chamber and cigarette smoke chamber. The chambers are constructed by outfitting anesthesia chambers with a computer controlled pumping system that delivers consistent amounts of E-vapor or cigarette smoke to rodents. Nicotine exposure is measured indirectly by quantifying pre and post-exposure serum cotinine levels. This exposure system can be modified to accommodate various types of E-cigarettes and tobacco cigarettes, and can be used to compare the effects of E-vapor and cigarette smoke in vivo. PMID- 28570523 TI - Cellular Redox Profiling Using High-content Microscopy. AB - Reactive oxygen species (ROS) regulate essential cellular processes including gene expression, migration, differentiation and proliferation. However, excessive ROS levels induce a state of oxidative stress, which is accompanied by irreversible oxidative damage to DNA, lipids and proteins. Thus, quantification of ROS provides a direct proxy for cellular health condition. Since mitochondria are among the major cellular sources and targets of ROS, joint analysis of mitochondrial function and ROS production in the same cells is crucial for better understanding the interconnection in pathophysiological conditions. Therefore, a high-content microscopy-based strategy was developed for simultaneous quantification of intracellular ROS levels, mitochondrial membrane potential (DeltaPsim) and mitochondrial morphology. It is based on automated widefield fluorescence microscopy and image analysis of living adherent cells, grown in multi-well plates, and stained with the cell-permeable fluorescent reporter molecules CM-H2DCFDA (ROS) and TMRM (DeltaPsim and mitochondrial morphology). In contrast with fluorimetry or flow-cytometry, this strategy allows quantification of subcellular parameters at the level of the individual cell with high spatiotemporal resolution, both before and after experimental stimulation. Importantly, the image-based nature of the method allows extracting morphological parameters in addition to signal intensities. The combined feature set is used for explorative and statistical multivariate data analysis to detect differences between subpopulations, cell types and/or treatments. Here, a detailed description of the assay is provided, along with an example experiment that proves its potential for unambiguous discrimination between cellular states after chemical perturbation. PMID- 28570525 TI - Full-root Aortic Valve Replacement by Stentless Aortic Xenografts in Patients with Small Aortic Roots. AB - In patients with small aortic roots who need an aortic valve replacement with biological valve substitutes, the implantation of the stented pericardial valve might not meet the functional needs. The implantation of a too-small stented pericardial valve, leading to an effective orifice area indexed to a body surface area less than 0.85 cm2/m2, is regarded as prosthesis-patient mismatch (PPM). A PPM negatively affects the regression of left ventricular hypertrophy and thus the normalization of left ventricular function and the alleviation of symptoms. Persistent left ventricular hypertrophy is associated with an increased risk of arrhythmias and sudden cardiac death. In the case of predictable PPM, there are three options: 1) accept the PPM resulting from the implantation of a stented pericardial valve when comorbidities of the patient forbid the more technically demanding operative technique of implanting a larger prosthesis, 2) enlarge the aortic root to accommodate a larger stented valve substitute, or 3) implant a stentless biological valve or a homograft. Compared to classical aortic valve replacement with stented pericardial valves, the full-root implantation of stentless aortic xenografts offers the possibility of implanting a 3-4 mm larger valve in a given patient, thus allowing significant reduction in transvalvular gradients. However, a number of cardiac surgeons are reluctant to transform a classical aortic valve replacement with stented pericardial valves into the more technically challenging full-root implantation of stentless aortic xenografts. Given the potential hemodynamic advantages of stentless aortic xenografts, we have adopted full-root implantation to avoid PPM in patients with small aortic roots necessitating an aortic valve replacement. Here, we describe in detail a technique for the full-root implantation of stentless aortic xenografts, with emphasis on the management of the proximal suture line and coronary anastomoses. Limitations of this technique and alternative options are discussed. PMID- 28570526 TI - Methods to Classify Cytoplasmic Foci as Mammalian Stress Granules. AB - Cells are often challenged by sudden environmental changes. Stress Granules (SGs), cytoplasmic ribonucleoprotein complexes that form in cells exposed to stress conditions, are implicated in various aspects of cell metabolism and survival. SGs modulate cellular signaling pathways, post-transcriptional gene expression, and stress response programs. The formation of these mRNA-containing granules is directly connected to cellular translation. SG assembly is triggered by inhibited translation initiation, and SG disassembly is promoted by translation activation or by inhibited translation elongation. This relationship is further highlighted by SG composition. Core SG components are stalled translation pre-initiation complexes, mRNA, and selected RNA-binding Proteins (RBPs). The purpose of SG assembly is to conserve cellular energy by sequestering translationally stalled housekeeping mRNAs, allowing for the enhanced translation of stress-responsive proteins. In addition to the core constituents, such as stalled translation preinitiation complexes, SGs contain a plethora of other proteins and signaling molecules. Defects in SG formation can impair cellular adaptation to stress and can thus promote cell death. SGs and similar RNA containing granules have been linked to a number of human diseases, including neurodegenerative disorders and cancer, leading to the recent interest in classifying and defining RNA granule subtypes. This protocol describes assays to characterize and quantify mammalian SGs. PMID- 28570527 TI - Induction of Cellular Differentiation and Single Cell Imaging of Vibrio parahaemolyticus Swimmer and Swarmer Cells. AB - The ability to study the intracellular localization of proteins is essential for the understanding of many cellular processes. In turn, this requires the ability to obtain single cells for fluorescence microscopy, which can be particularly challenging when imaging cells that exist within bacterial communities. For example, the human pathogen Vibrio parahaemolyticus exists as short rod-shaped swimmer cells in liquid conditions that upon surface contact differentiate into a subpopulation of highly elongated swarmer cells specialized for growth on solid surfaces. This paper presents a method to perform single cell fluorescence microscopy analysis of V. parahaemolyticus in its two differential states. This protocol very reproducibly induces differentiation of V. parahaemolyticus into a swarmer cell life-cycle and facilitates their proliferation over solid surfaces. The method produces flares of differentiated swarmer cells extending from the edge of the swarm-colony. Notably, at the very tip of the swarm-flares, swarmer cells exist in a single layer of cells, which allows for their easy transfer to a microscope slide and subsequent fluorescence microscopy imaging of single cells. Additionally, the workflow of image analysis for demographic representation of bacterial societies is presented. As a proof of principle, the analysis of the intracellular localization of chemotaxis signaling arrays in swimmer and swarmer cells of V. parahaemolyticus is described. PMID- 28570528 TI - Subsurface Defect Localization by Structured Heating Using Laser Projected Photothermal Thermography. AB - The presented method is used to locate subsurface defects oriented perpendicularly to the surface. To achieve this, we create destructively interfering thermal wave fields that are disturbed by the defect. This effect is measured and used to locate the defect. We form the destructively interfering wave fields by using a modified projector. The original light engine of the projector is replaced with a fiber-coupled high-power diode laser. Its beam is shaped and aligned to the projector's spatial light modulator and optimized for optimal optical throughput and homogeneous projection by first characterizing the beam profile, and, second, correcting it mechanically and numerically. A high performance infrared (IR) camera is set up according to the tight geometrical situation (including corrections of the geometrical image distortions) and the requirement to detect weak temperature oscillations at the sample surface. Data acquisition can be performed once a synchronization between the individual thermal wave field sources, the scanning stage, and the IR camera is established by using a dedicated experimental setup which needs to be tuned to the specific material being investigated. During data post-processing, the relevant information on the presence of a defect below the surface of the sample is extracted. It is retrieved from the oscillating part of the acquired thermal radiation coming from the so-called depletion line of the sample surface. The exact location of the defect is deduced from the analysis of the spatial-temporal shape of these oscillations in a final step. The method is reference-free and very sensitive to changes within the thermal wave field. So far, the method has been tested with steel samples but is applicable to different materials as well, in particular to temperature sensitive materials. PMID- 28570529 TI - Vegetated Treatment Systems for Removing Contaminants Associated with Surface Water Toxicity in Agriculture and Urban Runoff. AB - Urban stormwater and agriculture irrigation runoff contain a complex mixture of contaminants that are often toxic to adjacent receiving waters. Runoff may be treated with simple systems designed to promote sorption of contaminants to vegetation and soils and promote infiltration. Two example systems are described: a bioswale treatment system for urban stormwater treatment, and a vegetated drainage ditch for treating agriculture irrigation runoff. Both have similar attributes that reduce contaminant loading in runoff: vegetation that results in sorption of the contaminants to the soil and plant surfaces, and water infiltration. These systems may also include the integration of granulated activated carbon as a polishing step to remove residual contaminants. Implementation of these systems in agriculture and urban watersheds requires system monitoring to verify treatment efficacy. This includes chemical monitoring for specific contaminants responsible for toxicity. The current paper emphasizes monitoring of current use pesticides since these are responsible for surface water toxicity to aquatic invertebrates. PMID- 28570530 TI - Preparation of Plasma Membrane Vesicles from Bone Marrow Mesenchymal Stem Cells for Potential Cytoplasm Replacement Therapy. AB - We have previously reported on the generation of plasma membrane vesicles (PMVs) through the mechanical extrusion of mammalian cells. The fusion of PMVs with mitochondrial deficient Rho0 cells restored mitotic activity under normal culture conditions. Atherosclerosis, type 2 diabetes, Alzheimer's disease, and cancer are age-related diseases that have been reported to be associated with multiple mechanical and functional defects in the cytosol and organelles of a variety of cell types. Bone marrow mesenchymal stem cells (BMSCs) represent a unique cell population from the bone marrow that possess self-renewal capabilities while maintaining their multipotency. The supplementation of senescence cells with young cytoplasm from autologous BMSCs via the fusion of PMVs provides a promising approach to ameliorate or even reverse age-associated phenotypes. This protocol describes how to prepare PMVs from BMSCs via extrusion through a polycarbonate membrane with 3 um pores, determine the existence of mitochondria and examine the maintenance of membrane potential within PMVs using a confocal microscope, concentrate PMVs by centrifugation, and carry out the in vivo injection of PMVs into the gastrocnemius muscle of mice. PMID- 28570531 TI - A 5-mC Dot Blot Assay Quantifying the DNA Methylation Level of Chondrocyte Dedifferentiation In Vitro. AB - The dedifferentiation of hyaline chondrocytes into fibroblastic chondrocytes often accompanies monolayer expansion of chondrocytes in vitro. The global DNA methylation level of chondrocytes is considered to be a suitable biomarker for the loss of the chondrocyte phenotype. However, results based on different experimental methods can be inconsistent. Therefore, it is important to establish a precise, simple, and rapid method to quantify global DNA methylation levels during chondrocyte dedifferentiation. Current genome-wide methylation analysis techniques largely rely on bisulfite genomic sequencing. Due to DNA degradation during bisulfite conversion, these methods typically require a large sample volume. Other methods used to quantify global DNA methylation levels include high performance liquid chromatography (HPLC). However, HPLC requires complete digestion of genomic DNA. Additionally, the prohibitively high cost of HPLC instruments limits HPLC's wider application. In this study, genomic DNA (gDNA) was extracted from human chondrocytes cultured with varying number of passages. The gDNA methylation level was detected using a methylation-specific dot blot assay. In this dot blot approach, a gDNA mixture containing the methylated DNA to be detected was spotted directly onto an N+ membrane as a dot inside a previously drawn circular template pattern. Compared with other gel electrophoresis-based blotting approaches and other complex blotting procedures, the dot blot method saves significant time. In addition, dot blots can detect overall DNA methylation level using a commercially available 5-mC antibody. We found that the DNA methylation level differed between the monolayer subcultures, and therefore could play a key role in chondrocyte dedifferentiation. The 5-mC dot blot is a reliable, simple, and rapid method to detect the general DNA methylation level to evaluate chondrocyte phenotype. PMID- 28570532 TI - Orientational Transition in a Liquid Crystal Triggered by the Thermodynamic Growth of Interfacial Wetting Sheets. AB - In liquid crystal (LC) physical chemistry, molecules near the surface play a great role in controlling bulk orientation. Thus far, mainly to achieve desired molecular orientation states in LC displays, the "static" surface property of LCs, so-called surface anchoring, has been intensively studied. As a rule of thumb, once the initial orientation of LCs is "locked" by specific surface treatments, such as rubbing or treatment with a specific alignment layer, it hardly changes with temperature. Here, we present a system exhibiting an orientational transition upon temperature variation, which conflicts with the consensus. Right on the transition, the bulk LC molecules experience the orientational rotation, with 90 degrees between the planar (P) orientation at high temperatures and the vertical (V) orientation at low temperatures in the first-order transitional manner. We have tracked thermodynamic surface anchoring behavior by means of polarizing optical microscopy (POM), dielectric spectroscopy (DS), high-resolution differential scanning calorimetry (HR-DSC), and grazing incidence X-ray diffraction (GI-XRD) and reached a plausible physical explanation: that the transition is triggered by a growth of surface wetting sheets, which impose the V orientation locally against the P orientation in the bulk. This landscape would provide a general link explaining how the equilibrium bulk orientation is affected by surface-localized orientation in many LC systems. In our characterization, POM and DS are advantageous by offering information on the spatial distribution of the orientation of LC molecules. HR-DSC gives information about the precise thermodynamic information on transitions, which cannot be addressed by conventional DSC instruments due to limited resolution. GI XRD provides information on surface-specific molecular orientation and short range orderings. The goal of this paper is to present a protocol for preparing a sample that exhibits the transition and to demonstrate how the thermodynamic structural variation, both in the bulk and on surfaces, can be analyzed through the abovementioned methods. PMID- 28570533 TI - A Real-world What-Where-When Memory Test. AB - Episodic memory is a complex memory system which allows recall and mental re experience of previous episodes from one's own life. Real-life episodic memories are about events in their spatiotemporal context and are typically visuospatial, rather than verbal. Yet often, tests of episodic memory use verbal material to be recalled (word lists, stories). The Real-World What-Where-When memory test requires participants to hide a total of 16 different objects in 16 different locations over two temporal occasions, 2 h apart. Another two hours later, they are then asked to recall which objects (What) they had hidden in which locations (Where) and on which of the two occasions (When). In addition to counting the number of correctly recalled complete what-where-when combinations, this task can also be used to test real-world spatial memory and object memory. This task is sensitive to normal cognitive aging, and correlates well with performance on other episodic memory tasks, while at the same time providing more ecological validity and being cheap and easy to run. PMID- 28570534 TI - Quantification of Endosome and Lysosome Motilities in Cultured Neurons Using Fluorescent Probes. AB - In the brain, membrane trafficking systems play important roles in regulating neuronal functions, such as neuronal morphology, synaptic plasticity, survival, and glial communications. To date, numerous studies have reported that defects in these systems cause various neuronal diseases. Thus, understanding the mechanisms underlying vesicle dynamics may provide influential clues that could aid in the treatment of several neuronal disorders. Here, we describe a method for quantifying vesicle motilities, such as motility distance and rate of movement, using a software plug-in for the ImageJ platform. To obtain images for quantification, we labeled neuronal endosome-lysosome structures with EGFP-tagged vesicle marker proteins and observed the movement of vesicles using a time-lapse microscopy. This method is highly useful and simplify measuring vesicle motility in neurites, such as axons and dendrites, as well as in the soma of both neurons and glial cells. Furthermore, this method can be applied to other cell lines, such as fibroblasts and endothelial cells. This approach could provide a valuable advancement of our understanding of membrane trafficking. PMID- 28570535 TI - Visualization and Quantitative Analysis of Embryonic Angiogenesis in Xenopus tropicalis. AB - Blood vessels supply oxygen and nutrients throughout the body, and the formation of the vascular network is under tight developmental control. The efficient in vivo visualization of blood vessels and the reliable quantification of their complexity are key to understanding the biology and disease of the vascular network. Here, we provide a detailed method to visualize blood vessels with a commercially available fluorescent dye, human plasma acetylated low density lipoprotein DiI complex (DiI-AcLDL), and to quantify their complexity in Xenopus tropicalis. Blood vessels can be labeled by a simple injection of DiI-AcLDL into the beating heart of an embryo, and blood vessels in the entire embryo can be imaged in live or fixed embryos. Combined with gene perturbation by the targeted microinjection of nucleic acids and/or the bath application of pharmacological reagents, the roles of a gene or of a signaling pathway on vascular development can be investigated within one week without resorting to sophisticated genetically engineered animals. Because of the well-defined venous system of Xenopus and its stereotypic angiogenesis, the sprouting of pre-existing vessels, vessel complexity can be quantified efficiently after perturbation experiments. This relatively simple protocol should serve as an easily accessible tool in diverse fields of cardiovascular research. PMID- 28570537 TI - Brain Membrane Fractionation: An Ex Vivo Approach to Assess Subsynaptic Protein Localization. AB - Assessing the synaptic protein composition and function constitutes an important challenge in neuroscience. However, it is not easy to evaluate neurotransmission that occurs within synapses because it is highly regulated by dynamic protein protein interactions and phosphorylation events. Accordingly, when any method is used to study synaptic transmission, a major goal is to preserve these transient physiological modifications. Here, we present a brain membrane fractionation protocol that represents a robust procedure to isolate proteins belonging to different synaptic compartments. In other words, the protocol describes a biochemical methodology to carry out protein enrichment from presynaptic, postsynaptic, and extrasynaptic compartments. First, synaptosomes, or synaptic terminals, are obtained from neurons that contain all synaptic compartments by means of a discontinuous sucrose gradient. Of note, the quality of this initial synaptic membrane preparation is critical. Subsequently, the isolation of the different subsynaptic compartments is achieved with light solubilization using mild detergents at differential pH conditions. This allows for separation by gradient and isopycnic centrifugations. Finally, protein enrichment at the different subsynaptic compartments (i.e., pre-, post- and extrasynaptic membrane fractions) is validated by means of immunoblot analysis using well-characterized synaptic protein markers (i.e., SNAP-25, PSD-95, and synaptophysin, respectively), thus enabling a direct assessment of the synaptic distribution of any particular neuronal protein. PMID- 28570536 TI - Isolation of Intermediate Filament Proteins from Multiple Mouse Tissues to Study Aging-associated Post-translational Modifications. AB - Intermediate filaments (IFs), together with actin filaments and microtubules, form the cytoskeleton - a critical structural element of every cell. Normal functioning IFs provide cells with mechanical and stress resilience, while a dysfunctional IF cytoskeleton compromises cellular health and has been associated with many human diseases. Post-translational modifications (PTMs) critically regulate IF dynamics in response to physiological changes and under stress conditions. Therefore, the ability to monitor changes in the PTM signature of IFs can contribute to a better functional understanding, and ultimately conditioning, of the IF system as a stress responder during cellular injury. However, the large number of IF proteins, which are encoded by over 70 individual genes and expressed in a tissue-dependent manner, is a major challenge in sorting out the relative importance of different PTMs. To that end, methods that enable monitoring of PTMs on IF proteins on an organism-wide level, rather than for isolated members of the family, can accelerate research progress in this area. Here, we present biochemical methods for the isolation of the total, detergent soluble, and detergent-resistant fraction of IF proteins from 9 different mouse tissues (brain, heart, lung, liver, small intestine, large intestine, pancreas, kidney, and spleen). We further demonstrate an optimized protocol for rapid isolation of IF proteins by using lysing matrix and automated homogenization of different mouse tissues. The automated protocol is useful for profiling IFs in experiments with high sample volume (such as in disease models involving multiple animals and experimental groups). The resulting samples can be utilized for various downstream analyses, including mass spectrometry-based PTM profiling. Utilizing these methods, we provide new data to show that IF proteins in different mouse tissues (brain and liver) undergo parallel changes with respect to their expression levels and PTMs during aging. PMID- 28570538 TI - Uncontrolled Hemorrhagic Shock Modeled via Liver Laceration in Mice with Real Time Hemodynamic Monitoring. AB - Uncontrolled hemorrhage is an important cause of preventable deaths among trauma patients. We have developed a murine model of uncontrolled hemorrhage via a liver laceration that results in consistent blood loss, hemodynamic alterations, and survival. Mice undergo a standardized resection of the left-middle lobe of the liver. They are allowed to bleed without mechanical intervention. Hemostatic agents can be administered as pre-treatment or rescue therapy depending on the interest of the investigator. During the time of hemorrhage, real-time hemodynamic monitoring via a left femoral arterial line is performed. Mice are then sacrificed, blood loss is quantified, blood is collected for further analysis, and organs are harvested for analysis of injury. Experimental design is described to allow for simultaneous testing of multiple animals. Liver hemorrhage as a model of uncontrolled hemorrhage exists in the literature, primarily in rat and porcine models. Some of these models utilize hemodynamic monitoring or quantify blood loss but lack consistency. The present model incorporates quantification of blood loss, real-time hemodynamic monitoring in a murine model that offers the advantage of using transgenic lines and a high-throughput mechanism to further investigate the pathophysiologic mechanisms in uncontrolled hemorrhage. PMID- 28570539 TI - Monitoring ER/SR Calcium Release with the Targeted Ca2+ Sensor CatchER. AB - Intracellular calcium (Ca2+) transients evoked by extracellular stimuli initiate a multitude of biological processes in living organisms. At the center of intracellular calcium release are the major intracellular calcium storage organelles, the endoplasmic reticulum (ER) and the more specialized sarcoplasmic reticulum (SR) in muscle cells. The dynamic release of calcium from these organelles is mediated by the ryanodine receptor (RyR) and the inositol 1,4,5 triphosphate receptor (IP3R) with refilling occurring through the sarco/endoplasmic reticulum calcium ATPase (SERCA) pump. A genetically encoded calcium sensor (GECI) called CatchER was created to monitor the rapid calcium release from the ER/SR. Here, the detailed protocols for the transfection and expression of the improved, ER/SR-targeted GECI CatchER+ in HEK293 and C2C12 cells and its application in monitoring IP3R, RyR, and SERCA pump-mediated calcium transients in HEK293 cells using fluorescence microscopy is outlined. The receptor agonist or inhibitor of choice is dispersed in the chamber solution and the intensity changes are recorded in real time. With this method, a decrease in ER calcium is seen with RyR activation with 4-chloro-m-cresol (4-cmc), the indirect activation of IP3R with adenosine triphosphate (ATP), and inhibition of the SERCA pump with cyclopiazonic acid (CPA). We also discuss protocols for determining the in situ Kd and quantifying basal [Ca2+] in C2C12 cells. In summary, these protocols, used in conjunction with CatchER+, can elicit receptor mediated calcium release from the ER with future application in studying ER/SR calcium related pathologies. PMID- 28570540 TI - Recombinant Protein Expression, Crystallization, and Biophysical Studies of a Bacillus-conserved Nucleotide Pyrophosphorylase, BcMazG. AB - To overcome safety restrictions and regulations when studying genes and proteins from true pathogens, their homologues can be studied. Bacillus anthracis is an obligate pathogen that causes fatal inhalational anthrax. Bacillus cereus is considered a useful model for studying B. anthracis due to its close evolutionary relationship. The gene cluster ba1554 - ba1558 of B. anthracis is highly conserved with the bc1531- bc1535 cluster in B. cereus, as well as with the bt1364-bt1368 cluster in Bacillus thuringiensis, indicating the critical role of the associated genes in the Bacillus genus. This manuscript describes methods to prepare and characterize a protein product of the first gene (ba1554) from the gene cluster in B. anthracis using a recombinant protein of its ortholog in B. cereus, bc1531. PMID- 28570541 TI - Preparation and Characterization of Novel HDL-mimicking Nanoparticles for Nerve Growth Factor Encapsulation. AB - The objective of this article is to introduce preparation and characterization methods for nerve growth factor (NGF)-loaded, high-density, lipoprotein (HDL) mimicking nanoparticles (NPs). HDLs are endogenous NPs and have been explored as vehicles for the delivery of therapeutic agents. Various methods have been developed to prepare HDL-mimicking NPs. However, they are generally complicated, time consuming, and difficult for industrial scale-up. In this study, one-step homogenization was used to mix the excipients and form the prototype NPs. NGF is a water-soluble protein of 26 kDa. To facilitate the encapsulation of NGF into the lipid environment of HDL-mimicking NPs, protamine USP was used to form an ion pair complex with NGF to neutralize the charges on the NGF surface. The NGF/protamine complex was then introduced into the prototype NPs. Apolipoprotein A-I was finally coated on the surface of the NPs. NGF HDL-mimicking NPs showed preferable properties in terms of particle size, size distribution, entrapment efficiency, in vitro release, bioactivity, and biodistribution. With the careful design and exploration of homogenization in HDL-mimicking NPs, the procedure was greatly simplified, and the NPs were made scalable. Moreover, various challenges, such as separating unloaded NGF from the NPs, conducting reliable in vitro release studies, and measuring the bioactivity of the NPs, were overcome. PMID- 28570542 TI - Expression, Purification, and Antimicrobial Activity of S100A12. AB - Calgranulin proteins are important mediators of innate immunity and are members of the S100 class of the EF-hand family of calcium binding proteins. Some S100 proteins have the capacity to bind transition metals with high affinity and effectively sequester them away from invading microbial pathogens in a process that is termed "nutritional immunity". S100A12 (EN-RAGE) binds both zinc and copper and is highly abundant in innate immune cells such as macrophages and neutrophils. We report a refined method for the expression, enrichment and purification of S100A12 in its active, metal-binding configuration. Utilization of this protein in bacterial growth and viability analyses reveals that S100A12 has antimicrobial activity against the bacterial pathogen, Helicobacter pylori. The antimicrobial activity is predicated on the zinc-binding activity of S100A12, which chelates nutrient zinc, thereby starving H. pylori which requires zinc for growth and proliferation. PMID- 28570543 TI - A Simple Method to Identify Kinases That Regulate Embryonic Stem Cell Pluripotency by High-throughput Inhibitor Screening. AB - Embryonic stem cells (ESCs) can self-renew or differentiate into all cell types, a phenomenon known as pluripotency. Distinct pluripotent states have been described, termed "naive" and "primed" pluripotency. The mechanisms that control naive-primed transition are poorly understood. In particular, we remain poorly informed about protein kinases that specify naive and primed pluripotent states, despite increasing availability of high-quality tool compounds to probe kinase function. Here, we describe a scalable platform to perform targeted small molecule screens for kinase regulators of the naive-primed pluripotent transition in mouse ESCs. This approach utilizes simple cell culture conditions and standard reagents, materials and equipment to uncover and validate kinase inhibitors with hitherto unappreciated effects on pluripotency. We discuss potential applications for this technology, including screening of other small molecule collections such as increasingly sophisticated kinase inhibitors and emerging libraries of epigenetic tool compounds. PMID- 28570544 TI - A Simple Chamber for Long-term Confocal Imaging of Root and Hypocotyl Development. AB - Several aspects of plant development, such as lateral root morphogenesis, occur on time spans of several days. To study underlying cellular and subcellular processes, high resolution time-lapse microscopy strategies that preserve physiological conditions are required. Plant tissues must have adequate nutrient and water supply with sustained gaseous exchange but, when submerged and immobilized under a coverslip, they are particularly susceptible to anoxia. One strategy that has been successfully employed is the use of a perfusion system to maintain a constant supply of oxygen and nutrients. However, such arrangements can be complicated, cumbersome, and require specialized equipment. Presented here is an alternative strategy for a simple imaging system using perfluorodecalin as an immersion medium. This system is easy to set up, requires minimal equipment, and is easily mounted on a microscope stage, allowing several imaging chambers to be set up and imaged in parallel. In this system, lateral root growth rates are indistinguishable from growth rates under standard conditions on agar plates for the first two days, and lateral root growth continues at reduced rates for at least another day. Plant tissues are supplied with nutrients via an agar slab that can be used also to administer a range of pharmacological compounds. The system was established to monitor lateral root development but is readily adaptable to image other plant organs such as hypocotyls and primary roots. PMID- 28570545 TI - Transplantation of Zebrafish Pediatric Brain Tumors into Immune-competent Hosts for Long-term Study of Tumor Cell Behavior and Drug Response. AB - Tumor cell transplantation is an important technique to define the mechanisms controlling cancer cell growth, migration, and host response, as well as to assess potential patient response to therapy. Current methods largely depend on using syngeneic or immune-compromised animals to avoid rejection of the tumor graft. Such methods require the use of specific genetic strains that often prevent the analysis of immune-tumor cell interactions and/or are limited to specific genetic backgrounds. An alternative method in zebrafish takes advantage of an incompletely developed immune system in the embryonic brain before 3 days, where tumor cells are transplanted for use in short-term assays (i.e., 3 to 10 days). However, these methods cause host lethality, which prevents the long-term study of tumor cell behavior and drug response. This protocol describes a simple and efficient method for the long-term orthotopic transplantation of zebrafish brain tumor tissue into the fourth ventricle of a 2-day-old immune-competent zebrafish. This method allows: 1) long-term study of tumor cell behaviors, such as invasion and dissemination; 2) durable tumor response to drugs; and 3) re transplantation of tumors for the study of tumor evolution and/or the impact of different host genetic backgrounds. In summary, this technique allows cancer researchers to assess engraftment, invasion, and growth at distant sites, as well as to perform chemical screens and cell competition assays over many months. This protocol can be extended to studies of other tumor types and can be used to elucidate mechanisms of chemoresistance and metastasis. PMID- 28570546 TI - Electrophysiological Analysis of human Pluripotent Stem Cell-derived Cardiomyocytes (hPSC-CMs) Using Multi-electrode Arrays (MEAs). AB - Cardiomyocytes can now be derived with high efficiency from both human embryonic and human induced-Pluripotent Stem Cells (hPSC). hPSC-derived cardiomyocytes (hPSC-CMs) are increasingly recognized as having great value for modeling cardiovascular diseases in humans, especially arrhythmia syndromes. They have also demonstrated relevance as in vitro systems for predicting drug responses, which makes them potentially useful for drug-screening and discovery, safety pharmacology and perhaps eventually for personalized medicine. This would be facilitated by deriving hPSC-CMs from patients or susceptible individuals as hiPSCs. For all applications, however, precise measurement and analysis of hPSC CM electrical properties are essential for identifying changes due to cardiac ion channel mutations and/or drugs that target ion channels and can cause sudden cardiac death. Compared with manual patch-clamp, multi-electrode array (MEA) devices offer the advantage of allowing medium- to high-throughput recordings. This protocol describes how to dissociate 2D cell cultures of hPSC-CMs to small aggregates and single cells and plate them on MEAs to record their spontaneous electrical activity as field potential. Methods for analyzing the recorded data to extract specific parameters, such as the QT and the RR intervals, are also described here. Changes in these parameters would be expected in hPSC-CMs carrying mutations responsible for cardiac arrhythmias and following addition of specific drugs, allowing detection of those that carry a cardiotoxic risk. PMID- 28570547 TI - Evaluating the Procedure for Performing Awake Cystometry in a Mouse Model. AB - Awake filling cystometry has been used for a long time to evaluate bladder function in freely moving mice, however, the specific methods used, vary among laboratories. The goal of this study was to describe the microsurgical procedure used to implant an intravesical tube and the experimental technique for recording urinary bladder pressure in an awake, freely moving mouse. In addition, experimental data is presented to show how surgery, as well as tubing type and size, affect lower urinary tract function and recording sensitivity. The effect of tube diameter on pressure recording was assessed in both polyethylene and polyurethane tubing with different internal diameters. Subsequently, the best performing tube from both materials was surgically implanted into the dome of the urinary bladder of male C57BL/6 mice. Twelve-hour, overnight micturition frequency was recorded in healthy, intact animals and animals 2, 3, 5, and 7 days post-surgery. At harvest, bladders were assessed for signs of swelling using gross observation and were subsequently processed for pathological analysis. The greatest extent of bladder swelling was observed on day 2 and 3, which correlated with behavioral voiding data showing significantly impaired bladder function. By day 5, bladder histology and voiding frequency had normalized. Based on the literature and evidence provided by our studies, we propose the following steps for in vivo recording of intravesical pressure and voided volume in an awake mouse: 1) Perform the surgery using an operating microscope and microsurgical tools, 2) Use polyethylene-10 tubing to minimize movement artifacts, and 3) Perform cystometry on post-operative day 5, when bladder swelling resolves. PMID- 28570548 TI - A Protocol to Characterize the Morphological Changes of Clostridium difficile in Response to Antibiotic Treatment. AB - Assessment of antibiotic action with new drug development directed towards anaerobic bacteria is difficult and technically demanding. To gain insight into possible MOA, morphologic changes associated with antibiotic exposure can be visualized using scanning electron microscopy (SEM). Integrating SEM imaging with traditional kill curves may improve our insight into drug action and advance the drug development process. To test this premise, kill curves and SEM studies were conducted using drugs with known but different MOA (vancomycin and metronidazole). C. difficile cells (R20291) were grown with or without the presence of antibiotic for up to 48 h. Throughout the 48 h interval, cells were collected at multiple time points to determine antibiotic efficacy and for imaging on the SEM. Consistent with previous reports, vancomycin and metronidazole had significant bactericidal activity following 24 h of treatment as measured by colony-forming unit (CFU) counting. Using SEM imaging we determined that metronidazole had significant effects on cell length (> 50% reduction in cell length for each antibiotic; P< 0.05) compared to controls and vancomycin. While the phenotypic response to drug treatment has not been documented previously in this manner, they are consistent with the drug's MOA demonstrating the versatility and reliability of the imaging and measurements and the application of this technique for other experimental compounds. PMID- 28570549 TI - Non-invasive Assessment of Changes in Corticomotoneuronal Transmission in Humans. AB - The corticospinal pathway is the major pathway connecting the brain with the muscles and is therefore highly relevant for movement control and motor learning. There exists a number of noninvasive electrophysiological methods investigating the excitability and plasticity of this pathway. However, most methods are based on quantification of compound potentials and neglect that the corticospinal pathway consists of many different connections that are more or less direct. Here, we present a method that allows testing excitability of different fractions of the corticospinal transmission. This so called H-reflex conditioning technique allows one to assess excitability of the fastest (monosynaptic) and also polysynaptic corticospinal pathways. Furthermore, by using two different stimulation sites, the motor cortex and the cervicomedullary junction, it allows not only differentiation between cortical and spinal effects but also assessment of transmission at the corticomotoneural synapse. In this manuscript, we describe how this method can be used to assess corticomotoneural transmission after low frequency repetitive transcranial magnetic stimulation, a method that was previously shown to reduce excitability of cortical cells. Here we demonstrate that not only cortical cells are affected by this repetitive stimulation but also transmission at the corticomotoneuronal synapse at the spinal level. This finding is important for the understanding of basic mechanisms and sites of neuroplasticity. Besides investigation of basic mechanisms, the H-reflex conditioning technique may be applied to test changes in corticospinal transmission following behavioral (e.g., training) or therapeutic interventions, pathology or aging and therefore allows a better understanding of neural processes that underlie movement control and motor learning. PMID- 28570550 TI - Dissection and Culture of Mouse Embryonic Kidney. AB - The goal of this protocol is to describe a method for the dissection, isolation, and culture of mouse metanephric rudiments. During mammalian kidney development, the two progenitor tissues, the ureteric bud and the metanephric mesenchyme, communicate and reciprocally induce cellular mechanisms to eventually form the collecting system and the nephrons of the kidney. As mammalian embryos grow intrauterine and therefore are inaccessible to the observer, an organ culture has been developed. With this method, it is possible to study epithelial-mesenchymal interactions and cellular behavior during kidney organogenesis. Furthermore, the origin of congenital kidney and urogenital tract malformations can be investigated. After careful dissection, the metanephric rudiments are transferred onto a filter that floats on culture medium and can be kept in a cell culture incubator for several days. However, one must be aware that the conditions are artificial and could influence the metabolism in the tissue. Also, the penetration of test substances could be limited due to the extracellular matrix and basal membrane present in the explant. One main advantage of organ culture is that the experimenter can gain direct access to the organ. This technology is cheap, simple, and allows a large number of modifications, such as the addition of biologically active substances, the study of genetic variants, and the application of advanced imaging techniques. PMID- 28570551 TI - Assay to Measure Nucleocytoplasmic Transport in Real Time within Motor Neuron like NSC-34 Cells. AB - Nucleocytoplasmic transport refers to the import and export of large molecules from the cell nucleus. Recently, a number of studies have shown a connection between amyotrophic lateral sclerosis (ALS) and impairments in the nucleocytoplasmic pathway. ALS is a neurodegenerative disease affecting the motor neurons and resulting in paralysis and ultimately in death, within 2-5 years on average. Most cases of ALS are sporadic, lacking any apparent genetic linkage, but 10% are inherited in a dominant manner. Recently, hexanucleotide repeat expansions (HREs) in the chromosome 9 open reading frame 72 (C9orf72) gene were identified as a genetic cause of ALS and frontotemporal dementia (FTD). Importantly, different groups have recently proposed that these mutants affect nucleocytoplasmic transport. These studies have mostly shown the final outcome and manifestations caused by HREs on nucleocytoplasmic transport, but they do not demonstrate nuclear transport dysfunction in real time. As a result, only severe nucleocytoplasmic transport deficiency can be determined, mostly due to high overexpression or exogenous protein insertion. This protocol describes a new and very sensitive assay to evaluate and quantify nucleocytoplasmic transport dysfunction in real time. The rate of import of a NLS-NES-GFP protein (shuttle GFP) can be quantified in real time using fluorescent microscopy. This is performed by using an exportin inhibitor, thus allowing the shuttle GFP only to enter the nucleus. To validate the assay, the C9orf72 HRE translated dipeptide repeats, poly(GR) and poly(PR), which have been previously shown to disrupt nucleocytoplasmic transport, were used. Using the described assay, a 50% decrease in the nuclear import rate was observed compared to the control. Using this system, minute changes in nucleocytoplasmic transport can be examined and the ability of different factors to rescue (even partially) a nucleocytoplasmic transport defect can be determined. PMID- 28570552 TI - Development of Quality Indicators for Endoscopic Eradication Therapies in Barrett's Esophagus: The TREAT-BE (Treatment With Resection and Endoscopic Ablation Techniques for Barrett's Esophagus) Consortium. PMID- 28570554 TI - Role of metastasis-associated protein 1 in prognosis of patients with digestive tract cancers: A meta-analysis. AB - OBJECTIVES: Metastasis-associated protein 1 (MTA1) is a transcriptional regulator and significantly associated with prognosis of patients with cancer. However, its role as a potential prognostic marker in digestive tract cancer (DTC) is controversial. In this study, a meta-analysis was conducted to evaluate the MTA1 expression as a predictor of clinicopathology and survival of patients with DTC. METHODS: We searched PubMed, Ovid, Web of Science and Cochrane databases using multiple search strategies for eligible studies. STATA 11.0 software was used to pool the data and analyze the association, odds ratios (ORs) and 95% confidence intervals (CIs) were used to measure the strength of the association. Furthermore, the Newcastle-Ottawa scale was used to evaluate the quality of eligible studies. RESULTS: MTA1 overexpression was strongly associated with depth of invasion (OR = 1.88, 95%CI: 1.05-3.37, P = 0.03), lymph node metastasis (OR = 2.30, 95%CI: 1.76-3.01, P<0.001), vascular invasion (OR = 2.02, 95%CI: 1.40-2.91, P<0.001) and TNM stage (OR = 2.78, 95%CI: 1.63-4.74, P<0.001), and was related to 1- (RR = 1.84, 95%CI: 1.18-2.89, P = 0.008), 3- (RR = 1.74, 95%CI: 1.32-2.30, P<0.001) and 5-year (RR = 1.64, 95%CI: 1.18-2.27, P = 0.003) OS. Further, MTA1 was associated with 1- (RR = 4.16, 95%CI: 1.35-12.81, P = 0.01), 3- (RR = 1.90, 95%CI: 1.02-3.53, P = 0.04) and 5- (RR = 2.17, 95%CI: 1.41-3.32, P<0.001) year DFS. In subgroup analyses based on study quality and tumor type, MTA1 overexpression was obviously related to clinical parameters, such as lymph node metastasis and TNM stage, and was also associated with prognosis of patients with gastrointestinal or esophageal cancer. CONCLUSIONS: MTA1 expression is strongly correlated with metastasis-related variables, and represents a promising prognostic factor in DTC. PMID- 28570553 TI - Genetic rescue of an endangered domestic animal through outcrossing with closely related breeds: A case study of the Norwegian Lundehund. AB - Genetic rescue, outcrossing with individuals from a related population, is used to augment genetic diversity in populations threatened by severe inbreeding and extinction. The endangered Norwegian Lundehund dog underwent at least two severe bottlenecks in the 1940s and 1960s that each left only five inbred dogs, and the approximately 1500 dogs remaining world-wide today appear to descend from only two individuals. The Lundehund has a high prevalence of a gastrointestinal disease, to which all remaining dogs may be predisposed. Outcrossing is currently performed with three Nordic Spitz breeds: Norwegian Buhund, Icelandic Sheepdog, and Norrbottenspets. Examination of single nucleotide polymorphism (SNP) genotypes based on 165K loci in 48 dogs from the four breeds revealed substantially lower genetic diversity for the Lundehund (HE 0.035) than for other breeds (HE 0.209-0.284). Analyses of genetic structure with > 15K linkage disequilibrium-pruned SNPs showed four distinct genetic clusters. Pairwise FST values between Lundehund and the candidate breeds were highest for Icelandic Sheepdog, followed by Buhund and Norrbottenspets. We assessed the presence of outlier loci among candidate breeds and examined flanking genome regions (1 megabase) for genes under possible selection to identify potential adaptive differences among breeds; outliers were observed in flanking regions of genes associated with key functions including the immune system, metabolism, cognition and physical development. We suggest crossbreeding with multiple breeds as the best strategy to increase genetic diversity for the Lundehund and to reduce the incidence of health problems. For this project, the three candidate breeds were first selected based on phenotypes and then subjected to genetic investigation. Because phenotypes are often paramount for domestic breed owners, such a strategy could provide a helpful approach for genetic rescue and restoration of other domestic populations at risk, by ensuring the involvement of owners, breeders and managers at the start of the project. PMID- 28570555 TI - Geometric classification of scalp hair for valid drug testing, 6 more reliable than 8 hair curl groups. AB - INTRODUCTION: Curly hair is reported to contain higher lipid content than straight hair, which may influence incorporation of lipid soluble drugs. The use of race to describe hair curl variation (Asian, Caucasian and African) is unscientific yet common in medical literature (including reports of drug levels in hair). This study investigated the reliability of a geometric classification of hair (based on 3 measurements: the curve diameter, curl index and number of waves). MATERIALS AND METHODS: After ethical approval and informed consent, proximal virgin (6cm) hair sampled from the vertex of scalp in 48 healthy volunteers were evaluated. Three raters each scored hairs from 48 volunteers at two occasions each for the 8 and 6-group classifications. One rater applied the 6 group classification to 80 additional volunteers in order to further confirm the reliability of this system. The Kappa statistic was used to assess intra and inter rater agreement. RESULTS: Each rater classified 480 hairs on each occasion. No rater classified any volunteer's 10 hairs into the same group; the most frequently occurring group was used for analysis. The inter-rater agreement was poor for the 8-groups (k = 0.418) but improved for the 6-groups (k = 0.671). The intra-rater agreement also improved (k = 0.444 to 0.648 versus 0.599 to 0.836) for 6-groups; that for the one evaluator for all volunteers was good (k = 0.754). CONCLUSIONS: Although small, this is the first study to test the reliability of a geometric classification. The 6-group method is more reliable. However, a digital classification system is likely to reduce operator error. A reliable objective classification of human hair curl is long overdue, particularly with the increasing use of hair as a testing substrate for treatment compliance in Medicine. PMID- 28570556 TI - Ultra-widefield fundus autofluorescence in age-related macular degeneration. AB - BACKGROUND: Establish accuracy and reproducibility of subjective grading in ultra widefield fundus autofluorescence (FAF) imaging in patients with age-related macular degeneration (AMD), and determine if an association exists between peripheral FAF abnormalities and AMD. METHODS: This was a prospective, single blinded case-control study. Patients were consecutively recruited for the study. Patients were excluded if there was a history of prior or active ocular pathology other than AMD or image quality was insufficient for analysis as determined by two independent graders. Control patients were those without any evidence of AMD or other ophthalmic disease apart from cataract. Using the Optos 200Tx (Optos, Marlborough, MA, USA), a ResMax central macula and an ultra-widefield peripheral retina image was taken for each eye in both normal color and short wavelength FAF. Ultra-widefield photographs were modified to mask the macula. Each ResMax and ultra-widefield image was independently graded by two blinded investigators. RESULTS: There were 28 AMD patients and 11 controls. There was a significant difference in the average age between AMD patients and control groups (80 versus 64, respectively P<0.001). There was moderate, statistically significant agreement between observers regarding image interpretation (78.4%, K = 0.524, P<0.001), and 69.0% (K = 0.49, P<0.001) agreement between graders for FAF abnormality patterns. Patients with AMD were at greater risk for peripheral FAF abnormalities (OR: 3.43, P = 0.019) and patients with FAF abnormalities on central macular ResMax images were at greater risk of peripheral FAF findings (OR: 5.19, P = 0.017). CONCLUSION: Subjective interpretation of FAF images has moderate reproducibility and validity in assessment of peripheral FAF abnormalities. Peripheral FAF abnormalities are seen in both AMD and control patients. Those with AMD, poor visual acuity, and macular FAF abnormalities are at greater risk. PMID- 28570557 TI - Classification of breast cancer histology images using Convolutional Neural Networks. AB - Breast cancer is one of the main causes of cancer death worldwide. The diagnosis of biopsy tissue with hematoxylin and eosin stained images is non-trivial and specialists often disagree on the final diagnosis. Computer-aided Diagnosis systems contribute to reduce the cost and increase the efficiency of this process. Conventional classification approaches rely on feature extraction methods designed for a specific problem based on field-knowledge. To overcome the many difficulties of the feature-based approaches, deep learning methods are becoming important alternatives. A method for the classification of hematoxylin and eosin stained breast biopsy images using Convolutional Neural Networks (CNNs) is proposed. Images are classified in four classes, normal tissue, benign lesion, in situ carcinoma and invasive carcinoma, and in two classes, carcinoma and non carcinoma. The architecture of the network is designed to retrieve information at different scales, including both nuclei and overall tissue organization. This design allows the extension of the proposed system to whole-slide histology images. The features extracted by the CNN are also used for training a Support Vector Machine classifier. Accuracies of 77.8% for four class and 83.3% for carcinoma/non-carcinoma are achieved. The sensitivity of our method for cancer cases is 95.6%. PMID- 28570558 TI - Introducing the TrypanoGEN biobank: A valuable resource for the elimination of human African trypanosomiasis. PMID- 28570559 TI - Analysis of DNA polymerase nu function in meiotic recombination, immunoglobulin class-switching, and DNA damage tolerance. AB - DNA polymerase nu (pol nu), encoded by the POLN gene, is an A-family DNA polymerase in vertebrates and some other animal lineages. Here we report an in depth analysis of pol nu-defective mice and human cells. POLN is very weakly expressed in most tissues, with the highest relative expression in testis. We constructed multiple mouse models for Poln disruption and detected no anatomic abnormalities, alterations in lifespan, or changed causes of mortality. Mice with inactive Poln are fertile and have normal testis morphology. However, pol nu disrupted mice have a modestly reduced crossover frequency at a meiotic recombination hot spot harboring insertion/deletion polymorphisms. These polymorphisms are suggested to generate a looped-out primer and a hairpin structure during recombination, substrates on which pol nu can operate. Pol nu defective mice had no alteration in DNA end-joining during immunoglobulin class switching, in contrast to animals defective in the related DNA polymerase theta (pol theta). We examined the response to DNA crosslinking agents, as purified pol nu has some ability to bypass major groove peptide adducts and residues of DNA crosslink repair. Inactivation of Poln in mouse embryonic fibroblasts did not alter cellular sensitivity to mitomycin C, cisplatin, or aldehydes. Depletion of POLN from human cells with shRNA or siRNA did not change cellular sensitivity to mitomycin C or alter the frequency of mitomycin C-induced radial chromosomes. Our results suggest a function of pol nu in meiotic homologous recombination in processing specific substrates. The restricted and more recent evolutionary appearance of pol nu (in comparison to pol theta) supports such a specialized role. PMID- 28570560 TI - qPCR-High resolution melt analysis for drug susceptibility testing of Mycobacterium leprae directly from clinical specimens of leprosy patients. AB - BACKGROUND: Real-Time PCR-High Resolution Melting (qPCR-HRM) analysis has been recently described for rapid drug susceptibility testing (DST) of Mycobacterium leprae. The purpose of the current study was to further evaluate the validity, reliability, and accuracy of this assay for M. leprae DST in clinical specimens. METHODOLOGY/PRINCIPAL FINDINGS: The specificity and sensitivity for determining the presence and susceptibility of M. leprae to dapsone based on the folP1 drug resistance determining region (DRDR), rifampin (rpoB DRDR) and ofloxacin (gyrA DRDR) was evaluated using 211 clinical specimens from leprosy patients, including 156 multibacillary (MB) and 55 paucibacillary (PB) cases. When comparing the results of qPCR-HRM DST and PCR/direct DNA sequencing, 100% concordance was obtained. The effects of in-house phenol/chloroform extraction versus column based DNA purification protocols, and that of storage and fixation protocols of specimens for qPCR-HRM DST, were also evaluated. qPCR-HRM results for all DRDR gene assays (folP1, rpoB, and gyrA) were obtained from both MB (154/156; 98.7%) and PB (35/55; 63.3%) patients. All PCR negative specimens were from patients with low numbers of bacilli enumerated by an M. leprae-specific qPCR. We observed that frozen and formalin-fixed paraffin embedded (FFPE) tissues or archival Fite's stained slides were suitable for HRM analysis. Among 20 mycobacterial and other skin bacterial species tested, only M. lepromatosis, highly related to M. leprae, generated amplicons in the qPCR-HRM DST assay for folP1 and rpoB DRDR targets. Both DNA purification protocols tested were efficient in recovering DNA suitable for HRM analysis. However, 3% of clinical specimens purified using the phenol/chloroform DNA purification protocol gave false drug resistant data. DNA obtained from freshly frozen (n = 172), formalin-fixed paraffin embedded (FFPE) tissues (n = 36) or archival Fite's stained slides (n = 3) were suitable for qPCR HRM DST analysis. The HRM-based assay was also able to identify mixed infections of susceptible and resistant M. leprae. However, to avoid false positives we recommend that clinical specimens be tested for the presence of the M. leprae using the qPCR-RLEP assay prior to being tested in the qPCR-HRM DST and that all specimens demonstrating drug resistant profiles in this assay be subjected to DNA sequencing. CONCLUSION/SIGNIFICANCE: Taken together these results further demonstrate the utility of qPCR-HRM DST as an inexpensive screening tool for large-scale drug resistance surveillance in leprosy. PMID- 28570561 TI - Rabies surveillance in dogs in Lao PDR from 2010-2016. AB - BACKGROUND: Rabies is a fatal viral disease that continues to threaten both human and animal health in endemic countries. The Lao People's Democratic Republic (Lao PDR) is a rabies-endemic country in which dogs are the main reservoir and continue to present health risks for both human and animals throughout the country. METHODS: Passive, laboratory-based rabies surveillance was performed for suspected cases of dog rabies in Vientiane Capital during 2010-2016 and eight additional provinces between 2015-2016 using the Direct Fluorescent Antibody Test (DFAT). RESULTS: There were 284 rabies positive cases from 415 dog samples submitted for diagnosis. 257 cases were from Vientiane Capital (2010-2016) and the remaining 27 cases were submitted during 2015-2016 from Champassak (16 cases), Vientiane Province (4 cases), Xieng Kuang (3 cases), Luang Prabang (2 cases), Saravan (1 case), Saisomboun (1 case) and Bokeo (1 case). There was a significant increase in rabies cases during the dry season (p = 0.004) (November to April; i.e., <100mm of rainfall per month). No significant differences were noted between age, sex, locality of rabies cases. CONCLUSION: The use of laboratory-based rabies surveillance is a useful method of monitoring rabies in Lao PDR and should be expanded to other provincial centers, particularly where there are active rabies control programs. PMID- 28570562 TI - Anomalous diffusion on the servosphere: A potential tool for detecting inherent organismal movement patterns. AB - Tracking animal movements such as walking is an essential task for understanding how and why animals move in an environment and respond to external stimuli. Different methods that implemented image analysis and a data logger such as GPS have been used in laboratory experiments and in field studies, respectively. Recently, animal movement patterns without stimuli have attracted an increasing attention in search for common innate characteristics underlying all of their movements. However, it is difficult to track the movements in a vast and homogeneous environment without stimuli because of space constraints in laboratories or environmental heterogeneity in the field, hindering our understanding of inherent movement patterns. Here, we applied an omnidirectional treadmill mechanism, or a servosphere, as a tool for tracking two-dimensional movements of small animals that can provide both a homogenous environment and a virtual infinite space for walking. To validate the use of our tracking system for assessment of the free-walking behavior, we compared walking patterns of individual pillbugs (Armadillidium vulgare) on the servosphere with that in two types of experimental flat arenas. Our results revealed that the walking patterns on the servosphere showed similar diffusive characteristics to those observed in the large arena simulating an open space, and we demonstrated that our mechanism provides more robust measurements of diffusive properties compared to a small arena with enclosure. Moreover, we showed that anomalous diffusion properties, including Levy walk, can be detected from the free-walking behavior on our tracking system. Thus, our novel tracking system is useful to measure inherent movement patterns, which will contribute to the studies of movement ecology, ethology, and behavioral sciences. PMID- 28570563 TI - A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells. AB - The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the anti-apoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent. PMID- 28570564 TI - Identification of TIFY/JAZ family genes in Solanum lycopersicum and their regulation in response to abiotic stresses. AB - Plant phenotypic plasticity determines plant adaptation to changing environments and agricultural productivity. Phytohormones are essential plant signalling molecules regulating this plasticity through complex signalling networks. Jasmonates (JAs) are key phytohormones regulating many aspects of growth, development and defence responses. An important role of JAs in tolerance to abiotic stresses is also emerging. The expression of JAZ (JASMONATE-ZIM-DOMAIN PROTEIN) genes, encoding for the key repressors in the JA-pathway, is regulated by multiple abiotic stresses, suggesting a role for the JAZ proteins in response to these stresses. The JAZ proteins belong to the TIFY family, well described in many plant species. However, only the role of few tomato JAZ proteins in response to microbial infection has been analysed so far. Here, we identify the members of the tomato TIFY family, and characterize them phylogenetically. In addition, we analyse the transcriptional regulation of several SlJAZ in response to abiotic stresses and hormone treatments both in root and leaves to assess their specific expression in response to stresses. Most SlJAZ are JA-induced and responsive to one or more abiotic stresses, providing clues for functional analysis of JAZ genes in abiotic responses in tomato. PMID- 28570565 TI - Assessing computational genomics skills: Our experience in the H3ABioNet African bioinformatics network. AB - The H3ABioNet pan-African bioinformatics network, which is funded to support the Human Heredity and Health in Africa (H3Africa) program, has developed node assessment exercises to gauge the ability of its participating research and service groups to analyze typical genome-wide datasets being generated by H3Africa research groups. We describe a framework for the assessment of computational genomics analysis skills, which includes standard operating procedures, training and test datasets, and a process for administering the exercise. We present the experiences of 3 research groups that have taken the exercise and the impact on their ability to manage complex projects. Finally, we discuss the reasons why many H3ABioNet nodes have declined so far to participate and potential strategies to encourage them to do so. PMID- 28570567 TI - And, not or: Quality, quantity in scientific publishing. AB - Scientists often perceive a trade-off between quantity and quality in scientific publishing: finite amounts of time and effort can be spent to produce few high quality papers or subdivided to produce many papers of lower quality. Despite this perception, previous studies have indicated the opposite relationship, in which productivity (publishing more papers) is associated with increased paper quality (usually measured by citation accumulation). We examine this question in a novel way, comparing members of the National Academy of Sciences with themselves across years, and using a much larger dataset than previously analyzed. We find that a member's most highly cited paper in a given year has more citations in more productive years than in in less productive years. Their lowest cited paper each year, on the other hand, has fewer citations in more productive years. To disentangle the effect of the underlying distributions of citations and productivities, we repeat the analysis for hypothetical publication records generated by scrambling each author's citation counts among their publications. Surprisingly, these artificial histories re-create the above trends almost exactly. Put another way, the observed positive relationship between quantity and quality can be interpreted as a consequence of randomly drawing citation counts for each publication: more productive years yield higher-cited papers because they have more chances to draw a large value. This suggests that citation counts, and the rewards that have come to be associated with them, may be more stochastic than previously appreciated. PMID- 28570566 TI - Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches. AB - The Hippo signaling pathway, which is implicated in the regulation of organ size, has emerged as a potential target for the development of cancer therapeutics. YAP, TAZ (transcription co-activators) and TEAD (transcription factor) are the downstream transcriptional machinery and effectors of the pathway. Formation of the YAP/TAZ-TEAD complex leads to transcription of growth-promoting genes. Conversely, disrupting the interactions of the complex decreases cell proliferation. Herein, we screened a 1000-member fragment library using Thermal Shift Assay and identified a hit fragment. We confirmed its binding at the YAP/TAZ-TEAD interface by X-ray crystallography, and showed that it occupies the same hydrophobic pocket as a conserved phenylalanine of YAP/TAZ. This hit fragment serves as a scaffold for the development of compounds that have the potential to disrupt YAP/TAZ-TEAD interactions. Structure-activity relationship studies and computational modeling were also carried out to identify more potent compounds that may bind at this validated druggable binding site. PMID- 28570568 TI - The risk of tuberculosis disease in rheumatoid arthritis patients on biologics and targeted therapy: A 15-year real world experience in Taiwan. AB - The objective of this study is to determine the risk of tuberculosis (TB) disease in biologics users among rheumatoid arthritis (RA) patients in Taiwan from 2000 to 2015. This retrospective cohort study enrolled adult RA patients initiated on first biologics at Taichung Veterans General Hospital. TB risks were determined as hazard ratio (HR) with 95% confidence interval (CI) using cox regression. A total of 951 patients were recruited; etanercept (n = 443), adalimumab (n = 332), abatacept (n = 74), golimumab (n = 60), tocilizumab (n = 31) and tofacitinib (n = 11). Twenty-four TB cases were identified; 13 in etanercept and 11 in adalimumab group with the TB incidence rate of 889.3/ 100,000 and 1055.6/ 100,000 patient years respectively. There was no significant difference in TB risk between adalimumab and etanercept users with an incidence rate ratio of 1.27 (p = 0.556 by Poisson model). Significant 2-year TB risk factors included elderly patient >65 year-old (HR: 2.72, 95% CI: 1.06-6.99, p = 0.037), history of TB (HR: 6.24, 95% CI: 1.77-22.00, p = 0.004) and daily glucocorticoid use >=5mg (HR:5.01, 95% CI: 1.46-17.21, p = 0.010). Sulfasalazine treatment appeared to be protective (HR: 0.32, 95% CI: 0.11-0.97, p = 0.043). Risk management plan (RMP) for TB before initiation of biologics commenced in 2012. The 2-year TB risks after RMP was compared with that before 2012 (HR:0.67, 95% CI: 0.30-1.49, p = 0.323). Elderly RA patients with a history of previous TB infection and concomitant moderate dose glucocorticoid were at higher risk of TB disease. Concurrent sulfasalazine treatment appeared to be a protective factor against TB disease. PMID- 28570569 TI - Patterns of use and impact of standardised MedDRA query analyses on the safety evaluation and review of new drug and biologics license applications. AB - PURPOSE: Standardised MedDRA Queries (SMQs) have been developed since the early 2000's and used by academia, industry, public health, and government sectors for detecting safety signals in adverse event safety databases. The purpose of the present study is to characterize how SMQs are used and the impact in safety analyses for New Drug Application (NDA) and Biologics License Application (BLA) submissions to the United States Food and Drug Administration (USFDA). METHODS: We used the PharmaPendium database to capture SMQ use in Summary Basis of Approvals (SBoAs) of drugs and biologics approved by the USFDA. Characteristics of the drugs and the SMQ use were employed to evaluate the role of SMQ safety analyses in regulatory decisions and the veracity of signals they revealed. RESULTS: A comprehensive search of the SBoAs yielded 184 regulatory submissions approved from 2006 to 2015. Search strategies more frequently utilized restrictive searches with "narrow terms" to enhance specificity over strategies using "broad terms" to increase sensitivity, while some involved modification of search terms. A majority (59%) of 1290 searches used descriptive statistics, however inferential statistics were utilized in 35% of them. Commentary from reviewers and supervisory staff suggested that a small, yet notable percentage (18%) of 1290 searches supported regulatory decisions. The searches with regulatory impact were found in 73 submissions (40% of the submissions investigated). Most searches (75% of 227 searches) with regulatory implications described how the searches were confirmed, indicating prudence in the decision making process. CONCLUSIONS: SMQs have an increasing role in the presentation and review of safety analysis for NDAs/BLAs and their regulatory reviews. This study suggests that SMQs are best used for screening process, with descriptive statistics, description of SMQ modifications, and systematic verification of cases which is crucial for drawing regulatory conclusions. PMID- 28570570 TI - A machine learning approach for gait speed estimation using skin-mounted wearable sensors: From healthy controls to individuals with multiple sclerosis. AB - Gait speed is a powerful clinical marker for mobility impairment in patients suffering from neurological disorders. However, assessment of gait speed in coordination with delivery of comprehensive care is usually constrained to clinical environments and is often limited due to mounting demands on the availability of trained clinical staff. These limitations in assessment design could give rise to poor ecological validity and limited ability to tailor interventions to individual patients. Recent advances in wearable sensor technologies have fostered the development of new methods for monitoring parameters that characterize mobility impairment, such as gait speed, outside the clinic, and therefore address many of the limitations associated with clinical assessments. However, these methods are often validated using normal gait patterns; and extending their utility to subjects with gait impairments continues to be a challenge. In this paper, we present a machine learning method for estimating gait speed using a configurable array of skin-mounted, conformal accelerometers. We establish the accuracy of this technique on treadmill walking data from subjects with normal gait patterns and subjects with multiple sclerosis induced gait impairments. For subjects with normal gait, the best performing model systematically overestimates speed by only 0.01 m/s, detects changes in speed to within less than 1%, and achieves a root-mean-square-error of 0.12 m/s. Extending these models trained on normal gait to subjects with gait impairments yields only minor changes in model performance. For example, for subjects with gait impairments, the best performing model systematically overestimates speed by 0.01 m/s, quantifies changes in speed to within 1%, and achieves a root-mean square-error of 0.14 m/s. Additional analyses demonstrate that there is no correlation between gait speed estimation error and impairment severity, and that the estimated speeds maintain the clinical significance of ground truth speed in this population. These results support the use of wearable accelerometer arrays for estimating walking speed in normal subjects and their extension to MS patient cohorts with gait impairment. PMID- 28570571 TI - Construction and analyses of the microRNA-target gene differential regulatory network in thyroid carcinoma. AB - Thyroid-carcinoma (THCA) is the most common malignancy with an increasing incidence. Recent evidence has emphasized the role of microRNA (miRNA) in THCA. However, knowledge concerning the roles of miRNAs in THCA is still limited. We therefore use a miRNA-target gene differential regulatory network (MGDRN) to identify key miRNAs and characterize their synergistic regulation in THCA. Both miRNA-target gene interactions from multiple databases and negative expression correlations between miRNA-target genes were used to characterize the interactions. Then, two regulatory networks involving normal and tumor conditions were constructed, respectively. The MGDRN was finally constructed using different interactions between the above two regulatory networks. By analyzing topological features of the MGDRN, four miRNAs (hsa-mir-152-3p, hsa-mir-148a, hsa-mir-130b and hsa-mir-15b) are identified as key miRNAs in THCA. Over-expression of mir-152 3p inhibited proliferation and colony formation of TPC-1 cells. Furthermore, mir 152-3p negatively regulated ERBB3 by binding to the 3'-UTR of ERBB3, and down regulation of ERBB3 by small interfering (si)RNAs inhibited proliferation and colony formation of TPC-1 cells, indicating that mir-152-3p acted as an anti tumor miRNA by negatively regulating ERBB3. Finally, two synergistically dysregulated modules were identified which may contribute to the initiation and progression of THCA. Overall, the results provided a better understanding of the molecular basis of THCA, and suggested novel treatment strategies for this cancer. PMID- 28570572 TI - Optimal costs of HIV pre-exposure prophylaxis for men who have sex with men. AB - INTRODUCTION: Men who have sex with men (MSM) are disproportionately affected by HIV due to their increased risk of infection. Oral pre-exposure prophylaxis (PrEP) is a highly effictive HIV-prevention strategy for MSM. Despite evidence of its effectiveness, PrEP uptake in the United States has been slow, in part due to its cost. As jurisdictions and health organizations begin to think about PrEP scale-up, the high cost to society needs to be understood. METHODS: We modified a previously-described decision-analysis model to estimate the cost per quality adjusted life-year (QALY) gained, over a 1-year duration of PrEP intervention and lifetime time horizon. Using updated parameter estimates, we calculated: 1) the cost per QALY gained, stratified over 4 strata of PrEP cost (a function of both drug cost and provider costs); and 2) PrEP drug cost per year required to fall at or under 4 cost per QALY gained thresholds. RESULTS: When PrEP drug costs were reduced by 60% (with no sexual disinhibition) to 80% (assuming 25% sexual disinhibition), PrEP was cost-effective (at <$100,000 per QALY averted) in all scenarios of base-case or better adherence, as long as the background HIV prevalence was greater than 10%. For PrEP to be cost saving at base-case adherence/efficacy levels and at a background prevalence of 20%, drug cost would need to be reduced to $8,021 per year with no disinhibition, and to $2,548 with disinhibition. CONCLUSION: Results from our analysis suggest that PrEP drug costs need to be reduced in order to be cost-effective across a range of background HIV prevalence. Moreover, our results provide guidance on the pricing of generic emtricitabine/tenofovir disoproxil fumarate, in order to provide those at high risk for HIV an affordable prevention option without financial burden on individuals or jurisdictions scaling-up coverage. PMID- 28570573 TI - Evidence of selective reporting bias in hematology journals: A systematic review. AB - INTRODUCTION: Selective reporting bias occurs when chance or selective outcome reporting rather than the intervention contributes to group differences. The prevailing concern about selective reporting bias is the possibility of results being modified towards specific conclusions. In this study, we evaluate randomized controlled trials (RCTs) published in hematology journals, a group in which selective outcome reporting has not yet been explored. METHODS: Our primary goal was to examine discrepancies between the reported primary and secondary outcomes in registered and published RCTs concerning hematological malignancies reported in hematology journals with a high impact factor. The secondary goals were to address whether outcome reporting discrepancies favored statistically significant outcomes, whether a pattern existed between the funding source and likelihood of outcome reporting bias, and whether temporal trends were present in outcome reporting bias. For trials with major outcome discrepancies, we contacted trialists to determine reasons for these discrepancies. Trials published between January 1, 2010 and December 31, 2015 in Blood; British Journal of Haematology; American Journal of Hematology; Leukemia; and Haematologica were included. RESULTS: Of 499 RCTs screened, 109 RCTs were included. Our analysis revealed 118 major discrepancies and 629 total discrepancies. Among the 118 discrepancies, 30 (25.4%) primary outcomes were demoted, 47 (39.8%) primary outcomes were omitted, and 30 (25.4%) primary outcomes were added. Three (2.5%) secondary outcomes were upgraded to a primary outcome. The timing of assessment for a primary outcome changed eight (6.8%) times. Thirty-one major discrepancies were published with a P-value and twenty-five (80.6%) favored statistical significance. A majority of authors whom we contacted cited a pre-planned subgroup analysis as a reason for outcome changes. CONCLUSION: Our results suggest that outcome changes occur frequently in hematology trials. Because RCTs ultimately underpin clinical judgment and guide policy implementation, selective reporting could pose a threat to medical decision making. PMID- 28570574 TI - The dynamics of immune responses to Mycobacterium tuberculosis during different stages of natural infection: A longitudinal study among Greenlanders. AB - OBJECTIVE: Understanding human immunity to Mycobacterium tuberculosis (Mtb) during different stages of infection is important for development of an effective tuberculosis (TB) vaccine. We aimed to evaluate immunity to Mtb infection by measuring immune responses to selected Mtb antigens expressed during different stages of infection over time and to observe sustainability of immunity. METHODS: In a cohort study comprising East Greenlanders aged 17-22 years (2012 to 2014) who had either; undetectable Mtb infection, ongoing or prior Mtb infection at enrolment, we measured immunity to 15 antigens over a one-year period. Quantiferon-TB Gold testing (QFT) defined Mtb infection status (undetected/detected). The eligible study population of East Greenlanders aged 17 22 years was identified from the entire population using the Civil Registration System. From the source population 65 participants were selected by stratified random sampling according to information on Mtb infection stage. Retrospective and prospective information on notified TB (including treatment) was obtained through the mandatory TB notification system and was used to characterise Mtb infection stage (ongoing/prior). Immunity to 15 antigens including two QFT antigens, PPD and 12 non-QFT antigens (representing early, constitutive and latent Mtb infection) was assessed by measuring immune responses using whole blood antigen stimulation and interferon gamma measurement. RESULTS: Of 65 participants, 54 were considered Mtb-infected. Immunity to Mtb infection fluctuated with high annual risk of conversion (range: 6-69%) and reversion (range: 5-95%). During follow-up, five (8%) participants were notified with TB; neither conversion nor reversion was associated with an increased risk of progressing to TB. CONCLUSIONS: Our findings suggest that human immunity to natural Mtb infection over time is versatile with fluctuations, resulting in high levels of conversion and reversion of immunity, thus human immunity to Mtb is much more dynamic than anticipated. The study findings suggest future use of longitudinal assessment of immune responses when searching for TB vaccine candidate antigens. PMID- 28570575 TI - Phylogeny and diversity of neotropical monkey lizards (Iguanidae: Polychrus Cuvier, 1817). AB - Neotropical monkey lizards (Polychrus) are arboreal lizards with compressed bodies, partially fused eyelids and strikingly long, whip-like tails. The eight currently recognized species occur in the lowlands of South and Central America. Based on the largest taxon and character sampling to date, we analyze three mitochondrial and one nuclear gene using Bayesian methods to (1) infer the phylogeny of Polychrus under both concatenated-tree and species-tree methods; (2) identify lineages that could represent putative undescribed species; and (3) estimate divergence times. Our species tree places P. acutirostris as the sister taxon to all other species of Polychrus. While the phylogenetic position of P. gutturosus and P. peruvianus is poorly resolved, P. marmoratus and P. femoralis are strongly supported as sister to P. liogaster and P. jacquelinae, respectively. Recognition of P. auduboni and P. marmoratus sensu stricto as distinct species indicates that the populations of "P. marmoratus" from the Amazon and the Atlantic coast in Brazil represent separate species. Similarly, populations of P. femoralis from the Tumbes region might belong to a cryptic undescribed species. Relative divergence times and published age estimates suggest that the orogeny of the Andes did not play a significant role in the early evolution of Polychrus. PMID- 28570577 TI - Partial coupling delay induced multiple spatiotemporal orders in a modular neuronal network. AB - The influence of partial coupling delay on the spatiotemporal spiking dynamics is explored in a modular neuronal network. The modular neuronal network is composed of two subnetworks which present the small-world property and scale-free property, respectively. Numerical results show that spatiotemporal order that the modular network is most coherent in time and nearly synchronized in space can emerge intermittently when the coupling delays among neurons are appropriately tuned. The appropriately tuned delays are further detected to be integer multiples of the intrinsic spiking period of the modular neuronal network, which implies that the phenomenon of multiple spatiotemporal orders could be the result of a locking between the length of coupling delay and the intrinsic spiking period of the modular neuronal network. Moreover, the multiple spatiotemporal orders are verified to be robust against variations of the fraction of delayed connection as well as the key parameters of network architecture such as the rewiring probability, the average degree of small-world subnetwork, the initial nodes of scale-free subnetwork and the total size of the modular network. PMID- 28570576 TI - Characteristics of HIV target CD4 T cells collected using different sampling methods from the genital tract of HIV seronegative women. AB - BACKGROUND: Understanding the immune profile of CD4 T cells, the primary targets for HIV, in the female genital tract (FGT) is critical for evaluating and developing effective biomedical HIV prevention strategies in women. However, longitudinal investigation of HIV susceptibility markers expressed by FGT CD4 T cells has been hindered by low cellular yield and risk of sampling-associated trauma. We investigated three minimally invasive FGT sampling methods to characterize and compare CD4 T cell yield and phenotype with the goal of establishing feasible sampling strategies for immune profiling of mucosal CD4 T cells. METHODS AND RESULTS: FGT samples were collected bimonthly from 12 healthy HIV negative women of reproductive age in the following order: 1) Cervicovaginal lavage (CVL), 2) two sequential endocervical flocked swabs (FS), and 3) two sequential endocervical cytobrushes (CB1, CB2). Cells were isolated and phentoyped via flow cytometry. CD4 T cell recovery was highest from each individual CB compared to either CVL or FS (p < 0.0001). The majority of CD4 T cells within the FGT, regardless of sampling method, expressed CCR5 relative to peripheral blood (p < 0.01). Within the CB, CCR5+ CD4 T cells expressed significantly higher levels of alpha4beta7, CD69, and low levels of CD27 relative to CCR5- CD4 T cells (all p < 0.001). We also identified CD4 Treg lineage cells expressing CCR5 among CB samples. CONCLUSIONS: Using three different mucosal sampling methods collected longitudinally we demonstrate that CD4 T cells within the FGT express CCR5 and alpha4beta7 and are highly activated, attributes which could act in concert to facilitate HIV acquisition. FS and CB sampling methods can allow for investigation of strategies to reduce HIV target cells in the FGT and could inform the design and interpretation microbicide and vaccine studies in women. PMID- 28570578 TI - Effect of post-mortem delay on N-terminal huntingtin protein fragments in human control and Huntington disease brain lysates. AB - Huntington disease is associated with elongation of a CAG repeat in the HTT gene that results in a mutant huntingtin protein. Several studies have implicated N terminal huntingtin protein fragments in Huntington disease pathogenesis. Ideally, these fragments are studied in human brain tissue. However, the use of human brain tissue comes with certain unavoidable variables such as post mortem delay, artefacts from freeze-thaw cycles and subject-to-subject variation. Knowledge on how these variables might affect N-terminal huntingtin protein fragments in post mortem human brain is important for a proper interpretation of study results. The effect of post mortem delay on protein in human brain is known to vary depending on the protein of interest. In the present study, we have assessed the effect of post mortem delay on N-terminal huntingtin protein fragments using western blot. We mimicked post mortem delay in one individual control case and one individual Huntington disease case with low initial post mortem delay. The influence of subject-to-subject variation on N-terminal huntingtin fragments was assessed in human cortex and human striatum using two cohorts of control and Huntington disease subjects. Our results show that effects of post mortem delay on N-terminal huntingtin protein fragments are minor in our individual subjects. Additionally, one freeze-thaw cycle decreases the huntingtin western blot signal intensity in the cortex control subject, but does not introduce additional N-terminal huntingtin fragments. Our results suggest that subject-to-subject variation contributes more to variability in N-terminal huntingtin fragments than post mortem delay. PMID- 28570579 TI - Global transcriptome profiling identifies KLF15 and SLC25A10 as modifiers of adipocytes insulin sensitivity in obese women. AB - Although the mechanisms linking obesity to insulin resistance (IR) and type 2 diabetes (T2D) are not entirely understood, it is likely that alterations of adipose tissue function are involved. The aim of this study was to identify new genes controlling insulin sensitivity in adipocytes from obese women with either insulin resistant (OIR) or sensitive (OIS) adipocytes. Insulin sensitivity was first determined by measuring lipogenesis in isolated adipocytes from abdominal subcutaneous white adipose tissue (WAT) in a large observational study. Lipogenesis was measured under conditions where glucose transport was the rate limiting step and reflects in vivo insulin sensitivity. We then performed microarray-based transcriptome profiling on subcutaneous WAT specimen from a subgroup of 9 lean, 21 OIS and 18 obese OIR women. We could identify 432 genes that were differentially expressed between the OIR and OIS group (FDR <=5%). These genes are enriched in pathways related to glucose and amino acid metabolism, cellular respiration, and insulin signaling, and include genes such as SLC2A4, AKT2, as well as genes coding for enzymes in the mitochondria respiratory chain. Two IR-associated genes, KLF15 encoding a transcription factor and SLC25A10 encoding a dicarboxylate carrier, were selected for functional evaluation in adipocytes differentiated in vitro. Knockdown of KLF15 and SLC25A10 using siRNA inhibited insulin-stimulated lipogenesis in adipocytes. Transcriptome profiling of siRNA-treated cells suggested that KLF15 might control insulin sensitivity by influencing expression of PPARG, PXMP2, AQP7, LPL and genes in the mitochondrial respiratory chain. Knockdown of SLC25A10 had only modest impact on the transcriptome, suggesting that it might directly influence insulin sensitivity in adipocytes independently of transcription due to its important role in fatty acid synthesis. In summary, this study identifies novel genes associated with insulin sensitivity in adipocytes in women independently of obesity. KFL15 and SLC25A10 are inhibitors of insulin-stimulated lipogenesis under conditions when glucose transport is the rate limiting step. PMID- 28570580 TI - CT volumetric measurement of colorectal cancer helps predict tumor staging and prognosis. AB - PURPOSE: To evaluate feasibility of CT colonography (CTC) volumetry of colorectal cancer (CRC) and its correlation with disease stage and patients' survival. MATERIALS AND METHODS: CTC volumetry was performed for 126 patients who underwent preoperative CTC. Reproducibility of tumor volume (Tvol) between two readers was assessed. One-way ANOVA and ROC analysis evaluated correlation between Tvol and pTNM staging. ROC analysis compared diagnostic performance to predict pTNM staging between Tvol and radiologist. Kaplan-Meier test compared overall survival. RESULTS: Reproducibility among readers was excellent (interclass correlation = 0.9829). Mean Tvol showed an incremental trend with T stage and Tvol of pT4b stage was significantly larger than other stages (P<0.0001). Az value (0.780) of Tvol to predict pT4b stage was significantly larger than that (0.591) of radiologist (P = 0.004). However, Tvol was not significantly different according to pN stage. Az values (0.723~0.857) of Tvol to predict M1 or M1b were comparable to those (0.772~0.690) of radiologist (P>0.05). Smaller tumor burden (<=12.85cm3), <=T3, N0, M0 stages, and curative surgery were significantly associated with patients' longer survival (P<0.05). CONCLUSION: CT volumetry has a limited value to predict N stage; however, it may outperform the radiologist's performance when predicting pT4b and M1b stage and can be a useful prognostic marker. PMID- 28570581 TI - Environmental contaminants of honeybee products in Uganda detected using LC-MS/MS and GC-ECD. AB - Pollinator services and the development of beekeeping as a poverty alleviating tool have gained considerable focus in recent years in sub-Saharan Africa. An improved understanding of the pervasive environmental extent of agro-chemical contaminants is critical to the success of beekeeping development and the production of clean hive products. This study developed and validated a multi residue method for screening 36 pesticides in honeybees, honey and beeswax using LC-MS/MS and GC-ECD. Of the 36 screened pesticides, 20 were detected. The highest frequencies occurred in beeswax and in samples from apiaries located in the proximity of citrus and tobacco farms. Fungicides were the most prevalent chemical class. Detected insecticides included neonicotinoids, organophosphates, carbamates, organophosphorus, tetrazines and diacylhydrazines. All detected pesticide levels were below maximum residue limits (according to EU regulations) and the lethal doses known for honeybees. However, future risk assessment is needed to determine the health effects on the African genotype of honeybees by these pesticide classes and combinations of these. In conclusion, our data present a significant challenge to the burgeoning organic honey sector in Uganda, but to achieve this, there is an urgent need to regulate the contact routes of pesticides into the beehive products. Interestingly, the "zero" detection rate of pesticides in the Mid-Northern zone is a significant indicator of the large potential to promote Ugandan organic honey for the export market. PMID- 28570582 TI - Handling of thermal paper: Implications for dermal exposure to bisphenol A and its alternatives. AB - Bisphenol A (BPA) is an endocrine disrupting chemical used in a wide range of consumer products including photoactive dyes used in thermal paper. Recent studies have shown that dermal absorption of BPA can occur when handling these papers. Yet, regulatory agencies have largely dismissed thermal paper as a major source of BPA exposure. Exposure estimates provided by agencies such as the European Food Safety Authority (EFSA) are based on assumptions about how humans interact with this material, stating that 'typical' exposures for adults involve only one handling per day for short periods of time (<1 minute), with limited exposure surfaces (three fingertips). The objective of this study was to determine how individuals handle thermal paper in one common setting: a cafeteria providing short-order meals. We observed thermal paper handling in a college-aged population (n = 698 subjects) at the University of Massachusetts' dining facility. We find that in this setting, individuals handle receipts for an average of 11.5 min, that >30% of individuals hold thermal paper with more than three fingertips, and >60% allow the paper to touch their palm. Only 11% of the participants we observed were consistent with the EFSA model for time of contact and dermal surface area. Mathematical modeling based on handling times we measured and previously published transfer coefficients, concentrations of BPA in paper, and absorption factors indicate the most conservative estimated intake from handling thermal paper in this population is 51.1 ng/kg/day, similar to EFSA's estimates of 59 ng/kg/day from dermal exposures. Less conservative estimates, using published data on concentrations in thermal paper and transfer rates to skin, indicate that exposures are likely significantly higher. Based on our observational data, we propose that the current models for estimating dermal BPA exposures are not consistent with normal human behavior and should be reevaluated. PMID- 28570585 TI - Prevalence of depression and associated clinical and socio-demographic factors in people living with lymphatic filariasis in Plateau State, Nigeria. AB - BACKGROUND: Lymphatic filariasis is a chronic, disabling and often disfiguring condition that principally impacts the world's poorest people. In addition to the well-recognised physical disability associated with lymphedema and hydrocele, affected people often experience rejection, stigma and discrimination. The resulting emotional consequences are known to impact on the quality of life and the functioning of the affected individuals. However, the management of this condition has focused on prevention and treatment through mass drug administration, with scant attention paid to the emotional impact of the condition on affected individuals. This study aimed to determine the prevalence and severity of depression among individuals with physical disfigurement from lymphatic filariasis in Plateau State, Nigeria. METHODOLOGY: A cross-sectional 2 stage convenience study was conducted at 5 designated treatment centers across Plateau State, Nigeria. All available and consenting clients with clearly visible physical disfigurement were recruited. A semi-structured socio-demographic questionnaire, Rosenberg Self-esteem and a 9-item Patient Health Questionnaire (PHQ-9) were administered at the first stage. Those who screened positive (with a PHQ-9 score of five and above) were further interviewed using the Depression module of the Composite International Diagnostic Interview (CIDI). RESULTS: Ninety-eight individuals met the criteria and provided consent. Twenty percent of the respondents met criteria for depression, with the following proportions based on severity: Mild (42.1%), Moderate (31.6%) and Severe (26.3%). History of mental illness (OR 40.83, p = 0.008); Median duration of the illness was 17 years (IQR 7.0-30 years) and being unemployed (OR 12.71, p = 0.003) were predictive of depression. High self-esteem was negatively correlated (OR 0.09, p<0.004). CONCLUSION: Prevalence of depression is high among individuals with lymphatic filariasis and depression in sufferers is associated with low self-esteem and low levels of life satisfaction. PMID- 28570583 TI - Metabolomic and proteomic investigations of impacts of titanium dioxide nanoparticles on Escherichia coli. AB - In a previous study, it was demonstrated that the toxic impact of titanium dioxide nanoparticles on Escherichia coli starts at 10 ppm and is closely related to the presence of little aggregates. It was also assumed that only a part of the bacterial population is able to adapt to this stress and attempts to survive. Proteomic analyses, supported by results from metabolomics, reveal that exposure of E. coli to nano-TiO2 induces two main effects on bacterial metabolism: firstly, the up-regulation of proteins and the increase of metabolites related to energy and growth metabolism; secondly, the down-regulation of other proteins resulting in an increase of metabolites, particularly amino acids. Some proteins, e.g. chaperonin 1 or isocitrate dehydrogenase, and some metabolites, e.g. phenylalanine or valine, might be used as biomarkers of nanoparticles stress. Astonishingly, the ATP content gradually rises in relation with the nano-TiO2 concentration in the medium, indicating a dramatic release of ATP by the damaged cells. These apparently contradictory results accredit the thesis of a heterogeneity of the bacterial population. This heterogeneity is also confirmed by SEM images which show that while some bacteria are fully covered by nano-TiO2, the major part of the bacterial population remains free from nanoparticles, resulting in a difference of proteome and metabolome. The use of combined-omics has allowed to better understand the heterogeneous bacterial response to nano TiO2 stress due to heterogeneous contacts between the protagonists under environmental conditions. PMID- 28570586 TI - Inferring and analysis of social networks using RFID check-in data in China. AB - Social networks play an important role in our daily lives. However, social ties are rather elusive to quantify, especially for large groups of subjects over prolonged periods of time. In this work, we first propose a methodology for extracting social ties from long spatio-temporal data streams, where the subjects are 17,795 undergraduates from a university of China and the data streams are the 9,147,106 time-stamped RFID check-in records left behind by them during one academic year. By several metrics mentioned below, we then analyze the structure of the social network. Our results center around three main observations. First, we characterize the global structure of the network, and we confirm the small world phenomenon on a global scale. Second, we find that the network shows clear community structure. And we observe that younger students at lower levels tend to form large communities, while students at higher levels mostly form smaller communities. Third, we characterize the assortativity patterns by studying the basic demographic and network properties of users. We observe clear degree assortativity on a global scale. Furthermore, we find a strong effect of grade and school on tie formation preference, but we do not find any strong region homophily. Our research may help us to elucidate the structural characteristics and the preference of the formation of social ties in college students' social network. PMID- 28570584 TI - Characterisation of the canine faecal virome in healthy dogs and dogs with acute diarrhoea using shotgun metagenomics. AB - The virome has been increasingly investigated in numerous animal species and in different sites of the body, facilitating the identification and discovery of a variety of viruses. In spite of this, the faecal virome of healthy dogs has not been investigated. In this study we describe the faecal virome of healthy dogs and dogs with acute diarrhoea in Australia, using a shotgun metagenomic approach. Viral sequences from a range of different virus families, including both RNA and DNA families, and known pathogens implicated in enteric disease were documented. Twelve viral families were identified, of which four were bacteriophages. Eight eukaryotic viral families were detected: Astroviridae, Coronaviridae, Reoviridae, Picornaviridae, Caliciviridae, Parvoviridae, Adenoviridae and Papillomaviridae. Families Astroviridae, Picornaviridae and Caliciviridae were found only in dogs with acute diarrhoea, with Astroviridae being the most common family identified in this group. Due to its prevalence, characterisation the complete genome of a canine astrovirus was performed. These studies indicate that metagenomic analyses are useful for the investigation of viral populations in the faeces of dogs. Further studies to elucidate the epidemiological and biological relevance of these findings are warranted. PMID- 28570587 TI - Non-standard radiotherapy fractionations delay the time to malignant transformation of low-grade gliomas. AB - Grade II gliomas are slowly growing primary brain tumors that affect mostly young patients. Cytotoxic therapies (radiotherapy and/or chemotherapy) are used initially only for patients having a bad prognosis. These therapies are planned following the "maximum dose in minimum time" principle, i. e. the same schedule used for high-grade brain tumors in spite of their very different behavior. These tumors transform after a variable time into high-grade gliomas, which significantly decreases the patient's life expectancy. In this paper we study mathematical models describing the growth of grade II gliomas in response to radiotherapy. We find that protracted metronomic fractionations, i.e. therapeutical schedules enlarging the time interval between low-dose radiotherapy fractions, may lead to a better tumor control without an increase in toxicity. Other non-standard fractionations such as protracted or hypoprotracted schemes may also be beneficial. The potential survival improvement depends on the tumor's proliferation rate and can be even of the order of years. A conservative metronomic scheme, still being a suboptimal treatment, delays the time to malignant progression by at least one year when compared to the standard scheme. PMID- 28570589 TI - A hyperspectral vessel image registration method for blood oxygenation mapping. AB - Blood oxygenation mapping by the means of optical oximetry is of significant importance in clinical trials. This paper uses hyperspectral imaging technology to obtain in vivo images for blood oxygenation detection. The experiment involves dorsal skin fold window chamber preparation which was built on adult (8-10 weeks of age) female BALB/c nu/nu mice and in vivo image acquisition which was performed by hyperspectral imaging system. To get the accurate spatial and spectral information of targets, an automatic registration scheme is proposed. An adaptive feature detection method which combines the local threshold method and the level-set filter is presented to extract target vessels. A reliable feature matching algorithm with the correlative information inherent in hyperspectral images is used to kick out the outliers. Then, the registration images are used for blood oxygenation mapping. Registration evaluation results show that most of the false matches are removed and the smooth and concentrated spectra are obtained. This intensity invariant feature detection with outliers-removing feature matching proves to be effective in hyperspectral vessel image registration. Therefore, in vivo hyperspectral imaging system by the assistance of the proposed registration scheme provides a technique for blood oxygenation research. PMID- 28570588 TI - Predictive validity of the GOSLON Yardstick index in patients with unilateral cleft lip and palate: A systematic review. AB - Among the various indices developed for measuring the results of treatment in patients born with unilateral cleft lip and palate (UCLP), the GOSLON Yardstick index is the most widely used to assess the efficacy of treatment and treatment outcomes, which in UCLP cases are closely linked to jaw growth. The aim of this study was to conduct a systematic review to validate the predictability of growth using the GOSLON Yardstick in patients born with UCLP. A systematic literature review was conducted in four Internet databases: Medline, Cochrane Library, Scopus and Embase, complemented by a manual search and a further search in the databases of the leading journals that focus on this topic. An electronic search was also conducted among grey literature. The search identified a total of 131 articles. Duplicated articles were excluded and after reading titles and abstracts, any articles not related to the research objective were excluded, leaving a total of 21 texts. After reading the complete text, only three articles fulfilled the inclusion criteria. The results showed a predictive validity of between 42.2% and 64.7%, which points to a lack of evidence in the literature for the predictive validity of the GOSLON Yardstick index used in children born with UCLP. PMID- 28570590 TI - Influence of environmental factors on Cucumis melo L. var. agrestis Naud. seed germination and seedling emergence. AB - Cucumis melo L. var. agrestis Naud. (field muskmelon) is an annual invasive weed in many parts of Asia. However, there is very little available information about the germination and emergence of this species. Therefore, laboratory experiments were conducted to evaluate the effects of light, temperature, salt stress, osmotic stress, pH, and depth of planting on field muskmelon germination and seedling emergence. Light had no effect on seed germination, and the seeds germinated at a wide range of temperatures. More than 90% of the seeds germinated at constant temperatures between 20 degrees C and 35 degrees C, and fluctuating day/night temperatures between 15/25 and 30/40 degrees C. The seeds were tolerant to salinity as germination occurred up to the 200 mM NaCl treatment. However, the seeds were sensitive to osmotic stress as seed germination was completely inhibited at -0.6 MPa. The seeds germinated over a pH range of 4 to 10, which suggested that pH was not a limiting factor for germination. Seedling emergence was greatest (97.86%) when the seeds were planted on the soil surface, but emergence declined as the burial depth increased. Information from this study can be used to predict future infestations in China and help develop strategies to manage this species. PMID- 28570592 TI - A prospective study of the demographics, management and outcome of patients with acute kidney injury in Cape Town, South Africa. AB - AIM: To study the demographics and outcome of acute kidney injury (AKI) at Groote Schuur Hospital, Cape Town, South Africa. METHODS AND FINDINGS: A prospective observational study of AKI fulfilling the Kidney Disease: Improving Global Outcomes definition, from 8 July 2012 to 8 July 2013. Ethics approval was granted by the University of Cape Town Human Research Ethics Committee. Consent was waived because patient data was de-identified and patient management was not adversely affected by the study. A clerking sheet was used for data collection. Patients were reassessed after 3 months. Main outcomes were renal recovery and 3 month mortality. Descriptive statistics and multivariate logistic regression were carried out for risk factors. Over this period there were 10,750 hospital admissions and 366 patients with AKI giving an incidence of 3.4%. Median age was 44 years (IQR 14-82) and 214 (58.5%) were male, with 152 (41.5%) female. Most, 265 (72.4%), had community acquired AKI. Common underlying comorbidities were hypertension (n = 152, 41.5%), diabetes mellitus (n = 65, 17.8%) Human immunodeficiency virus (HIV) (n = 75, 20.6%), heart disease (n = 58, 16.1%), and chronic kidney disease (n = 37, 10.1%). Renal biopsies were performed in 36 (9.8%) patients. In total, 202 (55.2%) patients were in the intensive care unit, and of the whole study population 204 (55.7%) were dialysed. Those admitted to ICU who required dialysis amounted to 145 (39.6%). The overall 3 month mortality was 38.8%. Among the 145 patients dialysed in ICU, there were 71 deaths (49%) at 3 month follow up. Of the 119 patients with follow up serum creatinine, 95 (79.8%) had full renal recovery, and 4 (3.4%) had end-stage renal disease. On multivariate analysis, mechanical ventilation was associated with 3 month mortality (OR 2.46, p-value 0.019, 95% CI 1.41-4.03). Sepsis had a borderline significant association (OR 1.83, P-value 0.066, 95%CI 1.02-3.27), as did prolonged time to dialysis (OR 1.93, p-value 0.08, 095% CI 0.93-4.03). HIV status did not affect outcome. The main study limitations were the large numbers of patients with AKI stage 3, reflecting the fact that the institution is a tertiary referral centre and that patients with earlier stages of AKI tended not to be referred. Another study limitation was the low number of patients who were available for follow up for 3 month serum creatinine. CONCLUSIONS: The incidence of AKI in the population studied is 3.4% of hospital admissions and carries a high mortality risk, most significant in mechanically ventilated patients. Sepsis and late dialysis initiation may carry a risk of mortality, but HIV infection did not affect outcome. Follow up of patients at least 3 months after an episode of AKI is essential to detect and appropriately manage those with incomplete renal recovery. In this study 36 patients underwent a kidney biopsy, and in many of these the results guided patient management. This study demonstrates finally that it remains imperative that clinicians actively pursue underlying causes of acute decline in renal function, including urine analysis, renal ultrasonography and if indicated and safe, a renal biopsy. PMID- 28570593 TI - A review of active learning approaches to experimental design for uncovering biological networks. AB - Various types of biological knowledge describe networks of interactions among elementary entities. For example, transcriptional regulatory networks consist of interactions among proteins and genes. Current knowledge about the exact structure of such networks is highly incomplete, and laboratory experiments that manipulate the entities involved are conducted to test hypotheses about these networks. In recent years, various automated approaches to experiment selection have been proposed. Many of these approaches can be characterized as active machine learning algorithms. Active learning is an iterative process in which a model is learned from data, hypotheses are generated from the model to propose informative experiments, and the experiments yield new data that is used to update the model. This review describes the various models, experiment selection strategies, validation techniques, and successful applications described in the literature; highlights common themes and notable distinctions among methods; and identifies likely directions of future research and open problems in the area. PMID- 28570591 TI - Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1. AB - MACC1 (Metastasis Associated in Colon Cancer 1) is a key driver and prognostic biomarker for cancer progression and metastasis in a large variety of solid tumor types, particularly colorectal cancer (CRC). However, no MACC1 inhibitors have been identified yet. Therefore, we aimed to target MACC1 expression using a luciferase reporter-based high-throughput screening with the ChemBioNet library of more than 30,000 compounds. The small molecules lovastatin and rottlerin emerged as the most potent MACC1 transcriptional inhibitors. They remarkably inhibited MACC1 promoter activity and expression, resulting in reduced cell motility. Lovastatin impaired the binding of the transcription factors c-Jun and Sp1 to the MACC1 promoter, thereby inhibiting MACC1 transcription. Most importantly, in CRC-xenografted mice, lovastatin and rottlerin restricted MACC1 expression and liver metastasis. This is-to the best of our knowledge-the first identification of inhibitors restricting cancer progression and metastasis via the novel target MACC1. This drug repositioning might be of therapeutic value for CRC patients. PMID- 28570594 TI - Automated high throughput nucleic acid purification from formalin-fixed paraffin embedded tissue samples for next generation sequence analysis. AB - Curation and storage of formalin-fixed, paraffin-embedded (FFPE) samples are standard procedures in hospital pathology laboratories around the world. Many thousands of such samples exist and could be used for next generation sequencing analysis. Retrospective analyses of such samples are important for identifying molecular correlates of carcinogenesis, treatment history and disease outcomes. Two major hurdles in using FFPE material for sequencing are the damaged nature of the nucleic acids and the labor-intensive nature of nucleic acid purification. These limitations and a number of other issues that span multiple steps from nucleic acid purification to library construction are addressed here. We optimized and automated a 96-well magnetic bead-based extraction protocol that can be scaled to large cohorts and is compatible with automation. Using sets of 32 and 91 individual FFPE samples respectively, we generated libraries from 100 ng of total RNA and DNA starting amounts with 95-100% success rate. The use of the resulting RNA in micro-RNA sequencing was also demonstrated. In addition to offering the potential of scalability and rapid throughput, the yield obtained with lower input requirements makes these methods applicable to clinical samples where tissue abundance is limiting. PMID- 28570595 TI - Plasma brain natriuretic peptide levels are elevated in patients with cancer. AB - BACKGROUND: Natriuretic peptides have been proposed as biomarkers of cardiovascular disease, especially heart failure. Brain natriuretic peptide (BNP) has also been shown to be upregulated at the transcriptional and translational levels by pro-inflammatory cytokines in cardiac myocytes. Although we often measure plasma BNP levels in cancer patients, it remains unknown whether cancer related inflammation affects the plasma BNP levels. We investigated the relationship between the BNP and human cancers. METHODS: We retrospectively studied 2,923 patients in whom the plasma BNP levels and serum C-reactive protein (CRP) were measured and echocardiography was performed. Patients with clinically evident heart failure (NYHA II or higher), heart disease requiring medical treatment or surgery, renal dysfunction, and inflammatory disease were excluded. There were 234 patients in the final analysis. Blood sampling was performed before surgery and chemotherapy. In addition, we evaluated the relationship between the inflammation and plasma BNP levels in mouse models of colon cancer. RESULTS: Of the 234 patients, 80 were diagnosed with cancer. Both the plasma BNP and serum CRP levels were significantly higher in cancer patients than those without. There were no significant differences in the echocardiographic parameters. There was a significant positive correlation between the plasma BNP and serum CRP levels in cancer patients (r = 0.360, P<0.01) but not in those without. In cancer patients, only the CRP correlated with the BNP independent of the age, creatinine level, hypertension, and body mass index. In addition, in nude mice with subcutaneous colon cancer, the plasma BNP level was elevated compared with that in non-cancer mice, and there was a significant relationship between the plasma BNP and serum levels of the inflammatory markers. CONCLUSIONS: In cancer patients, as well as colon cancer model mice, the plasma BNP levels were elevated, possibly due to cancer-related inflammation. The effect of cancer on the BNP levels should be considered when using BNP as an indicator of heart failure in cancer patients. PMID- 28570596 TI - Implementing the PHMRC shortened questionnaire: Survey duration of open and closed questions in three sites. AB - BACKGROUND: More countries are using verbal autopsy as a part of routine mortality surveillance. The length of time required to complete a verbal autopsy interview is a key logistical consideration for planning large-scale surveillance. METHODS: We use the PHMRC shortened questionnaire to conduct verbal autopsy interviews at three sites and collect data on the length of time required to complete the interview. This instrument uses a novel checklist of keywords to capture relevant information from the open response. The open response section is timed separately from the section consisting of closed questions. RESULTS: We found the median time to complete the entire interview was approximately 25 minutes and did not vary substantially by age-specific module. The median time for the open response section was approximately 4 minutes and 60% of interviewees mentioned at least one keyword within the open response section. CONCLUSIONS: The length of time required to complete the interview was short enough for large scale routine use. The open-response section did not add a substantial amount of time and provided useful information which can be used to increase the accuracy of the predictions of the cause of death. The novel checklist approach further reduces the burden of transcribing and translating a large amount of free text. This makes the PHMRC instrument ideal for national mortality surveillance. PMID- 28570598 TI - Does optimal partitioning of color space account for universal color categorization? AB - A 2007 study by Regier, Kay, and Khetarpal purports to show that universal categories emerge as a result of optimal partitioning of color space. Regier, Kay, and Khetarpal only consider color categorizations of up to six categories. However, in most industrialized societies eleven color categories are observed. This paper shows that when applied to the case of eleven categories, Regier, Kay, and Khetarpal's optimality criterion yields unsatisfactory results. Applications of the criterion to the intermediate cases of seven, eight, nine, and ten color categories are also briefly considered and are shown to yield mixed results. We consider a number of possible explanations of the failure of the criterion in the case of eleven categories, and suggest that, as color categorizations get more complex, further criteria come to play a role, alongside Regier, Kay, and Khetarpal's optimality criterion. PMID- 28570597 TI - "I was in the darkness but the group brought me light": Development, relevance and feasibility of the Sondela HIV adjustment and coping intervention. AB - Developing interventions that address psychosocial wellbeing of people living with HIV is critical to ensure strong linkages to and retention in HIV care. This paper describes the development of Sondela, an HIV adjustment and coping intervention for heterosexual men and women living with HIV, and its relevance and feasibility in the South African context. Sondela is a six three-hour, small group-based, participatory workshop series. We followed an iterative, multi phased process of curriculum development that involved research, theoretical frameworks and piloting. A systematic review highlighted the absence of psychosocial interventions targeting heterosexual HIV positive populations living in high HIV prevalence and resource-poor settings. Formative studies demonstrated risk and social factors associated with adjustment and coping with HIV, emphasising the need for interventions that acknowledge gendered experiences. Our pilot of Sondela demonstrated high levels of relevance and feasibility. Men appreciated the workshop "space" to openly talk about their HIV positive status and what is means for their role as partners and fathers and friends. Women valued the skills and approaches because they were relevant to "real life" situations and not just about HIV. Sondela promises to be valuable in supporting health system initiatives and psychosocial support to strengthen linkages to and retention in HIV care, and this suggests a need for rigorous evaluation of Sondela to establish evidence for its effectiveness in a general population. PMID- 28570600 TI - 3D fractional moving blood volume (3D-FMBV) demonstrates decreased first trimester placental vascularity in pre-eclampsia but not the term, small for gestation age baby. AB - OBJECTIVE: To undertake an observational study to see whether first trimester placental vascularity, measured with a standardized power Doppler index: 3D-FMBV, is different in pregnancies which either develop pre-eclampsia or lead to term, normotensive small for gestational age (SGA) babies. METHODS: Women were scanned between 11 and 13+6 weeks. The placental volume (sPlaV) was estimated using our previously validated semi-automated tool. Estimates of 3D-FMBV were generated from the raw power Doppler signal for the whole utero-placental interface, UPI (FMBV-UPI) and 5mm into the placenta (FMBV-IVS). Differences in the placental volume and FMBV for pregnancies developing pre-eclampsia and resulting in term, normotensive SGA babies were compared with term, normotensive, appropriate for gestational age (AGA), controls. RESULTS: Results were available for 143 women. The placental volume (sPlaV) was reduced in both pre-eclampsia (p = 0.007) and term, normotensive SGA (p = 0.001) when compared with term normotensive AGA controls. 3D-FMBV estimates were significantly lower for pregnancies developing pre-eclampsia (FMBV-UPI, p = 0.03, FMBV-IVS, p = 0.01) but not for the normotensive SGA pregnancies (FMBV-UPI, p = 0.16, FMBV-IVS, p = 0.27). CONCLUSION: Pregnancies destined to develop pre-eclampsia are more likely to have small placentas with significantly reduced vascularity at 11-13 weeks. Those pregnancies which were normotensive throughout but resulted in an SGA baby delivered at term, had significantly smaller placentas but with similar vascularity to normotensive AGA pregnancies. PMID- 28570599 TI - Imatinib attenuates cardiac fibrosis by inhibiting platelet-derived growth factor receptors activation in isoproterenol induced model. AB - Cardiac fibrosis is a significant global health problem with limited treatment choices. Although previous studies have shown that imatinib (IMA) inhibited cardiac fibrosis, the anti-fibrotic mechanisms have not been clearly uncovered. The aim of this study is to evaluate whether IMA attenuates cardiac fibrosis by inhibiting platelet-derived growth factor receptors (PDGFR) on isoproterenol (ISO)-induced mice. Adult male C57BL/6 mice were treated with vehicle or ISO +/- IMA for one week. After echocardiography examination, the hearts of mice were used for histopathologic, RT-qPCR, and western blot analyses. We found that the ventricular wall thickness, cardiac hypertrophy, and apoptosis were enhanced following ISO treatment. IMA decreased the left ventricular wall thickness, prevented hypertrophy, and inhibited apoptosis induced by ISO. In addition, IMA attenuated the accumulation of collagens and alpha-smooth muscle actin (alpha SMA) (the markers of fibrosis) caused by ISO treatment. Moreover, the expression of fibrosis related genes, and the phosphorylation of PDGFRs in ISO-treated mice hearts were inhibited by IMA as well. However, IMA did not change the expression of the matrix metalloproteinase-9 (MMP-9) in ISO-treated hearts. Furthermore, IMA reduced the expressions of collagens as well as alpha-SMA caused by activation of PDGFRalpha in cardiac fibroblasts. Taken together, our data demonstrate that IMA attenuated the cardiac fibrosis by blocking the phosphorylation of PDGFRs in the ISO-induced mice model. This study indicates that IMA could be a potentially therapeutic option for cardiac fibrosis in clinical application. PMID- 28570601 TI - Characterization of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione resistance in pyomelanogenic Pseudomonas aeruginosa DKN343. AB - Pyomelanin is a reddish-brown pigment that provides bacteria and fungi protection from oxidative stress, and is reported to contribute to infection persistence. Production of this pigment can be inhibited by the anti-virulence agent 2-(2 nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). The Pseudomonas aeruginosa clinical isolate DKN343 exhibited high levels of resistance to NTBC, and the mechanism of pyomelanin production in this strain was uncharacterized. We determined that pyomelanin production in the clinical Pseudomonas aeruginosa isolate DKN343 was due to a loss of function in homogentisate 1,2-dioxygenase (HmgA). Several potential resistance mechanisms were investigated, and the MexAB OprM efflux pump is required for resistance to NTBC. DKN343 has a frameshift mutation in NalC, which is a known indirect repressor of the mexAB-oprM operon. This frameshift mutation may contribute to the increased resistance of DKN343 to NTBC. Additional studies investigating the prevalence of resistance in pyomelanogenic microbes are necessary to determine the future applications of NTBC as an anti-virulence therapy. PMID- 28570602 TI - A comparison of nucleosome organization in Drosophila cell lines. AB - Changes in the distribution of nucleosomes along the genome influence chromatin structure and impact gene expression by modulating the accessibility of DNA to transcriptional machinery. However, the role of genome-wide nucleosome positioning in gene expression and in maintaining differentiated cell states remains poorly understood. Drosophila melanogaster cell lines represent distinct tissue types and exhibit cell-type specific gene expression profiles. They thus could provide a useful tool for investigating cell-type specific nucleosome organization of an organism's genome. To evaluate this possibility, we compared genome-wide nucleosome positioning and occupancy in five different Drosophila tissue-specific cell lines, and in reconstituted chromatin, and then tested for correlations between nucleosome positioning, transcription factor binding motifs, and gene expression. Nucleosomes in all cell lines were positioned in accordance with previously known DNA-nucleosome interactions, with helically repeating A/T di-nucleotide pairs arranged within nucleosomal DNAs and AT-rich pentamers generally excluded from nucleosomal DNA. Nucleosome organization in all cell lines differed markedly from in vitro reconstituted chromatin, with highly expressed genes showing strong nucleosome organization around transcriptional start sites. Importantly, comparative analysis identified genomic regions that exhibited cell line-specific nucleosome enrichment or depletion. Further analysis of these regions identified 91 out of 16,384 possible heptamer sequences that showed differential nucleosomal occupation between cell lines, and 49 of the heptamers matched one or more known transcription factor binding sites. These results demonstrate that there is differential nucleosome positioning between these Drosophila cell lines and therefore identify a system that could be used to investigate the functional significance of differential nucleosomal positioning in cell type specification. PMID- 28570604 TI - Weed abundance is positively correlated with native plant diversity in grasslands of southern Australia. AB - Weeds are commonly considered a threat to biodiversity, yet interactions between native and exotic species in grasslands are poorly understood and reported results vary depending on the spatial scale of study, the factors controlled for and the response variables analysed. We tested whether weed presence and abundance is related to declines in biodiversity in Australian grasslands. We employed existing field data from 241 plots along a disturbance gradient and correlated species richness, cover and Shannon diversity for natives and exotics, controlling for seasonal rainfall, climatic gradients and nutrient status. We found no negative relationships in terms of emergent diversity metrics and occupation of space, indeed, many positive relationships were revealed. When split by land-use, differences were found along the disturbance gradient. In high moderately disturbed grasslands associated with land-uses such as cropping and modified pastures, positive associations were enhanced. Tolerance and facilitation mechanisms may be involved, such as complementary roles through different life history strategies: the exotic flora was dominated mainly by annual grasses and herbs whereas the native flora represented more diverse growth forms with a higher proportion of perennials. The positive relationships existing between native and exotic plant species in high-moderately disturbed grasslands of South Australia are most likely due to facilitation through different strategies in occupation of space given that the effect of habitat suitability was controlled for by including environmental and disturbance factors. Consequently, although particular weeds may negatively impact biodiversity, this cannot be generalised and management focusing on general weed eradication in grasslands might be ineffectual. PMID- 28570603 TI - Evolution of Salmonella Typhi outer membrane protein-specific T and B cell responses in humans following oral Ty21a vaccination: A randomized clinical trial. AB - : Vaccination against complex pathogens such as typhoidal and non-typhoidal Salmonella requires the concerted action of different immune effector mechanisms. Outer membrane proteins (Omps) of Salmonella Typhi are potent immunogens, which elicit long-lasting and protective immunity. Here, we followed the evolution of S. Typhi OmpC and F-specific T and B cell responses in healthy volunteers after vaccination with the vaccine strain Ty21a. To follow humoral and cellular immune responses, pre- and post-vaccination samples (PBMC, serum and stool) collected from 15 vaccinated and 5 non-vaccinated individuals. Immunoglobulin levels were assessed in peripheral blood by enzyme-linked immunosorbent assay. B cell and T cell activation were analyzed by flow cytometry. We observed a significant increase of circulating antibody-secreting cells and maximal Omp-specific serum IgG titers at day 25 post vaccination, while IgA titers in stool peaked at day 60. Likewise, Omp-specific CD4+ T cells in peripheral blood showed the highest expansion at day 60 post vaccination, concomitant with a significant increase in IFN-gamma and TNFalpha production. These results indicate that S. Typhi Omp specific B cell responses and polyfunctional CD4+ T cell responses evolve over a period of at least two months after application of the live attenuated vaccine. Moreover, these findings underscore the potential of S. Typhi Omps as subunit vaccine components. TRIAL REGISTRATION: ISRCTN18360696. PMID- 28570605 TI - Frameshift indels introduced by genome editing can lead to in-frame exon skipping. AB - The introduction of frameshift indels by genome editing has emerged as a powerful technique to study the functions of uncharacterized genes in cell lines and model organisms. Such mutations should lead to mRNA degradation owing to nonsense mediated mRNA decay or the production of severely truncated proteins. Here, we show that frameshift indels engineered by genome editing can also lead to skipping of "multiple of three nucleotides" exons. Such splicing events result in in-frame mRNA that may encode fully or partially functional proteins. We also characterize a segregating nonsense variant (rs2273865) located in a "multiple of three nucleotides" exon of LGALS8 that increases exon skipping in human erythroblast samples. Our results highlight the potentially frequent contribution of exonic splicing regulatory elements and are important for the interpretation of negative results in genome editing experiments. Moreover, they may contribute to a better annotation of loss-of-function mutations in the human genome. PMID- 28570606 TI - Effects of two different decellularization routes on the mechanical properties of decellularized lungs. AB - Considering the limited number of available lung donors, lung bioengineering using whole lung scaffolds has been proposed as an alternative approach to obtain lungs suitable for transplantation. However, some decellularization protocols can cause alterations on the structure, composition, or mechanical properties of the lung extracellular matrix. Therefore, the aim of this study was to compare the acellular lung mechanical properties when using two different routes through the trachea and pulmonary artery for the decellularization process. This study was performed by using the lungs excised from 30 healthy male C57BL/6 mice, which were divided into 3 groups: tracheal decellularization (TDG), perfusion decellularization (PDG), and control groups (CG). Both decellularized groups were subjected to decellularization protocol with a solution of 1% sodium dodecyl sulfate. The behaviour of mechanical properties of the acellular lungs was measured after decellularization process. Static (Est) and dynamic (Edyn) elastances were obtained by the end-inspiratory occlusion method. TDG and PDG showed reduced Est and Edyn elastances after lung decellularization. Scanning electron microscopy showed no structural changes after lung decellularization of the TDG and PDG. In conclusion, was demonstrated that there is no significant difference in the behaviour of mechanical properties and extracellular matrix of the decellularized lungs by using two different routes through the trachea and pulmonary artery. PMID- 28570607 TI - Discovery of a new hypotrich ciliate from petroleum contaminated soil. AB - Pollution after oil spill represents extreme habitat for survival and is a major concern for loss of species diversity in the affected area. In this study, we investigated soil samples collected from a petrochemical industry, Ulsan, South Korea. The soil was in the phase of recovery from the contamination of crude oil spill. Detailed investigation, based on morphology, ontogenesis, and molecular phylogenetic methods, resulted in discovery of a novel hypotrich ciliate, i.e., Metasterkiella koreana n. gen., n. sp., which is morphologically characterized by a semirigid body, undulating membranes in Oxytricha pattern, 18 frontal-ventral transverse cirri with cirrus V/3 placed posteriorly, one right and one left row of marginal cirri, four dorsal kineties, two dorsomarginal rows, and caudal cirri at the end of dorsal kineties 1, 2, and 4. Interestingly, during ontogenesis, formation of three common anlagen for the proter and the opisthe and involvement of cirrus V/3 in anlagen formation was observed. The dorsal ontogenesis was typical of oxytrichids, i.e., simple fragmentation of dorsal kinety 3 and formation of dorsomarginal rows close to the right marginal row. The new species was found to be similar with Sterkiella subtropica, except for some minor differences in morphometry, and at gene level with only one base pair difference. In phylogenetic analyses, based on SSU rRNA gene sequence, M. koreana cluster in a clade away from Sterkiella species, which could be explained by the differences in the morphogenetic pattern between these two genera. It is proposed that S. subtropica probably belongs to Metasterkiella; however, we do not perform changes and wait for the reinvestigation of its morphogenetic pattern. PMID- 28570608 TI - The spread of Wolbachia through mosquito populations. AB - In many regions of the world, mosquito-borne viruses pose a growing threat to human health. As an alternative to traditional control measures, the bacterial symbiont Wolbachia has been transferred from Drosophila into the mosquito Aedes aegypti, where it can block the transmission of dengue and Zika viruses. A recent paper has reported large-scale releases of Wolbachia-infected Ae. aegypti in the city of Cairns, Australia. Wolbachia, which is maternally transmitted, invaded and spread through the populations due to a sperm-egg incompatibility called cytoplasmic incompatibility. Over a period of 2 years, a wave of Wolbachia infection slowly spread out from 2 release sites, demonstrating that it will be possible to deploy this strategy in large urban areas. In line with theoretical predictions, Wolbachia infection at a third, smaller release site collapsed due to the immigration of Wolbachia-free mosquitoes from surrounding areas. This remarkable field experiment has both validated theoretical models of Wolbachia population dynamics and demonstrated that this is a viable strategy to modify mosquito populations. PMID- 28570609 TI - Construction of an enantiopure bivalent nicotine vaccine using synthetic peptides. AB - Clinical outcomes of anti-nicotine vaccines may be improved through enhancements in serum antibody affinity and concentration. Two strategies were explored to improve vaccine efficacy in outbred mice: the use of enantiopure haptens and formulation of a bivalent vaccine. Vaccines incorporating natural (-) nicotine haptens improved relative antibody affinities >10-fold over (+) haptens, stimulated a two-fold boost in nicotine serum binding capacity, and following injection with 3 cigarette equivalents of nicotine, prevented a larger proportion of nicotine (>85%) from reaching the brain. The activity of a bivalent vaccine containing (-) 3'AmNic and (-) 1'SNic haptens was then compared to dose-matched monovalent groups. It was confirmed that antisera generated by these structurally distinct haptens have minimal cross-reactivity and stimulate different B cell populations. Equivalent antibody affinities were detected between the three groups, but the bivalent group showed two-fold higher titers and an additive increase in nicotine serum binding capacity as compared to the monovalent groups. Mice immunized with the bivalent formulation also performed better in a nicotine challenge experiment, and prevented >85% of a nicotine dose equivalent to 12 cigarettes from reaching the brain. Overall, enantiopure conjugate vaccines appear to improve serum antibody affinity, while multivalent formulations increase total antibody concentration. These findings may help improve the performance of future clinical candidate vaccines. PMID- 28570610 TI - Bacterial community structure transformed after thermophilically composting human waste in Haiti. AB - Recycling human waste for beneficial use has been practiced for millennia. Aerobic (thermophilic) composting of sewage sludge has been shown to reduce populations of opportunistically pathogenic bacteria and to inactivate both Ascaris eggs and culturable Escherichia coli in raw waste, but there is still a question about the fate of most fecal bacteria when raw material is composted directly. This study undertook a comprehensive microbial community analysis of composting material at various stages collected over 6 months at two composting facilities in Haiti. The fecal microbiota signal was monitored using a high density DNA microarray (PhyloChip). Thermophilic composting altered the bacterial community structure of the starting material. Typical fecal bacteria classified in the following groups were present in at least half the starting material samples, yet were reduced below detection in finished compost: Prevotella and Erysipelotrichaceae (100% reduction of initial presence), Ruminococcaceae (98 99%), Lachnospiraceae (83-94%, primarily unclassified taxa remained), Escherichia and Shigella (100%). Opportunistic pathogens were reduced below the level of detection in the final product with the exception of Clostridium tetani, which could have survived in a spore state or been reintroduced late in the outdoor maturation process. Conversely, thermotolerant or thermophilic Actinomycetes and Firmicutes (e.g., Thermobifida, Bacillus, Geobacillus) typically found in compost increased substantially during the thermophilic stage. This community DNA-based assessment of the fate of human fecal microbiota during thermophilic composting will help optimize this process as a sanitation solution in areas where infrastructure and resources are limited. PMID- 28570611 TI - Lipid profile of different infant formulas for infants. AB - Situations including premature infants, or those in which there is a rejection to breastfeeding, require the use infant formulas for total or partial replacement of human milk. The objective of this study was to determine the lipid content and to identify the lipid profile of infant formulas. Samples were collected from ten different infant formulas, used as a substitute for breast milk at the Maternal and Child Hospital of Brasilia. The human milk sample consisted of a pool of samples from 10 mature milk donors at the milk bank of the University Hospital of Brasilia. The lipid content and lipid profile of the different infant formulas and human milk were analyzed. The experiment was conducted in a randomized block design, with eleven treatments and three replicates, in triplicate. The data obtained in this study indicated significant differences between infant formulas and human milk, and among the infant formulas analyzed in relation to the percentage of total lipids and the fatty acid profile, except for the fractions of linoleic acid and linolenic acid. Regarding the percentage of polyunsaturated fatty acids in relation to the total unsaturated fatty acids, only the Soy Protein Isolate-based Infant Formula (SPIIF) and Whey Protein Extensively Hydrolyzed Infant Formula (WPEHIF) resembled human milk. It was concluded that despite the observed differences, the use of infant formulas is a viable strategy for the development of infants subjected or not to specific physiological conditions. PMID- 28570612 TI - Caveolin1 protects against diet induced hepatic lipid accumulation in mice. AB - BACKGROUND AND AIM: Caveolin1 (CAV1) is involved in lipid homeostasis and endocytosis, but little is known about the significance of CAV1 in the pathogenesis and development of nonalcoholic fatty liver disease (NAFLD). This study aimed to determine the role of CAV1 in NAFLD. METHODS: Expression of CAV1 in the in vitro and in vivo models of NAFLD was analyzed. The effects of CAV1 knockdown or overexpression on free fatty acid (FFA)-induced lipid accumulation in L02 cells and AML12 cells were determined. CAV1 knockout (CAV1-KO) mice and their wild-type (WT) littermates were subjected to a high fat diet (HFD) for 4 weeks, and the functional consequences of losing the CAV1 gene and its subsequent molecular mechanisms were also examined. RESULTS: Noticeably, CAV1 expression was markedly reduced in NAFLD. CAV1 knockdown led to the aggravation of steatosis that was induced by FFA in both L02 cells and AML12 cells, while CAV1 overexpression markedly attenuated lipid accumulation in the cells. Consistent with CAV1 repression in the livers of HFD-induced mice, the CAV1-KO mice exhibited more severe hepatic steatosis upon HFD intake. In addition, increased cholesterol levels and elevated transaminases were detected in the plasma of CAV1 KO mice. The protein expression of SREBP1, a key gene involved in lipogenesis, was augmented following CAV1 suppression in FFA-treated hepatocytes and in the livers of HFD-fed CAV1-KO mice. CONCLUSIONS: CAV1 serves as an important protective factor in the development of NAFLD by modulating lipid metabolism gene expression. PMID- 28570613 TI - Clinical, ultrasound and molecular biomarkers for early prediction of large for gestational age infants in nulliparous women: An international prospective cohort study. AB - OBJECTIVE: To develop a prediction model for term infants born large for gestational age (LGA) by customised birthweight centiles. METHODS: International prospective cohort of nulliparous women with singleton pregnancy recruited to the Screening for Pregnancy Endpoints (SCOPE) study. LGA was defined as birthweight above the 90th customised centile, including adjustment for parity, ethnicity, maternal height and weight, fetal gender and gestational age. Clinical risk factors, ultrasound parameters and biomarkers at 14-16 or 19-21 weeks were combined into a prediction model for LGA infants at term using stepwise logistic regression in a training dataset. Prediction performance was assessed in a validation dataset using area under the Receiver Operating Characteristics curve (AUC) and detection rate at fixed false positive rates. RESULTS: The prevalence of LGA at term was 8.8% (n = 491/5628). Clinical and ultrasound factors selected in the prediction model for LGA infants were maternal birthweight, gestational weight gain between 14-16 and 19-21 weeks, and fetal abdominal circumference, head circumference and uterine artery Doppler resistance index at 19-21 weeks (AUC 0.67; 95%CI 0.63-0.71). Sensitivity of this model was 24% and 49% for a fixed false positive rate of 10% and 25%, respectively. The addition of biomarkers resulted in selection of random glucose, LDL-cholesterol, vascular endothelial growth factor receptor-1 (VEGFR1) and neutrophil gelatinase associated lipocalin (NGAL), but with minimal improvement in model performance (AUC 0.69; 95%CI 0.65-0.73). Sensitivity of the full model was 26% and 50% for a fixed false positive rate of 10% and 25%, respectively. CONCLUSION: Prediction of LGA infants at term has limited diagnostic performance before 22 weeks but may have a role in contingency screening in later pregnancy. PMID- 28570614 TI - Employment history indicators and mortality in a nested case-control study from the Spanish WORKing life social security (WORKss) cohort. AB - Employment has transitioned from stable to more flexible schemes. Little is known about the effects of dynamic working lives and mortality. We examined the association of employment, unemployment and inactivity on mortality among workers born in 1926-1988, in a nested case-control study of workers from the Spanish WORKss cohort. Cases were all deaths that occurred during 2004-2013 and controls were living persons, matched for sex and age at the time the case occurred. We had information on employment from 1981 to 2013. Logistic regression was used to measure the associations between the 3 employment history indicators separately by sex. There were 53,989 cases and an equal number of controls (n = 107,978). More than 16 years employed showed a protective effect against mortality in women (OR = 0.88, 95%CI: 0.81, 0.94) and men (OR = 0.76, 95%CI: 0.70, 0.79). The number of spells and time in unemployment and inactivity were significantly related to mortality in men, but not women. Sensitivity analyses by labor relationship showed stronger associations of unemployment (OR = 1.42, 95%CI: 1.13, 1.78) and inactivity (OR = 1.34; 95%CI: 1.09, 1.65) for temporary workers. Employment gaps are detrimental to health and have worse effects if the gaps occur without unemployment benefits or after temporary contracts. These results may drive improvement of labor and social policies that protect workers against the potential negative effects of dynamic work lives. PMID- 28570615 TI - Liver biopsy in type 2 diabetes mellitus: Steatohepatitis represents the sole feature of liver damage. AB - Recent studies report a prevalence of non-alcoholic fatty liver disease (NAFLD) of between 70% and 80% in patients with metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Nevertheless, it is not possible to differentiate between simple steatosis and non-alcoholic steatohepatitis (NASH) with non invasive tests. The aim of this study was to differentiate between simple steatosis and NASH by liver biopsy in patients with hypertransaminasemia and MS or T2DM. Two hundred and fifteen patients with increased ALT levels and MS, and 136 patients at their first diagnosis of T2DM regardless of ALT values were consecutively admitted to a tertiary hepatology center between January 2004 and November 2014. Exclusion criteria were other causes of liver disease/ALT increase. Each patient underwent a clinical, laboratory and ultrasound evaluation, and a liver biopsy. Gender distribution, age, and body mass index were similar in the two groups of patients, whereas cholesterol levels, glycemia and blood pressure were significantly different between the two groups. The prevalence of NAFLD was 94.82% in MS patients and 100% in T2DM patients. NASH was present in 58.52% of MS patients and 96.82% of T2DM. Consequently, this study reveals that, by using liver biopsy, almost all patients with T2DM or MS have NAFLD, which in patients with T2DM means NASH. Importantly, it suggests that NASH may be one of the early complications of T2DM due to its pathophysiological correlation with insulin resistance. PMID- 28570616 TI - Does expert knowledge improve automatic probabilistic classification of gait joint motion patterns in children with cerebral palsy? AB - BACKGROUND: This study aimed to improve the automatic probabilistic classification of joint motion gait patterns in children with cerebral palsy by using the expert knowledge available via a recently developed Delphi-consensus study. To this end, this study applied both Naive Bayes and Logistic Regression classification with varying degrees of usage of the expert knowledge (expert defined and discretized features). A database of 356 patients and 1719 gait trials was used to validate the classification performance of eleven joint motions. HYPOTHESES: Two main hypotheses stated that: (1) Joint motion patterns in children with CP, obtained through a Delphi-consensus study, can be automatically classified following a probabilistic approach, with an accuracy similar to clinical expert classification, and (2) The inclusion of clinical expert knowledge in the selection of relevant gait features and the discretization of continuous features increases the performance of automatic probabilistic joint motion classification. FINDINGS: This study provided objective evidence supporting the first hypothesis. Automatic probabilistic gait classification using the expert knowledge available from the Delphi-consensus study resulted in accuracy (91%) similar to that obtained with two expert raters (90%), and higher accuracy than that obtained with non-expert raters (78%). Regarding the second hypothesis, this study demonstrated that the use of more advanced machine learning techniques such as automatic feature selection and discretization instead of expert-defined and discretized features can result in slightly higher joint motion classification performance. However, the increase in performance is limited and does not outweigh the additional computational cost and the higher risk of loss of clinical interpretability, which threatens the clinical acceptance and applicability. PMID- 28570618 TI - Correction: Change in the Interstitial Cells of Cajal and nNOS Positive Neuronal Cells with Aging in the Stomach of F344 Rats. AB - [This corrects the article DOI: 10.1371/journal.pone.0169113.]. PMID- 28570617 TI - Environmental and phenotype-related risk factors for owner-reported allergic/atopic skin symptoms and for canine atopic dermatitis verified by veterinarian in a Finnish dog population. AB - The aim of this cross-sectional study was to observe whether environmental factors and phenotypic traits are associated with owner-reported skin problems and with veterinary diagnosed canine atopic dermatitis (CAD). Data were collected using the validated online DOGRISK questionnaire. Out of the data that the questionnaire provides for analysis, focus was first turned towards addressing questions regarding 'Atopy/allergy (skin symptoms)' using a total of 8643 dogs: 1585 dogs with owner-reported allergic/atopic skin symptoms and 7058 dogs without. A subsequent analysis compared dogs with veterinary-verified CAD (n = 322) as a case group against the 7058 dogs without owner-reported skin symptoms. The association between 21 factors related to the environment, canine phenotypes and breed groups within both populations were analysed using univariable and multivariable logistic regression. The environmental factors that showed a significant inverse association with the risk of owner-reported allergic/atopic skin symptoms were as following: whether the dog was living in a detached house, whether there were other dogs in the household, and whether the dog was born in the current household. Having over 50% white colour in the coat and living in an extremely clean household were significantly associated with an increased risk of owner-reported allergic/atopic skin symptoms. The five breeds demonstrating the highest proportion of owner-reported allergic/atopic skin symptoms were West Highland white terrier, Boxer, English bulldog, Dalmatian and French bulldog. The Federation Cynologique Internationale dog breed groups 3 (Terriers) and 6 (Scent hounds and related breeds) showed a significantly higher risk for owner-reported allergic/atopic skin symptoms than mixed breed dogs. In the second population, the inverse association was observed between the risk of CAD and the presence of other dogs in the household, and whether the dog had been born in the current household. The results indicate that some environmental factors and canine phenotypes are associated with CAD and owner-reported skin symptoms, but they still do not prove causality. PMID- 28570619 TI - Impact of magnesium:calcium ratio on calcification of the aortic wall. AB - OBJECTIVE: An inverse relationship between serum magnesium concentration and vascular calcification has been reported following observational clinical studies. Moreover, several studies have been suggesting a protective effect of magnesium on the vascular calcification. However, the exact mechanism remains elusive, and investigators have speculated among a myriad of potential actions. The effect of magnesium on calcification of the aortic wall is yet to be investigated. In the present study, the effects of magnesium and calcium on the metabolism of extracellular PPi, the main endogenous inhibitor of vascular calcification, were investigated in the rat aorta. APPROACH AND RESULTS: Calcium and magnesium have antagonist effects on PPi hydrolysis in the aortic wall. Km and Ki values for PPi hydrolysis in rat aortic rings were 1.1 mmol/L magnesium and 32 MUmol/L calcium, respectively, but ATP hydrolysis was not affected with calcium. Calcium deposition in the rat aortic wall dramatically increased when the magnesium concentration was increased (ratio of Mg:Ca = 1:1; 1.5 mmol/L calcium and 1.5 mmol/L magnesium) respect to low magnesium concentration (ratio Mg:Ca = 1:3, 1.5 mmol/L calcium and 0.75 mmol/L magnesium). CONCLUSION: Data from observational clinical studies showing that the serum magnesium concentration is inversely correlated with vascular calcification could be reinterpreted as a compensatory regulatory mechanism that reduces both PPi hydrolysis and vascular calcification. The impact of magnesium in vascular calcification in humans could be studied in association with calcium levels, for example, as the magnesium:calcium ratio. PMID- 28570620 TI - Viral etiologies in adult patients with encephalitis in Poland: A prospective single center study. AB - Encephalitis is a severe neurological syndrome associated with high morbidity and mortality as well as long-term neurological sequelae. Despite being an important public health problem, very few extensive population-based studies were conducted so far in the world and none in Central Europe. Altogether 114 consecutive patients meeting the initial criteria for encephalitis were enrolled at the Warsaw Hospital for Infectious Diseases between June 2012 and July 2015. Eighteen patients were secondarily excluded from the analysis due to incomplete data or noinfectious cause. Potential pathogen sequences were searched for by molecular methods in the cerebrospinal fluid (CSF) and specific antibodies were detected in CSF and sera. An infectious agent was identified in 41 patients (42.7%). The most frequently diagnosed infections were Human herpesvirus 1 (HHV-1) (22 cases, 24%) followed by Enterovirus (6 cases, 6.3%), Varicella zoster virus (VZV) (5 cases, 5.2%), Tick-borne encephalitis virus (TBEV) (6 cases, 6.3%) and Cytomegalovirus (CMV) (2 cases, 2.1%). There were no cases of human adenovirus, Human herpesvirus 6 (HHV-6) or West Nile virus (WNV) infection identified. In 55 cases (57.3%) the cause of encephalitis remained unknown. Compared to patients in whom the diagnosis was determined the latter group contained more women, was less likely to manifest fever and had lower CSF pleocytosis (p < 0.05) In summary, we identified HHV-1 followed by Enterovirus, VZV and TBEV as the most common causes of encephalitis among adult patients in Poland. In a large proportion of patients the cause of encephalitis remained unknown. PMID- 28570622 TI - Correction: MUC1 facilitates metabolomic reprogramming in triple-negative breast cancer. AB - [This corrects the article DOI: 10.1371/journal.pone.0176820.]. PMID- 28570621 TI - Effect of glaucoma on eye movement patterns and laboratory-based hazard detection ability. AB - PURPOSE: The mechanisms underlying the elevated crash rates of older drivers with glaucoma are poorly understood. A key driving skill is timely detection of hazards; however, the hazard detection ability of drivers with glaucoma has been largely unexplored. This study assessed the eye movement patterns and visual predictors of performance on a laboratory-based hazard detection task in older drivers with glaucoma. METHODS: Participants included 30 older drivers with glaucoma (71+/-7 years; average better-eye mean deviation (MD) = -3.1+/-3.2 dB; average worse-eye MD = -11.9+/-6.2 dB) and 25 age-matched controls (72+/-7 years). Visual acuity, contrast sensitivity, visual fields, useful field of view (UFoV; processing speeds), and motion sensitivity were assessed. Participants completed a computerised Hazard Perception Test (HPT) while their eye movements were recorded using a desk-mounted Tobii TX300 eye-tracking system. The HPT comprises a series of real-world traffic videos recorded from the driver's perspective; participants responded to road hazards appearing in the videos, and hazard response times were determined. RESULTS: Participants with glaucoma exhibited an average of 0.42 seconds delay in hazard response time (p = 0.001), smaller saccades (p = 0.010), and delayed first fixation on hazards (p<0.001) compared to controls. Importantly, larger saccades were associated with faster hazard responses in the glaucoma group (p = 0.004), but not in the control group (p = 0.19). Across both groups, significant visual predictors of hazard response times included motion sensitivity, UFoV, and worse-eye MD (p<0.05). CONCLUSIONS: Older drivers with glaucoma had delayed hazard response times compared to controls, with associated changes in eye movement patterns. The association between larger saccades and faster hazard response time in the glaucoma group may represent a compensatory behaviour to facilitate improved performance. PMID- 28570623 TI - Genetic diversity of hepatitis C virus in Ethiopia. AB - Hepatitis C virus (HCV) is genetically highly divergent and classified in seven major genotypes and approximately hundred subtypes. These genotypes/subtypes have different geographic distribution and response to antiviral therapy. In Ethiopia, however, little is known about their molecular epidemiology and genetic diversity. The aim of this study was to investigate the distribution and genetic diversity of HCV genotypes/subtypes in Ethiopia, using 49 HCV RNA positive samples. HCV genotypes and subtypes were determined based on the sequences of the core and the nonstructural protein 5B (NS5B) genomic regions. Phylogenetic analysis revealed that the predominant was genotype 4 (77.6%) followed by 2 (12.2%), 1 (8.2%), and 5 (2.0%). Seven subtypes were identified (1b, 1c, 2c, 4d, 4l, 4r and 4v), with 4d (34.7%), 4r (34.7%) and 2c (12.2%) as the most frequent subtypes. Consistent with the presence of these subtypes was the identification of a potential recombinant virus. One strain was typed as genotype 2c in the NS5B region sequence and genotype 4d in the core region. In conclusion, genotype 4 HCV viruses, subtypes 4d and 4r, are most prevalent in Ethiopia. This genotype is considered to be difficult to treat, thus, our finding has an important impact on the development of treatment strategies and patient management in Ethiopia. PMID- 28570624 TI - Macular Bruch's membrane defect and dome-shaped macula in high myopia. AB - PURPOSE: To examine an association between macular Bruch's membrane defects (MBMD) and a dome-shaped appearance of the macula (DSM). DESIGN: Retrospective, observational case series study. METHODS: The study included highly myopic individuals who were consecutively examined between May 2014 and December 2015. The patients underwent swept-source optical coherence tomography (OCT) for visualization of DSM and MBMDs defined as Bruch's membrane defects located at a distance of maximal 1500 MUm from the foveola. RESULTS: Out of 1983 highly myopic eyes (1057 patients), 166 eyes (8.4%; 95% confidence interval (CI):7.2%,9.6%)) showed a DSM and 534 eyes showed a MBMD. In multivariate binary regression analysis, higher prevalence of DSM was associated with a higher prevalence of a MBMD (P<0.001; OR: 1.96; 95%CI: 1.40, 2.75) after adjusting for longer axial length (P<0.001; odds ratio (OR): 1.27; 95%CI: 1.16, 1.38). In eyes with a DSM partially surrounded by a MBMD, the retina, retinal pigment epithelium (RPE) and choroid appeared relatively unchanged in the central region with Bruch's membrane (BM) preserved. In the ring-like BM-free region surrounding the central prominent island of the DSM, the RPE, the outer and middle retinal layers, the choriocapillaris and the middle-sized choroidal vessel layer were absent. In association with a DSM, three MBMD types were differentiated: MBMDs in patchy chorioretinal atrophy, MBMDs in choroidal neovascularization-related macular atrophy, and MBMDs as temporally extending large parapapillary gamma zone. CONCLUSIONS: Presence of a DSM was significantly associated with the presence of MBMDs. The morphology of the DSM in association with MBMDs may be associated with a focal relaxation of the posterior sclera, no longer pushed outward by an expanding BM but allowed to partially bulge inward, leading to the formation of a DSM. PMID- 28570625 TI - An androgen response element driven reporter assay for the detection of androgen receptor activity in prostate cells. AB - The androgen receptor (AR) transcription factor plays a key role in the development and progression of prostate cancer, as is evident from the efficacy of androgen-deprivation therapy, AR is also the most frequently mutated gene, in castration resistant prostate cancer (CRPC). AR has therefore become an even more attractive therapeutic target in aggressive and disseminated prostate cancer. To investigate mechanisms of AR and AR target gene activation in different subpopulations of prostate cancer cells, a toolkit of AR expressor and androgen response element (ARE) reporter vectors were developed. Three ARE reporter vectors were constructed with different ARE consensus sequences in promoters linked to either fluorescence or luciferase reporter genes in lentiviral vector backbones. Cell lines transduced with the different vectors expressed the reporters in an androgen-dependent way according to fluorescence microscopy, flow cytometry and multi-well fluorescent and luminescence assays. Interestingly, the background reporter activity in androgen-depleted medium was significantly higher in LNCaP cells compared to the prostate transit amplifying epithelial cell lines, EP156T-AR and 957E/hTERT-AR with exogenous AR. The androgen-induced signal to background was much higher in the latter benign prostate cells than in LNCaP cells. Androgen-independent nuclear localization of AR was seen in LNCaP cells and reduced ARE-signaling was seen following treatment with abiraterone, an androgen synthesis inhibitor. The ARE reporter activity was significantly stronger when stimulated by androgens than by beta-estradiol, progesterone and dexamethasone in all tested cell types. Finally, no androgen-induced ARE reporter activity was observed in tumorigenic mesenchymal progeny cells of EP156T cells following epithelial to mesenchymal transition. This underscores the observation that expression of the classical luminal differentiation transcriptome is restricted in mesenchymal type cells with or without AR expression, and presence of androgen. PMID- 28570627 TI - Effect of climate on incidence of respiratory syncytial virus infections in a refugee camp in Kenya: A non-Gaussian time-series analysis. AB - Respiratory syncytial virus (RSV) is one of the major causes of acute lower respiratory tract infections (ALRTI) in children. Children younger than 1 year are the most susceptible to RSV infection. RSV infections occur seasonally in temperate climate regions. Based on RSV surveillance and climatic data, we developed statistical models that were assessed and compared to predict the relationship between weather and RSV incidence among refugee children younger than 5 years in Dadaab refugee camp in Kenya. Most time-series analyses rely on the assumption of Gaussian-distributed data. However, surveillance data often do not have a Gaussian distribution. We used a generalized linear model (GLM) with a sinusoidal component over time to account for seasonal variation and extended it to a generalized additive model (GAM) with smoothing cubic splines. Climatic factors were included as covariates in the models before and after timescale decompositions, and the results were compared. Models with decomposed covariates fit RSV incidence data better than those without. The Poisson GAM with decomposed covariates of climatic factors fit the data well and had a higher explanatory and predictive power than GLM. The best model predicted the relationship between atmospheric conditions and RSV infection incidence among children younger than 5 years. This knowledge helps public health officials to prepare for, and respond more effectively to increasing RSV incidence in low-resource regions or communities. PMID- 28570628 TI - Meaning and coping orientation of bereaved parents: Individual and dyadic processes. AB - The present study aimed to examine whether bereaved parents "meaning-made" defined as results of attempts to reduce discrepancies between the meaning assigned to the death of the child and self and world-views-was influenced by their own and their partner's coping orientations. Coping orientations were conceptualized within the Dual Process Model, which entails loss coping orientation (LO; focus on the loss itself), restoration coping orientations (RO; focus on stressors that come about as an indirect consequence of the bereavement), and a flexible oscillation between both coping orientations. The sample consisted of 227 couples identified through obituary notices in local and national newspapers, who provided data at 6, 13, and 20 months after the death of their child. At all three points of measurement, both partners independently completed the Dual Coping Inventory (DCI) and a scale developed by the authors about meaning-made from the loss. Data were analyzed using a multi-level Actor Partner Interdependence Model. Results show that the combination of parents' own LO and RO (operationalized through the interaction effect between LO and RO) have a positive effect in parents' meaning-made. Partners' LO have a negative effect in parents' meaning-made. These results highlight the importance of, in the context of parental bereavement, being flexible by using both coping orientations, and of acknowledging the interdependence between partners, namely, the interpersonal process by which partner's coping affect one's meaning-made. PMID- 28570626 TI - Surface radiation dose comparison of a dedicated extremity cone beam computed tomography (CBCT) device and a multidetector computed tomography (MDCT) machine in pediatric ankle and wrist phantoms. AB - OBJECTIVES: To evaluate and compare surface doses of a cone beam computed tomography (CBCT) and a multidetector computed tomography (MDCT) device in pediatric ankle and wrist phantoms. METHODS: Thermoluminescent dosimeters (TLD) were used to measure and compare surface doses between CBCT and MDCT in a left ankle and a right wrist pediatric phantom. In both modalities adapted pediatric dose protocols were utilized to achieve realistic imaging conditions. All measurements were repeated three times to prove test-retest reliability. Additionally, objective and subjective image quality parameters were assessed. RESULTS: Average surface doses were 3.8 +/-2.1 mGy for the ankle, and 2.2 +/-1.3 mGy for the wrist in CBCT. The corresponding surface doses in optimized MDCT were 4.5 +/-1.3 mGy for the ankle, and 3.4 +/-0.7 mGy for the wrist. Overall, mean surface dose was significantly lower in CBCT (3.0 +/-1.9 mGy vs. 3.9 +/-1.2 mGy, p<0.001). Subjectively rated general image quality was not significantly different between the study protocols (p = 0.421), whereas objectively measured image quality parameters were in favor of CBCT (p<0.001). CONCLUSIONS: Adapted extremity CBCT imaging protocols have the potential to fall below optimized pediatric ankle and wrist MDCT doses at comparable image qualities. These possible dose savings warrant further development and research in pediatric extremity CBCT applications. PMID- 28570629 TI - Retinal artery occlusion and associated recurrent vascular risk with underlying etiologies. AB - BACKGROUND AND PURPOSE: RAO is caused by various etiologies and subsequent vascular events may be associated with underlying etiologies. Our aim is to investigate the etiologies of RAO, the occurrence of subsequent vascular events and their association in patients with RAO. METHODS: We analyzed data from 151 consecutive patients presenting with acute non-arteritic RAO between 2003 and 2013 in a single tertiary-care hospital. The primary outcome was the occurrence of a vascular event defined as stroke, myocardial infarction, and vascular death within 365 days of the RAO onset. The Kaplan-Meier survival analysis and Cox proportional hazard model were used to estimate the hazard ratio of the vascular events. RESULTS: Large artery atherosclerosis (LAA) was the etiology more frequently associated with of RAO (41.1%, 62/151). During the one year follow-up, ischemic stroke and vascular events occurred in 8.6% and 9.9% of patients, respectively. Ten vascular events occurred in RAO patients attributed to LAA and 4 occurred in undetermined etiology. RAO patients with LAA had a nearly four times higher risk of vascular events compared to those without LAA (hazard ratio 3.94, 95% confidence interval 1.21-12.81). More than a half of all events occurred within one month and over three fourths of ischemic strokes occurred ipsilateral to the RAO. CONCLUSION: After occurrence of RAO, there is a high risk of a subsequent vascular event, particularly ipsilateral stroke, within one month. LAA is an independent factor for the occurrence of a subsequent vascular event. Management for the prevention of secondary vascular events is necessary in patients with RAO especially with LAA. Large clinical trials are needed to confirm these findings. PMID- 28570630 TI - Multilocus sequence typing provides insights into the population structure and evolutionary potential of Brenneria goodwinii, associated with acute oak decline. AB - Brenneria goodwinii is one of the most frequently isolated Gram-negative bacteria from native oak species, Quercus robur and Q. petraea, affected by acute oak decline (AOD) in the UK. We investigated the population biology of this bacterial species using a multilocus sequence analysis to determine the population structure and evolutionary potential. Seven partial housekeeping genes were used in the analyses. Amongst 44 bacterial strains from seven different locations, we identified 22 unique sequence types [STs]; only one ST was found at two separate locations. Phylogenetic and cluster-based analyses suggested that B. goodwinii STs form two main distinct groups; however, no geographical pattern of their distribution could be observed. Clonality and recombination tests demonstrated that the studied population is primarily clonal, however both mutation and recombination processes play a role in shaping the genetic structure and evolution of the population. Our study suggests that the B. goodwinii population on oak in the UK has an endemic form, with background recombination appearing to generate new alleles more frequently than mutation, despite the introduction of nucleotide substitutions being approximately twice less likely than mutation. The newly emerged STs subsequently undergo clonal expansion to become dominant genotypes within their specific geographical locations and even within the individual host oak trees. PMID- 28570631 TI - Interference figures of polarimetric interferometry analysis of the human corneal stroma. AB - A rotating polarimetric 90 degrees -cross linear-filter interferometry system was used to detect the morphological characteristics and features of interference patterns produced in in-vivo corneal stroma in healthy human corneas of 23 subjects. The characteristic corneal isogyres presenting with an evident cross shaped pattern, grossly aligned with the fixation axis, were observed in all patients with centers within the pupillary dark area, impeding the exact determination of the center point. During the rotational scan in 78.3% of the eyes the cross-shaped pattern of the isogyre gradually separated to form two distinct hyperbolic arcs in opposite quadrants, reaching their maximal separation at 45 degrees with respect to angle of cross-shaped pattern formation. The corneal cross and hyperbolic-pattern repeated every 90 degrees throughout the 360 degrees rotational scan. While the interpretation of the isogyres presents particular difficulties, two summary parameters can be extracted for each cornea: the presence/orientation of a single or two dark areas in post-processed images and isochromes. However, the development of dedicated software for semi quantitative analysis of these parameters and enantiomorphism may become available in the near future. The possible application of polarimetric interferometry in the field of both corneal pathologies and corneal surgery may be of great interest for clinical purposes. PMID- 28570632 TI - Quantile regression of microgeographic variation in population characteristics of an invasive vertebrate predator. AB - Localized ecological conditions have the potential to induce variation in population characteristics such as size distributions and body conditions. The ability to generalize the influence of ecological characteristics on such population traits may be particularly meaningful when those traits influence prospects for successful management interventions. To characterize variability in invasive Brown Treesnake population attributes within and among habitat types, we conducted systematic and seasonally-balanced surveys, collecting 100 snakes from each of 18 sites: three replicates within each of six major habitat types comprising 95% of Guam's geographic expanse. Our study constitutes one of the most comprehensive and controlled samplings of any published snake study. Quantile regression on snake size and body condition indicated significant ecological heterogeneity, with a general trend of relative consistency of size classes and body conditions within and among scrub and Leucaena forest habitat types and more heterogeneity among ravine forest, savanna, and urban residential sites. Larger and more robust snakes were found within some savanna and urban habitat replicates, likely due to relative availability of larger prey. Compared to more homogeneous samples in the wet season, variability in size distributions and body conditions was greater during the dry season. Although there is evidence of habitat influencing Brown Treesnake populations at localized scales (e.g., the higher prevalence of larger snakes-particularly males-in savanna and urban sites), the level of variability among sites within habitat types indicates little ability to make meaningful predictions about these traits at unsampled locations. Seasonal variability within sites and habitats indicates that localized population characterization should include sampling in both wet and dry seasons. Extreme values at single replicates occasionally influenced overall habitat patterns, while pooling replicates masked variability among sites. A full understanding of population characteristics should include an assessment of variability both at the site and habitat level. PMID- 28570633 TI - Thin silica shell coated Ag assembled nanostructures for expanding generality of SERS analytes. AB - Surface-enhanced Raman scattering (SERS) provides a unique non-destructive spectroscopic fingerprint for chemical detection. However, intrinsic differences in affinity of analyte molecules to metal surface hinder SERS as a universal quantitative detection tool for various analyte molecules simultaneously. This must be overcome while keeping close proximity of analyte molecules to the metal surface. Moreover, assembled metal nanoparticles (NPs) structures might be beneficial for sensitive and reliable detection of chemicals than single NP structures. For this purpose, here we introduce thin silica-coated and assembled Ag NPs (SiO2@Ag@SiO2 NPs) for simultaneous and quantitative detection of chemicals that have different intrinsic affinities to silver metal. These SiO2@Ag@SiO2 NPs could detect each SERS peak of aniline or 4-aminothiophenol (4 ATP) from the mixture with limits of detection (LOD) of 93 ppm and 54 ppb, respectively. E-field distribution based on interparticle distance was simulated using discrete dipole approximation (DDA) calculation to gain insight into enhanced scattering of these thin silica coated Ag NP assemblies. These NPs were successfully applied to detect aniline in river water and tap water. Results suggest that SiO2@Ag@SiO2 NP-based SERS detection systems can be used as a simple and universal detection tool for environment pollutants and food safety. PMID- 28570634 TI - Neuroprotective effect of bilberry extract in a murine model of photo-stressed retina. AB - Excessive exposure to light promotes degenerative and blinding retinal diseases such as age-related macular degeneration and retinitis pigmentosa. However, the underlying mechanisms of photo-induced retinal degeneration are not fully understood, and a generalizable preventive intervention has not been proposed. Bilberry extract is an antioxidant-rich supplement that ameliorates ocular symptoms. However, its effects on photo-stressed retinas have not been clarified. In this study, we examined the neuroprotective effects of bilberry extract against photo-stress in murine retinas. Light-induced visual function impairment recorded by scotopic and phototopic electroretinograms showing respective rod and cone photoreceptor function was attenuated by oral administration of bilberry extract through a stomach tube in Balb/c mice (750 mg/kg body weight). Bilberry extract also suppressed photo-induced apoptosis in the photoreceptor cell layer and shortening of the outer segments of rod and cone photoreceptors. Levels of photo-induced reactive oxygen species (ROS), oxidative and endoplasmic reticulum (ER) stress markers, as measured by real-time reverse transcriptase polymerase chain reaction, were reduced by bilberry extract treatment. Reduction of ROS by N acetyl-L-cysteine, a well-known antioxidant also suppressed ER stress. Immunohistochemical analysis of activating transcription factor 4 expression showed the presence of ER stress in the retina, and at least in part, in Muller glial cells. The photo-induced disruption of tight junctions in the retinal pigment epithelium was also attenuated by bilberry extract, repressing an oxidative stress marker, although ER stress markers were not repressed. Our results suggest that bilberry extract attenuates photo-induced apoptosis and visual dysfunction most likely, and at least in part, through ROS reduction, and subsequent ER stress attenuation in the retina. This study can help understand the mechanisms of photo-stress and contribute to developing a new, potentially useful therapeutic approach using bilberry extract for preventing retinal photo damage. PMID- 28570635 TI - Probing planetary biodiversity with DNA barcodes: The Noctuoidea of North America. AB - This study reports the assembly of a DNA barcode reference library for species in the lepidopteran superfamily Noctuoidea from Canada and the USA. Based on the analysis of 69,378 specimens, the library provides coverage for 97.3% of the noctuoid fauna (3565 of 3664 species). In addition to verifying the strong performance of DNA barcodes in the discrimination of these species, the results indicate close congruence between the number of species analyzed (3565) and the number of sequence clusters (3816) recognized by the Barcode Index Number (BIN) system. Distributional patterns across 12 North American ecoregions are examined for the 3251 species that have GPS data while BIN analysis is used to quantify overlap between the noctuoid faunas of North America and other zoogeographic regions. This analysis reveals that 90% of North American noctuoids are endemic and that just 7.5% and 1.8% of BINs are shared with the Neotropics and with the Palearctic, respectively. One third (29) of the latter species are recent introductions and, as expected, they possess low intraspecific divergences. PMID- 28570637 TI - Temperature-mediated biosynthesis of the phytotoxin phaseolotoxin by Pseudomonas syringae pv. phaseolicola depends on the autoregulated expression of the phtABC genes. AB - Pseudomonas syringae pv. phaseolicola produces phaseolotoxin in a temperature dependent manner, being optimally synthesized between 18 degrees C and 20 degrees C, while no detectable amounts are present above 28 degrees C. The Pht cluster, involved in the biosynthesis of phaseolotoxin, contains 23 genes that are organized in five transcriptional units. The function of most of the genes from the Pht cluster is still unknown and little information about the regulatory circuitry leading to expression of these genes has been reported. The purpose of the present study was to investigate the participation of pht genes in the regulation of the operons coded into the Pht cluster. We conducted Northern blot, uidA fusions and reverse transcription-PCR assays of pht genes in several mutants unable to produce phaseolotoxin. This allowed us to determine that, in P. syringae pv. phaseolicola NPS3121, genes phtABC are essential to prevent their own expression at 28 degrees C, a temperature at which no detectable amounts of the toxin are present. We obtained evidence that the phtABC genes also participate in the regulation of the phtD, phtM and phtL operons. According to our results, we propose that PhtABC and other Pht product activities could be involved in the synthesis of the sulfodiaminophosphinyl moiety of phaseolotoxin, which indirectly could be involved in the transcriptional regulation of the phtA operon. PMID- 28570636 TI - Alport syndrome cold cases: Missing mutations identified by exome sequencing and functional analysis. AB - Alport syndrome (AS) is an inherited progressive renal disease caused by mutations in COL4A3, COL4A4, and COL4A5 genes. Despite simultaneous screening of these genes being widely available, mutation detection still remains incomplete in a non-marginal portion of patients. Here, we applied whole-exome sequencing (WES) in 3 Italian families negative after candidate-gene analyses. In Family 1, we identified a novel heterozygous intronic variant (c.2245-40A>G) -outside the conventionally screened candidate region for diagnosis- potentially disrupting COL4A5 exon29 splicing. Using a minigene-based approach in HEK293 cells we demonstrated that this variant abolishes exon29 branch site, causing exon skipping. Moreover, skewed X-inactivation of the c.2245-40A>G allele correlated with disease severity in heterozygous females. In Family 2, WES highlighted a novel COL4A5 hemizygous missense mutation (p.Gly491Asp), which segregates with the phenotype and impacts on a highly-conserved residue. Finally, in Family 3, we detected a homozygous 24-bp in-frame deletion in COL4A3 exon1 (NM_000091.4:c.30_53del:p.Val11_Leu18del or c.40_63del24:p.Leu14_Leu21del), which is ambiguously annotated in databases, although it corresponds to a recurrent AS mutation. Functional analyses showed that this deletion disrupts COL4A3 signal peptide, possibly altering protein secretion. In conclusion, WES -together with functional studies- was fundamental for molecular diagnosis in 3 AS families, highlighting pathogenic variants that escaped previous screenings. PMID- 28570639 TI - Cerclage position, cervical length and preterm delivery in women undergoing ultrasound indicated cervical cerclage: A retrospective cohort study. AB - OBJECTIVE: The objectives were to assess whether anatomical location of ultrasound (USS) indicated cervical cerclage and/or the degree of cervical shortening (cervical length; CL) prior to and following cerclage affects the risk of preterm birth (PTB). METHOD: A retrospective cohort study of 179 women receiving cerclage for short cervix (<=25mm) was performed. Demographic data, CL before and after cerclage insertion, height of cerclage (distance from external os) and gestation at delivery were collected. Relative risk (RR) and odds ratio (OR) of preterm delivery were calculated according to the anatomical location of the cerclage within the cervix and the CL before and after cerclage as categorical and continuous variables. Partition tree analysis was used to identify the threshold cerclage height that best predicts PTB. RESULTS: 25% (n = 45) delivered <34 weeks and 36% (n = 65) delivered <37 weeks. Risk of PTB was greater with cerclage in the distal 10mm (RR2.37, 95% CI 1.45-3.87) or the distal half of a closed cervix (RR2.16, 95% CI 1.45-3.87). Increasing absolute cerclage height was associated with a reduction in PTB (OR 0.87, 95% CI 0.82-0.94). A cerclage height <14.5 mm best predicts PTB (70.8%). Increasing CL following cerclage was associated with a reduction in PTB (OR0.87, 95% CI 0.82-0.94). Conversely, the risk of PTB was increased where CL remained static or shortened further following cerclage (RR2.34, 95% CI 1.04-5.25). CONCLUSION: The higher a cerclage was placed within a shortened cervix, the lower the subsequent odds of PTB. Women whose cerclage is placed in the distal 10mm of closed cervix or whose cervix fails to elongate subsequently, should remain under close surveillance as they have the highest risk of PTB. PMID- 28570638 TI - Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection. AB - The innate immune system is a critical component of host defence against microbial pathogens, but effective responses require an ability to distinguish between infectious and non-infectious insult to prevent inappropriate inflammation. Using the important obligate intracellular human pathogen Chlamydia trachomatis; an organism that causes significant immunopathology, we sought to determine critical host and pathogen factors that contribute to the induction of inflammasome activation. We assayed inflammasome activation by immunoblotting and ELISA to detect IL-1beta processing and LDH release to determine pyroptosis. Using primary murine bone marrow derived macrophages or human monocyte derived dendritic cells, infected with live or attenuated Chlamydia trachomatis we report that the live organism activates both canonical and non-canonical inflammasomes, but only canonical inflammasomes controlled IL-1beta processing which preceded pyroptosis. NADPH oxidase deficient macrophages were permissive to Chlamydia trachomatis replication and displayed elevated type-1 interferon and inflammasome activation. Conversely, attenuated, non-replicating Chlamydia trachomatis, primed but did not activate inflammasomes and stimulated reduced type-1 interferon responses. This suggested bacterial replication or metabolism as important factors that determine interferon responses and inflammasome activation. We identified STING but not cGAS as a central mediator of interferon regulated inflammasome activation. Interestingly, exogenous delivery of a Chlamydia trachomatis metabolite and STING ligand-cyclic di-AMP, recovered inflammasome activation to attenuated bacteria in a STING dependent manner thus indicating that a bacterial metabolite is a key factor initiating inflammasome activation through STING, independent of cGAS. These data suggest a potential mechanism of how the innate immune system can distinguish between infectious and non infectious insult and instigate appropriate immune responses that could be therapeutically targeted. PMID- 28570640 TI - Aspects of the ecology of phlebotomine sand flies (Diptera: Psychodidae) in the Private Natural Heritage Reserve Sanctuary Caraca. AB - Leishmaniases are a set of parasitic diseases of zoonotic origin that are transmitted by sandfly vectors in wild, rural and urban environments. Their distribution is dependent not only the distribution of vectors, but also on the distribution of mammalian reservoirs. Only by understanding the transmission cycle of these diseases, such as knowing the participating vectors and reservoirs, can one can understand the epidemiology and ecological relationships of leishmaniases. Ecotourism has become an important area of economic growth in Brazil. One of the most visited tourist attractions in the state of Minas Gerais, the Reserva Particular do Patrimonio Natural Santuario do Caraca (RPPNSC) is located in the Quadrilatero Ferrifero. The aim of this study was to contribute to the control of leishmaniasis among tourists of the RPPNPC by surveying its sand fly fauna and testing for the presence of Leishmania DNA in females. Twenty-five CDC light traps were exposed on 7 trails of the RPPNPC where samples were collected bimonthly for a year, starting in June 2013. A total of 376 specimens of 18 species and 10 genera of sandflies were captured. The predominant species were Psychodopygus lloydi (72.34%) and Pintomyia monticola (5.59%). HaeIII restriction enzyme detected and characterized Leishmania braziliensis DNA in 2 of the samples for an infection rate of 0.7% (2/266). Recent studies found specimens of Ps. lloyd infected with Leishmania braziliensis elsewhere in Minas Gerais, which may be an indication that this species is involved in the transmission of Leishmania in this state. PMID- 28570641 TI - Correlation study between facet joint cartilage and intervertebral discs in early lumbar vertebral degeneration using T2, T2* and T1rho mapping. AB - Recent advancements in magnetic resonance imaging have allowed for the early detection of biochemical changes in intervertebral discs and articular cartilage. Here, we assessed the feasibility of axial T2, T2* and T1rho mapping of the lumbar facet joints (LFJs) to determine correlations between cartilage and intervertebral discs (IVDs) in early lumbar vertebral degeneration. We recruited 22 volunteers and examined 202 LFJs and 101 IVDs with morphological (sagittal and axial FSE T2-weighted imaging) and axial biochemical (T2, T2* and T1rho mapping) sequences using a 3.0T MRI scanner. IVDs were graded using the Pfirrmann system. Mapping values of LFJs were recorded according to the degeneration grades of IVDs at the same level. The feasibility of T2, T2* and T1rho in IVDs and LFJs were analyzed by comparing these mapping values across subjects with different rates of degeneration using Kruskal-Wallis tests. A Pearson's correlation analysis was used to compare T2, T2* and T1rho values of discs and LFJs. We found excellent reproducibility in the T2, T2* and T1rho values for the nucleus pulposus (NP), anterior and posterior annulus fibrosus (PAF), and LFJ cartilage (intraclass correlation coefficients 0.806-0.955). T2, T2* and T1rho mapping (all P<0.01) had good Pfirrmann grade performances in the NP with IVD degeneration. LFJ T2* values were significantly different between grades I and IV (PL = 0.032, PR = 0.026), as were T1rho values between grades II and III (PL = 0.002, PR = 0.006) and grades III and IV (PL = 0.006, PR = 0.001). Correlations were moderately negative for T1rho values between LFJ cartilage and NP (rL = -0.574, rR = -0.551), and between LFJ cartilage and PAF (rL = -0.551, rR = -0.499). T1rho values of LFJ cartilage was weakly correlated with T2 (r = 0.007) and T2* (r = -0.158) values. Overall, we show that axial T1rho effectively assesses early LFJ cartilage degeneration. Using T1rho analysis, we propose a link between LFJ degeneration and IVD NP or PAF changes. PMID- 28570642 TI - Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology. AB - Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negative regulatory pathways to augment immunopathology. Inhibition of signalling through the PI3K/AKT/mTORC1 pathway increased matrix metalloproteinase-1 (MMP-1) gene expression and secretion, a collagenase central to TB pathogenesis, and multiple pro-inflammatory cytokines. In patients with confirmed pulmonary TB, PI3Kdelta expression was absent within granulomas. Furthermore, Mtb infection suppressed PI3Kdelta gene expression in macrophages. Interestingly, inhibition of the MNK pathway, downstream of pro-inflammatory p38 and ERK MAPKs, also increased MMP-1 secretion, whilst suppressing secretion of TH1 cytokines. Cross-talk between the PI3K and MNK pathways was demonstrated at the level of eIF4E phosphorylation. Mtb globally suppressed the MMP-inhibitory pathways in macrophages, reducing levels of mRNAs encoding PI3Kdelta, mTORC-1 and MNK-1 via upregulation of miRNAs. Therefore, Mtb disrupts negative regulatory pathways at multiple levels in macrophages to drive a tissue-destructive phenotype that facilitates transmission. PMID- 28570643 TI - Maternal outcome after abdominal packing for uncontrolled postpartum hemorrhage despite peripartum hysterectomy. AB - BACKGROUND: Intra-abdominal packing is a possible option for persistent bleeding following hysterectomy for postpartum hemorrhage. However, to date, only very limited data about maternal outcome after intra-abdominal packing for surgically uncontrolled hemorrhage following hysterectomy are available. The objective of the current study was to estimate maternal outcome after intra-abdominal packing following unsuccessful peripartum hysterectomy for postpartum hemorrhage. METHODS: A questionnaire was mailed to all maternity units performing more than 850 deliveries per year. Inclusion criteria were: all cases of abdominal packing performed following unsuccessful peripartum hysterectomy for postpartum hemorrhage between 2003 and 2013. The primary outcome was success of intra abdominal packing, defined as the arrest of hemorrhage with no need of additional procedure. RESULTS: The total number of deliveries during the study period that occurred in the 51 participating centers was 1,430,142. The centers reported a total of 718 (1 per 2000 deliveries) peripartum hysterectomies for PPH and 53 abdominal packings performed after unsuccessful peripartum hysterectomy (about 1 per 14 hysterectomies). A median of 5 [IQR 3-7] pads were used for packing. Abdominal packing was removed after a median of 39.5 hours [IQR 24-48]. The success rate of abdominal packing was 62% (33/53). Among the 20 (38%) women in whom bleeding did not stop following the use of abdominal packing, 6 required a second surgical intervention, 6 a pelvic artery embolization and the 8 other women had "only" further intensive resuscitation and pharmacological treatments. Finally, mortality rate was 24% (13/53). CONCLUSION: Our results suggest that abdominal packing, used for duration of 24 to 48 hours, seems to be an option as an ultimate procedure to control persistent life-threatening postpartum hemorrhage following peripartum hysterectomy. PMID- 28570644 TI - Comparison of the adolescent and adult mouse prefrontal cortex proteome. AB - Adolescence is a developmental period characterized by unique behavioral phenotypes (increased novelty seeking, risk taking, sociability and impulsivity) and increased risk for destructive behaviors, impaired decision making and psychiatric illness. Adaptive and maladaptive adolescent traits have been associated with development of the medial prefrontal cortex (mPFC), a brain region that mediates regulatory control of behavior. However, the molecular changes that underlie brain development and behavioral vulnerability have not been fully characterized. Using high-throughput 2D DIGE spot profiling with identification by MALDI-TOF mass spectrometry, we identified 62 spots in the PFC that exhibited age-dependent differences in expression. Identified proteins were associated with diverse cellular functions, including intracellular signaling, synaptic plasticity, cellular organization and metabolism. Separate Western blot analyses confirmed age-related changes in DPYSL2, DNM1, STXBP1 and CFL1 in the mPFC and expanded these findings to the dorsal striatum, nucleus accumbens, motor cortex, amygdala and ventral tegmental area. Ingenuity Pathway Analysis (IPA) identified functional interaction networks enriched with proteins identified in the proteomics screen, linking age-related alterations in protein expression to cellular assembly and development, cell signaling and behavior, and psychiatric illness. These results provide insight into potential molecular components of adolescent cortical development, implicating structural processes that begin during embryonic development as well as plastic adaptations in signaling that may work in concert to bring the cortex, and other brain regions, into maturity. PMID- 28570645 TI - How do SMA-linked mutations of SMN1 lead to structural/functional deficiency of the SMA protein? AB - Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease with dysfunctional alpha-motor neurons in the anterior horn of the spinal cord. SMA is caused by loss (~95% of SMA cases) or mutation (~5% of SMA cases) of the survival motor neuron 1 gene SMN1. As the product of SMN1, SMN is a component of the SMN complex, and is also involved in the biosynthesis of the small nuclear ribonucleoproteins (snRNPs), which play critical roles in pre-mRNA splicing in the pathogenesis of SMA. To investigate how SMA-linked mutations of SMN1 lead to structural/functional deficiency of SMN, a set of computational analysis of SMN related structures were conducted and are described in this article. Of extraordinary interest, the structural analysis highlights three SMN residues (Asp44, Glu134 and Gln136) with SMA-linked missense mutations, which cause disruptions of electrostatic interactions for Asp44, Glu134 and Gln136, and result in three functionally deficient SMA-linked SMN mutants, Asp44Val, Glu134Lys and Gln136Glu. From the computational analysis, it is also possible that SMN's Lys45 and Asp36 act as two electrostatic clips at the SMN-Gemin2 complex structure interface. PMID- 28570646 TI - Diurnal fluctuation in the number of hypocretin/orexin and histamine producing: Implication for understanding and treating neuronal loss. AB - The loss of specific neuronal phenotypes, as determined by immunohistochemistry, has become a powerful tool for identifying the nature and cause of neurological diseases. Here we show that the number of neurons identified and quantified using this method misses a substantial percentage of extant neurons in a phenotype specific manner. In mice, 24% more hypocretin/orexin (Hcrt) neurons are seen in the night compared to the day, and an additional 17% are seen after inhibiting microtubule polymerization with colchicine. We see no such difference between the number of MCH (melanin concentrating hormone) neurons in dark, light or colchicine conditions, despite MCH and Hcrt both being hypothalamic peptide transmitters. Although the size of Hcrt neurons did not differ between light and dark, the size of MCH neurons was increased by 15% in the light phase. The number of neurons containing histidine decarboxylase (HDC), the histamine synthesizing enzyme, was 34% greater in the dark than in the light, but, like Hcrt, cell size did not differ. We did not find a significant difference in the number or the size of neurons expressing choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, in the horizontal diagonal band (HBD) during the dark and light conditions. As expected, colchicine treatment did not increase the number of these neurons. Understanding the function and dynamics of transmitter production within "non-visible" phenotypically defined cells has fundamental implications for our understanding of brain plasticity. PMID- 28570647 TI - Differences in inflammation and acute phase response but similar genotoxicity in mice following pulmonary exposure to graphene oxide and reduced graphene oxide. AB - We investigated toxicity of 2-3 layered >1 MUm sized graphene oxide (GO) and reduced graphene oxide (rGO) in mice following single intratracheal exposure with respect to pulmonary inflammation, acute phase response (biomarker for risk of cardiovascular disease) and genotoxicity. In addition, we assessed exposure levels of particulate matter emitted during production of graphene in a clean room and in a normal industrial environment using chemical vapour deposition. Toxicity was evaluated at day 1, 3, 28 and 90 days (18, 54 and 162 MUg/mouse), except for GO exposed mice at day 28 and 90 where only the lowest dose was evaluated. GO induced a strong acute inflammatory response together with a pulmonary (Serum-Amyloid A, Saa3) and hepatic (Saa1) acute phase response. rGO induced less acute, but a constant and prolonged inflammation up to day 90. Lung histopathology showed particle agglomerates at day 90 without signs of fibrosis. In addition, DNA damage in BAL cells was observed across time points and doses for both GO and rGO. In conclusion, pulmonary exposure to GO and rGO induced inflammation, acute phase response and genotoxicity but no fibrosis. PMID- 28570648 TI - Performance of 18F-fluorodesoxyglucose positron-emission tomography combined with low-dose computed tomography for cancer screening in patients with unprovoked venous thromboembolism. AB - PURPOSE: Small series have suggested that Fluorodesoxyglucose Positron-Emission Tomography with Computed-Tomography (FDG-PET/CT) is feasible to screen for cancer in patients with unprovoked venous thromboembolism (VTE), but without validation in a large population. The aim was to assess diagnostic accuracy indices of FDG PET/CT for occult cancer diagnosis in patients with unprovoked VTE. MATERIALS AND METHODS: We analysed patients from the FDG-PET/CT group of a randomized trial that compared a screening strategy based on FDG-PET/CT with a limited screening strategy for occult malignancy detection in patients with unprovoked VTE. FDG PET/CT was interpreted as positive for cancer, as negative or as equivocal. Patients were considered as having cancer on the basis of screening results, or of any test performed during a two-years follow-up period. We ran two sets of analysis, considering patients with equivocal FDG-PET/CT as positive, then as negative for malignancy. RESULTS: Between March 2009, and August 2012, 172 patients were included. FDG-PET/CT was interpreted as positive for malignancy in 10 patients (5.8%), as equivocal in 23 patients (13.4%) and as negative in 139 patients (80.8%). Malignancy was diagnosed in 7/10 (70.0%), 2/23 (8.7%) and 1/139 (0.7%) patients, respectively. Grouping positive and equivocal results, sensitivity and specificity were 90% (95%CI 60% to 98%) and 85% (95%CI 79% to 90%), respectively. Grouping negative and equivocal results, sensitivity and specificity were 70% (95%CI 40% to 89%) and 98% (95%CI 95% to 99%), respectively. CONCLUSION: FDG-PET/CT showed good accuracy for occult cancer screening in patients with unprovoked VTE. Remaining challenges include the need to define specific interpretation criteria in this dedicated population. PMID- 28570649 TI - Antioxidant agents for delaying diabetic kidney disease progression: A systematic review and meta-analysis. AB - BACKGROUND: Oxidative stress is a key player in the genesis and worsening of diabetic kidney disease (DKD). We aimed at collecting all available information on possible benefits of chronic antioxidant supplementations on DKD progression. STUDY DESIGN: Systematic review and meta-analysis. POPULATION: Adults with DKD (either secondary to type 1 or 2 diabetes mellitus). SEARCH STRATEGY AND SOURCES: Cochrane CENTRAL, Ovid-MEDLINE and PubMed were searched for randomized controlled trials (RCTs) or quasi-RCTs without language or follow-up restriction. INTERVENTION: Any antioxidant supplementation (including but not limited to vitamin A, vitamin C, vitamin E, selenium, zinc, methionine or ubiquinone) alone or in combination. OUTCOMES: Primary outcome was progression to end-stage kidney disease (ESKD). Secondary outcomes were change in albuminuria, proteinuria, serum creatinine and renal function. RESULTS: From 13519 potentially relevant citations retrieved, 15 articles referring to 14 full studies (4345 participants) met the inclusion criteria. Antioxidant treatment significantly decreased albuminuria as compared to control (8 studies, 327 participants; SMD: -0.47; 95% CI -0.78, 0.16) but had apparently no tangible effects on renal function (GFR) (3 studies, 85 participants; MD -0.12 ml/min/1.73m2; 95% CI -0.06, 0.01). Evidence of benefits on the other outcomes of interest was inconclusive or lacking. LIMITATIONS: Small sample size and limited number of studies. Scarce information available on hard endpoints (ESKD). High heterogeneity among studies with respect to DKD severity, type and duration of antioxidant therapy. CONCLUSIONS: In DKD patients, antioxidants may improve early renal damage. Future studies targeting hard endpoints and with longer follow-up and larger sample size are needed to confirm the usefulness of these agents for retarding DKD progression. PMID- 28570650 TI - Cardiovascular health status between standard and nonstandard workers in Korea. AB - OBJECTIVES: The effect of employment insecurity on employee health is an important public health issue due to the recent effects of neoliberalism and the global financial crisis (2007-2008) on labor markets. This study aims to evaluate the differences in cardiovascular health status and the use of preventive screening services between standard and nonstandard workers. METHODS: Waged employees (N = 5,338) between the ages of 20 and 64 were grouped into standard (full-time, permanent) and nonstandard (part-time, temporary, or daily) employees. Data from the Fourth Korea National Health and Nutrition Examination Survey, 2007-2009, a nationwide representative survey, were examined, including cardiovascular health risk behaviors (tobacco, alcohol, physical inactivity), measured morbidities (blood pressure, blood glucose level, lipid profiles, body mass index), and the use of screening services for hypertension and diabetes mellitus. RESULTS: Female nonstandard employees tended to have higher blood pressure than did female standard employees (adjusted odds ratio, aOR 1.42, 95% confidence interval, CI 1.02 to 1.98). However, nonstandard employees (both men and women) were less likely to use preventive screening services for hypertension (aOR 0.72, 95% CI 0.54 to 0.94 in men; aOR 0.56, 95% CI 0.43 to 0.73 in women) and diabetes (aOR 0.58, 95% CI 0.43 to 0.79 in men; aOR 0.55, 95% CI 0.43 to 0.71 in women). CONCLUSION: Nonstandard work is associated with the underuse of screening services and poorer cardiovascular health in a specific population. Policies to reduce employment insecurity and encourage nonstandard employees to receive health screening services should be prioritized. PMID- 28570651 TI - Polydim-I antimicrobial activity against MDR bacteria and its model membrane interaction. AB - The rapid spread of multi-drug resistant pathogens represents a serious threat to public health, considering factors such as high mortality rates, treatment restrictions and high prevalence of multi-drug resistant bacteria in the hospital environment. Antimicrobial peptides (AMPs) may exhibit powerful antimicrobial activity against different and diverse microorganisms, also presenting the advantage of absence or low toxicity towards animal cells. In this study, the evaluation of the antimicrobial activity against multi-drug resistant bacteria of a recently described AMP from wasp, Polydim-I, was performed. Polydim-I presented activity against standard strains (non-carriers of multi-resistant genes) that are susceptible to commercial antimicrobials, and also against multi-drug resistant strains at concentrations bellow 1MUg/ml (0.41 MUM). This is a rather low concentration among those reported for AMPs. At this concentration we found out that Polydim-I inhibits almost 100% of the tested pathogens growth, while with the ATCC strains the minimum inhibitory concentration (MIC100) is 400 times higher. Also, in relation to in vitro activity of conventional drugs against multi-drug resistant bacteria strains, Polydim-I is almost 10 times more efficient and with broader spectrum. Cationic AMPs are known as multi-target compounds and specially for targeting the phospholipid matrix of bacterial membranes. Exploring the interactions of Polydim-I with lipid bilayers, we have confirmed that this interaction is involved in the mechanism of action. Circular dichroism experiments showed that Polydim-I undergoes a conformational transition from random coil to a mostly helical conformation in the presence of membrane mimetic environments. Zeta potential measurements confirmed the binding and partial charge neutralization of anionic asolectin vesicles, and also suggested a possible aggregation of peptide molecules. FTIR experiments confirmed that some peptide aggregation occurs, which is minimized in the presence of strongly anionic micelles of sodium dodecyl sulfate. Also, Polydim-I induced channel-like structures formation to asolectin lipid bilayers, as demonstrated in the electrophysiology experiments. We suggest that cationic Polydim-I targets the membrane lipids due to electrostatic attraction, partially accumulates, neutralizing the opposite charges and induces pore formation. Similar mechanism of action has already been suggested for other peptides from wasp venoms, especially mastoparans. PMID- 28570652 TI - Prediction model for 30-day morbidity after gynecological malignancy surgery. AB - OBJECTIVE: The potential risk of postoperative morbidity is important for gynecologic cancer patients because it leads to delays in adjunctive therapy and additional costs. We aimed to develop a preoperative nomogram to predict 30-day morbidity after gynecological cancer surgery. METHODS: Between 2005 and 2015, 533 consecutive patients with elective gynecological cancer surgery in our center were reviewed. Of those patients, 373 and 160 patients were assigned to the model development or validation cohort, respectively. To investigate independent predictors of 30-day morbidity, a multivariate Cox regression model with backward stepwise elimination was utilized. A nomogram based on this Cox model was developed and externally validated. Its performance was assessed using the concordance index and a calibration curve. RESULTS: Ninety-seven (18.2%) patients had at least one postoperative complication within 30 days after surgery. After bootstrap resampling, the final model indicated age, operating time, and serum albumin level as statistically significant predictors of postoperative morbidity. The bootstrap-corrected concordance index of the nomogram incorporating these three predictors was 0.656 (95% CI, 0.608-0.723). In the validation cohort, the nomogram showed fair discrimination [concordance index: 0.674 (95% CI = 0.619 0.732] and good calibration (P = 0.614; Hosmer-Lemeshow test). CONCLUSION: The 30 day morbidity after gynecologic cancer surgery could be predicted according to age, operation time, and serum albumin level. After further validation using an independent dataset, the constructed nomogram could be valuable for predicting operative risk in individual patients. PMID- 28570653 TI - Improved efficacy of allergen-specific immunotherapy by JAK inhibition in a murine model of allergic asthma. AB - BACKGROUND: Allergen-specific immunotherapy (AIT) is the only curative treatment for type-1 allergies, but sometimes shows limited therapeutic response as well as local and systemic side effects. Limited control of local inflammation and patient symptoms hampers its widespread use in severe allergic asthma. OBJECTIVE: Our aim was to evaluate whether AIT is more effective in suppression of local inflammation if performed under the umbrella of short-term non-specific immunomodulation using a small molecule inhibitor of JAK pathways. METHODS: In C57BL/6J mice, a model of ovalbumin (OVA)-induced allergic airway inflammation and allergen-specific immunotherapy was combined with the administration of Tofacitinib (TOFA, a FDA-approved JAK inhibitor) from 48 hours prior to 48 hours after therapeutic OVA-injection. The effect of TOFA on human FOXP3+CD4+ T cells was studied in vitro. RESULTS: AIT combined with short-term TOFA administration was significantly more effective in suppressing total cell and eosinophil infiltration into the lung, local cytokine production including IL-1beta and CXCL1 and showed a trend for the reduction of IL-4, IL-13, TNF-alpha and IL-6 compared to AIT alone. Furthermore, TOFA co-administration significantly reduced systemic IL-6, IL-1beta and OVA-specific IgE levels and induced IgG1 to the same extent as AIT alone. Additionally, TOFA enhanced the induction of human FOXP3+CD4+ T cells. CONCLUSIONS: This proof of concept study shows that JAK inhibition did not inhibit tolerance induction, but improved experimental AIT at the level of local inflammation. The improved control of local inflammation might extend the use of AIT in more severe conditions such as polyallergy, asthma and high-risk patients suffering from mastocytosis or anaphylaxis. PMID- 28570654 TI - Haplotypes on pig chromosome 3 distinguish metabolically healthy from unhealthy obese individuals. AB - We have established a pig resource population specifically designed to elucidate the genetics involved in development of obesity and obesity related co morbidities by crossing the obesity prone Gottingen Minipig breed with two lean production pig breeds. In this study we have performed genome wide association (GWA) to identify loci with effect on blood lipid levels. The most significantly associated single nucleotide polymorphisms (SNPs) were used for linkage disequilibrium (LD) and haplotype analyses. Three separate haploblocks which influence the ratio between high density lipoprotein cholesterol and total cholesterol (HDL-C/CT), triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) levels respectively were identified on Sus Scrofa chromosome 3 (SSC3). Large additive genetic effects were found for the HDL-C/CT and LDL-C haplotypes. Haplotypes segregating from Gottingen Minipigs were shown to impose a positive effect on blood lipid levels. Thus, the genetic profile of the Gottingen Minipig breed seems to support a phenotype comparable to the metabolic healthy obese (MHO) phenotype in humans. PMID- 28570655 TI - Circulating FGF19 closely correlates with bile acid synthesis and cholestasis in patients with primary biliary cirrhosis. AB - BACKGROUND AND AIM: Bile acid (BA) synthesis in the liver is regulated by Fibroblast Growth Factor 19 (FGF19) secreted from the ileum as an enterohepatic feedback mechanism. Although FGF19 mRNA is absent in normal liver, FGF19 gene expression was reported to increase in response to both extrahepatic and intrahepatic cholestasis. The impact of upregulated FGF19 expression on BA synthesis is unclear and the overall role of circulating FGF19 and BA synthesis under cholestatic conditions needs to be further investigated. METHODS: BA synthesis was directly quantified by measuring serum concentrations of 7alpha hydroxycholest-4-en-3-one (C4), along with serum FGF19 and other parameters, in 44 patients with primary biliary cirrhosis (PBC) and 10 healthy subjects. RESULTS: Serum C4 were substantially lower, while those of FGF19 were higher, in cirrhotic PBC patients, as compared to those of either healthy or non-cirrhotic PBC patients. Analyses of the relationships between circulating FGF19, BA synthesis and cholestasis revealed that circulating FGF19 was strongly correlated with BA synthesis (r = -0.735, p<0.0001) and the severity of cholestasis (r = 0.590, p<0.001). Moreover, BA synthesis was found to be strongly correlated with the degree of cholestasis (r = 0.522, p = 0.0005). CONCLUSION: These findings demonstrate that the regulation of BA synthesis in response to cholestasis is primarily controlled by circulating FGF19 and that under cholestatic conditions, the FGF19-BA synthesis feedback mechanism remains intact. Administering FGF19, or suitable mimetic, as a pharmacological intervention to increase circulating levels of FGF19 and suppress BA synthesis by inhibiting CYP7A1 gene expression is likely to provide therapeutic benefits for many PBC patients. PMID- 28570656 TI - Validation of a scale for assessing attitudes towards outcomes of genetic cancer testing among primary care providers and breast specialists. AB - OBJECTIVE: To develop a generic scale for assessing attitudes towards genetic testing and to psychometrically assess these attitudes in the context of BRCA1/2 among a sample of French general practitioners, breast specialists and gyneco obstetricians. STUDY DESIGN AND SETTING: Nested within the questionnaire developed for the European InCRisC (International Cancer Risk Communication Study) project were 14 items assessing expected benefits (8 items) and drawbacks (6 items) of the process of breast/ovarian genetic cancer testing (BRCA1/2). Another item assessed agreement with the statement that, overall, the expected health benefits of BRCA1/2 testing exceeded its drawbacks, thereby justifying its prescription. The questionnaire was mailed to a sample of 1,852 French doctors. Of these, 182 breast specialists, 275 general practitioners and 294 gyneco obstetricians completed and returned the questionnaire to the research team. Principal Component Analysis, Cronbach's alpha coefficient, and Pearson's correlation coefficients were used in the statistical analyses of collected data. RESULTS: Three dimensions emerged from the respondents' responses, and were classified under the headings: "Anxiety, Conflict and Discrimination", "Risk Information", and "Prevention and Surveillance". Cronbach's alpha coefficient for the 3 dimensions was 0.79, 0.76 and 0.62, respectively, and each dimension exhibited strong correlation with the overall indicator of agreement (criterion validity). CONCLUSIONS: The validation process of the 15 items regarding BRCA1/2 testing revealed satisfactory psychometric properties for the creation of a new scale entitled the Attitudes Towards Genetic Testing for BRCA1/2 (ATGT-BRCA1/2) Scale. Further testing is required to confirm the validity of this tool which could be used generically in other genetic contexts. PMID- 28570657 TI - Modeling of a viscoelastic damper and its application in structural control. AB - Conventional seismic rehabilitation methods may not be suitable for some buildings owing to their high cost and time-consuming foundation work. In recent years, viscoelastic dampers (VEDs) have been widely used in many mid- and high rise buildings. This study introduces a viscoelastic passive control system called rotary rubber braced damper (RRBD). The RRBD is an economical, lightweight, and easy-to-assemble device. A finite element model considering nonlinearity, large deformation, and material damage is developed to conduct a parametric study on different damper sizes under pushover cyclic loading. The fundamental characteristics of this VED system are clarified by analyzing building structures under cyclic loading. The result show excellent energy absorption and stable hysteresis loops in all specimens. Additionally, by using a sinusoidal shaking table test, the effectiveness of the RRBD to manage the response displacement and acceleration of steel frames is considered. The RRBD functioned at early stages of lateral displacement, indicating that the system is effective for all levels of vibration. Moreover, the proposed damper shows significantly better performance in terms of the column compression force resulting from the brace action compared to chevron bracing (CB). PMID- 28570658 TI - Estimation of preterm labor immediacy by nonlinear methods. AB - Preterm delivery affects about one tenth of human births and is associated with an increased perinatal morbimortality as well as with remarkable costs. Even if there are a number of predictors and markers of preterm delivery, none of them has a high accuracy. In order to find quantitative indicators of the immediacy of labor, 142 cardiotocographies (CTG) recorded from women consulting because of suspected threatened premature delivery with gestational ages comprehended between 24 and 35 weeks were collected and analyzed. These 142 samples were divided into two groups: the delayed labor group (n = 75), formed by the women who delivered more than seven days after the tocography was performed, and the anticipated labor group (n = 67), which corresponded to the women whose labor took place during the seven days following the recording. As a means of finding significant differences between the two groups, some key informational properties were analyzed by applying nonlinear techniques on the tocography recordings. Both the regularity and the persistence levels of the delayed labor group, which were measured by Approximate Entropy (ApEn) and Generalized Hurst Exponent (GHE) respectively, were found to be significantly different from the anticipated labor group. As delivery approached, the values of ApEn tended to increase while the values of GHE tended to decrease, suggesting that these two methods are sensitive to labor immediacy. On this paper, for the first time, we have been able to estimate childbirth immediacy by applying nonlinear methods on tocographies. We propose the use of the techniques herein described as new quantitative diagnosis tools for premature birth that significantly improve the current protocols for preterm labor prediction worldwide. PMID- 28570659 TI - Caffeic acid and hydroxytyrosol have anti-obesogenic properties in zebrafish and rainbow trout models. AB - Some natural products, known sources of bioactive compounds with a wide range of properties, may have therapeutic values in human health and diseases, as well as agronomic applications. The effect of three compounds of plant origin with well known dietary antioxidant properties, astaxanthin (ATX), caffeic acid (CA) and hydroxytyrosol (HT), on zebrafish (Danio rerio) larval adiposity and rainbow trout (Onchorynchus mykiss) adipocytes was assessed. The zebrafish obesogenic test (ZOT) demonstrated the anti-obesogenic activity of CA and HT. These compounds were able to counteract the obesogenic effect produced by the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, rosiglitazone (RGZ). CA and HT suppressed RGZ-increased PPARgamma protein expression and lipid accumulation in primary-cultured rainbow trout adipocytes. HT also significantly reduced plasma triacylglycerol concentrations, as well as mRNA levels of the fasn adipogenic gene in the adipose tissue of HT-injected rainbow trout. In conclusion, in vitro and in vivo approaches demonstrated the anti-obesogenic potential of CA and HT on teleost fish models that may be relevant for studying their molecular mode of action. Further studies are required to evaluate the effect of these bioactive components as food supplements for modulating adiposity in farmed fish. PMID- 28570660 TI - Epidemiological and economic impact of pandemic influenza in Chicago: Priorities for vaccine interventions. AB - The study objective is to estimate the epidemiological and economic impact of vaccine interventions during influenza pandemics in Chicago, and assist in vaccine intervention priorities. Scenarios of delay in vaccine introduction with limited vaccine efficacy and limited supplies are not unlikely in future influenza pandemics, as in the 2009 H1N1 influenza pandemic. We simulated influenza pandemics in Chicago using agent-based transmission dynamic modeling. Population was distributed among high-risk and non-high risk among 0-19, 20-64 and 65+ years subpopulations. Different attack rate scenarios for catastrophic (30.15%), strong (21.96%), and moderate (11.73%) influenza pandemics were compared against vaccine intervention scenarios, at 40% coverage, 40% efficacy, and unit cost of $28.62. Sensitivity analysis for vaccine compliance, vaccine efficacy and vaccine start date was also conducted. Vaccine prioritization criteria include risk of death, total deaths, net benefits, and return on investment. The risk of death is the highest among the high-risk 65+ years subpopulation in the catastrophic influenza pandemic, and highest among the high risk 0-19 years subpopulation in the strong and moderate influenza pandemics. The proportion of total deaths and net benefits are the highest among the high-risk 20-64 years subpopulation in the catastrophic, strong and moderate influenza pandemics. The return on investment is the highest in the high-risk 0-19 years subpopulation in the catastrophic, strong and moderate influenza pandemics. Based on risk of death and return on investment, high-risk groups of the three age group subpopulations can be prioritized for vaccination, and the vaccine interventions are cost saving for all age and risk groups. The attack rates among the children are higher than among the adults and seniors in the catastrophic, strong, and moderate influenza pandemic scenarios, due to their larger social contact network and homophilous interactions in school. Based on return on investment and higher attack rates among children, we recommend prioritizing children (0-19 years) and seniors (65+ years) after high-risk groups for influenza vaccination during times of limited vaccine supplies. Based on risk of death, we recommend prioritizing seniors (65+ years) after high-risk groups for influenza vaccination during times of limited vaccine supplies. PMID- 28570661 TI - Breakdown of local information processing may underlie isoflurane anesthesia effects. AB - The disruption of coupling between brain areas has been suggested as the mechanism underlying loss of consciousness in anesthesia. This hypothesis has been tested previously by measuring the information transfer between brain areas, and by taking reduced information transfer as a proxy for decoupling. Yet, information transfer is a function of the amount of information available in the information source-such that transfer decreases even for unchanged coupling when less source information is available. Therefore, we reconsidered past interpretations of reduced information transfer as a sign of decoupling, and asked whether impaired local information processing leads to a loss of information transfer. An important prediction of this alternative hypothesis is that changes in locally available information (signal entropy) should be at least as pronounced as changes in information transfer. We tested this prediction by recording local field potentials in two ferrets after administration of isoflurane in concentrations of 0.0%, 0.5%, and 1.0%. We found strong decreases in the source entropy under isoflurane in area V1 and the prefrontal cortex (PFC) as predicted by our alternative hypothesis. The decrease in source entropy was stronger in PFC compared to V1. Information transfer between V1 and PFC was reduced bidirectionally, but with a stronger decrease from PFC to V1. This links the stronger decrease in information transfer to the stronger decrease in source entropy-suggesting reduced source entropy reduces information transfer. This conclusion fits the observation that the synaptic targets of isoflurane are located in local cortical circuits rather than on the synapses formed by interareal axonal projections. Thus, changes in information transfer under isoflurane seem to be a consequence of changes in local processing more than of decoupling between brain areas. We suggest that source entropy changes must be considered whenever interpreting changes in information transfer as decoupling. PMID- 28570662 TI - Gait characteristics under different walking conditions: Association with the presence of cognitive impairment in community-dwelling older people. AB - BACKGROUND: Gait characteristics measured at usual pace may allow profiling in patients with cognitive problems. The influence of age, gender, leg length, modified speed or dual tasking is unclear. METHODS: Cross-sectional analysis was performed on a data registry containing demographic, physical and spatial temporal gait parameters recorded in five walking conditions with a GAITRite(r) electronic carpet in community-dwelling older persons with memory complaints. Four cognitive stages were studied: cognitively healthy individuals, mild cognitive impaired patients, mild dementia patients and advanced dementia patients. RESULTS: The association between spatial-temporal gait characteristics and cognitive stages was the most prominent: in the entire study population using gait speed, steps per meter (translation for mean step length), swing time variability, normalised gait speed (corrected for leg length) and normalised steps per meter at all five walking conditions; in the 50-to-70 years old participants applying step width at fast pace and steps per meter at usual pace; in the 70-to-80 years old persons using gait speed and normalised gait speed at usual pace, fast pace, animal walk and counting walk or steps per meter and normalised steps per meter at all five walking conditions; in over-80 years old participants using gait speed, normalised gait speed, steps per meter and normalised steps per meter at fast pace and animal dual-task walking. Multivariable logistic regression analysis adjusted for gender predicted in two compiled models the presence of dementia or cognitive impairment with acceptable accuracy in persons with memory complaints. CONCLUSION: Gait parameters in multiple walking conditions adjusted for age, gender and leg length showed a significant association with cognitive impairment. This study suggested that multifactorial gait analysis could be more informative than using gait analysis with only one test or one variable. Using this type of gait analysis in clinical practice could facilitate screening for cognitive impairment. PMID- 28570663 TI - Rectal administration of a chlamydial subunit vaccine protects against genital infection and upper reproductive tract pathology in mice. AB - In this study, we tested the hypothesis that rectal immunization with a VCG-based chlamydial vaccine would cross-protect mice against heterologous genital Chlamydia trachomatis infection and Chlamydia-induced upper genital tract pathologies in mice. Female mice were immunized with a C. trachomatis serovar D derived subunit vaccine or control or live serovar D elementary bodies (EBs) and the antigen-specific mucosal and systemic immune responses were characterized. Vaccine efficacy was determined by evaluating the intensity and duration of genital chlamydial shedding following intravaginal challenge with live serovar E chlamydiae. Protection against upper genital tract pathology was determined by assessing infertility and tubal inflammation. Rectal immunization elicited high levels of chlamydial-specific IFN-gamma-producing CD4 T cells and humoral immune responses in mucosal and systemic tissues. The elicited immune effectors cross reacted with the serovar E chlamydial antigen and reduced the length and intensity of genital chlamydial shedding. Furthermore, immunization with the VCG vaccine but not the rVCG-gD2 control reduced the incidence of tubal inflammation and protected mice against Chlamydia-induced infertility. These results highlight the potential of rectal immunization as a viable mucosal route for inducing protective immunity in the female genital tract. PMID- 28570664 TI - SCYL1 does not regulate REST expression and turnover. AB - A recent study identified SCYL1 as one of the components of the oncogenic STP axis, which promotes triple-negative breast cancer by regulating degradation of the REST tumor suppressor. Contrary to the findings of that study, herein we show by using 3 distinct genetic approaches that SCYL1 does not regulate REST turnover. Specifically, REST protein levels and turnover were identical in Scyl1+/+ and Scyl1-/- mouse embryonic fibroblasts. Similarly, targeted inactivation of SCYL1 in Hek293T cells by using CRIPSR-Cas9 technology did not affect REST steady-state level and turnover. Furthermore, RNA interference mediated depletion of SCYL1 in Hek293T or MDA-MB-231 cells did not alter REST steady-state level and turnover. Together, our findings indicate that SCYL1 does not contribute to REST turnover and thus do not support a previous study suggesting a role for SCYL1 in mediating REST degradation. PMID- 28570665 TI - PD-L1/PD-L2-expressing B-1 cells inhibit alloreactive T cells in mice. AB - B cells constitute a complex system of antigen-presenting cells (APCs) and exist as distinct subsets that differ in their lineage affiliation, surface molecule expression, and biological function, thus potentially regulating the immune response. In this study, we investigated the immune-regulatory roles of murine B cell subsets as regulatory APCs targeting alloreactive T cells. Either splenic B cells, peritoneal cavity (PerC) B cells, or non-B cells from Balb/c mice were intravenously injected into B6 mice. Serum levels of anti-Balb/c antibodies in the recipients of PerC B cells were significantly lower than those in the recipients of splenic B cells and PerC non-B cells, as determined over a 4-week period after the injection. Mixed-lymphocyte reaction (MLR) assays using splenocytes from the B6 mice at 2 weeks after the injection revealed the significantly reduced anti-Balb/c T cell-responses in the recipients of PerC B cells, as compared to those in the recipients of splenic B cells or untreated control mice. Since PerC B cells contained MHC class II+ CD80+ CD86+ PD-L1+ PD L2+ cells among the CD5+ B-1a cell subset, PerC B cells from Balb/c mice were pre incubated with anti-PD-L1/PD-L2 mAbs prior to injection. This treatment abrogated their immune-regulatory effects on anti-Balb/c T cells in the MLR assays. In addition, the inoculation with Balb/c PerC B cells significantly prolonged the survival of subsequently grafted Balb/c hearts in B6 mouse recipients, whereas that with SPL B cells did not. These findings indicate that the PerC B cells, including PD-L1/PD-L2 B-1a cells, may suppress T cells responding to allostimulation, and thus may be optimal for donor lymphocyte injection. PMID- 28570666 TI - Loose Panicle1 encoding a novel WRKY transcription factor, regulates panicle development, stem elongation, and seed size in foxtail millet [Setaria italica (L.) P. Beauv.]. AB - Panicle development is an important agronomic trait that aids in determining crop productivity. Foxtail millet and its wild ancestor green foxtail have recently been used as model systems to dissect gene functions. Here, we characterized a recessive mutant of foxtail millet, loose-panicle 1 (lp1), which showed pleiotropic phenotypes, such as a lax primary branching pattern, aberrant branch morphology, semi-dwarfism, and enlarged seed size. The loose panicle phenotype was attributed to increased panicle lengths and decreased primary branch numbers. Map-based cloning, combined with high-throughput sequencing, revealed that LP1, which encodes a novel WRKY transcription factor, is responsible for the mutant phenotype. A phylogenetic analysis revealed that LP1 belongs to the Group I WRKY subfamily, which possesses two WRKY domains (WRKY I and II). A single G-to-A transition in the fifth intron of LP1 resulted in three disorganized splicing events in mutant plants. For each of these aberrant splice variants, the normal C2H2 motif in the WRKY II domain was completely disrupted, resulting in a loss-of function mutation. LP1 mRNA was expressed in all of the tissues examined, with higher expression levels observed in inflorescences, roots, and seeds at the grain-filling stage. A subcellular localization analysis showed that LP1 predominantly accumulated in the nucleus, which confirmed its role as a transcriptional regulator. This study provides novel insights into the roles of WRKY proteins in regulating reproductive organ development in plants and may help to develop molecular markers associated with crop yields. PMID- 28570667 TI - Correction: The Single-Breath Diffusing Capacity of CO and NO in Healthy Children of European Descent. AB - [This corrects the article DOI: 10.1371/journal.pone.0113177.]. PMID- 28570668 TI - Cooperative inhibition of RIP1-mediated NF-kappaB signaling by cytomegalovirus encoded deubiquitinase and inactive homolog of cellular ribonucleotide reductase large subunit. AB - Several viruses have been found to encode a deubiquitinating protease (DUB). These viral DUBs are proposed to play a role in regulating innate immune or inflammatory signaling. In human cytomegalovirus (HCMV), the largest tegument protein encoded by UL48 contains DUB activity, but its cellular targets are not known. Here, we show that UL48 and UL45, an HCMV-encoded inactive homolog of cellular ribonucleotide reductase (RNR) large subunit (R1), target receptor interacting protein kinase 1 (RIP1) to inhibit NF-kappaB signaling. Transfection assays showed that UL48 and UL45, which binds to UL48, interact with RIP1 and that UL48 DUB activity and UL45 cooperatively suppress RIP1-mediated NF-kappaB activation. The growth of UL45-null mutant virus was slightly impaired with showing reduced accumulation of viral late proteins. Analysis of a recombinant virus expressing HA-UL45 showed that UL45 interacts with both UL48 and RIP1 during virus infection. Infection with the mutant viruses also revealed that UL48 DUB activity and UL45 inhibit TNFalpha-induced NF-kappaB activation at late times of infection. UL48 cleaved both K48- and K63-linked polyubiquitin chains of RIP1. Although UL45 alone did not affect RIP1 ubiquitination, it could enhance the UL48 activity to cleave RIP1 polyubiquitin chains. Consistently, UL45-null virus infection showed higher ubiquitination level of endogenous RIP1 than HA-UL45 virus infection at late times. Moreover, UL45 promoted the UL48-RIP1 interaction and re-localization of RIP1 to the UL48-containing virion assembly complex. The mouse cytomegalovirus (MCMV)-encoded DUB, M48, interacted with mouse RIP1 and M45, an MCMV homolog of UL45. Collectively, our data demonstrate that cytomegalovirus-encoded DUB and inactive R1 homolog target RIP1 and cooperatively inhibit RIP1-mediated NF-kappaB signaling at the late stages of HCMV infection. PMID- 28570669 TI - Extraocular motoneurons of the adult rat show higher levels of vascular endothelial growth factor and its receptor Flk-1 than other cranial motoneurons. AB - Recent studies show a relationship between the deficit of vascular endothelial growth factor (VEGF) and motoneuronal degeneration, such as that occurring in amyotrophic lateral sclerosis (ALS). VEGF delivery protects motoneurons from cell death and delayed neurodegeneration in animal models of ALS. Strikingly, extraocular motoneurons show lesser vulnerability to neurodegeneration in ALS compared to other cranial or spinal motoneurons. Therefore, the present study investigates possible differences in VEGF and its main receptor VEGFR-2 or Flk-1 between extraocular and non-extraocular brainstem motoneurons. We performed immunohistochemistry and Western blot to determine the presence of VEGF and Flk-1 in rat motoneurons located in the three extraocular motor nuclei (abducens, trochlear and oculomotor) and to compare it to that observed in two other brainstem nuclei (hypoglossal and facial) that are vulnerable to degeneration. Extraocular motoneurons presented higher amounts of VEGF and its receptor Flk-1 than other brainstem motoneurons, and thus these molecules could be participating in their higher resistance to neurodegeneration. In conclusion, we hypothesize that differences in VEGF availability and signaling could be a contributing factor to the different susceptibility of extraocular motoneurons, when compared with other motoneurons, in neurodegenerative diseases. PMID- 28570670 TI - Pneumonia is an independent risk factor for pyogenic liver abscess: A population based, nested, case-control study. AB - BACKGROUND: Bacteremic pneumonia is considered a potential cause of distal organ abscess formation. Therefore, we hypothesize that pneumonia is a risk factor for pyogenic liver abscess (PLA).The aim of this study is to explore the association between pneumonia and PLA. METHODOLOGY/PRINCIPAL FINDINGS: A nationwide, population-based, nested, case-control study was conducted using data from the Taiwan National Health Insurance Research Database. In total, 494 patients with PLA and 1,976 propensity score matched controls were enrolled. Conditional logistic regression was used to estimate adjusted odds ratios (aORs) in patients with exposure to pneumonia before PLA. After matched and adjusted for confounding factors including age, sex, urbanization, income, chronic liver disease, alcohol related disease, biliary stone, chronic kidney disease, diabetes mellitus, chronic liver disease, and cancer, hospitalization for pneumonia remained an independent risk factor for PLA with an aORs of 2.104 [95% confidence interval (CI) = 1.309-3.379, p = 0.0021]. Moreover, the aORs were significantly higher among patients hospitalized for pneumonia within 30 days (aORs = 10.73, 95% CI = 3.381-34.054), 30-90 days (aORs = 4.698, 95% CI = 1.541-14.327) and 90-180 (aORs = 4.000, 95% CI = 1.158-13.817) days before PLA diagnosis. CONCLUSION: Pneumonia is an independent risk factor for subsequent PLA. Moreover, hospitalization for pneumonia within 180 days before PLA diagnosis was associated with an increased risk of PLA. PMID- 28570671 TI - The rib cage stabilizes the human thoracic spine: An in vitro study using stepwise reduction of rib cage structures. AB - The stabilizing effect of the rib cage on the human thoracic spine is still not sufficiently analyzed. For a better understanding of this effect as well as the calibration and validation of numerical models of the thoracic spine, experimental biomechanics data is required. This study aimed to determine (1) the stabilizing effect of the single rib cage structures on the human thoracic spine as well as the effect of the rib cage on (2) the flexibility of the single motion segments and (3) coupled motion behavior of the thoracic spine. Six human thoracic spine specimens including the entire rib cage were loaded quasi statically with pure moments of +/- 2 Nm in flexion/extension (FE), lateral bending (LB), and axial rotation (AR) using a custom-built spine tester. Motion analysis was performed using an optical motion tracking system during load application to determine range of motion (ROM) and neutral zone (NZ). Specimens were tested (1) in intact condition, (2) after removal of the intercostal muscles, (3) after median sternotomy, after removal of (4) the anterior rib cage up to the rib stumps, (5) the right sixth to eighth rib head, and (6) all rib heads. Significant (p < 0.05) increases of the ROM were found after dissecting the intercostal muscles (LB: + 22.4%, AR: + 22.6%), the anterior part of the rib cage (FE: + 21.1%, LB: + 10.9%, AR: + 72.5%), and all rib heads (AR: + 5.8%) relative to its previous condition. Compared to the intact condition, ROM and NZ increased significantly after removing the anterior part of the rib cage (FE: + 52.2%, + 45.6%; LB: + 42.0%, + 54.0%; AR: + 94.4%, + 187.8%). Median sternotomy (FE: + 11.9%, AR: + 21.9%) and partial costovertebral release (AR: + 11.7%) significantly increased the ROM relative to its previous condition. Removing the entire rib cage increased both monosegmental and coupled motion ROM, but did not alter the qualitative motion behavior. The rib cage has a strong effect on thoracic spine rigidity, especially in axial rotation by a factor of more than two, and should therefore be considered in clinical scenarios, in vitro, and in silico. PMID- 28570672 TI - Mirasol pathogen reduction technology treatment of human whole blood does not induce acute lung injury in mice. AB - In resource-limited settings and in the military theater, fresh human whole blood is commonly transfused, but infectious risks are a concern. Sophisticated molecular testing for potential infectious agents in the whole blood is often unavailable. To address this unmet need, pathogen reduction technology (PRT) has been developed, and it is an effective approach to inactivate a broad range of pathogens found in human blood. However, studies are needed to determine if it is harmful to blood cells and whether these cells could damage the transfused recipient, including the development of acute lung injury/acute respiratory distress syndrome. In this study, we used a commercial PRT system to treat human whole blood that was then transfused into immunodeficient mice, and the development of acute lung injury was determined. In a model of transfusion related acute lung injury (TRALI), BALB/c SCID mice developed more robust lung injury when challenged with a MHC Class I monoclonal antibody compared to BALB/c wild-type and NOD/SCID mice. Transfusion of control versus Mirasol PRT-treated whole blood (25% blood volume exchange) into BALB/c SCID mice did not produce lung injury at storage day 1. However, mild lung injury at storage days 14 and 21 was observed without significant differences in lung injury measurements between Mirasol PRT-treated and control groups. The mild storage-dependent acute lung injury correlated with trends for increased levels of cell-free hemoglobin that accumulated in both the control and Mirasol PRT-treated groups. Neutrophil extracellular traps were elevated in the plasma of BALB/c SCID mice in the monoclonal antibody TRALI model, but were not different in mice that received exchange transfusions. In conclusion, exchange transfusion of human whole blood into immunodeficient mice produces mild lung injury that is storage-dependent and not related to pathogen reduction treatment. PMID- 28570673 TI - Determinants of adherence to recommendations for cancer prevention among Lynch Syndrome mutation carriers: A qualitative exploration. AB - BACKGROUND: Lynch Syndrome (LS) mutation carriers are at high risk for various cancer types, particularly colorectal cancer. Adherence to lifestyle and body weight recommendations for cancer prevention may lower this risk. To promote adherence to these recommendations, knowledge on determinants of adherence in LS mutation carriers is needed. Therefore, this study aimed to identify determinants of adherence to lifestyle recommendations for cancer prevention in LS mutation carriers. METHODS: Five focus groups were conducted with DNA confirmed LS mutation carriers (n = 29). Transcripts were analyzed by thematic analysis, using the Health Belief Model (HBM) as a theoretical framework. RESULTS: Tolerance of an unhealthy lifestyle because of the desire to enjoy life and avoidance of LS dominating their life were most frequently reported as important barriers of adherence to the recommendations. Most important facilitators of adherence to the recommendations were enhancement of wellbeing and intolerance of unhealthy foods due to colon surgery. CONCLUSIONS: This study provided a comprehensive overview of determinants of adherence to recommendations for cancer prevention. These determinants, of which some are typically and unique for LS mutation carriers, can be used to design a lifestyle intervention that meets the needs of LS mutation carriers. PMID- 28570674 TI - Genomic abundance is not predictive of tandem repeat localization in grass genomes. AB - Highly repetitive regions have historically posed a challenge when investigating sequence variation and content. High-throughput sequencing has enabled researchers to use whole-genome shotgun sequencing to estimate the abundance of repetitive sequence, and these methodologies have been recently applied to centromeres. Previous research has investigated variation in centromere repeats across eukaryotes, positing that the highest abundance tandem repeat in a genome is often the centromeric repeat. To test this assumption, we used shotgun sequencing and a bioinformatic pipeline to identify common tandem repeats across a number of grass species. We find that de novo assembly and subsequent abundance ranking of repeats can successfully identify tandem repeats with homology to known tandem repeats. Fluorescent in-situ hybridization shows that de novo assembly and ranking of repeats from non-model taxa identifies chromosome domains rich in tandem repeats both near pericentromeres and elsewhere in the genome. PMID- 28570676 TI - Shaofu Zhuyu decoction ameliorates obesity-mediated hepatic steatosis and systemic inflammation by regulating metabolic pathways. AB - Shaofu Zhuyu decoction (SFZYD, also known as Sobokchugeo-tang), a classical prescription drug in traditional East Asian medicine, has been used to treat blood stasis syndrome (BSS). Hepatic steatosis is the result of excess caloric intake, and its pathogenesis involves internal retention of phlegm and dampness, blood stasis, and liver Qi stagnation. To evaluate the effects of treatment with SFZYD on obesity-induced inflammation and hepatic steatosis, we fed male C57BL/6N mice a high fat diet (HFD) for 8 weeks and then treated them with SFZYD by oral gavage for an additional 4 weeks. The results of histological and biochemical examinations indicated that SFZYD treatment ameliorates systemic inflammation and hepatic steatosis. A partial least squares-discriminant analysis (PLS-DA) scores plot of serum metabolites showed that HFD mice began to produce metabolites similar to those of normal chow (NC) mice after SFZYD administration. We noted significant alterations in the levels of twenty-seven metabolites, alterations indicating that SFZYD regulates the TCA cycle, the pentose phosphate pathway and aromatic amino acid metabolism. Increases in the levels of TCA cycle intermediate metabolites, such as 2-oxoglutaric acid, isocitric acid, and malic acid, in the serum of obese mice were significantly reversed after SFZYD treatment. In addition to inducing changes in the above metabolites, treatment with SFZYD also recovered the expression of genes related to hepatic mitochondrial dysfunction, including Ucp2, Cpt1alpha, and Ppargc1alpha, as well as the expression of genes involved in lipid metabolism and inflammation, without affecting glucose uptake or insulin signaling. Taken together, these findings suggest that treatment with SFZYD ameliorated obesity-induced systemic inflammation and hepatic steatosis by regulating inflammatory cytokine and adipokine levels in the circulation and various tissues. Moreover, treatment with SFZYD also reversed alterations in the levels of metabolites of the TCA cycle, the pentose phosphate pathway and aromatic amino acid metabolism. PMID- 28570677 TI - Detecting early signs of heat and drought stress in Phoenix dactylifera (date palm). AB - Plants adapt to the environment by either long-term genome evolution or by acclimatization processes where the cellular processes and metabolism of the plant are adjusted within the existing potential in the genome. Here we studied the adaptation strategies in date palm, Phoenix dactylifera, under mild heat, drought and combined heat and drought by transcriptomic and metabolomic profiling. In transcriptomics data, combined heat and drought resembled heat response, whereas in metabolomics data it was more similar to drought. In both conditions, soluble carbohydrates, such as fucose, and glucose derivatives, were increased, suggesting a switch to carbohydrate metabolism and cell wall biogenesis. This result is consistent with the evidence from transcriptomics and cis-motif analysis. In addition, transcriptomics data showed transcriptional activation of genes related to reactive oxygen species in all three conditions (drought, heat, and combined heat and drought), suggesting increased activity of enzymatic antioxidant systems in cytosol, chloroplast and peroxisome. Finally, the genes that were differentially expressed in heat and combined heat and drought stresses were significantly enriched for circadian and diurnal rhythm motifs, suggesting new stress avoidance strategies. PMID- 28570679 TI - Correction: The perceptual saliency of fearful eyes and smiles: A signal detection study. AB - [This corrects the article DOI: 10.1371/journal.pone.0173199.]. PMID- 28570675 TI - Mitochondrial complex I bridges a connection between regulation of carbon flexibility and gastrointestinal commensalism in the human fungal pathogen Candida albicans. AB - Efficient assimilation of alternative carbon sources in glucose-limited host niches is critical for colonization of Candida albicans, a commensal yeast that frequently causes opportunistic infection in human. C. albicans evolved mechanistically to regulate alternative carbon assimilation for the promotion of fungal growth and commensalism in mammalian hosts. However, this highly adaptive mechanism that C. albicans employs to cope with alternative carbon assimilation has yet to be clearly understood. Here we identified a novel role of C. albicans mitochondrial complex I (CI) in regulating assimilation of alternative carbon sources such as mannitol. Our data demonstrate that CI dysfunction by deleting the subunit Nuo2 decreases the level of NAD+, downregulates the NAD+-dependent mannitol dehydrogenase activity, and consequently inhibits hyphal growth and biofilm formation in conditions when the carbon source is mannitol, but not fermentative sugars like glucose. Mannitol-dependent morphogenesis is controlled by a ROS-induced signaling pathway involving Hog1 activation and Brg1 repression. In vivo studies show that nuo2Delta/Delta mutant cells are severely compromised in gastrointestinal colonization and the defect can be rescued by a glucose-rich diet. Thus, our findings unravel a mechanism by which C. albicans regulates carbon flexibility and commensalism. Alternative carbon assimilation might represent a fitness advantage for commensal fungi in successful colonization of host niches. PMID- 28570678 TI - Bringing functional status into a big data world: Validation of national Veterans Affairs functional status data. AB - BACKGROUND: The ability to perform basic daily activities ("functional status") is key to older adults' quality of life and strongly predicts health outcomes. However, data on functional status are seldom collected during routine clinical care in a way that makes them available for clinical use and research. OBJECTIVES: To validate functional status data that Veterans Affairs (VA) medical centers recently started collecting during routine clinical care, compared to the same data collected in a structured research setting. DESIGN: Prospective validation study. SETTING: Seven VA medical centers that collected complete data on 5 activities of daily living (ADLs) and 8 instrumental activities of daily living (IADLs) from older patients attending primary care appointments. PARTICIPANTS: Randomly selected patients aged 75 and older who had new ADL and IADL data collected during a primary care appointment (N = 252). We oversampled patients with ADL dependence and applied these sampling weights to our analyses. MEASUREMENTS: Telephone-based interviews using a validated measure to assess the same 5 ADLs and 8 IADLs. RESULTS: Mean age was 83 years, 96% were male, and 75% were white. Of 85 participants whom VA data identified as dependent in 1 or more ADLs, 74 (87%) reported being dependent by interview; of 167 whom VA data identified as independent in ADLs, 149 (89%) reported being independent. The sample-weighted sensitivity of the VA data for identifying ADL dependence was 45% (95% CI, 29%, 62%) compared to the reference standard, the specificity was 99% (95% CI, 99%, >99%), and the positive predictive value was 87% (95% CI, 79%, 93%). The weighted kappa statistic was 0.55 (95% CI, 0.41, 0.68) for the agreement between VA data and research-collected data in identifying ADL dependence. CONCLUSION: Overall agreement of VA functional status data with a reference standard was moderate, with fair sensitivity but high specificity and positive predictive value. PMID- 28570680 TI - The correlation between HER-2 expression and the CEUS and ARFI characteristics of breast cancer. AB - OBJECTIVE: The purpose of the present study was to explore the correlation between the contrast-enhanced ultrasound (CEUS) and acoustic radiation force impulse (ARFI) characteristics of breast cancers and the expression of human epidermal growth factor receptor 2 (HER-2). METHODS: HER-2 expression levels in the tumor masses of 167 clearly diagnosed cases of breast cancer were measured and analyzed. The enhancement features and time intensity curve (TIC) of CEUS and virtual touch tissue imaging (VTI) and virtual touch tissue quantification (VTQ) technology of ARFI were employed to analyze the relationship between HER-2 expression and the CEUS and ARFI characteristics of breast cancer. RESULTS: (1) Statistically significant differences in the distribution of the contrast agent, perforator blood flow, the overranging phenomenon and perfusion defects between the study groups with different HER-2 expression levels (P < 0.05) were observed on CEUS. In addition, statistically significant differences in the TIC peak time (PT), slope of the ascending branch (K) and area under the curve (AUC) were found in the groups expressing different levels of HER-2 (P < 0.05). In contrast, the degree of contrast agent enhancement and TIC peak intensity (PI) were found to be independent of the expression status of HER-2, as they were not statistically significant (P > 0.05). (2) Statistically significant differences in the VTQ results between the groups with different HER-2 expression levels were found (P < 0.05). However, no statistically significant differences in VTI image characteristics were detected between the groups expressing different levels of HER-2 (P > 0.05). CONCLUSION: A correlation was found between the CEUS and ARFI characteristics of breast cancer and HER-2 expression levels. This correlation was principally reflected in perfusion defects, perforator blood flow, PI, PT, K and VTQ. PMID- 28570682 TI - ADAMTS-1 in abdominal aortic aneurysm. AB - INTRODUCTION: Extracellular matrix degradation is a hallmark of abdominal aortic aneurysm (AAA). Among proteases that are capable of degrading extracellular matrix are a disintegrin and metalloproteases with thrombospondin motifs (ADAMTS). Pathogenesis of these proteases in AAA has not been investigated until date. METHODS AND RESULTS: Human aneurysmal and control aortas were collected and analyzed with RT-PCR measuring the ADAMTS-1, 4,5,6,8,9,10,13,17 and ADAMTSL-1. Expression of a majority of the investigated ADAMTS members on mRNA level was decreased in aneurysm compared to control aorta. ADAMTS-1 was one of the members that was reduced most. Protein analysis using immunohistochemistry and western blot for localization and expression of ADAMTS-1 revealed that ADAMTS-1 was present predominantly in areas of SMCs and macrophages in aneurysmal aorta and higher expressed in AAA compared to control aortas. The role of ADAMTS-1 in AAA disease was further examined using ADAMTS-1 transgenic/apoE-/- mice with the experimental angiotensin II induced aneurysmal model. Transgenic mice overexpressing ADAMTS-1 showed to be similar to ADAMTS-1 wild type mice pertaining collagen, elastin content and aortic diameter. CONCLUSION: Several of the ADAMTS members, and especially ADAMTS-1, are down regulated at mRNA level in AAA, due to unknown mechanisms, at the same time ADAMTS-1 protein is induced. The cleavage of its substrates, don't seem to be crucial for the pathogenesis of AAA but rather more important in the development of thoracic aortic aneurysm and atherosclerosis as shown in previous studies. PMID- 28570681 TI - Activated E2F activity induces cell death in papillary thyroid carcinoma K1 cells with enhanced Wnt signaling. AB - Disruption of Wnt signaling often happens in tumorigenesis, but whether Wnt signaling affects the early stages of thyroid tumor, such as papillary thyroid carcinoma, is still a question, especially in the papillary thyroid carcinoma without genomic RET/PTC mutation. In this study, we demonstrated the important function of Wnt signaling in papillary thyroid carcinoma K1 cells, which have no RET/PTC mutation. We found that K1 cells have enhanced Wnt signaling in comparison to normal thyroid cells. We further demonstrated that K1 cells require the enhanced Wnt signaling for growth and survival. Interestingly, we identified that enhancing E2F activity by either knockdown of Rb or overexpression of Cyclin D1 induces cell death in K1 cells. And we further revealed that the cell death is caused by enhanced oxidative stress. Our studies present a novel cell model to support the key roles of Wnt signaling in early stage of thyroid tumor, and also provide an alternative way to limit thyroid cancer. PMID- 28570683 TI - Bacterial outer membrane vesicles at the plant-pathogen interface. PMID- 28570684 TI - Correction: A spatial method to calculate small-scale fisheries effort in data poor scenarios. AB - [This corrects the article DOI: 10.1371/journal.pone.0174064.]. PMID- 28570685 TI - Comparative transcription analysis of different Antirrhinum phyllotaxy nodes identifies major signal networks involved in vegetative-reproductive transition. AB - Vegetative-reproductive phase change is an indispensable event which guarantees several aspects of successful meristem behaviour and organ development. Antirrhinum majus undergoes drastic changes of shoot architecture during the phase change, including phyllotactic change and leaf type alteration from opposite decussate to spiral. However, the regulation mechanism in both of phyllotactic morphology changes is still unclear. Here, the Solexa/Illumina RNA seq high-throughput sequencing was used to evaluate the global changes of transcriptome levels among four node regions during phyllotactic development. More than 86,315,782 high quality reads were sequenced and assembled into 58,509 unigenes. These differentially expressed genes (DEGs) were classified into 118 pathways described in the KEGG database. Based on the heat-map analysis, a large number of DEGs were overwhelmingly distributed in the hormone signal pathway as well as the carbohydrate biosynthesis and metabolism. The quantitative real time (qRT)-PCR results indicated that most of DEGs were highly up-regulated in the swapping regions of phyllotactic morphology. Moreover, transcriptions factors (TFs) with high transcripts were also identified, controlling the phyllotactic morphology by the regulation of hormone and sugar-metabolism signal pathways. A number of DEGs did not align with any databases and might be novel genes involved in the phyllotactic development. These genes will serve as an invaluable genetic resource for understanding the molecular mechanism of the phyllotactic development. PMID- 28570686 TI - Acute bout of exercise induced prolonged muscle glucose transporter-4 translocation and delayed counter-regulatory hormone response in type 1 diabetes. AB - Previous studies have demonstrated that an acute bout of aerobic exercise induces a subsequent delayed onset of hypoglycemia among patients with type 1 diabetes. However, the mechanisms of exercise-induced hypoglycemia in type 1 diabetes are still unclear. Streptozotocin (STZ) was injected to 6-week-old male Wistar rats, and three days after STZ injection, animals were randomly assigned into 2 groups: STZ with insulin only (STZ) and STZ with insulin and exercise (STZ+EX). Normal Wistar rats with exercise were used as control (CON+EX). Insulin was intraperitoneally injected (0.5 U/kg) to both STZ groups (-0.5 h), and a bout of aerobic exercise (15 m/min for 30 min) was conducted at euglycemic conditions (0 h). Blood was collected at 0, 1, 3, and 5 h after exercise from the carotid artery. While the blood glucose level was stable during the post-exercise period (0-5 h) in the STZ and CON+EX groups, it decreased significantly only in the STZ+EX group at 3 h. Plasma glucagon, adrenalin, and noradrenalin levels significantly increased at 1 h in the STZ group, whereas significant hormonal responses were observed at 5 h in the STZ+EX group. In skeletal muscle glucose metabolism-related pathway, the level of glucose transporter-4 (GLUT-4) translocation was significantly higher at 1 h in the CON and STZ groups. However, in the STZ+EX group, these activations were maintained by 5 h, indicating a sustained glucose metabolism in the STZ+EX group. A single bout of aerobic exercise induced a delayed onset of hypoglycemia in STZ-treated rats. A prolonged enhancement of GLUT-4 translocation and delayed counter-regulatory hormone responses may have contributed to the induction of hypoglycemia. PMID- 28570687 TI - Intervention using a novel biodegradable hollow stent containing polylactic acid polyprolactone-polyethylene glycol complexes against lacrimal duct obstruction disease. AB - Lacrimal duct obstruction disease (LDOD) is a common ophthalmologic disease. Stent implantation surgery is one of the most effective therapies. In this study, we intended to find out the satisfactory biodegradable stents containing poly-L lactic acid-polycaprolactone-polyethylene glycol (PLLA- PCL- PEG) complexes for therapeutic application in LDOD. Stents made of PLLA- PCL- PEG complexes in various ratios, were prepared and used in vitro to determine stents with appropriate mechanical properties and shorter range of bio-degradation for study in vivo. Thirty-two rabbits were randomized into eight groups of four eyes each in advance for test in vivo. The selected stents were implanted into the left lacrimal ducts of 16 rabbits and silica gel stents as the control for the other 16 rabbits. At four points in time (1, 4, 10 and 16 weeks after the implantation), weight loss rate (WLR) of the stents was measured and analysed. To access the change of lacrimal duct, fluorescein excretion test, lacrimal duct endoscopy and histopathological testing were conducted. The stent containing PLLA: PCL6: 4+ 15%PEG was selected for study in vivo. Analysis of weight loss rate (WLR), fluorescein excretion test, lacrimal duct endoscopy and histopathological testing indicated that the selected stent was biodegradable and caused minimal stimulation and earlier tissue restoration in the lacrimal epithelium compared with the silica gel stent used as the control. The study results suggest that the PLLA: PCL6: 4+ 15% PEG stent is a satisfactory biodegradable stent as a promising alternative for therapeutic application in LDOD, which showed tissue compatibility, biodegradation and adequate mechanical intensity. PMID- 28570688 TI - Genetic diversity and accession structure in European Cynara cardunculus collections. AB - Understanding the distribution of genetic variations and accession structures is an important factor for managing genetic resources, but also for using proper germplasm in association map analyses and breeding programs. The globe artichoke is the fourth most important horticultural crop in Europe. Here, we report the results of a molecular analysis of a collection including globe artichoke and leafy cardoon germplasm present in the Italian, French and Spanish gene banks. The aims of this study were to: (i) assess the diversity present in European collections, (ii) determine the population structure, (iii) measure the genetic distance between accessions; (iv) cluster the accessions; (v) properly distinguish accessions present in the different national collections carrying the same name; and (vi) understand the diversity distribution in relation to the gene bank and the geographic origin of the germplasm. A total of 556 individuals grouped into 174 accessions of distinct typologies were analyzed by different types of molecular markers, i.e. dominant (ISSR and AFLP) and co-dominant (SSR). The data of the two crops (globe artichoke and leafy cardoon) were analyzed jointly and separately to compute, among other aims, the gene diversity, heterozygosity (He, Ho), fixation indexes, AMOVA, genetic distance and structure. The findings underline the huge diversity present in the analyzed material, and the existence of alleles that are able to discriminate among accessions. The accessions were clustered not only on the basis of their typology, but also on the basis of the gene bank they come from. Probably, the environmental conditions of the different field gene banks affected germplasm conservation. These outcomes will be useful in plant breeding to select accessions and to fingerprint varieties. Moreover, the results highlight the particular attention that should be paid to the method used to conserve the Cynara cardunculus germplasm and suggest to the preference of using accessions from different gene banks to run an association map. PMID- 28570690 TI - Correction: ExtremeDB: A Unified Web Repository of Extremophilic Archaea and Bacteria. AB - [This corrects the article DOI: 10.1371/journal.pone.0063083.]. PMID- 28570689 TI - Population dynamics of the critically endangered toad Atelopus cruciger and the fungal disease chytridiomycosis. AB - Harlequin toads (Atelopus) are among the most severely impacted amphibians by the emergence of chytridiomycosis, a fungal disease caused by the pathogen Batrachochytrium dendrobatidis (Bd). Many species disappeared while others suffered drastic contractions of their geographic distribution to lower altitudes. A diminished virulence of Bd in warm habitats was proposed to explain the survival of lowland populations of harlequin toads (i.e. thermal refuge hypothesis). To understand the mechanisms that allow some populations to reach an endemic equilibrium with this pathogen, we estimated demographic and epidemiological parameters at one remnant population of Atelopus cruciger in Venezuela using mark-recapture data from 2007-2013. We demonstrated that Bd is highly virulent for A. cruciger, increasing the odds of dying of infected adults four times in relation to uninfected ones and reducing the life expectancy of reproductive toads to a few weeks. Despite an estimated annual loss of 18% of the reproductive population due to Bd-induced mortality, this population has persisted in an endemic equilibrium for the last decade through the large recruitment of healthy adults every year. Given the high vulnerability of harlequin toads to Bd in lowland populations, thermal refuges need to be redefined as habitats of reduced transmission rather than attenuated virulence. PMID- 28570691 TI - Memory for faces and voices varies as a function of sex and expressed emotion. AB - We investigated how memory for faces and voices (presented separately and in combination) varies as a function of sex and emotional expression (anger, disgust, fear, happiness, sadness, and neutral). At encoding, participants judged the expressed emotion of items in forced-choice tasks, followed by incidental Remember/Know recognition tasks. Results from 600 participants showed that accuracy (hits minus false alarms) was consistently higher for neutral compared to emotional items, whereas accuracy for specific emotions varied across the presentation modalities (i.e., faces, voices, and face-voice combinations). For the subjective sense of recollection ("remember" hits), neutral items received the highest hit rates only for faces, whereas for voices and face-voice combinations anger and fear expressions instead received the highest recollection rates. We also observed better accuracy for items by female expressers, and own sex bias where female participants displayed memory advantage for female faces and face-voice combinations. Results further suggest that own-sex bias can be explained by recollection, rather than familiarity, rates. Overall, results show that memory for faces and voices may be influenced by the expressions that they carry, as well as by the sex of both items and participants. Emotion expressions may also enhance the subjective sense of recollection without enhancing memory accuracy. PMID- 28570693 TI - Mosquito co-infection with Zika and chikungunya virus allows simultaneous transmission without affecting vector competence of Aedes aegypti. AB - BACKGROUND: Zika virus (ZIKV) and chikungunya virus (CHIKV) are highly pathogenic arthropod-borne viruses that are currently a serious health burden in the Americas, and elsewhere in the world. ZIKV and CHIKV co-circulate in the same geographical regions and are mainly transmitted by Aedes aegypti mosquitoes. There is a growing number of case reports of ZIKV and CHIKV co-infections in humans, but it is uncertain whether co-infection occurs via single or multiple mosquito bites. Here we investigate the potential of Ae. aegypti mosquitoes to transmit both ZIKV and CHIKV in one bite, and we assess the consequences of co infection on vector competence. METHODOLOGY/PRINCIPAL FINDINGS: First, growth curves indicated that co-infection with CHIKV negatively affects ZIKV production in mammalian, but not in mosquito cells. Next, Ae. aegypti mosquitoes were infected with ZIKV, CHIKV, or co-infected via an infectious blood meal or intrathoracic injections. Infection and transmission rates, as well as viral titers of positive mosquitoes, were determined at 14 days after blood meal or 7 days after injection. Saliva and bodies of (co-)infected mosquitoes were scored concurrently for the presence of ZIKV and/or CHIKV using a dual-colour immunofluorescence assay. The results show that orally exposed Ae. aegypti mosquitoes are highly competent, with transmission rates of up to 73% for ZIKV, 21% for CHIKV, and 12% of mosquitoes transmitting both viruses in one bite. However, simultaneous oral exposure to both viruses did not change infection and transmission rates compared to exposure to a single virus. Intrathoracic injections indicate that the selected strain of Ae. aegypti has a strong salivary gland barrier for CHIKV, but a less profound barrier for ZIKV. CONCLUSIONS/SIGNIFICANCE: This study shows that Ae. aegypti can transmit both ZIKV and CHIKV via a single bite. Furthermore, co-infection of ZIKV and CHIKV does not influence the vector competence of Ae. aegypti. PMID- 28570692 TI - Natural killer T cell sensitization during neonatal respiratory syncytial virus infection induces eosinophilic lung disease in re-infected adult mice. AB - Respiratory syncytial virus (RSV) is a major viral pathogen that causes severe lower respiratory tract infections in infants and the elderly worldwide. Infants with severe RSV bronchiolitis tend to experience more wheezing and asthma in later childhood. Because invariant natural killer T (iNKT) cells are associated with the asthma pathology, we investigated whether neonatal iNKT cells are involved in the aggravation of pulmonary diseases following RSV infection in mice. Intranasal exposure to the iNKT cell ligand alpha-galactosylceramide (alpha GC) with RSV primary infection in neonatal mice elicited neither cytokine production (except for a slight increase of IL-5) nor pulmonary eosinophilia, despite the presence of both CD1d+ cells and NKT cells. Interestingly, in adult mice re-infected with RSV, neonatal iNKT cell sensitization by alpha-GC during RSV primary infection resulted in much higher levels of pulmonary Th2 cytokines and elevated eosinophilia with airway hyperresponsiveness, whereas this was not observed in cd1d knockout mice. In contrast, alpha-GC priming of adults during RSV re-infection did not induce more severe airway symptoms than RSV re-infection in the absence of alpha-GC. alpha-GC co-administration during RSV primary infection facilitated RSV clearance regardless of age, but viral clearance following re-infection was not iNKT cell-dependent. This study clearly demonstrates that RSV-induced immune responses can be altered by iNKT cells, suggesting that neonatal iNKT cell sensitization during RSV primary infection is associated with exacerbation of pulmonary diseases following RSV re-infection in adulthood. PMID- 28570694 TI - Trends of vaccine-preventable diseases in Afghanistan from the Disease Early Warning System, 2009-2015. AB - BACKGROUND: Afghanistan's public health system was neglected during decades of military and civil conflict, and trends in infectious disease occurrence remain poorly characterized. This study examines cyclical and long-term trends of six vaccine-preventable diseases: pneumonia, diarrhea, meningitis, typhoid, measles, and acute viral hepatitis. METHODS: Using weekly data collected between 2009 and 2015 through Afghanistan's Disease Early Warning System, we calculated monthly case counts, and fit a Poisson regression with a Fourier transformation for seasonal cycles and dummy variables for year. RESULTS: We found the greatest incidence of diarrhea and typhoid in the summer, pneumonia in the winter, and measles in the late spring. Meningitis and acute viral hepatitis did not demonstrate substantial seasonality. Rates of pneumonia and diarrhea were constant across years whereas rates of meningitis, typhoid, and acute viral hepatitis decreased. Measles incidence increased in 2015. CONCLUSIONS: Communicable disease reporting systems can guide public health operations-such as the implementation of new vaccines, and permit evaluation of health interventions. For example, measles supplementary immunization activities in Afghanistan have not slowed long-term transmission of the disease, but decreases in typhoid fever and acute viral hepatitis are probably tied to improvements in sanitation in the country. PMID- 28570697 TI - Correction: High fibroblast growth factor 23 levels are associated with decreased ferritin levels and increased intravenous iron doses in hemodialysis patients. AB - [This corrects the article DOI: 10.1371/journal.pone.0176984.]. PMID- 28570696 TI - An investigation of emotion dynamics in major depressive disorder patients and healthy persons using sparse longitudinal networks. AB - BACKGROUND: Differences in within-person emotion dynamics may be an important source of heterogeneity in depression. To investigate these dynamics, researchers have previously combined multilevel regression analyses with network representations. However, sparse network methods, specifically developed for longitudinal network analyses, have not been applied. Therefore, this study used this approach to investigate population-level and individual-level emotion dynamics in healthy and depressed persons and compared this method with the multilevel approach. METHODS: Time-series data were collected in pair-matched healthy persons and major depressive disorder (MDD) patients (n = 54). Seven positive affect (PA) and seven negative affect (NA) items were administered electronically at 90 times (30 days; thrice per day). The population-level (healthy vs. MDD) and individual-level time series were analyzed using a sparse longitudinal network model based on vector autoregression. The population-level model was also estimated with a multilevel approach. Effects of different preprocessing steps were evaluated as well. The characteristics of the longitudinal networks were investigated to gain insight into the emotion dynamics. RESULTS: In the population-level networks, longitudinal network connectivity was strongest in the healthy group, with nodes showing more and stronger longitudinal associations with each other. Individually estimated networks varied strongly across individuals. Individual variations in network connectivity were unrelated to baseline characteristics (depression status, neuroticism, severity). A multilevel approach applied to the same data showed higher connectivity in the MDD group, which seemed partly related to the preprocessing approach. CONCLUSIONS: The sparse network approach can be useful for the estimation of networks with multiple nodes, where overparameterization is an issue, and for individual-level networks. However, its current inability to model random effects makes it less useful as a population-level approach in case of large heterogeneity. Different preprocessing strategies appeared to strongly influence the results, complicating inferences about network density. PMID- 28570695 TI - Molecular basis for the binding and modulation of V-ATPase by a bacterial effector protein. AB - Intracellular pathogenic bacteria evade the immune response by replicating within host cells. Legionella pneumophila, the causative agent of Legionnaires' Disease, makes use of numerous effector proteins to construct a niche supportive of its replication within phagocytic cells. The L. pneumophila effector SidK was identified in a screen for proteins that reduce the activity of the proton pumping vacuolar-type ATPases (V-ATPases) when expressed in the yeast Saccharomyces cerevisae. SidK is secreted by L. pneumophila in the early stages of infection and by binding to and inhibiting the V-ATPase, SidK reduces phagosomal acidification and promotes survival of the bacterium inside macrophages. We determined crystal structures of the N-terminal region of SidK at 2.3 A resolution and used single particle electron cryomicroscopy (cryo-EM) to determine structures of V-ATPase:SidK complexes at ~6.8 A resolution. SidK is a flexible and elongated protein composed of an alpha-helical region that interacts with subunit A of the V-ATPase and a second region of unknown function that is flexibly-tethered to the first. SidK binds V-ATPase strongly by interacting via two alpha-helical bundles at its N terminus with subunit A. In vitro activity assays show that SidK does not inhibit the V-ATPase completely, but reduces its activity by ~40%, consistent with the partial V-ATPase deficiency phenotype its expression causes in yeast. The cryo-EM analysis shows that SidK reduces the flexibility of the A-subunit that is in the 'open' conformation. Fluorescence experiments indicate that SidK binding decreases the affinity of V-ATPase for a fluorescent analogue of ATP. Together, these results reveal the structural basis for the fine-tuning of V-ATPase activity by SidK. PMID- 28570698 TI - High prevalence of cognitive impairment after intracerebral hemorrhage. AB - BACKGROUND: Cognitive impairment seems to be frequent in intracerebral hemorrhage (ICH) survivors, but remains widely understudied. In this study, we investigated the frequency and patterns of vascular cognitive disorders (VCDs) in patients with cerebral amyloid angiopathy (CAA)-related and deep ICH compared to patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD) and healthy controls. METHODS: We prospectively recruited 20 patients with CAA-related lobar ICH, 20 with deep ICH, 20 with MCI-AD and 17 healthy controls. Patients with cognitive decline pre-ICH were excluded from the analysis. Each participant underwent a comprehensive neuropsychological assessment and a structural brain MRI. Cognitive assessment was performed at a median delay of 4 months after the acute phase in ICH patients, and more than 6 months after the first complaint in MCI-AD patients. Cognitive profiles were compared between groups. The prevalence of VCDs in the ICH groups was estimated using the recent VASCOG criteria. RESULTS: "Mild" and "major VCDs" were respectively observed in 87.5% and 2.5% of all ICH patients. Every patient in the CAA group had mild VCDs. No significant difference was observed in cognitive functioning between CAA-related and deep ICH patients. The most impaired process in the CAA group was naming, with a mean (+/ standard deviation) z-score of -5.2 +/-5.5, followed by processing speed (-4.1+/ 3.3), executive functioning (-2.6 +/-2.5), memory (-2.4 +/-3.5) and attention ( 0.9 +/-1.3). This cognitive pattern was different from the MCI-AD patients, but the groups were only different in gestural praxis, and by construction, in memory processes. CONCLUSIONS: VCDs are frequent after ICH. Cognitive patterns of patients with deep or CAA-related ICH did not differ, but there was impaired performance in specific domains distinct from the effects of Alzheimer's disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01619709. PMID- 28570699 TI - Vimentin is a potential prognostic factor for tongue squamous cell carcinoma among five epithelial-mesenchymal transition-related proteins. AB - We aimed to investigate the association of the expression levels of five epithelial-mesenchymal transition (EMT)-related proteins (Snail, Twist, E cadherin, N-cadherin, and Vimentin) with tumorigenesis, pathologic parameters and prognosis in tongue squamous cell carcinoma (TSCC) patients by immunohistochemistry of tissue microarray. The expression levels of Snail, E cadherin, N-cadherin and Vimentin were significantly different between the tumor adjacent normal and tumor tissues. In tumor tissues, lower E-cadherin and higher N-cadherin levels were associated with a higher grade of cell differentiation, advanced stage of disease, and lymph node metastasis. However, higher Vimentin expression was associated with poor cell differentiation and lymph node metastasis. Patients with low E-cadherin expression had poor disease-specific survival (DSS). Conversely, positive N-cadherin and higher Vimentin expression levels were associated with poor DSS and disease-free survival. Notably, our multivariate Cox regression model indicated that high Vimentin expression was an adverse prognostic factor for DSS in TSCC patients, even after the adjustment for cell differentiation, pathological stage, and expression levels of Snail, Twist, E-cadherin, and N-cadherin. Snail, E-cadherin, N-cadherin, and Vimentin were associated with tumorigenesis and pathological outcomes. Among the five EMT related proteins, Vimentin was a potential prognostic factor for TSCC patients. PMID- 28570700 TI - Transcriptome analysis of Phytophthora litchii reveals pathogenicity arsenals and confirms taxonomic status. AB - Litchi downy blight, caused by Peronophythora litchii, is one of the major diseases of litchi and has caused severe economic losses. P. litchii has the unique ability to produce downy mildew like sporangiophores under artificial culture. The pathogen had been placed in a new family Peronophytophthoraceae by some authors. In this study, the whole transcriptome of P. litchii from mycelia, sporangia, and zoospores was sequenced for the first time. A set of 23637 transcripts with an average length of 1284 bp was assembled. Using six open reading frame (ORF) predictors, 19267 representative ORFs were identified and were annotated by searching against several public databases. There were 4666 conserved gene families and various sets of lineage-specific genes among P. litchii and other four closely related oomycetes. In silico analyses revealed 490 pathogen-related proteins including 128 RXLR and 22 CRN effector candidates. Based on the phylogenetic analysis of 164 single copy orthologs from 22 species, it is validated that P. litchii is in the genus Phytophthora. Our work provides valuable data to elucidate the pathogenicity basis and ascertain the taxonomic status of P. litchii. PMID- 28570701 TI - Genetic diversity of Xanthoceras sorbifolium bunge germplasm using morphological traits and microsatellite molecular markers. AB - Xanthoceras sorbifolium Bunge has great potential for producing biodiesel. In order to select and evaluate appropriate germplasm to produce biodiesel, we analyzed the genetic diversity of Xanthoceras sorbifolium Bunge germplasm based on morphological traits and simple sequence repeats (SSRs) in this study. Fifty six germplasm samples were evaluated using nine morphological traits and 23 SSR loci. Significant differences among germplasms were observed in eight morphological characters. The SSR markers analysis showed high genetic diversity among the germplasms. All SSRs had polymorphisms, and we detected 77 alleles in total. The number of alleles at each locus ranged from two to six, averaging 3.35 per marker. The polymorphic information content values ranged from 0.36 to 0.61, averaging 0.49. Expected heterozygosity, observed heterozygosity, and Shannon's information index calculations detected large genetic variations among germplasms. The high average number of alleles per locus and the allelic diversity observed in the set of genotypes analyzed indicated that the genetic base of this species is relatively wide. Thus, microsatellite markers can be used to efficiently distinguish Xanthoceras sorbifolium Bunge germplasms and assess their genetic diversity. Hundred-grain weight and lateral diameter were positively correlated with monounsaturated fatty acids and depended on genotype. These results suggest that seeds with higher hundred-grain weight and lateral diameter could be more suitable to produce biodiesel. Our data will lay a foundation for selecting appropriate germplasm to produce biodiesel based on seed phenotype and will contribute to the conservation and management of this important plant genetic resource. PMID- 28570702 TI - Depletion of ATP and glucose in advanced human atherosclerotic plaques. AB - OBJECTIVE: Severe hypoxia develops close to the necrotic core of advanced human atherosclerotic plaques, but the energy metabolic consequences of this hypoxia are not known. In animal models, plaque hypoxia is also associated with depletion of glucose and ATP. ATP depletion may impair healing of plaques and promote necrotic core expansion. To investigate if ATP depletion is present in human plaques, we analyzed the distribution of energy metabolites (ATP, glucose, glycogen and lactate) in intermediate and advanced human plaques. APPROACH AND RESULTS: Snap frozen carotid endarterectomies from 6 symptomatic patients were analyzed. Each endarterectomy included a large plaque ranging from the common carotid artery (CCA) to the internal carotid artery (ICA). ATP, glucose, and glycogen concentrations were lower in advanced (ICA) compared to intermediate plaques (CCA), whereas lactate concentrations were higher. The lowest concentrations of ATP, glucose and glycogen were detected in the perinecrotic zone of advanced plaques. CONCLUSIONS: Our study demonstrates severe ATP depletion and glucose deficiency in the perinecrotic zone of human advanced atherosclerotic plaques. ATP depletion may impair healing of plaques and promote disease progression. PMID- 28570703 TI - Distributed optimization of multi-class SVMs. AB - Training of one-vs.-rest SVMs can be parallelized over the number of classes in a straight forward way. Given enough computational resources, one-vs.-rest SVMs can thus be trained on data involving a large number of classes. The same cannot be stated, however, for the so-called all-in-one SVMs, which require solving a quadratic program of size quadratically in the number of classes. We develop distributed algorithms for two all-in-one SVM formulations (Lee et al. and Weston and Watkins) that parallelize the computation evenly over the number of classes. This allows us to compare these models to one-vs.-rest SVMs on unprecedented scale. The results indicate superior accuracy on text classification data. PMID- 28570704 TI - One bout of open skill exercise improves cross-modal perception and immediate memory in healthy older adults who habitually exercise. AB - One single bout of exercise can be associated with positive effects on cognition, due to physiological changes associated with muscular activity, increased arousal, and training of cognitive skills during exercise. While the positive effects of life-long physical activity on cognitive ageing are well demonstrated, it is not well established whether one bout of exercise is sufficient to register such benefits in older adults. The aim of this study was to test the effect of one bout of exercise on two cognitive processes essential to daily life and known to decline with ageing: audio-visual perception and immediate memory. Fifty-eight older adults took part in a quasi-experimental design study and were divided into three groups based on their habitual activity (open skill exercise (mean age = 69.65, SD = 5.64), closed skill exercise, N = 18, 94% female; sedentary activity control group, N = 21, 62% female). They were then tested before and after their activity (duration between 60 and 80 minutes). Results showed improvement in sensitivity in audio-visual perception in the open skill group and improvements in one of the measures of immediate memory in both exercise groups, after controlling for baseline differences including global cognition and health. These findings indicate that immediate benefits for cross-modal perception and memory can be obtained after open skill exercise. However, improvements after closed skill exercise may be limited to memory benefits. Perceptual benefits are likely to be associated with arousal, while memory benefits may be due to the training effects provided by task requirements during exercise. The respective role of qualitative and quantitative differences between these activities in terms of immediate cognitive benefits should be further investigated. Importantly, the present results present the first evidence for a modulation of cross-modal perception by exercise, providing a plausible avenue for rehabilitation of cross modal perception deficits, which are emerging as a significant contributor to functional decline in ageing. PMID- 28570705 TI - vWF correlates with visceral and pericardial adipose tissue in patients with a recent stroke of suspected cardiogenic etiology. AB - AIMS: A chronically elevated level of von Willebrand factor (vWF) is a common finding in patients with cardiovascular diseases. Obesity is a well-recognized risk factor for thrombotic cardiovascular complications including ischemic stroke, and it has been linked with increased plasma vWF. We evaluated whether elevated plasma levels of vWF associate with areas of visceral (VAT), pericardial (PAT), and subcutaneous adipose tissue (SAT) compartments in patients with acute/subacute stroke. METHODS AND RESULTS: A total of 69 patients with stroke of suspected cardiogenic etiology were examined. The plasma level of vWF antigen (vWF-ag) was measured both in the acute phase and in the chronic phase three months after stroke. The areas of VAT and/or PAT were assessed with computed tomography. As expected, in stroke patients, the levels of plasma vWF-ag were significantly higher than in the national reference population both in the acute and in the chronic phase. The level of vWF-ag in the chronic phase correlated with the amounts of VAT and PAT, but not with subcutaneous adipose tissue. CONCLUSIONS: These results agree with previous observations of the chronic inflammation/prothrombotic tendency in patients with cerebrovascular disease. Future studies should seek to clarify the role of visceral type adipose tissue in the pathophysiology of ischemic stroke. PMID- 28570706 TI - Coplanar UHF RFID tag antenna with U-shaped inductively coupled feed for metallic applications. AB - In this paper, we present a novel compact, coplanar, tag antenna design for metallic objects. Electrically small antenna has designed for a UHF RFID (860-960 MHz) based on a proximity-coupled feed through. Furthermore, two symmetrical Via loaded coplanar grounds fed by a U-shaped inductively coupled feed through an embedded transmission line. This configuration results in an antenna with dimensions of 31 * 19.5 * 3.065 mm3 at 915 MHz, and the total gain for the antenna is 0.12 dBi. The Via-loaded coplanar and U-shaped inductively coupled feeds allow the antenna to provide flexible tuning in terms of antenna impedance. In addition, a figure of merit is applied for the proposed tag antenna, and the results are presented. The read range is measured to be 4.2 m, which is very close to simulated values. This antenna measurement shows very good agreement with simulations. PMID- 28570708 TI - Designing small molecules to target cryptic pockets yields both positive and negative allosteric modulators. AB - Allosteric drugs, which bind to proteins in regions other than their main ligand binding or active sites, make it possible to target proteins considered "undruggable" and to develop new therapies that circumvent existing resistance. Despite growing interest in allosteric drug discovery, rational design is limited by a lack of sufficient structural information about alternative binding sites in proteins. Previously, we used Markov State Models (MSMs) to identify such "cryptic pockets," and here we describe a method for identifying compounds that bind in these cryptic pockets and modulate enzyme activity. Experimental tests validate our approach by revealing both an inhibitor and two activators of TEM beta-lactamase (TEM). To identify hits, a library of compounds is first virtually screened against either the crystal structure of a known cryptic pocket or an ensemble of structures containing the same cryptic pocket that is extracted from an MSM. Hit compounds are then screened experimentally and characterized kinetically in individual assays. We identify three hits, one inhibitor and two activators, demonstrating that screening for binding to allosteric sites can result in both positive and negative modulation. The hit compounds have modest effects on TEM activity, but all have higher affinities than previously identified inhibitors, which bind the same cryptic pocket but were found, by chance, via a computational screen targeting the active site. Site-directed mutagenesis of key contact residues predicted by the docking models is used to confirm that the compounds bind in the cryptic pocket as intended. Because hit compounds are identified from docking against both the crystal structure and structures from the MSM, this platform should prove suitable for many proteins, particularly targets whose crystal structures lack obvious druggable pockets, and for identifying both inhibitory and activating small-molecule modulators. PMID- 28570709 TI - Magnitude and correlates of bird collisions at glass bus shelters in an urban landscape. AB - Wildlife residing in urban landscapes face many human-related threats to their survival. For birds, collision with glass on manmade structures has been identified as a major hazard, causing hundreds of millions of avian fatalities in North America every year. Although research has investigated factors associated with bird-glass collision mortality at buildings, no prior studies have focused on bird fatalities at glass-walled bus shelters. Our objectives in this study were to describe the magnitude of bird-bus shelter collisions in the city of Stillwater, Oklahoma and assess potential predictors of collision risk, including characteristics of shelters (glass area) and surrounding land cover (e.g., vegetative features). We surveyed for bird carcasses and indirect collision evidence at 18 bus shelters over a five-month period. Linear regression and model selection results revealed that the amount of glass on shelters and the area of lawn within 50 m of shelters were both positively related to fatal bird collisions; glass area was also positively associated with observations of collision evidence on glass surfaces. After accounting for scavenger removal of carcasses, we estimate that a minimum of 34 birds are killed each year between May and September by collision with the 36 bus shelters in the city of Stillwater. While our study provides an initial look at bird fatalities at bus shelters, additional research is needed to generate a large-scale estimate of collision mortality and to assess species composition of fatalities at a national scale. Designing new bus shelters to include less glass and retrofitting existing shelters to increase visibility of glass to birds will likely reduce fatal bird collisions at bus shelters and thus reduce the cumulative magnitude of anthropogenic impacts to birds in cities. PMID- 28570707 TI - De novo characterization of the pine aphid Cinara pinitabulaeformis Zhang et Zhang transcriptome and analysis of genes relevant to pesticides. AB - The pine aphid Cinara pinitabulaeformis Zhang et Zhang is the main pine pest in China, it causes pine needles to produce dense dew (honeydew) which can lead to sooty mold (black filamentous saprophytic ascomycetes). Although common chemical and physical strategies are used to prevent the disease caused by C. pinitabulaeformis Zhang et Zhang, new strategies based on biological and/or genetic approaches are promising to control and eradicate the disease. However, there is no information about genomics, proteomics or transcriptomics to allow the design of new control strategies for this pine aphid. We used next generation sequencing technology to sequence the transcriptome of C. pinitabulaeformis Zhang et Zhang and built a transcriptome database. We identified 80,259 unigenes assigned for Gene Ontology (GO) terms and information for a total of 11,609 classified unigenes was obtained in the Clusters of Orthologous Groups (COGs). A total of 10,806 annotated unigenes were analyzed to identify the represented biological pathways, among them 8,845 unigenes matched with 228 KEGG pathways. In addition, our data describe propagative viruses, nutrition-related genes, detoxification related molecules, olfactory related receptors, stressed-related protein, putative insecticide resistance genes and possible insecticide targets. Moreover, this study provides valuable information about putative insecticide resistance related genes and for the design of new genetic/biological based strategies to manage and control C. pinitabulaeformis Zhang et Zhang populations. PMID- 28570710 TI - PmRunt regulated by Pm-miR-183 participates in nacre formation possibly through promoting the expression of collagen VI-like and Nacrein in pearl oyster Pinctada martensii. AB - Heterodimeric PEBP2/CBFs are key regulators in diverse biological processes, such as haematopoietic stem-cell generation, bone formation and cancers. In this work, we cloned runt-like transcriptional factor (designated as PmRunt) and CBF beta (designated as PmCBF) gene, which comprise the heterodimeric transcriptional factor in Pinctada martensii. PmRunt was identified with an open reading frame that encodes 545 amino acids and has typical Runt domain. Phylogenetic analysis results speculated that runt-like transcriptional factors (RDs) in vertebrates and invertebrates are separated into two branches. In molluscs, PmRunt and other RDs are clustered in one of these branches. Direct interaction between PmRunt and PmCBF was evidenced by yeast two-hybrid assay results. Gene repression by RNA interference decreased the expression level of PmRunt, and subsequent observation of the inner surface of the nacre by scanning electron microscopy demonstrated disordered growth. The luciferase activities of reporters that contain promoter regions of Collagen VI-like (PmColVI) and PmNacrein were enhanced by PmRunt. Meanwhile, Pm-miR-183 apparently inhibited the relative luciferase activity of reporters containing the 3'-UTR of PmRunt. The expression level of PmRunt was repressed after Pm-miR-183 was overexpressed in the mantle tissue. Therefore, we proposed that PmRunt could be targeted by Pm-miR-183 and regulate the transcription of PmColVI and PmNacrein by increasing their transcriptional activity, thereby governing nacre formation. PMID- 28570711 TI - IGF1 and IGF2 specificities to the two insulin receptor isoforms are determined by insulin receptor amino acid 718. AB - METHODS: Alanine scan of insulin receptor (IR)-B exon 11 and site-directed mutagenesis of amino acid 718 in human IR-A and IR-B were performed. Ligand affinities to wild type and mutated receptors were studied by displacement of radioactive insulin in binding assay on secreted soluble midi receptors or solubilized semi-purified full length receptors stably expressed in Baby Hamster Kidney cells. Phosphorylation of IR in response to insulin, IGF1 and IGF2 was measured using ELISA. RESULTS: Insulin, insulin detemir and insulin glargine maximally showed two fold differences in affinity for human IR-A and IR-B, but IGF1 and IGF2 had up to 10 fold preference for IR-A. Alanine scan of exon 11 revealed that position 718 is important for low IGF1 affinity to IR-B. Mutational analysis of amino acid residue 718 in IR-A and IR-B demonstrated that charge is important for IGF1 and IGF2 affinity but not important for insulin affinity. The affinity of IGF1 and IGF2 for the mutant IR-A P718K was comparable to the wild type IR-B whereas the affinity of IGF1 and IGF2 for the mutant IR-B K718P was comparable to the wild type IR-A. Changes in affinity were also reflected in the IR activation pattern. CONCLUSION: Mutating position 718 in human IR-B to the proline found at position 718 in human IR-A increased IGF1 and IGF2 affinity to a level comparable to IR-A and mutating position 718 in IR-A to the lysine found at position 718 in IR-B decreased IGF1 and IGF2 affinity to a level comparable to IR B, whereas a negatively charged glutamate did not. These changes in the affinities were also reflected in the IR phosphorylation pattern, meaning that position 718 is important for both affinity and activation of the receptor. It should be emphasized that none of the mutations affected insulin affinity, indicating that the mutations did not alter the overall receptor structure and that the effect is ligand specific. PMID- 28570712 TI - Low pH reduces the virulence of black band disease on Orbicella faveolata. AB - Black band is a deadly coral disease found worldwide, which may become more virulent as oceanic conditions continue to change. To determine the effects of climate change and ocean acidification on black band disease virulence, Orbicella faveolata corals with black band were exposed to different temperature and pH conditions. Results showed a significant decrease in disease progression under low pH (7.7) conditions. Low pH also altered the relative abundance of the bacterial community of the black band disease consortium. Here, there was a significant decrease in Roseofilum, the cyanobacterium that typically dominates the black band mat. These results indicate that as oceanic pH decreases so may the virulence of a worldwide coral disease. PMID- 28570714 TI - Correction: Prediction of Impending Type 1 Diabetes through Automated Dual-Label Measurement of Proinsulin:C-Peptide Ratio. AB - [This corrects the article DOI: 10.1371/journal.pone.0166702.]. PMID- 28570713 TI - Does time-lapse imaging have favorable results for embryo incubation and selection compared with conventional methods in clinical in vitro fertilization? A meta-analysis and systematic review of randomized controlled trials. AB - OBJECTIVE: The present study aimed to undertake a review of available evidence assessing whether time-lapse imaging (TLI) has favorable outcomes for embryo incubation and selection compared with conventional methods in clinical in vitro fertilization (IVF). METHODS: Using PubMed, EMBASE, Cochrane library and ClinicalTrial.gov up to February 2017 to search for randomized controlled trials (RCTs) comparing TLI versus conventional methods. Both studies randomized women and oocytes were included. For studies randomized women, the primary outcomes were live birth and ongoing pregnancy, the secondary outcomes were clinical pregnancy and miscarriage; for studies randomized oocytes, the primary outcome was blastocyst rate, the secondary outcome was good quality embryo on Day 2/3. Subgroup analysis was conducted based on different incubation and embryo selection between groups. RESULTS: Ten RCTs were included, four randomized oocytes and six randomized women. For oocyte-based review, the pool-analysis observed no significant difference between TLI group and control group for blastocyst rate [relative risk (RR) 1.08, 95% CI 0.94-1.25, I2 = 0%, two studies, including 1154 embryos]. The quality of evidence was moderate for all outcomes in oocyte-based review. For woman-based review, only one study provided live birth rate (RR 1,23, 95% CI 1.06-1.44,I2 N/A, one study, including 842 women), the pooled result showed no significant difference in ongoing pregnancy rate (RR 1.04, 95% CI 0.80-1.36, I2 = 59%, four studies, including 1403 women) between two groups. The quality of the evidence was low or very low for all outcomes in woman based review. CONCLUSIONS: Currently there is insufficient evidence to support that TLI is superior to conventional methods for human embryo incubation and selection. In consideration of the limitations and flaws of included studies, more well designed RCTs are still in need to comprehensively evaluate the effectiveness of clinical TLI use. PMID- 28570717 TI - The Columella Retraction Suture: A Powerful Suture Technique. PMID- 28570715 TI - Exhaled volatile substances mirror clinical conditions in pediatric chronic kidney disease. AB - Monitoring metabolic adaptation to chronic kidney disease (CKD) early in the time course of the disease is challenging. As a non-invasive technique, analysis of exhaled breath profiles is especially attractive in children. Up to now, no reports on breath profiles in this patient cohort are available. 116 pediatric subjects suffering from mild-to-moderate CKD (n = 48) or having a functional renal transplant KTx (n = 8) and healthy controls (n = 60) matched for age and sex were investigated. Non-invasive quantitative analysis of exhaled breath profiles by means of a highly sensitive online mass spectrometric technique (PTR ToF) was used. CKD stage, the underlying renal disease (HUS; glomerular diseases; abnormalities of kidney and urinary tract or polycystic kidney disease) and the presence of a functional renal transplant were considered as classifiers. Exhaled volatile organic compound (VOC) patterns differed between CKD/ KTx patients and healthy children. Amounts of ammonia, ethanol, isoprene, pentanal and heptanal were higher in patients compared to healthy controls (556, 146, 70.5, 9.3, and 5.4 ppbV vs. 284, 82.4, 49.6, 5.30, and 2.78 ppbV). Methylamine concentrations were lower in the patient group (6.5 vs 10.1 ppbV). These concentration differences were most pronounced in HUS and kidney transplanted patients. When patients were grouped with respect to degree of renal failure these differences could still be detected. Ammonia accumulated already in CKD stage 1, whereas alterations of isoprene (linked to cholesterol metabolism), pentanal and heptanal (linked to oxidative stress) concentrations were detectable in the breath of patients with CKD stage 2 to 4. Only weak associations between serum creatinine and exhaled VOCs were noted. Non-invasive breath testing may help to understand basic mechanisms and metabolic adaptation accompanying progression of CKD. Our results support the current notion that metabolic adaptation occurs early during the time course of CKD. PMID- 28570716 TI - Host lipid droplets: An important source of lipids salvaged by the intracellular parasite Toxoplasma gondii. AB - Toxoplasma is an obligate intracellular parasite that replicates in mammalian cells within a parasitophorous vacuole (PV) that does not fuse with any host organelles. One mechanism developed by the parasite for nutrient acquisition is the attraction of host organelles to the PV. Here, we examined the exploitation of host lipid droplets (LD), ubiquitous fat storage organelles, by Toxoplasma. We show that Toxoplasma replication is reduced in host cells that are depleted of LD, or impaired in TAG lipolysis or fatty acid catabolism. In infected cells, the number of host LD and the expression of host LD-associated genes (ADRP, DGAT2), progressively increase until the onset of parasite replication. Throughout infection, the PV are surrounded by host LD. Toxoplasma is capable of accessing lipids stored in host LD and incorporates these lipids into its own membranes and LD. Exogenous addition of oleic acid stimulates LD biogenesis in the host cell and results in the overaccumulation of neutral lipids in very large LD inside the parasite. To access LD-derived lipids, Toxoplasma intercepts and internalizes within the PV host LD, some of which remaining associated with Rab7, which become wrapped by an intravacuolar network of membranes (IVN). Mutant parasites impaired in IVN formation display diminished capacity of lipid uptake from host LD. Moreover, parasites lacking an IVN-localized phospholipase A2 are less proficient in salvaging lipids from host LD in the PV, suggesting a major contribution of the IVN for host LD processing in the PV and, thus lipid content release. Interestingly, gavage of parasites with lipids unveils, for the first time, the presence in Toxoplasma of endocytic-like structures containing lipidic material originating from the PV lumen. This study highlights the reliance of Toxoplasma on host LD for its intracellular development and the parasite's capability in scavenging neutral lipids from host LD. PMID- 28570719 TI - Association Between Quality of Care for Breast Cancer and Health Insurance Exchange Coverage: An Analysis of Use of Radiation Therapy After Breast Conserving Surgery. PMID- 28570720 TI - Conventional Radiation Therapy Compared With Stereotactic Conformal Therapy-A Rare and Laudable Randomized Trial. PMID- 28570718 TI - Free Flap Reconstruction Monitoring Techniques and Frequency in the Era of Restricted Resident Work Hours. AB - Importance: Free flap reconstruction of the head and neck is routinely performed with success rates around 94% to 99% at most institutions. Despite experience and meticulous technique, there is a small but recognized risk of partial or total flap loss in the postoperative setting. Historically, most microvascular surgeons involve resident house staff in flap monitoring protocols, and programs relied heavily on in-house resident physicians to assure timely intervention for compromised flaps. In 2003, the Accreditation Council for Graduate Medical Education mandated the reduction in the hours a resident could work within a given week. At many institutions this new era of restricted resident duty hours reshaped the protocols used for flap monitoring to adapt to a system with reduced resident labor. Objectives: To characterize various techniques and frequencies of free flap monitoring by nurses and resident physicians; and to determine if adapted resident monitoring frequency is associated with flap compromise and outcome. Design, Setting, and Participants: This multi-institutional retrospective review included patients undergoing free flap reconstruction to the head and/or neck between January 2005 and January 2015. Consecutive patients were included from different academic institutions or tertiary referral centers to reflect evolving practices. Main Outcomes and Measures: Technique, frequency, and personnel for flap monitoring; flap complications; and flap success. Results: Overall, 1085 patients (343 women [32%] and 742 men [78%]) from 9 institutions were included. Most patients were placed in the intensive care unit postoperatively (n = 790 [73%]), while the remaining were placed in intermediate care (n = 201 [19%]) or in the surgical ward (n = 94 [7%]). Nurses monitored flaps every hour (q1h) for all patients. Frequency of resident monitoring varied, with 635 patients monitored every 4 hours (q4h), 146 monitored every 8 hours (q8h), and 304 monitored every 12 hours (q12h). Monitoring techniques included physical examination (n = 949 [87%]), handheld external Doppler sonography (n = 739 [68%]), implanted Doppler sonography (n = 333 [31%]), and needle stick (n = 349 [32%]); 105 patients (10%) demonstrated flap compromise, prompting return to the operating room in 96 patients. Of these 96 patients, 46 had complete flap salvage, 22 had partial loss, and 37 had complete loss. The frequency of resident flap checks did not affect the total flap loss rate (q4h, 25 patients [4%]; q8h, 8 patients [6%]; and q12h, 8 patients [3%]). Flap salvage rates for compromised flaps were not statistically different. Conclusions and Relevance: Academic centers rely primarily on q1h flap checks by intensive care unit nurses using physical examination and Doppler sonography. Reduced resident monitoring frequency did not alter flap salvage nor flap outcome. These findings suggest that institutions may successfully monitor free flaps with decreased resident burden. PMID- 28570721 TI - Assumptions of Quality Medicine: The Role of Uncertainty. PMID- 28570722 TI - Use of Corneal Confocal Microscopy to Detect Corneal Nerve Loss and Increased Dendritic Cells in Patients With Multiple Sclerosis. AB - Importance: Multiple sclerosis (MS) is characterized by demyelination, axonal degeneration, and inflammation. Corneal confocal microscopy has been used to identify axonal degeneration in several peripheral neuropathies. Objective: To assess corneal subbasal nerve plexus morphologic features, corneal dendritic cell (DC) density, and peripapillary retinal nerve fiber layer (RNFL) thickness in patients with MS. Design, Setting, and Participants: This single-center, cross sectional comparative study was conducted at a tertiary referral university hospital between May 27, 2016, and January 30, 2017. Fifty-seven consecutive patients with relapsing-remitting MS and 30 healthy, age-matched control participants were enrolled in the study. Corneal subbasal nerve plexus measures and DC density were quantified in images acquired with the laser scanning in vivo corneal confocal microscope, and peripapillary RNFL thickness was measured with spectral-domain optical coherence tomography. Main Outcomes and Measures: Corneal nerve fiber density, nerve branch density, nerve fiber length, DC density, peripapillary RNFL thickness, and association with the severity of neurologic disability as assessed by the Kurtzke Expanded Disability Status Scale (score range, 0-10; higher scores indicate greater disability) and Multiple Sclerosis Severity Score (score range, 0.01-9.99; higher scores indicate greater severity). Results: Of the 57 participants with MS, 42 (74%) were female and the mean (SD) age was 35.4 (8.9) years; of the 30 healthy controls, 19 (63%) were female and the mean (SD) age was 34.8 (10.2) years. Corneal nerve fiber density (mean [SE] difference, -6.78 [2.14] fibers/mm2; 95% CI, -11.04 to -2.52; P = .002), nerve branch density (mean [SE] difference, -17.94 [5.45] branches/mm2; 95% CI, -28.77 to -7.10; P = .001), nerve fiber length (mean [SE] difference, -3.03 [0.89] mm/mm2; 95% CI, -4.81 to -1.25; P = .001), and the mean peripapillary RNFL thickness (mean [SE] difference, -17.06 [3.14] MUm; 95% CI, -23.29 to -10.82; P < .001) were reduced in patients with MS compared with healthy controls. The DC density was increased (median [interquartile range], 27.7 [12.4-66.8] vs 17.3 [0 28.2] cells/mm2; P = .03), independent of a patient's history of optic neuritis. Nerve fiber density and RNFL thickness showed inverse associations with the Expanded Disability Status Scale (rho = -0.295; P = .03 for nerve fiber density and rho = -0.374; P = .004 for RNFL thickness) and the Multiple Sclerosis Severity Score (R = -0.354; P = .007 for nerve fiber density and R = -0.283; P = .03 for RNFL thickness), whereas other study measures did not. Conclusions and Relevance: These data suggest that corneal confocal microscopy demonstrates axonal loss and increased DC density in patients with MS. Additional longitudinal studies are needed to confirm the use of corneal confocal microscopy as an imaging biomarker in patients with MS. PMID- 28570724 TI - Opsoclonus Recorded by a Smartphone. PMID- 28570723 TI - Oral Tyrosine Kinase Inhibitor for Neovascular Age-Related Macular Degeneration: A Phase 1 Dose-Escalation Study. AB - Importance: An oral treatment for neovascular age-related macular degeneration would be less burdensome than repeated intravitreous injections. X-82 is an oral tyrosine kinase inhibitor active against vascular endothelial growth factor (VEGF) and platelet-derived growth factor. Objective: To undertake safety testing of oral X-82 administered for the treatment of neovascular AMD. Design, Setting, and Participants: Phase 1, open-label, uncontrolled, dose-escalation study at 5 US retinal clinics between November 2012 and March 2015 (Retina-Vitreous Associates Medical Group, Beverly Hills, California; Blanton Eye Institute, Houston Methodist Hospital, Retina Consultants of Houston, Houston, Texas; New England Retina Associates, Guilford, Connecticut; Elman Retina Group, Baltimore, Maryland; and Retina Research Institute of Texas, Abilene). Thirty-five participants with neovascular age-related macular degeneration, 7 of whom were treatment naive. Interventions: Participants received oral X-82 for 24 weeks at 50 mg alternate days (n = 3), 50 mg daily (n = 8), 100 mg alternate days (n = 4), 100 mg daily (n = 10), 200 mg daily (n = 7), and 300 mg daily (n = 3), with intravitreous anti-VEGF therapy using predefined retreatment criteria. Every 4 weeks, participants underwent best-corrected visual acuity measurement, fundus examination, and spectral-domain optical coherence tomography. Main Outcomes and Measures: The main outcome was adverse events. Other outcomes included visual acuity, central subfield retinal thickness, and number of anti-VEGF injections. Results: Of the 35 participants, the mean age was 76.8 years, 16 were men and 19 were women, and 33 were white and 2 were nonwhite. Of 25 participants (71%) who completed the 24 weeks of X-82 treatment, all except 1 maintained or improved their visual acuity (mean [SD], +3.8 [9.6] letters). Fifteen participants (60%) required no anti-VEGF injections (mean, 0.68). Mean [SD] central subfield thickness reduced by -50 [97] MUm, with 8 participants (all receiving at least 100 mg daily) demonstrating sustained reductions despite no anti-VEGF injections. The most common adverse events attributed to X-82 were diarrhea (n = 6), nausea (n = 5), fatigue (n = 5), and transaminase elevation (n = 4). A dose relationship to the transaminase elevations was not identified; all normalized when X-82 was discontinued. All but 1 were asymptomatic. Ten participants withdrew consent or discontinued prematurely, 6 owing to adverse events attributed to X-82 including leg cramps (n = 2), elevated alanine aminotransferase (n = 2), diarrhea (n = 1), and nausea/anorexia (n = 1). Conclusions and Relevance: X-82 can be associated with reversible, elevated liver enzymes; hence, liver function testing is needed to identify those unsuited to treatment. Although 17% of participants discontinued X-82 owing to AEs, those who completed the study had lower than expected anti-VEGF injection rates. Further studies appear justified, with a phase 2 randomized clinical study under way. PMID- 28570725 TI - An HIV-Positive Child With a Gingival Mass. PMID- 28570727 TI - Dose Escalation Optimization in Patients With Locally Advanced Non-Small-Cell Lung Cancer: The Right Dose, in the Right Location, to the Right Patient, at the Right Time. PMID- 28570726 TI - Cost-effectiveness of Early Division of the Forehead Flap Pedicle. AB - Importance: The paramedian forehead flap is considered the gold standard procedure to optimally reconstruct major defects of the nose, but this procedure generally requires 2 stages, where the flap pedicle is divided 3 weeks following the initial surgery to ensure adequate revascularization of the flap from the surrounding recipient tissue bed, which can cost a patient time out of work or away from normal social habits. It has previously been shown that the pedicle may be safely divided after 2 weeks in select patients where revascularization from the recipient bed was confirmed using intraoperative laser fluorescence angiography to potentially save the patient time and money. Objective: To demonstrate the cost-effectiveness of takedown of the paramedian forehead flap pedicle after 2 weeks using angiography with indocyanine green (ICG). Design, Setting, and Participants: Retrospective cohort study of all patients who underwent 2-week division of the forehead flap after nasal reconstruction. Patient, tumor, defect, and outcomes data were collected. Cost-minimization analysis was performed by comparing the overall costs of 2-week takedown with angiography to a hypothetical patient undergoing 3-week takedown without angiography. Intervention: Two-week division of the forehead flap after nasal reconstruction. Main Outcomes and Measures: Cost-minimization analysis performed by calculating the total variable costs for a patient in our cohort vs costs to a theoretical patient for whom angiography was not performed and the pedicle was divided at the 3-week mark. Results: A total of 22 patients were included (mean [SD] age, 70.3 [10.0] years; 8 women [36.4%] and 14 men [63.6%]). The selection criteria for 2-week division of the pedicle are a wound bed with at least 50% vascularized tissue present, partial-thickness defects, and absence of nicotine use. All were divided at the 2-week mark with no instances of flap necrosis. One patient had a squamous eccrine carcinoma histology before reconstruction, all other patients had basal cell carcinoma, squamous cell carcinoma, and melanoma. Cost-minimization analysis showed that the use of angiography with ICG results in cost savings of $177 per patient on average. Conclusions and Relevance: Two-week takedown of select paramedian forehead flap patients can be performed safely with verification using angiography with ICG. Although this technology inherently adds cost, it is cost-effective, saving a total of $177 per patient. Level of Evidence: NA. PMID- 28570728 TI - No Shortcuts on the Long Road to Evidence-Based Genomic Medicine. PMID- 28570729 TI - Tyrosine Kinase Inhibitors in Age-Related Macular Degeneration. PMID- 28570730 TI - Efficacy of Stereotactic Conformal Radiotherapy vs Conventional Radiotherapy on Benign and Low-Grade Brain Tumors: A Randomized Clinical Trial. AB - Importance: Evidence for application of stereotactic and other conformal radiotherapy techniques in treating brain tumors is largely based on data derived from dosimetric, retrospective, or small prospective studies. Therefore, we conducted a randomized clinical trial of stereotactic conformal radiotherapy (SCRT) compared with conventional radiotherapy (ConvRT) evaluating clinically meaningful end points. Objective: To compare neurocognitive and endocrine functional outcomes and survival at 5 years in young patients with residual and/or progressive benign or low-grade brain tumors treated with SCRT and ConvRT techniques. Design, Setting, and Participants: This phase 3 randomized clinical trial enrolled 200 young patients (ages 3-25 years) with residual or progressive benign or low-grade brain tumors at a single center between April 2001 to March 2012. Patients were randomly allocated (1:1) to either SCRT (n = 104) or ConvRT (n = 96) arms. Interventions: Patients were randomly assigned to either high precision SCRT or ConvRT to a dose of 54 Gy in 30 fractions over 6 weeks. Main Outcomes and Measures: Detailed neuropsychological and neuroendocrine assessments were performed at preradiotherapy baseline, at 6 months, and annually thereafter until 5 years on longitudinal follow-up. Change in these functional parameters was compared between the 2 arms as the primary end point and overall survival (OS) as the secondary end point. Results: In total, 200 young patients (median [interquartile range] age, 13 [9-17] years; 133 males and 67 females) were enrolled. Mean full-scale or global intelligence quotient (IQ) and performance IQ scores over a period of 5 years were significantly superior in patients treated with SCRT compared with those treated with ConvRT (difference in slope = 1.48; P = .04 vs difference in slope = 1.64; P = .046, respectively). Cumulative incidence of developing new neuroendocrine dysfunction at 5 years was significantly lower in patients treated with SCRT compared with ConvRT (31% vs 51%; P = .01) while developing a new neuroendocrine axis dysfunction in patients with preexisting dysfunction in at least 1 axis at baseline was also significantly lower in the SCRT arm compared with the ConvRT arm (29% vs 52%; P = .02). Five-year OS in SCRT and ConvRT arms was 86% and 91%, respectively (P = .54). Conclusions and Relevance: In young patients with residual and/or progressive benign or low-grade brain tumors requiring radiotherapy for long-term tumor control, SCRT compared with ConvRT achieves superior neurocognitive and neuroendocrine functional outcomes over 5 years without compromising survival. Trial Registration: clinicaltrials.gov Identifier: NCT00517959. PMID- 28570732 TI - Interventions to Improve Oral Chemotherapy Safety and Quality: A Systematic Review. AB - Importance: With the growing use of oral chemotherapy, there is an urgent need to develop safe and effective systems to administer and manage these agents. A comprehensive synthesis of literature on oral chemotherapy care delivery programs to which clinicians can look for best practices is lacking. Objective: To summarize the peer-reviewed and gray literature on interventions to improve oral chemotherapy care delivery toward describing best practices and identifying current gaps. Evidence Review: Using search terms pertaining to the concepts of oral chemotherapy, cancer, and interventions and outcomes, we performed a systematic review of PubMed, EMBASE, and CINAHL from January 1995 to May 24, 2016, to identify oral chemotherapy intervention programs. We searched the gray literature from January 1995 through February 2016 and contacted gray literature authors for further information. Four physician abstractors reviewed the titles, abstracts, and articles. Quality of the articles was assessed using SQUIRE2 guidelines. Interventions were evaluated in the categories of prescribing, preparation/dispensing, education, administration, monitoring, and storage/disposal. The population of interest included all ages and was limited to traditional cytotoxic and targeted anticancer oral agents. Findings: From 7984 abstracts identified in the peer-reviewed literature search, 16 full-text articles met inclusion criteria representing 3612 patients. Interventions focused on prescribing (n = 1), preparation/dispensing (n = 2), education (n = 11), administration (n = 5), monitoring (n = 14), and storage/disposal (n = 1). In the 10 articles with adherence as the primary outcome, 4 evaluation methods were used. Most improvements were seen in toxic effects/safety compared with adherence. Of the 7 interventions with statistically significant improvement in the primary outcome, 3 nursing phone calls to contact patients within the first few days after treatment initiation, 2 of them with standardized toxic effects management protocols. Interventions using technology to increase touch points between care teams and patients (including video directly observed therapy, automated voice response, and text messages) were not effective. Conclusions and Relevance: A framework for the oral chemotherapy management process with standardized outcome definitions is needed to ensure constructive research. Existing data suggest that a monitoring program should include personal contact with patients within the first weeks of treatment. Whether such contact can be enhanced by technology is uncertain. PMID- 28570731 TI - Consensus on Diagnostic Criteria of Idiopathic Orbital Inflammation Using a Modified Delphi Approach. AB - Importance: Current practice to diagnose idiopathic orbital inflammation (IOI) is inconsistent, leading to frequent misdiagnosis of other orbital entities, including cancer. By specifying criteria, diagnosis of orbital inflammation will be improved. Objective: To define a set of criteria specific for the diagnosis of IOI. Design, Setting, and Participants: A 3-round modified Delphi process with an expert panel was conducted from June 8, 2015, to January 25, 2016. Fifty-three orbital scientist experts, identified through membership in the Orbital Society, were invited to participate in on online survey and they scored, using 5-point Likert scales, items that are eligible as diagnostic criteria from the literature and from personal experience. The items were clustered around the anatomic subtypes of IOI: idiopathic dacryoadenitis and idiopathic orbital fat inflammation (2 nonmyositic IOIs), and idiopathic orbital myositis (myositic IOI). Items with dissensus were rescored in the second round, and all items with consensus (median, >=4; interquartile range, <=1) were ranked by importance in the third round. Main Outcomes and Measures: Consensus on items to be included in the criteria. Results: Of the 53 experts invited to participate, a multinational panel of 35 (66%) individuals with a mean (SD) years of experience of 31 (11) years were included. Consensus was achieved on 7 of 14 clinical and radiologic items and 5 of 7 pathologic items related to diagnosis of nonmyositic IOI, and 11 of 14 clinical and radiologic items and 1 of 5 pathologic items for myositic IOI. There was agreement among panelists to focus on surgical tissue biopsy results in the diagnosis of nonmyositic IOI and on a trial with systemic corticosteroids in myositic IOI. Panelists agreed that a maximum number of 30 IgG4-positive plasma cells per high-power field in the orbital tissue is compatible with the diagnosis of IOI. Conclusions and Relevance: An international panel of experts endorsed consensus diagnostic criteria of IOI. These criteria define a level of exclusion suggested for diagnosis and include tissue biopsy for lesions not confined to the extraocular muscles. This consensus is a step toward developing guidelines for the management of IOI, which needs to be followed by validation studies of the criteria. PMID- 28570733 TI - Results of a Randomized Clinical Trial of Aflibercept vs Panretinal Photocoagulation for Proliferative Diabetic Retinopathy: Is It Time to Retire Your Laser? PMID- 28570734 TI - Deconstructing Clinical Trials-Help From Oncology Value Frameworks. PMID- 28570736 TI - Preclinical PET Study of Intravitreal Injections. AB - Purpose: This work aimed at describing the time course of vitreous clearance through the use of positron emission tomography (PET) as a noninvasive tool for pharmacokinetic studies of intravitreal injection. Methods: The pharmacokinetic profile of intravitreal injections of molecules labeled with 18Fluorine (18F) was evaluated in adult Sprague Dawley rats by using a dedicated small-animal PET/computed tomography scanner. Different conditions were studied: three molecules radiolabeled with 18F (18F-FDG, 18F-NaF, and 18F-Choline), three volumes of intravitreal injections (7, 4, and 2 MUL), and absence or presence of eye inflammation (uveitis). Results: Our results showed that there are significant pharmacokinetic differences among the radiolabeled molecules studied but not among the injected volumes. The presence or absence of uveitis was an important factor in vitreous clearance, since the elimination of the drug was clearly increased when this condition is present. Conclusions: Intravitreal pharmacokinetic studies based on the use of dedicated PET imaging can be of potential interest as noninvasive tools in ophthalmic drug development in small animals. PMID- 28570735 TI - Accuracy of Billing Codes Used in the Therapeutic Care of Diabetic Retinopathy. AB - Importance: Insurance billing claim databases represent a growing field of scientific inquiry within ophthalmology. Validating the accuracy of billing claim codes used during the care of diabetic retinopathy is a necessary precursor to fully understanding the underlying data and subsequent results of these types of studies. Objective: To determine the accuracy of diagnostic, procedural, and therapeutic billing codes used in the treatment of diabetic retinopathy. Design, Setting, and Participants: This retrospective medical record review was conducted at 3 clinical practices (1 academic and 2 private). Insured patients with diabetic retinopathy were seen by the practices between 2011 and 2013. Each patient then had every visit for 2 years reviewed twice, once for billing data and the second for data from the medical record. Data were collected and analyzed from October 2015 to July 2016. Main Outcomes and Measures: The positive predictive value (PPV) and negative predictive value (NPV) for each code of interest. Sensitivity and specificity were secondary outcomes. Results: A total of 146 patients (mean [SD] age, 60.3 [12.5] years) from 11 physicians had 1072 encounters reviewed over 2 calendar years. Among the included patients, 49.3% were female (n = 72), 48.6% were white (n = 71), 37.0% were black (n = 54), and 18.5% had type 1 diabetes and a mean (SD) hemoglobin A1C level of 7.7% (1.8) (n = 27). Nearly all codes of interest that were used frequently also had a high PPV (range, 89.5%-100%) and NPV (88.6%-100%) including billing codes for intravitreal injection, focal laser, panretinal photocoagulation, laterality of procedure, ranibizumab, bevacizumab, fundus photographs, fluorescein angiography, and optical coherence tomography. Codes that were used infrequently (<20 instances) but still had a high PPV (all 100%) and NPV (99.7%-100%) were codes for aflibercept, triamcinolone, and the dexamethasone implant. Only the codes for infrequently used B-scan ultrasonography (PPV, 69.6%) and subtenon injection (PPV, 100%; NPV, 99.7%, but sensitivity of only 40%) were found to be of questionable accuracy. Other than subtenon injection (40%), all codes were also found to have a high sensitivity (range, 87.6%-100%) and a high specificity (range, 97.2%-100%). Conclusions and Relevance: These data suggest diagnostic, procedure, and therapeutic codes derived from insurance billing claims accurately reflect the medical record for patients with diabetic retinopathy. PMID- 28570737 TI - Subconjunctival Delivery of p75NTR Antagonists Reduces the Inflammatory, Vascular, and Neurodegenerative Pathologies of Diabetic Retinopathy. AB - Purpose: The p75NTR is a novel therapeutic target validated in a streptozotocin mouse model of diabetic retinopathy. Intravitreal (IVT) injection of small molecule p75NTR antagonist THX-B was therapeutic and resolved the inflammatory, vascular, and neurodegenerative phases of the retinal pathology. To simplify clinical translation, we sought a superior drug delivery method that circumvents risks associated with IVT injections. Methods: We compared the pharmacokinetics of a single 40 MUg subconjunctival (SCJ) depot to the reported effective 5 MUg IVT injections of THX-B. We quantified therapeutic efficacy, with endpoints of inflammation, edema, and neuronal death. Results: The subconjunctival depot affords retinal exposure equal to IVT injection, without resulting in detectable drug in circulation. At week 2 of diabetic retinopathy, the SCJ depot provided therapeutic efficacy similar to IVT injections, with reduced inflammation, reduced edema, reduced neuronal death, and a long-lasting protection of the retinal structure. Conclusions: Subconjunctival injections are a safe and effective route for retinal delivery of p75NTR antagonists. The subconjunctival route offers an advantageous, less-invasive, more compliant, and nonsystemic method to deliver p75NTR antagonists for the treatment of retinal diseases. PMID- 28570738 TI - Cellular Senescence Is Associated With Human Retinal Microaneurysm Formation During Aging. AB - Purpose: Microaneurysms are present in healthy old-age human retinas. However, to date, no age-related pathogenic mechanism has been implicated in their formation. Here, cellular senescence, a hallmark of aging and several age-related diseases, has been analyzed in the old-age human retina and in the retina of a progeric mouse. Methods: Retinas were obtained from 17 nondiabetic donors and from mice deficient in Bmi1. Cellular senescence was analyzed by immunohistochemistry, senescent-associated beta-galactosidase activity assay, Sudan black B staining, conventional transmission electron microscopy, and immunoelectronmicroscopy. Results: Neurons, but not neuroglia, and blood vessels undergo cellular senescence in the old-age human retina. The canonical senescence markers p16, p53, and p21 were up-regulated and coexisted with apoptosis in old-age human microaneurysms. Senescent endothelial cells were discontinuously covered by fibronectin, and p16 colocalized with the beta1 subunit of fibronectin receptor alpha5beta1 integrin under the endothelial cellular membrane, suggesting anoikis as a mechanism involved in endothelial cell apoptosis. In a progeric mouse model deficient in Bmi1, where p21 was overexpressed, the retinal blood vessels displayed an aging phenotype characterized by enlarged caveolae and lipofuscin accumulation. Although mouse retina is not prone to develop microaneurysms, Bmi1 deficient mice presented abundant retinal microaneurysms. Conclusions: Together, these results uncover cellular senescence as a player during the formation of microaneurysms in old-age human retinas. PMID- 28570740 TI - Chorioretinal Lesions and Symptoms of Elevated Intracranial Pressure. PMID- 28570739 TI - Exploring the spatio-temporal neural basis of face learning. AB - Humans are experts at face individuation. Although previous work has identified a network of face-sensitive regions and some of the temporal signatures of face processing, as yet, we do not have a clear understanding of how such face sensitive regions support learning at different time points. To study the joint spatio-temporal neural basis of face learning, we trained subjects to categorize two groups of novel faces and recorded their neural responses using magnetoencephalography (MEG) throughout learning. A regression analysis of neural responses in face-sensitive regions against behavioral learning curves revealed significant correlations with learning in the majority of the face-sensitive regions in the face network, mostly between 150-250 ms, but also after 300 ms. However, the effect was smaller in nonventral regions (within the superior temporal areas and prefrontal cortex) than that in the ventral regions (within the inferior occipital gyri (IOG), midfusiform gyri (mFUS) and anterior temporal lobes). A multivariate discriminant analysis also revealed that IOG and mFUS, which showed strong correlation effects with learning, exhibited significant discriminability between the two face categories at different time points both between 150-250 ms and after 300 ms. In contrast, the nonventral face-sensitive regions, where correlation effects with learning were smaller, did exhibit some significant discriminability, but mainly after 300 ms. In sum, our findings indicate that early and recurring temporal components arising from ventral face sensitive regions are critically involved in learning new faces. PMID- 28570741 TI - Association of Gender With Financial Relationships Between Industry and Academic Otolaryngologists. AB - Importance: Gender disparities continue to exist in the medical profession, including potential disparities in industry-supported financial contributions. Although there are potential drawbacks to industry relationships, such industry ties have the potential to promote scholarly discourse and increase understanding and accessibility of novel technologies and drugs. Objectives: To evaluate whether gender disparities exist in relationships between pharmaceutical and/or medical device industries and academic otolaryngologists. Design, Setting, and Participants: An analysis of bibliometric data and industry funding of academic otolaryngologists. Main Outcomes and Measures: Industry payments as reported within the CMS Open Payment Database. Methods: Online faculty listings were used to determine academic rank, fellowship training, and gender of full-time faculty otolaryngologists in the 100 civilian training programs in the United States. Industry contributions to these individuals were evaluated using the CMS Open Payment Database, which was created by the Physician Payments Sunshine Act in response to increasing public and regulatory interest in industry relationships and aimed to increase the transparency of such relationships. The Scopus database was used to determine bibliometric indices and publication experience (in years) for all academic otolaryngologists. Results: Of 1514 academic otolaryngologists included in this analysis, 1202 (79.4%) were men and 312 (20.6%) were women. In 2014, industry contributed a total of $4.9 million to academic otolaryngologists. $4.3 million (88.5%) of that went to men, in a population in which 79.4% are male. Male otolaryngologists received greater median contributions than did female otolaryngologists (median [interquartile range (IQR)], $211 [$86-$1245] vs $133 [$51-$316]). Median contributions were greater to men than women at assistant and associate professor academic ranks (median [IQR], $168 [$77-$492] vs $114 [$55-$290] and $240 [$87-$1314] vs $166 [$58-$328], respectively). Overall, a greater proportion of men received industry contributions than women (68.0% vs 56.1%,). By subspecialty, men had greater median contribution levels among otologists and rhinologists (median [IQR], $609 [$166-$6015] vs $153 [$56 $336] and $1134 [$286-$5276] vs $425 [$188-$721], respectively). Conclusions and Relevance: A greater proportion of male vs female academic otolaryngologists receive contributions from industry. These differences persist after controlling for academic rank and experience. The gender disparities we have identified may be owing to men publishing earlier in their careers, with women often surpassing men later in their academic lives, or as a result of previously described gender disparities in scholarly impact and academic advancement. PMID- 28570743 TI - A life course perspective on mental health problems, employment, and work outcomes. AB - Objectives Little is known about how employment and work outcomes among young adults are influenced by their life-course history of mental health problems. Therefore, the aims of this study were to (i) identify trajectories of mental health problems from childhood to young adulthood and (ii) investigate the association between these trajectories and employment and work outcomes among young adults. Methods Data were used from 360 participants of the Tracking Adolescents' Individual Lives Survey (TRAILS), a Dutch prospective cohort study, with 12-year follow-up. Trajectories of externalizing and internalizing problems were identified with latent class growth models. Employment conditions and work outcomes (ie, psychosocial work characteristics) were measured at age 22. We assessed the association between mental health trajectories and employment conditions and work outcomes. Results Four trajectories of mental health problems were identified: high-stable, decreasing, moderate-stable and low-stable. Young adults with high-stable trajectories of externalizing problems worked over six hours more [B=6.71, 95% confidence interval (95% CI) 2.82-10.6] and had a higher income [odds ratio (OR) 0.33, 95% CI 0.15-0.71], than young adults with low stable trajectories. Young adults with high-stable trajectories of internalizing problems worked six hours less per week (B=-6.07, 95% CI -10.1- -2.05) and reported lower income (OR 3.44, 95% CI 1.53-7.74) and poorer psychosocial work characteristics, compared to young adults with low-stable trajectories. Conclusions Among young adults who had a paid job at the age of 22 (and were not a student or unemployed), those with a history of internalizing problems are less likely to transition successfully into the labor market, compared to other young adults. PMID- 28570744 TI - In response to: "Is testis sparing surgery an acceptable option for small testicular malignant tumor with normal contralateral testicle?" PMID- 28570742 TI - Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non-Small-Cell Lung Cancer: A Phase 2 Clinical Trial. AB - Importance: Our previous studies demonstrated that tumors significantly decrease in size and metabolic activity after delivery of 45 Gy of fractionated radiatiotherapy (RT), and that metabolic shrinkage is greater than anatomic shrinkage. This study aimed to determine whether 18F-fludeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) acquired during the course of treatment provides an opportunity to deliver higher-dose radiation to the more aggressive areas of the tumor to improve local tumor control without increasing RT-induced lung toxicity (RILT), and possibly improve survival. Objective: To determine whether adaptive RT can target high-dose radiation to the FDG-avid tumor on midtreatment FDG-PET to improve local tumor control of locally advanced non-small-cell lung cancer (NSCLC). Design, Setting, and Participants: A phase 2 clinical trial conducted at 2 academic medical centers with 42 patients who had inoperable or unresectable stage II to stage III NSCLC enrolled from November 2008, to May 2012. Patients with poor performance, more than 10% weight loss, poor lung function, and/or oxygen dependence were included, providing that the patients could tolerate the procedures of PET scanning and RT. Intervention: Conformal RT was individualized to a fixed risk of RILT (grade >2) and adaptively escalated to the residual tumor defined on midtreatment FDG-PET up to a total dose of 86 Gy in 30 daily fractions. Medically fit patients received concurrent weekly carboplatin plus paclitaxel followed by 3 cycles of consolidation. Main Outcomes and Measures: The primary end point was local tumor control. The trial was designed to achieve a 20% improvement in 2-year control from 34% of our prior clinical trial experience with 63 to 69 Gy in a similar patient population. Results: The trial reached its accrual goal of 42 patients: median age, 63 years (range, 45-83 years); male, 28 (67%); smoker or former smoker, 39 (93%); stage III, 38 (90%). Median tumor dose delivered was 83 Gy (range, 63-86 Gy) in 30 daily fractions. Median follow-up for surviving patients was 47 months. The 2 year rates of infield and overall local regional tumor controls (ie, including isolated nodal failure) were 82% (95% CI, 62%-92%) and 62% (95% CI, 43%-77%), respectively. Median overall survival was 25 months (95% CI, 12-32 months). The 2 year and 5-year overall survival rates were 52% (95% CI, 36%-66%) and 30% (95% CI, 16%-45%), respectively. Conclusions and Relevance: Adapting RT-escalated radiation dose to the FDG-avid tumor detected by midtreatment PET provided a favorable local-regional tumor control. The RTOG 1106 trial is an ongoing clinical trial to validate this finding in a randomized fashion. Trial Registration: clinicaltrials.gov Identifier: NCT01190527. PMID- 28570745 TI - Nd:YAG laser vitreolysis versus pars plana vitrectomy for vitreous floaters. AB - BACKGROUND: The vitreous is the clear jelly of the eye and contains fine strands of proteins. Throughout life the composition of this vitreous changes, which causes the protein strands in it to bundle together and scatter light before it reaches the retina. Individuals perceive the shadows cast by these protein bundles as 'floaters'. Some people are so bothered by floaters that treatment is required to control their symptoms. Two major interventions for floaters include Nd:YAG laser vitreolysis and vitrectomy. Nd:YAG laser vitreolysis involves using laser energy to fragment the vitreous opacities via a non-invasive approach. Vitrectomy involves the surgical replacement of the patient's vitreous (including the symptomatic vitreous floaters) with an inert and translucent balanced salt solution, through small openings in the pars plana. OBJECTIVES: To compare the effectiveness and safety of Nd:YAG laser vitreolysis to pars plana vitrectomy for symptomatic vitreous floaters. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 12), MEDLINE Ovid (1946 to 17 January 2017), Embase Ovid (1947 to 17 January 2017), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 17 January 2017), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 17 January 2017, ClinicalTrials.gov (www.clinicaltrials.gov); searched 17 January 2017 and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 17 January 2017. We did not use any date or language restrictions in the electronic searches for trials. We also searched conference proceedings to identify additional studies. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) that compared Nd:YAG laser vitreolysis to pars plana vitrectomy for treatment of symptomatic floaters. DATA COLLECTION AND ANALYSIS: We planned to use methods recommended by Cochrane. The primary outcome we planned to measure was change in vision-related quality of life from baseline to 12 months, as determined by a vision-related quality of life questionnaire. The secondary outcomes we planned to measure were best corrected logMAR or Snellen visual acuity at 12 months for the treated eye(s) and costs. Adverse outcomes we planned to record were the occurrence of sight-threatening complications by 12 months (asymptomatic retinal tears, symptomatic retinal tears, retinal detachment, cataract formation, and endophthalmitis). MAIN RESULTS: No studies met the inclusion criteria of this review. AUTHORS' CONCLUSIONS: There are currently no RCTs that compare Nd:YAG laser vitreolysis with pars plana vitrectomy for the treatment of symptomatic floaters. Properly designed RCTs are needed to evaluate the treatment outcomes from the interventions described. We recommend future studies randomise participants to either a Nd:YAG laser vitreolysis group or a vitrectomy group, with participants in each group assigned to either receive treatment or a sham intervention. Future studies should follow participants at six months and 12 months after the intervention. Also they should use best corrected visual acuity (BCVA) using an Early Treatment of Diabetic Retinopathy Study (ETDRS) chart read at 4 metres, vision-related quality of life (VRQOL), and adverse outcomes as the outcome measures of the trial. PMID- 28570746 TI - Influence of extremely low frequency magnetic fields on Ca2+ signaling and double messenger system in mice hippocampus and reversal function of procyanidins extracted from lotus seedpod. AB - This research investigated the influence of extremely low frequency magnetic fields (ELF-MF; 50 Hz, 8 mT, 4 h per day, for 28 days) on calcium ion signaling and the double messenger system in the hippocampus of mice. Messengers that were studied included: G-protein, Ins(1,4,5)P3 (IP3 ), diacylglycerol (DAG), cAMP dependent protein kinase (PKA), and Ca2+ -dependent protein kinase C (PKC). The results showed that ELF-MF caused an increase in the levels of Gi protein, IP3, DAG, PKA and PKC beta, calcium and calmodulin-dependent protein phosphatase calcineuring (PP2B), and intracellular Ca2+ content, and a decrease in calcium/calmodulin-dependent protein kinase II (CaMK II) and PKC alpha. In addition, ELF-MF exposure decreased the level of brain-derived neurotrophic factor (BDNF), which played a key role in hippocampal neuronal cell death. However, oral administration of procyanidins from lotus seedpod (LSPCs) (especially 90 mg kg-1 ) significantly recovered these changes, and nearly reached normal levels. All these showed that LSPCs may mediate calcium signal and double messenger system through Ca2+ /CaMK II/CREB/BDNF and DG/PKC/MAPK signaling pathways to reverse the alteration caused by ELF-MF. Bioelectromagnetics. 38:436 446, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28570747 TI - Caspase14 expression is associated with triple negative phenotypes and cancer stem cell marker expression in breast cancer patients. AB - BACKGROUND AND OBJECTIVES: The Caspase14 (CASP14) was reported that the low expression of CASP14 in ovarian cancer and colon cancer was associated with cancer progression, on the other hand, that the CASP14 expression in breast cancer was higher than that of non-cancerous tissues. The purpose of this study is to determine the clinical significance of CASP14 in breast cancer. METHODS: We performed immunohistochemistry for CASP14, ER, PgR, HER2, Ki67, EGFR, CK5/6, CD44, CD24, ALDH1, claudins, and androgen receptor in 222 breast cancer patients including 55 TNBC cases, and evaluated the relationship of CASP14, above mentioned markers, and prognosis. Using public microarray database of breast cancer, the prognostic value of CASP14 was calculated. RESULTS: High CASP14 expression was significantly associated with TNBC subtype (P = 0.015), nuclear grade (P = 0.006), Ki67, EGFR (P < 0.001, P = 0.016), ALDH1, CD44 and CD24 (P < 0.001, P < 0.001, P = 0.001) in 222 breast cancer cases, and the high expression of claudin1 (P = 0.017), and androgen receptor (P = 0.002) in TNBC cases was related to the high CASP14. According to the public database, survival in the high CASP14 breast cancer patients was shorter than low CASP14 patients. CONCLUSIONS: High CASP14 expression is a marker of breast cancer aggressiveness in association with proliferation, TNBC phenotype, and cancer stemness. PMID- 28570748 TI - Sensitivity and specificity of indocyanine green near-infrared fluorescence imaging in detection of metastatic lymph nodes in colorectal cancer: Systematic review and meta-analysis. AB - This review aimed to determine the overall sensitivity and specificity of indocyanine green (ICG) near-infrared (NIR) fluorescence in sentinel lymph node (SLN) detection in Colorectal cancer (CRC). A systematic search in electronic databases was conducted. Twelve studies including 248 patients were reviewed. The median sensitivity, specificity, and accuracy rates were 73.7, 100, and 75.7. The pooled sensitivity and specificity rates were 71% and 84.6%. In conclusion, ICG NIR fluorescence is a promising technique for detecting SLNs in CRC. PMID- 28570749 TI - Comparison of sporadic and FAP-associated desmoid-type fibromatoses. AB - BACKGROUND AND OBJECTIVES: Desmoid-type fibromatosis is a rare disease of which 7.5-16% have been reported to be related to familial adenomatous polyposis (FAP). We sought to compare the characteristics and treatment of sporadic and FAP related desmoid-type fibromatoses. METHODS: Altogether 220 patients were included in the study after receiving a diagnosis of desmoid-type fibromatosis by the Pathology Department of Helsinki University Hospital, with adequate follow-up. Patients were included from January 1, 1980 until April 30, 2015. RESULTS: FAP related tumors were found in 22 (10%) patients. FAP-related desmoid-type fibromatoses were larger, more commonly multiple, and more often intra abdominally situated. Surgery was the treatment of choice for 179 (90%) of the sporadic patients and for 18 (82%) of FAP-related patients. Resections with non involved margins (R0) were more common in sporadic desmoid-type fibromatoses (55% vs. 23%, P = 0.048). The risk of recurrence was 25% in sporadic- and 44% in the FAP-related group. Three (14%) patients with FAP-related desmoid-type fibromatoses died from the disease. CONCLUSIONS: The predictors for FAP occurrence among desmoid tumor patients are large tumor size, intra-abdominal location, multiple tumors, and patient's young age. Desmoid-type fibromatosis patients suffer a high recurrence rate, also among those experiencing sporadic tumors, but the risk of death due to the tumor is low. Conversely, desmoid disease represents a substantial cause of death among FAP patients. PMID- 28570750 TI - Epithelial-mesenchymal transition inducer Snail1 and invasive potential of intraductal breast cancer. AB - BACKGROUND AND OBJECTIVES: Transcription factor Snail1 is a key inducer of epithelial-mesenchymal transition (EMT), a biological process implicated in the cancer progression and metastasis. The aim of the study was to investigate Snail1 expression in DCIS found on breast biopsy and assess its predictive value for the final invasion. METHODS: A total of 209 patients with histologically diagnosed pure DCIS entered the study. Snail1 reactivity was evaluated with immunohistochemistry in tumor tissue from stereotactic vacuum-assisted biopsy of suspicious microcalcifications. RESULTS: Snail1 staining was observed in 62% of tumors: weak, intermediate, and strong in 27%, 21%, and 14% of lesions, respectively. Positive Snail1 expression was significantly rarer in DCIS presenting as powdery microcalcifications, when compared with crushed stone-like and casting-type and was more common in DCIS with comedonecrosis. Correlation with other features was not significant. None of standard parameters significantly influenced the upgrading rate. In contrast, in uni- and multivariate analysis the risk of postoperative invasion was significantly associated with positive Snail1 immunoreactivity. Moreover, there was a significant stepwise increase of upgrading rate according to Snail1 expression in DCIS cells: weak 9%, intermediate 26%, and strong 55%, respectively. CONCLUSIONS: Snail1 can reflect the invasive potential of DCIS and help identify its more aggressive subtypes. PMID- 28570751 TI - Preoperative clinicopathological characteristics of patients with solitary encapsulated follicular variants of papillary thyroid carcinomas. AB - BACKGROUND AND OBJECTIVES: Clinical outcomes in patients with the follicular variant of papillary thyroid carcinoma (FVPTC) tend to vary according to the pathological subtypes. We aimed to evaluate the clinicopathological characteristics including preoperative radiological and cytopathological diagnoses in patients with solitary encapsulated FVPTCs (EFVPTCs) to prove the preoperative assessment dilemma. METHODS: Patients with solitary FVPTCs who underwent thyroid surgery were included. RESULTS: Of 271 patients, 194 patients (72%) had EFVPTCs, whereas 77 patients (28%) had infiltrative FVPTCs (IFVPTCs). EFVPTCs had larger tumor sizes (P < 0.001) and lower frequencies of extrathyroidal extension (P < 0.001) and cervical lymph node (LN) metastasis (P < 0.001) than IFVPTCs. There were significant differences in ultrasonography (US) findings, preoperative cytopathological diagnosis, and the prevalence of BRAF mutations between EFVPTCs and IFVPTCs. Invasive EFVPTCs were diagnosed in 89 patients (33%) and non-invasive EFVPTCs in 105 patients (39%). Non-invasive subtype had smaller tumor sizes (P = 0.001) and lower frequencies of vascular invasion (P = 0.04) and cervical LN metastasis (P = 0.02). There were no significant differences in preoperative US findings and cytopathological diagnoses between invasive and non-invasive EFVPTCs. CONCLUSIONS: Clinicopathological characteristics of EFVPTCs, including preoperative US findings, are different from those of IFVPTCs. However, preoperative radiological and cytopathological findings could not distinguish non-invasive and invasive EFVPTCs. PMID- 28570752 TI - External validation of the Arterial Based Complexity (ABC) scoring system in renal tumors treated by minimally invasive partial nephrectomy. AB - OBJECTIVE: To assess the role of the Arterial Based Complexity (ABC) scoring system in predicting clinically relevant outcomes of a minimally invasive partial nephrectomy (MIPN). PATIENTS AND METHODS: We retrospectively reviewed 350 consecutive patients who underwent a MIPN between 2013 and 2014. Tumor complexity was evaluated according to the ABC scoring system. Complications, surgical, and renal outcomes were recorded. RESULTS: There were respectively 36 (10.3%), 229 (65.4%), 43 (12.3%), and 42 (12.0%) patients in category 1, 2, 3S, 3H. Multivariate regression showed category assignment was associated with warm ischemia time (P < 0.001), estimated blood loss (P = 0.001), and operative time (P = 0.032). On multivariate analyses, tumor size was the only independent predictor of overall (P = 0.035) and minor (P = 0.032) complications, but ABC category failed to predict complications (P > 0.05 for all). For renal function, ABC category failed to predict postoperative estimated glomerular filtration rate at 1 day and 6 months (P > 0.05 for both). CONCLUSIONS: In MIPN, the ABC scoring system predicted a prolonged warm ischemia time and operative time, and an added estimated blood loss. This scoring system was not a predictor for the occurrence of complications and postoperative renal function. PMID- 28570754 TI - Is testis sparing surgery an acceptable option for small testicular malignant tumor with normal contralateral testicle? PMID- 28570753 TI - Screening for adult attention deficit/hyperactivity disorder in high-dose benzodiazepine dependent patients. AB - BACKGROUND AND OBJECTIVES: Adult attention-deficit/hyperactivity disorder (ADHD) is frequent in patients with substance use disorders (SUD), but information on its prevalence in high-dose benzodiazepine (BZD) dependence is lacking. We estimated the prevalence of adult ADHD in a group of treatment-seeking high-dose BZD dependent patients according to a valid screening tool, and explored the demographic and clinical characteristics of patients that screened positive for ADHD (ADHD+) in comparison to those that screened negative (ADHD-). METHODS: We prospectively recruited 167 consecutive patients with high-dose BZD dependence and screened them for adult ADHD with the World Health Organization Adult ADHD Self-Report Scale version 1.1 (ASRS-v1.1) Symptom Checklist Part A. We compared demographic and clinical characteristics in ADHD+ and ADHD- groups. RESULTS: Fifty-three patients (31.7% of the sample) were positive to adult ADHD screening. ADHD+ patients showed a significantly larger prevalence of poly-drug abuse than ADHD- ones. BZD formulation and active principle significantly differed between the two groups. The other clinical variables, including psychiatric comorbidity, as well as the demographic ones, did not differ in ADHD+ versus ADHD- comparison. DISCUSSION AND CONCLUSIONS: Adult ADHD may be common in treatment-seeking high dose BZD dependent patients according to ASRS-v1.1 Symptom Checklist Part A. SCIENTIFIC SIGNIFICANCE: Screening for ADHD in this type of SUD with this questionnaire is quick and may offer useful information for prognosis and treatment. (Am J Addict 2017;26:610-614). PMID- 28570755 TI - Personal and hospital factors associated with limited surgical resection for lung cancer, in-hospital mortality and complications in New York State. AB - BACKGROUND AND OBJECTIVES: Early stage lung cancer is generally treated with surgical resection. The objective of the study was to identify patient and hospital characteristics associated with the type of lung cancer surgical approach utilized in New York State (NYS), and to assess in-hospital adverse events. METHODS: A total of 33 960 lung cancer patients who underwent limited resection (LR) or lobectomy (L) were selected from the NYS Statewide Planning and Research Cooperative System database (1995-2012). RESULTS: LR patients were more likely to be older (adjusted odds ratio ORadj and [95% confidence interval]: 1.01 [1.01-1.02]), female (ORadj : 1.11 [1.06-1.16]), Black (ORadj : 1.17 [1.08 1.27]), with comorbidities (ORadj : 1.08 [1.03-1.14]), and treated in more recent years than L patients. Length of stay and complications were significantly less after LR than L (ORadj : 0.56 [0.53-0.58] and 0.65 [0.62-0.69]); in-hospital mortality was similar (ORadj : 0.93 [0.81-1.07]), and was positively associated with age and urgent/emergency admission, but inversely associated with female gender, private insurance, recent admission year, and surgery volume. CONCLUSIONS: There was a growing trend toward LR, which was more likely to be performed in older patients with comorbidities. In-hospital outcomes were better after LR than L, and were affected by patient and hospital characteristics. PMID- 28570756 TI - Two-Dimensional Haeckelite NbS2 : A Diamagnetic High-Mobility Semiconductor with Nb4+ Ions. AB - In all known Group 5 transition-metal dichalcogenide monolayers (MLs), the metal centers carry a spin, and their ground-state phases are either metallic or semiconducting with indirect band gaps. Here, on grounds of first-principles calculations, we report that the Haeckelite polytypes 1S-NbX2 (X=S, Se, Te) are diamagnetic direct-band-gap semiconductors even though the Nb atoms are in the 4+ oxidation state. In contrast, 1S-VX2 MLs are antiferromagnetically coupled indirect-band-gap semiconductors. The 1S phases are thermodynamically and dynamically stable but of slightly higher energy than their 1H and 1T ML counterparts. 1S-NbX2 MLs are excellent candidates for optoelectronic applications owing to their small band gaps (between 0.5 and 1 eV). Moreover, 1S NbS2 shows a particularly high hole mobility of 2.68*103 cm2 V-1 s-1 , which is significantly higher than that of MoS2 and comparable to that of WSe2 . PMID- 28570757 TI - Illuminating Iron: Mesoionic Carbenes as Privileged Ligands in Photochemistry. AB - The new iron age: The stabilization of an iron(III) complex with mesoionic carbenes has been shown to lead to record-breaking excited-state lifetimes and an unprecedented spin-allowed radiative decay from a 2 LMCT state. These results set the stage for a sustainable future in the new "iron age". PMID- 28570759 TI - Catalytic Asymmetric Conjugate Addition of Indolizines to alpha,beta-Unsaturated Ketones. AB - A catalytic enantioselective conjugate addition of indolizines to enones is described. The chiral phosphoric acid (S)-TRIP activates alpha,beta-unsaturated ketones, thereby promoting an enantioface-differentiating attack by indolizines. Using this reaction, several alkylated indolizines were synthesized in good yields and with enantiomeric ratios of up to 98:2. PMID- 28570760 TI - Immunoreduction of locally advanced orbito-conjunctival squamous cell carcinoma with intraorbital interferon alpha-2b injection: a globe saving approach. PMID- 28570758 TI - Variation in use of postoperative chemoradiation following surgery for T1 and T2 oropharyngeal squamous cell carcinoma; National Cancer Database. AB - BACKGROUND AND OBJECTIVES: Primary surgical treatment of patients with early T classification (T1-T2) oropharyngeal squamous cell carcinoma (OPSCC) has increased. We sought to determine how often these patients receive postoperative chemoradiation (CRT). METHODS: Patients with T1-T2 OPSCC in the National Cancer Database who underwent primary surgery were evaluated for receipt of postoperative CRT. Postoperative CRT use was examined among patients with high risk factors (positive margins and/or extracapsular spread [ECS]), intermediate risk factors (negative margins, no ECS, and either pT3-4 and/or N2-N3), and no apparent risk factors. RESULTS: Of 4833 patients with T1-T2 OPSCC who underwent primary surgery, 43% had high risk pathologic factors, of whom only 63% received postoperative CRT. Another 31% had no apparent risk factors, of whom 16% nonetheless received postoperative CRT. On multivariable analysis, in addition to tumor and demographic factors, patients treated at community hospitals were more likely to receive postoperative CRT (O.R. 1.41 C.I. 1.18-1.87, P = 0.001). CONCLUSIONS: Variation in postoperative CRT use indicates a lack of consensus and/or knowledge about its benefits and indications. Usage of postoperative CRT regardless of pathologic risk factors suggests an area where future efforts at implementation of best practices may be targeted. PMID- 28570761 TI - The Effect of Drug Loading on Micelle Properties: Solid-State NMR as a Tool to Gain Structural Insight. AB - The present study highlights the importance of understanding the structural changes of micelles induced by drug loading on their physico-chemical properties. A block copolymer with attached fructose, which interacts with GLUT5 receptor, was used and conjugated with a low and a high amount of platinum drugs. Against expectations, the low-loading micelle, despite having a less defined morphology and larger nanoparticle size according to TEM, displays higher cellular uptake and higher toxicity. This behaviour can only be understood when elucidating additional information on the structure of micelles. Extensive solid-state NMR measurements were therefore employed to reveal that the drug loading affected swelling and mobility of core and shell of the micelle. The results obtained from solid-state NMR spectroscopy could explain all the observations on this system. In summary, solid-state NMR spectroscopy is an excellent tool to understand the effects of drug loading on the behavior of micelles. PMID- 28570763 TI - Discovery of Potent Dual Binding Site Acetylcholinesterase Inhibitors via Homo- and Heterodimerization of Coumarin-Based Moieties. AB - Acetylcholinesterase (AChE) inhibitors still comprise the majority of the marketed drugs for Alzheimer's disease (AD). The structural arrangement of the enzyme, which features a narrow gorge that separates the catalytic and peripheral anionic subsites (CAS and PAS, respectively), inspired the development of bivalent ligands that are able to bind and block the catalytic activity of the CAS as well as the role of the PAS in beta amyloid (Abeta) fibrillogenesis. With the aim of discovering novel AChE dual binders with improved drug-likeness, homo- and heterodimers containing 2H-chromen-2-one building blocks were developed. By exploring diverse linkages of neutral and protonatable amino moieties through aliphatic spacers of different length, a nanomolar bivalent AChE inhibitor was identified (3-[2-({4-[(dimethylamino)methyl]-2-oxo-2H-chromen-7-yl}oxy)ethoxy] 6,7-dimethoxy-2H-chromen-2-one (6 d), IC50 =59 nm) from originally weakly active fragments. To assess the potential against AD, the disease-related biological properties of 6 d were investigated. It performed mixed-type AChE enzyme kinetics (inhibition constant Ki =68 nm) and inhibited Abeta self-aggregation. Moreover, it displayed an outstanding ability to protect SH-SY5Y cells from Abeta1-42 damage. PMID- 28570764 TI - Controllable N-Doped CuCo2 O4 @C Film as a Self-Supported Anode for Ultrastable Sodium-Ion Batteries. AB - Rational synthesis of flexible electrodes is crucial to rapid growth of functional materials for energy-storage systems. Herein, a controllable fabrication is reported for the self-supported structure of CuCo2 O4 nanodots (~3 nm) delicately inserted into N-doped carbon nanofibers (named as 3-CCO@C); this composite is first used as binder-free anode for sodium-ion batteries (SIBs). Benefiting from the synergetic effect of ultrasmall CuCo2 O4 nanoparticles and a tailored N-doped carbon matrix, the 3-CCO@C composite exhibits high cycling stability (capacity of 314 mA h g-1 at 1000 mA g-1 after 1000 cycles) and high rate capability (296 mA h g-1 , even at 5000 mA g-1 ). Significantly, the Na storage mechanism is systematically explored, demonstrating that the irreversible reaction of CuCo2 O4 , which decomposes to Cu and Co, happens in the first discharge process, and then a reversible reaction between metallic Cu/Co and CuO/Co3 O4 occurrs during the following cycles. This result is conducive to a mechanistic study of highly promising bimetallic-oxide anodes for rechargeable SIBs. PMID- 28570765 TI - Hierarchical and Heterogeneous Bioinspired Composites-Merging Molecular Self Assembly with Additive Manufacturing. AB - Biological composites display exceptional mechanical properties owing to a highly organized, heterogeneous architecture spanning several length scales. It is challenging to translate this ordered and multiscale structural organization in synthetic, bulk composites. Herein, a combination of top-down and bottom-up approach is demonstrated, to form a polymer-ceramic composite by macroscopically aligning the self-assembled nanostructure of polymerizable lyotropic liquid crystals via 3D printing. The polymer matrix is then uniformly reinforced with bone-like apatite via in situ biomimetic mineralization. The combinatorial method enables the formation of macrosized, heterogeneous composites where the nanostructure and chemical composition is locally tuned over microscopic distances. This enables precise control over the mechanics in specific directions and regions, with a unique intrinsic-extrinsic toughening mechanism. As a proof of-concept, the method is used to form large-scale composites mimicking the local nanostructure, compositional gradients and directional mechanical properties of heterogeneous tissues like the bone-cartilage interface, for mechanically stable osteochondral plugs. This work demonstrates the possibility to create hierarchical and complex structured composites using weak starting components, thus opening new routes for efficient synthesis of high-performance materials ranging from biomaterials to structural nanocomposites. PMID- 28570766 TI - Thermally Stable Metal-Organic Framework-Templated Synthesis of Hierarchically Porous Metal Sulfides: Enhanced Photocatalytic Hydrogen Production. AB - Porous nanostructured materials are demonstrated to be very promising in catalysis due to their well accessible active sites. Thermally stable metal organic frameworks (MOFs) as hard templates are successfully utilized to afford porous metal oxides and subsequently metal sulfides by a nanocasting method. The resultant metal oxides/sulfides show considerable Brunauer-Emmett-Teller (BET) surface areas, by partially inheriting the pore character of MOF templates. Preliminary investigation on the obtained hierarchically porous CdS for water splitting, as a proof of concept, demonstrates its much higher activity than both corresponding bulk and nanosized counterparts, under visible light irradiation. Given the structural diversity and tailorability of MOFs, such synthetic approach may open an avenue to the synthesis of advanced porous materials for functional applications. PMID- 28570767 TI - Polymeric Tubular Aromatic Amide Helices. AB - Conjugated polymers may be induced by intra- and/or intermolecular non-covalent forces to fold into helical conformations. Helices formed by aromatic amide, hydrazide, and urea polymers possess a well-organized cavity and depth, which is defined by their degree of polymerization. Driving forces may be intramolecular hydrogen bonding and/or solvophobicity, or guest induction. The resulting long helices represent a new class of unimacromolecular dynamic tubular architectures that exhibit unique properties or functions in, for example, molecular recognition, chirality transfer, and ion transporting. The recent advances are highlighted here. PMID- 28570768 TI - Electrostatic Mechanophores in Tuneable Light-Emitting Piezopolymer Nanowires. AB - Electromechanical coupling through piezoelectric polymer chains allows the emission of organic molecules in active nanowires to be tuned. This effect is evidenced by highly bendable arrays of counter-ion dye-doped nanowires made of a poly(vinylidenefluoride) copolymer. A reversible redshift of the dye emission is found upon the application of dynamic stress during highly accurate bending experiments. By density functional theory calculations it is found that these photophysical properties are associated with mechanical stresses applied to electrostatically interacting molecular systems, namely to counterion-mediated states that involve light-emitting molecules as well as charged regions of piezoelectric polymer chains. These systems are an electrostatic class of supramolecular functional stress-sensitive units, which might impart new functionalities in hybrid molecular nanosystems and anisotropic nanostructures for sensing devices and soft robotics. PMID- 28570769 TI - Incidental positive lymph nodes in patients with papillary thyroid cancer is independently associated with recurrent disease. AB - BACKGROUND AND OBJECTIVES: Pathological examination occasionally reveals incidental central lymph nodes metastasis (iLNM) after thyroidectomy for patients with papillary thyroid cancer (PTC) who did not undergo compartment-orientated lymphadenectomy. We aimed to investigate the risk of recurrence for patients with iLNM. METHODS: We conducted a retrospective review of all patients undergoing total thyroidectomy for PTC (January 2000 to January 2010). Patients with distant metastases, central- or lateral neck dissection and pre-operative suspicious lymph nodes (by ultrasound or clinical examination) were excluded. The association between iLNM and recurrent disease was investigated using Kaplan Meier survival estimates and Cox proportional hazards analysis. RESULTS: 225/1000 patients had incidental nodes after total thyroidectomy for PTC. 183 were node negative and 42 had iLNM. Mean age was 46 years and 201 (89%) were women. Mean number of resected nodes was 2.3. Disease recurred in 8/183 (4.4%) of patients with N0 versus 7/42 (17%) with iLNM. After adjusting for other factors, iLNM was independently associated with recurrent disease (hazard ratio = 4.01 [95% CI 1.21 13.3]). CONCLUSIONS: Positive incidental lymph nodes are independently associated with recurrent disease in patients with PTC. These patients should therefore be monitored more carefully. PMID- 28570770 TI - Stable Heterometallic Cluster Ions based on Werner's Hexol. AB - Large aqueous ions are interesting because they are useful in materials science (for example to generate thin films) but also because they serve as molecular models for the oxide-aqueous mineral interface where spectroscopy is difficult. Here we show that new clusters of the type M[(MU-OH)2 Co(NH3 )4 ]3 (NO3 )6 (M=Al, Ga) can be synthesized using Werner's century-old cluster as a substitutable framework. We substituted Group 13 metals into the hexol Co[(MU-OH)2 Co(NH3 )4 ]36+ ion to make diamagnetic heterometallic ions. The solid-state structure of the hexol-type derivatives were determined by single-crystal XRD and NMR spectroscopy and confirmed that the solid-state structure persists in solution after dissolution into either D2 O or [D6 ]DMSO. Other compositions besides these diamagnetic ions can undoubtedly be made using a similar approach, which considerably expands the number of stable aqueous heteronuclear ions. PMID- 28570771 TI - How exaptations facilitated photosensory evolution: Seeing the light by accident. AB - Exaptations are adaptations that have undergone a major change in function. By recruiting genes from sources originally unrelated to vision, exaptation has allowed for sudden and critical photosensory innovations, such as lenses, photopigments, and photoreceptors. Here we review new or neglected findings, with an emphasis on unicellular eukaryotes (protists), to illustrate how exaptation has shaped photoreception across the tree of life. Protist phylogeny attests to multiple origins of photoreception, as well as the extreme creativity of evolution. By appropriating genes and even entire organelles from foreign organisms via lateral gene transfer and endosymbiosis, protists have cobbled photoreceptors and eyespots from a diverse set of ingredients. While refinement through natural selection is paramount, exaptation helps illustrate how novelties arise in the first place, and is now shedding light on the origins of photoreception itself. PMID- 28570772 TI - Structural Transition in Liquid Crystal Bubbles Generated from Fluidic Nanocellulose Colloids. AB - The structural transition in micrometer-sized liquid crystal bubbles (LCBs) derived from rod-like cellulose nanocrystals (CNCs) was studied. The CNC-based LCBs were suspended in nematic or chiral nematic liquid-crystalline CNCs, which generated topological defects and distinct birefringent textures around them. The ordering and structure of the LCBs shifted from a nematic to chiral nematic arrangement as water evaporation progressed. These packed LCBs exhibited a specific photonic cross-communication property that is due to a combination of Bragg reflection and bubble curvature and size. PMID- 28570773 TI - Integrated care pathway for co-occurring major depressive and alcohol use disorders: Outcomes of the first two years. AB - BACKGROUND: Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD) are highly prevalent, comorbid, and have significant impact on morbidity, mortality, and socioeconomic burden in Canada. Combined psycho- and pharmacotherapies for both conditions promise better outcomes than treatment as usual (TAU). At the Centre for Addiction and Mental Health, Toronto, Canada, we developed and implemented an Integrated Care Pathway (ICP) specifically for treatment of concurrent MDD and AUD. The goal of the study is to assess the clinical effectiveness of the ICP approach in comparison to TAU. MATERIALS AND METHODS: Non-randomized design, clinical chart review, Chi-square and t-tests, Cohen's d, Linear Mixed Effects Models, Kaplan-Meier, and log-rank analyses. RESULTS: Eighty one ICP patients were included, matched to 81 controls by age, sex, severity of depressive symptoms, and patterns of drinking. ICP cohort had a significantly lower dropout rate (18.5% vs 69.1%, p < .001; at 16 weeks of treatment, respectively), both cohorts demonstrated significant reduction in the number of heavy drinking days (beta = .01, p < .001) and standard drinks per week (beta = .15, p < .001) with a significantly higher reduction of both indicators over time in the ICP cohort. Significant reduction in depressive symptoms severity (QIDS: 14.6 vs 10.0, p < .001; BDI: 26.3 vs 16.2, p < .001) was observed in ICP cohort (no data for TAU cohort). CONCLUSIONS: The ICP patients demonstrated improvements on several levels including depressive symptoms, and changes in alcohol drinking patterns. The study demonstrated the overall effectiveness of the ICP and apparent advantage over TAU, which must be corroborated through a randomized clinical trial. (Am J Addict 2017;26:602-609) SCIENTIFIC SIGNIFICANCE: This study is one of the first works showing the outcomes of an ICP developed in the mental health area and for co-occurring disorders. Despite the limitations, the relative advantage of the ICP methodology warrants future research in this area. PMID- 28570774 TI - A Generalized Strategy for the Synthesis of Large-Size Ultrathin Two-Dimensional Metal Oxide Nanosheets. AB - Two-dimensional (2D) nanomaterials show unique electrical, mechanical, and catalytic performance owing to their ultrahigh surface-to-volume ratio and quantum confinement effects. However, ways to simply synthesize 2D metal oxide nanosheets through a general and facile method is still a big challenge. Herein, we report a generalized and facile strategy to synthesize large-size ultrathin 2D metal oxide nanosheets by using graphene oxide (GO) as a template in a wet chemical system. Notably, the novel strategy mainly relies on accurately controlling the balance between heterogeneous growth and nucleation of metal oxides on the surface of GO, which is independent on the individual character of the metal elements. Therefore, ultrathin nanosheets of various metal oxides, including those from both main-group and transition elements, can be synthesized with large size. The ultrathin 2D metal oxide nanosheets also show controllable thickness and unique surface chemical state. PMID- 28570775 TI - Fe2 PO5 -Encapsulated Reverse Energetic ZnO/Fe2 O3 Heterojunction Nanowire for Enhanced Photoelectrochemical Oxidation of Water. AB - Zinc oxide is regarded as a promising candidate for application in photoelectrochemical water oxidation due to its higher electron mobility. However, its instability under alkaline conditions limits its application in a practical setting. Herein, we demonstrate an easily achieved wet-chemical route to chemically stabilize ZnO nanowires (NWs) by protecting them with a thin layer Fe2 O3 shell. This shell, in which the thickness can be tuned by varying reaction times, forms an intact interface with ZnO NWs, thus protecting ZnO from corrosion in a basic solution. The reverse energetic heterojunction nanowires are subsequently activated by introducing an amorphous iron phosphate, which substantially suppressed surface recombination as a passivation layer and improved photoelectrochemical performance as a potential catalyst. Compared with pure ZnO NWs (0.4 mA cm-2 ), a maximal photocurrent of 1.0 mA cm-2 is achieved with ZnO/Fe2 O3 core-shell NWs and 2.3 mA cm-2 was achieved for the PH3 -treated NWs at 1.23 V versus RHE. The PH3 low-temperature treatment creates a dual function, passivation and catalyst layer (Fe2 PO5 ), examined by X-ray photoelectron spectroscopy, TEM, photoelectrochemical characterization, and impedance measurements. Such a nano-composition design offers great promise to improve the overall performance of the photoanode material. PMID- 28570778 TI - A Binuclear Zinc Interaction Fold Discovered in the Homodimer of Alzheimer's Amyloid-beta Fragment with Taiwanese Mutation D7H. AB - Zinc-induced oligomerization of amyloid-beta peptide (Abeta) produces potentially pathogenic agents of Alzheimer's disease. Mutations and modifications in the metal binding domain 1-16 of Abeta peptide crucially affect its zinc-induced oligomerization by changing intermolecular zinc mediated interface. The 3D structure of this interface appearing in a range of Abeta species is a prospective drug target for disease modifying therapy. Using NMR spectroscopy, EXAFS spectroscopy, mass spectrometry, and isothermal titration calorimetry the interaction of zinc ions with Abeta fragments 1-7 and 1-10 carrying familial Taiwanese mutation D7H was studied. Zinc ions induce formation of a stable homodimer formed by the two peptide chains fastened by two zinc ions and stacking interactions of imidazole rings. A binuclear zinc interaction fold in the dimer structure was discovered. It can be used for designing zinc-regulated proteins and zinc-mediated self-assembling peptides. PMID- 28570776 TI - The personality basis of aggression: The mediating role of anger and the moderating role of emotional intelligence. AB - High neuroticism and low agreeableness have been found to predict higher levels of aggression through an increase of negative emotions such as anger. However, previous research has only investigated these indirect associations for physical aggression, whereas evidence for such indirect effects on other types of aggression (i.e., verbal or indirect aggression) is currently lacking. Moreover, no previous work has investigated the moderating role of Ability Emotional Intelligence (AEI), which may buffer against the effects of anger on aggression. The present study (N = 665) directly addresses these gaps in the literature. The results demonstrate that high neuroticism and low agreeableness were indirectly related to higher levels of physical, verbal, and indirect aggression via increased chronic accessibility to anger. Importantly however, the associations with physical aggression were significantly weaker for those higher (vs. lower) on AEI, confirming the buffering role of AEI. We discuss the implications of our findings for theoretical frameworks aiming to understand and reduce aggression and violent behavior. PMID- 28570779 TI - Electronic Origin of the Competitive Mechanisms in the Thermal Activation of Methane by the Heteronuclear Cluster Oxide [Al2 ZnO4 ]. AB - The thermal gas-phase reactions of [Al2 ZnO4 ].+ with methane have been explored by using FT-ICR mass spectrometry complemented by high-level quantum chemical calculations. Two competitive mechanisms, that is, hydrogen-atom transfer (HAT) and proton-coupled electron transfer (PCET) are operative. Interestingly, while the HAT process is influenced by the polarity of the transition structure, both the ionic nature of the metal-oxygen bond and the structural rigidity of the cluster oxide affect the PCET pathway. As compared to the previously reported homonuclear [Al2 O3 ].+ and [ZnO].+ , the heteronuclear oxide [Al2 ZnO4 ].+ exhibits a much higher chemoselectivity towards methane. The electronic origins of the doping effect have been explored. PMID- 28570780 TI - Development and validation of a nomogram to estimate the pretest probability of cancer in Chinese patients with solid solitary pulmonary nodules: A multi institutional study. AB - OBJECTIVES: To develop and validate a nomogram to estimate the pretest probability of malignancy in Chinese patients with solid solitary pulmonary nodule (SPN). MATERIALS AND METHODS: A primary cohort of 1798 patients with pathologically confirmed solid SPNs after surgery was retrospectively studied at five institutions from January 2014 to December 2015. A nomogram based on independent prediction factors of malignant solid SPN was developed. Predictive performance also was evaluated using the calibration curve and the area under the receiver operating characteristic curve (AUC). RESULTS: The mean age of the cohort was 58.9 +/- 10.7 years. In univariate and multivariate analysis, age; history of cancer; the log base 10 transformations of serum carcinoembryonic antigen value; nodule diameter; the presence of spiculation, pleural indentation, and calcification remained the predictive factors of malignancy. A nomogram was developed, and the AUC value (0.85; 95%CI, 0.83-0.88) was significantly higher than other three models. The calibration cure showed optimal agreement between the malignant probability as predicted by nomogram and the actual probability. CONCLUSIONS: We developed and validated a nomogram that can estimate the pretest probability of malignant solid SPNs, which can assist clinical physicians to select and interpret the results of subsequent diagnostic tests. PMID- 28570782 TI - A Bifunctional Spin Label for Ligand Recognition on Surfaces. AB - In situ monitoring of biomolecular recognition, especially at surfaces, still presents a significant technical challenge. Electron paramagnetic resonance (EPR) of biomolecules spin-labeled with nitroxides can offer uniquely sensitive and selective insights into these processes, but new spin-labeling strategies are needed. The synthesis and study of a bromoacrylaldehyde spin label (BASL), which features two attachment points with orthogonal reactivity is reported. The first examples of mannose and biotin ligands coupled to aqueous carboxy-functionalized gold nanoparticles through a spin label are presented. EPR spectra were obtained for the spin-labeled ligands both free in solution and attached to nanoparticles. The labels were recognized by the mannose-binding lectin, Con A, and the biotin binding protein avidin-peroxidase. Binding gave quantifiable changes in the EPR spectra from which binding profiles could be obtained that reflect the strength of binding in each case. PMID- 28570781 TI - The effect of antioxidants on the long-term stability of THC and related cannabinoids in sampled whole blood. AB - The stability of cannabinoids is complex and crucial for the assessment of impaired driving caused by cannabis. Therefore, the effect of antioxidants on the long-term stability of Delta9 -tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD), 11-hydroxy-Delta9 -tetrahydrocannabinol (THC-OH), and 11-nor-9 carboxy-Delta9 -tetrahydrocannabinol (THC-COOH) in whole blood samples preserved with fluoride citrate (FC) and fluoride oxalate (FX) mixtures was investigated at different temperatures. The measured concentrations of the cannabinoids in authentic whole blood preserved solely with FC or FX mixtures decreased significantly during prolonged storage at -20 degrees C. On average, less than 5% of the initial concentrations of THC and CBD were recovered after 19 weeks of storage interrupted by 5 thawing/freezing cycles. The rate of decrease was greatest in FC-preserved blood. The repeated thawing/freezing of the samples accelerated the instability progression. At 5 degrees C approximately 60% of the initial concentrations of THC and CBD were recovered after 19 weeks of storage. No significant decrease was observed in samples stored at -80 degrees C during the test period of 5 months. The instability at -20 degrees C was to a great extend avoided by adding 30 mM ascorbic acid (ASC) to the samples before storage. Samples preserved with a combination of the FX mixture and ASC showed no significant decrease in the recovered concentrations during a 5-month storage period interrupted by 6 thawing/freezing cycles. Samples preserved with a combination of the FC mixture and ASC showed almost similar improvements in cannabinoid stability. Other reducing agents such as sodium metabisulfite and glutathione also improved the stability in FX-preserved blood stored at -20 degrees C. PMID- 28570783 TI - On the importance of retaining stresses and strains in repositioning computational biomechanical models of the cervical spine. AB - Human body models are created in a specific posture and often repositioned and analyzed without retaining stresses that result from repositioning. For example, repositioning a human neck model within the physiological range of motion to a head-turned posture prior to an impact results in initial stresses within the tissues distracted from their neutral position. The aim of this study was to investigate the effect of repositioning on the subsequent kinetics, kinematics, and failure modes, of a lower cervical spine motion segment, to support future research at the full neck level. Repositioning was investigated for 3 modes (tension, flexion, and extension) and 3 load cases. The model was repositioned and loaded to failure in one continuous load history (case 1), or repositioned then restarted with retained stresses and loaded to failure (case 2). In case 3, the model was repositioned and then restarted in a stress-free state, representing current repositioning methods. Not retaining the repositioning stresses and strains resulted in different kinetics, kinematics, or failure modes, depending on the mode of loading. For the motion segment model, the differences were associated with the intervertebral disc fiber reorientation and load distribution, because the disc underwent the largest deformation during repositioning. This study demonstrated that repositioning led to altered response and tissue failure, which is critical for computational models intended to predict injury at the tissue level. It is recommended that stresses and strains be included and retained for subsequent analysis when repositioning a human computational neck model. PMID- 28570785 TI - Dual-Action Cancer Therapy with Targeted Porous Silicon Nanovectors. AB - There is a pressing need to develop more effective therapeutics to fight cancer. An idyllic chemotherapeutic is expected to overcome drug resistance of tumors and minimize harmful side effects to healthy tissues. Antibody-functionalized porous silicon nanoparticles loaded with a combination of chemotherapy drug and gold nanoclusters (AuNCs) are developed. These nanocarriers are observed to selectively deliver both payloads, the chemotherapy drug and AuNCs, to human B cells. The accumulation of AuNCs to target cells and subsequent exposure to an external electromagnetic field in the microwave region render them more susceptible to the codelivered drug. This approach represents a targeted two stage delivery nanocarrier that benefits from a dual therapeutic action that results in enhanced cytotoxicity. PMID- 28570787 TI - Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines. AB - Explosive growth of nanomedicines continues to significantly impact the therapeutic strategies for effective cancer treatment. Despite the significant progress in the development of advanced nanomedicines, successful clinical translation remains challenging. As cancer nanomedicine is a multidisciplinary field, the fundamental problem is that the knowledge gaps stem from different vantage points in the understanding of cancer nanomedicines. The complexities and heterogenecity of both nanomedicines and cancer are further demanding the integration of highly diverse expertise to develop clinically translatable cancer nanomedicines. This progress report aims to discuss the current understanding of cancer nanomedicines between different research areas in terms of nanoparticle engineering, formulation, tumor patho-physiology and clinical medicine, as well as to identify the knowledge gaps lying at the interface between the different fields of research in nanomedicine. Here we also highlight for the necessity to harmonize the multidisciplinary effort in the research of nanomedicines in order to bridge the knowledge and to advance the full understanding in cancer nanomedicines. A paradigm shift is needed in the strategic development of disease specific nanomedicines in order to foster the successful translation into clinic of future cancer nanomedicines. PMID- 28570788 TI - Thermoelectric Properties of Solution-Processed n-Doped Ladder-Type Conducting Polymers. PMID- 28570789 TI - New Members and Foreign Associates of the National Academy of Sciences New Fellows and Foreign Members of the Royal Society. PMID- 28570790 TI - Introducing JCP Weekly. PMID- 28570791 TI - Patients With Co-Occurring Bipolar Disorder and Posttraumatic Stress Disorder: A Rapid Review of the Literature. AB - OBJECTIVE: To summarize the current literature on epidemiology, clinical correlates, and treatment of individuals with co-occurring bipolar disorder and posttraumatic stress disorder (PTSD). DATA SOURCES: We conducted a focused, time sensitive review called "rapid review" in November 2015, using keyword searches (including keywords bipolar disorder, post-traumatic stress disorder, PTSD, and others) in PubMed for studies of adults with co-occurring bipolar disorder and PTSD. STUDY SELECTION: Results were sorted and systematically searched. An article was excluded if it did not describe adult patients with co-occurring PTSD and bipolar disorder or did not report original data on epidemiology, clinical correlates, or treatment. DATA EXTRACTION: Information on study characteristics including population studied and key findings were extracted onto a data collection tool. RESULTS: Thirty-two articles were included. Over two-thirds of articles reported epidemiology of co-occurring bipolar disorder and PTSD. Prevalence of PTSD among individuals with bipolar disorder ranged from 4% to 40%, with women and those with bipolar I versus bipolar II disorder experiencing higher prevalence of PTSD. Prevalence of bipolar disorder among individuals with PTSD ranged from 6% to 55%. Baseline PTSD or bipolar disorder was associated with incidence of the other illness. Individuals with co-occurring bipolar disorder and PTSD experienced high symptom burden and low quality of life. No studies evaluated prospective treatment of patients with co-occurring bipolar disorder and PTSD. CONCLUSIONS: Bipolar disorder and PTSD commonly co-occur and result in greater symptom burden than either condition alone. Few published treatment strategies exist for patients with both conditions. PMID- 28570792 TI - A Pilot, Randomized Controlled Study of Tai Chi With Passive and Active Controls in the Treatment of Depressed Chinese Americans. AB - OBJECTIVE: This pilot, randomized clinical trial investigates the effectiveness of tai chi as the primary treatment for Chinese Americans with major depressive disorder (MDD). METHODS: 67 Chinese Americans with DSM-IV MDD and no treatment for depression were recruited between March 2012 and April 2013 and randomized (1:1:1) into a tai chi intervention, an education program, or a waitlisted group for 12 weeks. The primary outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS17); positive response for this outcome was defined as a decrease in total score of 50% or more, and remission was defined as HDRS17 <= 7. RESULTS: Participants (N = 67) were 72% female with a mean age of 54 +/- 13 years. No serious adverse events were reported. After the end of the 12-week intervention, response rates were 25%, 21%, and 56%, and remission rates were 10%, 21%, and 50% for the waitlisted, education, and tai chi intervention groups, respectively. The tai chi group showed improved treatment response when compared to both the waitlisted group (odds ratio [OR] = 2.11; 95% CI, 1.01-4.46) and to the education group (OR = 8.90; 95% CI, 1.17-67.70). Tai chi intervention showed significantly improved remission rate over the waitlisted group (OR = 3.01; 95% CI, 1.25-7.10), and a trend of improved remission compared to the education group (OR = 4.40; 95% CI, 0.78-24.17). CONCLUSIONS: As the primary treatment, tai chi improved treatment outcomes for Chinese Americans with MDD over both passive and active control groups. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01619631. PMID- 28570793 TI - Anticonvulsant Medication Use in Veterans With Posttraumatic Stress Disorder. AB - OBJECTIVE: Anticonvulsants have been studied for many indications, including posttraumatic stress disorder (PTSD). The limited efficacy research on anticonvulsants for PTSD is mixed. However, anticonvulsants are prescribed widely to veterans with PTSD. Our objective was to measure trends and factors associated with anticonvulsant prescriptions among veterans with PTSD. METHODS: We obtained administrative and pharmacy data for veterans who initiated PTSD treatment in the US Department of Veterans Affairs (VA) between 2004 and 2013 (N = 731,520). We identified those who received anticonvulsants during the year following their initial clinical PTSD diagnosis and examined common indications for anticonvulsant use, patient characteristics, and service use characteristics. Using logistic regression, we determined the predictors of anticonvulsant initiation among those without an indication. RESULTS: Although 24.9% of patients in the cohort received an anticonvulsant during their initial year of PTSD treatment, 94.6% had an indication unrelated to PTSD and 51.2% initiated anticonvulsant use before their PTSD diagnosis. While there was growth in anticonvulsant initiation over the 10-year period, this was explained both by growth in indications unrelated to PTSD and by increased use of anticonvulsants for these indications. The rate of anticonvulsant initiation without an indication was stable at approximately 5% throughout the period, with patient and service use characteristics driving the selection of individual agents. CONCLUSIONS: A large and increasing proportion of veterans with PTSD receives anticonvulsant prescriptions. However, this may be appropriate use driven by increased prevalence of comorbid conditions that may be an indication for anticonvulsant use, including pain and headache disorders. PMID- 28570795 TI - Introduction. PMID- 28570794 TI - Usual Course of Treatment and Predictors of Treatment Utilization for Patients With Posttraumatic Stress Disorder. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) is a debilitating psychiatric illness that frequently remains undiagnosed and untreated. While extensive research has been conducted among veterans, little research has evaluated course of treatment for PTSD in a general hospital setting. METHODS: We utilized data from the Partners HealthCare Research Patient Data Registry to evaluate mental health treatment utilization, including psychotherapy and pharmacotherapy, by patients with recently diagnosed primary PTSD following DSM-IV criteria between January 1, 2002, and June 30, 2011. We additionally evaluated predictors of treatment utilization 6 months postdiagnosis. RESULTS: Among 2,475 patients with recently diagnosed primary PTSD, approximately half (55.7%) had any therapy visit and 10% had at least 12 therapy visits in the 6 months following diagnosis. Approximately half (47.0%) received a psychiatric prescription, with 29.3% receiving a selective serotonin reuptake inhibitor (SSRI), 11.8% receiving an atypical antipsychotic, and 24.4% receiving a benzodiazepine. Latinos were 25% (95% CL = 1.09, 1.43) more likely to have an SSRI prescription, 35% (95% CL = 1.05, 1.75) more likely to have an atypical antipsychotic prescription, and 28% (95% CL = 1.19, 1.38) more likely to receive any psychotherapy. Women were 49% (95% CL = 0.42, 0.63) less likely to have an atypical antipsychotic prescription. Patients with Medicare were 23% (95% CL = 0.67, 0.88) less likely to have any psychotherapy, and patients with Medicaid were 35% (95% CL = 0.46, 0.92) less likely to have 12 or more therapy visits. CONCLUSIONS: Many patients with a primary diagnosis of PTSD do not receive psychotherapy, and psychiatric prescriptions, including atypical antipsychotics and benzodiazepines, are common. Future research is needed to determine the quality of care received and explore subpopulation-specific barriers limiting access to care. PMID- 28570796 TI - Neonatal Discontinuation Syndrome in Serotonergic Antidepressant-Exposed Neonates. AB - OBJECTIVE: To determine whether infants exposed in utero to serotonin reuptake inhibitor (SRI) antidepressants or a DSM-IV-TR-defined mood disorder have significantly more neonatal discontinuation signs compared to an unexposed group of infants at 2-4 weeks after birth. METHODS: This secondary analysis was derived from 2 observational studies with enrollment from July 2000 to December 2011 in Cleveland, Ohio, and Pittsburgh, Pennsylvania. Mothers (n = 214) belonged to one of 3 groups based on exposure status during pregnancy: (1) Comparison-women who did not take psychotropics during pregnancy and had no major mood disorder; (2) SRI-exposed-women with a mood disorder who were taking an SRI but no benzodiazepines; and (3) Mood Disorder-women with depression or bipolar disorder who did not take psychotropic medications. The infants were examined for signs according to the Finnegan Scale by evaluators blind to maternal exposure status. RESULTS: The rates of sign presence (defined as a score >= 2 on the Finnegan Scale) in the SRI, Mood Disorder, and Comparison groups were similar at 34.1%, 35.1%, and 30.4%, respectively. Women in the SRI group had a significantly higher preterm birth rate (24.4%) compared to the other 2 groups (7.4% and 8.9% in the Mood Disorder and Comparison groups, respectively; P = .012). Preterm newborns had a significantly higher sign rate compared to full-term newborns (54% vs 31%, P = .020). We observed a significant relationship between Finnegan signs and preterm birth. CONCLUSIONS: The presence of neonatal signs at 2-4 weeks was more closely associated with prematurity than with in utero SRI or mood disorder exposure. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00279370 and NCT00585702. PMID- 28570798 TI - A Potential Gap in the Perinatal Depression Treatment Cascade. PMID- 28570797 TI - Depression and Anxiety in the Postpartum Period and Risk of Bipolar Disorder: A Danish Nationwide Register-Based Cohort Study. AB - OBJECTIVE: The first-onset affective episode requiring inpatient treatment in the postpartum period can be a marker of bipolar disorder, but it is unknown whether milder postpartum affective episodes are also indicators of underlying bipolarity. Therefore, we aimed to study whether women with a nonpsychotic postpartum affective episode treated with antidepressants have an increased risk of bipolar disorder. METHODS: A register-based cohort study was conducted in Denmark of 122,622 parous women without psychiatric history who received a first time antidepressant prescription during 1997-2012. We compared women with a first time antidepressant prescription, which was our indicator of a first-onset affective disorder, within 1 year postpartum to women with a first-time antidepressant prescription outside the postpartum period. Our outcome was psychiatric contact for bipolar disorder (ICD-10 criteria) during follow-up, and we estimated hazard ratios using Cox regressions. RESULTS: The risk of bipolar disorder among women with a postpartum affective episode was higher than that in women with an affective episode outside the postpartum period. The risk of bipolar disorder was 1.66 (95% CI, 1.12-2.48) for postpartum antidepressant monotherapy and 10.15 (95% CI, 7.13-14.46) for postpartum antidepressant therapy plus a subsequent prescription for anxiolytics when these therapies were compared to antidepressant monotherapy outside the postpartum period. CONCLUSIONS: First onset nonpsychotic postpartum affective disorder can be a marker of underlying bipolarity. Women who fill an antidepressant prescription following childbirth should be asked about hypomanic or manic symptoms and monitored long term. Clinically, when antidepressant monotherapy is ineffective or the individual woman experiences persistent and concerning symptoms, health professionals should consider a possible bipolar spectrum disorder. PMID- 28570799 TI - Dr Cox and Colleagues Reply. PMID- 28570800 TI - Correction. Suicide Risk Assessment in Hospitals: An Expert System-Based Triage Tool PMID- 28570801 TI - Lurasidone-Induced Rabbit Syndrome: A Case Report. PMID- 28570802 TI - Sensitive and Personalized Determinations of Likelihood of Being Helped or Harmed. PMID- 28570803 TI - Ketamine for Depression, 2: Diagnostic and Contextual Indications. AB - There is a substantial body of literature comprising anecdotal material and descriptions of uncontrolled and randomized controlled trials addressing the use of subanesthetic doses of ketamine for the off-label treatment of major depressive episodes. This article examines diagnostic indications for the off label use of ketamine as an antidepressant and possible contexts in which ketamine may be trialled. Ketamine is indicated in patients who are in a major depressive episode. Most of the research data have been collected from patients with major depressive disorder, but patients with bipolar depression have also been studied. Ketamine is effective in both diagnostic groups, but its benefits are impermanent, perhaps more so in bipolar depression. There are several contexts within this diagnostic framework when a ketamine trial may be considered. These include severe depression and depression that is refractory to conventional antidepressant medication; this is because there is little purpose in trialling an experimental treatment in patients who are less severely ill and those who are antidepressant responsive. More importantly, ketamine has demonstrated efficacy in the rapid reduction of suicidal symptoms and can therefore be trialled when rapid reduction in suicidality is necessary. Likewise, because of its swift and dramatic antidepressant action, it can be trialled in patients in whom improvement is urgently desired in order to allow the patient to attend to pressing life circumstances. Some data suggest that the use of ketamine early during the course of an antidepressant trial, or as anesthesia during electroconvulsive therapy, can improve early antidepressant outcomes. It is not clear whether the presence of psychotic symptoms is a contraindication for ketamine use. Issues related to these indications and contexts are briefly discussed. PMID- 28570805 TI - Silica-Derived Hydrophobic Colloidal Nano-Si for Lithium-Ion Batteries. AB - Silica can be converted to silicon by magnesium reduction. Here, this classical reaction is renovated for more efficient preparation of silicon nanoparticles (nano-Si). By reducing the particle size of the starting materials, the reaction can be completed within 10 min by mechanical milling at ambient temperature. The obtained nano-Si with high surface reactivity are directly reacted with 1 pentanol to form an alkoxyl-functionalized hydrophobic colloid, which significantly simplifies the separation process and minimizes the loss of small Si particles. Nano-Si in 5 g scale can be obtained in one single batch with laboratory scale setups with very high yield of 89%. Utilizing the excellent dispersion in ethanol of the alkoxyl-functionalized nano-Si, surface carbon coating can be readily achieved by using ethanol soluble oligomeric phenolic resin as the precursor. The nano-Si after carbon coating exhibit excellent lithium storage performance comparable to the state of the art Si-based anode materials, featured for the high reversible capacity of 1756 mAh.g-1 after 500 cycles at a current density of 2.1 A.g-1. The preparation approach will effectively promote the development of nano-Si-based anode materials for lithium ion batteries. PMID- 28570804 TI - Self-Assembled DNA Dendrimer Nanoparticle for Efficient Delivery of Immunostimulatory CpG Motifs. AB - Dendrimer-like DNA nanostructures have attractive properties such as mechanical stability, highly branched nanostructure, customized sizes, and biocompatibility. In this study, we construct programmable DNA dendrimeric nanoparticles as efficient vehicles to deliver immunostimulatory cytosine-phosphate-guanosine (CpG) sequences for activation of the immune response. DNA dendrimers decorated with CpG-containing hairpin-loops triggered stronger immune response characterized by pro-inflammatory cytokines production, in contrast to DNA dendrimers loading linear CpG. After further modification with TAT peptide, a typical cell-penetrating peptide, on the surface of the nanocarriers, CpG loops loaded DNA dendrimers showed the enhanced cell internalization and cytokines production. The TAT-DNA dendrimer-CpG loops constructs did not affect the viability of immune cells and no detectable cytotoxicity was observed. Our results demonstrate that the DNA dendrimers can serve as designable and safe vehicles for delivery of immune modulators and anticancer drugs. PMID- 28570806 TI - Second-Generation ReaxFF Water Force Field: Improvements in the Description of Water Density and OH-Anion Diffusion. AB - Hydronium (H3O+) and hydroxide (OH-) ions have anomalously large diffusion constants in aqueous solutions due to their combination of vehicular and Grotthuss hopping diffusion mechanisms. An improvement of the ReaxFF reactive water force field on the basis of our first-generation water force field (water 2010) is presented to describe the proton transfer (PT) mechanisms of H3O+ and OH in water. Molecular dynamics simulation studies with the water-2017 force field support the Eigen-Zundel-Eigen mechanism for PT in acidic aqueous solution and reproduce the hypercoordinated solvation structure of the OH- in a basic environment. In particular, it predicts the correct order of the diffusion constants of H2O, H3O+, and OH- and their values are in agreement with the experimental data. Another interesting observation is that the diffusion constants of H3O+ and OH- are close to each other at high concentration due to the strong correlation between OH- ions in basic aqueous solution. On the basis of our results, it is shown that ReaxFF provides a novel approach to study the complex acid-base chemical reactions in aqueous solution with any pH value. PMID- 28570807 TI - Mechanism of Formation of the Nonstandard Product in the Prenyltransferase Reaction of the G115T Mutant of FtmPT1: A Case of Reaction Dynamics Calling the Shots? AB - FtmPT1 is a fungal indole prenyltransferase that affords Tryprostatin B from Brevianamide F and dimethylallyl pyrophosphate; however, when a single residue in the active site is mutated (Gly115Thr), a novel five-membered ring compound is obtained as the major product with Tryprostatin B as the minor product. Herein, we describe detailed studies of the catalysis of the Gly115Thr mutant of FtmPT1 with a focus on the observed regioselectivity of the reaction. We employ one- and two-dimensional potential of mean force simulations to explore the catalytic mechanism, along with molecular dynamics simulations exploring the reaction dynamics of the prenyl transfer reaction. Single-point electronic structure calculations were also used to explore the performance of the self-consistent charge density functional tight-binding method to model specific reaction steps. Importantly, we observe that the two reaction pathways have comparable activation parameters and propose that the origin of the novel product is predicated, at least in part, on the topology of the potential energy surface as revealed by reaction dynamics studies. PMID- 28570808 TI - Development and Characterization of a Fluorescent Tracer for the Free Fatty Acid Receptor 2 (FFA2/GPR43). AB - The free fatty acid receptor 2 (FFA2/GPR43) is considered a potential target for treatment of metabolic and inflammatory diseases. Here we describe the development of the first fluorescent tracer for FFA2 intended as a tool for assessment of thermodynamic and kinetic binding parameters of unlabeled ligands. Starting with a known azetidine FFA2 antagonist, we used a carboxylic acid moiety known not to be critical for receptor interaction as attachment point for a nitrobenzoxadiazole (NBD) fluorophore. This led to the development of 4 (TUG 1609), a fluorescent tracer for FFA2 with favorable spectroscopic properties and high affinity, as determined by bioluminescence resonance energy transfer (BRET) based saturation and kinetic binding experiments, as well as a high specific to nonspecific BRET binding signal. A BRET-based competition binding assay with 4 was also established and used to determine binding constants and kinetics of unlabeled ligands. PMID- 28570809 TI - Reduced Iron-Containing Clay Minerals as Antibacterial Agents. AB - Previous work documented the general antibacterial mechanism of iron containing clays that involved hydroxyl radical (*OH) production from soluble Fe2+, and attack of cell membrane and intracellular proteins. Here we explore the role of clay structural Fe(II) in *OH production at near neutral pH and identify a lipid involved in the antibacterial process. Structural Fe(III) in nontronite NAu-2 was reduced (rNAu-2) and E. coli, a model bacterium, was exposed to rNAu-2 in oxic suspension. The antibacterial activity of rNAu-2 was dependent on pH and Fe(II) concentration, where E. coli were completely killed at pH 6, but survived at pH 7 and 8. In the presence of a *OH scavenger or in anaerobic atmosphere, E. coli survived better, suggesting that cell death may be caused by *OH generated from oxidation of structural Fe(II) in rNAu-2. In-situ imaging revealed damage of a membrane lipid, cardiolipin, in the polar region of E. coli cells, where reactive oxygen species and redox-active labile Fe were enriched. Our results advance the previous antibacterial model by demonstrating that the structural Fe(II) is the primary source of *OH, which damages cardiolipin, triggers the influx of soluble Fe2+ into the cell, and ultimately leads to cell death. PMID- 28570810 TI - Admittance Scanning for Whole Column Detection. AB - Whole column detection (WCD) is as old as chromatography itself. WCD requires an ability to interrogate column contents from the outside. Other than the obvious case of optical detection through a transparent column, admittance (often termed contactless conductance) measurements can also sense changes in the column contents (especially ionic content) from the outside without galvanic contact with the solution. We propose here electromechanically scanned admittance imaging and apply this to open tubular (OT) chromatography. The detector scans across the column; the length resolution depends on the scanning velocity and the data acquisition frequency, ultimately limited by the physical step resolution (40 MUm in the present setup). Precision equal to this step resolution was observed for locating an interface between two immiscible liquids inside a 21 MUm capillary. Mechanically, the maximum scanning speed was 100 mm/s, but at 1 kHz sampling rate and a time constant of 25 ms, the highest practical scan speed (no peak distortion) was 28 mm/s. At scanning speeds of 0, 4, and 28 mm/s, the S/N for 180 pL (zone length of 1.9 mm in a 11 MUm i.d. column) of 500 MUM KCl injected into water was 6450, 3850, and 1500, respectively. To facilitate constant and reproducible contact with the column regardless of minor variations in outer diameter, a double quadrupole electrode system was developed. Columns of significant length (>1 m) can be readily scanned. We demonstrate its applicability with both OT and commercial packed columns and explore uniformity of retention along a column, increasing S/N by stopped-flow repeat scans, etc. as unique applications. PMID- 28570811 TI - Allosteric Fine-Tuning of the Binding Pocket Dynamics in the ITK SH2 Domain by a Distal Molecular Switch: An Atomistic Perspective. AB - Although the regulation of function of proteins by allosteric interactions has been identified in many subcellular processes, molecular switches are also known to induce long-range conformational changes in proteins. A less well understood molecular switch involving cis-trans isomerization of a peptidyl-prolyl bond could induce a conformational change directly to the backbone that is propagated to other parts of the protein. However, these switches are elusive and hard to identify because they are intrinsic to biomolecules that are inherently dynamic. Here, we explore the conformational dynamics and free energy landscape of the SH2 domain of interleukin-2-inducible T-cell or tyrosine kinase (ITK) to fully understand the conformational coupling between the distal cis-trans molecular switch and its binding pocket of the phosphotyrosine motif. We use multiple microsecond-long all-atom molecular dynamics simulations in explicit water for over a total of 60 MUs. We show that cis-trans isomerization of the Asn286-Pro287 peptidyl-prolyl bond is directly coupled to the dynamics of the binding pocket of the phosphotyrosine motif, in agreement with previous NMR experiments. Unlike the cis state that is localized and less dynamic in a single free energy basin, the trans state samples two distinct conformations of the binding pocket-one that recognizes the phosphotyrosine motif and the other that is somewhat similar to that of the cis state. The results provide an atomic-level description of a less well understood allosteric regulation by a peptidyl-prolyl cis-trans molecular switch that could aid in the understanding of normal and aberrant subcellular processes and the identification of these elusive molecular switches in other proteins. PMID- 28570812 TI - Swelling of Graphene Oxide Membranes in Aqueous Solution: Characterization of Interlayer Spacing and Insight into Water Transport Mechanisms. AB - Graphene oxide (GO) has recently emerged as a promising 2D nanomaterial to make high-performance membranes for important applications. However, the aqueous-phase separation capability of a layer-stacked GO membrane can be significantly limited by its natural tendency to swell, that is, absorb water into the GO channel and form an enlarged interlayer spacing (d-spacing). In this study, the d-spacing of a GO membrane in an aqueous environment was experimentally characterized using an integrated quartz crystal microbalance with dissipation and ellipsometry. This method can accurately quantify a d-spacing in liquid and well beyond the typical measurement limit of ~2 nm. Molecular simulations were conducted to fundamentally understand the structure and mobility of water in the GO channel, and a theoretical model was developed to predict the d-spacing. It was found that, as a dry GO membrane was soaked in water, it initially maintained a d-spacing of 0.76 nm, and water molecules in the GO channel formed a semiordered network with a density 30% higher than that of bulk water but 20% lower than that of the rhombus shaped water network formed in a graphene channel. The corresponding mobility of water in the GO channel was much lower than in the graphene channel, where water exhibited almost the same mobility as in the bulk. As the GO membrane remained in water, its d-spacing increased and reached 6 to 7 nm at equilibrium. In comparison, the d-spacing of a GO membrane in NaCl and Na2SO4 solutions decreased as the ionic strength increased and was ~2 nm at 100 mM. PMID- 28570813 TI - Polymer Composite with Carbon Nanofibers Aligned during Thermal Drawing as a Microelectrode for Chronic Neural Interfaces. AB - Microelectrodes provide a direct pathway to investigate brain activities electrically from the external world, which has advanced our fundamental understanding of brain functions and has been utilized for rehabilitative applications as brain-machine interfaces. However, minimizing the tissue response and prolonging the functional durations of these devices remain challenging. Therefore, the development of next-generation microelectrodes as neural interfaces is actively progressing from traditional inorganic materials toward biocompatible and functional organic materials with a miniature footprint, good flexibility, and reasonable robustness. In this study, we developed a miniaturized all polymer-based neural probe with carbon nanofiber (CNF) composites as recording electrodes via the scalable thermal drawing process. We demonstrated that in situ CNF unidirectional alignment can be achieved during the thermal drawing, which contributes to a drastic improvement of electrical conductivity by 2 orders of magnitude compared to a conventional polymer electrode, while still maintaining the mechanical compliance with brain tissues. The resulting neural probe has a miniature footprint, including a recording site with a reduced size comparable to a single neuron and maintained impedance that was able to capture neural activities. Its stable functionality as a chronic implant has been demonstrated with the long-term reliable electrophysiological recording with single-spike resolution and the minimal tissue response over the extended period of implantation in wild-type mice. Technology developed here can be applied to basic chronic electrophysiological studies as well as clinical implementation for neuro-rehabilitative applications. PMID- 28570814 TI - Enhanced Electrochemiluminescence of One-Dimensional Self-Assembled Porphyrin Hexagonal Nanoprisms. AB - In this work, we synthesized the one-dimensional nanostructure of zinc 5,10,15,20 tetra(4-pyridyl)-21H,23H-porphine (ZnTPyP) via a self-assembly technique. Using sodium dodecyl sulfate (SDS) as "soft template", the self-assembled ZnTPyP (SA ZnTPyP) had the morphology of hexagonal nanoprisms with a uniform size (diameter of 100 nm). The SA-ZnTPyP exhibited remarkably different spectral properties compared to those of the original ZnTPyP. The as-prepared SA-ZnTPyP was used to modify glassy carbon electrodes (GCE), and the electrochemiluminescence (ECL) behaviors of the SA-ZnTPyP/GCE were investigated. The hydrophilic carbon dots (C dots) could efficiently prevent the dissolution of SA-ZnTPyP in DMF containing 0.1 mol L-1 TBAP and, simultaneously, could accelerate electron transfer. Therefore, the enhanced ECL was realized by C-dots/SA-ZnTPyP/GCE by using H2O2 as co-reactant. This amplification of ECL was further studied by ECL spectroscopies and cyclic voltammetry, and the corresponding mechanism was proposed. PMID- 28570815 TI - Co4N Nanosheet Assembled Mesoporous Sphere as a Matrix for Ultrahigh Sulfur Content Lithium-Sulfur Batteries. AB - High utilization and loading of sulfur in cathodes holds the key in the realization of Li-S batteries. We here synthesized a Co4N mesoporous sphere, which was made up of nanosheets, via an easy and convenient method. This material presents high affinity, speedy trapping, and absorbing capacity for polysulfides and acts as a bifunctional catalysis for sulfur redox processes; therefore it is an ideal matrix for S active material. With such a mesoporous sphere used as a sulfur host in Li-S batteries, extraordinary electrochemistry performance has been achieved. With a sulfur content of 72.3 wt % in the composite, the Co4N@S delivered a high specific discharge capacity of 1659 mAh g-1 at 0.1 C, almost reaching its theoretic capacity. Also, the battery exhibited a large reversible capacity of about 1100 mAh g-1 at 0.5 C and 1000 mAh g-1 at 1 C after 100 cycles. At a high rate of 2 C and 5 C, after 300 cycles, the discharge capacity finally stabilized at 805 and 585 mAh g-1. Even at a 94.88% sulfur content, the cathode can still deliver an extremely high specific discharge capacity of 1259 mAh g-1 with good cycle performance. PMID- 28570816 TI - Enzymatic Browning in Sugar Beet Leaves (Beta vulgaris L.): Influence of Caffeic Acid Derivatives, Oxidative Coupling, and Coupled Oxidation. AB - Sugar beet (Beta vulgaris L.) leaves of 8 month (8m) plants showed more enzymatic browning than those of 3 month (3m). Total phenolic content increased from 4.6 to 9.4 mg/g FW in 3m and 8m, respectively, quantitated by reverse-phase-ultrahigh performance liquid chromatography-ultraviolet-mass spectrometry (RP-UHPLC-UV-MS). The PPO activity was 6.7 times higher in extracts from 8m than from 3m leaves. Substrate content increased from 0.53 to 2.45 mg/g FW in 3m and 8m, respectively, of which caffeic acid glycosyl esters were most important, increasing 10-fold with age. Caffeic acid glycosides and vitexin derivatives were no substrates. In 3m and 8m, nonsubstrate-to-substrate ratios were 8:1 and 3:1, respectively. A model system showed browning at 3:1 ratio due to formation of products with extensive conjugated systems through oxidative coupling and coupled oxidation. The 8:1 ratio did not turn brown as oxidative coupling occurred without much coupled oxidation. We postulate that differences in nonsubstrate-to-substrate ratio and therewith extent of coupled oxidation explain browning. PMID- 28570817 TI - Insights into CC Chemokine Ligand 2/Chemokine Receptor 2 Molecular Recognition: A Step Forward toward Antichemotactic Agents. AB - Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein 1 (MCP 1), is a chemokine that recruits immune cells to inflammatory sites by interacting with G protein-coupled receptor CCR2. The CCL2/CCR2 axis is also involved in pathological processes such as tumor growth and metastasis and hence is currently considered as an important drug target. CCL2 exists in a dynamic monomer-dimer equilibrium that is modulated by CCR2 binding. We used solution nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulations to study the interactions between CCL2 and a sulfopeptide corresponding to the N terminal sequence of CCR2 (CCR218-31). Peptide binding induced the dissociation of CCL2 into monomers, forming stable CCL2/CCR218-31 complexes. NMR relaxation measurements indicated that residues around the CCR218-31 binding site, which are located at the dimer interface, undergo a complex regime of motions. NMR data were used to construct a three-dimensional structural model of the CCL2/CCR218-31 complex, revealing that CCR218-31 occupies a binding site juxtaposed to the dimer interface, partially replacing monomer-monomer contacts, explaining why CCR218-31 binding weakens the dimer interface and induces dissociation. We found that the main interactions governing receptor binding are highly stable salt bridges with conserved chemokine residues as well as hydrophobic interactions. These data provide new insights into the structure-function relationship of the CCL2-CCR2 interaction and may be helpful for the design of novel antichemotactic agents. PMID- 28570818 TI - Chirality Dependent Potency Enhancement and Structural Impact of Glycol Nucleic Acid Modification on siRNA. AB - Here we report the investigation of glycol nucleic acid (GNA), an acyclic nucleic acid analogue, as a modification of siRNA duplexes. We evaluated the impact of (S)- or (R)-GNA nucleotide incorporation on RNA duplex structure by determining three individual crystal structures. These structures indicate that the (S) nucleotide backbone adopts a conformation that has little impact on the overall duplex structure, while the (R)-nucleotide disrupts the phosphate backbone and hydrogen bonding of an adjacent base pair. In addition, the GNA-T nucleobase adopts a rotated conformation in which the 5-methyl group points into the minor groove, rather than the major groove as in a normal Watson-Crick base pair. This observation of reverse Watson-Crick base pairing is further supported by thermal melting analysis of GNA-C and GNA-G containing duplexes where it was demonstrated that a higher thermal stability was associated with isoguanine and isocytosine base pairing, respectively, over the canonical nucleobases. Furthermore, it was also shown that GNA nucleotide or dinucleotide incorporation increases resistance against snake venom phosphodiesterase. Consistent with the structural data, modification of an siRNA with (S)-GNA resulted in greater in vitro potencies over identical sequences containing (R)-GNA. A walk of (S)-GNA along the guide and passenger strands of a GalNAc conjugate duplex targeting mouse transthyretin (TTR) indicated that GNA is well tolerated in the seed region of both strands in vitro, resulting in an approximate 2-fold improvement in potency. Finally, these conjugate duplexes modified with GNA were capable of maintaining in vivo potency when subcutaneously injected into mice. PMID- 28570819 TI - Proposed Hydrogen-Bonding Index of Donor or Acceptor Reflecting Its Intrinsic Contribution to Hydrogen-Bonding Strength. AB - In this work, we tentatively propose that the hydrogen-bonding strength EHB (referring to the minimal hydrogen-bonding energy) and its corresponding hydrogen bond (HB) distance (referring to the optimal HB distance dHB) for simple mono-HB systems have an exponential relationship on the basis of MP2 and DFT computational results. We take a step further and propose that the hydrogen bonding indices of the donor (Idonor) and acceptor (Iacceptor), reflecting their intrinsic contributions to hydrogen-bonding strength, also have an exponential relation with the hypothetical effective hydrogen-bond radii of the donor (rdonor) and acceptor (racceptor), respectively. On the basis of extensive quantum-mechanical calculations, relevant assumptions about the hydrogen-bonding index are rationalized. Moreover, the hydrogen-bonding index is also suggested as an additional prefiltering criterion for virtual screening besides the widely accepted Lipinski's rule of five. Finally, a "Hydrogen-Bond Index Estimator (HBIE)" module has been implemented in our Visual Force Field Derivation Toolkit (VFFDT) program to approximately and rapidly estimate the hydrogen-bonding indices of any small molecules in batch and screen possible stronger donors or acceptors from the small-molecule database. To the best of our knowledge, the concept of the hydrogen-bonding index and its potential application are proposed here for the first time. PMID- 28570821 TI - Hydrophobic Effect of Alkyl Groups Stabilizing Self-Assembled Colloids in Water. AB - Self-assembling behavior of hydrophobic molecules in water confirms that the hydrophobic effect (HE) of alkyl groups stabilizes the aqueous colloids. Fe(CO){CO(CH2)n-1CH3}(Cp)(PPh3) molecules (FpCn) with a Fp head and alkyl tail are water-insoluble. FpC1 aggregates in water precipitated in hours, whereas the hydrophobic interaction (HI) of long alkyl groups drove FpCn (n = 6-18) molecules assemble into colloids in water. The alkyl tails interacted and stretched as indicated by IR analysis, while the separation of Fp head groups at the surface of colloids was indicated by the redox behavior of Fe elements. The molecules therefore arranged into a proposed "Y" shape with hydration cavities. The IR and cyclic voltammetry (CV) analyses indicated that the longer the alkyl tail, the larger the hydration cavity and the stronger the HI. Both HI and hydrophobic hydration (HH) were identified as the HE stabilizing the colloids in water. This knowledge is applicable for a broad range of disciplines, including biology, chemistry, and material science. PMID- 28570822 TI - Comment on "X-ray Reflectivity Study of the Interaction of an Imidazolium-Based Ionic Liquid with a Soft Supported Lipid Membrane". PMID- 28570820 TI - Human Milk Oligosaccharides Exhibit Antimicrobial and Antibiofilm Properties against Group B Streptococcus. AB - Streptococcus agalactiae (Group B Streptococcus, GBS) is a Gram-positive bacterial pathogen that causes invasive infections in both children and adults. During pregnancy, GBS is a significant cause of infection of the fetal membranes (chorioamnionitis), which can lead to intra-amniotic infection, preterm birth, stillbirth, and neonatal sepsis. Recently, breastfeeding has been thought to represent a potential mode of GBS transmission from mother to newborn, which might increase the risk for late-onset sepsis. Little is known, however, about the molecular components of breast milk that may support or prevent GBS colonization. In this study, we examine how human milk oligosaccharides (HMOs) affect the pathogenesis of GBS. HMOs from discrete donor samples were isolated and profiled by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). Growth and biofilm assays show that HMOs from mothers of specific milk groups can modulate the growth and biofilm formation of GBS. High resolution field-emission gun scanning electron microscopy (SEM) and confocal laser scanning microscopy confirmed the quantitative biofilm assays and demonstrated cell arrangement perturbations in bacterial cultures treated with specific oligosaccharides. These findings demonstrate that HMOs affect the growth and cell biology of GBS. Finally, this study provides the first example of HMOs functioning as antibiofilm agents against GBS. PMID- 28570823 TI - Formulation of Nonionic Surfactant Vesicles (NISV) Prepared by Microfluidics for Therapeutic Delivery of siRNA into Cancer Cells. AB - Small interfering RNAs (siRNA) have a broad potential as therapeutic agents to reversibly silence any target gene of interest. The clinical application of siRNA requires the use of safe and effective delivery systems. In this study, we investigated the use of nonionic surfactant vesicles (NISV) for the delivery of siRNA. Different types of NISV formulations were synthesized by microfluidic mixing and then evaluated for their physiochemical properties and cytotoxicity. The ability of the NISV to carry and transfect siRNA targeting green fluorescent protein (GFP) into A549 that stably express GFP (copGFP-A549) was evaluated. Flow cytometry and Western blotting were used to study the GFP expression knockdown, and significant knockdown was observed as a result of siRNA delivery to the cells by NISV. This occurred in particular when using Tween 85, which was able to achieve more than 70% GFP knockdown. NISV were thus demonstrated to provide a promising and effective platform for therapeutic delivery of siRNA. PMID- 28570824 TI - Protein Epitope Mimetics: From New Antibiotics to Supramolecular Synthetic Vaccines. AB - Protein epitope mimetics provide powerful tools to study biomolecular recognition in many areas of chemical biology. They may also provide access to new biologically active molecules and potentially to new classes of drug and vaccine candidates. Here we highlight approaches for the design of folded, structurally defined epitope mimetics, by incorporating backbone and side chains of hot residues onto a stable constrained scaffold. Using robust synthetic methods, the structural, biological, and physical properties of epitope mimetics can be optimized, by variation of both side chain and backbone chemistry. To illustrate the potential of protein epitope mimetics in medicinal chemistry and biotechnology, we present studies in two areas of infectology; the discovery of new antibiotics targeting essential outer membrane (OM) proteins in Gram-negative bacteria and the design of supramolecular synthetic vaccines. The discovery of new antibiotics with novel mechanisms of action, in particular to combat infections caused by Gram-negative pathogens, represents a major challenge in medicinal chemistry. We were inspired by naturally occurring cationic antimicrobial peptides to design structurally related peptidomimetics and to optimize their antimicrobial properties through library synthesis and screening. Through these efforts, we could show that antimicrobial beta-hairpin mimetics may have structures and properties that facilitate interactions with essential bacterial beta-barrel OM proteins. One recently discovered family of antimicrobial peptidomimetics targets the beta-barrel protein LptD in Pseudomonas spp. This protein plays a key role in lipopolysaccaride (LPS) transport to the cell surface during OM biogenesis. Through a highly selective interaction with LptD, the peptidomimetic blocks LPS transport, resulting in nanomolar antimicrobial activity against the important human pathogen P. aeruginosa. Epitope mimetics may also have great potential in the field of vaccinology, where structural information on complexes between neutralizing antibodies and their cognate epitopes can be taken as a starting point for B cell epitope mimetic design. In order to generate potent immune responses, an effective method of delivering epitope mimetics to relevant cells and tissues in the immune system is also required. For this, engineered synthetic nanoparticles (synthetic virus-like particles, SVLPs) prepared using supramolecular chemistry can be designed with optimal surface properties for efficient dendritic cell-mediated delivery of folded B-cell and linear T-cell epitopes, along with ligands for pattern recognition receptors, into lymphoid tissues. In this way, multivalent display of the epitope mimetics occurs over the surface of the nanoparticle, suitable for cross-linking B cell receptors. In this highly immunogenic format, strong epitope specific humoral immune responses can be elicited that target infections caused by pathogenic microorganisms. Other potential applications of epitope mimetics in next-generation therapeutics are also discussed. PMID- 28570825 TI - Effects of Cinnamoyloxy-mammeisin from Geopropolis on Osteoclast Differentiation and Porphyromonas gingivalis-Induced Periodontitis. AB - Bone-loss-related diseases such as rheumatoid arthritis, osteomyelitis, osteoporosis, and periodontitis are associated with high rates of morbidity worldwide. These disorders are characterized by an imbalance between the formation and activity of osteoblasts and osteoclasts, leading to bone loss. In this context, we evaluated the effect of cinnamoyloxy-mammeisin (CNM), an anti inflammatory coumarin found in Melipona scutellaris geopropolis, on key targets related to bone remodeling. In the present study we investigated the in vitro effects of CNM on osteoclast differentiation and M-CSF+RANKL-induced osteoclastogenic marker expression. Additionally, the interference of CNM treatment on osteoclast activity was evaluated by zymography and resorption area. Finally, we assessed the capacity of the compound to mitigate alveolar bone loss in vivo in experimental murine periodontitis induced by Porphyromonas gingivalis. We observed that treatment with CNM impaired osteoclast differentiation, as evidenced by a reduced number of tartrate-resistant acid-phosphatase-positive multinucleated cells (TRAP+) as well as the expression of osteoclastogenic markers upon M-CSF+RANKL-induced stimulation. Similarly, we observed reduced gelatinolytic and resorption capacity in M-CSF+RANKL-induced cells in vitro. Lastly, CNM attenuated alveolar bone loss in an experimental murine periodontitis model. These findings indicate that CNM may be considered a promising treatment for bone loss diseases. PMID- 28570826 TI - Specific Monoclonal Antibodies Recognizing the Endogenous Chicken High Mobility Group Box 1 Protein. AB - High mobility group box 1 (HMGB1) is a key member of the "danger associated molecular patterns" (DAMPs), which can localize in various compartments of the cell, and plays important roles in systemic inflammation. In the present study, monoclonal antibodies (MAbs) specifically against chicken HMGB1 were generated. The open reading frame of chicken HMGB1 was amplified by RT-PCR and cloned into the prokaryotic expression vector pET-28a to construct a recombinant plasmid pET chHMGB1. The recombinant chicken HMGB1 protein was expressed in Escherichia coli Rosetta under IPTG induction and then purified by Ni-NTA Purification System. BALB/c mice were immunized with the purified recombinant HMGB1 protein, and three strains of hybridoma cells named 1F10, 8C11, and 4D8 secreting MAbs of chicken HMGB1 were obtained by hybridoma technique. Western blot and indirect immunofluorescence assays showed that the endogenous HMGB1 in various cell lines and glycosylated HMGB1 could both be specifically recognized by the prepared MAbs. This work indicated that the MAbs against chicken HMGB1 would be a valuable tool for further studies of HMGB1-mediated signaling in virus-infected cells and investigates the role of HMGB1 in avian virus pathogenesis. PMID- 28570828 TI - The role of androgens in the regulation of muscle oxidative capacity following aerobic exercise training. AB - Reduced production or bioavailability of androgens, termed hypogonadism, occurs in a variety of pathological conditions. While androgens target numerous tissues throughout the body, hypogonadism specifically reduces the ability of skeletal muscle to produce adenosine triphosphate aerobically, i.e., muscle oxidative capacity. This has important implications for overall health as muscle oxidative capacity impacts a number of metabolic processes. Although androgen replacement therapy is effective at restoring muscle oxidative capacity in hypogonadal individuals, this is not a viable therapeutic option for all who are experiencing hypogonadism. While aerobic exercise may be a viable alternative to increase muscle oxidative capacity, it is unknown whether androgen depletion affects this adaptation. To determine this, sham and castrated mice were randomized to remain sedentary or undergo 8 weeks of aerobic treadmill exercise training. All mice were fasted overnight prior to sacrifice. Though exercise increased markers of muscle oxidative capacity independent of castration (cytochrome c oxidase subunit IV and cytochrome c), these measures were lower in castrated mice. This reduction was not due to a difference in peroxisome proliferator activated receptor gamma coactivator 1 alpha protein content, as expression was increased to a similar absolute value in sham and castrated animals following exercise training. However, markers of BCL2/Adenovirus E1B 19 kDa Interacting Protein 3 (BNIP3) mediated mitophagy were increased by castration independent of exercise. Together, these data show that exercise training can increase markers of muscle oxidative capacity following androgen depletion. However, these values are reduced by androgen depletion likely due in part to elevated BNIP3-mediated mitophagy. PMID- 28570827 TI - Race, Menopausal Hormone Therapy, and Invasive Breast Cancer in the Carolina Breast Cancer Study. AB - PURPOSE: The use of combined estrogen-progestin menopausal hormone therapy (MHT) has been shown to increase the risk of breast cancer, however, recent observational studies have suggested that the association between MHT and breast cancer may be modified by race. The objective of this study was to investigate the association between MHT use and incidence of invasive breast cancer in Black and White women aged >=40 years at diagnosis after accounting for racial differences in patterns of MHT use and formulation. METHODS: Data from the Carolina Breast Cancer Study, a population-based case-control study of Black and White women in North Carolina conducted between 1993 and 2001, was used to analyze 1474 invasive breast cancer cases and 1339 controls using unconditional logistic regression. RESULTS: Black women were less likely than White women to use any MHT and were more likely to use an unopposed-estrogen formulation. Combined estrogen-progestin MHT use was associated with a greater odds of breast cancer in White (adjusted odds ratio [OR] 1.48, 95% confidence interval [CI]: 1.03-2.13) and Black (OR 1.43, 95% CI: 0.76-2.70) women, although the estimate in Black women was imprecise. In contrast, use of unopposed-estrogen MHT among women with prior hysterectomy was not associated with breast cancer in women of either race. CONCLUSION: The association between MHT and invasive breast cancer appears to be similar in both Black and White women after accounting for differences in formulation and prior hysterectomy. These findings emphasize the importance of accounting for MHT formulation in race-stratified analyses of breast cancer risk. PMID- 28570829 TI - Therapeutic Hypothermia for Asphyxial Out-of-Hospital Cardiac Arrest Due to Drowning: A Systematic Review of Case Series and Case Reports. AB - The objective of this review was to summarize published evidence of the effectiveness of therapeutic hypothermia in patients with drowning-associated asphyxial out-of-hospital cardiac arrest (OHCA) and to explore any preliminary favorable factors in the management of therapeutic hypothermia to improve survival and neurological outcome. Drowning may result in asphyxial OHCA or hypothermic OHCA, but the former does not provide any potential neuroprotective effect as the latter may do. Electronic literature searches of Ovid Medline, Embase, Cochrane Library, and Scopus were performed for all years from inception to July 2016. Primary studies in the form of case reports, letters to the editor, and others with higher quality are included, but guidelines, reviews, editorials, textbook chapters, conference abstracts, and nonhuman studies are excluded. Non English articles are excluded. Relevant studies are then deemed eligible if the drowning OHCA patient's initial temperature was above 28 degrees C, which implies asphyxial cardiac arrest, and intentional therapeutic hypothermia was instituted. Because of the narrow scope of interest and strict definition of the condition, limited studies addressed it, and no randomized controlled trials (RCT) could be selected. Thirteen studies covering 35 patients are included. No quantitative synthesis, assessment of study quality, or assessment of bias was performed. It is conjectured that extended therapeutic hypothermia of 48-72 hours might help prevent reperfusion injury during the intermediate phase of postcardiac arrest care to benefit patients of drowning-associated asphyxial OHCA, but this finding only serves as preliminary observation for future research. No conclusive recommendation could be made regarding the duration of and the time of onset of therapeutic hypothermia. Future research should put effort on RCT, particularly the effect of extended duration of 48-72 hours. Important parameters should be reported in detail. Asphyxial and hypothermic OHCA should be differentiated. PMID- 28570830 TI - Comparison of Three Adiposity Indexes and Cutoff Values to Predict Metabolic Syndrome Among University Students. AB - PURPOSE: Obesity and high body fat are related to diabetes and metabolic syndrome (MetS) in all ethnic groups. Based on the International Diabetes Federation (IDF) definition of MetS, the aim of the present study was to compare body adiposity indexes (BAIs) and to assess their various cutoff values for the prediction of MetS in university students from Colombia. METHODS: A cross-sectional study was conducted on 886 volunteers (51.9% woman; age mean 21.4 years). Anthropometric characteristics (height, weight, waist circumference [WC], and hip circumference [HC]) were measured, and body composition was assessed by bioelectrical impedance analysis. MetS was defined as including >=3 of the metabolic abnormalities (WC, high-density lipoprotein cholesterol [HDL-C], triglycerides, fasting glucose, and systolic and diastolic blood pressure [BP]) in the definition provided by the IDF. The BAIs (i.e., BAI-HC [BAI], BAI-WC [BAI-w], and [BAI-p]) were calculated from formulas taking into account, height, weight, and WC, and for the visceral adiposity indexes, a formula, including WC, HDL-C, and triglycerides, was used. RESULTS: The overall prevalence of MetS was 5.9%, higher in men than in women. The most prevalent components were low HDL-C, high triglyceride levels, WC, and BP levels. The receiver operating characteristic curves analysis showed that BAI, BAI-w, and BAI-p could be useful tools to predict MetS in this population. CONCLUSION: For women, the optimal MetS threshold was found to be 30.34 (area under curve [AUC] = 0.720-0.863), 19.10 (AUC = 0.799-0.925), and 29.68 (AUC = 0.779-0.901), for BAI, BAI-w, and BAI-p, respectively. For men, the optimal MetS threshold was found to be 27.83 (AUC = 0.726-0.873), 21.48 (AUC = 0.755-0.906), and 26.18 (AUC = 0.766-0.894), for BAI, BAI-w, and BAI-p, respectively. The three indexes can be useful tools to predict MetS according to the IDF criteria in university students from Colombia. Data on larger samples are needed. PMID- 28570831 TI - Recovery of Salmonella enterica from Australian Layer and Processing Environments Following Outbreaks Linked to Eggs. PMID- 28570833 TI - Medicine, public health and the populist radical right. PMID- 28570832 TI - Spearcons for Patient Monitoring: Laboratory Investigation Comparing Earcons and Spearcons. AB - Objective We compared the effectiveness of single-tone earcons versus spearcons in conveying information about two commonly monitored vital signs: oxygen saturation and heart rate. Background The uninformative nature of many medical alarms-and clinicians' lack of response to alarms-is a widespread problem that can compromise patient safety. Auditory displays, such as earcons and spearcons (speech-based earcons), may help clinicians maintain awareness of patients' well being and reduce their reliance on alarms. Earcons are short abstract sounds whose properties represent different types and levels of information, whereas spearcons are time-compressed spoken phrases that directly state their meaning. Listeners might identify patient vital signs more accurately with spearcons than with earcons. Method In Experiment 1 we compared how accurately 40 nonclinician participants using either (a) single-tone earcons differentiated by timbre and tremolo or (b) Cantonese spearcons recorded using a female Cantonese voice could identify both oxygen saturation and heart rate levels. In Experiment 2 we tested the identification performance of six further nonclinician participants with spearcons recorded using a male Cantonese voice. Results In Experiment 1, participants using spearcons identified both vital signs together more accurately than did participants using earcons. Participants using Cantonese spearcons also learned faster, completed trials faster, identified individual vital signs more accurately, and felt greater ease and more confident when identifying oxygen saturation levels. Experiment 2 verified the previous findings with male-voice Cantonese spearcons. Conclusion Participants identified vital signs more accurately using spearcons than with the single-tone earcons. Application Spearcons may be useful for patient monitoring in situations in which intermittently presented information is desirable. PMID- 28570834 TI - In Vitro Antistaphylococcal Synergistic Effect of Isoflavone Metabolite Demethyltexasin with Amoxicillin and Oxacillin. AB - Staphylococcal infections are often hard to treat due to increasing resistance, especially to beta-lactams. Previous studies described the synergy between common antibiotics and isoflavonoids; however, little is yet known about the combinatory effects of antibiotics with products of human isoflavone metabolism. In this study, demethyltexasin (DT), a human body metabolite of soybean isoflavones, was evaluated for its possible antistaphylococcal combinatory effect with amoxicillin and oxacillin. For comparison, common therapeutically used combination of amoxicillin/clavulanic acid was tested. DT showed strong synergistic interactions against most of Staphylococcus aureus strains when combined with amoxicillin (sum of fractional inhibitory concentrations [SigmaFIC] 0.257-0.461) and oxacillin (SigmaFIC 0.109-0.484). When oxacillin was combined with DT, resistance to this antibiotic was overcome in many cases. Moreover, antibiotic/DT combinations were effective mainly against methicillin-resistant S. aureus (MRSA); however, the commonly used drug amoxicillin/clavulanic acid was effective only against sensitive strains. Our results indicated DT as a compound able to act synergistically with beta-lactams. In addition, some combinations are effective against MRSA and decrease staphylococcal resistance. To the best of our knowledge this is the first report of the antimicrobial synergistic effects of isoflavone human body metabolite with common antibiotics. DT seems to be a possible candidate for further research focused on antistaphylococcal drug development, especially against antibiotic-resistant strains. PMID- 28570835 TI - Lifestyle and Behavioral Management of Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS) is a common condition with serious physiological and psychological health consequences. It affects women across their reproductive lifespan and is associated with pregnancy complications, including gestational diabetes, preeclampsia, and large gestational-age babies. PCOS is associated with excess weight gain, which, in turn, exacerbates the health burden of PCOS. Therefore, weight management, including a modest weight loss, maintenance of weight loss, prevention of weight gain, and prevention of excess gestational weight gain, is a first-line treatment for women with PCOS during and independent of pregnancy. Despite evidence-based guidelines, international position statements, and Cochrane reviews promoting lifestyle interventions for PCOS, the optimal complexity, intensity, and behavioral components of lifestyle interventions for women with PCOS are not well understood. The focus of this narrative review is the evidence supporting the use of behavioral strategies in weight management interventions for reproductive-aged women to apply to PCOS. Behavioral theories, behavior change strategies, and psychological correlates of weight management have been thoroughly explored in weight loss interventions in the general population, reproductive-aged women, and peri-natal women. This article uses this parallel body of research to inform suggestions regarding lifestyle interventions in women with PCOS. Outcomes of weight management programs in women with PCOS are likely to be improved with the inclusion of behavioral and psychological strategies, including goal setting, self-monitoring, cognitive restructuring, problem solving, and relapse prevention. Strategies targeting improved motivation, social support, and psychological well-being are also important. These can be applied to the clinical management of women with PCOS at different reproductive life stages. PMID- 28570837 TI - High-Throughput Screening and Analysis of Charge Variants of Monoclonal Antibodies in Multiple Formulations. AB - Among different biopharmaceutical products, monoclonal antibodies (mAbs) show a high level of complexity, including heterogeneity due to differences in size, hydrophobicity, charge, and so forth. Such heterogeneity can be related to both cell-based production and any of the stages of purification, storage, and delivery that the mAb is subjected to. Choosing the right formulation composition providing both physical and chemical stabilities can be a very challenging process, especially when done in the limited time frame required for a typical drug development cycle. Charge variants, a common type of heterogeneity for mAbs, are easy to detect by ion exchange, specifically cation exchange chromatography (CEX). We have developed and implemented a high-throughput CEX-based approach for the rapid screening and analysis of charge modifications in multiple formulation conditions. In this work, 96 different formulations of antistreptavidin IgG1 and IgG2 molecules were automatically prepared and analyzed after incubation at high temperature. Design of experiment and statistical analysis tools have been utilized to determine the major formulation factors responsible for chemical stability of antibodies. Regression models were constructed to find the optimal formulation conditions. The methodology can be applied to different stages of preformulation and formulation development of mAbs. PMID- 28570836 TI - The Influence of Hepatitis C Virus Therapy on the DNA Base Excision Repair System of Peripheral Blood Mononuclear Cells. AB - Hepatitis C virus (HCV) can infect extrahepatic tissues, including lymphocytes, creating reservoir of the virus. Moreover, HCV proteins can interact with DNA damage response proteins of infected cells. In this article we investigated the influence of the virus infection and a new ombitasvir/paritaprevir/ritonavir +/- dasabuvir +/- ribavirin (OBV/PTV/r +/- DSV +/- RBV) anti-HCV therapy on the PBMCs (peripheral blood mononuclear cells, mainly lymphocytes) DNA base excision repair (BER) system. BER protein activity was analyzed in the nuclear and mitochondrial extracts (NE and ME) of PBMC isolated from patients before and after therapy, and from subjects without HCV, using modeled double-strand DNA, with 2'-deoxyuridine substitution as the DNA damage. The NE and ME obtained from patients before therapy demonstrated lower efficacy of 2'-deoxyuridine removal and DNA repair polymerization than those of the control group or patients after therapy. Moreover, the extracts from the patients after therapy had similar activity to those from the control group. However, the efficacy of apurinic/apyrimidinic site excision in NE did not differ between the studied groups. We postulate that infection of lymphocytes by the HCV can lead to a decrease in the activity of BER enzymes. However, the use of novel therapy results in the improvement of glycosylase activity as well as the regeneration of endonuclease and other crucial repair enzymes. PMID- 28570838 TI - A High-Throughput Screening Strategy to Identify Inhibitors of SSB Protein Protein Interactions in an Academic Screening Facility. AB - Antibiotic-resistant bacterial infections are increasingly prevalent worldwide, and there is an urgent need for novel classes of antibiotics capable of overcoming existing resistance mechanisms. One potential antibiotic target is the bacterial single-stranded DNA binding protein (SSB), which serves as a hub for DNA repair, recombination, and replication. Eight highly conserved residues at the C-terminus of SSB use direct protein-protein interactions (PPIs) to recruit more than a dozen important genome maintenance proteins to single-stranded DNA. Mutations that disrupt PPIs with the C-terminal tail of SSB are lethal, suggesting that small-molecule inhibitors of these critical SSB PPIs could be effective antibacterial agents. As a first step toward implementing this strategy, we have developed orthogonal high-throughput screening assays to identify small-molecule inhibitors of the Klebsiella pneumonia SSB-PriA interaction. Hits were identified from an initial screen of 72,474 compounds using an AlphaScreen (AS) primary screen, and their activity was subsequently confirmed in an orthogonal fluorescence polarization (FP) assay. As an additional control, an FP assay targeted against an unrelated eukaryotic PPI was used to confirm specificity for the SSB-PriA interaction. Nine potent and selective inhibitors produced concentration-response curves with IC50 values of <40 MUM, and two compounds were observed to directly bind to PriA, demonstrating the success of this screen strategy. PMID- 28570839 TI - miR-26b Promotes 3T3-L1 Adipocyte Differentiation Through Targeting PTEN. AB - microRNAs (miRNAs) play important roles in adipogenesis that is closely linked to obesity and energy homeostasis. Thus far, only a few miRNAs have been identified to regulate adipocyte development, arousing interest in the detailed function of miRNAs during adipogenesis. In this study, we found that the miR-26b expression showed an increasing trend during 3T3-L1 cells differentiation. To investigate the role of miR-26b in adipogenesis, the synthetic miR-26b agomirs and antagomirs were used to perform overexpression and knockdown experiment, respectively. Our data revealed that overexpression of miR-26b significantly accelerated the mRNA expression of the adipogenic markers, peroxisome proliferator-activated receptor gamma (PPARgamma), fatty acid synthase (FAS), CCAAT/enhancer binding protein alpha (C/EBPalpha), and lipoprotein lipase, and the protein level of PPARgamma and FAS. miR-26b overexpression also resulted in a significant increase in lipid accumulation. In contrast, inhibition of miR-26b expression decreased differentiation of 3T3-L1 cells. By target gene prediction and luciferase reporter assay, we demonstrated that miR-26b may directly bind to the 3' UTR of phosphatase and tensin homolog (PTEN). Taken together, these results demonstrate that miR-26b might participate in regulating adipogenic differentiation in 3T3-L1 cells by inhibiting the PTEN expression, further highlighting the importance of miRNA in adipogenesis. PMID- 28570841 TI - Gastrovascular Circulation in an Octocoral: Evidence of Significant Transport of Coral and Symbiont Cells. AB - The gastrovascular system in the Red Sea soft coral Parerythropodium fulvum fulvum comprises two interconnected networks of canals filled with fluid and circulating cells. The first network is composed of narrow canals (50-80 {mu}m in width) located below the upper ectodermal layer; the second network includes larger canals (300-500 {mu}m in width) that are located deeper in the coral tissue. Particle movement in the second network is faster than in the superficial network, but in both, coral cells with and without healthy zooxanthellae circulate freely. To investigate the movement of metabolites and cellular components within the colony, coral fragments were exposed to 14C-labeled seawater for 24 h in the laboratory and in situ under saturating photosynthetic photon flux and then grafted back to their original colonies. Grafts fused after 24 h. In the laboratory experiment, up to 45% of the fixed 14C was translocated to the unlabeled colony within 48 h after fusion. In the in situ experiment, significant translocation of labeled materials occurred at the furthest parts of the colonies, 390 mm away from the fusion line, in 24 h. Even though the amount of labeling varied between colonies, labeled material spread throughout all the unlabeled parts. It thus appears that the gastrovascular system in Parerythropodium fulvum fulvum functions as an effective circulatory apparatus for fast translocation of organic compounds and cellular components within the colony. PMID- 28570840 TI - Sex differences in the oxygen delivery, extraction, and uptake during moderate walking exercise transition. AB - Previous studies in children and older adults demonstrated faster oxygen uptake (VO2) kinetics in males compared with females, but young healthy adults have not been studied. We hypothesized that young men would have faster aerobic system dynamics in response to the onset of exercise than women. Interactions between oxygen supply and utilization were characterized by the dynamics of VO2, deoxyhemoglobin (HHb), tissue saturation index (TSI), cardiac output (Q), and calculated arteriovenous O2 difference (a-vO2diff) in women and men. Eighteen healthy active young women and men (9 of each sex) with similar aerobic fitness levels volunteered for this study. Participants performed an incremental cardiopulmonary treadmill exercise test and 3 moderate-intensity treadmill exercise tests (at 80% VO2 of gas exchange threshold). Data related to the moderate exercise were submitted to exponential data modelling to obtain parameters related to the aerobic system dynamics. The time constants of VO2, a vO2diff, HHb, and TSI (30 +/- 6, 29 +/- 1, 16 +/- 1, and 15 +/- 2 s, respectively) in women were statistically (p < 0.05) faster than the time constants in men (42 +/- 10, 49 +/- 21, 19 +/- 3, and 20 +/- 4 s, respectively). Although Q dynamics were not statistically different (p = 0.06) between groups, there was a trend to slower Q dynamics in men corresponding with the slower VO2 kinetics. These results indicated that the peripheral and pulmonary oxygen extraction dynamics were remarkably faster in women. Thus, contrary to the hypothesis, VO2 dynamics measured at the mouth at the onset of submaximal treadmill walking were faster in women compared with men. PMID- 28570842 TI - Paracellular Solute Uptake in the Freshwater Bivalves Corbicula fluminea and Toxolasma texasensis. AB - Two species of freshwater bivalve were exposed to hyperosmotic solutions of various nonelectrolytes to compare the paracellular permeability of their gill epithelia. In Corbicula fluminea, exposure resulted in an elevation of blood solutes that was primarily due to dehydration. After 36 h of exposure, the concentration of Na in the blood decreased precipitously, and the nonelectrolyte accumulated. When lanthanum was added to the solution as a diffusion tracer, its electron-dense precipitate was rarely observed to penetrate the paracellular spaces of the gill epithelial cells in the absence of hyperosmotic stress. In contrast, precipitated lanthanum was commonly observed in the paracellular junctional complexes of the gill in animals that were subjected to hyperosmotic conditions. When the second species, Toxolasma texasensis, was exposed to hyperosmotic solutions of nonelectrolyte, dehydration appeared to be minimal and a seemingly normal concentration of ions was maintained in the blood. This, however, was because of the simultaneous loss of ions and water and a small gain in nonelectrolytes. Longer exposure (12 h or more) produced a precipitous decrease in most blood solutes and an extensive accumulation of nonelectrolyte. More lanthanum precipitate was seen in the paracellular spaces of both control and hyperosmotically stressed T. texasensis than in identically treated C. fluminea. We conclude that the epithelial junctions found in C. fluminea are relatively tight, which probably contributes to the ability of this species to maintain the solute in its body fluid at concentrations higher than are possible in T. texasensis. PMID- 28570843 TI - Cloning by Ophiuroid Echinoderm Larvae. AB - Larvae of the brittle star Ophiopholis aculeata, common to the North Pacific coast of the United States, and an unidentified species of ophiuroid, collected from waters off the eastern coast of Florida, undergo asexual reproduction of the primary larva to produce a secondary larval clone. Generation of a secondary larva begins with the release of the larval posterolateral arms, which are initially retained by the settled juvenile. In O. aculeata, the released arms regenerate all the structures typical of the primary ophiopluteus. Tissue and energy reserves required for formation of the secondary feeding larva appear to be supplied by the absorption and reorganization of part of the posterolateral arms. Various developmental stages of the unidentified ophiopluteus were collected from plankton samples taken off the coast of Florida. These included just-released posterolateral arms, plutei, and metamorphosed juveniles with the posterolateral arms still attached. The identification of regenerating arms from the plankton demonstrates that asexual reproduction by ophiuroid larvae is not restricted to a single, laboratory-cultured species. In both O. aculeata and the unidentified Atlantic ophiopluteus, cloning involves the dedifferentiation of primary larval tissue and a developmental progression similar to that followed by the zygote, although it is not known whether the formation of the secondary larva follows the same pathway utilized by the primary larva or a novel developmental program. Asexually produced secondary larvae of O. aculeata undergo metamorphosis, settle to the benthos, and initiate a tertiary larval generation, indicating that cloned larvae could be added to the population as long as environmental conditions could support a planktonic existence. This phenomenon represents an unusual potential to increase the geographic range and the number of juveniles of a given parentage in future generations without additional reproductive input from the adult. PMID- 28570844 TI - Minerals of the Radular Apparatus of Falcidens sp. (Caudofoveata) and the Evolutionary Implications for the Phylum Mollusca. AB - Minerals have been found in the radular teeth of molluscs from the classes Caudofoveata, Polyplacophora, Monoplacophora, and Gastropoda (Patellogastropoda: Acmaeidae, Patellidae). Here we report the discovery of amorphous iron oxide and hydroxyapatite in the highly modified radular apparatus of Falcidens sp. (Caudofoveata). The mineralization process in Falcidens sp. is unique: the components of the radular apparatus, unlike those of other molluscs, are not renewed during the animal's lifetime. We propose that the presence of mineralized teeth among the molluscs is not necessarily connected to their manner of obtaining food and suggest that the molluscan common ancestor had mineralized teeth. PMID- 28570845 TI - Celestial Mechanics, Sea-Level Changes, and Intertidal Ecology. AB - Celestial mechanics has long been known to affect life on Earth, but exploration of these influences has been hampered by long temporal scales and complex biological relations. Here we report on a periodic fluctuation in tidal exposure driven by the 18.6-y oscillation of the moon's orbital inclination, which can change by almost 50% the average time that intertidal organisms are exposed to air. The temperature of nearshore water and the upper limits to mussels are shown to vary with the lunar oscillation. Such variation challenges the value of ecological and physiological generalizations based on snapshot measures, and highlights the value of long-term studies. PMID- 28570846 TI - Evaluation of the Effects of Extremely Low Frequency Electromagnetic Fields on Movement in the Marine Diatom Amphora coffeaeformis. AB - Published work has shown that population motility in the marine diatom Amphora coffeaeformis can be influenced by externally applied electromagnetic fields (EMFs). Here we report attempts to repeat these experiments, which have been proposed as a model for assessing the effects of EMFs on biological systems. Susceptibility to EMFs was tested using five strains of diatoms on agar plates at a very broad range of field conditions, but no effect on population motility was demonstrated. Exposure period to the EMFs, cell density, and position in the cell cycle had no effect on EMF susceptibility, and the direction and distance moved by the diatoms were not affected by EMFs. When tested after at least a month of preincubation at 20 {mu}T, diatoms of strains #2038, IIIB, and IIIF did show an EMF-induced increase in population motility over control cells (up to ~20%) at conditions predicted by the "ion cyclotron resonance" model, but this effect was ephemeral. Later, IIIB showed a similar increase that was abolished when (1) non pre-incubated cells were used, (2) the EMF-producing coils were not energized, and (3) even harmonics were used. On observing the response of diatoms to EMFs in real time, a significant increase (~2-fold) in diatom speed over control cells was evident at "ion cyclotron resonance" conditions, using strain #2038 (pre incubated at 20 {mu}T). The effect was abolished at an even harmonic. We conclude that EMFs can modulate diatom motility, but that the system is, as yet, not consistently reproducible. PMID- 28570847 TI - Carbohydrates of the Organic Shell Matrix and the Shell-Forming Tissue of the Snail Biomphalaria glabrata (Say). AB - Sulfated carbohydrates may play a role in the biomineralization of the molluscan shell. The carbohydrates of the extracted water-insoluble organic shell matrix (IM) of the freshwater snail Biomphalaria glabrata were identified as glucose, mannose, galactose, and N-acetyl-glucosamine, whereas the water-soluble organic matrix (SM) additionally contained N-acetyl-galactosamine. A specific lectin binding pattern of the matrix was obtained. One prominent protein of the SM, with a size of 19.6 kDa and a pI of 7.4, was shown to be a glycoprotein with terminal glucosyl or mannosyl moieties. The acidic constitutents of the matrix showed a variety of possible terminal sugars, indicating a heterogenous mixture of proteoglycans or glycosaminoglycans (GAGs) and glycoproteins. At the shell forming mantle edge, an alcian-blue-positive material was observed in the periostracum groove (PG), the belt, and apically in the cells of the outer mantle epithelium (OME). With the help of lectins, all sugars in question were detected in the PG and the belt, whereas the OME was bound by glucose/mannose- and GlcNac specific lectins only. Although the complete set of GAGs will be produced in the PG and the belt, a very acidic fraction of GAGs and the 19.6-kDa protein can also be delivered by the OME. PMID- 28570848 TI - Zebra Mussel Spawning Is Induced in Low Concentrations of Putative Serotonin Reuptake Inhibitors. AB - Serotonin (5-hydroxytryptamine, 5-HT) and its receptor ligands induce both oocyte maturation and spawning in zebra mussels (Dreissena polymorpha). The selective serotonin reuptake inhibitors (SSRIs) fluvoxamine ("Luvox"), fluoxetine ("Prozac"), and paroxetine ("Paxil") are commonly prescribed drugs for the treatment of depression in humans. They act to increase 5-HT neurotransmission by inhibiting reuptake transport proteins at synapses. I tested the efficacy of these drugs at inducing spawning in zebra mussels. All three compounds induced spawning in both sexes at concentrations lower than that for 5-HT itself. Fluvoxamine was particularly potent, inducing spawning in 100% of both sexes at 10-5 and 10-6 M. The concentration that induced a significant percentage of animals to spawn was as low as 10-9 M for males and and 10-7 M for females. The lowest concentration of fluvoxamine to induce spawning was 10-8 M for females (40%) and 10-10 M for males (20%). Gametes spawned in fluvoxamine (10-5 M and lower) were viable, and swimming trochophores were formed within 20 hours. Fluoxetine was also an effective spawning inducer, causing 100% of males to spawn at 5 x 10-6 M. The concentration of fluoxetine required to induce a significant percentage of spawning was as low as 5 x 10-8 M for males and 5 x 10-6 M for females. In both fluvoxamine and fluoxetine, more than 60% of the males spawned within the first hour of exposure. In contrast, paroxetine was a weak spawning inducer. At concentrations of 10-5 and 10-6 M it induced significant, but low (50% and 40%, respectively) percentages of males to spawn. Paroxetine did not induce significant spawning in females. Thus, fluvoxamine, fluoxetine, and paroxetine can induce spawning at low concentrations, and fluvoxamine is the most powerful spawning inducer in any bivalve. These may be useful agents for stimulating invertebrate serotonergic mechanisms without applying exogenous 5-HT, and they are potentially important in bivalve aquaculture. Moreover, these results suggest, for the first time, the presence of 5-HT reuptake transporters in bivalve molluscs. PMID- 28570849 TI - Role of Chemical Inducers in Larval Metamorphosis of Queen Conch, Strombus gigas Linnaeus: Relationship to Other Marine Invertebrate Systems. AB - Chemical cues are important in the exogenous and endogenous control of metamorphosis in many marine invertebrate larvae. In the queen conch, Strombus gigas Linnaeus, larval metamorphosis is induced by low molecular weight compounds associated with dominant species of red algae found in conch nursery grounds; these species include the foliose rhodophyte Laurencia poitei (Lamouroux). The responses of conch larvae to the algal-associated cues are dependent on concentration and length of exposure, with the initial events of metamorphosis occurring within 10 min of treatment with an aqueous extract of L. poitei. The free amino acids valine and isoleutine mimic the effects of the natural inducer, and they may bind to and be recognized by the same sites on the larvae as the algal cues. Hydrogen peroxide, vanadate, and {gamma}-aminobutyric acid (GABA), as well as elevated K+ concentrations (i.e., above ambient seawater levels), also induce larval metamorphosis. Acetylsalicylic acid decreases the responses of conch larvae to the algal-associated cues and to the free amino acids, but it has no effect on the induction triggered by hydrogen peroxide. The chemical induction of metamorphosis in conch larvae shares many general features with chemoreception in aquatic invertebrates. The natural inducers of metamorphosis, like the cues involved in olfactory responses in other marine organisms, are of low molecular weight and water soluble. In addition, the results of the experiments with hydrogen peroxide, vanadate, and GABA suggest that second messenger pathways are involved in conch metamorphosis. PMID- 28570850 TI - Ion Transport in the Freshwater Bivalve Corbicula fluminea. AB - In freshwater bivalves such as the mussel Corbicula fluminea, uptake of chloride depends on the external concentration of the chloride ion. In C. fluminea, Cl- uptake displayed saturation kinetics both in animals acclimated to pondwater and in those subjected to salt depletion by storage in deionized water. The transport capacity (Jmax) was 7.00 +/- 0.51 {mu}eq g-1 dry tissue h-1 and the transport affinity (Km) was 0.21 +/- 0.08 mM in animals acclimated to pondwater. Animals subjected to salt depletion had a higher rate of Cl- uptake than did animals acclimated to pondwater. After 4 weeks in deionized water, the longer the animals were salt-depleted, the higher their rate of Cl- uptake. Na+ and Cl- transport were independent in pondwater-acclimated C. fluminea. For salt-depleted animals, Cl- transport was Na+-independent, but Na+ transport depended partially on external Cl-. Serotonin stimulated Cl- and Na+ transport in pond-water-acclimated animals by increasing influx while having little influence on efflux. Acetazolamide increased the Cl- and Na+ efflux of salt-depleted animals. Both serotonin and acetazolamide elevated the net loss of titratable base. PMID- 28570851 TI - Effect of seminal plasma from high- and low-fertility bulls on cauda epididymal sperm function. AB - The aim of this study was to characterise the effect of seminal plasma (SP) from bulls of high or low fertility on sperm function. First, the effect of SP on the motility of fresh cauda epididymal spermatozoa (CES) and frozen-thawed ejaculated spermatozoa was assessed (Experiment 1a). Seminal plasma was then collected from bulls of known high and low fertility. Pooled CES were incubated in the SP from each bull, diluted and assessed for motility and viability on Days 1, 2, 3 and 5 after packaging as fresh semen (Experiment 1b). Also assessed were motility, kinematics, viability and mitochondrial membrane potential after thawing (Experiment 1c) as well as hypotonic resistance (Experiment 2) and fertilisation potential using in vitro fertilisation (Experiment 3). Seminal plasma increased the motility of CES (P<0.05); however, there was no effect of SP on the motility and viability of fresh CES or on CES post-thaw motility, viability and mitochondrial membrane potential (P>0.05). The hypotonic resistance of CES was reduced by SP (P<0.05), irrespective of whether the SP was from high- or low fertility bulls. Seminal plasma from high- or low-fertility bulls had no effect on cleavage or blastocyst rates (P>0.05). In conclusion, SP affects the physiological function of CES but there is no difference between SP from high- or low-fertility bulls. PMID- 28570852 TI - Synthesis of uniform cadmium sulphide thin film by the homogeneous precipitation method on cadmium telluride nanorods and its application in three-dimensional heterojunction flexible solar cells. AB - High-density CdTe nanorod arrays are successfully embedded in a uniform and compact CdS layer, forming a novel three-dimensional (3D) CdTe NRs/CdS heterojunction structure. The CdS layer is prepared by homogeneous precipitation (HP) method using decomposition of urea. The effects of temperature and concentration of reactants on the growth and composition of CdS film are investigated in detail. The results demonstrate that the temperature affects the thermal decomposition of urea significantly, and the concentration of CdCl2 and CS (NH2)2 plays an essential role in the compositional ratio of CdS film. Further investigations reveal that, in comparison with the traditional precipitation method, a better coverage of CdS on the surface of CdTe NRs can be obtained by HP method due to the slow and even hydrolysis of urea. Moreover, photovoltaic performance of the novel CdTe NRs/CdS 3D photovoltaic device is also investigated. This study demonstrates that the 3D heterostructure has potential application in thin film solar cells, and the successful deposition of CdS layer on the surface of CdTe NRs by HP method suggests a promising technique for large scale fabrication of these solar cells. PMID- 28570853 TI - Polyurethane foam membranes filled with humic acid-chitosan crosslinked gels for selective and simultaneous removal of dyes. AB - Polyurethane foam membrane filled with humic acid-chitosan crosslinked gels (HA CS-PUF) for dye removal was prepared by soaking the foams into humic acid chitosan (HA-CS) crosslinked gels and hot-pressing them into membranes. Scanning electron microscope, derivative thermogravimetry and X-ray photoelectron spectroscopy were used to characterize the HA-CS-PUF membrane. Results showed that the interaction of HA and CS was mainly through ionic cross-linking between carboxyl and protonated amino groups. Three types of dyes, including positively charged methylene blue (MB), neutrally charged rhodamine B (RB) and negatively charged methyl orange (MO), were used to test membranes properties through static adsorption and membrane filtration experiments. It revealed that adsorption process was better fitted with Pseudo-second-order and Freundlich model. In membrane filtration experiments, we found that the retention rates of membrane 1 (ratio of HA to CS was 0:1) to MO and RB were 99.7% and 65%, respectively, and nearly no retention to MB. While membrane 4 (ratio of HA to CS was 0.2:1) can retain 97.7% of MO, 71.6% of RB and 62.1% of MB. Based on the experimental results, membrane 1 possessed the ability of selectively separating MB from MO/MB and RB/MB solutions, and membrane 4 can simultaneously retain RB and MB from RB/MB solution. PMID- 28570854 TI - Fabrication of a transparent conducting electrode based on graphene/silver nanowires via layer-by-layer method for organic photovoltaic devices. AB - A solution-processed transparent conducting electrode was fabricated via layer-by layer (LBL) deposition of graphene oxide (GO) and silver nanowires (Ag NWs). First, graphite was oxidized with a modified Hummer's method to obtain negatively charged GO sheets, and Ag NWs were functionalized with cysteamine hydrochloride to acquire positively-charged silver nanowires. Oppositely-charged GO and Ag NWs were then sequentially coated on a 3-aminopropyltriethoxysilane modified glass substrate via LBL deposition, which provided highly controllable thin films in terms of optical transmittance and sheet resistance. Next, the reduction of GO sheets was performed to improve the electrical conductivity of the multilayer films. The resulting GO/Ag NWs multilayer was characterized by a UV-Vis spectrometer, field emission scanning electron microscope (FE-SEM), optical microscope (OM) and sheet resistance using a four-point probe method. The best result was achieved with a 2-bilayer film, resulting in a sheet resistance of 6.5Omega sq-1 with an optical transmittance of 78.2% at 550nm, which values are comparable to those of commercial ITO electrodes. The device based on a 2-bilayer hybrid film exhibited the highest device efficiency of 1.30% among the devices with different number of graphene/Ag NW LBL depositions. PMID- 28570855 TI - Dispersion characteristics of the flexural wave assessed using low frequency (50 150kHz) point-contact transducers: A feasibility study on bone-mimicking phantoms. AB - Guided waves-based techniques are currently under development for quantitative cortical bone assessment. However, the signal interpretation is challenging due to multiple mode overlapping. To overcome this limitation, dry point-contact transducers have been used at low frequencies for a selective excitation of the zeroth order anti-symmetric Lamb A0 mode, a mode whose dispersion characteristics can be used to infer the thickness of the waveguide. In this paper, our purpose was to extend the technique by combining a dry point-contact transducers approach to the SVD-enhanced 2-D Fourier transform in order to measure the dispersion characteristics of the flexural mode. The robustness of our approach is assessed on bone-mimicking phantoms covered or not with soft tissue-mimicking layer. Experiments were also performed on a bovine bone. Dispersion characteristics of measured modes were extracted using a SVD-based signal processing technique. The thickness was obtained by fitting a free plate model to experimental data. The results show that, in all studied cases, the estimated thickness values are in good agreement with the actual thickness values. From the results, we speculate that in vivo cortical thickness assessment by measuring the flexural wave using point-contact transducers is feasible. However, this assumption has to be confirmed by further in vivo studies. PMID- 28570856 TI - Identification of the mechanical moduli of flexible thermoplastic thin films using reflected ultrasonic waves: Inverse problem. AB - A method for the identification of the mechanical moduli and density of flexible, supple thermoplastic thin films placed on elastic substrates using ultrasonic waves has been developed. The composite medium immersed in a fluid host medium (water) was excited using a 50MHz transducer operating at normal incidence in reflection mode. Inverse problems involving experimental data pertaining to elastic wave propagation in the thin films on their substrates and theoretical fluid-solid interaction models for stratified media using elasticity theory were solved. Two configurations having different interface boundary conditions (BC) were modeled, transverse slip for the sliding contact interface in the case where the thin films were placed on the substrate without bonding; a bonded interface condition. The inverse problem for the recovery of the mechanical parameters were solved for the thin films under the bonded and slip BCs. Substrates made of different elastic materials having different geometries were also evaluated and their advantages discussed. PMID- 28570858 TI - Chronological narratives from smoking initiation through to pregnancy of Indigenous Australian women: A qualitative study. AB - OBJECTIVE: One in two Indigenous Australian pregnant women smoke, yet little is known about their trajectory of smoking. This study aimed to explore Aboriginal women's narratives from starting smoking through to pregnancy. METHODS: A female Aboriginal Researcher conducted individual face-to-face interviews with 20 Aboriginal women from New South Wales, Australia. Recruitment, through Aboriginal services and community networks, continued until saturation was reached. Audio recorded transcripts were independently open coded by two researchers, inductively analysed and reported using a three-dimensional structure of looking backwards, forwards, inwards, outwards and a sense of place, to elucidate the chronology of events, life stages, characters, environments, and turning points of the stories. RESULTS: A chronology emerged from smoking initiation in childhood, coming of age, becoming pregnant, through to attempts at quitting, and relapse post-partum. Several new themes emerged: the role mothers play in women's smoking and quitting; the contribution of nausea to spontaneous quitting; depression as a barrier to quitting; and the hopes of women for their own and their children's future. The epiphany of pregnancy was a key turning point for many - including the interplay of successive pregnancies; and the intensity of expressed regret. CONCLUSIONS: Aboriginal women report multiple influences in the progression of early smoking to pregnancy and beyond. Potential opportunities to intervene include: a) childhood, coming of age, pregnancy, post-natal, in-between births; b) key influencers; c) environments, and d) targeting concurrent substance use. Morning sickness appears to be a natural deterrent to continued smoking. Depression, and its relationship to smoking and quitting in Australian Indigenous pregnant women, requires further research. PMID- 28570857 TI - 'Even when you are afraid, you stay': Provision of maternity care during the Ebola virus epidemic: A qualitative study. AB - OBJECTIVE: to explore nurse-midwives understanding of their role in and ability to continue to provide routine and emergency maternity services during the time of the Ebola virus disease epidemic in Sierra Leone. DESIGN: a hermenuetic phenomenological approach was used to discover the lived experiences of nurse midwives through 66 face to face interviews. Following verbatim transcription, an iterative approach to data analysis was adopted using framework analysis to discover the essence of the lived experience. SETTING: health facilities designated to provide maternity care across all 14 districts of Sierra Leone. PARTICIPANTS: nurses, midwives, medical staff and managers providing maternal and newborn care during the Ebola epidemic in facilities designated to provide basic or emergency obstetric care. FINDINGS: the healthcare system in Sierra Leone was ill prepared to cope with the epidemic. Fear of Ebola and mistrust kept women from accessing care at a health facility. Healthcare providers continued to provide maternity care because of professional duty, responsibility to the community and religious beliefs. KEY CONCLUSIONS: nurse-midwives faced increased risks of catching Ebola compared to other health workers but continued to provide essential maternity care. IMPLICATIONS FOR PRACTICE: future preparedness plans must take into account the impact that epidemics have on the ability of the health system to continue to provide vital routine and emergency maternal and newborn health care. Healthcare providers need to have a stronger voice in health system rebuilding and planning and management to ensure that health service can continue to provide vital maternal and newborn care during epidemics. PMID- 28570859 TI - The contribution of task-choice response selection to the switch cost in voluntary task switching. AB - Mental flexibility not only enables us to switch between tasks but also to select the tasks we want to perform. The latter scenario is central to voluntary task switching, in which participants are free to select on each trial which task to perform. The present study argues that voluntary task switching also includes and additional component, namely task-choice response selection. Task-choice response selection refers to the whole chain of processes involved in the overt report or indication of the task that was selected by emitting an arbitrary response. Task choice response selection is not required to voluntarily switch between tasks, but serves the measurement of participants' covert task selection. The results of two experiments indicate that the contribution of task-choice response selection to switch performance in voluntary task switching is substantial. It is proposed that task-choice response selection delays the top-down retrieval of task rules in voluntary task switching. PMID- 28570860 TI - How humans use visual optic flow to regulate stepping during walking. AB - Humans use visual optic flow to regulate average walking speed. Among many possible strategies available, healthy humans walking on motorized treadmills allow fluctuations in stride length (Ln) and stride time (Tn) to persist across multiple consecutive strides, but rapidly correct deviations in stride speed (Sn=Ln/Tn) at each successive stride, n. Several experiments verified this stepping strategy when participants walked with no optic flow. This study determined how removing or systematically altering optic flow influenced peoples' stride-to-stride stepping control strategies. Participants walked on a treadmill with a virtual reality (VR) scene projected onto a 3m tall, 180 degrees semi cylindrical screen in front of the treadmill. Five conditions were tested: blank screen ("BLANK"), static scene ("STATIC"), or moving scene with optic flow speed slower than ("SLOW"), matched to ("MATCH"), or faster than ("FAST") walking speed. Participants took shorter and faster strides and demonstrated increased stepping variability during the BLANK condition compared to the other conditions. Thus, when visual information was removed, individuals appeared to walk more cautiously. Optic flow influenced both how quickly humans corrected stride speed deviations and how successful they were at enacting this strategy to try to maintain approximately constant speed at each stride. These results were consistent with Weber's law: healthy adults more-rapidly corrected stride speed deviations in a no optic flow condition (the lower intensity stimuli) compared to contexts with non-zero optic flow. These results demonstrate how the temporal characteristics of optic flow influence ability to correct speed fluctuations during walking. PMID- 28570861 TI - Cognitive tasks promote automatization of postural control in young and older adults. AB - Researchers looking at the effects of performing a concurrent cognitive task on postural control in young and older adults using traditional center-of-pressure measures and complexity measures found discordant results. Results of experiments showing improvements of stability have suggested the use of strategies such as automatization of postural control or stiffening strategy. This experiment aimed to confirm in healthy young and older adults that performing a cognitive task while standing leads to improvements that are due to automaticity of sway by using sample entropy. Twenty-one young adults and twenty-five older adults were asked to stand on a force platform while performing a cognitive task. There were four cognitive tasks: simple reaction time, go/no-go reaction time, equation and occurrence of a digit in a number sequence. Results demonstrated decreased sway area and variability as well as increased sample entropy for both groups when performing a cognitive task. Results suggest that performing a concurrent cognitive task promotes the adoption of an automatic postural control in young and older adults as evidenced by an increased postural stability and postural sway complexity. PMID- 28570862 TI - Monocyte inflammatory profile is specific for individuals and associated with altered blood lipid levels. AB - BACKGROUND AND AIMS: Atherogenesis is dependent upon monocyte influx into the vessel wall. In humans, three monocyte subsets exist, the number and function of which are significantly altered in cardiovascular disease (CVD). Whether such alterations arise in individuals with a perturbed lipid profile remains largely unanswered, but is important to delineate, as adoption of a pro-inflammatory state may promote plaque formation. Here, we compared the inflammatory status of monocyte subsets and determined whether monocyte inflammatory changes are evident in individuals with a perturbed lipid profile. METHODS: Monocyte subset cytokine production, inflammatory and anti-inflammatory marker expression were determined by whole blood flow cytometry and related to participants' lipid levels. RESULTS: The intermediate and non-classical monocytes were more inflammatory than classicals as seen by their higher cytokine production (TNF-alpha, IL-1beta, IL 6) and M1 marker (CD86) expression, but lower levels of M2 markers (CD93, CD163). More importantly, a considerable variation was seen between participants, with all monocytes of one individual being more inflammatory than those of another. Many inter-individual differences were related to participants' lipid levels. IL 1beta production correlated negatively with Apo A1 and HDL-C. CD86 and TLR2 correlated positively with Chol:HDL-C but negatively with HDL-C and Apo A1:Apo B. Interestingly, CD163 expression correlated positively with Chol:HDL-C but negatively with Apo A1:Apo B. CONCLUSIONS: Our data indicates that priming of all monocytes to an inflammatory state occurs in individuals with a perturbed lipid profile, overriding the normal functional distinction attributed to the different monocyte subsets. As such, all monocytes may be important in CVD. PMID- 28570863 TI - Closing the gap: long-term presynaptic plasticity in brain function and disease. AB - Synaptic plasticity is critical for experience-dependent adjustments of brain function. While most research has focused on the mechanisms that underlie postsynaptic forms of plasticity, comparatively little is known about how neurotransmitter release is altered in a long-term manner. Emerging research suggests that many of the features of canonical 'postsynaptic' plasticity, such as associativity, structural changes and bidirectionality, also characterize long term presynaptic plasticity. Recent studies demonstrate that presynaptic plasticity is a potent regulator of circuit output and function. Moreover, aberrant presynaptic plasticity is a convergent factor of synaptopathies like schizophrenia, addiction, and Autism Spectrum Disorders, and may be a potential target for treatment. PMID- 28570864 TI - Molecular mechanisms of astrocyte-induced synaptogenesis. AB - Astrocytes are morphologically complex cells that perform a wide variety of critical functions in the brain. As a structurally and functionally integrated component of the synapse, astrocytes secrete proteins, lipids, and small molecules that bind neuronal receptors to promote synaptogenesis and regulate synaptic connectivity. Additionally, astrocytes are key players in circuit formation, instructing the formation of synapses between distinct classes of neurons. This review highlights recent publications on the topic of astrocyte mediated synaptogenesis, with a focus on the molecular mechanisms through which astrocytes orchestrate the formation of synaptic circuits. PMID- 28570865 TI - Cyclic peptide natural products chart the frontier of oral bioavailability in the pursuit of undruggable targets. AB - As interest in protein-protein interactions and other previously-undruggable targets increases, medicinal chemists are returning to natural products for design inspiration toward molecules that transcend the paradigm of small molecule drugs. These compounds, especially peptides, often have poor ADME properties and thus require a more nuanced understanding of structure-property relationships to achieve desirable oral bioavailability. Although there have been few clinical successes in this chemical space to date, recent work has identified opportunities to introduce favorable physicochemical properties to peptidic macrocycles that maintain activity and oral bioavailability. PMID- 28570866 TI - Differentiated effects of deep brain stimulation and medication on somatosensory processing in Parkinson's disease. AB - OBJECTIVES: Deep brain stimulation (DBS) and dopaminergic medication effectively alleviate the motor symptoms in Parkinson's disease (PD) patients, but their effects on the sensory symptoms of PD are still not well understood. To explore early somatosensory processing in PD, we recorded magnetoencephalography (MEG) from thirteen DBS-treated PD patients and ten healthy controls during median nerve stimulation. METHODS: PD patients were measured during DBS-treated, untreated and dopaminergic-medicated states. We focused on early cortical somatosensory processing as indexed by N20m, induced gamma augmentation (31-45Hz and 55-100Hz) and induced beta suppression (13-30Hz). PD patients' motor symptoms were assessed by UPDRS-III. RESULTS: Using Bayesian statistics, we found positive evidence for differentiated effects of treatments on the induced gamma augmentation (31-45Hz) with highest gamma in the dopaminergic-medicated state and lowest in the DBS-treated and untreated states. In contrast, UPDRS-III scores showed beneficial effects of both DBS and dopaminergic medication on the patients' motor symptoms. Furthermore, treatments did not affect the amplitude of N20m. CONCLUSIONS: Our results suggest differentiated effects of DBS and dopaminergic medication on cortical somatosensory processing in PD patients despite consistent ameliorating effects of both treatments on PD motor symptoms. SIGNIFICANCE: The differentiated effect suggests differences in the effect mechanisms of the two treatments. PMID- 28570867 TI - Evoked potentials recorded during routine EEG predict outcome after perinatal asphyxia. AB - OBJECTIVE: To evaluate the added value of somatosensory (SEPs) and visual evoked potentials (VEPs) recorded simultaneously with routine EEG in early outcome prediction of newborns with hypoxic-ischemic encephalopathy under modern intensive care. METHODS: We simultaneously recorded multichannel EEG, median nerve SEPs, and flash VEPs during the first few postnatal days in 50 term newborns with hypoxic-ischemic encephalopathy. EEG background was scored into five grades and the worst two grades were considered to indicate poor cerebral recovery. Evoked potentials were classified as absent or present. Clinical outcome was determined from the medical records at a median age of 21months. Unfavorable outcome included cerebral palsy, severe mental retardation, severe epilepsy, or death. RESULTS: The accuracy of outcome prediction was 98% with SEPs compared to 90% with EEG. EEG alone always predicted unfavorable outcome when it was inactive (n=9), and favorable outcome when it was normal or only mildly abnormal (n=17). However, newborns with moderate or severe EEG background abnormality could have either favorable or unfavorable outcome, which was correctly predicted by SEP in all but one newborn (accuracy in this subgroup 96%). Absent VEPs were always associated with an inactive EEG, and an unfavorable outcome. However, presence of VEPs did not guarantee a favorable outcome. CONCLUSIONS: SEPs accurately predict clinical outcomes in newborns with hypoxic ischemic encephalopathy and improve the EEG-based prediction particularly in those newborns with severely or moderately abnormal EEG findings. SIGNIFICANCE: SEPs should be added to routine EEG recordings for early bedside assessment of newborns with hypoxic-ischemic encephalopathy. PMID- 28570868 TI - Fractional amplitude of low-frequency fluctuations is disrupted in Alzheimer's disease with depression. AB - OBJECTIVE: To explore brain activity in AD with depression (D-AD) based on fractional amplitude of low-frequency fluctuation (fALFF). METHODS: Twenty-two D AD and 21 AD without depression patients (nD-AD) were examined by magnetic resonance imaging during resting state. Neuropsychiatric Inventory and Hamilton Depression Rating Scale were employed to assess the severity of depression. We analysed the characteristics of fALFF in D-AD differing from nD-AD. We also examined the correlation between fALFF and the depression severity. RESULTS: D-AD patients had higher fALFF in right fusiform gyrus, left caudate nucleus, and right middle temporal gyrus (MTG), meanwhile lower fALFF in supplementary motor area (SMA) than nD-AD patients. CONCLUSIONS: Abnormal fALFF changes in fusiform gyrus, caudate nucleus, MTG and SMA may be important neuropathophysiologic characteristics of depression in AD. SIGNIFICANCE: We have clarified the potential neuropathological changes of depression in AD based on fALFF method, which is crucial for effective intervention. PMID- 28570869 TI - The Effect of Adding Neoadjuvant Chemotherapy to Concurrent Chemoradiotherapy in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma and Undetectable Pretreatment Epstein-Barr Virus DNA. AB - PURPOSE: To assess the effect of adding neoadjuvant chemotherapy (NACT) to concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and undetectable pretreatment Epstein-Barr virus (pEBV) DNA. MATERIALS AND METHODS: We enrolled 639 NPC patients with stage II to IVB and undetectable pEBV DNA to receive CCRT with or without NACT. Radiotherapy was 2.0 to 2.27 Gy per fraction with five daily fractions per week for 6 to 7 weeks to the primary tumor and 62 to 70 Gy to the involved neck area. NACT was cisplatin (80-100 mg/m2day 1) and 5-fluorouracil (800-1000 mg/m2, 120-hour continuous intravenous infusion) every 3 weeks for two or three cycles. CCRT was cisplatin (80-100 mg/m2day 1) every 3 weeks for three cycles. RESULTS: For all patients, the 5-year overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) rates were 91.9%, 92.2%, 95.0%, and 86.4%, respectively. There was no significant difference in OS (5-year OS 90.8% [NACT + CCRT group] vs 92.7% [CCRT alone]; hazard ratio [HR] 1.24; P=.486), LRFS (HR 1.13, 95% confidence interval [CI] 0.59-2.14, P=.715), DMFS (HR 0.78, 95% CI 0.34-1.78, P=.554), or PFS (HR 1.21, 95% CI 0.75-1.95, P=.472). CONCLUSION: CCRT with or without NACT produced a good treatment outcome in patients with locoregionally advanced NPC and undetectable pEBV DNA, but NACT before CCRT did not significantly improve survival rates. PMID- 28570870 TI - Tetraselmis as a challenge organism for validation of ballast water UV systems. AB - Transport and release of waterborne organisms as a result of ballasting and de ballasting operations is widely acknowledged to represent an important mechanism for invasions by non-indigenous species. Regulatory requirements have been implemented globally to require treatment of ballast water before its release to the environment as a means of minimizing risks of invasion. UV-based processes represent an option for ballast water treatment; however, their use will require development of appropriate methods for reactor validation. To address this need, Tetraselmis was examined as challenge organism using a most probable number (MPN) assay for quantification of the concentration of viable (reproductively active) cells in suspension. A low pressure collimated-beam reactor was used to investigate UV254 dose-response behavior of Tetraselmis. Based on the experimental conditions applied, Tetraselmis indicated 4.5-5 log10 units of inactivation for UV254 doses of approximately 120 mJ/cm2, with no apparent change of resistance resulting from repeated exposure. A medium pressure UV collimated beam reactor equipped with a series of narrow bandpass optical filters was used to investigate the action spectrum of Tetraselmis for wavelengths ranging from 228 nm-297 nm. Radiation with wavelengths in the range 254-280 nm was observed to be most efficient for inactivation of Tetraselmis. Additionally, DNA was extracted from Tetraselmis to allow measurement of its absorption spectrum. These results indicated strong absorbance from 254 nm to 280 nm, thereby suggesting that damage to DNA plays an important role in the inactivation of Tetraselmis sp. However, deviations of the action spectrum shape from the shape of the DNA absorption spectrum suggest that UV-induced damage to biomolecules other than DNA may contribute to Tetraselmis inactivation at some wavelengths in the UVC range. PMID- 28570871 TI - Influence of dissolved organic matter concentration and composition on the removal efficiency of perfluoroalkyl substances (PFASs) during drinking water treatment. AB - Drinking water treatment plants (DWTPs) are constantly adapting to a host of emerging threats including the removal of micro-pollutants like perfluoroalkyl substances (PFASs), while concurrently considering how background levels of dissolved organic matter (DOM) influences their removal efficiency. Two adsorbents, namely anion exchange (AE) and granulated active carbon (GAC) have shown particular promise for PFAS removal, yet the influence of background levels of DOM remains poorly explored. Here we considered how the removal efficiency of 13 PFASs are influenced by two contrasting types of DOM at four concentrations, using both AE (Purolite A-600(r)) and GAC (Filtrasorb 400(r)). We placed emphasis on the pre-equilibrium conditions to gain better mechanistic insight into the dynamics between DOM, PFASs and adsorbents. We found AE to be very effective at removing both PFASs and DOM, while largely remaining resistant to even high levels of background DOM (8 mg carbon L-1) and surprisingly found that smaller PFASs were removed slightly more efficiently than longer chained counterparts, In contrast, PFAS removal efficiency with GAC was highly variable with PFAS chain length, often improving in the presence of DOM, but with variable response based on the type of DOM and PFAS chain length. PMID- 28570872 TI - Quantitative characterization of organic diffusion using an analytical diffusion reaction model and its application to assessing BOD removal when treating municipal wastewater in a plug flow reactor. AB - The present study aimed to derive an analytical formula to quantify the diffusion of organic contaminant in a biofilm. The experiments were conducted to investigate the BOD degradation under the conditions of influent COD concentration from 50 to 300 mg/L, COD:N:P ratios of 100:5:1 and 100:15:3, with and without auxiliary aeration. The BOD removal rate was around 73% for non aerated influent COD of 50 mg/L with 1-h hydraulic retention time. The BOD removal rate increased as the influent loading and hydraulic retention time increased while the influent COD was no more than 150 mg/L. Without aeration, the removal rate dropped significantly when influent COD increased to the range no less than 200 mg/L, due to the fact that the BOD diffusive flux driven by the biomass uptake was not further enhanced by higher ambient organic loading. The diffusion coefficient was calculated to be 1.12 * 10-6 m2/d with influent COD of 50 mg/L at COD:N:P ratio of 100:5:1 and 1 h hydraulic retention time and aeration, and the coefficient increased to 3.35 * 10-6 m2/d as the influent COD concentration increased to 300 mg/L. The diffusion coefficient decreased to 4.09 * 10-7 m2/d as the retention time increased to 3 h. The overall diffusion coefficients showed an increasing trend as the influent organic loading increased. The difference in diffusion coefficients between 1 and 2 h was apparently greater than that between 2 and 3 h, indicating a smaller overall diffusive flux due to a longer retention time. Further analysis revealed that BOD diffusion activity exhibited a declining trend as the wastewater travelled through the system. An analytical diffusion-reaction model was developed to characterize the diffusion behaviour, and applied to estimating the treatment efficiency for real domestic sewage. The result showed that the estimated effluent BOD concentrations were quite comparable to those from experimental measurements. PMID- 28570873 TI - Biotransformation of nitrogen- and sulfur-containing pollutants during coking wastewater treatment: Correspondence of performance to microbial community functional structure. AB - Although coking wastewater is generally considered to contain high concentration of nitrogen- and sulfur-containing pollutants, the biotransformation processes of these compounds have not been well understood. Herein, a high throughput functional gene array (GeoChip 5.0) in combination with Illumina MiSeq sequencing of the 16S rRNA gene were used to identify microbial functional traits and their role in biotransformation of nitrogen- and sulfur-containing compounds in a bench scale aerobic coking wastewater treatment system operated for 488 days. Biotransformation of nitrogen and sulfur-containing pollutants deteriorated when pH of the bioreactor was increased to >8.0, and the microbial community functional structure was significantly associated with pH (Mantels test, P < 0.05). The release of ammonia nitrogen and sulfate was correlated with both the taxonomic and functional microbial community structure (P < 0.05). Considering the abundance and correlation with the release of ammonia nitrogen and sulfate, aromatic dioxygenases (e.g. xylXY, nagG), nitrilases (e.g. nhh, nitrilase), dibenzothiophene oxidase (DbtAc), and thiocyanate hydrolase (scnABC) were important functional genes for biotransformation of nitrogen- and sulfur containing pollutants. Functional characterization of taxa and network analysis suggested that Burkholderiales, Actinomycetales, Rhizobiales, Pseudomonadales, and Hydrogenophiliales (Thiobacillus) were key functional taxa. Variance partitioning analysis showed that pH and influent ammonia nitrogen jointly explained 25.9% and 35.5% of variation in organic pollutant degrading genes and microbial community structure, respectively. This study revealed a linkage between microbial community functional structure and the likely biotransformation of nitrogen- and sulfur-containing pollutants, along with a suitable range of pH (7.0-7.5) for stability of the biological system treating coking wastewater. PMID- 28570874 TI - Suitability of humic substances recovered from sewage sludge to remedy soils from a former As mining area - a novel approach. AB - Batch washing experiments were performed to evaluate the feasibility of using a solution of humic substances (HS) extracted from municipal sewage sludge as a washing agent to remove As from soils at a former As mining area. Soils (S1, S2, S3) differed in organic matter content, pH and As concentration. At pH 4 and a HS concentration of 4000mgTOCL-1, As removal efficiency ranged from 18% (S2) to 27% (S3). In all cases, As removal proceeded according to pseudo-second-order kinetics (equilibrium As concentrations ranged from 625mgkg-1 (S3) to 1250mgkg-1 (S3); rate constants, from 1.02*10-5kgmg-1min-1 (S1) to 2.05*10-5kgmg-1min-1 (S3). The time needed to reach equilibrium was 12h. With double washing, the efficiency of As removal was 1.5-times higher (on average) than with single washing. Double washing increased As stability, as indicated by the reduced partition index, especially in soils S1 and S3. Moreover, HS effectively decreased the content of the most toxic As(III) (by 95-97%). PMID- 28570875 TI - The impact of modified nano-carbon black on the earthworm Eisenia fetida under turfgrass growing conditions: Assessment of survival, biomass, and antioxidant enzymatic activities. AB - Modified nano-carbon adsorbents have been employed in the immobilization of heavy metals in soil due to their good adsorption capabilities regarding metal ions. However, an assessment of their risks has not been extensively performed with soil organisms. To assess the toxic effects of three types of modified nano carbon black (CB) on soil organisms, a laboratory test was conducted to expose the earthworm Eisenia fetida to artificial soil supplemented with 5% H2SO4-, HNO3 and KMnO4-modified nano-CB (SCB, NCB and KCB, respectively) under turfgrass growing conditions. The tested earthworms were systematically investigated for survival, biomass and the activities of antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT). SCB and NCB were found to be more toxic and ecologically dangerous to E. fetida because significant decreases in biomass and survival were observed after 35- and 60-d exposures and the survival rate showed a tendency to decrease with exposure duration. The activities of SOD, CAT and POD were inhibited in all treatments with modified nano-CBs at 35- and 60-d, which indicated that oxidative stress was induced by modified nano-CBs. The results suggest that there is potential harm to earthworms in soil with 5% modified nano-CB and that it deserves special attention. PMID- 28570876 TI - Novel N-rich porous organic polymers with extremely high uptake for capture and reversible storage of volatile iodine. AB - The imino group-contained porous organic polytriphenylamine, which originated from diphenylamine and 1,3,5-tris(4-bromophenyl)benzene, was designedly synthesized though Buchwald-Hartwig coupling reaction. The basic properties including morphologies, structure and thermal stability of the resulting POPs were investigated by scanning electron microscope(SEM), thermo gravimeter analysis (TGA), 13C CP/MAS solid state NMR and Fourier transform infrared spectroscope (FTIR). The pore size distribution of POPs present uniform mesoporous of sizes less than 50nm. Scanning electron microscope images show that the resulting POPs formed as an aggregation composed of nanospheres. The POPs were employed as a physicochemical stable porous medium for removal of radioactive iodine and an iodine uptake of up to 382wt% was obtained. To our knowledge, this is one of the highest adsorption value reported to date. Based on these findings, the resulting POPs shows great potential in the removal of radioactive iodine at different states, through a green, environmentally friendly, and sustainable way. PMID- 28570877 TI - Quinone-functionalized activated carbon improves the reduction of congo red coupled to the removal of p-cresol in a UASB reactor. AB - In this research was immobilized anthraquinone-2-sulfonate (AQS) on granular activated carbon (GAC) to evaluate its capacity to reduce congo red (CR) in batch reactor and continuous UASB reactors. The removal of p-cresol coupled to the reduction of CR was also evaluated. Results show that the immobilization of AQS on GAC (GAC-AQS) achieved 0.469mmol/g, improving 2.85-times the electron transferring capacity compared to unmodified GAC. In batch, incubations with GAC AQS achieved a rate of decolorization of 2.64-fold higher than the observed with GAC. Decolorization efficiencies in UASB reactor with GAC-AQS were 83.9, 82, and 79.9% for periods I, II, and III; these values were 14.9-22.8% higher than the obtained by reactor with unmodified GAC using glucose as energy source. In the fourth period, glucose and p-cresol were simultaneously fed, increasing the decolorization efficiency to 87% for GAC-AQS and 72% for GAC. Finally, reactors efficiency decreased when p-cresol was the only energy source, but systems gradually recovered the decolorization efficiency up to 84% (GAC-AQS) and 71% (GAC) after 250 d. This study demonstrates the longest and efficient continuous UASB reactor operation for the reduction of electron-accepting contaminant in presence of quinone-functionalized GAC, but also using a recalcitrant pollutant as electron donor. PMID- 28570879 TI - Acute onset of paraganglioma of filum terminale: A case report and surgical treatment. AB - INTRODUCTION: Paragangliomas of filum terminale are rare benign tumors, arising from the adrenal medulla or extra-adrenal paraganglia. These lesions usually present with chronic back pain and radiculopathy and only two cases of acute neurological deficit have been reported in literature. PRESENTATION OF CASE: A case with an acute paraplegia and cauda equina syndrome due to an hemorrhagic paraganglioma of the filum terminale is described. Magnetic resonance imaging showed an intradural tumor extending from L1 to L2 compressing the cauda equina, with an intralesional and intradural bleed. An emergent laminectomy with total removal of the tumor was performed allowing a post-operative partial sensory recovery. Histopathological examination diagnosed paraganglioma. DISCUSSION: Paragangliomas are solid, slow growing tumors arising from specialized neural crest cells, mostly occurring in the head and neck and rarely in cauda equina or filum terminale. MRI is gold standard radiological for diagnosis and follow-up of these lesions. They have no pathognomonic radiological and clinical features and are frequently misdiagnosed as other spinal lesions. No significant correlation was observed between the duration of symptoms and tumor dimension. Acute presentation is unusual and emergent surgical treatment is fondamental. The outcome is very good after complete excision and radiotherapical treatment is recommended after an incomplete resection. CONCLUSION: Early radiological assessment and timely surgery are mandatory to avoid progressive neurological deficits in case of acute clinical manifestation of paraganglioma of filum terminale. PMID- 28570878 TI - Porous chitosan/hydroxyapatite composite membrane for dyes static and dynamic removal from aqueous solution. AB - The unique characteristics of Chitosan (CS) such as resource abundance, good biocompatibility, film-forming ability and sufficient sites (NH2 and OH) for adsorption of heavy metals or organic pollutants make CS-based membranes a promising membrane adsorbent. In this work, a porous Chitosan/Hydroxyapatite (CS/HA) membrane with a sponge-like surface and a three-dimensional interpenetrated porous structure of about mean pore size less than 10MUm was developed. The most striking advantage of the proposed membrane lies on the integration of appreciably high adsorption capacity (as compared with current CS based membranes, also 2.5 times and 4 times higher than that of non-porous CS/HA membrane and the commercially available activate carbon) and the high-speed dynamic dye removal (98% or even better in less than 15min). Besides, the synthesis protocol for the proposed membrane is also much simpler, environmental friendly and economical. Moreover, the proposed membrane also featured repeated dye removal (above 80% after 5 cycles of dynamic adsorption at dye concentration of 150mgL-1). All the above advantages indicated the intriguing potential of the porous membrane in practical wastewater treatment. PMID- 28570880 TI - Giant epidermoid cyst in the breast: A common benign lesion at a rare site-A case report. AB - INTRODUCTION: Epidermoid cyst is a common clinical entity and it can occur anywhere in the body. But its occurrence and huge size in the breast is very rare and more liable to develop complications, including malignant transformation. PRESENTATION OF CASE: We present here an unusual case of a giant epidermoid cyst in the breast, which is about 7cm in greatest dimension. After proper preoperative diagnosis by clinical, imaging and histopathological findings, it was managed by total excision. DISCUSSION: Imaging and fine needle aspiration cytology is essential for accurate preoperative diagnosis. However, it is often very difficult to differentiate it from other benign and malignant conditions of breast. Infection and malignant transformation are its potential complications. Total excision along with its capsule is the treatment of an epidermoid cyst. CONCLUSION: Epidermoid cyst is an important differential diagnosis while managing benign breast disease. PMID- 28570881 TI - Magnetic resonance cholangiopancreatography uncovering massive gallbladder mucocele in a patient with ambiguous clinical and laboratory findings: A case report. AB - INTRODUCTION: Radiological imaging of the gallbladder is a fundamental aspect of assessing severity of acute cholecystitis in addition to guiding the optimal timing of surgical intervention. We present a case of acute severe cholecystitis with massive gallbladder mucocele initially presenting with equivocal and inconclusive clinical, laboratory, and ultrasound findings. Magnetic resonance cholangiopancreatography allowed accurate evaluation of cholelithiasis and demonstrated a massive gallbladder mucocele. CASE PRESENTATION: A 39-year-old Caucasian female presented with mild right upper quadrant pain coupled with intermittent epigastric discomfort after meals. Diagnostic abdominal ultrasound could not reliably detect cystic or common bile duct stones due to patient obesity and meteorism. Computed tomography was contraindicated due to severe contrast allergy. Magnetic resonance cholangiopancreatography allowed timely, accurate evaluation of cholelithiasis. This subsequently demonstrated a massive gallbladder mucocele requiring urgent laparoscopic cholecystectomy. CONCLUSION: Magnetic resonance cholangiopancreatography should be considered as a complementary imaging modality to assess patients presenting with atypical biliary symptoms, particularly when ultrasound is equivocal or inconclusive, clinical and laboratory findings are non-specific, and computer tomography is contraindicated. Magnetic resonance cholangiopancreatography can also be considered in patients with acute cholecystitis not adherent to a specific severity grade. PMID- 28570882 TI - Ileo-ileal intussusception of a sutured enterotomy site, 6days after laparotomy due to fetobezoar: A case report. AB - INTRODUCTION: Postoperative small bowel obstruction due to intussusception is a rare entity but can lead to severe morbidity and even mortality. We present a case of this rare complication produced by an unusual cause. CASE REPORT: A 22year old male, who is a fruitarian, presented to the E.R on day 6 after laparotomy due to obstructing fetobezors that were removed via gastrotomy and enterotomy. In his readmission, he had severe, diffuse abdominal pain, distended abdomen and diffuse peritonitis. Abdominal computed tomography (CT) showed a large amount of fluid in the abdomen, distended small bowel loops, a small amount of free air around the stomach and a suspected ileo-ileal intussusception. The patient underwent emergent laparotomy which revealed an ileo-ileal intussusception with the sutured enterotomy site from the previous operation as the lead point. In addition, a minor dehiscence of the gastrotomy site was identified. A reduction of the intussusception was performed with resection of the enterotomy site and side to side anastomosis. The gastrotomy site was debrided and re-sutured. Recovery was uneventful. CONCLUSION: Postoperative intussusception, although rare, is potentially a dangerous complication, often not involving the site of the primary operation. To our knowledge this is the first report of an intussusception with a sutured enterotomy site as the lead point. Clinicians should be aware of this entity when assessing a patient with abdominal pain and distention after surgery with enterotomy or resection of bowel. PMID- 28570883 TI - Terminal ileostomy and on-table enteroscopy-A case report describing a novel approach for retrieval of foreign bodies in the difficult abdomen. AB - INTRODUCTION: With any abdominal surgery in a difficult abdomen, the procedure is filled with potential hazards. In addition to a prolonged operative time, there is a risk of enterotomy or damage to blood vessels and ureters. An irradiated pelvis increases this risk and may cause additional morbidity such as delayed healing. An impacted foreign body can also be a challenging problem to deal with alone but when combined with a difficult abdomen can make the problem impossible. PRESENTATION OF CASE: A 67 year-old male presented with a small bowel obstruction secondary to a foreign body impacted in the distal. The patient had a history of prostate cancer with radiation to the pelvis and thereafter developed perforated diverticulitis, requiring end colostomy. Later he underwent a colostomy take-down but developed wound infection and dehiscence resulting in an incisional hernia which was repaired. The patient failed conservative management and operative intervention was undertaken. Due to the extensive scarring of his midline abdomen, a right sided transverse incision was used. An enterotomy was made in the terminal ileum allowing the endoscope to advance to the foreign body to be retrieved with a snare. The foreign body was found to be a 3.5cm piece of bone. Post-operative course was unremarkable. DISCUSSION: Foreign body ingestion is a rare cause of small bowel obstruction, and exploration and retrieval is recommended if the obstruction does not resolve or if the bowels perforate. The method of retrieval depends on the site of the foreign body. Fortunately, in the small bowel, the terminal ileum is the narrowest part and most likely the site of impaction. Operative retrieval is easier if there are no prior abdominal interventions. An irradiated pelvis or abdomen, multiple prior procedures and a frozen abdomen warrant an alternative approach. As it can be difficult or impossible to access the ileum using a colonoscope transanally, a limited right sided transverse incision can be employed allowing immediate access to the cecum and terminal ileum through which endoscopic retrieval could be performed. A review of the literature to date did not yield any other descriptions of this approach for foreign body retrieval, however, an appendostomy and endoscopy to rule out malignancy in patients with right sided diverticulitis has been documented. CONCLUSION: Consideration should be given to foreign body retrieval through an appendostomy or ileostomy if a midline laparotomy is considered too high risk in the setting of pelvic irradiation and multiple prior abdominal surgeries. PMID- 28570885 TI - Ex-situ catalytic co-pyrolysis of lignin and polypropylene to upgrade bio-oil quality by microwave heating. AB - Microwave-assisted fast co-pyrolysis of lignin and polypropylene for bio-oil production was conducted using the ex-situ catalysis technology. Effects of catalytic temperature, feedstock/catalyst ratio, and lignin/polypropylene ratio on product distribution and chemical components of bio-oil were investigated. The catalytic temperature of 250 degrees C was the most conducive to bio-oil production in terms of the yield. The bio-oil yield decreased with the addition of catalyst during ex-situ catalytic co-pyrolysis. When the feedstock/catalyst ratio was 2:1, the minimum char and coke values were 21.22% and 1.54%, respectively. The proportion of cycloalkanes decreased and the aromatics increased with the increasing catalyst loading. A positive synergistic effect was observed between lignin and polypropylene. The char yield dramatically deceased and the bio-oil yield improved during co-pyrolysis compared with those during lignin pyrolysis alone. The proportion of oxygenates dramatically and the minimum value of 6.74% was obtained when the lignin/polypropylene ratio was 1:1. PMID- 28570884 TI - Biosurfactant surfactin with pH-regulated emulsification activity for efficient oil separation when used as emulsifier. AB - In the present study, the pH-regulated emulsification activity of surfactin was studied and its potential application in oil separation towards enhanced oil recovery (EOR) was investigated. As demonstrated, surfactin can stabilize emulsions quite well beyond pH 7.4. An oil emulsification ratio of about 98% was obtained at pH 11.0; while this emulsification activity was rapidly and completely lost when pH decreased to below 3.0, having an oil separation ratio of over 98%. This pH-sensitive property is probably due to surfactin dissolution precipitation induced by the ionization-protonation of a carboxyl group in its structure under alkaline or acidic conditions. This property allows oil emulsification or oil separation to be readily achieved via simple pH adjustments when surfactin is used as an emulsifier. Furthermore, surfactin sustained its activity after demulsification and can be readily reused many times. The above obtained results indicated surfactin-based EOR processes have great application feasibility. PMID- 28570886 TI - Regularity and mechanism of wheat straw properties change in ball milling process at cellular scale. AB - To investigate the change of structure and physicochemical properties of wheat straw in ball milling process at cellular scale, a series of wheat straws samples with different milling time were produced using an ultrafine vibration ball mill. A multitechnique approach was used to analyze the variation of wheat straw properties. The results showed that the characteristics of wheat straw powder displayed regular changes as a function of the milling time, i.e., the powder underwent the inversion of breakage to agglomerative regime during wheat straw ball milling process. The crystallinity index, bulk density and water retention capacity of wheat straw were exponential relation with ball milling time. Moreover, ball milling continually converted macromolecules of wheat straw cell wall into water-soluble substances resulting in the water extractives proportional to milling time. PMID- 28570887 TI - Bacterial community shift and incurred performance in response to in situ microbial self-assembly graphene and polarity reversion in microbial fuel cell. AB - In this work, bacterial community shift and incurred performance of graphene modified bioelectrode (GM-BE) in microbial fuel cell (MFC) were illustrated by high throughput sequencing technology and electrochemical analysis. The results showed that Firmicutes occupied 48.75% in graphene modified bioanode (GM-BA), while Proteobacteria occupied 62.99% in graphene modified biocathode (GM-BC), both were dominant bacteria in phylum level respectively. Typical exoelectrogens, including Geobacter, Clostridium, Pseudomonas, Geothrix and Hydrogenophaga, were counted 26.66% and 17.53% in GM-BA and GM-BC. GM-BE was tended to decrease the bacterial diversity and enrich the dominant species. Because of the enrichment of exoelectrogens and excellent electrical conductivity of graphene, the maximum power density of MFC with GM-BA and GM-BC increased 33.1% and 21.6% respectively, and the transfer resistance decreased 83.8% and 73.6% compared with blank bioelectrode. This study aimed to enrich the microbial study in MFC and broaden the development and application for bioelectrode. PMID- 28570889 TI - Hydrochar production from watermelon peel by hydrothermal carbonization. AB - Watermelon peel waste was hydrothermally carbonized under 190 degrees C and 260 degrees C for 1h, 6h, and 12h, respectively. The hydrochar and spent liquor were collected and assayed for their properties. The results indicated that hydrochar yield was 2-5% and 46-95% on fresh and dry matter, respectively. Low temperature (190 degrees C) was conducive to high conversion efficiency. The hydrochar had higher C/N ratio (22.19-26.86), more alkyl C, aryl C, and carbonyl C, but lower H/C (0.98-1.22) and O/C ratios (0.13-0.38), and less O-alky C, carboxylic C, compared with feedstock. So the aliphaticity decreased, whereas aromaticity increased significantly, especially under severe conditions. It should be watchful for that the toxic compounds in hydrochar may induce environmental risk while it is amended into soil. The spent liquor with abundant nutrients could be used as a fertilizer. Further work is required for testing the application in soil. PMID- 28570888 TI - An integrated process to produce bio-ethanol and xylooligosaccharides rich in xylobiose and xylotriose from high ash content waste wheat straw. AB - A bio-refinery process of wheat straw pulping solid residue (waste wheat straw, WWS) was established by combining prewashing and liquid hot water pretreatment (LHWP). The results showed that employing a prewashing step prior to the LHWP remarkably improved enzymatic glucose yields from 39.7% to 76.6%. Moreover, after 96h simultaneous saccharification and fermentation (SSF), identical ethanol yields of 0.41g/g-cellulose were obtained despite varied solid loadings (5-30%). Beyond ethanol, enzymatic post-hydrolysis of the prehydrolyzate effectively increased xylobiose and xylotriose yields from 15mg/g-WWS and 14mg/g-WWS to 53mg/g-WWS and 20mg/g-WWS, respectively. For mass balance, about 10.9tons raw WWS will be consumed to produce 1ton ethanol, in addition to producing 614.8kg xylooligosaccharides (XOS) containing 334.3kg xylobiose and 124.8kg xylotriose. The results demonstrated that the integrated process for the WWS bio-refinery is promising, based on value-adding co-production in addition to robust ethanol yields. PMID- 28570890 TI - Air pollution tolerance index and heavy metal bioaccumulation in selected plant species from urban biotopes. AB - This research was carried out on plants Taraxacum officinale, Plantago lanceolata, Betula pendula and Robinia pseudoacacia growing in urban biotopes with different levels of heavy metal contamination in the city of Dabrowa Gornicza (southern Poland). Based on the pollution index, the highest heavy metal contamination was determined in the site 4 (connected with industry emitters) and 6 (high traffic). The metal accumulation index (MAI) values ranged within the biotopes in Dabrowa Gornicza between 7.3 and 20.6 for R. pseudoacacia, 4.71-23.1 for P. lanceolata, 4.68-28.1 for T. officinale and 10.5-27.2 for B. pendula. Increasing tendency in proline content in biotopes connected with high traffic was found in the leaves of investigated plants (except R. pseudoacacia). Similar tendency was observed for ascorbic acid content in the foliage of the plants as well as in T. officinalle in stands connected industrial emission. Non-protein thiols content increased especially in the leaves of R. pseudoacacia in biotopes with high traffic emissions as well as in T. officinale in stands connected with industry. The mean values of APTI (Air Pollution Tolerance Index) within the city of Dabrowa Gornicza for investigated plants were found in the following ascending order P. lanceolata < R. pseudoacacia < B. pendula < T. officinale. Among the investigated plants B. pendula and T. officinale may be postulated as appropriate plants in urban areas with considerable soil and air contamination, especially with heavy metals. The results indicate that species deemed tolerant according to APTI are suitable plants in barriers areas to combat atmospheric pollution. PMID- 28570891 TI - Silica nanoparticles inhibit macrophage activity and angiogenesis via VEGFR2 mediated MAPK signaling pathway in zebrafish embryos. AB - The safety evaluation of silica nanoparticles (SiNPs) are getting great attention due to its widely-used in food sciences, chemical industry and biomedicine. However, the adverse effect and underlying mechanisms of SiNPs on cardiovascular system, especially on angiogenesis is still unclear. This study was aimed to illuminate the possible mechanisms of SiNPs on angiogenesis in zebrafish transgenic lines, Tg(fli-1:EGFP) and Albino. SiNPs caused the cardiovascular malformations in a dose-dependent manner via intravenous microinjection. The incidences of cardiovascular malformations were observed as: Pericardial edema > Bradycardia > Blood deficiency. The area of subintestinal vessels (SIVs) was significant reduced in SiNPs-treated groups, accompanied with the weaken expression of vascular endothelial cells in zebrafish embryos. Using neutral red staining, the quantitative number of macrophage was declined; whereas macrophage inhibition rate was elevated in a dose-dependent way. Furthermore, SiNPs significantly decreased the mRNA expression of macrophage activity related gene, macrophage migration inhibitory factor (MIF) and the angiogenesis related gene, vascular endothelial growth factor receptor 2 (VEGFR2). The protein levels of p Erk1/2 and p-p38 MAPK were markedly decreased in zebrafish exposed to SiNPs. Our results implicate that SiNPs inhibited the macrophage activity and angiogenesis via the downregulation of MAPK singaling pathway. PMID- 28570892 TI - The genotoxicity and cytotoxicity of tannery effluent in bullfrog (Lithobates catesbeianus). AB - Some of the most polluting activities occur in bovine skin processing. Tannery generates effluents containing high concentrations of heavy metals and organic compounds. The phases composing the leather production process generate a large volume of tannery effluents that are often discarded in aquatic environments without any previous treatment. However, the effect these xenobiotics have on adult representatives belonging to the class Amphibia remains unknown. Thus, the aim of the present study is to assess the geno- and cytotoxic effects of tannery effluent on adult male bullfrogs (Lithobates castesbeianus) exposed to it. Accordingly, the animals were divided into the following groups: negative control (tannery effluent-free water), positive control (cyclophosphamide), and effluent (water added with 5% tannery effluent). The animals were euthanized for blood collection, and erythrocyte analyses were conducted after 35 and 90 days of exposure. The micronuclei (MN) frequency and the frequency of other nuclear abnormalities in each of the animals in the experimental groups were assessed in 2000 erythrocytes. According to the present results, the exposure to tannery effluents increased MN frequency as well as other nuclear abnormalities (i.e., lobed nuclei, binucleated cell, kidney-shaped nuclei, notched nuclei, and apoptotic cell) in the erythrocytes of animals in the effluent group and in the positive control group after 35 and 90 exposure days. Thus, the current study corroborated the hypothesis that the tannery effluent has aneugenic and clastogenic potential in adult male bullfrogs (L. castesbeianus). The present study is the first to report such effect. PMID- 28570893 TI - Dietary Zn and the subsequent organotropism in fish: No influence of food quality, frequency of feeding and environmental conditions (pH and temperature). AB - Trophic transfer of Zn in fish is affected by the type of food and environmental variables such as temperature. However, there is still a lack of knowledge regarding the effects of such factors on Zn organotropism. For this reason, a series of experimental studies have investigated how the distribution and the concentration of Zn is affected by some environmentally-relevant factors (food quality, food availability, water pH, and temperature) in turbot Scophthalmus maximus using radiotracer techniques. In three different experiments, Zn distribution in seven body compartments of juvenile turbot and the calculation of Zn concentration index (IC) for each compartment were compared. Its distribution as well as its concentration in the body compartments of juvenile turbots were not affected by the experimental conditions tested. This apparent consistency in the Zn organotropism can be explained by the ability of the fish to maintain Zn homeostasis at non-toxic Zn concentrations in their diet. These results are important to better understand the trophic transfer of Zn in fish under realistic environmental conditions. PMID- 28570894 TI - Effects of stereoscopic artificial floating wetlands on nekton abundance and biomass in the Yangtze Estuary. AB - Habitat degradation is one of the greatest existing threats to nekton biodiversity in estuarine and coastal habitats. Stereoscopic artificial floating wetlands (SAFWs) can provide new nekton habitats and have been widely used as conservation and management tools in freshwater and marine environments. In the current study, we constructed Phragmites australis SAFWs: the P. australis rhizomes were planted on the artificial floating beds, and palm slices were hung under the floating platforms to act as submerged plants. These SAFWs were anchored in the north channel of the Yangtze Estuary. To determine if SAFWs can serve as fish aggregation devices, fishes and crustaceans were sampled monthly using a bottom lift net during high-tide from July to October 2014. Our assessment was based on environmental parameters, nekton density, nekton species composition and the total length of the three most abundant fishes at the experimental and control sites. Nekton abundance was approximately three times greater in the SAFWs than that in the control habitats (108.2 +/- 27.56 ind./m2 vs. 28.37 +/- 15.88 ind./m2, respectively). There were no significant habitat specific differences in the size distribution of the three most abundant fish species (Acanthogobius ommaturus, Odontamblyopus rubicundus and Eleutheronema tetradactylum) because most of the individuals sampled were juveniles. This study demonstrates that SAFWs can form stable environments for nekton and increase habitat available to juvenile fish. PMID- 28570895 TI - Adsorption of Pb and Zn from binary metal solutions and in the presence of dissolved organic carbon by DTPA-functionalised, silica-coated magnetic nanoparticles. AB - The ability of diethylenetriaminepentaacetic acid (DTPA)-functionalised, silica coated magnetic nanoparticles to adsorb Pb and Zn from single and bi-metallic metal solutions and from solutions containing dissolved organic carbon was assessed. In all experiments 10 mL solutions containing 10 mg of nanoparticles were used. For single metal solutions (10 mg L-1 Pb or Zn) at pH 2 to 8, extraction efficiencies were typically >70%. In bi-metallic experiments, examining the effect of a background of either Zn or Pb (0.025 mmol L-1) on the adsorption of variable concentrations (0-0.045 mmol L-1) of the other metal (Pb or Zn, respectively) adsorption was well modelled by linear isotherms (R2 > 0.60; p <= 0.001) and Pb was preferentially adsorbed relative to Zn. In dissolved organic carbon experiments, the presence of fulvic acid (0, 2.1 and 21 mg DOC L 1) reduced Pb and Zn adsorption from 0.01, 0.1 and 1.0 mmol L-1 solutions. However, even at 21 mg DOC L-1 fulvic acid, extraction efficiencies from 0.01 to 0.1 mmol L-1 solutions remained >80% (Pb) and >50% (Zn). Decreases in extraction efficiency were significant between initial metal concentrations of 0.1 and 1.0 mmol L-1 indicating that at metal loadings between c. 100 mg kg-1 and 300 mg kg-1 occupancy of adsorption sites began to limit further adsorption. The nanoparticles have the potential to perform effectively as metal adsorbents in systems containing more than one metal and dissolved organic carbon at a range of pH values. PMID- 28570896 TI - High-efficiency and mechano-/photo- bi-catalysis of piezoelectric-ZnO@ photoelectric-TiO2 core-shell nanofibers for dye decomposition. AB - A mechano-/photo- bi-catalyst of piezoelectric-ZnO@photoelectric-TiO2 core-shell nanofibers was hydrothermally synthesized for Methyl Orange (10 mg L-1) decomposition. The mechano-/photo- bi-catalysis in ZnO@TiO2 is superior to mechano- or photo-catalysis in decomposing Methyl Orange, which is mainly attributed to the synergy effect of the piezoelectric-ZnO core's mechano catalysis and the thin photoelectric TiO2 shell's photo-catalysis. The heterostructure of the piezoelectric-ZnO@photoelectric-TiO2 core-shell interface, being helpful to reduce electron-hole pair recombination and to separate the piezoelectrically-/photoelectric ally- induced electrons and holes, may also make a great contribution to the enhanced catalysis performance. The mechano-/photo-bi catalysis in ZnO@TiO2 core-shell nanofibers possesses the advantages of high efficiency, non-toxicity and tractability and is potential in utilizing mechanical/solar energy to deal with dye wastewater. PMID- 28570897 TI - Simultaneous selenate reduction and denitrification by a consortium of enriched mine site bacteria. AB - Increasing selenium concentrations in aquatic environments downstream of mine sites is of great concern due to selenium's bioaccumulation propensity and teratogenic toxicity. Removal of selenium from mine influenced water is complicated by the presence of nitrate, which is also elevated in mine influenced water due to the use of explosives in mining. In many biological treatment processes, nitrate as a thermodynamically more preferable electron acceptor inhibits selenate reduction. Here we report on an enrichment of a bacterial assemblage from a mine impacted natural marsh sediment that was capable of simultaneous selenate reduction and denitrification. Selenate reduction followed first order kinetics with respect to the concentration of total dissolved selenium. The kinetic rate constant was independent of initial nitrate concentration over the range 3-143 mg L-1-NO3--N. The initial concentration of selenate inhibited selenate reduction kinetics over the range 1-24 mg-Se L-1. Dominant taxa that grew in selenate only medium were classified in the genera Pseudomonas, Lysinibacillus and Thauera. When nitrate was introduced in addition to selenate, previously rare taxa that became dominant were relatives of Exiguobacterium, Tissierella and Clostridium. Open reading frames (ORFs) associated with dissimilatory denitrification were identified for Pseudomonas, Thauera and Clostridium. In addition, ORFs were found that were homologous with known selenate reductase subunits (SerA and SerB). These findings suggest that native mine site bacteria can be used for removing selenate and nitrate from mine wastewater. PMID- 28570898 TI - Trace elements of concern affecting urban agriculture in industrialized areas: A multivariate approach. AB - The urban and peri-urban soils used for agriculture could be contaminated by atmospheric deposition or industrial releases, thus raising concerns about the potential risk to public health. Here we propose a method to evaluate potential soil pollution based on multivariate statistics, geostatistics (kriging), a novel soil pollution index, and bioavailability assessments. This approach was tested in two districts of a highly populated and industrialized city (Gijon, Spain). The soils showed anomalous content of several trace elements, such as As and Pb (up to 80 and 585 mg kg-1 respectively). In addition, factor analyses associated these elements with anthropogenic activity, whereas other elements were attributed to natural sources. Subsequent clustering also facilitated the differentiation between the northern area studied (only limited Pb pollution found) and the southern area (pattern of coal combustion, including simultaneous anomalies of trace elements and benzo(a)pyrene). A normalized soil pollution index (SPI) was calculated by kriging, using only the elements falling above threshold levels; therefore point-source polluted zones in the northern area and diffuse contamination in the south were identified. In addition, in the six mapping units with the highest SPIs of the fifty studied, we observed low bioavailability for most of the elements that surpassed the threshold levels. However, some anomalies of Pb contents and the pollution fingerprint in the central area of the southern grid call for further site-specific studies. On the whole, the combination of a multivariate (geo) statistic approach and a bioavailability assessment allowed us to efficiently identify sources of contamination and potential risks. PMID- 28570899 TI - Characterisation and potential source identification of polycyclic aromatic hydrocarbons in atmospheric particles (PM10) from urban and suburban residential areas in Shiraz, Iran. AB - Polycyclic aromatic hydrocarbons (PAHs) are a generally hazardous class of organic compounds that are identified as toxic, carcinogenic, mutagenic, and teratogenic, and are considered to be a concern for human health because of their potential for causing adverse health effects. The present study aims to determine the atmospheric concentration and potential sources of particulate-bound PAHs in urban and suburban atmospheric particulate matter (PM10) in Shiraz, Iran. Ambient air samples were collected from urban and suburban areas using a SKC sampling pump equipped with a size-selective air intake during the spring of 2015. The mean PM10 concentration at the urban station (62.73 +/- 23.38 MUg m-3) was higher than that at the suburban station (60.88 +/- 31.03 MUg m-3). The mean (+/-SD) concentrations of the 16 total PAHs in the particulate phase were 19.28 +/- 7.48 ng m-3and 17.80 +/- 9.17 ng m-3 at the urban and suburban stations, respectively. Among different types of PAHs, phenanthrene had the highest concentration in both stations. Various diagnostic ratios have been suggested, which were used in this study for identification of PAHs' sources. The results of these diagnostics showed that in Shiraz, the most dominant sources of PAHs were traffic emissions, especially vehicle emissions and petroleum automobiles emissions. PMID- 28570900 TI - Glutathione biosynthesis plays an important role against 4-tert-octylphenol induced oxidative stress in Ceratophyllum demersum. AB - 4-tert-octylphenol (OP) is a persistent environmental pollutant with an endocrine disrupting property. In the present study, we examined the effect of various concentrations of OP (0, 0.5, 1, 1.5, 2 and 3 mg L-1) applied to an aquatic plant, the submersed macrophyte Ceratophyllum demersum. The toxic effect caused by OP inhibited the plant's growth rate, reduced total chlorophyll content and increased levels of the reactive oxygen species (ROS) O2*- and H2O2. OP treatment significantly increased the activities of antioxidant enzymes including superoxide dismutase, guaiacol peroxidase, glutathione reductase and ascorbate peroxidase. The contents of the non-enzymatic antioxidant glutathione (GSH) and ratio of GSH to glutathione disulfide were markedly increased with OP treatment. Pretreatment with buthionine sulfoximine, a specific and potent inhibitor of GSH biosynthesis, significantly reduced total GSH content and conferred a more severe toxic phenotype on OP exposure. Thus, with OP-induced oxidative stress, C. demersum might actively regulate the antioxidant machinery, especially the biosynthesis and redox state of GSH. PMID- 28570901 TI - Hypoxia exacerbates the cardiotoxic effect of the polycyclic aromatic hydrocarbon, phenanthrene in Danio rerio. AB - The Deepwater Horizon oil spill of 2010 released a mixture of polycyclic aromatic hydrocarbons (PAHs) into the Gulf of Mexico presenting a complex exposure regime for native species. Concurrently, the Gulf has experienced an increase in hypoxic events due to agricultural runoff from the Mississippi River outflow. This combination presents a unique physiological challenge to native species and a challenge for researchers. The purpose of this study was to determine how the cardiotoxic PAH, phenanthrene interacts with hypoxia to affect the cardiovascular system of larval zebrafish (Danio rerio). We exposed zebrafish larvae to 0, 1, 100, and 1000 MUg/L of phenanthrene in combination with normoxia and hypoxia. At late hatching, video of hearts and vessels were used to measure heart rate (fH), stroke volume (SV), cardiac output (Q), red blood cell velocity, and caudal vessel diameter. We found that the highest concentration of phenanthrene caused a 58, 80, and 84% decrease in fH, Q, and arterial red blood cell velocity in normoxia and an 88, 98, and 99% decrease in hypoxia, respectively. Co-exposed larvae also experienced higher rates of edema and lordosis in addition to a 33% increase in mortality rate with co-exposure to hypoxia at the 1000 MUg/L concentration of phenanthrene. At 12 dpf, baseline swimming behavior was similar between treatments indicating partial recovery from embryonic exposure. This study shows that phenanthrene decreases cardiac parameters, most significantly heart rate and that this effect is exacerbated by simultaneous exposure to hypoxia. PMID- 28570902 TI - Bromate formation from the oxidation of bromide in the UV/chlorine process with low pressure and medium pressure UV lamps. AB - When a bromide-containing water is treated by the ultraviolet (UV)/chlorine process, hydroxyl radicals (HO) and halogen radicals such as Cl or Br are formed due to the UV photolysis of free halogens. These reactive species may induce the formation of bromate, which is a probable human carcinogen. Bromate formation in the UV/chlorine process using low pressure (LP) and medium pressure (MP) lamps in the presence of bromide was investigated in the present study. The UV/chlorine process significantly enhanced bromate formation as compared to dark chlorination. The bromate formation was elevated with increasing UV fluence, bromide concentration, and pH values under both LP and MP UV irradiations. It was significantly enhanced at pH 9 compared to those at pH 6 and 7 with MP UV irradiation, while it was slightly enhanced at pH 9 with LP UV. The formation by UV/chlorine process started with the formation of free bromine (HOBr/OBr-) through the reaction of chlorine and bromide, followed by a subsequent oxidation of free bromine and formation of BrO and bromate by reacting with radicals. PMID- 28570903 TI - The stratifying role of job level for sickness absence and the moderating role of gender and occupational gender composition. AB - The study investigates whether sickness absence is stratified by job level - understood as the authority and autonomy a worker holds - beyond the association with education, income, and occupation. A second objective is to establish the moderating role of gender and occupational gender composition on this stratification of sickness absence. Four competing hypotheses are developed that predict different patterns of moderation. Associations between job level and sickness absence are estimated for men and women in three groups of differing occupational gender composition, using data from the German Socio-Economic Panel Study (SOEP). For the purpose of moderation analysis, this study employs a new method based on Bayesian statistics, which enables the testing of complex moderation hypotheses. The data support the hypothesis that the stratification of sickness absence by job level is strongest for occupational minorities, meaning men in female-dominated and women in male-dominated occupations. PMID- 28570904 TI - Dual burden of chronic physical diseases and anxiety/mood disorders among Sao Paulo Megacity Mental Health Survey Sample, Brazil. AB - BACKGROUND: We assessed comorbid associations of 12-month DSM-IV mood/any anxiety disorders with chronic physical conditions within the Sao Paulo (SP) Megacity Mental Health cross-sectional survey of 5037 participants and explored whether strength of comorbid associations were modified when controlling for demographics. METHODS: Chi-square tests and logistic regressions were used to examine comorbid associations of DSM-IV mood/anxiety disorders as measured by the WHO Composite International Diagnostic Interview (CIDI 3.0), and self-reported chronic physical conditions among adults from the SP Megacity Mental Health Survey. RESULTS: Among those with any mood or anxiety disorder, chronic pain disorder was the most common physical condition (48.9% and 44.9%, respectively). Significant unadjusted odds ratios (OR) of comorbidity were found between diagnosis of two or more physical conditions and any mood disorders (3.08, 95% CI: 2.27-4.17), and any anxiety disorders (2.49, 95% CI: 1.95-3.17). Comorbidities remained significant when stratified by gender and controlling for marital status, household income, and education (latter two only included within anxiety models). LIMITATIONS: These results cannot be generalized to other cities or rural populations. Homeless and institutionalized populations were not surveyed. Due to cross-sectional study design, the direction of association between chronic disease/chronic disease risk factors and mood disorders is unclear. CONCLUSIONS: Dual burden of chronic physical conditions and mood/anxiety disorders is a notable problem among the Sao Paulo Megacity Survey population, with enhanced comorbidity experienced by community members with multiple physical conditions. Clinicians should consider these findings in understanding healthcare delivery for individuals suffering from both psychiatric disorders and chronic physical conditions. PMID- 28570905 TI - The role of affective evaluation in conflict adaptation: An LRP study. AB - Conflict between incompatible response tendencies is typically followed by control adjustments aimed at diminishing subsequent conflicts, a phenomenon often called conflict adaptation. Dreisbach and Fischer (2015, 2016) recently proposed that it is not the conflict per se but the aversive quality of a conflict that originally motivates this kind of sequential control adjustment. With the present study we tested the causal role of aversive signals in conflict adaptation in a more direct way. To this end, after each trial of a vertical Simon task participants rated whether they experienced the last trial as rather pleasant or unpleasant. Conflict adaptation was measured via lateralized readiness potentials as a measure of early motor-related activation that were computed on the basis of event-related brain potentials. Results showed the typical suppression of automatic response activation following trials rated as unpleasant, whereas suppression was relaxed following trials rated as pleasant. That is, sequential control adaptation was not based on previous conflict but on the subjective affective experience. This is taken as evidence that negative affect even in the absence of actual conflict triggers subsequent control adjustments. PMID- 28570906 TI - Green synthesis of biogenic silver nanoparticles using Solanum tuberosum extract and their interaction with human serum albumin: Evidence of "corona" formation through a multi-spectroscopic and molecular docking analysis. AB - Biogenic silver nanoparticles (AgNPs) have been synthesized by using Solanum tuberosum (potato) extract (PE) as a reducing as well as stabilizing agent which is reasonably cheaper, non-toxic and easily available material. The green synthesis of silver nanoparticles has been carried out by very simple method and the nanoparticles were characterized by surface plasmon band as well as TEM measurements. The PE-AgNPs were highly dispersed in the solution and found to be spherical with around 10nm in size. Interaction of these nanoparticles was studied with plasma protein HSA by means of various spectroscopies, such as, UV visible, fluorescence, DLS, CD and FTIR spectroscopies. The HSA was found to form the protein "corona" around the starch-capped PE-AgNPs. Absorption spectroscopy revealed that the interaction between HSA and PE-AgNPs resulted in the ground state complex formation. Due to the strong absorption of PE-AgNPs, the inner filter effect was corrected for the fluorescence data. PE-AgNPs were found to quench the fluorescence of HSA with a small blue shift attributed to the increase in the hydrophobicity near tryptophan residue due to the presence of amylopectin and amylose units in the starch. The value of n, Hill's constant, was found to be >1 which determines the existence of a cooperative binding between nanoparticle and albumin. Several parameters such as Stern-Volmer and binding constants in addition to the thermodynamic parameters have been analyzed and discussed which established that the complex formation has taken place via static quenching mechanism and the corona formation between albumin and PE-AgNPs was entropy driven process. Binding of biogenic PE-AgNPs to the HSA slightly affected the secondary structure of latter with a small decrease in alpha-helical contents resulting in the partial unfolding of the protein, though the structural motif remained the same. Molecular docking simulations revealed various possible binding modes between PE-AgNPs and albumin. PMID- 28570908 TI - New insight on the role of melatonin receptors in reproductive processes of seasonal breeders on the example of mature male European bison (Bison bonasus, Linnaeus 1758). AB - Melatonin receptors (MT1 and MT2) were shown to regulate proper functioning of reproductive system, especially in seasonally breeding animals. European bison is a unique endangered seasonal breeder and knowledge of the molecular mechanisms of its reproduction is crucial for the survival of the species. The aim of this study was to assess gene expression, protein synthesis and immunohistochemical localization of MT1 and MT2 receptors in testicular and spermatic cord vessels tissues collected in pre-rut (June) and post-rut (December) seasons from adult male European bisons in Bialowieza National Park. We confirmed the highest expression of MT1 and MT2 mRNA and protein levels in testis in December, while in spermatic cord gene expression was also highest in December, but protein amounts were comparable in both analyzed periods. Furthermore, immunohistochemical staining revealed the same amount of both receptors in arteries and veins of spermatic cord in both periods and increased amounts in December in Leydig, Sertoli and germ cells. The high level of testicular melatonin in December confirms the inhibition of spermatogenesis and increased anti-oxidant and anti inflammatory protection. In spermatic cord vessels, it may prevent from age related changes due to the overexploitation and ensure a constant temperature regardless of changing environmental conditions. This knowledge can contribute to finding a solution of problems associated with male infertility in general and also further explore the mechanisms regulating the proper functions of the male reproductive system. PMID- 28570907 TI - Melanin-gamma rays assistants for bismuth oxide nanoparticles synthesis at room temperature for enhancing antimicrobial, and photocatalytic activity. AB - Melanin pigment has been deemed as a natural photoprotector with strong hydrophobicity. It allured considerable compatibility with many applications in medicine, food, and nanotechnology. Penicillium chrysogenium has been devoted to the green synthesis of melanin whereby optimizing its culture and environmental conditions. The impacts of alternative economic L-tyrosine natural sources (unprecedented alternate origins) and gamma radiation were pledged for the potential growing of the pigment. Herein, notable increases in melanin yield (6.4mg/ml; much higher than nonoptimized one by 40 folds) was obtained by optimizing the culture, and environmental requirements [potato starch (3.0%), yeast extract (5.0%), copper sulfate (0.2mM), 0.25% L-tyrosine, 0.1% L-glycine, and 0.1% Tween 20 at pH5.0, and 30 degrees C for 7.0days using 180.0rpm shaking speed]. The addition of banana's peel (2.0%) has been led to increase the melanin production up to (8.3mg/ml; much higher than optimized one by 1.29 folds). It stimulated the induced enzymes, (i.e., tyrosinase) because it contained significant amounts of L-tyrosine, dopamine, and L-DOPA as resources for melanin biosynthesis. Then irradiated P. chrysogenium (2.5kGy) induced the pigment yield to 10.3mg/ml; much higher than optimized one by (1.61 folds). On the other hand, we tailored a methodology involved the product of melanin and gamma rays (25.0kGy) to an eco-friendly synthesis of Bismuth oxide nanoparticles (BiONPs) at the room temperature. Melanin under such alkaline condition functioning as simultaneously hydrolyzes, photoprotection of the Bi seeds, and stabilizer against the uncontrolled growth and the free radicals attack. Whereas the gamma irradiation induced the room temperature condensation reaction to occur, a novel mechanism proposal was discussed. BiONPs were characterized by UV-Vis., DLS, XRD, SEM, EDX, and FTIR. DLS and XRD calculations with TEM analysis exhibited the mean diameter of BiONPs was 29.82nm. Moreover, the as-prepared BiONPs presented a unique antimicrobial activity against some oral, standard ATCC, and multidrug resistant microbes with ultralow concentrations (0.8MUg/ml). Also, the photocatalytic degradation of Tartrazine dye (TZ), under the UV-Light irradiation, reached 85.0% in 140.0min. Thereby, owing to its unique characteristics such as cost-effective and scalability method with long-term stabilization, nontoxic nature, excellent chemical inertness, biocompatibility and active properties of BiONPs can find possible purposes in the medical, dental, and cosmetic approaches. PMID- 28570909 TI - Raman spectral characteristics of neck and head of femur in low-density lipoprotein receptor gene knockout mice submitted to treadmill aerobic training. AB - Hypercholesterolemia is associated with deterioration of bone tissue. Trough Raman spectroscopy, the present study aimed to assess the molecular changes in terms of mineral and organic bone-tissue remodeling in low-density lipoprotein receptor gene knockout mice (LDLr-/-) submitted to treadmill aerobic training. In order to evaluate alterations in trabecular bone and cartilage surface, neck and head femoral were assessed into four groups: (CON, n=7), the 1) animals did not perform any physical activity and had hypercholesterolemia (CON, n=7); The trained groups where animals underwent a protocols of low, moderate and high training for 8weeks and 4 times per week on a treadmill with progressive intensities: running speed (8-13m/min) and time of exercise (20-60min). These progressive intensities were needed to adjust the working load for the physical training to 2) 30-49% (LOW, n=7), 3) 50-79% (MOD, n=7), and 4) 80-100% (HIGH, n=7) of the maximum running speed. Each group was examined for molecular changes in both bone phases (mineral and organic) using principal components analysis (PCA). All exercised groups showed a significant increase (p<0.05) of bone remodeling in trabecular area and a higher content of proteins (organic content) in cartilage independently of physical activity intensity. Thus, this work demonstrated that physical training could act as a bone-protector factor in hyperlipidemic animal model as well as Raman technique associated with PCA analysis may be feasible methodology for assessment or monitoring of bone at the molecular level. PMID- 28570910 TI - The impact of anticancer activity upon Beta vulgaris extract mediated biosynthesized silver nanoparticles (ag-NPs) against human breast (MCF-7), lung (A549) and pharynx (Hep-2) cancer cell lines. AB - The present study tried for a phyto-synthetic method of producing silver nanoparticles (Ag-NPs) with size controlled as and eco-friendly route that can lead to their advanced production with decorative tranquil morphology. By inducing temperature fluctuation of the reaction mixture from 25 to 80 degrees C the plasmon resonance band raised slowly which had an ultimate effect on size and shape of Ag-NPs as shown by UV-visible spectroscopy and TEM results. The biosynthesized nanoparticles showed good cytotoxic impact against MCF-7, A549 and Hep2 cells compared to normal cell lines. Compared to control plates, the percentage of cell growth inhibition was found to be high with as concentrations of Ag-NPs becomes more as determined by MTT assay. The AO/EtBr staining observations demonstrated that the mechanism of cell death induced by Ag-NPs was due to apoptosis in cancer cells. These present results propose that the silver nanoparticles (Ag-NPs) may be utilized as anticancer agents for the treatment of various cancer types. However, there is a need for study of in vivo examination of these nanoparticles to find their role and mechanism inside human body. Further, studies we plan to do biomarker fabrication from the green synthesized plant extract nanoparticles like silver, gold and copper nanoparticles with optimized shape and sizes and their enhancement of these noble nanoparticles. PMID- 28570912 TI - Current suicidal ideation in treatment-seeking individuals in the United Kingdom with gambling problems. AB - BACKGROUND: Studies show higher lifetime prevalence of suicidality in individuals with pathological gambling. However, less is known about the relationship between pathological gambling and current suicidal ideation. OBJECTIVES: We investigated socio-demographic, clinical and gambling-related variables associated with suicidality in treatment-seeking individuals. METHODS: Bivariate analyses and logistic regression models were generated on data from 903 individuals to identify measures associated with aspects of suicidality. RESULTS: Forty-six percent of patients reported current suicidal ideation. People with current suicidal thoughts were more likely to report greater problem-gambling severity (p<0.001), depression (p<0.001) and anxiety (p<0.001) compared to those without suicidality. Logistic regression models suggested that past suicidal ideation (p<0.001) and higher anxiety (p<0.05) may be predictive factors of current suicidality. CONCLUSIONS: Our findings suggest that the severity of anxiety disorder, along with a lifetime history of suicidal ideation, may help to identify treatment-seeking individuals with pathological gambling with a higher risk of suicidality, highlighting the importance of assessing suicidal ideation in clinical settings. PMID- 28570913 TI - Impulsivity and history of behavioral addictions are associated with drug use in adolescents. AB - BACKGROUND: Previous literature suggests that trait impulsivity and engagement in non-drug-related behavioral addictions (e.g., Internet addiction, food addiction) are two risk factors for drug use. Here we further investigated the potential impact of having one or both of these risk factors on drug use in Los Angeles area adolescents. METHOD: High school students (N=1612; Mean age=14.1) completed self-report surveys measuring two potential risk factors (impulsivity, lifetime history of several behavioral addictions), and past 6-month use of tobacco, alcohol and marijuana. Participants who reported never using drugs completed questionnaires assessing their susceptibility for future use. RESULTS: In general, adolescents who endorsed either impulsivity alone or at least two behavioral addictions alone were more likely to have used tobacco, alcohol, or marijuana compared to individuals who had neither risk factor (OR=2.50-4.13), and individuals who endorsed both impulsivity and three or more behavioral addictions were the most likely to have used these drugs (OR=9.40-10.13). Similarly, among those who had never tried a drug, individuals with this combined set of risk factors were the most likely to be susceptible to future drug use (OR=3.37-5.04). DISCUSSION: These results indicate that the combination of trait impulsivity and a history of behavioral addictions increases the risk for current and future drug use in adolescents, to a greater extent than either risk factor alone. It may be useful for drug prevention efforts to target impulsive adolescents who also actively engage in other non-drug-related addictive behaviors. PMID- 28570911 TI - Binge-drinking and non-partner aggression are associated with gambling among Veterans with recent substance use in VA outpatient treatment. AB - BACKGROUND: Gambling is relatively under-assessed in Veterans Affairs (VA) substance use disorder (SUD) treatment settings, yet shared characteristics with substance addiction suggest the importance of understanding how gambling behaviors present in Veterans seeking SUD care. METHOD: We evaluated substance use, mental health, and violence-related correlates of past 30-day gambling among 833 Veterans (93% male, M age 48years, 72% Caucasian) seeking treatment in VA outpatient mental health and SUD clinics who completed screening for a randomized clinical trial. RESULTS: A total of 288 (35%) Veterans reported past 30-day gambling. Among those who gambled, 79% had cravings/urges to gamble, whereas between 20%-27% of gamblers reported perceived relationship, legal, and daily life problems related to gambling, as well as difficulty controlling gambling. A logistic regression analysis revealed that age, recent binge-drinking, and non partner physical aggression were associated with recent gambling. CONCLUSIONS: Gambling was associated with binge-drinking and non-partner physical aggression, supporting potential shared characteristics among these behaviors such as impulsivity and risk-taking, which may complicate SUD treatment engagement and effectiveness. Findings support the need to screen for gambling in the VA, and to adapt treatments to include gambling as a potential behavioral target or relapse trigger, particularly among heavy drinking patients. PMID- 28570915 TI - Evaluation of uncertainties in lung measurement of actinides due to non-uniform distribution of activity in lungs. AB - Various parameters can introduce uncertainties in the lung activity measurements of actinides. In this study, uncertainties due to non-uniform distribution of activity in the lungs are evaluated. To study the effect of non-uniform distribution, lungs of ICRP male thorax voxel and resized phantoms are divided into upper and lower parts of both right and left lungs as well as into anterior and posterior lung regions. Simulation of uniform and non-uniform distribution of activity in lungs is carried out using thorax voxel phantoms in FLUKA for Phoswich and an array of three HPGe detectors for 18-238keV photons. Source sampling for non-uniform distribution of activity is carried out by selecting the source points by varying the weightage to 0.4, 0.5, 0.6 and 1 in different parts of lungs. Uncertainties in lung activity estimation at different energies are quantified in the form of scattering factors (SFs) which are geometric standard deviations. The SFs due to non-uniform distribution of activity of the order of 0.4-0.6 in different parts of the lungs are found to be ~ 1.25 for Phoswich and HPGe array detectors above 18keV. PMID- 28570914 TI - The health consequences of aerial spraying illicit crops: The case of Colombia. AB - This paper exploits variations in aerial spraying across time and space in Colombia and employs a panel of individual health records in order to study the causal effects of the aerial spraying of herbicides (glyphosate) on short-term health-related outcomes. Our results show that exposure to the herbicide used in aerial spraying campaigns increases the number of medical consultations related to dermatological and respiratory illnesses, as well as the number of miscarriages. These findings are robust to the inclusion of individual fixed effects, which compare the prevalence of these medical conditions for the same person under different levels of exposure to the herbicide used in the aerial spraying program over a period of 5 years. Also, our results are robust to controlling for the extent of illicit coca cultivation in the municipality of residence. PMID- 28570916 TI - Theoretical assessment and targeted modeling of TiO2 in reactor towards the scandium radioisotopes estimation. AB - 47Sc radioisotope with beta particle emission can be used for targeted radionuclide therapy in nuclear medicine and can be produced by nuclear reactor (with high activities) and accelerator. In this work, the specific activity of 47Sc with the isotopic impurities produced through irradiating the enriched 47Tio2 and natural TiO2 targets have been calculated by the MCNPX-2.6 and the TALYS-1.8 codes and also theoretical approach in a fast neutron flux 3*1013ncm-2s 1 in the reactor. In addition, the cross sections of 46Ti(n,p)46Sc reaction have been interpolated in the 1-10MeV energy range and compared with the corresponding experimental data, as well. Moreover, the average cross sections of 46Ti(n,p)46Sc, 47Ti(n,p)47Sc and 48Ti(n,p)48Sc reactions were reproduced. Acceptable agreement between the experimental data and calculated results confirms the ability of the used methods to design and predict the production process in reactor. PMID- 28570917 TI - Improved method for preparing Ni(II) complex of (S)-tyrosine Schiff base and its use in the automated synthesis of O-(2'-[18F]fluoroethyl)-l-tyrosine using solid phase extraction purification. AB - O-(2'-[18F]fluoroethyl)-l-tyrosine is reportedly suitable for PET-imaging of brain tumours. We report here the synthesis of Ni(II)-complex of Schiff's base (S)-[N-2-(N'-benzylprolyl)amino]-benzophenone,((S)BPB) and alkylated l-tyrosine precursor, Ni(II)-(S)-BPB-l-Tyr-O-CH2-CH2-OTs by an improved method. A fully automated radio-synthesis including non-HPLC purification was developed with a radio-chemical yield of 24.6 +/- 2% in 70 +/- 2min (n = 5). Radiochemical and enantiomeric purity was > 98% and 94% respectively. Bio-distribution and micro PET studies in C57BL/6 mice bearing B16F10 melanoma showed tumor to brain ratio of 3.36 and 3.62 respectively at 60min post-injection. PMID- 28570918 TI - Purification of leucocin A for use on wieners to inhibit Listeria monocytogenes in the presence of spoilage organisms. AB - The aims of this study were to improve the method for purification of leucocin A to increase yield of peptide and to evaluate the efficacy of leucocin A and an analogue of leucocin A (leucocin N17L) to inhibit the growth of Listeria monocytogenes on wieners in the presence of spoilage organisms. Leucocin A was produced by Leuconostoc gelidum UAL187 and purified with a five-fold increase in yield; leucocin N17L was synthesized replacing asparagine at residue 17 with leucine. Five strains of L. monocytogenes associated with foodborne illness were used to assess bacteriocin efficacy in vitro and in situ. Minimum inhibitory concentrations could not be determined in broth; however, on agar the minimum inhibitory concentrations ranged from 11.7-62.5MUM and 62.5->500MUM for leucocin A and leucocin N17L, respectively. Leucocin N17L was less effective than the native bacteriocin at controlling the growth of L. monocytogenes. The inactivation profiles of L. monocytogenes in broth in the presence of leucocin A suggested each isolate had different levels of resistance to the bacteriocin as determined by the initial bactericidal effect. The formation of spontaneously resistance subpopulations were also observed for each strain of L. monocytogenes. In situ, wieners were inoculated with the spoilage organisms, Carnobacterium divergens and Brochothrix thermosphacta, followed by surface application of purified leucocin A, and inoculated with a cocktail of L. monocytogenes. Wieners were vacuum packaged and stored at 7 degrees C for 16d. Leucocin A reduced the counts L. monocytogenes on wieners during storage, regardless of the presence of C. divergens. B. thermosphacta was unaffected by the presence of leucocin A on wieners over the duration of storage. This study suggests that leucocin A may be beneficial to industry as a surface application on wieners to help reduce L. monocytogenes counts due to post-processing contamination even in the presence of spoilage organisms. However, further investigation on the ability of L. monocytogenes to form spontaneous resistance to class II bacteriocins on food matrices during prolonged storage is warranted. PMID- 28570919 TI - Calcein represses human papillomavirus 16 E1-E2 mediated DNA replication via blocking their binding to the viral origin of replication. AB - Human papillomaviruses are causative agents in several human diseases ranging from genital warts to ano-genital and oropharyngeal cancers. Currently only symptoms of HPV induced disease are treated; there are no antivirals available that directly target the viral life cycle. Previously, we determined that the cellular protein TopBP1 interacts with the HPV16 replication/transcription factor E2. This E2-TopBP1 interaction is essential for optimal E1-E2 DNA replication and for the viral life cycle. The drug calcein disrupts the interaction of TopBP1 with itself and other host proteins to promote cell death. Here we demonstrate that calcein blocks HPV16 E1-E2 DNA replication via blocking the viral replication complex forming at the origin of replication. This occurs at non toxic levels of calcein and demonstrates specificity as it does not block the ability of E2 to regulate transcription. We propose that calcein or derivatives could be developed as an anti-HPV therapeutic. PMID- 28570920 TI - Body dissatisfaction and associated factors among Brazilian adolescents: A longitudinal study. AB - We conducted a longitudinal investigation of body dissatisfaction in adolescent boys and girls, in order to evaluate the influence of biological, psychological, and sociocultural predictors for body dissatisfaction, and its association with eating disorder symptoms. Validated self-administered scales were selected, thereby assessing the various aspects of body image, symptoms of eating disorders, depression, and self-esteem. Four hundred and ninety-eight adolescents (236 girls) participated in the study. Most of the evaluated outcomes remained stable for over a year. Overall, results pointed to sociocultural influence, as evaluated by SATAQ-3, as the main influencing factor on body dissatisfaction in both boys and girls, with less drastic effects seen for both biological and psychological variables. Body dissatisfaction also predicted symptoms of eating disorders. These results produce longitudinal evidence of the importance of sociocultural influence on body image among Brazilian boys and girls. PMID- 28570921 TI - Airborne gamma-ray spectrometry data processing using 1.5D inversion. AB - Standard processing of Airborne Gamma-Ray Spectrometry data generally gives good results when the measurement conditions are almost constant within several footprint area sizes, with the possible exception of flight height variations in a small range. In practice, deviations, such as large or abrupt changes of flight height and/or rugged terrain are not so rare and lead to certain problems. This article proposes a different approach where the solutions of inverse problems are used for data processing. The approach is quite natural in the processing of field data measured along the flight lines: it explicitly takes into account 1.5D survey models and flight parameters - from topography to sources distribution on the surface. Also, it clearly demonstrates that the inverse problem of the Airborne Gamma-Ray Spectrometry does not have a unique solution. This feature can be used in accordance with the underlying geological problem since various formulations of inverse problems can lead to various geological solutions. The use of the approach is illustrated by several examples given for flight lines and survey areas. This approach can be particularly useful in situations where geological, geophysical and/or geographic survey conditions are far from the standard assumptions. PMID- 28570922 TI - The critical amino acids of a nephritogenic epitope on human Goodpasture autoantigen for binding to HLA-DRB1*1501. AB - BACKGROUND: Anti-GBM disease is caused by autoimmunity to Goodpasture antigen on alpha3(IV)NC1 and had strong associations with HLA-DRB1*1501. Previous studies identified alpha3127-148 (P14: TDIPPCPHGWISLWKGFSFIMF) as a T cell epitope. The present study was aimed to investigate the binding capacity of P14 to HLA DRB1*1501 and the critical amino acids for this binding. METHODS: A line of EBV transformed human B cells homozygous for HLA-DRB1*1501 was used to detect the binding capacity of peptides to HLA-DRB1*1501 using flow cytometry analysis. P14 was sequentially truncated into 8 peptides with 15 amino acids to identify the core binding motif. A set of alanine substituted peptides of P14-2 was then synthesized to identify its critical residues for binding to HLA-DRB1*1501. The structure of HLA-DR2b-Peptide-TCR complex was constructed by modeling to analyze the interaction of each amino acids of P14-2 with the HLA-DR2b molecule. RESULTS: P14 could bind to HLA-DRB1*1501 expressed on B cell surface. The N-terminus of P14 was the core binding motif and the truncated peptide P14-2 (DIPPCPHGWISLWKG) 128-142 had the strongest binding capacity. After sequential amino acid substitution, we found the binding capacity of P14-2 was completely lost by the substitution of cysteine (C) 132 and significantly decreased by the substitution of tryptophan (W) 136, lysine (K) 141, or glycine (G) 142, but still at a high level. The modeling showed that (C) 132 had a strong interaction with pocket 4 on the beta chain of DR2b. Thus, C132, W 136, K141, and G142 were defined as the critical amino acid residues for the binding capacity of P14 to HLA-DRB1*1501. CONCLUSION: We identified alpha3128-142 (DIPPCPHGWISLWKG) as the core binding motif of P14 to HLA-DRB1*1501 molecule. And the critical amino acid residues for this binding were further defined as C132, W 136, K 141, and G 142. PMID- 28570923 TI - 4-Nitrophenol (PNP) inhibits the expression of estrogen receptor beta and disrupts steroidogenesis during the ovarian development in female rats. AB - 4-nitrophenol (PNP), isolated from diesel exhaust particles, has estrogenic and anti-androgenic activities, and affects the hypothalamus-pituitary-gonad axis in male rats. However, the effect of PNP on the reproduction of the female rats is still unknown. The aim of the study was to investigate the effect of neonatal PNP exposure on the ovarian function of female rats. The neonatal female rats were exposed to PNP (10 mg/kg, subcutaneously injection), the ovary and serum samples were collected at postnatal day (PND) 7, 14 and 21. The results showed that the ratio of primordial and primary follicles increased whereas the ratio of antral follicles decreased in the PNP treated ovaries at PND21. Even though no abnormality was observed in cyclicity, there was a significantly delayed timing of vaginal opening in PNP treated rats. The ovarian expression of steroidogenic enzymes including StAR, P450scc, P450c17 and P450arom increased at PND14 in the PNP treated rats compared with the control rats. In consistent with the gene expression, the concentration of estradiol-17beta showed the similar pattern. However, PNP exposure failed to cause any significant change in the expression of steroidogenic enzymes in cultured neonatal ovaries. Furthermore, PNP suppressed the expression of estrogen receptor beta (ERbeta), but not estrogen receptor alpha (ERalpha), in cultured ovaries or developmental ovaries. These results suggested that PNP might directly affect the expression of ERbeta in the rat ovaries, resulting in the disrupted steroidogenesis during ovarian development and the delayed puberty. PMID- 28570924 TI - Effects of SGLT-2 inhibitors on diabetic ketoacidosis: A meta-analysis of randomised controlled trials. AB - AIMS: Diabetic ketoacidosis (DKA) associated with SGLT-2 inhibitors (SGLT-2i) is a possible adverse event. In fact, SGLT-2i are capable of stimulating the release of glucagon and ketone re-absorption in the renal tubuli, thus increasing the concentration of ketone bodies. METHODS: A Medline search for SGLT2i (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, ertugliflozin, luseogliflozin) was performed, collecting all randomized trials with a duration of treatment>=12weeks, enrolling patients with type 2 diabetes, and comparing a SGLT2i with placebo or other comparators. The principal outcome was the effect of SGLT2i on ketoacidosis as serious adverse event. RESULTS: Out of 72 trials reporting information on DKA, 9 reported at least one event of ketoacidosis; those eight trials enrolled 10,157 and 5396 in SGLT-2 inhibitors and comparator groups, respectively. No signal of increased risk for ketoacidosis was observed for SGLT2 inhibitors as a class (MH-OR [95% CI] 1.14 [0.45-2.88], p=0.78) or as individual molecule. The sensitivity analysis with continuity correction (inputing one event each in drug and comparator arms of each trial with zero events) suggested a reduced incidence of ketoacidosis in patients treated with SGLT-2 inhibitors (MH-OR 0.65 [0.47-0.90]; p=0.01). CONCLUSIONS: The results of clinical trials summarized in the present meta-analysis reassure us that, when the drug is properly prescribed, the risk of DKA is negligible. PMID- 28570925 TI - Exploring factors influencing HbA1c and psychosocial outcomes in people with type 1 diabetes after training in advanced carbohydrate counting. AB - AIMS: The purpose of this secondary analysis of the StenoABC Study was to identify determinants of the changes in HbA1c observed after training of people with type 1 diabetes in advanced carbohydrate counting (ACC) and automated bolus calculator (ABC) use, and further to investigate psychosocial effects of these insulin dosing approaches. METHODS: Validated diabetes-specific questionnaires were used to assess diabetes treatment satisfaction, problem areas in diabetes, fear of hypoglycemia and diabetes dependent quality of life before and one year after the training. In addition, numeracy was tested (using a non-validated test developed specifically for this study) and behavioral measures (number of daily blood glucose measurements and self-reported use of ACC) were obtained. Associations between change in HbA1c and these measures plus sex, age, diabetes duration and BMI were tested. RESULTS: Numeracy was the only baseline predictor of yearly change in HbA1c identified. Higher levels of numeracy were associated with greater reductions in HbA1c (P=0.031). No associations between change in HbA1c and the behavioral measures investigated were found, nor were any clinically relevant associations between changes in HbA1c and questionnaire scores. Treatment satisfaction increased in all users of ACC (P<0.001). People who also used an ABC reported significantly lower levels of fear of hypoglycemia than people who practiced ACC without such device (P=0.005). CONCLUSIONS: Improvements in HbA1c after training in ACC were inversely related to numeracy. Use of an ABC did not compensate for poor numeracy skills. However, device use reduced fear of hypoglycemia compared with ACC without ABC use. PMID- 28570926 TI - Predictive utility and measurement properties of the Strength of Implementation Intentions Scale (SIIS) for condom use. AB - BACKGROUND: Implementation intentions are situation-linked action plans that increase health behaviors such as condom use. Few studies have measured the strength of implementation intentions, especially regarding condom use. Non injection drug users are at high risk for HIV due to risky sexual practices. Substance use before sex may increase risky sexual behaviors, and implementation intentions are a promising, practical route for HIV prevention. PURPOSE: This prospective study assessed the measurement properties of the newly developed Strength of Implementation Intentions Scale (SIIS) for condom use and investigated whether the SIIS predicted condom use one-year later. The study evaluated whether behavioral intentions and alcohol or methamphetamine use before sex modified the relationship between the SIIS and condom use. METHODS: Participants were 590 non-injection drug users convicted of nonviolent drug offenses in court-mandated outpatient drug diversion programs. They completed self-directed computer assessments at baseline and at one-year follow-up. Measures included demographics, behavioral intentions to use condoms, the SIIS for condom use, alcohol and methamphetamine use before or during sex, and condom use. Psychometric properties, direct, and interaction effects of the SIIS were evaluated using structural equation modeling and general linear regressions. RESULTS: The SIIS, behavioral intentions, and condom use were positively correlated and there was discriminant validity between all three constructs. In addition, the SIIS predicted condom use one-year later in this high-risk population. No significant interactions were detected. CONCLUSIONS: The SIIS is predictive of condom use behavior, is psychometrically sound and distinct from behavioral intentions, and can be incorporated into HIV prevention interventions and used as a mediator variable. In addition, it can be used as an outcome measure where a follow-up is not feasible. The SIIS can also be tailored for additional HIV-related behaviors such as HIV-testing, adhering to antiretroviral medication, prescribing and adhering to pre-exposure prophylaxis, and other health behaviors. PMID- 28570927 TI - Girl child marriage as a risk factor for early childhood development and stunting. AB - This paper quantitatively examines the intergenerational effects of girl child marriage, or the developmental and health outcomes of children born to women who marry before age 18. The overall objective is to understand the mechanisms through which girl child marriage affects the health and well-being of children in sub-Saharan Africa, as well as the relative magnitude and impact of these mechanisms. We used data from 37,558 mother-child pairs identified through 16 national and sub-national cross-sectional surveys across sub-Saharan Africa conducted between 2010 and 2014 by the UNICEF Multiple Indicator Clusters Survey program. The Early Childhood Development Index was used to measure child development, and stunting was used to measure health. Using logistic regression, we found that the odds of being off-track for development and being stunted were 25% and 29% higher, respectively, for children born to women who married before age 18 compared to those whose mothers married later (p < 0.001). Geographic location and primary education, which were conceptualized as contextual factors, explained most of this relationship, controlling for country fixed-effects. In adjusted models, we found that early childbearing was not the sole pathway through which girl child marriage affected child development and health. Our final models revealed that disparities in advanced maternal education and wealth explained child development and stunting. We conclude that there are intergenerational consequences of girl child marriage on her child's well-being, and that through association with other contextual, socioeconomic, and biological factors, marrying early does matter for child development and health. Our findings resonate with existing literature and point toward important policy considerations for improving early childhood outcomes. PMID- 28570928 TI - Cross-situational word learning in aphasia. AB - Human learners can resolve referential ambiguity and discover the relationships between words and meanings through a cross-situational learning (CSL) strategy. Some people with aphasia (PWA) can learn word-referent pairings under referential uncertainty supported by online feedback. However, it remains unknown whether PWA can learn new words cross-situationally and if such learning ability is supported by statistical learning (SL) mechanisms. The present study examined whether PWA can learn novel word-referent mappings in a CSL task without feedback. We also studied whether CSL is related to SL in PWA and neurologically healthy individuals. We further examined whether aphasia severity, phonological processing and verbal short-term memory (STM) predict CSL in aphasia, and also whether individual differences in verbal STM modulate CSL in healthy older adults. Sixteen people with chronic aphasia underwent a CSL task that involved exposure to a series of individually ambiguous learning trials and a SL task that taps speech segmentation. Their learning ability was compared to 18 older controls and 39 young adults recruited for task validation. CSL in the aphasia group was below the older controls and young adults and took place at a slower rate. Importantly, we found a strong association between SL and CSL performance in all three groups. CSL was modulated by aphasia severity in the aphasia group, and by verbal STM capacity in the older controls. Our findings indicate that some PWA can preserve the ability to learn new word-referent associations cross situationally. We suggest that both PWA and neurologically intact individuals may rely on SL mechanisms to achieve CSL and that verbal STM also influences CSL. These findings contribute to the ongoing debate on the cognitive mechanisms underlying this learning ability. PMID- 28570929 TI - Patterning of the turtle shell. AB - Interest in the origin and evolution of the turtle shell has resulted in a most unlikely clade becoming an important research group for investigating morphological diversity in developmental biology. Many turtles generate a two component shell that nearly surrounds the body in a bony exoskeleton. The ectoderm covering the shell produces epidermal scutes that form a phylogenetically stable pattern. In some lineages, the bones of the shell and their ectodermal covering become reduced or lost, and this is generally associated with different ecological habits. The similarity and diversity of turtles allows research into how changes in development create evolutionary novelty, interacting modules, and adaptive physiology and anatomy. PMID- 28570930 TI - Activation of the semispinalis cervicis and splenius capitis with cervical pulley exercises. AB - STUDY DESIGN: Quasi-Experimental. OBJECTIVE: To assess the activation of semispinalis cervicis (d-SSC) and splenius capitis (s-SC) muscles, and the activation between the two during neck pulley and free weight exercises. BACKGROUND: Altered activation of cervical extensors may occur with neck pain, suggesting that exercises should be designed to target these muscles. METHODS: d SSC and s-SC activity was recorded unilaterally with intramuscular electromyography from healthy volunteers during cervical isometric exercises: 1) extension with a pulley rope angled from incline to vertical, 2) extension with right, left and central forehead hanging weight, and 3) rotation with pulley rope angled from incline to decline. RESULTS: Extension against a vertical force led to greater activation of d-SSC (P < 0.001) and s-SC (P < 0.001) compared to the inclined, declined and horizontal pulley. With each of these conditions, amplitude of muscle activity was higher for the d-SSC compared to the s-SC muscle (P < 0.0001). Extension with free weight hanging on right, left or central forehead, showed no differences across conditions, although in each condition, the d-SSC amplitude was higher than the s-SC. For cervical rotation, the declined pulley led to the greatest activation of both muscles (P < 0.05). Higher levels of activity were observed for the s-SC compared to the d-SSC (P < 0.01) for all rotation conditions. CONCLUSION: A vertical resistance during an extension exercise or a declined resistance during cervical rotation, increased neck extensor activation. The results from this preliminary study provide guidance for future work on the exploration and development of low-load exercise design for patients with neck pain disorders. PMID- 28570931 TI - IL-17A causes depression-like symptoms via NFkappaB and p38MAPK signaling pathways in mice: Implications for psoriasis associated depression. AB - Psoriasis has been shown to be associated with an increased prevalence of comorbid major depression. IL-17A plays an important role in both depression and psoriasis. IL-17A has been shown to be elevated in systemic circulation of psoriatic patients. IL-17A released from different immune cells during psoriasis may be responsible for the development of neuropsychiatric symptoms associated with depression. Therefore, this study explored the association of systemic IL 17A with depression. The present study utilized imiquimod model of psoriatic inflammation as well as IL-17A administration in mice to investigate the effect of IL-17A on depression-like behavior. Psoriatic inflammation led to enhanced IL 17A expression in peripheral immune cells of both innate and adaptive origin. This was associated with increased NFkappaB/p38MAPK signaling and inflammatory mediators in different brain regions, and depression-like symptoms (as reflected by sucrose preference and tail suspension tests). The role of IL-17A was further confirmed by administering it alone for ten days, followed by assessment of the same parameters. IL-17A administration produced effects similar to psoriasis-like inflammation on neurobehavior and NFkappaB/p38MAPK pathways. Moreover, both NFkappaB and p38MAPK inhibitors led to attenuation in IL-17A associated with depression-like behavior via reduction in inflammatory mediators, such as MCP-1, iNOS, IL-6, and CXCL-2. Furthermore, anti-IL17A antibody also led to a reduction in imiquimod-induced depression-like symptoms, as well as NFkappaB/p38MAPK signaling. The present study shows that IL-17A plays an important role in comorbid depression associated with psoriatic inflammation, where both NFkappaB and p38MAPK pathways play significant roles via upregulation of inflammatory mediators in the brain. PMID- 28570932 TI - Cytokines as biomarkers to monitoring the impact of multidrug therapy in immune response of leprosy patients. AB - Leprosy or Hansen's disease is a chronic infectious disease of the skin and nerves, caused by the intracellular bacilli Mycobacterium leprae. It is characterized by a spectrum of clinical forms depending on the host's immune response to M. leprae. Patients with tuberculoid (TT) leprosy have strong cell mediated immunity (CMI) with elimination of the bacilli, whereas patients with lepromatous (LL) leprosy exhibit defective CMI to M. leprae. Despite advances in the understanding of the pathogenesis of leprosy and the development of new therapeutic strategies, there is a need for the identification of biomarkers which be used for early diagnosis and to discrimination between different forms of the disease, as prognostic markers. Here, we analyzed the serum levels of IL 1beta, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IFN-gamma and TNF in order to address the contribution of these cytokines in late phase of M. leprae infection, and the impact of multidrug therapy (MDT). Our results demonstrated that patients of LL group presented higher expression of serum levels of inflammatory cytokines before MDT, while TT patients presented a balance between inflammatory and regulatory cytokines. MDT changes the profile of serum cytokines in M. leprae infected patients, as evidenced by the cytokine network, especially in TT patients. LL patients displayed a multifaceted cytokine system characterized by strong connecting axes involving inflammatory/regulatory molecules, while TT patients showed low involvement of regulatory cytokines in network overall. Cytokines can be identified as good biomarkers of the impact of MDT on the immune system and the effectiveness of treatment. PMID- 28570934 TI - Selective determination of aromatic amino acids by magnetic hydroxylated MWCNTs and MOFs based composite. AB - A novel magnetic solid-phase extraction (MSPE) based method was established for aromatic amino acids (AAAs) selective determination. Central to the method was the adopted extractant. An explored composite of metal organic frameworks (MOFs) and magnetic carbon nanotubes (CNTs) was employed for that, which exhibited superior adsorption affinity and selectivity to AAAs as compared to other amino acids with the mechanisms attributed to multiple hydrogen bonding and pi-pi electron-donor-acceptor (EDA) interactions. The morphology, structure and magnetic behavior of the composite were characterized and related MSPE procedure was established. Critical extraction conditions including pH, extraction time, temperature and salt addition were investigated and optimized. Subsequently the concentrations of three AAAs tryptophan (Trp), tyrosine (Tyr) and phenylalanine (Phe) in Lanzhou lily were determined by the composite based MSPE procedure coupled with high performance liquid chromatography-ultraviolet detection (HPLC UV). The composite provided a superior sample clean-up function and many of the matrix interferences were eliminated, thus ensured AAAs were accurately and efficiently determined. The results showed that the method had good linearities with the linear coefficients above 0.99, desirable recoveries ranged from 88.0% to 96.8% with the RSD less than 5.1%, satisfactory precision and low limits of detection (LODs) which were respectively 0.04, 0.11, and 0.87ng/g for Trp, Tyr and Phe. The composite based MSPE-HPLC-UV method has great potentials for the AAAs selective determination from complex matrix samples. PMID- 28570935 TI - Pharmacokinetics study of Erhuang decoction extracts in rats by HPLC-MS/MS. AB - To study the pharmacokinetics of Erhuang decoction extracts, a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was established for the determination of effective substances in rat plasma. The extracts prepared by water extraction (WE) method were given to rats by oral administration. After collected from the orbital venous plexus, plasma was treated by protein precipitation method. Then, the concentration of index components, including baicalin, liquiritin, berberine, palmatine and glycyrrhetinic acid, were determined by HPLC-MS/MS. Gradient elution mode was used to the chromatographic separation with an Inertsil ODS-SP column (100 mm*2.1mm, 5MUm), with acetonitrile and 0.1% formic acid containing 10mmolL-1 ammonium acetate as the mobile phase. MS analysis was conducted by multiple reactions monitoring (MRM) with Electrospray Ionization (ESI). The extraction recoveries of the five active ingredients from plasma were greater than 86.04%, and the intra- and inter-day precisions were less than 16.57%. Results indicated that active ingredients in plasma of rats with oral administration of extracts showed certain difference in the pharmacokinetic parameters, which proved that the active ingredients were effectively absorbed. The established HPLC-MS/MS analytical method was sensitive and accurate, suitable for the pharmacokinetic study of active ingredients in Erhuang decoction. PMID- 28570936 TI - A UPLC-MS/MS method for the quantitation of Ulipristal acetate in human serum. AB - The progesterone receptor modulator, Ulipristal acetate (UPA) has proven to be an effective emergency contraceptive. Conflicting data has been reported that suggests different efficacy of the drug in different populations, which may be explained by the systemic exposure to the drug. A UPLC-MS/MS method was developed and validated for the accurate and sensitive measurement of UPA in human serum to address this matter. UPA was extracted from human serum using liquid-liquid extraction with a combination of hexane and dichloromethane. An analytical platform comprising reverse-phase chromatographic separation followed by mass spectrometric detection by positive electrospray ionization in multiple reaction monitoring was used for quantitation of UPA within 7min. The method was linear from 0.1 to 250ng/mL. The matrix effect was minimal and intra- and inter-assay precision and accuracy were all within the acceptable limits. UPA was found to be stable at all processing and storage conditions. The method was used to investigate the pharmacokinetics of UPA in a clinical trial designed to explore the effect of obesity on its bioavailability. PMID- 28570937 TI - Recent advancements in supporting materials for immobilised photocatalytic applications in waste water treatment. AB - The aim of this paper is to provide a review on the usage of different anchoring media (supports) for immobilising commonly employed photocatalysts for degradation of organic pollutants. The immobilisation of nano-sized photocatalysts can eliminate costly and impractical post-treatment recovery of spent photocatalysts in largescale operations. Some commonly employed immobilisation aids such as glass, carbonaceous substances, zeolites, clay and ceramics, polymers, cellulosic materials and metallic agents that have been previously discussed by various research groups have been reviewed. The study revealed that factors such as high durability, ease of availability, low density, chemical inertness and mechanical stability are primary factors responsible for the selection of suitable supports for catalysts. Common techniques for immobilisation namely, dip coating, cold plasma discharge, polymer assisted hydrothermal decomposition, RF magnetron sputtering, photoetching, solvent casting, electrophoretic deposition and spray pyrolysis have been discussed in detail. Finally, some common techniques adopted for the characterisation of the catalyst particles and their uses are also discussed. PMID- 28570938 TI - Strategic planning in Brazilian protected areas: Uses and adjustments. AB - Management plans for protected areas commonly use strategic planning tools in their drafting. It is proposed that the adequate use of the instruments of planning and management of protected areas can improve their strategic competitiveness, providing greater financial and administrative independence, enabling them to be economically sustainable organizations. This study evaluated the application of concepts and strategy formulation, strategy principles and competitiveness, organizational diagnosis, strategic maps, scenarios, and other strategic planning instruments used for conservation management in Brazil. 25 management plans of 25 different protected areas were selected and studied, with special attention to the indicators used in each plan. Results indicate that there is a high suitability for the application of SP tools to the universe of protected areas, although management plans did not take full advantage of these tools. We also found that the broader use of these tools did not guarantee greater managerial effectiveness. We suggest that other governance variables beyond planning strategies must be improved, to ensure a better performance of protected areas. PMID- 28570939 TI - Removal of antibiotic sulfamethoxazole by zero-valent iron under oxic and anoxic conditions: Removal mechanisms in acidic, neutral and alkaline solutions. AB - Removal of antibiotic sulfamethoxazole (SMX) by zero-valent iron (ZVI) was examined in the range of pH from 3.0 to 11.0 under oxic and anoxic conditions to clarify mechanisms of SMX removal in acidic, neutral and alkaline solutions. SMX removal was affected by solution pH and related to the speciation of SMX. Under the oxic condition, the maximums of SMX removal efficiency and rate were obtained at pH 3.0. The SMX removal efficiency decreased from 100 to 32% with increasing pH in the acidic solutions (3 ? pH ? 5) and increased to 88% in neutral and moderately alkaline solutions (6 ? pH ? 10). In highly alkaline solution (pH = 11), the SMX removal was significantly suppressed due to the formation of passive layer on ZVI surface. The removal rate of SMX under the oxic condition significantly declined with increasing pH. Under the anoxic condition, SMX removal was completed within 300 min in the acidic solutions and remained to less than 70% after 300 min in neutral and moderately alkaline solutions. For pH ? 10, no SMX removal practically occurred. The removal rate of SMX under the anoxic condition approximately remained constant in the acidic solution and largely decreased in neutral and moderately alkaline solutions. SMX removal by ZVI was found to be dominated by the reductive degradation and adsorption under both the oxic and anoxic conditions. It was concluded that ZVI has the potential for effective removal of antibiotic SMX under the oxic and anoxic conditions. A kinetic model could reasonably simulate the dynamic profiles of SMX removal. PMID- 28570940 TI - Electrochemical sensors for identifying pyocyanin production in clinical Pseudomonas aeruginosa isolates. AB - In clinical practice, delays in obtaining culture results impact patient care and the ability to tailor antibiotic therapy. Despite the advancement of rapid molecular diagnostics, the use of plate cultures inoculated from swab samples continues to be the standard practice in clinical care. Because the inoculation culture process can take between 24 and 48h before a positive identification test can be run, there is an unmet need to develop rapid throughput methods for bacterial identification. Previous work has shown that pyocyanin can be used as a rapid, redox-active biomarker for identifying Pseudomonas aeruginosa in clinical infections. However, further validation is needed to confirm pyocyanin production occurs in all clinical strains of P. aeruginosa. Here, we validate this electrochemical detection strategy using clinical isolates obtained from patients with hospital-acquired infections or with cystic fibrosis. Square-wave voltammetric scans of 94 different clinical P. aeruginosa isolates were taken to measure the concentration of pyocyanin. The results showed that all isolates produced measureable concentrations of pyocyanin with production rates correlated with patient symptoms and comorbidity. Further bioinformatics analysis confirmed that 1649 genetically sequenced strains (99.9%) of P. aeruginosa possess the two genes (PhzM and PhzS) necessary to produce pyocyanin, supporting the specificity of this biomarker. Confirming the production of pyocyanin by all clinically relevant strains of P. aeruginosa is a significant step towards validating this strategy for rapid, point-of-care diagnostics. PMID- 28570933 TI - The Goldilocks model of immune symbiosis with Mycobacteria and Candida colonizers. AB - Mycobacteria and Candida species include significant human pathogens that can cause localized or disseminated infections. Although these organisms may appear to have little in common, several shared pathways of immune recognition and response are important for both control and infection-related pathology. In this article, we compare and contrast the innate and adaptive components of the immune system that pertain to these infections in humans and animal models. We also explore a relatively new concept in the mycobacterial field: biological commensalism. Similar to the well-established model of Candida infection, Mycobacteria species colonize their human hosts in equilibrium with the immune response. Perturbations in the immune response permit the progression to pathologic disease at the expense of the host. Understanding the immune factors required to maintain commensalism may aid with the development of diagnostic and treatment strategies for both categories of pathogens. PMID- 28570942 TI - The change in retinoic acid receptor signaling induced by prenatal marginal vitamin A deficiency and its effects on learning and memory. AB - This study investigated the prenatal marginal vitamin A deficiency (mVAD)-related impairment in learning and memory and the interactions between RARalpha, Src and NR1. Learning and memory were assessed in adult rats that were exposed to prenatal mVAD with Morris water maze. The average escape time was longer in mVAD rats, and they passed the hidden platform fewer times during the memory retention test than normal vitamin A intake (VAN) rats. The mRNA and protein levels of RARalpha, Src and NR1 in mVAD rats were significantly lower than those in VAN rats. RARalpha and Src, but not NR1, were in the same protein complex. RA treatment-induced increase in RARalpha, Src and NR1 expressions in mVAD neurons was much lower than that in VAN neurons. Overexpression of RARalpha gene in VAN neurons induced an increase in RARalpha, Src and NR1 expressions, while silencing of RARalpha gene induced a decrease in expressions of RARalpha and Src, but not that of of NR1. In mVAD neurons, however, overexpression of RARalpha did not induce an increase in NR1 expression, while silencing of RARalpha gene had no effect on Src and NR1 expressions. Furthermore, inhibition of Src was associated with a decrease in NR1 expression but not that of RARalpha. Prenatal mVAD was associated with impaired learning and memory in adult rats. It is possible that mVAD-related decrease in RARalpha led to a decrease in Src expression, which in turn down-regulated NR1 expression and Ca2+ influx and eventually caused learning and memory deficits. PMID- 28570941 TI - Diet-dependent retinoid effects on liver gene expression include stellate and inflammation markers and parallel effects of the nuclear repressor Shp. AB - For mice, a maternal vitamin A (VA)-deficient diet initiated from midgestation (GVAD) produces serum retinol deficiency in mature offspring. We hypothesize that the effects of GVAD arise from preweaning developmental changes. We compare the effect of this GVAD protocol in combination with a postweaning high-fat diet (HFD) or high-carbohydrate diet (LF12). Each is compared to an equivalent VA sufficient combination. GVAD extensively decreased serum retinol and liver retinol, retinyl esters, and retinoid homeostasis genes (Lrat, Cyp26b1 and Cyp26a1). These suppressions were each more effective with LF12 than with HFD. Postweaning initiation of VA deficiency with LF12 depleted liver retinoids, but serum retinol was unaffected. Liver retinoid depletion, therefore, precedes serum attenuation. Maternal LF12 decreased the obesity response to the HFD, which was further decreased by GVAD. LF12 fed to the mother and offspring extensively stimulated genes marking stellate activation (Col1a1, Timp2 and Cyp1b1) and novel inflammation markers (Ly6d, Trem2 and Nupr1). The GVAD with LF12 diet combination suppressed these responses. GVAD in combination with the HFD increased these same clusters. A further set of expression differences on the HFD when compared to a high-carbohydrate diet was prevented when GVAD was combined with HFD. Most of these GVAD gene changes match published effects from deletion of Nr0b2/Shp, a retinoid-responsive, nuclear co-repressor that modulates metabolic homeostasis. The stellate and inflammatory increases seen with the high-carbohydrate LF12 diet may represent postprandial responses. They depend on retinol and Shp, but the regulation reverses with an HFD. PMID- 28570943 TI - alpha-Glucosidase inhibitory effect of resveratrol and piceatannol. AB - Dietary polyphenols have been shown to inhibit alpha-glucosidase, an enzyme target of some antidiabetic drugs. Resveratrol, a polyphenol found in grapes and wine, has been reported to inhibit the activity of yeast alpha-glucosidase. This triggered our interest to synthesize analogs and determine their effect on mammalian alpha-glucosidase activity. Using either sucrose or maltose as substrate resveratrol, piceatannol and 3'-hydroxypterostilbene showed strong inhibition of mammalian alpha-glucosidase activity; pinostilbene, cis desoxyrhapontigenin and trans-desoxyrhapontigenin had moderate inhibition. Compared to acarbose (IC50 3-13 MUg/ml), piceatannol and resveratrol inhibited mammalian alpha-glucosidase to a lesser extent (IC50 14-84 and 111-120 MUg/ml, respectively). 3'-Hydroxypterostilbene (IC50 105-302 MUg/ml) was 23-35-fold less potent than acarbose. We investigated the effect of piceatannol and resveratrol on postprandial blood glucose response in high-fat-fed C57Bl/6 mice. Animals administered resveratrol (30 mg/kg body weight [BW]) or piceatannol (14 mg/kg BW) 60 min prior to sucrose or starch loading had a delayed absorption of carbohydrates, resulting in significant lowering of postprandial blood glucose concentrations, similar to the antidiabetic drug acarbose, while no significant effect was observed with the glucose-loaded animals. Our studies demonstrate that the dietary polyphenols resveratrol and piceatannol lower postprandial hyperglycemia and indicate that inhibition of intestinal alpha-glucosidase activity may be a potential mechanism contributing to their antidiabetic property. PMID- 28570944 TI - Oral feeding with polyunsaturated fatty acids fosters hematopoiesis and thrombopoiesis in healthy and bone marrow-transplanted mice. AB - Hematopoietic stem cells play the vital role of maintaining appropriate levels of cells in blood. Therefore, regulation of their fate is essential for their effective therapeutic use. Here we report the role of polyunsaturated fatty acids (PUFAs) in regulating hematopoiesis which has not been explored well so far. Mice were fed daily for 10 days with n-6/n-3 PUFAs, viz. linoleic acid (LA), arachidonic acid (AA), alpha-linolenic acid and docosahexanoic acid (DHA) in four separate test groups with phosphate-buffered saline fed mice as control set. The bone marrow cells of PUFA-fed mice showed a significantly higher hematopoiesis as assessed using side population, Lin-Sca-1+ckit+, colony-forming unit (CFU), long term culture, CFU-spleen assay and engraftment potential as compared to the control set. Thrombopoiesis was also stimulated in PUFA-fed mice. A combination of DHA and AA was found to be more effective than when either was fed individually. Higher incorporation of PUFAs as well as products of their metabolism was observed in the bone marrow cells of PUFA-fed mice. A stimulation of the Wnt, CXCR4 and Notch1 pathways was observed in PUFA-fed mice. The clinical relevance of this study was evident when bone marrow-transplanted recipient mice, which were fed with PUFAs, showed higher engraftment of donor cells, suggesting that the bone marrow microenvironment may also be stimulated by feeding with PUFAs. These data indicate that oral administration of PUFAs in mice stimulates hematopoiesis and thrombopoiesis and could serve as a valuable supplemental therapy in situations of hematopoietic failure. PMID- 28570945 TI - The impact of short term clinical placement in a developing country on nursing students: A qualitative descriptive study. AB - BACKGROUND: Offering nursing students' international clinical placement during the educational program is one response to meet the need of cultural competence among nurses. This paper provides insight into the impact of clinical placement, in a developing country, on third year nursing students. In the study we investigated how short term international clinical placement impacted Norwegian nursing students' development of cultural competency. DESIGN AND METHODS: In this study we utilised a qualitative descriptive design and used individual interviews with eighteen Norwegian nursing students who had all participated in an international clinical placement. The data were analysed using the principles of systematic text condensation. RESULTS: In spite the international clinical placement only was four weeks, the findings suggested that real life experience culturally awakened the students and forced an ongoing process developing cultural competence. However, it is important to give students time to reflection. CONCLUSIONS: Although increased cultural awareness and a growing cultural competence was identified by the students undertaking international clinical placement, further research is required. It is important to investigate the best methods to support the students' reflection such that the experiences lead to learning. PMID- 28570946 TI - Microfabricated blood vessels undergo neoangiogenesis. AB - The greatest ambition and promise of tissue engineering is to manufacture human organs. Before "made-to-measure" tissues can become a reality [1-3], however, three-dimensional tissues must be reconstructed and characterized. The current inability to manufacture operational vasculature has limited the growth of engineered tissues. Here, free-standing, small diameter blood vessels with organized cell layers that recapitulate normal biological functionality are fabricated using microfluidic technology. Over time in culture, the endothelial cells form a monolayer on the luminal wall and remodel the scaffold with human extracellular matrix proteins. After integration into three-dimensional gels containing fibroblasts, the microvessels sprout and generate extended hollow branches that anastomose with neighboring capillaries to form a network. Both the microfabricated vessels and the extended sprouts support perfusion of fluids and particles. The ability to create cellularized microvessels that can be designed with a diameter of choice, produced by the meter, and undergo angiogenesis and anastomoses will be an extremely valuable tool for vascularization of engineered tissues. To summarize, ultraviolet (UV) photo-crosslinkable poly(ethylene glycol) and gelatin methacrylate polymers used in combination with sheath-flow microfluidics allow for the fabrication of small diameter blood vessels which undergo neoangiogenesis as well as other developmental processes associated with normal human blood vessel maturation. Once mature, these vessels can be embedded; perfused; cryogenically stored and respond to stimuli such as chemokines and shear stresses to mimic native human blood vessels. The applications range from tissue-on-chip systems for drug screening, characterization of normal and pathologic processes, and creation and characterization of engineered tissues for organ repair. PMID- 28570947 TI - Aphasia in vascular lesions of the basal ganglia: A comprehensive review. AB - Between 1970 and 1990, the study of aphasia secondary to subcortical lesions (including the basal ganglia - BG) was largely driven by the advent of modern neuroimaging techniques such as MRI and PET. However, attempts to characterize a pattern of language abnormalities in patients with basal ganglia lesions proved unfruitful. We conducted a comprehensive review of language disturbances after vascular lesions in the BG. Literature search in Medline and LILACS (1966-2016) and PsychINFO (last 25years) was conducted, and returned 145 articles, with 57 eligible for the review yielding data on 303 patients. We report the clinical and neuroimaging features of these cases. Results showed that aphasias caused by BG lesions are heterogeneous with weak clinicoanatomical correlations. Data derived from follow-up and flow/metabolism studies suggest that subcortical aphasia caused by BG lesions involves hypoperfusion in the cortical territories of the middle cerebral/internal carotid arteries (MCA/ICA) and their branches. PMID- 28570951 TI - Dietary Lactobacillus plantarum supplementation enhances growth performance and alleviates aluminum toxicity in tilapia. AB - We investigated the protection offered by the probiotic Lactobacillus plantarum CCFM639 against waterborne Al exposure in tilapia. Fish were allocated to control, CCFM639-only, Al-only or Al plus CCFM639 groups. The fish were exposed to 2.73mg/L Al ions for 4 weeks. The probiotic was incorporated into the fish diet at 108 CFU/g and provided twice daily. Our results showed that L. plantarum CCFM639 significantly enhanced feed utilization, growth performance and antioxidant ability in the absence of waterborne Al exposure. When fish were exposed to Al, dietary supplementation with the strain effectively decreased the death rate and accumulation of Al in tissues, and enhanced growth performance. Moreover, Al-induced changes in hematobiochemical parameters and hepatic oxidative stress and histopathology were also alleviated. Therefore, L. plantarum CCFM639 may be a novel dietary supplement for fish to enhance growth performance and prevent aquaculture and food safety problems induced by Al pollution. PMID- 28570949 TI - Does hypoxia play a role in the development of sarcopenia in humans? Mechanistic insights from the Caudwell Xtreme Everest Expedition. AB - OBJECTIVES: Sarcopenia refers to the involuntary loss of skeletal muscle and is a predictor of physical disability/mortality. Its pathogenesis is poorly understood, although roles for altered hypoxic signaling, oxidative stress, adipokines and inflammatory mediators have been suggested. Sarcopenia also occurs upon exposure to the hypoxia of high altitude. Using data from the Caudwell Xtreme Everest expedition we therefore sought to analyze the extent of hypoxia induced body composition changes and identify putative pathways associated with fat-free mass (FFM) and fat mass (FM) loss. METHODS: After baseline testing in London (75m), 24 investigators ascended from Kathmandu (1300m) to Everest base camp (EBC 5300m) over 13 days. Fourteen investigators climbed above EBC, eight of whom reached the summit (8848m). Assessments were conducted at baseline, during ascent and after one, six and eight week(s) of arrival at EBC. Changes in body composition (FM, FFM, total body water, intra- and extra-cellular water) were measured by bioelectrical impedance. Biomarkers of nitric oxide and oxidative stress were measured together with adipokines, inflammatory, metabolic and vascular markers. RESULTS: Participants lost a substantial, but variable, amount of body weight (7.3+/-4.9kg by expedition end; p<0.001). A progressive loss of both FM and FFM was observed, and after eight weeks, the proportion of FFM loss was 48% greater than FM loss (p<0.008). Changes in protein carbonyls (p<0.001) were associated with a decline in FM whereas 4-hydroxynonenal (p<0.001) and IL-6 (p<0.001) correlated with FFM loss. GLP-1 (r=-0.45, p<0.001) and nitrite (r= 0.29, p<0.001) concentration changes were associated with FFM loss. In a multivariate model, GLP-1, insulin and nitrite were significant predictors of FFM loss while protein carbonyls were predicted FM loss. CONCLUSIONS: The putative role of GLP-1 and nitrite as mediators of the effects of hypoxia on FFM is an intriguing finding. If confirmed, nutritional and pharmacological interventions targeting these pathways may offer new avenues for prevention and treatment of sarcopenia. PMID- 28570950 TI - Cross-kingdom RNA trafficking and environmental RNAi for powerful innovative pre- and post-harvest plant protection. AB - Small RNA (sRNA) induces RNA interference (RNAi) in almost all eukaryotes. While sRNAs can move within an organism, they can also move between interacting organisms to induce gene silencing, a phenomenon called 'cross-kingdom RNAi'. Some sRNAs from pathogens or pests move into host cells and suppress host immunity in both plants and animals; whereas some host sRNAs travel into pathogen/pest cells to inhibit their virulence. Moreover, uptake of exogenous RNAs from the environment was recently discovered in certain fungal pathogens, which makes it possible to suppress fungal diseases by directly applying pathogen targeting RNAs on crops and post-harvest products. This new-generation of RNA based fungicides is powerful, environmentally friendly, and can be easily adapted to control multiple diseases simultaneously. PMID- 28570952 TI - Ecotoxicological evaluation of magnetic ionic liquids. AB - Although magnetic ionic liquids (MILs) are not yet industrially applied, their continued development and eventual commercial use may lead to their appearance into the aquatic ecosystem through accidental spills or effluents, consequently promoting aquatic contaminations. Furthermore, the deficient information and uncertainty surrounding the environmental impact of MILs could be a major barrier to their widespread industrial application and international registration. Thus, in the present work, a range of cholinium salt derivatives with magnetic properties was synthesized and their ecotoxicity was evaluated towards the luminescent bacteria Vibrio fischeri. The results suggest that all MILs structures tested are moderately toxic, or even toxic, to the bacteria. Furthermore, their toxicity is highly dependent on the structural modifications of the cation, namely the alkyl side chain length and the number of hydroxyethyl groups, as well as the atomic number of the metal anion. Finally, from the magnetic anions evaluated, the [MnCl4]2- is the less toxic. In order to improve the knowledge for the prospective design of environmentally safer MILs, it is important to expand this study to other aquatic organisms at different trophic levels. PMID- 28570948 TI - Direct 1O2 optical excitation: A tool for redox biology. AB - Molecular oxygen (O2) displays very interesting properties. Its first excited state, commonly known as singlet oxygen (1O2), is one of the so-called Reactive Oxygen Species (ROS). It has been implicated in many redox processes in biological systems. For many decades its role has been that of a deleterious chemical species, although very positive clinical applications in the Photodynamic Therapy of cancer (PDT) have been reported. More recently, many ROS, and also 1O2, are in the spotlight because of their role in physiological signaling, like cell proliferation or tissue regeneration. However, there are methodological shortcomings to properly assess the role of 1O2 in redox biology with classical generation procedures. In this review the direct optical excitation of O2 to produce 1O2 will be introduced, in order to present its main advantages and drawbacks for biological studies. This photonic approach can provide with many interesting possibilities to understand and put to use ROS in redox signaling and in the biomedical field. PMID- 28570953 TI - Oscillations, neural computations and learning during wake and sleep. AB - Learning and memory theories consider sleep and the reactivation of waking hippocampal neural patterns to be crucial for the long-term consolidation of memories. Here we propose that precisely coordinated representations across brain regions allow the inference and evaluation of causal relationships to train an internal generative model of the world. This training starts during wakefulness and strongly benefits from sleep because its recurring nested oscillations may reflect compositional operations that facilitate a hierarchical processing of information, potentially including behavioral policy evaluations. This suggests that an important function of sleep activity is to provide conditions conducive to general inference, prediction and insight, which contribute to a more robust internal model that underlies generalization and adaptive behavior. PMID- 28570954 TI - Intracellular transport and compartmentation of phosphate in plants. AB - Phosphate (Pi) is an essential macronutrient with structural and metabolic roles within every compartment of the plant cell. Intracellular Pi transporters direct Pi to each organelle and also control its exchange between subcellular compartments thereby providing the means to coordinate compartmented metabolic processes, including glycolysis, photosynthesis, and respiration. In this review we summarize recent advances in the identification and functional analysis of Pi transporters that localize to vacuoles, chloroplasts, non-photosynthetic plastids, mitochondria, and the Golgi apparatus. Electrical potentials across intracellular membranes and the pH of subcellular environments will also be highlighted as key factors influencing the energetics of Pi transport, and therefore pose limits for Pi compartmentation. PMID- 28570955 TI - 1H NMR spectral identification of medication in cerebrospinal fluid of pediatric meningitis. AB - Exploratory metabolomics studies of cerebrospinal fluid (CSF), using proton nuclear magnetic resonance (1H NMR) spectroscopy, hold major potential application in neurodiagnostics. Such studies, however, rely upon established databases of known metabolites. Here we address the 'unknowns' in the 1H NMR spectra of CSF from treated pediatric meningitis cases. Through knowledge of the clinical information given by the pediatrician and analytical application of 1H NMR spectroscopy on pure reference compounds of the medication used, we identified four of the previously unknown compounds in the 1H NMR CSF spectra - the drugs pyrazinamide, isoniazid, acyclovir, and sulfamethoxazole. We report on the one- and two-dimensional 1H NMR spectral data and chemical information of these four compounds. By expanding our knowledge of 1H NMR CSF spectra from treated meningitis cases, we are able to bring 1H NMR closer to the forefront of neurodiagnostics. PMID- 28570956 TI - Worry and risk perception of breast cancer in a prevention trial of low dose tamoxifen in midlife postmenopausal hormone users. AB - OBJECTIVE: There is increasing interest in combining postmenopausal hormone therapy (HT) and SERMs in midlife women. We previously showed that refusal to participate in a prevention trial of low dose tamoxifen in HT users was associated with higher worry about breast cancer. Given this counterintuitive finding, we studied which factors influenced worry and risk perception of breast cancer. METHODS: We assessed the relationships of breast cancer worry and risk perception with age, age at menopause, Gail risk, education, adherence to mammographic screening, BMI, smoking, physical activity, alcohol use, anxiety and depression in 457 midlife HT users who were eligible to participate in the trial. RESULTS: Women with menopause <48 years were more worried about breast cancer than women with menopause >52 years (OR = 5.0, 95% CI, 1.2-21.1). Worry was also associated with high absolute risk perception and former smoking. Factors associated with higher risk perception were age>60 years, at-risk life style, worry about breast cancer and depression. CONCLUSIONS: The inverse association between early menopause and worry about breast cancer is in contrast with the known protective effect of early menopause on breast cancer risk and seems to reflect a feeling of aging and disease vulnerability. Our findings indicate that worry about cancer has an affective construct which is independent of breast cancer biology but is engaged in health decision making. Increasing breast cancer risk awareness in subjects high in worry without a plan of emotional coping may therefore be counterproductive because of avoidant attitudes. PMID- 28570957 TI - Membrane technology costs and me. AB - A reflection of the place cost analysis holds in membrane process technology research and development is provided. The review encompassed two membrane processes and applications: (a) reverse osmosis (RO) for seawater desalination, and (b) membrane bioreactor (MBR) technology for wastewater treatment. The cost analysis undertaken extended to (i) the determination of operating expenditure (OPEX) trends using simple analytical expressions, (ii) the subsequent estimation of the sensitivity of OPEX to individual system parameters, and (iii) published data on CAPEX for individual full-scale installations or from cost analyses. An appraisal of the peer-reviewed literature through a survey of a leading scientific database was also carried out. This bibliometric analysis was based on authors' keywords; it aimed to establish the profile of process cost for each of the two applications when compared with other popular research topics. The OPEX analysis, ostensibly through a consideration of specific energy demand in kWh per m3 permeate, revealed it to relate primarily to hydrodynamics in the case of RO, and to both membrane fouling and air scouring for MBRs. The bibliometric analysis of research trends revealed a marked difference in emphasis on cost aspects between the two research areas, with the focus on cost specifically being 16 times greater for RO desalination of seawater than MBR treatment of wastewater. MBR research appears to be dominated by fouling and foulant characterisation, making up almost a quarter of all studies, notwithstanding evidence from practitioners that other process parameters are as important in determining MBR process OPEX and operability. PMID- 28570958 TI - Interplay between alternatively spliced Tissue Factor and full length Tissue Factor in modulating coagulant activity of endothelial cells. AB - BACKGROUND: Full length Tissue factor (flTF) is a key player in hemostasis and also likely contributes to venous thromboembolism (VTE), the third most common cardiovascular disease. flTF and its minimally coagulant isoform, alternatively spliced TF (asTF), have been detected in thrombi, suggesting participation of both isoforms in thrombogenesis, but data on participation of asTF in hemostasis is lacking. Therefore, we assessed the role of asTF in flTF cofactor activity modulation, using a co-expression system. OBJECTIVE: To investigate the interplay between flTF and asTF in hemostasis on endothelial cell surface. METHODS: Immortalized endothelial (ECRF) cells were adenovirally transduced to express asTF and flTF, after which flTF cofactor activity was measured on cells and microvesicles (MVs). To study co-localization of flTF/asTF proteins, confocal microscopy was performed. Finally, intracellular distribution of flTF was studied in the presence or absence of heightened asTF levels. RESULTS: Levels of flTF antigen and cofactor activity were not affected by asTF co-expression. asTF and flTF were found to localize in distinct subcellular compartments. Only upon heightened overexpression of asTF, lower flTF protein levels and cofactor activity were observed. Heightened asTF levels also induced a shift of flTF from non-raft to lipid raft plasma membrane fractions, and triggered the expression of ER stress marker BiP. Proteasome inhibition resulted in increased asTF - but not flTF - protein expression. CONCLUSION: At moderate levels, asTF appears to have negligible impact on flTF cofactor activity on endothelial cells and MVs; however, at supra-physiological levels, asTF is able to reduce the levels of flTF protein and cofactor activity. PMID- 28570959 TI - Non-survivor septic patients have persistently higher serum sCD40L levels than survivors. AB - INTRODUCTION: Soluble CD40 ligand (sCD40L) is a protein with proinflammatory and prothrombotic effects. Previously we found higher circulating sCD40L levels in non-survivor than in survivor patients at sepsis diagnosis. Now some questions arise such as how are serum sCD40L levels during the first week of severe sepsis?, is there an association between serum sCD40L levels during the first week and mortality?, and serum sCD40L levels during the first week could be used as sepsis mortality biomarker?. This study was developed to answer these asks. METHODS: Study from 6 Spanish Intensive Care Units with 291 severe septic patients. There were determined serum levels of sCD40L and tumor necrosis factor (TNF)-alpha during the first week. The end-point study was 30-day mortality. RESULTS: We found that serum sCD40L at days 1, 4, and 8 could predict mortality at 30days, and are associated with mortality. CONCLUSIONS: The novel findings of our study were that there were higher serum sCD40L levels persistently during the first week in non-survivor than in survivor patients, that there is an association between serum sCD40L levels during the first week and sepsis mortality, and that serum sCD40L levels during the first week could be used as sepsis mortality biomarker. PMID- 28570960 TI - Four phases of the Flint Water Crisis: Evidence from blood lead levels in children. AB - The Flint Water Crisis (FWC) is divisible into four phases of child water-lead exposure risk: Phase A) before the switch in water source to the Flint River (our baseline); Phase B) after the switch in water source, but before boil water advisories; Phase C) after boil water advisories, but before the switch back to the baseline water source of the Detroit Water and Sewerage Department (DWSD); and Phase D) after the switch back to DWSD. The objective of this work is to estimate water-lead attributable movements in child blood lead levels (BLLs) that correspond with the four phases in the FWC. With over 21,000 geo-referenced and time-stamped blood lead samples from children in Genesee County drawn from January 01, 2013 to July 19, 2016, we develop a series of quasi-experimental models to identify the causal effect of water-lead exposure on child BLLs in Flint. We find that the switch in water source (transitioning from phase A to B) caused mean BLLs to increase by about 0.5MUg/dL, and increased the likelihood of a child presenting with a BLL >= 5MUg/dL by a factor of 1.91-3.50, implying an additional 561 children exceeding 5MUg/dL. We conservatively estimate cohort social costs (through lost earnings alone) of this increase in water-lead exposed children at $65 million, contrasted with expected annual savings of $2 million from switching water source. On the switch from Phase B to C, we find BLLs decreased about 50% from their initial rise following boil water advisories and subsequent water avoidance behaviors by households. Finally, the return to the baseline source water (Phase D) returned child BLLs to pre-FWC levels further implicating water-lead exposure as a causal source of child BLLs throughout the FWC. PMID- 28570961 TI - Nonlinear responses to waterborne cadmium exposure in zebrafish. An in vivo study. AB - Cadmium (Cd) has proved to be associated with numerous toxic effects in aquatic organisms via waterborne exposure. With a view to investigate Cd toxicity along a broad spectrum of exposures reaching from environmental to toxic, we employed adult zebrafish (Danio rerio) for an in vivo study. A number of 10 fish per tank were placed in 40L tanks and were exposed for 30 days to 0.0, 5.0, 25, 50, 75, 100 and 1000MUgCd per liter. There were 2 tanks for each Cd exposure (duplicate experiment). Mortality was recorded daily, dead fish were collected and tissue samples were obtained for histologic observation, whereas remaining tissues were stored for Cd burden determination. Surviving fish were collected at the end of the experiment. Median overall survival (OS) in days was found to be 9.0, 11.0, 8.0 and 7.0 for 25MUg/L, 50MUg/L, 75MUg/L and 100MUg/L respectively, with all of them showing mortality greater than 50%. Remarkably, fish exposed to the highest Cd concentration (1000MUg/L) survived the longest exhibiting a mean OS of 29.2 days. Cd determination in fish tissue was conducted with an in house ICP-MS method and levels ranged from 3.1 to 29.1ng/mg. Log Cd tissue levels were significantly correlated with the log Cd exposure levels (r = 0.535, p < 0.001). The highest Cd burden was determined for fish exposed to 1000MUgCd /L (mean = 12.2ng/mg). Histopathology supported these results. Our findings disclose a deviation in toxic responses through the range of Cd concentrations, leading to nonlinear responses. These differentiated responses, could be linked to hormesis phenomena. PMID- 28570962 TI - Climate change policies: The role of democracy and social cognitive capital. AB - The impact of democracy on governments' choice of environmental policies has attracted significant academic attention in recent years. However, less attention has been devoted to the role of the social cognitive capital of the national population. Does society's cognitive capital matter in governmental choice regarding environmental policies, if at all? This study addresses this question through a large-N analysis of 94 countries accounting for the role of both political regimes and social capital in governmental choice of climate change policies. We find that higher social cognitive capital within a democratic state radically increases that state's commitment to adopt environmental policies. More specifically, a 1-point increase in the democracy index is associated with nearly 5 points increase in the adoption of the Climate Laws, Institutions and Measures Index (CLIMI). In a similar vein, a 10 points increase in social cognitive capital is associated with a nearly 16 points increase in CLIMI. The findings presented in this study aim to contribute to the ongoing debate on the impact of democracy and the cognitive capital of society on international environmentalism. The findings will also be interesting for scholars working on the impact of political institutional factors and the role of society in environmental policy choices made at the international level. PMID- 28570963 TI - Fatigue during treatment with antiepileptic drugs: A levetiracetam-specific adverse event? AB - PURPOSE: To examine the prevalence and clinical correlates of fatigue as an adverse event (AE) of antiepileptic drug (AED) treatment in patients with epilepsy. METHODS: Data from 443 adult outpatients with epilepsy assessed with the Adverse Event Profile (AEP) and the Neurological Disorder Depression Inventory for Epilepsy (NDDIE) were analysed. RESULTS: Fatigue is reported by 36.6% of patients as always a problem during AED treatment. Fatigue is more likely to be reported by females (64.8% vs. 35.2%; Chi-Square=16.762; df=3; p=0.001) and during treatment with levetiracetam (42.3% vs. 33.2%; Chi Square=11.462; df=3; p=0.009). The associations with the female gender and levetiracetam treatment were not mediated by depression, as identified with the NDDIE, and could not be simply explained by the large number of subjects on levetiracetam treatment, as analogous figures resulted from the analysis of a monotherapy subsample (41.7% vs. 30.3%; Chi-Square=11.547; df=3; p=0.009). CONCLUSIONS: One third of patients with epilepsy reports fatigue as a significant problem during AED treatment. Fatigue is more likely to be reported by females and seems to be specifically associated with LEV treatment. However, fatigue is not mediated by a negative effect of LEV on mood. PMID- 28570964 TI - Prenatal stress potentiates febrile seizure and leads to long-lasting increase in cortisol blood levels in children under 2years old. AB - Neurological disorders can be exacerbated in an offspring that is exposed to stress prenatally. This study is aimed to investigate the severity of febrile seizures (FS) in the offspring under 2years old that were prenatally stressed. In this study, 158 children below 2years old with FS were selected. Information about convulsion including seizure lasting, recurrence of seizure, age of the first seizure and type of FS was gathered. Blood samples were obtained from the offspring to measure the cortisol blood levels. Questionnaire was filled in to evaluate the perceived stress and exposure or non-exposure to major stresses during pregnancy. Results of this study showed that both high Perceived Stress Scores (PSS) during pregnancy and exposure to major stresses during pregnancy significantly increased seizure duration and seizure intensity. Also, the appearance of complex FS was significantly higher in prenatally stressed children than the unexposed ones. Further, cortisol blood levels were significantly higher in prenatally stressed subjects. It can be concluded that both higher PSS and/or exposure to major stresses during pregnancy potentiate FS parameters and lead to long lasting increase in cortisol blood levels in the offspring. PMID- 28570967 TI - Meta-analysis of radiocesium contamination data in Japanese forest trees over the period 2011-2013. AB - The fate and dispersion of radiocesium in forests affected by the Fukushima atmospheric fallouts have been efficiently characterized by Japanese scientists thanks to monitoring surveys of radioactive contents in contaminated soil, water, and vegetation samples at numerous sites. In this paper, we carry out a meta analysis of the field surveys conducted over the period 2011-2013 in evergreen coniferous and deciduous broadleaf forests of Fukushima or neighboring prefectures. The review focuses on contamination data acquired in tree vegetation - about 1500 spatio-temporal measurements of concentrations, inventories and depuration fluxes - with a particular interest for organs that were directly exposed to the atmospheric fallouts and subjected to depuration mechanisms (foliage, branches and outer bark). To reduce the spatial variability between the sites, radioactive data were normalized by the total deposit estimated at each site. Our analysis highlights the overall consistency of field observations despite the variety of experimental protocols, disparate sampling periods, differences in the forest stand characteristics and variability of the atmospheric deposition conditions. Assuming that the sites conformed to the same dynamics (within the range of residual variability), we then derive, discuss, and compare the mean representative evolutions of radiocesium contamination in the two categories of forest. Thanks to a simple mass balance approach, we finally demonstrate that: (i) about 90% of the radiocesium deposit was intercepted by evergreen coniferous vegetation, (ii) 80% of the deposit was gradually transferred to the forest floor in 3years, according to a well characterized depuration kinetics, and (iii) about 4% was readily absorbed by the foliage and translocated to internal organs (inner bark, stem wood and roots) at a rate of about 10-4d-1. PMID- 28570965 TI - Neurochemical evidence based suggested therapy for safe management of epileptogenesis. AB - Most of the clinically available antiepileptic drugs have only antiseizure effects and are reported unable to prevent epileptogenesis. In the past decade, several drugs underwent clinical trials for management of epileptogenesis, but none of the drugs tested was found effective. One of the major lacunas is availability of appropriate preclinical approaches to delineate mechanisms of epileptogenesis. Thus, the present study attempts to suggest a neurochemistry based approach for safe management of epileptogenesis. The altered neurochemical milieu in amygdala, cortex and hippocampus areas of the mice brain in naive, kindled and kindling resistant animals has been delineated. The endogenous natural antiepileptogenic neurochemical defense mechanism observed in kindling resistant animals may uncover neurochemical mechanisms of epileptogenesis and in turn suggest us novel interventions for safe management of epileptogenesis. The kindling epileptogenesis was carried out in two month old male Swiss albino mice by administering subconvulsive pentylenetetrazole (35mg/kg; i.p.) at an interval of 48+/-2h for 42days. 2h after the last pentylenetetrazole injection, the animals were subjected to behavioral evaluations. Four hours after behavioral evaluation, all animals were euthanized and discrete parts of brain (amygdala, cortex and hippocampus) were harvested for neurochemical analysis. Results revealed that 60% of animals responded to kindling as observed with decreased seizure threshold, while the rest were found resistant. The kindled animals were found to be associated with anxiety, depression and cognitive impairment; while in kindling resistant animals no such behavioral deficits were observed. The neurochemical analysis revealed that in kindled animals altered glutamate-GABA neurotransmission, and decreased taurine, glycine, d-serine, monoamine levels with elevated indoleamine 2,3-dioxygenase activity were observed, which may be convicted for progression of kindling epileptogenesis. However, in kindling resistant animals elevated GABA, taurine, tryptophan, serotonin, glycine, and d serine levels with decreased indoleamine 2,3-dioxygenase activity were observed as natural endogenous antiepileptogenic mechanisms, which may be foreseen as safe pharmacological targets for management of epileptogenesis. PMID- 28570966 TI - Enhancing quality of life among adolescents with bipolar disorder: A randomized trial of two psychosocial interventions. AB - BACKGROUND: Adolescents with bipolar disorder (BD) report lower quality of life (QoL) than adolescents with other psychiatric disorders. This study compared the efficacy of family-focused therapy for adolescents (FFT-A) plus pharmacotherapy to brief psychoeducation (enhanced care, or EC) plus pharmacotherapy on self rated QoL in adolescents with BD over 2 years. METHODS: Participants were 141 adolescents (mean age: 15.6+/-1.4yr) with BD I or II who had a mood episode in the previous 3 months. Adolescents and parents were randomly assigned to (1) FFT A, given in 21 sessions in 9 months of psychoeducation, communication enhancement training, and problem-solving skills training, or (2) EC, given in 3 family psychoeducation sessions. Study psychiatrists provided patient participants with protocol-based pharmacotherapy for the duration of the study. QoL was assessed with The KINDLRQuestionnaire (Ravens-Sieberer and Bullinger, 1998) during active treatment (baseline to 9 months) and during a post-treatment follow-up (9-24 months). RESULTS: The two treatment groups did not differ in overall QoL scores over 24 months. However, adolescents in FFT-A had greater improvements in quality of family relationships and physical well-being than participants in EC. For quality of friendships, the trajectory during active treatment favored EC, whereas the trajectory during post-treatment favored FFT-A. LIMITATIONS: We were unable to standardize medication use or adherence over time. Quality of life was based on self-report rather than on observable functioning. CONCLUSIONS: A short course of family psychoeducation and skills training may enhance relational functioning and health in adolescents with BD. The effects of different psychosocial interventions on peer relationships deserves further study. PMID- 28570968 TI - Sources of nitrogen and phosphorus emissions to Irish rivers and coastal waters: Estimates from a nutrient load apportionment framework. AB - More than half of surface water bodies in Europe are at less than good ecological status according to Water Framework Directive assessments, and diffuse pollution from agriculture remains a major, but not the only, cause of this poor performance. Agri-environmental policy and land management practices have, in many areas, reduced nutrient emissions to water. However, additional measures may be required in Ireland to further decouple the relationship between agricultural productivity and emissions to water, which is of vital importance given on-going agricultural intensification. The Source Load Apportionment Model (SLAM) framework characterises sources of phosphorus (P) and nitrogen (N) emissions to water at a range of scales from sub-catchment to national. The SLAM synthesises land use and physical characteristics to predict emissions from point (wastewater, industry discharges and septic tank systems) and diffuse sources (agriculture, forestry, etc.). The predicted annual nutrient emissions were assessed against monitoring data for 16 major river catchments covering 50% of the area of Ireland. At national scale, results indicate that total average annual emissions to surface water in Ireland are over 2700tyr-1 of P and 82,000tyr-1 of N. The proportional contributions from individual sources show that the main sources of P are from municipal wastewater treatment plants and agriculture, with wide variations across the country related to local anthropogenic pressures and the hydrogeological setting. Agriculture is the main source of N emissions to water across all regions of Ireland. These policy relevant results synthesised large amounts of information in order to identify the dominant sources of nutrients at regional and local scales, contributing to the national nutrient risk assessment of Irish water bodies. PMID- 28570969 TI - Estimation of total CH4 emission from Japanese rice paddies using a new estimation method based on the DNDC-Rice simulation model. AB - Methane (CH4) is a greenhouse gas, and paddy fields are one of its main anthropogenic sources. In Japan, country-specific emission factors (EFs) have been applied since 2003 to estimate national-scale CH4 emission from paddy field. However, these EFs did not consider the effects of factors that influence CH4 emission (e.g., amount of organic C inputs, field drainage rate, climate) and can therefore produce estimates with high uncertainty. To improve the reliability of national-scale estimates, we revised the EFs based on simulations by the DeNitrification-DeComposition-Rice (DNDC-Rice) model in a previous study. Here, we estimated total CH4 emission from paddy fields in Japan from 1990 to 2010 using these revised EFs and databases on independent variables that influence emission (organic C application rate, paddy area, proportions of paddy area for each drainage rate class and water management regime). CH4 emission ranged from 323 to 455ktCyr-1 (1.1 to 2.2 times the range of 206 to 285ktCyr-1 calculated using previous EFs). Although our method may have overestimated CH4 emissions, most of the abovementioned differences were presumably caused by underestimation by the previous method due to a lack of emission data from slow-drainage fields, lower organic C inputs than recent levels, neglect of regional climatic differences, and underestimation of the area of continuously flooded paddies. Our estimate (406ktC in 2000) was higher than that by the IPCC Tier 1 method (305ktC in 2000), presumably because regional variations in CH4 emission rates are not accounted for by the Tier 1 method. PMID- 28570970 TI - Altered humin compositions under organic and inorganic fertilization on an intensively cultivated sandy loam soil. AB - Humin is the most recalcitrant fraction of soil organic matter (SOM). However, little is known about quantitative structural information on humin and the roles of soil mircoorganisms involved in the humin formation. We applied advanced solid state 13C nuclear magnetic resonance (NMR) spectroscopy to provide deep insights into humin structural changes in response to long-term balanced fertilization on a Calcaric Fluvisol in the North China plain. The relationships between humin structure and microbiological properties such as microbial biomass, microbial quotient (qmic) and metabolic quotient (qCO2) were also studied. The humins had a considerable (35-44%) proportion of aromatic C being nonprotonated and the vast majority of O-alkyl and anomeric C being protonated. Alkyl (24-27% of all C), aromatic C (17-28%) and O-alkyl (13-20%) predominated in humins. Long-term fertilization promoted the aliphatic nature of humins, causing increases in O alkyl, anomeric and NCH functional groups and decreases in aromatic C and aromatic CO groups. All these changes were more prominent for treatments of organic fertilizer (OF) and combined mineral NPK fertilizer with OF (NPKOF) relative to the Control and NPK treatments. Fertilization also decreased the alkyl/O-alkyl ratio, aromaticity and hydrophobic characteristics of humins, suggesting a more decomposed and humified state of humin in the Control soil. Moreover, the soil microbiological properties had strong correlations with functional groups of humins. Particularly, microbial biomass C was a relatively sensitive indicator, having positive correlations with oxygen-containing functional groups, i.e., COO/NCO and protonated O-alkyl C, and negative correlations with nonprotonated aromatic C. The qmic and qCO2 were also significantly positively correlated with NCH and aromatic CO, respectively. Our results deepen our understanding of how long-term fertilization impacts the structure of humin, and highlight a linkage between microbiological properties and recalcitrant fraction of SOM besides labile fraction. PMID- 28570971 TI - The impact of land use and spatial mediated processes on the water quality in a river system. AB - River systems are highly complex, hierarchical and patchy systems which are greatly influenced by both catchment surroundings and in-stream processes. Natural and anthropogenic land uses and processes affect water quality (WQ) through different pathways and scales. Understanding under which conditions these different river and catchment properties become dominant towards water chemistry remains a challenge. In this study we analyzed the impact of land use and spatial scales on a range of WQ variables within the Kleine Nete catchment in Belgium. Multivariate statistics and spatial descriptors (Moran's and Asymmetric Eigenvector Maps) were used to assess changes in water chemistry throughout the catchment. Both land use and complex mixes of spatial descriptors of different scales were found to be significantly associated to WQ parameters. However, unidirectional, upstream-downstream changes in water chemistry, often described in river systems, were not found within the Kleine Nete catchment. As different sources and processes obscure and interact with each other, it is generally difficult to understand the correct impact of different pollution sources and the predominant pathways. Our results advocate for WQ management interventions on large and small scales where needed, taking the predominate pathways in to account. PMID- 28570972 TI - Bromine in plastic consumer products - Evidence for the widespread recycling of electronic waste. AB - A range of plastic consumer products and components thereof have been analysed by x-ray fluorescence (XRF) spectrometry in a low density mode for Br as a surrogate for brominated flame retardant (BFR) content. Bromine was detected in about 42% of 267 analyses performed on electronic (and electrical) samples and 18% of 789 analyses performed on non-electronic samples, with respective concentrations ranging from 1.8 to 171,000MUgg-1 and 2.6 to 28,500MUgg-1. Amongst the electronic items, the highest concentrations of Br were encountered in relatively small appliances, many of which predated 2005 (e.g. a fan heater, boiler thermostat and smoke detector, and various rechargers, light bulb collars and printed circuit boards), and usually in association with Sb, a component of antimony oxide flame retardant synergists, and Pb, a heavy metal additive and contaminant. Amongst the non-electronic samples, Br concentrations were highest in items of jewellery, a coffee stirrer, a child's puzzle, a picture frame, and various clothes hangers, Christmas decorations and thermos cup lids, and were often associated with the presence of Sb and Pb. These observations, coupled with the presence of Br at concentrations below those required for flame-retardancy in a wider range of electronic and non-electronic items, are consistent with the widespread recycling of electronic plastic waste. That most Br-contaminated items were black suggests the current and recent demand for black plastics in particular is met, at least partially, through this route. Given many Br-contaminated items would evade the attention of the end-user and recycler, their disposal by conventional municipal means affords a course of BFR entry into the environment and, for food-contact items, a means of exposure to humans. PMID- 28570974 TI - Photodegradation of micropollutants using V-UV/UV-C processes; Triclosan as a model compound. AB - Non-potable reuse of treated wastewater is becoming widespread as means to address growing water scarcity. Removal of micropollutants (MPs) from such water often requires advanced oxidation processes using OH radicals. OH can be generated in-situ via water photolysis under vacuum-UV (lambda<200nm) irradiation. The aim of this study was to investigate the potential of unmasking V-UV radiation from low pressure Hg lamps (emitting at 185 and 254nm), commonly used in decentralized treatment systems, for enhancing MPs removal efficiency. Triclosan, a biocide of limited biodegradability, served as a model compound for MPs that are not very biodegradable. Its degradation kinetics and identification of intermediate products were investigated under 254nm and under combined 254/185nm irradiation both in dry thin films and in aqueous solutions. In the latter, degradation was faster under combined 254/185nm radiation, although the 185nm radiation accounted for only 4% of the total UV light intensity. In contrast, triclosan photodegradation in dry film did not show significant differences between these irradiation wavelengths, suggesting that the enhanced degradation of dissolved triclosan under combined radiation is mainly due to oxidation by OH formed via water photolysis under V-UV. This conclusion was supported by slower TCS degradation in aqueous solution when methanol was added as OH scavenger. Under both irradiation types (254, 254/185nm) three transformation products (TPs) were identified: 2,8-dichlorodibenzo-p-dioxin, 5 chloro-2-(4- or 2-chlorophenoxy)phenol, and 2-hydroxy-8-chlorodibenzodioxin. In silico QSAR toxicity assessment predicted potential toxicity and moderate-to-low biodegradability of these TPs. Removal of these TPs was faster under 254/185nm irradiation. Considering the low cost, simple operation (i.e. no chemicals addition) and small size of such low-pressure mercury lamps, this is a promising direction. Further investigation of the process in flow-through reactors and real wastewater/greywater effluent is needed for its future implementation in small on site systems for post-treatment of persistent pollutants. PMID- 28570973 TI - Costs of coronary heart disease and mortality associated with near-roadway air pollution. AB - BACKGROUND: Emerging evidence indicates that the near-roadway air pollution (NRAP) mixture contributes to CHD, yet few studies have evaluated the associated costs. OBJECTIVE: We integrated an assessment of NRAP-attributable CHD in Southern California with new methods to value the associated mortality and hospitalizations. METHODS: Based on population-weighted residential exposure to NRAP (traffic density, proximity to a major roadway and elemental carbon), we estimated the inflation-adjusted value of NRAP-attributable mortality and costs of hospitalizations that occurred in 2008. We also estimated anticipated costs in 2035 based on projected changes in population and in NRAP exposure associated with California's plans to reduce greenhouse gas emissions. For comparison, we estimated the value of CHD mortality attributable to PM less than 2.5MUm in diameter (PM2.5) in both 2008 and 2035. RESULTS: The value of CHD mortality attributable to NRAP in 2008 was between $3.8 and $11.5 billion, 23% (major roadway proximity) to 68% (traffic density) of the $16.8 billion attributable to regulated regional PM2.5. NRAP-attributable costs were projected to increase to $10.6 to $22 billion in 2035, depending on the NRAP metric. Cost of NRAP attributable hospitalizations for CHD in 2008 was $48.6 million and was projected to increase to $51.4 million in 2035. CONCLUSIONS: We developed an economic framework that can be used to estimate the benefits of regulations to improve air quality. CHD attributable to NRAP has a large economic impact that is expected to increase by 2035, largely due to an aging population. PM2.5-attributable costs may underestimate total value of air pollution-attributable CHD. PMID- 28570976 TI - Assessing climate change impacts on fresh water resources of the Athabasca River Basin, Canada. AB - Proper management of blue and green water resources is important for the sustainability of ecosystems and for the socio-economic development of river basins such as the Athabasca River Basin (ARB) in Canada. For this reason, quantifying climate change impacts on these water resources at a finer temporal and spatial scale is often necessary. In this study, we used a Soil and Water Assessment Tool (SWAT) to assess climate change impacts on fresh water resources, focusing explicitly on the impacts to both blue and green water. We used future climate data generated by the Canadian Center for Climate Modelling and Analysis Regional Climate Model (CanRCM4) with a spatial resolution of 0.22 degrees *0.22 degrees (~25km) for two emission scenarios (RCP 4.5 and 8.5). Results projected the climate of the ARB to be wetter by 21-34% and warmer by 2-5.4 degrees C on an annual time scale. Consequently, the annual average blue and green water flow was projected to increase by 16-54% and 11-34%, respectively, depending on the region, future period, and emission scenario. Furthermore, the annual average green water storage at the boreal region was expected to increase by 30%, while the storage was projected to remain fairly stable or decrease in other regions, especially during the summer season. On average, the fresh water resources in the ARB are likely to increase in the future. However, evidence of temporal and spatial heterogeneity could pose many future challenges to water resource planners and managers. PMID- 28570975 TI - Nutrient dynamics and eutrophication in the Sea of Marmara: Data from recent oceanographic research. AB - This work was implemented to study the physicochemical and biological characteristics of the Sea of Marmara and the Turkish straits (TSS: Bosporus and Dardanelles straits) for the period 2010-2013 and to calculate winter and summer fluxes of nutrients (nitrates, phosphates) between the Aegean and Black Seas through the TSS. The brackish Black Sea waters reach the Dardanelles Strait with modified biochemical properties. The salinity and phosphates of the surface waters increased westwards. Biologically labile nutrients of Black Sea origin are utilized through biological processes in the Marmara Sea. On the other hand, increase of nutrients due to land based sources has led to eutrophication problems in the area. The sub surface water layer of Mediterranean origin is oxygen depleted (saturation<30%) and rich in nutrients. Higher oxygen values indicated water mixing of the Sea of Marmara during winter 2012. Ammonium was the predominant form of inorganic nitrogen. The study area has been classified from Moderate to Bad trophic status. Izmit Bay also faced serious eutrophication problems together with hypoxic conditions below the halocline. Nutrient fluxes through the TSS showed temporal variation in the upper and lower layers related to changes in both nutrient concentrations and the water mass volume fluxes. Surface nitrates and phosphates outflux from the Sea of Marmara to the Aegean Sea was higher than the influx from the Black Sea through Bosporus strait, indicating high enrichment of nutrients in the Sea of Marmara from anthropogenic sources. PMID- 28570977 TI - Design, synthesis and biological evaluation of nitrogen-containing macrocyclic bisbibenzyl derivatives as potent anticancer agents by targeting the lysosome. AB - A series of novel nitrogen-containing macrocyclic bisbibenzyl derivatives was designed, synthesized, and evaluated for antiproliferative activity against three anthropic cancer cell lines. Among these novel molecules, the tri-O-alkylated compound 18a displayed the most potent anticancer activity against the A549, MCF 7, and k562 cancer cell lines, with IC50 values of 0.51, 0.23, and 0.19 MUM, respectively, which were obviously superior to those of the parent compound riccardin D, and were 3-10-fold better than those of the clinical used drug ADR. The bis-Mannich derivative 11b also exhibited significantly enhanced antiproliferative potency, with submicromolar IC50 values. Structure-activity relationship analyses of these newly synthesized compounds were also performed. Mechanistic studies indicated that these compounds could target the lysosome to induce lysosomal membrane permeabilization, and could also induce cell death that displayed features characteristic of both apoptosis and necrosis. PMID- 28570978 TI - Inhibition of long noncoding RNA IGF2AS promotes angiogenesis in type 2 diabetes. AB - BACKGROUND: In this study, the angiogenic effect of long noncoding RNA (lncRNA), insulin growth factor 2 antisense (IGF2AS) in type 2 diabetes was evaluated. METHODS: Between Wistar rat and Goto-Kakizaki (GK) rat, a genetic model of type 2 diabetes, mRNA expressions of IGF2AS and IGF2 in myocardial microvascular endothelial (mMVE) cells were compared by qRT-PCR. In GK mMVE cells, IGF2AS was inhibited by siRNA. Its effects on cell proliferation and invasion were evaluated by MTT and wound-healing assays. Also, changes of IGF2, VEGF and IGF1 in siRNA transfected GK mMVE cells were evaluated by qRT-PCR and western blot. In IGF2AS inhibited GK mMVE cells, IGF2 was further downregulated to evaluate its role in IGF2AS-associated angiogenic regulation, using MTT, wound-healing qRT-PCR and western blot assays, respectively. RESULTS: IGF2AS was upregulated, whereas IGF2 was downregulated, in diabetic GK mMVE cells. IGF2AS inhibition augmented proliferation and invasion in GK mMVE cells. It also upregulated IGF2 and VEGF (not IGF1) at both molecular and protein levels. Conversely, IGF2 downregulation upregulated IGF2AS and reversely inhibited angiogenic effect of IGF2AS inhibition in GK mMVE cells. It also downregulated VEGF but had no effect on IGF1. CONCLUSION: IGF2AS inhibition has angiogenic effect in diabetic GK mMVE cells. The functions of IGF2AS in type 2 diabetes are very likely through the inverse regulation of IGF2, but independent of IGF1. PMID- 28570979 TI - Physcion 8-O-beta-glucopyranoside suppresses tumor growth of Hepatocellular carcinoma by downregulating PIM1. AB - Hepatocellular carcinoma (HCC) presents one of leading causes of cancer-related mortality worldwidely. This study is aimed to investigate the anti-tumor activity of physcion 8-O-beta-glucopyranoside (PG) in HCC. Our results have showed that PG significantly suppresses cell growth and induces apoptosis in vitro and in vivo. At molecular level, PG represses the expression of Pim family kinases 1 (PIM1), which is responsible for the anti-tumor effect of PG in HCC. Ectopic over expression of PIM1 significantly abrogates the suppressing effect of PG on cell growth and inducing effect of PG on apoptosis. In contrast, knockdown of PIM1 by siRNA enhances the anti-tumor effect of PG in HCC cells. PMID- 28570980 TI - Local infiltration of the surgical wounds with levobupivacaine, dexibuprofen, and norepinephrine to reduce postoperative pain: A randomized, vehicle-controlled, and preclinical study. AB - Postoperative pain may lead to poor wound healing, insomnia, and increased postoperative hospitalization. The objective of the study was to explore the effect of local infiltration of the surgical wound with levobupivacaine, dexibuprofen, and norepinephrine in postoperative pain. A randomized, parallel experimental design was applied in 40, 9-11-week-old Wister albino rats. A laparotomy was performed in all groups of 10 rats each. During surgery, the sutured muscle was infiltrated with 40MUL of a normal saline (vehicle group), a normal saline containing 0.25% v/v levobupivacaine, 0.2mg/mL dexibuprofen, and 0.1mg/mL norepinephrine (treatment group) before skin closure. The same combination (negative control group) and a 10-fold higher dose (positive control group) were administered systematically. Rat Grimace Scale scores, based on facial expression, 24h after suturing of the tissues, histopathology and tensile strength of the surgical wound, two weeks after suturing of the tissues were measured. The one-way ANOVA and the two-tailed paired t-test/the Dunnett multiple comparisons test were used to compare the Rat Grimace Scale scores for pain within the group and between groups. The Kruskal-Wallis test and the one-way ANOVA/the Dunnett multiple comparisons test were used to compare the histopathology study and the tensile strength. The difference for statistical analysis was considered significant at the 95% of confidence level. The mean Rat Grimace Scale score at 24h for the treatment, negative control, and positive control groups was 1.945 (p=0.0025; q=3.257), 1.1 (p=0.1), and 1.95 (p=0.0021 q=3.547) respectively. The reduction in postoperative pain started within 1h after the suturing of the tissues in the treatment group. There were significant difference for epidermal and dermal regeneration (p=0.043), granulation tissue thickness (p=0.025), and angiogenesis (p=0.002) between treatment group and vehicle group. Tensile strength for the treatment group was 0.82+/ 0.013N/cm2(p=0.003; q=5.231). The rapid infiltration of surgical wounds with a low-dose levobupivacaine, dexibuprofen, and norepinephrine may reduce postoperative pain and increase the wound regeneration process. PMID- 28570981 TI - Ethyl pyruvate alleviates radiation-induced lung injury in mice. AB - OBJECTIVE: Radiation-induced lung injury (RILI) is a common complication of thoracic cancer radiation therapy. Ethyl pyruvate (EP) was reported to have an ameliorating effect on a variety of systemic inflammation reactions, including acute lung injury. However, the protective effect of EP on RILI has not been explored. MATERIALS/METHODS: RILI was induced by a single thoracic irradiation of 16Gy X-rays in C57BL/6 mice. Mice were divided into four groups: control, radiation, 100mg/kg EP, and 200mg/kg dexamethasone. Inflammation and fibrosis grade of lung tissue were scored by H&E and Masson's trichrome staining. Cytokines include IL-1beta, IL-6, TNF-alpha, GM-CSF, M-CSF, TGF-beta1, and HMGB1 were measured after irradiation. Colony formation assay was performed to determine the protective effect of EP in RAW264.7 and HBE cells. The effect of EP on HMGB1 was also explored in vitro. RESULT: The cytoplasm of bronchial epithelium cells in mice was positive-stained of HMGB1 accompanying with an increase of HMGB1, IL-6, IL-1beta, GM-CSF, M-CSF, TNF-alpha, and TGF-beta1 after irradiation. EP prescription significantly reduced pulmonary inflammation infiltration of RILI, along with a decrease of HMGB1, IL-6, IL-1beta, and GM-CSF at 4 weeks after irradiation. Furthermore, EP decreased radiation-induced collagen deposition at 20 weeks after irradiation. Pro-fibrotic cytokines including TGF-beta1 and HMGB1 in irradiated lung tissue and plasma obviously decreased in EP administration group in the later stage. In vitro, EP administration protected HBE cells from radiation injury. EP also rescued radiation-induced release but not translocation of HMGB1 in RAW264.7 and HBE cells. CONCLUSION: EP treatment ameliorates RILI, including radiation-induced fibrosis in mice. The inhibition of production and release of pro-inflammatory or fibrotic cytokines, especially HMGB1, may partly attribute to its attenuating RILI effect. PMID- 28570982 TI - Synthesis of platinum nanoparticles using seaweed Padina gymnospora and their catalytic activity as PVP/PtNPs nanocomposite towards biological applications. AB - In the recent years, synthesis of nanomaterials using seaweeds and their diverse applications is escalating research in modern era. Among the noble metals, platinum nanoparticles (PtNPs) are of great importance owing to their catalytic property and less toxicity. The significance of this work is a simple one-step synthesis of PtNPs using aqueous extract of Indian brown seaweed Padina gymnospora and their catalytic activity with a polymer Polyvinylpyrrolidone (PVP) as PVP/PtNPs nanocomposite towards antimicrobial, haemolytic, cytotoxic (Artemia salina) and antioxidant properties. Fourier Transform Infrared (FT-IR) spectrum results showed diversified functional groups (biomoeities such as carbohydrates and proteins) present in the seaweed extract is responsible for the reduction of platinum ions (Pt+) to PtNPs. The seaweed mediated PtNPs was characterized by UV vis spectrophotometer, X-ray diffraction (XRD) pattern, Field Emission Scanning Electron Microscopy (FESEM) equipped with Energy Dispersive X-ray (EDX) spectroscopy and High Resolution Transmission Electron Microscopy (HRTEM) analysis. The synthesized PtNPs was found to be truncated octahedral in shape with the range of 5-50nm. Crystalline nature of the nanoparticles was evidenced by Selected Area Electron Diffraction (SAED) pattern with bright circular spots corresponding to (111), (200), (220) and (311) Bragg's reflection planes. The size of the PtNPs was further evidenced by Dynamic Light Scattering (DLS) analysis and it is originate to be stable at -22.5mV through Zeta Potential (ZP) analysis. The present study shows that the catalytic behavior of PtNPs as polymer/metal nanocomposite (PVP/PtNPs) preparation for an antibacterial activity against seven disease causing pathogenic bacterial strains with the maximum activity against Escherichia coli (15.6mm) followed by Lactococcus lactis (14.8mm) and Klebsiella pneumoniae (14.4mm). But no haemolytic activity was seen at their effective bactericidal concentration, whereas increase in the haeomyltic activity was seen only in higher concentrations (600, 900 and 1200MUgmL-1). On the other hand, PVP/PtNPs nanocomposite has shown cytotoxic activity at 100+/ 4MUgmL-1 (LC50) against Artemia salina nauplii. Furthermore, PVP/PtNPs nanocomposite showed an enhanced scavenging activity against 2,2-diphenyl-1 picrylhydrazyl (DPPH), superoxide, nitric oxide and hydroxyl radicals. PMID- 28570983 TI - Gauging the performance of some density functionals including dispersion and nonlocal corrections for relative energies of water 20-mers. AB - Currently, development of density functional theory approximations and their benchmarking for accurately modeling different types of molecular interactions become a very active field of research. In this report, performance of the dispersion (D3) and nonlocal (NL) corrected density functionals has been compared with generalized energy-based fragmentation approach at the complete basis set limit for predicting the relative energies of 10 low-energy isomers of water nanoclusters (H2O)20 as an illustrative example of hydrogen bonded systems. Considering a variety of exchange-correlation density functionals in combination with D3 and NL corrections we find that the D3 based approximations outperform the functionals incorporating NL correction. It is also shown that the LC omegaPBE-D3 and rPW86PBE-NL functionals have the best trend from the viewpoint of the order of stabilities in water nanoclusters under study. PMID- 28570984 TI - In silico identification of vaccine candidates against Klebsiella oxytoca. AB - Klebsiella oxytoca causes several diseases in immunocompromised as well as healthy individuals. Increasing resistance to a number of antibiotics makes treatment options limited. Prevention using vaccine could be an important solution to get rid of infections caused by Klebsiella oxytoca. In recent time, genome based approaches have contributed significantly in vaccine development. Our aim was to identify the most conserved and immunogenic antigens that can be considered as potential vaccine candidates. KEGG database was used to find out pathways unique to the bacteria. Subcellular localization of the protein sequences taken from the selected 36 pathways were predicted using PSORTb v3.0.2 and CELLO v2.5. Prediction of B cell epitope and the probability of the antigenicity were evaluated by using IEDB and Vaxijen respectively. BLASTp was done to find out the similarity of the selected proteins with the human proteome. Proteins failing to comply with the set parameters were filtered at each step. Finally, we identified 6 surface exposed proteins as potential vaccine candidates against Klebsiella oxytoca. PMID- 28570985 TI - Structural, electronic and spectral properties of carborane-containing boron dipyrromethenes (BODIPYs): A first-principles study. AB - In this work, we reported the geometrical structures, electronic and spectral properties of the carborane-containing BODIPYs complexes using the density functional theory calculations. In two structures, the calculated main bond lengths and bond angels of structural framework are consistent with X-ray experiment, and the two BODIPYs complexes are thermodynamically and kinetically stable. The strongest DOS band is mainly dominated by the BB and BH sigma-bonds of carborane fragment, whereas the pi-type MOs on the pyrromethene fragment contribute to the high-energy DOS bands. Analysis of the AdNDP chemical bonding indicates that the carborane cage can be stabilized by eleven delocalized 3c2e and two delocalized 4c2e sigma-bonds, while the pyrromethene fragment corresponds to five delocalized 3c2e pi-bonds. In addition, the main characteristic peaks of the two simulated IR spectra for the BODIPYs complexes are properly assigned. Hopefully, all these results will be helpful for understanding the electronic structures, and further stimulate the study on the biological and medical applications. PMID- 28570986 TI - Effect of the concentration of the dopants (Er3+, Yb3+ and Zn2+) and temperature on the upconversion emission behavior of Er3+/Yb3+ co-doped SrAl2O4 phosphor. AB - Er3+/Yb3+ co-doped SrAl2O4 (SRA: Er3+, Yb3+) phosphor has been synthesized by high temperature solid state reaction technique. The pure phase formation has been confirmed by X-ray diffraction (XRD) measurements. The surface morphology is studied by scanning electron microscopy (SEM) technique. The FTIR measurements give the information of vibrational bands arising due to sample. The intense UC emission from SRA: Er3+, Yb3+ phosphor has been monitored on excitation with 980nm diode laser. The SRA: Er3+, Yb3+ samples prepared at 1473K show a dominant green emission. On the other hand it shows dominant red emission when the sample is heated to 1623K. Variation of concentration of Er3+ and Yb3+ ions in SRA: Er3+, Yb3+ phosphor suggests two possible mechanisms involved in UC emission process viz. cross relaxation (CR) process and energy back transfer (EBT) process, respectively. The cross relaxation mechanism seems to play a major role. The UC emission efficiency is enhanced several times on co-doping of Zn2+ ion replacing Al3+ or Sr2+ in SRA: Er3+, Yb3+ phosphor sample. The color of the UC emission can be tuned from green to red region by varying the concentration of zinc. PMID- 28570987 TI - X-ray Photoelectron Spectroscopic and Raman microscopic investigation of the variscite group minerals: Variscite, strengite, scorodite and mansfieldite. AB - Several structurally related AsO4 and PO4 minerals, were studied with Raman microscopy and X-ray Photoelectron Spectroscopy (XPS). XPS revealed only Fe, As and O for scorodite. The Fe 2p, As 3d, and O 1s indicated one position for Fe2+, while 2 different environments for O and As were observed. The O 1s at 530.3eV and the As 3d 5/2 at 43.7eV belonged to AsO4, while minor bands for O 1s at 531.3eV and As 3d 5/2 at 44.8eV were due to AsO4 groups exposed on the surface possibly forming OH-groups. Mansfieldite showed, besides Al, As and O, a trace of Co. The PO4 equivalent of mansfieldite is variscite. The change in crystal structure replacing As with P resulted in an increase in the binding energy (BE) of the Al 2p by 2.9eV. The substitution of Fe3+ for Al3+ in the structure of strengite resulted in a Fe 2p at 710.8eV. An increase in the Fe 2p BE of 4.8eV was found between mansfieldite and strengite. The scorodite Raman OH-stretching region showed a sharp band at 3513cm-1 and a broad band around 3082cm-1. The spectrum of mansfieldite was like that of scorodite with a sharp band at 3536cm-1 and broader maxima at 3100cm-1 and 2888cm-1. Substituting Al in the arsenate structure instead of Fe resulted in a shift of the metal-OH-stretching mode by 23cm-1 towards higher wavenumbers due to a slightly longer H-bonding in mansfieldite compared to scorodite. The intense band for scorodite at 805cm-1 was ascribed to the symmetric stretching mode of the AsO4. The medium intensity bands at 890, 869, and 830cm-1 were ascribed to the internal modes. A significant shift towards higher wavenumbers was observed for mansfieldite. The strengite Raman spectrum in the 900-1150cm-1 shows a strong band at 981cm-1 accompanied by a series of less intense bands. The 981cm-1 band was assigned to the PO4 symmetric stretching mode, while the weak band at 1116cm-1 was the corresponding antisymmetric stretching mode. The remaining bands at 1009, 1023 and 1035cm-1 were assigned to upsilon1(A1) internal modes in analogy to the interpretation of the AsO4 bands for scorodite and mansfieldite. The variscite spectrum showed a shift towards higher wavenumbers in comparison to the strengite spectrum with the strongest band observed at 1030cm-1 and was assigned to the symmetric stretching mode of the PO4, while the corresponding antisymmetric stretching mode was observed at 1080cm-1. Due to the band splitting component bands were observed at 1059, 1046, 1013 and 940cm-1. The AsO4 symmetric bending modes for scorodite were observed at 381 and 337cm-1, while corresponding antisymmetric bending modes occurred at 424, 449 and 484cm-1. Comparison with other arsenate and phosphate minerals showed that both XPS and Raman spectroscopy are fast and non-destructive techniques to identify these minerals based on their differences in chemistry and the arsenate/phosphate vibrational modes due to changes in the symmetry and the unique fingerprint region of the lattice modes. PMID- 28570988 TI - Photon correlation spectroscopy applied to tear analysis. AB - This study aims to deepen the knowledge on tear film properties by the development of a protocol for analyses of Photon Correlation Spectroscopy (PCS) on human tears and by the comparison between PCS results obtained on tears of contact lens wearers and non-wearers. Tears (5MUL) were collected by a glass capillary. The analyses provide the hydrodynamic diameter of tear components by analyzing intensity fluctuations in time of scattered light. PCS appears a promising technique for studying tear features and for shedding light on specific eye conditions, such as on the clinical effects of CL wear. In fact, statistical difference (p<0.001) was found between the measured mean hydrodynamic diameter of tear components of wearers and non-wearers, the resulting value significantly higher for CL wearers. The scenario does not substantially change after (25+/ 5)min from the CL removal. The difference is attributed to changes in the interactions between tear constituents due to CL wear. In order to get deeper insights on the influence of CL wear on aggregation and structure of tear components, a preliminary Electron Spin Resonance (ESR) investigation was performed, monitoring Fe3+ species. ESR spectra on tears of both CL wearers and non-wearers showed the presence of intense signals, probably associated to iron (III) centers in proteins such as lactoferrin, and a weaker resonance attributable to Fe3+ species interacting with S-S bridges of lysozyme. Differences in ESR spectra between CL wearers and non-wearers were detected and tentatively ascribed to changes in coordination or in local environment of Fe3+ centers connected to aggregation phenomena induced by CL wear, which promote their interaction with other neighboring iron species. PMID- 28570989 TI - Quick and sensitive SPR detection of prion disease-associated isoform (PrPSc) based on its self-assembling behavior on bare gold film and specific interactions with aptamer-graphene oxide (AGO). AB - Herein, we constructed a novel sandwich surface plasmon resonance (SPR) detection assay for sensitive prion disease-associated isoform (PrPSc) detection, utilizing bare gold film and apatamer-graphene oxide (AGO). Due to the self-assembling behavior of PrPSc on gold surface, the non-modified gold surface can be directly used as sensing surface for the quick detection, for the purpose to avoid the interference from the traditional, complex and changeable probe-modified sensing surface. And due to the highly specific affinity of AGO towards PrPSc, the sandwich type SPR sensor exhibits excellent analytical performance towards the discrimination and quantitation of PrPSc. A good linear relationship was obtained between SPR responses and the logarithm of PrPSc concentrations over a range of 0.001-1ng/mL. The detection sensitivity for PrPSc was improved by ~156 orders of AGO compared with SPR direct detection format. Besides, morphological changes of the sensing film surfaces were investigated by high resolution AFM imaging, confirming the capture of PrPSc molecules and their further specific recognition by AGO. The specificity of the present biosensor was also investigated by PrPC and other regents as controls. By compared with other reported methods, the AGO enhanced sandwich SPR assay was confirmed to be efficient, sensitive, and with wide working range. PMID- 28570990 TI - Preparation for workplace adversity: Student narratives as a stimulus for learning. AB - Nursing students are not always well prepared for the kind of adverse events they may experience in the workplace and yet it seems apparent that future students could benefit from learning about such experiences so that they can be avoided, or their impact minimised. This research aimed to identify nursing students' experiences of adversity, collaborate with students to discern important lessons for future students in their experiences, and make recommendations for other educators on how to use these adversity stories as lessons. Seven Australian nursing students were interviewed using critical incident technique consisting of 7 questions. This paper focuses on the responses to the questions: "Does this story's message have a place in the curriculum?" and "How would you teach this lesson?" Data were analysed using critical discourse analysis. Four recurring discourses emerged including: power relationships are a two-way street; learn from mistakes to prevent mistakes; begin cultural consciousness-raising in first year, first semester; and become critically self-aware. Narratives derived from original stories of adversity may be a valuable source of learning about the realities of the workplace but to benefit fully, educators need to assist students to notice and analyse embedded messages. PMID- 28570991 TI - From Antarctica to the subtropics: Contrasted geographical concentrations of selenium, mercury, and persistent organic pollutants in skua chicks (Catharacta spp.). AB - Seabirds integrate bioaccumulative contaminants via food intake and have revealed geographical trends of contamination in a variety of ecosystems. Pre-fledging seabird chicks are particularly interesting as bioindicators of chemical contamination, because concentrations in their tissues reflect primarily dietary sources from the local environment. Here we measured 14 trace elements and 18 persistent organic pollutants (POPs) in blood of chicks of skuas that breed in four sites encompassing a large latitudinal range within the southern Indian Ocean, from Antarctica (Adelie Land, south polar skua Catharacta maccormicki), through subantarctic areas (Crozet and Kerguelen Islands, brown skua C. lonnbergi), to the subtropics (Amsterdam Island, C. lonnbergi). Stables isotopes of carbon (delta13C, feeding habitat) and nitrogen (delta15N, trophic position) were also measured to control for the influence of feeding habits on contaminant burdens. Concentrations of mercury (Hg) and selenium (Se) were very high at all the four sites, with Amsterdam birds having the highest concentrations ever reported in chicks worldwide (4.0 +/- 0.8 and 646 +/- 123 MUg g-1 dry weight, respectively). Blood Hg concentrations showed a clear latitudinal pattern, increasing from chicks in Antarctica to chicks in the subantarctic and subtropical islands. Interestingly, blood Se concentrations showed similar between-population differences to Hg, suggesting its involvement in protective mechanisms against Hg toxicity. Chicks' POPs pattern was largely dominated by organochlorine pesticides, in particular DDT metabolites and hexachlorobenzene (HCB). Skua chicks from subantarctic islands presented high concentrations and diversity of POPs. By contrast, chicks from the Antarctic site overall had the lowest concentrations and diversity of both metallic and organic contaminants, with the exception of HCB and arsenic. Skua populations from these sites, being naturally exposed to different quantities of contaminants, are potentially good models for testing toxic effects in developing chicks in the wild. PMID- 28570992 TI - Inhalation of concentrated PM2.5 from Mexico City acts as an adjuvant in a guinea pig model of allergic asthma. AB - Exposure to Particulate Matter (PM) could function as an adjuvant depending on the city of origin in mice allergic asthma models. Therefore, our aim was to determine whether inhalation of fine particles (PM2.5) from Mexico City could act as an adjuvant inducing allergic sensitization and/or worsening the asthmatic response in guinea pig, as a suitable model of human asthma. Experimental groups were Non-Sensitized (NS group), sensitized with Ovalbumin (OVA) plus Aluminum hydroxide (Al(OH)3) as adjuvant (S + Adj group), and sensitized (OVA) without adjuvant (S group). All the animals were exposed to Filtered Air (FA) or concentrated PM2.5 (5 h/daily/3 days), employing an aerosol concentrator system, PM2.5 composition was characterized. Lung function was evaluated by barometric plethysmography (Penh index). Inflammatory cells present in bronchoalveolar lavage were counted as well as OVA-specific IgG1 and IgE were determined by ELISA assay. Our results showed in sensitized animals without Al(OH)3, that the PM2.5 exposure (609 +/- 12.73 MUg/m3) acted as an adjuvant, triggering OVA-specific IgG1 and IgE concentration. Penh index increased ~9-fold after OVA challenge in adjuvant-sensitized animals as well as in S + PM2.5 group (~6-fold), meanwhile NS + FA and S + FA lacked response. S + Adj + PM2.5 group showed an increase significantly of eosinophils and neutrophils in bronchoalveolar lavage. PM2.5 composition was made up of inorganic elements and Polycyclic Aromatic Hydrocarbons, as well as endotoxins and beta-glucan, all these components could act as adjuvant. Our study demonstrated that acute inhalation of PM2.5 acted as an adjuvant, similar to the aluminum hydroxide effect, triggering allergic asthma in a guinea pig model. Furthermore, in sensitized animals with aluminum hydroxide an enhancing influence of PM2.5 exposure was observed as specific hyperresponsiveness to OVA challenge (quickly response) and eosinophilic and neutrophilic airway inflammation. Fine particles from Mexico City is a complex mix, which play a significant role as adjuvant in allergic asthma. PMID- 28570993 TI - Landscape care of urban vacant properties and implications for health and safety: Lessons from photovoice. AB - Care of vacant properties in urban environments is of particular interest to planners and residents alike. We report on a photovoice project completed by community leaders, researchers, and residents in two Detroit neighborhoods experiencing longtime systemic disinvestment. Participants photographed and discussed examples of care in a series of three focus groups in each neighborhood. Analyses highlight how acts of landscape care and visible cues to care contribute to changes in physical and social environments, and explore various links to health. We suggest theoretical and practical applications of residents' perspectives on landscape care and identify implications for well being and neighborhood stability. PMID- 28571004 TI - Health Literacy: Readability of ACC/AHA Online Patient Education Material. AB - OBJECTIVES: To determine whether the online patient education material offered by the American College of Cardiology (ACC) and the American Heart Association (AHA) is written at a higher level than the 6th-7th grade level recommended by the National Institute of Health (NIH). METHODS: Online patient education material from each website was subjected to reading grade level (RGL) analysis using the Readability Studio Professional Edition. One-sample t testing was used to compare the mean RGLs obtained from 8 formulas to the NIH-recommended 6.5 grade level and 8th grade national mean. RESULTS: In total, 372 articles from the ACC website and 82 from the AHA were studied. Mean (+/-SD) RGLs for the 454 articles were 9.6 +/- 2.1, 11.2 +/- 2.1, 11.9 +/- 1.6, 10.8 +/- 1.6, 9.7 +/- 2.1, 10.8 +/- 0.8, 10.5 +/ 2.6, and 11.7 +/- 3.5 according to the Flesch-Kincaid grade level (FKGL), Simple Measure of Gobbledygook (SMOG Index), Coleman-Liau Index (CLI), Gunning-Fog Index (GFI), New Dale-Chall reading level formula (NDC), FORCAST, Raygor Readability Estimate (RRE), and Fry Graph (Fry), respectively. All analyzed articles had significantly higher RGLs than both the NIH-recommended grade level of 6.5 and the national mean grade level of 8 (p < 0.00625). CONCLUSIONS: Patient education material provided on the ACC and AHA websites is written above the NIH recommended 6.5 grade level and 8th grade national mean reading level. Additional studies are required to demonstrate whether lowering the RGL of this material improves outcomes among patients with cardiovascular disease. PMID- 28571005 TI - Importance of Light Filters in Modern Vitreoretinal Surgery: An Update of the Literature. AB - PURPOSE: Direct endobulbar illumination during vitreoretinal surgery causes light induced retinal damage known as phototoxicity. Spectral filters have been proposed to eliminate hazardous wavelengths from the emission spectrum before entering the eye. The purpose of our paper is to review advances in vitreoretinal surgery, focusing on intraoperative light filters. METHODS: A PubMed and Medline database search was carried out using the terms "spectral filters" associated with "vitreoretinal surgery," "phototoxicity," and "vitrectomy." Original articles, reviews, and book chapters up to March 2017 were reviewed; a few select articles published before 2000 are included for historical purposes. Material from recent meeting presentations was also added. The preferred language for the reviewed literature was English. RESULTS: Spectral filters significantly reduce the risk of phototoxicity associated with endoillumination in vitreoretinal surgery, allowing higher exposure times than with optic light fibers alone. Spectral filters may affect intraoperative luminance, but do not alter color contrast. Amber filters showed superiority over green and yellow filters. CONCLUSION: The choice of light sources coupled to spectral filters is strongly suggested, especially in dye-assisted chromovitrectomy. Histological donor eye studies and large multicenter trials are needed to validate the amount of photoprotection provided by spectral filters before a general recommendation can be made. PMID- 28571006 TI - Extensive Sex Chromosome Polymorphism of Microtus thomasi/Microtus atticus Species Complex Associated with Cryptic Chromosomal Rearrangements and Independent Accumulation of Heterochromatin. AB - The sibling species Microtus thomasi and M. atticus represent probably the highest karyotypic diversity within the genus Microtus and are an interesting model for chromosomal evolution studies. In addition to variation in autosomes, they show a high intraspecific variation in the size and morphology of both sex chromosomes. We analyzed individuals with different sex chromosome constitutions using 3 painting probes, 2 from Y chromosome variants and 1 from the small arm of the submetacentric X chromosome. Our comparative painting approach uncovered 12 variants of Y and 14 variants of X chromosomes, which demonstrates that the polymorphism of sex chromosomes is substantially larger than previously reported. We suggest that 2 main processes are responsible for this sex chromosome polymorphism: change of morphology from acrocentric to submetacentric or metacentric chromosomes and increase in size due to accumulation of repetitive DNA sequences, generating heterochromatic blocks. Strong genetic drift in small and fragmented populations of these 2 species could be related to the origin and maintenance of the large polymorphism of sex chromosomes. We proposed that a similar polymorphism variation combined with random drift fixing the biggest sex chromosomes could have occurred in the origin of some of the actual Microtus species with giant sex chromosomes. PMID- 28571007 TI - Eplerenone Prevents Atrial Fibrosis via the TGF-beta Signaling Pathway. AB - OBJECTIVES: Eplerenone (EPL), an antagonist of the mineralocorticoid receptor, is beneficial for atrial fibrillation and atrial fibrosis. However, the underlying mechanism remains less well known. We aimed to investigate the effect of EPL on atrial fibrosis using a mouse with selective atrial fibrosis and to explore the underlying mechanisms. METHODS: EPL-treated MHC-TGFcys33ser transgenic mice that have selective atrial fibrosis (Tx+EPL mice), as well as control mice, were used for in vivo studies including histological analyses, Western blotting, and qRT PCR studies. TGF-beta1-stimulated atrial fibroblasts were treated with EPL or vehicle for the in vitro studies including Western blotting and qRT-PCR studies. In addition, Smad7 siRNA was used to knock down Smad7. RESULTS: EPL inhibited atrial fibrosis in the Tx mice. In addition, EPL suppressed the expression of fibrosis-related molecules induced by TGF-beta1 in vivo and in vitro. This occurred in concert with a downregulation of Smad7 protein expression and an upregulation of p-Smad2/3 protein expression. In addition, knockdown of Smad7 by siRNA abolished the protective roles of EPL. CONCLUSIONS: EPL inhibited atrial fibrosis in Tx mice. The underlying mechanism may involve increased protein expression of Smad7, which enhances the inhibitory feedback regulation of TGF beta1/Smad signaling. PMID- 28571008 TI - MicroRNA-200b Expression in the Vitreous Humor of Patients with Proliferative Diabetic Retinopathy. AB - BACKGROUND: The role of microRNA (miRNA)-200b in the pathogenesis of proliferative diabetic retinopathy (PDR) has been studied in diabetic animal models. The aim of this study was to assess miRNA-200b expression in the vitreous of patients with PDR and to determine its correlation with vascular endothelial growth factor (VEGF), one of the pathogenic mechanisms in PDR. METHODS: Quantitative reverse transcription polymerase chain reaction was used to measure miRNA-200b expression in the vitreous from 29 eyes with PDR and 30 eyes with idiopathic macular holes (IMH; control group). Vitreous VEGF was measured using an enzyme-linked immunosorbent assay. RESULTS: miRNA-200b expression was about 5 fold increased in the vitreous samples from eyes with PDR compared with the controls (p <= 0.001). Vitreous VEGF expression was also significantly higher in the PDR group than in the IMH group (p <= 0.001), but no significant correlation was found between miRNA-200b and VEGF. CONCLUSION: Both miRNA-200b and VEGF are increased in the vitreous of patients with PDR but in a noncorrelated pattern. miRNA-200b may be involved in the pathogenesis of PDR but through VEGF independent mechanisms. Further studies are needed to identify the miRNA-200b targeted genes involved in the pathogenesis of PDR and to examine the potential role of miRNA-200b as a target for PDR treatment. PMID- 28571009 TI - Surgery Is an Effective Option after Failure of Chemoradiation in Cancers of the Anal Canal and Anal Margin. AB - BACKGROUND: Surgery for anal canal cancer (ACC) and anal margin cancer (AMC) is the only curative option after failure of chemoradiotherapy (CRT). This study aimed to determine the efficacy of surgery for ACC or AMC after failed CRT. METHODS: This was a single-centre, retrospective study of 161 patients initially treated with CRT. We compared the survival rates of patients successfully treated by CRT with those of patients whose CRT failed (both surgically salvaged and treated palliatively). RESULTS: Thirty-one patients underwent surgery with curative intent, 20 received palliative treatment after failure of CRT, and 110 had effective CRT. The 5-year overall survival (OS) rate was significantly higher among patients with successful CRT than among patients who underwent surgery with curative intent (86 vs. 66%, p < 0.001). On the other hand, the 5-year OS of patients treated with curative surgery was significantly better than that of patients who underwent palliative treatment (66 vs. 13.5%, p < 0.001). The postoperative morbidity and mortality rates were 32 and 3%, respectively. Considering patients with failed CRT, curative surgery was the only factor prognostic of favourable OS in the multivariate analysis. CONCLUSION: Curative surgery after failure of CRT for ACC or AMC remains an effective treatment to improve survival in two-thirds of cases, resulting in high but manageable morbidity. PMID- 28571011 TI - Vasoinhibin Suppresses the Neurotrophic Effects of VEGF and NGF in Newborn Rat Primary Sensory Neurons. AB - BACKGROUND/AIMS: Studies on the biological actions of vasoinhibins have focused mainly on endothelial cells. However, there is incipient knowledge about how vasoinhibins affect the nervous system, even if the target cells and mechanisms of action involved in these effects are unknown. METHODS: In order to determine if neurons are direct targets of vasoinhibins, we examined cellular outcomes and the intracellular pathways involved in the neuronal actions of vasoinhibins using newborn rat dorsal root ganglion (DRG) neurons as a model system. RESULTS: Vascular endothelial growth factor (VEGF) or nerve growth factor (NGF) treatment for 48 h resulted in neurite outgrowth stimulation in both DRG cultured explants and isolated primary sensory neurons. Interestingly, a recombinant vasoinhibin containing the first 123 amino acids of human prolactin antagonized the VEGF- and NGF-induced stimulation of neurite outgrowth. Vasoinhibin significantly reduced the density of neurites in DRG explants and obliterated neuritogenesis in isolated DRG neurons in primary culture, supporting a direct neuronal effect of vasoinhibin. In cultures of isolated DRG cells, virtually all beta3-tubulin labeled cells express TrkA, and the majority of these cells also express VEGFR2. Short-term VEGF or NGF treatment of DRG explants resulted in increased ERK1/2 and AKT phosphorylation, whereas incubation of DRG with the combination of either VEGF or NGF together with vasoinhibin resulted in blunted VEGF- or NGF-induced phosphorylation of both ERK1/2 and AKT. CONCLUSION: Our results show that primary sensory neurons are direct targets of vasoinhibin, and suggest that vasoinhibin inhibition of neurite outgrowth involves the disruption of ERK and AKT phosphorylation cascades. PMID- 28571010 TI - Blood Pressure of Maintenance Hemodialysis Patients in the Dalmatian Region of Croatia: Differences between Hospital and Out-of-Hospital Dialysis Centers. AB - AIMS: This study was aimed at comparing the incidence of arterial hypertension and blood pressure (BP) variance in hospital and out-of-hospital hemodialysis (HD) patients during HD sessions. METHODS: A cross-sectional study was conducted for 1 week at all the HD centers in Dalmatia, Croatia. The pre-, intra-, and post dialysis BP values were collected for 3 consecutive HD sessions per patient. RESULTS: Of the 399 subjects, 73.9% were hypertensives, who showed higher interdialytic weight gain compared to the normotensives (2.58 vs. 2.40). Hospital and out-of-hospital HD patients received identical antihypertensive therapies, except that beta blockers were more frequently administered to out-of-hospital HD patients. Higher pre-, intra-, and post-dialysis BP values were recorded in patients at out-of-hospital HD centers. CONCLUSION: The differences in BP variability and antihypertensive therapies administered to hospital HD patients as compared to out-of-hospital HD patients may reflect differing approaches by the nephrologists at these centers. PMID- 28571012 TI - Challenges in Modern Anti-Doping Analytical Science. AB - The challenges facing modern anti-doping analytical science are increasingly complex given the expansion of target drug substances, as the pharmaceutical industry introduces more novel therapeutic compounds and the internet offers designer drugs to improve performance. The technical challenges are manifold, including, for example, the need for advanced instrumentation for greater speed of analyses and increased sensitivity, specific techniques capable of distinguishing between endogenous and exogenous metabolites, or biological assays for the detection of peptide hormones or their markers, all of which require an important investment from the laboratories and recruitment of highly specialized scientific personnel. The consequences of introducing sophisticated and complex analytical procedures may result in the future in a change in the strategy applied by the Word Anti-Doping Agency in relation to the introduction and performance of new techniques by the network of accredited anti-doping laboratories. PMID- 28571013 TI - Education in Anti-Doping: The Art of Self-Imposed Constraints. AB - The pillars of anti-doping are detection, deterrence, and prevention. Detection takes the form of testing for banned substances. Deterrence builds on testing and gathering evidence. Athletes who test positive are exposed to penalties. The main tool of prevention is education. Education takes many forms and can be implemented in many ways. This chapter addresses the nature and challenges of current anti-doping education. Firstly, general goals of education and their connection to sport are discussed. Secondly, three normative interpretations of sport are presented, and their implications for anti-doping education are examined. Instrumentalist interpretations and interpretations with emphasis on performance and enhancement challenge the anti-doping campaign. A human excellence interpretation is advocated in which anti-doping is considered a consistent and integral part of sport. Thirdly, future challenges for anti-doping education are reflected upon. PMID- 28571014 TI - A Moral Foundation for Anti-Doping: How Far Have We Progressed? Where Are the Limits? AB - Clarity about the ethical justification of anti-doping is essential. In its absence, critics multiply and confusion abounds. Three broad reasons are typically offered in anti-doping's defense: to protect athletes' health; to promote fairness; and to preserve meaning and values in sport - what the World Anti-Doping Agency (WADA) Code refers to as the spirit of sport. Protecting health is itself an important value, but many sports encourage athletes to take significant risks. The case against doping is buttressed by concern for athletes' health, but it cannot be the sole foundation. Promoting fairness is vital in all sports as the metaphor of the level playing field attests. But playing fields can be leveled by providing performance-enhancing drugs to all competitors. When doping is prohibited, fairness is aided by effective anti-doping. But the fundamental justification for anti-doping is found in the meanings and values we pursue in and through sport. PMID- 28571015 TI - Insulin-Like Growth Factors and Metabolic Syndrome in Obese Children. AB - BACKGROUND/AIMS: Insulin-like growth factor (IGF)-I is related to cardiometabolic risk in adults, whereas the metabolic role of IGF-II is unclear. The aim of this study was to assess IGFs in obese children and correlate them with metabolic syndrome (MetS) components. METHODS: This is a retrospective study including 574 obese children (11.34 +/- 3.16 years). All subjects underwent complete anthropometry and biochemical assessment. In a subgroup of 136 subjects, body composition was evaluated. IGF-I was measured in 300 obese subjects and IGF-II in 77 obese and 15 lean children. 177 subjects were divided according to the presence of 1 or more MetS criteria: group 1, subjects with 1 MetS criterion; group 2, subjects with 2 components; and group 3, subjects with MetS diagnosis. RESULTS: IGF-I, IGF-II, and IGF-I/insulin-like growth factor-binding protein-3 ratio were not different among subjects with an increasing number of MetS criteria and were not associated with single components of MetS as well as with body composition parameters. In children younger than 10 years, IGF-I directly correlated with high-density lipoprotein cholesterol (p < 0.005) even after controlling for confounders. IGF-II was significantly higher in obese children and correlated with parameters of insulin sensitivity (p < 0.05). CONCLUSION: IGFs were neither related to MetS nor to body composition parameters in obese children. Further studies are needed to clarify the mechanisms underlying the relationship between IGF-II and insulin sensitivity. PMID- 28571016 TI - Next Generation "Omics" Approaches in the "Fight" against Blood Doping. AB - Despite being prohibited by the World Anti-Doping Agency (WADA), blood manipulations such as the use of recombinant human erythropoietin and blood transfusions are a well-known method used by athletes to enhance performance. Direct detection of illicit blood manipulation has been partially successful due to the short detection window of the substances/methods, sample collection timing, and the use of sophisticated masking strategies. In response, WADA introduced the athlete biological passport (ABP) in 2009, which is an individualised longitudinal monitoring approach that tests primarily haematologic biomarkers of doping in order to identify atypical variability in response(s) in athletes, highlighting a potential doping violation. Although the implementation of the ABP has been an encouraging step forward in the quest for clean/drug-free sport, this detection method has some limitations. To reduce the risk of being detected by the ABP method, athletes are now resorting to microdoses of prohibited blood boosting substances to prevent abnormal fluctuations in haematologic biomarkers, thereby reducing the sensitivity of the ABP detection method. Recent studies from numerous laboratories, including our own, have confirmed the potential of transcriptomic microarrays, which can reveal distinct changes in gene expression after blood manipulations, to enhance the ABP. There is, therefore, an urgent need to intensify research efforts that involve transcriptomics and other state-of-the-art molecular methods, collectively known as "omics", e.g., proteomics (proteins) and metabolomics (metabolites), in order to identify new and even more robust molecular signatures of blood manipulation that can be used in combination with the ABP and, intriguingly, even as a stand alone test. PMID- 28571017 TI - Can We Better Integrate the Role of Anti-Doping in Sports and Society? A Psychological Approach to Contemporary Value-Based Prevention. AB - In sport, a wide array of substances with established or putative performance enhancing properties is used. Most substances are fully acceptable, whilst a defined set, revised annually, is prohibited; thus, using any of these prohibited substances is declared as cheating. In the increasingly tolerant culture of pharmacological and technical human enhancements, the traditional normative approach to anti-doping, which involves telling athletes what they cannot do to improve their athletic ability and performance, diverges from the otherwise positive values attached to human improvement and enhancement in society. Today, doping is the epitome of conflicting normative expectations about the goal (performance enhancement) and the means by which the goal is achieved (use of drugs). Owing to this moral-functional duality, addressing motivations for doping avoidance at the community level is necessary, but not sufficient, for effective doping prevention. Relevant and meaningful anti-doping must also recognise and respect the values of those affected, and consolidate them with the values underpinning structural, community level anti-doping. Effective anti-doping efforts are pragmatic, positive, preventive, and proactive. They acknowledge the progressive nature of how a "performance mindset" forms in parallel with the career transition to elite level, encompasses all levels and abilities, and directly addresses the reasons behind doping use with tangible solutions. For genuine integration into sport and society, anti-doping should consistently engage athletes and other stakeholders in developing positive preventive strategies to ensure that anti-doping education not only focuses on the intrinsic values associated with the spirit of sport but also recognises the values attached to performance enhancement, addresses the pressures athletes are under, and meets their needs for practical solutions to avoid doping. Organisations involved in anti- doping should avoid the image of "controlling" but, instead, work in partnerships with all stakeholders to involve and ensure integration of the targeted individuals in global community-based preventive interventions. PMID- 28571018 TI - Achievements and Challenges in Anti-Doping Research. AB - The most important element in achieving athlete compliance with anti-doping rules is the certainty of detection. Thus, scientific research plays a mission critical role in achieving clean competition. Many factors contribute to the advances in detection. Incremental advances in the ability to detect prohibited substances and methods, and identification of long-lived metabolites continue to lengthen detection windows. While the athlete biological passport hematological and steroidal modules hold great promise, experience shows that new research is needed to improve the sensitivity and specificity of the approach for current doping techniques. Indirect detection strategies using biomarkers or transcriptomic techniques have been increasingly investigated. The incorporation of more cost-effective sampling strategies using dried blood and plasma spots, oral fluid, and breath analysis show great promise toward increasing the number of tests while remaining within testing budget constraints. Despite the importance of research to ensuring rule compliance, a major challenge for anti doping research is achieving and maintaining sufficient funding in the reality of the myriad of new substances introduced for disease treatment but abused for performance enhancement. In addition, obtaining metabolism and population reference range data, particularly for new drugs or designer drugs that have not obtained approval for administration to human subjects, remains a significant problem. Nevertheless, research continues to contribute important data to support anti-doping efforts. PMID- 28571019 TI - High-Flux Dialysis: Clinical, Biochemical, and Proteomic Comparison with Low-Flux Dialysis and On-Line Hemodiafiltration. AB - Hemodiafiltration on-line (on-line HDF) is a more efficient treatment than low flux hemodialysis (HD). Unfortunately, it cannot be proposed to all patients. The aim of this study was to evaluate the safety, efficiency, and mechanisms of removal of toxins with high-flux HD vs. low-flux HD and on-line HDF. Randomized cross-over study designed to evaluate efficiency and tolerability of high-flux HD vs. low-flux HD in aged patients; to compare by means of biochemical and proteomic analyses the efficiency and mechanisms of removal of toxins with high flux HD vs. on-line HDF. The removal of small toxins was similar with high-flux and low-flux HD. beta2-microglobulin was removed only with high-flux HD, which had an excellent tolerability. The efficiency of high-flux HD was similar to on line HDF. Proteomic analysis demonstrated that only high-flux membranes remove and adsorb small proteins. High-flux HD may be an efficient alternative to on line HDF. PMID- 28571020 TI - Optimising Intravenous Volume Resuscitation of the Newborn in the Delivery Room: Practical Considerations and Gaps in Knowledge. AB - Volume resuscitation (VR) for the treatment of newborn shock is a rare but potentially lifesaving intervention. Conducting clinical studies to assess the effectiveness of VR in the delivery room during newborn stabilization is challenging. We review the available literature and current management guidelines to determine which infants will benefit from VR, the frequency of VR, and the choice of agents used. In addition, the potential role for placental transfusion in the prevention of newborn shock is explored. PMID- 28571021 TI - Brief History of Anti-Doping. AB - The fight against doping in sport as we know it today commenced by the creation of the International Olympic Committee (IOC) Medical Commission in 1961 following the death of a Danish cyclist during the Rome Olympic Games the year before. After a slow start, the fight got under way as from the early 1970s under the leadership of the IOC and of the International Association of Athletics Federations. Despite a lack of understanding and weak support even from the sports community, a series of measures were taken during the 1970s and 1980s which still form cornerstones of today's anti-doping strategy. In addition to information and education campaigns, the most important examples are the introduction of procedural rules for doping controls, the establishment and follow-up of a list of prohibited substances and methods, the accreditation of doping control laboratories, the introduction of in- and out-of-competition testing, rules for therapeutic use exemption, and the introduction of blood sampling. During the 1990s, the anti-doping fight gained increasing support both inside and outside the sport community. In order to harmonize the wide variety of rules that had developed both in sport organizations and at the domestic level and to promote anti-doping activities, the World Anti-Doping Agency (WADA) was jointly created by the Olympic movement and the public authorities in 1999. WADA is today carrying on the fight supported by the universally accepted WADA Code and an International Anti-Doping Convention under UNESCO. PMID- 28571022 TI - Therapeutic Use Exemptions. AB - The introduction, in 2004, of the World Anti-Doping Code and a standardized "prohibited list" of substances and methods proscribed in sport represented a consistent, international response to the escalating challenge of drug misuse in contemporary sport. Simultaneously, it was recognized that athletes experiencing illness or injury might legitimately require the use of "prohibited" medications or procedures, and the concept of the "therapeutic use exemption" (TUE) was introduced. The mechanisms of the TUE process are carefully defined and described in a specific WADA "international standard" (IS). As a consequence, anti-doping organizations (ADOs) were empowered to establish "Therapeutic Use Exemption Committees" (TUECs) whose membership and responsibilities were clearly delineated in the IS, and to whom an athlete and treating physician(s) could make appropriate application for a TUE. A careful review of such an application by a TUEC panel of physicians might allow permission for an otherwise prohibited course of treatment, provided that appropriate criteria had been met. Sport physicians have a clear responsibility to ensure accurate and complete documentation of the clinical circumstances requiring a TUE when completing such applications. Typically, applications for consideration by TUECs are forwarded to a national ADO, but depending on an applicant's level of competition, it may become necessary to involve an international federation or major event organization (e.g., International Olympic Committee, or Commonwealth Games Federation). Such organizations may receive, review, and grant TUEs specific to the competitions over which they preside. Increasingly, there is recognition of TUEs granted by other ADOs. However, this is not always the case; in certain circumstances, the decisions of other TUECs to grant or deny an application may be appealed. The advent of the TUE process ensures that an athlete with a genuine medical condition that necessitates the use of a prohibited substance or procedure can apply for permission to use such treatments and is not denied access to competition or training. PMID- 28571023 TI - Is the Fight against Doping in Sport a Legal Minefield like Any Other? AB - In the fight against doping, creating a level playing field across all sports is very challenging from a legal perspective. A harmonized approach presupposes first and foremost a supreme regulatory authority on a global level. This task cannot be attributed to the public sector, because there is no supranational authority of public international law capable of dealing with it. Thus, responsibility has to be assumed by a private law entity. This in turn requires complicated contractual agreements by which duties and responsibilities are transferred from the individual to the national level and from there to the top of the pyramid. In practice, this process is not only difficult and cumbersome, it also leads to an accumulation of power at the top of the sports pyramid that must be contained by organizational checks and balances, such as access to justice and the rule of law, accountability, transparency, and possibilities for the respective stakeholders to partake in the decision-making process. The weighting of all these different aspects is demanding and further complicated by the regulatory reach of the various national lawmakers. Since national laws differ considerably and a harmonized legislative approach is nowhere near in sight, a global approach in the fight against doping must push back national laws and legal concepts as much as possible. The purpose of this chapter is to give an overview on all these legal challenges. PMID- 28571025 TI - The Development of the World Anti-Doping Code. AB - This chapter addresses both the development and substance of the World Anti Doping Code, which came into effect in 2003, as well as the subsequent Code amendments, which came into effect in 2009 and 2015. Through an extensive process of stakeholder input and collaboration, the World Anti-Doping Code has transformed the hodgepodge of inconsistent and competing pre-2003 anti-doping rules into a harmonized and effective approach to anti-doping. The Code, as amended, is now widely recognized worldwide as the gold standard in anti-doping. The World Anti-Doping Code originally went into effect on January 1, 2004. The first amendments to the Code went into effect on January 1, 2009, and the second amendments on January 1, 2015. The Code and the related international standards are the product of a long and collaborative process designed to make the fight against doping more effective through the adoption and implementation of worldwide harmonized rules and best practices. PMID- 28571026 TI - Sport, Society, and Anti-Doping Policy: An Ethical Overview. AB - The purpose of this chapter is to provide an overview of the philosophical and ethical underpinnings of anti-doping policy. The nature of sport and its gratuitous logic is explored. The doping rules in sport, such as the Prohibited List, are ways of drawing a line to facilitate a certain sort of competition. Sports can be understood as a means of testing the natural physical abilities of the athlete, combined with the hard work they put into improving their performance. A test promoted by the anti-doping laws. Permitting certain forms of performance enhancement would threaten the special nature of such a test. Doping can be seen as a threat to the integrity of sport, not just because of the rule breaking doping currently entails. The chapter explores the ethical issues that arise with such forms of enhancement, such as fairness, harms to health, and indeed a refusal to accept human limitations. Finally, the criteria upon which a substance or method may be prohibited by the World Anti-Doping Agency (WADA) is addressed. The 3-part criteria, concerning (1) enhancement, (2) health, and (3) the spirit of sport are described, and literature that takes a critical line is addressed. Particular reference is made to the public health agenda explicit within anti-doping policy. PMID- 28571024 TI - Elevated Preoperative CA125 or CA19-9 in Borderline Ovarian Tumors: Could It Be Suggestive of Advanced Stage or a Poor Prognosis? AB - OBJECTIVES: To investigate whether elevated levels of CA125 (>=35 U/mL) and CA19 9 (>=37 U/mL) suggest advanced-stage disease (defined as stage II or higher) or poor prognosis in patients with borderline ovarian tumors (BOTs). STUDY DESIGN: We retrospectively identified 591 patients with BOTs. Multivariate logistic regressions and Cox proportional hazard regressions were used to determine the clinicopathologic factors associated with the presence of advanced-stage disease and the prognostic factors associated with recurrence-free survival. RESULTS: CA125 was elevated more often in serous than in mucinous tumors (50.6 vs. 35.5%; p = 0.003), whereas CA19-9 was elevated more often in mucinous than serous tumors (33.6 vs. 15.3%; p = 0.001). An elevated CA125 level was independently associated with the presence of advanced-stage disease in serous (p = 0.005) and in mucinous BOTs (p = 0.015). However, preoperative elevation of CA19-9, unlike CA125, was not associated with the advanced-stage disease. Elevated preoperative CA125 level (p = 0.037) was an independent prognostic factor for recurrence-free survival in patients with serous BOTs. However, neither CA125 nor CA19-9 had prognostic significance in mucinous BOTs. CONCLUSIONS: Elevated preoperative CA125, unlike CA19-9, is a diagnostic and prognostic biomarker associated with the presence of advanced-stage disease and risk of relapse in patients with serous BOTs. PMID- 28571027 TI - Structure and Development of the List of Prohibited Substances and Methods. AB - The list of prohibited substances and methods (the List) is the international standard that determines what is prohibited in sport both in- and out-of competition. Since 2004, the official text of the List is produced by the World Anti-Doping Agency (WADA), the international independent organization responsible for promoting, coordinating, and monitoring the fight against doping in sport. Originally based on the prohibited lists established by the International Olympic Committee, the List has evolved to incorporate new doping trends, distinguish permitted from prohibited routes of administration, and adjust to new analytical and pharmacological breakthroughs. In this chapter, the elements that compose the List as well as the updates over the years are presented. PMID- 28571028 TI - Integration of the Forensic Dimension into Anti-Doping Strategies. AB - Traditionally, research in anti-doping has been stimulated by the need for technological improvements to accommodate the expansion of the list of prohibited substances and methods. Nevertheless, in recent years, anti-doping found itself at a crossroads due to the increasing complexity and constant refinement of doping methods. As illustrated by the 2012 USADA (United States Anti-Doping Agency) versus Lance Armstrong case, a change in paradigm was necessary. The exploration of new scientific avenues to understand the mechanisms of doping and pinpoint its practice was most needed to allow designing more efficient preventive or disruptive strategies. In this context, and at the time of writing in 2017, transposing the concept of forensic intelligence to anti-doping was identified as a promising approach to address the different aspects of doping, from the individual athlete to organized doping and trafficking of substances in a proactive rather than a reactive way. Indeed, collection, structuring, and logical processing of multiple sources of information, and not strictly results of bioanalytical testing of urinary and blood samples, can bring additional value to detect and describe potential, emerging, or existing doping issues. This anti doping intelligence can provide anti-doping authorities and relevant stakeholders with timely, accurate, and usable information for decision making to solve, reduce, and/or prevent doping-related activities. The integration of intelligence to complement other anti-doping approaches is a potentially major step forward in the development of more effective and robust anti-doping strategies. PMID- 28571029 TI - Roles of High Mobility Group Box 1 in Cardiovascular Calcification. AB - Calcific disease of the cardiovascular system, including atherosclerotic calcification, medial calcification in diabetes and calcific aortic valve disease, is an important risk factor for many adverse cardiovascular events such as ischemic cardiac events and subsequent mortality. Although cardiovascular calcification has long been considered to be a passive degenerative occurrence, it is now recognized as an active and highly regulated process that involves osteochondrogenic differentiation, apoptosis and extracellular vesicle release. Nonetheless, despite numerous studies on the pathogenesis of cardiovascular calcification, the underlying mechanisms remain poorly understood. High mobility group box 1 (HMGB1), a nuclear protein bound to chromatin in almost all eukaryotic cells, acts as a damage-associated molecular pattern (DAMP) when released into the extracellular space upon cell activation, injury or death. Moreover, HMGB1 also functions as a bone-active cytokine participating in bone remodeling and ectopic calcification pathogenesis. However, studies on the roles of HMGB1 in promoting cardiovascular calcification are limited to date, and the mechanisms involved are still unclear. In this review, we summarize recent studies investigating the mechanism of cardiovascular calcification and discuss multiple roles of HMGB1 in its development. PMID- 28571030 TI - Less Fibrotic Burden Differently Affects the Long-Term Outcomes of Hepatocellular Carcinoma after Curative Resection. AB - BACKGROUND: The clinical features of hepatocellular carcinoma (HCC) differ in patients with and without cirrhosis. OBJECTIVE: We aimed to investigate the long term outcomes of noncirrhotic HCC patients after curative resection. METHODS: We retrospectively examined 649 consecutive patients with HCC who underwent curative resection from 1996 to 2012; 387 (59.6%) were cirrhotic and 262 (40.4%) were noncirrhotic. RESULTS: The mean age was 54.7 years, and 511 (78.7%) of the study participants were men. The most common cause of HCC was hepatitis B virus (n = 419, 64.6%). Noncirrhotic tumors were larger and more advanced than cirrhotic tumors. However, the noncirrhotic group showed better disease-free survival (DFS) and overall survival (OS) after resection than the cirrhotic group (median 64.0 vs. 56.0 months for OS and 48.0 vs. 31.0 months for DFS, p < 0.05). The predictors for HCC recurrence were cirrhosis, tumor number, portal vein invasion, and major surgery. CONCLUSIONS: Noncirrhotic HCC showed better DFS and OS after resection than cirrhotic HCC, although noncirrhotic HCC presented more aggressively. PMID- 28571031 TI - Perimortem Demonstration and Treatment of Recipient-to-Donor Transfusion in Monochorionic-Diamniotic Twin Gestation. AB - Twin-twin transfusion syndrome is a complication of monochorionic-diamniotic placentation. Should one twin die, ~30% of co-twins will also die, and if they survive, ~30% experience severe morbidity rates, each believed secondary to hemorrhage of the co-twin into the deceased twin. We report apparently the first ultrasound-documented case of perimortem hemorrhage in twin-twin transfusion syndrome and its treatment by emergent ultrasound-guided percutaneous cord occlusion followed by percutaneous fetal intravascular transfusion. The case illustrates three important pathophysiologic events. First, it confirms acute twin-to-twin hemorrhage occurs and reveals it can begin before the first twin dies. Thus, delivery of the survivor after its dead co-twin is discovered is unlikely to protect the survivor. Second, the elevated fetal middle cerebral artery peak systolic velocity due to acute anemia requires hours to develop. And thirdly, intracardiac epinephrine can correct the acute fetal bradycardia associated with hemorrhage that is presumably due to fetal hypotension. PMID- 28571033 TI - How to Develop Intelligence Gathering in Efficient and Practical Anti-Doping Activities. AB - Prior to the formation of the World Anti-Doping Agency (WADA), the fight against doping in sport was not unified; instead, it relied on individual approaches established by various stakeholders to make it effective. The scandal of the Festina Affair, during the Tour de France 1998, and other drug doping scandals revealed the ineffectiveness and inadequacy of such an approach. The resulting media scandal raised public authorities' awareness about the necessity to deal with doping in sport with a harmonized and a more effective approach. The International Olympic Committee interceded and convened a World Conference on Doping, bringing together all parties involved in the fight against doping. As a result, WADA was established on November 10, 1999, in Lausanne to promote and coordinate the fight against doping in sport internationally. In this regard, the World Anti-Doping Code (WADC or the Code) is the core document harmonizing anti doping rules and regulations within sport organizations and public authorities. The Code was instrumental in introducing the concept of "nonanalytical" rule violations, which are emphasized within the revised 2015 Code. Nonanalytical rule violations allow anti-doping organizations (ADOs) to apply sanctions in cases where there is no positive doping sample, but where there may still be evidence that a doping violation has occurred. This recognition of "nonanalytical" rule violations by WADA is the concrete result of taking into account lessons learned from prior infamous doping scandals. Thus, intelligence gathering, particularly through cooperation with global law enforcement agencies, is a key tool in the fight against doping. The 2015 Code and the international standards on testing and investigations establish and implement intelligence gathering as part of ADOs' routine activities in the fight against doping in sport. PMID- 28571034 TI - Remotely Programmed Deep Brain Stimulation of the Bilateral Subthalamic Nucleus for the Treatment of Primary Parkinson Disease: A Randomized Controlled Trial Investigating the Safety and Efficacy of a Novel Deep Brain Stimulation System. AB - BACKGROUND: Deep brain stimulation (DBS) is the most commonly performed surgery for the debilitating symptoms of Parkinson disease (PD). However, DBS systems remain largely unaffordable to patients in developing countries, warranting the development of a safe, economically viable, and functionally comparable alternative. OBJECTIVE: To investigate the efficacy and safety of wirelessly programmed DBS of bilateral subthalamic nucleus (STN) in patients with primary PD. METHODS: Sixty-four patients with primary PD were randomly divided into test and control groups (1:1), where DBS was initiated at either 1 month or 3 months, respectively, after surgery. Safety and efficacy of the treatment were compared between on- and off-medication states 3 months after surgery. Outcome measures included analysis of Unified Parkinson's Disease Rating Scale (UPDRS) scores, duration of "on" periods, and daily equivalent doses of levodopa. All patients were followed up both 6 and 12 months after surgery. RESULTS: Three months after surgery, significant decrease in the UPDRS motor scores were observed for the test group in the off-medication state (25.08 +/- 1.00) versus the control group (4.20 +/- 1.99). CONCLUSIONS: Bilateral wireless programming STN-DBS is safe and effective for patients with primary PD in whom medical management has failed to restore motor function. PMID- 28571035 TI - Serological Evaluation of Gastric Cancer Risk Based on Pepsinogen and Helicobacter pylori Antibody: Relationship to Endoscopic Findings. AB - BACKGROUNDS AND AIMS: The serological risk-prediction system combined the pepsinogen (PG) test, and anti-Helicobacter pylori antibody is available for evaluation of gastric cancer risk. In this system, chronic atrophic gastritis (CAG) or H. pylori infection is diagnosed. Subjects with H. pylori negative and PG test negative (group A) are supposed to be those who have never been infected with H. pylori and are at extremely low risk for gastric cancer. However, a certain proportion of patients with CAG has been identified as the extremely low risk group (group A). Here we examined endoscopic atrophy and investigated its relationship with the ABC classification system. METHODS: We examined 540 patients. All patients underwent an endoscopic examination for evaluating corpus atrophy. Fasting sera were collected and serum PGs and anti-H. pylori antibody (Hp-Ab) titer (E-plate Eiken) were evaluated. RESULTS: Of the 540 patients, 306 were classified into group A. However, 136 of them showed signs of endoscopic atrophy (group A with CAG). Group A with CAG frequently comprised the elderly. A new titer cut-off (<3 U/mL) of the Hp-Ab improved the discrimination of group A with CAG by 8%. CONCLUSION: The prevalence of group A with CAG patients is a critical problem, especially in elderly subjects. PMID- 28571036 TI - Sexual Dynamics of Married Women with Interpersonal Dependency: A Qualitative Study on Iranian Women. AB - BACKGROUND: Considering the lack of documented research on the sexuality of dependent persons, this qualitative study examined sexual dynamics among Iranian married women with excessive interpersonal dependency. METHODS: Interviews with 18 married women with high interpersonal dependency were coded using thematic analysis. RESULTS: Three major areas emerged from the data under which the themes clustered. These were (1) intrapersonal level which included confused sexual cognitions, intrusive thoughts during sex, preoccupation by sexual thoughts, low tolerance for reduction or interruption of sexual activity, and emotional distress during sex, (2) interactional dynamics including imposing pressure on the husband to have sex and assuming a submissive and receptive role during sex, and (3) contextual processes including social stigma and the effects of social phenomena. CONCLUSIONS: These findings presented a relatively clear understanding of the impacts of interpersonal dependency on the sexuality of Iranian women. The majority of the women reported maladaptive sexual strategies, attitudes, and emotions. Moreover, there were several similarities between the sexual dynamics of the women and those of individuals with anxious attachment style. These findings suffer from some limitations in terms of generalization due to the small size of the sample and clinical and cultural considerations. The implications of these findings for practitioners are also considered. PMID- 28571037 TI - Conclusion and Perspectives. PMID- 28571038 TI - How Will the Legal and Sport Environment Influence a Future Code? PMID- 28571039 TI - Johnny Can't Read and It Is Killing Him. PMID- 28571040 TI - Videolaryngoscopy during Conscious Sedation in Patients Not Suitable for Phonosurgery by Microlaryngoscopy: A Pilot Study. AB - BACKGROUND: Microlaryngoscopy is the preferred and most widely used technique in phonosurgery for the treatment of benign and early malignant glottic lesions. However, the procedure may be technically difficult or impossible due to alterations of the cervical spine that may not allow hyperextension of the head or may present general anesthesia contraindications. The aim of this study is to evaluate the efficacy and safety of our surgical approach for lesions of the vocal folds in patients who are not suitable for phonosurgery by microlaryngoscopy. This approach applies videolaryngoscopy during conscious sedation, which combines local anesthesia with moderate analgosedation by using midazolam and fentanyl with premedication. METHODS: A total of 235 patients affected by benign diseases or suspicious cancerous lesions of the vocal folds were retrospectively evaluated. RESULTS: The method has shown a success rate of 95.5, 89, 52.3, and 86.7% in cases of polyps of the vocal folds, Reinke's edema, cysts of the vocal folds, and suspicious lesions of the larynx, respectively. Only 3 patients (1.27%) have been reported to experience adverse events. CONCLUSION: The results suggest that the method is an effective and safe procedure without relevant local and/or general complications. PMID- 28571042 TI - MicroRNA-211-5p suppresses tumour cell proliferation, invasion, migration and metastasis in triple-negative breast cancer by directly targeting SETBP1. AB - BACKGROUND: Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer in women globally. This subtype often has early and high recurrence rates, resulting in poor survival, partially due to lack of targeted therapies. To date, the detailed molecular mechanisms underlying TNBC progression are unclear. Given the crucial role of microRNAs (miRNAs) in cancer metastasis, we aimed to analyse the expression and function of a metastasis-associated miRNA named miR-211-5p in TNBC. METHODS: MiRNA array analysis was performed to search for metastasis-associated miRNAs in TNBC. The miR-211-5p expression in tumour tissues, adjacent non-tumourous breast tissues of TNBC patients and cell lines were evaluated by real-time PCR. The protein expression levels were analysed by western blot, immunohistochemistry and in situ hybridisation. Luciferase reporter assays were employed to validate the target of miR-211-5p. The effect of miR-211 5p on TNBC progression was investigated in vitro and in vivo. RESULTS: MiR-211-5p was significantly downregulated in TNBC, and its expression level was associated with overall survival in TNBC. The expression of miR-211-5p suppressed TNBC cell proliferation, invasion, migration and metastasis in vitro and in vivo. Furthermore, SETBP1 was identified as a target of miR-211-5p. Through gain-of function and loss-of-function studies, SETBP1 was shown to significantly affect colony and cell number in vitro. Enforced expression of miR-211-5p inhibited the expression of SETBP1 significantly and the restoration of SETBP1 expression reversed the inhibitory effects of miR-211-5p on TNBC cell proliferation and metastasis. CONCLUSIONS: These findings collectively demonstrate a tumour suppressor role of miR-211-5p in TNBC progression by targeting SETBP1, suggesting that miR-211-5p could serve as a potential prognostic biomarker and therapeutic target for TNBC. PMID- 28571041 TI - CBF1 is clinically prognostic and serves as a target to block cellular invasion and chemoresistance of EMT-like glioblastoma cells. AB - BACKGROUND: Glioblastoma is the most common and most lethal primary brain cancer. CBF1 (also known as Recombination signal Binding Protein for immunoglobulin kappa J, RBPJ) is the cardinal transcriptional regulator of the Notch signalling network and has been shown to promote cancer stem-like cells (CSCs) in glioblastoma. Recent studies suggest that some of the malignant properties of CSCs are mediated through the activation of pro-invasive programme of epithelial to-mesenchymal transition (EMT). Little is known whether CBF1 is involved in the EMT-like phenotype of glioma cells. METHODS: In a collection of GBM neurosphere lines, we genetically inhibited CBF1 and investigated the consequences on EMT related properties, including in vitro invasiveness by Boyden chambers assay, chemoresistance using a clinical drug library screen and glycolytic metabolism assessing live-cell extracellular acidification rate. We also compared CBF1 expression in cells exposed to low and high oxygen tension. In silico analysis in large-scale Western and Eastern patient cohorts investigated the clinical prognostic value of CBF1 expression in low- and high-grade glioma as well as medulloblastoma. RESULTS: Mean CBF1 expression is significantly increased in isocitrate dehydrogenase 1 (IDH1) R132H mutant glioblastoma and serves as prognostic marker for prolonged overall survival in brain tumours, particularly after therapy with temozolomide. Hypoxic regions of glioblastoma have higher CBF1 activation and exposure to low oxygen can induce its expression in glioma cells in vitro. CBF1 inhibition blocks EMT activators such as zinc finger E-box-binding homeobox 1 (ZEB1) and significantly reduces cellular invasion and resistance to clinically approved anticancer drugs. Moreover, we indicate that CBF1 inhibition can impede cellular glycolysis. CONCLUSIONS: Mean CBF1 activation in bulk tumour samples serves as a clinical predictive biomarker in brain cancers but its intratumoral and intertumoral expression is highly heterogeneous. Microenvironmental changes such as hypoxia can stimulate the activation of CBF1 in glioblastoma. CBF1 blockade can suppress glioblastoma invasion in vitro in particular in cells undergone EMT such as those found in the hypoxic niche. Targeting CBF1 can be an effective anti-EMT therapy to impede invasive properties and chemosensitivity in those cells. PMID- 28571044 TI - A wealth of tobacco control research in New Zealand: time for the New Zealand Government to do its bit. PMID- 28571045 TI - New Zealand doctors' and nurses' views on legalising assisted dying in New Zealand. AB - BACKGROUND: Assisted dying (AD) has been legalised by statute or court decisions in at least 15 jurisdictions internationally. Nonetheless, only three medical professional bodies (and none in nursing) across those jurisdictions have proactively developed authorised policy, practice standards, guidelines or protocols, or other professional supports for health practitioners who may legally participate in AD services, and the majority internationally remain formally opposed to AD. There is a perceived likelihood that AD may be legalised in New Zealand soon. AIM: This study explored the views of doctors and nurses as to support for or opposition to legalising AD, including reasons for those views, what might deter generally willing doctors and nurses from providing AD services and what professional supports were perceived as essential or desirable to enable willing engagement in AD service provision. RESULTS: While only 37% of doctors supported legalising AD in New Zealand, 67% of nurses were supportive. Of those respondents who were willing in principle to provide AD services, large majorities identified a range of practical and ethical professional supports as essential to safe practitioner engagement. Those respondents overwhelmingly saw the provision of most of those supports as the responsibility of the medical and nursing professional bodies. CONCLUSION: There is a substantial cohort of doctors and nurses in New Zealand who support legalising AD, potentially sufficient for reasonable seeker access to AD services once legalised. However, many doctors in particular still oppose AD, and international research shows that the main barrier to access to legal AD is a lack of capacity and capability among health professionals, due in large part to several related factors, in particular: a lack of either accredited training and education for the AD provider tasks and roles; inadequate immunities within the legislation to protect participating professionals; and most importantly, a lack of practice standards and guidelines authorised by the relevant medical and nursing professional bodies. The challenge is for such protections to be available well in advance of legalisation, so that health practitioners are not at risk ethically or otherwise in early participation. PMID- 28571046 TI - New Zealand tobacco control experts' views towards policies to reduce tobacco availability. AB - AIM: Higher tobacco retailer density promotes smoking by making cigarettes more accessible and available, and by increasing environmental cues to smoke. We aimed to examine tobacco control experts' views on policies that could reduce tobacco retail availability. METHODS: Telephone interviews with 25 individuals drawn from academia, non-governmental organisations, Maori and Pacific health, smoking cessation services, district health boards and other public health-related organisations. We used a semi-structured interview guide to explore the perceived importance of reducing tobacco retail supply, views on different policy options and barriers to policy adoption. Qualitative content analysis was conducted using transcripts as the data source. RESULTS: Participants believed tobacco retailer licensing was an important short-term step towards the 2025 goal. In the long term, participants envisaged tobacco only being available at a small number of specialised outlets, either pharmacies or adult-only stores. To achieve that long term scenario, participants suggested a sinking-lid policy on licences or a zoning approach could be adopted to gradually reduce outlet density. Policies banning sales at certain types of outlet were not considered feasible. CONCLUSIONS: There is tension between the tobacco retail reduction policies seen as more likely to be politically acceptable, and the need to make substantial changes to the tobacco retail environment by 2025. Future research could investigate possible legal mechanisms for requiring existing tobacco retailers to transition out of selling tobacco. PMID- 28571043 TI - MicroRNA-7 suppresses the homing and migration potential of human endothelial cells to highly metastatic human breast cancer cells. AB - BACKGROUND: MicroRNA-7 (miR-7) has been observed as a potent tumour suppressor in multiple cancer types including breast cancer. The aim of this study was to investigate the response sensitivities of metastatic breast cancer cells to miR-7 and the roles of miR-7 in the interaction of endothelial cells and metastatic cancer cells. METHODS: Expression profile of miRNAs in a breast cancer specimen cohort and breast cancer cells were determined using real-time quantitative miRNA assays. Effect of the altering expression of miR-7 on migration, invasion, proliferation, interaction and underlying molecular mechanism of breast cancer cells and endothelial cells was investigated after treatment with the synthesised mimic of miR-7. Luciferase activity analysis was performed to validate Wave-3 as a novel target of miR-7. RESULTS: miR-7 expression was negatively correlated with the stage, grade and survival of the breast cancer patients. There was also differential expression of miRNAs including miR-7 in the breast cancer cells. The synthesised mimic of miR-7 inhibits the motility and wound healing potential of breast cancer cells. The highly metastatic MDA-MB-231 cells are more sensitive to the miR-7 treatment than the poorly invasive MCF-7 cells. Treatment with miR-7 downregulated the expression of EGFR, IGF1R and Wave3 in MDA-MB-231 cells but not in MCF-7 cells. In addition, we further demonstrated that miR-7 inhibited the proliferation, migration and invasion of endothelial cells. And more importantly, miR-7 suppressed the homing and migration of endothelial cells to more aggressive tumour cell conditions. CONCLUSIONS: Given the dual inhibitory effect of miR-7 on metastatic breast cancer cells alone and the interaction of endothelial cells with the tumour-conditioned microenvironment, we suggest miR-7 may be a new therapeutic candidate for its capacity not only to prevent breast cancer cell spreading but also to inhibit tumour-associated angiogenesis in the metastatic breast cancer. PMID- 28571047 TI - Perspectives of key stakeholders and smokers on a very low nicotine content cigarette-only policy: qualitative study. AB - AIMS: To investigate views of New Zealand key stakeholders (stakeholders) and smokers on very low nicotine content (VLNC) cigarettes, and a policy mandating that only VLNC cigarettes are available for sale. METHODS: Using a semi structured interview schedule, we interviewed 17 stakeholders and held focus groups with 21 smokers. Questions were asked about VLNC cigarettes and a VLNC cigarette-only policy. Smokers were given approximately 15 VLNC cigarettes to take home and smoke. One week after the focus groups, 17 smokers were interviewed. Data were analysed using a general inductive approach. RESULTS: Stakeholders and smokers were largely unconvinced of the value of a mandated reduction in nicotine in cigarettes. After smoking VLNC cigarettes, smokers had less interest in them but would support them being sold alongside high nicotine content (HNC) cigarettes at a much cheaper price. CONCLUSION: The government is not likely to mandate nicotine reduction in cigarettes if there is a perceived lack of support from stakeholders or smokers. However, they could make VLNC cigarettes available as an option for smokers utilising a differential tax favouring VLNC cigarettes. If this were combined with better access to nicotine containing e-cigarettes, smokers may shift away from HNC cigarettes. PMID- 28571048 TI - Reduced tobacco consumption, improved diet and life expectancy for 1988-1998: analysis of New Zealand and OECD data. AB - AIM: We compared changes in tobacco consumption and diet in relation to changes in life expectancy in 1988-1998 in 22 OECD (Organisation for Economic Cooperation and Development) countries. METHOD: Between 1985 and 1995 using regression analysis we estimated differences in tobacco consumption per adult and the differences in the sum of atherogenic and thrombogenic indices against life expectancy. Each index was derived from the various fats per gram of food from standard texts, and from the annual measurements of fat in the food balance sheets of each country. RESULTS: In 1985-1995, New Zealand showed the largest decrease in tobacco consumption per adult (41%) and the greatest decrease (except for Switzerland) in the sum of atherogenic and thrombogenic indices (17%) as a measure of diet. New Zealand ranked first for life expectancy increases from 1988 1998 for men (3.2 years), women (2.8 years) and both sexes combined. Regression analyses revealed that increases in life expectancy across the OECD for males, but not females, were strongly associated with decreases in tobacco consumption, with a weaker effect of diet improvement. CONCLUSION: These results suggest that reduced tobacco consumption in 1985-1995 likely contributed to New Zealand's gains in life expectancy from 1988-1998. PMID- 28571050 TI - A kick in the butt: time to address tobacco waste in New Zealand. AB - Tobacco consumption is a significant national public health issue. The waste it generates-tobacco product waste (TPW)-is also an environmental hazard. Targeting TPW through novel policies/regulations-such as a cigarette butt deposit scheme may serve the dual purposes of reducing an environment nuisance and progressing Aotearoa New Zealand to its goal of being smokefree by 2025. PMID- 28571049 TI - The combination of bed sharing and maternal smoking leads to a greatly increased risk of sudden unexpected death in infancy: the New Zealand SUDI Nationwide Case Control Study. AB - BACKGROUND: Despite a major reduction in overall infant mortality, sudden unexpected death in infancy (SUDI) continues to be of concern in New Zealand, as the rate is high by international standards, and is even higher in indigenous Maori. AIM: To identify modifiable risk factors for SUDI. METHODS: A three-year (1 March 2012-28 February 2015) nationwide case-control study was conducted in New Zealand. RESULTS: There were 137 SUDI cases, giving a SUDI mortality rate of 0.76/1,000 live births. The rate for Maori was 1.41/1,000, Pacific 1.01/1,000 and non-Maori non-Pacific (predominantly European) 0.50/1,000. The parent(s) of 97% of the SUDI cases were interviewed. Six hundred and forty-nine controls were selected and 258 (40%) were interviewed. The two major risk factors for SUDI were: maternal smoking in pregnancy (adjusted OR=6.01, 95% CI=2.97, 12.15) and bed sharing (aOR=4.96, 95% CI=2.55, 9.64). There was a significant interaction (p=0.002) between bed sharing and antenatal maternal smoking. Infants exposed to both risk factors had a markedly increased risk of SUDI (aOR=32.8, 95% CI=11.2, 95.8) compared with infants not exposed to either risk factor. Infants not sharing the parental bedroom were also at increased risk of SUDI (aOR=2.77, 95% CI=1.45, 5.30). Just 21 cases over the three-year study were not exposed to smoking in pregnancy, bed sharing or front or side sleeping position. CONCLUSIONS: This study has shown that many of the risk factors that were identified in the original New Zealand Cot Death Study (1987-1989) are still relevant today. The combination of maternal smoking in pregnancy and bed sharing is extremely hazardous for infants. Furthermore, our findings indicate that the SUDI prevention messages are still applicable today and should be reinforced. SUDI mortality could be reduced to just seven p.a. in New Zealand (approximately one in 10,000 live births). PMID- 28571051 TI - A comparison of the use of interpreters in New Zealand and the US. AB - Cultural competency in medicine is not possible unless language differences are addressed effectively. Many disparities that appear to be based on cultural, socioeconomic, demographic and other differences can be reduced or eliminated with the use of qualified medical interpretation and translation in multilingual situations. The development of this precious resource varies from country to country around the world as most developed countries face increasingly diverse groups of immigrants and refugees as well as inclusion of more indigenous groups of patients. The US has been one of the leaders in this area since the 1980s. Countries like New Zealand are in different stages of development and on different pathways. Increased international collaboration may facilitate evolution of cost-effective inclusion of professional medical interpreters as part of multidisciplinary health care teams. PMID- 28571053 TI - Intramural oesophageal haematoma-a rare complication of dabigatran. AB - An 85-year-old female presented to hospital with haemoptysis. She underwent investigations which confirmed oesophageal submucosal haematoma. Oesophageal haematoma along with Mallory-Weiss and Boerhaave's syndromes make up acute mucosal injury of the oesophagus. It can be managed conservatively in the majority of cases. PMID- 28571052 TI - Melioidosis with possible Haemophagocytic lymphohistiocytosis. PMID- 28571054 TI - Ocular exposure to paraquat resulting in keratopathy, pseudomembranous conjunctivitis and symblepharon. PMID- 28571055 TI - Potential Drug Interactions and Drug Risk during Pregnancy and Breastfeeding: An Observational Study in a Women's Health Intensive Care Unit AB - Introduction In the pregnancy-puerperal cycle, women may develop complications that require admission to the Intensive Care Unit (ICU). Thus, special attention to pharmacotherapy is necessary, particularly to potential drug interactions (PDIs) and to the effect of the drugs on the fetus and newborn. Objective The aim of this study was to determine the profile of PDIs and the potential risk of drugs used during pregnancy and breastfeeding among patients admitted to the ICU. Methods We conducted an observational, cross-sectional and prospective study, including pregnant and breastfeeding women admitted to the ICU at the Women's Hospital of a university in the city of Campinas, Brazil, for one year. Online databases were used to identify and classify the PDIs and the potential risk of the drugs used during pregnancy and breastfeeding. Results We evaluated 305 prescriptions of 58 women, 31 pregnant and 27 breastfeeding, and 284 (91%) prescriptions presented PDIs. A total of 175 different combinations of PDIs were identified in the prescriptions, and adverse effects caused by the simultaneous use of drugs were not actually observed in the clinical practice. A total of 26 (1.4%) PDIs were classified as contraindicated. We identified 15 (13.8%) drugs prescribed with risk D, and 2 (1.8%) with risk X for pregnant women, as well as 4 (4.9%) drugs prescribed with high risk for breastfeeding women. Conclusions This study demonstrates that there is a high incidence of PDIs in prescriptions. Most drugs used by pregnant and breastfeeding women at the ICU did not present serious risks to their fetus and newborns, but sometimes drugs with risk D or X are necessary in the course of the treatment. PMID- 28571056 TI - [Not Available]. PMID- 28571057 TI - [Not Available]. PMID- 28571058 TI - Beyond the Facelift: Procedures to Enhance Rhytidectomy. PMID- 28571060 TI - Surgical Anatomy for Facelift. PMID- 28571059 TI - The History of Rhytidectomy. PMID- 28571061 TI - Psychology of the Facelift Patient. AB - This paper presents an extensive literature review of the psychology of facelift patients as it has evolved over the past 50 years. Earlier studies revealed significant levels of pre and perioperative depression. Facelift patients generally exhibit emotional and social concerns about facial appearance that are higher than the general population. Many are undergoing midlife situational stresses and may lack the positive characteristics to deal with them. The most common diagnoses seen include depression, impulsivity, unstable personality, and passive dependence, albeit not necessarily serious. Improvement in body image is the major driver for surgery. Characteristics of female patients as defined by their age are described. These include the younger emotionally dependent group, the worker group of middle age, and the older grief group. Male patients are seen to have a higher level of psychological dysfunction, but a higher improvement in postoperative quality of life. Motivations for surgery include increasing self esteem, making new friends, improving relationships, and getting better jobs. Overall patient satisfaction is more than 95%, with improvement seen in positive changes in their life, increased self-confidence and self-esteem, decreased self consciousness about their appearance, and overall improvement in quality of life. Postoperative psychological reactions are seen in about half the patients, these primarily being anxiety and depression of varying degrees. Predictors of patient satisfaction include the desire for self-image improvement in contradistinction to a change in life situation. Negative predictors include male sex, young age, unrealistic expectations, relationship disturbances, and preexisting psychological pathology. The importance of good patient selection in achieving a satisfied patient is outlined and emphasized. PMID- 28571062 TI - The Superficial Musculoaponeurotic System Facelift: A Prudent Balance of Risks and Benefits. PMID- 28571064 TI - The Difficult Neck in Facelifting. AB - As the popularity and acceptance of facial and cervical rejuvenation procedures grows, surgeons are increasingly encountering patients with less favorable anatomical characteristics for rhytidectomy. These patients will typically display an obtuse cervicomental angle, underprojected chin, excess cervical adiposity, and platysmal banding, in addition to ptotic submandibular glands, tenacious jowls, and prejowl volume deficits. Recognition of these problems and the correct application of available techniques to address the difficult neck in facelifting are critical in maximizing success. PMID- 28571063 TI - The Horizontal Neck Lift. AB - The horizontal neck lift is a procedure involving direct excision of a horizontally oriented ellipse of skin from the neck. This procedure was developed for neck rejuvenation in patients with significant horizontal creases and excess skin of the middle and lower neck, areas that often cannot be adequately addressed with traditional techniques. This article describes the procedure, indications, patient counseling, and postoperative care in detail from the senior author's (H. M.) experience. PMID- 28571065 TI - Cheek and Chin Implants to Enhance Facelift Results. AB - The traditional rhytidectomy addresses facial and neck aging as it relates to soft tissue laxity. The modern volumetric facelift provides optimal results by addressing not only skin laxity but also the loss of volume secondary to tissue atrophy and bony resorption. While multiple techniques including fat grafting, dermal fillers, and tissue resuspension are used to correct the tissue loss, alloplastic midface augmentation remains the most permanent method. In our practice we often address midface cheek hollowness or atrophy with the placement of submalar implants at the time of rhytidectomy. In addition to midface volumetric rejuvenation, alloplastic chin implantation can help strengthen and further define a retrusive chin and weak jawline. In this article we discuss technique, indications, and benefits of performing alloplastic augmentation as an adjunct to rhytidectomy. PMID- 28571066 TI - Autologous Fat Grafting Combined with Facelifting. AB - There are multiple factors contributing to facial aging. Rejuvenation of the aging face, therefore, requires a multimodal approach to attain an overall natural and uniform result that is long lasting. Fat grafting has become a very important method for restoring facial soft-tissue atrophy, while facelifting procedures address the ptosis and descent of facial and neck tissue. These modalities performed together offer the patient a comprehensive approach to attain a more attractive and youthful facial appearance. PMID- 28571067 TI - Skin Resurfacing in Combination with Facelift Surgery. PMID- 28571068 TI - Rhytidectomy: Analysis of Videos Available Online. PMID- 28571069 TI - Lateral Crural Tensioning for Refinement of the Nasal Tip and Increasing Alar Stability: A Case Series. PMID- 28571070 TI - Preoperative Simulation in Planning Rhinoplasty: Evaluation from Patients' and Surgeons' Perspectives. AB - Among aesthetic surgery procedures, rhinoplasty is one of the most common. Preoperative simulations have become increasingly commonplace through the recent years along with a controversy regarding their use. Although capable of building a solid rapport between the surgeon and the patient by visualizing the end result, it can also prove to be a liability for a surgeon who is not confident about delivering the result which has been put on screen. The objective of this study is to evaluate the outlook of the surgeons and patients on preoperative simulations. Plastic surgeons who perform rhinoplasty and individuals who consider rhinoplasty were surveyed via an online questionnaire system. Their opinions about the practice of simulation were questioned and they were asked to distinguish between simulated and actual postoperative results. Statistical analyses were performed using SPSS software. Major factors influencing the decision-making process of patients were the availability of preoperative simulation, being shown appealing results of the surgeon's previous work and a personal reference from a patient with an appealing result. Within the health care professionals, it has been observed that experienced surgeons are more confident about using simulations, while inexperienced ones are daunted by being bound with a visual contract (p < 0.05). However, it has been noted that the preference of withholding the simulation or providing a copy to the patient was similar in all experience levels (p > 0.05). In conclusion, our findings suggest that the patients' self-consciousness regarding preoperative simulations seem to grow faster than the surgeons' confidence in their use. Level of evidence is Level V. PMID- 28571071 TI - V-Y Advancement Flap for Defects of the Lid-Cheek Junction. PMID- 28571072 TI - Revision Rhinoplasty: Retrospective Chart Review Analysis of Deformities and Surgical Maneuvers in Patients with Nasal Airway Obstruction-Five Years of Experience. AB - Nasal airway obstruction is one of the most frequent causes of revision rhinoplasty in patients after previous rhinoplasty procedure. Purpose of this study is to present the deformities and the surgical maneuvers conducted in revision rhinoplasty patients with functional complaint, anatomical sites at risk, and potential prophylactic maneuvers. This study is a retrospective chart review analysis of 46 consecutive revision rhinoplasty procedures in patients with nasal airway obstruction. Inclusion criteria were at least one previous rhinoplasty and nasal airway obstruction as the epicenter of patients' complaint. Thorough clinical examination to certify the obstruction was performed. Deformities noted were separated in three categories according to functional, cosmetic, and combination of functional and cosmetic implications. Surgical maneuvers conducted were reviewed. Deformities found were checked for statistically significant coexistences. The average patient age was 34.9 years. The mean number of previous septorhinoplasties was 1.33. Nasal ventilation obstruction mainly caused either by septum deviation or nasal valve dysfunction was identified in 91.3% of our patients. Surgical maneuvers conducted included placement of grafts in 89.1% of all cases, septoplasty in 76.1%, lateral wall support in 47.8%, and placement of spreader grafts in 39.1% of patients. The average preoperative Nasal Obstruction Symptom Evaluation (NOSE) score was 61 +/- 15 and it improved substantially, even from month 1, postoperatively. Owing to high prevalence of nasal airway obstruction after primary or secondary rhinoplasty, we conducted the first retrospective chart review study to identify the most common deformities in revision rhinoplasty patients with nasal airway obstruction and the appropriate surgical maneuvers to address them. Septum deviation and nasal valve dysfunction were the two pillars of nasal airway obstruction in those patients. PMID- 28571073 TI - Effects of Tumescent Solution on Fat Survival. PMID- 28571075 TI - Erratum: Rhytidoplasty: SMAS Imbrication Vector Comparison. PMID- 28571074 TI - Prophylactic Midface Lift in Midfacial Trauma. PMID- 28571076 TI - Erratum: Absorbable Implant to Treat Nasal Valve Collapse. PMID- 28571077 TI - A Systematic Review of Mechanisms of Change in Body-Oriented Yoga in Major Depressive Disorders. AB - INTRODUCTION: Despite empirical evidence for the efficacy of body-oriented yoga as add-on treatment for major depressive disorder (MDD), the specific mechanisms by which yoga leads to therapeutic changes remain unclear. By means of a systematic review, we evaluate how the field is progressing in its empirical investigation of mechanisms of change in yoga for MDD. METHODS: To identify relevant studies, a systematic search was conducted. RESULTS: The search produced 441 articles, of which 5 were included, that empirically examined 2 psychological mechanisms (mindfulness, rumination) and 3 biological mechanisms (vagal control, heart rate variability [HRV], brain-derived neurotrophic factor [BDNF], cortisol). 2 studies found that decreased rumination and 1 study that increased mindfulness was associated with the effect of yoga on treatment outcome. In addition, preliminary studies suggest that alterations in cortisol, BDNF, and HRV may play a role in how yoga exerts its clinical effect. DISCUSSION: The results suggest that body-oriented yoga could work through some of the theoretically predicted mechanisms. However, there is a need for more rigorous designs that can assess greater levels of causal specificity. PMID- 28571078 TI - Incidence of Sudden Unexpected Postnatal Collapse in the Therapeutic Hypothermia Era. PMID- 28571079 TI - Fetal Heart Function by Tricuspid Annular Plane Systolic Excursion and Ventricular Shortening Fraction Using STIC M-Mode: Reference Ranges and Validation. PMID- 28571080 TI - Bioactive Bafilomycins and a New N-Arylpyrazinone Derivative from Marine-derived Streptomyces sp. HZP-2216E. AB - A MeOH extract prepared from culture of an actinomycete Streptomyces sp. HZP 2216E isolated from marine green algae Ulva pertusa was found to significantly inhibit proliferation of human glioma cells. Two different media were applied to culture this marine actinomycete, which produced two new compounds of 23-O butyrylbafilomycin D and streptoarylpyrazinone A, together with known bafilomycin D, 9-hydroxybafilomycin D, and bafilomycin A1. Structures of new compounds were determined by extensive NMR spectroscopic analyses and HRESIMS data. Bioactive assay indicated that all isolated bafilomycins significantly inhibited the proliferation of different glioma cell lines and the growth of methicillin resistant Staphylococcus aureus with 23-O-butyrylbafilomycin D as the most active compound. Streptoarylpyrazinone A is a new N-arylpyrazinone derivative existing as a zwitterion, and this type of compounds was rarely found from natural resources. PMID- 28571081 TI - Emergency and Trauma in MSK Radiology. PMID- 28571082 TI - Upper Limbs Trauma in Pediatrics. PMID- 28571083 TI - Lower Limbs Trauma in Pediatrics. PMID- 28571084 TI - Trauma Imaging of the Acute Cervical Spine. PMID- 28571085 TI - Emergency and Trauma Imaging of the Thoracolumbar Spine. PMID- 28571086 TI - Emergency and Trauma of the Pelvic Ring. PMID- 28571087 TI - Hip and Pelvis: MRI of Musculotendinous Trauma and Mimickers. PMID- 28571088 TI - Emergency and Trauma of Hand and Wrist. PMID- 28571089 TI - Emergency and Trauma of the Elbow. PMID- 28571090 TI - Emergency and Trauma of the Ankle. PMID- 28571091 TI - Cone Beam CT of Trauma of Small Bones and Joints. PMID- 28571092 TI - Imaging Assessment of Thoracic Cage Injuries. PMID- 28571093 TI - Nontraumatic Emergency of the Spine. PMID- 28571094 TI - Imaging of Vascular Injuries of the Extremities. PMID- 28571095 TI - Percutaneous Treatment of Vertebral Fractures. PMID- 28571096 TI - Implant Alternatives for Tibial Osteotomies. PMID- 28571098 TI - Prenatal Brainstem Disruptions: Small Lesions-Big Problems. PMID- 28571100 TI - Diagnosis and New Treatment Avenues in Spinal Muscular Atrophy. PMID- 28571099 TI - Neurological Involvement in Pediatric Hemolytic Uremic Syndrome: A Symptom Oriented Analysis. PMID- 28571102 TI - Antiplatelet Therapy, Platelet Function Testing, and Bleeding Complications in Cardiac Surgery Patients. PMID- 28571101 TI - GNAQ Mutation in the Venous Vascular Malformation and Underlying Brain Tissue in Sturge-Weber Syndrome. PMID- 28571103 TI - Epidemiology and outcomes of missing admission medication history in severe trauma: A retrospective study. AB - OBJECTIVE: Anticoagulant and antiplatelet (ACAP) drugs are associated with increased mortality in trauma patients, therefore medication history on admission is important. Whether these medications are recorded on trauma admission has not been investigated, nor if absence of a medication history is associated with worse patient outcomes. METHODS: We conducted a retrospective database review combining demographic and outcome data from the St George Hospital (Sydney) trauma registry with admission medication history in the electronic record. To contrast medications with a known increased risk (ACAP) to patients with unknown risk, patients were divided into three groups: those on ACAPs, no-ACAP if medication history was present and no-ACAP documented, or no-Hx if no medication history recorded. Inclusion criteria were aged >16 and Injury Severity Score (ISS) >12. Admission demographic data and outcome data were compared between all three groups. RESULTS: Of 533 consecutive patients, 21% comprised the no-Hx group, while 22% were on an ACAP and 57% not on an ACAP. No-Hx patients had more severe head injuries and a younger median age compared to ACAP patients (42 vs 82 years old, P < 0.001). Mortality was higher for ACAP (24%; 95% CI 17-33%) compared to no-ACAP (11%; 95% CI 8-16%) or no-Hx patients (12%; 95% CI 7-20%) (P = 0.04). CONCLUSIONS: While a large number of severe trauma patients were admitted without a medication history, no-Hx patients did not appear at increased risk of adverse outcomes. ACAP patients had a higher mortality compared to no ACAP highlighting the vulnerability of this group. PMID- 28571104 TI - A review of the burns caseload of a physician-based helicopter emergency medical service. AB - OBJECTIVES: The aim of this study was to describe patient demographics, injuries, physiology and interventions performed by retrieval physicians in the care of burns patients in both a pre-hospital and interhospital setting. METHODS: A retrospective review of patient records from a large Australian Helicopter Emergency Medical Service was conducted. Demographics, injury, burn type, physiology and intervention data were extracted into a database for statistical analysis. Basic descriptive statistics were calculated, and patient physiology measures were compared at arrival and destination. RESULTS: A total of 490 burns cases were identified from a 5 year period (January 2010-August 2015). The majority (78.6%) were interhospital transfers conducted by road (49.4%) or helicopter (36.9%). Patients were predominantly men (75.7%) with a median age of 37 years (interquartile range [IQR] 23-50). Median estimated total body surface area burned was 15% (IQR 8.5-20) and 18% (IQR 10-30) in pre-hospital and interhospital groups, respectively; however, retrieval physicians tended to overestimate total body surface area burned in comparison to destination burns units. Flash burn or explosion were the predominant aetiology of burn (49.4%), although the majority (95.3%) of patients had no associated traumatic injuries. Sixty patients were intubated by the Service. Escharotomies were performed on eight occasions resulting in improvement in circulation or ventilation. Overall mortality was 3.7% at 24 h. CONCLUSIONS: The Service cares for 80-100 burns patients annually, a proportion of whom require complex interventions such as intubation and escharotomy, which was performed by retrieval physicians appropriately. Associated traumatic injuries were infrequent in patients who sustained burns from flashes or explosions. PMID- 28571105 TI - Visualising emergency department capacity in an 'Emergency Department Capacity Clock': A novel tool to assess and communicate overcrowding and access block. AB - Hospital-wide engagement is required to alleviate the problem of ED crowding and its associated adverse effects. To this end, the article describes a novel visualisation termed 'the ED Capacity Clock', which can be formatted using business intelligence software. This radial diagram represents ED capacity and its consumption in a format that can be understood intuitively and at a glance. The ED Capacity Clock is designed to promote common understanding and discussion between relevant hospital services and also acts as an auditing tool to monitor processes implemented to alleviate ED crowding. PMID- 28571106 TI - SDF-1alpha peptide tethered polyester facilitates tissue repair by endogenous cell mobilization and recruitment. AB - The design of bioactive scaffolds that can invoke host's own regenerative capabilities and facilitate endogenous tissue repair hold great promise. This study aims to evaluate the potential of stromal cell-derived factor 1 alpha (SDF 1alpha)-derived peptide and heparin tethered poly(L-lactide-co-epsilon caprolactone) (PLCL) copolymers for blood vessel regeneration applications. Amino acid analysis and toluidine blue assays confirm successful conjugation of SDF 1alpha peptide and heparin with the PLCL copolymers. Assessment of biocompatibility after subcutaneous implantation in rats discloses higher cell infiltration in SDF-1alpha peptide (SDF-1 group) or SDF-1 peptide and heparin (SDF-1/heparin group) than the control group. SDF-1 and SDF-1/heparin grafts also show more numbers of laminin+ blood vessels, CD90+ stem cells, and alpha smooth muscle actin+ cells than the control group. However, SDF-1 and SDF-1/heparin groups did not significantly differ in terms of blood vessel regeneration and stem cell recruitment. Evaluation of the inflammatory response reveal less numbers of CD68+ macrophages in SDF-1 and SDF-1/heparin groups compared with the control group; whereas three groups show similar numbers of CD206+ macrophages. These results indicate that completely synthetic, cell-free grafts can attract endogenous cells and enhance tissue repair. Bioactive polyesters can be fabricated into different shapes and structures for various tissue engineering applications. (c) 2017 Wiley Periodicals, Inc. J Biomater Res Part A: 105A: 2670 2684, 2017. PMID- 28571107 TI - Age-Specific Prevalence of Binge and High-Intensity Drinking Among U.S. Young Adults: Changes from 2005 to 2015. AB - BACKGROUND: This study examined changes during the past decade, from 2005 to 2015, in binge and high-intensity drinking in 7 separate age groups of U.S. 12th graders and young adults. METHODS: National longitudinal data (N = 6,711) from Monitoring the Future were used to examine trends in consuming 5+, 10+, and 15+ drinks on the same occasion in the past 2 weeks from ages 18 to 29/30 overall and by gender. Results were compared with trends in past 12-month and 30-day alcohol use for the same age groups. RESULTS: Between 2005 and 2015, binge (5+) and high intensity drinking (10+, 15+) generally decreased for individuals in their early 20s, remained somewhat stable for individuals in their mid-20s, and increased for individuals at the end of young adulthood (age 29/30). The observed historical trends in binge and high-intensity drinking were similar to those for past 12 month and past 30-day alcohol use for those aged 18 to 20, but diverged for most other age groups in young adulthood. Trends were generally similar for men and women, except that the increase in prevalence began earlier in young adulthood for women than for men. CONCLUSIONS: Binge and high-intensity drinking among U.S. 12th graders and young adults are dynamic phenomena. Prevention and intervention efforts aimed at reducing the harms resulting from 5+, 10+, and 15+ drinking should acknowledge and focus on differences in trends in these behaviors by age and gender. PMID- 28571109 TI - Fabrication of in situ polymerized poly(butylene succinate-co-ethylene terephthalate)/hydroxyapatite nanocomposite to fibrous scaffolds for enhancement of osteogenesis. AB - A combination of elastic poly(butylene succinate-co-ethylene terephthalate) and rigid nano-hydroxyapatite were used to prepare an in-situ synthesized nanocomposite mimicing bone structure. The microstructure, morphology, and dispersion of nanoparticles in the nanocomposites were studied using proton nuclear magnetic resonance (1 HNMR), scanning electron microscope (SEM), and transmission electron microscopy (TEM), respectively. Then, electrospinning method was used to produce nanofiber matrix with lowest fiber diameter. Presence of chemical bonds among nanoparticles and polymer leads to the excellent particle dispersion and solution phase stability. SEM results show that continuous and bead-free nanofibers were produced and incorporating nanoparticle slightly increased fibers diameter. Elastic modulus, tensile strength, crystallinity, hydrophilicity and hydrolytic degradability of resulted nanofiber increased with nanoparticle but elongation at break slightly decreased. Proliferation and osteogenic differentiation of human mesenchymal stem cell significantly improved by introducing nanoparticle which indicate that electrospun nanofibers could be used as scaffolds for bone tissue engineering. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2622-2631, 2017. PMID- 28571108 TI - Quinary interactions with an unfolded state ensemble. AB - Anfinsen's thermodynamic hypothesis states that the native three-dimensional fold of a protein represents the structure with the lowest Gibbs free energy. Changes in the free energy of denaturation can arise from changes to the folded state, the unfolded state, or both. It has been recently recognized that quinary interactions, transient contacts that take place only in cells, can modulate protein stability through interactions involving the folded state. Here we show that the cellular environment can also remodel the unfolded state ensemble. PMID- 28571110 TI - A new teaching model for demonstrating the movement of the extraocular muscles. AB - The extraocular muscles consist of the superior, inferior, lateral, and medial rectus muscles and the superior and inferior oblique muscles. This study aimed to create a new teaching model for demonstrating the function of the extraocular muscles. A coronal section of the head was prepared and sutures attached to the levator palpebral superioris muscle and six extraocular muscles. Tension was placed on each muscle from a posterior approach and movement of the eye documented from an anterior view. All movements were clearly seen less than that of the inferior rectus muscle. To our knowledge, this is the first cadaveric teaching model for demonstrating the movements of the extraocular muscles. Clin. Anat. 30:733-735, 2017. (c) 2017Wiley Periodicals, Inc. PMID- 28571111 TI - Occupational solvent exposure and adult chronic lymphocytic leukemia: No risk in a population-based case-control study in four Nordic countries. AB - The aim of this study was to assess the effect of occupational solvent exposure on the risk of adult chronic lymphocytic leukemia (CLL). The current case-control study was nested in the Nordic Occupational Cancer Study (NOCCA) cohort. 20,615 CLL cases diagnosed in 1961-2005 in Finland, Iceland, Norway, and Sweden, and 103,075 population-based controls matched by year of birth, sex, and country were included. Occupational histories for cases and controls were obtained from census records in 1960, 1970, 1980/1981, and 1990. Exposure to selected solvents was estimated by using the NOCCA job-exposure matrix (NOCCA-JEM). Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by using conditional logistic regression models. Overall, nonsignificant CLL risk elevations were observed for methylene chloride, perchloroethylene, and 1,1,1-trichloroethane. Compared to unexposed, significantly increased risks were observed for cumulative perchloroethylene exposure <=13.3 ppm-years (OR = 1.85, 95% CI 1.16-2.96) and average life-time perchloroethylene exposure <=2.5 ppm (1.61, 95% CI 1.01-2.56) among women, and cumulative methylene chloride exposure <=12.5 ppm-years (OR = 1.19, 95% CI 1.01-1.41) and 12.5-74.8 ppm-years (OR = 1.23, 95% CI 1.01-1.51) among men in an analysis with 5 years lag-time, though without dose-response pattern. Decreased CLL risk was observed for aliphatic and alicyclic hydrocarbon solvents and toluene. This study did not support associations for solvent exposure and CLL. Observed weak associations for methylene chloride, perchloroethylene, 1,1,1-trichloroethane exposures, aliphatic and alicyclic hydrocarbons and toluene were not consistent across sexes, and showed no gradient with amount of exposure. PMID- 28571112 TI - A Translational Systems Pharmacology Model for Abeta Kinetics in Mouse, Monkey, and Human. AB - A mechanistic model of amyloid beta production, degradation, and distribution was constructed for mouse, monkey, and human, calibrated and externally verified across multiple datasets. Simulations of single-dose avagacestat treatment demonstrate that the Abeta42 brain inhibition may exceed that in cerebrospinal fluid (CSF). The dose that achieves 50% CSF Abeta40 inhibition for humans (both healthy and with Alzheimer's disease (AD)) is about 1 mpk, one order of magnitude lower than for mouse (10 mpk), mainly because of differences in pharmacokinetics. The predicted maximal percent of brain Abeta42 inhibition after single-dose avagacestat is higher for AD subjects (about 60%) than for healthy individuals (about 45%). The probability of achieving a normal physiological level for Abeta42 in brain (1 nM) during multiple avagacestat dosing can be increased by using a dosing regimen that achieves higher exposure. The proposed model allows prediction of brain pharmacodynamics for different species given differing dosing regimens. PMID- 28571113 TI - Comparison of the effects of 45S5 and 1393 bioactive glass microparticles on hMSC behavior. AB - Bioactive glasses (BAGs) are highly interesting materials for bone regeneration applications in orthopedic and dental defects. It is quite well known that ionic release from BAGs influences cell behavior and function. Mindful of the clinical scenario, we hypothesized that local cell populations might additionally physically interact with the implanted BAG particles and respond differently than to just the ionic stimuli. We therefore studied the biological effect of two BAG types (45S5 and 1393) applied to human mesenchymal stromal cells (hMSCs) in three distinct presentation modes: (a) direct contact; and to dissolution products in (b) 2D, and (c) 3D culture. We furthermore investigated how the dose-dependence of these BAG particles, in concentrations ranging from 0.1 to 2.5 w/v %, influenced hMSC metabolic activity, proliferation, and cell spreading. These cellular functions were significantly hampered when hMSCs were exposed to high concentrations of either glasses, but the effects were more pronounced in the 45S5 groups and when the cells were in direct contact with the BAGs. Furthermore the biological effect of 1393 BAG outperformed that of 45S5 BAG in all tested presentation modes. These outcomes highlight the importance of investigating cell BAG interactions in experimental set-ups that recapitulate host cell interactions with BAG particles. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2772-2782, 2017. PMID- 28571115 TI - Improvement of covalent immobilization procedure of beta-galactosidase from Kluyveromyces lactis for galactooligosaccharides production: Modeling and kinetic study. AB - Galactooligosaccharides (GOS) are prebiotics produced from lactose through an enzymatic reaction. Employing an immobilized enzyme may result in cost reductions; however, the changes in its kinetics due to immobilization has not been studied. This study experimentally determined the optimal reaction conditions for the production of GOS from lactose by beta-galactosidase (EC 3.2.1.23) from Kluyveromyces lactis covalently immobilized to a polysiloxane polyvinyl alcohol (POS-PVA) polymer activated with glutaraldehyde (GA), and to study the transgalactosylation kinetics. Yield immobilization was 99 +/- 1.1% with 78.5 +/- 2.4% enzyme activity recovery. An experimental design 24 with 1 center point and 2 replicates was used. Factors were lactose [L], enzyme concentration [E], pH and temperature (T). Response variables were glucose and galactose as monosaccharides [G1], residual lactose [Lac]r and GOS as disaccharides [G2] and trisaccharides [G3]. Best conditions were pH 7.1, 40 degrees C, 270 gL-1 initial lactose concentration and 6 U mL-1 enzyme concentration, obtaining 25.46 +/- 0.01 gL-1 yield of trisaccharides. Although below the HPLC-IR detection limit, tetrasaccharides were also identified after 115 min of reaction. The immobilization protocol was then optimized by diminishing total reactant volumes : support ratio, resulting in improved enzyme activity synthesizing 43.53 +/- 0.02 gL-1 of trisaccharides and 13.79 +/- 0.21 gL 1 of tetrasaccharides, and after four cycles remaining relative activity was 94%. A reaction mechanism was proposed through which a mathematical model was developed and rate constants were estimated, considering a pseudo steady-state hypothesis for two concomitant reactions, and from this simplified analysis, the reaction yield could eventually be improved. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1568-1578, 2017. PMID- 28571116 TI - Plasma microRNA signature is associated with risk stratification in prostate cancer patients. AB - The aim of this study was to establish a unique expression profile of circulating cell-free microRNAs (miRNAs) capable of differentiating between prostate cancer (PCa) patients with high-risk and intermediate-risk Gleason scores. MiRNA expression profiles were determined in plasma samples from 79 treatment-naive PCa patients, 1-2 follow-up samples after radical prostatectomy (RP) from 51 out of the 79 PCa patients, and 33 healthy men, using a quantitative real-time PCR-based array containing 48 selected miRNAs. We identified 27 up- and 2 downregulated plasma miRNAs in PCa patients compared with healthy men. Most of the upregulated miRNA levels were also associated with increasing PSA levels and Gleason scores. Particularly, the levels of miR-16 (p = 0.002), miR-148a (p = 0.006) and miR-195 (p = 0.006) significantly correlated with high-risk Gleason scores, whereby miR 148a (p = 0.003) was also significantly associated with increasing PSA values. The high miRNA levels before RP remained increased in the postsurgical plasma samples. Our findings show a network of deregulated plasma miRNAs. In particular, miR-16, miR-148a and miR-195 are involved in the regulation of the PI3K/Akt signaling pathway. These miRNAs may be promising therapeutic targets for high risk PCa stratification. PMID- 28571114 TI - Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib-Treated Cancer. AB - The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR-2 and sVEGFR-3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C-II-005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-event (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD-guided strategies for the individualization of anti-angiogenic therapies. PMID- 28571117 TI - Do all adult orthopaedic injuries seen in emergency departments need to attend fracture clinic? A Queensland multicentred review. AB - OBJECTIVE: Musculoskeletal injuries account for a significant proportion of ED presentations annually, with a large percentage being referred to the fracture clinic (FC). A literature review found that many referrals could be safely managed outside the traditional model of care. The present study aims to review all adult presentations to FCs at two Queensland metropolitan hospitals, finding low-risk injuries that can safely and appropriately be managed by their general practitioner (GP) or allied health professionals (AHPs), potentially affording significant savings to the health system. METHODS: A retrospective study at Logan and Redland Hospitals was undertaken, reviewing all adult patients (>=16 years) referred to FCs over an eight week period. Injuries were categorised into those requiring FC care supervised by an orthopaedic surgeon (fracture clinic pathway) and those that could be safely managed by GPs or AHPs, with the aid of evidence based, protocol-driven guidelines known as the primary care pathway (PCP). RESULTS: A total of 1367 patients were referred to FC over the study period, of whom 546 (40%) were assessed as suitable candidates for PCP. Redland Hospital accounted for 65% of all PCP-suitable patients, whereas Logan Hospital accounted for 35%. Failure-to-attend rates were significantly higher (P < 0.001) in the PCP patients compared to other patients attending FCs. CONCLUSION: Adopting the PCP could potentially reduce fracture clinic referrals by 40%. Having a structured pathway has the potential to empower primary health professionals, which could result in a more streamlined process that aids in significant time and financial savings and maintains good patient satisfaction and outcomes. PMID- 28571118 TI - The role of oxidative stress in EBV lytic reactivation, radioresistance and the potential preventive and therapeutic implications. AB - Epstein-Barr virus (EBV) is an important cancer causing virus. Cancer associated with EBV account for approximately 1.5% of all cancers, and represent 1.8% of all cancer deaths worldwide. EBV reactivation plays an important role in the development of EBV-related diseases and is closely related with patients' survival and clinical stages of EBV-related cancers. The therapy regarding to EBV related cancers is very urgent, especially in endemic areas. Generating oxidative stress is a critical mechanism by which host cells defend against infection by virus. In addition, ROS-mediated oxidative stress plays a significant but paradoxical role acting as a "double-edged sword" to regulate cellular response to radiation, which is the main therapy strategy for EBV-related cancers, especially nasopharyngeal carcinoma. Therefore, in this review we primarily discuss the possible interplay among the oxidative stress, EBV lytic reactivation and radioresistance. Understanding the role of oxidative stress in EBV lytic reactivation and radioresistance will assist in the development of effective strategies for prevention and treatment of EBV-related cancers. PMID- 28571119 TI - Item Response Theory to Quantify Longitudinal Placebo and Paliperidone Effects on PANSS Scores in Schizophrenia. AB - As biomarkers are lacking, multi-item questionnaire-based tools like the Positive and Negative Syndrome Scale (PANSS) are used to quantify disease severity in schizophrenia. Analyzing composite PANSS scores as continuous data discards information and violates the numerical nature of the scale. Here a longitudinal analysis based on Item Response Theory is presented using PANSS data from phase III clinical trials. Latent disease severity variables were derived from item level data on the positive, negative, and general PANSS subscales each. On all subscales, the time course of placebo responses were best described with Weibull models, and dose-independent functions with exponential models to describe the onset of the full effect were used to describe paliperidone's effect. Placebo and drug effect were most pronounced on the positive subscale. The final model successfully describes the time course of treatment effects on the individual PANSS item-levels, on all PANSS subscale levels, and on the total score level. PMID- 28571120 TI - Development of Physiologically Based Organ Models to Evaluate the Pharmacokinetics of Drugs in the Testes and the Thyroid Gland. AB - We extended a generic whole-body physiologically based pharmacokinetic (PBPK) model for rats and humans for organs of the reproductive and endocrine systems (i.e., the testes and the thyroid gland). An extensive literature search was performed, first, to determine the most generic organ model structures for testes and thyroid across species, and, second, to identify the corresponding anatomic and physiological parameters in rats and humans. The testes and thyroid organ models were implemented in the PBPK modeling software PK-Sim and MoBi. The capability of the PBPK approach to simulate the testes and thyroid tissue concentration data was demonstrated using a series of test compounds. The presented organ model structures and parameterization yielded a close agreement between observed and simulated tissue concentrations over time. The organ models are ready to be used to predict the pharmacokinetics of passively entering drugs in the testes and thyroid tissue in a generic PBPK modeling framework. PMID- 28571121 TI - Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation: Report of an FDA Public Workshop. AB - On May 19, 2016, the US Food and Drug Administration (FDA) hosted a public workshop, entitled "Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation." The topic of mechanistic oral absorption modeling, which is one of the major applications of physiologically based pharmacokinetic (PBPK) modeling and simulation, focuses on predicting oral absorption by mechanistically integrating gastrointestinal transit, dissolution, and permeation processes, incorporating systems, active pharmaceutical ingredient (API), and the drug product information, into a systemic mathematical whole-body framework. PMID- 28571122 TI - Detecting the Non-physiological, Surgically Tailored Ileocolic Anastomosis Using the Wireless Motility Capsule. A Pre- and Post-operative, Prospective, Within Subject Trial. AB - Background/Aims: Wireless motility capsule (WMC) detects the ileocolic junction (ICJ) in most non-operated patients. We find no data concerning this examination in patients where the ileocolic valve is replaced by a per definition incompetent, surgically created ICJ. We wanted to see if WMC could detect the ICJ after a right colectomy and assess the competency. Methods: Prospective cohort study using a within-subject design to eliminate subject-subject variability. Selected patients operated with right colectomy underwent 3 WMC examinations (pre operatively, 3 weeks, and 6 months after surgery). Results: Twenty patients (8 men) included, 7 (4 men) excluded due to poor recordings (4) and unforeseen events (3). Thirteen patients (4 men), median age 63 years completed 3 tests. Median bowel lengths removed were 11 cm for ileum and 21 cm for colon. Thirty nine examinations analyzed by 2 physicians who found all 13 ICJs at 3 examinations with high inter-rater reliability (intra-class correlation coefficient: 0.99, 0.91, and 0.99 respectively), whereas the computer found 9, 8, and 10 out of the 13 ICJs, respectively. Computed values significantly more often deviated from the 2 raters. Mean magnitude and duration of pH-drop at the ICJ (3 examinations) was 1.16-1.02-1.13 pH units and 3.15-4.78-3.75 minutes, respectively. pH-drop was smaller and duration longer at 3 weeks. We found no differences between the pre-operative (competent ICJ) and post-operative 6-month examinations (incompetent ICJ). Highest pressure immediately prior to ICJ was equal before and after surgery. Conclusion: WMC can identify the non physiological ICJ after right colectomy. Ileocolic competence cannot be assessed. PMID- 28571123 TI - Correction: eIF3f reduces tumor growth by directly interrupting clusterin with anti-apoptotic property in cancer cells. PMID- 28571124 TI - Correction: PDGFRalpha depletion attenuates glioblastoma stem cells features by modulation of STAT3, RB1 and multiple oncogenic signals. PMID- 28571125 TI - Preinguinal Splitting and Reunion of Femoral Nerve Entrapping the Fleshy Fibres of Iliacus Muscle - A Case Report. AB - Division of nerves close to their origin and muscular entrapments by nerves in the limbs is not very common. Femoral nerve is the largest branch of the lumbar plexus and arises from dorsal divisions of ventral rami of L2 to L4 spinal nerves. During routine cadaveric dissection for first year medical students at Melaka Manipal Medical College (Manipal Campus), Karnataka, India, we observed a variation in the division and course of left femoral nerve in about 65-year-old male cadaver. The femoral nerve was split into two divisions above the inguinal ligament after its origin from the lumbar plexus. The lower division of the nerve passed deep to the iliopsoas muscle fibres and the upper division ran superficial to iliacus muscle deep to fascia iliaca. Both the divisions joined just above the inguinal ligament to form the trunk of the femoral nerve. Further course and distribution of the nerve was normal. The reports have shown that compression neuropathies of femoral nerve in the limbs are caused by neoplastic masses, vascular abnormalities and also by different anomalous muscles. Such neuropathies may also result from indirect compression of femoral nerve between the fibres of psoas major muscle and lateral pelvic wall. The potential clinical importance of above mentioned variations in the division of femoral nerve would emphasize the surgeons to diagnose the neuromuscular entrapments and consequent alterations of sensation in the anterior and medial aspects of the thigh. PMID- 28571126 TI - Study of Glycated Haemoglobin (HbA1c) In Non-Diabetic Subjects with Subclinical Hypothyroidism. AB - INTRODUCTION: India has the higher prevalence of prediabetes, diabetes and hypothyroidism. Subclinical Hypothyroidism (SH) is more prevalent in the females than in the males. Studies have shown the elevated HbA1c in the non-diabetic hypothyroid patients. SH is defined by normal serum triiodothyronine (T3), thyroxine (T4) levels and serum Thyroid Stimulating Hormone (TSH) level falling between 4.2 to 10 mU/L. AIM: To study the HbA1c level in the non-diabetic SH patients and to compare the HbA1c level with the controls. MATERIALS AND METHODS: This case-control study was conducted on 200 subjects. A total of 100 subjects of the SH without diabetes were selected on the basis of the serum TSH (> 4.2 to < 10 mU/L), Fasting Blood Sugar (FBS) (< 110 mg/dl) level and another 100 age and sex matched normal healthy individuals were selected as the control. The HbA1c levels were measured using Immunoturbidimetry method in the Cobas Integra 400 plus. An independent t-test is applied to find out the statistically significant difference in the level of HbA1c in the case and the control groups. RESULTS: Subjects with the non-diabetic SH had a significant higher level (5.70+/-0.35 %) of the HbA1c than the controls (5.26+/-0.17 %) (p<0.0001). There was no significant difference between the cases and the controls for the age, sex, FBS, vitamin D3, Haemoglobin (Hb), serum T3 and serum T4 levels. CONCLUSION: Our data suggest that the non-diabetic subjects with SH show misleadingly high levels of the HbA1c. Therefore, the effect of altered levels of the serum TSH on the HbA1c must be considered when interpreting the HbA1c for the diagnosis of diabetes in the SH patients. PMID- 28571127 TI - Physicochemical Characteristics of Rat Muscle Glycogen Fractions. AB - INTRODUCTION: Homogenization of animal tissues with cold Perchloric Acid (PCA) produces two fractions of glycogen, Acid Soluble Glycogen (ASG) and Acid Insoluble Glycogen (AIG). AIM: To determine some physicochemical characteristics of muscle glycogen fractions in two groups of rat. MATERIALS AND METHODS: An experimental study was conducted on two groups of five male rats. Rats in control group were kept at rest and in case group on 30 minutes physical activity. The content of carbohydrate, protein, phosphate, index and relative Molecular Weights (MWs) were determined for glycogen fractions. RESULTS: Total glycogen decreased following muscular activity (1.40+/-0.08, mg/g wet muscle vs. 0.97+/-0.11, p<0.05) and the change occurred totally in ASG (1.02+/-0.07 vs. 0.57+/-0.07, p=0.017), whereas, AIG changed insignificantly (0.39+/-0.05 vs. 0.36+/-0.02, p=0.5). The protein content of AIG was about 5.5 times of ASG fraction. The ratio of carbohydrate to protein was 0.33+/-0.01 (mg/mg) in ASG and decreased to 0.19+/ 0.02, p=0.01 after 30 minute activity. This ratio in AIG was about 6% of ASG fraction and did not change significantly during physical activity. The ratio of phosphate to protein was three times in ASG relative to AIG at rest and did not change following activity. The index of molecular weight was calculated for each fraction of glycogen as the ratio of concentration per osmolality (mg/mmol). The index was 1.82+/-0.02 for ASG at rest and decreased significantly to 1.07+/-0.12, p<0.05 following 30 minutes activity. The index did not change significantly for AIG fraction (0.56+/-0.05 vs. 0.48+/-0.10, p=0.4). The relative MW of the fractions of ASG to AIG was 3.3+/-0.3 at rest and decreased significantly to 2.2+/-0.6, p<0.05 following 30 minutes activity. CONCLUSION: Two fractions of muscle glycogen, ASG and AIG, differ in the relative carbohydrate: protein content and ASG have a higher mean of MW and is more metabolic active form. PMID- 28571128 TI - Association Between Serum Cystatin C and Creatinine in Chronic Kidney Disease Subjects Attending a Tertiary Health Care Centre. AB - INTRODUCTION: Chronic Kidney Disease (CKD) is an emerging health problem due to the increasing prevalence of conditions like diabetes mellitus and hypertension. Most patients are diagnosed during the later stages of CKD when the clinical symptoms become apparent. There is a need for early diagnosis to prevent disease progression and associated morbidities. Serum Creatinine (SCr) is commonly used among clinicians to determine renal function. However, SCr is affected by several factors and cannot be entirely relied upon. In pursuit of an alternative indicator of renal function, several biomarkers have been discovered and their utility in prompt diagnosis has been evaluated. Among such biomarkers, serum cystatin C (SCysC) has been extensively studied. AIM: To determine and compare the levels of SCr and SCysC in CKD subjects across various severity groups based on estimated Glomerular Filtration Rate (eGFR). MATERIALS AND METHODS: The study comprised of 120 CKD subjects. SCr was estimated by modified Jaffe's method and SCysC was estimated by particle enhanced immunoturbidimetric method. Estimated GFR (eGFR) was determined using Chronic Kidney Disease Epidemiology collaboration (CKD EPI) 2009 creatinine based formula. Based on eGFR, CKD subjects were further categorized into four groups. Statistical analysis was done using SPSS. Data were represented as median and interquartile range. Kruskal Wallis test was used for comparison between more than two groups. Correlation was done using Pearson's test. Statistical significance was considered as p <0.05. RESULTS: Both SCr and SCysC levels increased significantly across CKD groups (p<0.001). In CKD subjects with eGFR >= 60 ml/min/1.732 m2, the median value of SCr (1.01 mg/dl) was well within the normal range while median value of SCysC (1.34 mg/l) was found to be more than the upper reference limit. A positive correlation was present between SCysC and SCr (r=0.875, p<0.001). Both SCysC (r=-0.736) and SCr (r=-0.719) had a negative correlation with eGFR (p<0.001). CONCLUSION: SCysC is useful in detecting individuals with CKD having mild decrease in GFR compared to SCr. Both SCr and SCysC levels increase with decrease in eGFR. SCysC may be used to screen patients with poorly controlled diabetes mellitus or hypertension when SCr level is inconclusive. PMID- 28571129 TI - Comparative Diagnostic Utility of IS6110 PCR Assay in CSF and Peripheral Blood Samples of Tuberculous Meningitis Patients: A Pilot Study from Central India. AB - INTRODUCTION: Tuberculous Meningitis (TBM) is the most severe form of Central Nervous System Tuberculosis (CNS-TB) and constitutes about 6% of all Extrapulmonary TB (EPTB) cases. Most guidelines for the diagnosis and management of TBM agree on the use of simple Cerebrospinal Fluid (CSF) analysis using molecular tools like Polymerase Chain Reaction (PCR). However, the sensitivity of PCR varies while using a CSF sample. In the present study, we have compared the diagnostic utility of PCR assay in both peripheral blood and CSF sample collected from TBM cases. AIM: To evaluate the application of the peripheral blood PCR assay as an alternate tool for TBM diagnosis compared to conventional CSF-PCR based system. MATERIALS AND METHODS: A total of 50 TBM patients were prospectively recruited from in patient department wards of Central India Institute of Medical Sciences (CIIMS) between January 2014 - Feburary 2015. Mycobacterium tuberculosis (MTB) specific IS6110 PCR and BactT liquid culture were performed in 20 of recruited cases classified as Stage 1, 2 and 3 based on British Medical Research Council (BMRC) contemporary clinical criteria for the severity of TBM. Clinical characteristics were summarised in terms of percentages for categorical variables, i.e., age groups, gender, signs and symptoms. All statistical analysis was carried out using MedCalc software version 11.6. RESULTS: Overall IS6110 PCR positivity in CSF was around 80% (16/20), which was higher than culture (29.3%) and peripheral blood (39%). Out of 8 positive cases, stage wise positivity of peripheral blood PCR assay in three TBM stages was 0% (stage1) 50% (stage 2) and 67% (Stage 3) respectively. Positivity of peripheral blood PCR was significantly more (86%) in patients with CSF culture/ IS6110 PCR positive for MTB infection with sensitivity and specificity of 50 and 100% respectively. Increased positivity rates of peripheral blood PCR was observed with decreased CSF/Blood sugar ratio in stage 3 cases, suggesting enhanced probability of mycobacterial blood dissemination in cases of TBM severity. CONCLUSION: Our results suggest that although the molecular diagnosis of TBM infection in CSF remains the method of choice, peripheral blood based PCR can be used as a good alternative to CSF in case of TBM severity where the repeated CSF collection may be needed. However, study demands further validation in large cohorts to justify the present hypothesis. PMID- 28571130 TI - Effect of DOTS Treatment on Vitamin D Levels in Pulmonary Tuberculosis. AB - INTRODUCTION: Vitamin D (Vit D) modulates a variety of processes and regulatory systems including host defense, inflammation, immunity, and repair. Vit D Deficiency (VDD) is been implicated as a cause in diabetes, immune dysfunction and Tuberculosis (TB). Impaired metabolism of Vit D and an adverse outcome is associated with Pulmonary Tuberculosis (PTB). Directly Observed Treatment Short Course (DOTS) consist of drugs like rifampicin and isoniazid, which respectively cause accelerated loss of Vit D due to increased clearance and impairment of 25 hydroxylation causing diminished Vit D action. AIM: The aim of the present study was to estimate and compare serum Vit D status in newly diagnosed PTB patients before and after DOTS to validate the supplementation of Vit D in PTB patients. MATERIALS AND METHODS: Forty four newly diagnosed PTB patients of both the sexes in the age group of 18 to 60 years before starting DOTS were recruited to participate in this non- randomized controlled trial with their voluntary consent. Vit D status in these patients and the effect of DOTS on Vit D were evaluated. RESULTS: Mean Vit D levels of the study population aged 43+/-13 years was 20.74 ng/ml (normal >30 ng/ml) at the time of diagnosis. After completion of six months of therapy mean Vit D reduced to 17.49 ng/ml (p-value=0.041). On individual observations, 70% of the participants showed a decrease in Vit D levels from their baseline, whereas 30% showed an increase. Comparison between the two groups indicated the possible role of younger age in the improved status. CONCLUSION: VDD was seen in PTB patients, which worsened in majority of the study population after treatment; hence it would be advisable to recommend Vit D supplementation in PTB patients for a better outcome. PMID- 28571131 TI - Systemic and Local Effects of Warm Oxygen Exposure to the Lower Extremities in Healthy Volunteers. AB - INTRODUCTION: Warmth to the extremity is known to improve the cutaneous blood flow and tissue perfusion. Oxygen is essential for healing of chronic wounds. Topical oxygen therapy has become standard therapy in management of lower extremity wounds. A combination of local heat and oxygen is likely to be beneficial in many clinical scenarios of non-healing wounds without any systemic effects. AIM: To evaluate the local and systemic effects of the exposure of extremity to warm oxygen in healthy volunteers. MATERIALS AND METHODS: Thirty one volunteers were included in the study. The index foot was exposed to oxygen 7l/min, 93%-95% concentration at temperature of 43oC for 90 minutes with the device. The following parameters such as basal and periprocedural blood pressure, body temperature, heart rate, 24 lead ECG, temperatures at foot and plethysmographic waveforms from the index foot were measured. A NRS-11 questionnaire was asked to the patient to rate his or her pain from 0 to 10 and documented by health care worker at the end of the session. RESULTS: The skin temperature of index foot reached to 34oC from 32.9oC, (p=0.011). The average pulse amplitude changed from 39.8 mV to 79.8 mV over the duration of the experiment (p< 0.001). Overall heart rate and core body temperature decreased and not much change in blood pressure. CONCLUSION: The result of the study can be extrapolated to the healing of chronic non healing wounds using warm oxygen therapy. Further studies are required on patient population to prove benefits in clinical settings. PMID- 28571132 TI - Cardiovascular Response and Serum Interleukin-6 Level in Concentric Vs. Eccentric Exercise. AB - INTRODUCTION: Cardiovascular Disease (CVD) is a leading cause of morbidity and mortality in India. Resistance exercise is strongly recommended for implementation in CVD prevention programs. Dynamic resistance exercise comprises of concentric (muscle shortening) and eccentric (muscle lengthening) phase. The contraction of skeletal muscle promotes the synthesis and secretion of cytokines and peptides from myocytes, known as 'myokines'. Interleukin-6 (IL-6) is the first myokine to be released in the blood in response to exercise. AIM: To compare the cardiovascular response and serum IL-6 level in concentric and eccentric exercise done at same absolute workload. MATERIALS AND METHODS: In this non-randomised crossover study 24, apparently healthy and young male adults performed an acute bout of concentric and eccentric exercise. Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Heart Rate (HR), Mean Arterial Pressure (MAP), Pulse Pressure (PP) and serum IL-6 were measured just before and immediately after exercise. Paired t-test or Wilcoxon signed-rank test were applied to compare the data within-group and in-between group. RESULTS: SBP, HR, MAP, PP, DBP and IL-6 level increased significantly after both, concentric and eccentric exercise. The mean change in SBP, HR, MAP, PP, and IL-6 after concentric exercise (18.54+/-3.06, 57.21+/-10.73, 8.35+/-1.40, 15.25+/-5.29, 5.40+/-3.13 respectively) was significantly higher than after eccentric exercise (13.38+/-1.72, 43.25+/-8.34, 6.50+/-1.0, 10.21+/-3.16, 4.36+/-2.54 respectively). A non-significant rise in DBP was obtained after concentric exercise (3.25+/ 2.79) as compared to eccentric exercise (3.08+/-1.89). CONCLUSION: Eccentric exercise not only caused a lesser cardiovascular demand as compared to concentric exercise but also a significant increment in IL-6 level. Exercise-induced IL-6 may prevent the initiation and development of CVD. Hence, eccentric exercise training might be recommended for reducing morbidity and mortality in individuals with- or at a risk of developing CVD. PMID- 28571133 TI - Influence of Central Obesity Assessed by Conicity Index on Lung Age in Young Adults. AB - INTRODUCTION: Central obesity is an emerging public health problem in young adults which compromises lung mechanics. Conicity Index (CI) is a simple anthropometric measure to assess central adiposity. The concept of lung age relates to a person's current lung function at which his/her lung function would be considered abnormal in relation to the present actual age. AIM: To determine the effect of central obesity by CI on lung age in young adults. MATERIALS AND METHODS: A total of 319 young adults in the age group 18-25 years were recruited for this cross-sectional observational study. Written informed consent and Institutional Ethical Clearance (IEC) approval were obtained. Anthropometric parameters were measured and CI was calculated using the following formula: CI = Waist Circumference (WC) (m)/ [0.109 X? {Bodyweight (kg)/ Height (m)}] where 0.109 is a constant. Spirometry was performed and all the lung volumes and capacities were obtained. RESULTS: There was a significant increase in mean values of CI in obese young adults compared to non obese (1.36+/-0.15 and 1.16+/ 0.08, p<0.001). The effect of central obesity on lung age in young adults was compared using an independent t-test. Mean of lung age was significantly higher in centrally obese young adults compared to non obese 23.87+/-3.03 and 21.30+/ 2.6, p<0.001) which was statistically significant. CONCLUSION: Lung age is significantly increased in centrally obese young adults compared to non obese. Hence, lung age can be used as a potential psychological tool to show an individual with central obesity that there is premature aging of their lungs. PMID- 28571134 TI - Correlation of Body Mass Index (BMI) with Thyroid Function in Euthyroid Pregnant Women in Manipur, India. AB - INTRODUCTION: Body Mass Index (BMI) is significantly increased during pregnancy due to gain of weight with normal progression of pregnancy. The exact influence of thyroid function on BMI are ill defined in euthyroid pregnant women. AIM: To correlate serum levels of Free Triiodothyronine (FT3), Free Thyroxine (FT4) and Thyroid Stimulating Hormone (TSH) level with BMI of participant normal pregnant women in all the three trimesters. MATERIALS AND METHODS: In this cross-sectional comparative study, total of 210 healthy pregnant women comprising of 70 participants in each trimester, attending Obstetrics Outpatient Department (OPD) for antenatal check-up were consecutively selected. Estimation of serum FT3, FT4 and TSH level was done by ELISA based methods. The correlation of BMI with serum levels of FT3, FT4 and TSH was done using Pearson correlation test (r) by SPSS version 21.0 software. RESULTS: TSH level of participant normal pregnant women showed significant positive correlation with BMI during first (r=0.254 and p=0.034) and second trimester (r=0.263 and p=0.028) of pregnancy. FT4 level showed significant negative correlation in second (r= -0.454 and p<0.001) and third trimester (r= -0.351 and p=0.003) of pregnancy. Correlation between BMI and FT3 level showed no significant association in any of the trimesters. CONCLUSION: BMI correlates positively with TSH level in first and second trimesters while it correlates negatively with FT4 level in second and third trimesters, but, failed to demonstrate significant association with FT3 level in any of trimesters in euthyroid pregnant women. Serum TSH along with FT4 level appears more useful modality compared to serum TSH alone for targeted thyroid screening particularly in obese pregnant women. PMID- 28571135 TI - Moringa oleifera Leaf Extract: Beneficial Effects on Cadmium Induced Toxicities - A Review. AB - Environment has been contaminated by heavy metals ever since the original magma of earth has solidified. One such toxin is cadmium. Cadmium that has been around since the industrial age, is considered hazardous both to us and to the environment. From time immemorial man is dependent on plants available in nature for several health benefits. Moringa oleifera, has nutritional, pharmacological and antioxidant properties, thus having several medicinal applications. In the present article, we discuss the dose and time dependent damage due to exposure to cadmium on kidneys, liver, testis, lipid profile and haematological parameters in adult Wistar rats and the protective effects of Moringa oleifera (pre-treatment) on cadmium induced damage. PMID- 28571136 TI - Correspondance:Level of Motivation during Cardiac Efficiency Test; A Confounding Factor to Consider. PMID- 28571137 TI - Auxanographic Carbohydrate Assimilation Method for Large Scale Yeast Identification. AB - INTRODUCTION: The auxanographic carbohydrate assimilation had been an important method for differentiation of yeasts. Prevailing methods described in the literature for carbohydrate assimilation has limited scope for use in large scale yeast identification. AIM: To optimize the large scale auxanographic carbohydrate assimilation method for yeast identification. MATERIALS AND METHODS: A modified auxanographic carbohydrate assimilation method was developed and a total of 35 isolates of Candida species comprising of four ATCC (American Type Culture Collection) Candida strains (Candida albicans ATCC 90028, Candida tropicalis ATCC 90018, Candida parapsilosis ATCC 750, Candida krusei ATCC 6258) and 31 clinical isolates of Candida tropicalis (n=13), Candida krusei (n=7), Candida glabrata (n=3), Candida kefyr (n=3), Candida albicans (n=5) were validated. The carbohydrates tested were Glucose, Sucrose, Maltose, Lactose, Cellubiose, Raffinose, Trehalose, Xylose, Galactose and Dulcitol. RESULTS: A total of 35 Candida species were tested for their carbohydrate assimilative property and the results were consistent with the existing standard protocols. A well circumscribed opaque yeast growth indicated assimilation of the test carbohydrate and translucent to opalescent growth with the outline of initial inoculum alone indicated lack of assimilation. The control plate indicated no growth of the Candida species. CONCLUSION: The carbohydrate assimilation tests finds utility for yeast diversity studies exploring novel ecological niches. The technique described here facilitates testing of an extended range of carbohydrates and yeasts in a cost effective manner. PMID- 28571138 TI - Bacterial Contamination of Adult House Flies (Musca domestica) and Sensitivity of these Bacteria to Various Antibiotics, Captured from Hamadan City, Iran. AB - INTRODUCTION: House flies (Musca domestica) have been known as a mechanical vector in spreading infectious diseases such as cholera, shigellosis, salmonellosis and skin infections. AIM: To investigate the bacterial contaminations of house flies and determine the resistance of these bacteria against various antibiotics. MATERIALS AND METHODS: An analytical descriptive cross- sectional study was conducted. The study was performed from July to September 2015 in Hamadan University of Medical Sciences, Hamadan, Iran. A total number of 300 house flies were collected from four places, 75 flies from each place, including two educational hospitals belonging to Hamadan University of Medical Sciences, a fruit and vegetables center, and a livestock slaughter. The body surface of house flies was washed using the physiological sterile serum and the obtained solution was centrifuged at 2000 rpm for five minutes. The identification of bacteria was carried out using the phenotypic methods. The resistance of bacteria against various antibiotics was determined using the disk diffusion approach. Data were analysed by the employment of SPSS software package version 20.0. RESULTS: A total number of 394 bacterial strains were isolated from 275 house flies. The most prevalent type of bacteria was Bacillus spp which was detected in 31.1% of house flies. Moreover, Staphylococcusspp. (22.9%), Escherichiacoli (11.6%) were other prevalent species, whereas, Enterococcusspp. was the least prevalent type of bacteria in the collected house flies. In terms of resistance to antibiotics, it was identified that bacteria extracted from house flies which were collected from hospital environments were more resistant to antibiotics compared with the resistance of bacteria extracted from house flies which were collected from non hospital environments. The maximum bacterial isolation was found in houseflies from hospital No.1 environment from around the accumulation of garbage. CONCLUSION: It is a well-known fact that house flies are a source of bacterial contamination and can act as a mechanical carrier and cause bacterial diseases. It can be postulated that house flies play a major role in spreading antibiotic resistant bacteria. However, the flies from hospital environments were more contaminated, mainly because the people referring to health center are normally ill and carrier of many pathogens. Further, hospital environments should be controlled using administrative procedures. PMID- 28571139 TI - Invasive Mucormycosis in a Case of Aluminium Phosphide Poisoning. AB - Mucormycosis is a rapidly progressive disease with high mortality reported mostly in immunocompromised individuals. We report a case of Rhino-orbital mucormycosis (Lichtheimia corymbifera) in an immunocompetent individual with history of consumption of Aluminium Phosphide (ALP) tablets. We postulated the following effects of ALP poisoning that would have increased the chances of mucormycosis in this patient: 1) Metabolic acidosis; 2) Acute Kidney Injury (AKI); and 3) Liberation of free oxygen radicals. PMID- 28571141 TI - Evaluation of Masood's and Modified Masood's Scoring Systems in the Cytological Diagnosis of Palpable Breast Lump Aspirates. AB - INTRODUCTION: Fine Needle Aspiration Cytology (FNAC) has a leading role in the assessment of breast lesions. Masood's Scoring Index (MSI) and its modification (Modified Masood's scoring index; MMSI) has been proposed to aid in sub-grouping breast lesions and to help in subsequent management. AIM: To assess and compare the diagnostic accuracy of MSI and MMSI by subsequent correlation with histopathology. MATERIALS AND METHODS: The study was cross-sectional in nature and was conducted in a tertiary care setting. The study included 207 cases presenting as palpable breast lump, which had undergone FNAC and subsequent excision biopsy for histopathology. STATISTICAL ANALYSIS: The cases were grouped into four categories as suggested by Masood et al., (MSI) and Nandini et al., (MMSI) and concordance analysis with reference to histopathological diagnosis was done. RESULTS: In comparison to MSI, MMSI showed better concordance with histopathological diagnosis and superior diagnostic accuracy in non-proliferative breast disease category (p-value = 0.046) as well as in proliferative breast disease without atypia category. The overall diagnostic accuracy of the cytological scoring was 97.5%, with 94.5% sensitivity and 100% specificity. CONCLUSION: Though both MSI and MMSI were found effective in subcategorizing breast lesions, MMSI was found to have better concordance with histopathology. Inclusion of cellular pattern and background material may further help in increasing the accuracy. PMID- 28571140 TI - HER2/neu Testing In 432 Consecutive Breast Cancer Cases using FISH and IHC - A Comparative Study. AB - INTRODUCTION: The development of trastuzumab, a HER-2/neu targeted monoclonal antibody resulted in significant improvements in clinical response and survival in HER-2/neu gene amplified group of patients. Thus, accurate assessment of HER 2/neu status becomes critical. Fluorescence In Situ Hybridization (FISH) and Immunohistochemistry (IHC) are the most commonly used methods for this purpose and specific recommendations exist with regard to the concordance to be observed between the two tests. AIM: Here, we report and evaluate the concordance rate between FISH and IHC for HER-2/neu status in breast cancer specimens. MATERIALS AND METHODS: Archival paraffin blocks of tumour tissue from 450 patients of breast cancer were analyzed for Her-2/neu status using FISH and IHC. RESULTS: There was a highly significant concordance between the results of FISH and IHC assays in HER-2/neu status assessment in invasive breast cancer cases. There were inverse associations between the expression of Oestrogen Receptors/Progesterone Receptors (ER/PR) and HER-2/neu amplification. CONCLUSION: Although, IHC gave significant concordant results with FISH in determining HER-2/neu status, its subjective grading system precludes its use as a gold standard. FISH should always be used to determine true gene amplification when the IHC results are equivocal. PMID- 28571142 TI - Clinicopathological Evaluation of 223 Cases of Mature Cystic Teratoma, Ovary: 25 Year Experience in a Single Tertiary Care Centre in India. AB - INTRODUCTION: Mature Cystic Teratoma (MCT) is the most common benign neoplasm of the ovary constituting 10-20% of all the ovarian tumours. Although, much has been published about ovarian teratomas, in English literature, there are very few retrospective cross sectional studies from India to understand the epidemiology of the disease. AIM: To evaluate the prevalence, clinicopathological characteristics and complications of MCT of the ovary. MATERIALS AND METHODS: This was a retrospective study of 223 cases of MCT of ovary received over a period of 25 years from 1990 to 2014. The data regarding age, size, laterality, gross, morphological features, complications and surgery performed was retrieved from the archives of pathology department. Descriptive statistics was performed using SPSS software version 22 and the results were expressed as percentages. RESULTS: MCT constituted 20.2% of the total ovarian neoplasms and 78.5% of all the germ cell tumours. The mean age of the patients with MCT was 32.5+/-13.11 years and the mean size of tumour was 8.6+/-3.1 cm. Torsion was the most common complication of these tumours. Malignant transformation of this tumour though rare was seen in 3.5% of the cases. CONCLUSION: MCT are most common tumours of the ovary. Though predominantly seen in reproductive age group, they may also be seen in children and postmenopausal women. Torsion is the most common complication of this tumour. Age of the patient and the size of the tumour are important prognostic factors in terms of malignant transformation of teratomas. Since 8.9% of these tumours were bilateral it is essential to thoroughly examine the contralateral ovary to rule out bilaterality. Early diagnosis and early treatment is essential to preserve fertility in these patients. PMID- 28571143 TI - Histopathological Study of Central Nervous System Lesions: Emphasizing Association of Neoplasms with ABO Blood Groups. AB - INTRODUCTION: The Central Nervous System (CNS) lesions show considerable geographic and racial variations with respect to the incidence and the pattern of distribution of lesions. The ABO blood status is a readily accessible factor in genetic constitution of the patients. It has been shown to be associated with many diseases. But the influence of blood group status on the pathogenesis of brain tumours is still unclear. AIM: To study various histopathological patterns of CNS lesions and to evaluate the association of CNS tumours with the distribution of ABO blood groups in documented cases. MATERIALS AND METHODS: In the present study, 147 cases were analyzed. It was an analytical type of study, done at JSS Medical College, Mysore, over a period of 2 years and 8 months from January 2009 to August 2011. Histopathology slides were routinely stained by Haematoxylin and Eosin (H&E) stain. Special stains were performed in selected cases. Blood group of the patients and the control group were documented. Blood group distribution pattern was assessed in relation to histopathological diagnosis of various CNS tumours. RESULTS: Histopathological diagnosis of 147 cases included neoplastic lesions (84.35%) and non-neoplastic lesions (15.64%). Neoplastic lesions (84.35%) constituted the majority, which included neuroepithelial tumours (29.25%) as predominant pattern. Non-neoplastic lesions constituted only 15.64%, which included inflammatory lesion (8.16%) as the predominant pattern. ABO blood group data was available in 92 cases (84.4%) of neoplastic lesions, which included 71 cases (48.29%) of primary CNS neoplasms categorized according to WHO grades. The control group constituted 21,067 healthy voluntary donors. Blood group O was the most frequent blood group in neoplastic lesions (40.21%) and primary CNS neoplasms categorized according to WHO grades (45.07%). The association between the CNS neoplasms and ABO blood groups was not statistically significant (p = 0.055). But a definite change in the pattern of distribution of ABO blood groups observed between neoplastic lesions and control groups. CONCLUSION: The influence of blood group types on the development of brain tumours appears intriguing and needs to be well established. Though statistically insignificant, a definite change in the pattern of distribution of ABO blood groups was observed between neoplastic lesions and control groups. This necessitates attention and stratification of patients for effective management. PMID- 28571144 TI - Seroprevalence and Trends of Transfusion Transmissible Infections in Blood Donors in Andaman and Nicobar Islands- An Institutional Retrospective Study. AB - INTRODUCTION: Transfusion Transmissible Infections (TTIs) such as Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV), Hepatitis C Virus (HCV) and syphilis pose a threat to blood safety in a developing country like India. AIM: To determine the prevalence of TTIs among healthy donors in Andaman and Nicobar Islands, India, and to further help in determination of the population subset to be focused on for enhancing blood donor pool. MATERIALS AND METHODS: This retrospective cross-sectional study was conducted on all voluntary and replacement donors in a tertiary health care centre in Andaman and Nicobar Islands for a period of three years. Donor blood was screened for HIV, HBV, HCV, Syphilis and malarial parasite using rapid kits and ELISA. RESULTS: Out of 12,118 donors, 97.01% were males and 2.99% were females. 9409 (77.64%) were voluntary donors and 2709 (22.35%) were replacement donors. Majority of the screened donors belonged to 25 to 40 age group. Out of 12,118 donors, 265 (2.18%) were seropositive. Among them, 8 (0.066%) were HIV positive, 15 (0.124%) HCV positive, 128 (1.056%) HBsAg positive, 30 (0.247%) Syphilis positive and 84 (0.693%) were positive for malarial antigen. Yearly prevalence of seropositivity was 2.370%, 2.113% and 2.082% for three consecutive years. CONCLUSION: With high prevalence of TTIs among healthy donors, safe blood transfusion is still a challenge in developing countries. This continues to place unacceptable burden on health sector. There is a need for encouragement of voluntary blood donation, strict donor selection criteria and sensitive screening tests to minimize TTIs in Indian setting. PMID- 28571145 TI - Morphological Changes in Bone Marrow Post Imatinib Therapy in Chronic Phase CML: A Follow up Study on Sequential Bone Marrow Aspirates and Biopsies. AB - INTRODUCTION: Imatinib mesylate is used extensively for first line treatment of Chronic Myeloid Leukemia (CML). However, not many studies have documented morphological changes in bone marrow biopsies produced during Imatinib therapy with reference to myelofibrosis. AIM: To document the morphological changes produced in the bone marrow during Imatinib therapy. MATERIALS AND METHODS: This longitudinal study followed up 75 Philadelphia Chromosome Positive Chronic Myeloid Leukemia with chronic phase(Ph+ CML- CP) patients sequentially, receiving 400-600mg Imatinib over a period of 12 or more months. Haematologic parameters were measured at admission, 2 weeks, 1 month, 3 months, 6 months and 12 or more months. Morphologic changes in bone marrow aspirate and biopsy were evaluated at admission, 6 months and >=12 months of treatment in accordance with National Comprehensive Cancer Network(NCCN) guidelines. RESULTS: Complete Haematologic Response (CHR) was seen in 47.1%, 80%, 85.4%, 90.4% at >=1 month, 3 months, 6 months and 12 months respectively after therapy. It was noted that patients not showing CHR by 3 months were less likely to show CHR at 6 months and beyond. Bone marrow aspirates and biopsies showed reduction in cellularity and myeloid precursors with regeneration of erythroid precursors in 70-83% at >=12 months. A significant decrease in myelofibrosis (p-value< 0.04) was noted as early as 6 months. Mild to moderate hypoplasia was noted in 31.8% of biopsies within 6 months. Pseudo gaucher cells and benign lymphoid nodules were also seen. CONCLUSION: Sequential analysis showed that Imatinib reduced the grade of myelofibrosis significantly (p-value< 0.04). It also prevented development of myelofibrosis in patients who did not have it at presentation. Hence Imatinib is effective when used early in the course of CML-CP. PMID- 28571146 TI - Immunohistochemical Study of MUC1, MUC2 and MUC5AC Expression in Primary Breast Carcinoma. AB - INTRODUCTION: Breast Cancer (BC) is the second most common cancer among women in India and accounts for 7% of global burden of BC and one-fifth of all Cancers (CA) among women in India. AIM: This study was conducted for studying the expression of MUC1, MUC2 and MUC5AC in breast carcinoma. MATERIALS AND METHODS: Fifty cases of primary breast carcinoma diagnosed between years 2013 to 2015 were included in the study. Manual tissue array technique was applied for cases subjected to Immunohistochemistry (IHC). An analysis of the expression of IHC markers (MUC1, MUC2, MUC5AC, ER, PR and HER2/neu) was attempted. Results were subjected to statistical analysis. They were considered to be significant when the p-value was less than 0.05. RESULTS: The positivity for MUC1, MUC2 and MUC5AC in BC was 58%, 8% and 6% and for ER, PR and HER2 was 48%, 36% and 64% respectively. There was a significant correlation between MUC1 expression and ER and PR positivity. There was a significant correlation between MUC2 expression and ER positivity. No significant association was observed between MUC2 and PR expression, MUC5AC expression and ER and PR positivity. There was statistically significant correlation between negative MUC2 and MUC5AC expression and histopathological grade. It was noted that MUC2 and MUC5AC negative tumours were associated with higher tumour stage though not statistically significant. It was noted that MUC5AC negative tumours showed higher frequency of lymphovascular invasion though not statistically significant. CONCLUSION: Our experience with the present study highlights the role of mucins in the development and progression of BC. PMID- 28571147 TI - Expression of Alpha - Methylacyl - Coenzyme A Racemase (AMACR) in Colorectal Neoplasia. AB - INTRODUCTION: Red meat and dairy products have been implicated in colonic cancers. They are rich in branched chain fatty acids which require an enzyme Alpha-Methylacyl-Coenzyme A Racemase (AMACR) for their oxidation. Increased expression of AMACR in colorectal premalignant lesions and carcinomas suggests its possible role in carcinogenesis. AIM: To study the expression of AMACR in colorectal neoplasia and its correlation with the histological grade, stage and nodal status of colorectal malignancy. MATERIALS AND METHODS: All cases of colorectal neoplasms were included in the study. AMACR expression was studied in 56 cases which included 44 cases of adenocarcinoma and 12 cases of adenoma and a normal colonic mucosal tissue was used as a control. A tissue microarray was prepared by manual method. AMACR expression was studied by Immunohistochemistry (IHC) and it was correlated with the grade, stage and nodal status of the cancer. Chi-square test was used for analysis or results. The p-value of <0.05 was considered significant. RESULTS: Out of 12 cases of adenoma 25% (3/12) were negative; 50% (6/12) showed poor expression, 25% (3/12) had moderate expression and none showed strong expression. Nearly, 34.1% (15/44) case of carcinoma were negative; 45.45% (20/44) had poor; 13.63% (6/44) had moderate and 6.81% (3/44) had a strong expression. Normal colonic tissue showed no expression. There was no significant difference of AMACR expression between adenoma and carcinoma cases. AMACR expression was found to be increased in low grade carcinomas (G1 and G2). G1 showed AMACR positivity in 62% cases and G2 showed 71.4% positivity. No association was found between AMACR expression and different American Joint Committee on Cancer (AJCC) stages and nodal status of CRC. CONCLUSION: Increased expression of AMACR in adenomas and carcinomas as compared to non-neoplastic epithelium of colon implies that, it plays a role in colorectal neoplasia. Decreased expression of AMACR in high grade carcinomas suggests its role in differentiation of the tumour. PMID- 28571148 TI - De Novo Focal Segmental Glomerulosclerosis in Renal Allograft-Histological Presentation and Clinical Correlation: Single Centre Experience. AB - INTRODUCTION: Recurrent or de novo glomerulonephritis are one of the well-known causes for renal allograft dysfunction in early and late period after renal transplantation. Focal Segmental Glomerulosclerosis (FSGS) is a devastating lesion of the renal allograft. De novo FSGS is uncommon compared to recurrent FSGS. AIM: To find out the incidence of de novo FSGS. MATERIALS AND METHODS: A retrospective evaluation of renal allograft biopsies was performed from 2007 to 2015, by light microscopy and immunohistochemistry including patient-donor demographics. Graft function status in terms of serum creatinine (SCr) and proteinuria were evaluated. RESULTS: Out of 2,599 renal allograft biopsies performed, 1.6% biopsies were reported as de novo FSGS. Majority were live related females donors with mean age of 43.8 years. Mean time of biopsy was 1.1 years post-transplant with proteinuria of 2.95 grams/24 hours and SCr of 2.24 mg/dL. Histopathological variants were collapsing 47.6%, Not Otherwise Specified/ classical 35.7%, cellular 9.5% and perihilar 7.1% biopsies. Associated Antibody Mediated Rejection (AMR) with T-Cell Rejection (TCR) was observed in 35.7% biopsies, acute on chronic CNI toxicity (calcineurin inhibitor) in five biopsies. Majority of the patients were on CNI based maintenance immunosuppression regimen. Total 28.6% patients and 23.8% grafts were lost over a mean follow up of 2.40 years. The mean SCr of remaining patients was 1.98 mg/dL. CONCLUSION: De novo FSGS can occur after the first year of renal transplant with related Human Leukocyte Antigen (HLA)matched donors leading to poor allograft survival. Close monitoring of urinary proteinuria and evaluation of allograft biopsy help in appropriate therapeutic modification to improve long term outcome of graft function. PMID- 28571149 TI - VEGF Expression to Support Targeted Therapy in Ovarian Surface Epithelial Neoplasms. AB - INTRODUCTION: Vascular Endothelial Growth Factor (VEGF), a promoter of angiogenesis, is a promising target for anti-angiogenic therapy in ovarian cancer. In our study, we examined the expression of VEGF in the spectrum of epithelial ovarian neoplasms (benign, borderline and malignant) by Immunohistochemistry (IHC). AIM: Diagnosing ovarian epithelial neoplasms, examining the expression of VEGF in benign, borderline and malignant neoplasms and correlating it with histological grade and stage of malignant cases. MATERIALS AND METHODS: This is a cross-sectional, observational study where, total of 50 cases of surface epithelial ovarian neoplasms were examined for expression of VEGF by IHC. Scoring for VEGF expression was done for each case. RESULTS: A total of 42 of the 50 cases (84%) showed VEGF expression. Out of the 42 positive cases, 19 were high VEGF expressors and 23 were low VEGF expressors. VEGF expression was significantly higher in carcinomas as compared to benign and borderline neoplasms (p=<0.001). All neoplasms of serous morphology were positive for VEGF. High VEGF expression was significantly associated with high grade (p=0.003) and stage (p=0.001) of disease. CONCLUSION: Ovarian surface epithelial neoplasms significantly express VEGF. Though, some VEGF expression was noted in benign and some borderline neoplasms, high VEGF expression was noted only in carcinomas and one case of borderline serous papillary tumour. Thus, these results suggest that epithelial ovarian tumours are candidates for VEGF targeting therapy as most of them are dependent on VEGF for progression. PMID- 28571150 TI - Isolated Skull Metastasis of Follicular Carcinoma Thyroid in an Elderly Female: A Rare Case. AB - Isolated skull metastasis from a well differentiated follicular thyroid carcinoma, as the presenting feature is a rare manifestation. We report a case of a 79-year-old female who presented to us with only a painful, gradually increasing scalp swelling with associated pain and blurring of vision over the past few days. Neuroimaging findings strongly favoured a diagnosis of meningioma. A bifrontal craniotomy was performed and the tumour was excised. Histopathological examination of the same showed, it to be a case of metastatic thyroid carcinoma. We present this case not only because of the diagnostic challenge it posed, but also because the patient in our case is one of the oldest case of skull metastasis from follicular thyroid carcinoma till date. PMID- 28571151 TI - Leiomyosarcoma of Renal Vein - A Rare Case Report. AB - Leiomyosarcomas (LMS) arising from vascular channel are rare and more often arise from inferior vena cava and pulmonary arteries. Primary renal vein LMS are even rarer and occur predominantly in females with peak in fifth and sixth decade. Preoperative diagnosis is difficult because these are rare tumours and present with symptoms and radiological findings similar to Renal Cell Carcinoma (RCC). We report a case of 55-year-old female who presented with abdominal discomfort with radiology showing a renal mass with features of RCC, radical nephrectomy was done and resected tumour showed an attachment to the wall of renal vein with morphology resembling LMS. PMID- 28571152 TI - Oncogenic Osteomalacia: An Approach to Diagnosis with a Case Report. AB - Oncogenic osteomalacia, also known as tumour induced osteomalacia, is a rare paraneoplastic syndrome caused by mesenchymal tumours secreting Fibroblast Growth Factor-23 (FGF-23). The characteristic biochemical findings include hypophosphatemia and low 1,25-dihydroxy vitamin D. The differential diagnosis for hypophosphatemia are varied. We present a case of oncogenic osteomalacia in a 29 year-old female, who presented with complaints of generalized diffuse bone pain and walking difficulty for six months duration. Thus, we have discussed the approach to diagnosis in such a case. PMID- 28571153 TI - Osteosarcoma Arising in Carcinosarcoma De Novo Parotid Gland in a Young Man: An Unusual Case with Review of Literature. AB - Carcinosarcoma of the parotid gland, a true malignant mixed tumour is extremely rare. It may occur in a pre-existing pleomorphic adenoma or arise de novo. We report a case of carcinosarcoma de novo harbouring an osteosarcomatous element in a 35-year-old man along with review of the reported cases. Excision was done and histopathologic examination confirmed the diagnosis. Long term follow up has been recommended for these tumours owing to their high propensity of recurrence and metastasis. Our case discusses the importance of histopathology and limitation of preoperative imaging in the diagnosis of such an aggressive neoplasm; emphasizing the fact that possibility of carcinosarcoma should be kept in mind while dealing with salivary gland lesions even at a younger age. PMID- 28571154 TI - Fraternal Twin Tumours of the Oesophagus and Stomach Presenting in the Advanced Stage - A Rare Case with a Fatal End. AB - Synchronous primary tumours of the aerodigestive tract presenting with different histologies is a very rare event. A case with such an association is presented here. A 50-year-old lady presented with symptoms of abdominal obstruction like abdominal pain, distention and vomiting since one month. Her radiological imaging and biopsies revealed a primary oesophageal squamous cell carcinoma and primary gastric adenocarcinoma. Western medical literature has shown the occurrence of multiple synchronous cancers; however, cases from India have seldom been reported. Early screening, correct diagnosis and appropriate plans of management are crucial to reduce the morbidity and mortality of such patients who bear the burden of not just one, but multiple primary cancers. PMID- 28571155 TI - Metastatic Renal Cell Carcinoma Causing Small Intestinal Polyps with Intussusception: A Report of Two Cases. AB - Renal cell carcinomas have diverse clinical presentations. Patients may present with metastatic symptoms at the time of diagnosis or years after resection of primary tumour. Small intestine is a rare site for metastatic renal cell carcinoma. Presentation as polypoid metastasis with intussusception is extremely rare. Here, we report two cases with this rare presentation. Case 1 was a 65-year old male with multiple polypoid metastasis causing intussusception while on palliative chemotherapy for renal cell carcinoma. Case 2 was a 68-year-old female with history of nephrectomy presenting with single polypoid metastasis causing intussusception. PMID- 28571156 TI - Blastoid Variant of Mantle Cell Lymphoma with Leukemic Presentation - A Rare Case Report. AB - Mantle Cell Lymphoma (MCL) is a type of Non-Hodgkin's lymphoma and has a wide spectrum of histopathological subtypes of which the blastoid or the blastic variant constitutes 10-15% of all cases. It is difficult to diagnose blastoid variant of MCL on the basis of morphology alone as it mimics lymphoblastic lymphoma and centroblastic large cell lymphoma, hence additional analysis like immunophenotyping and molecular studies aid in its diagnosis. We present a case of 45-year-old male who presented to medicine OPD with chief complaints of fever, fatigability and inguinal swelling. Complete blood count, peripheral smear and bone marrow examination was performed. Peripheral smear showed thrombocytopenia along with 53% abnormal cells. On bone marrow examination 43% abnormal lymphoid cells were seen. This case was diagnosed as blastoid variant of MCL on the basis of routine morphology and immunohistochemistry on bone marrow biopsy and flow cytometric immunophenotyping on peripheral blood. PMID- 28571157 TI - A Rare Presentation of Metastasis to the Thyroid Gland. AB - The thyroid gland has a rich vascular supply. However, metastasis to the thyroid is exceedingly rare. The most common tumours that metastasize to the thyroid are breast and lung. The incidence of metastasis is on the rise due to better imaging techniques as well as procedures such as Fine Needle Aspitation Cytology (FNAC) and Immunohistochemistry (IHC). Secondaries from a prostate cancer are most commonly seen in bone, lung and liver. To our knowledge, metastasis from the prostate gland to the thyroid is exceedingly rare. Here, we report a case of metastatic prostatic adenocarcinoma to the thyroid gland two years after prostatectomy. PMID- 28571158 TI - Cytomorphology of Basaloid Squamous Cell Carcinoma: A Diagnostic Dilemma. AB - Basaloid Squamous Cell Carcinoma (BSCC) is an unusual and high grade variant of Squamous Cell Carcinoma (SCC) with a predilection for the upper aerodigestive tract. The cytomorphologic diagnosis of this tumour is challenging as it shares common cytomorphologic features with its differential diagnoses. However, a careful examination of the cytology can help in delivering a diagnosis of BSCC. In this case report we present the imprint cytology findings of histologically proven BSCC in a 60-year-old male who presented with an ulcerated lesion at the umbilical region. PMID- 28571159 TI - Anaplastic Pleomorphic Xanthoastrocytoma in a Case of Neurofibromatosis Type 1: A Case Report. AB - Pleomorphic Xanthoastrocytoma (PXA) is a rare brain tumour comprising only <1% of primary brain tumours which is seen in children and young adults. Only 9-20% of the PXA shows anaplastic features and this has a bad prognosis. PXA is a WHO grade II tumour while anaplastic PXA is a WHO grade III tumour. Neurofibromatosis type 1(NF1), which is an autosomal dominant condition, predisposes to tumours of the central nervous system; most of which are pilocytic astrocytomas. Association of PXA with NF1 is very rare and only a very few cases have been reported. Here, we present a case of 42-year-old male, a known case of NF1, with multiple neurofibromas, who presented with right sided hemiparesis, seizures and vomiting. The histopathology and immunohistochemistry features were suggestive of anaplastic PXA. PMID- 28571160 TI - Molecular Investigation of a Suspected Myeloproliferative Neoplasm in Patients with Basophilia. PMID- 28571161 TI - Emphysematous Pyelonephritis with Human Immunodeficiency Virus Infection. PMID- 28571162 TI - A Qualitative Study of Knowledge, Attitude and Practice towards Pharmacovigilance among Doctors and Nursing Staff in a Tertiary Care Hospital in India. AB - INTRODUCTION: Pharmacovigilance is the branch of science that deals with the detection, assessment, understanding and prevention of adverse reactions to medicines (i.e., adverse drug reactions or ADRs). The purpose of pharmacovigilance is to implement the safe and rational use of medicines, which ultimately helps in improving patient care. AIM: To investigate the Knowledge, Attitude And Practice (KAP) of clinicians, residents and nursing staff towards pharmacovigilance and Adverse Drug Events (ADE) reporting and to identify possible reasons for underreporting and to receive suggestions to improve the ADE reporting. MATERIALS AND METHODS: This was a qualitative study, conducted at Shree Krishna Hospital, attached to Pramukhswami Medical Collage, Karamsad, Gujarat, India. 'Focused Group Discussions' were organized which consisted of 5 10 clinicians and residents of the same departments and 10-15 nursing staff members. Their KAP regarding ADE reporting were assessed by using a structured open ended questionnaire. Data were analysed with qualitative methods. RESULTS: Total six sessions of Focused group discussion were conducted consisting of 42 clinicians and residents (16 were faculty members and 26 were residents) and seven sessions of Focused group discussion were conducted, consisting of 89 nursing staff members. Most of the participants knew the meaning of ADR and importance of ADR reporting. They all agreed that it's their responsibility also to report ADE. Some of the participants admitted, forgetfulness and workload as major constraints. There was a suggestion of display phone number of department of Pharmacology for coordination and maintaining a separate register for ADEs in each ward. CONCLUSION: In spite of awareness and willingness for reporting of ADEs amongst the clinicians and residents, the practice is lacking because they do not consider this work as their priority. PMID- 28571163 TI - Utilization Pattern of Potentially Inappropriate Medications in Geriatric Patients in a Tertiary Care Hospital: A Retrospective Observational Study. AB - INTRODUCTION: Geriatric population is on the rise throughout the world, hence the quality and the safety of prescribing in the elderly is a global healthcare concern. It is important for the healthcare providers to be aware of the limitations in prescribing certain drugs to the elderly. This study was an attempt to shed light on the utilization pattern of Potentially Inappropriate Medications (PIMs) in elderly patients admitted in the medicine wards in a tertiary care hospital in Goa. AIM: To measure the percentage prevalence of PIMs prescribed in the admitted geriatric patients. MATERIALS AND METHODS: In this retrospective observational study, 150 case records of patients aged 60 years or more were analysed. All the prescribed medications, for each case record, were then analysed by referring to the American Geriatrics Society (AGS) Beers Criteria 2015. Data was analysed using Statistical Package for Social Sciences (SPSS) software. RESULTS: Of the 150 patients, 99 (66%) received at least one PIM according to the Beers Criteria 2015 (including drugs to be used with caution). However, after excluding the drugs to be used with caution, the prevalence of PIMs decreased to 44%. The most commonly prescribed PIMs were ranitidine (17.33%) and prazosin (8.66%) and the most commonly prescribed drug to be used with caution was furosemide (35.33%). CONCLUSION: As the medication needs of the geriatric population are unique, it is essential that the healthcare professionals are aware of these needs and also follow the available guidelines and tools. Formulation of hospital policies and protocols in this regard would help to improve the scenario. Increased education, awareness and reporting of drug-related problems along with more doctor-patient interaction in these situations are some of the factors that could play an important role in promoting better and safer prescribing practices and a better quality of life to the older generations of our communities. PMID- 28571165 TI - The Study of Cognitive Change Process on Depression during Aerobic Exercises. AB - INTRODUCTION: Several studies have shown that aerobic exercise is effective in treating the depression and improving the mental health. There are various theories which explains why aerobic exercise is effective in the treatment of depression and improve mental health, but there are limited studies to show how cognitive components and depression improve during aerobic exercises. AIM: The current study was carried out to investigate the cognitive change process during aerobic exercises in depressed students. MATERIALS AND METHODS: This study was conducted through structural equation modeling; the study sample included 85 depressed students. Participants were selected through purposive sampling method. Beck Depression Inventory (BDI-II), Automatic Negative Thoughts (ATQ), and the Dysfunctional Attitude Scale (DAS) were used as the data collection instruments. The participants received eight sessions of aerobic exercise (three times a week). The obtained data was analysed by AMOS-18 & SPSS 18 software. RESULTS: The results showed that depression (p=0.001), automatic thoughts (ferquency p=0.413, beliefs p=0.676) and dysfunctional assumptions (p=0.219) reduce during aerobic exercise; however, it was only meaningful for the depression. The casual and consequential models were not fit to the data and partially and fully interactive models provided an adequate fit to the data. CONCLUSION: Fully interactive model provided the best fit of the data. It seems that aerobic exercise reduced cognitive components separately leading to reduce depression. PMID- 28571164 TI - A Retrospective Study to Assess the Effect of Proton Pump Inhibitors on Renal Profile in a South Indian Hospital. AB - INTRODUCTION: Proton Pump Inhibitors (PPIs) are arguably among the most commonly prescribed drugs in clinical practice, either as part of treatment or prophylaxis. Many clinicians prescribe these drugs as part of any prescription, without a proper rationale. Recent studies done outside India have shown that these drugs are not entirely safe, and they can result in the development of acute renal injury. AIM: To assess the effect of PPIs on blood urea and serum creatinine, when administered for at least seven consecutive days. MATERIALS AND METHODS: The study was conducted in a retrospective manner, using data from the medical records department. Values of blood urea and serum creatinine were taken twice, first before start of therapy and then after at least one week of therapy. RESULTS: A total of 175 subjects were selected for the study. When their case files were analysed, acute kidney injury was identified in 19 (10.86%) of them. Pantoprazole was the most common drug involved (84.21%). Renal injury was more common in the age group of over 50 years of age. CONCLUSION: PPIs are not entirely free of adverse effects, as assumed by several practitioners. A vigilant eye has to be maintained on the patient's renal profile so as to avoid any untoward decline in renal function, as evidenced in the current study. PMID- 28571167 TI - Gap between the Expectations and Perceptions of Students regarding the Educational Services Offered in a School of Nursing and Midwifery. AB - INTRODUCTION: Awareness of students' opinions about the various aspects of training provided is an essential factor to evaluate the quality of education. AIM: The aim of this study was to determine the gap between the students' expectations and perceptions from the educational services provided to them in the School of Nursing and Midwifery in Shahrekord University of Medical Sciences. MATERIALS AND METHODS: In this cross-sectional study, 320 students were selected by stratified random sampling method and data were collected by SERVQUAL questionnaire to examine the areas of assurance, responsiveness, empathy, tangibles and confidence. Data analysis was conducted by descriptive (frequency, percentage, mean+/-SD) and analytical (paired t-test, independent t-test and One Way ANOVA) statistics in SPSS 20. RESULTS: The mean scores of the students' expectations and perceptions of the educational services delivered to them were 4.34+/-0.63 and 3.56+/-0.68, respectively, with a significant, negative gap ( 0.77+/-0.77, p<0.001). The lowest gap of quality was derived for assurance ( 0.65) followed by reliability (-0.69), accountability (-0.74), and empathy ( 0.81), and the greatest gap observed in tangibles (-0.96). CONCLUSION: A negative gap was observed between the students' expectations and perceptions of the quality of educational services delivered to them. This means that the quality of services delivered to students was less than what they expected. The highest gap was related to the tangibles. In order to improve the educational services, paying attention to different areas of quality of educational services, especially, the tangibles, is necessary. PMID- 28571166 TI - The Relationship between Anxiety and Coping Strategies in Family Caregivers of Patients with Trauma. AB - INTRODUCTION: Traumatic events are of high incidence and affect not only the patient but also their family members, causing psychological problems such as stress and anxiety for caregivers of these patients. Therefore, the application of appropriate coping strategies by them seems necessary in order to promote mental health. AIM: To study the relationship of anxiety with coping strategies in family caregivers of trauma patients. MATERIALS AND METHODS: The present research was a descriptive-correlational study which was carried out on 127 family caregivers of patients with trauma in intensive care unit, surgery ward and emergency unit of Amir al-Mu'minin Hospital of Zabol, Sistan and Baluchestan Province. The respondents were selected based on the convenience sampling method. Demographics questionnaire, DASS-21, and Coping Strategies questionnaire were used for data collection. The obtained data were statistically analysed using descriptive statistics, Analysis of Variance (ANOVA), t-test, and Pearson correlation coefficient in statistical package for the Social Sciences (SPSS) version 21.0. RESULTS: Based on the results, 89.9% of family caregivers suffer from mild to severe anxiety. The most common type of coping strategy used by the respondents was emotion-focused. The results showed no relationship between anxiety and emotion-centrism, but an inverse relationship was found between problem-centrism and anxiety. CONCLUSION: The majority of family caregivers had anxiety. Given, the inverse relationship between the level of anxiety and the use of problem-based coping strategy, in addition to identifying and reducing the causes of anxiety in caregivers. It is recommended that appropriate coping strategies should be trained to them. PMID- 28571168 TI - AUDIT (Alcohol Use Disorders Identification Test) to Estimate the Pattern and Correlates of Alcohol Consumption among the Adult Population of West Bengal, India: A Community Based Cross-sectional Study. AB - INTRODUCTION: Pattern of alcohol consumption substantially changed in India with in last 20 to 25 years. Excessive alcohol consumption is a major risk factor for various morbidity and mortality. So, scientific study to identify alcohol consumption patterns and its correlates will be helpful to formulate preventive strategies. AIM: To estimate the pattern of alcohol consumption and to determine its correlates, among the adult population of the state of West Bengal in India. MATERIALS AND METHODS: A community based cross-sectional study was conducted among the adult population of the state of West Bengal at Gram Panchayat (GP) level. Ninety-nine (n=99) adult (>= 18 years) men and women of Guchati GP at Paschim Medinipur district, was selected using Lot Quality Assurance Sampling (LQAS) technique. The study participants were interviewed using a pre-designed and pre-tested schedule. RESULTS: It was estimated that the prevalence of low risk drinking or abstinence (Zone I) was 65.5% (95% CI 55.5% to 75.5%) and the prevalence of alcohol use in excess of low-risk (Zone II) was 17.6% (95% CI 7.6% to 27.6%), and the prevalence of harmful and hazardous drinking (Zone III) was 8.5% (95% CI 0% to 18.5%) and the prevalence alcohol dependence (Zone-IV) was 8.4% (0% to 18.4%). Logistic regression model shows that "gender" (p = 0.00) and "employment status" (p = 0.01) added significantly to the model with adjusted odds ratio of 82.27 (95% CI 18.17-372.58) and 0.13 (0.03-0.66). CONCLUSION: There is a need for comprehensive screening and treatment programme to deal with the problems of Alcohol Use Disorders among adults to achieve good health and well being for sustainable development. PMID- 28571169 TI - Significance of Platelet Volume Indices in STEMI Patients: A Case-Control Study. AB - INTRODUCTION: Platelets have been well known contributors in the pathogenesis of cardiovascular disorders such as atherosclerosis and its complications such as acute Myocardial Infarction (MI). AIM: To study the changes in platelet volume indices and platelet count in ST-Elevated Myocardial Infarction (STEMI) and assess their usefulness in predicting coronary events. MATERIALS AND METHODS: A case-control observational study was carried out on 173 cases diagnosed with STEMI and 191 controls from January 2015 to December 2015, considering the inclusion and exclusion criteria. In total, 364 patients were included, 173 patients with STEMI, from those patients admitted to the intensive care unit and the emergency ward. In addition, 191 healthy non diabetic non hypertensive age matched controls were enrolled. RESULTS: The mean age of cases was 59.4+/-11.9 years and of controls were 55.25+/-8.5 years. Males (74.6%) had higher incidence of STEMI then females (25.4%). The Mean Platelet Volume (MPV) was significantly higher in patients with STEMI (10.2+/-2.8) as compared to controls (8.5+/-6.9). The Platelet Distribution Width (PDW) was also significantly higher in cases compared to controls (p<0.05). According to Pearson correlation analysis, the positive relationship determined between MPV and Gensini score was statistically significant (p < 0.001, r = 0.132). CONCLUSION: High MPV and PDW seem to be an independent risk factor for STEMI and correlated with the severity of the STEMI. They can be used as a simple, reliable, and economical method for predicting an impending acute coronary event. PMID- 28571170 TI - Financial Burden of Out-of-Pocket Expenditures for Primary Health Care in Hilly Areas of Garhwal Region, Uttarakhand, North India. AB - INTRODUCTION: High total health expenditures via Out-of-Pocket (OOP) as formal user fees and informal payments put India in challenging situation to achieve towards universal health coverage. AIM: To assess the (OOP) expenditure and its determinants among outpatient in primary care settings of Uttarakhand, North India. MATERIALS AND METHODS: A hospital based cross-sectional study was conducted in a Outpatient Department of Urban Health Training Centre, Srinagar, Uttarakhand, India and Rural Health Training Centre, Kritinagar, Uttarakhand in 2015. A total of 200 patients were enrolled in the study using random sampling. Questionnaire covering costs like: travel cost, drug cost, investigation cost, and others was used for measuring OOP expenditure incurred toward health care by patients. RESULTS: Of the total 200 patients, 43.5% were males and 56.5% were females with mean age 40.36 (SD 19.45) in years. Average annual family income was 11718.5 INR+/-13457.3 INR. Of the total study subjects, 42.5% were unskilled or had no occupation (unemployed, student, and homemaker). The majority (68.5%) had travelled less than or equal to 10 km to reach the health facility. About 50% of the study subjects presented with communicable diseases and 20% with non communicable diseases. The health expenditure of the outpatient revealed that major part of the expenditure is the direct cost of the treatment, including registration fee, drugs, and investigation. Mean OOP expenditure for drugs and investigations was 509 INR and 673.1 INR, respectively. Mean total out-of-patient expenditure was 303.1 INR. The proportion of monthly family income spent on out of-patient expenditure was 2.58%. CONCLUSION: The implementation of primary health care needs to be further strengthened in order to improve access of public sector hospitals for curative care. PMID- 28571171 TI - A Goal Unrealized: Patient Empowerment on Hand Hygiene- A Web-Based Survey from India. AB - INTRODUCTION: Each year, millions of patients around the world are affected by Health Care Associated Infections (HCAIs). Understanding and assessing the global burden of HCAI is one of the key areas of work to improve the hand hygiene. AIM: To assess the patient empowerment and awareness on hand hygiene among online users. MATERIALS AND METHODS: A web-based cross-sectional survey was conducted during September 2013 to December 2013 among adults. A predesigned questionnaire to assess the awareness on hand hygiene was sent to volunteers through emails and social networking sites. The data were transferred to excel sheet and analyzed in Epi info and represented in proportions and percentages. RESULTS: Total 94 (57%) participants responded to the survey among which 51.1% were males and 48.9% were females. Majority of them belongs to the age group of 20 to 35 years. Only 28.7% of them said they will ever ask health care worker to wash their hands before they examine. A 27.7% of the participants reported that their country/community have a program that educates/communicates with patients about the importance of hand hygiene. CONCLUSION: Adherence and compliance to hand hygiene practices is suboptimal among people. There seems to be a lack of knowledge regarding hand hygiene. PMID- 28571174 TI - Comparison of Steroid and Itraconazole for Prevention of Recurrence in Allergic Fungal Rhinosinusitis: A Randomized Controlled Trial. AB - INTRODUCTION: Allergic Fungal Rhinosinusitis (AFRS) is due to the continuous exposure of fungal antigens to an atopic individual. Medical treatment following the surgery is the standard protocol often practiced for the treatment of AFRS. Steroid (systemic/topical) has been considered as the standard medical treatment for the control of the disease in AFRS although most of the patients show recurrence with long term follow up. Instead, antifungals (itraconazole) can be tried to decrease the recurrence rate which acts by inhibiting the fungal growth in the postoperative period. AIM: In the current study, we have compared the efficacy between steroid and the itraconazole in preventing the recurrence of the disease in patients with AFRS in postoperative period. MATERIALS AND METHODS: This prospective study was conducted in the Department of Otorhinolaryngology in a tertiary care referral hospital from October 2013 to February 2015. Total 60 patients with AFRS with nasal polyposis, diagnosed by Bent-Kuhn's criteria were included in the study. For patients of Group A (containing 30 patients), systemic steroid (oral prednisolone 30 mg OD) was continued for one month and afterwards topical steroid (nasal spray) was continued till six months after surgery. In Group B (containing 30 patients), oral itraconazole (100 mg BID) was continued for six months. Clinical and haematological parameters were compared at the end of six months. RESULTS: The average pre-treatment and post treatment scores of Absolute Eosinophil Count (AEC) in the patients of Group A was 532 MUg/l and 482 MUg/l respectively and the corresponding values in Group B were 578 MUg/L and 438 MUg/L respectively at the end of six months (p=0.912). Similarly, the preoperative and postoperative serum IgE level in Group A was 886.20 IU/ml and 620 IU/ml and the respective values in Group B were 935 IU/ml and 570 IU/ml (p=0.555). Mean preoperative and postoperative mean SNOT score in Group A and Group B were 52.5 in 34.3 and respective values in Group B were 55.7 and 29.5. CONCLUSION: Itraconazole can be considered as an effective treatment alternative to the steroid for postoperative management of AFRS. Although there was no significant difference noted between two groups, patients treated with itraconazole had a better symptomatic relief and endoscopic clearance of disease. PMID- 28571172 TI - Disparities in Oral Health Behaviour among Young Adults in Mangalore, India: A Psychosocial Perspective. AB - INTRODUCTION: Oral health inequalities imply unequal distribution of health and disease across socioeconomic gradients. Oral health related behaviour and its psychosocial antecedents can have a major impact on oral disease pathways in communities. AIM: To ascertain disparities in oral health behaviour and its psychosocial antecedents among young adults in Mangalore, Karnataka, India. MATERIALS AND METHODS: Present study was carried out among 341 degree students at three randomly chosen institutions belonging to government, aided and private colleges in Mangalore. Oral health behaviour was assessed by a structured, pre tested, self-administered questionnaire. Information about oral hygiene habits, tobacco use, sugar consumption, dental attendance patterns were collected. Respondent's self-reported gingivitis, perceived general and oral health, perceived need for care and locus of control were assessed. Information about demographic details was collected. Correlation analysis employed Pearson's correlation coefficient and binary logistic regression analysis was employed with snacking as dependent variable. RESULTS: Twice daily brushing was significantly associated with gender (r=0.142, p=0.009), type of college (r=-0.164, p=0.003) and father's occupation (r=0.107, p=0.049), while tobacco use was significantly associated with gender (r=0.284, p=0.000), religion (r=-0.234, p=0.000), type of college (r=0.312, p=0.000), father's education (r=0.130, p=0.017) and occupation (r=0.120, p=0.027). Self-perceived oral health was significantly associated with snacking (r=0.173, p=0.001) and tobacco use (r=-0.261, p=0.000), while locus of control was associated with snacking (r=0.140, p=0.009). Regression analysis revealed that father's education (OR=0.399, p=0.014), self-perceived need for care (OR=0.354, p=0.009), and locus of control (OR=0.166, p=0.003) emerged as significant predictors of snacking behaviour. CONCLUSION: Psychosocial antecedents were significantly associated with oral health behaviour among the respondents. Policy and decision makers should consider causes of causes while tackling oral health problems. Present study may contribute towards addressing oral health inequalities in developing nations, where oral health issues are compounded by a definite paucity of resources. PMID- 28571175 TI - Unilateral Absence of Ethmoid Sinus and Nasal Turbinates: A Rare Case Report. AB - A variety of anatomical variation of paranasal sinus and nasal turbinates exist, as its development is a complex and long standing process. Computerized Tomography (CT) of the paranasal sinuses is a very valuable tool in diagnosing these variations. Preoperatively defining the anatomical variations of the intranasal structures is essential in performing the safe functional endoscopic sinus surgery and to avoid unnecessary complications. Several degrees and combinations of aplasias and hypoplasias have been reported. We report a case of 37-year-old male who presented with bilateral nasal block and rhinorrhea and his CT paranasal sinuses showed gross septal spur in left side, absence of right middle, inferior and superior turbinates, absent right ethmoid air cells, aplastic right frontal sinus, left concha bullosa with bilateral maxillary sinusitis. PMID- 28571173 TI - Flat Foot in a Random Population and its Impact on Quality of Life and Functionality. AB - INTRODUCTION: Flat foot is a common deformity in adults. It is characterized by medial rotation and plantar flexion of the talus, eversion of the calcaneus, collapsed medial arch and abduction of the forefoot. AIM: The aim of this study was to determine the prevalence of flat foot and its impact on quality of life, dependence, foot pain, disability and functional limitation among random population of 40-year-old and above. MATERIALS AND METHODS: A cross-sectional study in a random population sample from Cambre (A Coruna-Spain) (n=835) was performed (alpha =0.05; Precision=+/-3.4%). The diagnosis of flat foot was stablished by the study of the footprint obtained with a pedograph. Anthropometric variables were studied, Charlson's Comorbidity Index, function and state of foot (Foot Function Index (FFI), Foot Health Status Questionnaire (FHSQ)), quality of life (SF-36), and dependence for activities of daily living (Barthel and Lawton index). A logistic and linear multiple regression analysis was performed. RESULTS: The prevalence of flat foot was 26.62%. Patients with flat foot were significantly older (65.73+/-11.04 vs 61.03+/-11.45-year-old), showed a higher comorbidity index (0.92+/-1.49 vs 0.50+/-0.98), had a greater BMI (31.45+/-5.55 vs 28.40+/-4.17) and greater foot size (25.16+/-1.66 vs 24.82+/ 1.65). The presence of flat foot diminishes the quality of life, as measured by the FHSQ, and foot function, measured by the FFI. The presence of flat foot does not alter the physical and mental dimension of the SF-36 or the degree of dependence. CONCLUSION: Flat foot was associated with age, Charlson's Comorbidity Index, BMI and foot size. The SF-36, Barthel and Lawton questionnaires remained unaltered by the presence of flat foot. The FHSQ and FFI questionnaires did prove to be sensitive to the presence of flat foot in a significant manner. PMID- 28571176 TI - Juvenile Nasopharyngeal Angiofibroma: A Case Report. AB - Juvenile nasopharyngeal angiofibroma is tumour almost exclusively seen in adolescent males, constituting less than 1% of all neoplasms in head and neck. They are benign and locally spreading and are highly vascular in nature and thus prove to be a surgical challenge because of its complex anatomical location. Here, we present a case report of a 18-year-old male presenting with a mass in his left nasal cavity, with recurrent epistaxis and nasal obstruction. Computed tomography imaging revealed a non-encapsulated lobulated heterogeneous mass lesion in the naso-pharynx and left posterior choana of the nasal cavity, extending to pterygopalatine and infratemporal fossa, masseter space of left side. The approach to its surgical management was a combined multi-disciplinary effort of otorhinolaryngology surgeons and maxillofacial surgeons. PMID- 28571177 TI - Quality of Life in People with Diabetic Retinopathy: Indian Study. AB - INTRODUCTION: Diabetic Retinopathy (DR) is a well-known consequence of long standing and poorly controlled Diabetes Mellitus (DM). Several studies have demonstrated both a qualitative and quantitative reduction in health related quality of life in persons with DR. But no such study has been done in the Indian population. AIM: To assess health related and vision related quality of life in people with DR. MATERIALS AND METHODS: The present study included two groups of patients with Type 1 and Type 2 diabetes. Cases included 97 patients with DR. The control group (n=26) consisted of diabetic cases with no clinically detectable DR changes. After taking informed consent, health and vision related quality of life was assessed using National Eye Institute 25-Item Visual Function Questionnaire (NEI-VFQ-25). Demographic information, social history and diabetic history were also obtained from all patients. DR was graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) classification. RESULTS: Of the 97 cases with DR, 42.3% were females. Of the 26 controls, 53.8% were females. The mean+/-SD age in years of the cases was 55.09+/-9.56 and controls were 54.12+/-13.01. The mean+/-SD of DM in years for the cases was 10.98+/-5.62 and for controls was 6.69+/-2.29. There were statistically significant (p<0.001) lower VFQ-25 composite and sub scale scores of the cases when compared with controls. As the grade of DR increased, VFQ-25 sub-scale scores decreased and this was statistically significant for composite and all sub scales (p<0.005) except ocular pain. Mann Whitney test Z-value was highest in general health, general vision, composite score and mental health. CONCLUSION: Quality of life was significantly lower in diabetics with DR when compared with those without DR with maximum effect seen on general health, general vision and mental health. Quality of life decreased as the duration of retinopathy and severity of retinopathy increased. PMID- 28571178 TI - A Case of Bilateral Corneal Perforation in a Patient with Severe Dry Eye. AB - Dry eye is a common problem affecting mainly the adult population. In severe cases, it can result in sterile corneal ulcer and perforation. We report a rare case of a 26-year-old male, a known patient of severe dry eye who presented with sterile corneal ulcer with corneal perforation in both the eyes. The patient was managed by applying cyanoacrylate glue and bandage contact lens in both eyes and topical antibiotic, topical cyclosporine and preservative free artificial tears at two hourly intervals. The patient was investigated for the systemic cause of severe dry eye but no cause could be ascertained. On follow up, the patient reported marked relief in photophobia. On examination, both eyes showed sealed perforation with well formed anterior chamber. In conclusion, one should examine a dry eye patient carefully and detect corneal ulcers and perforations in time so as to prevent its sequelae. PMID- 28571179 TI - Cow Urine Keratopathy: A Case Report. AB - Injury to the ocular surface has been described to occur with a wide variety of chemicals. In most cases the cause is industrial injury with acids or alkalis. We are reporting a case of ocular surface injury due to "Cow urine" which to the best of our knowledge is been reported for the first time. Cow urine is a well accepted medicinal ingredient in ancient Indian medicine. However, wrong formulation and inadvertent prescriptions by quacks can lead to severe ocular surface injury and morbidity. Here, with this case report we have discussed the possible culprit and possible mechanism of ocular injury due to instillation of a concoction containing cow urine as an active ingredient and also discuss legal aspects of quackery in India. PMID- 28571181 TI - Accuracy and Precision of Measured Blood Sugar Values by Three Glucometers Compared to the Standard Technique. AB - INTRODUCTION: The prevalence of diabetes mellitus has magnified, globally. Being cost effective and user friendly, using the glucometer systems has become more widespread. However, despite their advantages, there are controversies regarding their accuracy and precision. AIM: To determine the accuracy and precision of the common glucometers of Bionime, Accu-check, and Beurer compared with the laboratory technique. MATERIALS AND METHODS: In a cross-sectional study, 257 patients of a general internal unit of Imam Reza hospital of Kermanshah were recruited. The blood sample of the subjects was transferred to the laboratory, then, two samples of capillary blood were tested by the three glucometers. The data was entered into a checklist, then entered to SPSS-16.0 software, and analyzed by descriptive and inferential statistics. RESULTS: In this study, there was a positive correlation between the three blood glucose measurement methods with the standard approach, significantly, which indicates acceptable accuracy. However, this correlation was higher in the Beurer Glucometer (r=0.976, p<0.001). There were no significant differences in repeated measurements of blood glucose in the glucometers of Beurer (t=0.96, p=0.92), and Bionime (t=0.50, p=0.61) by paired t-test, but this test was significant for Accu-chek system (t=2.7, p=0.006). CONCLUSION: With respect to the acceptable accuracy and precision of Beurer and Bionime glucometers, it is suggested to use these methods for diabetic patients at homes as well as in the hospital units. PMID- 28571180 TI - Gastroesophageal Reflux Disease and its Association with Body Mass Index: Clinical and Endoscopic Study. AB - INTRODUCTION: Obesity is rapidly becoming a pandemic and poses a serious health risk to the individuals. Abdominal obesity is quite common in India and is a prime risk factor for diseases like diabetes, coronary artery disease, Gastroesophageal Reflux Disease (GERD), osteoarthritis etc. A complex and multifactorial aetiopathogenesis of GERD exists in presence of obesity. The current study focuses on high Body Mass Index (BMI), a marker of obesity, as a risk factor for GERD and aims for a better understanding of their complex association. AIM: To study the association between the BMI and symptoms as well as gross endoscopic appearance of GERD. MATERIALS AND METHODS: A prospective cross-sectional study was carried out at a tertiary care hospital in Maharashtra, India, between January 2016 and June 2016. A total of 176 patients referred for upper Gastrointestinal (GI) endoscopy due to dyspeptic symptoms of more than two months duration were selected. BMI (weight in kilograms/square of height in metres) was calculated for all patients and they were classified as normal weight (BMI 18.5 -24.9), overweight (BMI 25-29.9) and obese (BMI>=30). The frequency and severity of GERD symptoms was assessed by a self-administered questionnaire. Data on typical and atypical symptoms of GERD was collected. Upper GI endoscopy was done on all patients. Based on gross endoscopic appearance, the disease was divided as Endoscopy Negative Reflux Disease (ENRD) and true GERD (as per Los Angeles staging system). Association between BMI and frequency, severity and type of symptoms of GERD and also between BMI and gross endoscopic oesophagitis was studied using various statistical tests. All tests were two-tailed with a confidence level of 95%. A p-value < 0.05 was considered to be statistically significant. RESULTS: Typical symptoms of heartburn and acidic regurgitation were present in 71.6% subjects. The frequency and the severity of the dyspeptic symptoms increased significantly with increasing BMI (p<0.05). Based on the endoscopic gross appearance of the oesophageal mucosa, 48.3% participants had ENRD and 51.7% had erosive disease (GERD). High BMI had a statistically significant relationship with occurrence of both ENRD and GERD (p<0.05) but a statistically insignificant relationship with LA classification system for endoscopic oesophagitis. CONCLUSION: The prevalence, frequency and severity of symptoms of GERD increases with increase in the BMI. Erosive oesophagitis has significant correlation with increasing BMI, but the staging and classification of endoscopic erosive oesophagitis is independent of the BMI of the patients. PMID- 28571182 TI - Prevalence of Autonomic Neuropathy in Patients of Rheumatoid Arthritis and Its Correlation with Disease Severity. AB - INTRODUCTION: Autonomic Neuropathy (AN), found to be a strong predictor of sudden cardiac death, has been reported variably in patients with Rheumatoid Arthritis (RA). Manifesting as sweating disturbances, gastrointestinal irregularities, bladder or erectile dysfunction, AN can significantly affect a patient's quality of life and alter the course of the disease. AIM: This study was undertaken to find out the prevalence and severity of AN in RA patients attending the Rheumatology Clinic at a Tertiary Care Hospital in New Delhi, India and also to investigate its correlation with patient and disease factors such as age, gender, disease severity, duration and serological status. MATERIALS AND METHODS: In this cross-sectional study, AN was assessed subjectively by a survey of autonomic symptoms. Cardiac autonomic involvement was assessed by five cardiovascular reflex tests as described by Ewing: Heart Rate (HR) response to deep breathing, standing, and Valsalva and Blood Pressure (BP) response to standing and sustained handgrip. RESULTS: A total of 31 RA patients and 31 age and sex matched healthy volunteers were recruited. Upon analysis it was found that the prevalence of cardiac AN was significantly higher in patients (80.65%) as compared to controls (51.61%) (p=0.016). Positive correlation with disease severity was observed with the patient reported questionnaire but not with the objective cardiovascular reflex tests. No significant correlation between grade of AN and patient's age, gender, disease duration or serological status was established. CONCLUSION: At the end of the study, it was concluded that the pathological mechanisms responsible for autonomic dysfunction are more active in RA as compared to others. PMID- 28571183 TI - Effect of Ranolazine in Patients with Chest Pain and Normal Coronaries- A Hospital Based Study. AB - INTRODUCTION: There is an important role of coronary microcirculation in the clinical presentation and prognosis of patients who have typical chest pain despite normal epicardial coronary arteries (microvascular angina). Treatment of these patients is empirical because of the incomplete knowledge of its cause. Limited data has shown that ranolazine reduces angina and improves exercise performance in such patients with frequent angina. AIM: To evaluate the effect of ranolazine in patients with chest pain and normal epicardial coronaries (micro vascular angina). MATERIALS AND METHODS: Sixty-five patients with anginal symptoms with abnormal exercise stress test and normal epicardial coronaries were enrolled for the study. All participants had baseline demographic and health history questionnaires, including Seattle Angina Questionnaire (SAQ) and Duke Activity Status Index (DASI). After enrolment, patients were randomly divided into two groups. One group (group 1) was assigned to ranolazine for six weeks along with other indicated anti-anginal drugs. The other group (group 2) was assigned to anti-anginal drugs other than ranolazine. Patients were reassessed for symptomatic and functional improvement (SAQ, DASI) at six weeks. RESULTS: Mean age of patients examined were 49.03 years in group 1 and 49.77 years in group 2. Approximately 42.9% of patients in group 1 and 40% in group 2 were male. Despite current anti-anginal therapy, patients in both the groups were symptomatic. At six weeks, 60% of patients in group 1 had angina as compared to 88.6% at baseline (p<0.05). Similarly, scores of domains of SAQ were higher at six weeks as compared to baseline (p<0.05) except for treatment satisfaction. No improvement of DASI score and functional capacity were seen in either group at six weeks as compared to baseline (p>0.05). At six weeks, angina was significantly lower in group 1 as compared to group 2 (60 % vs 86.7%; p<0.05). Four out of five SAQ subscale score were higher in ranolazine group as compared to the other group (p<0.05). Treatment satisfaction trended lower on ranolazine group (p<0.05). There was no significant differences in DASI in the two groups (DASI score 30.59 vs 29.85, p>0.05). CONCLUSION: Ranolazine is safe and improves symptoms significantly in patients with micro-vascular angina. PMID- 28571185 TI - Determination and Validation of a Lower Cut Off Value of Cerebrospinal Fluid Adenosine Deaminase (CSF-ADA) Activity in Diagnosis of Tuberculous Meningitis. AB - INTRODUCTION: Tuberculous meningitis is an infection of the meninges caused by Mycobacterium tuberculosis. It is one of the most common infectious diseases of the Central Nervous System (CNS) and a major health problem in developing countries like India. If there is delay in diagnosis and initiation of specific treatment, it causes significant morbidity and mortality. CSF-ADA 10 U/l is the standard cut off value that is used for differentiation between Tuberculous (TBM) and Non-Tuberculous Meningitis (non-TBM). AIM: To determine and validate a lower cut off value for CSF-ADA for diagnosing TBM in an Indian setting. MATERIALS AND METHODS: This was a prospective study involving 85 cases of meningitis whose CSF were analysed and ADA estimated using an enzymatic deamination assay kit. Diagnosis of various types of meningitis was made based on specified diagnostic criteria. The comparison of mean value of CSF- ADA activity of the two types of meningitis was done using two Sample t-test. A p-value of <0.05 was considered as significant. Cut off value to differentiate between TBM and non-TBM meningitis was determined using ROC curve analysis. RESULTS: The CSF-ADA activity of TBM and non-TBM cases was compared. The mean CSF-ADA activity was found to be significantly higher in TBM patients (10.97+/-4.43; Mean+/-SD) than in non-TBM patients (5.09+/-1.53) which was statistically significant with a p-value of <0.001. A cut off value of 6.65 was calculated using ROC curve for the diagnosis of TBM which gave a sensitivity of 85.3% and a specificity of 84.3% for differentiating TBM from non-TBM. The positive predictive value was 78.3% and negative predictive value of 89.5% using the above cut off. The positive likelihood ratio was 5.44 and negative likelihood ratio of 0.17 when this lower cut off value was applied. CONCLUSION: This study has demonstrated that CSF-ADA can be used as an important diagnostic tool in early diagnosis of TBM using a cut off value of 6.65. This cut off value gave a good sensitivity and specificity in differentiating it from non-TBM. PMID- 28571184 TI - The Importance of Liver-Fatty Acid Binding Protein in Diagnosis of Liver Damage in Patients with Acute Hepatitis. AB - INTRODUCTION: Acute hepatitis is acute inflammation of liver elicited by a large number of causes. It sometimes spontaneously recovers, sometimes may progress to chronic hepatitis. Liver- Fatty Acid Binding Protein (L-FABP) is a small protein that is abundant in hepatocytes, and which binds most of the long-chain fatty acids present in the cytosol. AIM: The present study was aimed to investigate the levels of serum and urine L-FABP in acute hepatitis and diagnostic value of serum and urine L-FABP levels in patients with acute hepatitis. MATERIALS AND METHODS: The present study included a total of 85 patients. Total number of patients with acute hepatitis were 17 (five of acute hepatitis B, one of acute hepatitis A, two of acute hepatitis C, five of autoimmune hepatitis and four of toxic hepatitis), 19 of hepatic encephalopathy, 29 of liver cirrhosis, and 20 controls were included. Serum and urinary L-FABP levels were analyzed by the Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: Serum L-FABP levels were 9110+/-3352.5, 9410+/-1355, 9715+/-2462 and 3672+/-982.5 ng/l in patients with acute hepatitis, hepatic encephalopathy and cirrhosis and control subjects, respectively. There were statistically significant positive correlations between serum levels of L FABP and Aspartate Aminotransferases (AST), Alanine Aminotransferases (ALT), Creatinine (Cre) and Gamma Glutamyl Transferases (GGT) (p<0.001, p<0.001, p<0.001 and p<0.001, respectively). While the cut-off value of serum L-FABP for all of the patients was 5183 ng/l {p<0.001 and Area Under Curve (AUC) 0.985}, the sensitivity and specificity were 95.4% and 100%, respectively. Positive and negative predictive values for serum L-FABP were 100% and 87%, respectively. CONCLUSION: Serum and urine L-FABP may be a new diagnostic marker for liver damage in patients with acute hepatitis. However, our study showed that except of aminotransferases, L-FABP should be used for diagnosis of liver damage in patients with acute hepatitis, chronic hepatitis and also cirrhosis. PMID- 28571186 TI - Clinical and Laboratory Profile of Urinary Tract Infections in Type 2 Diabetics Aged over 60 Years. AB - INTRODUCTION: Urinary tract infections are frequently encountered among diabetic patients and the incidence rate increases with age. There have been growing research to identify the clinical profile of urinary tract infections in diabetic patients. However, such studies on elderly patients are rare. AIM: To determine the risk factors, clinical/laboratory profiles, causative organisms and antimicrobial susceptibilities in type 2 diabetics aged over 60 years. MATERIALS AND METHODS: This prospective single centre study was conducted at NRI Medical College and General Hospital, Guntur, India, between November 2012 and November 2014. A total of 100 consecutive patients with type 2 diabetes mellitus, aged over 60 years, with symptoms suggestive of urinary tract infection were examined. Subsequently, the demographic characteristics, detailed medical history, signs/symptoms of urinary tract infections, laboratory investigations for blood and urine samples, ultrasound abdomen findings were compared between bacteriuric and non bacteriuric patients. In addition, the organisms in urine cultures and antibiotic sensitivity patterns were investigated for bacteriuric patients. Two groups were compared using the Mann-Whitney test for continuous variables and the Chi-square or the Fisher's exact test for categorical respectively. RESULTS: Bacteriuria was found in 43% of type 2 diabetic patients aged over 60 years. Comparative analysis revealed that bacteriuria was more common among patients with female gender (p=0.028), diabetes duration of >15 years (p=0.011) and diabetes complications such as neuropathy (p=0.027) and diabetic foot (p=0.003). Age and uncontrolled fasting blood sugar or HbA1c levels did show an increased propensity for developing urinary tract infections. Increased frequency (76.7%), and urgency (67.4%), dysuria (65.1%) were significantly more common among bacteriuric patients than that in nonbacteriuric patients (p<0.05). Urine culture analysis revealed that E. coli (69.8%) was the most common causative organism, followed by Klebsiella (16.3%). Majority of isolated organisms were sensitive to antimicrobial agents like nitrofurantoin and imipenem. CONCLUSION: Bacteriuria was very common in elderly patients with diabetes. The observed trends in risk factors, clinical profile, laboratory profile, causative organism patterns, and antimicrobial susceptibilities will help to add the growing literature on this topic. PMID- 28571187 TI - Study of Short and Intermediate Term Clinical Outcomes of Patients with Protected and Unprotected LMCA Stenting. AB - INTRODUCTION: Significant unprotected Left Main Coronary Artery (LMCA) disease is detected in 5%-7% of cases undergoing Coronary Angiography (CAG). Present guidelines have revealed the significance of anatomical location in left main artery stenosis and syntax scores for determination of Major Adverse Cardiac Events (MACE). Debate still persists over the best treatment regarding outcomes of Coronary Artery Bypass Grafting (CABG) and LMCA stenting for patients with LMCA disease. AIM: Aim of the study was to evaluate short and intermediate term clinical outcomes of Percutaneous Coronary Intervention (PCI) in LMCA disease in respect to mortality, Cerebrovascular Accidents (CVA), reinfarction, stent restenosis and need for repeat target lesion revascularization. MATERIALS AND METHODS: From July 2013 to February 2015, 50 patients underwent LMCA stenting. All patients underwent detailed clinical assessment, detailed 2D echocardiographic assessment. Syntax score was calculated in all patients. Clinical in hospital and outpatient follow up was obtained at one, three, six, nine months and one year. RESULTS: Mean age was 53.14+/-9.60 years. On CAG 16 (32%) patients had ostial LMCA lesion, 8 (16%) had mid LMCA lesion, distal LMCA was diseased in 6 (12%). In emergency situation, two bail out LMCA stenting were done for treatment of LMCA dissection. A total of 42 (84%) patients had low syntax score, 6 (12%) had intermediate and 2 (4%) had high syntax score. Only LMCA stenting was done in 22 (44%) patients, LMCA to Left Anterior Descending (LAD) stenting was done in 22 (44%) and LMCA to Left Circumflex (LCX) stenting was done in 6 (12%) patients. Drug-Eluting Stent (DES) was used in 35 (70%) cases while Bare-Metal Stent (BMS) was used in 15 (30%). An 8% mortality and 8% target lesion revascularization rate were observed in our study. CONCLUSION: Our study revealed that LMCA stenting is a safe and feasible alternative mode of revascularization in selected patients. Patients most suitable for LMCA stenting in our study were those with isolated ostial/mid LMCA disease, with protected LMCA disease and those who underwent elective stenting procedure. PMID- 28571188 TI - Six Minute Walk Test: A Tool for Predicting Mortality in Chronic Pulmonary Diseases. AB - INTRODUCTION: Six Minute Walk Test (6MWT) is a simple test used to measure exercise capacity in Chronic Pulmonary Diseases (CPDs). Decreased exercise capacity significantly affects the quality of life. The 6MWT is a known tool to measure exercise capacity and quality of life in CPD. However, the role of change in follow up Six Minute Walk Distance (6MWD) in assessing mortality and its correlation with known prognostic factors haven't been tested to the best of our knowledge. AIM: To study the correlation of change in 6MWD with change in spirometry and to study the role of 6MWD in predicting mortality in CPD. SETTINGS AND DESIGN: Prospective cohort study. MATERIALS AND METHODS: A total of 139 CPD patients were grouped into obstructive, restrictive and post Tuberculosis (TB) sequelae. Optimized treatment was given and they were followed up regularly. Spirometry and 6MWT was done at the beginning and after one year. Mean decline in FEV1, FVC was correlated with mean decline in 6MWD. STATISTICAL ANALYSIS: With STATA 13.1 correlation between 6MWT and spirometric values were done using Wilcoxon signed rank test. Predictors of mortality were studied using multivariate analysis. RESULTS: Overall mean decline in 6MWD was 16.07 m/year. There was no correlation between mean change in 6MWD and change in FEV1, FVC, and FEV1/FVC. On multivariate analysis, 6MWD was the better predictor of mortality than FEV1 (p<0.001), FVC (p<0.001). At cut off value of 240 meters, sensitivity and specificity of 6MWT in predicting mortality was 71.05% and 81.94% respectively. CONCLUSION: The 6MWD changes independently and has no correlation with change in spirometry, it is an independent predictor of mortality in CPD. PMID- 28571189 TI - Evaluation of ECG Abnormalities in Patients with Asymptomatic Type 2 Diabetes Mellitus. AB - INTRODUCTION: Diabetes Mellitus (DM) is the most common chronic disease. DM is considered a Cardiovascular Disease (CVD) risk equivalent. Its macrovascular complications are associated with two-fold increased risk of premature atherosclerotic CVD. Most of the diabetics with cardiovascular involvement are asymptomatic. Electro Cardio Graph (ECG) abnormalities are found to be predictors of silent ischaemia in asymptomatic persons. An abnormal ECG response is associated with statistically significant high risk for cardiac mortality and morbidity. AIM: The aim of the study was to evaluate ECG changes in asymptomatic Type 2 DM patients. MATERIALS AND METHODS: A cross-sectional comparative study was conducted in a tertiary care hospital in North India. One hundred diabetics presenting to Medicine OPD/IPD were included in the study who had no symptoms of heart disease and no diabetic complications. Fifty person with age and sex matched controls were included in the study. Relevant history and physical examination findings were recorded in a protocol. The variables studied were: gender, age, smoking, physical activity, and waist circumference, Body Mass Index (BMI) and blood pressure. Resting ECG was recorded. RESULTS: Mean age of asymptomatic diabetic patients was 50.3+/-11.90 years (age range 25-75 years). In this study, none of the control group had ECG abnormality whereas, 26% asymptomatic diabetics had ECG abnormalities. Most of the asymptomatic cases with ECG changes had 5-10 year of duration of diabetes mellitus; 70% patients with ECG changes had poor glycaemic control, increased triglyceride and decreased High Density Lipoprotein (HDL) levels. Most common abnormality observed was ST-T changes, followed by Left Atrial Enlargement (LAE), Left Ventricular Hypertrophy (LVH), Left Bundle Branch Block (LBBB) and Right Bundle Branch Block (RBBB). CONCLUSION: ECG changes are present in quarter of asymptomatic Type 2 DM patients. However, nonspecific ST-T changes, LVH and LAE are common. PMID- 28571190 TI - The Study of Different Clinical Pattern of Diabetic Ketoacidosis and Common Precipitating Events and Independent Mortality Factors. AB - INTRODUCTION: Diabetic Ketoacidosis (DKA) is an important cause of morbidity and mortality among diabetic patients in spite of major advances in the pathogenesis and more standardized diagnosis and treatment. AIM: To find out the different patterns of clinical presentations, common precipitating factors and independent mortality factors in DKA. MATERIALS AND METHODS: This study was conducted in a tertiary care hospital, Mysuru on 110 patients from November 2007 to October 2009. Clinical presentation and precipitating factors of DKA were monitored. Univariate analysis was done to identify statistically significant risk factors contributing to DKA mortality and was used for multiple logistic regressions to identify independent mortality predictors. A scoring methodology was used to identify the risk of having multiple risk factors in an individual. RESULTS: In this study, the mean age was 42.33 years, with a male to female ratio of 1.2:1. The most common complaints were vomiting and generalized weakness seen in 55 (50%) and 49 (44.5%) cases respectively. The most common precipitating factors were infections and poor compliance to antidiabetic treatment seen in 57 (52%) and 23 (21%) cases respectively. The predictors of mortality included age equal to or more than 65 years, Depressed Mental State (DMS) in the first 24 hour, insulin requirement equal to or more than 50 units in the 12 hours to bring blood glucose to less than 300 mg%, fever in the first 24 hours, shock in the first 24 hours, RBS persistently equal to or more than 300 mg% even after 12 hours with standard treatment protocol, fluid requirement equal to or more than 6 L in the first 24 hours, pH less than 7.2 and bicarbonate less than 15 mmol/l at presentation were statistically significant predictors of mortality. Multivariate analysis failed to identify an independent mortality factor; but, adverse parameters of more than 5 was significantly associated with death. CONCLUSION: Risk stratification of patients with DKA is possible from simple clinical and laboratory variables available during the first day of hospitalization and further channeling the patients to ICU at the correct time to prevent mortalities. PMID- 28571191 TI - A Successfully Treated Case of Criminal Thallium Poisoning. AB - Thallium was once commonly used as a household rodent or ant killer, but many countries have banned such use due to unintentional or criminal poisonings of humans. A common initial clinical manifestation of thallium poisoning is gastrointestinal symptoms followed by delayed onset of neurological symptoms and alopecia. These clinical characteristics can provide important diagnostic clues regarding thallium poisoning. Here, we report a 23-year-old woman who was poisoned by a business colleague when she unknowingly drank tea containing the toxic substance several times. The patient was treated with multi-dose activated charcoal with airway protection and Prussian blue. PMID- 28571192 TI - Youngest Case of Allergic Broncho Pulmonary Aspergillosis in India: A Case Report from Arid Zone of India. AB - Allergic Broncho Pulmonary Aspergillosis (ABPA) is an immunological allergic disorder and asthmatic patients are predisposed to ABPA. Although, ABPA commonly develops in the third and fourth decades but no age group is unaffected from the disease. Youngest case of ABPA in India so far reported was four years of age. This case report is about a young child of bronchial asthma with ABPA aged four years and nine days only, from arid zone of country. Her diagnosis of ABPA was supported by clinical, serological and radiological findings. This case report concludes the importance of early diagnosis and treatment of ABPA along with general awareness for the disease. PMID- 28571193 TI - Recurrent Longitudinally Extensive Myelitis and Aquaporin-4 Seronegativity - The Expanding Spectrum of Neuromyelitis Optica. AB - Neuromyelitis Optica Spectrum Disorder (NMOSD) is a recently proposed unifying term for Neuromyelitis Optica (NMO), also known as Devic's disease and related syndromes. It is a relapsing inflammatory demyelinating disease that most commonly affects optic nerves and the spinal cord, leading to sudden vision loss or weakness in one or both eyes, and loss of sensation and bladder function. Though inflammation may also involve the brain, the lesions seen in NMO are different from Multiple Sclerosis (MS) which has a similar clinical course. Attacks of NMOSD tend to be more severe and often different in nature from MS. MS and NMOSD are often confused but require a different course of treatment for optimal results. Here, we describe a patient who had clinical features suggestive of NMO but showed seronegativity for anti-aquaporin antibodies, done twice. Initially he was managed on the lines of MS but showed a deteriorating clinical course on initiation of treatment with interferons. Later, his diagnosis was revised to seronegative NMO and he was started on immunosuppressive therapy with azathioprine to which he showed optimal response and achieved disease stabilization. PMID- 28571194 TI - Bilateral Cervical Lymphadenopathy Atypical Presentation of Malaria-A Rare Case Report. AB - Malaria, the most common parasitic disease of humans, remains a major health and economic burden in most tropical countries. An 18-year-old male from rural north eastern India presented with four days fever with chill. The patient was conscious, oriented but confused. Physical examination revealed bilateral multiple, discrete cervical lymphadenitis without organomegaly or sternal tenderness. Blood parameters were normal except transient thrombocytopenia. Blood smear and antigen were positive for both Plasmodium vivax and falciparum with negative viral markers. Fine Needle Aspiration Cytology (FNAC) of cervical lymph nodes showed non-specific reactive lymphadenitis which subsided with antimalarial treatment. Lymphadenitis is an extremely rare presentation in malaria and is considered as an important negative finding. We reported this case to highlight that such unusual manifestations may present in malaria in endemic areas which may baffle the clinicians. PMID- 28571195 TI - Primary Pulmonary Artery Intimal Sarcoma Case with Elevated Coagulation Markers. AB - Primary Sarcoma of the Pulmonary Artery (PAS) is a very rare and miserable disease. The clinical signs and symptoms of PAS are non- specific, which usually prevents diagnosis before surgery or autopsy. The current guidelines for the diagnosis and treatment of PAS have not been well established. Several reported cases of PAS have been mistaken for Pulmonary Artery Thromboembolism (PTE), because the clinical signs and symptoms of PAS are non-specific. Elevated coagulation markers are generally absent in PAS and therefore, support a differential diagnosis of PTE. We herein report a patient with PAS who presented with elevated coagulation markers and later showed rapidly improved values mimicking response of PTE to anticoagulant therapy. PMID- 28571196 TI - Addison's Disease Mimicking as Acute Pancreatitis: A Case Report. AB - Over past two decades there has been significant improvement in medical field in elucidating the underlying pathophysiology and genetics of Addison's disease. Adrenal insufficiency (Addison's disease) is a rare disease with an incidence of 0.8/100,000 cases. The diagnosis may be delayed if the clinical presentation mimics a gastrointestinal disorder or psychiatric illness. We report a case of Addison's disease presenting as acute pain in abdomen mimicking clinical presentation of acute pancreatitis. PMID- 28571197 TI - Cardiac Amyloidosis, An Infiltrative Heart Disease Presenting as Arrhythmia-A Case Report. AB - Cardiac amyloidosis is a manifestation of amyloidosis which is a multisystem disorder. This is difficult to diagnose, rare disease which eventually leads to the mortality. Diagnosis requires a high index of clinical suspicion along with echocardiographic clues like, diastolic dysfunction, bi-atrial enlargement and ventricular thickening. Treatment is mainly supportive with disappointing outcomes. We present a case of systemic amyloidosis with negative congo red staining, presenting with predominantly cardiac features. PMID- 28571198 TI - Deep Cerebral Vein Thrombosis: A Clinical Masquerader. AB - Cerebral Vein Thrombosis (CVT) is an uncommon cause of stroke. Thrombosis can occur in superficial veins, deep venous system or cortical veins of brain. The term Deep Cerebral Vein Thrombosis (DCVT) is used for thrombosis of internal cerebral vein, vein of Galen and basal vein of Rosenthal. Only 10% cases of CVT are because of thrombosis of deep cerebral vein. The diagnosis of DCVT is often missed because of its heterogenous presentation. Herein, we present a case of DCVT which was initially treated as meningoencephalitis. A timely advised brain imaging helped in making the diagnosis and patient recovered completely after institution of anticoagulation. PMID- 28571199 TI - An Unusual Case of Eosinophilia. AB - Various inflammatory markers have been used to show an association between welding and respiratory tract disorders due to inhalation of fumes. We hereby present a case of 19-year-old male, welder by occupation who presented with upper respiratory tract infection and was documented to have persistent moderate eosinophilia on serial Complete Blood Count (CBC) examination. This was also confirmed by bone marrow examination which was suggestive of increased eosinophilic precursors. Eosinophils are an inflammatory marker and are increased most commonly in respiratory tract of welders due to inhalation of metal fumes. Treatment with steroid is gratifying and provides short term symptomatic relief. Avoidance of metal fumes and/or change of job is the long term preventive measure. Welding occupation, as a risk factor, should be considered for causation of persistent respiratory tract inflammation with eosinophilia. PMID- 28571200 TI - Inhaled Insulin - Current Direction of Insulin Research. AB - Diabetes Mellitus (DM) is a metabolic disorder characterized by relative or absolute deficiency of insulin, resulting in hyperglycemia. Subcutaneous insulin and Oral Hypoglycaemic Agents (OHA) constitute the main treatment option for DM. Insulin is administered by injection or continuous infusion to control glucose levels mainly in Type I diabetes. Newer routes both oral and non oral, for insulin administration are current direction of insulin research as insulin injection therapy is burdensome and painful for many patients. Inhalational insulin is an attractive alternative for systemic administration of insulin given its accessibility and large alveolar-capillary network of lungs for drug absorption. Afrezza, inhaled insulin has been recently approved by Food and Drug Administration (FDA). It is a new, quicker acting inhalable insulin with a different and safer pharmacokinetic profile in comparison to previously failed inhaled form of insulin. PMID- 28571201 TI - Primary Hypothyroid and Secondary Adrenal Insufficiency-Searching the Missing Link. PMID- 28571202 TI - Vocal Hoarseness in Rheumatoid Arthritis: Early Recognition is Critical. PMID- 28571203 TI - A Comparative Study of Antegrade Air Pyelogram and Retrograde Air Pyelogram for Initial Puncture Access during Percutaneous Nephrolithotomy. AB - INTRODUCTION: Access into the collecting system is considered to be the most critical step for Percutaneous Nephrolithotomy (PCNL). AIM: The present study provides a comparative view into antegrade air pyelography and retrograde air pyelography procedures for percutaneous renal access. MATERIALS AND METHODS: A cross-sectional study was conducted on 100 patients with radiopaque renal calculi indicated for PCNL procedure. These patients were randomly assigned to two groups namely antegrade air pyelogram group (Group I) and retrograde air pyelogram group (Group II). In antegrade air pyelogram group, the collecting system was delineated by targeting the renal stone using a 22 gauge spinal needle where the patients were in the prone position. In another group, the collecting system was delineated by retrograde air pyelogram under fluoroscopy guidance. The method of tract dilatation and stone extraction were the same in both groups for comparison of outcome and complication. RESULTS: The mean age of patients was 41.7+/-13 and 41.4+/-13.6 years in Group-I and Group-II respectively. The male to female ratio in Groups I and II was 35/15 (70.00%) and 38/12 (76.00%) respectively. In Group-I the average duration of access was 2.66+/-1.0 minutes after prone positioning whereas it was recorded to be 19.48+/-5.0 minutes in Group-II, after lithotomy followed by prone positioning of the patient. Duration of radiation exposure was almost similar in both groups. Additional procedural cost was significantly higher in Group II. CONCLUSION: Our study indicated that access for PCNL using antegrade air pyelogram can be a cost-effective and acceptable alternative to retrograde air pyelogram with decreased access time. PMID- 28571204 TI - Impact of Biliary Calculi on the Liver. AB - INTRODUCTION: Gallstone is implicated for hepatocellular injury due to chronic extra hepatic large bile duct obstruction with or without repeated episodes of cholangitis. AIM: To study the liver changes in patients undergoing operative procedure for gallstone disease and to determine the relationship between severity of these changes with position of biliary calculus in biliary tree. MATERIALS AND METHODS: Sixty patients who underwent operative procedure for gallstone disease between October 2013 and September 2015 were evaluated. The Liver Function Test (LFT) was done preoperatively and postoperatively. Intraoperative liver biopsy was taken. The histopathological changes of liver and their severity were noted. RESULTS: The most commonly observed liver function abnormality both in cholelithiasis (12.8%) and choledocholithiasis patients (50%) was increased alkaline phosphatase. Most commonly observed liver histology changes in patients with cholelithiasis was nonspecific reactive hepatitis (46.9%) and in choledocholithiasis was chronic cholestasis (50%). Patient with choledocholithiasis showed significant changes (p<0.001) in liver histopathology and LFT as compared to cholelithiasis. CONCLUSION: Patients with gallstone diseases developed significant functional as well as structural hepatic changes. Though the change was more significant in patient with choledocholithiasis compared to cholelithiasis, early operative procedure is recommended in all gallstone disease patients to prevent potential liver damage, irrespective of position of biliary calculi in biliary tree to prevent morbidities associated with it. PMID- 28571205 TI - Postoperative Malignant Hyperthermia- A Medical Emergency: A Case Report and Review of Literature. AB - Malignant hyperthermia is a rare life threatening pharmacological disorder. Preoperative clinical diagnosis is not possible. Due to its rarity and severity, it must be taken as an important differential diagnosis for postoperative hyperthermia. We hereby report a case of postoperative malignant hyperthermia in a four-year-old female child, who was operated for type 1 choledochal cyst and had difficult postoperative sequel. We lost that child due to unavailability of Dantrolene sodium in emergency drug cart. PMID- 28571206 TI - Spontaneous Intracerebral Bleed Post Snake Envenomation. AB - Snakebite envenomation is a commonly encountered emergency in tropical countries with potentially fatal complications. Life threatening neurosurgical complications are rare and infrequently documented in literature. We discuss the case of 28-year-old gentleman, managed successfully for an intracerebral haemorrhage following a viper bite and attempt to obviate some management dilemmas often encountered in viperine envenomation. PMID- 28571207 TI - Bilateral Synchronous Paratesticular Leiomyoma - A Rare Entity. AB - Paratesticular region is an obscure anatomical region that includes spermatic cord and its contents, tunica of the testes, epididymis and appendices of epididymis and testis. Paratesticular tumours may closely resemble and be clinically indistinguishable from testicular tumours, resulting in a diagnostic dilemma. Preoperative distinction between the benign and malignant paratesticular tumour is extremely difficult, resulting in difficulty in diagnosis and management. We hereby present a case of a 56-year-old male who reported with a painless bilateral scrotal mass and underwent surgical excision of the same. The final biopsy report was paratesticular leiomyoma. The main purpose of this manuscript is to emphasize on the fact that it is imperative for the treating urologists to be aware of such potentially benign rare entity. A high index of clinical suspicion is mandatory, as lack of knowledge about this condition would result in an unnecessary radical orchidectomy. PMID- 28571208 TI - Giant Leiomyoma of the Oesophagus. AB - Leiomyomas are rare benign tumours of the oesophagus that remain silent in more than 50% of the cases. Giant leiomyomas measuring more than 5 cm are very rare. A 47-year-old female presented with chest pain, cough and dysphagia for two months. Imaging studies were indicative of a 12.1x11.9 cm mass lesion in the distal oesophagus, CT guided biopsy confirmed leiomyoma. The patient being taken up for surgery was found to have a 20x19x17 cm irregular lobulated and encapsulated mass lesion arising from distal oesophagus encapsulating submucosally. En bloc resection of the tumour along with distal oesophagus with a clearance of 4 cm above and below the oesophagogastric junction was done followed by gastro oesophageal anastomosis. Histopathologically, leiomyoma was confirmed. The patient had a smooth postoperative recovery. PMID- 28571209 TI - Pseudo Aneurysm of Aberrant Right Gastroepiploic Artery Mimicking Pseudocyst of Pancreas- A Rare Case Report. AB - Pseudoaneurysm of peripancreatic vessel is a rare complication of pancreatitis. The splenic artery is the most commonly affected vessels close to the pancreas. Pseudoaneurysm of right gastroepiploic artery is rare. It can rupture into Gastro Intestinal (GI) tract, retroperitoneum, peritoneal cavity, biliopancreatic duct or pseudocyst. Clinical diagnosis of unruptured pseudoaneurysm is rarely possible because there are no specific signs and symptoms. We hereby report a case of pseudoaneurysm of aberrant right gastroepiploic artery in 30-year-old male which presented with history of epigastric pain and lump with episode of haematemesis and malena. Diagnosis was suspected on Doppler Ultrasonography (USG), which was later confirmed by CECT and angiography. Patient was treated by coil embolization. The pain and lump in epigastrium disappeared within five to six days. Patient is symptom free after six months of follow up. PMID- 28571210 TI - Meckel's Diverticulum Enterolith: An Extremely Rare Cause of Intestinal Obstruction. AB - Meckel's diverticulum is usually asymptomatic but occasionally presents with complications. Formation of an enterolith inside a Meckel's diverticulum is very uncommon and dislodgement of such a stone causing obstruction is extremely rare. We herein present a case of a 48-year-old man who presented with small bowel obstruction. Preoperative radiologic studies revealed a stone-like lesion in the right lower quadrant. Upon laparotomy, an inflamed Meckel's diverticulum was found as well as a 2.5 cm stone obstructing the terminal ileum. The stone was removed and the diverticulum was excised. The differential diagnosis of acute intestinal obstruction should include this extremely rare clinical entity especially when the combination of small bowel obstruction with radiopaque stone like finding on preoperative x-rays is present. PMID- 28571211 TI - Pentazocine Alone Versus Pentazocine Plus Diclofenac for Pain Relief in the First 24 Hours after Caesarean Section: A Randomized Controlled Study. AB - INTRODUCTION: Postoperative pain is one of the main postoperative adverse outcomes following caesarean section. Its management still remains a challenge especially in a low resource setting. AIM: To compare the efficacy of intramuscular pentazocine alone and combined intramuscular pentazocine with diclofenac for pain relief within 24 hours after caesarean section. MATERIALS AND METHODS: This was a double blind randomized control study of post caesarean section pain management of 140 participants between April and December, 2015 at the Federal Teaching hospital, Abakaliki. Inclusion criteria involved consenting and low risk parturients who had caesarean section under spinal anaesthesia. The participants were randomly grouped into Pentazocine-Placebo (PP) group and Pentazocine-Diclofenac (PD) group. The PP group received pentazocine 30 mg every 4 hours for 24 hours and 3 milliliters of water for injection as placebo 12 hourly for 24 hours while the PD group received pentazocine 30 mg every 4 hours and diclofenac 75 mg every 12 hours for 24 hours. The level of pain control was assessed using the Visual Analog Scale (VAS). The data was analysed with IBM SPSS version 20.0. The level of significance was set at < 0.05. RESULTS: The use of PD for 24 hour post caesarean section analgesia achieved better pain relief, faster onset of postoperative ambulation, bowel sound auscultation and oral feeding than the use of PP (p-value <=0.002). However, the use of PD is more expensive than PP (p-value =0.0001). There was no difference between the two groups of participants on the passage of flatus and duration of hospital stay (p-value>=0.05). The use of PP was associated with more maternal side effects (p-value=0.009). There was no difference on the level of satisfaction between the two groups of participants (p-value>=0.05). CONCLUSION: The use of PD for post caesarean section analgesia is more effective in achieving a satisfactory pain relief and has less side effects. PMID- 28571212 TI - Disorders Affecting Quality of Life During Pregnancy: A Qualitative Study. AB - INTRODUCTION: Pregnancy is a special condition which results in unique physiological responses which is more than any other physiological event and it increase stress in women's body. Information about the changes experienced by pregnant women in physical, psychological, and social areas is limited, indicating that the quality of life and changeable areas in pregnant women require more attention. AIM: This study was aimed to identify the disorders affecting the quality of life during pregnancy. MATERIALS AND METHODS: A qualitative study was performed with the conventional content analysis approach. Participants included 16 pregnant women who were recruited using purposive sampling and performed with maximum variety. The semi-structured in depth interview started face to face with the general question and was followed with specific questions. The interviews were conducted in Fatemieh Hospital in Hamadan, Iran. Data analysis and data collection were conducted concurrently and the interviews were continued until achieving data saturation. RESULTS: Five main categories emerged in this study including "psychological disorders of pregnancy", "disorders of activities", "body-image disorder", "disorders in sexual intercourse" and "physical disorders" that were analyzed revolves common around of disorders affecting quality of life. CONCLUSION: Pregnancy can have undesirable effects on various aspects of women's lives in their point of view and lead to a decreased life quality. Therefore, it is essential in prenatal care. In addition to addressing the physical aspects of maternal health, other aspects are also evaluated, and in case of any disorder, the necessary consultation should be done. PMID- 28571213 TI - The Effect of Metoclopramide Addition to Lidocaine on Pain of Patients with Grades II and III Post-Episiotomy Repair. AB - INTRODUCTION: Episiotomy is the most common procedure used for dilatation of the vaginal opening for giving birth. Although episiotomy is associated with benefits for the mother, it may lead to short term and long term disabilities, including postpartum perineal pain that is secondary to perineal tearing. AIM: The aim of this study was to investigate the effect of subcutaneous lidocaine compared with lidocaine and metoclopramide on pain after episiotomy. MATERIALS AND METHODS: In this clinical trial study, the patients (83 for control group and 83 for case group) with episiotomy Grades II and III were enrolled and were asked to express their postpartum episiotomy pain as a number, from zero (no pain) to 10 (severest pain) Visual Analogue Scale (VAS score) at 0, 30 minute, 1 hour, 2 hour, 4 hour, 6 hour and 12 hour postpartum. Patients at the second stage of labour (crowning) were assigned to two groups: In the control group, 5 cc lidocaine 2% and in the case group, 5 cc lidocaine + 10 mg metoclopramide was injected for episiotomy. Then, the pain score was compared between the two groups. The data were analyzed by t-test and chi-square test with software SPSS version 20.0. RESULTS: Mean age of the women was 23.19+/-0.46 years in the control group and 23.96+/-0.58 years in the case group with no significant difference between the two groups (p<0.05). The mean pain score in the control group was 3.54+/-0.71 and in the case group 2.93+/-0.91 at 30 minutes after the injection, with a statistically significant difference. At other intervals, postnatal pain scores in the case group was lower than those of the control group (p<0.05). CONCLUSION: Injection of metoclopramide with lidocaine is more effective than lidocaine alone for relieving the pain after episiotomy. PMID- 28571215 TI - Carcinoma Cervix Presenting as Ischaemic Stroke in Young Female: A Case Report and Review of Literature. AB - Stroke is a disabling disease which increases the burden of already suffering cancer patients. Several mechanisms of stroke exist in cancer patients which includes - metastatic or non-metastatic such as coagulation disorders, infections or therapy related. Increased risk of ischaemic stroke has been validated for several cancers. However, there is scarce literature reported in carcinoma cervix patients. Review of literature suggests that stroke occurs more frequently in cancer patients than in the average population. We report an unusual case of a patient who presented with stroke but was later diagnosed as a case of carcinoma cervix. PMID- 28571214 TI - Segregation of Patients for Intrapartum Monitoring, using Robson's Classification. AB - INTRODUCTION: Monitoring labour by intermittent or continuous foetal heart rate monitoring has been discussed widely in literature. Robson's classification has categorized pregnant women in ten groups. The study proposes to examine in which patients one must recommend continuous or intermittent foetal heart rate monitoring. AIM: To study the effect of Continuous Electronic Foetal Monitoring (CEFM) on the overall rate of operative deliveries as well as the rate using Robson's classification and the neonatal outcome. MATERIALS AND METHODS: After Institutional Review Board approval, low risk parturients with a reactive foetal heart rate at arrival in labour were prospectively analysed. Women with a previous caesarean section, those requiring elective caesarean section and having high risk factors were excluded. Patient details, history, examination findings and the method of monitoring, whether continuous or intermittent was noted. 1803 women were monitored by CEFM and 2107 by intermittent auscultation. In both the groups of intrapartum monitoring, suspected foetal distress was followed by immediate intervention in the form of caesarean section or operative vaginal delivery without resorting to any other monitoring methods such as foetal scalp blood sampling, as per the institutional policy. Comparison was based on the need for operative deliveries in view of presumed foetal distress and the neonatal outcome between the two groups of monitoring and further in each Robson's class. Results were assessed using IBM(r) SPSS Version 22.0, Chi-square test, considering p<0.05 as significant. RESULTS: Operative deliveries in view of suspected foetal distress increased and the neonatal outcome was better with CEFM. Assessing in each Robson's class, only class 4A, 7A and 10A results were consistent with the overall outcome. In others (class 2A), women experienced reduced rate of operative deliveries and better neonatal outcome with CEFM. In yet others, there was no benefit with CEFM as there were increased operative deliveries without any difference in the neonatal outcome. CONCLUSION: Segregation of patients for intrapartum monitoring using Robson's classification would result in decreased operative deliveries and a better neonatal outcome. PMID- 28571216 TI - Plasmodium vivax Induced Acute Respiratory Distress Syndrome - A Diagnostic and Therapeutic Dilemma in Preeclampsia. AB - Malaria during pregnancy can cause various feto-maternal complications. Life threatening respiratory involvement is rare with vivax malaria but common with Plasmodium falciparum. In most of the cases severe respiratory involvement occurs, after beginning of anti-malarial treatment. We are reporting a case which involved a diagnostic and therapeutic challenge, as the pregnant woman with severe preeclampsia developed acute respiratory distress, actually caused by Plasmodium vivax. PMID- 28571217 TI - Missing IUCD Strings: Role of Imaging in Locating the Misplaced Device. PMID- 28571218 TI - Functional Results of Communited Intra-articular Distal Humerus Fractures Treated with Bicolumnar Plating. AB - INTRODUCTION: Communited intra-articular distal humerus fractures are commonly encountered in orthopaedic practice and they are present with unique difficulties for internal fixation. This problem is especially worse in the elderly due to osteoporotic bone. AIM: To evaluate the intermediate term results (minimum follow up of two years) of communited intra-articular distal humerus fractures treated with bicolumnar plating with or without olecranon osteotomy in elderly Indian population. MATERIALS AND METHODS: Sixty three consecutive patients operated with bicolumnar plating for communited intra-articular distal humerus fractures at the tertiary care centre were identified in the time period between 2009 and 2013. All patients had an age more than 60 years at the time of surgery. A minimum follow up of two years post surgery was a mandatory criteria. The Disabilities of Arm and Shoulder and Hand (DASH) score and the Mayo Elbow Performance (MEP) score calculated along with complete range of motion. RESULTS: The mean follow-up was 38 months. All patients achieved fracture union with mean MEP and DASH scores being 85 +/- 15.5 and 21.4 +/- 4.9 respectively. These scores although poor were comparable to the opposite side (90 and 12.2 respectively). Also the mean supination-pronation arc and flexion-extension arc was 156 degrees and 105 degrees respectively. This is well within the functional range of elbow. The mean block to extension was at 15 degrees with a mean maximal flexion of 120 degrees. CONCLUSION: Our study conclusively establishes that excellent functional outcome can be achieved with open reduction and internal fixation in Type C distal humerus fractures in elderly including the ones that are communited. Total elbow arthroplasty although a viable option, gives similar results to a well done internal fixation with added cost. PMID- 28571219 TI - Bi-Pedicle Fixation of Affected Vertebra in Thoracolumbar Burst Fracture. AB - INTRODUCTION: Burst fractures of the spine account for 14% of all spinal injuries and more than 50% of all thoracolumbar trauma. However, there is ambiguity while choosing the right treatment plan. Short Segment Pedicle screw Fixation (SSPF) has become an increasingly popular method of treatment of thoracolumbar burst fractures, providing the advantage of incorporating fewer motion segments in the fixation. Various biomechanical studies showed that the use of pedicle screws could achieve stable construct within short-segment fixation. AIM: To evaluate the efficacy of SSPF using longest possible screws in both pedicles of fractured vertebra. MATERIALS AND METHODS: A retrospective chart review of 25 single burst thoracolumbar fracture patients, operated between May 2009 to 2015 in a tertiary care trauma center, was conducted. Preoperative and post-operative plain radiographs were evaluated for kyphotic angulations using the traditional Cobb method. Anterior Vertebral Height (AVH), Posteriors Vertebral Height (PVH) were measured preoperatively and immediate postoperatively. Average percentage loss of AVH and mid-sagittal height were calculated on preoperative and postoperative X rays on follow up. RESULTS: Fourteen men and 11 women with an average age of 42.92 years comprised the study population. Mean age at the time of operation was 34.5+/-14.2 years. Mean operation time was 168+/-72 (minutes). Average hospitalization time was 9+/-7 (days). Mean blood loss was 515+/-485 (ml). There were two cases of postoperative infection and implant failure each. A mean of 15.2 degrees of kyphosis correction was attained from pre-operation to post operation (p<0.0001). Although, there was a 15 degrees average improvement of kyphosis post-fixation, loss of correction over time was nearly 8 degrees , resulting in a 7 degrees mean correction of kyphosis. A mean loss of AVH on postoperative radiograph was 6.12% and maintained 12.4% at the time of review (p<0.001). Similarly, there was 32.8% mid-sagittal height loss at time of injury, which was improved to only 12.6% as compare to initial height loss (p<0.0001). CONCLUSION: In this study, we propose SSPF using longest possible screws in both pedicle of fractured vertebra. Bi-pedicular fixation gives significant radiological corrections. PMID- 28571220 TI - Interlocking Nailing Versus Plating in Tibial Shaft Fractures in Adults: A Comparative Study. AB - INTRODUCTION: Tibial diaphyseal fractures are the commonest long bone fractures in adults, most commonly managed by intramedullary interlocking nailing. However, several meta-analysis show that locking plate osteosynthesis is equally effective in managing tibial diaphyseal fractures and are associated with less number of complications. AIM: To compare the results of fixation of tibial fractures following plating and nailing in terms of union, patient satisfaction and complications. MATERIALS AND METHODS: A hospital based non randomized clinical trial was performed from September 2013 to August 2016 where closed or open diaphyseal or metaphyseo- diaphyseal fractures of the tibia (closed or open Gustilo Anderson type 1 through 3B) were included. Simple sequential allocation was used for allotting the patients to two groups, one for interlocking nailing and other for plating. The patients were followed up for clinical, radiographic and functional results. RESULTS: Forty patients with 41 involved limbs completed follow up for one year. The duration of surgery and average blood loss during surgery was 75.45+/-3.03 minutes and 165.00+/-5.31 ml respectively in case of nailing and 85.05+/-2.54 minutes and184.29+/-5.33 ml respectively in case of plating and their difference was statistically significant. In our study union was achieved in less than 20 weeks in 29 (70.8%) of the patients and 25-30 weeks in nine (22%) cases. The average time of union in our study was 19.55+/-0.69 weeks in case of interlocking nailing and 20.38+/-1.39 weeks in case of plating and there was no statistically significant difference between the two. However, there is statistically significant difference in the functional score in between the two groups in terms of Lower Extremity Functional Score (LEFS). Delayed union in one case of nailing and two cases of plating, valgus malunion in one case of nailing and joint stiffness in two cases each of nailing and plating were the major complications observed. CONCLUSION: There was no difference between the two modalities in terms of fracture union. Complications were lesser but more serious in case of plating. Patient satisfaction was more with plating. PMID- 28571221 TI - A Comparative study of the Dynamic Hip Screw, the Cemented Bipolar Hemiarthroplasty and the Proximal Femoral Nail for the Treatment of Unstable Intertrochanteric Fractures. AB - INTRODUCTION: Fractures of the Intertrochanteric (IT) region are some of the most common fractures encountered by an orthopedic surgeon in his lifetime. With increase in life expectancy, the incidence of these fractures is also increasing. By 2040, the incidence of these fractures is expected to double. Unstable IT fractures are a major cause of concern in the elderly due to the associated increase in morbidity and mortality. AIM: The purpose of this study was to compare the intraoperative and postoperative parameters using the Dynamic Hip Screw (DHS), the Cemented Bipolar Hemiarthroplasty (BH) and the Proximal Femoral Nail (PFN) for the management of unstable IT fractures. MATERIALS AND METHODS: Fifty patients, having unstable IT fractures with age more than 60 years were randomly selected and were followed up averagely for 19 months (12- 30 months). The type of implant for a particular patient and a particular type of fracture was randomly selected and the same surgical team treated all patients. Total number of 19 patients were operated using the DHS (Group-1), 13 using the BH (Group-2) and 18 using the PFN (Group-3). All patients in the three groups were compared in terms of preoperative, intraoperative and postoperative parameters and functionally assessed using the Harris hip score and the mobility score of Parker and Palmer. RESULTS: Patients operated using the PFN had significantly lower mean blood loss as compared to the other two groups. The mean days to unaided Full Weight Bearing (FWB) was significantly higher in patients treated by the DHS as compared to the other two groups. All three groups were comparable in terms of functional assessment. CONCLUSION: Treatment of unstable IT fracture of femur is a matter open to debate. IT fractures of elderly must be treated with considering the age of the patient, mental status, bone quality, and the type of fracture. Level of Evidence according to OCEBM Levels of Evidence Working Group - Level 2. PMID- 28571222 TI - The Effect of Metformin as an Adjunct Therapy in Adolescents with Type 1 Diabetes. AB - INTRODUCTION: The strict control of blood glucose levels in adolescents with Type 1 Diabetes Mellitus (T1DM) is accompanied with a considerable long term decrease in microvasular and macrovascular complications. AIM: This study was conducted to investigate the effect of metformin as an adjunct therapy in adolescents with poorly controlled Type 1 diabetes. MATERIALS AND METHODS: It was a quasi experimental (an uncontrolled before and after) study. The study population consisted of the patients aged over 10 years with T1DM. Metformin tablet was added to patient's insulin therapy for 12 months. Haemoglobin A1c protein was measured in the beginning of the study and repeated with three months intervals till the end of it. Insulin dosage, Body Mass Index (BMI), serum lipid, creatinine and lactate level were measured twice; in the beginning of the study and at the end of it (after 12 months). Data was analysed by SPSS (version 18) software. Paired- t-test, Wilcoxon signed ranks test and Repeated Measure ANOVA were used to examine the study's hypothesis. A p-value <0.05 was considered as significant. RESULTS: Twenty nine patients were included in the study. HbA1c level and insulin dosage was significantly reduced (p<0.001) after one month of metformin as an adjunct therapy. Serum lipid was decreased (p=0.7). Weight (p<0.001) and BMI (p=0.007) were increased. CONCLUSION: Adjunctive metformin therapy reduced HbA1c value and the insulin dosage received in adolescents with T1DM. PMID- 28571224 TI - Waldmann's Disease (Primary Intestinal Lymphangiectasia) with Atrial Septal Defect. AB - Waldmann's disease or Primary Intestinal Lymphangiectasia (PIL) is a rare disorder of gastrointestinal tract characterized by dilated lymphatics and widened villi causing leakage of lymph into intestinal lumen. Loss of lymph leads to hypoalbuminemia, hyogammaglobulinemia and lymphopenia. Secondary lymphangiectasia occurs secondary to an elevated lymphatic pressure as in lymphoma, systemic lupus erythematosus, constrictive pericarditis, cardiac surgeries (Fontan's procedure), inflammatory bowel disease and malignancies. We, hereby present a five-year-old male child who presented with abdominal distension and poor weight gain. He had hypoalbuminemia, lymphocytopenia and hypogammaglobulinemia. Upper gastrointestinal endoscopy showed normal gastric mucosa and punctate white lesions in duodenal mucosa with biopsy confirming intestinal lymphangiectasia. Secondary causes of intestinal lymphangiectasia were ruled out. Echocardiography revealed atrial septal defect which is an uncommon association with Waldmann's disease. He was started on low fat, high protein diet and medium chain triglyceride supplementation following which he improved symptomatically. High index of suspicion, early diagnosis and appropriate dietary treatment are necessary to alleviate symptoms as well as to achieve a sustainable growth and development in these children. PMID- 28571223 TI - Neonatal Hyperthyroidism with Fulminant Liver Failure: A Case Report. AB - Neonatal hyperthyroidism is a rare disease that is seen in infants born to mothers with Graves' disease. Hepatic manifestation of neonatal hyperthyroidism is extremely rare. We describe a neonate with fulminant liver failure secondary to neonatal hyperthyroidism caused by maternal Graves's disease. The baby was admitted with low birth weight and hepatosplenomegaly. At day 2 of life, the baby was irritable and he developed respiratory distress and fulminant hepatic failure which required mechanical ventilation. All investigations of obstructive, infectious and metabolic causes of hepatic failure were negative. His hepatic dysfunction improvement was correlated with initiation carbimazole as anti thyroid medication. The conjugated hyperbilirubinemia, liver enzymes and International Normalised Ratio (INR) were gradually improved with normalization by eight weeks. This case has been reported to illustrate lessons learnt for early identification of neonate with hyperthyroidism as potential cause of cholestasis is important, because delayed treatment of hyperthyroidism might lead to irreversible consequences such as mental retardation or even death due to liver failure. PMID- 28571225 TI - Correspondence: Skeletal Maturation and Mineralization of Children with Moderate to Severe Spastic Quadriplegia. PMID- 28571226 TI - Optic Nerve Canal Relation to Posterior Paranasal Sinuses in Indian Ethnics: Review and Objective Classification. AB - INTRODUCTION: Posterior paranasal sinuses consisting of posterior ethmoid and sphenoid sinuses show varying pneumatization and relationship to Optic Nerve Canal (ONC). Most commonly ONC is superolateral to sphenoid sinus, however varied protrusion of ONC into the sinuses may occur. Rarely it may pass completely through the sinus. Optic Nerve (ON) is covered by a thin bony layer or by periosteum and sinus mucosa without bone. Extensive pneumatization of sphenoid sinus and bony dehiscence predisposes to ON injury. The posterior ethmoid cell namely the Onodi cell is of great surgical importance when the ON is along its lateral wall and surrounds the nerve. These varied relations imply that a detailed knowledge of the intimate relationship of ONC with the posterior paranasal sinuses is necessary to avoid unintentional complications during the surgeries involving the ONC region. AIM: To assess relationship of ONC to the posterior paranasal sinuses in Indian Ethnic study group. MATERIALS AND METHODS: Retrospective review of 100 paranasal sinus Computed Tomography (CT) scans were done using 64 row Multi Detector Computed Tomography (MDCT). Multiplanar reformation images were assessed for ONC relation to posterior ethmoid and sphenoid sinuses, wall dehiscence, and Pneumatization of Anterior Clinoid Process (PACP). RESULTS: 200 optic nerve canals were assessed and grouped into four types based on the modification of Delano et al., classification. The most common OCN was Type-1 (60%), followed by Type-2 (15%), Type-3 (14%) and Type-4 (11%). Dehiscence was seen in 35(17.5%) mostly in Type-3 canals. PACP was seen in 30 (15%). CONCLUSION: Knowledge of ON relationship to posterior paranasal sinuses will reduce the devastating complications during sinus surgeries. Our modified ONC classification is based on the bony canal morphology and the degree of protrusion into sinuses. As with other reported studies worldwide, Type-1 ONC is the commonest among the Indians also. Type-2 and 3 ONC with sinus wall dehiscence and PACP are the most important anatomical variations which may potentially predispose to risk of surgical injury to the optic nerves. PMID- 28571227 TI - Ultrasound Guided Percutaneous Injection of Thrombin: Effective Technique for Treatment of Iatrogenic Femoral Pseudoaneurysms. AB - INTRODUCTION: Arterial pseudoaneurysms are well known iatrogenic complication of percutaneous angiographic or interventional vascular procedures. In the past, the definitive treatment option was open surgical repair which is a relatively invasive procedure. In the last few years, Ultrasound (US) guided percutaneous thrombin injection has been gaining popularity as definitive treatment of pseudoaneurysms. AIM: To evaluate efficacy and safety of US guided percutaneous injection of thrombin for treatment of iatrogenic femoral pseudoanurysms at a tertiary care interventional radiological and cardiology centre. MATERIALS AND METHODS: A retrospective analysis was conducted on 38 consecutive patients, diagnosed to have iatrogenic femoral artery pseudoaneurysms by Doppler study, in the period from Jan 2013 to Jun 2016. All these patients were treated by US guided percutaneous injection of thrombin solution inside the pseudoaneurysm sac till contents became echogenic and flow inside the pseudoaneurysm stopped completely. One month further follow up in all these patients was done. RESULTS: The dose of thrombin injected varied from 200-1000 IU (mean 300 IU). Immediate thrombosis was seen in all the pseusdoaneurysms. Follow up at 24-48 hours showed complete thrombosis and regression of pseudoaneurysm in all the patients except one in whom a small residual sac was seen which thrombosed completely on second thrombin injection. Further follow up at one month showed regression of aneurysms in all the cases. No significant post procedural clinically significant complications were seen in any of the patients. CONCLUSION: US guided percutaneous thrombin injection is a highly successful and safe procedure for the treatment of iatrogenic femoral pseudoaneurysms. PMID- 28571228 TI - Imaging Evaluation of Enhancement Patterns of Flat Gall Bladder Wall Thickening and Its Correlation with Clinical and Histopathological Findings. AB - INTRODUCTION: Gall bladder Wall Thickening (GWT) is caused by wide spectrum of diseases. Initially Ultrasound (USG) was used as imaging modality for screening of acute abdomen because of its high sensitivity and real time character. Now, Computed Tomography (CT) is used because of its high temporal and spatial resolution. AIM: Evaluation of GWT and its enhancement patterns on contrast enhanced CT scan in a bid to differentiate benign from malignant causes and to correlate the imaging features with clinical and histopathological findings. MATERIALS AND METHODS: It was a hospital based prospective study in which USG was done as an initial modality for screening and Multi Detector Computed Tomography (MDCT) scan was done later on for detailed evaluation of enhancement patterns of GWT. The study cases were then divided into five CT patterns according to enhancement patterns. The diagnostic performance of MDCT was compared with histopathological and serological findings. Relevant history, clinical examination and routine investigations were done. RESULTS: The one layered pattern with a heterogeneously enhancing thick layered pattern (Type 1) was significantly associated with gall bladder cancer (p<0.001). The sensitivity and specificity of Type 1 enhancement pattern on CT for predicting the Gall Bladder (GB) malignancy were 90.476% and 97.43% respectively. The positive and negative predictive values were 95% and 95%, respectively. Focal wall thickening, irregular margin character and hepatic infiltration by GWT and lymphadenopathy were other findings that predict malignancy (p-value<0.05). CONCLUSION: MDCT enhancement patterns of a thickened GB wall and associated findings were helpful in differentiating malignant GWT from benign GWT. PMID- 28571229 TI - Role of Echocardiography in Prenatal Screening of Congenital Heart Diseases and its Correlation with Postnatal Outcome. AB - INTRODUCTION: Congenital Heart Defects (CHDs) are one of the most common forms of congenital anomalies. Fetal echocardiography performed during second trimester aims at early diagnosis of congenital heart disease which is instrumental in proper planning of delivery, perinatal care and counselling of parents. AIM: To evaluate the role of fetal echocardiography in prenatal screening of CHDs and to study the role of associated extracardiac anomalies. MATERIALS AND METHODS: This was a hospital based prospective and correlative type of study, done over a period of one year. Antenatal screening of fetal heart was done in mid-trimester high and low risk pregnancies. The prenatal echo findings were co-related with postnatal findings in case of any abnormality detected. The extra-cardiac anomalies associated with positive cases were evaluated and studied for their impact on postnatal outcome. RESULTS: A total of 1200 pregnancies were screened out of which 672 were low risk and 528 were high risk. The cases with abnormal echo findings were followed postnatally. The overall incidence of CHD in study population was 15 per 1000. The incidence in high and low risk pregnancies were 16.3 and 13.25 per thousand respectively. Complete agreement of 68.17% was found between prenatal and postnatal findings. The most frequent Extra-Cardiac Anomalies (ECA) in cases with CHD was of musculoskeletal system. The CHD cases with ECA were significantly of low birth weight, born preterm and delivered by Lower Segment Caesarean Section (LSCS). CONCLUSION: Fetal heart is the most overlooked part in every routine anomaly scan. We conclude that fetal echocardiography should be an integral part of every second trimester anomaly scan for all pregnant females irrespective of their risk factors. The associated ECAs are another factor that causes increased mortality both in antenatal and neonatal life, again warranting an early fetal echo. PMID- 28571230 TI - Comparison of Ultrasonography, Magnetic Resonance Imaging and Cone Beam Computed Tomography for Detection of Foreign Bodies in Maxillofacial Region. AB - INTRODUCTION: Foreign Bodies (FBs) entrapped in the maxillofacial region have a high prevalence due to trauma and accidents. Accurate localization of FBs and verifying their type and size are critical to assist the surgeon in their fast retrieval with minimal tissue damage. AIM: To assess and compare the imaging modalities including MRI, ultrasonography and Cone Beam Computed Tomography (CBCT) for detection of different types of FBs. MATERIALS AND METHODS: In this study, four types of FBs including pieces of normal glass, barium glass, wood and pebbles with equal sizes were placed randomly in two sheep heads in different locations such as upper lip, maxillary sinus and body of mandible as FBs and subjected to MRI, ultrasound and CBCT. The images were interpreted by expert observers and the data was analysed using the stata 11 software, kappa test and chi-square test. RESULTS: Sensitivity of CBCT, MRI and ultrasound for detecting foreign bodies was 79.19%, 20.83% and 33.33%, respectively. None of the imaging modalities could clearly visualize wooden FBs. Among different FBs, pebbles and barium glass were detected more accurately by radiographic imaging technique. The sensitivity of CBCT, ultrasound and MRI for pebbles was 100%, 33.33% and 16.67%, respectively. The sensitivity of CBCT, ultrasound and MRI for barium glass was 100%, 33.33% and 41.69%, respectively. The sensitivity of CBCT, ultrasound and MRI for wood was 33.33%, 33.33% and 16.67%, respectively. Specificity of all three imaging modalities was 100%. Diagnostic accuracy of all three imaging modalities was higher for detection of FBs in the upper lip than those in the body of mandible, and FBs in the latter location had higher detection accuracy than those in the maxillary sinus. CONCLUSION: Among the three imaging modalities, CBCT had the highest diagnostic sensitivity for the examined FBs. The highest diagnostic sensitivity was noted for pebbles and barium glass. PMID- 28571231 TI - Central Variant of Posterior Reversible Encephalopathy Syndrome - A Rare Case Report. AB - Posterior Reversible Encephalopathy Syndrome (PRES) is a clinicoradiological condition associated with headache, altered mental status, dizziness and white matter vasogenic oedema in parieto-occipital region. It is often associated with hypertension but can also occur in diverse clinical settings like immunosuppression, eclampsia, etc. It is due to failure of autoregulatory mechanism of posterior circulation in response to change in blood pressure. We hereby report a rare case of central variant of PRES secondary to severe hypertension diagnosed with 3T MRI. Objective of reporting this case was to describe the imaging findings of typical and rare atypical patterns of PRES. A 71 year-old male hypertensive patient was referred for brain imaging with history of short period of loss of consciousness, headache and dizziness. MRI brain showed central variant pattern of PRES with preferential involvement of brainstem, thalami and periventricular white matter with sparing of frontal, parietal and occipital lobes. The patient was treated with anti-hypertensive after which patient's symptoms subsided. The patient was followed up conservatively. Atypical variants of PRES should be borne in mind when pontine hyperintensity is encountered in hypertensive patient. PMID- 28571233 TI - Health Issues among Radiologists: Toll they Pay to their Profession. AB - In modern era, with tremendous competition, long working hours and more demanding workstyle, nearly every profession is associated with some or the other health hazards. These may develop and progress rapidly or in a gradual way but ultimately add up unwanted morbidities and in long run affects the production and work output. Unfortunately, doctors and other health professionals who look after the health of society, are not the exceptions to this rule and depending upon their specialty, they have to face some or the other health issues. This article highlights some important though underestimated health issues among radiologists and some remedies. It aims to sensitize radiologists about such health issues so that they can take timely remedial measures before it is really late. PMID- 28571232 TI - Morel-Lavallee Lesions-Review of Pathophysiology, Clinical Findings, Imaging Findings and Management. AB - Morel-Lavallee lesion is a post-traumatic soft tissue degloving injury. This is commonly associated with sports injury caused by a shearing force resulting in separation of the hypodermis from the deeper fascia. Most common at the greater trochanter, these injuries also occur at flank, buttock, lumbar spine, scapula and the knee. Separation of the tissue planes result in a complex serosanguinous fluid collection with areas of fat within it. The imaging appearance is variable and non specific, potentially mimicking simple soft tissue haematoma, superficial bursitis or necrotic soft tissue neoplasms. If not treated in the acute or early sub acute settings, these collections are at risk for superinfection, overlying tissue necrosis and continued expansion. In this review article, we discuss the clinical presentation, pathophysiology, imaging features and differential diagnostic considerations of Morel-Lavallee lesions. Role of imaging in guiding prompt and appropriate treatment has also been discussed. PMID- 28571234 TI - CLOVES Syndrome: Severe Neonatal Presentation. AB - Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi and Spinal Abnormalities (CLOVES syndrome) is a newly described and rare overgrowth disorder with serious morbidity. The course of this disease is not well understood and few cases have been reported among neonates. Moreover, not all of the signs of this syndrome are present at birth, making a high index of suspicion necessary. We present a cohort of three newborns with CLOVES syndrome who died due to septic and hemodynamic complications directly related to extensive vascular malformations. We discuss the clinical presentation in the neonatal period and propose a clinical classification. PMID- 28571235 TI - Effect of Dexmedetomidine Versus Fentanyl on Haemodynamic Response to Patients Undergoing Elective Laparoscopic Surgery: A Double Blinded Randomized Controlled Study. AB - INTRODUCTION: Dexmedetomidine, an alpha2 agonist, can be used as an adjuvant in general anaesthesia as it attenuates the stress response to various noxious stimuli and helps in maintaining the perioperative haemodynamic stability along with sedation and not causing any significant respiratory depression in the postoperative period. AIM: To study the difference in haemodynamic responses of dexmedetomidine and fentanyl in patients undergoing laparoscopic surgery. MATERIALS AND METHODS: Sixty patients were divided into two groups of 30 each randomly. In Group F, fentanyl 0.5 MUg/kg as loading dose over 10 minutes prior to induction followed by 0.2-0.7 MUg/kg/hr as maintenance dose and in Group D, Dexmedetomidine 0.5 MUg/kg as loading dose over 10 minutes prior to induction followed by 0.2 MUg/kg/hr-0.7 MUg/kg/hr as maintenance dose till surgery was over. Haemodynamic variables and Visual Analogue Scale (VAS) scores were recorded continuously. Postoperative sedation and recovery were assessed by modified Ramsay sedation score. RESULTS: Systolic Blood Pressure (SBP) fell by 9% in Group D as compared to no fall in Group F during intubation. After intubation, 9% increase is seen in Group D v/s 19% in Group F. During the period of pneumoperitoneum upto 5 minutes post extubation, the SBP in Group D was significantly lower as compared to Group F rest duration, the difference was not significant between both groups. Heart Rate (HR) remained stable throughout the study except at laryngoscopy when it rose. Heart rate was similar in both groups at intubation, decreased by 3.51% in Group D as compare to 11.11% rise in Group F. Post intubate on, heart rate fell by 2% in Group D vs 15% rise in Group F. Diastolic Blood Pressure (DBP) remained higher than baseline than throughout the study. After intubation, 3% higher in Group D where as 15% in Group F increase was seen. In intraoperative period the difference between both groups was not significant. There was significant difference between two groups at 10 minutes, 45 minutes of pneumoperitoneum. End Tidal CO2 (ETCO2) was similar in both groups. CONCLUSION: Dexmedetomidine is better drug as compared to fentanyl for maintaining the haemodynamic response during intubation and intraoperative period. PMID- 28571236 TI - The Effect of Sevoflurane Plus Propofol on Pain and Complications after Laminectomy: A Randomized Double Blind Clinical Trial. AB - INTRODUCTION: Pain is one of the most important reasons for the patients concern after surgery. The perfect sedative should have properties like rapid onset, least pain and adverse effects. AIM: To assess the effect of sevoflurane plus propofol on postoperative pain, haemodynamic stability and complication after lumbar disc surgery. MATERIALS AND METHODS: This was a randomized double- blind clinical trial. A total of 75 patients scheduled for elective lumbar disc surgery with simple random sampling design received sevoflurane (n=25, induced with Thiopentone and maintained with sevoflurane), propofol (n=25, induced and maintained with propofol) and sevoflurane plus propofol (n=25, induced with propofol and maintained with sevoflurane). Visual Analog Scale (VAS) was used to determine the intensity of postoperative pain. Complications after surgery and haemodynamic changes during surgery were recorded. RESULTS: The mean pain intensity and morphine consumption in the sevoflurane plus propofol group was lower compared to the propofol and sevoflurane groups at different intervals (p<0.001). The prevalence of shivering, nausea and vomiting in the sevoflurane plus propofol group was 24%, 28%, 28% respectively vs sevoflurane group 32%, 60%, 48% respectively and propofol group 32%, 16%, 12% respectively with p-value > 0.05, <0.001, <0.05 respectively. The mean blood pressure and heart rate were significantly lower in the sevoflurane plus propofol group compared to the propofol and sevoflurane groups (p<0.001). CONCLUSION: According to the effect on pain and complications after lumbar disc surgery sevoflurane plus propofol can be regarded as safe and alternative drug in general anaesthesia for these patients. PMID- 28571237 TI - Dexmedetomidine as an Additive to Spinal Anaesthesia in Orthopaedic Patients Undergoing Lower Limb Surgeries: A Randomized Clinical Trial Comparing Two Different Doses of Dexmedetomidine. AB - INTRODUCTION: Use of dexmedetomidine as an additive to spinal anaesthesia is gaining popularity; but there seems to be no clear consensus on the ideal dose to be used. Because of dose related prolongation of duration of motor blockade along with increase in the incidence of side effects of dexmedetomidine namely hypotension and bradycardia, use of higher doses is not recommended. AIM: To evaluate the efficacy of two different doses of dexmedetomidine (3 MUg and 5 MUg) given in combination with 0.5% hyperbaric bupivacaine via intrathecal route with regard to the quality of anaesthesia namely the time to attain highest sensory and motor blockade, side effects of dexmedetomidine and time to first rescue analgesia. MATERIALS AND METHODS: Sixty American Society of Anaesthesiologist (ASA) Grade I and II orthopaedic patients undergoing lower limb surgeries between the ages of 20-60 years and height >150 cm were randomly divided into two groups of 30 patients each: Group D3 to receive 3 MUg of Inj. Dexmedetomidine (0.5 ml, reconstituted using normal saline) along with 12.5 mg (2.5 ml) of 0.5% hyperbaric bupivacaine and Group D5 to receive 5 MUg of inj. Dexmedetomidine (0.5 ml, reconstituted using normal saline) along with 12.5 mg (2.5 ml) of 0.5% hyperbaric bupivacaine keeping the total volume of study drug constant in all 60 patients (3 ml). Data recordings were done for time to reach best sensory and motor block, intraoperative haemodynamic changes and time to first postoperative rescue analgesia. Statistical analysis was done using student's t-test and Chi-square test with p-value of <0.05 considered to be significant. RESULTS: The two groups analysed were similar in terms of demographic profile, time to reach highest sensory block (T10) dermatome, time to reach Bromage scale 4, time to surgical incision after spinal and the total duration of surgery (p>0.05). The change in haemodynamics was similar (p>0.05). A statistically significant difference (p<0.001) was observed in time to first rescue analgesia after skin closure with Group D3 having 206.47 minutes while in Group D5 the time was 271.33 minutes. CONCLUSION: Used in a dose of 5 MUg (in 0.5 ml volume) as an additive in spinal anaesthesia maximal beneficial effect of dexmedetomidine can be obtained without any side effects. PMID- 28571239 TI - Efficacy of Dexmedetomidine in two Different Doses as an Adjuvant to Lignocaine in Patients Scheduled for Surgeries under Axillary Block. AB - INTRODUCTION: The effect of adding dexmedetomidine (alpha2-adrenoceptor agonist) to local anaesthetics in brachial plexus blocks has been evaluated, however there has been no consensus regarding the ideal dose of dexmedetomidine. Without ultrasound axillary block has been considered as the safest approach for brachial block. AIM: To evaluate the efficacy of two doses of dexmedetomidine (0.5 MUg/kg and 1 MUg/kg) as an adjuvant to lignocaine in patients undergoing forearm surgeries under axillary brachial plexus block. MATERIALS AND METHODS: This prospective randomized controlled study was conducted on 104 adult patients, American Society of Anaesthesiologists (ASA) physical status 1 or 2. They were randomized and given following drug formulations, Group L (n=35) received 23 ml of 2% lignocaine with adrenaline + 7 ml of saline, Group LD0.5 (n=34) received 23 ml of 2% lignocaine with adrenaline + 0.5 MUg/kg of dexmedetomidine diluted in saline to make a volume of 7 ml, Group LD1 (n=35) was given 23 ml of 2% lignocaine with adrenaline + 1 MUg/kg of dexmedetomidine diluted in saline to make volume of 7 ml, the total volume of drug being 30 ml in each group and concentration of lignocaine 1.5%. The duration of postoperative analgesia and demand for rescue analgesia were the primary outcomes and block characteristics taken as secondary outcome. RESULTS: Sensory and motor block onset times were shorter in Group L than in group LD0.5, LD1 (p < 0.05). Sensory and motor blockade durations were longer in Group LD1, LD0.5 than Group L (p<0.01). Duration of analgesia was longer in Group LD1 than in group LD0.5 and least in Group L (p<0.05). CONCLUSION: Dexmedetomidine (0.5 MUg/kg and 1 MUg/kg) as an adjuvant in axillary brachial plexus increases the duration of postoperative analgesia and delays the requirement of first dose of analgesic in a dose dependent manner and 1 MUg/kg seems to be the near ideal dose of dexmedetomidine as an adjuvant in axillary block. PMID- 28571238 TI - Analgesic Effect of Intra-articular Morphine or Dexmedetomidine Added with Levobupivacaine in Arthroscopic Knee Surgeries - A Comparative Evaluation. AB - INTRODUCTION: Knee arthroscopy is associated with variable amount of postoperative pain. In an attempt to improve postoperative analgesia, intra articular injection of local anaesthetic in combination with other agent have been studied. However, the best combination is not known. AIM: To compare the analgesic efficacy of intra-articular injection of morphine and dexmedetomidine when added with levobupivacaine in arthroscopic knee surgeries. MATERIALS AND METHODS: Seventy eight patients, scheduled to undergo elective arthroscopic procedure under spinal anaesthesia were recruited for the study. All the patients received 18 ml of 0.25% levobupivacaine however in addition to this Group M patients received 8 mg (2 ml) morphine, Group D patients received 100MUg (2 ml) of dexmedetomidine while Group C patients received 2 ml of isotonic saline intra articularly. Postoperatively the intensity of pain was assessed using Numerical Rating Scale (NRS). Rescue analgesia was given at NRS >= 4. The duration of analgesia and total diclofenac consumption was noted. RESULTS: The mean duration of analgesia was longest in Group M (576.20+/-67.09 minutes) followed by Group D (460.93+/-38.95 minutes) and Group C (370.27+/-58.80 minutes) statistically this difference was found to be highly significant (p-value < 0.001). Total consumption of diclofenac in 24 hours was found lowest in group M (86.25+/-27.48 mg) followed by group D (110.87+/-44.48 mg) and group C (141.35+/-44.13 mg) this difference was found to be highly significant (p-value < 0.001). CONCLUSION: Morphine when added with levobupivacaine in patients undergoing arthroscopic knee surgery improves the quality and prolongs the duration of postoperative analgesia. PMID- 28571240 TI - Monitoring Microcirculatory Blood Flow during Cardiopulmonary Bypass in Paediatric Cardiac Surgery Patients as a Predictor for Anaerobic Metabolism. AB - INTRODUCTION: Improving tissue oxygenation is one of most important tasks in management of low cardiac output. Central venous oxygen saturation (ScvO2) and lactate are established criteria for monitoring the adequacy of tissue oxygenation. The venous-to-arterial carbon dioxide difference [P(v-a)CO2] is inversely associated with cardiac output. AIM: To study the use of P(v-a)CO2/C(a v)O2 ratio as a marker of low cardiac output during Cardiopulmonary Bypass (CPB) in paediatric cardiac surgical patients. MATERIALS AND METHODS: The present study was a prospective observational study conducted over a period of nine months from 1st August 2015 to 30th April 2016. A total of 110 children were enrolled, who underwent CPB during cardiac surgery. The CPB time, Mean Arterial Pressure (MAP), flow rate, cross clamp time, were recorded for all the patients as well as Arterial Blood Gas (ABG) and Venous Blood Gas (VBG) were checked at four different points of time: 1) Before CPB, 2) 10 minutes after initiation of CPB, 3) 30 minutes on CPB and 4) off CPB. RESULTS: The results indicated that Receiver Operating Characteristic curve (ROC curve) at 30 minute of CPB time P(v-a)CO2/C(a v)O2 was more specific and sensitive than lactate to detect anaerobic metabolism. Decrease platelet count was significant on second postoperative day. CONCLUSION: The present study suggests the use of P(v-a)CO2/C(a-v)O2 ratio as a marker to detect low flow on CPB. Our study was single centric and with a small size, studies involving large population and multiple centers are required to support the recent findings. PMID- 28571241 TI - Acute Respiratory Distress Syndrome Complicated by Amiodarone Induced Pulmonary Fibrosis: Don't Let Your Guard Down. AB - Amiodarone is an antiarrhythmic agent which is commonly used to treat both supraventricular and ventricular arrhythmias. This iodine containing compound has been associated with several adverse events like it tends to accumulate in several organs. Among those, the most serious is Amiodarone Pulmonary Toxicity (APT). While the incidence of this complication has decreased with the use of lower doses of amiodarone but it can occur with any dose. Pulmonary complications usually present as an acute or subacute pneumonitis. On chest X-ray and high resolution Computed Tomography (CT), diffuse infiltrates were found. Here, we present a case in which acute respiratory distress syndrome like features were detected which got subsided after stopping tablet amiodarone. The patient was a known case of atrial fibrillation for which she was taking tablet amiodarone for the last six months. PMID- 28571242 TI - The Efficacy of Mindfulness-Based Cognitive Therapy on Resilience among the Wives of Patients with Schizophrenia. AB - INTRODUCTION: The wives of patients with schizophrenia experience high levels of stress due to their spouses' disease, which leads to certain problems and decreased adaptability and efficiency in them. AIM: This study investigated the efficacy of Mindfulness-Based Cognitive Therapy (MBCT) on resilience in schizophrenia patients. MATERIALS AND METHODS: In this quasi-experimental study, 40 wives of patients with schizophrenia (20 assigned to experimental group and 20 to control group) whose husbands were kept in rehabilitation centers for mental disorders were enrolled according to convenience sampling. In the experimental group, the therapeutic protocol of MBCT was conducted. Accordingly, the patients were encouraged to process the experiences in a non-judgmental manner as they have been formed, and to change their relationship with and embrace challenging thoughts and feelings. Meanwhile, the control group underwent no intervention. The research instrument was Connor-Davidson Resilience Scale. Data were analysed by ANCOVA in SPSS 16. RESULTS: At post-test, mean resilience score of the experimental group (77.95+/-4.71) was much higher than that of the control group (71.75+/-5.81). There was a significant difference in the mean resilience score at post-test between the experimental and control groups (p<0.05). CONCLUSION: Training MBCT strategies was effective on resilience in the wives of schizophrenia patients. Therefore, this approach can be incorporated into mental health-related interventions for the families of patients with psychiatric disorders such as schizophrenia. PMID- 28571243 TI - Relationship between Maternal General and Specific-Pregnancy Stress, Anxiety, and Depression Symptoms and Pregnancy Outcome. AB - INTRODUCTION: Despite scientific advances in the field of physical problems during pregnancy, the effect of mental problems on the health of pregnant women is still an important issue that needs further research. AIM: To determine the association of symptoms of stress, anxiety and depression during pregnancy and there effect on the pregnancy outcome. MATERIALS AND METHODS: This was a descriptive correlational study. The population included 200 pregnant women of the urban and rural health centers affiliated with Babol University of Medical Sciences. There were 100 each in second and third trimester. Convenience multi stage cluster sampling was performed. Data collection was received through the Hospital Anxiety Depression Scale (HADS), Pregnancy Distress Questionnaire (PDQ), and Perceived Stress Scale (PSS-14) questionnaires. RESULTS: The correlation results showed a significant difference between variables of depression, stress, and anxiety with birth weight, birth height and head circumference and infants' APGAR score (p<0.05). Multiple regression analysis showed that interpersonal relationships on prediction of infant weight (B=-0.324), anxiety on prediction of infant height (B=-0.197), stress on prediction of head circumference (B=-0.350) and depression on prediction of APGAR score (B=-0.323) are effective (p<0.001). CONCLUSION: The findings emphasize the need to identify women with depression, anxiety and stress in pregnancy, and scheduling to avoid adverse consequences of the pregnancy outcome. PMID- 28571244 TI - Psychogenic Belching: A Case Report. AB - Conversion symptoms usually appear with emotional conflicts of the patient. Belching's psychogenic aetiology is not unheard of and can be a manifestation of conversion disorder though rare. Current case is of a middle aged woman presenting with belching unresponsive to medical management. The patient improved after supportive psychotherapy sessions and placebo medication. PMID- 28571245 TI - Rituximab: A Magic Bullet for Pemphigus. AB - INTRODUCTION: Pemphigus, an autoimmune disease, was fatal before the era of corticosteroids. With the advent of steroids, mortality decreased but morbidity was present due to the side effects of high dose steroids. Newer drugs targeted at the molecular level are said to have fewer side effects and improved effectiveness. AIM: The aim of our study was to assess the effectiveness of one such drug, Rituximab, a biological, in treating pemphigus vulgaris and to identify common adverse events. MATERIALS AND METHODS: It was an open label prospective interventional study, conducted from September 2013 to May 2015, in the Department of Dermatology, Stanley Medical College, Chennai, Tamil Nadu, India. Twenty patients with pemphigus were included in the study. Ten were refractory to conventional therapy and 10, new cases. Patients who satisfied inclusion and exclusion criteria were included in the study after informed, written consent. Rituximab was administered according to Rheumatoid arthritis protocol. The patients were followed up as out patients after discharge, end points and adverse events were noted. RESULTS: There were 14 females (70%) and six males (30%). The mean age of the study group was 41.35 years. The mean disease duration was 11.7 months. The mean duration of follow up being 14.25 months. After rituximab, 13 patients remained in remission for varying periods of 3-22 months. The mean duration of complete remission off- treatment with Dexamethasone Cyclophosphamide Pulse (DCP) was 3.6 months; with rituximab it was 8.8 months. Seven (35%) patients relapsed during the study of whom six had received rituximab after being refractory to conventional treatment. Patients who relapsed had higher mean disease duration (21 months) than the remission group (6.384 months). Two patients (10%) developed immediate adverse events. Six patients (30%) developed late adverse events the commonest being reactivation of herpes labialis. CONCLUSION: Rituximab was effective in treating pemphigus vulgaris, was significantly better than conventional treatment, decreased the need for additional steroids and other immunosuppressants and induced prolonged remission. Rituximab was more effective when given early in the disease process. Further studies may highlight the need for additional cycles of rituximab to maintain sustained remission. PMID- 28571246 TI - A Comparative Analysis of Two Different Dose Fractionation Regimens of High Dose Rate Intracavitary Brachytherapy in Treatment of Carcinoma of Uterine Cervix: A Prospective Randomized Study. AB - INTRODUCTION: High Dose Rate (HDR) intracavitary brachytherapy is an integral component in treatment of carcinoma uterine cervix. There is no consensus about optimal fractionation in HDR brachytherapy. AIM: To assess the feasibility, tolerability of HDR intracavitary brachytherapy schedule of 8 Gy per fraction per week for 3 fractions over 6Gy per fraction per week for 4 fractions with or without chemotherapy in the treatment of carcinoma of uterine cervix. MATERIALS AND METHODS: From 2013 to 2014 total 80 patients with carcinoma of the uterine cervix (Stages IIB and IIIB) were treated with External Beam Radiotherapy (EBRT) and High Dose Rate Intracavitary Brachytherapy (HDR- ICBT). During course of EBRT, those patients fit for brachytherapy were randomized to arm A- 6 Gy per fraction per week for 4 fractions and arm B - 8 Gy per fraction per week for 3 fractions. RESULTS: The median follow up was 30 months, local control was 90% in Arm A and 83.3% in Arm B (p= 0.21) and the disease-free survival was 90% in Arm A and 83.3% in Arm B (p= 0.39). There is no significance difference for late rectal and bladder toxicities between two arms (p=0.43). CONCLUSION: Taking into account of increased hospital burden of locally advanced cancer cervix patients in Indian context, HDR intracavitary brachytherapy schedule of 8 Gy per fraction per week x 3 fractions is the preferable option over 6 Gy per fraction per week x 4 fractions with regard to comparable loco-regional control, acute and late toxicity, disease free survival and better patients compliance to lesser fractionation schedule. PMID- 28571247 TI - Extramedullary Solitary Plasmacytoma: Demonstrating the Role of 18F-FDG PET Imaging. AB - An Extramedullary Plasmacytoma (EMP) is characterized by a neoplastic proliferation of clonal plasma cells outside the medullary cavity. EMPs are a rare occurrence compared to other malignant plasma cell disorders and account for approximately 3-5% of plasma-cell neoplasms. Although most cases of EMP are not immediately life threatening at diagnosis, EMPs can progress to Multiple Myeloma (MM) and thus, warrant monitoring. Currently, there are no standard guidelines for when and how to monitor patients who are diagnosed with or treated for a solitary plasmacytoma. We present a case of solitary EMP who was treated adequately and definitively but developed a distinct, non-contiguous subsequent solitary EMP and was only discovered due to surveillance 18F-Fludeoxyglucose Positron Emission Tomography (18F-FDG) (PET) scan. Uniform surveillance guidelines should be developed and the potential benefits of PET and other imaging techniques as well as their cost should be considered. PMID- 28571248 TI - Anaemia in CD5 Negative Chronic Lymphoproliferative Disorder: Importance of Bone Marrow Examination. PMID- 28571249 TI - Effectiveness of Various Endodontic Irrigants on the Micro-Hardness of the Root Canal Dentin: An in vitro Study. AB - INTRODUCTION: Irrigating solutions used for the elimination of micro-organisms during root canal preparation may affect the chemical and the physical properties of dentin thereby rendering the tooth more susceptible to fracture. Therefore careful and judicious selection of irrigant is required which have maximum benefits with minimum undesirable properties. AIM: The aim of the present study was to evaluate the effect of various endodontic irrigants on the micro-hardness of the root canal dentin. MATERIALS AND METHODS: This in vitro study was carried out on eighty freshly extracted mandibular premolars with single canals. They were decoronated at the cemento-enamel junction. Roots were sectioned longitudinally into two halves. They were then polished and placed in autopolymerised resin moulds with the polished surface facing outside. The samples were divided into four groups based on the irrigants in which they were immersed i.e., 3% Sodium Hypochlorite (3% NaOCl), 17% Ethylene Dioxide Tetra Acetic Acid (17% EDTA), 0.2% Chitosan and 6% Morindacitrifolia Juice (MCJ) for 15 minutes each. All the specimens were then subjected to micro-hardness testing using a Vickers micro-hardness tester. Statistical analysis was done using one way Analysis of Variance (ANOVA), Post-Hoc Tukey test and Paired t-test to compare the pre and post immersion micro-hardness values of the selected samples. RESULTS: The results of the present study indicated that 17% EDTA and 0.2% Chitosan, significantly decreased the micro-hardness of root dentin whereas 6% MCJ and 3% NaOCl had no significant effect on the microhardness before and after immersing in the irrigants. CONCLUSION: A 6% MCJ and 3% NaOCl which have significant antibacterial, antifungal, anti-inflammatory and smear layer removing properties showed negligible effect on the micro-hardness of root canal dentin making them suitable endodontic irrigating solution. PMID- 28571250 TI - Impact of Dental Disorders and its Influence on Self Esteem Levels among Adolescents. AB - INTRODUCTION: Self esteem is more of a psychological concept therefore, even the common dental disorders like dental trauma, tooth loss and untreated carious lesions may affect the self esteem thus influencing the quality of life. AIM: This study aims to assess the impact of dental disorders among the adolescents on their self esteem level. MATERIALS AND METHODS: The present cross-sectional study was conducted among 10 to 17 years adolescents. In order to obtain a representative sample, multistage sampling technique was used and sample was selected based on Probability Proportional to Enrolment size (PPE). Oral health assessment was carried out using WHO type III examination and self esteem was estimated using the Rosenberg Self Esteem Scale score (RSES). The descriptive and inferential analysis of the data was done by using IBM SPSS software. Logistic and linear regression analysis was executed to test the individual association of different independent clinical variables with self esteem. RESULTS: Total sample of 1140 adolescents with mean age of 14.95 +/-2.08 and RSES of 27.09 +/-3.12 were considered. Stepwise multiple linear regression analysis was applied and best predictors in relation to RSES in the descending order were Dental Health Component (DHC), Aesthetic Component (AC), dental decay {(aesthetic zone), (masticatory zone)}, tooth loss {(aesthetic zone), (masticatory zone)} and anterior fracture of tooth. CONCLUSION: It was found that various dental disorders like malocclusion, anterior traumatic tooth, tooth loss and untreated decay causes a profound impact on aesthetics and psychosocial behaviour of adolescents, thus affecting their self esteem. PMID- 28571251 TI - Evaluation of Interdental Spaces of the Mandibular Posterior Area for Orthodontic Mini-Implants with Cone-Beam Computed Tomography. AB - INTRODUCTION: The use of mini-implants has increased in recent years because of their role in absolute anchorage, but the placement sites may affect the success or failure of the procedure, so it is very important to determine the appropriate and safe location for orthodontic mini-implants. On the other hand, the Cone Beam Computed Tomography (CBCT), which offers clear 3-Dimentional (3D) images, has been widely used in orthodontics and implant dentistry for surgical guidance of mini-implant placement. AIM: The aim of this retrospective study was to evaluate inter-radicular spaces between mandibular canines to second molars using cone beam 3D images. MATERIALS AND METHODS: In this retrospective cross-sectional descriptive study, maxillofacial CBCT scan data were obtained from 40 adults. The 3D images were evaluated in five axial sections at 2, 4, 6, 8 and 10 mm from the cementoenamel Junction (CEJ). To determine inter-radicular spaces, tangent lines were drawn buccolingually to the roots in axial section and the minimum distance between these two lines was measured. The data was analysed using Friedman test with SPSS(ver.13). RESULTS: Interradicular spaces of canine to second molar increased from cervical to apical direction. The maximum distance was recorded at 4 mm from the CEJ between first and second molars. CONCLUSION: According to our findings there is a distinct pattern of inter-radicular space changes in mandible. Attention to this pattern during placement of mini-implants can ensure the safety of the procedure. PMID- 28571252 TI - Nature of Hard Tissues in Oral Pathological Lesions -Using Modified Gallego's Stain. AB - INTRODUCTION: Histological stains are dyes that bind to various tissues. Special stains form an integral part of routine histopathology as an adjunct to Haematoxylin and Eosin (H&E), and give meaningful diagnostic information of the tissues available. By using routine histological procedure like H&E alone, it is difficult to differentiate the various hard tissues present in the oral pathological lesions. Modified Gallego's stain can be used as one of the differential stain for these hard tissues. AIM: To differentiate various hard tissues of teeth and to identify the presence of hard tissue components in different oral pathological lesions using Modified Gallego's stain under light microscope. MATERIALS AND METHODS: A total sample of 20 cases, amongst which 10 were human extracted teeth and 10 oral pathological lesions were included. From 10 human extracted teeth, five ground sections and five decalcified sections were prepared. From pathological lesions, two slides of each lesion were prepared. All the sections were stained with Modified Gallego's stain and viewed under light microscopy. RESULTS: In properly stained slides, cementum stained red, dentin and bone stained green and enamel stained pink in colour. CONCLUSION: Modified Gallego's stain can be used as a differential stain for various hard tissues in oral pathological lesions and also for ground sections for which histochemical stains are very rare. PMID- 28571253 TI - Antibacterial Effects of Garlic Extracts and Ziziphora Essential Oil on Bacteria Associated with Peri-Implantitis. AB - INTRODUCTION: Peri-implantitis is an inflammatory process, characterized by loss of bone around implants and bleeding on probing. Colonization of bacteria in the pocket created around the implant is one of the most important aetiologic factors involved. Although antibiotics are routinely used and are effective agents against this bacterial infection, due to the side effects and drug resistance of these medications, researchers are more interested in using herbal derivatives. There are relatively limited number of studies in this respect. AIM: To evaluate and compare the antibacterial effects of the extracts of Allium sativum and Ziziphora clinopodioides essential oil on S. aureus and P. aeruginosa. MATERIALS AND METHODS: In this in vitro study conducted at Tabriz University of Medical Sciences between March 2016 and July 2016, aqueous and methanolic extracts of garlic and ziziphora essential oil were prepared and then their effects on one standard strain of P. aeruginosa and two standard strains of S. aureus and 18 clinical strains, (nine strains of P. aeruginosa and nine strains of S. aureus) which had been isolated from wound and blood cultures, were evaluated using the reference broth macro dilution method and disk diffusion technique. Data were evaluated with descriptive statistical techniques and t-test for independent groups, using SPSS 17. RESULTS: Aqueous and methanolic extracts of garlic did not exhibit inhibitory effects on S. aureus and P. aeruginosa. Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) for ziziphora essential oil against S. aureus were 0.25 and 0.5 MUg/mL, respectively. The mean diameter of growth inhibition zone for S. aureus in the ziziphora essential oil group (0.25MUg/mL) and Vancomycin group (10 MUg/mL) were 26.09+/-5.8 and 14.63+/ 1.20 mm respectively (p<0.001). Growth inhibition zone for P. aeruginosa were observed in only one (35 mm) and three cases (12.5+/-3.4 mm) in the ziziphora essential oil group (0.5 MUg/mL) and Nalidixic acid group (10 MUg/mL) respectively. CONCLUSION: The essential oil of ziziphora exhibited a favourable antibacterial effect on S. aureus; therefore, its extract can be used as an effective antimicrobial agent alone or in association with other antibiotics in the treatment of infections due to S. aureus. PMID- 28571254 TI - Quantitative Analysis of Remineralization of Artificial Carious Lesions with Commercially Available Newer Remineralizing Agents Using SEM-EDX- In Vitro Study". AB - INTRODUCTION: The basic principle of remineralization is by advocating a biological or non-invasive approach rather than the surgical approach for early enamel lesions. There are relatively newer products available for remineralization, latest being the resin-infiltration technique, commercially available as Icon. AIM: The aim of the study was to evaluate the remineralizing potential of Casein Phosphopeptide-Amorphous Calcium Phosphate (CPP-ACP), Vantej and Icon by the quantitative evaluation of mineral gain. MATERIALS AND METHODS: Seventy eight maxillary premolars were decoronated at Cemento-Enamel Junction (CEJ) and then sectioned mesio-distally using diamond disc into two halves. Mineral content of the sound specimens were recorded using Energy Dispersive X ray (EDAX) micro-analyser. The samples were then subjected to demineralization by using demineralizing solution. The samples were grouped (n=26) based on the remineralizing agent used, Group 1: Vantej, Group 2: CPP-ACP, Group 3: Icon. After the application of remineralizing agent, the mineral content was measured using EDAX. RESULTS: After remineralization, there was a significant difference between the groups when calcium and phosphorous ratios (Ca:P) were compared, showing greater potential of remineralization for CPP-ACP followed by Vantej and Icon group. CONCLUSION: CPP-ACP performed better than Vantej and Icon in remineralizing the demineralized enamel. PMID- 28571255 TI - Effect of Diclofenac Mouthwash on Postoperative Pain after Periodontal Surgery. AB - INTRODUCTION: Non-Steroidal AntiInflammatory Drugs (NSAIDs) are widely used drugs for the management of pain. Oral administration of NSAIDs has various adverse events like gastrointestinal alterations - nausea, dyspepsia and gastrointestinal bleeding, hepatotoxicity and blood dyscrasias. As orally given NSAIDs are associated with systemic side effects, it is preferred to alleviate pain and inflammation using topical medication. Thus, recently the focus has been on the development of topical administration of NSAIDs in the form of gels, toothpastes and rinses. AIM: To determine if diclofenac mouthwash, would be a better alternative to its systemic administration post surgery, in terms of patient acceptance and to minimize the adverse effects of orally administered drug. MATERIALS AND METHODS: The study was designed as a single blinded, randomized, controlled clinical trial. Thirty chronic periodontitis patients scheduled for full mouth flap surgeries were randomized to receive either Diclofenac Mouthwash (MW) or Diclofenac Tablets (TB), post surgery. The MW group patients (15) were advised to rinse undiluted 15 ml solution for 30 secs, twice daily for three days. TB group (15) was advised to take 50 mg tablet twice daily for three days. A 10 point Visual Analog Scale (VAS) and Wong Baker Facial Rating Scale (FRS) was recorded to measure the pain perception by the patients. Gingival status was assessed by the Modified Gingival Index (MGI) at Baseline and seventh day. Data pertaining to pain perception were analysed using repeated measures of ANOVA (Analysis of Variance) with post-hoc LSD test. RESULTS: Intra group comparisons showed a significant reduction in pain, post surgery. Inter group comparisons showed a significant reduction only in the MGI scores of MW group, when compared to TB group. Intergroup comparisons showed no significant reduction in pain scores between both the groups, stating that diclofenac mouthwash is as effective as oral administration. CONCLUSION: Diclofenac mouthwash is a better alternative to the systemic administration post surgery, in terms of patient acceptance and to minimize the adverse effects of orally administrated drug. PMID- 28571256 TI - Keeping up with Dental Literature: A Study on Continuing Professional Development among Dental Practitioners in Hubli-Dharwad, India. AB - INTRODUCTION: Continuing Professional Development (CPD) refers to skills and knowledge attained for both personal development and career advancement. In India, very few studies have been documented to discover the patterns of information update by dental practitioners. AIM: To discover the educational tools that dentists of Hubli - Dharwad, Karnataka, India, prefer for updating their knowledge on new therapeutic methods and to assess the perceived usefulness of these CPD activities. MATERIALS AND METHODS: Face to face interview was carried out using questionnaire comprising questions on various CPD activities among all the practicing dentists. Pearson's chi-square test was used to evaluate any association between the frequency of information update and perceived usefulness with gender, qualification, practice types and academic attachments. RESULTS: Out of 112 practicing dentists in Hubli-Dharwad, 104 consented for the study. Mean age group of the study population was 32.3+/-7.56 (SD) years. Discussion with colleagues and discussion with medical sales representatives were the most frequently utilized information sources. On the other hand, attending dental fairs was found to be the most rarely utilized method of information access. Discussion with colleagues, reading textbooks and accessing internet were rated as most useful CPD activities and discussion with sales representatives and attending dental fairs were rated as least useful CPD activities. CONCLUSION: Both conventional methods of information sources like discussions with colleagues and textbook reading as well as contemporary information sources like accessing internet were the preferred methods of information update by dental practitioners of Hubli-Dharwad. PMID- 28571257 TI - Comparative Assessment of Canal Transportation and Centering Ability of Reciproc and One Shape File Systems Using CBCT-An In Vitro Study. AB - INTRODUCTION: Root canal preparation leads to deviation of the canal anatomy causing canal transportation which affects the success of the treatment. Cone Beam Computed Tomography (CBCT) is a non invasive imaging technique to analyse the shape of the root canal before and after the preparation. AIM: The purpose of this study was to investigate and evaluate the canal transportation in curved mandibular molar root canals and centering ability of Reciproc and One Shape file systems after instrumentation using CBCT. MATERIALS AND METHODS: Twenty mandibular molars were taken and allocated into two groups (n=10): Group 1-One Shape and Group 2-Reciproc. The canals were then scanned using CS 3D CBCT scanner (Carestream) before and after preparation, to assess the transportation and centering values at different levels respectively from the apex. The data gathered were then assessed statistically with Mann-Whitney test. RESULTS: Analysis revealed that Reciproc and One Shape showed statistically no significant difference in terms of canal transportation and centering ability (p>0.05). CONCLUSION: One shape and Reciproc performed similar in terms of canal transportation & centering ability. PMID- 28571258 TI - Immediate Versus Delayed Loading of Implant for Replacement of Missing Mandibular First Molar: A Randomized Prospective Six Years Clinical Study. AB - INTRODUCTION: Emergence of dental implants made the replacement of missing tooth easy. During the early days of introduction, implants were loaded three to six months after implant insertion, but understanding of healing cascade and improved production technology has changed the phase of restoration from delayed to immediate loading. AIM: To evaluate and compare the clinical outcome of immediate and delayed loaded implant supported prosthesis for missing mandibular first molar. The objectives were bleeding on probing, probing depth, implant mobility, marginal bone level and peri-implant radiolucency were evaluated during follow up period. MATERIALS AND METHODS: Twenty patients were included in this study who were in the need of fixed implant supported prosthesis for missing mandibular first molar. Single tooth implant with immediate loading done within two days of implant insertion in one group and another group were loaded after three months of implant insertion. These groups were evaluated clinically and radiographically over a period of 72 months after loading using Wilcoxon matched pairs test and Mann-Whitney U test. RESULTS: The study consists of 14 male and six female patients with the age range of 19 to 31 years. There was no bleeding on probing and probing depth remained well within the normal range even after 72 months of loading among both the groups. Minimal marginal bone loss observed with no mobility and peri-implant radiolucency. CONCLUSION: Implant supported prosthesis for missing mandibular first molar with immediate loading can be used as a successful treatment modality. It reduces treatment time, provides early function and prevents undue migration of adjacent tooth. Immediate loading showed similar clinical and radiographic results as that of delayed loading, indicating it as an equally efficient technique for implant supported prosthesis. PMID- 28571259 TI - Comparative Evaluation of Two Bis-GMA Based Orthodontic Bonding Adhesives - A Randomized Clinical Trial. AB - INTRODUCTION: Of the various orthodontic bonding materials, orthofix is a fairly new entrant into this field. This material was exclusively introduced for orthodontic bonding purposes; however, the application of this material for orthodontic purpose has not been scientifically evaluated so far. AIM: The aim of the present study was to evaluate by an in-vivo double blinded split mouth rando mized clinical trial, the overall bond failure rates of two Bis-GMA based composite materials namely Transbond XT and Orthofix. MATERIALS AND METHODS: Thirty three participants who fulfilled the inclusion criteria were randomly allocated by lottery method into two groups. Group A participants had maxillary right and the mandibular left quadrants bonded using Orthofix and the remaining quadrants were bonded using Transbond XT. In Group B, the quadrants were reversed. Both groups were followed for a period of six months and were reviewed every 3-4 weeks. If a bond failed, the details were recorded and the duration of treatment before each breakage was calculated. Data were analyzed using Independent t-test and chi-square test. (p< 0.05) at 90% power. RESULTS: The overall bond failure rate for 263 brackets was 2.7% for Orthofix and 3.6% for Transbond XT. The mean esitmated survival time was 221.58 days for Transbond XT and for Orthofix was 220.07 days. The difference between these mean values were statistically insignificant (p>0.05). Similarly, failure rates of the anterior and posterior segment were compared and no difference was observed between the groups (p>0.05). The maxillary and mandibular teeth were compared and more failures were found in the mandibular teeth among both the groups but they were not statistically significant (p>0.05). CONCLUSION: The overall bond failure rate and mean survival time for Transbond XT was similar to Orthofix with no statistically significant difference. PMID- 28571260 TI - Anxiety Levels among Five-Year-Old Children Undergoing ART Restoration- A Cross Sectional Study. AB - INTRODUCTION: Atraumatic Restorative Treatment (ART) involves manually excavating the carious part of the tooth and restoring the prepared cavity with chemically adhesive restorative material [Glass Ionomer Cement (GIC)] and it may induce and/or impact the dental anxiety in children. It is well established that ART procedure is less anxiety producing when compared with other restorative procedures using dental drill. AIM: The aim of this study was to evaluate the anxiety levels among five-year-old children undergoing ART restoration in I.T.S. Dental College, Greater Noida, India. MATERIALS AND METHODS: A sample of 50, five year-old children visiting the Outpatient Department (OPD) of ITS Dental College, Greater Noida was selected for ART treatment using Fuji IX GIC. Modified Venham Anxiety Scale based on their behaviour and heart rate of the children were measured and recorded before, during and after the ART procedure. Heart rate was measured using Radial Pulse examination method. Chi-square test was used and tests were conducted using IBM SPSS software (ver.20.0; IBM, Chicago, IL, USA). RESULTS: Before the ART treatment, heart rates and Modified Venham Anxiety Scores of majority of children were higher than that after the treatment. A p-value was statistically significant (0.028 and 0.048 respectively) for association of gender with heart rate and Modified Venham's score before the ART treatment. No statistically significant relation was found between the variables during and after the ART treatment. CONCLUSION: The level of anxiety for ART treatment in children was higher before the treatment than that during and after the treatment. There is a correlation between the gender of children and their level of anxiety for ART treatment. PMID- 28571261 TI - Effect of Different Ferrule Length on Fracture Resistance of Endodontically Treated Teeth: An In vitro Study. AB - INTRODUCTION: A ferrule has been described as a key element of tooth preparation when using a post and a core. It is a vertical band of tooth structure at the gingival aspect of crown preparation. It lessens the stress transmission to the root which is due to forces from posts or bending during seating of the post. The incorporation of a ferrule can help to withstand the forces of occlusion, preserve the hermetic seal of the luting cement, and minimize the concentration of stresses at the junction of post and core. AIM: To evaluate and compare the effect of ferrule length on fracture resistance of endodontically treated mandibular premolar teeth, restored with prefabricated glass fiber post luted with resin cement, composite core and a full coverage metal crown. MATERIALS AND METHODS: Forty freshly extracted mandibular premolars were treated endodontically. They were randomly divided into four groups according to their ferrule height: 3 mm, 2 mm, 1 mm and 0 mm (no ferrule). All specimens were restored with prefabricated glass fibre posts (Reforpost, Angelus) and composite resin (FiltekTM Z250XT). Standardized preparation was done on each specimen to receive a cast metal crown. The specimens were thermocycled and compressive static load at a crosshead speed of 1 mm/min was applied at an angle of 30 degrees on lingual incline of buccal cusp of the crown until failure occurred. The load (N) at failure and mode of failure were recorded. Statistical analysis was performed with Kruskal Wallis test. RESULT: Fracture resistance values among the groups was found to be statistically significant (p<0.001). The 3 mm ferrule group had significantly higher failure load (971.99+/-133.07) compared to 2 mm (848.84+/-109.60), 1 mm (714.64+/-133.89) and 0 mm ferrule groups (529.36+/ 119.95). More favourable failure modes were observed in almost all groups. CONCLUSION: The results of this study showed that fracture resistance of endodontically treated teeth increases as ferrule length increases. PMID- 28571262 TI - Evaluation of Microleakage with Total Etch, Self Etch and Universal Adhesive Systems in Class V Restorations: An In vitro Study. AB - INTRODUCTION: Adhesive dentistry is overwhelmingly evolving with respect to the dental surgeon's and patient's perspective. Embracing the concept of minimally invasive dentistry which follows minimum intervention performed to produce good adhesion and tooth coloured restoration, in turn makes the newer generation bonding agents more acceptable and appropriate withstanding the demand for stable restoration. AIM: To study and compare the extent of microleakage between tooth and restoration interface in class V composite resin restorations applying one Total Etch (AdperTM single bond), two Self Etch (AdperTM SE Plus, AdperTM Easy One) and Universal bonding agents using dye penetration method. MATERIALS AND METHODS: A total of 120 freshly orthodontically extracted human maxillary and mandibular premolars were included in the study. Class V cavities were prepared with a cylindrical diamond bur on the facial surface of each tooth, having approximate dimensions of 3 mm * 2.5 mm * 1.5 mm. Teeth were divided into four groups (30 in each group). Group A AdperTM single bond 2 (3M ESPE), Group B AdperTM SE Plus (3M ESPE), Group C AdperTM Easy One (3M ESPE), Group D AdperTM Single Bond Universal (3M ESPE) bonding agents were applied as per the manufacturer's instructions and the cavities were then restored with nanohybrid composite resin (Tetric N Ceram Ivoclar Vivadent). Teeth were then thermocycled for 200 cycles at 5 degrees -55 degrees C with 60 seconds of dwell time. Specimens were subjected to a dye leakage test. Microleakage was evaluated using a stereomicroscope. Data was analysed using Kruskal- Wallis, Dunn and Mann Whitney test to assess the difference in microleakage among various adhesives. RESULTS: The present study revealed that the microleakage was more at the gingival margin when compared with occlusal and this was found to be statistically significant. At the occlusal margin statistical significant difference was found only between AdperTM Easy one and AdperTM SE Plus, on the other hand at gingival margin no statistical significant difference was found. CONCLUSION: One step self etch agents showed less microleakage than total etches and universal adhesive at occlusal margin. Higher degree of microleakage was observed at gingival margin compared to occlusal margin. PMID- 28571263 TI - The Effect of Accelerated Aging on the Colour Stability of Composite Resin Luting Cements using Different Bonding Techniques. AB - INTRODUCTION: The main criterion of successful aesthetic restoration is to match the colour of the adjacent teeth. Porcelain laminate veneer is widely practiced indirect restoration in the contemporary aesthetic dentistry. The underlying luting cement colour influences the final outcome of the thin, translucent veneer shade. Hence, colour stability of luting cement is important criteria during their selection. AIM: The objective of the study was to assess the colour stability of the different dentin bonding techniques in composite resin luting cements. MATERIALS AND METHODS: A total of forty intact, non carious teeth were prepared to receive Porcelain Laminate Veneers (PLV). The lithium disilicate PLV were fabricated, and fitting surface was conditioned with 5% hydrofluoric acid and silane application. According to the bonding technique employed for the cementation of the PLV, the teeth samples were randomly divided into the four groups of ten each. The Group I and Group II samples were conditioned with etch and wash; the polymerization of resin was accomplished with the dual cure for Group I and light cure for Group II. The Group III and Group IV samples were conditioned with self-etch and self-adhesive technique correspondingly. The teeth shade was recorded in similar locations with a spectrophotometer before and after subjecting them to the accelerated ageing process. The ageing process included the thermocycling process in water between 5 degrees C and 55 degrees C for 5000 cycles followed by 100 hours xenon light exposure. The data were analysed with SPSS 19.0 by ANOVA and LSD post-hoc comparison. RESULTS: The higher mean colour change was observed in Group I sample (etch washdual cure) with a ?E value of 2.491. The ?E value for Group II (etch wash-light cure) and Group III (selfetch) was 1.110 and 2.357 respectively. The lowest mean colour change was observed in Group IV (self-adhesive) with ?E at 0.614. Statistical analysis showed significant differences between Group IV and Group I; Group IV and Group III with p<0.05. CONCLUSION: The self-adhesive and etch-wash light cure luting cements were found to be less susceptible for colour changes due to accelerated ageing. PMID- 28571264 TI - Evaluation of Resting Tongue Position in Recently Extracted and Long Term Completely Edentulous Patients: A Prospective Interventional Study. AB - INTRODUCTION: Presence of abnormal resting tongue position can lead to poor denture retention and stability. The prevalence of retracted tongue position has been found to be higher in partially edentulous subjects compared to dentate subjects and is greatest in completely edentulous individuals. AIM: To evaluate resting tongue position in recently extracted and long term completely edentulous patients, and to evaluate the efficacy of achieving retracted tongue position by simple modification in complete denture along with certain tongue exercises. MATERIALS AND METHODS: A total of 62 study subjects were classified into two groups based on duration of edentulousness. Group A: Recently extracted completely edentulous subjects (<1 year), Group B: Long term completely edentulous subjects (>1-10 year). The patients with retracted tongue position were subjected to a simple modification in complete denture along with inclusion of certain tongue exercises. After eight months patients were recalled and evaluated. The data was analysed using SPSS statistical tests like mean, standard deviation, proportion, Chi square test and McNemar Test. RESULTS: Among the study subjects, 54.9% had retracted tongue position. Group B showed high proportion of retracted tongue position (68.8%) as compared to Group A. After the intervention, 42.8% study subjects gained normal resting tongue position. CONCLUSION: Long term completely edentulous subjects presented retracted tongue position in higher percentage when compared to the recently extracted group. The interventional method employed for the subjects with retracted tongue position, played a significant role to assume normal resting tongue position and showed improvement in denture stability and retention. PMID- 28571265 TI - Comparative Analyses of Smear Layer Removal Using Four Different Irrigant Solutions in the Primary Root Canals - A Scanning Electron Microscopic Study. AB - INTRODUCTION: A clinician's path to success is a clean root canal system with three dimensional seal. Mechanical instrumentation of root canals alone leaves behind a smear layer covering the dentinal walls. Instrumentation must always be supported by use of irrigants which are considered as an essential prerequisite for root canal debridement. AIM: The aim of this in vitro study was to compare the efficacy of four irrigating solutions in removing the smear layer in primary root canals after hand instrumentation. MATERIALS AND METHODS: A total number of 40 human primary incisors were decoronated and split longitudinally. The specimens were divided randomly into four groups (n=10): Group I: 5.25% Sodium Hypochloride (NaOCl), Group II: 6% citric acid solution, Group III: smear clear and Group IV: 0.2% chitosan. Scanning electron microscopic analysis was performed to assess the presence or absence of smear layer at the coronal, middle and the apical portion of each canal. The data was analysed using Stastical Package For Social Sciences (SPSS) version 19.0 Armonk, NY IBM Corp soft ware. RESULTS: The pictures from the scanning electron microscopy showed that Group II exhibited better efficacy in removing smear layer without altering the normal dentinal structures with lowest mean scores (p<0.001) followed by Group III, Group IV and Group I. The presence of debris was more evident in the apical third rather than in the middle and the coronal part of the root canal. CONCLUSION: A 6% citric acid removed the smear layer more efficiently than other test irrigants in primary root canals. PMID- 28571267 TI - Effect of Autologous Platelet Rich Fibrin in Human Mandibular Molar Grade II Furcation Defects- A Randomized Clinical Trial. AB - INTRODUCTION: The Furcation of multirooted teeth is difficult region to gain access for treatment due to their complex anatomy. Modifications have been made in the periodontal instrument armamentarium to facilitate treatment of furcations. Moreover, many new materials have been introduced to attempt regeneration in the furcation defects. AIM: This study evaluated the role of Platelet Rich Fibrin (PRF) in comparison with allograft and Guided Tissue Regeneration (GTR) in the treatment of Grade II mandibular molar furcations. MATERIALS AND METHODS: This was a parallel arm prospective randomized, interventional trial (NCT 02430519) conducted on 22 patients, with Grade II mandibular furcation defects. Patients were divided into two equal groups. Group A, were treated by the placement of PRF as a graft and as a membrane while in Group B, the defects were treated by the placement of allograft and Healiguide collagen membrane. Clinical parameters {Plaque Index (PI), Probing Depth (PD), Relative Vertical Clinical Attachment Level (RVCAL), Relative Horizontal Clinical Attachment Level (RHCAL), Gingival Marginal Level(GML), and amount of Bonefill using Radio-Visiography (RVGBF)}, were estimated at baseline and nine months postoperatively. Comparison between the groups was analysed by using independent sample t-test, whereas, paired t-test was used to assess the mean values within the groups. RESULTS: The intergroup comparison for PI, PD, RHCAL, GML, was statistically not significant. Pertaining to RVCAL, there was a statistically significant difference at nine months (p-value=0.04) in Group A. Also, there was a statistically significant difference related to RVGBF (p-value=0.006) in Group A at nine months. CONCLUSION: The efficacy of PRF should be ascertained by conducting more studies with a larger sample size, on a long term basis, in patients with molar Grade II furcation defects. PMID- 28571266 TI - Formulation and Evaluation of Sol-Gel Drug Delivery System for Intracanal pH Sensitive Controlled Delivery of Chlorhexidine. AB - INTRODUCTION: Persistence of viable micro-organisms even after thorough chemomechanical debridement has been cited as a major cause for endodontic failure. Chlorhexidine is a drug, which has shown marked efficacy against Enterococcus faecalis and Candida spp., which are mostly accounted for endodontic failure and it has demonstrated high degree of substantivity to dentin by adsorption. Another issue with chlorhexidine and other intracanal medicaments is the excessive or premature peaking of the drug leading to possible side effects. AIM: The objective of this experimental work undertaken was to formulate a pH sensitive sol-gel sustained drug delivery system containing chlorhexidine. MATERIALS AND METHODS: The formulations were prepared using different concentrations of GELRITE(r) (0.1% and 0.2%) and Chlorhexidine (0.1% and 0.2%). The prepared solutions were evaluated for pharmacological properties like sterility test, viscosity, drug content, drug release characteristics, drug excipient compatible study. RESULTS: The drug excipient compatibility studies showed no interaction between the excipient and the active constituent. The microbial analysis showed good efficacy against the test micro-organisms and Minimum Inhibitory Concentration (MIC) values against Candida albicans (ATCC(r) 14053TM) was observed as 4 MUl/ml for both formulation containing 0.1% and 0.2% of GELRITE(r) Gellan (polymer). Whereas, MIC values against Enterococcus faecalis was observed to be 3.2 MUl/ml and 6 MUl/ml for formulation containing 0.1% and 0.2% of GELRITE(r) Gellan (polymer) respectively. CONCLUSION: From the present study, it could be successfully demonstrated that sol-gel formulations can be simple, easy to administer mode of intracanal drug delivery system. Localized pH changes present within the canal can trigger sol-gel conversion thereby releasing the drug in sustained manner with less toxicity and side effects. PMID- 28571268 TI - Comparison of Serum Levels of Endothelin-1 in Chronic Periodontitis Patients Before and After Treatment. AB - INTRODUCTION: Endothelin-1 (ET-1) is a potent vasoconstrictive peptide with multi functional activity in various systemic diseases. Previous studies indicate the detection of ET-1 in gingival tissues and gingival crevicular fluid. AIM: The aim of this study was to estimate the serum ET-1 levels in clinically healthy subjects and subjects with chronic periodontitis, before and after treatment, and correlate it with the clinical parameters. MATERIALS AND METHODS: A total of 44 patients were included in the study. Group I comprised of 20 subjects with clinically healthy periodontium. Group II comprised of 24 subjects with chronic periodontitis. Group III comprised of same Group II subjects following periodontal management. Serum samples were collected from the subjects and an Enzyme Linked Immunosorbent Assay (ELISA) was done to estimate the ET-1 levels. The ET-1 levels were then correlated among the three groups with the clinical parameters namely, Plaque Index (PI), Sulcus Bleeding Index (SBI), probing pocket depth, clinical attachment loss and Periodontally Inflamed Surface Area (PISA). The independent t-test and paired t-test were used for comparison of clinical parameters and Pearson's correlation coefficient test was used for correlating the ET-1 levels. RESULTS: ET-1 levels in chronic periodontitis subjects were significantly higher compared to healthy subjects (p<0.001). However, the clinical parameters did not statistically correlate with the ET-1 levels. There was a significant decrease in ET-1 levels following treatment (p<0.001). CONCLUSION: Serum ET-1 is increased in chronic periodontitis and reduces after periodontal therapy. Further studies are required to establish ET-1 as a biomarker for periodontal disease. PMID- 28571269 TI - Effect of Pre-Procedural Chair-Side Finger Stretches on Pinch Strength amongst Dental Cohort- A Biomechanical Study. AB - INTRODUCTION: Ergonomics is the essential principle behind the health and successful practice for a dentist and dental hygienist. During the procedure of dental Scaling and Root Planing (SRP), a high level of pinch force is exerted by the finger muscles resulting in early muscle fatigue. AIM: This pilot study comparatively evaluated the Pinch Strength (PS) of the finger muscles, prior to and after SRP, amongst dental cohort performing chair-side hand and finger stretches to those not performing the same. MATERIALS AND METHODS: Forty dental professionals were recruited by purposive sampling for the study and allocated into a test and control group. PS was recorded for both groups following which the test group performed finger stretches comprising of rubber band stretch, tendon glide, finger flexion and extension, thumb flexion and finger webbing. The subjects of both the groups carried out SRP for 30 minutes after which PS was again recorded. Inter-group difference was analysed for variability at baseline and 30 minutes after SRP using independent samples/unpaired t-test. Within group comparison of PS measurement was done using paired t-test. RESULTS: The PS for the test group declined from 14.425+/-2.577 pounds (lbs) to 13.725+/-2.557 lbs, while for the control group, a decline in PS from 13.65+/-2.636 lbs to 10.675+/ 2.478 lbs after SRP was noted. On comparing the difference of means of both groups, a statistically significant result was obtained. CONCLUSION: Work-related musculoskeletal disorders can be reduced by performing a few simple chair-side stretches. These stretches can help prevent the finger muscle fatigue during SRP and thus, increase its efficacy. PMID- 28571270 TI - Incidence of Natal Teeth in Newborns in Government Medical College and Hospital, Chengalpattu: A Pilot Study. AB - INTRODUCTION: Natal teeth are teeth which are seen at birth and neonatal teeth erupt during the first thirty days after birth. Exact cause is however unknown but trauma, malnutrition, infection or environmental factor can be the causitive factor. Different studies have shown different incident rates. AIM: To find the incidence of natal teeth in neonates born in the hospital over a period of seven months and also to find out the most commonly occurring natal teeth among them. MATERIALS AND METHODS: The present study was conducted in the Government Medical College and Hospital, Chengalpattu, Chennai, Tamil Nadu, India, for a period of seven months. A questionnaire was given to the mothers for gaining relevant information regarding the age, gender of neonate, type of delivery, etc. The cohort of neonates delivered in the hospital was examined clinically to note the presence of natal teeth. RESULTS: Out of 4,341 children four neonates were born with natal teeth. Our study showed female preponderance and most commonly erupted teeth were mandibular anteriors. The type of delivery had no significant relation with the presence or absence of natal teeth. CONCLUSION: The presence of natal teeth was very rare in our study group. The neonates with natal teeth should be thoroughly examined and parent counselling is also important in these cases. PMID- 28571271 TI - Evaluation of Efficacy of 1% Curcuminoids as Local Application in Management of Oral Lichen Planus - Interventional Study. AB - INTRODUCTION: Oral Lichen Planus (OLP) is a chronic inflammatory mucocutaneous disease affecting the oral cavity which has been associated with severe burning sensation which in turn affects the quality of life of the patients. Currently, the effective treatment of choice remains the use of corticosteroids. The chronicity and recalcitrant nature of the disease demand the long term use of these drugs with ensuing adverse effects. Turmeric and its active ingredient, "curcumin", have been found to have anti-inflammatory, antioxidant and anticancer properties. Hence, this intervention study was done to evaluate the efficacy of curcumin oral gel in the management of oral lichen planus. AIM: The study was conducted to compare the efficacy of 1% curcumin gel with the conventional mid potent topical corticosteroid, triamcinolone acetonide 0.1% in managing the signs and symptoms of OLP. MATERIALS AND METHODS: An intervention study was conducted on 75 patients diagnosed with OLP divided into three groups, Group 1 (0.1% triamcinolone acetonide oral paste thrice daily in tapering doses), Group 2 (curcumin oral gel thrice daily) and Group 3 (curcumin oral gel six times daily). The patients were analysed for the symptom (burning) and sign (erythema and ulceration) using the numerical rating score and Modified Oral Mucositis Index (MOMI) for a period of three months on a bimonthly basis. The results were analysed using Students t-test and unpaired t-test. RESULTS: Intragroup comparison using paired t-test showed statistically significant reduction in burning sensation (p<0.001) as well as erythema and ulceration (p<0.001) in all the three groups. However, when the three groups were compared Group 1 showed the maximum reduction in burning sensation (77%) and erythema and ulceration (67%). Among the curcuminoid group, increased frequency was found to be more beneficial. CONCLUSION: Curcumin oral gel can bring about clinical improvements in OLP patients; however it cannot be used as a mainstay drug. Instead, it can be used as a maintenance drug after the patient is treated with an initial course of corticosteroids. Further studies with larger sample size and increased drug concentrations may be required. PMID- 28571272 TI - Effect of Oral Tissue Fluids on Compressive Strength of MTA and Biodentine: An In vitro Study. AB - INTRODUCTION: Over the past many years various root end filling materials have been used which have been tested for their physical properties but each of them had certain limitations. In clinical practice, root end filling materials are exposed to oral tissue fluids which may compromise their longevity. AIM: The aim of this study was to investigate the effects of oral tissue fluids on compressive strength of Mineral Trioxide Aggregate (MTA) and biodentine. MATERIALS AND METHODS: MTA and biodentine cylinders measuring 6 mm * 4 mm were prepared using acrylic blocks. They were divided into six groups; (Group 1) (MTA) (n=3), (Group 2) MTA contaminated with saliva, (MTA-S) (n=3), Group 3: MTA contaminated with blood, MTA-B (n=3), Group 4: Biodentine (BD), Group 5: Biodentine contaminated with saliva (BD-S) (n=5), Group 6: Biodentine contaminated with blood (BD-B) (n=5). The mould was contaminated with saliva and blood and incubated at 37 degrees C at 100% humidity for three days and compressive strength (MPa) was measured using universal testing machine and the data was analyzed statistically using one-way ANOVA test. RESULTS: There was no significant difference in the compressive strength between the three groups i.e., MTA, MTA-S, MTA-B (p > 0.05). However, there was higher compressive strength in the MTA-B group when compared to MTA and MTA-S. Also, there was no statistical significant difference between BD, BD-S, BD-B (p>0.05). CONCLUSION: This study showed that the compressive strength of MTA and biodentine was not adversely affected by contamination with oral tissue fluids like blood and saliva. PMID- 28571273 TI - An In-vivo Comparison of Vertical and Horizontal Distance between Incisive Papilla and Incisal Edge of Maxillary Central Incisors in Dentates with Different Arch Forms. AB - INTRODUCTION: The incisive papilla is one of the most stable landmarks for assessing the original position of certain key teeth. To place anterior artificial teeth back in its original position such as in denture construction and full mouth rehabilitation cases vertical and horizontal distance from incisive papilla in different arch forms, imparts a significant role. The average distance will be helpful for arrangement of teeth in its original position which not only provides a pleasing appearance and normal function but also will save the dentists' chair side effort. AIM: To determine the average vertical and horizontal distance of the maxillary central incisors from the incisive papilla in dentate individuals with different arch forms. MATERIALS AND METHODS: Primary impressions and casts were made for 72 dentate patients, sorted into different arch forms and mid point of the incisive papilla was established. The vertical and horizontal distances were measured with the digital vernier caliper. The mean and standard deviation were subjected to Students t-test. RESULTS: The range of horizontal distance was 4-7 mm, 6-8 mm, 5-8 mm and vertical distance was 4-6 mm in ovoid, square and tapered arch forms respectively. CONCLUSION: Horizontal distance of the maxillary central incisors from the incisive papilla varies in different arch forms whereas, vertical distance is almost same in all the arch forms. PMID- 28571274 TI - Reinforcement of Aluminum Oxide Filler on the Flexural Strength of Different Types of Denture Base Resins: An In vitro Study. AB - INTRODUCTION: Acrylic resins have been used extensively for the fabrication of denture bases because of their aesthetic qualities, ease of manipulation and repairability. Flexural fatigue of the denture base has been shown to be a factor in the clinical failure of polymethyl methacrylate resin dentures. Also, the fracture can result from impact, fatigue or degradation of the base material. Hence, there is a need to increase the strength of denture base resins. AIM: To evaluate the effect of reinforcing alumina oxide filler on the flexural strength of different acrylic resins. MATERIALS AND METHODS: A total of 180 acrylic specimens were fabricated, which were divided into three groups self cure acrylic resin (SC), conventional heat cure resin (HC) and high strength heat cure resin (HI). Each group was divided into four subgroups i.e., control group and the specimens of the remaining three groups were reinforced with aluminum oxide (Al2O3) powder by 5%, 10% and 15% by weight. Specimens were stored in distilled water for one week; flexural strength was tested by universal testing machine. Results were analysed by one-way analysis of variance and post-hoc Tukey paired group comparison tests. RESULTS: Flexural strength of SC increased by 9%, 13% and 19%, Flexural strength of HC increased by 8%, 15% and 19% and that of HI increased by 21%, 26% and 29% compared to control group by adding 5%,10% and 15% of alumina filler (p-value <0.001). Addition of 15% of alumina powder to SC showed high flexure strength compared to control group of HC (p-value <0.001). Addition of 10% and 15% of alumina powder to HC showed high flexural strength compared to control group of HI (p-value <0.001). CONCLUSION: Addition of alumina to self cure acrylic resin, conventional heat cure acrylic resin and high strength heat cure acrylic resin increased the flexural strength. Increasing the flexural strength of the acrylic resin base material could lead to more clinical success. PMID- 28571275 TI - In Vitro Cytotoxicity Evaluation of Novel Nano-Hydroxyapatite-Silica Incorporated Glass Ionomer Cement. AB - INTRODUCTION: Glass Ionomer Cements (GIC) are among the most popular restorative materials, but their use in dentistry is limited due to their physical properties. The hardness of GIC was improved by incorporation of nano hydroxyapatite-silica into GIC, to expand its applicability. AIM: To evaluate the cytotoxic effects of nano-hydroxyapatite-silica incorporated glass ionomer cement (HA-SiO2-GIC) on human Dental Pulp Stem Cells (DPSC) and compare it with conventional GIC and resin modified GIC. MATERIALS AND METHODS: Material extracts of Fuji IX, Fuji II LC and HA-SiO2-GIC were prepared into seven serial concentrations and applied to 96-well-plates seeded with DPSC. The 96-well-plates were incubated for 24 and 72 hours. The morphology of DPSC was observed under the inverted phase contrast microscope, and the cell viability was determined using MTT assay at both time intervals. Kruskal-Wallis test was performed for statistical analysis. RESULTS: At maximum concentration, DPSC appeared fewer in number, but the normal spindle morphology was maintained in all groups except for Fuji II LC. At lower concentrations, DPSC appeared normal and more confluent in all groups. The cytotoxic effects of all groups were dose dependent. Fuji IX demonstrated the lowest cytotoxicity, followed by HA-SiO2-GIC. Fuji II LC demonstrated the highest cytotoxicity. The difference was significant between all groups at 200 mg/ml concentration (p<0.05). At concentration <100 mg/ml, cytotoxicity of HA-SiO2-GIC was comparable to that of Fuji IX and lower than that of Fuji II LC. CONCLUSION: HA-SiO2-GIC showed a favourable cytotoxicity response and thus holds promise as a future potential restorative material in clinical dentistry. PMID- 28571276 TI - Demystifying the Mysteries: Sexual Dimorphism in Primary Teeth. AB - INTRODUCTION: One of the critical steps in the process of identification is the sex determination of an unknown individual. Many studies have shown that sex can be determined using the human skeleton, especially by examining the pelvis and skull. Odontometric analysis of the human sexual variation has been less investigated, especially of primary dentition. AIM: To verify the presence of sexual dimorphism in primary teeth of local population of Faridabad, Haryana, India. MATERIALS AND METHODS: The research was performed on dental casts of 500 children (250 boys and 250 girls, age range 3-5 years). Mesiodistal and buccolingual crown dimensions of maxillary and mandibular primary teeth were measured with a digital Vernier's caliper and were analysed for sexual dimorphism. Mann-Whitney-U test was used to check the statistical significance of difference in tooth dimensions among boys and girls. RESULTS: Differences were found in the mean values of mesiodistal and buccolingual diameters of primary teeth, in which boys generally had larger crown diameters than girls. CONCLUSION: Primary teeth may be used as an additional tool for sex identification of juvenile skeletons where other dimorphic features are not much developed. PMID- 28571277 TI - Periodontal and Dentition Status among Orphans and Children with Parents in Mysore City, India: A Comparative Study. AB - INTRODUCTION: Oral health symbolises the general health and quality of life of an individual. The socioeconomic status of the parents shows direct impact on oral health status of children. Thus, it can be hypothesised that the pattern of oral diseases would be different among children living with parents and orphans. AIM: To explore periodontal and dentition status among orphans and children with parents in Mysore city, India. MATERIALS AND METHODS: A cross-sectional study was conducted among six to 15-year-old children residing in eight orphanages. Equal number of age and gender matched children living with parents were selected from government schools (non orphans) located in the same geographical areas for comparison. Clinical examination was conducted by a single trained, calibrated examiner and oral findings were recorded according to World Health Organization (WHO) diagnostic criteria 2013. The data collected was analysed using Mann Whitney U test and Chi-square test. RESULTS: A total of 957 children (478 from orphanages and 479 from government schools) were examined in the study. The mean defs and DMFS were significantly higher among government school children (non orphans) (defs: 3.20+/-4.0; DMFS: 2.43+/-2.8) compared to children from orphanages (defs: 2.72+/-4.4; DMFS: 1.72+/-2.3). Prevalence of gingival bleeding among orphans (79.49%) was higher compared to non orphans (71.4%). CONCLUSION: The present study concluded that prevalence of caries was lower among orphans but periodontal status was poor among them as compared to non orphans. PMID- 28571278 TI - Applicability of the CIELAB and CIEDE2000 Formulae for Detection of Colour Changes in Colour-Changeable Chewing Gum for Evaluating Masticatory Function. AB - INTRODUCTION: Mastication is one of the essential stomatognathic functions and is impaired when mandibulectomy is performed for removal of head and neck lesions. AIM: The purpose of this study was to investigate the correlation between perceived chewing ability {Masticatory Score (MS)} and objective mixing ability (?E) in patients who had undergone marginal mandibulectomy. MATERIALS AND METHODS: Twenty normal dentate subjects as control group and twenty mandibulectomy patients who had undergone marginal mandibulectomy and wearing a dentomaxillary prosthesis were enrolled. Perceived chewing ability MS and objective ?E were evaluated using a food intake questionnaire and the colour changeable chewing gum, respectively. They were instructed to chew the gum continuously for 100 strokes on their usual side. The chewed gum was measured using the CIELAB colour space defined by a colourimeter and L, a* and b* were obtained. The change in colour of the gum after chewing was calculated using CIELAB (?Eab) and the CIEDE2000 (?E00) formula. The relationships of a*, ?Eab, and ?E00 with MS score were analyzed using the Spearman's rank correlation coefficient. RESULTS: A correlation was found between perceived chewing ability (MS) and objective mixing ability (index of the masticatory function {?E}) in marginal mandibulectomy patients. (?E00 = 0.481, a* = 0.587, ?Eab = 0.668). CONCLUSION: Within the limitations of this study, it can be concluded that the CIEDE2000 formula for calculation of colour difference can be used to evaluate masticatory function in patients who have undergone marginal mandibulectomy. PMID- 28571279 TI - Comparative Evaluation of Different Modes of Laser Assisted Endodontics in Primary Teeth: An In vitro Study. AB - INTRODUCTION: The presence of bacteria in root canals has been considered to be responsible for endodontic treatment failure, even in case of primary teeth. The use of lasers can be a valuable addition in removing bacterial load in areas where traditional methods may fail to succeed. Methods like direct laser irradiation of canals, Laser Activated Irrigation (LAI) with sodium hypochlorite (NaOCl) and Photodynamic Therapy (PDT) seem to be a promising alternative for disinfection. AIM: This study was designed to compare the efficacy of latest advancements in disinfection techniques using diode laser namely direct laser irradiation, photodynamic therapy and laser activated irrigation using sodium hypochlorite. MATERIALS AND METHODS: Sixty freshly extracted primary teeth either single or multi-rooted teeth with two third of their root length intact were collected. Instrumentation was completed to size 30 H-file. Teeth were randomly divided into Group 1- Direct Laser- irradiation, Group 2 - Photodynamic therapy; Group 3- Laser activated irrigation with 2.5% NaOCl. The tooth specimens were inoculated with Enterococcus faecalis. The bacterial colonies were counted preoperatively. Laser irradiation was performed for all groups in accordance to the groups each tooth belonged to. Postoperatively the bacterial colonies were counted. One-way Analysis was applied to compare bacterial count at baseline and post-test between three groups. Tukey's post-hoc test was applied for pairwise comparison between groups. Paired t-test was applied to compare the mean baseline bacterial count with post-test mean bacterial count. RESULTS: The results obtained with all the three groups postoperatively were highly significant (p value<0.001). Statistically significant difference between results of Group 1 and Group 2 and also between Group 1 and Group 3 was found (p-value<= 0.001). However, no statistical difference between Group 2 and Group 3 was found (p-value 0.96). CONCLUSION: Disinfection strategies using diode laser by techniques gives promising results. Techniques like laser activated irrigation and photoactivated disinfection are better than direct laser irradiation in eliminating Enterococcus feacalis. PMID- 28571280 TI - A Comparative Evaluation of Accuracy of the Dies Affected by Tray Type, Material Viscosity, and Pouring Sequence of Dual and Single Arch Impressions- An In vitro Study. AB - INTRODUCTION: The clinician's skill, impression techniques, and materials play a very important role in recording fine details in an impression for accuracy of fixed partial denture prosthesis. Impression of prepared teeth and of the opposing arch can be recorded simultaneously by dual-arch trays, while the full arch metal trays are used for impressions of prepared teeth in one arch. AIM: To measure and compare the accuracy of working dies made from impressions with metal and plastic dual arch trays and metal full arch trays, for two viscosities of impression material and by changing the sequence of pour of working and non working sides. MATERIALS AND METHODS: A balanced design with independent samples was used to study the three variables (tray type, impression material viscosity, and pouring sequence). An impression made by dual arch trays and single arch trays were divided in to three groups (Group A-plastic dual arch tray, Group B metal dual arch tray, Group C-full arch metal stock tray). Out of these three groups, two groups (Group A and B) were subdivided in to four subgroups each and one group (Group C) was subdivided in to two subgroups. A sample size of 30 was used in each subgroup yielding a total 300 impressions in three groups or ten subgroups. Impressions were made of a machined circular stainless steel die. All three dimensions (Occlusogingival, Mesiodistal, and Buccolingual) of the working dies as well as stainless steel standard die were measured three times, and the mean was used for the three standard sample values to which all working dies means were compared. Statistical analysis used for this study was a 3-factor analysis of variance with hypothesis testing at alpha =0.05. RESULTS: With respect to the selection of impression material viscosity statistically significant differences were found in the dies for the buccolingual and mesiodistal dimensions. Metal dual arch trays were slightly more accurate in the mesiodistal dimension in comparison to the plastic trays in reference of tray selection and in view of pouring sequence no differences were observed in occlusogingival dimension but in buccolingual and mesiodistal dimensions nonworking side was more accurate. CONCLUSION: The gypsum dies produced from the dual arch impressions were generally smaller in all three dimensions than the stainless steel standard die. Plastic dual-arch trays were more accurate with rigid impression material and there was not statistically significant difference for sequence of pouring. Metal dual-arch trays were more accurate with monophase impression material and working side was more accurate. Stock metal full arch trays were more accurate for monophase impression material. PMID- 28571281 TI - Assessment of Enamel Remineralisation After Treatment with Four Different Remineralising Agents: A Scanning Electron Microscopy (SEM) Study. AB - INTRODUCTION: Decades of research has helped to increase our knowledge of dental caries and reduce its prevalence. However, according to World Oral Health report, dental caries still remains a major dental disease. Fluoride therapy has been utilised in a big way to halt caries progression, but has been met with limitations. This has paved the way for the development of newer preventive agents that can function as an adjunct to fluoride or independent of it. AIM: The purpose of the present study was to evaluate the ability of Casein Phosphopeptide Amorphous Calcium Phosphate Fluoride (CPP ACPF), Bioactive Glass (BAG), fluoride enhanced Hydroxyapatite (HA) gel and self-assembling peptide P11-4 to remineralise artificial carious lesions in enamel in vitro using a 30 day pH cycling model through surface microhardness analysis and SEM. MATERIALS AND METHODS: Sixty enamel samples were divided into five groups of 12 samples each. The control Group A consisted of intact enamel samples, Group B: CPP-ACPF (Tooth Mousse Plus), Group C: BAG (SHY- NM), Group D: fluoride enhanced HA gel (ReminPro) and Group E: Self-assembling peptide P11-4 (Curodont Protect). All groups excluding the control group were subjected to demineralisation following which four of these groups were remineralised using the four remineralising agents. The treated groups were subjected to pH cycling over a period of 30 days. This was followed by assessment of surface microhardness and SEM for qualitative evaluation of surface changes. The results were analysed by One-Way Analysis Of Variance (ANOVA). Multiple comparisons between groups were performed by paired t test and post-hoc Tukey test. RESULTS: The results of the study revealed that remineralisation of enamel was the highest in samples of Group E (Self assembling peptide P11-4) followed by Group B (CPP-ACPF), Group C (BAG) and Group D (fluoride enhanced HA gel). There was a significant difference (p<0.05) in the remineralising ability between the self assembling peptide P11-4 group and BAG and fluoride enhanced HA gel group. Although no significant difference was observed between the self assembling peptide P11-4 and CPP-ACPF group, the self assembling peptide P11-4 remineralised the enamel lesions more effectively. SEM photomicrographs of the test groups demonstrated either amorphous crystals or particles scattered on the surface or lines of remineralisation along the prismatic borders. CONCLUSION: Self assembling peptide P11-4 demonstrated promising results by effectively and significantly remineralising the enamel lesions as compared to other test agents. PMID- 28571282 TI - Microhardness and Penetration of Artificial White Spot Lesions Treated with Resin or Colloidal Silica Infiltration. AB - INTRODUCTION: Infiltration of early enamel lesions by materials having remineralizing capacity seems to improve aesthetics and arrests caries progression. AIM: To evaluate and compare the surface microhardness and penetration depth of a low viscosity resin and colloidal silica nanoparticle infiltrates into artificially created white spot lesions. MATERIALS AND METHODS: Forty extracted human central incisors were embedded in acrylic resin blocks exposing the labial surfaces of the crowns. The specimens were immersed in demineralizing solution for 96 hours to create white spot lesions on labial surfaces. The samples were then divided into two groups (n=20 each), where in Group 1-resin infiltration (ICON DMG, Hamburg, Germany) and Group 2-colloidal silica infiltration (Arrow Fine chemicals, Rajkot, Gujarat, India) was done. Samples were subjected to vicker's microhardness testing at baseline, after demineralization and after treatment with resin or colloidal silica infiltrates. Then, the crowns were sectioned longitudinally and penetration depth of the infiltrants was measured using confocal laser scanning microscope and compared the readings to lesion depth. All the collected data was subjected to statistical analysis using t-test. RESULTS: Resin infiltration group showed significantly greater increase in microhardness compared to colloidal silica infiltration (p=0.001). The percentage of penetration of the resin group was 67.14% and that of colloidal silica group was 54.53% indicating significant difference between the two. CONCLUSION: Resin infiltrates performed better in regaining the baseline microhardness and penetrating deep into the porous white spot lesions, when compared to colloidal silica infiltrates. PMID- 28571283 TI - Estimation of DMFT, Salivary Streptococcus Mutans Count, Flow Rate, Ph, and Salivary Total Calcium Content in Pregnant and Non-Pregnant Women: A Prospective Study. AB - INTRODUCTION: Pregnancy, a period from conception till birth, causes changes in the functioning of the human body as a whole and specifically in the oral cavity that may favour the emergence of dental caries. Many studies have shown pregnant women at increased risk for dental caries, however, specific salivary caries risk factors and the particular period of pregnancy at heightened risk for dental caries are yet to be explored and give a scope of further research in this area. AIM: The aim of the present study was to assess the severity of dental caries in pregnant women compared to non-pregnant women by evaluating parameters like Decayed, Missing, Filled Teeth (DMFT) index, salivary Streptococcus mutans count, flow rate, pH and total calcium content. MATERIALS AND METHODS: A total of 50 first time pregnant women in the first trimester were followed during their second trimester, third trimester and postpartum period for the evaluation of DMFT by World Health Organization (WHO) scoring criteria, salivary flow rate by drooling method, salivary pH by pH meter, salivary total calcium content by bioassay test kit and salivary Streptococcus mutans count by semiautomatic counting of colonies grown on Mitis Salivarius (MS) agar supplemented by 0.2U/ml of bacitracin and 10% sucrose. The observations of pregnant women were then compared with same parameters evaluated in the 50 non-pregnant women. Paired t test and Wilcoxon sign rank test were performed to assess the association between the study parameters. RESULTS: Evaluation of different caries risk factors between pregnant and non-pregnant women clearly showed that pregnant women were at a higher risk for dental caries. Comparison of caries risk parameters during the three trimesters and postpartum period showed that the salivary Streptococcus mutans count had significantly increased in the second trimester, third trimester and postpartum period while the mean pH and mean salivary total calcium content decreased in the third trimester and postpartum period. These changes reflected on the DMFT score which increased in the third trimester and postpartum period. CONCLUSION: The results of this study suggest that there is a definite correlation between pregnancy and dental caries. We conclude that the third trimester and postpartum period of pregnancy are the periods during which the pregnant women are at a higher risk for development of dental caries. PMID- 28571284 TI - Evaluation of Periapical Healing of Apicomarginal Defect in Mandibular First Molar Treated with Platelet Rich Fibrin: A Case Report. AB - The presence of an apicomarginal defect is one of the reasons for the failure of endodontic treatment. The best treatment option to treat an apicomarginal defect is to perform endodontic surgery using Guided Tissue Regeneration (GTR) membranes. The present case report evaluated the healing of periapical lesion along with apicomarginal defect using Platelet Rich Fibrin (PRF) as membrane in periapical surgery of mandibular first molar. Recall examination was performed at 3 and 18 months post surgery. A satisfactory periapical healing was evident using PRF in apicomarginal defect of mandibular first molar. PRF may be considered as an alternative treatment for GTR membranes in the treatment of apicomarginal defects. PMID- 28571285 TI - Unicystic Ameloblastoma of Mandible with an Unusual Diverse Histopathology: A Rare Case Report. AB - Ameloblastomas of jaws are benign odontogenic tumours with four clinical variants being solid multicystic type, unicystic type, extra osseous type and desmoplastic type. Unicystic ameloblastoma accounts for only 13% of all the known cases in the scientific literature. Follicular and plexiform patterns are the commonly seen histopathological patterns in unicystic ameloblastoma. Though rare in itself, presence of granular cells along with acanthomatous changes occurring in unicystic ameloblastoma is a rare phenomenon. We present a rare case report of unicystic ameloblastoma of right mandible with an unusual histopathology. It exhibited both luminal and mural types as well as both acanthomatous and granular cell changes found together. As occurrence of unicystic ameloblastoma of jaws with such varied histopathology is rare, their course, clinical outcome, prognosis and recurrence rate are not clear. Documentation of more such cases in literature may make pathogenesis and nature of these lesions more insightful. PMID- 28571286 TI - Staged Hard and Soft Tissue Reconstruction Followed by Implant Supported Restoration in the Aesthetic Zone: A Case Report. AB - Alveolar ridge deficiency is a common clinical consequence following tooth loss due to chronic periodontitis complicating ideal implant placement. Advanced hard and soft tissue augmentation procedures have been developed in the recent past with predictable clinical outcomes. A male patient presented with a Grade III mobile upper right central incisor associated with advanced bone loss and soft tissue deficit. Following extraction of tooth #11, socket augmentation was done using an autogenous cortico-cancellous block graft and subsequent soft tissue augmentation was done with palatal connective tissue graft. At the end of six months, a tapered self tapping implant fixture was placed with adequate primary stability and after eight weeks, second stage implant surgery was done with the Misch technique in order to recreate papillae and the implant was prosthetically restored. The alveolar ridge was adequately recontoured following the staged surgical protocol. The implant was well integrated at the end of 15 months. Execution of sequential surgical procedures in a highly deficient edentulous site made it possible to achieve of optimal pink and white aesthetics with stable implant supported fixed prosthesis. PMID- 28571287 TI - Surgical Management of a Rare Case of Massive Compound Odontome Associated with Missing Primary Tooth. AB - Odontomes are considered to be the most common odontogenic tumours of the jaws. They are benign, mixed tumours arising from the remnants of both odontogenic epithelium and the ectomesenchyme resulting in the deposition of varied propotions of enamel, dentin, cementum and pulp tissues. As these lesions show deficiency only in structural arrangement, some authors consider odontomes as hamartomas or tumour like malformations. Though these lesions are more common in children, very few cases have been reported in less than five years age group. Blood loss is a major issue in paediatric surgery. Careful and safe surgery is the primary goal of the surgeon. The external carorid artery which is the only feeder of blood to the face and oral cavity can be ligated to control bleeding in extensive maxillofacial injuries and orofacial malignancies. Herewith, we report a massive odontome in a three and half-year-old child which was treated by surgical excision along with carotid control to prevent excess bleeding. PMID- 28571288 TI - Solitary Myofibroma of the Mandible in a Six-Year Old-Child: Diagnosis of a Rare Lesion. AB - Myofibroma is a benign uncommon fibroblastic tumour originating from the soft tissue, bone and may affect both children and adults. Radiographically myofibroma presents as unilocular radiolucency. Histologically, typical biphasic cellular arrangement is noted. Immunohistochemical markers are useful for definitive diagnosis of this uncommon neoplasm. Here, a case of six-year-old male child with a localized swelling in the left body of mandible is presented. The clinical, radiological, histological and immunohistochemical findings were corroborative of Infantile Myofibroma. PMID- 28571289 TI - A Custom Made Skeletal Class II Corrector Appliance in Late Adolescent Phase. AB - Skeletal Class II correction in deceleration phase of growth is both a challenge and dilemma with choice between extraction and myofunctional therapy. With marginal growth remaining the convenient choice is extraction for camouflage of the skeletal discrepancy. On the other hand, the treatment with Fixed Functional Appliances (FFAs) helps in resolution of the problem without sacrificing the dentition. However, the conventional FFAs requires a phase of alignment which results in further loss of time to utilize any remaining growth. The present report proposes the use of a novel custom made functional appliance for Class II skeletal correction which is simple to fabricate and convenient to use. PMID- 28571290 TI - Leprosy in an Eight-Year-Old Child - An Exceptional Case with Unusual Oral Manifestation. AB - Leprosy is a contagious and granulomatous disease which is caused by Mycobacterium leprae. The incubation period for leprosy is five to seven years and it can take as long as about 30 years before signs and symptoms of leprosy develop in some patients. It is a chronic systemic disease which mostly affects the skin and peripheral nerves. It has been seen that indeterminate leprosy is the most common type seen in childhood followed by tuberculoid variant. Borderline lepromatous and lepromatous leprosy are only occasionally encountered in children and rarely affects the oral cavity. Here, we report a rare case of an eight-year-old female child patient who presented primarily with oral manifestations and was subsequently diagnosed as having lepromatous leprosy. PMID- 28571291 TI - Membranous Basal Cell Adenoma - A Rare Entity in an Unusual Location. AB - Basal cell adenoma is a rare benign salivary gland neoplasm exhibiting an isomorphic basaloid tumour cell pattern, commonly occurring in the parotid. Membranous variant warrants separate consideration because of its recurrence and rate of malignant transformation. We report a case of membranous type basal cell adenoma occurring in minor salivary gland in a 61-year-old female patient. The histopathological diagnosis was supported by immunohistochemical analysis and serum Carcinoembryonic antigen level. PMID- 28571292 TI - Oral Spindle Cell Sarcoma: A Rare Case Report and Review of Literature. AB - Spindle cell lesions of the head and neck region are diverse in nature by means of clinical and biological heterogeneity. Though few lesions are found to be malignant, several others are benign or merely reactive in nature. Although these lesions are fairly common occurring in other parts of the body, they are very rare in the oral cavity, accounting for less than 1% of all tumours in the oral region. Herein, a case of 48-year-old man who presented with a polypoid lesion of the maxilla has been reported. Histopathological examination and immunohistochemistry revealed spindle cell sarcoma of the left maxillary sinus. We present this rare tumour to contribute to the better understanding and awareness of this rare malignancy where diagnosis can be very challenging. PMID- 28571293 TI - Management of Severely Atrophic Mandibular Ridge using Hollow Denture with an Analytical Discussion: A Clinical Case Report. AB - A severely resorbed edentulous mandibular ridge, although fairly common in occurrence, its rehabilitation poses a challenging clinical situation for the prosthodontist. This has implored prosthodontists to seek for ingenious modifications in the conventional prosthetic forms so as to gratify patient's expectations who have difficulty in wearing the mandibular complete dentures. Opting for the most suitable treatment modality mandates equilibrating the retention, stability and support triad to the fullest. Extreme resorption of the denture bearing tissue bed may lead to problems with achieving adequate levels of prosthetic satisfaction for the patient. One such entrusted treatment option, that has proven its mettle over tides of time in such a scenario, the hollow denture by virtue of its reduced excessive acrylic resin weight, efficaciously replaces the lost voluminous alveolar ridge in the increased inter-ridge space of the denture wearer. PMID- 28571294 TI - A Rare Case of Digoxin Associated Gingival Overgrowth. AB - This case report presents a case of drug induced gingival overgrowth in a 28-year old female patient with history of Coronary Artery Disease (CAD) and was prescribed digoxin in combination with furosemide and acitrom for the same. On clinical examination, the patient presented with severe gingival overgrowth. The volume of enlargement seen did not correlate solely with the diagnosis of inflammatory Gingival Enlargement (GE), hence an added drug induced component to the Gingival Overgrowth (GO) was suspected. It was decided to treat the condition using initial therapy {meticulous Scaling and Root Planning (SRP)} followed by a period of observation and maintenance. On recall, since there was no marked improvement, surgical intervention was planned. Periodic treatment combining surgery and maintenance ultimately produced the desired results clinically. Thus, this article within limits highlights that because of time-relationship between the starting of the medication that is digoxin and manifestation of GO, a causal relationship is likely. PMID- 28571295 TI - Dental Avengers: Taking Retainer Stability and Aesthetics into Next Era. AB - Adult patients are realizing that practical, realistic options now exist to "straighten" their teeth because the cosmetic dentistry revolution has begun to include even "adult short-term cosmetic orthodontics" as an integral part. Previously, the patients were bound to select between either the aesthetic benefits of ceramic or the bondability characteristic of composite, however this can now be fabricated in such a manner that still allows placement of a lingual splint so as to steady the orthodontic movement. This article describes a case study whereby the patient can attain the aesthetic benefits of an all ceramic crown or a veneer which was retained by incorporating/reinforcing a metal framework of crown itself. Orthodontic treatment was initiated to correct the alignment, overjet and overbite which were followed by endodontic, periodontic and prosthodontic rehabilitation with full ceramic crowns to achieve ideal aesthetics, and an improved occlusion and stable function. PMID- 28571296 TI - Maxillary Second Molar with Fused Root and Six Canals- A Case Report. AB - One of the known aberrations in root canal morphology of maxillary second permanent molars is the presence of collateral mesiobuccal canals. This case report describes the endodontic management of a maxillary second molar that had a single fused root with six canals that was successfully managed with the aid of dental operating microscope. Six canal orifices were located namely MB1 (Mesiobuccal), MB2, MB3, DB1 (Distobuccal), DB2 and palatal. During the cleaning and shaping, instrument separation occurred at the apical third of the palatal canal which was removed with ultrasonics. After cleaning and shaping, the canals were obturated with resin sealer and laterally condensed gutta-percha. The patient was recalled for periodic review. After two years of follow up the patient remained asymptomatic. Cone Beam Computed Tomography (CBCT) evaluation revealed satisfactory periapical status. PMID- 28571297 TI - Prosthetic Rehabilitation of an Insidiously Enlarged Traumatic Palatal Perforation after Orotracheal Intubation in a Young Diabetic Child. AB - This report describes an unusual case of an insidiously enlarged traumatic palatal perforation after orotracheal intubation in a four-year-old female child with Insulin Dependent Diabetes Mellitus (IDDM). The child was first diagnosed with diabetes at 10 months of age when she was hospitalized for pneumonia. Severe respiratory distress warranted assisted ventilation via orotracheal intubation. Multiple factors namely infection, relative immunodeficiency, poor wound healing, trauma via orotracheal intubation as well as uncontrolled glucose levels, all contributed to the formation and deterioration of the palatal perforation. A palatal obturator was fabricated as an interim treatment until surgical closure could be performed. PMID- 28571298 TI - Are we Training Enough of Communication Skills and Patient Psychology Required in Dental Practice. AB - The aim of this review is to discuss about lacunae in the areas of Communication skills and Patient psychology teaching in the dental set up in India. A literature search was performed using various databases and other resources. Data obtained was reviewed to obtain the work done in this field. It was found that there is currently no clear data in literature as to how much and how well students are taught about communication and behavioural skills and patient personality in dental curriculum in India. Pinpointing such lacunae can help dental colleges and universities to focus on the emphasis of their approaches to teaching about communication skills and psychology of the patient. Identification of future research area in this field is the need of the time for future discovery and progress in this overlooked field. PMID- 28571299 TI - Patient Centered Outcomes in Periodontal Treatment-An Evidenced Based Approach. AB - Transformation of research into clinical practice is the most challenging step in evidence based dental practice. Designing the most reliable research with applicable endpoint evaluation is very important as it can lead to successful research outcomes that can be accepted in clinical practice. In the periodontal research few accepted endpoints are used frequently as they are believed to be the gold standard in measuring the periodontal disease and the treatment outcomes. However, a wide range of endpoints used are surrogate endpoints and these endpoints have no direct correlation with the patient centered outcomes. Hence, a direct relationship of surrogate endpoints with true endpoints needs to be established. This review highlights the importance of true endpoints and challenges in implementing these in clinical research. Importance of patient's centered outcomes are also reviewed and duly discussed here. Need for conducting research which includes the true endpoints or the surrogate endpoints with clinical applicability and tangible outcomes, was also suggested in this review. PMID- 28571300 TI - Mucous Cell Prosoplasia in Oral Pathologies: A Brief Review. AB - One of the enigmas in cell differentiation process is prosoplasia, which is contemplated as forward differentiation. A well-known example of prosoplastic switch is mucous cell prosoplasia, which is the transformation of a simple squamous epithelial cell into mucous secreting cell. Numerous theories have been proposed for histogenesis of this phenomenon, which are comprehensively discussed in the present paper. Oral pathologies like odontogenic cysts and salivary gland tumours show mucous prosoplasia quite often; sometimes leading to diagnostic difficulties. In the present paper, efforts have been made to comprehensively discuss diverse aspects of mucous prosoplasia like histogenesis, theories and diagnostic importance in various oral pathologies. PMID- 28571301 TI - Images in Medicine - An Atypical Presentation of Unilateral Tongue Angioedema Caused by Acetaminophen. PMID- 28571303 TI - Ergonomically Designed Patient Drape. PMID- 28571302 TI - Successful Surgical Outcome for an Endodontic Failure using BiodentineTM as Retrograde Restoration in Conjunction with Platelet Rich Fibrin (PRF) for Progressive Healing. PMID- 28571304 TI - Slingshot - An Easy Way Out. AB - Orthodontic alignment of ectopically placed incisors or canines can be challenging and time consuming. A variety of techniques are used to align such palatally or lingually placed teeth including indirect ties with ligature wires, E-chains, piggy-back methods. This article presents two case reports to describe an effective technique using 'slingshot' method. It is a relatively simple and rapid method which is operator friendly and easily tolerated by the patients. PMID- 28571305 TI - Correction. AB - [This corrects the article DOI: 10.7860/JCDR/2015/10451.5465.]. PMID- 28571306 TI - Characterisation and antimicrobial activity of biosurfactant extracts produced by Bacillus amyloliquefaciens and Pseudomonas aeruginosa isolated from a wastewater treatment plant. AB - Biosurfactants are unique secondary metabolites, synthesised non-ribosomally by certain bacteria, fungi and yeast, with their most promising applications as antimicrobial agents and surfactants in the medical and food industries. Naturally produced glycolipids and lipopeptides are found as a mixture of congeners, which increases their antimicrobial potency. Sensitive analysis techniques, such as liquid chromatography coupled to mass spectrometry, enable the fingerprinting of different biosurfactant congeners within a naturally produced crude extract. Bacillus amyloliquefaciens ST34 and Pseudomonas aeruginosa ST5, isolated from wastewater, were screened for biosurfactant production. Biosurfactant compounds were solvent extracted and characterised using ultra-performance liquid chromatography (UPLC) coupled to electrospray ionisation mass spectrometry (ESI-MS). Results indicated that B. amyloliquefaciens ST34 produced C13-16 surfactin analogues and their identity were confirmed by high resolution ESI-MS and UPLC-MS. In the crude extract obtained from P. aeruginosa ST5, high resolution ESI-MS linked to UPLC-MS confirmed the presence of di- and monorhamnolipid congeners, specifically Rha-Rha C10-C10 and Rha-C10-C10, Rha-Rha-C8-C10/Rha-Rha-C10-C8 and Rha-C8-C10/Rha-C10-C8, as well as Rha-Rha-C12-C10/Rha-Rha-C10-C12 and Rha-C12-C10/Rha-C10-C12. The crude surfactin and rhamnolipid extracts also retained pronounced antimicrobial activity against a broad spectrum of opportunistic and pathogenic microorganisms, including antibiotic resistant Staphylococcus aureus and Escherichia coli strains and the pathogenic yeast Candida albicans. In addition, the rapid solvent extraction combined with UPLC-MS of the crude samples is a simple and powerful technique to provide fast, sensitive and highly specific data on the characterisation of biosurfactant compounds. PMID- 28571307 TI - Variants of lipopeptides and glycolipids produced by Bacillus amyloliquefaciens and Pseudomonas aeruginosa cultured in different carbon substrates. AB - The quantitative and qualitative effect of water immiscible and miscible carbon rich substrates on the production of biosurfactants, surfactin and rhamnolipids, by Bacillus amyloliquefaciens ST34 and Pseudomonas aeruginosa ST5, respectively, was analysed. A small-scale high throughput 96 deep-well micro-culture method was utilised to cultivate the two strains in mineral salt medium (MSM) supplemented with the water miscible (glucose, glycerol, fructose and sucrose) and water immiscible carbon sources (diesel, kerosene and sunflower oil) under the same growth conditions. The biosurfactants produced by the two strains were isolated by acid precipitation followed by an organic solvent extraction. Ultra performance liquid chromatography coupled to electrospray ionisation mass spectrometry was utilised to analyse yields and characterise the biosurfactant variants. For B. amyloliquefaciens ST34, maximum surfactin production was observed in the MSM supplemented with fructose (28 mg L-1). In addition, four surfactin analogues were produced by ST34 using the different substrates, however, the C13-C15 surfactins were dominant in all extracts. For P. aeruginosa ST5, maximum rhamnolipid production was observed in the MSM supplemented with glucose (307 mg L-1). In addition, six rhamnolipid congeners were produced by ST5 using different substrates, however, Rha-Rha-C10-C10 and Rha-C10-C10 were the most abundant in all extracts. This study highlights that the carbon sources utilised influences the yield and analogues/congeners of surfactin and rhamnolipids produced by B. amyloliquefaciens and P. aeruginosa, respectively. Additionally, glucose and fructose were suitable substrates for rhamnolipid and surfactin, produced by P. aeruginosa ST5 and B. amyloliquefaciens ST34, which can be exploited for bioremediation or as antimicrobial agents. PMID- 28571308 TI - Bright Single-Photon Source at 1.3 MUm Based on InAs Bilayer Quantum Dot in Micropillar. AB - A pronounced high count rate of single-photon emission at the wavelength of 1.3 MUm that is capable of fiber-based quantum communication from InAs/GaAs bilayer quantum dots coupled with a micropillar (diameter ~3 MUm) cavity of distributed Bragg reflectors was investigated, whose photon extraction efficiency has achieved 3.3%. Cavity mode and Purcell enhancement have been observed clearly in microphotoluminescence spectra. At the detection end of Hanbury-Brown and Twiss setup, the two avalanched single-photon counting modules record a total count rate of ~62,000/s; the time coincidence counting measurement demonstrates single photon emission, with the multi-photon emission possibility, i.e., g 2(0), of only 0.14. PMID- 28571309 TI - Multiplex Genome Editing by Natural Transformation (MuGENT) for Synthetic Biology in Vibrio natriegens. AB - Vibrio natriegens has recently emerged as an alternative to Escherichia coli for molecular biology and biotechnology, but low-efficiency genetic tools hamper its development. Here, we uncover how to induce natural competence in V. natriegens and describe methods for multiplex genome editing by natural transformation (MuGENT). MuGENT promotes integration of multiple genome edits at high-efficiency on unprecedented time scales. Also, this method allows for generating highly complex mutant populations, which can be exploited for metabolic engineering efforts. As a proof-of-concept, we attempted to enhance production of the value added chemical poly-beta-hydroxybutyrate (PHB) in V. natriegens by targeting the expression of nine genes involved in PHB biosynthesis via MuGENT. Within 1 week, we isolated edited strains that produced ~100 times more PHB than the parent isolate and ~3.3 times more than a rationally designed strain. Thus, the methods described here should extend the utility of this species for diverse academic and industrial applications. PMID- 28571310 TI - Brook Rearrangement as Trigger for Carbene Generation: Synthesis of Stereodefined and Fully Substituted Cyclobutenes. AB - Through a sequence that can be performed in a single vessel, involving regio- and diastereoselective copper-catalyzed carbomagnesiation of cyclopropenes, reaction with acylsilanes, and addition of THF as cosolvent, Brook rearrangement can be triggered to furnish a wide range of cyclobutenes with exceptional diastereoselectivity. Accordingly, stereodefined and highly substituted cyclobutenes with contiguous quaternary carbon centers can be synthesized easily and in high yield. The new strategy constitutes an unprecedented application of Brook rearrangement, one which involves the intermediacy of carbene species. PMID- 28571311 TI - Trichoderpyrone, a Unique Polyketide Hybrid with a Cyclopentenone-Pyrone Skeleton from the Plant Endophytic Fungus Trichoderma gamsii. AB - Trichoderpyrone (1), a unique polyketide with a cyclopentenone-pyrone hybrid skeleton, was isolated from the plant endophytic fungus Trichoderma gamsii. The structure of 1 was determined by detailed analysis of NMR data together with comparison of chemical shift values of similar fragments. The relative and absolute configurations were established by NOESY correlations and CD experiment. Trichoderpyrone (1) displayed weak cytotoxic activities against A549, HepG2, and HeLa cancer cell lines. 1 might originate from a hybrid biosynthetic pathway through two nonreduced (NR) polyketide megasynthetases. PMID- 28571312 TI - Identification of Indole Diterpenes in Ipomoea asarifolia and Ipomoea muelleri, Plants Tremorgenic to Livestock. AB - Ipomoea asarifolia has been associated with a tremorgenic syndrome in livestock in Brazil and was recently reported to contain tremorgenic indole diterpenes. Ipomoea muelleri has been reported to cause a similar tremorgenic syndrome in livestock in Australia. Ipomoea asarifolia and I. muelleri were investigated by high-performance liquid chromatography-high-resolution mass spectometry (HPLC HRMS) and high-performance liquid chromatography-tandem mass spectrometry (HPLC MS/MS) for indole diterpene composition. The high-resolution mass spectrometric data in combination with MS/MS fragmentation mass spectral data provided valuable information for indole diterpene characterization. The previous report of indole diterpenes in I. asarifolia was confirmed and expanded; and the presence of indole diterpenes in I. muelleri is reported for the first time. Two new indole diterpenes were isolated and their structures determined by 1D and 2D NMR spectroscopy and given the names 11-hydroxy-12,13-epoxyterpendole K and 6,7 dehydroterpendole A. The presence of terpendole K and terpendole E in I. asarifolia is unequivocally demonstrated for the first time. This is the first detailed MS analysis of known indole diterpenes and possible isomers in I. asarifolia and I. muelleri. PMID- 28571313 TI - Performance of Homeostatic Controller Motifs Dealing with Perturbations of Rapid Growth and Depletion. AB - An essential property of life is that cells and organisms have the ability to protect themselves against external disturbances/attacks by using homeostatic mechanisms. These defending mechanisms are based on negative feedback regulation and often contain additional features, such as integral control, where the integrated error between a controlled variable and its set-point is used to achieve homeostasis. Although the concept of integral control has its origin in industrial processes, recent findings suggest that biological systems are also capable of showing integral control. We recently described a basic set of negative feedback structures (controller motifs) where robust homeostasis is achieved against different but constant perturbations. As many perturbations in biology, such as infections, increase rapidly over time, we investigated how the different controller motifs equipped with different implementations of integral control perform in relation to rapidly changing perturbations, including exponential and hyperbolic changes. The findings show that the construction of an optimum biochemical controller design for time-dependent perturbations requires a certain match between the structure of the negative feedback loop, its signaling kinetics, and the kinetics of how integral control is implemented within the negative feedback loop. PMID- 28571314 TI - Photoconversion Mechanisms and the Origin of Second-Harmonic Generation in Metal Iodates with Wide Transparency, NaLn(IO3)4 (Ln = La, Ce, Sm, and Eu) and NaLa(IO3)4:Ln3+ (Ln = Sm and Eu). AB - Four new metal iodates, namely, NaLn(IO3)4 (Ln = La, Ce, Sm, and Eu), and a series of NaLa(IO3)4:Ln3+ (Ln = Sm and Eu) solid solutions were synthesized through hydrothermal reactions. The structures of the title compounds are similar to that of NaY(IO3)4 crystallizing in the acentric monoclinic space group Cc. The iodate materials reveal layered structures composed of LnO8 square antiprisms and IO3 polyhedra, in which each layer is connected by the I...O interactions. NaLa(IO3)4 suggests a great potential as a matrix for optical source attributed to its acentricity and broad transparency from visible to mid-IR region. The photoluminescence properties depending on the concentration of Sm3+ reveal that NaLa(IO3)4:Sm3+ undergoes a self-quenching relaxation over 7 mol % of Sm3+ by dipole-quadrupole interactions. Attributable to the asymmetric coordination environment of Ln3+, stronger electric dipole transitions compared to magnetic dipole transitions were observed for both compounds. In addition, the materials exhibit strong second-harmonic generation (SHG) responses and are type I phase matchable. The structural origin of the SHG properties for the reported iodates is elucidated. PMID- 28571315 TI - Tetraaza[1.1.1.1]m,p,m,p-cyclophane Diradical Dications Revisited: Tuning Spin States by Confronted Arenes. AB - Diradical dications of two kinds of alternate-meta-para-linked tetraazacyclophanes in which p-phenylene (1) and 9,10-anthracenylene (2a) moieties are embedded in their macrocyclic backbones were successfully isolated as air-stable salts. The structures of 12+ and 2a2+ were elucidated by X-ray analysis, and significantly different types of structural deformation led to different spin density distributions due to the steric demand of the confronted arene moieties. The singlet-triplet energy gaps were determined to be +0.3 kcal mol-1 (+151 K) and -1.0 kcal mol-1 (-503 K) by SQUID measurements, indicating the triplet ground state for 12+ and the singlet ground state for 2a2+. PMID- 28571317 TI - Correction to "Comment on 'Nanohole-Structured and Palladium-Embedded 3D Porous Graphene for Ultrahigh Hydrogen Storage and CO Oxidation Multifunctionalities'". PMID- 28571316 TI - Co-assembly of Peptide Amphiphiles and Lipids into Supramolecular Nanostructures Driven by Anion-pi Interactions. AB - Co-assembly of binary systems driven by specific non-covalent interactions can greatly expand the structural and functional space of supramolecular nanostructures. We report here on the self-assembly of peptide amphiphiles and fatty acids driven primarily by anion-pi interactions. The peptide sequences investigated were functionalized with a perfluorinated phenylalanine residue to promote anion-pi interactions with carboxylate headgroups in fatty acids. These interactions were verified here by NMR and circular dichroism experiments as well as investigated using atomistic simulations. Positioning the aromatic units close to the N-terminus of the peptide backbone near the hydrophobic core of cylindrical nanofibers leads to strong anion-pi interactions between both components. With a low content of dodecanoic acid in this position, the cylindrical morphology is preserved. However, as the aromatic units are moved along the peptide backbone away from the hydrophobic core, the interactions with dodecanoic acid transform the cylindrical supramolecular morphology into ribbon like structures. Increasing the ratio of dodecanoic acid to PA leads to either the formation of large vesicles in the binary systems where the anion-pi interactions are strong, or a heterogeneous mixture of assemblies when the peptide amphiphiles associate weakly with dodecanoic acid. Our findings reveal how co-assembly involving designed specific interactions can drastically change supramolecular morphology and even cross from nano to micro scales. PMID- 28571318 TI - Visible-Light-Mediated Thiol-Ene Reactions through Organic Photoredox Catalysis. AB - Synthetically useful radical thiol-ene reactions can be initiated by visible light irradiation in the presence of an organic photocatalyst, 9-mesityl-10 methylacridinum tetrafluoroborate. The key thiyl radical intermediates are generated upon quenching of the photoexcited catalyst with a variety of thiols. The success of this method requires only the use of near-stoichiometric levels of alkene coupling partners. Using these highly efficient metal-free conditions, thiol-ene reactions between carbohydrates and peptides can be accomplished in excellent yields. PMID- 28571319 TI - Isatin N,N'-Cyclic Azomethine Imine 1,3-Dipole and Base Catalyzed Michael Addition with beta-Nitrostyrene via C3 Umpolung of Oxindole. AB - A new isatin N,N'-cyclic azomethine imine 1,3-dipole was devised, and an unusual Michael addition with beta-nitrostyrene catalyzed by tributylamine under mild conditions has been developed. The new reaction featured the C3 umpolung of oxindole and an unusual formation of double bond. Notably, this new synthon performed as a donor rather than an acceptor. This protocol provided a promising method for the preparation of various 3-aminooxindoles with good yields in moderate diastereoselectivities. PMID- 28571320 TI - Combining Precipitation and Vitrification to Control the Number of Surface Patches on Polymer Nanocolloids. AB - In an effort to incorporate increasingly higher levels of functionality into soft nanoparticles, heterogeneously structured particles stand out as a simple means to enhance functionality by tailoring only particle architecture. Various means exist for the fabrication of particles with specific structural configurations; however, the tunability of particle morphology is still a challenging and often laborious task, especially in self-assembled systems where a single equilibrium configuration dominates. Improved strategies for multipatch particle assembly are therefore needed to allow for the tailoring of particle structure via a single, continuous assembly route. One means of accomplishing this is through kinetic trapping of particle morphologies along the path to the final equilibrium configuration in precipitation-induced, phase-separating polymer blends. Here, we demonstrate this capability by using rapid nanoprecipitation to control the overall size, composition, and patch distribution of soft colloids. In particular, we illustrate that polymer feed concentration, blend ratio, and polymer molecular weight can all serve as functional handles with which to consistently alter particle patch distributions in a self-assembling homopolymer system without redesigning the starting materials. We furthermore delineate the role of polymer vitrification in the determination of particle structure. PMID- 28571322 TI - La1+xBa1-xGa3O7+0.5x Oxide Ion Conductor: Cationic Size Effect on the Interstitial Oxide Ion Conductivity in Gallate Melilites. AB - Substitution of La3+ for Ba2+ in LaBaGa3O7 melilite yields a new interstitial oxide-ion conducting La1+xBa1-xGa3O7+0.5x solid solution, which only extends up to x = 0.35, giving a maximum interstitial oxygen content allowed in La1+xBa1 xGa3O7+0.5x as about half of those allowed in La1+x(Sr/Ca)1-xGa3O7+0.5x. La1.35Ba0.65Ga3O7.175 ceramic displays bulk conductivity ~1.9 * 10-3 S/cm at 600 degrees C, which is lower than those of La1.35(Sr/Ca)0.65Ga3O7.175, showing the reduced mobility for the oxygen interstitials in La1+xBa1-xGa3O7+0.5x than in La1+x(Sr/Ca)1-xGa3O7+0.5x. Rietveld analysis of neutron powder diffraction data reveals that the oxygen interstitials in La1.35Ba0.65Ga3O7.175 are located within the pentagonal tunnels at the Ga level between two La/Ba cations along the c-axis and stabilized via incorporating into the bonding environment of a three-linked GaO4 among the five GaO4 tetrahedra forming the pentagonal tunnels, similar to the Sr and Ca counterparts. Both static lattice atomistic simulation and density functional theory calculation show that LaBaGa3O7 has the largest formation energy for oxygen interstitial defects among La1+xM1-xGa3O7+0.5x (M = Ba, Sr, Ca), consistent with the large Ba2+ cations favoring interstitial oxygen defects in melilite less than the small cations Sr2+ and Ca2+. The cationic-size control of the ability to accommodate the oxygen interstitials and maintain high mobility for the oxygen interstitials in La1+xM1-xGa3O7+0.5x (M = Ba, Sr, Ca) gallate melilites is understood in terms of local structural relaxation to accommodate and transport the oxygen interstitials. The accommodation and migration of the interstitials in the melilite structure require the tunnel-cations being able to adapt to the synergic size expansion for the interstitial-containing tunnel and contraction for the tunnels neighboring the interstitial-containing tunnel and continuous tunnel-size expansion and contraction. However, the large oxygen bonding separation requirement of the large Ba2+ along the tunnel not only suppresses the ability to accommodate the interstitials in the tunnels neighboring the Ba2+-containing tunnel but also reduces the mobility of the oxygen interstitials among the pentagonal tunnels. PMID- 28571323 TI - Convergent Synthesis of the ent-ZA'B'C'D'-Ring System of Maitotoxin. AB - Stereoselective synthesis of the ent-ZA'B'C'D'-ring system of maitotoxin has been accomplished through a convergent strategy utilizing Suzuki-Miyaura cross coupling reaction of ZA'-ring alkylborane and C'D'-ring (Z)-vinyl iodide, and subsequent construction of the B'-ring by reduction of the O,S-acetal. PMID- 28571321 TI - EPR/ENDOR and Theoretical Study of the Jahn-Teller-Active [HIPTN3N]MoVL Complexes (L = N-, NH). AB - The molybdenum trisamidoamine (TAA) complex [Mo] {[3,5-(2,4,6-i Pr3C6H2)2C6H3NCH2CH2N]Mo} carries out catalytic reduction of N2 to ammonia (NH3) by protons and electrons at room temperature. A key intermediate in the proposed [Mo] nitrogen reduction cycle is nitridomolybdenum(VI), [Mo(VI)]N. The addition of [e-/H+] to [Mo(VI)]N to generate [Mo(V)]NH might, in principle, follow one of three possible pathways: direct proton-coupled electron transfer; H+ first and then e-; e- and then H+. In this study, the paramagnetic Mo(V) intermediate {[Mo]N}- and the [Mo]NH transfer product were generated by irradiating the diamagnetic [Mo]N and {[Mo]NH}+ Mo(VI) complexes, respectively, with gamma-rays at 77 K, and their electronic and geometric structures were characterized by electron paramagnetic resonance and electron nuclear double resonance spectroscopies, combined with quantum-chemical computations. In combination with previous X-ray studies, this creates the rare situation in which each one of the four possible states of [e-/H+] delivery has been characterized. Because of the degeneracy of the electronic ground states of both {[Mo(V)]N}- and [Mo(V)]NH, only multireference-based methods such as the complete active-space self consistent field (CASSCF) and related methods provide a qualitatively correct description of the electronic ground state and vibronic coupling. The molecular g values of {[Mo]N}- and [Mo]NH exhibit large deviations from the free-electron value ge. Their actual values reflect the relative strengths of vibronic and spin orbit coupling. In the course of the computational treatment, the utility and limitations of a formal two-state model that describes this competition between couplings are illustrated, and the implications of our results for the chemical reactivity of these states are discussed. PMID- 28571324 TI - Asymmetric Total Synthesis of Eburnamine and Eucophylline: A Biomimetic Attempt for the Total Synthesis of Leucophyllidine. AB - The first enantiospecific total synthesis of (+)-6 has been achieved employing a Friedlander quinoline synthesis as a key step. Asymmetric synthesis of the architecturally complex eburnamine 5 has also been accomplished utilizing an intramolecular acid-mediated cyclization of a carbinol amine lactone moiety. Highlights of the effective modular synthetic strategy include development of the common precursor 4 for the construction of the privileged scaffolds 5 and 6 with an all-carbon quaternary stereocenter utilizing a Johnson-Claisen rearrangement strategy. Attempts have been made to synthesize 1 by the biomimetic coupling of 5 and (+)-6; however, regioisomeric 26 was formed. PMID- 28571325 TI - Poly(ethylene) glycol hydrogel based on oxa-Michael reaction: Precursor synthesis and hydrogel formation. AB - This paper reported a facile strategy for the one-pot synthesis of vinyl sulfone (VS) group terminated hydrogel precursors [poly(ethylene) glycol (PEG)-VS] and PEG hydrogels via catalytic oxa-Michael reaction. Nine potential catalysts were investigated for the reaction between PEG and divinyl sulfone, among which 4 dimethylaminopyridine (DMAP) prevailed for its high catalytic activity. DMAP produced PEG-VS with a conversion of more than 90% in 2 h under a solvent-free condition at room temperature, which significantly simplifies the synthesis of PEG-VS. The preparation of PEG hydrogels was realized by adding glycerol as a crosslinker, and the physical and the mechanical properties were easily controlled by changing the crosslinker concentration as well as the PEG chain length. This strategy can also be applied to other polyhydroxy compounds as crosslinkers, and thus, a library of hydrogels with designed structures and desired properties could be prepared. The PEG hydrogels showed good antifouling properties, low cytotoxicity, and ability to release drugs at a tunable rate, indicating versatile potential bioapplications. PMID- 28571326 TI - Anomalous barrier escape: The roles of noise distribution and correlation. AB - We study numerically and analytically the barrier escape dynamics of a particle driven by an underlying correlated Levy noise for a smooth metastable potential. A "quasi-monochrome-color" Levy noise, i.e., the first-order derivative variable of a linear second-order differential equation subjected to a symmetric alpha stable white Levy noise, also called the harmonic velocity Levy noise, is proposed. Note that the time-integral of the noise Green function of this kind is equal to zero. This leads to the existence of underlying negative time correlation and implies that a step in one direction is likely followed by a step in the other direction. By using the noise of this kind as a driving source, we discuss the competition between long flights and underlying negative correlations in the metastable dynamics. The quite rich behaviors in the parameter space including an optimum alpha for the stationary escape rate have been found. Remarkably, slow diffusion does not decrease the stationary rate while a negative correlation increases net escape. An approximate expression for the Levy-Kramers rate is obtained to support the numerically observed dependencies. PMID- 28571327 TI - The covalent interaction between dihydrogen and gold: A rotational spectroscopic study of H2-AuCl. AB - The pure rotational transitions of H2-AuCl have been measured using a pulsed-jet cavity Fourier transform microwave spectrometer equipped with a laser ablation source. The structure was found to be T-shaped, with the H-H bond interacting with the gold atom. Both 35Cl and 37Cl isotopologues have been measured for both ortho and para states of H2. Rotational constants, quartic centrifugal distortion constants, and nuclear quadrupole coupling constants for gold and chlorine have been determined. The use of the nuclear spin-nuclear spin interaction terms Daa, Dbb, and Dcc for H2 were required to fit the ortho state of hydrogen, as well as a nuclear-spin rotation constant Caa. The values of the nuclear quadrupole coupling constant of gold are chiaa=-817.9929(35) MHz, chibb=504.0(27) MHz, and chicc=314.0(27). This is large compared to the eQq of AuCl, 9.63 312(13) MHz, which indicates a strong, covalent interaction between gold and dihydrogen. PMID- 28571328 TI - Unexpected behavior of ultra-thin films of blends of polystyrene/poly(vinyl methyl ether) studied by specific heat spectroscopy. AB - Specific heat spectroscopy (SHS) employing AC nanochip calorimetry was used to investigate the glassy dynamics of ultra-thin films (thicknesses: 10 nm-340 nm) of a polymer blend, which is miscible in the bulk. In detail, a Poly(vinyl methyl ether) (PVME)/Polystyrene (PS) blend with the composition of 25/75 wt. % was studied. The film thickness was controlled by ellipsometry while the film topography was checked by atomic force microscopy. The results are discussed in the framework of the balance between an adsorbed and a free surface layer on the glassy dynamics. By a self-assembling process, a layer with a reduced mobility is irreversibly adsorbed at the polymer/substrate interface. This layer is discussed employing two different scenarios. In the first approach, it is assumed that a PS rich layer is adsorbed at the substrate. Whereas in the second approach, a PVME rich layer is suggested to be formed at the SiO2 substrate. Further, due to the lower surface tension of PVME, with respect to air, a nanometer thick PVME-rich surface layer, with higher molecular mobility, is formed at the polymer/air interface. By measuring the glassy dynamics of the thin films of PVME/PS in dependence on the film thickness, it was shown that down to 30 nm thicknesses, the dynamic Tg of the whole film was strongly influenced by the adsorbed layer yielding a systematic increase in the dynamic Tg with decreasing the film thickness. However, at a thickness of ca. 30 nm, the influence of the mobile surface layer becomes more pronounced. This results in a systematic decrease in Tg with the further decrease of the film thickness, below 30 nm. These results were discussed with respect to thin films of PVME/PS blend with a composition of 50/50 wt. % as well as literature results. PMID- 28571329 TI - Erratum: "Polymer dynamics under cylindrical confinement featuring a locally repulsive surface: A quasielastic neutron scattering study" [J. Chem. Phys. 146, 203306 (2017)]. PMID- 28571330 TI - Influence of chemistry, interfacial width, and non-isothermal conditions on spatially heterogeneous activated relaxation and elasticity in glass-forming free standing films. AB - We employ the Elastically Collective Nonlinear Langevin Equation (ECNLE) theory of activated relaxation to study several questions in free standing thin films of glass-forming molecular and polymer liquids. The influence of non-universal chemical aspects on dynamical confinement effects is found to be relatively weak, but with the caveat that for the systems examined, the bulk ECNLE polymer theory does not predict widely varying fragilities. Allowing the film model to have a realistic vapor interfacial width significantly enhances the reduction of the film-averaged glass transition temperature, Tg, in a manner that depends on whether a dynamic or pseudo-thermodynamic averaging of the spatial mobility gradient is adopted. The nature of film thickness effects on the spatial profiles of the alpha relaxation time and elastic modulus is studied under non-isothermal conditions and contrasted with the corresponding isothermal behavior. Modest differences are found if a film-thickness dependent Tg is defined in a dynamical manner. However, adopting a pseudo-thermodynamic measure of Tg leads to a qualitatively new form of the alpha relaxation time gradient where highly mobile layers near the film surface coexist with strongly vitrified regions in the film interior. As a consequence, the film-averaged shear modulus can increase with decreasing film thickness, despite the Tg reduction and presence of a mobile surface layer. Such a behavior stands in qualitative contrast to the predicted mechanical softening under isothermal conditions. Spatial gradients of the elastic modulus are studied as a function of temperature, film thickness, probing frequency, and experimental protocol, and a rich behavior is found. PMID- 28571331 TI - Grafted polymer chains suppress nanoparticle diffusion in athermal polymer melts. AB - We measure the center-of-mass diffusion of poly(methyl methacrylate) (PMMA) grafted nanoparticles (NPs) in unentangled to slightly entangled PMMA melts using Rutherford backscattering spectrometry. These grafted NPs diffuse ~100 times slower than predicted by the Stokes-Einstein relation assuming a viscosity equal to bulk PMMA and a hydrodynamic NP size equal to the NP core diameter, 2Rcore = 4.3 nm. This slow NP diffusion is consistent with an increased effective NP size, 2Reff ~ 20 nm, nominally independent of the range of grafting density and matrix molecular weights explored in this study. Comparing these experimental results to a modified Daoud-Cotton scaling estimate for the brush thickness as well as dynamic mean field simulations of polymer-grafted NPs in athermal polymer melts, we find that 2Reff is in quantitative agreement with the size of the NP core plus the extended grafted chains. Our results suggest that grafted polymer chains of moderate molecular weight and grafting density may alter the NP diffusion mechanism in polymer melts, primarily by increasing the NP effective size. PMID- 28571332 TI - Exploring the broadening and the existence of two glass transitions due to competing interfacial effects in thin, supported polymer films. AB - In this report, we use ellipsometry to characterize the glass transition in ultra thin films of poly(2-vinyl pyridine) (P2VP) supported on a silicon substrate. P2VP is known to have attractive substrate interactions, which can increase the Tg of ultra-thin films compared to the bulk value. Here, we use an extended temperature range to show that the glass transition can be extremely broad, indicating that a large gradient of the dynamics exists through the film with slow dynamics near the substrate and enhanced dynamics at the free surface. To observe the effect of these two interfaces on the average thin film dynamics, cooling rate-dependent Tg (CR-Tg) measurements were used to indirectly probe the average relaxation times of the films. We demonstrate that ultra-thin films have lower fragility compared to bulk films, and, when cooled at slow cooling rates (<1 K/min), exhibit extreme broadening of the dynamics (<70 nm) and eventually complete decoupling between the free surface and substrate regions to produce films with two distinct Tg's (<16 nm). Tg,high increases with decreasing thickness in a similar manner to what has been observed in previous studies on P2VP, and Tg,low decreases with decreasing film thickness in a similar manner to what has been observed in polymer films with enhanced free surfaces and neutral substrate interactions. These observations indicate that the dynamics in thin films of P2VP can be strongly coupled over a length scale of ~10-20 nm, resulting in two co-existing layers with two distinct glass transitions when the range of the dynamical gradients become too large to sustain (breadth of the transition > 50 K). PMID- 28571333 TI - Focus: Structure and dynamics of the interfacial layer in polymer nanocomposites with attractive interactions. AB - In recent years it has become clear that the interfacial layer formed around nanoparticles in polymer nanocomposites (PNCs) is critical for controlling their macroscopic properties. The interfacial layer occupies a significant volume fraction of the polymer matrix in PNCs and creates strong intrinsic heterogeneity in their structure and dynamics. Here, we focus on analysis of the structure and dynamics of the interfacial region in model PNCs with well-dispersed, spherical nanoparticles with attractive interactions. First, we discuss several experimental techniques that provide structural and dynamic information on the interfacial region in PNCs. Then, we discuss the role of various microscopic parameters in controlling structure and dynamics of the interfacial layer. The analysis presented emphasizes the importance of the polymer-nanoparticle interactions for the slowing down dynamics in the interfacial region, while the thickness of the interfacial layer appears to be dependent on chain rigidity, and has been shown to increase with cooling upon approaching the glass transition. Aside from chain rigidity and polymer-nanoparticle interactions, the interfacial layer properties are also affected by the molecular weight of the polymer and the size of the nanoparticles. In the final part of this focus article, we emphasize the important challenges in the field of polymer nanocomposites and a potential analogy with the behavior observed in thin films. PMID- 28571334 TI - A simple model for electrical charge in globular macromolecules and linear polyelectrolytes in solution. AB - We present a model for calculating the net and effective electrical charge of globular macromolecules and linear polyelectrolytes such as proteins and DNA, given the concentration of monovalent salt and pH in solution. The calculation is based on a numerical solution of the non-linear Poisson-Boltzmann equation using a finite element discretized continuum approach. The model simultaneously addresses the phenomena of charge regulation and renormalization, both of which underpin the electrostatics of biomolecules in solution. We show that while charge regulation addresses the true electrical charge of a molecule arising from the acid-base equilibria of its ionizable groups, charge renormalization finds relevance in the context of a molecule's interaction with another charged entity. Writing this electrostatic interaction free energy in terms of a local electrical potential, we obtain an "interaction charge" for the molecule which we demonstrate agrees closely with the "effective charge" discussed in charge renormalization and counterion-condensation theories. The predictions of this model agree well with direct high-precision measurements of effective electrical charge of polyelectrolytes such as nucleic acids and disordered proteins in solution, without tunable parameters. Including the effective interior dielectric constant for compactly folded molecules as a tunable parameter, the model captures measurements of effective charge as well as published trends of pKa shifts in globular proteins. Our results suggest a straightforward general framework to model electrostatics in biomolecules in solution. In offering a platform that directly links theory and experiment, these calculations could foster a systematic understanding of the interrelationship between molecular 3D structure and conformation, electrical charge and electrostatic interactions in solution. The model could find particular relevance in situations where molecular crystal structures are not available or rapid, reliable predictions are desired. PMID- 28571335 TI - How thermal stress alters the confinement of polymers vitrificated in nanopores. AB - Understanding and controlling the glass transition temperature (Tg) and dynamics of polymers in confined geometries are of significance in both academia and industry. Here, we investigate how the thermal stress induced by a mismatch in the coefficient of thermal expansion affects the Tg behavior of polystyrene (PS) nanorods located inside cylindrical alumina nanopores. The size effects and molecular weight dependence of the Tg are also studied. A multi-step relaxation process was employed to study the relationship between thermal stress and cooling rate. At fast cooling rates, the imparted thermal stress would overcome the yield stress of PS and peel chains off the pore walls, while at slow cooling rates, chains are kept in contact with the pore walls due to timely dissipation of the produced thermal stress during vitrification. In smaller nanopores, more PS chains closely contact with pore walls, then stronger internal thermal stress would be generated between core and shell of PS nanorod, which results in a larger deviation between two Tgs. The core part of PS shows lower Tg than bulk value, which can induce faster dynamics in the center region. A complex and important role stress plays is supposed in complex confinement condition, e.g., in nanopores, during vitrification. PMID- 28571336 TI - Resolving dispersion and induction components for polarisable molecular simulations of ionic liquids. AB - One important development in interaction potential models, or atomistic force fields, for molecular simulation is the inclusion of explicit polarisation, which represents the induction effects of charged or polar molecules on polarisable electron clouds. Polarisation can be included through fluctuating charges, induced multipoles, or Drude dipoles. This work uses Drude dipoles and is focused on room-temperature ionic liquids, for which fixed-charge models predict too slow dynamics. The aim of this study is to devise a strategy to adapt existing non polarisable force fields upon addition of polarisation, because induction was already contained to an extent, implicitly, due to parametrisation against empirical data. Therefore, a fraction of the van der Waals interaction energy should be subtracted so that the Lennard-Jones terms only account for dispersion and the Drude dipoles for induction. Symmetry-adapted perturbation theory is used to resolve the dispersion and induction terms in dimers and to calculate scaling factors to reduce the Lennard-Jones terms from the non-polarisable model. Simply adding Drude dipoles to an existing fixed-charge model already improves the prediction of transport properties, increasing diffusion coefficients, and lowering the viscosity. Scaling down the Lennard-Jones terms leads to still faster dynamics and densities that match experiment extremely well. The concept developed here improves the overall prediction of density and transport properties and can be adapted to other models and systems. In terms of microscopic structure of the ionic liquids, the inclusion of polarisation and the down-scaling of Lennard-Jones terms affect only slightly the ordering of the first shell of counterions, leading to small decreases in coordination numbers. Remarkably, the effect of polarisation is major beyond first neighbours, significantly weakening spatial correlations, a structural effect that is certainly related to the faster dynamics of polarisable models. PMID- 28571337 TI - Irradiation- vs. vitrification-induced disordering: The case of ??-quartz and glassy silica. AB - Irradiation and vitrification can both result in the disordering of minerals. However, it remains unclear whether these effects are comparable or if the glassy state represents an upper limit for irradiation-induced disordering. By reactive molecular dynamics simulations, we compare the structure of irradiated quartz to that of glassy silica. We show that although they share some degree of similarity, the structure of irradiated quartz and glassy silica differs from each other, both at the short- (<3 A) and the medium-range (>3 A and <10 A). In particular, the atomic network of irradiated quartz is found to comprise coordination defects, edge-sharing units, and large rings, which are absent from glassy silica. These results highlight the different nature of irradiation- and vitrification-induced disordering. PMID- 28571338 TI - Adsorption of atmospheric gases on cementite 010 surfaces. AB - We study the adsorption of a series of small molecules on the nonstoichiometric {010} surface of cementite (theta-Fe3C) by means of first-principles calculations. We find that CO, N2, H2O, and CH4 prefer to adsorb over iron atoms in an atop configuration. O2, CO2, and the OH radical prefer a configuration bridging two iron atoms and CH2O adsorbs in a configuration bridging a surface iron atom and a surface carbon atom. Adsorption energies are small for H2, CO2, and CH4, indicating a physisorption process, while those for CO, CH2O and especially for O2 and the OH radical are large, indicating a strong chemisorption process. H2O and N2 display adsorption energies between these two extremes, indicating moderate chemisorption. The dissociation of H2, CH2O, the OH radical, and O2 is favoured on this surface. Comparison with adsorption on Fe{100} surfaces indicates that most of these gases have similar adsorption energies on both surfaces, with the exception of CO and the OH radical. In addition, we find similarities between the reactivities of cementite and Mo2C surfaces, due to the similar covalent character of both carbides. PMID- 28571339 TI - Unexpected impact of irreversible adsorption on thermal expansion: Adsorbed layers are not that dead. AB - We investigated the impact of irreversible adsorption on the mechanisms of thermal expansion of 1D confined polymer layers. For spincoated films (polystyrene on aluminum) of constant thickness, the thermal expansion coefficient of the melt drops upon annealing following the kinetics of irreversible adsorption of the chains onto the supporting substrate, while the thermal expansion of the glass is annealing invariant. These perturbations are explained in terms of the reduction in free volume content, upon immobilization of monomers onto the substrate. To shed more light on this phenomenon, we performed an extensive investigation of the thermal expansion of irreversibly adsorbed layers of polystyrene on silicon oxide. We verified that, contrarily to recent speculations, these films cannot be modeled as dead layers - immobilized slabs lacking of segmental relaxation. On the contrary, thin adsorbed layers show an increase in thermal expansion with respect to the bulk, due to packing frustration. Immobilization plays a role only when the thickness of the adsorbed layers overcomes ~10 nm. Finally, we show that for adsorbed layers the difference in thermal expansion between the melt and the glass is sufficiently high to investigate the glass transition down to 3 nm. Owing to this unique feature, not shared by spincoated films, adsorbed layers are the perfect candidate to study the properties of extremely thin polymer films. PMID- 28571340 TI - A transformation theory of stochastic evolution in Red Moon methodology to time evolution of chemical reaction process in the full atomistic system. AB - Atomistic information of a whole chemical reaction system, e.g., instantaneous microscopic molecular structures and orientations, offers important and deeper insight into clearly understanding unknown chemical phenomena. In accordance with the progress of a number of simultaneous chemical reactions, the Red Moon method (a hybrid Monte Carlo/molecular dynamics reaction method) is capable of simulating atomistically the chemical reaction process from an initial state to the final one of complex chemical reaction systems. In the present study, we have proposed a transformation theory to interpret the chemical reaction process of the Red Moon methodology as the time evolution process in harmony with the chemical kinetics. For the demonstration of the theory, we have chosen the gas reaction system in which the reversible second-order reaction H2 + I2 ? 2HI occurs. First, the chemical reaction process was simulated from the initial configurational arrangement containing a number of H2 and I2 molecules, each at 300 K, 500 K, and 700 K. To reproduce the chemical equilibrium for the system, the collision frequencies for the reactions were taken into consideration in the theoretical treatment. As a result, the calculated equilibrium concentrations [H2]eq and equilibrium constants Keq at all the temperatures were in good agreement with their corresponding experimental values. Further, we applied the theoretical treatment for the time transformation to the system and have shown that the calculated half-life tau's of [H2] reproduce very well the analytical ones at all the temperatures. It is, therefore, concluded that the application of the present theoretical treatment with the Red Moon method makes it possible to analyze reasonably the time evolution of complex chemical reaction systems to chemical equilibrium at the atomistic level. PMID- 28571341 TI - Molecular dynamics simulation of the capillary leveling of viscoelastic polymer films. AB - Surface tension-driven flow techniques have recently emerged as an efficient means of shedding light into the rheology of thin polymer films. Motivated by experimental and theoretical approaches in films bearing a varying surface topography, we present results on the capillary relaxation of a square pattern at the free surface of a viscoelastic polymer film, using molecular dynamics simulations of a coarse-grained polymer model. Height profiles are monitored as a function of time after heating the system above its glass-transition temperature and their time dependence is fitted to the theory of capillary leveling. Results show that the viscosity is not constant, but time dependent. In addition to providing a complementary insight about the local inner mechanisms, our simulations of the capillary-leveling process therefore probe the viscoelasticity of the polymer and not only its viscosity, in contrast to most experimental approaches. PMID- 28571342 TI - Dewetting and spreading transitions for active matter on random pinning substrates. AB - We show that sterically interacting self-propelled disks in the presence of random pinning substrates exhibit transitions among a variety of different states. In particular, from a phase separated cluster state, the disks can spread out and homogeneously cover the substrate in what can be viewed as an example of an active matter wetting transition. We map the location of this transition as a function of activity, disk density, and substrate strength, and we also identify other phases including a cluster state, coexistence between a cluster and a labyrinth wetted phase, and a pinned liquid. Convenient measures of these phases include the cluster size, which dips at the wetting-dewetting transition, and the fraction of sixfold coordinated particles, which drops when dewetting occurs. PMID- 28571343 TI - Spherical harmonics based descriptor for neural network potentials: Structure and dynamics of Au147 nanocluster. AB - We propose a highly efficient method for fitting the potential energy surface of a nanocluster using a spherical harmonics based descriptor integrated with an artificial neural network. Our method achieves the accuracy of quantum mechanics and speed of empirical potentials. For large sized gold clusters (Au147), the computational time for accurate calculation of energy and forces is about 1.7 s, which is faster by several orders of magnitude compared to density functional theory (DFT). This method is used to perform the global minimum optimizations and molecular dynamics simulations for Au147, and it is found that its global minimum is not an icosahedron. The isomer that can be regarded as the global minimum is found to be 4 eV lower in energy than the icosahedron and is confirmed from DFT. The geometry of the obtained global minimum contains 105 atoms on the surface and 42 atoms in the core. A brief study on the fluxionality in Au147 is performed, and it is concluded that Au147 has a dynamic surface, thus opening a new window for studying its reaction dynamics. PMID- 28571344 TI - Polymer and spherical nanoparticle diffusion in nanocomposites. AB - Nanoparticle and polymer dynamics in nanocomposites containing spherical nanoparticles were investigated by means of molecular dynamics simulations. We show that the polymer diffusivity decreases with nanoparticle loading due to an increase of the interfacial area created by nanoparticles, in the polymer matrix. We show that small sized nanoparticles can diffuse much faster than that predicted from the Stokes-Einstein relation in the dilute regime. We show that the nanoparticle diffusivity decreases at higher nanoparticle loading due to nanoparticle-polymer interface. Increase of the nanoparticle radius slows the nanoparticle diffusion. PMID- 28571345 TI - Using deposition rate to increase the thermal and kinetic stability of vapor deposited hole transport layer glasses via a simple sublimation apparatus. AB - Deposition rate is known to affect the relative stability of vapor-deposited glasses; slower rates give more stable materials due to enhanced mobility at the free surface of the film. Here we show that the deposition rate can affect both the thermodynamic and kinetic stabilities of N,N'-bis(3-methylphenyl)-N,N' diphenylbenzidine (TPD) and N,N'-di-[(1-naphthyl)-N,N'-diphenyl]-1,1'-biphenyl) 4,4'-diamine (NPD) glasses used as hole transport layers for organic light emitting diodes (OLEDs). A simple, low-vacuum glass sublimation apparatus and a high vacuum deposition chamber were used to deposit the glass. 50 MUm thick films were deposited in the sublimation apparatus and characterized by differential scanning calorimetry while 75 nm thick films were prepared in the high vacuum chamber and studied by hot-stage spectroscopic ellipsometry (SE). The thermodynamic stability from both preparation chambers was consistent and showed that the fictive temperature (Tfictive) was more than 30 K lower than the conventional glass transition temperature (Tg) at the slowest deposition rates. The kinetic stability, measured as the onset temperature (Tonset) where the glass begins to transform into the supercooled liquid, was 16-17 K greater than Tg at the slowest rates. Tonset was systematically lower for the thin films characterized by SE and was attributed to the thickness dependent transformation of the glass into the supercooled liquid. These results show the first calorimetric characterization of the stability of glasses for OLED applications made by vapor deposition and the first direct comparison of deposition apparatuses as a function of the deposition rate. The ease of fabrication will create an opportunity for others to study the effect of deposition conditions on glass stability. PMID- 28571346 TI - Descriptors for predicting the lattice constant of body centered cubic crystal. AB - The prediction of the lattice constant of binary body centered cubic crystals is performed in terms of first principle calculations and machine learning. In particular, 1541 binary body centered cubic crystals are calculated using density functional theory. Results from first principle calculations, corresponding information from periodic table, and mathematically tailored data are stored as a dataset. Data mining reveals seven descriptors which are key to determining the lattice constant where the contribution of descriptors is also discussed and visualized. Support vector regression (SVR) technique is implemented to train the data where the predicted lattice constants have the mean score of 83.6% accuracy via cross-validation and maximum error of 4% when compared to experimentally determined lattice constants. In addition, trained SVR is successful in predicting material combinations from a desired lattice constant. Thus, a set of descriptors for determining the lattice constant is identified and can be used as a base descriptor for lattice constants of further complex crystals. This would allow for the acceleration of the search for lattice constants of desired atomic compositions as well as the prediction of new materials based on a specified lattice constant. PMID- 28571347 TI - Interfacial interaction and glassy dynamics in stacked thin films of poly(methyl methacrylate). AB - Neutron reflectivity and dielectric permittivity of alternately stacked thin films of protonated and deuterated poly(methyl methacrylate) were measured to elucidate a correlation between the time evolution of the interfacial structure and the segmental dynamics in the stacked thin polymer films during isothermal annealing above the glass transition temperature. The roughness at the interface between two thin layers increases with the annealing time, whereas the relaxation rate and strength of the alpha-process decrease with an increase in the annealing time. A strong correlation between the time evolution of the interfacial structure and the dynamics of the alpha-process during annealing could be observed using neutron reflectivity and dielectric relaxation measurements. PMID- 28571348 TI - An intertwined method for making low-rank, sum-of-product basis functions that makes it possible to compute vibrational spectra of molecules with more than 10 atoms. AB - We propose a method for solving the vibrational Schrodinger equation with which one can compute spectra for molecules with more than ten atoms. It uses sum-of product (SOP) basis functions stored in a canonical polyadic tensor format and generated by evaluating matrix-vector products. By doing a sequence of partial optimizations, in each of which the factors in a SOP basis function for a single coordinate are optimized, the rank of the basis functions is reduced as matrix vector products are computed. This is better than using an alternating least squares method to reduce the rank, as is done in the reduced-rank block power method. Partial optimization is better because it speeds up the calculation by about an order of magnitude and allows one to significantly reduce the memory cost. We demonstrate the effectiveness of the new method by computing vibrational spectra of two molecules, ethylene oxide (C2H4O) and cyclopentadiene (C5H6), with 7 and 11 atoms, respectively. PMID- 28571350 TI - Dynamical heterogeneity in a vapor-deposited polymer glass. AB - Recently, there has been great interest in "ultrastable" glasses formed via vapor deposition, both because of emerging engineering applications of these materials (e.g., active layers in light-emitting diodes and photovoltaics) and, theoretically, as materials for probing the equilibrium properties of glassy materials below their glass transition, based on the conjecture that these materials are equivalent to glassy materials aged over astronomical time scales. We use molecular dynamics simulations to examine the properties of ultrastable vapor-deposited and ordinary polymer glasses. Based on the difference in the energy of the deposited and ordinary films, we estimate the effective cooling rate for the vapor deposited films to be 1 to 3 orders of magnitude larger than that of the ordinary film, depending on the deposition temperature. Similarly, we find an increase in the average segmental relaxation time of the vapor-deposited film compared to the ordinary glass. On the other hand, the normal mode spectrum is essentially identical for the vapor-deposited and the ordinary glass film, suggesting that the high-frequency dynamics should be similar. In short, the segmental relaxation dynamics of the polymer vapor-deposited glass are consistent with those of an ordinary polymer glass with a somewhat slower effective cooling rate. Of course, one would expect a larger effect on dynamics approaching the experimental glass transition, where the cooling rates are much slower than accessible in simulation. To more precisely probe the relationship between the dynamics of these glasses, we examine dynamical heterogeneity within the film. Due to the substantial mobility gradient in the glassy films, we find that it is crucial to distinguish the dynamics of the middle part of the film from those of the entire film. Considering the film as a whole, the average dynamical heterogeneity is dominated by the mobility gradient, and as a consequence the heterogeneity is nearly indistinguishable between the ordinary and vapor deposited glass films. In contrast, in the middle part of the film, where there is almost no mobility gradient, we find the dynamical heterogeneity within the deposited film is somewhat larger than that of the ordinary film at the same temperature. We further show that the scale of the interfacial region grows on cooling in the equilibrium film, but this trend reverses in the glass state. We attribute this reversal in part to a shrinking ratio of the relaxation time in the middle of the film to that of the interfacial layer in the non-equilibrium state. The dynamics in this mobile interfacial layer for the ordinary and deposited film are nearly the same, suggesting that the interfacial region is always in a near-equilibrium state. These results emphasize the importance of distinguishing between interfacial and internal relaxation processes in this emerging class of materials. PMID- 28571349 TI - Asymmetric osmotic water permeation through a vesicle membrane. AB - Understanding the water permeation through a cell membrane is of primary importance for biological activities and a key step to capture its shape transformation in salt solution. In this work, we reveal the dynamical behaviors of osmotically driven transport of water molecules across a vesicle membrane by molecular dynamics simulations. Of particular interest is that the water transport in and out of vesicles is highly distinguishable given the osmotic force are the same, suggesting an asymmetric osmotic transportation. This asymmetric phenomenon exists in a broad range of parameter space such as the salt concentration, temperature, and vesicle size and can be ascribed to the similar asymmetric potential energy of lipid-ion, lipid-water, lipid-solution, lipid lipid, and the lipid-lipid energy fluctuation. Specifically, the water flux has a linear increase with the salt concentration, similar to the prediction by Nernst Planck equation or Fick's first law. Furthermore, due to the Arrhenius relation between the membrane permeability and temperature, the water flux also exhibits excellent Arrhenius dependence on the temperature. Meanwhile, the water flux shows a linear increase with the vesicle surface area since the flux amount across a unit membrane area should be a constant. Finally, we also present the anonymous diffusion behaviors for the vesicle itself, where transitions from normal diffusion at short times to subdiffusion at long times are identified. Our results provide significant new physical insights for the osmotic water permeation through a vesicle membrane and are helpful for future experimental studies. PMID- 28571351 TI - A coarse-grain molecular dynamics study of oil-water interfaces in the presence of silica nanoparticles and nonionic surfactants. AB - In this work, we have studied the effect of hydrophilic silica nanoparticles (NPs), in the presence of nonionic surfactants (Triethylene glycol monododecyl ether and Tween 20), on the oil-water (n-octane-water, n-dodecane-water and n hexadecane-water) interfacial tensions (IFTs) at 300 K, using coarse-grained molecular dynamics simulations based on the MARTINI force field. Simulation results indicate that silica NPs solely do not affect the IFT. However, the silica NPs may or may not increase the IFT of oil-water containing nonionic surfactant, depending on the tendency of the surfactant to adsorb on the surface of NPs. The adsorption occurs due to the formation of hydrogen bonds, and adsorption increases with a decrease in pH, as seen in experimental studies. In this work, we found that the oil-water IFT increases with an increasing amount of adsorption of the surfactant on NPs. At a fixed amount of adsorption of the surfactant on NPs, the IFT behavior is indifferent to the change in concentration of NPs. However, the IFT decreases with an increase in surfactant concentration. We present a detailed analysis of the density profile and intrinsic width of the interface. The IFT behavior is found to correlate extremely well with the intrinsic width of the interface. The current study provides an explanation for the increase in IFT observed in a recent experiment [N. R. Biswal et al., J. Phys. Chem. B 120, 7265-7274 (2016)] for various types of NPs and nonionic surfactant systems. PMID- 28571352 TI - Polymer dynamics under cylindrical confinement featuring a locally repulsive surface: A quasielastic neutron scattering study. AB - We investigated the effect of intermediate cylindrical confinement with locally repulsive walls on the segmental and entanglement dynamics of a polymer melt by quasielastic neutron scattering. As a reference, the corresponding polymer melt was measured under identical conditions. The locally repulsive confinement was realized by hydrophilic anodic alumina nanopores with a diameter of 20 nm. The end-to-end distance of the hydrophobic infiltrated polyethylene-alt-propylene was close to this diameter. In the case of hard wall repulsion with negligible local attraction, several simulations predicted an acceleration of segmental dynamics close to the wall. Other than in attractive or neutral systems, where the segmental dynamics is slowed down, we found that the segmental dynamics in the nanopores is identical to the local mobility in the bulk. Even under very careful scrutiny, we could not find any acceleration of the surface-near segmental motion. On the larger time scale, the neutron spin-echo experiment showed that the Rouse relaxation was not altered by confinement effects. Also the entanglement dynamics was not affected. Thus at moderate confinement conditions, facilitated by locally repulsive walls, the dynamics remains as in the bulk melt, a result that is not so clear from simulations. PMID- 28571353 TI - The boomerang effect in electron-hydrogen molecule scattering as determined by time-dependent calculations. AB - The appearance of oscillations in the energy-dependent cross sections of the vibrational excitation nu=0->nu>=3 of the hydrogen molecule in its electronic ground state as predicted by Mundel, Berman, and Domcke [Phys. Rev. A 32, 181 (1985)] was confirmed in the electron scattering experiments by Allan [J. Phys. B: At. Mol. Phys. 18, L451 (1985)]. These unusual structures were obtained in spite of the extremely short lifetime of H2- in its ro-vibrational states. Based on the standard (Hermitian) time-independent scattering calculations, Horacek et al. [Phys. Rev. A 73, 022701 (2006)] associated these oscillations with the boomerang effect. Here, we show the boomerang effect as developed in time, based on our time-dependent nuclear wavepacket (WP) calculations. The nuclear WP dynamics of H2- is determined using the non-Hermitian quantum mechanics (NH-QM) which enables the use of the Born-Oppenheimer approximation with complex potential energy surfaces. This NH-QM approach, which enables us the association of the nuclear WP dynamics as obtained from the complex potential energy curve of H2- with the evolution of cross section in time, can enlighten the dynamics in other scattering experiments. PMID- 28571354 TI - Efficient evaluation of three-center Coulomb integrals. AB - In this study we pursue the most efficient paths for the evaluation of three center electron repulsion integrals (ERIs) over solid harmonic Gaussian functions of various angular momenta. First, the adaptation of the well-established techniques developed for four-center ERIs, such as the Obara-Saika, McMurchie Davidson, Gill-Head-Gordon-Pople, and Rys quadrature schemes, and the combinations thereof for three-center ERIs is discussed. Several algorithmic aspects, such as the order of the various operations and primitive loops as well as prescreening strategies, are analyzed. Second, the number of floating point operations (FLOPs) is estimated for the various algorithms derived, and based on these results the most promising ones are selected. We report the efficient implementation of the latter algorithms invoking automated programming techniques and also evaluate their practical performance. We conclude that the simplified Obara-Saika scheme of Ahlrichs is the most cost-effective one in the majority of cases, but the modified Gill-Head-Gordon-Pople and Rys algorithms proposed herein are preferred for particular shell triplets. Our numerical experiments also show that even though the solid harmonic transformation and the horizontal recurrence require significantly fewer FLOPs if performed at the contracted level, this approach does not improve the efficiency in practical cases. Instead, it is more advantageous to carry out these operations at the primitive level, which allows for more efficient integral prescreening and memory layout. PMID- 28571355 TI - The glass transition temperature of thin films: A molecular dynamics study for a bead-spring model. AB - Molecular dynamics simulations were carried out on free-standing liquid films of different thicknesses h using a bead-spring model of 10 beads per chain. The glass transition temperatures, Tg, of the various films were determined from plots of the internal energy versus temperature. We used these simulations to test the validity of our earlier conjecture that the glass transition of a confined liquid could be approximated by pre-averaging over the non-uniform density profile of the film. Using the density profiles from our simulations, we computed the average density of the free-standing films as a function of temperature. In all our film simulations we found, within the error of the simulation, that Tg of the film occurred at the same density (or packing fraction) as the bulk system at the bulk glass transition temperature TgB. By equating these densities at their respective glass transition temperatures, as suggested by the simulations, we deduced that Tg/TgB is proportional to h0/h. This is consistent with previous simulations and experimental data. Moreover, the parameter h0 is determinable in our model from the density profile of the films. PMID- 28571356 TI - Double photoionization of tropone and cyclooctatetraene. AB - We have studied the double-photoionization process of tropone (C7H6O) and cyclooctatetraene (C8H8) as a function of photon energy using monochromatized synchrotron radiation between 18 and 270 eV. We compare our results with previously published data for partially deuterated benzene (C6H3D3), which exhibits three distinct features in the ratio of doubly to singly charged parent ions, whereas pyrrole (C4H4N) exhibits only two of these features. The question that we address in this paper is how molecules with different molecular structures (pentagonal, hexagonal, heptagonal, and octagonal carbon rings) affect the photon-energy dependence of this ratio. PMID- 28571357 TI - Preface: Special Topic on Dynamics of Polymer Materials in Thin Films and Related Geometries. AB - The last twenty years have seen a substantial effort to understand relaxation, mechanics, diffusion, and the glass transition in thin polymer films and related geometries. Recent progress in this field is highlighted in this special issue of The Journal of Chemical Physics on "Dynamics of Polymer Materials in Thin Films and Related Geometries." With the goal of providing an entry point to these 35 papers for those not working in this field, we provide some background and perspective in this introduction to the special topic section. PMID- 28571358 TI - Complex nonequilibrium dynamics of stacked polystyrene films deep in the glassy state. AB - We investigate the kinetics of enthalpy recovery in stacked glassy polystyrene (PS) films with thickness from 30 to 95 nm over a wide temperature range below the glass transition temperature (Tg). We show that the time evolution toward equilibrium exhibits two mechanisms of recovery, in ways analogous to bulk PS. The fast mechanism, allowing partial enthalpy recovery toward equilibrium, displays Arrhenius temperature dependence with low activation energy, whereas the slow mechanism follows pronounced super-Arrhenius temperature dependence. In comparison to bulk PS, the time scales of the two mechanisms of recovery are considerably shorter and decreasing with the film thickness. Scaling of the equilibration times at various thicknesses indicates that the fast mechanism of recovery is compatible with the free volume holes diffusion model. Conversely, the slow mechanism of recovery appears to be accelerated with decreasing thickness more than predicted by the model and, therefore, its description requires additional ingredients. The implications, from both a fundamental and technological viewpoint, of the ability of thin polymer films to densify in relatively short time scales are discussed. PMID- 28571359 TI - Side-group size effects on interfaces and glass formation in supported polymer thin films. AB - Recent studies on glass-forming polymers near interfaces have emphasized the importance of molecular features such as chain stiffness, side-groups, molecular packing, and associated changes in fragility as key factors that govern the magnitude of Tg changes with respect to the bulk in polymer thin films. However, how such molecular features are coupled with substrate and free surface effects on Tg in thin films remains to be fully understood. Here, we employ a chemically specific coarse-grained polymer model for methacrylates to investigate the role of side-group volume on glass formation in bulk polymers and supported thin films. Our results show that bulkier side-groups lead to higher bulk Tg and fragility and are associated with a pronounced free surface effect on overall Tg depression. By probing local Tg within the films, however, we find that the polymers with bulkier side-groups experience a reduced confinement-induced increase in local Tg near a strongly interacting substrate. Further analyses indicate that this is due to the packing frustration of chains near the substrate interface, which lowers the attractive interactions with the substrate and thus lessens the surface-induced reduction in segmental mobility. Our results reveal that the size of the polymer side-group may be a design element that controls the confinement effects induced by the free surface and substrates in supported polymer thin films. Our analyses provide new insights into the factors governing polymer dynamics in bulk and confined environments. PMID- 28571360 TI - Interfacial and topological effects on the glass transition in free-standing polystyrene films. AB - United-atom molecular-dynamics computer simulations of atactic polystyrene (PS) were performed for the bulk and free-standing films of 2 nm-20 nm thickness, for both linear and cyclic polymers comprised of 80 monomers. Simulated volumetric glass-transition temperatures (Tg) show a strong dependence on the film thickness below 10 nm. The glass-transition temperature of linear PS is 13% lower than that of the bulk for 2.5 nm-thick films, as compared to less than 1% lower for 20 nm films. Our studies reveal that the fraction of the chain-end groups is larger in the interfacial layer with its outermost region approximately 1 nm below the surface than it is in the bulk. The enhanced population of the end groups is expected to result in a more mobile interfacial layer and the consequent dependence of Tg on the film thickness. In addition, the simulations show an enrichment of backbone aliphatic carbons and concomitant deficit of phenyl aromatic carbons in the interfacial film layer. This deficit would weaken the strong phenyl-phenyl aromatic (pi-pi) interactions and, hence, lead to a lower film-averaged Tg in thin films, as compared to the bulk sample. To investigate the relative importance of the two possible mechanisms (increased chain ends at the surface or weakened pi-pi interactions in the interfacial region), the data for linear PS are compared with those for cyclic PS. For the cyclic PS, the reduction of the glass-transition temperature is also significant in thin films, albeit not as much as for linear PS. Moreover, the deficit of phenyl carbons in the film interface is comparable to that observed for linear PS. Therefore, chain end effects alone cannot explain the observed pronounced Tg dependence on the thickness of thin PS films; the weakened phenyl-phenyl interactions in the interfacial region seems to be an important cause as well. PMID- 28571361 TI - Relaxation processes and glass transition of confined polymer melts: A molecular dynamics simulation of 1,4-polybutadiene between graphite walls. AB - Molecular dynamics simulations of a chemically realistic model for 1,4 polybutadiene in a thin film geometry confined by two graphite walls are presented. Previous work on melts in the bulk has shown that the model faithfully reproduces static and dynamic properties of the real material over a wide temperature range. The present work studies how these properties change due to nano-confinement. The focus is on orientational correlations observable in nuclear magnetic resonance experiments and on the local intermediate incoherent neutron scattering function, Fs(qz, z, t), for distances z from the graphite walls in the range of a few nanometers. Temperatures from about 2Tg down to about 1.15Tg, where Tg is the glass transition temperature in the bulk, are studied. It is shown that weakly attractive forces between the wall atoms and the monomers suffice to effectively bind a polymer coil that is near the wall. For a wide regime of temperatures, the Arrhenius-like adsorption/desorption kinetics of the monomers is the slowest process, while very close to Tg the Vogel-Fulcher-Tammann like alpha-relaxation takes over. The alpha-process is modified only for z<=1.2 nm due to the density changes near the walls, less than expected from studies of coarse-grained (bead-spring-type) models. The weakness of the surface effects on the glass transition in this case is attributed to the interplay of density changes near the wall with the torsional potential. A brief discussion of pertinent experiments is given. PMID- 28571362 TI - Dissociation cross sections for N2 + N -> 3N and O2 + O -> 3O using the QCT method. AB - Cross sections for the homo-nuclear atom-diatom collision induced dissociations (CIDs): N2 + N and O2 + O are calculated using Quasi-Classical Trajectory (QCT) method on ab initio Potential Energy Surfaces (PESs). A number of studies for these reactions carried out in the past focused on the CID cross section values generated using London-Eyring-Polanyi-Sato PES and seldom listed the CID cross section data. A highly accurate CASSCF-CASPT2 N3 and a new O3 global PES are used for the present QCT analysis and the CID cross section data up to 30 eV relative energy are also published. In addition, an interpolating scheme based on spectroscopic data is introduced that fits the CID cross section for the entire ro-vibrational spectrum using QCT data generated at chosen ro-vibrational levels. The rate coefficients calculated using the generated CID cross section compare satisfactorily with the existing experimental and theoretical results. The CID cross section data generated will find an application in the development of a more precise chemical reaction model for Direct Simulation Monte Carlo code simulating hypersonic re-entry flows. PMID- 28571363 TI - Applying Bogomolny's quantization method to generic classical systems. AB - The quantization method of Bogomolny [Nonlinearity 5, 805 (1992)] can potentially provide semiclassical estimates for energy levels of all bound states of arbitrary systems. This approach requires the formation of the transfer matrix TE as a function of energy E. Existing practical methods for calculating this matrix require a recalculation of many classical trajectories for each energy. This has hampered the application of Bogomolny's method to generic systems that do not possess special classical scaling properties. Generalizing earlier work [H. Barak and K. G. Kay, Phys. Rev. E 88, 062926 (2013)], we develop initial value representation formulas for TE that overcome this problem. These expressions are obtained from a generalized Herman-Kluk formula for the propagator that allows one to easily derive a family of semiclassical integral approximations for the Green's function that are, in turn, used to form the transfer matrix. Calculations for two-dimensional systems show that Bogomolny's method with the present expressions for TE produces accurate semiclassical energy levels from small transfer matrices. PMID- 28571364 TI - Erratum: "Gas phase hyper-Rayleigh scattering measurements" [J. Chem. Phys. 137, 044312 (2012)]. PMID- 28571365 TI - First-principle simulations of electronic structure in semicrystalline polyethylene. AB - In order to increase our fundamental knowledge about high-voltage cable insulation materials, realistic polyethylene (PE) structures, generated with a novel molecular modeling strategy, have been analyzed using first principle electronic structure simulations. The PE structures were constructed by first generating atomistic PE configurations with an off-lattice Monte Carlo method and then equilibrating the structures at the desired temperature and pressure using molecular dynamics simulations. Semicrystalline, fully crystalline and fully amorphous PE, in some cases including crosslinks and short-chain branches, were analyzed. The modeled PE had a structure in agreement with established experimental data. Linear-scaling density functional theory (LS-DFT) was used to examine the electronic structure (e.g., spatial distribution of molecular orbitals, bandgaps and mobility edges) on all the materials, whereas conventional DFT was used to validate the LS-DFT results on small systems. When hybrid functionals were used, the simulated bandgaps were close to the experimental values. The localization of valence and conduction band states was demonstrated. The localized states in the conduction band were primarily found in the free volume (result of gauche conformations) present in the amorphous regions. For branched and crosslinked structures, the localized electronic states closest to the valence band edge were positioned at branches and crosslinks, respectively. At 0 K, the activation energy for transport was lower for holes than for electrons. However, at room temperature, the effective activation energy was very low (~0.1 eV) for both holes and electrons, which indicates that the mobility will be relatively high even below the mobility edges and suggests that charge carriers can be hot carriers above the mobility edges in the presence of a high electrical field. PMID- 28571366 TI - Dynamics of poly(vinyl methyl ketone) thin films studied by local dielectric spectroscopy. AB - Local dielectric spectroscopy, which entails measuring the change in resonance frequency of the conducting tip of an atomic force microscope to determine the complex permittivity of a sample with high spatial (lateral) resolution, was employed to characterize the dynamics of thin films of poly(vinyl methyl ketone) (PVMK) having different substrate and top surface layers. A free surface yields the usual speeding up of the segmental dynamics, corresponding to a glass transition suppression of 6.5 degrees for 18 nm film thickness. This result is unaffected by the presence of a glassy, compatible polymer, poly-4-vinyl phenol (PVPh), between the metal substrate and the PVMK. However, covering the top surface with a thin layer of the PVPh suppresses the dynamics. The speeding up of PVMK segmental motions observed for a free surface is absent due to interfacial interactions of the PVMK with the glass layer, an effect not seen when the top layer is an incompatible polymer. PMID- 28571367 TI - The glass transition and enthalpy recovery of a single polystyrene ultrathin film using Flash DSC. AB - The kinetics of the glass transition are measured for a single polystyrene ultrathin film of 20 nm thickness using Flash differential scanning calorimetry (DSC). Tg is measured over a range of cooling rates from 0.1 to 1000 K/s and is depressed compared to the bulk. The depression decreases with increasing cooling rate, from 12 K lower than the bulk at 0.1 K/s to no significant change at 1000 K/s. Isothermal enthalpy recovery measurements are performed from 50 to 115 degrees C, and from these experiments, the temperature dependence of the induction time along the glass line is obtained, as well as the temperature dependence of the time scale required to reach equilibrium, providing a measure of the shortest effective glassy relaxation time and the longest effective equilibrium relaxation time, respectively. The induction time for the ultrathin film is found to be similar to the bulk at all temperatures presumably because the Tg values are the same due to the use of a cooling rate of 1000 K/s prior to the enthalpy recovery measurements. On the other hand, the times required to reach equilibrium for the ultrathin film and bulk are similar at 100 degrees C, and considerably shorter for the ultrathin film at 90 degrees C, consistent with faster dynamics under nanoconfinement at low temperatures. The magnitude of the "Tg depression" is smaller when using the equilibrium relaxation time from the structural recovery experiment as a measure of the dynamics than when measuring Tg after a cooling experiment. A relaxation map is developed to summarize the results. PMID- 28571368 TI - First principles centroid molecular dynamics simulation of hydride in nanoporous C12A7:H. AB - Hydrides in nanoporous [Ca24Al28O64]4+(H-)4 (C12A7:H-) were investigated via first principles centroid molecular dynamics (CMD). The quality of our CMD simulations was assessed by examining the temperature dependence of the distribution of hydrides in the cages constituting the C12A7 framework. The vibrational states of C12A7:H- were analyzed by using the trajectories of the centroids generated in our CMD simulations. We find that the rattling motions of H- and D- behave qualitatively differently, resulting in non-trivial isotope effects, which are suggested to be detectable by using infrared and Raman spectroscopy. PMID- 28571369 TI - Network confinement and heterogeneity slows nanoparticle diffusion in polymer gels. AB - Nanoparticle (NP) diffusion was measured in polyacrylamide gels (PAGs) with a mesh size comparable to the NP size, 21 nm. The confinement ratio (CR), NP diameter/mesh size, increased from 0.4 to 3.8 by increasing crosslinker density and from 0.4 to 2.1 by adding acetone, which collapsed the PAGs. In all gels, NPs either became localized, moving less than 200 nm, diffused microns, or exhibited a combination of these behaviors, as measured by single particle tracking. Mean squared displacements (MSDs) of mobile NPs decreased as CR increased. In collapsed gels, the localized NP population increased and MSD of mobile NPs decreased compared to crosslinked PAGs. For all CRs, van Hove distributions exhibited non-Gaussian displacements, consistent with intermittent localization of NPs. The non-Gaussian parameter increased from a maximum of 1.5 for crosslinked PAG to 5 for collapsed PAG, consistent with greater network heterogeneity in these gels. Diffusion coefficients decreased exponentially as CR increased for crosslinked gels; however, in collapsed gels, the diffusion coefficients decreased more strongly, which was attributed to network heterogeneity. Collapsing the gel resulted in an increasingly tortuous pathway for NPs, slowing diffusion at a given CR. Understanding how gel structure affects NP mobility will allow the design and enhanced performance of gels that separate and release molecules in membranes and drug delivery platforms. PMID- 28571370 TI - Surface transport mechanisms in molecular glasses probed by the exposure of nano particles. AB - For a glass-forming liquid, the mechanism by which its surface contour evolves can change from bulk viscous flow at high temperatures to surface diffusion at low temperatures. We show that this mechanistic change can be conveniently detected by the exposure of nano-particles native in the material. Despite its high chemical purity, the often-studied molecular glass indomethacin contains low concentration particles approximately 100 nm in size and 0.3% in volume fraction. Similar particles are present in polystyrene, another often-used model. In the surface-diffusion regime, particles are gradually exposed in regions vacated by host molecules, for example, the peak of a surface grating and the depletion zone near a surface crystal. In the viscous-flow regime, particle exposure is not observed. The surface contour around an exposed particle widens over time in a self-similar manner as 3 (Bt)1/4, where B is a surface mobility constant and the same constant obtained by surface grating decay. This work suggests that in a binary system composed of slow- and fast-diffusing molecules, slow-diffusing molecules can be stranded in surface regions vacated by fast-diffusing molecules, effectively leading to phase separation. PMID- 28571371 TI - Publisher's Note: "Perturbative density functional methods for cholesteric liquid crystals" [J. Chem. Phys. 146, 184504 (2017)]. PMID- 28571372 TI - Reactivity of O2 on Pd/Ru(0001) and PdRu/Ru(0001) surface alloys. AB - The reactivity of a Pd monolayer epitaxially grown on Ru(0001) toward O2 has been investigated by molecular beam techniques. O2 initial sticking coefficients were determined using the King and Wells method in the incident energy range of 40-450 meV and for sample temperatures of 100 K and 300 K, and compared to the corresponding values measured on the clean Ru(0001) and Pd(111) surfaces. In contrast to the high reactivity shown by Ru(0001) at 100 K, the Pd/Ru(0001) system exhibits a monotonic decrease in the sticking probability of O2 as a function of normal incident energy. At room temperature, the system was found to be inert. Thermal desorption measurements show that O2 is adsorbed molecularly at 100 K. A completely different behaviour has been measured for the Pd0.95Ru0.05/Ru(0001) surface alloy. On this surface, the O2 sticking probability increases with incident energy and resembles the one observed on the clean Ru(0001) surface, even at 300 K. Thermal desorption measurements point to dissociative adsorption of O2 in this system. Both the charge transfer from the Pd to the Ru substrate and the compressive strain on the Pd monolayer contribute to decrease in the reactivity of the Pd/Ru(0001) system well below those of both Ru(0001) and Pd(111). PMID- 28571373 TI - Excited state gradients for a state-specific continuum solvation approach: The vertical excitation model within a Lagrangian TDDFT formulation. AB - The accurate modeling of the environment response is a fundamental challenge for accurately describing the photophysics and photochemistry of molecules both in solution and in more complex embeddings. When large rearrangements of the electron density occur after an electronic transition, state-specific formulations, such as the vertical excitation model, are necessary to achieve a proper modeling of the processes. Such a state-specific model is fundamental not only to obtain accurate energies, but also to follow the geometrical relaxation accompanying the evolution of the excited-states. This study presents the analytical expression of the gradients of the vertical excitation model approach by a Lagrangian formulation in the time dependent density functional theory framework. Representative organic chromophores in solution are used to test the reliability of the implementation and provide comparisons with the linear response description. PMID- 28571374 TI - The relationship between dynamic and pseudo-thermodynamic measures of the glass transition temperature in nanostructured materials. AB - Despite decades of research on the effects of nanoconfinement on the glass transition temperature Tg, apparent discrepancies between pseudothermodynamic and dynamic measurements of these effects have raised questions regarding the presence of long-ranged interfacial dynamic gradients in glass-forming liquids. Here we show that these differences can be accounted for based on disparities in these methods' weightings over local Tg's within an interfacial gradient. This finding suggests that a majority of experimental data are consistent with a broad interfacial dynamic interphase in glass-forming liquids. PMID- 28571375 TI - Depth-resolved local conformation and thermal relaxation of polystyrene near substrate interface. AB - By means of sum-frequency generation spectroscopy, we report a depth-resolved measurement of the local conformation and chain relaxation of polystyrene (hPS) located at different distances from the quartz interface. To control the distance from the quartz interface, deuterated polystyrene (dPS) layers with thicknesses of 3.4, 7.5, and 20 nm were coated on the quartz substrates. The hPS chains in direct contact with the substrate surface predominantly orient their phenyl rings in a direction normal to the substrate. This conformation was found to be barely relaxed when the film was annealed for 24 h at 423 K, higher than the bulk glass transition temperature. In contrast, for the hPS chains supported on the dPS layer, the orientation of phenyl rings of hPS became weaker with the annealing and this trend was more significant with increasing distance from the quartz substrate. In particular, the orientation of phenyl rings of hPS after annealing vanished at a distance of 20 nm. These results might provide an important evidence of the difference in the relaxation dynamics of the PS chains located at different distances from the quartz interface. PMID- 28571376 TI - Dynamics of ultra-thin polystyrene with and without a (artificial) dead layer studied by resonance enhanced dynamic light scattering. AB - Using non-invasive, marker-free resonance enhanced dynamic light scattering, the dynamics of capillary waves on ultrathin polystyrene films' coupling to the viscoelastic and mechanical properties have been studied. The dynamics of ultrathin polymer films is still debated. In particular the question of what influence either the solid substrate and/or the fluid-gas interface has on the dynamics and the mechanical properties of films of glass forming liquids as polymers is in the focus of the present research. As a consequence, e.g., viscosity close to interfaces and thus the average viscosity of very thin films are prone to change. This study is focused on atactic, non-entangled polystyrene thin films on the gold surface. A slow dynamic mode was observed with Vogel Fulcher-Tammann temperature dependence, slowing down with decreasing film thickness. We tentatively attribute this relaxation mode to overdamped capillary waves because of its temperature dependence and the dispersion with a wave vector which was found. No signs of a more mobile layer at the air/polymer interface or of a "dead layer" at the solid/polymer interface were found. Therefore we investigated the influence of an artificially created dead layer on the capillary wave dynamics by introducing covalently bound polystyrene polymer brushes as anchors. The dynamics was slowed down to a degree more than expected from theoretical work on the increase of density close to the solid liquid interface instead of a "dead layer" of 2 nm, the interaction seems to extend more than 10 nm into the polymer. PMID- 28571377 TI - Reduced-mobility layers with high internal mobility in poly(ethylene oxide) silica nanocomposites. AB - A series of poly(ethylene oxide) nanocomposites with spherical silica was studied by proton NMR spectroscopy, identifying and characterizing reduced-mobility components arising from either room-temperature lateral adsorption or possibly end-group mediated high-temperature bonding to the silica surface. The study complements earlier neutron-scattering results for some of the samples. The estimated thickness of a layer characterized by significant internal mobility resembling backbone rotation ranges from 2 nm for longer (20 k) chains adsorbed on 42 nm diameter particles to 0.5 nm and below for shorter (2 k) chains on 13 nm particles. In the latter case, even lower adsorbed amounts are found when hydroxy endgroups are replaced by methyl endgroups. Both heating and water addition do not lead to significant changes of the observables, in contrast to other systems such as acrylate polymers adsorbed to silica, where temperature- and solvent induced softening associated with a glass transition temperature gradient was evidenced. We highlight the actual agreement and complementarity of NMR and neutron scattering results, with the earlier ambiguities mainly arising from different sensitivities to the component fractions and the details of their mobility. PMID- 28571378 TI - Molecular weight dependence of the intrinsic size effect on Tg in AAO template supported polymer nanorods: A DSC study. AB - Many studies have established a major effect of nanoscale confinement on the glass transition temperature (Tg) of polystyrene (PS), most commonly in thin films with one or two free surfaces. Here, we characterize smaller yet significant intrinsic size effects (in the absence of free surfaces or significant attractive polymer-substrate interactions) on the Tg and fragility of PS. Melt infiltration of various molecular weights (MWs) of PS into anodic aluminum oxide (AAO) templates is used to create nanorods supported on AAO with rod diameter (d) ranging from 24 to 210 nm. The Tg (both as Tg,onset and fictive temperature) and fragility values are characterized by differential scanning calorimetry. No intrinsic size effect is observed for 30 kg/mol PS in template supported nanorods with d = 24 nm. However, effects on Tg are present for PS nanorods with Mn and Mw >= ~175 kg/mol, with effects increasing in magnitude with increasing MW. For example, in 24-nm-diameter template-supported nanorods, Tg, rod - Tg, bulk = -2.0 to -2.5 degrees C for PS with Mn = 175 kg/mol and Mw = 182 kg/mol, and Tg, rod - Tg, bulk = ~-8 degrees C for PS with Mn = 929 kg/mol and Mw = 1420 kg/mol. In general, reductions in Tg occur when d <= ~2Rg, where Rg is the bulk polymer radius of gyration. Thus, intrinsic size effects are significant when the rod diameter is smaller than the diameter (2Rg) associated with the spherical volume pervaded by coils in bulk. We hypothesize that the Tg reduction occurs when chain segment packing frustration is sufficiently perturbed by confinement in the nanorods. This explanation is supported by observed reductions in fragility with the increasing extent of confinement. We also explain why these small intrinsic size effects do not contradict reports that the Tg-confinement effect in supported PS films with one free surface exhibits little or no MW dependence. PMID- 28571379 TI - Limited surface mobility inhibits stable glass formation for 2-ethyl-1-hexanol. AB - Previous work has shown that vapor-deposition can prepare organic glasses with extremely high kinetic stabilities and other properties that would be expected from liquid-cooled glasses only after aging for thousands of years or more. However, recent reports have shown that some molecules form vapor-deposited glasses with only limited kinetic stability when prepared using conditions expected to yield a stable glass. In this work, we vapor deposit glasses of 2 ethyl-1-hexanol over a wide range of deposition rates and test several hypotheses for why this molecule does not form highly stable glasses under normal deposition conditions. The kinetic stability of 2-ethyl-1-hexanol glasses is found to be highly dependent on the deposition rate. For deposition at Tsubstrate = 0.90 Tg, the kinetic stability increases by 3 orders of magnitude (as measured by isothermal transformation times) when the deposition rate is decreased from 0.2 nm/s to 0.005 nm/s. We also find that, for the same preparation time, a vapor deposited glass has much more kinetic stability than an aged liquid-cooled glass. Our results support the hypothesis that the formation of highly stable 2-ethyl-1 hexanol glasses is inhibited by limited surface mobility. We compare our deposition rate experiments to similar ones performed with ethylcyclohexane (which readily forms glasses of high kinetic stability); we estimate that the surface mobility of 2-ethyl-1-hexanol is more than 4 orders of magnitude less than that of ethylcyclohexane at 0.85 Tg. PMID- 28571380 TI - Local glass transition temperature Tg(z) of polystyrene next to different polymers: Hard vs. soft confinement. AB - The depth to which the local glass transition temperature Tg and alpha relaxations are perturbed near a boundary is believed to be related to the characteristic length scales associated with cooperative dynamics in dynamically heterogeneous glasses. Following our recent work [R. R. Baglay and C. R. Roth, J. Chem. Phys. 143, 111101 (2015)] that measured a very broad 350-400 nm local Tg(z) profile across a glassy-rubbery interface of polystyrene (PS)/poly(n-butyl methacrylate) (PnBMA), we compare here how the Tg(z) profile in PS varies when changing the neighboring polymer from a lower Tg material to a higher Tg material. Here we report local Tg(z) profiles for PS when in contact with polysulfone (PSF), poly(methyl methacrylate) (PMMA), and poly(isobutyl methacrylate) (PiBMA). We find that the distance from the interface before bulk Tg of PS (Tgbulk=101 degrees C) is recovered depends on whether PS forms the high-Tg glassy component experiencing so-called soft confinement, z ~ 225-250 nm for PS next to PiBMA (Tgbulk=62 degrees C) and PnBMA (Tgbulk=21 degrees C), or PS forms the low-Tg rubbery component experiencing hard confinement, z ~ 100-125 nm for PS next to PSF (Tgbulk=186 degrees C) and PMMA (Tgbulk=120 degrees C). The depth to which these Tg(z) perturbations persist and the magnitude of the local Tg perturbation at the interface are independent of the difference in Tgbulk between the two polymers, the interaction parameter, and the chemical structure. We demonstrate that these broad, extended Tg(z) length scales appear to be universal across these different systems but show that the strong dynamical coupling across the dissimilar polymer-polymer interface only occurs when this interface has been annealed to equilibrium. We consider why dissimilar polymer polymer interfaces exhibit continuous local dynamics across the interface in contrast to polymer-free surface, polymer-substrate, or polymer-liquid interfaces that show discontinuous local dynamics. PMID- 28571381 TI - Angular distributions for the inelastic scattering of NO(X2Pi) with O2(X3Sigmag ). AB - The inelastic scattering of NO(X2Pi) by O2(X3Sigmag-) was studied at a mean collision energy of 550 cm-1 using velocity-map ion imaging. The initial quantum state of the NO(X2Pi, v = 0, j = 0.5, Omega=0.5, ?? = -1, f) molecule was selected using a hexapole electric field, and specific Lambda-doublet levels of scattered NO were probed using (1+1') resonantly enhanced multiphoton ionization. A modified "onion-peeling" algorithm was employed to extract angular scattering information from the series of "pancaked," nested Newton spheres arising as a consequence of the rotational excitation of the molecular oxygen collision partner. The extracted differential cross sections for NO(X) f->f and f->e Lambda doublet resolved, spin-orbit conserving transitions, partially resolved in the oxygen co-product rotational quantum state, are reported, along with O2 fragment pair-correlated rotational state population. The inelastic scattering of NO with O2 is shown to share many similarities with the scattering of NO(X) with the rare gases. However, subtle differences in the angular distributions between the two collision partners are observed. PMID- 28571382 TI - Complex dynamics of capillary imbibition of poly(ethylene oxide) melts in nanoporous alumina. AB - Capillary penetration of a series of entangled poly(ethylene oxide) melts within nanopores of self-ordered alumina follows an approximate t1/2 behavior according to the Lucas-Washburn equation; t is the time. However, the dependence on the capillary diameter deviates from the predicted proportionality to d1/2; d is the pore diameter. We observed a reversal in the dynamics of capillary rise with polymer molecular weight. Chains with 50 entanglements (Mw <= 100 kg/mol) or less show a slower capillary rise than theoretically predicted as opposed to chains with more entanglements (Mw >= 500 kg/mol) that display a faster capillary rise. Although a faster capillary rise has been predicted by theory and observed experimentally, it is the first time to our knowledge that a slower capillary rise is observed for an entangled polymer melt under conditions of strong confinement (with 2Rg/d = 1). These results are discussed in the light of theoretical predictions for the existence of a critical length scale that depends on the molecular weight and separates the microscopic (d < d*) from the macroscopic (d > d*) regime. PMID- 28571384 TI - Description of poly(ethylenepropylene) confined in nanopores by a modified Rouse model. AB - A recent model for unentangled polymer chains in confinement [M. Dolgushev and M. Krutyeva, Macromol. Theory Simul. 21, 565 (2012)] is scrutinized by small-angle neutron scattering (SANS) with respect to its static prediction, the single-chain structure factor. We find a remarkable agreement although the model simplifies the effect of the confinement to a harmonic potential. The effective confinement size from fits of SANS data with the model agrees well with the actual pore size. Starting from this result we discuss the possibility of an experiment on the dynamic structure factor predicted by the model. It turns out that such an experiment would need a large ratio polymer dimension/pore size which is difficult but not impossible to achieve. PMID- 28571383 TI - An empirical correction for moderate multiple scattering in super-heterodyne light scattering. AB - Frequency domain super-heterodyne laser light scattering is utilized in a low angle integral measurement configuration to determine flow and diffusion in charged sphere suspensions showing moderate to strong multiple scattering. We introduce an empirical correction to subtract the multiple scattering background and isolate the singly scattered light. We demonstrate the excellent feasibility of this simple approach for turbid suspensions of transmittance T >= 0.4. We study the particle concentration dependence of the electro-kinetic mobility in low salt aqueous suspension over an extended concentration regime and observe a maximum at intermediate concentrations. We further use our scheme for measurements of the self-diffusion coefficients in the fluid samples in the absence or presence of shear, as well as in polycrystalline samples during crystallization and coarsening. We discuss the scope and limits of our approach as well as possible future applications. PMID- 28571385 TI - Direction-dependent elastic properties and phononic behavior of PMMA/BaTiO3 nanocomposite thin films. AB - Determination of the anisotropic mechanical properties of nanostructured hybrid films is of great importance to improve fabrication and to enable reliable utility. Here, we employ spontaneous Brillouin light spectroscopy to record the phononic dispersion relation along the two symmetry directions in a supported PMMA (poly(methylmethacrylate))-BaTiO3 hybrid superlattice (SL) with a lattice constant of about 140 nm. Several dispersive elastic modes are resolved for in plane wave propagation, whereas along the periodicity direction the SL opens a wide propagation stop band for hypersonic phonons and near UV photons both centered at about 280 nm. A thorough theoretical analysis based on the finite element method quantitatively captures the band diagrams along the two main symmetry directions, helps identify the large density mismatch effect on the unexpectedly low sound phase velocity, and reveals significant anisotropy of the SL elastic tensor. Phonon propagation is a sensitive index of the structure, density, and the mechanical moduli of nanocomposite films. PMID- 28571386 TI - Glassy dynamics of polymethylphenylsiloxane in one- and two-dimensional nanometric confinement-A comparison. AB - Glassy dynamics of polymethylphenylsiloxane (PMPS) is studied by broadband dielectric spectroscopy in one-dimensional (1D) and two-dimensional (2D) nanometric confinement; the former is realized in thin polymer layers having thicknesses down to 5 nm, and the latter in unidirectional (thickness 50 MUm) nanopores with diameters varying between 4 and 8 nm. Based on the dielectric measurements carried out in a broad spectral range at widely varying temperatures, glassy dynamics is analyzed in detail in 1D and in 2D confinements with the following results: (i) the segmental dynamics (dynamic glass transition) of PMPS in 1D confinement down to thicknesses of 5 nm is identical to the bulk in the mean relaxation rate and the width of the relaxation time distribution function; (ii) additionally a well separated surface induced relaxation is observed, being assigned to adsorption and desorption processes of polymer segments with the solid interface; (iii) in 2D confinement with native inner pore walls, the segmental dynamics shows a confinement effect, i.e., the smaller the pores are, the faster the segmental dynamics; on silanization, this dependence on the pore diameter vanishes, but the mean relaxation rate is still faster than in 1D confinement; (iv) in a 2D confinement, a pronounced surface induced relaxation process is found, the strength of which increases with the decreasing pore diameter; it can be fully removed by silanization of the inner pore walls; (v) the surface induced relaxation depends on its spectral position only negligibly on the pore diameter; (vi) comparing 1D and 2D confinements, the segmental dynamics in the latter is by about two orders of magnitude faster. All these findings can be comprehended by considering the density of the polymer; in 1D it is assumed to be the same as in the bulk, hence the dynamic glass transition is not altered; in 2D it is reduced due to a frustration of packaging resulting in a higher free volume, as proven by ortho-positronium annihilation lifetime spectroscopy. PMID- 28571387 TI - A theoretical study of the dissociative recombination of SH+ with electrons through the 2Pi states of SH. AB - A quantitative theoretical study of the dissociative recombination of SH+ with electrons has been carried out. Multireference, configuration interaction calculations were used to determine accurate potential energy curves for SH+ and SH. The block diagonalization method was used to disentangle strongly interacting SH valence and Rydberg states and to construct a diabatic Hamiltonian whose diagonal matrix elements provide the diabatic potential energy curves. The off diagonal elements are related to the electronic valence-Rydberg couplings. Cross sections and rate coefficients for the dissociative recombination reaction were calculated with a stepwise version of the multichannel quantum defect theory, using the molecular data provided by the block diagonalization method. The calculated rates are compared with the most recent measurements performed on the ion Test Storage Ring (TSR) in Heidelberg, Germany. PMID- 28571388 TI - Molecular dynamics and metadynamics simulations of electrosprayed water nanodroplets including sodium bis(2-ethylhexyl)sulfosuccinate micelles. AB - The behavior of aqueous solutions of sodium bis(2-ethylhexyl)sulfosuccinate (AOTNa) under conditions of electrospray ionization (ESI) has been investigated by molecular dynamics (MD) and well-tempered metadynamics (WTM) simulations at 300 K and 400 K. We have examined water droplets with initial fixed numbers of water molecules (1000) and AOT- anions (100), and with sodium cations in the range of 70-130. At 300 K, all charged droplets show the water evaporation rate increasing with the absolute value of the initial droplet charge state (Z), accompanied by ejection of an increasing number of solvated sodium ions or by expulsion of AOT- anions depending on the sign of Z and by fragmentation in the case of high |Z|. At 400 K, the water evaporation becomes more rapid and the fission process more extensive. In all cases, the AOTNa molecules, arranged as a direct micelle inside the aqueous system, undergo a rapid inversion in vacuo so that the hydrophilic heads and sodium ions surrounded by water molecules move toward the droplet interior. At the end of the 100-ns MD simulations, some water molecules remain within the aggregates at both temperatures. The subsequent metadynamics simulations accelerate the droplet evolution and show that all systems become anhydrous, in agreement with the experimental results of ESI mass spectrometry. This complete water loss is accompanied by sodium counterion emission for positively charged aggregates at 300 K. The analysis shows how the temperature and droplet charge state affect the populations of the generated surfactant aggregates, providing information potentially useful in designing future ESI experimental conditions. PMID- 28571389 TI - On the error in the nucleus-centered multipolar expansion of molecular electron density and its topology: A direct-space computational study. AB - The convergence of nucleus-centered multipolar expansion of the quantum-chemical electron density (QC-ED), gradient, and Laplacian is investigated in terms of numerical radial functions derived by projecting stockholder atoms onto real spherical harmonics at each center. The partial sums of this exact one-center expansion are compared with the corresponding Hansen-Coppens pseudoatom (HC-PA) formalism [Hansen, N. K. and Coppens, P., "Testing aspherical atom refinements on small-molecule data sets," Acta Crystallogr., Sect. A 34, 909-921 (1978)] commonly utilized in experimental electron density studies. It is found that the latter model, due to its inadequate radial part, lacks pointwise convergence and fails to reproduce the local topology of the target QC-ED even at a high-order expansion. The significance of the quantitative agreement often found between HC PA-based (quadrupolar-level) experimental and extended-basis QC-EDs can thus be challenged. PMID- 28571390 TI - Influence of bidisperse self-assembled monolayer structure on the slip boundary condition of thin polymer films. AB - Alkylsilane self-assembled monolayers (SAMs) are often used as model substrates for their ease of preparation and hydrophobic properties. We have observed that these atomically smooth monolayers also provide a slip boundary condition for dewetting films composed of unentangled polymers. This slip length, an indirect measure of the friction between a given liquid and different solids, is switchable and can be increased [R. Fetzer et al., Phys. Rev. Lett. 95, 127801 (2005); O. Baumchen et al., J. Phys.: Condens. Matter 24, 325102 (2012)] if the alkyl chain length is changed from 18 to 12 backbone carbons, for example. Typically, this change in boundary condition is affected in a quantized way, using one or the other alkyl chain length, thus obtaining one or the other slip length. Here, we present results in which this SAM structure is changed in a continuous way. We prepare bidisperse mixed SAMs of alkyl silanes, with the composition as a control parameter. We find that all the mixed SAMs investigated show an enhanced slip boundary condition as compared to the single-component SAMs. The slip boundary condition is accessed using optical and atomic force microscopy, and we describe these observations in the context of X-ray reflectivity measurements. The slip length, varying over nearly two orders of magnitude, of identical polymer melts on chemically similar SAMs is found to correlate with the density of exposed alkyl chains. Our results demonstrate the importance of a well characterized solid/liquid pair, down to the angstrom level, when discussing the friction between a liquid and a solid. PMID- 28571391 TI - Shape and energy consistent pseudopotentials for correlated electron systems. AB - A method is developed for generating pseudopotentials for use in correlated electron calculations. The paradigms of shape and energy consistency are combined and defined in terms of correlated-electron wave-functions. The resulting energy consistent correlated electron pseudopotentials (eCEPPs) are constructed for H, Li-F, Sc-Fe, and Cu. Their accuracy is quantified by comparing the relaxed molecular geometries and dissociation energies which they provide with all electron results, with all quantities evaluated using coupled cluster singles, doubles, and triples calculations. Errors inherent in the pseudopotentials are also compared with those arising from a number of approximations commonly used with pseudopotentials. The eCEPPs provide a significant improvement in optimised geometries and dissociation energies for small molecules, with errors for the latter being an order-of-magnitude smaller than for Hartree-Fock-based pseudopotentials available in the literature. Gaussian basis sets are optimised for use with these pseudopotentials. PMID- 28571393 TI - Laser-assisted chemical vapor deposition setup for fast synthesis of graphene patterns. AB - An automatic setup based on the laser-assisted chemical vapor deposition method has been developed for the rapid synthesis of graphene patterns. The key components of this setup include a laser beam control and focusing unit, a laser spot monitoring unit, and a vacuum and flow control unit. A laser beam with precision control of laser power is focused on the surface of a nickel foil substrate by the laser beam control and focusing unit for localized heating. A rapid heating and cooling process at the localized region is induced by the relative movement between the focalized laser spot and the nickel foil substrate, which causes the decomposing of gaseous hydrocarbon and the out-diffusing of excess carbon atoms to form graphene patterns on the laser scanning path. All the fabrication parameters that affect the quality and number of graphene layers, such as laser power, laser spot size, laser scanning speed, pressure of vacuum chamber, and flow rates of gases, can be precisely controlled and monitored during the preparation of graphene patterns. A simulation of temperature distribution was carried out via the finite element method, providing a scientific guidance for the regulation of temperature distribution during experiments. A multi-layer graphene ribbon with few defects was synthesized to verify its performance of the rapid growth of high-quality graphene patterns. Furthermore, this setup has potential applications in other laser-based graphene synthesis and processing. PMID- 28571392 TI - A comparison between quantum chemistry and quantum Monte Carlo techniques for the adsorption of water on the (001) LiH surface. AB - We present a comprehensive benchmark study of the adsorption energy of a single water molecule on the (001) LiH surface using periodic coupled cluster and quantum Monte Carlo theories. We benchmark and compare different implementations of quantum chemical wave function based theories in order to verify the reliability of the predicted adsorption energies and the employed approximations. Furthermore we compare the predicted adsorption energies to those obtained employing widely used van der Waals density-functionals. Our findings show that quantum chemical approaches are becoming a robust and reliable tool for condensed phase electronic structure calculations, providing an additional tool that can also help in potentially improving currently available van der Waals density functionals. PMID- 28571394 TI - Development of a novel precision instrument for high-resolution simultaneous normal and shear force measurements between small planar samples. AB - In the design and development of end effector pads for silicon wafer handling robots, it is imperative that the static friction/adhesion force properties of the pads with respect to a variety of planar surfaces be characterized. In this work, the overall design, calibration, and data acquisition procedure of an instrument developed for performing these measurements on small (<10 mm * 10 mm) planar samples is presented. This device was used to perform adhesion/maximum shear force measurements on polydimethylsiloxane, a silicon wafer, and custom carbon nanotubes forest surfaces. The device was successfully able to measure an effective, mean profile adhesion force of 715 MUN between a silicon wafer and a polydimethylsiloxane (2.768 * 10-6 m2) sample. In addition, a nonlinear maximum shear over normal force relationship was also measured between custom carbon nanotubes forest and the silicon wafer surfaces. The maximum shear over a normal force coefficient was found to decrease with increasing initial normal force. Currently, there are numerous devices for measuring normal/shear forces at the nano/micro- and macroscales; however, this device allows for the consistent measurement of these same types of forces on components with surface dimensions ranging from 0.1 mm to 10 mm. PMID- 28571395 TI - A low-drift, low-noise, multichannel dc voltage source for segmented-electrode Paul traps. AB - We present the design, construction, and characterization of a multichannel, low drift, low-noise dc voltage source specially designed for biasing the electrodes of segmented linear Paul traps. The system produces 20 output voltage pairs having a common-mode range of 0 to +120 V with 3.7 mV/LSB (least significant bit) resolution and differential ranges of +/-5 V with 150 MUV/LSB or +/-16 V with 610 MUV/LSB resolution. All common-mode and differential voltages are independently controllable, and all pairs share the same ground reference. The measured drift of the voltages after warm-up is lower than 1 LSB peak-to-peak on the time scale of 2 h. The noise of an output voltage measured with respect to ground is <10 MUVRMS within 10 Hz-100 kHz, with spectral density lower than 3 nV Hz-1/2 above 50 kHz. The performance of the system is limited by the external commercial multichannel DAC unit NI 9264, and in principle, it is possible to achieve higher stability and lower noise with the same voltage ranges. The system has a compact, modular, and scalable architecture, having all parts except for the DAC chassis housed within a single 19" 3HE rack. PMID- 28571396 TI - Analyzing X-ray tomographies of granular packings. AB - Starting from three-dimensional volume data of a granular packing, as, e.g., obtained by X-ray Computed Tomography, we discuss methods to first detect the individual particles in the sample and then analyze their properties. This analysis includes the pair correlation function, the volume and shape of the Voronoi cells, and the number and type of contacts formed between individual particles. We mainly focus on packings of monodisperse spheres, but we will also comment on other monoschematic particles such as ellipsoids and tetrahedra. This paper is accompanied by a package of free software containing all programs (including source code) and an example three-dimensional dataset which allows the reader to reproduce and modify all examples given. PMID- 28571397 TI - Simultaneous measurement of film thickness, temperature, and mass fraction of urea-water-solutions by multi-wavelength laser absorption spectroscopy. AB - Quantitative analysis for thickness, temperature, and mass fraction of liquid film is extremely crucial to the relevant industrial processes, but these parameters cannot be determined simultaneously by conventional measurement techniques. In the present work, a novel measurement method based on laser absorption spectroscopy was developed to measure the film temperature, thickness, and mass fraction of urea-water-solutions simultaneously by combining three wavelengths, 1420 nm, 1488 nm, and 1531 nm. Moreover, measurement accuracy of this method was validated by a calibration tool which provided liquid film with known film thickness, temperature, and mass fraction, respectively. It revealed that the deviation between the measured and known parameters with the developed method was 0.86%, 4.58%, and 3.85%, respectively. PMID- 28571398 TI - Online measurement of conductivity/permittivity of fluid by a new contactless impedance sensor. AB - By expanding the contactless conductivity detection (CCD) technique to contactless impedance detection technique, a new contactless impedance sensor is designed to implement the online measurement for both the conductivity of a conductive fluid and the permittivity of a non-conductive fluid. In the new contactless impedance sensor, a new simulated inductor is developed to overcome the unfavorable influences of the coupling capacitances by impedance elimination principle, and the digital phase-sensitive demodulation (DPSD) technique is adopted to realize the impedance measurement. To verify the effectiveness of the new contactless impedance sensor, simulation experiments (using different resistors, capacitors, and their combinations) and practical fluid experiments (using KCl solutions with different concentrations, eight organic solvents, and pure water) are carried out. The experimental results show that the development of the new contactless impedance sensor is successful and the conductivity/permittivity measurement performance of the new sensor is satisfactory. The maximum relative error of conductivity measurement is 3.1% and the maximum relative error of permittivity measurement is 5.5%. Compared with the conventional conductivity/permittivity sensors, the new sensor can implement the contactless online measurement of both the two electrical parameters of fluid. Meanwhile, the new contactless impedance sensor is suitable for industrial applications and has the advantages of simple construction and low cost. PMID- 28571399 TI - Alignment of a vector magnetometer to an optical prism. AB - A method for alignment of a vector magnetometer to a rigidly attached prism is presented. This enables optical comparison of the magnetometer axes to physical surfaces in the apparatus, and thus an absolute determination of the magnetic field direction in space. This is in contrast with more common techniques, which focus on precise determination of the relative angles between magnetometer axes, and so are more suited to measuring differences in the direction of magnetic fields. Here we demonstrate precision better than 500 MUrad on a fluxgate magnetometer, which also gives the coil orthogonality errors to a similar precision. The relative sensitivity of the three axes is also determined, with a precision of about 5 * 10-4. PMID- 28571400 TI - Design and calibration of hot-electron spectrometer array for angle-resolved measurement. AB - A hot-electron spectrometer array with two-dimensional distribution has been designed with a wide-angle range and high-energy resolution to measure the spatially resolved electron spectra for high-power-laser plasma interaction experiments. It consisted of 19 identical electron spectrometers set in three directions with an interval of 10 degrees . Each electron spectrometer was designed with a uniform magnetic field to detect electrons in the range from 20 to 500 keV. The spectrometers were calibrated using electrons from an accelerator. In an experiment, the spatially resolved electron energy spectra, which approximately had a Maxwell distribution, were obtained from an aluminum foil target irradiated by a 0.53-MUm laser pulse. PMID- 28571401 TI - A novel signal acquisition platform of human cardiovascular information with noninvasive method. AB - Cardiovascular diseases (CVDs) are considered the major cause of death worldwide, so more researchers pay more and more attention to the development of a non invasive method to obtain as much cardiovascular information (CVI) as possible for early screening and diagnosing. It is known that considerable brain information could be probed by a variety of stimuli (such as video, light, and sound). Therefore, it is quite possible that much more CVI could be extracted via giving the human body some special interrelated stimulus. Based on this hypothesis, we designed a novel signal platform to acquire more CVI with a special stimulus, which is to give a gradual decrease and a different settable constant pressure to six air belts placed on two-side brachia, wrists, and ankles, respectively. During the stimulating process, the platform is able to collect 24-channel dynamic signals related with CVI synchronously. Moreover, to improve the measurement accuracy of signal acquisition, a high precision reference chip and a software correction are adopted in this platform. Additionally, we have also shown some collection instances and analysis results in this paper for its reliability. The results suggest that our platform can not only be applied on study in a deep-going way of relationship between collected signals and CVDs but can also serve as the basic tool for developing a new noninvasive cardiovascular function detection instrument and system that can be used both at home and in the hospital. PMID- 28571402 TI - Highly efficient evaluation of a gas mixer using a hollow waveguide based laser spectral sensor. AB - This paper aims to provide a fast, sensitive, and accurate characterization of a Mass Flow Controller (MFC) based gas mixer. The gas mixer was evaluated by using a hollow waveguide based laser spectral sensor with high efficiency. Benefiting from the sensor's fast response, high sensitivity and continuous operation, multiple key parameters of the mixer, including mixing uncertainty, linearity, and response time, were acquired by a one-round test. The test results show that the mixer can blend multi-compound gases quite efficiently with an uncertainty of 1.44% occurring at a flow rate of 500 ml/min, with the linearity of 0.998 43 and the response time of 92.6 s. The results' reliability was confirmed by the relative measurement of gas concentration, in which the isolation of the sensor's uncertainty was conducted. The measured uncertainty has shown well coincidence with the theoretical uncertainties of the mixer, which proves the method to be a reliable characterization. Consequently, this sort of laser based characterization's wide appliance on gas analyzer's evaluations is demonstrated. PMID- 28571403 TI - Preface: Focus on imaging methods in granular physics. PMID- 28571404 TI - A novel dual-color bifocal imaging system for single-molecule studies. AB - In this paper, we report the design and implementation of a dual-color bifocal imaging (DBI) system that is capable of acquiring two spectrally distinct, spatially registered images of objects located in either same or two distinct focal planes. We achieve this by separating an image into two channels with distinct chromatic properties and independently focusing both images onto a single CCD camera. The two channels in our device are registered with subpixel accuracy, and long-term stability of the registered images with nanometer precision was accomplished by reducing the drift of the images to ~5 nm. We demonstrate the capabilities of our DBI system by imaging biomolecules labeled with spectrally distinct dyes and micro- and nano-sized spheres located in different focal planes. PMID- 28571405 TI - Note: Using a Kosters prism to create a fringe pattern. AB - The interference of two crossed laser beams results in a standing wave. Such fringe patterns are exploited in different instruments such as interferometers or laser-Doppler anemometers. We create a fringe pattern in the sample plane of a microscope using a compact apparatus based on a Kosters prism. The fringe pattern is shown to be spatially and temporally very stable, covers a large area, and its spacing is easily tunable. In addition, we exploit it to impose a sinusoidal potential on colloidal particles. PMID- 28571406 TI - Note: A dual-channel sensor for dew point measurement based on quartz crystal microbalance. AB - A new sensor with dual-channel was designed for eliminating the temperature effect on the frequency measurement of the quartz crystal microbalance (QCM) in dew point detection. The sensor uses active temperature control, produces condensation on the surface of QCM, and then detects the dew point. Both the single-channel and the dual-channel methods were conducted based on the device. The measurement error of the single-channel method was less than 0.5 degrees C at the dew point range of -2 degrees C-10 degrees C while the dual-channel was 0.3 degrees C. The results showed that the dual-channel method was able to eliminate the temperature effect and yield better measurement accuracy. PMID- 28571407 TI - Development of a linear-type double reflectron for focused imaging of photofragment ions from mass-selected complex ions. AB - An ion imaging apparatus with a double linear reflectron mass spectrometer has been developed, in order to measure velocity and angular distributions of mass analyzed fragment ions produced by photodissociation of mass-selected gas phase complex ions. The 1st and the 2nd linear reflectrons were placed facing each other and controlled by high-voltage pulses in order to perform the mass separation of precursor ions in the 1st reflectron and to observe the focused image of the photofragment ions in the 2nd reflectron. For this purpose, metal meshes were attached on all electrodes in the 1st reflectron, whereas the mesh was attached only on the last electrode in the 2nd reflectron. The performance of this apparatus was evaluated using imaging measurement of Ca+ photofragment ions from photodissociation reaction of Ca+Ar complex ions at 355 nm photoexcitation. The focused ion images were obtained experimentally with the double linear reflectron at the voltages of the reflection electrodes close to the predictions by ion trajectory simulations. The velocity and angular distributions of the produced Ca+ ([Ar] 4p1, 2P3/2) ion were analyzed from the observed images. The binding energy D0 of Ca+Ar in the ground state deduced in the present measurement was consistent with those determined theoretically and by spectroscopic measurements. The anisotropy parameter beta of the transition was evaluated for the first time by this instrument. PMID- 28571408 TI - Multipurpose setup for low-temperature conversion electron Mossbauer spectroscopy. AB - We describe an experimental setup for conversion electron Mossbauer spectroscopy (CEMS) at low temperature. The setup is composed of a continuous flow cryostat (temperature range of 4.2-500 K), detector housing, three channel electron multipliers, and corresponding electronics. We demonstrate the capabilities of the setup with CEMS measurements performed on a sample consisting of a thin enriched 57Fe film, with a thickness of 20 nm, deposited on a silicon substrate. We also describe exchangeable adaptations (lid and sample holder) which extend the applicability of the setup to emission Mossbauer spectroscopy as well as measurements under an applied magnetic field. PMID- 28571409 TI - A manipulative instrument with simultaneous gesture and end-effector trajectory planning and controlling. AB - To operate a redundant manipulator to accomplish the end-effector trajectory planning and simultaneously control its gesture in online programming, incorporating the human motion is a useful and flexible option. This paper focuses on a manipulative instrument that can simultaneously control its arm gesture and end-effector trajectory via human teleoperation. The instrument can be classified by two parts; first, for the human motion capture and data processing, marker systems are proposed to capture human gesture. Second, the manipulator kinematics control is implemented by an augmented multi-tasking method, and forward and backward reaching inverse kinematics, respectively. Especially, the local-solution and divergence problems of a multi-tasking method are resolved by the proposed augmented multi-tasking method. Computer simulations and experiments with a 7-DOF (degree of freedom) redundant manipulator were used to validate the proposed method. Comparison among the single-tasking, original multi-tasking, and augmented multi-tasking algorithms were performed and the result showed that the proposed augmented method had a good end-effector position accuracy and the most similar gesture to the human gesture. Additionally, the experimental results showed that the proposed instrument was realized online. PMID- 28571410 TI - Low-loss pigtail reflector for fiber lasers. AB - We demonstrate a low-loss pigtail reflector for a fiber laser comprising off-the shelf components. A pigtail configuration has the advantage of easy alteration of the reflection properties, which is highly desired for basic studies and metrological applications. Our proposed reflector consists of a dielectric-coated bulk mirror and an Ferrule connector (FC)-type fiber receptacle, which are fixed with a machined holder such that the FC-type connector at the fiber end can be attached onto the mirror surface with an appropriate amount of pressure, which is essential for minimal reflection loss. The measured reflection loss is 0.07 dB, which is one order of magnitude less than that of the typical connection loss, 0.52 dB, of an FC-FC interconnection; it is comparable to the typical splice loss of a single-mode fiber (0.05 dB). The benefit of the proposed method is its versatility that enables its application to various types of fiber lasers. PMID- 28571411 TI - A practical superconducting-microcalorimeter X-ray spectrometer for beamline and laboratory science. AB - We describe a series of microcalorimeter X-ray spectrometers designed for a broad suite of measurement applications. The chief advantage of this type of spectrometer is that it can be orders of magnitude more efficient at collecting X rays than more traditional high-resolution spectrometers that rely on wavelength dispersive techniques. This advantage is most useful in applications that are traditionally photon-starved and/or involve radiation-sensitive samples. Each energy-dispersive spectrometer is built around an array of several hundred transition-edge sensors (TESs). TESs are superconducting thin films that are biased into their superconducting-to-normal-metal transitions. The spectrometers share a common readout architecture and many design elements, such as a compact, 65 mK detector package, 8-column time-division-multiplexed superconducting quantum-interference device readout, and a liquid-cryogen-free cryogenic system that is a two-stage adiabatic-demagnetization refrigerator backed by a pulse-tube cryocooler. We have adapted this flexible architecture to mate to a variety of sample chambers and measurement systems that encompass a range of observing geometries. There are two different types of TES pixels employed. The first, designed for X-ray energies below 10 keV, has a best demonstrated energy resolution of 2.1 eV (full-width-at-half-maximum or FWHM) at 5.9 keV. The second, designed for X-ray energies below 2 keV, has a best demonstrated resolution of 1.0 eV (FWHM) at 500 eV. Our team has now deployed seven of these X-ray spectrometers to a variety of light sources, accelerator facilities, and laboratory-scale experiments; these seven spectrometers have already performed measurements related to their applications. Another five of these spectrometers will come online in the near future. We have applied our TES spectrometers to the following measurement applications: synchrotron-based absorption and emission spectroscopy and energy-resolved scattering; accelerator-based spectroscopy of hadronic atoms and particle-induced-emission spectroscopy; laboratory-based time resolved absorption and emission spectroscopy with a tabletop, broadband source; and laboratory-based metrology of X-ray-emission lines. Here, we discuss the design, construction, and operation of our TES spectrometers and show first-light measurements from the various systems. Finally, because X-ray-TES technology continues to mature, we discuss improvements to array size, energy resolution, and counting speed that we anticipate in our next generation of TES-X-ray spectrometers and beyond. PMID- 28571412 TI - Apparatus for the investigation of high-temperature, high-pressure gas-phase heterogeneous catalytic and photo-catalytic materials. AB - A high-temperature, high-pressure, pulsed-gas sampling and detection system has been developed for testing new catalytic and photocatalytic materials for the production of solar fuels. The reactor is fitted with a sapphire window to allow the irradiation of photocatalytic samples from a lamp or solar simulator light source. The reactor has a volume of only 3.80 ml allowing for the investigation of very small quantities of a catalytic material, down to 1 mg. The stainless steel construction allows the cell to be heated to 350 degrees C and can withstand pressures up to 27 bar, limited only by the sapphire window. High pressure sampling is made possible by a computer controlled pulsed valve that delivers precise gas flow, enabling catalytic reactions to be monitored across a wide range of pressures. A residual gas analyser mass spectrometer forms a part of the detection system, which is able to provide a rapid, real-time analysis of the gas composition within the photocatalytic reaction chamber. This apparatus is ideal for investigating a number of industrially relevant reactions including photocatalytic water splitting and CO2 reduction. Initial catalytic results using Pt-doped and Ru nanoparticle-doped TiO2 as benchmark experiments are presented. PMID- 28571413 TI - High sensitive and high temporal and spatial resolved image of reactive species in atmospheric pressure surface discharge reactor by laser induced fluorescence. AB - The current paucity of spatial and temporal characterization of reactive oxygen and nitrogen species (RONS) concentration has been a major hurdle to the advancement and clinical translation of low temperature atmospheric plasmas. In this study, an advanced laser induced fluorescence (LIF) system has been developed to be an effective antibacterial surface discharge reactor for the diagnosis of RONS, where the highest spatial and temporal resolution of the LIF system has been achieved to ~100 MUm scale and ~20 ns scale, respectively. Measurements on an oxidative OH radical have been carried out as typical RONS for the benchmark of the whole LIF system, where absolute number density calibration has been performed on the basis of the laser Rayleigh scattering method. Requirements for pixel resolved spatial distribution and outer plasma region detection become challenging tasks due to the low RONS concentration (~ppb level) and strong interference, especially the discharge induced emission and pulsed laser induced stray light. In order to design the highly sensitive LIF system, a self-developed fluorescence telescope, the optimization of high precision synchronization among a tunable pulsed laser, a surface discharge generator, intensified Charge Coupled Device (iCCD) camera, and an oscilloscope have been performed. Moreover, an image BOXCAR approach has been developed to remarkably improve the sensitivity of the whole LIF system by optimizing spatial and temporal gating functions via both hardware and software, which has been integrated into our automatic control and data acquisition system on the LabVIEW platform. In addition, a reciprocation averaging measurement has been applied to verify the accuracy of the whole LIF detecting system, indicating the relative standard deviation of ~3%. PMID- 28571414 TI - Temperature measurement using frequency comb absorption spectroscopy of CO2. AB - Absorption spectroscopy on CO2 for the determination of gas temperature is reported. Direct absorption of a frequency comb laser through a gas cell at atmospheric conditions is analysed with a virtually imaged phased array spectrometer. Several measurement and analysis techniques are investigated to find the parameters most sensitive to changes in the temperature. Some of these show qualitative agreement with theoretical predictions where the trend is similar to the calculated values. PMID- 28571415 TI - A physics-based solver to optimize the illumination of cylindrical targets in spherically distributed high power laser systems. AB - In recent years, our understanding of high energy density plasmas has played an important role in improving inertial fusion confinement and in emerging new fields of physics, such as laboratory astrophysics. Every new idea required developing innovative experimental platforms at high power laser facilities, such as OMEGA or NIF. These facilities, designed to focus all their beams onto spherical targets or hohlraum windows, are now required to shine them on more complex targets. While the pointing on planar geometries is relatively straightforward, it becomes problematic for cylindrical targets or target with more complex geometries. This publication describes how the distribution of laser beams on a cylindrical target can be done simply by using a set of physical laws as a pointing procedure. The advantage of the method is threefold. First, it is straightforward, requiring no mathematical enterprise besides solving ordinary differential equations. Second, it will converge if a local optimum exists. Finally, it is computationally inexpensive. Experimental results show that this approach produces a geometrical beam distribution that yields cylindrically symmetric implosions. PMID- 28571417 TI - Transient surface photovoltage measurement over 12 orders of magnitude in time. AB - The measurement of transient surface photovoltage (SPV) signals in a fixed capacitor arrangement over 12 orders of magnitude in time has been demonstrated for a SnO2:F/TiO2/In2S3 layer system under high vacuum. For this purpose, a high impedance buffer with a bandwidth above 200 MHz and an effective input resistance of 200-700 TOmega has been developed. Fast separation of photo generated charge carriers within ns and very slow relaxation of SPV signals excited with short laser pulses and the measurement of SPV spectra under continuous illumination with a halogen lamp were demonstrated. PMID- 28571416 TI - Sensitivity enhancement and fringe reduction in tunable diode laser spectroscopy using hemispherical diffusers. AB - The use of diffuse, highly reflective optical components, in particular, a hemispherical BaSO4 diffuser, at the point of light injection into non transparent or turbid media was evaluated as a means to increase the measurement sensitivity of spectroscopic absorption measurements. By performing the light injection from, e.g., an optical fiber through a component designed to make the light diffuse and to reflect (and thereby re-inject) light scattered from the sample, the total amount of light delivered into the sample is increased. Further, the occurrence of possible interference fringes is strongly reduced. PMID- 28571418 TI - Note: Evaluation of magnetometry data acquired from elongated samples. AB - We document and validate an analytic expression for the flux integral characterizing the response (or sensitivity) of a magnetometer equipped with second-order axial gradiometer coils to long, thin, uniformly magnetized samples. We then demonstrate an application inspired by this analysis, in which magnetometric sensitivity to weak magnetic signatures is readily and appreciably enhanced by increasing the sample volume (and hence the quantity of analyte) well beyond conventional limits. PMID- 28571419 TI - Four channel high power rf source with beam steering based on gyromagnetic nonlinear transmission lines. AB - The synchronized operation of four gyromagnetic nonlinear transmission lines (NLTLs) was tested with a pulse repetition frequency up to 1 kHz during 1 s bursts. High voltage pulses with a duration of ~5 ns from the solid state driver S-500 were split into four 48 Omega channels reaching about -200 kV in each channel with ~10% variation in the amplitude. The maximum peak voltage at the NLTL output was within 220-235 kV with the maximum modulation depth of decaying oscillations up to 90% at the center frequency near 2.1 GHz. The relative delay between channels reached the half-period of the center frequency of oscillations. The associated beam steering by four element array of conical helical antennas was demonstrated in a horizontal plane at 17 degrees . The effective potential of radiation reached 360 kV at the radiation axis. The effect of ferrite temperature on the shock wave velocity in gyromagnetic NLTL is observed. PMID- 28571420 TI - A versatile atomic force microscope integrated with a scanning electron microscope. AB - A versatile atomic force microscope (AFM), which can be installed in a scanning electron microscope (SEM), is introduced. The flexible design of the instrument enables correlated analysis for different experimental configurations, such as AFM imaging directly after nanoindentation in vacuum. In order to demonstrate the capabilities of the specially designed AFM installed inside a SEM, slip steps emanating around nanoindents in single crystalline brass were examined. This example showcases how the combination of AFM and SEM imaging can be utilized for quantitative dislocation analysis through the measurement of the slip step heights without the hindrance of oxide formation. Finally, an in situ nanoindentation technique is introduced, illustrating the use of AFM imaging during indentation experiments to examine plastic deformation occurring under the indenter tip. The mechanical indentation data are correlated to the SEM and AFM images to estimate the number of dislocations emitted to the surface. PMID- 28571421 TI - Combination volumetric and gravimetric sorption instrument for high accuracy measurements of methane adsorption. AB - The accurate measurement of adsorbed gas up to high pressures (~100 bars) is critical for the development of new materials for adsorbed gas storage. The typical Sievert-type volumetric method introduces accumulating errors that can become large at maximum pressures. Alternatively, gravimetric methods employing microbalances require careful buoyancy corrections. In this paper, we present a combination gravimetric and volumetric system for methane sorption measurements on samples between ~0.5 and 1 g. The gravimetric method described requires no buoyancy corrections. The tandem use of the gravimetric method allows for a check on the highest uncertainty volumetric measurements. The sources and proper calculation of uncertainties are discussed. Results from methane measurements on activated carbon MSC-30 and metal-organic framework HKUST-1 are compared across methods and within the literature. PMID- 28571422 TI - Lagrangian 3D tracking of fluorescent microscopic objects in motion. AB - We describe the development of a tracking device, mounted on an epi-fluorescent inverted microscope, suited to obtain time resolved 3D Lagrangian tracks of fluorescent passive or active micro-objects in microfluidic devices. The system is based on real-time image processing, determining the displacement of a x, y mechanical stage to keep the chosen object at a fixed position in the observation frame. The z displacement is based on the refocusing of the fluorescent object determining the displacement of a piezo mover keeping the moving object in focus. Track coordinates of the object with respect to the microfluidic device as well as images of the object are obtained at a frequency of several tenths of Hertz. This device is particularly well adapted to obtain trajectories of motile micro organisms in microfluidic devices with or without flow. PMID- 28571424 TI - Thermal diffusivity measurement of focused-ion-beam fabricated sample using photothermal reflectance technique. AB - Focused-Ion-Beam (FIB) can lift-off micrometer-sized samples from bulk materials for structural characterization and property measurement. The ability to determine thermophysical properties of such samples offers unique insight into the local microstructure-property relationship. A photothermal reflectance technique is developed to measure the thermal diffusivity of FIB-fabricated, micrometer-sized samples in this study. An analytic model is established to guide the experimental design and data analysis for the limited sample size and thickness. The thermal diffusivity of the sample can be extracted from a series of spatial-scan measurements at several modulated heating frequencies. To demonstrate the viability of the technique, a FIB-fabricated SiC plate with the size of 42 MUm * 31 MUm * 8 MUm was used to represent high conductivity materials, which pose more challenges for the technique. The result compares favorably with literature values of SiC. The measurement uncertainty is quantified and possible experimental error sources are discussed. This technique is specially promising for thermal property measurements on nuclear fuels and materials. PMID- 28571423 TI - A new method for measuring the neutron lifetime using an in situ neutron detector. AB - In this paper, we describe a new method for measuring surviving neutrons in neutron lifetime measurements using bottled ultracold neutrons (UCN), which provides better characterization of systematic uncertainties and enables higher precision than previous measurement techniques. An active detector that can be lowered into the trap has been used to measure the neutron distribution as a function of height and measure the influence of marginally trapped UCN on the neutron lifetime measurement. In addition, measurements have demonstrated phase space evolution and its effect on the lifetime measurement. PMID- 28571425 TI - Solution electrostatic levitator for measuring surface properties and bulk structures of an extremely supersaturated solution drop above metastable zone width limit. AB - We report on the first integrated apparatus for measuring surface and thermophysical properties and bulk structures of a highly supersaturated solution by combining electrostatic levitation with real-time laser/x-ray scattering. Even today, a proper characterization of supersaturated solutions far above their solubility limits is extremely challenging because heterogeneous nucleation sites such as container walls or impurities readily initiate crystallization before the measurements can be performed. In this work, we demonstrate simultaneous measurements of drying kinetics and surface tension of a potassium dihydrogen phosphate (KH2PO4) aqueous solution droplet and its bulk structural evolution beyond the metastable zone width limit. Our experimental finding shows that the noticeable changes of the surface properties are accompanied by polymerizations of hydrated monomer clusters. The novel electrostatic levitation apparatus presented here provides an effective means for studying a wide range of highly concentrated solutions and liquids in deep metastable states. PMID- 28571426 TI - Versatile synchronized real-time MEG hardware controller for large-scale fast data acquisition. AB - Versatile controllers for accurate, fast, and real-time synchronized acquisition of large-scale data are useful in many areas of science, engineering, and technology. Here, we describe the development of a controller software based on a technique called queued state machine for controlling the data acquisition (DAQ) hardware, continuously acquiring a large amount of data synchronized across a large number of channels (>400) at a fast rate (up to 20 kHz/channel) in real time, and interfacing with applications for real-time data analysis and display of electrophysiological data. This DAQ controller was developed specifically for a 384-channel pediatric whole-head magnetoencephalography (MEG) system, but its architecture is useful for wide applications. This controller running in a LabVIEW environment interfaces with microprocessors in the MEG sensor electronics to control their real-time operation. It also interfaces with a real-time MEG analysis software via transmission control protocol/internet protocol, to control the synchronous acquisition and transfer of the data in real time from >400 channels to acquisition and analysis workstations. The successful implementation of this controller for an MEG system with a large number of channels demonstrates the feasibility of employing the present architecture in several other applications. PMID- 28571428 TI - Deep cooling of optically trapped atoms implemented by magnetic levitation without transverse confinement. AB - We report a setup for the deep cooling of atoms in an optical trap. The deep cooling is implemented by eliminating the influence of gravity using specially constructed magnetic coils. Compared to the conventional method of generating a magnetic levitating force, the lower trap frequency achieved in our setup provides a lower limit of temperature and more freedoms to Bose gases with a simpler solution. A final temperature as low as ~6nK is achieved in the optical trap, and the atomic density is decreased by nearly two orders of magnitude during the second stage of evaporative cooling. This deep cooling of optically trapped atoms holds promise for many applications, such as atomic interferometers, atomic gyroscopes, and magnetometers, as well as many basic scientific research directions, such as quantum simulations and atom optics. PMID- 28571429 TI - Detection of particle motion using image processing with particular emphasis on rolling motion. AB - Image-processing has been used in granular systems for detecting particle positions and motion near optically accessible surfaces like sediment flow and bedload transport. We review the image-processing techniques used for single and multiple particles. To enhance reliability in particle recognition, tools like Canny edge and Hough transform are intensively used. We show exemplarily how they can be applied to detect not only particle positions but also rotatory motion. The different steps are described in detail and the algorithm is applied to different examples, which are discussed in view of the obtained accuracy. PMID- 28571430 TI - Note: Coincidence measurements of 3He and neutrons from a compact D-D neutron generator. AB - Tagging of neutrons (2.45 MeV) with their associated 3He particles from deuterium deuterium (D-D) fusion reactions has been demonstrated in a compact neutron generator setup enabled by a high brightness, microwave-driven ion source with a high fraction of deuterons. Energy spectra with well separated peaks of the D-D fusion reaction products, 3He, tritons, and protons, were measured with a silicon PIN diode. The neutrons were detected using a liquid scintillator detector with pulse shape discrimination. By correlating the 3He detection events with the neutron detection in time, we demonstrated the tagging of emitted neutrons with 3He particles detected with a Si PIN diode detector mounted inside the neutron generator vacuum vessel. PMID- 28571431 TI - Note: Photoluminescence measurement system for multi-junction solar cells. AB - We describe a photoluminescence spectroscopy system developed for studying phenomena of optical coupling in multiple-junction solar cells and processed/unprocessed wafers, under the high solar concentration levels typical of HCPV (High Concentration PhotoVoltaic) systems. The instrument operates at room temperature over two spectral ranges: 475 nm-1100 nm and 950 nm-1650 nm. Power densities exceeding 10 000 suns can be obtained on the sample. The system can host up to four compact focusable solid state laser sources, presently only three are mounted and operated at 450 nm, 520 nm, and 785 nm; they provide overlapped beams on the sample surface and can shine simultaneously the sample to study possible mutual interaction between the different junctions. PMID- 28571432 TI - Extension of the T-bridge method for measuring the thermal conductivity of two dimensional materials. AB - In this paper, the T-bridge method is extended to measure the thermal properties of two-dimensional nanomaterials. We present an analysis of the measureable positions, width, and thermal resistance of two-dimensional materials. For verification purposes, the thermal conductivity of a SiO2 nanoribbon was measured. To enhance the thermal contact between the nanoribbon and the heater in the setup, the nanoribbon was dipped into either isopropanol or water in order to promote a sticking force. Also, focused ion beam deposition was used to deposit the nanoribbon onto the contact. The thermal conductivities of all three cases were identical, showing that water dipping could be used to enhance the thermal contact. Due to the simple structure of this method and the analysis provided herein, the T-bridge method can be widely used for measuring the thermal conductivity of two-dimensional materials. PMID- 28571433 TI - Highly hydrogen-sensitive thermal desorption spectroscopy system for quantitative analysis of low hydrogen concentration (~1 * 1016 atoms/cm3) in thin-film samples. AB - We developed a highly hydrogen-sensitive thermal desorption spectroscopy (HHS TDS) system to detect and quantitatively analyze low hydrogen concentrations in thin films. The system was connected to an in situ sample-transfer chamber system, manipulators, and an rf magnetron sputtering thin-film deposition chamber under an ultra-high-vacuum (UHV) atmosphere of ~10-8 Pa. The following key requirements were proposed in developing the HHS-TDS: (i) a low hydrogen residual partial pressure, (ii) a low hydrogen exhaust velocity, and (iii) minimization of hydrogen thermal desorption except from the bulk region of the thin films. To satisfy these requirements, appropriate materials and components were selected, and the system was constructed to extract the maximum performance from each component. Consequently, ~2000 times higher sensitivity to hydrogen than that of a commercially available UHV-TDS system was achieved using H+-implanted Si samples. Quantitative analysis of an amorphous oxide semiconductor InGaZnO4 thin film (1 cm * 1 cm * 1 MUm thickness, hydrogen concentration of 4.5 * 1017 atoms/cm3) was demonstrated using the HHS-TDS system. This concentration level cannot be detected using UHV-TDS or secondary ion mass spectroscopy (SIMS) systems. The hydrogen detection limit of the HHS-TDS system was estimated to be ~1 * 1016 atoms/cm3, which implies ~2 orders of magnitude higher sensitivity than that of SIMS and resonance nuclear reaction systems (~1018 atoms/cm3). PMID- 28571434 TI - Generating circularly polarized radiation in the extreme ultraviolet spectral range at the free-electron laser FLASH. AB - A new device for polarization control at the free electron laser facility FLASH1 at DESY has been commissioned for user operation. The polarizer is based on phase retardation upon reflection off metallic mirrors. Its performance is characterized in three independent measurements and confirms the theoretical predictions of efficient and broadband generation of circularly polarized radiation in the extreme ultraviolet spectral range from 35 eV to 90 eV. The degree of circular polarization reaches up to 90% while maintaining high total transmission values exceeding 30%. The simple design of the device allows straightforward alignment for user operation and rapid switching between left and right circularly polarized radiation. PMID- 28571435 TI - Conceptual design of imaging bolometer for use of computed tomography in JT-60SA. AB - An InfraRed imaging Video Bolometer (IRVB) system in JT-60SA has been designed for the two-dimensional (2D) Computed Tomography (CT) analysis of radiation. To achieve complete viewing of the whole poloidal cross section for plasmas having a low aspect ratio, a new IRVB concept, which has two sets of pin-hole camera systems viewing two different directions, has been introduced. Fields of view of the IRVB have been successfully designed by moving apertures to be sufficient for CT use without installation in tangential ports. The size of the aperture, which determines the width of the sightline of the IRVB channels, has also been optimized with respect to the reconstruction error with well-established solvers of tomography. The optimization indicates that the 7 mm square aperture is the best for this system, and the CT measurement without this optimization can become degraded. A synthetic image using an estimated radiation profile shows that the signal to noise (S/N) ratio of the designed IRVB is large enough to identify the incident radiation power. The result indicates that the designed IRVB can be used for the 2D CT measurement of radiation in JT-60SA. PMID- 28571436 TI - Development of PZT-excited stroboscopic shearography for full-field nondestructive evaluation. AB - Nondestructive evaluation using shearography requires a way to stress the inspection target. This technique is able to directly measure the displacement gradient distribution on the object surface. Shearography visualizes the internal structural damages as the anomalous pattern in the shearograpic fringe pattern. A piezoelectric (PZT) excitation system is able to generate loadings in the vibrational, acoustic, and ultrasonic regimes. In this paper, we propose a PZT excited stroboscopic shearography. The PZT excitation could generate vibrational loading, a stationary wavefield, and a nonstationary propagation wave to fulfill the external loading requirement of shearography. The sweeping of the PZT excitation frequency, the formation of a standing wave, and a small shearing to suppress the incident wave were powerful controllable tools to detect the defects. The sweeping of the PZT excitation frequency enabled us to determine one of the defect-sensitive frequencies almost in real time. In addition, because the defect sensitive frequencies always existed in wide and plural ranges, the risk of the defect being overlooked by the inspector could be alleviated. The results of evaluation using stroboscopic shearography showed that an artificial 20 mm diameter defect could be visualized at the excitation frequencies of 5-8 kHz range and 12.5-15.5 kHz range. This technique provided full field reliable and repeatable inspection results. Additionally, the proposed method overcame the important drawback of the time-averaged shearography, being required to identify the resonance vibration frequency sensitive to the defect. PMID- 28571437 TI - Publisher's Note: "New method of extracting information of arterial oxygen saturation based on ?|Delta|" [Rev. Sci. Instrum. 88, 043107 (2017)]. PMID- 28571438 TI - The application of chaotic oscillator in detecting weak resonant signal of MEMS resonator. AB - In this paper, a detection model of a chaotic oscillator is applied in the weak signal detection of an electrothermal excitation MEMS resonator, and the maximum Lyapunov exponent is used to obtain the threshold value and monitor the motion transition of a detection system. The phase drift caused by the electrothermal excitation is studied theoretically and experimentally, and according to the results of above study, the phase of a reference current signal is set to eliminate the phase when the resonator is in a resonant state. Then a new detection algorithm is proposed to detect the resonant signal. The simulation experiment on a weak signal under different magnifications and different levels of noises is conducted, after the impact of the quality factor Q of a resonator on detection results is analyzed. Finally, experiments on the output signal of a detected sensor sample are carried out by a proposed algorithm. Simulation and experiment results show that the detection model can effectively detect the weak signal and accurately obtain the resonant frequency, and it is immune to the noises. PMID- 28571439 TI - Removal of anti-Stokes emission background in STED microscopy by FPGA-based synchronous detection. AB - In stimulated emission depletion (STED) microscopy, the role of the STED beam is to de-excite, via stimulated emission, the fluorophores that have been previously excited by the excitation beam. This condition, together with specific beam intensity distributions, allows obtaining true sub-diffraction spatial resolution images. However, if the STED beam has a non-negligible probability to excite the fluorophores, a strong fluorescent background signal (anti-Stokes emission) reduces the effective resolution. For STED scanning microscopy, different synchronous detection methods have been proposed to remove this anti-Stokes emission background and recover the resolution. However, every method works only for a specific STED microscopy implementation. Here we present a user-friendly synchronous detection method compatible with any STED scanning microscope. It exploits a data acquisition (DAQ) card based on a field-programmable gate array (FPGA), which is progressively used in STED microscopy. In essence, the FPGA based DAQ card synchronizes the fluorescent signal registration, the beam deflection, and the excitation beam interruption, providing a fully automatic pixel-by-pixel synchronous detection method. We validate the proposed method in both continuous wave and pulsed STED microscope systems. PMID- 28571440 TI - A trough for improved SFG spectroscopy of lipid monolayers. AB - Lipid monolayers are indispensable model systems for biological membranes. The main advantage over bilayer model systems is that the surface pressure within the layer can be directly and reliably controlled. The sensitive interplay between surface pressure and temperature determines the molecular order within a model membrane and consequently determines the membrane phase behavior. The lipid phase is of crucial importance for a range of membrane functions such as protein interactions and membrane permeability. A very reliable method to probe the structure of lipid monolayers is sum frequency generation (SFG) vibrational spectroscopy. Not only is SFG extremely surface sensitive but it can also directly access critical parameters such as lipid order and orientation, and it can provide valuable information about protein interactions along with interfacial hydration. However, recent studies have shown that temperature gradients caused by high power laser beams perturb the lipid layers and potentially obscure the spectroscopic results. Here we demonstrate how the local heating problem can be effectively reduced by spatially distributing the laser pulses on the sample surface using a translating Langmuir trough for SFG experiments at lipid monolayers. The efficiency of the trough is illustrated by the detection of enhanced molecular order due to reduced heat load. PMID- 28571441 TI - Filter-based ultralow-frequency Raman measurement down to 2 cm-1 for fast Brillouin spectroscopy measurement. AB - Simultaneous Stokes and anti-Stokes ultralow-frequency (ULF) Raman measurement down to ~2 cm-1 or 60 GHz is realized by a single-stage spectrometer in combination with volume-Bragg-grating-based notch filters. This system reveals its excellent performance by probing Brillouin signal of acoustic phonons in silicon, germanium, gallium arsenide, and gallium nitride. The deduced sound velocity and elastic constants are in good accordance with previous results determined by various methods. This system can shorten the integration time of the Brillouin signal with a good signal-to-noise ratio by more than 2000-fold compared to a Fabry-Perot interferometer (FPI). This study shows how a filter based ULF Raman system can be used to reliably achieve Brillouin spectroscopy for condensed materials with high sensitivity and high signal-to-noise ratio, stimulating fast Brillouin spectrum measurements to probe acoustic phonons in semiconductors. PMID- 28571442 TI - Design and analysis of an MR rotary brake for self-regulating braking torques. AB - This paper presents a novel Magneto-rheological (MR) brake system that can self regulate the output braking torques. The proposed MR brake can generate a braking torque at a critical rotation speed without an external power source, sensors, or controllers, making it a simple and cost-effective device. The brake system consists of a rotary disk, permanent magnets, springs, and MR fluid. The permanent magnets are attached to the rotary disk via the springs, and they move outward through grooves with two different gap distances along the radial direction of the stator due to the centrifugal force. Thus, the position of the magnets is dependent on the spin speed, and it can determine the magnetic fields applied to MR fluids. Proper design of the stator geometry gives the system unique torque characteristics. To show the performance of an MR brake system, the electromagnetic characteristics of the system are analyzed, and the torques generated by the brake are calculated using the result of the electromagnetic analysis. Using a baseline model, a parametric study is conducted to investigate how the design parameters (geometric shapes and material selection) affect the performance of the brake system. After the simulation study, a prototype brake system is constructed and its performance is experimentally evaluated. The experimental results show that the prototype produced the maximum torque of 1.2 N m at the rotational speed of 100 rpm. The results demonstrate the feasibility of the proposed MR brake as a speed regulator in rotating systems. PMID- 28571443 TI - Simultaneous measurement of the HT and DT fusion burn histories in inertial fusion implosions. AB - Measuring the thermonuclear burn history is an important way to diagnose inertial fusion implosions. Using the gas Cherenkov detectors at the OMEGA laser facility, we measure the HT fusion burn in a H2+T2 gas-fueled implosion for the first time. Using multiple detectors with varied Cherenkov thresholds, we demonstrate a technique for simultaneously measuring both the HT and DT burn histories from an implosion where the total reaction yields are comparable. This new technique will be used to study material mixing and kinetic phenomena in implosions. PMID- 28571444 TI - Photoelastic force measurements in granular materials. AB - Photoelastic techniques are used to make both qualitative and quantitative measurements of the forces within idealized granular materials. The method is based on placing a birefringent granular material between a pair of polarizing filters, so that each region of the material rotates the polarization of light according to the amount of local stress. In this review paper, we summarize the past work using the technique, describe the optics underlying the technique, and illustrate how it can be used to quantitatively determine the vector contact forces between particles in a 2D granular system. We provide a description of software resources available to perform this task, as well as key techniques and resources for building an experimental apparatus. PMID- 28571445 TI - Note: Development of real-time epithermal neutron detector for boron neutron capture therapy. AB - The real-time detection of epithermal neutrons forms an important aspect of boron neutron capture therapy. In this context, we developed an epithermal neutron detector based on the combination of a small Eu:LiCaAlF6 scintillator and a quartz fiber in order to fulfill the irradiation-field requirements for boron neutron capture therapy. The irradiation test is performed with the use of a reactor-based neutron source. The thermal and epithermal neutron sensitivities of our epithermal neutron detector are estimated to be 9.52 * 10-8 +/- 1.59 * 10-8 cm2 and 1.20 * 10-6 cm2 +/- 8.96 * 10-9 cm2, respectively. We also subject the developed epithermal neutron detector to actual irradiation fields, and we confirm that the epithermal neutron flux can be measured in realtime. PMID- 28571447 TI - An integrated and multi-purpose microscope for the characterization of atomically thin optoelectronic devices. AB - Optoelectronic devices based on graphene and other two-dimensional (2D) materials, such as transition metal dichalcogenides (TMDs), are the focus of wide research interest. They can be the key to improving bandwidths in telecommunications, capacity in data storage, and new features in consumer electronics, safety devices, and medical equipment. The characterization of these emerging atomically thin materials and devices strongly relies on a set of measurements involving both optical and electronic instrumentation ranging from scanning photocurrent mapping to Raman and photoluminescence (PL) spectroscopy. Furthermore, proof-of-concept devices are usually fabricated from micro-meter size flakes, requiring microscopy techniques to characterize them. Current state of-the-art commercial instruments offer the ability to characterize individual properties of these materials with no option for the in situ characterization of a wide enough range of complementary optical and electrical properties. Presently, the requirement to switch atomically thin materials from one system to another often radically affects the properties of these uniquely sensitive materials through atmospheric contamination. Here, we present an integrated, multi-purpose instrument dedicated to the optical and electrical characterization of devices based on 2D materials which is able to perform low frequency electrical measurements, scanning photocurrent mapping, and Raman, absorption, and PL spectroscopy in one single setup with full control over the polarization and wavelength of light. We characterize this apparatus by performing multiple measurements on graphene, transition metal dichalcogenides (TMDs), and Si. The performance and resolution of each individual measurement technique is found to be equivalent to that of commercially available instruments. Contrary to nowadays' commercial systems, a significant advantage of the developed instrument is that for the first time the integration of a wide range of complementary optoelectronic and spectroscopy characterization techniques is demonstrated in a single compact unit. Our design offers a versatile solution to face the challenges imposed by the advent of atomically thin materials in optoelectronic devices. PMID- 28571446 TI - Development of a programmable standard of ultra-low capacitance values. AB - A set of ultra-low value capacitance standards together with a programmable coaxial multiplexer (mux) have been developed. The mux allows the connection of these capacitances in parallel configuration and they together form the programmable capacitance standard. It is capable of producing decadic standard capacitances from 10 aF to at least 0.1 pF, which are later used to calibrate commercial precision capacitance bridges. This paper describes the realization and the characterization of this standard together with results obtained during the calibration of Andeen-Hagerling AH2700A bridges with a maximum uncertainty of 0.8 aF for all the capacitances generated ranging from 10 aF to 0.1 pF, at 1 kHz. These latter could be then integrated to functionalized AFMs or probe stations for quantitative capacitance measurements. Sources of uncertainties of the programmable capacitance standard, such as parasitic effects due to stray impedances, are evaluated and a method to overcome these hindrances is also discussed. PMID- 28571448 TI - Note: A SMA wire actuated extremely long-lifetime release actuator using two ball lock mechanisms. AB - A shape memory alloy (SMA)-wire actuated release actuator with an extremely long lifetime was designed and validated. To ensure the ability of repeated actuation, two stages of ball-lock mechanisms were adopted to reduce the load in the SMA wire. In addition, a length-increasing design of the SMA wire was employed. Validation tests, including function tests, vibration tests, shock tests, and thermal vacuum tests were conducted on prototypes. According to the test results, the actuator can release a maximum preload of 15 kN and has a lifetime of more than 693 cycles. Furthermore, the actuator can function well, even under severe thermal and vibration environments. PMID- 28571449 TI - Erratum: "Dual analyzer system for surface analysis dedicated for angle-resolved photoelectron spectroscopy at liquid surfaces and interfaces" [Rev. Sci. Instrum. 87, 045105 (2016)]. PMID- 28571450 TI - Interferometric characterization of rotation stages for X-ray nanotomography. AB - The field of three-dimensional multi-modal X-ray nanoimaging relies not only on high-brilliance X-rays but also on high-precision mechanics and position metrology. Currently available state-of-the-art linear and rotary drives can provide 3D position accuracy within tens to hundreds of nm, which is often insufficient for high resolution imaging with nanofocused X-ray beams. Motion errors are especially troublesome in the case of rotation drives and their correction is more complicated and relies on the metrology grade reference objects. Here we present a method which allows the characterisation and correction of the radial and angular errors of the rotary drives without the need for a highly accurate metrology object. The method is based on multi-probe error separation using fiber-laser interferometry and uses a standard cylindrical sample holder as a reference. The obtained runout and shape measurements are then used to perform the position corrections using additional drives. We demonstrate the results of the characterization for a piezo-driven small rotation stage. The error separation allowed us to measure the axis runout to be approximately +/ 1.25 MUm, and with active runout compensation this could be reduced down to +/-42 nm. PMID- 28571451 TI - Magnetic resonance imaging of granular materials. AB - Magnetic Resonance Imaging (MRI) has become one of the most important tools to screen humans in medicine; virtually every modern hospital is equipped with a Nuclear Magnetic Resonance (NMR) tomograph. The potential of NMR in 3D imaging tasks is by far greater, but there is only "a handful" of MRI studies of particulate matter. The method is expensive, time-consuming, and requires a deep understanding of pulse sequences, signal acquisition, and processing. We give a short introduction into the physical principles of this imaging technique, describe its advantages and limitations for the screening of granular matter, and present a number of examples of different application purposes, from the exploration of granular packing, via the detection of flow and particle diffusion, to real dynamic measurements. Probably, X-ray computed tomography is preferable in most applications, but fast imaging of single slices with modern MRI techniques is unmatched, and the additional opportunity to retrieve spatially resolved flow and diffusion profiles without particle tracking is a unique feature. PMID- 28571452 TI - Miniaturized thermocycler based on thermoelectric heating for diagnosis of sexually transmitted disease by DNA amplification. AB - Sexually transmitted disease (STD) is among the most common infectious diseases; therefore, it is necessary to develop sensitive early diagnostic techniques. As the gold standard, polymerase chain reaction (PCR) has been most widely employed for STD diagnosis; however, PCR requires large and expensive instruments. In this study, miniaturized thermal cycler using Peltier modules was developed for the PCR analysis. In comparison with the conventional PCR instrument, the Peltier based micro-PCR (P-mPCR) device developed in this study enables one to amplify and successfully distinguish between DNA of different sizes. Furthermore, by using the clinical vaginal sample collected with the vaginal swab and tampon, different kinds of STD bacteria could be detected with high accuracy (~94.19%) and high sensitivity (~95.6%). Therefore, the P-mPCR device will be applicable in STD diagnosis as well as the detection of other bacteria/viruses using DNA amplification in regions including those with limited resources. PMID- 28571453 TI - An open-source platform to study uniaxial stress effects on nanoscale devices. AB - We present an automatic measurement platform that enables the characterization of nanodevices by electrical transport and optical spectroscopy as a function of the uniaxial stress. We provide insights into and detailed descriptions of the mechanical device, the substrate design and fabrication, and the instrument control software, which is provided under open-source license. The capability of the platform is demonstrated by characterizing the piezo-resistance of an InAs nanowire device using a combination of electrical transport and Raman spectroscopy. The advantages of this measurement platform are highlighted by comparison with state-of-the-art piezo-resistance measurements in InAs nanowires. We envision that the systematic application of this methodology will provide new insights into the physics of nanoscale devices and novel materials for electronics, and thus contribute to the assessment of the potential of strain as a technology booster for nanoscale electronics. PMID- 28571454 TI - A frequency-modulated continuous-wave reflectometer for the Lithium Tokamak Experiment. AB - The frequency-modulated continuous-wave reflectometer on LTX (Lithium Tokamak Experiment) and the data analysis methods used for determining electron density profiles are described. The diagnostic uses a frequency range of 13.1-33.5 GHz, for covering a density range of 0.21-1.4*1013 cm-3 (in O-mode polarization) with a time resolution down to 8 MUs. The design of the diagnostic incorporates the concept of an "optimized" source frequency sweep, which minimizes the large variation in the intermediate frequency signal due to a long dispersive transmission line. The quality of the raw data is dictated by the tuning characteristics of the microwave sources, as well as the group delay ripple in the transmission lines, which can generate higher-order nonlinearities in the frequency sweep. Both effects are evaluated for our diagnostic and best practices are presented for minimizing "artifacts" generated in the signals. The quality of the reconstructed profiles is also improved using two additional data analysis methods. First, the reflectometer data are processed as a radar image, where clutter due to echoes from the wall and backscattering from density fluctuations can be easily identified and removed. Second, a weighed least-squares lamination algorithm POLAN (POLynomial ANalysis) is used to reconstruct the electron density profile. Examples of density profiles in LTX are presented, along with comparisons to measurements from the Thomson scattering and the lambda = 1 mm interferometer diagnostics. PMID- 28571455 TI - Spatially resolved measurements of micro-deformations in granular materials using diffusing wave spectroscopy. AB - This article is a tutorial on the practical implementation of a method of measurement of minute deformations based on multiple scattering. This technique has been recently developed and has proven to give new insights into the spatial repartition of strain in a granular material. We provide here the basics to understand the method by giving a synthetic review on diffusing wave spectroscopy and multiple scattering in granular materials. We detail a simple experiment using standard lab equipment to pedagogically demonstrate the implementation of the method. Finally we give a few examples of measurements that have been obtained in other works to discuss the potential of the method. PMID- 28571456 TI - Microchannel plate detector detection efficiency to monoenergetic electrons between 3 and 28 keV. AB - An unshielded microchannel plate (MCP) detector with an ultrafine pore diameter of 2 MUm was irradiated by an electron beam to determine the detection efficiency of electrons for creating detector signals, or counts. Tested electron energies spanned a range of 3 kiloelectron volts (keV) to 28 keV. Higher detection efficiencies were measured at the lower end of this energy range, 0.376 counts per incident electron at 3 keV down to 0.155 at 15 keV with an increase to 0.217 at 18 keV and then another decrease down to 0.15 counts per incident electron at 28 keV. The increase at 18 keV is attributed to primary electron interaction with the L shell electrons of lead (Pb), leading to an increase in secondary electron and X-ray generation within the MCP and thus an increase in detection efficiency. For the electron beam directed normal to the MCP surface, the lowest efficiency of 0.15 counts per incident electron was observed at 28 keV. Detection efficiency was also tested as a function of incident angle with angular steps of 5 degrees . Detection efficiency was more sensitive to the angle of incidence as the incident electron energy decreased. The detection efficiency at 3 keV decreased from 0.376 counts per electron at the zero degree angle (normal incidence to MCP surface) to 0.027 counts per electron at an incident angle of 50 degrees (average in both orientations). At 28 keV, the decrease in detection efficiency as a function of increasing angle was less pronounced, ranging from 0.15 counts per electron at zero degrees to 0.08 counts per electron at 50 degrees (average in both orientations). Experimental data showed lower detection efficiencies compared with previously published data. PMID- 28571457 TI - Ion cyclotron resonance heating (ICRH) systems for the Keda Mirror with AXisymmetry (KMAX). AB - In this paper, we describe the engineering work involved in constructing two ion cyclotron resonance heating (ICRH) systems for use in the Keda Mirror with AXisymmetry tandem mirror experiment. Because they offer an effective and robust heating method, ICRH systems have been widely used in a variety of plasma experiments. The goal of our system is to heat the hydrogen plasma contained in the central cell using the fundamental ion cyclotron frequency. Both systems can deliver a radiofrequency power of ~120 kW with adjustable operating frequencies that are tuned to be slightly lower than their local ion cyclotron frequencies. Two types of antennas are installed in the central cell in an attempt to launch both slow and fast waves. The heating mechanism is reliant on the magnetic beach effect for slow waves. PMID- 28571458 TI - Refractive index matched scanning and detection of soft particles. AB - We describe here how to apply the three-dimensional imaging technique of refractive index matched scanning to hydrogel spheres. Hydrogels are water based materials with a low refractive index, which allows for index matching with water based solvent mixtures. We discuss here various experimental techniques required to handle specifically hydrogel spheres as opposed to other transparent materials. The deformability of hydrogel spheres makes their identification in three-dimensional images non-trivial. We will also discuss numerical techniques that can be used in general to detect contacting, non-spherical particles in a three-dimensional image. The experimental and numerical techniques presented here give experimental access to the stress tensor of a packing of deformed particles. PMID- 28571459 TI - An experimental setup to study delayed electron emission upon photoexcitation of trapped polyatomic anions. AB - A Velocity Map Imaging (VMI) spectrometer has been designed and integrated with an electrostatic ion beam trap to study delayed electron emission from trapped polyatomic anions upon photodetachment. The VMI spectrometer is small in size and can record a wide range of photoelectron energies, with variable magnification. Delayed electron emission can be recorded in our experimental setup for any time duration after the photoexcitation of the polyatomic anions. Experiments were carried out with trapped O- and C5- ions to demonstrate the capability of the spectrometer. Delayed electron emissions from C5- as well as prompt photoelectrons from O- were detected by the VMI spectrometer upon photoexcitation. The design and performance of the spectrometer are presented in detail. PMID- 28571460 TI - Correlative imaging across microscopy platforms using the fast and accurate relocation of microscopic experimental regions (FARMER) method. AB - Imaging specific regions of interest (ROIs) of nanomaterials or biological samples with different imaging modalities (e.g., light and electron microscopy) or at subsequent time points (e.g., before and after off-microscope procedures) requires relocating the ROIs. Unfortunately, relocation is typically difficult and very time consuming to achieve. Previously developed techniques involve the fabrication of arrays of features, the procedures for which are complex, and the added features can interfere with imaging the ROIs. We report the Fast and Accurate Relocation of Microscopic Experimental Regions (FARMER) method, which only requires determining the coordinates of 3 (or more) conspicuous reference points (REFs) and employs an algorithm based on geometric operators to relocate ROIs in subsequent imaging sessions. The 3 REFs can be quickly added to various regions of a sample using simple tools (e.g., permanent markers or conductive pens) and do not interfere with the ROIs. The coordinates of the REFs and the ROIs are obtained in the first imaging session (on a particular microscope platform) using an accurate and precise encoded motorized stage. In subsequent imaging sessions, the FARMER algorithm finds the new coordinates of the ROIs (on the same or different platforms), using the coordinates of the manually located REFs and the previously recorded coordinates. FARMER is convenient, fast (3-15 min/session, at least 10-fold faster than manual searches), accurate (4.4 MUm average error on a microscope with a 100x objective), and precise (almost all errors are <8 MUm), even with deliberate rotating and tilting of the sample well beyond normal repositioning accuracy. We demonstrate this versatility by imaging and re-imaging a diverse set of samples and imaging methods: live mammalian cells at different time points; fixed bacterial cells on two microscopes with different imaging modalities; and nanostructures on optical and electron microscopes. FARMER can be readily adapted to any imaging system with an encoded motorized stage and can facilitate multi-session and multi-platform imaging experiments in biology, materials science, photonics, and nanoscience. PMID- 28571461 TI - Positron emission particle tracking and its application to granular media. AB - Positron emission particle tracking (PEPT) is a technique for tracking a single radioactively labelled particle. Accurate 3D tracking is possible even when the particle is moving at high speed inside a dense opaque system. In many cases, tracking a single particle within a granular system provides sufficient information to determine the time-averaged behaviour of the entire granular system. After a general introduction, this paper describes the detector systems (PET scanners and positron cameras) used to record PEPT data, the techniques used to label particles, and the algorithms used to process the data. This paper concentrates on the use of PEPT for studying granular systems: the focus is mainly on work at Birmingham, but reference is also made to work from other centres, and options for wider diversification are suggested. PMID- 28571462 TI - Analysis of granular packing structure by scattering of THz radiation. AB - Scattering methods are widely used to characterize the structure and constituents of matter on small length scales. This motivates this introductory text on identifying prospective approaches to scattering-based methods for granular media. A survey to light scattering by particles and particle ensembles is given. It is elaborated why the established scattering methods using X-rays and visible light cannot in general be transferred to granular media. Spectroscopic measurements using terahertz radiation are highlighted as they probe the scattering properties of granular media, which are sensitive to the packing structure. Experimental details to optimize a spectrometer for measurements on granular media are discussed. We perform transmission measurements on static and agitated granular media using Fourier transform spectroscopy at the THz beamline of the Bessy II storage ring. The measurements demonstrate the potential to evaluate degrees of order in the media and to track transient structural states in agitated bulk granular media. PMID- 28571463 TI - A Q-band low noise GaAs pHEMT MMIC power amplifier for pulse electron spin resonance spectrometer. AB - We present the design and development of a single stage pulse power amplifier working in the frequency range 32-38 GHz based on a monolithic microwave integrated circuit (MMIC). We have designed the MMIC power amplifier by using the commercially available packaged GaAs pseudomorphic high electron mobility transistor. The circuit fabrication and assembly process includes the elaboration of the matching networks for the MMIC power amplifier and their assembling as well as the topology outline and fabrication of the printed circuit board of the waveguide-microstrip line transitions. At room ambient temperature, the measured peak output power from the prototype amplifier is 35.5 dBm for 16.6 dBm input driving power, corresponding to 19 dB gain. The measured rise/fall time of the output microwave signal modulated by a high-speed PIN diode was obtained as 5-6 ns at 20-250 ns pulse width with 100 kHz pulse repetition rate frequency. PMID- 28571464 TI - Apparatus and test method for characterizing the temperature regulating properties of thermal functional porous polymeric materials. AB - In order to evaluate the temperature regulating properties of thermal functional porous polymeric materials such as fabrics treated with phase change material microcapsules, a new apparatus was developed. The apparatus and the test method can measure the heat flux, temperature, and displacement signals during the dynamic contact and then quickly give an evaluation for the temperature regulating properties by simulating the dynamic heat transfer and temperature regulating process when the materials contact the body skin. A series of indices including the psychosensory intensity, regulating capability index, and relative regulating index were defined to characterize the temperature regulating properties. The measurement principle, the evaluation criteria and grading method, the experimental setup and the test results discussion, and the gage capability analysis of the apparatus are presented. The new apparatus provides a method for the objective measurement and evaluation of the temperature regulating properties of thermal functional porous polymeric materials. PMID- 28571465 TI - A high-flux upgrade for the BRISP spectrometer at ILL. AB - To date, the BRISP spectrometer represents the state-of-the-art for every instrument aiming to perform Brillouin neutron scattering. Exploiting accurate ray-tracing McStas simulations, we investigate an improved configuration of the BRISP primary spectrometer to provide a higher flux at the sample position, while preserving all the present capabilities of the instrument. This configuration is based on a neutron guide system and is designed to fit the instrument platform with no modifications of the secondary spectrometer. These evaluations show that this setup can achieve a flux gain factor ranging from 3 to 6, depending on the wavelength. This can expand the experimental possibilities of BRISP towards smaller samples, possibly using also complex sample environments. PMID- 28571466 TI - Localized thin film damage sourced and monitored via pump-probe modulated thermoreflectance. AB - Damage in the form of dewetting and delamination of thin films is a major concern in applications requiring micro- or nano-fabrication. In non-contact nanoscale characterization, optical interrogation must be kept to energies below damage thresholds in order to conduct measurements such as pump-probe spectroscopy. In this study, we show that the thermoreflectance of thin films can indicate the degree of film damage induced by a modulated optical heating source. By adjusting the absorbed power of the pump heating event, we identify the characteristics of the change in the thermoreflectance signal when leading up to and exceeding the damage threshold of gold films of varying thicknesses on glass substrates. PMID- 28571467 TI - Acoustic spectrometer with minimized background dissipation. AB - Apparatus for measurements of internal friction from Q-1~10-6 and elastic moduli in the kilohertz frequency range in which external friction losses were minimized using a new-type of three-reed tuning fork as a sample under study is described. High sensitivity of the apparatus made it possible to observe a resonance plasticization of diamagnetic LiF crystals under the action of crossed magnetic fields (~100 MUT) in the EPR conditions. PMID- 28571468 TI - Radar for tracer particles. AB - We introduce a radar system capable of tracking a 5 mm spherical target continuously in three dimensions. The 10 GHz (X-band) radar system has a transmission power of 1 W and operates in the near field of the horn antennae. By comparing the phase shift of the electromagnetic wave traveling through the free space with an IQ-mixer, we obtain the relative movement of the target with respect to the antennae. From the azimuth and inclination angles of the receiving antennae obtained in the calibration, we reconstruct the target trajectory in a three-dimensional Cartesian system. Finally, we test the tracking algorithm with target moving in circular as well as in pendulum motions and discuss the capability of the radar system. PMID- 28571469 TI - Robust regression and its application in absolute gravimeters. AB - Maximum-likelihood estimation of robust regression is employed to process absolute gravimeter data because this method is insensitive to outliers. Gravity values obtained by both ordinary least squares and different approaches for robust regression are compared with the results obtained by the g9 processing software for the FG5 gravimeter. The results show that the accuracy of gravity data can be improved by rejecting certain outliers via adjustments to a suitable weighting function of time-distance pairs. A convenient method of identifying those outliers by their weight is also presented. PMID- 28571470 TI - Choosing the filter for catenary image enhancement method based on the non subsampled contourlet transform. AB - The quality of image enhancement plays an important role in the catenary fault diagnosis system based on the image processing technique. It is necessary to enhance the low contrast image of catenary for better detecting the state of catenary part. The Non-subsampled Contourlet transform (NSCT) is the improved Contourlet transform (CT), which can effectively solve the problem of artifact phenomenon in the enhanced catenary image. Besides, choosing the enhancement function and the filter of the NSCT will directly influence the image enhancement effect. In this paper, the proposed method is implemented by combining the NSCT with the nonlinear enhancement function to enhance the catenary image. First, how to choose the filter of the NSCT is discussed. Second, the NSCT is used to decompose the image. Then, the chosen nonlinear enhancement function is used to process the decomposed coefficient of the NSCT. Finally, the NSCT is inversed to obtain the enhanced image. In this paper, we evaluate our algorithm using the lifting wavelet transform, retinex enhancement method, dark channel enhancement method, curvelet transform, and CT method as a comparison to enhance a group of randomly selected low contrast catenary images, respectively. The results of comparative experiments conducted show that the proposed method can effectively enhance the catenary image, the contrast of image is improved, the catenary parts are obvious, and the artifact phenomenon is effectively eliminated, where image details (edges, textures, or smooth areas) are also well preserved. Besides, the values (detail variance-background variance, signal-to-noise ratio, and edge preservation index) of measuring the image enhancement capacity are improved, while the mean squared error value is decreased when compared to the CT method. These indicate that the proposed method is an excellent catenary image enhancement approach. PMID- 28571471 TI - Imaging at an x-ray absorption edge using free electron laser pulses for interface dynamics in high energy density systems. AB - Tuning the energy of an x-ray probe to an absorption line or edge can provide material-specific measurements that are particularly useful for interfaces. Simulated hard x-ray images above the Fe K-edge are presented to examine ion diffusion across an interface between Fe2O3 and SiO2 aerogel foam materials. The simulations demonstrate the feasibility of such a technique for measurements of density scale lengths near the interface with submicron spatial resolution. A proof-of-principle experiment is designed and performed at the Linac coherent light source facility. Preliminary data show the change of the interface after shock compression and heating with simultaneous fluorescence spectra for temperature determination. The results provide the first demonstration of using x ray imaging at an absorption edge as a diagnostic to detect ultrafast phenomena for interface physics in high-energy-density systems. PMID- 28571472 TI - A compact multi-wire-layered secondary winding for Tesla transformer. AB - A compact multi-wire-layered (MWL) secondary winding for a Tesla transformer is put forward. The basic principle of this winding is to wind the metal wire on a polymeric base tube in a multi-layer manner. The tube is tapered and has high electrical strength and high mechanical strength. Concentric-circle grooves perpendicular to the axis of the tube are carved on the surface of the tube to wind the wire. The width of the groove is basically equal to the diameter of the wire so that the metal wire can be fixed in the groove without glue. The depth of the groove is n times of the diameter of the wire to realize the n-layer winding manner. All the concentric-circle grooves are connected via a spiral groove on the surface of the tube to let the wire go through. Compared with the traditional one-wire-layered (OWL) secondary winding for the Tesla transformer, the most conspicuous advantage of the MWL secondary winding is that the latter is compact with only a length of 2/n of the OWL. In addition, the MWL winding has the following advantages: high electrical strength since voids are precluded from the surface of the winding, high mechanical strength because polymer is used as the material of the base tube, and reliable fixation in the Tesla transformer as special mechanical connections are designed. A 2000-turn MWL secondary winding is fabricated with a winding layer of 3 and a total length of 1.0 m. Experiments to test the performance of this winding on a Tesla-type pulse generator are conducted. The results show that this winding can boost the voltage to 1 MV at a repetition rate of 50 Hz reliably for a lifetime longer than 104 pulses, which proves the feasibility of the MWL secondary winding. PMID- 28571473 TI - An interferometric system for measuring thickness of parallel glass plates without 2pi ambiguity using phase analysis of quadrature Haidinger fringes. AB - An interferometric system is proposed for measuring the thickness of parallel glass plates by analyzing Haidinger fringes. Although a conventional Haidinger interferometer can measure thickness without 2pi ambiguity using positions of peak and valley points in the interferogram, measurement accuracy is directly affected by the number of these points involved in the calculation. The proposed method obtains phase values over the entire interferogram by analyzing the quadrature Haidinger fringes generated by a current modulated laser diode. Therefore, it can achieve high speed measurement and nanometric resolution without mechanical rotation and thickness limitation of specimens. In the experiments, the standard deviation of repeated thickness measurement was evaluated as less than 0.3 nm, and the measured thickness profile of the proposed system agreed with that of a conventional thickness interferometer within +/-15 nm. We also discussed the required accuracy of refractive index of specimens to implement the proposed method successfully and presented an exemplary measurement result of a multi-layer coated sample having a discontinuous thickness profile. PMID- 28571474 TI - Psychometric validation of the Persian nine-item Internet Gaming Disorder Scale - Short Form: Does gender and hours spent online gaming affect the interpretations of item descriptions? AB - Background and aims The nine-item Internet Gaming Disorder Scale - Short Form (IGDS-SF9) is brief and effective to evaluate Internet Gaming Disorder (IGD) severity. Although its scores show promising psychometric properties, less is known about whether different groups of gamers interpret the items similarly. This study aimed to verify the construct validity of the Persian IGDS-SF9 and examine the scores in relation to gender and hours spent online gaming among 2,363 Iranian adolescents. Methods Confirmatory factor analysis (CFA) and Rasch analysis were used to examine the construct validity of the IGDS-SF9. The effects of gender and time spent online gaming per week were investigated by multigroup CFA and Rasch differential item functioning (DIF). Results The unidimensionality of the IGDS-SF9 was supported in both CFA and Rasch. However, Item 4 (fail to control or cease gaming activities) displayed DIF (DIF contrast = 0.55) slightly over the recommended cutoff in Rasch but was invariant in multigroup CFA across gender. Items 4 (DIF contrast = -0.67) and 9 (jeopardize or lose an important thing because of gaming activity; DIF contrast = 0.61) displayed DIF in Rasch and were non-invariant in multigroup CFA across time spent online gaming. Conclusions Given the Persian IGDS-SF9 was unidimensional, it is concluded that the instrument can be used to assess IGD severity. However, users of the instrument are cautioned concerning the comparisons of the sum scores of the IGDS-SF9 across gender and across adolescents spending different amounts of time online gaming. PMID- 28571475 TI - Biological Sensitivity to the Effects of Childhood Family Adversity on Psychological Well-Being in Young Adulthood. AB - The theory of biological sensitivity to context may inform our understanding of why some children exposed to family adversity develop mental health problems in emerging adulthood whereas others demonstrate resilience. This study investigated the interactive effects of heart rate (HR) reactivity and childhood family adversity (maltreatment and changes in family structure) on depressive symptoms and positive affect among 150 undergraduate students (18-28 years old; 77% White, non-Hispanic; 61% female). Participants reported on childhood parental divorce or death, and child maltreatment, and current depressive symptoms and positive affect. HR reactivity was assessed in response to a laboratory interpersonal stressor. HR reactivity moderated the effects of child maltreatment on depressive symptoms and positive affect; higher maltreatment was associated with more depressive symptoms and less positive affect, but only among those with average and higher levels of HR reactivity. Results suggest that higher physiological reactivity may confer greater susceptibility to environmental contexts. PMID- 28571476 TI - The safety and tolerability of nintedanib in the treatment of idiopathic pulmonary fibrosis. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that primarily affects older individuals. Nintedanib, a tyrosine kinase inhibitor, has been approved for the treatment of IPF in several countries. The safety and tolerability of nintedanib have been investigated in clinical trials and in real-world studies (compassionate use programs and post marketing surveillance). Areas covered: Most frequent adverse events reported in patients treated with nintedanib (gastrointestinal); additional adverse events of special interest (elevations in liver enzymes, bleeding, cardiovascular adverse events); recommendations for managing adverse events. Expert opinion: Experience with nintedanib in real-world clinical practice suggests that it has a safety and tolerability profile consistent with that observed in clinical trials. Upon initiation of nintedanib, patient education, regular monitoring and proactive management of adverse events such as diarrhea are needed to minimize the risk of permanent treatment discontinuation. Algorithms are available to help manage diarrhea and liver enzyme elevations. Further investigation of the safety and tolerability profile of nintedanib when used in combination with pirfenidone is warranted. PMID- 28571477 TI - Cardiotoxicity of ErbB2-targeted therapies and its impact on drug development, a spotlight on trastuzumab. AB - INTRODUCTION: Trastuzumab, a therapeutic monoclonal antibody directed against ErbB2, is often noted as a successful example of targeted therapy. Trastuzumab improved outcomes for many patients with ErbB2-positive breast and gastric cancers, however, cardiac side effects [e.g., left ventricular dysfunction and congestive heart failure (CHF)] were reported in the early phase clinical studies. This finding, subsequently corroborated by multiple clinical studies, raised concerns that the observed cardiotoxicity induced by trastuzumab might adversely impact the clinical development of other therapeutics targeting ErbB family members. Areas covered: In this review we summarize both basic research and clinical findings regarding trastuzumab-induced cardiotoxicity and assess if there has been an impact of trastuzumab-induced cardiotoxicity on the development of other agents targeting ErbB family members. Expert opinion: There are a number of scientific gaps that are critically important to address for the continued success of HER2-targeted agents. These include: 1) elucidating the molecular mechanisms contributing to cardiotoxicity; 2) developing relevant preclinical testing systems for predicting cardiotoxicity; 3) developing clinical strategies to identify patients at risk of cardiotoxicity; and 4) enhancing management of clinical symptoms of cardiotoxicity. PMID- 28571478 TI - Nutriepigenomics and malnutrition. AB - Epigenetics is defined as the modulation of gene expression without changes to the underlying DNA sequence. Epigenetic alterations, as a consequence of in utero malnutrition, may play a role in susceptibility to develop adulthood diseases and inheritance. However, the mechanistic link between epigenetic modifications and abnormalities in nutrition remains elusive. This review provides an update on the association of suboptimal nutritional environment and the high propensity to produce adult-onset chronic illnesses with a particular focus on modifications in genome functions that occur without alterations to the DNA sequence. We will mention the drivers of the phenotype and pattern of epigenetic markers set down during the reprogramming along with novel preventative and therapeutic strategies. New knowledge of epigenetic alterations is opening a gate toward personalized medicine. PMID- 28571479 TI - Assessing the therapeutic readiness of stem cells for cardiovascular repair. PMID- 28571480 TI - New routes in frontotemporal dementia drug discovery. AB - INTRODUCTION: Research into the pathogenic mechanisms behind frontotemporal dementia (FTD) has yielded several new targets for therapeutic intervention; such targets include specific new pathways uncovered by mutations as well as targets involving the modulation, formation and degradation of protein aggregates. Areas covered: Herein, the authors outline the principal molecular causes underlying FTD to date and the research that has been performed in these areas with respect to an eventual corrective strategy. Expert opinion: While it is worthwhile targeting pathways affected by specific mutations with a causative loss of function linked to FTD, research still has to contend with issues including the remaining presence of protein aggregates or that treatments are rarely universally applicable. Aiming to recover function in a downstream target caused by the protein aggregates will likely be insufficient due to the large cascade of events affected. It is our belief that the clearance of these aggregates and the inhibition of protein misfolding are more appropriate and direct routes to an eventual therapy. PMID- 28571481 TI - Blood biomarkers of kidney transplant rejection, an endless search? AB - INTRODUCTION: The tailoring of immunosuppressive treatment is recognized as a promising strategy to improve long-term kidney graft outcome. To guide the standard care of transplant recipients, physicians need objective biomarkers that can identify an ongoing pathology with the graft or low intensity signals that will be later evolved to accelerated transplant rejection. The early identification of 'high-risk /low-risk' patients enables the adjustment of standard of caring, including managing the frequency of clinical visits and the immunosuppression dosing. Given their ease of availability and the compatibility with a large technical array, blood-based biomarkers have been widely scrutinized for use as potential predictive and diagnostic biomarkers. Areas covered: Here, the authors report on non-invasive biomarkers, such as modification of immune cell subsets and mRNA and miRNA profiles, identified in the blood of kidney transplant recipients collected before or after transplantation. Expert commentary: Combined with functional tests, the identification of biomarkers will improve our understanding of pathological processes and will contribute to a global improvement in clinical management. PMID- 28571482 TI - Introduction to selected papers from the 8th International Conference on Bioinformatics and Computational Biology (BICOB 2016). PMID- 28571483 TI - An efficient method for significant motifs discovery from multiple DNA sequences. AB - Identification of transcription factor binding sites or biological motifs is an important step in deciphering the mechanisms of gene regulation. It is a classic problem that has eluded a satisfactory and efficient solution. In this paper, we devise a three-phase algorithm to mine for biologically significant motifs. In the first phase, we generate all the possible string motifs, this phase is followed by a filtering process where we discard all motifs that do not meet the constraints. And in the final phase, motifs are scored and ranked using a combination of stochastic techniques and [Formula: see text]-value. We show that our method outperforms some very well-known motif discovery tools, e.g. MEME and Weeder on well-established benchmark data suites. We also apply the algorithm on the non-coding regions of M. tuberculosis and report significant motifs of size 10 with excellent [Formula: see text]-values in a fraction of the time MEME and MoSDi did. In fact, among the best 10 motifs ([Formula: see text]-value wise) in the non-coding regions of M. tuberculosis reported by the tools MEME, MoSDi and ours, five were discovered by our approach which included the third and the fourth best ones. All this in 1/17 and 1/6 the time which MEME and MoSDi (respectively) took. PMID- 28571484 TI - Sclerostin Deficiency Promotes Reparative Dentinogenesis. AB - In humans, the SOST gene encodes sclerostin, an inhibitor of bone growth and remodeling, which also negatively regulates the bone repair process. Sclerostin has also been implicated in tooth formation, but its potential role in pulp healing remains unknown. The aim of this study was to explore the role of sclerostin in reparative dentinogenesis using Sost knockout mice ( Sost-/-). The pulps of the first maxillary molars were mechanically exposed in 3-mo-old Sost-/- and wild-type (WT) mice ( n = 14 mice per group), capped with mineral trioxide aggregate cement, and the cavities were filled with a bonded composite resin. Reparative dentinogenesis was dynamically followed up by micro-computed tomography and characterized by histological analyses. Presurgical analysis revealed a significantly lower pulp volume in Sost-/- mice compared with WT. At 30 and 49 d postsurgery, a large-forming reparative mineralized bridge, associated with osteopontin-positive mineralization foci, was observed in the Sost-/- pulps, whereas a much smaller bridge was detected in WT. At the longer time points, the bridge, which was associated with dentin sialoprotein-positive cells, had expanded in both groups but remained significantly larger in Sost-/- pulps. Sclerostin expression in the healing WT pulps was detected in the cells neighboring the forming dentin bridge. In vitro, mineralization induced by Sost-/ dental pulp cells (DPCs) was also dramatically enhanced when compared with WT DPCs. These observations were associated with an increased Sost expression in WT cells. Taken together, our data show that sclerostin deficiency hastened reparative dentinogenesis after pulp injury, suggesting that the inhibition of sclerostin may constitute a promising therapeutic strategy for improving the healing of damaged pulps. PMID- 28571485 TI - Continuous Autoregulatory Indices Derived from Multi-Modal Monitoring: Each One Is Not Like the Other. AB - We assess the relationships between various continuous measures of autoregulatory capacity in a cohort of adults with traumatic brain injury (TBI). We assessed relationships between autoregulatory indices derived from intracranial pressure (ICP: PRx, PAx, RAC), transcranial Doppler (TCD: Mx, Sx, Dx), brain tissue oxygenation (ORx), and spatially resolved near infrared spectroscopy (NIRS resolved: TOx, THx). Relationships between indices were assessed using Pearson correlation coefficient, Friedman test, principal component analysis (PCA), agglomerative hierarchal clustering (AHC) and k-means cluster analysis (KMCA). All analytic techniques were repeated for a range of temporal resolutions of data, including minute-by-minute averages, moving means of 30 samples, and grand mean for each patient. Thirty-seven patients were studied. The PRx displayed strong association with PAx/RAC across all the analytical techniques: Pearson correlation (r = 0.682/r = 0.677, p < 0.0001), PCA, AHC, and KMCA in the grand mean data sheet. Most TCD-based indices (Mx, Dx) were correlated and co-clustered on PCA, AHC, and KMCA. The Sx was found to be more closely associated with ICP derived indices on Pearson correlation, PCA, AHC, and KMCA. The NIRS indices displayed variable correlation with each other and with indices derived from ICP and TCD signals. Of interest, TOx and THx co-cluster with ICP-based indices on PCA and AHC. The ORx failed to display any meaningful correlations with other indices in neither of the analytical method used. Thirty-minute moving average and minute-by-minute data set displayed similar results across all the methods. The RAC, Mx, and Sx were the strongest predictors of outcome at six months. Continuously updating autoregulatory indices are not all correlated with one another. Caution must be advised when utilizing less commonly described autoregulation indices (i.e., ORx) for the clinical assessment of autoregulatory capacity, because they appear to not be related to commonly measured/establish indices, such as PRx. Further prospective validation is required. PMID- 28571486 TI - Repositionable self-expanding aortic bioprosthesis. AB - INTRODUCTION: Transcatheter aortic valve implantation/replacement (TAVI or TAVR) has been established as a first line therapy in patients with symptomatic severe aortic stenosis (AS) at high or prohibitive surgical risk and as an alternative in elderly patients with intermediate surgical risk. Since its first-in-human procedure in 2002, the past 15-years have shown rapid developments in TAVI technology with the introduction and further improvement of new transcatheter heart valves (THV). Areas covered: There are currently several THV systems available, based on balloon-expandable, self-expandable or other technologies. Some of these are repositionable and retrievable even after partial or full deployment, potentially reducing the risk of malpositioning. The aim of this review is to describe such repositionable self-expandable THV systems. Expert commentary: Repositionability potentially represents a crucial step towards higher safety and efficacy of TAVI. It is unclear if full self-expandability or a combination of self and mechanical expansion will be more advantageous. PMID- 28571490 TI - Laboratory animal science course in Switzerland: participants' points of view and implications for organizers. AB - Switzerland has implemented a mandatory training in laboratory animal science since 1999; however a comprehensive assessment of its effects has never been undertaken so far. The results from the analysis of participants in the Swiss Federation of European Laboratory Animal Science Associations (FELASA) Category B compulsory courses in laboratory animal science run in 2010, 2012, 2014 and 2016 showed that the participants fully appreciated all elements of the course. The use of live animals during the course was supported and explained by six arguments characterized with cognitive, emotional and forward-looking factors. A large majority considered that the 3R (replacement, reduction and refinement) principles were adequately applied during the course. Responses to an open question offered some ideas for improvements. This overall positive picture, however, revealed divergent answers from different subpopulations in our sample (for example, scientists with more hindsight, scientists trained in biology, or participants from Asian countries). PMID- 28571491 TI - Insights into unbound-bound states of GPR142 receptor in a membrane-aqueous system using molecular dynamics simulations. AB - G protein coupled receptors (GPCRs) are source machinery in signal transduction pathways and being one of the major therapeutic targets play a significant in drug discovery. GPR142, an orphan GPCR, has been implicated in the regulation of insulin, thereby having a crucial role in Type II diabetes management. Deciphering of the structures of orphan, GPCRs (O-GPCRs) offer better prospects for advancements in research in ion translocation and transduction of extracellular signals. As the crystallographic structure of GPR142 is not available in PDB, therefore, threading and ab initio-based approaches were used for 3D modeling of GPR142. Molecular dynamic simulations (900 ns) were performed on the 3D model of GPR142 and complexes of GPR142 with top five hits, obtained through virtual screening, embedded in lipid bilayer with aqueous system using OPLS force field. Compound 1, 3, and 4 may act as scaffolds for designing potential lead agonists for GPR142. The finding of GPR142 MD simulation study provides more comprehensive representation of the functional properties. The concern for Type II diabetes is increasing worldwide and successful treatment of this disease demands novel drugs with better efficacy. PMID- 28571489 TI - Thioredoxin-1, chemokine (C-X-C motif) ligand-9 and interferon-gamma expression in the neoplastic cells and macrophages of Hodgkin lymphoma: clinicopathologic correlations and potential prognostic implications. AB - Expression of thioredoxin-1 (TXN) and CXCL9 is not restricted to THRLBCL macrophages, but may be observed in histiocytes and neoplastic (HRS) cells of EBV + mixed cellularity (MC) classical Hodgkin lymphoma (cHL) and nodular lymphocyte predominant HL. We aimed to validate and extend the above observations in 174 cHL patients evaluating the immunohistochemical expression of TXN, CXCL9 and IFN gamma. HRS-cell CXCL9 expression was higher in latent membrane protein-1 (LMP1)+, MC and Stage IV. TXN and CXCL9 expression by cHL histiocytes was more frequent in LMP1+, MC and older patients (only for CXCL9). TXN expression by HRS cells (>=80%) was independently associated with better failure-free survival. In conclusion, markers of TCHRLBCL histiocytes (TXN, CXCL9), as well as IFN-gamma are also expressed by histiocyte subsets and neoplastic cells of cHL. The expression of some of them is more prominent in EBV + MC, but not restricted to this subtype. The prognostic implication of TXN needs further evaluation. PMID- 28571487 TI - Targeting of Streptococcus mutans Biofilms by a Novel Small Molecule Prevents Dental Caries and Preserves the Oral Microbiome. AB - Dental caries is a costly and prevalent disease characterized by the demineralization of the tooth's enamel. Disease outcome is influenced by host factors, dietary intake, cariogenic bacteria, and other microbes. The cariogenic bacterial species Streptococcus mutans metabolizes sucrose to initiate biofilm formation on the tooth surface and consequently produces lactic acid to degrade the tooth's enamel. Persistence of S. mutans biofilms in the oral cavity can lead to tooth decay. To date, no anticaries therapies that specifically target S. mutans biofilms but do not disturb the overall oral microbiome are available. We screened a library of 2-aminoimidazole antibiofilm compounds with a biofilm dispersion assay and identified a small molecule that specifically targets S. mutans biofilms. At 5 uM, the small molecule annotated 3F1 dispersed 50% of the established S. mutans biofilm but did not disperse biofilms formed by the commensal species Streptococcus sanguinis or Streptococcus gordonii. 3F1 dispersed S. mutans biofilms independently of biofilm-related factors such as antigen I/II and glucosyltransferases. 3F1 treatment effectively prevented dental caries by controlling S. mutans in a rat caries model without perturbing the oral microbiota. Our study demonstrates that selective targeting of S. mutans biofilms by 3F1 was able to effectively reduce dental caries in vivo without affecting the overall oral microbiota shaped by the intake of dietary sugars, suggesting that the pathogenic biofilm-specific treatment is a viable strategy for disease prevention. PMID- 28571493 TI - Optimizing beta-lactams treatment in critically-ill patients using pharmacokinetics/pharmacodynamics targets: are first conventional doses effective? AB - INTRODUCTION: The pharmacokinetic/pharmacodynamic index determining beta-lactam activity is the percentage of the dosing interval (%T) during which their free serum concentration remains above a critical threshold over the minimum inhibitory concentration (MIC). Regrettably, neither the value of %T nor that of the threshold are clearly defined for critically-ill patients. Areas covered: We review and assess the targets proposed for beta-lactams in critical illness by screening the literature since 1997. Depending on the study intention (clinical cure vs. suppression of resistance), targets proposed range from 20%T > 1xMIC to 100%T > 5xMIC. Assessment and comparative analysis of their respective clinical efficacy suggest that a value of 100%T > 4xMIC may be needed. Simulation studies, however, show that this target will not be reached at first dose for the majority of critically-ill patients if using the most commonly recommended doses. Expert commentary: Considering that critically-ill patients are highly vulnerable and likely to experience antibiotic underexposure, and because effective initial treatment is a key determinant of clinical outcome, we support the use of a target of 100%T > 4xMIC, which could not only maximize efficacy but also minimize emergence of resistance. Clinical and microbiological studies are needed to test for the feasibility and effectiveness of reaching such a demanding target. PMID- 28571494 TI - Cardiovascular pleiotropic effects of statins and new onset diabetes: is there a common link: do we need to evaluate the role of KATP channels? AB - INTRODUCTION: Statins are considered the main stay of treatment in the prevention of cardio-vascular morbidity and mortality. They have multiple pleiotropic effects, like stabilization of atherosclerotic plaques, inhibition of platelet aggregation, and vascular smooth muscle proliferation; in addition to their lipid lowering action. Statins manifest these pleiotropic effects because they activate KATP channels in the cardiac and vascular tissue. Simultaneous activation of the KATP channels by statins in beta cells of pancreas may inhibit insulin release which may lead to diabetes. Areas covered: Literature published between 1980 and 2016 on cholesterol biosynthesis, new onset diabetes and on the pleiotropic effects of statins, was reviewed. A comprehensive search on PubMed, Embase and Cochrane databases was carried out. Expert opinion: Statins exert their beneficial pleiotropic effects on the cardiovascular system by activating KATP channels in the cardiac and vascular tissue. However, simultaneous activation of KATP channels in the beta cells of pancreas leads to inhibition of insulin release. This disturbs the carbohydrate metabolism and probably leads to diabetes. In our opinion, use of stains should be more judicious and restricted to secondary prevention only. PMID- 28571495 TI - Phytochemical characterisation and bioprospection for antibacterial and antioxidant activities of Lippia alba Brown ex Britton & Wilson (Verbenaceae). AB - Ethanol extract and fractions obtained from fresh and dry aerial parts of Lippia alba were examined in order to determine their phytochemical composition, antioxidant capacity and antibacterial activities. The ethanol extracts and fractions exhibited an antioxidant effect by the DPPH assay, especially samples of fresh plant. HPLC analysis of the ethyl acetate fractions identified the presence of phenolic acids and flavonoids. The ethanol extract and fractions showed activity against reference and multidrug-resistant strains of Staphylococcus aureus and Enterococcus faecalis (MIC range 2000-250 MUg/mL). The hexane and dichloromethane fractions of fresh plant showed better activity against reference strains of Escherichia coli (MIC of 250 and 125 MUg/mL, respectively), but all extracts and fractions were less active against multidrug resistant strains of all the Gram-negative species evaluated. The results showed that the extract and fractions of L alba aerial parts showed antibacterial activity, even against multidrug-resistant Gram-positive bacteria, and antioxidant effect (DPPH assay). PMID- 28571492 TI - Eccentric Exercise to Enhance Neuromuscular Control. AB - CONTEXT: Neuromuscular alterations are a major causal factor of primary and secondary injuries. Though injury prevention programs have experienced some success, rates of injuries have not declined, and after injury, individuals often return to activity with functionality below clinical recommendations. Considering alternative therapies to the conventional concentric exercise approach, such as one that can target neuromuscular injury risk and postinjury alterations, may provide for more effective injury prevention and rehabilitation protocols. EVIDENCE ACQUISITION: Peer-reviewed sources available on the Web of Science and MEDLINE databases from 2000 through 2016 were gathered using searches associated with the keywords eccentric exercise, injury prevention, and neuromuscular control. HYPOTHESIS: Eccentric exercise will reduce injury risk by targeting specific neural and morphologic alterations that precipitate neuromuscular dysfunction. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Neuromuscular control is influenced by alterations in muscle morphology and neural activity. Eccentric exercise beneficially modifies several underlying factors of muscle morphology (fiber typing, cross-sectional area, working range, and pennation angle), and emerging evidence indicates that eccentric exercise is also beneficial to peripheral and central neural activity (alpha motorneuron recruitment/firing, sarcolemma activity, corticospinal excitability, and brain activation). CONCLUSION: There is mounting evidence that eccentric exercise is not only a therapeutic intervention influencing muscle morphology but also targets unique alterations in neuromuscular control, influencing injury risk. PMID- 28571496 TI - Occupational Variation in End-of-Life Care Intensity. AB - BACKGROUND: End-of-life (EOL) care intensity is known to vary by secular and geographic patterns. US physicians receive less aggressive EOL care than the general population, presumably the result of preferences shaped by work-place experience with EOL care. OBJECTIVE: We investigated occupation as a source of variation in EOL care intensity. METHODS: Across 4 states, we identified 660 599, nonhealth maintenance organization Medicare beneficiaries aged >=66 years who died between 2004 and 2011. Linking death certificates, we identified beneficiaries with prespecified occupations: nurses, farmers, clergy, mortuary workers, homemakers, first-responders, veterinary workers, teachers, accountants, and the general population. End-of-life care intensity over the last 6 months of life was assessed using 5 validated measures: (1) Medicare expenditures, rates of (2) hospice, (3) surgery, (4) intensive care, and (5) in-hospital death. RESULTS: Occupation was a source of large variation in EOL care intensity across all measures, before and after adjustment for sex, education, age-adjusted Charlson Comorbidity Index, race/ethnicity, and hospital referral region. For example, absolute and relative adjusted differences in expenditures were US$9991 and 42% of population mean expenditure ( P < .001 for both). Compared to the general population on the 5 EOL care intensity measures, teachers (5 of 5), homemakers (4 of 5), farmers (4 of 5), and clergy (3 of 5) demonstrated significantly less aggressive care. Mortuary workers had lower EOL care intensity (4 of 5) but small numbers limited statistical significance. CONCLUSION: Occupations with likely exposure to child development, death/bereavement, and naturalistic influences demonstrated lower EOL care intensity. These findings may inform patients and clinicians navigating choices around individual EOL care preferences. PMID- 28571497 TI - Strategies to Improve Quality of Life at the End of Life: Interdisciplinary Team Perspectives. AB - This ethnographic study draws on the experiences of members of interdisciplinary care teams working with end-of-life care patients to identify strategies to improve quality of life through care practices. We surveyed 133 staff and volunteers (physicians, physician assistants, nurse practitioners, registered nurses, social workers, chaplains, administrators, and volunteers) who provide end-of-life care to patients in both home and institutional settings for 4 organizations in 2 counties in Upstate New York. Survey responses were analyzed using qualitative content analysis. The results identified numerous strategies to enhance and safeguard quality of life for end-of-life care patients and their family members. These strategies can be categorized into 6 domains: organization philosophy and mission; organizational policies; caregivers' behaviors and practices; symptom management; facility design, operation and management; and patient, family member, and caregiver experience. The diverse list of identified strategies indicates that improving care to address the unique, complex, multilayered dimensions of quality of life at the end of life requires a multidisciplinary approach and consistency among care providers, including administration, clinical management, front-line caregivers, and support staff. When all of these strategies are used in harmony, care can truly be enhanced. PMID- 28571498 TI - Preliminary Analysis of a Modified Screening Tool to Increase the Frequency of Palliative Care Consults. AB - PURPOSE: Palliative care interventions have been shown to improve patient quality of life but the benefit may be less if interventions occur late in the patient's disease process. The objective of this study was to evaluate whether an objective screening tool could improve the frequency and timeliness of palliative care consultation. METHODS: Using a quasi-experimental design with 2 geographically separate medical intensive care units (MICUs), the control MICU continued existing consultation practice and the intervention MICU implemented a screening tool with each new admission. Any item checked on the screening tool triggered a palliative care consult within 24 hours of admission to the MICU. RESULTS: A total of 223 MICU admissions were evaluated: 156 patients in the control group and 67 patients in the intervention group. More consults were generated in the intervention group (22.39%) compared to the control group (7.05%; P < .001). The median time to consultation was lower in the intervention group compared to the control group (1 day vs 2 days; P < .01). CONCLUSION: Implementing a simple, objective screening tool increased palliative consultation rates and decreased median time to palliative consultation in our institution's MICU. PMID- 28571499 TI - Amelioration of hyperglycaemia and modulation of antioxidant status by Alcea rosea seeds in alloxan-induced diabetic rats. AB - CONTEXT: Alcea rosea L. (Malvaceae) has various medicinal uses including anticancer, anti-inflammatory and analgesic properties. However, there is no report on its antidiabetic activity. OBJECTIVE: Alcea rosea seed extracts were evaluated for antihyperglycaemic and antioxidative potential in diabetic rats. MATERIALS AND METHODS: Single intra-peritoneal injection of alloxan (130 mg/kg b.w.) was used for induction of diabetes in Albino Wistar rats. Antihyperglycaemic and antioxidant activities of methanol and aqueous extracts of Alcea rosea seed (100 and 300 mg/kg b.w.), administered orally on daily basis for 15 days, were assessed in vivo for fasting blood glucose level and antioxidant status of liver and pancreas. Metformin was used as a positive control. RESULTS: Aqueous and methanol extracts (300 mg/kg b.w.) decreased blood glucose level in diabetic rats by 24% and 46%, respectively. Administration of aqueous and methanol extracts at 300 mg/kg b.w. significantly (p < 0.01) modulated the antioxidant status of liver in diabetic rats by increasing levels of GR (22.5 +/- 1.0, 24.4 +/- 1.02 MUg GSSG utilized/min/mg of protein), GPx (20.7 +/- 1.2, 23.6 +/- 2.04 MUg GSH utilized/min/mg of protein), SOD (36.1 +/- 1.7, 39.05 +/- 1.5 units/mg of protein) and CAT (1744.5 +/- 132.5, 1956.6 +/- 125.2 nmol H2O2 decomposed/min/mg of protein), respectively. Similar results were observed for pancreas. DISCUSSION AND CONCLUSIONS: Antihyperglycaemic and antioxidative potentials of Alcea rosea seeds suggest its usefulness in management of diabetes and its complications. This is the first report on antidiabetic activity of this plant. PMID- 28571501 TI - CT-P13 in the treatment of rheumatoid arthritis. AB - INTRODUCTION: The first biosimilar infliximab, CT-P13 infliximab-dyyb was approved in 2013 by the European Medicines Agency (EMA) and in 2016 by the United States Food and Drug Administration (FDA) and has been used for the treatment of rheumatoid arthritis (RA) for 4 years. Areas covered: CT-P13 with the three brand names on the market has highly similar efficacy and safety profiles but lower price than originator infliximab and are approved in more than 80 countries. One of the most important determinants of the implementation of CT-P13 in the treatment of RA is scientific evidence from clinical studies and real-world pharmacovigilance data. Here, we review all available clinical data supporting the similarity of CT-P13 to originator infliximab in its clinical efficacy and safety for the treatment of RA and related arthritis. In addition, we consider the role of CT-P13 in therapeutic strategies for RA treatment. Expert commentary: With its highly similar efficacy and safety profile to originator infliximab and its lower price, CT-P13 is expected to be very useful in RA treatment, whether it is applied earlier or switched from originator infliximab or other biologics. Future educational initiatives will be important to overcome misunderstandings about biosimilars and to improve the implementation of CT-P13. PMID- 28571500 TI - Safety of oral tenofovir disoproxil fumarate-based HIV pre-exposure prophylaxis use in lactating HIV-uninfected women. AB - INTRODUCTION: In settings where HIV is prevalent in heterosexual populations, pregnancy and postpartum breastfeeding periods can be associated with substantial HIV acquisition risk. Pre-exposure prophylaxis (PrEP) with daily oral tenofovir disoproxil fumarate (TDF)/emtricitabine is an attractive HIV prevention option for women who are lactating but data are limited on its safety during the lactation period. Areas covered: We provide a concise synthesis and summary of current evidence on the safety of TDF-based PrEP during breastfeeding. We conducted a review, searching Pubmed database and major PrEP conferences for primary studies with TDF-based PrEP exposure during postpartum breastfeeding. Expert opinion: TDF-based oral PrEP is an effective female-controlled HIV prevention option. There is evidence supporting the safety of TDF use for infant outcomes during breastfeeding in antiretroviral treatment regimens for HIV and hepatitis B virus, and more limited, but consistently safe, data from use of TDF as PrEP. The potential for risk is arguably outweighed for at-risk individuals by HIV prevention benefits, including indirect protection to the infant as a result of preventing HIV in the breastfeeding mother. As PrEP delivery is scaled up in heterosexual populations in high HIV prevalence settings and for at-risk persons in other settings, implementation science studies can provide a framework to increase the accrual of safety, acceptability, and use data related to PrEP during lactation. PMID- 28571502 TI - Liver toxicity mechanisms of herbs commonly used in Latin America. AB - Mexico owns approximately 4500 medicinal plants species, a great diversity that position it at the second place after China. According to the Mexican health department, 90% of common population consumes them to treat various diseases. Additionally, herbal remedies in Latin America (LA) are considered a common practice, but the frequency of use and the liver damage related to its consumption is still unknown. Despite the high prevalence and indiscriminate herbal consumption, the exact mechanism of hepatotoxicity and adverse effects is not fully clarified and is still questioned. Some herb products associated with herb induced liver injury (HILI) are characterized by presenting a different chemical composition that may vary from batch to batch, also the biological activity of many medicinal plants and other natural products are directly related to their most active component and its concentration. There are two main biological components that are associated with liver damage, alkaloids, and flavonoids, which are frequent constituents of commonly used herbs. The interaction with the different cytochrome P-450 isoforms, inflammatory, and oxidative activities seem to be the main damage pathway involved in the liver. It is important to know the herbal adverse effects and mechanisms involved; therefore, this article is focused on the beneficial and deleterious effects as well as the possible toxicity mechanisms and interactions of the herbs that are frequently used in LA, since the herb-host interaction may not always be the expected or desired depending on the clinical context in which it is administered. PMID- 28571503 TI - Managing side effects of JAK inhibitors for myelofibrosis in clinical practice. AB - INTRODUCTION: Myelofibrosis (MF) is characterized by bone marrow fibrosis, abnormalities in peripheral counts, extramedullary hematopoiesis, splenomegaly and an increased risk of transformation to acute myeloid leukaemia. The disease course is often heterogeneous and management can range from observation alone through to allogeneic stem cell transplantation. As of 2017, the only approved medication for MF remains the JAK Inhibitor (JAKi), ruxolitinib (Novartis Pharmaceuticals, Basel, Switzerland; Incyte, Wilmington, Detroit, USA) although several others have reached advanced stages of clinical trials. Areas covered: In this review, we focus on the management of both common and uncommon side effects arising from the use of currently approved and clinical trial JAKi. Most of the discussion concerns ruxolitinib although we also cover both pacritinib (CTI BioPharma) and momelotinib (Gilead Sciences, Foster City, California) which have been in recent large, multinational phase III trials. The various approaches to management of JAKi-related side effects are discussed - with particular emphasis to anaemia, thrombocytopaenia and infection risk. Expert commentary: JAK inhibitors are effective in many individuals with MF and have revolutionized the current treatment paradigm. The side effect profile, in the most, is predictable and manageable with high degrees of clinical surveillance and dose modifications. PMID- 28571504 TI - Impact of protein D-containing pneumococcal conjugate vaccines on non-typeable Haemophilus influenzae acute otitis media and carriage. AB - INTRODUCTION: Protein D-containing vaccines may decrease acute otitis media (AOM) burden and nasopharyngeal carriage of non-typeable Haemophilus influenzae (NTHi). Protein D-containing pneumococcal conjugate vaccine PHiD-CV (Synflorix, GSK Vaccines) elicits robust immune responses against protein D. However, the phase III Clinical Otitis Media and PneumoniA Study (COMPAS), assessing PHiD-CV efficacy against various pneumococcal diseases, was not powered to demonstrate efficacy against NTHi; only trends of protective efficacy against NTHi AOM in children were shown. Areas covered: This review aims to consider all evidence available to date from pre-clinical and clinical phase III studies together with further evidence emerging from post-marketing studies since PHiD-CV has been introduced into routine clinical practice worldwide, to better describe the clinical utility of protein D in preventing AOM due to NTHi and its impact on NTHi nasopharyngeal carriage. Expert commentary: Protein D is an effective carrier protein in conjugate vaccines and evidence gathered from pre-clinical, clinical and observational studies suggest that it also elicits immune response that can help to reduce the burden of AOM due to NTHi. There remains a need to develop improved vaccines for prevention of NTHi disease, which could be achieved by combining protein D with other antigens. PMID- 28571505 TI - Buprenorphine implants in medical treatment of opioid addiction. AB - INTRODUCTION: Opioid use disorder is a chronic, relapsing disease that encompasses use of both prescription opioids and heroin and is associated with a high annual rate of overdose deaths. Medical treatment has proven more successful than placebo treatment or psychosocial intervention, and the partial u-opioid receptor agonist and kappa-opioid receptor antagonist buprenorphine is similar in efficacy to methadone while offering lower risk of respiratory depression. However, frequent dosing requirements and potential for misuse and drug diversion contribute to significant complications with treatment adherence for available formulations. Areas covered: This review describes the development of and preliminary data from clinical trials of an implantable buprenorphine formulation. Efficacy and safety data from comparative studies with other administrations of buprenorphine, including tablets and sublingual film, will be described. Key premises of the Risk Evaluation and Mitigation Strategy program for safely administering buprenorphine implants, which all prescribing physicians must complete, are also discussed. Expert commentary: Long-acting implantable drug formulations that offer consistent drug delivery and lower risk of misuse, diversion, or accidental pediatric exposure over traditional formulations represent a promising development for the effective treatment of opioid use disorder. PMID- 28571506 TI - Longitudinal Study of Caries Development from Childhood to Adolescence. AB - The World Health Organization (WHO) stated that globally, dental caries is the most important oral condition. To develop effective prevention strategies requires an understanding of how this condition develops and progresses over time, but there are few longitudinal studies of caries onset and progression in children. The aim of the study was to establish the pattern of caries development from childhood into adolescence and to explore the role of potential risk factors (age, sex, ethnicity, and social deprivation). Of particular interest was the disease trajectory of dentinal caries in the permanent teeth in groups defined by the presence or absence of dentinal caries in the primary teeth. Intraoral examinations to assess oral health were performed at 4 time points by trained and calibrated dentist examiners using a standardized, national diagnostic protocol. Clinical data were available from 6,651 children. Mean caries prevalence (% D3MFT > 0) was 16.7% at the first clinical examination (ages 7-9 y), increasing to 31.0%, 42.2%, and 45.7% at subsequent examinations. A population-averaged model (generalized estimating equations) was used to model the longitudinal data. Estimated mean values indicated a rising D3MFT count as pupils aged (consistent with new teeth emerging), which was significantly higher (4.49 times; 95% confidence interval, 3.90-5.16) in those pupils with caries in their primary dentition than in those without. This study is one of the few large longitudinal studies to report the development of dental caries from childhood into adolescence. Children who developed caries in their primary dentition had a very different caries trajectory in their permanent dentition compared to their caries free contemporaries. In light of these results, caries-free and caries-active children should be considered as 2 separate populations, suggesting different prevention strategies are required to address their different risk profiles. PMID- 28571507 TI - The genetic basis of antiplatelet and anticoagulant therapy: A pharmacogenetic review of newer antiplatelets (clopidogrel, prasugrel and ticagrelor) and anticoagulants (dabigatran, rivaroxaban, apixaban and edoxaban). AB - INTRODUCTION: The study of pharmacogenomics presents the possibility of individualised optimisation of drug therapy tailored to each patients' unique physiological traits. Both antiplatelet and anticoagulant drugs play a key role in the management of cardiovascular disease. Despite their importance, there is a substantial volume of literature to suggest marked person-to-person variability in their effect. Areas covered: This article reviews the data available for the genetic cause for this inter-patient variability of antiplatelet and anticoagulant drugs. The genetic basis for traditional antiplatelets (i.e. aspirin) is compared with the newly available antiplatelet medicines (clopidogrel, prasugrel and ticagrelor). Similarly, the pharmacogenetics of warfarin is compared with the newer direct oral anticoagulants (DOACs) in detail. Expert Opinion: We identify strengths and weaknesses in the research thus far; including shortcomings in trial design and a review of newer analytical techniques. The direction of this research and its real-world implications are discussed. PMID- 28571508 TI - From Neoliberalism to Neofascism. PMID- 28571509 TI - A long history of breakdowns: A historiographical review. AB - The introduction to this special issue argues that network breakdowns play an important and unacknowledged role in the shaping and emergence of scientific knowledge. It focuses on transnational scientific networks from the early modern Republic of Letters to 21st-century globalized science. It attempts to unite the disparate historiography of the early modern Republic of Letters, the literature on 20th-century globalization, and the scholarship on Actor-Network Theory. We can perceive two, seemingly contradictory, changes to scientific networks over the past four hundred years. At the level of individuals, networks have become increasing fragile, as developments in communication and transportation technologies, and the emergence of regimes of standardization and instrumentation, have made it easier both to create new constellations of people and materials, and to replace and rearrange them. But at the level of institutions, collaborations have become much more extensive and long-lived, with single projects routinely outlasting even the arc of a full scientific career. In the modern world, the strength of institutions and macro-networks often relies on ideological regimes of standardization and instrumentation that can flexibly replace elements and individuals at will. PMID- 28571510 TI - Panacea or diagnosis? Imaginaries of innovation and the 'MIT model' in three political cultures. AB - Innovation studies continue to struggle with an apparent disconnect between innovation's supposedly universal dynamics and a sense that policy frameworks and associated instruments of innovation are often ineffectual or even harmful when transported across regions or countries. Using a cross-country comparative analysis of three implementations of the 'MIT model' of innovation in the UK, Portugal and Singapore, we show how key features in the design, implementation and performance of the model cannot be explained as mere variations on an identical solution to the same underlying problem. We draw on the concept of sociotechnical imaginaries to show how implementations of the 'same' innovation model - and with it the notion of 'innovation' itself - are co-produced with locally specific diagnoses of a societal deficiency and equally specific understandings of acceptable remedies. Our analysis thus flips the conventional notion of 'best-practice transfer' on its head: Instead of asking 'how well' an innovation model has been implemented, we analyze the differences among the three importations to reveal the idiosyncratic ways in which each country imagines the purpose of innovation. We replace the notion of innovation as a 'panacea' - a universal fix for all social woes - with that of innovation-as-diagnosis in which a particular 'cure' is 'prescribed' for a 'diagnosed' societal 'pathology,' which may in turn trigger 'reactions' within the receiving body. This approach offers new possibilities for theorizing how and where culture matters in innovation policy. It suggests that the 'successes' and 'failures' of innovation models are not a matter of how well societies are able to implement a sound, universal model, but more about how effectively they articulate their imaginaries of innovation and tailor their strategies accordingly. PMID- 28571511 TI - Grain-Boundary Engineering for Aging and Slow-Crack-Growth Resistant Zirconia. AB - Ceramic materials are prone to slow crack growth, resulting in strength degradation over time. Although yttria-stabilized zirconia (Y-TZP) ceramics have higher crack resistance than other dental ceramics, their aging susceptibility threatens their long-term performance in aqueous environments such as the oral cavity. Unfortunately, increasing the aging resistance of Y-TZP ceramics normally reduces their crack resistance. Our recently conducted systematic study of doping 3Y-TZP with various trivalent cations revealed that lanthanum oxide (La2O3) and aluminum oxide (Al2O3) have the most potent effect to retard the aging kinetics of 3Y-TZP. In this study, the crack-propagation behavior of La2O3 and Al2O3 co doped 3Y-TZP ceramics was investigated by double-torsion methods. The grain boundaries were examined using scanning transmission electron microscopy and energy-dispersive spectroscopy (STEM-EDS). Correlating these analytic data with hydrothermal aging studies using different doping systems, a strategy to strongly bind the segregated dopant cations with the oxygen vacancies at the zirconia grain boundary was found to improve effectively the aging resistance of Y-TZP ceramics without affecting the resistance to crack propagation. PMID- 28571513 TI - A Pulmonary Embolism Response Team: initial experiences and future directions. AB - INTRODUCTION: Acute pulmonary embolism (PE) is a common cardiovascular condition resulting in significant morbidity and mortality. Consensus recommendations suggest risk stratification of patients into three main categories: high-risk or 'massive' PE, intermediate-risk or 'submassive' PE, and low-risk PE. Given the relative dearth of prospective, randomized clinical trials delineating optimal selection of the diverse medical, interventional, and surgical treatment approaches, clinical care requires a multidisciplinary expert approach to patients with PE. Areas covered: The Massachusetts General Hospital (MGH) Pulmonary Embolism Response Team (PERT) was the first of its kind to create a multidisciplinary, rapid response team for acute PE, integrated within a research and educational framework. The MGH PERT has treated more than 700 patients with PE, the majority of which are in the 'massive' or 'submassive' categories. The PERT ConsortiumTM was founded in 2015 as a collaborative network between the growing number of PERT programs internationally, with greater than 80 institutions participating within one year of establishment. Expert commentary: Since its advent, the PERT model has expanded throughout the United States and internationally through a collaborative institutional and research network. PERT may represent a new standard for the care of patients with acute PE. PMID- 28571512 TI - Relationships among Bone Quality, Implant Osseointegration, and Wnt Signaling. AB - A variety of clinical classification schemes have been proposed as a means to identify sites in the oral cavity where implant osseointegration is likely to be successful. Most schemes are based on structural characteristics of the bone, for example, the relative proportion of densely compact, homogenous (type I) bone versus more trabeculated, cancellous (type III) bone. None of these schemes, however, consider potential biological characteristics of the bone. Here, we employed multiscale analyses to identify and characterize type I and type III bones in murine jaws. We then combined these analytical tools with in vivo models of osteotomy healing and implant osseointegration to determine if one type of bone healed faster and supported osseointegration better than another. Collectively, these studies revealed a strong positive correlation between bone remodeling rates, mitotic activity, and osteotomy site healing in type III bone and high endogenous Wnt signaling. This positive correlation was strengthened by observations showing that the osteoid matrix that is responsible for implant osseointegration originates from Wnt-responsive cells and their progeny. The potential application of this knowledge to clinical practice is discussed, along with a theory unifying the role that biology and mechanics play in implant osseointegration. PMID- 28571515 TI - Advanced clinical interpretation of the Delis-Kaplan Executive Function System: multivariate base rates of low scores. AB - OBJECTIVE: Multivariate base rates allow for the simultaneous statistical interpretation of multiple test scores, quantifying the normal frequency of low scores on a test battery. This study provides multivariate base rates for the Delis-Kaplan Executive Function System (D-KEFS). METHOD: The D-KEFS consists of 9 tests with 16 Total Achievement scores (i.e. primary indicators of executive function ability). Stratified by education and intelligence, multivariate base rates were derived for the full D-KEFS and an abbreviated four-test battery (i.e. Trail Making, Color-Word Interference, Verbal Fluency, and Tower Test) using the adult portion of the normative sample (ages 16-89). RESULTS: Multivariate base rates are provided for the full and four-test D-KEFS batteries, calculated using five low score cutoffs (i.e. <=25th, 16th, 9th, 5th, and 2nd percentiles). Low scores occurred commonly among the D-KEFS normative sample, with 82.6 and 71.8% of participants obtaining at least one score <=16th percentile for the full and four-test batteries, respectively. Intelligence and education were inversely related to low score frequency. CONCLUSIONS: The base rates provided herein allow clinicians to interpret multiple D-KEFS scores simultaneously for the full D-KEFS and an abbreviated battery of commonly administered tests. The use of these base rates will support clinicians when differentiating between normal variations in cognitive performance and true executive function deficits. PMID- 28571514 TI - Obstetric ultrasound aids prompt referral of gestational trophoblastic disease in marginalized populations on the Thailand-Myanmar border. AB - BACKGROUND: The use of obstetric ultrasound in the diagnosis of gestational trophoblastic disease (GTD) in high-income settings is well established, leading to prompt management and high survival rates. Evidence from low-income settings suggests ultrasound is essential in identifying complicated pregnancies, but with limited studies reviewing specific conditions including GTD. OBJECTIVE: The aim of this study is to review the role of ultrasound in diagnosis and management of GTD in a marginalized population on the Thailand-Myanmar border. Antenatal ultrasound became available in this rural setting in 2001 and care for women with GTD has been provided by Thailand public hospitals for 20 years. DESIGN: Retrospective record review. RESULTS: The incidence of GTD was 103 of 57,004 pregnancies in Karen and Burmese women on the Thailand-Myanmar border from 1993 2013. This equates to a rate of 1.8 (95% CI 1.5-2.2) per 1000 or 1 in 553 pregnancies. Of the 102 women with known outcomes, one (1.0%) died of haemorrhage at home. The median number of days between first antenatal clinic attendance and referral to hospital was reduced from 20 (IQR 5-35; range 1-155) to 2 (IQR 2-6; range 1-179) days (p = 0.002) after the introduction of ultrasound. The proportion of severe outcomes (death and total abdominal hysterectomy) was 25% (3/12) before ultrasound compared to 8.9% (8/90) with ultrasound (p = 0.119). A recurrence rate of 2.5% (2/80) was observed in the assessable population. The presence of malaria parasites in maternal blood was not associated with GTD. CONCLUSIONS: The rate of GTD in pregnancy in this population is comparable to rates previously reported within South-East Asia. Referral time for uterine evacuation was significantly shorter for those women who had an ultrasound. Ultrasound is an effective method to improve diagnosis of GTD in low-income settings and an effort to increase availability in marginalized populations is required. PMID- 28571516 TI - NSAIDs as potential treatment option for preventing amyloid beta toxicity in Alzheimer's disease: an investigation by docking, molecular dynamics, and DFT studies. AB - Aggregation of amyloid beta (Abeta) protein considered as one of contributors in development of Alzheimer's disease (AD). Several investigations have identified the importance of non-steroidal anti-inflammatory drugs (NSAIDs) as Abeta aggregation inhibitors. Here, we have examined the binding interactions of 24 NSAIDs belonging to eight different classes, with Abeta fibrils by exploiting docking and molecular dynamics studies. Minimum energy conformation of the docked NSAIDs were further optimized by density functional theory (DFT) employing Becke's three-parameter hybrid model, Lee-Yang-Parr (B3LYP) correlation functional method. DFT-based global reactivity descriptors, such as electron affinity, hardness, softness, chemical potential, electronegativity, and electrophilicity index were calculated to inspect the expediency of these descriptors for understanding the reactive nature and sites of the molecules. Few selected NSAID-Abeta fibrils complexes were subjected to molecular dynamics simulation to illustrate the stability of these complexes and the most prominent interactions during the simulated trajectory. All of the NSAIDs exhibited potential activity against Abeta fibrils in terms of predicted binding affinity. Sulindac was found to be the most active compound underscoring the contribution of indene methylene substitution, whereas acetaminophen was observed as least active NSAID. General structural requirements for interaction of NSAIDs with Abeta fibril include: aryl/heteroaryl aromatic moiety connected through a linker of 1-2 atoms to a distal aromatic group. Considering these structural requirements and electronic features, new potent agents can be designed and developed as potential Abeta fibril inhibitors for the treatment of AD. PMID- 28571517 TI - Mechanistic insights into the activity of Ptf1-p48 (pancreas transcription factor 1a): probing the interactions levels of Ptf1-p48 with E2A-E47 (transcription factor E2-alpha) and ID3 (inhibitor of DNA binding 3). AB - Ptf1-p48 (Pancreas specific transcription factor 1a) is transcription regulatory protein known for the activation of exocrine specific genes. Downregulation of its expression formulates early stages of pancreatic adenocarcinoma as deduced by its association with oncogenic bHLH (Basic Helix-Loop-Helix) protein ID3 (Inhibitor of DNA binding 3) protein whose overexpression induces cytoplasmic mislocalization of Ptf1-p48. The precise mechanism and/or functional role of Ptf1 p48in promoting pancreatic cancer is vague. The structural features of the Ptf1 p48 and its dimerization with E47 (Transcription factor E2-alpha) and ID3 mediated by their HLH (Helix-Loop-Helix) domain were perceived through MD (Molecular Dynamics) simulations of 50 ns. The interactions formed by the HLH domain in both Ptf1-E47 and Ptf1-ID3 complexes are favored by the synergistic movement of their domain helices. Accordingly, in the Ptf1-E47 complex alpha7 of Ptf1-p48 and alpha1 helix of E47 along with the loop residues of their HLH domain exhibit transitions marked by inward movement toward each other and forms polar and charged interactions. In the Ptf1-ID3 complex, alpha8 of Ptf1-p48 moves toward the alpha3 helix of ID3 and forms hydrogen bonds. The interface analysis also reveals better interface in the Ptf1-p48 complex than the Ptf1-ID3 evident by energetics and number of hydrogen bonds. The interactions in each of these complexes, supported by angular displacement and mode vector analyzes, comprehensibly describe the considerable structural changes induced upon dimer formation. It thereby gives an insight into the interfaces that could help in designing of potential inhibitors for ID3 to curb the cancer cell growth. PMID- 28571518 TI - Anetoderma due to secondary syphilis: Report of two cases and discussion of the histopathological findings. AB - Anetoderma is a rare benign condition of diverse etiology whose characteristic is the diminution or absence of the dermal elastic fibers. Classified as primary and secondary, the latter associated with tumors, inflammatory, and infectious diseases. Although the etiology of the lesions is well described in literature, the pathogenesis is still poorly determined. Anetoderma in syphilis is rare, and occurs even in the most uncommon cutaneous manifestations of the disease, such as the nodular form. In order to better understand the changes that lead to elastolysis, we propose a better correlation with the histopathological findings of the lesions that precede it. We present two cases of anetoderma secondary to syphilis, whose clinical aspects resembled the pattern of their initial secondary syphilis rash. PMID- 28571519 TI - Using lean manufacturing principles to evaluate wait times for HIV-positive patients in an urban clinic in Kenya. AB - As human immunodeficiency virus (HIV) treatment programs expand in Africa, delivery systems must be strengthened to support patient retention. Clinic characteristics may affect retention, but a relationship between clinic flow and attrition is not established. This project characterized HIV patient experience and flow in an urban Kenyan clinic to understand how these may affect retention. We used Toyota's lean manufacturing principles to guide data collection and analysis. Clinic flow was evaluated using value stream mapping and time and motion techniques. Clinic register data were analyzed. Two focus group discussions were held to characterize HIV patient experience. Results were shared with clinic staff. Wait times in the clinic were highly variable. We identified four main barriers to patient flow: inconsistent patient arrivals, inconsistent staffing, filing system defects, and serving patients out of order. Focus group participants explained how clinic operations affected their ability to engage in care. Clinic staff were eager to discuss the problems identified and identified numerous low-cost potential solutions. Lean manufacturing methodologies can guide efficiency interventions in low-resource healthcare settings. Using lean techniques, we identified bottlenecks to clinic flow and low-cost solutions to improve wait times. Improving flow may result in increased patient satisfaction and retention. PMID- 28571520 TI - Profiles of Elderly People Infected with HIV and Response to Antiretroviral Treatment in Burkina Faso: A Retrospective Cohort Study. AB - BACKGROUND: In sub-Saharan Africa, few studies exist on elderly HIV-positive populations. Therefore, we aimed to examine the profiles of elderly people living with HIV (PLHIV) in Burkina Faso and their response to antiretroviral therapy (ART). METHODS: We reviewed the monitoring and treatment of PLHIV over the age of 50 years and then compared with the monitoring and treatment of PLHIV under 50 years. RESULTS: A total of 3367 patients were included. The median age of elderly people was 54.5 years and of young people was 34.9 years ( P = .03). In both the groups, screening was performed following clinical suspicion (64.9% in elderly versus 56% in young people; P < .001). Cardiovascular risk factors were generally more significant in the elderly people. The risk of death while on ART was 2.3 times higher in elderly people ( P < .001). CONCLUSION: HIV infection in older people occurs in those who already have some cardiovascular risk factors. Particular attention should be given to multidisciplinary care for the elderly individuals. PMID- 28571521 TI - Estimating age-specific reproductive numbers-A comparison of methods. AB - Large outbreaks, such as those caused by influenza, put a strain on resources necessary for their control. In particular, children have been shown to play a key role in influenza transmission during recent outbreaks, and targeted interventions, such as school closures, could positively impact the course of emerging epidemics. As an outbreak is unfolding, it is important to be able to estimate reproductive numbers that incorporate this heterogeneity and to use surveillance data that is routinely collected to more effectively target interventions and obtain an accurate understanding of transmission dynamics. There are a growing number of methods that estimate age-group specific reproductive numbers with limited data that build on methods assuming a homogenously mixing population. In this article, we introduce a new approach that is flexible and improves on many aspects of existing methods. We apply this method to influenza data from two outbreaks, the 2009 H1N1 outbreaks in South Africa and Japan, to estimate age-group specific reproductive numbers and compare it to three other methods that also use existing data from social mixing surveys to quantify contact rates among different age groups. In this exercise, all estimates of the reproductive numbers for children exceeded the critical threshold of one and in most cases exceeded those of adults. We introduce a flexible new method to estimate reproductive numbers that describe heterogeneity in the population. PMID- 28571523 TI - Association of heterogenicity of Helicobacter pylori cag pathogenicity island with peptic ulcer diseases and gastric cancer. AB - OBJECTIVE: To investigate the frequency and integrity of certain cag pathogenicity island genes (cagPAI) in Helicobacter pylori strains and their association with peptic ulcer disease (PUD) and gastric cancer. MATERIAL AND METHODS: We enrolled 240 adult patients [120 with functional dyspepsia (FD), 50 with PUD and 70 with gastric cancer] undergoing upper gastrointestinal endoscopy. H. pylori infection was diagnosed when either culture or any two of the three tests (rapid urease test, histopathology and specific ureA PCR) were positive. DNA extracted from H. pylori isolates and positive gastric tissues were tested by PCR for the presence of different genes of cagPAI using specific primers. RESULTS: A total of 122 (51%) patients were H. pylori positive. Frequencies of cagPAI genes cagA, cagE, cagT and cagM in H. pylori strains from different groups of patients were as follows: functional dyspepsia 73, 83, 76 and 60%, PUD 70, 94, 91, 70% and gastric cancer 75, 95, 90 and 70%, respectively. Risk associated for the presence of PUD and gastric cancer with cagPAI genes cagE, cagT and cagM was 5.0-, 4.6- and 4.1- and 3.0-, 2.8- and 2.5-folds, respectively. Prevalence of intact cagPAI was significantly higher in PUD and gastric cancer compared to functional dyspepsia (PUD vs. functional dyspepsia, 71% vs. 38%, P = 0.01; gastric cancer vs. functional dyspepsia, 75% vs. 38%, P < 0.01). Intact cagPAI was associated with increased risk for the presence of PUD (odds ratio 5.2, 95% CI 2.4-11.3) and for the presence of gastric cancer (odds ratio 4.5, 95% CI 2.3 7.1). CONCLUSIONS: cagPAI integrity and its different genes are linked to different forms of gastric disease and so may have a role in pathogenesis, diagnosis and management. PMID- 28571522 TI - Risk factors predicting the survival of pediatric patients with relapsed/refractory non-Hodgkin lymphoma who underwent hematopoietic stem cell transplantation: a retrospective study from the Turkish pediatric bone marrow transplantation registry. AB - We examined outcomes of 62 pediatric patients with relapsed or refractory non Hodgkin lymphoma (rr-NHL) who underwent hematopoietic stem cell transplantation (HSCT). The overall survival (OS) and event-free survival (EFS) rates were 65% and 48%, respectively. Survival rates for patients with chemosensitive disease at the time of HSCT were significantly higher than those of patients with chemoresistant disease (69% vs. 37%, p = .019 for OS; 54% vs. 12%, p < .001 for EFS; respectively). A chemoresistant disease at transplantation was the only factor that predicted a limited OS (hazard ratio = 10.00) and EFS (hazard ratio = 16.39) rates. Intensive chemotherapy followed by HSCT could be an effective strategy for treating children with rr-NHL and may offer improved survival for a significant group of pediatric patients, particularly those with chemosensitive disease at transplantation. PMID- 28571524 TI - Implementation of lung cancer CT screening in the Nordic countries. AB - INTRODUCTION: We review the current knowledge of CT screening for lung cancer and present an expert-based, joint protocol for the proper implementation of screening in the Nordic countries. MATERIALS AND METHODS: Experts representing all the Nordic countries performed literature review and concensus for a joint protocol for lung cancer screening. RESULTS AND DISCUSSION: Areas of concern and caution are presented and discussed. We suggest to perform CT screening pilot studies in the Nordic countries in order to gain experience and develop specific and safe protocols for the implementation of such a program. PMID- 28571525 TI - An influenza A virus agglutination test using antibody-like polymers. AB - Antibodies are commonly used in diagnostic routines to identify pathogens. The testing protocols are relatively simple, requiring a certain amount of a specific antibody to detect its corresponding pathogen. Antibody functionality can be mimicked by synthesizing molecularly imprinted polymers (MIPs), i.e. polymers that can selectively recognize a given template structure. Thus, MIPs are sometimes termed 'plastic antibody (PA)'. In this study, we have synthesized new granular MIPs using influenza A virus templates by precipitation polymerization. The selective binding of influenza A to the MIP particles was assessed and subsequently contrasted with other viruses. The affinities of influenza A virus towards the MIP was estimated based on an agglutination test by measuring the amount of influenza subtypes absorbed onto the MIPs. The MIPs produced using the H1N1 template showed specific reactivity to H1N1 while those produced using H5N1 and H3N2 templates showed cross-reactivity. PMID- 28571526 TI - TRPA1 Channels Mediate Human Gingival Fibroblast Response to Phenytoin. AB - Drug-induced gingival enlargement (GE) is a frequent adverse effect observed in patients treated with anticonvulsant, immunosuppressant, and some antihypertensive medications-the antiepileptic phenytoin being the main drug associated with GE due to its high incidence (around 50%). The molecular mechanisms behind drug-induced gingival overgrowth are still unknown. By reverse transcription polymerase chain reaction, we demonstrate that the calcium permeable ion channels TRPA1, TRPV1, and its capsaicin-insensitive isoform TRPV1b are expressed in human gingival fibroblasts (HGFs), the most abundant cellular type in periodontal tissue. Cultured HGFs responded with intracellular calcium elevations to phenytoin and to the canonical TRPA1 agonist allyl isothiocyanate. Application of phenytoin activated a nonselective cationic current in HGFs with a typical signature for TRPA1 channels. Moreover, this activation was blocked by HC030031, a specific TRPA1 blocker. Similarly, the use of shRNAs against hTRPA1 in HGFs reduced TRPA1 expression and activation by phenytoin. In addition, we show that phenytoin increased intracellular calcium levels in cells transfected with mouse or human TRPA1 channels. Responses to phenytoin were not observed in untransfected cells or cells expressing TRPM8 or TRPV1. The activation of HGFs by phenytoin was markedly reduced in the presence of antioxidant vitamins: ascorbic acid, folic acid, and alpha-tocopherol. By performing cell proliferation assays, we found that phenytoin did not augment the proliferation rate of HGFs. In contrast, alcian blue and picrosirius red staining of long-term HGFs cultures indicated that phenytoin induces extracellular matrix accumulation of collagen. Collectively, these findings support an important role of TRPA1 channels in phenytoin-induced GE, provide insight into the pathophysiologic mechanism, and offer novel therapeutic opportunities for its treatment. PMID- 28571529 TI - Implementation and evaluation of an algorithm-based order set for the outpatient treatment of urinary tract infections in the spinal cord injury population in a VA Medical Center. AB - BACKGROUND: Treatment of urinary tract infections (UTI) in the spinal cord injury (SCI) population is often difficult due to the lack of symptoms, increased resistance, and increased morbidity and mortality associated with UTIs. OBJECTIVE: To develop an algorithm-based order set for the treatment of UTIs for patients with SCI based on SCI-specific antibiogram data in order to assess and improve current antimicrobial prescribing practices at the Clement J. Zablocki Veterans Affairs Medical Center (ZVAMC). METHODS: This study is a retrospective, pre- and post-implementation analysis of an order set based on SCI antibiogram data. Descriptive statistics were used to compare baseline data and characteristics and chi squared tests were used to evaluate the primary outcome and all secondary outcomes. To achieve a power of 80% with an effect size of 0.3, the goal was to assess 45 antimicrobial treatment courses in the pre implementation group and 45 antimicrobial treatment courses in the post implementation group. RESULTS: The percentage of appropriate antimicrobial treatment courses increased from 47.9% in the pre-intervention group (n = 73) to 71.8% in the post-intervention group (n = 39), which was statistically significant (P = 0.015). CONCLUSIONS: Patients with SCI treated for UTIs within the ZVAMC had a significantly higher percentage of appropriate treatment courses following the implementation of a unit-specific antibiogram, electronic order set, and educational in-service for providers. An order set and unit-specific antibiogram with related education may be beneficial in improving antimicrobial therapy from a stewardship perspective. PMID- 28571528 TI - Antioxidant activity against H2O2-induced cytotoxicity of the ethanol extract and compounds from Pyrola decorate leaves. AB - CONTEXT: The leaves of Pyrola decorate H. Andr (Pyrolaceae), known as Luxiancao, have long been used for treating kidney deficiency, gastric haemorrhage and rheumatic arthritic diseases in traditional Chinese medicine. OBJECTIVE: The phytochemicals and antioxidant capacities in vitro of P. decorate leaves were investigated. MATERIALS AND METHODS: Ethanol, petroleum ether, acetidin, n-butyl alcohol and aqueous extracts of Pyrola decorate leaves were prepared by solvent sequential process, and then isolated and purified to obtain phytochemicals. Cell viability was measured by MTT assay. PC12 cells were pretreated for 24 h with different extractions of P. decorate leaves at concentrations of 0.1, 0.5, 1, 5 and 10 mg/mL, then H2O2 of 0.4 mM was added in all samples for an additional 2 h. The antioxidant capacities of betulin, ursolic acid and monotropein were determined in PC12 cells against H2O2 induced cytotoxicity in vitro as well. RESULTS: Nine compounds (1-9) were isolated and structurally determined by spectroscopic methods, especially 2D NMR analyses. Ethanol extract treated groups showed inhibitory activity with IC50 value of 10.83 mg/mL. Betulin, ursolic acid and monotropein were isolated from P. decorate, and demonstrated with IC50 values of 6.88, 6.15 and 6.13 MUg/mL, respectively. DISCUSSION AND CONCLUSIONS: In conclusion, Pyrola decorate is a potential antioxidative natural plant and worth testing for further pharmacological investigation in the treatment of oxidative stress related neurological disease. PMID- 28571530 TI - Plasma-treated Ce/TiO2-SiO2 catalyst for the NH3-SCR of NOx. AB - Ce/TiO2-SiO2 catalysts with different Ti/Si molar ratios are prepared by the incipient impregnation method and their NH3-SCR activities are evaluated at 100 500 degrees C on a fixed reactor. The Ce/TiO2-SiO2 (3/1) catalyst, modified by non-thermal plasma (NTP) treatment and then activated by thermal treatment at 500 degrees C for 4 h, exhibits best performance. Comprehensive deNOx performance of the catalyst is evidently improved and its efficiency reaches up to 99.21% at 350 degrees C. NO conversion efficiency of the treated catalyst doped with K remains about 90.23% at 300 degrees C and the catalyst also shows improved activity at lower temperatures. Various characterization methods show that the activity enhancement is correlated only with NTP treatment, as it increases the number of Ce3+ species, which generates more chemisorbed oxygen, leads to improved dispersion of Bronsted and Lewis acidic sites and finally has an inherent etching effect. PMID- 28571527 TI - Assessment and management of acute spinal cord injury: From point of injury to rehabilitation. AB - CONTEXT: Spinal cord injury (SCI) is a devastating condition that can lead to significant neurological impairment and reduced quality of life. Despite advancements in our understanding of the pathophysiology and secondary injury mechanisms involved in SCI, there are currently very few effective treatments for this condition. The field, however, is rapidly changing as new treatments are developed and key discoveries are made. METHODS: In this review, we outline the pathophysiology, management, and long-term rehabilitation of individuals with traumatic SCI. We also provide an in-depth overview of emerging therapies along the spectrum of the translational pipeline. EVIDENCE SYNTHESIS: The concept of "time is spine" refers to the concept which emphasizes the importance of early transfer to specialized centers, early decompressive surgery, and early delivery of other treatments (e.g. blood pressure augmentation, methylprednisolone) to affect long-term outcomes. Another important evolution in management has been the recognition and prevention of the chronic complications of SCI including respiratory compromise, bladder dysfunction, Charcot joints, and pressure sores through directed interventions along with early integration of physical rehabilitation and mobilization. There have also been significant advances in neuroprotective and neuroregenerative strategies for SCI, many of which are actively in clinical trial including riluzole, Cethrin, stem cell transplantation, and the use of functional electrical stimulation. CONCLUSION: Pharmacologic treatments, cell-based therapies, and other technology-driven interventions will likely play a combinatorial role in the evolving management of SCI as the field continues to evolve. PMID- 28571531 TI - C-Abl Inhibition; A Novel Therapeutic Target for Parkinson's Disease. AB - Parkinson's disease (PD) is the most prevalent movement disorder in the world. The major pathological hallmarks of PD are death of dopaminergic neurons and the formation of Lewy bodies. At the moment, there is no cure for PD; current treatments are symptomatic. Investigators are searching for neuroprotective agents and disease modifying strategies to slow the progress of neurodegeneration. However, due to lack of data about the main pathological sequence of PD, many drug targets failed to provide neuroprotective effects in human trials. Recent evidence suggests the involvement of C-Abelson (c-Abl) tyrosine kinase enzyme in the pathogenesis of PD. Through parkin inactivation, alpha synuclein aggregation, and impaired autophagy of toxic elements. Experimental studies showed that (1) c-Abl activation is involved in neurodegeneration and (2) c-Abl inhibition shows neuroprotective effects and prevents dopaminergic neuronal' death. Current evidence from experimental studies and the first in-human trial shows that c-Abl inhibition holds the promise for neuroprotection against PD and therefore, justifies the movement towards larger clinical trials. In this review article, we discussed the role of c-Abl in PD pathogenesis and the findings of preclinical experiments and the first in-human trial. In addition, based on lessons from the last decade and current preclinical evidence, we provide recommendations for future research in this area. PMID- 28571532 TI - Rapid Access to Oxazine Fused Furocoumarins and in vivo and in silico Studies of theirs Biological Activity. AB - BACKGROUND: The synthesis of 1,2-oxazine-fused linear furocoumarins was performed involving the transition metal catalysis reaction of plant coumarin oreoselone derivatives. OBJECTIVE AND METHOD: The Pd-catalyzed desulfonative cross-coupling reactions of 2-(tosyl)oreoselone with terminal alkynes and the successive treatment of the obtained 2-(arylethynyl)furocoumarins with an excess of hydroxylamine gave the expected (Z,E)-3-(hydroxyimino)-2 (arylethynyl)furocoumarins with an (Z:E) ratio of about 1:0.5. The gold(III) catalyzed cycloisomerization of furocoumarin beta,gamma-acetylenic (Z)-oximes led to a new group of heterocyclic compounds - chromeno[6',7':4,5]furo[3,2 c][1,2]oxazine. The (E)-isomer in this condition was transformed into (E)-3 (hydroxyimino)-2-(propan-2-ylidene) furocoumarin. RESULTS: Pharmacological screening of the synthesized 1,2-oxazine-fused linear furocoumarins for anti inflammatory and analgesic activity in vivo revealed that this compounds possessed high activity which was depend on the substitution in the aromatic ring of the oxazine unit. The results of experimental studies were found to be in accordance with that of the in silico docking results. CONCLUSION: The moderate toxicity of compounds (LD50 value was more than 2000 mg/kg) encouraged the further design of therapeutically relevant analogues based on this novel type of fused linear furocoumarins. PMID- 28571533 TI - Cdc42 Signaling Pathway Inhibition as a Therapeutic Target in Ras- Related Cancers. AB - BACKGROUND: The frequency of pro-oncogenic mutations and development of drug resistance are major challenges for successful Ras-related cancer treatment. Novel targets in the Ras-signaling pathway may address these challenges. Cell division cycle protein 42 (Cdc42) is a classical member of the Rho family of small GTPases in the Ras oncogene superfamily. Enhanced Cdc42-signaling facilitates Ras-mediated cellular transformation, tumorigenesis, and metastasis. Cdc42, Ras, and EGFR are involved in an activation loop that prolongs their signaling. This review evaluates the benefits of targeting Cdc42 signaling as an anti-Ras cancer target. METHODS: We review the link between Ras and Cdc42 and summarize the roles of Cdc42 and select effectors in cancers. We discuss the discovery/development of Cdc42-signaling modulators and highlight studies that report the inhibition of the Cdc42-signaling pathway in several Ras-related cancer cell lines. RESULTS: Compared to EGFR and Ras, mutations that lead to the prolonged activation of Cdc42 are less common. Activation of upstream signals, changes in regulator expression, and alterations of Cdc42 protein expression play an important role in regulating Cdc42 activity. Eight selected effectors/adaptors of Cdc42 play a role in oncogenic Ras signaling. Of the fourteen natural and synthetic Cdc42 inhibitors discussed, eight small molecule inhibitors of Cdc42 have been used effectively in Ras-related cancer lines derived from breast, colon, lung, and pancreatic cancer. CONCLUSIONS: Cdc42 is a putative therapeutic target in Ras-related cancers since Cdc42 functions downstream of EGFR and Ras, Cdc42 promotes/activates EGFR and Ras signaling, and Cdc42 inhibition in Ras related cancers elicits anticancer effects. PMID- 28571534 TI - The Evaluation and Utilization of Marine-derived Bioactive Compounds with Anti obesity Effect. AB - BACKGROUND: Obesity is a global epidemic throughout the world. There is thus increasing interest in searching for natural bioactive compounds with anti obesity effect. A number of marine compounds have been regarded as potential sources of bioactive compounds and are associated with an anti-obesity effect. OBJECTIVE: Marine-derived compounds with anti-obesity effect and their current applications, methods and indicators for the evaluation of anti-obesity activity are summarized in this review. in order to make contributions to the development of marine-derived functional food against obesity. RESULTS: In this review, an overview of marine-derived compounds with anti-obesity effect, including marine polysaccharides, marine lipid, marine peptides, marine carotenoids is intensively made with an emphasis on their efficacy and mechanism of action. Meanwhile, methods and indicators for the evaluation of anti-obesity activity are discussed. We summarize these methods into three categories: in vitro assay (including adsorption experiments and enzyme inhibitory assay), cell line study, animal experiments and clinical experiments. In addition, a brief introduction of the current applications of marine bioactive compounds with anti-obesity activity is discussed. CONCLUSION: Marine environment is a rich source of both biological and chemical diversity. In the past decades, numerous novel compounds with anti obesity activity have been obtained from marine organisms, and many of them have been applied to industrial production such as functional foods and pharmaceuticals. Further studies are needed to explore the above-mentioned facts. PMID- 28571535 TI - Nonsteroidal Anti-Inflammatory Drugs: Exploiting Bivalent COXIB/ TP Antagonists for the Control of Cardiovascular Risk. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most widely prescribed or dispensed over the counter analgesics and antipyretics that act by inhibiting prostaglandins and thromboxane synthesis. After the identification of a second isoform of COX, the pharmaceutical research focused on developing COX-2- selective drugs (COXIBs) considered as second generation NSAIDs that would retain the anti-inflammatory and analgesic activities of traditional NSAID without blunting the gastrointestinal cytoprotection sustained by COX1 derived products such as PGE2. However, while several clinical trials confirmed a gastrointestinal safer profile of COXIBs vs unselective COX inhibitors, increasing evidence for potential cardiovascular risk associated with COXIBs rapidly emerged. Today, there are no really safe NSAIDs to be used in chronic pain and anti-inflammatory treatments, as an adequate therapy associated with a minimal gastrointestinal damage and cardiovascular toxicity is yet to be developed. OBJECTIVE: Here, we present evidences that combining the anti aggregating and antiatherotrombotic activities of a thromboxane receptor antagonist with the antiinflammatory activity of a COXIB we could obtain a new multitarget drug providing protection against the harmful activities mediated by the COXIB component, yet exploiting its recognized therapeutic advantages as a gastrointestinal-safer anti-inflammatory drug. We also summarize recent progress achieved in this field of research and possible new strategies to obtain a new bivalent compound. CONCLUSION: This possible third-generation NSAID with a safer pharmacological profile, will have all the pharmacological characteristics for the long-term therapy of chronic disorders such as inflammatory diseases or selected forms of cancer. PMID- 28571536 TI - AMP-activated Protein Kinase as a Drug Target in Chronic Kidney Disease. AB - BACKGROUND: Chronic kidney disease (CKD) is a condition increasingly affecting millions of individuals worldwide and is ranked as the ninth leading cause of death in the United States. AMPactivated protein kinase (AMPK) is an energy sensor that plays a pivotal role in cellular homoeostasis. Deficiency in AMPK activity and autophagic signaling, and sustained activation of mammalian target of rapamycin (mTOR) signaling and endoplasmic reticulum (ER) stress have been shown to promote epithelial-to-mesenchymal transition (EMT) and renal cell apoptosis and contribute to CKD. Emerging evidences demonstrate that AMPK acts as a modulator of the aforementioned pathways that underpin the pathophysiology of CKD. Furthermore, pharmacological activators of AMPK such as metformin have been shown to exert renoprotective effects in experimental studies and improve clinical outcomes in patients with CKD. OBJECTIVE: The current review focuses on the nephroprotective effects of AMPK and its utility as a therapeutic target for the prevention and treatment of CKD. PMID- 28571537 TI - Synthesis and Biological Evaluation of New Tyrosol-Salicylate Derivatives as Potential Anti-Inflammatory Agents. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medications in inflammatory illnesses. However, the gastrointestinal bleeding and toxicity associated with NSAIDs long term use prompted the quest towards investigations for new anti-inflammatory agents. Natural and natural-derived molecules proved its anti-inflammatory efficacy in vitro as well as in vivo. Given this background, the scope of this research involves structural changes of the natural polyphenol (tyrosol) generating two new salicylate derivatives and testing their biological properties, focusing on anti-inflammatory effects assessed in vitro and in vivo assays. The first molecular modification was the introduction of a carboxylic acid group adjacent to the phenol group present in this compound, which creates a new salicylate-like tyrosol. In addition, the acetylation of phenol group in this molecule produced an acetylsalicylate derivative, which may be regarded as aspirin-like natural polyphenol. Interestingly, tyrosol and its novel derivatives attenuated the edema in acute inflammatory response on carrageenan- induced local inflammation in mice. In addition, our results demonstrated that tyrosol and its novel derivatives were able to reduce the chemotaxis of neutrophil assessed in vitro model by chemo attractant (fMLP). Furthermore, only derivative 2 was able to reduce this effect in the acute inflammatory model. In (DPPH)- scavenging activity, tyrosol derivatives demonstrated a minor antioxidant activity, which may suggest that radical scavenging is not a major pathway involved in the anti-inflammatory effects of these derivatives. Salicylate-like tyrosol derivatives are of particular interest for future studies. PMID- 28571538 TI - High Throughput Screening Assay to Identify Modulators of IL-17 Expression. AB - OBJECTIVE: Herein we demonstrate the successful development of a new RORgammat enhanced IL-17F promoter-luciferase reporter assay and its use in a parallel high throughput screening approach, alongside a RORgammat TR-FRET assay, to rapidly identify new small molecule RORgammat/IL-17 inhibitors and evaluate their mode of action. MATERIAL & METHODS: We sought to identify cell-permeable small-molecule inhibitors of RORgammat for rapid progression into hit-to-lead chemistry. As such, we developed the IL-17F promoter luciferase reporter assay in a stable human T-cell (Jurkat) line expressing the RORgammat receptor and miniaturised it to a final volume of 8 uL in 1536 well plates for HTS use in screening a library of > 350k compounds. In parallel, a RORgammat TR-FRET binding assay was employed to cross-screen the same set of compounds. This enabled the rapid identification of a small number of cell permeable RORgammat antagonists showing promising activity in both assays and also highlighted a larger group of potentially very interesting hits which inhibited IL-17 reporter activity, but did not appear to modulate RORgammat directly. RESULT: A rigorous triaging process of the novel non RORgammat IL-17 antagonists was followed, making use of in-silico filtering, historical screening data, selectivity screening using an IL-2 reporter assay with an identical cellular background, and final profiling in a phenotypic PBMC IL-17A production assay. This resulted in the identification of a set of promising small molecule compounds which show IL-17 inhibition via potentially novel pathways. CONCLUSION: This technique for the fast identification of cell permeable IL-17 modulators acting through different mechanisms, highlights the benefits of adopting a parallel approach combining high throughput profiling of hits in multiple assay formats, with robust in-silico triaging. PMID- 28571539 TI - Polymer-supported (-)-8-phenylmenthyl Auxiliary as an Effective Solidphase Chiral Inductor in the Addition of Nucleophiles to N-acyliminium Ions. AB - AIM AND OBJECTIVE: According to our interest in developing new methods for the construction of intricate molecules, a reliable polymer-supported (-)-8 phenylmenthyl chiral auxiliary for the addition of different nucleophiles to chiral-supported N-acyliminium precursors were developed. MATERIALS AND METHODS: Merrifield resin was employed to anchor (-)-8-phenylmenthol, which was prepared by nitration of (-)-8-phenylmenthyl chloroacetate followed by reduction of nitro group and subsequent Merrifield resin coupling. Treatment of a suspension of polymer-supported chloroformate and piperidinone in the presence of Et3N resulted in attachment of the substrate onto the solid-support. Treatment of the resulting resin with LiEt3BH/MeOH afforded methoxypiperidine in 87% yield. Then, the addition of allyltrimethylsilane, TMSCN, 2-(trimethylsiloxy)propene and triisopropylsilyloxyfuran and others to the N-acyliminium ion derived from chiral 2- methoxypiperidine carbamate was studied. RESULTS: The stereochemical outcome of the addition of nucleophiles to the supported N-acyliminium ion derived from 2 methoxypiperidine carbamate was proposed through the Si-face, affording after resin cleavage 2-substituted piperidines in 70%-84% yields and selectivities ranging from 4:1-11.1. Moreover, the key intermediates of chiral piperidines have been employed for the synthesis of simple chiral alkaloids such as (R)-pipecolic acid, (R)-pelletierine, (S)-coniine and (R,R)-myrtine. CONCLUSION: The proposed supported-chiral auxiliary for asymmetric approach may be expected to result not only in efficient solid-phase syntheses of a wide range of alkaloids but also in the development of useful new solid-phase methodologies, particularly for the asymmetric additions to iminium precursors. This work describes the first example of solid-phase synthesis by using supported (-)-8-phenylmenthyl as an effective chiral inductor and would be useful for the synthesis of chiral building block libraries. PMID- 28571540 TI - Caffeic Acid in Dermatological Formulations: In Vitro Release Profile and Skin Absorption. AB - AIM AND OBJECTIVE: Caffeic acid (CA) is a cinnamic acid derivative, found in many vegetable products, with powerful antioxidant activity, the ability to increase collagen production and capacity to prevent premature aging of the skin. The classic emulsions of CA are widely used by the consumer to provide a pleasant, refreshing sensorial experience; however, preparations developed in the form of dry film are presented as a technological alternative due to its facile and safe transportation. The aim of this study was to evaluate the release, permeation, and retention of CA in a film and emulsion through in vitro experiments. MATERIAL AND METHODS: The release evaluation of CA from the emulsion and the film was performed using modified Franz diffusion cells, with an area of 1.77 cm2, using Microette equipment (Hanson Research) with a cellulose membrane. The evaluation of the permeation of CA from the formulations was conducted using a similar technique of release, except that a biological membrane was used. RESULTS: High release of active compound and reduced permeation was observed, indicating that CA was able to be retained in the epidermis/dermis, where it should have the desired action. The concentration of caffeic acid in the skin was higher for the film formulation than for the emulsion. This demonstrates a greater efficiency of this type of innovative release system, besides its facile and safe transportation. CONCLUSION: The formulations tested in this paper can release caffeic acid with a Higuchi kinetic profile, in which release of active ingredient occurs by a diffusion process. The film formulations exhibited a lower permeation rate and higher retention in the skin, which is essential for a cosmetic product. The concentration of CA in the skin was also higher for the film formulation when compared to the emulsion. This demonstrates a greater efficiency of this type of innovative release system, in addition to its easy and safe transportation. Therefore, it is possible to suggest CA as a promising substance for dermal use due to its antioxidant, anti-inflammatory, antimicrobial, and collagen production stimulating activity. PMID- 28571541 TI - Investigation of Methylene Blue Release from Functional Polymeric Systems Using Dielectric Analysis. AB - BACKGROUND: Methylene blue (MB) is a photosensitizer used in photodynamic therapy (PDT) to treat colorectal cancer tumors and leishmaniasis infection. The clinical efficacy of PDT using MB is dependent on the physicochemical characteristics of the formulation. Bioadhesive thermoresponsive systems containing poloxamer 407 and Carbopol 934P have been proposed as platforms for PDT. However, the effect of MB on the physicochemical properties of these platforms is not fully understood, particularly in light of the MB availability. OBJECTIVE: The aim of this study was to investigate the dielectric characteristics of functional polymeric systems containing MB and their influence on mucoadhesion and drug release. METHODS: Binary polymeric systems containing different concentrations of poloxamer 407, Carbopol 934P and MB were evaluated as dielectric and mucoadhesive properties, as well as in vitro drug release profile. RESULTS: MB, temperature and polymeric composition influenced the physicochemical properties of the systems. The presence of MB altered the supramolecular structure of the preparations. The mucoadhesive properties of systems were influenced by MB presence and the formulation with the lowest amount of MB displayed faster release. CONCLUSION: The lower MB concentration in the systems displayed better results in terms of ionic mobility and drug release, and is indicative of a suitable clinical performance. PMID- 28571542 TI - Folic acid Targeted Polymeric Micelles Based on Tocopherol Succinate- Pulluan as an Effective Carrier for Epirubicin: Preparation, Characterization and In-vitro Cytotoxicity Assessment. AB - BACKGROUND: Chemotherapy still encounters a serious drawback, the lack of selectivity of anticancer drugs toward neoplastic cells, thus, the normal cells are affected by the cytotoxic action of the drugs. This causes a narrow therapeutic index in most anticancer drugs. OBJECTIVE: We describe the preparation of pullulan-tocopherol succinate-folic acid (Pu-TS-FA) micelles for the first time to targeted delivery of Epirubicin (EPI) to Hela and MCF-7 cell lines. METHODS: We confirmed the structure of conjugate using spectroscopic methods. The degree of substitution for both folic acid and tocopherol succinate was calculated using 1HNMR. We prepared the micelles via direct dissolution method. All the physicochemical properties of micelles including size, zeta potential, polydispersity index (PDI), critical micelle concentration (CMC), entrapment efficiency (EE %) and release efficiency (RE24%) were determined. The morphology of particles was studied using transmission electron microscopy (TEM), and the in-vitro cell cytotoxicity of EPI loaded micelles was studied using MTT assay on MCF-7 and Hela cell lines. RESULTS: The optimized micelles showed the particle size of 149.5 nm, the zeta potential of -6.49 mV, a polydispersity index of 0.259 +/- 0.07, LE% of 88 %, and RE24% of 63 +/- 2.45 % with a relatively low CMC 194.87 ug/ml. TEM showed the relatively uniform spherical structure for particles and in vitro MTT assay showed that EPI loaded micelles were more toxic on Hela cell line than MCF7 as expected. CONCLUSION: Since the Pu-TS-FA micelle could improve the anticancer activity of epirubicin and would be a promising candidate for EPI treatment of cancers. PMID- 28571543 TI - Aspartame: Should Individuals with Type II Diabetes be Taking it? AB - BACKGROUND: Individuals with Type II Diabetes (T2D) have to manage blood glucose levels to sustain health and longevity. Artificial sweeteners (including aspartame) are suggested sugar alternatives for these individuals. The safety of aspartame in particular, has long been the centre of debate. Although it is such a controversial product, many clinicians recommend its use to T2D patients, during a controlled diet and as part of an intervention strategy. Aspartame is 200 times sweeter than sugar and has a negligible effect on blood glucose levels, and it is suggested for use so that T2D can control carbohydrate intake and blood glucose levels. However, research suggests that aspartame intake may lead to an increased risk of weight gain rather than weight loss, and cause impaired blood glucose tolerance in T2D. OBJECTIVE: This review consolidates knowledge gained from studies that link aspartame consumption to the various mechanisms associated with T2D. METHOD: We review literature that provides evidence that raise concerns that aspartame may exacerbate T2D and add to the global burden of disease. RESULT: Aspartame may act as a chemical stressor by increasing cortisol levels, and may induce systemic oxidative stress by producing excess free radicals, and it may also alter gut microbial activity and interfere with the N-methyl D aspartate (NMDA) receptor, resulting in insulin deficiency or resistance. CONCLUSION: Aspartame and its metabolites are safe for T2D is still debatable due to a lack of consistent data. More research is required that provides evidence and raise concerns that aspartame may exacerbate prevalence of pathological physiology in the already stressed physiology of T2D. PMID- 28571544 TI - Programmed Cell Death after Intracerebral Hemorrhage. AB - BACKGROUND: Intracerebral hemorrhage (ICH) accounts for up to 15% of all strokes and is characterized by high rates of mortality and morbidity. The post-ICH brain injury can be distinguished in 1) primary, which are caused by disruption and mechanical deformation of brain tissue due to hematoma growth and 2) secondary, which are induced by microglia activation, mitochondrial dysfunction, neurotransmitter and inflammatory mediator release. Although these events typically lead to necrosis, the occurrence of programmed cell death has also been reported after ICH. METHODS: We reviewed recent publications describing advance in pre- and clinic ICH research. RESULTS: At present, treatment of ICH patients is based on oral anticoagulant reversal, management of blood pressure and other medical complications. Several pre-clinical studies showed promising results and demonstrated that anti-oxidative and anti-inflammatory treatments reduced neuronal cell death, however, to date, all of these attempts have failed in randomized controlled clinical trials. Yet, the time frame of administration may be crucial in translation from animal to clinical studies. Furthermore, the latest pre-clinical research points toward the existence of other, apoptosisunrelated forms kinds of programmed cell death. CONCLUSION: Our review summarizes current knowledge of pathways leading to programmed cell death after ICH in addition to data from clinical trials. Some of the pre-clinical results have not yet demonstrated clinical confirmation, however they significantly contribute to our understanding of post-ICH pathology and can contribute to development of new therapeutic approaches, decreasing mortality and improving ICH patients' quality of life. PMID- 28571547 TI - Potential of Macroalgae Ulva lactuca as a Source Feedstock for Biodiesel Production. AB - BACKGROUND: The aim of this study was to investigate the possibility of growing of algae Ulva lactuca L.under different salinity levels coupled with varied KNO3 concentrations (source of N) as a potential source of oil for biodiesel production. METHODS: U. lactuta was cultured in 10.0% NaCl coupled with either 2.5 g/L (S1+ 1N) or 1.0 g/L KNO3 (S1+ 2N) and in 30.0% NaCl coupled with 2.5 g/L (S2+ 1N) or 1.0 g/L KNO3 (S2+ 2N) nutrient medium. Among all algae cultures, biomass (dry weight) and lipid accumulation (total lipid content, TL) were significantly different (P>0.5%), with various degrees. The TL was increased (8.21% to 15.95%, g/100g) by increasing the NaCl % (from 10% to 30%) coupled with the depletion of KNO3 level (from 2.5% to 1%) in culture medium. High lipid content (15.95%) was obtained in S2+ 2N culture, this lipid showed physical (density, viscosity and average molecular weight) and chemical (iodine, acid, saponification and peroxide values) properties suitable for biodiesel production. RESULTS: The fatty acid methyl esters (FAME, biodiesel) prepared by trans esterifiction reaction under acidic condition were mainly composed of saturated (50.33%), monounsaturated (MUFA, 36.12%) and polyunsaturated (13.55%) esters. C 18:1 was found to be the main MUFA, representing 25.76% of total FAME. On the other hand, the values of some critical of physiochemical parameter (density, kinematic viscosity, iodine value, acid value and oxidation stability) of biodiesel were found to meet the standards for a high quality biodiesel. CONCLUSION: Hence, U. lactuta could be serving as a valuable renewable biomass of oil for biodiesel production. There are recent patents also suggesting use of oil of U. lactuta marine biomass for biodiesel production. PMID- 28571546 TI - Chromatin Changes Associated with Neuronal Maintenance and Their Pharmacological Application. AB - BACKGROUND: The transcriptional control of neuronal specification and early development has been intensively studied over the past few decades. However, relatively little is known about transcriptional programs associated with the maintenance of terminally differentiated neuronal cells with respect to their functions, structures, and cell type-specific identity features. METHODS: Notably, largely because of the recent advances in related techniques such as next generation sequencing and chromatin immunoprecipitation sequencing, the physiological implications of system-wide regulation of gene expression through changes in chromatin states have begun to be extensively studied in various contexts and systems, including the nervous system. RESULTS: Here, we attempt to review our current understanding of the link between chromatin changes and neuronal maintenance in the period of life after the completion of neuronal development. Perturbations involving chromatin changes in the system-wide transcriptional control are believed to be closely associated with diverse aspects of neuronal aging and neurodegenerative conditions. CONCLUSION: In this review, we focused on heterochromatin and epigenetic dysregulation in neurodegenerative conditions as well as neuronal aging, the most important risk factor leading to neuronal degeneration, in order to highlight the close association between chromatin changes and neuronal maintenance. Lastly, we reviewed the currently available and potential future applications of pharmacological control of the chromatin states associated with neuronal maintenance. PMID- 28571545 TI - Potential Medications or Compounds Acting on Toll-like Receptors in Cerebral Ischemia. AB - BACKGROUND: Toll-like receptors play an integral role in the process of inflammatory response after ischemic injury. The therapeutic potential acting on TLRs is worth of evaluations. The aim of this review was to introduce readers some potential medications or compounds which could alleviate the ischemic damage via TLRs. METHODS: Research articles online on TLRs were reviewed. Categorizations were listed according to the follows, methods acting on TLRs directly, modulations of MyD88 or TRIF signaling pathway, and the ischemic tolerance induced by the preconditioning or postconditioning with TLR ligands or minor cerebral ischemia via acting on TLRs. RESULTS: There are only a few studies concerning on direct effects. Anti-TLR4 or anti-TLR2 therapies may serve as promising strategies in acute events. Approaches targeting on inhibiting NF kappaB signaling pathway and enhancing interferon regulatory factor dependent signaling have attracted great interests. Not only drugs but compounds extracted from traditional Chinese medicine have been used to identify their neuroprotective effects against cerebral ischemia. In addition, many researchers have reported the positive therapeutic effects of preconditioning with agonists of TLR2, 3, 4, 7 and 9. Several trails have also explored the potential of postconditioning, which provide a new idea in ischemic treatments. Considering all the evidence above, many drugs and new compounds may have great potential to reduce ischemic insults. CONCLUSION: This review will focus on promising therapies which exerting neuroprotective effects against ischemic injury by acting on TLRs. PMID- 28571548 TI - Intermittent Transient Motor Aphasia Associated with Acute Lithium Toxicity: A Case Report and Brief Review. AB - BACKGROUND: Lithium is known to cause certain neurological deficits. However, reports of aphasia secondary to lithium toxicity are scant. We report the case of a 70 year old African American woman with a history of schizoaffective disorder and mild dementia who developed transient intermittent aphasia secondary to lithium toxicity. METHODS: Patient was admitted because of agitation, delusional behavior, and pressured speech. Her previous medications included divalproex sodium 500 mg po bid, valproic acid 250 mg po qd, risperidone 3.5 mg po bid, lorazepam 1 mg po bid, amlodipine besylate 5 mg po qd, levothyroxine sodium 25 mcg po qd, gabapentin 300 mg po qd, amantadine HCl 100 mg po bid, and aspirin 81 mg po qd. Since patient's symptoms have not improved, she was started on lithium 300mg po bid and titrated up to 300 mg po bid and 450 mg po qhs over 7-8 days. Her lithium levels ranged from 0.4 mEq/L on 11/11/16 to 1.5 mEq/L on 11/22/16. Patient was observed to have aphasia symptoms intermittently at lithium level of 1.5 mEq/L. CT scan of head and neurology consultations were unremarkable. The Naranjo Adverse Drug Reaction Probability Scale score was 8 in the probable range for an adverse drug reaction. Patient's sodium was also found to be high at 148 mmol/L. RESULTS: Lithium was discontinued and patient rehydrated with intravenous fluids. Patients aphasia resolved completely in 2-3 days. CONCLUSION: Clinicians should be aware of this rarely reported side effect of lithium particularly in patients at risk for volume depletion and closely monitor fluid intake, lithium level, and potential side effects. PMID- 28571549 TI - Nanoemulsion-Based Transdermal Drug Delivery System for the Treatment of Tuberculosis. AB - BACKGROUND: The nanoemulsion based carriers are the most suitable delivery systems for poorly soluble drugs to improve the drugs solubility, permeation of drugs and ultimately increase bioavailability by transdermal therapeutic system. The nanoemulsion for poorly soluble drugs is admirable and offered several advantages over others drug delivery. METHODS: For nanoemulsions formulation, they have to deliver the energetic element at the specific organ with nominal uneasiness. Because of the prevention of hepatic first pass uptake transdermal course excel usual crest and trough plasma shape that usually comfort the administration. The antitubercular drugs relate to the formulation of Poly DL Lactide-Co-Glycolide nanoparticles having an active substance encapsulated within and that the encapsulated substances are stable with respect to each other. CONCLUSION: The present study aimed to explore the challenges and methods in order to increase the solubility of poorly aqueous soluble drug for improved bioavailability alongwith relative study of toxicity problems related to anti tubercular drug. PMID- 28571550 TI - An Overwiev of ORF Virus Infection in Humans and Animals. AB - BACKGROUND: Orf virus is a DNA virus that belongs to the Parapoxvirus genus. The virus is a causative agent of orf in humans or contagious ecthyma in animals which is mostly seen in sheep, goat and cattle. DISCUSSION: Orf is an emerging zoonosis with an increasing number of worldwide outbreaks that have been reported. It is a contagious disease that tends to spread very fast among livestock. The morbidity rate is very high, particularly among young unvaccinated animals. The fatality rate is low but can be seen due to secondary infections. The disease has a significant effect on livestock health and may lead to economical losses. Humans may become infected if they have a direct contact with animal lesions. The disease is seen as a cutaneous lesion with a mild clinical outcome. Human to human transmission exists but is very rare. Nosocomial transmission was reported with one outbreak in a burn unit. The diagnosis is mostly based on the history of animal contact and clinical findings. Molecular tests are used to confirm clinical diagnose. There is no specific treatment but a live vaccine is available for animals. Surveillance implementations and infection control measurements are very important for the prevention of infection. Currently, there are limited studies on orf or contagious ecthyma. It has been observed that there are few studies that have resulted in patents. CONCLUSION: The aim of this paper was to review the current relevant patents, epidemiological features, clinical presentations, the diagnosis and treatment of orf. PMID- 28571551 TI - Application of Bone Marrow Stem Cell Based Therapy in Bone Loss Diseases. AB - Hematopoietic bone marrow stem cell transplantation has been regularly used in clinical practice for over 40 years. Further research indicates that bone marrow stromal cells are also stem cells that are capable of self-renewal, proliferation and differentiation. With appropriate induction, the bone marrow stromal cells can differentiate into bone, cartilage, tendon, adipose tissue and fibrous tissue, which would potentially be applied for treating bone loss diseases. This review outlines research in understanding role of bone marrow stem cells and stem cells from other origins in bone repair, and highlight the current and potential stem cell based treatment for bone loss diseases in the future. PMID- 28571552 TI - Micro-RNA Profiling as a Predictor of Clinical Outcomes for Head and Neck Cancer Patients. AB - Head and neck cancer is one of the leading malignancies worldwide. Due to the lack of symptoms in the early stage of the disease, about two thirds of patients present with locally advanced disease at the time of diagnosis. Even with significantly improved survival rates over the past two decades due to advanced imaging and treatment modalities, locoregional recurrence rates in patients with advanced disease ranges from 16% to 35%. Alternative therapeutic targets are being developed to improve survival outcomes. MicroRNAs (miRNA or miRs) are a family of small non-coding RNA species that have been demonstrated to regulate all cellular, physiological and developmental processes. Recently, there has been an exponential increase in the number of studies suggesting that miRNA is involved in regulating tumor metastasis, chemoresistance, radioresistance and survival outcomes. MiRNA candidates have been identified as potential prognostic biomarkers to diagnose cancer stages and progression, as well as to monitor follow-up treatment. In this review, we will discuss the miRNA profile in each stage of head and neck patients' therapy, with an emphasis on its application to clinical outcome prognosis. PMID- 28571553 TI - Parasite Polyamines as Pharmaceutical Targets. AB - There is an urgent need for the identification and validation of new therapeutic targets in protozoan parasites because currently available drugs are limited in number and usefulness, and no vaccines are available. The discovery that alpha difluoromethylornithine, an inhibitor of polyamine biosynthesis, is an efficacious treatment for African Sleeping Sickness caused by the protozoan parasite Trypanosoma brucei, has validated the polyamine pathway as a target in protozoan parasites. Polyamines are ubiquitous organic cations that play critical roles in key cellular processes such as growth, differentiation, and macromolecular biosynthesis. In recent years, remarkable progress has been made in the characterization of the polyamine pathway in a variety of protozoan parasites and this review will highlight surprising and unique features that could lead to new therapeutic strategies. PMID- 28571554 TI - Methotrexate in the Treatment of Psoriasis and Rheumatoid Arthritis: Mechanistic Insights, Current Issues and Novel Delivery Approaches. AB - Our review is focused on the use of methotrexate in drug therapy of two autoimmune diseases, psoriasis and rheumatoid arthritis (RA). The article describes the pathogenesis of psoriasis and RA, the role of methotrexate in the treatment of these diseases with more focused review on the mechanism behind the clinical benefits of methotrexate therapy. Methotrexate due to its cytotoxic, anti-inflammatory and immune modulatory activities provides clinical benefits in the therapy of the selected diseases. This review also gives a panorama of the problems associated with the use of methotrexate in the selected diseases and the guidelines provided by FDA for its safe use. The novel colloidal drug delivery systems of methotrexate, with particular emphasis on advantages offered by liposomal formulation, niosomal gel, hydrogel, albumin conjugates, nanoparticles and nano structured lipid carriers in psoriasis and RA are also reviewed. It seemed that the use of newer colloidal carriers with improved skin permeability by minimizing its systemic availability will be a useful strategy to reduce the toxic effects of the drug in psoriatic patients. In rheumatoid arthritis patients, the development of newer therapeutic strategies using appropriate targeting ligands that specifically deliver the drug to the inflamed joint space will help to overcome its toxic effects by minimizing the systemic exposure. PMID- 28571555 TI - Editorial: Lipoprotein (a), More than Just Cholesterol? PMID- 28571556 TI - Interactions of VDAC with Proteins Involved in Neurodegenerative Aggregation: An Opportunity for Advancement on Therapeutic Molecules. AB - BACKGROUND: The Voltage Dependent Anion Channel (VDAC) proteins represent the most important pore-forming proteins of the mitochondrial outer membrane, directly involved in metabolism and apoptosis regulation. Literature has highlighted a key role of VDACs in mitochondrial dysfunction typical of many neurodegenerative disorders. In particular, the principal isoform VDAC1 represents the main mitochondrial docking site of many misfolded proteins, such as amyloid beta and Tau in Alzheimer's disease, alpha-synuclein in Parkinson's disease and several SOD1 mutants in Amyotrophic Lateral Sclerosis. The interaction of misfolded proteins with VDAC1 has a strong impact on both cellular bioenergetics and apoptosis' pathways alteration. Therefore, VDACs represent a promising therapeutic target in neurodegeneration. OBJECTIVE: This review summarizes the roles of VDAC isoforms, and particularly of VDAC1, in the most common neurological disorders and analyzes in detail molecules and peptides available so far, able to interact and modulate VDAC1 in any considered pathological condition. CONCLUSION: This review offers a description of the most promising therapeutic strategies acting on VDAC1, for the treatment of neurodegenerative diseases. PMID- 28571557 TI - Recent Advances of Individual BODIPY and BODIPY-Based Functional Materials in Medical Diagnostics and Treatment. AB - BACKGROUND: The group of fluorophores on boron dipyrrin platform (4,4- difluoro-4 bora3a,4a-diaza-s-indacene, also known as BODIPY) has attracted much attention in the field of molecular sensorics, including sensing of biomolecules and bioprocesses. Structural diversity of existing BODIPY with ample opportunities of directed modification of compounds makes this class of fluorophores attractive for medical and biological purposes. The recent progress in the design and functionalization of BODIPY allows using them for modification of drug micro- and nanocarriers in order to improve their therapeutic effect in cancer treatment. At the same time, integration of BODIPY into drug carriers provides the possibility of in vitro and in vivo real time imaging of used drug carriers. The high fluorescent intensity and low toxicity of BODIPY granted for conjugation with different biomolecules. RESULTS: The present review focuses on the recent advances for application of individual BODIPY in medical diagnostics, antimicrobial activity, as well as establishing the role of BODIPY in labeling of biomolecules (e.g. proteins, hormones and DNA). Also the review highlights the potential of BODIPY in functionalization of drug micro- and nanocarriers in order to achieve better therapeutic efficiency compared with non-modified materials. The advantages derived from the use of BODIPY for preparation and modification of drug carriers are critically evaluated and potential for future challenges, especially concerning the design of innovative multi-functional BODIPY-based nanocarriers, is discussed in detail using representative examples from literature. CONCLUSION: Our objective was to show that BODIPY are powerful tools for bioimaging, labeling of biomolecules and construction of new multifunctional drug carriers. PMID- 28571558 TI - Protein Profile Analysis of Two Australian Snake Venoms by One- Dimensional Gel Electrophoresis and MS/MS Experiments. AB - The Pseudechis colletti and Pseudechis butleri venoms were analyzed by 1-D gel electrophoresis, followed by mass spectrometric analysis of tryptic peptides obtained from the protein bands. Both venoms contain highly potent pharmacologically active components, which were assigned to the following protein families: basic and acidic phospholipases A2 (PLA2s), L-amino acid oxidases (LAAOs), P-III metalloproteinases (P-III SVMPs), 5'- nucleotidases (5'-NTDs), cysteine-rich secretory proteins (CRISPs), venom nerve growth factors (VNGFs) and post-synaptic neurotoxins. Considerable predominance of PLA2s over other toxins is a characteristic feature of both venoms. The major differences in the venom compositions are the higher concentration of SVMPs and CRISPs in the P. butleri venom, as well as the presence of post-synaptic neurotoxins. Furthermore, the analysis revealed a high concentration of proteins with myotoxic, coagulopathic and apoptotic activities. PLA2s are responsible for the myotoxic and anticoagulant effects observed in patients after envenomation (4). The other protein families, encountered in the two venoms, probably contribute to the major symptoms described for these venoms. These results explain the observed clinical effects of the black snake envenomation. The analyzed venoms contain group P-III metalloproteinases of medical importance with the potency to be used for diagnostic purposes of von Willebrand factor (vWF) disease, for regulation of vWF in thrombosis and haemostasis, for studying the function of the complement system in host defense and in the pathogenesis of diseases. Comparison of venomic data showed similarities in the major venom components of snakes from the genus Pseudechis, resulting in common clinical effects of envenomation, and demonstrating close relationships between venom toxins of Elapidae snakes. PMID- 28571559 TI - A Mini-Review on Thalidomide: Chemistry, Mechanisms of Action, Therapeutic Potential and Anti-Angiogenic Properties in Multiple Myeloma. AB - Thalidomide is a drug with interesting therapeutic properties but also with severe side effects which require a careful and monitored use. Potential immunomodulatory, antiinflammatory, anti-angiogenic and sedative properties make thalidomide a good candidate for the treatment of several diseases such as multiple myeloma. Through an increase in the degradation of TNFalpha-mRNA, thalidomide reduces the production of TNFalpha by monocytes and macrophages stimulated by lipopolysaccharide or by T lymphocytes induced by mitogenic stimuli. The decreased level of TNFalpha alters the mechanisms of intracellular transduction by preventing the activation of NF-kB and by decreasing the synthesis of proteins, in particular IL-6, involved in cell proliferation, inflammation, angiogenesis and protection from apoptosis. Furthermore, thalidomide affects VEGF levels by down-regulating its expression. Nowadays, new safer and less toxic drugs, analogs of thalidomide, are emerging as beneficial for a more targeted treatment of multiple myeloma and several other diseases such as Crohn';s disease, rheumatoid arthritis, sarcoidosis, erythema nodosum leprosum, graft-versus-host disease. PMID- 28571560 TI - The Use of Biomarkers in Sepsis: A Systematic Review. AB - BACKGROUND: Despite the extended laboratory and clinical study of sepsis, its diagnosis remains a clinical challenge. The initiation of sepsis activates many different biochemical and immunological pathways being expressed by alterations of various molecules in human tissues. The detection and measurement of the concentration of such molecules, known as biomarkers, may be a diagnostic tool of great significance for clinicians dealing with suspected sepsis. Additionally, biomarkers may predict patients ' outcome and may play a role in monitoring response to therapy. METHODS: Most relevant clinical and experimental biomarker studies on sepsis were retrieved and reviewed in this article. RESULTS: Although many biomarkers were evaluated for the diagnosis and prognosis in sepsis, until now not one has been proven to be absolutely reliable in the clinical field. Currently C-reactive proteine (CPR) and procalcitonin (PCT) are used worldwide routinely, nevertheless their values may elevate in clinical settings without sepsis, while they often fail to provide reliable prediction of the patient outcome. CONCLUSION: This review outlines most relevant circulating biomarkers in sepsis. PMID- 28571561 TI - High Sensitivity Troponin I and T Reflect the Presence of Obstructive and Multi Vessel Coronary Artery Disease Being Assessed by Coronary Computed Tomography Angiography. AB - BACKGROUND: This study evaluates the association between high sensitivity troponin I (hsTnI) and T (hsTnT) in patients with suspected stable Coronary Artery Disease (CAD) undergoing Coronary Computed Tomography Angiography (CCTA). METHODS: Patients undergoing CCTA were enrolled prospectively. CCTA was indicated in patients with angina and a low to intermediate pre-test probability for CAD during routine clinical care. Blood samples were taken at the time of CCTA to measure cardiac biomarkers. RESULTS: A total of 99 patients were enrolled with 43 % revealing no CAD, 30 % with non-obstructive and 26 % with obstructive CAD. Out of these, 61 % had single-vessel and 39 % had multi-vessel CAD. Both hsTnI and hsTnT levels increased significantly according to the presence and extent of CAD (p = 0.0001) and were able to discriminate the presence of both obstructive (AUC range: 0.775 - 0.785; p = 0.0001) and multi-vessel CAD (AUC range: 0.740 - 0.749; p = 0.01). In multivariate logistic regression models adjusted for cardiovascular risk factors and NT-proBNP, both hsTn were still associated significantly with obstructive CAD (range of odds ratios (OR): 8.3-32.3; p < 0.02). DISCUSSION: This study shows that high sensitivity troponin I and T reflect the presence and extent of CAD being diagnosed by CCTA in patients with a low to intermediate pretest probability for CAD. PMID- 28571562 TI - Advantages and Limitations of Current Biomarker Research: From Experimental Research to Clinical Application. AB - BACKGROUND: Biomarkers are indispensable tools for screening, diagnosis, and prognosis in cardiovascular diseases and their clinical application increases steadily. As cardiovascular diseases include various pathophysiological processes, no single biomarker, even natriuretic peptides, can be regarded as ideal fulfilling all necessary criteria for a comprehensive diagnostic or prognostic assessment revealing optimal clinical application. Hence, multi-marker approaches using different biomarkers reflecting different pathophysiologies were highlighted recently. Advances in biomedical technologies expanded the spectrum of novel blood-derived biomarkers, such as micro-RNA (miRNA) or "omics"- data potentially providing a more advanced knowledge about pathogenesis of cardiovascular disease. CONCLUSION: This review describes the advantages and limitations of blood circulating biomarkers with regard to proteins, metabolomics and transcriptional level both within single as well as multi-marker strategies. Moreover, their usefulness is focused on clinical decision-making in cardiovascular diseases. PMID- 28571563 TI - The design and development of a complex multifactorial falls assessment intervention for falls prevention: The Prevention of Falls Injury Trial (PreFIT). AB - BACKGROUND: This paper describes the design and development of a complex multifactorial falls prevention (MFFP) intervention for implementation and testing within the framework of a large UK-based falls prevention randomised controlled trial (RCT). METHODS: A complex intervention was developed for inclusion within the Prevention of Falls Injury Trial (PreFIT), a multicentre pragmatic RCT. PreFIT aims to compare the clinical and cost-effectiveness of three alternative primary care falls prevention interventions (advice, exercise and MFFP), on outcomes of fractures and falls. Community-dwelling adults, aged 70 years and older, were recruited from primary care in the National Health Service (NHS), England. RESULTS: Development of the PreFIT MFFP intervention was informed by the existing evidence base and clinical guidelines for the assessment and management of falls in older adults. After piloting and modification, the final MFFP intervention includes seven falls risk factors: a detailed falls history interview with consideration of 'red flags'; assessment of balance and gait; vision; medication screen; cardiac screen; feet and footwear screen and home environment assessment. This complex intervention has been fully manualised with clear, documented assessment and treatment pathways for each risk factor. Each risk factor is assessed in every trial participant referred for MFFP. Referral for assessment is based upon a screening survey to identify those with a history of falling or balance problems. Intervention delivery can be adapted to the local setting. CONCLUSION: This complex falls prevention intervention is currently being tested within the framework of a large clinical trial. This paper adheres to TIDieR and CONSORT recommendations for the comprehensive and explicit reporting of trial interventions. Results from the PreFIT study will be published in due course. The effectiveness and cost-effectiveness of the PreFIT MFFP intervention, compared to advice and exercise, on the prevention of falls and fractures, will be reported at the conclusion of the trial. PMID- 28571564 TI - Systemic treatment in advanced soft tissue sarcoma: what is standard, what is new. AB - For metastatic soft tissue sarcoma (STS) patients not eligible for surgery, systemic treatments, including standard chemotherapy and newer biological compounds, still play the most relevant role in the management of the disease. An anthracycline and alkylating agent combination has formed the cornerstone of chemotherapy in STS for more than 30 years, with its value over that of administration of anthracycline as a single agent still being debated. Efforts have been made to improve the activity and minimise the toxicity of the combination, as well as to explore the upfront efficacy of agents known to be active in sarcoma and to develop new biological compounds. Nevertheless, beyond the first line, evidence for medical treatment in STS is less robust and all the more driven by histology. Thus, the introduction of kinases and small molecule inhibitors in the treatment armamentarium for STS is a major achievement in this setting. Preliminary data on immunotherapy are also available and discussed in this review. PMID- 28571565 TI - C-reactive protein is differentially modulated by co-existing infections, vitamin deficiencies and maternal factors in pregnant and lactating indigenous Panamanian women. AB - BACKGROUND: The usefulness of C-reactive protein (CRP) as a non-specific marker of inflammation during pregnancy and lactation is unclear in impoverished populations where co-existing infections and vitamin deficiencies are common. METHODS: This cross-sectional study in Panama recruited 120 pregnant and 99 lactating Ngabe-Bugle women from 14 communities in rural Panama. Obstetric history, indoor wood smoke exposure, fieldwork, BMI, vitamins A, B12, D, and folic acid, and inflammation markers (CRP, neutrophil/lymphocyte ratio (NLR), plateletcrit and cytokines) were measured. Multiple regressions explored both associations of CRP with other inflammatory markers and associations of CRP and elevated CRP based on trimester-specific cut-offs with maternal factors, infections and vitamin deficiencies. RESULTS: CRP was higher in pregnancy (51.4 +/- 4.7 nmol/L) than lactation (27.8 +/- 3.5 nmol/L) and was elevated above trimester specific cut-offs in 21% of pregnant and 30% of lactating women. Vitamin deficiencies were common (vitamin A 29.6%; vitamin D 68.5%; vitamin B12 68%; folic acid 25.5%) and over 50% of women had two or more concurrent deficiencies as well as multiple infections. Multiple regression models highlighted differences in variables associated with CRP between pregnancy and lactation. In pregnancy, CRP was positively associated with greater indoor wood smoke exposure, caries and hookworm and negatively associated with Ascaris and vaginal Lactobacillus and Bacteroides/Gardnerella scores. Consistent with this, greater wood smoke exposure, caries as well as higher diplococcal infection score increased the odds of trimester-elevated CRP concentrations whereas longer gestational age lowered the likelihood of a trimester-elevated CRP. During lactation, folic acid deficiency was associated with higher CRP whereas parity, number of eosinophils and Mobiluncus score were associated with lower CRP. Also, a higher BMI and Trichomonas vaginalis score increased the likelihood of an elevated CRP whereas higher parity and number of eosinophils were associated with lower likelihood of an elevated CRP. CONCLUSIONS: Infections both raise and lower CRP concentrations in pregnant and lactating mothers. Only folic acid deficiency during lactation was associated with higher CRP concentrations. Caution is required when interpreting CRP concentrations in pregnant and lactating women who have co-existing nutrient deficiencies and multiple infections. PMID- 28571566 TI - Knowledge, attitude and practice related to diabetes mellitus among the general public in Galle district in Southern Sri Lanka: a pilot study. AB - BACKGROUND: Type 2 diabetes mellitus (DM) has become a global epidemic with significant disability and premature death. Identification of the level of knowledge, attitude and practice (KAP) related to diabetes among the general public is important in strategies for prevention of diabetes mellitus. METHODS: This study was conducted as a community based cross sectional study in three Medical Officers of Health (MOH) areas in Galle district. Previously healthy literate individuals who have not attended any diabetes education program in the last two years were selected for this study. RESULTS: A total of 277 participants were included in the study. The majority (77%) had either moderate (39%) or above moderate knowledge (38%) on diabetes mellitus. Even though, level of education was significantly and positively associated with knowledge (p = 0.001), the association of gender and age with knowledge was not significant. Unlike knowledge, the attitude towards diabetes was poor in majority (90%) and level of education had no significant effect on attitude. With regards to practices, more than half of study subjects never had their blood sugar checked and, about 65% used to take refined sugar liberally and a large majority (80%) had no regular exercise activity. CONCLUSIONS: Even though the majority (77%) had moderate or above moderate knowledge on diabetes, their attitudes towards diabetes was poor (88%). It appears that the higher knowledge on diabetes did not translate into good practices as over 50% of study subjects did not involve with any preventive measures. Therefore, more emphasis should be given to address the issue of poor attitude and practices towards diabetes mellitus among general public in Sri Lanka. PMID- 28571567 TI - Clostridium butyricum maximizes growth while minimizing enzyme usage and ATP production: metabolic flux distribution of a strain cultured in glycerol. AB - BACKGROUND: The increase in glycerol obtained as a byproduct of biodiesel has encouraged the production of new industrial products, such as 1,3-propanediol (PDO), using biotechnological transformation via bacteria like Clostridium butyricum. However, despite the increasing role of Clostridium butyricum as a bio production platform, its metabolism remains poorly modeled. RESULTS: We reconstructed iCbu641, the first genome-scale metabolic (GSM) model of a PDO producer Clostridium strain, which included 641 genes, 365 enzymes, 891 reactions, and 701 metabolites. We found an enzyme expression prediction of nearly 84% after comparison of proteomic data with flux distribution estimation using flux balance analysis (FBA). The remaining 16% corresponded to enzymes directionally coupled to growth, according to flux coupling findings (FCF). The fermentation data validation also revealed different phenotype states that depended on culture media conditions; for example, Clostridium maximizes its biomass yield per enzyme usage under glycerol limitation. By contrast, under glycerol excess conditions, Clostridium grows sub-optimally, maximizing biomass yield while minimizing both enzyme usage and ATP production. We further evaluated perturbations in the GSM model through enzyme deletions and variations in biomass composition. The GSM predictions showed no significant increase in PDO production, suggesting a robustness to perturbations in the GSM model. We used the experimental results to predict that co-fermentation was a better alternative than iCbu641 perturbations for improving PDO yields. CONCLUSIONS: The agreement between the predicted and experimental values allows the use of the GSM model constructed for the PDO-producing Clostridium strain to propose new scenarios for PDO production, such as dynamic simulations, thereby reducing the time and costs associated with experimentation. PMID- 28571568 TI - Environmental temperature variation influences fitness trade-offs and tolerance in a fish-tapeworm association. AB - BACKGROUND: Increasing temperatures are predicted to strongly impact host parasite interactions, but empirical tests are rare. Host species that are naturally exposed to a broad temperature spectrum offer the possibility to investigate the effects of elevated temperatures on hosts and parasites. Using three-spined sticklebacks, Gasterosteus aculeatus L., and tapeworms, Schistocephalus solidus (Muller, 1776), originating from a cold and a warm water site of a volcanic lake, we subjected sympatric and allopatric host-parasite combinations to cold and warm conditions in a fully crossed design. We predicted that warm temperatures would promote the development of the parasites, while the hosts might benefit from cooler temperatures. We further expected adaptations to the local temperature and mutual adaptations of local host-parasite pairs. RESULTS: Overall, S. solidus parasites grew faster at warm temperatures and stickleback hosts at cold temperatures. On a finer scale, we observed that parasites were able to exploit their hosts more efficiently at the parasite's temperature of origin. In contrast, host tolerance towards parasite infection was higher when sticklebacks were infected with parasites at the parasite's 'foreign' temperature. Cold-origin sticklebacks tended to grow faster and parasite infection induced a stronger immune response. CONCLUSIONS: Our results suggest that increasing environmental temperatures promote the parasite rather than the host and that host tolerance is dependent on the interaction between parasite infection and temperature. Sticklebacks might use tolerance mechanisms towards parasite infection in combination with their high plasticity towards temperature changes to cope with increasing parasite infection pressures and rising temperatures. PMID- 28571569 TI - Erratum to Acupuncture to improve live birth rates for women undergoing in vitro fertilization: a protocol for a randomized controlled trial. PMID- 28571570 TI - Immunological and virological characterization of HIV-1 viremia controllers in the North Region of Brazil. AB - BACKGROUND: A rare phenotype of clinical non-progressors to AIDS is not well understood and the new protocol for universal treatment, may block the understanding of viral control thus it is crucial to define this controversial group. METHODS: A cohort of 30 persons followed a criteria for viremia control groups 1 (VC1; n = 2) and 2 (VC2; n = 7) and non-viral controllers (NC; n = 21) including number of years of diagnosis, LTCD4+, LTCD8+ counts, plasma viral load and the absence of ART; 241 uninfected control persons were matched to age and sex. Infected persons were regularly examined and submitted to two or three annual laboratory measurements. Polymorphisms and allele frequencies of CCR5Delta32 and SDF1-3'A were detected in the genomic DNA. Plasma levels of cytokines (IL-2, IL-4, IL-5, IL-9, IL-10, IL-13, IL-17 and IFN-y) were measured. RESULTS: The group investigated is originated from a miscigenetic population and demographic and social characteristics were not significantly relevant. LTCD4+ median values were higher among VC than NC, but significantly lower than uninfected controls. Evolution of LTCD4+ and LTCD8+ counts, showed a slight increase of LTCD4+ among VC, but a significant decrease in the NC. The percentage of annual change in LTCD4+ was also significantly different between the groups. LTCD4+/LTCD8+ ratio was inverted but not significant among the VC, thus the ratio may be a useful biomarker for the VC. A clear signature indicated a change from Th1 to Th2 cytokine profiles from VC to NC, respectively. CONCLUSIONS: The knowledge of viral controllers characteristics in different population groups is important to define a strict universal definition for the sake of learning about the pathogenesis of HIV-1. Data on LTCD4+ seems to be stable and repetitive from published data, but the LTCD8+ response and the significance of LTCD4+/LTCD8+ ratio values are in need to further exploration as biomarkers. The change from Th1 to Th2 cytokine profile may help to design and adjust specific treatment protocols for the group. PMID- 28571572 TI - Assessment of climate-driven variations in malaria incidence in Swaziland: toward malaria elimination. AB - BACKGROUND: Swaziland aims to eliminate malaria by 2020. However, imported cases from neighbouring endemic countries continue to sustain local parasite reservoirs and initiate transmission. As certain weather and climatic conditions may trigger or intensify malaria outbreaks, identification of areas prone to these conditions may aid decision-makers in deploying targeted malaria interventions more effectively. METHODS: Malaria case-surveillance data for Swaziland were provided by Swaziland's National Malaria Control Programme. Climate data were derived from local weather stations and remote sensing images. Climate parameters and malaria cases between 2001 and 2015 were then analysed using seasonal autoregressive integrated moving average models and distributed lag non-linear models (DLNM). RESULTS: The incidence of malaria in Swaziland increased between 2005 and 2010, especially in the Lubombo and Hhohho regions. A time-series analysis indicated that warmer temperatures and higher precipitation in the Lubombo and Hhohho administrative regions are conducive to malaria transmission. DLNM showed that the risk of malaria increased in Lubombo when the maximum temperature was above 30 degrees C or monthly precipitation was above 5 in. In Hhohho, the minimum temperature remaining above 15 degrees C or precipitation being greater than 10 in. might be associated with malaria transmission. CONCLUSIONS: This study provides a preliminary assessment of the impact of short-term climate variations on malaria transmission in Swaziland. The geographic separation of imported and locally acquired malaria, as well as population behaviour, highlight the varying modes of transmission, part of which may be relevant to climate conditions. Thus, the impact of changing climate conditions should be noted as Swaziland moves toward malaria elimination. PMID- 28571573 TI - Comparison of molecular serotyping approaches of Streptococcus agalactiae from genomic sequences. AB - BACKGROUND: Group B streptococcus (GBS) capsular polysaccharide is one of the major virulence factors underlying invasive GBS disease and a component of forthcoming vaccines. Serotype classification of GBS is based on the capsule polysaccharide of which ten variants are known to exist (Ia, Ib, II-IX). Current methods for GBS serotype assignment rely on latex agglutination or PCR while more recently a whole genome sequencing method was reported. In this study, three distinct algorithms for serotype assignment from genomic data were assessed using a panel of 790 clinical isolates. METHODS: The first approach utilised the entire capsular locus coupled with a mapping methodology. The second approach continues from the first and utilised a SNP-based methodology across the conserved cpsD-G region to differentiate serotypes Ia-VII and IX. Finally the third approach used the variable cpsG -K region coupled with a mapping methodology. All three approaches were assessed for typeability (percentage of isolates assigned a serotype) and concordance to the latex agglutination methodology. RESULTS: Following comparisons, the third approach using the variable cpsG-K region demonstrated the best performance with 99.9% typeability and 86.7% concordance. Overall, of the 105 discordant isolates, 71 were resolved following retesting of latex agglutination and whole genome sequencing, 20 failed to assign a serotype using latex agglutination and only 14 were found to be truly discordant on re testing. Comparison of this final approach with the previously described assembly based approach returned identical results. CONCLUSIONS: These results demonstrated that molecular capsular typing using whole genome sequencing and a mapping-based approach is a viable alternative to the traditional, latex agglutination-based serotyping method and can be implemented in a public health microbiology setting. PMID- 28571574 TI - The use of Local Ecological Knowledge as a complementary approach to understand the temporal and spatial patterns of fishery resources distribution. AB - BACKGROUND: Acquiring fast and accurate information on ecological patterns of fishery resources is a basic first step for their management. However, some countries may lack the technical and/or the financial means to undergo traditional scientific samplings to get such information; therefore affordable and reliable alternatives need to be sought. METHODS: We compared two different approaches to identify occurrence patterns and catch for three main fish species caught with bottom-set gillnets used by artisanal fishers from northeast Brazil: (1) scientific on-board record data of small-scale fleet (n = 72 trips), and (2) interviews with small-scale fishers on Local Ecological Knowledge (LEK) (n = 32 interviews). We correlated (Pearson correlations) the months cited by fishers (LEK) as belonging to the rainy or to the dry season with observed periods of higher and lower precipitation (SK). The presence of the three main fish species at different depths was compared between LEK and SK by Spearman correlations. Spearman correlations were also used to compare the depths of greatest abundance (with the highest Capture per Unit Effort - CPUE) of these species; the CPUEs were descendly ordered. RESULTS: Both methods provided similar and complementary bathymetric patterns of species occurrence and catch. The largest catches occured in deeper areas, which also happened to be less intensively fished. The preference for fishing in shallower and less productive areas was mostly due to environmental factors, such as weaker currents and less drifting algae at such depths. CONCLUSION: Both on-board and interview methods were accurate and brought complementary information, even though fishers provided faster data when compared to scientific on-board observations. When time and funding are not limited, integrative approaches such as the one presented here are likely the best option to obtain information, otherwise fishers' LEK could be a better choice for when a compromise between speed, reliability and cost needs to be reached. PMID- 28571575 TI - Active case-finding for tuberculosis by mobile teams in Myanmar: yield and treatment outcomes. AB - BACKGROUND: Since 2005, the Myanmar National Tuberculosis Programme (NTP) has been implementing active case finding (ACF) activities involving mobile teams in hard-to-reach areas. This study revealed the contribution of mobile team activities to total tuberculosis (TB) case detection, characteristics of TB patients detected by mobile teams and their treatment outcomes. METHODS: This was a descriptive study using routine programme data between October 2014 and December 2014. Mobile team activities were a one-stop service and included portable digital chest radiography (CXR) and microscopy of two sputum samples. The algorithm of the case detection included screening patients by symptoms, then by CXR followed by sputum microscopy for confirmation. Diagnosed patients were started on treatment and followed until a final outcome was ascertained. RESULTS: A total of 9 349 people with symptoms suggestive of TB were screened by CXR, with an uptake of 96.6%. Of those who were meant to undergo sputum smear microscopy, 51.4% had sputum examinations. Finally, 504 TB patients were identified by the mobile teams and the overall contribution to total TB case detection in the respective townships was 25.3%. Among total cases examined by microscopy, 6.4% were sputum smear positive TB. Treatment success rate was high as 91.8% in study townships compared to national rate 85% (2014 cohort). CONCLUSIONS: This study confirmed the feasibility and acceptability of ACF by mobile teams in hard-to reach contexts, especially when equipped with portable, digital CXR machines that provided immediate results. However, the follow-up process of sputum examination created a significant barrier to confirmation of the diagnosis. In order to optimize the ACF through mobile team activity, future ACF activities were needed to be strengthened one stop service including molecular diagnostics or provision of sputum cups to all presumptive TB cases prior to CXR and testing if CXR suggestive of TB. PMID- 28571571 TI - Renal association clinical practice guideline in post-operative care in the kidney transplant recipient. AB - These guidelines cover the care of patients from the period following kidney transplantation until the transplant is no longer working or the patient dies. During the early phase prevention of acute rejection and infection are the priority. After around 3-6 months, the priorities change to preservation of transplant function and avoiding the long-term complications of immunosuppressive medication (the medication used to suppress the immune system to prevent rejection). The topics discussed include organization of outpatient follow up, immunosuppressive medication, treatment of acute and chronic rejection, and prevention of complications. The potential complications discussed include heart disease, infection, cancer, bone disease and blood disorders. There is also a section on contraception and reproductive issues.Immediately after the introduction there is a statement of all the recommendations. These recommendations are written in a language that we think should be understandable by many patients, relatives, carers and other interested people. Consequently we have not reworded or restated them in this lay summary. They are graded 1 or 2 depending on the strength of the recommendation by the authors, and AD depending on the quality of the evidence that the recommendation is based on. PMID- 28571576 TI - Matriptase zymogen supports epithelial development, homeostasis and regeneration. AB - BACKGROUND: Matriptase is a membrane serine protease essential for epithelial development, homeostasis, and regeneration, as well as a central orchestrator of pathogenic pericellular signaling in the context of inflammatory and proliferative diseases. Matriptase is an unusual protease in that its zymogen displays measurable enzymatic activity. RESULTS: Here, we used gain and loss of function genetics to investigate the possible biological functions of zymogen matriptase. Unexpectedly, transgenic mice mis-expressing a zymogen-locked version of matriptase in the epidermis displayed pathologies previously reported for transgenic mice mis-expressing wildtype epidermal matriptase. Equally surprising, mice engineered to express only zymogen-locked endogenous matriptase, unlike matriptase null mice, were viable, developed epithelial barrier function, and regenerated the injured epithelium. Compatible with these observations, wildtype and zymogen-locked matriptase were equipotent activators of PAR-2 inflammatory signaling. CONCLUSION: The study demonstrates that the matriptase zymogen is biologically active and is capable of executing developmental and homeostatic functions of the protease. PMID- 28571577 TI - Protocol for the Emory University African American Vaginal, Oral, and Gut Microbiome in Pregnancy Cohort Study. AB - BACKGROUND: Adverse birth and neonatal outcomes disproportionately affect African American women and infants compared to those of other races/ethnicities. While significant research has sought to identify underlying factors contributing to these disparities, current understanding remains limited, constraining prevention, early diagnosis, and treatment. With the development of next generation sequencing techniques, the contribution of the vaginal microbiome to adverse maternal and neonatal outcomes has come under consideration. However, most microbiome in pregnancy studies include few African American women, do not consider the potential contribution of non-vaginal microbiome sites, and do not consider the effects of sociodemographic or behavioral factors on the microbiome. METHODS: We conceived our on-going, 5-year longitudinal study, Biobehavioral Determinants of the Microbiome and Preterm Birth in Black Women, as an intra-race study to enable the investigation of risk and protective factors within the disparate group. We aim to recruit over 500 pregnant African American women, enrolling them into the study at 8-14 weeks of pregnancy. Participants will be asked to complete questionnaires and provide oral, vaginal, and gut microbiome samples at enrollment and again at 24-30 weeks. Chart review will be used to identify pregnancy outcomes, infections, treatments, and complications. DNA will be extracted from the microbiome samples and sequencing of the V3 and V4 regions of the 16S rRNA gene will be conducted. Processing and mapping will be completed with QIIME and operational taxonomic units (OTUs) will be mapped to Greengenes version 13_8. Community state types (CSTs) and diversity measures at each site and time will be identified and considered in light of demographic, psychosocial, clinical, and biobehavioral variables. DISCUSSION: This rich data set will allow future consideration of risk and protective factors, between and within groups of women, providing the opportunity to uncover the roots of the persistent health disparity experienced by African American families. PMID- 28571579 TI - How could we enhance translation of sepsis immunology to inform immunomodulation trials in sepsis? AB - Sepsis results in complex alterations to the immune system. Our understanding of how these alterations in immune responses could help characterize extreme immune phenotypes, identify biomarkers with the ability to stratify patients for therapeutic interventions, surrogates in the causal pathway of clinical end points, and treatable traits are still rudimentary. A methodologically rigorous, consensus-based approach should enrich sepsis immune subpopulations to increase the probability of successful trials. PMID- 28571578 TI - Immunotherapy in head and neck cancer: aiming at EXTREME precision. AB - BACKGROUND: Locoregionally advanced, recurrent, and metastatic squamous cell carcinomas of the head and neck (SCCHN) remain difficult to treat disease entities, in which systemic treatment often forms an integral part of their management. Immunotherapy is based on functional restoration of the host immune system, helping to counteract various tumour evasion strategies. Broadly, immunotherapeutic approaches encompass tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating agents. Until 2015, the epidermal growth factor receptor inhibitor cetuximab, a tumour specific antibody, represented the only Food and Drug Administration (FDA) approved targeted therapy for SCCHN. Subsequently, in 2016, the results from two prospective trials employing the immune-modulating antibodies nivolumab and pembrolizumab heralded a new era of anticancer treatment. DISCUSSION: Nivolumab and pembrolizumab are monoclonal antibodies against programmed cell death protein 1 (PD-1), an 'immune checkpoint' receptor. Found on the surface of T-cells, PD-1 negatively regulates their activation and can thus be exploited during carcinogenesis. The second-line phase III trial CheckMate-141 randomly assigned 361 patients with recurrent and/or metastatic SCCHN in a 2:1 ratio to receive either single-agent nivolumab (3 mg/kg intravenously every 2 weeks) or standard monotherapy (methotrexate, docetaxel, or cetuximab). Nivolumab improved the objective response rate (13% versus 6%) and median overall survival (OS; 7.5 versus 5.1 months, p = 0.01) without increasing toxicity. Exploratory biomarker analyses indicated that patients treated with nivolumab had longer OS than those given standard therapy, regardless of tumour PD-1 ligand (PD-L1) expression or p16 status. In the non-randomised, multicohort phase Ib study KEYNOTE-012, treatment with pembrolizumab achieved comparable results. Importantly, most of the responding patients had a long-lasting response. CONCLUSION: Based on recent results, nivolumab and pembrolizumab have been approved by the FDA as new standard-of-care options for the second-line treatment of recurrent and/or metastatic SCCHN. Generally well tolerated, these novel drugs demonstrated modest response rates, with tumour regressions usually being durable, even in platinum resistant/refractory cases. The next step will be to extend the observed benefit to first-line treatment, currently dominated by the EXTREME regimen (platinum/5 fluorouracil/cetuximab), and to the locoregionally advanced setting, where concurrent chemoradiation with cisplatin is standard. Regimens combining immunotherapy with other modalities will probably further improve outcomes. PMID- 28571580 TI - Exposure to trace amounts of sulfonylurea herbicide tribenuron-methyl causes male sterility in 17 species or subspecies of cruciferous plants. AB - BACKGROUND: For most cruciferous plants, which are known as important crops and a number of weeds, hybrid breeding is hampered by the unavailability of a pollination control system. Male sterility induced by a gametocide can be useful for the utilization of plant heterosis. RESULTS: The gametocidal effect of sulfonylurea herbicide tribenuron-methyl was tested across seventeen cruciferous species or subspecies including Brassica juncea, B. carinata, B. oleracea ssp. capitata, B. oleracea ssp. acephala, B. rapa ssp. pekinensis, B. rapa ssp. chinensis, B. rapa ssp. parachinensis, B. nigra, Orychophragmus violaceus, Matthiola incana, Raphanus sativa, Sisymbrium altissimum, Eruca sativa, Sinapis alba, Sinapis arvensis, Capsella bursa-pastoris and Camelina sativa. The plants of 23 cultivars in these species or subspecies were foliar sprayed with 10 ml of 0.2 or 0.4 mg/L of tribenuron-methyl before the vacuolated microspore formed in the largest flower buds; the application was repeated ten to twelve days afterwards. Tribenuron-methyl exposure significantly changed the flowering phenology and reproductive function. The treated plants demonstrated a one to four day delay in flowering time and a shortened duration of flowering, as well as other slight phytotoxic effects including a reduction in plant height and floral organ size. Approximately 80% to 100% male sterility, which was estimated by both pollen staining and selfing seed-set rate, was induced in the plants. As a result, plants were rendered functionally able to out-cross, with an average 87% and 54% manually pollinated seed-set rate compared to the corresponding controls at the 0.2 mg/L and 0.4 mg/L doses, respectively. CONCLUSIONS: The results suggested that male reproductive function was much more sensitive to tribenuron-methyl exposure than female function. This sulfonylurea herbicide has a promising use as the gametocide for hybrid production in cruciferous plants. PMID- 28571581 TI - Erratum to Protective intraoperative ventilation with higher versus lower levels of positive end-expiratory pressure in obese patients (PROBESE): study protocol for a randomized controlled trial. PMID- 28571582 TI - The 150 most important questions in cancer research and clinical oncology series: questions 31-39 : Edited by Chinese Journal of Cancer. AB - To accelerate our endeavors to overcome cancer, Chinese Journal of Cancer has launched a program of publishing 150 most important questions in cancer research and clinical oncology. In this article, 9 more questions are presented as follows. Question 31: How does aging process inhibit the formation of sarcoma? Question 32: Is intratumoral morphological heterogeneity the consequence of tumor genomic instability or the cause of aggressive tumor behavior? Can we identify more aggressive tumors by computationally analyzing the morphological heterogeneity of the tumor tissues? Question 33: How to pre-surgically differentiate irradiation-induced ulceration from cancerous ulceration? Question 34: Why is epidermal growth factor receptor (EGFR) 19 Del-positive tumor more sensitive to targeted therapy than EGFR 21 L858R-positive tumor in patients with non-small cell lung cancer? Question 35: Can an Epstein-Barr virus vaccine be developed to reduce the incidence of EBV-related malignancies? Question 36: What is the unique feature in sarcoma vasculature that causes the intrinsic resistance of sarcoma against anti-angiogenic therapy? Question 37: How many ways can sarcoma cells protect themselves from the attacks of cytotoxic drugs? Question 38: How stable does the tumor heterogeneity remain along with cytotoxic chemotherapy? Question 39: How to generate a prognostic classifier for diffuse low-grade gliomas by integrating genetic and epigenetic signatures with histological features? PMID- 28571583 TI - Effect of user preferences on ITN use: a review of literature and data. AB - BACKGROUND: Insecticide-treated bed nets (ITNs) are the primary tool for vector control, and optimizing ITN use is a key concern of national programmes. Available evidence indicates that bed net users often have preferences for shape, colour, size, and other attributes, but it is unclear whether these preferences are strong enough to have any significant effect on bed net use, and whether countries and donors should invest in more expensive attributes in order to maximize ITN use. The link between bed net attributes, preferences, and use was investigated using a literature review and review of publicly available, nationally representative household surveys from sub-Saharan Africa. METHODS: A literature search was conducted to identify publications with data on preferences for net attributes and on associations between net attributes and use. Publicly available DHS and MIS datasets were screened for variables on net preferences and net attributes. Wald tests were run to obtain odds ratios and confidence intervals for the use of nets of various attributes in univariate analysis. A multilevel logistic regression was constructed to assess the odds of a net's use, controlling for background variables and adding random effects variables at the household and cluster level. RESULTS: Preferences for certain net attributes exist, but do not impede high rates of net use in countries where data were available. Stated preferences for shape and colour do not significantly influence net use to degrees that would require action by programme planners. By and large, people are using the nets they receive, and when they do not, it is for reasons unrelated to shape and size (primarily perceived mosquito density, heat or an excess of nets). Households in higher wealth quintiles tend to own greater numbers of conical nets, indicating that they have the ability to obtain or purchase these nets on their own, and individuals resident in higher wealth quintile households also use conical nets preferentially. CONCLUSIONS: The increased manufacturing costs for conical nets are not outweighed by the very small, often non-existent, increases in use rates in sub-Saharan Africa. Programmes that wish to explore the relationship between net attributes, preferences and use rates should include these questions in nationally representative household surveys to be able to capture trends across geographic and socio-economic groups. PMID- 28571584 TI - Spotlight on landmark oncology trials: the latest evidence and novel trial designs. AB - The era of precision oncology is marked with prominent successes in the therapy of advanced soft tissue sarcomas, breast cancer, ovarian cancer and haematological neoplasms, among others. Moreover, recent trials of immune checkpoint inhibitors in melanoma, non-small cell lung carcinoma, and head and neck cancers have significantly influenced the therapeutic landscape by providing promising evidence for immunotherapy efficacy in the adjuvant setting in high risk locoregional disease. To speed up the introduction of targeted therapy for cancer patients, novel phase II trials are being designed, and may likely form the basis for the 'landmark trials' of the future. A special article collection in BMC Medicine, "Spotlight on landmark oncology trials", features articles from invited experts on recent clinical practice-changing trials. PMID- 28571585 TI - Number needed to treat (NNT) in clinical literature: an appraisal. AB - BACKGROUND: The number needed to treat (NNT) is an absolute effect measure that has been used to assess beneficial and harmful effects of medical interventions. Several methods can be used to calculate NNTs, and they should be applied depending on the different study characteristics, such as the design and type of variable used to measure outcomes. Whether or not the most recommended methods have been applied to calculate NNTs in studies published in the medical literature is yet to be determined. The aim of this study is to assess whether the methods used to calculate NNTs in studies published in medical journals are in line with basic methodological recommendations. METHODS: The top 25 high impact factor journals in the "General and/or Internal Medicine" category were screened to identify studies assessing pharmacological interventions and reporting NNTs. Studies were categorized according to their design and the type of variables. NNTs were assessed for completeness (baseline risk, time horizon, and confidence intervals [CIs]). The methods used for calculating NNTs in selected studies were compared to basic methodological recommendations published in the literature. Data were analyzed using descriptive statistics. RESULTS: The search returned 138 citations, of which 51 were selected. Most were meta-analyses (n = 23, 45.1%), followed by clinical trials (n = 17, 33.3%), cohort (n = 9, 17.6%), and case-control studies (n = 2, 3.9%). Binary variables were more common (n = 41, 80.4%) than time-to-event (n = 10, 19.6%) outcomes. Twenty-six studies (51.0%) reported only NNT to benefit (NNTB), 14 (27.5%) reported both NNTB and NNT to harm (NNTH), and 11 (21.6%) reported only NNTH. Baseline risk (n = 37, 72.5%), time horizon (n = 38, 74.5%), and CI (n = 32, 62.7%) for NNTs were not always reported. Basic methodological recommendations to calculate NNTs were not followed in 15 studies (29.4%). The proportion of studies applying non recommended methods was particularly high for meta-analyses (n = 13, 56.5%). CONCLUSIONS: A considerable proportion of studies, particularly meta-analyses, applied methods that are not in line with basic methodological recommendations. Despite their usefulness in assisting clinical decisions, NNTs are uninterpretable if incompletely reported, and they may be misleading if calculating methods are inadequate to study designs and variables under evaluation. Further research is needed to confirm the present findings. PMID- 28571588 TI - Expression profiling indicating low selenium-sensitive microRNA levels linked to cell cycle and cell stress response pathways in the CaCo-2 cell line. AB - Se is an essential micronutrient for human health, and fluctuations in Se levels and the potential cellular dysfunction associated with it may increase the risk for disease. Although Se has been shown to influence several biological pathways important in health, little is known about the effect of Se on the expression of microRNA (miRNA) molecules regulating these pathways. To explore the potential role of Se-sensitive miRNA in regulating pathways linked with colon cancer, we profiled the expression of 800 miRNA in the CaCo-2 human adenocarcinoma cell line in response to a low-Se (72 h at <40 nm) environment using nCounter direct quantification. These data were then examined using a range of in silico databases to identify experimentally validated miRNA-mRNA interactions and the biological pathways involved. We identified ten Se-sensitive miRNA (hsa-miR-93 5p, hsa-miR-106a-5p, hsa-miR-205-5p, hsa-miR-200c-3p, hsa-miR-99b-5p, hsa-miR 302d-3p, hsa-miR-373-3p, hsa-miR-483-3p, hsa-miR-512-5p and hsa-miR-4454), which regulate 3588 mRNA in key pathways such as the cell cycle, the cellular response to stress, and the canonical Wnt/beta-catenin, p53 and ERK/MAPK signalling pathways. Our data show that the effects of low Se on biological pathways may, in part, be due to these ten Se-sensitive miRNA. Dysregulation of the cell cycle and of the stress response pathways due to low Se may influence key genes involved in carcinogenesis. PMID- 28571586 TI - Complement C5a-C5aR1 signalling drives skeletal muscle macrophage recruitment in the hSOD1G93A mouse model of amyotrophic lateral sclerosis. AB - BACKGROUND: The terminal pathway of the innate immune complement system is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Terminal complement activation leads to generation of C5a, which through its receptor, C5aR1, drives immune cell recruitment and activation. Importantly, genetic or pharmacological blockage of C5aR1 improves motor performance and reduces disease pathology in hSOD1G93A rodent models of ALS. In this study, we aimed to explore the potential mechanisms of C5aR1-mediated pathology in hSOD1G93A mice by examining their skeletal muscles. RESULTS: We found elevated levels of C1qB, C4, fB, C3, C5a, and C5aR1 in tibialis anterior muscles of hSOD1G93A mice, which increased with disease progression. Macrophage cell numbers also progressively increased in hSOD1G93A muscles in line with disease progression. Immuno localisation demonstrated that C5aR1 was expressed predominantly on macrophages within hSOD1G93A skeletal muscles. Notably, hSOD1G93A * C5aR1-/- mice showed markedly decreased numbers of infiltrating macrophages, along with reduced neuromuscular denervation and improved grip strength in hind limb skeletal muscles, when compared to hSOD1G93A mice. CONCLUSION: These results indicate that terminal complement activation and C5a production occur in skeletal muscle tissue of hSOD1G93A mice, and that C5a-C5aR1 signalling contributes to the recruitment of macrophages that may accelerate muscle denervation in these ALS mice. PMID- 28571587 TI - Supplementation of grazing beef cows during gestation as a strategy to improve skeletal muscle development of the offspring. AB - The appropriate supply of nutrients in pregnant cows has been associated with the optimal development of foetal tissues, performance of their progeny and their meat quality. The aim of this study was to evaluate supplementation effects of grazing cows in different stages of gestation on skeletal muscle development and performance of the progeny. Thereby, 27 Nellore cows were divided into three groups (n=9 for each group) and their progeny as follows: UNS, unsupplemented during gestation; MID, supplemented from 30 to 180 days of gestation; LATE, supplemented from 181 to 281 days of gestation. The percentage composition of the supplement provided for the matrices was the following: ground corn (26.25%), wheat bran (26.25%) and soya bean meal (47.5%). The supplement was formulated to contain 30% CP. Supplemented matrices received 150 kg of supplement (1 and 1.5 kg/day for cows in the MID and LATE groups, respectively). After birth, a biopsy was performed to obtain samples of skeletal muscle tissue from calves to determine number and size of muscle fibres and for messenger RNA (mRNA) expression analysis. The percentage composition of the supplement provided for the progeny was the following: ground corn grain (30%), wheat bran (30%), soya bean meal (35%) and molasses (5%). The supplement was formulated to contain 25% CP and offered in an amount of 6 g/kg BW. Performance of the progeny was monitored throughout the suckling period. Means were submitted to ANOVA and regression, and UNS, MID and LATE periods of supplementation were compared. Differences were considered at P0.10). Similarly, no differences were observed between calves for nutrient intake (P>0.10). However, greater subcutaneous fat thickness (P=0.006) was observed in the calves of LATE group. The ribeye area (P=0.077) was greater in calves born from supplemented compared with UNS cows. The supplementation of pregnant cows did not affect the muscle fibre size of their progeny (P=0.208). On the other hand, calves born from dams supplemented at mid-gestation had greater muscle fibre number (P=0.093) compared with calves from UNS group. Greater mRNA expression of peroxysome proliferator-activated receptor alpha (P=0.073) and fibroblast growth factor 2 (P=0.003) was observed in the calves born from MID cows. Although strategic supplementation did not affect the BW of offspring, it did cause changes in carcass traits, number of myofibres, and mRNA expression of a muscle hypertrophy and lipid oxidation markers in skeletal muscle of the offspring. PMID- 28571589 TI - Computer-Assisted Antimicrobial Recommendations for Optimal Therapy: Analysis of Prescribing Errors in an Antimicrobial Stewardship Trial. AB - Clinician education and prospective audit and feedback interventions, deployed separately and concurrently, did not reduce antimicrobial use errors or rates compared to a control group of general medicine inpatients at our public hospital. Additional research is needed to define the optimal scope and intensity of hospital antimicrobial stewardship interventions. Infect Control Hosp Epidemiol 2017;38:857-859. PMID- 28571591 TI - Dietary inflammatory index and risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma: a population-based case-control study. AB - The dietary inflammatory index (DIITM) is a novel composite score based on a range of nutrients and foods known to be associated with inflammation. DII scores have been linked to the risk of a number of cancers, including oesophageal squamous cell cancer and oesophageal adenocarcinoma (OAC). Given that OAC stems from acid reflux and that the oesophageal epithelium undergoes a metaplasia dysplasia transition from the resulting inflammation, it is plausible that a high DII score (indicating a pro-inflammatory diet) may exacerbate risk of OAC and its precursor conditions. The aim of this analytical study was to explore the association between energy-adjusted dietary inflammatory index (E-DIITM) in relation to risk of reflux oesophagitis, Barrett's oesophagus and OAC. Between 2002 and 2005, reflux oesophagitis (n 219), Barrett's oesophagus (n 220) and OAC (n 224) patients, and population-based controls (n 256), were recruited to the Factors influencing the Barrett's Adenocarcinoma Relationship study in Northern Ireland and the Republic of Ireland. E-DII scores were derived from a 101-item FFQ. Unconditional logistic regression analysis was applied to determine odds of oesophageal lesions according to E-DII intakes, adjusting for potential confounders. High E-DII scores were associated with borderline increase in odds of reflux oesophagitis (OR 1.87; 95 % CI 0.93, 3.73), and significantly increased odds of Barrett's oesophagus (OR 2.05; 95 % CI 1.22, 3.47), and OAC (OR 2.29; 95 % CI 1.32, 3.96), when comparing the highest with the lowest tertiles of E-DII scores. In conclusion, a pro-inflammatory diet may exacerbate the risk of the inflammation-metaplasia-adenocarcinoma pathway in oesophageal carcinogenesis. PMID- 28571592 TI - Hyperkinesia in ancient China: perspectives and prescriptions. PMID- 28571593 TI - Structure, signaling and the drug discovery of the Ras oncogene protein. AB - Mutations in Ras GTPase are among the most common genetic alterations in human cancers. Despite extensive research investigating Ras proteins, their functions still remain a challenge over a long period of time. The currently available data suggests that solving the outstanding issues regarding Ras could lead to development of effective drugs that could have a significant impact on cancer treatment. Developing a better understanding of their biochemical properties or modes of action, along with improvements in their pharmacologic profiles, clinical design and scheduling will enable the development of more effective therapies. [BMB Reports 2017; 50(7): 355-360]. PMID- 28571595 TI - Message from the Board. PMID- 28571596 TI - American association of heart failure nurses (AAHFN) position statement on patient access to healthcare. PMID- 28571594 TI - Dual TORCs driven and B56 orchestrated signaling network guides eukaryotic cell migration. AB - Different types of eukaryotic cells may adopt seemingly distinct modes of directional cell migration. However, several core aspects are regarded common whether the movement is either ameoboidal or mesenchymal. The region of cells facing the attractive signal is often termed leading edge where lamellipodial structures dominates and the other end of the cell called rear end is often mediating cytoskeletal F-actin contraction involving Myosin-II. Dynamic remodeling of cell-to-matrix adhesion involving integrin is also evident in many types of migrating cells. All these three aspects of cell migration are significantly affected by signaling networks of TorC2, TorC1, and PP2A/B56. Here we review the current views of the mechanistic understanding of these regulatory signaling networks and how these networks affect eukaryotic cell migration. [BMB Reports 2017; 50(9): 437-444]. PMID- 28571598 TI - Breaking Bad: The Heartbreak of Drug Abuse. PMID- 28571597 TI - Clinical Characteristics, Histopathological Features, and Clinical Outcome of Methamphetamine-Associated Cardiomyopathy. AB - OBJECTIVES: This study aimed to assess characteristics including endomyocardial biopsy and outcome of patients with methamphetamine (MA)-associated cardiomyopathy in a series of patients treated in Germany. BACKGROUND: MA abuse is an increasing problem worldwide. METHODS: The cases of 30 consecutive MA abusing patients with a left ventricular (LV) ejection fraction of <40% and endomyocardial biopsy performed at initial diagnosis were analyzed. Baseline characteristics were collected retrospectively, whereas follow-up was prospective. The primary endpoint was a composite of death, nonfatal stroke, and rehospitalization for heart failure. RESULTS: Patients were 30.3 +/- 1.9 years of age, predominantly male (93.3%), and highly symptomatic; 83.3% had New York Heart Association functional class III or IV dyspnea. Echocardiography revealed marked LV dilatation (mean LV end-diastolic diameter 67.1 +/- 7.4 mm) and impaired LV ejection fraction (mean 19 +/- 6%). One-third of the patients had intraventricular thrombi. Endomyocardial biopsy revealed markers of inflammation and fibrosis; the fibrosis correlated with the duration of MA abuse. At follow up, discontinuation of MA abuse together with medical therapy partially improved cardiac function (LV ejection fraction, 19 +/- 6 vs. 43 +/- 13; p < 0.001) and symptoms (p = 0.056), whereas patients with continued abuse did not show any improvement. The improvement in cardiac function was independently associated with the extent of fibrosis. The primary endpoint occurred more often in patients with continued MA abuse (57.1% vs. 13.0%; p = 0.037). CONCLUSIONS: MA-associated cardiomyopathy is characterized by severe heart failure and depressed cardiac function. The extent of myocardial fibrosis seems to predict the recoverability of LV function. Cessation of MA abuse is associated with improvement in cardiac function and symptoms, whereas continued MA abuse leads to ongoing heart failure and worse outcome. PMID- 28571599 TI - Patients Not Meeting PARADIGM-HF Enrollment Criteria Are Eligible for Sacubitril/Valsartan on the Basis of FDA Approval: The Need to Close the Gap. PMID- 28571600 TI - Development of Acute Decompensated Heart Failure Therapies: Is the Journey Over? PMID- 28571601 TI - Decreased Mortality With Beta-Blockers in Patients With Heart Failure and Coexisting Atrial Fibrillation. PMID- 28571602 TI - Reply: Decreased Mortality With Beta-Blockers in Patients With Heart Failure and Coexisting Atrial Fibrillation. PMID- 28571603 TI - All Roads Lead to Rome: Myocardial Fibrosis. PMID- 28571604 TI - Is Left Ventricular Ejection Fraction by Echo in Patients With Atrial Fibrillation Reliable? PMID- 28571606 TI - ? PMID- 28571605 TI - Survivorship After Cancer. PMID- 28571607 TI - The theory of change of the evaluation support program: Enhancing the role of community organizations in providing an ecology of care for neurological disorders. AB - This paper discusses the Ontario Brain Institute's theory of change for the Evaluation Support Program, a program designed to enhance the role of community organizations in providing care and services for people living with a brain disorder. This is done by helping community organizations build evaluation capacity and foster the use of evidence to inform their activities and services. Helping organizations to build capacities to track the 'key ingredients' of their successes will help ensure that successes are replicated and services can be improved to maximize the benefit that people receive from them. This paper describes the hypothesized outcomes and early impacts of the Evaluation Support Program, as well as how the program will contribute to the field of evaluation capacity building. PMID- 28571608 TI - Editorial for special issue - 'Improving cyclist safety through scientific research'. PMID- 28571609 TI - Erratum. PMID- 28571610 TI - [Erosive pustular dermatosis]. PMID- 28571611 TI - Incorporation of ion and solvent structure into mean-field modeling of the electric double layer. AB - An electric double layer forms when the small mobile ions of an electrolyte interact with an extended charged object, a macroion. The competition between electrostatic attraction and translational entropy loss of the small ions results in a diffuse layer of partially immobilized ions in the vicinity of the macroion. Modeling structure and energy of the electric double layer has a long history that has lead to the classical Poisson-Boltzmann theory and numerous extensions that account for ion-ion correlations and structural ion and solvent properties. The present review focuses on approaches that instead of going beyond the mean field character of Poisson-Boltzmann theory introduce structural details of the ions and the solvent into the Poisson-Boltzmann modeling framework. The former include not only excluded volume effects but also the presence of charge distributions on individual ions, spatially extended ions, and internal ionic degrees of freedom. The latter treat the solvent either explicitly as interacting Langevin dipoles or in the form of effective non-electrostatic interactions, in particular Yukawa interactions, that are added to the Coulomb potential. We discuss how various theoretical models predict structural properties of the electric double layer such as the differential capacitance and compare some of these predictions with computer simulations. PMID- 28571612 TI - Microbiological quality of Argentinian paprika. AB - The aim of this study was to evaluate the microbiological quality of paprika produced in Catamarca, Argentina. Microbiological analyses were carried out for the enumeration of total aerobic mesophilic bacteria, coliforms, yeasts and molds, and the detection of Salmonella in samples obtained from different local producers during three consecutive years. The mycobiota was identified paying special attention to the mycotoxigenic molds. Standard plate counts of aerobic mesophilic bacteria ranged from 2.7*105 to 3.7*107CFU/g. Coliform counts ranged from <10 to 8.1*104CFU/g. Salmonella was not detected in any of the samples tested. Fungal counts (including yeasts and molds) ranged between 2*102 and 1.9*105CFU/g. These results showed a high level of microbial contamination, exceeding in several samples the maximum limits set in international food regulations. The study of the mycobiota demonstrated that Aspergillus was the predominant genus and Aspergillus niger (potential producer of ochratoxin A) the most frequently isolated species, followed by Aspergillus flavus (potential producer of aflatoxins). Other species of potential toxigenic fungi such as Aspergillus ochraceus, Aspergillus westerdijkiae, Penicillium chrysogenum, Penicillium crustosum, Penicillium commune, Penicillium expansum and Alternaria tenuissima species group were encountered as part of the mycobiota of the paprika samples indicating a risk of mycotoxin contamination. A. westerdijkiae was isolated for the first time in Argentina. PMID- 28571614 TI - Canis familiaris As a Model for Non-Invasive Comparative Neuroscience. AB - There is an ongoing need to improve animal models for investigating human behavior and its biological underpinnings. The domestic dog (Canis familiaris) is a promising model in cognitive neuroscience. However, before it can contribute to advances in this field in a comparative, reliable, and valid manner, several methodological issues warrant attention. We review recent non-invasive canine neuroscience studies, primarily focusing on (i) variability among dogs and between dogs and humans in cranial characteristics, and (ii) generalizability across dog and dog-human studies. We argue not for methodological uniformity but for functional comparability between methods, experimental designs, and neural responses. We conclude that the dog may become an innovative and unique model in comparative neuroscience, complementing more traditional models. PMID- 28571615 TI - Reinforcement Learning: Computing the Temporal Difference of Values via Distinct Corticostriatal Pathways: (Trends in Neurosciences 35, 457-467; 2012). PMID- 28571616 TI - Advances in translational inner ear stem cell research. AB - Stem cell research is expanding our understanding of developmental biology as well as promising the development of new therapies for a range of different diseases. Within hearing research, the use of stem cells has focused mainly on cell replacement. Stem cells however have a broad range of other potential applications that are just beginning to be explored in the ear. Mesenchymal stem cells are an adult derived stem cell population that have been shown to produce growth factors, modulate the immune system and can differentiate into a wide variety of tissue types. Potential advantages of mesenchymal/adult stem cells are that they have no ethical constraints on their use. However, appropriate regulatory oversight seems necessary in order to protect patients from side effects. Disadvantages may be the lack of efficacy in many preclinical studies. But if proven safe and efficacious, they are easily translatable to clinical trials. The current review will focus on the potential application on mesenchymal stem cells for the treatment of inner ear disorders. PMID- 28571617 TI - Brain activity underlying the recovery of meaning from degraded speech: A functional near-infrared spectroscopy (fNIRS) study. AB - The purpose of this study was to establish whether functional near-infrared spectroscopy (fNIRS), an emerging brain-imaging technique based on optical principles, is suitable for studying the brain activity that underlies effortful listening. In an event-related fNIRS experiment, normally-hearing adults listened to sentences that were either clear or degraded (noise vocoded). These sentences were presented simultaneously with a non-speech distractor, and on each trial participants were instructed to attend either to the speech or to the distractor. The primary region of interest for the fNIRS measurements was the left inferior frontal gyrus (LIFG), a cortical region involved in higher-order language processing. The fNIRS results confirmed findings previously reported in the functional magnetic resonance imaging (fMRI) literature. Firstly, the LIFG exhibited an elevated response to degraded versus clear speech, but only when attention was directed towards the speech. This attention-dependent increase in frontal brain activation may be a neural marker for effortful listening. Secondly, during attentive listening to degraded speech, the haemodynamic response peaked significantly later in the LIFG than in superior temporal cortex, possibly reflecting the engagement of working memory to help reconstruct the meaning of degraded sentences. The homologous region in the right hemisphere may play an equivalent role to the LIFG in some left-handed individuals. In conclusion, fNIRS holds promise as a flexible tool to examine the neural signature of effortful listening. PMID- 28571613 TI - Declining Skeletal Muscle Function in Diabetic Peripheral Neuropathy. AB - PURPOSE: The present review highlights current concepts regarding the effects of diabetic peripheral neuropathy (DPN) in skeletal muscle. It discusses the lack of effective pharmacologic treatments and the role of physical exercise intervention in limb protection and symptom reversal. It also highlights the importance of magnetic resonance imaging (MRI) techniques in providing a mechanistic understanding of the disease and helping develop targeted treatments. METHODS: This review provides a comprehensive reporting on the effects of DPN in the skeletal muscle of patients with diabetes. It also provides an update on the most recent trials of exercise intervention targeting DPN pathology. Lastly, we report on emerging MRI techniques that have shown promise in providing a mechanistic understanding of DPN and can help improve the design and implementation of clinical trials in the future. FINDINGS: Impairments in lower limb muscles reduce functional capacity and contribute to altered gait, increased fall risk, and impaired balance in patients with DPN. This finding is an important concern for patients with DPN because their falls are likely to be injurious and lead to bone fractures, poorly healing wounds, and chronic infections that may require amputation. Preliminary studies have shown that moderate-intensity exercise programs are well tolerated by patients with DPN. They can improve their cardiorespiratory function and partially reverse some of the symptoms of DPN. MRI has the potential to bring new mechanistic insights into the effects of DPN as well as to objectively measure small changes in DPN pathology as a result of intervention. IMPLICATIONS: Noninvasive exercise intervention is particularly valuable in DPN because of its safety, low cost, and potential to augment pharmacologic interventions. As we gain a better mechanistic understanding of the disease, more targeted and effective interventions can be designed. PMID- 28571619 TI - Elevated NT-proBNP is associated with unfavorably altered plasma fibrin clot properties in atrial fibrillation. AB - BACKGROUND: Dense fibrin clot formation and hypofibrinolysis have been reported in atrial fibrillation (AF). It is unclear which factors affect fibrin clot properties in AF. METHODS AND RESULTS: We investigated plasma fibrin clot permeability (Ks), clot lysis time (CLT), endogenous thrombin potential (ETP) as well as other coagulation and fibrinolysis parameters along with N-terminal pro-B type natriuretic peptide (NT-proBNP) in 160 AF patients (median age, 70.5years). Previous stroke (n=15; 9.4%) was associated with decreased Ks (P=0.04) and longer CLT (P=0.005), together with higher antiplasmin (P=0.03) and lower tissue-type plasminogen activator (P=0.01). Lower Ks (P=0.04) and tendency towards longer CLT (P=0.10) were observed in patients with a left atrium diameter>40mm. Patients with a CHA2DS2-VASc score of 3 or more (82.5%) were characterized by higher thrombin-activatable fibrinolysis inhibitor antigen (P=0.009). Ks was inversely correlated with log NT-proBNP (r=-0.34, P<0.0001), plasminogen activator inhibitor-1 (PAI-1) antigen (r=-0.24, P=0.002) and C-reactive protein (r=-0.18, P=0.02), while CLT was positively correlated with log NT-proBNP (R=0.61, P<0.0001) and ETP (r=0.37, P<0.0001), which were interrelated (r=0.59, P<0.0001). After adjustment for potential confounders, PAI-1 (odds ratio [OR]: 1.14; 95% confidence interval [CI]: 1.02-1.26) was the only independent predictor of low Ks (the lowest quartile,<=6*10-9cm2), while NT-proBNP (OR: 1.21; 95% CI: 1.12-1.31) and PAI-1 (OR: 1.30; 95% CI: 1.12-1.51) both predicted prolonged CLT (the top quartile,>=109min). CONCLUSION: In AF patients prothrombotic fibrin clot properties assessed ex vivo are determined by PAI-1 and NT-proBNP and this phenotype is associated with prior ischemic stroke. PMID- 28571618 TI - Repetitive use of levosimendan in advanced heart failure: need for stronger evidence in a field in dire need of a useful therapy. AB - Patients in the latest stages of heart failure are severely compromised, with poor quality of life and frequent hospitalizations. Heart transplantation and left ventricular assist device implantation are viable options only for a minority, and intermittent or continuous infusions of positive inotropes may be needed as a bridge therapy or as a symptomatic approach. In these settings, levosimendan has potential advantages over conventional inotropes (catecholamines and phosphodiesterase inhibitors), such as sustained effects after initial infusion, synergy with beta-blockers, and no increase in oxygen consumption. Levosimendan has been suggested as a treatment that reduces re-hospitalization and improves quality of life. However, previous clinical studies of intermittent infusions of levosimendan were not powered to show statistical significance on key outcome parameters. A panel of 45 expert clinicians from 12 European countries met in Rome on November 24-25, 2016 to review the literature and envision an appropriately designed clinical trial addressing these needs. In the earlier FIGHT trial (daily subcutaneous injection of liraglutide in heart failure patients with reduced ejection fraction) a composite Global Rank Score was used as primary end-point where death, re-hospitalization, and change in N-terminal prohormone-brain natriuretic peptide level were considered in a hierarchical order. In the present study, we tested the same end-point post hoc in the PERSIST and LEVOREP trials on oral and repeated i.v. levosimendan, respectively, and demonstrated superiority of levosimendan treatment vs placebo. The use of the same composite end-point in a properly powered study on repetitive levosimendan in advanced heart failure is strongly advocated. PMID- 28571620 TI - Cardiovascular risk and hypertension control in Italy. Data from the 2015 World Hypertension Day. AB - BACKGROUND: Cardiovascular diseases (CVD) are the first cause of death and disability in western countries. Despite therapeutic advances, their prevalence is constantly increasing. Detailed assessment of modifiable CV risk factors could improve CVD prevention and management. METHODS: to assess CV risk and hypertension control in a sample of the Italian population, individuals participating to the 2015 "World Hypertension Day" were interviewed in 62sites all over Italy. Blood pressure was measured with a validated auscultatory or oscillometric device and information on demography and prevalence of CVD risk factors was collected by an anonymous questionnaire. An ad-hoc modified version of the Systematic COronary Risk Evaluation (SCORE) system was then applied. RESULTS: 8657 recruited individuals (43%women, aged 56.68+/-16years) were subdivided into 3 age groups (40-49y, 50-59y, 60-69y) for analysis. CV risk was low in 62.4%, 18.0% and 0%; moderate in 26.0%, 66.0% and 62.5%; high/very high in 11.6%, 16% and 37.4%, respectively. Smoking was mainly responsible for increased CV risk among those aged 40-49y (26%smokers), while hypertension was the main factor in the whole sample and in subjects over 50y (36% and 42% respectively). Overall, BP control was unsatisfactory in 36% of individuals (28%, 48% and 31% of those who declared to be normotensive, hypertensive on treatment or unaware of their BP condition, respectively). CONCLUSIONS: In this sample of the Italian population, CV risk was alarmingly high, irrespectively of age, mostly due to presence of modifiable risk factors, including hypertension, which should thus be better addressed, especially in the youngsters. PMID- 28571622 TI - Reprint of: Development of methods for avian oil toxicity studies using the double crested cormorant (Phalacrocorax auritus). AB - Oral and external dosing methods replicating field exposure were developed using the double crested cormorant (DCCO) to test the toxicity of artificially weathered Deepwater Horizon Mississippi Canyon 252 oil. The majority of previous oil dosing studies conducted on wild-caught birds used gavage methods to dose birds with oil and determine toxicity. However, rapid gut transit time of gavaged oil likely reduces oil absorption. In the present studies, dosing relied on injection of oil into live feeder fish for oral dosing of these piscivorous birds, or applying oil to body contour feathers resulting in transdermal oil exposure and oral exposure through preening. Both oral and external oil dosing studies identified oil-related toxicity endpoints associated with oxidative stress such as hemolytic anemia, liver and kidney damage, and immuno-modulation or compromise. External oil application allowed for controlled study of thermoregulatory stress as well. Infrared thermal images indicated significantly greater surface temperatures and heat loss in treated birds following external oil applications; however, measurements collected by coelomically implanted temperature transmitters showed that internal body temperatures were stable over the course of the study period. Birds exposed to oil externally consumed more fish than control birds, indicating metabolic compensation for thermal stress. Conversely, birds orally dosed with oil experienced hypothermia and consumed less fish compared to control birds. PMID- 28571623 TI - Reprint of: Assay Validation of the Cardiac Isoform of Troponin I in Double Crested Cormorant (Phalacrocorax auritus) Plasma for Diagnosis of Cardiac Damage. AB - Cardiac abnormalities, initially found in Deepwater Horizon weathered MC252 crude oil exposed Double Crested Cormorants (DCCOs) upon gross necropsy, were further investigated using echocardiography. Clinical and statistically significant changes including decreased ventricular myocardial contractility and arrhythmia were elucidated by echocardiography and interpreted by boarded cardiologists as potentially life threatening. The objective of this investigation was to initiate development of an antemortem, sensitive blood screening test for cardiac damage due to oil exposure of avian species. An assay for the cardiac isoform of troponin I (cTnI) which is known to be highly cross-reactive across mammalian species was chosen and analytically validated in DCCO. This is the first time this test has been analytically validated in avian species. All plasma samples from birds assessed as healthy had trace concentrations (<0.016ng/ml). The assays was precise and accurate revealing a coefficient of variation <3% and an R2>0.99. Diagnostic investigation revealed that the test appears to have diagnostic potential for the diagnosis of cardiomyocyte damage. Diagnostic sensitivity and specificity were 91% and 73% in this laboratory population. Due to an equivocal sample population in which health could not be proven, further investigation is needed to diagnostically validate troponin I in the assessment of oil exposure in DCCO. PMID- 28571624 TI - Reprint of: CYP1A protein expression and catalytic activity in double-crested cormorants experimentally exposed to Deepwater Horizon Mississippi Canyon 252 oil. AB - Double-crested cormorants (Phalacrocorax auritus, DCCO) were orally exposed to Deepwater Horizon Mississippi Canyon 252 (DWH) oil to investigate oil-induced toxicological impacts. Livers were collected for multiple analyses including cytochrome P4501A (CYP1A) enzymatic activity and protein expression. CYP1A enzymatic activity was measured by alkoxyresorufin O-dealkylase (AROD) assays. Activities specific to the O-dealkylation of four resorufin ethers are reported: benzyloxyresorufin O-debenzylase (BROD), ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), and pentoxyresorufin O-depentylase (PROD). CYP1A protein expression was measured by western blot analysis with a CYP1A1 mouse monoclonal antibody. In study 1, hepatic BROD, EROD, and PROD activities were significantly induced in DCCO orally exposed to 20ml/kg body weight (bw) oil as a single dose or daily for 5 days. Western blot analysis revealed hepatic CYP1A protein induction in both treatment groups. In study 2 (5ml/kg bw oil or 10ml/kg bw oil, 21day exposure), all four hepatic ARODs were significantly induced. Western blots showed an increase in hepatic CYP1A expression in both treatment groups with a significant induction in birds exposed to 10ml/kg oil. Significant correlations were detected among all 4 AROD activities in both studies and between CYP1A protein expression and both MROD and PROD activities in study 2. EROD activity was highest for both treatment groups in both studies while BROD activity had the greatest fold-induction. While PROD activity values were consistently low, the fold-induction was high, usually 2nd highest to BROD activity. The observed induced AROD profiles detected in the present studies suggest both CYP1A4/1A5 DCCO isoforms are being induced after MC252 oil ingestion. A review of the literature on avian CYP1A AROD activity levels and protein expression after exposure to CYP1A inducers highlights the need for species-specific studies to accurately evaluate avian exposure to oil. PMID- 28571621 TI - Hemodynamic, catecholamine, vasomotor and vascular responses: Determinants of myocardial ischemia during mental stress. AB - AIMS: Mental stress-induced myocardial ischemia (MSIMI) in patients with coronary artery disease (CAD) is associated with adverse cardiovascular outcomes. We aim to assess hemodynamic, neuro-hormonal, endothelial, vasomotor and vascular predictors of MSIMI. METHODS AND RESULTS: We subjected 660 patients with stable CAD to 99mTc sestamibi myocardial perfusion imaging at rest, with mental (speech task) and with conventional (exercise/pharmacological) stress. Endothelium dependent flow-mediated dilation (FMD), microvascular reactivity [reactive hyperemia index (RHI)] and arterial stiffness [pulse wave velocity (PWV)] were measured at rest and 30-min after mental stress. The digital microvascular vasomotor response during mental stress was assessed using peripheral arterial tonometry (PAT). A total of 106(16.1%) patients had MSIMI. Mental stress was accompanied by significant increases in rate-pressure-product (heart rate x systolic blood pressure; RPP), epinephrine levels and PWV, and significant decreases in FMD and PAT ratio denoting microvascular constriction. In comparison to those with no MSIMI, patients with MSIMI had higher hemodynamic and digital vasoconstrictive responses (p<0.05 for both), but did not differ in epinephrine, endothelial or macrovascular responses. Only presence of ischemia during conventional stress (OR of 7.1, 95%CI of 4.2, 11.9), high hemodynamic response (OR for RPP response>=vs=ROC cutoff of 2.1, 95%CI of 1.3, 3.3) were independent predictors of MSIMI. CONCLUSION: Ischemia during conventional stress testing and hemodynamic and vasoconstrictive responses to mental stress can help predict subjects with CAD at greater risk of developing MSIMI. PMID- 28571625 TI - Staff perceptions of a patient at risk team: A survey design. AB - INTRODUCTION: Whilst research demonstrates the benefits of critical care outreach, limited research describes staffs' perspective of these teams. OBJECTIVE: This study examined ward nurses' and doctors' perceptions of the service provided by a nurse-led 24hours a day, seven days a week Patient at Risk team. DESIGN: Using an exploratory survey research design and a previously used instrument, data were collected between January and March (2016). The instruments' reliability was assessed using Cronbach's alpha (a=0.90). RESULTS: 339 participants, including 255 nurses and 84 doctors, completed the questionnaire (70.48% response rate). Most participants agreed the Patient at Risk team 1) were accessible and approachable, 2) recognised deterioration and reduced serious events, 3) provided ward staff teaching and coaching and 4) aided allied health referral and improved transfer of patients from critical care. More nurses than doctors perceived the team's role more positively in some aspects of the service they provided. Whilst most comments were positive, some comments identified improvements could be made to the service. CONCLUSION: Ward nurses' and doctors' perceived the Patient at Risk team contributed to improving care of deteriorating ward patients. The instrument used in this study may be useful to other outreach teams to identify service improvements. PMID- 28571626 TI - Effects of reduced plantar cutaneous sensation on static postural control in individuals with and without chronic ankle instability. AB - OBJECTIVES: The purpose of this study was to determine how reduced plantar cutaneous sensation influences static postural control in individuals with and without CAI. DESIGN: A case-control study design. METHODS: Twenty-six individuals with self-reported CAI and 26 matched healthy controls participated in this study. The plantar aspect of the participants' foot was then submersed in ice water (0 degrees C) for 10min to reduce plantar sensation. Before and after the cooling procedure, plantar cutaneous sensation thresholds and single leg balance with eyes open and closed were assessed. RESULTS: Significantly, higher scores were observed in both groups after ice water submersion (p<0.001) indicating a significant reduction in the plantar cutaneous sensitivity after the cooling procedure. In single limb balance with eyes open, there were significant intervention main effects for the TTB ML mean (p<0.001), TTB AP mean (p=0.035) and TTB ML SD (p=0.021); indicating postural control improvement in both groups post-cooling. In single limb balance with eyes closed, Group*Intervention interactions were observed for the TTB AP mean (p=0.003) and TTB AP SD (p=0.017); indicating postural control deficits in CAI group post-cooling, but no changes in the control group. CONCLUSIONS: The main finding of this study was that reduced plantar cutaneous sensation induced by an ice submersion procedure caused eyes closed postural control impairments in those with CAI but not healthy controls. The present investigation demonstrated that the ability to dynamically reweight among sensory inputs to maintain postural stability appears to be diminished in CAI patients compared to healthy controls. PMID- 28571627 TI - Directed evolution of Thermomyces lanuginosus lipase to enhance methanol tolerance for efficient production of biodiesel from waste grease. AB - Engineering a methanol tolerant lipase is of great importance in biodiesel production. Here, the first semi-rational method for directed enzyme evolution to enhance methanol tolerance by targeting high B-factor residues for iterative saturation mutagenesis (ISM) is reported. The best double mutant, TLL-S105C/D27R, retained 71% of its original activity after incubation in methanol, showing 30% greater methanol tolerance than TLL. TLL-S105C/D27R also displayed 27% higher activity over TLL. Structure modelling suggested that the increased stability of TLL-S105C/D27R was caused by the formation of a new hydrogen bond which stabilized the protein structure. E. coli (TLL-S105C/D27R)-catalyzed biotransformation of waste grease produced biodiesel in 81% yield in 8h, showing improvement over the 67% yield for E. coli (TLL), while retaining 92% productivity after 4 cycles of biotransformation of waste grease. The engineered TLL mutant shows high potential for commercial biodiesel production. PMID- 28571628 TI - Enhancing sludge biodegradability and volatile fatty acid production by tetrakis hydroxymethyl phosphonium sulfate pretreatment. AB - A new pretreatment method based on tetrakis hydroxymethyl phosphonium sulfate (THPS) biocide was tried to enhance sludge disintegration, and improved sludge biodegradability and subsequent volatile fatty acid (VFA) production. Sludge activity decreased to less than 10% after 2 days pretreatment using 20mg/g-TSS THPS, which also obviously destroyed EPS and cell membrane, and dissolved more biodegradable substances (48.8%) than raw sludge (19.7%). Moreover, 20mg/g-TSS THPS pretreatment shortened fermentation time to 4days and improved VFA production to 2778mg COD/L (4.35 times than that in control). Therein, the sum of n-butyric, n-valeric and iso-valeric acids unexpectedly accounted for 60.5% of total VFA (only 20.1% of that in control). The more high molecular weight VFAs (C4-C5) than low molecular VFAs (C2-C3) resulted from THPS pretreatment benefited to subsequent medium-chain volatile acids (C6-C12) generation to realize the separation and recovery of organic carbon more efficiently. PMID- 28571629 TI - Ubiquity of microplastics in coastal seafloor sediments. AB - Microplastic pollutants occur in marine environments globally, however estimates of seafloor concentrations are rare. Here we apply a novel method to quantify size-graded (0.038-4.0mm diam.) concentrations of plastics in marine sediments from 42 coastal and estuarine sites spanning pollution gradients across south eastern Australia. Acid digestion/density separation revealed 9552 individual microplastics from 2.84l of sediment across all samples; equating to a regional average of 3.4 microplastics.ml-1 sediment. Microplastics occurred as filaments (84% of total) and particle forms (16% of total). Positive correlations between microplastic filaments and wave exposure, and microplastic particles with finer sediments, indicate hydrological/sediment-matrix properties are important for deposition/retention. Contrary to expectations, positive relationships were not evident between microplastics and other pollutants (heavy metals/sewage), nor were negative relationships with neighbouring reef biota detected. Rather, microplastics were ubiquitous across sampling sites. Positive associations with some faunal-elements (i.e. invertebrate species richness) nevertheless suggest high potential for microplastic ingestion. PMID- 28571630 TI - Occipital transcranial magnetic stimulation discriminates transient neurological symptoms of vascular origin from migraine aura without headache. AB - OBJECTIVES: The diagnosis of transient neurological attacks (TNA) relies on medical history. Transient ischemic attack is often considered until proven otherwise, because of lack of objective paraclinical tools that can help discriminate TIA from differential diagnoses such as migraine aura. This may lead to needless and potentially harmful stroke secondary prevention in many cases. This study aimed at determining the yield of occipital transcranial magnetic stimulation (oTMS) in discriminating TNA of vascular origin from migraine aura without headache (MAWH). METHODS: Ten patients with acute TNA of vascular origin and ten patients with migraine aura without headache (MAWH), without prior history of migrainous headache, were prospectively included. TNA of vascular origin were considered for individuals presenting unilateral focal symptoms with full resolution within 24hours and positive diffusion weighted imaging (DWI+). For individuals with MAWH, diagnostic criteria were either ICHD-III beta or Fischer criteria for a first episode of MAWH. All participants underwent one session of oTMS. Induction and threshold of phosphene induction were recorded. RESULTS: In TNA of vascular origin, MRI disclosed cortical lesions in nine and one sub-cortical lesion. Phosphenes were induced in 9/10 subjects with MAWH with a mean threshold of 66% of the maximal intensity, whereas oTMS induced phosphenes in only one subject with TNA of vascular origin at a threshold of 85%. CONCLUSIONS: In this pilot study, oTMS was found to be an effective tool to discriminate between MAWH and transient neurological symptoms of vascular origin. PMID- 28571632 TI - Anticoagulation Therapy for Pregnant Women With Mechanical Prosthetic Heart Valves: How to Improve Safety? PMID- 28571631 TI - Maternal and Fetal Outcomes of Anticoagulation in Pregnant Women With Mechanical Heart Valves. AB - BACKGROUND: Anticoagulation for mechanical heart valves during pregnancy is essential to prevent thromboembolic events. Each regimen has drawbacks with regard to maternal or fetal risk. OBJECTIVES: This meta-analysis sought to estimate and compare the risk of adverse maternal and fetal outcomes in pregnant women with mechanical heart valves who received different methods of anticoagulation. METHODS: Studies were identified using a Medline search including all publications up to June 5, 2016. Study inclusion required reporting of maternal death, thromboembolism, and valve failure, and/or fetal spontaneous abortion, death, and congenital defects in pregnant women treated with any of the following: 1) a vitamin K antagonist (VKA) throughout pregnancy; 2) low-molecular weight heparin (LMWH) throughout pregnancy; 3) LMWH for the first trimester, followed by a VKA (LMWH and VKA); or 4) unfractionated heparin for the first trimester, followed by a VKA (UFH and VKA). RESULTS: A total of 800 pregnancies from 18 publications were included. Composite maternal risk was lowest with VKA (5%), compared with LMWH (16%; ratio of averaged risk [RAR]: 3.2; 95% confidence interval [CI]: 1.5 to 7.5), LMWH and VKA (16%; RAR: 3.1; 95% CI: 1.2 to 7.5), or UFH and VKA (16%; RAR: 3.1; 95% CI: 1.5 to 7.1). Composite fetal risk was lowest with LMWH (13%; RAR: 0.3; 95% CI: 0.1 to 0.8), compared with VKA (39%), LMWH and VKA (23%), or UFH and VKA (34%). No significant difference in fetal risk was observed between women taking <=5 mg daily warfarin and those with an LMWH regimen (RAR: 0.9; 95% CI: 0.3 to 2.4). CONCLUSIONS: VKA treatment was associated with the lowest risk of adverse maternal outcomes, whereas the use of LMWH throughout pregnancy was associated with the lowest risk of adverse fetal outcomes. Fetal risk was similar between women taking <=5 mg warfarin daily and women treated with LMWH. PMID- 28571633 TI - Trends in Use of High-Intensity Statin Therapy After Myocardial Infarction, 2011 to 2014. AB - BACKGROUND: Data prior to 2011 suggest that a low percentage of patients hospitalized for acute coronary syndromes filled high-intensity statin prescriptions upon discharge. Black-box warnings, generic availability of atorvastatin, and updated guidelines may have resulted in a change in high intensity statin use. OBJECTIVES: The aim of this study was to examine trends and predictors of high-intensity statin use following hospital discharge for myocardial infarction (MI) between 2011 and 2014. METHODS: Secular trends in high intensity statin use following hospital discharge for MI were analyzed among patients 19 to 64 years of age with commercial health insurance in the MarketScan database (n = 42,893) and 66 to 75 years of age with U.S. government health insurance through Medicare (n = 75,096). Patients filling statin prescriptions within 30 days of discharge were included. High-intensity statins included atorvastatin 40 or 80 mg and rosuvastatin 20 or 40 mg. RESULTS: The percentage of beneficiaries whose first statin prescriptions filled following hospital discharge for MI were for high-intensity doses increased from 33.5% in January through March 2011 to 71.7% in October through November 2014 in MarketScan and from 24.8% to 57.5% in Medicare. Increases in high-intensity statin use following hospital discharge occurred over this period among patients initiating treatment (30.6% to 72.0% in MarketScan and 21.1% to 58.8% in Medicare) and those taking low- or moderate-intensity statins prior to hospitalization (from 27.8% to 62.3% in MarketScan and from 12.6% to 45.1% in Medicare). In 2014, factors associated with filling high-intensity statin prescriptions included male sex, filling beta blocker and antiplatelet agent prescriptions, and attending cardiac rehabilitation within 30 days following discharge. CONCLUSIONS: The use of high intensity statins following hospitalization for MI increased progressively from 2011 through 2014. PMID- 28571634 TI - Statins in Secondary Prevention: Intensity Matters. PMID- 28571636 TI - The Swing of beta-Blockers: Time for a System Reboot. PMID- 28571637 TI - Interventional Treatment of Patients With Congenital Heart Disease: Nationwide Danish Experience Over 39 Years. AB - BACKGROUND: The treatment of congenital heart (CHD) has changed rapidly. OBJECTIVES: The authors reviewed CHD treatment through a 39-year nationwide population-based study on congenital heart surgery and catheter-based interventions, unbiased by referral patterns. METHODS: Using medical registries, the authors identified children (<18 years of age) treated for CHD in Denmark from 1977 to 2015, their need for reinterventions, and their long-term survival. Ten controls per patient, matched by sex and year of birth, allowed comparison with the background population. Survival was described using Kaplan-Meier curves. RESULTS: A total of 9,372 patients underwent 11,968 cardiac surgeries and 1,912 catheter-based interventions. Median age at first procedure decreased from 3.4 years (5th and 95th percentiles: 0.01 to 15.4 years) in 1977 to 1989 (period 1), 0.8 years (5th and 95th percentiles: 0.003 to 13.8 years) in 1990 to 2002 (period 2), and to 0.6 years (5th and 95th percentiles: 0.0 to 14.9 years) in 2003 to 2015 (period 3). More patients were born preterm (<37 weeks) in period 3 compared with those in period 1 (18.5% vs. 6.7%). Catheter-based interventions, not recorded before 1990, were increasingly used as the initial procedure in 5.8% of patients in period 2 and 25.9% of patients in period 3. An increasing part of the population did not undergo surgery at all (4.8% in period 2; 24.0% in period 3). Thirty-day survival increased from 97% (period 1) to 98% (period 2) to 100% (period 3). Ten-year survival increased from 80% (period 1) to 87% (period 2) to 93% (period 3). Compared with the background population, CHD was associated with lower survival in all 3 time periods. CONCLUSIONS: Interventional treatment of CHD has evolved from 1977 to 2015 and is now performed on younger and more preterm patients, often with catheter-based interventions. However, compared with the background population, survival remains significantly reduced. PMID- 28571635 TI - beta-Blockers and Mortality After Acute Myocardial Infarction in Patients Without Heart Failure or Ventricular Dysfunction. AB - BACKGROUND: For acute myocardial infarction (AMI) without heart failure (HF), it is unclear if beta-blockers are associated with reduced mortality. OBJECTIVES: The goal of this study was to determine the association between beta-blocker use and mortality in patients with AMI without HF or left ventricular systolic dysfunction (LVSD). METHODS: This cohort study used national English and Welsh registry data from the Myocardial Ischaemia National Audit Project. A total of 179,810 survivors of hospitalization with AMI without HF or LVSD, between January 1, 2007, and June 30, 2013 (final follow-up: December 31, 2013), were assessed. Survival-time inverse probability weighting propensity scores and instrumental variable analyses were used to investigate the association between the use of beta-blockers and 1-year mortality. RESULTS: Of 91,895 patients with ST-segment elevation myocardial infarction and 87,915 patients with non-ST-segment elevation myocardial infarction, 88,542 (96.4%) and 81,933 (93.2%) received beta-blockers, respectively. For the entire cohort, with >163,772 person-years of observation, there were 9,373 deaths (5.2%). Unadjusted 1-year mortality was lower for patients who received beta-blockers compared with those who did not (4.9% vs. 11.2%; p < 0.001). However, after weighting and adjustment, there was no significant difference in mortality between those with and without beta-blocker use (average treatment effect [ATE] coefficient: 0.07; 95% confidence interval [CI]: -0.60 to 0.75; p = 0.827). Findings were similar for ST-segment elevation myocardial infarction (ATE coefficient: 0.30; 95% CI: -0.98 to 1.58; p = 0.637) and non-ST-segment elevation myocardial infarction (ATE coefficient: -0.07; 95% CI: -0.68 to 0.54; p = 0.819). CONCLUSIONS: Among survivors of hospitalization with AMI who did not have HF or LVSD as recorded in the hospital, the use of beta blockers was not associated with a lower risk of death at any time point up to 1 year. (beta-Blocker Use and Mortality in Hospital Survivors of Acute Myocardial Infarction Without Heart Failure; NCT02786654). PMID- 28571638 TI - Congenital Heart Defects: Amazing Advances and Ongoing Challenges. PMID- 28571640 TI - Cardiorespiratory Fitness, Not the Severity of the Condition, Dictates Late Outcomes After Fontan Procedures. PMID- 28571641 TI - A Test in Context: Fractional Flow Reserve: Accuracy, Prognostic Implications, and Limitations. AB - Fractional flow reserve (FFR) is an invasive procedure used during coronary angiography to determine the functional significance of coronary stenoses. Its use is particularly helpful in intermediate or angiographically ambiguous lesions in the absence of noninvasive functional studies. Randomized clinical trials have reported improved clinical outcomes with the use of FFR to guide coronary revascularization, including a reduction in cardiac death or myocardial infarction, as well as costs, with an FFR-based strategy compared with a conventional angiography-based approach. Current societal guidelines provide a Class II, Level of Evidence: A recommendation to perform FFR in angiographically intermediate stenoses in the absence of stress testing or in the presence of discordant stress test results and angiographic findings. However, despite the relative ease of use of FFR, multiple technical factors can impair its accuracy, and attention to detail is critical when performing the test. This review focuses on the fundamental basics of FFR testing, clinical evidence, and limitations. PMID- 28571639 TI - Longitudinal Outcomes of Patients With Single Ventricle After the Fontan Procedure. AB - BACKGROUND: Multicenter longitudinal objective data for survival into adulthood of patients who have undergone Fontan procedures are lacking. OBJECTIVES: This study sought to describe transplant-free survival and explore relationships between laboratory measures of ventricular performance and functional status over time. METHODS: Exercise testing, echocardiography, B-type natriuretic peptide, functional health assessment, and medical history abstraction were repeated 9.4 +/- 0.4 years after the Fontan Cross-Sectional Study (Fontan 1) and compared with previous values. Cox regression analysis explored risk factors for interim death or cardiac transplantation. RESULTS: From the original cohort of 546 subjects, 466 were contacted again, and 373 (80%) were enrolled at 21.2 +/- 3.5 years of age. Among subjects with paired testing, the percent predicted maximum oxygen uptake decreased (69 +/- 14% vs. 61 +/- 16%; p < 0.001; n = 95), ejection fraction decreased (58 +/- 11% vs. 55 +/- 10%; p < 0.001; n = 259), and B-type natriuretic peptide increased (median [interquartile range] 13 [7 to 25] pg/mol vs. 18 [9 to 36] pg/mol; p < 0.001; n = 340). At latest follow-up, a lower Pediatric Quality of Life Inventory physical summary score was associated with poorer exercise performance (R2 adjusted = 0.20; p < 0.001; n = 274). Cumulative complications since the Fontan procedure included additional cardiac surgery (32%), catheter intervention (62%), arrhythmia treatment (32%), thrombosis (12%), and protein-losing enteropathy (8%). Since Fontan 1, 54 subjects (10%) have received a heart transplant (n = 23) or died without transplantation (n = 31). The interval risk of death or/cardiac transplantation was associated with poorer ventricular performance and functional health status assessed at Fontan 1, but it was not associated with ventricular morphology, the subject's age, or the type of Fontan connection. CONCLUSIONS: Interim transplant-free survival over 12 years in this Fontan cohort was 90% and was independent of ventricular morphology. Exercise performance decreased and was associated with worse functional health status. Future interventions might focus on preserving exercise capacity. (Relationship Between Functional Health Status and Ventricular Performance After Fontan-Pediatric Heart Network; NCT00132782). PMID- 28571642 TI - LOX-1 in Atherosclerosis and Myocardial Ischemia: Biology, Genetics, and Modulation. AB - Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), one of the scavenger receptors for oxidized low-density lipoprotein cholesterol (ox-LDL), plays a crucial role in the uptake of ox-LDL by cells in the arterial wall. Mounting evidence suggests a role for LOX-1 in various steps of the atherosclerotic process, from initiation to plaque destabilization. Studies of the genetic structure of LOX-1 have also uncovered various genetic polymorphisms that could modulate the risk of atherosclerotic cardiovascular events. As evidence supporting the vital role of LOX-1 in atherogenesis keeps accumulating, there is growing interest in LOX-1 as a potential therapeutic target. This review discusses the discovery and genetics of LOX-1; describes existing evidence supporting the role of LOX-1 in atherogenesis and its major complication, myocardial ischemia; and summarizes LOX-1 modulation by some naturally occurring compounds and efforts toward development of small molecules and biologics that could be of therapeutic use. PMID- 28571643 TI - Multiple Biomarkers in the Context of Conventional Risk Factors in Patients With Coronary Artery Disease. PMID- 28571644 TI - Serum Magnesium Levels and In-Hospital Mortality in Acute Myocardial Infarction. PMID- 28571645 TI - Concerns About the Stability of hsTnI Assay After 20 Years of Storage. PMID- 28571646 TI - Relativism and Low-Density Lipoprotein Cholesterol: Absolute or Relative Truth? PMID- 28571647 TI - Risk of Adverse Neurocognitive Outcomes With PCSK-9 Inhibitors. PMID- 28571648 TI - Reply: Acute and Recurrent Pericarditis: Still Idiopathic? PMID- 28571649 TI - Acute and Recurrent Pericarditis: Still Idiopathic? PMID- 28571650 TI - Correction. PMID- 28571651 TI - Timing therapeutic donor inseminations in natural cycles: human chorionic gonadotrophin administration versus urinary LH monitoring. AB - This cohort study assessed whether timing therapeutic donor sperm inseminations (TDI) in natural cycles (NC) using ultrasound monitoring and ovulation trigger with human chorionic gonadotrophin (US/HCG) improves cumulative live birth rates (LBR) compared with detection of LH surge with urinary kits (u-LH). It included 232 normo-ovulatory women aged <=40 years, undergoing 538 TDI in NC between 2011 and 2014. In the u-LH group (113 women, 267 cycles), TDI was performed the day following a positive test. In the US/HCG group (119 women, 271 cycles), ovulation was triggered with HCG when a follicle >=17 mm was noted, and TDI performed 36 h later. The first three cycles were analysed per patient. Groups were comparable for baseline characteristics. Cumulative LBR were comparable between u-LH and US/HCG groups (31.47% versus 23.11%, respectively) (log-rank test). A generalized estimating equation analysis was performed to compare outcomes per cycle. The LBR per started cycle was comparable between the u-LH and US/HCG groups (12.4% versus 9.2%, respectively). Cancellation rate was significantly higher with u-LH (19.1% versus 11.4%, P = 0.011), but did not impact overall outcomes. In conclusion, urinary LH monitoring is as effective as ultrasound monitoring and ovulation trigger with HCG in TDI performed in NC. PMID- 28571653 TI - CSF ApoE predicts clinical progression in nondemented APOEepsilon4 carriers. AB - Possible associations between cerebrospinal fluid (CSF) and plasma apolipoprotein E (ApoE) concentration and early clinical and pathophysiological manifestation of Alzheimer's disease were studied in a large and well-defined population of nondemented patients. CSF and plasma ApoE concentrations were related to CSF Abeta42, Tau and pTau levels and clinical characteristics in patients with subjective cognitive decline (n = 207) or mild cognitive impairment (n = 213) aged 64.2 +/- 9.0 years, with a 2.5 +/- 1.5 years follow-up. A 1 standard deviation increase in log-transformed CSF ApoE concentrations increased the risk of clinical progression in APOEepsilon4 carriers 1.5 times (hazard ratio [95% confidence interval] 1.5 [1.1-2.0]), while this was not the case in APOEepsilon4 noncarriers (hazard ratio [95% confidence interval] 1.0 [0.8-1.2]). Plasma ApoE did not predict clinical progression. Using linear regression models, strong associations between CSF ApoE levels and CSF Tau (beta 0.51 [0.38-0.65]) and pTau (beta 0.53 [0.40-0.60]) values were observed in APOEepsilon4 carriers. We hypothesize CSF ApoE4 increases risk of clinical progression through its association with CSF Tau in APOEepsilon4 carriers. Development of Alzheimer's disease in APOEepsilon4 noncarriers may be unrelated to ApoE concentration. PMID- 28571652 TI - Functional neuroanatomy of speech signal decoding in primary progressive aphasias. AB - The pathophysiology of primary progressive aphasias remains poorly understood. Here, we addressed this issue using activation fMRI in a cohort of 27 patients with primary progressive aphasia (nonfluent, semantic, and logopenic variants) versus 15 healthy controls. Participants listened passively to sequences of spoken syllables in which we manipulated 3-key auditory speech signal characteristics: temporal regularity, phonemic spectral structure, and pitch sequence entropy. Relative to healthy controls, nonfluent variant patients showed reduced activation of medial Heschl's gyrus in response to any auditory stimulation and reduced activation of anterior cingulate to temporal irregularity. Semantic variant patients had relatively reduced activation of caudate and anterior cingulate in response to increased entropy. Logopenic variant patients showed reduced activation of posterior superior temporal cortex to phonemic spectral structure. Taken together, our findings suggest that impaired processing of core speech signal attributes may drive particular progressive aphasia syndromes and could index a generic physiological mechanism of reduced computational efficiency relevant to all these syndromes, with implications for development of new biomarkers and therapeutic interventions. PMID- 28571654 TI - Is Nutrient Content and Other Label Information for Prescription Prenatal Supplements Different from Nonprescription Products? AB - BACKGROUND: Prenatal supplements are often recommended to pregnant women to help meet their nutrient needs. Many products are available, making it difficult to choose a suitable supplement because little is known about their labeling and contents to evaluate their appropriateness. OBJECTIVE: To determine differences between prescription and nonprescription prenatal supplements available in the United States regarding declared nutrient and nonnutrient ingredients and the presence of dosing and safety-related information. DESIGN: Using two publicly available databases with information about prenatal supplement products, information from prescription and nonprescription product labels were extracted and evaluated. For the 82 prescription and 132 nonprescription products, declared label amounts of seven vitamins and minerals, docosahexaenoic acid (DHA), the presence of other nonnutrient components, and the presence of key safety and informational elements as identified in two Department of Health and Human Services Office of Inspector General (OIG)'s 2003 reports were compiled and compared. RESULTS: Compared with nonprescription products, prescription products contained significantly fewer vitamins (9+/-0.2 vs 11+/-0.3; P<=0.05) and minerals (4+/-0.1 vs 8+/-0.3; P<=0.05). Declared amounts of folic acid were higher in prescription products, whereas vitamin A, vitamin D, iodine, and calcium were higher in the nonprescription products. Amounts of iron, zinc, and DHA were similar. Virtually all products contained levels of one or more nutrients that exceeded the Recommended Dietary Allowances for pregnant and/or lactating women. Product type also influenced ingredients added. Fewer prescription products contained botanical ingredients (6% prescription vs 33% nonprescription) and probiotics (2% prescription vs 8% nonprescription). Only prescription products contained the stool softener docusate sodium. CONCLUSIONS: Our analysis of prenatal supplements indicates that prescription and nonprescription supplements differ in terms of declared composition and nutrient strength, but have labels that are similarly sparse regarding aspects of use such as dosing information. PMID- 28571655 TI - A Novel Approach to Predict 24-Hour Energy Expenditure Based on Hematologic Volumes: Development and Validation of Models Comparable to Mifflin-St Jeor and Body Composition Models. AB - BACKGROUND: Accurate prediction of 24-hour energy expenditure (24EE) relies on knowing body composition, in particular fat-free mass (FFM), the largest determinant of 24EE. FFM is closely correlated with hematologic volumes: blood volume (BV), red cell mass (RCM), and plasma volume (PV). However, it is unknown whether predicted hematologic volumes, based on easily collected variables, can improve 24EE prediction. OBJECTIVE: The aim was to develop and validate equations to predict 24EE based on predicted BV, RCM, and PV and to compare the accuracy and agreement with models developed from FFM and with the Mifflin-St Jeor equation, which is recommended for clinical use by the Academy of Nutrition and Dietetics. DESIGN: Participants had body composition measured by underwater weighing and 24EE by respiratory chamber. BV, RCM, and PV were calculated from five published equations. PARTICIPANTS/SETTING: Native American and white men and women were studied (n=351). Participants were healthy adults aged 18 to 49 years from the Phoenix, AZ, metropolitan area. MAIN OUTCOME MEASURE: Accuracy to within +/-10% of measured 24EE and agreement by Bland-Altman analysis. STATISTICAL ANALYSIS: Regression models to predict 24EE from hematologic and body composition variables were developed in half the dataset and validated in the other half. RESULTS: Hematologic volumes were all strongly correlated with FFM in both men and women (r>=0.94). Whereas the accuracy of FFM alone was 69%, four hematologic volumes were individually more accurate (75% to 78%) in predicting 24EE. Equations based on hematologic volumes plus demographics had mean prediction errors comparable to those based on body composition plus demographics; although the Mifflin-St Jeor had modestly better mean prediction error, body composition, hematologic, and Mifflin-St Jeor models all had similar accuracy (approximately 80%). CONCLUSIONS: Prediction equations based on hematologic volumes were developed, validated, and found to be comparable to Mifflin-St Jeor and body composition models in this population of healthy adults. PMID- 28571656 TI - Development of a novel method for amniotic fluid stem cell storage. AB - BACKGROUND AIMS: Current procedures for collection of human amniotic fluid stem cells (hAFSCs) indicate that cells cultured in a flask for 2 weeks can then be used for research. However, hAFSCs can be retrieved directly from a small amount of amniotic fluid that can be obtained at the time of diagnostic amniocentesis. The aim of this study was to determine whether direct freezing of amniotic fluid cells is able to maintain or improve the potential of a sub-population of stem cells. METHODS: We compared the potential of the hAFSCs regarding timing of freezing, cells obtained directly from amniotic fluid aspiration (D samples) and cells cultured in a flask before freezing (C samples). Colony-forming-unit ability, proliferation, morphology, stemness-related marker expression, senescence, apoptosis and differentiation potential of C and D samples were compared. RESULTS: hAFSCs isolated from D samples expressed mesenchymal stem cells markers until later passages, had a good proliferation rate and exhibited differentiation capacity similar to hAFSCs of C samples. Interestingly, direct freezing induced a higher concentration of cells positive for pluripotency stem cell markers, without teratoma formation in vivo. CONCLUSIONS: This study suggests that minimal processing may be adequate for the banking of amniotic fluid cells, avoiding in vitro passages before the storage and exposure to high oxygen concentration, which affect stem cell properties. This technique might be a cost-effective and reasonable approach to the process of Good Manufacturing Process accreditation for stem-cell banks. PMID- 28571657 TI - Transplantation of bone marrow stromal stem cells overexpressing tropomyosin receptor kinase A for peripheral nerve repair. AB - BACKGROUND AIMS: Previously we reported that overexpression of tropomyosin receptor kinase A (TrkA) could improve the survival and Schwann-like cell differentiation of bone marrow stromal stem cells (BMSCs) in nerve grafts for bridging rat sciatic nerve defects. The aim of this study was to investigate how TrkA affects the efficacy of BMSCs transplantation on peripheral nerve regeneration and functional recovery. METHODS: Rat BMSCs were infected with recombinant lentiviruses to construct TrkA-overexpressing BMSCs and TrkA-shRNA expressing BMSCs, which were then seeded in acellular nerve allografts for bridging 10-mm rat sciatic nerve defects. RESULTS: At 8 weeks post transplantation, compared with Vector and Control BMSCs-laden groups, TrkA overexpressing BMSCs-laden group demonstrated obviously improved axon growth, such as significantly higher expression of myelin basic protein and superior results of myelinated fiber density, axon diameter and myelin sheaths thickness. In accordance with this increased nerve regeneration, the animals of TrkA overexpressing BMSCs-laden group showed significantly better restoration of sciatic nerve function, manifested as greater sciatic function index value and superior electrophysiological parameters including shorter onset latency and higher peak amplitude of compound motor action potentials and faster nerve conduction velocity. However, these beneficial effects could be reversed in TrkA shRNA-expressing BMSCs-laden group, which showed much fewer and smaller axons with thinner myelin sheaths and correspondingly poor functional recovery. CONCLUSIONS: These results demonstrated that TrkA may regulate the regenerative potential of BMSCs in nerve grafts, and TrkA overexpression can enhance the efficacy of BMSCs on peripheral nerve regeneration and functional recovery, which may help establish novel strategies for repairing peripheral nerve injuries. PMID- 28571658 TI - [Primary pulmonary sarcoma in a patient with pulmonary fibrosis and emphysema]. PMID- 28571659 TI - Gut Microbiota, Endocrine-Disrupting Chemicals, and the Diabetes Epidemic. AB - Diabetes is rapidly emerging as one of the biggest health concerns worldwide, with profound implications for disability, mortality, and costs. This suddenly escalating rate of diabetes correlates with global industrialization and the production of plastics, pesticides, synthetic fertilizers, electronic waste, and food additives that release endocrine-disrupting chemicals (EDCs) into the environment and the food chain. Emerging evidence indicates an association between exposure of EDCs and diabetes. In humans, these chemicals are also metabolized by the gut microbiota and thereby their toxicodynamics are altered. In this review we highlight studies that focus on the role of gut microbiota in EDC-induced hyperglycemia and dysregulated glucose homeostasis. We also discuss the translational implications of understanding EDC-microbiota interactions for the diagnosis and treatment of diabetes. PMID- 28571660 TI - Routine use of bronchoscopy in percutaneous tracheostomy. PMID- 28571661 TI - [Evaluation and perioperative management of patients with diabetes mellitus. A challenge for the anesthesiologist]. AB - Diabetes mellitus (DM) is characterized by alteration in carbohydrate metabolism, leading to hyperglycemia and increased perioperative morbidity and mortality. It evolves with diverse and progressive physiological changes, and the anesthetic management requires attention regarding this disease interference in multiple organ systems and their respective complications. Patient's history, physical examination, and complementary exams are important in the preoperative management, particularly glycosylated hemoglobin (HbA1c), which has a strong predictive value for complications associated with diabetes. The goal of surgical planning is to reduce the fasting time and maintain the patient's routine. Patients with Type 1 DM must receive insulin (even during the preoperative fast) to meet the basal physiological demands and avoid ketoacidosis. Whereas patients with Type 2 DM treated with multiple injectable and/or oral drugs are susceptible to develop a hyperglycemic hyperosmolar state (HHS). Therefore, the management of hypoglycemic agents and different types of insulin is fundamental, as well as determining the surgical schedule and, consequently, the number of lost meals for dose adjustment and drug suspension. Current evidence suggests the safe target to maintain glycemic control in surgical patients, but does not conclude whether it should be obtained with either moderate or severe glycemic control. PMID- 28571662 TI - Benefits, challenges and critical factors of success for Zero Waste: A systematic literature review. AB - Considering the growing concern with solid wastes problems and the pressing need for a holistic approach to their management, this study developed a literature review about the subject "Zero Waste". To that end, a systematic literature review was executed, through which 102 published articles were analyzed with the aim to, initially, comprehend the concept of Zero Waste, and, then, map its benefits, challenges, and critical success factors. The results show that scholars have not reached a consensus regarding the concept of ZW. While some studies fully address this philosophy, other studies are based on just one or on some of its topics. The benefits were grouped and organized into four dimensions: benefits to the community, financial-economic benefits, benefits to the environment and benefits to the industry and stakeholders. As to the challenges, barriers were identified both in the macro environment (mainly political and cultural) and in the meso and micro environments (stakeholders, industries, and municipalities). The analysis of the articles enabled listing critical success factors, supported by a set of activities that must be carried out. Regarding future studies, it is worth noting that more empirical studies about ZW implementation are necessary, particularly with regard to educational practices designed to promote changes in user behavior. PMID- 28571663 TI - Quantification of greenhouse gas emissions from a biological waste treatment facility. AB - Whole-site emissions of methane and nitrous oxide, from a combined dry anaerobic digestion and composting facility treating biowaste, were quantified using a tracer dispersion technique that combines a controlled tracer gas release from the treatment facility with time-resolved concentration measurements downwind of the facility. Emission measurements were conducted over a period of three days, and in total, 80 plume traverses were obtained. On-site screening showed that important processes resulting in methane emissions were aerobic composting reactors, anaerobic digester reactors, composting windrows and the site's biofilter. Average whole-site methane emissions measured during the three days were 27.5+/-7.4, 28.5+/-6.1 and 30.1+/-11.4kg CH4 h-1, respectively. Turning the windrows resulted in an increase in methane emission from about 26.3-35.9kg CH4 h 1. Lower emissions (21.5kg CH4 h-1) were measured after work hours ended, in comparison to emissions measured during the facility's opening hours (30.2kg CH4 h-1). Nitrous oxide emission was too small for a downwind quantification. Direct on-site measurements, however, suggested that the main part of the emitted nitrous oxide came from the biofilter (about 1.4kg N2O h-1). Whole-site emissions were compared to emissions previously measured at different point sources on site. Whole-site fugitive emissions were three to eight times higher than the sum of emissions measured at on-site sources. The magnitude of the emissions had a significant influence on the overall environmental impact of the treatment facility, assessed by consequential life cycle assessment. Including the higher whole-site fugitive emissions led to an increase in global warming potential, from a saving of 97kgCO2-eq.tonne-1 of treated waste (wet weight) to a loading of 71kg CO2-eq. tonne-1, ultimately flipping the environmental profile of the treatment facility. PMID- 28571664 TI - The Role of Patients: Shared Decision-Making. AB - Shared decision-making affords patients and their families the autonomy to make difficult decisions after receiving comprehensive information about medical facts and treatment options. It is essential that patients' values are respected. The essential steps include first informing patients of the need for a decision, then explaining the various facts involved; after which, it is important to elicit patients' preferences and goals. Once the treatment options and outcomes important to patients are identified, an actual decision can be made. This activity is complex and requires a commitment of time and is enhanced through employment of a multidisciplinary team approach. PMID- 28571665 TI - Decision Making for Diagnosis and Management: A Consensus Comes to Life. AB - The diagnosis and treatment of head and neck cancer is extremely complex. As a result, multiple medical providers are involved in a patient's care, and the multidisciplinary tumor boards provide a forum whereby they can share and discuss the intricacies of each individual patient's case. When recommendations are presented to the patient and decisions are to be finalized, the patient should benefit from the collective wisdom of a team of providers to achieve and implement a patient-centric and clinically sound consensus. PMID- 28571666 TI - Including values in evidence-based policy making for breast screening: An empirically grounded tool to assist expert decision makers. AB - Values are an important part of evidence-based decision making for health policy: they guide the type of evidence that is collected, how it is interpreted, and how important the conclusions are considered to be. Experts in breast screening (including clinicians, researchers, consumer advocates and senior administrators) hold differing values in relation to what is important in breast screening policy and practice, and committees may find it difficult to incorporate the complexity and variety of values into policy decisions. The decision making tool provided here is intended to assist with this process. The tool is modified from more general frameworks that are intended to assist with ethical decision making in public health, and informed by data drawn from previous empirical studies on values amongst Australian breast screening experts. It provides a structured format for breast screening committees to consider and discuss the values of themselves and others, suggests relevant topics for further inquiry and highlights areas of need for future research into the values of the public. It enables committees to publicly explain and justify their decisions with reference to values, improving transparency and accountability. It is intended to act alongside practices that seek to accommodate the values of individual women in the informed decision making process for personal decision making about participation in breast screening. PMID- 28571667 TI - The role of the European Structural and Investment Funds in Financing Health System in Lithuania: Experience from 2007 to 2013 funding period and implications for the future. AB - European Structural and Investment Funds (ESIF) are a major source of investments in the newer EU member states. In Lithuania's health sector, the amount for the 2007-2013 funding period reached more than ?400 million. In this paper we aim to (i) identify the key areas in the health sector which were supported by ESIF, (ii) determine the extent to which ESIF assisted the implementation of the ongoing health system reform; and (iii) assess whether the use of funds has led to expected improvements in healthcare. We review the national strategic documents and legislation, and perform calculations to determine funding allocations by specific area, based on the available data. We analyse changes according to a set of selected indicators. We find that implementation of programmes funded by the ESIF lacks formal evaluation. Existing evidence suggests that some improvement has been achieved by 2013. However, there are persisting challenges, including failure to reach a broad agreement on selection of health and healthcare indicators, lack of transparency in allocations, and absence of coherent assessment measures of healthcare quality and accessibility. PMID- 28571668 TI - Thermodynamic stability of biomolecules and evolution. AB - The thermodynamic stability of biomolecules in the perspective of evolution is a complex issue and needs discussion. Intra molecular bonds maintain the structure and the state of internal energy (E) of a biomolecule at "local minima". In this communication, possibility of loss in internal energy level of a biomolecule through the changes in the bonds has been discussed, that might earn more thermodynamic stability for the molecule. In the process variations in structure and functions of the molecule could occur. Thus, E of a biomolecule is likely to have energy stature for minimization. Such change in energy status is an intrinsic factor for evolving biomolecules buying more stability and generating variations in the structure and function of DNA molecules undergoing natural selection. Thus, the variations might very well contribute towards the process of evolution. A brief discussion on conserved sequence in the light of proposition in this communication has been made at the end. Extension of the idea may resolve certain standing problems in evolution, such as maintenance of conserved sequences in genome of diverse species, pre- versus post adaptive mutations, 'orthogenesis', etc. PMID- 28571669 TI - Fetal programming and eating disorder risk. AB - Fetal programming describes the process by which environmental stimuli impact fetal development to influence disease development later in life. Our analysis summarizes evidence for the role of fetal programming in eating disorder etiology through review of studies demonstrating specific obstetric complications and later eating risk of anorexia or bulimia. Using Pubmed, we found thirteen studies investigating obstetric factors and eating disorder risk published between 1999 and 2016. We then discuss modifiable maternal risk factors, including nutrition and stress, that influence anorexia or bulimia risk of their offspring. Translation of these findings applies to preventative strategies by health organizations and physicians to provide optimal health for mothers and their children to prevent development of medical and psychiatric illnesses. PMID- 28571670 TI - Accuracy and Interobserver Variability in Reporting of PI-RADS Version 2. PMID- 28571671 TI - The Microbiome of Infants Recruited to a Randomised Placebo-controlled Probiotic Trial (PiPS Trial). AB - The microbial dysbiosis associated with necrotizing enterocolitis (NEC) in preterm infants suggests that early exposure to probiotics may decrease and antibiotics may increase NEC risk. However, administration of Bifidobacterium breve strain BBG-001 to preterm infants did not affect NEC incidence in a multicenter randomised controlled phase 3 trial (PiPS trial). Using a subset of these subjects we compared the fecal microbiome of probiotic and placebo groups and assessed the impact of early antibiotic treatment. Extracted DNA from 103 fecal samples collected at 36weeks post-menstrual age underwent PCR amplification of a fragment of the 16S rRNA gene. Heatmaps were constructed showing the proportions of sequences from bacterial families present at >1% of the community. Stepwise logistic regression assessed the association between early antibiotic exposure and microbiome group. There was no difference in the microbial richness and diversity of the microbiome of preterm infants following treatment with probiotic or a placebo. Conversely, early antimicrobial exposure was associated with different patterns of colonisation, specifically a relative abundance of Proteobacteria. These findings highlight that the potential influence of probiotics on the microbiome of preterm infants remains unclear whereas the modulatory effect of antibiotic exposure on microbial colonisation requires further research. PMID- 28571673 TI - A Toe Flexion NIRS assisted Test for Rapid Assessment of Foot Perfusion in Peripheral Arterial Disease: Feasibility, Validity, and Diagnostic Accuracy. AB - OBJECTIVES: Feasibility, validity, and diagnostic accuracy of a non-invasive dynamic ambulatory test were assessed with near infrared spectroscopy (NIRS) evaluating foot perfusion in peripheral arterial disease (PAD). METHODS: This was a prospective observational study. Eighty PAD patients (63 males, 71 +/- 9 years), including 41 patients with coexisting diabetes, participated. Thirteen healthy subjects (8 males, 26 +/- 8 years) were also studied by echo colour Doppler providing 160 diseased and 26 non-diseased limbs. Under identical clinostatic conditions, participants performed a 10-repetition toe flexion tests with NIRS probes on the dorsum of each foot; the area under the curve of the oxygenated haemoglobin trace ("toflex area") was calculated and the ankle brachial index (ABI) was measured. Time of execution, rate of wrong tests, and adverse reactions were recorded. Within session reliability was assessed by administering the test twice, with a 5 minute interval between tests. The validity was assessed determining whether the toflex area was (a) dependent on the oxygen delivery from the lower limb arteries simulating PAD conditions by a progressive blood flow restriction (40-120% of systolic pressure) in healthy subjects; (b) consistent with the degree of PAD ranked by ABI and correlated with ABI and ankle pressure values in PAD patients. The diagnostic accuracy in detecting PAD was compared with examination using echo colour Doppler ultrasound. RESULTS: All tests were rapidly, satisfactorily (<1% mistakes), and safely performed. Toflex area values, superimposable in the two sessions (intra-class correlation coefficient 0.92), were comparable to PAD values following blood flow restriction, consistent with PAD severity, correlated with dorsal pedis artery pressure (r = .21; p = .007) and ABI (r = .65; p < .001) in PAD, but not in the presence of diabetes. Toflex area was similar to echo colour Doppler for detecting PAD following receiver operating characteristic curve analysis (area = 0.987, p < .001; toflex area values <= -28 arbitrary units, sensitivity/specificity 95.6/100). CONCLUSION: The toe flexion test enables ambulatory assessment of foot perfusion and PAD detection, even in the presence of non-measurable ABI or diseases affecting the microcirculation. PMID- 28571674 TI - Gillies temporal incision: an alternate approach to superficial temporal artery biopsy. AB - The main complications of a biopsy of the superficial temporal artery using a standard preauricular approach include scars on the face, weakness of the temporal branch of the facial nerve, and the possible harvest of a disease-free segment of artery. We describe a modification of the Gillies temporal approach, which when placed at the junction of the frontal and parietal branch can be easily modified to harvest either branch. It avoids scarring to the face as it is hidden within the hairline. The incision placed with specific measurements and palpation is easily reproducible. In patients with giant cell arteritis, arterial wall thickening, and narrowing of the lumen, reduced blood flow makes it harder to identify the artery with a Doppler scan. A procedure based on measurements and palpation is therefore likely to yield better results. PMID- 28571672 TI - Targeting CD147 for T to NK Lineage Reprogramming and Tumor Therapy. AB - CD147 is highly expressed on the surface of numerous tumor cells to promote invasion and metastasis. Targeting these cells with CD147-specific antibodies has been validated as an effective approach for lung and liver cancer therapy. In the immune system, CD147 is recognized as a co-stimulatory receptor and impacts the outcome of thymic selection. Using T cell-specific deletion, we showed here that in thymus CD147 is indispensable for the stable alphabeta T cell lineage commitment: loss of CD147 biases both multipotent DN (double negative) and fully committed DP (double positive) cells into innate NK-like lineages. Mechanistically, CD147 deficiency results in impaired Wnt signaling and expression of BCL11b, a master transcription factor in determining T cell identity. In addition, functional blocking of CD147 by antibody phenocopies genetic deletion to enrich NK-like cells in the periphery. Furthermore, using a melanoma model and orthotopic liver cancer transplants, we showed that the augmentation of NK-like cells strongly associates with resistance against tumor growth upon CD147 suppression. Therefore, besides its original function in tumorigenesis, CD147 is also an effective surface target for immune modulation in tumor therapy. PMID- 28571675 TI - Re: Wrong tooth extraction: an examination of 'Never Event' data. PMID- 28571676 TI - Long non-coding RNA PCAT-1 over-expression promotes proliferation and metastasis in gastric cancer cells through regulating CDKN1A. AB - Prostate cancer-associated transcript1 (PCAT-1) is a novel lncRNA that involved in cell apoptosis and proliferation of prostate cancer. However, the role of PCAT 1 on gastric cancer remains unclear. In the present study, we found that PCAT-1 was increased in gastric cancer tissues and cell lines. Over-expression of PCAT-1 was correlated with poor overall survival in gastric cancer patients. PCAT-1 knockdown through shRNA in AGS and MGC-803 cells inhibited cell proliferation, migration and invasion by regulating CDKN1A. Our data suggested that PCAT-1 could play an oncogenic role in gastric cancer progression. Silencing PCAT-1 is a potential novel therapeutic approach for gastric cancer. PMID- 28571678 TI - Central airway obstruction due to inflammatory bowel disease and rescue with extracorporeal membrane oxygenation. PMID- 28571677 TI - BRM promoter insertion polymorphisms increase the risk of cancer: A meta analysis. AB - INTRODUCTION: Many studies have suggested that the BRM promoter insertion polymorphisms might be associated with susceptibility to many different types of cancer. However, previous studies reported contradictory results. This current meta-analysis was performed to address this issue. EVIDENCE ACQUISITION: A comprehensive search was conducted in multiple databases, including PubMed, Embase and China National Knowledge Infrastructure (CNKI). We collected relevant articles to explore the association between the BRM insertion polymorphisms and susceptibility of cancers. EVIDENCE SYNTHESIS: For the BRM-741 polymorphism, a total of 2901 cases and 3667 controls from 6 studies were included. For the BRM 1321 polymorphism, a total of 2899 cases and 3769 controls from 6 studies were included. Overall, a significant difference was observed in BRM-741 (OR 0.81; 95%CI 0.68, 0.96; P=0.02) and BRM-1321 (OR 0.76; 95%CI 0.66, 0.88; P<0.01) for allele frequency (D versus I). In the subgroup analysis, for the BRM-741, a significant difference was observed in Asian (OR 0.88; 95%CI 0.78, 0.99; P=0.03) for D versus I. Similarly, for the BRM-1321, a significant difference was observed in Asian (OR 0.43; 95%CI 0.32, 0.58; P<0.001) and Caucasian (OR 0.74; 95%CI 0.62, 0.88; P<0.001) for DD versus II. CONCLUSIONS: BRM-741 and BRM-1321 insertion polymorphisms are associated with susceptibility to cancer. Further studies are warranted to verify the clinical utility of BRM promoter insertion polymorphisms in human tumors. PMID- 28571679 TI - Side-to-Side Refluxing Nondismembered Ureterocystotomy: A Novel Strategy to Address Obstructed Megaureters in Children. AB - PURPOSE: A nonrefluxing megaureter is a relatively common cause of antenatal hydronephrosis. Although nonoperative management is favored, surgical intervention is sometimes warranted. However, there is controversy regarding the best approach, particularly in young children. We describe our experience with nondismembered side-to-side refluxing ureterocystotomy as a simple option to address obstruction. MATERIALS AND METHODS: Between January 2012 and January 2017, 32 patients underwent ureterocystotomy at 4 referral centers in North America. Demographics, surgical indications, complications, need for further interventions and change in hydronephrosis were captured. Patients were monitored clinically and with serial ultrasounds. RESULTS: Mean age at surgery was 3.7 months (range 0 to 33) and 25 (78%) patients were male. Unilateral procedures were performed in 29 patients. All patients were initially identified based on the presence of antenatal hydronephrosis and symptoms developed in 10. The procedure was conducted for primary nonrefluxing megaureter in 27 patients and to address secondary obstruction in the remainder. Mean followup was 34.3 months (range 6 to 58). At the most recent evaluation most children demonstrated significant improvement in dilation (86%). To date, 6 patients have undergone further procedures, including a circumcision and 2 ureteral reimplantations for recurrent infections. CONCLUSIONS: Our results suggest that side-to-side refluxing ureterocystotomy is a straightforward, minimally invasive alternative for the surgical management of nonrefluxing megaureter. Despite the trade-off of relieving obstruction and creating reflux, it can be considered a potentially definitive procedure in patients who remain infection-free, particularly circumcised boys. Extended followup with close monitoring is critical to document long-term results with this intervention. PMID- 28571680 TI - Reproductive effects of irisin: Initial in vitro studies. AB - The recently discovered myo- and adipokine irisin affects insulin sensitivity in classical insulin target tissues (adipose tissue, skeletal muscle and liver), but the reproductive effects of this hormone, if any, remain largely unexplored. We hypothesized that irisin may have effects on the hypothalamic-pituitary-gonadal axis. To test this hypothesis, we used murine pituitary mPit12 and human ovarian granulosa cells. GnRH treatment resulted in significant (up to 2.5-fold, p<0.0005) and dose-dependent stimulation of LH production by the mPit12 cells. Treating these cells with irisin alone showed a significant stimulatory effect on LH synthesis only at irisin concentration of 100ng/ml. When used together with GnRH, irisin abolished the stimulatory effect of GnRH on LH production. Human ovarian granulosa cells were treated with insulin, irisin or a combination of both and the estradiol (E2) production was measured. Both insulin or irisin stimulated granulosa cell E2 production (1.4-fold, p<0.05 and 2.5-fold, p=0.0002, respectively), but when insulin and irisin were used in combination, this stimulatory effect on E2 production was abolished. We conclude that irisin may have reproductive axis effects in the pituitary and in the ovary. Further studies are needed to confirm these initial observations and to explore the mechanisms of irisin effects in the reproductive system. PMID- 28571681 TI - Harnessing the Potential of the Tea Tree Genome. PMID- 28571682 TI - Home parenteral nutrition for advanced cancer patients: Contributes to survival? AB - OBJECTIVES: Patients with advanced cancer often suffer from severe malnutrition and gastrointestinal obstruction. This population could benefit from home parenteral nutrition (HPN). The aim of this study was to observe the outcome of patients with advanced cancer patients who were eligible for HPN. METHODS: All patients in the nutrition clinic who received HPN over the past 7 y were included in the present study. We compared patients with advanced cancer with the noncancer population in terms of hospitalization rate and mortality. RESULTS: Of 221 advanced cancer patients, 153 who had no oral/enteral intake and who received HPN survived. Of these, 35% survived for 6 mo, 27% for 1 y, 18.9% survived 2 y, and 3.9% survived for the 7 y of the follow-up. Hospitalization rate was not significantly different from the noncancer population. CONCLUSION: These results show that HPN is a relevant palliative therapy for patients with advanced cancer patients without oral or enteral feeding access. PMID- 28571683 TI - Erratum to "The impact of nutrition support on clinical outcome and cost effectiveness analysis in patients at nutritional risk: a prospective cohort study with propensity score matching," Nutrition (2017) 37C, 53-59. PMID- 28571684 TI - Mediterranean diet to prevent/treat nonalcoholic fatty liver disease in children: A promising approach. PMID- 28571685 TI - Activation of the aryl hydrocarbon receptor decreases rifampicin-induced CYP3A4 expression in primary human hepatocytes and HepaRG. AB - The role of the cross-talk between nuclear receptors in the regulation of Cytochrome P450 expression in the liver is well-documented. Most studies have focused on the cross-talk between the pregnane X receptor (PXR) and other receptors, such as the constitutive androstane receptor. However, cross-talk between PXRs and aryl hydrocarbon receptors (AhRs) has also been suggested, but reports regarding this cross-talk are conflicting. In the present study, we treated HepaRG and primary human hepatocytes (PHHs) with both a strong (TCDD) and weak (3-methylindole; 3MI) AhR activator to investigate their impact on PXR regulated expression of CYP3A4. Moreover, we investigated the effect of co activation of PXR, using rifampicin, and AhR, using TCDD and 3MI, on the regulation of CYP3A4 induction. We also investigated whether knockdown of AhR using siRNA affected the basal expression of PXR and CYP3A4 and induction of CYP3A4 by rifampicin, TCDD and 3MI. The results showed that the treatment of HepaRG cells, but not of PHHs, with AhR activators decreased mRNA expression of CYP3A4 and PXR. Moreover, in both HepaRG and PHHs, AhR activation decreased rifampicin-induced expression of CYP3A4 mRNA. Knock-down of AhR in PHHs increased both basal and rifampicin-induced expression of CYP3A4 mRNA. In conclusion, the presented results suggested that the cross-talk between PXR and AhR plays a role in the regulation of CYP3A4 gene expression. PMID- 28571686 TI - Agonistic and antagonistic effects of phthalates and their urinary metabolites on the steroid hormone receptors ERalpha, ERbeta, and AR. AB - Phthalate plasticizers have been reported to exert adverse effects via activation of the estrogen receptors ERalpha and ERbeta and inhibition of the androgen receptor AR as molecular initiating events. After oral uptake, phthalates are metabolized to their corresponding monoesters and subsequently to oxidized phthalate monoester derivatives, which are in turn conjugated to glucuronic acid and finally excreted with the urine. In contrast to the parent phthalates, toxicological data regarding their primary and secondary metabolites are rare. The present study aimed at the characterization of potential endocrine effects of 15 phthalates and 19 phthalate metabolites by using reporter gene assays to monitor human ERalpha, ERbeta, and AR activity. In these in vitro assays, the phthalates either stimulated or inhibited ERalpha and ERbeta activity and inhibited AR activity, whereas the phthalate metabolites had no impact on the activity of these human hormone receptors. In contrast, the metabolites of di-(2 ethylhexyl) phthalate (DEHP) stimulated transactivation of the human peroxisome proliferator-activated receptors PPARalpha and PPARgamma in analogous reporter gene assays, although DEHP itself did not activate these nuclear receptors. Therefore, primary and secondary phthalate metabolites appear to exert different effects at the molecular level compared to the parent compounds. PMID- 28571687 TI - Next-generation sequencing virulome analysis of a Yersinia enterocolitica subsp. palearctica bioserotype 4/O:3 ST18 isolated from human blood in Brazil. AB - Yersinia enterocolitica is a widespread Gram-negative bacterium that causes gastrointestinal disease and other clinical manifestations in humans. Potentially pathogenic Y. enterocolitica has been isolated in Brazil, from human, environmental, food, and animal sources. Herein we report a genome sequence of Y. enterocolitica subsp. palearctica strain YE 19, serotype O:3, biotype 4, sequence type 18, with virulence determinants isolated from human blood in Rio de Janeiro in 2005. The results corroborate other findings that this strain harbors a set of virulence determinants that could play a role in host pathoadaptation and may also justify the successful dissemination of bioserotype 4/O:3 in Brazil. The presence of strains harboring all of these virulence genes in Brazil is a potential threat to young children and immunocompromised individuals, for whom yersiniosis are a significant source of morbidity and mortality. The results of a genomic data analysis will help understand the virulence of Brazilian strains and provide data for Y. enterocolitica studies worldwide. PMID- 28571688 TI - Systematic Review of Brain Metastases in Patients With Non-Small-Cell Lung Cancer in the United States, European Union, and Japan. AB - Brain metastases (BRM) occur frequently in non-small-cell lung cancer (NSCLC) and present a substantial unmet medical need. Previous literature on global BRM prevalence, treatment patterns, costs, and outcomes typically has described a subset of these factors. The primary objective of this systematic literature review was to summarize BRM-related epidemiology, treatment patterns, costs, and survival of patients with NSCLC in the United States, European Union, and Japan. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards. Literature searches were conducted in PubMed, Ovid MedLine, and Embase to identify studies published between 2003 and 2014. Peer-reviewed, English language, and human observational studies of patients with NSCLC and BRM were identified. Demographic characteristics, treatment patterns, histology subtype, costs, and survival data were extracted into Microsoft Excel and descriptively analyzed using SAS version 9.2 (SAS Institute, Inc). Of 8257 studies, 243 were eligible. Data from 46,422 patients with NSCLC and 27,907 patients with BRM were summarized. Radiation therapy was used by 70.7% (n = 19,736) of the total BRM population, followed by systemic therapy (8.9%, n = 2497), and surgery (6.1%, n = 1690). Reported median survival was 9.78 months ranging from 2.5 to 38 months. Radiation therapy had the best outcome at 10.0 months with 41.6% (n = 101) of the studies reporting the use of stereotactic radiosurgery. Highly variable median survival and treatment patterns were reported between countries. Costs and histology subtype data were not reported for most countries, highlighting the need for additional research to describe the economic burden of BRM and improve the diagnosis, prognosis, and prescription of effective therapies. PMID- 28571689 TI - Consequences of Referral Time and Volume Doubling Time in Inoperable Patients With Early Stage Lung Cancer. AB - BACKGROUND: Inoperable patients with early stage lung cancer are referred late. The purpose was to calculate the referral time and the volume doubling time (VDT), and to investigate its consequence with regard to staging and survival in 117 inoperable patients with early stage lung cancer treated with stereotactic body radiotherapy. MATERIALS AND METHODS: Tumor VDT was calculated using the modified Schwartz formula of exponential growth model and was on the basis of volumes measured on initial diagnostic computed tomography (CT) scans and the planning CT scan. VDT was defined as fast (<100 days), moderate (100-249 days), slow (250-399 days), and no growth (>=400 days). The referral time is the time between the diagnostic CT scan and the radiotherapy planning CT scan. RESULTS: The median referral time was 86 days. The VDT was fast in 53 patients [45%] of tumors. No significant difference in VDT was found between different tumor or patient characteristics. Patients with T1 tumors that progressed to T2 had a significant worse median survival (P = .01). The overall survival at 5 years according to VDT was 21% for fast-growing tumors, 19% for moderate growth, 31% for slow, and 46% for no growth. CONCLUSION: The median referral time was almost 3 months. VDT was considered as fast in almost half of tumors examined. This resulted in significant growth and upstaging in 35% of the tumors, with a significant worse survival if T1 tumors progressed to T2 tumors. Therefore, medically inoperable patients should also be offered a fast workup and referral. PMID- 28571690 TI - The Definition of Healing Depends on How One Defines Health. PMID- 28571691 TI - [Factors associated with the satisfaction of prescribers of blood products in Burkina Faso]. AB - BACKGROUND: The National Blood Transfusion Centre, unique operator of blood transfusion in Burkina Faso is engaged into the quality process according to ISO 9001. Therefore, the assessment of customer satisfaction is a main part of its system. Our study conceives "customer satisfaction" as dependant to the perceived service quality based on SERVQUAL model. OBJECTIVES: To identify factors associated with the satisfaction of blood products prescribers in order to help decision-makers for continuous improvement of services. MATERIAL AND METHODS: We conducted a cross-sectional survey among prescribers of blood components in Ouagadougou, between February 27 and April 30, 2015. We used an anonymous self administered questionnaire, including 13 items associated to the 5 dimensions of SERVQUAL model. The different satisfaction gaps were calculated and linear regression was used to determine statistical associations with a significance level of 5%. RESULTS: The return rate was 94.5% about the 256 questionnaires distributed. A total of 30% of respondents were satisfied to very satisfied. The overall global gap of satisfaction was -5.74. The product delivery time, the efficacy and safety of blood products, the medical and clinical support, the pro activity of the communication, the management of blood products reservation and the satisfaction of needs in blood products were the factors associated with the prescribers' satisfaction. CONCLUSION: This first study in blood transfusion services in our context was been useful to assess customer satisfaction and identify the main axes on which targeting priority actions in order to effectively use available resources. PMID- 28571693 TI - Molecular insights into the multilayered regulation of ADAM17: The role of the extracellular region. AB - In contrast to many other signalling mechanisms shedding of membrane-anchored proteins is an irreversible process. A Disintegrin And Metalloproteinase (ADAM) 17 is one of the major sheddases involved in a variety of physiological and pathophysiological processes including regeneration, differentiation, and cancer progression. Due to its central role in signalling the shedding activity of ADAM17 is tightly regulated, especially on the cell surface, where shedding events take place. The activity of ADAM17 can be subdivided into a catalytic activity and the actual shedding activity. Whereas the catalytic activity is constitutively present, the shedding activity has to be induced and is tightly controlled to prevent pathological situations induced by the release of its substrates. The regulation of the shedding activity of ADAM17 is multilayered and different regions of the protease are involved. Intriguingly, its extracellular domains play crucial roles in different regulatory mechanisms. We will discuss the role of these domains in the control of ADAM17 activity. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John. PMID- 28571694 TI - [French teaching in nephrology: What is the residents' feeling? Results from the first national survey]. PMID- 28571692 TI - Understanding long-term silver release from surface modified porous titanium implants. AB - : Prevention of orthopedic device related infection (ODRI) using antibiotics has met with limited amount of success and is still a big concern during post surgery. As an alternative, use of silver as an antibiotic treatment to prevent surgical infections is being used due to the well-established antimicrobial properties of silver. However, in most cases silver is used in particulate form with wound dressings or with short-term devices such as catheters but not with load-bearing implants. We hypothesize that strongly adherent silver to load bearing implants can offer longer term solution to infection in vivo. Keeping that in mind, the focus of this study was to understand the long term release study of silver ions for a period of minimum 6months from silver coated surface modified porous titanium implants. Implants were fabricated using a LENSTM system, a powder based additive manufacturing technique, with at least 25% volume porosity, with and without TiO2 nanotubes in phosphate buffer saline (pH 7.4) to see if the total release of silver ions is within the toxic limit for human cells. Considering the fact that infection sites may reduce the local pH, silver release was also studied in acetate buffer (pH 5.0) for a period of 4weeks. Along with that, the osseointegrative properties as well as cytotoxicity of porous titanium implants were assessed in vivo for a period of 12weeks using a rat distal femur model. In vivo results indicate that porous titanium implants with silver coating show comparable, if not better, biocompatibility and bonding at the bone-implant interface negating any concerns related to toxicity related to silver to normal cells. The current research is based on our recently patented technology, however focused on understanding longer-term silver release to mitigate infection related problems in load-bearing implants that can even arise several months after the surgery. STATEMENT OF SIGNIFICANCE: Prevention of orthopedic device related infection using antibiotics has met with limited success and is still a big concern during post-surgery. Use of silver as an antibiotic treatment to prevent surgical infections is being explored due to the well-established antimicrobial properties of silver. However, in most cases silver is used in particulate form with wound dressings or with short-term devices such as catheters but not with load-bearing implants. We hypothesize that strongly adherent silver to load-bearing implants can offer longer-term solution towards infection in vivo. Keeping that in mind, the focus of this study was to understand the long-term release of silver ions, for a period of minimum 6months, from silver coated surface modified porous titanium implants. PMID- 28571695 TI - Influenza viruses production: Evaluation of a novel avian cell line DuckCelt(r) T17. AB - The influenza vaccine manufacturing industry is looking for production cell lines that are easily scalable, highly permissive to multiple viruses, and more effective in term of viral productivity. One critical characteristic of such cell lines is their ability to grow in suspension, in serum free conditions and at high cell densities. Influenza virus causing severe epidemics both in human and animals is an important threat to world healthcare. The repetitive apparition of influenza pandemic outbreaks in the last 20years explains that manufacturing sector is still looking for more effective production processes to replace/supplement embryonated egg-based process. Cell-based production strategy, with a focus on avian cell lines, is one of the promising solutions. Three avian cell lines, namely duck EB66(r)cells (Valneva), duck AGE.CR(r) cells (Probiogen) and quail QOR/2E11 cells (Baxter), are now competing with traditional mammalian cell platforms (Vero and MDCK cells) used for influenza vaccine productions and are currently at advance stage of commercial development for the manufacture of influenza vaccines. The DuckCelt(r)-T17 cell line presented in this work is a novel avian cell line developed by Transgene. This cell line was generated from primary embryo duck cells with the constitutive expression of the duck telomerase reverse transcriptase (dTERT). The DuckCelt(r)-T17 cells were able to grow in batch suspension cultures and serum-free conditions up to 6.5*106cell/ml and were easily scaled from 10ml up to 3l bioreactor. In the present study, DuckCelt(r) T17 cell line was tested for its abilities to produce various human, avian and porcine influenza strains. Most of the viral strains were produced at significant infectious titers (>5.8 log TCID50/ml) with optimization of the infection conditions. Human strains H1N1 and H3N2, as well as all the avian strains tested (H5N2, H7N1, H3N8, H11N9, H12N5) were the most efficiently produced with highest titre reached of 9.05 log TCID50/ml for A/Panama/2007/99 influenza H3N2. Porcine strains were also greatly rescued with titres from 4 to 7 log TCID50/ml depending of the subtypes. Interestingly, viral kinetics showed maximal titers reached at 24h post-infection for most of the strains, allowing early harvest time (Time Of Harvest: TOH). The B strains present specific production kinetics with a delay of 24h before reaching the maximal viral particle release. Process optimization on H1N1 2009 human pandemic strain allowed identifying best operating conditions for production (MOI, trypsin concentration, cell density at infection) allowing improving the production level by 2 log. Our results suggest that the DuckCelt(r) T17 cell line is a very promising platform for industrial production of influenza viruses and particularly for avian viral strains. PMID- 28571696 TI - Functional electrical stimulation improves muscle strength and endurance in patients after cardiac surgery: a randomized controlled trial. AB - BACKGROUND: Functional electrical stimulation (FES) has shown benefits in patients with chronic heart failure. Therefore, it is possible that FES can benefit patients similarly after cardiac surgery. OBJECTIVE: This randomized placebo-controlled trial aimed to evaluate the effects of FES on lower limb functional capacity, strength, endurance, and muscle mass after discharge from cardiac surgery. METHODS: Twenty patients were allocated (1:1) to the group receiving FES to the quadriceps (FESG) or FES placebo (FESPG). FES was applied at a frequency of 15Hz, with 0.5ms pulse width, 5s contraction time, and 10s resting time, twice a week for 40min over a period of eight weeks. Functional capacity was assessed using the six-minute walk test (6MWT), lower limb muscle strength using the one repetition maximum test (1RM), endurance using the sit-and-stand test (SST), and muscle using the perimeter of the thighs. RESULTS: Both groups increased the distance covered in the 6MWT (FESG: 49.6m, 95% CI 15.9-83.3; FESPG: 41.5m, 95% CI 7.8-75.2), but without a difference between groups. There were significant between-group differences for quadriceps muscle strength (7.2kg, 95% CI 0.2-14.2) and muscle endurance (2.2 repetitions, 95% CI 1.0-3.4) in favor of the FESG. CONCLUSION: FES improves lower limb muscle strength and endurance in patients after cardiac surgery. Larger trials are needed to confirm our findings. PMID- 28571697 TI - Effects of monochromatic infrared phototherapy in patients with diabetic peripheral neuropathy: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Monochromatic infrared energy (MIRE) or phototherapy has been used to improve plantar sensitivity and pain in lower limbs of patients with diabetic sensorimotor peripheral neuropathy (DSPN), but the available primary results are inconsistent. OBJECTIVE: To review systematically the effects of MIRE on plantar sensitivity and neuropathic pain in patients with DSPN. METHODS: Medline, EMBASE, Cochrane CENTRAL, and Google Scholar were searched up to September 2016. Randomized controlled trials addressing the effects of MIRE on plantar sensitivity and neuropathic pain in patients with DSPN were selected. Study inclusion, risk of bias and quality assessment, and data extraction were completed by two independent reviewers. RESULTS: Of 2549 records identified, six studies met the selection criteria, with 304 patients (594 feet) randomized. MIRE was not associated with improvement in plantar tactile sensitivity (SMD=0.22, 95%CI -0.07 to 0.51, low quality of evidence). Subgroups of studies with short term (up to 2 weeks) follow-up showed significant improvement in plantar sensitivity (SMD=0.41, 95% CI 0.18-0.64). Neuropathic pain increased significantly in patients who received MIRE (MD=0.49, 95% CI 0.30-0.68, low quality of evidence). CONCLUSIONS: There was limited evidence that MIRE results in short-term improvement of tactile sensitivity probably not sustained over time. Limited evidence also suggested that MIRE does not provide relief for neuropathic pain. As quality of evidence is low, further studies are likely to change the estimated effect. PMID- 28571698 TI - A novel antimicrobial peptide against dental-caries-associated bacteria. AB - Dental caries, a highly prevalent oral disease, is primarily caused by pathogenic bacteria infection, and most of them are anaerobic. Herein, we investigated the activity of a designed antimicrobial peptide ZXR-2, and found it showed broad spectrum activity against a variety of Gram-positive and Gram-negative oral bacteria, particularly the caries-related taxa Streptococcus mutans. Time-course killing assays indicated that ZXR-2 killed most bacterial cells within 5 min at 4 * MIC. The mechanism of ZXR-2 involved disruption of cell membranes, as observed by scanning electron microscopy. Moreover, ZXR-2 inhibited the formation of S. mutans biofilm, but showed limited hemolytic effect. Based on its potent antimicrobial activity, rapid killing, and inhibition of S. mutans biofilm formation, ZXR-2 represents a potential therapeutic for the prevention and treatment of dental caries. PMID- 28571699 TI - Acute gastrointestinal bleeding: A slowly changing paradigm. PMID- 28571700 TI - Diabetic retinopathy and dysregulated innate immunity. AB - Diabetic retinopathy (DR) is the progressive degeneration of retinal blood vessels and neurons. Inflammation is known to play an important role in the pathogenesis of DR. During diabetes, metabolic disorder leads to the release of damage-associated molecular patterns (DAMPs) both in the retina and elsewhere in the body. The innate immune system provides the first line of defense against the DAMPs. In the early stages of DR when the blood retinal barrier (BRB) is intact, retinal microglia and the complement system are activated at low levels. This low level of inflammation (para-inflammation) is believed to be essential to maintain homeostasis and restore functionality. However, prolonged stimulation by DAMPs in the diabetic eye leads to maladaptation of the innate immune system and dysregulated para-inflammation may contribute to DR development. In the advanced stages of DR where immune privilege is comprised, circulating immune cells and serum proteins may infiltrate the retina and participate in retinal chronic inflammation and retinal vascular and neuronal damage. This review discusses how the innate immune system is activated in diabetes and DR. The view also discusses why the protective immune response becomes detrimental in DR. PMID- 28571701 TI - Adaptation effects in grasping the Muller-Lyer illusion. AB - Recent results have shown that effects of pictorial illusions in grasping may decrease over the course of an experiment. This can be explained as an effect of sensorimotor learning if we consider a pictorial size illusion as simply a perturbation of visually perceived size. However, some studies have reported very constant illusion effects over trials. In the present paper, we apply an error correction model of adaptation to experimental data of N=40 participants grasping the Muller-Lyer illusion. Specifically, participants grasped targets embedded in incremental and decremental Muller-Lyer illusion displays in (1) the same block in pseudo-randomised order, and (2) separate blocks of only one type of illusion each. Consistent with predictions of our model, we found an effect of interference between the two types when they were presented intermixed, explaining why adaptation rates may vary depending on the experimental design. We also systematically varied the number of object sizes per block, which turned out to have no effect on the rate of adaptation. This was also in accordance with our model. We discuss implications for the illusion literature, and lay out how error correction models can explain perception-action dissociations in some, but not all grasping-of-illusion paradigms in a parsimonious and plausible way, without assuming different illusion effects. PMID- 28571702 TI - Corrigendum to "A reconnaissance analysis of groundwater quality in the Eagle Ford shale region reveals two distinct bromide/chloride populations" [Sci. Total Environ. 575 (2017) 672-680]. PMID- 28571703 TI - Diagnosis of intracranial calcification and hemorrhage in pediatric patients: Comparison of quantitative susceptibility mapping and phase images of susceptibility-weighted imaging. AB - PURPOSE: To prospectively compare the diagnostic capabilities of quantitative susceptibility mapping (QSM) with those of phase images of susceptibility weighted imaging (SWI) in the detection and differentiation of intracranial calcification and hemorrhage in pediatric patients. METHOD: Sixteen pediatric patients (9 girls, 7 boys) with a mean age of 9.4+/-6.3 (SD) years (range, 6 days 15 years) were included. Fifty-nine calcifications and 31 hemorrhages were detected. Sensitivities and specificities of the two magnetic resonance (MR) imaging techniques were calculated and compared using McNemar test. RESULTS: QSM had a sensitivity of 84.7% and specificity of 100% for the detection of calcification. SWI phase images had a sensitivity of 49.1% and specificity of 100%. For the detection of hemorrhage, QSM had a sensitivity of 90.3% and a specificity of 98.3% whereas SWI phase images yielded a sensitivity of 64.5% and specificity of 96.6%. Overall, QSM displayed significantly better sensitivity than SWI phase images in identification of calcification and hemorrhage (P<0.05). CONCLUSION: QSM is more reliable than SWI phase images in the identification of intracranial calcification and hemorrhage in pediatric patients using MR imaging. PMID- 28571704 TI - Percutaneous radiofrequency ablation of lung metastases from colorectal carcinoma under C-arm cone beam CT guidance. AB - PURPOSE: The aim of this study was to assess the feasibility, safety and efficacy of percutaneous radiofrequency ablation of lung metastases from colorectal carcinoma using C-arm cone beam computed tomography (CBCT) guidance. MATERIAL AND METHODS: This single-center prospective observational study was performed from August 2013 to August 2016, and included consecutive patients referred for radiofrequency ablation of lung metastases from colorectal cancer. Radiofrequency ablation procedures were performed under C-arm CBCT guidance. Feasibility was assessed by probe accuracy placement, time to accurate placement and number of C arm CBCT acquisitions to reach the target lesion. Safety was assessed by the report of adverse event graded using the common terminology criteria for adverse events (CTCAE-V4.0). Efficacy was assessed by metastases response rate using RECIST 1.1 and 18FDG-PET-CT tumor uptake at 6months. RESULTS: Fifty-four consecutive patients (32 men, 22 women) with a mean age of 63+/-8 (SD) years (range: 51-81years) with a total of 56 lung metastasis from colorectal metastases were treated in a single session. The mean tumor diameter was 25.6+/-4.5 (SD)mm (range: 17-31mm). Median time to insert the needle into the target lesion was 10min (range: 5-25min). Median number of needles repositioning and C-arm CBCT acquisition per patient was 1 (range: 0-3) and 4 (range: 3-6) respectively. The accuracy for radiofrequency ablation probe placement was 2+/-0.2 (SD)mm (range: 0 9mm). Pneumothorax requiring chest tube placement occurred in one patient (CTCAE V4.0 grade 3). At 6months, all patients were alive with tumor response rate of 27% and had no significant activity on the 18FDG-PET CT follow-up. CONCLUSION: Percutaneous radiofrequency ablation of lung metastases from colorectal cancer under C-arm CBCT guidance is feasible and safe, with immediate and short-term results similar to those obtained using conventional CT guidance. PMID- 28571705 TI - Factors affecting fracture location in atypical femoral fractures: A cross sectional study with 147 patients. AB - INTRODUCTION: Many studies have tried to determine the characteristics of atypical femoral fractures (AFFs) through age-, sex-, and ethnicity-matched comparison with non-AFFs. However, we hypothesized that diaphyseal AFFs would have characteristics different from those of subtrochanteric AFFs. The aim of this study was to evaluate the clinical features of diaphyseal/subtrochanteric AFFs and determine the factors related to fracture location. PATIENTS AND METHODS: One hundred forty-seven patients with AFF were enrolled, 114 patients (78%) had a history of bisphosphonate use. Forty-nine patients (33%) had bilateral lesion, and 35% of patients had thigh pain. Patients were divided into two groups according to fracture location: 52 patients (35.4%) with subtrochanteric AFF and 95 patients (64.6%) with diaphyseal AFF. The patient demographics and fracture characteristics of the two groups were compared. Multivariate logistic regression analysis was used to adjust for variables related to fracture location. RESULTS: The patients in the diaphyseal AFFs group were older and had lower BMI, lower BMD, and larger lateral and anterior bowing. Multivariate analysis revealed that age greater than 65 years and low BMD were related with diaphyseal location. With greater lateral bowing angle, the AFF location was moved from the subtrochanteric area to the diaphyseal area. CONCLUSION: This study demonstrated that patients with diaphyseal AFFs had different characteristics compared with those with subtrochanteric AFFs. PMID- 28571706 TI - Lactated Ringer-based storage solutions are equally well suited for the storage of fresh osteochondral allografts as cell culture medium-based storage solutions. AB - BACKGROUND: Due to the rising interest in Europe to treat large cartilage defects with osteochondrale allografts, research aims to find a suitable solution for long-term storage of osteochondral allografts. This is further encouraged by the fact that legal restrictions currently limit the use of the ingredients from animal or human sources that are being used in other regions of the world (e.g. in the USA). Therefore, the aim of this study was A) to analyze if a Lactated Ringer (LR) based solution is as efficient as a Dulbecco modified Eagle's minimal essential medium (DMEM) in maintaining chondrocyte viability and B) at which storage temperature (4 degrees C vs. 37 degrees C) chondrocyte survival of the osteochondral allograft is optimally sustained. METHODS: 300 cartilage grafts were collected from knees of ten one year-old Black Head German Sheep. The grafts were stored in four different storage solutions (one of them DMEM-based, the other three based on Lactated Ringer Solution), at two different temperatures (4 and 37 degrees C) for 14 and 56days. At both points in time, chondrocyte survival as well as death rate, Glycosaminoglycan (GAG) content, and Hydroxyproline (HP) concentration were measured and compared between the grafts stored in the different solutions and at the different temperatures. RESULTS: Independent of the storage solutions tested, chondrocyte survival rates were higher when stored at 4 degrees C compared to storage at 37 degrees C both after short-term (14days) and long-term storage (56days). At no point in time did the DMEM-based solution show a superior chondrocyte survival compared to lactated Ringer based solution. GAG and HP content were comparable across all time points, temperatures and solutions. CONCLUSION: LR based solutions that contain only substances that are approved in Germany may be just as efficient for storing grafts as the USA DMEM based solution gold standard. Moreover, in the present experiment storage of osteochondral allografts at 4 degrees C was superior to storage at 37 degrees C. PMID- 28571707 TI - Intraoperative MRI for the management of brain lesions adjacent to eloquent areas. AB - BACKGROUND: The aim of our study was to report the usefulness of intraoperative MRI guidance in the resection of brain lesions adjacent to eloquent areas. PATIENTS AND METHODS: A single center prospective series of gliomas amenable to optimized resection with intraoperative MRI between September 2014 and December 2015. RESULTS: The study included 56 patients. The median duration of the first intraoperative MRI was 38min, interquartile range (IQR 30-46). Fourteen patients (40%) underwent a second intraoperative MRI, which had a median duration of 26min (IQR, 18-30). The median total operative time was 265min (IQR, 242-337). After the first intraoperative MRI, the median residual glioma volume of the 35 gliomas adjacent to eloquent areas was 7.04cm3 (IQR, 2.22-13.8), which did not significantly differ from the other gliomas (P=0.07). After the second intraoperative MRI, the median residual glioma volume was 3.86cm3 (IQR, 0.82 6.99), which did not significantly differ from the other patients (P=0.700). On the postoperative MRI, the median extent of the glioma resections adjacent to eloquent areas was 99.78% (IQR, 88.9-100), which was not significantly different from the rest of the population (P=0.290). At 6 months after surgery, the median Karnofsky Performance Score was 90, and 2.8% of the patients presented a permanent new neurological deficit. CONCLUSION: Our results suggest that intraoperative MRI is an effective and safe technique to improve the extent of brain lesion resections close to eloquent areas. PMID- 28571708 TI - Quality assurance of the jaws only-intensity modulated radiation therapy plans for head-and-neck cancer. AB - Intensity-modulated radiation therapy (IMRT) is a treatment technique which has become routine in developed countries. In most centers this technique is delivered with multi-leaf collimators (MLCs). However, the use of MLCs is not mandatory. Several oncology centres in developing countries are still using linear accelerators (LINAC) without MLCs, and can potentially deliver IMRT plans with the use of collimator jaws. In this report, we present the results of quality assurance of this Jaws-Only-IMRT (JO-IMRT) technique in treating nasopharyngeal carcinoma (NPC) patients. Twenty-five plans of nasopharyngeal patients were randomly chosen. For each patient, a JO-IMRT plan was generated and a series of pre-treatment verification measurements was performed including (1) point dose measurement with an ionization chamber, (2) planar dose measurement with a 2D-array detector and (3) 3-dimensional dose measurement using a rotatable phantom with a 2D-array detector. The average differences between the measured and TPS-calculated point doses were found to be 1.26+/-0.77%, which is within the institution's dose constraint limits. For the planar dose and 3D dose measurements, the average gamma index based on 3%/3mm criteria were 96.77+/-2.33% and 94.72+/-2.67%, respectively. Our measurements showed that the JO-IMRT treatment plans applied to the H&N patients were accurate for the treatment delivery based on our established pass criteria. PMID- 28571711 TI - Reply. PMID- 28571710 TI - Identification of odorant binding proteins in Carpomya vesuviana and their binding affinity to the male-borne semiochemicals and host plant volatiles. AB - Carpomya vesuviana (Costa; Diptera: Tephritidae) is an agricultural pest that causes serious damage to jujube fruits. However, the mechanism of olfaction, which is critical for host identification, is not well understood in this pest. In this study, we have identified for the first time five protein types involved in the olfactory signal transduction of C. vesuviana by using transcriptome sequencing. These include 6 odorant-binding proteins (OBPs), 15 odorant receptors (ORs), 22 gustatory receptors (GRs), 2 chemosensory proteins (CSPs), and 2 sensory neuron membrane proteins (SNMPs). Amino acids alignment and phylogenetic analysis showed that all 6 OBPs have a signal peptide at their respective N termini with four OBPs belonging with the classic OBPs, and OBP2 and OBP5 belonging to the Minus-C family. OBP3 clustered with the OBP83a/83b clade, which comprised pheromone binding protein related proteins (PBPRPs). Moreover, volatiles from C. vesuviana adults and its host plants were collected and identified by using solid phase microextraction (SPME) and gas chromatography/mass spectrometry (GC/MS). The results indicated that male adults emitted nonanal, and five other compounds, caryophyllene, chamigrene, camphene, (Z)-3-hexen-1-ol acetate, and ocimene were identified in the fruits of jujubes. Electroantennogram (EAG) assays revealed that adult C. vesuviana responded to all six compounds along with two additional pheromones (geranyl acetate and alpha farnesene) from other tephritids and the values ranged from 0.50mV to 1.26mV. To further explore the interaction between OBPs and volatiles, competitive binding assays were carried out. The results showed that only CvesOBP2 had binding affinity to (Z)-3-hexen-1-ol acetate. OBP5 and OBP6 exhibited broad spectrum binding to compounds with relatively low molecular weights, and OBP1 and OBP4 had some affinity to caryophyllene and chamigrene. However, OBP3 exhibited relatively high binding affinity to alpha-farnesene. The findings of this study provide insights into the olfactory mechanisms and the potential functions of OBPs in the olfactory reception pathway in C. vesuviana. The OBPs identified in this study could be used as potential targets to develop attractants to monitor this insect pest for effective pest control. PMID- 28571709 TI - Phospho-specific antibodies targeting the amino terminus of the human dopamine transporter. AB - The dopamine transporter (DAT), which mediates the inactivation of released dopamine through its reuptake, is the primary molecular target for the actions of psychostimulants. An increasing number of studies support an essential role for phosphorylation of serines (Ser) in the distal amino (N) terminus of DAT in regulating its function. Still, the molecular details of the regulation of phosphorylation and its impact on function are not fully understood. To address this, we have developed and characterized two distinct phospho-antibodies that recognize human DAT when it is phosphorylated at Ser7 or Ser12. Our data show that treatment of cells with phorbol 12-myristate 13-acetate (PMA), amphetamine (AMPH) or okadaic acid (OA) leads to an increase in the phosphorylation of DAT at both residues and that these responses are dependent on the activity of protein kinase C. We also show that AMPH-induced and OA-induced phosphorylation of DAT are dependent on Ca2+/calmodulin-dependent protein kinase alpha. Our data further suggest that the lipid raft localization of DAT is necessary for efficient N terminal phosphorylation and for the associated behavioral effects of AMPH, demonstrating the potential of these novel antibodies as powerful tools to study DAT regulation and function in vivo. PMID- 28571712 TI - Effects of weight loss on adipose visceral and subcutaneous tissue in overweight adults. AB - BACKGROUND & AIMS: Weight loss is an important strategy for mitigating the complications of obesity. However, weight reduction does not provide detailed information on relative changes in bodily behaviors and in abdominal fat deposits (adipose visceral tissue (AVT) and adipose subcutaneous tissue (AST)). The aim of this study was to evaluate the effect of weight loss based on calorie restriction on AVT and AST in overweight individuals (1); to verify the metabolic benefits resulting from AVT reduction (2); and to the analyze the influence of covariates in AVT and AST reduction (3). METHODS: Clinical intervention study involving overweight adult patients, seen at a public hospital in the Northeast of Brazil, who underwent three months of calorie restriction. AVT and AST were quantified using computed tomography at the baseline and at the end of a follow up. RESULTS: 51 patients were evaluated (50.2 +/- 11.3 years old), for whom it was verified that a 5.8(+/-6.2)% weight reduction in the men resulted in a 11.2(+/-7.9)% reduction in AVT and 6.8(+/-11.2)% in AST. Among the women, a 4.1(+/-2.5)% reduction in initial weight resulted in a 11.1(+/-8.8)% decrease in AVT and 5.6(+/-7.4)% in AST. Simple linear regression showed that a reduction in AVT caused a 54.9% reduction in triglyceride concentrations in the men and a 12.2% reduction in cholesterol and 31.4% in triglyceride levels in women. Multiple regression identified different factors that influenced the reduction in visceral and subcutaneous fat. The predictive models explained 42.9% and 54.8% of the AVT reduction in the females and males, respectively; and 39.9% and 86.7% of the AST reduction in the females and males, respectively. CONCLUSIONS: A modest 5% weight loss caused substantial AVT and AST mobilization, with potential benefits to cardiometabolic profile. PMID- 28571713 TI - Protein-enriched familiar foods and drinks improve protein intake of hospitalized older patients: A randomized controlled trial. AB - BACKGROUND & AIMS: Adequate protein intake is important in preventing and treating undernutrition. Hospitalized older patients are recommended to consume 1.2-1.5 g of protein per kg body weight per day (g/kg/d) but most of them fail to do so. Therefore, we investigated whether a range of newly developed protein enriched familiar foods and drinks were effective in increasing protein intake of hospitalized older patients. METHODS: This randomized controlled trial involved 147 patients of >=65 years (mean age: 78.5 +/- 7.4 years). The control group (n = 80) received the standard energy and protein rich hospital menu. The intervention group (n = 67) received the same menu with various protein-enriched intervention products replacing regular products or added to the menu. Macronutrient intake on the fourth day of hospitalization, based on food ordering data, was compared between the two groups by using Independent T-tests and Mann Whitney U-tests. RESULTS: In the intervention group 30% of total protein was provided by the intervention products. The intervention group consumed 105.7 +/- 34.2 g protein compared to 88.2 +/- 24.4 g in the control group (p < 0.01); corresponding with 1.5 vs 1.2 g/kg/d (p < 0.01). More patients in the intervention group than in the control group reached a protein intake of 1.2 g/kg/d (79.1% vs 47.5%). Protein intake was significantly higher in the intervention group at breakfast, during the morning between breakfast and lunch, and at dinner. CONCLUSIONS: This study shows that providing protein-enriched familiar foods and drinks, as replacement of regular products or as additions to the hospital menu, better enables hospitalized older patients to reach protein intake recommendations. This trial is registered on ClinicalTrials.gov, Identifier: NCT02213393. PMID- 28571716 TI - Post-translational dysfunctions in channelopathies of the nervous system. AB - Channelopathies comprise various diseases caused by defects of ion channels. Modifications of their biophysical properties are common and have been widely studied. However, ion channels are heterogeneous multi-molecular complexes that are extensively modulated and undergo a maturation process comprising numerous steps of structural modifications and intracellular trafficking. Perturbations of these processes can give rise to aberrant channels that cause pathologies. Here we review channelopathies of the nervous system associated with dysfunctions at the post-translational level (folding, trafficking, degradation, subcellular localization, interactions with associated proteins and structural post translational modifications). We briefly outline the physiology of ion channels' maturation and discuss examples of defective mechanisms, focusing in particular on voltage-gated sodium channels, which are implicated in numerous neurological disorders. We also shortly introduce possible strategies to develop therapeutic approaches that target these processes. This article is part of the Special Issue entitled 'Channelopathies.' PMID- 28571717 TI - Mysticism in the history of mathematics. AB - We examine the relationship between mysticism and mathematical creativity through case studies from the history of mathematics. PMID- 28571715 TI - The novel multitarget iron chelating and propargylamine drug M30 affects APP regulation and processing activities in Alzheimer's disease models. AB - In many of the neurodegenerative diseases, such as Alzheimer's disease (AD) and AD-related disorders, as well as in the regular ageing process, excessive generation of oxidative stress (OS) and accumulation of iron levels and deposition have been observed in specific affected-brain regions and thus, regarded as contributing factors to the pathogenesis of the diseases. In AD, iron promotes amyloid beta (Abeta) neurotoxicity by producing free radical damage and OS in brain areas affected by neurodegeneration, presumably by facilitating the aggregation of Abeta. In addition, it was shown that iron modulates intracellular levels of the holo amyloid precursor protein (APP) by iron-responsive elements (IRE) RNA stem loops in the 5' untranslated region (5'UTR) of the APP transcript. As a consequence of these observations, iron chelation is one of the major new therapeutic strategies for the treatment of AD. This review describes the benefits and importance of the multimodal brain permeable chimeric iron chelating/propargylamine drug M30, concerning its neuroprotective/neurorestorative inter-related activities relevant of the pathological features ascribed to AD, with a special focus on the effect of the drug on APP regulation and processing. PMID- 28571718 TI - Effects of simulated ischemia on the transmural differences in the Frank-Starling relationship in isolated mouse ventricular cardiomyocytes. AB - The electrical and mechanical functions of cardiomyocytes differ in relation to the spatial locations of cells in the ventricular wall. This physiological heterogeneity may change under pathophysiological conditions, providing substrates for arrhythmia and contractile dysfunctions. Previous studies have reported distinctions in the electrophysiological and mechanical responses to ischemia of unloaded subendocardial (ENDO) and subepicardial (EPI) single cardiomyocytes. In this paper, we briefly recapitulated the available experimental data on the ischemia effects on the transmural cellular gradient in the heart ventricles and for the first time evaluated the preload-dependent changes in passive and active forces in ENDO and EPI cardiomyocytes isolated from mouse hearts subjected to simulated ischemia. Combining the results obtained in mechanically loaded contracting cardiomyocytes with data from previous studies, we showed that left ventricular ENDO and EPI cardiomyocytes are different in their mechanical responses to metabolic inhibition. Simulated ischemia showed opposite effects on the stiffness of ENDO and EPI cells and greatly prolonged the time course of contraction in EPI cells than in ENDO cells, thereby changing the normal transmural gradient in the cellular mechanics. PMID- 28571719 TI - Blockade of chondroitin sulfate proteoglycans-induced axonal growth inhibition by LOTUS. AB - Chondroitin sulfate proteoglycans (CSPGs) are axon growth inhibitors in the glial scar, and restrict axon regeneration following damage to the adult mammalian central nervous system. CSPGs have recently been identified as functional ligands for Nogo receptor-1 (NgR1), which is the common receptor for Nogo proteins, myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp) and B lymphocyte stimulator (BLyS). We have previously reported that through its binding to NgR1, lateral olfactory tract usher substance (LOTUS) suppresses Nogo, MAG, OMgp, and BLyS-induced axon growth inhibition. However, it remains unknown whether LOTUS also exerts this suppressive action on CSPG-induced axon growth inhibition. LOTUS overexpression rescued CSPG-induced growth cone collapse and neurite outgrowth inhibition in cultured dorsal root ganglion neurons, which only weakly express endogenous LOTUS. In cultured olfactory bulb neurons, which endogenously express LOTUS, the growth cone was insensitive to CSPG-induced collapse, but was sensitive to collapse induced by CSPGs in lotus-deficient mice. Our data demonstrate that LOTUS suppresses CSPG-induced axon growth inhibition, suggesting that LOTUS may represent a promising therapeutic agent for promoting axon regeneration. PMID- 28571714 TI - L-Tyrosine availability affects basal and stimulated catecholamine indices in prefrontal cortex and striatum of the rat. AB - We previously found that L-tyrosine (L-TYR) but not D-TYR administered by reverse dialysis elevated catecholamine synthesis in vivo in medial prefrontal cortex (MPFC) and striatum of the rat (Brodnik et al., 2012). We now report L-TYR effects on extracellular levels of catecholamines and their metabolites. In MPFC, reverse dialysis of L-TYR elevated in vivo levels of dihydroxyphenylacetic acid (DOPAC) (L-TYR 250-1000 MUM), homovanillic acid (HVA) (L-TYR 1000 MUM) and 3 methoxy-4-hydroxyphenylglycol (MHPG) (L-TYR 500-1000 MUM). In striatum L-TYR 250 MUM elevated DOPAC. We also examined L-TYR effects on extracellular dopamine (DA) and norepinephrine (NE) levels during two 30 min pulses (P2 and P1) of K+ (37.5 mM) separated by t = 2.0 h. L-TYR significantly elevated the ratio P2/P1 for DA (L-TYR 125 MUM) and NE (L-TYR 125-250 MUM) in MPFC but lowered P2/P1 for DA (L TYR 250 MUM) in striatum. Finally, we measured DA levels in brain slices using ex vivo voltammetry. Perfusion with L-TYR (12.5-50 MUM) dose-dependently elevated stimulated DA levels in striatum. In all the above studies, D-TYR had no effect. We conclude that acute increases within the physiological range of L-TYR levels can increase catecholamine metabolism and efflux in MPFC and striatum. Chronically, such repeated increases in L-TYR availability could induce adaptive changes in catecholamine transmission while amplifying the metabolic cost of catecholamine synthesis and degradation. This has implications for neuropsychiatric conditions in which neurotoxicity and/or disordered L-TYR transport have been implicated. PMID- 28571720 TI - Astrocytes in Memory Function: Pioneering Findings and Future Directions. AB - Astrocytes have been generally believed to perform mainly homeostatic and supportive functions for neurons in the central nervous system. Recently, a growing body of evidence suggests previously unrecognized and surprising functions for astrocytes, including regulation of synaptic formation, transmission and plasticity, all of which are considered as the infrastructure for information processing and memory formation and stabilization. This review discusses the involvement of astrocytes in memory functions and the possible mechanisms that may underlie it. We review the important breakthroughs obtained in this field, as well as some of the controversies that arose from the past difficulty to manipulate these cells in a cell type-specific and non-invasive manner. Finally, we present new research avenues based on the advanced tools becoming available in recent years: optogenetics and chemogenetics, and the potential ways in which these tools may further illuminate the role of astrocytes in memory processes. PMID- 28571721 TI - Transcriptome Analysis Revealed Impaired cAMP Responsiveness in PHF21A-Deficient Human Cells. AB - Potocki-Shaffer Syndrome is a rare neurodevelopmental syndrome associated with microdeletion of a region of Chromosome 11p11.2. Genetic evidence has implicated haploinsufficiency of PHF21A, a gene that encodes a histone-binding protein, as the likely cause of intellectual disability and craniofacial abnormalities in Potocki-Shaffer Syndrome. However, the molecular consequences of reduced PHF21A expression remain elusive. In this study, we analyzed by RNA-Sequencing (RNA-Seq) two patient-derived cell lines with heterozygous loss of PHF21A compared to unaffected individuals and identified 1,885 genes that were commonly misregulated. The patient cells displayed down-regulation of key pathways relevant to learning and memory, including Cyclic Adenosine Monophosphate (cAMP) signaling pathway genes. We found that PHF21A is required for full induction of a luciferase reporter carrying cAMP-responsive elements (CRE) following stimulation by the cAMP analog, forskolin. Finally, PHF21A-deficient patient-derived cells exhibited a delayed induction of immediate early genes following forskolin stimulation. These results suggest that an impaired response to cAMP signaling might be involved in the pathology of PHF21A deficiency. This article is part of a Special Issue entitled: [SI: Molecules & Cognition]. PMID- 28571722 TI - Arthroscopic Reconstruction of Segmental Defects of the Hip Labrum: Results in 22 Patients With Mean 2-Year Follow-Up. AB - PURPOSE: To report mean 2-year patient-reported outcomes (PROs) and the incidence of revision hip arthroscopy or conversion to total hip arthroplasty (THA) in patients who had undergone arthroscopic reconstruction of the hip labrum for segmental defects. METHODS: Data were prospectively collected and retrospectively reviewed on all patients who had undergone hip arthroscopy from April 2008 to April 2013. All patients who underwent arthroscopic labral reconstruction with either a semitendinosus allograft or a gracilis autograft with mean 2-year follow up were part of the inclusion criteria. The following outcomes were recorded: modified Harris hip score, nonarthritic athletic hip score, hip outcome score sports-specific subscale, hip outcome score-activities of daily living subscale, visual analog scale, for pain, patient satisfaction, revision hip arthroscopies, and conversion to THA. A 2-tailed Student's t-test was used to assess for statistically significant differences between the mean of preoperative and postoperative PROs. P values less than .05 were considered statistically significant. RESULTS: A total of 22 patients (14 females, 8 males) met the inclusion criteria. There was 100% follow-up. The mean age of the study population was 32.2 years. Twelve patients had reconstruction as part of a revision procedure and 10 patients had a reconstruction at the time of primary arthroscopy. Concomitant arthroscopic procedures included acetabuloplasty and femoroplasty. There was statistically significant improvement in all PROs (P = .013 to < .001). The mean changes for the modified Harris hip score, nonarthritic athletic hip score, hip outcome score-sports-specific subscale, and hip outcome score-activities of daily living subscale were 11.0 +/- 19.5, 22.2 +/- 15.0, 23.1 +/- 30.9, and 19.1 +/- 17.5 points, respectively. The mean improvement in the visual analog scale was 3.33 +/- 2.92 points (P < .001), and the mean patient satisfaction was 6.73 out of 10 points. One patient required conversion to THA for presumed progression of osteoarthritis and 2 patients required a revision procedure for adhesions. CONCLUSIONS: This arthroscopic technique for labral reconstruction was associated with a significant improvement in PROs and function. Conversion to THA with the procedure was 4.5%. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28571723 TI - Opioid Consumption After Rotator Cuff Repair. AB - PURPOSE: Rising perioperative opioid use in the United States is of increasing concern. The purposes of this study were (1) to define opioid consumption after rotator cuff repair (RCR) in the United States and (2) to evaluate patient factors that may be associated with prolonged opioid use after arthroscopic RCR. METHODS: All arthroscopic RCRs performed between 2007 and 2014 were identified by use of Current Procedural Terminology code (29,827). Patients who filled opioid prescriptions preoperatively were divided into those who filled prescriptions at 1 to 3 months preceding RCR and those who filled opioid prescriptions only in the 1 month preceding RCR. Risk ratios (RRs) were calculated by dividing the cumulative incidence of opioid prescriptions in patients with each patient factor by the cumulative incidence in those without each patient factor. RESULTS: During the study period, 35,155 arthroscopic RCRs were performed. Of the patients, approximately 43% had filled an opioid prescription in the 3 months before RCR. At 3 months after RCR, patients who filled opioid prescriptions at 1 to 3 months before RCR were 7.45 (95% confidence interval [CI], 6.95-7.98) times more likely to be filling opioid medication prescriptions than those who had not been prescribed opioid medications before surgery; patients who filled opioid prescriptions in the month before RCR were 3.04 (95% CI, 2.8-3.29) times more likely to be filling opioid prescriptions at 3 months after RCR. Patients with psychiatric diagnoses (RR, 1.94; 95% CI, 1.85-2.04), myalgia (RR, 1.67; 95% CI, 1.6-1.75), and low-back pain (RR, 2.09; 95% CI, 2-2.2) were also found to be at risk of filling opioid prescriptions at 3 months postoperatively. CONCLUSIONS: We found approximately 43% of patients undergoing RCR received opioid medications before RCR. Patients who are prescribed narcotics before RCR are at increased risk of postoperative opioid demand. Patients with psychiatric diagnoses, myalgia, and low-back pain may be at increased risk of prolonged opioid use after surgery. LEVEL OF EVIDENCE: Level III, retrospective case-control study. PMID- 28571724 TI - Premenstrual disorders. AB - Premenstrual disorders include premenstrual syndrome, premenstrual dysphoric disorder, and premenstrual worsening of another medical condition. While the underlying causes of these conditions continue to be explored, an aberrant response to hormonal fluctuations that occurs with the natural menstrual cycle and serotonin deficits have both been implicated. A careful medical history and daily symptom monitoring across 2 menstrual cycles is important in establishing a diagnosis. Many treatments have been evaluated for the management of premenstrual disorders. The most efficacious treatments for premenstrual syndrome and premenstrual dysphoric disorder include serotonin reuptake inhibitors and contraceptives with shortened to no hormone-free interval. Women who do not respond to these and other interventions may benefit from gonadotropin-releasing hormone agonist treatment. PMID- 28571725 TI - The scapular dyskinesis test: Reliability, agreement, and predictive value in patients with subacromial impingement syndrome. AB - STUDY DESIGN: Prospective cohort. INTRODUCTION: Assessment of scapular dysfunction is considered important in the clinical evaluation and treatment of patients with symptoms of subacromial impingement. However, sparse research has been conducted into the reliability and predictive value of clinical tests with which to identify scapular dyskinesis. PURPOSE OF THE STUDY: To evaluate intrarater and interrater reliability and predictive value of the Scapular Dyskinesis Test (SDT) in patients with subacromial impingement syndrome. METHODS: Forty-five patients with subacromial impingement syndrome were included. The presence of scapular dyskinesis was classified by 2 raters using the SDT. Intrarater and interrater reliabilities were examined and compared. Patients with and without scapular dyskinesis were compared in terms of Oxford Shoulder Score and EQ-5D-5L scores at baseline and 3 months, as well rating of overall improvement in shoulder condition. RESULTS: SDT could not be performed in 5 patients, leaving 40 patients for further analysis. Kappa with squared weights was 0.64 for rater A and 0.86 for rater B; the intrarater agreement was 88% for A and 96% for B. For interrater comparison, the Kappa value was 0.59 and agreement 86%. No statically significant differences in Oxford Shoulder Score and EQ-5D-5L baseline and change scores or overall improvement in shoulder condition at 3 months were observed between patients with or without scapular dyskinesis. CONCLUSIONS: Intrarater and interrater reliability and agreement of the SDT were determined. The findings that functional impairment and outcomes did not differ between patients with or without the presences of scapular dyskinesis may question the clinical value of the SDT in patients with subacromial impingement syndrome. LEVEL OF EVIDENCE: 1b. PMID- 28571726 TI - Anti-tumor effect of Scutellaria barbata D. Don extracts on ovarian cancer and its phytochemicals characterisation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria barbata D. Don is a widely used medicinal herb in China. It possess various medicinal properties including antioxidative, anti-inflammatory and anti-cancer effects. The aim of this study was to explore whether Scutellaria barbata D. Don could inhibit the growth of ovarian cancer cells in vitro and further investigate the underlying mechanisms. MATERIALS AND METHODS: Effects of Scutellaria barbata D. Don on the viability of ovarian cancer A2780 cells were measured by MTT assay. Apoptosis was measured by cell morphologic observation through DAPI staining and Annexin V-FITC staining assay for apoptosis analysis. The migration of ovarian cancer cells which exposed to Scutellaria barbata D. Don were measured by wound healing and transwell chamber assays. The protein levels of caspase 3/9, Bcl-2 and MMP-2/9 in human ovarian cancer cells treated with Scutellaria barbata D. Don were assessed by western blotting analysis. The potential bioactive compounds were characterized by HPLC-Q-TOF-MS. RESULTS: The present study was to investigate the anticancer effects of crude extracts from Scutellaria barbata D. Don on ovarian cancer A2780 cells by MTT, DAPI staining, wound healing assay, transwell migration assay and western blotting analysis. Our study showed that Scutellaria barbata D. Don reduced the viability of A2780 cells and induced apoptosis by down-regulated Bcl 2 protein and increased Caspase 3/9 proteins. Furthermore, migration of A2780 cells were significantly inhibited by Scutellaria barbata D. Don and the underlying mechanism may be related to the decrease of MMP-2/9. The main constituents from Scutellaria barbata D. Don were identified to be thirteen flavonoids. A HPLC-Q-TOF-MS analysis of Scutellaria barbata D. Don indicated the presence of 14 flavonoids compounds, which may contribute to the anticancer activity of the Scutellaria barbata D. Don. CONCLUSIONS: Scutellaria barbata D. Don could inhibit proliferation and induce apoptosis in A2780 cells through mitochondrial pathway. Moreover, the inhibitory effect of Scutellaria barbata D. Don on the migration of ovarian cancer cells was associated with the down regulation of MMP-2/9 expression. These findings could shed a light on the therapy of ovarian cancer. PMID- 28571727 TI - Efficacy of Mentha pulegium extract in the treatment of functional dyspepsia: A randomized double-blind placebo-controlled clinical trial. AB - ETHNOPHARMACOLOGICAL EVIDENCE: Mentha pulegium L. leaves are used in the Iranian traditional medicine for the treatment of functional dyspepsia. AIM OF STUDY: To study the efficacy and safety of M. pulegium in the treatment of functional dyspepsia patients fulfilling the Rome III criteria. MATERIALS AND METHODS: The efficacy and safety of a standardized Mentha pulegium leaf extract (drug extract ratio: 15.9:1, extraction solvent: 70% v/v aqueous ethanol) (330mg three times daily taken for 2 months) as add-on to one famotidine 40mg tablet per day in the treatment of 50 functional dyspepsia patients were compared with those of a parallel placebo group (n =50). RESULTS: The extract significantly decreased the total dyspepsia score measured by the Hong Kong dyspepsia index compared to the placebo and baseline (P=0.011 and P<0.001 respectively). The stomach pain, upper abdominal bloating, upper abdominal dull ache, belching and total dyspepsia scores were decreased from baseline in the extract group significantly compared to the placebo (P<0.001, P<0.001, P=0.003, P<0.001 and P<0.001 respectively). However, the decreases of other dyspepsia symptoms scores from baseline in the extract group were not significant compared to the placebo (P>0.05). The extract improved the quality of life measured by the SF-36 questionnaire significantly compared to the placebo and baseline (P=0.003 and P<0.001 respectively). Moreover, the extract lowered the rate of H. pylori infection determined by the urease test significantly compared to the placebo and baseline (P=0.001 and P<0.001 respectively). The extract did not significantly affect the complete blood count and liver and kidney function tests (P>0.05). The patients did not experience any adverse drug effect. CONCLUSIONS: M. pulegium extract (genuine drug extract ratio: 19.4:1; extraction solvent: 70% v/v aqueous ethanol) 270mg three times daily taken for 2 months as adjunct to one famotidine 40mg tablet per day seems safe, improves dyspeptic symptoms and quality of life and eradicates H. pylori in functional dyspepsia patients. PMID- 28571728 TI - Light source is critical to induce glioblastoma cell death by photodynamic therapy using chloro-aluminiumphtalocyanine albumin-based nanoparticles. AB - Selection of an efficient light source is fundamental in the development of photodynamic therapy (PDT) protocols. However, few studies provide a comparison of different light sources with regard to phototoxic effects. Here, we compared the cell death induced by photoactivation of chloro-aluminiumphtalocyanine (AlClPc)-loaded human serum albumin nanoparticles under irradiation with different light sources: continuous laser (CL), pulsed laser (PL), and light emitting diode (LED). Cells were exposed to three different AlClPc concentrations (1, 3, and 5MUM) and three different light doses (200, 500, and 700mJ/cm2) for each light source. Cell death and differentiation of apoptosis and necrosis pathway were measured by flow cytometry. CL was the best light source for improving the photodynamic action of AlClPc-loaded albumin nanoparticles in glioblastoma cells and avoiding undesirable side effects, especially at low photosensitizer doses (200mJ/cm2). In addition, apoptosis was the main cell death pathway in all evaluated cases (70% for CL, and greater than 50% for PL and LED). In conclusion, the search for optimal light sources and light/photosensitizer doses is a crucial step in improving PDT outcomes and enhancing the clinical translation of PDT. PMID- 28571729 TI - Corrigendum to "Non-Invasive Lung Impedance-Guided Preemptive Treatment in Chronic Heart Failure Patients: A Randomized Controlled Trial (Impedance-HF Trial)": Journal of Cardiac Failure Vol. 22 No. 9, pp. 713-722. PMID- 28571730 TI - Serum Neuronal Biomarkers in Neonates With Congenital Heart Disease Undergoing Cardiac Surgery. AB - BACKGROUND: Newborns with congenital heart disease have associated brain damage that affects short-and long-term neurodevelopment. Several neuronal biomarkers exist that could predict brain damage. We investigated the pattern of neuron specific enolase (NSE) and s100B levels after cardiopulmonary bypass surgery in neonates with congenital heart disease. METHODS: We completed a prospective observational study of neonates with congenital heart disease who were undergoing cardiopulmonary bypass surgery. NSE and s100B levels were measured from serum samples obtained preoperatively, immediately postoperatively, and once daily on postoperative days one to seven. Cranial ultrasounds were obtained preoperatively and postoperatively and findings were scored using an internally developed scoring system. RESULTS: Eighteen neonates were included. Immediate postoperative and peak levels of both NSE (58.0 [21.6] and 68.1 [55.7] MUg/L) and s100B (0.14 [0.3] and 0.14 [0.3] MUg/L) were significantly increased when compared with preoperative levels (34.0 [21.6] MUg/L; P < 0.01 and 0.08 [0.1] MUg/L; P < 0.02). By postoperative day seven, NSE and s100B levels were lower than preoperative levels: NSE (18 [5.7]; P = 0.09) and s100B (0.03 [0.05]; P < 0.01). Postoperative s100B levels were negatively correlated with age at surgery and positively correlated with circulatory arrest time. Although there was no significant correlation between either NSE or s100B levels and intensive care unit length of stay, hospital length of stay, and pediatric cerebral performance category score, there was a negative correlation between postoperative levels of NSE and ventriculomegaly. CONCLUSIONS: NSE and s100B levels increase after bypass surgery and return below preoperative baseline levels by postoperative day seven. The levels of s100B were positively correlated with circulatory arrest time and negatively correlated with age at time of surgery. This finding may be supportive of pre-existing prenatal brain injury that could be enhanced by longer surgical times but also of some brain protection effect associated with longer wait until surgery. PMID- 28571731 TI - Epigenetic therapies, still in the midway between facts and fiction. PMID- 28571732 TI - Editorial Comment. PMID- 28571733 TI - Editorial Comment. PMID- 28571734 TI - Author Reply. PMID- 28571735 TI - Author Reply. PMID- 28571736 TI - Thin layer chitosan-coated cellulose filter paper as substrate for immobilization of catalytic cobalt nanoparticles. AB - A facile approach utilizing synthesis of cobalt nanoparticles in green polymers of chitosan (CS) coating layer on high surface area cellulose microfibers of filter paper (CFP) is described for the catalytic reduction of nitrophenol and an organic dye using NaBH4. Simple steps of CFP coating with 1wt% CS aqueous solution followed by Co2+ ions adsorption from 0.2M CoCl2 aqueous solution were carried out to prepare pre-catalytic strips. The Co2+ loaded pre-catalytic strips of CS-CFP were treated with 0.19M NaBH4 aqueous solution to convert the ions into nanoparticles. Successful Co nanoparticles formation was assessed by various characterization techniques of FESEM, EDX and XRD analyzes. TGA analyses were carried out on CFP, CS-CFP, and Co-CS-CFP for the determination of the amount of Co particles formed on the CS-FP, and to track their thermal properties. Furthermore, we demonstrated that the Co-CS-CFP showed an excellent catalytic activity and reusability in the reduction reactions a nitroaromatic compound of 2,6-dintirophenol (2,6-DNP) and brilliant cresyl blue (BCB) dye by NaBH4. The Co CS-CFP catalyzed the reduction reactions of 2,6-DNP and BCB by NaBH4 with psuedo first order rate constants of 0.0451 and 0.1987min-1, respectively. PMID- 28571737 TI - Fabrication and characterization of electrospun gelatin nanofibers crosslinked with oxidized phenolic compounds. AB - In this study, the ability of oxidized phenolic compounds of tannic, gallic, ferulic and caffeic acids to crosslink gelatin (G) was investigated. The electrospun crosslinked gelatin nanofibers were assessed in terms of gelatin solution properties, fiber morphology, thermal properties, FTIR spectra, XRD pattern and antioxidant activity. Tannic acid showed the most crosslinking activity towards gelatin (13.3 vs 7.44, 4.65, and 3.45% for caffeic, gallic and ferulic, respectively). Crosslinking enhanced roughly electrical conductivity of gelatin solution while the surface tension and viscosity reduced. According to scanning electron microscopy (SEM) results, the fibrous structure of crosslinked gelatin nanofibers didn't change while their diameter increased to the highest value of 280nm for gelatin-tannic. Gelatin-gallic sample showed the highest total phenolic content (86.3mg gallic acid equivalent/g) and antioxidant activity (86.5%). Surprisingly, from differential scanning calorimetry (DSC) curves, it was found that crosslinking led to the reduction of thermal stability of gelatin nanofibers. PMID- 28571738 TI - GPR3 and GPR6, novel molecular targets for cannabidiol. AB - GPR3 and GPR6 are members of a family of constitutively active, Gs protein coupled receptors. Previously, it has been reported that GPR3 is involved in Alzheimer's disease whereas GPR6 plays potential roles in Parkinson's disease. GPR3 and GPR6 are considered orphan receptors because there are no confirmed endogenous agonists for them. However, GPR3 and GPR6 are phylogenetically related to the cannabinoid receptors. In this study, the activities of endocannabinoids and phytocannabinoids were tested on GPR3 and GPR6 using a beta-arrestin2 recruitment assay. Among the variety of cannabinoids tested, cannabidiol (CBD), the major non-psychoactive component of marijuana, significantly reduced beta arrestin2 recruitment to both GPR3 and GPR6. In addition, the inhibitory effects of CBD on beta-arrestin2 recruitment were concentration-dependent for both GPR3 and GPR6, with a higher potency for GPR6. These data show that CBD acts as an inverse agonist at both GPR3 and GPR6 receptors. These results demonstrate for the first time that both GPR3 and GPR6 are novel molecular targets for CBD. Our discovery that CBD acts as a novel inverse agonist on both GPR3 and GPR6 indicates that some of the potential therapeutic effects of CBD (e.g. treatment of Alzheimer's disease and Parkinson's disease) may be mediated through these important receptors. PMID- 28571739 TI - Amelioration of adjuvant-induced arthritis in CCDC134-overexpressing transgenic mice. AB - CCDC134 might be an immune cytokine and plays important and complex roles in the process in vivo. It was proved to illustrate its potent antitumor effects by augmenting CD8+ T-cell-mediated immunity, but its role in the development of rheumatoid arthritis (RA) remains unclear. In this study, we demonstrated that development of adjuvant-induced arthritis and pro-inflammatory responses were more ameliorated in CCDC134-overexpressing transgenic mice than those in WT mice. The underlying mechanism of CCDC134-induced effects involved inhibition of T helper (Th) 1 and Th17 cell differentiation. These findings indicate that overexpression of CCDC134 exerts potent anti-inflammatory effects through selective modulation of pathogenic Th1 and Th17 cells, and might provide insights into the role of CCDC134 as a unique therapeutic agent for the treatment of rheumatoid arthritis. PMID- 28571740 TI - Phytol increases adipocyte number and glucose tolerance through activation of PI3K/Akt signaling pathway in mice fed high-fat and high-fructose diet. AB - It has been shown that adipose tissue hyperplasia (increased adipocyte number or adipogenesis) has beneficial effects on metabolic health. The aim of the present study was to determine whether phytol could modulate hyperplasia/adipogenesis and glucose homeostasis, and to explore the underlying mechanisms in mice fed high fat and high fructose diet (HFFD). Our results demonstrated that phytol administration decreased body weight gain and inguinal subcutaneous white adipose tissue (iWAT) weight. However, phytol significantly increased the adipocyte number in iWAT, with the smaller average adipocyte diameter. Meanwhile, OGTT result showed that phytol improved glucose tolerance. In accord, phytol administration markedly increased expression of marker genes associated with adipogenesis (PPARgamma and C/EBPalpha) and glucose uptake (AS160 and GLUT4) and activated PI3K/Akt signaling pathway in mice iWAT. In agreement with the in vivo findings, the in vitro results indicated that 100 MUM phytol significantly enhanced 3T3-L1 adipogenesis and glucose uptake, and activated PI3K/Akt signaling pathway. However, phytol-induced enhancement of 3T3-L1 adipognesis and glucose uptake, activation of PI3K/Akt signaling pathway, elevation of marker genes involved in adipogensis and glucose uptake, as well as translocation of GLUT4 from cytoplasm to membrane were abolished by Wortmannin, a specific PI3K/Akt inhibitor. Taken together, phytol increased adipocyte number in iWAT and improved glucose tolerance in mice fed HFFD, which was coincident with the enhanced adipogenesis and glucose uptake in 3T3-L1, and was associated with activation of PI3K/Akt signaling pathway. These data suggested the application of phytol as a potential nutritional agent to combat obesity and type 2 diabetes. PMID- 28571741 TI - Circular RNA hsa_circ_0010729 regulates vascular endothelial cell proliferation and apoptosis by targeting the miR-186/HIF-1alpha axis. AB - Circular RNAs (circRNAs) are a group of non-protein-coding RNAs generated from back splicing. Emerging evidence has demonstrated its vital regulation on angiogenesis. However, the underlying mechanism responsible for circRNAs effects on vascular endothelial cells is still unclear. In the present study, we screened the expression profiles and investigated the physiological role of circRNAs in hypoxia-induced human umbilical vein endothelial cells (HUVECs). Using circRNA microarray analysis, we identified 36 circRNAs that were significantly dysregulated including 14 down-regulated circRNAs and 22 up-regulated with 2-fold change (P < 0.05). From the over-expressed circRNAs, hsa_circ_0010729 was selected as candidate circRNA and which was validated to be significantly up regulated using RT-PCR. In loss-of-function experiments of HUVECs, hsa_circ_0010729 knockdown suppressed the proliferation and migration ability and enhanced apoptosis. Bioinformatic prediction and luciferase assay revealed that hsa_circ_0010729 and hypoxia inducible factor 1 alpha (HIF-1alpha) were targeted by miR-186. Validation experiments verified that hsa_circ_0010729 was co expressed with HIF-1alpha, being negatively correlated with miR-186. Moreover, rescue experiments demonstrated that miR-186 inhibitor could reverse the role of hsa_circ_0010729 knockdown on HUVECs progression. Overall, the present study identifies the crucial regulation of hsa_circ_0010729 on vascular endothelial cell proliferation and apoptosis via targeting miR-186/HIF-1alpha axis. PMID- 28571742 TI - Characterization and enzymatic properties of protein kinase ACR4 from Arabidopsis thaliana. AB - Serine/threonine-protein kinase-like protein ARABIDOPSIS CRINKLY4 (ACR4), a transmembrane protein of Arabidopsis thaliana, plays important roles in cell division and differentiation. Although accumulating studies shed light on the function of ACR4, the structure and catalytic mechanism of ACR4 remain to be elucidated. Here, we report the purification and enzymatic properties of the intracellular kinase domain (residues 464-799) of ACR4 (ACR4IKD). Through Ni affinity chromatography and gel filter chromatography methods, we successfully obtain high-purity ACR4IKD protein from Escherichia coli. Dynamic light scattering and gel-filtration methods reveal that ACR4IKD distributes with high homogeneity and exists as a monomer in solution. In addition, the ACR4IKD protein has typical kinase activity with myelin basic protein (MBP) as the substrate. Our study may lay the foundation for structure determination of ACR4IKD and further functional research, for example, screening significant substrates of ACR4 in Arabidopsis thaliana. PMID- 28571743 TI - On the use of the experimentally determined enzyme inhibition constant as a measure of absolute binding affinity. AB - Defined as a state function representing an inhibitor's absolute affinity for its target enzyme, the experimentally determined enzyme inhibition constant (Ki) is widely used to rank order binding affinities of different inhibitors for a common enzyme or different enzymes for a common inhibitor and to benchmark computational approaches to predicting binding affinity. Herein, we report that adsorption of bis(7)-tacrine to the glass container surface increased its Ki against Electrophorus electricus acetylcholinesterase (eeAChE) to 3.2 +/- 0.1 nM (n = 5) compared to 2.9 +/- 0.4 pM (n = 5) that was determined using plastic containers with other assay conditions kept the same. We also report that, due to binding or "adsorption" of bis(7)-tacrine to the inactive eeAChE, the bis(7)-tacrine Ki increased from 2.9 +/- 0.4 pM (n = 5) to 734 +/- 70 pM (n = 5) as the specific eeAChE activity decreased from 342 U/mg to 26 U/mg while other assay conditions were kept the same. These results caution against using Kis to rank order binding potencies, define selectivity, or benchmark computational methods without knowing detailed assay conditions. PMID- 28571745 TI - Acetylation of MKL1 by PCAF regulates pro-inflammatory transcription. AB - Inflammation is considered a fundamental host defense mechanism and, when aberrantly activated, contributes to a host of human diseases. Previously we have reported that the transcriptional regulator megakaryocytic leukemia 1 (MKL1) plays a role programming cellular inflammatory response by modulating NF-kappaB activity. Here we report that MKL1 was acetylated in vivo and pro-inflammatory stimuli (TNF-alpha and LPS) augmented MKL1 acetylation accompanying increased MKL1 binding to NF-kappaB target promoters. Further analysis revealed that the lysine acetyltransferase PCAF mediated MKL1 acetylation: TNF-alpha and LPS promoted the interaction between MKL1 and PCAF whereas depletion of PCAF abrogated the induction of MKL1 acetylation by TNF-alpha and LPS. Acetylation of MKL1 was necessary for MKL1 to activate the transcription of pro-inflammatory genes because mutation of four conserved lysine residues in MKL1 attenuated its capacity as a trans-activator of NF-kappaB target genes. Mechanistically, MKL1 acetylation served to promote MKL1 nuclear enrichment, to enhance the MKL1-NF kappaB interaction, and to stabilize the binding of MKL1 on target promoters. In conclusion, our data unveil an important pathway that contributes to the transcriptional regulation of inflammatory response. PMID- 28571746 TI - Experimental Theileria lestoquardi infection in sheep: Biochemical and hematological changes. AB - Malignant theileriosis (Theileria lestoquardi infection) is a hemoparasitic tick borne disease that affects both wild and domestic small ruminants. The aim of this study was to evaluate biochemical and hematological characteristics of sheep after being experimentally infected by T. lestoquardi. T. lestoquardi infection was induced in seven Baluchi sheep of six-to-eight months old via experimentally infected Hyalomma anatolicum adult ticks. Biochemical and hematological parameters were measured twice a week during the three weeks' post infection. Twenty-three biochemical analytes and seven hematological ones were measured. After three to four days infection, body temperature rose above 40 degrees C. Maximum and minimum parasitaemia were 3.3% and 0.28%, respectively. Piroplasms and schizont were seen on average from days 7.2 and 4 post infection, respectively. The concentrations and activities of Alb, HDL, ALT, T3, T4, Ca, Fe, Mg, iP, WBC, RBC, PCV, Hb, Plt, neutrophil and lymphocytes significantly decreased (P<=0.05) during experimental infection. However, concentrations and activities of BT, GGT, Glu, BUN, Crea, FIB and Cu significantly increased (P<=0.05). There was no significant change in the serum amounts of Chol, LDL, TG, VLDL and Zn. The observed hypoalbuminemia and increase of FIB concentrations referred to pro-inflammatory cytokines production. Moreover, the raising of GGT activity indicates liver damage, cholestatic disorders or schizont infiltration. The disease stress and corticosteroids are suspected to cause the Glu concentration increase. The present study is aimed at improving the knowledge of malignant theileriosis. PMID- 28571744 TI - Kr-POK (ZBTB7c) regulates cancer cell proliferation through glutamine metabolism. AB - Kr-POK (ZBTB7c) is a kidney cancer-related POK transcription factor that not only represses transcription of CDKN1A but also increases expression of FASN. However, precisely how Kr-POK affects cell metabolism by controlling gene expression in response to an energy source in rapidly proliferating cells remains unknown. In this study, we characterized the molecular and functional features of Kr-POK in the context of tumor growth and glutamine metabolism. We found that cells expressing Kr-POK shRNA exhibited more severe cell death than control cells in glucose-deprived medium, and that knockdown of Kr-POK decreased glutamine uptake. Glutamine is critical for tumor cell proliferation. Glutaminase (GLS1), which is activated by p-STAT1, catalyzes the initial reaction in the pathway of glutaminolysis. Kr-POK interacts with PIAS1 to disrupt the interaction between PIAS1 and p-STAT1, and free p-STAT1 can activate GLS1 transcription through an interaction with p300. Kr-POK can be also sumoylated by PIAS1, facilitating Kr POK degradation by the ubiquitin-mediated proteasomal pathway. Finally, we showed that repression of Kr-POK inhibited tumor growth in vivo in a xenograft model by repressing GLS1 expression. Taken together, our data reveal that Kr-POK activates GLS1 transcription and increases glutamine uptake to support rapid cancer cell proliferation. PMID- 28571747 TI - Cancer cell mechanics with altered cytoskeletal behavior and substrate effects: A 3D finite element modeling study. AB - A robust computational model of a cancer cell is presented using finite element modeling. The model accurately captures nuances of the various components of the cellular substructure. The role of degradation of cytoskeleton on overall elastic properties of the cancer cell is reported. The motivation for degraded cancer cellular substructure, the cytoskeleton is the observation that the innate mechanics of cytoskeleton is disrupted by various anti-cancer drugs as therapeutic treatments for the destruction of the cancer tumors. We report a significant influence on the degradation of the cytoskeleton on the mechanics of cancer cell. Further, a simulations based study is reported where we evaluate mechanical properties of the cancer cell attached to a variety of substrates. The loading of the cancer cell is less influenced by nature of the substrate, but low modulus substrates such as osteoblasts and hydrogels indicate a significant change in unloading behavior and also the plastic deformation. Overall, softer substrates such as osteoblasts and other bone cells result in a much altered unloading response as well as significant plastic deformation. These substrates are relevant to metastasis wherein certain type of cancers such as prostate and breast cancer cells migrate to the bone and colonize through mesenchymal to epithelial transition. The modeling study presented here is an important first step in the development of strong predictive methodologies for cancer progression. PMID- 28571748 TI - Corrigendum to "Recombinant expression of surfactant protein H (SFTA3) in Escherichia coli" [Ann. Anat. 208C (2016) 129-134]. PMID- 28571749 TI - Altered expression of epidermal lipid bio-synthesis enzymes in atopic dermatitis skin is accompanied by changes in stratum corneum lipid composition. AB - BACKGROUND: The barrier dysfunction in atopic dermatitis (AD) skin correlates with stratum corneum (SC) lipid abnormalities including reduction of global lipid content, shorter ceramide (CER) as well as free fatty acid (FFA) chain length and altered CER subclass levels. However, the underlying cause of these changes in lipid composition has not been fully investigated. AIM: We investigated whether the expression of CER and FFA biosynthesis enzymes are altered in AD skin compared with control skin and determine whether changes in enzyme expression can be related with changes in lipid composition. METHODS: In AD patients and controls the expression of enzymes involved in the biosynthesis of FFAs and CERs was analyzed in relation to the SC lipid composition. These enzymes include stearoyl CoA desaturase (SCD), elongase 1 (ELOVL1) and ELOVL6 involved in FFA synthesis and beta-glucocerebrosidase (GBA), acid-sphingomyelinase (aSmase), ceramide synthase 3 (CerS3) involved in CER synthesis. In TH2 treated human skin equivalents (AD HSEs) mimicking lesional AD skin, the mRNA expression of these enzymes was investigated. RESULTS: The results reveal an altered expression of SCD and ELOVL1 in AD lesional skin. This was accompanied by functional changes displayed by increased unsaturated FFAs (SCD) and reduced FFA C22-C28 (ELOVL1) in AD lesional skin. The expression of GBA, aSmase and CerS3 were also altered in lesional skin. The CER composition in AD lesional skin showed corresponding changes such as increased CER AS and NS (aSmase) and decreased esterified omega hydroxy CERs (CerS3). In support of the results from AD skin, the AD HSEs showed reduced mRNA ELOVL1, GBA and a Smase levels. CONCLUSION: This study shows that alterations in the expression of key enzymes involved in SC lipid synthesis contribute to changes in the lipid composition in AD skin and inflammation may influence expression of these enzymes. PMID- 28571750 TI - Measuring O-GlcNAc cleavage by OGA and cell lysates on a peptide microarray. AB - O-GlcNAcylation is a post-translational modification resulting from the addition of an N-acetylglucosamine moiety to the hydroxyl groups of serine and threonine residues of nuclear and cytoplasmic proteins. In addition, O-GlcNAcylated proteins can be phosphorylated, which suggests the possibility for crosstalk between O-GlcNAcylation and phosphorylation. Dysregulation of O-GlcNAcylation affects cell signaling, transcriptional regulation, cell cycle control and can e.g. lead to tumorigenesis and tumor metastasis. There is a strong demand for efficient analytical techniques to better detect and investigate this abundant modification and its role in cancer. Herein we demonstrated the utility of an O GlcNAcylated peptide array to examine O-GlcNAcase (OGA) activity and substrate specificity of both purified protein as well cell lysates of different cancer cell lines. Using this microarray, we clearly observed OGA activity and also inhibition thereof by OGA inhibitor thiamet G. Interestingly, different levels of OGA activity were observed of lysates derived from different cancer cell lines. This suggests that the tool may be useful in cancer research and biomarker development. PMID- 28571751 TI - Plasma-induced selectivity in bone cancer cells death. AB - BACKGROUND: Current therapies for bone cancers - either primary or metastatic - are difficult to implement and unfortunately not completely effective. An alternative therapy could be found in cold plasmas generated at atmospheric pressure which have already demonstrated selective anti-tumor action in a number of carcinomas and in more relatively rare brain tumors. However, its effects on bone cancer are still unknown. METHODS: Herein, we employed an atmospheric pressure plasma jet (APPJ) to validate its selectivity towards osteosarcoma cell line vs. osteoblasts & human mesenchymal stem cells. RESULTS: Cytotoxicity following direct interaction of APPJ with cells is comparable to indirect interaction when only liquid medium is treated and subsequently added to the cells, especially on the long-term (72h of cell culture). Moreover, following contact of the APPJ treated medium with cells, delayed effects are observed which lead to 100% bone cancer cell death through apoptosis (decreased cell viability with incubation time in contact with APPJ treated medium from 24h to 72h), while healthy cells remain fully viable and unaffected by the treatment. CONCLUSIONS: The high efficiency of the indirect treatment indicates that an important role is played by the reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the gaseous plasma stage and then transmitted to the liquid phase, which overall lead to lethal and selective action towards osteosarcoma cells. These findings open new pathways for treatment of metastatic bone disease with a minimally invasive approach. PMID- 28571753 TI - Real-time 3D transesophageal echocardiography-guided closure of a complicated patent ductus arteriosus in a dog. AB - Advanced imaging modalities are becoming more widely available in veterinary cardiology, including the use of transesophageal echocardiography (TEE) during occlusion of patent ductus arteriosus (PDA) in dogs. The dog in this report had a complex history of attempted ligation and a large PDA that initially precluded device placement thereby limiting the options for PDA closure. Following a second thoracotomy and partial ligation, the morphology of the PDA was altered and device occlusion was an option. Angiographic assessment of the PDA was limited by the presence of hemoclips, and the direction of ductal flow related to the change in anatomy following ligature placement. Intra-operative TEE, in particular real time three-dimensional imaging, was pivotal for assessing the PDA morphology, monitoring during the procedure, selecting the device size, and confirming device placement. The TEE images increased operator confidence that the size and location of the device were appropriate before release despite the unusual position. This report highlights the benefit of intra-operative TEE, in particular real-time three-dimensional imaging, for successful PDA occlusion in a complicated case. PMID- 28571754 TI - Nonlinear adaptive control based on fuzzy sliding mode technique and fuzzy-based compensator. AB - It is difficult to efficiently control nonlinear systems in the presence of uncertainty and disturbance (UAD). One of the main reasons derives from the negative impact of the unknown features of UAD as well as the response delay of the control system on the accuracy rate in the real time of the control signal. In order to deal with this, we propose a new controller named CO-FSMC for a class of nonlinear control systems subjected to UAD, which is constituted of a fuzzy sliding mode controller (FSMC) and a fuzzy-based compensator (CO). Firstly, the FSMC and CO are designed independently, and then an adaptive fuzzy structure is discovered to combine them. Solutions for avoiding the singular cases of the fuzzy-based function approximation and reducing the calculating cost are proposed. Based on the solutions, fuzzy sliding mode technique, lumped disturbance observer and Lyapunov stability analysis, a closed-loop adaptive control law is formulated. Simulations along with a real application based on a semi-active train-car suspension are performed to fully evaluate the method. The obtained results reflected that vibration of the chassis mass is insensitive to UAD. Compared with the other fuzzy sliding mode control strategies, the CO-FSMC can provide the best control ability to reduce unwanted vibrations. PMID- 28571752 TI - Insights into the differential toxicological and antioxidant effects of 4 phenylchalcogenil-7-chloroquinolines in Caenorhabditis elegans. AB - Organic selenium and tellurium compounds are known for their broad-spectrum effects in a variety of experimental disease models. However, these compounds commonly display high toxicity and the molecular mechanisms underlying these deleterious effects have yet to be elucidated. Thus, the need for an animal model that is inexpensive, amenable to high-throughput analyses, and feasible for molecular studies is highly desirable to improve organochalcogen pharmacological and toxicological characterization. Herein, we use Caenorhabdtis elegans (C. elegans) as a model for the assessment of pharmacological and toxicological parameters following exposure to two 4-phenylchalcogenil-7-chloroquinolines derivatives (PSQ for selenium and PTQ for tellurium-containing compounds). While non-lethal concentrations (NLC) of PTQ and PSQ attenuated paraquat-induced effects on survival, lifespan and oxidative stress parameters, lethal concentrations (LC) of PTQ and PSQ alone are able to impair these parameters in C. elegans. We also demonstrate that DAF-16/FOXO and SKN-1/Nrf2 transcription factors underlie the mechanism of action of these compounds, as their targets sod 3, gst-4 and gcs-1 were modulated following exposures in a daf-16- and skn-1 dependent manner. Finally, in accordance with a disturbed thiol metabolism in both LC and NLC, we found higher sensitivity of trxr-1 worm mutants (lacking the selenoprotein thioredoxin reductase 1) when exposed to PSQ. Finally, our study suggests new targets for the investigation of organochalcogen pharmacological effects, reinforcing the use of C. elegans as a powerful platform for preclinical approaches. PMID- 28571755 TI - New methods of Laguerre pole optimization for the ARX model expansion on Laguerre bases. AB - The ARX-Laguerre model is a very important reduced complexity representation of linear system. However a significant reduction of this model is subject to an optimal choice of both Laguerre poles. Therefore we propose in this paper two new methods to estimate, from input/output measurements, the optimal values of Laguerre poles of the ARX-Laguerre model. The first method is based on the Newton Raphson's iterative technique where we prove that the gradient and the Hessian can be expressed analytically. The second method is based on Genetic Algorithms. Both proposed algorithms are tested on a numerical example and on a heating benchmark. PMID- 28571756 TI - Further triple integral approach to mixed-delay-dependent stability of time-delay neutral systems. AB - This paper studies the asymptotic stability for a class of neutral systems with mixed time-varying delays. Through utilizing some Wirtinger-based integral inequalities and extending the convex combination technique, the upper bound on derivative of Lyapunov-Krasovskii (L-K) functional can be estimated more tightly and three mixed-delay-dependent criteria are proposed in terms of linear matrix inequalities (LMIs), in which the nonlinearity and parameter uncertainties are also involved, respectively. Different from those existent works, based on the interconnected relationship between neutral delay and state one, some novel triple integral functional terms are constructed and the conservatism can be effectively reduced. Finally, two numerical examples are given to show the benefits of the proposed criteria. PMID- 28571757 TI - HMGB1 promotes HLF-1 proliferation and ECM production through activating HIF1 alpha-regulated aerobic glycolysis. AB - Aerobic glycolysis is a crucial event in fibroblast differentiation, and extracellular matrix (ECM) production in the progression of pulmonary fibrosis (PF). Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of PF. However, whether aerobic glycolysis contributes to HMGB1 induced fibroblast proliferation and ECM production in PF has not yet been determined. In this study, we investigated the effects of HMGB1 on human embryonic lung fibroblast (HLF-1) proliferation, ECM production, and aerobic glycolysis. The lactate dehydrogenase inhibitor oxamic acid (OA), and PFKFB3 inhibitor 3PO were used to block certain crucial steps of aerobic glycolysis. As a result, we observed an increase of HMGB1 in bronchoalveolar lavage fluid (BALF) in bleomycin (BLM)-treated rats as compared to non-treated rats (control group). A concentration-dependent increase of HLF-1 proliferation and expression of alpha SMA and alpha-collagen I were observed in the HMGB1 group, as well as increases of LDHA activation, glucose uptake levels, glycolytic rate, lactate level, and ATP production. OA and 3PO, or suppression of HIF1-alpha, blocked the effects of HMGB1. In summary, HMGB1 promotes fibroblast proliferation and ECM production though upregulating expression of HIF1-alpha to induce an increase of aerobic glycolysis. PMID- 28571758 TI - Killer-cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) class I genetic diversity in four South African populations. AB - Killer-cell Immunoglobulin-like Receptor (KIR) and Human Leukocyte Antigen (HLA) genotypes vary considerably between individuals and populations due to KIR/HLA allelic variation and variable haplotype configurations of KIR. HLA mediate natural killer cell activity by serving as KIR ligands. KIR/HLA polymorphisms associate with both disease susceptibility and severity. We determined the frequencies of KIR, KIR genotypes and KIR-HLA combinations in 364 healthy individuals from four South African populations. Study participants included black African (n=167), Caucasian (n=97), Mixed ancestry (n=50) and Indian (n=50) individuals. We identified 48 KIR genotypes that included two genotypes not previously reported. Based on KIR gene content, Indian individuals represented the most distinct group, showing the highest frequencies of KIR2DL2, KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3 and KIR3DS1, the lowest frequencies of KIR2DL3, KIR2DS4 and KIR3DL1; and a KIR2DL4-negative individual. KIR2DS1 and KIR3DS1 were infrequent in black African populations. HLA-C2 was more common in black African individuals, while HLA-C1 predominated in the other populations. Indian individuals were more likely to possess KIR2DL2 paired with HLA-C1, while Caucasian individuals exhibited the highest frequencies of KIR2DL3 paired with HLA-C1. This report provides comprehensive reference data for further study of the roles of KIR/HLA in non-communicable and infectious diseases in South African populations. PMID- 28571759 TI - Efficient production of recombinant adeno-associated viral vector, serotype DJ/8, carrying the GFP gene. AB - The purpose of this study was to establish an efficient method for the preparation of an adeno-associated viral (AAV), serotype DJ/8, carrying the GFP gene (AAV-DJ/8-GFP). We compared the yields of AAV-DJ/8 vector, which were produced by three different combination methods, consisting of two plasmid DNA transfection methods (lipofectamine and calcium phosphate co-precipitation; CaPi) and two virus DNA purification methods (iodixanol and cesium chloride; CsCl). The results showed that the highest yield of AAV-DJ/8-GFP vector was accomplished with the combination method of lipofectamine transfection and iodixanol purification. The viral protein expression levels and the transduction efficacy in HEK293 and CHO cells were not different among four different combination methods for AAV-DJ/8-GFP vectors. We confirmed that the AAV-DJ/8-GFP vector could transduce to human and murine hepatocyte-derived cell lines. These results show that AAV-DJ/8-GFP, purified by the combination of lipofectamine and iodixanol, produces an efficient yield without altering the characteristics of protein expression and AAV gene transduction. PMID- 28571760 TI - A bivalent dendrimeric peptide bearing a T-cell epitope from foot-and-mouth disease virus protein 3A improves humoral response against classical swine fever virus. AB - Three dendrimeric peptides were synthesized in order to evaluate their immunogenicity and their potential protection against classical swine fever virus (CSFV) in domestic pigs. Construct 1, an optimized version of a previously used dendrimer, had four copies of a B-cell epitope derived from CSFV E2 glycoprotein connected to an also CSFV-derived T-cell epitope through maleimide instead of thioether linkages. Construct 2 was similarly built but included only two copies of the B-cell epitope, and in also bivalent construct 3 the CSFV T-cell epitope was replaced by a previously described one from the 3A protein of foot-and-mouth disease virus (FMDV). Animals were inoculated twice with a 21-day interval and challenged 15days after the second immunization. Clinical signs were recorded daily and ELISA tests were performed to detect antibodies against specific peptide and E2. The neutralising antibody response was assessed 13days after challenge. Despite the change to maleimide connectivity, only partial protection against CSFV was again observed. The best clinical protection was observed in group 3. Animals inoculated with constructs 2 and 3 showed higher anti-peptide humoral response, suggesting that two copies of the B-cell epitope are sufficient or even better than four copies for swine immune recognition. In addition, for construct 3 higher neutralizing antibody titres against CSFV were detected. Our results support the immunogenicity of the CSFV B-cell epitope and the cooperative role of the FMDV 3A T-cell epitope in inducing a neutralising response against CSFV in domestic pigs. This is also the first time that the FMDV T-cell epitope shows effectivity in improving swine immune response against a different virus. Our findings highlight the relevance of dendrimeric peptides as a powerful tool for epitope characterization and antiviral strategies development. PMID- 28571761 TI - The temperature dependence of the BK channel activity - kinetics, thermodynamics, and long-range correlations. AB - Large-conductance, voltage dependent, Ca2+-activated potassium channels (BK) are transmembrane proteins that regulate many biological processes by controlling potassium flow across cell membranes. Here, we investigate to what extent temperature (in the range of 17-37 degrees C with DeltaT=5 degrees C step) is a regulating parameter of kinetic properties of the channel gating and memory effect in the series of dwell-time series of subsequent channel's states, at membrane depolarization and hyperpolarization. The obtained results indicate that temperature affects strongly the BK channels' gating, but, counterintuitively, it exerts no effect on the long-range correlations, as measured by the Hurst coefficient. Quantitative differences between dependencies of appropriate channel's characteristics on temperature are evident for different regimes of voltage. Examining the characteristics of BK channel activity as a function of temperature allows to estimate the net activation energy (Eact) and changes of thermodynamic parameters (DeltaH, DeltaS, DeltaG) by channel opening. Larger Eact corresponds to the channel activity at membrane hyperpolarization. The analysis of entropy and enthalpy changes of closed to open channel's transition suggest the entropy-driven nature of the increase of open state probability during voltage activation and supports the hypothesis about the voltage-dependent geometry of the channel vestibule. PMID- 28571762 TI - Filling bone defects with beta-TCP in maxillofacial surgery: A review. AB - Reconstruction of bone defects prior to implant placement now involves synthetic substitutes such as beta-TCP because of its ability to promote bone remodeling. Its capacity to be progressively substituted by the patient's bone allows to regenerate a dense bone volume. In addition, its availability in large quantities, avoiding the morbidity observed with harvesting autogenous bone, widens the operative indications. In this paper, the main indications of beta-TCP in maxillofacial surgery (dentistry, parodontology and dental implant surgery) are reviewed. They include periodontal bone disease, bone disjunction, pre implant surgery (sinus floor elevation and lateralization of the inferior alveolar nerve). PMID- 28571763 TI - Effect of target-enriched multiplex polymerase chain reaction on patient outcomes and costs during the 2013-14 influenza season. AB - The US Centers for Disease Control and Prevention recommends the initial use of rapid antigen influenza diagnostic test (RIDT) for the detection of influenza A (H1N1-09). Nasopharyngeal samples were tested from 246 patients for H1N1-09 using target-enriched multiplex polymerase chain reaction (TEM-PCR), of which 163 were additionally tested via RIDT. RIDTs had a sensitivity of 18.7% compared with TEM PCR as the reference standard. Patients with false-negative RIDTs were withheld from 111 days of oseltamivir and 65 days of isolation. Patients negative for H1N1 via TEM-PCR had antiviral therapy immediately stopped, thereby evading 408 days of oseltamivir and 315 days of unnecessary isolation. This cost avoidance saved US$208,982. PMID- 28571764 TI - Protein kinase C (PKC) isoforms in cancer, tumor promotion and tumor suppression. AB - The AGC family of serine/threonine kinases (PKA, PKG, PKC) includes more than 60 members that are critical regulators of numerous cellular functions, including cell cycle and differentiation, morphogenesis, and cell survival and death. Mutation and/or dysregulation of AGC kinases can lead to malignant cell transformation and contribute to the pathogenesis of many human diseases. Members of one subgroup of AGC kinases, the protein kinase C (PKC), have been singled out as critical players in carcinogenesis, following their identification as the intracellular receptors of phorbol esters, which exhibit tumor-promoting activities. This observation attracted the attention of researchers worldwide and led to intense investigations on the role of PKC in cell transformation and the potential use of PKC as therapeutic drug targets in cancer diseases. Studies demonstrated that many cancers had altered expression and/or mutation of specific PKC genes. However, the causal relationships between the changes in PKC gene expression and/or mutation and the direct cause of cancer remain elusive. Independent studies in normal cells demonstrated that activation of PKC is essential for the induction of cell activation and proliferation, differentiation, motility, and survival. Based on these observations and the general assumption that PKC isoforms play a positive role in cell transformation and/or cancer progression, many PKC inhibitors have entered clinical trials but the numerous attempts to target PKC in cancer has so far yielded only very limited success. More recent studies demonstrated that PKC function as tumor suppressors, and suggested that future clinical efforts should focus on restoring, rather than inhibiting, PKC activity. The present manuscript provides some historical perspectives on the tumor promoting function of PKC, reviewing some of the observations linking PKC to cancer progression, and discusses the role of PKC in the pathogenesis of cancer diseases and its potential usage as a therapeutic target. PMID- 28571765 TI - Potential of synthetic endoperoxides against Trichomonas vaginalis in vitro. AB - Metronidazole is well known for medicine against Trichomonas vaginalis infection, but it has side effects though it is effective, and especially because reports of metronidazole-tolerant species are increasing, the development of new medicine is being required. Here, we noticed the killing effects of endoperoxide compounds, N 89 and N-251 as new antimalarial drug candidates, on T. vaginalis and searched the possibility of development of new medicine. We added each of metronidazole, artemisinin, and two of new endoperoxides (N-89 and N-251) to metronidazole resistant and -sensitive species and compared its anti-trichomonal efficacy. For metronidazole, IC50 value, 50% of killing concentration for T. vaginalis, was very low for metronidazole-sensitive isolates (11.7 to 22.8MUM), but was high for metronidazole-resistant ones (182.9 to 730.4MUM). The IC50 values of N-89 and N 251 were 41.0 to 60.0MUM, and 82.0 to 300.0MUM for metronidazole-sensitive and resistant isolates, respectively. In conclusion, we found the endoperoxides, N-89 and N-251, have anti-trichomonal effect against metronidazole-resistant T. vaginalis as well as metronidazole-sensitive ones. These results indicate that the anti-trichomonal effects for our endoperoxides are equivalent or better in metronidazole-resistant T. vaginalis in comparison to metronidazole. PMID- 28571766 TI - Evaluation of novel oocyst wall protein candidates of Toxoplasma gondii. AB - Oocyst stage of Toxoplasma gondii is characterized by a durable wall that confers a strong protection to this protozoan parasite in face of harsh environmental conditions. Thus, it is considered the key for transmission of T. gondii. Analysis of oocyst wall composition is mandatory therefore; the aim of this study was to identify novel T. gondii oocyst wall proteins and test their use in detection of these oocysts in environmental samples. Five candidates of novel T. gondii oocyst wall proteins (TgOWPs) were identified and named TgOWP8 through TgOWP12. Recombinant protein of TgOWP8 was expressed in E. coli using glutathione S-transferase as fusion protein. Polyclonal antibody was produced and validated by indirect immunofluorescence antibody assay (IFA). For detection by IFA, we used different methods for fixation and permeabilization of oocysts to improve the antigen-antibody detection. Specificity to wall of T. gondii oocyst was confirmed and revealed absence of cross reactivity with bradyzoite cyst wall and tachyzoites. Although some TgOWPs were identified previously, our study represents a continuation of molecular investigations of oocyst wall proteins as an essential structure for the longevity and infectivity of this stage and also provided new trial to improve T. gondii oocysts detection. PMID- 28571767 TI - Good epidemiological practice: a narrative review of appropriate scientific methods to evaluate the impact of antimicrobial stewardship interventions. AB - AIMS: In this narrative review, we provide a framework for assessing the quality of evidence provided by studies investigating antimicrobial stewardship (AMS) interventions, and inform the design and planning stage for future AMS evaluation studies to determine the best strategies to keep antimicrobial resistance at bay. SOURCES: Cochrane/Pubmed. CONTENT: As AMS is mostly applied in a complex, real world setting, bias and random time effects can jeopardize the validity of causal inference. The most important risks include simultaneously implemented infection prevention strategies and regression to the mean. Inclusion of homogeneous intervention and control arms, through randomization of the intervention, can limit these risks. However, contamination can play an important role for AMS; therefore, randomization at cluster-level, instead of randomization at individual level, is recommended. It can be challenging to identify enough representative clusters, and implementation of a cluster-RCT (cRCT) can be costly. Controlled interrupted time series (ITS) design has a high validity as well, and is relatively straightforward to implement, although time-varying confounding should be considered. Independent of the study design, it is crucial to include multiple process, clinical outcome, microbiological and financial measures, to be able to detect possible, unintended consequences. IMPLICATIONS: Future studies assessing the impact of new AMS strategies should produce compelling evidence by opting for cRCTs, or ITS including a control arm. Furthermore, a holistic view of intended and unintended consequences should be reported, and a detailed process evaluation should be provided to adequately inform implementation of successful AMS strategies to battle the rising burden of AMR. PMID- 28571768 TI - Copper activation of organophosporus compounds detoxication by chicken serum. AB - Avian species contain low levels of enzymes that hydrolyze organophosphorus compounds (OPs), and chickens are used as a model of OPs delayed neurotoxicity. For both reasons, we studied the ability of chicken tissue for OP detoxication. A significant activating effect of Cu2+ on the hydrolysis of O-hexyl O-2,5 dichlorophenyl phosphoramidate (HDCP) was observed in hen plasma and the microsomal fractions of the liver, brain, and mainly in hen serum, by spectrophotometric and chiral chromatography methods. The concentration of 1 mM of Cu2+ or Zn2+ showed 200% and 168% activation, respectively, in hen plasma compared with the Ca2+-dependent hydrolysis, whereas these cations had an inhibitory effect on soluble liver and brain fractions. An increase of 1.5 to 19.5 fold in HDCP hydrolyzing activity was obtained for the 30-250 MUM Cu2+ range when using chicken serum instead of hen plasma. This Cu2+-dependent hydrolysis in chicken serum was stereoselective for the R-(+)-HDCP isomer, which proved the opposite to the Ca2+-dependent stereoselective hydrolysis of the S-(-)-HDCP isomer reported in rat and rabbit serum. The level of copper needed to exert this effect should be further evaluated for its suitability for potential therapeutic and biotechnological applications. PMID- 28571769 TI - An effect-directed strategy for characterizing emerging chemicals in food contact materials made from paper and board. AB - Food contact materials (FCM) are any type of item intended to come into contact with foods and thus represent a potential source for human exposure to chemicals. Regarding FCMs made of paper and board, information pertaining to their chemical constituents and the potential impacts on human health remains scarce, which hampers safety evaluation. We describe an effect-directed strategy to identify and characterize emerging chemicals in paper and board FCMs. Twenty FCMs were tested in eight reporter gene assays, including assays for the AR, ER, AhR, PPARgamma, Nrf2 and p53, as well as mutagenicity. All FCMs exhibited activities in at least one assay. As proof-of-principle, FCM samples obtained from a sandwich wrapper and a pizza box were carried through a complete step-by-step multi-tiered approach. The pizza box exhibited ER activity, likely caused by the presence of bisphenol A, dibutyl phthalate, and benzylbutyl phthalate. The sandwich wrapper exhibited AR antagonism, likely caused by abietic acid and dehydroabietic acid. Migration studies confirmed that the active chemicals can transfer from FCMs to food simulants. In conclusion, we report an effect-directed strategy that can identify hazards posed by FCMs made from paper and board, including the identification of the chemical(s) responsible for the observed activity. PMID- 28571770 TI - Leptin induces CREB-dependent aromatase activation through COX-2 expression in breast cancer cells. AB - Leptin plays a key role in the control of adipocyte formation, as well as in the associated regulation of energy intake and expenditure. The goal of this study was to determine if leptin-induced aromatase enhances estrogen production and induces tumor cell growth stimulation. To this end, breast cancer cells were incubated with leptin in the absence or presence of inhibitor pretreatment, and changes in aromatase and cyclooxygenase-2 (COX-2) expression were evaluated at the mRNA and protein levels. Transient transfection assays were performed to examine the aromatase and COX-2 gene promoter activities and immunoblot analysis was used to examine protein expression. Leptin induced aromatase expression, estradiol production, and promoter activity in breast cancer cells. Protein levels of phospho-STAT3, PKA, Akt, ERK, and JNK were increased by leptin. Leptin also significantly increased cAMP levels, cAMP response element (CRE) activation, and CREB phosphorylation. In addition, leptin induced COX-2 expression, promoter activity, and increased the production of prostaglandin E2. Finally, a COX-2 inhibitor and aromatase inhibitor suppressed leptin-induced cell proliferation in MCF-7 breast cancer cells. Together, our data show that leptin increased aromatase expression in breast cancer cells, which was correlated with COX-2 upregulation, mediated through CRE activation and cooperation among multiple signaling pathways. PMID- 28571771 TI - The lemon balm extract ALS-L1023 inhibits obesity and nonalcoholic fatty liver disease in female ovariectomized mice. AB - Increasing evidence indicates that angiogenesis inhibitors regulate obesity. This study aimed to determine whether the lemon balm extract ALS-L1023 inhibits diet induced obesity and nonalcoholic fatty liver disease (NAFLD) in female ovariectomized (OVX) mice. OVX mice received a low fat diet (LFD), a high fat diet (HFD) or HFD supplemented with ALS-L1023 (ALS-L1023) for 15 weeks. HFD mice exhibited increases in visceral adipose tissue (VAT) angiogenesis, body weight, VAT mass and VAT inflammation compared with LFD mice. In contrast, all of these effects were reduced in ALS-L1023 mice compared with HFD mice. Serum lipids and liver injury markers were improved in ALS-L1023 mice. Hepatic lipid accumulation, inflammatory cells and collagen levels were lower in ALS-L1023 mice than in HFD mice. ALS-L1023 mice exhibited a tendency to normalize hepatic expression of genes involved in lipid metabolism, inflammation and fibrosis to levels in LFD mice. ALS-L1023 also induced Akt phosphorylation and increased Nrf2 mRNA expression in livers of obese mice. Our results indicate that the angiogenesis inhibitor ALS-L1023 can regulate obesity, hepatic steatosis and fibro inflammation, in part through improvement of VAT function, in obese OVX mice. These findings suggest that angiogenesis inhibitors may contribute to alleviation of NAFLD in post-menopausal women with obesity. PMID- 28571772 TI - Consumption of cosmetic products by the French population. Third part: Product exposure amount. AB - A recent study in France provided valuable data on the frequency and amount of use of cosmetic products (Ficheux et al., 2015, 2016a). The aim of the present study was to generate Product Exposure Amount data, i.e. the amounts of cosmetics applied to the skin among the French population using the raw data collected during the previous enquiry. These data are useful to derive Consumer exposure level data which are paramount for skin sensitization risk assessments. Exposure data were generated for 69 different cosmetics, classified as products for the hair, face, buccal hygiene, hands, feet, body, shaving and depilation, sunscreens as well as products specifically intended for babies. Exposure was calculated using a probabilistic Monte Carlo method. The main strength of this work was the break-down of data by age and sex. The results showed that some data used by the International Fragrance Association in skin sensitization risk assessments, in particular facial care products and deodorants, could be unsuitable for the protection of French consumers. For the first time, data were also generated for products intended for babies' nappy area. These data will be useful for the implementation of the Quantitative Risk Assessment for skin sensitization among the French population. PMID- 28571773 TI - DATS sensitizes glioma cells to TRAIL-mediated apoptosis by up-regulation of death receptor 5 via ROS. AB - Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is a promising anticancer reagent for antitumor therapy. However, many cancer cells, including malignant glioma cells, tend to be resistant to TRAIL, due to repeat treat to cancer cells, highlighting the need for strategies to overcome TRAIL resistance. Here we present that in combination with diallyl trisulfide (DATS), exposure to TRAIL induced apoptosis in TRAIL-resistant glioma cells. Surprisingly, we found that subtoxic concentrations of DATS significantly potentiated TRAIL-induced cytotoxicity and apoptosis in glioma cells. DATS dramatically upregulated DR5 receptor expression but had no effects on DR4 receptor. In addition, DATS enhances TRAIL-induced apoptosis through the downregulation of anti-apoptotic protein (Mcl-1) and the upregulation of DR5 receptors through actions on the ROS- induced-p53. PMID- 28571774 TI - Modulatory effects of metformin on mutagenicity and epithelial tumor incidence in doxorubicin-treated Drosophila melanogaster. AB - Metformin (MET) is an anti-diabetic drug used to prevent hepatic glucose release and increase tissue insulin sensitivity. Diabetic cancer patients are on additional therapy with anticancer drugs. Doxorubicin (DXR) is a cancer chemotherapeutic agent that interferes with the topoisomerase II enzyme and generates free radicals. MET (2.5, 5, 10, 25 or 50 mM) alone was examined for mutagenicity, recombinogenicity and carcinogenicity, and combined with DXR (0.4 mM) for antimutagenicity, antirecombinogenicity and anticarcinogenicity, using the Somatic Mutation and Recombination Test and the Test for Detecting Epithelial Tumor Clones in Drosophila melanogaster. MET alone did not induce mutation or recombination. Modulating effects of MET on DXR-induced DNA damage were observed at the highest concentrations. In the evaluation of carcinogenesis, MET alone did not induce tumors. When combined with DXR, MET also reduced the DXR-induced tumors at the highest concentrations. Therefore, in the present experimental conditions, MET alone did not present mutagenic/recombinogenic/carcinogenic effects, but it was able to modulate the effect of DXR in the induction of DNA damage and of tumors in D. melanogaster. It is believed that this modulating effect is mainly related to the antioxidant, anti-inflammatory and apoptotic effects of this drug, although such effects have not been directly evaluated. PMID- 28571775 TI - Critical role of CA1 muscarinic receptors on memory acquisition deficit induced by total (TSD) and REM sleep deprivation (RSD). AB - AIM: Despite different theories regarding sleep physiological function, an overall census indicates that sleep is useful for neural plasticity which eventually strengthens cognition and brain performance. Different studies show that sleep deprivation (SD) leads to impaired learning and hippocampus dependent memory. According to some studies, cholinergic system plays an important role in sleep (particularly REM sleep), learning, memory, and its retrieval. So this study has been designed to investigate the effect of CA1 Cholinergic Muscarinic Receptors on memory acquisition deficit induced by total sleep deprivation (TSD) and REM sleep deprivation (RSD). METHOD: A modified water box (locomotor activity may be provide a limiting factor in this method of SD) or multiple platforms were used for induction of TSD or RSD, respectively. Inhibitory passive avoidance apparatus has been used to determine the effects of SD and its changes by physostigmine (as cholinesterase inhibitor) or scopolamine (muscarinic receptor antagonist) on memory formation. Because locomotor activity and pain perception induce critical roles in passive avoidance memory formation, we also measured these factors by open field and hot-plate instruments, respectively. RESULTS: The results showed that TSD and RSD for 24 hours impaired memory formation but they did not alter locomotor activity. TSD also induced analgesia effect, but RSD did not alter it. Intra-CA1 injection of physostigmine (0.0001MUg/rat) and scopolamine (0.01MUg/rat) did not alter memory acquisition in the sham-TSD or sham-RSD, by themselves. Moreover, intra-CA1 injection of sub-threshold dose of physostigmine (0.0001MUg/rat) and scopolamine (0.01MUg/rat) could restore the memory acquisition deficit induced by RSD, while scopolamine could restore TSD induced amnesia. Both drugs reversed analgesia induced by TSD. None of previous interventions altered locomotor activity. CONCLUSION: According to this study, CA1 cholinergic muscarinic receptors play an important role in amnesia induced by both TSD and RSD. However further studies are needed for showing cellular and molecular mechanisms of surprising result of similar pharmacological effects using compounds with opposite profiles. PMID- 28571776 TI - Neurodevelopmental theory of depression. AB - The aim of research studies in the field of psychiatry conducted in recent years is to formulate a consistent theory that would exhaustively explain the aetiology of depression. So far, biochemical, genetic, anatomical and environmental factors, which may play a role in the occurrence of the first symptoms of depressive disorders, have been sought. The authors of this paper present a theory that combines the previously mentioned elements into one whole and links them to one another. We have called our theory "neurodevelopmental" to underline the importance and impact of earlier stages of human life, including the prenatal period, on the occurrence of depressive disorders. We will make an attempt to find an answer to why this time in the life of a human being is so important, what kind of biological mechanisms are activated then, and what aspects of our later functioning are affected by them. PMID- 28571777 TI - Postpartum screening practices, progression to abnormal glucose tolerance and its related risk factors in Asian women with a known history of gestational diabetes: A systematic review and meta-analysis. AB - AIMS: Rate of postpartum screening and progression to glucose intolerance (diabetes and/or pre-diabetes) in Asian women with prior GDM and risk factors of diversion to abnormal glucose tolerance were reviewed. MATERIALS AND METHODS: We searched Pub Med, Cochrane Library, Web of Science, EMBASE, and Ovid data base. About 1300 studies were screened and 27 articles were selected. Meta-analysis using Comprehensive Meta -Analysis software was conducted. All results were reported at the pooled ORs and 95% CI. Quantitative heterogeneity (I2) was assessed. To estimate the variances between studies, the statistical method "tau squared" was applied. Statistical models like fixed effect or Mantel-Haenszel, and random effect (REM) or Dersimonian-laird were used for the analysis and integration of results. RESULTS: Rate of glucose testing ranged from 13.1% to 81.9%. Prevalence of pre-diabetes was 3.9%-50.9%. Diabetes was reported in 2.8% 58% of women with history of gestational diabetes based on length of follow-up. Factor associated with postpartum diabetes mellitus included family History of diabetes mellitus, gestational age at diagnosis of GDM, insulin use during pregnancy and pre-pregnancy BMI. CONCLUSIONS: Rate of postpartum screening in most of the Asian countries population is sub-optimal, in spite of high rate of glucose intolerance in this high risk group of women. Risk factors of progression to pre-diabetes and diabetes are similar to previous reported in developed countries. PMID- 28571779 TI - Clinical and molecular characterization of 6 children with glutamate-cysteine ligase deficiency causing hemolytic anemia. AB - Glutathione (gamma-glutamylcysteinylglycine) has diverse functions including free radicals scavenging and modulating many critical cellular processes. Glutathione is synthesized by the consecutive action of the enzymes glutamate-cysteine ligase (GCL) and glutathione synthetase. GCL is composed of a catalytic subunit encoded by the GCLC gene and a regulatory subunit encoded by the GCLM gene. GCL deficiency due to homozygous mutations in GCLC has been reported in 6 individuals from 4 independent families. All presented with hemolytic anemia and 4 had additional neurological manifestations including cognitive impairment, neuropathy, ataxia, and myopathy. In this report, we present additional 6 children from 2 independent consanguineous families with GCL deficiency. All the children presented with neonatal hemolytic anemia. Beyond the neonatal period, they did not have jaundice or hemolysis, but continued to have mild anemia. They all had normal development and neurological examination. The affected children from the first family had the homozygous mutation c.1772G>A (p.S591N) and the second family had the homozygous mutation c.514T>A (p.S172T) in GCLC. GCL deficiency can have a mild non-neurological phenotype or a more severe phenotype with neurological manifestations. GCL deficiency can be an underdiagnosed cause of hemolytic anemia, thus awareness may aid in early diagnosis, appropriate genetic counseling, and management. PMID- 28571778 TI - Long-term outcomes in ypT0 rectal cancers: An international multi-centric investigation on behalf of Italian Society of Surgical Oncology Young Board (YSICO). AB - AIM: To investigate the outcome and pattern of survivals of rectal cancer patients presenting a complete or nearly complete tumor response after neo adjuvant treatment. METHODS: Young surgeons <40 years old affiliated to the Italian Society of Surgical Oncology (YSICO) from 13 referral centers for colorectal cancer treatment, were invited to participate a retrospective study. Records from patients treated from 2005 to 2015 with a pathological diagnosis of ypT0/ypTis were retrieved and pooled in a common data-base for statistical purposes. All clinical and pathological variables were reviewed. Univariate and multivariate analyses were conducted with the end-point of survivals. RESULTS: Two hundreds and sixty-one patients were analyzed including 237 ypT0 and 24 ypTis. Nodal positive patients were 8.7%. More than sixty-six percent of the patients did not perform adjuvant chemotherapy, with a statistical difference comparing N0 versus N+ patients (66.8% vs 40.9%, p 0.02). Mean follow-up was of 47.6 months. Twenty-two relapses were observed, 91.6% at a distant site. The mean time to recurrence was of 35.3 months. On univariate analysis, the use of adjuvant chemotherapy correlated with better OS exclusively in ypT0N + patients and not in ypT0N0. Univariate and multivariate analyses documented nodal positivity as the only prognostic factor correlated with a worse OS. CONCLUSION: Recurrences were mostly diagnosed at a distant site and within the third year of follow-up. Nodal positivity was the only variable independently correlated with a worse OS. Univariate analysis documented a benefit for the use of adjuvant chemotherapy treatment exclusively in ypT0N + rectal cancers. PMID- 28571780 TI - The first report of chronic myelogenous leukemia with e19a2 micro-BCR/ABL1 presenting with massive myelofibrosis. PMID- 28571781 TI - Development of a Sigma-2 Receptor affinity filter through a Monte Carlo based QSAR analysis. AB - For the first time in sigma-2 (sigma2) receptor field, a quantitative structure activity relationship (QSAR) model has been built using pKi values of the whole set of known selective sigma2 receptor ligands (548 compounds), taken from the Sigma-2 Receptor Selective Ligands Database (S2RSLDB) (http://www.researchdsf.unict.it/S2RSLDB/), through the Monte Carlo technique and employing the software CORAL. The model has been developed by using a large and structurally diverse set of compounds, allowing for a prediction of different populations of chemical compounds endpoint (sigma2 receptor pKi). The statistical quality reached, suggested that model for pKi determination is robust and possesses a satisfactory predictive potential. The statistical quality is high for both visible and invisible sets. The screening of the FDA approved drugs, external to our dataset, suggested that sixteen compounds might be repositioned as sigma2 receptor ligands (predicted pKi>=8). A literature check showed that six of these compounds have already been tested for affinity at sigma2 receptor and, of these, two (Flunarizine and Terbinafine) have shown an experimental sigma2 receptor pKi>7. This suggests that this QSAR model may be used as focusing screening filter in order to prospectively find or repurpose new drugs with high affinity for the sigma2 receptor, and overall allowing for an enhanced hit rate respect to a random screening. PMID- 28571782 TI - Importance of reversed-phase chromatographic parameters in predicting biopharmaceutical and pharmacokinetic descriptors on the group of androgen derivatives. AB - Nowadays the standard measure of lipophilicity, the logarithm of n-octanol-water partition coefficient, logP, is proposed to be replaced with chromatographic techniques. Chromatography techniques (reversed phase thin layer chromatography RPTLC and reversed phase thin layer chromatography RPHPLC) are the most widely used alternatives to the shake flask method. However, it is shown that, by changing the temperature or concentration of organic modifier in the chromatography experiment, it is possible to derive data matrix of retention parameters from which, by principle component analysis, structural characteristics of the examined molecules can be gained. The question may be asked which of the chromatography experimentally obtained and calculated parameters: capacity factor k, DeltaGx (the change in Gibbs energy of binding of molecule for stationary phase), DeltaHx (the change in enthalpy of binding of molecule for stationary phase) or DeltaSx (the change in the entropy of binding of molecule for stationary phase) is the most suitable in describing hydrophobicity. The canonical correlation analysis (CCA) method is used to evaluate the importance of the n functions in explaining the variance of molecular descriptors connected to pharmaceutical processes and wherein molecule's hydrophobicity is expressed and possible differences between molecular descriptors with realistic conformations of the analyzed molecules steroid skeleton are discussed. Conformational analysis showed that structure of steroid skeleton in hydrophobicity is most completely described with k or DeltaGx, and connection between conformation of the steroid skeleton and hydrophobicity to a lesser extent is projected on temperature dependence on DeltaHx and similarly on DeltaSx, so in describing molecules hydrophobicity it is necessary to observe entropic as well as enthalpic contribution together, expressed with DeltaGx function. Canonical conformation analysis (CCA) showed that hydrophobicity contained in DeltaGx and k explains 61% of variance represented in in silico descriptors. Analyzed molecular descriptors, derived from different molecules fragments don't map conformational specifics of those molecules in small groups so recommendation is to use them complementary with chromatographic data in describing hydrophobicity. PMID- 28571783 TI - Improving the physicochemical properties of bicalutamide by complex formation with bovine serum albumin. AB - Bicalutamide-bovine serum albumin (Bic-BSA) complexes were prepared by anti solvent precipitation. Bovine serum albumin (BSA) was used as a stabilizer for particle growth. The physicochemical properties of Bic-BSA were analyzed by scanning electron microscopy, X-ray powder diffraction and differential scanning calorimetry. The interaction between Bic and BSA was characterized by Fourier transform infrared spectroscopy, Raman spectroscopy, fluorescence spectroscopy and molecular docking. The particle size could be easily reduced to 1-10MUm with a good lognormal distribution. The Bic-BSA complexes exhibited nonporous spherical morphology with a uniformly plicated surface. Moreover, the crystal form and thermostability of Bic were altered in the presence of BSA. Bic was found to make hydrogen bonding and hydrophobic interactions with BSA by spectroscopic studies and molecular docking. Results from the Van't Hoff equation and binding free energy calculations indicated that the improvement of physicochemical properties was the consequence of a variety of interactions in the Bic-BSA system. Bic-BSA tablets showed significantly enhanced dissolution. It was concluded that BSA plays an important role in improving the physicochemical properties of Bic due to strong multiple interactions between Bic and BSA. PMID- 28571784 TI - Predictive modeling for classification of positive valence system symptom severity from initial psychiatric evaluation records. AB - In response to the challenges set forth by the CEGS N-GRID 2016 Shared Task in Clinical Natural Language Processing, we describe a framework to automatically classify initial psychiatric evaluation records to one of four positive valence system severities: absent, mild, moderate, or severe. We used a dataset provided by the event organizers to develop a framework comprised of natural language processing (NLP) modules and 3 predictive models (two decision tree models and one Bayesian network model) used in the competition. We also developed two additional predictive models for comparison purpose. To evaluate our framework, we employed a blind test dataset provided by the 2016 CEGS N-GRID. The predictive scores, measured by the macro averaged-inverse normalized mean absolute error score, from the two decision trees and Naive Bayes models were 82.56%, 82.18%, and 80.56%, respectively. The proposed framework in this paper can potentially be applied to other predictive tasks for processing initial psychiatric evaluation records, such as predicting 30-day psychiatric readmissions. PMID- 28571785 TI - Harnessing Peer Support in an Online Intervention for Older Adults with Depression. AB - OBJECTIVE: This pilot study evaluated the feasibility and efficacy of two methods of delivering a cognitive behaviorally informed Internet intervention for depression for adults 65 years and older. METHODS: Forty-seven participants were enrolled and assigned to receive one of two versions of the Internet intervention, either delivered individually (III) or with peer support (II+PS), or to a wait list control group (WLC). Primary outcomes included change in depressive symptoms from baseline to post-intervention (week 8), site use, self reported usability, and coach time. Secondary outcomes included measures of social support and isolation and anxiety. RESULTS: Follow-up data were provided by 85.1% (40 of 47) of enrolled participants. There were significant differences in depression change across groups (F(2,37) = 3.81, p = 0.03). Greater reductions in depressive symptoms were found for the III (p = 0.02) and II+PS (p = 0.03) compared with WLC, and significantly less coach time was required in the II+PS (p = 0.003). CONCLUSIONS: These results highlight the potential of cognitive behaviorally informed Internet interventions for older adults with depression, and indicate that peer-supported programs are both acceptable and equivalent to individually delivered Internet interventions. Including peer support may be a viable and potentially more cost-effective option for disseminating online treatments for depression for older adults. PMID- 28571786 TI - Biodegradation of 7-Ketocholesterol by Rhodococcus erythropolis MTCC 3951: Process optimization and enzymatic insights. AB - The oxidation of cholesterol results in the formation of oxysterols such as 7 ketocholesterol (7KC), which are implicated in a number of age-related disorders such as atherosclerosis, Alzheimers' disease and macular degeneration. Current modalities use antioxidants and other natural or synthetic molecules to reduce 7KC-induced cytotoxity. The alternative application of enzymes from microbial sources to degrade oxysterols in vitro and in vivo is an innovative approach. The present study aims to assess the potential of the bacteria Rhodococcus erythropolis MTCC 3951 in degrading 7KC and mining relevant enzymes involved. This strain has been previously reported to be a degrader of xenobiotics such as polyphenols, toluene and catechol. Under optimized conditions, Rhodococcus erythropolis MTCC 3951 is found to degrade 93% of 1g/l concentration of 7KC within 15days of incubation. The extra- and intra-cellular extracts were also able to hydrolyse the compound indicating the involvement of enzymatic systems in the process. The strain produced cholesterol oxidase, lipase, dehydrogenase and reductase in the presence of 7KC. We have also identified a few intermediate products to predict the degradation pathway. PMID- 28571787 TI - Probing topology and dynamics of the second transmembrane domain (M2delta) of the acetyl choline receptor using magnetically aligned lipid bilayers (bicelles) and EPR spectroscopy. AB - Characterizing membrane protein structure and dynamics in the lipid bilayer membrane is very important but experimentally challenging. EPR spectroscopy offers a unique set of techniques to investigate a membrane protein structure, dynamics, topology, and distance constraints in lipid bilayers. Previously our lab demonstrated the use of magnetically aligned phospholipid bilayers (bicelles) for probing topology and dynamics of the membrane peptide M2delta of the acetyl choline receptor (AchR) as a proof of concept. In this study, magnetically aligned phospholipid bilayers and rigid spin labels were further utilized to provide improved dynamic information and topology of M2delta peptide. Seven TOAC labeled AchR M2delta peptides were synthesized to demonstrate the utility of a multi-labeling amino acid substitution alignment strategy. Our data revealed the helical tilts to be 11 degrees , 17 degrees , 9 degrees , 17 degrees , 16 degrees , 11 degrees , 9 degrees +/-4 degrees for residues I7TOAC, Q13TOAC, A14TOAC, V15TOAC, C16TOAC, L17TOAC, and L18TOAC, respectively. The average helical tilt of the M2delta peptide was determined to be ~13 degrees . This study also revealed that the TOAC labels were attached to the M2delta peptide with different dynamics suggesting that the sites towards the C-terminal end are more rigid when compared to the sites towards the N-terminus. The dynamics of the TOAC labeled sites were more resolved in the aligned samples when compared to the randomly disordered samples. This study highlights the use of magnetically aligned lipid bilayer EPR technique to determine a more accurate helical tilt and more resolved local dynamics of AchR M2delta peptide. PMID- 28571788 TI - Shape change in the atlas with congenital midline non-union of its posterior arch: a morphometric geometric study. AB - BACKGROUND CONTEXT: The congenital midline non-union of the posterior arch of the atlas is a developmental variant present at a frequency ranging from 0.7% to 3.9%. Most of the reported cases correspond to incidental findings during routine medical examination. In cases of posterior non-union, hypertrophy of the anterior arch and cortical bone thickening of the posterior arches have been observed and interpreted as adaptive responses of the atlas to increased mechanical stress. PURPOSE: We sought to determine if the congenital non-union of the posterior arch results in a change in the shape of the atlas. STUDY DESIGN/SETTING: This study is an analysis of the first cervical vertebrae from osteological collections through morphometric geometric techniques. METHODS: A total of 21 vertebrae were scanned with a high-resolution three-dimensional scanner (Artec Space Spider, Artec Group, Luxembourg). To capture vertebral shape, 19 landmarks and 100 semilandmarks were placed on the vertebrae. Procrustes superimposition was applied to obtain size and shape data (MorphoJ 1.02; Klingenberg, 2011), which were analyzed through principal component analysis (PCA) and mean shape comparisons. RESULTS: The PCA resulted in two components explaining 22.32% and 18.8% of the total shape variance. The graphic plotting of both components indicates a clear shape difference between the control atlas and the atlas with posterior non-union. This observation was supported by statistically significant differences in mean shape comparisons between both types of vertebra (p<.0001). Changes in shape were observed in the superior and inferior articular facets, the transverse processes, and the neural canal between the control and non-union vertebrae. CONCLUSIONS: Non-union of the posterior arch of the atlas is associated with significant changes in the shape of the vertebra. PMID- 28571789 TI - Virtual reality-based simulators for spine surgery: a systematic review. AB - BACKGROUND CONTEXT: Virtual reality (VR)-based simulators offer numerous benefits and are very useful in assessing and training surgical skills. Virtual reality based simulators are standard in some surgical subspecialties, but their actual use in spinal surgery remains unclear. Currently, only technical reviews of VR based simulators are available for spinal surgery. PURPOSE: Thus, we performed a systematic review that examined the existing research on VR-based simulators in spinal procedures. We also assessed the quality of current studies evaluating VR based training in spinal surgery. Moreover, we wanted to provide a guide for future studies evaluating VR-based simulators in this field. STUDY DESIGN AND SETTING: This is a systematic review of the current scientific literature regarding VR-based simulation in spinal surgery. METHODS: Five data sources were systematically searched to identify relevant peer-reviewed articles regarding virtual, mixed, or augmented reality-based simulators in spinal surgery. A qualitative data synthesis was performed with particular attention to evaluation approaches and outcomes. Additionally, all included studies were appraised for their quality using the Medical Education Research Study Quality Instrument (MERSQI) tool. RESULTS: The initial review identified 476 abstracts and 63 full texts were then assessed by two reviewers. Finally, 19 studies that examined simulators for the following procedures were selected: pedicle screw placement, vertebroplasty, posterior cervical laminectomy and foraminotomy, lumbar puncture, facet joint injection, and spinal needle insertion and placement. These studies had a low-to-medium methodological quality with a MERSQI mean score of 11.47 out of 18 (standard deviation=1.81). CONCLUSIONS: This review described the current state and applications of VR-based simulator training and assessment approaches in spinal procedures. Limitations, strengths, and future advancements of VR-based simulators for training and assessment in spinal surgery were explored. Higher quality studies with patient-related outcome measures are needed. To establish further adaptation of VR-based simulators in spinal surgery, future evaluations need to improve the study quality, apply long-term study designs, and examine non technical skills, as well as multidisciplinary team training. PMID- 28571790 TI - Iron chelation for the treatment of uveitis. AB - Inflammatory eye diseases such as uveitis are common and may eventually result in vision loss. Iron can play a critical role in ocular inflammation via promoting the generation of oxygen free radicals and it is also nutritionally essential for microbial growth. Considering this involvement of iron in inflammation and microbial infection, we hypothesize that administration of iron chelators has potential to function as a novel therapy in uveitis and help improve clinical outcomes. PMID- 28571791 TI - Unus pro omnibus, omnes pro uno: A novel, evidence-based, unifying theory for the pathogenesis of endometriosis. AB - The theory of retrograde menstruation as aetiopathogenesis of endometriosis formulated by John Sampson in 1927 shows clear shortcomings: this does not explain why retrograde menstruation is a physiological process that affects 90% of women, while endometriosis occurs in only 10% of cases; it also does not explain the endometriotic foci distant from the pelvis, nor explains the cases of endometriosis in male patients. The immunological alterations of the peritoneal fluid explains the effects of disease, such as the inhibition of the physiological processes of cytolysis, but does not explain the cause. There is evidence to support the hypothesis that ectopic mullerian remnants of the endometrium, endocervix and endosalpinx are items from the genital ridge leaked during organogenesis. It is known that tissues derived from coelomatic epithelial and mesenchymal cells have the potential to metaplastically differentiate into epithelium and stroma. In addition, the phenotype of the ectopic endometrial cells is significantly different from those ectopic. There is scientific evidence that, during organogenesis, the genes of the Homeobox and Wingless family play a fundamental role in the differentiation of the ducts of Muller and development of the anatomical structure of the urogenital tract. We present here a hypothesis that deregulation of genes and the Wnt signaling pathway Wnt/beta-catenin leads to aberrations and deregulation within the mesoderm, thus, may cause aberrant placement of stem cells. In addition, immune cells, adhesion molecules, extracellular matrix metalloproteinase and pro-inflammatory cytokines activate/alter peritoneal microenvironment, creating the conditions for differentiation, adhesion, proliferation and survival of ectopic endometrial cells. PMID- 28571792 TI - Papillary carcinoma of the thyroid in patients with primary hyperparathyroidism: Is there a link? AB - Primary hyperparathyroidism (PHPT) is present in up to 0.1% of the general population. The incidence is higher in women and increases with age. The majority of the cases is asymptomatic and up to 85% are due to single gland adenoma. Parathyroidectomy is the treatment of choice after localization of the hyperactive gland. Papillary Thyroid Carcinoma (PTC) is the most common cancer of the thyroid and constitutes more than 70% of thyroid malignancies. PTC can present as a single nodule or can be Multifocal. The incidence is higher in women. Early treatment favors a good prognosis. PTC with PHPT has been reported in 2.3-4.3% of patients undergoing surgery for PHPT. The coexistence of parathyroid adenoma and incidental PTC is thought to be rare. The mechanisms underlying the relationship between PHPT and PTC have not been established. We suggest a possible hypothesis for the relationship based on shared embryological origin and genes, high parathyroid hormone (PTH), low 1,25 hydroxy vitamin D, hypercalcemia resulting in high levels of angiogenic growth factors. This promotes the formation of parathyroid adenomas and papillary thyroid carcinoma. Presence of these two diseases can complicate patient management due to untreated hypercalcemia, unrecognized thyroid cancer and need for second surgery if not screened for both diseases carefully. PMID- 28571793 TI - Saturated fatty acids recognition by the CD14-TLR4-MD2 complex may engage in the presurgical anxiety-induced persistent postsurgical pain. AB - It has been proved that presurgical anxiety can induce the development and progression of persistent postsurgical pain through elevating circulating corticosterone levels and activating the glucocorticoids receptor. Under stressful circumstances, the concentration of blood saturated fatty acids (SFAs) increases rapidly to provide enough ATP for individuals' survival owing to stress hormones such as glucocorticoid, catecholamine and glucagon. It is reported that SFAs can trigger an inflammatory response through CD14-TLR4-MD2 complex. The role of TLR4 and its downstream signaling pathway has been confirmed in the pathogenesis of cancer pain and inflammatory pain. Furthermore, a newly clinical research uncovers that the children with recurrent abdominal pain, which is triggered by early psychosomatic stress, have higher levels of SFAs than healthy individuals. We therefore put forward the hypothesis that the elevated level of SFAs induced by stress hormones may be engaged in the presurgical anxiety-induced persistent postsurgical pain. If established, it's of important clinical significance, which will make great contributions to the prevention and treatment of the presurgical anxiety-induced persistent postsurgical pain. PMID- 28571794 TI - Playing brass instruments by breast cancer patients: A way of combating anxiety. PMID- 28571795 TI - Misophonia: A new mental disorder? AB - Misophonia, a phenomenon first described in the audiology literature, is characterized by intense emotional reactions (e.g., anger, rage, anxiety, disgust) in response to highly specific sounds, particularly sounds of human origin such as oral or nasal noises made by other people (e.g., chewing, sniffing, slurping, lip smacking). Misophonia is not listed in any of the contemporary psychiatric classification systems. Some investigators have argued that misophonia should be regarded as a new mental disorder, falling within the spectrum of obsessive-compulsive related disorders. Other researchers have disputed this claim. The purpose of this article is to critically examine the proposition that misophonia should be classified as a new mental disorder. The clinical and research literature on misophonia was examined and considered in the context of the broader literature on what constitutes a mental disorder. There have been growing concerns that diagnostic systems such as DSM-5 tend to over pathologize ordinary quirks and eccentricities. Accordingly, solid evidence is required for proposing a new psychiatric disorder. The available evidence suggests that (a) misophonia meets many of the general criteria for a mental disorder and has some evidence of clinical utility as a diagnostic construct, but (b) the nature and boundaries of the syndrome are unclear; for example, in some cases misophonia might be simply one feature of a broader pattern of sensory intolerance, and (c) considerably more research is required, particularly work concerning diagnostic validity, before misophonia, defined as either as a disorder or as a key feature of some broader syndrome of sensory intolerance, should be considered as a diagnostic construct in the psychiatric nomenclature. A research roadmap is proposed for the systematic evaluation as to whether misophonia should be considered for future editions of DSM or ICD. PMID- 28571796 TI - Connecting the dots: Overlaps between autism and cancer suggest possible common mechanisms regarding signaling pathways related to metabolic alterations. AB - Common features between autism spectrum disorders (ASDs) and cancer have been discerned using methodologies from a number of disciplines, including genetics, bioinformatics and epidemiological studies. To understand such apparent overlaps between these two conditions and the mechanisms that may underlie these linkages, it is important to look at their multi-level systems context. Here we discuss ASDs and cancer linkages across levels ranging from genes to pathways and systems, as well as from the vantage points of mechanism and of clinical and epidemiological studies. Review of existing findings yielded evidence that ASDs and cancer overlap extensively in signal transduction pathways that are involved in metabolic processes. We hypothesize that further studies focusing on illuminating the relationships between ASDs and cancer, specifically with regard to signaling pathways that regulate metabolic activities, could help shed new insight on these conditions and develop treatment strategies that, by targeting underlying mechanisms, may be more efficient and effective for both conditions. PMID- 28571797 TI - Towards the targeted management of aggressive periodontitis. PMID- 28571798 TI - Olfactory vector hypothesis for encephalitis lethargica. AB - Viruses have long been implicated in the pathogenesis of classical encephalitis lethargica, which was first described by Constantin von Economo in 1917. In this article, I propose the hypothesis that an airborne virus travels along the olfactory conduit to infect the olfactory bulb; this local infection or induced neuroinflammation, in turn, retrogradely targets certain neuronal populations with sleep-wake regulatory functions in the hypothalamus and midbrain, leading to the development of wakeful inactivity, a hallmark clinical feature of the disease. Furthermore, the olfactory vector hypothesis may also explain the pathomechanism of the debilitating complication of the disease, i.e., postencephalitic parkinsonism, in terms of a recently discovered nigro-olfactory projection. PMID- 28571799 TI - Human body may produce bacteria. AB - "Human body may produce bacteria" proposes that human body may produce bacteria and represent an independent source of infections contrary to the current paradigm of infectious disorders proposed by Louis Pasteur in 1880. The following observations are consistent with this hypothesis: A. Bidirectional transformations of both living and nonliving things have been commonly observed in nature. B. Complex multicellular organisms harbor the necessary properties to produce bacteria (water, nitrogen and oxygen). C. Physical laws suggest any previously observed phenomenon or action will occur again (life began on earth; a non living thing). D. Animal muscle cells may generate energy (fermentation). E. Sterilized food products (i.e. boiled eggs), may produce bacteria and fungus under special conditions and without any exposure to foreign living cells. "Human body may produce bacteria" may challenge the current medical paradigm that views human infectious disorders as the exclusive causative byproducts of invading foreign cells. It may also introduce new avenues to treat infectious disorders. PMID- 28571800 TI - The length and complexity of mesentery are related to the locoregional recurrence of the carcinoma in gut. AB - Local-regional relapse is the main recurrence pattern of the carcinoma in gut, and leads to poor prognosis. With the development of the total mesorectal and complete mesocolic excision (TME/CME), the local relapse rate of colorectal cancer has significantly decreased. People attributed it to the improvement of lymphadenectomy, but lymphatic metastasis is difficult to explain the local relapse in N0 patients. Previously, we have proven the existence of "Metastasis V" in mesogastrium and mesocolorectum, and supposed that it is one of the major risk factors in local recurrence. Therefore, we think complete mesentery excision can effectively reduce "Metastasis V", prevent cancer leak and improve patients' outcome. Due to the different length and complexity of mesentery, the difficulty of mesentery excision varies. Meanwhile, there is an obvious distinction of local relapse rate in different alimentary tract, even in different segment of a same organ. Thus we assume that the length and complexity of mesentery may be a risk factor of the locoregional recurrence of the carcinoma in gut. PMID- 28571801 TI - Hypothesis: Exosomal microRNAs as potential biomarkers for schizophrenia. AB - Schizophrenia is a serious mental disorder with lifelong morbidity and increased mortality. Currently, the diagnosis of the disorder is based on patient history and clinical examination, but it has a low inter-rater reliability and validity. Various biological variables, such as event related potentials, hormonal levels, brain ventricular volume and hippocampal size, have been put forth as objective markers to diagnose schizophrenia, but none with the desired sensitivity and specificity. It has been shown that microRNAs play a vital role in gene regulation in schizophrenia and have been proposed as possible biomarkers for the disease. When compared to the free microRNAs in the body fluids, exosomal microRNAs are more resistant to degradation and are easier to isolate. There are no studies reporting exosomal microRNAs as biomarkers for schizophrenia, but we hypothesize that exosomal microRNAs will be found to be potential biomarkers for diagnosis, prognosis assessment and medication response to patients with this disease. PMID- 28571803 TI - In Brucella: Selective pressure may turn some genes on instead of default off position. AB - Brucellosis is a major zoonosis with worldwide prevalence; more than half a million new human cases are expected every year. The genus Brucella (B) encompasses 12 accepted nomo-species and brucellae were described as Gram negative, aerobic, non-motile and non-haemolytic facultative intracellular bacteria. The Brucella genome contains flagella-specific genes and various hemolysins, but no flagella are formed and nor hemolysis is seen. Selective pressure can cause accumulation of mutations that turn those genes on instead of default off position and provoked the motile and hemolytic phenotypes. The ability of brucellae to change from a non-haemolytic to a haemolytic phenotype might influence their pathogenicity and could provide a substantial insight to explain the correlation of acute brucellosis and hemolytic anemia in humans. PMID- 28571802 TI - A homologous stem cell therapy for obesity and its related metabolic disorders. AB - Obesity and overweight have become a leading health problem in the world. But we have not yet had any optimal therapy to prevent this health issue. Accumulating evidence suggests that there is existence of functional brown/brite adipocytes in both infants and adult humans, and the activated brown/brite can burn energy by generating heat. These adipocytes can be differentiated from stem cells and transplantation of pre-activated human thermogenic adipocytes in vitro benefits to glucose homeostasis, insulin sensitivity and reduces body fat in normal or obese immunodeficient mice. These investigations lead us to hypothesize a homologous stem cell therapy to treat obesity and its related disorders. The therapy bases on functional brown/brite adipocytes which are differentiated from homologous stem cells isolated from fat depot of an obese person, and those adipocytes are activated to have a full thermogenic program before being transplanted back to that patient to improve glucose homeostasis and reduce fat content. PMID- 28571804 TI - Bacterial resistance and failure of clinical cure could be produced by oxidative stress in patients with diabetes or cardiovascular diseases during fluoroquinolone therapy. AB - Fluoroquinolone agents are used widely for the treatment of infectious diseases which are a common cause of deaths around the world. The level of oxidative stress in patients taking fluoroquinolone antibiotics has not been considered a factor to reduce the clinical efficacy of this kind of drugs. Patients with diabetes and/or cardiovascular diseases present abnormal levels of oxidative stress in the blood stream. In this regards, our hypothesis supposes that patients with diabetes and/or cardiovascular disease suffering a bacterial disease could experience a therapeutic failure and bacterial resistance when treated with fluoroquinolones. The crucial mechanism could be an inefficient blood distribution of the drug via red blood cell dysfunction induced by oxidative stress that might reduce the pharmacokinetic-pharmacodinamic ratios. In this way, we review the scientific information to support our hypothesis alongside possible implications. Additionally, this work exhibits the urgent need of studies considering these conditions for quinolone agents. PMID- 28571805 TI - Gallium and silicon synergistically promote osseointegration of dental implant in patients with osteoporosis. AB - Over the last few decades, a wide variety of dental implants have been successfully placed in jaw bones to restore tooth function. But major challenges still remain in patients with osteoporosis involving compromised osseointegration, and the therapeutic methods is far from optimism. Gallium can directly inhibit bone osteolysis, prevent bone calcium release and augment bone mass, which makes Ga unique among the potential antiresorptive drugs. Silicon, as an indispensable modulator in bone formation, presents its bone anabolic effects, while reduces, at least doesn't increase, bone resorption. We hypothesize that the combination of bone anabolic effects of Si and antiresorptive effects of Ga will result in synergistic effects on the improvement of osteointegration under osteoporotic condition. In our strategy, in order to maximize the efficacy while minimize the side effects of ions, a novel titania mesoporous layer fabricated by electrochemical anodization on the surface of titanium implant will be employed as a promising local drug delivery system. The synergistic effects of Ga and Si on improving osseointegration will be verified by animal experiments, and be furthered by clinical trials. Our hypothesis could help to create an option to improve success rate of dental implants in osteoporotic patients. PMID- 28571806 TI - Bioinformatics approach to prioritize known drugs towards repurposing for tuberculosis. AB - New drugs are urgently needed to cure tuberculosis (TB) in a short period of time without causing any adverse effects since currently used drugs for the treatment of multi drug-resistant TB cause several adverse effects with poor success rate. Therefore, we aimed to prioritize known drugs towards repurposing for TB by employing bioinformatics approach in the present study. A total of 1554 FDA approved drugs were obtained from DrugBank. Serine/threonine-protein kinase, pknB (Rv0014c) of Mycobacterium tuberculosis (Mtb) was selected as the drug target since it involves in several vital functions of the Mtb. All of the 1554 drugs were subjected to molecular docking with pknB. Glide and AutoDock Vina were employed using rigid docking followed by induced fit docking protocol for prioritization of drugs. Out of 14 drugs prioritized, six are suggested as high confident drugs towards repurposing for TB as they were consistently found within top 10 ranks of both methods, and strongly binding in the active site of the pknB. We also found atorvastatin as one of the high-confident drugs, which has already been demonstrated to be active against Mtb under in vitro conditions by other researchers. Therefore, we propose that the prioritized six high-confident drugs as potential candidates for repurposing for TB and suggest for further experimental studies. We also suggest that the bioinformatics procedure we have employed in this study could be effectively applied for prioritization of drugs for other diseases. PMID- 28571807 TI - Dilated cardiomyopathy-induced disruption of basement membrane alters the lever systems acting on the heart. AB - Dilated cardiomyopathy (DCM) is considered the most common form of non-ischemic heart diseases. DCM, occurs in response to both non-genetic and genetic factors, and has been associated with cytoskeletal protein mutations, impairing the contractile apparatus of cardiac myocytes. However, the pathology underlying the marked left ventricular dilatation remains unclear. Moreover, patients with end stage DCM show alterations in the composition of the extracellular matrix (ECM), and myocardial fibrosis even when the cardiac myocytes are intact. Therefore we hypothesize that DCM is a disease of basement membrane, which functions to support sarcomeric interactions with the ECM, and not only impaired cardiac contractility. We propose that under physiological conditions, the heart could be considered a second-class lever system. Disruption of the basement membrane in DCM would cause disarray in the alignment of cardiac myocytes and alteration in the second-class lever system of the heart. Thus, current inotropic agents show minimal or no effect on therapy as they target cardiac contractility rather than cardiac architecture and the lever systems of the heart. PMID- 28571808 TI - Nanoparticle-loaded biodegradable light-responsive in situ forming injectable implants for effective peptide delivery to the posterior segment of the eye. AB - Diseases affecting the posterior segment the eye, such as age-related macular degeneration (AMD), are the leading cause of blindness worldwide. Conventional dosage forms, such as eye drops, have to surmount several elimination mechanisms and complex barriers to achieve therapeutic concentrations at the target site often resulting in low anterior segment bioavailability (ca. 2-5%) with generally none of the drug reaching posterior segment tissues. Thus, frequent intravitreal injections are currently required to treat retinal conditions which have been associated with poor patient compliance due to pain, risk of infection, hemorrhages, retinal detachment and high treatment related costs. To partially overcome these issues, ocular implants have been developed for some posterior segment indications; however, the majority require surgical implantation and removal at the end of the intended treatment period. The transparent nature of the cornea and lens render light-responsive systems an attractive strategy for the management of diseases affecting the back of the eye. Light-responsive in situ forming injectable implants (ISFIs) offer various benefits such as ease of application in a minimally invasive manner and more site specific control over drug release. Moreover, the biodegradable nature of such implants avoids the need for surgical removal after release of the payload. Incorporating drug-loaded polymeric nanoparticles (NPs) into these implants may reduce the high initial burst release from the polymeric matrix and further sustain drug release thus avoiding the need for frequent injections as well as minimizing associated side effects. However, light-responsive systems for ophthalmic application are still in their early stages of development with limited reports on their safety and effectiveness. We hypothesize that the innovative design and properties of NP containing light-responsive ISFIs can serve as a platform for effective management of ocular diseases requiring long term treatment. PMID- 28571809 TI - Was aneurysm rupture a frequent cause of death in past population? PMID- 28571810 TI - Predictive role of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in normal-tension glaucoma. AB - As a type of primary open-angle glaucoma, normal-tension glaucoma (NTG) is a health problem that manifests itself with low intraocular pressure (IOP) levels and preserves its importance for public health care. In population-based screenings, which take the IOP levels of 21mmHg as a cut-off for the diagnosis of glaucoma, the diagnosis is usually delayed, and the treatment is started in an advanced stage by the referred ophthalmologists. NTG is associated with some autoimmune conditions and systemic diseases, such as paraproteinemia, nocturnal hypotension, and migraine. Recently, a simple and cheap test (namely the hemogram) was defined as measure of systemic inflammation, measuring the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). A recent study displayed an altered platelet function in NTG patients. We hypothesize that an automated hemogram analysis for NLR together with IOP measurements may be used to screen NTG patients who are admitted to primary care clinics if any relationship between NTG and NLR could be demonstrated in future researches. PMID- 28571811 TI - Can modifying content of hallucinations be a strategy to treat schizophrenia? PMID- 28571812 TI - A hypothesis for mechanism for brain oedema due to glycine. AB - Death following the use the glycine distension solution in transurethral prostatectomy (TURP) or hysteroscopic surgery has been attributed to the toxic effect of glycine on the brain through the glycine receptors and hyperammonemia, contending that glycine-associated hyponatremia is isosmotic and therefore would not cause brain oedema. Here we propose a hypothesis that the mechanism of brain oedema and death is actually osmotic brain oedema caused by selective diffusion of glycine into the brain while sodium cannot diffuse out of the brain despite favourable concentration gradient because of the absence of sodium transporter on the cerebral capillaries needed for the exit of sodium from the brain. The mechanism for unidirectional diffusion of solutes into the brain in glycine associated hyponatremia is explained. PMID- 28571813 TI - Might tumor secreted cathepsin proteases leave specific molecular signals in skin, hair and nails years before a cancer becomes clinically apparent? AB - X-ray fiber diffraction analysis (FDA) of the fibrous macromolecules in hair, nails and skin has been shown to non-invasively diagnose various cancers, at sites remote from the cancer, years before the cancer becomes clinically apparent. The technology is not widely accepted because of reproducibility issues (that can be easily resolved) and lack of an explanation as to how a clinically unapparent tumor can leave molecular "signatures" at remote sites. However, there is evidence that tumor-specific cathepsins (lysosomal proteases) circulate systemically long before a cancer is clinically apparent. As such, we hypothesize that cathepsins, by virtue of their proteolytic activity, impart molecular changes in tissues remote from the primary tumor. These subtle molecular changes, which are specific for various tumors, can be readily detected by FDA of hair, nails and skin. We call for more research in the utility of FDA and tumor specific cathepsins for the early and non-invasive diagnosis of various malignancies. PMID- 28571814 TI - Polycystic ovary syndrome in men. PMID- 28571815 TI - Hypothesis: Co-transfer of genuine embryos and implantation-promoting compounds via artificial containers improve endometrium receptivity. AB - As with other organs endometrial functions are altered with the advancing age. Age related decrease in reproductive functions leads to decline in the number of oocytes retrieved and the synthesis of endometrial receptivity molecules. Despite the significant improvement in assisted reproductive technologies we do not have so many options to enhance endometrial receptivity. Due to lack of drugs having endometrium receptivity enhancement properties, oocyte donation seems to be the only solution for women with implantation failure. The euploid oocytes come from young and healthy donors may overcome age associated endometrial receptivity defect. Nevertheless, many reasons restrict us from using oocyte donation in women with implantation failure. We, therefore, hypothesized that by mimicking a young blastocyst's effect on endometrium, the transfer of genuine embryos and implantation-promoting compounds together might be the new treatment option for infertile women with recurrent implantation failure. Artificial beads, MI or GV oocytes, and empty zona can be used as a container for intrauterine replacement of implantation-promoting compounds. PMID- 28571816 TI - The role of predictive coding in the pathogenesis of delirium. AB - Delirium and dementia represent an emerging global crisis in healthcare. Attempts have been made to identify the pathognomonic feature that would make delirium stand out from dementia but unfortunately the global neural dysfunction of both disorders has made the establishment of a direct measurement difficult. Modern conceptualisations of delirium have been influenced by the assessment tools used to assess, detect, and analyse its complex and transient nature. Recent publication of the DSM-V criteria for delirium has marginally altered the previous DSM-IV criteria with a focus upon inattention with vague terms such as consciousness downplayed. Such an alteration has been found to be restrictive and thus impact upon delirium case identification. Although these findings are approximating the empirical state of delirium as measured by validated instruments, a more refined neuroscientifically informed phenomenological framework is required in order to enhance the theoretical understanding of delirium assessment and resolve these challenges. One such application is the predictive coding (PC) model, also known as the hierarchical Bayesian inference model, to interpreting delirium pathophysiology. Therefore, the aims of this paper are to 1) propose the hypothesis that delirium pathophysiology can be explained in terms of the PC model, 2) support this hypothesis by applying this model to current methods of assessing delirium phenomenology, particularly attention, and 3) outline a future programme of research to test many of the parameters of this application. PMID- 28571817 TI - Development of orbital adipose-derived stem cells as a model for studying the formation of baggy lower eyelids. AB - In old population, there is often a protrusion of the orbital fat pad underlying the skin in the lower eyelids, giving an aspect of palpable pouches. It is generally thought that orbital fat hyperplasia is the main contributing factor to the formation of baggy lower eyelids, and resection of excessive orbital fat pad is routinely performed during the eyelid cosmetic surgery. In our clinical study, however, it was revealed that the adipocytes in orbital fat tissue from older people became smaller compared to those from the young individuals. Based on this finding, we hypothesize that the orbital fat size may not increase, but decrease with age, and the declined fat depot volume is related to the reduced fat cell size and impaired differentiation of preadipocytes into fat cells. Adipose derived stem cells (ASCs) are a population of postnatal stem cells residing in the fat tissue, capable of differentiating into preadipocytes and subsequently into mature fat cells throughout the lifespan. As preadipocytes are a substantial component of fat tissue and can greatly influence the fat composition and function, we speculate that orbital adipose-derived stem cells can be used as an excellent model to determine effects of aging on orbital fat. By evaluating the age-related changes in preadipocyte number, replication, and differentiation, we can reveal alterations in orbital fat cellularity and function with age, and investigate the relationship between orbital fat volume and the of baggy lower eyelid formation. PMID- 28571818 TI - Association between oxidative status and the composition of intestinal microbiota along the gastrointestinal tract. AB - Studies have shown that the microbiota along the gastrointestinal tract (GIT) plays an important role when it comes to the maintenance of its proper functions. Many studies exist that have analyzed the composition of the bacterial community in the different regions of the GIT of humans and model animals. Microbial imbalance leads to several systemic disorders, including cardiovascular and renal disease. The imbalance between the production of reactive oxygen species (ROS) and their elimination by antioxidants leads to oxidative stress. Oxidative stress plays an important role in a variety of physiological processes, as well as disease. The continuous formation of ROS in the GIT is the result of the interaction between intestinal mucosa, symbiotic bacteria and dietary factors. It has also been proven that ROS play a role in the pathogenesis of several GI disorders, including IBD. We hypothesized that the levels of advanced glycation end products (AGEs) would be the highest in the ileum, caecum or colon, where the microbiota mostly consist of butyrate producing bacteria, Bacterioides, Clostridium, Ruminococcus or Bifidobacterium, which derive energy through carbohydrate fermentation. We also assumed that advanced oxidation protein products (AOPP) mostly act in the segments, where bacteria reside and which are responsible for the amino acid fermentation, such as caecum or colon. Lipid hydroxyperoxides are generated during digestion in the stomach, which contains absorbed oxygen and has a low pH. According to this we hypothesized that the highest concentration of thiobarbituric acid reacting substances (TBARS) could be in the stomach, which, however, has not been confirmed. Because Lactobacilli are able to produce catalase, an endogenous antioxidant, and are abundant in the small intestine, we hypothesized that antioxidant capacity (measured by ferric reducing ability) would be the highest here. The highest levels of AGEs were found in the caecum. The highest level of TBARS was found in the jejunum of the rats. The assessment of our hypothesis also revealed high levels of AOPP in the caecum. It has been shown that AOPP contributes to the progression of IBD. The ferric reducing ability of tissue was the lowest in the colon of the experimental animals, which is in accordance with previous studies that show that rat colon has a lower total antioxidant capacity than the small bowel. In summary, we offer some insight into the differences between the oxidative status along the GIT of rats and some advice concerning supportive antioxidant therapy of gastrointestinal diseases. PMID- 28571819 TI - Chronic eczematous dermatitis in patients with neurodegenerative diseases may be an early marker of bullous pemphigoid. AB - The number of elderly patients with chronic pruritus has been gradually increasing in aging countries. Bullous pemphigoid, a common autoimmune blister disease in the elderly, is always heralded by pruritic eczematous dermatitis and is often associated with neurodegenerative diseases. We hypothesized that chronic eczematous dermatitis in patients with neurodegenerative diseases may be an early marker of bullous pemphigoid. By conducting retrospective chart review, we found neurodegenerative diseases are more prevalent in elderly patients with chronic eczematous dermatitis. The mean time delay between the diagnosis of neurodegenerative diseases and onset of skin lesions is 4.17years. In all 6 patients who received skin biopsy, eosinophils in the upper dermis or at the dermo-epidermal junction were obvious, which are remnant of the pathological finding of bullous pemphigoid. Together with the well-known association between bullous pemphigoid and neurodegenerative diseases, the results suggested that unlocalized eczematous dermatitis in the elderly may be an early manifestation of bullous pemphigoid. Inter-discipline communication among neurology, dermatology and geriatrics/gerontology is required to tailor specific managements for elderly patients with pruritus and neurodegenerative diseases. PMID- 28571820 TI - Cannabinoid hyperemesis syndrome: A disorder of the HPA axis and sympathetic nervous system? AB - Cannabinoid hyperemesis syndrome (CHS), a variant of cyclic vomiting syndrome, is an enigmatic and challenging clinical disorder. As cannabis legalization, use, and potency has increased worldwide over the past decade, so has the prevalence of CHS. These patients often require acute care and inpatient treatment for refractory emesis, electrolyte derangement, dehydration, acute renal failure, and injury to the upper gastrointestinal tract. Routinely-prescribed antiemetics are frequently associated with treatment failure in CHS, necessitating use of sedating agents such as benzodiazepines and antipsychotics. Hydrotherapy with hot water provides short-term symptomatic relief from acute episodes of CHS. The reasons for this may be from chronic and/or excessive cannabis use leading to abnormal stimulation of the hypothalamic-pituitary-adrenal axis (HPA) and sympathetic nervous system (SNS) in CHS patients. Overuse of cannabis may also lead to dysfunction of the endocannabinoid system, which is essential for allostasis of the autonomic nervous system after stress. PMID- 28571821 TI - Rhinitis and sleep disorders: The trigeminocardiac reflex link? AB - Rhinitis, allergic or non-allergic, is an inflammatory condition of the nose. It is associated with a wide range of sleep disorders that are generally attributed to nasal congestion and presence of inflammatory mediators like cytokines and interleukins. However, the pathophysiological mechanisms behind these sleep disorders remain unclear. On the other hand, the trigeminocardiac reflex (TCR) has recently been linked to various sleep disorders like obstructive sleep apnea, sleep bruxism and rapid eye movement (REM) sleep apnea. TCR can be incited by stimulation of the trigeminal nerve or the area innervated by its branches including the nasal mucosa. Trigeminal nasal afferents can be activated on exposure to noxious stimuli (mechanical or chemical) like ammonia vapors, carbon dioxide, nicotine, hypertonic saline, air-puffs and smoke. In rhinitis, there is associated neuronal hyper-responsiveness of sensory nasal afferents due to inflammation (which can be suppressed by steroids). This may further lead to increased occurrence of TCR in rhinitis. Moreover, there is involvement of autonomic nervous system both in rhinitis and TCR. In TCR, parasympathetic over activity and sympathetic inhibition leads to sudden onset bradycardia, hypotension, apnea and gastric motility. Also, the autonomic imbalance reportedly plays a significant role in the pathophysiology of rhinitis. Thus, considering these facts we hypothesize that the TCR could be the link between rhinitis and sleep disorders and we believe that further research in this direction may yield significant development in our understanding of sleep disorders in rhinitis. PMID- 28571822 TI - Minor phenolics from Angelica keiskei and their proliferative effects on Hep3B cells. AB - A new coumarin, (-)-cis-(3'R,4'R)-4'-O-angeloylkhellactone-3'-O-beta-d glucopyranoside (1) and two new chalcones, 3'-[(2E)-5-carboxy-3-methyl-2 pentenyl]-4,2',4'-trihydroxychalcone (4) and (+/-)-4,2',4'-trihydroxy-3'-{2 hydroxy-2-[tetrahydro-2-methyl-5-(1-methylethenyl)-2-furanyl]ethyl}chalcone (5) were isolated from the aerial parts of Angelica keiskei (Umbelliferae), together with six known compounds: (R)-O-isobutyroyllomatin (2), 3'-O-methylvaginol (3), ( )-jejuchalcone F (6), isoliquiritigenin (7), davidigenin (8), and (+/-) liquiritigenin (9). The structures of the new compounds were determined by interpretation of their spectroscopic data including 1D and 2D NMR data. All known compounds (2, 3, and 6-9) were isolated as constituents of A. keiskei for the first time. To identify novel hepatocyte proliferation inducer for liver regeneration, 1-9 were evaluated for their cell proliferative effects using a Hep3B human hepatoma cell line. All isolates exhibited cell proliferative effects compared to untreated control (DMSO). Cytoprotective effects against oxidative stress induced by glucose oxidase were also examined on Hep3B cells and mouse fibroblast NIH3T3 cells and all compounds showed significant dose-dependent protection against oxidative stress. PMID- 28571823 TI - Synthesis and in vitro evaluation of three novel radiotracers for imaging of metabotropic glutamate receptor subtype 2 in rat brain. AB - The purpose of this study was to develop three new radiotracers, 1 (cyclopropylmethyl)-4-([11C/18F]substituted-phenyl)piperidin-1-yl-2-oxo-1,2 dihydropyridine-3-carbonitrile ([11C]1, [11C]2, and [18F]4), and to examine their specific bindings with metabotropic glutamate receptor subtype 2 (mGluR2) in rat brain sections by using in vitro autoradiography. These compounds were found to possess potent in vitro binding affinities (Ki: 8.0-34.1nM) for mGluR2 in rat brain homogenate. [11C]1, [11C]2, and [18F]4 were synthesized by [11C/18F]alkylation of the corresponding phenol precursors with [11C]methyl iodide or [18F]fluoroethyl bromide with >98% radiochemical purity and 80 130GBq/MUmol specific activity at the end of synthesis. In vitro autoradiography indicated that these radiotracers showed heterogeneous specific bindings in mGluR2-rich brain regions, such as the cerebral cortex, striatum, hippocampus, and granular layer of the cerebellum. PMID- 28571824 TI - Design, synthesis and SAR of new-di-substituted pyridopyrimidines as ATP competitive dual PI3Kalpha/mTOR inhibitors. AB - PI3Kalpha/mTOR ATP-competitive inhibitors are considered as one of the promising molecularly targeted cancer therapeutics. Based on lead compound A from the literature, two similar series of 2-substituted-4-morpholino-pyrido[3,2 d]pyrimidine and pyrido[2,3-d]pyrimidine analogs were designed and synthesized as PI3Kalpha/mTOR dual inhibitors. Interestingly, most of the series gave excellent inhibition for both enzymes with IC50 values ranging from single to double digit nM. Unlike many PI3Kalpha/mTOR dual inhibitors, our compounds displayed selectivity for PI3Kalpha. Based on its potent enzyme inhibitory activity, selectivity for PI3Kalpha and good therapeutic index in 2D cell culture viability assays, compound 4h was chosen to be evaluated in 3D culture for its IC50 against MCF7 breast cancer cells as well as for docking studies with both enzymes. PMID- 28571825 TI - Evaluation of the antiprotozoan properties of 5'-norcarbocyclic pyrimidine nucleosides. AB - Carbocyclic nucleoside analogues have a distinguished history as anti-infectious agents, including key antiviral agents. Toxicity was initially a concern but this was reduced by the introduction of 5'-nor variants. Here, we report the result of our preliminary screening of a series of 5'-norcarbocyclic uridine analogues against protozoan parasites, specifically the major pathogens Leishmania mexicana and Trypanosoma brucei. The series displayed antiparasite activity in the low to mid-micromolar range and establishes a preliminary structure-activity relationship, with the 4',N3-di-(3,5-dimethylbenzoyl)-substituted analogues showing the most prominent activity. Utilizing an array of specially adapted cell lines, it was established that this series of analogues likely act through a common target. Moreover, the strong correlation between the trypanocidal and anti leishmanial activities indicates that this mechanism is likely shared between the two species. EC50 values were unaffected by the disabling of pyrimidine biosynthesis in T. brucei, showing that these uridine analogues do not act directly on the enzymes of pyrimidine nucleotide metabolism. The lack of cross resistance with 5-fluorouracil, also establishes that the carbocyclic analogues are not imported through the known uracil transporters, thus offering forth new insights for this class of nucleosides. The lack of cross-resistance with current trypanocides makes this compound class interesting for further exploration. PMID- 28571826 TI - Mucinous Signet-Ring Urachal Carcinoma of the Bladder: Case Report and Review of the Literature. PMID- 28571828 TI - Offline: Dear Tedros.... PMID- 28571829 TI - Corrigendum to "A clinical, randomized, controlled study on the use of desensitizing agents during tooth bleaching" [J. Dent. 43 (9) (2015) 1099-1105]. PMID- 28571827 TI - Effect on Overall Survival of Locoregional Treatment in a Cohort of De Novo Metastatic Prostate Cancer Patients: A Single Institution Retrospective Analysis From the Royal Marsden Hospital. AB - BACKGROUND: The optimal management of the primary tumor in metastatic at diagnosis (M1) prostate cancer (PCa) patients is not yet established. We retrospectively evaluated the effect of locoregional treatment (LRT) on overall survival (OS) hypothesizing that this could improve outcome through better local disease control and the induction of an antitumor immune response (abscopal effect). PATIENTS AND METHODS: M1 at diagnosis PCa patients referred to the Prostate Targeted Therapy Group at the Royal Marsden between June 2003 and December 2013 were identified. LRT was defined as either surgery, radiotherapy (RT) or transurethral prostatectomy (TURP) administered to the primary tumor at any time point from diagnosis to death. Kaplan-Meier analyses generated OS data. The association between LRT and OS was evaluated in univariate (UV) and multivariate (MV) Cox regression models. RESULTS: Overall 300 patients were identified; 192 patients (64%) experienced local symptoms at some point during their disease course; 72 patients received LRT (56.9% TURP, 52.7% RT). None of the patients were treated with prostatectomy. LRT was more frequently performed in patients with low volume disease (35.4% vs. 16.2%; P < .001), lower prostate specific antigen (PSA) level at diagnosis (median PSA: 75 vs. 184 ng/mL; P = .005) and local symptoms (34.2% vs. 4.8%; P < .001). LRT was associated in UV and MV analysis with longer OS (62.1 vs. 55.8 months; hazard ratio [HR], 0.74; P = .044), which remained significant for RT (69.4 vs. 55.1 months; HR, 0.54; P = .002) but not for TURP. RT was associated with better OS independent of disease volume at diagnosis. CONCLUSION: These data support the conduct of randomized phase III trials to evaluate the benefit of local control in patients with M1 disease at diagnosis. PMID- 28571830 TI - Effect of bulk-fill base material on fracture strength of root-filled teeth restored with laminate resin composite restorations. AB - OBJECTIVES: To evaluate the effect of using a bulk-fill flowable base material on fracture strength and fracture patterns of root-filled maxillary premolars with MOD preparations restored with laminate restorations. METHODS: Fifty extracted maxillary premolars were selected for the study. Standardized MOD cavities with endodontic treatment were prepared for all teeth, except for intact control. The teeth were divided randomly into five groups (n=10); (Group 1) sound teeth, (Group 2) unrestored teeth; (Group 3) MOD cavities with Vitrebond base and resin based composite (Ceram. X One Universal); (Group 4) MOD cavities with 2mm GIC base (Fuji IX GP) and resin-based composite (Ceram. X One Universal) open laminate, (Group 5) MOD cavities were restored with 4mm of bulk-fill flowable base material (SDR) and resin-based composite (Ceram. X One Universal). All teeth were thermocycled and subjected to a 45 degrees ramped oblique load in a universal testing machine. Fracture load and fracture patterns were recorded. Data were analyzed using one-way ANOVA and Dunnett's T3 test. RESULTS: Restoration in general increased the fracture strength compared to unrestored teeth. The fracture strength of group 5 (bulk-fill) was significantly higher than the fracture strength of the GIC laminate groups and not significantly different from the intact teeth (355+/-112N, P=0.118). The type of failure was unfavorable for most of the groups, with the majority being mixed failures. CONCLUSIONS: The use of a bulk-fill flowable base material significantly increased the fracture strength of extracted root-filled teeth with MOD cavities; however it did not improve fracture patterns to more favorable ones. CLINICAL SIGNIFICANCE: Investigating restorative techniques that may improve the longevity of root filled premolar teeth restored with direct resin restorations. PMID- 28571831 TI - Sustainable waste-to-value biogas plants for developing countries. PMID- 28571833 TI - Review of Prenatal Maternal Mental Health and the Development of Infant Temperament. AB - OBJECTIVE: To present a systematic review of literature and evaluate effects of prenatal maternal depression and anxiety on the development of infant temperament. DATA SOURCES: A literature search for studies published between January 1981 and January 2017 was undertaken using the electronic databases PsycINFO and PubMed, as well as reference lists from select resources. Search terms included variations on infant temperament, prenatal/pregnancy, depression, mood, and anxiety. STUDY SELECTION: Studies were included if researchers measured psychological distress during pregnancy as indicated by maternal depression, anxiety, pregnancy-specific anxiety, or a combination of these factors in relation to the development of infant temperament (i.e., parent report or laboratory observations of temperament from 1 to 12 months). In total, 34 articles met inclusion criteria. DATA EXTRACTION: Authors, year of publication, country of origin, sample information, methods, timing, and applicable results were summarized and compared across studies. DATA SYNTHESIS: No standardized data analysis was conducted because of methodologic differences across the identified studies. Of the 34 identified studies, 22 included an indicator of depression (11 with significant results), 26 included an indicator of anxiety (14 with significant results), and 9 included an indicator of pregnancy-specific anxiety (7 with significant results). CONCLUSION: Overall research outcomes were equivocal. Across studies on symptoms of depression and anxiety, findings related to the potential effect on infant temperament were mixed. Nonetheless, support for the role of prenatal psychological factors in the development of infant temperament emerged in a subset of population-based studies, including research to target the effects of pregnancy-specific anxiety. Future research is needed with greater consistency across studies with respect to methods (e.g., timing and assessment tools). Specific recommendations for nurses and providers include more routine screening and psychoeducation for expectant mothers about prenatal symptoms of depression and anxiety and about pregnancy-specific anxiety in particular. PMID- 28571832 TI - De Novo Gene Expression Reconstruction in Space. AB - The biological function of a gene often depends on spatial context, and an atlas of transcriptional regulation could be instrumental in defining functional elements across the genome. Despite recent advances in single-cell RNA sequencing and in situ RNA imaging, fundamental barriers limit the speed, genome-wide coverage, and resolution of de novo transcriptome assembly in space. Here, I discuss potential next-generation approaches for the de novo assembly of the transcriptome in space, and propose more efficient methods of detecting long range spatial variations in gene expression. Finally, I discuss future in situ sequencing chemistries for visualizing biological pathways and processes in tissues so that genomics technologies might be more easily applied to conditions of human health and disease. PMID- 28571834 TI - Self-powered therapeutic release from conducting polymer/graphene oxide films on magnesium. AB - Magnesium's complete in vivo degradation is appealing for medical implant applications. Rapid corrosion and hydrogen bubble generation along with inflammatory host tissue response have limited its clinical use. Here we electropolymerized a poly (3,4-ethylenedioxythiophene) (PEDOT) and graphene oxide (GO) film directly on Mg surface. GO acted as nano-drug carrier to carry anti inflammatory drug dexamethasone (Dex). PEDOT/GO/Dex coatings improved Mg corrosion resistance and decreased the rate of hydrogen production. Dex could be released driven by the electrical current generated from Mg corrosion. The anti inflammatory activity of the released Dex was confirmed in microglia cultures. This PEDOT/GO/Dex film displayed the ability to both control Mg corrosion and act as an on demand release coating that delivers Dex at the corrosion site to minimize detrimental effects of corrosion byproducts. Such multi-functional smart coating will improve the clinical use of Mg implants. Furthermore, the PEDOT/GO/Drug/Mg system may be developed into self-powered implantable drug delivery devices. PMID- 28571836 TI - [Congenital anterior Staphyloma: Case report]. PMID- 28571835 TI - [Cataract surgery among 50 Alzheimer's patient (55 eyes)]. AB - OBJECTIVE: Cataract surgery for 50 Alzheimer patients (55 eyes). METHODS: Cinquante Alzheimer's patients with 0<=MMS<=25, with bilateral disabling cataracts were included for surgery. The surgical technique is analyzed. RESULTS AND CONCLUSION: The preoperative examination of Alzheimer's patients is time consuming and requires experience in this area, which is important to integrate into the practice of ophthalmology. The type of cataract is unusual, with a predilection for pseudoexfoliation syndrome and zonular fragility that has to be managed during surgery. The procedure may be performed under local anesthesia. Three months after surgery, Alzheimer's patients demonstrated improved visual acuity (P<0.001) with no worsening of their dementia. PMID- 28571837 TI - [Prevalence and causes of pain after cataract surgery: Comparison of 1st and 2nd eyes]. AB - INTRODUCTION: In our practice, patients undergoing bilateral cataract surgery complain of more significant pain after the 2nd eye surgery. The goal of this study was to compare postoperative pain between the 1st and 2nd eyes with cataract surgery under topical anesthesia and to identify the causes of this pain. PATIENTS AND METHODS: We conducted a prospective observational study between May and September 2015. We included 69 consecutive adults scheduled for bilateral cataract surgery under topical anesthesia within 2 months by the same surgeon. A self-assessment questionnaire of anxiety (the Amsterdam Preoperative Anxiety and Information Scale [APAIS]) was completed before each procedure. Postoperative pain was assessed by the visual analogue scale (VAS) in the recovery room. RESULTS: Among the 69 included patients (mean age: 70+/-1.3 years), 13 (19%) experienced more pain after the 2nd eye procedure. The median VAS was 0 (EI: 0-1) after the first eye versus 0 (EI: 0-2) after the second eye (P=0.836). The patients with the most pain after the second eye surgery had a median anxiety score of 5 (EI: 4 to 9.5), which was comparable to those without pain (P=0.589). On bivariate analysis, women had more pain after second eye surgery (27%) than men (4%) (P=0.026). However, this association lost its significance when the analysis was adjusted for the level of anxiety (adjusted OR 7.7, 95% CI [0.91; 64.6]). In fact, women were more anxious [median anxiety score of 6 (EI: 4 to 8.5)] before 2nd eye surgery than men [median score: 4 (EI: 4-6); P=0.013]. DISCUSSION: Pain levels appeared to be very moderate on both sides when measured postoperatively, as opposed to statements often made in the immediate postoperative period. There is a discrepancy with the literature data. However, each study had small sample sizes. CONCLUSION: We did not find any significant difference in pain between 1st and 2nd eye cataract surgery under topical local anesthesia. While postoperative pain appeared greater among women, we have noted the possible influence of anxiety, which could justify specific preoperative support. PMID- 28571838 TI - [Spasm of iris dilator muscle or tadpole-shaped pupil]. PMID- 28571839 TI - [Perception of glaucoma and therapeutic adherence: A multicenter observational study]. AB - INTRODUCTION: The purpose of this study was to evaluate medication adherence of glaucoma patients through the "Glaucoma treatment compliance assessment tool (GTCAT)" questionnaire and to correlate the results with clinical parameters. PATIENTS AND METHODS: This multicenter prospective observational study was performed in the Departement hospitalo-universitaire (DHU) Sight Restore, Paris, France. All patients had been followed for chronic open angle glaucoma (COAG) for at least 3 years. A French version of the GTCAT questionnaire was administered to patients. The results were correlated with clinical parameters of glaucoma, such as duration of disease, medications used, intraocular pressure (IOP) and mean deviation (MD) of the most recent visual field. RESULTS: Seventy-three patients were included in our study, with 60.9% declaring that they fully adhered to the treatment. There was a correlation between the amount of days missing treatment and difficulties using the eye drops. The main cause of missing the drops was forgetfulness (75%), followed by unavailability of the drop when it was time to take it (37.5%). The impact of glaucoma on quality of life was correlated to the amount of adverse effects of topical medications. The patient's perception of the importance of preserving vision was correlated to the level of confidence in the physician concerning the diagnosis of glaucoma. CONCLUSION: In glaucoma patients, the use of the GTCAT questionnaire confirmed the complex relationship between the patient, the disease and its treatment, and even his or her relationship with the ophthalmologist. These results emphasized the importance of therapeutic education but also the negative role of side effects of the eye drops on treatment adherence in glaucoma patients. PMID- 28571840 TI - Staphylococcus aureus delta-toxin in aqueous solution: Behavior in monomeric and multimeric states. AB - delta-Toxin is a 26 amino acid peptide capable of lysing several mammalian cell types and subcellular structures. Structurally, delta-toxin predominantly exhibits a alpha-helical secondary structure in membranes but, in aqueous solution, it adopts varying helical content. As no atomic-level data is available for this peptide in aqueous solutions and for the water-to-membrane transition, this work aims to characterize delta-toxin behavior in these conditions through molecular dynamics simulations in triplicates employing four different parameter sets. Our results, validated on previous experimental data, suggest that the peptide has from 4 to 16 residues folded as alpha-helix in aqueous solution, and a water-to-membrane foldamer comprising residues 14-18. Considering a previously proposed stable tetramer form in aqueous solutions, protein-protein docking and molecular dynamics studies were performed, suggesting that delta-toxin increases its alpha-helical content in such organization. The obtained results are expected to contribute in future studies on delta-toxin aggregation and interaction to biomembranes. PMID- 28571841 TI - Are article's social media mentions associated to citation counts? An analysis in highly influential medical journals. PMID- 28571842 TI - [Evaluation of multidisciplinary team meeting; the example of gynecological mammary cancers in a tertiary referral center in Morocco]. AB - The multidisciplinary team meeting has become a standard medical practice in oncology. However, no evaluation of this activity was carried out in Morocco. The aim of this study was to evaluate the multidisciplinary team meeting of gynecological mammary cancers in a National Tertiary Referral Center. The study was carried out by retrospective analysis of 207 cases of patients randomly selected among the 1190 cases recruited during the year 2015. Completeness and quality criteria were evaluated. The global completeness rate of passage in multidisciplinary team meeting is 38%. According to the therapeutic specialities, the completeness of passage in multidisciplinary team meeting is 68% of surgery, 35% of medical oncology and 19% of radiotherapy. As far as localizations are concerned, the completeness of passage in multidisciplinary team meeting is 43% for the breast and only 19% for the cervix. A quorum was met 100% of the cases. In 96% of cases the treatment performed is in accordance with the decision of the multidisciplinary team meeting. Eighty-four percent of cases performed multidisciplinary team meeting within less than one month. This analysis shows that the completeness of the transition to multidisciplinary team meeting has not reached the 100% planned by our institution. However, the requirements for conducting the multidisciplinary team meeting were generally met. This study shows an organizational evolution of our structure based on collective and multidisciplinary medical decision. The national obligation measure of multidisciplinary team meeting is necessary. PMID- 28571843 TI - Size distribution, directional source contributions and pollution status of PM from Chengdu, China during a long-term sampling campaign. AB - Long-term and synchronous monitoring of PM10 and PM2.5 was conducted in Chengdu in China from 2007 to 2013. The levels, variations, compositions and size distributions were investigated. The sources were quantified by two-way and three way receptor models (PMF2, ME2-2way and ME2-3way). Consistent results were found: the primary source categories contributed 63.4% (PMF2), 64.8% (ME2-2way) and 66.8% (ME2-3way) to PM10, and contributed 60.9% (PMF2), 65.5% (ME2-2way) and 61.0% (ME2-3way) to PM2.5. Secondary sources contributed 31.8% (PMF2), 32.9% (ME2 2way) and 31.7% (ME2-3way) to PM10, and 35.0% (PMF2), 33.8% (ME2-2way) and 36.0% (ME2-3way) to PM2.5. The size distribution of source categories was estimated better by the ME2-3way method. The three-way model can simultaneously consider chemical species, temporal variability and PM sizes, while a two-way model independently computes datasets of different sizes. A method called source directional apportionment (SDA) was employed to quantify the contributions from various directions for each source category. Crustal dust from east-north-east (ENE) contributed the highest to both PM10 (12.7%) and PM2.5 (9.7%) in Chengdu, followed by the crustal dust from south-east (SE) for PM10 (9.8%) and secondary nitrate & secondary organic carbon from ENE for PM2.5 (9.6%). Source contributions from different directions are associated with meteorological conditions, source locations and emission patterns during the sampling period. These findings and methods provide useful tools to better understand PM pollution status and to develop effective pollution control strategies. PMID- 28571844 TI - An economic assessment of the health effects and crop yield losses caused by air pollution in mainland China. AB - Air pollution is severe in China, and pollutants such as PM2.5 and surface O3 may cause major damage to human health and crops, respectively. Few studies have considered the health effects of PM2.5 or the loss of crop yields due to surface O3 using model-simulated air pollution data in China. We used gridded outputs from the WRF-Chem model, high resolution population data, and crop yield data to evaluate the effects on human health and crop yield in mainland China. Our results showed that outdoor PM2.5 pollution was responsible for 1.70-1.99 million cases of all-cause mortality in 2006. The economic costs of these health effects were estimated to be 151.1-176.9 billion USD, of which 90% were attributed to mortality. The estimated crop yield losses for wheat, rice, maize, and soybean were approximately 9, 4.6, 0.44, and 0.34 million tons, respectively, resulting in economic losses of 3.4 billion USD. The total economic losses due to ambient air pollution were estimated to be 154.5-180.3 billion USD, accounting for approximately 5.7%-6.6% of the total GDP of China in 2006. Our results show that both population health and staple crop yields in China have been significantly affected by exposure to air pollution. Measures should be taken to reduce emissions, improve air quality, and mitigate the economic loss. PMID- 28571845 TI - Mitigation of atrazine, S-metolachlor, and diazinon using common emergent aquatic vegetation. AB - By the year 2050, the population of the United States is expected to reach over 418 million, while the global population will reach 9.6 billion. To provide safe food and fiber, agriculture must balance pesticide usage against impacts on natural resources. Challenges arise when storms cause runoff to be transported to aquatic receiving systems. Vegetated systems such as drainage ditches and constructed wetlands have been proposed as management practices to alleviate pesticide runoff. Twelve experimental mesocosms (1.3*0.71*0.61m) were filled with sediment and planted with a monoculture of one of three wetland plant species (Typha latifolia, Leersia oryzoides, and Sparganium americanum). Three mesocosms remained unvegetated to serve as controls. All mesocosms were amended with 9.2+/ 0.8MUg/L, 12+/-0.4MUg/L, and 3.1+/-0.2MUg/L of atrazine, metolachlor, and diazinon, respectively, over a 4hr hydraulic retention time to simulate storm runoff. Following the 4hr amendment, non-amended water was flushed through mesocosms for an additional 4hr. Outflow water samples were taken hourly from pre amendment through 8hr, and again at 12, 24, 48, 72, and 168hr post-amendment. L. oryzoides and T. latifolia had mean atrazine, metolachlor, and diazinon retentions from 51%-55% for the first 4hr of the experiment. Aside from S. americanum and atrazine (25% retention), unvegetated controls had the lowest pesticide retention (17%-28%) of all compared mesocosms. While native aquatic vegetation shows promise for mitigation of pesticide runoff, further studies increasing the hydraulic retention time for improved efficiency should be examined. PMID- 28571847 TI - Impact of microbial communities from tropical soils on the mobilization of trace metals during dissolution of cinnabar ore. AB - Biodissolution experiments on cinnabar ore (mercury sulphide and other sulphide minerals, such as pyrite) were performed with microorganisms extracted directly from soil. These experiments were carried out in closed systems under aerobic and anaerobic conditions with 2 different soils sampled in French Guyana. The two main objectives of this study were (1) to quantify the ability of microorganisms to mobilize metals (Fe, Al, Hg) during the dissolution of cinnabar ore, and (2) to identify the links between the type and chemical properties of soils, environmental parameters such as season and the strategies developed by indigenous microorganisms extracted from tropical natural soils to mobilize metals. Results indicate that microbial communities extracted directly from various soils are able to (1) survive in the presence of cinnabar ore, as indicated by consumption of carbon sources and, (2) leach Hg from cinnabar in oxic and anoxic dissolution experiments via the acidification of the medium and the production of low molecular mass organic acids (LMMOAs). The dissolution rate of cinnabar in aerobic conditions with microbial communities ranged from 4.8*10-4 to 2.6*10-3MUmol/m2/day and was independent of the metabolites released by the microorganisms. In addition, these results suggest an indirect action by the microorganisms in the cinnabar dissolution. Additionally, because iron is a key element in the dynamics of Hg, microbes were stimulated by the presence of this metal, and microbes released LMMOAs that leached iron from iron-bearing minerals, such as pyrite and oxy-hydroxide of iron, in the mixed cinnabar ore. PMID- 28571846 TI - Removal of Cs+ from water and soil by ammonium-pillared montmorillonite/Fe3O4 composite. AB - To remove cesium ions from water and soil, a novel adsorbent was synthesized by following a one-step co-precipitation method and using non-toxic raw materials. By combining ammonium-pillared montmorillonite (MMT) and magnetic nanoparticles (Fe3O4), an MMT/Fe3O4 composite was prepared and characterized. The adsorbent exhibited high selectivity of Cs+ and could be rapidly separated from the mixed solution under an external magnetic field. Above all, the adsorbent had high removal efficiency in cesium-contaminated samples (water and soil) and also showed good recycling performance, indicating that the MMT/Fe3O4 composite could be widely applied to the remediation of cesium-contaminated environments. It was observed that the pH, solid/liquid ratio and initial concentration affected adsorption capacity. In the presence of coexisting ions, the adsorption capacity decreased in the order of Ca2+>Mg2+>K+>Na+, which is consistent with our theoretical prediction. The adsorption behavior of this new adsorbent could be expressed by the pseudo-second-order model and Freundlich isotherm. In addition, the adsorption mechanism of Cs+ was NH4+ ion exchange and surface hydroxyl group coordination, with the former being more predominant. PMID- 28571848 TI - Catalytic removal of phenol from gas streams by perovskite-type catalysts. AB - Three perovskite-type catalysts prepared by citric acid method are applied to remove phenol from gas streams with the total flow rate of 300mL/min, corresponding to a GHSV of 10,000/hr. LaMnO3 catalyst is first prepared and further partially substituted with Sr and Cu to prepare La0.8Sr0.2MnO3 and La0.8Sr0.2Mn0.8Cu0.2O3, and catalytic activities and fundamental characteristics of these three catalysts are compared. The results show that phenol removal efficiency achieved with La0.8Sr0.2Mn0.8Cu0.2O3 reaches 100% with the operating temperature of 200 degrees C and the rate of mineralization at 300 degrees C is up to 100%, while the phenol removal efficiencies achieved with La0.8Sr0.2MnO3 and LaMnO3 are up to 100% with the operating temperature of 300 degrees C and 400 degrees C, respectively. X-ray photoelectron spectroscopy (XPS) analysis shows that the addition of Sr and Cu increases the lattice oxygen of La0.8Sr0.2Mn0.8Cu0.2O3, and further increases mobility or availability of lattice oxygen. The results indicate that La0.8Sr0.2Mn0.8Cu0.2O3 has the best activity for phenol removal among three catalysts prepared and the catalytic activity of phenol oxidation is enhanced by the introduction of Sr and Cu into LaMnO3. Apparent activation energy of 48kJ/mol is calculated by Mars-Van Krevelen Model for phenol oxidation with La0.8Sr0.2Mn0.8Cu0.2O3 as catalyst. PMID- 28571849 TI - Assessment of the maximum allowed acid deposition load at current stage in China. AB - Soil acidification caused by acid deposition has been significant in some forests in southern China. We present an approach for assessing the current stage maximum allowed load (SML) of acid deposition for terrestrial system in the country. The main idea was that soil base cation exchange as a finite buffer to acidity was included in the soil acidity mass balance calculation at current acidification stage. We calculated the SML for five forests in southern China. The usual critical loads for the same forests were also calculated by the steady state mass balance model for comparison. The results showed that the SML is a more tolerant limit than the critical load for the forests with soils not acidified seriously at current stage. However, the SML become a more stringent limit to acid deposition when the forest soils have acidified seriously to very low base cation saturation. In this case the SML assessment is beneficial for the soils recovering from a serious acidified state. Based on a national scale database, the SML mapping for non-agricultural soil system in China was carried out. PMID- 28571850 TI - Activated carbon adsorption of quinolone antibiotics in water: Performance, mechanism, and modeling. AB - The extensive use of antibiotics has led to their presence in the aquatic environment, and introduces potential impacts on human and ecological health. The capability of powdered activated carbon (PAC) to remove six frequently used quinolone (QN) antibiotics during water treatment was evaluated to improve drinking water safety. The kinetics of QN adsorption by PAC was best described by a pseudo second-order equation, and the adsorption capacity was well described by the Freundlich isotherm equation. Isotherms measured at different pH showed that hydrophobic interaction, electrostatic interaction, and pi-pi dispersion force were the main mechanisms for adsorption of QNs by PAC. A pH-dependent isotherm model based on the Freundlich equation was developed to predict the adsorption capacity of QNs by PAC at different pH values. This model had excellent prediction capabilities under different laboratory scenarios. Small relative standard derivations (RSDs), i.e., 0.59%-0.92% for ciprofloxacin and 0.09%-3.89% for enrofloxacin, were observed for equilibrium concentrations above the 0.3mg/L level. The RSDs increased to 11.9% for ciprofloxacin and 32.1% for enrofloxacin at MUg/L equilibrium levels, which is still acceptable. This model could be applied to predict the adsorption of other chemicals having different ionized forms. PMID- 28571851 TI - Drinking water treatment using a submerged internal-circulation membrane coagulation reactor coupled with permanganate oxidation. AB - A submerged internal circulating membrane coagulation reactor (MCR) was used to treat surface water to produce drinking water. Polyaluminum chloride (PACl) was used as coagulant, and a hydrophilic polyvinylidene fluoride (PVDF) submerged hollow fiber microfiltration membrane was employed. The influences of trans membrane pressure (TMP), zeta potential (ZP) of the suspended particles in raw water, and KMnO4 dosing on water flux and the removal of turbidity and organic matter were systematically investigated. Continuous bench-scale experiments showed that the permeate quality of the MCR satisfied the requirement for a centralized water supply, according to the Standards for Drinking Water Quality of China (GB 5749-2006), as evaluated by turbidity (<1 NTU) and total organic carbon (TOC) (<5mg/L) measurements. Besides water flux, the removal of turbidity, TOC and dissolved organic carbon (DOC) in the raw water also increased with increasing TMP in the range of 0.01-0.05MPa. High ZP induced by PACl, such as 5 9mV, led to an increase in the number of fine and total particles in the MCR, and consequently caused serious membrane fouling and high permeate turbidity. However, the removal of TOC and DOC increased with increasing ZP. A slightly positive ZP, such as 1-2mV, corresponding to charge neutralization coagulation, was favorable for membrane fouling control. Moreover, dosing with KMnO4 could further improve the removal of turbidity and DOC, thereby mitigating membrane fouling. The results are helpful for the application of the MCR in producing drinking water and also beneficial to the research and application of other coagulation and membrane separation hybrid processes. PMID- 28571852 TI - Structure and activity of thermophilic methanogenic microbial communities exposed to quaternary ammonium sanitizer. AB - Food processing facilities often use antimicrobial quaternary ammonium compound (QAC) sanitizers to maintain cleanliness. These QACs can end up in wastewaters used as feedstock for anaerobic digestion. The aim of this study was to measure the effect of QAC contamination on biogas production and structure of microbial communities in thermophilic digester sludge. Methane production and biogas quality data were analyzed in batch anaerobic digesters containing QAC at 0, 15, 50, 100 and 150mg/L. Increasing sanitizer concentration in the bioreactors negatively impacted methane production rate and biogas quality. Microbial community composition data was obtained through 16S rRNA gene sequencing from the QAC-contaminated sludges. Sequencing data showed no significant restructuring of the bacterial communities. However, significant restructuring was observed within the archaeal communities as QAC concentration increased. Further studies to confirm these effects on a larger scale and with a longer retention time are necessary. PMID- 28571853 TI - Effect of MoO3 on vanadium based catalysts for the selective catalytic reduction of NOx with NH3 at low temperature. AB - The selective catalytic reduction (SCR) activities of the MoO3 doped V/WTi catalysts prepared by the incipient wetness impregnation method at low temperature were investigated. The results showed that the addition of MoO3 could enhance the NOx conversion at low temperature and the best SCR activity was obtained when the dosage of MoO3 reached 5wt.%. The NH3-TPD and DRIFTS experiments indicated that the addition of MoO3 changed the type and number of acid sites on the surface of catalysts and reaction activities of acid sites were altered at the same time. The redox capacity and amount of active oxygen species got improved for V3Mo5/WTi catalyst, which could be confirmed by the H2-TPR and transient response experiments. Water vapor inhibited the NOx conversion at low temperature. Deposition of ammonium sulfate or bisulfate might be main reason for the loss of catalytic activity in the presence of SO2 at low temperature. Choosing the suitable NH3/NO ratio and elevation of reaction temperature both could weaken the influence of SO2 on the SCR activity of the V3Mo5/WTi catalyst. Thermal treatment of the deactivated catalyst at 350 degrees C could get the low temperature activity recovered. The decrease of GHSV improved the deNOx efficiency at low temperature and we speculated that the rational technological process and operation parameters could contribute to the application of this kind of catalysts in real industrial environment. PMID- 28571854 TI - Effects of aging process on adsorption-desorption and bioavailability of fomesafen in an agricultural soil amended with rice hull biochar. AB - Biochar has been introduced as an acceptable soil amendment due to its environmental benefits such as sequestering soil contaminants. However, the aging process in biochar amended soil probably decreases the adsorption capacity of biochar through changing its physico-chemical properties. Adsorption, leaching and bioavailability of fomesafen to corn in a Chinese soil amended by rice hull biochar after 0, 30, 90 and 180days were investigated. Results showed that the addition of 0.5%-2% fresh biochar significantly increases the adsorption of fomesafen 4-26 times compare to unamended soil due to higher SSA of biochar. Biochar amendment also decreases fomesafen concentration in soil pore water by 5% 23% resulting lower risk of the herbicide for cultivated plants. However, the aging process decreased the adsorption capacity of biochar since the adsorption coefficient values which was 1.9-12.4 in 0.5%-2% fresh biochar amended soil, declined to 1.36-4.16, 1.13-2.78 and 0.95-2.31 in 1, 3 and 6-month aged treatments, respectively. Consequently, higher desorption, leaching and bioavailable fraction of fomesafen belonged to 6-month aged treatment. Nevertheless, rice hull biochar was effective for sequestering fomesafen as the adsorption capacity of biochar amended soil after 6months of aging was still 2.5 5 times higher compared to that of unamended soil. PMID- 28571855 TI - Effects and mechanism of freeze-thawing cycles on the soil N2O fluxes in the temperate semi-arid steppe. AB - High nitrous oxide (N2O) emissions during freeze-thawing period (FTP) have been observed in many different ecosystems. However, the knowledge about the dynamic of soil N2O emissions and its main driving mechanism during the freeze-thawing processes in grassland ecosystem is still limited. An in-situ experiment was conducted during the FTP on the sites with 0 and 15% surplus of the average rainfall and two levels of N addition (0,10gN/(m2.year)) during growing season (marked as W0N0, W15N0, W0N10, W15N10, respectively) to explore the effects of water and N background on soil N2O emissions during FTPs and the relationship between soil N2O emissions and environmental factors. The results indicated that water and N treatments conducted during growing season did not show significant effect on the N2O effluxes of FTP, but the soil mineral N contents of W0N10 treatment were significantly higher than those of W0N0, W15N0, W15N10 treatments (p<0.05). The soil PLFA concentrations of microbial groups monitored during 2015 spring freeze-thawing period (2015S-FTP) were lower than those during winter freeze-thawing period of 2014 (2014W-FTP), while cumulative soil N2O emissions of 2015S-FTP were higher than those of 2014W-FTP. The correlations between soil N2O effluxes and most of the measured environmental factors were insignificant, multiple stepwise regression analysis indicated that the soil temperature, soil NH4+-N content and air temperature were the major environmental factors which significantly influenced the N2O effluxes during 2014W-FTP, and air temperature and soil water content were the significant influencing factors during 2015S-FTP. PMID- 28571856 TI - Ag-AgBr/TiO2/RGO nanocomposite: Synthesis, characterization, photocatalytic activity and aggregation evaluation. AB - Ag-AgBr/TiO2 supported on reduced graphene oxide (Ag-AgBr/TiO2/RGO) with different mass ratios of grapheme oxide (GO) to TiO2 were synthesized via a facile solvothermal-photo reduction method. Compared to the single-, two- and three-component nanocomposites, the four-component nanocomposite, Ag AgBr/TiO2/RGO-1 with mass ratio of GO to TiO2 at 1%, exhibited a much higher photocatalytic activity for the degradation of penicillin G (PG) under white light-emitting diode (LED-W) irradiation. The PG degradation efficiency increased with the increase of mass ratio of GO to TiO2 from 0.2% to 1%, then it decreased with the increase of mass ratio of GO to TiO2 from 1% to 5%. The zeta potentials of RGO-nanocomposites became more negative with the presence of humic acid (HA) due to the negatively charged HA adsorption, resulting in the shift of points of zero charge to lower values of pH. The aggregations of nanocomposites were more significant due to the bridging effect of HA. Furthermore, the aggregated particle sizes were larger for RGO-nanocomposites compared to other nanoparticles, due to the bindings of the carboxylic and phenolic functional groups in HA with the oxygen-containing functional groups in the RGO nanocomposites. The microfiltration (MF) membrane was effective for the nanocomposites separation. In the continuous flow through submerged membrane photoreactor (sMPR) system, backwashing operation could efficiently reduce membrane fouling and recover TiO2, and thus indirectly facilitate the PG removal. PMID- 28571857 TI - Identification of long-range transport pathways and potential sources of PM2.5 and PM10 in Beijing from 2014 to 2015. AB - Trajectory clustering, potential source contribution function (PSCF) and concentration-weighted trajectory (CWT) methods were applied to investigate the transport pathways and identify potential sources of PM2.5 and PM10 in different seasons from June 2014 to May 2015 in Beijing. The cluster analyses showed that Beijing was affected by trajectories from the south and southeast in summer and autumn. In winter and spring, Beijing was not only affected by the trajectories from the south and southeast, but was also affected by trajectories from the north and northwest. In addition, the analyses of the pressure profile of backward trajectories showed that backward trajectories, which have important influence on Beijing, were mainly distributed above 970hPa in summer and autumn and below 950hPa in spring and winter. This indicates that PM2.5 and PM10 were strongly affected by the near surface air masses in summer and autumn and by high altitude air masses in winter and spring. Results of PSCF and CWT analyses showed that the largest potential source areas were identified in spring, followed by winter and autumn, then summer. In addition, potential source regions of PM10 were similar to those of PM2.5. There were a clear seasonal and spatial variation of the potential source areas of Beijing and the airflow in the horizontal and vertical directions. Therefore, more effective regional emission reduction measures in Beijing's surrounding provinces should be implemented to reduce emissions of regional sources in different seasons. PMID- 28571859 TI - Development of a method for comprehensive water quality forecasting and its application in Miyun reservoir of Beijing, China. AB - Water quality forecasting is an essential part of water resource management. Spatiotemporal variations of water quality and their inherent constraints make it very complex. This study explored a data-based method for short-term water quality forecasting. Prediction of water quality indicators including dissolved oxygen, chemical oxygen demand by KMnO4 and ammonia nitrogen using support vector machine was taken as inputs of the particle swarm algorithm based optimal wavelet neural network to forecast the whole status index of water quality. Gubeikou monitoring section of Miyun reservoir in Beijing, China was taken as the study case to examine effectiveness of this approach. The experiment results also revealed that the proposed model has advantages of stability and time reduction in comparison with other data-driven models including traditional BP neural network model, wavelet neural network model and Gradient Boosting Decision Tree model. It can be used as an effective approach to perform short-term comprehensive water quality prediction. PMID- 28571858 TI - Effects of silver adsorbed on fumed silica, silver phosphate glass, bentonite organomodified with silver and titanium dioxide in aquatic indicator organisms. AB - In order to reduce the level of transmission of diseases caused by bacteria and fungi, the development of antimicrobial additives for use in personal care, hygiene products, clothing and others has increased. Many of these additives are based on metals such as silver and titanium. The disposal of these products in the environment has raised concerns pertaining to their potential harmfulness for beneficial organisms. The objective of this study was to evaluate the influence of the shape, surface chemistry, size and carrier of three additives containing silver and one with titanium dioxide (TiO2) on microcrustacean survival. Daphnia magna was used as a bioindicator for acute exposure test in suspensions from 0.0001 to 10,000ppm. Ceriodaphnia dubia was used for chronic test in TiO2 suspensions from 0.001 to 100ppm. D. magna populations presented high susceptibility to all silver based additives, with 100% mortality after 24hr of exposure. A different result was found in the acute experiments containing TiO2 suspensions, with mortality rates only after 48hr of incubation. Even on acute and chronic tests, TiO2 did not reach a linear concentration-response versus mortality, with 1ppm being more toxic than 10,000ppm on acute test and 0.001 more toxic than 0.01ppm on chronic assay. Silver based material toxicity was attributed to silver itself, and had no relation to either form (nano or ion) or carrier (silica, phosphate glass or bentonite). TiO2 demonstrated to have a low acute toxicity against D. magna. PMID- 28571860 TI - Pollution characteristics of polycyclic aromatic hydrocarbons in common used mineral oils and their transformation during oil regeneration. AB - The pollution characteristic of polycyclic aromatic hydrocarbons (PAHs) in common used mineral oils, semi-refined oils, refined oils and solid wastes produced during the used mineral oil regeneration process was analyzed. The results showed that total PAHs content in six common used mineral oils was as follows: used engine oil>used quenching oil>used casting oil>used hydraulic oil>used antirust oil>used industrial lubricating oil. Furthermore, this order was dependent on the source of PAHs and oil working temperatures. Additionally, total PAHs content in regenerated oils was as follows: semi-refined oil>refined oil>crude oil, which was related to the catalytic cracking process of crude oil and adsorption refining process of semi-refined oil. The ranking of total PAHs content in regenerated wastes varied depending on the regeneration technology used as follows: waste adsorption sand>acid sludge>waste clay>precipitation sludge>cracked residue. In all types of used mineral oils and regenerated wastes, the maximum and minimum proportions of the total PAHs content were composed of 2 3 ring-PAHs and 5-6 ring-PAHs, respectively. The majority of PAHs in the used mineral oils entered into regenerated wastes during regeneration process, while a small number remained in the regenerated oil. PMID- 28571861 TI - High-throughput metagenomic analysis of petroleum-contaminated soil microbiome reveals the versatility in xenobiotic aromatics metabolism. AB - The soil with petroleum contamination is one of the most studied soil ecosystems due to its rich microorganisms for hydrocarbon degradation and broad applications in bioremediation. However, our understanding of the genomic properties and functional traits of the soil microbiome is limited. In this study, we used high throughput metagenomic sequencing to comprehensively study the microbial community from petroleum-contaminated soils near Tianjin Dagang oilfield in eastern China. The analysis reveals that the soil metagenome is characterized by high level of community diversity and metabolic versatility. The metageome community is predominated by gamma-Proteobacteria and alpha-Proteobacteria, which are key players for petroleum hydrocarbon degradation. The functional study demonstrates over-represented enzyme groups and pathways involved in degradation of a broad set of xenobiotic aromatic compounds, including toluene, xylene, chlorobenzoate, aminobenzoate, DDT, methylnaphthalene, and bisphenol. A composite metabolic network is proposed for the identified pathways, thus consolidating our identification of the pathways. The overall data demonstrated the great potential of the studied soil microbiome in the xenobiotic aromatics degradation. The results not only establish a rich reservoir for novel enzyme discovery but also provide putative applications in bioremediation. PMID- 28571862 TI - Zeolite A synthesized from alkaline assisted pre-activated halloysite for efficient heavy metal removal in polluted river water and industrial wastewater. AB - High quality zeolite A was synthesized through a hydrothermal process using alkaline-assisted pre-activated halloysite mineral as the alumina and silica source. The synthesis conditions employed in this study were finely tuned by varying the activating temperature, sodium hydroxide content, water content and Si/Al ratio. The obtained zeolite A showed excellent adsorption properties for both single metal cation solutions and mixed cation solutions when the concentrations of the mixed cations were comparable with those in polluted natural river water and industrial wastewater. High adsorptive capacities for Ag+ (123.05mg/g) and Pb2+ (227.70mg/g) were achieved using the synthesized zeolite A. This observation indicates that the zeolite A synthesized from alkaline-assisted pre-activated halloysite can be used as a low-cost and relatively effective adsorbent to purify heavy metal cation polluted natural river water and industrial wastewater. PMID- 28571863 TI - An insight into the removal of fluoroquinolones in activated sludge process: Sorption and biodegradation characteristics. AB - The detailed sorption steps and biodegradation characteristics of fluoroquinolones (FQs) including ciprofloxacin, enrofloxacin, lomefloxacin, norfloxacin, and ofloxacin were investigated through batch experiments. The results indicate that FQs at a total concentration of 500MUg/L caused little inhibition of sludge bioactivity. Sorption was the primary removal pathway of FQs in the activated sludge process, followed by biodegradation, while hydrolysis and volatilization were negligible. FQ sorption on activated sludge was a reversible process governed by surface reaction. Henry and Freundlich models could describe the FQ sorption isotherms well in the concentration range of 100-300MUg/L. Thermodynamic parameters revealed that FQ sorption on activated sludge is spontaneous, exothermic, and enthalpy-driven. Hydrophobicity-independent mechanisms determined the FQ sorption affinity with activated sludge. The zwitterion of FQs had the strongest sorption affinity, followed by cation and anion, and aerobic condition facilitated FQ sorption. FQs were slowly biodegradable, with long half-lives (>100hr). FQ biodegradation was enhanced with increasing temperature and under aerobic condition, and thus was possibly achieved through co-metabolism during nitrification. This study provides an insight into the removal kinetics and mechanism of FQs in the activated sludge process, but also helps assess the environmental risks of FQs resulting from sludge disposal. PMID- 28571864 TI - Inhibition effects of perfluoroalkyl acids on progesterone production in mLTC-1. AB - Perfluoroalkyl substances (PFASs) are a class of fluorine substituted carboxylic acid, sulfonic acid and alcohol, structurally similar to their corresponding parent compounds. Previous study demonstrated the potential endocrine disruption and reproductive toxicity of perfluorooctane sulfonic acid and perfluorooctanoic acid, two dominant PFASs in animals and humans. We explored the relationship between eleven perfluoroalkyl acids (PFAAs) with different carbon chain length and their ability to inhibit progesterone production in mouse Leydig tumor cells (mLTC-1). We found an obvious dose-response relationship between progesterone inhibition rate and PFAA exposure concentration in mLTC-1. The relative inhibition rate of progesterone by PFAAs was linearly related to the carbon chain length and molar refractivity of PFAAs. Mitochondrial membrane potential (MMP) decreased after PFAA exposure at the half-maximal inhibitory effect concentration (IC50) of progesterone production in mLTC-1, while the reactive oxygen species (ROS) content increased significantly. These results imply that the inhibition effect of PFAAs on progesterone production might be due, in part, to ROS damage and the decrease in MMP in mLTC-1. PMID- 28571865 TI - Mobilization of arsenic from contaminated sediment by anionic and nonionic surfactants. AB - The increasing manufacture of surfactants and their wide application in industry, agriculture and household detergents have resulted in large amounts of surfactant residuals being discharged into water and distributed into sediment. Surfactants have the potential to enhance arsenic mobility, leading to risks to the environment and even human beings. In this study, batch and column experiments were conducted to investigate arsenic mobilization from contaminated sediment by the commercial anionic surfactants sodium dodecylbenzenesulfonate (SDBS), sodium dodecyl sulfate (SDS), sodium laureth sulfate (AES) and nonionic surfactants phenyl-polyethylene glycol (Triton X-100) and polyethylene glycol sorbitan monooleate (Tween-80). The ability of surfactants to mobilize arsenic followed the order AES>SDBS>SDS~Triton X-100>Tween 80. Arsenic mobilization by AES and Triton X-100 increased greatly with the increase of surfactant concentration and pH, while arsenic release by SDBS, SDS and Tween-80 slightly increased. The divalent ion Ca2+ caused greater reduction of arsenic mobilization than Na+. Sequential extraction experiments showed that the main fraction of arsenic mobilized was the specifically adsorbed fraction. Solid phase extraction showed that arsenate (As(V)) was the main species mobilized by surfactants, accounting for 65.05%-77.68% of the total mobilized arsenic. The mobilization of arsenic was positively correlated with the mobilization of iron species. The main fraction of mobilized arsenic was the dissolved fraction, accounting for 70% of total mobilized arsenic. PMID- 28571866 TI - The influence of environmental factors on the carbon dioxide flux across the water-air interface of reservoirs in south-eastern Poland. AB - Studies concerning the emission of carbon dioxide (CO2) were carried out in 2009 2012 for six reservoirs located in four provinces of south-eastern Poland. The CO2 flux across the water-air interface was measured using the "static chamber" method. The measured fluxes of CO2 (FCO2) ranged from -30.64 to 183.78mmol/m2/day, and the average values varied in the range from -3.52 to 82.11mmol/m2/day. In most of the cases, emission of CO2 to the atmosphere was observed. The obtained values of CO2 fluxes were comparable to values typical for other temperate reservoirs. Analysis of the influence of selected environmental factors on the FCO2 showed that it depends on parameters characterizing both the sediments and surface water. The CO2 flux at the water-air interface was positively correlated with parameters of bottom sediments such as porosity, content of organic carbon and total nitrogen; and negatively with pH value and delta13C of organic carbon. In the case of the parameters characterizing surface water, positive dependences on the concentrations of nitrate and total nitrogen, and negative relationships with water temperature and chlorophyll a concentrations, were found. PMID- 28571867 TI - Arsenic speciation in fish from Greek coastal areas. AB - Arsenic speciation analysis was conducted on fish samples (sardine and anchovy) collected from six areas along the Greek coastline, i.e. Artemisium Straits, Thermaikos Gulf, Amvrakikos Gulf, Strymonian Gulf, Thracian Sea, and Elefsina Gulf. Total arsenic levels ranging from 11.8 to 62.6mg As/kg dry weight were determined. Arsenobetaine, a non-toxic form of arsenic, was found to be the main arsenic species, present at 8.6 to 58.8mg As/kg dry weight, accounting for 67-95% of the total arsenic. Also detected in all fish samples was dimethylarsinic acid, although at considerably lower concentrations, ranging from 0.072-0.956mg As/kg dry weight. Monomethylarsonic acid was detected at low levels in all anchovy samples, and only in sardines from one area. Finally, inorganic arsenic in the form of arsenate was detected only in fish at one area, indicating the possible effect of an environmental parameter on its presence at detectable amounts. Statistical analysis revealed the environmental variables, such as salinity, total organic carbon and nitrogen, ammonium, phosphate, total phosphorus, dissolved oxygen and pressure index, are potentially correlated to As species concentrations. Furthermore, based on factor analysis, the biological parameters, such as fish weight, lipids, protein and ash content, that are correlated to As species concentrations of fish were also identified. The interrelationship of arsenobetaine and dimethylarsinic acid concentrations within each fish species was evaluated. PMID- 28571868 TI - Genotoxicity of drinking water treated with different disinfectants and effects of disinfection conditions detected by umu-test. AB - The genotoxicity of drinking water treated with 6 disinfection methods and the effects of disinfection conditions were investigated using the umu-test. The pretreatment procedure of samples for the umu-test was optimized for drinking water analysis. The results of the umu-test were in good correlation with those of the Ames-test. The genotoxicity and production of haloacetic acids (HAAs) were the highest for chlorinated samples. UV+chloramination is the safest disinfection method from the aspects of genotoxicity, HAA production and inactivation effects. For chloramination, the effects of the mass ratio of Cl2 to N of chloramine on genotoxicity were also studied. The changes of genotoxicity were different from those of HAA production, which implied that HAA production cannot represent the genotoxic potential of water. The genotoxicity per chlorine decay of chlorination and chloramination had similar trends, indicating that the reaction of organic matters and chlorine made a great contribution to the genotoxicity. The results of this study are of engineering significance for optimizing the operation of waterworks. PMID- 28571869 TI - Simulated reaction of formaldehyde and ambient atmospheric particulate matter using a chamber. AB - The reaction of HCHO with Beijing winter's real ambient particulate matter (PM) inside a 3.3m3 Teflon Chamber was conducted in this study. NO2, O3 and H2O gases were removed from the ambient aerosol before entering into the chamber. The decays of HCHO were monitored (acetylacetone spectrophotometry method) during the reactions at different PM number concentrations (Na) and relative humidities (RHs), and the formed particulate formate was detected by IC and XPS techniques. The results showed that when RH was 10%-15%, the decay rate of HCHO in the chamber was higher with the existence of PM from relatively clean days (with number concentration (Na)<200,000particle/L, 0.35-22.5MUm) compared to dirty days (Na>200,000particle/L, 0.35-22.5MUm). When RH increased to 30%-45%, PM can hardly have significant influences on the decay of HCHO. The formations of formate on the reacted PM were consistent with the HCHO decay rates at different ambient PM Na and RH conditions. This is a first study related to the "real" ambient PM reacted with HCHO and suggested that in the clean and low RH days, PM could be an effective medium for the conversion of HCHO to formate. PMID- 28571870 TI - Numerical simulation study on air quality in aircraft cabins. AB - Air pollution is one of the main factors that affect the air quality in aircraft cabins, and the use of different air supply modes could influence the distribution of air pollutants in cabins. Based on the traditional ceiling air supply mode used on the B737NG, this study investigated another 3 different kinds of air supply modes for comparison: luggage rack air supply mode, joint mode combining ceiling and luggage rack air supply, and joint mode combining ceiling and individual air supply. Under the above 4 air supply modes, the air velocity, temperature and distribution of air pollutants in a cabin full of passengers were studied using computational fluid dynamics (CFD), and carbon dioxide (CO2) and formaldehyde were selected as 2 kinds of representative air pollutants. The simulation results show that the joint mode combining ceiling and individual air supply can create a more uniform distribution of air velocity and temperature, has a better effect on the removal of CO2 and formaldehyde, and can provide better air quality in cabins than the other 3 modes. PMID- 28571871 TI - Case study of dust event sources from the Gobi and Taklamakan deserts: An investigation of the horizontal evolution and topographical effect using numerical modeling and remote sensing. AB - A severe dust event occurred from April 23 to April 27, 2014, in East Asia. A state-of-the-art online atmospheric chemistry model, WRF/Chem, was combined with a dust model, GOCART, to better understand the entire process of this event. The natural color images and aerosol optical depth (AOD) over the dust source region are derived from datasets of moderate resolution imaging spectroradiometer (MODIS) loaded on a NASA Aqua satellite to trace the dust variation and to verify the model results. Several meteorological conditions, such as pressure, temperature, wind vectors and relative humidity, are used to analyze meteorological dynamic. The results suggest that the dust emission occurred only on April 23 and 24, although this event lasted for 5days. The Gobi Desert was the main source for this event, and the Taklamakan Desert played no important role. This study also suggested that the landform of the source region could remarkably interfere with a dust event. The Tarim Basin has a topographical effect as a "dust reservoir" and can store unsettled dust, which can be released again as a second source, making a dust event longer and heavier. PMID- 28571872 TI - Achieving partial nitrification by inhibiting the activity of Nitrospira-like bacteria under high-DO conditions in an intermittent aeration reactor. AB - It is generally accepted that a low dissolved oxygen (DO) concentration is more beneficial for achieving partial nitrification than high-DO. In this study, partial nitrification was not established under low-DO conditions in an intermittent aeration reactor for treating domestic wastewater. During the operational period of low-DO conditions (DO: 0.3+/-0.14mg/L), stable complete nitrification was observed. The abundance of Nitrospira-like bacteria, which were the major nitrite-oxidizing bacteria, increased from 1.03*106 to 2.64*106cells/mL. At the end of the low-DO period, the batch tests showed that high-DO concentration (1.5, 2.0mg/L) could inhibit nitrite oxidation, and enhance ammonia oxidation. After switching to the high-DO period (1.8+/-0.32mg/L), partial nitrification was gradually achieved. Nitrospira decreased from 2.64*106 to 8.85*105cells/mL. It was found that suddenly switching to a high-DO condition could inhibit the activity and abundance of Nitrospira-like bacteria, resulting in partial nitrification. PMID- 28571873 TI - Biosynthesis of gold nanoparticles by Trichoderma sp. WL-Go for azo dyes decolorization. AB - Developing an eco-friendly approach for metallic nanoparticles synthesis is important in current nanotechnology research. In this study, green synthesis of gold nanoparticles (AuNPs) was carried out by a newly isolated strain Trichoderma sp. WL-Go. UV-vis spectra of AuNPs showed a surface plasmon resonance peak at 550nm, and transmission electron microscopy images revealed that the AuNPs were of varied shape with well dispersibility. The optimal conditions for AuNPs synthesis were HAuCl4 1.0mmol/L, biomass 0.5g and pH7-11. Moreover, the bio-AuNPs could efficiently catalyze the decolorization of various azo dyes. This research provided a new microbial resource candidate for green synthesis of AuNPs and demonstrated the potential application of bio-AuNPs for azo dye decolorization. PMID- 28571874 TI - Organic ligand-induced dissolution kinetics of antimony trioxide. AB - The influence of low-molecular-weight dissolved organic matter (LMWDOM) on the dissolution rate of Sb2O3 was investigated. Some representative LMWDOMs with carboxyl, hydroxyl, hydrosulfuryl and amidogen groups occurring naturally in the solution were chosen, namely oxalic acid, citric acid, tartaric acid, EDTA, salicylic acid, phthalandione, glycine, thiolactic acid, xylitol, glucose and catechol. These LMWDOMs were dissolved in inert buffers at pH=3.7, 6.6 and 8.6 and added to powdered Sb2O3 in a stirred, thermostatted reactor (25 degrees C). The addition of EDTA, tartaric acid, thiolactic acid, citric acid and oxalic acid solutions at pH3.7 and catechol at pH8.6 increased the rate of release of antimony. In the 10mmol/L thiolactic acid solution, up to 97% by mass of the antimony was released after 120min reaction. There was no effect on the dissolution of Sb2O3 for the other ligands. A weak correlation between dissolution rate with the dissociation constant of ligands and the stability of the dissolved complex was also found. All the results showed that the extent of the promoting effect of ligands on the dissolution of Sb2O3 was not determined by the stability of the dissolved complex, but by the dissociation constant of ligands and detachment rate of surface chelates from the mineral surface. This study can not only help in further understanding the effect of individual low molecular-weight organic ligands, but also provides a reference to deduce the effect of natural organic matters with oxygen-bearing functional groups on the dissolution of antimony oxide minerals. PMID- 28571875 TI - Structure and flow calculation of cake layer on microfiltration membranes. AB - Submerged membrane bioreactors (SMBR) are widely used in wastewater treatment. The permeability of a membrane declines rapidly because of the formation of a cake layer on the membrane surface. In this paper, a multiple staining protocol was conducted to probe the four major foulants in the cake layer formed on a filtration membrane. Fluorescent images of the foulants were obtained using a confocal laser scanning microscope (CLSM). The three dimensional structure of the cake layer was reconstructed, and the internal flow was calculated using computational fluid dynamics (CFD). Simulation results agreed well with the experimental data on the permeability of the cake layer during filtration and showed better accuracy than the calculation by Kozeny-Carman method. beta-d Glucopyranose polysaccharides and proteins are the two main foulants with relatively large volume fractions, while alpha-d-glucopyranose polysaccharides and nucleic acids have relatively large specific surface areas. The fast growth of beta-d-glucopyranose polysaccharides in the volume fraction is mainly responsible for the increase in cake volume fraction and the decrease in permeability. The specific area, or the aggregation/dispersion of foulants, is less important to its permeability compared to its volume fraction. PMID- 28571876 TI - Experience-induced transgenerational (re-)programming of neuronal structure and functions: Impact of stress prior and during pregnancy. AB - This review focuses on the inter- and transgenerational effects of stress experience prior to and during gestation. We provide an overview of findings from studies in humans as well as in animal models on brain structural and physiological functions and on the development of cognitive and executive functions. We also discuss the concept of stress-induced (re-)programming in more detail by highlighting epigenetic mechanisms and particularly those affecting the development of monoaminergic transmitter systems, which constitute the brains reward system. As the majority of studies have focused on male individuals we will emphasize sex-specific differences in stress vulnerability and resilience. Finally, we offer some perspectives on the development of protective and therapeutic interventions in cognitive and emotional disturbances resulting from pre-conception and prenatal stress. PMID- 28571878 TI - Response to Letter to the Editor: Prevalence of vestibular and balance disorders in children and adolescents according to age category: A multi-center study in Korea. PMID- 28571879 TI - Letter to the Editor, regarding the article: "Prevalence of vestibular and balance disorders in children and adolescents according to age: A multi-centre study" (2017; 94: 36-39). PMID- 28571877 TI - Shaping vulnerability to addiction - the contribution of behavior, neural circuits and molecular mechanisms. AB - Substance use disorders continue to impose increasing medical, financial and emotional burdens on society in the form of morbidity and overdose, family disintegration, loss of employment and crime, while advances in prevention and treatment options remain limited. Importantly, not all individuals exposed to abused substances effectively develop the disease. Genetic factors play a significant role in determining addiction vulnerability and interactions between innate predisposition, environmental factors and personal experiences are also critical. Thus, understanding individual differences that contribute to the initiation of substance use as well as on long-term maladaptations driving compulsive drug use and relapse propensity is of critical importance to reduce this devastating disorder. In this paper, we discuss current topics in the field of addiction regarding individual vulnerability related to behavioral endophenotypes, neural circuits, as well as genetics and epigenetic mechanisms. Expanded knowledge of these factors is of importance to improve and personalize prevention and treatment interventions in the future. PMID- 28571880 TI - alpha-Tocopherol, especially alpha-tocopherol phosphate, exerts antiapoptotic and angiogenic effects on rat bone marrow-derived endothelial progenitor cells under high-glucose and hypoxia conditions. AB - OBJECTIVE: Considering the poor efficacy of local intramuscular injections with endothelial progenitor cells (EPCs) for critical limb ischemia in patients with diabetes, the study aimed to investigate the effect of alpha-tocopherol (alpha-T) and alpha-tocopherol phosphate (alpha-TP) on apoptosis and angiogenesis in a rat model under oxidative stress conditions. METHODS: Primary EPCs from Sprague Dawley rats were harvested and treated with alpha-T and alpha-TP for 24 hours. Gene transcription and protein expression were evaluated by real-time polymerase chain reaction and Western blot, respectively. Cell apoptosis, migration, and tube formation ability were detected by flow cytometry, Transwell assay (Chemicon International, Temecula, Calif), and Matrigel-based angiogenesis assay (Corning Inc, Corning, NY). The in vivo experiments were carried out using 30 single hind limb ischemic models of diabetic rats that were treated with allogeneic EPCs. Capillary density was evaluated by immunohistochemistry. RESULTS: alpha-T and alpha-TP attenuated high glucose/hypoxia-induced cell apoptosis by promoting Bcl 2 and Akt and inhibiting nuclear factor kappaB p65, JNK, Notch-1, and p38MAPK genes. Furthermore, alpha-T and alpha-TP promoted the transcription and expression of vascular endothelial growth factor receptor 2 and decreased the transcription and expression of Tie-2 and Notch-1 in EPCs under high glucose/hypoxic conditions. Moreover, alpha-T and especially alpha-TP enhanced the migratory activity of EPCs under high-glucose/hypoxic conditions. Capillary density of ischemic hind limbs was increased on day 14 after administration of EPCs pretreated with alpha-T and alpha-TP. CONCLUSIONS: alpha-T, especially alpha TP, possesses therapeutic potential in the inhibition of apoptosis and increases the migratory capacity of EPCs under high-glucose/hypoxic conditions. It promotes angiogenesis by upregulating Bcl-2, Akt, and vascular endothelial growth factor receptor 2 and decreasing nuclear factor kappaB p65, p38MAPK, Notch-1, JNK, and Tie-2. PMID- 28571881 TI - Radial artery access for peripheral endovascular procedures. AB - OBJECTIVE: The radial artery is often used for coronary angiography, with a demonstrated decrease in local complications and an increase in postoperative mobility of the patient. Data on radial artery access for peripheral endovascular procedures, however, are limited. We describe our experience with radial artery access for diagnostic and endovascular interventions. METHODS: Between February 2012 and March 2015, there were 95 endovascular procedures performed using radial artery access in 80 unique patients. Demographic and clinical data were recorded. Perioperative, postoperative, and 30-day follow-up data were evaluated retrospectively for major and minor complications. Major adverse events included any immediate hospitalization admission, stroke, hand amputation, bleeding requiring transfusion, hematoma requiring surgery, and death. Minor complications included superficial bleeding and hematoma. RESULTS: The patients (52.6% male, 47.4% female) had a mean age of 72.1 +/- 9.4 years. Radial artery access was used for diagnostic purposes in 15.8% of all procedures and for therapeutic intervention, including angioplasty and stenting, in 84.2%. The radial artery was the only access point in 80% of patients and was accessed in conjunction with other sites in 20%. Percutaneous access was achieved in 100% of patients with a 100% technical success rate. Hemostasis after catheterization was achieved by manual compression (22.1%) and TR band (Terumo Medical, Tokyo, Japan; 77.9%). Major adverse events occurred in three cases (3.2%) and were unrelated to radial artery access. Radial artery access site-related complications occurred in three cases (3.2%), all of which were minor hematomas that required no treatment. The risk of radial artery complication was not associated with procedure type, vessels treated, or use of heparin. The incidence of stroke, hand ischemia, and upper extremity limb or finger loss was 0%. CONCLUSIONS: Radial artery access for peripheral endovascular procedures appears to be safe and effective and should be considered more often. Complication rates are lower than those reported for femoral artery access. PMID- 28571882 TI - Re: Sungmin Woo, Chong Hyun Suh, Sang Youn Kim, Jeong Yeon Cho, Seung Hyup Kim. Diagnostic Performance of Magnetic Resonance Imaging for the Detection of Bone Metastasis in Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2017.03.042. PMID- 28571883 TI - Reply from Authors re: Girish S. Kulkarni, Zachary Klaassen. Trimodal Therapy is Inferior to Radical Cystectomy for Muscle-invasive Bladder Cancer using Population-level Data: Is There Evidence in the (Lack of) Details? Eur Urol 2017;72:488-9: Using the National Cancer Data Base to Compare Treatment Modalities for Localized Muscle-invasive Bladder Cancer. PMID- 28571884 TI - Prediction is "Still" Difficult when it is About the Past. PMID- 28571885 TI - Value of Prostate Cancer Care: New Information on New Therapies Suggest Less is More. PMID- 28571886 TI - Re: Thomas Powles, Robert A. Huddart, Tony Elliott, et al. Phase III, Double blind, Randomized Trial that Compared Maintenance Lapatinib versus Placebo after First-line Chemotherapy in Patients with Human Epidermal Growth Factor Receptor 1/2-positive Metastatic Bladder Cancer. J Clin Oncol 2017;35:48-55: Knowing HER2 Status is Not Enough: A Molecular Subtype Approach to Bladder Cancer is Also Needed. PMID- 28571888 TI - Management of the airway through cervical faringostoma by radionecrosis. PMID- 28571889 TI - The interrelatedness between infants' communicative gestures and lexicon size: A longitudinal study. AB - Research has shown a close relationship between gestures and language development. In this study, we investigate the cross-lagged relationships between different types of gestures and two lexicon dimensions: number of words produced and comprehended. Information about gestures and lexical development was collected from 48 typically developing infants when these were aged 0;9, 1;0 and 1;3. The European Portuguese version of the MacArthur-Bates Communicative Development Inventory: Words and Gestures (PT CDI:WG) was used. The results indicated that the total number of actions and gestures and the number of early gestures produced at 0;9 and at 1;0 year predicted the number of words comprehended three months later. Actions and gestures' predictive power of the number of words produced was limited to the 0;9-1;0 year interval. The opposite relationship was not found: word comprehension and production did not predict action and gestures three months later. These results highlight the importance of non-verbal communicative behavior in language development. PMID- 28571887 TI - An evaluation of motion mitigation techniques for pancreatic SBRT. AB - BACKGROUND AND PURPOSE: Ablative radiation therapy can be beneficial for pancreatic cancer, and motion mitigation helps to reduce dose to nearby organs-at risk. Here, we compared two competing methods of motion mitigation-abdominal compression and respiratory gating. MATERIALS AND METHODS: CBCT scans of 19 pancreatic cancer patients receiving stereotactic body radiation therapy were acquired with and without abdominal compression, and 3D target motion was reconstructed from CBCT projection images. Daily target motion without mitigation was compared against motion with compression and with simulated respiratory gating. Gating was free-breathing and based on an external surrogate. Target coverage was also evaluated for each scenario by simulating reduced target margins. RESULTS: Without mitigation, average daily target motion in LR/AP/SI directions was 5.3, 7.3, and 13.9mm, respectively. With abdominal compression, these values were 5.2, 5.3, and 8.5mm, and with respiratory gating they were 3.2, 3.9, and 5.5mm, respectively. Reductions with compression were significant in AP/SI directions, while reductions with gating were significant in all directions. Respiratory gating also demonstrated better coverage in the reduced margins scenario. CONCLUSION: Respiratory gating is the most effective strategy for reducing motion in pancreatic SBRT, and may allow for dose escalation through a reduction in target margin. PMID- 28571890 TI - A clinical method for quantification of tissue microvascular blood perfusion in absolute terms [blood-volume/(time.tissue-area)]. AB - Fluorescence-mediated photoplethysmography (FM-PPG) was developed to facilitate determination of tissue microvascular (capillary) blood perfusion, requiring intra-venous injection of a small bolus (~0.33mL) of dye (25mg/mL ICG) and acquisition of high-speed angiogram images (>15images/s). The methodology is applicable to microvascular capillary beds of tissues that can be optically imaged, directly or laparoscopically. Proof of concept of the methodology and feasibility of its implementation are demonstrated in human forearm skin and in the choroid of a monkey eye, determined to have blood perfusion rates on the order of 1e-5mL/(s.mm2) and 10e-5mL/(s.mm2), respectively. Ability to obtain absolute quantified tissue perfusion data ultimately can provide the means by which to characterize blood flow information at the nutritive capillary-vessel level in an objective and universally understood manner, in much the same sense that body temperature or blood pressure are. PMID- 28571892 TI - LPE-1, an orally active pyrimidine derivative, inhibits growth and mobility of human esophageal cancers by targeting LSD1. AB - Histone lysine specific demethylase 1 (LSD1) plays an important role in epigenetic modifications, and aberrant expression of LSD1 predicts tumor progression and poor prognosis in human esophageal cancers. In this study, a series of LSD1 inhibitors were synthesized and proved to be highly potent against human esophageal squamous cell carcinoma (ESCC). Our data showed that these LSD1 inhibitors selectively suppressed the viability of esophageal cancer cell line (EC-109) bearing overexpressed LSD1. Among these, compound LPE-1 (LSD1 IC50=0.336+/-0.003MUM) significantly suppressed proliferation, induced apoptosis, arrested cell cycle of EC109 cells at G2/M phase, and caused changes of the associated protein markers correspondingly. We also found that compound LPE-1 potently inhibited the migration and invasion of EC-109 cells. Docking studies showed that the cyano group formed hydrogen bonds with Val811 and Thr810. Additionally, the thiophene moiety formed arene-H interaction with Trp761 residue. In vivo studies showed that compound LPE-1 inhibited tumor growth of xenograft models bearing EC-109 without obvious toxicity. Collectively, our findings indicate that LSD1 may be a potential therapeutic target in ESCC, and compound LPE-1 could serve as a lead compound for further development for anti ESCC drug discovery. PMID- 28571893 TI - Selective Serotonin Reuptake Inhibitors and Cataract Risk: A Case-Control Analysis. AB - PURPOSE: Use of selective serotonin reuptake inhibitors (SSRIs) has been associated with an increased cataract risk. We aimed to assess cataract risk after exposure to SSRI or to other antidepressant drugs in a large electronic primary care database. DESIGN: Case-control study. PARTICIPANTS: The study population was derived from the UK-based Clinical Practice Research Datalink (CPRD). We included patients with first-time cataract aged >=40 years between 1995 and 2015 and an equal number of cataract-free controls matched on age, sex, general practice, date of cataract recording (i.e., index date), and years of history in the CPRD before the index date. METHODS: We conducted conditional logistic regression analyses adjusted for body mass index, smoking, hypertension, diabetes, and systemic steroid use. Exposure of interest was the number of SSRI prescriptions and prescriptions for other antidepressant drugs. We further explored mutually exclusive use of single SSRI substances. In sensitivity analyses, we shifted the index date backwards by 2 years, and we restricted our analyses to cases and controls without a prior glaucoma diagnosis. MAIN OUTCOME MEASURES: Relative risk estimates as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: We identified 206 931 cataract cases and the same number of matched controls. Current long-term use of SSRI (>=20 prescriptions) was not associated with an increased cataract risk (adjusted OR, 0.99; 95% CI, 0.94-1.03). However, in a subset of patients aged 40 to 64 years, we found a slightly increased risk of cataract for long-term SSRI users (adjusted OR, 1.24; 95% CI, 1.15-1.34) compared with nonusers. CONCLUSIONS: In these data, use of SSRI was not associated with an increased risk of cataract. The slightly increased OR for individuals younger than 65 years of age in association with long-term SSRI use needs to be investigated in further studies. PMID- 28571894 TI - ZIKA virus: A new threat to the eyes. PMID- 28571895 TI - Timing of syncope during blood sampling - The Maastricht Study. PMID- 28571896 TI - [Short-term relevance of lower respiratory viral coinfection in inpatients under 2 years of age]. AB - INTRODUCTION: Advances in molecular diagnosis have made it possible to detect previously unknown viral agents as causative agents of lower respiratory tract infections (LRTI). The frequency and relevance of viral coinfections is still debatable. OBJECTIVE: compare clinical presentation and severity between single virus infection and viral coinfection in children admitted for LRTI. METHODS: A 3 year period observational study (2012-2015) included children younger than two years admitted for LRTI. Viral identification was performed using PCR technique for 16 viruses. Clinical data and use of health resources was gathered during hospital stay using a standard collection form and we compared single virus infection and viral coinfections. RESULTS: The study included 524 samples (451 patients); 448 (85,5%) had at least one virus identified. Viral coinfections were found in 159 (35,5%). RSV and HRV were the most commonly identified virus; bronchiolitis and pneumonia the most frequent diagnosis. Patients with viral coinfections were older, attended day-care centers, had previous recurrent wheezing more frequently and were more symptomatic at admission. These patients did not have more complementary exams performed but were prescribed medications more often. Viral coinfection group did not show longer length of hospital stay and oxygen need, more need for ICU nor ventilatory support. DISCUSSION: Our study showed a significant proportion of viral coinfections in young infants admitted with LRTI and confirmed previous data showing that prescription was more frequent in inpatients with viral coinfections, without an association with worst clinical outcome. PMID- 28571897 TI - [Implication of a national outbreak of Serratia marcescens associated with a contaminated solution of chlorhexidine in a paediatric hospital]. PMID- 28571891 TI - Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease. AB - A collective century of discoveries establishes the importance of the renin angiotensin aldosterone system in maintaining blood pressure, fluid volume and electrolyte homeostasis via autocrine, paracrine and endocrine signaling. While research continues to yield new functions of angiotensin II and angiotensin-(1 7), the gap between basic research and clinical application of these new findings is widening. As data accumulates on the efficacy of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers as drugs of fundamental importance in the treatment of cardiovascular and renal disorders, it is becoming apparent that the achieved clinical benefits is suboptimal and surprisingly no different than what can be achieved with other therapeutic interventions. We discuss this issue and summarize new pathways and mechanisms effecting the synthesis and actions of angiotensin II. The presence of renin-independent non canonical pathways for angiotensin II production are largely unaffected by agents inhibiting renin angiotensin system activity. Hence, new efforts should be directed to develop drugs that can effectively block the synthesis and/or action of intracellular angiotensin II. Improved drug penetration into cardiac or renal sites of disease, inhibiting chymase the primary angiotensin II forming enzyme in the human heart, and/or inhibiting angiotensinogen synthesis would all be more effective strategies to inhibit the system. Additionally, given the role of angiotensin II in the maintenance of renal homeostatic mechanisms, any new inhibitor should possess greater selectivity of targeting pathogenic angiotensin II signaling processes and thereby limit inappropriate inhibition. PMID- 28571898 TI - [Recommendations for respiratory support in the newborn (IV). High frequency ventilation, ex-utero intrapartum treatment (EXIT), extracorporeal membrane oxygenation (ECMO)]. AB - The recommendations included in this document will be part a series of updated reviews of the literature on respiratory support in the newborn infant. These recommendations are structured into 12 modules, and in this work module 8 is presented. Each module is the result of a consensus process amongst all members of the Surfactant and Respiratory Group of the Spanish Society of Neonatology. They represent a summary of the published papers on each specific topic, as well as the clinical experience of each one of the members of the group. PMID- 28571901 TI - How can we identify patients with delirium in the emergency department?: A review of available screening and diagnostic tools. AB - Delirium is a widespread and serious but under-recognized problem. Increasing evidence argues that emergency health care providers need to assess the mental status of the patient as the "sixth vital sign". A simple, sensitive, time efficient, and cost-effective tool is needed to identify delirium in patients in the emergency department (ED); however, a stand-alone measurement has not yet been established despite previous studies partly because the differential diagnosis of dementia and delirium superimposed on dementia (DSD) is too difficult to achieve using a single indicator. To fill up the gap, multiple aspects of a case should be assessed including inattention and arousal. For instance, we proposed the 100 countdown test as an effective means of detecting inattention. Further dedicated studies are warranted to shed light on the pathophysiology and better management of dementia, delirium and/or "altered mental status". We reviewed herein the clinical questions and controversies concerning delirium in an ED setting. PMID- 28571899 TI - Genetic strategies to analyze primary TRP channel-expressing cells in mice. AB - Transient receptor potential (TRP) ion channels regulate fundamental biological processes throughout the body. TRP channel dysfunction has been causally linked to a number of disease states and thus establishes these channels as promising therapeutic targets. In order to dissect the physiological role of individual TRP channels in specific tissues, a detailed understanding of the expression pattern of the different TRP channels throughout the organism is essential. We provide an overview of recent efforts to generate novel TRP channel reporter mouse strains for all 28 TRP channels encoded in the mouse genome to understand expression of these channels with a single-cell resolution in an organism-wide manner. The reporter mice will enable both the visualization and manipulation of all primary TRP channel-expressing cells allowing an unprecedented wealth in variety to investigate TRP channel function in vivo. As proof of principle, we provide preliminary results documenting TRPM5 expression throughout the entire body of juvenile and adult mice. PMID- 28571902 TI - Purtscher-like retinopathy associated with dermatomyositis and hemophagocytic lymphohistiocytosis. AB - CASE REPORT: An 11 year-old girl with progressive muscle weakness due to dermatomyositis and hemophagocytic lymphohistiocytosis in which multiple cotton exudates, venous tortuosity and flame haemorrhages are detected in the funduscopic examination, leading to the diagnosis of Purtscher-like retinopathy. DISCUSSION: Purstcher's retinopathy is a microvascular disorder with clinical signs of probable thrombotic origin. Its treatment is controversial, with systemic corticosteroids being the most widespread choice. PMID- 28571903 TI - Next generation sequencing in the diagnosis of Stargardt's disease. AB - INTRODUCTION: Stargardt's disease is the most frequent form of inherited macular dystrophy in children and adults. It is a genetic eye disorder caused by mutations in ABCA4 gene with an autosomal recessive inheritance. ABCA4 is a very polymorphic and large gene containing 50 exons. The development of next generation sequencing (NGS) can be used for the genetic diagnosis of this disease. PATIENTS AND METHODS: A report is presented on two patients with a clinical diagnosis of Stargardt's disease whose genetic confirmation was performed by a NGS panel of 298 genes. RESULTS: Clinically, the patients showed bull's eye maculopathy and absence of flecks, and genetically they shared the Gly1961Glu mutation that could explain their common phenotype, together with c.C3056T:p.T1019M for case 1, and c.287del:p.Asn96Thrfs*19 for case 2. CONCLUSIONS: NGS is particularly useful in the diagnosis of Stargardt's disease as ABCA4 is a large gene with a high allelic heterogeneity that causes a wide range of clinical manifestations. PMID- 28571900 TI - Racial disparities in health among nonpoor African Americans and Hispanics: The role of acute and chronic discrimination. AB - Racial disparities in health tend to be more pronounced at the upper ends of the socioeconomic (SES) spectrum. Despite having access to above average social and economic resources, nonpoor African Americans and Latinos report significantly worse health compared to nonpoor Whites. We combine data from the parents and children of the 1979 National Longitudinal Survey of Youth (NLSY79) to address two specific research aims. First, we generate longitudinal SES trajectories over a 33-year period to estimate the extent to which socioeconomic mobility is associated with exposure to discrimination (acute and chronic) across different racial/ethnic groups (nonHispanic Whites, nonHispanic Blacks, and Hispanics). Then we determine if the disparate relationship between SES and self-rated health across these groups can be accounted for by more frequent exposure to unfair treatment. For Whites, moderate income gains over time result in significantly less exposure to both acute and chronic discrimination. Upwardly mobile African Americans and Hispanics, however, were significantly more likely to experience acute and chronic discrimination, respectively, than their socioeconomically stable counterparts. We also find that differential exposure to unfair treatment explains a substantial proportion of the Black/White, but not the Hispanic/White, gap in self-rated health among this nationally representative sample of upwardly mobile young adults. The current study adds to the debate that the shape of the SES/health gradient differs, in important ways, across race and provides empirical support for the diminishing health returns hypothesis for racial/ethnic minorities. PMID- 28571904 TI - Co-delivery of evodiamine and rutaecarpine in a microemulsion-based hyaluronic acid hydrogel for enhanced analgesic effects on mouse pain models. AB - The aim of this study was to improve the analgesic effect of evodiamine and rutaecarpine, using a microemulsion-based hydrogel (ME-Gel) as the transdermal co delivery vehicle, and to assess hyaluronic acid as a hydrogel matrix for microemulsion entrapment. A microemulsion was formulated with ethyl oleate as the oil core to improve the solubility of the alkaloids and was loaded into a hyaluronic acid-structured hydrogel. Permeation-enhancing effects of the microemulsion enabled evodiamine and rutaecarpine in ME-Gel to achieve 2.60- and 2.59-fold higher transdermal fluxes compared with hydrogel control (p<0.01). The hyaluronic acid hydrogel-containing microemulsion exhibited good skin biocompatibility, whereas effective ME-Gel co-delivery of evodiamine and rutaecarpine through the skin enhanced the analgesic effect in mouse pain models compared with hydrogel. Notably, evodiamine and rutaecarpine administered using ME-Gel effectively down-regulated serum levels of prostaglandin E2, interleukin 6, and tumor necrosis factor alpha in formaldehyde-induced mouse pain models, possibly reflecting the improved transdermal permeability of ME-Gel co-delivered evodiamine and rutaecarpine, particularly with hyaluronic acid as the hydrogel matrix. PMID- 28571905 TI - Extremely small-sized globular poly(ethylene glycol)-cyclic RGD conjugates targeting integrin alphavbeta3 in tumor cells. AB - In this study, we report an extremely small-sized globular poly(ethylene glycol) (gPEG) conjugated with cyclic arginine-glycine-aspartic acid (cRGD) peptide and chlorin e6 (Ce6). This nanoparticle design takes advantage of the biocompatible functional gPEG (3-4nm in diameter) as an extremely small-sized drug carrier, the tumor targeting ability of cRGD, and the photodynamic tumor ablation ability of Ce6. We found that gPEG conjugated with cRGD and Ce6 (cRGD-gPEG-Ce6) exhibited much higher phototoxicity in SKOV-3 tumor cells (which have a very high density of integrin alphavbeta3 receptors) than in KB cells (which have a very low density of integrin alphavbeta3 receptors). Accordingly, cRGD-gPEG-Ce6 treatment resulted in a significant regression of in vivo SKOV-3 tumors, highlighting the potential of an extremely small-sized drug carrier platform for site-specific receptor-mediated tumor therapy. PMID- 28571906 TI - Limited Utility of Pulmonary Nodule Risk Calculators for Managing Large Nodules. AB - RATIONALE AND OBJECTIVES: The optimal management of large pulmonary nodules, at higher risk for lung cancer, has not been determined, and it remains unclear as to which patients should undergo follow-up imaging vs invasive tissue diagnosis via biopsy or surgical resection. MATERIALS AND METHODS: Through search of radiology reports, 86 nodules from our institution were identified using the inclusion criterion of solid nodules measuring greater than 8mm. We evaluated these nodules with a number of risk prediction calculators, including the Brock University model, and compared these against the proven diagnosis. RESULTS: Of 86 nodules, 59 (69%) nodules were malignant. The most accurate predictive model, the Brock University calculator, underestimated the risk for this group at 33%. At its optimal threshold, this model had a positive predictive value of 81% and negative predictive value of 53%. Notwithstanding the low negative predictive value, the positive predictive value was no better than patients clinically selected for biopsy (86% of biopsies were malignant). CONCLUSION: Existing nodule risk prediction calculators are of limited usage in guiding the management of large pulmonary nodules. At present, the accuracy of these models in this setting is inferior to expert clinical judgment, and future work is needed to develop management algorithms for higher-risk nodules. PMID- 28571907 TI - Magnetic Resonance Imaging Evaluation of Urothelial Cell Carcinoma: Histopathological Correlation, Staging, and Treatment Planning. PMID- 28571908 TI - The sFlt-1/PlGF ratio as a predictor for poor pregnancy and neonatal outcomes. AB - BACKGROUND: Soluble fms-like tyrosine kinase receptor-1 (sFlt-1)/placental growth factor (PlGF) ratio has been studied extensively as a predictive marker for pre eclampsia. However, its usefulness for predicting neonatal outcomes remains unknown. This study aimed to evaluate the association of sFlt-1/PlGF ratio with pregnancy outcomes, neonatal morbidities and short-term postnatal growth patterns in pregnant women and their babies. METHODS: sFlt-1 and PlGF were measured in women with fetal intrauterine growth retardation (IUGR) or pre-eclampsia during gestational age (GA) of 16-36 weeks. These women were classified into high- and low-ratio groups with a sFlt-1/PlGF cut-off ratio of 85. The maternal and neonatal outcomes were retrospectively reviewed and compared between the two groups. RESULTS: A total of 25 pregnant women were recruited. Thirteen of them had a sFlt-1/PlGF ratio over 85 and twelve had a ratio of less than 85. The median duration from elevation of sFlt-1/PlGF to delivery was 4.5 weeks. Women in the high SFlt-1/PlGF ratio group had higher rates of intrauterine fetal demise (2/13 vs. 0/12) and early termination (1/13 vs. 0/12). The surviving offspring in this group had a higher incidence of preterm birth (GA: 31.4 +/- 2.9 weeks vs. 37.3 +/- 1.3 weeks, p < 0.001), lower birth weight (1142 +/- 472 g vs. 2311 +/- 236 g, p < 0.001), higher incidence of respiratory distress syndrome (6/10 vs. 0/12, p = 0.002) and bronchopulmonary dysplasia (4/10 vs. 0/12, p = 0.01). However, the percentile of body weight, height and head circumference at 28 days of age, 56 days of age and the corrected age of 6 months were comparable between groups. CONCLUSIONS: High sFlt-1/PlGF ratio in pregnant women is associated with poor pregnancy and neonatal outcomes. Therefore, the monitoring of sFlt-1/PlGF ratio in pregnant women with fetal IUGR and timely management for placenta associated diseases are recommended. PMID- 28571909 TI - The presence of contaminations in sewage sludge - The current situation. AB - Sewage sludge/biosolids are by-wastes of municipal and industrial wastewater treatment. As sources of nutrients (C, N, P) they are widely used in intensive farming where large supplementation of organic matter to maintain fertility and enhance crop yields is needed. However, according to the report of European Commission published in 2010, only 39% of produced sewage sludge is recycled into agriculture in the European Union. This situation occurs mainly due to the fact, that the sewage sludge may contain a dangerous volume of different contaminants. For over decades, a great deal of attention has been focused on total concentration of few heavy metals and pathogenic bacteria Salmonella and Escherichia coli. The Sewage Sludge Directive (86/278/EEC) regulates the allowable limits of Zn, Cu, Ni, Pb, Cd, Cr and Hg and pathogens and allows for recovery of sludge on land under defined sanitary and environmentally sound conditions. In this paper, a review on quality of sewage sludge based on the publications after 2010 has been presented. Nowadays there are several papers focusing on new serious threats to human health and ecosystem occurring in sewage sludge - both chemicals (such as toxic trace elements - Se, Ag, Ti; nanoparticles; polyaromatic hydrocarbons; polychlorinated biphenyl; perfluorinated surfactants, polycyclic musks, siloxanes, pesticides, phenols, sweeteners, personal care products, pharmaceuticals, benzotriazoles) and biological traits (Legionella, Yersinia, Escherichia coli O157:H7). PMID- 28571911 TI - A spotlight on intraoperative neurophysiological monitoring of the lower brainstem. PMID- 28571910 TI - Alzheimer's disease disrupts alpha and beta-band resting-state oscillatory network connectivity. AB - OBJECTIVE: Neuroimaging studies in Alzheimer's disease (AD) yield conflicting results due to selective investigation. We conducted a comprehensive magnetoencephalography study of connectivity changes in AD and healthy ageing in the resting-state. METHODS: We performed a whole-brain, source-space assessment of oscillatory neural signalling in multiple frequencies comparing AD patients, elderly and young controls. We compared eyes-open and closed group oscillatory envelope activity in networks obtained through temporal independent component analysis, and calculated whole-brain node-based amplitude and phase connectivity. RESULTS: In bilateral parietotemporal areas, oscillatory envelope amplitude increased with healthy ageing, whereas both local amplitude and node-to-global connectivity decreased with AD. AD-related decreases were spatially specific and restricted to the alpha and beta bands. A significant proportion of the variance in areas of peak group difference was explained by cognitive integrity, in addition to group. None of the groups differed in phase connectivity. Results were highly similar for eyes-open and closed resting-state. CONCLUSIONS: These results support the disconnection syndrome hypothesis and suggest that AD shows distinct and unique patterns of disrupted neural functioning, rather than accelerated healthy ageing. SIGNIFICANCE: Whole-brain assessments show that disrupted regional oscillatory envelope amplitude and connectivity in the alpha and beta bands play a key role in AD. PMID- 28571912 TI - "Influence of possible predictor variables on the outcome of primary oral squamous cell carcinoma: a retrospective study of 392 consecutive cases at a single centre"- methodological issues. PMID- 28571913 TI - Multidisciplinary design and analytic approaches to advance prospective research on the multilevel determinants of child health. AB - PURPOSE: Characterizing the determinants of child health and development over time, and identifying the mechanisms by which these determinants operate, is a research priority. The growth of precision medicine has increased awareness and refinement of conceptual frameworks, data management systems, and analytic methods for multilevel data. This article reviews key methodological challenges in cohort studies designed to investigate multilevel influences on child health and strategies to address them. METHODS: We review and summarize methodological challenges that could undermine prospective studies of the multilevel determinants of child health and ways to address them, borrowing approaches from the social and behavioral sciences. RESULTS: Nested data, variation in intervals of data collection and assessment, missing data, construct measurement across development and reporters, and unobserved population heterogeneity pose challenges in prospective multilevel cohort studies with children. We discuss innovations in missing data, innovations in person-oriented analyses, and innovations in multilevel modeling to address these challenges. CONCLUSIONS: Study design and analytic approaches that facilitate the integration across multiple levels, and that account for changes in people and the multiple, dynamic, nested systems in which they participate over time, are crucial to fully realize the promise of precision medicine for children and adolescents. PMID- 28571915 TI - 3D-spheroids: What can they tell us about pancreatic ductal adenocarcinoma cell phenotype? AB - We aimed at analyzing the effect of the 3D-arrangement on the expression of some genes and proteins which play a key role in pancreatic adenocarcinoma (PDAC) progression in HPAF-II, HPAC and PL45 PDAC cells cultured in either 2D-monolayers or 3D-spheroids. Cytokeratins 7, 8, 18, 19 were differently expressed in 3D spheroids compared to 2D-monolayers. Syndecan 1 was upregulated in HPAF-II and PL45 3D-spheroids, and downregulated in HPAC. Heparanase mRNA levels were almost unchanged in HPAF-II, and increased in HPAC and PL45 3D-spheroids. Hyaluronan synthase (HAS) 2 and 3 mRNA increased in all 3D-spheroids compared to 2D monolayers. CD44 and CD44s were expressed to a lower extent in HPAF-II and HPAC 3D-spheroids. By contrast, the CD44s/v3 and the CD44s/v6 ratio increased in HPAC and PL45 3D-spheroids, compared to 2D-monolayers. The expression of MMP-7 was strongly upregulated in 3D-spheroids. STAT3 was similarly expressed 3D-spheroids or 2D-monolayers, while pSTAT3 was almost undetectable in 2D-monolayers and strongly upregulated in 3D-spheroids. These results suggest that 3D-spheroids represent a cell culture model that allows the characterization of PDAC cell phenotype, adding new information that contributes to a better understanding of the biology and behavior of PDAC cells. PMID- 28571914 TI - Individual- and neighborhood-level contextual factors are associated with Mycobacterium tuberculosis transmission: genotypic clustering of cases in Michigan, 2004-2012. AB - PURPOSE: Using genotyping data of Mycobacterium tuberculosis isolates from new cases reported to the tuberculosis (TB) surveillance program, we evaluated risk factors for recent TB transmission at both the individual- and neighborhood- levels among U.S.-born and foreign-born populations. METHODS: TB cases (N = 1236) reported in Michigan during 2004 to 2012 were analyzed using multivariable Poisson regression models to examine risk factors for recent transmission cross sectionally for U.S.-born and foreign-born populations separately. Recent transmission was defined based on spoligotype and 12-locus-mycobacterial interspersed repetitive unit-variable number tandem repeat typing matches of bacteria from cases that were diagnosed within 1 year of each other. Four classes of predictor variables were examined: demographic factors, known TB risk factors, clinical characteristics, and neighborhood-level factors. RESULTS: Overall, 22% of the foreign-born cases resulted from recent transmission. Among the foreign born, race and being a contact of an infectious TB case were significant predictors of recent transmission. More than half (52%) of U.S.-born cases resulted from recent transmission. Among the U.S.-born, recent transmission was predicted by both individual- and neighborhood-level sociodemographic characteristics. CONCLUSIONS: Interventions aimed at reducing TB incidence among foreign-born should focus on reducing reactivation of latent infection. However, reducing TB incidence among the U.S.-born will require decreasing transmission among socially disadvantaged groups at the individual- and neighborhood- levels. This report fills an important knowledge gap regarding the contemporary social context of TB in the United States, thereby providing a foundation for future studies of public health policies that can lead to the development of more targeted, effective TB control. PMID- 28571916 TI - A general ionic liquid pH-zone-refining countercurrent chromatography method for separation of alkaloids from Nelumbo nucifera Gaertn. AB - The alkaloids from lotus (Nelumbo nucifera Gaertn) are effective in lowering hyperlipemia and level of cholesterol. However, there is not a general method for their separation. In this work, a general ionic liquid pH-zone-refining countercurrent chromatography method for isolation and purification of six alkaloids from the whole lotus plant was successfully established by using ionic liquids as the modifier of the two-phase solvent system. The conditions of ionic liquid pH-zone-refining countercurrent chromatography, involving solvent systems, concentration of retainer and eluter, types of ionic liquids, the content of ionic liquids as well as ionic liquids posttreatment, were optimized to improve extraction efficiency. Finally, the separation of these six alkaloids was performed with a two-phase solvent system composed of n-hexane-ethyl acetate methanol-water-[C4mim][PF6] at a volume ratio of 5:2:2:8:0.1, where 10mM TEA was added to the organic stationary phase as a retainer and 3mM HCl was added to the aqueous mobile phase as an eluter. As a result, six alkaloids including N nornuciferine, liensinine, nuciferine, isoliensinine, roemerine and neferine were successfully separated with the purities of 97.0%, 90.2%, 94.7%, 92.8%, 90.4% and 95.9%, respectively. The established general method has been respectively applied to the crude samples of lotus leaves and lotus plumules. A total of 37.3mg of liensinine, 57.7mg of isoliensinine and 179.9mg of neferine were successfully purified in one run from 1.00g crude extract of lotus plumule with the purities of 93.2%, 96.5% and 98.8%, respectively. Amount of 45.6mg N-nornuciferine, 21.6mg nuciferine and 11.7mg roemerine was obtained in one step separation from 1.05g crude extract of lotus leaves with the purity of 96.9%, 95.6% and 91.33%, respectively. PMID- 28571918 TI - Colonic polypoid mucosa-associated lymphoid tissue lymphoma. PMID- 28571919 TI - Conventional esophageal manometry in clinical practice: Current impact of its use on patient management. PMID- 28571917 TI - Targeting miR-21 with Sophocarpine Inhibits Tumor Progression and Reverses Epithelial-Mesenchymal Transition in Head and Neck Cancer. AB - A major challenge for cancer chemotherapy is the development of safe and clinically effective chemotherapeutic agents. With its low toxicity profile, sophocarpine (SC), a naturally occurring tetracyclic quinolizidine alkaloid derived from Sophora alopecuroides L, has shown promising therapeutic properties, including anti-inflammatory, anti-nociceptive, and antivirus activities. However, the antitumor efficacy of SC and its underlying mechanisms have not been completely delineated. In the present study, the inhibitory effect of SC on head and neck squamous cell carcinoma (HNSCC) progression and possible mechanisms for this effect involving microRNA-21 (miR-21) regulation were investigated. By cell viability, Transwell, and wound healing assays, we show that SC effectively inhibited proliferation, invasion, and migration of HNSCC cells. Moreover, SC exerted its growth-inhibitory effect via the downregulation of miR-21 expression by blocking Dicer-mediated miR-21 maturation. Furthermore, SC treatment led to the increased expression of PTEN and p38MAPK phosphorylation as well as the reversal of epithelial-mesenchymal transition (EMT), which was rescued by ectopic expression of miR-21 in cells. Notably, SC dramatically repressed tumor growth without observable tissue cytotoxicity in a mouse xenograft model of HNSCC. Our findings offer a preclinical proof of concept for SC as a leading natural agent for HNSCC cancer therapy. PMID- 28571920 TI - Mobile bearing medial unicompartmental knee arthroplasty in patients whose lifestyles involve high degrees of knee flexion: A 10-14year follow-up study. AB - BACKGROUND: Because Asian populations have different lifestyles, such as squatting and sitting on the floor, from those of Western populations, it is possible that the clinical results and survival rate of unicompartmental knee arthroplasty (UKA) for Asian patients may be different. This study described outcomes of mobile bearing medial UKA for Korean patients. METHODS: A total of the 164 knees treated with mobile bearing UKAs in 147 patients (14 males and 133 females) were reviewed. The mean follow-up period was 12.1years (range 10.1-14). RESULTS: The clinical outcomes, such as the Hospital for Special Surgery Knee score, the Oxford Knee Score and the Knee Society rating system, showed statistically significant improvement from pre-operative to final follow-up (P<0.05). A total of 26 UKAs (15.8%) required revision; the most common reason was bearing dislocation. The 95% confidence interval of survival rate at 12years was 84.1%, with revision for any reason as the end point. CONCLUSIONS: Minimally invasive mobile bearing UKA in Asian patients who required high degrees of knee flexion showed rapid recovery and good clinical outcome. However, they also showed relatively high rates of bearing dislocation and aseptic loosening. Therefore, mobile bearing UKA should only be performed in patients whose lifestyle involves high flexions after carefully considering these risks and benefits. PMID- 28571923 TI - Talar head fracture in a professional baseball player: A case report. PMID- 28571922 TI - A decrease in glutamic acid decarboxylase autoantibody levels with sitagliptin use in patients with latent autoimmune diabetes in adults. PMID- 28571921 TI - Variability in static alignment and kinematics for kinematically aligned TKA. AB - BACKGROUND: Total knee arthroplasty (TKA) significantly improves pain and restores a considerable degree of function. However, improvements are needed to increase patient satisfaction and restore kinematics to allow more physically demanding activities that active patients consider important. The aim of our study was to compare the alignment and motion of kinematically and mechanically aligned TKAs. METHODS: A patient specific musculoskeletal computer simulation was used to compare the tibio-femoral and patello-femoral kinematics between mechanically aligned and kinematically aligned TKA in 20 patients. RESULTS: When kinematically aligned, femoral components on average resulted in more valgus alignment to the mechanical axis and internally rotated to surgical transepicondylar axis whereas tibia component on average resulted in more varus alignment to the mechanical axis and internally rotated to tibial AP rotational axis. With kinematic alignment, tibio-femoral motion displayed greater tibial external rotation and lateral femoral flexion facet centre (FFC) translation with knee flexion than mechanical aligned TKA. At the patellofemoral joint, patella lateral shift of kinematically aligned TKA plateaued after 20 to 30 degrees flexion while in mechanically aligned TKA it decreased continuously through the whole range of motion. CONCLUSIONS: Kinematic alignment resulted in greater variation than mechanical alignment for all tibio-femoral and patello-femoral motion. Kinematic alignment places TKA components patient specific alignment which depends on the preoperative state of the knee resulting in greater variation in kinematics. The use of computational models has the potential to predict which alignment based on native alignment, kinematic or mechanical, could improve knee function for patient's undergoing TKA. PMID- 28571924 TI - Long-term preservation of Tetraselmis indica (Chlorodendrophyceae, Chlorophyta) for flow cytometric analysis: Influence of fixative and storage temperature. AB - Immediate enumeration of phytoplankton is seldom possible. Therefore, fixation and subsequent storage are required for delayed analysis. This study investigated the influence of glutaraldehyde (GA) concentrations (0.25%, 0.5%, and 1%) and storage temperatures (-80 degrees CLN2, -80 degrees C, -20 degrees C, and 5 degrees C) on Tetraselmis indica for flow cytometric analysis. Cell recovery, granularity, and membrane permeability were independent of GA concentration whereas cell size and chlorophyll autofluorescence were concentration dependent. After an initial cell loss (16-19%), no cell loss was observed when samples were stored at 5 degrees C. Cell recovery was not influenced by storage temperature until 4months but later samples preserved at -80 degrees CLN2, -80 degrees C, and -20 degrees C resulted in ~41% cell loss. Although maximum cell recovery with minimal effect on cell integrity was obtained at 5 degrees C, autofluorescence was retained better at -80 degrees CLN2 and -80 degrees C. This suggests that in addition to fixative, the choice of storage temperature is equally important. Thus for long-term preservation, especially to retain autofluorescence, the use of lower concentration (0.25%) of GA when stored at a lower temperature (-80 degrees CLN2 and -80 degrees C) while a higher concentration (1%) of GA when stored at a higher temperature (5 degrees C) is recommended. PMID- 28571925 TI - Reprint of: Contribution of enrichments and resampling for sulfate reducing bacteria diversity assessment by high-throughput cultivation. AB - The development of new high-throughput cultivation methods aims to increase the isolation efficiency as compared to standard techniques that often require enrichment procedures to compensate the low microbial recovery. In the current study, estuarine sulfate-reducing bacteria were isolated using an anaerobic isolation procedure in 384-well microplates. Ninety-nine strains were recovered from initial sediments. Isolates were identified according to their partial 16S rRNA sequences and clustered into 13 phylotypes. Besides, the increase in species richness obtained through enrichments or resampling was investigated. Forty-four enrichment procedures were conducted and shifts in sulfate-reducing bacterial communities were investigated through dsrAB gene fingerprinting. Despite efforts in conducting numerous enrichment conditions only few of them were statistically different from initial sample. The cultural diversity obtained from 3 of the most divergent enrichments, as well as from resampled sediments equally contributed to raise the sulfate-reducing diversity up to 22 phylotypes. Enrichments (selection of metabolism) or resampling (transient populations and micro-heterogeneity) may still be helpful to assess new microbial phylotypes. Nevertheless, all the newly cultivated strains were all representatives of minor Operational Taxonomic Units and could eventually be recovered by maintaining high-throughput isolation effort from the initial sediments. PMID- 28571926 TI - Urinary sodium excretion after gastric bypass surgery. AB - BACKGROUND: Gut-kidney signaling is implicated in sodium homeostasis and thus blood pressure regulation. Roux-en-Y gastric bypass (RYGB) surgery for morbid obesity confers a pronounced and long-lasting blood pressure lowering effect in addition to significant weight loss. OBJECTIVES: We set out to establish whether RYGB is associated with an intrinsic change in urinary sodium excretion that may contribute to the reported blood pressure lowering effects of the procedure. SETTING: University hospital METHODS: Five female patients (age range: 28-50 yr) without metabolic or hypertensive co-morbidities were included in a study involving four 24-hour residential visits: once before surgery and 10 days, 3 months, and 20 months after surgery. Creatinine and sodium were measured in fasting plasma samples and 24-hour urine samples and creatinine clearance, estimated glomerular filtration rate, and indices of urinary sodium excretion were calculated. Fasting and 60-minute postprandial blood samples from each study day were assayed for pro-B-type natriuretic peptide (NT-proBNP). RESULTS: Increases in weight-normalized urinary sodium excretion of up to 2.3-fold in magnitude occurred at 20 months after surgery. Median fractional excretion of sodium at 20 months was double that seen before surgery. Fasting NT-proBNP levels were stable or increased (1.5- to 5-fold). Moreover, a small postprandial increase in NT-proBNP was observed after surgery. CONCLUSIONS: Renal fractional excretion of sodium is increased after RYGB. A shift toward increased postoperative basal and meal associated levels of NT-proBNP coincides with increased urinary sodium excretion. The data support a working hypothesis that an enhanced natriuretic gut-kidney signal after RYGB may be of mechanistic importance in the blood pressure lowering effects of this procedure. PMID- 28571927 TI - Comment on: Long-term success and failure with sleeve gastrectomy is predictable by 3 months: a multivariate model using simple office markers. PMID- 28571929 TI - Trans-Oral Robotic Surgery for a Ewing's sarcoma of tongue in a pediatric patient: a case report. PMID- 28571928 TI - Free tissue flaps in head and neck reconstruction: clinical application and analysis of 93 patients of a single institution. AB - INTRODUCTION: Reconstruction with a free flap is routine in head and neck surgery because of better functional outcomes, improved esthetics, and generally higher success rates. OBJECTIVE: To evaluate the clinical outcomes in patients undergoing different microvascular free flap reconstructions. METHODS: This was a retrospective study of 93 patients undergoing reconstructions with free flaps from 2007 to 2015. Four types of free flap were performed: anterolateral thigh (76.3%), radial forearm (16.1%), fibula (4.3%) and jejunum (3.3%). Patients' demographic data were collected, and the outcomes measured included flap survival and complications. Postoperative functional and oncological outcome were also analyzed. RESULTS: The patients included 73 men and 20 women, with a mean age of 56.1 years. The most common tumor location was the tongue. Squamous cell carcinoma represented the vast majority of the diagnosed tumors (89.2%). The most common recipient vessels were the superior thyroid artery (77.4%) and the internal jugular vein (91.4%). Nine patients required emergency surgical re exploration and the overall flap success rate was 90.3%. Venous thrombosis was the most common cause for re-exploration. Other complications included wound infection (5.4%), wound dehiscence (1.1%), partial flap necrosis (9.7%), fistula formation (10.8%), and 1 bleeding (1.1%). The majority of patients had satisfactory cosmetic and functional results of both donor site and recipient site after 46.7 months of mean follow-up. CONCLUSION: Microsurgical free flap is shown to be a valuable and reliable method in head and neck surgery. It can be used safely and effectively with minimal morbidity in selected patients. The reconstruction can be performed by appropriately skilled surgeons with acceptable outcomes. Success rate appears to increase as clinical experience is gained. PMID- 28571930 TI - HOKF: High Order Kalman Filter for Epilepsy Forecasting Modeling. AB - Epilepsy forecasting has been extensively studied using high-order time series obtained from scalp-recorded electroencephalography (EEG). An accurate seizure prediction system would not only help significantly improve patients' quality of life, but would also facilitate new therapeutic strategies to manage epilepsy. This paper thus proposes an improved Kalman Filter (KF) algorithm to mine seizure forecasts from neural activity by modeling three properties in the high-order EEG time series: noise, temporal smoothness, and tensor structure. The proposed High Order Kalman Filter (HOKF) is an extension of the standard Kalman filter, for which higher-order modeling is limited. The efficient dynamic of HOKF system preserves the tensor structure of the observations and latent states. As such, the proposed method offers two main advantages: (i) effectiveness with HOKF results in hidden variables that capture major evolving trends suitable to predict neural activity, even in the presence of missing values; and (ii) scalability in that the wall clock time of the HOKF is linear with respect to the number of time-slices of the sequence. The HOKF algorithm is examined in terms of its effectiveness and scalability by conducting forecasting and scalability experiments with a real epilepsy EEG dataset. The results of the simulation demonstrate the superiority of the proposed method over the original Kalman Filter and other existing methods. PMID- 28571931 TI - An ABO blood grouping discrepancy: Probable B(A) phenotype. AB - In B(A) phenotype, an autosomal dominant phenotype, there is a weak A expression on group B RBCs. We herein report a case of a probable B(A) phenotype in a first time 20-year old male donor. The cell and serum grouping were done using tube technique and also with blood grouping gel card (Diaclone, ABD cards for donors, BioRad, Switzerland). The antisera used were commercial monoclonal IgM type. To check for the weak subgroup of A, cold adsorption and heat elution was performed. The cell grouping was AweakB RhD positive while the serum grouping was B. There was no agglutination with O cells and the autologous control was also negative. It was a group II ABO discrepancy with or without group IV discrepancy. Results for both the eluate and last wash were negative. Hence, the possibility of weak subgroup of A was unlikely. Blood grouping gel card also showed a negative reaction in the anti-A column. One lot of anti-A was showing 'weak +' agglutination while the other lot was showing 'negative' reaction with the donor RBCs by tube technique. There was no agglutination observed with anti-A1 lectin. Our case highlights the serological characteristics of a B(A) phenotype. This case emphasizes the vital role of cell and serum grouping in detecting such discrepancies especially in donors which can lead to mislabeling of the blood unit and may be a potential risk for the transfusion recipient if not resolved appropriately. PMID- 28571932 TI - Detection of the relatively slow-growing Propionibacterium acnes in seven matrices of blood components and advanced therapeutical medicinal products. AB - BACKGROUND: Relatively slow-growing bacteria like Propionibacterium acnes represent a challenge for quality control investigations in sterility release testing of blood components and advanced therapeutic medicinal products (ATMPs). METHODS: A convenient validation with 7 matrices was performed using buffy coat, stem cells, islet cells, natural killer cells, red blood cells, platelets and plasma in the microbial detection system Bact/Alert(r)3D incubator. All matrix samples were spiked twofold with Propionibacterium acnes with approximately 50 colony forming units (CFUs) per bottle in iAST and iNST culture bottles for 14days using a multishot bioball. Additionally, the stem cell preparations were also incubated in iFAplus and iFNplus culture bottles, which include neutralizing polymers. RESULTS: The Bact/Alert(r)3D-System detected Propionibacterium acnes in anaerobic culture bottles in buffy coat [3.3 d (=positive signal day to detection as mean value)], red blood cells [3.2 d], platelets [3.3], plasma [3.7 d], natural killer cells [3.3 d] and islet cells [4.9 d], resp. No growth of Propionibacterium was found in autologous stem cells using iAST and iNST culture bottles. However, Propionibacterium was safely detected in the iFNplus culture bottle with polymers in the stem cell matrix. A successful validation of media was performed. CONCLUSIONS: Our study shows that Bact/Alert(r)3D-System safely detects the relatively slow-growing bacterium Propionibacterium acnes in different matrices in a practical way except stem cells. Using the iFNplus culture bottle for stem cell products positive signals were observed. PMID- 28571934 TI - Intensive glycemic control in younger and older U.S. adults with type 2 diabetes. AB - AIMS: To determine the extent to which older vs. younger adults with diabetes intensively control glycemia. METHODS: Participants were age>=40years who self reported a physician diagnosis of diabetes in the 2009-2014 National Health and Nutrition Examination Surveys (N=1554). Intensive glycemic control was defined as A1c<7.0% and taking insulin, sulfonylureas, or >=2 glycemic medications. Logistic regression was used to determine the adjusted odds of intensive control in older (>=65years) vs. younger adults (age 40-64years). RESULTS: The prevalence of intensive control was greater for older (33.4%) vs. younger (21.3%) adults (p<0.001). In logistic regression, intensive control was significantly higher in older vs. younger adults after fully adjusting for sociodemographics, diabetes duration, comorbidities, disability, use of multiple medications, and depression (OR=1.72, 1.09-2.69). The multivariable adjusted prevalence of intensive control was 40% higher in adults >=75years (35.6%) compared to adults 40-49years (21.7%). CONCLUSIONS: Older adults are being treated more aggressively than younger adults to achieve A1c<7.0% despite the presence of comorbidities, duration of diabetes, disability, and depression. Glycemic guidelines for individualized therapy are not being widely followed. PMID- 28571933 TI - Predicting readmission risk of patients with diabetes hospitalized for cardiovascular disease: a retrospective cohort study. AB - OBJECTIVE: To develop and validate a tool that predicts 30d readmission risk of patients with diabetes hospitalized for cardiovascular disease (CVD), the Diabetes Early Readmission Risk Indicator-CVD (DERRI-CVDTM). METHODS: A cohort of 8189 discharges was retrospectively selected from electronic records of adult patients with diabetes hospitalized for CVD. Discharges of 60% of the patients (n=4950) were randomly selected as a training sample and the remaining 40% (n=3219) were the validation sample. RESULTS: Statistically significant predictors of all-cause 30d readmission risk were identified by multivariable logistic regression modeling: education level, employment status, living within 5miles of the hospital, pre-admission diabetes therapy, macrovascular complications, admission serum creatinine and albumin levels, having a hospital discharge within 90days pre-admission, and a psychiatric diagnosis. Model discrimination and calibration were good (C-statistic 0.71). Performance in the validation sample was comparable. Predicted 30d readmission risk was similar in the training and validation samples (38.6% and 35.1% in the highest quintiles). CONCLUSIONS: The DERRI-CVDTM may be a valid tool to predict all-cause 30d readmission risk of patients with diabetes hospitalized for CVD. Identifying high risk patients may encourage the use of interventions targeting those at greatest risk, potentially leading to better outcomes and lower healthcare costs. PMID- 28571935 TI - Dissociation of local and global skeletal muscle oxygen transport metrics in type 2 diabetes. AB - AIMS: Exercise capacity is impaired in type 2 diabetes, and this impairment predicts excess morbidity and mortality. This defect appears to involve excess skeletal muscle deoxygenation, but the underlying mechanisms remain unclear. We hypothesized that reduced blood flow, reduced local recruitment of blood volume/hematocrit, or both contribute to excess skeletal muscle deoxygenation in type 2 diabetes. METHODS: In patients with (n=23) and without (n=18) type 2 diabetes, we recorded maximal reactive hyperemic leg blood flow, peak oxygen utilization during cycling ergometer exercise (VO2peak), and near-infrared spectroscopy-derived measures of exercise-induced changes in skeletal muscle oxygenation and blood volume/hematocrit. RESULTS: We observed a significant increase (p<0.05) in skeletal muscle deoxygenation in type 2 diabetes despite similar blood flow and recruitment of local blood volume/hematocrit. Within the control group skeletal muscle deoxygenation, local recruitment of microvascular blood volume/hematocrit, blood flow, and VO2peak are all mutually correlated. None of these correlations were preserved in type 2 diabetes. CONCLUSIONS: These results suggest that in type 2 diabetes 1) skeletal muscle oxygenation is impaired, 2) this impairment may occur independently of bulk blood flow or local recruitment of blood volume/hematocrit, and 3) local and global metrics of oxygen transport are dissociated. PMID- 28571938 TI - Editorial Comment. PMID- 28571936 TI - Sex differences in the drinking response to angiotensin II (AngII): Effect of body weight. AB - Sex differences in fluid intake stimulated by angiotensin II (AngII) have been reported, but the direction of the differences is inconsistent. To resolve these discrepancies, we measured water intake by male and female rats given AngII. Males drank more than females, but when intake was normalized to body weight, the sex difference was reversed. Weight-matched males and females, however, had no difference in intake. Using a linear mixed model analysis, we found that intake was influenced by weight, sex, and AngII dose. We used linear regression to disentangle these effects further. Comparison of regression coefficients revealed sex and weight differences at high doses of AngII. Specifically, after 100ng AngII, weight was a predictor of intake in males, but not in females. Next, we tested for differences in AngII-induced intake in male and females allowed to drink both water and saline. Again, males drank more water than females, but females showed a stronger preference for saline. Drinking microstructure analysis suggested that these differences were mediated by postingestive signals and more bottle switches by the females. Finally, we probed for differences in the expression of components of the renin-angiotensin system in the brains of males and females and found sex differences in several genes in discrete brain regions. These results provide new information to help understand key sex differences in ingestive behaviors, and highlight the need for additional research to understand baseline sex differences, particularly in light of the new NIH initiative to balance sex in biomedical research. PMID- 28571937 TI - Thermal modulation of anthropogenic estrogen exposure on a freshwater fish at two life stages. AB - Human-mediated environmental change can induce changes in the expression of complex behaviors within individuals and alter the outcomes of interactions between individuals. Although the independent effects of numerous stressors on aquatic biota are well documented (e.g., exposure to environmental contaminants), fewer studies have examined how natural variation in the ambient environment modulates these effects. In this study, we exposed reproductively mature and larval fathead minnows (Pimephales promelas) to three environmentally relevant concentrations (14, 22, and 65ng/L) of a common environmental estrogen, estrone (E1), at four water temperatures (15, 18, 21, and 24 degrees C) reflecting natural spring and summer variation. We then conducted a series of behavioral experiments to assess the independent and interactive effects of temperature and estrogen exposure on intra- and interspecific interactions in three contexts with important fitness consequences; reproduction, foraging, and predator evasion. Our data demonstrated significant independent effects of temperature and/or estrogen exposure on the physiology, survival, and behavior of larval and adult fish. We also found evidence suggesting that thermal regime can modulate the effects of exposure on larval survival and predator-prey interactions, even within a relatively narrow range of seasonally fluctuating temperatures. These findings improve our understanding of the outcomes of interactions between anthropogenic stressors and natural abiotic environmental factors, and suggest that such interactions can have ecological and evolutionary implications for freshwater populations and communities. PMID- 28571939 TI - Editorial Comment. PMID- 28571940 TI - Image Analysis in Plant Sciences: Publish Then Perish. AB - Image analysis has become a powerful technique for most plant scientists. In recent years dozens of image analysis tools have been published in plant science journals. These tools cover the full spectrum of plant scales, from single cells to organs and canopies. However, the field of plant image analysis remains in its infancy. It still has to overcome important challenges, such as the lack of robust validation practices or the absence of long-term support. In this Opinion article, I: (i) present the current state of the field, based on data from the plant-image-analysis.org database; (ii) identify the challenges faced by its community; and (iii) propose workable ways of improvement. PMID- 28571941 TI - Clinical Predictors of Isolated Tubal Torsion: A Case Series. AB - STUDY OBJECTIVE: A rare cause of adolescent abdominal pain includes isolated tubal torsion (ITT). Presentation is nonspecific and few studies have investigated ITT in adolescents. Our study objective was to describe the presentation and management of ITT in a large case series. DESIGN: Retrospective observational case series. SETTING: Tertiary care children's hospital. PARTICIPANTS: Participants were female and aged 3-21 years, presenting to Children's Hospital Colorado and diagnosed with ITT between January 2004 and August 2015. INTERVENTIONS AND MAIN OUTCOME MEASURES: Clinical presentation, physical exam, laboratory findings, surgical diagnosis, and treatment provided. RESULTS: A total of 19 cases were included. Average age was 13.3 (range, 11-18) years. In patients with unilateral abdominal pain (n = 16), there was 100% correlation with side of adnexal pathology. Ultrasound examination in 14 of 18 cases (78%) noted abnormal findings ipsilateral to the ITT. Most cases were managed with laparoscopy (84%; n = 16 of 19) and detorsion with or without cystectomy (74%; n = 14 of 19). Salpingectomy was more common with prolonged pain greater than 24 hours (relative risk 5.6, 95% confidence interval, 0.7-39.0). The most common intraoperative finding was a paratubal cyst (74%; n = 14 of 19). When Doppler flow was performed, it was present in 88% (n = 16 of 18) of the affected adnexa. ITT was more common on the left side (68%; n = 13 of 19). CONCLUSION: The high occurrence of paratubal cysts might suggest pathologic predisposition for ITT. Providers should maintain a high index of suspicion for ITT, particularly if associated with a paratubal cyst. Classic examination findings of surgical abdomen, leukocytosis, fever, and absence of Doppler flow are infrequently present. Laparoscopy and detorsion are appropriate treatments for managing ITT. PMID- 28571942 TI - Corrigendum to "interaction of casein kinase 1 delta (CK1) with the light chain LC2 of microtubule associated protein 1A (MAP1A)" [Biochim. Biophys. Acta 1745/2 (2005) 196-2006]. PMID- 28571943 TI - Hematological alterations and splenic T lymphocyte polarization at the crest of snake venom induced acute kidney injury in adult male mice. AB - Snake venom induced acute kidney injury (SAKI) is of great clinical relevance in tropical countries. Involvement of T cell, a key mediator of AKI and its remission, is least explored in SAKI. In the present study the in vivo hematological alterations and associated splenic T cell polarization is probed in order to investigate the immune response at the crest of Russell's viper venom (RVV) induced AKI in experimental murine model. Based on a dose and time kinetic study intra muscular injection dose of 20 MUg RVV/100 gm body weight of mice and incubation period of 60 h was selected for induction of SAKI. Renal involvement in SAKI group was confirmed from oliguria, significantly elevated urinary microprotein (p < 0.001), decreased urinary creatinine (p = 0.003) and creatinine clearance (p < 0.001) compared to control. Hematological analyses revealed a significant neutrophilic leukocytosis (p < 0.001) associated with a reduced lymphocyte percentage (p < 0.001) favoring a state of acute inflammation in SAKI group. Immunophenotyping study of splenocytes showed a significant decrease in CD4+/CD8+ ratio (p < 0.001) with a significant increase in regulatory (CD25+FoxP3+) helper and cytotoxic subset of T cell (p < 0.001). Significant increase in IL-10+ regulatory helper and cytotoxic T cell (p < 0.001) further confirmed the internal milieu favoring immunosuppression. Apart from these the CD25-FoxP3+ reservoir regulatory T cells were also found to be significantly elevated in SAKI group compared to that of control (p < 0.001). Taken together, the results of the present study clearly indicated a state of acute inflammation and splenic T cell polarization towards regulatory subset at the crest of SAKI. PMID- 28571945 TI - Applying the Lists of Risk Drugs for Thai Elderly (LRDTE) as a mechanism to account for patient age and medicine severity in assessing potentially inappropriate medication use. AB - BACKGROUND: Potential inappropriate medication (PIM) prescribing is a medication that puts patients at risk rather than having benefits. PIM use has been associated with hospitalization, morbidity, and mortality resulting from ADRs in elderly patients. The Lists of Risk Drugs for Thai Elderly (LRDTE) was developed as the new screening tool to identify PIMs use. The prevalence of PIM use using the LRDTE has not been determined in Thailand. PURPOSE: The main purpose of this study was to examine the prevalence of PIM use based on the LRDTE. In addition, this aimed to address the PIM problem by identifying factors that influenced PIM use among elderly patients in Thailand. METHODS: A retrospective cross-sectional descriptive study was conducted using the computerized database at four community hospitals in Thailand during fiscal year 2014. The LRDTE criteria were used as a screening tool for identifying the medicine items of PIM use. Descriptive statistics and multivariate logistic regression were used to identify common and Thai region-specific predictors of PIM use. RESULTS: Of a total of 13274 elderly patients, 79% were prescribed at least one PIM, as indicated by the LRDTE criteria. Amlodipine (32%), omeprazole (30%), and tramadol (18%) were the most commonly prescribed PIMs in elderly patients aged 60 years and older. Hospital and physician characteristics were identified as independent predictors after adjustment for patient and utilization factors. CONCLUSION: PIM use in Thai elderly patients was highly prevalent in community hospitals because the LRDTE criteria reflected clinical practice in Thailand. Hospital and physician factors were identified as region-specific factors that were highly associated with PIM use. Revision of hospital formularies and educational programs for physicians are needed to improve prescribing and avoid PIM use. PMID- 28571944 TI - Indocyanine Green versus Radiotracer with or without Blue Dye for Sentinel Lymph Node Mapping in Stage >IB1 Cervical Cancer (>2 cm). AB - STUDY OBJECTIVE: To compare sentinel lymph node (SLN) mapping in women with cervical cancer stage >IB1 (tumor size >2 cm) using indocyanine green (ICG) versus the standard technique using radioisotope technetium 99m radiocolloid (Tc99m) radiotracer with or without blue dye. DESIGN: European multicenter, retrospective observational study (Canadian Task Force classification II-2). SETTING: Four academic medical centers. PATIENTS: Ninety-five women with stage IB1 cervical cancer (>2 cm) who underwent SLN mapping with Tc99m with or without blue dye or ICG and radical hysterectomy. INTERVENTION: The detection rate and bilateral mapping rate were compared between ICG and standard Tc99m radiotracer with or without blue dye. Lymphadenectomy was performed, and the false-negative rate was assessed. MEASUREMENTS AND MAIN RESULTS: Forty-seven patients underwent SLN mapping with Tc99m with or without blue dye, and 48 did so with ICG. All patients underwent radical hysterectomy with or without bilateral salpingo oophorectomy between 2008 and 2016. The overall detection rate of SLN mapping was 91.5% for Tc99m with or without blue dye and 100% for ICG. A 91.7% rate of bilateral migration was achieved for ICG, significantly higher than the 66% obtained with Tc99m with or without blue dye (p = .025). Nine of the 23 SLN positive patients (39.1%) were diagnosed exclusively as a result of the ultrastaging used to identify micrometastases or isolated tumor cells only. CONCLUSIONS: In advanced cervical cancer (stage IB1 >2 cm), the detection rate and bilateral migration rate on real-time fluorescent SLN mapping were higher with ICG than with Tc99m radiotracer with or without blue dye. SLN mapping and ultrastaging can provide additional information for nodal staging in advanced cervical cancer. In this setting, ICG is a promising tool for mapping, appearing less affected by higher disease stage compared with traditional methods. PMID- 28571946 TI - Gangliosides and hearing. AB - Severe auditory impairment observed in GM3 synthase-deficient mice and humans indicates that glycosphingolipids, especially sialic-acid containing gangliosides, are indispensable for hearing. Gangliosides associate with glycoproteins to form membrane microdomains, the composition of which plays a special role in maintaining the structural and functional integrity of hair cells. These microdomains, also called lipid rafts, connect with intracellular signaling and cytoskeletal systems to link cellular responses to environmental cues. During development, ganglioside species are expressed in distinctive spatial and temporal patterns throughout the cochlea. In both mice and humans, blocking particular steps of ganglioside metabolism produces distinctive neurological and auditory phenotypes. Thus each ganglioside species may have specific, non-overlapping functions within the cochlea, central auditory network, and brain. PMID- 28571948 TI - Intermittent Projectile Urethraggia: An Unusual Sequela of a Skateboarding Accident in an Adolescent Male. AB - Our patient suffered a perineal straddle injury, resulting in right cavernosal artery pseudoaneurysm in combination with a cavernosal-urethral fistula. The urethra failed to heal after several weeks, and the patient presented with severe intermittent urethral bleeding. The pseudoaneurysm was successfully treated by coil embolization, with resolution of the bleeding. The patient recovered completely, with normal erectile and voiding function. This type of injury is very rare in the literature: traumatic cavernosal arterial pseudoaneurysm is known to cause high flow priapism, but in this case additional cavernosal urethral fistula resulted in a severe urethraggia. This is the only case, to our knowledge, of delayed urethral bleeding from cavernosal artery pseudoaneursym in combination with a cavernosal-urethral fistula. PMID- 28571947 TI - Boron nitride nanotubes for gene silencing. AB - BACKGROUND: Non-viral gene delivery is increasingly investigated as an alternative to viral vectors due to low toxicity and immunogenicity, easy preparation, tissue specificity, and ability to transfer larger sizes of genes. METHODS: In this study, boron nitride nanotubes (BNNTs) are functionalized with oligonucleotides (oligo-BNNTs). The morpholinos complementary to the oligonucleotides attached to the BNNTs (morpholino/oligo-BNNTs) are hybridized to silence the luciferase gene. The morpholino/oligo-BNNTs conjugates are administered to luciferase-expressing cells (MDA-MB-231-luc2) and the luciferase activity is monitored. RESULTS: The luciferase activity is decreased when MDA-MB 231-luc2 cells were treated with morpholino/oligo-BNNTs. CONCLUSIONS: The study suggests that BNNTs can be used as a potential vector to transfect cells. GENERAL SIGNIFICANCE: BNNTs are potential new nanocarriers for gene delivery applications. PMID- 28571949 TI - Low-energy Shock Wave Therapy-A Novel Treatment Option for Erectile Dysfunction in Men With Cardiovascular Disease. AB - Patients with cardiovascular disease (CVD) are prone to developing erectile dysfunction (ED) owing to the common risk factors and pathogenesis underlying ED and CVD. As a result, ED affects nearly 80% of male patients with CVD. The efficacy of phosphodiesterase type 5 inhibitors, vacuum erection devices, or intracavernosal injection of vasodilating agents is well established in the treatment of ED; however, their use is limited. Low-energy shock wave therapy is a novel modality that may become a causative treatment for ED. This review aims to assess the efficacy and safety of low-energy shock wave therapy in the treatment of ED in men with CVD. PMID- 28571950 TI - Under-reporting of tuberculosis disease. PMID- 28571951 TI - Update in mild traumatic brain injury. AB - There has been concern for many years regarding the identification of patients with mild traumatic brain injury (TBI) at high risk of developing an intracranial lesion (IL) that would require neurosurgical intervention. The small percentage of patients with these characteristics and the exceptional mortality associated with mild TBI with IL have led to the high use of resources such as computerised tomography (CT) being reconsidered. The various protocols developed for the management of mild TBI are based on the identification of risk factors for IL, which ultimately allows more selective indication or discarding both the CT application and the hospital stay for neurological monitoring. Finally, progress in the study of brain injury biomarkers with prognostic utility in different clinical categories of TBI has recently been incorporated by several clinical practice guidelines, which has allowed, together with clinical assessment, a more accurate prognostic approach for these patients to be established. PMID- 28571952 TI - Anemia induced by linezolid. PMID- 28571953 TI - AA amyloidosis associated with recurrent infections in the hyperimmunoglobulin E syndrome. PMID- 28571954 TI - Optimization of genetic diagnosis of oculopharyngeal muscular dystrophy and its application in the analysis of a family pedigree from La Palma Island (Canary Islands, Spain). PMID- 28571956 TI - Clinical characteristics of acute respiratory infections caused by parainfluenzavirus 1-4 in adults. PMID- 28571955 TI - Interaction between levofloxacin and phenytoin: report of two cases. PMID- 28571957 TI - Maternal microbiota and the major obstetric syndromes: When the enemy becomes an ally. PMID- 28571958 TI - A decade of a quick diagnosis unit. PMID- 28571959 TI - Strategic infarcts of the thalamus: an uncommon cause of vascular dementia. PMID- 28571960 TI - Osmotic demyelination syndrome in a patient with uncontrolled hyperglycemia. PMID- 28571961 TI - Kayser-Fleischer rings. PMID- 28571962 TI - Aggression against health workers: Substantial changes in the crime of attack against authorities and public servants after 2015. PMID- 28571963 TI - Number needed to treat for direct oral anticoagulants over warfarin in atrial fibrillation. PMID- 28571964 TI - Pulmonary fibrosis idiopathic: Diagnostic study with 10 clinical actions. PMID- 28571965 TI - Bone health in Down syndrome. AB - Patients with Down syndrome have a number of risk factors that theoretically could predispose them to osteoporosis, such as early aging, development disorders, reduced physical activity, limited sun exposure, frequent comorbidities and use of drug therapies which could affect bone metabolism. In addition, the bone mass of these people may be affected by their anthropometric and body composition peculiarities. In general terms, studies in adults with Down syndrome reported that these people have lower areal bone mineral density (g/cm2) than the general population. However, most of them have not taken the smaller bone size of people with Down syndrome into account. In fact, when body mineral density is adjusted by bone size and we obtain volumetric body mineral density (g/cm3), the difference between both populations disappears. On the other hand, although people with Down syndrome have risk factor of hypovitaminosis D, the results of studies regarding 25(OH)D in this population are not clear. Likewise, the studies about biochemical bone markers or the prevalence of fractures are not conclusive. PMID- 28571966 TI - Carcinomatous myositis secondary to gastric cancer. PMID- 28571967 TI - Diagnostic errors in emergency departments. AB - Diagnostic errors have to be recognised as a possible adverse event inherent to clinical activity and incorporate them as another quality indicator. Different sources of information report their frequency, although they may still be underestimated. Contrary to what one could expect, in most cases, it does not occur in infrequent diseases. Causes can be complex and multifactorial, with individual cognitive aspects, as well as the health system. These errors can have an important clinical and socioeconomic impact. It is necessary to learn from diagnostic errors in order to develop an accurate and reliable system with a high standard of quality. PMID- 28571968 TI - Determination of the protein expression profiles of Propsilocerus akamusi (Tokunaga) Malpighian tubules response to cadmium stress by iTRAQ coupled LC MS/MS. AB - : Propsilocerus akamusi (Tokunaga) is an important prey species for fish and aquatic birds, which represent an important link in the aquatic food chain as other species of Chironomidae. Malpighian tubules (MT) play an important role in metabolism and detoxification of harmful compounds and metal accumulation. Our previous studies have reported that P. akamusi have an extraordinary resistance to Cd. In this paper, iTRAQ-based proteomics technology was first used to study the differential proteomics of MT of Propsilocerus akamusi under sublethal Cd stress for different time courses. 118 differential expressed proteins (DEPs) were identified through LC-MS/MS and further classified into 26 GO functional groups. Our results showed that metabolic process was the main biological functional categories. Cluster of orthologous groups of proteins (COG) analysis was also performed based on the number of unique proteins identified in each functional category, 21 metabolism-related DEPs were identified. P. akamusi adapted to Cd stress mainly by inducing the processes of lipid metabolism of MT and lipid may play a possible protection role in cadmium resistance in MT. The results provide important information for research on molecular mechanisms of Cd stress adaption in Malpighian tubules of P. akamusi. BIOLOGICAL SIGNIFICANCE: Propsilocerus akamusi (old species name: Tokunagayusurika akamusi) is an important prey species for fish and aquatic birds, which represent an important link in the aquatic food web as other species of Chironomidae. Malpighian tubules constitute a versatile organ which is able to exert excretory of chemical compounds, acting in the insect metabolism and detoxification of harmful compounds and metal accumulation. Our previous studies have reported that P. akamusi have an extraordinary resistance to Cd. However, up to now, there has been a lack of research on the molecular mechanisms of adaption to Cd stress in the Malpighian tubules of this species. Study on the adaptive mechanisms to Cd stress in Malpighian tubules of Propsilocerus akamusi through comparative proteome analysis is one important way to solve this problem. The aim of the present study was to understand the molecular mechanisms of adaption of the Malpighian tubules of P. akamusi exposed to Cd stress and assess the high expression of proteins involved in cellular adaptation to Cd stress. This will provide information about how this organ is responding to disturbances of contaminated ecosystems. PMID- 28571969 TI - Proteomic fingerprinting of mistletoe (Viscum album L.) via combinatorial peptide ligand libraries and mass spectrometry analysis. AB - : Combinatorial peptide ligand libraries (CPLLs), coupled to mass spectrometry (MS) analysis, have been used to investigate in depth the proteome of Viscum album L. (VA), commonly named European mistletoe, in order to provide a first proteomic fingerprinting. For this purpose, the proteins were captured via CPLLs at two different pH values (acidic and neutral). A total of 648 non-redundant proteins were identified by using two different databases. The two pH values, chosen for bead incubations, have contributed to increment the capture ability: 56% and 31% of CPLLs species were respectively recognized at pH7.2 and at pH2.2. Finally the biological function of identified proteins was evaluated in order to understand their role on human health and the potential benefits of mistletoe extracts in medicine. SIGNIFICANCE: Viscum album L. (VA) extracts are recently used as supporting medicine for cancer therapy, improving patients' survival and increasing their quality of life in medicine. These anticancer effects are investigated and they are probably due to mistletoe's capability to favor tumor cell's death and to modulate the immune system. Although the increasing interest in VA medical benefits, the role of its components in human health remains unclear. In order to exploit this aspect, it is important to comprehensively study proteins present in Viscum album L. (VA) extracts. Nevertheless, since plant proteomics analysis is in most cases handicapped by the presence of high abundance proteins masking the detection of the low-abundance ones, it is important to overcome this challenge. In this sense, combinatorial peptide ligand libraries (CPLLs) have been used to reduce the dynamic protein concentration range to enable the identification of a higher amount of proteins than employing conventional methods. In this work, a total of 648 non-redundant proteins were identified: 56% and 31% of CPLLs species were respectively recognized at pH7.2 and at pH2.2. This deep proteome identification was useful to investigate the biological functions of proteins in order to evaluate their potential role in human health. PMID- 28571970 TI - Oxidative imbalance in low/intermediate-1-risk myelodysplastic syndrome patients: The influence of iron overload. AB - OBJECTIVE: To assess the generation of reactive oxygen species (ROS) and the involvement of the main antioxidant pathways in low/intermediate-1-risk myelodysplastic syndromes (MDS) with iron overload (IOL). METHODS: We examined the levels of superoxide anion (O2-), hydrogen peroxide (H2O2), antioxidants (glutathione, GSH; superoxide dismutase, SOD; catalase, CAT; and glutathione peroxidase, GPx), mitochondrial membrane potential (DeltaPsim), and by-products of oxidative damage (8-isoprostanes and 8-oxo-7,8-dihydro-2'-deoxyguanosine, 8 oxo-dG) in 42 MDS patients (28 without IOL at diagnosis, and 14 who developed IOL) and 20 healthy subjects. RESULTS: Patients with IOL showed higher O2- levels (39.4 MFI) than normal controls (22.7 MFI, p=0.0356) and patients at diagnosis (19.4 MFI, p=0.0049). Antioxidant systems, except SOD activity, exhibited significant changes in IOL patients with respect to controls (CAT: 7.1 vs 2.7nmol/ml/min, p=0.0023; GPx: 50.9 vs 76.4nmol/ml/min, p=0.0291; GSH: 50.2 vs 24.1 MFI, p=0.0060). Furthermore, mitochondrial dysfunction was only detected in IOL cases compared to controls (DeltaPsim: 3.6 vs 6.4 MFI, p=0.0225). Finally, increased levels of 8-oxo-dG were detected in both groups of patients. CONCLUSION: Oxidative stress is an important but non-static phenomenon in MDS disease, whose status is influenced by, among other factors, the presence of injurious iron. PMID- 28571971 TI - Biological reproducibility of circulating P-Selectin, Thrombopoietin, GPIIb/IIIa and Thrombomodulin over one year. AB - BACKGROUND: Enhanced platelet activation has been implicated in several pathophysiological processes. Here, we evaluated the biological reproducibility of circulating P-Selectin, Thrombomodulin (TM), Thrombopoietin (TPO), and Glycoprotein IIb/IIIa (GPIIb/IIIa) to assess whether these analytes can be used as reliable biomarkers of platelet activation in epidemiological studies. METHODS: We measured circulating P-Selectin, TM, TPO and GPIIb/IIIa by immunoassays in two blood samples of 78 participants of the EPIC Heidelberg study (47-80years, 50% female) that were collected one year apart. Biological reproducibility of biomarker levels over time and associations with routine biochemistry parameters were assessed by Spearman's correlation coefficients. RESULTS: Statistical analyses revealed good reproducibility over one year for two of the analyzed markers, with Spearman coefficients of rho=0.80 (P-Selectin) and rho=0.73 (TPO) and reasonable reproducibility for TM (rho=0.63) and GPIIb/IIIa (rho=0.51). Levels of P-Selectin, TM, TPO and GPIIb/IIIa were not significantly associated with routine biochemistry parameters, such as glucose, HbA1c, LDL, HDL, Triglycerides and CRP. CONCLUSIONS: Our findings suggest that a single assessment of P-Selectin, TM, TPO and GPIIb/IIIa at baseline in prospective epidemiological studies is appropriate to investigate associations between platelet activation and risks of chronic diseases. PMID- 28571972 TI - Discovery of Novel and Potent Stearoyl Coenzyme A Desaturase 1 (SCD1) Inhibitors as Anticancer Agents. AB - A lead compound A was identified previously as an stearoyl coenzyme A desaturase (SCD) inhibitor during research on potential treatments for obesity. This compound showed high SCD1 binding affinity, but a poor pharmacokinetic (PK) profile and limited chemical accessibility, making it suboptimal for use in anticancer research. To identify potent SCD1 inhibitors with more promising PK profiles, we newly designed a series of 'non-spiro' 4, 4-disubstituted piperidine derivatives based on molecular modeling studies. As a result, we discovered compound 1a, which retained moderate SCD1 binding affinity. Optimization around 1a was accelerated by analyzing Hansch-Fujita and Hammett constants to obtain 4 phenyl-4-(trifluoromethyl)piperidine derivative 1n. Fine-tuning of the azole moiety of 1n led to compound 1o (T-3764518), which retained nanomolar affinity and exhibited an excellent PK profile. Reflecting the good potency and PK profile, orally administrated compound 1o showed significant pharmacodynamic (PD) marker reduction (at 0.3mg/kg, bid) in HCT116 mouse xenograft model and tumor growth suppression (at 1mg/kg, bid) in 786-O mouse xenograft model. In conclusion, we identified a new series of SCD1 inhibitors, represented by compound 1o, which represents a promising new chemical tool suitable for the study of SCD1 biology as well as the potential development of novel anticancer therapies. PMID- 28571973 TI - Development of novel N-3-bromoisoxazolin-5-yl substituted 2,3-benzodiazepines as noncompetitive AMPAR antagonists. AB - In this work, we designed and synthesized novel N-3-bromoisoxazolin-5-yl substituted 2,3-benzodiazepines as noncompetitive AMPAR antagonists, with the aim that this heterocycle could establish favourable interactions with a putative binding pocket of the receptor, like the thiadiazole nucleus of GYKI 47409 does. Within this investigation, we identified some active molecules and, among these 2,3-benzodiazepines, 4c showed a much improved inhibitory potency as compared with unsubstituted 2,3-benzodiazepines. PMID- 28571974 TI - Effect of the 3-halo substitution of the 2'-deoxy aminopyridinyl-pseudocytidine derivatives on the selectivity and stability of antiparallel triplex DNA with a CG inversion site. AB - Triplex formation against a target duplex DNA has the potential to become a tool for the genome research. However, there is an intrinsic restriction on the duplex DNA sequences capable of forming the triplex DNA. Recently, we demonstrated the selective formation of the stable antiparallel triplexes containing the CG inversion sites using the 2'-deoxy-1-methylpseudocytidine derivative (PsidC), whose amino group was conjugated with the 2-aminopyridine at its 5-position as an additional hydrogen bonding unit (AP-PsidC). The 1-N of 2-aminopyridine was supposed to be protonated to form the hydrogen bond with the guanine of the CG inversion site. In this study, to test the effect of the 3-substitution of the 2 aminopyridine unit of AP-PsidC on the triplex stability, we synthesized the 3 halogenated 2-aminopyridine derivatives of AP-PsidC. The pKa values 1-N of the 2 aminopyridine unit of AP-PsidC as the monomer nucleoside were determined to be 6.3 for 3-CH3 (MeAP-PsidC), 6.1 for 3-H (AP-PsidC), 4.3 for 3-Cl (ClAP-PsidC), 4.4 for 3-Br (BrAP-PsidC), and 4.7 for 3-I (IAP-PsidC), suggesting that all the halogenated AP-PsidCs are not protonated under neutral conditions. Interestingly, although the recognition selectivity depends on the sequence context, the TFO having the sequence of the 3'-G-(IAP-PsidC)-A-5' context showed the selective triplex formation with the CG inversion site. These results suggest that the protonation at the 1-N position plays an important role in the stable and selective triplex formation of AP-PsidC derivatives in any sequences. PMID- 28571975 TI - Synthesis, spectroscopic characterization and biological evaluation of unsymmetrical aminosquarylium cyanine dyes. AB - New unsymmetrical aminosquarylium cyanine dyes were synthesized and their potential as photosensitizers evaluated. New dyes, derived from benzothiazole and quinoline, were prepared by nucleophilic substitution of the corresponding O methylated, the key intermediate that was obtained by methylation with CF3SO3CH3 of the related zwitterionic unsymmetrical dye, with ammonia and methylamine, respectively. All three news dyes herein described displayed intense and narrow bands in the Vis/NIR region (693-714nm) and their singlet oxygen formation quantum yields ranged from 0.03 to 0.05. In vitro toxicity, in Caco-2 and HepG2 cells, indicated that dark toxicity was absent for concentrations up to 5uM (for the less active dye) or up to 1uM (for the two more active dyes). The three dyes present potential as photosensitizers, differing in irradiation conditions and period of incubation in the presence of irradiated dye. The less active dye needs a longer irradiation period to exhibit phototoxicity which is only evident after longer period of contact with cells (24h). However, the remaining two more active dyes produce higher phototoxicity, even at shorter incubation periods (1h), with shorter irradiation time (7min). Although in different extents, these dyes show promising in vitro results as photosensitizers. PMID- 28571977 TI - The systematic review of TCE cardiac defects (Makris et al., 2016). PMID- 28571976 TI - Reliability of the diaphragmatic compound muscle action potential evoked by cervical magnetic stimulation and recorded via chest wall surface EMG. AB - INTRODUCTION: Stimulation of the phrenic nerve via cervical magnetic stimulation (CMS) elicits a compound muscle action potential (CMAP) that allows for assessment of diaphragm activation. The reliability of CMS to evoke the CMAP recorded by chest wall surface EMG has yet to be comprehensively examined. METHODS: CMS was performed on healthy young males (n=10) and females (n=10). Surface EMG electrodes were placed on the right and left hemi-diaphragm between the 6-8th intercostal spaces. CMAPs were analysed for: latency, duration, peak-to peak amplitude, and area. Reliability within and between experimental sessions was assessed using intraclass correlation coefficients (ICC). Bilateral (right left) and sex-based (male-female) comparisons were also made (independent samples t-test). RESULTS: All CMAP characteristics demonstrated high reproducibility within (ICCs>0.96) and between (ICCs>0.89) experimental sessions. No statistically significant bilateral or sex-based differences were found (p>0.05). DISCUSSION: CMS is a reliable and non-invasive method to evaluate phrenic nerve conduction. PMID- 28571978 TI - Functional effects of diphosphomimetic mutations at cAbl-mediated phosphorylation sites on Rad51 recombinase activity. AB - Homologous Recombination enables faithful repair of the deleterious double strand breaks of DNA. This pathway relies on Rad51 to catalyze homologous DNA strand exchange. Rad51 is known to be phosphorylated in a sequential manner on Y315 and then on Y54, but the effect of such phosphorylation on Rad51 function remains poorly understood. We have developed a phosphomimetic model in order to study all the phosphorylation states. With the purified phosphomimetic proteins we performed in vitro assays to determine the activity of Rad51. Here we demonstrate the inhibitory effect of the double phosphomimetic mutant and suggest that it may be due to a defect in nucleofilament formation. PMID- 28571979 TI - Impact of high-fat diet on the intestinal microbiota and small intestinal physiology before and after the onset of obesity. AB - The modulation of the intestinal microbiota by high-fat diet (HFD) has a major impact on both immunological and metabolic functions of the host. Taking this into consideration, the aim of this contribution is to review the impact of HFD on microbiota profile and small intestinal physiology before and after the onset of obesity and its metabolic complications. Evidence from animal studies suggest that before the onset of obesity and its metabolic complications, HFD induces intestinal dysbiosis - encompassing changes in composition balance and massive redistribution with bacteria occupying intervillous spaces and crypts - associated with early physiopathological changes, predominantly in the ileum, such as low-grade inflammation, decreased antimicrobial peptides expression, impaired mucus production, secretion and layer's thickness, and decreased expression of tight junction proteins. With time, major inflammatory signals (e.g. toll-like receptor-4 dependent) become activated, thereby stimulating proinflammatory cytokines secretion in the small intestine. This inflammatory state might subsequently exacerbate disruption of the mucus layer barrier and increase epithelial permeability of the small intestine, thereby creating an environment that facilitates the passage of bacterial components (e.g. lipopolysaccharide, peptidoglycan and flagellin) and metabolites from the intestinal lumen (e.g. secondary bile acids) to the circulation and peripheral tissues (i.e. leaky gut), eventually promoting the development of systemic inflammation, obesity, adiposity, insulin resistance and glucose intolerance preceding hyperglycemia. Although the mechanisms are still not completely understood, prebiotics, probiotics, polyphenols, peroxisome proliferator activated receptor-gamma agonists (such as rosiglitazone) and exercise have been shown to reverse HFD-induced intestinal phenotype and to attenuate the severity of obesity and its associated metabolic complications. PMID- 28571980 TI - Effectiveness of cleaning-disinfection wipes and sprays against multidrug resistant outbreak strains. AB - BACKGROUND: Hospital rooms play an important role in the transmission of several health care-associated pathogens. During the last few years, a number of innovative cleaning-disinfecting products have been brought to market. In this study, commercially available products combining cleaning and disinfection were compared, using 2 different application methods. The aim was to determine which product was most effective in simultaneous cleaning and disinfection of surfaces. METHODS: Seven cleaning-disinfecting wipes and sprays based on different active ingredients were tested for their efficacy in removal of microbial burden and proteins. Efficacy was tested with known Dutch outbreak strains: vancomycin resistant enterococci (VRE), Klebsiella pneumoniae OXA-48, or Acinetobacter baumannii. RESULTS: For all bacteria, ready-to-use cleaning-disinfecting products reduced the microbial count with a log10 reduction >5 with a 5-minute exposure time, with the exception of a spray based on hydrogen peroxide. Omitting the aforementioned hydrogen peroxide spray, there were no significant differences between use of a wipe or spray in bacterial load reduction. Using adenosine triphosphate (ATP) measurements, a significant difference in log10 relative light units (RLU) reduction between various bacteria (P <= .001) was observed. CONCLUSIONS: In general, a >5 log10 reduction of colony forming units (CFU) for tested wipes and sprays was obtained for all tested bacteria strains, with exception of hydrogen peroxide spray and VRE. Although ATP may show a difference between pre- and postcleaning, RLU reduction does not correlate with actual CFU reductions. PMID- 28571981 TI - Outbreak of CTX-M-15-producing Enterobacter cloacae associated with therapeutic beds and syphons in an intensive care unit. AB - An outbreak of extended-spectrum beta-lactamase-producing Enterobacter cloacae (ESBL-ECL) occurred in our intensive care unit (ICU) and involved 18 patients (8 infected and 10 colonized). The mean age of patients was 69 years, and all infected patients had underlying medical conditions. Within hours' recognition of the spread of ESBL-ECL, the infection control team requested for staff education, reinforcement of infection control measures, and environmental screening. New transmissions were observed in the institution after weeks of enhanced infection control measures. Microbial swabbing revealed bacterial contamination of some mattresses and syphons with epidemiologic links between environmental, screening, and clinical isolates. This outbreak resulted in the temporary closure of the ICU for complete biocleaning. PMID- 28571982 TI - Carbapenem-resistant Enterobacteriaceae at a low prevalence tertiary care center: Patient-level risk factors and implications for an infection prevention strategy. AB - Limited treatment options and a growing global threat from carbapenem-resistant Enterobacteriaceae (CRE) infections illustrate the importance of understanding the epidemiology of CRE. Using a retrospective chart review and point prevalence testing demonstrated specific patient risk factors for CRE-positive clinical cultures in a tertiary medical center with a low CRE prevalence. PMID- 28571983 TI - Trained-user opinion about Welfare Quality measures and integrated scoring of dairy cattle welfare. AB - The Welfare Quality (WQ) protocol for on-farm dairy cattle welfare assessment describes 27 measures and a stepwise method for integrating values for these measures into 11 criteria scores, grouped further into 4 principle scores and finally into an overall welfare categorization with 4 levels. We conducted an online survey to examine whether trained users' opinions of the WQ protocol for dairy cattle correspond with the integrated scores (criteria, principles, and overall categorization) calculated according to the WQ protocol. First, the trained users' scores (n = 8-15) for reliability and validity and their ranking of the importance of all measures for herd welfare were compared with the degree of actual effect of these measures on the WQ integrated scores. Logistic regression was applied to identify the measures that affected the WQ overall welfare categorization into the "not classified" or "enhanced" categories for a database of 491 European herds. The smallest multivariate model maintaining the highest percentage of both sensitivity and specificity for the "enhanced" category contained 6 measures, whereas the model for "not classified" contained 4 measures. Some of the measures that were ranked as least important by trained users (e.g., measures relating to drinkers) had the highest influence on the WQ overall welfare categorization. Conversely, measures rated as most important by the trained users (e.g., lameness and mortality) had a lower effect on the WQ overall category. In addition, trained users were asked to allocate criterion and overall welfare scores to 7 focal herds selected from the database (n = 491 herds). Data on all WQ measures for these focal herds relative to all other herds in the database were provided. The degree to which expert scores corresponded to each other, the systematic difference, and the correspondence between median trained-user opinion and the WQ criterion scores were then tested. The level of correspondence between expert scoring and WQ scoring for 6 of the 12 criteria and for the overall welfare score was low. The WQ scores of the protocol for dairy cattle thus lacked correspondence with trained users on the importance of several welfare measures. PMID- 28571984 TI - Processing characteristics of dairy cow milk are moderately heritable. AB - Milk processing attributes represent a group of milk quality traits that are important to the dairy industry to inform product portfolio. However, because of the resources required to routinely measure such quality traits, precise genetic parameter estimates from a large population of animals are lacking for these traits. Milk processing characteristics considered in the present study-rennet coagulation time, curd-firming time, curd firmness at 30 and 60 min after rennet addition, heat coagulation time, casein micelle size, and milk pH-were all estimated using mid-infrared spectroscopy prediction equations. Variance components for these traits were estimated using 136,807 test-day records from 5 to 305 d in milk (DIM) from 9,824 cows using random regressions to model the additive genetic and within-lactation permanent environmental variances. Heritability estimates ranged from 0.18 +/- 0.01 (26 DIM) to 0.38 +/- 0.02 (180 DIM) for rennet coagulation time; from 0.26 +/- 0.02 (5 DIM) to 0.57 +/- 0.02 (174 DIM) for curd-firming time; from 0.16 +/- 0.01 (30 DIM) to 0.56 +/- 0.02 (271 DIM) for curd firmness at 30 min; from 0.13 +/- 0.01 (30 DIM) to 0.48 +/- 0.02 (271 DIM) for curd firmness at 60 min; from 0.08 +/- 0.01 (17 DIM) to 0.24 +/- 0.01 (180 DIM) for heat coagulation time; from 0.23 +/- 0.02 (30 DIM) to 0.43 +/- 0.02 (261 DIM) for casein micelle size; and from 0.20 +/- 0.01 (30 DIM) to 0.36 +/- 0.02 (151 DIM) for milk pH. Within-trait genetic correlations across DIM weakened as the number of days between compared intervals increased but were mostly >0.4 except between the peripheries of the lactation. Eigenvalues and associated eigenfunctions of the additive genetic covariance matrix for all traits revealed that at least the 80% of the genetic variation among animals in lactation profiles was associated with the height of the lactation profile. Curd firming time and curd firmness at 30 min were weakly to moderately genetically correlated with milk yield (from 0.33 +/- 0.05 to 0.59 +/- 0.05 for curd-firming time, and from -0.62 +/- 0.03 to -0.21 +/- 0.06 for curd firmness at 30 min). Milk protein concentration was strongly genetically correlated with curd firmness at 30 min (0.84 +/- 0.02 to 0.94 +/- 0.01) but only weakly genetically correlated with milk heat coagulation time (-0.27 +/- 0.07 to 0.19 +/- 0.06). Results from the present study indicate the existence of exploitable genetic variation for milk processing characteristics. Because of possible indirect deterioration in milk processing characteristics due to selection for greater milk yield, emphasis on milk processing characteristics is advised. PMID- 28571985 TI - Host-pathogen interactions in bovine mammary epithelial cells and HeLa cells by Staphylococcus aureus isolated from subclinical bovine mastitis. AB - Staphylococcus aureus is a common pathogen that causes subclinical bovine mastitis due to several virulence factors. In this study, we analyzed S. aureus isolates collected from the milk of cows with subclinical mastitis that had 8 possible combinations of bap, icaA, and icaD genes, to determine their capacity to produce biofilm on biotic (bovine primary mammary epithelial cells and HeLa cells) and abiotic (polystyrene microplates) surfaces, and their ability to adhere to and invade these cells. We also characterized isolates for microbial surface components recognizing adhesive matrix molecules (MSCRAMM) and agr genes, and for their susceptibility to cefquinome sulfate in the presence of biofilm. All isolates adhered to and invaded both cell types, but invasion indexes were higher in bovine primary mammary epithelial cells. Using tryptic soy broth + 1% glucose on abiotic surfaces, 5 out of 8 isolates were biofilm producers, but only the bap+icaA+icaD+ isolate was positive in Dulbecco's Modified Eagle's medium. The production of biofilm on biotic surfaces occurred only with this isolate and only on HeLa cells, because the invasion index for bovine primary mammary epithelial cells was too high, making it impossible to use these cells in this assay. Of the 5 biofilm producers in tryptic soy broth + 1% glucose, 4 presented with the bap/fnbA/clfA/clfB/eno/fib/ebpS combination, and all were protected from cefquinome sulfate. We found no predominance of any agr group. The high invasive potential of S. aureus made it impossible to observe biofilm in bovine primary mammary epithelial cells, and we concluded that cells with lower invasion rates, such as HeLa cells, were more appropriate for this assay. PMID- 28571986 TI - Characterization of the variability and repeatability of gonadotropin-releasing hormone-induced luteinizing hormone responses in dairy cows within a synchronized ovulation protocol. AB - The primary objective was to determine the variability and repeatability of GnRH induced LH responses. The secondary objective was to evaluate the associations among plasma LH, FSH, estradiol (E2), and progesterone (P4) concentrations. One hundred lactating Holstein cows (35 primiparous, 65 multiparous) were initially subjected to a presynchronization protocol (d 0, PGF2alpha; d 3, GnRH) followed 7 d later by Ovsynch (d 10, GnRH; d 17, PGF2alpha; 56 h later, GnRH) and timed artificial insemination 16 h after the last GnRH. Blood samples were collected immediately before the GnRH injection of presynchronization and the second GnRH of Ovsynch to determine plasma concentrations of LH, FSH, and P4. A second blood sample was collected 2 h after each of the above GnRH injections to determine GnRH-induced LH and FSH concentrations. Plasma concentrations of E2 were also determined in samples collected immediately before the second GnRH of Ovsynch. Cows that (1) had higher LH concentrations at 0 h than at 2 h after GnRH, (2) showed an ongoing spontaneous LH surge, (3) did not respond to GnRH, and (4) had P4 >= 0.5 ng/mL at GnRH of presynchronization and the second GnRH of Ovsynch were excluded from the analysis. The variability (coefficient of variation) and repeatability [between animal variance/(within animal variance + between animal variance)] of GnRH-induced LH response were determined from samples collected 2 h after the GnRH of presynchronization and the second GnRH of Ovsynch. The associations among plasma LH, FSH, E2, and P4 were determined at the second GnRH of Ovsynch. Mean (+/-SEM) LH concentrations before GnRH were 0.5 +/- 0.04 and 0.6 +/- 0.03 ng/mL, whereas mean LH concentrations 2 h after GnRH were 9.8 +/- 1.0 and 12.1 +/- 0.8 ng/mL at GnRH of presynchronization and the second GnRH of Ovsynch, respectively. The variability of GnRH-induced LH was 76.1 and 52.1% at GnRH of presynchronization and the second GnRH of Ovsynch, respectively. The repeatability estimate for GnRH-induced LH concentration between GnRH of presynchronization and Ovsynch assessments was 0.10. Plasma concentrations of LH were positively associated with FSH and E2 (r = 0.61 and 0.30, respectively) and negatively associated with P4 (r = -0.46) at the second GnRH of Ovsynch. In summary, GnRH-induced LH responses were highly variable and unrepeatable, and LH concentrations were positively associated with FSH and E2 and negatively associated with P4. PMID- 28571987 TI - A survey of dairy calf management practices among farms using manual and automated milk feeding systems in Canada. AB - Dairy calves in North America traditionally are housed individually and fed by manual milk feeding (MMF) systems with buckets or bottles. Automated milk feeders (AMF) allow for more natural milk feeding frequencies and volumes, and calves are usually housed in groups. The objectives of this study were to (1) determine the prevalence of various milk-fed calf management and feeding practices and (2) compare these practices between dairy farms using MMF and AMF systems. A national online survey was performed from January to May 2015 to quantify management practices for the care of milk-fed dairy calves in Canada. A total of 670 responses were received (6% of all dairy farms in Canada). Among respondents, 16% used AMF and 84% used MMF. Seventy percent of the farms using AMF had freestall barns compared with only 48% of those using MMF. A greater proportion of AMF farms (30%) also had automatic milking systems (AMS) compared with MMF farms (8%). Among tiestall farms, a herd size of >80 milking cows was associated with having an AMF [odds ratio (OR) = 3.8; 95% confidence interval (CI): 1.6-11.4]. For freestall or bedded-pack farms, a herd size of >80 milking cows (OR = 3.5; CI: 1.8-6.6), having an AMS (OR = 3.1; CI: 1.6-5.7), and use of cow brushes (OR = 3.1; CI: 1.3-6.9) were associated with having an AMF. Calves fed with AMS typically were housed in groups of 10 to 15, whereas almost 76% of the farms with MMF housed calves individually. Although both AMF and MMF farms fed similar amounts of milk in the first week of life (median = 6 L/d), the cumulative volume fed in the first 4 wk differed significantly, with a median of 231 versus 182 L for AMF and MMF, respectively. Median peak milk allowance was higher for AMF than for MMF (10 vs. 8 L/d, respectively). In summary, farms using AMF were larger, provided more milk to calves, and used more automation in general (i.e., in other areas of their operation). These data provide insights into calf-rearing practices across Canada and into how the use of AMF is affecting calf feeding and management on dairy farms. PMID- 28571989 TI - An attempt at predicting blood beta-hydroxybutyrate from Fourier-transform mid infrared spectra of milk using multivariate mixed models in Polish dairy cattle. AB - Fourier transform mid-infrared (FT-MIR) spectra of milk are commonly used for phenotyping of traits of interest through links developed between the traits and milk FT-MIR spectra. Predicted traits are then used in genetic analysis for ultimate phenotypic prediction using a single-trait mixed model that account for cows' circumstances at a given test day. Here, this approach is referred to as indirect prediction (IP). Alternatively, FT-MIR spectral variable can be kept multivariate in the form of factor scores in REML and BLUP analyses. These BLUP predictions, including phenotype (predicted factor scores), were converted to single-trait through calibration outputs; this method is referred to as direct prediction (DP). The main aim of this study was to verify whether mixed modeling of milk spectra in the form of factors scores (DP) gives better prediction of blood beta-hydroxybutyrate (BHB) than the univariate approach (IP). Models to predict blood BHB from milk spectra were also developed. Two data sets that contained milk FT-MIR spectra and other information on Polish dairy cattle were used in this study. Data set 1 (n = 826) also contained BHB measured in blood samples, whereas data set 2 (n = 158,028) did not contain measured blood values. Part of data set 1 was used to calibrate a prediction model (n = 496) and the remaining part of data set 1 (n = 330) was used to validate the calibration models, as well as to evaluate the DP and IP approaches. Dimensions of FT-MIR spectra in data set 2 were reduced either into 5 or 10 factor scores (DP) or into a single trait (IP) with calibration outputs. The REML estimates for these factor scores were found using WOMBAT. The BLUP values and predicted BHB for observations in the validation set were computed using the REML estimates. Blood BHB predicted from milk FT-MIR spectra by both approaches were regressed on reference blood BHB that had not been used in the model development. Coefficients of determination in cross-validation for untransformed blood BHB were from 0.21 to 0.32, whereas that for the log-transformed BHB were from 0.31 to 0.38. The corresponding estimates in validation were from 0.29 to 0.37 and 0.21 to 0.43, respectively, for untransformed and logarithmic BHB. Contrary to expectation, slightly better predictions of BHB were found when univariate variance structure was used (IP) than when multivariate covariance structures were used (DP). Conclusive remarks on the importance of keeping spectral data in multivariate form for prediction of phenotypes may be found in data sets where the trait of interest has strong relationships with spectral variables. PMID- 28571988 TI - Seasonal and regional occurrence of heat-resistant spore-forming bacteria in the course of ultra-high temperature milk production in Tunisia. AB - Spore-forming bacteria, principally Bacillus species, are important contaminants of milk. Because of their high heat resistance, Bacillus species spores are capable of surviving the heat treatment process of milk and lead to spoilage of the final product. To determine the factors influencing the contamination of milk, spore-forming bacteria occurrence throughout the UHT milk production line during winter, spring, and summer was studied. The obtained results confirm that the total viable rate decreases rapidly throughout the production line of UHT milk showing the efficiency of thermal treatments used. However, the persistent high rate of spore-forming bacteria indicates their high heat resistance, especially in spring and summer. In addition, a significant variation of the quality of raw milk according to the location of the collecting centers was revealed. The molecular identification showed a high degree of diversity of heat resistant Bacillus species, which are isolated from different milk samples. The distribution of Bacillus species in raw milk, stored milk, bactofuged milk, pasteurized milk, and UHT milk were 28, 10, 16, 13, and 33%, respectively. Six Bacillus spp. including Bacillus licheniformis (52.38%), Bacillus pumilus (9.52%), Bacillus sp. (4.76%), Bacillus sporothermodurans (4.76%), Terribacillus aidingensis (4.76%), and Paenibacillus sp. (4.76%) were identified in different milk samples. PMID- 28571990 TI - Optimal ratios of essential amino acids stimulate beta-casein synthesis via activation of the mammalian target of rapamycin signaling pathway in MAC-T cells and bovine mammary tissue explants. AB - Amino acids are the building blocks of proteins and serve as key molecular components upstream of the signaling pathways that regulate protein synthesis. The objective of this study was to systematically investigate the effect of essential AA ratios on milk protein synthesis in vitro and to elucidate some of the underlying mechanisms. Triplicate cultures of MAC-T cells and bovine mammary tissue explants (MTE) were incubated with the optimal AA ratio (OPAA; Lys:Met, 2.9:1; Thr:Phe, 1.05:1; Lys:Thr, 1.8:1; Lys:His, 2.38:1; and Lys:Val, 1.23:1) in the presence of rapamycin (control), OPAA, a Lys:Thr ratio of 2.1:1, a Lys:Thr ratio of 1.3:1, a Lys:His ratio of 3.05:1, or a Lys:Val ratio of 1.62:1 for 12 h; the other AA concentrations were equal to OPAA. In some experiments, the cells were cultured with OPAA with or without rapamycin (100 ng/mL) or with mammalian target of rapamycin (mTOR) small interference RNA, and the MTE were exposed to OPAA with rapamycin for beta-casein expression. Among the treatments, the expression of beta-casein was greatest in the MTE cultured with OPAA. In MAC-T cells, the OPAA upregulated the mRNA expression of SLC1A5 and SLC7A5 but downregulated the expression of IRS1, AKT3, EEF1A1, and EEF2 compared with the control. The OPAA had no effect on the mTOR phosphorylation status but increased the phosphorylation of S6K1 and RPS6. When the MTE were treated with rapamycin in the presence of OPAA, the expression of beta-casein was markedly decreased. The phosphorylation of RPS6 and 4EBP1 also was reduced in MAC-T cells. A similar negative effect on the expression of RPS6KB1 and EIF4EBP1 was detected when the cells were cultured with either rapamycin or mTOR small interference RNA. The optimal AA ratio stimulated beta-casein expression partly by enhancing the transport of AA into the cells, cross-talk with insulin signaling and a subsequent enhancement of mTOR signaling, or translation elongation in both MAC-T cells and bovine MTE. PMID- 28571991 TI - Short communication: Use of fecal starch concentration as an indicator of dry feed digestion in preweaned dairy calves. AB - Fecal starch (FS) has been used as a tool to evaluate starch and diet digestibility in lactating dairy cows and feedlot steers. Some on-farm advisors also use FS to evaluate calf starter digestibility in preweaned dairy calves. Our objective was to evaluate the influence of starter intake (SI), starch and organic matter digestibility, milk replacer (MR) feeding rate, and age on FS concentrations in preweaned dairy calves. Male Holstein calves (43 +/- 2.9 kg of body weight; n = 35) from a single farm were fed different amounts of MR ranging from 0.44 to 1.10 kg of dry matter (DM) daily (27% crude protein, 17% fat) and weaned by 7 wk of age. Starter ingredient composition was 37% whole corn, 20% whole oats, 35% protein pellet, and 3% molasses and contained 43 +/- 1.9% starch. Fecal grab samples were taken at 3 (n = 20), 6 (n = 20), and 8 wk (n = 35) of age. Twelve fecal samples per calf were taken via rectal palpation over a 5-d period each week, frozen daily, combined on an equal wet-weight basis, and subsampled for analysis. Chromic oxide was used as an external digestibility marker at 3 and 6 wk (included in MR), whereas acid-insoluble ash was used as an internal marker at 8 wk. Milk replacer and starter intakes (offered and refused) were recorded daily during collection periods. Multiple and linear regression of organic matter digestibility (% of DM), total-tract starch digestibility (TTSD; % of DM), MR intake (kg/d), SI (kg/d), and age (week) versus FS (% of fecal DM) were determined using PROC REG of SAS (version 9.2, SAS Institute Inc., Cary, NC). Prior to weaning, SI, age, and MR rate explained 89% of the variation in TTSD, where TTSD = [19.7 * SI (+/-4.25)] + [3.8 * age (+/-0.79)] - [24.8 * MR (+/ 3.19)] + 56.2 (+/-3.39). At 3 wk of age, TTSD increased (coefficient of determination = 0.53) and SI decreased (coefficient of determination = 0.20) with increasing FS. At 6 wk of age, TTSD and SI were unrelated to FS. In 8-wk-old calves (with 2 trials), SI, MR rate, FS, and trial explained 92% of the variation in TTSD, where TTSD = -[2.6 * SI (+/-0.67)] - [2.4 * MR (+/-0.56)] - [0.6 * FS (+/-0.04)] + [1.1 * trial (+/-0.33)] + 100.4 (+/-1.02). Postweaning, TTSD decreased linearly as FS increased (coefficient of determination = 0.86), whereas FS and SI were unrelated, a relationship in contrast to the previously observed result in calves still consuming milk replacer. In the current study, FS was not a good estimate of TTSD or dry feed intake in the preweaned calf, but has potential for evaluating TTSD in calves after weaning. PMID- 28571992 TI - Rapid consumer-based sensory characterization of requeijao cremoso, a spreadable processed cheese: Performance of new statistical approaches to evaluate check-all that-apply data. AB - We investigated the performance of multidimensional alignment analysis and multidimensional scaling on phi coefficient values to evaluate check-all-that apply questionnaire data. We evaluated 6 dairy foods belonging to the category of requeijao cremoso processed cheese (traditional, with starch, or with starch and vegetable fat). We obtained sensory descriptors using trained assessors in descriptive analysis for comparison. A check-all-that-apply questionnaire used with 121 consumers (77 women and 44 men; 18 to 57 yr old) proved to be a suitable alternative for sensory profiling, providing descriptions similar to descriptive analysis and discriminating between products. Multidimensional alignment analysis and multidimensional scaling were efficient and logical approaches for obtaining a deeper understanding of the data, allowing us to clarify the relationships between sensory descriptors and products and contribute to optimizing the different formulations of requeijao cremoso. PMID- 28571993 TI - Genetic parameters of blood beta-hydroxybutyrate predicted from milk infrared spectra and clinical ketosis, and their associations with milk production traits in Norwegian Red cows. AB - The aim of this study was to estimate genetic parameters for blood beta hydroxybutyrate (BHB) predicted from milk spectra and for clinical ketosis (KET), and to examine genetic association of blood BHB with KET and milk production traits (milk, fat, protein, and lactose yields, and milk fat, protein, and lactose contents). Data on milk traits, KET, and milk spectra were obtained from the Norwegian Dairy Herd Recording System with legal permission from TINE SA (As, Norway), the Norwegian Dairy Association that manages the central database. Data recorded up to 120 d after calving were considered. Blood BHB was predicted from milk spectra using a calibration model developed based on milk spectra and blood BHB measured in Polish dairy cows. The predicted blood BHB was grouped based on days in milk into 4 groups and each group was considered as a trait. The milk components for test-day milk samples were obtained by Fourier transform mid infrared spectrometer with previously developed calibration equations from Foss (Hillerod, Denmark). Veterinarian-recorded KET data within 15 d before calving to 120 d after calving were used. Data were analyzed using univariate or bivariate linear animal models. Heritability estimates for predicted blood BHB at different stages of lactation were moderate, ranging from 0.250 to 0.365. Heritability estimate for KET from univariate analysis was 0.078, and the corresponding average estimate from bivariate analysis with BHB or milk production traits was 0.002. Genetic correlations between BHB traits were higher for adjacent lactation intervals and decreased as intervals were further apart. Predicted blood BHB at first test day was moderately genetically correlated with KET (0.469) and milk traits (ranged from -0.367 with protein content to 0.277 with milk yield), except for milk fat content from across lactation stages that had near zero genetic correlation with BHB (0.033). These genetic correlations indicate that a lower BHB is genetically associated with higher milk protein and lactose contents, but with lower yields of milk, fat, protein, and lactose, and with lower frequency of KET. Estimates of genetic correlation of KET with milk production traits were from -0.333 (with protein content) to 0.178 (with milk yield). Blood BHB can routinely be predicted from milk spectra analyzed from test-day milk samples, and thereby provides a practical alternative for selecting cows with lower susceptibility to ketosis, even though the correlations are moderate. PMID- 28571995 TI - Is peritoneal dialysis feasible after laparotomy in children? A case-control series to compare outcomes. AB - OBJECTIVES: Peritoneal dialysis (PD) is the modality of choice for children with end-stage renal disease (ESRD) awaiting renal transplant; however, this option is sometimes avoided for those with previous laparotomy. The goal of this study was to compare the outcomes of PD in patients with and without previous laparotomy. PATIENTS AND METHODS: Twenty-four patients who had been started on peritoneal dialysis were retrospectively analysed. Group LAP consisted of six patients with previous laparotomy, and Group NO-LAP of 18 controls with either retroperitoneal or no abdominal surgery. The percentage of theoretical maximum volume of infusion, time to reach it, complications (infection and drainage difficulties), and number of catheters needed to finish therapy were analysed. RESULTS: The characteristics of patients and technique of insertion are presented in Table. The percentage of maximum theoretical volume of infusion was similar in both groups. Median of catheter survival was similar in both groups. Complications were divided into malfunction (slow drainage, obstruction or leak) and infection. Incidence of complications per catheter and per month of dialysis was ten times lower in Group NO-LAP. Peritoneal dialysis failed in one patient with recurrent intraperitoneal adhesions after adhesiolysis in Group LAP. CONCLUSION: Despite a higher incidence of complications (malfunction and infections), PD remains an acceptable option after laparotomy. In this series, it was sufficient in achieving adequate filtration in five patients. PMID- 28571994 TI - Acquisition of a second multi-drug resistance-encoding element by IncM1 plasmid pACM130 abolished conjugative transfer. AB - Within the IncM plasmid family there is a lineage that has a transposon Tn1721 based multiple-resistance island inserted in the backbone gene mucB. So far, this group includes R1215, p202c, pIGT15, pARM26, and pACM1, from Europe and the USA. A new member of this group, pACM130, was isolated at the same American hospital as pACM1 and has a similar resistance island, but also carries a copy of Tn1331 that interrupts the traY gene in the conjugation operon. The conjugative phenotype of this plasmid has been abolished, though pACM130 could be mobilized by an intact traY cloned into a laboratory vector and transformed into the same donor bacterium. PMID- 28571996 TI - The effect of the use of a TNF-alpha inhibitor in hypothermic machine perfusion on kidney function after transplantation. AB - One of the most important problems in transplantation medicine is the ischemia/reperfusion injury of the organs to be transplanted. The aim of the present study was to assess the effect of tumor necrosis factor-alpha (TNF-alpha) inhibitor etanercept on the machine perfusion hypothermia of renal allograft kidney function and organ perfusion. No statistically significant differences were found in the impact of the applied intervention on kidney machine perfusion during which the average flow and vascular resistance were evaluated. There were no statistically significant differences in the occurrence of delayed graft function (DGF). Fewer events in patients who received a kidney from the etanercept treated Group A compared to the patients who received a kidney from the control Group B were observed when comparing the functional DGF and occurrence of acute rejection episodes, however, there was no statistically significant difference. In summary, no effect of treatment with etanercept an inhibitor of TNF-alpha in a hypothermic machine perfusion on renal allograft renal survival and its perfusion were detected in this study. However, treatment of the isolated organ may be important for the future of transplantation medicine. PMID- 28571997 TI - Rationale and design of the ENhancing outcomes through Goal Assessment and Generating Engagement in Diabetes Mellitus (ENGAGE-DM) pragmatic trial. AB - BACKGROUND: Poor glycemic control among patients with diabetes may stem from poor medication and lifestyle adherence or a failure to appropriately intensify therapy. A patient-centered approach could discern the most likely possibility and would then, as appropriate, address patient barriers to non-adherence (using behavioral interviewing methods such as motivational interviewing) or help facilitate choices among treatment augmentation options (using methods such as shared decision-making). OBJECTIVE: To test the impact of a novel telephone-based patient-centered intervention on glycemic control for patients with poorly controlled diabetes. METHODS/DESIGN: ENGAGE-DM (ENhancing outcomes through Goal Assessment and Generating Engagement in Diabetes Mellitus) is a pragmatic trial of patients with poorly-controlled diabetes receiving treatment with an oral hypoglycemic agent. We randomized 1400 patients in a large health insurer to intervention or usual care. The intervention is delivered over the telephone by a pharmacist and consists of a 2-step process that integrates brief negotiated interviewing and shared decision-making to identify patient-concordant goals and options for enhancing patients' diabetes management. The trial's primary outcome is disease control, assessed using glycosylated hemoglobin values. Secondary outcomes include medication adherence measures, assessed using pharmacy claims data. CONCLUSIONS: This trial will determine whether a novel highly-scalable patient engagement strategy improves disease control and adherence to medications among individuals with poorly-controlled diabetes. PMID- 28571998 TI - [Henri Hartmann (1860-1952): Great master of 20th century colorectal surgery]. PMID- 28571999 TI - Sex steroids and neurogenesis. AB - The brain has long been known as a dimorphic organ and as a target of sex steroids. It is also a site for their synthesis. Sex steroids in numerous ways can modify cerebral physiology, and along with many processes adult neurogenesis is also modulated by sex steroids. This review will focus on the effects of the main steroids, estrogens, androgens and progestogens, and unveil some aspects of their partly disclosed mechanisms of actions. Gonadal steroids act on different steps of neurogenesis: cell proliferation seems to be increased by estrogens only, while androgens and progestogens favor neuronal renewal by increasing cell survival; differentiation is a common target. Aging is characterized by a cognitive deficiency, paralleled by a decrease in the rate of neuronal renewal and in the levels of circulating gonadal hormones. Therefore, the effects of gonadal hormones on the aging brain are important to consider. The review will also be expanded to related molecules which are agonists to the nuclear receptors. Sex steroids can modify adult neuronal renewal and the extensive knowledge of their actions on neurogenesis is essential, as it can be a leading pathway to therapeutic perspectives. PMID- 28572000 TI - C-type lectin interacting with beta-integrin enhances hemocytic encapsulation in the cotton bollworm, Helicoverpa armigera. AB - The encapsulation reaction in invertebrates is analogous to granuloma formation in vertebrates, and this reaction is severely compromised when ecdysone signaling is blocked. However, the molecular mechanism underlying the encapsulation reaction and its regulation by ecdysone remains obscure. In our previous study, we found that the C-type lectin HaCTL3, from the cotton bollworm Helicoverpa armigera, is involved in anti-bacterial immune response, acting as a pattern recognition receptor (PRR). In the current study, we demonstrate that HaCTL3 is involved in defense against parasites and directly binds to the surface of nematodes. Our in vitro and in vivo studies indicate that HaCTL3 enhances hemocytic encapsulation and melanization, whereas H. armigera beta-integrin (Habeta-integrin), located on the surface of hemocytes, participates in encapsulation. Additionally, co-immunoprecipitation experiments reveal HaCTL3 interacts with Habeta-integrin, and knockdown of Habeta-integrin leads to reduced encapsulation of HaCTL3-coated beads. These results indicate that Habeta-integrin serves as a hemocytic receptor of HaCTL3 during the encapsulation reaction. Furthermore, we demonstrate that 20-hydroxyecdysone (20E) treatment dramatically induces the expression of HaCTL3, and knockdown of the 20E receptor (EcR)/ultraspiracle (USP), abrogates this response. Overall, this study provides the first evidence of the presence of a hemocytic receptor (Habeta-integrin), that interacts with the PRR HaCTL3 to facilitate encapsulation reaction in insects and demonstrates the regulation of this process by the steroid hormone ecdysone. PMID- 28572001 TI - Quantitative FLAIR MRI in Amyotrophic Lateral Sclerosis. AB - RATIONALE AND OBJECTIVES: T2-weighted magnetic resonance imaging (MRI) hyperintensity assessed visually in the corticospinal tract (CST) lacks sensitivity for a diagnosis of amyotrophic lateral sclerosis (ALS). We sought to explore a quantitative approach to fluid-attenuated inversion recovery (FLAIR) MRI intensity across a range of ALS phenotypes. MATERIALS AND METHODS: Thirty three classical ALS patients, 10 with a flail arm presentation, and six with primary lateral sclerosis underwent MRI at 3 Tesla. Comparisons of quantitative FLAIR intensity in the CST and corpus callosum were made between 21 healthy controls and within patient phenotypic subgroups, some of whom were studied longitudinally. RESULTS: Mean FLAIR intensity was greater in patient groups. The cerebral peduncle intensity provided the strongest subgroup classification. FLAIR intensity increased longitudinally. The rate of change of FLAIR within CST correlated with rate of decline in executive function and ALS functional rating score. CONCLUSIONS: FLAIR MRI encodes quantifiable information of potential diagnostic, stratification, and monitoring value. PMID- 28572003 TI - Radial access in cardiac catheterization: Can we do even better? PMID- 28572004 TI - alpha-Dystroglycan hypoglycosylation affects cell migration by influencing beta dystroglycan membrane clustering and filopodia length: A multiscale confocal microscopy analysis. AB - Dystroglycan (DG) serves as an adhesion complex linking the actin cytoskeleton to the extracellular matrix. DG is encoded by a single gene as a precursor, which is constitutively cleaved to form the alpha- and beta-DG subunits. alpha-DG is a peripheral protein characterized by an extensive glycosylation that is essential to bind laminin and other extracellular matrix proteins, while beta-DG binds the cytoskeleton proteins. The functional properties of DG depend on the correct glycosylation of alpha-DG and on the cross-talk between the two subunits. A reduction of alpha-DG glycosylation has been observed in muscular dystrophy and cancer while the inhibition of the interaction between alpha- and beta-DG is associated to aberrant post-translational processing of the complex. Here we used confocal microscopy based techniques to get insights into the influence of alpha DG glycosylation on the functional properties of the beta-DG, and its effects on cell migration. We used epithelial cells transfected with wild-type and with a mutated DG harboring the mutation T190M that has been recently associated to dystroglycanopathy. We found that alpha-DG hypoglycosylation, together with an increased protein instability, reduces the membrane dynamics of the beta-subunit and its clustering within the actin-rich domains, influencing cell migration and spontaneous cell movement. These results contribute to give novel insights into the involvement of aberrant glycosylation of DG in the developing of muscular dystrophy and tumor metastasis. PMID- 28572002 TI - Toward an international consensus-Integrating lipoprotein apheresis and new lipid lowering drugs. AB - BACKGROUND: Despite advances in pharmacotherapy of lipid disorders, many dyslipidemic patients do not attain sufficient lipid lowering to mitigate risk of atherosclerotic cardiovascular disease. Several classes of novel lipid-lowering agents are being evaluated to reduce atherosclerotic cardiovascular disease risk. Lipoprotein apheresis (LA) is effective in acutely lowering the plasma concentrations of atherogenic lipoproteins including low-density lipoprotein cholesterol and lipoprotein(a), and novel lipid-lowering drugs may dampen the lipid rebound effect of LA, with the possibility that LA frequency may be decreased, in some cases even be discontinued. SOURCES OF MATERIAL: This document builds on current American Society for Apheresis guidelines and, for the first time, makes recommendations from summarized data of the emerging lipid-lowering drug classes (inhibitors of proprotein convertase subtilisin/kexin type 9 or microsomal triglyceride transfer protein, high-density lipoprotein mimetic), including the available evidence on combination therapy with LA with respect to the management of patients with dyslipidemia. ABSTRACT OF FINDINGS: Recommendations for different indications are given based on the latest evidence. However, except for lomitapide in homozygous familial hypercholesterolemia and alirocumab/evolocumab in heterozygous familial hypercholesterolemia subjects, limited data are available on the effectiveness and safety of combination therapy. More studies on combining LA with novel lipid-lowering drugs are needed. CONCLUSION: Novel lipid-lowering agents have potential to improve the performance of LA, but more evidence is needed. The Multidisciplinary International Group for Hemapheresis TherapY and Metabolic DIsturbances Contrast scientific society aims to establish an international registry of clinical experience on LA combination therapy to expand the evidence on this treatment in individuals at high cardiovascular disease risk. PMID- 28572005 TI - Reelin protects from colon pathology by maintaining the intestinal barrier integrity and repressing tumorigenic genes. AB - We previously reported that reelin, an extracellular matrix protein first known for its key role in neuronal migration, reduces the susceptibility to dextran sulphate sodium (DSS)-colitis. The aim of the current study was to determine whether reelin protects from colorectal cancer and how reelin defends from colon pathology. In the colon of wild-type and of mice lacking reelin (reeler mice) we have analysed the: i) epithelium cell renewal processes, ii) morphology, iii) Sox9, Cdx2, Smad5, Cyclin D1, IL-6 and IFNgamma mRNA abundance in DSS-treated and untreated mice, and iv) development of azoxymethane/DSS-induced colorectal cancer, using histological and real time-PCR methodologies. The reeler mutation increases colitis-associated tumorigenesis, with increased tumours number and size. It also impairs the intestinal barrier because it reduces cell proliferation, migration, differentiation and apoptosis; decreases the number and maturation of goblet cells, and expands the intercellular space of the desmosomes. The intestinal barrier impairment might explain the increased susceptibility to colon pathology exhibited by the reeler mice and is at least mediated by the down-regulation of Sox9 and Cdx2. In response to DSS-colitis, the reeler colon increases the mRNA abundance of IL-6, Smad5 and Cyclin D1 and decreases that of IFNgamma, conditions that might result in the increased colitis associated tumorigenesis found in the reeler mice. In conclusion, the results highlight a role for reelin in maintaining intestinal epithelial cell homeostasis and providing resistance against colon pathology. PMID- 28572006 TI - Electroencephalographic and biochemical long-lasting abnormalities in animal model of febrile seizure. AB - Febrile seizures (FS) are convulsions associated with high body temperature. It has a high incidence in children from the age of 6months to 5years and may have adverse consequences in adulthood. The experimental model of FS could be induced in animals via hyperthermia. The present study was designed to investigate persistent electroencephalographic (EEG), neurochemical and behavioral alterations in adult animals that had experienced complex FS at their immature age. EEG signals were obtained from the cortex of both FS and control normothermic groups of animals. A spectrophotometric assay was carried out to determine oxidative stress parameters (malondialdehyde, nitric oxide, reduced glutathione) and acetylcholinesterase activity in the cortex and hippocampus of FS and control animals. Behavioral assessment of seizure threshold and severity were investigated via a sub-convulsive dose of nicotine in adult animals. Alterations in the oxidant/antioxidant system and AChE activity were obtained in the cortex and hippocampus of FS animals in comparison to control animals. EEG spectral analysis displayed significant changes in all EEG frequency bands. A decrease in seizure latency and an increase in seizure severity were also observed. The present study provides evidence for long-lasting abnormalities in the cortex and hippocampus of adult animals subjected to complex FS at their developmental age, which may be correlated to the underlying mechanism of epileptogenesis and its related co-morbidities. PMID- 28572008 TI - Irritable Bowel Syndrome-Type Symptoms Are Associated With Psychological Comorbidity, Reduced Quality of Life, and Health Care Use in Patients With Inflammatory Bowel Disease. PMID- 28572007 TI - Reading the mind in the touch: Neurophysiological specificity in the communication of emotions by touch. AB - Touch is central to interpersonal interactions. Touch conveys specific emotions about the touch provider, but it is not clear whether this is a purely socially learned function or whether it has neurophysiological specificity. In two experiments with healthy participants (N = 76 and 61) and one neuropsychological single case study, we investigated whether a type of touch characterised by peripheral and central neurophysiological specificity, namely the C tactile (CT) system, can communicate specific emotions and mental states. We examined the specificity of emotions elicited by touch delivered at CT-optimal (3cm/s) and CT suboptimal (18cm/s) velocities (Experiment 1) at different body sites which contain (forearm) vs. do not contain (palm of the hand) CT fibres (Experiment 2). Blindfolded participants were touched without any contextual cues, and were asked to identify the touch provider's emotion and intention. Overall, CT-optimal touch (slow, gentle touch on the forearm) was significantly more likely than other types of touch to convey arousal, lust or desire. Affiliative emotions such as love and related intentions such as social support were instead reliably elicited by gentle touch, irrespective of CT-optimality, suggesting that other top-down factors contribute to these aspects of tactile social communication. To explore the neural basis of this communication, we also tested this paradigm in a stroke patient with right perisylvian damage, including the posterior insular cortex, which is considered as the primary cortical target of CT afferents, but excluding temporal cortex involvement that has been linked to more affiliative aspects of CT-optimal touch. His performance suggested an impairment in 'reading' emotions based on CT-optimal touch. Taken together, our results suggest that the CT system can add specificity to emotional and social communication, particularly with regards to feelings of desire and arousal. On the basis of these findings, we speculate that its primary functional role may be to enhance the 'sensual salience' of tactile interactions. PMID- 28572009 TI - How to Gain Expertise in Translational Research During Training. PMID- 28572010 TI - Making Cancer Quiescent: SPDEF De-Cycles Beta-Catenin. PMID- 28572011 TI - Sno(RNA)wing and Pancreatic Cancer Metastasis. PMID- 28572012 TI - Defeating Cancer by Boosting the Adenoma Detection Rate: The Circle of Life. PMID- 28572014 TI - Recovery From Heavy Vocal Loading in Women With Different Degrees of Functional Voice Problems. AB - TYPE OF STUDY: This is a longitudinal, case-control clinical trial. OBJECTIVES: This study aims to track recovery time following a vocal loading task (VLT) imposing vocal fatigue and to explore if patients with functional dysphonia (FD) are worse affected by vocal loading, and if these patients take longer than others to recover. METHODS: Fifty (n = 50) female participants in four vocal subgroups on a spectrum of everyday vocal loading and functional voice complaints, including n = 20 patients with FD, took part in a clinical VLT, inflicting vocal fatigue through loud speech in ambient noise. Short-term recovery was explored through self-assessment of unspecified voice problems every 15 minutes for 2 hours following loading. Long-term recovery was tracked through self-assessments of specific voice symptoms during 3 days following vocal loading. Effects of heavy vocal loading were evaluated through voice recordings, long-time-average spectrum, perceptual assessments, and assessments of digital imaging performed pre- and post vocal loading. RESULTS: Patients with FD did not return to baseline for unspecified voice problems within 2 hours of vocal loading and were worse affected by vocal loading than other groups. Women with high everyday vocal loading with no voice complaints identified vocal loading more evidently than other groups. Long-term recovery took 7-20 hours for all groups. CONCLUSIONS: Short-term recovery is slower for patients with FD and these patients are worse affected by a VLT than others. PMID- 28572013 TI - Comparison of in vitro toxicological effects of biomass smoke from different sources of animal dung. AB - Worldwide, over 4 million premature deaths each year are attributed to the burning of biomass fuels for cooking and heating. Epidemiological studies associate household air pollution with lung diseases, including chronic obstructive pulmonary disease, lung cancer, and respiratory infections. Animal dung, a biomass fuel used by economically vulnerable populations, generates more toxic compounds per mass burned than other biomass fuels. The type of animal dung used varies widely depending on local agro-geography. There are currently neither standardized experimental systems for dung biomass smoke research nor studies assessing the health impacts of different types of dung smoke. Here, we used a novel reproducible exposure system to assess outcomes related to inflammation and respiratory infections in human airway cells exposed to six different types of dung biomass smoke. We report that dung biomass smoke, regardless of species, is pro-inflammatory and activates the aryl hydrocarbon receptor and JNK transcription factors; however, dung smoke also suppresses interferon responses after a challenge with a viral mimetic. These effects are consistent with epidemiological data, and suggest a mechanism by which the combustion of animal dung can directly cause lung diseases, promote increased susceptibility to infection, and contribute to the global health problem of household air pollution. PMID- 28572015 TI - Validation of the Lithuanian Version of the Speech Handicap Index. AB - OBJECTIVE: The objective is to study the cultural adaptation and validation of the Speech Handicap Index (SHI) questionnaire to the Lithuanian language. METHODS: Cultural adaptation and validation of the translated Lithuanian version of the SHI (SHI-LT) was performed as described by the Scientific Advisory Committee of the Medical Outcomes Trust. The SHI-LT was completed by 46 patients after total laryngectomy and by 60 healthy subjects of the control group. Validity and reliability of the SHI-LT were evaluated. RESULTS: The SHI-LT showed a statistically significant high internal consistency and test-retest reliability (Cronbach's alpha = 0.96-0.98). Good validity of SHI-LT was reflected by statistically significant (P < 0.001) difference between the mean scores of the patients and control groups (74.7 +/- 26.9 and 5.5 +/- 6.5, respectively). No age or gender dependence of SHI-LT was found (P > 0.05). Receiver operating characteristic test indicated that SHI-LT scores exceeding 17.0 points (cutoff value) distinguish patients from healthy controls, with a sensitivity of 97.8% and specificity of 95.0%. CONCLUSION: SHI-LT is considered to be a valid and reliable speech assessment tool for Lithuanian-speaking patients after laryngectomy. PMID- 28572016 TI - The Exploration of an Objective Model for Roughness With Several Acoustic Markers. AB - OBJECTIVE: In voice assessment, the evaluation of voice quality is a major component in which roughness has received wide acceptance as a major subtype of abnormal voice quality. The aim of the present study was to develop a new multivariate acoustic model for the evaluation of roughness. METHOD: In total, 970 participants with dysphonia and 88 participants with normal voice were included. Concatenated voice samples of continuous speech and sustained vowel [a:] were perceptually judged on roughness severity. Acoustic analyses were conducted on the voiced segments of the continuous speech sample plus sustained vowel as well. A stepwise multiple linear regression analysis was applied to construct an acoustic model of the best acoustic predictors. Concurrent validity, diagnostic accuracy, and cross-validation were verified on the basis of Spearman correlation coefficient (rs), several estimates of the receiver operating characteristics plus the likelihood ratio, and iterated internal cross correlations. RESULTS: Six experts were included for perceptual analysis based on acceptable rater reliability. Stepwise multiple regression analysis yielded a 12 variable acoustic model. A marked correlation was identified between the model and the perceptual judgment (rs = 0.731, P = 0.000). The cross-correlations confirmed a high comparable degree of association. However, the receiver operating characteristics and likelihood ratio results showed the best diagnostic outcome at a threshold of 2.92, with a sensitivity of 51.9% and a specificity of 94.9%. CONCLUSIONS: Currently, the newly developed roughness model is not recommended for clinical practice. Further research is needed to detect the acoustic complexity of roughness (eg, multiplophonia, irregularity, chaotic structure, glottal fry, etc). PMID- 28572017 TI - Age at introduction of ultra-processed food among preschool children attending day-care centers. AB - OBJECTIVE: To identify the age of introduction of ultra-processed food and its associated factors among preschool children. METHODS: Cross-sectional study carried out from March to June 2014 with 359 preschool children aged 17 to 63 months attending day-care centers. Time until ultra-processed food introduction (outcome variable) was described by the Kaplan-Meier analysis, and the log-rank test was used to compare the survival functions of independent variables. Factors associated with ultra-processed food introduction were investigated using the multivariate Cox proportional hazards model. The results were shown as hazard ratios with their respective 95% confidence intervals. RESULTS: The median time until ultra-processed food introduction was six months. Between the 3rd and 6th months, there is a significant increase in the probability of introducing ultra processed food in the children's diet; and while the probability in the 3rd month varies from 0.15 to 0.25, at six months the variation ranges from 0.6 to 1.0. The final Cox proportional hazards model showed that unplanned pregnancy (1.32 [1.05 1.65]), absence of prenatal care (2.50 [1.02-6.16]), and income >2 minimum wages (1, 50 [1.09-2.06]) were independent risk factors for the introduction of ultra processed food. CONCLUSION: Up to the 6th month of life, approximately 75% of preschool children had received one or more ultra-processed food in their diet. In addition, it was observed that the poorest families, as well as unfavorable prenatal factors, were associated with early introduction of ultra-processed food. PMID- 28572018 TI - Performance of different diagnostic criteria of overweight and obesity as predictors of metabolic syndrome in adolescents. AB - OBJECTIVE: To analyze the performance of three different diagnostic criteria of overweight and obesity (WHO, IOTF and Conde and Monteiro) using body mass index (BMI) as predictors of metabolic syndrome (MetS) in a representative sample of adolescents. METHODS: A sample of 1035 adolescents aged 12-20 years (565 girls and 470 boys) was used in the study. BMI was calculated through the quotient of weight (kg)/height squared (m)2, and MetS was defined according to the criteria of the International Diabetes Federation. Sensitivity, specificity, and overall accuracy (area under the curve) were estimated using the receiver operating characteristic (ROC) curves method and used to describe the predictive performance. RESULTS: The three diagnostic criteria showed higher absolute values of sensitivity and specificity for predicting MetS in boys and older adolescents. The highest sensitivity to identify MetS was found using the IOTF criterion (60 85%), while specificity values >= 90% were found for the three criteria. The Conde and Monteiro diagnostic criterion pointed to a significantly lower overall accuracy (0.52-0.64) than that of the WHO (0.70-0.84) and IOTF (0.75-0.89) diagnostic criterion. CONCLUSIONS: Overweight and obesity using BMI showed a moderate association with MetS, regardless of the diagnostic criteria used. However, the IOTF criterion showed better predictive capacity for the presence of MetS than the WHO and the Conde and Monteiro criteria. PMID- 28572019 TI - Socioeconomic inequality in preterm birth in four Brazilian birth cohort studies. AB - OBJECTIVE: To analyze economic inequality (absolute and relative) due to family income in relation to the occurrence of preterm births in Southern Brazil. METHODS: Four birth cohort studies were conducted in the years 1982, 1993, 2004, and 2011. The main exposure was monthly family income and the primary outcome was preterm birth. The inequalities were calculated using the slope index of inequality and the relative index of inequality, adjusted for maternal skin color, education, age, and marital status. RESULTS: The prevalence of preterm births increased from 5.8% to approximately 14% (p-trend<0.001). Late preterm births comprised the highest proportion among the preterm births in all studies, although their rates decreased over the years. The analysis on the slope index of inequality demonstrated that income inequality arose in the 1993, 2004, and 2011 studies. After adjustment, only the 2004 study maintained the difference between the poorest and the richest subjects, which was 6.3 percentage points. The relative index of inequality showed that, in all studies, the poorest mothers were more likely to have preterm newborns than the richest. After adjustment for confounding factors, it was observed that the poorest mothers only had a greater chance of this outcome in 2004. CONCLUSION: In a final model, economic inequalities resulting from income were found in relation to preterm births only in 2004, although a higher prevalence of prematurity continued to be observed in the poorest population, in all the studies. PMID- 28572020 TI - Factor structure of the Montreal Cognitive Assessment items in a sample with early Parkinson's disease. AB - INTRODUCTION: The Montreal Cognitive Assessment (MoCA) is a frequently utilized cognitive screening tool that has attractive clinical attributes when utilized in individuals with Parkinson's disease. However, the construct validity of this instrument has not been well-characterized in Parkinson's samples. The purpose of this study is to explore the underlying factor structure of the MoCA in individuals with early stage Parkinson's disease. METHOD: Item responses from the MoCA in 357 individuals with Parkinson's disease from the Parkinson's Progression Markers Initiative were analyzed first for frequency of errors and polychoric inter item correlations. This correlation matrix was then analyzed with exploratory factor analysis. RESULTS: Omitting items with ceiling effects, three factors emerged which explained the majority of the variance. These factors were reflective of executive dysfunction, memory, and verbal attention. Scores on the MoCA and all of its subscales were significantly different between individuals with Parkinson's disease-no cognitive impairment and those who met criteria for mild cognitive impairment. CONCLUSIONS: In keeping with prior studies in Parkinson's disease, executive dysfunction seems to underpin performance of many items of the MoCA. Implications of this finding both in terms of optimizing the MoCA for use in this population and further steps to validate the constructs behind the MoCA are discussed. PMID- 28572021 TI - Death certificate data and causes of death in patients with parkinsonism. AB - INTRODUCTION: Assessment of variables related to mortality in Parkinson disease (PD) and other parkinsonian syndromes relies, among other sources, on accurate death certificate (DC) documentation. We assessed the documentation of the degenerative disorder on DCs and evaluated comorbidities and causes of death among parkinsonian patients. METHODS: Demographic and clinical data were systematically and prospectively collected on deceased patients followed at a tertiary movement disorder clinic. DCs data included the documentation of parkinsonism, causes, and place of death. RESULTS: Among 138 cases, 84 (60.9%) male, mean age 77.9 years, mean age of onset 66.7, and mean disease duration 10.9 years. Clinical diagnoses included PD (73.9%), progressive supranuclear palsy (10.9%), multiple system atrophy (7.2%), Lewy body dementia (7.2%) and corticobasal degeneration (0.7%). Psychosis occurred in 60.1% cases, dementia in 48.5%. Most PD patients died due to heterogeneous causes before reaching advanced stages. Non-PD parkinsonian patients died earlier due to causes linked to the advanced neurodegenerative process. PD was documented in 38.4% of DCs with different forms of inconsistencies. That improved, but remained significant when it was signed by a specialist. CONCLUSIONS: More than half of PD cases died while still ambulatory and independent, after a longer disease course and due to causes commonly seen in that age group. Deaths among advanced PD patients occurred due to causes similar to what we found in non-PD cases. These findings can be useful for clinical, prognostic and counseling purposes. Underlying parkinsonian disorders are poorly documented in DCs, undermining its' use as sources of data collection. PMID- 28572022 TI - [Long term radiological outcomes of unstable thoraco-lumbar fractures without neurological deficit]. AB - OBJECTIVE: To analyse the radiological outcomes in the long term of unstable thoraco-lumbar fractures. MATERIAL AND METHODS: Retrospective review of 100 patients with unstable thoracolumbar fractures treated with posterolateral fusion and short screw fixation for compression and flexion-distraction type fractures, and long segment posterior fixation for fractures-dislocations or more than one vertebra fractured, between 2000 and 2010 at three different hospital centers. Six radiological parameters were measured annually during a 4-year period: Fracture angle, kyphotic deformity, sagittal index, percentage of compression, degree of displacement and deformation angle. RESULTS: A total of 100 patients were included with a median age of 36,4 years and a median follow-up period of 7.2 years. Fracture angle rose from 11,6 degrees to 14,5 degrees (increase of 25%), kyphotic deformity from 14,5 degrees to 16,7 degrees (increase of 15,17%), sagittal index from 8,7 to 10,8 (increase of 24,13%), percentage of compression from 31,8% to 36,5% (increase of 6,88%), degree of displacement from 2,8mm to 4,6mm (increase of 14,77%) and deformation angle from 19.7 degrees to 21.4 degrees (increase of 8,62%). DISCUSSION: All the radiological parameters studied lost correction throughout the 48 months of follow-up, being the fracture angle the most affected one. Nevertheless, the greatest loss of correction occurs in the first postoperative year, stabilizing the parameters afterwards over the 4 years of follow up. We routinely recommend the measurement of all previous parameters for the follow up of unstable thoracolumbar fractures. PMID- 28572024 TI - Maternal exposure to polybrominated diphenyl ether (BDE-209) during lactation affects germ cell survival with altered testicular glucose homeostasis and oxidative status through down-regulation of Cx43 and p27Kip1 in prepubertal mice offspring. AB - BDE-209, a congener of polybrominated diphenyl ethers (PBDEs), is mainly used as flame retardant and accounts for over 82% of total PBDE usage. PBDEs have recently been detected in human milk and cord blood. BDE-209 possesses weak estrogenic/anti-estrogenic properties and evokes hyperglycemia through impaired glucose homeostasis in rat liver. However, little is known of the effect of lactational exposure to BDE-209 on germ cell survival in relation to testicular glucose homeostasis, estradiol and oxidative status during prepubertal period. The present study, therefore, evaluated the effect of maternal exposure to BDE 209 during lactation on above-mentioned parameters with reference to Cx43 and p27Kip1 in prepubertal Parkes (P) mice offspring. Lactating female P mice were orally gavaged with 500, and 700mg/kg body weight of BDE-209 in corn oil from postnatal day (PND) 0 to PND 28; male pups were euthanized at PND 21 and 28. Maternal exposure to BDE-209 during lactation increased germ cell apoptosis with altered expressions of various cell survival and apoptotic markers along with decreased expression of Cx43 and p27Kip1 in prepubertal mice offspring. Testicular glucose and lactate concentrations were markedly reduced in these pups with down-regulation in GLUT3 and GLUT8 expressions and decreased LDH activity. Rise in oxidative stress in testes with increased estrogen level in these pups was also noted. In conclusion, our results suggest that maternal BDE-209 exposure during lactation affects germ cell survival with altered testicular glucose homeostasis and oxidative status through down-regulation of Cx43 and p27Kip1 in prepubertal mice offspring. PMID- 28572023 TI - Bisphenol A impairs the memory function and glutamatergic homeostasis in a sex dependent manner in mice: Beneficial effects of diphenyl diselenide. AB - Bisphenol A (BPA) is a compound integrated in commodities, which consequently increases the human exposure to this toxicant. The deleterious effects of BPA exposure during periods of brain development have been documented mainly concerning the impairment in memory functions. Diphenyl diselenide (PhSe)2, an organoselenium compound, shows protective/restorative effects against memory deficits in experimental models. Thus, this study investigated the effects of (PhSe)2 on the memory impairments induced by BPA exposure to male and female mice and the possible involvement of glutamatergic system in these effects. Three-week old male and female Swiss mice received BPA (5mg/kg), intragastrically, from 21st to 60th postnatal day. After, the animals were intragastrically treated with (PhSe)2 (1mg/kg) during seven days. The mice performed the behavioral memory tests and the [3H] glutamate uptake and NMDA receptor subunits (2A and 2B) analyses were carried out in the hippocampus and cerebral cortex of mice. The results demonstrated that the BPA exposure induced impairment of object recognition memory in both sexes. However, it caused impairments in spatial memory in female and in the passive avoidance memory in male mice. Besides, BPA caused a decrease in the [3H] glutamate uptake and NMDA receptor subunit levels in the cortical and hippocampal regions depending on the sex. Treatment with (PhSe)2 reversed in a sex-independent manner the behavioral impairments and molecular alterations. In conclusion, BPA had a negative effect in different memory types as well as in the glutamatergic parameters in a sex-dependent manner and (PhSe)2 treatment was effective against these alterations. PMID- 28572026 TI - Resistin and interleukin 6 as predictive factors for recurrence and long-term prognosis in renal cell cancer. AB - OBJECTIVES: The aim of the present study was to investigate prognostic factors for long-term outcome of renal cell cancer (RCC) in a cohort of patients treated before new antiangiogenic therapy modalities were introduced. Our specific aim was to explore resistin and interleukin 6 (IL-6) levels to find out cytokines potential to predict recurrence and survival in patients with RCC. MATERIALS AND METHODS: Our prospective study population consisted of 91 patients who underwent radical nephrectomy or partial resection for RCC at Tampere University Hospital between 1994 and 2001. At the time of surgery, 25 patients were diagnosed to have an advanced tumor and 66 patients a local tumor; 34 patients in the latter group developed a recurrence during the follow-up period of 15 years. Serum samples were collected preoperatively and at 3, 9, and 15 months and at 2, 3, 4, and 5 years postoperatively. IL-6 and resistin levels in serum were measured by immunoassay. RESULTS: Preoperative values of IL-6 (P = 0.006) and resistin (P<0.001) were higher in patients with advanced RCC when compared to patients with local tumors. Patients with local RCC who developed a recurrence during the follow-up period had higher preoperative IL-6 values (P = 0.003) than patients without a recurrence. Based on trajectory analysis of IL-6 and resistin levels, the patients were divided into 3 trajectory groups. According to multivariate analysis, the patients in the trajectory class of the increasing resistin values during the follow-up period had a statistically significantly higher risk for RCC progression (hazard ratio [HR] = 3.73, 95% CI: 1.52-9.13) and for poor survival (HR = 4.93, 95% CI: 1.79-13.6) than the patients in the lowest trajectory class. Furthermore, the patients in the trajectory class of the highest IL-6 values showed a significantly elevated risk for RCC progression (HR = 7.03, 95% CI: 3.00 16.5) and for RCC-related poor survival (HR = 6.09, 95% CI: 2.53-14.7), when compared to the patients in the trajectory class of the lowest IL-6 values. CONCLUSION: In patients with RCC, the elevated preoperative resistin levels associated strongly with an advanced disease. Based on Cox regression models and trajectory analysis, resistin values were associated with disease progression and a poor survival. PMID- 28572025 TI - Cobalt toxicity in humans-A review of the potential sources and systemic health effects. AB - Cobalt (Co) and its compounds are widely distributed in nature and are part of numerous anthropogenic activities. Although cobalt has a biologically necessary role as metal constituent of vitamin B12, excessive exposure has been shown to induce various adverse health effects. This review provides an extended overview of the possible Co sources and related intake routes, the detection and quantification methods for Co intake and the interpretation thereof, and the reported health effects. The Co sources were allocated to four exposure settings: occupational, environmental, dietary and medical exposure. Oral intake of Co supplements and internal exposure through metal-on-metal (MoM) hip implants deliver the highest systemic Co concentrations. The systemic health effects are characterized by a complex clinical syndrome, mainly including neurological (e.g. hearing and visual impairment), cardiovascular and endocrine deficits. Recently, a biokinetic model has been proposed to characterize the dose-response relationship and effects of chronic exposure. According to the model, health effects are unlikely to occur at blood Co concentrations under 300MUg/l (100MUg/l respecting a safety factor of 3) in healthy individuals, hematological and endocrine dysfunctions are the primary health endpoints, and chronic exposure to acceptable doses is not expected to pose considerable health hazards. However, toxic reactions at lower doses have been described in several cases of malfunctioning MoM hip implants, which may be explained by certain underlying pathologies that increase the individual susceptibility for Co-induced systemic toxicity. This may be associated with a decrease in Co bound to serum proteins and an increase in free ionic Co2+. As the latter is believed to be the primary toxic form, monitoring of the free fraction of Co2+ might be advisable for future risk assessment. Furthermore, future research should focus on longitudinal studies in the clinical setting of MoM hip implant patients to further elucidate the dose-response discrepancies. PMID- 28572028 TI - Isolated Peripheral Nerve Palsies in Thoracic Outlet Syndrome. AB - Thoracic outlet syndrome (TOS) poses a difficult diagnostic entity with varied etiology and clinical presentation. We present a 35-year-old gentleman with unilateral long thoracic nerve palsy and contralateral subscapular paralysis caused by aberrant scalenus medius anatomy. TOS ought to be considered in patients presenting with isolated nerve palsies. PMID- 28572027 TI - Clinical outcome of patients who reduced sunitinib or pazopanib during first-line treatment for advanced kidney cancer. AB - OBJECTIVES: To investigate the different outcomes in patients with metastatic renal cell carcinoma (mRCC) who receive a reduced first-line dose of sunitinib or pazopanib compared to those who continue at the standard dose. PATIENTS AND METHODS: All the patients treated in 11 oncological centers in Italy for mRCC who started first-line treatment with sunitinib or pazopanib at the standard dose. Descriptive statistical tests were used to highlight differences among groups. Survival was estimated by the Kaplan-Meier method and compared across the groups using log-rank tests, the Cox proportional hazards model adjusted for statistically significant variables was also done. RESULTS: A total of 591 patients were included in the study. Of these, 45.7% received a reduced dose of sunitinib or pazopanib after a median treatment time of 3.6 months at the standard dose. The median overall survival in the patients who continued to receive the standard dose was 24.0 months compared to 49.4 months for those who received a reduced dose (hazard ratio = 1.80; 95% CI: 1.42-2.29; P<0.001). Only 45% of the patients received second-line therapy: 42.5% had an mTOR and 54.1% a tyrosine kinase inhibitor. Second-line overall survival was 19.8 and 11.8 months, respectively, in the patients who received, or did not, a reduced dose during first-line therapy (P = 0.007). CONCLUSIONS: Toxicity-related dose reduction is a common event in mRCC patients who have started first-line therapy with either sunitinib or pazopanib. This is positively related to the outcomes of both first- and second-line therapy. PMID- 28572029 TI - Risk Factor Modification Behaviors of Practicing Vascular Surgeons. AB - BACKGROUND: National smoking rates have declined; however, it remains the primary modifiable risk factor for nearly all vascular disease. While vascular surgeons have the availability to treat patients via medical or surgical/endovascular means, involvement in risk factor modification may be lacking. This study seeks to understand vascular surgeons' involvement in tobacco cessation and risk factor modification and to determine if practice variables had any effect on provision of these services to vascular surgery patients. METHODS: Anonymous electronic surveys examining tobacco cessation and risk factor modification were sent to the Vascular & Endovascular Surgery Society members (n = 633). Influence of time from training, practice type (dichotomized into academic and nonacademic vascular surgeons), hospital size, region, and workload was assessed, and data were analyzed by univariate contingency tables. RESULTS: A total of 149 (24%) surveys were completed. While the majority of respondents ask patient's smoking status (97%), assess willingness to quit (84%), and advise patients to quit (95%), only 34% prescribe medications to assist in cessation, 7% see patients in tobacco cessation follow-up, and 3% verify cessation with cotinine levels or carbon monoxide monitoring. Surgeons who prescribed medications for cessation are more likely to assess patient's willingness to quit, prescribe/advise nicotine replacement, or prescribe initial statin or other lipid-lowering medications. There was no difference in perceived education received during training in risk factor modification, but only 26% of respondents thought they were well trained. Comparing academic to private practice vascular surgeons, there was no difference in cessation techniques used; however, academic surgeons were less likely to perform endovascular procedures for claudication in patients who continued to smoke (29% vs. 46%, P = 0.03) and more likely to prescribe an initial antihyperlipid medication (65% vs. 39%, P = 0.0018). CONCLUSIONS: Tobacco dependence remains a critical issue for vascular surgery patients; however, there is wide variation in cessation techniques used. The majority of vascular surgeons are not well versed in cessation techniques and risk factor modification, and thus, efforts should be made to provide this education in vascular surgery training programs. PMID- 28572031 TI - Review: Environmental impact on ocular surface disorders: Possible epigenetic mechanism modulation and potential biomarkers. AB - Throughout life, external and the internal environments interact in normal development and tissue homeostasis as well as in onset of disease. Epigenetic modifications occur in response to environmental changes and play a fundamental role in controlling gene expression without modification of the DNA base sequence. Aging, inflammation, drugs, infections and ultraviolet exposure may have profound effects on epigenetic modifications and trigger susceptibility to diseases. Increasing evidence has demonstrated that epigenetic mechanisms play a key role in regulating the physiopathology of the ocular surface. The evaluation of epigenetic factors in ocular disease would lead to further investigation regarding the potential use of therapeutic targets and diagnostic biomarkers. This review examines specific epigenetic and biochemical mechanisms that may occur in the ocular surface microenvironment. Potential correlation between epigenetic factors and targets should be considered in future approaches to prevention and/or treatment of specific ocular surface disorders. PMID- 28572032 TI - Suppressed neural complexity during ketamine- and propofol-induced unconsciousness. AB - Ketamine and propofol have distinctively different molecular mechanisms of action and neurophysiological features, although both induce loss of consciousness. Therefore, identifying a common feature of ketamine- and propofol-induced unconsciousness would provide insight into the underlying mechanism of losing consciousness. In this study we search for a common feature by applying the concept of type-II complexity, and argue that neural complexity is essential for a brain to maintain consciousness. To test this hypothesis, we show that complexity is suppressed during loss of consciousness induced by ketamine or propofol. We analyzed the randomness (type-I complexity) and complexity (type-II complexity) of electroencephalogram (EEG) signals before and after bolus injection of ketamine or propofol. For the analysis, we use Mean Information Gain (MIG) and Fluctuation Complexity (FC), which are information-theory-based measures that quantify disorder and complexity of dynamics respectively. Both ketamine and propofol reduced the complexity of the EEG signal, but ketamine increased the randomness of the signal and propofol decreased it. The finding supports our claim and suggests EEG complexity as a candidate for a consciousness indicator. PMID- 28572030 TI - Streamlined duplex live-dead microplate assay for cultured cells. AB - A duplex fluorescence assay to assess the viability of cells cultured in multi well plates is described, which can be carried out in the original culture plate using a plate reader, without exchanges of culture or assay medium, or transfer of cells or cell supernatant. The method uses freshly prepared reagents and does not rely on a proprietary, commercially supplied kit. Following experimental treatment, calcein acetoxymethyl ester (CaAM) is added to each well of cultured cells; after 30 min, the fluorescence intensity (emission lambdamax ~ 530 nm) is measured. The signal is due to formation of calcein, which is produced from CaAM by action of esterase activity found in intact live cells. Since live cells may express plasma membrane multidrug transport proteins, especially of the ABC transporter family, the CaAM incubation is carried out in the presence of an inhibitor of this efflux process, thereby improving the dynamic range of the assay. Next, SYTOX(r) Orange (SO) is added to the culture wells, and, after a 30 min incubation, fluorescence intensity (emission lambdamax ~ 590 nm) is measured again. SO is excluded from cells that have an intact plasma membrane, but penetrates dead/dying cells and can diffuse into the nucleus, where it binds to and forms a fluorescent complex with DNA. The CaAM already added to the wells causes no interference with the latter fluorescent signal. At the conclusion of the duplex assay, both live and dead cells remain in the culture wells and can be documented by digital imaging to demonstrate correlation of cellular morphology with the assay output. Two examples of the application of this method are provided, using cytotoxic compounds having different mechanisms of action. PMID- 28572034 TI - Decreased middle temporal gyrus connectivity in the language network in schizophrenia patients with auditory verbal hallucinations. AB - As the most common symptoms of schizophrenia, the long-term persistence of obstinate auditory verbal hallucinations (AVHs) brings about great mental pain to patients. Neuroimaging studies of schizophrenia have indicated that AVHs were associated with altered functional and structural connectivity within the language network. However, effective connectivity that could reflect directed information flow within this network and is of great importance to understand the neural mechanisms of the disorder remains largely unknown. In this study, we utilized stochastic dynamic causal modeling (DCM) to investigate directed connections within the language network in schizophrenia patients with and without AVHs. Thirty-six patients with schizophrenia (18 with AVHs and 18 without AVHs), and 37 healthy controls participated in the current resting-state functional magnetic resonance imaging (fMRI) study. The results showed that the connection from the left inferior frontal gyrus (LIFG) to left middle temporal gyrus (LMTG) was significantly decreased in patients with AVHs compared to those without AVHs. Meanwhile, the effective connection from the left inferior parietal lobule (LIPL) to LMTG was significantly decreased compared to the healthy controls. Our findings suggest aberrant pattern of causal interactions within the language network in patients with AVHs, indicating that the hypoconnectivity or disrupted connection from frontal to temporal speech areas might be critical for the pathological basis of AVHs. PMID- 28572035 TI - Reduction in the prevalence of AmpC beta-lactamase CMY-2 in Salmonella from chicken meat following cessation of the use of ceftiofur in Japan. PMID- 28572033 TI - Blood-brain barrier disruption in diabetic mice is linked to Nrf2 signaling deficits: Role of ABCB10? AB - Blood-brain barrier (BBB) damage is a critical neurovascular complication of diabetes mellitus that adversely affects the CNS health and function. Previously, we showed the protective role of NF-E2 related factor-2 (Nrf2), a redox sensitive transcription factor, in regulation of BBB integrity. Given the pathogenic role of mitochondrial oxidative stress in diabetes-related microvascular complications, we focused on assessing: 1) the impact of diabetes on brain Nrf2 in correlation with BBB permeability and 2) Nrf2-dependent regulation of the mitochondrial transporter ABCB10, an essential player in mitochondrial function and redox balance at BBB endothelium. Using live animal fluorescence imaging, we demonstrated a strong increase in BBB permeability to 70kDa dextran in db/db diabetic mice that correlated with significant down-regulation of brain Nrf2 protein. Further, Nrf2 gene silencing in human BBB endothelial cells markedly suppressed ABCB10 protein, while Nrf2 activation by sulforaphane up-regulated ABCB10 expression. Interestingly, ABCB10 knockdown resulted in a strong-induction of Nrf2 driven anti-oxidant responses as evidenced by increased expression of Nrf2 and its downstream targets. Nrf2 or ABCB10 silencing elevated endothelial monocyte adhesion suggesting an activated inflammatory cascade. Thus, our results demonstrate a novel mechanism of ABCB10 regulation driven by Nrf2. In summary, Nrf2 dysregulation and ABCB10 suppression could likely mediate endothelial oxidative/inflammatory stress and BBB disruption in diabetic subjects. PMID- 28572036 TI - Draft genome sequence of a multidrug-resistant OXA-23-producing Acinetobacter baumannii ST191 clinical isolate from China. AB - Acinetobacter baumannii has emerged worldwide as a dominant pathogen in nosocomial infections. In this study, we report the draft genome sequence of a clinical multidrug-resistant (MDR) A. baumannii ST191 (CC92) strain. Whole-genome sequencing of the isolate was performed using an Illumina HiSeqTM 2500 system, and bioinformatics analysis was also performed. The draft genome length was 4,259,210bp, harbouring 14 gene sequences relevant to antibiotic resistance. Antimicrobial susceptibility testing revealed that the isolate was resistant to all of the tested antibiotics except for tigecycline and colistin. These data will facilitate further understanding of the genomic and resistance features of MDR A. baumannii. PMID- 28572037 TI - Persistence of blaCMY-2-producing Proteus mirabilis in two gull colonies at a 1 year interval in Southern France. PMID- 28572038 TI - Detection of the optrA gene in a clinical ST16 Enterococcus faecalis isolate in Denmark. PMID- 28572039 TI - AST to Platelet Ratio Index and fibrosis 4 calculator scores for non-invasive assessment of hepatic fibrosis in patients with non-alcoholic fatty liver disease. AB - BACKGROUND & AIMS: Liver fibrosis is the single most important prognostic factor in patients with non-alcoholic fatty liver disease (NAFLD). The predictive value of the AST to Platelet Ratio Index (APRI) score, originally developed for fibrosis assessment in hepatitis C virus (HCV) patients, is much less known in the context of NAFLD patients. METHODS: We retrospectively compared the performance of APRI and fibrosis 4 calculator (FIB-4) scores in NAFLD patients with documented liver biopsies, to their performance in chronic HCV patients. RESULTS: 153 patients with biopsy-proven NAFLD and 297 patients with biopsy proven chronic HCV infection were included. The APRI score was a good predictor for advanced fibrosis in NAFLD patients (area under the ROC curve 0.8307) although it was modestly inferior as compared to the well-validated FIB-4 score (area under the ROC curve 0.8959). The predictive value of APRI score in NALFD patients was inferior as compared to its predictive value in HCV patients (area under the ROC curve of 0.8307 versus 0.9965). In contrast to FIB-4, APRI score was not a good discriminator between intermediate stages of fibrosis in NAFLD patients. CONCLUSIONS: APRI and Fib-4 scores are reasonable tools to allocate NAFLD patients with advanced fibrosis. FIB-4 may better discriminate between intermediate fibrosis stages. PMID- 28572040 TI - Measuring influenza RNA quantity after prolonged storage or multiple freeze/thaw cycles. AB - In this study, we aim to determine what effects prolonged storage and repeated freeze/thaw cycles have on the stability of influenza A(H1N1)pdm09 (influenza A/H1N1)RNA. Cloned influenza A/H1N1 RNA transcripts were serially diluted from 8.0-1.0 log10 copies/MUl. RT-qPCR was used to measure RNA loss in transcripts stored at -80 degrees C, -20 degrees C, 4 degrees C and 25 degrees C for up to 84days or transcripts undergoing a total of 10 freeze/thaw cycles. Viral load was measured in clinical specimens stored at-80 degrees C for three years (n=89 influenza A RNA extracts; n=35 primary specimens) and in 10 clinical specimens from the 2015/2016 influenza season that underwent 7 freeze/thaw cycles. RNA stored at -80 degrees C, -20 degrees C, 4 degrees C and 25 degrees C is stable for up to 56, 56, 21, and 7days respectively or up to 9 freeze/thaw cycles when stored at -80 degrees C. There is no difference in viral load in clinical specimens that have been stored for up to three years at -80 degrees C if they are re-extracted. Similarly, clinical specimens undergoing up to 7 freeze/thaw cycles are stable if they are re-extracted between cycles. Influenza specimens can be stored for up to three years at -80 degrees C or undergo up to 7 freeze/thaw cycles without loss of RNA quantity if re-extracted. PMID- 28572041 TI - Real-time quantitative PCR assay for the quantification of virus and satellites causing leaf curl disease in cotton in Pakistan. AB - Cotton leaf curl disease (CLCuD) is the major biotic constraint to cotton production in Pakistan and northwestern India. The disease is caused by monopartite begomoviruses in association with a specific DNA satellite, Cotton leaf curl Multan betasatellite. The virus-betasatellite complex is also frequently associated with another DNA satellite-like molecule; an alphasatellite. A quantitative real-time PCR (qPCR) assay to detect all three components of the monopartite begomovirus/betasatellite/alphasatellite complex which causes CLCuD was established. This was used to investigate the relationship between symptoms and virus/satellite titre. Not surprisingly the analysis showed that, overall, there was a reasonable correlation between symptom severity and virus/satellite titre - more severe symptoms usually being associated with more virus/satellite. However, cotton plants were identified with no or very mild symptoms with relatively high virus/satellite titres and plants with severe symptoms but relatively low virus/satellite titres. This may be attributed to the resistance/susceptibility of the cotton variety - tolerant plants being able to sustain a relatively high virus/satellite titre whilst exhibiting mild symptoms. The usefulness of this qPCR procedure in the screening for resistance in cotton against CLCuD is discussed. PMID- 28572043 TI - Prelaminated extended temporoparietal fascia flap without tissue expansion for hemifacial reconstruction. AB - BACKGROUND: Disfigurement of the face caused by postburn scars, resected congenital nevi and vascular malformations has both functional and psychological consequences. Ideal reconstruction of the facial components requires producing not only function but also the better appearance of the face. The skin of the neck, supraclavicular or cervicothoracic regions are the most commonly used and the most likely source of skin for facial reconstruction in those techniques which prefabrications with tissue expansion are used. This retrospective cohort study describes the two staged prelaminated temporoparietal fascia flap which eliminates the usage of tissue expansion by using skin graft harvested from the neck and occipital region and the application of this flap for the lower three fourths of the face. METHOD: 5 patients received prelaminated temporoparietal fascia flap without tissue expansion for facial resurfacing. The mean age at surgery was 39, 2 years (range, 17-60 years). The average follow up was 21.6 months (range, 10-48 months). RESULT: The size of the raised prelaminated temporoparietal fascia flaps ranged from 9 * 8 cm to 14 * 10 cm. All flaps survived after second stage. Varied degrees of venous congestion were observed after flap insets in all cases but none required any further treatment for the congestion. The entire lesion could not be resected due to the large size of the lesion in all patients. CONCLUSION: Two stage prelaminated temporoparietal fascia flap with skin graft is an effective technique for the reconstruction of partial facial defects in selected patients. It is simple, quick, safe and reliable, and requires no expansion of skin or no microsurgery. PMID- 28572042 TI - An analysis of the operative experience of plastic surgery trainees in the United Kingdom using eLogbook. AB - INTRODUCTION: We performed a comprehensive analysis of the operative experience of UK Plastic Surgery Trainees using the web-based eLogbook. METHODS: An analysis of data recorded prospectively by Plastic Surgery Registrars 2010-2014 in eLogbook. RESULTS: The eLogbook data of 336 Specialty Registrars entered from 2010 to 2014 was analysed. Over the six-year training programme, trainees participated in a mean of 2117 procedures and performed a mean of 1571 procedures with or without supervision. We also determined the mean number of procedures for 14 indicative operative domains performed during training and compared these to current (2012) indicative numbers required prior to the award of a Certificate of Completion of Training (CCT). CONCLUSION: The eLogbook contains valuable data to determine the operative experience of UK Plastic Surgery trainees. This new data will be reflected in the updated indicative numbers required for CCT. Both trainees and trainers may use the data to monitor the acquisition of operative experience over time and target training where necessary. PMID- 28572044 TI - Cost analysis of percutaneous fixation of hand fractures in the main operating room versus the ambulatory setting. AB - PURPOSE: To date, there have been no studies identifying the cost differential for performing closed reduction internal fixation (CRIF) of hand fractures in the operating room (OR) versus an ambulatory setting. Our goal was to analyse the cost and efficiency of performing CRIF in these two settings and to investigate current practice trends in Canada. METHODS: A detailed analysis of the costs involved both directly and indirectly in the CRIF of a hand fracture was conducted. Hospital records were used to calculate efficiency. A survey was distributed to practicing plastic surgeons across Canada regarding their current practice of managing hand fractures. RESULTS: In an eight-hour surgical block we are able to perform five CRIF in the OR versus eight in an ambulatory setting. The costs of performing a CRIF in the OR under local anaesthetic, not including surgeon compensation, is $461.27 Canadian (CAD) compared to $115.59 CAD in the ambulatory setting, a 299% increase. The use of a regional block increases the cost to $665.49 CAD, a 476% increase. The main barrier to performing CRIFs in an outpatient setting is the absence of equipment necessary to perform these cases effectively, based on survey results. CONCLUSION: The use of the OR for CRIF of hand fractures is associated with a significant increase in cost and hospital resources with decreased efficiency. For appropriately selected hand fractures, CRIF in an ambulatory setting is less costly and more efficient compared to the OR and resources should be allocated to facilitate CRIF in this setting. PMID- 28572045 TI - The integration of multiple signaling pathways provides for bidirectional control of CRHR1 gene transcription in rat pituitary cell during hypoxia. AB - Hypoxia upregulates hypothalamic corticotrophin releasing hormone (CRH) and its receptor type-1 (CRHR1) expression and activates the HPA axis and induces hypoxic sickness and behavioral change. The transcriptional mechanism by which hypoxia differently regulates CRHR1 expression remains unclear. Here we report hypoxia time-dependently induced biphasic expression of CRHR1mRNA in rat pituitary during different physiological status. Short exposure of gestational dams to hypoxia reduced CRHR1mRNA in the pituitary of P1-P14 male rat offspring. A short- and prolonged-hypoxia evoked biphasic response of CRHR1mRNA characterized initially by decreases and subsequently by persistent increases, mediated by a rapid negative feedback via CRHR1 signaling and positive transcriptional control via NF kappaB, respectively. Further analysis of CRHR1 promoter in cultured primary anterior pituitary and AtT20 cells showed that c-Jun/AP-1 delivered negative while HIF-1alpha and NF-kappaB delivered positive control of transcription at CRHR1 promoter. The negative and positive inputs are integrated by hypoxic initiation and duration in CRHR1 transcription. PMID- 28572047 TI - ER stress and cancer: The FOXO forkhead transcription factor link. AB - The endoplasmic reticulum (ER) is a cellular organelle with central roles in maintaining proteostasis due to its involvement in protein synthesis, folding, quality control, distribution and degradation. The accumulation of misfolded proteins in the ER lumen causes 'ER stress' and threatens overall cellular proteostasis. To restore ER homeostasis, cells evoke an evolutionarily conserved adaptive signalling and gene expression network collectively called the 'unfolded protein response (UPR)', a complex biological process which aims to restore proteostasis. When ER stress is overwhelming and beyond rectification, the normally pro-survival UPR can shift to induce cell termination. Emerging evidence from mammalian, fly and nematode worm systems reveals that the FOXO Forkhead proteins integrate upstream ER stress and UPR signals with the transcriptional machinery to decrease translation, promote cell survival/termination and increase the levels of ER-resident chaperones and of ER-associated degradation (ERAD) components to restore ER homeostasis. The high rates of protein synthesis/translation associated with cancer cell proliferation and metabolism, as well as mutations resulting in aberrant proteins, also induce ER stress and the UPR. While the pro-survival side of the UPR underlies its ability to sustain and promote cancers, its apoptotic functions can be exploited for cancer therapies by offering the chance to 'flick the proteostatic switch'. To this end, further studies are required to fully reevaluate the roles and regulation of these UPR signalling molecules, including FOXO proteins and their targets, in cancer initiation and progression as well as the effects on inhibiting their functions in cancer cells. This information will help to establish these UPR signalling molecules as possible therapeutic targets and putative biomarkers in cancers. PMID- 28572046 TI - Understanding the molecular functions of the second extracellular loop (ECL2) of the calcitonin gene-related peptide (CGRP) receptor using a comprehensive mutagenesis approach. AB - The extracellular loop 2 (ECL2) region is the most conserved of the three ECL domains in family B G protein-coupled receptors (GPCRs) and has a fundamental role in ligand binding and activation across the receptor super-family. ECL2 is fundamental for ligand-induced activation of the calcitonin gene related peptide (CGRP) receptor, a family B GPCR implicated in migraine and heart disease. In this study we apply a comprehensive targeted non-alanine substitution analysis method and molecular modelling to the functionally important residues of ECL2 to reveal key molecular interactions. We identified an interaction network between R274/Y278/D280/W283. These amino acids had the biggest reduction in signalling following alanine substitution analysis and comprise a group of basic, acidic and aromatic residues conserved in the wider calcitonin family of class B GPCRs. This study identifies key and varied constraints at each locus, including diverse biochemical requirements for neighbouring tyrosine residues and a W283H substitution that recovered wild-type (WT) signalling, despite the strictly conserved nature of the central ECL2 tryptophan and the catastrophic effects on signalling of W283A substitution. In contrast, while the distal end of ECL2 requires strict conservation of hydrophobicity or polarity in each position, mutation of these residues never has a large effect. This approach has revealed linked networks of amino acids, consistent with structural models of ECL2 and likely to represent a shared structural framework at an important ligand-receptor interface that is present across the family B GPCRs. PMID- 28572048 TI - The role of endothelial cells in the vasculopathy of systemic sclerosis: A systematic review. AB - INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by fibroproliferative vasculopathy, immunological abnormalities and progressive fibrosis of multiple organs including the skin. In this study, all English speaking articles concerning the role of endothelial cells (ECs) in SSc vasculopathy and representing biomarkers are systematically reviewed and categorized according to endothelial cell (EC) (dys)function in SSc. METHODS: A sensitive search on behalf of the EULAR study group on microcirculation in Rheumatic Diseases was developed in Pubmed, The Cochrane Library and Web of Science to identify articles on SSc vasculopathy and the role of ECs using the following Mesh terms: (systemic sclerosis OR scleroderma) AND pathogenesis AND (endothelial cells OR marker). All selected papers were read and discussed by two independent reviewers. The selection process was based on title, abstract and full text level. Additionally, both reviewers further searched the reference lists of the articles selected for reading on full text level for supplementary papers. These additional articles went through the same selection process. RESULTS: In total 193 resulting articles were selected and the identified biomarkers were categorized according to description of EC (dys)function in SSc. The most representing and reliable biomarkers described by the selected articles were adhesion molecules for EC activation, anti-endothelial cell antibodies for EC apoptosis, vascular endothelial growth factor (VEGF), its receptor VEGFR-2 and endostatin for disturbed angiogenesis, endothelial progenitors cells for defective vasculogenesis, endothelin-1 for disturbed vascular tone control, Von Willebrand factor for coagulopathy and interleukin (IL)-33 for EC-immune system communication. Emerging, relatively new discovered biomarkers described in the selected articles, are VEGF165b, IL-17A and the adipocytokines. Finally, myofibroblasts involved in tissue fibrosis in SSc can derive from ECs or epithelial cells through a process known as endothelial-to mesenchymal transition. CONCLUSION: This systematic review emphasizes the growing evidence that SSc is primarily a vascular disease where EC dysfunction is present and prominent in different aspects of cell survival (activation and apoptosis), angiogenesis and vasculogenesis and where disturbed interactions between ECs and various other cells contribute to SSc vasculopathy. PMID- 28572049 TI - Autophagy in neuroinflammatory diseases. AB - Autophagy is a metabolically-central process that is crucial in diverse areas of cell physiology. It ensures a fair balance between life and death molecular and cellular flows, and any disruption in this vital intracellular pathway can have consequences leading to major diseases such as cancer, metabolic and neurodegenerative disorders, and cardiovascular and pulmonary diseases. Recent pharmacological studies have shown evidence that small molecules and peptides able to activate or inhibit autophagy might be valuable therapeutic agents by down- or up-regulating excessive or defective autophagy, or to modulate normal autophagy to allow other drugs to repair some cell alteration or destroy some cell subsets (e.g. in the case of cancer concurrent treatments). Here, we provide an overview of neuronal autophagy and of its potential implication in some inflammatory diseases of central and peripheral nervous systems. Based on our own studies centred on a peptide called P140 that targets autophagy, we highlight the validity of autophagy processes, and in particular of chaperone-mediated autophagy, as a particularly pertinent pathway for developing novel selective therapeutic approaches for treating some neuronal diseases. Our findings with the P140 peptide support a direct cross-talk between autophagy and certain central and peripheral neuronal diseases. They also illustrate the fact that autophagy alterations are not evenly distributed across all organs and tissues of the same individual, and can evolve in different stages along the disease course. PMID- 28572050 TI - Myocarditis in auto-immune or auto-inflammatory diseases. AB - Myocarditis is a major cause of heart disease in young patients and a common precursor of heart failure due to dilated cardiomyopathy. Some auto-immune and/or auto-inflammatory diseases may be accompanied by myocarditis, such as sarcoidosis, Behcet's disease, eosinophilic granulomatosis with polyangiitis, myositis, and systemic lupus erythematosus. However, data concerning myocarditis in such auto-immune and/or auto-inflammatory diseases are sparse. New therapeutic strategies should better target the modulation of the immune system, depending on the phase of the disease and the type of underlying auto-immune and/or auto inflammatory disease. PMID- 28572051 TI - Late-onset Rasmussen Encephalitis: A literature appraisal. AB - Rasmussen Encephalitis (RE) is classically described as a childhood encephalopathy due to a unilateral inflammation of the cerebral cortex with a presumed immune-mediated pathophysiological basis. Unusual variant forms, including adolescent and adult-onset RE have been described but there is still a doubt whether these atypical cases correspond to classical RE patients. To review evidence, a systematic PubMed search was conducted to retrieve papers addressing late onset RE to assess (i) the positivity rate of classical childhood-onset diagnostic criteria for RE in late-onset RE, (ii) the specific clinical and radiological features that could help earlier diagnosis and therapeutic interventions, (iii) the arguments for an autoimmune pathophysiology including (iiia) the association with autoimmune markers or diseases and (iiib) the effects of immunomodulatory or immunosuppressive treatments. A total of 50 papers were considered. We identified 102 late-onset RE patients with a sex ratio of 8 women for 2 men. 67% fulfilled the consensus diagnostic criteria for RE. As compared to classical RE, the late-onset RE patients exhibited: i) more frequent focal complex partial seizures, ii) less frequent epilepsia partialis continua throughout evolution, iii) a slower evolution with a delayed occurrence of cortical deficit, iv) less cognitive deterioration and v) a better outcome. A specific association with autoimmune markers or diseases was not found. Immunomodulatory therapies, even performed in a late stage, improved late-onset RE patients in 61% of cases. This review proves that late-onset RE is a reality with specific clinical and radiological features. The good response to immunomodulatory treatments brings further arguments for an immune-regulated process. PMID- 28572052 TI - Hematopoietic stem cell transplantation in autoimmune disorders: From immune regulatory processes to clinical implications. AB - Autoimmune diseases are characterized by the development of autoreactive T- and B cells targeting self-antigens, which eventually can result in chronic and persistent organ damage. The autologous hematopoietic stem cell transplantation (AHSCT) opened new avenues in the treatment of patients with severe, treatment resistant autoimmune diseases. This paper reviews the immune-regulatory mechanisms behind AHSCT, and also summarizes the experiences of clinical practice related to the therapy in organ-specific and systemic autoimmune diseases. It seems that the intricate interplay of various immune competent cells with regulatory capacity control in a synergistic manner the repopulated immune system after AHSCT, which potentially leads to a significant clinical improvement in certain autoimmune diseases. However, the widespread use of AHSCT was intrinsically limited, due to the serious side-effects of conditioning treatment and relatively high treatment-related mortality; moreover, the development of new effective and safe therapeutic approaches and the dawn of biological agents further limited its indications in the last decade. Nevertheless, with an appropriate patient selection and increased experience of transplant centres, the risks can be minimized, and AHSCT remained still a reasonable choice in multiple sclerosis and systemic sclerosis when the conventional therapy failed and further progression of disease is inevitable. PMID- 28572053 TI - Auto-antibodies and cancer in systemic sclerosis. PMID- 28572055 TI - Estrogen regulates spatially distinct cardiac mitochondrial subpopulations. AB - Increased susceptibility to permeability transition pore (mPTP) is a significant concern to decreased cardiac performance in postmenopausal females. The goal of this study was to assess the effects of estrogen deficiency on the two spatially distinct mitochondrial subpopulations from left ventricle: subsarcolemmal mitochondria (SSM) and intermyofibrillar mitochondria (IFM) based on: morphology, membrane potential, oxidative phosphorylation, mPTP and reactive oxygen species production. Female rats (8weeks old) that underwent bilateral ovariectomy were randomly assigned to receive daily treatment with placebo (OVX), estrogen replacement (OVX+E2) and Sham for 60days. The yield for IFM was found higher in the OVX group and lower in the SSM. SSM internal complexity and size were higher in the OVX group, although membrane potential was not different. The maximal rate of mitochondrial respiration, states 3 and 4, using glutamate+malate as substrate, were higher in IFM and SSM from the OVX group. The respiratory control ratio (RCR - state3/state 4), was not different in both SSM and IFM with glutamate+malate. The ADP:O ratio was found lower in IFM and SSM from OVX compared to Sham. When pyruvate was used, state 3 was found unchanged in both IFM and SSM, state 4 was greater in IFM from OVX rats compared to Sham and the ADP/O ratio was decreased. The RCR was unchanged in both subpopulations. The IFM from OVX rats presented a lower Ca2+retention capacity compared to Sham, however, the SSM remained unchanged. Hydrogen peroxide formation was found increased in the IFM from OVX animals with glutamate+malate and rotenone+succinate as substrates. The SSM showed increased ROS production only with rotenone+succinate. Western blot analyzes showed decreased levels of PGC-1alpha and NRF-1 in the OVX group. Estrogen replacement was able to restore most of the alterations induced by ovariectomy. In conclusion, our data shows that estrogen deficiency has distinct effects on the two spatially distinct mitochondrial subpopulations in oxidative phosphorylation, morphology, calcium retention capacity and ROS production. PMID- 28572057 TI - Transcranial direct current stimulation (tDCS) to improve naming ability in post stroke aphasia: A critical review. AB - PURPOSE: Transcranial Direct Current Stimulation (tDCS) is a non-invasive neuromodulation tool that can be used to influence cortical brain activity to induce measurable behavioral changes. Although there is growing evidence that tDCS combined with behavioural language therapy could boost language recovery in patients with post-stroke aphasia, there is great variability in patient characteristics, treatment protocols, and outcome measures in these studies that poses challenges for analyzing the evidence. The purpose of this study is to critically analyze the methodological rigor of the evidence regarding the use of tDCS for post-stroke anomia. METHOD: This critical review was conducted by searching four databases (MEDLINE, EMBase, PsycINFO, and CINAHL). Nineteen studies fully met the inclusion criteria. Three critical appraisal tools and Robey and Schultz's (1998) five- phase model for conducting clinical outcome research were adopted to evaluate and analyze the current level of evidence. Methodological issues of the studies were also identified. RESULTS: The current level of evidence for using tDCS for anomia is at the pre-efficacy level with emerging evidence at the efficacy level. Lack of proper evaluation of carry-over effects in cross-over studies, lack of or unclear randomization, allocation concealment, and incomplete data handling were the main methodological issues that could threaten the validity of the tDCS for anomia studies. CONCLUSIONS: Several methodological issues have been identified in pre-efficacy studies that pose challenges in determining whether tDCS is a beneficial adjunct to behavioral aphasia therapy. Future studies need to improve the quality of the methods used to investigate the effect of tDCS for anomia. PMID- 28572056 TI - Effects of exercise on depressive behavior and striatal levels of norepinephrine, serotonin and their metabolites in sleep-deprived mice. AB - Exercise is a promising adjunctive therapy for depressive behavior, sleep/wake abnormalities, cognition and motor dysfunction. Conversely, sleep deprivation impairs mood, cognition and functional performance. The objective of this study is to evaluate the effects of exercise on anxiety and depressive behavior and striatal levels of norepinephrine (NE), serotonin and its metabolites in mice submitted to 6h of total sleep deprivation (6h-TSD) and 72h of Rapid Eye Movement (REM) sleep deprivation (72h-REMSD). Experimental groups were: (1) mice submitted to 6h-TSD by gentle handling; (2) mice submitted to 72h-REMSD by the flower pot method; (3) exercise (treadmill for 8 weeks); (4) exercise followed by 6h-TSD; (5) exercise followed by 72h-REMSD; (6) control (home cage). Behavioral tests included the Elevated Plus Maze and tail-suspension. NE, serotonin and its metabolites were determined in the striatum using high-performance liquid chromatography (HPLC). Sleep deprivation increased depressive behavior (time of immobilization in the tail-suspension test) and previous exercise hindered it. Sleep deprivation increased striatal NE and previous exercise reduced it. Exercise only was associated with higher levels of serotonin. Furthermore, exercise reduced serotonin turnover associated with sleep deprivation. In brief, previous exercise prevented depressive behavior and reduced striatal high NE levels and serotonin turnover. The present findings confirm the effects of exercise on behavior and neurochemical alterations associated with sleep deprivation. These findings provide new avenues for understanding the mechanisms of exercise. PMID- 28572054 TI - Targeting the programmed cell death-1 pathway in rheumatoid arthritis. AB - Since the introduction of TNF-alpha inhibitors and other biologic agents, the clinical outcome for many treated rheumatoid arthritis patients has significantly improved. However, there are still a substantial proportion of patients that are intolerant, or have inadequate responses, with current agents that have become the standards of care. While the majority of these agents are designed to affect the inflammatory features of the disease, there are also agents in the clinic that instead target lymphocyte subsets (e.g., rituximab) or interfere with lymphocyte co-receptor signaling pathways (e.g., abatacept). Due in part to their ability to orchestrate downstream inflammatory responses that lead to joint damage and disease progression, pathogenic expansions of T and B lymphocytes are appreciated to play key roles in the pathogenesis of rheumatoid arthritis. New insights into immune regulation have suggested novel approaches for the pharmacotherapeutic targeting of lymphocytes. In this review, we discuss deepening insights into human genetics and our understanding of the interface with rheumatoid arthritis pathogenesis providing a strong rationale for exploiting the co-inhibitory receptor programmed cell death-1 signaling pathway as a better approach for the treatment of this chronic, often progressive destructive joint disease. PMID- 28572058 TI - Behavioral, inflammatory and neurochemical disturbances in LPS and UCMS-induced mouse models of depression. AB - The immuno-inflammatory activation triggered by various stresses play an important role in pathophysiology of depression. The immune responses display differential pathological characters in different stresses. However, comparative data and analysis on behavioural, inflammatory and neurochemical changes in different stress-induced depression is limited. To imitate different stressful situations, in this study, mice were subjected to a single injection of LPS (0.5 mg/kg, i.p.) and UCMS (4 week period), respectively. LPS-stressed mice showed more immobility time in FST and TST, as well as more time in periphery in OFT than UCMS-stressed mice. Further, LPS-stressed mice showed robuster expression and release of TNF-alpha, IL-1beta and IL-6 in serum and depression-related brain areas (prefrontal cortex, hippocampus and striatum) as compared to UCMS-stressed mice. The ELISA results showed that IDO expression was significantly increased following LPS and UCMS stresses, but more increased IDO expression was observed in prefrontal cortex and hippocampus of LPS-stressed mice. The decrease of 5-HT and BDNF was detected only in hippocampus of LPS-stressed mice, but in overall all the brain areas assessed in UCMS-stressed mice as compared to control. The data indicate that LPS induced more severe depressive-like behaviours and robuster immune activation than UCMS. Our study strongly imply that hippocampus is relatively more vulnerable to acute inflammatory challenge in depression, while chronic psychological stress is more likely to cause the multidimensional symptoms of clinical depression. Our findings provide more insight into pathophysiology in various stress-induced depression and also implicate a potential suitability of different stress models. PMID- 28572060 TI - Multifocal tDCS targeting the resting state motor network increases cortical excitability beyond traditional tDCS targeting unilateral motor cortex. AB - Scientists and clinicians have traditionally targeted single brain regions with stimulation to modulate brain function and disease. However, brain regions do not operate in isolation, but interact with other regions through networks. As such, stimulation of one region may impact and be impacted by other regions in its network. Here we test whether the effects of brain stimulation can be enhanced by simultaneously targeting a region and its network, identified with resting state functional connectivity MRI. Fifteen healthy participants received two types of transcranial direct current stimulation (tDCS): a traditional two-electrode montage targeting a single brain region (left primary motor cortex [M1]) and a novel eight-electrode montage targeting this region and its associated resting state network. As a control, 8 participants also received multifocal tDCS mismatched to this network. Network-targeted tDCS more than doubled the increase in left M1 excitability over time compared to traditional tDCS and the multifocal control. Modeling studies suggest these results are unlikely to be due to tDCS effects on left M1 itself, however it is impossible to completely exclude this possibility. It also remains unclear whether multifocal tDCS targeting a network selectively modulates this network and which regions within the network are most responsible for observed effects. Despite these limitations, network-targeted tDCS appears to be a promising approach for enhancing tDCS effects beyond traditional stimulation targeting a single brain region. Future work is needed to test whether these results extend to other resting state networks and enhance behavioral or therapeutic effects. PMID- 28572061 TI - Functional organization of the face-sensitive areas in human occipital-temporal cortex. AB - Human occipital-temporal cortex features several areas sensitive to faces, presumably forming the biological substrate for face perception. To date, there are piecemeal insights regarding the functional organization of these regions. They have come, however, from studies that are far from homogeneous with regard to the regions involved, the experimental design, and the data analysis approach. In order to provide an overall view of the functional organization of the face sensitive areas, it is necessary to conduct a comprehensive study that taps into the pivotal functional properties of all the face-sensitive areas, within the context of the same experimental design, and uses multiple data analysis approaches. In this study, we identified the most robustly activated face sensitive areas in bilateral occipital-temporal cortices (i.e., AFP, aFFA, pFFA, OFA, pcSTS, pSTS) and systemically compared their regionally averaged activation and multivoxel activation patterns to 96 images from 16 object categories, including faces and non-faces. This condition-rich and single-image analysis approach critically samples the functional properties of a brain region, allowing us to test how two basic functional properties, namely face-category selectivity and face-exemplar sensitivity are distributed among these regions. Moreover, by examining the correlational structure of neural responses to the 96 images, we characterize their interactions in the greater face-processing network. We found that (1) r-pFFA showed the highest face-category selectivity, followed by l-pFFA, bilateral aFFA and OFA, and then bilateral pcSTS. In contrast, bilateral AFP and pSTS showed low face-category selectivity; (2) l-aFFA, l-pcSTS and bilateral AFP showed evidence of face-exemplar sensitivity; (3) r-OFA showed high overall response similarities with bilateral LOC and r-pFFA, suggesting it might be a transitional stage between general and face-selective information processing; (4) r-aFFA showed high face-selective response similarity with r-pFFA and r-OFA, indicating it was specifically involved in processing face information. Results also reveal two properties of these face sensitive regions across the two hemispheres: (1) the averaged left intra-hemispheric response similarity for the images was lower than the averaged right intra-hemispheric and the inter hemispheric response similarity, implying convergence of face processing towards the right hemisphere, and (2) the response similarities between homologous regions in the two hemispheres decreased as information processing proceeded from the early, more posterior, processing stage (OFA), indicating an increasing degree of hemispheric specialization and right hemisphere bias for face information processing. This study contributes to an emerging picture of how faces are processed within the occipital and temporal cortex. PMID- 28572059 TI - Linking dopaminergic reward signals to the development of attentional bias: A positron emission tomographic study. AB - The attention system is shaped by reward history, such that learned reward cues involuntarily draw attention. Recent research has begun to uncover the neural mechanisms by which learned reward cues compete for attention, implicating dopamine (DA) signaling within the dorsal striatum. How these elevated priority signals develop in the brain during the course of learning is less well understood, as is the relationship between value-based attention and the experience of reward during learning. We hypothesized that the magnitude of the striatal DA response to reward during learning contributes to the development of a learned attentional bias towards the cue that predicted it, and examined this hypothesis using positron emission tomography with [11C]raclopride. We measured changes in dopamine release for rewarded versus unrewarded visual search for color-defined targets as indicated by the density and distribution of the available D2/D3 receptors. We then tested for correlations of individual differences in this measure of reward-related DA release to individual differences in the degree to which previously reward-associated but currently task-irrelevant stimuli impair performance in an attention task (i.e., value driven attentional bias), revealing a significant relationship in the right anterior caudate. The degree to which reward-related DA release was right hemisphere lateralized was also predictive of later attentional bias. Our findings provide support for the hypothesis that value-driven attentional bias can be predicted from reward-related DA release during learning. PMID- 28572064 TI - Taking Stock. PMID- 28572062 TI - The United Kingdom Diabetic Retinopathy Electronic Medical Record Users Group: Report 3: Baseline Retinopathy and Clinical Features Predict Progression of Diabetic Retinopathy. AB - PURPOSE: To determine the time and risk factors for developing proliferative diabetic retinopathy (PDR) and vitreous hemorrhage (VH). DESIGN: Multicenter, national cohort study. METHODS: Anonymized data of 50 254 patient eyes with diabetes mellitus at 19 UK hospital eye services were extracted at the initial and follow-up visits between 2007 and 2014. Time to progression of PDR and VH were calculated with Cox regression after stratifying by baseline diabetic retinopathy (DR) severity and adjusting for age, sex, race, and starting visual acuity. RESULTS: Progression to PDR in 5 years differed by baseline DR: no DR (2.2%), mild (13.0%), moderate (27.2%), severe nonproliferative diabetic retinopathy (NPDR) (45.5%). Similarly, 5-year progression to VH varied by baseline DR: no DR (1.1%), mild (2.9%), moderate (7.3%), severe NPDR (9.8%). Compared with no DR, the patient eyes that presented with mild, moderate, and severe NPDR were 6.71, 14.80, and 28.19 times more likely to develop PDR, respectively. In comparison to no DR, the eyes with mild, moderate, and severe NPDR were 2.56, 5.60, and 7.29 times more likely to develop VH, respectively. In severe NPDR, the eyes with intraretinal microvascular abnormalities (IRMA) had a significantly increased hazard ratio (HR) of developing PDR (HR 1.77, 95% confidence interval [CI] 1.25-2.49, P = .0013) compared with those with venous beading, whereas those with 4-quadrant dot-blot hemorrhages (4Q DBH) had 3.84 higher HR of developing VH (95% CI 1.39-10.62, P = .0095). CONCLUSIONS: Baseline severities and features of initial DR are prognostic for PDR development. IRMA increases risk of PDR whereas 4Q DBH increases risk of VH. PMID- 28572063 TI - Pattern of Local Recurrence After I-125 Episcleral Brachytherapy for Uveal Melanoma in a Spanish Referral Ocular Oncology Unit. AB - PURPOSE: To describe the time, frequency, and clinical characteristics of treatment failure after I-125 brachytherapy in patients with uveal melanoma treated and followed in a Spanish referral ocular oncology unit. DESIGN: Prospective, consecutive, interventional case series. METHODS: Patients diagnosed with uveal melanoma from 1995 to 2016 and treated with episcleral brachytherapy were included. Demographic data collection, ophthalmic evaluation, ultrasound scan, and systemic studies were performed at baseline, every 6 months thereafter for 5 years, and subsequently at annual intervals. Recurrence was defined as presence of tumor growth after treatment. Baseline analysis was performed by descriptive methods and survival by Kaplan-Meier curves. RESULTS: From 732 patients diagnosed with uveal melanoma, 311 were treated with brachytherapy. In the follow-up (mean 79 months, standard deviation = 55), 16 local tumor recurrences (5.1%) were detected. All relapsing patients had choroidal tumors and 15 presented with visual symptoms. All patients were treated with I-125 brachytherapy, and 2 received associated transpupillary thermotherapy. All the eyes were enucleated after recurrence. Kaplan-Meier analysis showed a mean time of recurrence of 3.7 years (standard deviation = 2.94 years, ranging from 1 to 12 years). Three patients had metastasis in the follow-up. Kaplan-Meier analysis showed worse survival for patients with recurrence. CONCLUSION: Local treatment failure was a relatively infrequent event after I-125 brachytherapy in our series. Recurrences appear not only early but also late in the follow-up. They do not have a distinctive clinical pattern and are associated with poorer survival. PMID- 28572065 TI - Optimal Eligibility Criteria for Trials in Heart Failure With Preserved Ejection Fraction. PMID- 28572067 TI - Texture-dependent effects of pseudo-chewing sound on perceived food texture and evoked feelings in response to nursing care foods. AB - Because chewing sounds influence perceived food textures, unpleasant textures of texture-modified diets might be improved by chewing sound modulation. Additionally, since inhomogeneous food properties increase perceived sensory intensity, the effects of chewing sound modulation might depend on inhomogeneity. This study examined the influences of texture inhomogeneity on the effects of chewing sound modulation. Three kinds of nursing care foods in two food process types (minced-/pureed-like foods for inhomogeneous/homogeneous texture respectively) were used as sample foods. A pseudo-chewing sound presentation system, using electromyogram signals, was used to modulate chewing sounds. Thirty healthy elderly participants participated in the experiment. In two conditions with and without the pseudo-chewing sound, participants rated the taste, texture, and evoked feelings in response to sample foods. The results showed that inhomogeneity strongly influenced the perception of food texture. Regarding the effects of the pseudo-chewing sound, taste was less influenced, the perceived food texture tended to change in the minced-like foods, and evoked feelings changed in both food process types. Though there were some food-dependent differences in the effects of the pseudo-chewing sound, the presentation of the pseudo-chewing sounds was more effective in foods with an inhomogeneous texture. In addition, it was shown that the pseudo-chewing sound might have positively influenced feelings. PMID- 28572066 TI - Validation of prospective portion size and latency to eat as measures of reactivity to snack foods. AB - In experimental studies that investigate reactivity to the sight and smell of highly palatable snack foods, ad libitum food intake is commonly used as a behavioural outcome measure. However, this measure has several drawbacks. The current study investigated two intake-related measures not yet validated for food cue exposure research involving common snack foods: prospective portion size and latency to eat. We aimed to validate these measures by assessing prospective portion size and eating latencies in female undergraduate students who either underwent snack food exposure or a control exposure. Furthermore, we correlated prospective portion size and latency to eat with commonly used measures of food cue reactivity, i.e., self-reported desire to eat, salivation, and ad libitum food intake. Results showed increases in prospective portion size after food cue exposure but not after control exposure. Latency to eat did not differ between the two conditions. Prospective portion size correlated positively with desire to eat and food intake, and negatively with latency to eat. Latency to eat was also negatively correlated with desire to eat and food intake. It is concluded that the current study provides initial evidence for the prospective portion size task as a valid measure of reactivity to snack foods in a Dutch female and mostly healthy weight student population. PMID- 28572068 TI - Seeing is doing. The implicit effect of TV cooking shows on children's use of ingredients. AB - Prior research has established that TV viewing and food marketing influence children's eating behavior. However, the potential impact of popular TV cooking shows has received far less attention. TV cooking shows may equally affect children's food selection and consumption by distributing both food cues and portion-size cues. In an experimental study, elementary school children were randomly exposed to a cooking show, that either did or did not display a portion size cue, or a non-food TV show. Results showed that children used significantly more sugar on their pancakes, and consumed significantly more of the pancakes after watching a TV cooking show compared to a non-food TV show. However, observing a portion-size cue in a TV cooking show only influenced sugar selection in older children (5th grade), but not in younger children (1st grade). The findings suggest that food cues in TV cooking shows stimulate consumption by inducing food cravings in children. Actual portion-size cues only appeared to affect older children's food selection. PMID- 28572069 TI - Consumption of dark chocolate attenuates subsequent food intake compared with milk and white chocolate in postmenopausal women. AB - BACKGROUND: Chocolate has a reputation for contributing to weight gain due to its high fat, sugar and calorie content. However, the effect of varying concentrations of cocoa in chocolate on energy intake and appetite is not clear. OBJECTIVE: To compare the acute effect of consuming an isocaloric dose of dark, milk and white chocolate on subsequent energy intake, appetite and mood in postmenopausal women. METHODS: Fourteen healthy postmenopausal women (57.6 +/- 4.8yr) attended an introductory session followed by three experimental trials performed in a counterbalanced order at a standardised time of day, each separated by one week. Ad libitum energy intake, perceived appetite, mood and appetite-related peptides were assessed in response to consumption of 80% cocoa [dark chocolate], 35% cocoa [milk chocolate] and cocoa butter [white chocolate] (2099 kJ), prepared from a single-origin cacao bean. RESULTS: Ad libitum energy intake was significantly lower following dark (1355 +/- 750 kJ) compared with both milk (1693 +/- 969 kJ; P = 0.008) and white (1842 +/- 756 kJ; P = 0.001) chocolate consumption. Blood glucose and insulin concentrations were transiently elevated in response to white and milk chocolate consumption compared with the dark chocolate (P < 0.05), while pancreatic polypeptide was elevated in response to higher cocoa content chocolate (dark and milk) compared with white chocolate (P < 0.05). No differences in active ghrelin or leptin were observed between conditions, nor was mood altered between conditions (P > 0.05). CONCLUSIONS: Dark chocolate attenuates subsequent food intake in postmenopausal women, compared to the impact of milk and white chocolate consumption. PMID- 28572070 TI - Class and eating: Family meals in Britain. AB - This paper examines social differentiation in eating patterns in Britain. It focuses on family meals among individuals with under-age children. Eating with family members has been associated with improvement in wellbeing, nutritional status, and school performance of the children. Modern lifestyles may pose a challenge to commensal eating for all groups, but the scale of the impact varies between social classes, with some groups at higher risk of shortening or skipping family meal time. Eating patterns are differentiated by individual's social class; they have also been associated with educational attainment, work schedules, and household composition. The objective of this study is to disaggregate the effect of these variables. Using data from the 2014/2015 UK Time Use Survey I analyse the net effect of social class, education, income, work and family characteristics on the frequency and duration of family meals. Individuals in the highest occupational class dedicate more time overall to family meals. However, class effect becomes insignificant when other variables, such as education or income, are controlled for. This study finds that higher educated individuals have more frequent family meals, and more affluent individuals spend more time at the table with their household members. Work characteristics are associated with frequency of meals, but not with their duration. Finally, household composition matters for how people eat. Parents of younger children eat with their family members more frequently than parents of teenagers. Single parents, a notoriously time-poor category, spend the least amount of time eating with their families and have fewer commensal meals. PMID- 28572071 TI - Social approval bias in self-reported fruit and vegetable intake after presentation of a normative message in college students. AB - OBJECTIVE: To determine the accuracy of self-reported data regarding Fruit and Vegetable (FV) intake in college students at Utah State University after being presented with a descriptive normative message. INTERVENTION: Participants (N = 167) were recruited from general education courses and asked to complete a baseline survey containing a FV screener from the National Cancer Institute. They were then randomized to receive one of four messages one week after the initial survey and asked to immediately complete the same FV screener. The Control group received no FV message. The Recommendation group received a message that the recommendation for FV is 4-5 cups per day. The two normative groups received a message that either 80% of students ate more (Low) or less (High) FV than they did, regardless of actual intake, in addition to the recommended intake. ANALYSIS: Repeated measures ANOVA was used to assess differences in reported FV intake and perceived FV intake of peers between the first and second assessment. RESULTS AND CONCLUSIONS: Those receiving the message that they were in the lowest 20th percentile of intake reported a half-cup increase in self-reported FV intake and a one-cup increase in perception of peers' intake (p = 0.037 and p=<0.001, respectively). No significant differences were observed in other groups. These results indicate that normative messaging may influence self-reported FV intake and perception of peer intake of college students when this message indicates that the participant is in the lowest percentile of their peers. PMID- 28572073 TI - Tigecycline treatment in an infant with extensively drug-resistant Acinetobacter baumannii bacteremia. AB - The successful use of tigecycline in a 12-month old liver transplant recipient with extensively drug-resistant Acinetobacter baumannii bacteremia is presented. Tigecycline serum concentrations were monitored to help improve antibiotic efficacy and minimize side effects. A literature review identified 11 additional pediatric cases of A. baumannii infection treated with tigecycline since 2011. Tigecycline treatment should be considered in children with extensively drug resistant bacterial infections. PMID- 28572072 TI - The critical role of cognitive-based trait differences in transcranial direct current stimulation (tDCS) suppression of food craving and eating in frank obesity. AB - Obesity remains a major public health concern and novel treatments are needed. Transcranial direct current stimulation (tDCS) is a neuromodulation technique shown to reduce food craving and consumption, especially when targeting the dorsolateral prefrontal cortex (DLPFC) with a right anode/left cathode electrode montage. Despite the implications to treat frank (non-bingeeating) obesity, no study has tested the right anode/left cathode montage in this population. Additionally, most tDCS appetite studies have not controlled for differences in traits under DLPFC control that may influence how well one responds to tDCS. Hence, N = 18 (10F/8M) adults with frank obesity completed the Dutch Eating Behavior Questionnaire-Restraint and Barratt Impulsiveness Scale, and received 20 min of 2 mA active tDCS and control tDCS session. Craving and eating was assessed at both sessions with a food photo "wanting" test and in-lab measures of total, preferred, and less-preferred kilocalories consumed of three highly palatable snack foods. While main effects of tDCS vs. control were not found, significant differences emerged when trait scores were controlled. tDCS reduced food craving in females with lower attention-type impulsiveness (p = 0.047), reduced preferred food consumption in males with lower intent to restrict calories (p = 0.024), and reduced total food consumption in males with higher non-planning-type impulsiveness (p = 0.009) compared to control tDCS. This is the first study to find significant reductions in food craving and consumption in a sample with frank obesity using the most popular tDCS montage in appetite studies. The results also highlight the cognitive-based heterogeneity of individuals with obesity and the importance of considering these differences when evaluating the efficacy of DLPFC-targeted tDCS in future studies aimed at treating obesity. PMID- 28572074 TI - Characterization of Variability in Toxicokinetics and Toxicodynamics of Tetrachloroethylene Using the Collaborative Cross Mouse Population. AB - BACKGROUND: Evaluation of interindividual variability is a challenging step in risk assessment. For most environmental pollutants, including perchloroethylene (PERC), experimental data are lacking, resulting in default assumptions being used to account for variability in toxicokinetics and toxicodynamics. OBJECTIVE: We quantitatively examined the relationship between PERC toxicokinetics and toxicodynamics at the population level to test whether individuals with increased oxidative metabolism are be more sensitive to hepatotoxicity following PERC exposure. METHODS: Male mice from 45 strains of the Collaborative Cross (CC) were orally administered a single dose of PERC (1,000 mg/kg) or vehicle (Alkamuls EL620) and euthanized at various time points (n = 1/strain/time). Concentration time profiles were generated for PERC and its primary oxidative metabolite trichloroacetate (TCA) in multiple tissues. Toxicodynamic phenotyping was also performed. RESULTS: Significant variability among strains was observed in toxicokinetics of PERC and TCA in every tissue examined. Based on area under the curve (AUC), the range of liver TCA levels spanned nearly an order of magnitude (~8-fold). Expression of liver cytochrome P4502E1 did not correlate with TCA levels. Toxicodynamic phenotyping revealed an effect of PERC on bodyweight loss, induction of peroxisome proliferator activated receptor-alpha (PPARalpha) regulated genes, and dysregulation of hepatic lipid homeostasis. Clustering was observed among a) liver levels of PERC, TCA, and triglycerides; b) TCA levels in liver and kidney; and c) TCA levels in serum, brain, fat, and lung. CONCLUSIONS: Using the CC mouse population model, we have demonstrated a complex and highly variable relationship between PERC and TCA toxicokinetics and toxicodynamics at the population level. https://doi.org/10.1289/EHP788. PMID- 28572076 TI - Puffy hand syndrome. PMID- 28572075 TI - Estimating Inorganic Arsenic Exposure from U.S. Rice and Total Water Intakes. AB - BACKGROUND: Among nonoccupationally exposed U.S. residents, drinking water and diet are considered primary exposure pathways for inorganic arsenic (iAs). In drinking water, iAs is the primary form of arsenic (As), while dietary As speciation techniques are used to differentiate iAs from less toxic arsenicals in food matrices. OBJECTIVES: Our goal was to estimate the distribution of iAs exposure rates from drinking water intakes and rice consumption in the U.S. population and ethnic- and age-based subpopulations. METHODS: The distribution of iAs in drinking water was estimated by population, weighting the iAs concentrations for each drinking water utility in the Second Six-Year Review data set. To estimate the distribution of iAs concentrations in rice ingested by U.S. consumers, 54 grain-specific, production-weighted composites of rice obtained from U.S. mills were extracted and speciated using both a quantitative dilute nitric acid extraction and speciation (DNAS) and an in vitro gastrointestinal assay to provide an upper bound and bioaccessible estimates, respectively. Daily drinking water intake and rice consumption rate distributions were developed using data from the What We Eat in America (WWEIA) study. RESULTS: Using these data sets, the Stochastic Human Exposure and Dose Simulation (SHEDS) model estimated mean iAs exposures from drinking water and rice were 4.2 MUg/day and 1.4 MUg/day, respectively, for the entire U.S. population. The Tribal, Asian, and Pacific population exhibited the highest mean daily exposure of iAs from cooked rice (2.8 MUg/day); the mean exposure rate for children between ages 1 and 2 years in this population is 0.104 MUg/kg body weight (BW)/day. CONCLUSIONS: An average consumer drinking 1.5 L of water daily that contains between 2 and 3 ng iAs/mL is exposed to approximately the same amount of iAs as a mean Tribal, Asian, and Pacific consumer is exposed to from rice. https://doi.org/10.1289/EHP418. BACKGROUND: Among nonoccupationally exposed U.S. residents, drinking water and diet are considered primary exposure pathways for inorganic arsenic (iAs). In drinking water, iAs is the primary form of arsenic (As), while dietary As speciation techniques are used to differentiate iAs from less toxic arsenicals in food matrices. OBJECTIVES: Our goal was to estimate the distribution of iAs exposure rates from drinking water intakes and rice consumption in the U.S. population and ethnic- and age-based subpopulations. METHODS: The distribution of iAs in drinking water was estimated by population, weighting the iAs concentrations for each drinking water utility in the Second Six-Year Review data set. To estimate the distribution of iAs concentrations in rice ingested by U.S. consumers, 54 grain-specific, production-weighted composites of rice obtained from U.S. mills were extracted and speciated using both a quantitative dilute nitric acid extraction and speciation (DNAS) and an in vitro gastrointestinal assay to provide an upper bound and bioaccessible estimates, respectively. Daily drinking water intake and rice consumption rate distributions were developed using data from the What We Eat in America (WWEIA) study. RESULTS: Using these data sets, the Stochastic Human Exposure and Dose Simulation (SHEDS) model estimated mean iAs exposures from drinking water and rice were [Formula: see text] and [Formula: see text], respectively, for the entire U.S. population. The Tribal, Asian, and Pacific population exhibited the highest mean daily exposure of iAs from cooked rice ([Formula: see text]); the mean exposure rate for children between ages 1 and 2 years in this population is [Formula: see text] body weight (BW)/day. CONCLUSIONS: An average consumer drinking 1.5 L of water daily that contains between 2 and [Formula: see text] is exposed to approximately the same amount of iAs as a mean Tribal, Asian, and Pacific consumer is exposed to from rice. https://doi.org/10.1289/EHP418. PMID- 28572077 TI - Assessment of adherence to malaria chemoprophylaxis in a French Navy frigate deployed in Southeast Asia. AB - During a 2-month mission in Southeast Asia, including numerous stopovers in coastal cities, the crew of a frigate of the French Navy received doxycycline for antimalarial prophylaxis. Adherence to this chemoprophylaxis was evaluated with an anonymous questionnaire distributed at the end of the malaria exposure period. The response rate was 74 % (72 crew members). Among them, 67 sailors felt they had received clear information about the risks of malaria. Overall, 19 (27 %) respondents reported adherence (one forgotten pill, by no more than 15 days), 18 (25 %) irregular adherence (one or more pills forgotten weekly or stopped during the mission), and 35 recognized that they had not taken the treatment. These results, in the light of recent international recommendations, suggest that strategies for the prevention of malaria without systematic use of chemoprophylaxis (personal vector protection measures, an "Army posture" strategy), would be more suitable for medicalized ships cruising in this area. PMID- 28572078 TI - The Effect of Core Stabilization Exercise on the Kinematics and Joint Coordination of the Lumbar Spine and Hip During Sit-to-Stand and Stand-to-Sit in Patients With Chronic Nonspecific Low Back Pain (COSCIOUS): Study Protocol for a Randomized Double-Blind Controlled Trial. AB - BACKGROUND: Chronic nonspecific low back pain (CNLBP) is among the most prevalent health problems. Lumbar spine and hips kinematics and coordination can be affected in CNLBP. The effects of exercises on the kinematics and coordination of lumbar spine and hips during sit-to-stand (STS) and its reverse have not been evaluated. OBJECTIVE: The aim of this study is to investigate the effect of core stabilization exercise on the kinematics and joint coordination of the lumbar spine and hip during STS and its reverse in CNLBP patients. METHODS: COSCIOUS is a parallel randomized double-blind controlled trial. A total of 30 CNLBP patients and 15 asymptomatic participants will be included. The kinematics and joint coordination of the lumbar spine and hips will be evaluated during STS and its reverse using a motion capture system. The participants will be asked to sit in their usual posture on a stool. Reflective markers will be placed over the T12, S2, anterior and posterior superior iliac spines, greater trochanters, and lateral femoral epicondyles of both legs. The participants will be instructed to stand up at natural speed, remain in the erect posture for 3 seconds, and then sit down. Kinematic variables of the lumbar spine and hip will be computed. Afterward, the CNLBP participants will be allocated at random to receive one of 2 interventions: core stabilization or general exercise. Treatment sessions will be held 3 times per week for 16 sessions. After intervention, CNLBP participants will be assessed again. RESULTS: Funding for the study was provided in 2016 by Iran University of Medical Sciences. The study is expected to last approximately 12 months, depending on recruitment. Findings on the study's primary outcomes are expected to be finalized by December 2017. The results of the study will be published in a peer-reviewed journal. CONCLUSIONS: This investigation will evaluate the effects of core stabilization exercise on the kinematics and joint coordination of the lumbar spine and hip during STS and its reverse in patients with CNLBP. In addition, the effects of CNLBP on STS and its reverse will be investigated in COSCIOUS. TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT2016080812953N2; http://en.search.irct.ir/view/32003?format=xml (Archived by WebCite at http://www.webcitation.org/6qjTWd4Az). PMID- 28572080 TI - George Lewith. PMID- 28572079 TI - Mobile Text Messaging to Improve Medication Adherence and Viral Load in a Vulnerable Canadian Population Living With Human Immunodeficiency Virus: A Repeated Measures Study. AB - BACKGROUND: Combination antiretroviral therapy (cART) as treatment for human immunodeficiency virus (HIV) infection is effective and available, but poor medication adherence limits benefits, particularly in vulnerable populations. In a Kenyan randomized controlled trial, a weekly text-messaging intervention (WelTel) improved cART adherence and HIV viral load (VL). Despite growing evidence for short message service (SMS) text-message interventions in HIV care, there is a paucity of data utilizing these interventions in marginalized or female cohorts. OBJECTIVE: This study was undertaken to assess whether the standardized WelTel SMS text-message intervention applied to a vulnerable, predominantly female, population improved cART adherence and VL. METHODS: We conducted a repeated measures study of the WelTel intervention in high-risk HIV positive persons by measuring change in VL, CD4 count, and self-reported adherence 12 months before and 12 months after the WelTel intervention was introduced. Inclusion criteria included VL >=200 copies/mL, indication for treatment, and meeting vulnerability criteria. Participants were given a mobile phone with unlimited texting (where required), and weekly check-in text messages were sent for one year from the WelTel computer platform. Clinical data were collected for control and intervention years. Participants were followed by a multidisciplinary team in a clinical setting. Outcomes were assessed using Wilcoxon signed ranks tests for change in CD4 and VL from control year to study end and mixed-effects logistic regressions for change in cART adherence and appointment attendance. A secondary analysis was conducted to assess the effect of response rate on the outcome by modeling final log10 VL by number of responses while controlling for mean log10 VL in the control year. RESULTS: Eighty-five participants enrolled in the study, but 5 withdrew (final N=80). Participants were predominantly female (90%, 72/80) with a variety of vulnerabilities. Mean VL decreased from 1098 copies/mL in the control year to 439 copies/mL at study end (P=.004). Adherence to cART significantly improved (OR 1.14, IQR 1.10-1.18; P<.001), whereas appointment attendance decreased slightly with the intervention (OR 0.81, IQR 0.67-0.99; P=.03). A response was received for 46.57% (1753/3764) of messages sent and 9.62% (362/3764) of text messages sent were replied to with a problem. An outcome analysis examining relationship between reply rate and VL did not meet statistical significance (P=.07), but may be worthy of investigating further in a larger study. CONCLUSIONS: WelTel may be an effective tool for improving cART adherence and reducing VLs among high-risk, vulnerable HIV positive persons. TRIAL REGISTRATION: Clinicaltrials.gov NCT02603536; https://clinicaltrials.gov/ct2/show/NCT02603536 (Archived by WebCite at http://www.webcitation.org/6qK57zCwv). PMID- 28572081 TI - Revisiting the diet-heart hypothesis: critical appraisal of the Minnesota Coronary Experiment. PMID- 28572082 TI - Rogue surgeon Paterson is sentenced to 15 years after performing unnecessary operations. PMID- 28572083 TI - Oatmeal particle size alters glycemic index but not as a function of gastric emptying rate. AB - The aim of this study was to determine the extent to which oat particle size in a porridge could alter glucose absorption, gastric emptying, gastrointestinal hormone response, and subjective feelings of appetite and satiety. Porridge was prepared from either oat flakes or oat flour with the same protein, fat, carbohydrate, and mass. These were fed to eight volunteers on separate days in a crossover study, and subjective appetite ratings, gastric contents, and plasma glucose, insulin, and gastrointestinal hormones were determined over a period of 3 h. The flake porridge gave a lower glucose response than the flour porridge, and there were apparent differences in gastric emptying in both the early and late postprandial phases. The appetite ratings showed similar differences between early- and late-phase behavior. The structure of the oat flakes remained sufficiently intact to delay their gastric emptying, leading to a lower glycemic response, even though initial gastric emptying rates were similar for the flake and flour porridge. This highlights the need to take food structure into account when considering relatively simple physiological measures and offering nutritional guidance.NEW & NOTEWORTHY The impact of food structure on glycemic response even in simple foods such as porridge is dependent on both timing of gastric emptying and the composition of what is emptied as well as duodenal starch digestion. Thus structure should be accounted for when considering relatively simple physiological measures and offering nutritional guidance. PMID- 28572084 TI - Ductular and proliferative response of esophageal submucosal glands in a porcine model of esophageal injury and repair. AB - Esophageal injury is a risk factor for diseases such as Barrett's esophagus (BE) and esophageal adenocarcinoma. To improve understanding of signaling pathways associated with both normal and abnormal repair, animal models are needed. Traditional rodent models of esophageal repair are limited by the absence of esophageal submucosal glands (ESMGs), which are present in the human esophagus. Previously, we identified acinar ductal metaplasia in human ESMGs in association with both esophageal injury and cancer. In addition, the SOX9 transcription factor has been associated with generation of columnar epithelium and the pathogenesis of BE and is present in ESMGs. To test our hypothesis that ESMGs activate after esophageal injury with an increase in proliferation, generation of a ductal phenotype, and expression of SOX9, we developed a porcine model of esophageal injury and repair using radiofrequency ablation (RFA). The porcine esophagus contains ESMGs, and RFA produces a consistent and reproducible mucosal injury in the esophagus. Here we present a temporal assessment of this model of esophageal repair. Porcine esophagus was evaluated at 0, 6, 18, 24, 48, and 72 h and 5 and 7 days following RFA and compared with control uninjured esophagus. Following RFA, ESMGs demonstrated an increase in ductal phenotype, echoing our prior studies in humans. Proliferation increased in both squamous epithelium and ESMGs postinjury with a prominent population of SOX9-positive cells in ESMGs postinjury. This model promises to be useful in future experiments evaluating mechanisms of esophageal repair.NEW & NOTEWORTHY A novel porcine model of injury and repair using radiofrequency ablation has been developed, allowing for reproducible injury to the esophagus to study repair in an animal model with esophageal submucosal glands, a key anatomical feature and missing in rodent models but possibly harboring progenitor cells. There is a strong translational component to this porcine model given the anatomical and physiological similarities between pigs and humans. PMID- 28572085 TI - CDX2 upregulates SLC26A3 gene expression in intestinal epithelial cells. AB - SLC26A3 [downregulated in adenoma (DRA)] plays a key role in mammalian intestinal NaCl absorption, in that it mediates apical membrane Cl-/[Formula: see text] exchange. DRA function and expression are significantly decreased in diarrhea associated with inflammatory bowel disease. DRA is also considered to be a marker of cellular differentiation and is predominantly expressed in differentiated epithelial cells. Caudal-type homeobox protein-2 (CDX2) is known to regulate genes involved in intestinal epithelial differentiation and proliferation. Reduced expression of both DRA and CDX2 in intestinal inflammation prompted us to study whether the DRA gene is directly regulated by CDX2. Our initial studies utilizing CDX2 knockout (CDX2fV/fV;Cre+) mice showed a marked reduction in DRA mRNA and protein levels in proximal and distal colon. In silico analysis of the DRA promoter showed two consensus sites for CDX2 binding. Therefore, we utilized Caco-2 cells as an in vitro model to examine if DRA is a direct target of CDX2 regulation. siRNA-mediated silencing of CDX2 in Caco-2 cells resulted in a marked (~50%) decrease in DRA mRNA and protein levels, whereas ectopic overexpression of CDX2 upregulated DRA expression and also stimulated DRA promoter activity, suggesting transcriptional regulation. Electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated direct binding of CDX2 to one of the two putative CDX2 binding sites in the DRA promoter (+645/+663). In summary, our studies, for the first time, demonstrate transcriptional regulation of DRA expression by CDX2, implying that reduced expression of DRA in inflammatory bowel disease-associated diarrhea may, in part, be due to downregulation of CDX2 in the inflamed mucosa.NEW & NOTEWORTHY SLC26A3 [downregulated in adenoma (DRA)] mediates intestinal luminal NaCl absorption and is downregulated in inflammatory bowel disease-associated diarrhea. Since both DRA and caudal-type homeobox protein-2 (CDX2) are reduced in intestinal inflammation and the DRA promoter harbors CDX2 binding sites, we examined whether the DRA gene is regulated by CDX2. Our studies, for the first time, demonstrate transcriptional regulation of DRA expression by CDX2 via direct binding to the DRA promoter, suggesting that reduced expression of DRA in inflammatory bowel disease-associated diarrhea could, in part, be attributed to downregulation of CDX2. PMID- 28572087 TI - Philip Michael John Tombleson. PMID- 28572088 TI - MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. PMID- 28572086 TI - Functional morphology of the lower esophageal sphincter and crural diaphragm determined by three-dimensional high-resolution esophago-gastric junction pressure profile and CT imaging. AB - The smooth muscles of the lower esophageal sphincter (LES) and skeletal muscles of the crural diaphragm (CD) provide a closure/antireflux barrier mechanism at the esophago-gastric junction (EGJ). A number of questions in regard to the pressure profile of the LES and CD remain unclear, e.g., 1) Why is the LES pressure profile circumferentially asymmetric, 2) Is the crural diaphragm (CD) contraction also circumferentially asymmetric, and 3) Where is the LES and CD pressure profile located in the anatomy of the esophagus and stomach? The three dimensional (3-D) high-resolution esophageal manometry (HRM) catheter can record a detailed profile of the EGJ pressure; however, it does not allow the determination of the circumferential orientation of individual pressure transducers in vivo. We used computed tomography (CT) scan imaging in combination with 3-D EGJ pressure recordings to determine the functional morphology of the LES and CD and its relationship to the EGJ anatomy. A 3-D-HRM catheter with 96 transducers (12 rings, 7.5 mm apart, located over 9-cm length of the catheter, with eight transducers in each ring, 45 degrees apart (Medtronics), was used to record the EGJ pressure in 10 healthy subjects. A 0.5-mm diameter metal ball (BB) was taped to the catheter, adjacent to transducer 1 of the catheter. The EGJ was recorded under the following conditions: 1) end-expiration (LES pressure) before swallow, after swallow, and after edrophonium hydrochloride; and 2) peak inspiration (crural diaphragm contraction) for tidal inspiration and forced maximal inspiration. A CT scan was performed to localize the circumferential orientation of the BB. The CT scan imaging allowed the determination of the circumferential orientation of the LES and CD pressure profiles. The LES pressure under the three end-expiration conditions were different; however, the shape of the pressure profile was unique with the LES length longer toward the lesser curvature of the stomach as compared with the greater curvature. The pressure profile revealed circular and axial pressure asymmetry, with greatest pressure and shortest cranio-caudal length on the left (close to the angle of His). The CD contraction with tidal and forced inspiration increases pressure in the cranial half of the LES pressure profile, and it was placed horizontally across the recording. The CD, esophagus, and stomach were outlined in the CT scan images to construct a 3-D anatomy of the region; it revealed that the hiatus (CD) is placed obliquely across the esophagus; however, because of the bend of the esophagus to the left at the upper edge of the hiatus, the two were placed at right angle to each other, which resulted in a horizontal pressure profile of the CD on the LES. Our observations suggest a unique shape of the LES, CD, and the anatomical relationship between the two, which provides a possible explanation as to why the LES pressure shows circumferential and axial asymmetry. Our findings have implication for the length and circumferential orientation of myotomy incision required for the ablation of LES pressure in achalasia esophagus.NEW & NOTEWORTHY We used computed tomography scan imaging with three-dimensional esophago-gastric junction (EGJ) pressure recordings to determine functional morphology of the lower esophageal sphincter (LES) and crural diaphragm and its relationship to EGJ anatomy. The LES pressure profile was unique with the LES length longer and pressures lower toward the lesser curvature of the stomach, as compared with the greater curvature. Our findings have implications for the length and circumferential orientation of myotomy incision required for the ablation of LES pressure in the achalasia esophagus. PMID- 28572089 TI - What happens when targets for waiting times change? PMID- 28572090 TI - GDF15 is a heart-derived hormone that regulates body growth. AB - The endocrine system is crucial for maintaining whole-body homeostasis. Little is known regarding endocrine hormones secreted by the heart other than atrial/brain natriuretic peptides discovered over 30 years ago. Here, we identify growth differentiation factor 15 (GDF15) as a heart-derived hormone that regulates body growth. We show that pediatric heart disease induces GDF15 synthesis and secretion by cardiomyocytes. Circulating GDF15 in turn acts on the liver to inhibit growth hormone (GH) signaling and body growth. We demonstrate that blocking cardiomyocyte production of GDF15 normalizes circulating GDF15 level and restores liver GH signaling, establishing GDF15 as a bona fide heart-derived hormone that regulates pediatric body growth. Importantly, plasma GDF15 is further increased in children with concomitant heart disease and failure to thrive (FTT). Together these studies reveal a new endocrine mechanism by which the heart coordinates cardiac function and body growth. Our results also provide a potential mechanism for the well-established clinical observation that children with heart diseases often develop FTT. PMID- 28572093 TI - Heart rhythm conundrum. PMID- 28572091 TI - The Ser/Thr Protein Kinase Protein-Protein Interaction Map of M. tuberculosis. AB - Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, the leading cause of death among all infectious diseases. There are 11 eukaryotic like serine/threonine protein kinases (STPKs) in Mtb, which are thought to play pivotal roles in cell growth, signal transduction and pathogenesis. However, their underlying mechanisms of action remain largely uncharacterized. In this study, using a Mtb proteome microarray, we have globally identified the binding proteins in Mtb for all of the STPKs, and constructed the first STPK protein interaction (KPI) map that includes 492 binding proteins and 1,027 interactions. Bioinformatics analysis showed that the interacting proteins reflect diverse functions, including roles in two-component system, transcription, protein degradation, and cell wall integrity. Functional investigations confirmed that PknG regulates cell wall integrity through key components of peptidoglycan (PG) biosynthesis, e.g. MurC. The global STPK-KPIs network constructed here is expected to serve as a rich resource for understanding the key signaling pathways in Mtb, thus facilitating drug development and effective control of Mtb. PMID- 28572095 TI - Vitamin D: Way More Important in Critical Care Than We May Have Recognized. PMID- 28572097 TI - Corrections. PMID- 28572096 TI - Corrections. PMID- 28572092 TI - Cylindromatosis Tumor Suppressor Protein (CYLD) Deubiquitinase is Necessary for Proper Ubiquitination and Degradation of the Epidermal Growth Factor Receptor. AB - Cylindromatosis tumor suppressor protein (CYLD) is a deubiquitinase, best known as an essential negative regulator of the NFkB pathway. Previous studies have suggested an involvement of CYLD in epidermal growth factor (EGF)-dependent signal transduction as well, as it was found enriched within the tyrosine phosphorylated complexes in cells stimulated with the growth factor. EGF receptor (EGFR) signaling participates in central cellular processes and its tight regulation, partly through ubiquitination cascades, is decisive for a balanced cellular homeostasis. Here, using a combination of mass spectrometry-based quantitative proteomic approaches with biochemical and immunofluorescence strategies, we demonstrate the involvement of CYLD in the regulation of the ubiquitination events triggered by EGF. Our data show that CYLD regulates the magnitude of ubiquitination of several major effectors of the EGFR pathway by assisting the recruitment of the ubiquitin ligase Cbl-b to the activated EGFR complex. Notably, CYLD facilitates the interaction of EGFR with Cbl-b through its Tyr15 phosphorylation in response to EGF, which leads to fine-tuning of the receptor's ubiquitination and subsequent degradation. This represents a previously uncharacterized strategy exerted by this deubiquitinase and tumors suppressor for the negative regulation of a tumorigenic signaling pathway. PMID- 28572098 TI - Prophylactic Acid-Suppressive Therapy in Hospitalized Adults: Indications, Benefits, and Infectious Complications. AB - Acid-suppressive therapy for prophylaxis of stress ulcer bleeding is commonly prescribed for hospitalized patients. Although its use in select, at-risk patients may reduce clinically significant gastrointestinal bleeding, the alteration in gastric pH and composition may place these patients at a higher risk of infection. Although any pharmacologic alteration of the gastric pH and composition is associated with an increased risk of infection, the risk appears to be highest with proton pump inhibitors, perhaps owing to the potency of this class of drugs in increasing the gastric pH. With the increased risk of infection, universal provision of pharmacologic acid suppression to all hospitalized patients, even all critically ill patients, is inappropriate and should be confined to patients meeting specific criteria. Nurses providing care in critical care areas may be instrumental in screening for appropriate use of acid-suppressive therapy and ensuring the drugs are discontinued upon transfer out of intensive care or when risk factors are no longer present. PMID- 28572099 TI - Nurse-Directed Blood Glucose Management in a Medical Intensive Care Unit. AB - BACKGROUND: Insulin-delivery algorithms for achieving glycemic control in the intensive care unit require frequent checks of blood glucose level and thus increase nursing workload. Hypoglycemia is a serious complication associated with intensive insulin therapy. OBJECTIVES: To evaluate a nurse-directed protocol for blood glucose management that allows individualized insulin delivery within a predefined blood glucose corridor, intended to avoid hypoglycemia while maintaining adequate control of blood glucose level without increasing nursing workload. METHODS: A nurse-directed protocol for blood glucose management was developed by an interprofessional team, and the protocol's performance was investigated in 175 patients compared with 384 historical controls. RESULTS: With the nurse-directed protocol, hypoglycemia incidents declined significantly (31% vs 12%, P < .001), and minimum blood glucose levels increased significantly (80 mg/dL vs 93 mg/dL, P < .001). Mean and maximum blood glucose levels, the proportion of glucose readings within the target range (31% vs 26%, P = .06), and the number of blood glucose checks (59 vs 58, P = .85) remained unchanged with use of the protocol. CONCLUSION: Implementation of the nurse-directed protocol for blood glucose management did not increase nursing workload but reduced hypoglycemia incidents significantly while maintaining adequate glycemic control. PMID- 28572100 TI - Decreasing Catheter-Associated Urinary Tract Infections in the Neurological Intensive Care Unit: One Unit's Success. AB - BACKGROUND: Catheter-associated urinary tract infections are preventable adverse outcomes that increase hospital morbidity, mortality, and costs. These infections are particularly prevalent in intensive care units. OBJECTIVES: To describe the success of an 18-bed neurological intensive care unit in using several nurse implemented strategies that reduced the number of catheter-associated urinary tract infections. METHODS: A prospective, interventional design with application of evidence-based practices to reduce catheter-associated urinary tract infections was used. RESULTS: Before implementation of the strategies, 40 catheter-associated urinary tract infections were reported for 2012 and 38 for 2013. The standardized infection ratio was 2.04 for 2012 (95% CI, 1.456-2.775) and 2.34 (95% CI, 1.522-3.312) for 2013. After implementation of the strategies, significantly fewer catheter-associated urinary tract infections were reported. In 2014, a total of 15 infections were reported, and the standardized infection ratio was less than 1.0 (95% CI, 0.685-1.900). CONCLUSIONS: Application of current evidence-based practices resulted in a substantial decrease in the number of catheter-associated urinary tract infections and a lower standardized infection ratio. These findings support current recommendations for "bundling" to maximize outcomes. PMID- 28572101 TI - Effect of pH Test-Strip Characteristics on Accuracy of Readings. AB - BACKGROUND: Little is known about characteristics of colorimetric pH test strips that are most likely to be associated with accurate interpretations in clinical situations. OBJECTIVES: To compare the accuracy of 4 pH test strips with varying characteristics (ie, multiple vs single colorimetric squares per calibration, and differing calibration units [1.0 vs 0.5]). METHODS: A convenience sample of 100 upper-level nursing students with normal color vision was recruited to evaluate the accuracy of the test strips. Six buffer solutions (pH range, 3.0 to 6.0) were used during the testing procedure. Each of the 100 participants performed 20 pH tests in random order, providing a total of 2000 readings. The sensitivity and specificity of each test strip was computed. In addition, the degree to which the test strips under- or overestimated the pH values was analyzed using descriptive statistics. RESULTS: Our criterion for correct readings was an exact match with the pH buffer solution being evaluated. Although none of the test strips evaluated in our study was 100% accurate at all of the measured pH values, those with multiple squares per pH calibration were clearly superior overall to those with a single test square. CONCLUSIONS: Test strips with multiple squares per calibration were associated with greater overall accuracy than test strips with a single square per calibration. However, because variable degrees of error were observed in all of the test strips, use of a pH meter is recommended when precise readings are crucial. PMID- 28572102 TI - Complementary Health Practitioners in the Acute and Critical Care Setting: Nursing Considerations. AB - In response to the rising demand by patients and their families for complementary health approaches, hospitals are increasingly integrating complementary health approaches with their conventional medical practices to create healing environments. Results of the 2010 Complementary and Alternative Medicine Survey of Hospitals indicated that the top 6 inpatient modalities included pet therapy, massage therapy, music or art therapy, guided imagery, relaxation therapy, and Reiki and therapeutic touch. Whether complementary health approaches are provided by complementary health practitioners through hospital-based integrative medicine programs, volunteer practitioners, or bedside nurses, the regulatory, legal, ethical, and safety concerns remain constant. Previous articles in this column of Critical Care Nurse provided an overview of complementary health approaches that nurses may encounter in their practices, with specific attention to implications for acute and critical care nurses, as well as important legal, ethical, safety, quality, and financial implications that acute and critical care nurses should consider when integrating complementary health approaches with conventional care. This column provides the acute and critical care nurse with key information about validation of credentials, experience, and competence of nurses and volunteers providing complementary health approaches, as well as about institutional policies and scope of practice. PMID- 28572103 TI - Interprofessional Team's Perception of Care Delivery After Implementation of a Pediatric Pain and Sedation Protocol. AB - BACKGROUND: Pain and agitation are common experiences of patients in pediatric cardiac intensive care units. Variability in assessments by health care providers, communication, and treatment of pain and agitation creates challenges in management of pain and sedation. OBJECTIVES: To develop guidelines for assessment and treatment of pain, agitation, and delirium in the pediatric cardiac intensive unit in an academic children's hospital and to document the effects of implementation of the guidelines on the interprofessional team's perception of care delivery and team function. METHODS: Before and after implementation of the guidelines, interprofessional team members were surveyed about the members' perception of analgesia, sedation, and delirium management RESULTS: Members of the interprofessional team felt more comfortable with pain and sedation management after implementation of the guidelines. Team members reported improvements in team communication on patients' comfort. Members thought that important information was less likely to be lost during transfer of care. They also noted that the team carried out comfort management plans and used pharmacological and nonpharmacological therapies better after implementation of the guidelines than they did before implementation. CONCLUSIONS: Guidelines for pain and sedation management were associated with perceived improvements in team function and patient care by members of the interprofessional team. PMID- 28572104 TI - Being Visible. PMID- 28572105 TI - Evidence-Based Practice: Percussion and Vibration Therapy. PMID- 28572110 TI - Prevention of Aspiration in Adults. PMID- 28572112 TI - Delirium in Children: Identification, Prevention, and Management. AB - Delirium in children is an often underrecognized but serious complication of hospitalization. Delirium in this age group has been described as behaviors such as refractory agitation and restlessness, visual or auditory hallucinations, children being "not themselves," and a lethargic state. Often, children with delirium are at risk for harming themselves by dislodging tubes, falling, or refusing care. Pediatric nurses must recognize and intervene to prevent and treat delirium in hospitalized children because the delirium may be an indicator of worsening clinical status and is associated with high mortality and morbidity in children of all ages and with posttraumatic stress disorder. Pediatric nurses are uniquely positioned to design care interventions to both reduce risk for delirium and treat active delirium. Many treatment recommendations are nonpharmacological and are part of excellent nursing care. PMID- 28572111 TI - Patients' Hand Washing and Reducing Hospital-Acquired Infection. AB - BACKGROUND: Hand hygiene is important to prevent hospital-acquired infections. Patients' hand hygiene is just as important as hospital workers' hand hygiene. Hospital-acquired infection rates remain a concern across health centers. OBJECTIVES: To improve patients' hand hygiene through the promotion and use of hand washing with soap and water, hand sanitizer, or both and improve patients' education to reduce hospital-acquired infections. METHODS: In August 2013, patients in a cardiothoracic postsurgical step-down unit were provided with individual bottles of hand sanitizer. Nurses and nursing technicians provided hand hygiene education to each patient. Patients completed a 6-question survey before the intervention, at hospital discharge and 1, 2, and 3 months after the intervention. Hospital-acquired infection data were tracked monthly by infection prevention staff. RESULTS: Significant correlations were found between hand hygiene and rates of infection with vancomycin-resistant enterococci (P = .003) and methicillin-resistant Staphylococcus aureus (P = .01) after the intervention. After the implementation of hand hygiene interventions, rates of both infections declined significantly and patients reported more staff offering opportunities for and encouraging hand hygiene. CONCLUSION: This quality improvement project demonstrates that increased hand hygiene compliance by patients can influence infection rates in an adult cardiothoracic step-down unit. The decreased infection rates and increased compliance with hand hygiene among the patients may be attributed to the implementation of patient education and the increased accessibility and use of hand sanitizer. PMID- 28572113 TI - Oral Care for Acutely and Critically Ill Patients. PMID- 28572114 TI - Prevention of Ventilator-Associated Pneumonia in Adults. PMID- 28572116 TI - KDM5A demethylase: Erasing histone modifications to promote repair of DNA breaks. AB - Repairing DNA breaks within the complexity of the cell chromatin is challenging. In this issue, Gong et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201611135) identify the histone demethylase KDM5A as a critical editor of the cells' "histone code" that is required to recruit DNA repair complexes to DNA breaks. PMID- 28572115 TI - Histone demethylase KDM5A regulates the ZMYND8-NuRD chromatin remodeler to promote DNA repair. AB - Upon DNA damage, histone modifications are dynamically reshaped to accommodate DNA damage signaling and repair within chromatin. In this study, we report the identification of the histone demethylase KDM5A as a key regulator of the bromodomain protein ZMYND8 and NuRD (nucleosome remodeling and histone deacetylation) complex in the DNA damage response. We observe KDM5A-dependent H3K4me3 demethylation within chromatin near DNA double-strand break (DSB) sites. Mechanistically, demethylation of H3K4me3 is required for ZMYND8-NuRD binding to chromatin and recruitment to DNA damage. Functionally, KDM5A deficiency results in impaired transcriptional silencing and repair of DSBs by homologous recombination. Thus, this study identifies a crucial function for KDM5A in demethylating H3K4 to allow ZMYND8-NuRD to operate within damaged chromatin to repair DSBs. PMID- 28572117 TI - Dynein is regulated by the stability of its microtubule track. AB - How dynein motors accurately move cargoes is an important question. In budding yeast, dynein moves the mitotic spindle to the predetermined site of cytokinesis by pulling on astral microtubules. In this study, using high-resolution imaging in living cells, we discover that spindle movement is regulated by changes in microtubule plus-end dynamics that occur when dynein generates force. Mutants that increase plus-end stability increase the frequency and duration of spindle movements, causing positioning errors. We find that dynein plays a primary role in regulating microtubule dynamics by destabilizing microtubules. In contrast, the dynactin complex counteracts dynein and stabilizes microtubules through a mechanism involving the shoulder subcomplex and the cytoskeletal-associated protein glycine-rich domain of Nip100/p150glued Our results support a model in which dynein destabilizes its microtubule substrate by using its motility to deplete dynactin from the plus end. We propose that interplay among dynein, dynactin, and the stability of the microtubule substrate creates a mechanism that regulates accurate spindle positioning. PMID- 28572119 TI - Right ventricular dyssynchrony and exercise capacity in idiopathic pulmonary arterial hypertension. AB - Survival in patients with pulmonary arterial hypertension (PAH) is determined by right ventricular (RV) function adaptation to afterload. How altered RV function impacts on exercise capacity in PAH is not exactly known.104 idiopathic PAH (IPAH) patients aged 52+/-14 years underwent a diagnostic right heart catheterisation, a comprehensive echocardiography including two-dimensional speckle tracking for RV dyssynchrony evaluation and a cardiopulmonary exercise test. Multivariate analyses were performed to identify independent predictors of peak oxygen uptake (peak V'O2 ).A first multivariate analysis of only resting haemodynamic variables identified cardiac index, right atrial (RA) pressure and pulmonary arterial compliance as independent predictors, with low predictive capacity (r2=0.31; p<0.001). A second multivariate analysis model which considered only echocardiographic parameters but without RV dyssynchrony, identified RV fractional area change (FAC) and RA area as independent predictors with still low predictivity (r2=0.35; p<0.001). Adding RV dyssynchrony to the second model increased its predictivity (r2=0.48; p<0.001). Repetition of the three multivariate analyses in patients with preserved RVFAC confirmed that inclusion of RV dyssynchrony results in the highest predictive capability of peak V'O2 (r2=0.53; p=0.001).A comprehensive echocardiography with speckle tracking derived assessment of the heterogeneity of RV contraction improves the prediction of aerobic exercise capacity in IPAH. PMID- 28572118 TI - Obstructive sleep apnoea is not a risk factor for incident hospitalised depression: a historical cohort study. AB - We evaluated whether obstructive sleep apnoea (OSA) was related to the incidence of hospitalisation for depression, a robust end-point that is unlikely to result from misdiagnosis.All adults referred with suspected OSA who underwent a diagnostic sleep study at a large urban academic hospital between 1994 and 2010 and were linked to provincial health administrative data between 1991 and 2015 were included. Cox regression analysis was used to investigate the association between OSA symptoms and severity and incident hospitalised depression, the primary outcome.Over a median follow-up of 9.7 years, 136 (1.3%) out of 10 149 participants were hospitalised for depression. A significant crude effect of OSA symptoms (waking unrefreshed and impact on memory and concentration) on hospitalised depression became nonsignificant after controlling for confounders. Apnoea-hypopnoea index was not significantly associated with the outcome: adjusted hazard ratio (33 versus 6 events.h-1) 1.13 (95% CI 0.91-1.40). Factors associated with hospitalised depression were female sex, younger age, use of hypnotics, alcoholism and unemployment.In a large clinical cohort with suspected OSA, controlling for confounders, OSA symptoms and severity were not related to the risk of hospitalisation for depression, suggesting that previously reported links between OSA and depression may be due to overlapping diagnostic criteria. However, our findings cannot exclude a potential link between OSA and milder depression. PMID- 28572120 TI - Burden of disease and change in practice in critically ill infants with bronchiolitis. AB - Bronchiolitis represents the most common cause of non-elective admission to paediatric intensive care units (ICUs).We assessed changes in admission rate, respiratory support, and outcomes of infants <24 months with bronchiolitis admitted to ICU between 2002 and 2014 in Australia and New Zealand.During the study period, bronchiolitis was responsible for 9628 (27.6%) of 34 829 non elective ICU admissions. The estimated population-based ICU admission rate due to bronchiolitis increased by 11.76 per 100 000 each year (95% CI 8.11-15.41). The proportion of bronchiolitis patients requiring intubation decreased from 36.8% in 2002, to 10.8% in 2014 (adjusted OR 0.35, 95% CI 0.27-0.46), whilst a dramatic increase in high-flow nasal cannula therapy use to 72.6% was observed (p<0.001). We observed considerable variability in practice between units, with six-fold differences in risk-adjusted intubation rates that were not explained by ICU type, size, or major patient factors. Annual direct hospitalisation costs due to severe bronchiolitis increased to over USD30 million in 2014.We observed an increasing healthcare burden due to severe bronchiolitis, with a major change in practice in the management from invasive to non-invasive support that suggests thresholds to admittance of bronchiolitis patients to ICU have changed. Future studies should assess strategies for management of bronchiolitis outside ICUs. PMID- 28572121 TI - Individualised risk in patients undergoing lung volume reduction surgery: the Glenfield BFG score. AB - Lung volume reduction surgery (LVRS) has been shown to be beneficial in patients with chronic obstructive pulmonary disease, but there is low uptake, partly due to perceived concerns of high operative mortality. We aimed to develop an individualised risk score following LVRS.This was a cohort study of patients undergoing LVRS. Factors independently predicting 90-day mortality and a risk prediction score were identified. Reliability of the score was tested using area under the receiver operating characteristic curve (AUROC).237 LVRS procedures were performed. The multivariate analysis factors associated independently with death were: body mass index (BMI)<18.5 kg.m-2 (OR 2.83, p=0.059), forced expiratory volume in 1 s (FEV1)<0.71 L (OR 5.47, p=0.011) and transfer factor of the lung for carbon monoxide (TLCO) <20% (OR 5.56, p=0.031). A risk score was calculated and total score assigned. AUROC for the risk score was 0.80 and a better predictor than individual components (p<0.01). The score was stratified into three risk groups. Of the total patients, 46% were classified as low risk. Similar improvements in lung function and health status were seen in all groups. The score was introduced and tested in a further 71 patients. AUROC for 90-day mortality in this cohort was 0.84.It is possible to provide an individualised predictive risk score for LVRS, which may aid decision making for both clinicians and patients. PMID- 28572123 TI - Cellular analysis in bronchoalveolar lavage: inherent limitations of current standard procedure. PMID- 28572122 TI - Chemotherapy for pulmonary large cell neuroendocrine carcinomas: does the regimen matter? AB - Pulmonary large cell neuroendocrine carcinoma (LCNEC) is rare. Chemotherapy for metastatic LCNEC ranges from small cell lung carcinoma (SCLC) regimens to nonsmall cell lung carcinoma (NSCLC) chemotherapy regimens. We analysed outcomes of chemotherapy treatments for LCNEC.The Netherlands Cancer Registry and Netherlands Pathology Registry (PALGA) were searched for patients with stage IV chemotherapy-treated LCNEC (2003-2012). For 207 patients, histology slides were available for pathology panel review. First-line platinum-based combined chemotherapy was clustered as "NSCLC-t", comprising gemcitabine, docetaxel, paclitaxel or vinorelbine; "NSCLC-pt", with pemetrexed treatment only; and "SCLC t", consisting of etoposide chemotherapy.A panel review diagnosis of LCNEC was established in 128 out of 207 patients. NSCLC-t chemotherapy was administered in 46% (n=60), NSCLC-pt in 16% (n=20) and SCLC-t in 38% (n=48) of the patients. The median (95% CI) overall survival for NSCLC-t chemotherapy was 8.5 (7.0-9.9) months, significantly longer than patients treated with NSCLC-pt, with a median survival of 5.9 (5.0-6.9) months (hazard ratio 2.51, 95% CI 1.39-4.52; p=0.002) and patients treated with SCLC-t chemotherapy, with a median survival of 6.7 (5.0 8.5) months (hazard ratio 1.66, 95% CI 1.08-2.56; p=0.020).In patients with LCNEC, NSCLC-t chemotherapy results in longer overall survival compared to NSCLC pt and SCLC-t chemotherapy. PMID- 28572125 TI - The effect of 100% oxygen on tidal breathing parameters in preschool children. PMID- 28572124 TI - The association between chronic airflow obstruction and poverty in 12 sites of the multinational BOLD study. AB - Poverty is strongly associated with mortality from COPD, but little is known of its relation to airflow obstruction.In a cross-sectional study of adults aged >=40 years from 12 sites (N=9255), participating in the Burden of Obstructive Lung Disease (BOLD) study, poverty was evaluated using a wealth score (0-10) based on household assets. Obstruction, measured as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) (%) after administration of 200 MUg salbutamol, and prevalence of FEV1/FVC=2 nights. Previously validated questionnaires were used to assess parent participation in hospital care and psychological distress (defined here as symptoms of anxiety/depression). A modified version of the Bereaved Parent Needs Assessment was used to assess perceived need fulfillment. The association between perceived need fulfillment and each outcome variable was examined using multiple linear regression analyses. RESULTS: Of 186 eligible parents, 166 were enrolled (1 declined, 19 missed/not present). In multivariable analyses, greater perceived need fulfillment was associated with greater participation in hospital care and fewer symptoms of depression, even after controlling for relevant covariates. Exploratory analyses identified needs that were differentially important within groups of parents at risk for distress. CONCLUSIONS: This study suggests that assessing and supporting parent needs during a child's hospitalization may improve parent and child outcomes by increasing parents' ability to participate in hospital care and decreasing psychological distress. Future research is needed to investigate the impact of interventions targeting specific parent needs. PMID- 28572147 TI - Head-to-Head Visual Comparison between Brain Perfusion SPECT and Arterial Spin Labeling MRI with Different Postlabeling Delays in Alzheimer Disease. AB - BACKGROUND AND PURPOSE: Arterial spin-labeling MR imaging has been recently developed as a noninvasive technique with magnetically labeled arterial blood water as an endogenous contrast medium for the evaluation of CBF. Our aim was to compare arterial spin-labeling MR imaging and SPECT in the visual assessment of CBF in patients with Alzheimer disease. MATERIALS AND METHODS: In 33 patients with Alzheimer disease or mild cognitive impairment due to Alzheimer disease, CBF images were obtained by using both arterial spin-labeling-MR imaging with a postlabeling delay of 1.5 seconds and 2.5 seconds (PLD1.5 and PLD2.5, respectively) and brain perfusion SPECT. Twenty-two brain regions were visually assessed, and the diagnostic confidence of Alzheimer disease was recorded. RESULTS: Among all arterial spin-labeling images, 84.9% of PLD1.5 and 9% of PLD2.5 images showed the typical pattern of advanced Alzheimer disease (ie, decreased CBF in the bilateral parietal, temporal, and frontal lobes). PLD1.5, PLD2.5, and SPECT imaging resulted in obviously different visual assessments. PLD1.5 showed a broad decrease in CBF, which could have been due to an early perfusion. In contrast, PLD2.5 did not appear to be influenced by an early perfusion but showed fewer pathologic findings than SPECT. CONCLUSIONS: The distinctions observed by us should be carefully considered in the visual assessments of Alzheimer disease. Further studies are required to define the patterns of change in arterial spin-labeling-MR imaging associated with Alzheimer disease. PMID- 28572148 TI - High-Resolution Hybrid Imaging Could Improve Cordotomy Lesions and Outcomes. PMID- 28572149 TI - Spinal Cord, Spinal Root, and Brain MRI Abnormalities in Congenital Zika Syndrome. PMID- 28572151 TI - Is an Intact Posterior Vertebral Body Cortex Protective for Percutaneous Ablation? PMID- 28572150 TI - Percutaneous Spinal Ablation in a Sheep Model: Protective Capacity of an Intact Cortex, Correlation of Ablation Parameters with Ablation Zone Size, and Correlation of Postablation MRI and Pathologic Findings. AB - BACKGROUND AND PURPOSE: Despite the growing use of percutaneous ablation therapy for the treatment of metastatic spine disease, several issues have yet to be fully addressed. Our aims were to determine whether the vertebral body cortex protects against ablation-induced spinal cord injury; correlate radiofrequency, cryo-, and microwave ablation parameters with resulting spinal ablation zone dimensions and describe normal spinal marrow postablation changes on MR imaging. MATERIALS AND METHODS: Ten thoracolumbar vertebrae in 3 sheep were treated with radiofrequency ablation, cryoablation, or microwave ablation under fluoroscopic guidance. Technique parameters were chosen to produce ablation zones that exceeded the volume of the vertebral bodies in sheep 1 and were confined to the vertebrae in sheep 2 and 3. Expected ablation zone dimensions were based on data provided by the device manufacturers. Postablation MR imaging was performed at 48 hours (sheep 1) or 7 days (sheep 2 and 3). RESULTS: In sheep 1, cryoablation and microwave ablations extended into the spinal canal and caused histologically confirmed neurologic injury, but radiofrequency ablation did not. The mean difference between the lengths of the radiofrequency ablation zone dimensions measured on gross pathology compared with those expected was 9.6 +/- 4.1 mm. The gross pathologic cryo- and microwave ablation zone dimensions were within 1 mm of those expected. All modalities produced a nonenhancing ablation zone with a rim of enhancement, corresponding histologically to marrow necrosis and hemorrhagic congestion. CONCLUSIONS: An intact cortex appears to protect against radiofrequency ablation-induced spinal cord injury, but not against non-impedance based modalities. Ablation dimensions produced by microwave and cryoablation are similar to those expected, while radiofrequency ablation dimensions are smaller. Ablation of normal marrow produces a rim of enhancement at the margin of the ablation zone on MR imaging. PMID- 28572152 TI - Temporal Evolution of Disc in Young Patients with Low Back Pain and Stress Reaction in Lumbar Vertebrae. AB - BACKGROUND AND PURPOSE: Although stress-induced bony changes often resolve with conservative treatment, the long-term effects of such mechanical stresses on intervertebral discs have not been studied. We aimed to assess the differences in the temporal evolution of disc in segments of the lumbar spine with and without signs of increased mechanical stresses. MATERIALS AND METHODS: Using MR imaging performed >6 months apart, 2 radiologists evaluated lumbar intervertebral discs for degenerative changes affecting the annulus fibrosus, the nucleus pulposus, and the endplates in 42 patients (22 male, 20 female; mean age, 16.0 +/- 3.7 years [range, 7-25 years]) with low back pain and imaging evidence of stress reaction/fracture in the lumbar spine. Data were analyzed for differences in the presence and progression of disc degeneration in stressed versus nonstressed segments. RESULTS: At baseline, stressed discs had a higher burden of annular fissures, radial fissures, herniation, and nuclear degeneration. Endplate defect burden was comparable in stressed and control discs. At follow-up, the burden of new annular fissures and endplate defects was comparable for stressed and control discs. However, a higher proportion of stressed discs showed worsening nuclear signal intensity grade (14.3% versus 0% control discs; P = .008) and worsening nuclear degeneration grade (11.9% versus 0% control discs; P = .02). An increased risk of progressive nuclear degeneration of stressed discs was observed irrespective of the outcome of bony changes. CONCLUSIONS: Stressed discs exhibit a higher burden of nuclear and annular degeneration at baseline. These discs have a higher risk of progressive nuclear degeneration irrespective of improvement or worsening of stress-related bony changes. PMID- 28572153 TI - Diffusional Kurtosis Imaging of the Corticospinal Tract in Multiple Sclerosis: Association with Neurologic Disability. AB - BACKGROUND AND PURPOSE: Multiple sclerosis is an autoimmune disorder resulting in progressive neurologic disability. Our aim was to evaluate the associations between diffusional kurtosis imaging-derived metrics for the corticospinal tract and disability in multiple sclerosis. MATERIALS AND METHODS: Forty patients with MS underwent brain MR imaging including diffusional kurtosis imaging. After we masked out T2 hyperintense lesions, the fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, mean kurtosis, radial kurtosis, and axial kurtosis were estimated for the corticospinal tract. Disability was quantified by using the Expanded Disability Status Scale at the time of MR imaging and 12 months post-MR imaging. The Pearson correlation coefficient and linear regression analyses were conducted to evaluate the associations between diffusion metrics and disability. RESULTS: Significant correlations were found between the Expanded Disability Status Scale scores during the baseline visit and age (r = 0.47), T2 lesion volume (r = 0.38), corticospinal tract mean diffusivity (r = 0.41), radial diffusivity (r = 0.41), axial diffusivity (r = 0.34), fractional anisotropy (r = 0.36), and radial kurtosis (r = -0.42). Significant correlations were also found between the Expanded Disability Status Scale scores at 12-month follow-up and age (r = 0.38), mean diffusivity (r = 0.45), radial diffusivity (r = 0.41), axial diffusivity (r = 0.45), mean kurtosis (r = -0.42), radial kurtosis (r = -0.56), and axial kurtosis (r = -0.36). Linear regression analyses demonstrated significant associations among radial kurtosis, age, and Expanded Disability Status Scale score during the baseline visit, while radial kurtosis was the only variable associated with Expanded Disability Status Scale score for the 12-month follow-up. CONCLUSIONS: Radial kurtosis of the corticospinal tract may have an association with neurologic disability in MS. PMID- 28572154 TI - Novel role of NPY in neuroimmune interaction and lung growth after intrauterine growth restriction. AB - Individuals with intrauterine growth restriction (IUGR) are at risk for chronic lung disease. Using a rat model, we showed in our previous studies that altered lung structure is related to IL-6/STAT3 signaling. As neuropeptide Y (NPY), a coneurotransmitter of the sympathetic nervous system, regulates proliferation and immune response, we hypothesized that dysregulated NPY after IUGR is linked to IL 6, impaired myofibroblast function, and alveolar growth. IUGR was induced in rats by isocaloric low-protein diet; lungs were analyzed on embryonic day (E) 21, postnatal day (P) 3, P12, and P23. Finally, primary neonatal lung myofibroblasts (pnF) and murine embryonic fibroblasts (MEF) were used to assess proliferation, apoptosis, migration, and IL-6 expression. At E21, NPY and IL-6 expression was decreased, and AKT/PKC and STAT3/AMPKalpha signaling was reduced. Early reduction of NPY/IL-6 was associated with increased chord length in lungs after IUGR at P3, indicating reduced alveolar formation. At P23, however, IUGR rats exhibited a catch-up of body weight and alveolar growth coupled with more proliferating myofibroblasts. These structural findings after IUGR were linked to activated NPY/PKC, IL-6/AMPKalpha signaling. Complementary, IUGR-pnF showed increased survival, impaired migration, and reduced IL-6 compared with control-pnF (Co pnF). In contrast, NPY induced proliferation, migration, and increased IL-6 synthesis in fibroblasts. Additionally, NPY-/- mice showed reduced IL-6 signaling and less proliferation of lung fibroblasts. Our study presents a novel role of NPY during alveolarization: NPY regulates 1) IL-6 and lung STAT3/AMPKalpha signaling, and 2) proliferation and migration of myofibroblasts. These new insights in pulmonary neuroimmune interaction offer potential strategies to enable lung growth. PMID- 28572155 TI - Elastin receptor (S-gal) occupancy by elastin peptides modulates T-cell response during murine emphysema. AB - Chronic obstructive pulmonary disease and emphysema are associated with increased elastin peptides (EP) production because of excessive breakdown of lung connective tissue. We recently reported that exposure of mice to EP elicited hallmark features of emphysema. EP effects are largely mediated through a receptor complex that includes the elastin-binding protein spliced-galactosidase (S-gal). In previous studies, we established a correlation between cytokine production and S-gal protein expression in EP-treated immune cells. In this study, we investigated the S-gal-dependent EP effects on T-helper (Th) and T cytotoxic (Tc) responses during murine EP-triggered pulmonary inflammation. C57BL/6J mice were endotracheally instilled with the valine-glycine-valine alanine-proline-glycine (VGVAPG) elastin peptide, and, 21 days after treatment, local and systemic T-lymphocyte phenotypes were analyzed at cytokine and transcription factor expression levels by multicolor flow cytometry. Exposure of mice to the VGVAPG peptide resulted in a significant increase in the proportion of the CD4+ and CD8+ T cells expressing the cytokines IFN-gamma or IL-17a and the transcription factors T-box expressed in T cells or retinoic acid-related orphan receptor-gammat (RORgammat) without effects on IL-4 and Gata-binding protein 3 to DNA sequence [A/T]GATA[A/G] expression. These effects were maximized when each T cell subpopulation was challenged ex vivo with EP, and they were inhibited in vivo when an analogous peptide antagonizing the EP/S-gal interactions was instilled together with the VGVAPG peptide. This study demonstrates that, during murine emphysema, EP-S-gal interactions contribute to a Th-1 and Th-17 proinflammatory T-cell response combined with a Tc-1 response. Our study also highlights the S-gal receptor as a putative pharmacological target to modulate such an immune response. PMID- 28572156 TI - G-protein-coupled receptor kinase-2 is a critical regulator of TNFalpha signaling in colon epithelial cells. AB - G-protein-coupled receptor kinase-2 (GRK2) belongs to the GRK family of serine/threonine protein kinases critical in the regulation of G-protein-coupled receptors. Apart from this canonical role, GRK2 is also involved in several signaling pathways via distinct intracellular interactomes. In the present study, we examined the role of GRK2 in TNFalpha signaling in colon epithelial cell biological processes including wound healing, proliferation, apoptosis, and gene expression. Knockdown of GRK2 in the SW480 human colonic cells significantly enhanced TNFalpha-induced epithelial cell wound healing without any effect on apoptosis/proliferation. Consistent with wound-healing effects, GRK2 knockdown augmented TNFalpha-induced matrix metalloproteinases (MMPs) 7 and 9, as well as urokinase plasminogen activator (uPA; factors involved in cell migration and wound healing). To assess the mechanism by which GRK2 affects these physiological processes, we examined the role of GRK2 in TNFalpha-induced MAPK and NF-kappaB pathways. Our results demonstrate that while GRK2 knockdown inhibited TNFalpha induced IkappaBalpha phosphorylation, activation of ERK was significantly enhanced in GRK2 knockdown cells. Our results further demonstrate that GRK2 inhibits TNFalpha-induced ERK activation by inhibiting generation of reactive oxygen species (ROS). Together, these data suggest that GRK2 plays a critical role in TNFalpha-induced wound healing by modulating MMP7 and 9 and uPA levels via the ROS-ERK pathway. Consistent with in vitro findings, GRK2 heterozygous mice exhibited enhanced intestinal wound healing. Together, our results identify a novel role for GRK2 in TNFalpha signaling in intestinal epithelial cells. PMID- 28572157 TI - Characterization of the oligomeric states of the CK2 alpha2beta2 holoenzyme in solution. AB - The regulatory mechanism of protein kinase CK2 has still to be fully clarified. The prevailing hypothesis is that CK2 is controlled by a self-polymerisation mechanism leading to inactive supramolecular assemblies that, when needed, can be disassembled into the alpha2beta2 monomer, the active form of the holoenzyme. In vitro, monomeric alpha2beta2 seems present only at high ionic strengths, typically 0.35-0.50 M NaCl, while at lower salt concentrations oligomers are formed. In the present study, size-exclusion chromatography (SEC), dynamic light scattering (DLS), small-angle X-ray scattering (SAXS) and mutagenesis have been employed for the characterization of the oligomeric states of CK2 in solution. SAXS measurements at 0.35 M NaCl show for the first time the shape of the alpha2beta2 active monomer in solution. At 0.25 M salt, despite single average properties indicating an aggregated holoenzyme, deconvolution analysis of SAXS data reveals an equilibrium involving not only circular trimeric and linear oligomeric (3-4 units) forms of alpha2beta2, but also considerable amounts of the monomer. Together SAXS and mutagenesis confirm the presence in solution of the oligomers deduced by crystal structures. The lack of intermediate species such as alphabeta2, alpha or beta2 indicates that the holoenzyme is a strong complex that does not spontaneously dissociate, challenging what was recently proposed on the basis of mass spectrometry data. A significant novel finding is that a considerable amount of monomer, the active form of CK2, is present also at low salt. The solution properties of CK2 shown in the present study complement the model of regulation by polymerization. PMID- 28572158 TI - Plasminogen Activator Inhibitor-1 Is a Marker and a Mediator of Senescence. AB - PAI-1 (plasminogen activator inhibitor-1) is a member of the evolutionarily conserved serine protease inhibitor family and a potent and rapid-acting inhibitor of both of the mammalian plasminogen activators. Organismal homeostasis requires physiological levels of endogenous PAI-1, and increased PAI-1 production guides the onset and progression of numerous human diseases and contributes to the multimorbidity of aging. Both chronological and stress-induced accelerated aging are associated with cellular senescence and accompanied by marked increases in PAI-1 expression in tissues. Recent studies suggest that PAI-1 is not only a marker but also a key mediator of cellular senescence and organismal aging. Here, we review the significance of PAI-1 as a bonafide marker, as well as a critical mediator, of cellular senescence associated with aging and aging-related pathologies. PMID- 28572159 TI - APOL1 Risk Variants and Cardiovascular Disease: Results From the AASK (African American Study of Kidney Disease and Hypertension). AB - OBJECTIVE: Among African Americans, the apolipoprotein L1 (APOL1) risk variants have been associated with various types of kidney disease and chronic kidney disease progression. We aimed to determine whether these same risk variants also confer an increased risk for cardiovascular disease. APPROACH AND RESULTS: In a cohort of African Americans with hypertension-attributed chronic kidney disease followed for up to 12 years, we used Cox proportional hazards models to estimate the relative hazard of a composite cardiovascular disease outcome (cardiovascular death or hospitalization for myocardial infarction, cardiac revascularization procedure, heart failure, or stroke) for the APOL1 high- (2 risk variants) versus low-risk (0-1 risk variant) genotypes. We adjusted for age, sex, ancestry, smoking, heart disease history, body mass index, cholesterol, randomized treatment groups, and baseline and longitudinal estimated glomerular filtration rate, systolic blood pressure, and proteinuria. Among 693 participants with APOL1 genotyping available (23% high risk), the high-risk group had lower mean estimated glomerular filtration rate (44.7 versus 50.1 mL/min per 1.73 m2) and greater proteinuria (median 0.19 versus 0.06) compared with the low-risk group at baseline. There was no significant association between APOL1 genotypes and the composite cardiovascular disease outcome in both unadjusted (hazard ratio=1.23; 95% confidence interval: 0.83-1.81) and fully adjusted (hazard ratio=1.16; 95% confidence interval: 0.77-1.76) models; however, in using an additive model, APOL1 high-risk variants were associated with increased cardiovascular mortality. CONCLUSIONS: Among African Americans with hypertension-attributed chronic kidney disease, APOL1 risk variants were not associated with an overall risk for cardiovascular disease although some signals for cardiovascular mortality were noted. PMID- 28572160 TI - Oxidized Phospholipids and Risk of Calcific Aortic Valve Disease: The Copenhagen General Population Study. AB - OBJECTIVE: Lipoprotein(a) is causally associated with calcific aortic valve disease (CAVD). Lipoprotein(a) carries proinflammatory and procalcific oxidized phospholipids (OxPL). We tested whether the CAVD risk is mediated by the content of OxPL on lipoprotein(a). APPROACH AND RESULTS: A case-control study was performed within the Copenhagen General Population Study (n=87 980), including 725 CAVD cases (1977-2013) and 1413 controls free of cardiovascular disease. OxPL carried by apoB (apolipoprotein B-100; OxPL-apoB) or apolipoprotein(a) (OxPL apo(a)) containing lipoproteins, lipoprotein(a) levels, LPA kringle IV type 2 repeat, and rs10455872 genetic variants were measured. OxPL-apoB and OxPL-apo(a) levels correlated with lipoprotein(a) levels among cases (r=0.75 and r=0.95; both P<0.001) and controls (r=0.65 and r=0.93; both P<0.001). OxPL-apoB levels associated with risk of CAVD with odds ratios of 1.2 (95% confidence interval [CI]:1.0-1.6) for 34th to 66th percentile levels, 1.6 (95% CI, 1.2-2.1) for 67th to 90th percentile levels, 2.0 (95% CI, 1.3-3.0) for 91st to 95th percentile levels, and 3.4 (95% CI, 2.1-5.5) for levels >95th percentile, versus levels <34th percentile (trend, P<0.001). Corresponding odds ratios for OxPL-apo(a) were 1.2 (95% CI, 1.0-1.5), 1.2(95% CI, 0.9-1.6), 2.1(95% CI, 1.4-3.1), and 2.9(95% CI, 1.9-4.5; trend, P<0.001) and were similar for lipoprotein(a). LPA genotypes associated with OxPL-apoB, OxPL-apo(a), and lipoprotein(a) levels and explained 34%, 46%, and 39%, respectively, of the total variation in levels. LPA genotypes associated with risk of CAVD; a doubling in genetically determined OxPL-apoB, OxPL-apo(a), and lipoprotein(a) levels associated with odds ratio of CAVD of 1.18 (95% CI, 1.10-1.27), 1.09 (95% CI, 1.05-1.13), and 1.09 (95% CI, 1.05-1.14), respectively, comparable to the corresponding observational estimates of 1.27 (95% CI, 1.16-1.39), 1.13 (95% CI, 1.08-1.18), and 1.11 (95% CI, 1.06-1.17). CONCLUSIONS: OxPL-apoB and OxPL-apo(a) are novel genetic and potentially causal risk factors for CAVD and may explain the association of lipoprotein(a) with CAVD. PMID- 28572161 TI - Ultrasensitive detection of acute myeloid leukemia minimal residual disease using single molecule molecular inversion probes. AB - The identification of minimal residual disease is the primary diagnostic finding which predicts relapse in patients treated for acute myeloid leukemia. Ultrasensitive detection of minimal residual disease would enable better patient risk stratification and could open opportunities for early therapeutic intervention. Herein we apply single molecule molecular inversion probe capture, a technology combining multiplexed targeted sequencing with error correction schemes based on molecular barcoding, in order to detect mutations identifying minimal residual disease with ultrasensitive and quantitative precision. We designed a single molecule molecular inversion probe capture panel spanning >50 kb and targeting 32 factors relevant to acute myeloid leukemia pathogenesis. We demonstrate linearity and quantitative precision over 100-fold relative abundance of mutant cells (1 in 100 to 1 in 1,500), with estimated error rates approaching 1 in 1,200 base pairs sequenced and maximum theoretical limits of detection exceeding 1 in 60,000 mutant alleles. In 3 of 4 longitudinally collected specimens from patients with acute myeloid leukemia, we find that single molecule molecular inversion probe capture detects somatic mutations identifying minimal residual disease at substantially earlier time points and with greater sensitivity than clinical diagnostic approaches used as current standard of care (flow cytometry and conventional molecular diagnosis), and identifies persisting neoplastic cells during clinical remission. In 2 patients, single molecule molecular inversion probe capture detected heterogeneous, subclonal acute myeloid leukemia populations carrying distinct mutational signatures. Single molecule molecular inversion probe technology uniquely couples scalable target enrichment with sequence read error correction, providing an integrated, ultrasensitive approach for detecting minimal residual disease identifying mutations. PMID- 28572162 TI - CRISPR-Cas9-induced t(11;19)/MLL-ENL translocations initiate leukemia in human hematopoietic progenitor cells in vivo. AB - Chromosomal translocations that generate oncogenic fusion proteins are causative for most pediatric leukemias and frequently affect the MLL/KMT2A gene. In vivo modeling of bona fide chromosomal translocations in human hematopoietic stem and progenitor cells is challenging but essential to determine their actual leukemogenic potential. We therefore developed an advanced lentiviral CRISPR-Cas9 vector that efficiently transduced human CD34+ hematopoietic stem and progenitor cells and induced the t(11;19)/MLL-ENL translocation. Leveraging this system, we could demonstrate that hematopoietic stem and progenitor cells harboring the translocation showed only a transient clonal growth advantage in vitro In contrast, t(11;19)/MLL-ENL-harboring CD34+ hematopoietic stem and progenitor cells not only showed long-term engraftment in primary immunodeficient recipients, but t(11;19)/MLL-ENL also served as a first hit to initiate a monocytic leukemia-like disease. Interestingly, secondary recipients developed acute lymphoblastic leukemia with incomplete penetrance. These findings indicate that environmental cues not only contribute to the disease phenotype, but also to t(11;19)/MLL-ENL-mediated oncogenic transformation itself. Thus, by investigating the true chromosomal t(11;19) rearrangement in its natural genomic context, our study emphasizes the importance of environmental cues for the pathogenesis of pediatric leukemias, opening an avenue for novel treatment options. PMID- 28572163 TI - Incidence of second primary malignancies and related mortality in patients with imatinib-treated chronic myeloid leukemia. AB - The majority of patients with chronic myeloid leukemia are successfully managed with life-long treatment with tyrosine kinase inhibitors. In patients in chronic phase, other malignancies are among the most common causes of death, raising concerns on the relationship between these deaths and the off-target effects of tyrosine kinase inhibitors. We analyzed the incidence of second primary malignancies, and related mortality, in 514 chronic myeloid leukemia patients enrolled in clinical trials in which imatinib was given as first-line treatment. We then compared the observed incidence and mortality with those expected in the age- and sex-matched Italian general population, calculating standardized incidence and standardized mortality ratios. After a median follow-up of 74 months, 5.8% patients developed second primary malignancies. The median time from chronic myeloid leukemia to diagnosis of the second primary malignancies was 34 months. We did not find a higher incidence of second primary malignancies compared to that in the age- and sex-matched Italian general population, with standardized incidence ratios of 1.06 (95% CI: 0.57-1.54) and 1.61 (95% CI: 0.92 2.31) in males and females, respectively. Overall, 3.1% patients died of second primary malignancies. The death rate in patients with second primary malignancies was 53% (median overall survival: 18 months). Among females, the observed cancer related mortality was superior to that expected in the age- and sex-matched Italian population, with a standardized mortality ratio of 2.41 (95% CI: 1.26 - 3.56). In conclusion, our analysis of patients with imatinib-treated chronic myeloid leukemia did not reveal a higher incidence of second primary malignancies; however, the outcome of second primary malignancies in such patients was worse than expected. Clinicaltrials.gov: NCT00514488, NCT00510926. PMID- 28572164 TI - Risk of cardiovascular events and pulmonary hypertension following splenectomy - a Danish population-based cohort study from 1996-2012. AB - Splenectomized patients are at increased risk of cardiovascular events, but it remains unclear whether this is due to lack of the spleen or due to the underlying disease leading to splenectomy. We aimed to assess the risk of myocardial infarction, pulmonary hypertension, and stroke following splenectomy. We identified patients splenectomized in Denmark between 1996 and 2012. We constructed two comparison cohorts: an age- and sex-matched general population cohort and a disease-matched cohort based on the splenectomy-related underlying disease. We computed 5-year cumulative incidences and adjusted hazard ratios of myocardial infarction, pulmonary hypertension, and stroke for the three cohorts. The study included 5,306 splenectomized patients, 53,060 members of the general population, and 11,651 disease-matched patients. During the 5-year follow-up, 1.3% of splenectomized patients had a myocardial infarction versus 1.8% of the population cohort. The adjusted hazard ratio for myocardial infarction in splenectomized patients versus the population cohort was 1.24 (95% confidence interval: 1.01-1.52). The 5-year cumulative incidence of pulmonary hypertension was 0.4% among splenectomized subjects and 0.2% in the population cohort [adjusted hazard ratio 3.25 (95% confidence interval: 1.93-5.45)], while that of stroke was 3.3% among splenectomized patients versus 2.6% in the population cohort [adjusted hazard ratio 2.04 (95% confidence interval: 1.78-2.35)]. When comparing splenectomized subjects with the disease-matched cohort, only stroke risk was elevated, with 5-year risks of 3.0% and 2.3%, respectively [adjusted hazard ratio 1.56 (95% confidence interval: 1.26-1.92)]. In conclusion, splenectomized patients were at increased risk of stroke. Additionally, we found that underlying splenectomy-related diseases explained the increased risk of myocardial infarction and pulmonary hypertension following splenectomy. PMID- 28572166 TI - Modifications to vancomycin raise hope for combating antibiotic resistance. PMID- 28572165 TI - Long-term impact of joint bleeds in von Willebrand disease: a nested case-control study. AB - Patients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified joint bleeds were matched for age, sex and Factor VIII level or von Willebrand Factor activity in a nested case control study within the Willebrand in the Netherlands study. Assessments included the Hemophilia Joint Health Score (0-124), Pettersson score (0-13 per joint X-ray), Hemophilia Activity List score (0-100), joint pain (Visual Analog Scale 0-10), and the Impact on Participation and Autonomy questionnaire (0-20). Arthropathy was defined as a Hemophilia Joint Health Score of 10 or higher, or a Pettersson score over 3 of at least one joint. We included 48 patients with verified joint bleeds (cases) and 48 controls: 60% males, mean age 46 years (range 18-80), median von Willebrand Factor activity 5 versus 8 IU/dL and Factor VIII 24 versus 36 IU/dL. Arthropathy occurred in 40% of the cases versus 10% of the controls (P<0.01). The cases reported more functional limitations compared to the controls (median Hemophilia Activity List score: 88 vs. 100, P<0.01). Arthropathy was related to joint pain and less social participation (Visual Analog Scale>3: 13 of 19 vs. 3 of 28, P<0.01, and median score on the participation questionnaire 6.1 vs. 0.9, P<0.01). In conclusion, arthropathy occurs in 40% of VWD patients after joint bleeds and is associated with pain, radiological abnormalities, functional limitations, and less social participation (Dutch trial register: NTR4548). PMID- 28572167 TI - Colony-Stimulating Factor 1 Receptor Blockade Inhibits Tumor Growth by Altering the Polarization of Tumor-Associated Macrophages in Hepatocellular Carcinoma. AB - Colony-stimulating factor-1 (CSF-1) and its receptor, CSF-1R, regulate the differentiation and function of macrophages and play an important role in macrophage infiltration in the context of hepatocellular carcinoma. The therapeutic effects of CSF-1R blockade in hepatocellular carcinoma remain unclear. In this study, we found that CSF-1R blockade by PLX3397, a competitive inhibitor with high specificity for CSF-1R tyrosine kinase, significantly delayed tumor growth in mouse models. PLX3397 inhibited the proliferation of macrophages in vitro, but intratumoral macrophage infiltration was not decreased by PLX3397 in vivo Gene expression profiling of tumor-associated macrophages (TAM) showed that TAMs from the PLX3397-treated tumors were polarized toward an M1-like phenotype compared with those from vehicle-treated tumors. In addition, PLX3397 treatment increased CD8+ T-cell infiltration, whereas CD4+ T-cell infiltration was decreased. Further study revealed that tumor cell-derived CSF-2 protected TAMs from being depleted by PLX3397. In conclusion, CSF-1R blockade delayed tumor growth by shifting the polarization rather than the depletion of TAMs. CSF-1R blockade warrants further investigation in the treatment of hepatocellular carcinoma. Mol Cancer Ther; 16(8); 1544-54. (c)2017 AACR. PMID- 28572168 TI - Preclinical Efficacy and Molecular Mechanism of Targeting CDK7-Dependent Transcriptional Addiction in Ovarian Cancer. AB - Ovarian cancer remains a significant cause of gynecologic cancer mortality, and novel therapeutic strategies are urgently needed in clinic as new treatment options. We previously showed that BET bromodomain inhibitors displayed promising efficacy for the treatment of epithelial ovarian cancer by downregulating pivot transcription factors. However, the potential antitumor activities and molecular mechanisms of other epigenetic or transcriptional therapies have not been systematically determined. Here, by performing an unbiased high-throughput drug screen to identify candidate compounds with antineoplastic effects, we identified THZ1, a recently developed covalent CDK7 inhibitor, as a new transcription targeting compound that exerted broad cytotoxicity against ovarian tumors. Mechanistically, CDK7 represented a previously unappreciated actionable vulnerability in ovarian cancer, and CDK7 inhibition led to a pronounced dysregulation of gene transcription, with a preferential repression of E2F regulated genes and transcripts associated with super-enhancers. Our findings revealed the molecular underpinnings of THZ1 potency and established pharmaceutically targeting transcriptional addiction as a promising therapeutic strategy in aggressive ovarian cancer. Mol Cancer Ther; 16(9); 1739-50. (c)2017 AACR. PMID- 28572170 TI - New developments in crystallography: exploring its technology, methods and scope in the molecular biosciences. AB - Since the Protein Data Bank (PDB) was founded in 1971, there are now over 120,000 depositions, the majority of which are from X-ray crystallography and 90% of those made use of synchrotron beamlines. At the Cambridge Structure Database (CSD), founded in 1965, there are more than 800,000 'small molecule' crystal structure depositions and a very large number of those are relevant in the biosciences as ligands or cofactors. The technology for crystal structure analysis is still developing rapidly both at synchrotrons and in home labs. Determination of the details of the hydrogen atoms in biological macromolecules is well served using neutrons as probe. Large multi-macromolecular complexes cause major challenges to crystallization; electrons as probes offer unique advantages here. Methods developments naturally accompany technology change, mainly incremental but some, such as the tuneability, intensity and collimation of synchrotron radiation, have effected radical changes in capability of biological crystallography. In the past few years, the X-ray laser has taken X ray crystallography measurement times into the femtosecond range. In terms of applications many new discoveries have been made in the molecular biosciences. The scope of crystallographic techniques is indeed very wide. As examples, new insights into chemical catalysis of enzymes and relating ligand bound structures to thermodynamics have been gained but predictive power is seen as not yet achieved. Metal complexes are also an emerging theme for biomedicine applications. Our studies of coloration of live and cooked lobsters proved to be an unexpected favourite with the public and schoolchildren. More generally, public understanding of the biosciences and crystallography's role within the field have been greatly enhanced by the United Nations International Year of Crystallography coordinated by the International Union of Crystallography. This topical review describes each of these areas along with illustrative results to document the scope of each methodology. PMID- 28572169 TI - Tumor-targeted Nanoparticle Delivery of HuR siRNA Inhibits Lung Tumor Growth In Vitro and In Vivo By Disrupting the Oncogenic Activity of the RNA-binding Protein HuR. AB - Selective downregulation of the human antigen R (HuR) protein by siRNA may provide a powerful approach for treating lung cancer. To this end, we investigated the efficacy of transferrin receptor-targeted liposomal nanoparticle based HuR siRNA (HuR-TfNP) therapy and compared with control siRNA (C)-TfNP therapy both, in vitro and in vivo using lung cancer models. In vitro studies showed HuR-TfNP, but not C-TfNP, efficiently downregulated HuR and HuR-regulated proteins in A549, and HCC827 lung cancer cells, resulting in reduced cell viability, inhibition of cell migration and invasion, and induction of G1 cell cycle arrest culminating in apoptosis. However, HuR-TfNP activity in normal MRC-9 lung fibroblasts was negligible. In vivo biodistribution study demonstrated that fluorescently labeled HuR-siRNA or ICG dye-loaded TfNP localized in tumor tissues. Efficacy studies showed intratumoral or intravenous administration of HuR-TfNP significantly inhibited A549 (>55% inhibition) and HCC827 (>45% inhibition) subcutaneous tumor growth compared with C-TfNP. Furthermore, HuR-TfNP treatment reduced HuR, Ki67, and CD31 expression and increased caspase-9 and PARP cleavage and TUNEL-positive staining indicative of apoptotic cell death in tumor tissues compared with C-TfNP treatment. The antitumor activity of HuR-TfNP was also observed in an A549-luc lung metastatic model, as significantly fewer tumor nodules (9.5 +/- 3.1; P < 0.001; 88% inhibition) were observed in HuR-TfNP treated group compared with the C-TfNP-treated group (77.7 +/- 20.1). Significant reduction in HuR, Ki67, and CD31 expression was also observed in the tumor tissues of HuR-TfNP-treatment compared with C-TfNP treatment. Our findings highlight HuR-TfNP as a promising nanotherapeutic system for lung cancer treatment. Mol Cancer Ther; 16(8); 1470-86. (c)2017 AACR. PMID- 28572171 TI - The comparison of the performance of four whole genome amplification kits on ion proton platform in copy number variation detection. AB - With the development and clinical application of genomics, more and more concern is focused on single-cell sequencing. In the process of single-cell sequencing, whole genome amplification is a key step to enrich sample DNA. Previous studies have compared the performance of different whole genome amplification (WGA) strategies on Illumina sequencing platforms, but there is no related research aimed at Ion Proton platform, which is also a popular next-generation sequencing platform. Here by amplifying cells from six cell lines with different karyotypes, we estimated the data features of four common commercial WGA kits (PicoPLEX WGA Kit, GenomePlex Single Cell Whole Genome Amplification Kit, MALBAC Single Cell Whole Genome Amplification Kit, and REPLI-g Single Cell Kit), including median absolute pairwise difference, uniformity, reproducibility, and fidelity, and examined their performance of copy number variation detection. The results showed that both MALBAC and PicoPLEX could yield high-quality data and had high reproducibility and fidelity; and as for uniformity, PicoPLEX was slightly superior to MALBAC. PMID- 28572172 TI - Hacking the stem cell niche. PMID- 28572173 TI - A glimmer of hope for a devastating complication. PMID- 28572174 TI - Go with the flow: perforin and CD107a in HLH. PMID- 28572175 TI - Genomic biomarker in sickle cell disease. PMID- 28572176 TI - Giant granule and platelets... PMID- 28572177 TI - Development and Validation of the Homeostasis Concept Inventory. AB - We present the Homeostasis Concept Inventory (HCI), a 20-item multiple-choice instrument that assesses how well undergraduates understand this critical physiological concept. We used an iterative process to develop a set of questions based on elements in the Homeostasis Concept Framework. This process involved faculty experts and undergraduate students from associate's colleges, primarily undergraduate institutions, regional and research-intensive universities, and professional schools. Statistical results provided strong evidence for the validity and reliability of the HCI. We found that graduate students performed better than undergraduates, biology majors performed better than nonmajors, and students performed better after receiving instruction about homeostasis. We used differential item analysis to assess whether students from different genders, races/ethnicities, and English language status performed differently on individual items of the HCI. We found no evidence of differential item functioning, suggesting that the items do not incorporate cultural or gender biases that would impact students' performance on the test. Instructors can use the HCI to guide their teaching and student learning of homeostasis, a core concept of physiology. PMID- 28572178 TI - Evaluating Psychosocial Mechanisms Underlying STEM Persistence in Undergraduates: Evidence of Impact from a Six-Day Pre-College Engagement STEM Academy Program. AB - The persistence of undergraduate students in science, technology, engineering, and mathematics (STEM) disciplines is a national issue based on STEM workforce projections. We implemented a weeklong pre-college engagement STEM Academy (SA) program aimed at addressing several areas related to STEM retention. We validated an instrument that was developed based on existing, validated measures and examined several psychosocial constructs related to STEM (science identity, self efficacy, sense of belonging to the university and to STEM, career expectancies, and intention to leave STEM majors) before and after the program. We also compared students in the SA program with a matched comparison group of first-year students. Results show that SA students significantly increased in science identity and sense of belonging to STEM and to the university, all predictive of increased STEM retention and a primary aim of the program. Relative to the matched comparison group, SA students began their first semester with higher STEM self-efficacy, sense of belonging, and science identity, positive career expectancies, and lower intention to leave STEM. The SA cohort showed 98% first year retention and 92% STEM major retention. The SA program serves as a model of a scalable, first-level, cocurricular engagement experience to enhance psychosocial factors that impact undergraduate persistence in STEM. PMID- 28572179 TI - Examining Summer Laboratory Research Apprenticeships for High School Students as a Factor in Entry to MD/PhD Programs at Matriculation. AB - Do summer laboratory research apprenticeships during high school have an impact on entry into MD/PhD programs? Apart from the nearly decade-long span of time between high school and matriculation into an MD/PhD program, young people have many life-shaping experiences that presumably impact their education and career trajectories. This quantitative study (n = 236,432) examines the connection between early laboratory research apprenticeship experiences at the high school level and matriculation into one of the more rigorous educational programs for scientific research training. The span of time covered by this analysis reaches across more than a decade, examining the potential importance of research experiences during the precollege years in the educational trajectory of young people. Intertwined with this question on research experiences is a second major concern regarding diversity in the life sciences research corps. Diversity in this wide-ranging discipline refers specifically to the underrepresentation of Blacks/African Americans, Hispanics/Latino/as, and American Indians/Alaska Natives among the ranks of research scientists. Thus, this study includes analyses that specifically focus on research apprenticeships of Blacks/African Americans and Hispanics/Latino/as and their entrance into MD/PhD programs. PMID- 28572180 TI - University Students' Conceptual Knowledge of Randomness and Probability in the Contexts of Evolution and Mathematics. AB - Students of all ages face severe conceptual difficulties regarding key aspects of evolution-the central, unifying, and overarching theme in biology. Aspects strongly related to abstract "threshold" concepts like randomness and probability appear to pose particular difficulties. A further problem is the lack of an appropriate instrument for assessing students' conceptual knowledge of randomness and probability in the context of evolution. To address this problem, we have developed two instruments, Randomness and Probability Test in the Context of Evolution (RaProEvo) and Randomness and Probability Test in the Context of Mathematics (RaProMath), that include both multiple-choice and free-response items. The instruments were administered to 140 university students in Germany, then the Rasch partial-credit model was applied to assess them. The results indicate that the instruments generate reliable and valid inferences about students' conceptual knowledge of randomness and probability in the two contexts (which are separable competencies). Furthermore, RaProEvo detected significant differences in knowledge of randomness and probability, as well as evolutionary theory, between biology majors and preservice biology teachers. PMID- 28572181 TI - How Do You Like Your Science, Wet or Dry? How Two Lab Experiences Influence Student Understanding of Science Concepts and Perceptions of Authentic Scientific Practice. AB - This study examines how two kinds of authentic research experiences related to smoking behavior-genotyping human DNA (wet lab) and using a database to test hypotheses about factors that affect smoking behavior (dry lab)-influence students' perceptions and understanding of scientific research and related science concepts. The study used pre and post surveys and a focus group protocol to compare students who conducted the research experiences in one of two sequences: genotyping before database and database before genotyping. Students rated the genotyping experiment to be more like real science than the database experiment, in spite of the fact that they associated more scientific tasks with the database experience than genotyping. Independent of the order of completing the labs, students showed gains in their understanding of science concepts after completion of the two experiences. There was little change in students' attitudes toward science pre to post, as measured by the Scientific Attitude Inventory II. However, on the basis of their responses during focus groups, students developed more sophisticated views about the practices and nature of science after they had completed both research experiences, independent of the order in which they experienced them. PMID- 28572182 TI - Checking Equity: Why Differential Item Functioning Analysis Should Be a Routine Part of Developing Conceptual Assessments. AB - We provide a tutorial on differential item functioning (DIF) analysis, an analytic method useful for identifying potentially biased items in assessments. After explaining a number of methodological approaches, we test for gender bias in two scenarios that demonstrate why DIF analysis is crucial for developing assessments, particularly because simply comparing two groups' total scores can lead to incorrect conclusions about test fairness. First, a significant difference between groups on total scores can exist even when items are not biased, as we illustrate with data collected during the validation of the Homeostasis Concept Inventory. Second, item bias can exist even when the two groups have exactly the same distribution of total scores, as we illustrate with a simulated data set. We also present a brief overview of how DIF analysis has been used in the biology education literature to illustrate the way DIF items need to be reevaluated by content experts to determine whether they should be revised or removed from the assessment. Finally, we conclude by arguing that DIF analysis should be used routinely to evaluate items in developing conceptual assessments. These steps will ensure more equitable-and therefore more valid scores from conceptual assessments. PMID- 28572183 TI - Genetic Dissection of Heritable Traits in Yeast Using Bulk Segregant Analysis. AB - Bulk segregant analysis (BSA) is commonly used to determine the genetic basis of complex traits in yeast. This technique involves phenotyping progeny from a cross and then selectively genotyping pooled subsets of offspring with extreme phenotypes. Analysis of these genotype data can identify loci that show skewed allele frequencies in a group of phenotypically extreme individuals and that are likely to contribute to a trait. BSA can be applied to diverse strain crosses, including ones involving nonreference isolates. Further, given the high throughput of next-generation sequencing, it is possible to conduct many BSA experiments in parallel. Here, we present a BSA protocol for the generation of recombinant cross progeny. We then describe general BSA strategies for conducting phenotyping, causal loci detection, and candidate gene identification in a statistically powerful manner. PMID- 28572184 TI - Construction, Growth, and Harvesting of Fission Yeast Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) Strains. AB - Stable isotope labeling by amino acids in cell culture (SILAC) enables the relative quantification of protein amounts and posttranslational modifications in complex biological samples through the use of stable heavy isotope-labeled amino acids. Here we describe methods for the application of SILAC to fission yeast Schizosaccharomyces pombe using either labeled lysine or a combination of labeled lysine and labeled arginine. The latter approach is more complicated than the use of labeled lysine alone but may yield a more comprehensive (phospho)proteomic analysis. The protocol includes methods for construction of SILAC-compatible strains, growth of cultures in labeled medium, cell harvesting, and protein extraction. PMID- 28572185 TI - Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC)-Based Quantitative Proteomics and Phosphoproteomics in Fission Yeast. AB - Modern mass spectrometry (MS)-based approaches are capable of identifying and quantifying thousands of proteins and phosphorylation events in a single biological experiment. Here we present a (phospho)proteomic workflow based on in solution proteome digestion of samples labeled by stable isotope labeling by amino acids in cell culture (SILAC) and phosphopeptide enrichment using strong cation exchange (SCX) and TiO2 chromatographies. These procedures are followed by high-accuracy MS measurement on an Orbitrap mass spectrometer and subsequent bioinformatic processing using MaxQuant software. PMID- 28572186 TI - Concentrating Nucleic Acids by Extraction with Butanol. AB - During extraction of aqueous solutions with solvents such as secondary butyl alcohol (isobutanol) or n-butyl alcohol (n-butanol), a proportion of the water molecules is partitioned into the organic phase. Nucleic acids remain in the aqueous phase. By performing several sequential cycles of extraction, the volume of a nucleic acid solution can be reduced significantly. This method of concentration can be used to reduce the volume of dilute solutions to the point where the nucleic acid can be recovered easily by precipitation with ethanol. PMID- 28572187 TI - Immunometric Antibody Sandwich Enzyme-Linked Immunosorbent Assay. AB - The antibody sandwich enzyme-linked immunosorbent assay (ELISA) is the most commonly used assay for rapid and accurate detection of antigens. It displays greater sensitivity compared with the indirect ELISA and can be used to determine absolute antigen concentrations in unknown samples provided purified antigen standards are available, although it requires the use of two different antibodies. Briefly, wells are coated with antigen-specific capture antibody then incubated with samples containing unknown antigen. Washing removes unbound antigen and exogenous sample protein before incubation with a second antigen specific detection antibody, washing, and reincubation with a reporter-labeled tertiary antibody. After tertiary antibody is washed off, substrate is added and hydrolysis is measured spectrophotometrically. The signal intensity is directly proportional to the concentration of the antigen in the test sample. PMID- 28572188 TI - Immunometric Double-Antibody Sandwich Enzyme-Linked Immunosorbent Assay. AB - The double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) is preferentially used to determine the concentration of unknown antibody in a sample. Pure antigen is not required in this assay; however, the use of a reporter-labeled detection antibody is essential. The double-antibody sandwich ELISA is suitable for epitope mapping of different monoclonal antibodies that have been generated against a single antigen. First, plates are coated with a capture antibody specific for immunoglobulins generated by immunization of a host species. Next, the test antibody solution (e.g., serum) is incubated with the capture antibody to facilitate binding. The plates are washed to remove unbound antibody, and then antigen is added. The plates are washed again followed by the addition of an antigen-specific reporter-labeled antibody. Following incubation, unbound reporter antibody is washed off, and reporter-specific substrate is added. Reporter-mediated substrate hydrolysis is visualized and measured. The signal is proportional to the number of test antibodies present in the serum. PMID- 28572189 TI - Cutting Thick Sections Using a Vibratome. AB - Sectioning with a vibrating microtome (vibratome) is a valuable procedure for generating thick sections that can be used for immunohistochemistry and in situ hybridization. It is particularly useful for revealing histological and 3D detail in tissues and embryos that have been subjected to various whole-mount histological procedures such as beta-galactosidase and alkaline phosphatase staining, and fluorescent and DAB (diaminobenzidine) immunostaining. Vibratome sectioning does not involve any harsh organic solvents and is therefore suited for processing specimens stained with fluorescent antibodies or dyes. In addition, live tissue can be sectioned for subsequent culture, manipulation, and live imaging. Very few materials are required for vibratome sectioning, and it is a relatively straightforward procedure that is quickly mastered. This protocol describes basic vibratome sectioning that can be used for any staining procedure typically used in histology. PMID- 28572190 TI - Mounting Mouse Embryos for Microscopic Observation and Imaging. AB - This protocol is used to create a convenient chamber for mouse embryos for microscopic observation and imaging. PMID- 28572191 TI - Differentiating Mouse Embryonic Stem Cells into Embryoid Bodies in AggreWell Plates. AB - Embryonic stem (ES) cells can develop into many types of differentiated tissues if they are placed into a differentiating environment. This can occur in vivo when the ES cells are injected into or aggregated with an embryo, or in vitro if their culture conditions are modified to induce differentiation. Many times ES cell differentiation proceeds through an intermediate stage called the embryoid body (EB). EBs are round structures composed of ES cells that have undergone some of the initial stages of differentiation. EBs can then be manipulated further to generate more specific cell types. The method described here makes use of commercially available AggreWell 400 plates with prefabricated indentations that cradle each EB. Although these plates are relatively expensive, they may be suitable for some high-throughput experiments. This protocol describes the preparation of embryoid bodies of defined size and shape in a large-scale format (approximately 1200 embryoid bodies per preparation). PMID- 28572192 TI - Examining Cholinergic Synaptic Signaling in the Thalamic Reticular Nucleus. AB - This protocol describes how to obtain monosynaptic cholinergic responses in neurons of the thalamic reticular nucleus (TRN) by making use of extracellular stimulation techniques. These methods are easy to implement and allow for the study of various forms of cholinergic synaptic plasticity and modulation. For many synapses throughout the mammalian brain, short-term plasticity is mediated by endocannabinoids released from postsynaptic neurons that activate presynaptic type I cannabinoid receptors (CB1Rs), resulting in the inhibition of presynaptic Ca2+ channels and a reduction of release probability. Neurons in the TRN are known to liberate endocannabinoids that can control transmitter release at GABAergic terminals. However, expression of CB1Rs on cholinergic terminals contacting the TRN has not been demonstrated. Here we outline strategies aimed to record stable postsynaptic responses and to quantify changes in cholinergic synaptic strength, using presynaptic modulation of acetylcholine (ACh) release by a CB1R agonist as an illustrative example. PMID- 28572193 TI - Yeast Nitrogen Base Agar Plates. PMID- 28572194 TI - Yeast Sporulation Medium. PMID- 28572195 TI - Alkylation Buffer (with IAA). PMID- 28572196 TI - Denaturation Buffer. PMID- 28572197 TI - Elution Solution. PMID- 28572198 TI - HPLC Loading Solvent. PMID- 28572199 TI - HPLC Solvent A. PMID- 28572200 TI - HPLC Solvent B. PMID- 28572201 TI - Reduction Buffer (with DTT). PMID- 28572202 TI - SCX Solvent A. PMID- 28572203 TI - SCX Solvent B. PMID- 28572204 TI - SILAC Amino Acids. PMID- 28572205 TI - TiO2 Loading Solution. PMID- 28572206 TI - Washing Solution for TiO2 Beads. PMID- 28572207 TI - EMM2-LowAmm. PMID- 28572208 TI - PBT for Whole-Mount Embryos. PMID- 28572209 TI - Artificial Cerebrospinal Fluid (ACSF) with Antagonists for Glutamatergic and GABAergic Receptors. PMID- 28572210 TI - Genetic Analysis of Complex Traits in Saccharomyces cerevisiae. AB - Defining the relationship between genotype and phenotype is a central challenge in biology. A powerful approach to this problem is to determine the genetic architecture and molecular basis of phenotypic differences among genetically diverse individuals. Saccharomyces cerevisiae is an important model system for such work. Current genetic mapping approaches for this species exploit high throughput phenotyping and sequencing to facilitate the detection of a large fraction of the genomic loci that underlie trait variation among isolates. Once identified, several methods exist to determine the specific genes and genetic variants that underlie these loci and cause phenotypic variations. In this introduction, we provide a brief overview of research on complex traits in yeast and discuss different genetic mapping approaches applied to yeast studies. PMID- 28572211 TI - Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) Technology in Fission Yeast. AB - Shotgun proteomics combined with stable isotope labeling by amino acids in cell culture (SILAC) is a powerful approach to quantify proteins and posttranslational modifications across the entire proteome. SILAC technology in Schizosaccharomyces pombe must cope with the "arginine conversion problem," in which isotope-labeled arginine is converted to other amino acids. This can be circumvented by either using stable isotope-marked lysine only (as opposed to the more standard lysine/arginine double labeling) or using yeast genetics to create strains that only very inefficiently convert arginine. Both strategies have been used successfully in large-scale (phospho)proteomics projects in S. pombe Here we introduce methods for performing a typical SILAC-based experiment in fission yeast, including generation of SILAC-compatible strains, sample preparation, and measurement by mass spectrometry. PMID- 28572212 TI - Fast Cholinergic Synaptic Transmission in the Mammalian Central Nervous System. AB - Release of acetylcholine (ACh) in the brain controls several cognitive processes, and a number of disorders including Alzheimer's and Parkinson's diseases are associated with a loss of cholinergic function. Despite the importance of ACh signaling in modulating information processing in thalamocortical circuits, understanding the dynamics of cholinergic function has long been limited by a lack of in vitro model systems. Recent studies employing both electrical as well as optogenetic stimulation techniques have overcome this challenge, resulting in the identification of multiple forms of fast cholinergic signaling throughout the mammalian brain. Here we highlight a simple strategy making use of extracellular electrical stimulation techniques that allows for the study of cholinergic synaptic inputs onto neurons in the thalamic reticular nucleus (TRN). PMID- 28572213 TI - Cardiorespiratory Fitness and Reclassification of Risk for Incidence of Heart Failure: The Veterans Exercise Testing Study. AB - BACKGROUND: It is well established that cardiorespiratory fitness (CRF) is inversely associated with cardiovascular and all-cause mortality. However, little is known regarding the association between CRF and incidence of heart failure (HF). METHODS AND RESULTS: Between 1987 and 2014, we assessed CRF in 21 080 HF free subjects (58.3+/-11 years) at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, CA. Subjects were classified by age-specific quintiles of CRF. Multivariable Cox models were used to determine the association between HF incidence and clinical and exercise test variables. Reclassification characteristics of fitness relative to standard clinical risk factors were determined using the category-free net reclassification improvement and integrated discrimination improvement indices. During the follow-up (mean 12.3+/ 7.4 years), 1902 subjects developed HF (9.0%; average annual incidence rate, 7.4 events per 1000 person-years). When CRF was considered as a binary variable (unfit/fit), low fitness was the strongest predictor of risk for HF among clinical and exercise test variables (hazard ratio, 1.91; 95% confidence interval, 1.74-2.09; P<0.001). In a fully adjusted model with the least-fit group as the reference, there was a graded and progressive reduction in risk for HF as fitness level was higher. Risks for developing HF were 36%, 41%, 67%, and 76% lower among increasing quintiles of fitness compared with the least-fit subjects (P<0.001). Adding CRF to standard risk factors resulted in a net reclassification improvement of 0.37 (P<0.001). CONCLUSIONS: CRF is strongly, inversely, and independently associated with the incidence of HF in veterans referred for exercise testing. PMID- 28572214 TI - Impact of Preeclampsia on Clinical and Functional Outcomes in Women With Peripartum Cardiomyopathy. AB - BACKGROUND: Preeclampsia is a risk factor for the development of peripartum cardiomyopathy (PPCM), but it is unknown whether preeclampsia impacts clinical or left ventricular (LV) functional outcomes. This study sought to assess clinical and functional outcomes in women with PPCM complicated by preeclampsia. METHODS AND RESULTS: This retrospective cohort study included women diagnosed with PPCM delivering at Barnes-Jewish Hospital between 2004 to 2014. The primary outcome was one-year event-free survival rate for the combined end point of death and hospital readmission. The secondary outcome was recovery of LV ejection fraction. Seventeen of 39 women (44%) with PPCM had preeclampsia. The groups had similar mean LV ejection fraction at diagnosis (29.6 with versus 27.3 without preeclampsia; P=0.5). Women with preeclampsia had smaller mean LV end-diastolic diameters (5.2 versus 6.0 cm; P=0.001), greater relative wall thickness (0.41 versus 0.35 mm Hg; P=0.009), and lower incidence of eccentric remodeling (12% versus 48%; P=0.03). Clinical follow-up was available for 32 women; 5 died of cardiovascular complications within 1 year of diagnosis (4/15 with versus 1/17 without preeclampsia; P=0.16). In time to event analysis, patients with preeclampsia had worse event-free survival during 1-year follow-up (P=0.047). Echocardiographic follow-up was available in 10 survivors with and 16 without preeclampsia. LV ejection fraction recovered in 80% of survivors with versus 25% without preeclampsia (P=0.014). CONCLUSIONS: PPCM with concomitant preeclampsia is associated with increased morbidity and mortality and different patterns of LV remodeling and recovery of LV function when compared with patients with PPCM that is not complicated by preeclampsia. PMID- 28572215 TI - Correction: Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT. PMID- 28572217 TI - Targeting limited NHS resources to affect optimal care. PMID- 28572218 TI - Regulation needs new legislation to get lighter. PMID- 28572219 TI - Is replacement modality choice knowledge important in the non-renal multidisciplinary team? Experience from a single UK centre. AB - Dialysis remains the mainstay treatment for patients with end stage renal disease. In the UK, there has been a significant decline in home dialysis despite its benefits and cost effectiveness. Patients with chronic kidney disease (CKD) are often known to other specialties who they may continue to consult when approaching dialysis. We wished to assess the knowledge of the non-renal multidisciplinary team (MDT) regarding home dialysis and establish whether further education was warranted. This was assessed using an online survey sent to specialties likely to deal with CKD patients. In total, 364 questionnaires were sent out with a 26.4% response rate. According to the survey responses, 81.5% of non-renal MDTs lack confidence in discussing home dialysis options with patients and 74.55% feel that they need further education about home dialysis. Targeted education may increase home dialysis uptake by multimorbid CKD patients who have a consistent message delivered by all relevant healthcare teams about the benefits of home dialysis. PMID- 28572220 TI - mSOAR: an effective bedside stroke prognosis tool. AB - The modified-SOAR (mSOAR) score is composed of the stroke subtype, Oxfordshire Community Stroke Project classification, age, pre-stroke modified Rankin score (mRS) and the National Institutes of Health Stroke Scale score. It has previously been shown to be a reliable predictor of mortality and length of -hospital stay. This study sought to identify whether the mSOAR can also be used to predict patient disability on discharge. A post-hoc calculation of mSOAR using Sentinel Stroke National Audit Programme (SSNAP) data and electronic discharge -summaries was performed on all stroke admissions to Bridgend Hospital over an 11-month period. This study included 230 patients, of which 88% had suffered infarcts and 23% had experienced a previous cerebrovascular episode or transient ischaemic attack; 52% were female. The mortality rate was 13% and 57% had slight disability or less (mRS<=2) on discharge. Each increase in mSOAR score was associated with significantly worse discharge disability (p<0.05). We conclude that the mSOAR score is an excellent tool for predicting both discharge disability and mortality. As such, it's useful for admission prognosis discussions with patients, their relatives and the multidisciplinary team and for early supported discharge decision making. PMID- 28572216 TI - Genetic subclone architecture of tumor clone-initiating cells in colorectal cancer. AB - A hierarchically organized cell compartment drives colorectal cancer (CRC) progression. Genetic barcoding allows monitoring of the clonal output of tumorigenic cells without prospective isolation. In this study, we asked whether tumor clone-initiating cells (TcICs) were genetically heterogeneous and whether differences in self-renewal and activation reflected differential kinetics among individual subclones or functional hierarchies within subclones. Monitoring genomic subclone kinetics in three patient tumors and corresponding serial xenografts and spheroids by high-coverage whole-genome sequencing, clustering of genetic aberrations, subclone combinatorics, and mutational signature analysis revealed at least two to four genetic subclones per sample. Long-term growth in serial xenografts and spheroids was driven by multiple genomic subclones with profoundly differing growth dynamics and hence different quantitative contributions over time. Strikingly, genetic barcoding demonstrated stable functional heterogeneity of CRC TcICs during serial xenografting despite near complete changes in genomic subclone contribution. This demonstrates that functional heterogeneity is, at least frequently, present within genomic subclones and independent of mutational subclone differences. PMID- 28572221 TI - The 2016 update to NICE CG95 guideline for the -investigation of new onset stable chest pain: more -innovation, but at a cost? AB - The National Institute for Health and Care Excellence (NICE) published an update on its guideline on chest pain of recent onset in 2016. The new guideline makes three key changes to the 2010 version. NICE recommend that the previously proposed pre-test probability risk score should no longer be used. They also recommend that a calcium score of zero should no longer be used to rule out coronary artery disease in patients with low pre-test probability. However, the most radical change is that NICE now recommend that all patients with new onset chest pain should be investigated with a computerised tomography coronary angiogram as a first-ine investigation. We discuss the recent trial evidence that has informed the NICE update and consider the impact of the new guidelines. PMID- 28572222 TI - Portal vein thrombosis - a primer for the general physician. AB - Portal vein thrombosis (PVT) is thrombosis of the portal -circulation, which may present with varied symptoms. However, increased use of abdominal imaging has noted a large number of incidental PVT. At the same time, PVT may be overlooked in the absence of the characteristic symptoms. More recently, a JAK2 mutation has been recognised as a cause of PVT. Anticoagulation is the mainstay of treatment, but can pose a dilemma because of the associated coagulopathy, the presence of varices and thrombocytopenia. PMID- 28572223 TI - Developments in therapy with monoclonal antibodies and related proteins. AB - Monoclonal antibody therapeutics have been approved for over 30 targets and diseases, most commonly cancer. Antibodies have become the new backbone of the pharmaceutical industry, which previously relied on small molecules. Compared with small molecules, monoclonal antibodies (mAbs) have exquisite target selectivity and hence less toxicity as a result of binding other targets. The clinical value of both mAbs and ligand traps has been proven. New applications of mAbs are being tested and mAbs have now been designed to target two (bi-specific, eg TNF-alpha and IL-17) or more targets simultaneously, augmenting their therapeutic potential. Because of space limitations and the wide ranging scope of this review there are regrettably, but inevitably, omissions and missing citations. We have chosen to highlight the first successes in inflammatory diseases and cancer, but a broader overview of approved mAbs and related molecules can be found in Table 1. PMID- 28572224 TI - Drug therapy in anticoagulation: which drug for which patient? AB - Four non-vitamin K oral anticoagulants (NOACs) are now licensed and available in the UK, offering unprecedented choices in anticoagulant therapy for clinicians and patients. NOACs have many clear benefits over warfarin, the most striking being the reduction in intracranial haemorrhage. However, a number of uncertainties remain: their efficacy in certain situations, utility of drug assays, significance of drug interactions and management of bleeding. In the absence of any direct comparative trials, it is not clear that any of the NOACs is significantly better than the others in any of the licensed indications. The differential activities, pharmacokinetics, metabolism, excretion and side effects of the agents should be considered when selecting the most appropriate anticoagulant. In this article, we discuss how, with careful selection for the relevant indication, NOACs can simplify therapy while improving outcomes. We aim to provide clinicians with the information needed to select the most suitable anticoagulant drug for an individual patient in a given situation. PMID- 28572225 TI - An unusual case of orthopnea. AB - Bilateral diaphragmatic paralysis is a known cause of respiratory failure. Diagnosis can be difficult, particularly in the acute setting. We present the case of a gentleman diagnosed with bilateral diaphragmatic paralysis secondary to phrenic neuropathy in the setting of cervical spondylosis. PMID- 28572226 TI - A clinical enigma of ongoing constrictive pericarditis. AB - A 59-year-old lady presented with a 1-week history of orthopnoea, paroxysmal nocturnal dyspnoea, night sweats and a productive cough. She had no recent history of travel. Transthoracic echocardiogram revealed preserved left ventricular systolic function with abnormal pericardial thickening and restrictive left ventricular filling consistent with pericardial constriction. Cardiac magnetic resonance imaging confirmed a globally thickened pericardium and showed evidence of pericardial inflammation and constrictive physiology. She did not respond to diuresis, pulsed intravenous steroids or broad spectrum antibiotics and multiple investigations were negative, including autoimmune screen and tuberculosis cultures. Eventually a serum sample was found to be positive for Strongyloides stercoralis and it emerged that this lady had travelled to Egypt 8 years previously, where it is thought that she contracted S stercoralis leading to her developing constrictive pericarditis. This case report summarises the presentation and progression of this case and rare diagnosis. PMID- 28572227 TI - Medical problems in pregnancy. AB - The prevalence of medical problems in pregnancy is increasing because of a complex interplay between demographic and lifestyle factors, and developments in modern medicine. Maternal mortality and morbidity resulting from treatable medical conditions, such as venous thromboembolism, epilepsy and autoimmune disease, have not decreased in recent years. This is despite a marked decrease in overall maternal mortality. It is vital that all physicians acquire a basic knowledge and understanding of medical problems in pregnancy. This includes prepregnancy measures such as counselling and optimisation of medical therapy, as well as multidisciplinary management throughout pregnancy and the postpartum period. Prompt recognition and treatment of acute and chronic illness is of clear benefit, and most drugs and many radiological investigations may be used in pregnancy. PMID- 28572228 TI - Adrenal insufficiency - recognition and management. AB - Adrenal insufficiency is characterised by inadequate -glucocorticoid production owing to destruction of the adrenal cortex or lack of adrenocorticotropic hormone stimulation. In primary adrenal insufficiency, lack of mineralocorticoids is also a feature. Patients can present with an insidious onset of symptoms, or acutely in adrenal crisis, which requires prompt recognition and treatment. Chronic glucocorticoid therapy is the most common cause of adrenal insufficiency. The diagnosis of adrenal insufficiency is made by -demonstrating low basal and/or stimulated serum cortisol and should be -followed by appropriate investigations to establish the -underlying aetiology. Maintenance glucocorticoid -replacement is usually given as a twice or thrice daily hydrocortisone preparation. Patients with primary adrenal insufficiency also require mineralocorticoid. Regular monitoring for features of under- and over- replacement is essential during follow-up. Patient education is a key feature of management of this condition. PMID- 28572229 TI - Hyponatraemia - presentations and management. AB - Hyponatraemia is the most common electrolyte disturbance encountered in clinical practice. It is associated with -significant morbidity and mortality, thus appropriate investigation and treatment is essential. Hyponatraemia presents with a spectrum of clinical presentations ranging from no symptoms to life-threatening neurological sequelae. Hyponatraemia has multiple aetiologies and distinguishing the underlying aetiology facilitates appropriate treatment. This review provides an overview of the presentations and approaches to management of this common clinical condition. PMID- 28572230 TI - Hypercalcaemia - presentation and management . AB - Hypercalcaemia is a common disorder normally caused by primary hyperparathyroidism (PHPT) or malignancy. A proportion of cases present as an emergency, which carries a significant mortality. Emergency management of hypercalcaemia is based on intravenous rehydration with normal saline but when this is inadequate, bisphosphonate therapy is used; more recently the novel anti resorbtive agent denosumab has been shown to have a useful role in treatment. It is estimated that up to 10% of all cases of PHPT presenting under the age of 45 years have an underlying genetic predisposition; nine potentially causative genes are now recognised and may be screened in routine clinical practice. Although parathyroidectomy is the only curative treatment for PHPT, this is indicated in a minority of cases. Many cases can be adequately managed conservatively and guidance from the 4th international workshop on the management of asymptomatic PHPT has recently been updated in a consensus statement. PMID- 28572231 TI - Thyrotoxicosis - investigation and management . AB - Graves' disease (GD) and toxic nodular (TN) goitre account for most cases of thyrotoxicosis associated with hyperthyroidism. Hyperthyroidism is confirmed with measurement of a suppressed serum thyrotropin concentration (TSH) and elevated free thyroid hormones. The three therapeutic options are antithyroid drugs, radioactive iodine and surgery. Thionamides achieve long-term remission in 35% of cases. Many centres administer fixed doses of iodine-131; larger doses result in improved rates of cure at the cost of hypothyroidism. Surgery is usually considered for patients who have a large goitre, compressive symptoms or significant ophthalmopathy. PMID- 28572232 TI - CME Endocrinology (108461): self-assessment questionnaire. PMID- 28572233 TI - Lesson of the month 1: Septic arthritis with normal acute phase reactants and white cell count in a patient receiving tocilizumab. AB - Septic arthritis represents 8-27% of cases of monoarthritis presenting to the emergency department. Tocilizumab is an interleukin-6 blocking monoclonal antibody with the mechanistic potential to interfere with the body's normal inflammatory response to an infectious insult. We present a case of septic arthritis with a normal white cell count, C-reactive protein, erythrocyte sedimentation rate and fibrinogen in a patient treated with tocilizumab. PMID- 28572234 TI - Lesson of the month 2: Contusion confusion. AB - This lesson of the month highlights that certain radiology terminology may be used to report bleeding on head computerised tomography (CT) reports. On-call junior doctors should not be expected to interpret CT head images, so often their decisions will be based on the written report. The wording used can change the clinical decision and therefore the treatment given by a junior doctor. Clinical teams and junior doctors should be educated on terminology in relation to bleeding on CT head reports. PMID- 28572235 TI - Image of the month: Gallstone ileus. PMID- 28572236 TI - Meeting the clinical needs of patients with progressive multiple sclerosis. PMID- 28572237 TI - Central lines and the general medical register - time for a change in the curriculum? PMID- 28572238 TI - Lead or be led: an update on leadless cardiac devices for general physicians. PMID- 28572240 TI - Healthcare professionals need more training about human trafficking and the safe use of interpreters. PMID- 28572242 TI - Response by Boulouis et al to Letter Regarding Article, "Primary Angiitis of the Central Nervous System: Magnetic Resonance Imaging Spectrum of Parenchymal, Meningeal, and Vascular Lesions at Baseline". PMID- 28572243 TI - Letter by Stanley et al Regarding Article, "Primary Angiitis of the Central Nervous System Magnetic Resonance Imaging Spectrum of Parenchymal, Meningeal, and Vascular Lesions at Baseline". PMID- 28572241 TI - PKC/Nedd4-2 Signaling Pathway Regulates the Cell Surface Expression of Drug Transporter hOAT1. AB - Human organic anion transporter-1 (hOAT1) regulates the absorption, distribution, and excretion of a wide range of clinically important drugs. Our previous work demonstrated that hOAT1 is a dynamic membrane transporter, constitutively internalizing from and recycling back to the cell plasma membrane. Short-term activation (<30 minutes) of protein kinase C (PKC) promotes the attachment of a lysine 48-linked polyubiquitin chain to hOAT1, a process catalyzed by ubiquitin ligase neural precursor cell expressed developmentally down-regulated 4-2 (Nedd4 2). The ubiquitination of hOAT1 then triggers an accelerated endocytosis of the transporter from plasma membrane, which results in reduced hOAT1 expression at the cell surface and decreased hOAT1 transport activity. In the present study, we investigated the long-term effect of PKC on hOAT1. We showed that long-term activation (>2 hours) of PKC significantly enhanced hOAT1 degradation, and such action was partially blocked by ubiquitin mutant Ub-K48R, which has its lysine (K) 48 mutated to arginine (R) and is incapable of forming a K48-linked polyubiquitin chain. The ubiquitin ligase Nedd4-2 was also found to augment hOAT1 degradation. These results suggest that PKC-regulated and Nedd4-2-catalyzed attachment of a lysine 48-linked polyubiquitin chain to hOAT1 is important for hOAT1 stability. We further showed through coimmunoprecipitation experiments that there was a direct association between hOAT1 and Nedd4-2, and such interaction was weakened when the WW3 and WW4 domains of the ligase were mutated. Mutating WW3 and WW4 domains of the ligase also impaired its ability to ubiquitinate hOAT1. Therefore, WW3 and WW4 domains of Nedd4-2 are critical for its association with and modulation of the transporter. PMID- 28572244 TI - Richard Paul Hyde Dunnill. PMID- 28572245 TI - More ways to successfully supplement vitamin D. PMID- 28572246 TI - Reply to JP van Wouwe and CI Lanting. PMID- 28572247 TI - Dietary fat restrictions in young children and the later risk of obesity. PMID- 28572248 TI - Meta-analysis of red meat intake and cardiovascular risk factors: methodologic limitations. PMID- 28572249 TI - Reply to MF Rolland-Cachera et al. PMID- 28572254 TI - Base Pairs to Populations. PMID- 28572250 TI - Reply to A Satija et al. PMID- 28572255 TI - Unmet Needs in Clinical Research in Breast Cancer: Where Do We Need to Go? AB - This CCR Focus highlights areas in breast cancer research with the greatest potential for clinical and therapeutic application. The articles in this CCR Focus address the state of the science in a broad range of areas with a focus on "hot" although sometimes controversial topics, unanswered questions, and unmet need. From mutational signatures, the cancer genomic revolution, and new inroads in immunotherapy for breast cancer to unique concerns of vulnerable populations as well as national and global health disparities, these works represent much of the promise of breast cancer research as well as the challenges in the coming years. Each review focuses not only on recent discoveries but also on putting the topic in context, including limitations to overcome. This overview is designed to further contextualize the highlighted issues within the broader research landscape. We also present new information from a poll of ALLIANCE for Clinical Trials in Oncology Breast Committee members regarding the most needed and viable potential future National Cancer Institute (NCI)-supported clinical trials in breast cancer. The great challenge is to translate the potential benefits of greater scientific knowledge reflected in this CCR Focus section into improvements in outcomes for individuals and populations with breast cancer. A unifying theme across the six articles contained in this CCR Focus is the increasingly recognized value and necessity of collaboration across disciplines from bench to bedside to populations. Only continued and iteratively amplified scientific, clinical, and governmental commitment to creating, testing, and implementing new knowledge will reduce the global morbidity and mortality of breast cancer. Clin Cancer Res; 23(11); 2611-6. (c)2017 AACRSee all articles in this CCR Focus section, "Breast Cancer Research: From Base Pairs to Populations." PMID- 28572257 TI - Translational Genomics: Practical Applications of the Genomic Revolution in Breast Cancer. AB - The genomic revolution has fundamentally changed our perception of breast cancer. It is now apparent from DNA-based massively parallel sequencing data that at the genomic level, every breast cancer is unique and shaped by the mutational processes to which it was exposed during its lifetime. More than 90 breast cancer driver genes have been identified as recurrently mutated, and many occur at low frequency across the breast cancer population. Certain cancer genes are associated with traditionally defined histologic subtypes, but genomic intertumoral heterogeneity exists even between cancers that appear the same under the microscope. Most breast cancers contain subclonal populations, many of which harbor driver alterations, and subclonal structure is typically remodeled over time, across metastasis and as a consequence of treatment interventions. Genomics is deepening our understanding of breast cancer biology, contributing to an accelerated phase of targeted drug development and providing insights into resistance mechanisms. Genomics is also providing tools necessary to deliver personalized cancer medicine, but a number of challenges must still be addressed. Clin Cancer Res; 23(11); 2630-9. (c)2017 AACRSee all articles in this CCR Focus section, "Breast Cancer Research: From Base Pairs to Populations." PMID- 28572256 TI - Mutational Signatures in Breast Cancer: The Problem at the DNA Level. AB - A breast cancer genome is a record of the historic mutagenic activity that has occurred throughout the development of the tumor. Indeed, every mutation may be informative. Although driver mutations were the main focus of cancer research for a long time, passenger mutational signatures, the imprints of DNA damage and DNA repair processes that have been operative during tumorigenesis, are also biologically illuminating. This review is a chronicle of how the concept of mutational signatures arose and brings the reader up-to-date on this field, particularly in breast cancer. Mutational signatures have now been advanced to include mutational processes that involve rearrangements, and novel cancer biological insights have been gained through studying these in great detail. Furthermore, there are efforts to take this field into the clinical sphere. If validated, mutational signatures could thus form an additional weapon in the arsenal of cancer precision diagnostics and therapeutic stratification in the modern war against cancer. Clin Cancer Res; 23(11); 2617-29. (c)2017 AACRSee all articles in this CCR Focus section, "Breast Cancer Research: From Base Pairs to Populations." PMID- 28572259 TI - Emerging Data and Current Challenges for Young, Old, Obese, or Male Patients with Breast Cancer. AB - There are distinct subgroups of patients who have historically been underrepresented in most prospective clinical trials in breast cancer, including the youngest and oldest patients, male patients, and those struggling with obesity. Herein, we review current and future directions in research for each of these special populations with breast cancer, highlighting significant knowledge gaps and priorities in tumor biology and heterogeneity, therapeutic decision making promotion of adherence, supportive care, and psychosocial and functional well-being. In younger women, future study should focus on the biological underpinnings of aggressive disease and optimizing adherence and treatment decision making while addressing their unique survivorship needs. The latter includes generating a scientific basis for interruption of therapy for pregnancy. Among older patients, interventions should focus on increasing clinical trial accrual, predicting and mitigating toxicity so that functional status can be optimized, tailoring needs for dose modification, and anticipating life expectancy in the context of competing causes of death. For men with breast cancer, we need worldwide collaboration to answer even basic questions on optimal treatment, supportive care, and survivorship strategies. Finally, for those struggling with obesity, we need to better understand the biological associations with cancer incidence, prognosis and outcome, and how we can best intervene to assure weight loss at the "right time." It is only through highly collaborative, far-reaching, prospective, multidisciplinary, patient-centered, and patient engaged efforts that we can optimize the physical and psychologic outcomes for all patients with breast cancer. Clin Cancer Res; 23(11); 2647-54. (c)2017 AACRSee all articles in this CCR Focus section, "Breast Cancer Research: From Base Pairs to Populations." PMID- 28572258 TI - Immunotherapy for Breast Cancer: What Are We Missing? AB - The recent demonstration of modest single-agent activity of programmed death ligand 1 (PD-L1) and programmed death receptor-1 (PD-1) antibodies in patients with breast cancer has generated hope that breast cancer can be made amenable to immunotherapy. Depending on the subtype of breast cancer, it is now clear in both primary and metastatic disease that the extent of tumor-infiltrating T cells is not only prognostic for survival but predictive of response to nonimmune, standard therapies. Despite these findings, immune cytolytic activity in spontaneous breast tumors, the burden of nonsynonymous tumor mutations, and the predicted load of neoepitopes-factors linked to response to checkpoint blockade in other malignancies-are all relatively modest in breast cancer compared with melanoma or lung cancer. Thus, in breast cancer, combinations of immune agents with nonredundant mechanisms of action are high-priority strategies. For most breast cancers that exhibit relatively modest T-cell infiltration, major challenges include immune suppression in the tumor microenvironment as well as failed or suboptimal T-cell priming. Agents that trigger de novo T-cell responses may be critical for the successful development of cancer immunotherapy and immune prevention in breast cancer. Success may also require reaching beyond nonsynonymous mutations as the T-cell epitopes to target, especially as numerous unmutated proteins were validated as breast cancer-associated antigens in the pre checkpoint era. A deeper understanding of the immunobiology of breast cancer will be critical for immunotherapy to become broadly relevant in this disease. Clin Cancer Res; 23(11); 2640-6. (c)2017 AACRSee all articles in this CCR Focus section, "Breast Cancer Research: From Base Pairs to Populations." PMID- 28572261 TI - Pediatric Cancer Predisposition and Surveillance: An Overview, and a Tribute to Alfred G. Knudson Jr. AB - The prevalence of childhood cancer attributable to genetic predisposition was generally considered very low. However, recent reports suggest that at least 10% of pediatric cancer patients harbor a germline mutation in a cancer predisposition gene. Although some of these children will have a family history suggestive of a cancer predisposition syndrome, many others will not. Evidence from recent pediatric studies suggests that surveillance and early detection of cancer in individuals carrying a germline cancer predisposing mutation may result in improved outcomes. However, there is a lack of consistency in the design of cancer surveillance regimens across centers both nationally and internationally. To standardize approaches, the Pediatric Cancer Working Group of the American Association for Cancer Research (AACR) convened a workshop, during which consensus screening recommendations for children with the most common cancer predisposition syndromes were developed. In general, we considered a 5% or greater chance of developing a childhood cancer to be a reasonable threshold to recommend screening. Conditions for which the cancer risk was between 1% to 5% were addressed individually. In a series of manuscripts accompanying this article, we provide recommendations for surveillance, focusing on when to initiate and/or discontinue specific screening measures, which modalities to use, and the frequency of screening. Points of controversy are also reviewed. We present the outcome of our deliberations on consensus screening recommendations for specific disorders in 18 position articles as Open Access publications, which are freely available on an AACR-managed website. Clin Cancer Res; 23(11); e1-e5. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28572262 TI - Pediatric Cancer Predisposition Imaging: Focus on Whole-Body MRI. AB - The American Association for Cancer Research convened a meeting of international pediatric oncologists, geneticists, genetic counselors, and radiologists expert in childhood cancer predisposition syndromes (CPS) in October 2016 to propose consensus surveillance guidelines. Imaging plays a central role in surveillance for most, though not all, syndromes discussed. While encompassing the full gamut of modalities, there is increasing emphasis on use of nonionizing radiation imaging options such as magnetic resonance imaging (MRI) in children and adolescents, especially in the pediatric CPS population. In view of rapid evolution and widespread adoption of whole-body MRI (WBMRI), the purpose of our review is to address WBMRI in detail. We discuss its place in the surveillance of a range of pediatric CPS, the technical and logistical aspects of acquiring and interpreting these studies, and the inherent limitations of WBMRI. We also address issues associated with sedation and use of gadolinium-based contrast agents in MRI in children. Clin Cancer Res; 23(11); e6-e13. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28572260 TI - Breast Cancer Disparities at Home and Abroad: A Review of the Challenges and Opportunities for System-Level Change. AB - Sizeable disparities exist in breast cancer outcomes, both between Black and White patients in the United States, and between patients in the United States and other high-income countries compared with low- and middle-income countries (LMIC). In both settings, health system factors are key drivers of disparities. In the United States, Black women are more likely to die of breast cancer than Whites and have poorer outcomes, even among patients with similar stage and tumor subtype. Over-representation of higher risk "triple-negative" breast cancers contributes to breast cancer mortality in Black women; however, the greatest survival disparities occur within the good-prognosis hormone receptor-positive (HR+) subtypes. Disparities in access to treatment within the complex U.S. health system may be responsible for a substantial portion of these differences in survival. In LMICs, breast cancer mortality rates are substantially higher than in the United States, whereas incidence continues to rise. This mortality burden is largely attributable to health system factors, including late-stage presentation at diagnosis and lack of availability of systemic therapy. This article will review the existing evidence for how health system factors in the United States contribute to breast cancer disparities, discuss methods for studying the relationship of health system factors to racial disparities, and provide examples of health system interventions that show promise for mitigating breast cancer disparities. We will then review evidence of global breast cancer disparities in LMICs, the treatment factors that contribute to these disparities, and actions being taken to combat breast cancer disparities around the world. Clin Cancer Res; 23(11); 2655-64. (c)2017 AACRSee all articles in this CCR Focus section, "Breast Cancer Research: From Base Pairs to Populations." PMID- 28572263 TI - Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions. AB - Leukemia, the most common childhood cancer, has long been recognized to occasionally run in families. The first clues about the genetic mechanisms underlying familial leukemia emerged in 1990 when Li-Fraumeni syndrome was linked to TP53 mutations. Since this discovery, many other genes associated with hereditary predisposition to leukemia have been identified. Although several of these disorders also predispose individuals to solid tumors, certain conditions exist in which individuals are specifically at increased risk to develop myelodysplastic syndrome (MDS) and/or acute leukemia. The increasing identification of affected individuals and families has raised questions around the efficacy, timing, and optimal methods of surveillance. As part of the AACR Childhood Cancer Predisposition Workshop, an expert panel met to review the spectrum of leukemia-predisposing conditions, with the aim to develop consensus recommendations for surveillance for pediatric patients. The panel recognized that for several conditions, routine monitoring with complete blood counts and bone marrow evaluations is essential to identify disease evolution and enable early intervention with allogeneic hematopoietic stem cell transplantation. However, for others, less intensive surveillance may be considered. Because few reports describing the efficacy of surveillance exist, the recommendations derived by this panel are based on opinion, and local experience and will need to be revised over time. The development of registries and clinical trials is urgently needed to enhance understanding of the natural history of the leukemia predisposing conditions, such that these surveillance recommendations can be optimized to further enhance long-term outcomes. Clin Cancer Res; 23(11); e14 e22. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28572265 TI - Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood. AB - Replication proofreading is crucial to avoid mutation accumulation in dividing cells. In humans, proofreading and replication repair is maintained by the exonuclease domains of DNA polymerases and the mismatch repair system. Individuals harboring germline mutations in genes involved in this process are at increased risk of early cancers from multiple organs. Biallelic mutations in any of the four mismatch repair genes MSH2, MSH6, MLH1, and PMS2 result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency or constitutional mismatch repair deficiency syndrome (CMMRD). Data gathered in the last decade allow us to better define the clinical manifestations, tumor spectrum, and diagnostic algorithms for CMMRD. In this article, we summarize this information and present a comprehensive consensus surveillance protocol for these individuals. Ongoing research will allow for further definition of replication repair-deficient cancer syndromes, assessing the cost-effectiveness of such surveillance protocols and potential therapeutic interventions for these children and families. Clin Cancer Res; 23(11); e32-e37. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28572264 TI - Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders. AB - DNA repair syndromes are heterogeneous disorders caused by pathogenic variants in genes encoding proteins key in DNA replication and/or the cellular response to DNA damage. The majority of these syndromes are inherited in an autosomal recessive manner, but autosomal-dominant and X-linked recessive disorders also exist. The clinical features of patients with DNA repair syndromes are highly varied and dependent on the underlying genetic cause. Notably, all patients have elevated risks of syndrome-associated cancers, and many of these cancers present in childhood. Although it is clear that the risk of cancer is increased, there are limited data defining the true incidence of cancer and almost no evidence based approaches to cancer surveillance in patients with DNA repair disorders. This article is the product of the October 2016 AACR Childhood Cancer Predisposition Workshop, which brought together experts from around the world to discuss and develop cancer surveillance guidelines for children with cancer-prone disorders. Herein, we focus on the more common of the rare DNA repair disorders: ataxia telangiectasia, Bloom syndrome, Fanconi anemia, dyskeratosis congenita, Nijmegen breakage syndrome, Rothmund-Thomson syndrome, and Xeroderma pigmentosum. Dedicated syndrome registries and a combination of basic science and clinical research have led to important insights into the underlying biology of these disorders. Given the rarity of these disorders, it is recommended that centralized centers of excellence be involved directly or through consultation in caring for patients with heritable DNA repair syndromes. Clin Cancer Res; 23(11); e23-e31. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28572268 TI - Oral fluid testing for marijuana intoxication: enhancing objectivity for roadside DUI testing. AB - Reducing marijuana-impaired driving is an important part of any strategy to prevent motor vehicle traffic injuries. In Colorado, the first of eight US states and the District of Columbia to legalise marijuana for recreational use, drivers with positive tests for the presence of marijuana accounted for a larger proportion of fatal MVCs after marijuana commercialisation. The use of blood tests to screen for marijuana intoxication, in Colorado and elsewhere in the USA, poses a number of challenges. Many high-income countries use oral fluid drug testing (OF) to provide roadside evidence of marijuana intoxication. A 2009 Belgium policy implementing OF roadside testing increased true positives and decreased false positives of suspected marijuana-related driving under the influence (DUI) arrests. US policy-makers should consider using roadside OF to increase objectivity and reliability for tests used in marijuana-related DUI arrests. PMID- 28572266 TI - Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome. AB - Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited condition caused by germline mutations of the TP53 tumor suppressor gene encoding p53, a transcription factor triggered as a protective cellular mechanism against different stressors. Loss of p53 function renders affected individuals highly susceptible to a broad range of solid and hematologic cancers. It has recently become evident that children and adults with LFS benefit from intensive surveillance aimed at early tumor detection. In October 2016, the American Association for Cancer Research held a meeting of international LFS experts to evaluate the current knowledge on LFS and propose consensus surveillance recommendations. Herein, we briefly summarize clinical and genetic aspects of this aggressive cancer predisposition syndrome. In addition, the expert panel concludes that there are sufficient existing data to recommend that all patients with LFS be offered cancer surveillance as soon as the clinical or molecular LFS diagnosis is established. Specifically, the panel recommends adoption of a modified version of the "Toronto protocol" that includes a combination of physical exams, blood tests, and imaging. The panel also recommends that further research be promoted to explore the feasibility and effectiveness of these risk adapted surveillance and cancer prevention strategies while addressing the psychosocial needs of individuals and families with LFS. Clin Cancer Res; 23(11); e38-e45. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28572269 TI - Estimated total costs from non-fatal and fatal bicycle crashes in the USA: 1997 2013. AB - INTRODUCTION: Emergency department visits and hospital admissions resulting from adult bicycle trauma have increased dramatically. Annual medical costs and work losses of these incidents last were estimated for 2005 and quality-of-life losses for 2000. METHODS: We estimated costs associated with adult bicycle injuries in the USA using 1997-2013 non-fatal incidence data from the National Electronic Injury Surveillance System with cost estimates from the Consumer Product Safety Commission's Injury Cost Model, and 1999-2013 fatal incidence data from the National Vital Statistics System costed by similar methods. RESULTS: Approximately 3.8 million non-fatal adult bicycle injuries were reported during the study period and 9839 deaths. In 2010 dollars, estimated adult bicycle injury costs totalled $24.4 billion in 2013. Estimated injury costs per mile bicycled fell from $2.85 in 2001 to $2.35 in 2009. From 1999 to 2013, total estimated costs were $209 billion due to non-fatal bicycle injuries and $28 billion due to fatal injuries. Inflation-free annual costs in the study period increased by 137% for non-fatal injuries and 23% for fatal injuries. The share of non-fatal costs associated with injuries to riders age 45 and older increased by 1.6% (95% CI 1.4% to 1.9%) annually. The proportion of costs due to incidents that occurred on a street or highway steadily increased by 0.8% (95% CI 0.4% to 1.3%) annually. CONCLUSIONS: Inflation-free costs per case associated with non-fatal bicycle injuries are increasing. The growth in costs is especially associated with rising ridership, riders 45 and older, and street/highway crashes. PMID- 28572270 TI - Editorial: Modulation of HMGB1 holds promise for managing sepsis immune paralysis. PMID- 28572271 TI - Editorial: IL-27 expression following TLR activation in bone: sounding the alarm for repair. PMID- 28572272 TI - A novel prion protein variant in a patient with semantic dementia. PMID- 28572273 TI - Laughter, crying and sadness in ALS. AB - BACKGROUND: Pseudobulbar affect (PBA) is prevalent in amyotrophic lateral sclerosis (ALS), but there is limited information on its associations and course. OBJECTIVES: Explore prevalence, associations, course and manifestations of PBA in outpatient cohort of patients with ALS and examine its relationship to depression. METHODS: Self-reported measures of PBA and depression (Center for Neurologic Study-Lability Scale (CNS-LS) and Patient Health Questionnaire (PHQ 9), respectively) were obtained from consecutive patients with ALS using tablet devices in waiting rooms (Knowledge Program). RESULTS: PBA (CNS-LS >=13) was seen in 209/735 patients (28.4%). PBA was associated with bulbar onset and dysfunction, upper motor neuron dysfunction, cognitive impairment, depression and lower quality of life. A multivariable model that included lower bulbar and gross motor subscores, female gender, younger age and shorter duration of disease predicted PBA with 74% accuracy. CNS-LS scores increased only slowly with time. Women with PBA reported more crying than men. Crying (but not laughter) correlated with depression, and crying was associated with poorer quality of life. Exploratory factor analysis of pooled questions of CNS-LS and PHQ-9 identified three underlying factors (laughter, crying and depression) loaded on appropriate questions of the respective instruments. CONCLUSION: This study identifies associations of PBA and additionally finds PBA (especially crying predominant PBA) more prevalent in women with ALS. Although the two self-report instruments (CNS-LS and PHQ-9) discriminate well between PBA and depression, there is significant overlap between depression and crying in PBA. Studies of PBA should stratify for gender, examine crying and laughter as separate outcomes and adjust for depression. PMID- 28572274 TI - CASPR2 autoantibodies are raised during pregnancy in mothers of children with mental retardation and disorders of psychological development but not autism. AB - BACKGROUND, METHODS AND OBJECTIVES: Maternal autoantibodies to neuronal proteins may be one cause of neurodevelopmental disorders. This exploratory study used the Danish archived midgestational sera and their nationwide registers to search for antibodies to the N-methyl-D-aspartate receptor (NMDAR) and contactin-associated protein-like 2 (CASPR2) in maternal sera, and to relate them to subsequent psychiatric diagnoses in the woman or her child. RESULTS: In a sample of 192 women, there was no association between antibody status and subsequent psychosis in the mothers. However, NMDAR antibodies (n=4) or CASPR2 antibodies (n=1) were identified in 5/11 (45.5%) women whose children were given a diagnosis of mild or unspecified mental retardation or disorders of psychological and motor development (collectively abbreviated as mental retardation and/or disorders of psychological development (MR/DPD)) compared with 9/176 (5.1%) of the remaining mother (p<0.001). These findings were followed up in a specifically selected cohort, in which CASPR2 antibodies were detected in 7/171 (4.1%) mothers of MR/DPD progeny, compared with only 1/171 (0.6%) control mother (p=0.067). The combined sample showed a significantly higher frequency of CASPR2 antibodies in mothers of MD/DPD children (p=0.01). These autoantibodies were not increased in mothers of children with autistic spectrum disorder. CONCLUSIONS: These findings complement the known roles of CASPR2 in brain development, and warrant further epidemiological and experimental studies to clarify the role of CASPR2 and possibly other antibodies in neurodevelopmental disorders. PMID- 28572276 TI - Sir Henry Head FRS (1861-1940): a life in science and society. PMID- 28572275 TI - Truncating mutations in SPAST patients are associated with a high rate of psychiatric comorbidities in hereditary spastic paraplegia. AB - BACKGROUND: The hereditary spastic paraplegias (HSPs) are a rare and heterogeneous group of neurodegenerative disorders that are clinically characterised by progressive lower limb spasticity. They are classified as either 'pure' or 'complex' where spastic paraplegia is complicated with additional neurological features. Mutations in the spastin gene (SPAST) are the most common cause of HSP and typically present with a pure form. METHODS: We assessed in detail the phenotypic and genetic spectrum of SPAST-related HSP focused on 118 patients carrying SPAST mutations. RESULTS: This study, one of the largest cohorts of genetically confirmed spastin patients to date, contributes with the discovery of a significant number of novel SPAST mutations. Our data reveal a high rate of complex cases (25%), with psychiatric disorders among the most common comorbidity (10% of all SPASTpatients). Further, we identify a genotype phenotype correlation between patients carrying loss-of-function mutations in SPAST and the presence of psychiatric disorders. PMID- 28572278 TI - Epilepsy treatment priorities: answering the questions that matter. PMID- 28572279 TI - A painful lesion on the abdomen. PMID- 28572277 TI - Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response. AB - OBJECTIVE: To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD). DESIGN: This is a retrospective cohort study conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4 antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes. RESULTS: 265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-beta (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-beta, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065). CONCLUSIONS: Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-beta. PMID- 28572284 TI - BAX inhibitor-1 regulates autophagy by controlling the IRE1alpha branch of the unfolded protein response. PMID- 28572283 TI - Impact of Mean Transaortic Pressure Gradient on Long-Term Outcome in Patients With Severe Aortic Stenosis and Preserved Left Ventricular Ejection Fraction. AB - BACKGROUND: Mean transaortic pressure gradient (MTPG) has never been validated as a predictor of mortality in patients with severe aortic stenosis. We sought to determine the value of MTPG to predict mortality in a large prospective cohort of severe aortic stenosis patients with preserved left ventricular ejection fraction and to investigate the cutoff of 60 mm Hg, proposed in American guidelines. METHODS AND RESULTS: A total of 1143 patients with severe aortic stenosis defined by aortic valve area <=1 cm2 and MTPG >=40 mm Hg were included. The population was divided into 3 groups according to MTPG: between 40 and 49 mm Hg, between 50 and 59 mm Hg, and >=60 mm Hg. The end point was all-cause mortality. MTPG was >=60 mm Hg in 392 patients. Patients with MTPG >=60 mm Hg had a significantly increase risk of mortality compared with patients with MTPG <60 mm Hg (hazard ratio [HR]=1.62 [1.27-2.05] P<0.001), even for the subgroup of asymptomatic or minimally symptomatic patients (HR=1.56 [1.04-2.34] P=0.032). After adjustment for established outcome predictors, patients with MTPG >=60 mm Hg had a significantly higher risk of mortality than patients with MTPG <60 mm Hg (HR=1.71 [1.33-2.20] P<0.001), even after adjusting for surgery as a time-dependent variable (HR=1.71 [1.43-2.11] P<0.001). Similar results were observed for the subgroup of asymptomatic or minimally symptomatic patients (HR=1.70 [1.10-2.32] P=0.018 and HR=1.68 [1.20-2.36] P=0.003, respectively). CONCLUSIONS: This study shows the negative prognostic impact of high MTPG (>=60 mm Hg), on long-term outcome of patients with severe aortic stenosis with preserved left ventricular ejection fraction, irrespective of symptoms. PMID- 28572280 TI - Blood-Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke. PMID- 28572282 TI - CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage. AB - BACKGROUND: Intracerebral hemorrhage (ICH) is an acute neurological disorder with high mortality and no effective treatment. In addition to the initial bleeding event, rebleeding and hematoma expansion are associated with poor outcome in these patients. We studied the effectiveness of the new antifibrinolytic agent CM352, a short-half-life matrix metalloproteinase inhibitor, for achieving early hemostasis and improving functional recovery in a rat model of collagenase induced ICH. METHODS AND RESULTS: ICH was induced by striatal injection of collagenase, and 1 hour later, rats received an intravenous injection of saline (n=6) or CM352 (1 mg/kg, n=6). Hematoma (basal and after 3 and 24 hours) and lesion (14 days) volumes were quantified on T2-weighted (T2) magnetic resonance images. Neurological and functional recovery was evaluated by using Bederson score and a cylinder test (basal, 24 hours, and 14 days). Early treatment (1 hour) with CM352 was efficient reducing hematoma expansion at 3 hours (P<0.01) and, more markedly, at 24 hours (P<0.01). Decreased bleeding after antifibrinolytic treatment was accompanied by reduced interleukin-6 levels at 3 hours (P<0.05) and smaller lesion volume at 14 days (P<0.01). CM352 drastically reduced sensorimotor impairment (cylinder test) after ICH in rats at 24 hours (P<0.01) and 14 days (P<0.01). Similarly, it also attenuated neurological deficit (Bederson scale) at 24 hours (P<0.01) and 14 days (P<0.01). Interestingly, late (3 hours) CM352 administration also resulted in reduced lesion size and better functional outcome. CONCLUSIONS: CM352, a new antifibrinolytic agent and matrix metalloproteinase inhibitor, effectively prevented hematoma growth and reduced lesion size in ICH in association with improved functional and neurological recovery. PMID- 28572285 TI - Plant virus-mediated induction of miR168 is associated with repression of ARGONAUTE1 accumulation. PMID- 28572281 TI - Recurrent Stroke in Minor Ischemic Stroke or Transient Ischemic Attack With Metabolic Syndrome and/or Diabetes Mellitus. AB - BACKGROUND: We aimed to determine the risk conferred by metabolic syndrome (METS) and diabetes mellitus (DM) to recurrent stroke in patients with minor ischemic stroke or transient ischemic attack from the CHANCE (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events) trial. METHODS AND RESULTS: In total, 3044 patients were included. Patients were stratified into 4 groups: neither, METS only, DM only, or both. METS was defined using the Chinese Diabetes Society (CDS) and International Diabetes Foundation (IDF) definitions. The primary outcome was new stroke (including ischemic and hemorrhagic) at 90 days. A multivariable Cox regression model was used to assess the relationship of METS and DM status to the risk of recurrent stroke adjusted for potential covariates. Using the CDS criteria of METS, 53.2%, 17.2%, 19.8%, and 9.8% of patients were diagnosed as neither, METS only, DM only, and both, respectively. After 90 days of follow-up, there were 299 new strokes (293 ischemic, 6 hemorrhagic). Patients with DM only (16.1% versus 6.8%; adjusted hazard ratio 2.50, 95% CI 1.89-3.39) and both (17.1% versus 6.8%; adjusted hazard ratio 2.76, 95% CI 1.98-3.86) had significantly increased rates of recurrent stroke. No interaction effect of antiplatelet therapy by different METS or DM status for the risk of recurrent stroke (P=0.82 for interaction in the fully adjusted model of CDS) was observed. Using the METS (IDF) criteria demonstrated similar results. CONCLUSIONS: Concurrent METS and DM was associated with an increased risk of recurrent stroke in patients with minor stroke and transient ischemic attack. PMID- 28572286 TI - Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll-like receptor-2. AB - The symbiotic gut microbiota play pivotal roles in host physiology and the development of cardiovascular diseases, but the microbiota-triggered pattern recognition signaling mechanisms that impact thrombosis are poorly defined. In this article, we show that germ-free (GF) and Toll-like receptor-2 (Tlr2) deficient mice have reduced thrombus growth after carotid artery injury relative to conventionally raised controls. GF Tlr2-/- and wild-type (WT) mice were indistinguishable, but colonization with microbiota restored a significant difference in thrombus growth between the genotypes. We identify reduced plasma levels of von Willebrand factor (VWF) and reduced VWF synthesis, specifically in hepatic endothelial cells, as a critical factor that is regulated by gut microbiota and determines thrombus growth in Tlr2-/- mice. Static platelet aggregate formation on extracellular matrix was similarly reduced in GF WT, Tlr2 /- , and heterozygous Vwf+/- mice that are all characterized by a modest reduction in plasma VWF levels. Defective platelet matrix interaction can be restored by exposure to WT plasma or to purified VWF depending on the VWF integrin binding site. Moreover, administration of VWF rescues defective thrombus growth in Tlr2-/- mice in vivo. These experiments delineate an unexpected pathway in which microbiota-triggered TLR2 signaling alters the synthesis of proadhesive VWF by the liver endothelium and favors platelet integrin-dependent thrombus growth. PMID- 28572287 TI - How I treat chronic myelomonocytic leukemia. AB - Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that may deserve specific management. Defined by a persistent peripheral blood monocytosis >=1 * 109/L and monocytes accounting for >=10% of the white blood cells, this aging-associated disease combines cell proliferation as a consequence of myeloid progenitor hypersensitivity to granulocyte-macrophage colony stimulating factor with myeloid cell dysplasia and ineffective hematopoiesis. The only curative option for CMML remains allogeneic stem cell transplantation. When transplantation is excluded, CMML is stratified into myelodysplastic (white blood cell count <13 * 109/L) and proliferative (white blood cell count >=13 * 109/L) CMML. In the absence of poor prognostic factors, the management of myelodysplastic CMML is largely inspired from myelodysplastic syndromes, relying on erythropoiesis-stimulating agents to cope with anemia, and careful monitoring and supportive care, whereas the management of proliferative CMML usually relies on cytoreductive agents such as hydroxyurea, although ongoing studies will help delineate the role of hypomethylating agents in this patient population. In the presence of excessive blasts and other poor prognostic factors, hypomethylating agents are the preferred option, even though their impact on leukemic transformation and survival has not been proved. The therapeutic choice is illustrated by 4 clinical situations among the most commonly seen. Although current therapeutic options can improve patient's quality of life, they barely modify disease evolution. Improved understanding of CMML pathophysiology will hopefully lead to the exploration of novel targets that potentially would be curative. PMID- 28572288 TI - Prospective Evaluation of Changes in Tumor Size and Tumor Metabolism in Patients with Advanced Gastric Cancer Undergoing Chemotherapy: Association and Clinical Implication. AB - A change in tumor size is a well-validated and commonly used value for evaluating response to chemotherapy in cancer. Metabolic changes induced by chemotherapy are related to prognosis in several tumor types. However, the clinical implication of metabolic changes in patients with advanced gastric cancer (AGC) undergoing chemotherapy remains unclear. We aimed to evaluate response of tumor size and metabolism in AGC during chemotherapy and to reveal the relationship between them in view of their impact on patient survival. Methods: We prospectively enrolled patients with AGC before the initiation of first-line palliative chemotherapy. Using baseline and follow-up contrast-enhanced CT and 18F-FDG PET, we assessed the tumor diameter, SUVmax, and total lesion glycolysis in each lesion and their changes during chemotherapy at the same time. We included all lesions with the maximal longest diameters over 1 cm on CT, and each lesion was evaluated by matched 18F-FDG PET. We analyzed the association between changes in tumor metabolism and tumor size and performed outcome analysis on overall survival (OS) and progression-free survival (PFS). Results: Seventy-four patients were enrolled, and the number of all lesions included in this study was 620. Compared with adenocarcinomas, poorly cohesive carcinomas demonstrated lower SUVmax irrespective of tumor size (P < 0.001). Human epidermal growth factor receptor 2 (HER2)-positive tumors showed higher SUVmax than HER2-negative tumors (P = 0.002). The changes in SUVmax due to chemotherapy had a linear correlation with the changes in tumor size of each lesion, and a 30% tumor size reduction was associated with a 50% SUVmax reduction (P < 0.001). Total lesion glycolysis changes also correlated with tumor size changes (P < 0.001). Better OS and PFS were obtained in patients with both tumor size and SUVmax reduction than in patients with either size or SUVmax reduction only (OS, P = 0.003; PFS, P = 0.038). Conclusion: Changes in tumor metabolism induced by chemotherapy correlated with changes in tumor size in AGC. Considering both changes in metabolism and size could help predict a more accurate prognosis for AGC patients undergoing chemotherapy. PMID- 28572291 TI - Online Social Media Practices in Nuclear Medicine and Molecular Imaging: A Concept to Incentivize Creation of Digital and Web-Based Content. PMID- 28572289 TI - Parametric Method Performance for Dynamic 3'-Deoxy-3'-18F-Fluorothymidine PET/CT in Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Carcinoma Patients Before and During Therapy. AB - The objective of this study was to validate several parametric methods for quantification of 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET in advanced-stage non-small cell lung carcinoma (NSCLC) patients with an activating epidermal growth factor receptor mutation who were treated with gefitinib or erlotinib. Furthermore, we evaluated the impact of noise on accuracy and precision of the parametric analyses of dynamic 18F-FLT PET/CT to assess the robustness of these methods. Methods: Ten NSCLC patients underwent dynamic 18F-FLT PET/CT at baseline and 7 and 28 d after the start of treatment. Parametric images were generated using plasma input Logan graphic analysis and 2 basis functions-based methods: a 2-tissue-compartment basis function model (BFM) and spectral analysis (SA). Whole tumor-averaged parametric pharmacokinetic parameters were compared with those obtained by nonlinear regression of the tumor time-activity curve using a reversible 2-tissue-compartment model with blood volume fraction. In addition, 2 statistically equivalent datasets were generated by countwise splitting the original list-mode data, each containing 50% of the total counts. Both new datasets were reconstructed, and parametric pharmacokinetic parameters were compared between the 2 replicates and the original data. Results: After the settings of each parametric method were optimized, distribution volumes (VT) obtained with Logan graphic analysis, BFM, and SA all correlated well with those derived using nonlinear regression at baseline and during therapy (R2 >= 0.94; intraclass correlation coefficient > 0.97). SA-based VT images were most robust to increased noise on a voxel-level (repeatability coefficient, 16% vs. >26%). Yet BFM generated the most accurate K1 values (R2 = 0.94; intraclass correlation coefficient, 0.96). Parametric K1 data showed a larger variability in general; however, no differences were found in robustness between methods (repeatability coefficient, 80%-84%). Conclusion: Both BFM and SA can generate quantitatively accurate parametric 18F-FLT VT images in NSCLC patients before and during therapy. SA was more robust to noise, yet BFM provided more accurate parametric K1 data. We therefore recommend BFM as the preferred parametric method for analysis of dynamic 18F-FLT PET/CT studies; however, SA can also be used. PMID- 28572290 TI - The Variability of Translocator Protein Signal in Brain and Blood of Genotyped Healthy Humans Using In Vivo 123I-CLINDE SPECT Imaging: A Test-Retest Study. AB - 123I-CLINDE is a radiotracer developed for SPECT and targets the 18-kDa translocator protein (TSPO). TSPO is upregulated in glial cells and used as a measure of neuroinflammation in a variety of central nervous system diseases. The aim of this study was to examine the test-retest variability of 123I-CLINDE binding in healthy subjects. Methods: SPECT scans were acquired over 90 min in 16 healthy controls (9 women, 8 mixed-affinity binders [MABs] and 8 high-affinity binders [HABs] twice with an interval of 35 +/- 15 d). Arterial input functions were based on individual blood measurements in 8 subjects and a population-based approach in combination with individual whole-blood time-activity curves in the other 8 subjects. Seven brain volumes of interest were extracted and quantified by SUVs and by 2-tissue-compartment modeling for calculation of distribution volumes (VT). Test-retest variability was measured by percentage difference (PD), the absolute PD, intraclass correlation coefficient (ICC), and coefficient of variation. Results: The absolute PD of brain SUV and the VT had similar values. The ICC values were higher for VTs than for brain SUVs, which were both moderate to high; however, lower ICC values were observed when calculated separately for HABs and MABs. Test-retest reproducibility was higher in subjects with immediate centrifugation of blood samples. The population-based method efficiently recovered data with delayed centrifugation. The VT of a 49-y-old male HAB was 7.5 +/- 1.4 mL/cm3 compared with 4.6 +/- 1.4 mL/cm3 of a sex- and age-matched MAB. The SUVs of a 49-y-old male HAB and MAB were 1.03 +/- 0.14 and 0.88 +/- 0.15 g/mL, respectively. Conclusion: The test-retest reproducibility of 123I-CLINDE is comparable or better than that reported for commonly used PET TSPO tracers. Because of the binding of 123I-CLINDE to blood cells and peripheral tissues, SUV is not a sufficient surrogate of VT from 2-tissue-compartment modeling. The population-adjusted method has the potential to reduce the complexity of blood analyses of TSPO tracers. PMID- 28572296 TI - MURR Files for NRC Isotope Production Approval. PMID- 28572294 TI - From the ABNM: Making MOC Simpler. PMID- 28572299 TI - This Month in JNM. PMID- 28572297 TI - SNMMI Leadership Update: An Exciting Time for Nuclear Medicine and Molecular Imaging. PMID- 28572300 TI - Appropriate Use Criteria for Hepatobiliary Scintigraphy in Abdominal Pain: Summary and Excerpts. PMID- 28572302 TI - Future Earth--linking research on health and environmental sustainability. PMID- 28572304 TI - Complete Genomic Sequence of Dengue virus 1, Isolated from Plasma Collected from a Haitian Child in 2014. AB - An outbreak of dengue fever followed a chikungunya fever outbreak in Haiti in 2014. We detected Dengue virus 1 (DENV-1) in plasma samples collected between May 2014 and February 2015. A representative isolate was fully sequenced, and phylogenetic analyses indicate that it groups within the genotype V South American and Caribbean DENV-1 clades. PMID- 28572305 TI - Genome Sequence of Escherichia coli E28, a Multidrug-Resistant Strain Isolated from a Chicken Carcass, and Its Spontaneously Inducible Prophage. AB - In this study, we sequenced the complete genome of the multidrug-resistant Escherichia coli strain E28, which was used as an indicator strain for phage therapy in vivo We used a combination of single-molecule real-time and Illumina sequencing technology to reveal the presence of a spontaneously inducible prophage. PMID- 28572303 TI - Maternal Exercise Improves Glucose Tolerance in Female Offspring. AB - Poor maternal diet can lead to metabolic disease in offspring, whereas maternal exercise may have beneficial effects on offspring health. In this study, we determined ifmaternal exercise could reverse the detrimental effects of maternal high-fat feeding on offspring metabolism of female mice. C57BL/6 female mice were fed a chow (21%) or high-fat (60%) diet and further divided by housing in static cages or cages with running wheels for 2 weeks prior to breeding and throughout gestation. Females were bred with chow-fed sedentary C57BL/6 males. High fat-fed sedentary dams produced female offspring with impaired glucose tolerance compared with offspring of chow-fed dams throughout their first year of life, an effect not present in the offspring from high fat-fed dams that had trained. Offspring from high fat-fed trained dams had normalized glucose tolerance, decreased fasting insulin, and decreased adiposity. Liver metabolic function, measured by hepatic glucose production in isolated hepatocytes, hyperinsulinemic-euglycemic clamps, liver triglyceride content, and liver enzyme expression, was enhanced in offspring from trained dams. In conclusion, maternal exercise negates the detrimental effects of a maternal high-fat diet on glucose tolerance and hepatocyte glucose metabolism in female offspring. The ability of maternal exercise to improve the metabolic health of female offspring is important, as this intervention could combat the transmission of obesity and diabetes to subsequent generations. PMID- 28572306 TI - Draft Genome Sequences of Listeria monocytogenes, Isolated from Fresh Leaf Vegetables in Owerri City, Nigeria. AB - Here, we report the draft genome sequences of three Listeria monocytogenes isolates from fresh leaves collected in Nigeria, belonging to sequence types ST5 and ST155 (sublineages SL5 and SL155, respectively). PMID- 28572307 TI - Complete Genome Sequence of Veillonella atypica OK5, the First Transformable Strain in the Species. AB - The Veillonella atypica strain OK5 was isolated from a human saliva sample and was the first strain shown to be genetically transformable in the Veillonella genus. Genetic studies using this strain have helped us gain much insight into the ecology of human oral biofilms. Here, we report the complete genome sequence of V. atypica OK5. PMID- 28572308 TI - Complete Genome Sequence of Foot-and-Mouth Disease Virus Serotype O Strain YNTBa from Yunnan Province of China. AB - YNTBa is a rabbit-passaged attenuated strain of foot-and-mouth disease virus (FMDV) serotype O. Here, we announce the complete genome sequence of YNTBa, which provides data for further studies on replication, virulence, its determinants, and cell and host tropism of YNTBa. PMID- 28572309 TI - Genome Sequence of Roseovarius mucosus Strain SMR3, Isolated from a Culture of the Diatom Skeletonema marinoi. AB - We present the genome of Roseovarius mucosus strain SMR3, a marine bacterium isolated from the diatom Skeletonema marinoi strain RO5AC sampled from top layer sediments at 14 m depth. Its 4,381,426 bp genome consists of a circular chromosome and two circular plasmids and contains 4,178 coding sequences (CDSs). PMID- 28572310 TI - Draft Genome Sequences of Thermophiles Isolated from Yates Shaft, a Deep Subsurface Environment. AB - The whole-genome sequences of seven thermophiles that could grow at >55 degrees C, but not at 37 degrees C, were generated. These thermophilic bacteria will play a useful role as model microorganisms, and analyzing their genomes will help to understand the observed production of novel bioactive compounds, including thermozymes and macromolecules. PMID- 28572312 TI - Four Complete Paenibacillus larvae Genome Sequences. AB - Four complete genome sequences of genetically distinct Paenibacillus larvae strains have been determined. Pacific BioSciences single-molecule real-time (SMRT) sequencing technology was used as the sole method of sequence determination and assembly. The chromosomes exhibited a G+C content of 44.1 to 44.2% and a molecular size range of 4.29 to 4.67 Mbp. PMID- 28572311 TI - Draft Genome Sequences of Mycobacterium kansasii Clinical Strains. AB - Mycobacterium kansasii is a nontuberculous mycobacterial (NTM) pathogen, frequently isolated from clinical samples and responsible for a large part of NTM infections in the human population. Here, we report the draft genome sequences of 12 M. kansasii strains isolated from clinical and host-associated sources from the Netherlands, Germany, and Poland. PMID- 28572313 TI - Draft Genome Sequence of Blood Disease Bacterium A2 HR-MARDI, a Pathogen Causing Banana Bacterial Wilt. AB - Blood disease bacterium A2 HR-MARDI was isolated from banana plants infected with banana blood disease and which were planted in Kuala Kangsar, Malaysia. Here, we report a draft genome sequence of blood disease bacterium A2 HR-MARDI, which could provide important information on the virulence mechanism of this pathogen. PMID- 28572315 TI - Deeper Insight in Beehives: Metagenomes of Royal Jelly, Pollen, and Honey from Lavender, Chestnut, and Fir Honeydew and Epiphytic and Endophytic Microbiota of Lavender and Rose Flowers. AB - Microbiota of beehive products are very little known. We report here for the first time six metagenomes of royal jelly, pollen, and different types of honey from wild and cultivated lavender, chestnut, and fir honeydew. Four metagenomes of epiphytic and endophytic microbiota of lavender and rose flowers are also reported. PMID- 28572314 TI - First Insights into the Genome of the Cr(VI)-Reducing Bacterium Clostridium chromiireducens DSM 23318. AB - Clostridium chromiireducens is an obligate, anaerobic, Gram-positive, rod-shaped, and spore-forming bacterium that is able to reduce Cr(VI). The draft genome consists of one chromosome (5,448 Mb) and contains 4,773 predicted protein encoding genes. PMID- 28572317 TI - Complete Genome Assembly of Pantoea stewartii subsp. stewartii DC283, a Corn Pathogen. AB - The phytopathogen Pantoea stewartii subsp. stewartii DC283 causes Stewart's wilt disease in corn after transmission from the corn flea beetle insect vector. Here, we report that the complete annotated genome of P. stewartii DC283 has been fully assembled into one circular chromosome, 10 circular plasmids, and one linear phage. PMID- 28572316 TI - Draft Genome Sequence of Rice Orange Leaf Phytoplasma from Guangdong, China. AB - The genome of rice orange leaf phytoplasma strain LD1 from Luoding City, Guangdong, China, was sequenced. The draft LD1 genome is 599,264 bp, with a G+C content of 28.2%, 647 predicted open reading frames, and 33 RNA genes. PMID- 28572318 TI - Complete Genome Sequences of Two Geographically Distinct Legionella micdadei Clinical Isolates. AB - Legionella is a highly diverse genus of intracellular bacterial pathogens that cause Legionnaire's disease (LD), an often severe form of pneumonia. Two L. micdadei sp. clinical isolates, obtained from patients hospitalized with LD from geographically distinct areas, were sequenced using PacBio SMRT cell technology, identifying incomplete phage regions, which may impact virulence. PMID- 28572319 TI - Complete Genome Sequence of Escherichia coli BLR(DE3), a recA-Deficient Derivative of E. coli BL21(DE3). AB - Escherichia coli BLR(DE3) is a commercially available recA-deficient derivative of BL21(DE3), one of the most widely used strains for recombinant protein expression. Here, we present the full-genome sequence of BLR(DE3) and highlight additional differences with its parent strain BL21(DE3) which were previously unreported but may affect its physiology. PMID- 28572320 TI - Complete Genome Sequencing of Streptomyces sp. Strain MOE7, Which Produces an Extracellular Polysaccharide with Antioxidant and Antitumor Activities. AB - Streptomyces sp. strain MOE7 is a Gram-positive filamentous bacterium isolated from agricultural soil in Columbia, Missouri, USA. Strain MOE7 produces an extracellular polysaccharide with antioxidant and antitumor activities. Through PacBio RSII sequencing, the MOE7 genome was found to be a linear chromosome of 8,399,509 bp with 6,782 protein-coding sequences. PMID- 28572321 TI - Draft Genome Sequence of Streptomyces sp. B9173, a Producer of Indole Diketopiperazine Maremycins. AB - Streptomyces sp. B9173 is a producer of maremycins, a group of naturally occurring 2,5-diketopiperazines. Here, we report the draft genome sequence of Streptomyces sp. B9173, which comprises ~8.77 Mb, with a G+C content of 71.8%. PMID- 28572322 TI - Complete Genome Sequence of Escherichia coli Strain M8, Isolated from ob/ob Mice. AB - Escherichia coli is one of the common inhabitants of the mammalian gastrointestinal track. We isolated a strain from an ob/ob mouse and performed whole-genome sequencing, which yielded a chromosome of ~5.1 Mb and three plasmids of ~160 kb, ~6 kb, and ~4 kb. PMID- 28572324 TI - Draft Genome Sequence of the Vancomycin-Resistant Clinical Isolate Staphylococcus aureus VRS3b. AB - We report here the draft genome sequence of the vancomycin-resistant strain Staphylococcus aureus VRS3b. The 2.8-Mb genome, assembled into 46 contigs, harbored 2,915 putative coding sequences. The G+C content of the genome was 32.7%. PMID- 28572325 TI - Draft Genome Sequence of a Porcine Commensal, Rothia nasimurium, Encoding a Nonribosomal Peptide Synthetase Predicted To Produce the Ionophore Antibiotic Valinomycin. AB - We report the draft whole-genome sequence of Rothia nasimurium isolated from a porcine tonsil. The genome encodes a nonribosomal peptide synthetase predicted to produce valinomycin, a cyclic dodecadepsipeptide ionophore. Previously, valinomycin was known to be produced only by Streptomyces species and isolates belonging to the Bacillus pumilus group. PMID- 28572323 TI - Complete Genome Sequence of Staphylococcus epidermidis 1457. AB - Staphylococcus epidermidis 1457 is a frequently utilized strain that is amenable to genetic manipulation and has been widely used for biofilm-related research. We report here the whole-genome sequence of this strain, which encodes 2,277 protein coding genes and 81 RNAs within its 2.4-Mb genome and plasmid. PMID- 28572326 TI - Complete Genome Sequence of a Recombinant Porcine Reproductive and Respiratory Syndrome Virus Strain from Two Genotype 1 Modified Live Virus Vaccine Strains. AB - This paper provides information on the complete genome sequence of a porcine reproductive and respiratory syndrome virus (PRRSV) strain isolated on a French pig farm which was identified as a recombinant strain from two commercial modified live virus vaccine strains of genotype 1 (VP-046BIS and DV strains). PMID- 28572327 TI - Complete Genome Sequences of Three Salmonella enterica subsp. enterica Serovar Saintpaul Isolates Associated with a 2013 Multistate Outbreak in the United States. AB - In 2013, a multistate outbreak of Salmonella enterica subsp. enterica serovar Saintpaul from cucumber caused 84 cases of salmonellosis in the United States. In this announcement, we report the complete genome sequences of three clinical Salmonella Saintpaul isolates associated with the 2013 outbreak. PMID- 28572328 TI - Complete Genome of a Panresistant Pseudomonas aeruginosa Strain, Isolated from a Patient with Respiratory Failure in a Canadian Community Hospital. AB - We report here the complete genome sequence of a panresistant Pseudomonas aeruginosa strain, isolated from a patient with respiratory failure in Canada. No carbapenemase genes were identified. Carbapenem resistance is attributable to a frameshift in the oprD gene; the basis for colistin resistance remains undetermined. PMID- 28572330 TI - Draft Genome Sequence of the Clover (Trifolium repens L.) Root Endophyte Paraburkholderia sp. Strain A27. AB - Paraburkholderia sp. strain A27, isolated from the root material of white clover, has plant growth-promoting activity on a range of agriculturally important plants. The draft genome of this bacterium is 7,393,089 bp and harbors a range of genes putatively involved in host colonization. PMID- 28572329 TI - Complete Genome Sequence of a Community-Associated Methicillin-Resistant Staphylococcus aureus Hypervirulent Strain, USA300-C2406, Isolated from a Patient with a Lethal Case of Necrotizing Pneumonia. AB - USA300 is a predominant community-associated methicillin-resistant Staphylococcus aureus strain causing significant morbidity and mortality. We present here the full annotated genome of a USA300 hypervirulent clinical strain, USA300-C2406, isolated from a patient with a lethal case of necrotizing pneumonia, to gain a better understanding of USA300 hypervirulence. PMID- 28572331 TI - Complete Genome Sequence of Bacillus subtilis GQJK2, a Plant Growth-Promoting Rhizobacterium with Antifungal Activity. AB - Bacillus subtilis GQJK2 is a plant growth-promoting rhizobacterium with antifungal activity which was isolated from Lycium barbarum L. rhizosphere. Here, we report the complete genome sequence of B. subtilis GQJK2. Ten gene clusters involved in the biosynthesis of antagonistic compounds were predicted. PMID- 28572332 TI - Complete Genome Sequences of Four Avian Paramyxoviruses of Serotype 10 Isolated from Rockhopper Penguins on the Falkland Islands. AB - The first complete genome sequences of four avian paramyxovirus serotype 10 (APMV 10) isolates are described here. The viruses were isolated from rockhopper penguins on the Falkland Islands, sampled in 2007. All four genomes are 15,456 nucleotides in length, and phylogenetic analyses show them to be closely related. PMID- 28572333 TI - Draft Genome Sequence of a Strain of Bacillus intestinalis sp. nov., a New Member of Sporobiota Isolated from the Small Intestine of a Single Patient with Intestinal Cancer. AB - We report here the draft genome sequence of Bacillus intestinalis strain 1731, a novel spore-forming bacterium isolated from the small intestine of a patient with intestinal cancer. The genome comprised 4,047,276 bp, with 43.9% G+C content. There were 3,913 predicted protein-coding genes, including those associated with antibiotic resistance and virulence. PMID- 28572334 TI - Dropping in to "drop-in" sexual health clinics is not easy. PMID- 28572337 TI - Erratum for the Research Article "Cassini finds molecular hydrogen in the Enceladus plume: Evidence for hydrothermal processes" by J. H. Waite, C. R. Glein, R. S. Perryman, B. D. Teolis, B. A. Magee, G. Miller, J. Grimes, M. E. Perry, K. E. Miller, A. Bouquet, J. I. Lunine, T. Brockwell, S. J. Bolton. PMID- 28572338 TI - Erratum for the Letter "Brazil's public universities in crisis" by C. C. Siqueira and C. F. D. Rocha. PMID- 28572335 TI - A genetic signature of the evolution of loss of flight in the Galapagos cormorant. AB - We have a limited understanding of the genetic and molecular basis of evolutionary changes in the size and proportion of limbs. We studied wing and pectoral skeleton reduction leading to flightlessness in the Galapagos cormorant (Phalacrocorax harrisi). We sequenced and de novo assembled the genomes of four cormorant species and applied a predictive and comparative genomics approach to find candidate variants that may have contributed to the evolution of flightlessness. These analyses and cross-species experiments in Caenorhabditis elegans and in chondrogenic cell lines implicated variants in genes necessary for transcriptional regulation and function of the primary cilium. Cilia are essential for Hedgehog signaling, and humans affected by skeletal ciliopathies suffer from premature bone growth arrest, mirroring skeletal features associated with loss of flight. PMID- 28572336 TI - Redox stratification of an ancient lake in Gale crater, Mars. AB - In 2012, NASA's Curiosity rover landed on Mars to assess its potential as a habitat for past life and investigate the paleoclimate record preserved by sedimentary rocks inside the ~150-kilometer-diameter Gale impact crater. Geological reconstructions from Curiosity rover data have revealed an ancient, habitable lake environment fed by rivers draining into the crater. We synthesize geochemical and mineralogical data from lake-bed mudstones collected during the first 1300 martian solar days of rover operations in Gale. We present evidence for lake redox stratification, established by depth-dependent variations in atmospheric oxidant and dissolved-solute concentrations. Paleoclimate proxy data indicate that a transition from colder to warmer climate conditions is preserved in the stratigraphy. Finally, a late phase of geochemical modification by saline fluids is recognized. PMID- 28572339 TI - Shortsighted priorities. PMID- 28572340 TI - News at a glance. PMID- 28572341 TI - Deep in a mine, earthquake gold awaits. PMID- 28572342 TI - Mysterious unchanging DNA finds a purpose in life. PMID- 28572343 TI - NIH overhead plan draws fire. PMID- 28572345 TI - Space ripples may untangle black hole tango. PMID- 28572344 TI - Egyptian mummy DNA, at last. PMID- 28572346 TI - Siberia yields earliest evidence for dog breeding. PMID- 28572347 TI - The post-op brain. PMID- 28572348 TI - Bat patrol. PMID- 28572349 TI - Decoding the evolution of species. PMID- 28572350 TI - Gearing up molecular rotary motors. PMID- 28572351 TI - A microbiome variable in the HIV-prevention equation. PMID- 28572352 TI - Applying plasmonics to a sustainable future. PMID- 28572353 TI - Is ice sheet collapse in West Antarctica unstoppable? PMID- 28572355 TI - Making the rounds. PMID- 28572356 TI - Idiosyncratic desires. PMID- 28572354 TI - Committing to socially responsible seafood. PMID- 28572357 TI - The pet trade's role in defaunation. PMID- 28572358 TI - Sex matters: Report experimenter gender. PMID- 28572359 TI - NextGen VOICES: Submit now! PMID- 28572360 TI - Chemical safety must extend to ecosystems. PMID- 28572361 TI - Building coral skeletons. PMID- 28572362 TI - A step on the path to a Lassa vaccine. PMID- 28572363 TI - Coupled motion in a light-activated rotor. PMID- 28572364 TI - Entangle, swap, purify, repeat. PMID- 28572365 TI - Methane takes the quick way out. PMID- 28572366 TI - Local specificity of growth signals. PMID- 28572367 TI - Vaginal microbiome influences HIV acquisition. PMID- 28572369 TI - No escape for KRAS mutant tumors. PMID- 28572368 TI - Human impacts on rainfall distribution. PMID- 28572370 TI - Loss of flight in the Galapagos cormorant. PMID- 28572371 TI - The depths of an ancient lake on Mars. PMID- 28572372 TI - Detecting unusual oscillations. PMID- 28572374 TI - Probing the structure of the magnetopause. PMID- 28572375 TI - A versatile synthesis of pleuromutilin. PMID- 28572373 TI - Localizing light at the nanometer scale. PMID- 28572376 TI - Will ice sheets collapse in West Antarctica? PMID- 28572377 TI - Differentiating myeloid cells. PMID- 28572378 TI - Flexible geckos. PMID- 28572380 TI - Greening the Antarctic. PMID- 28572379 TI - Arabidopsis out of Africa. PMID- 28572381 TI - Orchestrating pathogen defenses in the skin. PMID- 28572382 TI - Milky Way satellites going in circles. PMID- 28572383 TI - A quantum-well magnetic tunnel junction. PMID- 28572384 TI - Less oxygen in a warmer ocean. PMID- 28572386 TI - Entanglement distillation between solid-state quantum network nodes. AB - The impact of future quantum networks hinges on high-quality quantum entanglement shared between network nodes. Unavoidable imperfections necessitate a means to improve remote entanglement by local quantum operations. We realize entanglement distillation on a quantum network primitive of distant electron-nuclear two-qubit nodes. The heralded generation of two copies of a remote entangled state is demonstrated through single-photon-mediated entangling of the electrons and robust storage in the nuclear spins. After applying local two-qubit gates, single shot measurements herald the distillation of an entangled state with increased fidelity that is available for further use. The key combination of generating, storing, and processing entangled states should enable the exploration of multiparticle entanglement on an extended quantum network. PMID- 28572385 TI - Structural basis for antibody-mediated neutralization of Lassa virus. AB - The arenavirus Lassa causes severe hemorrhagic fever and a significant disease burden in West Africa every year. The glycoprotein, GPC, is the sole antigen expressed on the viral surface and the critical target for antibody-mediated neutralization. Here we present the crystal structure of the trimeric, prefusion ectodomain of Lassa GP bound to a neutralizing antibody from a human survivor at 3.2-angstrom resolution. The antibody extensively anchors two monomers together at the base of the trimer, and biochemical analysis suggests that it neutralizes by inhibiting conformational changes required for entry. This work illuminates pH driven conformational changes in both receptor-binding and fusion subunits of Lassa virus, illustrates the unique assembly of the arenavirus glycoprotein spike, and provides a much-needed template for vaccine design against these threats to global health. PMID- 28572387 TI - Biological control of aragonite formation in stony corals. AB - Little is known about how stony corals build their calcareous skeletons. There are two prevailing hypotheses: that it is a physicochemically dominated process and that it is a biologically mediated one. Using a combination of ultrahigh resolution three-dimensional imaging and two-dimensional solid-state nuclear magnetic resonance (NMR) spectroscopy, we show that mineral deposition is biologically driven. Randomly arranged, amorphous nanoparticles are initially deposited in microenvironments enriched in organic material; they then aggregate and form ordered aragonitic structures through crystal growth by particle attachment. Our NMR results are consistent with heterogeneous nucleation of the solid mineral phase driven by coral acid-rich proteins. Such a mechanism suggests that stony corals may be able to sustain calcification even under lower pH conditions that do not favor the inorganic precipitation of aragonite. PMID- 28572389 TI - Bloch oscillations in the absence of a lattice. AB - The interplay of strong quantum correlations and far-from-equilibrium conditions can give rise to striking dynamical phenomena. We experimentally investigated the quantum motion of an impurity atom immersed in a strongly interacting one dimensional Bose liquid and subject to an external force. We found that the momentum distribution of the impurity exhibits characteristic Bragg reflections at the edge of an emergent Brillouin zone. Although Bragg reflections are typically associated with lattice structures, in our strongly correlated quantum liquid they result from the interplay of short-range crystalline order and kinematic constraints on the many-body scattering processes in the one dimensional system. As a consequence, the impurity exhibits periodic dynamics, reminiscent of Bloch oscillations, although the quantum liquid is translationally invariant. Our observations are supported by large-scale numerical simulations. PMID- 28572388 TI - Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. AB - Antiretroviral-based strategies for HIV prevention have shown inconsistent results in women. We investigated whether vaginal microbiota modulated tenofovir gel microbicide efficacy in the CAPRISA (Centre for the AIDS Program of Research in South Africa) 004 trial. Two major vaginal bacterial community types-one dominated by Lactobacillus (59.2%) and the other where Gardnerella vaginalis predominated with other anaerobic bacteria (40.8%)-were identified in 688 women profiled. Tenofovir reduced HIV incidence by 61% (P = 0.013) in Lactobacillus dominant women but only 18% (P = 0.644) in women with non-Lactobacillus bacteria, a threefold difference in efficacy. Detectible mucosal tenofovir was lower in non Lactobacillus women, negatively correlating with G. vaginalis and other anaerobic bacteria, which depleted tenofovir by metabolism more rapidly than target cells convert to pharmacologically active drug. This study provides evidence linking vaginal bacteria to microbicide efficacy through tenofovir depletion via bacterial metabolism. PMID- 28572390 TI - Massive blow-out craters formed by hydrate-controlled methane expulsion from the Arctic seafloor. AB - Widespread methane release from thawing Arctic gas hydrates is a major concern, yet the processes, sources, and fluxes involved remain unconstrained. We present geophysical data documenting a cluster of kilometer-wide craters and mounds from the Barents Sea floor associated with large-scale methane expulsion. Combined with ice sheet/gas hydrate modeling, our results indicate that during glaciation, natural gas migrated from underlying hydrocarbon reservoirs and was sequestered extensively as subglacial gas hydrates. Upon ice sheet retreat, methane from this hydrate reservoir concentrated in massive mounds before being abruptly released to form craters. We propose that these processes were likely widespread across past glaciated petroleum provinces and that they also provide an analog for the potential future destabilization of subglacial gas hydrate reservoirs beneath contemporary ice sheets. PMID- 28572391 TI - Observation of Anderson localization in disordered nanophotonic structures. AB - Anderson localization is an interference effect crucial to the understanding of waves in disordered media. However, localization is expected to become negligible when the features of the disordered structure are much smaller than the wavelength. Here we experimentally demonstrate the localization of light in a disordered dielectric multilayer with an average layer thickness of 15 nanometers, deep into the subwavelength regime. We observe strong disorder induced reflections that show that the interplay of localization and evanescence can lead to a substantial decrease in transmission, or the opposite feature of enhanced transmission. This deep-subwavelength Anderson localization exhibits extreme sensitivity: Varying the thickness of a single layer by 2 nanometers changes the reflection appreciably. This sensitivity, approaching the atomic scale, holds the promise of extreme subwavelength sensing. PMID- 28572392 TI - A modular and enantioselective synthesis of the pleuromutilin antibiotics. AB - The tricyclic diterpene fungal metabolite (+)-pleuromutilin has served as a starting point for antibiotic development. Semisynthetic modification of its glycolic acid subunit at C14 provided the first analogs fit for human use, and derivatization at C12 led to 12-epi-pleuromutilins with extended-spectrum antibacterial activity, including activity against Gram-negative pathogens. Given the inherent limitations of semisynthesis, however, accessing derivatives of (+) pleuromutilin with full control over their structure presents an opportunity to develop derivatives with improved antibacterial activities. Here we disclose a modular synthesis of pleuromutilins by the convergent union of an enimide with a bifunctional iodoether. We illustrate our approach through synthesis of (+)-12 epi-mutilin, (+)-11,12-di-epi-mutilin, (+)-12-epi-pleuromutilin, (+)-11,12-di-epi pleuromutilin, and (+)-pleuromutilin itself in 17 to 20 steps. PMID- 28572393 TI - Structure, force balance, and topology of Earth's magnetopause. AB - The magnetopause deflects the solar wind plasma and confines Earth's magnetic field. We combine measurements made by the four spacecraft of the Magnetospheric Multiscale mission to demonstrate how the plasma and magnetic forces at the boundary affect the interaction between the shocked solar wind and Earth's magnetosphere. We compare these forces with the plasma pressure and examine the electron distribution function. We find that the magnetopause has sublayers with thickness comparable to the ion scale. Small pockets of low magnetic field strength, small radius of curvature, and high electric current mark the electron diffusion region. The flow of electrons, parallel and antiparallel to the magnetic field, reveals a complex topology with the creation of magnetic ropes at the boundary. PMID- 28572394 TI - Locked synchronous rotor motion in a molecular motor. AB - Biological molecular motors translate their local directional motion into ordered movement of other parts of the system to empower controlled mechanical functions. The design of analogous geared systems that couple motion in a directional manner, which is pivotal for molecular machinery operating at the nanoscale, remains highly challenging. Here, we report a molecular rotary motor that translates light-driven unidirectional rotary motion to controlled movement of a connected biaryl rotor. Achieving coupled motion of the distinct parts of this multicomponent mechanical system required precise control of multiple kinetic barriers for isomerization and synchronous motion, resulting in sliding and rotation during a full rotary cycle, with the motor always facing the same face of the rotor. PMID- 28572395 TI - mTORC1 activity repression by late endosomal phosphatidylinositol 3,4 bisphosphate. AB - Nutrient sensing by mechanistic target of rapamycin complex 1 (mTORC1) on lysosomes and late endosomes (LyLEs) regulates cell growth. Many factors stimulate mTORC1 activity, including the production of phosphatidylinositol 3,4,5 trisphosphate [PI(3,4,5)P3] by class I phosphatidylinositol 3-kinases (PI3Ks) at the plasma membrane. We investigated mechanisms that repress mTORC1 under conditions of growth factor deprivation. We identified phosphatidylinositol 3,4 bisphosphate [PI(3,4)P2], synthesized by class II PI3K beta (PI3KC2beta) at LyLEs, as a negative regulator of mTORC1, whereas loss of PI3KC2beta hyperactivated mTORC1. Growth factor deprivation induced the association of PI3KC2beta with the Raptor subunit of mTORC1. Local PI(3,4)P2 synthesis triggered repression of mTORC1 activity through association of Raptor with inhibitory 14-3 3 proteins. These results unravel an unexpected function for local PI(3,4)P2 production in shutting off mTORC1. PMID- 28572397 TI - Let's talk about language barriers. PMID- 28572399 TI - The treatment of paroxysmal atrial fibrillation in UK primary care. AB - OBJECTIVE: To determine whether patients with paroxysmal atrial fibrillation (AF) are less likely to be treated with anticoagulants than patients with persistent/permanent AF and to investigate trends in treatment between 2000 and 2015. UK and European guidelines recommend that anticoagulants are offered to all patients with AF at increased risk of stroke, irrespective of AF type. METHODS: Sixteen sequential cross-sectional analyses from 2000 to 2015 were carried out with index dates on 1st of May each year. The data source was primary care data from 648 practices across the UK contributing to The Health Improvement Network database. All patients with a diagnosis of AF aged >=35 years and registered for at least 1 year were included. The main outcome measure was prescription of anticoagulant medication. RESULTS: The proportion of patients with AF with a diagnosis of paroxysmal AF increased from 7.4% (95% CI 7.0 to 7.8) in 2000 to 14.0% (95% CI 13.7 to 14.3) in 2015. Among patients with a CHADS2 score of >=1, between 2000 and 2015 the proportion prescribed anticoagulants increased from 18.8% (95% CI 16.4 to 21.4) to 56.2% (95% CI 55.0 to 57.3) and from 34.2% (95% CI 33.3 to 35.0) to 69.4% (95% CI 68.9 to 69.8) in patients with paroxysmal and other (persistent/permanent) AF, respectively; RR for treatment of patients with paroxysmal AF compared with patients with other AF increased from 0.48 (95% CI 0.42 to 0.55) to 0.76 (95% CI 0.74 to 0.77). Adjusting for age, sex, Townsend score and presence or absence of contraindications had little effect on the results. CONCLUSIONS: In 2000, eligible patients with paroxysmal AF were half as likely to be treated with anticoagulants as patients with other AF; this has improved over time, but in 2015, eligible patients with paroxysmal AF were still around 20% less likely to be prescribed anticoagulant medication. PMID- 28572402 TI - Deficiency in outer dense fiber 1 is a marker and potential driver of idiopathic male infertility. PMID- 28572401 TI - ABCB1 gene polymorphism associated with clinical factors can predict drug resistant tuberculosis. AB - Polymorphism in the ABCB1 gene encoding P-glycoprotein, a transmembrane drug efflux pump, contributes to drug resistance and has been widely studied. However, their association with rifampicin and ethambutol resistance in tuberculosis (TB) patients is still unclear. Genotype/allele/haplotype frequencies in c.1236C > T (rs1128503), c.2677G > T/A (rs2032582), and c.3435C > T (rs1045642) were obtained from 218 patients. Of these, 80 patients with rifampicin and/or ethambutol resistance were selected as the case group and 138 patients were selected for the control group through the results of their culture and drug-sensitive tests. Patients aged <18 years and HIV-positive serologic tests were excluded. ABCB1 polymorphisms were determined using a PCR direct-sequencing approach, and restriction fragment length polymorphism (RFLP). A nomogram was constructed to simulate a combined prediction of the probability of anti-TB drug resistance, with factors including genotype c.1236C > T (rs1128503) (P=0.02), clinical form (P=0.03), previous treatment (P=0.01), and skin color (P=0.03), contributing up to 90% chance of developing anti-TB drug resistance. Considering genotype analyses, CT (rs1128503) demonstrated an increased chance of anti-TB drug resistance (odds ratio (OR): 2.34, P=0.02), while the analyses for ethambutol resistance revealed an association with a rare A allele (rs2032582) (OR: 12.91, P=0.01), the haplotype TTC (OR: 5.83, P=0.05), and any haplotype containing the rare A allele (OR: 7.17, P=0.04). ABCB1 gene polymorphisms in association with others risk factors contribute to anti-TB drug resistance, mainly ethambutol. The use of the nomogram described in the present study could contribute to clinical decision-making prior to starting TB treatment. PMID- 28572400 TI - Hepatocyte growth factor demonstrates racial heterogeneity as a biomarker for coronary heart disease. AB - OBJECTIVE: To determine if hepatocyte growth factor (HGF), a promising biomarker of coronary heart disease (CHD) given its release into circulation in response to endothelial damage, is associated with subclinical and clinical CHD in a racial/ethnic diverse population. METHODS: HGF was measured in 6738 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Highest mean HGF values (pg/mL) were observed in Hispanic, followed by African, non-Hispanic white, then Chinese Americans. RESULTS: In all races/ethnicities, HGF levels were associated with older age, higher systolic blood pressure (SBP) and body mass index, lower high-density lipoprotein, diabetes and current smoking. In fully adjusted models, each SD higher HGF was associated with an average increase in coronary artery calcium (CAC) of 55 Agatston units for non-Hispanic whites (p<0.001) and 51 Agatston units for African-Americans (p=0.007) but was not in the other race/ethnic groups (interaction p=0.02). There were 529 incident CHD events, and CHD risk was 41% higher in African (p<0.001), 17% in non-Hispanic white (p=0.026) and Chinese (p=0.36), and 6% in Hispanic Americans (p=0.56) per SD increase in HGF. CONCLUSION: In a large and diverse population-based cohort, we report that HGF is associated with subclinical and incident CHD. We demonstrate evidence of racial/ethnic heterogeneity within these associations, as the results are most compelling in African-Americans and non-Hispanic white Americans. We provide evidence that HGF is a biomarker of atherosclerotic disease that is independent of traditional risk factors. PMID- 28572403 TI - Erratum for Yu et al. Increases in plasma tryptophan are inversely associated with incident cardiovascular disease in the Prevencion con Dieta Mediterranea (PREDIMED) Study. J Nutr 2017;147:314-22. PMID- 28572405 TI - Profile of King-Wai Yau. PMID- 28572408 TI - Aligning Scope of Practice with Periodontology Education. PMID- 28572409 TI - Change Is Here: ADEA CCI 2.0-A Learning Community for the Advancement of Dental Education. AB - On May 12, 2005, the inaugural meeting of the American Dental Education Association Commission on Change and Innovation in Dental Education (ADEA CCI) was convened. Comprised of thought leaders representative of dental education and practice, the ADEA CCI published groundbreaking white papers that effectively helped bring dental education across the threshold of the 21st century. Twelve years later, a new ADEA CCI has been convened-ADEA CCI 2.0. The ADEA CCI 2.0 is a broad-ranging, strategically interconnected, flexible, and multifarious community of stakeholders situated within and across all facets of oral health education and practice. Whereas the first iteration of the ADEA CCI made the case for change regarding revisions of the dental curriculum and learning environment, the ADEA CCI 2.0 will focus on external domains that are having a global impact on the content and delivery of health care and health professions education and, ultimately, how health care benefits people. The principal work of the ADEA CCI 2.0 will be to create educational and implementation resources and opportunities for dental educators to contemplate, investigate, and ultimately define the future needs of their academic dental institutions in this constantly changing world. PMID- 28572407 TI - Simultaneous analysis of the LFP and spiking activity reveals essential components of a visuomotor transformation in the frontal eye field. AB - The frontal eye field (FEF) is a key brain region to study visuomotor transformations because the primary input to FEF is visual in nature, whereas its output reflects the planning of behaviorally relevant saccadic eye movements. In this study, we used a memory-guided saccade task to temporally dissociate the visual epoch from the saccadic epoch through a delay epoch, and used the local field potential (LFP) along with simultaneously recorded spike data to study the visuomotor transformation process. We showed that visual latency of the LFP preceded spiking activity in the visual epoch, whereas spiking activity preceded LFP activity in the saccade epoch. We also found a spatially tuned elevation in gamma band activity (30-70 Hz), but not in the corresponding spiking activity, only during the delay epoch, whose activity predicted saccade reaction times and the cells' saccade tuning. In contrast, beta band activity (13-30 Hz) showed a nonspatially selective suppression during the saccade epoch. Taken together, these results suggest that motor plans leading to saccades may be generated internally within the FEF from local activity represented by gamma activity. PMID- 28572406 TI - How an alloreactive T-cell receptor achieves peptide and MHC specificity. AB - T-cell receptor (TCR) allorecognition is often presumed to be relatively nonspecific, attributable to either a TCR focus on exposed major histocompatibility complex (MHC) polymorphisms or the degenerate recognition of allopeptides. However, paradoxically, alloreactivity can proceed with high peptide and MHC specificity. Although the underlying mechanisms remain unclear, the existence of highly specific alloreactive TCRs has led to their use as immunotherapeutics that can circumvent central tolerance and limit graft-versus host disease. Here, we show how an alloreactive TCR achieves peptide and MHC specificity. The HCV1406 TCR was cloned from T cells that expanded when a hepatitis C virus (HCV)-infected HLA-A2- individual received an HLA-A2+ liver allograft. HCV1406 was subsequently shown to recognize the HCV nonstructural protein 3 (NS3):1406-1415 epitope with high specificity when presented by HLA-A2. We show that NS3/HLA-A2 recognition by the HCV1406 TCR is critically dependent on features unique to both the allo-MHC and the NS3 epitope. We also find cooperativity between structural mimicry and a crucial peptide "hot spot" and demonstrate its role, along with the MHC, in directing the specificity of allorecognition. Our results help explain the paradox of specificity in alloreactive TCRs and have implications for their use in immunotherapy and related efforts to manipulate TCR recognition, as well as alloreactivity in general. PMID- 28572410 TI - An Innovative, Comprehensive Faculty Recruitment and Development Program at One U.S. Dental School: Early Results. AB - Dental faculty recruitment and development are critical to replenish and cultivate sufficient and adequately prepared educators to educate future generations of dentists. At Rutgers School of Dental Medicine, the From Practice to Preceptor (FP2P) program, now in the last of its five years of funding from the U.S. Health Resources and Services Administration (HRSA), has an overall aim of recruiting, training, and retaining a diverse and well-prepared dental faculty workforce. The FP2P program introduced novel methods for recruiting and preparing new faculty members since its goal is to help participants transition from being practicing dentists to becoming part- or full-time faculty members. The recruitment and selection process has emphasized reaching community practitioners in general or pediatric dentistry, individuals from underrepresented groups, and those with a passion for teaching. The two-year program with weekly meetings was designed to develop participants' skills to meet the teaching, clinical, and administrative roles of dental faculty. The aims of this study were to determine if the program recruitment methods used would result in participants who were more ethnically and racially diverse than the school's current faculty and to determine if, after training, participants perceived they had increased knowledge, skills, and abilities in specified areas as compared to before training. Participants completed pre- and post-program surveys assessing their perceived level of preparedness in critical competencies for dental faculty. Surveys were completed by 94% of participants in cohorts one through four; 75% (n=15) of cohorts two and three completed both the pre- and post-program surveys, which were used for this analysis. Over 30% of the 35 participants to date were from an underrepresented group. Survey results suggest the participants increased their perceived preparedness in administrative, clinical, and educational competencies. Follow-up is needed to ascertain how many go on to become dental educators and whether they are better prepared to succeed as new faculty compared to nonparticipants. PMID- 28572411 TI - New Clinical Faculty Training Program: Transforming Practicing Dentists into Part Time Dental Faculty Members. AB - At Indiana University School of Dentistry, a New Clinical Faculty Training (NCFT) program was created with the primary goals of informing new part-time faculty members of clinical policies and assessment guidelines and thus developing qualified and satisfied faculty members. The aim of this study was to determine if participation in the training program improved the participants' satisfaction and competence in comparison to their colleagues who did not participate in the program. Two cohorts were compared: a control group of part-time faculty members who did not receive formal training when they were hired (n=21; response rate 58.3%); and the intervention group, who had participated in the NCFT program (n=12; response rate 80%). A survey of faculty members in the control group gathered information on their experiences when initially hired, and a pretest was administered to measure their knowledge of clinical policies. After the control group was given an overview of the program, their feedback was collected through post surveys, and a posttest identical to the pretest was given that found statistically significant increases on questions one (p=0.003) and four (p=0.025). In February 2014, 15 new faculty members participated in the pilot implementation of the NCFT program. Of those 15, 12 (the intervention group) completed follow-up surveys identical to the pre survey used with the control group. Statistically significant differences were found for the factors clinical teaching (p=0.005) and assessment training (p=0.008) with better responses for the NCFT group. These results suggest that participation in the program was associated with improved clinical teaching knowledge and job satisfaction. PMID- 28572412 TI - The Effect of Calibration on Caries Risk Assessment Performance by Students and Clinical Faculty. AB - Caries management requires a complete oral examination and an accurate caries risk assessment (CRA). Performing Caries Management by Risk Assessment (CAMBRA) is inefficient when the caries risk level assignment is incorrect. The aim of this study was to evaluate the ability of faculty members and students at one U.S. dental school to correctly assign caries risk levels for 22 CRA cases, followed by calibration with guidelines on how to use the CRA form and a post calibration test two months after calibration. Inter-examiner reliability to a gold standard (consensus of three experts) was assessed as poor, fair, moderate, good, and very good. Of the 162 students and 125 faculty members invited to participate, 13 students and 20 faculty members returned pre-calibration tests, for response rates of 8% and 16%, respectively. On the post-calibration test, eight students and 13 faculty members participated for response rates of 5% and 10%, respectively. Without guidelines and calibration, both faculty members and students when evaluated as one group performed only poor to fair in assigning correct caries risk levels. After calibration, levels improved to good and very good agreements with the gold standard. When faculty and students were evaluated separately, in the pre-calibration test they correctly assigned the caries risk level on average in only one-quarter of the cases (students 24.1%+/-13.3%; faculty 23.6%+/-17.5%). After calibration, both groups significantly improved their correct assignment rate. Faculty members (73.8% correct assignments) showed even significantly higher correct assignment rates than students (47.7% correct assignments). These findings suggest that calibration with a specific set of guidelines improved CRA outcomes for both the faculty members and students. Improved guidelines on how to use a CRA form should lead to improved caries risk assessment and proper treatment strategy for patients. PMID- 28572413 TI - Impact of Faculty Development Workshops in Student-Centered Teaching Methodologies on Faculty Members' Teaching and Their Students' Perceptions. AB - The aim of this study was to assess, after one year, the impact of faculty development in teaching and learning skills focused on a learner-centered approach on faculty members' perceptions of and approaches to teaching and on their students' learning experiences and approaches. Before training (2014), all 176 faculty members at a dental school in Chile were invited to complete the Approaches to Teaching Inventory (ATI) to assess their teaching approaches (student- vs. teacher-focused). In 2015, all 496 students were invited to complete the Study Process Questionnaire (R-SPQ-2F) to assess their learning approaches (deep or surface) and the Course Experience Questionnaire (CEQ) to measure their teaching quality perceptions. Subsequently, faculty development workshops on student-centered teaching methodologies were delivered, followed by peer observation. In March 2016, all 176 faculty members and 491 students were invited to complete a second ATI (faculty) and R-SPQ-2 and CEQ (students). Before (2014) and after (2016) the training, 114 (65%) and 116 (66%) faculty members completed the ATI, respectively, and 89 (49%) of the then-181 faculty members completed the perceptions of skills development questionnaire in September 2016. In 2015, 373 students (75%) completed the R-SPQ-2F and CEQ; 412 (83%) completed both questionnaires in 2016. In 2014, the faculty results showed that student focused teaching was significantly higher in preclinical and clinical courses than in the basic sciences. In 2016, teacher-focused teaching fell significantly; basic science teaching improved the most. Students in both the 2015 and 2016 cohorts had lower mean scores for deep learning approaches from year 1 on, while they increased their scores for surface learning. The students' perceptions of faculty members' good teaching, appropriate assessment, clear goals, and e learning improved significantly, but perception of appropriate workload did not. Teaching and learning skills development produced significant gains in student centered teaching for these faculty members and in some students' perceptions of teaching quality. However, student workload needs to be considered to support deep learning. PMID- 28572414 TI - Is the Advanced Dental Admission Test (ADAT) the Metric Needed to Assist with Postgraduate Admissions? Two Viewpoints: Viewpoint 1: The ADAT Provides a Viable Solution to Help Postgraduate Programs Differentiate Applicants and Viewpoint 2: The ADAT Has Questionable Utility and Value for Postgraduate Admissions. AB - In 2012, when the National Board Dental Examination (NBDE) was changed from a numerical scoring system to pass/fail, advanced dental education programs lost a metric widely used for differentiating applicants to those programs. The American Dental Association (ADA) has developed the Advanced Dental Admission Test (ADAT) to address this issue. Implementation of the ADAT began in 2016 with a pilot program, which has not yet been widely accepted in the overall admissions process. This Point/Counterpoint explores the benefits and challenges of using the ADAT for postgraduate admissions. Viewpoint 1 supports use of the ADAT, arguing that the test provides a viable, long-term solution to this immediate need. In contrast, Viewpoint 2 questions the need for and appropriateness of this additional academic measure for postgraduate admissions. PMID- 28572415 TI - Factors Influencing Dental Students' Interest in Advanced Periodontal Education: Perspectives of Department Chairs. AB - The number of graduates of U.S. dental schools enrolled in U.S. postdoctoral programs in periodontics has been decreasing. The aims of this study were to determine the perspectives of periodontics department chairs regarding 1) features of a school's predoctoral curriculum that promote student interest in advanced periodontal education and 2) characteristics of a periodontal residency program that make it more attractive to dental students over other specialty programs. In 2015, a 14-question survey was designed and sent to chairs of periodontics departments at all 65 U.S. dental schools at the time. Questions addressed number of instructional hours; specialty clinic rotations; elective courses; number of applicants to periodontal residency; existence of a residency program; length of the residency program; and externships, fellowships, and financial stipends offered. The survey response rate was 73.8%. The results showed that departments offering more than seven clinical credit hours in periodontics to predoctoral students had the greatest number of residency applicants. Most of the applicants were from institutions that offered specialty clinic rotations, elective courses, and residency programs in periodontics. The number of applicants did not change significantly if a stipend or fellowship was offered. However, the availability of an externship was significantly associated with a greater number of applicants (p=0.042). These results suggest that offering periodontal clinical rotations, elective courses, and especially externships in periodontics during predoctoral education may encourage more graduating students to pursue postdoctoral periodontal education. PMID- 28572417 TI - Going Global: Toward Competency-Based Best Practices for Global Health in Dental Education. AB - The Global Oral Health Interest Group of the Consortium of Universities for Global Health (GOHIG-CUGH) published recommended competencies to support development of competency-based global health education in dental schools. However, there has been no comprehensive, systematically derived, or broadly accepted framework for creating and delivering competency-based global health education to dental students. This article describes the results of a collaborative workshop held at the 2016 American Dental Education Association (ADEA) Annual Session & Exhibition designed to build on the GOHIG-CUGH competencies and start to develop systematic approaches for their practical application. Workshop organizers developed a preliminary theoretical framework for guiding the development of global health in dental education, grounded in published research. Collectively, workshop participants developed detailed outcomes for the theoretical framework with a focus on three educational practices: didactic, experiential, and research learning and how each can meet the competencies. Participants discussed learning objectives, keys to implementation, ethical considerations, challenges, and examples of success. Outcomes demonstrated that no educational practice on its own meets all 33 recommended competencies for dental students; however, the three educational practices combined may potentially cover all 33. Participants emphasized the significance of sustainable approaches to student learning for both students and communities, with identified partners in the communities to collaborate on the development, implementation, evaluation, and long-term maintenance of any student global health activity. These findings may represent early steps toward professional consensus and best practices for global health in dental education in the United States. PMID- 28572416 TI - Graduate Periodontics Programs' Integration of Implant Provisionalization in Core Curricula: Implementation of CODA Standard 4-10.2.d. AB - The aim of this descriptive study was to provide an overview of the status of implementation of Commission on Dental Accreditation (CODA) Standard 4-10.2.d (Provisionalization of Dental Implants) by U.S. graduate periodontics programs since its introduction in 2013. Surveys were sent in May 2015 to 56 accredited postdoctoral periodontics program directors to ascertain program director characteristics; status of planning, implementation, and curriculum resulting from adoption of Standard 4-10.2.d; preferred clinical protocols for implant provisionalization; interdisciplinary educational collaborators; and competency assessment mechanisms. The survey response rate was 52% (N=29); the majority were male, aged 55 or older, and had held their position for less than ten years. Among the responding programs, 93% had formal educational curricula established in implant provisionalization. Graduate periodontics (96%) and prosthodontics (63%) faculty members were predominantly involved with curriculum planning. Of these programs, 96% used immediate implant provisionalization, with direct (chairside) provisionalization protocols (86%) being preferred over indirect protocols (14%) and polyethylethylketone provisional abutments (75%) being preferred to titanium (25%) provisional abutments. Straight and concave transmucosal emergence profile designs (46% each) were preferred in teaching, with only 8% of programs favoring convex transmucosal profiles. A majority of responding programs (67%) lacked protocols for communicating to the restorative referral a mechanism to duplicate the mature peri-implant mucosal architecture. Regional location did not play a significant role in any educational component related to implant provisionalization for these graduate periodontal programs. Overall, this study found that a clear majority of graduate periodontics programs had established formal curricula related to implant provisionalization, with substantial clinical and philosophical consensus within the specialty. PMID- 28572418 TI - Using Intervention Mapping to Develop an Oral Health e-Curriculum for Secondary Prevention of Eating Disorders. AB - Preventing oral-systemic health issues relies on evidence-based interventions across various system-level target groups. Although the use of theory- and evidence-based approaches has been encouraged in developing oral health behavior change programs, the translation of theoretical constructs and principles to behavior change interventions has not been well described. Based on a series of six systematic steps, Intervention Mapping provides a framework for effective decision making with regard to developing, implementing, and evaluating theory- and evidence-informed, system-based behavior change programs. This article describes the application of the Intervention Mapping framework to develop the EAT (evaluating, assessing, and treating) evidence-based intervention with the goal of increasing the capacity of oral health providers to engage in secondary prevention of oral-systemic issues associated with disordered eating behaviors. Examples of data and deliverables for each step are described. In addition, results from evaluation of the intervention via randomized control trial are described, with statistically significant differences observed in behavioral outcomes in the intervention group with effect sizes ranging from r=0.62 to 0.83. These results suggest that intervention mapping, via the six systematic steps, can be useful as a framework for continued development of preventive interventions. PMID- 28572419 TI - Using Assessments of Dental Students' Entrepreneurial Self-Efficacy to Aid Practice Management Education. AB - In the past, the typical practice management curriculum in U.S. dental schools was found to place a heavy emphasis on customer service, whereas areas typically stressed in business entrepreneurship and management courses (e.g., long-range planning, competing strategies, and supplier relationship) received less attention. However, future dentists will likely have many points in their careers at which they must decide whether to begin a new business or to associate with a practice, and entrepreneurial and management training can help them make and implement those decisions. The aim of this exploratory study was to investigate the impact of one dental school's practice management education on students' entrepreneurial self-efficacy (ESE), a construct examined for the first time in dental education. ESE is an individual's belief that he or she is personally capable of planning for, operating, and managing a successful business. In December 2014, all students in all four classes were asked to complete a survey measuring their ESE. The response rates for each class were D1 94%, D2 91%, D3 87%, and D4 79%. The results showed that the mean scores of the fourth-year class were higher on all five examined dimensions than those of the other three classes. The same was true for the mean for each class with the exception of the competency regarding an individual's perception of his or her abilities to deploy and manage human resources, in which the first-year class had a higher score than the fourth-year class (149.07>146.06). The fourth-year class had statistically significant higher scores than the third-year class, consistent with the implementation of practice management courses in the curriculum. PMID- 28572420 TI - Partial Ceramic Crowns Prepared by Dental Students: Clinical Performance Up to Five Years. AB - Partial ceramic crowns (PCCs) are an accepted treatment option for the restoration of posterior teeth with deficient tooth substance. Data on the survival of PCCs fabricated by dental students are scarce. The aim of this retrospective clinical study was to investigate the clinical performance and longevity of PCCs placed by dental students in the last year of their training program at the University of Basel, Switzerland. Eighty-eight patients who had received at least one PCC (n=108) in the program were considered for clinical assessment; their records were analyzed to detect previous complications or failures; and they were contacted by telephone. Criteria regarding aesthetic, functional, and biological aspects were rated with a scoring system from 1=clinically excellent to 5=clinically poor. The response rate was 66.3% (55 of 83 included patients), and 72.2% (n=78) of the PCCs were included in the analysis. Five PCCs had been lost within ten to 78 months after treatment. Six PCCs were recorded as failures (score 5), and ten received clinically unsatisfactory gradings (score 4). The risk of a clinically poor outcome was 14% after five years (86% survival), while the overall success rate was 63.5%. These results suggest that the clinical procedure of PCCs was successfully implemented by these students with satisfactory clinical survival. PMID- 28572421 TI - Do Dental Students' Personality Types and Group Dynamics Affect Their Performance in Problem-Based Learning? AB - The aim of this study was to determine whether the personality types of dental students and their group dynamics were linked to their problem-based learning (PBL) performance. The Myers-Briggs Type Indicator (MBTI) instrument was used with 263 dental students enrolled in Seoul National University School of Dentistry from 2011 to 2013; the students had participated in PBL in their first year. A four-session PBL setting was designed to analyze how individual personality types and the diversity of their small groups were associated with PBL performance. Overall, the results showed that the personality type of PBL performance that was the most prominent was Judging. As a group became more diverse with its different constituent personality characteristics, there was a tendency for the group to be higher ranked in terms of PBL performance. In particular, the overperforming group was clustered around three major profiles: Extraverted Intuitive Thinking Judging (ENTJ), Introverted Sensing Thinking Judging (ISTJ), and Extraverted Sensing Thinking Judging (ESTJ). Personality analysis would be beneficial for dental faculty members in order for them to understand the extent to which cooperative learning would work smoothly, especially when considering group personalities. PMID- 28572424 TI - Expression of Concern: Chromosomal breaks during mitotic catastrophe trigger gammaH2AX-ATM-p53-mediated apoptosis. Gabriela Imreh, Helin Vakifahmetoglu Norberg, Stefan Imreh, Boris Zhivotovsky. J. Cell Sci. doi: 10.1242/jcs.081612. PMID- 28572422 TI - Teaching Dental Students to Understand the Temporomandibular Joint Using MRI: Comparison of Conventional and Digital Learning Methods. AB - The aims of this study were to evaluate and compare the performance of dental students in interpreting the temporomandibular joint (TMJ) with magnetic resonance imaging (MRI) scans using two learning methods (conventional and digital interactive learning) and to examine the usability of the digital learning object (DLO). The DLO consisted of tutorials about MRI and anatomic and functional aspects of the TMJ. In 2014, dental students in their final year of study who were enrolled in the elective "MRI Interpretation of the TMJ" course comprised the study sample. After exclusions for nonattendance and other reasons, 29 of the initial 37 students participated in the study, for a participation rate of 78%. The participants were divided into two groups: a digital interactive learning group (n=14) and a conventional learning group (n=15). Both methods were assessed by an objective test applied before and after training and classes. Aspects such as support and training requirements, complexity, and consistency of the DLO were also evaluated using the System Usability Scale (SUS). A significant between-group difference in the posttest results was found, with the conventional learning group scoring better than the DLO group, indicated by mean scores of 9.20 and 8.11, respectively, out of 10. However, when the pretest and posttest results were compared, both groups showed significantly improved performance. The SUS score was 89, which represented a high acceptance of the DLO by the users. The students who used the conventional method of learning showed superior performance in interpreting the TMJ using MRI compared to the group that used digital interactive learning. PMID- 28572429 TI - An architect for mental health: an appreciation of Michele Tansella. AB - Michele Tansella, Professor of Psychiatry at the University of Verona, died in 2015. This editorial pays tribute to his contributions to scholarship in the field of psychiatric epidemiology and health service research, and to his highly effective efforts to improve mental healthcare, locally, nationally and internationally. PMID- 28572430 TI - Suicide is a complex problem that requires a range of prevention initiatives and methods of evaluation. AB - A range of factors can contribute to suicide, which means that a multifactorial approach to suicide prevention is necessary. Whereas randomised controlled trials may be suitable for evaluation of some interventions, others require different approaches for assessment of their impact. Also, suicide itself will not always be the most feasible outcome measure. PMID- 28572432 TI - Predictive properties of risk assessment instruments following self-harm. AB - This month's BJPsych publishes two important studies concerned with the use of risk assessment scales after self-harm, one a systematic review and the other a multicentre cohort study. We agree with the authors: that each study adds weight to the existing evidence that points towards avoiding the use of such scales in clinical practice. PMID- 28572435 TI - Poor uptake of depression care in cardiology. PMID- 28572436 TI - Authors' reply. PMID- 28572438 TI - Authors' reply. PMID- 28572437 TI - Communication skills training for psychiatrists. PMID- 28572444 TI - Protein malnutrition blunts the increment of taurine transporter expression by a high-fat diet and impairs taurine reestablishment of insulin secretion. AB - Taurine (Tau) restores beta-cell function in obesity; however, its action is lost in malnourished obese rodents. Here, we investigated the mechanisms involved in the lack of effects of Tau in this model. C57BL/6 mice were fed a control diet (CD) (14% protein) or a protein-restricted diet (RD) (6% protein) for 6 wk. Afterward, mice received a high-fat diet (HFD) for 8 wk [CD + HFD (CH) and RD + HFD (RH)] with or without 5% Tau supplementation after weaning on their drinking water [CH + Tau (CHT) and RH + Tau (RHT)]. The HFD increased insulin secretion through mitochondrial metabolism in CH and RH. Tau prevented all those alterations in CHT only. The expression of the taurine transporter (Tau-T), as well as Tau content in pancreatic islets, was increased in CH but had no effect on RH. Protein malnutrition programs beta cells and impairs Tau-induced restoration of mitochondrial metabolism and biogenesis. This may be associated with modulation of the expression of Tau-T in pancreatic islets, which may be responsible for the absence of effect of Tau in protein-malnourished obese mice. Branco, R. C. S., Camargo, R. L., Batista, T. M., Vettorazzi, J. F., Borck, P. C., dos Santos-Silva, J. C. R., Boschero, A. C., Zoppi, C. C., Carneiro, E. M. Protein malnutrition blunts the increment of taurine transporter expression by a high-fat diet and impairs taurine reestablishment of insulin secretion. PMID- 28572443 TI - Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids. AB - Unlike other agonists that cause transient endothelial cell (EC) response, the products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC) oxidation that contain cyclopenthenone groups, which recapitulate prostaglandin like structure, cause sustained enhancement of the pulmonary EC barrier. The mechanisms that drive the sustained effects by oxidized PAPC (OxPAPC) remain unexplored. On the basis of the structural similarity of isoprostanoid moieties that are present in full-length oxygenated PAPC species, we used an inhibitory approach to perform the screening of prostanoid receptors as potential candidates that mediate OxPAPC effects. Results show that only prostaglandin E receptor-4 (EP4) was involved and mediated the sustained phase of the barrier-enhancing effects of OxPAPC that are associated with the activation of Rac GTPase and its cytoskeletal targets. EC incubation with OxPAPC also induced EP4 mRNA expression in pulmonary ECs and lung tissue. EP4 knockdown using gene-specific small interfering RNA did not affect the rapid phase of OxPAPC-induced EC barrier enhancement or the protective effects against thrombin-induced EC permeability, but abolished the advanced barrier enhancement phase and suppressed the protective effects of OxPAPC against more sustained EC barrier dysfunction and cell inflammatory response caused by TNF-alpha. Endothelial-specific knockout of the EP4 receptor in mice attenuated the protective effect of intravenous OxPAPC administration in the model of acute lung injury caused by intratracheal injection of LPS. Taken together, these results demonstrate a novel role for prostaglandin receptor EP4 in the mediation of barrier-enhancing and anti inflammatory effects caused by oxidized phospholipids.-Oskolkova, O., Gawlak, G., Tian, Y., Ke, Y., Sarich, N., Son, S., Andreasson, K., Bochkov, V. N., Birukova, A. A., Birukov, K. G. Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids. PMID- 28572445 TI - Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction. AB - Polymicrobial sepsis in mice causes myocardial dysfunction after generation of the complement anaphylatoxin, complement component 5a (C5a). C5a interacts with its receptors on cardiomyocytes (CMs), resulting in redox imbalance and cardiac dysfunction that can be functionally measured and quantitated using Doppler echocardiography. In this report we have evaluated activation of MAPKs and Akt in CMs exposed to C5a in vitro and after cecal ligation and puncture (CLP) in vivo In both cases, C5a in vitro caused activation (phosphorylation) of MAPKs and Akt in CMs, which required availability of both C5a receptors. Using immunofluorescence technology, activation of MAPKs and Akt occurred in left ventricular (LV) CMs, requiring both C5a receptors, C5aR1 and -2. Use of a water soluble p38 inhibitor curtailed activation in vivo of MAPKs and Akt in LV CMs as well as the appearance of cytokines and histones in plasma from CLP mice. When mouse macrophages were exposed in vitro to LPS, activation of MAPKs and Akt also occurred. The copresence of the p38 inhibitor blocked these activation responses. Finally, the presence of the p38 inhibitor in CLP mice reduced the development of cardiac dysfunction. These data suggest that polymicrobial sepsis causes cardiac dysfunction that appears to be linked to activation of MAPKs and Akt in heart. Fattahi, F., Kalbitz, M., Malan, E. A., Abe, E., Jajou, L., Huber-Lang, M. S., Bosmann, M., Russell, M. W., Zetoune, F. S., Ward, P. A. Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction. PMID- 28572447 TI - Eleanor Joan Carmichael. PMID- 28572446 TI - Histone deacetylase 1 activates PU.1 gene transcription through regulating TAF9 deacetylation and transcription factor IID assembly. AB - Histone acetyltransferases and histone deacetylases (HDACs) are important epigenetic coregulators. It has been thought that HDACs associate with corepressor complexes and repress gene transcription; however, in this study, we have found that PU.1-a key master regulator for hematopoietic self-renewal and lineage specification-requires HDAC activity for gene activation. Deregulated PU.1 gene expression is linked to dysregulated hematopoiesis and the development of leukemia. In this study, we used erythroid differentiation as a model to analyze how the PU.1 gene is regulated. We found that active HDAC1 is directly recruited to active PU.1 promoter in progenitor cells, whereas acetylated HDAC1, which is inactive, is on the silenced PU.1 promoter in differentiated erythroid cells. We then studied the mechanism of HDAC1-mediated activation. We discovered that HDAC1 activates PU.1 gene transcription via deacetylation of TATA-binding protein-associated factor 9 (TAF9), a component in the transcription factor IID (TFIID) complex. Treatment with HDAC inhibitor results in an increase in TAF9 acetylation. Acetylated TAF9 does not bind to the PU.1 gene promoter and subsequently leads to the disassociation of the TFIID complex and transcription repression. Thus, these results demonstrate a key role for HDAC1 in PU.1 gene transcription and, more importantly, uncover a novel mechanism of TFIID recruitment and gene activation.-Jian, W., Yan, B., Huang, S., Qiu, Y. Histone deacetylase 1 activates PU.1 gene transcription through regulating TAF9 deacetylation and transcription factor IID assembly. PMID- 28572449 TI - The future is in our hands. PMID- 28572450 TI - An Unrestricted Restriction Endeavor. PMID- 28572448 TI - Structural and functional dissection of the interplay between lipid and Notch binding by human Notch ligands. AB - Recent data have expanded our understanding of Notch signalling by identifying a C2 domain at the N-terminus of Notch ligands, which has both lipid- and receptor binding properties. We present novel structures of human ligands Jagged2 and Delta-like4 and human Notch2, together with functional assays, which suggest that ligand-mediated coupling of membrane recognition and Notch binding is likely to be critical in establishing the optimal context for Notch signalling. Comparisons between the Jagged and Delta family show a huge diversity in the structures of the loops at the apex of the C2 domain implicated in membrane recognition and Jagged1 missense mutations, which affect these loops and are associated with extrahepatic biliary atresia, lead to a loss of membrane recognition, but do not alter Notch binding. Taken together, these data suggest that C2 domain binding to membranes is an important element in tuning ligand-dependent Notch signalling in different physiological contexts. PMID- 28572452 TI - Turning the tide of high-dose inhaled corticosteroids. PMID- 28572453 TI - Nanoscale nuclear magnetic resonance with chemical resolution. AB - Nuclear magnetic resonance (NMR) spectroscopy is a key analytical technique in chemistry, biology, and medicine. However, conventional NMR spectroscopy requires an at least nanoliter-sized sample volume to achieve sufficient signal. We combined the use of a quantum memory and high magnetic fields with a dedicated quantum sensor based on nitrogen vacancy centers in diamond to achieve chemical shift resolution in 1H and 19F NMR spectroscopy of 20-zeptoliter sample volumes. We demonstrate the application of NMR pulse sequences to achieve homonuclear decoupling and spin diffusion measurements. The best measured NMR linewidth of a liquid sample was ~1 part per million, mainly limited by molecular diffusion. To mitigate the influence of diffusion, we performed high-resolution solid-state NMR by applying homonuclear decoupling and achieved a 20-fold narrowing of the NMR linewidth. PMID- 28572455 TI - miR-183 cluster scales mechanical pain sensitivity by regulating basal and neuropathic pain genes. AB - Nociception is protective and prevents tissue damage but can also facilitate chronic pain. Whether a general principle governs these two types of pain is unknown. Here, we show that both basal mechanical and neuropathic pain are controlled by the microRNA-183 (miR-183) cluster in mice. This single cluster controls more than 80% of neuropathic pain-regulated genes and scales basal mechanical sensitivity and mechanical allodynia by regulating auxiliary voltage gated calcium channel subunits alpha2delta-1 and alpha2delta-2. Basal sensitivity is controlled in nociceptors, and allodynia involves TrkB+ light-touch mechanoreceptors. These light-touch-sensitive neurons, which normally do not elicit pain, produce pain during neuropathy that is reversed by gabapentin. Thus, a single microRNA cluster continuously scales acute noxious mechanical sensitivity in nociceptive neurons and suppresses neuropathic pain transduction in a specific, light-touch-sensitive neuronal type recruited during mechanical allodynia. PMID- 28572456 TI - Intracellular Motility of Intermediate Filaments. AB - SUMMARYThe establishment and continuous cell type-specific adaptation of cytoplasmic intermediate filament (IF) networks are linked to various types of IF motility. Motor protein-driven active transport, linkage to other cellular structures, diffusion of small soluble subunits, and intrinsic network elasticity all contribute to the motile behavior of IFs. These processes are subject to regulation by multiple signaling pathways. IF motility is thereby connected to and involved in many basic cellular processes guarding the maintenance of cell and tissue integrity. Disturbances of IF motility are linked to diseases that are characterized by cytoplasmic aggregates containing IF proteins together with other cellular components. PMID- 28572454 TI - Neurodevelopmental protein Musashi-1 interacts with the Zika genome and promotes viral replication. AB - A recent outbreak of Zika virus in Brazil has led to a simultaneous increase in reports of neonatal microcephaly. Zika targets cerebral neural precursors, a cell population essential for cortical development, but the cause of this neurotropism remains obscure. Here we report that the neural RNA-binding protein Musashi-1 (MSI1) interacts with the Zika genome and enables viral replication. Zika infection disrupts the binding of MSI1 to its endogenous targets, thereby deregulating expression of factors implicated in neural stem cell function. We further show that MSI1 is highly expressed in neural progenitors of the human embryonic brain and is mutated in individuals with autosomal recessive primary microcephaly. Selective MSI1 expression in neural precursors could therefore explain the exceptional vulnerability of these cells to Zika infection. PMID- 28572457 TI - A Central Role for Triacylglycerol in Membrane Lipid Breakdown, Fatty Acid beta Oxidation, and Plant Survival under Extended Darkness. AB - Neutral lipid metabolism is a key aspect of intracellular homeostasis and energy balance and plays a vital role in cell survival under adverse conditions, including nutrient deprivation in yeast and mammals, but the role of triacylglycerol (TAG) metabolism in plant stress response remains largely unknown. By thoroughly characterizing mutants defective in SUGAR-DEPENDENT1 (SDP1) triacylglycerol lipase or PEROXISOMAL ABC TRANSPORTER 1 (PXA1), here we show that TAG is a key intermediate in the mobilization of fatty acids from membrane lipids for peroxisomal beta-oxidation under prolonged dark treatment. Disruption of SDP1 increased TAG accumulation in cytosolic lipid droplets and markedly enhanced plant tolerance to extended darkness. We demonstrate that blocking TAG hydrolysis enhances plant tolerance to dark treatment via two distinct mechanisms. In pxa1 mutants, in which free fatty acids accumulated rapidly under extended darkness, SDP1 disruption resulted in a marked decrease in levels of cytotoxic lipid intermediates such as free fatty acids and phosphatidic acid, suggesting a buffer function of TAG accumulation against lipotoxicity under fatty acid overload. In the wild type, in which free fatty acids remained low and unchanged under dark treatment, disruption of SDP1 caused a decrease in reactive oxygen species production and hence the level of lipid peroxidation, indicating a role of TAG in protection against oxidative damage. Overall, our findings reveal a crucial role for TAG metabolism in membrane lipid breakdown, fatty acid turnover, and plant survival under extended darkness. PMID- 28572460 TI - Capecitabine Extends Survival for Biliary Tract Cancer. AB - Based on results of the phase III BILCAP study, adjuvant capecitabine should become standard treatment for patients with biliary tract cancer. Among 430 patients who were treated according to the study protocol, capecitabine was associated with a 25% lower risk of death than observation. PMID- 28572458 TI - The DnaJ-Like Zinc-Finger Protein HCF222 Is Required for Thylakoid Membrane Biogenesis in Plants. AB - To understand the biogenesis of the thylakoid membrane in higher plants and to identify auxiliary proteins required to build up this highly complex membrane system, we have characterized the allelic nuclear mutants high chlorophyll fluorescence222-1 (hcf222-1) and hcf222-2 and isolated the causal gene by map based cloning. In the ethyl methanesulfonate-induced mutant hcf222-1, the accumulation of the cytochrome b6f (Cytb6f) complex was reduced to 30% compared with the wild type. Other thylakoid membrane complexes accumulated to normal levels. The T-DNA knockout mutant hcf222-2 showed a more severe defect with respect to thylakoid membrane proteins and accumulated only 10% of the Cytb6f complex, accompanied by a reduction in photosystem II, the photosystem II light harvesting complex, and photosystem I. HCF222 encodes a protein of 99 amino acids in Arabidopsis (Arabidopsis thaliana) that has similarities to the cysteine-rich zinc-binding domain of DnaJ chaperones. The insulin precipitation assay demonstrated that HCF222 has disulfide reductase activity in vitro. The protein is conserved in higher plants and bryophytes but absent in algae and cyanobacteria. Confocal fluorescence microscopy showed that a fraction of HCF222 green fluorescent protein was detectable in the endoplasmic reticulum but that it also could be recognized in chloroplasts. A fusion construct of HCF222 containing a plastid transit peptide targets the protein into chloroplasts and was able to complement the mutational defect. These findings indicate that the chloroplast targeted HCF222 is indispensable for the maturation and/or assembly of the Cytb6f complex and is very likely involved in thiol-disulfide biochemistry at the thylakoid membrane. PMID- 28572461 TI - The Effects of 5-year Etanercept Therapy on Cardiovascular Risk Factors in Patients with Psoriatic Arthritis. AB - OBJECTIVE: To investigate the effects of etanercept (ETN) on lipid metabolism and other known cardiovascular disease (CVD) risk factors in patients with psoriatic arthritis (PsA). METHODS: In an observational cohort of 118 consecutive patients with PsA, CVD risk factors were assessed over 5 years. Mixed-model analyses were performed to investigate the effects of ETN therapy on CVD risk factors over time. RESULTS: Disease Activity Score in 28 joints, C-reactive protein (CRP), and erythrocyte sedimentation rate decreased during therapy with ETN. There was an increase in total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), and low-density lipoprotein cholesterol. The TC/HDLc ratio remained unaltered. The apolipoprotein B to apolipoprotein A-I (apoB/apoA-I) ratio decreased significantly. An increase in CRP was associated with an increase in the apoB/apoA-1 ratio. CONCLUSION: Serum lipid concentrations showed small changes over a 5-year period of ETN therapy and were inversely associated with inflammatory markers. Other CVD risk factors remained stable. The apoB/apoA-1 ratio decreased over time and an increase in disease activity was associated with an increase in this ratio. However, this modest lipid modulation cannot explain the observed beneficial CV effects of ETN, and ETN likely exerts those effects through inflammation-related mechanisms. PMID- 28572459 TI - AACR Project GENIE: Powering Precision Medicine through an International Consortium. AB - The AACR Project GENIE is an international data-sharing consortium focused on generating an evidence base for precision cancer medicine by integrating clinical grade cancer genomic data with clinical outcome data for tens of thousands of cancer patients treated at multiple institutions worldwide. In conjunction with the first public data release from approximately 19,000 samples, we describe the goals, structure, and data standards of the consortium and report conclusions from high-level analysis of the initial phase of genomic data. We also provide examples of the clinical utility of GENIE data, such as an estimate of clinical actionability across multiple cancer types (>30%) and prediction of accrual rates to the NCI-MATCH trial that accurately reflect recently reported actual match rates. The GENIE database is expected to grow to >100,000 samples within 5 years and should serve as a powerful tool for precision cancer medicine.Significance: The AACR Project GENIE aims to catalyze sharing of integrated genomic and clinical datasets across multiple institutions worldwide, and thereby enable precision cancer medicine research, including the identification of novel therapeutic targets, design of biomarker-driven clinical trials, and identification of genomic determinants of response to therapy. Cancer Discov; 7(8); 818-31. (c)2017 AACR.See related commentary by Litchfield et al., p. 796This article is highlighted in the In This Issue feature, p. 783. PMID- 28572463 TI - Cardiovascular Risk Factors and Disease Characteristics Are Consistently Associated with Arterial Function in Rheumatoid Arthritis. AB - OBJECTIVE: Arterial properties influence cardiovascular disease (CVD) risk. We identified potential determinants of arterial function in patients with rheumatoid arthritis (RA). METHODS: Relationships of traditional cardiovascular risk factors and RA characteristics with arterial stiffness (pulse wave velocity), wave reflection (augmentation index, reflected wave pressure, and reflection magnitude), and pressure pulsatility (central systolic and pulse pressure, peripheral pulse pressure, pulse pressure amplification, and forward wave pressure) were identified in multivariable backward regression models among 177 patients without established CVD (118 white, 32 Asian, 22 black, 5 mixed ancestry). RESULTS: Recorded characteristics explained 37% (pulse wave velocity) to 71% (reflected wave pressure) of the variability in arterial function. These factors were particularly associated with wave reflection and pressure pulsatility: RA duration (p = 0.04), rheumatoid factor status (p = 0.01 to 0.03), leukocyte counts (p = 0.02 to 0.05), and total cholesterol (p < 0.01 to 0.03). Body mass index (p < 0.01 to 0.02) and insulin resistance (p < 0.01 to 0.01) were related to reduced wave reflection and peripheral pulse pressure. Exercise (p = 0.02) and alcohol consumption (p < 0.01) were associated with increased pulse pressure amplification and decreased peripheral pulse pressure, respectively. Tumor necrosis factor-alpha inhibition (p < 0.01) was related to reduced pulse wave velocity, and tetracycline use (p = 0.02) to decreased peripheral pulse pressure. CONCLUSION: Traditional cardiovascular risk factors and disease characteristics are consistently associated with vascular hemodynamic alterations in RA. The relative effect of arterial stiffness, wave reflection, and pressure pulsatility on CVD risk in RA needs further study. PMID- 28572462 TI - Development and Reliability of a Preliminary Foot Osteoarthritis Magnetic Resonance Imaging Score. AB - OBJECTIVE: Foot osteoarthritis (OA) is very common but underinvestigated musculoskeletal condition and there is little consensus as to common magnetic resonance imaging (MRI) features. The aim of this study was to develop a preliminary foot OA MRI score (FOAMRIS) and evaluate its reliability. METHODS: This preliminary semiquantitative score included the hindfoot, midfoot, and metatarsophalangeal joints. Joints were scored for joint space narrowing (JSN; 0 3), osteophytes (0-3), joint effusion/synovitis, and bone cysts (present/absent). Erosions and bone marrow lesions (BML) were scored (0-3) and BML were evaluated adjacent to entheses and at sub-tendon sites (present/absent). Additionally, tenosynovitis (0-3) and midfoot ligament pathology (present/absent) were scored. Reliability was evaluated in 15 people with foot pain and MRI-detected OA using 3.0T MRI multi-sequence protocols, and assessed using ICC as an overall score and per anatomical site. RESULTS: Intrareader agreement (ICC) was generally good to excellent across the foot in joint features (JSN 0.90, osteophytes 0.90, effusion/synovitis 0.46, cysts 0.87), bone features (BML 0.83, erosion 0.66, BML entheses 0.66, BML sub-tendon 0.60) and soft tissue features (tenosynovitis 0.83, ligaments 0.77). Interreader agreement was lower for joint features (JSN 0.43, osteophytes 0.27, effusion/synovitis 0.02, cysts 0.48), bone features (BML 0.68, erosion 0.00, BML entheses 0.34, BML sub-tendon 0.13), and soft tissue features (tenosynovitis 0.35, ligaments 0.33). CONCLUSION: This preliminary FOAMRIS demonstrated good intrareader reliability and fair interreader reliability when assessing the total feature scores. Further development is required in cohorts with a range of pathologies and to assess the psychometric measurement properties. PMID- 28572464 TI - A Comparative Evaluation of the 2011 and 2016 Criteria for Fibromyalgia. AB - OBJECTIVE: In 2016, a revised version of the 2010 American College of Rheumatology fibromyalgia (FM) criteria and the 2011 self-report (survey) FM criteria were published. The 2016 criteria preserved the distinction between physician and patient criteria, but made the individual criteria items identical, added a "generalized pain" criterion, and changed ascertainment and scoring methods, among other changes. In this study, we evaluated diagnostic differences relating to 2016 changes. METHODS: We used the National Data Bank for Rheumatic Diseases and evaluated 16,987 participants with painful rheumatic disorders using the 2011 and 2016 methodologies. RESULTS: There were 4731 patients (27.9%) who satisfied the 2011 criteria and 4077 (24.0%) the 2016 revision. This resulted in agreement in 96.2% of cases and disagreement in 3.9%. All disagreements occurred in the 4731 2011-positive cases who failed to meet the 2016 criteria. This result came about because 654 (13.8%) of the 2011-positive cases failed to meet the new generalized pain requirement. When using the approximate polysymptomatic distress diagnostic method, diagnostic misclassification ranged between 7% and 13%. CONCLUSION: The 2016 FM criteria further refined and increased the usefulness of symptom-based diagnosis of FM by excluding patients with regional pain syndromes. However, these changes, useful as they are, underscore the social construction of symptom-based diagnosis and the inherent limitations in reliability and validity associated with FM criteria. PMID- 28572465 TI - Relationship Between Polymorphisms in Methotrexate Pathway Genes and Outcome of Methotrexate Treatment in a Cohort of 119 Patients with Juvenile Idiopathic Arthritis. AB - OBJECTIVE: To identify clinical and pharmacogenetic determinants of efficacy and toxicity of methotrexate (MTX) in juvenile idiopathic arthritis (JIA) over time. METHODS: A cohort of 119 consecutive patients with JIA treated with MTX was reviewed. The Juvenile Arthritis Disease Activity Score including 71 joints was used to measure disease activity. Nonresponders were patients who did not reach a minimum of 30% improvement after 6 months of treatment or were switched to biologic drugs in the first 6 months because of inefficacy. All adverse events (AE) were noted. Genotyping of single-nucleotide polymorphisms (SNP) in the genes coding for MTX transporters, folate pathway, and adenosine pathway was performed using real-time PCR methods. Univariate and multivariable penalized logistic and Cox regression were used to analyze data. RESULTS: Thirty patients (25.8%) were defined as nonresponders and 55 (47.2%) were switched to biologics during the followup. Sixty-five patients (54.5%) reported AE in a total of 405 patient years, and 10 patients (8.4%) discontinued MTX because of AE. AMPD1 rs17602729 and MTHFD1 rs2236225 were associated with gastrointestinal AE while the latter together with MTRR rs1801394 also demonstrated associations with developing hepatoxicity. MTHFR rs1801131, ABCG2 rs2231137, wild-type of MTR rs1805087, and wild-type of ABCC2 rs2273697 were identified as potential markers for discontinuing MTX treatment because of AE. MTHFR rs1801133, MTRR rs1801394, and ABCC2 rs2273697 were associated with switching to biologics. CONCLUSION: SNP in different MTX metabolic pathways influence treatment with MTX. Genetic variability is a better marker for toxicity than efficacy. PMID- 28572467 TI - Comparison of Composite Indices Tailored for Psoriatic Arthritis Treated with csDMARD and bDMARD: A Cross-sectional Analysis of a Longitudinal Cohort. AB - OBJECTIVE: In a complex disease such as psoriatic arthritis (PsA), several methods are available to define remission or low disease activity (LDA), including the assessment of different clinical features. The aim of this study was to compare the composite indices tailored for PsA in patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARD) and biological DMARD (bDMARD). METHODS: Patients with PsA classified with the ClASsification criteria for Psoriatic ARthritis criteria and with > 6 months followup treated with first csDMARD and bDMARD were consecutively enrolled. To assess disease activity, composite indices tailored for PsA were used, such as the Disease Activity Index for Psoriatic Arthritis (DAPSA), clinical DAPSA (cDAPSA), Psoriatic Arthritis Disease Activity Score (PASDAS), minimal disease activity (MDA) 5/7, and MDA 7/7. DAPSA and cDAPSA score <= 4, MDA 7/7, and PASDAS <= 1.9 identified remission. MDA 5/7, DAPSA score <= 14, cDAPSA score <= 13, and PASDAS < 3.2 identified the MDA and LDA criteria. RESULTS: One hundred nine patients with PsA were enrolled: 79 patients were receiving stable treatment with bDMARD and 30 with csDMARD. Overall, 28 (25.6%), 23 (21.1%), 19 (17.4%), and 13 patients (11.9%) were in cDAPSA remission, DAPSA remission, MDA 7/7, and PASDAS <= 1.9, respectively. Moreover, 54 (49.5%), 80 (73.3%), 79 (72.3%), and 38 patients (34.8%) were in MDA 5/7, DAPSA LDA, cDAPSA LDA, and PASDAS LDA. Patients treated with bDMARD had significantly lower median DAPSA, cDAPSA, and PASDAS score than patients treated with csDMARD. CONCLUSION: Patients with PsA receiving bDMARD are more likely to achieve a status of MDA and remission when compared with csDMARD. PASDAS <= 1.9 and MDA 7/7 seem to be stringent remission criteria. PMID- 28572468 TI - Longterm Prognosis of 121 Patients with Eosinophilic Granulomatosis with Polyangiitis in Japan. AB - OBJECTIVE: We investigated the risk factors for relapse or prognosis of eosinophilic granulomatosis with polyangiitis (EGPA) in Japanese patients presenting to our hospital. METHODS: From June 1999 through March 2015, we retrospectively recruited 121 patients with EGPA according to the American College of Rheumatology criteria. Frequent relapse was defined as disease occurrence at least once every 2 years after a period of initial remission. The study endpoint was the last examination performed. We used multiple logistic regression to analyze risk factors for relapse or survival in EGPA. RESULTS: Gastrointestinal (GI) involvement with both abnormalities on endoscopy and biopsy (p < 0.01) and symptoms; myocardial involvement with both abnormalities on 1 or more cardiac investigations and symptoms (p < 0.01); and treatment at initial or maintenance with immunosuppressants (p < 0.01) or administration of intravenous immunoglobulin (IVIG; p < 0.01) were associated significantly more often with frequent relapse than with infrequent. Overall 5-, 10-, and 20-year survival rates were 91.1%, 83.7%, and 68.6%, respectively. Survival in EGPA was associated with age of onset < 65 years. Age at onset of EGPA was the only significant predictor of survival (p < 0.01). Myocardial or GI tract involvement did not affect mortality risk. CONCLUSION: Patients with myocardial or GI tract involvement had frequent relapses, but these conditions were not reflected in increased mortality. Treatment with immunosuppressants or IVIG in addition to corticosteroids might have improved the prognosis in Japanese patients with EGPA. PMID- 28572466 TI - Longterm Outcome of Patients with Primary Antiphospholipid Syndrome: A Retrospective Multicenter Study. AB - OBJECTIVE: To assess the longterm frequency of thrombotic recurrences, obstetrical complications, organ damage, severe comorbidities, and evolution toward connective tissue disease (CTD) in primary antiphospholipid syndrome (PAPS). METHODS: Medical records of patients with PAPS followed in 6 centers for >= 15 years were retrospectively reviewed. RESULTS: One hundred fifteen patients were studied: 88% women, followed between 1983 and 2014 with a mean (+/- SD) age at diagnosis of 33 (+/- 10) years. During a median followup of 18 years (range 15 30), 50 patients (44%) had at least a thrombotic event for a total of 75 events and an annual incidence of 3.5%. Thromboses were more frequent in patients with previous thrombotic history (p = 0.002). A catastrophic antiphospholipid syndrome occurred in 6 patients (5%). The use of oral anticoagulants in patients with thrombotic onset did not appear to be protective against recurrences (p = 0.26). Fifty-two women had 87 pregnancies, successful in 78%. Twenty-nine percent of patients accrued functional damage. Damage was significantly associated with a thrombotic history (p = 0.004) and with arterial events (p < 0.001), especially stroke, but not with demographics, serology, or treatment. Twenty-four major bleeding episodes were recorded in 18 patients, all receiving anticoagulants. Severe infections affected 6 patients (5%), with 1 fatality. A solid cancer was diagnosed in 8 patients (7%). Altogether, 16 patients (14%) developed an autoimmune disease and 13 (11%) a full-blown picture of CTD. CONCLUSION: Despite therapy, a high proportion of patients experienced new thrombotic events and organ damage, while evolution toward CTD was infrequent. PMID- 28572469 TI - Magnetic Resonance Imaging (MRI) of the Knee as an Outcome Measure in Juvenile Idiopathic Arthritis: An OMERACT Reliability Study on MRI Scales. AB - OBJECTIVE: There is increasing evidence that early therapeutic intervention improves longterm joint outcome in juvenile idiopathic arthritis (JIA). Given the existence of highly effective treatments, there is an urgent need for reliable and accurate measures of disease activity and joint damage in JIA. Our objective was to assess the reliability of 2 magnetic resonance imaging (MRI) scoring methods: the Juvenile Arthritis MRI Scoring (JAMRIS) system and the International Prophylaxis Study Group (IPSG) consensus score, for evaluating disease status of the knee in patients with JIA. METHODS: Four international readers independently scored an MRI dataset of 25 JIA patients with clinical knee involvement. Synovial thickening, joint effusion, bone marrow changes, cartilage lesions, bone erosions, and subchondral cysts were scored using the JAMRIS and IPSG systems. Further, synovial enhancement, infrapatellar fat pad heterogeneity, tendinopathy, and enthesopathy were scored. Interreader reliability was analyzed by using the generalized kappa, ICC, and the smallest detectable difference (SDD). RESULTS: ICC regarding interreader reliability ranged from 0.33 (95% CI 0.12-0.52, SDD = 0.29) for enthesopathy up to 0.95 (95% CI 0.92-0.97, SDD = 3.19) for synovial thickening. Good interreader reliability was found concerning joint effusion (ICC 0.93, 95% CI 0.89-0.95, SDD = 0.51), synovial enhancement (ICC 0.90, 95% CI 0.85 0.94, SDD = 9.85), and bone marrow changes (ICC 0.87, 95% CI 0.80-0.92, SDD = 10.94). Moderate to substantial reliability was found concerning cartilage lesions and bone erosions (ICC 0.55-0.72, SDD 1.41-13.65). CONCLUSION: The preliminary results are promising for most of the scored JAMRIS and IPSG items. However, further refinement of the scoring system is warranted for unsatisfactorily reliable items such as bone erosions, cartilage lesions, and enthesopathy. PMID- 28572471 TI - Fish Oil and Inflammation - A Fresh Look. PMID- 28572470 TI - Risk of Knee Osteoarthritis Over 24 Months in Individuals Who Decrease Walking Speed During a 12-Month Period: Data from the Osteoarthritis Initiative. AB - OBJECTIVE: To assess the association between change in walking speed over a 12 month period and risk of developing radiographic knee osteoarthritis (rKOA) over a 24-month period. METHODS: We included participants without rKOA from the Osteoarthritis Initiative. Change in walking speed was determined from a 20-m walk assessment, calculated using walking speed at 12-month followup minus baseline speed and/or 24-month followup walking speed minus 12-month speed. Incident rKOA was defined as progressing to Kellgren-Lawrence arthritis grading scale >= 2 within 24 months (i.e., incidence between 12 and 36 mos or 24 and 48 mos). Self-reported significant knee injury during the exposure period, age, body mass index (BMI), and Physical Activity Scale for the Elderly (PASE) score were adjusted for analytically. RESULTS: We included 2638 observations among 1460 unique participants (58% women; aged 59 +/- 9 yrs, range 45-79). The mean change in walking speed over 12 months was 0.001 +/- 0.13 m/s (range -0.6271 to 1.4968). About 5% of the sample (n = 122) developed rKOA over a 24-month period. After controlling for significant knee injury, age, BMI, and PASE score, we found an 8% relative increase in risk of developing rKOA for every 0.1 m/s decrease in walking speed over a 12-month period (risk ratio 1.08, 95% CI 1.00-1.15, p = 0.05). CONCLUSION: Evaluating change in speed over a 12-month period using a 20-m walk test may be useful in identifying individuals at increased risk of developing rKOA over the subsequent 24 months. Identification of patients at high risk for developing rKOA would allow medical providers to implement early interventions to maximize joint health. PMID- 28572472 TI - The Economic Value of Genetic Testing for Tolerance of Allopurinol in Gout. PMID- 28572473 TI - Nurse-led Care and Patients as Partners Are Essential Aspects of the Future of Rheumatology Care. PMID- 28572474 TI - Antimelanoma Differentiation-associated Gene 5 Dermatomyositis. PMID- 28572475 TI - Symptomatic Narcolepsy in Sjogren Syndrome. PMID- 28572476 TI - Reliability of Radiographic Assessment of Sacroiliac Joints in Patients with Suspected Early Spondyloarthritis: Methodological Issue. PMID- 28572477 TI - Back to Basics: Clinical versus Radiologic Recognition of Spondyloarthropathy. PMID- 28572478 TI - Dr. Christiansen, et al, reply. PMID- 28572479 TI - Pediatric Neuromyelitis Optica Spectrum Disorder and Sjogren Syndrome: More Common Than Previously Thought? PMID- 28572480 TI - Herpes Zoster Vaccination Compliance: The Role of Specialist Rheumatology Nurses. PMID- 28572481 TI - Dr. Janow, et al reply. PMID- 28572482 TI - Drs. Sheth and Aggarwal reply. PMID- 28572483 TI - Slow Advances in Supply of Canadian Rheumatologists. PMID- 28572484 TI - High Accuracy and Significant Savings Using Tag-SNP Genotyping to Determine HLA B*27 Status. PMID- 28572485 TI - Dr. Barber replies. PMID- 28572487 TI - Biodistribution and Radiation Dosimetry of 18F-FTC-146 in Humans. AB - The purpose of this study was to assess safety, biodistribution, and radiation dosimetry in humans for the highly selective sigma-1 receptor PET agent 18F-6-(3 fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one (18F-FTC-146). Methods: Ten healthy volunteers (5 women, 5 men; age +/- SD, 34.3 +/- 6.5 y) were recruited, and written informed consent was obtained from all participants. Series of whole-body PET/MRI examinations were acquired for up to 3 h after injection (357.2 +/- 48.8 MBq). Blood samples were collected, and standard vital signs (heart rate, pulse oximetry, and body temperature) were monitored at regular intervals. Regions of interest were delineated, time-activity curves were calculated, and organ uptake and dosimetry were estimated. Results: All subjects tolerated the PET/MRI examination well, and no adverse reactions to 18F-FTC-146 were reported. High accumulation of 18F-FTC-146 was observed in sigma-1 receptor dense organs such as the pancreas and spleen, moderate uptake in the brain and myocardium, and low uptake in bone and muscle. High uptake was also observed in the kidneys and bladder, indicating renal tracer clearance. The effective dose of 18F-FTC-146 was 0.0259 +/- 0.0034 mSv/MBq (range, 0.0215-0.0301 mSv/MBq). Conclusion: First-in-human studies with clinical-grade 18F-FTC-146 were successful. Injection of 18F-FTC-146 is safe, and absorbed doses are acceptable. The potential of 18F-FTC-146 as an imaging agent for a variety of neuroinflammatory diseases is currently under investigation. PMID- 28572488 TI - Detection of Synchronous Primary Malignancies with 68Ga-Labeled Prostate-Specific Membrane Antigen PET/CT in Patients with Prostate Cancer: Frequency in 764 Patients. AB - We evaluated the incidence of synchronous primary malignancies in patients undergoing 68Ga-labeled prostate-specific membrane antigen PET/CT for prostate cancer (PC). Methods: Reports for 764 PC patients were reviewed. Incidental lesions atypical for PC metastases and suggestive of a synchronous primary malignancy were identified. Follow-up was obtained to confirm etiology. Results: Lesions atypical for PC metastases were found in 49 (6.4%) of 764 patients, and a synchronous primary malignancy was confirmed in 5 patients (0.7%; 2 lung, 1 lymphoma, 1 thyroid, and 1 base of tongue). In 8 patients (1.0%), lesions were proven to be atypical metastases from PC. In 24 patients (3.1%), lesions had a benign etiology. Follow-up was not available in 12 patients (1.6%). Conclusion: Synchronous 68Ga-labeled prostate-specific membrane antigen-avid malignancies were rare (0.7%) in PC patients; atypical lesions were more commonly unusual PC metastases (1.0%) or benign (3.1%). PMID- 28572489 TI - Head-to-Head Comparison of Chest X-Ray/Head and Neck MRI, Chest CT/Head and Neck MRI, and 18F-FDG PET/CT for Detection of Distant Metastases and Synchronous Cancer in Oral, Pharyngeal, and Laryngeal Cancer. AB - The purpose of this study was to determine the detection rate of distant metastasis and synchronous cancer, comparing clinically used imaging strategies based on chest x-ray + head and neck MRI (CXR/MRI) and chest CT + head and neck MRI (CHCT/MRI) with 18F-FDG PET/CT upfront in the diagnostic workup of patients with oral, pharyngeal, or laryngeal cancer. Methods: This was a prospective cohort study based on paired data. Consecutive patients with histologically verified primary head and squamous cell carcinoma at Odense University Hospital from September 2013 to March 2016 were considered for the study. Included patients underwent CXR/MRI and CHCT/MRI as well as PET/CT on the same day and before biopsy. Scans were read masked by separate teams of experienced nuclear physicians or radiologists. The true detection rate of distant metastasis and synchronous cancer was assessed for CXR/MRI, CHCT/MRI, and PET/CT. Results: A total of 307 patients were included. CXR/MRI correctly detected 3 (1%) patients with distant metastasis, CHCT/MRI detected 11 (4%) patients, and PET/CT detected 18 (6%) patients. The absolute differences of 5% and 2%, respectively, were statistically significant in favor of PET/CT. Also, PET/CT correctly detected 25 (8%) synchronous cancers, which was significantly more than CXR/MRI (3 patients, 1%) and CHCT/MRI (6 patients, 2%). The true detection rate of distant metastasis or synchronous cancer with PET/CT was 13% (40 patients), which was significantly higher than 2% (6 patients) for CXR/MRI and 6% (17 patients) for CHCT/MRI. Conclusion: A clinical imaging strategy based on PET/CT demonstrated a significantly higher detection rate of distant metastasis or synchronous cancer than strategies in current clinical imaging guidelines, of which European ones primarily recommend CXR/MRI, whereas U.S. guidelines preferably point to CHCT/MRI in patients with head and neck squamous cell carcinoma. PMID- 28572490 TI - A Modular Dual-Labeling Scaffold That Retains Agonistic Properties for Somatostatin Receptor Targeting. AB - Fluorescence-guided surgery is an emerging imaging technique that can enhance the ability of surgeons to detect tumors when compared with visual observation. To facilitate characterization, fluorescently labeled probes have been dual-labeled with a radionuclide to enable cross-validation with nuclear imaging. In this study, we selected the somatostatin receptor imaging agent DOTATOC as the foundation for developing a dual-labeled analog. We hypothesized that a customized dual-labeling approach with a multimodality chelation (MMC) scaffold would minimize steric effects of dye conjugation and retain agonist properties. Methods: An MMC conjugate (MMC-TOC) was synthesized on solid-phase and compared with an analog prepared using conventional methods (DA-TOC). Both analogs were conjugated to IRDye 800 using copper-free click chemistry. The resulting compounds, MMC(IR800)-TOC and DA(IR800)-TOC, were labeled with Cu and 64Cu and tested in vitro in somatostatin receptor subtype 2-overexpressing HEK-293 cells to assess agonist properties, and in AR42J rat pancreatic cancer cells to determine receptor binding characteristics. Multimodality imaging was performed in AR42J xenografts. Results: Cu-MMC(IR800)-TOC demonstrated higher potency for cyclic adenosine monophosphate inhibition (half maximal effective concentration [EC50]: 0.21 +/- 0.18 vs. 1.38 +/- 0.54 nM) and receptor internalization (EC50: 41.9 +/- 29.8 vs. 455 +/- 299 nM) than Cu-DA(IR800)-TOC. Radioactive uptake studies showed that blocking with octreotide caused a dose-dependent reduction in 64Cu-MMC(IR800)-TOC uptake whereas 64Cu-DA(IR800)-TOC was not affected. In vivo studies revealed higher tumor uptake for 64Cu-MMC(IR800)-TOC than 64Cu-DA(IR800) TOC (5.2 +/- 0.2 vs. 3.6 +/- 0.4 percentage injected dose per gram). In vivo blocking studies with octreotide reduced tumor uptake of 64Cu-MMC(IR800)-TOC by 66%. Excretion of 64Cu-MMC(IR800)-TOC was primarily through the liver and spleen whereas 64Cu-DA(IR800)-TOC was cleared through the kidneys. Ex vivo analysis at 24 h confirmed PET/CT data by showing near-infrared fluorescence signal in tumors and a tumor-to-muscle ratio of 5.3 +/- 0.8 as determined by gamma-counting. Conclusion: The findings demonstrate that drug design affected receptor pharmacology and suggest that the MMC scaffold is a useful tool for the development of dual-labeled imaging agents. PMID- 28572491 TI - New Fetal Radiation Doses for 18F-FDG Based on Human Data. AB - Current standard values of fetal dosimetry deriving from 18F-FDG injection in pregnant women are estimated from animal data. The present communication offers a revision of fetal dosimetry values calculated from recently published human data, in which fetal 18F-FDG uptake was directly observed in vivo. The final doses were obtained from the observed time-integrated activity coefficients and a new generation of anthropomorphic voxel-based pregnancy phantoms. PMID- 28572493 TI - Regulation of blood volume in lowlanders exposed to high altitude. AB - Humans ascending to high altitude (HA) experience a reduction in arterial oxyhemoglobin saturation and, as a result, arterial O2 content ([Formula: see text]). As HA exposure extends, this reduction in [Formula: see text] is counteracted by an increase in arterial hemoglobin concentration. Initially, hemoconcentration is exclusively related to a reduction in plasma volume (PV), whereas after several weeks a progressive expansion in total red blood cell volume (RCV) contributes, although often to a modest extent. Since the decrease in PV is more rapid and usually more pronounced than the expansion in RCV, at least during the first weeks of exposure, a reduction in circulating blood volume is common at HA. Although the regulation of hematological responses to HA has been investigated for decades, it remains incompletely understood. This is not only related to the large number of mechanisms that could be involved and the complexity of their interplay but also to the difficulty of conducting comprehensive experiments in the often secluded HA environment. In this review, we present our understanding of the kinetics, the mechanisms and the physiological relevance of the HA-induced reduction in PV and expansion in RCV. PMID- 28572492 TI - Beta-1 vs. beta-2 adrenergic control of coronary blood flow during isometric handgrip exercise in humans. AB - During exercise, beta-adrenergic receptors are activated throughout the body. In healthy humans, the net effect of beta-adrenergic stimulation is an increase in coronary blood flow. However, the role of vascular beta1 vs. beta2 receptors in coronary exercise hyperemia is not clear. In this study, we simultaneously measured noninvasive indexes of myocardial oxygen supply (i.e., blood velocity in the left anterior descending coronary artery; Doppler echocardiography) and demand [i.e., rate pressure product (RPP) = heart rate * systolic blood pressure) and tested the hypothesis that beta1 blockade with esmolol improves coronary exercise hyperemia compared with nonselective beta-blockade with propranolol. Eight healthy young men received intravenous infusions of esmolol, propranolol, and saline on three separate days in a single-blind, randomized, crossover design. During each infusion, subjects performed isometric handgrip exercise until fatigue. Blood pressure, heart rate, and coronary blood velocity (CBV) were measured continuously, and RPP was calculated. Changes in parameters from baseline were compared with paired t-tests. Esmolol (Delta = 3296 +/- 1204) and propranolol (Delta = 2997 +/- 699) caused similar reductions in peak RPP compared with saline (Delta = 5384 +/- 1865). In support of our hypothesis, DeltaCBV with esmolol was significantly greater than with propranolol (7.3 +/- 2.4 vs. 4.5 +/- 1.6 cm/s; P = 0.002). This effect was also evident when normalizing DeltaCBV to DeltaRPP. In summary, not only does selective beta1 blockade reduce myocardial oxygen demand during exercise, but it also unveils beta2-receptor-mediated coronary exercise hyperemia.NEW & NOTEWORTHY In this study, we evaluated the role of vascular beta1 vs. beta2 receptors in coronary exercise hyperemia in a single blind, randomized, crossover study in healthy men. In response to isometric handgrip exercise, blood flow velocity in the left anterior descending coronary artery was significantly greater with esmolol compared with propranolol. These findings increase our understanding of the individual and combined roles of coronary beta1 and beta2 adrenergic receptors in humans. PMID- 28572494 TI - Erythrocyte purinergic signaling components underlie hypoxia adaptation. AB - Erythrocytes are vital to human adaptation under hypoxic conditions because of their abundance in number and irreplaceable function of delivering oxygen (O2). However, although multiple large-scale altitude studies investigating the overall coordination of the human body for hypoxia adaptation have been conducted, detailed research with a focus on erythrocytes was missing due to lack of proper techniques. The recently maturing metabolomics profiling technology appears to be the answer to this limitation. Metabolomics profiling provides unbiased high throughput screening data that reveal the overall metabolic status of erythrocytes. Recent studies have exploited this new technology and provided novel insight into erythrocyte physiology and pathology. In particular, a series of studies focusing on erythrocyte purinergic signaling have reported that adenosine signaling, coupled with 5' AMP-activated protein kinase (AMPK) and the production of erythrocyte-enriched bioactive signaling lipid sphingosine 1 phosphate, regulate erythrocyte glucose metabolism for more O2 delivery. Moreover, an adenosine-dependent "erythrocyte hypoxic memory" was discovered that provides an explanation for fast acclimation upon re-ascent. These findings not only shed new light on our understanding of erythrocyte function and hypoxia adaptation, but also offer a myriad of novel therapeutic possibilities to counteract various hypoxic conditions. PMID- 28572495 TI - Comparison of the vasodilatory effects of sodium nitroprusside vs. nitroglycerin. AB - The vasodilatory mechanism of Nntroglycerin (NTG) is similar to sodium nitroprusside (SNP) in regard to action on guanosine 3'5'-monophosphate (cyclic GMP) via nitric oxide. However, it is unknown whether NTG can achieve the same magnitude of vasodilation in the forearm as SNP. Therefore, the purpose of the study was to evaluate the differences in forearm blood flow (FBF) and forearm vascular conductance (FVC) during escalating infusions of NTG vs. SNP at similar concentration doses and rates. We measured FBF using venous occlusion plethysmography (VOP) and Doppler ultrasound in eight young, healthy participants (mean age = 28 +/- 2 yr) during four forearm volume (FAV)-specific doses (0.25, 0.5, 1, and 2 ug.100 ml FAV-1.min-1) of SNP and NTG infused via a brachial artery catheter. There was a significant difference in FVC of SNP vs. NTG only at the higher doses, as measured by VOP (14.9 +/- 1.4 and 18.3 +/- 1.5 vs. 11.6 +/- 1.2 and 12.5 +/- 1.2 ml/dl FAV-1.min-1.100 mmHg-1). FVC as measured by Doppler ultrasound unadjusted for FAV was significantly different at the lowest and the higher two doses of SNP compared with NTG (202.1 +/- 25.8, 329.4 +/- 46.7, and 408 +/- 63.5 vs. 142.9 +/- 22.4, 217.2 +/- 18.8, and 247.5 +/- 18.2 ml.min-1.100 mmHg-1). SNP induces significantly higher vasodilatory actions compared with NTG. However, NTG is comparable in eliciting equivalent vasodilator effects to SNP during low concentration doses when measured by VOP. Importantly, for forearm pharmacology studies, NTG can elicit marked endothelium-independent forearm vasodilation.NEW & NOTEWORTHY We compared the vasodilatory capacities of NTG vs. SNP at similar concentration doses and rates into the forearm. Based on the results of the study, it may be feasible to use intra-arterial NTG as a measure of endothelial-independent vasodilator in research studies. However, NTG dosing may need to be higher if used as an endothelial-independent vasodilator due to significant differences in the vasodilatory effects during higher doses of SNP compared with NTG. PMID- 28572496 TI - Effect of age, diet, and tissue type on PCr response to creatine supplementation. AB - Creatine/phosphorylcreatine (PCr) responses to creatine supplementation may be modulated by age, diet, and tissue, but studies assessing this possibility are lacking. Therefore we aimed to determine whether PCr responses vary as a function of age, diet, and tissue. Fifteen children, 17 omnivorous and 14 vegetarian adults, and 18 elderly individuals ("elderly") participated in this study. Participants were given placebo and subsequently creatine (0.3 g.kg-1.day-1) for 7 days in a single-blind fashion. PCr was measured through phosphorus magnetic resonance spectroscopy (31P-MRS) in muscle and brain. Creatine supplementation increased muscle PCr in children (P < 0.0003) and elderly (P < 0.001), whereas the increase in omnivores did not reach statistically significant difference (P = 0.3348). Elderly had greater PCr increases than children and omnivores (P < 0.0001 for both), whereas children experienced greater PCr increases than omnivores (P = 0.0022). In relation to diet, vegetarians (P < 0.0001), but not omnivores, had significant increases in muscle PCr content. Brain PCr content was not affected by creatine supplementation in any group, and delta changes in brain PCr (-0.7 to +3.9%) were inferior to those in muscle PCr content (+10.3 to +27.6%; P < 0.0001 for all comparisons). PCr responses to a standardized creatine protocol (0.3 g.kg-1.day-1 for 7 days) may be affected by age, diet, and tissue. Whereas creatine supplementation was able to increase muscle PCr in all groups, although to different extents, brain PCr was shown to be unresponsive overall. These findings demonstrate the need to tailor creatine protocols to optimize creatine/PCr accumulation both in muscle and in brain, enabling a better appreciation of the pleiotropic properties of creatine.NEW & NOTEWORTHY A standardized creatine supplementation protocol (0.3 g.kg-1.day-1 for 7 days) effectively increased muscle, but not brain, phosphorylcreatine. Older participants responded better than younger participants whereas vegetarians responded better than omnivores. Responses to supplementation are thus dependent on age, tissue, and diet. This suggests that a single "universal" protocol, originally designed for increasing muscle creatine in young individuals, may lead to heterogeneous muscle responses in different populations or even no responses in tissues other than skeletal muscle. PMID- 28572497 TI - UBC-Nepal expedition: markedly lower cerebral blood flow in high-altitude Sherpa children compared with children residing at sea level. AB - Developmental cerebral hemodynamic adaptations to chronic high-altitude exposure, such as in the Sherpa population, are largely unknown. To examine hemodynamic adaptations in the developing human brain, we assessed common carotid (CCA), internal carotid (ICA), and vertebral artery (VA) flow and middle cerebral artery (MCA) velocity in 25 (9.6 +/- 1.0 yr old, 129 +/- 9 cm, 27 +/- 8 kg, 14 girls) Sherpa children (3,800 m, Nepal) and 25 (9.9 +/- 0.7 yr old, 143 +/- 7 cm, 34 +/- 6 kg, 14 girls) age-matched sea level children (344 m, Canada) during supine rest. Resting gas exchange, blood pressure, oxygen saturation and heart rate were assessed. Despite comparable age, height and weight were lower (both P < 0.01) in Sherpa compared with sea level children. Mean arterial pressure, heart rate, and ventilation were similar, whereas oxygen saturation (95 +/- 2 vs. 99 +/- 1%, P < 0.01) and end-tidal Pco2 (24 +/- 3 vs. 36 +/- 3 Torr, P < 0.01) were lower in Sherpa children. Global cerebral blood flow was ~30% lower in Sherpa compared with sea level children. This was reflected in a lower ICA flow (283 +/- 108 vs. 333 +/- 56 ml/min, P = 0.05), VA flow (78 +/- 26 vs. 118 +/- 35 ml/min, P < 0.05), and MCA velocity (72 +/- 14 vs. 88 +/- 14 cm/s, P < 0.01). CCA flow was similar between Sherpa and sea level children (425 +/- 92 vs. 441 +/- 81 ml/min, P = 0.52). Scaling flow and oxygen uptake for differences in vessel diameter and body size, respectively, led to the same findings. A lower cerebral blood flow in Sherpa children may reflect specific cerebral hemodynamic adaptations to chronic hypoxia.NEW & NOTEWORTHY Cerebral blood flow is lower in Sherpa children compared with children residing at sea level; this may reflect a cerebral hemodynamic pattern, potentially due to adaptation to a hypoxic environment. PMID- 28572500 TI - Neuromuscular electrical stimulation improves skeletal muscle regeneration through satellite cell fusion with myofibers in healthy elderly subjects. AB - The aim of this study was to determine whether neuromuscular electrical stimulation (NMES) affects skeletal muscle regeneration through a reduction of oxidative status in satellite cells of healthy elderly subjects. Satellite cells from the vastus lateralis skeletal muscle of 12 healthy elderly subjects before and after 8 wk of NMES were allowed to proliferate to provide myogenic populations of adult stem cells [myogenic precursor cells (MPCs)]. These MPCs were then investigated in terms of their proliferation, their basal cytoplasmic free Ca2+ concentrations, and their expression of myogenic regulatory factors (PAX3, PAX7, MYF5, MYOD, and MYOG) and micro-RNAs (miR-1, miR-133a/b, and miR 206). The oxidative status of these MPCs was evaluated through superoxide anion production and superoxide dismutase and glutathione peroxidase activities. On dissected single skeletal myofibers, the nuclei were counted to determine the myonuclear density, the fiber phenotype, cross-sectional area, and tension developed. The MPCs obtained after NMES showed increased proliferation rates along with increased cytoplasmic free Ca2+ concentrations and gene expression of MYOD and MYOG on MPCs. Muscle-specific miR-1, miR-133a/b, and miR-206 were upregulated. This NMES significantly reduced superoxide anion production, along with a trend to reduction of superoxide dismutase activity. The NMES-dependent stimulation of muscle regeneration enhanced satellite cell fusion with mature skeletal fibers. NMES improved the regenerative capacity of skeletal muscle in elderly subjects. Accordingly, the skeletal muscle strength and mobility of NMES stimulated elderly subjects significantly improved. NMES may thus be further considered for clinical or ageing populations.NEW & NOTEWORTHY The neuromuscular electrical stimulation (NMES) effect on skeletal muscle regeneration was assessed in healthy elderly subjects for the first time. NMES improved the regenerative capacity of skeletal muscle through increased myogenic precursor cell proliferation and fusion with mature myofibers. The increased cytoplasmic free Ca2+ concentration along with MYOD, MYOG, and micro-RNA upregulation could be related to reduced O2.- production, which, in turn, favors myogenic regeneration. Accordingly, the skeletal muscle strength of NMES-stimulated lower limbs of healthy elderly subjects improved along with their mobility. PMID- 28572499 TI - Effect of calf-raise training on rapid force production and balance ability in elderly men. AB - This study examined whether home-based, high-speed calf-raise training changes the rate of torque development (RTD) during plantar flexion contractions and balance performance in elderly men. Thirty-four healthy elderly men (73 +/- 5 yr) were randomly assigned to a training or control group (n = 17 in each group). The subjects in the training group completed 8 wk (3 times/wk) of home-based bilateral calf-raise training using body mass. Before and after the intervention, RTD during plantar flexion contractions and center-of-pressure (COP) displacement during single-leg standing were measured. Surface electromyographic amplitude of the triceps surae and tibialis anterior during the strength and single-leg standing was measured. Clinical magnitude-based inferences were used to interpret the training effect, with the smallest worthwhile effect assumed to be 0.2 of the baseline SD. The peak RTD increased 21% (90% confidence limits, +/-19%) relative to the control group, which was accompanied by corresponding changes of the medial gastrocnemius (MG) and soleus (SOL) activations. The effect on COP displacement was possibly trivial (0%, +/-13%), whereas substantial reduction in the MG (-19%, +/-15%) and SOL (-25%, +/-13%) activations during standing was observed. Our findings indicate that calf-raise training at home, performed without special equipment or venue, induces a substantial increase in the plantar flexors' rapid force-generating capability and triceps surae activations. Although the training effect on standing balance performance was not substantial, observed changes in the triceps surae activations during standing are expected to contribute to future balance performance improvement.NEW & NOTEWORTHY Calf-raise training with the intent to move rapidly, without special equipment or venue, induces an improvement of explosive plantar flexion force, which is attributable to neuromuscular rather than musculotendinous adaptations. Although the training effect on balance performance was trivial, we found a sign of improvement (i.e., neuromuscular adaptations during standing). In conclusion, functional neuromuscular capacity can be enhanced by home-based calf-raise exercise in elderly men, which may protect against mobility loss with aging. PMID- 28572501 TI - Reflex cardiorespiratory events from esophageal origin are heightened by preterm birth. AB - The involvement of gastroesophageal refluxes in cardiorespiratory events of preterm infants remains controversial. While a few studies in full-term newborn animals have shown that stimulation of esophageal receptors leads to cardiorespiratory reflexes, the latter remain largely unknown, especially after premature birth. The present study aimed to 1) characterize the cardiorespiratory reflexes originating from esophageal receptors in newborn lambs and 2) test the hypotheses that preterm birth enhances reflex cardiorespiratory inhibition and that C-fibers are involved in these reflexes. Eight full-term lambs and 10 lambs born 14 days prematurely were studied. Following surgical instrumentation, a 6-h polysomnography was performed without sedation to record electrocardiogram, respiratory movements, arterial pressure, laryngeal constrictor muscle activity, state of alertness, and hemoglobin oxygen saturation. Five esophageal stimulations of the upper and/or lower esophagus, including rapid balloon inflation and/or HCl injection, were performed in random order. A second recording was performed in full-term lambs 24 h later, after C-fiber blockade by capsaicin. Results confirmed that esophageal stimulations induced inhibitory cardiorespiratory reflexes combined with protective mechanisms, including laryngeal closure, swallowing, coughing, increased arterial pressure, and arousal. Preterm birth heightened cardiorespiratory inhibition. The strongest cardiorespiratory inhibition was observed following simultaneous stimulation of the lower and upper esophagus. Finally, cardiorespiratory inhibition was decreased after C-fiber blockade. In conclusion, esophageal stimulation induces inhibitory cardiorespiratory reflexes, which are partly mediated by C-fibers and more pronounced in preterm lambs. Clinical relevance of these findings requires further studies, especially in conditions associated with increased cardiorespiratory events, e.g., neonatal infection.NEW & NOTEWORTHY Preterm birth heightens the cardiorespiratory events triggered by esophageal stimulation. The most extensive cardiorespiratory events are induced by simultaneous stimulation of the proximal and distal esophagus. PMID- 28572502 TI - Experimental intermittent ischemia augments exercise-induced inflammatory cytokine production. AB - Acute exercise-induced inflammation is implicated in mediating the beneficial adaptations to regular exercise. Evidence suggests that reduced oxygen and/or blood flow to contracting muscle alters cytokine appearance. However, the acute inflammatory responses to hypoxic/ischemic exercise have been documented with inconsistent results and may not accurately reflect the ischemia produced during exercise in patients with ischemic cardiovascular diseases. Therefore, we determined the extent to which local inflammation is involved in the response to ischemic exercise. Fourteen healthy males performed unilateral isometric forearm contractions for 30 min with and without experimental ischemia. Blood was drawn at baseline, 5 and 10 min into exercise, at the end of exercise, and 30, 60, and 120 min after exercise. Oxygen saturation levels, as measured by near-infrared spectroscopy, were reduced by 10% and 41% during nonischemic and ischemic exercise, respectively. Nonischemic exercise did not affect cytokine values. Ischemia enhanced concentrations of basic fibroblast growth factor, interleukin (IL)-6, IL-10, tumor necrosis factor-alpha, and vascular endothelial growth factor during exercise, but IL-8 was not influenced by ischemic exercise. In conclusion, the present study demonstrates that ischemic, small-muscle endurance exercise elicits local inflammatory cytokine production compared with nonischemic exercise.NEW & NOTEWORTHY We demonstrate that ischemic, small-muscle endurance exercise elicits local inflammatory cytokine production compared with nonischemic exercise. The present study advances our knowledge of the inflammatory response to exercise in a partial ischemic state, which may be relevant for understanding the therapeutic effects of exercise training for people with ischemic cardiovascular disease-associated comorbidities. PMID- 28572505 TI - Correction: Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer. PMID- 28572498 TI - Exercise: Teaching myocytes new tricks. AB - Endurance exercise training promotes numerous cellular adaptations in both cardiac myocytes and skeletal muscle fibers. For example, exercise training fosters changes in mitochondrial function due to increased mitochondrial protein expression and accelerated mitochondrial turnover. Additionally, endurance exercise training alters the abundance of numerous cytosolic and mitochondrial proteins in both cardiac and skeletal muscle myocytes, resulting in a protective phenotype in the active fibers; this exercise-induced protection of cardiac and skeletal muscle fibers is often referred to as "exercise preconditioning." As few as 3-5 consecutive days of endurance exercise training result in a preconditioned cardiac phenotype that is sheltered against ischemia-reperfusion-induced injury. Similarly, endurance exercise training results in preconditioned skeletal muscle fibers that are resistant to a variety of stresses (e.g., heat stress, exercise induced oxidative stress, and inactivity-induced atrophy). Many studies have probed the mechanisms responsible for exercise-induced preconditioning of cardiac and skeletal muscle fibers; these studies are important, because they provide an improved understanding of the biochemical mechanisms responsible for exercise induced preconditioning, which has the potential to lead to innovative pharmacological therapies aimed at minimizing stress-induced injury to cardiac and skeletal muscle. This review summarizes the development of exercise-induced protection of cardiac myocytes and skeletal muscle fibers and highlights the putative mechanisms responsible for exercise-induced protection in the heart and skeletal muscles. PMID- 28572506 TI - Correction: Chromosome Instability Modulated by BMI1-AURKA Signaling Drives Progression in Head and Neck Cancer. PMID- 28572507 TI - Correction: Connective Tissue Growth Factor Activates Pluripotency Genes and Mesenchymal-Epithelial Transition in Head and Neck Cancer Cells. PMID- 28572504 TI - A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant. AB - A major barrier to successful use of allogeneic hematopoietic cell transplantation is acute graft-versus-host disease (aGVHD), a devastating condition that arises when donor T cells attack host tissues. With current technologies, aGVHD diagnosis is typically made after end-organ injury and often requires invasive tests and tissue biopsies. This affects patient prognosis as treatments are dramatically less effective at late disease stages. Here, we show that a novel PET radiotracer, 2'-deoxy-2'-[18F]fluoro-9-beta-D arabinofuranosylguanine ([18F]F-AraG), targeted toward two salvage kinase pathways preferentially accumulates in activated primary T cells. [18F]F-AraG PET imaging of a murine aGVHD model enabled visualization of secondary lymphoid organs harboring activated donor T cells prior to clinical symptoms. Tracer biodistribution in healthy humans showed favorable kinetics. This new PET strategy has great potential for early aGVHD diagnosis, enabling timely treatments and improved patient outcomes. [18F]F-AraG may be useful for imaging activated T cells in various biomedical applications. Cancer Res; 77(11); 2893 902. (c)2017 AACR. PMID- 28572508 TI - Cardioprotective Role of Tumor Necrosis Factor Receptor-Associated Factor 2 by Suppressing Apoptosis and Necroptosis. AB - BACKGROUND: Programmed cell death, including apoptosis, mitochondria-mediated necrosis, and necroptosis, is critically involved in ischemic cardiac injury, pathological cardiac remodeling, and heart failure progression. Whereas apoptosis and mitochondria-mediated necrosis signaling is well established, the regulatory mechanisms of necroptosis and its significance in the pathogenesis of heart failure remain elusive. METHODS: We examined the role of tumor necrosis factor receptor-associated factor 2 (Traf2) in regulating myocardial necroptosis and remodeling using genetic mouse models. We also performed molecular and cellular biology studies to elucidate the mechanisms by which Traf2 regulates necroptosis signaling. RESULTS: We identified a critical role for Traf2 in myocardial survival and homeostasis by suppressing necroptosis. Cardiac-specific deletion of Traf2 in mice triggered necroptotic cardiac cell death, pathological remodeling, and heart failure. Plasma tumor necrosis factor alpha level was significantly elevated in Traf2-deficient mice, and genetic ablation of TNFR1 largely abrogated pathological cardiac remodeling and dysfunction associated with Traf2 deletion. Mechanistically, Traf2 critically regulates receptor-interacting proteins 1 and 3 and mixed lineage kinase domain-like protein necroptotic signaling with the adaptor protein tumor necrosis factor receptor-associated protein with death domain as an upstream regulator and transforming growth factor beta-activated kinase 1 as a downstream effector. It is important to note that genetic deletion of RIP3 largely rescued the cardiac phenotype triggered by Traf2 deletion, validating a critical role of necroptosis in regulating pathological remodeling and heart failure propensity. CONCLUSIONS: These results identify an important Traf2-mediated, NFkappaB-independent, prosurvival pathway in the heart by suppressing necroptotic signaling, which may serve as a new therapeutic target for pathological remodeling and heart failure. PMID- 28572509 TI - Dynamic distinctions in the Na+/Ca2+ exchanger adopting the inward- and outward facing conformational states. AB - Na+/Ca2+ exchanger (NCX) proteins operate through the alternating access mechanism, where the ion-binding pocket is exposed in succession either to the extracellular or the intracellular face of the membrane. The archaeal NCX_Mj (Methanococcus jannaschii NCX) system was used to resolve the backbone dynamics in the inward-facing (IF) and outward-facing (OF) states by analyzing purified preparations of apo- and ion-bound forms of NCX_Mj-WT and its mutant, NCX_Mj-5L6 8. First, the exposure of extracellular and cytosolic vestibules to the bulk phase was evaluated as the reactivity of single cysteine mutants to a fluorescent probe, verifying that NCX_Mj-WT and NCX_Mj-5L6-8 preferentially adopt the OF and IF states, respectively. Next, hydrogen-deuterium exchange-mass spectrometry (HDX MS) was employed to analyze the backbone dynamics profiles in proteins, preferentially adopting the OF (WT) and IF (5L6-8) states either in the presence or absence of ions. Characteristic differences in the backbone dynamics were identified between apo NCX_Mj-WT and NCX_Mj-5L6-8, thereby underscoring specific conformational patterns owned by the OF and IF states. Saturating concentrations of Na+ or Ca2+ specifically modify HDX patterns, revealing that the ion bound/occluded states are much more stable (rigid) in the OF than in the IF state. Conformational differences observed in the ion-occluded OF and IF states can account for diversifying the ion-release dynamics and apparent affinity (Km ) at opposite sides of the membrane, where specific structure-dynamic elements can effectively match the rates of bidirectional ion movements at physiological ion concentrations. PMID- 28572510 TI - The BMP4-Smad signaling pathway regulates hyperandrogenism development in a female mouse model. AB - Polycystic ovary syndrome is a common endocrine disorder and a major cause of anovulatory sterility in women at reproductive age. Most patients with polycystic ovary syndrome have hyperandrogenism, caused by excess androgen synthesis. Bone morphogenetic protein 4 (BMP4) is an essential regulator of embryonic development and organ formation, and recent studies have also shown that BMP4 may be involved in female steroidogenesis process. However, the effect of BMP4 on hyperandrogenism remains unknown. Here, using a female mouse model of hyperandrogenism, we found that ovarian BMP4 levels were significantly decreased in hyperandrogenism. Elevated androgens inhibited BMP4 expression via activation of androgen receptors. Moreover, BMP4 treatment suppressed androgen synthesis in theca cells and promoted estrogen production in granulosa cells by regulating the expression of steroidogenic enzymes, including CYP11A, HSD3B2, CYP17A1, and CYP19A1 Consistently, knockdown of BMP4 augmented androgen levels and inhibited estrogen levels. Mechanistically, Smad signaling rather than the p38 MAPK pathway regulated androgen and estrogen formation, thereby mediating the effect of BMP4. Of note, BMP4-transgenic mice were protected against hyperandrogenism. Our observations clarify a vital role of BMP4 in controlling sex hormone levels and offer new insights into intervention for managing hyperandrogenism by targeting the BMP4-Smad signaling pathway. PMID- 28572511 TI - Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B12-trafficking proteins ABCD4 and LMBD1. AB - Vitamin B12 (cobalamin (Cbl)), in the cofactor forms methyl-Cbl and adenosyl-Cbl, is required for the function of the essential enzymes methionine synthase and methylmalonyl-CoA mutase, respectively. Cbl enters mammalian cells by receptor mediated endocytosis of protein-bound Cbl followed by lysosomal export of free Cbl to the cytosol and further processing to these cofactor forms. The integral membrane proteins LMBD1 and ABCD4 are required for lysosomal release of Cbl, and mutations in the genes LMBRD1 and ABCD4 result in the cobalamin metabolism disorders cblF and cblJ. We report a new (fifth) patient with the cblJ disorder who presented at 7 days of age with poor feeding, hypotonia, methylmalonic aciduria, and elevated plasma homocysteine and harbored the mutations c.1667_1668delAG [p.Glu556Glyfs*27] and c.1295G>A [p.Arg432Gln] in the ABCD4 gene. Cbl cofactor forms are decreased in fibroblasts from this patient but could be rescued by overexpression of either ABCD4 or, unexpectedly, LMBD1. Using a sensitive live-cell FRET assay, we demonstrated selective interaction between ABCD4 and LMBD1 and decreased interaction when ABCD4 harbored the patient mutations p.Arg432Gln or p.Asn141Lys or when artificial mutations disrupted the ATPase domain. Finally, we showed that ABCD4 lysosomal targeting depends on co expression of, and interaction with, LMBD1. These data broaden the patient and mutation spectrum of cblJ deficiency, establish a sensitive live-cell assay to detect the LMBD1-ABCD4 interaction, and confirm the importance of this interaction for proper intracellular targeting of ABCD4 and cobalamin cofactor synthesis. PMID- 28572513 TI - Domain alternation and active site remodeling are conserved structural features of ubiquitin E1. AB - E1 enzymes for ubiquitin (Ub) and Ub-like modifiers (Ubls) harbor two catalytic activities that are required for Ub/Ubl activation: adenylation and thioester bond formation. Structural studies of the E1 for the Ubl small ubiquitin-like modifier (SUMO) revealed a single active site that is transformed by a conformational switch that toggles its competency for catalysis of these two distinct chemical reactions. Although the mechanisms of adenylation and thioester bond formation revealed by SUMO E1 structures are thought to be conserved in Ub E1, there is currently a lack of structural data supporting this hypothesis. Here, we present a structure of Schizosaccharomyces pombe Uba1 in which the second catalytic cysteine half-domain (SCCH domain) harboring the catalytic cysteine has undergone a 106 degrees rotation that results in a completely different network of intramolecular interactions between the SCCH and adenylation domains and translocation of the catalytic cysteine 12 A closer to the Ub C terminus compared with previous Uba1 structures. SCCH domain alternation is accompanied by conformational changes within the Uba1 adenylation domains that effectively disassemble the adenylation active site. Importantly, the structural and biochemical data suggest that domain alternation and remodeling of the adenylation active site are interconnected and are intrinsic structural features of Uba1 and that the overall structural basis for adenylation and thioester bond formation exhibited by SUMO E1 is indeed conserved in Ub E1. Finally, the mechanistic insights provided by the novel conformational snapshot of Uba1 presented in this study may guide efforts to develop small molecule inhibitors of this critically important enzyme that is an active target for anticancer therapeutics. PMID- 28572512 TI - Deletion of interleukin 1 receptor-associated kinase 1 (Irak1) improves glucose tolerance primarily by increasing insulin sensitivity in skeletal muscle. AB - Chronic inflammation may contribute to insulin resistance via molecular cross talk between pathways for pro-inflammatory and insulin signaling. Interleukin 1 receptor-associated kinase 1 (IRAK-1) mediates pro-inflammatory signaling via IL 1 receptor/Toll-like receptors, which may contribute to insulin resistance, but this hypothesis is untested. Here, we used male Irak1 null (k/o) mice to investigate the metabolic role of IRAK-1. C57BL/6 wild-type (WT) and k/o mice had comparable body weights on low-fat and high-fat diets (LFD and HFD, respectively). After 12 weeks on LFD (but not HFD), k/o mice (versus WT) had substantially improved glucose tolerance (assessed by the intraperitoneal glucose tolerance test (IPGTT)). As assessed with the hyperinsulinemic euglycemic glucose clamp technique, insulin sensitivity was 30% higher in the Irak1 k/o mice on chow diet, but the Irak1 deletion did not affect IPGTT outcomes in mice on HFD, suggesting that the deletion did not overcome the impact of obesity on glucose tolerance. Moreover, insulin-stimulated glucose-disposal rates were higher in the k/o mice, but we detected no significant difference in hepatic glucose production rates (+/- insulin infusion). Positron emission/computed tomography scans indicated higher insulin-stimulated glucose uptake in muscle, but not liver, in Irak1 k/o mice in vivo Moreover, insulin-stimulated phosphorylation of Akt was higher in muscle, but not in liver, from Irak1 k/o mice ex vivo In conclusion, Irak1 deletion improved muscle insulin sensitivity, with the effect being most apparent in LFD mice. PMID- 28572518 TI - Challenges in the diagnosis and management of dementia in Hong Kong. PMID- 28572514 TI - Cell-surface copper transporters and superoxide dismutase 1 are essential for outgrowth during fungal spore germination. AB - During fungal spore germination, a resting spore returns to a conventional mode of cell division and resumes vegetative growth, but the requirements for spore germination are incompletely understood. Here, we show that copper is essential for spore germination in Schizosaccharomyces pombe Germinating spores develop a single germ tube that emerges from the outer spore wall in a process called outgrowth. Under low-copper conditions, the copper transporters Ctr4 and Ctr5 are maximally expressed at the onset of outgrowth. In the case of Ctr6, its expression is broader, taking place before and during outgrowth. Spores lacking Ctr4, Ctr5, and the copper sensor Cuf1 exhibit complete germination arrest at outgrowth. In contrast, ctr6 deletion only partially interferes with formation of outgrowing spores. At outgrowth, Ctr4-GFP and Ctr5-Cherry first co-localize at the spore contour, followed by re-location to a middle peripheral spore region. Subsequently, they move away from the spore body to occupy the periphery of the nascent cell. After breaking of spore dormancy, Ctr6 localizes to the vacuole membranes that are enriched in the spore body relative to the germ tube. Using a copper-binding tracker, results showed that labile copper is preferentially localized to the spore body. Further analysis showed that Ctr4 and Ctr6 are required for copper-dependent activation of the superoxide dismutase 1 (SOD1) during spore germination. This activation is critical because the loss of SOD1 activity blocked spore germination at outgrowth. Taken together, these results indicate that cell-surface copper transporters and SOD1 are required for completion of the spore germination program. PMID- 28572515 TI - An allene oxide and 12-oxophytodienoic acid are key intermediates in jasmonic acid biosynthesis by Fusarium oxysporum. AB - Fungi can produce jasmonic acid (JA) and its isoleucine conjugate in large quantities, but little is known about the biosynthesis. Plants form JA from 18:3n 3 by 13S-lipoxygenase (LOX), allene oxide synthase, and allene oxide cyclase. Shaking cultures of Fusarium oxysporum f. sp. tulipae released over 200 mg of jasmonates per liter. Nitrogen powder of the mycelia expressed 10R-dioxygenase epoxy alcohol synthase activities, which was confirmed by comparison with the recombinant enzyme. The 13S-LOX of F. oxysporum could not be detected in the cell free preparations. Incubation of mycelia in phosphate buffer with [17,17,18,18,18 2H5]18:3n-3 led to biosynthesis of a [2H5]12-oxo-13-hydroxy-9Z,15Z octadecadienoic acid (alpha-ketol), [2H5]12-oxo-10,15Z-phytodienoic acid (12 OPDA), and [2H5]13-keto- and [2H5]13S-hydroxyoctadecatrienoic acids. The alpha ketol consisted of 90% of the 13R stereoisomer, suggesting its formation by nonenzymatic hydrolysis of an allene oxide with 13S configuration. Labeled and unlabeled 12-OPDA were observed following incubation with 0.1 mM [2H5]18:3n-3 in a ratio from 0.4:1 up to 47:1 by mycelia of liquid cultures of different ages, whereas 10 times higher concentration of [2H5]13S-hydroperoxyoctadecatrienoic acid was required to detect biosynthesis of [2H5]12-OPDA. The allene oxide is likely formed by a cytochrome P450 or catalase-related hydroperoxidase. We conclude that F. oxysporum, like plants, forms jasmonates with an allene oxide and 12-OPDA as intermediates. PMID- 28572517 TI - Development of extracorporeal membrane oxygenation in Hong Kong: current challenges and future development. PMID- 28572516 TI - Jaspine B induces nonapoptotic cell death in gastric cancer cells independently of its inhibition of ceramide synthase. AB - Sphingolipids (SLs) have been extensively investigated in biomedical research due to their role as bioactive molecules in cells. Here, we describe the effect of a SL analog, jaspine B (JB), a cyclic anhydrophytosphingosine found in marine sponges, on the gastric cancer cell line, HGC-27. JB induced alterations in the sphingolipidome, mainly the accumulation of dihydrosphingosine, sphingosine, and their phosphorylated forms due to inhibition of ceramide synthases. Moreover, JB provoked atypical cell death in HGC-27 cells, characterized by the formation of cytoplasmic vacuoles in a time and dose-dependent manner. Vacuoles appeared to originate from macropinocytosis and triggered cytoplasmic disruption. The pan caspase inhibitor, z-VAD, did not alter either cytotoxicity or vacuole formation, suggesting that JB activates a caspase-independent cell death mechanism. The autophagy inhibitor, wortmannin, did not decrease JB-stimulated LC3-II accumulation. In addition, cell vacuolation induced by JB was characterized by single-membrane vacuoles, which are different from double-membrane autophagosomes. These findings suggest that JB-induced cell vacuolation is not related to autophagy and it is also independent of its action on SL metabolism. PMID- 28572519 TI - The Hong Kong Reference Frameworks-for our doctors and our community. PMID- 28572520 TI - Clinical management of sepsis. AB - Sepsis is a common cause of hospital admission worldwide and contributes significantly to morbidity and mortality. The definition of sepsis has evolved from the 1991 American College of Chest Physicians/Society of Critical Care Medicine definition based on the criteria of systemic inflammatory response syndrome, to the 2016 Sepsis-3 definition that incorporates the Sequential Organ Failure Assessment score. The landmark trial on protocolised early goal-directed therapy was published in 2001, but three subsequent multicentre randomised controlled trials (ProCESS, ARISE, and ProMISe) in 2014-2015 did not confirm a survival benefit with protocolised care. Over the years, there has been considerable improvement in sepsis outcome and management that hinges on early detection; timely source control; prompt, appropriate, and correctly dosed antibiotics; aggressive fluid resuscitation; and shock reversal. These are all directed by repeated bedside assessment. This article summarises recent developments and landmark trials that should guide current sepsis management. PMID- 28572521 TI - The feeding paradox in advanced dementia: a local perspective. AB - Feeding problems are common in older people with advanced dementia. When eating difficulties arise tube feeding is often initiated, unless there is a valid advance directive that refuses enteral feeding. Tube feeding has many pitfalls and complications. To date, no benefits in terms of survival, nutrition, or prevention of aspiration pneumonia have been demonstrated. Careful hand feeding is an alternative to tube feeding with advanced dementia. In Hong Kong, the Hospital Authority has established clear ethical guidelines for careful hand feeding. Notwithstanding, there are many practical issues locally if tube feeding is not used in older patients with advanced dementia. Training of doctors, nurses, and other members of the health care team is vital to the promulgation of careful hand feeding. Support from the government and Hospital Authority policy, health care staff training, public education, and promotion of advance care planning and advance directive are essential to reduce the reliance on tube feeding in advanced dementia. PMID- 28572522 TI - Mondor's disease: sclerosing thrombophlebitis of subcutaneous veins in a patient with occult carcinoma of the breast. PMID- 28572523 TI - Self-inflicted transorbital brain injury by chopsticks in a patient with acute psychosis. PMID- 28572524 TI - Adjuvant S-1 chemotherapy after curative resection of gastric cancer. PMID- 28572525 TI - Authors' reply. PMID- 28572526 TI - Re: Screening for retinopathy of prematurity and treatment outcome in a tertiary hospital in Hong Kong. PMID- 28572530 TI - Assessment of GSK1904529A as a promising anti-osteosarcoma agent. AB - The insulin growth factor-I receptor (IGF1R) signaling is a key mechanism for osteosarcoma (OS) cell proliferation. GSK1904529A is a novel small molecule IGF1R kinase inhibitor. Its activity against OS cells was tested. In both established OS cell lines (Saos-2 and MG-63) and primary human OS cells, treatment with GSK1904529A (at nM concentrations) significantly inhibited cell proliferation. At the molecular level, GSK1904529A almost completely blocked IGF1R activation in OS cells, and inhibited downstream AKT-ERK activation. IGF1R silence by targeted shRNA also inhibited AKT-ERK activation and Saos-2 cell proliferation. Significantly, GSK1904529A was unable to further inhibit proliferation of IGF1R silenced Saos-2 cells. In vivo, GSK1904529A administration orally inhibited Saos 2 tumor growth in nude mice. Together, these results suggest that targeting IGF1R by GSK1904529A inhibits OS cell growth in vitro and in vivo. PMID- 28572531 TI - EGFR G796D mutation mediates resistance to osimertinib. AB - Osimertinib is an effective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved in multiple countries and regions for patients with EGFR T790M mutation-positive non-small cell lung cancer (NSCLC). Despite impressive initial tumor responses, development of drug resistance ultimately limits the benefit of this compound. Mechanisms of resistance to osimertinib are just beginning to emerge, such as EGFR C797S and L718Q mutations, BRAF V600E and PIK3CA E545K mutations, as well as ERBB2 and MET amplification. However, a comprehensive view is still missing. In this study, we presented the first case of Chinese NSCLC patient who developed resistance to osimertinib, and discovered de novo EGFR G796D mutation as a potential mechanism. Our findings provided insights into mechanisms of resistance to osimertinib and highlighted tumor heterogeneity and clonal evolution during the development of drug resistance. PMID- 28572533 TI - HAF mediates the evasive resistance of anti-angiogenesis TKI through disrupting HIF-1alpha and HIF-2alpha balance in renal cell carcinoma. AB - Anti-angiogenesis has emerged as a standard of care for metastatic renal cell carcinoma. However, long-lasting efficacy is seldom reached, and evasive resistance eventually occurs under anti-angiogenic tyrosine kinase inhibitor (TKI) therapy. To establish new therapeutic strategies, investigating the molecular mechanism of resistance is critically important. In our study, human umbilical vascular endothelial cells (HUVECs) were incubated with TKI treatment in conditioned medium derived from renal cancer cells (RCCs) to demonstrate cell viability. Quantitative real time PCR or Western blotting analysis detected the fluctuation of transcriptional factors HIF-1alpha and HIF-2alpha in RCCs under TKI treatment. We demonstrated the alteration of a specific cytokine produced from RCCs under normoxia or hypoxia incubation by utilizing a cytokine RT-PCR primer array. We found that the anti-angiogenic TKI sunitinib disrupted the balance between HIF-1alpha and HIF-2alpha in RCCs and led to a protective effect on HUVECs against sunitinib treatment when cultured with conditioned medium. Mechanistically, RCCs treated with sunitinib resulted in down-regulation of HIF 1alpha, but not HIF-2alpha, through reduction of both mRNA and protein levels. The down-regulation of HIF-1alpha by sunitinib occurred via hypoxia associated factor (HAF), which also enhanced HIF-2alpha transactivation activity to increase the production of pro-angiogenic factors and cytokines and promote HUVEC proliferation. This phenomenon was observed in ACHN and A498 cells, which express both HIF-1alpha and HIF-2alpha, but was not observed in 786-O cells, which express only HIF-2alpha. Our results illustrated that targeting both angiogenesis and hypoxia pathways might provide a resolution to dealing with the devastating effects of anti-angiogenesis resistance. PMID- 28572534 TI - Contrast media enhancement reduction predicts tumor response to presurgical molecular-targeting therapy in patients with advanced renal cell carcinoma. AB - BACKGROUND AND OBJECTIVE: A quantitative tumor response evaluation to molecular targeting agents in advanced renal cell carcinoma (RCC) is debatable. We aimed to evaluate the relationship between radiologic tumor response and pathological response in patients with advanced RCC who underwent presurgical therapy. RESULTS: Of 34 patients, 31 underwent scheduled radical nephrectomy. Presurgical therapy agents included axitinib (n = 26), everolimus (n = 3), sunitinib (n = 1), and axitinib followed by temsirolimus (n = 1). The major presurgical treatment related adverse event was grade 2 or 3 hypertension (44%). The median radiologic tumor response by RECIST, Choi, and CMER were -19%, -24%, and -49%, respectively. Among the radiologic tumor response tests, CMER showed a higher association with tumor necrosis in surgical specimens than others. Ki67/MIB1 status was significantly decreased in surgical specimens than in biopsy specimens. The magnitude of the slope of the regression line associated with the tumor necrosis percentage was greater in CMER than in Choi and RECIST. MATERIALS AND METHODS: Between March 2012 and December 2016, we prospectively enrolled 34 locally advanced and/or metastatic RCC who underwent presurgical molecular-targeting therapy followed by radical nephrectomy. Primary endpoint was comparison of radiologic tumor response among Response Evaluation Criteria in Solid Tumors (RECIST), Choi, and contrast media enhancement reduction (CMER). Secondary endpoint included pathological downstaging, treatment related adverse events, postoperative complications, Ki67/MIB1 status, and tumor necrosis. CONCLUSIONS: CMER may predict tumor response after presurgical molecular-targeting therapy. Larger prospective studies are needed to develop an optimal tumor response evaluation for molecular-targeting therapy. PMID- 28572536 TI - The detection and significance of EGFR and BRAF in cell-free DNA of peripheral blood in NSCLC. AB - OBJECTIVE: Although driver mutation status is crucial to targeted therapy decision-making in non-small cell lung cancer (NSCLC), due to unavailable or inadequate biopsies, there are still many patients with unknown mutation status. A promising way to solve this problem is liquid biopsy, such as cell-free DNA (cfDNA) in peripheral blood. Additionally, due to the little amount of cfDNA, detecting methods with high sensitivity, specificity and economy are required in clinical practice. Here, we explored the feasibility of Competitive Allele Specific TaqMan(r) PCR (CastPCR) detecting driver mutations in cfDNA from plasma in lung adenocarcinoma patients. RESULTS: Sensitivity, specificity, concordance, PPV and NPV of CastPCR detecting EGFR mutations in cfDNA was 56.4% (31/55), 94.2% (49/52), 74.8% (80/107), 91.2% (31/34) and 67.1% (49/73), respectively. Notably, specificity and PPV for p.T790M both reached 100.0%. For BRAF detection, it was 28.6% (2/7), 93.0% (93/100), 88.8% (95/107), 22.2% (2/9) and 94.9% (93/98), respectively. MATERIALS AND METHODS: Plasma specimens of 107 lung adenocarcinoma patients and their matched tumor formalin fixed paraffin embedded (FFPE) samples were analyzed. CastPCR was used to detect EGFR (c.2235_2249del, c.2236_2250del, c.2369C>T p.T790M, c.2573T>G p.L858R) and BRAF (c.1406G>C p.G469A, c.1799T>A p.V600E, c.1781A>G p.D594G) mutations. Mutation results of tumor tissue was set as gold standard, and the sensitivity, specificity, concordance, positive predictive value (PPV) and negative predictive value (NPV) were calculated for each mutation. CONCLUSIONS: For patients whose tumor tissue is unavailable or inadequate, EGFR mutation detection in cfDNA with CastPCR could be first choice. Mutation positive results may provide reference for further clinical medication. While negative results indicate that detection in tissue should be considered as the following step. In this way, tumor tissue could be economized to the maximum extent and the risk of repeated percutaneous transthoracic lung biopsy could also be lowered to the maximum extent. For BRAF detection in cfDNA, CastPCR is a specific method while the sensitivity needs further exploration. PMID- 28572542 TI - Is there a future for topological analysis in experimental charge-density research? AB - Topological analysis using Bader and co-worker's Atoms in Molecules theory has seen many applications in theoretical chemistry and experimental charge-density research. A brief overview of successful early developments, establishing topological analysis as a research tool for characterizing intramolecular chemical bonding, is provided. A lack of vision in many 'descriptive but not predictive' subsequent studies is discussed. Limitations of topology for providing accurate energetic estimates of intermolecular interaction energies are put into perspective. It is recommended that topological analyses of well understood bonding situations are phased out and are only reported for unusual bonding. Descriptive studies of intermolecular interactions should have a clear research focus. PMID- 28572543 TI - The future of topological analysis in experimental charge-density research. AB - In a recent paper, Dittrich (2017) critically discussed the benefits of analysing experimental electron density within the framework of the quantum theory of atoms in molecules, often called simply the topological analysis of the charge density. The point he raised is important because it challenges the scientific production of a very active community. The question whether this kind of investigation is still sensible is intriguing and it fosters a multifaceted answer. Granted that none can predict the future of any field of science, but an alternative point of view emerges after answering three questions: Why should we investigate the electron charge (and spin) density? Is the interpretative scheme proposed by the quantum theory of atoms in molecules useful? Is an experimental charge density necessary? PMID- 28572537 TI - Down-regulation of UBC9 increases the sensitivity of hepatocellular carcinoma to doxorubicin. AB - UBC9 is an E2-conjugating enzyme that is required for SUMOylation and has been implicated in regulating several critical cellular pathways. UBC9 is overexpressed in certain tumors, such as lung adenocarcinoma, ovarian carcinoma and melanoma, which implies that it has special clinical significance. However, the role of UBC9 in Hepatocellular carcinoma (HCC) drug responsiveness is not clear. In this study, we investigated the clinicopathological significance of UBC9 in HCC and investigated the mechanism of UBC9-mediated chemosensitivity to doxorubicin (DOX) in hepatocellular carcinoma cells. We found that relative to adjacent normal tissues, UBC9 was markedly overexpressed in HCC, which closely correlated with tumor size, tumor microsatellite formation, and tumor encapsulation. Our results also showed that down-regulation of UBC9 by shRNA reduced the expression of Bcl-2 and Bcl-xl and increased the expression of cleaved-Caspase3, which is a proapoptotic protein. These changes were associated with reduced apoptosis in response to DOX. Furthermore, we observed a mechanism involving modulation of the P38 and ERK1/2 signaling pathways. Together, our results indicate that down-regulation of UBC9 sensitizes cells to anticancer drugs, is possibly associated with the regulation of ERK1/2 and P38 activation and interacts with the intrinsic apoptosis pathway. Thus, knockdown of UBC9 may have a tumor suppressor effect and UBC9 could be a potential target for the treatment of HCC cancer. PMID- 28572544 TI - Temperature-induced reversible structural phase transition and X-ray diffuse scattering in 2-amino-3-nitropyridinium hydrogen sulfate. AB - The novel polar material 2-amino-3-nitropyridinium hydrogen sulfate, C5H6N3O2(HSO4) (abbreviated as 2A3NP-HS), was obtained and structurally characterized by means of single-crystal X-ray diffraction. At room temperature, 2A3NP-HS crystallizes as a non-centrosymmetric disordered phase (I) in the orthorhombic Pna21 space group. On cooling below 298 K, 2A3NP-HS undergoes a reversible phase transition to phase (II) with the monoclinic non-centrosymmetric P21 space group. This transition might be classified as an 'order-disorder' type. The structural details in both phases are analysed. Additionally, for phase (I), in the 304-365 K temperature range, diffuse scattering was found to be present in the form of elongated streaks parallel to the a* direction. This can be unravelled when implementing a short-range order affecting anionic cationic ribbons occurring in the structure, with correlations acting both in the a direction and in the bc-plane. The results of Monte Carlo simulations, adapting a two-dimensional Ising-type model, reveal the formation of domains, which are b elongated and thin along a. Locally, the stacking of the ribbons in the domains reflects the ordered arrangement observed in the low-temperature monoclinic phase (II). PMID- 28572546 TI - Identification of a deleterious phase in photocatalyst based on Cd1 - xZnxS/Zn(OH)2 by simulated XRD patterns. AB - The X-ray diffraction (XRD) pattern of a deleterious phase in the photocatalyst based on Cd1 - xZnxS/Zn(OH)2 contains two relatively intense asymmetric peaks with d-spacings of 2.72 and 1.56 A. Very small diffraction peaks with interplanar distances of (d) ? 8.01, 5.40, 4.09, 3.15, 2.49 and 1.35 A are characteristic of this phase but not always observed. To identify this phase, the XRD patterns for sheet-like hydroxide beta-Zn(OH)2 and sheet-like hydrozincite Zn5(CO3)2(OH)6 as well as for turbostratic hydrozincite were simulated. It is shown that the XRD pattern calculated on the basis of the last model gives the best correspondence with experimental data. Distances between layers in the turbostratically disordered hydrozincite fluctuate around d ? 8.01 A. This average layer-to-layer distance is significantly higher than the interlayer distance 6.77 A in the ordered Zn5(CO3)2(OH)6 probably due to a deficiency of CO32- anions, excess OH- and the presence of water molecules in the interlayers. It is shown by variable temperature XRD and thermogravimetric analysis (TGA) that the nanocrystalline turbostratic nonstoichiometric hydrozincite-like phase is quite thermostable. It decomposes into ZnO in air above 473 K. PMID- 28572545 TI - Growth, crystal structure, Hirshfeld surface, optical, piezoelectric, dielectric and mechanical properties of bis(L-asparaginium hydrogensquarate) single crystal. AB - Molecular organic single crystals of bis(L-asparaginium hydrogensquarate) monohydrate [BASQ; (C8H10N2O7)2.H2O] have been grown by solution technique. Crystallographic information was investigated by single-crystal X-ray diffraction (SCXRD) analysis. Hirshfeld surface and fingerprint plot studies were performed to understand the intermolecular interactions of the BASQ crystal in graphical representation. Functional group identification was studied with FT-IR (Fourier transform-IR) spectroscopy. The positions of proton and carbon atoms in the BASQ compound were analyzed using NMR spectroscopy. High transparency and a wide band gap of 3.49 eV were observed in the linear optical study by UV-vis-NIR spectroscopy. Intense and broad photoluminescence emissions at room temperature were observed in blue and blue-green regions. The frontier molecular orbitals of the BASQ molecule were obtained by the DFT/B3LYP method employing 6-311G** as the basis set. The dielectric study was carried out with temperature at various frequency ranges. The piezoelectric charge coefficient (d33) value of BASQ crystal was found to be 2 pC/N, which leads to its application in energy harvesting, mechanical sensors and actuators applications. In the non-linear optical study, the BASQ crystal showed promising SHG conversion efficiency. Mechanical properties of the BASQ crystal were studied experimentally by Vicker's microhardness technique, which revealed that the grown crystal belonged to the softer category. BASQ crystal void estimation reveals the mechanical strength and porosity of the material. PMID- 28572547 TI - Could incommensurability in sulfosalts be more common than thought? The case of meneghinite, CuPb13Sb7S24. AB - The structure of meneghinite (CuPb13Sb7S24), from the Bottino mine in the Apuan Alps (Italy), has been solved and refined as an incommensurate structure in four dimensional superspace. The structure is orthorhombic, superspace group Pnma(0beta0)00s, cell parameters a = 24.0549 (3), b = 4.1291 (6), c = 11.3361 (16) A, modulation vector q = 0.5433 (4)b*. The structure was refined from 6604 reflections to a final R = 0.0479. The model includes modulation of both atomic positions and displacement parameters, as well as occupational waves. The driving forces stabilizing the modulated structure of meneghinite are linked to the occupation modulation of Cu and some of the Pb atoms. As a consequence of the Cu/[] and Pb/Sb modulations, three- to sevenfold coordinations of the M cations (Pb/Sb) occur in different parts of the structure. The almost bimodal distribution of the occupation of Cu/[] and Pb/Sb at M5 conforms with the coupled substitution Sb3+ + [] -> Pb2+ + Cu+, thus corroborating the hypothesis deduced previously for the incorporation of copper in the meneghinite structure. The very small departure (~0.54 versus 0.50) from the commensurate value of the modulation raises the question of whether other sulfosalts considered superstructures have been properly described, and, in this light, if incommensurate modulation in sulfosalts could be much more common than thought. PMID- 28572548 TI - Ordered vacancy distribution in 2/1 mullite: a superspace model. AB - A mullite single crystal with composition Al4.84Si1.16O9.58 (2) exhibiting sharp satellite reflections was investigated by means of X-ray diffraction. For the refinement of a superspace model in the superspace group Pbam(alpha01/2)0ss different scale factors for main and satellite reflections were used in order to describe an ordered mullite structure embedded in a disordered polymorph. The ordered fraction of the mullite sample exhibits a completely ordered vacancy distribution and can be described as a block structure of vacancy blocks (VBs) that alternate with vacancy-free blocks (VFBs) along a and c. The incommensurate nature of mullite originates from a modulation of the block size, which depends on the composition. The displacive modulation is analyzed with respect to the vacancy distribution and a possible Al/Si ordering scheme is derived, although the measurement itself is not sensitive to the Al/Si distribution. An idealized, commensurate approximation for 2/1 mullite is also presented. Comparison of the ordered superspace model with different preceding models reconciles many key investigations of the last decades with partly contradicting conclusions, where mullite was usually treated as either ordered or disordered instead of considering simultaneously different states of order. PMID- 28572549 TI - The impact of anion ordering on octahedra distortion and phase transitions in SrTaO2N and BaTaO2N. AB - In this work we synthesized BaTaO2N and SrTaO2N using a two-step high-temperature solid-state reaction method and analysed the structural distortions, relative to the ideal cubic perovskite structure, according to group theory. From a complete distortion analysis/refinement using high-resolution neutron diffraction data in the temperature range 8 to 613 K, we identified tetragonal structures for BaTaO2N [P4/mmm (No. 123)] and SrTaO2N [I4/mcm (No. 140)]. In contrast to an anion disordered cubic perovskite (Pm ?overline{3}m No. 221) with Ta at the cell center, both systems show a site preference for oxygen anions in the two opposite corners (along the c axis) of the Ta-O/N octahedra rather than the four square corners in the ab plane (Gamma3+ occupancy distortion), which induces a tetragonal elongation of the unit cell with the c axis being longer than the a axis. A further Ta-O/N octahedra displacement [R5-(a,0,0), rotation about the c axis] distortion was observed in SrTaO2N. This distortion mode is accompanied by an increased unit-cell distortion that decreases as the temperature increases. Ultimately a second-order phase transition caused by the loss of the R5-(a,0,0) mode was observed at 400-450 K. PMID- 28572550 TI - Synthesis, crystallization, X-ray structural characterization and solid-state assembly of a cyclic hexapeptoid with propargyl and methoxyethyl side chains. AB - The synthesis and the structural characterization of a cyclic hexapeptoid with four methoxyethyl and two propargyl side chains have disclosed the presence of a hydrate crystal form [form (I)] and an anhydrous crystal form [form (II)]. The relative amounts of form (I) and form (II) in the as-purified product were determined by Rietveld refinement and depend on the purification procedures. In crystal form (I), peptoid molecules assemble in a columnar arrangement by means of side-chain-to-backbone C=CH...OC hydrogen bonds. In the anhydrous crystal form (II), cyclopeptoid molecules form ribbons by means of backbone-to-backbone CH2...OC hydrogen bonds, thus mimicking beta-sheet secondary structures in proteins. In both crystal forms side chains act as joints among the columns or the ribbons and contribute to the stability of the whole solid-state assembly. Water molecules in the hydrate crystal form (I) bridge columns of cyclic peptoid molecules, providing a more efficient packing. PMID- 28572551 TI - An ordering phase transition, short hydrogen bonds and high Z' in the structure of Ni(Hpydc)2.3H2O. AB - The structure of Ni(Hpydc)2.3H2O (H2pydc = pyridine-2,6-dicarboxylic acid, also known as dipicolinic acid) has been reinvestigated at variable temperatures. At room temperature, it matches the known structure in the space group P21/c, but at 180 K it undergoes a phase transformation to a twinned structure in Cc. By 120 K, the structure is ordered and twinned with Z' = 4, and shows interesting short hydrogen-bonding interactions that include the formation of hydroxonium species. PMID- 28572552 TI - Structural and Raman spectroscopic characterization of pyroxene-type compounds in the CaCu1-xZnxGe2O6 solid-solution series. AB - Pyroxene-type germanate compounds with the composition CaCuGe2O6-CaZnGe2O6 have been synthesized via a solid-state ceramic sintering route. Phase-pure polycrystalline and small single-crystal material was obtained all over the series, representing a complete solid-solution series. Differential thermal analysis, single-crystal X-ray diffraction and Raman spectroscopy were used to characterize phase stability, phase changes and structural alterations induced by the substitution of Cu2+ with Zn2+. Whereas pure CaCuGe2O6 exhibits P21/c symmetry with a strong distortion of the M1 octahedra and two different Ge sites, one of them with an unusual fivefold coordination, the replacement of Cu2+ by Zn2+ induces a chemically driven phase change to the C2/c symmetry. The phase change takes place around Zn2+ contents of 0.12 formula units and is associated with large changes in the unit-cell parameters. Here, the increase of c by as much as 3.2% is remarkable and it is mainly controlled by an expansion of the tetrahedral chains. Further differences between the P21/c and C2/c structures are a more regular chain of edge-sharing M1 octahedra as a consequence of more and more reduced Jahn-Teller distortion and a less kinked, symmetry-equivalent tetrahedral chain. The coordination of the Ca site increases from sevenfold to eightfold with large changes in the Ca-O bond lengths during the phase change. Raman spectroscopy was mainly used to monitor the P21/c to C2/c phase change as a function of composition, but also as a function of temperature and to follow changes in specific Raman modes throughout the solid-solution series. PMID- 28572553 TI - Formation and distortion of iodidoantimonates(III): the first isolated [SbI6]3- octahedron. AB - The ability to intentionally construct, through different types of interactions, inorganic-organic hybrid materials with desired properties is the main goal of inorganic crystal engineering. The primary deformation, related to intrinsic interactions within inorganic substructure, and the secondary deformation, mainly caused by the hydrogen bond interactions, are both responsible for polyhedral distortions of halogenidoantimonates(III) with organic cations. The evolution of structural parameters, in particular the Sb-I secondary- and O/N/C-H...I hydrogen bonds, as a function of temperature assists in understanding the contribution of those two distortion factors to the irregularity of [SbI6]3- polyhedra. In tris(piperazine-1,4-diium) bis[hexaiodidoantimonate(III)] pentahydrate, (C4H12N2)3[SbI6]2.5H2O (TPBHP), where the isolated [SbI6]3- units were found, distortion is governed only by O/N/C-H...I hydrogen bonds, whereas in piperazine 1,4-diium bis[tetraiodidoantimonate(III)] tetrahydrate, (C4H12N2)[SbI4]2.4H2O (PBTT), both primary and O-H...I secondary factors cause the deformation of one dimensional [{SbI4}n]n- chains. The larger in spatial dimensions piperazine-1,4 diium cations, in contrast to the smaller water of crystallization molecules, do not significantly contribute to the octahedral distortion, especially in PBTT. The formation of isolated [SbI6]3- ions in TPBHP is the result of specific second coordination sphere hydrogen bond interactions that stabilize the hybrid structure and simultaneously effectively separate and prevent [SbI6]3- units from mutual interactions. The temperature-induced changes, further supported by the analysis of data retrieved from the Cambridge Structural Database, illustrate the significance of both primary and secondary distortion factors on the deformation of octahedra. Also, a comparison of packing features in the studied hybrids with those in the non-metal containing piperazine-1,4-diium diiodide diiodine (C4H12N2)I2.I2 (PDD) confirms the importance and hierarchy of different types of interactions. PMID- 28572554 TI - [Die Symmetrie von Spiralketten]. AB - In crystals, polymeric chain molecules often adopt helical structures. Neglecting small distortions possibly caused by an anisotropic environment within the crystal, the symmetry of the single helix can be described by a rod group, which has translational symmetry in one dimension. The rod groups have Hermann-Mauguin symbols similar to space groups, beginning with a script style ?scr p followed by a screw-axis symbol; the order of the screw axis can adopt any value. In a crystal, the rod-site symmetry, the so-called penetration rod group, must be a common crystallographic rod subgroup of the molecular rod group and the space group. Instructions are given for the derivation of the rod subgroups in question for a molecular helical rod group of any order. In polymer chemistry, a helix is designated by a (chemical) symbol like 7/2, which means 7 repeating units in 2 coil turns of covalent bonds per translational period. The corresponding Hermann Mauguin screw-axis symbol is easily derived with a simple formula from this chemical symbol; for a 7/2 helix it is 73 or 74, depending on chirality. However, it is not possible to deduce the chemical symbol from the Hermann-Mauguin symbol, because it depends on where the covalent bonds are assumed to exist. Covalent bonds are irrelevant for symmetry considerations; a symmetry symbol does not depend on them. A chemically right-handed helix can have a left-handed screw axis. The derivation of the Hermann-Mauguin symbol of a multiple helix is not that easy, as it depends on the mutual position of the interlocked helices; conversion formulae for simpler cases are presented. Instead of covalent bonds, other kinds of linking can serve to define the chemical helix, for example, edge- or face-sharing coordination polyhedra. PMID- 28572555 TI - Searching for stereoisomerism in crystallographic databases: algorithm, analysis and chiral curiosities. AB - The automated identification of chiral centres in molecular residues is a non trivial task. Current tools that allow the user to analyze crystallographic data entries do not identify chiral centres in some of the more complex ring structures, or lack the possibility to determine and compare the chirality of multiple structures. This article presents an approach to identify asymmetric C atoms, which is based on the atomic walk count algorithm presented by Rucker & Rucker [(1993), J. Chem. Inf. Comput. Sci. 33, 683-695]. The algorithm, which we implemented in a computer program named ChiChi, is able to compare isomeric residues based on the chiral centres that were identified. This allows for discrimination between enantiomers, diastereomers and constitutional isomers that are present in crystallographic databases. ChiChi was used to process 254 354 organic entries from the Cambridge Structural Database (CSD). A thorough analysis of stereoisomerism in the CSD is presented accompanied by a collection of chiral curiosities that illustrate the strength and versatility of this approach. PMID- 28572556 TI - Sr1/2Ce5/14?1/7WO4: a new modulated ternary scheelite compound. AB - For the first time, a ternary tetragonal scheelite structure tungstate with strontium and cerium cations, (Sr,Ce)WO4, was synthesized. As much as 35% Ce could be inserted into the structure, leaving 1?over 7 of the (Sr,Ce) cation sites vacant. Partial ordering of Sr and Ce, with atomic displacements, were shown by high-resolution electron microscopy. Two-dimensional incommensurate modulations occur in this material, in small domains 20 nm in size. The band gap of this compound is significantly lower than the band gap of SrWO4 and this was related to the distortions of WO4 and (Sr,Ce)O8 polyhedra. The band gap value of 3.2 eV makes Sr1/2Ce5/14?1/7WO4 a promising candidate for violet luminescence. PMID- 28572557 TI - The hydrogen bond between N-H or O-H and organic fluorine: favourable yes, competitive no. AB - A study was made of X-H...F-C interactions (X = N or O) in small-molecule crystal structures. It was primarily based on 6728 structures containing X-H and C-F and no atom heavier than chlorine. Of the 28 451 C-F moieties in these structures, 1051 interact with X-H groups. However, over three-quarters of these interactions are either the weaker components of bifurcated hydrogen bonds (so likely to be incidental contacts) or occur in structures where there is a clear insufficiency of good hydrogen-bond acceptors such as oxygen, nitrogen or halide. In structures where good acceptors are entirely absent, there is about a 2 in 3 chance that a given X-H group will donate to fluorine. Viable alternatives are X-H...pi hydrogen bonds (especially to electron-rich aromatics) and dihydrogen bonds. The average H...F distances of X-H...F-C interactions are significantly shorter for CR3F (R = C or H) and Csp2-F acceptors than for CRF3. The X-H...F angle distribution is consistent with a weak energetic preference for linearity, but that of H...F-C suggests a flat energy profile in the range 100-180 degrees . X H...F-C interactions are more likely when the acceptor is Csp2-F or CR3F, and when the donor is C-NH2. They also occur significantly more often in structures containing tertiary alcohols or solvent molecules, or with Z' > 1, i.e. when there may be unusual packing problems. It is extremely rare to find X-H...F-C interactions in structures where there are several unused good acceptors. When it does happen, there is often a clear reason, e.g. awkwardly shaped molecules whose packing isolates a donor group from the good acceptors. PMID- 28572558 TI - Synthesis and crystal structure of pyrroloquinoline quinol (PQQH2) and pyrroloquinoline quinone (PQQ). AB - Pyrroloquinoline quinone (PQQ) is a water-soluble quinone compound first identified as a cofactor of alcohol- and glucose-dehydrogenases (ADH and GDH) in bacteria. For example, in the process of ADH reaction, alcohol is oxidized to the corresponding aldehyde, and inversely PQQ is reduced to pyrroloquinoline quinol (PQQH2). PQQ and PQQH2 molecules play an important role as a cofactor in ADH and GDH reactions. However, crystal structure analysis has not been performed for PQQ and PQQH2. In the present study, the synthesis of PQQH2 powder crystals was performed under air, by utilizing vitamin C as a reducing agent. By reacting a trihydrate of disodium salt of PQQ (PQQNa2.3H2O) with excess vitamin C in H2O at 293 and 343 K, yellowish brown and black powder crystals of PQQH2 having different properties were obtained in high yield, respectively. The former was PQQH2 trihydrate (PQQH2.3H2O) and the latter was PQQH2 anhydrate (PQQH2). Furthermore, sodium-free red PQQ powder crystal (a monohydrate of PQQ, PQQ.H2O) was prepared by the reaction of PQQNa2.3H2O with HCl in H2O. Single crystals of PQQH2 and PQQ were prepared from Me2SO/CH3CN mixed solvent, and we have succeeded in the crystal structure analyses of PQQH2 and PQQ for the first time. PMID- 28572559 TI - Crystallographic and optical study of LiNb1 - xTaxO3. AB - Powders of lithium niobate-tantalate across the full compositional range have been made and crystals grown using a lithium vanadate flux growth technique. The Li-content of a lithium tantalate crystal has been determined using the zero birefringence temperature and Curie measurements, confirming the Li content is between that of congruent and stoichiometric crystals. X-ray diffraction measurements show the Nb/Ta displacement and octahedral tilt both decrease as the Ta content is increased. This also results in a decrease in the lattice parameters from lithium niobate to lithium tantalate. Birefringence measurements on the crystals as a function of temperature have been used to determine the point that the crystals become zero-birefringent, and by comparison with the structural studies have confirmed that it is not related to a phase transition and the structures remain polar through the zero-birefringence points. PMID- 28572560 TI - Chiral and achiral crystals, charge-assisted hydrogen-bond patterns and self organization of selected solid diaminium thiosulfates. AB - A series of diaminium thiosulfates, derivatives of diamines: NH2CH2CH(CH3)NH2 (1) and NH2(CH2)nNH2, n = 3-6 [(2)-(5)] and thiosulfuric acid were prepared and their structures determined by single-crystal X-ray diffraction analysis. Compounds (1), (2) and (4) turned out to be hydrates. The crystal structure of 1,2 propylenediaminium thiosulfate is chiral and exhibits spontaneous resolution. Crystals for both enantiomers [(1a) and (1b)] were obtained with high enantiometric excess and examined. An extended network of strong, charge-assisted hydrogen bonding of the +N-H...O- type (also O-H...O and O-H...S for hydrates) is most likely the main factor defining crystal packing and the variable conformation of the cations. The formation of chiral hydrogen-bond motifs - distorted cubans - seems to induce the formation of chiral solid-state structure from achiral components in the case of (4). Diaminium thiosulfates with an odd number of C atoms in the alkyl chain [compounds (1), (2) and (4)] form three dimensional supramolecular networks, while in the case of diaminium salts with an even number of C atoms [(3) and (5)], two-dimensional layers of hydrogen-bond domains are observed. The aminium thiosulfates were also characterized by elemental analysis, NMR and Fourier transform (FT)-IR spectroscopy. The conformations of alpha,omega-alkyldiaminium cations in the solid state are discussed and rationalized by DFT calculations. PMID- 28572561 TI - Follicular B Cell Lymphoma with Accompanying Ischemic Gastritis Completely Resolved by Rituximab. AB - BACKGROUND Follicular B cell lymphomas account for a significant portion of all newly diagnosed non-Hodgkin's lymphomas. While involvement can be varied, the most common extranodal presentation is within the gastrointestinal tract beyond the stomach. In addition, the stomach has a diffuse multivessel vascular supply, which decreases the likelihood of developing ischemic gastritis. CASE REPORT An 89-year-old woman with history of diabetes, deep venous thromboembolism, and hypertension was referred due to a newly diagnosed retroperitoneal mass. Biopsy of a left para-aortic node was consistent with low-grade follicular B cell lymphoma. Following mainstream treatment guidelines, rituximab was administered. Approximately 12 hours later, the patient presented to the Emergency Department with intractable vomiting and nausea. After admission, an esophagogastroduodenoscopy (EGD) revealed extensive ischemic gastritis. Due to recurrent ascites requiring frequent paracenteses, and the clinical aggressiveness of the patient's underlying lymphoma, a second dose of rituximab was administered with concurrent initiation of total parenteral nutrition. Approximately 1 week later, the patient underwent a repeat EGD for quality of life planning while in hospice. The repeat EGD revealed resolved ischemic gastritis. Her diet was advanced and she was subsequently discharged home. CONCLUSIONS Rituximab alone shows promise in treating extensive follicular B cell lymphoma complicated by ischemic gastritis, which has not been previously reported in the literature. PMID- 28572562 TI - Resolvin D1 Attenuates Mpp+-Induced Parkinson Disease via Inhibiting Inflammation in PC12 Cells. AB - BACKGROUND We investigated the influence of Resolvin D1 (RvD1) on the inflammatory response in PC12 cells (a cell model of Parkinson disease, PD). MATERIAL AND METHODS 4 mmol/L 1-methyl-4-phenylpyridinium ion (Mpp+) was used in PC12 cells for an in vitro PD model. 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2 H-tetrazolium bromide (MTT) assay was used to explore PC12 cell viability. Western blot (WB) experiments were used to identify nuclear factor-kappaB (NF kappaB), phosphorylated extracellular signal-regulated kinase (p-ERK)/p-Jun N terminal kinase (JNK)/p-P38 mitogen-activated protein kinase (MAPK), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 protein levels. Transcription levels of inflammatory factors, for instance, TNF-alpha and IL-6, were explored by real-time quantitative polymerase chain reaction (RT-QPCR). Lactic dehydrogenase (LDH) level was detected by enzyme-linked immunosorbent (ELISA). Cell apoptosis was assessed by Annexin-V Fluorescein (FITC) kit. RESULTS RvD1 dose-dependently inhibited MPP+ induced upregulation of PC12 cell apoptosis/cellular damage/TNF-alpha and p-P38/p-ERK/NF-kappaB as well as downregulation of PC12 cell viability. CONCLUSIONS We can draw the conclusion that RvD1 attenuates PD via inhibiting Mpp+-induced inflammation in PC12 cells. PMID- 28572563 TI - Effect of Recipient Age at Liver Transplantation on Prevalence of Post-Transplant Donor-Specific HLA Antibody. AB - BACKGROUND Post-transplant donor-specific HLA antibodies (DSA) may have a detrimental effect on long-term outcomes of organ transplantation. The aim of this study was to specifically evaluate the effect of recipient age on the prevalence of DSA over a long-term follow-up after living donor liver transplantation (LDLT). MATERIAL AND METHODS A retrospective analysis of DSA evaluations was performed in 50 pediatric patients with HLA data available. Patients were divided into 2 groups based on their age at the time of LDLT: younger (Y) group, age <3 years; older (O) group, age >=3 years. DSA evaluation was performed using Luminex single-antigen bead assays, with a mean fluorescence intensity >=1000 used as a cut-off for positive results. RESULTS There were no between-group differences in terms of sex, ABO incompatibility or acute rejection. Only one of our 50 patients tested positive for class I DSA. Significantly more patients tested positive for HLA-DR DSA in group Y (40.6%) than in group O (11.1%; p=0.02). Recipients <3 years of age at the time of LDLT may be at a higher risk of testing positive for class II DSA. CONCLUSIONS These findings can inform the implementation of cost-effective screening of post transplant DSA in pediatric LDLT recipients. PMID- 28572565 TI - Thickness-dependent Crack Propagation in Uniaxially Strained Conducting Graphene Oxide Films on Flexible Substrates. AB - We demonstrate that crack propagation in uniaxially strained reduced graphene oxide (rGO) films is substantially dependent on the film thickness, for films in the sub-micron regime. rGO film on flexible polydimethylsiloxane (PDMS) substrate develop quasi-periodic cracks upon application of strain. The crack density and crack width follow contrasting trends as film thickness is increased and the results are described in terms of a sequential cracking model. Further, these cracks also have a tendency to relax when the strain is released. These features are also reflected in the strain-dependent electrical dc and ac conductivity studies. For an optimal thickness (3-coat), the films behave as strain-resistant, while for all other values it becomes strain-responsive, attributed to a favorable combination of crack density and width. This study of the film thickness dependent response and the crack propagation mechanism under strain is a significant step for rationalizing the application of layered graphene-like systems for flexible optoelectronic and strain sensing applications. When the thickness is tuned for enhanced extent of crack propagation, strain-sensors with gauge factor up to ~470 are realized with the same material. When thickness is chosen to suppress the crack propagation, strain-resistive flexible TiO2- rGO UV photoconductor is realized. PMID- 28572564 TI - Plasmacytoid dendritic cells appear inactive during sub-microscopic Plasmodium falciparum blood-stage infection, yet retain their ability to respond to TLR stimulation. AB - Plasmacytoid dendritic cells (pDC) are activators of innate and adaptive immune responses that express HLA-DR, toll-like receptor (TLR) 7, TLR9 and produce type I interferons. The role of human pDC in malaria remains poorly characterised. pDC activation and cytokine production were assessed in 59 malaria-naive volunteers during experimental infection with 150 or 1,800 P. falciparum-parasitized red blood cells. Using RNA sequencing, longitudinal changes in pDC gene expression were examined in five adults before and at peak-infection. pDC responsiveness to TLR7 and TLR9 stimulation was assessed in-vitro. Circulating pDC remained transcriptionally stable with gene expression altered for 8 genes (FDR < 0.07). There was no upregulation of co-stimulatory molecules CD86, CD80, CD40, and reduced surface expression of HLA-DR and CD123 (IL-3R-alpha). pDC loss from the circulation was associated with active caspase-3, suggesting pDC apoptosis during primary infection. pDC remained responsive to TLR stimulation, producing IFN alpha and upregulating HLA-DR, CD86, CD123 at peak-infection. In clinical malaria, pDC retained HLA-DR but reduced CD123 expression compared to convalescence. These data demonstrate pDC retain function during a first blood stage P. falciparum exposure despite sub-microscopic parasitaemia downregulating HLA-DR. The lack of evident pDC activation in both early infection and malaria suggests little response of circulating pDC to infection. PMID- 28572566 TI - Genome-Wide Comparative Analysis of Miniature Inverted Repeat Transposable Elements in 19 Arabidopsis thaliana Ecotype Accessions. AB - Miniature inverted repeat transposable elements (MITEs) are prevalent in eukaryotic genomes. They are known to critically influence the process of genome evolution and play a role in gene regulation. As the first study concentrated in the transposition activities of MITEs among different ecotype accessions within a species, we conducted a genome-wide comparative analysis by characterizing and comparing MITEs in 19 Arabidopsis thaliana accessions. A total of 343485 MITE putative sequences, including canonical, diverse and partial ones, were delineated from all 19 accessions. Within the entire population of MITEs sequences, 80.7% of them were previously unclassified MITEs, demonstrating a different genomic distribution and functionality compared to the classified MITEs. The interactions between MITEs and homologous genes across 19 accessions provided a fine source for analyzing MITE transposition activities and their impacts on genome evolution. Moreover, a significant proportion of MITEs were found located in the last exon of genes besides the ordinary intron locality, thus potentially modifying the end of genes. Finally, analysis of the impact of MITEs on gene expression suggests that migrations of MITEs have no detectable effect on the expression level for host genes across accessions. PMID- 28572567 TI - Ultrasensitive Multi-Functional Flexible Sensors Based on Organic Field-Effect Transistors with Polymer-Dispersed Liquid Crystal Sensing Layers. AB - Ultrasensitive flexible sensors with multi-sensing functions are required for various applications in flexible electronics era. Here we demonstrate flexible polymer-dispersed liquid crystal (PDLC)-integrated-organic field-effect transistors (OFETs) (PDLC-i-OFETs), which sensitively respond to various stimulations including weak gas (air) flow, direct physical touch, light, and heat. The flexible PDLC-i-OFETs were fabricated by spin-coating the poly(methyl methacrylate) (PMMA)-dispersed 4,4'-pentyl-cyanobiphenyl (5CB) layers on the poly(3-hexylthiophene) (P3HT) channel layers of OFETs with 200 MUm-thick poly(ethylene naphthalate) (PEN) substrates. The flexible PDLC-i-OFET devices could sense very weak nitrogen gas flow (0.3 sccm), which cannot be felt by human skins, and stably responded to direct physical touches (0.6~4.8 g load). In addition, the present devices showed very sensitive photoresponses to a visible light and exhibited excellent heat-sensing characteristics at a temperature of 25~70 degrees C. In particular, the present flexible PDLC-i-OFET devices could sense two different stimulations at the same time, indicative of promising multi sensing capabilities. PMID- 28572568 TI - Hydrologic Evaluation of TRMM Multisatellite Precipitation Analysis for Nanliu River Basin in Humid Southwestern China. AB - The accuracy of Tropical Rainfall Measuring Mission (TRMM) multi-satellite precipitation analysis (TMPA) daily accumulated precipitation products (3B42RTV7 and 3B42V7) was evaluated for a small basin (the Nanliu river basin). A direct comparison was performed against gauge observations from a period of 9 years (2000-2009) at temporal and spatial scales. The results show that the temporal spatial precipitation characteristics of the Nanliu river basin are highly consistent with 3B42V7 relative to 3B42RTV7, with higher correlation coefficient (CC) approximately 0.9 at all temporal scales except for the daily scale and a lower relative bias percentage. 3B42V7 slightly overestimates precipitation at all temporal scales except the yearly scale; it slightly underestimates the precipitation at the daily spatial scale. The results also reveal that the precision of TMPA products increases with longer time-aggregated data, and the detection capability of daily TMPA precipitation products are enhanced by augmentation with daily precipitation rates. In addition, daily TMPA products were input into the Xin'anjiang hydrologic model; the results show that 3B42V7 based simulated outputs were well in line with actual stream flow observations, with a high CC (0.90) and Nash-Sutcliffe efficiency coefficient (NSE, 0.79), and the results adequately captured the pattern of the observed flow curve. PMID- 28572569 TI - Young children display an increase in prosocial donating in response to an upwards shift in generosity by a same-aged peer. AB - Adult humans frequently engage in the reciprocal exchange of resources with other individuals. However, despite the important role that reciprocity plays in maintaining co-operative exchange we know relatively little of when, and how, reciprocity develops. We first asked whether pairs of young children (M = 74 months) would engage in direct reciprocity in a 'prosocial choice test' where a donor could select either a higher, or a lower, value reward (1v 2) for a partner at no cost to themselves (1v 1). In a subsequent retest we asked, for the first time, whether young children increase their level of prosocial donating in response to an upwards shift in generosity from an initially selfish partner. In order to determine whether interacting with another child was fundamental to the development of reciprocity we included a novel yoked non-agent condition. The results suggest that the children were engaging in a calculated form of reciprocity where the prior behavior of their child partner influenced their subsequent level of donation days after the initial exchange. Crucially we show that the children were not influenced by the value of the rewards received per se, rather selection by a human agent was key to reciprocity. PMID- 28572570 TI - A molecular roadmap for induced multi-lineage trans-differentiation of fibroblasts by chemical combinations. PMID- 28572571 TI - A molecular roadmap for induced multi-lineage trans-differentiation of fibroblasts by chemical combinations. PMID- 28572572 TI - Inverse Tunnel Magnetocapacitance in Fe/Al-oxide/Fe3O4. AB - Magnetocapacitance (MC) effect, observed in a wide range of materials and devices, such as multiferroic materials and spintronic devices, has received considerable attention due to its interesting physical properties and practical applications. A normal MC effect exhibits a higher capacitance when spins in the electrodes are parallel to each other and a lower capacitance when spins are antiparallel. Here we report an inverse tunnel magnetocapacitance (TMC) effect for the first time in Fe/AlOx/Fe3O4 magnetic tunnel junctions (MTJs). The inverse TMC reaches up to 11.4% at room temperature and the robustness of spin polarization is revealed in the bias dependence of the inverse TMC. Excellent agreement between theory and experiment is achieved for the entire applied frequency range and the wide bipolar bias regions using Debye-Frohlich model (combined with the Zhang formula and parabolic barrier approximation) and spin dependent drift-diffusion model. Furthermore, our theoretical calculations predict that the inverse TMC effect could potentially reach 150% in MTJs with a positive and negative spin polarization of 65% and -42%, respectively. These theoretical and experimental findings provide a new insight into both static and dynamic spin-dependent transports. They will open up broader opportunities for device applications, such as magnetic logic circuits and multi-valued memory devices. PMID- 28572573 TI - Protein tyrosine phosphatase 1B is a mediator of cyclic ADP ribose-induced Ca2+ signaling in ventricular myocytes. AB - Cyclic ADP-ribose (cADPR) releases Ca2+ from ryanodine receptor (RyR)-sensitive calcium pools in various cell types. In cardiac myocytes, the physiological levels of cADPR transiently increase the amplitude and frequency of Ca2+ (that is, a rapid increase and decrease of calcium within one second) during the cardiac action potential. In this study, we demonstrated that cADPR levels higher than physiological levels induce a slow and gradual increase in the resting intracellular Ca2+ ([Ca2+]i) level over 10 min by inhibiting the sarcoendoplasmic reticulum Ca2+ ATPase (SERCA). Higher cADPR levels mediate the tyrosine dephosphorylation of alpha-actin by protein tyrosine phosphatase 1B (PTP1B) present in the endoplasmic reticulum. The tyrosine dephosphorylation of alpha actin dissociates phospholamban, the key regulator of SERCA, from alpha-actin and results in SERCA inhibition. The disruption of the integrity of alpha-actin by cytochalasin B and the inhibition of alpha-actin tyrosine dephosphorylation by a PTP1B inhibitor block cADPR-mediated Ca2+ increase. Our results suggest that levels of cADPR that are relatively higher than normal physiological levels modify calcium homeostasis through the dephosphorylation of alpha-actin by PTB1B and the subsequent inhibition of SERCA in cardiac myocytes. PMID- 28572574 TI - Survive or thrive: tradeoff strategy for cellular senescence. AB - Aging-dependent cellular behaviors toward extrinsic stress are characterized by the confined localization of certain molecules to either nuclear or perinuclear regions. Although most growth factors can activate downstream signaling in aging cells, they do not in fact have any impact on the cells because the signals cannot reach their genetic targets in the nucleus. For the same reason, varying apoptotic stress factors cannot stimulate the apoptotic pathway in senescent cells. Thus, the operation of a functional nuclear barrier in an aging-dependent manner has been investigated. To elucidate the mechanism for this process, the housekeeping transcription factor Sp1 was identified as a general regulator of nucleocytoplasmic trafficking (NCT) genes, including various nucleoporins, importins, exportins and Ran GTPase cycle-related genes. Interestingly, the posttranslational modification of Sp1 is readily influenced by extrinsic stress, including oxidative and metabolic stress. The decrease in SP1 O-GlcNAcylation under oxidative stress or during replicative senescence makes it susceptible to proteosomal degradation, resulting in defective NCT functions and leading to nuclear barrier formation. The operation of the nuclear barrier in aging provides a fundamental mechanism for cellular protection against stress and promotes survival at the expense of growth via stress-sensitive transcriptional control. PMID- 28572576 TI - EMBuilder: A Template Matching-based Automatic Model-building Program for High resolution Cryo-Electron Microscopy Maps. AB - The resolution of electron-potential maps in single-particle cryo-electron microscopy (cryoEM) is approaching atomic or near- atomic resolution. However, no program currently exists for de novo cryoEM model building at resolutions exceeding beyond 3.5 A. Here, we present a program, EMBuilder, based on template matching, to generate cryoEM models at high resolution. The program identifies features in both secondary-structure and Calpha stages. In the secondary structure stage, helices and strands are identified with pre-computed templates, and the voxel size of the entire map is then refined to account for microscopic magnification errors. The identified secondary structures are then extended from both ends in the Calpha stage via a log-likelihood (LLK) target function, and if possible, the side chains are also assigned. This program can build models of large proteins (~1 MDa) in a reasonable amount of time (~1 day) and thus has the potential to greatly decrease the manual workload required for model building of high-resolution cryoEM maps. PMID- 28572575 TI - The Argi system: one-step purification of proteins tagged with arginine-rich cell penetrating peptides. AB - The discovery of cell penetrating peptides (CPPs) opened new perspectives for the delivery of proteins into human cells. It is considered that in the future CPP mediated transport of therapeutic proteins may find applications in the treatment of human diseases. Despite this fact a fast and simple method for the purification of CPP-tagged proteins, free of additional tags, was not available to date. To fill this gap we developed the Argi system for one-step purification of proteins tagged with arginine rich CPPs. PMID- 28572577 TI - Three-Dimensional Geometry of Collagenous Tissues by Second Harmonic Polarimetry. AB - Collagen is a biological macromolecule capable of second harmonic generation, allowing label-free detection in tissues; in addition, molecular orientation can be determined from the polarization dependence of the second harmonic signal. Previously we reported that in-plane orientation of collagen fibrils could be determined by modulating the polarization angle of the laser during scanning. We have now extended this method so that out-of-plane orientation angles can be determined at the same time, allowing visualization of the 3-dimensional structure of collagenous tissues. This approach offers advantages compared with other methods for determining out-of-plane orientation. First, the orientation angles are directly calculated from the polarimetry data obtained in a single scan, while other reported methods require data from multiple scans, use of iterative optimization methods, application of fitting algorithms, or extensive post-optical processing. Second, our method does not require highly specialized instrumentation, and thus can be adapted for use in almost any nonlinear optical microscopy setup. It is suitable for both basic and clinical applications. We present three-dimensional images of structurally complex collagenous tissues that illustrate the power of such 3-dimensional analyses to reveal the architecture of biological structures. PMID- 28572578 TI - Integrated fiber optical receiver reducing the gap to the quantum limit. AB - Experimental results of a single-photon avalanche diode (SPAD) based optical fiber receiver integrated in 0.35 um PIN-photodiode CMOS technology are presented. To cope with the parasitic effects of SPADs an array of four receivers is implemented. The SPADs consist of a multiplication zone and a separate thick absorption zone to achieve a high photon detection probability (PDP). In addition cascoded quenchers allow to use a quenching voltage of twice the usual supply voltage, i.e. 6.6 V instead of 3.3 V, in order to increase the PDP further. Measurements result in sensitivities of -55.7 dBm at a data rate of 50 Mbit/s and -51.6 dBm at 100 Mbit/s for a wavelength of 635 nm and a bit-error ratio of 2 * 10-3, which is sufficient to perform error correction. These sensitivities are better than those of linear-mode APD receivers integrated in the same CMOS technology. These results are a major advance towards direct detection optical receivers working close to the quantum limit. PMID- 28572579 TI - Trichogenic-selenium nanoparticles enhance disease suppressive ability of Trichoderma against downy mildew disease caused by Sclerospora graminicola in pearl millet. AB - Trichoderma spp. are well known biocontrol agents used against phytopathogens. In the present work Trichoderma-mediated Selenium nanoparticles (SeNPs) were synthesized and extent of downy mildew (DM) disease control in pearl millet (PM) was studied. Six species of Trichoderma namely, T. asperellum, T. harzianum, T. atroviride, T. virens, T. longibrachiatum and T. brevicompactum were evaluated in the form of culture filtrate (CF), cell lysate (CL) and crude cell wall (CW) to synthesize SeNPs. All these components produced SeNPs, but CF was significant than CL and CW. The size of SeNPs ranged from 49.5 to 312.5 nm with zeta potential of +3.3 mv to -200 mv. The nanoparticles suppressed the growth, sporulation and zoospore viability of Sclerospora graminicola and these biological activities were inversely proportional to the size of SeNPs. Under greenhouse conditions, application of SeNPs and T. asperellum together enhanced the early plant growth and suppressed DM incidence as compared to their individual application. This study demonstrated the ability of Trichogenic-SeNPs to suppress growth and proliferation of S. graminicola, the incitant of DM of PM and their activity is inversely proportional to size of nanoparticles. PMID- 28572580 TI - UROPA: a tool for Universal RObust Peak Annotation. AB - The annotation of genomic ranges of interest represents a recurring task for bioinformatics analyses. These ranges can originate from various sources, including peaks called for transcription factor binding sites (TFBS) or histone modification ChIP-seq experiments, chromatin structure and accessibility experiments (such as ATAC-seq), but also from other types of predictions that result in genomic ranges. While peak annotation primarily driven by ChiP-seq was extensively explored, many approaches remain simplistic ("most closely located TSS"), rely on fixed pre-built references, or require complex scripting tasks on behalf of the user. An adaptable, fast, and universal tool, capable to annotate genomic ranges in the respective biological context is critically missing. UROPA (Universal RObust Peak Annotator) is a command line based tool, intended for universal genomic range annotation. Based on a configuration file, different target features can be prioritized with multiple integrated queries. These can be sensitive for feature type, distance, strand specificity, feature attributes (e.g. protein_coding) or anchor position relative to the feature. UROPA can incorporate reference annotation files (GTF) from different sources (Gencode, Ensembl, RefSeq), as well as custom reference annotation files. Statistics and plots transparently summarize the annotation process. UROPA is implemented in Python and R. PMID- 28572581 TI - Role of interfaces on the stability and electrical properties of Ge2Sb2Te5 crystalline structures. AB - GeSbTe-based materials exhibit multiple crystalline phases, from disordered rocksalt, to rocksalt with ordered vacancy layers, and to the stable trigonal phase. In this paper we investigate the role of the interfaces on the structural and electrical properties of Ge2Sb2Te5. We find that the site of nucleation of the metastable rocksalt phase is crucial in determining the evolution towards vacancy ordering and the stable phase. By properly choosing the substrate and the capping layers, nucleation sites engineering can be obtained, thus promoting or preventing the vacancy ordering in the rocksalt structure or the conversion into the trigonal phase. The vacancy ordering occurs at lower annealing temperatures (170 degrees C) for films deposited in the amorphous phase on silicon (111), compared to the case of SiO2 substrate (200 degrees C), or in presence of a capping layer (330 degrees C). The mechanisms governing the nucleation have been explained in terms of interfacial energies. Resistance variations of about one order of magnitude have been measured upon transition from the disordered to the ordered rocksalt structure and then to the trigonal phase. The possibility to control the formation of the crystalline phases characterized by marked resistivity contrast is of fundamental relevance for the development of multilevel phase change data storage. PMID- 28572582 TI - Coordination Between the Sexes Constrains the Optimization of Reproductive Timing in Honey Bee Colonies. AB - Honeybees are an excellent model system for examining how trade-offs shape reproductive timing in organisms with seasonal environments. Honeybee colonies reproduce two ways: producing swarms comprising a queen and thousands of workers or producing males (drones). There is an energetic trade-off between producing workers, which contribute to colony growth, and drones, which contribute only to reproduction. The timing of drone production therefore determines both the drones' likelihood of mating and when colonies reach sufficient size to swarm. Using a linear programming model, we ask when a colony should produce drones and swarms to maximize reproductive success. We find the optimal behavior for each colony is to produce all drones prior to swarming, an impossible solution on a population scale because queens and drones would never co-occur. Reproductive timing is therefore not solely determined by energetic trade-offs but by the game theoretic problem of coordinating the production of reproductives among colonies. PMID- 28572583 TI - Perioperative and anesthesia-related cardiac arrests in geriatric patients: a systematic review using meta-regression analysis. AB - The worldwide population is aging, and the number of surgeries performed in geriatric patients is increasing. This systematic review evaluated anesthetic procedures to assess global data on perioperative and anesthesia-related cardiac arrest (CA) rates in geriatric surgical patients. Available data on perioperative and anesthesia-related CA rates over time and by the country's Human Development Index (HDI) were evaluated by meta-regression, and a pooled analysis of proportions was used to compare perioperative and anesthesia-related CA rates by HDI and time period. The meta-regression showed that perioperative CA rates did not change significantly over time or by HDI, whereas anesthesia-related CA rates decreased over time (P = 0.04) and in high-HDI (P = 0.015). Perioperative and anesthesia-related CA rates per 10,000 anesthetic procedures declined in high HDI, from 38.6 before the 1990s to 7.7 from 1990-2017 (P < 0.001) and from 9.2 before the 1990s to 1.3 from 1990-2017 (P < 0.001), respectively. The perioperative CA rate from 1990-2017 was higher in low-HDI than in high-HDI countries (P < 0.001). Hence, a reduction in anesthesia-related CA rates over time was observed. Both perioperative and anesthesia-related CA rates only decreased with a high-HDI between time periods, and perioperative CA rates during 1990-2017 were 4-fold higher with low- compared to high-HDI in geriatric patients. PMID- 28572584 TI - Comparative de novo transcriptome profiles in Asparagus officinalis and A. kiusianus during the early stage of Phomopsis asparagi infection. AB - Asparagus kiusianus, an important wild relative of cultivated asparagus (A. officinalis), exhibits resistance to stem blight disease caused by Phomopsis asparagi. However, the mechanisms underlying this resistance are not understood and no transcriptomic or genetic resources are available for this species. De novo transcriptome sequencing of A. officinalis and A. kiusianus stems was performed 24 h after inoculation with P. asparagi. In total, 35,259 and 36,321 transcripts were annotated in A. officinalis and A. kiusianus, respectively. 1,027 up-regulated and 752 down-regulated transcripts were differentially expressed in the two Asparagus species. RNA sequencing data were validated using quantitative real-time reverse transcription PCR. Several defense-related genes including peroxidase 4, cationic peroxidase SPC4-like, pathogenesis-related protein-1-like, and jasmonic acid biosynthesis and signaling-related genes including phospholipase D alpha 1, 12-oxophytodienoate reductase and jasmonate induced protein 23 KD were up-regulated in A. kiusianus relative to A. officinalis. In addition, infected A. kiusianuns exhibited a substantial increase in jasmonic acid and methyl jasmonate relative to A. officinalis. Peroxidase activity was significantly elevated in infected A. kiusianus compared with infected A. officinalis. Our transcriptomic database provides a resource for identifying novel genes and molecular markers-associated with Phomopsis disease resistance and will facilitate breeding and improvement of cultivated asparagus varieties. PMID- 28572585 TI - Gene-body CG methylation and divergent expression of duplicate genes in rice. AB - Gene and genome duplication fosters genetic novelty, but redundant gene copies would undergo mutational decay unless preserved via selective or neutral forces. Molecular mechanisms mediating duplicate preservation remain incompletely understood. Several recent studies showed an association between DNA methylation and expression divergence of duplicated genes and suggested a role of epigenetic mechanism in duplicate retention. Here, we compare genome-wide gene-body CG methylation (BCGM) and duplicate gene expression between a rice mutant null for OsMet1-2(a major CG methytransferase in rice) and its isogenic wild-type. We demonstrate a causal link between BCGM divergence and expression difference of duplicate copies. Interestingly, the higher- and lower-expressing copies of duplicates as separate groups show broadly different responses with respect to direction of expression alteration upon loss of BCGM. A role for BCGM in conditioning expression divergence between copies of duplicates generally holds for duplicates generated by whole genome duplication (WGD) or by small-scale duplication processes. However, differences are evident among these categories, including a higher proportion of WGD duplicates manifesting expression alteration, and differential propensities to lose BCGM by the higher- and lower expression copies in the mutant. Together, our results support the notion that differential epigenetic marking may facilitate long-term retention of duplicate genes. PMID- 28572586 TI - Neck circumference associated with arterial blood pressures and hypertension: A cross-sectional community-based study in northern Han Chinese. AB - Although several studies have investigated the associations of neck circumference (NC) with arterial blood pressures (BPs) and hypertension, no such studies have been conducted among Northern Chinese population. Between April and June 2015, a total of 2631 subjects aged >=35 years old were recruited from Northeastern China. NC and arterial BPs were measured by trained personnel. Generalized linear and logistic regression analyses were applied to examine the associations of NC with arterial BPs and hypertension risk. The optimal cut-off points of NC for predicting hypertension were assessed by the receiver operating characteristic analysis. We found that NC was significantly associated with arterial BPs and hypertension risk in the Northeastern Chinese adults, even after adjusting for many covariates including body mass index, waist circumference or waist-to-hip ratio. The optimal cut-off values for NC to predict hypertension differed with sex, age, and body mass index. Our study suggests that NC may play an independent role in predicting hypertension beyond the classical anthropometric indices, and that it could be used as a valuable anthropometric measurement for routine assessment in primary care clinics and future epidemiological studies. PMID- 28572587 TI - Electrically driven deep ultraviolet MgZnO lasers at room temperature. AB - Semiconductor lasers in the deep ultraviolet (UV) range have numerous potential applications ranging from water purification and medical diagnosis to high density data storage and flexible displays. Nevertheless, very little success was achieved in the realization of electrically driven deep UV semiconductor lasers to date. In this paper, we report the fabrication and characterization of deep UV MgZnO semiconductor lasers. These lasers are operated with continuous current mode at room temperature and the shortest wavelength reaches 284 nm. The wide bandgap MgZnO thin films with various Mg mole fractions were grown on c-sapphire substrate using radio-frequency plasma assisted molecular beam epitaxy. Metal semiconductor-metal (MSM) random laser devices were fabricated using lithography and metallization processes. Besides the demonstration of scalable emission wavelength, very low threshold current densities of 29~33 A/cm2 are achieved. Numerical modeling reveals that impact ionization process is responsible for the generation of hole carriers in the MgZnO MSM devices. The interaction of electrons and holes leads to radiative excitonic recombination and subsequent coherent random lasing. PMID- 28572588 TI - Hippocampal atrophy and altered brain responses to pleasant tastes among obese compared with healthy weight children. AB - OBJECTIVE: The hippocampus is a key structure implicated in food motivation and intake. Research has shown that the hippocampus is vulnerable to the consumption of a western diet (i.e., high saturated fat and simple carbohydrates). Studies of patients with obesity (OB), compared with healthy weight (HW), show changes in hippocampal volume and response to food cues. Moreover, evidence suggests that OB children, relative to HW, have greater hippocampal response to taste. However, no study has examined the association of hippocampal volume with taste functioning in children. We hypothesized that OB children, relative to HW, would show a significant reduction in hippocampal volume and that decreased volume would be significantly associated with greater activation to taste. Finally, we explored whether hippocampal activation would be associated with measures on eating and eating habits. SUBJECTS: Twenty-five 8-12-year-old children (i.e., 13 HW, 12 OB) completed a magnetic resonance imaging scan while participating in a taste paradigm (i.e., 1 ml of 10% sucrose or ionic water delivered pseudorandomly every 20 s). RESULTS: Children with OB, relative to HW, showed reduced left hippocampal volume (t=1.994, P=0.03, 95% confidence interval (CI)=-40.23, 755.42), and greater response to taste in three clusters within the left hippocampus (z=3.3, P=0.001, 95% CI=-0.241, -0.041; z=3.3, P=0.001, 95% CI=-0.2711, -0.0469; z=2.7, P=0.007, 95% CI=-0.6032, -0.0268). Activation within the hippocampus was associated with eating in the absence of hunger (EAH%; t=2.408, P=0.025, 95% CI= 1.751708, 23.94109) and two subscales on a measure of eating behaviors (Food responsiveness, t=2.572, P=0.017, 95% CI= 0.9565195, 9.043440; Food enjoyment, t=2.298, P=0.032, 95% CI=0.2256749, 4.531298). CONCLUSION: As hypothesized, OB children, relative to HW, had significantly reduced hippocampal volume, and greater hippocampal activation to taste. Moreover, hippocampal activation was associated with measures of eating. These results contribute to research on the relationship between OB, overeating and cognitive impairment. PMID- 28572589 TI - Oncopig Soft-Tissue Sarcomas Recapitulate Key Transcriptional Features of Human Sarcomas. AB - Human soft-tissue sarcomas (STS) are rare mesenchymal tumors with a 5-year survival rate of 50%, highlighting the need for further STS research. Research has been hampered by limited human sarcoma cell line availability and the large number of STS subtypes, making development of STS cell lines and animal models representative of the diverse human STS subtypes critical. Pigs represent ideal human disease models due to their similar size, anatomy, metabolism, and genetics compared to humans. The Oncopig encodes inducible KRAS G12D and TP53 R167H transgenes, allowing for STS modeling in a spatial and temporal manner. This study utilized Oncopig STS cell line (fibroblast) and tumor (leiomyosarcoma) RNA seq data to compare Oncopig and human STS expression profiles. Altered expression of 3,360 and 7,652 genes was identified in Oncopig STS cell lines and leiomyosarcomas, respectively. Transcriptional hallmarks of human STS were observed in Oncopig STS, including altered TP53 signaling, Wnt signaling activation, and evidence of epigenetic reprogramming. Furthermore, master regulators of Oncopig STS expression were identified, including FOSL1, which was previously identified as a potential human STS therapeutic target. These results demonstrate the Oncopig STS model's ability to mimic human STS transcriptional profiles, providing a valuable resource for sarcoma research and cell line development. PMID- 28572590 TI - Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors. AB - Developing therapeutics that target multiple receptor signaling pathways in tumors is critical as therapies targeting single specific biomarker/pathway have shown limited efficacy in patients with cancer. In this study, we extensively characterized a bi-functional molecule comprising of epidermal growth factor receptor (EGFR) targeted nanobody (ENb) and death receptor (DR) targeted ligand TRAIL (ENb-TRAIL). We show that ENb-TRAIL has therapeutic efficacy in tumor cells from different cancer types which do not respond to either EGFR antagonist or DR agonist monotherapies. Utilizing pharmacological inhibition, genetic loss of function and FRET studies, we show that ENb-TRAIL blocks EGFR signalling via the binding of ENb to EGFR which in turn induces DR5 clustering at the plasma membrane and thereby primes tumor cells to caspase-mediated apoptosis. In vivo, using a clinically relevant orthotopic resection model of primary glioblastoma and engineered stem cells (SC) expressing ENb-TRAIL, we show that the treatment with synthetic extracellular matrix (sECM) encapsulated SC-ENb-TRAIL alleviates tumor burden and significantly increases survival. This study is the first to report novel mechanistic insights into simultaneous targeting of receptor mediated proliferation and cell death signaling pathways in different tumor types and presents a promising approach for translation into the clinical setting. PMID- 28572591 TI - Morphologic and biometric evaluation of chick embryo eyes in ovo using 7 Tesla MRI. AB - The purposes of this study were (1) to characterize embryonic eye development during incubation in ovo and (2) to analyze the putative influence of repetitive ultrahigh-field MRI (UHF-MRI) measurements on this development. A population of 38 fertilized chicken eggs was divided into two sub-groups: two eggs (Group A) were examined repeatedly during the developmental period from embryonic day 1 (E1) to embryonic day 20 (E20) to evaluate the influence of daily MRI scanning. A second larger group of 36 eggs was examined pairwise on one day only, from E3 to E20, and the embryos were sacrificed immediately after MR imaging (Group B). Fast T2-weighted MR sequences provided biometric data on the eye with an in-plane resolution of 74 MUm. The data show rapid growth of the eye with a steep increase in intraocular dimensions in all axis directions and in eyeball volume during initial development up to E10, followed by a phase of reduced growth rate in later developmental stages. Comparison of the two groups revealed no differences in ocular development. PMID- 28572592 TI - Shoulder kinetics and ultrasonography changes after performing a high-intensity task in spinal cord injury subjects and healthy controls. AB - This corrects the article DOI: 10.1038/sc.2015.140. PMID- 28572594 TI - Socio-economic inequalities in C-reactive protein and fibrinogen across the adult age span: Findings from Understanding Society. AB - Systemic inflammation has been proposed as a physiological process linking socio economic position (SEP) to health. We examined how SEP inequalities in inflammation -assessed using C-reactive protein (CRP) and fibrinogen- varied across the adult age span. Current (household income) and distal (education) markers of SEP were used. Data from 7,943 participants (aged 25+) of Understanding Society (wave 2, 1/2010-3/2012) were employed. We found that SEP inequalities in inflammation followed heterogeneous patterns by age, which differed by the inflammatory marker examined rather than by SEP measures. SEP inequalities in CRP emerged in 30s, increased up to mid-50s or early 60 s when they peaked and then decreased with age. SEP inequalities in fibrinogen decreased with age. Body mass index (BMI), smoking, physical activity and healthy diet explained part, but not all, of the SEP inequalities in inflammation; in general, BMI exerted the largest attenuation. Cumulative advantage theories and those considering age as a leveler for the accumulation of health and economic advantages across the life-span should be dynamically integrated to better understand the observed heterogeneity in SEP differences in health across the lifespan. The attenuating roles of health-related lifestyle indicators suggest that targeting health promotion policies may help reduce SEP inequalities in health. PMID- 28572595 TI - Microwave-activated Ni/carbon catalysts for highly selective hydrogenation of nitrobenzene to cyclohexylamine. AB - Biocarbon supported Ni catalysts have been prepared by facile impregnation of Ni species by microwave-heating and used for selective hydrogenation of nitrobenzene to cyclohexylamine. These catalysts were characterized by X-ray diffraction, Raman spectra, N2 sorption measurement, X-ray photoelectron spectroscopy, temperature programmed reduction of H2 and H2 temperature-programmed desorption. The morphology and particle size of catalysts were imaged by scanning electron microscope and transmission electron microscope. For the hydrogenation of nitrobenzene to cyclohexylamine, 10%Ni/CSC-II(b) exhibits the best catalytic activity to achieve 100 mol% conversion of nitrobenzene and 96.7% selectivity of cyclohexylamine under reaction conditions of 2.0 MPa H2 and 200 degrees C, ascribed to high dispersion of Ni species and formation of nanosized Ni particles on the support aided by microwave-heating. Thus-prepared Ni/CSC catalyst is greatly activated, in which the addition of precious metal like Rh is totally avoided. PMID- 28572596 TI - Nutrient and herbivore alterations cause uncoupled changes in producer diversity, biomass and ecosystem function, but not in overall multifunctionality. AB - Altered nutrient cycles and consumer populations are among the top anthropogenic influences on ecosystems. However, studies on the simultaneous impacts of human driven environmental alterations on ecosystem functions, and the overall change in system multifunctionality are scarce. We used estuarine tidal flats to study the effects of changes in herbivore density and nutrient availability on benthic microalgae (diversity, abundance and biomass) and ecosystem functions (N2 fixation, denitrification, extracellular polymeric substances -EPS- as a proxy for sediment cohesiveness, sediment water content as a proxy of water retention capacity and sediment organic matter). We found consistent strong impacts of modified herbivory and weak effects of increased nutrient availability on the abundance, biomass and diversity of benthic microalgae. However, the effects on specific ecosystem functions were disparate. Some functions were independently affected by nutrient addition (N2-fixation), modified herbivory (sediment organic matter and water content), or their interaction (denitrification), while others were not affected (EPS). Overall system multifunction remained invariant despite changes in specific functions. This study reveals that anthropogenic pressures can induce decoupled effects between community structure and specific ecosystem functions. Our results highlight the need to address several ecosystem functions simultaneously for better ecosystem characterization and management. PMID- 28572597 TI - Visual Detection of Denatured Glutathione Peptides: A Facile Method to Visibly Detect Heat Stressed Biomolecules. AB - Every year pharmaceutical companies use significant resources to mitigate aggregation of pharmaceutical drug products. Specifically, peptides and proteins that have been denatured or degraded can lead to adverse patient reactions such as undesired immune responses. Current methods to detect aggregation of biological molecules are limited to costly and time consuming processes such as high pressure liquid chromatography, ultrahigh pressure liquid chromatography and SDS-PAGE gels. Aggregation of pharmaceutical drug products can occur during manufacturing, processing, packaging, shipment and storage. Therefore, a facile in solution detection method was evaluated to visually detect denatured glutathione peptides, utilizing gold nanoparticle aggregation via 3 Aminopropyltreithoxysilane. Glutathione was denatured using a 70 degrees C water bath to create an accelerated heat stressed environment. The peptide, gold nanoparticle and aminosilane solution was then characterized via, UV-Vis spectroscopy, FTIR spectroscopy, dynamic light scattering and scanning electron microscopy. Captured images and resulting absorbance spectra of the gold nanoparticle, glutathione, and aminosilane complex demonstrated visual color changes detectable with the human eye as a function of the denaturation time. This work serves as an extended proof of concept for fast in solution detection methods for glutathione peptides that have experienced heat stress. PMID- 28572598 TI - Metallization and Electrical Transport Behaviors of GaSb under High-Pressure. AB - The high-pressure metallization and electrical transport behaviors of GaSb were systematically investigated using in situ temperature-dependent electrical resistivity measurements, Hall effect measurements, transmission electron microscopy analysis, and first-principles calculations. The temperature-dependent resistivity measurements revealed pressure-induced metallization of GaSb at approximately 7.0 GPa, which corresponds to a structural phase transition from F 43m to Imma. In addition, the activation energies for the conductivity and Hall effect measurements indicated that GaSb undergoes a carrier-type inversion (p type to n-type) at approximately 4.5 GPa before metallization. The first principles calculations also revealed that GaSb undergoes a phase transition from F-43m to Imma at 7.0 GPa and explained the carrier-type inversion at approximately 4.5 GPa. Finally, transmission electron microscopy analysis revealed the effect of the interface on the electrical transport behavior of a small-resistance GaSb sample and explained the discontinuous change of resistivity after metallization. Under high pressure, GaSb undergoes grain refinement, the number of interfaces increases, and carrier transport becomes more difficult, increasing the electrical resistivity. PMID- 28572599 TI - Comparisons of microvascular and macrovascular changes in aldosteronism-related hypertension and essential hypertension. AB - Case-control observational study to evaluate the microvascular and macrovascular changes in patients with hypertension secondary to primary aldosteronism (PA), essential hypertension (EH) and healthy subjects. Measurements of arterial stiffness including augmentation index (AIx) and pulse wave velocity (PWV) were assessed using a TensioClinic arteriograph system. Retinal microcirculation was imaged by a Retinal Vessel Analyzer (RVA) and a non-midriatic camera (Topcon-TRC NV2000). IMEDOS software analyzed the retinal artery diameter (RAD), retinal vein diameters (RVD) and arteriole-to-venule ratio (AVR) of the vessels coming off the optic disc. Thirty, 39 and 35 patients were included in the PA, EH and control group, respectively. The PA group showed higher PWV values compared only with the control group. The mean brachial and aortic AIx values did not show significant difference between groups. In the PA group, the mean RVD and AVR values were significantly lower than in the EH and control groups, whereas the parameters did not differ between the EH and control groups. In conclusion, AVR appears significantly modified in the PA group compared with the EH group and could represent an early and more reliable indicator of microvascular remodeling. PMID- 28572600 TI - A nucleotide-controlled conformational switch modulates the activity of eukaryotic IMP dehydrogenases. AB - Inosine-5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme for nucleotide metabolism and cell proliferation. Despite IMPDH is the target of drugs with antiviral, immunosuppressive and antitumor activities, its physiological mechanisms of regulation remain largely unknown. Using the enzyme from the industrial fungus Ashbya gossypii, we demonstrate that the binding of adenine and guanine nucleotides to the canonical nucleotide binding sites of the regulatory Bateman domain induces different enzyme conformations with significantly distinct catalytic activities. Thereby, the comparison of their high-resolution structures defines the mechanistic and structural details of a nucleotide-controlled conformational switch that allosterically modulates the catalytic activity of eukaryotic IMPDHs. Remarkably, retinopathy-associated mutations lie within the mechanical hinges of the conformational change, highlighting its physiological relevance. Our results expand the mechanistic repertoire of Bateman domains and pave the road to new approaches targeting IMPDHs. PMID- 28572601 TI - Dysregulation of angiogenesis-specific signalling in adult testis results in xenograft degeneration. AB - Ectopic xenografting of testis is a feasible option for preservation of male fertility and angiogenesis plays a pivotal role in xenograft survival and functionality. When compared to immature testis, the adult testis is unable to establish functional xenografts due to potentially lower efficiency to induce angiogenesis. The precise molecular mechanism, however, remains elusive. In the present study, we compared adult and immature testis xenografts for survival, maturation and germ cell differentiation. Further, we evaluated differential expression of angiogenesis signalling-specific proteins in adult and immature testis and their xenografts. Results showed that adult testis xenografts degenerated whereas immature testis xenografts survived and established spermatogenesis with the production of haploid germ cells. Protein expression analysis demonstrated that immature testis xenografts were able to establish angiogenesis either through eNOS activation via VEGF and PI3K/AKT or through EGFR mediated STAT3 pathway. The role of ERK/MAPK pathway in xenograft angiogenesis was ruled out. The absence or reduced expression of angiogenesis-specific proteins in adult testis and its xenografts possibly resulted in poor angiogenesis and in their subsequent degeneration. This study provides insight into angiogenesis mechanism that can be utilized to augment testis xenografting efficiency. PMID- 28572602 TI - In vivo imaging of uterine cervix with a Mueller polarimetric colposcope. AB - Mueller polarimetric imaging enables the detection and quantification of modifications of the collagen fibers in the uterine cervix due to the development of a precancerous lesion. This information is not accessible through the use of the classic colposcope, a low magnification microscope used in current practice for cervical cancer screening. However, the in vivo application of Mueller polarimetric imaging poses an instrumental challenge: the device should be sufficiently compact, while still being able to perform fast and accurate acquisition of Mueller matrices in real-world conditions. In this study, the first wide field Mueller Polarimetric Colposcope (MPC) for the in vivo analysis of uterine cervix is presented. The MPC has been fabricated by grafting a miniaturized Mueller polarimetric imager on a classic colposcope. This new imaging tool performs the fast acquisition of Mueller polarimetric images, thus eliminating any blurring effects due to patient movements. It can be easily used by a practitioner with little change to their existing practice. Finally, the MPC was tested in vivo on a number of patients in the field. PMID- 28572605 TI - Experimental evidence for anisotropic double exchange interaction driven anisotropic transport in manganite heterostructures. AB - An anisotropic double exchange interaction driven giant transport anisotropy is demonstrated in a canonic double exchange system of La2/3Sr1/3MnO3 ultrathin films epitaxially grown on NdGaO3 (110) substrates. The oxygen octahedral coupling at the La2/3Sr1/3MnO3/NdGaO3 interface induces a planar anisotropic Mn-O Mn bond bending, which causes a significant anisotropic overlap of neighboring Mn orbitals. Due to the anisotropic double exchange interaction, it is found that the conductivity of the La2/3Sr1/3MnO3 film is enhanced when current is applied along the in-plane short crystalline axis. However, the anisotropic behavior is absent in the high temperature paramagnetic phase. Our results demonstrate anisotropic transport in the clean limit where phase separation is absent and the role of anisotropic phase percolation can be excluded. PMID- 28572604 TI - Enhanced thermal conductivity of epoxy composites filled with silicon carbide nanowires. AB - In this study, we report a facile approach to fabricate epoxy composite incorporated with silicon carbide nanowires (SiC NWs). The thermal conductivity of epoxy/SiC NWs composites was thoroughly investigated. The thermal conductivity of epoxy/SiC NWs composites with 3.0 wt% filler reached 0.449 Wm-1 K-1, approximately a 106% enhancement as compared to neat epoxy. In contrast, the same mass fraction of silicon carbide micron particles (SiC MPs) incorporated into epoxy matrix showed less improvement on thermal conduction properties. This is attributed to the formation of effective heat conduction pathways among SiC NWs as well as a strong interaction between the nanowires and epoxy matrix. In addition, the thermal properties of epoxy/SiC NWs composites were also improved. These results demonstrate that we developed a novel approach to enhance the thermal conductivity of the polymer composites which meet the requirement for the rapid development of the electronic devices. PMID- 28572603 TI - Release of Cytochrome C from Bax Pores at the Mitochondrial Membrane. AB - How cytochrome C is released from the mitochondria to the cytosol via Bax oligomeric pores, a process which is required for apoptosis, is still a mystery. Based on experimentally measured residue-residue distances, we recently solved the first atomic model for Bax oligomeric pores at the membranes using computational approaches. Here, we investigate the mechanism at the microsecond time- and nanometer space- scale using MD simulations. Our free energy landscape depicts a low barrier for the permeation of cytochrome C into the Bax C-terminal mouth, with the pathway proceeding to the inner cavity and exiting via the N terminal mouth. Release is guided by organized charged/hydrophilic surfaces. The hydrophilicity and negative charge of the pore surface gradually increase along the release pathway from the pore entry to the exit opening. Rather than inert passing of the cytochrome C through a rigid pore, the flexible pore may selectively aid the cytochrome C passage. Once the Bax pore is formed in the membrane, with a low energy barrier, the release of cytochrome C may be readily achieved through energy fluctuations. Collectively, our work provides mechanistic insight in atomic detail into the release of cytochrome C through Bax oligomeric pores. PMID- 28572606 TI - Automated screening for Fragile X premutation carriers based on linguistic and cognitive computational phenotypes. AB - Millions of people globally are at high risk for neurodegenerative disorders, infertility or having children with a disability as a result of the Fragile X (FX) premutation, a genetic abnormality in FMR1 that is underdiagnosed. Despite the high prevalence of the FX premutation and its effect on public health and family planning, most FX premutation carriers are unaware of their condition. Since genetic testing for the premutation is resource intensive, it is not practical to screen individuals for FX premutation status using genetic testing. In a novel approach to phenotyping, we have utilized audio recordings and cognitive profiling assessed via self-administered questionnaires on 200 females. Machine-learning methods were developed to discriminate FX premutation carriers from mothers of children with autism spectrum disorders, the comparison group. By using a random forest classifier, FX premutation carriers could be identified in an automated fashion with high precision and recall (0.81 F1 score). Linguistic and cognitive phenotypes that were highly associated with FX premutation carriers were high language dysfluency, poor ability to organize material, and low self monitoring. Our framework sets the foundation for computational phenotyping strategies to pre-screen large populations for this genetic variant with nominal costs. PMID- 28572607 TI - Human papilloma virus E7 oncoprotein abrogates the p53-p21-DREAM pathway. AB - High risk human papilloma viruses cause several types of cancer. The HPV oncoproteins E6 and E7 are essential for oncogenic cell transformation. E6 mediates the degradation of the tumor suppressor p53, and E7 can form complexes with the retinoblastoma pRB tumor suppressor. Recently, it has been shown that HPV E7 can also interfere with the function of the DREAM transcriptional repressor complex. Disruption of DREAM-dependent transcriptional repression leads to untimely early expression of central cell cycle regulators. The p53-p21-DREAM pathway represents one important means of cell cycle checkpoint activation by p53. By activating this pathway, p53 can downregulate transcription of genes controlled by DREAM. Here, we present a genome-wide ranked list of genes deregulated by HPV E7 expression and relate it to datasets of cell cycle genes and DREAM targets. We find that DREAM targets are generally deregulated after E7 expression. Furthermore, our analysis shows that p53-dependent downregulation of DREAM targets is abrogated when HPV E7 is expressed. Thus, p53 checkpoint control is impaired by HPV E7 independently of E6. In summary, our analysis reveals that disruption of DREAM through the HPV E7 oncoprotein upregulates most, if not all, cell cycle genes and impairs p53's control of cell cycle checkpoints. PMID- 28572608 TI - Genetic insights into juvenile idiopathic arthritis derived from deep whole genome sequencing. AB - Deep whole genome sequencing (WGS) allows for the comprehensive study of genetic landscapes at finer resolution than array based methods. We conducted deep WGS on children with the polyarticular form of juvenile idiopathic arthritis (JIA), using 2 independent cohorts to ascertain the sequencing fidelity. Genome wide SNP density analysis identified 18 SNP hotspots with comparison to the 1000 Genome Projects (1KGP) data. A subset of the genes adjacent to SNP hotspots showed statistically significant enrichment in immunological processes. Genes adjacent to indel hotspots were functionally related to G-protein coupled signaling pathways. Further analyses elucidated significantly more JIA SNPs with regulatory potential compared to 1KGP data. Furthermore, SNPs located within linkage disequibilium (LD) blocks containing previously identified JIA-associated SNPs demonstrated higher regulation potential compared to SNPs outside LD blocks. We also demonstrated enrichment of novel JIA variants in histone modification peaks and DNase hypersensitivity sites in B cells. This study greatly expands the number of genetic variants that may contribute to JIA and give us some clues into what may trigger this disease. To date, this study is the first deep WGS effort on children with JIA and provides useful genetic resources for research communities particularly in understanding JIA etiology. PMID- 28572609 TI - The Toxic Effects of Tetrachlorobisphenol A in Saccharomyces cerevisiae Cells via Metabolic Interference. AB - Tetrachlorobisphenol A (TCBPA) is a common flame retardant detected in different environments. However, its toxic effects on animals and humans are not fully understood. Here, the differential intracellular metabolites and associated gene expression were used to clarify the metabolic interference of TCBPA in Saccharomyces cerevisiae, a simple eukaryotic model organism. The results indicated that TCBPA treatment promoted the glycolysis pathway but inhibited the tricarboxylic acid (TCA) cycle, energy metabolism and the hexose monophosphate pathway (HMP) pathway. Thus, the HMP pathway produced less reducing power, leading to the accumulation of reactive oxygen species (ROS) and aggravation of oxidative damage. Accordingly, the carbon flux was channelled into the accumulation of fatty acids, amino acids and glycerol instead of biomass production and energy metabolism. The accumulation of these metabolites might serve a protective function against TCBPA stress by maintaining the cell membrane integrity or providing a stable intracellular environment in S. cerevisiae. These results enhance our knowledge of the toxic effects of TCBPA on S. cerevisiae via metabolic interference and pave the way for clarification of the mechanisms underlying TCBPA toxicity in animals and humans. PMID- 28572610 TI - GLP-1 receptor signalling promotes beta-cell glucose metabolism via mTOR dependent HIF-1alpha activation. AB - Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic beta cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. Since GLP-1-induced insulin secretion requires glucose metabolism, we aimed to address the hypothesis that GLP-1 receptor (GLP-1R) signalling can modulate glucose uptake and utilization in beta-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 beta-cells and rodent islets to the GLP-1R agonist Exendin-4 (50 nM). Here we report for the first time that prolonged stimulation of the GLP-1R for 18 hours promotes metabolic reprogramming of beta-cells. This is evidenced by up-regulation of glycolytic enzyme expression, increased rates of glucose uptake and consumption, as well as augmented ATP content, insulin secretion and glycolytic flux after removal of Exendin-4. In our model, depletion of Hypoxia-Inducible Factor 1 alpha (HIF-1alpha) impaired the effects of Exendin-4 on glucose metabolism, while pharmacological inhibition of Phosphoinositide 3-kinase (PI3K) or mTOR completely abolished such effects. Considering the central role of glucose catabolism for stimulus-secretion coupling in beta-cells, our findings suggest that chronic GLP 1 actions on insulin secretion include elevated beta-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression. PMID- 28572611 TI - Transcriptome responses of Lactobacillus acetotolerans F28 to a short and long term ethanol stress. AB - Lactobacillus acetotolerans is a major microbe contributing to the Chinese liquor fermentation with unknown function. It can be grown well in a high concentration of ethanol. RNA sequencing (RNA-seq) was performed on L. acetotolerans F28 growing in 12% ethanol to determine important genetic mechanisms for both a short and long term adaption to this environment. A genome-wide transcriptional analysis revealed that the most important genetic elements for L. acetotolerans F28 grown in ethanol are related to high levels of stress response and fatty acid biosynthesis, and a reduction of amino acid transport and metabolism after both a short and long time stress. The fatty acid methyl ester analyses showed that most fatty acids were increased in L. acetotolerans F28 after exposure to ethanol while the unsaturated fatty acid octadecenoic acid (C18:1) was significantly increased. The increasing unsaturated fatty acid biosynthesis in L. acetotolerans F28 might enhance cell membrane fluidity and protect the cells against high concentration of ethanol. Overall, the transcriptome and functional analysis indicated that the elevated stress response and fatty acid biosynthesis, and the decrease of amino acid transport and metabolism might play important roles for L. acetotolerans F28 to adapt to environmental ethanol. PMID- 28572612 TI - One-month spaceflight compromises the bone microstructure, tissue-level mechanical properties, osteocyte survival and lacunae volume in mature mice skeletons. AB - The weightless environment during spaceflight induces site-specific bone loss. The 30-day Bion-M1 mission offered a unique opportunity to characterize the skeletal changes after spaceflight and an 8-day recovery period in mature male C57/BL6 mice. In the femur metaphysis, spaceflight decreased the trabecular bone volume (-64% vs. Habitat Control), dramatically increased the bone resorption (+140% vs. Habitat Control) and induced marrow adiposity invasion. At the diaphysis, cortical thinning associated with periosteal resorption was observed. In the Flight animal group, the osteocyte lacunae displayed a reduced volume and a more spherical shape (synchrotron radiation analyses), and empty lacunae were highly increased (+344% vs. Habitat Control). Tissue-level mechanical cortical properties (i.e., hardness and modulus) were locally decreased by spaceflight, whereas the mineral characteristics and collagen maturity were unaffected. In the vertebrae, spaceflight decreased the overall bone volume and altered the modulus in the periphery of the trabecular struts. Despite normalized osteoclastic activity and an increased osteoblast number, bone recovery was not observed 8 days after landing. In conclusion, spaceflight induces osteocyte death, which may trigger bone resorption and result in bone mass and microstructural deterioration. Moreover, osteocyte cell death, lacunae mineralization and fatty marrow, which are hallmarks of ageing, may impede tissue maintenance and repair. PMID- 28572613 TI - Mesenchymal stem cells correct haemodynamic dysfunction associated with liver injury after extended resection in a pig model. AB - In patients, acute kidney injury (AKI) is often due to haemodynamic impairment associated with hepatic decompensation following extended liver surgery. Mesenchymal stem cells (MSCs) supported tissue protection in a variety of acute and chronic diseases, and might hence ameliorate AKI induced by extended liver resection. Here, 70% liver resection was performed in male pigs. MSCs were infused through a central venous catheter and haemodynamic parameters as well as markers of acute kidney damage were monitored under intensive care conditions for 24 h post-surgery. Cytokine profiles were established to anticipate the MSCs' potential mode of action. After extended liver resection, hyperdynamic circulation, associated with hyponatraemia, hyperkalaemia, an increase in serum aldosterone and low urine production developed. These signs of hepatorenal dysfunction and haemodynamic impairment were corrected by MSC treatment. MSCs elevated PDGF levels in the serum, possibly contributing to circulatory homeostasis. Another 14 cytokines were increased in the kidney, most of which are known to support tissue regeneration. In conclusion, MSCs supported kidney and liver function after extended liver resection. They probably acted through paracrine mechanisms improving haemodynamics and tissue homeostasis. They might thus provide a promising strategy to prevent acute kidney injury in the context of post-surgery acute liver failure. PMID- 28572614 TI - Early Detection and Serial Monitoring of Anthracycline-Induced Cardiotoxicity Using T1-mapping Cardiac Magnetic Resonance Imaging: An Animal Study. AB - A reliable, non-invasive diagnostic method is needed for early detection and serial monitoring of cardiotoxicity, a well-known side effect of chemotherapy. This study aimed to assess the feasibility of T1-mapping cardiac magnetic resonance imaging (CMR) for evaluating subclinical myocardial changes in a doxorubicin-induced cardiotoxicity rabbit model. Adult male New Zealand White rabbits were injected twice-weekly with doxorubicin and subjected to CMR on a clinical 3T MR system before and every 2-4 weeks post-drug administration. Native T1 and extracellular volume (ECV) values were measured at six mid-left ventricle (LV) and specific LV lesions. Histological assessments evaluated myocardial injury and fibrosis. Three pre-model and 11 post-model animals were included. Myocardial injury was observed from 3 weeks. Mean LV myocardium ECV values increased significantly from week 3 before LV ejection fraction decreases (week 6), and ECVs of the RV upper/lower insertion sites and papillary muscle exceeded those of the LV. The mean native T1 value in the mid-LV increased significantly increased from week 6, and LV myocardium ECV correlated strongly with the degree of fibrosis (r = 0.979, p < 0.001). Myocardial T1 mapping, particularly ECV values, reliably and non-invasively detected early cardiotoxicity, allowing serial monitoring of chemotherapy-induced cardiotoxicity. PMID- 28572615 TI - Characterization of pertussis-like toxin from Salmonella spp. that catalyzes ADP ribosylation of G proteins. AB - Salmonella Typhimurium definitive phage type (DT) 104 produces a pertussis-like toxin (ArtAB-DT104), which catalyzes ADP-ribosylation of pertussis toxin sensitive G proteins. However, the prevalence of ArtAB and its toxicity have not been established. We report here that, in addition to DT104, S. Worthington, and S. bongori, produce ArtAB homologs, designated ArtAB-SW and ArtAB-Sb, respectively. We purified and characterized these ArtAB toxins, which comprise a 27-kDa A subunit (ArtA) and 13.8-kDa pentameric B subunits (ArtB). While the sequence of the A subunit, which is ADP-ribosyltransferase, is similar to the A subunit sequences of other ArtABs, the B subunit of ArtAB-Sb is divergent compared to the B subunit sequences of other ArtABs. Intraperitoneal injection of purified ArtABs was fatal in mice; the 50% lethal doses of ArtAB-DT104 and ArtAB SW were lower than that of ArtAB-Sb, suggesting that ArtB plays an influential role in the toxicity of ArtABs. ArtABs catalyzed ADP-ribosylation of G proteins in RAW 264.7 murine macrophage-like cells, and increased intracellular cyclic AMP levels. ArtAB-DT104 and ArtAB-SW, but not ArtAB-Sb, stimulated insulin secretion in mice; however, unlike Ptx, ArtABs did not induce leukocytosis. This disparity in biological activity may be explained by differences in ADP-ribosylation of target G proteins. PMID- 28572616 TI - Comparison of non-invasive biomarkers faecal BAFF, calprotectin and FOBT in discriminating IBS from IBD and evaluation of intestinal inflammation. AB - Faecal calprotectin and faecal occult blood test (FOBT) were widely used in the diagnosis and assessment of intestinal inflammation in inflammatory bowel disease (IBD). Recently we identified an excellent new biomarker B cell-activating factor (BAFF) for IBD. Here in this study we compared the efficacy of faecal BAFF, calprotectin and FOBT to find the "best non-invasive marker". Results showed that for discriminating IBD from IBS, BAFF >=227.3 pg/ml yield 84% sensitivity, 100% specificity, 100% positive predictive value (PPV) and 64% negative predictive value (NPV) while calprotectin >=50 ug/g yield 76% sensitivity, 93% specificity, 97% PPV and 53% NPV. FOBT yield 65% sensitivity, 93% specificity, 97% PPV and 43% NPV. Combining BAFF with calprotectin tests yield 94% sensitivity, 93% specificity, 98% PPV, 81% NPV. Faecal BAFF level showed the stronger correlation with endoscopic inflammatory score as compared to calprotectin not only in UC (correlation coefficient [r] = 0.69, p < 0.0001 vs. r = 0.58, p < 0.0001), but also in CD (r = 0.58, p < 0.0001 vs. r = 0.52, p = 0.0003). Our results indicating that faecal BAFF is a promising non-invasive biomarker in IBD differential diagnosis and monitoring of intestinal inflammation. PMID- 28572618 TI - Uncovering and Predicting the Dynamic Process of Collective Attention with Survival Theory. AB - The subject of collective attention is in the center of this era of information explosion. It is thus of great interest to understand the fundamental mechanism underlying attention in large populations within a complex evolving system. Moreover, an ability to predict the dynamic process of collective attention for individual items has important implications in an array of areas. In this report, we propose a generative probabilistic model using a self-excited Hawkes process with survival theory to model and predict the process through which individual items gain their attentions. This model explicitly captures three key ingredients: the intrinsic attractiveness of an item, characterizing its inherent competitiveness against other items; a reinforcement mechanism based on sum of each previous attention triggers; and a power-law temporal relaxation function, corresponding to the aging in the ability to attract new attentions. Experiments on two population-scale datasets demonstrate that this model consistently outperforms the state-of-the-art methods. PMID- 28572617 TI - Independent and cumulative effects of resting heart rate and pulse pressure with type 2 diabetes mellitus in Chinese rural population. AB - The purpose was to explore the effects of resting heart rate (RHR) and pulse pressure (PP) independently as well as their cumulative effects on the risk of type 2 diabetes mellitus (T2DM) through cross-sectional study plus meta-analysis. A total of 8276 subjects aged 35-74 years from the Rural Diabetes, Obesity and Lifestyle (RuralDiab) study were included in the study. Meanwhile, two meta analyses were conducted to validate the results of the epidemiological research. The results showed that RHR and PP were associated with higher risk of T2DM, and the corresponding adjusted OR(95%CI) for each quartiles were 1.00, 0.99(0.68 1.42), 1.58(1.13-2.20), 2.93(2.15-3.98) and 1.00, 1.06(0.75-1.48), 1.11(0.79 1.56), 1.45(1.03-2.03), respectively. The cumulative effect analysis indicated that the adjusted OR(95%CI) in the fast RHR-high PP were 3.36(2.26-4.99), 2.60(1.47-4.59), and 3.60(2.09-6.20) compared with the slow RHR-low PP for total population, male and female, respectively. Meta-analysis showed that the pooled effect values for RHR and PP were 1.94(1.64-2.31) and 1.25(1.04-1.51), respectively. This study demonstrated that elevated RHR and PP are independently associated with the risk of T2DM as well as the influences of conventional confounders, and fast RHR with high PP might cumulatively increase the risk of T2DM. However, the potential clinical application remains to be determined. PMID- 28572620 TI - Generation of a planar direct-current glow discharge in atmospheric pressure air using rod array electrode. AB - Scaling up atmospheric pressure glow discharge to large volume is desirable for low-temperature plasma applications. In this paper, an approach to generate a glow discharge in a planar shape with a fairly large volume is proposed in atmospheric pressure air through utilizing a direct-current excited rod array electrode. The planar discharge with a wide gap originates from three discrete discharges with a narrow gap. Based on electrical method and optical emission spectroscopy, it is found that gap voltage increases, while discharge current remains constant with increasing the gap width. Temperature and electron density of the discharge decrease with increasing the gap width. PMID- 28572619 TI - Fatty Acid Binding Protein 3 And Transzonal Projections Are Involved In Lipid Accumulation During In Vitro Maturation Of Bovine Oocytes. AB - Oocytes that undergo in vitro maturation (IVM) are metabolically abnormal and accumulate excess lipid content. However, the mechanism of lipid accumulation and the role of cumulus cells in this process are unclear. Recently, it was shown that fatty acid binding proteins (FABPs) performed intra- and extracellular fatty acid transport. We postulated that FABP3 might be responsible for fatty acid transport from cumulus cells to the oocytes via transzonal projections (TZPs) during IVM. Transcript and protein levels of FABP3 were analyzed in both in vivo- and in vitro-matured cumulus-oocyte-complexes and were increased in IVM samples. Further analysis showed increased lipid content in oocytes and cumulus cells in IVM samples compared to in vivo-derived. We therefore speculated that altered traffic of fatty acids via FABP3 during IVM was the mechanism leading to the excess of lipids accumulated within IVM oocytes. Furthermore, we demonstrated an increase in FABP3 levels and lipid content during the first 9 h of IVM, further strengthening the possibility of fatty acid transport via FABP3 and TZPs. Additionally, disruptions of TZPs during IVM decreased lipid accumulation in oocytes. Our results shed light on a possible mechanism involving FABP3 and TZPs that causes excess lipid accumulation in oocytes during IVM. PMID- 28572621 TI - Expression and integrated network analyses revealed functional divergence of NHX type Na+/H+ exchanger genes in poplar. AB - The Na+/H+ antiporters (NHXs) are secondary ion transporters to exchange H+ and transfer the Na+ or K+ across membrane, they play crucial roles during plant development and stress responses. To gain insight into the functional divergence of NHX genes in poplar, eight PtNHX were identified from Populus trichocarpa genome. PtNHXs containing 10 transmembrane helices (TMH) and a hydrophilic C terminal domain, the TMH compose a hollow cylinder to provide the channel for Na+ and H+ transport. The expression patterns and cis-acting elements showed that all the PtNHXs were response to single or multiple stresses including drought, heat, cold, salinity, MV, and ABA. Both the co-expression network and protein-protein interaction network of PtNHXs implying their functional divergence. Interestingly, although PtNHX7 and PtNHX8 were generated by whole genome duplication event, they showed significant differences in expression pattern, protein structure, co-expressed genes, and interacted proteins. Only PtNHX7 interact with CBL and CIPK, indicating PtNHX7 is the primary NHX involved in CBL CIPK pathway during salt stress responses. Natural variation analysis based on 549 P. trichocarpa individuals indicated the frequency of SNPs in PtNHX7 was significantly higher than other PtNHXs. Our findings provide new insights into the functional divergence of NHX genes in poplar. PMID- 28572622 TI - Probing the action of a novel anti-leukaemic drug therapy at the single cell level using modern vibrational spectroscopy techniques. AB - Acute myeloid leukaemia (AML) is a life threatening cancer for which there is an urgent clinical need for novel therapeutic approaches. A redeployed drug combination of bezafibrate and medroxyprogesterone acetate (BaP) has shown anti leukaemic activity in vitro and in vivo. Elucidation of the BaP mechanism of action is required in order to understand how to maximise the clinical benefit. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, Synchrotron radiation FTIR (S-FTIR) and Raman microspectroscopy are powerful complementary techniques which were employed to probe the biochemical composition of two AML cell lines in the presence and absence of BaP. Analysis was performed on single living cells along with dehydrated and fixed cells to provide a large and detailed data set. A consideration of the main spectral differences in conjunction with multivariate statistical analysis reveals a significant change to the cellular lipid composition with drug treatment; furthermore, this response is not caused by cell apoptosis. No change to the DNA of either cell line was observed suggesting this combination therapy primarily targets lipid biosynthesis or effects bioactive lipids that activate specific signalling pathways. PMID- 28572623 TI - Voluntary Vaccination through Self-organizing Behaviors on Locally-mixed Social Networks. AB - Voluntary vaccination reflects how individuals weigh the risk of infection and the cost of vaccination against the spread of vaccine-preventable diseases, such as smallpox and measles. In a homogeneously mixing population, the infection risk of an individual depends largely on the proportion of vaccinated individuals due to the effects of herd immunity. While in a structured population, the infection risk can also be affected by the structure of individuals' social network. In this paper, we focus on studying individuals' self-organizing behaviors under the circumstance of voluntary vaccination in different types of social networks. Specifically, we assume that each individual together with his/her neighbors forms a local well-mixed environment, where individuals meet equally often as long as they have a common neighbor. We carry out simulations on four types of locally-mixed social networks to investigate the network effects on voluntary vaccination. Furthermore, we also evaluate individuals' vaccinating decisions through interacting with their "neighbors of neighbors". The results and findings of this paper provide a new perspective for vaccination policy-making by taking into consideration human responses in complex social networks. PMID- 28572625 TI - Node Attribute-enhanced Community Detection in Complex Networks. AB - Community detection involves grouping the nodes of a network such that nodes in the same community are more densely connected to each other than to the rest of the network. Previous studies have focused mainly on identifying communities in networks using node connectivity. However, each node in a network may be associated with many attributes. Identifying communities in networks combining node attributes has become increasingly popular in recent years. Most existing methods operate on networks with attributes of binary, categorical, or numerical type only. In this study, we introduce kNN-enhance, a simple and flexible community detection approach that uses node attribute enhancement. This approach adds the k Nearest Neighbor (kNN) graph of node attributes to alleviate the sparsity and the noise effect of an original network, thereby strengthening the community structure in the network. We use two testing algorithms, kNN-nearest and kNN-Kmeans, to partition the newly generated, attribute-enhanced graph. Our analyses of synthetic and real world networks have shown that the proposed algorithms achieve better performance compared to existing state-of-the-art algorithms. Further, the algorithms are able to deal with networks containing different combinations of binary, categorical, or numerical attributes and could be easily extended to the analysis of massive networks. PMID- 28572624 TI - Diacylglycerol Kinase alpha is Involved in the Vitamin E-Induced Amelioration of Diabetic Nephropathy in Mice. AB - Diabetic nephropathy (DN) is one of vascular complications of diabetes and is caused by abnormal protein kinase C activation as a result of increased diacylglycerol (DG) production in diabetic hyperglycaemia. Diacylglycerol kinase (DGK) converts DG into phosphatidic acid. Therefore, it is expected that the activation of DGK would ameliorate DN. Indeed, it has been reported that vitamin E (VtE) ameliorates DN in rat by activating DGK, and we recently reported that VtE specifically activates DGKalpha isoform in vitro. However, whether DGKalpha is involved in the VtE-induced amelioration of DN in vivo remains unknown. Therefore, we investigated the VtE-induced amelioration of DN in wild-type (DGKalpha+/+) and DGKalpha-deficient (DGKalpha-/-) mice in which diabetes was induced by streptozocin. Several symptoms of DN were ameliorated by VtE treatment in the DGKalpha+/+ mice but not in the DGKalpha-/- mice. Moreover, transmission electron microscopy of glomeruli and immunofluorescent staining of glomerular epithelial cells (podocytes) indicated that VtE ameliorates podocyte pathology and prevents podocyte loss in the DGKalpha+/+ mice but not in the DGKalpha-/- mice. We showed that VtE can ameliorate DN in mice and that DGKalpha is involved in the VtE-induced amelioration of DN in vivo, suggesting that DGKalpha is an attractive therapeutic target for DN. PMID- 28572626 TI - A randomised cross-over study assessing the "blue pyjama syndrome" in major depressive episode. AB - This paper introduces a "blue pyjama syndrome" (whereby wearing hospital pyjamas results in an exaggerated impression of severity). We performed a 5-day, prospective, randomized, cross-over study in a French mood disorder unit for inpatients. At Day 1 (D1) and Day 5 (D5), two 5-minute video interviews were recorded with patients in pyjamas or in day clothes (the sequence was randomly allocated). Psychiatrists unaware of the study objective assessed the videos and scored their clinical global impressions (CGI, with scores ranging from 1 to 7). Of 30 participants with major depressive episode selected for inclusion, 26 participants (69% women) provided useable data for an evaluation by 10 psychiatrists. Pyjamas significantly increased the psychiatrists' CGI ratings of disease severity by 0.65 [0.27; 1.02] points. The psychiatrists' global impressions also rated patients as significantly less severe at D5 in comparison with D1 by -0.66 [-1.03; -0.29] points. The "blue pyjama syndrome" is in the same order of magnitude as the difference observed after a week of hospitalisation. This potentially calls into question the reliability and validity of observer ratings of depression. PMID- 28572629 TI - Novel approach for accurate tissue-based protein colocalization and proximity microscopy. AB - Fluorescence colocalization microscopy is frequently used to assess potential links between distinct molecules; however, this method can lead to striking false positive results and erroneous conclusions. Here we developed a novel approach with more sophisticated mathematical colocalization analyses together with visualization of physical proximity using fluorescence resonance energy transfer (FRET). To verify our results we used the proximity ligation assay (PLA). With these methods we could demonstrate that distinct neurodegeneration-related proteins either not or only rarely interact in human brain tissue. PMID- 28572627 TI - MicroRNA-150 modulates intracellular Ca 2+ levels in naive CD8+ T cells by targeting TMEM20. AB - Regulation of intracellular Ca2+ signaling is a major determinant of CD8+ T cell responsiveness, but the mechanisms underlying this regulation of Ca2+ levels, especially in naive CD8+ T cells, are not fully defined. Here, we showed that microRNA-150 (miR-150) controls intracellular Ca2+ levels in naive CD8+ T cells required for activation by suppressing TMEM20, a negative regulator of Ca2+ extrusion. miR-150 deficiency increased TMEM20 expression, which resulted in increased intracellular Ca2+ levels in naive CD8+ T cells. The subsequent increase in Ca2+ levels induced expression of anergy-inducing genes, such as Cbl b, Egr2, and p27, through activation of NFAT1, as well as reduced cell proliferation, cytokine production, and the antitumor activity of CD8+ T cells upon antigenic stimulation. The anergy-promoting molecular milieu and function induced by miR-150 deficiency were rescued by reinstatement of miR-150. Additionally, knockdown of TMEM20 in miR-150-deficient naive CD8+ T cells reduced intracellular Ca2+ levels. Our findings revealed that miR-150 play essential roles in controlling intracellular Ca2+ level and activation in naive CD8+ T cells, which suggest a mechanism to overcome anergy induction by the regulation of intracellular Ca2+ levels. PMID- 28572630 TI - Environmentally driven sexual segregation in a marine top predator. AB - Sexual segregation in foraging occurs in many animal species, resulting in the partitioning of resources and reduction of competition between males and females, yet the patterns and drivers of such segregation are still poorly understood. We studied the foraging movements (GPS-tracking), habitat use (habitat modelling) and trophic ecology (stable isotope analysis) of female and male Cory's shearwaters Calonectris borealis during the mid chick-rearing period of six consecutive breeding seasons (2010-2015). We found a clear sexual segregation in foraging in years of greater environmental stochasticity, likely years of lower food availability. When food became scarce, females undertook much longer foraging trips, exploited more homogeneous water masses, had a larger isotopic niche, fed on lower trophic level prey and exhibited a lower body condition, when compared to males. Sexual competition for trophic resources may be stronger when environmental conditions are poor. A greater foraging success of one sex may result in differential body condition of pair mates when enduring parental effort, and ultimately, in an increased probability of breeding failure. PMID- 28572628 TI - Adipose tissue dysfunction as a central mechanism leading to dysmetabolic obesity triggered by chronic exposure to p,p'-DDE. AB - Endocrine-disrupting chemicals such as p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), are bioaccumulated in the adipose tissue (AT) and have been implicated in the obesity and diabetes epidemic. Thus, it is hypothesized that p,p'-DDE exposure could aggravate the harm of an obesogenic context. We explored the effects of 12 weeks exposure in male Wistar rats' metabolism and AT biology, assessing a range of metabolic, biochemical and histological parameters. p,p'-DDE -treatment exacerbated several of the metabolic syndrome-accompanying features induced by high-fat diet (HF), such as dyslipidaemia, glucose intolerance and hypertension. A transcriptome analysis comparing mesenteric visceral AT (vAT) of HF and HF/DDE groups revealed a decrease in expression of nervous system and tissue development-related genes, with special relevance for the neuropeptide galanin that also revealed DNA methylation changes at its promoter region. Additionally, we observed an increase in transcription of dipeptidylpeptidase 4, as well as a plasmatic increase of the pro-inflammatory cytokine IL-1beta. Our results suggest that p,p'-DDE impairs vAT normal function and effectively decreases the dynamic response to energy surplus. We conclude that p,p'-DDE does not merely accumulate in fat, but may contribute significantly to the development of metabolic dysfunction and inflammation. Our findings reinforce their recognition as metabolism disrupting chemicals, even in non-obesogenic contexts. PMID- 28572631 TI - Understanding the mechanisms of dormancy in an invasive alien Sycamore lace bug, Corythucha ciliata through transcript and metabolite profiling. AB - The sycamore lace bug, Corythucha ciliata, is a pest of sycamore trees. In China, it is found in the most northern border where it has been known to become dormant during harsh winters. But the molecular and metabolic basis for dormancy in this insect is still unknown. In this study, we analyzed the transcript and metabolite profiles of this bug to identify key genes and metabolites that are significantly regulated during dormancy in adult females and males. In total, 149 differentially expressed genes (DEGs) were significantly up-regulated and 337 DEGs were significantly down-regulated in dormant adults (both females and males). We found major differences in heat shock protein (HSPs), immunity responsive genes, NAD-dependent deacetylase sirtuin-1 (SIRT1) and genes involved in the spliceosome pathway that is known to regulate stress. Among the 62 metabolites identified by GC-MS, 12 metabolites including glycerol, trehalose, and alanine were significantly increased during C. ciliata dormancy. By integrating the transcriptome and metabolite datasets, we found that the metabolites in glycolysis/gluconeogenesis and citrate cycle (TCA) were significantly reduced. This study is the first to report both transcript and metabolite profiles of the overwintering responses of C. ciliata to cold stress at the molecular level. PMID- 28572632 TI - Label-Free Fluorescence Spectroscopy for Detecting Key Biomolecules in Brain Tissue from a Mouse Model of Alzheimer's Disease. AB - In this study, label-free fluorescence spectroscopy was used for the first time to determine spectral profiles of tryptophan, reduced nicotinamide adenine dinucleotide (NADH), and flavin denine dinucleotide (FAD) in fresh brain samples of a mouse model of Alzheimer's disease (AD). Our results showed that the emission spectral profile levels of tryptophan and NADH were higher in AD samples than normal samples. The intensity ratio of tryptophan to NADH and the change rate of fluorescence intensity with respect to wavelength also increased in AD brain. These results yield an optical method for detecting early stage of AD by comparing spectral profiles of biomolecules. PMID- 28572633 TI - Cognitive ability and physical health: a Mendelian randomization study. AB - Causes of the association between cognitive ability and health remain unknown, but may reflect a shared genetic aetiology. This study examines the causal genetic associations between cognitive ability and physical health. We carried out two-sample Mendelian randomization analyses using the inverse-variance weighted method to test for causality between later life cognitive ability, educational attainment (as a proxy for cognitive ability in youth), BMI, height, systolic blood pressure, coronary artery disease, and type 2 diabetes using data from six independent GWAS consortia and the UK Biobank sample (N = 112 151). BMI, systolic blood pressure, coronary artery disease and type 2 diabetes showed negative associations with cognitive ability; height was positively associated with cognitive ability. The analyses provided no evidence for casual associations from health to cognitive ability. In the other direction, higher educational attainment predicted lower BMI, systolic blood pressure, coronary artery disease, type 2 diabetes, and taller stature. The analyses indicated no causal association from educational attainment to physical health. The lack of evidence for causal associations between cognitive ability, educational attainment, and physical health could be explained by weak instrumental variables, poorly measured outcomes, or the small number of disease cases. PMID- 28572634 TI - Analysis of Parasitic Protozoa at the Single-cell Level using Microfluidic Impedance Cytometry. AB - At present, there are few technologies which enable the detection, identification and viability analysis of protozoan pathogens including Cryptosporidium and/or Giardia at the single (oo)cyst level. We report the use of Microfluidic Impedance Cytometry (MIC) to characterise the AC electrical (impedance) properties of single parasites and demonstrate rapid discrimination based on viability and species. Specifically, MIC was used to identify live and inactive C. parvum oocysts with over 90% certainty, whilst also detecting damaged and/or excysted oocysts. Furthermore, discrimination of Cryptosporidium parvum, Cryptosporidium muris and Giardia lamblia, with over 92% certainty was achieved. Enumeration and identification of (oo)cysts can be achieved in a few minutes, which offers a reduction in identification time and labour demands when compared to existing detection methods. PMID- 28572635 TI - Structures and thermodynamics of water encapsulated by graphene. AB - Understanding phase behaviors of nanoconfined water has driven notable research interests recently. In this work, we examine water encapsulated under a graphene cover that offers an ideal testbed to explore its molecular structures and thermodynamics. We find layered water structures for up to ~1000 trapped water molecules, which is stabilized by the spatial confinement and pressure induced by interfacial adhesion. For monolayer encapsulations, we identify representative two-dimensional crystalline lattices as well as defects therein. Free energy analysis shows that the structural orders with low entropy are compensated by high formation energies due to the pressurized confinement. There exists an order to-disorder transition for this condensed phase at ~480-490 K, with a sharp reduction in the number of hydrogen bonds and increase in the entropy. Fast diffusion of the encapsulated water demonstrates anomalous temperature dependence, indicating the solid-to-fluid nature of this structural transition. These findings offer fundamental understandings of the encapsulated water that can be used as a pressurized cell with trapped molecular species, and provide guidance for practical applications with its presence, for example, in the design of nanodevices and nanoconfined reactive cells. PMID- 28572636 TI - Nicotine delivery from the refill liquid to the aerosol via high-power e cigarette device. AB - To offer an enhanced and well-controlled nicotine delivery from the refill liquid to the aerosol is a key point to adequately satisfy nicotine cravings using electronic nicotine delivery systems (ENDS). A recent high-power ENDS, exhibiting higher aerosol nicotine delivery than older technologies, was used. The particle size distribution was measured using a cascade impactor. The effects of the refill liquid composition on the nicotine content of each size-fraction in the submicron range were investigated. Nicotine was quantified by liquid chromatography coupled with tandem mass spectrometry. Particle size distribution of the airborne refill liquid and the aerosol nicotine demonstrated that the nicotine is equally distributed in droplets regardless of their size. Results also proved that the nicotine concentration in aerosol was significantly lower compared to un-puffed refill liquid. A part of the nicotine may be left in the ENDS upon depletion, and consequently a portion of the nicotine may not be transferred to the user. Thus, new generation high-power ENDS associated with propylene glycol/vegetable glycerin (PG/VG) based solvent were very efficient to generate carrier-droplets containing nicotine molecules with a constant concentration. Findings highlighted that a portion of the nicotine in the refill liquid may not be transferred to the user. PMID- 28572637 TI - Transgenic hepatitis B: a new model of HBV infection. AB - Chronic hepatitis B infection (HBV) is major cause of morbidity and mortality throughout the world. Currently there is limited understanding on the cellular proteins and related molecules involved in the critical steps of viral entry into the cytoplasm and persistent viral replication in cell culture. In order to address these fundamental questions, we designed and implemented a new model of hepatitis B: infectious transgenic hepatitis B virus composed of a complete virus plus a foreign gene. The foreign gene allows identification of cells that are infected by the transgenic virus. The transgenic virus was used in a functional assay to identify cellular proteins necessary for viral replication. This assay repeatedly identified the protein UQCR10. After restoring UQCR10 levels in HepG2 and Huh7 cells, they can be infected by intact virions of transgenic hepatitis B. These results demonstrate the usefulness of this new transgenic hepatitis B model. PMID- 28572639 TI - Construction of novel repeat proteins with rigid and predictable structures using a shared helix method. AB - Generating artificial protein assemblies with complex shapes requires a method for connecting protein components with stable and predictable structures. Currently available methods for creating rigid protein assemblies rely on either complicated calculations or extensive trial and error. We describe a simple and efficient method for connecting two proteins via a fused alpha helix that is formed by joining two preexisting helices into a single extended helix. Because the end-to-end ligation of helices does not guarantee the formation of a continuous helix, we superimposed 1-2 turns of pairs of connecting helices by using a molecular graphics program. Then, we chose amino acids from the two natural sequences that would stabilize the connecting helix. This "shared helix method" is highly efficient. All the designed proteins that could be produced in Escherichia coli were readily crystallized and had the expected fusion structures. To prove the usefulness of this method, we produced two novel repeat proteins by assembling several copies of natural or artificial proteins with alpha helices at both termini. Their crystal structures demonstrated the successful assembly of the repeating units with the intended curved shapes. We propose that this method could dramatically expand the available repertoire of natural repeat proteins. PMID- 28572638 TI - Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock. AB - Hemorrhagic shock is a leading cause of death in people under the age of 45 and accounts for almost half of trauma-related deaths. In order to develop a treatment strategy based on potentiating mitochondrial function, we investigated the effect of the orphan drug dichloroacetate (DCA) on survival in an animal model of hemorrhagic shock in the absence of fluid resuscitation. Hemorrhagic shock was induced in rats by withdrawing 60% of the blood volume and maintaining a hypotensive state. The studies demonstrated prolonged survival of rats subjected to hemorrhagic injury (HI) when treated with DCA. In separate experiments, using a fluid resuscitation model we studied mitochondrial functional alterations and changes in metabolic networks connected to mitochondria following HI and treatment with DCA. DCA treatment restored cardiac mitochondrial membrane potential and tissue ATP in the rats following HI. Treatment with DCA resulted in normalization of several metabolic and molecular parameters including plasma lactate and p-AMPK/AMPK, as well as Ach-mediated vascular relaxation. In conclusion we demonstrate that DCA can be successfully used in the treatment of hemorrhagic shock in the absence of fluid resuscitation; therefore DCA may be a good candidate in prolonged field care following severe blood loss. PMID- 28572640 TI - Density-controlled quantum Hall ferromagnetic transition in a two-dimensional hole system. AB - Quantum Hall ferromagnetic transitions are typically achieved by increasing the Zeeman energy through in-situ sample rotation, while transitions in systems with pseudo-spin indices can be induced by gate control. We report here a gate controlled quantum Hall ferromagnetic transition between two real spin states in a conventional two-dimensional system without any in-plane magnetic field. We show that the ratio of the Zeeman splitting to the cyclotron gap in a Ge two dimensional hole system increases with decreasing density owing to inter-carrier interactions. Below a critical density of ~2.4 * 1010 cm-2, this ratio grows greater than 1, resulting in a ferromagnetic ground state at filling factor nu = 2. At the critical density, a resistance peak due to the formation of microscopic domains of opposite spin orientations is observed. Such gate-controlled spin polarizations in the quantum Hall regime opens the door to realizing Majorana modes using two-dimensional systems in conventional, low-spin-orbit-coupling semiconductors. PMID- 28572642 TI - Continuing Medical Education Questions: June 2017. PMID- 28572643 TI - Continuing Medical Education Questions: June 2017. PMID- 28572641 TI - Application of nuclear magnetic resonance spectroscopy in food adulteration determination: the example of Sudan dye I in paprika powder. AB - Carcinogenic Sudan I has been added illegally into spices for an apparent freshness. 1H solution and solid-state (SS) nuclear magnetic resonance (NMR) spectroscopies were applied and compared for determination of Sudan I in paprika powders (PPs). For solution NMR, PPs spiked with Sudan I were extracted with acetonitrile, centrifuged, rotor-evaporated, and re-dissolved in DMSO-d6 for spectral collection. For SSNMR, Sudan I contaminated PPs were mixed with DMSO-d6 solution and used for spectral collection. Linear regression models constructed for quantitative analyses resulted in the average accuracies for unknown samples as 98% and 105%, respectively. Limits of detection for the solution NMR and SSNMR spectrometers were 6.7 and 128.6 mg kg-1, while the limits of quantification were 22.5 and 313.7 mg kg-1. The overall analysis time required by both methods was similar (35 and 32 min). Both NMR techniques are feasible for rapid and accurate determination of Sudan I adulteration in PPs. PMID- 28572644 TI - Recurrent Gastrointestinal Bleeding due to Multiple Pyogenic Granulomas in the Stomach. PMID- 28572646 TI - A Risky Relationship: The Splenic Artery and Walled-Off Pancreatic Necrosis. PMID- 28572645 TI - Editorial: Making Fecal Microbiota Transplantation Easier to Swallow: Freeze Dried Preparation for Recurrent Clostridium difficile Infections. AB - Fecal microbiota transplant (FMT) has emerged as an effective and increasingly popular therapy for recurrent Clostridium difficile infections in patients that have failed standard antimicrobial treatment. Patient access to FMT is hampered by the logistics of manufacturing, storing, and delivering the inocula. An observational study describes the development and clinical efficacy of freeze dried FMT capsules for oral administration. While awaiting the emergence of defined bacterial therapeutics for Clostridium difficile infections, this refinement of FMT is an encouraging step toward simplifying FMT treatment. Randomized controlled trials are required to further establish the efficacy and safety of lyophilized FMT. PMID- 28572647 TI - Wild Mushrooms: An Exclusive Delicacy or Last Meal. PMID- 28572648 TI - Successful and Safe Endoscopic Removal of a Dental Prosthesis from the Colon Using an Adapted Capuchon Hood. PMID- 28572649 TI - Response to Toyoda et al. PMID- 28572650 TI - A Case of Type II Enteropathy-Associated T-Cell Lymphoma in a Patient With Ulcerative Colitis. PMID- 28572652 TI - Pancreatic Carcinoma Diagnosed by Peroral Pancreatoscopy Using the SpyGlass System. PMID- 28572651 TI - Editorial: Clinical Implications of Diagnosing Irritable Bowel Syndrome: Do All Roads Need to Lead to Rome? AB - Irritable bowel syndrome (IBS) is one of the most common diagnoses made by healthcare providers. Yet the majority of patients with IBS are undiagnosed. The study by Sayuk et al. allows insight into the characteristics of different patient groups, e.g., with and without a formal diagnosis of diarrhea predominant IBS (IBS-D). We discuss the questions raised by this study regarding the importance of making a confident diagnosis, conveying it to patients and their implications for clinical practice. PMID- 28572653 TI - Continuing Medical Education: June 2017. PMID- 28572655 TI - When to Stop Testing. PMID- 28572654 TI - Editorial: Functional Dyspepsia Treatment: Trials and Tribulations of Targeted Strategies. AB - While functional dyspepsia (FD) is an exceedingly common disorder, the number of treatment options remains limited, and strategies for the individualized implementation of these therapies largely are lacking. In the current issue of American Journal of Gastroenterology, Saito and colleagues report on a secondary analysis of data from the Functional Dyspepsia Treatment Trial, specifically examining the role of two candidate genetic markers in predicting FD response to antidepressant treatments. Though the current study yielded a negative result, it nevertheless emphasizes the importance of our continued pursuit of therapeutic biomarkers in order to move beyond "one-size-fits-all" approaches to the treatment of FD and related disorders. PMID- 28572656 TI - Hepatitis B Core-Related Antigen: A Possible Indicator for the Termination of Prophylactic Nucleos(t)ide Analogue Therapy in Patients After Immunosuppressive Therapy. PMID- 28572657 TI - The Impact on Endoscopic Resource Utilization After A Targeted Intervention for Cost-Minimization of EGD and Colonoscopy. PMID- 28572658 TI - Response to Kane et al. PMID- 28572659 TI - IgG4-Related Sclerosing Mesenteritis. PMID- 28572660 TI - Continuing Medical Education: June 2017. PMID- 28572662 TI - Discovery of a polystyrene binding peptide isolated from phage display library and its application in peptide immobilization. AB - Phage peptide display is a powerful technique for discovery of various target specific ligands. However, target-unrelated peptides can often be obtained and cause ambiguous results. Peptide PB-TUP has been isolated repeatedly in our laboratory on different targets and we conducted a research on PB-TUP phage to investigate their binding properties and rate of propagation. ELISA and phage recovery assay demonstrated that PB-TUP phage had a significant superior affinity to polystyrene solid surface compared with control phage clones. In this study, some incidental bindings are excluded like blocking agents and non-specific binding of secondary antibodies. Propagation rate assays of the selected phage clones showed that the growth rate of PB-TUP phage was not superior to the control phages. Furthermore, the binding of PB-TUB to polystyrene was concentration dependent and varied with solution pH. Molecular modeling revealed that stable structures of alpha-helix and beta-turn may contribute to the binding of PB-TUP to polystyrene plate. The PB-TUP sequence was fused to the N-terminus of peptide P2 and the fusion peptide significantly increased the binding affinity to polystyrene. The fusion peptide also enhanced the cell adhesion ability of peptide P2 with human umbilical vein endothelial cell (HUVEC). The addition of the polystyrene binding peptide provided a convenient method for peptide immobilization. PMID- 28572664 TI - Mapping Refrigerant Gases in the New York City Skyline. AB - Cities are now home to more than 50% of the world's population and emit large quantities of pollutants from sources such as fossil fuel combustion and the leakage of refrigerants. We demonstrate the utility of persistent synoptic longwave hyperspectral imaging to study the ongoing leakage of refrigerant gases in New York City, compounds that either deplete the stratosphere ozone or have significant global warming potential. In contrast to current monitoring programs that are based on country-level reporting or aggregate measures of emissions, we present the identification of gaseous plumes with high spatial and temporal granularity in real-time over the skyline of Manhattan. The reported data highlights the emission of chemicals scheduled for phase-out. Our goal is to contribute to better understanding of the composition, sources, concentration, prevalence and patterns of emissions for the purposes of both research and policy. PMID- 28572663 TI - Time-order-errors and duration ranges in the Episodic Temporal Generalization task. AB - The current model of the Episodic Temporal Generalization task, where subjects have to judge whether pairs of auditory stimuli are equal in duration, predicts that results are scale-free and unaffected by the presentation order of the stimuli. To test these predictions, we conducted three experiments assessing sub- and supra-second standards and taking presentation order into account. Proportions were spaced linearly in Experiments 1 and 2 and logarithmically in Experiment 3. Critically, we found effects of duration range and presentation order with both spacing schemes. Our results constitute the first report of presentation order effects in the Episodic Temporal Generalization task and demonstrate that future studies should always consider duration range, number of trials and presentation order as crucial factors modulating performance. PMID- 28572665 TI - Microscopic description of insulator-metal transition in high-pressure oxygen. AB - Unusual metallic states involving breakdown of the standard Fermi-liquid picture of long-lived quasiparticles in well-defined band states emerge at low temperatures near correlation-driven Mott transitions. Prominent examples are ill understood metallic states in d- and f-band compounds near Mott-like transitions. Finding of superconductivity in solid O2 on the border of an insulator-metal transition at high pressures close to 96 GPa is thus truly remarkable. Neither the insulator-metal transition nor superconductivity are understood satisfactorily. Here, we undertake a first step in this direction by focussing on the pressure-driven insulator-metal transition using a combination of first principles density-functional and many-body calculations. We report a striking result: the finding of an orbital-selective Mott transition in a pure p-band elemental system. We apply our theory to understand extant structural and transport data across the transition, and make a specific two-fluid prediction that is open to future test. Based thereupon, we propose a novel scenario where soft multiband modes built from microscopically coexisting itinerant and localized electronic states are natural candidates for the pairing glue in pressurized O2. PMID- 28572666 TI - Strategies for reducing the fertilizer application rate in the ridge and furrow rainfall harvesting system in semiarid regions. AB - The ridge and furrow rainwater harvesting (RFRH) system is a promising water saving planting technique for dryland farming, but we lack a full understanding of the effects of different fertilizer rates (N:P) on plant nutrient uptake and nutrient use efficiency (NuUE) in foxtail millet using this planting method, as well as the available nutrient residues in the soil. We conducted field studies (Loess Plateau, China) comparing RFRH planting (R) and traditional flat planting (T) at four different fertilizer rates to determine suitable fertilizer application rates for R during 2013-2015. Compared with T, R improved the soil moisture and the utilization of rainwater and fertilizer, thereby enhancing the grain yield, water use efficiency (WUE), grain nutrient uptake, and NUE in a dry year, but with no improvements in a rainy year. The grain yield and WUE exhibited parabolic increasing trends as the fertilizer application rate increased over three years, but no significant increase was found when the fertilizer rate exceeded 189:96 kg N:P ha-1 under R, which significantly reduced the NuUE and might waste nutrients. Therefore, we recommend R combined with 189:96 kg N:P ha-1 as a promising planting strategy for foxtail millet in semiarid areas. PMID- 28572667 TI - Erratum: Genomic variants in mouse model induced by azoxymethane and dextran sodium sulfate improperly mimic human colorectal cancer. AB - A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 28572668 TI - Cathelicidin-trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stability. AB - Cathelicidins are regarded as promising antibiotics due to their capability against antibiotic-resistant bacteria without cytotoxicity. However, some concerns about the balance of cytotoxicity and antimicrobial activity, weak stability and enzymatic susceptibility sually restrict their therapeutic use. Here, we designed a series of shortened variants, Hc1~15, based on our previously characterized Hc-CATH. Hc3, the one with the best activity, after point mutation was engineered with a trypsin inhibitor loop, ORB-C, to obtain four hybrid peptides: H3TI, TIH3, H3TIF and TIH3F. All four except TIH3 were found possessing an appreciable profile of proteases inhibitory and antimicrobial characteristics without increase in cytotoxicity. Among them, TIH3F exhibited the most potent and broad-spectrum antimicrobial and anti-inflammatory activities. Fluorescence spectroscopy has demonstrated a quick induction of bacterial membrane permeability by TIH3F leading to the cell death, which also accounts for its fast anti-biofilm activity. Such mode of antimicrobial action was mainly attributed to peptides' amphiphilic and helical structures determined by CD and homology modeling. Besides, TIH3F exhibited good tolerance to salt, serum, pH, and temperature, indicating a much better physiological stability in vitro than Hc3, Most importantly, in the case of resistance against proteases hydrolysis, current hybrid peptides displayed a remarkable enhancement than their original templates. PMID- 28572669 TI - Smooth anti-reflective three-dimensional textures for liquid phase crystallized silicon thin-film solar cells on glass. AB - Recently, liquid phase crystallization of thin silicon films has emerged as a candidate for thin-film photovoltaics. On 10 MUm thin absorbers, wafer-equivalent morphologies and open-circuit voltages were reached, leading to 13.2% record efficiency. However, short-circuit current densities are still limited, mainly due to optical losses at the glass-silicon interface. While nano-structures at this interface have been shown to efficiently reduce reflection, up to now these textures caused a deterioration of electronic silicon material quality. Therefore, optical gains were mitigated due to recombination losses. Here, the SMooth Anti-Reflective Three-dimensional (SMART) texture is introduced to overcome this trade-off. By smoothing nanoimprinted SiO x nano-pillar arrays with spin-coated TiO x layers, light in-coupling into laser-crystallized silicon solar cells is significantly improved as successfully demonstrated in three-dimensional simulations and in experiment. At the same time, electronic silicon material quality is equivalent to that of planar references, allowing to reach V oc values above 630 mV. Furthermore, the short-circuit current density could be increased from 21.0 mA cm-2 for planar reference cells to 24.5 mA cm-2 on SMART textures, a relative increase of 18%. External quantum efficiency measurements yield an increase for wavelengths up to 700 nm compared to a state-of-the-art solar cell with 11.9% efficiency, corresponding to a j sc, EQE gain of 2.8 mA cm-2. PMID- 28572670 TI - Functional analysis of the role of hydrogen sulfide in the regulation of dark induced leaf senescence in Arabidopsis. AB - There is growing evidence that hydrogen sulfide (H2S) is involved in many physiological processes in plants, but the role of H2S in dark-induced leaf senescence remains unknown. In this work, we found that H2S not only inhibited chlorophyll degradation but also caused the accumulation of photoreactive pheide a in detached leaves under extended darkness. Despite this, transcript levels of senescence-associated genes (SAGs) were less affected in H2S-treated detached leaves compared with those in H2S-untreated detached leaves. Furthermore, cell death/rapid bleaching occurred in both H2S-treated detached and attached leaves after transfer from extended darkness to light. Unlike the lack of effect of H2S on SAG transcripts in darkened detached leaves, exogenous H2S induced higher SAG transcript levels in attached leaves than untreated attached leaves. Genetic evidence further underlined the positive correlation between SAG expression in attached leaves and H2S. In addition, effects of H2S on SAG expression in attached leaves were compromised in the S-nitrosoglutathione reductase-deficient mutant, gsnor1. Taken together, our results suggest that H2S suppresses chlorophyll degradation of detached leaves by regulating a dark-dependent reaction, and that this gas positively modulates SAG expression in attached leaves under prolonged darkness in a GSNOR1-dependent manner. PMID- 28572672 TI - Control of light absorbance using plasmonic grating based perfect absorber at visible and near-infrared wavelengths. AB - Conventional metamaterial absorbers have multilayer designs, where the dielectric interlayer is sandwiched between a top patterned metallic structure and bottom metallic film. Here, we demonstrate that a highly polarization-sensitive perfect absorber canbe realized by replacing the bottom metallic film with a plasmonic grating. Designs for broadband and narrowband of wavelength are proposed and numerically investigated. The designed absorbers perform high light absorption, which is above 90% over the wavelength range of 0.4-1.4 um for the broadband absorber and 98% for the absorption peak in case of the narrowband design, with a specific polarization of incident light. We find that the absorption is tunable by changing the polarization. Such absorbers offer new approach for active control of light absorbance with strong impacts for solar energy harvesting, light emitting and sensing. PMID- 28572671 TI - Interaction studies of carbon nanomaterials and plasma activated carbon nanomaterials solution with telomere binding protein. AB - Most cancer cells have telomerase activity because they can express the human telomerase reverse transcriptase (hTERT) gene. Therefore, the inhibition of the hTERT expression can play an important role in controlling cancer cell proliferation. Our current study aims to inhibit hTERT expression. For this, we synthesized graphene oxide (GO) and a functionalized multiwall carbon nanotube (f MWCNT), latter treated them with cold atmospheric pressure plasma for further analysis of the hTERT expression. The inhibition of hTERT expression by GO, f MWCNT, plasma activated GO solution (PGOS), and plasma activated f-MWCNT solution (PCNTS), was studied using two lung cancer cell lines, A549 and H460. The hTERT experimental results revealed that GO and PGOS sufficiently decreased the hTERT concentration, while f-MWCNT and PCNTS were unable to inhibit the hTERT concentration. Therefore, to understand the inhibition mechanism of hTERT, we studied the binding properties of GO and PGOS with telomere binding protein (AtTRB2). The interaction studies were carried out using circular dichroism, fluorescence, 1H-15N NMR spectroscopy, and size-exclusion chromatography (SEC) binding assay. We also used docking simulation to have an better understanding of the interactions between GO nanosheets and AtTRB2 protein. Our results may provide new insights that can benefit in biomedical treatments. PMID- 28572673 TI - Simple, rapid and efficient transformation of genotype Nisqually-1: a basic tool for the first sequenced model tree. AB - Genotype Nisqually-1 is the first model woody plant with an available well annotated genome. Nevertheless, a simple and rapid transformation of Nisqually-1 remains to be established. Here, we developed a novel shoot regeneration method for Nisqually-1 using leaf petiole and stem segment explants. Numerous shoots formed in the incision of explants within two weeks. The optimized shoot regeneration medium (SRM) contained 0.03 mg l-1 6-benzylaminopurine, 0.02 mg l-1 indole-3-butyric acid and 0.0008 mg l-1 thidiazuron. Based on this, Agrobacterium mediated genetic transformation of stem explants was examined using the vector pBI121 that contains the beta-glucuronidase (GUS) as a reporter gene. Consequently, factors affecting transformation frequency of GUS-positive shoots were optimized as follows: Agrobacteria cell suspension with an OD600 of 0.4, 20 min infection time, 2 days of co-cultivation duration and the addition of 80 uM acetosyringone into Agrobacteria infective suspension and co-cultivation SRM. Using this optimized method, transgenic plantlets of Nisqually-1 - with an average transformation frequency of 26.7% - were obtained with 2 months. Southern blot and GUS activity staining confirmed the integration of the foreign GUS gene into Nisqually-1. This novel transformation system for Nisqually-1 was rapid, efficient, and simple to operate and will improve more genetic applications in this model tree. PMID- 28572674 TI - Cytokine profiling in the sub-silicone oil fluid after vitrectomy surgeries for refractory retinal diseases. AB - Silicone oil (SO) is an intraocular surgical adjuvant that reduces the surgical complications in refractory retinal diseases, although membrane and cellular proliferation is often seen even in SO-filled eyes. We hypothesised that the fluid in the space between the SO and the retina, named the "sub-silicone oil fluid (SOF)", enhances these biological responses. We proposed a safe method for SOF extraction. We also analysed inflammatory cytokine expressions and SOF osmotic pressures from eyes with rhegmatogenous retinal detachment (RRD), proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR) and macular hole-associated retinal detachment (MHRD). Interleukin (IL)-10, IL 12p40, IL-6, monocyte chemotactic protein-1, and vascular endothelial growth factor (VEGF) in the SOF with PVR were significantly higher than in those with RRD or MHRD. Fibroblast growth factor-2, IL-10, IL-12p40, IL-8, VEGF, and transforming growth factor beta 1 levels in eyes with exacerbated PDR indicated a significantly higher expression than those with simple PDR. IL-6 and tumour necrosis factor alpha in eyes with exacerbated PVR demonstrated a significantly higher expression than in those with simple PVR. However, there was no difference in SOF osmotic pressure between group of each disease. These studies indicate that disease-specific SOF is a significant reflection of disease status. PMID- 28572675 TI - Predictive assessment in pharmacogenetics of Glutathione S-transferases genes on efficacy of platinum-based chemotherapy in non-small cell lung cancer patients. AB - The influences of glutathione s-transferase P1, M1, and T1 variants on the efficacy of platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients were inconsistent in previous studies. Our meta-analysis enrolled 31 publications including 5712 patients and provided more convincing and reliable conclusions. Results showed that GSTP1 IIe105Val IIe/Val and Val/Val Asian patients were more likely to have better response rates compared to IIe/IIe patients (odds ratio (OR) = 1.592, 95% confidence intervals (CIs), 1.087-2.332, P = 0.017). The Asian patients bearing the favorable GSTM1 null genotype were more likely to have better response rates to platinum-based chemotherapy compared to those patients with the unfavorable GSTM1 present genotype (OR = 1.493 (1.192 1.870), P < 0.001). Caucasian lung cancer patients bearing GSTT1 null genotype might be more closely associated with shorter survival time and higher risks of death than the GSTT1 present patients (hazard ratio (HR) = 1.423, CI = 1.084 1.869, P = 0.011). Our meta-analysis suggested that the GSTP1 IIe105Val, GSTM1 and GSTT1 null variants might be predictive factors for the efficacy of platinum based chemotherapy to NSCLC patients. The use of GSTP1 IIe105Val, GSTM1 and GSTT1 null polymorphisms as predictive factors of efficacy of personalized platinum based chemotherapy to NSCLC patients requires further verification with multi center, multi-ethnic and large-sample-size pharmacogenetic studies. PMID- 28572676 TI - Fiber-utilizing capacity varies in Prevotella- versus Bacteroides-dominated gut microbiota. AB - The gut microbiota of individuals are dominated by different fiber-utilizing bacteria, which ferment dietary fiber into short chain fatty acids (SCFAs) known to be important for human health. Here, we show that the dominance of Prevotella versus Bacteroides in fecal innocula, identified into two different enterotypes, differentially impacts in vitro fermentation profiles of SCFAs from fibers with different chemical structures. In a microbiome of the Prevotella enterotype, fructooligosaccharides, and sorghum and corn arabinoxylans significantly promoted one single Prevotella OTU with equally high production of total SCFAs with propionate as the major product. Conversely, in the Bacteroides-dominated microbiota, the three fibers enriched different OTUs leading to different levels and ratios of SCFAs. This is the first report showing how individual differences in two enterotypes cause distinctly different responses to dietary fiber. Microbiota dominated by different fiber-utilizing bacteria may impact host health by way of producing different amounts and profiles of SCFAs from the same carbohydrate substrates. PMID- 28572678 TI - Room-Temperature Superplasticity in an Ultrafine-Grained Magnesium Alloy. AB - Superplasticity, a phenomenon of high tensile elongation in polycrystalline materials, is highly effective in fabrication of complex parts by metal forming without any machining. Superplasticity typically occurs only at elevated homologous temperatures, where thermally-activated deformation mechanisms dominate. Here, we report the first observation of room-temperature superplasticity in a magnesium alloy, which challenges the commonly-held view of the poor room-temperature plasticity of magnesium alloys. An ultrafine-grained magnesium-lithium (Mg-8 wt.%Li) alloy produced by severe plastic deformation demonstrated 440% elongation at room temperature (0.35 T m) with a strain-rate sensitivity of 0.37. These unique properties were associated with enhanced grain boundary sliding, which was approximately 60% of the total elongation. This enhancement originates from fast grain-boundary diffusion caused by the Li segregation along the grain boundaries and the formation of Li-rich interphases. This discovery introduces a new approach for controlling the room-temperature superplasticity by engineering grain-boundary composition and diffusion, which is of importance in metal forming technology without heating. PMID- 28572677 TI - Intraspecific differences in molecular stress responses and coral pathobiome contribute to mortality under bacterial challenge in Acropora millepora. AB - Disease causes significant coral mortality worldwide; however, factors responsible for intraspecific variation in disease resistance remain unclear. We exposed fragments of eight Acropora millepora colonies (genotypes) to putatively pathogenic bacteria (Vibrio spp.). Genotypes varied from zero to >90% mortality, with bacterial challenge increasing average mortality rates 4-6 fold and shifting the microbiome in favor of stress-associated taxa. Constitutive immunity and subsequent immune and transcriptomic responses to the challenge were more prominent in high-mortality individuals, whereas low-mortality corals remained largely unaffected and maintained expression signatures of a healthier condition (i.e., did not launch a large stress response). Our results suggest that lesions appeared due to changes in the coral pathobiome (multiple bacterial species associated with disease) and general health deterioration after the biotic disturbance, rather than the direct activity of any specific pathogen. If diseases in nature arise because of weaknesses in holobiont physiology, instead of the virulence of any single etiological agent, environmental stressors compromising coral condition might play a larger role in disease outbreaks than is currently thought. To facilitate the diagnosis of compromised individuals, we developed and independently cross-validated a biomarker assay to predict mortality based on genes whose expression in asymptomatic individuals coincides with mortality rates. PMID- 28572679 TI - Ultra-large non-volatile modulation of magnetic moments in PbZr0.2Ti0.8O3/MgO/La0.7Sr0.3MnO3 heterostructure at room temperature via interfacial polarization mediation. AB - Multiferroic hybrid structures PbZr0.2Ti0.8O3 (PZT)/La0.7Sr0.3MnO3 (LSMO) and PZT/MgO/LSMO were epitaxially deposited on (001) Nb:SrTiO3 crystals. Crystallinity and ferroelectric domain structures were investigated for the PZT/LSMO heterostructure. Interestingly, relatively high non-volatile magnetoelectric coupling effects were observed in both heterostructures at room temperature. The change of chemical valence for Mn and Ti at the PZT/MgO/LSMO interface may play a dominant role rather than external strain or orbital reconstruction, which lead to a large modulation of the magnetization. Correspondingly, the transport behavior of the PZT/MgO/LSMO heterostructure is investigated to confirm the role of oxygen vacancies motion. Our result indicates that the PZT/MgO/LSMO heterostructure have a promising application for future high-density non-volatile memories. PMID- 28572680 TI - Using remote sensing environmental data to forecast malaria incidence at a rural district hospital in Western Kenya. AB - Malaria surveillance data provide opportunity to develop forecasting models. Seasonal variability in environmental factors correlate with malaria transmission, thus the identification of transmission patterns is useful in developing prediction models. However, with changing seasonal transmission patterns, either due to interventions or shifting weather seasons, traditional modelling approaches may not yield adequate predictive skill. Two statistical models,a general additive model (GAM) and GAMBOOST model with boosted regression were contrasted by assessing their predictive accuracy in forecasting malaria admissions at lead times of one to three months. Monthly admission data for children under five years with confirmed malaria at the Siaya district hospital in Western Kenya for the period 2003 to 2013 were used together with satellite derived data on rainfall, average temperature and evapotranspiration(ET). There was a total of 8,476 confirmed malaria admissions. The peak of malaria season changed and malaria admissions reduced overtime. The GAMBOOST model at 1-month lead time had the highest predictive skill during both the training and test periods and thus can be utilized in a malaria early warning system. PMID- 28572681 TI - Stopping power beyond the adiabatic approximation. AB - Energetic ions traveling in solids deposit energy in a variety of ways, being nuclear and electronic stopping the two avenues in which dissipation is usually treated. This separation between electrons and ions relies on the adiabatic approximation in which ions interact via forces derived from the instantaneous electronic ground state. In a more detailed view, in which non-adiabatic effects are explicitly considered, electronic excitations alter the atomic bonding, which translates into changes in the interatomic forces. In this work, we use time dependent density functional theory and forces derived from the equations of Ehrenfest dynamics that depend instantaneously on the time-dependent electronic density. With them we analyze how the inter-ionic forces are affected by electronic excitations in a model of a Ni projectile interacting with a Ni target, a metallic system with strong electronic stopping and shallow core level states. We find that the electronic excitations induce substantial modifications to the inter-ionic forces, which translate into nuclear stopping power well above the adiabatic prediction. In particular, we observe that most of the alteration of the adiabatic potential in early times comes from the ionization of the core levels of the target ions, not readily screened by the valence electrons. PMID- 28572682 TI - Seismic anisotropy evidence for dehydration embrittlement triggering intermediate depth earthquakes. AB - It has been proposed that dehydration embrittlement of hydrous materials can trigger intermediate-depth earthquakes and form a double seismic zone in a subducting slab. Seismic anisotropy may provide a possible insight into intermediate-depth intraslab seismicity, because anisotropic properties of minerals change with varying water distribution, temperature and pressure. Here we present a high-resolution model of P-wave radial anisotropy tomography of the Japan subduction zone down to ~400 km depth, which is obtained using a large number of arrival-time data of local earthquakes and teleseismic events. Our results reveal a close correlation between the pattern of intermediate-depth seismicity and anisotropic structures. The seismicity occurs in portions of the Pacific and Philippine Sea slabs where positive radial anisotropy (i.e., horizontal velocity being faster than vertical one) dominates due to dehydration, whereas the inferred anhydrous parts of the slabs are found to be aseismic where negative radial anisotropy (i.e., vertical velocity being faster than horizontal one) dominates. Our anisotropic results suggest that intermediate-depth earthquakes in Japan could be triggered by dehydration embrittlement of hydrous minerals in the subducting slabs. PMID- 28572683 TI - Cell-free DNA from human plasma and serum differs in content of telomeric sequences and its ability to promote immune response. AB - Circulating cell-free DNA (cfDNA) may be involved in immune response regulation. We studied the variations in abundance of telomeric sequences in plasma and serum in young healthy volunteers and the ability of cfDNA contained in these samples to co-activate the TNF-alpha m RNA expression in monocytes. We performed qPCR to determine relative telomere length (T/S ratios) in plasma, serum and whole blood of 36 volunteers. Using paired samples of plasma and serum and DNase treatment, we analysed the contribution of cfDNA to the co-activation of TNF-alpha mRNA expression in THP1 monocytic cell line. We found significant differences between paired plasma and serum samples in relative T/S ratios (median 1.38 +/- 1.1 vs. 0.86 +/- 0.25, respectively) and in total amounts of cfDNA and in estimated total amounts of telomeres which were significantly higher in serum than in plasma. TNF alpha mRNA expression in THP1 cells increased significantly after DNase treatment of all samples used for stimulation. The highest TNF-alpha mRNA expressions were observed after stimulation with DNase treated serum samples. Our results suggest that the different content of telomeric sequences in plasma and serum may contribute to the tuning of immune response. Further studies of this interesting phenomenon are needed. PMID- 28572685 TI - VEGF-A Stimulates STAT3 Activity via Nitrosylation of Myocardin to Regulate the Expression of Vascular Smooth Muscle Cell Differentiation Markers. AB - Vascular endothelial growth factor A (VEGF-A) is a pivotal player in angiogenesis. It is capable of influencing such cellular processes as tubulogenesis and vascular smooth muscle cell (VSMC) proliferation, yet very little is known about the actual signaling events that mediate VEGF-A induced VSMC phenotypic switch. In this report, we describe the identification of an intricate VEGF-A-induced signaling cascade that involves VEGFR2, STAT3, and Myocardin. We demonstrate that VEGF-A promotes VSMC proliferation via VEGFR2/STAT3-mediated upregulating the proliferation of markers like Cyclin D1 and PCNA. Specifically, VEGF-A leads to nitrosylation of Myocardin, weakens its effect on promoting the expression of contractile markers and is unable to inhibit the activation of STAT3. These observations reinforce the importance of nitric oxide and S-nitrosylation in angiogenesis and provide a mechanistic pathway for VEGF-A-induced VSMC phenotypic switch. In addition, Myocardin, GSNOR and GSNO can create a negative feedback loop to regulate the VSMC phenotypic switch. Thus, the discovery of this interactive network of signaling pathways provides novel and unexpected therapeutic targets for angiogenesis-dependent diseases. PMID- 28572684 TI - phiBO1E, a newly discovered lytic bacteriophage targeting carbapenemase-producing Klebsiella pneumoniae of the pandemic Clonal Group 258 clade II lineage. AB - The pandemic dissemination of KPC carbapenemase-producing Klebsiella pneumoniae (KPC-KP) represents a major public health problem, given their extensive multidrug resistance profiles and primary role in causing healthcare-associated infections. This phenomenon has largely been contributed by strains of Clonal Group (CG) 258, mostly of clade II, which in some areas represent the majority of KPC-KP isolates. Here we have characterized a newly discovered lytic Podoviridae, named phiBO1E, targeting KPC-KP strains of clade II lineage of CG258. Genomic sequencing revealed that phiBO1E belongs to the Kp34virus genus (87% nucleotide identity to vB_KpnP_SU552A). PhiBO1E was stable over a broad pH and temperature range, exhibited strict specificity for K. pneumoniae strains of clade II of CG258, and was unable to establish lysogeny. In a Galleria mellonella infection model, phiBO1E was able to protect larvae from death following infection with KPC KP strains of clade II of CG258, including one colistin resistant strain characterized by a hypermucoviscous phenotype. To our best knowledge phiBO1E is the first characterized lytic phage targeting K. pneumoniae strains of this pandemic clonal lineage. As such, it could be of potential interest to develop new agents for treatment of KPC-KP infections and for decolonization of subjects chronically colonized by these resistant superbugs. PMID- 28572687 TI - Defining risk variables causing gas embolism in loggerhead sea turtles (Caretta caretta) caught in trawls and gillnets. AB - Incidental capture, or 'bycatch' in fishing gear is a major global threat to sea turtle populations. A recent study showed that underwater entrapment in fishing gear followed by rapid decompression may cause gas bubble formation within the blood stream (embolism) and tissues leading to organ injury, impairment, and even mortality in some bycaught individuals. We analyzed data from 128 capture events using logistic and ordinal regression to examine risk factors associated with gas embolism in sea turtles captured in trawls and gillnets. Likelihood of fatal decompression increases with increasing depth of gear deployment. A direct relationship was found between depth, risk and severity of embolism, which has not been previously demonstrated in any breath-hold diving species. For the trawl fishery in this study, an average trawl depth of 65 m was estimated to result in 50% mortality in by-caught turtles throughout the year. This finding is critical for a more accurate estimation of sea turtle mortality rates resulting from different fisheries and for devising efforts to avoid or minimize the harmful effects of capture. PMID- 28572686 TI - Use of Patterned Collagen Coated Slides to Study Normal and Scleroderma Lung Fibroblast Migration. AB - Systemic sclerosis (SSc) is a spreading fibrotic disease affecting the skin and internal organs. We aimed to model pathogenic fibroblast migration in SSc in order to identify enhancing factors, measure the effect of migrating cells on underlying extracellular matrix (ECM) and test possible therapeutic inhibitors. Novel patterned collagen substrates were used to investigate alignment and migration of skin and lung fibroblasts from SSc patients and healthy controls. Normal lung but not skin fibroblasts consistently elongated and aligned with underlying collagen and migrated dependent on PDGF or serum. SSc lung fibroblasts remained growth factor dependent, did not migrate more rapidly and were less restricted to alignment of the collagen. Multiple collagen proline and lysine modifying enzymes were identified in SSc but not control fibroblast extracellular matrix preparations, indicating differential levels of ECM modification by the diseased cells. Profiling of migrating cells revealed a possible SCF/c-Kit paracrine mechanism contributing to migration via a subpopulation of cells. Heparin, which binds ligands including PDGF and SCF, and imatininib which blocks downstream tyrosine kinase receptors, both inhibited lung fibroblast migration individually but showed synergy in SSc cells. Pathologic lung fibroblasts from SSc patients modify ECM during migration but remain growth factor dependent and sensitive to inhibitors. PMID- 28572688 TI - Isolated Congenital Anosmia and CNGA2 Mutation. AB - Isolated congenital anosmia (ICA) is a rare condition that is associated with life-long inability to smell. Here we report a genetic characterization of a large Iranian family segregating ICA. Whole exome sequencing in five affected family members and five healthy members revealed a stop gain mutation in CNGA2 (OMIM 300338) (chrX:150,911,102; CNGA2. c.577C > T; p.Arg193*). The mutation segregates in an X-linked pattern, as all the affected family members are hemizygotes, whereas healthy family members are either heterozygote or homozygote for the reference allele. cnga2 knockout mice are congenitally anosmic and have abnormal olfactory system physiology, additionally Karstensen et al. recently reported two anosmic brothers sharing a CNGA2 truncating variant. Our study in concert with these findings provides strong support for role of CNGA2 gene with pathogenicity of ICA in humans. Together, these results indicate that mutations in key olfactory signaling pathway genes are responsible for human disease. PMID- 28572689 TI - A field deployable method for a rapid screening analysis of inorganic arsenic in seaweed. AB - Inorganic arsenic (iAs) in 13 store-bought edible seaweed samples and 34 dried kelp (Laminaria digitata) samples was determined by a newly developed, field deployable method (FDM) with the aid of a field test kit for arsenic in water. Results from the FDM were compared to results from speciation analysis achieved by using high performance liquid chromatography coupled to inductively coupled plasma mass spectrometry (HPLC-ICP-MS). The FDM consisted of a simple extraction method using diluted HNO3 to quantitatively extract iAs without decomposing the organoarsenicals to iAs followed by the selective volatilisation of iAs as arsine (AsH3) and subsequent chemo-trapping on a filter paper soaked in mercury bromide (HgBr2) solution. Method optimization with a sub-set of samples showed 80-94% iAs recovery with the FDM with no matrix effect from organo-arsenic species in the form of dimethylarsinic acid (DMA) on the iAs concentration. The method displayed good reproducibility with an average error of +/-19% and validation by HPLC-ICP MS showed that the results from the FDM were comparable (slope = 1.03, R2 = 0.70) to those from speciation analysis with no bias. The FDM can be conducted within an hour and the observed limit of quantification was around 0.05 mg kg-1 (dry weight). This method is well suited for on-site monitoring of iAs in seaweed before it is harvested and can thus be recommended for use as a screening method for iAs in seaweed. Graphical abstractScreening seaweed for their inorganic arsenic concentration within one hour without bias has been made possible in the field by using a field deployable arsenic kit. Its accuracy and precision was compared to HPLC-ICPMS. PMID- 28572691 TI - Multiple extreme environmental conditions of intermittent soda pans in the Carpathian Basin (Central Europe). AB - Soda lakes and pans represent saline ecosystems with unique chemical composition, occurring on all continents. The purpose of this study was to identify and characterise the main environmental gradients and trophic state that prevail in the soda pans (n=84) of the Carpathian Basin in Central Europe. Underwater light conditions, dissolved organic matter, phosphorus and chlorophyll a were investigated in 84 pans during 2009-2010. Besides, water temperature was measured hourly with an automatic sensor throughout one year in a selected pan. The pans were very shallow (median depth: 15 cm), and their extremely high turbidity (Secchi depth median: 3 cm, min: 0.5 cm) was caused by high concentrations of inorganic suspended solids (median: 0.4 g L-1, max: 16 g L-1), which was the dominant (>50%) contributing factor to the vertical attenuation coefficient in 67 pans (80%). All pans were polyhumic (median DOC: 47 mg L-1), and total phosphorus concentration was also extremely high (median: 2 mg L-1, max: 32 mg L-1). The daily water temperature maximum (44 degrees C) and fluctuation maximum (28 degrees C) were extremely high during summertime. The combination of environmental boundaries: shallowness, daily water temperature fluctuation, intermittent hydroperiod, high turbidity, polyhumic organic carbon concentration, high alkalinity and hypertrophy represent a unique extreme aquatic ecosystem. PMID- 28572692 TI - Joint coverage probability in a simulation study on Continuous-Time Markov Chain parameter estimation. AB - Parameter dependency within data sets in simulation studies is common, especially in models such as Continuous-Time Markov Chains (CTMC). Additionally, the literature lacks a comprehensive examination of estimation performance for the likelihood-based general multi-state CTMC. Among studies attempting to assess the estimation, none have accounted for dependency among parameter estimates. The purpose of this research is twofold: 1) to develop a multivariate approach for assessing accuracy and precision for simulation studies 2) to add to the literature a comprehensive examination of the estimation of a general 3-state CTMC model. Simulation studies are conducted to analyze longitudinal data with a trinomial outcome using a CTMC with and without covariates. Measures of performance including bias, component-wise coverage probabilities, and joint coverage probabilities are calculated. An application is presented using Alzheimer's disease caregiver stress levels. Comparisons of joint and component wise parameter estimates yield conflicting inferential results in simulations from models with and without covariates. In conclusion, caution should be taken when conducting simulation studies aiming to assess performance and choice of inference should properly reflect the purpose of the simulation. PMID- 28572690 TI - Simplification, Innateness, and the Absorption of Meaning from Context: How Novelty Arises from Gradual Network Evolution. AB - How does new genetic information arise? Traditional thinking holds that mutation happens by accident and then spreads in the population by either natural selection or random genetic drift. There have been at least two fundamental conceptual problems with imagining an alternative. First, it seemed that the only alternative is a mutation that responds "smartly" to the immediate environment; but in complex multicellulars, it is hard to imagine how this could be implemented. Second, if there were mechanisms of mutation that "knew" what genetic changes would be favored in a given environment, this would have only begged the question of how they acquired that particular knowledge to begin with. This paper offers an alternative that avoids these problems. It holds that mutational mechanisms act on information that is in the genome, based on considerations of simplicity, parsimony, elegance, etc. (which are different than fitness considerations). This simplification process, under the performance pressure exerted by selection, not only leads to the improvement of adaptations but also creates elements that have the capacity to serve in new contexts they were not originally selected for. Novelty, then, arises at the system level from emergent interactions between such elements. Thus, mechanistically driven mutation neither requires Lamarckian transmission nor closes the door on novelty, because the changes it implements interact with one another globally in surprising and beneficial ways. Finally, I argue, for example, that genes used together are fused together; that simplification leads to complexity; and that evolution and learning are conceptually linked. PMID- 28572693 TI - Fundamental limits of image registration performance: Effects of image noise and resolution in CT-guided interventions. AB - PURPOSE: In image-guided procedures, image acquisition is often performed primarily for the task of geometrically registering information from another image dataset, rather than detection / visualization of a particular feature. While the ability to detect a particular feature in an image has been studied extensively with respect to image quality characteristics (noise, resolution) and is an ongoing, active area of research, comparatively little has been accomplished to relate such image quality characteristics to registration performance. METHODS: To establish such a framework, we derived Cramer-Rao lower bounds (CRLB) for registration accuracy, revealing the underlying dependencies on image variance and gradient strength. The CRLB was analyzed as a function of image quality factors (in particular, dose) for various similarity metrics and compared to registration accuracy using CT images of an anthropomorphic head phantom at various simulated dose levels. Performance was evaluated in terms of root mean square error (RMSE) of the registration parameters. RESULTS: Analysis of the CRLB shows two primary dependencies: 1) noise variance (related to dose); and 2) sum of squared image gradients (related to spatial resolution and image content). Comparison of the measured RMSE to the CRLB showed that the best registration method, RMSE achieved the CRLB to within an efficiency factor of 0.21, and optimal estimators followed the predicted inverse proportionality between registration performance and radiation dose. CONCLUSIONS: Analysis of the CRLB for image registration is an important step toward understanding and evaluating an intraoperative imaging system with respect to a registration task. While the CRLB is optimistic in absolute performance, it reveals a basis for relating the performance of registration estimators as a function of noise content and may be used to guide acquisition parameter selection (e.g., dose) for purposes of intraoperative registration. PMID- 28572694 TI - C-arm Positioning Using Virtual Fluoroscopy for Image-Guided Surgery. AB - INTRODUCTION: Fluoroscopically guided procedures often involve repeated acquisitions for C-arm positioning at the cost of radiation exposure and time in the operating room. A virtual fluoroscopy system is reported with the potential of reducing dose and time spent in C-arm positioning, utilizing three key advances: robust 3D-2D registration to a preoperative CT; real-time forward projection on GPU; and a motorized mobile C-arm with encoder feedback on C-arm orientation. METHOD: Geometric calibration of the C-arm was performed offline in two rotational directions (orbit alpha, orbit beta). Patient registration was performed using image-based 3D-2D registration with an initially acquired radiograph of the patient. This approach for patient registration eliminated the requirement for external tracking devices inside the operating room, allowing virtual fluoroscopy using commonly available systems in fluoroscopically guided procedures within standard surgical workflow. Geometric accuracy was evaluated in terms of projection distance error (PDE) in anatomical fiducials. A pilot study was conducted to evaluate the utility of virtual fluoroscopy to aid C-arm positioning in image guided surgery, assessing potential improvements in time, dose, and agreement between the virtual and desired view. RESULTS: The overall geometric accuracy of DRRs in comparison to the actual radiographs at various C arm positions was PDE (mean +/- std) = 1.6 +/- 1.1 mm. The conventional approach required on average 8.0 +/- 4.5 radiographs spent "fluoro hunting" to obtain the desired view. Positioning accuracy improved from 2.6 degrees +/- 2.3 degrees (in alpha) and 4.1 degrees +/- 5.1 degrees (in beta) in the conventional approach to 1.5 degrees +/- 1.3 degrees and 1.8 degrees +/- 1.7 degrees , respectively, with the virtual fluoroscopy approach. CONCLUSION: Virtual fluoroscopy could improve accuracy of C-arm positioning and save time and radiation dose in the operating room. Such a system could be valuable to training of fluoroscopy technicians as well as intraoperative use in fluoroscopically guided procedures. PMID- 28572695 TI - Image Enhancement and Quality Measures for Dietary Assessment Using Mobile Devices. AB - Measuring accurate dietary intake is considered to be an open research problem in the nutrition and health fields. We are developing a system, known as the mobile device food record (mdFR), to automatically identify and quantify foods and beverages consumed based on analyzing meal images captured with a mobile device. The mdFR makes use of a fiducial marker and other contextual information to calibrate the imaging system so that accurate amounts of food can be estimated from the scene. Food identification is a difficult problem since foods can dramatically vary in appearance. Such variations may arise not only from non rigid deformations and intra-class variability in shape, texture, color and other visual properties, but also from changes in illumination and viewpoint. To address the color consistency problem, this paper describes illumination quality assessment methods implemented on a mobile device and three post color correction methods. PMID- 28572697 TI - Mobile Image Based Color Correction Using Deblurring. AB - Dietary intake, the process of determining what someone eats during the course of a day, provides valuable insights for mounting intervention programs for prevention of many chronic diseases such as obesity and cancer. The goals of the Technology Assisted Dietary Assessment (TADA) System, developed at Purdue University, is to automatically identify and quantify foods and beverages consumed by utilizing food images acquired with a mobile device. Color correction serves as a critical step to ensure accurate food identification and volume estimation. We make use of a specifically designed color checkerboard (i.e. a fiducial marker) to calibrate the imaging system so that the variations of food appearance under different lighting conditions can be determined. In this paper, we propose an image quality enhancement technique by combining image de-blurring and color correction. The contribution consists of introducing an automatic camera shake removal method using a saliency map and improving the polynomial color correction model using the LMS color space. PMID- 28572696 TI - A Mobile Phone User Interface for Image-Based Dietary Assessment. AB - Many chronic diseases, including obesity and cancer, are related to diet. Such diseases may be prevented and/or successfully treated by accurately monitoring and assessing food and beverage intakes. Existing dietary assessment methods such as the 24-hour dietary recall and the food frequency questionnaire, are burdensome and not generally accurate. In this paper, we present a user interface for a mobile telephone food record that relies on taking images, using the built in camera, as the primary method of recording. We describe the design and implementation of this user interface while stressing the solutions we devised to meet the requirements imposed by the image analysis process, yet keeping the user interface easy to use. PMID- 28572698 TI - Phosphorylation of Histone H2A.X in Peripheral Blood Mononuclear Cells May Be a Useful Marker for Monitoring Cardiometabolic Risk in Nondiabetic Individuals. AB - Phosphorylation of H2A.X (serine 139) in the histone H2A family located in the downstream of the DNA damage kinase signaling cascade is an important indicator of DNA damage. Recently, phosphorylation of H2A.X was proposed as a sensitive biomarker of aging. This study investigated if phosphorylation of H2A.X in peripheral blood mononuclear cells (PBMCs) is associated with cardiometabolic risk in nondiabetic individuals. Basic parameters and oxidative stress/inflammatory markers were measured in nondiabetic healthy Koreans (n = 119). Phosphorylation of H2A.X was measured randomly among the study subjects using a flow cytometer. According to the number of metabolic syndrome risk factor (MetS-RF), the study subjects were subdivided into "super healthy" (MetS - RF = 0, n = 71) and "MetS-risk" (MetS - RF >= 1, n = 48) groups. Phosphorylation of H2A.X in PBMCs (percentages and mean fluorescence intensity) was significantly higher in the MetS-risk group than in the super healthy group after adjusting for age, sex, cigarette smoking, and alcohol consumption. Phosphorylated H2A.X was positively correlated with the number of MetS-RF as well as waist circumference, blood pressures, triglyceride, HbA1C, oxidized LDL, high sensitivity C-reactive protein, tumor necrosis factor-alpha, and alanine aminotransferase after the adjustment. The present study suggested that phosphorylated H2A.X in circulating PBMCs measured by flow cytometer may be a useful marker for monitoring cardiometabolic risk in nondiabetic individuals. PMID- 28572699 TI - Associations between Interleukin-31 Gene Polymorphisms and Dilated Cardiomyopathy in a Chinese Population. AB - To explore the role of Interkeulin-31 (IL-31) in dilated cardiomyopathy (DCM), in our study, two SNPs of IL-31, rs4758680 (C/A) and rs7977932 (C/G), were analyzed in 331 DCM patients and 493 controls in a Chinese Han population. The frequencies of C allele and CC genotype of rs4758680 were significantly increased in DCM patients (P = 0.005, P = 0.001, resp.). Compared to CC genotype of rs4758680, the A carriers (CA/AA genotypes) were the protect factors in DCM susceptibility while the frequencies of CA/AA genotypes were decreased in the dominant model for DCM group (P < 0.001, OR = 0.56, 95%CI = 0.39-0.79). Moreover, IL-31 mRNA expression level of white blood cells was increased in DCM patients (0.072 (0.044-0.144) versus 0.036 (0.020-0.052), P < 0.001). In survival analysis of 159 DCM patients, Kaplan-Meier curve revealed the correlation between CC homozygote of rs4758680 and worse prognosis for DCM group (P = 0.005). Compared to CC genotype, the CA/AA genotypes were the independent factors in both univariate (HR = 0.530, 95%CI = 0.337-0.834, P = 0.006) and multivariate analyses after age, gender, left ventricular end-diastolic diameter, and left ventricular ejection fraction adjusted (HR = 0.548, 95%CI = 0.345-0.869, P = 0.011). Thus, we concluded that IL 31 gene polymorphisms were tightly associated with DCM susceptibility and contributed to worse prognosis in DCM patients. PMID- 28572700 TI - Peritumoral EpCAM Is an Independent Prognostic Marker after Curative Resection of HBV-Related Hepatocellular Carcinoma. AB - Accumulating evidence suggests that the tumor microenvironment has a profound influence on tumor initiation and progression, opening a new avenue for studying tumor biology. Nonetheless, the prognostic values of the peritumoral expression of EpCAM and CD13 remain to be elucidated in hepatocellular carcinoma (HCC) patients. In this study, the expression of EpCAM and CD13 was assessed by immunohistochemistry in peritumoral liver hepatocytes from 106 hepatitis B virus- (HBV-) related HCC patients who had undergone curative hepatectomy. The peritumoral EpCAM-positive group had a significantly worse overall survival (OS) (p = 0.003) and recurrence-free survival (RFS) (p = 0.022) compared to the negative group. Peritumoral CD13-positive patients were also associated with poor OS (p = 0.038), while not significantly associated with RFS. The adjusted multivariate COX proportional hazard regression analysis suggested that only the positive expression of peritumoral EpCAM precisely predicted poor OS. Being peritumoral EpCAM positive was also significantly associated with a larger tumor size, liver cirrhosis, and more frequent vascular invasion; however, no statistically significant association was observed between CD13 and any clinicopathological features. Taken together, peritumoral EpCAM and CD13 expression was associated with a poor prognosis, but EpCAM may be a better prognostic marker than CD13 in HBV-related HCC patients. In the future, peritumoral EpCAM could be a good target for adjuvant therapy after curative hepatectomy. PMID- 28572702 TI - Changing the Dimensionality of Cesium Lead Bromide Nanocrystals by Reversible Postsynthesis Transformations with Amines. PMID- 28572703 TI - Efficient and Stable Luminescence from Mn2+ in Core and Core-Isocrystalline Shell CsPbCl3 Perovskite Nanocrystals. AB - There has been a growing interest in applying CsPbX3 (X = Cl, Br, I) nanocrystals (NCs) for optoelectronic application. However, research on doping of this new class of promising NCs with optically active and/or magnetic transition metal ions is still limited. Here we report a facile room temperature method for Mn2+ doping into CsPbCl3 NCs. By addition of a small amount of concentrated HCl acid to a clear solution containing Mn2+, Cs+, and Pb2+ precursors, Mn2+-doped CsPbCl3 NCs with strong orange luminescence of Mn2+ at ~600 nm are obtained. Mn2+-doped CsPbCl3 NCs show the characteristic cubic phase structure very similar to the undoped counterpart, indicating that the nucleation and growth mechanism are not significantly modified for the doping concentrations realized (0.1 at. % - 2.1 at. %). To enhance the Mn2+ emission intensity and to improve the stability of the doped NCs, isocrystalline shell growth was applied. Growth of an undoped CsPbCl3 shell greatly enhanced the emission intensity of Mn2+ and resulted in lengthening the radiative lifetime of the Mn2+ emission to 1.4 ms. The core-shell NCs also show superior thermal stability and no thermal degradation up to at least 110 degrees C, which is important in applications. PMID- 28572701 TI - Protease-Sensitive Nanomaterials for Cancer Therapeutics and Imaging. AB - Many diseases can be characterized by the abnormal activity exhibited by various biomolecules, the targeting of which can provide therapeutic and diagnostic utility. Recent trends in medicine and nanotechnology have prompted the development of protease-sensitive nanomaterials systems for therapeutic, diagnostic, and theranostic applications. These systems can act specifically in response to the target enzyme and its associated disease conditions, thus enabling personalized treatment and improved prognosis. In this Review, we discuss recent advancements in the development of protease-responsive materials for imaging and drug delivery and analyze several representative systems to illustrate their key design principles. PMID- 28572704 TI - Multiporous Supramolecular Microspheres for Artificial Photosynthesis. AB - Artificial photosynthesis shows a promising potential for sustainable supply of nutritional ingredients. While most studies focus on the assembly of the light sensitive chromophores to 1-D architectures in an artificial photosynthesis system, other supramolecular morphologies, especially bioinspired ones, which may have more efficient light-harvesting properties, have been far less studied. Here, MCpP-FF, a bioinspired building block fabricated by conjugating porphyrin and diphenylalanine, was designed to self-assemble into nanofibers-based multiporous microspheres. The highly organized aromatic moieties result in extensive excitation red-shifts and notable electron transfer, thus leading to a remarkable attenuated fluorescence decay and broad-spectrum light sensitivity of the microspheres. Moreover, the enhanced photoelectron production and transfer capability of the microspheres are demonstrated, making them ideal candidates for sunlight-sensitive antennas in artificial photosynthesis. These properties induce a high turnover frequency of NADH, which can be used to produce bioproducts in biocatalytic reactions. In addition, the direct electron transfer makes external mediators unnecessary, and the insolubility of the microspheres in water allows their easy retrieval for sustainable applications. Our findings demonstrate an alternative to design new platforms for artificial photosynthesis, as well as a new type of bioinspired, supramolecular multiporous materials. PMID- 28572705 TI - Monodisperse Iron Oxide Nanoparticles by Thermal Decomposition: Elucidating Particle Formation by Second-Resolved in Situ Small-Angle X-ray Scattering. AB - The synthesis of iron oxide nanoparticles (NPs) by thermal decomposition of iron precursors using oleic acid as surfactant has evolved to a state-of-the-art method to produce monodisperse, spherical NPs. The principles behind such monodisperse syntheses are well-known: the key is a separation between burst nucleation and growth phase, whereas the size of the population is set by the precursor-to-surfactant ratio. Here we follow the thermal decomposition of iron pentacarbonyl in the presence of oleic acid via in situ X-ray scattering. This method allows reaction kinetics and precursor states to be followed with high time resolution and statistical significance. Our investigation demonstrates that the final particle size is directly related to a phase of inorganic cluster formation that takes place between precursor decomposition and particle nucleation. The size and concentration of clusters were shown to be dependent on precursor-to-surfactant ratio and heating rate, which in turn led to differences in the onset of nucleation and concentration of nuclei after the burst nucleation phase. This first direct observation of prenucleation formation of inorganic and micellar structures in iron oxide nanoparticle synthesis by thermal decomposition likely has implications for synthesis of other NPs by similar routes. PMID- 28572706 TI - Electroactive Nanoporous Metal Oxides and Chalcogenides by Chemical Design. AB - The archetypal silica- and aluminosilicate-based zeolite-type materials are renowned for wide-ranging applications in heterogeneous catalysis, gas-separation and ion-exchange. Their compositional space can be expanded to include nanoporous metal chalcogenides, exemplified by germanium and tin sulfides and selenides. By comparison with the properties of bulk metal dichalcogenides and their 2D derivatives, these open-framework analogues may be viewed as three-dimensional semiconductors filled with nanometer voids. Applications exist in a range of molecule size and shape discriminating devices. However, what is the electronic structure of nanoporous metal chalcogenides? Herein, materials modeling is used to describe the properties of a homologous series of nanoporous metal chalcogenides denoted np-MX2, where M = Si, Ge, Sn, Pb, and X = O, S, Se, Te, with Sodalite, LTA and aluminum chromium phosphate-1 structure types. Depending on the choice of metal and anion their properties can be tuned from insulators to semiconductors to metals with additional modification achieved through doping, solid solutions, and inclusion (with fullerene, quantum dots, and hole transport materials). These systems form the basis of a new branch of semiconductor nanochemistry in three dimensions. PMID- 28572707 TI - Thermostable phycocyanin from the red microalga Cyanidioschyzon merolae, a new natural blue food colorant. AB - The demand for natural food colorants is growing as consumers question the use of artificial colorants more and more. The phycobiliprotein C-phycocyanin of Arthospira platensis is used as a natural blue colorant in certain food products. The thermoacidophilic red microalga Cyanidioschyzon merolae might provide an alternative source of phycocyanin. Cyanidioschyzon merolae belongs to the order Cyanidiophyceae of the phylum Rhodophyta. Its natural habitat are sulfuric hot springs and geysers found near volcanic areas in, e.g., Yellowstone National Park in the USA and in Java, Indonesia. It grows optimally at a pH between 0.5 and 3.0 and at temperatures up to 56 degrees C. The low pH at which C. merolae grows minimizes the risk of microbial contamination and could limit production loss. As C. merolae lacks a cell wall, phycocyanin with a high purity number of 9.9 could be extracted by an osmotic shock using a simple ultrapure water extraction followed by centrifugation. The denaturation midpoint at pH 5 was 83 degrees C, being considerably higher than the A. platensis phycocyanin (65 degrees C). The C. merolae phycocyanin was relatively stable at pH 4 and 5 up to 80 degrees C. The high thermostability at slightly acidic pH makes the C. merolae phycocyanin an interesting alternative to A. platensis phycocyanin as a natural blue food colorant. PMID- 28572709 TI - Determination of the toxicity of the freshwater cyanobacterium Woronichinia naegeliana (Unger) Elenkin. AB - Cyanobacterial blooms are undesirable for ecological and health reasons. While Woronichinia naegeliana is a cyanobacterial species that appears frequently in freshwater, information about it is limited. An evaluation of its toxicity was conducted via tests based on the crustaceans Thamnocephalus platyurus and Daphnia pulex. The greatest effect of the aqueous extract obtained from W. naegeliana cells was observed for T. platyurus. The denoted semi-lethal concentration (LC50) after 24 h of exposure was 0.99 mg of dry weight (d.w.) mL-1. A lower toxicity was displayed for D. pulex, although it grew with time. Among the 18 fractions separated from cyanobacterial extract, only one containing the microginin FR3 (MG FR3) displayed biological activeness against T. platyurus. The remaining products synthesized by W. naegeliana displayed an absence or a low level of toxicity making it impossible to determine the LC50 value. Detailed research revealed that MG-FR3 did not affect the activity of enzymes such as trypsin, chymotrypsin, elastase and thrombin, which indicates another mode of action. The results demonstrated that blooms of W. naegeliana showed toxic activity towards invertebrate zooplankton. PMID- 28572710 TI - Novel rapid method for the characterisation of polymeric sugars from macroalgae. AB - Laminarins are storage polysaccharides found only in brown seaweeds, specifically Laminarialaes and Fucales. Laminarin has been shown to have anti-apoptotic and anti-tumoural activities and is considered as a nutraceutical component that can positively influence human health. The structure is species dependent, generally composed of linear beta(1-3) glucans with intrachain beta(1-6) branching and varies according to harvest season and environmental factors. Current methods for analysis of molar mass and DP length are technically demanding and are not widely available. Here, we present a simple inexpensive method which enables rapid analysis of laminarins from macroalgal biomass using high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) without the need for hydrolysis or further processing. This is based on the linear relationship observed between log10 DP and retention time following separation of laminarins on a CarboPac PA-100 column (Dionex) using standard 1,3-beta-d-gluco oligosaccharides ranging in DP from 2 to 8. This method was applied to analyse laminarin oligomers in extracts from different species harvested from within the intertidal zone on Welsh rocky shores containing laminarin polymers with different ranges of DP. The degree of polymerisation and extrapolated molar mass agreed well with values estimated by LC-ESI/MS n analysis and those reported in the literature. PMID- 28572708 TI - Bioremediation efficacy-comparison of nutrient removal from an anaerobic digest waste-based medium by an algal consortium before and after cryopreservation. AB - An algal consortium was isolated from an integrated steelmaking site at TATA Steel Strip Products Ltd. in Port Talbot, UK, and its bioremediation capacity tested. Excellent "bioremediation" was observed when the mixed culture was "applied" to diluted effluent from an enhanced anaerobic digestion plant at Dwr Cymru Welsh Water at Port Talbot, UK. After 5 days of cultivation in a 600-L photobioreactor, 99% of the total nitrogen (initial level, 4500 MUmol L-1) and total phosphorus (initial level, 690.4 MUmol L-1) were removed from the waste stream. The consortium was deposited in the Culture Collection of Algae and Protozoa (CCAP), an international depository authority for microalgal patents, as CCAP 293/1. This material has been successfully cryopreserved using a two-step cryopreservation protocol with dimethyl sulphoxide (5% v/v) used as a cryoprotectant. On recovery of samples after 3 months storage at -196 degrees C, the specific bioremediation activity of the revived consortium was tested. The capacity of the revived culture to bioremediate effluent was not significantly different (p < 0.05) from a non-cryopreserved control, with 99% of total nitrogen and phosphorus remediated by day 4. Although non-axenic algal cultures have previously been cryopreserved, this is the first report of the successful cryopreservation of mixed algal consortium, with validation of its ability to bioremediate after thawing comparing non-cryopreserved cultures with a revived post-thaw algal consortium. The study also highlights the need to ensure the long term security and the requirement to validate the functionality of conserved inocula with biotechnological/bioremediation potential. PMID- 28572712 TI - Methylprednisolone Administration Following Spinal Cord Injury Reduces Aquaporin 4 Expression and Exacerbates Edema. AB - Spinal cord injury (SCI) is an incapacitating condition that affects motor, sensory, and autonomic functions. Since 1990, the only treatment administered in the acute phase of SCI has been methylprednisolone (MP), a synthetic corticosteroid that has anti-inflammatory effects; however, its efficacy remains controversial. Although MP has been thought to help in the resolution of edema, there are no scientific grounds to support this assertion. Aquaporin 4 (AQP4), the most abundant component of water channels in the CNS, participates in the formation and elimination of edema, but it is not clear whether the modulation of AQP4 expression by MP plays any role in the physiopathology of SCI. We studied the functional expression of AQP4 modulated by MP following SCI in an experimental model in rats along with the associated changes in the permeability of the blood-spinal cord barrier. We analyzed these effects in male and female rats and found that SCI increased AQP4 expression in the spinal cord white matter and that MP diminished such increase to baseline levels. Moreover, MP increased the extravasation of plasma components after SCI and enhanced tissue swelling and edema. Our results lend scientific support to the increasing motion to avoid MP treatment after SCI. PMID- 28572714 TI - Computational Aberration Correction for Human Retinal Imaging. PMID- 28572711 TI - Buprenorphine Alters Inflammatory and Oxidative Stress Molecular Markers in Arthritis. AB - Buprenorphine is recommended for use as an analgesic in animal models including in murine models of collagen-induced arthritis (CIA). However, the effect of buprenorphine on the expression of disease-associated biomarkers is not well defined. We examined the effect of buprenorphine administration on disease progression and the expression of inflammatory and oxidative stress markers, in a murine model of CIA. Buprenorphine administration altered the expression of cytokines, IFN-gamma, IL-6, and MMP-3, and oxidative markers, for example, iNOS, superoxide dismutase (SOD1), and catalase (CAT), in the CIA mice. As buprenorphine is an analgesic, we further monitored the association of expression of these biomarkers with pain scores in a human cohort of early rheumatoid arthritis (RA). Serum MMP-3 levels and blood mRNA expression of antioxidants sod1 and cat correlated with pain scores in the RA cohort. We have demonstrated that administration of buprenorphine alters the expression of inflammatory and oxidative stress-related molecular markers in a murine model of CIA. This caveat needs to be considered in animal experiments using buprenorphine as an analgesic, as it can be a confounding factor in murine studies used for prediction of response to therapy. Furthermore, the antioxidant enzymes that showed an association with pain scores in the human cohort may be explored as biomarkers for pain in future studies. PMID- 28572713 TI - Specific Gene- and MicroRNA-Expression Pattern Contributes to the Epithelial to Mesenchymal Transition in a Rat Model of Experimental Colitis. AB - The aim of this study was to determine the gene- and microRNA-expression profile contributing to epithelial to mesenchymal transition in a rat model of experimental colitis. For this, inflammation was induced by injecting 2,4,6 trinitrobenzene sulphonic acid to the colon of male Wistar rats. Samples were taken from both inflamed and uninflamed regions of the same colon, total RNA was isolated, and the mRNA and microRNA expressions were monitored. We have determined that the expression of genes responsible for inducing mesenchymal phenotype, such as Egr1, Fgf2, Fgf7, Jak2, Notch2, Hif1alpha, Zeb2, Mmp9, Lox, and Vim, was all significantly induced in the inflamed regions of the affected colons while the epithelial marker E-cadherin (Cdh1) was downregulated. In contrast, the expression of microRNAs miR-192, miR-143, miR-375, miR-30a, miR 107, and miR-200b responsible for the regulation of the above mentioned genes was significantly downregulated in inflamed colon. Importantly, we detected moderate induction in the expression of five out of six tested microRNAs in the uninflamed regions. In summary, we identified numerous interacting genes and microRNAs with mutually exclusive expression pattern in inflamed regions of colitis-induced rats. These findings suggest that-among others-an important step in the epithelial to mesenchymal transition in experimental colitis is the dysregulated microRNA expression. PMID- 28572715 TI - Emotion Regulation Among Preschoolers on a Continuum of Risk: The Role of Maternal Emotion Coaching. AB - Parental emotion coaching involves acknowledging and validating children's feelings, as well as guiding them on how to manage intense or negative feelings. Although parental emotion coaching has been identified as a potentially important factor for children's emotional development, research into this topic is scant. The present study examined whether maternal emotion coaching can play a mediational role between family risk (i.e. economic disadvantage, family stress, and maltreatment) and emotion regulation in preschoolers. Seventy-four preschoolers, aged 46-58 months, and their maternal caregivers participated in an observational laboratory study, including a narrative task in which mothers and children reminisced about a mildly upsetting event. We coded these conversations for maternal emotion coaching behaviors with the Family Emotional Communication Scoring System. A family risk score was obtained via the Family Events Checklist and demographic data. We measured children's emotion regulation with the Emotion Regulation Checklist. Increased family risk was associated with both reduced child emotion regulation and reduced maternal emotion coaching. Maternal emotion coaching partially mediated the relation between family risk and child emotion regulation, in particular child emotional lability. The findings support further research into the possibilities of training mothers in high risk families in emotion coaching skills in order to foster their children's emotional development. PMID- 28572716 TI - On the Link between Perceived Parental Rearing Behaviors and Self-conscious Emotions in Adolescents. AB - This study examined relationships between the self-conscious emotions of guilt and shame in both clinical (N = 104) and non-clinical (N = 477) (young) adolescents aged 11-18 years, who completed a questionnaire to assess perceived parental rearing behaviors (EMBU-C) and a scenario-based instrument to measure proneness to guilt and shame (SCEMAS). Results indicated that parental rearing dimensions were positively related to self-conscious emotions. Regarding the non clinical sample, both favourable (emotional warmth) and unfavourable (rejection) paternal and maternal rearing dimensions were significant correlates of guilt- and shame-proneness. The results for the clinical sample were less conclusive: only maternal emotional warmth and rejection were found to be significantly associated with guilt and shame. Interestingly, no associations between any of the paternal rearing dimensions and self-conscious emotions emerged. Taken together, these results are in keeping with the notion that parental rearing factors are involved in the development of both adaptive and maladaptive self conscious emotions in adolescents. PMID- 28572717 TI - Parental Attributions of Control for Child Behaviour and Their Relation to Discipline Practices in Parents of Children with and Without Developmental Delays. AB - Children with developmental delays (DD) are at risk for developing behavior problems. Research suggests that parents' causal attributions for child behavior are related to parenting. This study investigated this association in parents of children with DD compared to parents of typically developing (TD) children. It specifically focused on attributions of child control by separating these from attributions of responsibility, blame and intent, and from attributions of parent control and responsibility. Fifty-one parents of children with DD and 69 parents of TD children completed two questionnaires. The Written Analogue Questionnaire measured causal attributions. The Parenting Scale measured dysfunctional discipline practices. Parents of children with DD viewed the child's role in problematic behavior more positively while also viewing misbehavior as more fixed than parents of TD children. Parents of TD children who viewed their child as more in control over misbehavior used less dysfunctional discipline, but this association was not found for parents of children with DD. The results advance understanding of how parents perceive behavior problems in children with DD and the important role these perceptions play in parental behavior management strategies. More importantly, these perceptions relate to discipline practices differently for parents of children with DD compared to parents of TD children, highlighting that parent interventions should be adapted to the specific needs of parents of children with DD. PMID- 28572718 TI - Longitudinal Associations Between Parental Bonding, Parenting Stress, and Executive Functioning in Toddlerhood. AB - Early executive functioning is an important predictor for future development of children's cognitive skills and behavioral outcomes. Parenting behavior has proven to be a key environmental determinant of child executive functioning. However, the association of parental affect and cognitions directed to the child with child executive functioning has been understudied. Therefore, in the present study we examine the associations between parental bonding (i.e., the affective tie from parent to child), parenting stress, and child executive functioning. At 26 weeks of pregnancy, and at 6 months and 24 months postpartum the quality of the maternal (N = 335) and paternal (N = 261) bond with the infant was assessed. At 24 months, postnatal parenting stress and child executive functioning were measured by means of parent-report questionnaires. Results indicated that for both mothers and fathers feelings of bonding negatively predicted experienced parenting stress over time. In addition, for both parents a negative indirect effect of bonding on child executive functioning problems was found via experienced parenting stress. These findings indicate the importance of monitoring parents who experience a low level and quality of early parent-child bonding, as this makes them vulnerable to parenting stress, consequently putting their children at risk for developing executive functioning problems. PMID- 28572719 TI - Multi-GPU Acceleration of Branchless Distance Driven Projection and Backprojection for Clinical Helical CT. AB - Model-based image reconstruction (MBIR) techniques have the potential to generate high quality images from noisy measurements and a small number of projections which can reduce the x-ray dose in patients. These MBIR techniques rely on projection and backprojection to refine an image estimate. One of the widely used projectors for these modern MBIR based technique is called branchless distance driven (DD) projection and backprojection. While this method produces superior quality images, the computational cost of iterative updates keeps it from being ubiquitous in clinical applications. In this paper, we provide several new parallelization ideas for concurrent execution of the DD projectors in multi-GPU systems using CUDA programming tools. We have introduced some novel schemes for dividing the projection data and image voxels over multiple GPUs to avoid runtime overhead and inter-device synchronization issues. We have also reduced the complexity of overlap calculation of the algorithm by eliminating the common projection plane and directly projecting the detector boundaries onto image voxel boundaries. To reduce the time required for calculating the overlap between the detector edges and image voxel boundaries, we have proposed a pre-accumulation technique to accumulate image intensities in perpendicular 2D image slabs (from a 3D image) before projection and after backprojection to ensure our DD kernels run faster in parallel GPU threads. For the implementation of our iterative MBIR technique we use a parallel multi-GPU version of the alternating minimization (AM) algorithm with penalized likelihood update. The time performance using our proposed reconstruction method with Siemens Sensation 16 patient scan data shows an average of 24 times speedup using a single TITAN X GPU and 74 times speedup using 3 TITAN X GPUs in parallel for combined projection and backprojection. PMID- 28572720 TI - An in silico high-throughput screen identifies potential selective inhibitors for the non-receptor tyrosine kinase Pyk2. AB - The non-receptor tyrosine kinase proline-rich tyrosine kinase 2 (Pyk2) is a critical mediator of signaling from cell surface growth factor and adhesion receptors to cell migration, proliferation, and survival. Emerging evidence indicates that signaling by Pyk2 regulates hematopoietic cell response, bone density, neuronal degeneration, angiogenesis, and cancer. These physiological and pathological roles of Pyk2 warrant it as a valuable therapeutic target for invasive cancers, osteoporosis, Alzheimer's disease, and inflammatory cellular response. Despite its potential as a therapeutic target, no potent and selective inhibitor of Pyk2 is available at present. As a first step toward discovering specific potential inhibitors of Pyk2, we used an in silico high-throughput screening approach. A virtual library of six million lead-like compounds was docked against four different high-resolution Pyk2 kinase domain crystal structures and further selected for predicted potency and ligand efficiency. Ligand selectivity for Pyk2 over focal adhesion kinase (FAK) was evaluated by comparative docking of ligands and measurement of binding free energy so as to obtain 40 potential candidates. Finally, the structural flexibility of a subset of the docking complexes was evaluated by molecular dynamics simulation, followed by intermolecular interaction analysis. These compounds may be considered as promising leads for further development of highly selective Pyk2 inhibitors. PMID- 28572721 TI - Outcome of stroke patients receiving different doses of recombinant tissue plasminogen activator. AB - BACKGROUND AND PURPOSE: Intravenous recombinant tissue plasminogen activator (tPA) at a dose of 0.9 mg/kg body weight is associated with a high hemorrhagic transformation (HT) rate. Low-dose tPA (0.6 mg/kg) may have a lower hemorrhage rate but the mortality and disability rates at 90 days cannot be confirmed as non inferior to standard-dose tPA. Whether the doses 0.7 and 0.8 mg/kg have better efficacy and safety needs further investigation. Therefore, this study is to compare the efficacy and safety of each dose of tPA (0.6, 0.7, 0.8, and 0.9 mg/kg body weight) and to investigate the factors affecting early neurological improvement (ENI) and early neurological deterioration (END). METHODS: For this observational study, data were obtained from 274 patients who received tPA thrombolytic therapy in Chia-Yi Christian Hospital stroke unit. The tPA dose was given at the discretion of each physician. The definition of ENI was a >8 point improvement (compared with baseline) at 24 h following thrombolytic therapy or an improvement in the National Institutes of Health Stroke Score (NIHSS) to 0 or 1 toward the end of tPA infusion. The definition of END was a >4 point increase in NIHSS (compared with baseline) within 24 h of tPA infusion. The primary objective was to investigate whether 0.7 and 0.8 mg/kg of tPA have higher ENI rate, lower END rate, and better outcome at 6 months. Poor outcome was defined as having a modified Rankin Scale of 3 to 6 (range, 0 [no symptoms] to 6 [death]). The secondary objective was to investigate whether low-dose tPA has a lower risk of intracerebral HT than that with standard-dose tPA. We also investigated the factors affecting ENI, END, HT, and 6-month outcome. RESULTS: A total of 274 patients were included during the study period, of whom 260 were followed up for >6 months. There was a trend for the HT rate to increase as the dose increased (P=0.02). The symptomatic HT rate was not significantly different among the low dose and standard-dose groups. The ENI and END (P=0.52) were not significantly different among the four dosage groups. The clinical functional outcome at 6 months after stroke onset was poorer in the standard-dose group (P=0.02). Stroke severity (P<0.01), stroke type (P=0.03), and diabetes mellitus (P=0.04) affected the functional outcome at 6 months. CONCLUSION: Among the 274 patients receiving tPA thrombolytic therapy, the HT rate increased as dose increased. The symptomatic HT, ENI and END rates were not significantly different among the low dose (0.6, 0.7, and 0.8 mg/kg) and standard-dose groups. Stroke severity (NIHSS >12), stroke type (cardioembolism and large artery atherosclerosis) and diabetes mellitus were associated with poor outcome at 6 months. PMID- 28572722 TI - Shared decision-making for biologic treatment of autoimmune disease: influence on adherence, persistence, satisfaction, and health care costs. AB - BACKGROUND: Shared decision-making (SDM), a process whereby physicians and patients collaborate to select interventions, is not well understood for biologic treatment of autoimmune conditions. METHODS: This was a cross-sectional survey of adults initiating treatment for Crohn's disease or ulcerative colitis (inflammatory bowel disease, IBD) or psoriatic arthritis or rheumatoid arthritis (RA/PA). Survey data were linked to administrative claims for 6 months before (baseline) and after (follow-up) therapy initiation. Measures included the Shared Decision Making Questionnaire, Patient Activation Measure (PAM), Morisky Medication Adherence Scale (MMAS), general health, and treatment satisfaction. Claims-based Quan-Charlson comorbidity scores, persistence, medication possession ratio (MPR), and health care costs were examined. Patients were compared by participation (SDM) and nonparticipation (non-SDM) in SDM. RESULTS: Among 453 respondents, 357 were eligible, and 306 patients (204 RA/PA and 102 IBD) were included in all analyses. Overall (n=357), SDM participants (n=120) were more often females (75.0% vs 62.5%, P=0.018), had lower health status (48.0 vs 55.4, P=0.005), and higher Quan-Charlson scores (1.0 vs 0.7, P=0.035) than non-SDM (n=237) participants. Lower MMAS scores (SDM 0.17 vs non-SDM 0.41; P<0.05) indicated greater likelihood of adherence; SDM participants also reported higher satisfaction with medication and had greater activation (PAM: SDM vs non-SDM: 66.9 vs 61.6; P<0.001). Mean MPR did not differ, but persistence was longer among SDM participants (111.2 days vs 102.2 days for non-SDM; P=0.029). Costs did not differ by SDM status overall, or among patients with RA/PA. The patients with IBD, however, experienced lower (P=0.003) total costs ($9,404 for SDM vs $25,071 for non-SDM) during follow-up. CONCLUSION: This study showed greater likelihood of adherence and satisfaction for patients who engaged in SDM and reduced health care costs among patients with IBD who engaged in SDM. This study provides a basis for defining SDM participation and detecting differences by SDM participation for biologic treatment selection for autoimmune conditions. PMID- 28572723 TI - The impact of a pharmacist-led educational interview on medication adherence of Saudi patients with epilepsy. AB - PURPOSE: To evaluate the effectiveness of a pharmacist-led educational interview in terms of adherence to antiepileptic drug administration among adult patients with epilepsy. METHOD: Sixty adult patients with epilepsy who fulfilled the inclusion criteria were recruited. A pharmacist-led educational interview was conducted with the intervention group (n=30). Patients in the control group (n=30) were interviewed and contacted 6 weeks after the initial visit without receiving any intervention. Antiepileptic drug adherence was measured during clinic visits, and 6 weeks afterwards using the 8-item Morisky Medication Adherence Scale. This prospective interventional study was conducted between September and December 2013. RESULTS: Only 29 control patients and 27 intervention patients completed the 6 weeks post-intervention adherence measurement. The adherence score average in the intervention group was 5.26+/ 0.98 at baseline and improved to 6.7+/-0.823 (P<0.0001) after intervention. In the control group, the adherence score average was 5.76+/-1.806 at baseline and 5.83+/-1.627 at 6 weeks (P=0.792). While there was no statistically significant difference in adherence score between intervention and control groups at baseline, the post-intervention difference was significant (P=0.024). CONCLUSION: Our study suggests that pharmacist-led educational interviews had a positive impact on medication adherence in patients with epilepsy. PMID- 28572724 TI - Surface-functionalized cockle shell-based calcium carbonate aragonite polymorph as a drug nanocarrier. AB - Calcium carbonate aragonite polymorph nanoparticles derived from cockle shells were prepared using surface functionalization method followed by purification steps. Size, morphology, and surface properties of the nanoparticles were characterized using transmission electron microscopy, field emission scanning electron microscopy, dynamic light scattering, zetasizer, X-ray powder diffraction, and Fourier transform infrared spectrometry techniques. The potential of surface-functionalized calcium carbonate aragonite polymorph nanoparticle as a drug-delivery agent were assessed through in vitro drug-loading test and drug-release test. Transmission electron microscopy, field emission scanning electron microscopy, and particle size distribution analyses revealed that size, morphology, and surface characterization had been improved after surface functionalization process. Zeta potential of the nanoparticles was found to be increased, thereby demonstrating better dispersion among the nanoparticles. Purification techniques showed a further improvement in the overall distribution of nanoparticles toward more refined size ranges <100 nm, which specifically favored drug-delivery applications. The purity of the aragonite phase and their chemical analyses were verified by X-ray powder diffraction and Fourier transform infrared spectrometry studies. In vitro biological response of hFOB 1.19 osteoblast cells showed that surface functionalization could improve the cytotoxicity of cockle shell-based calcium carbonate aragonite nanocarrier. The sample was also sensitive to pH changes and demonstrated good abilities to load and sustain in vitro drug. This study thus indicates that calcium carbonate aragonite polymorph nanoparticles derived from cockle shells, a natural biomaterial, with modified surface characteristics are promising and can be applied as efficient carriers for drug delivery. PMID- 28572725 TI - Synthesis, characterization, and in vitro activity against Candida spp. of fluconazole encapsulated on cationic and conventional nanoparticles of poly(lactic-co-glycolic acid). AB - In this study, nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA) loaded with fluconazole (FLZ) and FLZ-NPs coated with the cationic polymer polyethylenimine (PEI) (FLZ-NP-PEI) were synthetized in order to improve antimycotic activity against four strains of Candida spp. of clinical relevance. FLZ-NPs and FLZ-NP-PEI were synthesized by double emulsion solvent-diffusion (DES D) and characterized. Minimum inhibitory concentration (MIC50) and minimum fungicide concentration (MFC) were determined in vitro by culturing Candida strains in the presence of these nanocompounds. FLZ-NPs were spherical in shape with hydrodynamic sizes of ~222 nm and surface charge of -11.6 mV. The surface charges of these NPs were successfully modified using PEI (FLZ-NP-PEI) with mean hydrodynamic sizes of 281 nm and surface charge of 23.5 mV. The efficiency of encapsulation (~53%) and a quick release of FLZ (>=90% after 3 h) were obtained. Cytotoxicity assay showed a good cell viability for FLZ-NPs (>=86%), and PEI modified NPs presented a decrease in cell viability (~38%). FLZ-NPs showed an increasing antifungal activity of FLZ for sensitive (Candida parapsilosis ATCC22019 and Candida albicans ATCC10231, MIC50 =0.5 and 0.1 ug/mL, respectively) and resistant strains (Candida glabrata EMLM14 and Candida krusei ATCC6258, MIC50 =0.1 and 0.5 ug/mL, respectively). FLZ-NP-PEI showed fungicidal activity even against C. glabrata and C. krusei (MFC =4 and 8 ug/mL, respectively). MIC50 values showed best results for FLZ-NPs and FLZ-NP-PEI. Nevertheless, only FLZ-NP PEI displayed fungicidal activity against the studied strains. PMID- 28572726 TI - Photoacoustic imaging of tumor targeting with riboflavin-functionalized theranostic nanocarriers. AB - Photoacoustic imaging is an emerging method in the molecular imaging field, providing high spatiotemporal resolution and sufficient imaging depths for many clinical applications. Therefore, the aim of this study was to use photoacoustic imaging as a tool to evaluate a riboflavin (RF)-based targeted nanoplatform. RF is internalized by the cells through a specific pathway, and its derivatives were recently shown as promising tumor-targeting vectors for the drug delivery systems. Here, the RF amphiphile synthesized from a PEGylated phospholipid was successfully inserted into a long-circulating liposome formulation labeled with the clinically approved photoacoustic contrast agent - indocyanine green (ICG). The obtained liposomes had a diameter of 124 nm (polydispersity index =0.17) and had a negative zeta potential of -26 mV. Studies in biological phantoms indicated a stable and concentration-dependent photoacoustic signal (Vevo(r) LAZR) of the ICG-containing RF-functionalized liposomes. In A431 cells, a high uptake of RF functionalized liposomes was found and could be blocked competitively. First, studies in mice revealed ~3 times higher photoacoustic signal in subcutaneous A431 tumor xenografts (P<0.05) after injection of RF-functionalized liposomes compared to control particles. In this context, the application of a spectral unmixing protocol confirmed the initial quantitative data and improved the localization of liposomes in the tumor. In conclusion, the synthesized RF amphiphile leads to efficient liposomal tumor targeting and can be favorably detected by photoacoustic imaging with a perspective of theranostic applications. PMID- 28572727 TI - Organic effects of associating paclitaxel with a lipid-based nanoparticle system on a nonhuman primate, Cebus apella. AB - Lipid-based nanoparticle systems have been used as vehicles for chemotherapeutic agents in experimental cancer treatments. Those systems have generally been credited with attenuating the severe toxicity of chemotherapeutic agents. This study aimed to investigate the effects of associating paclitaxel (PTX) with a lipid-based nanoparticle system on a nonhuman primate, Cebus apella, documenting the toxicity as measured by serum biochemistry, which is a detailed analysis of blood and tissue. Eighteen C. apella were studied: three animals were treated with cholesterol-rich nanoemulsion (LDE) only, without PTX, administered intravenously every 3 weeks, during six treatment cycles; six animals were treated with PTX associated with LDE at the same administration scheme, three with lower (175 mg/m2) and three with higher (250 mg/m2) PTX doses; and six animals were treated with commercial PTX, three with the lower and three with the higher doses. In the LDE-PTX group, no clinical toxicity appeared, and the weight food consumption curve was similar to that of the controls. Two animals treated with commercial PTX presented weight loss, nausea and vomiting, diarrhea, skin flaking, 70% loss of body hair, and decreased physical activity. The use of LDE as a carrier at both lower and higher doses reduced the toxicity of the drug in this species, which is closely related to human subjects. This was observed not only by clinical, biochemical, and hematological profiles but also by the histopathological analysis. The results of this study support the assumption that lipid-based nanoparticle systems used as drug carriers can serve as valuable tools to decrease the toxicity and increase the safety of chemotherapeutic agents. PMID- 28572728 TI - Analysis of the cytotoxicity of hierarchical nanoporous graphenic carbon against human glioblastoma grade IV cells. AB - A newly produced hierarchical, nanoporous carbon (HNC) material is studied for the first time in a biological model. The material consists of uniform particles and is characterized by a mean diameter <150 nm, a high specific surface area of 1,000 m2/g, well-developed porosity, and high electrical conductivity. These unique properties and ability to transfer charge create a possibility of employing HNC as a moderator of tumor cell growth. As the charge of HNC may interfere with cell membranes by adhesion and by bonding with cell receptors, it may block the supply of nutrients. The interactions of HNC with the U87 cells can also lead to the excessive generation of reactive oxygen species (ROS) and activate apoptotic mechanisms in cancer cells. The investigation was performed using U87 human glioblastoma and PCS-201-010 normal fibroblast cell lines, where cell morphology and ultrastructure, viability, ROS production, type of cell death, mitochondrial transmembrane potential, and the expression of genes engaged in apoptosis pathways are studied. The results demonstrate that cytotoxicity of HNC particles increases with concentration from 5 to 100 ug/mL by activation of apoptosis through the mitochondrial pathway, without inducing necrosis. Our research indicates the potential applicability of HNC in cancer therapy. PMID- 28572729 TI - Efficacy of radiosensitizing doped titania nanoparticles under hypoxia and preparation of an embolic microparticle. AB - The aim of this study was to develop a manufacturing protocol for large-scale production of doped titania radiosensitizing nanoparticles (NPs) to establish their activity under hypoxia and to produce a multimodal radiosensitizing embolic particle for cancer treatment. We have previously shown that radiosensitizing NPs can be synthesized from titania doped with rare earth elements, especially gadolinium. To translate this technology to the clinic, a crucial step is to find a suitable, scalable, high-throughput method. Herein, we have described the use of flame spray pyrolysis (FSP) to generate NPs from titanium and gadolinium precursors to produce titania NPs doped with 5 at% gadolinium. The NPs were fully characterized, and their capacity to act as radiosensitizers was confirmed by clonogenic assays. The integrity of the NPs in vitro was also ascertained due to the potentially adverse effects of free gadolinium in the body. The activity of the NPs was then studied under hypoxia since this is often a barrier to effective radiotherapy. In vitro radiosensitization experiments were performed with both the hypoxia mimetics deferoxamine and cobalt chloride and also under true hypoxia (oxygen concentration of 0.2%). It was shown that the radiosensitizing NPs were able to cause a significant increase in cell death even after irradiation under hypoxic conditions such as those found in tumors. Subsequently, the synthesized NPs were used to modify polystyrene embolization microparticles. The NPs were sintered to the surface of the microparticles by heating at 230 degrees C for 15 minutes. This resulted in a good coverage of the surface and to generate embolization particles that were shown to be radiosensitizing. Such multimodal particles could therefore result in occlusion of the tumor blood vessels in conjunction with localized reactive oxygen species generation, even under hypoxic conditions such as those found in the center of tumors. PMID- 28572730 TI - Characteristics, burden of illness, and physical functioning of patients with relapsing-remitting and secondary progressive multiple sclerosis: a cross sectional US survey. AB - BACKGROUND: Although most patients with relapsing-remitting multiple sclerosis (RRMS) will develop secondary progressive multiple sclerosis (SPMS), little is known about the burden of multiple sclerosis by disease subtype. This study describes the burden of disease in terms of demographics, disease severity, symptoms, health care resource and disease-modifying therapy (DMT) utilization, work and activity impairment, and physical functioning of SPMS and RRMS patients. METHODS: SPMS and RRMS patient responses from the 2012 and 2013 waves of the US National Health and Wellness Survey were evaluated to detect differences in demographics, disease severity, symptoms, and health care resource and DMT utilization. In addition, data from the Work Productivity and Activity Impairment and Short Form-36 questionnaires were analyzed. RESULTS: SPMS patients were older than RRMS patients (mean age 55.7 vs 48.9 years; P<0.001); a lower proportion were female (56.2% with SPMS vs 71.6% with RRMS; P=0.002), and fewer SPMS than RRMS patients were employed (20.0% vs 39.7%; P<0.001). SPMS patients described their disease as more severe, reporting several neurological symptoms more frequently and higher hospitalization rates than RRMS patients. A lower percentage of SPMS than RRMS patients reported DMT use. SPMS patients had greater overall work and activity impairment than RRMS patients. After controlling for baseline characteristics, impairment in physical functioning was greater in SPMS patients. CONCLUSION: Overall, SPMS patients had a higher burden of illness than RRMS patients, underscoring the need to treat RRMS patients early to delay disability progressing using therapies that are effective in real-world settings. PMID- 28572731 TI - Understanding the associations between psychosocial factors and severity of crime in juvenile delinquency: a cross-sectional study. AB - PURPOSE: Juvenile delinquency is a serious and common problem. To date, several studies have focused on possible psychosocial risk factors for delinquency among youths and on the implications of childhood mental illness on child criminality. However, the literature on prevalence of psychopathology and predictors of crime severity among delinquent youths in Turkey is sparse. Therefore, the aim of this study was to show the associations between crime severity and psychosocial factors such as gender, age, criminal history, concomitant attention deficit hyperactivity disorder (ADHD) and other comorbid psychiatric conditions, along with behavioral problem domains of Child Behavior Checklist (CBCL). PARTICIPANTS AND METHODS: This analytical cross-sectional study sample consisted of 52 individuals (30 females and 22 males) who were sent to a pilot detention facility in Istanbul, Turkey. The participants' age ranged from 8 to 18 years (M =13.4; SD =2.9). Self-rating scales were administered in an interview format, and the crime severity information was provided by participants' admission documents. RESULTS: No differences were found in terms of gender, age, children's past history of crime and substance abuse. However, family crime history was significantly higher in the high severity crime group (P=0.026). Having one or more comorbid psychiatric disorder was associated with high crime severity (P=0.018). The most common psychiatric disorders were found to be ADHD, oppositional defiant disorder, conduct disorder (CD) and anxiety disorder. CONCLUSION: Findings suggest that a family history of crime comes across as a very strong predictor of severity of crime. Among psychiatric factors, ADHD and CD were associated with commitment of more severe crimes in delinquent youths in our sample. Anxious/depressed traits as depicted by CBCL are found to be associated with less severe crimes. PMID- 28572733 TI - The Jordan Food and Drug Administration: Comparison of its Registration Process with Australia, Canada, Saudi Arabia and Singapore. AB - OBJECTIVE: This study outlines the current regulatory review process and good review practices (GRevPs) at the Jordan Food and Drug Administration (JFDA) and compares them with those of regulatory agencies in Australia, Canada, Saudi Arabia and Singapore to gauge how well the JFDA is performing. We identify opportunities for further development of the JFDA as a key global reference agency. METHODS: Personnel within the JFDA completed a questionnaire comprising four sections: organisation, key milestones, review timelines, and GRevPs. The same questionnaire was used concurrently to gather information from Australia's Therapeutic Goods Administration (TGA), Health Canada, the Saudi Food and Drug Authority (SFDA) and Singapore's Health Sciences Authority (HSA). RESULTS: The JFDA conducts an abridged review for new active substances and requires a certificate of pharmaceutical product (CPP) at the time of submission and 6 months of pharmacovigilance data at the time of the final review as well as full pharmaceutical, chemistry, manufacturing and controls (CMC) and clinical data at the time of submission. A written summary and tabulated data are required for non clinical data. The four comparator agencies conduct full assessments; the SFDA also requires a CPP, and the JFDA and SFDA both require pricing information at submission. All agencies have established target timelines, and the JFDA, SFDA, TGA and HSA currently exceed those targets. All agencies have also developed GRevPs as well as training and continuous-improvement processes. CONCLUSIONS: The JFDA has achieved significant success in its role as a regulatory agency by setting and implementing clear regulations in line with international guidance. It is recognised as a training centre in the region, with considerable achievements in the development of its activities by simplifying and improving requirements, procedures and actions. It also publishes information regarding guidance, procedures, drug application submissions and registration dates for all new chemical entities on its website. The relationship between the JFDA and the pharmaceutical sector in Jordan has resulted in balanced, practical, internationally compatible regulations and demonstrates a viable model of collaboration. To assist the JFDA in its efforts to become a key global reference agency, it is suggested that the agency explore a risk-stratification approach to the regulatory review; accept CPPs after dossier submission or use alternatives to the CPP; conduct pricing evaluations in parallel with scientific assessments; establish defined target times for review milestones and improve internal tracking systems to monitor these milestones; and make certain information transparent to all stakeholders by publishing a summary basis of approval. PMID- 28572732 TI - Totally laparoscopic aortobifemoral bypass surgery in the treatment of aortoiliac occlusive disease or abdominal aortic aneurysms - a systematic review and critical appraisal of literature. AB - PURPOSE: This systematic review aims to evaluate the published literature regarding totally laparoscopic aortobifemoral bypass (LABF) surgery in the treatment of aortoiliac occlusive disease (AIOD) or abdominal aortic aneurysms (AAA), compared with open aortobifemoral bypass surgery. MATERIALS AND METHODS: A systematic review of the medical literature between 1990 and 2016 was performed, searching the medical databases Cochrane Library, OVID Medline, Embase and PubMed. Studies concerning totally LABF with or without control group and containing more than 10 patients were included in the analysis. Operative and aortic cross-clamping times, blood loss, rate of conversion to open surgery, mortality and morbidity within the first 30 postoperative days, hospital stay and primary and secondary patency of the graft were extracted and compared with open surgery when possible. RESULTS: Sixty-six studies were deemed eligible for inclusion in this review, 16 of them matched the inclusion criteria for quantitative synthesis. The patient material consisted of 588 patients undergoing totally LABF, 22 due to AAA, and the remaining 566 for AIOD. Five comparative studies regarding AIOD compared 211 totally LABF procedures with 246 open procedures. Only one study concerning AAA was eligible for inclusion, and this study did not provide a comparison against an open group. The operating and aortic cross-clamping times were shorter in the open group. Conversion rates ranged from 0% to 27%. There was no statistically significant difference in mortality between the two groups (p=0.64). Hospital stays ranged from 4.0 to 12.1 and 5.0 to 12.8 days in the laparoscopic group and open group, respectively. Most of the studies provided low levels of evidence, mainly due to lack of blinding, randomization and correction of bias. CONCLUSION: Totally laparoscopic aortoiliac surgery seems to be a feasible technique with unaffected mortality and trend toward benefits in hospital stay and possibly also in complication rates. The literature published this far is sparse and with inconsistent results. More randomized controlled trials are required before this method can be widely implemented. PMID- 28572734 TI - FOLFOX regimen plus dendritic cells-cytokine-induced killer cells immunotherapy for the treatment of colorectal cancer: a meta-analysis. AB - PURPOSE: To systematically investigate the efficacy and safety of the combination of FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) regimen and cocultured dendritic cells and cytokine-induced killer cells (DC-CIK) immunotherapy for the treatment of colorectal cancer (CRC). METHODS: Publications reporting the clinical trials' responses or safety of FOLFOX regimen combined with DC-CIK immunotherapy in treating CRC patients were searched in PubMed, Embase, Cochrane Library, China National Knowledge Internet, and Wanfang databases. Trials meeting the selection criteria were analyzed. The overall survival (OS), overall response rate (ORR), disease control rate (DCR), tumor markers, immune function, and adverse events were evaluated. RESULTS: Ten trials including 881 CRC patients were analyzed in this meta-analysis. The combined therapy showed advantages over FOLFOX treatment-alone in 2-year OS (odds ratio [OR] =2.77, confidence interval [CI] =1.58-4.86, P=0.0004), ORR (OR =1.85, CI =1.34-2.56, P=0.0002), and DCR (OR =2.54, CI =1.76-3.67, P<0.00001), with statistical significance. After immunotherapy, lymphocyte subset percentages of CD3+ (P=0.0006) and CD4+ (P=0.01), CD4+/CD8+ ratio (P=0.0003), and levels of cytokines IFN-gamma (P=0.003) and IL-2 (P=0.01) were significantly increased, whereas analysis of CD8+, CD3 CD56+, CD3+CD56+, CD4+CD25+, IL-6, and TNF-alpha did not show any significant difference (P>0.05). Moreover, the level of carcinoembryonic antigen was also decreased significantly upon immunotherapy (P<0.00001). CONCLUSION: The combination of FOLFOX regimen and DC-CIK immunotherapy was safe and effective for CRC patients. PMID- 28572735 TI - The novel long noncoding RNA RP11-357H14.17 acts as an oncogene by promoting cell proliferation and invasion in diffuse-type gastric cancer. AB - Current evidence indicates that long noncoding RNAs (lncRNAs) play pivotal roles in human cancers. The present study aims to assess differentially expressed lncRNAs related to diffuse-type gastric carcinoma (DGC). Next-generation RNA sequencing was carried out to detect aberrantly expressed lncRNAs in DGC. Real time polymerase chain reaction (RT-PCR) was performed to evaluate RP11-357H14.17 gene expression levels in DGC cell lines/tissues comparatively with normal gastric epithelial cell lines and adjacent normal tissues. The associations of RP11-357H14.17 expression levels with the clinicopathological features were also analyzed. The regulatory effects of RP11-357H14.17 on the biological behaviors of DGC cells were evaluated by MTT, colony formation assays, flow cytometry for apoptosis, wound healing assay, and transwell migration and invasion assays. RP11 357H14.17 expression was remarkably increased in DGC tissues and cell lines compared with normal gastric epithelial cells and adjacent normal tissues. High levels of RP11-357H14.17 were associated with increased tumor size, deeper depth of invasion, lymphatic metastasis, and advanced pathological stage. Further experiments demonstrated that the DGC cells MGC-803 transfected with si-RP11 357H14.17 showed reduced cell proliferation, migration, invasion, enhanced G1 phase arrest and cell apoptosis. These findings suggest that the novel lncRNA RP11-357H14.17 is associated with poor prognosis, and may serve as a potential prognostic biomarker and target for new antineoplastic therapies in human DGC. PMID- 28572736 TI - Asthma-like airway inflammation and responses in a rat model of atopic dermatitis induced by neonatal capsaicin treatment. AB - Recent studies have shown that approximately 70% of patients with severe atopic dermatitis (AD) develop asthma. Development of AD in infancy and subsequent other atopic diseases such as asthma in childhood is referred to as atopic march. However, a causal link between the diseases of atopic march has remained largely unaddressed, possibly due to lack of a proper animal model. Recently, we developed an AD rat model showing chronically relapsing dermatitis and scratching behaviors induced by neonatal capsaicin treatment. Here, we investigated whether our model also showed asthmatic changes, with the aim of expanding our AD model into an atopic march model. First, we confirmed that capsaicin treatment (50 mg/kg within 24 h after birth) induced dermatitis and scratching behaviors until 6 weeks of age. After that, the mRNA expression of Th1 and Th2 cytokines, such as IFN-gamma and TNF-alpha, and IL-4, IL-5, and IL-13, respectively, was quantified with quantitative real-time polymerase chain reaction in the skin and the lungs. The number of total cells and eosinophils was counted in bronchoalveolar lavage (BAL) fluid. The levels of IgE in the serum and BAL fluid were determined with enzyme-linked immunosorbent assay. Paraffin-embedded sections (4 MUm) were stained with hematoxylin/eosin to analyze the morphology of the lung and the airway. Airway responsiveness was measured in terms of airway resistance and compliance using the flexiVent system. In the capsaicin-treated rats, persistent dermatitis developed, and scratching behaviors increased over several weeks. The levels of IgE in the serum and BAL fluid as well as the mRNA expression of Th2 cytokines, including IL-4, IL-5, and IL-13, in both the skin and the lungs were elevated, and the number of eosinophils in the BAL fluid was also increased in the capsaicin-treated rats compared to control rats. Morphological analysis of the airway revealed smooth muscle hypertrophy and extensive mucus plug in the capsaicin-treated rats. Functional studies demonstrated an increment of the airway resistance and a decrement of lung compliance in the capsaicin-treated rats compared to control rats. Taken together, our findings suggested that neonatal capsaicin treatment induced asthma-like airway inflammation and responses in juvenile rats. PMID- 28572737 TI - Observational study to calculate addictive risk to opioids: a validation study of a predictive algorithm to evaluate opioid use disorder. AB - BACKGROUND: Opioid abuse in chronic pain patients is a major public health issue, with rapidly increasing addiction rates and deaths from unintentional overdose more than quadrupling since 1999. PURPOSE: This study seeks to determine the predictability of aberrant behavior to opioids using a comprehensive scoring algorithm incorporating phenotypic risk factors and neuroscience-associated single-nucleotide polymorphisms (SNPs). PATIENTS AND METHODS: The Proove Opioid Risk (POR) algorithm determines the predictability of aberrant behavior to opioids using a comprehensive scoring algorithm incorporating phenotypic risk factors and neuroscience-associated SNPs. In a validation study with 258 subjects with diagnosed opioid use disorder (OUD) and 650 controls who reported using opioids, the POR successfully categorized patients at high and moderate risks of opioid misuse or abuse with 95.7% sensitivity. Regardless of changes in the prevalence of opioid misuse or abuse, the sensitivity of POR remained >95%. CONCLUSION: The POR correctly stratifies patients into low-, moderate-, and high risk categories to appropriately identify patients at need for additional guidance, monitoring, or treatment changes. PMID- 28572739 TI - Patient comfort from the technologist perspective: factors to consider in mammographic imaging. AB - A sample size of 280 certified mammography technologists were surveyed to understand what factors affect patient discomfort during breast imaging. Given mammography technologists' level of patient involvement, they are uniquely positioned to observe factors that affect patient comfort. The findings suggest that according to technologists, multiple factors, including patient ethnicity, breast density, previous biopsy and lumpectomy experience, as well as psychological factors, impact breast discomfort during mammography. Additionally, with respect to imaging protocols, technologists attributed 80% of moderate-to extreme discomfort to "length of compression time" (27%) and "compression force" (53%). Technologists also attributed "pinching at chest wall" and "hard edges of breast platform" to "very high" discomfort significantly more times (P<0.05) than "coolness and edges of paddle". These findings confirm some of what has been reported to date and challenge other findings. Given that recent decline in breast cancer mortality has been attributed to improvements in early detection and treatment, approaches to reduce discomfort should be considered in order to promote screening compliance. Although more research is needed, it is apparent that the patient experience of comfort and pain during mammography is an area warranting increased research and solutions. PMID- 28572738 TI - Sleep and somatic complaints in university students. AB - BACKGROUND: Sleep problems are common among university students. Poor sleep is associated with impaired daily functioning, increased risk of psychiatric symptoms, and somatic complaints such as pain. Previous results suggest that poor sleep exacerbates pain, which in turn negatively affects sleep. The purpose of the present study was to determine prevalence rates, comorbidity, and role of depression as a factor of moderating the relationship between sleep and physical complaints in German university students. SAMPLES AND METHODS: In total, 2443 German university students (65% women) completed a web survey. Self-report measures included the Pittsburg Sleep Quality Index, three modules of the Patient Health Questionnaire, and a questionnaire on the functional somatic syndromes (FSSs). RESULTS: More than one-third (36.9%) reported poor sleep as assessed by the Pittsburgh Sleep Quality Index. Somatoform syndrome was identified in 23.5%, and the prevalence of any FSS was 12.8%. Self-reported sleep quality, sleep onset latency, sleep disturbances, use of sleep medications, and daytime dysfunctioning were significant predictors of somatoform syndrome, whereas sleep efficiency and sleep duration influenced somatic complaints indirectly. Moderate correlations were found between stress, anxiety, somatoform syndrome, depression, and overall sleep quality. The effect of somatic complaints on sleep quality was associated with the severity of depression. Anxiety shows direct effects on somatization and depression but only indirect associations with sleep quality. PMID- 28572740 TI - An integrated epidemiological and neural net model of the warfarin effect in managed care patients. AB - INTRODUCTION: Risk assessment tools are utilized to estimate the risk for stroke and need of anticoagulation therapy for patients with atrial fibrillation (AF). These risk stratification scores are limited by the information inputted into them and a reliance on time-independent variables. The objective of this study was to develop a time-dependent neural net model to identify AF populations at high risk of poor clinical outcomes and evaluate the discriminatory ability of the model in a managed care population. METHODS: We performed a longitudinal, cohort study within a health-maintenance organization from 1997 to 2008. Participants were identified with incident AF irrespective of warfarin status and followed through their duration within the database. Three clinical outcome measures were evaluated including stroke, myocardial infarction, and hemorrhage. A neural net model was developed to identify patients at high risk of clinical events and defined to be an "enriched" patient. The model defines the enrichment based on the top 10 minimum mean square error output parameters that describe the three clinical outcomes. Cox proportional hazard models were utilized to evaluate the outcome measures. RESULTS: Among 285 patients, the mean age was 74+/-12 years with a mean follow-up of 4.3+/-2.6 years, and 154 (54%) were treated with warfarin. After propensity score adjustment, warfarin use was associated with a slightly increased risk of adverse outcomes (including stroke, myocardial infarction, and hemorrhage), though it did not attain statistical significance (adjusted hazard ratio [aHR] =1.22; 95% confidence interval [CI] 0.75-1.97; p=0.42). Within the neural net model, subjects at high risk of adverse outcomes were identified and labeled as "enriched." Following propensity score adjustment, enriched subjects were associated with an 81% higher risk of adverse outcomes as compared to nonenriched subjects (aHR=1.81; 95% CI, 1.15-2.88; p=0.01). CONCLUSION: Enrichment methodology improves the statistical discrimination of meaningful endpoints when used in a health records-based analysis. PMID- 28572741 TI - Teng-Long-Bu-Zhong-Tang induces p21-dependent cell senescence in colorectal carcinoma LS174T cells via histone acetylation. AB - Teng-Long-Bu-Zhong-Tang (TLBZT) is a Chinese herbal formula for colorectal carcinoma treatment. TLBZT effectively induces cell senescence in colorectal carcinoma, accompanied by p21 upregulation. In this study, we further explored the role of p21 in TLBZT-induced cell senescence, as well as the mechanism by which TLBZT upregulates p21. Specific knockdown of p21 expression by small interfering RNA significantly attenuated TLBZT-induced cell senescence in human colorectal carcinoma LS174T cells. Silencing of p53 by small interfering RNA did not affect TLBZT-induced p21 upregulation. Meanwhile, TLBZT inhibited histone deacetylase activity. Furthermore, TLBZT increased acetylation levels of histone H3 and H4, enhancing their binding to the p21 promoter. These data suggested that TLBZT induces cell senescence in LS174T cells through a mechanism involving p21 upregulation via histone H3 and H4 acetylation. This study provides new insights into the application of TLBZT for colorectal carcinoma treatment. PMID- 28572742 TI - Real-life effectiveness and safety of the inhalation suspension budesonide comparator vs the originator product for the treatment of patients with asthma: a historical cohort study using a US health claims database. AB - OBJECTIVE: The objective of this study was to determine whether the effectiveness of budesonide comparator is non-inferior to budesonide reference in the prevention of asthma exacerbations. Asthma-related hospitalizations and safety were also examined. METHODS: This study used a matched, historic cohort design. Data were drawn from the ClinformaticsTM Data Mart US claims database and included a 1-year baseline, starting 1 year before the index prescription date, and a 1-year outcome period. Patients received budesonide comparator or reference treatment. The primary outcome was the rate of asthma exacerbations. Non inferiority for budesonide comparator vs budesonide reference was established if the 95% confidence interval (CI) upper limit of mean difference in proportions between treatments was <15%. Secondary outcomes examined rate of asthma-related hospitalizations and adverse events (AEs). RESULTS: The budesonide comparator and reference-matched cohorts each included 3109 patients. The adjusted upper 95% CI for the difference in proportions of patients experiencing asthma exacerbations was 0.035 (3.5%), demonstrating non-inferiority. Cohorts did not significantly differ in the rate of asthma exacerbations (adjusted rate ratio [RR]=1.04, 95% CI: 0.95-1.14) or rate of asthma-related hospitalizations (adjusted RR=1.10, 95% CI: 0.99-1.24) after adjusting for baseline confounders. No asthma exacerbations occurred during the outcome period in 72.9% of budesonide comparator patients and 71.8% of budesonide reference patients. No asthma-related hospitalizations occurred in 77.9% of patients in the budesonide comparator cohort and 79.0% of patients in the budesonide reference cohort. The most frequent AEs were throat irritation (<=0.4% of patients) and hoarseness/dysphonia (0.02% of patients). AEs did not significantly differ between treatment cohorts. CONCLUSION: In this real life study, non-inferiority of the budesonide comparator vs reference was met for the primary end point of asthma exacerbation rates. Asthma-related hospitalization and AE rates did not differ between the two treatment cohorts. The budesonide comparator is an effective and safe treatment alternative for asthma exacerbations. PMID- 28572743 TI - Design and rationale of the high-sensitivity Troponin T Rules Out Acute Cardiac Insufficiency Trial. AB - BACKGROUND: Acute heart failure (AHF) is a common presentation in the Emergency Department (ED), and most patients are admitted to the hospital. Identification of patients with AHF who have a low risk of adverse events and are suitable for discharge from the ED is difficult, and an objective tool would be useful. METHODS: The highly sensitive Troponin T Rules Out Acute Cardiac Insufficiency Trial (TACIT) will enroll ED patients being treated for AHF. Patients will undergo standard ED evaluation and treatment. High-sensitivity troponin T (hsTnT) will be drawn at the time of enrollment and 3 hours after the initial draw. The initial hsTnT draw will be no more than 3 hours after initiation of therapy for AHF (vasodilator, loop diuretic, noninvasive ventilation). Treating clinicians will be blinded to hsTnT results. We will assess whether hsTnT, as a single measurement or in series, can accurately predict patients at low risk of short term adverse events. CONCLUSION: TACIT will explore the value of hsTnT measurements in isolation, or in combination with other markers of disease severity, for the identification of ED patients with AHF who are at low risk of short-term adverse events. PMID- 28572744 TI - Berberine regulates the protein expression of multiple tumorigenesis-related genes in hepatocellular carcinoma cell lines. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the seventh most common malignancy and the third leading cause of cancer-related death worldwide with an extremely grim prognosis. Berberine (BBR) has been found to inhibit proliferation of human HCC cells, although the underlying mechanism(s) are unclear. METHODS: Protein expression was detected by Western blots. Cell viability was determined by using the CellTiter Assay kit. RESULTS: We confirm that BBR treatment inhibits HepG2, Hep3B, and SNU-182 cell viability, and suggest that it regulates this proliferation via the modulation of multiple tumorigenesis-related genes protein expression. BBR treatment up-regulated protein expression of tumor suppressor genes, including Kruppel-like factor 6 (KLF6), activating transcription factor 3 (ATF3) and p21, while down-regulating the expression of selected oncogenes, including E2F transcription factor 1 (E2F1) and pituitary tumor transforming gene 1 (PTTG1). The specific extracellular signal-regulated kinases 1/2 (ERK1/2) inhibitor, PD98059, partially inhibited BBR effects including reduction of cell viability, and up-regulation of KLF6 and ATF3 expressions; although, PD98059 did not alter the down-regulation of E2F1 and PTTG1 expression by BBR. CONCLUSIONS: Our results suggest that BBR inhibits HCC cell viability by modulating multiple tumorigenesis-related genes, and that up-regulation of tumor suppressor genes by BBR is in part the result of ERK1/2 action. The results of this study augment our understanding of the mechanisms underlying the effect of BBR on hepatocellular cancers and provide further evidence as to the biological plausibility of this agent's role in the treatment of these malignancies. PMID- 28572745 TI - The effect of microbial challenge on the intestinal proteome of broiler chickens. AB - BACKGROUND: In poultry production intestinal health and function is paramount to achieving efficient feed utilisation and growth. Uncovering the localised molecular mechanisms that occur during the early and important periods of growth that allow birds to grow optimally is important for this species. The exposure of young chicks to used litter from older flocks, containing mixed microbial populations, is a widely utilised model in poultry research. It rarely causes mortality but effects an immunogenic stimulation sufficient enough to cause reduced and uneven growth that is reflective of a challenging growing environment. METHODS: A mixed microbial challenge was delivered as used litter containing Campylobacter jejuni and coccidial oocysts to 120 male Ross 308 broiler chicks, randomly divided into two groups: control and challenged. On day 12, 15, 18 and 22 (pre- and 3, 6 and 10 days post-addition of the used litter) the proximal jejunum was recovered from 6 replicates per group and differentially abundant proteins identified between groups and over time using 2D DiGE. RESULTS: The abundance of cytoskeletal proteins of the chicken small intestinal proteome, particularly actin and actin associated proteins, increased over time in both challenged and control birds. Villin-1, an actin associated anti-apoptotic protein, was reduced in abundance in the challenged birds indicating that many of the changes in cytoskeletal protein abundance in the challenged birds were as a result of an increased rate of apoptosis. A number of heat shock proteins decreased in abundance over time in the intestine and this was more pronounced in the challenged birds. CONCLUSIONS: The small intestinal proteome sampled from 12 to 22 days of age showed considerable developmental change, comparable to other species indicating that many of the changes in protein abundance in the small intestine are conserved among vertebrates. Identifying and distinguishing the changes in proteins abundance and molecular pathways that occur as a result of normal growth from those that occur as a result of a challenging microbial environment is important in this major food producing animal. PMID- 28572746 TI - MODEL-BASED FOOD VOLUME ESTIMATION USING 3D POSE. AB - We are developing a dietary assessment system to automatically identify and quantify foods and beverages consumed by analyzing meal images captured with a mobile device. After food items are segmented and identified, accurately estimating the volume of the food in the image is important for determining the nutrient content of the food. In this paper, we proposed a novel food portion size estimation method for rigid food items using a single image. First, we create a 3D graphical model during the training step using 3D reconstruction from multiple views. Then, for each food image, we determine the translation and elevation parameters of each of the food items, which are relative to the camera coordinate through camera calibration. Using these geometric parameters we project the pre-built 3D model of each food item back to the image plane. Subsequently, the remaining degrees-of-freedom (DOF) for the final pose is estimated by image similarity measure. The experimental results of our volume estimation method for four food categories validate the accuracy and reliability of our model-based approach. PMID- 28572747 TI - CONTEXT BASED FOOD IMAGE ANALYSIS. AB - We are developing a dietary assessment system that records daily food intake through the use of food images. Recognizing food in an image is difficult due to large visual variance with respect to eating or preparation conditions. This task becomes even more challenging when different foods have similar visual appearance. In this paper we propose to incorporate two types of contextual dietary information, food co-occurrence patterns and personalized learning models, in food image analysis to reduce ambiguity in food visual appearance and improve food recognition accuracy. We evaluate our model on 1453 food images acquired by 45 participants in natural eating conditions. The result shows that incorporating contextual dietary information improves the food categorization accuracy by about 10%. PMID- 28572748 TI - ANALYSIS OF FOOD IMAGES: FEATURES AND CLASSIFICATION. AB - In this paper we investigate features and their combinations for food image analysis and a classification approach based on k-nearest neighbors and vocabulary trees. The system is evaluated on a food image dataset consisting of 1453 images of eating occasions in 42 food categories which were acquired by 45 participants in natural eating conditions. The same image dataset is used to test the classification system proposed in the previously reported work [1]. Experimental results indicate that using our combination of features and vocabulary trees for classification improves the food classification performance about 22% for the Top 1 classification accuracy and 10% for the Top 4 classification accuracy. PMID- 28572750 TI - Effects of a genetically modified potato on a non-target aphid are outweighed by cultivar differences. AB - Insect-plant interactions may be unintentionally affected when introducing genetically modified (GM) crops into an agro-ecosystem. Our aim was to test the non-target effects of a late blight-resistant GM potato on Myzus persicae in greenhouse and climate room experiments and understand how position and number of R gene insertions can affect non-targets in GM events. We also aimed to compare results to baseline differences among three conventional potato varieties varying in resistance to late blight. Aphid development and survival were affected by some GM events in the first generation, though effects disappeared in the second generation. Effects were not dependent on the presence of a marker gene or the insertion of a second resistance gene. Positional effects of gene insertion influenced aphid performance on certain GM events. However, aphid fitness varied considerably more between conventional potato varieties than between Desiree and the GM events. Comparing different GM events to the non-transformed variety is relevant, since unintended effects of insertion can occur. Our protocols can be recommended for in planta risk assessments with aphids. Ecological perspective is gained by selecting several measured endpoints and by comparing the results with a baseline of conventional cultivars. PMID- 28572751 TI - Effect of probiotic supplementation on total lactobacilli, bifidobacteria and short chain fatty acids in 2-5-year-old children. AB - Background: Consumption of Lactobacillus paracasei Lpc-37 or Bifidobacterium lactis HN019 by 2-5-year-old children was found to reduce risk for diarrhoea and fever during the rainy season. Objective: Can changes in faecal short chain fatty acids (SCFAs) or branched chain fatty acids (BCFAs) explain the observed positive influence of probiotics and their role on nutritional status and diarrhoea risk? Design: Faecal samples were analysed for SCFAs and BCFAs and correlated to Bifidobacterium and Lactobacillus levels; both at the start and after nine months' consumption of either of the two probiotic strains, or placebo. Results: No differences in SCFAs, BCFAs, Lactobacillus or Bifidobacterium levels were found between boys and girls. Severely underweight children were observed to have the highest Lactobacillus levels. Probiotic intervention was found to be associated with higher levels of selected SCFAs and BCFAs in subjects who had experienced diarrhoea. Treatment with either of the probiotics led to changes in SCFAs and BCFAs. SCFAs, acetate, propionate and butyrate, were found to correlate with each other. Likewise, BCFAs isobutyrate, 2-methylbutyrate and isovalerate correlated with each other. After the intervention, L. paracasei Lpc-37 correlated positively with total Bifidobacterium counts and isovalerate levels. B. lactis HN019 counts were found to correlate positively with total bacterial counts and negatively with propionate levels. Conclusions: Nutritional status was associated with higher levels of faecal lactobacilli; the meaning of this requires further investigation. The intervention with the two probiotics was observed to influence the levels of faecal SCFAs and BCFAs and there is a differential response in those who developed diarrhoea and those who did not. It is, however, not clear to what extent this is a mechanism that explains the earlier observed effect the strains had on diarrhoea risk. PMID- 28572749 TI - The effect of acute pomegranate extract supplementation on oxygen uptake in highly-trained cyclists during high-intensity exercise in a high altitude environment. AB - BACKGROUND: Recent research has indicated that pomegranate extract (POMx) may improve performance during aerobic exercise by enhancing the matching of vascular oxygen (O2) provision to muscular requirements. POMx is rich in ellagitannin polyphenols and nitrates (NO3-), which are both associated with improvements in blood flow and O2 delivery. Primarily, this study aimed to determine whether POMx improves performance in a cycling time trial to exhaustion at 100%VO2max (TTE100%) in highly-trained cyclists. In addition, we investigated if the O2 cost (VO2) of submaximal exercise was lower with POMx, and whether any changes were greater at high altitude where O2 delivery is impaired. METHODS: Eight cyclists exercised at three submaximal intensities before completing a TTE100% at sea level (SEA) and at 1657 m of altitude (ALT), with pre-exercise consumption of 1000 mg of POMx or a placebo (PLAC) in a randomized, double-blind, crossover design. Data were analysed using a three way (treatment x altitude x intensity) or two-way (treatment x altitude) repeated measures ANOVA with a Fisher's LSD post-hoc analysis. Significance was set at p <= 0.05. The effect size of significant interactions was calculated using Cohen's d. RESULTS: TTE100% performance was reduced in ALT but was not influenced by POMx (p > 0.05). Plasma NO3- were 10.3 MUmol greater with POMx vs. PLAC (95% CI, 0.8, 19.7,F1,7 = 7.83, p < 0.04). VO2 measured at five minutes into the TTE100% was significantly increased in ALTPOMx vs. ALTPLAC (+3.8 ml.min-1kg-1, 95% CI, -5.7, 9.5, F1,7 = 29.2, p = 0.001, ES = 0.6) but unchanged in SEAPOMx vs. SEAPLAC (p > 0.05). Submaximal VO2 values were not affected by POMx (p >= 0.05). CONCLUSIONS: The restoration of SEA VO2 values at ALT is likely driven by the high polyphenol content of POMx, which is proposed to improve nitric oxide bioavailability. Despite an increase in VO2, no change in exercise performance occurred and therefore this study does not support the use of POMx as an ergogenic supplement. PMID- 28572752 TI - Chronic alcohol overconsumption may alter gut microbial metabolism: a retrospective study of 719 13C-D-xylose breath test results. AB - Objective: Alterations of gut microbiota composition or function may participate in the pathophysiology of several diseases. We aimed to explore the effect of chronic alcohol overconsumption on gut microbial metabolism, as assessed by evaluating 13C-D-xylose breath test results. Materials and methods: We investigated all 13C-D-xylose breath tests performed at Lovisenberg Diaconal Hospital during the years 2005 to 2011, using patient files for diagnosing the patients into one of three patient categories: alcohol overconsumption, coeliac disease and functional bowel disorder. In addition, a group of healthy controls was included. The time curves of 13CO2 excretion in breath samples were divided into two phases, evaluating small intestinal absorption (0-60 min) and colonic microbial metabolism (90-240 min), respectively. Results: A total of 719 patients underwent 13C-D-xylose breath testing during the inclusion period. Thirty-five had a history of alcohol overconsumption, 66 had coeliac disease, and 216 had a functional bowel disorder, while 44 healthy controls were included for comparison. The alcohol overconsumption group had similar small intestinal phase results as the group of patients with untreated coeliac disease. During the colonic phase, the group of patients with alcohol overconsumption differed from all the other groups in terms of 13C-xylose recovery, with significantly less 13CO2 excretion compared to the other groups. Conclusion: The results suggest that patients with a history of alcohol overconsumption suffer from both small intestinal malabsorption and impaired colonic microbial metabolism. The role of gut microbiota in chronic alcohol overconsumption should be investigated further. PMID- 28572753 TI - Changes in vaginal community state types reflect major shifts in the microbiome. AB - Background: Recent studies of various human microbiome habitats have revealed thousands of bacterial species and the existence of large variation in communities of microorganisms in the same habitats across individual human subjects. Previous efforts to summarize this diversity, notably in the human gut and vagina, have categorized microbiome profiles by clustering them into community state types (CSTs). The functional relevance of specific CSTs has not been established. Objective: We investigate whether CSTs can be used to assess dynamics in the microbiome. Design: We conduct a re-analysis of five sequencing based microbiome surveys derived from vaginal samples with repeated measures. Results: We observe that detection of a CST transition is largely insensitive to choices in methods for normalization or clustering. We find that healthy subjects persist in a CST for two to three weeks or more on average, while those with evidence of dysbiosis tend to change more often. Changes in CST can be gradual or occur over less than one day. Upcoming CST changes and switches to high-risk CSTs can be predicted with high accuracy in certain scenarios. Finally, we observe that presence of Gardnerella vaginalis is a strong predictor of an upcoming CST change. Conclusion: Overall, our results show that the CST concept is useful for studying microbiome dynamics. PMID- 28572754 TI - Functional amplification and preservation of human gut microbiota. AB - Background: The availability of fresh stool samples is a prerequisite in most gut microbiota functional studies. Objective: Strategies for amplification and long term gut microbiota preservation from fecal samples would favor sample sharing, help comparisons and reproducibility over time and between laboratories, and improve the safety and ethical issues surrounding fecal microbiota transplantations. Design: Taking advantage of in vitro gut-simulating systems, we amplified the microbial repertoire of a fresh fecal sample and assessed the viability and resuscitation of microbes after preservation with some common intracellular and extracellular acting cryoprotective agents (CPAs), alone and in different combinations. Preservation efficiencies were determined after 3 and 6 months and compared with the fresh initial microbiota diversity and metabolic activity, using the chemostat-based Environmental Control System for Intestinal Microbiota (ECSIM) in vitro model of the gut environment. Microbial populations were tested for fermentation gas, short-chain fatty acids, and composition of amplified and resuscitated microbiota, encompassing methanogenic archaea. Results: Amplification of the microbial repertoire from a fresh fecal sample was achieved with high fidelity. Dimethylsulfoxide, alone or mixed with other CPAs, showed the best efficiency for functional preservation, and the duration of preservation had little effect. Conclusions: The amplification and resuscitation of fecal microbiota can be performed using specialized in vitro gut models. Correct amplification of the initial microbes should ease the sharing of clinical samples and improve the safety of fecal microbiota transplantation. Abbreviations: CDI, Clostridium difficile infection; CPA, cryoprotective agent; D, DMSO, dimethylsulfoxide; FMT, fecal microbiota transplantation; G, glycerol; IBD, inflammatory bowel disease; P, PEG-4000, polyethylene glycol 4000 g.mol-1; SCFA, short-chain fatty acid; SNR, signal-to-noise ratio. PMID- 28572756 TI - Differences and Similarities for Spatial and Feature-Based Selective Attentional Orienting. AB - Using selective attention, we prioritize behaviorally relevant information out of all surrounding stimulation. Attention can be oriented intentionally to spatial and/or non-spatial properties (feature-based attention). When comparing spatial and feature-based attention, previous studies identified a common fronto-parietal network, although some reported specific activation for spatial attention and few found higher activation for feature-based attention. Most studies examining differences between attention types investigated the cueing epoch. We examined reorienting processing (after invalid cueing) and correctly focused attention (after valid cueing) for spatial and feature-based orienting using fMRI in two human samples with 40 participants overall and identical stimuli, stimulus probabilities, and timing for all conditions. A fronto-parietal network including parts of the ventral orienting network was activated for reorienting and focused attention for both attention types. Common activity over validities and attention types was located in bilateral IPL/SMG, bilateral IFG/insula, and the cerebellum. A network of mainly posterior areas showed higher activity for spatial compared to feature-based orienting. Conversely, no specialized areas for spatial focused attention or for feature-based attention (reorienting/focusing) was observed. The posterior clusters specialized for spatial reorienting showed overlapping activity with clusters involved in common spatial and feature-based reorienting as well as focused attention over attention types. Therefore, the results hint at a superordinate fronto-parietal network for both attention types during reorienting and focusing, with a spatial specialization of posterior sub-regions. PMID- 28572755 TI - Graded Hypercapnia-Calibrated BOLD: Beyond the Iso-metabolic Hypercapnic Assumption. AB - Calibrated BOLD is a promising technique that overcomes the sensitivity of conventional fMRI to the cerebrovascular state; measuring either the basal level, or the task-induced response of cerebral metabolic rate of oxygen consumption (CMRO2). The calibrated BOLD method is susceptible to errors in the measurement of the calibration parameter M, the theoretical BOLD signal change that would occur if all deoxygenated hemoglobin were removed. The original and most popular method for measuring M uses hypercapnia (an increase in arterial CO2), making the assumption that it does not affect CMRO2. This assumption has since been challenged and recent studies have used a corrective term, based on literature values of a reduction in basal CMRO2 with hypercapnia. This is not ideal, as this value may vary across subjects and regions of the brain, and will depend on the level of hypercapnia achieved. Here we propose a new approach, using a graded hypercapnia design and the assumption that CMRO2 changes linearly with hypercapnia level, such that we can measure M without assuming prior knowledge of the scale of CMRO2 change. Through use of a graded hypercapnia gas challenge, we are able to remove the bias caused by a reduction in basal CMRO2 during hypercapnia, whilst simultaneously calculating the dose-wise CMRO2 change with hypercapnia. When compared with assuming no change in CMRO2, this approach resulted in significantly lower M-values in both visual and motor cortices, arising from significant dose-dependent hypercapnia reductions in basal CMRO2 of 1.5 +/- 0.6%/mmHg (visual) and 1.8 +/- 0.7%/mmHg (motor), where mmHg is the unit change in end-tidal CO2 level. Variability in the basal CMRO2 response to hypercapnia, due to experimental differences and inter-subject variability, is accounted for in this approach, unlike previous correction approaches, which use literature values. By incorporating measurement of, and correction for, the reduction in basal CMRO2 during hypercapnia in the measurement of M-values, application of our approach will correct for an overestimation in both CMRO2 task response values and absolute CMRO2. PMID- 28572757 TI - Muscle Contraction Regulates BDNF/TrkB Signaling to Modulate Synaptic Function through Presynaptic cPKCalpha and cPKCbetaI. AB - The neurotrophin brain-derived neurotrophic factor (BDNF) acts via tropomyosin related kinase B receptor (TrkB) to regulate synapse maintenance and function in the neuromuscular system. The potentiation of acetylcholine (ACh) release by BDNF requires TrkB phosphorylation and Protein Kinase C (PKC) activation. BDNF is secreted in an activity-dependent manner but it is not known if pre- and/or postsynaptic activities enhance BDNF expression in vivo at the neuromuscular junction (NMJ). Here, we investigated whether nerve and muscle cell activities regulate presynaptic conventional PKC (cPKCalpha and betaI) via BDNF/TrkB signaling to modulate synaptic strength at the NMJ. To differentiate the effects of presynaptic activity from that of muscle contraction, we stimulated the phrenic nerve of rat diaphragms (1 Hz, 30 min) with or without contraction (abolished by MU-conotoxin GIIIB). Then, we performed ELISA, Western blotting, qRT-PCR, immunofluorescence and electrophysiological techniques. We found that nerve-induced muscle contraction: (1) increases the levels of mature BDNF protein without affecting pro-BDNF protein or BDNF mRNA levels; (2) downregulates TrkB.T1 without affecting TrkB.FL or p75 neurotrophin receptor (p75) levels; (3) increases presynaptic cPKCalpha and cPKCbetaI protein level through TrkB signaling; and (4) enhances phosphorylation of cPKCalpha and cPKCbetaI. Furthermore, we demonstrate that cPKCbetaI, which is exclusively located in the motor nerve terminals, increases activity-induced acetylcholine release. Together, these results show that nerve-induced muscle contraction is a key regulator of BDNF/TrkB signaling pathway, retrogradely activating presynaptic cPKC isoforms (in particular cPKCbetaI) to modulate synaptic function. These results indicate that a decrease in neuromuscular activity, as occurs in several neuromuscular disorders, could affect the BDNF/TrkB/PKC pathway that links pre- and postsynaptic activity to maintain neuromuscular function. PMID- 28572758 TI - Activation of CHK1 in Supporting Cells Indirectly Promotes Hair Cell Survival. AB - The sensory hair cells of the inner ear are exquisitely sensitive to ototoxic insults. Loss of hair cells after exposure to ototoxic agents causes hearing loss. Chemotherapeutic agents such as cisplatin causes hair cell loss. Cisplatin forms DNA mono-adducts as well as intra- and inter-strand DNA crosslinks. DNA cisplatin adducts are repaired through the DNA damage response. The decision between cell survival and cell death following DNA damage rests on factors that are involved in determining damage tolerance, cell survival and apoptosis. Cisplatin damage on hair cells has been the main focus of many ototoxic studies, yet the effect of cisplatin on supporting cells has been largely ignored. In this study, the effects of DNA damage response in cochlear supporting cells were interrogated. Supporting cells play a major role in the development, maintenance and oto-protection of hair cells. Loss of supporting cells may indirectly affect hair cell survival or maintenance. Activation of the Phosphoinositide 3-Kinase (PI3K) signaling was previously shown to promote hair cell survival. To test whether activating PI3K signaling promotes supporting cell survival after cisplatin damage, cochlear explants from the neural subset (NS) Cre Pten conditional knockout mice were employed. Deletion of Phosphatase and Tensin Homolog (PTEN) activates PI3K signaling in multiple cell types within the cochlea. Supporting cells lacking PTEN showed increased cell survival after cisplatin damage. Supporting cells lacking PTEN also showed increased phosphorylation of Checkpoint Kinase 1 (CHK1) levels after cisplatin damage. Nearest neighbor analysis showed increased numbers of supporting cells with activated PI3K signaling in close proximity to surviving hair cells in cisplatin damaged cochleae. We propose that increased PI3K signaling promotes supporting cell survival through phosphorylation of CHK1 and increased survival of supporting cells indirectly increases hair cell survival after cisplatin damage. PMID- 28572759 TI - Dendritic Actin Cytoskeleton: Structure, Functions, and Regulations. AB - Actin is a versatile and ubiquitous cytoskeletal protein that plays a major role in both the establishment and the maintenance of neuronal polarity. For a long time, the most prominent roles that were attributed to actin in neurons were the movement of growth cones, polarized cargo sorting at the axon initial segment, and the dynamic plasticity of dendritic spines, since those compartments contain large accumulations of actin filaments (F-actin) that can be readily visualized using electron- and fluorescence microscopy. With the development of super resolution microscopy in the past few years, previously unknown structures of the actin cytoskeleton have been uncovered: a periodic lattice consisting of actin and spectrin seems to pervade not only the whole axon, but also dendrites and even the necks of dendritic spines. Apart from that striking feature, patches of F-actin and deep actin filament bundles have been described along the lengths of neurites. So far, research has been focused on the specific roles of actin in the axon, while it is becoming more and more apparent that in the dendrite, actin is not only confined to dendritic spines, but serves many additional and important functions. In this review, we focus on recent developments regarding the role of actin in dendrite morphology, the regulation of actin dynamics by internal and external factors, and the role of F-actin in dendritic protein trafficking. PMID- 28572760 TI - A Quantitative Electroencephalography Study on Cochlear Implant-Induced Cortical Changes in Single-Sided Deafness with Tinnitus. AB - The mechanism of tinnitus suppression after cochlear implantation (CI) in single sided deafness (SSD) is not fully understood. In this regard, by comparing pre- and post-CI quantitative electroencephalography (qEEG), we explored cortical changes relevant to tinnitus improvement. In SSD patients who underwent CI, qEEG data were collected: (1) before CI, (2) 6 months post-operatively with CI-on, and (3) 30 min after CI-off and source-localized cortical activity/functional connectivity analyses were performed. Compared to the pre-operative baseline, the CI-on condition demonstrated significantly decreased activity in the right auditory- and orbitofrontal cortices (OFC) for the delta frequency band as well as decreased connectivity between the auditory cortex/posterior cingulate cortex for the delta/beta2 bands. Meanwhile, compared to the CI-off condition, the CI-on condition displayed decreased activity in the right auditory cortices/OFC for the delta band, and in bilateral auditory cortices, left inferior frontal cortex/OFC for the gamma band. However, qEEG analyses showed no significant differences between the CI-off and baseline conditions. CI induced overall decreased cortical activity and functional connectivity. However, judging from no differences between the CI-off and baseline conditions, CI-induced cortical activity and functional connectivity changes are not by cortical plastic changes, but by dynamic peripheral reafferentation. PMID- 28572761 TI - Ten Minutes of alpha-tACS and Ambient Illumination Independently Modulate EEG alpha-Power. AB - Transcranial alternating current stimulation (tACS) sees increased use in neurosciences as a tool for the exploration of brain oscillations. It has been shown that tACS stimulation in specific frequency bands can result in aftereffects of modulated oscillatory brain activity that persist after the stimulation has ended. The general relationship between persistency of the effect and duration of stimulation is sparsely investigated but previous research has shown that the occurrence of tACS aftereffects depends on the brain state before and during stimulation. Early alpha neurofeedback research suggests that particularly in the alpha band the responsiveness to a manipulation depends on the ambient illumination during measurement. Therefore, in the present study we assessed the brain's susceptibility to tACS at the individual alpha frequency during darkness compared to ambient illumination. We measured alpha power after 10 min of stimulation in 30 participants while they continuously performed a visual vigilance task. Our results show that immediately after stimulation, the alpha power in the illumination condition for both the stimulated and sham group has increased by only about 7%, compared to about 20% in both groups in the 'dark' condition. For the group that did not receive stimulation, the power in darkness remained stable after stimulation, whereas the power in light increased by an additional 10% during the next 30 min. For the group that did receive stimulation, alpha power during these 30 min increased by another 11% in light and 22% in darkness. Since alpha power already increased by about 10% without stimulation, the effect of illumination does not seem to have interacted with the effect of stimulation. Instead, both effects seem to have added up linearly. Although our findings do not show that illumination-induced differences in oscillatory activity influence the susceptibility toward tACS, they stress the importance of controlling for factors like ambient light that might add an independent increase or decrease to the power of brain oscillations during periods, where possible persistent effects of stimulation are explored. PMID- 28572762 TI - Evaluating and Improving Automatic Sleep Spindle Detection by Using Multi Objective Evolutionary Algorithms. AB - Sleep spindles are brief bursts of brain activity in the sigma frequency range (11-16 Hz) measured by electroencephalography (EEG) mostly during non-rapid eye movement (NREM) stage 2 sleep. These oscillations are of great biological and clinical interests because they potentially play an important role in identifying and characterizing the processes of various neurological disorders. Conventionally, sleep spindles are identified by expert sleep clinicians via visual inspection of EEG signals. The process is laborious and the results are inconsistent among different experts. To resolve the problem, numerous computerized methods have been developed to automate the process of sleep spindle identification. Still, the performance of these automated sleep spindle detection methods varies inconsistently from study to study. There are two reasons: (1) the lack of common benchmark databases, and (2) the lack of commonly accepted evaluation metrics. In this study, we focus on tackling the second problem by proposing to evaluate the performance of a spindle detector in a multi-objective optimization context and hypothesize that using the resultant Pareto fronts for deriving evaluation metrics will improve automatic sleep spindle detection. We use a popular multi-objective evolutionary algorithm (MOEA), the Strength Pareto Evolutionary Algorithm (SPEA2), to optimize six existing frequency-based sleep spindle detection algorithms. They include three Fourier, one continuous wavelet transform (CWT), and two Hilbert-Huang transform (HHT) based algorithms. We also explore three hybrid approaches. Trained and tested on open-access DREAMS and MASS databases, two new hybrid methods of combining Fourier with HHT algorithms show significant performance improvement with F1-scores of 0.726-0.737. PMID- 28572763 TI - A Statistical Analysis of the Relationship between Harmonic Surprise and Preference in Popular Music. AB - Studies have shown that some musical pieces may preferentially activate reward centers in the brain. Less is known, however, about the structural aspects of music that are associated with this activation. Based on the music cognition literature, we propose two hypotheses for why some musical pieces are preferred over others. The first, the Absolute-Surprise Hypothesis, states that unexpected events in music directly lead to pleasure. The second, the Contrastive-Surprise Hypothesis, proposes that the juxtaposition of unexpected events and subsequent expected events leads to an overall rewarding response. We tested these hypotheses within the framework of information theory, using the measure of "surprise." This information-theoretic variable mathematically describes how improbable an event is given a known distribution. We performed a statistical investigation of surprise in the harmonic structure of songs within a representative corpus of Western popular music, namely, the McGill Billboard Project corpus. We found that chords of songs in the top quartile of the Billboard chart showed greater average surprise than those in the bottom quartile. We also found that the different sections within top-quartile songs varied more in their average surprise than the sections within bottom-quartile songs. The results of this study are consistent with both the Absolute- and Contrastive-Surprise Hypotheses. Although these hypotheses seem contradictory to one another, we cannot yet discard the possibility that both absolute and contrastive types of surprise play roles in the enjoyment of popular music. We call this possibility the Hybrid-Surprise Hypothesis. The results of this statistical investigation have implications for both music cognition and the human neural mechanisms of esthetic judgments. PMID- 28572764 TI - The Effects of Modified Constraint-Induced Movement Therapy in Acute Subcortical Cerebral Infarction. AB - Background: Constraint-induced movement therapy (CIMT) promotes upper extremity recovery post stroke, however, it is difficult to implement clinically due to its high resource demand and safety of the restraint. Therefore, we propose that modified CIMT (mCIMT) be used to treat individuals with acute subcortical infarction. Objective: To evaluate the therapeutic effects of mCIMT in patients with acute subcortical infarction, and investigate the possible mechanisms underlying the effect. Methods: The role of mCIMT was investigated in 26 individuals experiencing subcortical infarction in the preceding 14 days. Patients were randomly assigned to either mCIMT or standard therapy. mCIMT group was treated daily for 3 h over 10 consecutive working days, using a mitt on the unaffected arm for up to 30% of waking hours. The control group was treated with an equal dose of occupational therapy and physical therapy. During the 3-month follow-up, the motor functions of the affected limb were assessed by the Wolf Motor Function Test (WMFT) and Motor Activity Log (MAL). Altered cortical excitability was assessed via transcranial magnetic stimulation (TMS). Results: Treatment significantly improved the movement in the mCIMT group compared with the control group. The mean WMF score was significantly higher in the mCIMT group compared with the control group. Further, the appearance of motor-evoked potentials (MEPs) were significantly higher in the mCIMT group compared with the baseline data. A significant change in ipsilesional silent period (SP) occurred in the mCIMT group compared with the control group. However, we found no difference between two groups in motor function or electrophysiological parameters after 3 months of follow-up. Conclusions: mCIMT resulted in significant functional changes in timed movement immediately following treatment in patients with acute subcortical infarction. Further, early mCIMT improved ipsilesional cortical excitability. However, no long-term effects were seen. PMID- 28572765 TI - White Matter Structural Connectivity Is Not Correlated to Cortical Resting-State Functional Connectivity over the Healthy Adult Lifespan. AB - Structural connectivity (SC) of white matter (WM) and functional connectivity (FC) of cortical regions undergo changes in normal aging. As WM tracts form the underlying anatomical architecture that connects regions within resting state networks (RSNs), it is intuitive to expect that SC and FC changes with age are correlated. Studies that investigated the relationship between SC and FC in normal aging are rare, and have mainly compared between groups of elderly and younger subjects. The objectives of this work were to investigate linear SC and FC changes across the healthy adult lifespan, and to define relationships between SC and FC measures within seven whole-brain large scale RSNs. Diffusion tensor imaging (DTI) and resting-state functional MRI (rs-fMRI) data were acquired from 177 healthy participants (male/female = 69/108; aged 18-87 years). Forty cortical regions across both hemispheres belonging to seven template-defined RSNs were considered. Mean diffusivity (MD), fractional anisotropy (FA), mean tract length, and number of streamlines derived from DTI data were used as SC measures, delineated using deterministic tractography, within each RSN. Pearson correlation coefficients of rs-fMRI-obtained BOLD signal time courses between cortical regions were used as FC measure. SC demonstrated significant age-related changes in all RSNs (decreased FA, mean tract length, number of streamlines; and increased MD), and significant FC decrease was observed in five out of seven networks. Among the networks that showed both significant age related changes in SC and FC, however, SC was not in general significantly correlated with FC, whether controlling for age or not. The lack of observed relationship between SC and FC suggests that measures derived from DTI data that are commonly used to infer the integrity of WM microstructure are not related to the corresponding changes in FC within RSNs. The possible temporal lag between SC and FC will need to be addressed in future longitudinal studies to better elucidate the links between SC and FC changes in normal aging. PMID- 28572768 TI - Gait Change Is Associated with Cognitive Outcome after an Acute Ischemic Stroke. AB - Background: Cognition and gait have often been studied separately after stroke whereas it has been suggested that these two domains could interact through a cognitive-motor interference. Objective: To evaluate the influence of gait changes on cognitive outcome after an ischemic stroke (IS). Methods: We conducted a prospective and monocentric study including patients admitted for an acute supratentorial IS with a National Institute of Health Stroke Score <= 15. Cognition, gait and motor disability were evaluated at baseline, 3 months and 1 year post-stroke, using the Montreal Cognitive Assessment (MoCA), the 10-m walking test (10-MWT) and the Fugl-Meyer motor assessment (FMMA). The effect of changes in 10-MWT over the year of follow-up on MoCA changes was estimated using a generalized linear mixed model with FMMA, age and gender as covariates. Results: Two hundred and Twelve patients were included (71% male, age 64 +/- 13 years old). 10-MWT improved from baseline to 1 year (p < 0.001), as did MoCA (p < 0.001) and FMMA (p < 0.001) scores. Ninety-nine patients (47%) had a MoCA <26 at 1 year. Changes in 10-MWT were independently associated with changes in MoCA (beta = -0.2, 95% CI -0.24 to -0.07, Bonferroni-corrected p-value = 0.002). Analyses of MoCA sub-scores suggested that changes in gait performance was associated with changes in executive functions and recall. Conclusion: Gait performance is associated with cognitive outcome after a mild to moderate IS, suggesting that they should be managed together to improve post-stroke independence. PMID- 28572770 TI - In Vivo Cannabidiol Treatment Improves Endothelium-Dependent Vasorelaxation in Mesenteric Arteries of Zucker Diabetic Fatty Rats. AB - Background and purpose: We have shown that in vitro treatment with cannabidiol (CBD, 2 h) enhances endothelial function in arteries from Zucker diabetic fatty (ZDF) rats, partly due to a cyclooxygenase (COX)-mediated mechanism. The aim of the present study was to determine whether treatment with CBD in vivo would also enhance endothelial function. Experimental approach: Male ZDF rats, or ZDF Lean rats, were treated for 7 days (daily i.p. injection) with either 10mg/kg CBD or vehicle (n = 6 per group). Sections of mesenteric resistance arteries, femoral arteries and thoracic aortae were mounted on a wire myograph, and cumulative concentration-response curves to endothelium-dependent (acetylcholine, ACh, 1 nM 100 MUM) or endothelium-independent (sodium nitroprusside, SNP, 1 nM-100 MUM) agents were constructed. Multiplex analysis was used to measure serum metabolic and cardiovascular biomarkers. Key results: Vasorelaxation to ACh was significantly enhanced in mesenteric arteries from CBD-treated ZDF rats, but not ZDF Lean rats. The enhanced vasorelaxation in ZDF mesenteric arteries was no longer observed after COX inhibition using indomethacin or nitric oxide (NO) inhibition using L-NAME. Increased levels of serum c-peptide, insulin and intracellular adhesion molecule-1 observed in the ZDF compared to ZDF Lean rats were no longer significant after 7 days CBD treatment. Conclusion and implications: Short-term in vivo treatment with CBD improves ex vivo endothelium dependent vasorelaxation in mesenteric arteries from ZDF rats due to COX- or NO mediated mechanisms, and leads to improvements in serum biomarkers. PMID- 28572767 TI - Glia Maturation Factor and Mitochondrial Uncoupling Proteins 2 and 4 Expression in the Temporal Cortex of Alzheimer's Disease Brain. AB - Alzheimer's disease (AD) is characterized by the presence of neuropathological lesions containing amyloid plaques (APs) and neurofibrillary tangles (NFTs). AD is associated with mitochondrial dysfunctions, neuroinflammation and neurodegeneration in the brain. We have previously demonstrated enhanced expression of the proinflammatory protein glia maturation factor (GMF) in glial cells near APs and NFTs in the AD brains. Parahippocampal gyrus consisting of entorhinal and perirhinal subdivisions of temporal cortex is the first brain region affected during AD pathogenesis. Current paradigm implicates oxidative stress-mediated neuronal damage contributing to the early pathology in AD with mitochondrial membrane potential regulating reactive oxygen species (ROS) production. The inner mitochondrial membrane anion transporters called the uncoupling proteins (UCPs), function as regulators of cellular homeostasis by mitigating oxidative stress. In the present study, we have analyzed the expression of GMF and mitochondrial UCP2 and UCP4 in the parahippocampal gyrus of AD and non-AD brains by immunostaining techniques. APs were detected by thioflavin-S fluorescence staining or immunohistochemistry (IHC) with 6E10 antibody. Our current results suggest that upregulation of GMF expression is associated with down-regulation of UCP2 as well as UCP4 in the parahippocampal gyrus of AD brains as compared to non-AD brains. Further, GMF expression is associated with up-regulation of inducible nitric oxide synthase (iNOS), the enzyme that induces the production of nitric oxide (NO), as well as nuclear factor kB p65 (NF-kappaB p65) expression. Also, GMF appeared to localize to the mitochondria in AD brains. Based on our current observations, we propose that enhanced expression of GMF down-regulates mitochondrial UCP2 and UCP4 thereby exacerbating AD pathophysiology and this effect is potentially mediated by iNOS and NF-kappaB. Thus, GMF functions as an activator protein that interferes with the cytoprotective mechanisms in AD brains. PMID- 28572769 TI - Corrigendum: Melatonin and Nitrones As Potential Therapeutic Agents for Stroke. AB - [This corrects the article on p. 281 in vol. 8, PMID: 27932976.]. PMID- 28572773 TI - Measuring Ventilatory Activity with Structured Light Plethysmography (SLP) Reduces Instrumental Observer Effect and Preserves Tidal Breathing Variability in Healthy and COPD. AB - The use of a mouthpiece to measure ventilatory flow with a pneumotachograph (PNT) introduces a major perturbation to breathing ("instrumental/observer effect") and suffices to modify the respiratory behavior. Structured light plethysmography (SLP) is a non-contact method of assessment of breathing pattern during tidal breathing. Firstly, we validated the SLP measurements by comparing timing components of the ventilatory pattern obtained by SLP vs. PNT under the same condition; secondly, we compared SLP to SLP+PNT measurements of breathing pattern to evaluate the disruption of breathing pattern and breathing variability in healthy and COPD subjects. Measurements were taken during tidal breathing with SLP alone and SLP+PNT recording in 30 COPD and healthy subjects. Measurements included: respiratory frequency (Rf), inspiratory, expiratory, and total breath time/duration (Ti, Te, and Tt). Passing-Bablok regression analysis was used to evaluate the interchangeability of timing components of the ventilatory pattern (Rf, Ti, Te, and Tt) between measurements performed under the following experimental conditions: SLP vs. PNT, SLP+PNT vs. SLP, and SLP+PNT vs. PNT. The variability of different ventilatory variables was assessed through their coefficients of variation (CVs). In healthy: according to Passing-Bablok regression, Rf, TI, TE and TT were interchangeable between measurements obtained under the three experimental conditions (SLP vs. PNT, SLP+PNT vs. SLP, and SLP+PNT vs. PNT). All the CVs describing "traditional" ventilatory variables (Rf, Ti, Te, Ti/Te, and Ti/Tt) were significantly smaller in SLP+PNT condition. This was not the case for more "specific" SLP-derived variables. In COPD: according to Passing-Bablok regression, Rf, TI, TE, and TT were interchangeable between measurements obtained under SLP vs. PNT and SLP+PNT vs. PNT, whereas only Rf, TE, and TT were interchangeable between measurements obtained under SLP+PNT vs. SLP. However, most discrete variables were significantly different between the SLP and SLP+PNT conditions and CVs were significantly lower when COPD patients were assessed in the SLP+PNT condition. Measuring ventilatory activity with SLP preserves resting tidal breathing variability, reduces instrumental observer effect and avoids any disruptions in breathing pattern induced by the use of PNT mouthpiece-nose-clip combination. PMID- 28572772 TI - Moderate Treadmill Exercise Training Improves Cardiovascular and Nitrergic Response and Resistance to Trypanosoma cruzi Infection in Mice. AB - There is evidence suggesting that exercise training (ET) acts as a factor toward resistance to Trypanosoma cruzi infection. However, the effects of mean arterial pressure (MAP), heart rate (HR), and nitric oxide (NO) during the acute phase of infection has not been elucidated yet. Swiss mice were randomly assigned into four groups: sedentary control (SC, n = 30), trained control (TC, n = 30), sedentary infected (SI, n = 30), and trained infected (TI, n = 30). ET was performed on the treadmill for 9 weeks. After training, the mice were infected with 5 * 103 trypomastigotes of T. cruzi (Y strain) or PBS. We observed resting bradycardia and improved performance in trained animals compared with sedentary ones. On the 20th day post-infection (DPI), we found a decrease in HR in SI animals compared to TI animals (699.73 +/- 42.37 vs. 742.11 +/- 25.35 bpm, respectively, P < 0.05). We also observed increased production of NO in cardiac tissue on the 20th DPI in the SI group, normalized in TI group (20.73 +/- 2.74 vs. 6.51 +/- 1.19 MUM, respectively). Plasma pro-inflammatory cytokines (IL-12, TNF-alpha, IFN-gamma,) and MCP-1 were increased in SI animals, but decreased in TI animals. The increase in parasitemia on the 15th and 17th DPI in the SI group was attenuated in the TI group. Our results suggest that previous ET plays a preventive role in resistance to T. cruzi infection, modulating cardiovascular aspects, inflammatory reaction, and NO levels of infected mice. PMID- 28572775 TI - Perceptions of the Coach-Athlete Relationship Predict the Attainment of Mastery Achievement Goals Six Months Later: A Two-Wave Longitudinal Study among F. A. Premier League Academy Soccer Players. AB - All football teams that compete within the F. A. Premier League possess an academy, whose objective is to produce more and better home-grown players that are capable of playing professionally. These young players spend a large amount of time with their coach, but little is known about player's perception of the coach-athlete relationship within F. A. Premier League Academies. The objectives of this study were to examine whether perceptions of the coach-athlete relationship changed over six months and if the coach-athlete relationship predicted self-reported goal achievement among F. A. Premier League academy players. This study included cross-sectional (n = 104) and longitudinal (n = 52) assessments, in which academy soccer players completed a measure of the coach athlete relationship and goal achievement across either one or two time periods. The cross-sectional data were subjected to bivariate correlations, whereas the longitudinal data were analyzed using multiple regressions. Perceptions of the coach-athlete relationship remained stable over time. The coach-athlete relationship predicted the achievement of mastery goals six months later. Enhancing the quality of the coach-athlete relationship among elite adolescent athletes appears to be a suitable way of maximizing mastery achievement goals, particularly among developmental athletes who participate in team sports. PMID- 28572771 TI - Measures of Heart Rate Variability in 24-h ECGs Depend on Age but Not Gender of Healthy Children. AB - Many methods computing heart rate variability (HRV) have been applied in studies in children. Not all of these methods have a comprehensive physiological interpretation, and not all of studies are in agreement with the Task Force Standards on HRV from 1996, and the New Joint Position Statement on the advances of HRV from 2015. The study aim was to analyse HRV in the 24-h ECGs of healthy children by the Poincare plots and Lomb-Scargle periodograms, and to follow proper HRV recommendations. Additionally, we investigated the associations between age, children's sex and measured HRV indices. One hundred healthy children, aged 3-18 underwent 24-h ECG Holter monitoring. HRV was analyzed by the Poincare plots and spectral by Lomb-Scargle periodograms of RR intervals. The Mann-Whitney test was used to compare sex differences in HRV, the van Elteren's test was used to correct for the age-gender interaction, and non-parametric Spearman correlation was applied to analyse the association between age and HRV indices. None of the HRV measures differed significantly between boys and girls. None of the HRV indices was modified by the age-gender interaction. There were statistically significant associations of age with measures of ultra-low (rho = 0.42; p < 0.0001), very low (rho = 0.35; p = 00004) and low (rho = 0.30; p = 0.0028) frequency powers, the ratio of the low to high frequency power (rho = 0.38; p = 0.0001), indices of long-term (SD2; rho = 0.37; p = 0.0002) and total (SDNN; rho = 0.33; p = 0.0008) HRV, and the contribution of the long-term HRV to total HRV (CL; rho = 0.32; p = 0.0012). In general, HRV parameters derived from the analyses of Poincare plots and Lomb-Scargle periodograms appear not to be affected by gender, however, most of them increase with age in the 24-h ECG recordings in healthy children. PMID- 28572774 TI - An Under-the-Table Leg-Movement Apparatus and Changes in Energy Expenditure. AB - Introduction: Deskwork contributes substantially to sedentariness. Here, we evaluated an under-the-table apparatus that was designed to promote leg movement (fidgeting) while seated. Our hypothesis was that the under-the-table apparatus would increase energy expenditure. Methods: We measured energy expenditure and heart rate in 26 people while they sat and worked using a standard chair, walked on a treadmill, and sat and worked using an under-the-desk apparatus that encouraged leg movement. Results: Energy expenditure increased significantly while using the under-the-table apparatus when compared to the standard office chair (standard chair, 81 +/- 18 kcal/h; under-the-table apparatus, 96 +/- 23 kcal/h) (P < 0.001); representing an 18 +/- 16% increase. The changes in energy expenditure were not as great as walking (1 mph, 168 +/- 46 kcal/h, P < 0.001; 2 mph, 205 +/- 51 kcal/, P < 0.001), representing 107 +/- 37% and 155 +/- 48% increases over baseline, respectively. Conclusions: An under-the-table apparatus that promotes leg movement can increase energy expenditure by approximately 20%. Dynamic sitting is promoted by this apparatus and may be among a lexicon of options to help people move more while seated at work. PMID- 28572776 TI - 'Talkin' 'Bout My Generation': Using a Mixed-Methods Approach to Explore Changes in Adolescent Well-Being across Several European Countries. AB - The promotion of positive mental health is a becoming priority worldwide. Despite all the efforts invested in preventive and curative work, it is estimated that one in four persons will experience a mental health condition at some point in their lives. Even more worrying is the fact that up to a half of all mental health problems have their onset before the age of 14. Recent statistics (national and international surveys, meta-analyses, international reports) point out to the fact that child and adolescent mental health problems are on the rise. The present study will try to corroborate these results and further explore their meaning, by employing a sequential mixed methods research design (quantitative qualitative). The quantitative part will analyze time trends using Health Behaviors in School-aged Children data (four survey cycles: 2002, 2006, 2010, 2014) on mental well-being from four European countries (the Czechia, Germany, Italy, and United Kingdom). The qualitative part will rely on focus groups to explore the perspectives of 13- and 15-year-old boys and girls on gender differences and on the changes in adolescent mental well-being over time, as well as measures through which these issues could be addressed. Thematic analysis will be employed to analyze qualitative data. The results of this study could make a major contribution to our understanding of the current trends in adolescent mental well-being, as well as the ways in which existing data could be linked to international and national health policies. PMID- 28572778 TI - Models of Disability in Children's Pretend Play: Measurement of Cognitive Representations and Affective Expression Using the Affect in Play Scale. AB - Play is a natural mode of children's expression and constitutes a fundamental aspect of their life. Cognitive, affective, and social aspects can be assessed through play, considered as a "window" to observe a child's functioning. According to Russ's model, cognitive and affective components and their reciprocal connections can be assessed through the Affect in Play Scale (APS). The aim of the present study was to investigate children's representations of the three main models of disability (medical, social, and biopsychosocial) and how these models affected cognitive and affective components of children's play. Sixty-three children, aged 6-10 years, were assessed by means of the APS. Participants were randomly assigned to one of two APS task orders: the standard APS task followed by the modified APS task (including a wheelchair toy), or vice versa. The standard and modified APS sessions were coded according to the APS system. The modified APS sessions were also coded for the model of disability expressed by children. A one-way ANOVA conducted on the APS affective and cognitive indexes revealed an effect of condition on the affective components of play and no effect on cognitive components and variety of affect as assessed by the APS. In addition, when children are involved in pretend play from which concepts of disability emerge, these concepts are almost exclusively related to the medical model of disability. Results suggested implications for intervention with children in educational contexts that aim to teach children about disability. PMID- 28572777 TI - Attractiveness Is Multimodal: Beauty Is Also in the Nose and Ear of the Beholder. AB - Attractiveness plays a central role in human non-verbal communication and has been broadly examined in diverse subfields of contemporary psychology. Researchers have garnered compelling evidence in support of the evolutionary functions of physical attractiveness and its role in our daily lives, while at the same time, having largely ignored the significant contribution of non-visual modalities and the relationships among them. Acoustic and olfactory cues can, separately or in combination, strongly influence the perceived attractiveness of an individual and therefore attitudes and actions toward that person. Here, we discuss the relative importance of visual, auditory and olfactory traits in judgments of attractiveness, and review neural and behavioral studies that support the highly complex and multimodal nature of person perception. Further, we discuss three alternative evolutionary hypotheses aimed at explaining the function of multiple indices of attractiveness. In this review, we provide several lines of evidence supporting the importance of the voice, body odor, and facial and body appearance in the perception of attractiveness and mate preferences, and therefore the critical need to incorporate cross-modal perception and multisensory integration into future research on human physical attractiveness. PMID- 28572779 TI - Differences in Cortisol Response to Trauma Activation in Individuals with and without Comorbid PTSD and Depression. AB - Background: Although depression symptoms are often experienced by individuals who develop posttraumatic stress disorder (PTSD) following trauma exposure, little is know about the biological correlates associated with PTSD and depression co morbidity vs. those associated with PTSD symptoms alone. Methods: Here we examined salivary cortisol responses to trauma activation in a sample of 60 survivors of the World Trade Center attacks on September 11, 2001. Participants recalled the escape from the attacks 7 months post 9/11. Salivary cortisol levels were measured before and after their recollection of the trauma. PTSD, depression, and somatic symptoms were also assessed. From the behavioral assessment scales, the participants were grouped into three conditions: those with comorbid PTSD and depressive symptoms, PTSD alone symptoms, or no-pathology. Results: Baseline and cortisol response levels differed between the comorbid, PTSD alone, and no-pathology groups. Individuals endorsing co-morbid symptoms had higher PTSD and somatic symptom severity and their cortisol response decreased following their trauma reminder while a trend of an elevated response to the trauma was found in the PTSD alone group. Our findings show distinct psychological and biological correlates related to the endorsement of PTSD with and without depression comorbidity. Conclusions: The findings suggest that comorbidity symptoms manifestation entails a separate trauma induced condition from PTSD. Future research on biological correlates of comorbid PTSD and depression is warranted. PMID- 28572781 TI - Integration of the Forced-Choice Questionnaire and the Likert Scale: A Simulation Study. AB - The Thurstonian item response theory (IRT) model allows estimating the latent trait scores of respondents directly through their responses in forced-choice questionnaires. It solves a part of problems brought by the traditional scoring methods of this kind of questionnaires. However, the forced-choice designs may still have their own limitations: The model may encounter underidentification and non-convergence and the test may show low test reliability in simple test designs (e.g., test designs with only a small number of traits measured or short length). To overcome these weaknesses, the present study applied the Thurstonian IRT model and the Graded Response Model to a different test format that comprises both forced-choice blocks and Likert-type items. And the Likert items should have low social desirability. A Monte Carlo simulation study is used to investigate how the mixed response format performs under various conditions. Four factors are considered: the number of traits, test length, the percentage of Likert items, and the proportion of pairs composed of items keyed in opposite directions. Results reveal that the mixed response format can be superior to the forced choice format, especially in simple designs where the latter performs poorly. Besides the number of Likert items needed is small. One point to note is that researchers need to choose Likert items cautiously as Likert items may bring other response biases to the test. Discussion and suggestions are given to construct personality tests that can resist faking as much as possible and have acceptable reliability. PMID- 28572780 TI - Modeling Psychological Attributes in Psychology - An Epistemological Discussion: Network Analysis vs. Latent Variables. AB - Network Analysis is considered as a new method that challenges Latent Variable models in inferring psychological attributes. With Network Analysis, psychological attributes are derived from a complex system of components without the need to call on any latent variables. But the ontological status of psychological attributes is not adequately defined with Network Analysis, because a psychological attribute is both a complex system and a property emerging from this complex system. The aim of this article is to reappraise the legitimacy of latent variable models by engaging in an ontological and epistemological discussion on psychological attributes. Psychological attributes relate to the mental equilibrium of individuals embedded in their social interactions, as robust attractors within complex dynamic processes with emergent properties, distinct from physical entities located in precise areas of the brain. Latent variables thus possess legitimacy, because the emergent properties can be conceptualized and analyzed on the sole basis of their manifestations, without exploring the upstream complex system. However, in opposition with the usual Latent Variable models, this article is in favor of the integration of a dynamic system of manifestations. Latent Variables models and Network Analysis thus appear as complementary approaches. New approaches combining Latent Network Models and Network Residuals are certainly a promising new way to infer psychological attributes, placing psychological attributes in an inter-subjective dynamic approach. Pragmatism-realism appears as the epistemological framework required if we are to use latent variables as representations of psychological attributes. PMID- 28572782 TI - Timing of Gun Fire Influences Sprinters' Multiple Joint Reaction Times of Whole Body in Block Start. AB - Experienced sprinters are specifically adapted to pre-planning an advanced motor program. Herein, sprinters are able to immediately accelerate their center of mass forward with a whole-body coordinated motion, following a steady state crouched position. We examined the effect of variable timing of reaction signals on multiple joint reaction times (RT) and whole-body RT for specialist sprinters. Twenty well-experienced male sprinters performed five start-dashes from a block start under five variable foreperiod (FP) length conditions (1.465, 1.622, 1.780, 1.938, and 2.096 s), with trials randomly timed between a warning and an imperative tone. Participants' sprinting motion and ground reaction forces of their four limbs during the block start were measured simultaneously. Whole-body RT was significantly shorter when FP length was longer; the values of whole-body RT were 117 +/- 5 ms, 129 +/- 5 ms, 125 +/- 4 ms, 133 +/- 6 ms, and 156 +/- 8 ms in the 2.096, 1.938, 1.780, 1.622, and 1.465-s FP-length conditions, respectively. A repeated-measures analysis of variance found a significant joint by-FP length interaction in joint-moment RT. These findings suggest that FP length affects coordinated motion in four limbs and whole-body RT. This information will be able to lead to new methods for start signals in sprint running events and advance our understanding of the association between FP length and dynamic coordinated motion. PMID- 28572783 TI - A structural Model of Self-efficacy in Handball Referees. AB - The study aimed to identify factors predicting self-efficacy in a sample of 248 Italian handball referees. The main hypothesis was that perception of teamwork efficacy would be a significant predictor of self-efficacy in handball referees. Participants completed an online questionnaire including Referee Self-Efficacy Scale (alpha = 0.85), Self-Determination Scale (alpha = 0.78), and an adaptation for Referees of the Sport Commitment Model (alpha = 0.80). Two hierarchical regression analyses have identified: (1) Enjoyment (beta = 0.226), Couple Efficacy (beta = 0.233), and Personal Awareness (beta = 0.243), as predictors of Self-Efficacy; (2) Span of Co-Refereeing (beta = 0.253), Perceived Quality of the Relationship (beta = 0.239), and Mutual Agreement (beta = 0.274), as predictors of Couple Self-Efficacy. A further SEM analysis confirmed the fit of a structural model of Self-efficacy considering the reciprocal influence of Couple Efficacy, Enjoyment and Awareness (chi2: 5.67; RMSEA: 0.000; SRMR: 0.019). The study underlines the importance of teamwork (or co-refereeing) as it relates to enjoyment and awareness in officiating and how it enhances the psychological well being of handball referees. Future studies should investigate the relationship between factors influencing perceived teamwork efficacy and officiating performance outcome. PMID- 28572784 TI - Inertial Sensors to Assess Gait Quality in Patients with Neurological Disorders: A Systematic Review of Technical and Analytical Challenges. AB - Gait disorders are major causes of falls in patients with neurological diseases. Understanding these disorders allows prevention and better insights into underlying diseases. InertiaLocoGraphy (ILG) -the quantification of gait by using inertial measurement units (IMUs) -shows great potential to address this public health challenge, but protocols vary widely and normative values of gait parameters are still unavailable. This systematic review critically compares ILG protocols, questions features extracted from inertial signals and proposes a semeiological analysis of clinimetric characteristics for use in neurological clinical routine. For this systematic review, PubMed, Cochrane and EMBASE were searched for articles assessing gait quality by using IMUs that were published from January 1, 2014 to August 31, 2016. ILG was used to assess gait in a wide range of neurological disorders - including Parkinson disease, mild cognitive impairment, Alzheimer disease, cerebral palsy, and cerebellar atrophy - as well as in the faller or frail older population and in people presenting rheumatological pathologies. However, results have not yet been driving changes in clinical practice. One reason could be that studies mainly aimed at comparing pathological gait to healthy gait, but there is stronger need for semiological descriptions of gait perturbation, severity or prognostic assessment. Furthermore, protocols used to assess gait using IMUs are too many. Likely, outcomes are highly heterogeneous and difficult to compare across large panels of studies. Therefore, homogenization is needed to foster the use of ILG to assess gait quality in neurological routine practice. The pros and cons of each protocol are emphasized so that a compromise can be reached. As well, analysis of seven complementary clinical criteria (springiness, sturdiness, smoothness, steadiness, stability, symmetry, synchronization) is advocated. PMID- 28572785 TI - Age of Acquisition Effects on Word Processing for Chinese Native Learners' English: ERP Evidence for the Arbitrary Mapping Hypothesis. AB - The present study aimed at distinguishing processing of early learned L2 words from late ones for Chinese natives who learn English as a foreign language. Specifically, we examined whether the age of acquisition (AoA) effect arose during the arbitrary mapping from conceptual knowledge onto linguistic units. The behavior and ERP data were collected when 28 Chinese-English bilinguals were asked to perform semantic relatedness judgment on word pairs, which represented three stages of word learning (i.e., primary school, junior and senior high schools). A 3 (AoA: early vs. intermediate vs. late) * 2 (regularity: regular vs. irregular) * 2 (semantic relatedness: related vs. unrelated) * 2 (hemisphere: left vs. right) * 3 (brain area: anterior vs. central vs. posterior) within subjects design was adopted. Results from the analysis of N100 and N400 amplitudes showed that early learned words had an advantage in processing accuracy and speed; there is a tendency that the AoA effect was more pronounced for irregular word pairs and in the semantic related condition. More important, ERP results showed early acquired words induced larger N100 amplitudes for early AoA words in the parietal area and more negative-going N400 than late acquire words in the frontal and central regions. The results indicate the locus of the AoA effect might derive from the arbitrary mapping between word forms and semantic concepts, and early acquired words have more semantic interconnections than late acquired words. PMID- 28572786 TI - Editorial: Novel Approaches to Teaching Scientific Thinking: Psychological Perspectives. PMID- 28572787 TI - Childhood Depression: Relation to Adaptive, Clinical and Predictor Variables. AB - The study had two goals: (1) to explore the relations between self-assessed childhood depression and other adaptive and clinical variables (2) to identify predictor variables of childhood depression. Participants were 420 students aged 7-10 years old (53.3% boys, 46.7% girls). Results revealed: (1) positive correlations between depression and clinical maladjustment, school maladjustment, emotional symptoms, internalizing and externalizing problems, problem behaviors, emotional reactivity, and childhood stress; and (2) negative correlations between depression and personal adaptation, global self-concept, social skills, and resilience (sense of competence and affiliation). Linear regression analysis including the global dimensions revealed 4 predictors of childhood depression that explained 50.6% of the variance: high clinical maladjustment, low global self-concept, high level of stress, and poor social skills. However, upon introducing the sub-dimensions, 9 predictor variables emerged that explained 56.4% of the variance: many internalizing problems, low family self-concept, high anxiety, low responsibility, low personal self-assessment, high social stress, few aggressive behaviors toward peers, many health/psychosomatic problems, and external locus of control. The discussion addresses the importance of implementing prevention programs for childhood depression at early ages. PMID- 28572788 TI - Corrigendum: What the Heck Is Salience? How Predictive Language Processing Contributes to Sociolinguistic Perception. AB - [This corrects the article on p. 1115 in vol. 7, PMID: 27536257.]. PMID- 28572789 TI - Impaired Baroreflex Sensitivity after Bilateral Convulsive Seizures in Patients with Focal Epilepsy. AB - BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is probably due to an autonomic failure in the early postictal phase after bilateral convulsive seizures (BCS) in the majority of cases. The baroreflex sensitivity (BRS) is an established and reliable biomarker of autonomic function and sudden cardiac death. OBJECTIVE: To investigate whether postictal BRS depends on seizure type. METHODS: Beat-to-beat systemic blood pressure and heart rate were continuously and non-invasively recorded with the ccNexfin(r) device in patients with focal epilepsy undergoing video-EEG monitoring. BRS was calculated using the sequence as well as the spectral method. A random mixed linear model was applied to analyze the influence of seizure type on BRS during three different time periods of 15-min length each (interictal, preictal, and postictal). In addition, the possible effects of other factors (hypertension, hemispheric lateralization of ictal activity, epilepsy type, body position, vigilance state) were explored. Data are given as median with interquartile range. RESULTS: A total of 26 seizures of 26 patients were analyzed. In BCS (n = 7), BRS significantly dropped from a preictal value of 15.0 ms/mm Hg (13.0-19.4) and an interictal value of 15.6 ms/mm Hg (12.0-20.4) to 3.1 ms/mm Hg (2.7-10.5) during the postictal period (p < 0.0001) according to the sequence method. This finding was replicated with the spectral method. In contrast, focal seizures (n = 19) did not lead to significant alterations of BRS in the postictal phase. CONCLUSION: Postictal BRS depends on the seizure type and is markedly impaired after BCS. The present study provides further evidence for a disturbed autonomic function following BCS. These findings might be related to cardiovascular failure in the context of SUDEP. PMID- 28572790 TI - Photolysis of Caged-GABA Rapidly Terminates Seizures In Vivo: Concentration and Light Intensity Dependence. AB - The therapy of focal epilepsy remains unsatisfactory for as many as 25% of patients. The photolysis of caged-gamma-aminobutyric acid (caged-GABA) represents a novel and alternative option for the treatment of intractable epilepsy. Our previous experimental results have demonstrated that the use of blue light produced by light-emitting diode to uncage ruthenium-bipyridine triphenylphosphine-c-GABA (RuBi-GABA) can rapidly terminate paroxysmal seizure activity both in vitro and in vivo. However, the optimal concentration of RuBi GABA, and the intensity of illumination to abort seizures, remains unknown. The aim of this study was to explore the optimal anti-seizure effects of RuBi-GABA by using implantable fibers to introduce blue light into the neocortex of a 4 aminopyridine-induced acute seizure model in rats. We then investigated the effects of different combinations of RuBi-GABA concentrations and light intensity upon seizure. Our results show that the anti-seizure effect of RuBi-GABA has obvious concentration and light intensity dependence. This is the first example of using an implantable device for the photolysis of RuBi-GABA in the therapy of neocortical seizure, and an optimal combination of RuBi-GABA concentration and light intensity was explored. These results provide important experimental data for future clinical translational studies. PMID- 28572791 TI - Hunger and Satiety Gauge Reward Sensitivity. AB - Many of the neurocircuits and hormones known to underlie the sensations of hunger and satiety also substantially alter the activity of the dopaminergic reward system. Much interest lies in the ways that hunger, satiety, and reward tie together, as the epidemic of obesity seems tied to the recent development and mass availability of highly palatable foods. In this review, we will first discuss the basic neurocircuitry of the midbrain and basal forebrain reward system. We will elaborate how several important mediators of hunger-the agouti related protein neurons of the arcuate nucleus, the lateral hypothalamic nucleus, and ghrelin-enhance the sensitivity of the dopaminergic reward system. Then, we will elaborate how mediators of satiety-the nucleus tractus solitarius, pro opiomelanocortin neurons of the arcuate nucleus, and its peripheral hormonal influences such as leptin-reduce the reward system sensitivity. We hope to provide a template by which future research may identify the ways in which highly rewarding foods bypass this balanced system to produce excessive food consumption. PMID- 28572792 TI - Lactic Acid Bacteria and Bifidobacteria with Potential to Design Natural Biofunctional Health-Promoting Dairy Foods. AB - Consumer interest in healthy lifestyle and health-promoting natural products is a major driving force for the increasing global demand of biofunctional dairy foods. A number of commercial sources sell synthetic formulations of bioactive substances for use as dietary supplements. However, the bioactive-enrichment of health-oriented foods by naturally occurring microorganisms during dairy fermentation is in increased demand. While participating in milk fermentation, lactic acid bacteria can be exploited in situ as microbial sources for naturally enriching dairy products with a broad range of bioactive components that may cover different health aspects. Several of these bioactive metabolites are industrially and economically important, as they are claimed to exert diverse health-promoting activities on the consumer, such as anti-hypertensive, anti inflammatory, and anti-diabetic, anti-oxidative, immune-modulatory, anti cholesterolemic, or microbiome modulation. This review aims at discussing the potential of these health-supporting bacteria as starter or adjunct cultures for the elaboration of dairy foods with a broad spectrum of new functional properties and added value. PMID- 28572793 TI - Bacteriocin-Producing Enterococcus faecium LCW 44: A High Potential Probiotic Candidate from Raw Camel Milk. AB - Bacterial isolates from raw camel milk were screened for antibacterial activity using the agar diffusion assay. Ten isolates selected for their inhibition of Gram-positive bacteria were identified by 16S sequencing as Enterococcus faecium or durans. An isolate named E. faecium LCW 44 exhibited the broadest antibacterial spectrum with an inhibitory activity against several Gram-positive strains belonging to the genera Clostridium, Listeria, Staphylococcus, and Lactobacillus. E. faecium LCW 44 was shown to produce N-formylated enterocins L50A and L50B, as revealed by mass spectrometry and PCR analyses. This isolate did not harbor any of the virulence factors tested and was shown to be sensitive to all tested antibiotics. It showed high resistance to gastric and intestinal conditions (78 +/- 4% survival). Its adhesion index was evaluated at 176 +/- 86 and 24 +/- 86 on Caco-2 cells and HT-29 cells, respectively, and it significantly reduced adhesion of Listeria monocytogenes by 65 and 49%, respectively. In Macfarlane broth (simulating the nutrient content of the colon), counts of L. monocytogenes were reduced by 2 log10 cycles after 24 h in co-culture with E. faecium LCW 44, compared to the increase of 4 log10 cycles when cultured alone. Comparison with a bacteriocin-non-producing mutant of E. faecium LCW 44 strongly suggests that inhibition of L. monocytogenes was due to bacteriocin production. Altogether, E. faecium LCW 44 thus has potential for use as a probiotic for humans and veterinary medicine. PMID- 28572795 TI - Cephalosporin-Glycopeptide Combinations for Use against Clinical Methicillin Resistant Staphylococcus aureus Isolates: Enhanced In vitro Antibacterial Activity. AB - The empirical combination of both a beta-lactam and glycopeptide to counter potential staphylococcal pathogens may improve the clinical outcomes for cases of Staphylococcus aureus bacteremia. We reported comparative in vitro studies of combination effects of different cephalosporins (i.e., cefazolin, cefmetazole, cefotaxime, and cefepime) combined with glycopeptides for 34 randomly selected methicillin-resistant S. aureus (MRSA) isolates by three methods, including the checkerboard, time-killing, and combination MIC measurement methods. Thirteen SCCmec type III isolates with a cefazolin MIC of >= 128 MUg/mL were classified as the high-cefazolin MIC (HCM) group, whereas 13 SCCmec type IV and 8 SCCmec type V isolates were classified as the low-cefazolin MIC (LCM) group. With the checkerboard method, synergism was present for vancomycin-based combinations at 30.8-69.2 and 13.6-66.7%, as well as teicoplanin-based combinations of 38.5-84.6 and 0-47.6%, of the HCM and LCM isolates, respectively. No antagonism was noted. The in vitro inhibitory activity was evident even at a low concentration of 1/512x MIC of cephalosporin combined with sub-inhibitory concentrations (1/2x MIC) of a glycopeptide. With time-killing assays, synergism was noted at 1/2x or 1x susceptible breakpoint concentrations (SBCs) of a cephalosporin combined with 1/4 or 1/2 MIC of a glycopeptide. In the presence of 1/2 SBC of a cephalosporin, vancomycin or teicoplanin MICs decreased an average of 2.0- to 6.6- or 1.6- to 5.5-fold, respectively. With 8 MUg/mL cephalosporin, the decline of glycopeptide MICs was most obvious in the presence of cefmetazole. In conclusion, cephalosporin-glycopeptide combinations at clinically achievable concentrations can exhibit in vitro synergistic antibacterial activity against clinical MRSA isolates. Such combinations require more clinical data to support their application for use in human MRSA infections. PMID- 28572794 TI - New Genotypes of Enterocytozoon bieneusi Isolated from Sika Deer and Red Deer in China. AB - To examine the occurrence and genotype distribution of Enterocytozoon bieneusi in cervids, 615 fecal samples were collected from red deer (Cervus elaphus) and sika deer (Cervus nippon) on 10 different farms in Henan and Jilin Province. Enterocytozoon bieneusi was identified and genotyped with a nested PCR analysis of the internal transcribed spacer (ITS) region of the rRNA genes, showing an average infection rate of 35.9% (221/615). In this study, 25 ITS genotypes were identified including seven known genotypes (BEB6, EbpC, EbpA, D, HLJDI, HLJD-IV, and COS-I) and 18 novel genotypes (designated JLD-I to JLD-XIV, HND-I to HND-IV). Among these, BEB6 (131/221, 59.3%) was the predominant genotype (P < 0.01), followed by HLJDI (18/221, 8.1%) and JLD-VIII (16/221, 7.2%). BEB6 has recently been detected in humans and nonhuman primates in China. The phylogenetic analysis showed that BEB6, HLJDI, HLJD-IV, COS-I, and 10 novel genotypes (JLD-VII to JLD XIV, HND-III to HND-IV) clustered in group 2. Genotype D, EbpC, and EbpA, known to cause human microsporidiosis worldwide, clustered in group 1, the members of which have zoonotic potential, together with eight novel genotypes (JLD-I to JLD VI, HND-I to HND-II). Therefore, deer may play a role in the transmission of E. bieneusi to humans. PMID- 28572797 TI - Electrochemical Potential Influences Phenazine Production, Electron Transfer and Consequently Electric Current Generation by Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa has gained interest as a redox mediator (phenazines) producer in bioelectrochemical systems. Several biotic and abiotic factors influence the production of phenazines in synergy with the central virulence factors production regulation. It is, however, not clear how the electrochemical environment may influence the production and usage of phenazines by P. aeruginosa. We here determined the influence of the electrochemical potential on phenazine production and phenazine electron transfer capacity at selected applied potentials from -0.4 to +0.4 V (vs. Ag/AgClsat) using P. aeruginosa strain PA14. Our study reveals a profound influence of the electrochemical potential on the amount of phenazine-1-carboxylate production, whereby applied potentials that were more positive than the formal potential of this dominating phenazine (E degrees 'PCA = -0.24 V vs. Ag/AgClsat) stimulated more PCA production (94, 84, 128, and 140 MUg mL-1 for -0.1, 0.1, 0.2, and 0.3 V, respectively) compared to more reduced potentials (38, 75, and 7 MUg mL-1 for -0.4, -0.3, and -0.24 V, respectively). Interestingly, P. aeruginosa seems to produce an additional redox mediator (with E degrees ' ~ 0.052 V) at applied potentials below 0 V, which is most likely adsorbed to the electrode or present on the cells forming the biofilm around electrodes. At fairly negative applied electrode potentials, both PCA and the unknown redox compound mediate cathodic current generation. This study provides important insights applicable in optimizing the BES conditions and cultures for effective production and utilization of P. aeruginosa phenazines. It further stimulates investigations into the physiological impacts of the electrochemical environment, which might be decisive in the application of phenazines for electron transfer with P. aeruginosa pure- or microbial mixed cultures. PMID- 28572798 TI - Phylogenetic Diversity of T4-Type Phages in Sediments from the Subtropical Pearl River Estuary. AB - Viruses are an abundant and active component of marine sediments and play a significant role in microbial ecology and biogeochemical cycling at local and global scales. To obtain a better understanding of the ecological characteristics of the viriobenthos, the abundance and morphology of viruses and the diversity and community structure of T4-type phages were systematically investigated in the surface sediments of the subtropical Pearl River Estuary (PRE). Viral abundances ranged from 4.49 * 108 to 11.7 * 108 viruses/g and prokaryotic abundances ranged from 2.63 * 108 to 9.55 * 108 cells/g, and both decreased from freshwater to saltwater. Diverse viral morphotypes, including tailed, spherical, filamentous, and rod-shaped viruses, were observed using transmission electron microscopy. Analysis of the major capsid gene (g23) indicated that the sediment T4-type phages were highly diverse and, similar to the trend in viral abundances, their diversity decreased as the salinity increased. Phylogenetic analysis suggested that most of the g23 operational taxonomic units were affiliated with marine, paddy soil, and lake groups. The T4-type phage communities in freshwater and saltwater sediments showed obvious differences, which were related to changes in the Pearl River discharge. The results of this study demonstrated both allochthonous and autochthonous sources of the viral community in the PRE sediments and the movement of certain T4-type viral groups between the freshwater and saline water biomes. PMID- 28572796 TI - Host-Parasite Interactions in Human Malaria: Clinical Implications of Basic Research. AB - The malaria parasite, Plasmodium, is one of the oldest parasites documented to infect humans and has proven particularly hard to eradicate. One of the major hurdles in designing an effective subunit vaccine against the malaria parasite is the insufficient understanding of host-parasite interactions within the human host during infections. The success of the parasite lies in its ability to evade the human immune system and recruit host responses as physiological cues to regulate its life cycle, leading to rapid acclimatization of the parasite to its immediate host environment. Hence understanding the environmental niche of the parasite is crucial in developing strategies to combat this deadly infectious disease. It has been increasingly recognized that interactions between parasite proteins and host factors are essential to establishing infection and virulence at every stage of the parasite life cycle. This review reassesses all of these interactions and discusses their clinical importance in designing therapeutic approaches such as design of novel vaccines. The interactions have been followed from the initial stages of introduction of the parasite under the human dermis until asexual and sexual blood stages which are essential for transmission of malaria. We further classify the interactions as "direct" or "indirect" depending upon their demonstrated ability to mediate direct physical interactions of the parasite with host factors or their indirect manipulation of the host immune system since both forms of interactions are known to have a crucial role during infections. We also discuss the many ways in which this understanding has been taken to the field and the success of these strategies in controlling human malaria. PMID- 28572799 TI - An Endophytic Bacterial Strain Isolated from Eucommia ulmoides Inhibits Southern Corn Leaf Blight. AB - Bacillus subtilis DZSY21 isolated from the leaves of Eucommia ulmoides oliv. was labeled by antibiotic marker and found to effectively colonize the leaves of maize plant. Agar diffusion assays and biocontrol effect experiments showed that strain DZSY21 and its lipopeptides had antagonistic activity against Bipolaris maydis, as well as high biocontrol effects on southern corn leaf blight caused by B. maydis. Using MALDI-TOF-MS analysis, we detected the presence of antimicrobial surfactin A, surfactin B, and fengycin in the strain DZSY21. Signaling pathways mediated by DZSY21 were analyzed by testing the expression of key plant genes involved in regulation of salicylic acid (SA) or JA/ET pathways, the defense related genes PR1 and LOX were concurrently expressed in the leaves of DZSY21 treated plants; this corresponded to slight increase in the expression level of PDF1.2 and decreases in ERF gene transcription levels. The results indicated an induced systemic response that is dependent on the SA and jasmonic acid (JA) pathways. Thus, we hypothesized that the strain DZSY21 inhibits B. maydis by producing antifungal lipopeptides and activating an induced systemic response through SA- and JA-dependent signaling pathways. This work describes a mechanism behind reduced disease severity in plants inoculated with the endophytic bacteria DZSY21. PMID- 28572800 TI - Profiling of Campylobacter jejuni Proteome in Exponential and Stationary Phase of Growth. AB - Campylobacter jejuni has been reported as a major cause of bacterial food-borne enteritides in developed countries during the last decade. Despite its fastidious growth requirements, including low level of oxygen and high level of CO2, this pathogen is able to persist in the environment without permanent loss of its viability and virulence. As C. jejuni is not able to multiply outside a host, the cells spend significant amount of time in stationary phase of growth. The entry into the stationary phase is often correlated to resistance to various stresses in bacteria. The switching between exponential and stationary phases is frequently mediated by the regulator sigma S (RpoS). However, this factor is absent in C. jejuni and molecular mechanisms responsible for transition of cells to the stationary phase remain elusive. In this work, proteomic profiles of cells from exponential and stationary phases were compared using 2-D electrophoresis (2DE) fingerprinting combined with mass spectrometry analysis and qRT-PCR. The identified proteins, whose expression differed between the two phases, are mostly involved in protein biosynthesis, carbon metabolism, stress response and motility. Altered expression was observed also in the pleiotropic regulator CosR that was over-expressed during stationary phase. A shift between transcript and protein level evolution of CosR throughout the growth of C. jejuni was observed using qRT-PCR and (2DE). From these data, we hypothesized that CosR could undergo a negative autoregulation in stationary phase. A consensus sequence resulting from promoter sequence alignment of genes potentially regulated by CosR, including its own upstream region, among C. jejuni strains is proposed. To verify experimentally the potential autoregulation of CosR at the DNA level, electrophoretic mobility shift assay was performed with DNA fragments of CosR promoter region and rCosR. Different migration pattern of the promoter fragments indicates the binding capacity of CosR, suggesting its auto-regulation potential. PMID- 28572801 TI - Elevated Levels of Proinflammatory Cytokines in Cerebrospinal Fluid of Multiple Sclerosis Patients. AB - Multiple sclerosis (MS) is an autoimmune neurodegenerative disease characterized by chronic brain inflammation. Leukocyte infiltration of brain tissue causes inflammation, demyelination, and the subsequent formation of sclerotic plaques, which are a hallmark of MS. Activation of proinflammatory cytokines is essential for regulation of lymphocyte migration across the blood-brain barrier. We demonstrate increased levels of many cytokines, including IL-2RA, CCL5, CCL11, MIF, CXCL1, CXCL10, IFNgamma, SCF, and TRAIL, were upregulated in cerebrospinal fluid (CSF), whereas IL-17, CCL2, CCL3, CCL4, and IL-12(p40) were activated in MS serum. Interaction analysis of cytokines in CSF demonstrated a connection between IFNgamma and CCL5 as well as MIF. Many cells can contribute to production of these cytokines including CD8 and Th1 lymphocytes and astrocytes. Therefore, we suggest that IFNgamma released by Th1 lymphocytes can activate astrocytes, which then produce chemoattractants, including CCL5 and MIF. These chemokines promote an inflammatory milieu and interact with multiple chemokines including CCL27 and CXCL1. Of special note, upregulation of CCL27 was found in CSF of MS cases. This observation is the first to demonstrate CCL27 as a potential contributor of brain pathology in MS. Our data suggest that CCL27 may be involved in activation and migration of autoreactive encephalitogenic immune effectors in the brain. Further, our data support the role of Th1 lymphocytes in the pathogenesis of brain inflammation in MS, with several cytokines playing a central role. PMID- 28572803 TI - Insulin-Like Growth Factor Binding Protein 6 in Rheumatoid Arthritis: A Possible Novel Chemotactic Factor? AB - OBJECTIVES: Immune cell migration from the bloodstream to target tissues is a hallmark of rheumatoid arthritis (RA) pathogenesis. The role of chemoattractants, mainly chemokines, and their possible targeting for therapeutic purposes have been under intense investigation over the last few years but the results were not as satisfactory as expected. The insulin-like growth factor binding protein 6 (IGFBP6), a direct inhibitor of insulin-like growth factor (IGF)-II, also exerts IGF-independent effects including tumor cell migration in vitro. We aimed to assess the expression of this protein in serum, synovial fluid, and synovial tissue (ST) of RA patients and to identify its possible chemotactic role in this disorder. METHODS: IGFBP6 was measured in RA patients and healthy donors (HD) sera by Luminex xMAP(r) technology and in ST of RA patients and osteoarthritis (OA) controls by immunofluorescence. The identification of circulating IGFBP6+ cells was evaluated by flow cytometry and an in vitro migration assay was arranged. RESULTS: We demonstrated that IGFBP6 is able to induce greater in vitro migration of RA as compared to HD and OA T lymphocytes and is overexpressed in serum and ST of RA patients. This in vitro chemotactic activity can be partially inhibited by dexamethasone. CONCLUSION: Our findings suggest a pathogenic role of IGFBP6 in RA and support its possible targeting for therapeutic purposes. PMID- 28572802 TI - Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity. AB - Significant progress has been made in recent years toward realizing the potential of natural killer (NK) cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also the established NK cell line NK-92 is being developed for adoptive immunotherapy, and general safety of infusion of irradiated NK-92 cells has been established in phase I clinical trials with clinical responses observed in some of the cancer patients treated. To enhance their therapeutic utility, NK-92 cells have been modified to express chimeric antigen receptors (CARs) composed of a tumor-specific single chain fragment variable antibody fragment fused via hinge and transmembrane regions to intracellular signaling moieties such as CD3zeta or composite signaling domains containing a costimulatory protein together with CD3zeta. CAR-mediated activation of NK cells then bypasses inhibitory signals and overcomes NK resistance of tumor cells. In contrast to primary NK cells, CAR-engineered NK-92 cell lines suitable for clinical development can be established from molecularly and functionally well-characterized single cell clones following good manufacturing practice compliant procedures. In preclinical in vitro and in vivo models, potent antitumor activity of NK-92 variants targeted to differentiation antigens expressed by hematologic malignancies, and overexpressed or mutated self-antigens associated with solid tumors has been found, encouraging further development of CAR-engineered NK-92 cells. Importantly, in syngeneic mouse tumor models, induction of endogenous antitumor immunity after treatment with CAR-expressing NK 92 cells has been demonstrated, resulting in cures and long-lasting immunological memory protecting against tumor rechallenge at distant sites. Here, we summarize the current status and future prospects of CAR-engineered NK-92 cells as off-the shelf cellular therapeutics, with special emphasis on ErbB2 (HER2)-specific NK-92 cells that are approaching clinical application. PMID- 28572804 TI - Serum Cytokine Profiles Differentiating Hemorrhagic Fever with Renal Syndrome and Hantavirus Pulmonary Syndrome. AB - Hantavirus infection is an acute zoonosis that clinically manifests in two primary forms, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). HFRS is endemic in Europe and Russia, where the mild form of the disease is prevalent in the Tatarstan region. HPS is endemic in Argentina, as well as other countries of North and South American. HFRS and HPS are usually acquired via the upper respiratory tract by inhalation of virus contaminated aerosol. Although the pathogenesis of HFRS and HPS remains largely unknown, postmortem tissue studies have identified endothelial cells as the primary target of infection. Importantly, cell damage due to virus replication, or subsequent tissue repair, has not been documented. Since no single factor has been identified that explains the complexity of HFRS or HPS pathogenesis, it has been suggested that a cytokine storm may play a crucial role in the manifestation of both diseases. In order to identify potential serological markers that distinguish HFRS and HPS, serum samples collected during early and late phases of the disease were analyzed for 48 analytes using multiplex magnetic bead-based assays. Overall, serum cytokine profiles associated with HPS revealed a more pro inflammatory milieu as compared to HFRS. Furthermore, HPS was strictly characterized by the upregulation of cytokine levels, in contrast to HFRS where cases were distinguished by a dichotomy in serum cytokine levels. The severe form of hantavirus zoonosis, HPS, was characterized by the upregulation of a higher number of cytokines than HFRS (40 vs 21). In general, our analysis indicates that, although HPS and HFRS share many characteristic features, there are distinct cytokine profiles for these diseases. These profiles suggest a strong activation of an innate immune and inflammatory responses are associated with HPS, relative to HFRS, as well as a robust activation of Th1-type immune responses. Finally, the results of our analysis suggest that serum cytokines profiles of HPS and HFRS cases are consistent with the presence of extracellular matrix degradation, increased mononuclear leukocyte proliferation, and transendothelial migration. PMID- 28572806 TI - Impaired Autophagy and Defective T Cell Homeostasis in Mice with T Cell-Specific Deletion of Receptor for Activated C Kinase 1. AB - Autophagy plays a central role in maintaining T cell homeostasis. Our previous study has shown that hepatocyte-specific deficiency of receptor for activated C kinase 1 (RACK1) leads to lipid accumulation in the liver, accompanied by impaired autophagy, but its in vivo role in T cells remains unclear. Here, we report that mice with T cell-specific deletion of RACK1 exhibit normal intrathymic development of conventional T cells and regulatory T (Treg) cells but reduced numbers of peripheral CD4+ and CD8+ T cells. Such defects are cell intrinsic with impaired mitochondrial clearance, increased sensitivity to cell death, and decreased proliferation that could be explained by impaired autophagy. Furthermore, RACK1 is essential for invariant natural T cell development. In vivo, T cell-specific loss of RACK1 dampens concanavalin A-induced acute liver injury. Our data suggest that RACK1 is a key regulator of T cell homeostasis. PMID- 28572805 TI - Factor H Family Proteins in Complement Evasion of Microorganisms. AB - Human-pathogenic microbes possess various means to avoid destruction by our immune system. These include interactions with the host complement system that may facilitate pathogen entry into cells and tissues, expression of molecules that defuse the effector complement components and complexes, and acquisition of host complement inhibitors to downregulate complement activity on the surface of the pathogen. A growing number of pathogenic microorganisms have acquired the ability to bind the complement inhibitor factor H (FH) from body fluids and thus hijack its host protecting function. In addition to FH, binding of FH-related (FHR) proteins was also demonstrated for several microbes. Initial studies assumed that these proteins are complement inhibitors similar to FH. However, recent evidence suggests that FHR proteins may rather enhance complement activation both directly and also by competing with the inhibitor FH for binding to certain ligands and surfaces. This mini review focuses on the role of the main alternative pathway regulator FH in host-pathogen interactions, as well as on the emerging role of the FHR proteins as enhancers of complement activation. PMID- 28572807 TI - A New Adjuvant MTOM Mediates Mycobacterium tuberculosis Subunit Vaccine to Enhance Th1-Type T Cell Immune Responses and IL-2+ T Cells. AB - The only licensed vaccine Mycobacterium bovis Bacillus Calmette-Guerin (BCG) cannot prevent the prevalence of tuberculosis (TB), which remains a major public health problem worldwide. A more effective TB vaccine than BCG is urgently needed. Subunit vaccine is a promising strategy, and suitable adjuvants will benefit the development of effective TB subunit vaccines. MTO, consisting of monophosphoryl lipid A (MPLA), trehalose-6,6'-dibehenate (TDB), and MF59, was developed as an adjuvant of TB vaccine because of its ability to evoke the Th1 type T cell responses, while it is insufficient to induce single and multifunctional IL-2+ T cells and has a limited ability to confer protection against Mycobacterium tuberculosis infection. Heat-killed Mycobacterium vaccae (Mv), which can evoke cytotoxic CD8+ and CD4+ T cell responses and has adjuvanticity, was, in this study, combined with MTO to produce a new adjuvant, called MTOM. The TB fusion protein Rv3407-PhoY2-Ag85A-Rv2626c-RpfB (WH121) was mixed with MTO, Mv, and MTOM to produce three subunit vaccines, and the protective efficacy and immune responses were compared in C57BL/6 mice. WH121/MTOM provided better protection against TB than the other two vaccines, matching the performance of BCG vaccine. MTOM showed stronger ability to increase single and multifunctional IL-2+ T cells and induce Th1-type responses than MTO or Mv. Therefore, MTOM might be a promising adjuvant that could contribute to the development of TB subunit vaccines. PMID- 28572808 TI - Transcriptome-Wide Analysis of Botrytis elliptica Responsive microRNAs and Their Targets in Lilium Regale Wilson by High-Throughput Sequencing and Degradome Analysis. AB - MicroRNAs, as master regulators of gene expression, have been widely identified and play crucial roles in plant-pathogen interactions. A fatal pathogen, Botrytis elliptica, causes the serious folia disease of lily, which reduces production because of the high susceptibility of most cultivated species. However, the miRNAs related to Botrytis infection of lily, and the miRNA-mediated gene regulatory networks providing resistance to B. elliptica in lily remain largely unexplored. To systematically dissect B. elliptica-responsive miRNAs and their target genes, three small RNA libraries were constructed from the leaves of Lilium regale, a promising Chinese wild Lilium species, which had been subjected to mock B. elliptica treatment or B. elliptica infection for 6 and 24 h. By high throughput sequencing, 71 known miRNAs belonging to 47 conserved families and 24 novel miRNA were identified, of which 18 miRNAs were downreguleted and 13 were upregulated in response to B. elliptica. Moreover, based on the lily mRNA transcriptome, 22 targets for 9 known and 1 novel miRNAs were identified by the degradome sequencing approach. Most target genes for elliptica-responsive miRNAs were involved in metabolic processes, few encoding different transcription factors, including ELONGATION FACTOR 1 ALPHA (EF1a) and TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR 2 (TCP2). Furthermore, the expression patterns of a set of elliptica-responsive miRNAs and their targets were validated by quantitative real-time PCR. This study represents the first transcriptome-based analysis of miRNAs responsive to B. elliptica and their targets in lily. The results reveal the possible regulatory roles of miRNAs and their targets in B. elliptica interaction, which will extend our understanding of the mechanisms of this disease in lily. PMID- 28572809 TI - Hybrid Performance of an Immortalized F2 Rapeseed Population Is Driven by Additive, Dominance, and Epistatic Effects. AB - Genomics-based prediction of hybrid performance promises to boost selection gain. The main goal of our study was to investigate the relevance of additive, dominance, and epistatic effects for determining hybrid seed yield in a biparental rapeseed population. We re-analyzed 60,000 SNP array and seed yield data points from an immortalized F2 population comprised of 318 hybrids and 180 parental lines by performing genome-wide QTL mapping and predictions in combination with five-fold cross-validation. Moreover, an additional set of 37 hybrids were genotyped and phenotyped in an independent environment. The decomposition of the phenotypic variance components and the cross-validated results of the QTL mapping and genome-wide predictions revealed that the hybrid performance in rapeseed was driven by a mix of additive, dominance, and epistatic effects. Interestingly, the genome-wide prediction accuracy in the additional 37 hybrids remained high when modeling exclusively additive effects but was severely reduced when dominance or epistatic effects were also included. This loss in accuracy was most likely caused by more pronounced interactions of environments with dominance and epistatic effects than with additive effects. Consequently, the development of robust hybrid prediction models, including dominance and epistatic effects, required much deeper phenotyping in multi-environmental trials. PMID- 28572811 TI - Direct and Pollinator-Mediated Effects of Herbivory on Strawberry and the Potential for Improved Resistance. AB - The global decline in pollinators has partly been blamed on pesticides, leading some to propose pesticide-free farming as an option to improve pollination. However, herbivores are likely to be more prevalent in pesticide-free environments, requiring knowledge of their effects on pollinators, and alternative crop protection strategies to mitigate any potential pollination reduction. Strawberry leaf beetles (SLB) Galerucella spp. are important strawberry pests in Northern Europe and Russia. Given that SLB attack both leaf and flower tissue, we hypothesized pollinators would discriminate against SLB damaged strawberry plants (Fragaria vesca, cultivar 'Rugen'), leading to lower pollination success and yield. In addition we screened the most common commercial cultivar 'Rugen' and wild Swedish F. vesca genotypes for SLB resistance to assess the potential for inverse breeding to restore high SLB resistance in cultivated strawberry. Behavioral observations in a controlled experiment revealed that the local pollinator fauna avoided strawberry flowers with SLB-damaged petals. Low pollination, in turn, resulted in smaller more deformed fruits. Furthermore, SLB damaged flowers produced smaller fruits even when they were hand pollinated, showing herbivore damage also had direct effects on yield, independent of indirect effects on pollination. We found variable resistance in wild woodland strawberry to SLB and more resistant plant genotypes than the cultivar 'Rugen' were identified. Efficient integrated pest management strategies should be employed to mitigate both direct and indirect effects of herbivory for cultivated strawberry, including high intrinsic plant resistance. PMID- 28572810 TI - Roles, Regulation, and Agricultural Application of Plant Phosphate Transporters. AB - Phosphorus (P) is an essential mineral nutrient for plant growth and development. Low availability of inorganic phosphate (orthophosphate; Pi) in soil seriously restricts the crop production, while excessive fertilization has caused environmental pollution. Pi acquisition and homeostasis depend on transport processes controlled Pi transporters, which are grouped into five families so far: PHT1, PHT2, PHT3, PHT4, and PHT5. This review summarizes the current understanding on plant PHT families, including phylogenetic analysis, function, and regulation. The potential application of Pi transporters and the related regulatory factors for developing genetically modified crops with high phosphorus use efficiency (PUE) are also discussed in this review. At last, we provide some potential strategies for developing high PUE crops under salt or drought stress conditions, which can be valuable for improving crop yields challenged by global scarcity of water resources and increasing soil salinization. PMID- 28572812 TI - Halophytes: Potential Resources for Salt Stress Tolerance Genes and Promoters. AB - Halophytes have demonstrated their capability to thrive under extremely saline conditions and thus considered as one of the best germplasm for saline agriculture. Salinity is a worldwide problem, and the salt-affected areas are increasing day-by-day because of scanty rainfall, poor irrigation system, salt ingression, water contamination, and other environmental factors. The salinity stress tolerance mechanism is a very complex phenomenon, and some pathways are coordinately linked for imparting salinity tolerance. Though a number of salt responsive genes have been reported from the halophytes, there is always a quest for promising stress-responsive genes that can modulate plant physiology according to the salt stress. Halophytes such as Aeluropus, Mesembryanthemum, Suaeda, Atriplex, Thellungiella, Cakile, and Salicornia serve as a potential candidate for the salt-responsive genes and promoters. Several known genes like antiporters (NHX, SOS, HKT, VTPase), ion channels (Cl-, Ca2+, aquaporins), antioxidant encoding genes (APX, CAT, GST, BADH, SOD) and some novel genes such as USP, SDR1, SRP etc. were isolated from halophytes and explored for developing stress tolerance in the crop plants (glycophytes). It is evidenced that stress triggers salt sensors that lead to the activation of stress tolerance mechanisms which involve multiple signaling proteins, up- or down-regulation of several genes, and finally the distinctive or collective effects of stress-responsive genes. In this review, halophytes are discussed as an excellent platform for salt responsive genes which can be utilized for developing salinity tolerance in crop plants through genetic engineering. PMID- 28572813 TI - Cytosolic and Nuclear Co-localization of Betalain Biosynthetic Enzymes in Tobacco Suggests that Betalains Are Synthesized in the Cytoplasm and/or Nucleus of Betalainic Plant Cells. AB - Betalains replace anthocyanins as color pigments in most families of Caryophyllales. Unlike anthocyanins, betalains are derived from tyrosine via three enzymatic steps: hydroxylation of L-tyrosine to L-3,4 dihydroxyphenylalanine (L-DOPA; step 1), and conversion of L-DOPA to betalamic acid (step 2), and to cyclo-DOPA (cDOPA; step 3). The principal enzymes responsible for these reactions have been elucidated at the molecular level, but their subcellular localizations have not been explored; hence, the intracellular compartments wherein betalains are biosynthesized remain unknown. Here, we report on the subcellular localization of these principal enzymes. Bioinformatic predictors and N- and C-terminal GFP tagging in transgenic tobacco, showed that Beta vulgaris CYP76AD1 which mediates both steps 1 and 3, DODA1 that catalyzes step 2, and CYP76AD6 which also mediates step 1, were similarly localized to the cytoplasm and nucleus (although the P450s were also weakly present in the endoplasmic reticulum). These two compartments were also the principal locations of Mirabilis jalapa cDOPA5GT. The cytoplasmic and nuclear co-localization of these key enzymes in tobacco suggests that betalains are biosynthesized in the cytoplasm and/or nucleus of betalain-containing plant cells. Elucidation of the subcellular compartmentation of betalain biosynthesis will facilitate the bioengineering of the betalain biosynthetic pathway in non-betalain-containing plants. PMID- 28572815 TI - Corrigendum: Transcriptome Analysis of the Melon-Fusarium oxysporum f. sp. melonis Race 1.2 Pathosystem in Susceptible and Resistant Plants. AB - [This corrects the article on p. 362 in vol. 8, PMID: 28367157.]. PMID- 28572814 TI - Use of Blue-Green Fluorescence and Thermal Imaging in the Early Detection of Sunflower Infection by the Root Parasitic Weed Orobanche cumana Wallr. AB - Although the impact of Orobanche cumana Wallr. on sunflower (Helianthus annuus L.) becomes evident with emergence of broomrape shoots aboveground, infection occurs early after sowing, the host physiology being altered during underground parasite stages. Genetic resistance is the most effective control method and one of the main goals of sunflower breeding programmes. Blue-green fluorescence (BGF) and thermal imaging allow non-destructive monitoring of plant diseases, since they are sensitive to physiological disorders in plants. We analyzed the BGF emission by leaves of healthy sunflower plantlets, and we implemented BGF and thermal imaging in the detection of the infection by O. cumana during underground parasite development. Increases in BGF emission were observed in leaf pairs of healthy sunflowers during their development. Lower BGF was consistently detected in parasitized plants throughout leaf expansion and low pigment concentration was detected at final time, supporting the interpretation of a decrease in secondary metabolites upon infection. Parasite-induced stomatal closure and transpiration reduction were suggested by warmer leaves of inoculated sunflowers throughout the experiment. BGF imaging and thermography could be implemented for fast screening of sunflower breeding material. Both techniques are valuable approaches to assess the processes by which O. cumana alters physiology (secondary metabolism and photosynthesis) of sunflower. PMID- 28572817 TI - Development of a Novel Motor Imagery Control Technique and Application in a Gaming Environment. AB - We present a methodology for a hybrid brain-computer interface (BCI) system, with the recognition of motor imagery (MI) based on EEG and blink EOG signals. We tested the BCI system in a 3D Tetris and an analogous 2D game playing environment. To enhance player's BCI control ability, the study focused on feature extraction from EEG and control strategy supporting Game-BCI system operation. We compared the numerical differences between spatial features extracted with common spatial pattern (CSP) and the proposed multifeature extraction. To demonstrate the effectiveness of 3D game environment at enhancing player's event-related desynchronization (ERD) and event-related synchronization (ERS) production ability, we set the 2D Screen Game as the comparison experiment. According to a series of statistical results, the group performing MI in the 3D Tetris environment showed more significant improvements in generating MI associated ERD/ERS. Analysis results of game-score indicated that the players' scores presented an obvious uptrend in 3D Tetris environment but did not show an obvious downward trend in 2D Screen Game. It suggested that the immersive and rich-control environment for MI would improve the associated mental imagery and enhance MI-based BCI skills. PMID- 28572816 TI - Ergosterol isolated from the basidiomycete Pleurotus salmoneostramineus affects Trypanosoma cruzi plasma membrane and mitochondria. AB - BACKGROUND: Major drawbacks of the available treatment against Chagas disease (American trypanosomiasis) include its toxicity and therapeutic inefficiency in the chronic phase of the infection, which makes it a concern among neglected diseases. Therefore, the discovery of alternative drugs for treating chronic Chagas disease requires immediate action. In this work, we evaluated the mushroom Pleurotus salmoneostramineus in the search for potential antiparasitic compounds. METHODS: Fruit bodies of the basidiomycete Pleurotus salmoneostramineus were triturated and submitted to organic solvent extraction. After liquid-liquid partition of the crude extract, three fractions were obtained and the bioguided fractionation study was conducted to isolate the active metabolites. The elucidation of the chemical structure was performed using GC-MS and NMR techniques. The biological assays for antiparasitic activity were carried out using trypomastigotes of Trypanosoma cruzi and murine macrophages for mammalian cytotoxicity. The mechanism of action of the isolated compound used different fluorescent probes to evaluate the plasma membrane permeability, the potential of the mitochondrial membrane and the intracellular levels of reactive oxygen species (ROS). RESULTS: The most abundant fraction showing the antiparasitic activity was isolated and chemically elucidated, confirming the presence of ergosterol. It showed anti-Trypanosoma cruzi activity against trypomastigotes, with an IC50 value of 51.3 MUg/mL. The compound demonstrated no cytotoxicity against mammalian cells to the maximal tested concentration of 200 MUg/mL. The mechanism of action of ergosterol in Trypanosoma cruzi trypomastigotes resulted in permeabilization of the plasma membrane, as well as depolarization of mitochondrial membrane potential, leading to parasite death. Nevertheless, no increase in ROS levels could be observed, suggesting damages to plasma membrane rather than an induction of oxidative stress in the parasite. CONCLUSIONS: The selection of naturally antiparasitic secondary metabolites in basidiomycetes, such as ergosterol, may provide potential scaffolds for drug design studies against neglected diseases. PMID- 28572818 TI - Serum Alanine Aminotransferase Levels within Normal Range Have Different Associations with Augmentation Index and Other Cardiometabolic Risk Factors in Nondrinkers and Drinkers: A Chinese Community-Based Analysis. AB - BACKGROUND: To investigate whether serum alanine aminotransferase (ALT) levels within normal range were associated with augmentation index (AIx) and cardiometabolic risk factors in nondrinkers and drinkers in Chinese community dwelling population. METHODS: There were 4165 participants with serum ALT levels within normal range. RESULTS: Alcohol drinking was observed in 1173 participants (28.2%). In multivariate analysis, serum ALT levels of nondrinkers were independently associated with age, sex, body mass index (BMI), hypertension, diabetes mellitus, diastolic blood pressure, triglyceride, low-density lipoprotein-cholesterol (LDL-c), and AIx, while serum ALT levels of drinkers were independently associated with age, sex, BMI, triglyceride, and LDL-c (p < 0.05 for all). CONCLUSIONS: Associations of serum ALT levels within normal range with age, sex, body height and weight, and blood lipid were simultaneously present in participants with and without alcohol drinking, while associations of serum ALT levels within normal range with AIx, blood pressure, and glucose were seen in nondrinkers rather than in drinkers. These findings not only provide the evidence that serum ALT levels, even within the normal range, have different associations with arteriosclerosis and cardiometabolic risk factors in nondrinkers and drinkers but also are helpful in understanding the underlying pathophysiologic mechanisms linking the hepatic function to arteriosclerosis and cardiometabolic risk factors. PMID- 28572819 TI - The Validity and Reliability between Automated Oscillometric Measurement of Ankle Brachial Index and Standard Measurement by Eco-Doppler in Diabetic Patients with or without Diabetic Foot. AB - OBJECTIVE: To evaluate the concordance between oscillometric ABI and standard Doppler ABI in diabetic Chinese patients with or without diabetic foot. METHODS: 230 consecutive diabetic patients (n = 459 limbs) were included. The right and left ABIs were determined with both devices by the same investigator. The concordance and agreement were assessed by kappa index and the Bland-Altman method. RESULTS: The average Doppler ABI was 1.003 +/- 0.286 on the right and 0.990 +/- 0.287 on the left, while oscillometric ABI was 1.002 +/- 0.332 and 0.993 +/- 0.319, which had no significance. The average time for oscillometric ABI was 8.600 versus 16.980 minutes for Doppler ABI (p < 0.001). There was good agreement between the two measurements, with a kappa value of 0.869 on the right and 0.919 on the left. Regarding the Doppler ABI as the gold standard, the accuracy, sensitivity, specificity, +LR, and -LR of oscillometric ABI reached 95.22%, 94.34%, 95.48%, 20.873%, and 0.059% on the right. For the left, it was 96.94%, 96.43%, 97.11%, 33.364%, and 0.036%. CONCLUSIONS: The oscillometric measurement is a reliable, convenient, and less time-consuming alternative to standard Doppler ABI in patients. It should be widely used for PAD detection. PMID- 28572820 TI - TSH Variability of Patients Affected by Differentiated Thyroid Cancer Treated with Levothyroxine Liquid Solution or Tablet Form. AB - BACKGROUND: Recent guidelines from the American Thyroid Association (ATA) indicate that, in many patients affected by differentiated thyroid cancer (DTC), the serum TSH should be maintained between 0.1 and 0.5 mU/L. The purpose of this study was to evaluate the TSH variability of patients affected by DTC treated with liquid L-T4 formulation or in tablet form. PATIENTS AND METHODS: Patients were eligible if (a) they were submitted to a total thyroidectomy and 131I remnant ablation for DTC in our institution and (b) they were classified low-risk patients according to ATA guidelines 2009. Patients were randomized (1 : 1) to receive treatment of hypothyroidism with liquid L-T4 or tablet form. The first check-up evaluation was made from 8 to 12 months after 131I remnant ablation. TSH values were established again after further 12 months. RESULTS: A significant increase in TSH values (median) was observed in patients taking tablets [TSH (min max): 0.28 (0.1-0.45) versus 0.34 (0.01-0.78) mIU/L, p = 0.041] as compared to those taking liquid formulation [TSH (min-max): 0.28 (0.1-0.47) versus 0.30 (0.1 0.55) mIU/L, p = 0.345]. CONCLUSIONS: The use of L-T4 liquid formulation, as compared to that of tablets, resulted in a significantly higher number of DTC patients maintaining TSH values in range for the ATA risk score, reducing TSH variability over the time. PMID- 28572822 TI - Correlation of Salivary Statherin and Calcium Levels with Dental Calculus Formation: A Preliminary Study. AB - BACKGROUND: Salivary constituents have a wide range of functions including oral calcium homeostasis. Salivary proteins such as statherin inhibit crystal growth of calcium phosphate in supersaturated solutions and interact with several oral bacteria to adsorb on hydroxyapatite. Concurrently, saliva, which is supersaturated with respect to calcium phosphates, is the driving force for plaque mineralization and formation of calculus. Thus, the aim of the present study was to estimate and correlate salivary statherin and calcium concentration to the dental calculus formation. METHODS: A cross-sectional study was conducted to assess the relationship between salivary statherin, calcium, and dental calculus among 70 subjects, aged 20-55 years. Subjects were divided into 3 groups based on the calculus scores as interpreted by Calculus Index which was followed by collection of whole saliva using Super*SALTM. Salivary calcium levels were assessed by calorimetric method using Calcium Assay kit (Cayman Chemical, Michigan, USA) and statherin levels by using ELISA Kit (Cusabio Biotech). RESULTS: Statherin levels showed a weak negative correlation with the calcium levels and with calculus formation. The mean salivary statherin and calcium concentration were found to be 0.96 MUg/ml and 3.87 mg/ml, respectively. Salivary statherin levels differed significantly among the three groups (p < 0.05). CONCLUSIONS: Our preliminary data indicates that statherin could possibly play a role in the formation of dental calculus. PMID- 28572821 TI - Association of Baseline Neutrophil-to-Lymphocyte Ratio with Clinicopathological Characteristics of Papillary Thyroid Carcinoma. AB - OBJECTIVE: To investigate the potential association of neutrophil-to-lymphocyte ratio (NLR), a surrogate systemic inflammatory biomarker, with clinical and pathological characteristics of papillary thyroid cancers. METHODS: 205 patients with papillary carcinoma were identified from the institutional thyroid cancer database between 2006 and 2015 (55 males, 150 females, mean age 51.2 +/- 14.7 years). NLR was calculated as the absolute neutrophil count divided by the absolute lymphocyte count, based on the preoperative complete blood cell counts. RESULTS: NLR was significantly higher in carcinomas with extrathyroidal invasion (2.74 +/- 01.24 versus 2.39 +/- 0.96, p = 0.04) and bilateral (2.67 +/- 1.15 versus 2.35 +/- 0.96, p = 0.03) and multifocal tumours (2.65 +/- 1.08 versus 2.29 +/- 0.96, p = 0.01), as well as lymph node-positive tumours (3.12 +/- 1.07 versus 2.41 +/- 1.02, p = 0.03). On the other hand, NLR values were not associated with gender, age, tumour size, histologic subtype, the presence of thyroiditis, and TNM staging. CONCLUSIONS: As an index of inflammation, NLR is inexpensive, readily available, and easy to extract from routine blood tests. We found increased NLR values in papillary carcinomas with poorer histopathological profile and more aggressive clinical behaviour. Whether this systemic inflammatory response, as expressed by the NLR, represents the inflammatory microenvironment leading to tumourigenesis, or is a tumour-associated phenomenon, remains to be elucidated and warrants further study. PMID- 28572823 TI - Stabilisation of Collagen Sponges by Glutaraldehyde Vapour Crosslinking. AB - Glutaraldehyde is a well-recognised reagent for crosslinking and stabilising collagens and other protein-based materials, including gelatine. In some cases, however, the use of solutions can disrupt the structure of the material, for example, by causing rapid dispersion or distortions from surface interactions. An alternative approach that has been explored in a number of individual cases is the use of glutaraldehyde vapour. In this study, the effectiveness of a range of different glutaraldehyde concentrations in the reservoir providing vapour, from 5% to 25% (w/v), has been explored at incubation times from 5 h to 48 h at room temperature. These data show the effectiveness of the glutaraldehyde vapour approach for crosslinking collagen and show that materials with defined, intermediate stability could be obtained, for example, to control resorption rates in vivo. PMID- 28572825 TI - Antidiabetic Compounds in Syzygium cumini Decoction and Ready to Serve Herbal Drink. AB - Herbal beverages with desirable sensory attributes are an ideal way to offer consumers with phytochemicals having specific health promoting functionalities. Syzygium cumini bark decoction is used in treating diabetes mellitus in Ayurveda medicine. This work attempted to prove the presence of antidiabetic compounds in the S. cumini decoction and the ready to serve (RTS) herbal drink developed using the decoction. Activity guided fractionation of the decoction of the S. cumini was carried out by sequential extraction with organic solvents of different polarities. Thin Layer Chromatography (TLC) with authentic compounds and HPLC were performed for identification and confirmation of the compounds in the decoction and the RTS herbal drink. Presence of gallic and ellagic acids in the decoction and RTS herbal drink was proven and confirmed with HPLC. The LC UV-VIS spectra of the two compounds were identical with the corresponding spectra of the library. Further, gallic acid and umbelliferone were determined as the active compounds in the decoction by TLC and were confirmed by cochromatography with authentic compounds. The present investigation confirmed the presence of gallic acid, ellagic acid, and umbelliferone which are proven to have antidiabetic activities in the decoction and the RTS herbal drink prepared with the decoction. PMID- 28572826 TI - Medical Benefits of Honeybee Products. PMID- 28572824 TI - Cytokine, Chemokine, and Growth Factor Profile Characterization of Undifferentiated and Osteoinduced Human Adipose-Derived Stem Cells. AB - Bone is the second most manipulated tissue after blood. Adipose-derived stem cells (ASCs) may become a convenient source of MSC for bone regenerative protocols. Surprisingly, little is known about the most significant biomolecules these cells produce and release after being osteoinduced. Therefore, the present study aimed at dosing 13 candidates chosen among the most representative cytokines, chemokines, and growth factors within the conditioned media of osteodifferentiated and undifferentiated ASCs. Two acknowledged osteoblastic cell models, that is, MG-63 and SaOs-2 cells, were compared. Notably, IL-6, IL-8, MCP 1, and VEGF were highly produced and detectable in ASCs. In addition, while IL-6 and IL-8 seemed to be significantly induced by the osteogenic medium, no such effect was seen for MCP-1 and VEGF. Overall SaOS-2 had a poor expression profile, which may be consistent with the more differentiated phenotype of SaOs-2 compared to ASCs and MG-63. Instead, in maintaining medium, MG-63 displayed a very rich production of IL-12, MCP-1, IP-10, and VEGF, which were significantly reduced in osteogenic conditions, with the only exception of MCP-1. The high expression of MCP-1 and VEGF, even after the osteogenic commitment, may support the usage of ASCs in bone regenerative protocols by recruiting both osteoblasts and osteoclasts of the host. PMID- 28572827 TI - Protective Effect of 18beta-Glycyrrhetinic Acid against Triptolide-Induced Hepatotoxicity in Rats. AB - Triptolide (TP) is the major active component of Tripterygium wilfordii Hook F (TWHF) and possesses multiple pharmacological effects. However, hepatotoxicity of TP which is one of the toxic properties slows its progression in clinical application. 18beta-Glycyrrhetinic acid (GA) is the main bioactive ingredient of Licorice (Glycyrrhiza glabra L.), a herbal medicine famous for its detoxification. This study aims to investigate whether GA possesses protective effect against TP-induced hepatotoxicity in rats. TP interference markedly elevated serum levels of ALT, AST, and ALP, caused evident liver histopathological changes, and elevated hepatic TNF-alpha, IL-6, IL-1beta, and IFN-gamma as well as nuclear translocation of NF-kappaB. TP also significantly elevated liver MDA and declined hepatic activities of SOD, CAT, and GSH-Px. Assay of TUNEL and apoptosis proteins (Bax, Bcl-2, and active caspase-3) showed that TP induced severe hepatocellular apoptosis. In contrast, low-dose GA (50 mg/kg) significantly reversed TP-induced changes above. However, high-dose GA (100 mg/kg) had no such effect. Overall, these findings indicated that low-dose GA but not high-dose GA exhibited a protective effect against TP-induced hepatotoxicity in rats by anti-inflammation, antioxidation, and antiapoptosis, which suggests that the doses of GA/Licorice should be carefully considered when used together with TWHF or TWHF preparations. PMID- 28572828 TI - Apigenin Inhibits Human SW620 Cell Growth by Targeting Polyamine Catabolism. AB - Apigenin is a nonmutagenic flavonoid that has antitumor properties. Polyamines are ubiquitous cellular polycations, which play an important role in the proliferation and differentiation of cancer cells. Highly regulated pathways control the biosynthesis and degradation of polyamines. Ornithine decarboxylase (ODC) is the rate-limiting enzyme in the metabolism, and spermidine/spermine-N1 Acetyl transferase (SSAT) is the rate-limiting enzyme in the catabolism of polyamines. In the current study, the effect of increasing concentrations of apigenin on polyamine levels, ODC and SSAT protein expression, mRNA expression, cell proliferation and apoptosis, and the production of reactive oxygen species (ROS) was investigated in SW620 colon cancer cells. The results showed that apigenin significantly reduced cell proliferation, decreased the levels of spermidine and spermine, and increased previously downregulated putrescine contents. Apigenin also enhanced SSAT protein and mRNA levels and the production of reactive oxygen species in SW620 cells, though it had no significant effect on the levels of ODC protein or mRNA. Apigenin appears to decrease the proliferation rate of human SW620 cells by facilitating SSAT expression to induce polyamine catabolism and increasing ROS levels to induce cell apoptosis. PMID- 28572829 TI - Investigating Potential Modes of Actions of Mimusops kummel Fruit Extract and Solvent Fractions for Their Antidiarrheal Activities in Mice. AB - BACKGROUND: Fruits of Mimusops kummel A. DC. (Sapotaceae) are traditionally used for the treatment of diarrhea. The present study aimed at investigating modes of actions of this fruits for antidiarrheal action to guide future drug development process. METHODS: Fractions of chloroform, n-butanol, and water were obtained from 80% methanol extract, which was prepared by maceration. Antidiarrheal activities and the modes of actions were investigated in mice. RESULTS: In castor oil induced diarrheal model, the extract delayed onset of diarrhea and reduced number and weight of feces at all tested doses significantly. In this model all fractions significantly delayed onset of diarrhea at all tested doses. Charcoal meal test showed that the extract and all the fractions produced a significant antimotility effect at all tested doses. Enteropooling test showed that the extract as well as n-butanol and aqueous fractions at all tested doses produced a significant decline in volume and weight of intestinal contents, whereas chloroform fraction had substantial effect only at high dose. CONCLUSION: This study demonstrated that the extract and solvent fractions produced antidiarrheal activities due to dual inhibitory effect, intestinal motility, and fluid secretion, with the aqueous fraction being the most active among fractions in three models. PMID- 28572830 TI - Astragalus Extract Mixture HT042 Improves Bone Growth, Mass, and Microarchitecture in Prepubertal Female Rats: A Microcomputed Tomographic Study. AB - Astragalus extract mixture HT042 is a standardized multiherbal mixture comprising Astragalus membranaceus, Eleutherococcus senticosus, and Phlomis umbrosa, which has proven to promote children's height growth. The aim of this study was to investigate the effects of HT042 on longitudinal bone growth, bone mass, and bone microstructure in growing rats using a high-resolution microcomputed tomography system. Four-week-old female rats were fed an HT042-containing diet for 2 weeks. Tibial length was measured at baseline and weekly in vivo. At the end of the study, volumetric bone mineral density (vBMD) and microarchitectural parameters were estimated in the trabecular and cortical bone of the tibia. Tibial length gain was significantly increased by HT042 compared to that reported with the control diet. In the proximal tibial metaphysis, HT042-treated rats had significantly higher trabecular vBMD, bone volume fraction, and trabecular number and lower trabecular separation, trabecular pattern factor, and structure model index values than control rats did. Total cross-sectional area and bone area of the cortical bone in the tibial diaphysis also increased. These findings suggest that HT042 increases longitudinal bone growth rate, improves trabecular bone mass, and enhances the microarchitecture of trabecular and cortical bone during growth. PMID- 28572831 TI - The Effect of Pudilan Anti-Inflammatory Oral Liquid on the Treatment of Mild Recurrent Aphthous Ulcers. AB - Recurrent aphthous ulcers are the most common recurrent oral mucosal lesions characterized by recurrence and pain. The aim of this research is to evaluate the short-term curative effect of the traditional Chinese medicine "Pudilan anti inflammatory oral liquid" on mild recurrent aphthous ulcers. A total of 234 patients were divided into a treatment group and a control group. Both groups used vitamin B2 as the basis of treatment. The treatment group took a Pudilan anti-inflammatory oral solution for 8 days while the control group was given a liquid placebo. The ulcer size, pseudomembrane, peripheral congestion, and pain scores of the treatment group were lower than before treatment. The curative effect on the Pudilan group was statistically significant compared with the control group. The final therapeutic effect on the treatment group was better than that on the control group. The healing time of mild recurrent aphthous ulcers can be shortened by Pudilan anti-inflammatory oral liquid, and pain is relieved without adverse reactions. Pudilan provides a new reference drug for the treatment of mild recurrent oral ulcers. PMID- 28572832 TI - A case report of Lhermitte-Duclos disease revealed by psychiatric disturbances. AB - BACKGROUND: Lhermitte-Duclos disease (LDD) is a rare cerebellar lesion characterized by a hamartomatous lesion in the posterior fossa. Mainly diagnosed by MRI, the clinical presentation is usually made of neurological symptoms. CASE PRESENTATION: We present here a rare case of a woman who developed depressive symptoms that inaugurated the clinical presentation of LDD. CONCLUSION: Psychiatric symptoms may occur in all brain lesions, delaying the diagnosis and causing therapeutic escalation. More attention should be given by practitioners to psychiatric aspects of LDD. PMID- 28572833 TI - Development of high-throughput methods to screen disease caused by Rhizoctonia solani AG 2-1 in oilseed rape. AB - BACKGROUND: Rhizoctonia solani (Kuhn) is a soil-borne, necrotrophic fungus causing damping off, root rot and stem canker in many cultivated plants worldwide. Oilseed rape (OSR, Brassica napus) is the primary host for anastomosis group (AG) 2-1 of R. solani causing pre- and post-emergence damping-off resulting in death of seedlings and impaired crop establishment. Presently, there are no known resistant OSR genotypes and the main methods for disease control are fungicide seed treatments and cultural practices. The identification of sources of resistance for crop breeding is essential for sustainable management of the disease. However, a high-throughput, reliable screening method for resistance traits is required. The aim of this work was to develop a low cost, rapid screening method for disease phenotyping and identification of resistance traits. RESULTS: Four growth systems were developed and tested: (1) nutrient media plates, (2) compost trays, (3) light expanded clay aggregate (LECA) trays, and (4) a hydroponic pouch and wick system. Seedlings were inoculated with virulent AG 2-1 to cause damping-off disease and grown for a period of 4-10 days. Visual disease assessments were carried out or disease was estimated through image analysis using ImageJ. CONCLUSION: Inoculation of LECA was the most suitable method for phenotyping disease caused by R. solani AG 2-1 as it enabled the detection of differences in disease severity among OSR genotypes within a short time period whilst allowing measurements to be conducted on whole plants. This system is expected to facilitate identification of resistant germplasm. PMID- 28572834 TI - StreAM-[Formula: see text]: algorithms for analyzing coarse grained RNA dynamics based on Markov models of connectivity-graphs. AB - BACKGROUND: In this work, we present a new coarse grained representation of RNA dynamics. It is based on adjacency matrices and their interactions patterns obtained from molecular dynamics simulations. RNA molecules are well-suited for this representation due to their composition which is mainly modular and assessable by the secondary structure alone. These interactions can be represented as adjacency matrices of k nucleotides. Based on those, we define transitions between states as changes in the adjacency matrices which form Markovian dynamics. The intense computational demand for deriving the transition probability matrices prompted us to develop StreAM-[Formula: see text], a stream based algorithm for generating such Markov models of k-vertex adjacency matrices representing the RNA. RESULTS: We benchmark StreAM-[Formula: see text] (a) for random and RNA unit sphere dynamic graphs (b) for the robustness of our method against different parameters. Moreover, we address a riboswitch design problem by applying StreAM-[Formula: see text] on six long term molecular dynamics simulation of a synthetic tetracycline dependent riboswitch (500 ns) in combination with five different antibiotics. CONCLUSIONS: The proposed algorithm performs well on large simulated as well as real world dynamic graphs. Additionally, StreAM-[Formula: see text] provides insights into nucleotide based RNA dynamics in comparison to conventional metrics like the root-mean square fluctuation. In the light of experimental data our results show important design opportunities for the riboswitch. PMID- 28572835 TI - Symmetry-controlled time structure of high-harmonic carrier fields from a solid. AB - High-harmonic (HH) generation in crystalline solids1-6 marks an exciting development, with potential applications in high-efficiency attosecond sources7, all-optical bandstructure reconstruction8,9, and quasiparticle collisions10,11. Although the spectral1-4 and temporal shape5 of the HH intensity has been described microscopically1-6,12, the properties of the underlying HH carrier wave have remained elusive. Here we analyse the train of HH waveforms generated in a crystalline solid by consecutive half cycles of the same driving pulse. Extending the concept of frequency combs13-15 to optical clock rates, we show how the polarization and carrier-envelope phase (CEP) of HH pulses can be controlled by crystal symmetry. For some crystal directions, we can separate two orthogonally polarized HH combs mutually offset by the driving frequency to form a comb of even and odd harmonic orders. The corresponding CEP of successive pulses is constant or offset by pi, depending on the polarization. In the context of a quantum description of solids, we identify novel capabilities for polarization- and phase-shaping of HH waveforms that cannot be accessed with gaseous sources. PMID- 28572837 TI - Serum EBV antibodies and LMP-1 in Polish patients with oropharyngeal and laryngeal cancer. AB - BACKGROUND: The association between Epstein-Barr virus (EBV) and the development of head and neck cancer was reported by many researchers. The aim of the present study was to detect EBV DNA and EBV antibodies in 110 Polish patients with oropharyngeal and laryngeal cancer compared to 40 healthy individuals. METHODS: Frozen tumor tissue fragments were tested using nested PCR assay for EBV DNA detection. Sera from all individuals were investigated using ELISA tests to detect the presence of VCA IgM and IgG, EBNA IgG, EA IgG. RESULTS: EBV DNA was detected in 52.7% of the patients (25% in controls). EBVCA were detected in 94.5%, EBNA in 96.4% and EA in 94.5% of patients. The significantly higher level of EA in the patients suggests EBV reactivation. The majority of patients (83%) were infected with wild-type EBV. CONCLUSION: Our study showed that this variant seems to be associated with oropharyngeal and laryngeal cancer in the Polish population. PMID- 28572836 TI - LPS promotes resistance to TRAIL-induced apoptosis in pancreatic cancer. AB - BACKGROUND: Though TRAIL has been hailed as a promising drug for tumour treatment, it has been observed that many tumour cells have developed escape mechanisms against TRAIL-induced apoptosis. As a receptor of LPS, TLR 4, which is expressed on a variety of cancer cells, can be associated with TRAIL-resistance of tumour cells and tumour progression as well as with the generation of an anti tumour immune response. METHODS: In this study, the sensitivity to TRAIL-induced apoptosis as well as the influence of LPS-co-stimulation on the cell viability of the pancreatic cancer cell lines PANC-1, BxPC-3 and COLO 357 was examined by FACS analyses and a cell viability assay. Subsequently, the expression of TRAIL receptors was detected via FACS analyses. Levels of osteoprotegerin (OPG) were also determined using an enzyme-linked immunosorbent assay. RESULTS: PANC-1 cells were shown to be resistant to TRAIL-induced apoptosis. This was accompanied by significantly increased osteoprotegerin levels and a significantly decreased expression of DR4. In contrast, TRAIL significantly induced apoptosis in COLO 357 cells and to a lesser degree in BxPC-3 cells. Co-stimulation of COLO 357 as well as BxPC-3 cells combining TRAIL and LPS resulted in a significant decrease in TRAIL-induced apoptosis. In COLO 357 cells TRAIL-stimulation decreased the levels of OPG thereby not altering the expression of the TRAIL-receptors 1-4 resulting in a high susceptibility to TRAIL-induced apoptosis. Co-stimulation with LPS and TRAIL completely reversed the effect of TRAIL on OPG levels reaching a 2-fold increase beyond the level of non-stimulated cells resulting in a lower susceptibility to apoptosis. In BxPC-3, TRAIL stimulation decreased the expression of DR4 and significantly increased the decoy receptors TRAIL-R3 and TRAIL-R4 leading to a decrease in TRAIL-induced apoptosis. OPG levels remained unchanged. Co-stimulation with TRAIL and LPS further enhanced the changes in TRAIL-receptor-expression promoting apoptosis resistance. CONCLUSIONS: Here it has been shown that TRAIL-resistance in pancreatic cancer cells can be mediated by the inflammatory molecule LPS as well as by different expression patterns of functional and non-functional TRAIL-receptors. PMID- 28572839 TI - Non-pulmonary cancer risk following tuberculosis: a nationwide retrospective cohort study in Lithuania. AB - BACKGROUND: Lithuania remains one of the highest tuberculosis burden countries in Europe. Epidemiological studies have long pointed to infections as important factors of cancer aetiology, but the association between tuberculosis and the risk of non-pulmonary cancers has rarely been tested and results have been inconsistent. The aim of this population-based cohort study was to examine the risk of cancer among patients diagnosed with tuberculosis using data from Lithuanian Tuberculosis, Cancer and Resident's Registries. METHODS: The study cohort included 21,986 tuberculosis patients yielding 1583 cancers diagnosed during follow-up (1998-2012). Standardized incidence ratios (SIRs) and 95% confidence intervals (95% CIs) were calculated to compare the incidence of cancer among cohort participants with the general population for overall, non-pulmonary, site-specific cancers, as well as for subgroups of smoking-related, alcohol related, hormone-related and haematological cancers. RESULTS: The SIRs of all cancers combined were 1.89, 95% CI: 1.79-2.00 in men and 1.34, 95% CI: 1.19-1.50 in women. Risk was increased 3-fold within the first year following diagnosis; it decreased during later years, although remained significantly elevated for >=5 years. Elevated long-term increased risks persisted for non-pulmonary cancers overall, and for cancers of mouth and pharynx, oesophagus, stomach, larynx, cervix uteri and leukaemias. Tuberculosis was associated with a decreased risk of melanoma. Increased risks were observed for smoking-related cancers in men (SIR 1.95, 95% CI: 1.79-2.13) and women (SIR 1.46, 95% CI: 1.22-1.73), alcohol-related cancers in men (SIR 2.40; 95% CI: 2.14-2.68) and haematological cancers in men (SIR 1.73, 95% CI: 1.33-2.23). The risk of hormone-related cancers was 18% lower (SIR = 0.82, 95% CI: 0.66-0.997) among women, the inverse association was weaker among men (SIR = 0.95, 95% CI: 0.84-1.07). CONCLUSIONS: The risk of total and several non-pulmonary cancers was elevated in a cohort of tuberculosis patients. The recommendation for the awareness of this association among physicians is warranted. Analysis suggests a reduction in risk of hormone-related cancers and melanoma. PMID- 28572838 TI - Seroprevalence of antibodies against Kaposi's sarcoma-associated herpesvirus among HIV-negative people in China. AB - BACKGROUND: Little information on the prevalence of Kaposi's sarcoma associated herpesvirus (KSHV) among HIV-negative individuals is available from Asia. METHODS: In the present study, we report findings from a new survey of KSHV in 983 HIV-negative male migrants from Shanghai and their combination with previous similar surveys of 600 female migrants, 600 female sex-workers (FSW), 1336 sexually transmitted infection (STI) clinic male patients, 439 intravenous drug users (IVDU), and 226 men having sex with men (MSM) from China. KSHV-specific antibodies against latent and lytic antigens were assessed using Sf9 and BC3 monoclonal immunofluorescence assay. Age-adjusted prevalence ratios (PR) and 95% confidence interval (95% CI) for KSHV-positivity were estimated using Poisson regression. RESULTS: In total, 4184 HIV-negative participants were included. KSHV prevalence ranged from 9.8% (95% CI: 7.9%-11.7%) in male migrants to 32.3% (95% CI: 24.1%-34.1%) in MSM. IVDU show intermediate level (17.5%, 95%CI: 14.1% 21.4%). KSHV was associated with syphilis (PR = 2.03, 95% CI: 1.38-2.98) in MSM but not in other groups. An association with human herpes virus 2 was also found among MSM (PR = 1. 83, 95%: 1.22-2.75) but not in migrant workers or FSW. CONCLUSIONS: KSHV prevalence in HIV-negative heterosexuals, FSW, and STI male patients from China is approximately 10%, but 2- and 3-fold higher in IVDU and MSM, respectively. Associations of KSHV with STIs among MSM only suggest that sexual transmission of the virus is important in MSM but not in heterosexuals. PMID- 28572840 TI - Low levels of viral suppression among refugees and host nationals accessing antiretroviral therapy in a Kenyan refugee camp. AB - BACKGROUND: Refugees and host nationals who accessed antiretroviral therapy (ART) in a remote refugee camp in Kakuma, Kenya (2011-2013) were compared on outcome measures that included viral suppression and adherence to ART. METHODS: This study used a repeated cross-sectional design (Round One and Round Two). All adults (>=18 years) receiving care from the refugee camp clinic and taking antiretroviral therapy (ART) for >=30 days were invited to participate. Adherence was measured by self-report and monthly pharmacy refills. Whole blood was measured on dried blood spots. HIV-1 RNA was quantified and treatment failures were submitted for drug resistance testing. A remedial intervention was implemented in response to baseline testing. The primary outcome was viral load <5000 copies/mL. The two study rounds took place in 2011-2013. RESULTS: Among eligible adults, 86% (73/85) of refugees and 84% (86/102) of Kenyan host nationals participated in the Round One survey; 60% (44/73) and 58% (50/86) of Round One participants were recruited for Round Two follow-up viral load testing. In Round One, refugees were older than host nationals (median age 36 years, interquartile range, IQR 31, 41 vs 32 years, IQR 27, 38); the groups had similar time on ART (median 147 weeks, IQR 38, 64 vs 139 weeks, IQR 39, 225). There was weak evidence for a difference between proportions of refugees and host nationals who were virologically suppressed (<5000 copies/mL) after 25 weeks on ART (58% vs 43%, p = 0.10) and no difference in the proportions suppressed at Round Two (74% vs 70%, p = 0.66). Mean adherence within each group in Round One was similar. Refugee status was not associated with viral suppression in multivariable analysis (adjusted odds ratio: 1.69, 95% CI 0.79, 3.57; p = 0.17). Among those not suppressed at either timepoint, 69% (9/13) exhibited resistance mutations. CONCLUSIONS: Virologic outcomes among refugees and host nationals were similar but unacceptably low. Slight improvements were observed after a remedial intervention. Virologic monitoring was important for identifying an underperforming ART program in a remote facility that serves refugees alongside host nationals. This work highlights the importance of careful laboratory monitoring of vulnerable populations accessing ART in remote settings. PMID- 28572842 TI - Grid-based stochastic search for hierarchical gene-gene interactions in population-based genetic studies of common human diseases. AB - BACKGROUND: Large-scale genetic studies of common human diseases have focused almost exclusively on the independent main effects of single-nucleotide polymorphisms (SNPs) on disease susceptibility. These studies have had some success, but much of the genetic architecture of common disease remains unexplained. Attention is now turning to detecting SNPs that impact disease susceptibility in the context of other genetic factors and environmental exposures. These context-dependent genetic effects can manifest themselves as non additive interactions, which are more challenging to model using parametric statistical approaches. The dimensionality that results from a multitude of genotype combinations, which results from considering many SNPs simultaneously, renders these approaches underpowered. We previously developed the multifactor dimensionality reduction (MDR) approach as a nonparametric and genetic model-free machine learning alternative. Approaches such as MDR can improve the power to detect gene-gene interactions but are limited in their ability to exhaustively consider SNP combinations in genome-wide association studies (GWAS), due to the combinatorial explosion of the search space. We introduce here a stochastic search algorithm called Crush for the application of MDR to modeling high-order gene-gene interactions in genome-wide data. The Crush-MDR approach uses expert knowledge to guide probabilistic searches within a framework that capitalizes on the use of biological knowledge to filter gene sets prior to analysis. Here we evaluated the ability of Crush-MDR to detect hierarchical sets of interacting SNPs using a biology-based simulation strategy that assumes non-additive interactions within genes and additivity in genetic effects between sets of genes within a biochemical pathway. RESULTS: We show that Crush-MDR is able to identify genetic effects at the gene or pathway level significantly better than a baseline random search with the same number of model evaluations. We then applied the same methodology to a GWAS for Alzheimer's disease and showed base level validation that Crush-MDR was able to identify a set of interacting genes with biological ties to Alzheimer's disease. CONCLUSIONS: We discuss the role of stochastic search and cloud computing for detecting complex genetic effects in genome-wide data. PMID- 28572844 TI - Editorial. PMID- 28572843 TI - Malignant Struma ovarii in a 30-year old nulliparous patient. AB - BACKGROUND: Struma ovarii is a rare monodermal germ cell tumor where the ovary is comprised of at least half thyroid tissue. This phenomenon may indicate an embryological origin. CASE PRESENTATION: A 30-year old nulliparous woman presented with acute right lower quadrant pain and underwent laparoscopic right salpingo-oophorectomy. The excised ovarian mass showed evidence of struma-derived papillary thyroid carcinoma. Ultrasound of the thyroid showed mild enlargement with two solid nodules. A fine needle aspirate of a thyroid nodule was positive for malignancy and a total thyroidectomy was performed. Microscopic features of the thyroid were consistent with papillary thyroid carcinoma. The two tumours were considered as synchronous independent primaries based on their histological presentation. CONCLUSIONS: We believe that aggressive surgical management followed by radioiodine therapy is best to reduce recurrence risk and optimize survival. The broad scope of interventions needed to treat malignant struma ovarii require a strong interdisciplinary team. PMID- 28572841 TI - De novo assembly, functional annotation, and analysis of the giant reed (Arundo donax L.) leaf transcriptome provide tools for the development of a biofuel feedstock. AB - BACKGROUND: Arundo donax has attracted renewed interest as a potential candidate energy crop for use in biomass-to-liquid fuel conversion processes and biorefineries. This is due to its high productivity, adaptability to marginal land conditions, and suitability for biofuel and biomaterial production. Despite its importance, the genomic resources currently available for supporting the improvement of this species are still limited. RESULTS: We used RNA sequencing (RNA-Seq) to de novo assemble and characterize the A. donax leaf transcriptome. The sequencing generated 1249 million clean reads that were assembled using single-k-mer and multi-k-mer approaches into 62,596 unique sequences (unitranscripts) with an N50 of 1134 bp. TransDecoder and Trinotate software suites were used to obtain putative coding sequences and annotate them by mapping to UniProtKB/Swiss-Prot and UniRef90 databases, searching for known transcripts, proteins, protein domains, and signal peptides. Furthermore, the unitranscripts were annotated by mapping them to the NCBI non-redundant, GO and KEGG pathway databases using Blast2GO. The transcriptome was also characterized by BLAST searches to investigate homologous transcripts of key genes involved in important metabolic pathways, such as lignin, cellulose, purine, and thiamine biosynthesis and carbon fixation. Moreover, a set of homologous transcripts of key genes involved in stomatal development and of genes coding for stress-associated proteins (SAPs) were identified. Additionally, 8364 simple sequence repeat (SSR) markers were identified and surveyed. SSRs appeared more abundant in non-coding regions (63.18%) than in coding regions (36.82%). This SSR dataset represents the first marker catalogue of A. donax. 53 SSRs (PolySSRs) were then predicted to be polymorphic between ecotype-specific assemblies, suggesting genetic variability in the studied ecotypes. CONCLUSIONS: This study provides the first publicly available leaf transcriptome for the A. donax bioenergy crop. The functional annotation and characterization of the transcriptome will be highly useful for providing insight into the molecular mechanisms underlying its extreme adaptability. The identification of homologous transcripts involved in key metabolic pathways offers a platform for directing future efforts in genetic improvement of this species. Finally, the identified SSRs will facilitate the harnessing of untapped genetic diversity. This transcriptome should be of value to ongoing functional genomics and genetic studies in this crop of paramount economic importance. PMID- 28572845 TI - The Foundation of the British Elbow and Shoulder Society (BESS). PMID- 28572846 TI - Legal and psychological considerations for obtaining informed consent for reverse total shoulder arthroplasty. AB - This paper seeks to outline recent legal developments and requirements pertinent to obtaining informed consent. We argue that this is of particular relevance to patients considering a reverse total shoulder arthroplasty, due to the high complication rate associated with this procedure. By examining the cognitive processes involved in decision-making, and other clinician-related factors such as delivery of information, gender bias and conflict of interest, we explore some of the barriers that can undermine the processes of shared decision-making and obtaining genuine informed consent. We argue that these issues highlight the importance for surgeons in understanding the cognitive processes and other influential factors involved in patients' comprehension and decision-making. We recommend, based on strong evidence, that decision aids could prove useful in overcoming such challenges and could provide one way of mitigating the ethical, professional and legal consequences of failing to obtain proper informed consent. They are not widely used in orthopaedics at present, although it would be in the interests of both the surgeon and patient for such measures to be explored. PMID- 28572847 TI - Outcome of partial repair of massive rotator cuff tears with and without human tissue allograft bridging repair. AB - BACKGROUND: The surgical management of massive rotator cuff tears remains a challenge. It is suggested that, even in a massive tear that appears irreparable, attempting to repair it as much as possible can be helpful in improving functional outcomes. However the results can be short term and variable. The purpose of our study was to determine if human tissue allograft bridged repair of massive irreparable rotator cuff tears to achieve a complete repair produces similar outcomes compared to partial repair alone. METHODS: We prospectively reviewed outcome scores in 13 patients who underwent partial repair alone for massive irreparable rotator cuff tears and compared them to 13 patients who had partial repairs bridged with allograft. Oxford and Constant scores were compared pre-operatively and at a minimum follow-up of 2 years (range 2 years to 5 years). RESULTS: The mean improvement in the Constant score at final follow-up compared to pre-operative scores was 27.7 points in the partial repair group and 42.8 points in the allograft group (p < 0.01). The Oxford Shoulder Score improved mean of 19.3 points in the partial repair group and 29 points in the allograft group (p < 0.02) at 2 years. CONCLUSIONS: Human tissue matrix allograft provides a better outcome for open bridging of irreparable rotator cuff tears than partial repair alone. PMID- 28572849 TI - Ulnohumeral dislocation despite intact radiocapitellar joint: a rare Monteggia variant. AB - We treated one patient with a mid-diaphyseal radius fracture and concomitant anteromedial facet fracture of the coronoid. The ulnohumeral joint was severely unstable by complete ligament detachment and interosseous membrane rupture. Despite this gross instability, the radiocapitellar was congruent and stable. The possible mechanism of radiocapitellar stability is discussed and the concept of concavity-compression stability across the radiocapitellar joint is emphasized. PMID- 28572848 TI - Shoulder impingement syndrome: a systematic review of clinical trial participant selection criteria. AB - BACKGROUND: Shoulder impingement syndrome (SIS) is a common diagnosis for patients with pain and dysfunction of the shoulder. Variations in the signs and symptoms might lead to uncertainty regarding the definition of SIS. The aim of this review is to explore the participant selection criteria used in the literature when investigating SIS and to assess differences in criteria among treating professions. METHODS: This is a PRISMA systematic review of publications from 2009 to 2014 from MEDLINE, PubMed, The Cochrane Library, Embase, Scopus and CINAHL. RESULTS: Ninety-seven articles met inclusion criteria for this review. Twenty-five different surgical and nonsurgical treatments were investigated. Impingement-specific index tests were used in all studies. Exclusion index tests were used in 62% of studies. Twenty index tests were identified. Radiological investigations were reported in 53% of all studies, of which a further 53% reported using two or more radiological investigations. CONCLUSIONS: This systematic review has illustrated that studies investigating SIS test for various signs and symptoms, which is in keeping with describing the condition as a 'syndrome'. However, there are inconsistencies in participant selection criteria between health disciplines, highlighting a need for harmonization of the selection criteria in the form of an international editorial consensus. PMID- 28572850 TI - The treatment of multidirectional instability of the shoulder with a rehabilitation programme: Part 2. AB - BACKGROUND: The most commonly recommended initial treatment for multidirectional instability is a rehabilitation program. Although there is evidence to support the effect of conservative management on this condition, the published literature provides little information on the exercise parameters of such programs. METHODS: This paper is the second part of a two-part series that outlines a six-stage rehabilitation program for multidirectional instability with a focus on scapula control and exercise drills into functional positions. This paper outlines stages 3 to 6 of this rehabilitation program. RESULTS AND CONCLUSIONS: This clinical protocol is currently being tested for efficacy as part of a randomized controlled trial (Australian New Zealand Clinical Trials Registry #ACTRN12613001240730). The information in this paper and additional online supplementary files will provide therapists with adequate detail to replicate the rehabilitation program in the clinical setting. PMID- 28572851 TI - The validity and reliability of ultrasound on identifying supraspinatus tears during passive external rotation from 0 degrees to 30 degrees : a pilot project. AB - BACKGROUND: Controversy exists regarding how much external rotation should be allowed following rotator cuff repair. Clinicians may use ultrasound imaging (USI) to visualize the supraspinatus (SSp) tendon during passive external rotation. However, the validity and reliability of USI used to assess supraspinatus tendon gap formation during external rotation needs to be established prior to using this technique in patient cohorts. METHODS: Ten subjects with magnetic resonance imaging (MRI) confirmation of full-thickness SSp tears were matched to 10 control subjects. Images of the SSp were obtained at 0 degrees , 10 degrees , 20 degrees and 30 degrees of external rotation by a blinded tester on two occasions to establish both validity and reliability of the measure. RESULTS: Validity was established as 70% agreement between the USI and MRI confirmed SSp tear group; reliability was established at greater than 0.90 at all positions of external rotation measured. CONCLUSIONS: USI may be used to detect SSp tears with 70% validity, and the technique is reliable in all positions of external rotation. PMID- 28572853 TI - Corrigendum. AB - [This corrects the article DOI: 10.1177/1758573216652086.]. PMID- 28572854 TI - Corrigendum. AB - [This corrects the article DOI: 10.1177/1758573216666705.]. PMID- 28572852 TI - Primary elbow arthroplasty: problems and solutions. AB - Prosthetic replacement of the elbow joint has continued to improve over time. Widespread implantation of certain designs has led to identification a few successful elements of elbow arthroplasty, as well as several opportunities for improvement. Current hot topics in elbow arthroplasty include triceps-preserving exposures, implantation of components with better-expected wear performance, management of the ulnar nerve, prevention of infection, and the development of successful cementless components. Total elbow arthroplasty has the potential to improve pain, function and quality of life for many patients with articular destruction secondary to inflammatory arthropathy or as a consequence of trauma. Continued advances in this field are key to make this operation as reliable and lasting as hip or knee arthroplasty. PMID- 28572855 TI - Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is associated with the metabolic syndrome and its individual components. AB - BACKGROUND: The metabolic syndrome (MetS) comprises several cardiometabolic risk factors associated with increased risk for both type 2 diabetes and cardiovascular disease. Skin autofluorescence (SAF), a non-invasive biomarker of advanced glycation end products accumulation, is associated with cardiovascular complications in subjects with diabetes. The aim of the present study was to examine the association between SAF and the presence of MetS as well as its individual components in a general population. METHODS: For this cross-sectional analysis, we included 78,671 non-diabetic subjects between 18 and 80 years of age who participated in the LifeLines Cohort Study and had SAF measurement obtained non-invasively using the AGE Reader. MetS was defined according to the revised NCEP ATP III criteria. Students unpaired t test was used to test differences between groups. Both logistic and linear regression analyses were performed in order to test associations between the individual MetS components and SAF. RESULTS: Subjects with MetS had higher SAF (2.07 +/- 0.45 arbitrary units, AU) compared to individuals without MetS (1.89 +/- 0.42 AU) (p < 0.001). There was a positive association between the number of MetS components and higher SAF Z scores (p < 0.001). Individuals in the highest SAF tertile had a higher presence of MetS (OR 2.61; 95% CI 2.48-2.75) and some of the individual components compared to subjects in the lowest SAF tertile. After correction for age, gender, creatinine clearance, HbA1c and smoking status, only elevated blood pressure and low HDL cholesterol remained significantly associated with higher SAF (p = 0.002 and p = 0.001 respectively). CONCLUSION: Skin autofluorescence was associated with the presence of MetS and some of its individual components. In addition, increasing SAF Z-scores were observed with a higher number of MetS components. Prospective studies are needed to establish whether SAF can be used as an (additional) screening tool to predict both cardiovascular disease and type 2 diabetes in high-risk populations. PMID- 28572857 TI - Changes in health-related quality of life in elderly men after 12 weeks of strength training. AB - BACKGROUND: Muscular strength is associated with functional ability in elderly, and older adults are recommended to perform muscle-strengthening exercise. Understanding how improved muscle strength and -mass influence general and specific domains of quality of life is important when planning health promotion efforts targeting older adults. The aims of the present study were to describe changes in health-related quality of life (HRQOL) in older men participating in 12 weeks of systematic strength training, and to investigate whether improvements in muscle strength and muscle mass are associated with enhancements in HRQOL. METHODS: We recruited 49 men aged 60-81 years to participate in an intervention study with pre-post assessment. The participants completed a 12-week strength training program consisting of three sessions per week. Tests and measurements aimed at assessing change in HRQOL, and changes in physical performance (maximal strength) and physiological characteristics. HRQOL was measured using the 12-item short-form survey (SF-12). Muscle mass was assessed based on changes in lean mass (leg, trunk, arm, and total), and strength was measured as one-repetition maximum in leg extension, leg press, and biceps curl. RESULTS: Two of the eight HRQOL SF 12 scores, role physical and general health, and the physical component summary scores, increased significantly during the intervention period. Small significant positive correlations were identified between improvements in muscle strength, and better physical and social function. Moreover, a significant increase in total muscle mass was seen during the intervention period. CONCLUSIONS: The positive, findings from this study would suggest that systematic strength training seems to be a beneficial intervention to improve HRQOL, muscle strength and muscle mass in older men. PMID- 28572856 TI - Unacylated ghrelin modulates circulating angiogenic cell number in insulin resistant states. AB - BACKGROUND: Type 2 diabetes (T2D) is associated with reduced numbers and impaired function of circulating angiogenic cells (CAC) which contributes to the progression of atherosclerosis and microvascular disease. Previous studies suggest that short-term infusion of unacylated ghrelin (UAG) normalizes CAC number in patients with T2D. To determine dose-dependent effects of short-term infusion of UAG in T2D patients using a cross-over model, and of long-term infusion of UAG in obese mice, on differentiation of monocyte progenitors into CAC. METHODS: Eight overweight T2D patients were infused overnight with 3 and 10 ug/kg/h of UAG in a double-blind, placebo-controlled cross-over study. To assess the effects of long-term UAG treatment, obese mice were infused with UAG for 4 weeks. Monocyte progenitors were assessed for their ability to differentiate into CAC in vitro. RESULTS: In T2D patients, UAG treatment caused a reduction in differentiation of CAC, dependent on UAG dose and differentiation method. However, mice treated with UAG showed a significant increase in differentiation of bone marrow progenitors into CAC. CONCLUSION: UAG causes a minor suppressive effect on CAC development after short-term treatment in humans, but experiments in mice suggest that long-term treatment has beneficial effects on CAC formation. The Netherlands Trial Register: TC=2487. PMID- 28572858 TI - Determinants of Bullying at School Depending on the Type of Community: Ecological Analysis of Secondary Schools in Poland. AB - Ecological studies, when the school is the unit of analysis, may help to design and evaluate school intervention programs. The paper discusses selected contextual determinants of bullying, using data collected in Poland in 2015 and aggregated to school level (4085 students; 70 junior high schools). The main hypothesis is related to the neighborhood social capital as protective factor and the type of community as a modifier. The main dependent variable was the combined index of bullying which included three perspectives (victim, perpetrator, bystander). Student delinquent behavior was taken into account as potential determinant, along with selected characteristics of the school and neighborhood. The analyses were adjusted for the percentage of the surveyed boys. The overall bullying index ranged, depending on the school, from 0.88 to 4.07 points (out of 12 possible); intraclass coefficient ICC = 2.8%. In the entire sample, the main predictors of bullying were student delinquent behaviors as a risk factor and the school social climate as a protective factor (R2 = 56.3%). The stratification of schools due to their location influences the inference regarding those main determinants. The dominating influence of delinquent behavior is visible only in big cities where bullying index showed the highest dispersion. In smaller towns and rural areas, the neighborhood social capital becomes an important protective factor; highly correlated with the school climate. We can conclude that strong social bonds in the community are supportive for school climate and can reduce the level of bullying at schools. PMID- 28572859 TI - Mental Health and School Functioning for Girls in the Child Welfare System: the Mediating Role of Future Orientation and School Engagement. AB - This study investigated the association between mental health problems and academic and behavioral school functioning for adolescent girls in the child welfare system and determined whether school engagement and future orientation meditated the relationship. Participants were 231 girls aged between 12 and 19 who had been involved with the child welfare system. Results indicated that 39% of girls reported depressive symptoms in the clinical range and 54% reported posttraumatic symptoms in the clinical range. The most common school functioning problems reported were failing a class (41%) and physical fights with other students (35%). Participants reported a mean number of 1.7 school functioning problems. Higher levels of depression and PTSD were significantly associated with more school functioning problems. School engagement fully mediated the relationship between depression and school functioning and between PTSD and school functioning, both models controlling for age, race, and placement stability. Future orientation was not significantly associated with school functioning problems at the bivariate level. Findings suggest that school engagement is a potentially modifiable target for interventions aiming to ameliorate the negative influence of mental health problems on school functioning for adolescent girls with histories of abuse or neglect. PMID- 28572860 TI - Pulmonary microRNA profiling: implications in upper lobe predominant lung disease. AB - BACKGROUND: Numerous pulmonary diseases manifest with upper lobe predominance including cystic fibrosis, smoking-related chronic obstructive pulmonary disease, and tuberculosis. Zonal hypoxia, characteristic of these pulmonary maladies, and oxygen stress in general is known to exert profound effects on various important aspects of cell biology. Lung macrophages are major participants in the pulmonary innate immune response and regional differences in macrophage responsiveness to hypoxia may contribute in the development of lung disease. MicroRNAs are ubiquitous regulators of human biology and emerging evidence indicates altered microRNA expression modulates respiratory disease processes. The objective of this study is to gain insight into the epigenetic and cellular mechanisms influencing regional differences in lung disease by investigating effect of hypoxia on regional microRNA expression in the lung. All studies were performed using primary alveolar macrophages (n = 10) or bronchoalveolar lavage fluid (n = 16) isolated from human subjects. MicroRNA was assayed via the NanoString nCounter microRNA assay. RESULTS: Divergent molecular patterns of microRNA expression were observed in alternate lung lobes, specifically noted was disparate expression of miR-93 and miR-4454 in alveolar macrophages along with altered expression of miR-451a and miR-663a in bronchoalveolar lavage fluid. Gene ontology was used to identify potential downstream targets of divergent microRNAs. Targets include cytokines and matrix metalloproteinases, molecules that could have a significant impact on pulmonary inflammation and fibrosis. CONCLUSIONS: Our findings show variant regional microRNA expression associated with hypoxia in alveolar macrophages and BAL fluid in the lung-upper vs lower lobe. Future studies should address whether these specific microRNAs may act intracellularly, in a paracrine/endocrine manner to direct the innate immune response or may ultimately be involved in pulmonary host-to-pathogen trans kingdom cross-talk. PMID- 28572862 TI - Prognostic significance of LINE-1 hypomethylation in oropharyngeal squamous cell carcinoma. AB - BACKGROUND: Inclusion of new biomarkers to improve a personalized treatment approach for oropharyngeal squamous cell carcinoma (OPSCC) is urgently needed. Hypomethylation of the Long interspersed nucleotide element-1 (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was found to be associated with a poor prognosis in several cancers. At present, no studies have investigated the influence of LINE-1 methylation levels on OPSCC relapse. The main goal of this study was the evaluation of the prognostic value of LINE-1 methylation status in predicting early tumor relapse in locally advanced OPSCC. METHODS: We retrospectively reviewed a cohort of 77 patients with stage III-IVB OPSCC. Methylation of LINE-1 repetitive sequences was evaluated by real-time quantitative methylation-specific PCR in formalin-fixed paraffin embedded tissues. The prognostic relevance of LINE-1 methylation was assessed by comparing patients who relapsed within 2 years from the end of treatment (cases) with those who did not (controls). Results were validated in an independent cohort of 33 patients with OPSCC. RESULTS: With respect to early OPSCC relapse, the mean LINE-1 methylation level was significantly lower in relapsed cases than in control group (p < 0.01). Interestingly, LINE-1 methylation was lower in relapsed cases than in controls in both HPV16-negative and HPV16-positive OPSCC patients, even if statistical significance was reached only for the former group (p = 0.01). LINE-1 methylation levels were also significantly reduced in relapsed cases with respect to the controls in OPSCC current smokers (p = 0.02). Consistently, in HPV16-negative current smokers, OPSCC relapse was significantly associated with decreased levels of LINE-1 methylation (p = 0.02). Using logistic regression model, we found that patients with hypomethylated LINE-1 were associated with a 3.5 higher risk of early relapse than hypermethylated ones (OR = 3.51; 95% CI 1.03-12.00). Adjustment for potential confounders did not substantially change the risk magnitude. Results from the validation cohort confirmed the lower LINE-1 methylation in patients who early relapsed compared to relapse-free patients. CONCLUSIONS: LINE-1 hypomethylation is associated with higher risk of early relapse in stage III-IVB OPSCC. Further validation in a prospective study is needed for its application in daily clinical practice. PMID- 28572861 TI - Genome-wide DNA methylation profiling integrated with gene expression profiling identifies PAX9 as a novel prognostic marker in chronic lymphocytic leukemia. AB - BACKGROUND: In chronic lymphocytic leukemia (CLL), epigenomic and genomic studies have expanded the existing knowledge about the disease biology and led to the identification of potential biomarkers relevant for implementation of personalized medicine. In this study, an attempt has been made to examine and integrate the global DNA methylation changes with gene expression profile and their impact on clinical outcome in early stage CLL patients. RESULTS: The integration of DNA methylation profile (n = 14) with the gene expression profile (n = 21) revealed 142 genes as hypermethylated-downregulated and; 62 genes as hypomethylated-upregulated in early stage CLL patients compared to CD19+ B-cells from healthy individuals. The mRNA expression levels of 17 genes identified to be differentially methylated and/or differentially expressed was further examined in early stage CLL patients (n = 93) by quantitative real time PCR (RQ-PCR). Significant differences were observed in the mRNA expression of MEIS1, PMEPA1, SOX7, SPRY1, CDK6, TBX2, and SPRY2 genes in CLL cells as compared to B-cells from healthy individuals. The analysis in the IGHV mutation based categories (Unmutated = 39, Mutated = 54) revealed significantly higher mRNA expression of CRY1 and PAX9 genes in the IGHV unmutated subgroup (p < 0.001). The relative risk of treatment initiation was significantly higher among patients with high expression of CRY1 (RR = 1.91, p = 0.005) or PAX9 (RR = 1.87, p = 0.001). High expression of CRY1 (HR: 3.53, p < 0.001) or PAX9 (HR: 3.14, p < 0.001) gene was significantly associated with shorter time to first treatment. The high expression of PAX9 gene (HR: 3.29, 95% CI 1.172-9.272, p = 0.016) was also predictive of shorter overall survival in CLL. CONCLUSIONS: The DNA methylation changes associated with mRNA expression of CRY1 and PAX9 genes allow risk stratification of early stage CLL patients. This comprehensive analysis supports the concept that the epigenetic changes along with the altered expression of genes have the potential to predict clinical outcome in early stage CLL patients. PMID- 28572864 TI - Time-to-Boundary Function to Study the Development of Upright Stance Control in Children. AB - BACKGROUND: The development of postural control across the primary school time horizon is a complex process, which entails biomechanics modifications, the maturation of cognitive ability and sensorimotor organization, and the emergence of anticipatory behaviour. Postural stability in upright stance has been thus object of a multiplicity of studies to better characterize postural control in this age span, with a variety of methodological approaches. The analysis of the Time-to-Boundary function (TtB), which specifies the spatiotemporal proximity of the Centre of Pressure (CoP) to the stability boundaries in the regulation of posture in upright stance, is among the techniques used to better characterize postural stability in adults, but, as of now, it has not yet been introduced in developmental studies. The aim of this study was thus to apply this technique to evaluate the development of postural control in a sample population of primary school children. METHODS: In this cross-sectional study, upright stance trials under eyes open and eyes closed were administered to 107 healthy children, divided into three age groups (41 for Seven Years' Group, Y7; 38 for Nine Years' Group, Y9; 28 for Eleven Years' Group, Y11). CoP data were recorded to calculate the Time-to-Boundary function (TtB), from which four spatio-temporal parameters were extracted: the mean value and the standard deviation of TtB minima (Mmin, Stdmin), and the mean value and the standard deviation of the temporal distance between two successive minima (Mdist, Stddist). RESULTS: With eyes closed, Mmin and Stdmin significantly decreased and Mdist and Stddist increased for the Y7 group, at Y9 Mmin significantly decreased and Stddist increased, while no effect of vision resulted for Y11. Regarding age groups, Mmin was significantly higher for Y9 than Y7, and Stdmin for Y9 was higher than both Y7 and Y11; Mdist and Stddist resulted higher for Y11 than for Y9. CONCLUSION: From the combined results from the spatio-temporal TtB parameters, it is suggested that, at 9 years, children look more efficient in terms of exploring their limits of stability than at 7, and at 11 the observed TtB behaviour hints at the possibility that, at that age, they have almost completed the maturation of postural control in upright stance, also in terms of integration of the spatio temporal information. PMID- 28572865 TI - Electrocardiographic Changes After Suicidal Digoxin Intoxication in a Healthy Woman. AB - BACKGROUND: Suicidal digoxin intoxication is a rare clinical entity. Clinical suspicious remains of paramount importance as adequate interpretation of the electrocardiographic changes enable to readily initiate treatment. METHOD: We describe a case of suicidal attempt after massive digoxin intake that was satisfactory managed with conservative management strategy that involved a close clinical surveillance of the evolving electrocardiographic changes and digoxin serum levels. PMID- 28572863 TI - Epi-drugs in combination with immunotherapy: a new avenue to improve anticancer efficacy. AB - Immune checkpoint factors, such as programmed cell death protein-1/2 (PD-1, PD-2) or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) receptors, are targets for monoclonal antibodies (MAbs) developed for cancer immunotherapy. Indeed, modulating immune inhibitory pathways has been considered an important breakthrough in cancer treatment. Although immune checkpoint blockade therapy used to treat malignant diseases has provided promising results, both solid and haematological malignancies develop mechanisms that enable themselves to evade the host immune system. To overcome some major limitations and ensure safety in patients, recent strategies have shown that combining epigenetic modulators, such as inhibitors of histone deacetylases (HDACi) or DNA methyltransferases (DNMTi), with immunotherapeutics can be useful. Preclinical data generated using mouse models strongly support the feasibility and effectiveness of the proposed approaches. Indeed, co-treatment with pan- or class I-selective HDACi or DNMTi improved beneficial outcomes in both in vitro and in vivo studies. Based on the evidence of a pivotal role for HDACi and DNMTi in modulating various components belonging to the immune system, recent clinical trials have shown that both HDACi and DNMTi strongly augmented response to anti-PD-1 immunotherapy in different tumour types. This review describes the current strategies to increase immunotherapy responses, the effects of HDACi and DNMTi on immune modulation, and the advantages of combinatorial therapy over single-drug treatment. PMID- 28572867 TI - Prolaris Cell Cycle Progression Test for Localized Prostate Cancer: A Health Technology Assessment. AB - BACKGROUND: Prostate cancer is very common and many localized tumours are non aggressive. Determining which cancers are aggressive is important for choosing the most appropriate treatment (e.g., surgery, radiation, active surveillance). Current clinical risk stratification is reliable in forecasting the prognosis of groups of men with similar clinical and pathologic characteristics, but there is residual uncertainty at the individual level. The Prolaris cell cycle progression (CCP) test, a genomic test that estimates how fast tumour cells are proliferating, could potentially be used to improve the accuracy of individual risk assessment. This health technology assessment sought to determine the clinical utility, economic impact, and patients' perceptions of the value of the CCP test in low- and intermediate-risk localized prostate cancer. METHODS: We conducted a systematic review of the clinical and economic evidence of the CCP test in low-and intermediate-risk, localized prostate cancer. Medical and health economic databases were searched from 2010 to June or July 2016. The critical appraisal of the clinical evidence included risk of bias and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We also analyzed the potential budget impact of adding the CCP test into current practice, from the perspective the Ontario Ministry of Health and Long-Term Care. Finally, we conducted qualitative interviews with men with prostate cancer, on the factors that influenced their treatment decision-making. RESULTS: For the review of clinical effectiveness, we screened 3,021 citations, and two before-after studies met our inclusion criteria. In one study, the results of the CCP test appeared to change the treatment plan (from initial to final plan) in 64.9% of cases overall (GRADE rating of the quality of evidence: Very low). In the other study, the CCP test changed the treatment received in nearly half of cases overall, compared with the initial plan (GRADE: Very low). No evidence was available on clinical outcomes of patients whose treatment was informed by CCP results. For the review of cost-effectiveness, 100 citations were identified and screened. No studies met the inclusion criteria. In our economic evaluation, we estimated that publicly funding the CCP test would result in a total net budget impact of $41.3 million in the first 5 years, mostly due to the cost of the CCP test. In our model, the relatively small cost savings ($7.3 million) due to treatment change (increased use of active surveillance and decreased use of interventional treatment) was not large enough to offset the high cost of the test. Patients viewed the test as potentially helpful but, due to the complexity of treatment decision-making, were unsure the test would ultimately change their treatment choices. CONCLUSIONS: We found no evidence to demonstrate the impact of the Prolaris CCP test on patient-important clinical outcomes. The limited evidence available shows that the test appears to provide information that, when considered in addition to clinical risk stratification, may change the treatment plan or actual treatment for some low- and intermediate risk prostate cancer patients. As a result, there is insufficient data to inform the cost-effectiveness of the CCP test. Publicly funding the CCP test would result in a large incremental cost to the provincial budget. PMID- 28572866 TI - Hyperbaric Oxygen Therapy for the Treatment of Diabetic Foot Ulcers: A Health Technology Assessment. AB - BACKGROUND: About 15% to 25% of people with diabetes will develop a foot ulcer. These wounds are often resistant to healing; therefore, people with diabetes experience lower limb amputation at about 20 times the rate of people without diabetes. If an ulcer does not heal with standard wound care, other therapeutic interventions are offered, one of which is hyperbaric oxygen therapy (HBOT). However, the effectiveness of this therapy is not clearly known. The objectives of this health technology assessment were to assess the safety, clinical effectiveness, and cost-effectiveness of standard wound care plus HBOT versus standard wound care alone for the treatment of diabetic foot ulcers. We also investigated the preferences and perspectives of people with diabetic foot ulcers through lived experience. METHODS: We performed a review of the clinical and economic literature for the effectiveness and cost-effectiveness of hyperbaric oxygen therapy, as well as the budget impact of HBOT from the perspective of the Ministry of Health and Long-Term Care. We assessed the quality of the body of clinical evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. To better understand the preferences, perspectives, and values of patients with diabetic foot ulcers and their experience with HBOT, we conducted interviews and administered an online survey. RESULTS: Seven randomized controlled trials and one nonrandomized controlled trial met the inclusion criteria. Comparing standard wound care plus HBOT with standard wound care alone, we found mixed results for major amputation rates (GRADE quality of evidence: low), a significant difference in favour of standard wound care plus HBOT on ulcers healed (GRADE quality of evidence: low), and no difference in terms of adverse events (GRADE quality of evidence: moderate). There is a large degree of uncertainty associated with the evaluation of the cost-effectiveness of standard wound care plus HBOT. However, results appear to suggest that this treatment results in lower costs and better outcomes than standard wound care alone. Funding HBOT will result in a budget impact of $4 million per year in immediate treatment costs for the Ontario Ministry of Health and Long-Term Care. This cost decreases to $0.5 million per year when downstream costs are considered. There is a substantial daily burden of care and emotional weight associated with living with diabetic foot ulcers, both of which are compounded by concern regarding possible amputation. Patients feel that HBOT is an effective treatment and reported that they were satisfied with how their ulcers healed and that this improved their quality of life. CONCLUSIONS: The evidence makes it difficult to draw any definitive conclusions on the clinical and cost effectiveness of standard wound care plus HBOT versus standard wound care alone for the treatment of diabetic foot ulcers. PMID- 28572869 TI - COVARIATE-ADAPTIVE CLUSTERING OF EXPOSURES FOR AIR POLLUTION EPIDEMIOLOGY COHORTS. AB - Cohort studies in air pollution epidemiology aim to establish associations between health outcomes and air pollution exposures. Statistical analysis of such associations is complicated by the multivariate nature of the pollutant exposure data as well as the spatial misalignment that arises from the fact that exposure data are collected at regulatory monitoring network locations distinct from cohort locations. We present a novel clustering approach for addressing this challenge. Specifically, we present a method that uses geographic covariate information to cluster multi-pollutant observations and predict cluster membership at cohort locations. Our predictive k-means procedure identifies centers using a mixture model and is followed by multi-class spatial prediction. In simulations, we demonstrate that predictive k-means can reduce misclassification error by over 50% compared to ordinary k-means, with minimal loss in cluster representativeness. The improved prediction accuracy results in large gains of 30% or more in power for detecting effect modification by cluster in a simulated health analysis. In an analysis of the NIEHS Sister Study cohort using predictive k-means, we find that the association between systolic blood pressure (SBP) and long-term fine particulate matter (PM2.5) exposure varies significantly between different clusters of PM2.5 component profiles. Our cluster based analysis shows that for subjects assigned to a cluster located in the Midwestern U.S., a 10 MUg/m3 difference in exposure is associated with 4.37 mmHg (95% CI, 2.38, 6.35) higher SBP. PMID- 28572868 TI - Prostate Cancer Patient Perspectives on the Use of Information in Treatment Decision-Making: A Systematic Review and Qualitative Meta-synthesis. AB - BACKGROUND: Men with low- to intermediate-risk prostate cancer are typically asked to choose from a variety of treatment options, including active surveillance, radical prostatectomy, or brachytherapy. The Prolaris cell cycle progression test is intended to provide additional information on personal risk status to assist men with prostate cancer in their choice of treatment. To assist with assessing that new technology, this report synthesizes qualitative research on how men with prostate cancer use information to make decisions about treatment options. METHODS: We performed a systematic review and qualitative meta-synthesis to retrieve and synthesize findings across primary qualitative studies that report on patient perspectives during prostate cancer treatment decision-making. RESULTS: Of 8,610 titles and abstracts reviewed, 29 studies are included in this report. Most men diagnosed with prostate cancer express that their information seeking pathway extends beyond the medical information received from their health care provider. They access other social resources to attain additional medical information, lived-experience information, and medical administrative information to help support their final treatment decision. Men value privacy, trust, honesty, control, power, organization, and open communication during interactions with their health care providers. They also emphasize the importance of gaining comfort with their treatment choice, having a chance to confirm their health care provider's recommendations (validation of treatment plan), and exercising their preferred level of independence in the treatment decision-making process. CONCLUSIONS: Although each prostate cancer patient is unique, studies suggest that most patients seek extensive information to help inform their treatment decisions. This may happen before, during, and after the treatment choice is made. Given the amount of information patients may access, it is important that they also establish the trustworthiness of the various types and sources of information. When information conflicts, patients may be unsure about how to proceed. Open collaboration between patients and their health care providers can help patients manage and navigate their concerns so that their values and perspectives are captured in their treatment choices. PMID- 28572870 TI - Positively and Negatively Charged Cesium and (C60) m Cs n Cluster Ions. AB - We report on the formation and ionization of cesium and C60Cs clusters in superfluid helium nanodroplets. Size distributions of positively and negatively charged (C60) m Cs n+/- ions have been measured for m <= 7, n <= 12. Reproducible intensity anomalies are observed in high-resolution mass spectra. For both charge states, (C60) m Cs3+/- and (C60) m Cs5+/- are particularly abundant, with little dependence on the value of m. Distributions of bare cesium cluster ions also indicate enhanced stability of Cs3+/- and Cs5+/-, in agreement with theoretical predictions. These findings contrast with earlier reports on highly Cs-doped cationic fullerene aggregates which showed enhanced stability of C60Cs6 building blocks attributed to charge transfer. The dependence of the (C60) m Cs3- anion yield on electron energy shows a resonance that, surprisingly, oscillates in strength as m increases from 1 to 6. PMID- 28572871 TI - Comparison of Body Composition Measurements Using a New Caliper, Two Established Calipers, Hydrostatic Weighing, and BodPod. AB - PURPOSES: (1) To compare the Lafayette Instruments (LI) skinfold caliper to the Lange (L) and Harpenden (H) calipers using a diverse subject population. (2) To determine the validity of the LI caliper in a subset of subjects by comparing body compositions from skinfold thicknesses to those measured by hydrostatic weighing (HW) and air displacement plethysmography (ADP). (3) To compare measurements obtained by experienced (EX) and inexperienced (IX) technicians using all three calipers. METHODS: Skinfold measurements were performed by both EX and IX technicians using three different calipers on 21 younger (21.2 +/- 1.5 yrs) and 20 older (59.2 +/- 4 yrs) subjects. Body compositions were calculated using the Jackson-Pollock seven-site and three-site formulas. HW and ADP tests were performed on a subset of subjects (10 younger, 10 older). RESULTS: No significant differences existed between LI and L or H when measurements were made by EX. Further, the LI-EX measurements were highly correlated to both H-EX and L EX. No significant differences existed in the subgroup between LI-EX and HW or ADP. Skinfold determinations made by EX and IX were similar. CONCLUSIONS: Similar body compositions determined using LI, H, and L suggest that LI determines body composition as effectively as H and L. High correlations between the three calipers support this notion. Similar results between LI and HW/ADP subgroup suggest that the LI caliper may be a valid method of measuring body composition. Overall, performance by IX was similar to EX and suggests similar ease of use for all three calipers. PMID- 28572873 TI - FOOD IMAGE ANALYSIS: SEGMENTATION, IDENTIFICATION AND WEIGHT ESTIMATION. AB - We are developing a dietary assessment system that records daily food intake through the use of food images taken at a meal. The food images are then analyzed to extract the nutrient content in the food. In this paper, we describe the image analysis tools to determine the regions where a particular food is located (image segmentation), identify the food type (feature classification) and estimate the weight of the food item (weight estimation). An image segmentation and classification system is proposed to improve the food segmentation and identification accuracy. We then estimate the weight of food to extract the nutrient content from a single image using a shape template for foods with regular shapes and area-based weight estimation for foods with irregular shapes. PMID- 28572874 TI - Association of trainee participation with adenoma and polyp detection rates. AB - AIM: To investigate whether adenoma and polyp detection rates (ADR and PDR, respectively) in screening colonoscopies performed in the presence of fellows differ from those performed by attending physicians alone. METHODS: We performed a retrospective review of all patients who underwent a screening colonoscopy at Grady Memorial Hospital between July 1, 2009 and June 30, 2015. Patients with a history of colon polyps or cancer and those with poor colon preparation or failed cecal intubation were excluded from the analysis. Associations of fellowship training level with the ADR and PDR relative to attendings alone were assessed using unconditional multivariable logistic regression. Models were adjusted for sex, age, race, and colon preparation quality. RESULTS: A total of 7503 colonoscopies met the inclusion criteria and were included in the analysis. The mean age of the study patients was 58.2 years; 63.1% were women and 88.2% were African American. The ADR was higher in the fellow participation group overall compared to that in the attending group: 34.5% vs 30.7% (P = 0.001), and for third year fellows it was 35.4% vs 30.7% (aOR = 1.23, 95%CI: 1.09-1.39). The higher ADR in the fellow participation group was evident for both the right and left side of the colon. For the PDR the corresponding figures were 44.5% vs 40.1% (P = 0.0003) and 45.7% vs 40.1% (aOR = 1.25, 95%CI: 1.12-1.41). The ADR and PDR increased with increasing fellow training level (P for trend < 0.05). CONCLUSION: There is a stepwise increase in ADR and PDR across the years of gastroenterology training. Fellow participation is associated with higher adenoma and polyp detection. PMID- 28572872 TI - Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases. AB - Low-density lipoprotein (LDL) plays a key role in the development and progression of atherosclerosis and cardiovascular disease. LDL consists of several subclasses of particles with different sizes and densities, including large buoyant (lb) and intermediate and small dense (sd) LDLs. It has been well documented that sdLDL has a greater atherogenic potential than that of other LDL subfractions and that sdLDL cholesterol (sdLDL-C) proportion is a better marker for prediction of cardiovascular disease than that of total LDL-C. Circulating sdLDL readily undergoes multiple atherogenic modifications in blood plasma, such as desialylation, glycation, and oxidation, that further increase its atherogenicity. Modified sdLDL is a potent inductor of inflammatory processes associated with cardiovascular disease. Several laboratory methods have been developed for separation of LDL subclasses, and the results obtained by different methods can not be directly compared in most cases. Recently, the development of homogeneous assays facilitated the LDL subfraction analysis making possible large clinical studies evaluating the significance of sdLDL in the development of cardiovascular disease. Further studies are needed to establish guidelines for sdLDL evaluation and correction in clinical practice. PMID- 28572875 TI - Nerve preserving vs standard laparoscopic sacropexy: Postoperative bowel function. AB - AIM: To compare our developed nerve preserving technique with the non-nerve preserving one in terms of de novo bowel symptoms. METHODS: Patients affected by symptomatic apical prolapse, admitted to our department and treated by nerve preserving laparoscopic sacropexy (LSP) between October, 2010 and April, 2013 (Group A or "interventional group") were compared to those treated with the standard LSP, between September, 2007 and December, 2009 (Group B or "control group"). Functional and anatomical data were recorded prospectively at the first clinical review, at 1, 6 mo, and every postsurgical year. Questionnaires were filled in by the patients at each follow-up clinical evaluation. RESULTS: Forty three women were enrolled, 25/43 were treated by our nerve preserving technique and 18/43 by the standard one. The data from the interventional group were collected at a similar follow-up (> 18 mo) as those collected for the control group. No cases of de novo bowel dysfunction were observed in group A against 4 cases in group B (P = 0.02). Obstructed defecation syndrome (ODS) was highlighted by an increase in specific questionnaires scores and documented by the anorectal manometry. There were no cases of de novo constipation in the two groups. No major intraoperative complications were reported for our technique and it took no longer than the standard procedure. Apical recurrence and late complications were comparable in the two groups. CONCLUSION: Our nerve preserving technique seems superior in terms of prevention of de novo bowel dysfunction compared to the standard one and had no major intraoperative complications. PMID- 28572876 TI - Adult intussusception: A case series and review. AB - AIM: To identify factors differentiating pathologic adult intussusception (AI) from benign causes and the need for an operative intervention. Current evidence available from the literature is discussed. METHODS: This is a case series of eleven patients over the age of 18 and a surgical consultation for "Intussusception" at a single veteran's hospital over a five-year period (2011 2016). AI was diagnosed on computed tomography (CT) scan and or flexible endoscopy (colonoscopy). Surgical referrals were from the emergency room, endoscopy suites and the radiologists. RESULTS: A total of 11 cases, 9 males and 2 females were diagnosed with AI. Median age was 58 years. Abdominal pain and change in bowel habits were most common symptoms. CT scan and or colonoscopy diagnosed AI, in ten/eleven (90%) patients. There were 6 small bowel-small bowel, 4 ileocecal, and 1 sigmoid-rectal AI. 8 patients (72%) needed an operation. Bowel resection was required and definitive pathology was diagnosed in 7 patients (63%). Five patients had malignant and 2 patients had benign etiology. Small bowel enteroscopy excluded pathology in 4 cases (37%) with AI. Younger patients tend to have a benign diagnosis. CONCLUSION: Majority of AI have malignant etiology however idiopathic intussusception is being seen more frequently. Operative intervention remains the mainstay however, certain small bowel intussusception especially in younger patients may be a benign, physiological, transient phenomenon and laparoscopy with reduction or watchful waiting may be an acceptable strategy. These patients should undergo endoscopic or capsule endoscopy to exclude intrinsic luminal lesions. PMID- 28572877 TI - Does music reduce anxiety and discomfort during flexible sigmoidoscopy? A systematic review and meta-analysis. AB - AIM: To investigate the role of music in reducing anxiety and discomfort during flexible sigmoidoscopy. METHODS: A systematic review of all comparative studies up to November 2016, without language restriction that were identified from MEDLINE and the Cochrane Controlled Trials Register (1960-2016), and EMBASE (1991 2016). Further searches were performed using the bibliographies of articles and abstracts from major conferences such as the ESCP, NCRI, ASGBI and ASCRS. MeSH and text word terms used included "sigmoidoscopy", "music" and "endoscopy" and "anxiety". All comparative studies reporting on the effect of music on anxiety or pain during flexible sigmoidoscopy, in adults, were included. Outcome data was extracted by 2 authors independently using outcome measures defined a priori. Quality assessment was performed. RESULTS: A total of 4 articles published between 1994 and 2010, fulfilled the selection criteria. Data were extracted and analysed using OpenMetaAnalyst. Patients who listened to music during their flexible sigmoidoscopy had less anxiety compared to control groups [Random effects; SMD: 0.851 (0.467, 1.235), S.E = 0.196, P < 0.001]. There was no statistically significant heterogeneity (Q = 0.085, df = 1, P = 0.77, I2 = 0). Patients who listened to music during their flexible sigmoidoscopy had less pain compared to those who did not, but this difference did not reach statistical significance [Random effects; SMD: 0.345 (-0.014, 0.705), S.E = 0.183, P = 0.06]. Patients who listened to music during their flexible sigmoidoscopy felt it was a useful intervention, compared to those who did not (P < 0.001). There was no statistically significant heterogeneity (P = 0.528, I2 = 0). CONCLUSION: Music appeared to benefit patients undergoing flexible sigmoidoscopies in relation to anxiety and was deemed a helpful intervention. Pain may also be reduced however further investigation is required to ascertain this. PMID- 28572878 TI - Successful endoscopic treatment of an intraductal papillary neoplasm of the bile duct. AB - We present a case of a 76-year-old man with right upper quadrant abdominal pain and weight loss, who was found to have an intraductal papillary neoplasm of the bile duct (IPNB) of the pancreaticobiliary subtype, deemed curatively resectable. The patient declined surgery and opted for endoscopic therapy. He underwent two sessions of endoscopic retrograde cholangiopancreatography (ERCP)-guided radiofrequency ablation (RFA). Ten months later, no evidence of recurrence was identified on repeat ERCP. To our knowledge, this is the first reported case of successful use of RFA as a primary treatment modality for resectable IPNB. PMID- 28572879 TI - Effects of glycaemic management on diabetic kidney disease. AB - Hyperglycaemia contributes to the onset and progression of diabetic kidney disease (DKD). Observational studies have not consistently demonstrated a glucose threshold, in terms of HbA1c levels, for the onset of DKD. Tight glucose control has clearly been shown to reduce the incidence of micro- or macroalbuminuria. However, evidence is now also emerging to suggest that intensive glucose control can slow glomerular filtration rate loss and possibly progression to end stage kidney disease. Achieving tight glucose control needs to be balanced against the increasing appreciation that glucose targets for the prevention of diabetes related complications need be individualised for each patient. Recently, empagliflozin which is an oral glucose lowering agent of the sodium glucose cotransporter-2 inhibitor class has been shown to have renal protective effects. However, the magnitude of empagliflozin's reno-protective properties are over and above that expected from its glucose lowering effects and most likely largely result from mechanisms involving alterations in intra-renal haemodynamics. Liraglutide and semaglutide, both injectable glucose lowering agents which are analogues of human glucagon like peptide-1 have also been shown to reduce progression to macroalbuminuria through mechanisms that remain to be fully elucidated. Here we review the evidence from observational and interventional studies that link good glucose control with improved renal outcomes. We also briefly review the potential reno-protective effects of newer glucose lowering agents. PMID- 28572880 TI - Effect of medicinal mushrooms on blood cells under conditions of diabetes mellitus. AB - Diabetes mellitus (DM) is the third most common non-infectious disease leading to early disability and high mortality. Moreover, the number of patients is growing every year. The main symptom of DM is hyperglycemia. Increased levels of blood glucose activate polyol, hexosamine, and protein kinase metabolic pathways cause the intensification of non-enzymatic glycosylation and nitration of macromolecules. This, in turn, leads to the development of oxidative and nitrative stresses and secondary complications, such as different kinds of micro- and macroangiopathies. Metabolic disorders caused by insulin deficiency in diabetes significantly impede the functioning of a homeostasis system, which change the physical, biochemical, morphological, and functional properties of blood cells. As a result, the oxygen-transport function of red blood cells (RBCs), rheological properties of the blood, and functions of immunocompetent cells as well as the process of apoptosis are primarily affected. Modern pharmacotherapy focuses on the search for new preparations that aim to decrease blood glucose levels. Undesirable side effects and adverse reactions caused by synthetic medicines led to the search and investigation of new preparations of natural origin. Medicinal mushrooms play an important role among such new preparations. They are a source of a large number of high- and low-molecular compounds with pronounced biological effects. Our investigations show pronounced hypoglycemic and anti-anemic action of submerged cultivated mycelium powder of medicinal mushrooms Agaricus brasiliensis (A. brasiliensis) and Ganoderma lucidum (G. lucidum) on streptozotocin-induced DM in rats. Also, we showed that mycelium powders have membrane protective properties as evidenced by the redistribution of RBC populations towards the growth of full functional cell numbers. Normalization of parameters of leukocyte formula and suppression of apoptosis of white blood cells in diabetic rats treated with A. brasiliensis and G. lucidum mycelia indicates pronounced positive effects of these strains of mushrooms. Thus, the use of medicinal mushrooms for treatment of DM and in prevention development of its secondary complications might be a new effective approach of this disease's cure. This article is aimed at summarizing and analyzing the literature data and basic achievements concerning DM type 1 treatment using medicinal mushrooms and showing the results obtained in our research. PMID- 28572881 TI - Association between dairy intake, lipids and vascular structure and function in diabetes. AB - AIM: To determine lipid species that change in response to a change in dairy consumption. In addition, to investigate whether dairy associated lipid species are correlated with changes in measures of vascular structure and function. METHODS: A 12-mo randomised controlled trial was conducted to determine the effect of increased consumption of fruit, vegetables and dairy, compared to usual diet, on measures of vascular structure and function in adults with type 1 and type 2 diabetes (n = 108). This paper comprises post-hoc analyses investigating the relationship between dairy intake, serum lipid species and vascular health. Central and peripheral blood pressure, carotid femoral pulse wave velocity, augmentation index, serum lipid species and dietary intake were measured at baseline and 3-mo. Common carotid artery intima media thickness was measured at baseline and 12-mo. RESULTS: Serum lipid species [lysophosphatidylcholine (LPC) 14:0, LPC 15:0, LPC 16:1, phosphatidylcholine (PC) 29:0 PC 30:0, PC 31:0 and cholesterol ester (CE) 14:0] were associated with the change in full fat dairy consumption (rho 0.19-0.25; P < 0.05). The 3-mo change in some lipids was positively associated with the 3-mo change in central systolic [LPC 14:0 (rho 0.30; P = 0.007), PC 30:0 (rho 0.28; P = 0.010)] and diastolic blood pressure [LPC 14:0 (rho 0.32; P = 0.004), LPC 15:0 (rho 0.23; P = 0.04), LPC 16:1 (rho 0.23; P = 0.035), PC 29:0 (rho 0.28; P = 0.01), PC 30:0 (rho 0.36; P = 0.001), PC 31:0 (rho 0.30; P = 0.007)] and 12-mo change in common carotid artery intimal medial thickness [CE 14:0 (rho 0.22; P = 0.02)]. Pulse wave velocity and augmentation index were unrelated to dairy and lipid species. CONCLUSION: An increase in dairy associated lipids appears to be associated with an increase in blood pressure and common carotid intimal medial thickness. PMID- 28572882 TI - Nonsurgical periodontal-therapy improves glycosylated hemoglobin levels in pre diabetic patients with chronic periodontitis. AB - AIM: To evaluate the effect of nonsurgical periodontal therapy on glycosylated haemoglobin levels in pre-diabetic patients with chronic periodontitis (CHP). METHODS: Sixty pre-diabetic patients with CHP were selected and equally allocated to case and control group. All subjects were evaluated at base line for periodontal parameters (plaque index, oral hygiene index, modified gingival index, probing pocket depth, clinical attachment level) and systemic parameters [glycosylated hemoglobin (HbA1c), fasting lipid profile, and fasting blood glucose]. The case group received non-surgical periodontal therapy. Subjects were re-evaluated for periodontal and systemic parameters after three months. RESULTS: Both groups were comparable at baseline. Three months after non surgical periodontal therapy (NSPT), there was significant improvement in periodontal parameters in case group. The mean difference in systemic parameters like HbA1c and fasting plasma glucose from baseline to fourth month for case group was 0.22 +/- 0.11 and 3.90 +/- 8.48 respectively and control group was -0.056 +/- 0.10 and -1.66 +/- 6.04 respectively, which was significant between case and control group (P < 0.05). In the case group there was a significant decrease in HbA1c from baseline to three months following NSPT (P < 0.05). CONCLUSION: This study showed that periodontal inflammation could affect the glycemic control in otherwise systemically healthy individuals. Periodontal therapy improved periodontal health status and decreased glycosylated haemoglobin levels, thus reducing the probability of occurrence of inflammation induced prediabetes in patients with CHP. PMID- 28572883 TI - Impact of creatinine methodology on glomerular filtration rate estimation in diabetes. AB - AIM: To evaluate the influence of creatinine methodology on the performance of chronic kidney disease (CKD)-Epidemiology Collaboration Group-calculated estimated glomerular filtration rate (CKD-EPI-eGFR) for CKD diagnosis/staging in a large cohort of diabetic patients. METHODS: Fasting blood samples were taken from diabetic patients attending our clinic for their regular annual examination, including laboratory measurement of serum creatinine and eGFR. RESULTS: Our results indicated an overall excellent agreement in CKD staging (kappa = 0.918) between the Jaffe serum creatinine- and enzymatic serum creatinine-based CKD-EPI eGFR, with 9% of discordant cases. As compared to the enzymatic creatinine, the majority of discordances (8%) were positive, i.e., associated with the more advanced CKD stage re-classification, whereas only 1% of cases were negatively discordant if Jaffe creatinine was used for eGFR calculation. A minor proportion of the discordant cases (3.5%) were re-classified into clinically relevant CKD stage indicating mildly to moderately decreased kidney function (< 60 mL/min per 1.73 m2). Significant acute and chronic hyperglycaemia, assessed as plasma glucose and HbA1c levels far above the recommended glycaemic goals, was associated with positively discordant cases. Due to a very low frequency, positive discordance is not likely to present a great burden for the health-care providers, while intensified medical care may actually be beneficial for the small number of discordant patients. On the other hand, a very low proportion of negatively discordant cases (1%) at the 60 mL/min per 1.73 m2 eGFR level indicate a negligible possibility to miss the CKD diagnosis, which could be the most prominent clinical problem affecting patient care, considering high risk of CKD for adverse patient outcomes. CONCLUSION: This study indicate that compensated Jaffe creatinine procedure, in spite of the glucose-dependent bias, is not inferior to enzymatic creatinine in CKD diagnosis/staging and therefore may provide a reliable and cost-effective tool for the renal function assessment in diabetic patients. PMID- 28572884 TI - Second Primary Cancer Screening: Role of the Primary Care Physician. PMID- 28572886 TI - Breast and Cervical Cancer Screening Behavior in Female Cancer Survivors: The Korea National Health and Nutrition Examination Survey, 2007-2012. AB - BACKGROUND: The aim of this study was to compare breast and cervical cancer screening rates between female cancer survivors and a population without cancer to identify factors related to cervical and breast cancer screening in cancer survivors. METHODS: We included 17,765 adults (738 cancer survivors and 17,027 individuals without cancer) in this study, all of whom who were 30 years of age or older and participated in the Fourth and Fifth Korean National Health and Nutritional Examination Surveys from 2007-2012. Multiple logistic regression analysis was performed to identify factors related to cervical and breast cancer screening uptake in female cancer survivors. RESULTS: The screening rate for breast cancer was 56.6%, which was higher than that in the non-cancer control group (P=0.001). The screening rate for cervical cancer was 51.4%, which was not different from that of the non-cancer control group. In terms of breast cancer screening, cancer survivors showed no significant difference in the rate of screening 5 years after their cancer diagnosis. However, cervical cancer survivors were less likely to have cervical cancer screening 10 years after their cancer diagnosis. There was no significant association between cancer screening and sociodemographic factors. CONCLUSION: Breast and cervical cancer screening rates in Korean female cancer survivors are low. Secondary primary cancer screening of female cancer survivors needs to be planned in a comprehensive manner, with the consideration of influences beyond sociodemographic factors. PMID- 28572885 TI - Physical Inactivity, Sedentary Behavior and Chronic Diseases. AB - New research into physical activity suggests that it is no longer sufficient just to meet minimum levels recommended by health guidelines in order to reduce cardiovascular risk. Both physical inactivity and sedentary behavior have their own health hazards and need to be addressed separately, in order to explore their different deleterious mechanisms. The aim of this review was to define and to characterize both concepts, and their relationship with major non-communicable chronic diseases. A PubMed database search was undertaken, using the following key words: physical activity, physical inactivity, sedentarism, sedentary behavior, and non-communicable chronic disease. This literature review provides an updated view on physical inactivity and sedentary behavior, and reevaluates their prevalence and association with major non-communicable chronic disease. PMID- 28572887 TI - Association between Weight Changes after Smoking Cessation and Cardiovascular Disease among the Korean Population. AB - BACKGROUND: Cigarette smoking is a risk factor for cardiovascular disease (CVD) and has both beneficial and harmful effects in CVD. We hypothesized that weight gain following smoking cessation does not attenuate the CVD mortality of smoking cessation in the general Korean population. METHODS: Study subjects comprised 2.2% randomly selected patients from the Korean National Health Insurance Corporation, between 2002 and 2013. We identified 61,055 subjects who were classified as current smokers in 2003-2004. After excluding 21,956 subjects for missing data, we studied 30,004 subjects. We divided the 9,095 ex-smokers into two groups: those who gained over 2 kg (2,714), and those who did not gain over 2 kg (6,381, including weight loss), after smoking cessation. Cox proportional hazards regression models were used to estimate the association between weight gain following smoking cessation and CVD mortality. RESULTS: In the primary analysis, the hazard ratios of all-cause deaths and CVD deaths were assessed in the three groups. The CVD risk factors and Charlson comorbidity index adjusted hazard ratios (aHRs) for CVD deaths were 0.80 (95% confidence interval [CI], 0.37 to 1.75) for ex-smokers with weight gain and 0.80 (95% CI, 0.50 to 1.27) for ex smokers with no weight gain, compared to one for sustained smokers. The associations were stronger for events other than mortality. The aHRs for CVD events were 0.69 (95% CI, 0.54 to 0.88) and 0.81 (95% CI, 0.70 to 0.94) for the ex-smokers with and without weight gain, respectively. CONCLUSION: Although smoking cessation leads to weight gain, it does not increase the risk of CVD death. PMID- 28572888 TI - Association between the Eating Family Meal and the Prevalence of Metabolic Syndrome Using Data from Korea National Health and Nutrition Examination Survey (2007-2012). AB - BACKGROUND: Several studies have shown that family meals promote a well-balanced and healthier diet and weight status. Metabolic syndrome is related to eating behavior. This study investigated the association between eating family meals and the prevalence of metabolic syndrome. METHODS: This cross-sectional study included 4,529 subjects who participated in the Korea National Health and Nutrition Examination Survey IV and V (2007-2012). A self-reported questionnaire was used to assess dietary status. Metabolic syndrome was defined according to the guidelines of the modified version of the National Cholesterol Education Program Adult Treatment Panel III. We compared the overall quality of dietary intake in family meal. RESULTS: Nutritional adequacy ratios for energy, protein, calcium, vitamin A, vitamin B1, vitamin B2, vitamin C, niacin, and potassium, and the mean adequacy ratio were significantly higher in the family meal group (P<0.05). The prevalence of metabolic syndrome was lower in the family meal group (P<0.05). However, we observed no significant association between eating family meals and the prevalence of metabolic syndrome. CONCLUSION: This study demonstrated that eating family meals appeared to be associated with nutrient adequacy. However, we observed no significant differences in prevalence of metabolic syndrome between the 2 groups. PMID- 28572889 TI - Decomposing Socioeconomic Inequality Determinants in Suicide Deaths in Iran: A Concentration Index Approach. AB - BACKGROUND: It is recognized that socioeconomic status (SES) has a significant impact on health and wellbeing; however, the effect of SES on suicide is contested. This study explored the effect of SES in suicide deaths and decomposed inequality into its determinants to calculate relative contributions. METHODS: Through a cross-sectional study, 546 suicide deaths and 6,818 suicide attempts from January 1, 2010 to December 31, 2014 in Ilam Province, Western Iran were explored. Inequality was measured by the absolute concentration index (ACI) and decomposed contributions were identified. All analyses were performed using STATA ver. 11.2 (Stata Corp., College Station, TX, USA). RESULTS: The overall ACI for suicide deaths was -0.352 (95% confidence interval, -0.389 to -0.301). According to the results, 9.8% of socioeconomic inequality in suicide deaths was due to addiction in attempters. ACI ranged from -0.34 to -0.03 in 2010-2014, showing that inequality in suicide deaths declined over time. CONCLUSION: Findings showed suicide deaths were distributed among the study population unequally, and our results confirmed a gap between advantaged and disadvantaged attempters in terms of death. Socioeconomic inequalities in suicide deaths tended to diminish over time, as suicide attempts progressed in Ilam Province. PMID- 28572890 TI - Association of Coffee Consumption with Sarcopenia in Korean Elderly Men: Analysis Using the Korea National Health and Nutrition Examination Survey, 2008-2011. AB - BACKGROUND: Sarcopenia is an age-related loss of muscle mass and strength. Coffee has antioxidant and anti-inflammatory properties that have been shown to be inversely related to the mechanism of sarcopenia. While there have been some studies on the effect of coffee on sarcopenia in animals, studies on the topic in humans are rare. Therefore, we investigated this relationship in elderly Korean men. METHODS: The cross-sectional data were derived from the 2008-2011 Korea National Health and Nutrition Examination Survey. After applying the exclusion criteria, the study sample consisted of 1,781 men who were at least 60 years of age. Study participants were identified as having sarcopenia if their appendicular skeletal muscle mass divided by height squared was less than two standard deviations below the gender-specific mean of this value for young adults. Daily coffee consumption amounts were categorized as <1 cup, 1 cup, 2 cups, and >=3 cups. RESULTS: Compared to the group of individuals who drank less than one cup of coffee a day, people who consumed at least 3 cups (adjusted odds ratio, 0.43; 95% confidence interval, 0.20 to 0.94) showed significantly decreased sarcopenia; however, the decrease was not significant when the daily coffee consumption was 1 or 2 cups. In multivariate logistic regression models, significant associations were observed between sarcopenia and coffee consumption (P for trend=0.039). CONCLUSION: The results of this study suggest that consuming at least 3 cups of coffee per day was associated with a lower prevalence of sarcopenia in elderly Korean elderly men. PMID- 28572891 TI - Factors Positively Influencing Health Are Associated with a Lower Risk of Development of Metabolic Syndrome in Korean Men: The 2007-2009 Korean National Health and Nutrition Examination Survey. AB - BACKGROUND: The prevalence of metabolic syndrome (MetS) has risen rapidly worldwide, including in South Korea. Factors related to lifestyle are closely associated with the development of MetS. The aim of this study was to investigate the association between MetS and a number of factors positively influencing health, namely non-smoking, low-risk drinking, sufficient sleep, regular exercise, and the habit of reading food labels, among Korean men. METHODS: This cross-sectional study included 3,869 men from the 2007-2009 Korean National Health and Nutrition Examination Survey. Information on five factors positively influencing their health was obtained using a self-reported questionnaire. We categorized subjects into four groups, depending on the number of positive factors reported (group I, 0-1 factor; group II, 2 factors; group III, 3 factors; group IV, 4-5 factors). RESULTS: Men who reported a greater number of positive health factors had better laboratory and anthropometric values than men who reported fewer positive health factors. The prevalence of MetS was 29.1, 27.2, 20.7, and 14.6% in groups I to IV, respectively. Compared to group I, odds ratios (95% confidence intervals) for MetS were 0.96 (0.78-1.19) in group II, 0.67 (0.52 0.87) in group III, and 0.52 (0.35-0.76) in group IV, after adjusting for confounding factors. Odds ratios for abdominal obesity, glucose intolerance, and hypertriglyceridemia were statistically significant. CONCLUSION: A greater number of positive lifestyle factors influencing health were associated with a lower risk of developing MetS, in a nationally representative sample of Korean men. PMID- 28572892 TI - Relationship between Chronic Kidney Disease and Depression in Elderly Koreans Using the 2013 Korea National Health and Nutrition Examination Survey Data. AB - BACKGROUND: Depression is prevalent in patients with chronic kidney disease (CKD) and continues to increase in elderly adults. Therefore, the aim of our study was to examine the relationship between CKD and depression in older patients. METHODS: We conducted a cross-sectional study based on 2013 Korea National Health and Nutrition Examination Survey data. In total, data of 973 subjects aged >=65 years were analyzed, and the estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: The prevalence of depression in older adults was 4.1% in men and 8.8% in women (P=0.004). The prevalence of depression did not differ according to CKD stage in women (normal eGFR and CKD stages 1 and 2 women, 41/474 [8.6%]) vs. CKD stages 3-5 women, 6/63 [9.5%]); however, the prevalence of depression in men with CKD stages 3-5 (8/83 [9.6%]) was significantly higher than in men with normal eGFR and CKD stage 1 and 2 (10/353 [2.8%], P=0.010). Multivariate logistic regression analysis showed that the odds ratio for depression in men with CKD stages 3-5 was 3.822 (95% confidence interval, 1.229 to 11.879) after adjusting for social status and chronic diseases (P=0.021). CONCLUSION: The prevalence of depression was higher in elderly women than in men, while the prevalence of depression increased in elderly men with CKD stages 3-5 and was almost equal to that of women. Therefore, elderly men with progressive renal function impairment should be counseled and monitored for psychological problems. PMID- 28572893 TI - Intravesical Migration of an Intrauterine Contraceptive Device with Secondary Calculus Formation. AB - Intrauterine contraceptive devices (IUCDs) are a common form of reversible contraception owing to fewer systemic side effects and low cost, especially in a developing country like India. However, IUCDs are not without complications. Migration of a device into adjacent organs is the most morbid of all the documented complications. A patient who presents with a history that suggests loss or disappearance of an IUCD thread associated with urinary symptoms should raise suspicions that a device may have migrated into the bladder. Physicians should also be aware of possible secondary vesical calculus formation. Further radiological investigations and appropriate management are warranted. We present a case report describing the migration of an IUCD into the bladder with secondary calculus formation. PMID- 28572894 TI - Superior Vena Cava Syndrome Due to Mediastinal Tuberculous Lymphadenitis. AB - Superior vena cava (SVC) syndrome refers to a medical emergency resulting from compression of the SVC. It requires early diagnosis and treatment, and is usually caused by malignant tumors; rarely, mediastinal tuberculous lymphadenitis can cause SVC syndrome. Here, we present a case study of an immunocompetent 61-year old woman who presented with acute onset SVC syndrome and was diagnosed with tuberculous lymphadenitis on thoracotomy; the symptoms resolved with anti tuberculosis therapy. This unusual case highlights the importance of the differential diagnosis in patients presenting with acute onset SVC syndrome; a timely diagnosis and appropriate treatment lead to complete recovery. PMID- 28572895 TI - Link between Short Sleep Duration and Hypertension. PMID- 28572896 TI - How molecular motors work - insights from the molecular machinist's toolbox: the Nobel prize in Chemistry 2016. AB - The Nobel prize in Chemistry for 2016 was awarded to Jean Pierre Sauvage, Sir James Fraser Stoddart, and Bernard (Ben) Feringa for their contributions to the design and synthesis of molecular machines. While this field is still in its infancy, and at present there are no commercial applications, many observers have stressed the tremendous potential of molecular machines to revolutionize technology. However, perhaps the most important result so far accruing from the synthesis of molecular machines is the insight provided into the fundamental mechanisms by which molecular motors, including biological motors such as kinesin, myosin, FoF1 ATPase, and the flagellar motor, function. The ability to "tinker" with separate components of molecular motors allows asking, and answering, specific questions about mechanism, particularly with regard to light driven vs. chemistry driven molecular motors. PMID- 28572898 TI - Harnessing non-covalent interactions to exert control over regioselectivity and site-selectivity in catalytic reactions. AB - Asymmetric catalysis has been revolutionised by the realisation that attractive non-covalent interactions such as hydrogen bonds and ion pairs can act as powerful controllers of enantioselectivity when incorporated into appropriate small molecule chiral scaffolds. Given these tremendous advances it is surprising that there are still a relatively limited number of examples of non-covalent interactions being harnessed for control of regioselectivity or site-selectivity in catalysis, two other fundamental selectivity aspects facing the synthetic chemist. This perspective examines the progress that has been made in this area thus far using non-covalent interactions in conjunction with transition metal catalysis as well as in the context of purely organic catalysts. We hope this will highlight the great potential in this approach for designing selective catalytic reactions. PMID- 28572899 TI - Luminescent chemosensors by using cyclometalated iridium(iii) complexes and their applications. AB - Luminescent metal complexes have found increasing use in multiple areas of science and technology, including in chemosensing, light-emitting devices and photochemistry. In particular, the use of cyclometalated iridium(iii) complexes as chemosensors has received increasing attention in the recent literature. Phosphorescent metal complexes enjoy a number of advantages (e.g., long-lived phosphorescence, high quantum efficiency and modular syntheses) that render them as suitable alternatives to organic dyes for sensing a variety of analytes. This review describes recent examples of cyclometalated iridium(iii) complexes that act as luminescent chemosensors for cations, anions or small molecules. PMID- 28572897 TI - Recent developments in and perspectives on three-coordinate boron materials: a bright future. AB - The empty p z -orbital of a three-coordinate organoboron compound leads to its electron-deficient properties, which make it an excellent pi-acceptor in conjugated organic chromophores. The empty p-orbital in such Lewis acids can be attacked by nucleophiles, so bulky groups are often employed to provide air stable materials. However, many of these can still bind fluoride and cyanide anions leading to applications as anion-selective sensors. One electron reduction generates radical anions. The pi-acceptor strength can be easily tuned by varying the organic substituents. Many of these compounds show strong two-photon absorption (TPA) and two-photon excited fluorescence (TPEF) behaviour, which can be applied for e.g. biological imaging. Furthermore, these chromophores can be used as emitters and electron transporters in OLEDs, and examples have recently been found to exhibit efficient thermally activated delayed fluorescence (TADF). The three-coordinate organoboron unit can also be incorporated into polycyclic aromatic hydrocarbons. Such boron-doped compounds exhibit very interesting properties, distinct from their all-carbon analogues. Significant developments have been made in all of these areas in recent years and new applications are rapidly emerging for this class of boron compounds. PMID- 28572900 TI - Bioinspired integrated nanosystems based on solid-state nanopores: "iontronic" transduction of biological, chemical and physical stimuli. AB - The ability of living systems to respond to stimuli and process information has encouraged scientists to develop integrated nanosystems displaying similar functions and capabilities. In this regard, biological pores have been a source of inspiration due to their exquisite control over the transport of ions within cells, a feature that ultimately plays a major role in multiple physiological processes, e.g. transduction of physical stimuli into nervous signals. Developing abiotic nanopores, which respond to certain chemical, biological or physical inputs producing "iontronic" signals, is now a reality thanks to the combination of "soft" surface science with nanofabrication techniques. The interplay between the functional richness of predesigned molecular components and the remarkable physical characteristics of nanopores plays a critical role in the rational integration of molecular functions into nanopore environments, permitting us to envisage nanopore-based biomimetic integrated nanosystems that respond to a variety of external stimuli such as pH, redox potential, molecule concentration, temperature, or light. Transduction of these stimuli into a predefined "iontronic" response can be amplified by exploiting nanoconfinement and physico chemical effects such as charge distribution, steric constraints, equilibria displacement, or local changes in ionic concentration, to name but a few examples. While in past decades the focus has been mostly on their fundamental aspects and the in-depth study of their interesting transport properties, for several years now nanopore research has started to shift towards specific practical applications. This work is dedicated to bringing together the latest developments in the use of nanopores as "iontronic" transducing elements. Our aim is to show the wide potential of abiotic nanopores in sensing and signal transduction and also to promote the potential of this technology among doctoral students, postdocs, and researchers. We believe that even a casual reader of this perspective will not fail to be impressed by the wealth of opportunities that solid-state nanopores can offer to the transduction of biological, physical and chemical stimuli. PMID- 28572902 TI - Bioinspired M-13 bacteriophage-based photonic nose for differential cell recognition. AB - A bioinspired M-13 bacteriophage-based photonic nose was developed for differential cell recognition. The M-13 bacteriophage-based photonic nose exhibits characteristic color patterns when phage bundle nanostructures, which were genetically modified to selectively capture vapor phase molecules, are structurally deformed. We characterized the color patterns of the phage bundle nanostructure in response to cell proliferation via several biomarkers differentially produced by cells, including hydrazine, o-xylene, ethylbenzene, ethanol and toluene. A specific color enables the successful identification of different types of molecular and cellular species. Our sensing technique utilized the versatile M-13 bacteriophage as a building block for fabricating bioinspired photonic crystals, which enables ease of fabrication and tunable selectivity through genetic engineering. Our simple and versatile bioinspired photonic nose could have possible applications in sensors for human health and national security, food discrimination, environmental monitoring, and portable and wearable sensors. PMID- 28572903 TI - pH controlled assembly of a self-complementary halogen-bonded dimer. AB - Phenols and their corresponding phenoxide anions can form halogen bonds with neutral iodotriazoles. The strength of these interactions depends critically on the protonation state of the oxygen atom - the interaction of the phenoxide anion is more than an order of magnitude stronger than the corresponding phenol. The assembly of a molecule bearing both an iodotriazole and a phenoxide anion into a self-complementary dimer, stabilised by two halogen bonds between the phenoxide anions and the neutral iodotriazoles has been demonstrated. The corresponding phenol shows no halogen bond mediated assembly either in the solid or in the solution state. This assembly process can be actuated simply by a change in protonation state - treatment of the phenol with one equivalent of base results in deprotonation and assembly of the dimer. The structure of the homodimer formed by the phenoxide-bearing iodotriazole has been determined in the solid state and 19F NMR spectroscopy demonstrates that the assembled dimer persists in solution and that it has significant stability. 19F NMR spectroscopy has also been used to demonstrate that the assembly process is completely reversible. PMID- 28572904 TI - Au(iii)-aryl intermediates in oxidant-free C-N and C-O cross-coupling catalysis. AB - Au(iii)-aryl species have been unequivocally identified as reactive intermediates in oxidant-free C-O and C-N cross coupling catalysis. The crystal structures of cyclometalated neutral and cationic Au(iii) species are described and their key role in 2 electron-redox Au(i)/Au(iii) catalysis in C-O and C-N cross couplings is shown. Nucleophiles compatible with Au-catalyzed cross couplings include aromatic and aliphatic alcohols and amines, as well as water and amides. PMID- 28572901 TI - Allosteric DNA nanoswitches for controlled release of a molecular cargo triggered by biological inputs. AB - Here we demonstrate the rational design of a new class of DNA-based nanoswitches which are allosterically regulated by specific biological targets, antibodies and transcription factors, and are able to load and release a molecular cargo (i.e. doxorubicin) in a controlled fashion. In our first model system we rationally designed a stem-loop DNA-nanoswitch that adopts two mutually exclusive conformations: a "Load" conformation containing a doxorubicin-intercalating domain and a "Release" conformation containing a duplex portion recognized by a specific transcription-factor (here Tata Binding Protein). The binding of the transcription factor pushes this conformational equilibrium towards the "Release" state thus leading to doxorubicin release from the nanoswitch. In our second model system we designed a similar stem-loop DNA-nanoswitch for which conformational change and subsequent doxorubicin release can be triggered by a specific antibody. Our approach augments the current tool kit of smart drug release mechanisms regulated by different biological inputs. PMID- 28572905 TI - Reactivity of the copper(iii)-hydroxide unit with phenols. AB - Kinetic studies of the reactions of two previously characterized copper(iii) hydroxide complexes (LCuOH and NO2 LCuOH, where L = N,N'-bis(2,6 diisopropylphenyl)-2,6-pyridine-dicarboxamide and NO2 L = N,N'-bis(2,6 diisopropyl-4-nitrophenyl)pyridine-2,6-dicarboxamide) with a series of para substituted phenols (XArOH where X = NMe2, OMe, Me, H, Cl, NO2, or CF3) were performed using low temperature stopped-flow UV-vis spectroscopy. Second-order rate constants (k) were determined from pseudo first-order and stoichiometric experiments, and follow the trends CF3 < NO2 < Cl < H < Me < OMe < NMe2 and LCuOH < NO2 LCuOH. The data support a concerted proton-electron transfer (CPET) mechanism for all but the most acidic phenols (X = NO2 and CF3), for which a more complicated mechanism is proposed. For the case of the reactions between NO2 ArOH and LCuOH in particular, competition between a CPET pathway and one involving initial proton transfer followed by electron transfer (PT/ET) is supported by multiwavelength global analysis of the kinetic data, formation of the phenoxide NO2 ArO- as a reaction product, observation of an intermediate [LCu(OH2)]+ species derived from proton transfer from NO2 ArOH to LCuOH, and thermodynamic arguments indicating that initial PT should be competitive with CPET. PMID- 28572906 TI - Identification of monodentate oxazoline as a ligand for copper-promoted ortho-C-H hydroxylation and amination. AB - The use of a weakly coordinating monodentate directing group for copper mediated ortho-hydroxylation and amination reactions allows for the identification of an external oxazoline ligand as a promoter. PMID- 28572908 TI - The IPEA dilemma in CASPT2. AB - Multi-configurational second order perturbation theory (CASPT2) has become a very popular method for describing excited-state properties since its development in 1990. To account for systematic errors found in the calculation of dissociation energies, an empirical correction applied to the zeroth-order Hamiltonian, called the IPEA shift, was introduced in 2004. The errors were attributed to an unbalanced description of open-shell versus closed-shell electronic states and is believed to also lead to an underestimation of excitation energies. Here we show that the use of the IPEA shift is not justified and the IPEA should not be used to calculate excited states, at least for organic chromophores. This conclusion is the result of three extensive analyses. Firstly, we survey the literature for excitation energies of organic molecules that have been calculated with the unmodified CASPT2 method. We find that the excitation energies of 356 reference values are negligibly underestimated by 0.02 eV. This value is an order of magnitude smaller than the expected error based on the calculation of dissociation energies. Secondly, we perform benchmark full configuration interaction calculations on 137 states of 13 di- and triatomic molecules and compare the results with CASPT2. Also in this case, the excited states are underestimated by only 0.05 eV. Finally, we perform CASPT2 calculations with different IPEA shift values on 309 excited states of 28 organic small and medium sized organic chromophores. We demonstrate that the size of the IPEA correction scales with the amount of dynamical correlation energy (and thus with the size of the system), and gets immoderate already for the molecules considered here, leading to an overestimation of the excitation energies. It is also found that the IPEA correction strongly depends on the size of the basis set. The dependency on both the size of the system and of the basis set, contradicts the idea of a universal IPEA shift which is able to compensate for systematic CASPT2 errors in the calculation of excited states. PMID- 28572907 TI - Linker-free incorporation of carbohydrates into in vitro displayed macrocyclic peptides. AB - We report a strategy for efficient post-translational modification of a library of ribosomally-translated peptides by activation and elimination of cysteine to dehydroalanine then conjugate addition of a range of exogenous thiols, with an emphasis on carbohydrates. These reactions are selective for cysteine, and do not interfere with amplification of the nucleic acid component of an mRNA-displayed peptide. Furthermore, these reactions are shown to be compatible with two different macrocyclisation chemistries, and when applied to a peptide containing an N-terminal cysteine give a ketone that can be functionalised in an orthogonal manner. This new strategy can overcome a limitation of ribosomal translation, providing a means to incorporate untranslatable groups such as carbohydrates in amino acid side chains, and will allow for the ribosomal generation of glycopeptides, requiring only the introduction of a free thiol in the molecule to be incorporated. In combination with in vitro selection techniques, this strategy is envisaged to allow the discovery of biologically-active glycopeptides with a near-natural, but hydrolytically stable, thioglycosidic bond. PMID- 28572909 TI - Green- to far-red-emitting fluorogenic tetrazine probes - synthetic access and no wash protein imaging inside living cells. AB - Fluorogenic probes for bioorthogonal labeling chemistry are highly beneficial to reduce background signal in fluorescence microscopy imaging. 1,2,4,5-Tetrazines are known substrates for the bioorthogonal inverse electron demand Diels-Alder reaction (DAinv) and tetrazine substituted fluorophores can exhibit fluorogenic properties. Herein, we report the synthesis of a palette of novel fluorogenic tetrazine dyes derived from widely-used fluorophores that cover the entire emission range from green to far-red. We demonstrate the power of the new fluorogenic probes in fixed and live cell labeling experiments and present the first example of intracellular live cell protein imaging using tetrazine-based probes under no-wash conditions. PMID- 28572911 TI - Cycloelatanene A and B: absolute configuration determination and structural revision by the crystalline sponge method. AB - Cycloelatanene A and B are marine natural products first reported a few years ago. Their relative structures had been elucidated by an extensive NMR study and found to be epimers. However, their absolute configurations had not been established because they were isolated in only minute quantities as oily compounds. In this study, the complete structures of cycloelatanene A and B, including absolute configurations, were determined by the crystalline sponge method. The structure analysis confirmed the unique tricyclic structure involving a spiro[5.5]undecene skeleton. One stereogenic centre at C4 was revised as a result of this analysis. Since it only took 1-2 weeks to complete the experiments using the crystalline sponge method (guest-soaking followed by crystallographic analysis), this method is now highly recommended as a first port of call to achieve complete natural product structure elucidation. PMID- 28572910 TI - A supramolecular Troger's base derived coordination zinc polymer for fluorescent sensing of phenolic-nitroaromatic explosives in water. AB - A V-Shaped 4-amino-1,8-napthalimide derived tetracarboxylic acid linker (L; bis [N-(1,3-benzenedicarboxylic acid)]-9,18-methano-1,8-naphthalimide [b,f][1,5]diazocine) comprising the Troger's base (TB) structural motif was rationally designed and synthesised to access a nitrogen-rich fluorescent supramolecular coordination polymer. By adopting the straight forward precipitation method, a new luminescent nanoscale Zn(ii) coordination polymer (TB Zn-CP) was synthesized in quantitative yield using Zn(OAc)2.2H2O and tetraacid linker L (1 : 0.5) in DMF at room temperature. The phase-purity of as-synthesised TB-Zn-CP was confirmed by X-ray powder diffraction analysis, infra-red spectroscopy, and elemental analysis. Thermogravimetric analysis suggests that TB Zn-CP is thermally stable up to 330 degrees C and the morphological features of TB-Zn-CP was analysed by SEM and AFM techniques. The N2 adsorption isotherm of thermally activated TB-Zn-CP at 77 K revealed a type-II reversible adsorption isotherm and the calculated Brunauer-Emmett-Teller (BET) surface area was found to be 72 m2 g-1. Furthermore, TB-Zn-CP displayed an excellent CO2 uptake capacity of 76 mg g-1 at 273 K and good adsorption selectivity for CO2 over N2 and H2. The aqueous suspension of as-synthesized TB-Zn-CP showed strong green fluorescence (lambdamax = 520 nm) characteristics due to the internal-charge transfer (ICT) transition and was used as a fluorescent sensor for the discriminative sensing of nitroaromatic explosives. The aqueous suspension of TB-Zn-CP showed the largest quenching responses with high selectivity for phenolic-nitroaromatics (4-NP, 2,4 DNP and PA) even in the concurrent presence of other potentially competing nitroaromatic analytes. The fluorescence titration studies also provide evidence that TB-Zn-CP detects picric acid as low as the parts per billion (26.3 ppb) range. Furthermore, the observed fluorescence quenching responses of TB-Zn-CP towards picric acid were highly reversible. The highly selective fluorescence quenching responses including the reversible detection efficiency make the nanoscale coordination polymer TB-Zn-CP a potential material for the discriminative fluorescent sensing of nitroaromatic explosives. PMID- 28572912 TI - Chemoselective oxidation of aryl organoboron systems enabled by boronic acid selective phase transfer. AB - We report the direct chemoselective Brown-type oxidation of aryl organoboron systems containing two oxidizable boron groups. Basic biphasic reaction conditions enable selective formation and phase transfer of a boronic acid trihydroxyboronate in the presence of boronic acid pinacol (BPin) esters, while avoiding speciation equilibria. Spectroscopic investigations validate a base promoted phase-selective discrimination of organoboron species. This phenomenon is general across a broad range of organoboron compounds and can also be used to invert conventional protecting group strategies, enabling chemoselective oxidation of BMIDA species over normally more reactive BPin substrates. We also demonstrate the selective oxidation of diboronic acid systems with chemoselectivity predictable a priori. The utility of this method is exemplified through the development of a chemoselective oxidative nucleophile coupling. PMID- 28572913 TI - HDAC9 is an epigenetic repressor of kidney angiotensinogen establishing a sex difference. AB - BACKGROUND: Sexual difference has been shown in the pathogenesis of chronic kidney disease induced by hypertension. Females are protected from hypertension and related end-organ damage. Augmentation of renal proximal tubular angiotensinogen (AGT) expression can promote intrarenal angiotensin formation and the development of associated hypertension and kidney injury. Female rodents exhibit lower intrarenal AGT levels than males under normal conditions, suggesting that the suppressed intrarenal AGT production by programmed mechanisms in females may provide protection from these diseases. This study was performed to examine whether epigenetic mechanisms serve as repressors of AGT. METHODS: Male and female Sprague Dawley rats were used to investigate sex differences of systemic, hepatic, and intrarenal AGT levels. All histone deacetylase (HDAC) mRNA levels in the kidneys were determined using a PCR array. HDAC9 protein expression in the kidneys and cultured renal proximal tubular cells (PTC) was analyzed by Western blot analysis and immunohistochemistry. The effects of HDAC9 on AGT expression were evaluated by using an inhibitor and siRNA. ChIP assay was performed to investigate the interaction between the AGT promoter and HDAC9. RESULTS: Plasma and liver AGT levels did not show differences between male and female Sprague-Dawley rats. In contrast, females exhibited lower AGT levels than males in the renal cortex and urine. In the absence of supplemented sex hormones, primary cultured renal cortical cells isolated from female rats sustained lower AGT levels than those from males, suggesting that the kidneys have a unique mechanism of AGT regulation controlled by epigenetic factors rather than sex hormones. HDAC9 mRNA and protein levels were higher in the renal cortex of female rats versus male rats (7.09 +/- 0.88, ratio to male) while other HDACs did not exhibit a sex difference. HDAC9 expression was localized in PTC which are the primary source of intrarenal AGT. Importantly, HDAC9 knockdown augmented AGT mRNA (1.92 +/- 0.35-fold) and protein (2.25 +/- 0.50-fold) levels, similar to an HDAC9 inhibitor. Furthermore, an interaction between HDAC9 and a distal 5' flanking region of AGT via a histone complex containing H3 and H4 was demonstrated. CONCLUSIONS: These results indicate that HDAC9 is a novel suppressing factor involved in AGT regulation in PTC, leading to low levels of intrarenal AGT in females. These findings will help to delineate mechanisms underlying sex differences in the development of hypertension and renin-angiotensin system (RAS) associated kidney injury. PMID- 28572916 TI - iPSCs are safe! AB - Induced pluripotent stem cells (iPSCs) hold great promises in cell therapy. However, the potential safety issues have dampened the enthusiasm of their clinical development. One of the biggest concerns came from the observations that genomic alterations exist in iPSCs. Using next generation sequencing of clonal skin fibroblasts and the iPSC clones derived from the same skin fibroblasts, Dr. Liu and his colleagues in the National Human Genome Research Institute, National Institutes of Health (NIH), USA, in collaboration with Dr. Dunbar's group in the National Heart, Lung, and Blood Institute, NIH, USA, have now elegantly demonstrated that most of the observed genomic alterations in iPSCs were inherited rare alterations from the parental cells. Their findings suggest that reprogramming process does not appear to be more mutagenic than simple subcloning of cultured cells and that iPSCs are safe for cell therapy. PMID- 28572915 TI - APOBEC3B, a molecular driver of mutagenesis in human cancers. AB - Human cancers results in large part from the accumulation of multiple mutations. The progression of premalignant cells is an evolutionary process in which mutations provide the fundamental driving force for genetic diversity. The increased mutation rate in premalignant cells allows selection for increased proliferation and survival and ultimately leads to invasion, metastasis, recurrence, and therapeutic resistance. Therefore, it is important to understand the molecular determinants of the mutational processes. Recent genome-wide sequencing data showed that apolipoprotein B mRNA editing catalytic polypeptide like 3B (APOBEC3B) is a key molecular driver inducing mutations in multiple human cancers. APOBEC3B, a DNA cytosine deaminase, is overexpressed in a wide spectrum of human cancers. Its overexpression and aberrant activation lead to unexpected clusters of mutations in the majority of cancers. This phenomenon of clustered mutations, termed kataegis (from the Greek word for showers), forms unique mutation signatures. In this review, we will discuss the biological function of APOBEC3B, its tumorigenic role in promoting mutational processes in cancer development and the clinical potential to develop novel therapeutics by targeting APOBEC3B. PMID- 28572914 TI - Sex differences in the development of vascular and renal lesions in mice with a simultaneous deficiency of Apoe and the integrin chain Itga8. AB - BACKGROUND: Apoe-deficient (Apoe-/-) mice develop progressive atherosclerotic lesions with age but no severe renal pathology in the absence of additional challenges. We recently described accelerated atherosclerosis as well as marked renal injury in Apoe-/- mice deficient in the mesenchymal integrin chain Itga8 (Itga8-/-). Here, we used this Apoe-/-, Itga8-/- mouse model to investigate the sex differences in the development of atherosclerosis and concomitant renal injury. We hypothesized that aging female mice are protected from vascular and renal damage in this mouse model. METHODS: Apoe-/- mice were backcrossed with Itga8-/- mice. Mice were kept on a normal diet. At the age of 12 months, the aortae and kidneys of male and female Apoe-/-Itga8+/+ mice or Apoe-/-Itga8-/- mice were studied. En face preparations of the aorta were stained with Sudan IV (lipid deposition) or von Kossa (calcification). In kidney tissue, immunostaining for collagen IV, CD3, F4/80, and PCNA and real-time PCR analyses for Il6, Vegfa, Col1a1 (collagen I), and Ssp1 (secreted phosphoprotein 1, synonym osteopontin) as well as ER stress markers were performed. RESULTS: When compared to male mice, Apoe-/-Itga8+/+ female mice had a lower body weight, equal serum cholesterol levels, and lower triglyceride levels. However, female mice had increased aortic lipid deposition and more aortic calcifications than males. Male Apoe-/- mice with the additional deficiency of Itga8 developed increased serum urea, glomerulosclerosis, renal immune cell infiltration, and reduced glomerular cell proliferation. In females of the same genotype, these renal changes were less pronounced and were accompanied by lower expression of interleukin-6 and collagen I, while osteopontin expression was higher and markers of ER stress were not different. CONCLUSIONS: In this model of atherosclerosis, the female sex is a risk factor to develop more severe atherosclerotic lesions, even though serum fat levels are higher in males. In contrast, female mice are protected from renal damage, which is accompanied by attenuated inflammation and matrix deposition. Thus, sex affects vascular and renal injury in a differential manner. PMID- 28572917 TI - Mobilizing for a war on the home front against sugar-related morbidity and mortality. AB - In Israel today, there are 420,200 Israelis diagnosed with diabetes, and every year, Israelis sustain thousands of diabetes-related deaths and tens of thousands of diabetes-related amputations. As such, in Israel, as in much of the world, there is a silent and deadly public health war against obesity and diabetes taking place on the home front -- one in which clinicians, patients, and families fight thousands of life- and limb-threatening battles daily, involving preventable heart disease, diabetes, strokes and amputations. Yet the global clinical and scientific communities, indeed society at large, have barely begun to mobilize. Fighting this war requires confronting and altering "obesogenic" and "diabetogenic" economic and social factors, including food and beverage marketing and pricing that push diets engorged with processed sugars. Ginsberg, in a study recently published in IJHPR, contributes to our understanding of the combined sugar-related health burdens in Israel, producing an epidemiology and health economics study that estimates the health burdens of obesity, overweight, and dental caries in Israel today. He projects the reductions resulting from that portion of disease burden and associated costs if sugar consumption declined to 10 or 5% of daily caloric consumption as a result of multifaceted public health interventions. Projected over 70 years, these reductions in sugar consumption would prevent 16,590 and 34,580 deaths, respectively. These numbers of Israeli deaths averted are similar to, or exceed, the total resulting from armed conflict or terrorism over the past 70 years. While overconsumption of sugar is only one of many factors that drive cardio-metabolic disease, the study by Ginsberg suggests a path through which we can overcome the numerous internal and external obstacles that societies face in making a public policy commitment to fight the warm on the home front: promoting health by reducing added sugar exposure. PMID- 28572919 TI - Proximate and biochemical characterization of burrito (Bachydeuterus auritus) and flying gurnard (Dactylopterus volitans). AB - With limited protein resources and depleting commercial fish species there is the need to improve utilization of some of the lesser known species which are underutilized, for example, big eye grunt (burrito), Bachydeuterus auritus, and the flying gurnard (Dactylopterus volitans), (other names Cephalocanthus volitans (local) Pampansre). This study was to characterize some of the proximate and biochemical properties of burrito and the flying gurnard so as to evaluate their potential for use in human nutrition and other value-added products. Proximate and chemical analysis were determined by the methods of AOAC. Fatty acid profiles were determined following the method of Saaed and Howell (1999). Amino acid profiles for the species were determined according to Bidlingmeyer et al. (1987). The protein content of both the water soluble and salt soluble protein extracts of the fish species were determined by the Bradford Protein Assay method (Bradford 1976). Rancidity of the fish species was assessed by thiobarbituric acid reactive substances (TBARS) and Peroxide value (PV) as described by Saeed and Howell (1999). Burrito contained 18% protein, whereas the flying gurnard contained 22.3%. Calcium content was 296 mg/100 g for burrito and 185 mg/100 g for flying gurnard, whereas iron content was 4.1 mg/100 g and 1.0 mg/100 g for burrito and the flying gurnard, respectively. Palmitic acid (C16) was 27% and 14.3% for the flying gurnard and burrito, respectively. C17: 1omega8 was 3% in the flying gurnard and 0.2% in burrito. Oleic (C18:1omega9) was 17% in the flying gurnard and 6% in burrito. C20:4omega6 was 1.6% in the flying gurnard and 3% in burrito. Docosahexaenoic acid (C22:6omega3) was 4.9% in the flying gurnard and 4.0% in burrito. Both burrito and the flying gurnard are of high nutritional quality as they had a high protein content, good general amino acid profile and abundance of polyunsaturated fatty acids. PMID- 28572920 TI - Nutrient content of fish powder from low value fish and fish byproducts. AB - Consuming small-sized fish species whole, and bones of large fish could contribute significantly to reducing the level of micronutrient and protein malnutrition. These fish products are more affordable and could therefore meet the needs of poor, vulnerable groups, particularly in rural and urban areas where limited economic resources prevent dietary diversity. The objectives of the study were to produce fish powder from dried edible byproducts from fish processing factories, an underutilized fish species, burrito and to determine the physical, micromineral, macronutrient and microbiological quality of the dried fish powder. Edible fish processing byproducts and an underutilized fish, burrito (Brachydeuterus auritus) were cleaned thoroughly and dried with a Council for Scientific and Industrial Research-Food Research Institute (CSIR-FRI) gas-fuelled oven at 55 degrees C for 8 h or until dried. The dried products were milled into powder, and packaged into polythene bags. Proximate analysis of the fish powder was done Official Methods of Analysis (AOAC) methods. Minerals and heavy metals in the fish powder were determined by atomic absorption spectrophotometry (AAS). Microbiological quality was determined by Nordic Committee on Food Analysis Method (NMLK) methods. Tuna trimmings contained 80.71 g/100 g protein, whereas burrito contained 70.40 g/100 g protein. Concentrations of cadmium, arsenic, and mercury varied from <1.00 to 1 mg/kg. Lead was found at 0.04 mg/100 g in tuna frames and gills only. All fish byproducts contained high levels of iron, for example, trimmings contained 16.58 mg/100 g, whereas tuna frames and gills also contained 16.82 and 19.54 mg/100 g, respectively. Burrito contained 8.92 mg/100 g. Zinc levels also ranged from 0.41 mg/100 g in tuna trimmings to 1.88 mg/100 g in tuna gills. The powdered samples according to the standards set by Ghana Standard Authority, were acceptable. Consuming small- sized fish species whole, and bones of large fish could contribute significantly to reducing the level of micronutrient and protein malnutrition. These are more affordable and could therefore meet the needs of poor, vulnerable groups. PMID- 28572922 TI - Migration of nonylphenol and plasticizers from polyvinyl chloride stretch film into food simulants, rapeseed oil, and foods. AB - Nonylphenol (NP) has been suspected as an endocrine-disrupting chemical. Japanese polyvinyl chloride (PVC) stretch films contained 0.5-3.3 mg/g of NP and 100-400 mg/g of plasticizers such as diisononyl adipate (DINA), di-n-alkyl adipate (DAA), and diacetyllauroyl glycerol (DALG). Migration of NP and plasticizers from PVC stretch films into food simulants (water; 4% acetic acid; 20%, 50%, and 95% ethanol; and heptane), rapeseed oil, and foods was investigated. Plasticizers migrated only in small amounts into aqueous simulants and foods, although they migrated at much higher levels into 50% and 95% ethanol, heptane, rapeseed oil, and fatty foods, whereas NP more easily migrated into aqueous simulants and foods. At 5 degrees C for 24 hr, migration of NP into vegetable and fruit was 2.9%-6.4% of their contents, and that of DINA and DAA was 0.1%-0.3%. The migration ratios of NP into aqueous foods were much higher than those of DINA and DAA. The migration ratio of NP into fatty foods, such as minced tuna and pork, was 33% and 24%, which was almost similar to that of DINA and DAA. The estimated daily intakes of NP and DINA for Japanese individuals of those days were 35 and 1,050 MUg, respectively, and should not be associated with any safety concerns. PMID- 28572923 TI - The rehydration behavior of microwave-dried amaranth (Amaranthus dubius) leaves. AB - The effect of temperature (35, 50, and 60 degrees C) on the rehydration behavior of microwave-dried amaranth (Amaranthus dubius) leaves was investigated. Leaves were dried at 700 W power level before rehydrating in water. The higher the rehydration temperature, the higher the equilibrium moisture content of the leaves, although the effect was not statistically significant. The increase in rehydration ratio was significant only as temperature increased from 50 to 60 degrees C. The process was adequately described by the Peleg sorption model, with the Peleg rate constant (K1) and the Peleg capacity constant (K2), both decreasing as rehydration temperature increased. While the color difference (DeltaE) between fresh leaves and leaves rehydrated at 35 degrees C was significantly higher than for the leaves rehydrated at 50 and 60 degrees C, this difference was not visible. Cooking of leaves occurred beyond 120 min at the higher rehydration temperatures . Based on the results, rehydration of microwave dried leaves was successfully carried out at 35 degrees C, however, rehydrated leaves were darker than the fresh leaves. Increasing the temperature to 50 degrees C improved the rehydration capacity and the color of the leaves, however, cooking of leaves occurred by the second hour of the process. PMID- 28572921 TI - Hydroxycinnamic acids in cooked potato tubers from Solanum tuberosum group Phureja. AB - Hydroxycinnamic acids are phenolic compounds and are considered to have health promotion properties due to their antioxidant activity. Potato tubers of 113 genotypes of Solanum tuberosum group Phureja belonging to the Colombian Central Collection, landraces of potatoes, and commercial cultivars were evaluated for their hydroxycinnamic acids content. The composition of these compounds was analyzed using cooked tubers in two different agro-climatic conditions. The genotypes were analyzed for chlorogenic acid, neo-chlorogenic acid, crypto chlorogenic acid, and caffeic acid by ultrahigh-performance liquid chromatography (UHPLC). Chlorogenic acid was the major representative and varied between 0.77 to 7.98 g kg-1 DW (dry weight) followed by crypto-chlorogenic acid (from 0.09 to 1.50 g kg-1 DW). Under moorland agro-climatic conditions even though the chlorogenic acid levels increased with respect to flatland agro-climatic conditions, the related isomer neo-chlorogenic acid decreased as compared to flatland conditions. The correlation between chlorogenic acid with the isomers, and with caffeic acid was positive. This study demonstrated that there is a wide variation in hydroxycinnamic acids contents in the germplasm studied, which can be exploited in breeding programs to contribute to human health. PMID- 28572918 TI - Multi-morbidities of allergic rhinitis in adults: European Academy of Allergy and Clinical Immunology Task Force Report. AB - This report has been prepared by the European Academy of Allergy and Clinical Immunology Task Force on Allergic Rhinitis (AR) comorbidities. The aim of this multidisciplinary European consensus document is to highlight the role of multimorbidities in the definition, classification, mechanisms, recommendations for diagnosis and treatment of AR, and to define the needs in this neglected area by a literature review. AR is a systemic allergic disease and is generally associated with numerous multi-morbid disorders, including asthma, eczema, food allergies, eosinophilic oesophagitis (EoE), conjunctivitis, chronic middle ear effusions, rhinosinusitis, adenoid hypertrophy, olfaction disorders, obstructive sleep apnea, disordered sleep and consequent behavioural and educational effects. This report provides up-to-date usable information to: (1) improve the knowledge and skills of allergists, so as to ultimately improve the overall quality of patient care; (2) to increase interest in this area; and (3) to present a unique contribution to the field of upper inflammatory disease. PMID- 28572925 TI - Origins, production, and utilization of cassava in Burkina Faso, a contribution of a neglected crop to household food security. AB - Cassava (Manihot esculenta Crantz) is a food plant introduced in Africa from America by the Portuguese in 1558. The objective of this study is to establish cassava origins, production, and utilization in Burkina Faso. The investigation was carried out in the regions of Center West, Cascades, Boucle du Mouhoun, Hauts Bassins, South West, and Center East of Burkina Faso. Eighteen cassava processing units and 226 farmers in 57 communities from the selected regions have been involved in the survey. The investigation showed that cassava was introduced to Burkina Faso, former Upper Volta from the costal countries, Gold Coast (now Ghana), by both local traders and the Roman Catholic White missionaries. This happened between the second half of the 19th century and the beginning of the 20th century. The main variety introduced was Banfti. Some improved varieties like V5 (94/0270), Banke (V2), 68.61, 30572, KTMA developed by research are now available and used by farmers along with the traditional varieties like manchien, santidougou, tchinda yaar, leo. The cases of intoxication evoked by some farmers are evidence that some of those varieties may have a high level of cyanohydric acid content. Cassava is available all the year throughout the country. But the top of cassava production is reached in July. Most of the small-scale farmers (98%) grow cassava both for household use and as income generator. About 83.92% of cassava farmers have less than 10 tons as annual production and only 1.72% of them can produce more than 100 tons. The main food products based on cassava found in communities are raw roots, boiled roots, roasted roots, to, attieke, tapioca, ragout, beignets, boiled leaves, soup (with leaves), cassava juice, etc. And the main cassava-processed products in the processing units are attieke, gari, tapioca, and flour. Cassava contributes greatly to household food security during food shortage period. It sustains families for weeks as food and is also exchanged with other foods or sold to buy food or meet household needs. PMID- 28572924 TI - Physicochemical, functional, and nutritional characteristics of stabilized rice bran form tarom cultivar. AB - Extrusion is a multistep thermal process which has been utilized in a wide spectrum of food preparations. The effect of extrusion processing on the physicochemical, nutritional, and functional properties of Tarom cultivar rice bran was studied. However, the color of rice bran was improved by extrusion processing, but the protein content was reduced in the stabilized rice bran, which can be related to the denaturation of protein. Extrusion had also a reduction significant effect on the phytic acid as well as vitamin E in rice bran. However, the content of niacin, riboflavin, pantothenic acid, and folic acid remained unchanged, but the dietary fiber was enhanced which has beneficial health effect on human consumption. In comparison with unstabilized rice bran, water holding capacity was enhanced, but the oil absorption capacity was reduced. Foaming capacity and foaming stability of extruded rice bran was more than that of untreated rice bran, although they were less than that of rice bran protein concentrate/isolate. In general, the extrusion process improves some functional and nutritional properties of rice bran which are valuable to industrial applications and have potential as ingredient in food to improve consumer health. PMID- 28572927 TI - A sensory assessment of color and textural quality of refrigerated tomatoes preserved with different concentrations of potassium permanganate. AB - Freshly harvested mature tomato fruits were treated with different concentrations of potassium permanganate to evaluate their effect on color and texture of the fruits. This was to determine the degree of acceptability and shelf life of the tomatoes. Fifty grams of mature unripe tomato fruits was washed and weighed into a transparent plastic container containing different concentrations of potassium permanganate (control, 2.5 ppm, 5.0 ppm, 7.5 ppm. 10.0 ppm, 12.5 ppm, and 15.0 ppm). The experiment was carried out in a complete randomized design and replicated four times. All the treatments were refrigerated at a temperature range 14-18 degrees C and a sensory assessment of color and textural changes was carried out through a team of selected panelists using the hedonic scale ranking to determine the degree of acceptability. Results obtained were analyzed using analysis of variance DMRT at 5% level of probability and least significant difference (LSD). Results obtained indicated that 7.5 ppm of potassium permanganate had a preservative effect on color and texture of refrigerated tomatoes. Therefore, the tomatoes were of acceptable color and texture for a period of 21 days as revealed in the result. Color quality had a mean score of 1.64 and texture ranking was 1.73 after 3 weeks of storage. PMID- 28572926 TI - Evidence for decreased interaction and improved carotenoid bioavailability by sequential delivery of a supplement. AB - Despite the notable health benefits of carotenoids for human health, the majority of human diets worldwide are repeatedly shown to be inadequate in intake of carotenoid-rich fruits and vegetables, according to current health recommendations. To address this deficit, strategies designed to increase dietary intakes and subsequent plasma levels of carotenoids are warranted. When mixed carotenoids are delivered into the intestinal tract simultaneously, competition occurs for micelle formation and absorption, affecting carotenoid bioavailability. Previously, we tested the in vitro viability of a carotenoid mix designed to deliver individual carotenoids sequentially spaced from one another over the 6 hr transit time of the human upper gastrointestinal system. We hypothesized that temporally and spatially separating the individual carotenoids would reduce competition for micelle formation, improve uptake, and maximize efficacy. Here, we test this hypothesis in a double-blind, repeated-measure, cross-over human study with 12 subjects by comparing the change of plasma carotenoid levels for 8 hr after oral doses of a sequentially spaced carotenoid mix, to a matched mix without sequential spacing. We find the carotenoid change from baseline, measured as area under the curve, is increased following consumption of the sequentially spaced mix compared to concomitant carotenoids delivery. These results demonstrate reduced interaction and regulation between the sequentially spaced carotenoids, suggesting improved bioavailability from a novel sequentially spaced carotenoid mix. PMID- 28572928 TI - Effect of soy flour on nutritional, physicochemical, and sensory characteristics of gluten-free bread. AB - The aim of this study was to assess the effect of soy flour on nutritional, physicochemical, and sensory characteristics of gluten-free (GF) bread. In this study, corn flour was replaced with soy flour at different levels 5%, 10%, and 15% to produce a more nutritionally balanced GF bread. Physical and chemical properties, sensory evaluation and crust and crumb color were measured in bread samples. The results of evaluations showed that protein content of soy flour supplemented GF bread significantly increased from 9.8% to 12.9% as compared to control along with an increased in fat (3.3%-4.1%), fiber (0.29%- 0.38%), and ash (1.7%-2.2%) content. Moisture (27.9%-26.5%) and carbohydrate (58.3-52.3) content decreased with the incremental addition of soybean flour. The highest total score of sensory evaluation was for the bread sample containing 15% soybean flour. The evaluation of crust and crumb showed that bread samples with 15% soy flour were significantly darker than the other bread samples. In conclusion, adding higher levels of soybean flour into GF bread can improve bread quality, sensory characteristics, and nutritional properties of bread. Nutritional status in patients with celiac disease (CD) can be improved through the produce GF bread in this way. PMID- 28572929 TI - Development and standardization of the "Let's Shop" questionnaire: an assessment of shopping habits and executive functions in people with obesity. AB - Overweight and obesity are epidemic in Western countries and the literature suggests a relationship between overweight and executive functions (EF). Shopping is a regular, everyday activity that is strongly related to executive functioning. To date, no assessment tool has been developed to evaluate EF in adults with overweight and obesity, with a focus on the activity of shopping. To determine the factorial validity of the newly developed "Let's Shop" questionnaire. A convenience sample which included three groups of 93 men and women aged 35-60 were included in the study. Thirty three overweight participants and 30 obese participants who sought a clinical dietitian constituted the two research groups, and 30 normal weight participants recruited from a physician's waiting room constituted the control group and were matched to the two research groups by age, gender, education, and socioeconomic status. The "Let's Shop" questionnaire was administered to all participants. An exploratory principal factor extraction with oblimin rotation was conducted for the "Let's Shop" questionnaire. Twenty-one items were entered into the equation; the analysis revealed four distinct factors comprised of 17 items. The cumulative percentage of variance accounted for by the four factors was 44.74%. The four factors were as follows: "planning in action" alpha = 0.63; "planning ahead" alpha = 0.71; "impulsivity" alpha = 0.67; and "habits" alpha = 0.63. The "Let's Shop" questionnaire was reduced to 17 items. This brief questionnaire will enable rapid administration by researchers and practitioners and determine a potential association between EF in the supermarket arena and weight status. PMID- 28572930 TI - Bacterial contaminants from frozen puff pastry production process and their growth inhibition by antimicrobial substances from lactic acid bacteria. AB - Seventy-five bacterial contaminants which still persisted to cleaning system from three puff pastry production lines (dough forming, layer and filling forming, and shock freezing) were identified using 16S rDNA as seven genera of Bacillus, Corynebacterium, Dermacoccus, Enterobacter, Klebsiella, Pseudomonas, and Staphylococcus with detection frequencies of 24.00, 2.66, 1.33, 37.33, 1.33, 2.66, and 30.66, respectively. Seventeen species were discovered while only 11 species Bacillus cereus, B. subtilis, B. pumilus, Corynebacterium striatum, Dermacoccus barathri, Enterobacter asburiae, Staphylococcus kloosii, S. haemolyticus, S. hominis, S. warneri, and S. aureus were detected at the end of production. Based on their abundance, the highest abundance of E. asburiae could be used as a biomarker for product quality. While a low abundance of the mesophile pathogen C. striatum, which causes respiratory and nervous infection and appeared only at the shock freezing step was firstly reported for its detection in bakery product. Six antimicrobial substances (AMSs) from lactic acid bacteria, FF1-4, FF1-7, PFUR-242, PFUR-255, PP-174, and nisin A were tested for their inhibition activities against the contaminants. The three most effective were FF1-7, PP-174, and nisin A exhibiting wide inhibition spectra of 88.00%, 85.33%, and 86.66%, respectively. The potential of a disinfectant solution containing 800 AU/ml of PP-174 and nisin A against the most resistant strains of Enterobacter, Staphylococcus, Bacillus and Klebsiella was determined on artificially contaminated conveyor belt coupons at 0, 4, 8, 12, and 16 hr. The survival levels of the test strains were below 1 log CFU/coupon at 0 hr. The results suggested that a combined solution of PP-174 and nisin A may be beneficial as a sanitizer to inhibit bacterial contaminants in the frozen puff pastry industry. PMID- 28572931 TI - Modeling of drying kiwi slices and its sensory evaluation. AB - In this study, monolayer drying of kiwi slices was simulated by a laboratory scale hot-air dryer. The drying process was carried out at three different temperatures of 50, 60, and 70 degrees C. After the end of drying process, initially, the experimental drying data were fitted to the 11 well-known drying models. The results indicated that Two-term model gave better performance compared with other models to monitor the moisture ratio (with average R2 value equal .998). Also, this study used artificial neural network (ANN) in order to feasibly predict dried kiwi slices moisture ratio (y), based on the time and temperature drying inputs (x1, x2). In order to do this research, two main activation functions called logsig and tanh, widely used in engineering calculations, were applied. The results revealed that, logsig activation function base on 13 neurons in first and second hidden layers were selected as the best configuration to predict the moisture ratio. This network was able to predict moisture ratio with R2 value .997. Furthermore, kiwi slice favorite is evaluated by sensory evaluation. In this test, sense qualities as color, aroma, flavor, appearance, and chew ability (tissue brittleness) are considered. PMID- 28572932 TI - Comparison of phenolic content and antioxidant activities of millet varieties grown in different locations in Sri Lanka. AB - Soluble and bound phenolic compounds were extracted from different varieties of millet types namely, finger millet, foxtail, and proso millet cultivated at dry and intermediate climatic zones in Sri Lanka. The extracts were examined for their total phenolic content (TPC), total flavonoid content (TFC), and proanthocyanidin content (PC). The antioxidant activities were meassured by reducing power (RP), trolox equivalent antioxidant capacity (TEAC), 2,2-diphenyl 1-picrylhydrazyl (DPPH) radical scavenging activity, ferrous ion chelating ability (FICA), and using a beta carotene linoleate model system. The ferulic acid content of extracts were determined using high-performance liquid chromatoghraphy (HPLC). Finger millet showed the highest phenolic content and antioxidant activities compared to proso and foxtail millets. The phenolic content as well as antioxidant activites of soluble and bound phenolic extracts of millets were affected by variety and cultivated location. The highest phenolic content and antioxidant activites were reported for millet samples cultivated in areas belonging to the dry zone in Sri Lanka. PMID- 28572934 TI - Evaluation of different solvents to extract antibacterial compounds from jalapeno peppers. AB - Chili peppers (Capsicum spp.) may possess antibacterial properties and have potential to be used in foods as antimicrobial. The complete chili pepper extract should be evaluated to determine which compounds are responsible for the antimicrobial activity. Extraction of compounds from the pepper is completed using a solvent. The type of solvent used for extraction influences which compounds are isolated, therefore the best extraction method needs to be determined. The purpose of this study was to identify which solvent is most successful at extracting unknown antibacterial compounds from jalapeno peppers. Fresh jalapeno peppers were chopped, weighed, and blended with a solvent (sterilized hot water, 70% methanol, 95% methanol, 70% ethanol, or 95% ethanol) at a 1:1 ratio (g/g) until the mixture was homogenized, followed by shaking for 15 min. The slurry was centrifuged; supernatant was removed and used for antibacterial testing against Listeria monocytogenes, Escherichia coli O157:H7, and Salmonella enterica. The diameter of growth inhibition was measured and statistically evaluated using ANOVA to determine the extract with the greatest antimicrobial activity. Solvents were tested alone as a control. There was greater bacterial inhibition from extracts created with methanol and ethanol than hot water. Listeria monocytogenes was significantly more susceptible to the extracts than E. coli or Salmonella isolates. Each solvent extract was then analyzed using high-performance liquid chromatography (HPLC) and fractions (A-G) were collected and used for subsequent disk diffusion analysis against L. monocytogenes. Fractions E and F (eluded between 20 and 30 min) exhibited the most antibacterial activity. There were no differences between solvents used (p = .05). Further investigation into specific compounds within these extracts will be completed in the future. PMID- 28572935 TI - Waffle production: influence of batter ingredients on sticking of fresh egg waffles at baking plates-Part I: effect of starch and sugar components. AB - Fresh egg waffles are a sweet convenience product typically baked from eggs, water, sugar, flour, fat, leavening agents, emulsifiers, preservatives, and flavors. In industrial production, waffles are baked continuously in high amounts of up to 200 kg raw material per hour. Therefore, it is important that the waffles do not stick onto the baking plates, which can cause significant product loss and increased costs due to interruption of the baking process, required cleaning procedures, and restarting of the energy-consuming start-up phase. Sticking of waffles is greatly influenced not only by baking plate material, release agent, baking temperature, and time, but also by the batter ingredients. In this study, effects of different starches and sugar components were investigated. Within the selected starches, potato starch demonstrated the highest effects on increasing waffle stability and releasing properties compared to wheat and lupine flour (less than 7% sticking waffles). Rice flour performed worst, with almost 50% of sticking waffles. Most of these waffles were broken during take-off, due to their crumbly texture. Within the sugar components, glycerine was better suitable than sorbitol and crystal sugar was superior compared to powdered sugar. They required less take-off force. It could be demonstrated that waffles with increased stability and texture were those that showed the least number of sticking waffles, thus the main aim of batter ingredients was to improve waffle quality. Waffle quality was influenced by batter parameters, significant correlations could be found, for example, a positive correlation between pH- and L-value, negative correlations between pH- and a-value, or density and aw-value. This resulted in significant correlations with take-off-force, which was correlated with L*- and b*-value (negative) and positive to a*-value. Sticking behavior was strongly associated with b*-value (positive) and to a*-value (negative). PMID- 28572933 TI - Anti-inflammatory and anti-insulin resistance activities of aqueous extract from Anoectochilus burmannicus. AB - This study investigated biological activities including antioxidative stress, anti-inflammation, and anti-insulin resistance of Anoectochilus burmannicus aqueous extract (ABE). The results showed abilities of ABE to scavenging DPPH and ABTS free radicals in a dose-dependent manner. Besides, ABE significantly reduced nitric oxide (NO) production in the lipopolysaccharide (LPS)-treated RAW 264.7 via inhibition of mRNA and protein expressions of nitric oxide synthase (iNOS). The LPS-induced mRNA expressions of cyclooxygenase-2 (COX-2) and interleukin 1beta (IL-1beta) were suppressed by ABE. Moreover, ABE exerted anti-insulin resistance activity as it significantly improved the glucose uptake in tumor necrosis factor (TNF)-alpha treated 3T3-L1 adipocytes. In addition, ABE at the concentration of up to 200 MUg/mL was not toxic to human peripheral blood mononuclear cells (PBMCs) and did not induce mutations. Finally, the results of our study suggest the potential use of A. burmannicus as anti-inflammatory, anti insulin resistance agents, or food supplement for prevention of chronic diseases. PMID- 28572936 TI - Waffle production: influence of batter ingredients on sticking of waffles at baking plates-Part II: effect of fat, leavening agent, and water. AB - Fresh egg waffles are continuously baked in tunnel baking ovens in industrial scale. Waffles that partly or fully stick to the baking plates cause significant product loss and increased costs. The aim of this study was, therefore, to investigate the effect of different recipe ingredients on the sticking behavior of waffles. In this second part, ingredients investigated were different leavening agents (sodium acid pyrophosphate, ammonium bicarbonate, magnesium hydroxide carbonate, or monocalcium phosphate), different fat sources (rapeseed oil, cocos fat, butter, or margarine), and different water sources (tap water 12 degrees dH and distilled water). Within the different types of fats, solid fats with high amount of short-chain fatty acids (cocos fat or butter) decreased the number of sticking waffles compared to liquid oils (rapeseed oil). Regarding leavening agents, magnesium hydroxide carbonate and ammonium bicarbonate were superior to sodium acid pyrophosphate or monocalcium phosphate. Between the two water sources, effects were small. PMID- 28572937 TI - Heat penetration attributes of milkfish (Chanos chanos) thermal processed in flexible pouches: a comparative study between steam application and water immersion. AB - The difference in the heating penetration characteristics of product processed in retort by steam-air application and water immersion was studied. Fresh milkfish (Chanos chanos) packed in dry pack and in oil medium, both in flexible pouches, was thermal processed to minimum F0 value of 7.77 at 121.1 degrees C. Heat penetration values were recorded for each minute of processing with the aid Ellab (TM 9608, Denmark) temperature recorder. Retort come up time to achieve 121.1 degrees C was observed to be less in steam-air which invariably led to a lower Ball's process time (B) and the total process time (T) observed in steam-air as compared to water immersion. Obtained data were plotted on a semi-logarithmic paper with temperature deficit on x-axis against time on the y-axis. PMID- 28572938 TI - The effect of proteolytic activity of starter cultures on technologically important properties of yogurt. AB - In this study, the effects of proteolytic activity of yogurt starter bacteria on physicochemical and technological properties of yogurt were investigated. Moreover, impact of proteolytic activity and production of exopolysaccharide (EPS) on the performance of each strain were screened. In order to compare the textural properties of yogurt samples, four parameters were evaluated: syneresis, water-holding capacity, cohesiveness, and hardness. Results showed that strains with high proteolytic activity had lower acidifying activity during fermentation and storage. Samples containing EPS-producing starter cultures had low proteolytic activity except samples K, L, and M. These differences related to nature and characteristics of each strain. Counts of starter cultures in samples produced using strains with high proteolytic activity were higher than other samples. Textural analysis data showed significant differences (p < .05) among strains in the four tested parameters. Strains with high proteolytic activity showed lower texture properties than other samples. Evaluation of sensory characteristics also showed samples prepared using strains with low or medium proteolytic activity and produced with EPS-producing strains have higher overall acceptability than other samples. Accordingly, microbial, physicochemical, and sensory properties of produced yogurts confirm that proteolytic activity is one of the most effective factors in quality of product and performance of each strain. PMID- 28572766 TI - Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images. AB - Neuroimaging measurements derived from magnetic resonance imaging provide important information required for detecting changes related to the progression of mild cognitive impairment (MCI). Cortical features and changes play a crucial role in revealing unique anatomical patterns of brain regions, and further differentiate MCI patients from normal states. Four cortical features, namely, gray matter volume, cortical thickness, surface area, and mean curvature, were explored for discriminative analysis among three groups including the stable MCI (sMCI), the converted MCI (cMCI), and the normal control (NC) groups. In this study, 158 subjects (72 NC, 46 sMCI, and 40 cMCI) were selected from the Alzheimer's Disease Neuroimaging Initiative. A sparse-constrained regression model based on the l2-1-norm was introduced to reduce the feature dimensionality and retrieve essential features for the discrimination of the three groups by using a support vector machine (SVM). An optimized strategy of feature addition based on the weight of each feature was adopted for the SVM classifier in order to achieve the best classification performance. The baseline cortical features combined with the longitudinal measurements for 2 years of follow-up data yielded prominent classification results. In particular, the cortical thickness produced a classification with 98.84% accuracy, 97.5% sensitivity, and 100% specificity for the sMCI-cMCI comparison; 92.37% accuracy, 84.78% sensitivity, and 97.22% specificity for the cMCI-NC comparison; and 93.75% accuracy, 92.5% sensitivity, and 94.44% specificity for the sMCI-NC comparison. The best performances obtained by the SVM classifier using the essential features were 5-40% more than those using all of the retained features. The feasibility of the cortical features for the recognition of anatomical patterns was certified; thus, the proposed method has the potential to improve the clinical diagnosis of sub-types of MCI and predict the risk of its conversion to Alzheimer's disease. PMID- 28572939 TI - Effect of cooking and preservation on nutritional and phytochemical composition of the mushroom Amanita zambiana. AB - The effect of different cooking and preservation methods on the nutritional and phytochemical composition of the mushroom, Amanita zambiana, was investigated. Fresh mushrooms were boiled in water, fried, or microwaved. In addition, fresh mushrooms were either air-dried for 7 days or frozen at -20 degrees C for 14 days. The protein, lipid, carbohydrate, and phenolic content of the treated mushrooms were measured and compared to the fresh mushroom contents. Frying increased the protein (2.01% +/- 0.2% [fresh mushroom] to 2.23% +/- 0.09%), lipid (14.68% +/- 0.9% to 15.56% +/- 0.34%), and carbohydrate (0.89% +/- 0.01% to 2.69% +/- 0.03%) content, while microwaving increased the protein (2.01% +/- 0.2% to 3.64% +/- 0.08%) and carbohydrate content (0.89% +/- 0.01% to 2.26% +/- 0.09%). Boiling only increased the carbohydrate content (0.89% +/- 0.01% to 1.71% +/- 0.05%) of the mushroom and significantly decreased (p < .05) the phenolic content (8.77 +/- 0.1 to 1.46 +/- 0.2 mg gallic acid equivalent (GAE)/g mushroom). Drying resulted in significant increase (p < .05) in protein (2.01 +/- 0.2% to 24.36 +/- 0.09%), carbohydrate (0.89% +/- 0.01% to 58.67% +/- 3.29%), and phenolic contents (8.77 +/- 0.1 to 119.8 +/- 0.7 mg GAE/g mushroom), while freezing only increased the carbohydrate content (0.89% +/- 0.01% to 1.77% +/- 0.03%). From the three cooking methods studied, frying is recommended as the most effective cooking procedure in retaining or enhancing the mushroom nutrients, while drying is a better preservation method than freezing. PMID- 28572941 TI - Effect of psyllium and gum Arabic biopolymers on the survival rate and storage stability in yogurt of Enterococcus duransIW3 encapsulated in alginate. AB - Different herbal biopolymers were used to encapsulate Enterococcus durans IW3 to enhance its storage stability in yogurt and subsequently its endurance in gastrointestinal condition. Nine formulations of encapsulation were performed using alginate (ALG), ALG-psyllium (PSY), and ALG-gum Arabic (GA) blends. The encapsulation efficiency of all formulations, tolerance of encapsulated E. durans IW3 against low pH/high bile salt concentration, storage lifetime, and release profile of cells in natural condition of yogurt were evaluated. Result revealed 98.6% encapsulation efficiency and 76% survival rate for all formulation compared with the unencapsulated formulation cells (43%). The ALG-PSY and ALG-GA formulations have slightly higher survival rates at low pH and bile salt condition (i.e., 76-93% and 81-95%, respectively) compared with the ALG formulation. All encapsulated E. durans IW3 was released from the prepared beads of ALG after 90 min, whereas both probiotics encapsulated in ALG-GA and ALG-PSY were released after 60 min. Enterococcus durans IW3 was successfully encapsulated in ALG, ALG-GA, and ALG-PSY beads prepared by extrusion method. ALG-GA and ALG PSY beads are suitable delivery carriers for the oral administration of bioactive compounds like probiotics. The GA and PSY gels exhibited better potential for encapsulation of probiotic bacteria cells because of the amendment of ALG difficulties and utilization of therapeutic and prebiotic potentials of these herbal biopolymers. PMID- 28572940 TI - Influence of storage temperature and low-temperature conditioning on the levels of health-promoting compounds in Rio Red grapefruit. AB - Commercial operations use low-temperature conditioning of citrus fruits to reduce the incidence of chilling injury (CI) during cold storage and quarantine treatments. Rio Red grapefruits (Citrus paradisi Macf) were stored for 12 weeks at 11 degrees C or 5 degrees C; an additional set was temperature conditioned at 16 degrees C for 7 days before storing at 5 degrees C (CD). Every 3 weeks, samples were assessed for chilling injury (CI) and health-promoting compounds such as ascorbic acid, carotenoids, limonoids, flavonoids, and furocoumarins. Low temperature conditioning significantly reduced CI but did not affect the total soluble solids, acidity, and ripening ratio. After 12 weeks of storage, grapefruits showed no significant differences in lycopene, narirutin, poncirin, furocoumarins, and radical scavenging activity in all the three treatments. Limonin was significantly higher (p < .05) in CD fruits, nomilin was significantly higher in fruits stored at 11 degrees C, whereas fruits stored at 5 degrees C had lower levels of naringin, neohesperidin, and didymin after 12 weeks of storage. Low-temperature conditioning treatment helped fruits to retain similar or higher levels of most of the health-promoting compounds by the end of storage period while maintaining better quality than the nonconditioned fruits. PMID- 28572942 TI - Sensory optimization of crackers developed from high-quality cassava flour, starch, and prawn powder. AB - Crackers produced from high-quality cassava flour (HQCF), cassava starch, and prawn powder were optimized based on sensory preference testing. Ten different formulations of crackers were produced using mixture design. These were subjected to sensory evaluation using attributes such as taste, crispiness, puffiness, and acceptability on a 7-point hedonic scale. A mean score of 4.7, 5.6, 5.2, and 5.2 was obtained correspondingly for taste, crispiness, puffiness, and acceptability. Scores for these attributes indicated that the crackers were acceptable. Mixture regression models were used to generate contour plots for the sensory attributes and these were superimposed to obtain an optimal region, from where an optimum formulation was chosen. Verification of the optimal formulation with acceptability studies confirmed that the newly developed snack had a likeness score of 6.3 and was highly acceptable to consumers. The study demonstrates the suitability of HQCF in processing value added snack products. PMID- 28572945 TI - Packaging methods and storage duration affect essential oil content and composition of lemon verbena (Lippia citriodora Kunth.). AB - Changes in essential oils (EOs) content and composition of lemon verbena leave at different packaging methods (packaged with air, nitrogen, or under vacuum) and during storage period (0, 2, 4, 6 and 8 months) were determined. All the samples were hydrodistilled every 2 months during storage for EO content evaluation. EO composition was determined by gas chromatography and gas chromatography-mass spectrometry. The results showed that by extending the storage period in all packaging methods, EO content was significantly decreased. Parallel to the increase in the storage duration in all packaging methods, citral content was decreased, whereas the amounts of limonene and 1,8-cineole were increased. Packaging of lemon verbena leaves with nitrogen preserved the highest EO content during 8 months of storage and achieved the desired amounts of citral, limonene, and 1,8-cineole. This investigation also showed camphene may be a useful marker for the indication of storage duration of lemon verbena. PMID- 28572944 TI - A potential bioactive hard-stock fat replacer comprised of a molecular gel. AB - Short-chain ceramides, such as N-acetoyl-d-erythro-sphingosine (C2), have a remarkable ability to structure edible oils, such as canola oil, into self standing organogels without any added saturated or trans fats. These short-chain ceramides are ubiquitously found in foods ranging from eggs to soybeans. As the ceramide fatty acid chain length increases, there is an increase in the melting temperature of the organogel and a decrease in the elastic modulus. Gelation ability is lost at 2 wt% when the fatty acid chain length increases to six carbons; however, organogels form at 5 wt% up to 18 carbons. Short-chain ceramides, C2, decrease cell viability of colon, prostate, ovarian, and leukemia cell lines, while ceramides with long-chain fatty acids, C18, do not affect the viability of these cancer cell lines. This suggests that a bioactive spreadable fat, with no trans or added saturated fat, with the potential to alter the viability of cancer cell growth, is possible. PMID- 28572948 TI - Application of starter cultures in the production of Enturire - a traditional sorghum-based alcoholic beverage. AB - Enturire is an alcoholic sorghum- and honey-based beverage traditionally produced by spontaneous fermentation. Its fermentation process is lengthy (5-7 days), does not guarantee product quality and safety and thus necessitates use of pure starter cultures. This study compared a modified production process of Enturire, with honey added at the start to the traditional one (honey added 3 days into the fermentation). The study also evaluated two starter culture combinations (L. plantarum MNC 21 + S. cerevisiae MNC 21 Y) and (L. plantarum MNC 21 + W. confusa MNC 20 + S. cerevisiae MNC 21Y). Microbial counts, pH, alcohol content, titratable acidity, (TA) and consumer acceptability of the Enturire were determined. Lactic acid bacteria (LAB) and yeast counts increased from 4-6 log cfu/ml to 8-9 log cfu/ml and 3-4 log cfu/ml to 5-8 log cfu/ml, respectively. Acidification of Enturire to pH <4.5 was significantly (p < .05) faster (12 hr) with starter fermentations than in the modified (18 hr) and the traditional processes (31 hr). More alcohol (9.2%-9.4%) was produced by the starters than the spontaneous fermentations (3.24%-4.38%). The modified process without starters produced a more acceptable (p < .05) product than the traditional process. The starters produced acceptable Enturire within 12 hr with pH, acidity, and alcohol content of about 3.8, 0.7%, and 2.5%-3.5%. Both starter combinations can thus be used to produce safe and acceptable Enturire in a short time. PMID- 28572949 TI - Consumer knowledge, preference, and perceived quality of dried tomato products in Ghana. AB - Postharvest losses (PHL) are incurred in the tomato value chain in Ghana and solar drying of tomato is a promising technology for reducing the loss. However, there are concerns on the usage, functionality and sensory appeal of the dried products to consumers, compounded with the lack of information and research on dried tomato processing in Ghana. A survey was carried out by administering semistructured questionnaires to 395 randomly selected and willing respondents in the Accra Metropolis. Information was obtained on the socioeconomic profile, consumption pattern, knowledge, and acceptance of tomato processing technologies and assessment of quality attributes important to consumers. Most consumers (74%) preferred tomato powder that is conveniently packaged to retain the characteristic intense taste and the flavor using Friedman's rank mean procedure. The study indicated that consumers were more concerned about good manufacturing practices during the production of solar-dried tomato (48.8%) rather than the quality attributes (8.6%). These findings indicate the need for safe solar drying procedures in order to increase consumer acceptability of solar-dried tomato products in Ghana. PMID- 28572943 TI - Influence of low dose of gamma radiation and storage on some vitamins and mineral elements of dried oyster mushrooms (Pleurotus ostreatus). AB - Mushrooms contain some of the most potent natural medicines on the planet. Vitamins A, C, D, Mineral elements, contents, as well as total soluble solids (Brixo) of dried composition of Pleurotus ostreatus were investigated after exposing to gamma radiation doses of 0 (control), 0.5, 1, 1.5, and 2 kGy at a dose rate of 1.7 kGy per hour in air from a Cobalt 60 source (SLL 515, Hungary) batch irradiator prior to storage (0 month) and after storage (12 months) at room temperature (28 +/- 2 degrees C). Results obtained showed some significant (p < .05) differences due to irradiation and storage. Before storage, vitamins A, C, and D contents of dried and irradiated mushrooms ranged 0.003 +/- 0.08-0.014 +/- 0.08, 0.042 +/- 1.06-0.132 +/- 1.06, and 0.040 +/- 0.76-0.057 +/- 0.76 mg/g, respectively. After 12 months, vitamin contents decreased and ranged 0.0029 +/- 0.08-0.010 +/- 0.08, 0.038 +/- 1.06-0.125 +/- 1.06, and 0.031 +/- 0.76-0.05 +/- 0.76 mg/g for vitamins A, C, and D, respectively. Total soluble solids recorded 1.5 Brixo, however, showed no significant difference (p > .05) and did not change in 12 months after gamma irradiation up to 2 kGy. Sodium ranged from 14.00 +/- 0.7 to 14.90 +/- 0.8 mg/100 g. Potassium content varied from 30.20 +/- 0.5 to 33.10 +/- 0.6 mg/100 g. Magnesium content ranged 1.27 +/- 0.15-3.53 +/- 0.04 mg/100 g. Calcium ranged 11.00 +/- 0.4-12.53 +/- 0.4 +/- 0.03 mg/100 g. Phosphorus content ranged 6.11 +/- 0.30-6.41 +/- 0.35 mg/100 g, whereas Nitrogen content was found to be 3.00 +/- 0.03-3.60 +/- 0.25 mg/100 g. Microelements or heavy metals included Copper; detected ranged 0.00 +/- 0.00-0.02 +/- 0.001 mg/100 g, Zinc content ranged 0.01 +/- 0.002-0.03 +/- 0.001 mg/100 g. Iron content was found to be in the range 0.29 +/- 0.01-0.37 +/- 0.1 mg/100 g. Manganese content was found to be in the range 0.03 +/- 0.001-0.04 +/- 0.01 mg/100 g. Lead content was found to be 0.00 +/- 0.00-0.03 +/- 0.001 mg/100 g. Food processing and storage has the potential to slightly alter the stability of vitamins in foods. Pleurotus ostreatus showed appreciable levels of mineral elemental composition, essential vitamins A, C, and D, and can be endorsed as a natural medicinal food product in the food and pharmaceutical industries. The heavy metals detected were with also below the upper limits permissible by the WHO standards and is thus safe for human consumption. PMID- 28572946 TI - Experimental and modeling investigation of mass transfer during combined infrared vacuum drying of Hayward kiwifruits. AB - In this work, we tried to evaluate mass transfer during a combined infrared vacuum drying of kiwifruits. Infrared radiation power (200-300 W) and system pressure (5-15 kPa), as drying parameters, are evaluated on drying characteristics of kiwifruits. Both the infrared lamp power and vacuum pressure affected the drying time of kiwifruit slices. Nine different mathematical models were evaluated for moisture ratios using nonlinear regression analysis. The results of regression analysis indicated that the quadratic model is the best to describe the drying behavior with the lowest SE values and highest R value. Also, an increase in the power led to increase in the effective moisture diffusivity between 1.04 and 2.29 * 10-9 m2/s. A negative effect was observed on the DeltaE with increasing in infrared power and with rising in infrared radiation power it was increased. Chroma values decreased during drying. PMID- 28572947 TI - Development of a fermented quinoa-based beverage. AB - Quinoa is a crop that originated from the Andes. It has high nutritional value, outstanding agro-ecological adaptability, and low water requirements. Quinoa is an excellent crop alternative to help overcome food shortages, and it can also have a role in the prevention of developed world lifestyle diseases, such as type 2 diabetes, cardiovascular diseases, osteoporosis, inflammatory and autoimmune diseases, etc. In order to expand the traditional uses of quinoa and to provide new, healthier and more nutritious food products, a fermented quinoa-based beverage was developed. Two quinoa varieties (Rosada de Huancayo and Pasankalla) were studied. The fermentation process, viscosity, acidity, and metabolic activity during the preparation and storage of the drink were monitored, as well as the preliminary organoleptic acceptability of the product. The drink had viable and stable microbiota during the storage time and the fermentation proved to be mostly homolactic. Both quinoa varieties were suitable as base for fermented products; Pasankalla, however, has the advantage due to higher protein content, lower saponin concentration, and lower loss of viscosity during the fermentation process. These results suggest that the differences between quinoa varieties may have substantial effects on food processes and on the properties of final products. This is a factor that should be taken into account when planning novel products based on this grain. PMID- 28572954 TI - Effect of drying methods and blending ratios on dough rheological properties, physical and sensory properties of wheat-taro flour composite bread. AB - The study was conducted to evaluate the effect of taro drying methods and blending ratios on the physical quality attributes and sensory quality of wheat taro bread and rheological properties of the blend dough. Farinographic properties like water absorption capacity, dough development time, dough stability time, time to break down, mixing tolerance index, and farinographic quality number were significantly (p < .05) affected by drying methods and blending ratio and their interaction. Increased taro flour (10-20 g) per 100 g of wheat flour resulted in an increased water absorption capacity (57.38%-58.23%) and mixing tolerance index (67.33-70.21 FU). The sensory analysis had revealed that as taro flour blending ratio increased the acceptability of blended breads were reduced. With respect to physical and sensory properties, the control bread had better acceptability than that of 10, 15, and 20 g taro flour-mixed bread. The study revealed that there is possibility of incorporating taro flour up to 15 g per 100 g of wheat flour with acceptable sensory attributes of the composite bread. PMID- 28572951 TI - Value-added probiotic development by high-solid fermentation of sweet potato with Saccharomyces boulardii. AB - Controlled fermentation of Sweet potato (Ipomoea batatas) var. Beauregard by yeast, Saccharomyces boulardii (MAY 796) to enhance the nutritional value of sweet potato was investigated. An average 8.00 * 1010 Colony Forming Units (CFU)/g of viable cells were obtained over 5-day high-solid fermentation. Yeast cell viability did not change significantly over time at 4 degrees C whereas the number of viable yeast cells reduced significantly at room temperature (25 degrees C), which was approximately 40% in 12 months. Overall, the controlled fermentation of sweet potato by MAY 796 enhanced protein, crude fiber, neutral detergent fiber, acid detergent fiber, amino acid, and fatty acid levels. Development of value-added sweet potato has a great potential in animal feed and human nutrition. S. boulardii- fermented sweet potato has great potential as probiotic-enriched animal feed and/or functional food for human nutrition. PMID- 28572950 TI - Relative validation of a short questionnaire to assess the dietary habits of pregnant American Indian women. AB - The objective of this study was to compare a short dietary screener developed to assess diet quality with interviewer-administered telephone 24-hour dietary recalls in a population of pregnant Northern Plains (NP) American Indian women. Participants were recruited from NP clinical sites of the Prenatal Alcohol and SIDS and Stillbirth (PASS) Network, as part of a large, prospective, multidisciplinary study. Prenatal PASS participants who enrolled prior to 24 weeks gestation were eligible to participate. Repeated 24-hour dietary recalls were collected using the Nutrition Data System for Research (NDSR) software and a short dietary screener was administered intended to capture usual dietary intake during pregnancy. The available recalls were averaged across days for analysis. Items were grouped from the recalls to match the food group data estimates for the screener (e.g., total vegetables, total fruit, total dairy, total and whole grains). Deattenuated Pearson correlation coefficients were calculated between the two data sources after correcting for the within-person variation in the 24 hour recall data. A total of 164 eligible women completed the screener and at least two 24-hour dietary recalls and were included in the analyses. Pearson deattenuated correlation coefficients between the diet screener and the dietary recalls for the majority of food groups were 0.40 or higher. This short diet screener to assess usual diet appears to be a valid instrument for use in evaluating diet quality among pregnant American Indian women. PMID- 28572952 TI - Comparison of antioxidant activities among four kinds of Japanese traditional fermented tea. AB - Antioxidant activities of four kinds of Japanese traditional fermented tea, Gishi cha, Ishizuchi-kurocha, Awa-bancha, and Batabatacha, were compared. Antioxidant activity was evaluated by three parameters: copper ion reduction ability, radical trapping ability, and oxygen consumption rate. Processes of fermentation of these fermented teas are different. Goichi-cha and Ishizuchi-kurocha are produced by a two-stage fermentation process, aerobic fermentation and subsequent anaerobic fermentation. Awa-bancha is produced by anaerobic fermentation. And batabata-cha is produced by aerobic fermentation. Additionally, unfermented green tea was also employed as control. These tea leaves were extracted by boiling water and measured antioxidant activities. And concentrations of caffeine and catechins were measured in green tea and in the four kinds of fermented tea: Ishizuchi kurocha, Goishi-cha, Awa-Bancha, and Batabata-cha. Concentrations of caffeine and catechins were lower in the fermented teas than in green tea. Among the fermented teas, epigallocatechin content was the highest in Ishizuchi-kurocha, whereas Batabata-cha hardly contained any epigallocatechin. Goichi-cha, Ishizuchi kurocha, and Awa-bancha showed antioxidative activity regardless of measurement method. Batabatacha had hardly any antioxidative activity. Among the fermented teas, Ishizuchi-kurocha had the strongest antioxidant activity. The antioxidative activities of green tea and the four kinds of fermented tea were significantly different among each other (p < .01). Implication of this study is as follows: although contents of catechins were lower than that of green tea, three kinds of fermented tea showed antioxidative activity comparable to green tea. The results suggest that anaerobic fermentation process is beneficial at least for antioxidative activity. PMID- 28572953 TI - Investigation of the profile of phenolic compounds in the leaves and stems of Pandiaka heudelotii using gas chromatography coupled with flame ionization detector. AB - The profile of phenolic compounds in the leaves and stems of Pandiaka heudelotii was investigated using gas chromatography coupled with flame ionization detector. The leaves and stems had high flavonoids and benzoic acid derivatives content, and moderate levels of lignans and hydroxycinnamates. Twenty-eight known flavonoids were detected, which consisted mainly of kaempferol (41.93% in leaves and 47.97% in stems), (+)-catechin (17.12% in leaves and 16.11% in stems), quercetin (13.83% in leaves and 9.39% in stems), luteolin (7.34% in leaves and 7.71% in stems), and artemetin (6.53% in leaves and 4.83% in stems). Of the six known hydroxycinnamates detected, chlorogenic acid (80.79% in leaves and 87.56% in stems) and caffeic acid (18.98% in leaves and 12.30% in stems) were the most abundant, while arctigenin (77.81% in leaves and 83.40% in stems) and retusin (13.82% in leaves and 10.59% in stems) were the most abundant of the nine known lignans detected. Twelve known benzoic acid derivatives were detected, consisting mainly of ellagic acid (65.44% in leaves and 72.89% in stems), p-hydroxybenzoic acid (25.10% in leaves and 18.95% in stems), and vanillic acid (8.80% in leaves and 7.30% in stems). The rich phytochemical profile of the leaves and stems is an indication of their ability to serve as sources of nutraceuticals. PMID- 28572955 TI - Retention of iron and zinc in yam flour and boiled yam processed from white yam (D. rotundata) varieties. AB - This study investigated the impact of processing on retention of iron and zinc in D. rotundata. Fresh tubers were processed into boiled yam and yam flour and analyzed for zinc, iron, and physicochemical properties. Percent true retention (%TR) was assessed using paired samples and a formula that compensated for loss or gain of moisture and soluble solids. The retention of iron ranged from 55.5% to 98.7% in boiled yam and 25.2% to 54.9% in yam flour; retention of zinc ranged from 49.3% to 97.5% in boiled yam and 18. 9% to 43.1% in yam flour. The amount of iron retained in boiled yam correlated with the amount in the fresh samples (r = .79), likewise in yam flour (r = .82). A similar trend was observed for zinc. From our study, we conclude that retention of iron and zinc is dependent on the variety and processing method used. The information from this study can be used by food scientists and nutritionists in choosing the appropriate processing to increase the retention of high levels of micronutrient in yams and by the yam breeders to adjust their germplasm breeding activities. PMID- 28572956 TI - Effect of Persian and almond gums as fat replacers on the physicochemical, rheological, and microstructural attributes of low-fat Iranian White cheese. AB - The effect of Persian and almond gums (0, 0.1 and 0.2% (w/w)) as fat replacers and milk fat (0.4, 0.9, and 1.4% (w/w)) on physicochemical and rheological characteristics and microstructure of low-fat Iranian White cheese was studied. Persian and almond gums both effectively increased moisture-to-protein (M:P) ratio of low-fat cheese samples which in turn led to a significant reduction in the hardness parameters fracture stress and Young's and storage (G') moduli (p < .05); however, the effect of Persian gum was more pronounced (p < .01). Gum addition promoted cheese yield and proteolysis rate (p < .05). Response surface optimization described that supplementation of cheese milk containing 0.9% fat with 0.2% Persian gum and 0.12% almond gum would result in a low-fat cheese with textural properties similar to its full-fat counterpart. Scanning electron microscopy revealed that the fat replacers produced full-fat-like structure in the low-fat Iranian White cheese, when incorporated at the optimum levels. PMID- 28572957 TI - Effect of spices formulations on the physicochemical and sensory properties of Nnam gon, a Cameroonian dish prepared with cucurbitaceae seeds. AB - Nnam gon, a cake made by steam cooking a mixture of Cucurbitaceae seeds paste and others ingredients specially spices, is a highly prized dish in Central African region. A preliminary investigation conducted as part of this study highlighted that formulations used in the processing of Nnam gon vary according to the spices used. This study was carried out to determine the best formulation for the preparation of this dish. For this purpose, Nnam gon samples were produced from four formulations which differ according to the number of spices used: F0 (no spices); F1 (0.91 g of Allium cepa paste); F2 (0.88 g of A. cepa paste, 0.35 g of Allium sativum paste, 0.41 g of fresh Officinale zingiber paste, 0.41 g of fresh Petroselinum crispum paste, 0.33 g of Monodora myristica, 0.48 g of fresh Celery graveolens paste, 1.19 g of fresh Allium porrum paste, 0.13 g of Allium lepidophyllus powder, and 0.13 g of Piper nigrum), and F3 (0.90 g of A. cepa paste, 0.35 g of A. sativum paste, and 0.42 g of fresh O. zingiber paste). The samples were evaluated for their physicochemical characteristics and sensory profile (Quantitative Descriptive Analysis). The results revealed that proteins (16.56-17.38%), carbohydrates (4.71-5.10%), lipids (23.14-24.25%), ash (4.03 5.92%), and fibers (2.17-2.68%) increased significantly (p < .05) with spices adding. The increase in polyphenols (310.55-592.80 mg/100 g FM) and phytates (2.23-12.49 mg/100 g FM) contents was positively correlated with antioxidant properties of Nnam gon which also increased with spices adding. Significant differences were observed between the samples for all attributes generated (appearance, odor, taste, flavor, texture, and oral texture). Spices adding induced a decrease in hardness, cohesivity, elasticity, and granulous of cake but enhanced oily. Nnam gon produced with spicy formulation (F2 and F3) had higher mean score for general acceptance which was highly correlated (p < .05) with spice odor (r = .99), spice taste (r = .92), and color (r = .84). From this study, it is suggested that spicy Cucurbitaceae paste could improve nutritional value, antioxidant properties, and general acceptance of Nnam gon. PMID- 28572958 TI - Optimization of durum wheat bread enriched with bran. AB - An attempt is made in this study to balance the nutritional and sensory quality of bread. In particular, the formulation of a functional durum wheat bread enriched with bran at high concentration has been developed. Organogel concentration and bran particle size have been used as process variables for bread optimization. Bran concentration was increased at value as high as 15%, thus increasing the nutritional content, even though the sensory quality decreased. Bread was scored barely acceptable at 15% bran concentration. Therefore, the organogel concentration and bran particle size have been optimized to enhance bread sensory quality. Results show that it is possible to prepare bread with a significant bran enrichment without compromising its acceptability by adding proper concentration of organogel and using bran in appropriate particles size. PMID- 28572959 TI - Bioactive phytochemicals in an aqueous extract of the leaves of Talinum triangulare. AB - An aqueous leaf extract of Talinum triangulare was screened for the presence of bioactive molecules, using gas chromatography coupled with pulse and flame ionization detectors. It had high carotenoids; moderate benzoic acid derivatives, hydroxycinnamates and flavonoids; and low terpenes, alkaloids, phytosterols, allicins, glycosides, saponins, and lignans contents. Ten known carotenoids (mainly 50.42% carotene and 33.30% lycopene), nine benzoic acid derivatives (mainly 84.63% ferulic acid and 11.92% vanillic acid), and six hydroxycinnamates (55.44% p-coumaric acid and 44.46% caffeic acid) were detected. Also detected were eight lignans (88.02% retusin) and thirty flavonoids (50.35% quercetin and 39.36% kaempferol). The medicinal properties of the major components of these phytochemical families that were detected in the aqueous extract of the leaves were discussed herein and proposed to be explored for their potential health benefits. The great number of potentially active biomolecules and their multifunctional properties make Talinum triangulare a ready source of health promoting substances. PMID- 28572960 TI - Production of organic flavor compounds by dominant lactic acid bacteria and yeasts from Obushera, a traditional sorghum malt fermented beverage. AB - Single and mixed starter cultures of lactic acid bacteria (LAB): Weissella confusa MNC20, Lactobacillus plantarum MNC21, Lactococcus lactis MNC24 and Lactobacillus fermentum MNC34 and yeasts: Issatchenkia orientalis MNC20Y and Saccharomyces cerevisiae MNC21Y were used to produce Obushera, a fermented sorghum beverage. Microbial counts, pH, sugars, organic acids, and volatile compounds in starter culture and spontaneous fermentations were monitored during 48 hrs. Maximum counts of LAB (8.4-9.4 log cfu g-1) and yeasts (7.5 +/- 0.1 cfu g 1) starter cultures were attained in 6-48 hrs. Weissella confusa, Lc. lactis, and Lb. fermentum showed possible acid sensitivity while I. orientalis produced surface films. LAB starter cultures and their combinations with S. cerevisiae lowered pH from 5.83 to <4.5 (3.50-4.13) in a shorter time (12 hrs) than spontaneous fermentations (24 hrs). Lactococcus lactis and W. confusa metabolized glucose the fastest (p < .05) during the first 6 hrs. Lactobacillus fermentum, Lb. plantarum, and S. cerevisiae utilized glucose and maltose concurrently. Lactobacillus plantarum and S. cerevisiae additionally utilized fructose. S. cerevisiae metabolized sugars the fastest (p < .05) during the first 12-24 hrs. Lactobacillus plantarum and W. confusa produced the highest (p < .05) amounts of lactate (5.43 g kg-1) and diacetyl (9.5 mg kg-1), respectively. LAB also produced acetate, ethanol, acetaldehyde, acetone, and acetoin. Coculturing LAB with S. cerevisiae reduced (p < .05) lactate and diacetyl yield. Yeasts produced high amounts of acetaldehyde and methyl alcohols. Issatchenkia orientalis produced higher (p < .05) amounts of 2-methy-1-propanol and 3-methyl-1-butanol than S. cerevisiae. Combinations of LAB with S. cerevisiae produced a profile flavor compounds close to that of spontaneously fermented Obushera. These combinations can be adopted for controlled fermentation of Obushera and related fermented cereal products. PMID- 28572962 TI - Amino acid profile and protein quality in tuber and leaf of Coccnia abyssinica (Lam.) (Cogn.) accessions of Ethiopia. AB - The protein content and amino acid profile of Anchote (Coccinia abyssinica) leaves and tubers were determined from ten different accessions taken from Debre Zeit Agricultural Research Center, Ethiopia. Crude protein content was determined by Kjeldahl method and amino acid profile was analyzed using performic acid oxidation and acid hydrolysis by ninhydrin-derivatized analysis with amino acid analyzer. Crude protein content of Anchote tuber ranged from 10.70% +/- 0.26% to 13.72% +/- 0.10%, whereas the crude protein content in leaves were ranged between 30.38 +/- 0.01% ("240407-1") and 35.42 +/- 0.05% ("223109-1"). Total amino acid content ranged from 45.12 to 62.89 and 67.31 to 75.69 g/100 g protein for tuber and leaf samples, respectively. The mean values of essential, conditionally essential and nonessential amino acids were 37.22 & 36.79%; 28.62 & 24.10%; and 34.16 & 39.11% for tubers and leaves, respectively. Arginine in tubers and glutamic acid in leaves ranked the highest of all amino acids; while the least dominant essential amino acid was methionine in both parts. Among the essential amino acids, leucine was dominant in all accessions tested with values ranged from 3.12 to 5.32 g/100 g protein in tubers and from 5.15 to 5.65 g/100 g protein in leaves. In general, the average amino acid content was higher in the leaves (71.08 g/100 g protein) compared to the tubers (51.11 g/100 g protein). The nutritional quality of Coccinia abyssinica leaves and tubers range as follows: total essential amino acids (TEAA)/ total amino acids (TAA) (37.57 & 36.82%), TEAA/total non-essential amino acids (TNEAA) ratio (0.60 & 0.58), The predicted protein efficiency ratio (P-PER) (1.22 & 1.80), Essential amino acid index (EAAI) (35.28 & 53.93%), Predicted biological value (P-BV) (26.76 & 47.09%), Nutritional index (4.11 & 17.71%), and Amino acid score (73 & 108) for tuber and leaf sample, respectively. A significant variability was observed in protein and amino acid profile among accessions and plant parts, and the leaf part were found to be richer in protein content and associated nutritional quality. PMID- 28572961 TI - Development and evaluation of floating alginate microspheres for oral delivery of anthocyanins - A preliminary investigation. AB - The goal of this study was to develop floating microspheres that could be used as gastroretentive systems for the delivery of anthocyanins (ACNs). These compounds are absorbed in the stomach and small intestine, and insufficient residence time in these organs could result in limited absorption and contribute to degradation. The microparticles containing freeze-dried haskap berry extract (321.96 +/- 8.35 mg cyanidin 3-glucoside equivalents per g) were prepared by ionotropic gelation of alginate (9%, w/w) with calcium ions (CaCl2 at 2%, w/v) in the gelation bath, with calcium carbonate as the gas-generating compound (added at different ratios in the alginate/extract mixture). The effect of acetic acid concentration (2 and 10%, v/v) in the gelation medium was investigated. Increasing the carbonate : alginate weigh ratio from 0 to 3:4 resulted in different degrees of floatability, larger particles, higher encapsulation efficiency, and lower amount of ACN released. The power law equation fitted the experimental data well, indicating that release occurred mainly by diffusion. This is the first time floating microspheres are proposed as gastroretentive platforms for the delivery of ACNs. PMID- 28572964 TI - Sensory evaluation of selected formulated milk barberry drinks using the fuzzy approach. AB - Amid rigid competition in marketing to accomplish customers' needs, the cost of disappointment is too high. In an effort to escape market disappointment, one of the options to be considered is probing for customer satisfaction through sensory evaluation. This study aims to rank the six selected milk-barberry drink formulae out of 24 (code numbers S3, S4, S15, S16, S17 and S18) each having different milk:barberry:pectin amount (7: 3: 0.2; 6: 4: 0.2; 7: 3: 0.4, 6: 4: 0.4, 5: 5: 0.4 and 6: 4: 0.4), respectively, and to determine the best of quality attribute through sensory evaluation, using the fuzzy decision-making model. The selection was based on pH, total solid content, and degree of serum separation and rheological properties of the drinks. The results showed that the S4 had the highest acceptability, rated under the "very good" category, whereas the lowest acceptability was reported for the S3 which was classified under the "satisfactory" category. In summary, the ranking of the milk-barberry drinks was S4 > S17 > S16 > S15 > S18 > S3. Furthermore, quality attributes were ranked as taste > mouth feel > aroma > color. Results suggest that the fuzzy approach could be appropriately used to evaluate this type of sensory data. PMID- 28572963 TI - Antibacterial activity of jalapeno pepper (Capsicum annuum var. annuum) extract fractions against select foodborne pathogens. AB - Capsicum annuum fruits have been investigated for antimicrobial activity in a number of studies. Capsaicin or other cinnamic acid pathway intermediates are often suggested to be the antimicrobial component, however there are conflicting results. No research has specifically fractionated jalapeno pepper (Capsicum annuum var. annuum) extract to isolate and identify compound(s) responsible for inhibition. In this study, fractions were collected from jalapeno pepper extracts using reverse-phase HPLC and tested for antibacterial activity using the disk diffusion method. Following initial fractionation, two fractions (E and F) displayed antibacterial activity against all three pathogens (p > .05). Commercial standards were screened to determine when they elude and it was found that capsaicin elutes at the same time as fraction E. Fractions E and F were subject to further HPLC fractionation and antibacterial analysis using two methods. The only fraction to display clear inhibition using both was fraction E1, inhibiting the growth of L. monocytogenes. Fraction E1 was analyzed using HPLC-MS. The resulting mass spectra revealed fraction E1 contained compounds belonging to a group of C. annuum-specific compounds known as capsianosides. Limited research is available on antibacterial activity of capsianosides, and a pure commercial standard is not available. In order to confirm the potential antimicrobial activity of the compound(s) isolated, methods need to be developed to isolate and purify capsianosides specifically from jalapeno peppers. PMID- 28572965 TI - Nutrient composition, functional, and pasting properties of unripe cooking banana, pigeon pea, and sweetpotato flour blends. AB - This study investigated some quality attributes of unripe cooking banana (UBF), pigeon pea (PPF), and sweetpotato (SPF) flour blends. Simplex centroid mixture design was used to obtain 17 blends from the flours. The nutrient composition, color, and functional properties of the blends were evaluated using standard methods. Data were subjected to analysis of variance and treatment means were compared using Duncan's multiple range test at 5% probability level. There were significant (p < .05) differences in the nutrient composition, and functional and pasting properties of the blends. The crude protein, crude fiber, ash, foaming capacity, emulsion capacity, and least gelation capacity of the blends increased as the PPF level increased. The blends had Na/K ratio of <1.0. The dispersibility, bulk density, water, and oil absorption capacities of the blends increased as SPF and UBF increased. The peak, setback, and final viscosities increased as UBF and SPF inclusion increased,whereas pasting temperature and time increased as the PPF level increased. The L*, a*, and b* values of the flour blends which were significantly (p < .05) different ranged from 79.58 to 102.71, 0.15 to 2.79, and 13.82 to 23.69, respectively. Cooking banana-pigeon pea sweetpotato flour blends are desirable for alleviating malnutrition in Nigeria and developing new food formulations. PMID- 28572966 TI - Effects of starch concentration on calcium-enhanced black bullhead catfish protein gels. AB - Calcium-enhanced protein recovered from black bullhead catfish was used to develop gels containing increasing amounts of potato starch (0-20 g/kg protein paste) and the effects of starch on functional, textural, and color properties were tested. Energy required to unfold protein groups was greater with the addition of 5 g starch/kg protein paste. Gels containing starch were harder, chewier, and less springy (p < .05) than gels without starch. For most measurements, regression analysis showed that increasing the starch concentration beyond 5 g/kg did not contribute to further significant textural changes. Torsional shear stress and strain along with Kramer shear force increased as the concentration of starch increased (R2 = .79, .79, and .53, respectively). The addition of >=10 g starch/kg protein paste resulted in darker gels and gels got darker as more starch was added (R2 = .71). Results showed no benefit to increasing starch concentration in gels beyond 5 g starch/kg protein paste. PMID- 28572967 TI - Which product characteristics are preferred by Chinese consumers when choosing pork? A conjoint analysis on perceived quality of selected pork attributes. AB - Due to the economic growth achieved by China over the past 20 years, Chinese consumers have changed their purchasing behavior regarding meat. Instead of buying locally produced pork, they are increasingly willing to purchase imported pork. A conjoint analysis investigated how intrinsic pork attributes (fat content and processing) and extrinsic pork attributes (origin, price, and packaging) relate to the perceived quality of pork and the choices made by Chinese consumers. A questionnaire distributed among a sample of Chinese consumers (n = 81) revealed that processing (fresh/frozen) is the most important determinant of pork choice (36%), followed by fat content (27%), origin (18%), price (12%), and packaging (6.6%). Estimates of utility showed that Chinese consumers value fresh pork highly (0.147), followed by lean pork (0.111) and pork imported from countries other than China (0.073). The findings indicate that Chinese consumer's value both intrinsic and extrinsic attributes, and these results may help the meat industry improve China's competitive meat market by developing new and more products that are tailored to the needs of the consumer. PMID- 28572968 TI - Fresh preservation of alfalfa sprouts and mushroom slices by soaking with thymol and resveratrol solutions. AB - The preservation of fresh produce served as salads through soaking with solutions containing naturally occurring phenolic ingredients is of merit. For a primary assay, thymol and resveratrol at 0-500 ppm were prepared and used to inhibit growth and survival of Escherichia coli and Staphylococcus aureus. Thymol and resveratrol exhibited potent inhibitory activities against the growth of both bacteria. For S. aureus, cells treated with thymol at 250 ppm or resveratrol at 500 ppm, the durations to achieve 3 log reduction (3LR) were 40 and 20 min, respectively. When the cells were treated with thymol combined with resveratrol, both at 250 ppm, the 3LR value was achieved in under 5 min. Synergistic antibacterial activity between thymol and resveratrol was apparent. The antibacterial and known health-enhancing activities of resveratrol are of interest. PMID- 28572969 TI - Optimization of the extraction of the p-menthadienol isomers and aristolone contained in the essential oil from Elyonurus hensii using a 23 full factorial design. AB - The aim of this study was to optimize the extraction of p-menthadienol isomers and aristolone from the essential oil of Elyonurus hensii by hydrodistillation. The study of the seasonal variation in the chemical composition has shown that the plant material has been subject to a natural selection regarding the biosynthesis of the p-menthadienol isomers: during periods of water stress, the extracts are rich in cis and trans-p-mentha-1(7),8-dien-2-ol and poor in cis and trans-p-mentha-2,8-dien-1-ol. Regarding the modeling, eight experiments were carried out by considering three easily interpretable factors (the extraction duration, the residual water content and the state of the division of the plant material). The average yield was 1.33% for the aerial part and 0.74% for the roots. The residual water content is the most important factor, which significantly influences the average yield of the essential oil and the content of the major constituents. Regarding the aerial part, a low residual water content of the plant material varies the essential oil yield (from 0.40% to 2.11%) and the content of cis and trans-p-mentha-2.8-dien-1-ol (from 15.87% to 23.24%). At the root level, the samples that have a very low residual water content provide extracts richer in aristolone. The combined effects of the extraction duration, the state of division, and the residual water content influence greatly the extraction of aristolone (from 36.68% to 54.55%). However, these interactions are more complex and difficult to assess. PMID- 28572971 TI - Nutritional and sensory properties: Snack food made from high-quality cassava flour and legume blend. AB - The nutritional benefits of grain legumes such as cowpea and soybean in sub Saharan Africa have not been fully utilized to alleviate problem of protein malnutrition in this region. This study aimed to evaluate and compare the nutritional properties and sensory evaluation of snack food made from high quality cassava flour (HQCF) and soybeans (50:50), and HQCF and cowpea (50:50). Sensory evaluation was conducted among panellists in Nigeria and DR Congo. Results showed that the soy variant of the snack contained significantly higher protein than the cowpea variant. There was cross-cultural difference in snack preference between panellists in Nigeria and DR Congo. Panellists in DR Congo preferred the aroma of the unboiled soy variant, whereas panellists in Nigeria preferred the boiled soy variant more. This study showed the potential of legumes and cassava in the snack food sector not only as a partial substitute for wheat flour but as a major ingredient and also form basis for the new product development in the snacks food industry. The developed product could be possibly used to alleviate the protein-malnutrition among the vulnerable groups of most developing countries. PMID- 28572970 TI - Home-based preparation approaches altered the availability of health beneficial components from carrot and blueberry. AB - This study investigated the effects of different home food preparation methods on availability of total phenolic contents (TPC) and radical scavenging components, as well as the selected health beneficial compounds from fresh blueberry and carrot. High performance liquid chromatography (HPLC) analysis revealed that ground carrots using blenders released significantly greater amount of beta carotene than their chopped counterpart, and blueberry samples prepared with different commercial blenders/grinders released different levels of cyaniding-3-O glucoside and malvidin-3-O-glucoside. Furthermore, microwaving was able to significantly alter the releasable amounts of cyaniding-3-O-glucoside and malvidin-3-O-glucoside from blueberries. In addition, carrots and blueberries processed using different blenders and chopping with or without microwaving differed in their available levels of TPC, and radical scavenging components against DPPH *, oxygen radicals and HO *, as well as their potential anti inflammatory activities. Taking together, these results indicated that home food preparation approaches may alter the availability of health components from carrots and blueberries. The results also suggested that the influence may depend on the fruit and vegetable type, but not the price of blenders/grinders. PMID- 28572972 TI - Effect of precooking and polyphosphate treatment on the quality of microwave cooked catfish fillets. AB - In the U.S. market place, there are many examples of precooked poultry products designed to be reheated in a microwave oven and, to a lesser extent, fish products such as tilapia. However, few U.S. catfish products are designed to be microwave cooked or reheated. The first objective of this study was to examine the properties of microwave cooked raw frozen catfish fillets and oven precooked (to 62.8 degrees C) frozen fillets and then reheated by microwave cooking. The second objective was to evaluate changes in properties as a consequence of treatment with a commercial polyphosphate blend (Individually Quick Frozen [IQF]). The sample analysis included weight loss, proximate content, color (CIE L*a*b*), pH, mechanical texture (hardness), and lipid peroxidation (TBARS) measurements. Frozen fillets which contained polyphosphate showed <4% moisture loss after microwave cooking, relative to a 12% moisture loss for fillets without polyphosphate. A large cooking loss of ~40% was observed for precooked fillets after microwave cooking, correlated with a higher percent moisture loss (11% and 13% for fillets with and without polyphosphate, respectively) to comparable samples that were not precooked. For both types of fillets, an increased amount of yellow color was observed for precooked fillets after microwave cooking, relative to comparable fillets that were not precooked. Fillet hardness determined by peak force revealed an overall harder texture (~1.1-1.8 times) for fillets without polyphosphate than fillets with polyphosphate. This study will be used to develop precooked catfish products that can be reheated in a microwave oven. PMID- 28572973 TI - Spray drying of pomegranate juice using maltodextrin/cyclodextrin blends as the wall material. AB - Microencapsulation protects sensitive nutrients, masks flavors, or enhances delivery. Ratios of maltodextrin and gamma-cyclodextrin (20:0, 19:1, and 17:3% w/w) were dissolved in water and mixed with pomegranate juice for spray drying with inlet temperatures of 120, 140, and 160 degrees C. The effects on physical properties (water activity, % water content, color, pH, soluble solids (Brix), and methyl cellulose precipitable tannin assay (MCPTA) were examined. Based on the principle component analysis, formulation influenced color parameters and pH accounted for 46.8% of the variation in the data. Temperature influenced Chroma and water-holding capacity with 31.8% of the variation. The pH of the reconstituted spray-dried powder significantly influenced color. Blending of gamma-cyclodextrins to maltodextrins slightly increased the water-holding capacity, increased pH, slightly affected color, and preserved the color over time, slightly better. Increased inlet temperature affected color, decreased water-holding capacity, and decreased astringency index. Small additions of gamma cyclodextrin affect spray-dried powders. PMID- 28572974 TI - Nutritional advantages of sous-vide cooking compared to boiling on cereals and legumes: Determination of ashes and metals content in ready-to-eat products. AB - In order to guarantee the highest quality of ready-to-eat cereals and legumes, two different cooking methods have been applied: traditional cooking and sous vide. Ashes and metals content (magnesium, potassium, iron, zinc, and copper) has been determined and compared in 50 samples of red lentils, peas, Borlotti beans, pearl barley, and cereals soup. All the samples cooked with sous-vide showed a significant increase in the content of minerals with the exception of potassium in cereal soup, iron in Borlotti beans, and magnesium in pearl barley. Ash content increased in legumes and in cereal soup cooked with sous-vide method. The higher different ashes concentration between total samples cooked with traditional cooking and with sous-vide was registered in zinc (+862 mg), iron (+314 mg), potassium (+109 mg), and copper (+95 mg). Sous-vide is preferred as it provides products with a higher concentration of metals compared to the ones cooked with traditional cooking. PMID- 28572975 TI - The community structure of Methanomassiliicoccales in the rumen of Chinese goats and its response to a high-grain diet. AB - BACKGROUND: The newly proposed methanogenic order 'Methanomassiliicoccales' is the second largest archaeal population in the rumen, second only to the Methanobrevibacter population. However, information is limited regarding the community of this new order in the rumen. METHODS: This study used real-time PCR and 454 pyrosequencing to explore the abundance and community composition of Methanomassiliicoccales in the rumen of Chinese goats fed a hay (0% grain, n = 5) or a high grain (65% grain, n = 5) diet. RESULTS: Real-time PCR analysis showed that the relative abundance of Methanomassiliicoccales (% of total archaea) in the goat rumen was significantly lower in the high-grain-diet group (0.5% +/- 0.2%) than that in the hay-diet group (8.2% +/- 1.1%, P < 0.05). The pyrosequencing results showed that a total of 208 operational taxonomic units (OTUs) were formed from ten samples at 99% sequence identity. All the sequences were identified as Methanomassiliicoccaceae at the family level, and most of the sequences (96.82% +/- 1.64%) were further classified as Group 8, 9, and 10 at the Methanomassiliicoccales genus level in each sample based on the RIM-DB database. No significant differences were observed in the number of OTUs or Chao1's, Shannon's or Pielou's evenness indexes between the hay- and high-grain-diet groups (P >= 0.05). PCoA analysis showed that diet altered the community of Methanomassiliicoccales. At the genus level, the relative abundances of Group 10 (67.25 +/- 12.76 vs. 38.13 +/- 15.66, P = 0.012) and Group 4 (2.07 +/- 1.30 vs. 0.27 +/- 0.30, P = 0.035) were significantly higher in the high-grain-diet group, while the relative abundance of Group 9 was significantly higher in the hay-diet group (18.82 +/- 6.20 vs. 47.14 +/- 17.72, P = 0.020). At the species level, the relative abundance of Group 10 sp. (67.25 +/- 12.76 vs. 38.13 +/- 15.66, P = 0.012) and Group 4 sp. MpT1 (2.07 +/- 1.30 vs. 0.27 +/- 0.30, P = 0.035) were significantly higher in the high-grain-diet group, while the relative abundance of Group 9 sp. ISO4-G1 was significantly higher in the hay-diet group (12.83 +/- 3.87 vs. 42.44 +/- 18.47, P = 0.022). CONCLUSIONS: Only a few highly abundant phylogenetic groups dominated within the Methanomassiliicoccales community in the rumens of Chinese goats, and these were easily depressed by high-grain-diet feeding. The relatively low abundance suggests a small contribution on the part of Methanomassiliicoccales to the rumen methanogenesis of Chinese goats. PMID- 28572976 TI - Processing of ingredients and diets and effects on nutritional value for pigs. AB - A conventional diet based on corn and soybean meal fed to pigs is usually provided in a mash form and in most cases, processing other than grinding and mixing is not used. However, due to the high cost of energy in pig diets, use of high fiber ingredients such as soybean hulls, distillers dried grains with solubles, and wheat middlings has increased. High fiber concentrations in the diet usually results in reduced energy and nutrient digestibility due to the low capacity of pigs to digest fiber, which negatively impacts growth performance and carcass composition of the pigs. Feed processing technologies such as changes in grinding procedures, expansion, extrusion, pelleting, use of enzymes or chemical treatments may, however, be used to solubilize some of the cellulose and hemicellulose fractions that form the cell wall of plants in the ingredients, and therefore, increase nutrient availability. This may have a positive effect on energy digestibility, and therefore, also on pig growth performance and carcass composition, but effects of different feed technologies on the nutritional value of feed ingredients and diets fed to pigs are not fully understood. It has however, been demonstrated that reduced particle size of cereal grains usually results in increased digestibility of energy, primarily due to increased digestibility of starch. Extrusion or expansion of ingredients or diets may also increase energy digestibility and it appears that the increase is greater in high fiber diets than in diets with lower concentrations of fiber. Chemical treatments have not consistently improved energy or nutrient digestibility, but a number of different enzymes may be used to increase the digestibility of phosphorus, calcium, or energy. Thus, there are several opportunities for using feed technology to improve the nutritional value of diets fed to pigs. PMID- 28572977 TI - Acoustic and thermal characterization of agar based phantoms used for evaluating focused ultrasound exposures. AB - BACKGROUND: This study describes a series of experimental work completed towards characterizing candidate materials for fabricating brain and muscle tissue mimicking phantoms. METHODS: The acoustic speed, attenuation, impedance, thermal diffusivity, specific heat and thermal conductivity were measured. RESULTS: The resulting brain (2% w/v agar-1.2% w/v Silica Dioxide-25%v/v evaporated milk) and muscle tissue recipe (2% w/v agar-2% w/v Silica Dioxide-40%v/v evaporated milk) introduced a total attenuation coefficient of 0.59 dB/cm-MHz and 0.99 dB/cm-MHz respectively. Acrylonitrile Butadiene Styrene (ABS) possessed an attenuation coefficient of 16 dB/cm at 1 MHz which was found within the very wide range of attenuation coefficient values of human bones in literature. The thermal conductivity of the brain tissue phantom was estimated at 0.52 W/m degrees C and at 0.57 W/m. degrees Cfor the muscle. These values demonstrated that the proposed recipes conducted heat similar to the majority of most soft tissues found from bibliography. The soft tissue phantoms were also evaluated for their thermal repeatability after treating them repeatedly at different locations with the same sonication protocol and configuration. The average coefficient of variation of the maximum temperature at focus between the different locations was 2.6% for the brain phantom and 2.8% for the muscle phantom. CONCLUSIONS: The proposed phantom closely matched the acoustic and thermal properties of tissues. Experiments using MR thermometry demonstrated the usefulness of this phantom to evaluate ultrasonic exposures. PMID- 28572978 TI - Erratum to: Differential intratumoral distributions of CD8 and CD163 immune cells as prognostic biomarkers in breast cancer. AB - [This corrects the article DOI: 10.1186/s40425-017-0240-7.]. PMID- 28572979 TI - Complex effects of high-flow nasal cannula therapy on hemodynamics in the pediatric patient after cardiac surgery. AB - BACKGROUND: The high-flow nasal cannula (HFNC) system has been widely used for children in various clinical settings. However, the physiological and clinical impact of HFNC therapy on the pediatric patient with respiratory distress after cardiac surgery has not been thoroughly investigated. MAIN BODY OF THE ABSTRACT: It seems logical to use HFNC as a primary therapy for post-extubation respiratory failure after congenital heart surgery, in which low cardiac output syndrome and upper airway obstruction are commonly encountered; the HFNC therapy alleviates the work of breathing and large negative swings of intrathoracic pressure, which in turn helps to decrease the systemic ventricular afterload. When applying HFNC to patients after congenital heart surgery, however, consideration must be given to its diverse effects on hemodynamics because of the complex respiratory and cardiac pathophysiology in these patients. The positive pressure generated by HFNC can exert different effects on pulmonary vascular resistance depending on the lung condition, while its impact on cardiac output may also differ depending on the cardiac physiology. The hemodynamic effects of HFNC may become even more complex in a patient with a single ventricle. To better assess its physiologic effects in patients after cardiac surgery, future studies could utilize various modalities including esophageal balloon catheters, electrical impedance tomography, and near-infrared spectroscopy. At the same time, studies should focus on specific types of cardiac pathophysiology or surgery when evaluating the effects of HFNC, since it may exert various effects, depending on the cardiac physiology or preoperative pulmonary hemodynamics. Lastly, the optimal flow rate at which the benefit of HFNC is maximized through favorable cardiopulmonary interactions should be determined in future studies. SHORT CONCLUSION: Further studies are needed to better understand the effect of HFNC in different cardiac and respiratory physiologies, given their complexity in pediatric patients after cardiac surgery. PMID- 28572980 TI - The role of contact system in septic shock: the next target? An overview of the current evidence. AB - BACKGROUND: Septic shock remains challenging to intensive care units worldwide, despite recent documented improvement in mortality over the years. Multiple new therapies have been attempted without success in large clinical trials. Evidence concerning the role of the contact system and bradykinin on septic shock physiological manifestations is shown by this article. OBJECTIVES: The objective of the study is to review the current evidence linking contact system activation and septic shock, as well as efficacy of available therapies targeting this pathophysiological pathway and to evaluate the potential of further researching the matter. RESULTS: Multiple animal studies are already available and suggestive of a meaningful role of contact system activation on septic shock. However, human trials are still scarce, and the ones available are not enough to establish such a strong connection. Furthermore, attempted therapies have been successful across multiple species, but not as much in humans. Therefore, contact system and septic shock relationship remains plentiful in questions to be answered in the coming years or decades. CONCLUSIONS: Whether the contact system is not as relevant in humans as it is in animals or there is only lack of evidence remains to be explained. The subject is an attractive open field for further research aiming to aid in tackling such a burdensome condition. PMID- 28572981 TI - The application of anticoagulant therapy to sepsis. AB - Since the withdrawal of recombinant-activated protein C, the anticoagulant therapy for sepsis was taken no notice. For instance, the international sepsis guidelines did not share a space for this therapy. However, we can see the signs of change recently. The Surviving Sepsis Campaign Guidelines 2016 introduced the development of recombinant thrombomodulin, and the European Society of Intensive Care Medicine released comments on this subject. However, since small but important discrepancy was recognized between the standpoints of Japan (more aggressive) and other countries (rather conservative), we intend to discuss on this point. PMID- 28572982 TI - Overweight and obesity prevalence among public servants in Nadowli district, Ghana, and associated risk factors: a cross-sectional study. AB - BACKGROUND: Globally, overweight and obesity are becoming a mounting concern, impacting negatively on the health of populations especially in low-income settings. However, there is paucity of epidemiological information available in Ghana to support intervention activities. We conducted a study among public servants to estimate overweight/obesity, hypertension and diabetes prevalence and associated risk factors. METHODS: A descriptive cross sectional survey involving 271 purposively sampled public servants aged 20 to 59 years was conducted. We used a structured questionnaire to collect data on eating patterns, risk factors for overweight and obesity, as well as data on socio-demographics and physical activity. Anthropometric measurements were carried out and body mass index (BMI) calculated. Information on blood pressure and diabetes was also gathered. We used descriptive statistical and logistic regression analyses to, respectively, estimate overweight/obesity prevalence, and examine associations between behavioral factors and overweight/obesity and hypertension/diabetes. RESULTS: The overall hypertension/diabetes, overweight and obesity prevalence were 20, 29.9 and 4.8% respectively. The study found that marital status (p < 0.001), leisure time with physical activity and level of physical activity during work (p < 0.035) as well as morbidities such as diabetes and hypertension (p < 0.012) were significantly associated with BMI. Findings showed no significant relationship between mealtime, eating habits, education, age and body mass index. Even though prevalence of overweight/obesity was higher among respondents who travelled to work by car compared to respondents who used motor bikes or walked, the association between weight status and means of transport was not statistically significant. Both smoking (p = 0.730) and alcohol consumption (p = 0.109) were not linked to weight status. CONCLUSION: Population-based interventions are needed to promote nutritious food selection and consumption, physical activity and healthy life styles. We also recommend that age and gender-specific interventions should be designed and implemented by relevant authorities to promote and support healthy living and healthy-lifestyles at home and in workplaces. PMID- 28572983 TI - Childhood overweight, obesity and associated factors among primary school children in dire dawa, eastern Ethiopia; a cross-sectional study. AB - BACKGROUND: Obesity in children is increasing worldwide. Malnutrition has become a double burden challenge of public health concern in developing countries. Childhood obesity increases the risk of chronic disease in childhood as well as adulthood. However, information is very scarce about childhood obesity in developing countries specifically in Ethiopia. Therefore, we aimed to assess childhood overweight, obesity and associated factors among primary school children at Dire Dawa, Eastern Ethiopia. METHODS: A school based cross-sectional study was conducted in Dire Dawa from 1st to 30th March, 2016. Study participants were selected using multistage sampling method. Pre-tested self-administered questionnaire, face to face interview technique and anthropometric measurements were used to collect data by eight well trained data collectors. Data were coded, cleaned and entered into EpiData software version 3.5.1, and exported into SPSS (version 21.0) statistical software, for data analysis. Bivariate and multivariate logistic regression were carried out to identify associated factors with childhood overweight and obesity. Statistical significance was declared using Adjusted Odds Ratio (AOR) at 95% CI and p-value less than 0.05. RESULTS: The prevalence of overweight and obesity were 14.7% (95% CI: 11.7, 18.0) and 5.8% (95% CI: 3.6, 8.0), respectively. Children who were from private school (AOR = 3.4, 95% CI: 1.4, 8.5), from families belonged to high socioeconomic class (AOR = 16.9, 95% CI: 6.5, 23.9), preferred sweetened foods (AOR = 2.3, 95% CI: 1.1, 5.1), had not engaged in regular physical exercise (AOR = 3.8, 95% CI: 1.5, 9.8), had experienced sedentary life style like spent their free time watching TV (AOR = 3.6, 95% CI: 1.6, 7.9), play computer game (AOR = 4.6, 95% CI:1.4,15.4), and were not having close friends (AOR = 2.9, 95% CI: 1.4, 6.2) were significantly associated with overweight/obesity risk. CONCLUSION: Overweight/obesity in children is on alarming stage in the study area. Therefore, more attention should be given to creating awareness about healthy diet and improving life style through school and public media in collaboration with concerned bodies. PMID- 28572984 TI - Nature of the optical band shapes in polymethine dyes and H-aggregates: dozy chaos and excitons. Comparison with dimers, H*- and J-aggregates. AB - Results on the theoretical explanation of the shape of optical bands in polymethine dyes, their dimers and aggregates are summarized. The theoretical dependence of the shape of optical bands for the dye monomers in the vinylogous series in line with a change in the solvent polarity is considered. A simple physical (analytical) model of the shape of optical absorption bands in H aggregates of polymethine dyes is developed based on taking the dozy-chaos dynamics of the transient state and the Frenkel exciton effect in the theory of molecular quantum transitions into account. As an example, the details of the experimental shape of one of the known H-bands are well reproduced by this analytical model under the assumption that the main optical chromophore of H aggregates is a tetramer resulting from the two most probable processes of inelastic binary collisions in sequence: first, monomers between themselves, and then, between the resulting dimers. The obtained results indicate that in contrast with the compact structure of J-aggregates (brickwork structure), the structure of H-aggregates is not the compact pack-of-cards structure, as stated in the literature, but a loose alternate structure. Based on this theoretical model, a simple general (analytical) method for treating the more complex shapes of optical bands in polymethine dyes in comparison with the H-band under consideration is proposed. This method mirrors the physical process of molecular aggregates forming in liquid solutions: aggregates are generated in the most probable processes of inelastic multiple binary collisions between polymethine species generally differing in complexity. The results obtained are given against a background of the theoretical results on the shape of optical bands in polymethine dyes and their aggregates (dimers, H*- and J-aggregates) previously obtained by V.V.E. PMID- 28572985 TI - Dopamine disruption increases cleanerfish cooperative investment in novel client partners. AB - Social familiarization is a process of gaining knowledge that results from direct or indirect participation in social events. Cooperative exchanges are thought to be conditional upon familiarity with others. Indeed, individuals seem to prefer to engage with those that have previously interacted with them, which are more accurate predictors of reward than novel partners. On the other hand, highly social animals do seek novelty. Truth is that the physiological bases underlying how familiarity and novelty may affect cooperative decision-making are still rather obscure. Here, we provide the first experimental evidence that the level of the dopaminergic influence in cooperative exchanges is constrained to mechanisms of social familiarization and novelty in a cleanerfish, Labroides dimidiatus. Cleaners were tested against familiar and novel Ctenochaetus striatus surgeonfish (a common client species) in laboratorial conditions, and were found to spend more time providing physical contact (also referred to as tactile stimulation) to familiar fish clients. Cleaners use tactile stimulation as a way to reduce the risk of a non-rewarding outcome, a behavioural response that is even more pronounced when blocking dopamine (DA) D1 receptors. We discovered that the influence of DA disruption on cleaners' provision of physical contact was dependent on the level of familiarity with its partner, being highly exacerbated whenever the client is novel, and unnoticed when dealing with a familiar one. Our findings demonstrate that DA mediation influences the valuation of partner stimuli and the enhancing investment in novel partners, mechanisms that are similar to other vertebrates, including humans. PMID- 28572986 TI - Social associations between California sea lions influence the use of a novel foraging ground. AB - Social relationships define an individual's position in its social network, which can influence the acquisition and spread of information and behavioural variants through the population. Thus, when nuisance behaviours spread through wildlife populations, identifying central individuals may provide valuable insights for problem-species management. We studied the effects of network position on California sea lion (Zalophus californianus) discovery and foraging success at a novel foraging ground-the salmonids that aggregate at the Bonneville Dam tail race, 235 km up the Columbia River. We found that an individual's centrality in their social network influenced discovery of the Bonneville Dam and whether they returned the next year. Foraging success once at the dam was independent of network position. Extensive lethal and non-lethal removal efforts have been implemented at Bonneville Dam and focused on reducing the number of individual sea lions at the dam. Since social relationships forged at the opening of the Columbia River influence both the discovery and return to the Bonneville Dam, efforts to increase salmon recovery may be enhanced by breaking apart social networks at the opening of the river. PMID- 28572988 TI - Efficient quantum circuits for dense circulant and circulant like operators. AB - Circulant matrices are an important family of operators, which have a wide range of applications in science and engineering-related fields. They are, in general, non-sparse and non-unitary. In this paper, we present efficient quantum circuits to implement circulant operators using fewer resources and with lower complexity than existing methods. Moreover, our quantum circuits can be readily extended to the implementation of Toeplitz, Hankel and block circulant matrices. Efficient quantum algorithms to implement the inverses and products of circulant operators are also provided, and an example application in solving the equation of motion for cyclic systems is discussed. PMID- 28572987 TI - State anxiety and emotional face recognition in healthy volunteers. AB - High trait anxiety has been associated with detriments in emotional face processing. By contrast, relatively little is known about the effects of state anxiety on emotional face processing. We investigated the effects of state anxiety on recognition of emotional expressions (anger, sadness, surprise, disgust, fear and happiness) experimentally, using the 7.5% carbon dioxide (CO2) model to induce state anxiety, and in a large observational study. The experimental studies indicated reduced global (rather than emotion-specific) emotion recognition accuracy and increased interpretation bias (a tendency to perceive anger over happiness) when state anxiety was heightened. The observational study confirmed that higher state anxiety is associated with poorer emotion recognition, and indicated that negative effects of trait anxiety are negated when controlling for state anxiety, suggesting a mediating effect of state anxiety. These findings may have implications for anxiety disorders, which are characterized by increased frequency, intensity or duration of state anxious episodes. PMID- 28572989 TI - Negative effects of restricted sleep on facial appearance and social appeal. AB - The importance of assessing evolutionarily relevant social cues suggests that humans should be sensitive to others' sleep history, as this may indicate something about their health as well as their capacity for social interaction. Recent findings show that acute sleep deprivation and looking tired are related to decreased attractiveness and health, as perceived by others. This suggests that one might also avoid contact with sleep-deprived, or sleepy-looking, individuals, as a strategy to reduce health risk and poor interactions. In this study, 25 participants (14 females, age range 18-47 years) were photographed after 2 days of sleep restriction and after normal sleep, in a balanced design. The photographs were rated by 122 raters (65 females, age range 18-65 years) on how much they would like to socialize with the participants. They also rated participants' attractiveness, health, sleepiness and trustworthiness. The results show that raters were less inclined to socialize with individuals who had gotten insufficient sleep. Furthermore, when sleep-restricted, participants were perceived as less attractive, less healthy and more sleepy. There was no difference in perceived trustworthiness. These findings suggest that naturalistic sleep loss can be detected in a face and that people are less inclined to interact with a sleep-deprived individual. PMID- 28572990 TI - Assessing the use of mobile phone data to describe recurrent mobility patterns in spatial epidemic models. AB - The recent availability of large-scale call detail record data has substantially improved our ability of quantifying human travel patterns with broad applications in epidemiology. Notwithstanding a number of successful case studies, previous works have shown that using different mobility data sources, such as mobile phone data or census surveys, to parametrize infectious disease models can generate divergent outcomes. Thus, it remains unclear to what extent epidemic modelling results may vary when using different proxies for human movements. Here, we systematically compare 658 000 simulated outbreaks generated with a spatially structured epidemic model based on two different human mobility networks: a commuting network of France extracted from mobile phone data and another extracted from a census survey. We compare epidemic patterns originating from all the 329 possible outbreak seed locations and identify the structural network properties of the seeding nodes that best predict spatial and temporal epidemic patterns to be alike. We find that similarity of simulated epidemics is significantly correlated to connectivity, traffic and population size of the seeding nodes, suggesting that the adequacy of mobile phone data for infectious disease models becomes higher when epidemics spread between highly connected and heavily populated locations, such as large urban areas. PMID- 28572991 TI - Sex-specific but not sexually explicit: pupillary responses to dressed and naked adults. AB - Dilation of the pupils is an indicator of an observer's sexual interest in other people, but it remains unresolved whether this response is strengthened or diminished by sexually explicit material. To address this question, this study compared pupillary responses of heterosexual men and women to naked and dressed portraits of male and female adult film actors. Pupillary responses corresponded with observers' self-reported sexual orientation, such that dilation occurred during the viewing of opposite-sex people, but were comparable for naked and dressed targets. These findings indicate that pupillary responses provide a sex specific measure, but are not sensitive to sexually explicit content. PMID- 28572992 TI - Putting the waste out: a proposed mechanism for transmission of the mycoparasite Escovopsis between leafcutter ant colonies. AB - The attine ant system is a remarkable example of symbiosis. An antagonistic partner within this system is the fungal parasite Escovopsis, a genus specific to the fungal gardens of the Attini. Escovopsis parasitizes the Leucoagaricus symbiont that leaf-cutting ants (Acromyrmex, Atta) have been farming over the past 8-12 Myr. However, it has been a puzzle how Escovopsis reaches its host. During a seasonal survey of nests of Acromyrmex subterraneus subterraneus in Atlantic rainforest in Brazil, Escovopsis was detected in all the sampled fungal garden waste tips or middens (n = 111). Middens were built strategically; always below the nest entrances. Here, we report the first evidence of a putative mechanism for horizontal transmission of Escovopsis between attine colonies. It is posited that leaf-cutting ants pick up the spores from soil and litter during foraging and vector the mycoparasite between attine colonies. Field and laboratory experiments, using At. laevigata and Ac. subterraneus subterraneus, confirm that Escovopsis spores are phoretic, and have an inbuilt dormancy, broken by the presence of their Leucoagaricus host. However, in the coevolutionary arms race, Atta ants may lose out-despite most species in the genus investing in a more advanced waste disposal system-due to the insanitary habits of their Acromyrmex neighbours. PMID- 28572993 TI - Emergence of leadership in a robotic fish group under diverging individual personality traits. AB - Variations of individual's personality traits have been identified before as one of the possible mechanisms for the emergence of leadership in an interactive collective, which may lead to benefits for the group as a whole. Complementing the large number of existing literatures on using simulation models to study leadership, we use biomimetic robotic fish to gain insight into how the fish's behaviours evolve under the influence of the physical hydrodynamics. In particular, we focus in this paper on understanding how robotic fish's personality traits affect the emergence of an effective leading fish in repeated robotic foraging tasks when the robotic fish's strategies, to push or not to push the obstacle in its foraging path, are updated over time following an evolutionary game set-up. We further show that the robotic fish's personality traits diverge when the group carries out difficult foraging tasks in our experiments, and self-organization takes place to help the group to adapt to the level of difficulties of the tasks without inter-individual communication. PMID- 28572994 TI - Experimental priming of independent and interdependent activity does not affect culturally variable psychological processes. AB - Cultural psychologists have shown that people from Western countries exhibit more independent self-construal and analytic (rule-based) cognition than people from East Asia, who exhibit more interdependent self-construal and holistic (relationship-based) cognition. One explanation for this cross-cultural variation is the ecocultural hypothesis, which links contemporary psychological differences to ancestral differences in subsistence and societal cohesion: Western thinking formed in response to solitary herding, which fostered independence, while East Asian thinking emerged in response to communal rice farming, which fostered interdependence. Here, we report two experiments that tested the ecocultural hypothesis in the laboratory. In both, participants played one of two tasks designed to recreate the key factors of working alone and working together. Before and after each task, participants completed psychological measures of independent-interdependent self-construal and analytic-holistic cognition. We found no convincing evidence that either solitary or collective tasks affected any of the measures in the predicted directions. This fails to support the ecocultural hypothesis. However, it may also be that our priming tasks are inappropriate or inadequate for simulating subsistence-related behavioural practices, or that these measures are fixed early in development and therefore not experimentally primable, despite many previous studies that have purported to find such priming effects. PMID- 28572995 TI - Assessing the anti-fungal efficiency of filters coated with zinc oxide nanoparticles. AB - Air filters support fungal growth, leading to generation of conidia and volatile organic compounds, causing allergies, infections and food spoilage. Filters that inhibit fungi are therefore necessary. Zinc oxide (ZnO) nanoparticles have anti fungal properties and therefore are good candidates for inhibiting growth. Two concentrations (0.012 M and 0.12 M) were used to coat two types of filters (melt blown and needle-punched) for three different periods (0.5, 5 and 50 min). Rhizopus stolonifer and Penicillium expansum isolated from spoiled pears were used as test organisms. Conidial suspensions of 105 to 103 spores ml-1 were prepared in Sabouraud dextrose agar at 50 degrees C, and a modified slide-culture technique was used to test the anti-fungal properties of the filters. Penicillium expansum was the more sensitive organism, with inhibition at 0.012 M at only 0.5 min coating time on the needle-punched filter. The longer the coating time, the more effective inhibition was for both organisms. Furthermore, it was also determined that the coating process had only a slight effect on the Young's Moduli of the needle-punched filters, while the Young's Moduli of the melt-blown filters is more susceptible to the coating method. This work contributes to the assessment of the efficacy of filter coating with ZnO nanopaticles aimed at inhibiting fungal growth. PMID- 28572996 TI - Green synthesis of carbon quantum dots embedded onto titanium dioxide nanowires for enhancing photocurrent. AB - The green synthesis of nanowired photocatalyst composed of carbon quantum dots titanium hybrid-semiconductors, CQDs/TiO2, are reported. Where graphite-based CQDs with a size less than 5 nm are directly synthesized in pure water electrolyte by a one-step electrochemistry approach and subsequently electrodeposited onto as-prepared TiO2 nanowires through a voltage-driven reduction process. Electron paramagnetic resonance studies show that the CQDs can generate singlet oxygen and/or oxygen radicals to decompose the kinetic H2O2 intermediate species upon UV light illumination. With the effect of peroxidase like CQDs, photocurrent density of CQDs/TiO2 is remarkably enhanced by a 6.4 factor when compared with that of as-prepared TiO2. PMID- 28572997 TI - A superlinear iteration method for calculation of finite length journal bearing's static equilibrium position. AB - Solving the static equilibrium position is one of the most important parts of dynamic coefficients calculation and further coupled calculation of rotor system. The main contribution of this study is testing the superlinear iteration convergence method-twofold secant method, for the determination of the static equilibrium position of journal bearing with finite length. Essentially, the Reynolds equation for stable motion is solved by the finite difference method and the inner pressure is obtained by the successive over-relaxation iterative method reinforced by the compound Simpson quadrature formula. The accuracy and efficiency of the twofold secant method are higher in comparison with the secant method and dichotomy. The total number of iterative steps required for the twofold secant method are about one-third of the secant method and less than one eighth of dichotomy for the same equilibrium position. The calculations for equilibrium position and pressure distribution for different bearing length, clearance and rotating speed were done. In the results, the eccentricity presents linear inverse proportional relationship to the attitude angle. The influence of the bearing length, clearance and bearing radius on the load-carrying capacity was also investigated. The results illustrate that larger bearing length, larger radius and smaller clearance are good for the load-carrying capacity of journal bearing. The application of the twofold secant method can greatly reduce the computational time for calculation of the dynamic coefficients and dynamic characteristics of rotor-bearing system with a journal bearing of finite length. PMID- 28572998 TI - Mobulid rays feed on euphausiids in the Bohol Sea. AB - Mobulid rays have a conservative life history and are caught in direct fisheries and as by-catch. Their subsequent vulnerability to overexploitation has recently been recognized, but fisheries management can be ineffective if it ignores habitat and prey preferences and other trophic interactions of the target species. Here, we assessed the feeding ecology of four mobulids (Manta birostris, Mobula tarapacana, M. japanica, M. thurstoni) in the Bohol Sea, Philippines, using stomach contents analysis of fisheries specimens landed between November and May in 2013-2015. We show that the mobulids feed heavily on euphausiid krill while they are in the area for approximately six months of the year. We found almost no trophic separation among the mobulid species, with Euphausia diomedeae as the major prey item for all species, recorded in 81 of 89 total stomachs (91%). Mobula japanica and M. thurstoni almost exclusively had this krill in their stomach, while M. tarapacana had a squid and fish, and Ma. birostris had myctophid fishes and copepods in their stomachs in addition to E. diomedeae. This krill was larger than prey for other planktivorous elasmobranchs elsewhere and contributed a mean of 61 364 kcal per stomach (+/-105 032 kcal s.e., range = 0 631 167 kcal). Our results show that vertically migrating mesopelagic species can be an important food resource for large filter feeders living in tropical seas with oligotrophic surface waters. Given the conservative life history of mobulid rays, the identification of common foraging grounds that overlap with fishing activity could be used to inform future fishing effort. PMID- 28572999 TI - Ageing and agency: age-related changes in susceptibility to illusory experiences of control. AB - Sense of agency (SoAg) is the feeling of control over one's actions and their effects. It can be augmented or attenuated by internal signals and by external cues. Research has shown a reduction in the SoAg in older adulthood, but the reasons behind this change remain unclear. We investigated agency processing differences that may underpin age-related changes in SoAg. Using a modified version of a vicarious agency paradigm, we tested the modulation of SoAg by manipulating external situational agency cues in younger and older adults. Our results show that the illusion of vicarious agency was less pronounced in older adults. These results were replicated in a second experiment which also showed that older adults performed significantly better in interoception and proprioception tasks. We suggest that increased reliance on internal cues may explain differences in agency processing in older adulthood. PMID- 28573001 TI - Early social environment influences the behaviour of a family-living lizard. AB - Early social environment can play a significant role in shaping behavioural development. For instance, in many social mammals and birds, isolation rearing results in individuals that are less exploratory, shyer, less social and more aggressive than individuals raised in groups. Moreover, dynamic aspects of social environments, such as the nature of relationships between individuals, can also impact the trajectory of development. We tested if being raised alone or socially affects behavioural development in the family-living tree skink, Egernia striolata. Juveniles were raised in two treatments: alone or in a pair. We assayed exploration, boldness, sociability and aggression repeatedly throughout each juvenile's first year of life, and also assessed social interactions between pairs to determine if juveniles formed dominant-subordinate relationships. We found that male and/or the larger skinks within social pairs were dominant. Developing within this social environment reduced skink growth, and subordinate skinks were more prone to tail loss. Thus, living with a conspecific was costly for E. striolata. The predicted negative effects of isolation failed to materialize. Nevertheless, there were significant differences in behavioural traits depending on the social environment (isolated, dominant or subordinate member of a pair). Isolated skinks were more social than subordinate skinks. Subordinate skinks also became more aggressive over time, whereas isolated and dominant skinks showed invariable aggression. Dominant skinks became bolder over time, whereas isolated and subordinate skinks were relatively stable in their boldness. In summary, our study is evidence that isolation rearing does not consistently affect behaviour across all social taxa. Our study also demonstrates that the social environment plays an important role in behavioural development of a family-living lizard. PMID- 28573002 TI - Image-based modelling of lateral magma flow: the Basement Sill, Antarctica. AB - The McMurdo Dry Valleys magmatic system, Antarctica, provides a world-class example of pervasive lateral magma flow on a continental scale. The lowermost intrusion (Basement Sill) offers detailed sections through the now frozen particle microstructure of a congested magma slurry. We simulated the flow regime in two and three dimensions using numerical models built on a finite-element mesh derived from field data. The model captures the flow behaviour of the Basement Sill magma over a viscosity range of 1-104 Pa s where the higher end (greater than or equal to 102 Pa s) corresponds to a magmatic slurry with crystal fractions varying between 30 and 70%. A novel feature of the model is the discovery of transient, low viscosity (less than or equal to 50 Pa s) high Reynolds number eddies formed along undulating contacts at the floor and roof of the intrusion. Numerical tracing of particle orbits implies crystals trapped in eddies segregate according to their mass density. Recovered shear strain rates (10-3-10-5 s-1) at viscosities equating to high particle concentrations (around more than 40%) in the Sill interior point to shear-thinning as an explanation for some types of magmatic layering there. Model transport rates for the Sill magmas imply a maximum emplacement time of ca 105 years, consistent with geochemical evidence for long-range lateral flow. It is a theoretically possibility that fast flowing magma on a continental scale will be susceptible to planetary-scale rotational forces. PMID- 28573000 TI - Sex-specific association patterns in bonobos and chimpanzees reflect species differences in cooperation. AB - In several group-living species, individuals' social preferences are thought to be influenced by cooperation. For some societies with fission-fusion dynamics, sex-specific association patterns reflect sex differences in cooperation in within- and between-group contexts. In our study, we investigated this hypothesis further by comparing sex-specific association patterns in two closely related species, chimpanzees and bonobos, which differ in the level of between-group competition and in the degree to which sex and kinship influence dyadic cooperation. Here, we used long-term party composition data collected on five chimpanzee and two bonobo communities and assessed, for each individual of 10 years and older, the sex of its top associate and of all conspecifics with whom it associated more frequently than expected by chance. We found clear species differences in association patterns. While in all chimpanzee communities males and females associated more with same-sex partners, in bonobos males and females tended to associate preferentially with females, but the female association preference for other females is lower than in chimpanzees. Our results also show that, for bonobos (but not for chimpanzees), association patterns were predominantly driven by mother-offspring relationships. These species differences in association patterns reflect the high levels of male-male cooperation in chimpanzees and of mother-son cooperation in bonobos. Finally, female chimpanzees showed intense association with a few other females, and male chimpanzees showed more uniform association across males. In bonobos, the most differentiated associations were from males towards females. Chimpanzee male association patterns mirror fundamental human male social traits and, as in humans, may have evolved as a response to strong between-group competition. The lack of such a pattern in a closely related species with a lower degree of between-group competition further supports this notion. PMID- 28573003 TI - Development of cyclic shedding teeth from semi-shedding teeth: the inner dental arcade of the stem osteichthyan Lophosteus. AB - The numerous cushion-shaped tooth-bearing plates attributed to the stem group osteichthyan Lophosteus superbus, which are argued here to represent an early form of the osteichthyan inner dental arcade, display a previously unknown and presumably primitive mode of tooth shedding by basal hard tissue resorption. They carry regularly spaced, recumbent, gently recurved teeth arranged in transverse tooth files that diverge towards the lingual margin of the cushion. Three dimensional reconstruction from propagation phase-contrast synchrotron microtomography (PPC-SRuCT) reveals remnants of the first-generation teeth embedded in the basal plate, a feature never previously observed in any taxon. These teeth were shed by semi-basal resorption with the periphery of their bases retained as dentine rings. The rings are highly overlapped, which evidences tooth shedding prior to adding the next first-generation tooth at the growing edge of the plate. The first generation of teeth is thus diachronous. Successor teeth at the same sites underwent cyclical replacing and shedding through basal resorption, producing stacks of buried resorption surfaces separated by bone of attachment. The number and spatial arrangement of resorption surfaces elucidates that basal resorption of replacement teeth had taken place at the older tooth sites before the addition of the youngest first-generation teeth at the lingual margin. Thus, the replacement tooth buds cannot have been generated by a single permanent dental lamina at the lingual edge of the tooth cushion, but must have arisen either from successional dental laminae associated with the individual predecessor teeth, or directly from the dental epithelium of these teeth. The virtual histological dissection of these Late Silurian microfossils broadens our understanding of the development of the gnathostome dental systems and the acquisition of the osteichthyan-type of tooth replacement. PMID- 28573004 TI - A new ankylosaurine dinosaur from the Judith River Formation of Montana, USA, based on an exceptional skeleton with soft tissue preservation. AB - The terrestrial Judith River Formation of northern Montana was deposited over an approximately 4 Myr interval during the Campanian (Late Cretaceous). Despite having been prospected and collected continuously by palaeontologists for over a century, few relatively complete dinosaur skeletons have been recovered from this unit to date. Here we describe a new genus and species of ankylosaurine dinosaur, Zuul crurivastator, from the Coal Ridge Member of the Judith River Formation, based on an exceptionally complete and well-preserved skeleton (ROM 75860). This is the first ankylosaurin skeleton known with a complete skull and tail club, and it is the most complete ankylosaurid ever found in North America. The presence of abundant soft tissue preservation across the skeleton, including in situ osteoderms, skin impressions and dark films that probably represent preserved keratin, make this exceptional skeleton an important reference for understanding the evolution of dermal and epidermal structures in this clade. Phylogenetic analysis recovers Zuul as an ankylosaurin ankylosaurid within a clade of Dyoplosaurus and Scolosaurus, with Euoplocephalus being more distantly related within Ankylosaurini. The occurrence of Z. crurivastator from the upper Judith River Formation fills a gap in the ankylosaurine stratigraphic and geographical record in North America, and further highlights that Campanian ankylosaurines were undergoing rapid evolution and stratigraphic succession of taxa as observed for Laramidian ceratopsids, hadrosaurids, pachycephalosaurids and tyrannosaurids. PMID- 28573005 TI - Drug delivery in a tumour cord model: a computational simulation. AB - The tumour vasculature and microenvironment is complex and heterogeneous, contributing to reduced delivery of cancer drugs to the tumour. We have developed an in silico model of drug transport in a tumour cord to explore the effect of different drug regimes over a 72 h period and how changes in pharmacokinetic parameters affect tumour exposure to the cytotoxic drug doxorubicin. We used the model to describe the radial and axial distribution of drug in the tumour cord as a function of changes in the transport rate across the cell membrane, blood vessel and intercellular permeability, flow rate, and the binding and unbinding ratio of drug within the cancer cells. We explored how changes in these parameters may affect cellular exposure to drug. The model demonstrates the extent to which distance from the supplying vessel influences drug levels and the effect of dosing schedule in relation to saturation of drug-binding sites. It also shows the likely impact on drug distribution of the aberrant vasculature seen within tumours. The model can be adapted for other drugs and extended to include other parameters. The analysis confirms that computational models can play a role in understanding novel cancer therapies to optimize drug administration and delivery. PMID- 28573006 TI - A new fossil dolphin Dilophodelphis fordycei provides insight into the evolution of supraorbital crests in Platanistoidea (Mammalia, Cetacea). AB - Many odontocete groups have developed enlarged facial crests, although these crests differ in topography, composition and function. The most elaborate crests occur in the South Asian river dolphin (Platanista gangetica), in which they rise dorsally as delicate, pneumatized wings anterior of the facial bones. Their position wrapping around the melon suggests their involvement in sound propagation for echolocation. To better understand the origin of crests in this lineage, we examined facial crests among fossil and living Platanistoidea, including a new taxon, Dilophodelphis fordycei, nov. gen. and sp., described herein, from the Early Miocene Astoria Formation of Oregon, USA. We measured the physical extent and thickness of platanistoid crests, categorized their relative position and used computed tomography scans to examine their internal morphology and relative bone density. Integrating these traits in a phylogenetic context, we determined that the onset of crest elaboration or enlargement and the evolution of crest pneumatization among the platanistoids were separate events, with crest enlargement beginning in the Oligocene. However, we find no evidence for pneumatization until possibly the Early Miocene, although certainly by the Middle Miocene. Such an evolutionary context, including data from the fossil record, should inform modelling efforts that seek to understand the diversity of sound generation morphology in Odontoceti. PMID- 28573007 TI - Depth-dependent effects of culling-do mesophotic lionfish populations undermine current management? AB - Invasive lionfish (Pterois volitans and P. miles) have spread widely across the western Atlantic and are recognized as a major threat to native marine biodiversity. Although lionfish inhabit both shallow reefs and mesophotic coral ecosystems (MCEs; reefs from 30 to 150 m depth), the primary management response implemented by many countries has been diver-led culling limited to reefs less than 30 m. However, many reef fish undergo ontogenetic migrations, with the largest and therefore most fecund individuals found at greatest depths. Here, we study lionfish density, body size, maturity and dietary patterns across the depth gradient from the surface down to 85 m on heavily culled reefs around Utila, Honduras. We found lionfish at increased densities, body size and weight on MCEs compared with shallow reefs, with MCEs also containing the greatest proportion of actively spawning females, while shallow reefs contained the greatest proportion of immature lionfish. We then compared lionfish behaviour in response to divers on shallow culled and mesophotic unculled Utilan reefs, and on shallow unculled reefs in Tela Bay, on the Honduran mainland. We found that mesophotic lionfish exhibited high alert distances, consistent with individuals previously exposed to culling despite being below the depth limits of removal. In addition, when examining stomach content, we found that fish were the major component of lionfish diets across the depth gradient. Importantly, our results suggest that despite adjacent shallow culling, MCEs retain substantial lionfish populations that may be disproportionately contributing towards continued lionfish recruitment onto the shallow reefs of Utila, potentially undermining current culling-based management. PMID- 28573008 TI - Common reef-building coral in the Northern Red Sea resistant to elevated temperature and acidification. AB - Coral reefs are currently experiencing substantial ecological impoverishment as a result of anthropogenic stressors, and the majority of reefs are facing immediate risk. Increasing ocean surface temperatures induce frequent coral mass bleaching events-the breakdown of the nutritional photo-symbiosis with intracellular algae (genus: Symbiodinium). Here, we report that Stylophora pistillata from a highly diverse reef in the Gulf of Aqaba showed no signs of bleaching despite spending 1.5 months at 1-2 degrees C above their long-term summer maximum (amounting to 11 degree heating weeks) and a seawater pH of 7.8. Instead, their symbiotic dinoflagellates exhibited improved photochemistry, higher pigmentation and a doubling in net oxygen production, leading to a 51% increase in primary productivity. Nanoscale secondary ion mass spectrometry imaging revealed subtle cellular-level shifts in carbon and nitrogen metabolism under elevated temperatures, but overall host and symbiont biomass proxies were not significantly affected. Now living well below their thermal threshold in the Gulf of Aqaba, these corals have been evolutionarily selected for heat tolerance during their migration through the warm Southern Red Sea after the last ice age. This may allow them to withstand future warming for a longer period of time, provided that successful environmental conservation measures are enacted across national boundaries in the region. PMID- 28573009 TI - Characterizing and quantifying human movement patterns using GPS data loggers in an area approaching malaria elimination in rural southern Zambia. AB - In areas approaching malaria elimination, human mobility patterns are important in determining the proportion of malaria cases that are imported or the result of low-level, endemic transmission. A convenience sample of participants enrolled in a longitudinal cohort study in the catchment area of Macha Hospital in Choma District, Southern Province, Zambia, was selected to carry a GPS data logger for one month from October 2013 to August 2014. Density maps and activity space plots were created to evaluate seasonal movement patterns. Time spent outside the household compound during anopheline biting times, and time spent in malaria high and low-risk areas, were calculated. There was evidence of seasonal movement patterns, with increased long-distance movement during the dry season. A median of 10.6% (interquartile range (IQR): 5.8-23.8) of time was spent away from the household, which decreased during anopheline biting times to 5.6% (IQR: 1.7 14.9). The per cent of time spent in malaria high-risk areas for participants residing in high-risk areas ranged from 83.2% to 100%, but ranged from only 0.0% to 36.7% for participants residing in low-risk areas. Interventions targeted at the household may be more effective because of restricted movement during the rainy season, with limited movement between high- and low-risk areas. PMID- 28573010 TI - Contradicting habitat type-extinction risk relationships between living and fossil amphibians. AB - Trait analysis has become a crucial tool for assessing the extinction risk of species. While some extinction risk-trait relationships have been often identical between different living taxa, a temporal comparison of fossil taxa with related current taxa was rarely considered. However, we argue that it is important to know if extinction risk-trait relations are constant or changing over time. Herein we investigated the influence of habitat type on the persistence length of amphibian species. Living amphibians are regarded as the most threatened group of terrestrial vertebrates and thus of high interest to conservationists. Species from different habitat types show differences in extinction risk, i.e. species depending on flowing waters being more threatened than those breeding in stagnant sites. After assessing the quality of the available amphibian fossil data, we show that today's habitat type-extinction risk relationship is reversed compared to fossil amphibians, former taxa persisting longer when living in rivers and streams, thus suggesting a change of effect direction of this trait. Neither differences between amphibian orders nor environmentally caused preservation effects could explain this pattern. We argue this change to be most likely a result of anthropogenic influence, which turned a once favourable strategy into a disadvantage. PMID- 28573011 TI - Behaviour of free ranging wild boar towards their dead fellows: potential implications for the transmission of African swine fever. AB - The behaviour of free ranging wild boar (Sus scrofa) towards carcasses of their conspecifics potentially infected with African swine fever (ASF) may significantly influence the course of an ASF epidemic. This study aims to better understand the behaviour of wild boar towards their dead fellows. Thirty-two wild boar carcasses on nine study sites in northeast Germany were monitored under field conditions by photo-trapping from October 2015 until October 2016. During this period, a total of 122 160 pictures were taken, thereof 16 111 pictures of wild boar. In both winter and summer, wild boar seemed to be particularly interested in the soil next to and underneath the carcasses. About one third of the visits of wild boar led to direct contact with dead conspecifics. The contacts consisted mostly in sniffing and poking on the carcass. Under the given ecological and climatic conditions, there was no evidence for intra-species scavenging. However, piglets were observed several times chewing bare bones once skeletonization of the carcasses was complete. It must be assumed that all these types of contact may represent a risk of transmission. Both the high tenacity of ASF virus and the long time wild boar carcasses can remain in the environment, allow the persistence of the virus for several months or even years. We therefore consider the rapid detection and removal (or destruction on the spot) of contaminated carcasses as an important control measure against ASF in wild boar. PMID- 28573012 TI - Effects of ligand distribution on receptor-diffusion-mediated cellular uptake of nanoparticles. AB - Biophysical-factor-dependent cellular uptake of nanoparticles (NPs) through receptor-diffusion-mediated endocytosis bears significance in pathology, cellular immunity and drug-delivery systems. Advanced nanotechnology of NP synthesis provides methods for modifying NP surface with different ligand distributions. However, no report discusses effects of ligand distribution on NP surface on receptor-diffusion-mediated cellular uptake. In this article, we used a statistical dynamics model of receptor-diffusion-mediated endocytosis to examine ligand-distribution-dependent cellular uptake dynamics by considering that ligand receptor complexes drive engulfing to overcome resistance to membrane deformation and changes in configuration entropy of receptors. Results showed that cellular internalization of NPs strongly depended on ligand distribution and that cellular uptake efficiency of NPs was high when ligand distribution was within a range around uniform distribution. This feature of endocytosis ensures robust infection ability of viruses to enter host cells. Interestingly, results also indicated that optimal ligand distribution associated with highest cellular-uptake efficiency slightly depends on distribution pattern of ligands and density of receptors, and the optimal distribution becomes uniform when receptor density is sufficiently large. Position of initial contact point is also a factor affecting dynamic wrapping. This study explains why most enveloped viruses present almost homogeneous ligand distribution and is useful in designing controlled-release drug-delivery systems. PMID- 28573013 TI - Thin Al1-x Ga x As0.56Sb0.44 diodes with extremely weak temperature dependence of avalanche breakdown. AB - When using avalanche photodiodes (APDs) in applications, temperature dependence of avalanche breakdown voltage is one of the performance parameters to be considered. Hence, novel materials developed for APDs require dedicated experimental studies. We have carried out such a study on thin Al1-x Ga x As0.56Sb0.44 p-i-n diode wafers (Ga composition from 0 to 0.15), plus measurements of avalanche gain and dark current. Based on data obtained from 77 to 297 K, the alloys Al1-x Ga x As0.56Sb0.44 exhibited weak temperature dependence of avalanche gain and breakdown voltage, with temperature coefficient approximately 0.86-1.08 mV K-1, among the lowest values reported for a number of semiconductor materials. Considering no significant tunnelling current was observed at room temperature at typical operating conditions, the alloys Al1-x Ga x As0.56Sb0.44 (Ga from 0 to 0.15) are suitable for InP substrates-based APDs that require excellent temperature stability without high tunnelling current. PMID- 28573014 TI - The contact process on scale-free networks evolving by vertex updating. AB - We study the contact process on a class of evolving scale-free networks, where each node updates its connections at independent random times. We give a rigorous mathematical proof that there is a transition between a phase where for all infection rates the infection survives for a long time, at least exponential in the network size, and a phase where for sufficiently small infection rates extinction occurs quickly, at most polynomially in the network size. The phase transition occurs when the power-law exponent crosses the value four. This behaviour is in contrast with that of the contact process on the corresponding static model, where there is no phase transition, as well as that of a classical mean-field approximation, which has a phase transition at power-law exponent three. The new observation behind our result is that temporal variability of networks can simultaneously increase the rate at which the infection spreads in the network, and decrease the time at which the infection spends in metastable states. PMID- 28573015 TI - Density-dependent coral recruitment displays divergent responses during distinct early life-history stages. AB - Population growth involves demographic bottlenecks that regulate recruitment success during various early life-history stages. The success of each early life history stage can vary in response to population density, interacting with intrinsic (e.g. behavioural) and environmental (e.g. competition, predation) factors. Here, we used the common reef-building coral Acropora millepora to investigate how density-dependence influences larval survival and settlement in laboratory experiments that isolated intrinsic effects, and post-settlement survival in a field experiment that examined interactions with environmental factors. Larval survival was exceptionally high (greater than 80%) and density independent from 2.5 to 12 days following spawning. By contrast, there was a weak positive effect of larval density on settlement, driven by gregarious behaviour at the highest density. When larval supply was saturated, settlement was three times higher in crevices compared with exposed microhabitats, but a negative relationship between settler density and post-settlement survival in crevices and density-independent survival on exposed surfaces resulted in similar recruit densities just one month following settlement. Moreover, a negative relationship was found between turf algae and settler survival in crevices, whereas gregarious settlement improved settler survival on exposed surfaces. Overall, our findings reveal divergent responses by coral larvae and newly settled recruits to density dependent regulation, mediated by intrinsic and environmental interactions. PMID- 28573016 TI - Social media enhances languages differentiation: a mathematical description. AB - Understanding and predicting the evolution of competing languages is a topic of high interest in a world with more than 6000 languages competing in a highly connected environment. We consider a reasonable mathematical model describing a situation of competition between two languages and analyse the effect of the speakers' connectivity (i.e. social networks). Surprisingly, instead of homogenizing the system, a high degree of connectivity helps to introduce differentiation for the appropriate parameters. PMID- 28573017 TI - A CRISPR Cas9 high-throughput genome editing toolkit for kinetoplastids. AB - Clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR associated gene 9 (Cas9) genome editing is set to revolutionize genetic manipulation of pathogens, including kinetoplastids. CRISPR technology provides the opportunity to develop scalable methods for high-throughput production of mutant phenotypes. Here, we report development of a CRISPR-Cas9 toolkit that allows rapid tagging and gene knockout in diverse kinetoplastid species without requiring the user to perform any DNA cloning. We developed a new protocol for single-guide RNA (sgRNA) delivery using PCR-generated DNA templates which are transcribed in vivo by T7 RNA polymerase and an online resource (LeishGEdit.net) for automated primer design. We produced a set of plasmids that allows easy and scalable generation of DNA constructs for transfections in just a few hours. We show how these tools allow knock-in of fluorescent protein tags, modified biotin ligase BirA*, luciferase, HaloTag and small epitope tags, which can be fused to proteins at the N- or C-terminus, for functional studies of proteins and localization screening. These tools enabled generation of null mutants in a single round of transfection in promastigote form Leishmania major, Leishmania mexicana and bloodstream form Trypanosoma brucei; deleted genes were undetectable in non-clonal populations, enabling for the first time rapid and large-scale knockout screens. PMID- 28573018 TI - Yolk vitamin E prevents oxidative damage in gull hatchlings. AB - Oxidative stress experienced during early development can negatively affect diverse life-history traits, and organisms have evolved complex defence systems against its detrimental effects. Bird eggs contain maternally derived exogenous antioxidants that play a major role in embryo protection from oxidative damage, including the negative effects on telomere dynamics. In this study on the yellow legged gull (Larus michahellis), we manipulated the concentration of vitamin E (VE) in the egg yolk and analysed the consequences on oxidative status markers and telomere length in the hatchlings. This study provides the first experimental evidence that, contrary to the expectation, a physiological increase in yolk VE concentration boosted total antioxidant capacity and reduced the concentration of pro-oxidant molecules in the plasma, but did not reduce telomere attrition or ameliorate oxidative damage to proteins and lipids in the early postnatal period. PMID- 28573019 TI - Sensitivity of commercial pumpkin yield to potential decline among different groups of pollinating bees. AB - The yield of animal-pollinated crops is threatened by bee declines, but its precise sensitivity is poorly known. We therefore determined the yield dependence of Hokkaido pumpkin in Germany on insect pollination by quantifying: (i) the relationship between pollen receipt and fruit set and (ii) the cumulative pollen deposition of each pollinator group. We found that approximately 2500 pollen grains per flower were needed to maximize fruit set. At the measured rates of flower visitation, we estimated that bumblebees (21 visits/flower lifetime, 864 grains/visit) or honeybees (123 visits, 260 grains) could individually achieve maximum crop yield, whereas halictid bees are ineffective (11 visits, 16 grains). The pollinator fauna was capable of delivering 20 times the necessary amount of pollen. We therefore estimate that pumpkin yield was not pollination-limited in our study region and that it is currently fairly resilient to single declines of honeybees or wild bumblebees. PMID- 28573020 TI - A single migrant enhances the genetic diversity of an inbred puma population. AB - Migration is essential for maintaining genetic diversity among populations, and pumas (Puma concolor) provide an excellent model for studying the genetic impacts of migrants on populations isolated by increasing human development. In densely populated southern California, USA, puma populations on the east and west side of interstate highway 15 (I-15) have become fragmented into a small inbred population on the west side (Santa Ana Mountains) and a relatively larger, more diverse population on the east side (Eastern Peninsular Range). From 146 sampled pumas, genetic analyses indicate seven pumas crossed I-15 over the last 15 years, including four males from west to east, and three males from east to west. However, only a single migrant (named M86) was detected to have produced offspring and contribute to gene flow across the I-15 barrier. Prior to the M86 migration, the Santa Ana population exhibited inbreeding and had significantly lower genetic diversity than the Eastern Peninsular Range population. After M86 emigrated, he sired 11 offspring with Santa Ana females, decreasing inbreeding measures and raising heterozygosity to levels similar to pumas in the Eastern Peninsular Range. The emigration of M86 also introduced new alleles into the Santa Ana population, although allelic richness still remained significantly lower than the Eastern Peninsular population. Our results clearly show the benefit of a single migrant to the genetics of a small, isolated population. However, ongoing development and habitat loss on both sides of I-15 will increasingly strengthen the barrier to successful migration. Further monitoring, and potential human intervention, including minimizing development effects on connectivity, adding or improving freeway crossing structures, or animal translocation, may be needed to ensure adequate gene flow and long-term persistence of the Santa Ana puma population. PMID- 28573021 TI - Dog growls express various contextual and affective content for human listeners. AB - Vocal expressions of emotions follow simple rules to encode the inner state of the caller into acoustic parameters, not just within species, but also in cross species communication. Humans use these structural rules to attribute emotions to dog vocalizations, especially to barks, which match with their contexts. In contrast, humans were found to be unable to differentiate between playful and threatening growls, probably because single growls' aggression level was assessed based on acoustic size cues. To resolve this contradiction, we played back natural growl bouts from three social contexts (food guarding, threatening and playing) to humans, who had to rate the emotional load and guess the context of the playbacks. Listeners attributed emotions to growls according to their social contexts. Within threatening and playful contexts, bouts with shorter, slower pulsing growls and showing smaller apparent body size were rated to be less aggressive and fearful, but more playful and happy. Participants associated the correct contexts with the growls above chance. Moreover, women and participants experienced with dogs scored higher in this task. Our results indicate that dogs may communicate honestly their size and inner state in a serious contest situation, while manipulatively in more uncertain defensive and playful contexts. PMID- 28573022 TI - Ocean acidification impacts spine integrity but not regenerative capacity of spines and tube feet in adult sea urchins. AB - Increasing atmospheric carbon dioxide (CO2) has resulted in a change in seawater chemistry and lowering of pH, referred to as ocean acidification. Understanding how different organisms and processes respond to ocean acidification is vital to predict how marine ecosystems will be altered under future scenarios of continued environmental change. Regenerative processes involving biomineralization in marine calcifiers such as sea urchins are predicted to be especially vulnerable. In this study, the effect of ocean acidification on regeneration of external appendages (spines and tube feet) was investigated in the sea urchin Lytechinus variegatus exposed to ambient (546 uatm), intermediate (1027 uatm) and high (1841 uatm) partial pressure of CO2 (pCO2) for eight weeks. The rate of regeneration was maintained in spines and tube feet throughout two periods of amputation and regrowth under conditions of elevated pCO2. Increased expression of several biomineralization-related genes indicated molecular compensatory mechanisms; however, the structural integrity of both regenerating and homeostatic spines was compromised in high pCO2 conditions. Indicators of physiological fitness (righting response, growth rate, coelomocyte concentration and composition) were not affected by increasing pCO2, but compromised spine integrity is likely to have negative consequences for defence capabilities and therefore survival of these ecologically and economically important organisms. PMID- 28573023 TI - Big city Bombus: using natural history and land-use history to find significant environmental drivers in bumble-bee declines in urban development. AB - Native bee populations are critical sources of pollination. Unfortunately, native bees are declining in abundance and diversity. Much of this decline comes from human land-use change. While the effects of large-scale agriculture on native bees are relatively well understood, the effects of urban development are less clear. Understanding urbanity's effect on native bees requires consideration of specific characteristics of both particular bee species and their urban landscape. We surveyed bumble-bee (Bombus spp.) abundance and diversity in gardens across multiple urban centres in southeastern Michigan. There are significant declines in Bombus abundance and diversity associated with urban development when measured on scales in-line with Bombus flight ability. These declines are entirely driven by declines in females; males showed no response to urbanization. We hypothesize that this is owing to differing foraging strategies between the sexes, and it suggests reduced Bombus colony density in more urban areas. While urbanity reduced Bombus prevalence, results in Detroit imply that 'shrinking cities' potentially offer unique urban paradigms that must be considered when studying wild bee ecology. Results show previously unidentified differences in the effects of urbanity on female and male bumble-bee populations and suggest that urban landscapes can be managed to support native bee conservation. PMID- 28573024 TI - Does behaviour affect the dispersal of flatback post-hatchlings in the Great Barrier Reef? AB - The ability of individuals to actively control their movements, especially during the early life stages, can significantly influence the distribution of their population. Most marine turtle species develop oceanic foraging habitats during different life stages. However, flatback turtles (Natator depressus) are endemic to Australia and are the only marine turtle species with an exclusive neritic development. To explain the lack of oceanic dispersal of this species, we predicted the dispersal of post-hatchlings in the Great Barrier Reef (GBR), Australia, using oceanographic advection-dispersal models. We included directional swimming in our models and calibrated them against the observed distribution of post-hatchling and adult turtles. We simulated the dispersal of green and loggerhead turtles since they also breed in the same region. Our study suggests that the neritic distribution of flatback post-hatchlings is favoured by the inshore distribution of nesting beaches, the local water circulation and directional swimming during their early dispersal. This combination of factors is important because, under the conditions tested, if flatback post-hatchlings were entirely passively transported, they would be advected into oceanic habitats after 40 days. Our results reinforce the importance of oceanography and directional swimming in the early life stages and their influence on the distribution of a marine turtle species. PMID- 28573025 TI - Chimpanzee intellect: personality, performance and motivation with touchscreen tasks. AB - Human intellect is characterized by intercorrelated psychological domains, including intelligence, academic performance and personality. Higher openness is associated with higher intelligence and better academic performance, yet high performance among individuals is itself attributable to intelligence, not openness. High conscientiousness individuals, although not necessarily more intelligent, are better performers. Work with other species is not as extensive, yet animals display similar relationships between exploration- and persistence related personality traits and performance on cognitive tasks. However, previous studies linking cognition and personality have not tracked learning, performance and dropout over time-three crucial elements of cognitive performance. We conducted three participatory experiments with touchscreen cognitive tasks among 19 zoo-housed chimpanzees, whose personalities were assessed 3 years prior to the study. Performance and participation were recorded across experiments. High conscientiousness chimpanzees participated more, dropped out less and performed better, but their performance could be explained by their experience with the task. High openness chimpanzees tended to be more interested, perform better and continue to participate when not rewarded with food. Our results demonstrate that chimpanzees, like humans, possess broad intellectual capacities that are affected by their personalities. PMID- 28573026 TI - Non-invasive biophysical measurement of travelling waves in the insect inner ear. AB - Frequency analysis in the mammalian cochlea depends on the propagation of frequency information in the form of a travelling wave (TW) across tonotopically arranged auditory sensilla. TWs have been directly observed in the basilar papilla of birds and the ears of bush-crickets (Insecta: Orthoptera) and have also been indirectly inferred in the hearing organs of some reptiles and frogs. Existing experimental approaches to measure TW function in tetrapods and bush crickets are inherently invasive, compromising the fine-scale mechanics of each system. Located in the forelegs, the bush-cricket ear exhibits outer, middle and inner components; the inner ear containing tonotopically arranged auditory sensilla within a fluid-filled cavity, and externally protected by the leg cuticle. Here, we report bush-crickets with transparent ear cuticles as potential model species for direct, non-invasive measuring of TWs and tonotopy. Using laser Doppler vibrometry and spectroscopy, we show that increased transmittance of light through the ear cuticle allows for effective non-invasive measurements of TWs and frequency mapping. More transparent cuticles allow several properties of TWs to be precisely recovered and measured in vivo from intact specimens. Our approach provides an innovative, non-invasive alternative to measure the natural motion of the sensilla-bearing surface embedded in the intact inner ear fluid. PMID- 28573027 TI - Operating length and velocity of human M. vastus lateralis fascicles during vertical jumping. AB - Humans achieve greater jump height during a counter-movement jump (CMJ) than in a squat jump (SJ). However, the crucial difference is the mean mechanical power output during the propulsion phase, which could be determined by intrinsic neuro muscular mechanisms for power production. We measured M. vastus lateralis (VL) fascicle length changes and activation patterns and assessed the force-length, force-velocity and power-velocity potentials during the jumps. Compared with the SJ, the VL fascicles operated on a more favourable portion of the force-length curve (7% greater force potential, i.e. fraction of VL maximum force according to the force-length relationship) and more disadvantageous portion of the force velocity curve (11% lower force potential, i.e. fraction of VL maximum force according to the force-velocity relationship) in the CMJ, indicating a reciprocal effect of force-length and force-velocity potentials for force generation. The higher muscle activation (15%) could therefore explain the moderately greater jump height (5%) in the CMJ. The mean fascicle-shortening velocity in the CMJ was closer to the plateau of the power-velocity curve, which resulted in a greater (15%) power-velocity potential (i.e. fraction of VL maximum power according to the power-velocity relationship). Our findings provide evidence for a cumulative effect of three different mechanisms-i.e. greater force-length potential, greater power-velocity potential and greater muscle activity-for an advantaged power production in the CMJ contributing to the marked difference in mean mechanical power (56%) compared with SJ. PMID- 28573028 TI - Detection and perception of generic host volatiles by mosquitoes: responses to CO2 constrains host-seeking behaviour. AB - Natural selection has favoured specialization in anthropophilic mosquito host choice, yet in the absence of human hosts, females feed on a selected range of vertebrates. For host recognition, we hypothesize that mosquitoes primarily rely on generic host volatiles. Detection and perception of such compounds would provide the mosquito with a flexible, yet constrained, odour coding system that could delineate host preference. In this study, we show that the quintessential generic volatile for host-seeking, carbon dioxide, activates and attracts the malaria mosquito, Anopheles coluzzii, and the arbovirus vectors, Aedes aegypti and Culex quinquefasciatus, within boundaries set by the dynamic range and coding capacity of the CO2-sensitive olfactory receptor neurons. These boundaries are sufficiently broad to elicit behavioural responses to various hosts within their preferred host range. This study highlights the significance of the sensitivity of the carbon dioxide detection system and its regulation of host seeking and recognition. PMID- 28573029 TI - First empirical evidence of naturally occurring androgenesis in vertebrates. AB - Androgenesis among vertebrates is considered a rare phenomenon, with some cases reported so far, but linked to experiments involving gamete manipulation (artificial androgenesis). Herein, we report the first empirical evidence of the natural occurrence of spontaneous androgenesis in a vertebrate, the Squalius alburnoides allopolyploid complex. A genetically screened random sample of a natural population was allowed to reproduce in an isolated pond without any human interference, and the viable offspring obtained was later analysed for paternity. Both nuclear and mitochondrial markers showed that the only allodiploid fish found among all the allotriploid offspring was androgenetically produced by an allodiploid male. This specimen had no female nuclear genomic input, and the sequence of the mitochondrial fragment examined differed from that of the male progenitor, matching one of the parental females available in the pond, probably the mother. The possible role of androgenesis in the reproductive dynamics of this highly successful vertebrate complex is discussed. PMID- 28573030 TI - Graphic kinematics, visual virtual work and elastographics. AB - In this paper, recent progress in graphic statics is combined with Williot displacement diagrams to create a graphical description of both statics and kinematics for two- and three-dimensional pin-jointed trusses. We begin with reciprocal form and force diagrams. The force diagram is dissected into its component cells which are then translated relative to each other. This defines a displacement diagram which is topologically equivalent to the form diagram (the structure). The various contributions to the overall Virtual Work appear as parallelograms (for two-dimensional trusses) or parallelopipeds (for three dimensional trusses) that separate the force and the displacement pieces. Structural mechanisms can be identified by translating the force cells such that their shared faces slide across each other without separating. Elastic solutions can be obtained by choosing parallelograms or parallelopipeds of the appropriate aspect ratio. Finally, a new type of 'elastographic' diagram-termed a deformed Maxwell-Williot diagram (two-dimensional) or a deformed Rankine-Williot diagram (three-dimensional)-is presented which combines the deflected structure with the forces carried by its members. PMID- 28573031 TI - Trajectory energy minimization for cell growth tracking and genealogy analysis. AB - Cell growth experiments with a microfluidic device produce large-scale time-lapse image data, which contain important information on cell growth and patterns in their genealogy. To extract such information, we propose a scheme to segment and track bacterial cells automatically. In contrast with most published approaches, which often split segmentation and tracking into two independent procedures, we focus on designing an algorithm that describes cell properties evolving between consecutive frames by feeding segmentation and tracking results from one frame to the next one. The cell boundaries are extracted by minimizing the distance regularized level set evolution (DRLSE) model. Each individual cell was identified and tracked by identifying cell septum and membrane as well as developing a trajectory energy minimization function along time-lapse series. Experiments show that by applying this scheme, cell growth and division can be measured automatically. The results show the efficiency of the approach when testing on different datasets while comparing with other existing algorithms. The proposed approach demonstrates great potential for large-scale bacterial cell growth analysis. PMID- 28573032 TI - The evolution of an ancient technology. AB - We investigate pattern and process in the transmission of traditional weaving cultures in East and Southeast Asia. Our investigation covers a range of scales, from the experiences of individual weavers ('micro') to the broad-scale patterns of loom technologies across the region ('macro'). Using published sources, we build an empirical model of cultural transmission (encompassing individual weavers, the household and the community), focussing on where cultural information resides and how it is replicated and how transmission errors are detected and eliminated. We compare this model with macro-level outcomes in the form of a new dataset of weaving loom technologies across a broad area of East and Southeast Asia. The lineages of technologies that we have uncovered display evidence for branching, hybridization (reticulation), stasis in some lineages, rapid change in others and the coexistence of both simple and complex forms. There are some striking parallels with biological evolution and information theory. There is sufficient detail and resolution in our findings to enable us to begin to critique theoretical models and assumptions that have been produced during the last few decades to describe the evolution of culture. PMID- 28573033 TI - Inducible versus constitutive social immunity: examining effects of colony infection on glucose oxidase and defensin-1 production in honeybees. AB - Honeybees use a variety of defence mechanisms to reduce disease infection and spread throughout the colony. Many of these defences rely on the collective action of multiple individuals to prevent, reduce or eradicate pathogens-often referred to as 'social immunity'. Glucose oxidase (GOX) and some antimicrobial peptides (e.g. defensin-1 or Def1) are secreted by the hypopharyngeal gland of adult bees on larval food for their antiseptic properties. Because workers secrete these compounds to protect larvae, they have been used as 'biomarkers' for social immunity. The aim of this study was to investigate if GOX and Def1 are induced after pathogen exposure to determine whether its production by workers is the result of a collective effort to protect the brood and colony in response to a pathogen challenge. Specifically, we quantified GOX and Def1 in honeybee adults before and after colony-level bacterial infection by American foulbrood ((AFB), Paenibacillus larvae). Overall, our results indicate that levels of GOX and Def1 are not induced in response to pathogenic infections. We therefore conclude that GOX and Def1 are highly constitutive and co-opted as mechanisms of social immunity, and these factors should be considered when investigating immunity at the individual and colony level in social insects. PMID- 28573034 TI - A technical note on variable inter-frame interval as a cause of non-physiological experimental artefacts in ultrasound. AB - Ultrasound (US) imaging is a well-recognized technique for the study of static tissues but its suitability for studying tissue dynamics depends upon accurate frame time information, which may not always be available to users. Here we present methods to quantify the inter-frame interval (IFI) variability, and evaluate different procedures for collecting temporal information from two US imaging devices. The devices tested exhibited variable IFIs that could only be confirmed by direct measures of timing signals, available by means of electrical signals (triggers) and/or temporal information contained in the software used for the US data collection. Interpolating frame-by-frame measures of dynamic changes within image sequences using individual IFI values provided improved synchronization between measures of skeletal muscle movement and activation; validating US as a valuable technique for the study of musculoskeletal tissue dynamics, when correctly implemented. PMID- 28573035 TI - Expression of a symbiosis-specific gene in Symbiodinium type A1 associated with coral, nudibranch and giant clam larvae. AB - Symbiodinium are responsible for the majority of primary production in coral reefs and found in a mutualistic symbiosis with multiple animal phyla. However, little is known about the molecular signals involved in the establishment of this symbiosis and whether it initiates during host larval development. To address this question, we monitored the expression of a putative symbiosis-specific gene (H+-ATPase) in Symbiodinium A1 ex hospite and in association with larvae of a scleractinian coral (Mussismilia hispida), a nudibranch (Berghia stephanieae) and a giant clam (Tridacna crocea). We acquired broodstock for each host, induced spawning and cultured the larvae. Symbiodinium cells were offered and larval samples taken for each host during the first 72 h after symbiont addition. In addition, control samples including free-living Symbiodinium and broodstock tissue containing symbionts for each host were collected. RNA extraction and RT PCR were performed and amplified products cloned and sequenced. Our results show that H+-ATPase was expressed in Symbiodinium associated with coral and giant clam larvae, but not with nudibranch larvae, which digested the symbionts. Broodstock tissue for coral and giant clam also expressed H+-ATPase, but not the nudibranch tissue sample. Our results of the expression of H+-ATPase as a marker gene suggest that symbiosis between Symbiodinium and M. hispida and T. crocea is established during host larval development. Conversely, in the case of B. stephanieae larvae, evidence does not support a mutualistic relationship. Our study supports the utilization of H+-ATPase expression as a marker for assessing Symbiodinium-invertebrate relationships with applications for the differentiation of symbiotic and non-symbiotic associations. At the same time, insights from a single marker gene approach are limited and future studies should direct the identification of additional symbiosis-specific genes, ideally from both symbiont and host. PMID- 28573037 TI - Reviewers in 2016. PMID- 28573036 TI - Oilbirds produce echolocation signals beyond their best hearing range and adjust signal design to natural light conditions. AB - Oilbirds are active at night, foraging for fruits using keen olfaction and extremely light-sensitive eyes, and echolocate as they leave and return to their cavernous roosts. We recorded the echolocation behaviour of wild oilbirds using a multi-microphone array as they entered and exited their roosts under different natural light conditions. During echolocation, the birds produced click bursts (CBs) lasting less than 10 ms and consisting of a variable number (2-8) of clicks at 2-3 ms intervals. The CBs have a bandwidth of 7-23 kHz at -6 dB from signal peak frequency. We report on two unique characteristics of this avian echolocation system. First, oilbirds reduce both the energy and number of clicks in their CBs under conditions of clear, moonlit skies, compared with dark, moonless nights. Second, we document a frequency mismatch between the reported best frequency of oilbird hearing (approx. 2 kHz) and the bandwidth of their echolocation CBs. This unusual signal-to-sensory system mismatch probably reflects avian constraints on high-frequency hearing but may still allow oilbirds fine-scale, close-range detail resolution at the upper extreme (approx. 10 kHz) of their presumed hearing range. Alternatively, oilbirds, by an as-yet unknown mechanism, are able to hear frequencies higher than currently appreciated. PMID- 28573038 TI - Oldest skeleton of a plesiadapiform provides additional evidence for an exclusively arboreal radiation of stem primates in the Palaeocene. AB - Palaechthonid plesiadapiforms from the Palaeocene of western North America have long been recognized as among the oldest and most primitive euarchontan mammals, a group that includes extant primates, colugos and treeshrews. Despite their relatively sparse fossil record, palaechthonids have played an important role in discussions surrounding adaptive scenarios for primate origins for nearly a half century. Likewise, palaechthonids have been considered important for understanding relationships among plesiadapiforms, with members of the group proposed as plausible ancestors of Paromomyidae and Microsyopidae. Here, we describe a dentally associated partial skeleton of Torrejonia wilsoni from the early Palaeocene (approx. 62 Ma) of New Mexico, which is the oldest known plesiadapiform skeleton and the first postcranial elements recovered for a palaechthonid. Results from a cladistic analysis that includes new data from this skeleton suggest that palaechthonids are a paraphyletic group of stem primates, and that T. wilsoni is most closely related to paromomyids. New evidence from the appendicular skeleton of T. wilsoni fails to support an influential hypothesis based on inferences from craniodental morphology that palaechthonids were terrestrial. Instead, the postcranium of T. wilsoni indicates that it was similar to that of all other plesiadapiforms for which skeletons have been recovered in having distinct specializations consistent with arboreality. PMID- 28573039 TI - Correction to 'Deliberation favours social efficiency by making people disregard their relative shares: evidence from USA and India'. AB - [This corrects the article DOI: 10.1098/rsos.160605.]. PMID- 28573040 TI - Correction to 'The geometry of structural equilibrium'. AB - [This corrects the article DOI: 10.1098/rsos.160759.]. PMID- 28573042 TI - Correction to 'The mountains of giants: an anthropometric survey of male youths in Bosnia and Herzegovina'. AB - [This corrects the article DOI: 10.1098/rsos.161054.]. PMID- 28573041 TI - Isotocin neuronal phenotypes differ among social systems in cichlid fishes. AB - Social living has evolved numerous times across a diverse array of animal taxa. An open question is how the transition to a social lifestyle has shaped, and been shaped by, the underlying neurohormonal machinery of social behaviour. The nonapeptide neurohormones, implicated in the regulation of social behaviours, are prime candidates for the neuroendocrine substrates of social evolution. Here, we examined the brains of eight cichlid fish species with divergent social systems, comparing the number and size of preoptic neurons that express the nonapeptides isotocin and vasotocin. While controlling for the influence of phylogeny and body size, we found that the highly social cooperatively breeding species (n = 4) had fewer parvocellular isotocin neurons than the less social independently breeding species (n = 4), suggesting that the evolutionary transition to group living and cooperative breeding was associated with a reduction in the number of these neurons. In a complementary analysis, we found that the size and number of isotocin neurons significantly differentiated the cooperatively breeding from the independently breeding species. Our results suggest that isotocin is related to sociality in cichlids and may provide a mechanistic substrate for the evolution of sociality. PMID- 28573045 TI - Danish translation of a physical function item bank from the Patient-Reported Outcome Measurement Information System (PROMIS). AB - BACKGROUND: The Patient-Reported Outcome Measurement Information System (PROMIS) is an assessment system that aims to provide more valid, reliable, responsive, and precise patient-reported outcome (PRO) measures than has been previously available. This paper documents the translation of the Physical Function item bank into Danish. METHODS: We followed the PROMIS standard procedure, including: 1) two independent translations, 2) back translation, 3) independent reviews of translation quality, and 4) cognitive interviews with a representative sample of the adult population from the municipality of Copenhagen. After each phase, the new information was reviewed and the Danish version of the PROMIS Physical Function items was revised, if warranted. RESULTS: Relatively few problems were related to translation in itself and such problems could be fixed by changes in item wordings to fit the Danish context. Cognitive testing revealed problem of a general issue: annoyance in case of mismatch between respondents' functional level and question difficulty, problems imagining performance on activities that the respondents did not usually do, and uncertainty whether mobility aids (e.g., canes and walkers) should be considered when performing an activity. Solutions to the more general issues would require revisions to the original items. CONCLUSIONS: The standard translation methodology was successful in eliminating problems in translation, and pointed to problems of a general issue in some of the original questions, producing translated Danish versions of the PROMIS Physical Functioning items. Translation and validation studies provide a valuable source when revising and improving PROs in a clinical setting or for research. The present paper exemplifies this with experiences from Denmark. The study describes how the use of PROs when measuring physical functioning in a Danish context can be improved-hence improving the items used for research, future trials and in clinical settings. PMID- 28573043 TI - A safety evaluation of profound hypothermia-induced suspended animation for delayed resuscitation at 90 or 120 min. AB - BACKGROUND: The successful treatment of military combat casualties with penetrating injuries is significantly dependent on the time needed to get the patient to an adequate treatment facility. Profound hypothermia-induced suspended animation for delayed resuscitation (SADR) is a novel approach for inducing cardiac arrest and buying additional time for such injuries. However, the time used to safely administer circulatory arrest (CA) is controversial. The goal of this study was to evaluate the safety of hypothermia-induced SADR over 90 and 120 min time intervals. METHODS: Sixteen male BAMA minipigs were randomized into two groups: CA90 group (90 min, n = 8) and CA120 group (120 min, n = 8). Cannulation of the right common carotid arteries and internal jugular veins was performed to establish cardiopulmonary bypass for each animal. Through the perfusion of cold organ preservation solution (OPS), cardioplegia and profound hypothermia (15 degrees C) were induced. After CA, cardiopumonary bypass (CPB) was restarted, and the animals were gradually re-warmed and resuscitated. The animals were assisted with ventilators until spontaneous breathing was achieved. The index of hemodynamic perioperative serum chemistry values [alanine transaminase (ALT), aspartate aminotransferase (AST), creatinine (CR), lactic dehydrogenase (LDH) and troponin T (TnT)] and survival were observed from pre-operation to 7 days post operation. RESULTS: Fifteen animals were enrolled in the experiment, while 1 animal in CA120 group died from surgical error. All 8 animals in CA90 group recovered, with only 1 animal displaying mild disability. However, in CA120 group, only 2 animals survived with severe disability, and the other 5 animals died after 2 days post-operation. In CA90 group, the perioperative serum chemistry values increased at 1 day post-operation (ALT 84.43 +/- 18.65 U/L; AST 88.99 +/- 23.19 U/L; Cr 87.90 +/- 24.49 MUmol/L; LDH 1894.13 +/- 322.26 U/L; TnT 0.849 +/- 0.135 ng/ml) but decreased to normal or almost normal levels at 7 days post-operation (ALT 52.48 +/- 9.04 U/L; AST 75.23 +/- 21.46 U/L; Cr 82.69 +/- 18.41 MUmol/L; LDH 944.67 +/- 834.32 U/L; TnT 0.336 +/- 0.076 ng/ml). CONCLUSIONS: Profound hypothermia-induced SADR is an effective method for inducing cardiac arrest. Our results indicate that inducing CA for 90 min (at 15 degrees C) is safer than doing so for 120 min. Our results indicate that 120 min of CA at 15 degrees C is dangerous and can result in high mortality and severe neurological complications. Further experimentation is needed to determine whether 120 min of CA at temperatures lower than 15 degrees C can lead to safe recovery. PMID- 28573046 TI - A Comparative Study: The Use of Collagen Implant versus Mitomycin-C in Combined Trabeculotomy and Trabeculectomy for Treatment of Primary Congenital Glaucoma. AB - PURPOSE: To compare Ologen implant versus mitomycin-C (MMC) in combined trabeculotomy and trabeculectomy as a treatment of primary congenital glaucoma. SETTING: Sohag University Hospital, Egypt. DESIGN: A prospective comparative study. METHODS: Thirty-four eyes of twenty-one patients with primary congenital glaucoma were included in this study. All patients were subjected to preoperative evaluation including complete anterior segment examination under general anesthesia. The patients were divided into two groups: patients of the first group (group A) underwent combined trabeculotomy and trabeculectomy with Ologen implantation while those of the second group (group B) underwent combined trabeculotomy and trabeculectomy with MMC application. RESULTS: Postoperatively, the IOP in group A was as follows: 8 eyes developed IOP levels less than 14 mmHg (complete success), 3 eyes had levels between 14 and 16 mmHg (accepted result), 2 eyes had levels between 16 and 20 mmHg (guarded result), and only 2 eyes showed levels exceeding 20 mmHg (failed procedure), while in group B, 7 eyes showed complete success, 3 eyes had accepted result, 3 eyes had guarded result, and 2 eyes had failed procedure. CONCLUSION: Ologen is a safe and effective adjuvant in combined trabeculotomy and trabeculectomy for treatment of primary congenital glaucoma. PMID- 28573044 TI - The impacts of different embolization techniques on splenic artery embolization for blunt splenic injury: a systematic review and meta-analysis. AB - BACKGROUND: Splenic artery embolization (SAE) has been an effective adjunct to the Non-operative management (NOM) for blunt splenic injury (BSI). However, the optimal embolization techniques are still inconclusive. To further understand the roles of different embolization locations and embolic materials in SAE, we conducted this system review and meta-analyses. METHODS: Clinical studies related to SAE for adult patients were researched in electronic databases, included PubMed, Embase, ScienceDirect and Google Scholar Search (between October 1991 and March 2013), and relevant information was extracted. To eliminate the heterogeneity, a sensitivity analysis was conducted on two reduced study sets. Then, the pooled outcomes were compared and the quality assessments were performed using Newcastle-Ottawa Scale (NOS). The SAE success rate, incidences of life-threatening complications of different embolization techniques were compared by chi2 test in 1st study set. Associations between different embolization techniques and clinical outcomes were evaluated by fixed-effects model in 2nd study set. RESULTS: Twenty-three studies were included in 1st study set. And then, 13 of them were excluded, because lack of the necessary details of SAE. The remaining 10 studies comprised 2nd study set, and quality assessments were performed using NOS. In 1st set, the primary success rate is 90.1% and the incidence of life-threatening complications is 20.4%, though the cases which required surgical intervention are very few (6.4%). For different embolization locations, there was no obvious association between primary success rate and embolization location in both 1st and 2nd study sets (P > 0.05). But in 2nd study set, it indicated that proximal embolization reduced severe complications and complications needed surgical management. As for the embolic materials, the success rate between coil and gelfoam is not significant. However, coil is associated with a lower risk of life-threatening complications, as well as less complications requiring surgical management. CONCLUSIONS: Different embolization techniques affect the clinical outcomes of SAE. The proximal embolization is the best option due to the less life-threatening complications. For commonly embolic material, coil is superior to gelfoam for fewer severe complications and less further surgery management. PMID- 28573047 TI - Simultaneous Fluorescein Angiography and Spectral Domain Optical Coherence Tomography Correlate Retinal Thickness Changes to Vascular Abnormalities in an In Vivo Mouse Model of Retinopathy of Prematurity. AB - BACKGROUND: Retinopathy of prematurity (ROP) is a condition of abnormal retinal vascular development (RVD) in premature infants. Fluorescein angiography (FA) has depicted phases (early, mid, late, and mature) of RVD in oxygen-induced retinopathy (OIR) mice. We sought to establish the relationship between retinal structural and vascular changes using simultaneous FA and spectral domain optical coherence tomography (SD-OCT). METHOD: 63 mice were exposed to 77% oxygen at postnatal day 7 (P7) for 5 days, while 63 mice remained in room air (RA). Total retinal thickness (TRT), inner retinal thickness (IRT), and outer retinal thickness (ORT) were calculated at early (P19), mid (P24), late (P32), and mature (P47) phases of RVD. RESULTS: TRT was reduced in OIR (162.66 +/- 17.75 MUm, n = 13) compared to RA mice at P19 (197.57 +/- 3.49 MUm, n = 14), P24, P32, and P49 (P < 0.0001). ORT was similar in RA and OIR mice at all ages (P > 0.05). IRT was reduced in OIR (71.60 +/- 17.14 MUm) compared to RA (103.07 +/- 3.47 MUm) mice at P19 and all ages (P < 0.0001). CONCLUSION: We have shown the spatial and temporal relationship between retinal structure and vascular development in OIR. Significant inner retinal thinning in OIR mice persisted despite revascularization of the capillary network; further studies will elucidate its functional implications in ROP. PMID- 28573048 TI - Brain Oscillations Elicited by the Cold Pressor Test: A Putative Index of Untreated Essential Hypertension. AB - OBJECTIVE: Essential hypertension is associated with reduced pain sensitivity of unclear aetiology. This study explores this issue using the Cold Pressor Test (CPT), a reliable pain/stress model, comparing CPT-related EEG activity in first episode hypertensives and controls. METHOD: 22 untreated hypertensives and 18 matched normotensives underwent 24-hour ambulatory blood pressure monitoring (ABPM). EEG recordings were taken before, during, and after CPT exposure. RESULTS: Significant group differences in CPT-induced EEG oscillations were covaried with the most robust cardiovascular differentiators by means of a Canonical Analysis. Positive correlations were noted between ABPM variables and Delta (1-4 Hz) oscillations during the tolerance phase; in high-alpha (10-12 Hz) oscillations during the stress unit and posttest phase; and in low-alpha (8-10 Hz) oscillations during CPT phases overall. Negative correlations were found between ABPM variables and Beta2 oscillations (16.5-20 Hz) during the posttest phase and Gamma (28.5-45 Hz) oscillations during the CPT phases overall. These relationships were localised at several sites across the cerebral hemispheres with predominance in the right hemisphere and left frontal lobe. CONCLUSIONS: These findings provide a starting point for increasing our understanding of the complex relationships between cerebral activation and cardiovascular functioning involved in regulating blood pressure changes. PMID- 28573051 TI - Sensory Eye Dominance in Treated Anisometropic Amblyopia. AB - Amblyopia results from inadequate visual experience during the critical period of visual development. Abnormal binocular interactions are believed to play a critical role in amblyopia. These binocular deficits can often be resolved, owing to the residual visual plasticity in amblyopes. In this study, we quantitatively measured the sensory eye dominance in treated anisometropic amblyopes to determine whether they had fully recovered. Fourteen treated anisometropic amblyopes with normal or corrected to normal visual acuity participated, and their sensory eye dominance was assessed by using a binocular phase combination paradigm. We found that the two eyes were unequal in binocular combination in most (11 out of 14) of our treated anisometropic amblyopes, but none of the controls. We concluded that the treated anisometropic amblyopes, even those with a normal range of visual acuity, exhibited abnormal binocular processing. Our results thus suggest that there is potential for improvement in treated anisometropic amblyopes that may further enhance their binocular visual functioning. PMID- 28573052 TI - Decoronation: An Alternative Treatment for Replacement Root Resorption. AB - INTRODUCTION: Ankylosis and disrupted or altered root development are frequent complications associated with intrusive luxation and tooth avulsion lesions. Various forms of treatment have been described according to the severity of the trauma and root development. The literature shows that decoronation is an ideal treatment in cases where replacement resorption occurs. METHODS: Two clinical cases are presented: involving intrusive luxation [15-year-old female patient with an affected maxillary left lateral incisor (2.2)] and a replanted avulsed tooth [8-year-old male patient with avulsion of the right maxillary central incisor (1.1)]; both cases presented advanced root resorption so that decoronation with a prosthetic tooth replacement was decided as the final treatment option. RESULTS: In the short-term follow-up, patients were asymptomatic and had no functional problems. Radiographs showed that crestal bone height had been preserved. CONCLUSIONS: Preserving the decoronated root in the alveolar process not only helps to maintain bone volume but also enables vertical bone growth and facilitates the future insertion of an implant. PMID- 28573050 TI - Right Hemisphere Grey Matter Volume and Language Functions in Stroke Aphasia. AB - The role of the right hemisphere (RH) in recovery from aphasia is incompletely understood. The present study quantified RH grey matter (GM) volume in individuals with chronic stroke-induced aphasia and cognitively healthy people using voxel-based morphometry. We compared group differences in GM volume in the entire RH and in RH regions-of-interest. Given that lesion site is a critical source of heterogeneity associated with poststroke language ability, we used voxel-based lesion symptom mapping (VLSM) to examine the relation between lesion site and language performance in the aphasic participants. Finally, using results derived from the VLSM as a covariate, we evaluated the relation between GM volume in the RH and language ability across domains, including comprehension and production processes both at the word and sentence levels and across spoken and written modalities. Between-subject comparisons showed that GM volume in the RH SMA was reduced in the aphasic group compared to the healthy controls. We also found that, for the aphasic group, increased RH volume in the MTG and the SMA was associated with better language comprehension and production scores, respectively. These data suggest that the RH may support functions previously performed by LH regions and have important implications for understanding poststroke reorganization. PMID- 28573053 TI - Humoral Hypercalcemia of Malignancy with a Parathyroid Hormone-Related Peptide Secreting Intrahepatic Cholangiocarcinoma Accompanied by a Gastric Cancer. AB - Humoral hypercalcemia of malignancy (HHM) is caused by the oversecretion of parathyroid hormone-related peptide (PTHrP) from malignant tumors. Although any tumor may cause HHM, that induced by intrahepatic cholangiocarcinoma (ICC) or gastric cancer (GC) is rare. We report here a 74-year-old male who displayed HHM with both ICC and GC and showed an elevated serum PTHrP level. Treatment of the hypercalcemia with saline, furosemide, elcatonin, and zoledronic acid corrected his serum calcium level and improved symptoms. Because treatment of ICC should precede that of GC, we chose chemotherapy with cisplatin (CDDP) and gemcitabine (GEM). Chemotherapy reduced the size of the ICC and decreased the serum PTHrP level. One year after diagnosis, the patient was alive in the face of a poor prognosis for an ICC that produced PTHrP. Immunohistochemical staining for PTHrP was positive for the ICC and negative for the GC, leading us to believe that the cause of the HHM was a PTHrP-secreting ICC. In conclusion, immunohistochemical staining for PTHrP may be useful in discovering the cause of HHM in the case of two cancers accompanied by an elevated serum PHTrP level. Chemotherapy with CDDP and GEM may be the most appropriate treatment for a PTHrP-secreting ICC. PMID- 28573049 TI - Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners. AB - Neuropathic pain is relatively less responsive to opioids than other types of pain, which is possibly due to a disrupted opioid system partially caused by the profound microglial cell activation that underlines neuroinflammation. We demonstrated that intrathecally injected biphalin, a dimeric enkephalin analog, diminished symptoms of neuropathy in a preclinical model of neuropathic pain in rats (CCI, chronic constriction injury of the sciatic nerve) at day 12 postinjury. Using primary microglial cell cultures, we revealed that biphalin did not influence cell viability but diminished NO production and expression of Iba1 in LPS-stimulated cells. Biphalin also diminished MOP receptor level, as well as pronociceptive mediators (iNOS, IL-1beta, and IL-18) in an opioid receptor dependent manner, and it was correlated with diminished p-NF-kappaB, p-IkappaB, p p38MAPK, and TRIF levels. Biphalin reduced IL-6, IL-10, TNFalpha, p-STAT3, and p ERK1/2 and upregulated SOCS3, TLR4, and MyD88; however, this effect was not reversed by naloxone pretreatment. Our study provides evidence that biphalin diminishes neuropathy symptoms, which might be partially related to reduced pronociceptive mediators released by activated microglia. Biphalin may be a putative drug for future pain therapy, especially for the treatment of neuropathic pain, when the lower analgesic effects of morphine are correlated with profound microglial cell activation. PMID- 28573054 TI - Locally Advanced Thyroglossal Duct Cyst Carcinoma Presenting as a Neck Mass. AB - Thyroglossal duct cyst carcinoma is rare and occurs in just 1% of cases with thyroglossal duct cysts. It is not always possible to distinguish a thyroglossal cyst harboring malignancy from its benign counterparts unless biopsied, thus posing the dilemma. Currently there is no clear consensus on the optimal management of thyroglossal duct cyst carcinoma. Here we present the case of a 69 year-old female who presented with a midline neck mass and dysphagia and was found to have papillary thyroid cancer in the biopsy specimen of the neck mass. She underwent excision of the mass and the thyroglossal duct cyst along with total thyroidectomy; however, the thyroidectomy specimen showed no malignancy. Her lymph node mapping was negative and she is awaiting radioactive iodine treatment. PMID- 28573056 TI - Antiglomerular Basement Membrane Disease in a Pediatric Patient: A Case Report and Review of the Literature. AB - Goodpasture's syndrome (GPS) remains a very rare disease entity in the pediatric population characterized by the presence of pulmonary hemorrhage and rapidly evolving glomerulonephritis. We hereby describe the case of a 2-year-old girl who presented with renal failure and was diagnosed with GPS. A brief review of the literature in regard to data on demographics, pathogenesis, clinical features, diagnosis, treatment, and prognosis for renal recovery is also provided. PMID- 28573057 TI - Cisplatin-Induced Renal Salt Wasting Requiring over 12 Liters of 3% Saline Replacement. AB - Cisplatin is known to induce Fanconi syndrome and renal salt wasting (RSW). RSW typically only requires transient normal saline (NS) support. We report a severe RSW case that required 12 liters of 3% saline. A 57-year-old woman with limited stage small cell cancer was admitted for cisplatin (80 mg/m2) and etoposide (100 mg/m2) therapy. Patient's serum sodium (SNa) decreased from 138 to 133 and 125 mEq/L within 24 and 48 hours of cisplatin therapy, respectively. A diagnosis of syndrome of inappropriate antidiuretic hormone secretion (SIADH) was initially made. Despite free water restriction, patient's SNa continued to decrease in association with acute onset of headaches, nausea, and dizziness. Three percent saline (3%S) infusion with rates up to 1400 mL/day was required to correct and maintain SNa at 135 mEq/L. Studies to evaluate Fanconi syndrome revealed hypophosphatemia and glucosuria in the absence of serum hyperglycemia. The natriuresis slowed down by 2.5 weeks, but 3%S support was continued for a total volume of 12 liters over 3.5 weeks. Attempts of questionable benefits to slow down glomerular filtration included the administration of ibuprofen and benazepril. To our knowledge, this is the most severe case of RSW ever reported with cisplatin. PMID- 28573055 TI - Gastric Schwannoma: A Tumor Must Be Included in Differential Diagnoses of Gastric Submucosal Tumors. AB - Gastric schwannoma (GS) is a rare neoplasm of the stomach. It accounts for 0.2% of all gastric tumors and is mostly benign, slow-growing, and asymptomatic. Due to its rarity, GS is not widely recognized by clinicians, and the precise differential diagnosis between GS and other gastric submucosal tumors remains difficult preoperatively. The present study reports a case of GS misdiagnosed as gastrointestinal stromal tumor and reviews the clinical, imaging, and pathological features, treatment, and follow-up of 221 patients with GS previously reported in the English literature. Although GS is rare, the case reported in the current study highlights the importance of including GS in differential diagnoses of gastric submucosal tumors. Furthermore, the findings of the review suggest that although many cases are asymptomatic, the most common symptoms are abdominal pain or discomfort, not gastrointestinal bleeding, and malignant GSs present with clinical symptoms more commonly. Although large-sample multicenter studies on the efficacy, safety, and oncological outcomes of minimally invasive techniques are required, the findings presented herein may be helpful for clinicians when diagnosing or treating GS. PMID- 28573058 TI - Uncommon Etiology for Seizure: Cerebral Hyperperfusion Syndrome. AB - Cerebral hyperperfusion syndrome (CHS) is a rare life-threatening complication of carotid endarterectomy (CEA) and carotid artery stenting (CAS) for carotid artery stenosis. The incidence varies between 0 and 3%, depending on the severity of the stenosis, perioperative hypertension, and contralateral carotid stenosis. This case report reports a 53-year-old female patient presenting with decreased alertness and multiple tonic-clonic seizures, in the background of bilateral CEA. She was found to have bilateral carotid stenosis. Her left CEA was performed three months prior and right CEA was four days prior to her current presentation with seizures. After bilateral CEA, the imaging showed extensive pathologic process involving primarily the subcortical white matter and overlying cortex, more on the right cerebral hemisphere. On follow-up six weeks later, she reported no recurrent seizures and imaging showed decrease in abnormal signal intensity of the grey and white matter. This was indicative of near complete resolution of hyperperfusion damage. CHS is a rare complication due to the loss of autoregulation of the cerebrovascular system and increased blood flow status after bilateral CEA. This case is reported because of a rare and unique presentation of seizures in the background of bilateral CEA. PMID- 28573059 TI - Denosumab Therapy for Giant Cell Tumor of Bone Pulmonary Metastasis. AB - CASE: A 68-year-old female was diagnosed with giant cell tumor of bone (GCTB) metastatic to her lungs. The patient was treated with IV denosumab for the course of 4.5 years for these metastases. The metastatic tumor burden decreased significantly after only 3 months of therapy. The size of the metastases has been stable for over 4 years. CONCLUSION: Denosumab therapy has promise in the treatment of GCTB, including pulmonary metastasis. However, the long-term role of denosumab for pulmonary metastases is yet to be determined. PMID- 28573060 TI - Temporary Frontal Paralysis Secondary to Blunt Trauma Frontal Sinus Fracture. AB - Frontal sinus fractures (FSF) are relatively uncommon and can be challenging for trauma surgeons to manage. Patients with FSF typically present with facial swelling, pain, and nasofrontal ecchymosis. Here we present a rare case of a patient with FSF and anterior table fracture where the main presenting symptom was bilateral frontal paralysis. We outline our management strategy and review the current literature in regard to management of FSF. PMID- 28573061 TI - Pseudologia Fantastica in the Emergency Department: A Case Report and Review of the Literature. AB - Psychiatrists commonly encounter deception in the emergency department. This article presents the case of a patient who presents to the emergency department with an unusual and elaborate web of deceptions along multiple themes including feigning medical illness, multiple losses, and grandiose academic and athletic achievements. We review the clinical characteristics of pseudologia fantastica and discuss how this patient's constellation of malingering, factitious disorder, and personality disorder suggests this diagnosis. PMID- 28573062 TI - Regional Cerebral Blood Flow in Mild Cognitive Impairment and Alzheimer's Disease Measured with Arterial Spin Labeling Magnetic Resonance Imaging. AB - Alzheimer's disease (AD) depicts dynamic changes in regional brain function from early stages of the disease. Arterial spin labeling- (ASL-) based MRI methods have been applied for detecting regional cerebral blood flow (rCBF) perfusion changes in patients with AD and mild cognitive impairment (MCI). Nevertheless, the results obtained from ASL studies in AD and MCI are still controversial, since rCBF maps may show both hypoperfusion or hyperperfusion areas in brain structures involved in different cognitive functions. The goal of this review is to provide the current state of the art regarding the role of ASL for detecting distinctive perfusion patterns in subjects with MCI and/or AD. The ability to obtain this information using a noninvasive and widely available modality such as ASL should greatly enhance the knowledge into the broad range of hemodynamically related changes taking place during the cognitive decline process in AD. PMID- 28573068 TI - Rectification of oxygen transfer through the rat colonic epithelium. AB - AIM: To assess whether higher sensitivity of colonic epithelium to hypoxia at the serosal side is associated with oxygen transfer asymmetry. METHODS: Rats were fed either with normal chow or a low-sodium diet. Tissues were mounted as flat sheets in a modified, airtight Ussing chamber with oxygen meters in each hemichamber. Mucosal samples from normal diet animals were studied under control conditions, in low-chloride solution and after adding chloride secretion inhibitors and chloride secretagogues. Samples from sodium-deprived rats were studied before and after ouabain addition. In separate experiments, the correlation between short circuit current and oxygen consumption was analyzed. Finally, hypoxia was induced in one hemichamber to assess the relationship between its oxygen content and the oxygen pressure difference between both hemichambers. RESULTS: In all studied conditions, oxygen consumption was larger in the serosal hemichamber than in the mucosal one (P = 0.0025 to P < 0.0001). Short-circuit current showed significant correlation with both total oxygen consumption (r = 0.765; P = 0.009) in normoxia and oxygen consumption in the serosal hemichamber (r = 0.754; P = 0.011) during mucosal hypoxia, but not with oxygen consumption in the mucosal hemichamber. When hypoxia was induced in the mucosal hemichamber, an oxygen pressure difference of 13 kPa with the serosal hemichamber was enough to keep its oxygen content constant. However, when hypoxia was induced in the serosal hemichamber, the oxygen pressure difference with the mucosal hemichamber necessary to keep its oxygen content constant was 40 kPa (P < 0.0001). CONCLUSION: Serosal oxygen supply is more readily available to support short-circuit current. This may be partly due to a rectifying behavior of transepithelial oxygen transfer. PMID- 28573067 TI - Non-alcoholic fatty liver disease and cardiovascular risk. AB - Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with insulin resistance and metabolic syndrome. The spectrum of disease ranges from simple steatosis to steatohepatitis and progression to cirrhosis. Compelling evidence over the past several years has substantiated a significant link between NAFLD and cardiovascular disease ranging from coronary artery disease to subclinical carotid atherosclerosis. Close follow up, treatment of risk factors for NAFLD, and cardiovascular risk stratification are necessary to predict morbidity and mortality in this subset of patients. PMID- 28573066 TI - Embrionary way to create a fatty liver in portal hypertension. AB - Portal hypertension in the rat by triple partial portal vein ligation produces an array of splanchnic and systemic disorders, including hepatic steatosis. In the current review these alterations are considered components of a systemic inflammatory response that would develop through three overlapping phenotypes: The neurogenic, the immune and the endocrine. These three inflammatory phenotypes could resemble the functions expressed during embryonic development of mammals. In turn, the inflammatory phenotypes would be represented in the embryo by two functional axes, that is, a coelomic-amniotic axis and a trophoblastic yolk-sac or vitelline axis. In this sense, the inflammatory response developed after triple partial portal vein ligation in the rat would integrate both functional embryonic axes on the liver interstitial space of Disse. If so, this fact would favor the successive development of steatosis, steatohepatitis and fibrosis. Firstly, these recapitulated embryonic functions would produce the evolution of liver steatosis. In this way, this fat liver could represent a yolk-sac-like in portal hypertensive rats. After that, the systemic recapitulation of these embryonic functions in experimental prehepatic portal hypertension would consequently induce a gastrulation-like response in which a hepatic wound healing reaction or fibrosis occur. In conclusion, studying the mechanisms involved in embryonic development could provide key results for a better understanding of the nonalcoholic fatty liver disease etiopathogeny. PMID- 28573069 TI - Combination curcumin and vitamin E treatment attenuates diet-induced steatosis in Hfe-/- mice. AB - AIM: To investigate the synergistic hepato-protective properties of curcumin and vitamin E in an Hfe-/- high calorie diet model of steatohepatitis. METHODS: Hfe-/ C57BL/6J mice were fed either a high calorie diet or a high calorie diet with 1 mg/g curcumin; 1.5 mg/g vitamin E; or combination of 1 mg/g curcumin + 1.5 mg/g vitamin E for 20 wk. Serum and liver tissue were collected at the completion of the experiment. Liver histology was graded by a pathologist for steatosis, inflammation and fibrosis. RNA and protein was extracted from liver tissue to examine gene and protein expression associated with fatty acid oxidation, mitochondrial biogenesis and oxidative stress pathways. RESULTS: Hfe-/- mice fed the high calorie diet developed steatohepatitis and pericentral fibrosis. Combination treatment with curcumin and vitamin E resulted in a greater reduction of percent steatosis than either vitamin E or curcumin therapy alone. Serum alanine aminotransferase and non-alcoholic fatty liver disease (NAFLD) activity score were decreased following combination therapy with curcumin and vitamin E compared with high calorie diet alone. No changes were observed in inflammatory or fibrosis markers following treatment. Epididymal fat pad weights were significantly reduced following combination therapy, however total body weight and liver weight were unchanged. Combination therapy increased the mRNA expression of AdipoR2, Ppar-alpha, Cpt1a, Nrf-1 and Tfb2m suggesting enhanced fatty acid oxidation and mitochondrial biogenesis. In addition, combination treatment resulted in increased catalase activity in Hfe-/- mice. CONCLUSION: Combination curcumin and vitamin E treatment decreases liver injury in this steatohepatitis model, indicating that combination therapy may be of value in NAFLD. PMID- 28573063 TI - Alleviating Promotion of Inflammation and Cancer Induced by Nonsteroidal Anti Inflammatory Drugs. AB - CLINICAL RELEVANCE: Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) including aspirin are of intensive use nowadays. These drugs exert their activity via the metabolism of arachidonic acid (AA) by cyclooxygenase inhibition. Though beneficial for health in some instances, both unspecific and specific cyclooxygenase inhibitor activity interfere with AA metabolism producing also proinflammatory lipids that may promote cancer. MATERIALS AND METHODS: This review is based on available literature on clinical uses, biochemical investigations, molecular medicine, pharmacology, toxicity, and epidemiology clinical studies on NSAIDs and other drugs that may be used accordingly, which was collected from electronic (SciFinder, Medline, Science Direct, and ACS among others) and library searches of books and journals. RESULTS: Relevant literature supports the notion that NDSAID use may also promote proinflammatory biochemical events that are also related to precancerous predisposition. Several agents are proposed that may be employed in immediate future to supplement and optimize treatment with NSAIDs. In this way serious side effects arising from promotion of inflammation and cancer, especially in chronic NSAID users and high risk groups of patients, could be avoided. PMID- 28573064 TI - Nonalcoholic fatty liver disease: Diagnostic biomarkers. AB - Nonalcoholic fatty liver disease is a common medical condition worldwide and its prevalence has increased notably in the past few years due to the increases in prevalence of obesity and metabolic syndrome. However, diagnosis of this disease is still a matter of debate because of disease variations and pathophysiologic alterations. Specific single markers have gained considerable attention recently, among them markers related to hepatic pathophysiology, inflammation, adipocytokines and so forth. But, it seems that no single marker is sufficient for diagnosis and staging of the disease, and applying a panel including different types of tests may be more useful. PMID- 28573070 TI - Endoscopic therapy for biliary strictures complicating living donor liver transplantation: Factors predicting better outcome. AB - AIM: To identify factors predicting outcome of endoscopic therapy in bile duct strictures (BDS) post living donor liver transplantation (LDLT). METHODS: Patients referred with BDS post LDLT, were retrospectively studied. Patient demographics, symptoms (Pruritus, Jaundice, cholangitis), intra-op variables (cold ischemia time, blood transfusions, number of ducts used, etc.), peri-op complications [hepatic artery thrombosis (HAT), bile leak, infections], stricture morphology (length, donor and recipient duct diameters) and relevant laboratory data both pre- and post-endotherapy were studied. Favourable response to endotherapy was defined as symptomatic relief with > 80% reduction in total bilirubin/serum gamma glutamyl transferase. Statistical analysis was performed using SPSS 20.0. RESULTS: Forty-one patients were included (age: 8-63 years). All had right lobe LDLT with duct-to-duct anastomosis. Twenty patients (48.7%) had favourable response to endotherapy. Patients with single duct anastomosis, aggressive stent therapy (multiple endoscopic retrograde cholagiography, upsizing of stents, dilatation and longer duration of stents) and an initial favourable response to endotherapy were independent predictors of good outcome (P < 0.05). Older donor age, HAT, multiple ductal anastomosis and persistent bile leak (> 4 wk post LT) were found to be significant predictors of poor response on multivariate analysis (P < 0.05). CONCLUSION: Endoscopic therapy with aggressive stent therapy especially in patients with single duct-to-duct anastomosis was associated with a better outcome. Multiple ductal anastomosis, older donor age, shorter duration of stent therapy, early bile leak and HAT were predictors of poor outcome with endotherapy in these patients. PMID- 28573065 TI - Celiac disease: From pathophysiology to treatment. AB - Celiac disease, also known as "celiac sprue", is a chronic inflammatory disorder of the small intestine, produced by the ingestion of dietary gluten products in susceptible people. It is a multifactorial disease, including genetic and environmental factors. Environmental trigger is represented by gluten while the genetic predisposition has been identified in the major histocompatibility complex region. Celiac disease is not a rare disorder like previously thought, with a global prevalence around 1%. The reason of its under-recognition is mainly referable to the fact that about half of affected people do not have the classic gastrointestinal symptoms, but they present nonspecific manifestations of nutritional deficiency or have no symptoms at all. Here we review the most recent data concerning epidemiology, pathogenesis, clinical presentation, available diagnostic tests and therapeutic management of celiac disease. PMID- 28573071 TI - Differential diagnosis in ulcerative colitis in an adolescent: Chronic granulomatous disease needs extra attention. AB - Chronic granulomatous disease (CGD) is a primary immune deficiency that is commonly diagnosed under the age of 5 years (95%) and is rarely seen in adulthood. CGD may manifest as inflammatory bowel disease (IBD) in childhood. Without proper diagnosis, these patients may be monitored for years as IBD; some may even be regarded as steroid-resistant ulcerative colitis (UC) and end up having a colectomy. In this case report, we described a patient who had been followed-up for years as UC and subsequently underwent colectomy, but was finally diagnosed in adulthood as primary immune deficiency. PMID- 28573072 TI - Duodenal localization of plasmablastic myeloma. AB - Gastrointestinal involvement in plasma cell neoplasms, either as primary localizations (extramedullary plasmacytomas) or as secondary involvement in systemic multiple myeloma, is a well-known event. Accurate histological examination is crucial in defining the diagnosis. In this report, an uncommon case of duodenal localization of myeloma with plasmablastic features is described, with emphasis on the role of clinical data and findings from ancillary immunostaining techniques to avoid misdiagnosis. PMID- 28573073 TI - Late onset pulmonary metastasis more than 10 years after primary sigmoid carcinoma. AB - According to current guidelines, follow-up of patients with colorectal cancer is ended after five years. Also, chest X-ray is not part of standard investigation during follow-up. We describe a case of a 74-year-old patient, more than ten years after a sigmoid resection because of carcinoma of the sigmoid. No recurrence was detected during intensive follow-up. However, ten years after resection of the sigmoid adenocarcinoma, complaints of coughing induced further examination with as result the detection of a solitary metastasis in the left lung of the patient. Within half-a-year after metastasectomy of the lung metastasis, she presented herself with thoracic pain and dyspnea resulting in discovering diffuse metastasis on pulmonary, pleural, costal and muscular level. Five year follow-up of colorectal carcinoma without chest X-ray can be questioned to be efficient. The growing knowledge of tumor biology might in future adjust the duration and frequency of diagnostic follow-up to prevent (late) recurrence in patients with colorectal carcinoma. PMID- 28573074 TI - Living with Ultra-Low Vision: An Inventory of Self-Reported Visually Guided Activities by Individuals with Profound Visual Impairment. AB - PURPOSE: To understand how individuals with profound visual impairment (ultra-low vision, ULV) use their remaining vision. METHODS: Forty-six participants with ULV (visual acuity <= 200/500 in the better seeing eye) were divided into nine focus groups (4-6 individuals per group) and met either in person (n = 2) or over the phone (n = 7). Discussions were guided by the Massof Activity Inventory. Audio recordings were transcribed and analyzed for visual activities that were then classified along two visual categorizations - functional domains and visual aspects. The latter was based on a Grounded Theory classification of participants' descriptions. RESULTS: Seven hundred sixty activities were reported. By functional domain they were classified as reading/shape recognition (10%), mobility (17%), visual motor (24%), and visual information gathering (49%). By visual aspects, they were classified as contrast (43%), luminance (17%), environmental lighting (9%), familiarity (3%), motion perception (5%), distance (7%), size (9%), eccentricity (5%), depth perception (1%), and other/miscellaneous (1%). More than one visual aspect may be critical for an activity: participants reported that contrast plays a role in 68% of visual activities, followed by luminance (27%), environmental lighting (14%), and size (14%). CONCLUSIONS: Visual aspects, primarily contrast, were found to be critical factors enabling ULV individuals to perform visual activities. TRANSLATIONAL RELEVANCE: This inventory, part of the Prosthetic Low Vision Rehabilitation (PLoVR) curriculum development study, provides a unique perspective into the visual world of the nearly blind, and can be used in the development of a Visual Functioning Questionnaire (VFQ) and visual performance measures suited for ULV populations. PMID- 28573075 TI - Development of the Ultra-Low Vision Visual Functioning Questionnaire (ULV-VFQ). AB - PURPOSE: To develop and psychometrically evaluate a visual functioning questionnaire (VFQ) in an ultra-low vision (ULV) population. METHODS: Questionnaire items, based on visual activities self-reported by a ULV population, were categorized by functional visual domain (e.g., mobility) and visual aspect (e.g., contrast) to ensure a representative distribution. In Round 1, an initial set of 149 items was generated and administered to 90 participants with ULV (visual acuity [VA] <= 20/500; mean [SD] age 61 [15] years), including six patients with a retinal implant. Psychometric properties were evaluated through Rasch analysis and a revised set (150 items) was administered to 80 participants in Round 2. RESULTS: In Round 1, the person measure distribution (range, 8.6 logits) was centered at -1.50 logits relative to the item measures. In Round 2, the person measure distribution (range, 9.5 logits) was centered at 0.86 relative to the item mean. The reliability index in both rounds was 0.97 for Items and 0.99 for Persons. Infit analysis showed four underfit items in Round 1, five underfit items in Round 2 with a z-score greater than 4 cutoff. Principal component analysis on the residuals found 69.9% explained variance; the largest component in the unexplained variance was less than 3%. CONCLUSIONS: The ULV-VFQ, developed with content generated from a ULV population, showed excellent psychometric properties as well as superior measurement validity in a ULV population. TRANSLATIONAL RELEVANCE: The ULV-VFQ, part of the Prosthetic Low Vision Rehabilitation (PLoVR) development program, is a new VFQ developed for assessment of functional vision in ULV populations. PMID- 28573076 TI - Optimizing the ULV-VFQ for Clinical Use Through Item Set Reduction: Psychometric Properties and Trade-Offs. AB - PURPOSE: We examine the dimensionality of the 150-item visual functioning questionnaire for individuals with ultralow vision (ULV-VFQ) and develop representative abbreviated versions, facilitating clinical use, while retaining compatibility with a 17-item performance assessment. METHODS: Subsets with 50 and 23 items covering the full difficulty range were selected, with evenly spaced item measures (IMs) and good representation of visual aspects and functional domains. Person measures (PMs) for the anchored subsets were derived through Rasch analysis of data from 80 respondents. RESULTS: Fit statistics for the reduced item sets were similar to those for the full set, with reliabilities at or above 95%. Mean PMs in the reduced sets were within 0.8 standard errors (SEs) of those in the full set. SEs of the PMs increased from the SE for 150 items, roughly in inverse proportion with the square root of the set size. Unexplained variance levels (24%-27%) and variance of the first unexplained factor (3.3% 3.9%) were close to those (30% and 2.6%) for 150 items. Differential item functions for omitted items were negligible. Aspects and domains are adequately represented in the reduced sets. CONCLUSIONS: Self-reported visual ability can be measured accurately using appropriately chosen anchored subsets of the ULV-VFQ. Functional ability of individuals with ULV is characterized adequately by a single dimension. TRANSLATIONAL RELEVANCE: The ULV-VFQ50 and ULV-VFQ23, using anchored IMs from the 150-item ULV-VFQ, provide an efficient and reliable self report assessment of visual ability in individuals whose visual impairment is too severe for assessment with VFQs currently in use. PMID- 28573079 TI - A Special Issue for The 13th Annual Conference of the Taiwan Society for Mass Spectrometry. PMID- 28573078 TI - Petroleum Carcinogenicity and Aerodigestive Tract: In Context of Developing Nations. AB - Head and neck cancers from a diverse group of neoplasms, the occurrence of which can be attributed to habitual tobacco use, race, alcohol consumption, ultraviolet (UV) exposure, occupational exposure, viruses, and diet. The surging incidence rates reflect the prevalence of risk factors such as tobacco use (smoked and smokeless), betel nut chewing, urbanization and issues relating to urban air quality. Urbanization and development have catalyzed a multifold rise in levels of pollution in metropolitan cities. Ever-increasing consumption of fuels to meet demands of the growing population coupled with industrial activity has adversely affected the air quality, especially in developing countries. The cause most neglected in risk assessment of aerodigestive tract cancer research is that from petroleum exposure. The global issue of petroleum carcinogenicity has assumed high proportions. Polycyclic aromatic hydrocarbons and heavy metals are essential constituents of total petroleum hydrocarbons which infiltrate into the environment and are recognized worldwide as priority pollutants because of their toxicity and carcinogenicity. High levels of sulfur dioxide, nitrogen dioxide, ozone, carbon monoxide, ammonia and particulate matter PM10 has skyrocketed aerodigestive tract diseases especially carcinomas. The identification of specific biomarkers and role of metal ions in aerodigestive tract cancers will indicate the molecular basis of disease to provide quality care for patients confronting new threats from climate-sensitive pathologies. There is an urgent need to evaluate existing public health infrastructure so as to take ameliorative and adaptive measures. PMID- 28573077 TI - CRISPR-Cas Genome Surgery in Ophthalmology. AB - Genetic disease affecting vision can significantly impact patient quality of life. Gene therapy seeks to slow the progression of these diseases by treating the underlying etiology at the level of the genome. Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated systems (Cas) represent powerful tools for studying diseases through the creation of model organisms generated by targeted modification and by the correction of disease mutations for therapeutic purposes. CRISPR-Cas systems have been applied successfully to the visual sciences and study of ophthalmic disease - from the modification of zebrafish and mammalian models of eye development and disease, to the correction of pathogenic mutations in patient-derived stem cells. Recent advances in CRISPR-Cas delivery and optimization boast improved functionality that continues to enhance genome-engineering applications in the eye. This review provides a synopsis of the recent implementations of CRISPR-Cas tools in the field of ophthalmology. PMID- 28573080 TI - Rapid Identification of Psychoactive Drugs in Drained Gastric Lavage Fluid and Whole Blood Specimens of Drug Overdose Patients Using Ambient Mass Spectrometry. AB - Psychoactive drug overdoses are life-threatening and require prompt and proper treatment in the emergency room to minimize morbidity and mortality. Prompt identification of the ingested psychoactive drugs is challenging, since witness recall is unreliable and patients' symptoms do not necessarily explain their loss of consciousness. Gas and liquid chromatography mass spectrometric analyses have been the traditionally employed methods to detect and identify abused substances; however, these techniques are time-consuming and labor-intensive. In this study, thermal desorption electrospray ionization mass spectrometry, an ambient mass spectrometric technique, was applied to rapidly characterize flunitrazepam, lysergic acid diethylamide, and 3,4-methylenedioxy-methamphetamine in drained gastric lavage fluid, and ketamine, cocaine, amphetamine and norketamine in whole blood samples. No pretreatment of the gastric lavage fluid specimens was required and the entire analytical process took less than 30 s per specimen. Liquid-liquid extraction, followed by centrifugation, was performed on the whole blood samples. The corresponding compounds were identified through matching the obtained mass spectrometric data with those provided by commercial databases. The limits-of detection of the tested drugs in both drained gastric lavage fluid and whole blood samples are at sub ppm levels. This is sensitive enough for emergency medical application, since the quantities of medications ingested by overdosed abusers are much higher than the amounts that were tested. PMID- 28573081 TI - Comparative Proteomic Analysis of Rat Bronchoalveolar Lavage Fluid after Exposure to Zinc Oxide Nanoparticles. AB - Zinc oxide nanoparticles (ZnO NPs) are one of the most widely used nanomaterials in consumer products and industrial applications. As a result of all these uses, this has raised concerns regarding their potential toxicity. We previously found that candidate markers of idiopathic pulmonary fibrosis and lung cancer were significantly up-regulated in rat bronchoalveolar lavage fluid (BALF) following exposure to ZnO NPs by using a liquid chromatography (LC)-based proteomic approach. To achieve comprehensive protein identification analysis, we conducted the two-dimensional gel electrophosis (2-DE)-based proteomic workflow to analyze the differences in BALF proteins from rats that had been exposed to a high dose of 35 nm ZnO NPs. A total of 31 differentially expressed protein spots were excised from the gels and analyzed by nanoLC-tandem mass spectrometry (MS/MS). Gene ontology (GO) annotation of these proteins showed that most of the differentially expressed proteins were involved in response to stimulus and inflammatory response processes. Moreover, pulmonary surfactant-associated protein D and gelsolin, biomarkers of idiopathic pulmonary fibrosis, were significantly up-regulated in rat BALF after ZnO NPs exposure (2.42- and 2.84 fold, respectively). The results obtained from this present study could provide a complementary consequence with our previous study and contribute to a better understanding of the molecular mechanisms involved in ZnO NP-induced lung disorders. PMID- 28573082 TI - Electrospray Modifications for Advancing Mass Spectrometric Analysis. AB - Generation of analyte ions in gas phase is a primary requirement for mass spectrometric analysis. One of the ionization techniques that can be used to generate gas phase ions is electrospray ionization (ESI). ESI is a soft ionization method that can be used to analyze analytes ranging from small organics to large biomolecules. Numerous ionization techniques derived from ESI have been reported in the past two decades. These ion sources are aimed to achieve simplicity and ease of operation. Many of these ionization methods allow the flexibility for elimination or minimization of sample preparation steps prior to mass spectrometric analysis. Such ion sources have opened up new possibilities for taking scientific challenges, which might be limited by the conventional ESI technique. Thus, the number of ESI variants continues to increase. This review provides an overview of ionization techniques based on the use of electrospray reported in recent years. Also, a brief discussion on the instrumentation, underlying processes, and selected applications is also presented. PMID- 28573084 TI - Desorption Flame-Induced Atmospheric Pressure Chemical Ionization Mass Spectrometry for Rapid Real-World Sample Analysis. AB - Flame-induced atmospheric pressure chemical ionization (FAPCI) is a solvent and high voltage-free APCI technique. It uses a flame to produce charged species that reacts with analytes for ionization, and generates intact molecular ions from organic compounds with minimal fragmentation. In this study, desorption FAPCI/MS was developed to rapidly characterize thermally stable organic compounds in liquid, cream, and solid states. Liquid samples were introduced into the ion source through a heated nebulizer, and the analytes formed in the heated nebulizer reacted with charged species in the source. For cream and solid sample analysis, the samples were positioned near the flame of the FAPCI source for thermal desorption and ionization. This approach provided a useful method to directly characterize samples with minimal pretreatment. Standards and real-world samples, such as drug tablets, ointment, and toy were analyzed to demonstrate the capability of desorption FAPCI/MS for rapid organic compound analysis. PMID- 28573083 TI - Exposure Marker Discovery of Phthalates Using Mass Spectrometry. AB - Phthalates are chemicals widely used in industry and the consequences on human health caused by exposure to these agents are of significant interest currently. The urinary metabolites of phthalates can be measured and used as exposure markers for the assessment of the actual internal contamination of phthalates coming from different sources and absorbed by various ways. The purpose of this paper is to review the markers for exposure and risk assessment of phthalates such as di-methyl phthalate (DMP), di-ethyl phthalate (DEP), di-butyl phthalate (DBP), benzylbutyl phthalate (BBP), di-(2-ethylhexyl)phthalate (DEHP), di-(2 propylheptyl)phthalate (DPHP), di-iso-nonyl phthalate (DINP), di-n-octyl phthalate (DnOP) and di-iso-decyl phthalate (DIDP), and introduction of the analytical approach of three metabolomics data processing approaches that can be used for chemical exposure marker discovery in urine with high-resolution mass spectrometry (HRMS) data. PMID- 28573085 TI - Development and validation of the Pachinko/Pachi-Slot Playing Ambivalence Scale. AB - BACKGROUND: A scale aimed at measuring ambivalence among people with pachinko/pachi-slot playing disorder, the Pachinko/Pachi-Slot Playing Ambivalence Scale (PPAS), was developed and its reliability and validity ascertained. METHODS: A total of 522 participants (average year: 48.0) who were residing in Tokyo Metropolitan Area, and had played pachinko within the previous year completed questions relating to demographics, four gambling-related scales (including South Oaks Gambling Screen) and two general ambivalence scales (including Ambivalence over Emotional Expressiveness Questionnaire). RESULTS: Internal consistency (alpha = 0.87) and test-retest reliability (r = 0.66) were confirmed. The PPAS's score was associated with each related scale's score (r = 0.37-0.62). CONCLUSIONS: The PPAS was shown to be consistent with previous scales and useful in clinical settings. PMID- 28573086 TI - FOOD TEXTURE DESCRIPTORS BASED ON FRACTAL AND LOCAL GRADIENT INFORMATION. AB - This work is motivated by the desire to use image analysis methods to identify and characterize images of food items to aid in dietary assessment. This paper introduces three texture descriptors for texture classification that can be used to classify images of food. Two are based on the multifractal analysis, namely, entropy-based categorization and fractal dimension estimation (EFD), and a Gabor based image decomposition and fractal dimension estimation (GFD). Our third texture descriptor is based on the spatial relationship of gradient orientations (GOSDM), by obtaining the occurrence rate of pairs of gradient orientations at different neighborhood scales. The proposed methods are evaluated in texture classification and food categorization tasks using the entire Brodatz database and a customized food dataset with a wide variety of textures. Results show that for food categorization our methods consistently outperform several widely used techniques for both texture and object categorization. PMID- 28573087 TI - Structural and nucleic acid binding properties of hepatitis delta virus small antigen. AB - AIM: To further characterize the structure and nucleic acid binding properties of the 195 amino acid small delta antigen, S-HDAg, a study was made of a truncated form of S-HDAg, comprising amino acids 61-195 (?60HDAg), thus lacking the domain considered necessary for dimerization and higher order multimerization. METHODS: Circular dichroism, and nuclear magnetic resonance experiments were used to assess the structure of ?60HDAg. Nucleic acid binding properties were investigated by gel retardation assays. RESULTS: Results showed that the truncated ?60HDAg protein is intrinsically disordered but compact, whereas the RNA binding domain, comprising residues 94-146, adopts a dynamic helical conformation. We also found that ?60HDAg fails to multimerize but still contains nucleic acid binding activity, indicating that multimerization is not essential for nucleic acid binding. Moreover, in agreement with what has been previously reported for full-length protein, no apparent specificity was found for the truncated protein regarding nucleic acid binding. CONCLUSION: Taken together these results allowed concluding that ?60HDAg is intrinsically disordered but compact; ?60HDAg is not a multimer but is still capable of nucleic acid binding albeit without apparent specificity. PMID- 28573088 TI - Matrix metalloproteases and their tissue inhibitors in non-alcoholic liver fibrosis of human immunodeficiency virus-infected patients. AB - AIM: To investigate the relationships among diverse metalloproteases (MMPs) and their tissue inhibitors (TIMPs) and non-alcoholic liver fibrosis in human immunodeficiency virus (HIV)-infected patients. METHODS: Single nucleotide polymorphisms (SNPs) in MMPs, TNF-alpha and CCR5 genes, and serum levels of MMPs and TIMPs were determined in HIV-infected individuals with/out hepatitis C virus (HCV) coinfection. A total of 158 patients were included, 57 of whom were HCV coinfected. All patients drank < 50 g ethanol/day. Diverse SNPs (MMP-1 -1607 1G/2G, MMP-8 -799C/T, MMP-9 -1562 C/T, MMP-13 -77A/G, TNF-alpha -308 G/A, CCR5 ?32), and serum levels of MMPs (2, 3, 8, 9 and 10) and TIMPs (1, 2 and 4) were assessed. Liver fibrosis was determined by transient elastometry, although other non-invasive markers of fibrosis were also considered. Significant liver fibrosis (F >= 2) was defined by a transient elastometry value >= 7.1 kPa. RESULTS: A total of 34 patients (21.5%) had liver fibrosis >= F2. MMP-2 and TIMP-2 serum levels were higher in patients with liver fibrosis >= F2 (P = 0.02 and P = 0.03, respectively) and correlated positively with transient elastometry values (P = 0.02 and P = 0.0009, respectively), whereas MMP-9 values were negatively correlated with transient elastometry measurements (P = 0.01). Multivariate analyses showed that high levels of MMP-2 (OR = 2.397; 95%CI: 1.191-4.827, P = 0.014) were independently associated with liver fibrosis >= F2 in the patients as a whole. MMP-2 (OR = 7.179; 95%CI: 1.210-42.581, P = 0.03) and male gender (OR = 10.040; 95%CI: 1.621-62.11, P = 0.013) were also independent predictors of fibrosis >= F2 in the HCV-infected subgroup. Likewise, MMP-2, TIMP-2 and MMP-9 were independently associated with transient elastometry values and other non invasive markers of liver fibrosis. None of the six SNPs evaluated had any significant association with liver fibrosis >= F2. CONCLUSION: Certain MMPs and TIMPs, particularly MMP-2, seems to be associated with non-alcoholic liver fibrosis in HIV-infected patients with/without HCV coinfection. PMID- 28573089 TI - Pakistan needs to speed up its human immunodeficiency virus control strategy to achieve targets in fast-track acquired immune deficiency syndrome response. AB - In last fifteen years remarkable success in the fight against human immunodeficiency virus (HIV) is achieved globally. The number of HIV infections has decreased and the number of people on antiretroviral therapy is increased. This all is possible by strong political commitments and heavy investments in the fight against HIV. Pakistan is among few Asian countries in which HIV cases are increasing year by year since 1990. There are 94000 cases of HIV in Pakistan and only 14000 are registered with government. The main source of HIV infection in Pakistan is the use of contaminated injection equipment among people who inject drugs (PWID). The overall prevalence of HIV among PWID in Pakistan is 27.2%. There are five cities in Pakistan in which HIV prevalence is above 40% in PWIDs. In June 2016, United Nations political declaration on acquired immune deficiency syndrome (AIDS) provided a global mandate to fast-track the AIDS response over the next five years to achieve the targets in Sustainable Development Goals. To achieve the targets in fast-track AIDS response, the global leaders showed strong commitments to invest $ 26 billion per year by 2020. Pakistan needs to speed up its HIV control program. There is a dire need to locate all HIV positive people and enroll them in the treatment program. Pakistan also needs to calculate exact number of people living with HIV, increase HIV treatment centers and increase HIV awareness. Recently, Global Fund invested handsome money in the fight against HIV. Let's hope the country will have effective HIV control strategy to achieve the HIV elimination target by 2030. PMID- 28573090 TI - Peer Review Processes and Desirable Attitudes for Peer Reviewers. PMID- 28573091 TI - Virtual Reality and Augmented Reality in Plastic Surgery: A Review. AB - Recently, virtual reality (VR) and augmented reality (AR) have received increasing attention, with the development of VR/AR devices such as head-mounted displays, haptic devices, and AR glasses. Medicine is considered to be one of the most effective applications of VR/AR. In this article, we describe a systematic literature review conducted to investigate the state-of-the-art VR/AR technology relevant to plastic surgery. The 35 studies that were ultimately selected were categorized into 3 representative topics: VR/AR-based preoperative planning, navigation, and training. In addition, future trends of VR/AR technology associated with plastic surgery and related fields are discussed. PMID- 28573093 TI - Hydrogel and Platelet-Rich Plasma Combined Treatment to Accelerate Wound Healing in a Nude Mouse Model. AB - BACKGROUND: Platelet-rich plasma (PRP) contains high concentrations of growth factors involved in wound healing. Hydrogel is a 3-dimensional, hydrophilic, high molecular, reticular substance generally used as a dressing formulation to accelerate wound healing, and also used as a bio-applicable scaffold or vehicle. This study aimed to investigate the effects of PRP and hydrogel on wound healing, in combination and separately, in an animal wound model. METHODS: A total of 64 wounds, with 2 wounds on the back of each nude mouse, were classified into 4 groups: a control group, a hydrogel-only group, a PRP-only group, and a combined treatment group. All mice were assessed for changes in wound size and photographed on scheduled dates. The number of blood vessels was measured in all specimens. Immunohistochemical staining was used for the analysis of vascular endothelial growth factor (VEGF) expression. RESULTS: Differences in the decrease and change in wound size in the combined-treatment group were more significant than those in the single-treatment groups on days 3, 5, 7, and 10. Analysis of the number of blood vessels through histological examination showed a pattern of increase over time that occurred in all groups, but the combined-treatment group exhibited the greatest increase on days 7 and 14. Immunohistochemical staining showed that VEGF expression in the combined-treatment group exhibited its highest value on day 7. CONCLUSIONS: This experiment demonstrated improved wound healing using a PRP-hydrogel combined treatment compared to either treatment individually, resulting in a decrease in wound size and a shortening of the healing period. PMID- 28573092 TI - Current Methods for the Treatment of Alveolar Cleft. AB - Alveolar cleft is a tornado-shaped bone defect in the maxillary arch. The treatment goals for alveolar cleft are stabilization and provision of bone continuity to the maxillary arch, permitting support for tooth eruption, eliminating oronasal fistulas, providing an improved esthetic result, and improving speech. Treatment protocols vary in terms of the operative time, surgical techniques, and graft materials. Early approaches including boneless bone grafting (gingivoperiosteoplasty) and primary bone graft fell into disfavor because they impaired facial growth, and they remain controversial. Secondary bone graft (SBG) is not the most perfect method, but long-term follow-up has shown that the graft is absorbed to a lesser extent, does not impede facial growth, and supports other teeth. Accordingly, SBG in the mixed dentition phase (6-11 years) has become the preferred method of treatment. The most commonly used graft material is cancellous bone from the iliac crest. Recently, many researchers have investigated the use of allogeneic bone, artificial bone, and recombinant human bone morphogenetic protein, along with growth factors because of their ability to decrease donor-site morbidity. Further investigations of bone substitutes and additives will continue to be needed to increase their effectiveness and to reduce complications. PMID- 28573094 TI - Long-Term Follow-Up Study of Young Adults Treated for Unilateral Complete Cleft Lip, Alveolus, and Palate by a Treatment Protocol Including Two-Stage Palatoplasty: Speech Outcomes. AB - BACKGROUND: No consensus exists on the optimal treatment protocol for orofacial clefts or the optimal timing of cleft palate closure. This study investigated factors influencing speech outcomes after two-stage palate repair in adults with a non-syndromal complete unilateral cleft lip and palate (UCLP). METHODS: This was a retrospective analysis of adult patients with a UCLP who underwent two stage palate closure and were treated at our tertiary cleft centre. Patients >=17 years of age were invited for a final speech assessment. Their medical history was obtained from their medical files, and speech outcomes were assessed by a speech pathologist during the follow-up consultation. RESULTS: Forty-eight patients were included in the analysis, with a mean age of 21 years (standard deviation, 3.4 years). Their mean age at the time of hard and soft palate closure was 3 years and 8.0 months, respectively. In 40% of the patients, a pharyngoplasty was performed. On a 5-point intelligibility scale, 84.4% received a score of 1 or 2; meaning that their speech was intelligible. We observed a significant correlation between intelligibility scores and the incidence of articulation errors (P<0.001). In total, 36% showed mild to moderate hypernasality during the speech assessment, and 11%-17% of the patients exhibited increased nasalance scores, assessed through nasometry. CONCLUSIONS: The present study describes long-term speech outcomes after two-stage palatoplasty with hard palate closure at a mean age of 3 years old. We observed moderate long-term intelligibility scores, a relatively high incidence of persistent hypernasality, and a high pharyngoplasty incidence. PMID- 28573095 TI - Correction of Minor-Form and Microform Cleft Lip Using Modified Muscle Overlapping with a Minimal Skin Incision. AB - BACKGROUND: In treating minor-form or microform cleft lip, obtaining an optimal result is a challenge because of the visible scarring caused by traditional surgery. We present a refined method using muscle overlapping with a minimal skin incision in patients younger than 3 years, a group characterized by thin muscle. METHODS: The surgical technique involves restoration of the notched vermillion using Z-plasty, formation of the philtral column using overlapping of an orbicularis oris muscle flap through an intraoral incision, and correction of the cleft lip nasal deformity using a reverse-U incision and V-Y plasty. A single radiologist evaluated ultrasonographic images of the upper lip. RESULTS: Sixty patients were treated between September 2008 and June 2014. The age at the time of operation ranged from 6 to 36 months (mean, 26 months). The follow-up period ranged from 8 to 38 months (mean, 20 months) in minor-form cases and from 14 to 64 months (mean, 37 months) in microform cases. A notched cupid's bow was corrected in 10 minor-form cases and 50 microform cases. Ultrasonographic images were obtained from 3 patients with minor-form cleft lip and 9 patients with microform cleft lip 12 months after surgery. The average muscle thickness was 4.5 mm on the affected side and 4.1 mm on the unaffected side. CONCLUSIONS: The advantages of the proposed procedure include the creation of an anatomically natural philtrum with minimal scarring. This method also preserves the continuity and function of the muscle and provides sufficient augmentation of the philtral column and nostril sill. PMID- 28573097 TI - Validation of a Cognitive Task Simulation and Rehearsal Tool for Open Carpal Tunnel Release. AB - BACKGROUND: Carpal tunnel release is one of the most common surgical procedures performed by hand surgeons. The authors created a surgical simulation of open carpal tunnel release utilizing a mobile and rehearsal platform app. This study was performed in order to validate the simulator as an effective training platform for carpal tunnel release. METHODS: The simulator was evaluated using a number of metrics: construct validity (the ability to identify variability in skill levels), face validity (the perceived ability of the simulator to teach the intended material), content validity (that the simulator was an accurate representation of the intended operation), and acceptability validity (willingness of the desired user group to adopt this method of training). Novices and experts were recruited. Each group was tested, and all participants were assigned an objective score, which served as construct validation. A Likert-scale questionnaire was administered to gauge face, content, and acceptability validity. RESULTS: Twenty novices and 10 experts were recruited for this study. The objective performance scores from the expert group were significantly higher than those of the novice group, with surgeons scoring a median of 74% and medical students scoring a median of 45%. The questionnaire responses indicated face, content, and acceptability validation. CONCLUSIONS: This mobile-based surgical simulation platform provides step-by-step instruction for a variety of surgical procedures. The findings of this study help to demonstrate its utility as a learning tool, as we confirmed construct, face, content, and acceptability validity for carpal tunnel release. This easy-to-use educational tool may help bring surgical education to a new-and highly mobile-level. PMID- 28573096 TI - Mucoperiosteal Flap Necrosis after Primary Palatoplasty in Patients with Cleft Palate. AB - BACKGROUND: The prevalence of flap necrosis after palatoplasty in patients with cleft palate. The prevalence of mucoperiosteal flap necrosis after palatoplasty remains unknown, and this complication is rare. This event is highly undesirable for both the patient and the surgeon. We present here a new scale to evaluate the degree of hypoplasia of the palate and identify patients with cleft palate at high risk for the development of this complication. METHODS: In this case series, a 20-year retrospective analysis (1994-2014) identified patients from our records (medical records and screening day registries) with nonsyndromic cleft palate who underwent operations at 3 centers. All of these patients underwent operations using 2-flap palatoplasty and also underwent a physical examination with photographs and documentation of the presence of palatal flap necrosis after primary palatoplasty. RESULTS: Palatal flap necrosis was observed in 4 cases out of 1,174 palatoplasties performed at these centers. The observed prevalence of palatal flap necrosis in these groups was 0.34%. CONCLUSIONS: The prevalence of flap necrosis can be reduced by careful preoperative planning, and prevention is possible. The scale proposed here may help to prevent this complication; however, further studies are necessary to validate its utility. PMID- 28573098 TI - Axillary Reconstruction for Hidradenitis Suppurativa with an Inner-Arm Transposition Flap Creating a Brachioplasty Effect. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic skin condition that can affect any area with apocrine sweat glands and has the potential to involve multiple sites concurrently. Commonly affected sites include the axilla, groin, perineum and perianal areas. In this study we performed a literature review on the surgical methods for HS and describe an innovative technique for reconstructing axilla HS using an inner-arm transposition flap. METHODS: We reviewed all cases (5 cases from 4 patients) of transposition flap reconstruction performed by the senior author at a single London tertiary hospital from 2008 2013. Patient related outcome measures were collected using the Derriford appearance scale (DAS 24) and a study specific questionnaire. RESULTS: All patients were satisfied with their final result. One out of five cases had a complication but did not result in flap failure. There is no disease recurrence to date. DAS 24 scores collected demonstrated acceptable postoperative distress that did not deviate far from the norm tables while study specific questionnaire reveal desirable outcomes. CONCLUSIONS: We have managed to achieve our aim through the use of the innovative inner-arm transposition flap. Our study hopes to provide an additional technique for axillary reconstruction. This technique offers the effective concealment of scars with the benefit of tightening of the arm tissue producing 'brachioplasty like' effects. All things considered it would be reasonable to conclude the innovative flap technique is a reliable, effective, and simple method that results in multiple benefits. PMID- 28573099 TI - Acellular Dermal Matrices and Paraffinoma: A Modern Tool for a Nearly Obsolete Disease. AB - Paraffinoma is a destructive complication of paraffin oil injection, usually associated with massive tissue destruction, thus requiring radical surgery and subsequent complex reconstruction. Although breast and penile paraffinomas have been widely described and their management is quite standardized, paraffinomas of the knee are still rare and only few case reports or small case series are available in the current literature. We describe the case of a 77-year-old man with a large paraffinoma of the right knee that occurred after self-injection of paraffin oil, 58 years before. He underwent wide surgical resection of the soft tissues overlying the knee and subsequent two-stage reconstruction by using acellular dermal matrix and, after 20 days, split-thickness skin grafts. Follow up after 16 months showed no signs of skin ulcerations or inflammation, with an overall improvement in function. Even though conventional flap reconstructions may be still useful, the authors believe that acellular dermal matrices represent a safe, reliable, and less invasive alternative for challenging soft tissue reconstructions even in elderly patients with multiple medical problems. PMID- 28573100 TI - Vascular Augmentation in Renal Transplantation: Supercharging and Turbocharging. AB - The most common anatomic variant seen in donor kidneys for renal transplantation is the presence of multiple renal arteries, which can cause an increased risk of complications. Accessory renal arteries should be anastomosed to the proper source arteries to improve renal perfusion via the appropriate vascular reconstruction techniques. In microsurgery, 2 kinds of vascular augmentation methods, known as 'supercharging' and 'turbocharging,' have been introduced to ensure vascular perfusion in the transferred flap. Supercharging uses a distant source of the vessels, while turbocharging uses vascular sources within the same flap territory. These technical concepts can also be applied in renal transplantation, and in this report, we describe 2 patients who underwent procedures using supercharging and turbocharging. In one case, the ipsilateral deep inferior epigastric artery was transposed to the accessory renal artery (supercharging), and in the other case, the accessory renal artery was anastomosed to the corresponding main renal artery with a vascular graft (turbocharging). The transplanted kidneys showed good perfusion and proper function. No cases of renal failure, hypertension, rejection, or urologic complications were observed. These microsurgical techniques can be safely utilized for renal transplantation with donor kidneys that have multiple arteries with a lower complication rate and better outcome. PMID- 28573101 TI - Using a Thermal Imaging Camera to Locate Perforators on the Lower Limb. AB - Reconstruction of the lower limb presents a complex problem after skin cancer surgery, as proximity of skin and bone present vascular and technical challenges. Studies on vascular anatomy have confirmed that the vascular plane on the lower limb lies deep to the deep fascia. Yet, many flaps are routinely raised superficial to this plane and therefore flap failure rates in the lower limb are high. Fascio-cutaneous flaps based on perforators offer a better cosmetic alternative to skin grafts. In this paper, we detail use of a thermal imaging camera to identify perforator 'compartments' that can help in designing such flaps. PMID- 28573102 TI - Late-Onset Methicillin-Resistant Staphylococcus aureus Infection after Facial Poly-L-Lactic Acid Injection. PMID- 28573103 TI - Spontaneous Pseudoaneurysm of the Proximal Occipital Artery Presenting as a Neck Mass. PMID- 28573104 TI - Faces of the Face. PMID- 28573105 TI - Atypical Presentation: Metastatic Uveal Melanoma in a Young Patient without Visual Complaints. AB - BACKGROUND: Uveal melanoma is a rare and aggressive subtype of melanoma, with singular characteristics that separate it from the most famous cutaneous melanoma. This uncommon condition becomes even rarer if we look at young population. Common chemotherapy regimens does not work with this aggressive disease in its metastatic scenario, and the new armament like targeted and immunotherapies are still looking for more robust evidence. CASE PRESENTATION: We report a rare case of uveal melanoma in a patient younger than 20 years, with abdominal pain as his initial complaint. He did not present the typical visual symptoms of the primary site because of an auto accident suffered 4 months before the presentation, letting him blind of the eye affected by the tumor development. CONCLUSION: There is always a possibility of the diagnosis of uveal melanoma in cases with associated isolated hepatic metastases, even in a young population, where this hypothesis is often rejected by the epidemiological frequency of other tumors. This rare case is a useful example. PMID- 28573106 TI - No Functional Role for microRNA-342 in a Mouse Model of Pancreatic Acinar Carcinoma. AB - The intronic microRNA (miR)-342 has been proposed as a potent tumor-suppressor gene. miR-342 is found to be downregulated or epigenetically silenced in multiple different tumor sites, and this loss of expression permits the upregulation of several key oncogenic pathways. In several different cell lines, lower miR-342 expression results in enhanced proliferation and metastasis potential, both in vitro and in xenogenic transplant conditions. Here, we sought to determine the function of miR-342 in an in vivo spontaneous cancer model, using the Ela1-TAg transgenic model of pancreatic acinar carcinoma. Through longitudinal magnetic resonance imaging monitoring of Ela1-TAg transgenic mice, either wild-type or knockout for miR-342, we found no role for miR-342 in the development, growth rate, or pathogenicity of pancreatic acinar carcinoma. These results indicate the importance of assessing miR function in the complex physiology of in vivo model systems and indicate that further functional testing of miR-342 is required before concluding it is a bona fide tumor-suppressor-miR. PMID- 28573108 TI - Spreading of Pandemic Vibrio parahaemolyticus O3:K6 and Its Serovariants: A Re analysis of Strains Isolated from Multiple Studies. AB - In China, V. parahaemolyticus has been a leading cause of foodborne outbreaks and bacterial infectious diarrhea since the 1990s, and most infections have been associated with the pandemic V. parahaemolyticus O3:K6 and its serovariants. However, a comprehensive overview of the sero-prevalence and genetic diversity of the pandemic V. parahaemolyticus clone in China is lacking. To compensate for this deficiency, pandemic isolates in both clinical and environmental Chinese samples collected from multiple studies were analyzed in this study. Surprisingly, as many as 27 clinical pandemic serovariants were identified and were widely distributed across nine coastal provinces and two inland provinces (Beijing and Sichuan). O3:K6, O4:K68, and O1:KUT represented the predominant clinical serovars. Only four environmental pandemic serovariants had previously been reported, and they were spread throughout Shanghai (O1:KUT, O3:K6), Jiangsu (O3:K6, O4:K48), Zhejiang (O3:K6), and Guangdong (O4:K9). Notably, 24 pandemic serovariants were detected within a short time frame (from 2006 to 2012). The pandemic isolates were divided into 15 sequence types (STs), 10 of which fell within clonal complex (CC) 3. Only three STs (ST3, ST192, and ST305) were identified in environmental isolates. Substantial serotypic diversity was mainly observed among isolates within pandemic ST3, which comprised 21 combinations of O/K antigens. The pandemic O3:K6 serotype showed a high level of sequence diversity, which was shared by eight different STs (ST3, ST227, ST431, ST435, ST487, ST489, ST526, and ST672). Antimicrobial susceptibility testing revealed that most isolates shared similar antibiotic susceptibility profiles. They were resistant to ampicillin but sensitive to most other drugs that were tested. In conclusion, the high levels of serotypic and genetic diversity of the pandemic clone suggest that the involved regions are becoming important reservoirs for the emergence of novel pandemic strains. We underscore the need for routine monitoring to prevent pandemic V. parahaemolyticus infection, which includes monitoring antimicrobial responses to avoid excessive misuse of antibiotics. Further investigations are also needed to delineate the specific mechanisms underlying the possible seroconversion of pandemic isolates. PMID- 28573107 TI - RegA Plays a Key Role in Oxygen-Dependent Establishment of Persistence and in Isocitrate Lyase Activity, a Critical Determinant of In vivo Brucella suis Pathogenicity. AB - For aerobic human pathogens, adaptation to hypoxia is a critical factor for the establishment of persistent infections, as oxygen availability is low inside the host. The two-component system RegB/A of Brucella suis plays a central role in the control of respiratory systems adapted to oxygen deficiency, and in persistence in vivo. Using an original "in vitro model of persistence" consisting in gradual oxygen depletion, we compared transcriptomes and proteomes of wild type and DeltaregA strains to identify the RegA-regulon potentially involved in the set-up of persistence. Consecutive to oxygen consumption resulting in growth arrest, 12% of the genes in B. suis were potentially controlled directly or indirectly by RegA, among which numerous transcriptional regulators were up regulated. In contrast, genes or proteins involved in envelope biogenesis and in cellular division were repressed, suggesting a possible role for RegA in the set up of a non-proliferative persistence state. Importantly, the greatest number of the RegA-repressed genes and proteins, including aceA encoding the functional IsoCitrate Lyase (ICL), were involved in energy production. A potential consequence of this RegA impact may be the slowing-down of the central metabolism as B. suis progressively enters into persistence. Moreover, ICL is an essential determinant of pathogenesis and long-term interactions with the host, as demonstrated by the strict dependence of B. suis on ICL activity for multiplication and persistence during in vivo infection. RegA regulates gene or protein expression of all functional groups, which is why RegA is a key regulator of B. suis in adaptation to oxygen depletion. This function may contribute to the constraint of bacterial growth, typical of chronic infection. Oxygen-dependent activation of two-component systems that control persistence regulons, shared by several aerobic human pathogens, has not been studied in Brucella sp. before. This work therefore contributes significantly to the unraveling of persistence mechanisms in this important zoonotic pathogen. PMID- 28573111 TI - Minimally invasive autopsies: a promise to revive the procedure. PMID- 28573109 TI - Persistence of Innate Immune Pathways in Late Stage Human Bacterial and Fungal Keratitis: Results from a Comparative Transcriptome Analysis. AB - Microbial keratitis (MK) is a major cause of blindness worldwide. Despite adequate antimicrobial treatment, tissue damage can ensue. We compared the human corneal transcriptional profile in late stage MK to normal corneal tissue to identify pathways involved in pathogenesis. Total RNA from MK tissue and normal cadaver corneas was used to determine transcriptome profiles with Illumina HumanHT-12 v4 beadchips. We performed differential expression and network analysis of genes in bacterial keratitis (BK) and fungal keratitis (FK) compared with control (C) samples. Results were validated by RTqPCR for 45 genes in an independent series of 183 MK patients. For the microarray transcriptome analysis, 27 samples were used: 12 controls, 7 BK culture positive for Streptococcus pneumoniae (n = 6), Pseudomonas aeruginosa (n = 1), and 8 FK, culture positive for Fusarium sp. (n = 5), Aspergillus sp. (n = 2), or Lasiodiplodia sp. (n = 1). There were 185 unique differentially expressed genes in BK, 50 in FK, and 339 common to both [i.e., genes with fold-change (FC) < -4 or >=4 and false discovery rate (FDR) adjusted P < 0.05]. MMP9 had the highest FC in BK (91 FC, adj p = 3.64 E-12) and FK (FC 64, adj. p = 6.10 E-11), along with other MMPs (MMP1, MMP7, MMP10, MMP12), pro-inflammatory cytokines (IL1B, TNF), and PRRs (TLR2, TLR4). HIF1A and its induced genes were upregulated uniquely in BK. Immune/defense response and extracellular matrix terms were the most enriched Gene Ontology terms in both BK and FK. In the network analysis, chemokines were prominent for FK, and actin filament reorganization for BK. Microarray and RTqPCR results were highly correlated for the same samples tested with both assays, and with the larger RTqPCR series. In conclusion, we found a great deal of overlap in the gene expression profile of late stage BK and FK, however genes unique to fungal infection highlighted a corneal epithelial wound healing response and for bacterial infection the prominence of HIF1A-induced genes. These sets of genes may provide new targets for future research into therapeutic agents. PMID- 28573112 TI - Sister Mary Joseph nodule: it does not bode well. PMID- 28573113 TI - The post-mortem diagnosis of vasocclusive crisis in sickle cell disease. PMID- 28573110 TI - Nocardia cyriacigeogica from Bovine Mastitis Induced In vitro Apoptosis of Bovine Mammary Epithelial Cells via Activation of Mitochondrial-Caspase Pathway. AB - Nocardia is one of the causing agents of bovine mastitis and increasing prevalence of nocardial mastitis in shape of serious outbreaks has been reported from many countries. However, the mechanisms by which this pathogen damages the bovine mammary epithelial cells (bMECs) is not yet studied. Therefore, this study was designed with the aim to evaluate the apoptotic effects elicited by Nocardia and to investigate the pathway by which the Nocardia induce apoptosis in bMECs. Clinical Nocardia cyriacigeorgica strain from bovine mastitis was used to infect the bMECs for different time intervals, viz. 1, 3, 6, 12, and 18 h, and then the induced effects on bMECs were studied using adhesion and invasion assays, release of lactate dehydrogenase (LDH), apoptosis analysis by annexin V and propidium iodide (PI) double staining, morphological, and ultrastructural observations under scanning electron microscope (SEM) and transmission electron microscope (TEM), mitochondrial transmembrane potential (DeltaPsim) assay using flow cytometry, and the protein quantification of mitochondrial cytochrome c and caspase-9 and caspase-3 by western blotting. The results of this study showed that N. cyriacigeorgica possessed the abilities of adhesion and invasion to bMECs. N. cyriacigeorgica was found to collapse mitochondrial transmembrane potential, significantly (p < 0.05) release mitochondrial cytochrome c and ultimately induce cell apoptosis. Additionally, it promoted casepase-9 (p < 0.01) and casepase-3 (p < 0.05) levels, significantly (p < 0.01) increased the release of LDH and promoted DNA fragmentation which further confirmed the apoptosis. Furthermore, N. cyriacigeorgica induced apoptosis/necrosis manifested specific ultrastructure features under TEM, such as swollen endoplasmic reticulum, cristae degeneration, and swelling of mitochondria, vesicle formation on the cell surface, rupturing of cell membrane and nuclear membrane, clumping, fragmentation, and margination of chromatin. The present study is the first comprehensive insight into patho-morphological ultrastructural features of apoptosis/necrosis induced by N. cyriacigeorgica, which concluded that the clinical N. cyriacigeorgica induced apoptotic changes in the bMECs through mitochondrial-caspase dependent apoptotic pathway. PMID- 28573114 TI - Otomastoiditis caused by Sphingomonas paucimobilis: case report and literature review. AB - Sphingomonas paucimobilis is an aerobic Gram-negative bacillus that, although rare in humans, most commonly infects immunocompromised and hospitalized patients. Among the 59 pediatric cases of S. paucimobilis infection reported in the literature, the most common diagnosis involves isolated bacteremia. These cases are related to sporadic or epidemic infections. Death related to this infection occurred in only one case. The authors report a case of an 11-year-old boy with the diagnosis of Sphingomonas paucimobilis otomastoiditis and a thorough review of the literature on this infection in pediatrics. The patient presented a 20-day history of fever, otalgia, otorrhea, and progressive retroauricular swelling with protrusion of the left ear; despite 15 days of amoxicillin regimen. His past medical history included chronic bilateral otitis media, but no cause of immunosuppression was found. A brain computed tomography scan showed left otomastoiditis associated with a large circumscribed fluid collection with deep involvement of the soft tissues of the temporal region, including the subperiosteal space. Blood tests showed neutrophilia and elevated C-reactive protein. Surgical manipulation of the cited collection drained a large amount of a fetid purulent secretion. Ceftazidime and clindamycin were empirically initiated. The outcome was favorable, with fever defervescence and resolution of the scalp deformation. Culture of the drained secretion was positive for S. paucimobilis. Ciprofloxacin was scheduled for a further 10 days after discharge. The follow-up showed complete recovery. As far as we know, this is the first case of S. paucimobilis otomastoiditis, complicated with subperiosteal abscess in an immunocompetent child. The authors call attention to the increasing number of reports on S. paucimobilis infection over the years, and therefore to the importance of this pathogen, which was previously underestimated. PMID- 28573115 TI - Classic form of hypoplastic left heart syndrome diagnosed post-natally: an autopsy report. AB - Hypoplastic left heart syndrome (HLHS) is a congenital heart disease, which, despite the current improved knowledge about its management and surgical treatment, is still associated with high mortality, especially in the early neonatal period and before the second stage of reconstruction surgery. The low rate of prenatal diagnosis and delayed diagnostic suspicion results in unsuccessful therapeutic intervention, even though the real impact of early diagnosis and intervention on mortality and quality of life of patients is still uncertain. Fortunately, this syndrome of challenging treatment is not that frequent. It involves a spectrum of obstructions to the blood flow within the left heart and is characterized by an inappropriate size of the left ventricle associated with a wide variety of valvular dysfunctions. Treatment ranges from heart transplantation to palliative surgical procedures. The authors describe a case of a newborn with HLHS, whose diagnosis was made after birth because of early respiratory failure. Despite the use of prostaglandin the newborn died. An autopsy was performed and the anatomical findings were described. PMID- 28573116 TI - Community-acquired Pseudomonas aeruginosa-pneumonia in a previously healthy man occupationally exposed to metalworking fluids. AB - Although the Pseudomonas aeruginosa infection is well known and frequently found in hospitals and nursing care facilities, many cases are also reported outside these boundaries. In general, this pathogen infects debilitated patients either by comorbidities or by any form of immunodeficiency. In cases of respiratory infection, tobacco abuse seems to play an important role as a risk factor. In previously healthy patients, community-acquired pneumonia (CAP) with P. aeruginosa as the etiological agent is extremely rare, and unlike the cases involving immunocompromised or hospitalized patients, the outcome is severe, and is fatal in up to 61.1% of cases. Aerosolized contaminated water or solutions are closely linked to the development of respiratory tract infection. In this setting, metalworking fluids used in factories may be implicated in CAP involving previously healthy people. The authors report the case of a middle-aged man who worked in a metalworking factory and presented a right upper lobar pneumonia with a rapid fatal outcome. P. aeruginosa was cultured from blood and tracheal aspirates. The autopsy findings confirmed a hemorrhagic necrotizing pneumonia with bacteria-invading vasculitis and thrombosis. A culture of the metalworking fluid of the factory was also positive for P. aeruginosa. The pulsed-field gel electrophoresis showed that both strains (blood culture and metalworking fluid) were genetically indistinguishable. The authors highlight the occupational risk for the development of this P.aeruginosa-infection in healthy people. PMID- 28573118 TI - Advanced small-cell ovarian carcinoma, hypercalcemic type: a challenging therapeutic entity. AB - Small-cell ovarian carcinoma (SCOC) is a rare and aggressive neoplasia, predominantly affecting young women who are frequently first diagnosed with advanced stage disease. Platinum-based chemotherapy (ChT) can provide high response rates and rapidly ameliorate symptoms in this scenario. However, progression after chemotherapy usually occurs quickly, leading to high mortality rates. In addition, ChT complications, such as tumor lysis syndrome (TLS) can also occur, jeopardizing the patient's outcome. We present a case of metastatic SCOC in a 47-year-old patient who achieved tumor response after platinum-based chemotherapy and developed TLS, from which she recovered with supportive treatment. After the second ChT cycle, she developed febrile neutropenia and died 8 weeks after the diagnosis of SCOC. Although SCOC is a chemo-sensitive tumor, short-lived responses and frequent chemotherapy complications lead to a dismal prognosis. PMID- 28573117 TI - Septic pelvic thrombophlebitis of unknown origin: an ever threatening entity. AB - Septic pelvic thrombophlebitis (SPT) is a rare and severe entity, which may occur after abortion, delivery, gynecological diseases, or surgeries. Diagnosis is challenging when no risk factor is clearly present, since clinically, symptoms are non-specific. Nowadays, with the aid of imaging methods, diagnosis has become more achievable, but the treatment still bears some uncertainties. The authors present a fatal case of SPT in a young woman who sought medical care already presenting signs of septic shock, referring fever and non-characteristic abdominal pain. The patient evolved rapidly to multiple organ failure and respiratory distress, which was also due to septic pulmonary embolism. The autopsy confirmed the computed tomographic findings of a right ovarian vein septic thrombophlebitis and multiple septic pulmonary embolization foci. The patient did not present any of the recognized risk factors; neither did she present signs of pelvic inflammatory disease on admission or at autopsy. However, an intrauterine device was present. The authors call attention to this entity in the differential diagnosis of a woman with fever and abdominal pain, as well as for an empiric broad-spectrum antibiotic regimen in these cases. PMID- 28573119 TI - Cardiac angiosarcoma: an unexpected diagnosis. AB - Cardiac angiosarcoma is a rare entity. The incidence through autopsy findings ranges between 0.001% and 0.03%. The disease usually presents with non-specific symptoms, although asymptomatic cases are frequent; therefore, diagnosis is unexpected and consequently delayed. The authors report the case of a middle-aged man with a recent onset cough and dyspnea. He sought medical care several times without receiving a definite diagnosis until a plain chest radiography was taken showing a mediastinal enlargement, which was the reason why he was hospitalized for clinical investigation. During the diagnostic workup, an echodopplercardiogram and a thoracic computed tomography were performed, showing a heterogeneous soft-tissue mass infiltrating the pericardium and the anterior atrial wall. Multiple and scattered pulmonary nodules were also present. A pulmonary nodule was biopsied, which revealed an angiosarcoma. The clinical features added to the radiological and histological findings permitted the diagnosis of right atrial angiosarcoma. The authors highlight the unexpected pattern in the presentation of cardiac tumors. PMID- 28573120 TI - Microperforated hymen: a case of delayed diagnosis. AB - Although the incidence of microperforated hymen (MH) is unclear, this hymenal subocclusive anomaly is considered a rare entity. Differently from imperforated hymen, MH may be asymptomatic until puberty when the women's quality of life is jeopardized. Depending on the size of the microperforation, MH's clinical features me be very similar to those found in imperforated hymen cases. However, MH may present infectious complications since the accumulated secretion retained in the vaginal canal has contact with the external environment and therefore represents a source of entry for infectious agents. The authors report a case of a 28-year-old woman who sought the gynecologist complaining of inability to have vaginal intercourse. She referred normal menses, but in fact, although regular, bleeding was filiform and was exteriorized only through the right side of the vagina. Physical examination and imaging disclosed a microperforation of the hymenal membrane at 10 o'clock position. Hymenotomy under general anesthesia was undertaken. Outcome was favorable and the patient could thenceforth have a normal life. We conclude that this anomaly may be overlooked, interfering on its incidence determination. The delayed onset of symptoms and psychological embarrassing aspects, which postpone gynecological consultation, may contribute for misdiagnoses. We call attention to a mandatory detailed anamnesis and thorough physical examination to diagnose this anomaly before the puberty, when complications are less frequent and treatment is advisable. PMID- 28573122 TI - Paediatric pathology: a work in progress. PMID- 28573123 TI - Focal nodular hyperplasia of the liver. PMID- 28573121 TI - Rectal tuberculosis in an HIV-infected patient: case report. AB - The gastrointestinal (GI) tract has been increasingly affected by tuberculosis, especially in immunocompromised patients. Although strict rectal involvement is rare, the GI site mostly affected is the ileocecal region. Thus, tuberculosis should always be considered in the differential diagnosis of perianal and rectal lesions, and more so in patients infected by the HIV virus. The authors report the case of a 32-year-old man presenting a long-term history of fever, night sweats, weight loss, bloody diarrhea, fecal incontinence, tenesmus, and rectal pain. HIV serology was positive. The patient underwent anoscopy and biopsy, which disclosed the diagnosis of rectal tuberculosis. Thus the patient was referred to an outpatient clinic to follow the standard treatment. PMID- 28573124 TI - Cardiac amyloidosis: a challenging diagnosis. AB - Cardiovascular involvement of amyloidosis is present in 90% of cases, which is frequently associated with the primary form of the disease (AL amyloidosis). Clinical manifestations are represented by heart failure due to restrictive myocardiopathy and electrical impulse conduction abnormalities, which are clinically remarkable in up to 50% of the cases. The prognosis of patients with systemic amyloidosis is directly associated with the presence of cardiac involvement, such that survival does not usually exceed 4 months after the onset of heart failure signs and symptoms. The authors report a case of primary systemic amyloidosis, diagnosed only at autopsy, with severe cardiac involvement. PMID- 28573125 TI - Hemophagocytic lymphohistiocytosis associated with hepatosplenic T-cell lymphoma: case report. AB - Hepatosplenic T-cell lymphoma (HSTCL) is a rare non-Hodgkin lymphoma, marked by liver, spleen, and bone marrow sinusoidal infiltration, with an aggressive clinical course, which represents a difficult diagnostic task for clinicians and pathologists. Another equally severe and challenging condition is the hemophagocytic lymphohistiocytosis (also called hemophagocytic syndrome [HS]), which is often associated with hematologic malignancies and infectious diseases. The authors report the case of a 56-year-old woman diagnosed with HSTCL based on bone marrow aspirate flow cytometry and skin biopsy. The patient underwent a cycle of chemotherapy but the outcome was unfavorable with multiple organ failure. The laboratory analysis was consistent with HS. The autopsy confirmed both the remaining lymphoma in the pulmonary vessels and the hemophagocytic cells in the spleen and bone marrow. PMID- 28573126 TI - Nodal Epstein-Barr virus-positive T-cell/NK-cell lymphoma associated with immunodeficiency: a rare condition looking for recognition. AB - The authors describe a peculiar form of Epstein-Barr virus (EBV)-associated T cell lymphoma in an HIV-positive patient presenting an aggressive clinical course. Unlike most other EBV-positive T-cell/natural-killer (NK)-cell lymphomas, the disease was characterized by predominant nodal involvement at presentation. T cell lineage was confirmed by T-cell receptor-rearrangement, and neoplastic cells exhibited strong and diffuse CD56 expression. A marked intravascular component was detected in the skin, the liver, and the lung parenchyma. This entity was not predicted in the WHO 2008 classification, but has been recently identified in immunocompromised patients. This case report refers to a middle-aged man with AIDS, who presented a 4-month history of weight loss, fever, hepatosplenomegaly, peripheral and deep-chain lymphadenopathy. A blood smear showed lymphocytosis with a marked presence of atypia. The outcome was unfavorable and the patient could not be treated. The autopsy revealed multivisceral involvement, including lymph nodes, spleen, bone marrow, liver, lungs, skin, and kidneys. PMID- 28573127 TI - Prune-belly syndrome: an autopsy case report. AB - Prune-belly syndrome (PBS) is a rare congenital anomaly characterized by a spectrum of mild-to-severe presentations of urinary tract malformations, deficient abdominal wall musculature, and cryptorchidism in male newborns or genital abnormalities in the female newborns. Currently, antenatal diagnosis is feasible with ultrasound examination, and treatment is based on case report experience. More recently, intrauterine management has been undertaken with encouraging results. The authors report a case of PBS diagnosed at the seventeenth gestation week, when ultrasonographic examination revealed the presence of ascites, distended bladder, thickened bladder wall and posterior urethral valve. The fetus was submitted to an intrauterine intervention at the nineteenth gestational week. Delivery occurred at 34 weeks of gestation and the newborn examination was consistent with PBS. On the second day of life, the newborn was submitted to abdominoplasty, colostomy, and orchiopexy. However, the outcome was unfavorable with respiratory failure and death on the fifteenth day of life. The autopsy confirmed the diagnosis of PBS, but the immediate cause of death was attributed to aspiration pneumonia. PMID- 28573128 TI - Effectiveness of surgical decompression in the treatment of a calcifying cystic odontogenic tumor. AB - The calcifying odontogenic cystic tumor (CCOT) is a benign lesion of odontogenic origin characterized by an ameloblastoma-like epithelium with ghost cells that may calcify. Despite broadly considered as a cyst, some investigators prefer to classify it as a neoplasm. Clinically, it occurs predominantly during the third decade of life. No difference in gender prevalence has been observed nor predilection of the lesion between maxilla and mandible. The most affected region extends from the incisor tooth to bicuspids. The classic treatment of the lesion is full excision, although a different approach may be determined by the possible association with another odontogenic tumor. Depending on the tumor size and the vicinity with important structures, decompression may be undertaken before its complete removal. The present report describes a case of CCOT with large proportions, located at the right maxilla and extending to the maxillary sinus, nasal cavity, and orbital floor. The treatment option was surgical decompression as the initial procedure, with satisfactory outcome. After partial remission, the lesion was fully removed, and the post-operative follow-up was uneventful. PMID- 28573129 TI - Placental mesenchymal dysplasia: case report with gross and histological findings. AB - Placental mesenchymal dysplasia (PMD) is a rare placental disorder characterized by placental enlargement and areas of abnormal, enlarged, grape-like villi. This condition may resemble a partial hydatidiform mole and may occur associated with Beckwith-Wiedemann syndrome (BWS) or in phenotypically normal fetuses. There were 110 cases reported so far. We describe one case with typical gross and microscopic placental lesions. PMID- 28573130 TI - Plasmacytoid urothelial carcinoma: a case of histological variant of urinary bladder cancer with aggressive behavior. AB - Plasmocytoid variant urothelial carcinoma (PVUC) of the urinary bladder is a rare histological variant of transitional cell carcinoma. Data regarding PVUC shows that this neoplasia presents a distinctive clinical outcome represented by aggressive behavior and poor survival rate. The authors report a case of a 57 year-old male patient with a 3-month history of hematuria and pelvic pain. Radical cystectomy with lymphadenectomy was performed and pathological examination showed a pT3pN0 PVUC of the bladder. The patient remained free of recurrence for 8 months, but the disease recurred involving the abdominal wall and subcutaneous tissue. Chemotherapy provided a positive clinical response and relief of symptoms. The authors call attention to the aggressiveness of this rare variant of bladder cancer and recommend radical surgery and multidisciplinary management of this neoplasm. PMID- 28573131 TI - Severe cognitive dysfunction and shrinking lung syndrome in systemic lupus erythematous. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect any organ or system. Neuropsychiatric and pulmonary involvement can occur in 40 and 50% of patients respectively, and may occur in several different clinical forms. While the main neuropsychiatric manifestations are represented by cognitive impairment, organic cerebral syndromes, delirium, psychosis, seizures, and peripheral neuropathies, the main forms of pulmonary involvement are pleurisy with or without pleural effusion, pneumonitis, interstitial disease, pulmonary hypertension, and alveolar hemorrhage. The authors report the case of a 49-year old woman whose first manifestation of SLE was represented by two rare manifestations: rapidly progressive cognitive impairment, which was associated with respiratory failure caused by the shrinking lung syndrome. The authors call attention to the under-diagnosis of lupus pulmonary complications and its association with severe cognitive impairment that often necessitates aggressive treatment. PMID- 28573133 TI - Regulation of Osteoclast Growth and Fusion by mTOR/raptor and mTOR/rictor/Akt. AB - Osteoclasts are giant bone cells formed by fusion from monocytes and uniquely capable of a complete destruction of mineralized tissues. Previously, we have demonstrated that in energy-rich environment not only osteoclast fusion index (the number of nuclei each osteoclast contains), but also cytoplasm volume per single nucleus was increased. The goal of this study was to investigate the regulation of metabolic sensor mTOR during osteoclast differentiation in energy rich environment simulated by addition of pyruvate. We have found that in the presence of pyruvate, the proportion of mTOR associated with raptor increased, while mTOR-rictor-mediated Akt phosphorylation decreased. Inhibition of mTOR with rapamycin (10 nM) significantly interfered with all aspects of osteoclastogenesis. However, rapamycin at 1 nM, which preferentially targets mTOR raptor complex, was only effective in control cultures, while in the presence of pyruvate osteoclast fusion index was successfully increased. Inhibition of Akt drastically reduced osteoclast fusion, however in energy-rich environment, osteoclasts of comparable size were formed through increased cytoplasm growth. These data suggest that mTOR-rictor mediated Akt signaling regulates osteoclast fusion, while mTOR-raptor regulation of protein translation contributes to fusion independent cytoplasm growth. We demonstrate that depending on the bioenergetics microenvironment osteoclastogenesis can adjust to occur through preferential multinucleation or through cell growth, implying that attaining large cell size is part of the osteoclast differentiation program. PMID- 28573132 TI - Prebiotics: A Novel Approach to Treat Hepatocellular Carcinoma. AB - Hepatocellular carcinoma is one of the fatal malignancies and is considered as the third leading cause of death. Mutations, genetic modifications, dietary aflatoxins, or impairments in the regulation of oncogenic pathways may bring about liver cancer. An effective barrier against hepatotoxins is offered by gut liver axis as a change in gut permeability and expanded translocation of lipopolysaccharides triggers the activation of Toll-like receptors which stimulate the process of hepatocarcinogenesis. Prebiotics, nondigestible oligosaccharides, have a pivotal role to play when it comes to inducing an antitumor effect. A healthy gut flora balance is imperative to downregulation of inflammatory cytokines and reducing lipopolysaccharides induced endotoxemia, thus inducing the antitumor effect. PMID- 28573134 TI - High-Fat and Fat-Enriched Diets Impair the Benefits of Moderate Physical Training in the Aorta and the Heart in Rats. AB - AIM: Millions of people die each year due to cardiovascular disease (CVD). A Western lifestyle not only fuses a significant intake of fat with physical inactivity and obesity but also promotes CVD. Recent evidence suggests that dietary fat intake impairs the benefits of physical training. We investigated whether aerobic training could reverse the adverse effects of a high-fat diet (HFD) on the aorta. Then, we explored whether this type of exercise could reverse the damage to the heart that is imposed by fat-enriched diet (FED). METHODS: Rats were randomly assigned to two experiments, which lasted 8 weeks each. First, rats swam for 60 min and were fed either a regular diet [standard diet (STD)] or an HFD. After aortic samples had been collected, the rats underwent a histopathological analysis for different biomarkers. Another experiment subjected rats that were fed either an STD or an FED to swimming for 20 or 90 min. RESULTS: The first experiment revealed that rats that were subjected to an HFD-endured increased oxidative damage in the aorta that exercises could not counteract. Together with increased cyclooxygenase 2 expression, an HFD in combination with physical training increased the number of macrophages. A reduction in collagen fibers with an increased number of positive alpha-actin cells and expression of matrix metalloproteinase-2 occurred concomitantly. Upon analyzing the second experiment, we found that physically training rats that were given an FED for 90 min/day decreased the cardiac adipose tissue density, although it did not protect the heart from fat-induced oxidative damage. Even though the physical training lowered cholesterol levels that were promoted by the FED, the levels were still higher than those in the animals that were given an STD. Feeding rats an FED impaired the swimming protocol's effects on lowering triglyceride concentration. Additionally, exercise was unable to reverse the fat-induced deregulation in hepatic antioxidant and lipid peroxidation activities. CONCLUSION: Our findings reveal that an increased intake of fat undermines the potential benefits of physical exercise on the heart and the aorta. PMID- 28573135 TI - Towards a Better Understanding of Sickness Absence in Adolescence: A Qualitative Study among Dutch Intermediate Vocational Education Students. AB - An adequate approach to sickness absence can reduce school dropout which is a major problem in Intermediate Vocational Education (IVE). This practice-based study explores the sickness absence reasons and factors influencing reporting the sickness, from a student's perspective. Semistructured interviews were held until saturation. Data were collected and analysed by a multidisciplinary research team including youth health care physicians working with IVE students. The results show that, according to the students, reasons for sickness reporting were health related or related to problems at home or in school. Students view their sickness absence as necessity, as asking for understanding, or as pardonable. Their views depended on (1) the perception of medical legitimacy, (2) feeling able to take their own responsibility, (3) feeling being taken seriously at school, and (4) the perception that the sickness reporting procedure at school is anonymous and easy. In conclusion, reporting sickness seems more a reaction to a necessity or opportunity than the result of a conscious decision-making process. Personalizing the sickness reporting procedures and demonstrating interest rather than control while discussing the sickness absence with the individual IVE student might very well affect their sickness absence levels. PMID- 28573136 TI - Effects of Wenxin Keli on Cardiac Hypertrophy and Arrhythmia via Regulation of the Calcium/Calmodulin Dependent Kinase II Signaling Pathway. AB - We investigated the effects of Wenxin Keli (WXKL) on the Calcium/Calmodulin dependent kinase II (CaMK II) signal transduction pathway with transverse aortic constriction (TAC) rats. Echocardiographic measurements were obtained 3 and 9 weeks after the surgery. Meanwhile, the action potentials (APDs) were recorded using the whole-cell patch clamp technique, and western blotting was used to assess components of the CaMK II signal transduction pathway. At both 3 and 9 weeks after treatment, the fractional shortening (FS%) increased in the WXKL group compared with the TAC group. The APD90 of the TAC group was longer than that of the Sham group and was markedly shortened by WXKL treatment. Western blotting results showed that the protein expressions of CaMK II, phospholamban (PLB), and ryanodine receptor 2 (RYR2) were not statistically significant among the different groups at both treatment time points. However, WXKL treatment decreased the protein level and phosphorylation of CaMK II (Thr-286) and increased the protein level and phosphorylation of PLB (Thr-17) and the phosphorylation of RYR2 (Ser-2814). WXKL also decreased the accumulation of type III collagen fibers. In conclusion, WXKL may improve cardiac function and inhibit the arrhythmia by regulating the CaMK II signal transduction pathway. PMID- 28573137 TI - Rituximab for Treatment of Membranoproliferative Glomerulonephritis and C3 Glomerulopathies. AB - Membranoproliferative glomerulonephritis (MPGN) is a histological pattern of injury resulting from predominantly subendothelial and mesangial deposition of immunoglobulins or complement factors with subsequent inflammation and proliferation particularly of the glomerular basement membrane. Recent classification of MPGN is based on pathogenesis dividing MPGN into immunoglobulin associated MPGN and complement-mediated C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Current guidelines suggest treatment with steroids, cytotoxic agents with or without plasmapheresis only for subjects with progressive disease, that is, nephrotic range proteinuria and decline of renal function. Rituximab, a chimeric B-cell depleting anti-CD20 antibody, has emerged in the last decade as a treatment option for patients with primary glomerular diseases such as minimal change disease, focal-segmental glomerulosclerosis, or idiopathic membranous nephropathy. However, data on the use of rituximab in MPGN, C3GN, and DDD are limited to case reports and retrospective case series. Patients with immunoglobulin-associated and idiopathic MPGN who were treated with rituximab showed partial and complete responses in the majorities of cases. However, rituximab was not effective in few cases of C3GN and DDD. Despite promising results in immunoglobulin-associated and idiopathic MPGN, current evidence on this treatment remains weak, and controlled and prospective data are urgently needed. PMID- 28573138 TI - Lurasidone in the Treatment of Bipolar Depression: Systematic Review of Systematic Reviews. AB - INTRODUCTION: A burgeoning number of systematic reviews considering lurasidone in the treatment of bipolar depression have occurred since its Food and Drug Administration extended approval in 2013. While a paucity of available quantitative evidence still precludes preliminary meta-analysis on the matter, the present quality assessment of systematic review of systematic reviews, nonetheless, aims at highlighting current essential information on the topic. METHODS: Both published and unpublished systematic reviews about lurasidone mono- or adjunctive therapy in the treatment of bipolar depression were searched by two independent authors inquiring PubMed/Cochrane/Embase/Scopus from inception until October 2016. RESULTS: Twelve included systematic reviews were of moderate-to high quality and consistent in covering the handful of RCTs available to date, suggesting the promising efficacy, safety, and tolerability profile of lurasidone. Concordance on the drug profile seems to be corroborated by a steadily increasing number of convergent qualitative reports on the matter. LIMITATIONS: Publication, sponsorship, language, citation, and measurement biases. CONCLUSIONS: Despite being preliminary in nature, this overview stipulates the effectiveness of lurasidone in the acute treatment of Type I bipolar depression overall. As outlined by most of the reviewed evidence, recommendations for future research should include further controlled trials of extended duration. PMID- 28573139 TI - Analysis of Differentially Expressed Proteins in Mycobacterium avium-Infected Macrophages Comparing with Mycobacterium tuberculosis-Infected Macrophages. AB - Mycobacterium avium (MA) belongs to the intracellular parasitic bacteria. To better understand how MA survives within macrophages and the different pathogenic mechanisms of MA and Mycobacterium tuberculosis (MTB), tandem mass tag (TMT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis have been used to determine the proteins which are differentially expressed in MA-infected and MTB-infected macrophages. 369 proteins were found to be differentially expressed in MA-infected cells but not in MTB-infected cells. By using certain bioinformatics methods, we found the 369 proteins were involved in molecular function, biological process, and cellular component including binding, catalytic activity, metabolic process, cellular process, and cell part. In addition, some identified proteins were involved in multiple signaling pathways. These results suggest that MA probably survive within macrophages by affecting the expression of some crucial proteins. PMID- 28573141 TI - c-Kit-Positive Adipose Tissue-Derived Mesenchymal Stem Cells Promote the Growth and Angiogenesis of Breast Cancer. AB - BACKGROUND: Adipose tissue-derived mesenchymal stem cells (ASCs) improve the regenerative ability and retention of fat grafts for breast reconstruction in cancer patients following mastectomy. However, ASCs have also been shown to promote breast cancer cell growth and metastasis. For the safety of ASC application, we aimed to identify specific markers for the subpopulation of ASCs that enhance the growth of breast cancer. METHODS: ASCs and bone marrow-derived vascular endothelial progenitor cells (EPCs) were isolated from Balb/c mice. c Kit-positive (c-Kit+) or c-Kit-negative (c-Kit-) ASCs were cocultured with 4T1 breast cancer cells. Orthotropic murine models of 4T1, EPCs + 4T1, and c-Kit+/ ASCs + 4T1/EPCs were established in Balb/c mice. RESULTS: In coculture, c-Kit+ ASCs enhanced the viability and proliferation of 4T1 cells and stimulated c-Kit expression and interleukin-3 (IL-3) release. In mouse models, c-Kit+ASCs + 4T1/EPCs coinjection increased the tumor volume and vessel formation. Moreover, IL-3, stromal cell-derived factor-1, and vascular endothelial growth factor A in the c-Kit+ASCs + 4T1/EPCs coinjection group were higher than those in the 4T1, EPCs + 4T1, and c-Kit-ASCs + 4T1/EPCs groups. CONCLUSIONS: c-Kit+ ASCs may promote breast cancer growth and angiogenesis by a synergistic effect of c-Kit and IL-3. Our findings suggest that c-Kit+ subpopulations of ASCs should be eliminated in fat grafts for breast reconstruction of cancer patients following mastectomy. PMID- 28573142 TI - Advances in the Diagnosis and Treatment of Acute Kidney Injury in Cirrhosis Patients. AB - Liver cirrhosis is a common progressive and chronic clinical liver disease. Due to the strong compensation ability of the liver, no obvious symptoms develop in the early stage. However, multiple systems are involved in decompensation of the liver. Acute kidney injury (AKI) is one of the most serious complications, characterized by a sharp drop in the glomerular filtration rate (GFR); a rapid increase in Scr and BUN, as well as sodium and water storage; and a disturbance of acid-base balance. The mortality rate is high, and the prognosis is very poor. Thus, it is important to make a definite diagnosis and initiate treatment in the early stage to decrease mortality and improve the prognosis. Although diagnosing liver cirrhosis with serum creatinine has many shortcomings, a dynamic change in this marker is still the main diagnostic criterion for AKI. Identifying new markers of kidney injury with clinical value has also become an increasing focus of research. In this text, we review recent changes regarding categorization of AKI diagnostic criteria as well as new markers of AKI and treatments for cirrhosis-related AKI. PMID- 28573143 TI - Combination of Neuroprotective and Regenerative Agents for AGE-Induced Retinal Degeneration: In Vitro Study. AB - To determine the most effective combination of neuroprotective and regenerative agents for cultured retinal neurons from advanced glycation end products- (AGEs-) induced degeneration, retinal explants of 7 adult Sprague-Dawley rats were three dimensionally cultured in collagen gel and incubated in serum-free media and in 7 media; namely, AGEs, AGEs + 100 MUM citicoline, AGEs + 10 ng/mL NT-4, AGEs + 100 MUM TUDCA, AGEs + 100 MUM citicoline + TUDCA (doublet), and AGEs + 100 MUM citicoline + TUDCA + 10 ng/mL NT-4 (triplet) were examined. The number of regenerating neurites was counted after 7 days of culture, followed by performing TUNEL and DAPI staining. The ratio of TUNEL-positive cells to the number of DAPI stained nuclei was calculated. Immunohistochemical examinations for the active form of caspase-9 and JNK were performed. All of the neuroprotectants increased the number of neurites and decreased the number of TUNEL-positive cells. However, the number of neurites was significantly higher, and the number of TUNEL-positive cells and caspase-9- and JNK-immunopositive cells was fewer in the retinas incubated with the combined three agents. Combination solutions containing citicoline, TUDCA, and NT-4 should be considered for neuroprotective and regenerative therapy for AGE-related retinal degeneration. PMID- 28573144 TI - Prevalence of Laboratory Critical Results in Eye Patients from an Eye Hospital in Southern China. AB - OBJECTIVES: To investigate the prevalence of laboratory critical results (CRs) and associated risk factors in patients with eye diseases in a tertiary eye hospital. METHODS: Blood samples were collected from both inpatients and outpatients at Zhongshan Ophthalmic Center, Guangzhou, China, from June 1, 2012, to May 31, 2014, and samples were sent to the hospital's clinical laboratory for blood routine, biochemistry, and blood coagulation tests. Laboratory CRs for blood glucose, sodium, potassium, white blood cell count, platelet count, prothrombin time, fibrinogen, international normalized ratio, and activated partial thromboplastin time were included in the current analysis. RESULTS: A total of 60403 subjects were enrolled in the current analysis. CRs were identified in 339 tests from 336 patients with a prevalence of 5.70/00. Age was positively associated with the presence of CRs. Compared to patients with lens diseases, patients with strabismus, oculoplastics, and ocular trauma were less likely to have CRs (P < 0.05), while patients with tumors were more likely to have CRs (P < 0.001). CONCLUSIONS: The prevalence of CRs in eye patients is low but calls for medication attention. It is important for medical personnel, especially ophthalmologists, to increase awareness of the importance, as well as the prevalence and risk factors of CRs. PMID- 28573145 TI - Cardio-Ankle Vascular Index and Indices of Diabetic Polyneuropathy in Patients with Type 2 Diabetes. AB - The cardio-ankle vascular index (CAVI) is used to test vascular function and is an arterial stiffness marker and potential predictor of cardiovascular events. This study aimed to analyze the relation between objective indices of diabetic polyneuropathy (DPN) and the CAVI. One hundred sixty-six patients with type 2 diabetes mellitus were included in this study. We used nerve conduction studies (NCSs) and the coefficient of variation of the R-R interval to evaluate DPN. We estimated arteriosclerosis by the CAVI. Simple and multiple linear regression analyses were performed between neuropathy indices and the CAVI. In univariate analysis, the CAVI showed significant associations with sural sensory nerve conduction velocity and median F-wave conduction velocity. Multiple linear regression analysis for the CAVI showed that sural nerve conduction velocity and median F-wave conduction velocity were significant explanatory variables second only to age. In multiple linear regression analysis for sural nerve conduction velocity among neuropathy indices, the CAVI remained the most significant explanatory variable. In multiple linear regression analysis for median nerve F wave conduction velocity among neuropathy indices, the CAVI remained the second most significant explanatory variable following HbA1c. These results suggest a close relationship between macroangiopathy and DPN. PMID- 28573146 TI - Prevalence of Positive Diabetes-Associated Autoantibodies among Type 2 Diabetes and Related Metabolic and Inflammatory Differences in a Sample of the Bulgarian Population. AB - BACKGROUND: The study aimed to estimate the prevalence of unrecognized cases with positive autoantibodies among type 2 diabetes (T2D) in a sample of the Bulgarian population and to compare some metabolic and inflammatory markers to those of patients having negative autoantibodies and subjects with latent autoimmune diabetes (LADA). METHODS: Patients with T2D, patients with LADA, and control participants were enrolled. Antiglutamic acid decarboxylase, anti-insulinoma associated 2, and antizinc transporter 8 autoantibodies were assayed through ELISA. C-reactive protein and interleukin 6 (IL-6) and tumor necrosis factor alpha were assessed. RESULTS: Ten percent of patients with T2D had positive autoantibodies. They had lower body mass index (p = 0.014), worse glycemic control (HbA1c, p = 0.033), and better HDL cholesterol (p = 0.026) than those in negative autoantibodies cases. Compared to LADA, glycemia and anthropometric data did not differ significantly but metabolic syndrome was more prevalent among newly found cases with positive autoantibodies (p = 0.046). Their level of inflammatory markers was similar to that of patients having negative autoantibodies (p > 0.05), but IL-6 was higher when compared to LADA (p = 0.002). CONCLUSION: Prevalence of patients having positive autoantibodies within T2D in the analyzed sample of the Bulgarian population was 10%. They shared common metabolic features with subjects with LADA, but inflammatory phenotype was closer to that of T2D. PMID- 28573148 TI - A promising tool for surgical lipotransfer: a constant pressure and quantity injection device in facial fat grafting. AB - BACKGROUND: The purpose of this study was to preliminarily assess a constant pressure and quantity fat granule injection device for minimal invasive properties in clinic. METHODS: A retrospective controlled study was carried out, from October 2013 to January 2015, on 76 female healthy patients aged between 26 and 53 years at the General Hospital of Lanzhou Military Command, China. To achieve small volume, high thrust, and precision requirements of facial fat grafting, an integrated handheld controller and motor design was adopted, reducing the volume and weight of the fat transplantation injection device. The 76 patients underwent 90 procedures each side of the face; each patient was treated with the aforementioned device on the face's left side, while a conventional hand-push injection device was used on the right side as control. The outcome was assessed on pre- and postoperative images, with 6-24 months follow-up. RESULTS: The current device consistently allowed deposition of fat threads at about 55 MUL/cm after cannula withdrawal; the volume of fat injected could be precisely adjusted to 0.04 mL/s. This device had the advantages of small volume injection and convenient operation. The patients exhibited a good, stable shape and a smooth contour line in both sides. The long term satisfaction was higher for the left side than for the right one. Nodules and unevenness occurred only on the right side. Ecchymosis occurred significantly less frequent on the left side than the right one. Intraoperative pain was significantly lower for the left side than the right one. CONCLUSIONS: This device offered superior control compared with the conventional one and constitutes a promising tool for surgeons practicing lipotransfer. PMID- 28573147 TI - The progress of Chinese burn medicine from the Third Military Medical University in memory of its pioneer, Professor Li Ao. AB - Professor Li Ao was one of the founders of Chinese burn medicine and one of the most renowned doctors and researchers of burns in China. He established one of the Chinese earliest special departments for burns at Third Military Medical University (TMMU) in 1958. To memorialize Professor Li Ao on his 100th birthday in 2017 and introduce our extensive experience, it is our honor to briefly review the development and achievement of the Chinese burn medicine from TMMU. The epidemiology and outcomes of admitted burn patients since 1958 were reviewed. Furthermore, main achievements of basic and clinical research for the past roughly 60 years were presented. These achievements mainly included the Chinese Rule of Nine, fluid resuscitation protocol, experience in inhalation injury, wound treatment strategies, prevention and treatment of burn infections, nutrition therapy, organ support therapies, and rehabilitation. The progress shaped and enriched modern Chinese burn medicine and promoted the development of world burn medicine. PMID- 28573149 TI - Stem cells and stroke-how glowing neurons illuminate new paths. AB - A reliable method of cell tracing is essential in evaluating potential therapeutic procedures based on stem cell transplantation. Here we present data collected using neural stem cells isolated from a transgenic mouse line Thy1-YFP. When transplanted into a stroke affected brain these cells give rise to neurons that express a fluorescent signal which can be used for their detection and tracing. Observed processes were compared with those taking place during normal embryonic neurogenesis as well as during in vitro differentiation. Since the same neurogenic patterns were observed, we confirm that neural stem cell transplantation fits well into the paradigm of neuronal birth and differentiation. PMID- 28573150 TI - Notch/Hes signaling and miR-9 engage in complex feedback interactions controlling neural progenitor cell proliferation and differentiation. AB - Canonical Notch signaling has diverse functions during nervous system development and is critical for neural progenitor self-renewal, timing of differentiation and specification of various cell fates. A key feature of Notch-mediated self-renewal is its fluctuating activity within the neural progenitor cell population and the oscillatory expression pattern of the Notch effector Hes1 and its target genes. A negative feedback loop between Hes1 and neurogenic microRNA miR-9 was found to be part of this oscillatory clock. In a recent study we discovered that miR-9 expression is further modulated by direct binding of the Notch intracellular domain/RBPj transcriptional complex to the miR-9_2 promoter. In turn, miR-9 not only targets Hes1 but also Notch2 to attenuate Notch signaling and promote neuronal differentiation. Here, we discuss how the two interwoven feedback loops may provide an additional fail-save mechanism to control proliferation and differentiation within the neural progenitor cell population. Furthermore, we explore potential implications of miR-9-mediated regulation of Notch/Hes1 signaling with regard to neural progenitor homeostasis, patterning, timing of differentiation and tumor formation. PMID- 28573151 TI - Nervous system development relies on endosomal trafficking. AB - Accumulating findings have begun to unveil the important role of the endosomal machinery in the nervous system development. Endosomes have been linked to the differential segregation of cell fate determining molecules in asymmetrically dividing progenitors during neurogenesis. Additionally, the precise removal and reinsertion of membrane components through endocytic trafficking regulates the spatial and temporal distribution of signaling receptors and adhesion molecules, which determine the morphology and motility of migrating neurons. Emerging evidence suggests that the role of the endosomal sorting adaptors is dependent upon cell type and developmental stage. The repertoire of the signaling receptors and/or adhesion molecules sorted by the endosome during these processes remains to be explored. In this commentary, we will briefly address the progress in this research field. PMID- 28573140 TI - Colorectal Cancer: From the Genetic Model to Posttranscriptional Regulation by Noncoding RNAs. AB - Colorectal cancer is the third most common form of cancer in developed countries and, despite the improvements achieved in its treatment options, remains as one of the main causes of cancer-related death. In this review, we first focus on colorectal carcinogenesis and on the genetic and epigenetic alterations involved. In addition, noncoding RNAs have been shown to be important regulators of gene expression. We present a general overview of what is known about these molecules and their role and dysregulation in cancer, with a special focus on the biogenesis, characteristics, and function of microRNAs. These molecules are important regulators of carcinogenesis, progression, invasion, angiogenesis, and metastases in cancer, including colorectal cancer. For this reason, miRNAs can be used as potential biomarkers for diagnosis, prognosis, and efficacy of chemotherapeutic treatments, or even as therapeutic agents, or as targets by themselves. Thus, this review highlights the importance of miRNAs in the development, progression, diagnosis, and therapy of colorectal cancer and summarizes current therapeutic approaches for the treatment of colorectal cancer. PMID- 28573152 TI - Cell Therapy in Myology: Dynamics of Muscle Precursor Cell Death after Intramuscular Administration in Non-human Primates. AB - Cell therapy could be useful for the treatment of myopathies. A problem observed in mice, with different results and interpretations, is a significant death among the transplanted cells. We analyzed this problem in non-human primates, the animal model more similar to humans. Autologous or allogeneic myoblasts (with or without a reporter gene) were proliferated in vitro, labeled with [14C]thymidine, and intramuscularly injected in macaques. Some monkeys were immunosuppressed for long-term follow-up. Cell-grafted regions were biopsied at different intervals and analyzed by radiolabel quantification and histology. Most radiolabel was lost during the first week after injection, regardless of whether the cells were allogeneic or autologous, the culture conditions, and the use or not of immunosuppression. There was no significant difference between 1 hr and 1 day post-transplantation, a significant decrease between days 1 and 3 (45% to 83%), a significant decrease between days 3 and 7 (80% to 92%), and no significant differences between 7 days and 3 weeks. Our results confirmed in non-human primates a progressive and significant death of the grafted myoblasts during the first week after administration, relatively similar to some observations in mice but with different kinetics. PMID- 28573153 TI - Optical imaging of the rat brain suggests a previously missing link between top down and bottom-up nervous system function. AB - Optical imaging with voltage-sensitive dyes enables the visualization of extensive yet highly transient coalitions of neurons (assemblies) operating throughout the brain on a subsecond time scale. We suggest that operating at the mesoscale level of brain organization, neuronal assemblies may provide a functional link between "bottom-up" cellular mechanisms and "top-down" cognitive ones within anatomically defined regions. We demonstrate in ex vivo rat brain slices how varying spatiotemporal dynamics of assemblies reveal differences not previously appreciated between: different stages of development in cortical versus subcortical brain areas, different sensory modalities (hearing versus vision), different classes of psychoactive drugs (anesthetics versus analgesics), different effects of anesthesia linked to hyperbaric conditions and, in vivo, depths of anesthesia. The strategy of voltage-sensitive dye imaging is therefore as powerful as it is versatile and as such can now be applied to the evaluation of neurochemical signaling systems and the screening of related new drugs, as well as to mathematical modeling and, eventually, even theories of consciousness. PMID- 28573154 TI - Improving voltage-sensitive dye imaging: with a little help from computational approaches. AB - Voltage-sensitive dye imaging (VSDI) is a key neurophysiological recording tool because it reaches brain scales that remain inaccessible to other techniques. The development of this technique from in vitro to the behaving nonhuman primate has only been made possible thanks to the long-lasting, visionary work of Amiram Grinvald. This work has opened new scientific perspectives to the great benefit to the neuroscience community. However, this unprecedented technique remains largely under-utilized, and many future possibilities await for VSDI to reveal new functional operations. One reason why this tool has not been used extensively is the inherent complexity of the signal. For instance, the signal reflects mainly the subthreshold neuronal population response and is not linked to spiking activity in a straightforward manner. Second, VSDI gives access to intracortical recurrent dynamics that are intrinsically complex and therefore nontrivial to process. Computational approaches are thus necessary to promote our understanding and optimal use of this powerful technique. Here, we review such approaches, from computational models to dissect the mechanisms and origin of the recorded signal, to advanced signal processing methods to unravel new neuronal interactions at mesoscopic scale. Only a stronger development of interdisciplinary approaches can bridge micro- to macroscales. PMID- 28573155 TI - Integration of color, orientation, and size functional domains in the ventral pathway. AB - Functional specialization within the extrastriate areas of the ventral pathway associated with visual form analysis is poorly understood. Studies comparing the functional selectivities of neurons within the early visual areas have found that there are more similar than different between the areas. We simultaneously imaged visually evoked activation over regions of V2 and V4 and parametrically varied three visual attributes for which selectivity exists in both areas: color, orientation, and size. We found that color selective regions were observed in both areas and were of similar size and spatial distribution. However, two major areal distinctions were observed: V4 contained a greater number and diversity of color-specific regions than V2 and exhibited a higher degree of overlap between domains for different functional attributes. In V2, size and color regions were largely segregated from orientation domains, whereas in V4 both color and size regions overlapped considerably with orientation regions. Our results suggest that higher-order composite selectivities in the extrastriate cortex may arise organically from the interactions afforded by an overlap of functional domains for lower order selectivities. PMID- 28573157 TI - Specular Highlight Removal For Image-Based Dietary Assessment. AB - Traditional dietary assessment methods, consisting of written and orally reported methods, are not widely acceptable or feasible for everyday monitoring. The development of builtin cameras for mobile devices provides a new way of collecting dietary information by acquiring images of foods and beverages. The ability of image analysis techniques to automatically segment and identify food items from food images becomes imperative. Food images, usually consisting of plates, bowls and glasses, are often affected by lighting and specular highlights which present difficulties for image analysis. In this paper, we propose a novel single-image specular highlight removal method to detect and remove specular highlights in food images. We use independent components analysis (ICA) to separate the specular and diffuse components from the original image using only one image. This paper describes the details of the proposed model and also presents experimental results on food images to demonstrate the effectiveness of our approach. PMID- 28573158 TI - Mouse Embryonic Fibroblast Cell Culture and Stimulation. AB - Culture of mouse embryonic fibroblast (MEF) cells represents a powerful system to test gene function due to their easy accessibility, rapid growth rates, and the possibility of a large number of experiments. Fibroblasts are a group of heterogeneous resident cells of mesenchymal origin that have various locations, diverse appearances and distinctive activities. Because of their ubiquitous distribution as tissue cells, these cells are poised to respond to factors released by newly activated innate immune cells, thus becoming a useful tool to study inflammation and immunity. Here, we describe procedures for mouse embryonic fibroblast cell isolation, primary culture, and stimulation. Specifically, we have optimized a step of serum starvation prior to stimulation. This step is necessary to maintain the quiescent status of these cells before they are exposed to pro-inflammatory stimuli for optimal responses. As shown in our previous studies, these mouse fibroblasts do not express Tnf, Csf2, or Il2 mRNAs at levels readily detectable by routine northern blotting techniques (Lai WS et al., 2006). PMID- 28573156 TI - Study of single and multidigit activation in monkey somatosensory cortex using voltage-sensitive dye imaging. AB - Toward the goal of understanding cutaneous sensory integration during manual behavior, we used voltage-sensitive dye (VSD) imaging to study the organization and dynamics of anesthetized monkey primary somatosensory cortex (SI) in response to single and multidigit tactile stimulation. We find that in both macaque and squirrel monkey SI, VSD reveals clear focal digit topography consistent with previous electrophysiological and intrinsic signal imaging studies. VSD also reveals interactions in SI in response to multidigit stimulation. With a tactile funneling paradigm in areas 3b and 1 in squirrel monkeys, VSD reveals two-digit induction of subthreshhold influences, consistent with lateral intracortical inhibition. In response to tactile apparent motion stimuli, VSD reveals preferential response to motion stimuli over static tactile stimuli in both areas 1 and 3b. Comparison of the response at different digit locations to "toward digit" stimuli suggests the presence of direction-selective response in area 1; however, further study is needed. These exciting results indicate that VSD constitutes a powerful tool for studying somatosensory cortical processing in nonhuman primates and should be further developed for future somatosensory studies in awake behaving monkeys. PMID- 28573159 TI - High Fat Diet-induced Breast Cancer Model in Rat. AB - Obesity has been linked to breast cancer progression but the underlying mechanisms remain obscure. Being overweight or obese for a woman at the time she is diagnosed with breast cancer is linked to a high risk of recurrence regardless of treatment factors. In rodents, high body weight is also associated with increased incidence of spontaneous and chemically induced tumors. To study the complex interaction between the mammary epithelia and the microenvironment, with a focus on the mechanism underlying the role obesity plays in the regulation of the cancer stem cell traits and the development of mammary cancer in vivo, we have established a diet-induced obesity (DIO) rat model of breast cancer (Chang et al., 2015). PMID- 28573160 TI - Quantification of 2-Hydroxyglutarate Enantiomers by Liquid Chromatography-mass Spectrometry. AB - Two enantiomers of 2-hydroxyglutarate (2HG), L (L2HG) and D (D2HG), are metabolites of unknown function in mammalian cells that were initially associated with separate and rare inborn errors of metabolism resulting in increased urinary excretion of 2HG linked to neurological deficits in children (Chalmers et al., 1980; Duran et al., 1980; Kranendijk et al., 2012). More recently, investigators have shown that D2HG is produced by mutant isocitrate dehydrogenase enzymes associated with a variety of human malignancies, such as acute myeloid leukemia, glioblastoma multiforme, and cholangiocarcinoma (Cairns and Mak, 2013; Dang et al., 2009; Ward et al., 2010). By contrast, we and others have shown that L2HG accumulates in response to cellular reductive stressors like hypoxia, activation of hypoxia inducible factors, and mitochondrial electron transport chain defects (Oldham et al., 2015; Reinecke et al., 2011; Intlekofer et al., 2015; Mullen et al., 2015). Each enantiomer is produced and metabolized in independent biochemical pathways in reactions catalyzed by separate enzymes and utilizing different cofactors with presumably different consequences for cellular metabolism (Kranendijk et al., 2012). Therefore, as research into the roles of D2HG and L2HG in human metabolism continues, it becomes increasingly important for investigators to consider each enantiomer independently (Struys, 2013). Several methods for quantification of biochemically relevant enantiomers in general have been developed and typically include enzymatic assays using enzymes specific for one enantiomeric species or the other, the use of chiral chromatography medium to facilitate chromatographic separation of enantiomers prior to spectroscopy, or the use of chiral derivatization reagents to convert a mixture of enantiomers to diastereomers with differing physical and chemical properties facilitating their chromatographic separation. In this protocol, we report the adaptation of a previously published derivatization method using diacetyl-l-tartaric anhydride (DATAN) for the quantification of 2HG enantiomers (Figure 1) (Oldham et al., 2015; Struys et al., 2004). PMID- 28573161 TI - BODIPY 493/503 Staining of Neutral Lipid Droplets for Microscopy and Quantification by Flow Cytometry. AB - Lipid droplets (LDs) are ubiquitous, dynamic organelles and function as a storage depot for neutral lipids, including triglycerides and cholesterol esters (Walther and Farese, 2012). The movement of lipid species into and out of LDs impacts a variety of cellular processes, such as energy homeostasis, lipid-based signaling, and membrane homeostasis (Greenberg et al., 2011). For example, neutral lipid storage is enhanced upon increased synthesis or uptake of lipid species. On the other hand, extracellular signals can enhance the release of lipid species packaged within neutral LDs. Thus, the investigation of topics involving lipid metabolism may require the assessment of cellular neutral lipid content. In this protocol, we describe the use of the fluorescent neutral lipid dye 4,4-difluoro 1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY 493/503) to facilitate quantification of neutral lipid content by flow cytometry and observation of LDs by microscopy. PMID- 28573162 TI - Measurement of Transferrin- and Non-transferrin-bound Iron Uptake by Mouse Tissues. AB - Iron in blood plasma is bound to its transport protein transferrin, which delivers iron to most tissues. In iron overload and certain pathological conditions, the carrying capacity of transferrin can become exceeded, giving rise to non-transferrin-bound iron, which is taken up preferentially by the liver, kidney, pancreas, and heart. The measurement of tissue transferrin- and non transferrin-bound iron (TBI and NTBI, respectively) uptake in vivo can be achieved via intravenous administration of 59Fe-labeled TBI or NTBI followed by gamma counting of various organs. Here we describe a detailed protocol for the measurement of TBI and NTBI uptake by mouse tissues. PMID- 28573163 TI - Non-radioactive in vitro PINK1 Kinase Assays Using Ubiquitin or Parkin as Substrate. AB - This protocol describes the in vitro phosphorylation of ubiquitin and Parkin by the kinase PINK1 using recombinant proteins. Both substrates, ubiquitin and Parkin, are phosphorylated at the conserved serine 65 residue (pS65-ubiquitin and pS65-Parkin). The protocol also includes the use of monomeric and K48- and K63 linked poly-ubiquitin chains as alternative substrates. Although there are commercially available antibodies, we have not tested their performance in this assay since, but used validated antibodies from our laboratory. An alternative antibody-independent method, the use of phostag gels to detect pS65-ubiquitin and pS65-Parkin, is described in addition. PMID- 28573164 TI - Sulforhodamine B (SRB) Assay in Cell Culture to Investigate Cell Proliferation. AB - The SRB assay has been used since its development in 1990 (Skehan et al., 1990) to inexpensively conduct various screening assays to investigate cytotoxicity in cell based studies (Vichai and Kirtikara, 2006). This method relies on the property of SRB, which binds stoichiometrically to proteins under mild acidic conditions and then can be extracted using basic conditions; thus, the amount of bound dye can be used as a proxy for cell mass, which can then be extrapolated to measure cell proliferation. The protocol can be divided into four main steps: preparation of treatment, incubation of cells with treatment of choice, cell fixation and SRB staining, and absorbance measurement. This assay is limited to manual or semiautomatic screening, and can be used in an efficient and sensitive manner to test chemotherapeutic drugs or small molecules in adherent cells. It also has applications in evaluating the effects of gene expression modulation (knockdown, gene expression upregulation), as well as to study the effects of miRNA replacement on cell proliferation (Kasinski et al., 2015). PMID- 28573165 TI - Apparatus and General Methods for Exposing Rats to Audiogenic Stress. AB - Most organisms react innately to the sudden onset of environmental stimulation. Audiogenic or loud noise in rodents provides an effective threatening signal to study the central nervous circuits responsible for the elaboration of various responses typically elicited by threatening/stressful environmental stimulation. Audiogenic stress offers many advantages over other environmental stimulation, including exquisite control over timing, intensity, and frequency, using off-the shelf components that produce easily reproducible results. This protocol provides blueprints for the construction of sound attenuation chambers, the associated sound generation, amplification, and delivery equipment, and general procedures sufficient to elicit multimodal responses to loud noises in rodents. PMID- 28573166 TI - Halo Assay for Toxic Peptides and Other Compounds in Microorganisms. AB - : We describe an assay for determination of toxicity in S. cerevisiae involving spotting of a toxic peptide on a lawn of yeast cells. This assay may be generalized to determine toxicity of a variety of compounds by substituting a putative toxic compound in place of the peptide. The general protocol may also be used to determine toxicity of any small compound toward another microorganism by replacing S. cerevisiae with the target microbe and modifying growth conditions accordingly. BACKGROUND: Di-/tripeptides are one of the major sources of nitrogen, carbon, and amino acids for all organisms. Synthetic peptides containing a toxic amino acid residue provide an experimental approach to measure peptide transport and/or utilization in Saccharomyces cerevisiae. Hydrolysis of internalized peptides by intracellular peptidases or proteases releases the toxic residue leading to an easily detectable zone (halo) of growth arrest on a lawn of cells plated in a Petri plate. For example, upon intracellular hydrolysis the toxic peptide Ala-Eth releases ethionine (Eth), a methionine antagonist which interferes with the incorporation of amino acids into proteins and with the normal methylation of DNA and other methylation pathways, thereby leading to cell death. When spotted onto a lawn of yeast cells, the transported dipeptide Ala-Eth will inhibit growth, and a clear 'halo' will form in the lawn of cells around the region where the Eth-containing toxic peptide is spotted (Figure 1A). The assay described here for determination of peptide toxicity in S. cerevisiae may be generalized as follows: (1) it may be modified to determine toxicity of any substrate by simply using a putative toxic compound in place of a peptide containing a toxic amino acid, or (2) it may be modified to determine toxicity of a substrate toward any microorganism by replacing S. cerevisiae in the assay with the target organism. It is a simple, inexpensive and relatively rapid method for determining substrate toxicities as modified for the specific organism and toxic moiety assayed. PMID- 28573167 TI - Preparation of Purified Gram-positive Bacterial Cell Wall and Detection in Placenta and Fetal Tissues. AB - Cell wall is a complex biopolymer on the surface of all Gram-positive bacteria. During infection, cell wall is recognized by the innate immune receptor Toll-like receptor 2 causing intense inflammation and tissue damage. In animal models, cell wall traffics from the blood stream to many organs in the body, including brain, heart, placenta and fetus. This protocol describes how to prepare purified cell wall from Streptococcus pneumoniae, detect its distribution in animal tissues, and study the tissue response using the placenta and fetal brain as examples. PMID- 28573168 TI - Analysis of in vivo Interaction between RNA Binding Proteins and Their RNA Targets by UV Cross-linking and Immunoprecipitation (CLIP) Method. AB - RNA metabolism is tightly controlled across different tissues and developmental stages, and its dysregulation is one of the molecular hallmarks of cancer. Through direct binding to specific sequence element(s), RNA binding proteins (RBPs) play a pivotal role in co- and post-transcriptional RNA regulatory events. We have recently demonstrated that, in pancreatic cancer cells, acquisition of a drug resistant (DR)-phenotype relied on upregulation of the polypyrimidine tract binding protein (PTBP1), which in turn is recruited to the pyruvate kinase pre mRNA and favors splicing of the oncogenic PKM2 variant. Herein, we describe a step-by-step protocol of the ultraviolet (UV) light cross-linking and immunoprecipitation (CLIP) method to determine the direct binding of a RBP to specific regions of its target RNAs in adherent human cell lines. PMID- 28573169 TI - Surface Inoculation and Quantification of Pseudomonas syringae Population in the Arabidopsis Leaf Apoplast. AB - Bacterial pathogens must enter the plant tissue in order to cause a successful infection. Foliar bacterial pathogens that are not able to directly penetrate the plant epidermis rely on wounds or natural openings to internalize leaves. This protocol describes a procedure to estimate the population size of Pseudomonas syringae in the leaf apoplast after surface inoculation of Arabidopsis rosettes. PMID- 28573171 TI - Topical lidocaine inhibits spasm during colonoscopy: a double-blind, randomized controlled trial (with video). AB - BACKGROUND AND STUDY AIMS: Topical peppermint oil prevents intestinal spasm, but can cause rebound spasm. Lidocaine hydrochloride, a local anesthetic, may work as an antispasmodic by blocking Na + channels. The aim of this study was to investigate the effect of topical lidocaine on the inhibition of colonic spasm during colonoscopy, compared with peppermint oil. PATIENTS AND METHODS: A randomized, controlled double-blind trial was conducted in an academic endoscopy unit. Patients requiring endoscopic resection were randomly allocated to colonoscopy with topical administration of lidocaine (n = 30) or peppermint oil (n = 30). Similar vials containing different solutions were randomly numbered. Allocation was made based on the vial number. The solution used and the vial number were not revealed during the study. Two endoscopists performed all procedures using midazolam, without anticholinergic agents. When a pre-selected lesion was identified, the solution in the assigned vial was dispersed and the bowel observed for 5 minutes. The primary endpoint was the duration of spasm inhibition, and a secondary endpoint was the occurrence of rebound spasm stronger than before dispersion. RESULTS: There were no significant differences in patient demographics. Spasm was inhibited in almost all patients in both groups, with a similar median duration (lidocaine 227 sec vs. peppermint 212.5 sec, P = 0.508). In contrast, rebound spasm occurred less frequently in the lidocaine group (lidocaine 7 % vs. peppermint 47 %, P = 0.001). There were no adverse events or symptoms associated with administration of the solutions. CONCLUSIONS: The inhibitory effect of lidocaine is not superior to peppermint oil. However, lidocaine significantly decreases the frequency of rebound spasms. PMID- 28573172 TI - Topical antispasmodics during colonoscopy: do they have a role? PMID- 28573170 TI - Laparoscopic Cholecystectomy in the Elderly: An Experience at a Tertiary Care Hospital in Western Nepal. AB - BACKGROUND: The incidence of gallstone increases with increasing age. No studies have been reported in the elderly population with laparoscopic cholecystectomy from developing nations. The aim of this study was to compare perioperative outcomes of laparoscopic cholecystectomy between the elderly (>=60 years old) and the young (<60 years old). METHODS: From July 2015 to June 2016, a retrospective review of medical records of 78 elderly patients (>=60 years old) and 164 young patients (<60 years old) who underwent laparoscopic cholecystectomy was done. The patients' demographics and perioperative outcomes were analyzed. RESULTS: Median ages were 65 years (range: 60-80) and 45 years (range: 21-59) for the elderly group and the young group. The majority of patients were female (62.8 and 72%). There were no significant differences in the conversion rate (9 and 7.9%, P = 0.78), postoperative complications (17.9 and 14.6%, P = 0.50), and length of stay in the hospital (4 days for both groups, P = 0.35) between the two groups. There was no mortality in either of the groups. CONCLUSION: Our results of laparoscopic cholecystectomy in elderly patients are comparable with those in young patients. Therefore, laparoscopic cholecystectomy is safe even in the elderly population. PMID- 28573173 TI - Ex vivo experimental study on the Thulium laser system: new horizons for interventional endoscopy (with videos). AB - BACKGROUND AND STUDY AIMS: The Thulium laser system (TLS) is an emerging interventional tool adopted in many surgical specialties. Its 2.0-MUm wavelength allows precise coagulation (0.2 - 0.4 mm in depth) and cutting, limiting the possibilities of collateral injuries. We tested the impact of the TLS for gastric endoscopic submucosal dissection (ESD) and per oral endoscopic myotomy (POEM) ex vivo in pigs. MATERIALS AND METHODS: Ex vivo porcine stomach and esophagus models underwent 2 POEMs, and 3 ESDs (mean diameter 3.5 cm) with TLS using a 272 um and a 365-um thick optical fibers. Both continuous and pulsed laser emission were evaluated. Subsequent histopathological analysis was performed by an expert GI pathologist on the whole porcine models. RESULTS: Complete POEMs and gastric ESDs were successfully performed in all cases in 30 to 70 and 15 to 20 minutes. Both optical fibers were equally effective and precise. The best power output for mucosal incision was 25 to 30 W during ESD and 25 W for POEM using continuous laser emission. During submucosal dissection and tunneling the favorite power output was 20 W and 15 to 20 W, respectively, operating in continuous mode. No transmural perforation occurred throughout the operations and histopathology confirmed the absence of accidental muscular layer damage. CONCLUSIONS: The TLS stands out as a precise and manageable instrument in ex vivo models. This technique appears to be a promising tool for advanced interventional endoscopy. PMID- 28573174 TI - Optimal intake of clear liquids during preparation for afternoon colonoscopy with low-volume polyethylene glycol plus ascorbic acid. AB - BACKGROUND AND STUDY AIMS : The standard colonoscopy preparation regimen in Japan for afternoon procedures is sequential intake of 1 L of polyethylene glycol electrolyte lavage solution containing ascorbic acid (PEG-ASC), 0.5 L of clear liquid, 0.5 L of PEG-ASC, and finally 0.25 L of clear fluids (all at a rate of 0.25 L every 15 min). However, this regimen seems poorly tolerated and complicated for many patients compared to previous regimen of polyethylene glycol electrolyte lavage solution. The aim of this study was to evaluate an alternate regimen of 0.5 L of PEG-ASC followed by 0.25 L clear liquids, repeated 3 times. PATIENTS AND METHODS : This was a single-blinded, non-inferiority, randomized controlled study. Subjects were randomized to the standard regimen or the alternate regimen using a web-based registry system. All patients were instructed to eat a pre-packaged, low residue diet and to take sodium picosulfate hydrate the day before colonoscopy. The Boston Bowel Preparation Scale was used to evaluate bowel cleansing, and a 3-point scale was used to assess mucosal visibility. The primary endpoint was successful bowel cleansing. The acceptability, tolerability, safety, and endoscopic findings of these two regimens were secondary endpoints. RESULTS: A total of 409 patients were randomized to either the standard regimen (n = 204, males 54.0 %, mean age 65.5 years) or the alternate regimen (n = 205, 54.6 %, 65.0 years). The rates of successful bowel cleansing were 71.1 % (64.3 - 77.2 %) with the standard regimen vs. 75.1 % (68.6 - 80.9 %) with the alternate regimen (95 % lower confidence limit, for the difference = - 4.6, non-inferiority P < 0.05). No significant differences were found in tolerability, safety, and endoscopic findings. CONCLUSION: The alternate regimen and standard regimen are clinically equivalent with respect to cleansing efficacy and acceptability, tolerability, safety, and endoscopic findings. These results are good news for patients with difficulty drinking the first liter of PEG-ASC. PMID- 28573175 TI - Lubiprostone improves visualization of small bowel for capsule endoscopy: a double-blind, placebo-controlled 2-way crossover study. AB - BACKGROUND AND STUDY AIMS: Lubiprostone has been reported to be an anti constipation drug. The aim of the study was to investigate the usefulness of lubiprostone both for bowel preparation and as a propulsive agent in small bowel endoscopy. PATIENTS AND METHODS: This was a double-blind, placebo-controlled, 2 way crossover study of subjects who volunteered to undergo capsule endoscopy (CE). A total of 20 subjects (16 male and 4 female volunteers) were randomly assigned to receive a 24-MUg tablet of lubiprostone 120 minutes prior to capsule ingestion for CE (L regimen), or a placebo tablet 120 minutes prior to capsule ingestion for CE (P regimen). Main outcome was gastric transit time (GTT) and small-bowel transit time (SBTT). Secondary outcome was adequacy of small-bowel cleansing and the fluid score in the small bowel. The quality of the capsule endoscopic images and fluid in the small bowel were assessed on 5-point scale. RESULTS: The capsule passed into the small bowel in all cases. Median GTT was 57.3 (3 - 221) minutes for the P regimen and 61.3 (10 - 218) minutes for the L regimen ( P = 0.836). Median SBTT was 245.0 (164 - 353) minutes for the P regimen and 228.05 (116 - 502) minutes for the L regimen ( P = 0.501). The image quality score in the small bowel was 3.05 +/- 1.08 for the P regimen and 3.80 +/- 0.49 for the L regimen ( P < 0.001). The fluid score in the small bowel was 2.04 +/- 1.58 for the P regimen and 2.72 +/- 1.43 for the L regimen ( P < 0.001). There was a significant difference between the 2 regimens with regard to image quality. The fluid score was more plentiful for the L regimen than for the P regimen. There were no cases of capsule retention or serious adverse events in this study. CONCLUSION: Our study showed that use of lubiprostone prior to CE significantly improved visualization of the small bowel during CE as a result of inducing fluid secretion into the small bowel. PMID- 28573177 TI - Efficacy and safety of a combination of hyaluronic acid, chondroitin sulfate, and poloxamer 407 as a submucosal injection solution for endoscopic resection: pilot study on a swine model. AB - BACKGROUND AND AIMS: Endoscopic resection techniques require use of submucosal injection. The aim of this study was to assess a new solution that combines hyaluronic acid, chondroitin sulfate, and poloxamer 407 for submucosal injection. METHODS: A total of 48 gastric submucosal cushions were created in fresh porcine stomachs using gelafundin (n = 16) or the new solution diluted at 50 % (n = 16), or 80 % (n = 16). The duration of mucosal elevation was measured. In an in vivo model, 10 gastric submucosal cushions were created by injecting 2 mL of the new solution at 80 % and the animal was euthanized 30 minutes after the last injection. RESULTS: Submucosal cushions with the new solution at 80 % and 50 % concentration lasted longer than with gelafundin (23.13 +/- 15.57, 13.1 +/- 6.6, 3.94 +/- 1.53 minutes, respectively; P = 0.000). In the in vivo study, no damage or necrosis was observed in the mucosa or muscularis propria. CONCLUSION: The combination of hyaluronic acid, chondroitin sulfate, and poloxamer 407 produces a long-lasting submucosal cushion and does not seem to induce acute damage in the tissue making it suitable for submucosal injection. PMID- 28573176 TI - Recurrence of intestinal metaplasia and early neoplasia after endoscopic eradication therapy for Barrett's esophagus: a systematic review and meta analysis. AB - BACKGROUND: Conflicting data exist with regard to recurrence rates of intestinal metaplasia (IM) and dysplasia after achieving complete eradication of intestinal metaplasia (CE-IM) in Barrett's esophagus (BE) patients. AIM: (i) To determine the incidence of recurrent IM and dysplasia achieving CE-IM and (ii) to compare recurrence rates between treatment modalities [radiofrequency ablation (RFA) with or without endoscopic mucosal resection (EMR) vs stepwise complete EMR (SRER)]. METHODS: A systematic search was performed for studies reporting on outcomes and estimates of recurrence rates after achieving CE-IM. Pooled incidence [per 100 patient-years (PY)] and risk ratios with 95 %CI were obtained. Heterogeneity was measured using the I2 statistic. Subgroup analyses, decided a priori, were performed to explore heterogeneity in results. RESULTS: A total of 39 studies were identified (25-RFA, 13-SRER, and 2 combined). The pooled incidence of any recurrence was 7.5 (95 %CI 6.1 - 9.0)/100 PY with a pooled incidence of IM recurrence rate of 4.8 (95 %CI 3.8 - 5.9)/100 PY, and dysplasia recurrence rate of 2.0 (95 %CI 1.5 - 2.5)/100 PY. Compared to the SRER group, the RFA group had significantly higher overall [8.6 (6.7 - 10.5)/100 PY vs. 5.1 (3.1 - 7)/100 PY, P = 0.01] and IM recurrence rates [5.8 (4.3 - 7.3)/100 PY vs. 3.1 (1.7 - 4)/100 PY, P < 0.01] with no difference in recurrence rates of dysplasia. Significant heterogeneity between studies was identified. The majority of recurrences were amenable to repeat endoscopic eradication therapy (EET). CONCLUSION: The results of this study demonstrate that the incidence rates of overall, IM, and dysplasia recurrence rates post-EET are not inconsiderable and reinforce the importance of close surveillance after achieving CE-IM. PMID- 28573178 TI - Endoscopic esophagogastric anastomosis with luminal apposition Axios stent (LAS) approach: a new concept for hybrid "Lewis Santy". AB - BACKGROUND AND STUDY AIMS: Esophagogastric anastomosis (EGA) has a high risk of leakage. Based upon our experience in endoscopic gastrojejunal anastomosis using LAS, the aim of this study was to verify the technical feasibility and the safety of performing an EGA using a hybrid approach (endoscopic and surgical). MATERIALS AND METHODS: A pilot prospective study was performed on 8 survival pigs. The procedure was carried out in 2 stages: (i) surgical step consisting of an esogastrectomy by laparotomy with separated suture of the esophagus and stomach; (ii) endoscopic esophagogastric anastomosis using the LAS. The first 2 pigs allowed for the setting of the 2 steps procedure, and 6 were included in the study for assessing the efficacy and safety of the procedure with a 3-week survival course. The primary endpoint was morbidity and mortality. RESULTS: All procedures were successfull. The mean operative time was 98 minutes, with a mean endoscopic time of 46 minutes. Three early deaths occurred within the first weeks, unrelated to the LAS anastomosis. At 3 weeks, endoscopic assessment followed by necropsy demonstrated the right position and the endoscopic removability of the stent with good patency of the esophagogastric anastomosis, without leakage of the endoscopic suture. Pathological examination confirmed the patency of the anastomosis with fusion of mucosal and muscle layers. CONCLUSION: Endoscopic esophagogastric anastomosis with LAS is feasible and reproducible, without anastomotic leakage. It could be a new alternative to perform safe anastomoses, as part of a hybrid approach (surgical and endoscopic). PMID- 28573180 TI - Retrospective analysis of large bowel obstruction or perforation caused by oral preparation for colonoscopy. AB - BACKGROUND AND STUDY AIMS: Patients undergoing bowel preparation for colonoscopy are at risk of potentially severe adverse events such as large-bowel obstruction (LBO) and perforation. These patients usually need emergency surgery and the consequences may be fatal. Little is known about the risk factors for LBO and perforation in these circumstances. We sought to establish the natural history of LBO and perforation caused by oral preparation for colonoscopy. PATIENTS AND METHODS: We retrospectively analyzed data from 20 patients with LBO or perforation associated with oral preparation for colonoscopy. All patients were treated at the Showa University Northern Yokohama Hospital (SUNYH) between April 2001 and December 2015. Drugs used for bowel preparation, age, sex, indication for colonoscopy, pathogenesis and treatment were recorded. RESULTS: Eighteen of the patients had LBO and 2 had perforation. Fourteen events occurred at SUNYH, which accounted for 0.016 % of patients who underwent bowel preparation during this period. Seventeen patients were symptomatic when the decision to undertake colonoscopy was made (including 7 who complained of constipation and 4 who complained of abdominal pain; 3e were asymptomatic). Nineteen patients ultimately required surgery, 13 within 3 days of presentation. Eleven patients ultimately required colostomy. There was no perioperative mortality in our cases. CONCLUSION: Large bowel obstruction and perforation are rare events associated with oral preparation for colonoscopy, but frequently require surgery. Exacerbation of constipation might be a risk factor for LBO or perforation. Potentially catastrophic situations can be avoided by early detection and treatment. PMID- 28573179 TI - Small bowel malignancy in patients undergoing capsule endoscopy at a tertiary care academic center: Case series and review of the literature. AB - BACKGROUND AND STUDY AIMS : Small bowel cancer is rare, accounting for < 5 % of all gastrointestinal neoplasms. Capsule endoscopy has become the procedure of choice for non-invasive diagnosis of small bowel diseases. Data on capsule endoscopy diagnosis of small bowel cancer are limited. The objective of the study was to determine the frequency, indications and diagnostic work-up of patients with small bowel malignancy found by capsule endoscopy at a Scottish tertiary center. PATIENTS AND METHODS : In this retrospective study, records all patients who underwent small bowel capsule endoscopy at our center over a 10-year period were reviewed for possible malignancy. Further data were gathered on preceding and subsequent investigations, management and outcome of these patients. RESULTS : From 1949 studies, small bowel malignancies were diagnosed in only 7 patients (0.36 %; 2F/5M; median age 50, range 34 - 67). The main indication was iron deficiency anemia (n = 5). Prior to capsule endoscopy, 6 of 7 patients had bidirectional endoscopies and one had gastroscopy. All prior investigations were normal or nondiagnostic. Two of 7 experienced capsule retention. Five of 7 underwent surgery. Four patients died, giving a 5-year survival rate of 42.9 %. CONCLUSION: Small bowel malignancies diagnosed by capsule endoscopy are rare, and the median age of 50 indicates they are more common in relatively younger patients. Capsule endoscopy is effective at diagnosing a rare malignancy when other imaging modalities have failed. PMID- 28573181 TI - Rings in the esophagus are not always eosinophilic esophagitis: Case series of ring forming lymphocytic esophagitis and review of the literature. AB - Background and study aims Lymphocytic esophagitis (LyE) is a form of chronic esophagitis characterized by edema and lymphocytic infiltration of the epithelial peripapillary fields, without eosinophils. Its significance is unclear, as it was previously thought to have little clinical impact. More recent literature, however, describes a paradigm shift suggesting a distinct entity. We report on 3 patients with dysphagia who were found to have esophageal rings on endoscopy. Histology was consistent with LyE. Additional features reported in this cohort included an esophageal web, esophageal pseudodiverticula and esophageal erythema. We also report a current literature review of the topic. The literature review reported here includes another 37 patients with LyE and rings, for a total of 40 patients. Patients with LyE may present with esophageal rings and other findings. LyE should be considered in the differential diagnosis of esophageal rings. PMID- 28573182 TI - Cecum intubation rate as quality indicator in clinical versus screening colonoscopy. AB - BACKGROUND AND STUDY AIMS : Some guidelines recommend a minimum standard of 90 % cecal intubation rate (CIR) in routine clinics and 95 % in screening colonoscopy, while others have not made this distinction - both with limited evidence to support either view. This study questions the rationale for making such differentiation. PATIENTS AND METHODS: We assessed cecum intubation rates amongst colonoscopies recorded in the Norwegian national quality register Gastronet by 35 endoscopists performing both clinical and screening colonoscopies. Colonoscopies were categorized into primary screening colonoscopy, work-up colonoscopy of screen-positives and clinical colonoscopy or surveillance. Cases with insufficient bowel preparation or mechanical obstruction were excluded. Endoscopists were categorized into "junior" and "senior" endoscopists depending on training and experience. Univariable and multivariable logistic regression analyses were applied. RESULTS : During a 2-year period, 10,267 colonoscopies were included (primary screening colonoscopy: 746; work-up colonoscopy of screen-positives: 2,604; clinical colonoscopy or surveillance: 6917). The crude CIR in clinical routine colonoscopy, primary screening colonoscopy and work-up colonoscopy was 97.1 %, 97.1 % and 98.6 %, respectively. In a multiple logistic regression analysis, there were no differences in CIR between the 3 groups. Poor bowel cleansing and female sex were independent predictors for intubation failure. CONCLUSION : Cecal intubation rate in clinical colonoscopies and colonoscopy screening are similar. There is no reason to differentiate between screening and clinical colonoscopy with regard to CIR. PMID- 28573183 TI - Fiducial markers coupled with 3D PET/CT offer more accurate radiation treatment delivery for locally advanced esophageal cancer. AB - BACKGROUND AND AIMS: The role of three-dimensional positron emission tomography/computed tomography (3 D PET/CT) in esophageal tumors that move with respiration and have potential for significant mucosal inflammation is unclear. The aim of this study was to determine the correlation between gross tumor volumes derived from 3 D PET/CT and endoscopically placed fiducial markers. METHODS: This was a retrospective, IRB approved analysis of 40 patients with esophageal cancer with fiducials implanted and PET/CT. The centroid of each fiducial was identified on PET/CT images. Distance between tumor volume and fiducials was measured using axial slices. Image features were extracted and tested for pathologic response predictability. RESULTS: The median adaptively calculated threshold value of the standardized uptake value (SUV) to define the metabolic tumor volume (MTV) border was 2.50, which corresponded to a median 23 % of the maximum SUV. The median distance between the inferior fiducial centroid and MTV was - 0.60 cm (- 3.9 to 2.7 cm). The median distance between the superior fiducial centroid and MTV was 1.25 cm (- 4.2 to 6.9 cm). There was no correlation between MTV-to-fiducial distances greater than 2 cm and the gastroenterologist who performed the fiducial implantation. Eccentricity demonstrated statistically significant correlations with pathologic response. CONCLUSIONS: There was a stronger correlation between inferior fiducial location and MTV border compared to the superior extent. The etiology of the discordance superiorly is unclear, potentially representing benign secondary esophagitis, presence of malignant nodes, inflammation caused by technical aspects of the fiducial placement itself, or potential submucosal disease. Given the concordance inferiorly and the ability to more precisely set up the patient with daily image guidance matching to fiducials, it may be possible to minimize the planning tumor volume (PTV) margin in select patients, thereby, limiting dose to normal structures. PMID- 28573184 TI - A Comparative Study of Replication-Incompetent and -Competent Adenoviral Therapy Mediated Immune Response in a Murine Glioma Model. AB - Oncolytic virotherapy is a treatment approach with increasing clinical relevance, as indicated by the marked survival benefit seen in animal models and its current exploration in human patients with cancer. The use of an adenovirus vector for this therapeutic modality is common, has significant clinical benefit in animals, and its efficacy has recently been linked to an anti-tumor immune response that occurs following tumor antigen presentation. Here, we analyzed the adaptive immune system's response following viral infection by comparing replication incompetent and replication-competent adenoviral vectors. Our findings suggest that cell death caused by replication-competent adenoviral vectors is required to induce a significant anti-tumor immune response and survival benefits in immunocompetent mice bearing intracranial glioma. We observed significant changes in the repertoire of immune cells in the brain and draining lymph nodes and significant recruitment of CD103+ dendritic cells (DCs) in response to oncolytic adenoviral therapy, suggesting the active role of the immune system in anti-tumor response. Our data suggest that the response to oncolytic virotherapy is accompanied by local and systemic immune responses and should be taken in consideration in the future design of the clinical studies evaluating oncolytic virotherapy in patients with glioblastoma multiforme (GBM). PMID- 28573185 TI - HCV T Cell Receptor Chain Modifications to Enhance Expression, Pairing, and Antigen Recognition in T Cells for Adoptive Transfer. AB - T cell receptor (TCR)-gene-modified T cells for adoptive cell transfer can mediate objective clinical responses in melanoma and other malignancies. When introducing a second TCR, mispairing between the endogenous and introduced alpha and beta TCR chains limits expression of the introduced TCR, which can result in impaired efficacy or off-target reactivity and autoimmunity. One approach to promote proper TCR chain pairing involves modifications of the introduced TCR genes: introducing a disulfide bridge, substituting murine for human constant regions, codon optimization, TCR chain leucine zipper fusions, and a single-chain TCR. We have introduced these modifications into our hepatitis C virus (HCV) reactive TCR and utilize a marker gene, CD34t, which allows us to directly compare transduction efficiency with TCR expression and T cell function. Our results reveal that of the TCRs tested, T cells expressing the murine Cbeta2 TCR or leucine zipper TCR have the highest levels of expression and the highest percentage of lytic and interferon-gamma (IFN-gamma)-producing T cells. Our studies give us a better understanding of how TCR modifications impact TCR expression and T cell function that may allow for optimization of TCR-modified T cells for adoptive cell transfer to treat patients with malignancies. PMID- 28573186 TI - Lifelong Prophylaxis With Trimethoprim-Sulfamethoxazole for Prevention of Outbreak of Pneumocystis jirovecii Pneumonia in Kidney Transplant Recipients. AB - BACKGROUND: Outbreaks of Pneumocystis jirovecii pneumonia (PCP) in kidney transplant recipients are frequently reported worldwide. However, the general guidelines propose only short-term prophylaxis with trimethoprim-sulfamethoxazole after kidney transplantation. We experienced 3 PCP outbreaks in the last 10 years despite providing the recommended prophylaxis. The purpose of this study was to find a prophylaxis regimen that could successfully prevent future PCP outbreaks in immunosuppressed kidney transplant recipients. METHODS: Occurrence of PCP at our hospital since 2004 was reviewed. A total of 48 cases were diagnosed from July 2004 through December 2014. Genotypes of P. jirovecii were determined in these cases. RESULTS: Three PCP outbreaks by 3 different genotypes of P. jirovecii in each outbreak occurred with 2-year intervals in last 10 years. Molecular analysis showed that each intraoutbreak was caused by identical P. jirovecii, whereas interoutbreaks were caused by different genotypes. Although short-term prophylaxis was provided to all kidney recipients after each outbreak after identification of a single PCP case, additional outbreaks were not prevented because the universal prophylaxis had already been completed when new case of PCP emerged. CONCLUSIONS: The contagious nature of P. jirovecii allows easy development of outbreaks of PCP in immunosuppressed kidney transplant recipients. Although the universal short-term prophylaxis is effective in controlling ongoing outbreak, lifelong prophylaxis of kidney transplant recipients should be considered to prevent new outbreaks. PMID- 28573187 TI - The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, Guide. AB - BACKGROUND: Allografts from living donors survive longer than those from deceased donors but the role of HLA mismatching in living kidney donation is still in question. We examined the effect of HLA compatibility on kidney allograft survival from living donors by studying all first adult kidney transplants performed in the United States over 25 years. METHODS: Using the United Network for Organ Sharing data, we identified first kidney transplants between October 1, 1987, and December 31, 2013. Recipients were classified by their number of HLA mismatches and stratified by donor origin. Cox multivariate regression analyses adjusting for recipient and donor transplant characteristics were performed to determine impact of HLA compatibility on kidney allograft survival for all living donors and for living related and living unrelated subsets. RESULTS: There were 66 596 first adult transplants from living donors with 348 960 years of follow up. We found a linear relationship between HLA mismatch and allograft survival. In adjusted analyses, among all living donors, 1 mismatch conferred a 44% higher risk, whereas 6 mismatches conferred a twofold higher risk of allograft failure. When using 0-mismatched full siblings as a reference, living-donor kidneys reduce the hazard of failure by approximately 34% when compared with deceased donors. Twenty-five years of transplant experience, stratified by donor source, was summarized and presented as a guide for allocation. CONCLUSIONS: These data reinforce the importance of optimizing HLA matching to further improve survival in first adult kidney allografts in the future, especially in living unrelated donations, when possible. PMID- 28573188 TI - A Hyper-Crosslinked Carbohydrate Polymer Scaffold Facilitates Lineage Commitment and Maintains a Reserve Pool of Proliferating Cardiovascular Progenitors. AB - BACKGROUND: Cardiovascular progenitor cells (CPCs) have been cultured on various scaffolds to resolve the challenge of cell retention after transplantation and to improve functional outcome after cell-based cardiac therapy. Previous studies have reported successful culture of fully differentiated cardiomyocytes on scaffolds of various types, and ongoing efforts are focused on optimizing the mix of cardiomyocytes and endothelial cells as well as on the identification of a source of progenitors capable of reversing cardiovascular damage. A scaffold culture that fosters cell differentiation into cardiomyocytes and endothelial cells while maintaining a progenitor reserve would benefit allogeneic cell transplantation. METHODS: Isl-1 + c-Kit + CPCs were isolated as clonal populations from human and sheep heart tissue. After hyper-crosslinked carbohydrate polymer scaffold culture, cells were assessed for differentiation, intracellular signaling, cell cycling, and growth factor/chemokine expression using real time polymerase chain reaction, flow cytometry, immunohistochemistry, and calcium staining. RESULTS: Insulin-like growth factor 1, hepatocyte growth factor, and stromal cell derived factor 1alpha paracrine factors were induced, protein kinase B signaling was activated, extracellular signal-regulated kinase phosphorylation was reduced and differentiation into both cardiomyocytes and endothelial cells was induced by scaffold-based cell culture. Interestingly, movement of CPCs out of the G1 phase of the cell cycle and increased expression of pluripotency genes PLOU5F1 (Oct4) and T (Brachyury) within a portion of the cultured population occurred, which suggests the maintenance of a progenitor population. Two-color immunostaining and 3-color fluorescence-activated cell sorting analysis confirmed the presence of both Isl-1 expressing undifferentiated cells and differentiated cells identified by troponin T and von Willebrand factor expression. Ki-67 labeling verified the presence of proliferating cells that remained in situ alongside the differentiated functional derivatives. CONCLUSIONS: Cloned Isl-1 + c-kit + CPCs maintained on a hyper-cross linked polymer scaffold retain dual potential for proliferation and differentiation, providing a scaffold-based stem cell source for transplantation of committed and proliferating cardiovascular progenitors for functional testing in preclinical models of cell-based repair. PMID- 28573189 TI - Outcome in Pancreas Grafts After BK Virus Viremia in Simultaneous Pancreas-Kidney Transplants: A Single-Center Case Report. PMID- 28573190 TI - Randomized Trial of Machine Perfusion Versus Cold Storage in Recipients of Deceased Donor Kidney Transplants With High Incidence of Delayed Graft Function. AB - BACKGROUND: This study compared the use of static cold storage versus continuous hypothermic machine perfusion in a cohort of kidney transplant recipients at high risk for delayed graft function (DGF). METHODS: In this national, multicenter, and controlled trial, 80 pairs of kidneys recovered from brain-dead deceased donors were randomized to cold storage or machine perfusion, transplanted, and followed up for 12 months. The primary endpoint was the incidence of DGF. Secondary endpoints included the duration of DGF, hospital stay, primary nonfunction, estimated glomerular filtration rate, acute rejection, and allograft and patient survivals. RESULTS: Mean cold ischemia time was high but not different between the 2 groups (25.6 +/- 6.6 hours vs 25.05 +/- 6.3 hours, 0.937). The incidence of DGF was lower in the machine perfusion compared with cold storage group (61% vs. 45%, P = 0.031). Machine perfusion was independently associated with a reduced risk of DGF (odds ratio, 0.49; 95% confidence interval, 0.26-0.95). Mean estimated glomerular filtration rate tended to be higher at day 28 (40.6 +/- 19.9 mL/min per 1.73 m2 vs 49.0 +/- 26.9 mL/min per 1.73 m2; P = 0.262) and 1 year (48.3 +/- 19.8 mL/min per 1.73 m2 vs 54.4 +/- 28.6 mL/min per 1.73 m2; P = 0.201) in the machine perfusion group. No differences in the incidence of acute rejection, primary nonfunction (0% vs 2.5%), graft loss (7.5% vs 10%), or death (8.8% vs 6.3%) were observed. CONCLUSIONS: In this cohort of recipients of deceased donor kidneys with high mean cold ischemia time and high incidence of DGF, the use of continuous machine perfusion was associated with a reduced risk of DGF compared with the traditional cold storage preservation method. PMID- 28573193 TI - Miraculous Chemistry on the Han River. PMID- 28573192 TI - Modeling the Effect of the Aryl Hydrocarbon Receptor on Transplant Immunity. AB - BACKGROUND: Exposure to pollutants through inhalation is a risk factor for lung diseases including cancer, asthma, and lung transplant rejection, but knowledge of the effects of inhaled pollutants on pathologies outside of the lung is limited. METHODS: Using the minor-mismatched model of male C57BL/6J (B6) to female B6 skin grafts, recipient mice were treated with an inhaled urban dust particle sample every 3 days before and after grafting. Graft survival time was determined, and analysis of the resulting immune response was performed at time before rejection. RESULTS: Significant prolongation of male skin grafts occurred in recipient female mice treated with urban dust particles compared with controls and was found to be dependent on aryl hydrocarbon receptor (AHR) expression in the recipient mouse. T cell responses to the male histocompatibility antigen (H Y) Dby were not altered by exposure to pollutants. A reduction in the frequency of IFNgamma-producing CD4 T cells infiltrating the graft on day 7 posttransplant was observed. Flow cytometry analysis revealed that AHR expression is upregulated in IFNgamma-producing CD4 T cells during immune responses in vitro and in vivo. CONCLUSIONS: Surprisingly, inhalation of a pollutant standard was found to prolong graft survival in a minor-mismatched skin graft model in an AHR-dependent manner. One possible mechanism may be an effect on IFNgamma-producing CD4 T cells responding to donor antigen. The increased expression of AHR in this CD4 T cell subset suggests that AHR ligands within the particulate matter may be directly affecting the type 1 T helper cell response in this model. PMID- 28573191 TI - Invasive Candida Infections in Liver Transplant Recipients: Clinical Features and Risk Factors for Mortality. AB - BACKGROUND: Invasive fungal infections remain a leading cause of morbidity and mortality among liver transplant recipients (LTRs). In this patient population, invasive Candida infections (ICIs) account for the large majority of cases. To date, only small studies and case-series analysing clinical presentation and risk factors for mortality in LTRs with ICIs are available. METHODS: We performed a retrospective multicenter multinational study in 10 centers in Europe and Brazil. All consecutive LTRs developing ICIs during the period January 2011 to December 2013 were included in the study. RESULTS: A total of 42 LTRs were included. Median age was 52.5 years, and 78.6% of patients were men. Viral hepatitis was the most common cause for liver transplantation (42.9%). Candidemia represented the majority of cases (24, 57.1%), followed by intra-abdominal candidiasis (18, 42.9%). Overall 30-day mortality was 23.8%, with higher mortality in patients with candidemia compared with intra-abdominal candidiasis (37.5% vs 5.6%, P = 0.02). Multivariate analysis showed candidemia to be a risk factor associated with mortality among LTRs presenting ICIs (odds ratio, 11.86; 95% confidence interval, 1.5-280; P = 0.01). Candida albicans represented the most common isolate (59.5%). High rates of antifungal resistances were found, with 16.7% and 4.8% of isolates displaying resistance to azoles and caspofungin, respectively. CONCLUSIONS: Our study confirms the occurrence of high mortality rates in LTRs developing ICIs. Mortality rates varied according to the type of infection, with candidemia representing a risk factor for mortality. The high rates of antifungal resistance should be considered in the choice of the empiric antifungal regimen. PMID- 28573194 TI - A Conversation with Peter Hore. PMID- 28573195 TI - Tiny Temperature Sensors. PMID- 28573196 TI - Enhancing the Catalytic Activity in the Solid State: Metal-Organic Frameworks to the Rescue. PMID- 28573197 TI - An Electric Field Induced Breath for Metal-Organic Frameworks. PMID- 28573198 TI - Concerted One-Electron Two-Proton Transfer Processes in Models Inspired by the Tyr-His Couple of Photosystem II. AB - Nature employs a TyrZ-His pair as a redox relay that couples proton transfer to the redox process between P680 and the water oxidizing catalyst in photosystem II. Artificial redox relays composed of different benzimidazole-phenol dyads (benzimidazole models His and phenol models Tyr) with substituents designed to simulate the hydrogen bond network surrounding the TyrZ-His pair have been prepared. When the benzimidazole substituents are strong proton acceptors such as primary or tertiary amines, theory predicts that a concerted two proton transfer process associated with the electrochemical oxidation of the phenol will take place. Also, theory predicts a decrease in the redox potential of the phenol by ~300 mV and a small kinetic isotope effect (KIE). Indeed, electrochemical, spectroelectrochemical, and KIE experimental data are consistent with these predictions. Notably, these results were obtained by using theory to guide the rational design of artificial systems and have implications for managing proton activity to optimize efficiency at energy conversion sites involving water oxidation and reduction. PMID- 28573199 TI - Combinatorial Discovery of Defined Substrates That Promote a Stem Cell State in Malignant Melanoma. AB - The tumor microenvironment is implicated in orchestrating cancer cell transformation and metastasis. However, specific cell-ligand interactions between cancer cells and the extracellular matrix are difficult to decipher due to a dynamic and multivariate presentation of many signaling molecules. Here we report a versatile peptide microarray platform that is capable of screening for cancer cell phenotypic changes in response to ligand-receptor interactions. Using a screen of 78 peptide combinations derived from proteins present in the melanoma microenvironment, we identify a proteoglycan binding and bone morphogenic protein 7 (BMP7) derived sequence that selectively promotes the expression of several putative melanoma initiating cell markers. We characterize signaling associated with each of these peptides in the activation of melanoma pro-tumorigenic signaling and reveal a role for proteoglycan mediated adhesion and signaling through Smad 2/3. A defined substratum that controls the state of malignant melanoma may prove useful in spatially normalizing a heterogeneous population of tumor cells for discovery of therapeutics that target a specific state and for identifying new drug targets and reagents for intervention. PMID- 28573200 TI - Electrically Induced Breathing of the MIL-53(Cr) Metal-Organic Framework. AB - The breathing behavior of the MIL-53(Cr) metal-organic framework (MOF) has been explored previously upon guest-adsorption and thermal and mechanical stimuli. Here, advanced molecular simulations based on the use of an accurate force field to describe the flexibility of this porous framework demonstrate that the application of an electrical field induces the structural switching of this MOF leading to a first-order transition and a volume change of more than 40%. This motivated us to electrically tune the pore size of MIL-53(Cr) with the idea to propose a new concept to selectively capture CO2 over CH4 via a molecular sieving that paves the way toward the optimization of current separation-based processes. PMID- 28573201 TI - Materials Genomics Screens for Adaptive Ion Transport Behavior by Redox Switchable Microporous Polymer Membranes in Lithium-Sulfur Batteries. AB - Selective ion transport across membranes is critical to the performance of many electrochemical energy storage devices. While design strategies enabling ion selective transport are well-established, enhancements in membrane selectivity are made at the expense of ionic conductivity. To design membranes with both high selectivity and high ionic conductivity, there are cues to follow from biological systems, where regulated transport of ions across membranes is achieved by transmembrane proteins. The transport functions of these proteins are sensitive to their environment: physical or chemical perturbations to that environment are met with an adaptive response. Here we advance an analogous strategy for achieving adaptive ion transport in microporous polymer membranes. Along the polymer backbone are placed redox-active switches that are activated in situ, at a prescribed electrochemical potential, by the device's active materials when they enter the membrane's pore. This transformation has little influence on the membrane's ionic conductivity; however, the active-material blocking ability of the membrane is enhanced. We show that when used in lithium-sulfur batteries, these membranes offer markedly improved capacity, efficiency, and cycle-life by sequestering polysulfides in the cathode. The origins and implications of this behavior are explored in detail and point to new opportunities for responsive membranes in battery technology development. PMID- 28573202 TI - Rich Dynamics Underlying Solution Reactions Revealed by Sampling and Data Mining of Reactive Trajectories. AB - Efficient sampling in both configuration and trajectory spaces, combined with mechanism analyses via data mining, allows a systematic investigation of the thermodynamics, kinetics, and molecular-detailed dynamics of chemical reactions in solution. Through a Bayesian learning algorithm, the reaction coordinate(s) of a (retro-)Claisen rearrangement in bulk water was variationally optimized. The bond formation/breakage was found to couple with intramolecular charge separation and dipole change, and significant dynamic solvent effects manifest, leading to the "in-water" acceleration of Claisen rearrangement. In addition, the vibrational modes of the reactant and the solvation states are significantly coupled to the reaction dynamics, leading to heterogeneous and oscillatory reaction paths. The calculated reaction rate is well interpreted by the Kramers' theory with a diffusion term accounting for solvent-solute interactions. These findings demonstrated that the reaction mechanisms can be complicated in homogeneous solutions since the solvent-solute interactions can profoundly influence the reaction dynamics and the energy transfer process. PMID- 28573203 TI - Influence of Vapor Deposition on Structural and Charge Transport Properties of Ethylbenzene Films. AB - Organic glass films formed by physical vapor deposition exhibit enhanced stability relative to those formed by conventional liquid cooling and aging techniques. Recently, experimental and computational evidence has emerged indicating that the average molecular orientation can be tuned by controlling the substrate temperature at which these "stable glasses" are grown. In this work, we present a comprehensive all-atom simulation study of ethylbenzene, a canonical stable-glass former, using a computational film formation procedure that closely mimics the vapor deposition process. Atomistic studies of experimentally formed vapor-deposited glasses have not been performed before, and this study therefore begins by verifying that the model and method utilized here reproduces key structural features observed experimentally. Having established agreement between several simulated and experimental macroscopic observables, simulations are used to examine the substrate temperature dependence of molecular orientation. The results indicate that ethylbenzene glasses are anisotropic, depending upon substrate temperature, and that this dependence can be understood from the orientation present at the surface of the equilibrium liquid. By treating ethylbenzene as a simple model for molecular semiconducting materials, a quantum chemical analysis is then used to show that the vapor-deposited glasses exhibit decreased energetic disorder and increased magnitude of the mean-squared transfer integral relative to isotropic, liquid-cooled films, an effect that is attributed to the anisotropic ordering of the molecular film. These results suggest a novel structure-function simulation strategy capable of tuning the electronic properties of organic semiconducting glasses prior to experimental deposition, which could have considerable potential for organic electronic materials design. PMID- 28573205 TI - Prediction of Organic Reaction Outcomes Using Machine Learning. AB - Computer assistance in synthesis design has existed for over 40 years, yet retrosynthesis planning software has struggled to achieve widespread adoption. One critical challenge in developing high-quality pathway suggestions is that proposed reaction steps often fail when attempted in the laboratory, despite initially seeming viable. The true measure of success for any synthesis program is whether the predicted outcome matches what is observed experimentally. We report a model framework for anticipating reaction outcomes that combines the traditional use of reaction templates with the flexibility in pattern recognition afforded by neural networks. Using 15 000 experimental reaction records from granted United States patents, a model is trained to select the major (recorded) product by ranking a self-generated list of candidates where one candidate is known to be the major product. Candidate reactions are represented using a unique edit-based representation that emphasizes the fundamental transformation from reactants to products, rather than the constituent molecules' overall structures. In a 5-fold cross-validation, the trained model assigns the major product rank 1 in 71.8% of cases, rank <=3 in 86.7% of cases, and rank <=5 in 90.8% of cases. PMID- 28573204 TI - A Fluorescence in Situ Hybridization Method To Quantify mRNA Translation by Visualizing Ribosome-mRNA Interactions in Single Cells. AB - Single-molecule fluorescence in situ hybridization (smFISH) is a simple and widely used method to measure mRNA transcript abundance and localization in single cells. A comparable single-molecule in situ method to measure mRNA translation would enable a more complete understanding of gene regulation. Here we describe a fluorescence assay to detect ribosome interactions with mRNA (FLARIM). The method adapts smFISH to visualize and characterize translation of single molecules of mRNA in fixed cells. To visualize ribosome-mRNA interactions, we use pairs of oligonucleotide probes that bind separately to ribosomes (via rRNA) and to the mRNA of interest, and that produce strong fluorescence signals via the hybridization chain reaction (HCR) when the probes are in close proximity. FLARIM does not require genetic manipulation, is applicable to practically any endogenous mRNA transcript, and provides both spatial and temporal information. We demonstrate that FLARIM is sensitive to changes in ribosome association with mRNA upon inhibition of global translation with puromycin. We also show that FLARIM detects changes in ribosome association with an mRNA whose translation is upregulated in response to increased concentrations of iron. PMID- 28573206 TI - Heterogeneous Epoxide Carbonylation by Cooperative Ion-Pair Catalysis in Co(CO)4- Incorporated Cr-MIL-101. AB - Despite the commercial desirability of epoxide carbonylation to beta-lactones, the reliance of this process on homogeneous catalysts makes its industrial application challenging. Here we report the preparation and use of a Co(CO)4- incorporated Cr-MIL-101 (Co(CO)4?Cr-MIL-101, Cr-MIL-101 = Cr3O(BDC)3F, H2BDC = 1,4-benzenedicarboxylic acid) heterogeneous catalyst for the ring-expansion carbonylation of epoxides, whose activity, selectivity, and substrate scope are on par with those of the reported homogeneous catalysts. We ascribe the observed performance to the unique cooperativity between the postsynthetically introduced Co(CO)4- and the site-isolated Lewis acidic Cr(III) centers in the metal-organic framework (MOF). The heterogeneous nature of Co(CO)4?Cr-MIL-101 allows the first demonstration of gas-phase continuous-flow production of beta-lactones from epoxides, attesting to the potential applicability of the heterogeneous epoxide carbonylation strategy. PMID- 28573207 TI - Epidithiodiketopiperazines: Strain-Promoted Thiol-Mediated Cellular Uptake at the Highest Tension. AB - The disulfide dihedral angle in epidithiodiketopiperazines (ETPs) is near 0 degrees . Application of this highest possible ring tension to strain-promoted thiol-mediated uptake results in efficient delivery to the cytosol and nucleus. Compared to the previous best asparagusic acid (AspA), ring-opening disulfide exchange with ETPs occurs more efficiently even with nonactivated thiols, and the resulting thiols exchange rapidly with nonactivated disulfides. ETP-mediated cellular uptake is more than 20 times more efficient compared to AspA, occurs without endosomal capture, depends on temperature, and is "unstoppable" by inhibitors of endocytosis and conventional thiol-mediated uptake, including siRNA against the transferrin receptor. These results suggest that ETP-mediated uptake not only maximizes delivery to the cytosol and nucleus but also opens the door to a new multitarget hopping mode of action. PMID- 28573208 TI - Compaction of Duplex Nucleic Acids upon Native Electrospray Mass Spectrometry. AB - We report on the fate of nucleic acids conformation in the gas phase as sampled using native mass spectrometry coupled to ion mobility spectrometry. On the basis of several successful reports for proteins and their complexes, the technique has become popular in structural biology, and the conformation survival becomes more and more taken for granted. Surprisingly, we found that DNA and RNA duplexes, at the electrospray charge states naturally obtained from native solution conditions (>=100 mM aqueous NH4OAc), are significantly more compact in the gas phase compared to the canonical solution structures. The compaction is observed for all duplex sizes (gas-phase structures are more compact than canonical B-helices by ~20% for 12-bp, and by up to ~30% for 36-bp duplexes), and for DNA and RNA alike. Molecular modeling (density functional calculations on small helices, semiempirical calculations on up to 12-bp, and molecular dynamics on up to 36-bp duplexes) demonstrates that the compaction is due to phosphate group self solvation prevailing over Coulomb repulsion. Molecular dynamics simulations starting from solution structures do not reproduce the experimental compaction. To be experimentally relevant, molecular dynamics sampling should reflect the progressive structural rearrangements occurring during desolvation. For nucleic acid duplexes, the compaction observed for low charge states results from novel phosphate-phosphate hydrogen bonds formed across both grooves at the very late stages of electrospray. PMID- 28573209 TI - Noncanonical Function of a Small-Molecular Virulence Factor Coronatine against Plant Immunity: An In Vivo Raman Imaging Approach. AB - Coronatine (1), a small-molecular virulence factor produced by plant-pathogenic bacteria, promotes bacterial infection by inducing the opening of stomatal pores, the major route of bacterial entry into the plant, via the jasmonate-mediated COI1-JAZ signaling pathway. However, this pathway is also important for multiple plant functions, including defense against wounding by herbivorous insects. Thus, suppression of the COI1-JAZ signaling pathway to block bacterial infection would concomitantly impair plant defense against herbivorous wounding. Here, we report additional, COI1-JAZ-independent, action of 1 in Arabidopsis thaliana guard cells. First, we found that a stereoisomer of 1 regulates the movement of Arabidopsis guard cells without affecting COI1-JAZ signaling. Second, we found using alkyne-tagged Raman imaging (ATRI) that 1 is localized to the endoplasmic reticulum (ER) of living guard cells of Arabidopsis. The use of arc6 mutant lacking chloroplast formation was pivotal to circumvent the issue of autofluorescence during ATRI. These findings indicate that 1 has an ER-related action on Arabidopsis stomata that bypasses the COI1-JAZ signaling module. It may be possible to suppress the action of 1 on stomata without impairing plant defense responses against herbivores. PMID- 28573210 TI - Topology Engineering of Proteins in Vivo Using Genetically Encoded, Mechanically Interlocking SpyX Modules for Enhanced Stability. AB - Recombinant proteins are traditionally limited to linear configuration. Herein, we report in vivo protein topology engineering using highly efficient, mechanically interlocking SpyX modules named AXB and BXA. SpyX modules are protein domains composed of p53dim (X), SpyTag (A), and SpyCatcher (B). The p53dim guides the intertwining of the two nascent protein chains followed by autocatalytic isopeptide bond formation between SpyTag and SpyCatcher to fulfill the interlocking, leading to a variety of backbone topologies. Direct expression of AXB or BXA produces protein catenanes with distinct ring sizes. Recombinant proteins containing SpyX modules are obtained either as mechanically interlocked obligate dimers if the protein of interest is fused to the N- or C-terminus of SpyX modules, or as star proteins if the protein is fused to both N- and C termini. As examples, cellular syntheses of dimers of (GB1)2 (where GB1 stands for immunoglobulin-binding domain B1 of streptococcal protein G) and of four-arm elastin-like star proteins were demonstrated. Comparison of the catenation efficiencies in different constructs reveals that BXA is generally much more effective than AXB, which is rationalized by the arrangement of three domains in space. Mechanical interlocking induces considerable stability enhancement. Both AXB and BXA have a melting point ~20 degrees C higher than the linear controls and the BXA catenane has a melting point ~2 degrees C higher than the cyclic control BX'A. Notably, four-arm elastin-like star proteins demonstrate remarkable tolerance against trypsin digestion. The SpyX modules provide a convenient and versatile approach to construct unconventional protein topologies via the "assembly-reaction" synergy, which opens a new horizon in protein science for stability enhancement and function reinforcement via topology engineering. PMID- 28573211 TI - A Comparison of Photocatalytic Activities of Gold Nanoparticles Following Plasmonic and Interband Excitation and a Strategy for Harnessing Interband Hot Carriers for Solution Phase Photocatalysis. AB - Light driven excitation of gold nanoparticles (GNPs) has emerged as a potential strategy to generate hot carriers for photocatalysis through excitation of localized surface plasmon resonance (LSPR). In contrast, carrier generation through excitation of interband transitions remains a less explored and underestimated pathway for photocatalytic activity. Photoinduced oxidative etching of GNPs with FeCl3 was investigated as a model reaction in order to elucidate the effects of both types of transitions. The quantitative results show that interband transitions more efficiently generate hot carriers and that those carriers exhibit higher reactivity as compared to those generated solely by LSPR. Further, leveraging the strong pi-acidic character of the resulting photogenerated Au+ hole, an interband transition induced cyclization reaction of alkynylphenols was developed. Notably, alkyne coordination to the Au+ hole intercepts the classic oxidation event and leads to the formation of the catalytically active gold clusters on subnanometer scale. PMID- 28573212 TI - Bio-Orthogonal Mediated Nucleic Acid Transfection of Cells via Cell Surface Engineering. AB - The efficient delivery of foreign nucleic acids (transfection) into cells is a critical tool for fundamental biomedical research and a pillar of several biotechnology industries. There are currently three main strategies for transfection including reagent, instrument, and viral based methods. Each technology has significantly advanced cell transfection; however, reagent based methods have captured the majority of the transfection market due to their relatively low cost and ease of use. This general method relies on the efficient packaging of a reagent with nucleic acids to form a stable complex that is subsequently associated and delivered to cells via nonspecific electrostatic targeting. Reagent transfection methods generally use various polyamine cationic type molecules to condense with negatively charged nucleic acids into a highly positively charged complex, which is subsequently delivered to negatively charged cells in culture for association, internalization, release, and expression. Although this appears to be a straightforward procedure, there are several major issues including toxicity, low efficiency, sorting of viable transfected from nontransfected cells, and limited scope of transfectable cell types. Herein, we report a new strategy (SnapFect) for nucleic acid transfection to cells that does not rely on electrostatic interactions but instead uses an integrated approach combining bio-orthogonal liposome fusion, click chemistry, and cell surface engineering. We show that a target cell population is rapidly and efficiently engineered to present a bio-orthogonal functional group on its cell surface through nanoparticle liposome delivery and fusion. A complementary bio-orthogonal nucleic acid complex is then formed and delivered to which chemoselective click chemistry induced transfection occurs to the primed cell. This new strategy requires minimal time, steps, and reagents and leads to superior transfection results for a broad range of cell types. Moreover the transfection is efficient with high cell viability and does not require a postsorting step to separate transfected from nontransfected cells in the cell population. We also show for the first time a precision transfection strategy where a single cell type in a coculture is target transfected via bio-orthogonal click chemistry. PMID- 28573214 TI - SegAuth: A Segment-based Approach to Behavioral Biometric Authentication. AB - Many studies have been conducted to apply behavioral biometric authentication on/with mobile devices and they have shown promising results. However, the concern about the verification accuracy of behavioral biometrics is still common given the dynamic nature of behavioral biometrics. In this paper, we address the accuracy concern from a new perspective-behavior segments, that is, segments of a gesture instead of the whole gesture as the basic building block for behavioral biometric authentication. With this unique perspective, we propose a new behavioral biometric authentication method called SegAuth, which can be applied to various gesture or motion based authentication scenarios. SegAuth can achieve high accuracy by focusing on each user's distinctive gesture segments that frequently appear across his or her gestures. In SegAuth, a time series derived from a gesture/motion is first partitioned into segments and then transformed into a set of string tokens in which the tokens representing distinctive, repetitive segments are associated with higher genuine probabilities than those tokens that are common across users. An overall genuine score calculated from all the tokens derived from a gesture is used to determine the user's authenticity. We have assessed the effectiveness of SegAuth using 4 different datasets. Our experimental results demonstrate that SegAuth can achieve higher accuracy consistently than existing popular methods on the evaluation datasets. PMID- 28573213 TI - Chemoproteomic Profiling of Bile Acid Interacting Proteins. AB - Bile acids (BAs) are a family of endogenous metabolites synthesized from cholesterol in liver and modified by microbiota in gut. Being amphipathic molecules, the major function of BAs is to help with dietary lipid digestion. In addition, they also act as signaling molecules to regulate lipid and glucose metabolism as well as gut microbiota composition in the host. Remarkably, recent discoveries of the dedicated receptors for BAs such as FXR and TGR5 have uncovered a number of novel actions of BAs as signaling hormones which play significant roles in both physiological and pathological conditions. Disorders in BAs' metabolism are closely related to metabolic syndrome and intestinal and neurodegenerative diseases. Though BA-based therapies have been clinically implemented for decades, the regulatory mechanism of BA is still poorly understood and a comprehensive characterization of BA-interacting proteins in proteome remains elusive. We herein describe a chemoproteomic strategy that uses a number of structurally diverse, clickable, and photoreactive BA-based probes in combination with quantitative mass spectrometry to globally profile BA interacting proteins in mammalian cells. Over 600 BA-interacting protein targets were identified, including known endogenous receptors and transporters of BA. Analysis of these novel BA-interacting proteins revealed that they are mainly enriched in functional pathways such as endoplasmic reticulum (ER) stress response and lipid metabolism, and are predicted with strong implications with Alzheimer's disease, non-alcoholic fatty liver disease, and diarrhea. Our findings will significantly improve the current understanding of BAs' regulatory roles in human physiology and diseases. PMID- 28573215 TI - Molecular, Histologic, and Radiologic Findings of High-Grade Invasive Adenocarcinoma Arising in Oncocytic Subtype of Intraductal Papillary Mucinous Neoplasm: A Case Report and Review of Literature. AB - Background: We present a case of adenocarcinoma arising in the oncocytic subtype of intraductal papillary mucinous neoplasm (O-IPMN), with emphasis on the molecular findings in the adenocarcinoma component. Tissue microdissection and next-generation sequencing were performed using a 26 gene panel (AKT1, ALK, APC, BRAF, CDH1, CTNNB1, EGFR, ERBB2, FBXW7, FGFR2, FOXL2, GNAQ, GNAS, KIT, KRAS, MAP2K1, MET, MSH6, NRAS, PDGFRA, PIK3CA, PTEN, SMAD4, SRC, STK11, TP53) of cancer related genes. Case Presentation: A 69-year-old Caucasian female presented with chest pain and was found to have findings consistent with acute pancreatitis. During her work-up, computed tomography scan revealed a large cystic and solid mass in the tail of the pancreas. She recovered from her acute pancreatitis and was discharged home. She later returned for resection of her mass. Results: Evaluation of three microdissected regions of tumor demonstrated no identifiable nonsynonymous alterations in any of the three regions, within the targeted genes. Conclusion: This case demonstrates that the O-IPMN is a molecularly distinct subtype, and we conclude that adenocarcinoma arising in these neoplasms shows molecularly distinct tumorigenesis from traditional pancreatic ductal adenocarcinoma. These differences may help explain the improved survival with invasive adenocarcinoma arising from these lesions compared with traditional ductal adenocarcinoma. PMID- 28573216 TI - ANTIOXIDANT ACTIVITY AND A-AMYLASE INHIBITORY POTENTIAL OF ROSA CANINA L. AB - BACKGROUND: Diabetes mellitus is one of the most common endocrinal disorders and medicinal plants continue to play an important role in the management of this disease. In this study, Rosa canina was investigated for the antioxidant and alpha-amylase inhibition activities. MATERIALS AND METHODS: Methanolic extract of Rosa canina was investigated for its potential antioxidant activity. The extracts' total phenolic and flavonoid contents and scavenging capacity for free radicals were evaluated. The alpha-amylase inhibition assay was also carried. RESULTS: Rosa canina extract exhibits a total Phenolic and flavonoid levels respectively (21.918 mg GAE/g and 2.647mg ER/g). The free radical scavenging activity was found to be prominent against DPPH with an IC50 of 0.668 mg/ml and against ABTS with an IC50 of 0.467 mg/ml. Extract showed a significant ferric ion reducing activities with an IC50 of4.962 mg/ml. CONCLUSION: Rosa canina exerted a higher inhibitory activity against alpha-amylase. The obtained results support the antidiabetic use of rosa canina. PMID- 28573218 TI - EFFECT OF THAI SARAPHI FLOWER EXTRACTS ON WT1 AND BCR/ABL PROTEIN EXPRESSION IN LEUKEMIC CELL LINES. AB - BACKGROUND: Saraphi (Mammea siamensis) is a Thai traditional herb. In this study, the cytotoxic effects of crude ethanolic and fractional extracts including hexane, ethyl acetate, and methanol fractions from M. siamensis flowers were investigated in order to determine their effect on WT1 expression in Molt4 and K562 cells and Bcr/Abl expression in K562 cells. MATERIALS AND METHODS: The flowers of M. siamensis were extracted using ethanol. The ethanol flower extract was further fractionated with hexane, ethyl acetate, and methanol. Cytotoxic effects were measured by the MTT assay. Bcr/Abl and WT1 protein levels after treatments were determined by Western blotting. The total cell number was determined via the typan blue exclusion method. RESULTS: The hexane fraction showed the strongest cytotoxic activity on Molt4 and K562 cells, with IC50 values of 2.6 and 77.6 MUg/ml, respectively. The hexane extract decreased Bcr/Abl protein expression in K562 cells by 74.6% and WT1 protein expressions in Molt4 and K562 cells by 68.4 and 72.1%, respectively. Total cell numbers were decreased by 66.2 and 48.7% in Molt4 and K562 cells, respectively. Mammea E/BB (main active compound) significantly decreased both Bcr/Abl and WTlprotein expressions by 75 and 49.5%, respectively when compared to vehicle control. CONCLUSION: The hexane fraction from M. siamensis flowers inhibited cell proliferation via the suppression of WT1 expression in Molt4 and K562 cells and Bcr/Abl expression in K562 cells. The active compound may be mammea E/BB. Extracts from M. siamensis flowers show promise as naturally occurring anti-cancer drugs. PMID- 28573217 TI - ANTIBACTERIAL AND ANTIOXIDANT POTENTIAL OF STEM BARK EXTRACT OF BOMBAX CEIBA COLLECTED LOCALLY FROM SOUTH PUNJAB AREA OF PAKISTAN. AB - BACKGROUND: Ethnic medication systems have been used extensively by humans since their origin. Now a day, in the developing countries these systems are being used due to their effectiveness and affordability. Especially inhabitants of rural areas still rely on these systems as first line of treatment against diseased conditions. Till now, majority of medicines is derived from the natural origin particularly plants owing to their little side effects and cost effectiveness. MATERIALS AND METHODS: In the present work, we evaluated antibacterial and antioxidant activity of methanolic extract of Bombax ceiba stem bark. Total phenolic and flavonoid contents were also assessed in the extract. The antioxidant capacity was determined by DPPH, Nitric Oxide scavenging and reducing power activity. For antibacterial activity, Gram-negative (Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi) and Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus) were used. RESULTS: Phenolic content was 133.21+/-1.56 MUg GAE/mg of extract while Flavonoid content was 997.93+/-2.14 MUg QE/mg. Plant extract demonstrated strong antiradical activity with EC50 18.78 +/- 0.69 and 23.62 +/- 1.99fg/ml for Nitric Oxide and DPPH assay respectively while EC50 in case of reducing power activity was 139.4 +/- 0.98MUg/ml. Plant extract displayed inhibitory effect against microbial growth with S. typhi as the most resistant strain and Staphylococcus aureus the most sensitive one. CONCLUSION: This study revealed that Bombax ceiba of local origin has broad spectrum antibacterial activity and it can also provide defense against oxidative stress. PMID- 28573219 TI - PROTECTIVE ROLE OF CARNITINE SYNERGIZED WITH VITAMIN E AGAINST ISOPROTERENOL INDUCED CARDIAC INFARCTION IN RATS. AB - BACKGROUND: The current study aimed to evaluate the role of carnitine in combination with vitamin E in protection against myocardial infarction induced by isoproterenol (ISO) in rats. MATERIALS AND METHODS: Rats were grouped into 5 (each 10 rats): Group I. Control fed a standard diet. Group III: Rats were injected with vitamin E (100 IU/kg bw, i.p) daily. Group IV: Rats were given carnitine (20 mg/kg bw, i.p) daily. Group V: Rats were injected with both vitamin E (100 IU/kg bw, i.p) and carnitine (20 mg/kg bw, i.p) daily. On 7th, 8th, and 9th day, rats in groups (II-V) were injection i.p with ISO (55mg/kg b.w for successive three days). The treatment with carnitine and vitamin E were continuous for 21 days. RESULTS: Canirine combined with vitamin E significantly increased coronary flow (CF) (P<0.001) in rats injected with ISO. The recovery of rate pressure product (RPP) and left ventricular developed pressure (LVDP) were significantly improved in treated rats in comparison to untreated. The rats administrated with ISO resulted in a significant elevation of serum enzymes (CK MB and LDH) compared with control group (p<0.001). However, it returned to about normal. ISO administration resulted in a significant elevation in the levels of malondialdehyde (MDA) and nitric oxide (NO) as compared with control (p<0.001) and a significant reduction in the activities of GSPxase and GSRase (p<0.001) compared with control group. The levels of cardiac inflammatory markers interleukine-6 (IL-6) and tumor necrosis factor (TNF-alpha) were markedly elevated in rats injected with ISO compared with control group. Vitamin E combined with carnitine reversed these effects. However, pretreatment with vitamin E or carnitine or combined together showed a significant reduction in MDA and NO (p<0.001) and a significant elevation in the activities of GSPxase and GSRase (p<0.001) as compared to ISO injected group. The combined effect was more significant than individual ones. CONCLUSION: Vitamin E combined with carnitine exerts potential protective effect against MI through suppression of inflammatory mediators and enhancement of antioxidant activity. PMID- 28573221 TI - EFFICACY AND SAFETY OF BAN HUANG ORAL LIQUID FOR TREATING BOVINE RESPIRATORY DISEASES. AB - BACKGROUND: Ban Huang oral liquid was developed as a veterinary compound preparation by the Lanzhou Institute of Husbandry and Pharmaceutical Sciences of the Chinese Academy of Agricultural Sciences (CAAS). The purpose of this study was to determine whether the oral liquid preparation of traditional Chinese medicine, Ban Huang, is safe and effective for treating respiratory diseases in cattle. MATERIALS AND METHODS: Acute oral toxicity experiments were conducted in Wistar rats and Kunming mice via oral administration. The minimum inhibitory concentration of the drug against Mycoplasma bovis in vitro with the double dilution method was 500 mg/mL, indicating good sensitivity. The results of laboratory pathogen testing, analysis of clinical symptoms, and analysis of pathological anatomy were combined to diagnose bovine respiratory diseases in 147 Simmental cattle caused by mixed infections of M. bovis, bovine respiratory syncytial virus, bovine parainfluenza virus type 3, and Mannheimia haemolytica. These cattle were randomly divided into three groups: drug treatment group 1 (treated via Tilmicosin injection), drug treatment group 2 (treated with Shuang Huang Lian oral liquid combined with Tilmicosin injection), and drug treatment group 3 (treated with Ban Huang oral liquid combined with Tilmicosin injection). Treatment effects were observed within 7 days. RESULTS: The results showed no toxicity and a maximum tolerated dose greater than 20 g/kg BW. For the 87 cattle in drug-treatment group, the cure rate was 90.80%, whereas the response rate was 94.25%. The cure rate of drug treatment group was increased by 14.13% in comparison with that of drug control group 1 and by 7.47% in comparison with that of drug control group 2 (both P < 0.05). CONCLUSION: This study demonstrates that Ban Huang oral liquid is a safe and effective treatment for bovine respiratory diseases, especially for mixed infection caused by M. bovis, bacteria, and viruses. PMID- 28573220 TI - JIEYUANSHEN DECOCTION EXERTS ANTIDEPRESSANT EFFECTS ON DEPRESSIVE RAT MODEL VIA REGULATING HPA AXIS AND THE LEVEL OF AMINO ACIDS NEUROTRANSMITTER. AB - BACKGROUND: Jieyuanshen decoction (JYAS-D) - a traditional Chinese medicine was invented by Professor Nie based on classic formulas, chaihu jia longgu muli decoction has been proved as having favorable curative effects on depression in clinical practices. The aim of this study was to investigate the antidepressant effects and its molecular mechanism of JYAS-D. MATERIALS AND METHODS: The model of depression was established by Chronic Unpredictable Stress. Different doses (8.2 g/kg, 16.3 g/kg, 32.7 g/kg) of JYAS-D was orally administered; Fluoxetine was orally administered with 10mg/kg. All treatments lasted for 28 days. Sucrose preference and open-field tests were adopted to observe the behavior of rats. OPA (ortho-phthalaldehyde) derivatization method was used to detect the contents of amino acid neurotransmitter. RIA (Radiation immunity analysis) method was used to measure the serum concentrations of CORT (Corticosterone), ACTH (Adrenocorticotropic hormone) and CRH (Corticotropin-releasing hormone). ELISA (Enzyme linked immunosorbent assay) method was adopted to examine the contents of Glucocorticoid receptor (GR) and Mineralocorticoid receptor (MR) in hippocampus. RESULTS: Compared with the model group, sucrose preference was increased in all treatment groups. The concentration of serum CORT was reduced in the middle dose of JYAS-D and control groups; the concentration of serum ACTH was reduced in the low and high-dose of JYAS-D; the concentration of serum CRH was reduced in the middle and high-dose of JYAS-D. The content of hippocampus GR was increased in the middle and high-dose of JYAS-D; the content of hippocampus Glu (Glutamic acid) was reduced among the low, middle and high-dose of JYAS-D and fluoxetine group, the ratio of Glu/gamma-GABA (y-aminobutyric acid was reduced in the low and high-dose of JYAS-D. CONCLUSION: JYAS-D had a significant antidepressant-like effect on rat model through regulating serum concentration of CORT, ACTH and CRH, increasing the content of hippocampus GR and regulating the equilibrium of amino acids neurotransmitter. PMID- 28573222 TI - THE BIOLOGICAL ACTIVITIES OF MOLTKIA AUREA BOISS., AN ENDEMIC SPECIES TO TURKEY. AB - BACKGROUND: Staphylococcus aureus is the direct reason of mastitis. Mastitis is a disease characterized by pathological changes in mammary glands as well as physical, chemical, bacteriological changes in milk. This disease causes loses in milk yield and quality. In recent years, it is reported that mastitis pathogens have developed a resistance to antibiotics as a natural consequence of widespread use of it. Today's researches are focused on discovering and using new antibiotics against bacteria. The aim of this paper is to examine the antibacterial properties of Moltkia aurea Boiss.][o] (an endemic species to Turkey), and its other biological activities. MATERIALS AND METHODS: All of the extracts were tested by disc diffusion assay in order to screen antibacterial activity. MIC values were evaluated as antibacterial activities of plant extracts. The non-enzymatic antioxidative activities including DPPH radical scavenging effects were studied in vitro. RESULTS AND CONCLUSIONS: Results shown that the extracts had strong antibacterial effects on three bacteria (S. aureus- 17, S. aureus-18 and CNS-37) and the range of inhibition zone was 4-6mm. This three bacteria screened the lowest sensitivity to 65000 MUg /mL concentration. Besides, the extracts were tested for non-enzymatic antioxidant activities. As a result, the methanol extract of the flower displayed a strong antioxidant activity. The various extracts of Moltkia aurea have different antibacterial and antioxidant properties. PMID- 28573224 TI - ANTITUMOR AND APOPTOTIC EFFECTS OF CUCURBITACIN A IN A-549 LUNG CARCINOMA CELLS IS MEDIATED VIA G2/M CELL CYCLE ARREST AND M-TOR/PI3K/AKT SIGNALLING PATHWAY. AB - BACKGROUND: The main aim of this study was to demonstrate the antitumor potential of cucurbitacin A on A-549 NSCLC (non-small cell lung cancer cells). The effects of Cucurbitacin A on apoptotic induction, cell physic, cell cycle failure and m TOR/PI3K/Akt signalling pathway were also investigated in the present study. MATERIALS AND METHODS: MTT assay and clonogenic assay were carried out to study effects of this compound on cell cytotoxicity and colony forming tendency in A 549 cells. Moreover, phase and fluorescence microscopic techniques were used to examine the effects on cell morphology and induction of apoptosis. The effects on cell cycle phase distribution were investigated by flow cytometry and effects on m-TOR/PI3K/Akt signalling proteins were assessed by western blot analysis. RESULTS: Results showed that cucurbitacin A induced dose-dependent cytotoxic effects along with suppressing the colony forming tendency in these cells. Cucurbitacin A also induced morphological changes in these cells featuring chromatin condensation, cell shrinkage and apoptotic body formation. G2/M phase cell cycle collapse was also induced by Cucurbitacin A along with inhibition of expression levels of m-TOR/PI3K/Akt proteins. CONCLUSIONS: In conclusion, cucurbitacin A inhibits cancer growth in A-549 NSCLC cells by inducing apoptosis, targeting m-TOR/PI3K/Akt signalling pathway and G2/M cell cycle. PMID- 28573223 TI - CARDIOPROTECTIVE ROLES OF THE CHINESE MEDICINAL FORMULA BAO-XIN-TANG ON ACUTE MYOCARDIAL INFARCTION IN RATS. AB - BACKGROUND: Bao-Xin-Tang (BXT) is a traditional Chinese medicinal formula used for the treatment of coronary heart disease and known to have favorable therapeutic benefits. The current study was designed to determine whether BXT has a cardioprotective role for acute myocardial infarction. The underlying mechanisms were also explored. MATERIALS AND METHODS: The Sprague-Dawley rat model of acute myocardial infarction was established by occluding the left anterior descending branch of the coronary artery. After a 3-h ischemic period, we determined the myocardial infarction size, inflammatory components, and antioxidant activities. RESULTS: The data showed that BXT could reduce the infarction size and lower the levels of C-reactive protein, interleukin-6, and myeloperoxidase, and increase the activities of superoxide dismutase and the anti inflammatory cytokine, interleukin-10. These results indicate that administration of BXT, following acute myocardial infarction, could reduce infarct size. CONCLUSION: The effects of BXT may be related to its anti-inflammatory and anti oxidative properties. PMID- 28573226 TI - EVALUATION OF THE CHELATING EFFECT OF METHANOLIC EXTRACT OF CORIANDRUM SATIVUM AND ITS FRACTIONS ON WISTAR RATS POISONED WITH LEAD ACETATE. AB - BACKGROUND: The rate of lead poisoning has decreased in recent years due to increased health control in industries that use this metal. However, it is still a public health problem worldwide. The use of various plants with chelating properties has been a topic of research today. In traditional medicine, it is said that Coriandrum sativum has chelating properties, but there is no scientific evidence to support this fact. The purpose of this research is to evaluate the chelating effect of methanol extract of coriander and its fractions on Wistar rats intoxicated with lead. MATERIALS AND METHODS: In this research, male Wistar rats were poisoned with 50 mg/kg of lead acetate and treated with 50 mg/kg of methanol extract and its fractions. The extract and its fractions were administered to four treatment groups. Positive and negative controls were established. Hemoglobin, hematocrit and lead concentrations were analyzed; liver was evaluated histologically in control and treatment groups. RESULTS: The methanol extract of coriander presented a LD50 >1000 mg/dL. The group administered with the methanol extract showed significant difference in the levels of hemoglobin and hematocrit compared to the negative control group. Lead concentration in treatment groups showed a decrease compared to the positive control. Histological evaluation of tissue showed less damage in groups administered with methanolic extract and its fractions compared to the positive control which presented structural alterations. CONCLUSION: Coriander extracts protect liver and lower lead concentration in rats intoxicated with lead in contrast to the positive control group. PMID- 28573225 TI - EMODIN DOWNREGULATES CELL PROLIFERATION MARKERS DURING DMBA INDUCED ORAL CARCINOGENESIS IN GOLDEN SYRIAN HAMSTERS. AB - BACKGROUND: Cell-cycle disruption is the major characteristic features of neoplastic transformation and the status of cell-cycle regulators can thus be utilized to assess the prognostic significance in patients with cancer. The PCNA, cyclin D1, CDK4, CDK6 and survivin expression in the buccal mucosa was utilized to evaluate the Emodin efficacy on abnormal cell proliferation during 7,12 dimethylbenz(a)anthracene (DMBA) induced oral carcinogenesis in golden Syrian hamsters. MATERIALS AND METHODS: Topical application of DMBA, three times a week for 14 weeks, on the hamsters' buccal pouches developed well differentiated squamous cell carcinoma. RESULTS: Cyclin D1 and PCNA over-expression and up regulation of CDK4, CDK6 and survivin were noticed in the buccal mucosa of hamsters treated with DMBA alone. Emodin administration (50mg/kg b.w) orally to hamsters treated with DMBA down-regulated the expression of cell proliferation markers in the buccal mucosa. CONCLUSIONS: The anti-cell proliferative role of Emodin is owing to its modulating efficacy on cell-cycle markers towards the tumor suppression during DMBA induced oral carcinogenesis. PMID- 28573228 TI - MOXIBUSTION HAS A POSITIVE EFFECT ON PULMONARY FIBROSIS: AN ALTERNATIVE APPROACH. AB - BACKGROUND: An increasing number of people suffered idiopathic fibrosis (IPF) and the current treatment was far from clinical satisfaction. Moxibustion, another effective and safe unconventional therapy, had been introduced to treat this refractory disease. The study aimed to investigate the effect of moxibustion on a bleomycin A5-induced pulmonary fibrosis model. MATERIALS AND METHODS: Sprague dawley (SD) rats were randomly allocated to the blank group, model group, moxibustion group, and prednisone group, for which they received no treatment, modeling, moxibustion treatment and prednisone treatment. After four-week treatment, the rats were euthanized for Hematoxylin and Eosin (H.E.) staining, and TGF-beta1 and IFN-gamma protein and mRNA detection in lungs. RESULTS: In the model group, TGF-beta1 was significantly increased and IFN-gamma was significantly decreased at both protein and mRNA levels in comparison to the blank group. In the moxibustion and prednisone group, however, TGF-beta1 was decreased and IFN-gamma was increased at both protein and mRNA levels in comparison to the model groups. Compared with prednisone, moxibustion showed comparable effect in lowing TGF-beta1 (P>0.05) and better effect in up-regulating IFN-gamma (P>0.05). CONCLUSION: The study concludes moxibustion protected pulmonary fibrosis by downregulating TGF-beta1 and upregulating IFN-gamma cytokines at both mRNA and protein levels, and the effect was comparable to prednisone. Moxibustion could be used as a therapeutic alternative treatment for pulmonary fibrosis. PMID- 28573227 TI - EFFECTS OF SALVIA MILTIORRHIZAE ON THE KIDNEY OF RATS WITH SEVERE ACUTE PANCREATITIS AND OBSTRUTIVE JAUNDICE. AB - BACKGROUND: Severe acute pancreatitis (SAP) and obstructive jaundice (OJ) are frequent recurring diseases that bring about huge threat to human health. Some reports have demonstrated that Salviae miltiorrhizae can protect multiple organs of SAP and OJ model animals or patients, but their related mechanisms were not clear. In this study, we observed the effects of Salvia miltiorrhizae injection on apoptosis and NF-kappaB expression in kidney and explored the protective effect and mechanism of Salvia miltiorrhizae on the kidney of SAP or OJ rats. The results obtained will provide a theoretical basis for clinical application of Salvia miltiorrhizae. MATERIAL AND METHODS: A total of 288 rats were used for SAP -and OJ-associated experiments. The mortality rates of rats, the contents of serum BUN and CREA, the expression levels of Bax, NF-kappaB proteins and the apoptosis index were observed, respectively. RESULTS: The pathological changes in the kidney of SAP or OJ rats in treated group were mitigated to varying degrees. At 6 and 12 hours after operation in SAP rats or on 21 and 28 days after operation in OJ rats, the contents of serum CREA in treated group were significantly lower than those in model control group; At 3 and 6 hours after operation, the staining intensity of Bax protein of kidney in treated group was significantly lower than that in model control group; on 14 days after operation, the apoptosis index in the kidney of OJ rats in treated group was significantly lower than that in model control group. CONCLUSION: Salvia miltiorrhizae can exert protective effects on the kidney of SAP and OJ rats. PMID- 28573229 TI - ANALYSIS OF PHENOLIC AND FLAVONOIDS OF WILD EPHEDRA ALATA PLANT EXTRACTS BY LC/PDA AND LC/MS AND THEIR ANTIOXIDANT ACTIVITY. AB - BACKGROUND: Ephedra is among Palestinian medicinal plants that are traditionally used in folkloric medicine for treating many diseases. Ephedra is known to have antibacterial and antioxidant effects. The goal of this study is to evaluate the antioxidant activity of different extracts from the Ephedra alata plant growing wild in Palestine, and to analyze their phenolic and flavonoid constituents by HPLC/PDA and HPLC/MS. MATERIALS AND METHODS: Samples of the Ephedra alata plant grown wild in Palestine were extracted with three different solvents namely, 100% water, 80% ethanol, and 100% ethanol. The extracts were analyzed for their total phenolic content (TPC), total flavonoid content (TFC), antioxidant activity (AA), as well as phenolic and flavonoids content by HPLC/PDA/MS. RESULTS: The results revealed that the polarity of the extraction solvent affects the TPC, TFC, and AA of extracts. It was found that both TPC and AA are highest for plant extracted with 80% ethanol, followed by 100% ethanol, and finally with 100% water. TFC however was highest in the following order: 100% ethanol > 80% ethanol > water. Pearson correlation indicated that there is a significant correlation between AA and TPC, but there is no correlation between AA and TFC. Simultaneous HPLC-PDA and UHPLC-MS analysis of the ethanolic plant extracts revealed the presence of Luteolin-7-O-glucuronide flavone, Myricetin 3-rhamnoside and some other major polyphenolic compounds that share myricetin skeleton. CONCLUSION: Ephedra alata extract is rich in potent falvonoid glycosidic compounds as revealed by their similar overlaid UV-Vis spectra and UHPLC-MS results. On the basis of these findings, it is concluded that Ephedra alata constitutes a natural source of potent antioxidants that may prevent many diseases and could be potentially used in food, cosmetics, and pharmaceutical products. PMID- 28573230 TI - ANTI-CANCER ACTIVITY OF ASTER TATARICUS ON SCC-9 HUMAN ORAL SQUAMOUS CARCINOMA. AB - BACKGROUND: Oral squamous carcinoma is a head and neck cancer, which is one of the types of malignant cancers. Present study evaluates the anticancer activity of Aster tataricus (AT) on SCC-9 human oral squamous carcinoma. MATERIALS AND METHODS: Ethanol extract of AT was prepared by a standard procedure of maceration. AT extract was used in different concentrations like 10, 20, 40, 80, 160, 320 and 640 MUg/ml for the evaluation of its anticancer activity. Effect of AT extract on SCC9 cells were observed by microscope and cytotoxicity by 3-(4, 5 Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay. Moreover, clonogenic assay was used for the estimation of effect of AT extract on colony forming ability of SCC9 cells. RESULT: Result of the study suggested that treatment with AT extract causes cytotoxicity to SCC9 cancerous cells. In addition, AT extract treatment reduces clonogenic potential of SCC9 cell and it also inhibits the proliferation of cell significantly (p<0.001) in G2/M phase. CONCLUSION: Thus, given study concludes that AT extract effectively attenuates the growth of SCC-9 cancerous cells by the virtue of its cytotoxic and anti clonogenic activity. PMID- 28573231 TI - MOXIBUSTION ALLEVIATES GASTRIC PRECANCEROUS LESIONS IN RATS BY PROMOTING CELL APOPTOSIS AND INHIBITING PROLIFERATION-RELATED ONCOGENES. AB - BACKGROUND: It is well known that gastric mucosa dysplasia and intestinal metaplasia are gastric precancerous lesions (GPL). Moxibustion treatment of Liangmen (ST21) and Zusanli (ST36) alleviated the inflammatory response and dysplasia of gastric mucosa in our previous study. The purpose of this study was to further examine the underlying mechanism of moxibustion treatment of ST21 and ST36 on GPL. MATERIALS AND METHODS: Sixty SD rats were divided into five groups and rats with GPL were treated with either moxibustion (ST), moxibustion (Sham), or vitacoenzyme. B-cell lymphoma 2 (bcl-2), tumor protein p53 (P53) and cellular Myc (C-MYC), which are related to cell apoptosis, proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), argyrophilic nucleolar organizer region proteins (Ag-NORs), which are associated with cell proliferation, and cell signaling proteins, nuclear factor kappa B (NF-kappaB), epidermal growth factor receptor (EGFR) and phosphorylated extracellular signal regulated kinase (p-ERK), were measured after moxibustion treatment. RESULTS: Compared with Control group, gastric mucosa in GPL group showed abnormal mucosal proliferation and pathological mitotic figure, the mRNA expression of bcl-2, P53 and C-MYC increased significantly (P < 0.01), the protein expression of PCNA, VEGF, Ag-NORs and the activity of NF-kappabeta as well as EGFR/ERK signaling proteins also increased significantly (P < 0.01). Moxibustion treatment decreased gastric mucosal proliferation and pathological mitotic figure, down-regulated the mRNA expression of bcl-2, P53, C-MYC (P < 0.01), decreased the protein expression of PCNA, VEGF, Ag-NORs and the activity of NF-kappabeta as well as EGFR/ERK signaling proteins significantly (P < 0.01). But moxibustion treatment of Sham didn't show the same effect on GPL. CONCLUSION: Moxibustion treatment inhibited cell apoptosis and reduced gastric mucosa dysplasia by inhibiting the expression of bcl-2, P53, C-MYC and decreased the activity of NF-kappabeta as well as EGFR/ERK signaling proteins. PMID- 28573232 TI - ANTIMICROBIAL ACTIVITIES OF SOME SAUDI ARABIAN HERBAL PLANTS. AB - BACKGROUND: Several edible plants are used in Kingdom of Saudi Arabia since early time to control microbial infections. In the present study, twenty-four Saudi Arabian medicinal plants d according to traditionally used were select and investigated for the antimicrobial activities. MATERIALS AND METHODS: This study was designed at evaluating the antimicrobial activities of the methanol extracts of twenty-four species of sixteen plant families used in the traditional medicine by Saudi Arabian people for the treatment of numerous ailments of the microbial and non-microbial origin against four Gram-positive, four Gram-negative bacteria and four fungi and yeast using the agar well diffusion method. RESULTS: Of most of the plants tested were found to be active against two to eight organisms. Five plants were active against eight organisms. The data appeared that extracts of Echium arabicum (SY-176), Rhantarium epapposum (SY-Rumex vesicarus (SY-181), Ziziphus nummularia (SY-188), Caylusea hexagyna (SY-197) and Artemisia monosperma (SY-198) have anti-microbial activity against the most of tested bacteria, fungi and yeast. Whereas (SY-, the extracts of Teucrium oliverianum (SY-175), Zilla spinosa (SY-187), and Rhazya stricta (SY-195) have poor action against the tested bacteria, fungi and yeast. CONCLUSION: The antimicrobial activity of plant extracts against bacteria was more effective than against fungi. PMID- 28573233 TI - GENO PROTECTIVE AND ANTI-APOPTOTIC EFFECT OF GREEN TEA AGAINST PERINATAL LIPOPOLYSACCHARIDE-EXPOSURE INDUCED LIVER TOXICITY IN RAT NEWBORNS. AB - BACKGROUND: This study aims to examine the protective effect of green tea on the disturbances in oxidative stress and apoptosis related factors, mostly produced due to perinatal lipopolysaccharide (LPS) exposure, that subsequently induces liver cell damage. MATERIALS AND METHODS: Anti-free radical, Antioxidant, scavenging, geno-protective, and antiapoptotic activity of aqueous green tea extract (AGTE) were assessed against LPS-induced hepatic dysfunction in newborn rats. AGTE at doses of 100 & 200 mg/kg was orally administered daily to rat dams, during gestation and lactation. RESULTS: AGTE was observed to exhibit protective effects by significantly attenuating LPS-induced alterations in serum AST, ALT, bilirubin, and albumin levels. Significant increase in the total antioxidant capacity (TAC), DNA contents, and reduction in nitric oxide (NO) levels were observed in AGTE treated rats comparing LPS-toxicated ones. Additionally, AGTE treatment significantly down-regulated apoptotic markers and this effect was directly correlated to the degree of hepatic fibrosis. The possible mechanisms of the potential therapeutic-liver protective effect of AGTE could be due to free radical scavenging potential and antiapoptotic properties caused by the presence of antioxidant polyphenolic components in AGTE. CONCLUSION: We thereby propose, based on our findings, that the anti-free radical and anti-apoptotic inducing properties of AGTE active constituents attribute to its functional efficacy as anti-fibrotic agent. PMID- 28573234 TI - EVALUATION OF ANTIBACTERIAL, ANTITUMOR, ANTIOXIDANT ACTIVITIES AND PHENOLIC CONSTITUENTS OF FIELD-GROWN AND IN VITRO-GROWN LYSIMACHIA VULGARIS L. AB - BACKGROUND: Lysimachia vulgaris L. (Yellow loosestrife) is a medicinal plant in the family Myrsinaceae. It has been used in the treatment of fever, ulcer, diarrhea and wounds in folk medicine. It has also analgesic, expectorant, astringent and anti-inflammatory activities. Two different sources of the plant (field-grown and in vitro-grown) were used to evaluate the biological activities (antibacterial, antitumor and antioxidant) of L. vulgaris. In vitro-grown plant materials were collected from L. vulgaris plants that were previously regenerated in our laboratory. MATERIALS AND METHODS: Plant materials were extracted with water, ethanol and acetone. For antibacterial test, disc diffusion method and 10 different pathogenic bacteria were used. Antioxidant activity was indicated by using DPPH method. The total phenol amount by using Folin-Ciocaltaeu method and the total flavonoid amount by using aluminum chloride (AlCl3) colorimetric method were determined. RESULTS: Generally, yellow loosestrife extracts demonstrated antibacterial activity against Gram-positive bacteria (Staphylococcus aureus, S. epidermidis and Streptococcus pyogenes). Strong antitumor activity of yellow loosestrife was observed via potato disc diffusion bioassay. Nine different phenolics were also determined and compared by using High-Performance Liquid Chromatography (HPLC). CONCLUSION: Future investigations should be focused on fractionation of the extracts to identify active components for biological activity. PMID- 28573235 TI - IN VIVO AND IN VITRO ANTILEISHMANIAL EFFECTS OF METHANOLIC EXTRACT FROM BARK OF BURSERA APTERA. AB - BACKGROUND: Cutaneous leishmaniasis lacks effective and well-tolerated treatments. The current therapies mainly rely on antimonial drugs that are inadequate because of their poor efficacy. Traditional medicine offers a complementary alternative for the treatment of various diseases. Additionally, several plants have shown success as anti-leishmanial agents. Therefore, we sought to evaluate the in vitro and in vivo activity of MEBA against Leishmania mexicana. MATERIALS AND METHODS: Methanolic extract of B. aptera was obtained by macetration, after we determined in vitro anti-leishmanial activity of MEBA by MTT assay and the induced apoptosis in promastigotes by flow cytometry. To analyze the in vivo anti-leishmanial activity, we used infected mice that were treated and not treated with MEBA and we determined the levels of cytokines using ELISA. The phytochemical properties were determined by CG-MS and DPPH assay. RESULTS: We determined of LC50 of 0.408 mg/mL of MEBA for in vitro anti leishmanial activity. MEBA induced apoptosis in promastigotes (15.3% +/- 0.86). Treated mice exhibited smaller lesions and contained significantly fewer parasites than did untreated mice; in addition, we found that IFN-gamma and TNF alpha increased in the sera of MEBA-treated mice. GC-MS analysis showed that podophyllotoxin was the most abundant compound. Evaluation of the activity by DPPH assay demonstrated an SC50 of 11.72 MUg/mL. CONCLUSION: Based on the above data, it was concluded that MEBA is a good candidate in the search for new anti leishmanial agents. PMID- 28573236 TI - QUANTIFICATION OF GLYCYRRHIZIN BIOMARKER IN GLYCYRRHIZA GLABRA RHIZOME AND BABY HERBAL FORMULATIONS BY VALIDATED RP-HPTLC METHODS. AB - BACKGROUND: A simple and sensitive thin-layer chromatographic method has been established for quantification of glycyrrhizin in Glycyrrhiza glabra rhizome and baby herbal formulations by validated Reverse Phase HPTLC method. MATERIALS AND METHODS: RP-HPTLC Method was carried out using glass coated with RP-18 silica gel 60 F254S HPTLC plates using methanol-water (7: 3 v/v) as mobile phase. RESULTS: The developed plate was scanned and quantified densitometrically at 256 nm. Glycyrrhizin peaks from Glycyrrhiza glabra rhizome and baby herbal formulations were identified by comparing their single spot at Rf = 0.63 +/- 0.01. Linear regression analysis revealed a good linear relationship between peak area and amount of glycyrrhizin in the range of 2000-7000 ng/band. CONCLUSION: The method was validated, in accordance with ICH guidelines for precision, accuracy, and robustness. The proposed method will be useful to enumerate the therapeutic dose of glycyrrhizin in herbal formulations as well as in bulk drug. PMID- 28573237 TI - PROTECTIVE EFFECT OF MORINGA PEREGRINA LEAVES EXTRACT ON ACETAMINOPHEN -INDUCED LIVER TOXICITY IN ALBINO RATS. AB - BACKGROUND: Acetaminophen is a common antipyretic drug but at overdose can cause severe hepatotoxicity that may further develop into liver failure and hepatic centrilobular necrosis in experimental animals and humans. This study was undertaken to assess the ameliorative role of Moringa peregrina leaves extract against acetaminophen toxicity in rats. MATERIALS AND METHODS: Induction of hepatotoxicity was done by chronic oral administration of acetaminophen (750 mg/kg bwt) for 4 weeks. To study the possible hepatoprotective effect, Moringa peregrina leaves extract (200 mg/kg bwt) or Silymarin (50 mg/kg bwt) was administered orally, for 4 weeks, along with acetaminophen. RESULTS: acetaminophen significantly increased serum liver enzymes and caused oxidative stress, evidenced by significantly increased tissue malondialdehyde, glutathione peroxidase, hepatic DNA fragmentation, and significant decrease of glutathione and antioxidant enzymes in liver, blood and brain. On the other hand, administration of Moringa peregrina leaves extract reversed acetaminophen-related toxic effects through: powerful malondialdehyde suppression, glutathione peroxidase normalization and stimulation of the cellular antioxidants synthesis represented by significant increase of glutathione, catalase and superoxide dismutase in liver, blood and brain, besides, DNA fragmentation was significantly decreased in the liver tissue. CONCLUSION: acetaminophen induced oxidative damage can be improved by Moringa peregrina leaves extract-treatment, due to its antioxidant potential. PMID- 28573238 TI - KIRKIA ACUMINATA OLIV.: A REVIEW OF ITS ETHNOBOTANY AND PHARMACOLOGY. AB - BACKGROUND: Local communities in sub-Saharan Africa have a long history of medicinal plant usage. Like in other parts of the developing world, rural and urban communities are still dependent on herbal medicines for primary health care, and the use of herbal medicines is still an integral part of their daily life and socio-cultural life style. The objective of this paper is to summarise information on the ethnobotany and pharmacology of Kirkia acuminata Oliv. throughout its distributional range. MATERIALS AND METHODS: The information documented in this article is derived from books, theses, scientific journals and reports obtained from library collections, Scopus, Pubmed, MEDLINE, ISI Web of Science, Google Scholar and Science Direct. RESULTS: Kirkia acuminata is the most known and widely distributed Kirkia species in the genus and is one of the most popular and promising plant resources due to its several beneficial uses. Kirkia acuminata is used to treat abdominal pains, backache, cholera, constipation, cough, diarrhea, dysentery, snake bites, toothache and wounds. Other applications include its use as charcoal; hedge, ornamental or shade; stock feed, timber and source of water during drought periods. Preliminary phytochemical assessment of roots and stem bark of K. acuminata showed presence of lignans, neo-lignans, nor carotinoids and other compounds. The extracts of K. acuminata exhibited antibacterial and antimycobacterial activities. These phytochemical compounds may be responsible for the medicinal uses and biological activities demonstrated by K. acuminata. CONCLUSION: Detailed research is required aimed at exploring mode of action of bioactive compounds of Kirkia acuminata that are responsible for the documented pharmacological effects. Kirkia acuminata is an important plant species that has potential to contribute to the primary health care and livelihood improvement of local communities in the geographical areas where it is indigenous and found in abundance. PMID- 28573239 TI - THERAPEUTIC POTENTIALS OF ETHANOLIC EXTRACT OF LEAVES OF HOLARRHENA FLORIBUNDA (G. DON) DUR. AND SCHINZ (APOCYNACEAE). AB - BACKGROUND: Holarrhena floribunda is a plant of wide usage in the Togolese folk medicine. A previous ethnobotanical survey on the latex plants of the Maritime region of the country revealed that this plant was included in several recipes curing malaria and microbial infections. Therefore, this study aimed to seek for the effectiveness of the ethanolic extract of the plant in the treatment of these diseases. METHODS: The antimicrobial test was performed using the agar well diffusion and the NCCLS broth microdilution methods, while the in vivo antimalarial activity was evaluated following the four-day suppressive test of Peters. The acute toxic effects of the extract were monitored after a single oral dose (5,000 mg/kg body weight) administration in NMRI mice. RESULTS: The results indicated that the ethanolic extract of leaves of H. floribunda was active on Staphylococcus aureus ATCC 29213 and clinical strains of Staphylococcus aureus, Salmonella typhi and Klebsiella pneumoniae with MICs ranging from 0.62 to 1.25 mg/mL. The extract also showed significant parasitaemia suppression in a dose dependent manner. In the acute toxicity assay, the oral administration of the extract to the mice did not affect the relative weight of vital organs, and there were no signs of toxicity or death during the study period. The LD50 of the tested extract was found to be greater than 5,000 mg/kg, indicating its safety. CONCLUSION: This study demonstrates the antibacterial and antimalarial activities of leaves of H. floribunda and then, supports its medicinal use in the treatment of microbial infections. PMID- 28573240 TI - SIGNALING PATHWAYS REGULATED BY BRASSICACEAE EXTRACT INHIBIT THE FORMATION OF ADVANCED GLYCATED END PRODUCTS IN RAT BRAIN. AB - BACKGROUND: The goal of this study was identification signaling molecules mediated the formation of AGEs in brain of rats injected with CdCl2 and the role of camel whey proteins and Brassicaceae extract on formation of AGEs in brain. METHODS: Ninety male rats were randomly grouped into five groups; Normal control (GpI) and the other rats (groups II-V) were received a single dose of cadmium chloride i.p (5 MUg/kg/b.w) for induction of neurodegeneration. Rats in groups III-V were treated daily with whey protein (1g/kg b.w) or Brassicaceae extract (1mg/kg b.w) or combined respectively for 12 weeks. RESULTS: It was found that whey protein combined with Brassicaceae extract prevented the formation of AGEs and enhance the antioxidant activity compared with untreated group (p <0.001). Serum tumor necrosis factor (TNF-alpha) and interleukine (IL-6) levels were significantly decreased (p<0.01) in rats treated with whey protein and Brassicaceae extract formation compared with untreated. The combined treatment showed a better impact than individual ones (p<0.001). The level of cAMP but not cGMP were lowered in combined treatment than individual (p<0.01). CONCLUSION: It can be postulated that Whey protein + Brassicaceae extract formation could have potential benefits in the prevention of the onset and progression of neuropathy in patients. PMID- 28573241 TI - MECHANISMS UNDERLYING ACTION OF XINMAILONG INJECTION, A TRADITIONAL CHINESE MEDICINE IN CARDIAC FUNCTION IMPROVEMENT. AB - BACKGROUND: As a bioactive composite extracted from American cockroach, Xinmailong injection (XML) is used for the treatment of congestive heart failure (CHF) in China. Clinical data has provided evidence that XML has positive inotropic properties. The objective of this study was to assess the mechanisms involved in the therapeutical effect of XML on CHF. MATERIALS AND METHODS: The effects of XML on the cardiac function in isolated rat heart were measured. A Ca2+ imaging technology was used in rat cardiomyocytes (H9c2 cells) to reveal the role of XML on Ca2+ channels. Meanwhile, the effects of XML on the activities of Na+/K+ ATPase and sodium/calcium exchanger were measured. In addition, the level of reactive oxygen species and the protein expressions for the superoxide dismutase and hemeoxygenase were determined in the cardiomyocytes. RESULTS: The results showed that XML increased the electrical impulse-induced [Ca2+]i in H9c2 cells, which was dependant on extracellular Ca2+ and was abolished by ML218-HCl (a T-type Ca2+channels antagonist) but not nimodipine (a L-type Ca2+channels antagonist). Ouabain, a Na+/K+-ATPase inhibitor, increased the electrical impulse induced [Ca2+]i, which was significantly inhibited by XML. Moreover, XML markedly inhibited the Na+/K+ ATPase activity in H9c2 cells. In addition, XML notably reduced the production of reactive oxygen species and enhanced the protein expressions of antioxidant enzymes including superoxide dismutase 1, superoxide dismutase 2 and hemeoxygenase 1 in H9c2 cell. CONCLUSION: Our findings pave the ways to the better understandings of the therapeutic effects of XML on cardiovascular system. PMID- 28573242 TI - NEW INSIGHTS INTO THE PRESENCE OF BILIRUBIN IN A PLANT SPECIES STRELITZIA NICOLAI (STRELITZIACEAE). AB - BACKGROUND: The fortuitous discovery of an animal pigment bilirubin found in the plant Strelitzia nicolai has opened an enormous number of questions regarding bilirubin's formation and its ultimate function in the human body. MATERIALS AND METHODS: A methodical review of bilirubin in humans and animals was carried out, information was gathered using published scientific journals, books and conference proceedings. Articles based on case studies of elevated levels of bilirubin were analysed thoroughly. RESULTS: Even though for numerous years bilirubin was assumed to be merely a desecrate product of the heme catabolic pathway by greatest, and a likely lethal compound at worst; statistics from the last few decades clearly shows that placidly high serum bilirubin levels are robustly related to have abundant beneficial effects on the human body. CONCLUSION: This study reveals new insights into the presence of the only animal pigment found in Strelitzia nicolai arils, the potential advantages of bilirubin found in a plant and its therapeutic value indications. This review hopes to resuscitate researchers' credence regarding bilirubin as a toxic compound. PMID- 28573243 TI - IN VITRO EFFICACY OF EXTRACTS FROM PLANTS USED BY SMALL-HOLDER FARMERS IN THE TREATMENT OF DERMATOPHILOSIS IN CATTLE. AB - BACKGROUND: Bovine dermatophilosis, an important skin disease of cattle caused by Dermatophilus congolensis, negatively impacts the livelihoods of small-holder farmers in Zimbabwe. This impact is through, morbidity, loss of draught animal power, costs incurred to manage the disease, losses associated with devalued damaged hides and the resultant culling of some of the affected cattle. Due to the inaccessibility of conventional drugs to manage bovine dermatophilosis, farmers have been reported to use local medicinal plants to manage the disease. The aim of the study was to evaluate the in vitro antimicrobial activities of three plants that small-holder farmers in Zimbabwe used to manage bovine dermatophilosis. METHODS: Dried plant materials were ground into powder and extracted individually using, water, 80 % acetone and 80 % methanol. The antimicrobial properties of the plants were evaluated against two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and one Gram-positive (Staphylococcus aureus) reference bacterial strains. They were further evaluated against a field isolate of Dermatophilus congolensis. The assays used were the disc diffusion, minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). RESULTS: Acetone and methanol extracts had superior inhibitory activities than did those of water. Pterocarpus angolensis DC extracts had better inhibitory properties with absolute MIC values of 0.156 - 5 mg/ml, Cissus Quadrangularis L had MIC values in the range 0.156 - 5 mg/ml while that of Catunaregam spinosa Thunb, Terveng was 0.156 - 10 mg/ml. Dermatophilus congolensis was more sensitive to Pterocarpus angolensis DC average MIC = 0.63 mg/ml than to Cissus quadrangularis L average MIC = 1.25 mg/ml and Catunaregam. spinosa Thunb, Terveng average MIC = 2.08 mg/ml. CONCLUSION: These results suggest the potential antibacterial activities of extracts of the three plants and hence farmers are, in a way, justified in using the plants. Better results (lower MIC) could be obtained by extracting and evaluating pure active compounds of the plants. PMID- 28573244 TI - INVESTIGATION OF ANTIHEMOLYTIC, XANTHINE OXIDASE INHIBITION, ANTIOXIDANT AND ANTIMICROBIAL PROPERTIES OF SALVIA VERBENACA L. AERIAL PART EXTRACTS. AB - BACKGROUND: In this study, Salvia verbenaca L. aerial part extracts (SVEs): were screened for their antihemolytic, xanthine oxidase (XO) inhibition, antioxidant and antimicrobial activities. MATERIAL AND METHODS: To investigate SVEs antihemolytic activity, the 2,2,-azobis (2-amidinopropane) dihydrochloride (AAPH) was used to induce erythrocyte oxidative hemolysis. In XO inhibition test, xanthine was used as substrate and cytochrome c for generating superoxide anions. The antioxidant activity of SVEs was examined by means of reducing power, DPPH free radical scavenging and iron chelating assays. In addition, SVEs were tested for their antimicrobial effects by evaluating antibacterial and antifungal activities. RESULTS: Ethyl acetate extract (EAE) contains the highest amount of total polyphenols and flavonoids (661.78 +/- 4.00 mg GAE / g E) and (28.81 +/- 0.38 mg QE / g E) respectively. In antihemolytic test EAE was the most active extract with an HT50 value of 165 min. SVEs gave significant inhibitory effects on XO, especially the chloroform extract (ChE) with IC50 value of 0.0088 +/- 0.000 mg/ml. EAE was the most active extract in reducing power essay (EC50: 0.0047 +/- 0.000 mg/ml) and in DPPH radical scavenging essay (IC50: 0.0086 +/- 0.000 mg/ml). Finally, the EAE has inhibited the growth of nine bacterial strains with inhibition zone diameters of (12 to 16 mm), but no activities have found against fungal strains. CONCLUSION: S. verbenaca could be considered as a potential source of natural antihemolytic, enzyme modulator, antioxidant and antibacterial agents. PMID- 28573245 TI - ANTIPROLIFERATIVE EFFECT ON BREAST CANCER (MCF7) OF MORINGA OLEIFERA SEED EXTRACTS. AB - BACKGROUND: Moringa oleifera belongs to plant family, Moringaceae and popularly called "wonderful tree", for it is used traditionally to cure many diseases including cancer in Africa and Asia, however, there is limited knowledge on cytotoxic activity of Moringa oleifera seeds on MCF7 breast cancer cell. The present study evaluated antiproliferative effect on MCF7 of the seed. MATERIALS AND METHODS: Seeds of Moringa oleifera were grinded to powder and its phytochemicals were extracted using water and 80% ethanol solvents, part of the ethanolic extract were sequentially partitioned to fractions with four solvents (hexane, dichloromethane, chloroform, and n-butanol). Antiproliferative effects on MCF7 of the samples were determined. Finally, potent samples that significantly inhibited MCF7 growth were tested on MCF 10A. RESULTS: Crude water extract, hexane and dichloromethane fractions of the seeds inhibited the proliferation of MCF7 with the following IC50 values 280 MUg/ml, 130 MUg/ml and 26 MUg/ml respectively, however, of the 3 samples, only hexane fraction had minimal cytotoxic effect on MCF 10A (IC50 > 400MUg/ml). CONCLUSION: Moringa oleifera seed has antiproliferative effect on MCF7. PMID- 28573246 TI - THE EFFECT OF BODY AWARENESS THERAPY AND AEROBIC EXERCISES ON PAIN AND QUALITY OF LIFE IN THE PATIENTS WITH TENSION TYPE HEADACHE. AB - BACKGROUND: This study is to investigate the effect of Body Awareness Therapy (BAT) and Aerobic Exercises on pain and quality of life in patients with Tension Type Headache (TTH). MATERIALS AND METHOD: Sixty individuals with TTH diagnosis who referred Neurologist were incorporated into study. The individuals were randomly grouped into 3 as BAT (n=20), aerobic exercise (n=20) and control group (n=20). Pain severity of the individuals was evaluated by Visual Analog Scale (VAS) and pain diary, disability with ache; by Pain Disability Index (PDI) and Headache Impact Tests (HIT) and quality of life was evaluated by SF-36. Subsequent to first assessments, 3 sessions of 60 minutes per week throughout 6 weeks totally. RESULTS: When the groups were compared at the end of the study, a significant decrease was observed in VAS, PDI and HIT values in the individuals in the BAT and aerobic exercise groups. With the individuals in group BAT and aerobic exercise all parameters of quality of life were observed to be increased significantly. CONCLUSION: BAT and aerobic exercise programs to be applied on TTH patients were concluded to be important in decreasing the pain, in increasing the quality of life and in reducing pain-related daily constraints of the individuals. PMID- 28573247 TI - IN VITRO STUDY OF CONCENTRATION-EFFECT AND TIME-COURSE PATTERN OF WHITE ALUM ON ESCHERICHIA COLI O157:H7 GROWTH. AB - BACKGROUND: Nowadays, the demand for antibacterial fabrics has increased. White alum is used for oral aphthous ulcers treatment in traditional medicine of Sistan city, Sistan and Baluchistan Province, Iran, and also as a flocculent for water purification. This study is aimed to evaluate the effect of concentration and time on antibacterial activity of white alum on Escherichia coli O157:H7. MATERIALS AND METHODS: 0.25, 0.5, 1 and 2% concentrations of white alum were added to 108 CFU of Escherichia coli O157:H7. Optical Density was recorded for 4 hours. Data obtained were analyzed using Repeated Measure and One-way ANOVA by SPSS. RESULTS: Results revealed the effectiveness of white alum in the growth of the tested bacterium. The white alum was found to be potent against Escherichia coli O157:H7 at a concentration above 1% (p<0.05). Also, its effect is dose and time dependent, as well as other disinfectants. CONCLUSION: A wide variety of natural products has been under scrutiny for their clinical potential, both in terms of prevention and treatment. Strong antibacterial activity of white alum compared with control was shown against tested bacterium. In conclusion, white alum can be used as an inhibitor of bacterial growth, especially for Escherichia coli O157:H7. PMID- 28573248 TI - WITHAFERIN A INDUCES APOPTOSIS IN RAT C6 GLIOMA CELLS THROUGH REGULATING NF-KB NUCLEAR TRANSLOCATION AND ACTIVATION OF CASPASE CASCADE. AB - BACKGROUND: The demand for the chemopreventive drug from the plant source is increasing in recent times, owing to its various biological activities without any adverse effect. The intention of this current study was to examine the anti glioma effect of Withaferin A (WFA) on C6 glioma cell line model. MATERIALS AND METHODS: C6 glioma cells were administrated with different concentration of WFA (50, 100, 200 and 500 MUg/mL) and DMSO (control) group to examine its anti proliferative, anti-inflammatory and pro-apoptotic activities. RESULTS: Treatment with WFA showed a significant decline in the glioma cell count in a dose dependent manner and thus proving its anti-proliferative effect. Similarly, inflammatory markers were also substantially lowered upon treatment with different concentration of WFA. However, DNA fragmentation and apoptotic markers like Caspase-3 and 9 were concomitantly enhanced after co-cultured with different concentration of WFA and thus exhibiting its cytotoxicity efficacy. Furthermore, the protein expression of Bcl2 and Bax were markedly downregulated and upregulated respectively; upon treatment with WFA on C6 glioma cells. CONCLUSION: The outcome of this study evidently demonstrates that C6 glioma cells co-cultured with increased concentration of WFA, showed an anti-proliferative, anti inflammatory and pro-apoptotic effect in a dose-dependent fashion. PMID- 28573249 TI - HERBAL PRODUCT USE BY THE CANCER PATIENTS IN BOTH THE PRE AND POST SURGERY PERIODS AND DURING CHEMOTHERAPY. AB - BACKGROUND: The aim of this study was to evaluate of the use of herbal products in patients in both pre- and post- surgery periods and during chemotherapy, and to determine the factors behind it. MATERIALS AND METHODS: This study was conducted as a descriptive study with 281 patients in 4 centers. The data of the study were collected by using a survey form prepared by the researcher, depending on literature and interview with the participants face-to-face. RESULTS: While the average age of the patients involved in the study is 49.1+/-12.8, 51.6% of them were females, 34.6% graduate of elementary school, and 34.5% were housewives. While the prevelance of the use of herbal product prior to surgical treatment is 38.9%, it was observed that this rate increased to 54.1% during chemotherapy. It was observed that the most frequently used product was garlic prior to surgical treatment (19.2%), that it was urtica dioica (13.8%) during chemotherapy. Before the surgical treatment, 94.3% of the patients, and during chemotherapy treatment, 81.7% of the patients, stated that the use of herbal product had not been questioned by the physician or nurse. CONCLUSION: Analysis of the results indicates that health professionals need to obtain information regarding the use of herbal products by cancer patients during both pre- and post surgery periods, as well as during chemotherapy. Patients should be provided with information and guidance about the advantages and disadvantages of using herbal products. PMID- 28573250 TI - THE USE OF RHEUM PALMATUM L. IN THE TREATMENT OF ACUTE RESPIRATORY DISTRESS SYNDROME: A META-ANALYSIS OF RANDOMIZED, CONTROLLED TRIALS. AB - BACKGROUND: Chinese medicine theory shows that "lung being connected with large intestine", and the modern western medicine also shows that the lung and intestinal tract affect each other in physiological and pathological conditions. If the lung ventilation dysfunction is caused by inflammatory exudate or secretions obstruction of the small airway ventilation, blood gas partial pressure is increased and intestinal gas absorption difficulty may lead to intestinal inflation and dysfunction (Wang N et al., 2011). Rheum palmatum L. can play the roles of anti-coagulation and anti-thrombosis, and improve microcirculation through lowering the endotoxin-induced permeability of microvascular tissue, reducing tissue oedema, decreasing inflammatory exudation and necrosis, and enhancing cyto-protection mechanism (Yang TZ et al., 2014). Therefore, systemic evaluation of the evidence pertaining to the usage of Rheum palmatum L. in treating acute lung injury and acute respiratory distress syndrome (ARDS) has significant clinical significance. MATERIALS AND METHODS: Various Electronic Databases CBM, CNKI, VIP, Wanfang, PubMed and Cochrane Library were searched until December 2015. Numerous randomized-controlled trials (RCTs) evaluating the efficacy of Rheum palmatum L. for the treatment of acute lung injury and acute respiratory distress syndrome were collected. The quality of the included studies was evaluated and a meta-analysis was performed using the RevMan5.0 software. RESULTS: Eight RCTs involving 489 patients were selected for this review. The results of the Meta-analysis revealed that Rheum palmatum L. therapy, combined with routine comprehensive treatment, was significantly superior to that of routine comprehensive treatment alone, in the areas of decreasing mortality, the mechanical ventilation time, the level of interleukin 6,8 and the untoward effect, and also in improving arterial blood gas (PaO2/FiO2, PaO2) (P<0.05). CONCLUSION: Compared with treatment with routine comprehensive alone, Rheum palmatum L. treatment combined with routine comprehensive, has been shown to effectively decrease the mortality, mechanical ventilation time and ameliorate the arterial blood gas, the cytokine levels, and the untoward effect. However, the evidence appears not to be very compelling due to the poor quality of the original studies. PMID- 28573251 TI - MORIN MITIGATES OXIDATIVE STRESS, APOPTOSIS AND INFLAMMATION IN CEREBRAL ISCHEMIC RATS. AB - BACKGROUND: Morin is a flavanoid which exhibits potent antioxidant activity in various oxidative stress related diseases. The current study was attempted to scrutinize the preclinical bio-efficacy of morin on focal ischemia. METHODS: The animal model of focal cerebral ischemic injury was done by midbrain carotid artery occlusion (MCAO) method, followed by Morin (30mg/kg) administration for seven days. RESULTS: The outcome of the study showed that treatment with morin displayed positive effects in reducing the focal cerebral ischemia. This effect was evident with the improvements in neurological deficits, reduction in MDA content and elevation of antioxidant levels (SOD, GSH and Gpx). Furthermore, protein expression of Bax and caspase-3 were effectively down-regulated, whilst the expression of Bcl-2 was significantly elevated. On the other hand, the mRNA expression of proinflammatory cytokines was significantly reduced in focal cerebral ischemic rats upon morin intervention. CONCLUSION: Thus, the beneficial effects of morin on cerebral ischemia assault may result from the reduction of oxidative stress, inhibition of apoptosis and inflammation. The neuroprotective effects of morin supplement may serve as potent adjuvant in the amelioration of ischemic stroke. PMID- 28573252 TI - INDUCTION OF CELL CYCLE ARREST AND APOPTOSIS BY ORMENIS ERIOLEPIS A MORROCAN ENDEMIC PLANT IN VARIOUS HUMAN CANCER CELL LINES. AB - BACKGROUND: Ormenis eriolepis Coss (Asteraceae) is an endemic Moroccan subspecies, traditionally named "Hellala" or "Fergoga". It's usually used for its hypoglycemic effect as well as for the treatment of stomacal pain. As far as we know, there is no scientific exploration of anti tumoral activity of Ormenis eriolepis extracts. MATERIALS AND METHODS: In this regard, we performed a screening of organic extracts and fractions in a panel of both hematological and solid cancer cell lines, to evaluate the potential in vitro anti tumoral activity and to elucidate the respective mechanisms that may be responsible for growth arrest and cell death induction. The plant was extracted using organic solvents, and four different extracts were screened on Jurkat, Jeko-1, TK-6, LN229, SW620, U2OS, PC-3 and NIH3T3 cells. RESULTS: Cell viability assays revealed that, the IC50 values were (11,63+/-5,37MUg/ml) for Jurkat, (13,33+/-1,67MUg/ml) for Jeko 1, (41,67+/-1,98MUg/ml) for LN229 and (19,31+/-4,88MUg/ml) for PC-3 cells upon treatment with Oe-DF and Oe-HE respectively. Both the fraction and extract exhibited no effects on TK6 and NIH3T3. Cytometry analysis accompanied by DNA damage signaling protein levels monitoring (p-H2A.X), showed that both the Dichloromethane Fraction and Hexanic extract induce DNA double stranded breaks (DSBs) accompanied by cell cycle arrest in G1 (Jurkat, Jeko -1 and LN22) and G2/M (PC-3) phases which is agreed with the caspase activity observed. Additional experiments with selective inhibitors of stress and survival pathways (JNK, MAPK, Rho, p53, and JAK3) indicated that none of these pathways was significantly involved in apoptosis induction. The bioactive compound analysis by CG/MS indicated that the major compounds in Oe-DF were: Linoleic Acid (15,89%), Podophyllotoxin (17,89%) and Quercetin (22,95%). For Oe-HE the major molecules were: Linoleic Acid (9,76%), alpha-curcumene (7,07%), alpha-bisabolol (5,49%), Campesterol (4,41%), Stigmasterol (14,08%) and beta-sitosterol (7,49%). CONCLUSION: Our data suggest that bioactive compounds present in Ormenis eriolepis show significant anti proliferative activity inducing cell cycle arrest and cell death operating through apoptosis pathway. PMID- 28573255 TI - Image-Based Food Volume Estimation. AB - In this paper, we propose an extension to our previous work on food portion size estimation using a single image and a multi-view volume estimation method. The single-view technique estimates food volume by using prior information (segmentation and food labels) generated from food identification methods we described earlier. For multi-view volume estimation, we use"Shape from Silhouettes"to estimate the food portion size. The experimental results of our volume estimation methods demonstrate our results with respect to accuracy and reliability. PMID- 28573253 TI - IN VIVO CARBON TETRACHLORIDE-INDUCED HEPATOPROTECTIVE AND IN VITRO CYTOTOXIC ACTIVITIES OF GARCINIA HOMBRONIANA (SEASHORE MANGOSTEEN). AB - BACKGROUND: Garcinia hombroniana, known as "manggis hutan" (jungle mangosteen) in Malaysia, is distributed in tropical Asia, Borneo, Thailand, Andaman, Nicobar Islands, Vietnam and India. In Malaysia, its ripened crimson sour fruit rind is used as a seasoning agent in curries and culinary dishes. Its roots and leaves decoction is used against skin infections and after child birth. This study aimed to evaluate in vivo hepatoprotective and in vitro cytotoxic activities of 20% methanolic ethyl acetate (MEA) G. hombroniana bark extract. MATERIALS AND METHODS: In hepatoprotective activity, liver damage was induced by treating rats with 1.0 mL carbon tetrachloride (CCl4)/kg and MEA extract was administered at a dose of 50, 250 and 500 mg/kg 24 h before intoxication with CCl4. Cytotoxicity study was performed on MCF-7 (human breast cancer), DBTRG (human glioblastoma), PC-3 (human prostate cancer) and U2OS (human osteosarcoma) cell lines. 1H, 13C NMR (nuclear magnetic resonance), and IR (infrared) spectral analyses were also conducted for MEA extract. RESULTS: In hepatoprotective activity evaluation, MEA extract at a higher dose level of 500 mg/kg showed significant (p<0.05) potency. In cytotoxicity study, MEA extract was more toxic towards MCF-7 and DBTRG cell lines causing 78.7% and 64.3% cell death, respectively. MEA extract in 1H, 13C NMR, and IR spectra exhibited bands, signals and J (coupling constant) values representing aromatic/phenolic constituents. CONCLUSIONS: From the results, it could be concluded that MEA extract has potency to inhibit hepatotoxicity and MCF 7 and DBTRG cancer cell lines which might be due to the phenolic compounds depicted from NMR and IR spectra. PMID- 28573256 TI - Low Complexity Image Quality Measures for Dietary Assessment Using Mobile Devices. AB - Many chronic diseases, such as heart disease, diabetes, and obesity, can be related to diet. Hence, the need to accurately measure diet becomes imperative. We are developing image analysis tools for the identification and quantification of foods consumed at a meal. Our system relies on a single meal image from the user for doing food identification and quantity estimation. Therefore, it is very important to assist the user in acquiring a good quality image by providing immediate feedback about the image quality. This paper presents low complexity image quality measures which are deployed on handheld mobile devices. PMID- 28573254 TI - STRUCTURAL CHARACTERISTICS AND ANTIHYPERTENSIVE EFFECTS OF ANGIOTENSIN-I CONVERTING ENZYME INHIBITORY PEPTIDES IN THE RENIN-ANGIOTENSIN AND KALLIKREIN KININ SYSTEMS. AB - BACKGROUND: The commercially available synthetic angiotensin-I-converting enzyme (ACE) inhibitors are known to exert negative side effects which have driven many research groups globally to discover the novel ACE inhibitors. METHOD: Literature search was performed within the PubMed, ScienceDirect.com and Google Scholar. RESULTS: The presence of proline at the C-terminal tripeptide of ACE inhibitor can competitively inhibit the ACE activity. The effects of other amino acids are less studied leading to difficulties in predicting potent peptide sequences. The broad specificity of the enzyme may be due to the dual active sites observed on the somatic ACE. The inhibitors may not necessarily competitively inhibit the enzyme which explains why some reported inhibitors do not have the common ACE inhibitor characteristics. Finally, the in vivo assay has to be carried out before the peptides as the antihypertensive agents can be claimed. The peptides must be absorbed into circulation without being degraded, which will affect their bioavailability and potency. Thus, peptides with strong in vitro IC50 values do not necessarily have the same effect in vivo and vice versa. CONCLUSION: The relationship between peptide amino acid sequence and inhibitory activity, in vivo studies of the active peptides and bioavailability must be studied before the peptides as antihypertensive agents can be claimed. PMID- 28573257 TI - Image Segmentation for Image-Based Dietary Assessment: A Comparative Study. AB - There is a health crisis in the US related to diet that is further exacerbated by our aging population and sedentary lifestyles. Six of the ten leading causes of death in the United States can be directly linked to diet. Dietary assessment, the process of determining what someone eats during the course of a day, is essential for understanding the link between diet and health. We are developing imaging based tools to automatically obtain accurate estimates of what foods a user consumes. Accurate food segmentation is essential for identifying food items and estimating food portion sizes. In this paper, we present a quantitative evaluation of automatic image segmentation methods for food image analysis used for dietary assessment. The experiments indicate that local variation is more suitable for food image segmentation in general dietary assessment studies where the food images acquired have complex background. PMID- 28573259 TI - A Printer Indexing System for Color Calibration with Applications in Dietary Assessment. AB - In image based dietary assessment, color is a very important feature in food identification. One issue with using color in image analysis in the calibration of the color imaging capture system. In this paper we propose an indexing system for color camera calibration using printed color checkerboards also known as fiducial markers (FMs). To use the FM for color calibration one must know which printer was used to print the FM so that the correct color calibration matrix can be used for calibration. We have designed a printer indexing scheme that allows one to determine which printer was used to print the FM based on a unique arrangement of color squares and binarized marks (used for error control) printed on the FM. Using normalized cross correlation and pattern detection, the index corresponding to the printer for a particular FM can be determined. Our experimental results show this scheme is robust against most types of lighting conditions. PMID- 28573258 TI - The Use of Temporal Information in Food Image Analysis. AB - We have developed a dietary assessment system that uses food images captured by a mobile device. Food identification is a crucial component of our system. Achieving a high classification rates is challenging due to the large number of food categories and variability in food appearance. In this paper, we propose to improve food classification by incorporating temporal information. We employ recursive Bayesian estimation to incrementally learn from a person's eating history. We show an improvement of food classification accuracy by 11% can be achieved. PMID- 28573260 TI - Trend Analysis of Betel Nut-associated Oral Cancer ?and Health Burden in China. AB - OBJECTIVE: To forecast the future trend of betel nut-associated oral cancer and the resulting burden on health based on historical oral cancer patient data in Hunan province, China. METHODS: Oral cancer patient data in five hospitals in Changsha (the capital city of Hunan province) were collected for the past 12 years. Three methods were used to analyse the data; Microsoft Excel Forecast Sheet, Excel Trendline, and the Logistic growth model. A combination of these three methods was used to forecast the future trend of betel nut-associated oral cancer and the resulting burden on health. RESULTS: Betel nut-associated oral cancer cases have been increasing rapidly in the past 12 years in Changsha. As of 2016, betel nuts had caused 8,222 cases of oral cancer in Changsha and close to 25,000 cases in Hunan, resulting in about Y5 billion in accumulated financial loss. The combined trend analysis predicts that by 2030, betel nuts will cause more than 100,000 cases of oral cancer in Changsha and more than 300,000 cases in Hunan, and more than Y64 billion in accumulated financial loss in medical expenses. CONCLUSION: The trend analysis of oral cancer patient data predicts that the growing betel nut industry in Hunan province will cause a humanitarian catastrophe with massive loss of human life and national resources. To prevent this catastrophe, China should ban betel nuts and provide early oral cancer screening for betel nut consumers as soon as possible. PMID- 28573261 TI - Development of Oral Health Impacts on Daily Living Questionnaire Items - a Qualitative Study. AB - OBJECTIVE: To develop an instrument to measure Oral Health-related Quality of Life (OHQoL) and the changes after dental treatment among older adults in Hong Kong, in order to understand their views on the influences of oral health problems and generate relevant items to design the instrument. METHODS: A qualitative study was conducted among adults aged 55 and over. Information on their perceived oral health impacts was collected during semi-structured interviews. A framework approach was used to identify the oral health impacts and to understand the meaning of those impacts on the perception of life satisfaction. RESULTS: A total of 39 participants (average age 72 years) underwent the semi-structured interviews; 20 were seeking dental treatment and 19 had already received dental treatment for 1 to 3 months. In total, 308 statements on oral health impacts were drawn from the participants' descriptions. After four steps of item reduction and refinement, a list of 20 items was generated before being classified into eight domains: Cleansing, Eating, Speaking, Appearance, Social, Psychological, Awareness, and Health and Finance. CONCLUSION: Older adults in Hong Kong perceive that oral health impacts on different aspects of life. The face validity and content validity of the developed Oral Health Impact on Daily Living (OHIDL) was proved through qualitative study. PMID- 28573262 TI - Proposing a Novel, Three-level Definition of Periodontitis ?using Probing Depth, Clinical Attachment Loss and Bleeding on Probing: Analysis of a Rural Chinese Population. AB - OBJECTIVE: To propose a novel, three-level (severe, moderate, mild) case definition using probing depth (PD), clinical attachment loss (CAL) and bleeding on probing (BOP) for epidemiologic studies on periodontitis. METHODS: Case definitions (DEF) 1-30 with PD, CAL and BOP were made. Based on data from epidemiologic research in Chengde (Hebei Province, China) in 1992, prevalence of periodontitis by DEF1-30 was calculated and compared with a reference (definitions by Centers for Disease Control and Prevention/American Academy of Periodontology in 2012). Sensitivity, specificity, Youden Index, Cohen's kappa coefficient (CKC) and the area under the receiver operator characteristic curve (AUC) were calculated for the definitions selected. RESULTS: DEF1 and DEF18 for periodontitis, DEF2, DEF3, DEF19 for moderate and severe periodontitis, and DEF5, DEF13, DEF14, DEF21 and DEF25 for severe periodontitis, which were similar for estimation of periodontitis prevalence compared with the reference, were selected. DEF18 for periodontitis, DEF19 for moderate and severe periodontitis, and DEF5 for severe periodontitis were selected because they showed higher values for the Youden Index, CKC and AUC, and formed a three-level definition. CONCLUSION: A novel three-level case classification of periodontitis using three parameters of PD, CAL and BOP was proposed. The estimated periodontitis prevalence according to the novel proposed definition is close to the prevalence according to the CDC/AAP definition. PMID- 28573263 TI - Risk Factors associated with Early Childhood Caries. AB - OBJECTIVE: To analyse factors associated with the susceptibility of early childhood caries (ECC), populations with a high risk of ECC were screened and guidance for ECC prevention was proposed. METHODS: A total of 392 children aged 24 to 71 months were selected for oral examination in Qingdao. Parents or guardians of the participants completed the questionnaires and decayed missing filled surface (dmfs) were recorded. Differences in caries condition and oral health behaviour in different families were compared. Risk factors related to ECC were screened. The subjects were finally grouped based on the obtained dmfs into three groups: caries-free, ECC and S-ECC (severe ECC). Association of risk factors with the caries status was analysed using the Kruskal-Wallis test, the chi-square test and logistic regression analysis. RESULTS: There were significant differences among the caries-free, ECC and S-ECC groups in three parameters: eating too many sweets each day, brushing before and after sleeping, and whether parents helped to brush (P < 0.01). Combined factors such as the parents' level of education, oral health knowledge, attitudes, the family's annual income, the age of children when they start to brush and not brushing regularly were also significantly related to ECC (P < 0.05). No significant differences were observed among the three groups for these factors, including birth condition and nursing state, physical condition of the mother during pregnancy, feeding situation, if a pacifier was used during sleep, duration of brushing, frequency of mouth rinsing after meals each day and brushing with fluoride toothpaste (P > 0.05). CONCLUSION: Eating a lot of sweets, an incorrect brushing method, starting brushing at a later stage and not brushing regularly are susceptible factors for ECC. Emphasising oral health knowledge to parents and guardians, conducting proper brushing methods, limiting the frequency of sweets being eaten and avoiding an inappropriate habit of eating sweets are very important factors in the prevention of ECC. PMID- 28573264 TI - Effects of Combining Insulin-like Growth Factor 1 and Platelet-derived Growth Factor on Osteogenesis around ?Dental Implants. AB - OBJECTIVE: To explore the effects of the combination of insulin-like growth factor 1 (IGF-1) and platelet-derived growth factor (PDGF) on bone formation around dental implants. METHODS: A total of 24 adult rabbits were included in this experiment. Titanium machine-polished dental implants were placed in the iliac bones to simulate dental implants in the alveolar bone. The rabbits were randomly divided into four groups; a saline treated control group (NS), an IGF-1 treated group, a PDGF-BB treated group, and a combination of IGF-1 and PDGF-BB treated group. The rabbits were sacrificed after 3, 7, and 10 days, and implants and soft tissues around implants were histologically evaluated. RESULTS: All of the rabbits began to recover their appetite, move freely and the operation area started detumescence until after the fourth day. H&E staining showed that the granulation tissue formation, multinucleated giant cells, a small amount of calcium salt deposition and bone tissue were observed in the IGF-1 group and the PDGF-BB group. In the IGF-1 + PDGF-BB group, the granulation tissue had turned into fibrous connective tissue, and calcium salt deposit had formed bone tissue. Masson's trichrome staining showed that the IGF-1 group and the PDGF-BB group had more collagen fibre compared with the NS group. In the ?IGF-1 + PDGF-BB group, collagen fibre hyperplasia and repairing fibres appeared earlier than in other groups. CONCLUSION: When applying IGF-1 or PDGF-BB alone, either has the effect of accelerating the wound healing in the short term; while in combination, earlier collagen fibre hyperplasia appeared. PMID- 28573265 TI - A Rare Case of Malignant Melanoma of the Mandible: ?CT and MRI Findings. AB - Malignant melanoma of the mandibular gingiva is extremely rare. It is a malignant tumour of melanocytes or their precursor cells, and often misinterpreted as a benign pigmented process. A few reports have described computed tomography (CT) and magnetic resonance imaging (MRI) findings of malignant melanoma in the oral cavity. We report a rare case of malignant melanoma of the mandible and the related CT and MRI findings. Soft tissue algorithm contrast-enhanced CT showed an expansile mass and irregular destruction of alveolar bone in the right side of the mandibular molar area. MR images showed an enhancing mass and the tumour had a low to intermediate signal intensity and a high-signal intensity. Soft tissue algorithm contrast-enhanced CT and MR images showed lymphadenopathy involving the submandibular lymph nodes. Histopathological examination confirmed the diagnosis of malignant melanoma. PMID- 28573266 TI - The workings of ferritin: a crossroad of opinions. AB - Biochemistry of the essential element iron is complicated by radical chemistry associated with Fe(ii) ions and by the extremely low solubility of the Fe(iii) ion in near-neutral water. To mitigate these problems cells from all domains of life synthesize the protein ferritin to take up and oxidize Fe(ii) and to form a soluble storage of Fe(iii) from which iron can be made available for physiology. A long history of studies on ferritin has not yet resulted in a generally accepted mechanism of action of this enzyme. In fact strong disagreement exists between extant ideas on several key steps in the workings of ferritin. The scope of this review is to explain the experimental background of these controversies and to indicate directions towards their possible resolution. PMID- 28573267 TI - Correction: Iron isotopic composition of blood serum in anemia of chronic kidney disease. AB - Correction for 'Iron isotopic composition of blood serum in anemia of chronic kidney disease' by Yulia Anoshkina et al., Metallomics, 2017, DOI: 10.1039/c7mt00021a. PMID- 28573268 TI - Atmospheric gas-to-particle conversion: why NPF events are observed in megacities? AB - In terms of the global aerosol particle number load, atmospheric new particle formation (NPF) dominates over primary emissions. The key for quantifying the importance of atmospheric NPF is to understand how gas-to-particle conversion (GTP) takes place at sizes below a few nanometers in particle diameter in different environments, and how this nano-GTP affects the survival of small clusters into larger sizes. The survival probability of growing clusters is tied closely to the competition between their growth and scavenging by pre-existing aerosol particles, and the key parameter in this respect is the ratio between the condensation sink (CS) and the cluster growth rate (GR). Here we define their ratio as a dimensionless survival parameter, P, as P = (CS/10-4 s-1)/(GR/nm h-1). Theoretical arguments and observations in clean and moderately-polluted conditions indicate that P needs to be smaller than about 50 for a notable NPF to take place. However, the existing literature shows that in China, NPF occurs frequently in megacities such as in Beijing, Nanjing and Shanghai, and our analysis shows that the calculated values of P are even larger than 200 in these cases. By combining direct observations and conceptual modelling, we explore the variability of the survival parameter P in different environments and probe the reasons for NPF occurrence under highly-polluted conditions. PMID- 28573269 TI - Liquid crystal elastomers: emerging trends and applications. PMID- 28573270 TI - Hybrid colloidal microswimmers through sequential capillary assembly. AB - Active colloids, also known as artificial microswimmers, are self-propelled micro and nanoparticles that convert uniform sources of fuel (e.g. chemical) or uniform external driving fields (e.g. magnetic or electric) into directed motion by virtue of asymmetry in their shape or composition. These materials are currently attracting enormous scientific attention as models for out-of equilibrium systems and with the promise to be used as micro- and nanoscale devices. However, current fabrication of active colloids is limited in the choice of available materials, geometries, and modes of motion. Here, we use sequential capillarity-assisted particle assembly (sCAPA) to link microspheres of different materials into hybrid clusters of prescribed shapes ("colloidal molecules") that can actively translate, circulate and rotate powered by asymmetric electro hydrodynamic flows. We characterize the active motion of the clusters and highlight the range of parameters (composition and shape) that can be used to tune their trajectories. Further engineering provides active colloids that switch motion under external triggers or perform simple pick-up and transport tasks. By linking their design, realization and characterization, our findings enable and inspire both physicists and engineers to create customized active colloids to explore novel fundamental phenomena in active matter and to investigate materials and propulsion schemes that are compatible with future applications. PMID- 28573271 TI - A dielectric anomaly observed for doubly reduced mixed-valence polyoxometalate. AB - Benzimidazolium is revealed to form quasi-isostructural crystals of mixed-valence molecular metal oxides that consist of [PMoMoO40]5- and fully oxidized [BWO40]5-. The structure and dielectric behaviour were compared and a dielectric anomaly was evident due to the electric dipole relaxation in the mixed-valence system. PMID- 28573272 TI - Lipid rafts enhance the binding constant of membrane-anchored receptors and ligands. AB - Gaining insights into the binding of membrane-anchored receptors and ligands that mediate cell adhesion and signal transduction is of great significance for understanding numerous physiological processes driven by intercellular communication. Lipid rafts, microdomains in cell membranes enriched in cholesterol and saturated lipids such as sphingomyelin, are believed to serve as the essential platforms to recruit protein molecules for biological functions. An important question remains how the lipid rafts affect the binding constant of membrane-anchored receptors and ligands. We have investigated the adhesion of multicomponent membranes by using Monte Carlo simulations of a mesoscopic model with biologically relevant parameters. We find that the preferential partitioning of membrane-anchored receptor and ligand proteins in the lipid rafts significantly increases the binding constant of those proteins, in cooperation with the shape fluctuations of the membranes caused by thermal excitations. The binding constant can even be greater than that of the same receptors and ligands anchored to two apposing supported, planar membranes without shape fluctuations. The membrane shape fluctuations facilitate the binding of the anchored receptors and ligands, in contrast to the case of homogeneous membranes. Our results suggest that cells might regulate the binding of membrane-anchored receptor and ligand proteins by modulating the properties of lipid rafts such as area fraction, size and the affinity of rafts to the proteins. PMID- 28573273 TI - Quantitative isotopic measurements of gas-phase alcohol mixtures using a broadly tunable swept external cavity quantum cascade laser. AB - A swept-ECQCL is used for broadband IR spectroscopy of isotopic mixtures of CH3OH, CH3OD, CH3CH2OH, and CH3CH2OD in a static gas cell over a wavelength range of 9.5 to 10.4 MUm. A weighted least squares fitting approach with quantitative library spectra illustrates that significant spectral congestion does not negatively impact the ability for in situ quantification of large isotopic species in a mixture. The noise equivalent concentrations for CH3OH, CH3OD, CH3CH2OH, and CH3CH2OD are 19 ppbv m, 28 ppbv m, 450 ppbv m, and 350 ppbv m respectively for a 50 seconds integration time. Based on the observed NECs, isotopic precisions of 0.070/00 and 0.790/00 for a 50 s integration time are calculated for measurements of the [MeOD]/[MeOH] and [EtOD]/[EtOH] isotope ratios, respectively, for the species concentrations in the gas cell. PMID- 28573274 TI - Laser post-ionisation combined with a high resolving power orbitrap mass spectrometer for enhanced MALDI-MS imaging of lipids. AB - Coupling laser post-ionisation with a high resolving power MALDI Orbitrap mass spectrometer has realised an up to ~100-fold increase in the sensitivity and enhanced the chemical coverage for MALDI-MS imaging of lipids relative to conventional MALDI. This could constitute a major breakthrough for biomedical research. PMID- 28573275 TI - Hybridization chain reaction: a versatile molecular tool for biosensing, bioimaging, and biomedicine. AB - Developing powerful, simple and low-cost DNA amplification techniques is of great significance to bioanalysis and biomedical research. Thus far, many signal amplification strategies have been developed, such as polymerase chain reaction (PCR), rolling circle amplification (RCA), and DNA strand displacement amplification (SDA). In particular, hybridization chain reaction (HCR), a type of toehold-mediated strand displacement (TMSD) reaction, has attracted great interest because of its enzyme-free nature, isothermal conditions, simple protocols, and excellent amplification efficiency. In a typical HCR, an analyte initiates the cross-opening of two DNA hairpins, yielding nicked double helices that are analogous to alternating copolymers. As an efficient amplification platform, HCR has been utilized for the sensitive detection of a wide variety of analytes, including nucleic acids, proteins, small molecules, and cells. In recent years, more complicated sets of monomers have been designed to develop nonlinear HCR, such as branched HCR and even dendritic systems, achieving quadratic and exponential growth mechanisms. In addition, HCR has attracted enormous attention in the fields of bioimaging and biomedicine, including applications in fluorescence in situ hybridization (FISH) imaging, live cell imaging, and targeted drug delivery. In this review, we introduce the fundamentals of HCR and examine the visualization and analysis techniques for HCR products in detail. The most recent HCR developments in biosensing, bioimaging, and biomedicine are subsequently discussed with selected examples. Finally, the review provides insight into the challenges and future perspectives of HCR. PMID- 28573277 TI - Synthesis of BaTaO2N oxynitride from Ba-rich oxide precursor for construction of visible-light-driven Z-scheme overall water splitting. AB - Barium tantalum oxynitride (BaTaO2N) with an absorption edge of ca. 660 nm is one of the most promising photocatalysts for solar water splitting, and is usually synthesized by nitriding a mixture of Ba and Ta-containing compounds with a Ba/Ta molar ratio of unity under ammonia flow at high temperature, usually causing a high density of defect sites. Herein, we introduce a novel synthesis method for BaTaO2N (BTON) by employing Ba-rich LiBa4Ta3O12, prepared by a flux method, as a precursor of nitridation. As a comparison, BaTaOx was prepared by conventional solid state reaction and used as the precursor. The as-nitrided samples were correspondingly denoted as BTON-Flux and BTON-SSR. It was found that well crystallized BTON oxynitride can be similarly obtained by both methods, but the BTON-Flux sample exhibits significantly decreased defect density and enhanced surface area relative to the BTON-SSR sample. As a result of their structural differences, the photocatalytic water splitting performance of the BTON-Flux sample, regardless of the H2-evolving half reaction in the presence of methanol or Z-scheme overall water splitting, is much better than that of BTON-SSR. This study may open up a novel strategy for preparing oxynitride photocatalyst with decreased defect density for the promotion of solar water splitting. PMID- 28573278 TI - A luminescent ratiometric pH sensor based on a nanoscale and biocompatible Eu/Tb mixed MOF. AB - The precise and real-time monitoring of localized pH changes is of great importance in many engineering and environmental fields, especially for monitoring small pH changes in biological environments and living cells. Metal organic frameworks (MOFs) with their nanoscale processability show very promising applications in bioimaging and biomonitoring, but the fabrication of nanoscale MOFs is still a challenge. In this study, we synthesized a nanoscale mixed lanthanide metal-organic framework by a microemulsion method. The morphology and size of the NMOF can be simply adjusted by the addition of different amounts of the CTAB surfactant. This NMOF exhibits significant pH-dependent luminescence emission, which can act as a self-referenced pH sensor based on two emissions of Tb3+ at 545 nm and Eu3+ at 618 nm in the pH range from 3.00 to 7.00. The MTT assay and optical microscopy assay demonstrate the low cytotoxicity and good biocompatibility of the nanosensor. PMID- 28573276 TI - Reaction mechanism of the metallohydrolase CpsB from Streptococcus pneumoniae, a promising target for novel antimicrobial agents. AB - CpsB is a metal ion-dependent hydrolase involved in the biosynthesis of capsular polysaccharides in bacterial organisms. The enzyme has been proposed as a promising target for novel chemotherapeutics to combat antibiotic resistance. The crystal structure of CpsB indicated the presence of as many as three closely spaced metal ions, modelled as Mn2+, in the active site. While the preferred metal ion composition in vivo is obscure Mn2+ and Co2+ have been demonstrated to be most effective in reconstituting activity. Using isothermal titration calorimetry (ITC) we have demonstrated that, in contrast to the crystal structure, only two Mn2+ or Co2+ ions bind to a monomer of CpsB. This observation is in agreement with magnetic circular dichroism (MCD) and electron paramagnetic resonance (EPR) data that indicate the presence of two weakly ferromagnetically coupled Co2+ ions in the active site of catalytically active CpsB. While CpsB is known to be a phosphoesterase we have also been able to demonstrate that this enzyme is efficient in hydrolyzing the beta-lactam substrate nitrocefin. Steady state and stopped-flow kinetics measurements further indicated that phosphoesters and nitrocefin undergo catalysis in a conserved manner with a metal ion-bridging hydroxide acting as a nucleophile. Thus, the combined physicochemical studies demonstrate that CpsB is a novel member of the dinuclear metallohydrolase family. PMID- 28573279 TI - An automated and portable microfluidic chemiluminescence immunoassay for quantitative detection of biomarkers. AB - Microfluidic platforms capable of automated, rapid, sensitive, and quantitative detection of biomarkers from patient samples could make a major impact on clinical or point-of-care (POC) diagnosis. In this work, we realize an automated diagnostic platform composed of two main components: (1) a disposable, self contained, and integrated microfluidic chip and (2) a portable instrument that carries out completely automated operations. To demonstrate its potential for real-world application, we use injection molding for mass fabrication of the main components of disposable microfluidic chips. The assembled three-layered chip with on-chip mechanical valves for fluid control consists of (1) a top silicone fluidic layer with embedded zigzag microchannels, reagent reservoirs and a negative pressure port, (2) a middle tinfoil layer with patterned antibody/antigen stripes, and (3) a bottom silicone substrate layer with waste reservoirs. The versatility of the microfluidics-based system is demonstrated by implementation of a chemiluminescence immunoassay for quantitative detection of C reactive protein (CRP) and testosterone in real clinical samples. This lab-on-a chip platform with features of quantitation, portability and automation provides a promising strategy for POC diagnosis. PMID- 28573280 TI - Thermodynamic stability of driven open systems and control of phase separation by electro-autocatalysis. AB - Motivated by the possibility of electrochemical control of phase separation, a variational theory of thermodynamic stability is developed for driven reactive mixtures, based on a nonlinear generalization of the Cahn-Hilliard and Allen-Cahn equations. The Glansdorff-Prigogine stability criterion is extended for driving chemical work, based on variations of nonequilibrium Gibbs free energy. Linear stability is generally determined by the competition of chemical diffusion and driven autocatalysis. Novel features arise for electrochemical systems, related to controlled total current (galvanostatic operation), concentration-dependent exchange current (Butler-Volmer kinetics), and negative differential reaction resistance (Marcus kinetics). The theory shows how spinodal decomposition can be controlled by solo-autocatalytic charge transfer, with only a single faradaic reaction. Experimental evidence is presented for intercalation and electrodeposition in rechargeable batteries, and further applications are discussed in solid state ionics, electrovariable optics, electrochemical precipitation, and biological pattern formation. PMID- 28573281 TI - Three dimensional porous Hofmann clathrate [MIIPtII(CN)4]infinity (M = Co, Ni) synthesized by using postsynthetic reductive elimination. AB - We synthesized cyano-bridged three dimensional metal-organic frameworks [MII(H2O)2PtIV(CN)4Br2]infinity.n(H2O) (1: M = Co, 2: M = Ni) with an NbO type topology. Although 1 and 2 have no accessible pores, these MOFs were found to undergo reductive elimination of the axial bromides on the PtIV ions as well as removal of water molecules upon heating to form porous [MIIPtII(CN)4]infinity (1': M = Co, 2': M = Ni) with retention of their crystallinity. PMID- 28573282 TI - Structural transformation of selenidostannates from 1D to 0D and 2D via a stepwise amine-templated assembly strategy. AB - We investigated the amine-induced structure transformation of four selenidostannates, i.e. [Sn3Se7Fe(TEPA)]n (1), {[Sn2Se6].4(H+-PR)} (2), {[Sn2Se6].2[Fe(en)3]} (3), and {[Sn3Se7]n.2n(H+-DBN)} (4) (TEPA = tetraethylenepentamine, PR = piperidine, en = ethylenediamine, DBN = 1,5 diazabicyclo[4.3.0]non-5-ene), which were characterized by single-crystal X-ray diffraction and UV-vis spectroscopy. The TEPA-induced 1D chain structure of [Sn3Se7Fe(TEPA)]n in 1 can undergo cleavage of Se-Fe and Se-Sn bonds to form a 0D dimer unit of [Sn2Se6]2- observed in 2 and 3, induced by PR and en, respectively. More interestingly, under the induction of en and DBN templates, such a 1D chain can counterintuitively fuse into a 2D layered structure of [Sn3Se7]n2n- through the removal of [Fe(TEPA)] species and reformation of Sn-Se bonds. Moreover, these selenidostannates with different structural dimensionalities display photocurrent responses, which make them hold some promise as a potential semiconducting material applied in photoelectric devices. PMID- 28573283 TI - The effect of global transcriptional regulators on the anaerobic fermentative metabolism of Escherichia coli. AB - Global transcription factors are known to regulate the anaerobic growth of Escherichia coli on glucose. These transcription factors help the organism to sense oxygen and accordingly regulate the synthesis of mixed acid producing enzymes. Five global transcription factors, namely ArcA, Fnr, IhfA-B, Crp and Fis, are known to play an important role in the growth phenotype of the organism in the transition from anaerobic to aerobic conditions. The effect of deletion of most of these global transcription factors on the growth phenotype has not been characterized under strict anaerobic fermentation conditions. In order to enumerate the role of global transcription factors in central carbon metabolism, experiments were performed using single deletion mutants of the above mentioned global transcription regulators. The mutants demonstrated lower growth rates, ranging from 3-75% lower growth as compared to the wild-type strain along with varying glucose uptake rates. Global transcription regulators help in lowering formate and acetate synthesis, thereby effectively channeling the carbon towards redox balance (through ethanol formation) and biomass synthesis. Flux analysis of mutant strains indicated that deletion of a single transcription factor alone does not play a significant role in the normalized flux distribution of the central carbon metabolism. PMID- 28573284 TI - Is enzymatic hydrolysis a reliable analytical strategy to quantify glucuronidated and sulfated polyphenol metabolites in human fluids? AB - Phenolic compounds are present in human fluids (plasma and urine) mainly as glucuronidated and sulfated metabolites. Up to now, due to the unavailability of standards, enzymatic hydrolysis has been the method of choice in analytical chemistry to quantify these phase II phenolic metabolites. Enzymatic hydrolysis procedures vary in enzyme concentration, pH and temperature; however, there is a lack of knowledge about the stability of polyphenols in their free form during the process. In this study, we evaluated the stability of 7 phenolic acids, 2 flavonoids and 3 prenylflavanoids in urine during enzymatic hydrolysis to assess the suitability of this analytical procedure, using three different concentrations of beta-glucuronidase/sulfatase enzymes from Helix pomatia. The results indicate that enzymatic hydrolysis negatively affected the recovery of the precursor and free-form polyphenols present in the sample. Thus, enzymatic hydrolysis does not seem an ideal analytical strategy to quantify glucuronidated and sulfated polyphenol metabolites. PMID- 28573285 TI - Stereospecific control of the helical orientation of indolocarbazole-pyridine hybrid foldamers by rational modification of terminal chiral appendages. AB - The helical handedness excess of an indolocarbazole-pyridine hybrid oligomer capable of folding into a stable helical structure was achieved up to 96% by rational modification of terminal chiral residues. PMID- 28573292 TI - Enantioselective incorporation of dicarboxylate guests by octacalcium phosphate. AB - Enantioselectivity by octacalcium phosphate (OCP) is revealed through the incorporation of (S)-(-)-methylsuccinic acid (MeSuc) into its crystal lattice, with hardly any (R)-(+)-MeSuc incorporated. This phenomenon clearly indicates that OCP recognizes the steric structures of guest molecules, extending chiral recognition in inorganic materials to three-dimensional crystal growth. PMID- 28573291 TI - Mechanisms of iron and copper-frataxin interactions. AB - Frataxin is a mitochondrial protein whose deficiency is the cause of Friedreich's ataxia, a hereditary neurodegenerative disease. This protein plays a role in iron sulfur cluster biosynthesis, protection against oxidative stress and iron metabolism. In an attempt to provide a better understanding of the role played by metals in its metabolic functions, the mechanisms of mitochondrial metal binding to frataxin in vitro have been investigated. A purified recombinant yeast frataxin homolog Yfh1 binds two Cu(ii) ions with a Kd1(CuII) of 1.3 * 10-7 M and a Kd2(CuII) of 3.1 * 10-4 M and a single Cu(i) ion with a higher affinity than for Cu(ii) (Kd(CuI) = 3.2 * 10-8 M). Mn(ii) forms two complexes with Yfh1 (Kd1(MnII) = 4.0 * 10-8 M; Kd2(MnII) = 4.0 * 10-7 M). Cu and Mn bind Yfh1 with higher affinities than Fe(ii). It is established for the first time that the mechanisms of the interaction of iron and copper with frataxin are comparable and involve three kinetic steps. The first step occurs in the 50-500 ms range and corresponds to a first metal uptake. This is followed by two other kinetic processes that are related to a second metal uptake and/or to a change in the conformation leading to thermodynamic equilibrium. Frataxin deficient Deltayfh1 yeast cells exhibited a marked growth defect in the presence of exogenous Cu or Mn. Mitochondria from Deltayfh1 strains also accumulated higher amounts of copper, suggesting a functional role of frataxin in vivo in copper homeostasis. PMID- 28573293 TI - Contractility in an extensile system. AB - Essentially all biology is active and dynamic. Biological entities autonomously sense, compute, and respond using energy-coupled ratchets that can produce force and do work. The cytoskeleton, along with its associated proteins and motors, is a canonical example of biological active matter, which is responsible for cargo transport, cell motility, division, and morphology. Prior work on cytoskeletal active matter systems showed either extensile or contractile dynamics. Here, we demonstrate a cytoskeletal system that can control the direction of the network dynamics to be either extensile, contractile, or static depending on the concentration of filaments or weak, transient crosslinkers through systematic variation of the crosslinker or microtubule concentrations. Based on these new observations and our previously published results, we created a simple one dimensional model of the interaction of filaments within a bundle. Despite its simplicity, our model recapitulates the observed activities of our experimental system, implying that the dynamics of our finite networks of bundles are driven by the local filament-filament interactions within the bundle. Finally, we show that contractile phases can result in autonomously motile networks that resemble cells. Our results reveal a fundamentally important aspect of cellular self organization: weak, transient interacting species can tune their interaction strength directly by tuning the local concentration to act like a rheostat. In this case, when the weak, transient proteins crosslink microtubules, they can tune the dynamics of the network to change from extensile to contractile to static. Our experiments and model allow us to gain a deeper understanding of cytoskeletal dynamics and provide an new understanding of the importance of weak, transient interactions to soft and biological systems. PMID- 28573294 TI - Transition from nematic to gyroid-type cubic soft self-assembly by side-chain engineering of pi-conjugated sticky rods. AB - A sequence of liquid crystalline phases, involving cybotactic nematics, a lamellar phase, bicontinuous cubics and triangular honeycombs, was observed for oligo(phenylene ethynylene) based X-shaped bolapolyphiles with two long lateral alkyl chains and sticky ends provided by glycerol groups. In the cubic phase with Ia3[combining macron]d lattice - which is tailored by alkyl chain engineering - the aromatic cores are organized on the gyroid minimal surface in 3D curved layers of almost parallel aligned pi-conjugated rods. It is shown that this type of cubic phase is a general mode of soft self-assembly of X-shaped bolapolyphiles at the cross-over from the (long or short range) lamellar to the triangular honeycomb-like organization. Cubic phase formation is found only in a narrow range with respect to temperature and chain-length for the non-fluorinated compounds and in much wider ranges for related core-fluorinated molecules. PMID- 28573295 TI - What shapes eukaryotic transcriptional bursting? AB - Isogenic cells in a common environment present a large degree of heterogeneity in gene expression. Part of this variability is attributed to transcriptional bursting: the stochastic activation and inactivation of promoters that leads to the discontinuous production of mRNA. The diversity in bursting patterns displayed by different genes suggests the existence of a connection between bursting and gene regulation. Experimental strategies such as single-molecule RNA FISH, MS2-GFP or short-lived protein reporters allow the quantification of transcriptional bursting and the comparison of bursting kinetics between conditions, allowing therefore the identification of molecular mechanisms modulating transcriptional bursting. In this review we recapitulate the impact on transcriptional bursting of different molecular aspects of transcription such as the chromatin environment, nucleosome occupancy, histone modifications, the number and affinity of regulatory elements, DNA looping and transcription factor availability. More specifically, we examine their role in tuning the burst size or the burst frequency. While some molecular mechanisms involved in transcription such as histone marks can affect every aspect of bursting, others predominantly influence the burst size (e.g. the number and affinity of cis-regulatory elements) or frequency (e.g. transcription factor availability). PMID- 28573296 TI - Facile routes to abnormal-NHC-cobalt(ii) complexes. AB - Deprotonation of [IPrPh]I (1) with Co{N(SiMe3)2}2 readily affords the abnormal N heterocyclic carbene (aNHC) complex (aIPrPh)2CoI2 (2) (aIPrPh = 1,3-bis(2,6 iPr2C6H3)-2-phenyl-imidazol-4-ylidene). Treatment of 1 with NaHBEt3 yields (aIPrPh)BEt3 (3) that serves as an aNHC-transfer agent and yields (aIPrPh)Co{N(SiMe3)2}2 (4) on reaction with Co{N(SiMe3)2}2. PMID- 28573302 TI - Roughening up polymer microspheres and their diffusion in a liquid. AB - A simple, versatile approach for the roughening of polymer microparticles surfaces via a deformation technique in the presence of an inorganic matrix is presented here. The process consists of straightforward steps: (1) preparation of a bicomposite colloidal sol, that is polymer particles and inorganic particles, dispersed in a liquid, (2) drying of the mixture onto a suitable hard substrate, (3) heating the dried film above the glass transition temperature of the polymer, and (4) re-dispersion and chemical etching of the inorganic medium. The primary driver is capillary imbibition of the polymer melt into the inorganic colloidal template. In addition, 2D particle tracking experiments of dispersed rough particles in water were performed to probe the diffusional behaviour of the roughened objects in comparison with their smooth precursors. We show that, despite large scale roughness (up to 10% asperity size with respect to particle diameter), Stokes law is obeyed and the particle motion can be modelled simply with the Stokes-Einstein-Sutherland relation. PMID- 28573303 TI - Non-monotonic knotting probability and knot length of semiflexible rings: the competing roles of entropy and bending energy. AB - We consider self-avoiding rings of up to 1000 beads and study, by Monte Carlo techniques, how their equilibrium knotting properties depend on the bending rigidity. When the rings are taken from the rigid to fully-flexible limit, their average compactness increases, as expected. However, this progressive compactification is not parallelled by a steady increase of the abundance of knots. In fact the knotting probability, Pk, has a prominent maximum when the persistence length is a few times larger than the bead size. At similar bending rigidities, the knot length has, instead, a minimum. We show that the observed non-monotonicity of Pk arises from the competition between two effects. The first one is the entropic cost of introducing a knot. The second one is the gain in bending energy due to the presence of essential crossings. These, in fact, constrain the knotted region and keep it less bent than average. The two competing effects make knots maximally abundant when the persistence length is 5 10 times larger than the bead size. At such intermediate bending rigidities, knots in the chains of 500 and 1000 beads are 40 times more likely than in the fully-flexible limit. PMID- 28573304 TI - Universal signal generator for dynamic cell stimulation. AB - Dynamic cell stimulation is a powerful technique for probing gene networks and for applications in stem cell differentiation, immunomodulation and signaling. We developed a robust and flexible method and associated microfluidic devices to generate a wide-range of precisely formulated dynamic chemical signals to stimulate live cells and measure their dynamic response. This signal generator is capable of digital to analog conversion (DAC) through combinatoric selection of discrete input concentrations, and outperforms existing methods by both achievable resolution, dynamic range and simplicity in design. It requires no calibration, has minimal space requirements and can be easily integrated into microfluidic cell culture devices. The signal generator hardware and software we developed allows to choose the waveform, period and amplitude of chemical input signals and features addition of well-defined chemical noise to study the role of stochasticity in cellular information processing. PMID- 28573305 TI - Uniform distribution of post-synthetic linker exchange in metal-organic frameworks revealed by Rutherford backscattering spectrometry. AB - Rutherford backscattering spectrometry (RBS) has been used for the first time to study post-synthetic linker exchange (PSE) in metal-organic frameworks. RBS is a non-invasive method to quantify the amount of introduced linker, as well as providing a means for depth profiling in order to identify the preferred localization of the introduced linker. The exchange of benzenedicarboxylate (bdc) by similarly sized 2-iodobenzenedicarboxylate (I-bdc) proceeds considerably slower than migration of I-dbc through the UiO-66 crystal. Consequently, the I bdc is found evenly distributed throughout the UiO-66 samples, even at very short PSE exposure times. PMID- 28573306 TI - Two-photon imaging of formaldehyde in live cells and animals utilizing a lysosome targetable and acidic pH-activatable fluorescent probe. AB - Lyso-TPFP presents lysosomal targetability and an acidic pH-activatable response toward formaldehyde. Thus, it exclusively visualizes lysosomal formaldehyde and is immune against it in neutral cytosol and other organelles. In addition, two photon fluorescence imaging endows Lyso-TPFP with the capability of in situ tracking formaldehyde in live cells and animals. PMID- 28573307 TI - Evidence of field induced slow magnetic relaxation in cis-[Co(hfac)2(H2O)2] exhibiting tri-axial anisotropy with a negative axial component. AB - We report a combined experimental characterization and theoretical modeling of the hexa-coordinated high-spin Co(ii) complex cis-[Co(hfac)2(H2O)2] (I). The magnetic static field (DC) data and EPR spectra (measurements were carried out on the powder samples of diluted samples cis-[Co0.02Zn0.98 (hfac)2(H2O)2]) were analyzed with the aid of the parametric Griffith Hamiltonian for the high-spin Co(ii) supported by the ab initio calculations of the crystal field (CF) parameters, g-factors and superexchange parameters between H-bonded Co(ii) ions in the neighboring molecules in a 1D network. This analysis suggests the presence of the easy axis of magnetic anisotropy and also shows the existence of a significant rhombic component. The detected frequency dependent (AC) susceptibility signal shows that complex I exhibits slow paramagnetic relaxation in the applied DC field belonging thus to the class of non-uniaxial field induced single ion magnets with a negative axial component of anisotropy. It is demonstrated that the main contributions to the relaxation come from the direct one-phonon process dominating at low temperatures, while the contribution of the two-phonon Raman process becomes important with increasing temperature. PMID- 28573308 TI - Serial practice impairs motor skill consolidation. AB - Recent reports have revealed that motor skill learning is impaired if two skills are practiced one after the other, that is before the first skill has had the time to become consolidated. This suggests that motor skills should be practiced in isolation from one another to minimize interference. At the moment, little is known about the effect of practice schedules high in contextual interference on motor skill consolidation. In Experiment 1, we investigated whether a serial practice schedule impairs motor skill consolidation. Participants had to learn two distinct sequences of finger movements (A and B) under either a blocked practice schedule or a serial practice schedule before being retested the following day. A control group also practiced Sequence A only. Our results revealed that a blocked practice schedule led to no interference between the sequences, whereas a serial practice schedule impaired the consolidation of Sequence B. In Experiment 2, we investigated the origin of the interference caused by a serial practice schedule by replacing the physical practice of Sequence A with either the observation of a model performing Sequence A or by asking participants to produce random finger movements. Our results revealed that both tasks interfered with the consolidation of Sequence B. Thus, we suggest that a serial practice schedule impairs motor skill consolidation through a conflict in the brain networks involved in the acquisition of the cognitive representation of the sequence and its execution. PMID- 28573309 TI - Neurophysiological features of tactile versus visual guidance of ongoing movement. AB - Although studies have investigated tactile and visual processing for perception, sensory processing for ongoing action remains poorly understood. The purpose of this study was to explore modality-specific patterns of cortical activation and functional connectivity in a practiced trajectory tracking task. Participants traced irregular shapes with their index finger using either touch or vision for guidance. In 60 tactile-motor (TM) trials, movement was guided only by tactile feedback of semicircular bumps on a plastic tile. In 60 visuo-motor (VM) trials, movement was guided only by vision of dots on a screen seen through a small window at the finger tip. The order of TM and VM trials was counterbalanced across 16 participants. Electroencephalography (EEG) was used to estimate cortical activation (task-related spectral power) and functional connectivity (task-related magnitude-squared coherence) in the alpha (8-12 Hz) and beta (13-30 Hz) bands during the last 12 movement trials in each sensorimotor task. TM vs. VM tasks exhibited a larger drop in global beta cortical activation, and greater alpha coherence between central, parietal, and occipital regions. VM vs. TM tasks were characterized by low global alpha coherence. Trace time and cortical activation of the last 12 VM trials were reduced in the group performing the VM task after the TM task compared to those performing the VM task first. Beta connectivity initiated by the first task was maintained on the subsequent second task, regardless of the task order. Identification of modality- and order specific EEG characteristics provides insight into the sensory control of movement. PMID- 28573310 TI - Inhibition of neuropathic hyperalgesia by intrathecal bone marrow stromal cells is associated with alteration of multiple soluble factors in cerebrospinal fluid. AB - Injury-induced neuropathic pain remains a serious clinical problem. Recent studies indicate that bone marrow stromal cells (BMSCs) effectively attenuate chronic neuropathic pain in animal models. Here, we examined the therapeutic effect of intrathecal administration of BMSCs isolated from young (1-month-old) rats on pain hypersensitivity induced by tibial nerve injury. Cerebrospinal fluid (CSF) was collected and analyzed to examine the effect of BMSC administration on the expression of 67 soluble factors in CSF. A sustained remission in injury induced mechanical hyperalgesia was observed in BMSC-treated rats but not in control animals. Engrafted BMSCs were observed in spinal cords and dorsal root ganglia at 5 weeks after cell injection. Injury significantly decreased the levels of six soluble factors in CSF: intercellular adhesion molecule 1 (ICAM-1), interleukin-1beta (IL-1beta), IL-10, hepatocyte growth factor (HGF), Nope protein, and neurogenic locus notch homolog protein 1 (Notch-1). Intrathecal BMSCs significantly attenuated the injury-induced reduction of ICAM-1, IL-1beta, HGF, IL-10, and Nope. This study adds to evidence supporting the use of intrathecal BMSCs in pain control and shows that this effect is accompanied by the reversal of injury-induced reduction of multiple CSF soluble factors. Our findings suggest that these soluble factors may be potential targets for treating chronic pain. PMID- 28573313 TI - Low-dose nivolumab-induced responses in acute lymphoblastic leukaemia relapse after allogeneic haematopoietic stem cell transplantation. PMID- 28573311 TI - Kinematics in the brain: unmasking motor control strategies? AB - In rhythmical movement performance, our brain has to sustain movement while correcting for biological noise-induced variability. Here, we explored the functional anatomy of brain networks during voluntary rhythmical elbow flexion/extension using kinematic movement regressors in fMRI analysis to verify the interest of method to address motor control in a neurological population. We found the expected systematic activation of the primary sensorimotor network that is suggested to generate the rhythmical movement. By adding the kinematic regressors to the model, we demonstrated the potential involvement of cerebellar frontal circuits as a function of the irregularity of the variability of the movement and the primary sensory cortex in relation to the trajectory length during task execution. We suggested that different functional brain networks were related to two different aspects of rhythmical performance: rhythmicity and error control. Concerning the latter, the partitioning between more automatic control involving cerebellar-frontal circuits versus less automatic control involving the sensory cortex seemed thereby crucial for optimal performance. Our results highlight the potential of using co-registered fine-grained kinematics and fMRI measures to interpret functional MRI activations and to potentially unmask the organisation of neural correlates during motor control. PMID- 28573312 TI - The alpha-lipoic acid derivative DHLHZn: a new therapeutic agent for acute lung injury in vivo. AB - OBJECTIVE AND DESIGN: An animal experiment was performed to demonstrate the anti inflammatory effects of an alpha-lipoic acid (ALA) derivative, dihydrolipoyl histidinate zinc complex (DHLHZn) for acute lung injury (ALI) and to investigate the mechanism of action. MATERIAL: Rats were randomly divided into three experimental groups: control group (n = 17), DHLHZn(-) group (n = 11, ALI model rats), and DHLHZn(+) group (n = 12, ALI model rats treated by DHLHZn). TREATMENT: Lipopolysaccharides (LPS, 10 mg/kg) were administered intratracheally in the DHLHZn(-) group and the DHLHZn(+) group. For the DHLHZn(+) group, DHLHZn (100 mg/kg) was administered intraperitoneally 2 h prior to LPS administration. METHODS: Four hours after LPS administration, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The findings were analyzed using the Mann-Whitney U test. RESULTS: Total number of cells, number of neutrophils and lymphocytes, levels of various inflammatory cytokines, and NF-kB p65 concentration of BALF were significantly lower in the DHLHZn(+) group than in the DHLHZn(-) group (p < 0.05). ALI pathology scores were significantly lower in the DHLHZn(+) group than in the DHLHZn(-) group (p < 0.001). CONCLUSIONS: Anti-inflammatory effects of DHLHZn for ALI were demonstrated by BALF and histopathological findings. The mechanism of action of DHLHZn was considered to be via inhibition of the NF-kB signaling pathway. DHLHZn is thus suggested to be a new prophylactic agent for ALI. PMID- 28573314 TI - Reduced toxicity, myeloablative HLA-haploidentical hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for sickle cell disease. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) offers the possibility of cure for sickle cell disease (SCD) patients. Unfortunately, the probability of finding an HLA-matched donor for SCD patients is low. HSCT from HLA haploidentical donors using reduced intensity conditioning, unmanipulated bone marrow and post-transplantation cyclophosphamide (ptCy) has resulted in negligible toxicity but high rates of graft rejection. We hypothesized that combining ptCy with a myeloablative reduced toxicity conditioning including serotherapy to increase immune ablation would allow for better engraftment. In a pilot approach, we treated three patients with SCD (5, 8, and 20 years old) lacking a matched donor. All patients had severe disease-related complications despite standard treatment. They received unmanipulated bone marrow from parental HLA-haploidentical donors. Conditioning consisted of alemtuzumab 0.2 mg/kg/day on days -9 and -8, fludarabine 30 mg/m2/day on days -7 to -3, treosulfan 14 g/m2/day on days -7 to -5, thiotepa 2 * 5 mg/kg/day on day -4, and cyclophosphamide 14.5 mg/kg/day on days -3 and -2. GVHD prophylaxis was performed using cyclophosphamide 2 * 50 mg/kg on days +3 and +4 and mycophenolate mofetil, tacrolimus from day +5. After a follow-up of 11, 14, and 30 months, all three patients are alive and well, off immunosuppression, and without symptoms of SCD. One patient experienced mild skin GVHD grade I, none showed chronic GVHD. Asymptomatic CMV reactivation was seen in two patients. HLA-haploidentical HSCT can extend the donor pool for patients with SCD. Whether intensification of the conditioning regimen and intensive immunosuppression leads to improvement in engraftment rates while still allowing a favorable toxicity profile deserves further investigation. PMID- 28573315 TI - Pediatric renal transplant biopsy with ultrasound guidance: the 'core' essentials. AB - This review provides a comprehensive and practical approach to pediatric percutaneous renal transplant biopsies, highlighting techniques and strategies to optimize adequate sample yield and ensure patient safety. In children with end stage renal disease, transplantation is the preferred choice of therapy, providing for overall lower long-term morbidity and mortality compared with dialysis. In the ongoing management of renal transplant patients, core tissue sampling via a percutaneous renal biopsy remains the gold standard when transplant dysfunction is suspected. Indications for renal transplant biopsy and techniques/tools for adequate sample yield are discussed. Strategies for common challenges such as poor visualization and renal transplant mobility are addressed. We discuss the clinical signs, techniques and imaging findings for common complications including hematomas, arteriovenous fistulas and pseudoaneurysms. Although the percutaneous renal transplant biopsy procedure is generally safe with rare complications, care must be taken to ensure major complications are promptly recognized and treated. Adequate tissue samples obtained via renal biopsy are imperative to promptly identify transplant rejection to provide valuable information for patient diagnosis, treatment and outcomes. Radiologist and nephrologist attention to proper ultrasound techniques and optimal biopsy tools are critical to ensure tissue adequacy and minimize complications. PMID- 28573316 TI - [Sarcoidosis : Dermatological view of a rare multisystem disease]. AB - Sarcoidosis is a rare multisystem inflammatory disease of largely unknown etiology. While pulmonary sarcoidosis is the most abundant organ manifestation, involvement of the skin that occurs in up to 30% of patients is the most common extrapulmonary presentation of the disease. Dermatologists therefore play an important role not only for establishing the diagnosis and delineating it from potential differential diagnoses but also for the interdisciplinary care of the patient. The clinical presentation of skin sarcoidosis is manifold, which occasionally aggravates making the final diagnosis. Specific skin lesions (with granulomas) and nonspecific skin manifestations (without granulomas) can be differentiated. Since a variety of organ systems can be affected, multidisciplinary cooperation is mandatory. Therapy of sarcoidosis is difficult; evidence-based studies and therapy guidelines are widely lacking. Our review intends to outline the characteristic clinical presentations of cutaneous sarcoidosis, describe the diagnostic approach and how to assure or exclude extracutaneous manifestations of sarcoidosis, and suggest a therapy algorithm for the treatment of skin sarcoidosis. PMID- 28573317 TI - Further optimization of peptide substrate enhanced assay performance for BoNT/A detection by MALDI-TOF mass spectrometry. AB - Rapid and sensitive detection of botulinum neurotoxins (BoNTs), which cause botulism, is essential in a public health emergency or bioterrorism event. We have previously developed a mass spectrometry (MS)-based functional method, Endopep-MS assay, for the fast detection and differentiation of all BoNT serotypes by affinity enriching the toxin and detecting the serotype-specific cleavage products of peptide substrates derived from the in vivo targets. To improve the performance of the Endopep-MS assay, we report here the further optimization of the peptide substrate for the detection of serotype A botulinum neurotoxins. An increased substrate cleavage was achieved by extending the original peptide N-terminus with optimized amino acid sequence, increasing the detection sensitivity of the method. In addition, the resistance of the substrate to nonspecific hydrolysis was dramatically improved by selectively substituting amino acids at the scissile bond and various other positions of the extended peptide. Moreover, incorporating the N-terminal hydrophobic residues dramatically improved the relative intensity of the cleavage products in the mass spectra. This allowed easy detection of the cleavage products, further enhancing the performance of the assay. The limit of detection for spiked serum sample was enhanced from 0.5 to 0.1 mouseLD50 and from 0.5 to 0.2 mouseLD50 for spiked stool. Graphical abstract Mass spectra of optimized and old peptide substrates with BoNT/A. PMID- 28573318 TI - Simple and sensitive determination of trace nitrite in water by zero-crossing first-derivative synchronous fluorescence spectrometry using 6-amino-1,3- naphthalenedisulfonic acid as a new fluorescent probe. AB - A new fluorescent probe, 6-amino-1,3-naphthalenedisulfonic acid (ANDSA), has been developed for the determination of trace nitrite in different waters. This probe is based on the selective reaction of nitrite with ANDSA in hydrochloric acid solution to form the corresponding diazonium acid in sodium hydroxide solution at room temperature. The diazonium acid produced has high fluorescence intensity at 488 nm (excitation at 367 nm), whereas ANDSA has high fluorescence intensity at 465 nm (excitation at 354 nm). The synchronous fluorescence (Deltalambda = 121 nm) spectrum and the first-derivative synchronous fluorescence spectrum of diazonium acid greatly overlapped with those of ANDSA. The zero-crossing method was used to measure the first-derivative value (dF/dlambda) of the first derivative spectra, in which physical separation of excess ANDSA was unnecessary. The zero-crossing point was located at 351.2 nm for ANDSA, at which dF/dlambda of diazonium acid was proportional to the nitrite concentration. Therefore, dF/dlambda at 351.2 nm was selected as the analytical signal. Under the optimized experimental conditions, the signal intensity was linear over a nitrite concentration range of 0.006-0.075 mg L-1, with a correlation coefficient better than 0.9994. The limit of detection was 2.1 MUg L-1 for the determination of nitrite by the proposed method. The relative standard deviation of the method for the determination of nitrite in real water samples was below 2.45%, and the corresponding recoveries were between 95.7% and 104.1%. The validity of the proposed method was further confirmed by comparison with the reference method with use of the t test. Graphical abstract ANDSA reacts with nitrite to form diazonium acid with higher fluorescence intensity. For ANDSA, dF/dlambda was zero at 351.2 nm, whereas dF/dlambda of diazonium acid at 351.2 nm was close to the maximum value. PMID- 28573319 TI - Rapid multiresidue determination of bisphenol analogues in soil with on-line derivatization. AB - Bisphenol analogues are compounds extensively used which have been potentially linked to adverse health effects. Nevertheless, few studies reported the analysis of compounds, other than bisphenol A, in environmental solid samples and none in soil samples. In this study, a rapid and sensitive analytical method is presented for the simultaneous determination of 13 bisphenols in soil samples. The method combines ultrasonic-assisted extraction of samples placed in small columns and GC MS/MS analysis. Manual and on-line derivatizations were compared and results showed that significant higher chromatographic responses were achieved with on line derivatization. Different parameters such as the quantity of derivatization agent, the extraction solvent, or the extraction time were assayed. The detection limits for all target bisphenols ranged from 0.04 to 0.27 ng g-1, for BPC and BPA, respectively. Analysis of spiked soil samples gave satisfactory recovery results, from 70 to 111%, for all the compounds. Finally, the validated method was applied to soil samples from several Spanish areas, and 3 of the 13 target bisphenols (BPAF, BPF, and BPA) were detected, although only BPF and BPA could be quantified with levels up to 127 ng g-1. Graphical abstract Schematic diagram of the developed method for the determination of bisphenol analogues. PMID- 28573320 TI - Automated chromatographic laccase-mediator-system activity assay. AB - To study the interaction of laccases, mediators, and substrates in laccase mediator systems (LMS), an on-line measurement was developed using high performance anion exchange chromatography equipped with a CarboPacTM PA 100 column coupled to pulsed amperometric detection (HPAEC-PAD). The developed method was optimized for overall chromatographic run time (45 to 120 min) and automated sample drawing. As an example, the Trametes versicolor laccase induced oxidation of 1-(3,4-dimethoxyphenyl)-2-(2-methoxyphenoxy)-1,3-dihydroxypropane (adlerol) using 1-hydroxybenzotriazole (HBT) as mediator was measured and analyzed on-line. Since the Au electrode of the PAD detects only hydroxyl group containing substances with a limit of detection being in the milligram/liter range, not all products are measureable. Therefore, this method was applied for the quantification of adlerol, and-based on adlerol conversion-for the quantification of the LMS activity at a specific T. versicolor laccase/HBT ratio. The automated chromatographic activity assay allowed for a defined reaction start of all laccase-mediator-system reactions mixtures, and the LMS reaction progress was automatically monitored for 48 h. The automatization enabled an integrated monitoring overnight and over-weekend and minimized all manual errors such as pipetting of solutions accordingly. The activity of the LMS based on adlerol consumption was determined to 0.47 U/mg protein for a laccase/mediator ratio of 1.75 U laccase/g HBT. In the future, the automated method will allow for a fast screening of combinations of laccases, mediators, and substrates which are efficient for lignin modification. In particular, it allows for a fast and easy quantification of the oxidizing activity of an LMS on a lignin-related substrate which is not covered by typical colorimetric laccase assays. ?. PMID- 28573322 TI - Plasmonic gold nanoparticles for detection of fungi and human cutaneous fungal infections. AB - Fungi, which are common in the environment, can cause a multitude of diseases. Warm, humid conditions allow fungi to grow and infect humans via the respiratory, digestive and reproductive tracts, genital area and other bodily interfaces. Fungi can be detected directly by microscopy, using the potassium hydroxide test, which is the gold standard and most popular method for fungal screening. However, this test requires trained personnel operating specialist equipment, including a fluorescent microscope and culture facilities. As most acutely infected patients seek medical attention within the first few days of symptoms, the optimal diagnostic test would be rapid and self-diagnostic simplifying and improving the therapeutic outcome. In suspensions of gold nanoparticles, Aspergillus niger can cause a colour change from red to blue within 2 min, as a result of changes in nanoparticle shape. A similar colour change was observed in the supernatant of samples of human toenails dispersed in water. Scanning electron microscopy, UV/Vis and Raman spectroscopy were employed to monitor the changes in morphology and surface plasmon resonance of the nanoparticles. The correlation of colour change with the fungal infection was analysed using the absorbance ratio at 520 nm/620 nm. We found a decrease in the ratio when the fungi concentration increased from 1 to 16 CFU/mL, with a detection limit of 10 CFU/mL. The test had an 80% sensitivity and a 95% specificity value for the diagnosis of athlete's foot in human patients. This plasmonic gold nanoparticle-based system for detection of fungal infections measures the change in shape of gold nanoparticles and generates coloured solutions with distinct tonality. Our application has the potential to contribute to self-diagnosis and hygiene control in laboratories/hospitals with fewer resources, just using the naked eye. Graphical abstract Colorimetric method for fungi detection with gold nano particles. PMID- 28573321 TI - An efficient direct competitive nano-ELISA for residual BSA determination in vaccines. AB - A simple, fast, and highly sensitive direct competitive enzyme-linked immunosorbent assay (ELISA) based on bovine serum albumin (BSA) antigen labeled amine-terminated silicon dioxide (SiO2-NH-BSA) nanoparticles was developed to determine residual BSA in vaccines. As nano-ELISA using nanomaterials with a very high surface-to-volume ratio has emerged as a promising strategy, SiO2-NH-BSA nanoparticles were prepared in this study by the coupling of BSA to SiO2 nanoparticles modified with amidogen, followed by the quantification of BSA via a direct competitive binding of BSA-antigen-labeled SiO2 nanoparticles to anti-BSA antibody conjugated with horseradish peroxidase. The validation study showed that the linear range of this method was from 1 to 90 ng/mL (r = 0.998) and the limit of detection was 0.67 ng/mL. The intra-assay and interassay coefficients of variation were less than 10% at three concentrations (10, 40, and 70 ng/mL), and the recovery was 92.4%, indicating good specificity. As a proof of principle, this new method was applied in the analysis of residual BSA in five different vaccines. Bland-Altman plots revealed that there was no significant difference in the accuracy and precision between our new method and the most commonly used sandwich ELISA. From the results taken together, the new method developed in this study is more sensitive and facile with lower cost and thus demonstrated potential to be applied in the quality control of biological products. Graphical Abstract Illustration of the procedures of the direct competitive enzyme immunoassay. PMID- 28573324 TI - Development of a sensitive and robust online dual column liquid chromatography tandem mass spectrometry method for the analysis of natural and synthetic estrogens and their conjugates in river water and wastewater. AB - An online ultra-high-performance-liquid chromatography-triple quadrupole tandem mass spectrometry (UHPLC-MS/MS) method for detection and quantification of natural and synthetic estrogens and their conjugates in aqueous matrices was developed. Target compounds include the natural estrogen estradiol (E2) and its main metabolites estrone (E1) and estriol (E3), the synthetic estrogens ethinylestradiol (EE2) and diethylstilbestrol (DES) and their conjugates estrone 3-sulfate (E1-3S), estriol 3-sulfate (E3-3S), estradiol 17-glucuronide (E2-17G), estrone 3-glucuronide (E1-3G), and estriol 16-glucuronide (E3-16G). After pH adjustment, sample filtration and addition of internal standards (IS), water samples (5 mL) were preconcentrated on a Hypersil GOLD aQ column after which chromatographic separation was achieved on a Kinetex C18 column using methanol and water as a mobile phase. The experimental parameters, such as sample loading flow rate, elution time, the percentage of organic solvent in the aqueous-organic eluent mixture, pH, and volume of analyzed samples, were optimized in detail. The benefits of the method compared to previously published methods include minimum sample manipulation, lower detection limits, reduced total analysis time, and overall increased method accuracy and precision. Method detection limits (MDLs) are in subnanogram per liter, complying with the requirements of the EC Decision 2015/495 (Watch list) for hormones listed therein. Applicability of the developed method was confirmed by analysis of river and raw wastewater samples taken directly from urban sewerage systems before being discharged into the river. Graphical abstract Sheme of online SPE-UHPLC-MS/MS system. PMID- 28573323 TI - Optical microalgal biosensors for aqueous contaminants using organically doped silica as cellular hosts. AB - Optical biosensors for the detection of toxic species in aqueous media were developed via the encapsulation of microalgae in sol-gel matrices. In a first step, the effect of cadmium(II), lead(II), and anthracene on the chlorophyll a fluorescence intensity of Anabaena flos-aquae, Chlorella vulgaris, and Euglena gracilis microalgae in suspension was studied. Complementary ATP-metry measurements demonstrated a direct relationship between optical response and pollutant toxicity, in a cell- and dose-dependent manner. In a second step, microalgae were successfully encapsulated in silicate-colloidal silica nanocomposite matrices. However, a complete loss of cell response to pollutant addition was observed, despite the preservation of cell viability. Introduction of a low amount (5 mol%) of amine- or ethyl-bearing silanes in the matrix formulation allowed the recovery of the sensing capacity of the immobilized microalgae, without impacting on the response time (30 s). Porosimetry and 29Si solid-state NMR spectroscopy showed that the organic moieties are fully integrated into the inorganic network, tuning the ability of the target pollutant to diffuse and reach the encapsulated algae. This versatile strategy could be useful for the easy and fast assessment of contamination levels in polluted waters. Graphical Abstract Microalgal biosensors for aqueous contaminants using organically doped silica as cellular hosts. PMID- 28573325 TI - Implications of the World Health Organization definition of atypia on surgically treated functional and non-functional pituitary adenomas. AB - BACKGROUND: The World Health Organization (WHO) defines atypical pituitary adenomas as tumours with a MIB-1 labelling index >=3%, p53 positivity and increased mitotic activity. Although a few reports have described the clinical and radiological correlates of atypia in pituitary adenomas, its impact on postoperative outcomes is not clearly defined. METHOD: We reviewed preoperative and postoperative records of patients undergoing surgery for pituitary adenomas. Postoperative outcomes for functional adenomas (FPAs) were assessed according to contemporary definitions of remission and recurrence. For non-functional pituitary adenomas (NFPAs), extent of resection and disease progression were defined on the basis of postoperative magnetic resonance imaging. RESULTS: Of 394 patients included for analysis, 29 cases (7.4%) fulfilled criteria for atypia. Patients with atypical tumours were significantly younger than those with typical adenomas. Remission was possible in 47.4% of FPAs, and was unrelated to the presence of atypia. In NFPAs, local invasiveness was negatively associated with extent of resection (OR, 0.255; 95% CI, 0.086-0.753; p < 0.001). In 93 NFPAs followed postoperatively with serial imaging over a mean duration of 37.5 months, disease progression/recurrence was significantly associated with the presence of atypia (OR, 5.058; 95% CI, 1.273-20.098; p = 0.021) on multivariate analysis. CONCLUSIONS: Patients with atypical non-functional pituitary adenomas are at risk for postoperative recurrence and disease progression, suggesting a need for adjuvant therapy. However, only a small fraction of pituitary tumours demonstrate atypia, as defined by the WHO, limiting its clinical utility. PMID- 28573326 TI - [Law and the phase of life old age]. AB - In spite of the greatly increased role, which the law attributes to the design of individual life styles and living of elderly people, there is no special legal area known in the German legal system, such as "rights of the elderly", which is the case in the field of the youth law. Special legal regulations covering the concerns/issues of elderly people were always considered to be in danger, as they may have the potential to discrimination, either in a positive or negative way. Due to this fact, the rights of the elderly can be described as synthetic and are subject to constant changes, as can be observed within the pension act. The legal areas and legal regulations, which are of particular importance for the life style and living situations of elderly people are presented. The legal need for action regarding the special protection of vulnerable elderly people is discussed and in the further course utilized for a conception of "rights of the elderly". PMID- 28573327 TI - [Social Work with old people and Social Gerontology]. AB - The current article outlines the development of Social Work with older people in the German social state and the role of gerontological discourses in this process. Some theories of Social work are introduced to show the mutual benefit that it has, when Social Work with older people and Gerontology continuously engage in common theoretical debates. PMID- 28573328 TI - Human CD200 suppresses macrophage-mediated xenogeneic cytotoxicity and phagocytosis. AB - PURPOSE: Various strategies, such as the generation of alpha-1,3 galactosyltransferase knocked-out pigs and CD55 transgenic pigs, have been investigated to inhibit pig to human xenogeneic rejection. Our aim is to develop strategies to overcome the hurdle of not only hyper acute rejection, but also that of cellular xenogeneic rejection (CXR). Although macrophages have been well known to play a critical role in CXR, monocyte/macrophage-mediated xenogeneic rejection has not been well studied. In this study, we evaluated the effect of CD200 in xenogeneic rejection by macrophages. METHODS: Naive swine endothelial cells (SEC) and SEC/CD200 were co-cultured with M0 macrophages and the cytotoxicity was measured by a WST-8 assay. The phagocytosis of SEC and SEC/CD200 by macrophages was analyzed by flow cytometry. RESULTS: While CD200 failed to suppress a significant amount of cytotoxicity against SEC by monocytes, M0 macrophage-mediated cytotoxicity was significantly suppressed by human CD200. The phagocytosis by M0 macrophages was also tested. The phagocytosis assay revealed that human CD200 suppresses M0 macrophage-mediated phagocytosis. CONCLUSIONS: Our findings indicate that human CD200 suppresses the xenogeneic rejection by CD200R+ macrophages and that the generation of hCD200 transgenic pigs for use in xenografts is very attractive for preventing the macrophage-mediated rejection. PMID- 28573330 TI - Diffuse 18F-FDG uptake throughout the spinal cord in the acute phase of Neuromyelitis Optica Spectrum disorder. PMID- 28573329 TI - Therapy assessment in multiple myeloma with PET. AB - Multiple myeloma is a plasma cell dyscrasia producing bone lytic lesions. In recent years, a wide spectrum of therapeutic approaches are available to treat the disease: an accurate therapy assessment has, therefore, become of utmost importance. In this field, imaging is becoming a cornerstone, especially in association with clinical parameters. Among imaging procedures, FDG PET/CT is recognized to provide reliable information, achieved in a very safe and fast procedure. The literature has produced very concordant results from different groups assessing the value of FDG PET/CT as a prognostic factor in general and in therapy assessment, but some issues remain regarding a standardization of image interpretation especially in borderline cases. So far, no data regarding nor other imaging compounds and the use of hybrid tomographs PET/MR are available to define therapy assessment in PET. PMID- 28573331 TI - FDG-PET/CT for systemic staging of patients with newly diagnosed breast cancer. PMID- 28573332 TI - A new comprehensive ecological risk index for risk assessment on Luanhe River, China. AB - With the enhancement of human activities which influence the physical and chemical integrity of ecosystem, it was bound to increase ecological risk to the ecosystem, and the risk assessment of small scale, single pollutant, or only on water quality have been not satisfied the demand of sustainable development of basin water environment. Based on the response relationship between environmental flow requirements guarantee ratio (GEF) and river ecological risk index (ERI), the Sediment Quality Guideline Quotient index (SQG-Q), and the Biotic Index (BI), we construct a new comprehensive ecological risk index (CERI) to evaluate the ecological risk of Luanhe River, China. According to the response relationship between GEF and ERI, upper and lower reaches of Luanhe River (Goutaizi to Hanjiaying) were at moderate risk level (0.41 < ERI < 0.56) in dry season, and all sites were at low risk level (ERI < 0.40) in wet season; considering the contribution of heavy metals contamination in the SQG-Q, the Luanhe River was the most influenced by higher levels of heavy metals in dry season and wet season; when this index was applied to the PAHs levels, only 30 and 20% of the sampling sites appeared to be moderately impacted (0.1 < SQG-Q PAHs < 0.5) by the PAHs in dry season and wet season, respectively. The results of BI showed that half of the sites appeared to be at moderately polluted level (50% of the sites, 0.25 < BI < 0.32) and heavily polluted level (Zhangbaiwan, BI = 0.36) in dry season, and 40% of the sites appeared to be at moderately polluted level (0.26 < BI < 0.29) in wet season. The CERI showed that 70 and 30% of the sites were at moderate risk level in dry season (0.25 < CERI < 0.36) and wet season (0.26 < CERI < 0.29), respectively. The results could give insight into risk assessment of water environment and decision-making for water source security. PMID- 28573333 TI - Incorporating equity in economic evaluations: a multi-attribute equity state approach. AB - In publicly funded health care systems, decision makers must continually balance often conflicting priorities of efficiency and equity. Health economists have developed a set of highly sophisticated analytical methods for assessing efficiency, but less attention has been paid to formally incorporating equity considerations into analyses. As a result, where equity is considered is often informal, ad hoc and/or simplistic. This paper is a proposal for a mechanism for formally incorporating equity within the decision process. It begins with an overview of the current literature on equity weighting. It then considers the case of a single equity domain and illustrates how this is currently applied in practice by the UK's National Institute for Health and Care Excellence. It then proposes a more comprehensive method for considering the multi-attribute equity state, where a population exhibits more than one trait considered worthy of differential weighting. Finally, the paper proposes a mechanism by which this could be applied in practice, and concludes with a discussion of the challenges for applying multi-attribute equity weighting. PMID- 28573334 TI - Retrieval of Migrated Volume Coils Using Different Clot Retrievers in a Porcine Model. AB - PURPOSE: During endovascular treatment of intracranial aneurysms using coils, migration is a serious complication that increases neurological morbidity. The aim of this experimental study was to assess the effectiveness and complications of retrieving volume coils with different, currently available clot retrievers in a porcine model. METHODS: Volume coils of three-dimensional (3D) shape and different sizes were placed in the axillary artery of pigs. By means of 4 different clot retrievers (Trevo ProVue; Solitaire FR; 3D-Separator; ERIC) a total of 40 retrieval maneuvers (10 per retriever) were performed by deploying the retrievers within the migrated coils and trying to trap parts of the coils by advancing the microcatheter. Retrieval rates, retrieval duration, retrieval attempts, and complications were assessed. RESULTS: Overall coil retrieval was successful in 31 of 40 cases (77.5%). Retrieval rates using the Trevo ProVue (9/10), Solitaire FR (8/10), and the 3D-Separator (9/10) were higher than when using the ERIC (5/10). Duration of retrieval and retrieval attempts were significantly higher using the ERIC (p < 0.05). Complications like inadvertent deployment were only observed in one case using the Solitaire FR. Additional entrapment of the coil-retriever complex at the intermediate catheter was seen in 9 cases (22.5%). There was no case of vasospasm, perforation, or dissection. CONCLUSIONS: Retrieval of migrated volume coils using new-generation clot retrievers is a feasible and effective method. Retrieval rates and duration with the Trevo ProVue, Solitaire FR, and 3D-Separator are superior when compared to the ERIC. PMID- 28573335 TI - Combined effect of 24-epibrassinolide and salicylic acid mitigates lead (Pb) toxicity by modulating various metabolites in Brassica juncea L. seedlings. AB - The present study demonstrated the combined effect of 24-epibrassinolide and salicylic acid against lead (Pb, 0.25, 0.50, and 0.75 mM) toxicity in Brassica juncea seedlings. Various parameters including water status, metal uptake, total water- and lipid-soluble antioxidants, metal chelator content (total thiols, protein-bound thiols, and non-protein-bound thiols), phenolic compounds (flavonoids, anthocyanins, and polyphenols), and organic acids were studied in 10 day-old seedlings. Dry matter content and the heavy metal tolerance index were reduced by 42.24 and 52.3%, respectively, in response to Pb treatment. Metal uptake, metal-chelating compounds, phenolic compounds, and organic acids were increased in Pb-treated seedlings as compared to control plants. The treatment of Pb-stressed seedlings with combination of EBL and SA resulted in enhancement of heavy metal tolerance index by 40.07%, water content by 1.84%, and relative water content by 23.45%. The total water- and lipid-soluble antioxidants were enhanced by 21.01 and 2.21%, respectively. In contrast, a significant decline in dry weight, metal uptake, thiol, and polyphenol contents was observed following the application of 24-epibrassinolide and salicylic acid. These observations indicate that Pb treatment has an adverse effect on B. juncea seedlings. However, co application of 24-epibrassinolide and salicylic acid mitigates the negative effects of Pb, by lowering Pb metal uptake and enhancing the heavy metal tolerance index, water content, relative water content, antioxidative capacities, phenolic content, and organic acid levels. PMID- 28573336 TI - The influence of mitochondrial dynamics on mitochondrial genome stability. AB - Mitochondria are dynamic organelles that fuse and divide. These changes alter the number and distribution of mitochondrial structures throughout the cell in response to developmental and metabolic cues. We have demonstrated that mitochondrial fission is essential to the maintenance of mitochondrial DNA (mtDNA) under changing metabolic conditions in wild-type Saccharomyces cerevisiae. While increased loss of mtDNA integrity has been demonstrated for dnm1-? fission mutants after growth in a non-fermentable carbon source, we demonstrate that growth of yeast in different carbon sources affects the frequency of mtDNA loss, even when the carbon sources are fermentable. In addition, we demonstrate that the impact of fission on mtDNA maintenance during growth in different carbon sources is neither mediated by retrograde signaling nor mitophagy. Instead, we demonstrate that mitochondrial distribution and mtDNA maintenance phenotypes conferred by loss of Dnm1p are suppressed by the loss of Sod2p, the mitochondrial matrix superoxide dismutase. PMID- 28573338 TI - Characterization of Inducible ccdB Gene as a Counterselectable Marker in Escherichia coli Recombineering. AB - Recombineering is a homologous-based DNA cloning and modification technique. Recombineering-mediated chromosomal gene knock-in usually involves a selectable/counterselectable cassette. Though a variety of selectable/counterselectable cassettes were developed; however, a specifically designed gene deletion strain or minimal medium is often required. Herein, we describe a novel selectable/counterselectable cassette Plac-ccdB-aacC1 in which aacC1 (gentamicin resistance gene) is used as the selectable marker for the homologous arm-flanked cassette knock-in, while the IPTG inducible ccdB gene is used as the counterselectable marker for chromosomal gene knock-in. The counterselection is achieved via supplementing 1 mM IPTG in the LB agar medium. An oligonucleotide designed to evade the mismatch repair system was utilized to engineer an Escherichia coli DH10B-derived gyrA462 strain that was used to as the host for the plasmid harboring the Plac-ccdB-aacC1 cassette. By using the Plac ccdB-aacC1 cassette, a linear-linear homologous recombination (LLHR) system was generated by knocking a 6.2 kb araC-PBAD-redgamma-recET-recA DNA fragment into the E. coli DH10B chromosome. The functional of the LLHR recombineering system was characterized by cloning of the target DNA from PCR product as well as from the genomic DNA mixture. The Plac-ccdB-aacC1 cassette will be a useful tool in E. coli recombineering. PMID- 28573337 TI - Immunological characterization of a rigid alpha-Tn mimetic on murine iNKT and human NK cells. AB - The ability of a rigid alpha-Tn mimetic (compound 1) to activate murine invariant natural killer T (iNKT) and human natural killer (NK) cells, two subsets of lymphocytes involved in cancer immunesurveillance, was investigated. For this purpose, the mimetic 1 was properly conjugated to a stearic acid containing glycerol-based phospholipid (compound 5) to be presented, in the context of the conserved non polymorphic major histocompatibility complex class I-like molecules (CD1d), to iNKT cells. On the contrary, the mimetic 1 was conjugated to a multivalent peptide-based scaffold (compound 6) to induce NK cell activation. PMID- 28573339 TI - Heterologous Expression of the Carrot Hsp17.7 gene Increased Growth, Cell Viability, and Protein Solubility in Transformed Yeast (Saccharomyces cerevisiae) under Heat, Cold, Acid, and Osmotic Stress Conditions. AB - In industrial fermentation of yeast (Saccharomyces cerevisiae), culture conditions are often modified from the optimal growth conditions of the cells to maintain large-scale cultures and/or to increase recombinant protein production. However, altered growth conditions can be stressful to yeast cells resulting in reduced cell growth and viability. In this study, a small heat shock protein gene from carrot (Daucus carota L.), Hsp17.7, was inserted into the yeast genome via homologous recombination to increase tolerance to stress conditions that can occur during industrial culture. A DNA construct, Translational elongation factor gene promoter-carrot Hsp17.7 gene-Phosphoribosyl-anthranilate isomerase gene (an auxotrophic marker), was generated by a series of PCRs and introduced into the chromosome IV of the yeast genome. Immunoblot analysis showed that carrot Hsp17.7 accumulated in the transformed yeast cell lines. Growth rates and cell viability of these cell lines were higher than control cell lines under heat, cold, acid, and hyperosmotic stress conditions. Soluble protein levels were higher in the transgenic cell lines than control cell lines under heat and cold conditions, suggesting the molecular chaperone function of the recombinant Hsp17.7. This study showed that a recombinant DNA construct containing a HSP gene from carrot was successfully expressed in yeast by homologous recombination and increased tolerances to abiotic stress conditions. PMID- 28573340 TI - Photonic Potential of Haloarchaeal Pigment Bacteriorhodopsin for Future Electronics: A Review. AB - Haloarchaea are known for its adaptation in extreme saline environment. Halophilic archaea produces carotenoid pigments and proton pumps to protect them from extremes of salinity. Bacteriorhodopsin (bR) is a light-driven proton pump that resides in the membrane of haloarchaea Halobacterium salinarum. The photocycle of Bacteriorhodopsin passes through several states from K to O, finally liberating ATP for host's survival. Extensive studies on Bacteriorhodopsin photocycle has provided in depth knowledge on their sequential mechanism of converting solar energy into chemical energy inside the cell. This ability of Bacteriorhodopsin to harvest sunlight has now been experimented to exploit the unexplored and extensively available solar energy in various biotechnological applications. Currently, bacteriorhodopsin finds its importance in dye-sensitized solar cell (DSSC), logic gates (integrated circuits, IC's), optical switching, optical memories, storage devices (random access memory, RAM), biosensors, electronic sensors and optical microcavities. This review deals with the optical and electrical applications of the purple pigment Bacteriorhodopsin. PMID- 28573341 TI - Identification of Methicillin-Resistant Staphylococcus aureus (MRSA) Using Simultaneous Detection of mecA, nuc, and femB by Loop-Mediated Isothermal Amplification (LAMP). AB - The aim of this study was to develop a rapid detection assay to identify methicillin-resistant Staphylococcus aureus by simultaneous testing for the mecA, nuc, and femB genes using the loop-mediated isothermal amplification (LAMP) method. LAMP primers were designed using online bio-software ( http://primerexplorer.jp/e/ ), and amplification reactions were performed in an isothermal temperature bath. The products were then examined using 2% agarose gel electrophoresis. MecA, nuc, and femB were confirmed by triplex TaqMan real-time PCR. For better naked-eye inspection of the reaction result, hydroxy naphthol blue (HNB) was added to the amplification system. Within 60 min, LAMP successfully amplified the genes of interest under isothermal conditions at 63 degrees C. The results of 2% gel electrophoresis indicated that when the Mg2+ concentration in the reaction system was 6 MUmol, the amplification of the mecA gene was relatively good, while the amplification of the nuc and femB genes was better at an Mg2+ concentration of 8 MUmol. Obvious color differences were observed by adding 1 MUL (3.75 mM) of HNB into 25 MUL reaction system. The LAMP assay was applied to 128 isolates cases of methicillin-resistant Staphylococcus aureus, which were separated from the daily specimens and identified by Vitek microbial identification instruments. The results were identical for both LAMP and PCR. LAMP offers an alternative detection assay for mecA, nuc, and femB and is faster than other methods. PMID- 28573342 TI - A gaping research gap regarding the climate change impact on health in poor countries. PMID- 28573343 TI - [Preoperative evaluation of adult patients before elective, noncardiothoracic surgery : Joint recommendation of the German Society of Anesthesiology and Intensive Care Medicine, the German Society of Surgery, and the German Society of Internal Medicine]. AB - Evaluation of the patient's medical history and a physical examination are the cornerstones of risk assessment prior to elective surgery and may help to optimize the patient's preoperative medical condition and to guide perioperative management. Whether the performance of additional technical tests (e. g. blood chemistry, ECG, spirometry, chest x-ray) can contribute to a reduction of perioperative risk is often not very well known or is controversial. Similarly, there is considerable uncertainty among anesthesiologists, internists and surgeons with respect to the perioperative management of the patient's long-term medication. Therefore, the German Scientific Societies of Anesthesiology and Intensive Care Medicine (DGAI), Internal Medicine (DGIM) and Surgery (DGCH) have joined to elaborate recommendations on the preoperative evaluation of adult patients prior to elective, noncardiothoracic surgery, which were initially published in 2010. These recommendations have now been updated based on the current literature and existing international guidelines. In the first part the general principles of preoperative evaluation are described (part A). The current concepts for extended evaluation of patients with known or suspected major cardiovascular disease are presented in part B. Finally, the perioperative management of patients' long-term medication is discussed (part C). The concepts proposed in these interdisciplinary recommendations endorsed by the DGAI, DGIM and DGCH provide a common basis for a structured preoperative risk assessment and management. These recommendations aim to ensure that surgical patients undergo a rational preoperative assessment and at the same time to avoid unnecessary, costly and potentially dangerous testing. The joint recommendations reflect the current state-of-the-art knowledge as well as expert opinions because scientific based evidence is not always available. These recommendations will be subject to regular re-evaluation and updating when new validated evidence becomes available. PMID- 28573345 TI - Evaluation of retromolar canals on cone beam computerized tomography scans and digital panoramic radiographs. AB - PURPOSE: The purpose of this study was to carry out morphologic and topographic analyses of retromolar canals on cone beam computerized tomography (CBCT) scans, comparing findings to others obtained from the corresponding digital panoramic radiographs. METHODS: Sixty-one CBCT scans were analysed digitally, as well as their corresponding digital panoramic radiographs. The prevalence and distribution of these canals, foramen diameters, and intraosseous communications were also evaluated. RESULTS: On CBCT scans, we found that 24.6% of individuals had at least one retromolar canal. The mean foramen diameter was slightly higher than 1 mm and we could not determine the intraosseous anatomical connections in most cases. The morphology and topography of the retromolar canals were not affected by gender and antimere. In addition, only 22.2% of all tomographically identified canals could be confirmed on digital panoramic radiographs (26.7% of such patients). Regarding all sample, 6.6% of individuals showed retromolar canals on digital panoramic radiographs. CONCLUSION: We may consider that these structures are clinically relevant findings and, due to the low accuracy of the panoramic radiographs, high-quality tomographic exams should always be asked for presurgical treatment planning. PMID- 28573344 TI - [Residual neuromuscular blockade]. AB - Even small degrees of residual neuromuscular blockade, i. e. a train-of-four (TOF) ratio >0.6, may lead to clinically relevant consequences for the patient. Especially upper airway integrity and the ability to swallow may still be markedly impaired. Moreover, increasing evidence suggests that residual neuromuscular blockade may affect postoperative outcome of patients. The incidence of these small degrees of residual blockade is relatively high and may persist for more than 90 min after a single intubating dose of an intermediately acting neuromuscular blocking agent, such as rocuronium and atracurium. Both neuromuscular monitoring and pharmacological reversal are key elements for the prevention of postoperative residual blockade. PMID- 28573346 TI - A critical assessment of finite element modeling approach for protein dynamics. AB - Finite element (FE) modeling approach has emerged as an efficient way of calculating the dynamic properties of supramolecular protein structures and their complexes. Its efficiency mainly stems from the fact that the complexity of three dimensional shape of a molecular surface dominates the computational cost rather than the molecular size or the number of atoms. However, no critical evaluation of the method has been made yet particularly for its sensitivity to the parameters used in model construction. Here, we make a close investigation on the effect of FE model parameters by analyzing 135 representative protein structures whose normal modes calculated using all-atom normal mode analysis are publicly accessible online. Results demonstrate that it is more beneficial to use a contour surface of electron densities as the molecular surface, in general, rather than to employ a solvent excluded surface, and that the solution accuracy is almost insensitive to the model parameters unless we avoid extreme values leading to an inaccurate depiction of the characteristic shapes. PMID- 28573347 TI - MolAlign: an algorithm for aligning multiple small molecules. AB - In small molecule drug discovery projects, the receptor structure is not always available. In such cases it is enormously useful to be able to align known ligands in the way they bind in the receptor. Here we shall present an algorithm for the alignment of multiple small molecule ligands. This algorithm takes pre generated conformers as input, and proposes aligned assemblies of the ligands. The algorithm consists of two stages: the first stage is to perform alignments for each pair of ligands, the second stage makes use of the results from the first stage to build up multiple ligand alignment assemblies using a novel iterative procedure. The scoring functions are improved versions of the one mentioned in our previous work. We have compared our results with some recent publications. While an exact comparison is impossible, it is clear that our algorithm is fast and produces very competitive results. PMID- 28573348 TI - Measurement of smaller colon polyp in CT colonography images using morphological image processing. AB - PURPOSE: Automated measurement of the size and shape of colon polyps is one of the challenges in Computed tomography colonography (CTC). The objective of this retrospective study was to improve the sensitivity and specificity of smaller polyp measurement in CTC using image processing techniques. METHODS: A domain knowledge-based method has been implemented with hybrid method of colon segmentation, morphological image processing operators for detecting the colonic structures, and the decision-making system for delineating the smaller polyp based on a priori knowledge. RESULTS: The method was applied on 45 CTC dataset. The key finding was that the smaller polyps were accurately measured. In addition to 6-9 mm range, polyps of even <5 mm were also detected. The results were validated qualitatively and quantitatively using both 2D MPR and 3D view. Implementation was done on a high-performance computer with parallel processing. It takes [Formula: see text] min for measuring the smaller polyp in a dataset of 500 CTC images. With this method, [Formula: see text] and [Formula: see text] were achieved. CONCLUSIONS: The domain-based approach with morphological image processing has given good results. The smaller polyps were measured accurately which helps in making right clinical decisions. Qualitatively and quantitatively the results were acceptable when compared to the ground truth at [Formula: see text]. PMID- 28573349 TI - Motion-based signaling in sympatric species of Australian agamid lizards. AB - Signaling species occurring in sympatry are often exposed to similar environmental constraints, so similar adaptations to enhance signal efficacy are expected. However, potentially opposing selective pressures might be present to ensure species recognition. Here, we analyzed the movement-based signals of two pairs of sympatric lizard species to consider how reliable communication is maintained while avoiding misidentification. Our novel approach allows us to quantify signal contrast with plant motion noise at any site we measure, including those utilized by other species. Ctenophorus caudicinctus and Gowidon longirostris differed in display complexity and motor pattern use. They also differed in overall morphology, but their signal contrast scores are strikingly similar. These results demonstrate similar adaptations to their shared environment while maintaining species recognition cues. In contrast, Ctenophorus fordi and Ctenophorus pictus are much closer in appearance, but C. pictus produces considerably higher signal contrast scores, which we suggest is attributable to the absence of territoriality in C. fordi. Taken together, our data provide evidence for adaptation to the local environment in movement-based signals, while also meeting species recognition requirements, but the selective pressure to deal with local conditions is mediated by signal function. PMID- 28573350 TI - Regional and temporal variation in minor ions in groundwater of a part of a large river delta, southern India. AB - Impact of agricultural activities on groundwater can be determined from the concentration of nutrients present in groundwater. This study was carried out with the aim to assess the minor ions content of groundwater and to identify its sources, spatial, and seasonal variations in a part of the Cauvery River basin, southern India. Groundwater samples were collected from July 2007 to September 2009 and were analyzed for minor ions. These ions were in the order of dominance of nitrate> phosphate> bromide> fluoride> ammonium= nitrite> lithium. The concentration of ions tends to increase towards the coast except for fluoride. Increased concentration of ions identified in shallow wells than in deep wells with an exception of few locations indicates the impact of human activities. Relatively high concentration of agriculture-sourced nitrate was identified which pose a threat to groundwater suitability for agriculture and domestic usage. Combined influence of use of agrochemicals, improper sewage disposal, aquaculture activities, seawater intrusion due to heavy pumping near the coast, and natural weathering of aquifer materials are the major sources. Also, fine grain sediments of this area aid in poor flushing of the ions towards the sea resulting in accumulation of higher concentration of ions. A sustainable management strategy is essential to control the concentration of these ions, especially nitrate. Reduced use of fertilizers, increasing the rainfall recharge for diluting the pollutants in groundwater and maintaining the river flow for sufficiently longer period to reduce dependence on groundwater for irrigation can help to improve the situation. PMID- 28573352 TI - Risk-based framework for optimizing residual chlorine in large water distribution systems. AB - Managing residual chlorine in large water distribution systems (WDS) to minimize human health risk is a daunting task. In this research, a novel risk-based framework is developed and implemented in a distribution network spanning over 64 km2 for supplying water to the city of Al-Khobar (Saudi Arabia) through 473-km long water mains. The framework integrates the planning of linear assets (i.e., pipes) and placement of booster stations to optimize residual chlorine in the WDS. Failure mode and effect analysis are integrated with the fuzzy set theory to perform risk analysis. A vulnerability regarding the probability of failure of pipes is estimated from historical records of water main breaks. The consequence regarding residual chlorine availability has been associated with the exposed population depending on the land use characteristics (i.e., defined through zoning). EPANET simulations have been conducted to predict residual chlorine at each node of the network. A water quality index is used to assess the effectiveness of chlorine practice. Scenario analysis is also performed to evaluate the impact of changing locations and number of booster stations, and rehabilitation and/or replacement of vulnerable water mains. The results revealed that the proposed methodology could facilitate the utility managers to optimize residual chlorine effectively in large WDS. PMID- 28573353 TI - Anything impossible with CRISPR/Cas9? PMID- 28573351 TI - Mitigating potential of Melissa officinale against As3+-induced cytotoxicity and transcriptional alterations of Hsp70 and Hsp27 in fish, Channa punctatus (Bloch). AB - The mitigating potential of Melissa officinale (MO) (Lamiaceae) against arsenite (As3+)-induced oxidative stress, cytogenotoxicity, and expression of stress genes in fish, Channa punctatus (Bloch), teleost, was explored. After confirming the composition of MO extract, caffeic acid (0.96%), hesperidin (1.73%), naringenin (7.70%), lutenolin (3.29%), kaempferol (11.46%) and hesperetin (6.24%), by HPLC PDA analysis, the experiment was set up in six groups (G1-G6), each containing 10 specimens. Blood, muscle, gills and liver tissues of control and treated fishes were excised at an interval of 24 till 96 h. Ameliorative potential of MO was confirmed by satisfactory restoration of altered activities of malondialdehyde, hydrogen peroxide, superoxide dismutase, catalase, glutathione peroxidise, glutathione reductase, reduced glutathione and ascorbate peroxidase in G4, G5 and G6, co-exposed with 96 h-LC50/10 As3+ with MO. A significant (p < 0.05) recovery in the frequencies of cytogenotoxic markers, micronuclei, disintegrated nucleus and echinocytes, which were expressed significantly (p < 0.05) in G3 exposed to sub-lethal concentration of ATO alone, was recorded in fish groups (G4, G5 and G6) together treated with 96 h-LC50/10 of ATO and 2, 4 and 8 ppm of MO, respectively. Moreover, the expression of Hsp70 gene was downregulated (2.29 fold); whereas, Hsp27 gene was upregulated (1.16-fold) in G6, the group co exposed with 96 h-LC50/10 As3+ with 8 ppm of MO in comparison with G3 (3.11-fold for Hsp70; 0.51-fold for Hsp27) after 96 h of exposure period. Thus, it can be inferred that the MO at its tested concentration can be effectively used to mitigate As3+ generated toxicities in C. punctatus. PMID- 28573355 TI - A 6-year update of the health policy and advocacy priorities of the Society of Behavioral Medicine. AB - Government policy affects virtually every topic of interest to health behavior researchers, from research funding to reimbursement for clinical services to application of evidence to impact health outcomes. This paper provides a 6-year update on the expansion of Society of Behavioral Medicine's (SBM) public policy and advocacy agenda and proposed future directions. SBM's Health Policy Council is responsible for ensuring coordination of the policy-related activities of the Health Policy Committee (HPC), the Civic and Public Engagement Committee (CPEC), and the Scientific and Professional Liaison Council (SPLC). These committees and councils have written letters to Congress, signed onto advocacy letters with hundreds of organizations, and developed and disseminated 15 health policy briefs, the majority of which have been presented to legislative staffers on Capitol Hill. With the assistance of the SPLC, SBM has collaborated on policy efforts with like-minded organizations to increase the impact of the Society's policy work. Moving forward, SBM plans to continue to increase efforts to disseminate policy work more broadly and develop long-term relationships with Congressional staffers. SBM leadership realizes that to remain relevant, demonstrate impact, and advance the role of behavioral medicine, we must advance a policy agenda that reflects our mission of better health through behavior change. PMID- 28573354 TI - Optimal feedback control to describe multiple representations of primary motor cortex neurons. AB - Primary motor cortex (M1) neurons are tuned in response to several parameters related to motor control, and it was recently reported that M1 is important in feedback control. However, it remains unclear how M1 neurons encode information to control the musculoskeletal system. In this study, we examined the underlying computational mechanisms of M1 based on optimal feedback control (OFC) theory, which is a plausible hypothesis for neuromotor control. We modelled an isometric torque production task that required joint torque to be regulated and maintained at desired levels in a musculoskeletal system physically constrained by muscles, which act by pulling rather than pushing. Then, a feedback controller was computed using an optimisation approach under the constraint. In the presence of neuromotor noise, known as signal-dependent noise, the sensory feedback gain is tuned to an extrinsic motor output, such as the hand force, like a population response of M1 neurons. Moreover, a distribution of the preferred directions (PDs) of M1 neurons can be predicted via feedback gain. Therefore, we suggest that neural activity in M1 is optimised for the musculoskeletal system. Furthermore, if the feedback controller is represented in M1, OFC can describe multiple representations of M1, including not only the distribution of PDs but also the response of the neuronal population. PMID- 28573356 TI - Active involved community partnerships: co-creating implementation infrastructure for getting to and sustaining social impact. AB - Active involved community partnerships (AICPs) are essential to co-create implementation infrastructure and translate evidence into real-world practice. Across varied forms, AICPs cultivate community and tribal members as agents of change, blending research and organizational knowledge with relationships, context, culture, and local wisdom. Unlike selective engagement, AICPs enable active involvement of partners in the ongoing process of implementation and sustainability. This includes defining the problem, developing solutions, detecting practice changes, aligning organizational supports, and nurturing shared responsibility, accountability, and ownership for implementation. This paper builds on previously established active implementation and scaling functions by outlining key AICP functions to close the research-practice gap. Part of a federal initiative, California Partners for Permanency (CAPP) integrated AICP functions for implementation and system change to reduce disproportionality and disparities in long-term foster care. This paper outlines their experience defining and embedding five AICP functions: (1) relationship building; (2) addressing system barriers; (3) establishing culturally relevant supports and services; (4) meaningful involvement in implementation; and (5) ongoing communication and feedback for continuous improvement. Planning for social impact requires the integration of AICP with other active implementation and scaling functions. Through concrete examples, authors bring multilevel AICP roles to life and discuss implications for implementation research and practice. PMID- 28573359 TI - Proceedings of the RAMI Intern Section Meeting. PMID- 28573358 TI - Comparison of Perioperative Outcomes between Open, Laparoscopic, and Robotic Distal Pancreatectomy: an Analysis of 1815 Patients from the ACS-NSQIP Procedure Targeted Pancreatectomy Database. AB - BACKGROUND: Robotic surgery is gaining acceptance for distal pancreatectomy (DP). Nevertheless, no multi-institutional data exist to demonstrate the ideal clinical circumstances for use and the efficacy of the robot compared to the open or laparoscopic techniques, in terms of perioperative outcomes. METHODS: The 2014 ACS-NSQIP procedure-targeted pancreatectomy data for patients undergoing DP were analyzed. Demographics and clinicopathological and perioperative variables were compared between the three approaches. Univariate and multivariable analyses were used to evaluate outcomes. RESULTS: One thousand eight hundred fifteen DPs comprised 921 open distal pancreatectomies (ODPs), 694 laparoscopic distal pancreatectomies (LDPs), and 200 robotic distal pancreatectomies (RDPs). The three groups were comparable with respect to demographics, ASA score, relevant comorbidities, and malignant histology subtype. Compared to the ODP group, patients undergoing RDP had lower T-stages of disease (P = 0.0192), longer operations (P = 0.0030), shorter hospital stays (P < 0.0001), and lower postoperative 30-day morbidity (P = 0.0476). Compared to the LDP group, RDPs were longer operations (P < 0.0001) but required fewer concomitant vascular resections (P = 0.0487) and conversions to open surgery (P = 0.0068). On multivariable analysis, neoadjuvant therapy (P = 0.0236), malignant histology (P = 0.0124), pancreatic reconstruction (P = 0.0006), and vascular resection (P = 0.0008) were the strongest predictors of performing an ODP. CONCLUSIONS: The open, laparoscopic, and robotic approaches to distal pancreatectomy offer particular advantages for well-selected patients and specific clinicopathological contexts; therefore, clearly demonstrating the most suitable use and superiority of one technique over another remains challenging. PMID- 28573357 TI - Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients. AB - BACKGROUND: Neuregulin 1 (NRG1), a ligand for human epidermal growth factor (HER) 3 and HER4, can activates cell signaling pathways to promote carcinogenesis and metastasis. METHODS: To investigate the clinicopathologic significance of NRG1 and its receptors, immunohistochemistry was performed for NRG1, HER3, and HER4 in 502 consecutive gastric cancers (GCs). Furthermore, HER2, microsatellite instability (MSI), and Epstein-Barr virus (EBV) status were investigated. NRG1 gene copy number (GCN) was determined by dual-color fluorescence in situ hybridization (FISH) in 388 available GCs. RESULTS: NRG1 overexpression was observed in 141 (28.1%) GCs and closely correlated with HER3 (P = 0.034) and HER4 (P < 0.001) expression. NRG1 overexpression was significantly associated with aggressive features, including infiltrative tumor growth, lymphovascular, and neural invasion, high pathologic stage, and poor prognosis (all P < 0.05), but not associated with EBV, MSI, or HER2 status. Multivariate analysis identified NRG1 overexpression as an independent prognostic factor for survival (P = 0.040). HER3 and HER4 expressions were observed in 157 (31.3%) and 277 (55.2%), respectively. In contrast to NRG1, expression of these proteins was not associated with survival. NRG1 GCN gain (GCN >= 2.5) was detected in 14.7% patients, including two cases of amplification, and was moderately correlated with NRG1 overexpression (kappa, 0.459; P < 0.001). CONCLUSIONS: Although our results indicate a lack of prognostic significance of HER3 and HER4 overexpression in GC, overexpression of their ligand, NRG1, was associated with aggressive clinical features and represented an independent unfavorable prognostic factor. Therefore, NRG1 is a potential prognostic and therapeutic biomarker in GC patients. PMID- 28573360 TI - Dual System for Enhancing Cognitive Abilities of Children with ADHD Using Leap Motion and eye-Tracking Technologies. AB - Attention Deficit Hyperactivity Disorder (ADHD) is a brain disorder marked by an ongoing pattern of inattention and/or hyperactivity-impulsivity that affects with development or functioning. It affects 3-5% of all American and European children. The objective of this paper is to develop and test a dual system for the rehabilitation of cognitive functions in children with ADHD. A technological platform has been developed using the ". NET framework", which makes use of two physiological sensors, -an eye-tracker and a hand gesture recognition sensor- in order to provide children with the opportunity to develop their learning and attention skills. The two physiological sensors we utilized for the development are the Tobii X1 Light Eye Tracker and the Leap Motion. SUS and QUIS questionnaires have been carried out. 19 users tested the system and the average age was 10.88 years (SD = 3.14). The results obtained after tests were performed were quite positive and hopeful. The learning of the users caused by the system and the interfaces item got a high punctuation with a mean of 7.34 (SD = 1.06) for SUS questionnaire and 7.73 (SD = 0.6) for QUIS questionnaire. We didn't find differences between boys and girls. The developed multimodal rehabilitation system can help to children with attention deficit and learning issues. Moreover, the teachers may utilize this system to track the progression of their students and see their behavior. PMID- 28573361 TI - Exploring anesthesiologists' understanding of situational awareness: a qualitative study. AB - PURPOSE: This study explored how anesthesiologists understand situational awareness (SA) and how they think SA is learned, taught, and assessed. METHODS: Semi-structured interviews were performed with practicing anesthesiologists involved in teaching. This qualitative study was conducted using constructivist grounded theory techniques (i.e., line-by-line coding, memoing, and constant comparison) in a thematic analysis of interview transcripts. Group meetings were held to develop and review themes emerging from the data. RESULTS: Eighteen anesthesiologists were interviewed. Respondents displayed an understanding of SA using a mixture of examples from clinical experience and everyday life. Despite agreeing on the importance of SA, formal definitions of SA were lacking, and the participants did not explicate the topic of SA in either their practice or their teaching activities. Situational awareness had been learned informally through increasing independence in the clinical context, role modelling, reflection on errors, and formally through simulation. Respondents taught SA through modelling and discussing scanning behaviour, checklists, verbalization of thought processes, and debriefings. Although trainees' understanding of SA was assessed as part of the decision-making process for granting clinical independence, respondents found it difficult to give meaningful feedback on SA to their trainees. CONCLUSION: Although SA is an essential concept in anesthesiology, its use remains rather tacit, primarily due to the lack of a common operational definition of the term. Faculty development is required to help anesthesiologists teach and assess SA more explicitly in the clinical environment. PMID- 28573362 TI - Resource Utilization in Emergency Department Patients with Known or Suspected Poisoning. AB - INTRODUCTION: Previous work has shown poisoning-related emergency department (ED) visits are increasing, and these visits are resource-intensive. Little is known, however, about how resource utilization for patients with known or suspected poisoning differs from that of general ED patients. METHODS: We reviewed 4 years of operational data at a single ED. We identified visits due to known or suspected poisoning (index cases), and paired them with time-matched controls. In the primary analysis, we compared the groups with respect to a broad array of resource utilization characteristics. In a secondary analysis, we performed the same comparison after excluding patients ultimately transferred to a psychiatric facility. RESULTS: There were 405 index cases and 802 controls in the primary analysis, and 374 index cases and 741 controls in the secondary analysis. In the primary/secondary analyses, patients with known or suspected poisoning had longer ED lengths of stay in minutes (370 vs. 232/295 vs. 234), higher rates of laboratory results per patient (40.4 vs. 26.8/39.6 vs. 26.8), greater administration of intravenous medications and fluids per patient (2.0 vs. 1.6/2.1 vs. 1.6), higher rates of transfer to a psychiatric facility (7.7 vs. 0.2%/not applicable), and higher rates of both admission (40.2 vs. 32.8/43.6 vs. 33.1%) and admission to an advanced care bed (21.5 vs. 7.6/23.3 vs. 7.8%). Patients with known or suspected poisoning had lower rates of imaging per patient, for both plain radiographs (0.4 vs. 0.5/0.4 vs. 0.5) and advanced imaging studies (0.3 vs. 0.5/0.4 vs. 0.5). CONCLUSIONS: ED patients with known or suspected poisoning are more resource intensive than general ED patients. These results may have implications for both resource allocation (particularly for departments that might see a high volume of such patients) and ED operations management. PMID- 28573363 TI - [Risk genes in myopathies and mitochondrial diseases]. AB - Myopathies and mitochondrial diseases pose a major challenge in diagnosis due to the multitude of different entities and - in the case of mitochondriopathies - the possible involvement of multiple organs. Furthermore, there is broad clinical variability within particular diseases; patients with hereditary myopathy, for example, can show great phenotypic variability despite identical genetic defects. In addition to environmental factors, gender-specific influences, and the degree of heteroplasmy in mitochondrial diseases, the existence of disease-modifying genes has long been assumed as an explanation. In recent years, risk genes, which can influence the course of disease, have been identified for some myopathies and mitochondrial diseases. The precise role of these disease-modifying genes in the pathogenesis of the diseases is largely unexplained and requires further research. PMID- 28573364 TI - [Genetic architecture of amyotrophic lateral sclerosis and frontotemporal dementia : Overlap and differences]. AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) overlap not only clinically, but also with respect to shared neuropathology and genes. A large number of novel genes has recently been identified which underlie both diseases, e. g., C9orf72, TARDBP, GRN, TBK1, UBQLN2, VCP, CHCHD10, or SQSTM1. In contrast, other genes are still largely associated with only one of the two diseases, e. g., SOD1 with ALS or MAPT with FTD. These genetic findings indicate a large number of shared mechanisms, yet along with still a certain cell-specific vulnerability. The recently identified genes are not only key to investigate the pathophysiology underlying ALS and FTD, but also the first step in the development of causal gene- or pathway-specific therapies. Mutations in these genes are also found in a substantial share of seemingly "sporadic" ALS and FTD patients. Given the large genetic heterogeneity with more than >25 genes having been identified for ALS and FTD, genetic diagnostics should - after exclusion of C9orf72 repeat expansions - no longer resort to single gene-diagnostics, but rather use next generation sequencing panels or whole exome sequencing. PMID- 28573365 TI - [Home treatment for people with acute mental illnesses]. AB - Home treatment has been proposed as an alternative to acute psychiatric inpatient treatment. Health insurance systems in Germany and in Switzerland hinder the nationwide implementation of home treatment teams into mental health systems, although the German S3 guidelines for psychosocial treatments of severe mental illnesses recommend provision of acute care at home. Evidence for home treatment is positive, yet there are only few up-to-date studies from Europe and differential indication criteria are lacking. The aim of home treatment is to reduce inpatient bed-days by nonadmission or early discharge. Home treatment teams are mobile, interdisciplinary, and provide 24 h services. The average treatment length in home treatment should not exceed the duration of the inpatient treatment. The home treatment team usually takes the responsibility for the gatekeeping for inpatient treatment. Future research should focus on precise definitions of the structures and interventions of home treatment teams. Home treatment for severely mental ill patients should be distinguished from assertive community treatment and case management, which offer continuing rather than acute crises care. PMID- 28573366 TI - [Antibiotic Stewardship 2.0. Individualization of therapy]. AB - Antibiotic resistance is a part of bacterial evolution and therefore unavoidable. In the context of missing novel treatment options, the restrictive use of available antibiotics in order to decelerate the spread of resistance is of high importance. This is the aim of Antibiotic Stewardship (ABS). ABS consists of two sides: a structural one and an individual one. The former deals with the formation of ABS teams, the analysis of antibiotic usage and resistance development, and the implementation of certain measures to improve antibiotic use; the latter is reflected by concrete bedside decisions: How can (broad) spectrum antibiotics be spared without harming the patient? This can be achieved, for example, by de-escalation, limiting duration of treatment, and avoiding nonindicated use. Typical nonindicated uses in both in- and outpatients are viral respiratory tract infections, asymptomatic bacteriuria and nonbacterial exacerbations of chronic obstructive pulmonary disease. Furthermore, respiratory colonization in ventilated patients, ventilator-associated tracheobronchitis, "prolonged" perioperative prophylaxis, and contaminated blood cultures reflect situations where antibiotics should be avoided. In the future, ABS will benefit from accelerated pathogen and resistance detection because early adequate treatment not only lowers the usage of antibiotics but can also improve patient outcome. PMID- 28573368 TI - How common is depression in patients with polymyalgia rheumatica? AB - Depression is common in inflammatory disorders such as rheumatoid arthritis and systemic lupus erythematosus and negatively impacts on outcomes. Given the long term nature of polymyalgia rheumatica (PMR) and its glucocorticoid treatment, these patients may be at an increased risk of depression, although few studies exist to date. This study aimed to investigate the prevalence of, and factors associated with, depression in PMR patients. Prevalent PMR patients (with a first diagnostic code for PMR in the last 3 years) were mailed a postal questionnaire (n = 704) examining PMR symptoms, glucocorticoid use and patient reported comorbidities. Depressive symptoms were assessed using the Patient Health Questionnaire-8 (PHQ-8), with a score of >=10 defined as current depressive symptoms. Logistic regression was used to examine association between demographics, comorbidity and current depressive symptoms. Five hundred fifty (78%) patients responded, of which 365 (66%) were female, with a mean (SD) age of 74.1 years (8.4). The prevalence of current depressive symptoms was 15% (n = 81) and was significantly associated with female gender: OR 1.87 (95%CI 1.08-3.22), current PMR symptoms: OR 2.1 (1.11-3.97), self-reported acid reflux: OR 1.75 (1.05-2.93) and diabetes: OR 2.86 (1.6-5.09). Older patients were less likely to report current depressive symptoms (OR 0.35 (0.13-0.9) for those >80 years versus those aged 50-59 years). Depressive symptoms are common in patients with PMR patients, especially younger patients and those with comorbidities. Clinicians should consider screening these patients for depressive symptoms and managing them appropriately, as untreated depression may negatively impact on health related outcomes and quality of life. PMID- 28573367 TI - 3D Microfabricated Scaffolds and Microfluidic Devices for Ocular Surface Replacement: a Review. AB - In recent years, there has been increased research interest in generating corneal substitutes, either for use in the clinic or as in vitro corneal models. The advancement of 3D microfabrication technologies has allowed the reconstruction of the native microarchitecture that controls epithelial cell adhesion, migration and differentiation. In addition, such technology has allowed the inclusion of a dynamic fluid flow that better mimics the physiology of the native cornea. We review the latest innovative products in development in this field, from 3D microfabricated hydrogels to microfluidic devices. PMID- 28573370 TI - Association of tumor necrosis factor-alpha (G-308A) genetic variant with matrix metalloproteinase-9 activity and joint destruction in early rheumatoid arthritis. AB - Matrix metalloproteinases (MMPs) are the key enzymes responsible for the joint destruction. Their activity is regulated by the level of proinflammatory cytokines. The aim of this study was to examine the impact of TNF-alpha G-308A polymorphism on MMP-9 levels in blood plasma (BP) and synovial fluid (SF) of patients with rheumatoid arthritis (RA) and their role in progression of joint destruction. One hundred thirty-four subjects were enrolled in this study. TNF alpha G-308A polymorphism was determined using PCR-RFLP method. ELISA assay was used for the detection of MMP-9 activity in BP and SF. Joint damage was estimated by hands and feet radiography. Larsen score and annual changes in LS were used for quantitative evaluation of joint destruction and radiographic progression of disease. MMP-9 activity in BP and SF was significantly higher in RA compared to controls, as well as in SF of patients with erosive compared to nonerosive RA. Faster radiographic progression and increased MMP-9 activity in BP and SF were detected in the group A (GA or AA genotype carriers) compared to the group G (GG genotype carriers). However, statistical significance was revealed only for MMP-9 activity in SF (p < 0.05). MMP-9 activity in BP and SF is significantly higher in RA patients compared to patients with osteoarthritis. The presence of TNF-alpha 308A allele is associated with increased MMP-9 activity in SF of patients with early RA and may be a predictor of rapid radiographic progression of disease. PMID- 28573369 TI - Systolic and pulse pressure associate with incident knee osteoarthritis: data from the Osteoarthritis Initiative. AB - We evaluated the relationship of systolic blood pressure, diastolic blood pressure, pulse pressure, and treatment with antihypertensives with knee osteoarthritis incidence in a US cohort. We performed a longitudinal study (2004 2010) nested within the Osteoarthritis Initiative Study including only individuals without knee osteoarthritis at baseline. Systolic blood pressure, diastolic blood pressure, and pulse pressure were assessed at baseline, 12-, 24-, and 36-month visits. Knee radiographs at baseline, 12-, 24-, 36- and 48-month visits defined radiographic osteoarthritis, Kellgren and Lawrence grade >=2. We performed logistic regression, adjusting for age, sex, body mass index, NSAID use, number of antihypertensive medications, diabetic medications, and cholesterol medications. One thousand nine hundred and thirty people (6040 observations) were included. Annual incidence rates of radiographic osteoarthritis by systolic blood pressure quartiles (lowest to highest) were 2.1, 3.4, 3.7, and 3.7%. Fully adjusted odds ratios of incident radiographic osteoarthritis (OA) for the 2nd-4th quartiles were 1.6, 1.7, and 1.6 relative to the lowest quartile (p for trend = 0.03). Pulse pressure results were similar. There was no association with diastolic blood pressure. Compared to those not taking any antihypertensive medications, those taking >=3 had decreased odds (0.4, 0.1-1.0) of developing incident OA. In a US cohort, higher systolic blood pressure and pulse pressure are associated with increased incidence of radiographic knee osteoarthritis while treatment with >=3 antihypertensive medications was associated with reduced incidence. These findings suggest a new and promising avenue for research on disease modification in knee osteoarthritis. PMID- 28573371 TI - Frequency of familial Mediterranean fever (MEFV) gene mutations in patients with biopsy-proven primary glomerulonephritis. AB - Primary glomerulopathies are those disorders that affect glomerular structure, function, or both in the absence of a multisystem disorder. We aimed to evaluate the frequency of MEFV gene mutation to show possible coexistence of FMF in patients diagnosed with biopsy-proven primary glomerulonephritis (GN). A total of 64 patients with biopsy-proven primary GN were included in the study. MEFV gene mutations examined retrospectively. The mean age of patients was 39.6 +/- 13.4 (range 18-69), 35 of patients were female and 29 of patients were male. Of the 64 patients, 17 were mesangial proliferative glomerulonephritis (MsPGN), 15 were IgA nephropathy (IgAN), 12 were membranous glomerulonephritis (MGN), 11 were focal segmental glomerulosclerosis (FSGS), three were membranous proliferative glomerulonephritis (MPGN), three were immune complex glomerulonephritis (ICGN), two were minimal change disease (MCD), and one was IgM nephropathy (IgMN). MEFV gene mutation was detected in 35.9% (23) of these patients. The most frequently detected mutations were E148Q and M694V. Twelve cases (18.75% of GN patients) with MEFV gene mutation were diagnosed as FMF phenotype I. The frequency of MEFV gene mutation was detected at a high rate of 35.9%. Further studies with larger populations are needed to clarify the importance of these mutations on clinical progression of glomerulonephritis. PMID- 28573373 TI - Erratum to: Exercise increases lactoferrin, but decreases lysozyme in salivary granulocytes. PMID- 28573372 TI - A survey of anatomical items relevant to the practice of rheumatology: pelvis, lower extremity, and gait. AB - This study aimed to generate a minimum list of structural and functional anatomical items about the pelvis/hip, knee, ankle/foot, gait, and lower limb innervation, which are most relevant to the practice of rheumatology. To determine their perceived relevance to clinical practice, seven members of the Mexican Clinical Anatomy Task Force compiled an initial list of 470 anatomical items. Ten local and international experts according to a 0-10 Likert scale ranked these items. Of the original list, 101 (21.48%) items were considered relevant (global rate >40). These included 36/137 (26.27%) pelvis and hip items, 25/82 (30.48%) knee items, 22/168 (13.98%) ankle/foot items, 11/68 (16.17%) neurologic items, and 7/15 (46.66%) gait-related items. We propose that these 101 anatomical items of the lower extremity, when added to the 115 anatomic items of the upper extremity and spine we previously reported, may represent an approximation to the minimal anatomical knowledge central to the competent practice of rheumatology. The meager representation of ankle and foot items may reflect a lesser emphasis in these anatomical regions during rheumatologic training. Attention to these and related items during rheumatologic training and beyond may sharpen the rheumatologist's ability in the differential diagnosis of regional pain syndromes as well as strengthen an endangered art: the rheumatologic physical examination. PMID- 28573374 TI - Effects of TRPV1 and TRPA1 activators on the cramp threshold frequency: a randomized, double-blind placebo-controlled trial. AB - PURPOSE: Previous data indicate that a strong sensory input from orally administered TRPV1 and TRPA1 activators alleviates muscle cramps in foot muscles by reducing the alpha-motor neuron hyperexcitability. We investigated if TRP activators increase the cramp threshold frequency of the medial gastrocnemius. METHODS: We randomly assigned 22 healthy male participants to an intervention (IG) and a control group (CG). While participants of the IG ingested a mixture of TRPV1 and TRPA1 activators, the CG received a placebo. We tested the cramp threshold frequency (CTF), the cramp intensity (EMG activity), and the perceived pain of electrically induced muscle cramps before (pre), and 15 min, 4, 8, and 24 h after either treatment. We further measured the maximal isometric force of knee extensors at pre, 4, and 24 h to assess potential side-effects on the force output. RESULTS: When we included all measurement time points, no group-by-time interaction was observed for the CTF. However, when only pre and 15 min values were incorporated, a significant interaction, with a slightly greater CTF increase in IG (3.1 +/- 1.5) compared to the CG (2.0 +/- 1.5), was observed. No significant group by time interaction was found for the cramp intensity, the perceived pain, and the maximal isometric force. CONCLUSION: Our data indicate that orally administered TRPV1 and TRPA1 activators exert a small short-term effect on the CTF, but not on the other parameters tested. Future studies need to investigate whether such small CTF increments are sufficient to prevent exercise associated muscle cramps. PMID- 28573375 TI - Chronic maxillary atelectasis and silent sinus syndrome: two faces of the same clinical entity. AB - Chronic maxillary atelectasis (CMA) and silent sinus syndrome (SSS) are rare clinical entities characterized by an implosion of the maxillary sinus that may or may not be associated with sinonasal symptoms, and are complicated by ipsilateral enophthalmos. The objective of this article is to discuss the definitions, physiopathology, clinical and radiographic characteristics, and surgical management of these entities. We retrospectively reviewed 18 patients (7 women, 11 men, aged 12-70 years) diagnosed and treated in the ear, nose, and throat departments of four Belgian teaching hospitals between 2000 and 2015. Nine patients had a history of sinus disease. In all cases, a computed tomography scan showed downward displacement of the orbital floor, increased orbital volume, and maxillary sinus contraction. Five patients met the criteria for grade II CMA and 13 for grade III CMA. Four patients met the criteria for SSS. All patients underwent wide endoscopic middle maxillary antrostomy. There were no orbital complications and all patients experienced resolution or a dramatic reduction of their symptomatology. Only one patient asked for an orbital floor reconstruction to correct a persisting cosmetic deformity. Although CMA and SSS are usually regarded as different entities in the literature, we believe that they lie on the same clinical spectrum. Treatment for both conditions is similar, i.e., middle meatal antrostomy to halt or even reverse the pathological evolution and reconstruction of the orbital floor in the event of persistent cosmetic deformity. PMID- 28573376 TI - Maximal clique method for the automated analysis of NMR TOCSY spectra of complex mixtures. AB - Characterization of the chemical components of complex mixtures in solution is important in many areas of biochemistry and chemical biology, including metabolomics. The use of 2D NMR total correlation spectroscopy (TOCSY) experiments has proven very useful for the identification of known metabolites as well as for the characterization of metabolites that are unknown by taking advantage of the good resolution and high sensitivity of this homonuclear experiment. Due to the complexity of the resulting spectra, automation is critical to facilitate and speed-up their analysis and enable high-throughput applications. To better meet these emerging needs, an automated spin-system identification algorithm of TOCSY spectra is introduced that represents the cross peaks and their connectivities as a mathematical graph, for which all subgraphs are determined that are maximal cliques. Each maximal clique can be assigned to an individual spin system thereby providing a robust deconvolution of the original spectrum for the easy extraction of critical spin system information. The approach is demonstrated for a complex metabolite mixture consisting of 20 compounds and for E. coli cell lysate. PMID- 28573378 TI - Quantifying the Harms and Benefits from Serosorting Among HIV-Negative Gay and Bisexual Men: A Systematic Review and Meta-analysis. AB - We conducted a systematic review and meta-analysis of the association between serosorting and HIV infection among HIV-negative men who have sex with men (MSM). Compared to no condomless anal sex (i.e., consistent condom use or no anal sex), serosorting was associated with increased HIV risk (RR = 1.64, 95% CI 1.37-1.96). Compared to condomless discordant anal sex, serosorting was associated with reduced HIV risk (RR = 0.46, 95% CI 0.33-0.65). Serosorting may be an important harm reduction strategy when condoms are not consistently used, but can be harmful if HIV-negative MSM who consistently use condoms shift to using serosorting as their primary prevention strategy. The protective effects of serosorting and ways in which MSM are operationalizing serosorting are becoming more complex as additional factors affecting risk are considered (e.g., durable viral load suppression, PrEP). Understanding the potential risk and benefit of serosorting continues to be important, particularly within the context of other prevention strategies. PMID- 28573377 TI - The effects of a patient activation intervention on smoking and excessive drinking cessations: results from the PAADRN randomized controlled trial. AB - : Patients may exhibit risky bone health behaviors. In a large pragmatic clinical trial, we tested whether a tailored patient activation DXA result letter accompanied by a bone health brochure led to smoking and excessive drinking cessations. The intervention did not, however, alter these risky bone health behaviors. INTRODUCTION: Besides dual-energy x-ray absorptiometry (DXA) screening and pharmacotherapy when indicated, beneficial bone health behaviors including proper calcium and vitamin D intake and weight-bearing and muscle-strengthening exercise should be encouraged. Similarly, risky bone health behaviors like smoking and excessive drinking should be discouraged. We examined whether a direct-to-patient activation intervention led to smoking and excessive drinking cessations. METHODS: The Patient Activation after DXA Result Notification (PAADRN) pragmatic clinical trial enrolled 7749 patients between February 2012 and August 2014. Interviews occurred at baseline and 12 and 52 weeks later. Intervention subjects were mailed an individually tailored DXA results letter accompanied by a bone health educational brochure 4 weeks post-DXA. Usual care subjects were not sent these materials. Smoking and excessive drinking were assessed by self-report at each interview. Intention-to-treat linear probability models were used. RESULTS: Mean age was 66.6 years, 83.8% were women, and 75.3% were Non-Hispanic-Whites. Smoking was reported at baseline by 7.6% of the intervention group vs. 7.7% of the usual care group (p = 0.873). Excessive drinking was reported at baseline by 6.5% of the intervention group vs. 6.5% of the usual care group (p = 0.968). Intention-to-treat analyses indicated no significant differences between the intervention vs. usual care groups at either 12 or 52 weeks post-DXA (all p values >= 0.346). CONCLUSION: An individually tailored DXA result letter accompanied by an educational brochure did not lead to smoking or excessive drinking cessations in patients who received DXA. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT01507662. PMID- 28573379 TI - Timing of INR reversal using fresh-frozen plasma in warfarin-associated intracerebral hemorrhage. AB - Rapid reversal of coagulopathy is recommended in warfarin-associated intracerebral hemorrhage (WAICH). However, rapid correction of the INR has not yet been proven to improve clinical outcomes, and the rate of correction with fresh-frozen plasma (FFP) can be variable. We sought to determine whether faster INR reversal with FFP is associated with decreased hematoma expansion and improved outcome. We performed a retrospective analysis of a prospectively collected cohort of consecutive patients with WAICH presenting to an urban tertiary care hospital from 2000 to 2013. Patients with baseline INR > 1.4 treated with FFP and vitamin K were included. The primary outcomes are occurrence of hematoma expansion, discharge modified Rankin Scale (mRS), and 30-day mortality. The association between timing of INR reversal, ICH expansion, and outcome was investigated with logistic regression analysis. 120 subjects met inclusion criteria (mean age 76.9, 57.5% males). Median presenting INR was 2.8 (IQR 2.3-3.4). Hematoma expansion is not associated with slower INR reversal [median time to INR reversal 9 (IQR 5-14) h vs. 10 (IQR 7-16) h, p = 0.61]. Patients with ultimately poor outcome received more rapid INR reversal than those with favorable outcome [9 (IQR 6-14) h vs. 12 (8-19) h, p = 0.064). We find no evidence of an association between faster INR reversal and either reduced hematoma expansion or better outcome. PMID- 28573380 TI - The contrasting effects of short-term climate change on the early recruitment of tree species. AB - Predictions of plant responses to climate change are frequently based on organisms' presence in warmer locations, which are then assumed to reflect future performance in cooler areas. However, as plant life stages may be affected differently by environmental changes, there is little empirical evidence that this approach provides reliable estimates of short-term responses to global warming. Under this premise, we analyzed 8 years of early recruitment data, seed production and seedling establishment and survival, collected for two tree species at two latitudes. We quantified recruitment to a wide range of environmental conditions, temperature, soil moisture and light, and simulated recruitment under two forecasted climatic scenarios. Annual demographic transitions were affected by the particular conditions taking place during their onset, but the effects of similar environmental shifts differed among the recruitment stages; seed production was higher in warmer years, while seedling establishment and survival peaked during cold years. Within a species, these effects also varied between latitudes; increasing temperatures at the southern location will have stronger detrimental effects on recruitment than similar changes at the northern locations. Our simulations illustrate that warmer temperatures may increase seed production, but they will have a negative effect on establishment and survival. When the three early recruitment processes were simultaneously considered, simulations showed little change in recruitment dynamics at the northern site and a slight decrease at the southern site. It is only when we considered these three stages that we were able to assess likely changes in early recruitment under the predicted conditions. PMID- 28573381 TI - Integrated population models reveal local weather conditions are the key drivers of population dynamics in an aerial insectivore. AB - Changes to weather patterns under a warming climate are complex: while warmer temperatures are expected virtually worldwide, decreased mean precipitation is expected at mid-latitudes. Migratory birds depend on broad-scale weather patterns to inform timing of movements, but may be more susceptible to local weather patterns during sedentary periods. We constructed Bayesian integrated population models (IPMs) to assess whether continental or local weather effects best explained population dynamics in an environmentally sensitive aerial insectivorous bird, the tree swallow (Tachycineta bicolor), along a transcontinental gradient from British Columbia to Saskatchewan to New York, and tested whether population dynamics were synchronous among sites. Little consistency existed among sites in the demographic rates most affecting population growth rate or in correlations among rates. Juvenile apparent survival at all sites was stable over time and greatest in New York, whereas adult apparent survival was more variable among years and sites, and greatest in British Columbia and Saskatchewan. Fledging success was greatest in Saskatchewan. Local weather conditions explained significant variation in adult survival in Saskatchewan and fledging success in New York, corroborating the hypothesis that local more than continental weather drives the population dynamics of this species and, therefore, demographic synchrony measured at three sites was limited. Nonetheless, multi-population IPMs can be a powerful tool for identifying correlated population trajectories caused by synchronous demographic rates, and can pinpoint the scale at which environmental drivers are responsible for changes. We caution against applying uniform conservation actions for populations where synchrony does not occur or is not fully understood. PMID- 28573385 TI - ? PMID- 28573382 TI - A novel function of hepatocyte growth factor in the activation of checkpoint kinase 1 phosphorylation in colon cancer cells. AB - The ATR/checkpoint kinase 1 (Chk1) pathway plays an essential role in modulating the DNA damage response and homologous recombination. Particularly, Chk1 phosphorylation is related to cancer prognosis and therapeutic resistance. Some receptor tyrosine kinases participate in the regulation of Chk1 phosphorylation; however, the effect of hepatocyte growth factor (HGF) on Chk1 phosphorylation is unknown. In the present study, we demonstrated that HGF moderately activated Chk1 phosphorylation in colon cancer cells by upregulating TopBP1 and RAD51, and promoting TopBP1-ATR complex formation. Furthermore, AKT activity, which was promoted by HGF, served as an important mediator linking HGF/MET signaling and Chk1 phosphorylation. Depleting AKT activity attenuated basal expression of p Chk1 and HGF-induced Chk1 activation. Moreover, AKT activity directly regulated TopBP1 and RAD51 expression. AKT inhibition suppressed HGF-induced upregulation of TopBP1 and RAD51, and enhanced TopBP1/ATR complex formation. Our results show that HGF was involved in regulating Chk1 phosphorylation, and further demonstrate that AKT activity was responsible for this HGF-induced Chk1 phosphorylation. These findings might potentially result in management of prognosis and therapeutic sensitivity in cancer therapy. PMID- 28573383 TI - Increased expression of damage-associated molecular patterns (DAMPs) in osteoarthritis of human knee joint compared to hip joint. AB - Osteoarthritis (OA) is a degenerative disease characterized by the destruction of cartilage. The greatest risk factors for the development of OA include age and obesity. Recent studies suggest the role of inflammation in the pathogenesis of OA. The two most common locations for OA to occur are in the knee and hip joints. The knee joint experiences more mechanical stress, cartilage degeneration, and inflammation than the hip joint. This could contribute to the increased incidence of OA in the knee joint. Damage-associated molecular patterns (DAMPs), including high-mobility group box-1, receptor for advanced glycation end products, and alarmins (S100A8 and S100A9), are released in the joint in response to stress mediated chondrocyte and cartilage damage. This facilitates increased cartilage degradation and inflammation in the joint. Studies have documented the role of DAMPs in the pathogenesis of OA; however, the comparison of DAMPs and its influence on OA has not been discussed. In this study, we compared the DAMPs between OA knee and hip joints and found a significant difference in the levels of DAMPs expressed in the knee joint compared to the hip joint. The increased levels of DAMPs suggest a difference in the underlying pathogenesis of OA in the knee and the hip and highlights DAMPs as potential therapeutic targets for OA in the future. PMID- 28573384 TI - A simple computational algorithm of model-based choice preference. AB - A broadly used computational framework posits that two learning systems operate in parallel during the learning of choice preferences-namely, the model-free and model-based reinforcement-learning systems. In this study, we examined another possibility, through which model-free learning is the basic system and model based information is its modulator. Accordingly, we proposed several modified versions of a temporal-difference learning model to explain the choice-learning process. Using the two-stage decision task developed by Daw, Gershman, Seymour, Dayan, and Dolan (2011), we compared their original computational model, which assumes a parallel learning process, and our proposed models, which assume a sequential learning process. Choice data from 23 participants showed a better fit with the proposed models. More specifically, the proposed eligibility adjustment model, which assumes that the environmental model can weight the degree of the eligibility trace, can explain choices better under both model-free and model based controls and has a simpler computational algorithm than the original model. In addition, the forgetting learning model and its variation, which assume changes in the values of unchosen actions, substantially improved the fits to the data. Overall, we show that a hybrid computational model best fits the data. The parameters used in this model succeed in capturing individual tendencies with respect to both model use in learning and exploration behavior. This computational model provides novel insights into learning with interacting model free and model-based components. PMID- 28573386 TI - Uremic Toxicity and Bone in CKD. AB - Patients with chronic kidney disease (CKD), especially those on dialysis treatment, are at high risk of bone fracture. In CKD-mineral and bone disorder (CKD-MBD), secondary hyperparathyroidism in patients with advanced CKD induces bone abnormalities, and skeletal resistance to parathyroid hormone (PTH) starts in the early stages of kidney disease. Uremic toxins such as indoxyl sulfate and p-cresyl sulfate reduce the expression of PTH receptor as well as PTH-induced cyclic adenosine 3',5' monophosphate production in osteoblasts. CKD also impairs bone strength, especially quality. In a rat model, kidney damage reduces the bone storage modulus and changes the cortical bone chemical composition with or without hyperparathyroidism. The oral charcoal adsorbent AST-120 improves CKD induced bone abnormalities as blood levels of indoxyl sulfate decrease. Uremic osteoporosis, a new concept of CKD-related bone fragility, is a main cause of CKD induced bone abnormalities, particularly impaired bone quality. There is limited information about the effect and safety of anti-osteoporotic drugs for patients with CKD, especially those on dialysis, but the use of AST-120 and renin angiotensin system inhibitors may modulate bone quality and decrease the incidence of fracture. Thus, the management of CKD-MBD plus use of other therapeutic interventions for uremic osteoporosis is necessary to prevent bone fragility in patients with CKD. PMID- 28573387 TI - The impact of change of renal replacement therapy modality on sleep quality in patients with end-stage renal disease: a systematic review and meta-analysis. AB - BACKGROUND: Sleep disorders are common and multi-factorial in patients with advanced chronic kidney disease and end-stage renal disease (ESRD). Sleep disorders and disturbance have a negative impact on wellbeing and quality of life. OBJECTIVE: To assess the impact of a change in renal replacement therapy (RRT) modality on sleep quality and sleep disturbance in patients with ESRD. DATA SOURCES: Multiple electronic databases were searched without publication type/period restrictions. The reference lists of all included articles were manually searched for additional citations. Non-published data was identified by hand searching key conference abstracts. STUDY ELIGIBILITY CRITERIA: Participants of interest were adult patients with ESRD requiring RRT [conventional haemodialysis (HD), short daily HD, nocturnal HD, continuous ambulatory peritoneal dialysis (CAPD), continuous cycler-assisted peritoneal dialysis (CCPD) or transplantation]. The exposure or intervention of interest was switch of RRT modality. STUDY APPRAISAL: Two reviewers independently assessed all studies for inclusion and extracted relevant data. RESULTS: Sixteen studies with a combined total of 670 patients and 191 controls were included for review and described in detail. Looking specifically at restless leg syndrome, symptoms resolved in over 60% of affected patients with a switch to increased intensity RRT (either intensive HD, CCPD or transplant). Meta-analysis of the nine studies that looked specifically at sleep apnoea parameters again favoured intensive RRT over standard/conventional RRT (conventional HD or CAPD) with statistical significance [Risk ratio 0.66 (95% CI 0.51-0.84)]. Meta-analysis of all studies favoured a switch to increased intensity RRT in terms of overall sleep quality, with statistical significance [Risk ratio 0.58 (95% CI 0.40-8.83)]. LIMITATIONS: Restriction to the English language may have introduced selection bias. Funnel plot analysis suggested there was also an element of publication bias. Studies were heterogeneous in terms of patient selection, means of sleep quality assessment and modality switch. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Sleep disturbance, sleep apnoea and restless legs syndrome all tend to improve when a switch is made to intensive dialysis or transplant. This is important information for patients struggling with disturbed sleep and marked fatigue. This hypothesis-generating review highlights the need for more high quality prospective research in the area. PMID- 28573389 TI - Effect of multiple cycles of freeze-thawing on the RNA quality of lung cancer tissues. AB - RNA degradation is a major problem in tissue banking. We explored the effect of thawing flash-frozen biospecimens on the quality and integrity of RNA for genetic testing as well as for other cancer research studies. The histological quality of the frozen tumor sections was evaluated by using hematoxylin and eosin staining. RNA extraction from 60 lung cancer tissue samples subjected to various freeze/thaw cycles was performed using the RNeasy Plus isolation kit. RNA integrity was assessed by using an Agilent bioanalyzer to obtain RNA integrity numbers (RIN). Furthermore, RNA from different groups was used for fluorescence Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene mutation to verify whether it can be used for research or clinical testing. Highly variable RIN values were observed among the samples, which showed no correlation with the number of freeze/thaw cycles conducted. However, after 3 freeze/thaw cycles (each thaw event lasted for 10 min), an increasing number of changes in peak intensity in RINs were observed. After 5 freeze/thaw cycles, RNA integrity decreased to approximately 35%. After 3 freeze/thaw cycles, the RNA could still be used for RT-PCR analysis of EML4-ALK fusion gene mutations; whereas those subjected to 5 freeze/thaw cycles could not. Limited (<3) freeze/thaw cycles did not adversely affect the quality of RNA extracted from tumor tissues and subsequent RT-PCR analysis. Our data could be utilized in the establishment of a standardized procedure for tissue biospecimen collection and storage. PMID- 28573390 TI - Comments on Morelli et al.: Extracorporeal carbon dioxide removal (ECCO2R) in patients with acute respiratory failure. PMID- 28573391 TI - Driving airway pressure: should we use a static measure to describe a dynamic phenomenon? PMID- 28573388 TI - Medical Management of the Severe Traumatic Brain Injury Patient. AB - Severe traumatic brain injury (sTBI) is a major contributor to long-term disability and a leading cause of death worldwide. Medical management of the sTBI patient, beginning with prehospital triage, is aimed at preventing secondary brain injury. This review discusses prehospital and emergency department management of sTBI, as well as aspects of TBI management in the intensive care unit where advances have been made in the past decade. Areas of emphasis include intracranial pressure management, neuromonitoring, management of paroxysmal sympathetic hyperactivity, neuroprotective strategies, prognostication, and communication with families about goals of care. Where appropriate, differences between the third and fourth editions of the Brain Trauma Foundation guidelines for the management of severe traumatic brain injury are highlighted. PMID- 28573392 TI - Remembering Vivian Weil. PMID- 28573395 TI - A comparative study reveals the higher resolution of RAPD over ARDRA for analyzing diversity of Nostoc strains. AB - Nostoc is a diverse genus of filamentous cyanobacteria with tremendous potential for agricultural and industrial applications. Morphometric methods and routine 16S rDNA-based identification undermines the genetic diversity and impedes strain level differentiation. A comparative study to deduce the discriminatory power of random amplified polymorphic DNA (RAPD) and amplified ribosomal DNA restriction analysis (ARDRA) for analyzing the genetic diversity of 20 Nostoc strains of diverse geographical origin was carried out. The RAPD primer used in the study generated 100% polymorphic profile. HIP TG primer produced the highest number of bands and fragments. Five primers, viz. OPA 08, OPA 11, HIP GC, OPAH 02 and OPF 05 could produce unique bands for 11 strains. Cluster analysis using the RAPD profile showed 12.5-25% similarity among the strains. Following in silico restriction analysis, two restriction enzymes, viz. HaeIII and HinfI were selected for ARDRA. However, clustering based on the restriction pattern showed 22.5-100% similarity. Results of the present study clearly indicate higher resolution of RAPD which can be reliably used for strain-level differentiation of Nostoc strains. PMID- 28573393 TI - Genetic risk scores in the prediction of plasma glucose, impaired insulin secretion, insulin resistance and incident type 2 diabetes in the METSIM study. AB - AIMS/HYPOTHESIS: Many SNPs have been associated with glycaemic traits and type 2 diabetes, but their joint effects on glycaemic traits and the underlying mechanisms leading to hyperglycaemia over time are largely unknown. We aimed to investigate the association of six genetic risk scores (GRSs) with changes in plasma glucose, insulin sensitivity, insulin secretion and incident type 2 diabetes in the prospective METabolic Syndrome In Men (METSIM) study. METHODS: We generated weighted GRSs for fasting plasma glucose ([FPG] GRSFPG, 35 SNPs), 2 h plasma glucose ([2hPG] GRS2hPG, 9 SNPs), insulin secretion (GRSIS, 17 SNPs), insulin resistance (GRSIR, 9 SNPs) and BMI (GRSBMI, 95 SNPs) and a non-weighted GRS for type 2 diabetes (GRST2D, 76 SNPs) in up to 8749 non-diabetic Finnish men. Linear regression was used to test associations of the GRSs with changes in glycaemic traits over time. RESULTS: GRST2D, GRSFPG and GRSIS were associated with an increase in FPG, GRST2D with an increase in glucose AUC and a decrease in insulin secretion, and GRS2hPG with an increase in 2hPG during the follow-up (p < 0.0017 for all models). GRST2D, GRSFPG and GRSIS were associated with incident type 2 diabetes (p < 0.008 for all models). GRSBMI and GRSIR were not significantly associated with any changes in glycaemic traits. CONCLUSIONS/INTERPRETATION: In the METSIM follow-up study, GRST2D, GRSFPG and GRSIS were associated with the worsening of FPG and an increase in incident type 2 diabetes. GRST2D was additionally associated with a decrease in insulin secretion, and GRS2hPG with an increase in 2hPG. PMID- 28573394 TI - Cancer risk among insulin users: comparing analogues with human insulin in the CARING five-country cohort study. AB - AIMS/HYPOTHESIS: The aim of this work was to investigate the relationship between use of certain insulins and risk for cancer, when addressing the limitations and biases involved in previous studies. METHODS: National Health Registries from Denmark (1996-2010), Finland (1996-2011), Norway (2005-2010) and Sweden (2007 2012) and the UK Clinical Practice Research Datalink database (1987-2013) were used to conduct a cohort study on new insulin users (N = 327,112). By using a common data model and semi-aggregate approach, we pooled individual-level records from five cohorts and applied Poisson regression models. For each of ten cancer sites studied, we estimated the rate ratios (RRs) by duration (<=0.5, 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-6 and >6 years) of cumulative exposure to insulin glargine or insulin detemir relative to that of human insulin. RESULTS: A total of 21,390 cancer cases occurred during a mean follow-up of 4.6 years. No trend with cumulative treatment time for insulin glargine relative to human insulin was observed in risk for any of the ten studied cancer types. Of the 136 associations tested in the main analysis, only a few increased and decreased risks were found: among women, a higher risk was observed for colorectal (RR 1.54, 95% CI 1.06, 2.25) and endometrial cancer (RR 1.78, 95% CI 1.07, 2.94) for <=0.5 years of treatment and for malignant melanoma for 2-3 years (RR 1.92, 95% CI 1.02, 3.61) and 4-5 years (RR 3.55, 95% CI 1.68, 7.47]); among men, a lower risk was observed for pancreatic cancer for 2-3 years (RR 0.34, 95% CI 0.17, 0.66) and for liver cancer for 3-4 years (RR 0.36, 95% CI 0.14, 0.94) and >6 years (RR 0.22, 95% CI 0.05, 0.92). Comparisons of insulin detemir with human insulin also showed no consistent differences. CONCLUSIONS/INTERPRETATION: The present multi-country study found no evidence of consistent differences in risk for ten cancers for insulin glargine or insulin detemir use compared with human insulin, at follow-up exceeding 5 years. PMID- 28573396 TI - Toxicity assessment of magnetosomes in different models. AB - Magnetosomes are nanosized iron oxide particles surrounded by lipid membrane synthesized by magnetotactic bacteria (MTB). Magnetosomes have been exploited for a broad range of biomedical and biotechnological applications. Due to their enormous potential in the biomedical field, its safety assessment is necessary. Detailed research on the toxicity of the magnetosomes was not studied so far. This study focuses on the toxicity assessment of magnetosomes in various models such as Human RBC's, WBC's, mouse macrophage cell line (J774), Onion root tip and fish (Oreochromis mossambicus). The toxicity in RBC models revealed that the RBC's are unaltered up to a concentration of 150 ug/ml, and its morphology was not affected. The genotoxicity studies on WBC's showed that there were no detectable chromosomal aberrations up to a concentration of 100 ug/ml. Similarly, there were no detectable morphological changes observed on the magnetosome treated J774 cells, and the viability of the cells was above 90% at all the tested concentrations. Furthermore, the magnetosomes are not toxic to the fish (O. mossambicus), as no mortality or behavioural changes were observed in the magnetosome-treated groups. Histopathological analysis of the same reveals no damage in the muscle and gill sections. Overall, the results suggest that the magnetosomes are safe at lower concentration and does not pose any potential risk to the ecosystem. PMID- 28573397 TI - Statistical investigation of extraction parameters of keratin from chicken feather using Design-Expert. AB - Uncontrolled disposal of feathers from the poultry industry and slaughterhouses is environmentally undesirable. The feathers are composed of approximately 90% of keratin which is an important ingredient of cosmetics, shampoos and hair treatment creams. This study aimed to determine the optimum conditions for the extraction of keratin from chicken feathers. The extraction of keratin using various reducing agents was studied using statistical experimental design. In the extraction process, pH, temperature, ratio of reducing agents, mass of chicken feathers and incubation time were analyzed. The keratin in the total extracted protein was purified by size exclusion chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and further characterized using amino acids profile analysis. The surface morphology and chemical composition were studied by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) analysis. Sodium sulfide (Na2S) yielded 84.5% of keratin as compared to sodium hydroxide (43.8), urea mixture (50.6), mixture of sodium dodecyl sulfate (SDS) and sodium bisulfite (18.3) and a mixture of Na2S and sodium hydroxide (41.5%) under optimized conditions. The optimum yield of keratin was achieved at 80.9 degrees C in 9.5 h with 0.05 M sodium sulfide using response surface methodology (RSM). Among the five parameters screened, pH was found not to be significant because the p value was greater than 0.05. PMID- 28573398 TI - High-fidelity PCR enzyme with DNA-binding domain facilitates de novo gene synthesis. AB - Nowadays enzymatic synthesis of genes is the most powerful tool for fast resolution of the various tasks in the field of basic and applied biological research. PCR-based gene assembly from overlapping oligonucleotides has become a widely used strategy. However, all the methods described in the literature are not perfect and need an extra processing step. In this study we are verifying Phusion high-fidelity polymerase as a tool to reduce nucleotide mismatches in de novo gene synthesis, thus facilitating subsequent cloning. To test the efficiency of the polymerase, we selected Fel d 4 gene, which is a 581 bp DNA sequence encoding the lipocalin allergen protein, one of the major cat allergens. The approach described here, therefore, would be useful in DNA sequences creation. PMID- 28573399 TI - Development of PR genes panel for screening aphid-tolerant cultivars in Brassica juncea. AB - The exorbitant yield loss incurred by Indian farmers every year (10-90%) in rapeseed-mustard (Brassica juncea) is chiefly attributed to the progressive infestation of mustard fields by Lipaphis erysimi (Kalt.), a major insect pest belonging to the family of Homoptera. Currently there are no successful tolerant cultivars developed by conventional means in Brassica juncea with systemic plant responses in the form of direct or indirect defenses against aphid attack. Lack of specific methods for screening large numbers of genotypes required in breeding for selection of tolerant cultivars in mustard is one of the main causes of slow progress in developing resistant varieties of Brassica juncea. Traditional phenotype-based breeding has to be augmented with recent molecular approaches for potential genotype selection and cultivar development in Brassica juncea. In current study a pathogen-responsive gene panel was developed which could be used for expression-assisted breeding program in mustard for selection of tolerant types against aphid infestation, minimizing the huge crop losses suffered by farmers every year. PMID- 28573400 TI - Species specific PCR based detection of Escherichia coli from Indian foods. AB - Escherichia coli is a faecal indicator and certain virotypes are known as pathogens. Therefore, detection and prevention of E. coli in food is very important. The existing rapid methods concentrate on detecting the pathogenic E. coli instead of total E. coli population. Present study evaluates the use of two molecular markers (uidA and flanking region of uspA) specific for the E. coli in combination with microbiological method for confirmation. Majority of the isolates (77%) were positive for both the genes tested. However, 22% of the E. coli isolates were positive for any one of the two primer sets [uidA (9%) and flanking region of uspA (13%)]. High levels of E. coli incidences (92% samples) were observed in beef while low occurrence (19% samples) was found in sprouts. Low percentage (7.3%) of E. coli isolates was positive for virulence genes tested (lt, ipaH, aggR, eaeA, stx1 and stx2). Two isolates were positive for stx genes. However, none of the isolates including stx positive isolates were E. coli 0157:H7. Maximum number of the E. coli (44%) isolates was characterized under phylogenetic group B2. This phylogenetic group comprises of extra intestinal and virulent E. coli strains. PMID- 28573401 TI - Effects of Supervised vs. Unsupervised Training Programs on Balance and Muscle Strength in Older Adults: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Balance and resistance training can improve healthy older adults' balance and muscle strength. Delivering such exercise programs at home without supervision may facilitate participation for older adults because they do not have to leave their homes. To date, no systematic literature analysis has been conducted to determine if supervision affects the effectiveness of these programs to improve healthy older adults' balance and muscle strength/power. OBJECTIVES: The objective of this systematic review and meta-analysis was to quantify the effectiveness of supervised vs. unsupervised balance and/or resistance training programs on measures of balance and muscle strength/power in healthy older adults. In addition, the impact of supervision on training-induced adaptive processes was evaluated in the form of dose-response relationships by analyzing randomized controlled trials that compared supervised with unsupervised trials. DATA SOURCES: A computerized systematic literature search was performed in the electronic databases PubMed, Web of Science, and SportDiscus to detect articles examining the role of supervision in balance and/or resistance training in older adults. STUDY ELIGIBILITY CRITERIA: The initially identified 6041 articles were systematically screened. Studies were included if they examined balance and/or resistance training in adults aged >=65 years with no relevant diseases and registered at least one behavioral balance (e.g., time during single leg stance) and/or muscle strength/power outcome (e.g., time for 5-Times-Chair-Rise-Test). Finally, 11 studies were eligible for inclusion in this meta-analysis. STUDY APPRAISAL: Weighted mean standardized mean differences between subjects (SMDbs) of supervised vs. unsupervised balance/resistance training studies were calculated. The included studies were coded for the following variables: number of participants, sex, age, number and type of interventions, type of balance/strength tests, and change (%) from pre- to post-intervention values. Additionally, we coded training according to the following modalities: period, frequency, volume, modalities of supervision (i.e., number of supervised/unsupervised sessions within the supervised or unsupervised training groups, respectively). Heterogeneity was computed using I 2 and chi 2 statistics. The methodological quality of the included studies was evaluated using the Physiotherapy Evidence Database scale. RESULTS: Our analyses revealed that in older adults, supervised balance/resistance training was superior compared with unsupervised balance/resistance training in improving measures of static steady state balance (mean SMDbs = 0.28, p = 0.39), dynamic steady-state balance (mean SMDbs = 0.35, p = 0.02), proactive balance (mean SMDbs = 0.24, p = 0.05), balance test batteries (mean SMDbs = 0.53, p = 0.02), and measures of muscle strength/power (mean SMDbs = 0.51, p = 0.04). Regarding the examined dose response relationships, our analyses showed that a number of 10-29 additional supervised sessions in the supervised training groups compared with the unsupervised training groups resulted in the largest effects for static steady state balance (mean SMDbs = 0.35), dynamic steady-state balance (mean SMDbs = 0.37), and muscle strength/power (mean SMDbs = 1.12). Further, >=30 additional supervised sessions in the supervised training groups were needed to produce the largest effects on proactive balance (mean SMDbs = 0.30) and balance test batteries (mean SMDbs = 0.77). Effects in favor of supervised programs were larger for studies that did not include any supervised sessions in their unsupervised programs (mean SMDbs: 0.28-1.24) compared with studies that implemented a few supervised sessions in their unsupervised programs (e.g., three supervised sessions throughout the entire intervention program; SMDbs: -0.06 to 0.41). LIMITATIONS: The present findings have to be interpreted with caution because of the low number of eligible studies and the moderate methodological quality of the included studies, which is indicated by a median Physiotherapy Evidence Database scale score of 5. Furthermore, we indirectly compared dose response relationships across studies and not from single controlled studies. CONCLUSIONS: Our analyses suggest that supervised balance and/or resistance training improved measures of balance and muscle strength/power to a greater extent than unsupervised programs in older adults. Owing to the small number of available studies, we were unable to establish a clear dose-response relationship with regard to the impact of supervision. However, the positive effects of supervised training are particularly prominent when compared with completely unsupervised training programs. It is therefore recommended to include supervised sessions (i.e., two out of three sessions/week) in balance/resistance training programs to effectively improve balance and muscle strength/power in older adults. PMID- 28573402 TI - The Psychological Effects of Strength Exercises in People who are Overweight or Obese: A Systematic Review. AB - BACKGROUND: Overweightness and obesity represent a high burden on well-being and society. Strength training has positive effects on body composition and metabolic health for people who are overweight or obese. The evidence for psychological effects of strength exercises is unclear. OBJECTIVE: The aim of this study was to assess the psychological effects of strength exercises for people who are overweight or obese. METHODS: Relevant literature was identified by use of the PubMed and PsycINFO databases. For each study, effect sizes and corresponding variance estimates were extracted or calculated for the main effects of strength exercises on psychological outcomes. RESULTS: Seventeen studies were included. There was almost no overlap among the various measures of psychological constructs. The constructs were ordered into eight broad categories. Meta analytical techniques revealed substantial heterogeneity in effect sizes, and combined with the low number of effect size estimates for each outcome measure, this precluded meta-analysis. Organization of the data showed that the evidence base so far does not show convincing effects of strength training on psychological outcome measures. Some weak effects emerged on self-efficacy, self esteem, inhibition, and psychological disorders (e.g., anxiety and depression). No additional or comparable effects to other interventions were found for mood, outcome expectations, quality of life, and stress. DISCUSSION: The main finding of this review is that despite a strong theoretical basis for expecting positive effects of strength training on psychological outcomes, the literature shows a large gap in this area. The existing research does not show a clear picture: some positive results might exist, but there is a strong need to accumulate more evidence before drawing conclusions. PMID- 28573403 TI - A Kinetic Model Describing Injury-Burden in Team Sports. AB - BACKGROUND: Injuries in team sports are normally characterised by the incidence, severity, and location and type of injuries sustained: these measures, however, do not provide an insight into the variable injury-burden experienced during a season. Injury burden varies according to the team's match and training loads, the rate at which injuries are sustained and the time taken for these injuries to resolve. At the present time, this time-based variation of injury burden has not been modelled. OBJECTIVES: To develop a kinetic model describing the time-based injury burden experienced by teams in elite team sports and to demonstrate the model's utility. METHODS: Rates of injury were quantified using a large eight season database of rugby injuries (5253) and exposure (60,085 player-match-hours) in English professional rugby. Rates of recovery from injury were quantified using time-to-recovery analysis of the injuries. RESULTS: The kinetic model proposed for predicting a team's time-based injury burden is based on a composite rate equation developed from the incidence of injury, a first-order rate of recovery from injury and the team's playing load. The utility of the model was demonstrated by examining common scenarios encountered in elite rugby. CONCLUSIONS: The kinetic model developed describes and predicts the variable injury-burden arising from match play during a season of rugby union based on the incidence of match injuries, the rate of recovery from injury and the playing load. The model is equally applicable to other team sports and other scenarios. PMID- 28573404 TI - Minors and euthanasia: a systematic review of argument-based ethics literature. AB - : Euthanasia was first legalised in the Netherlands in 2002, followed by similar legislation in Belgium the same year. Since the beginning, however, only the Netherlands included the possibility for minors older than 12 years to request euthanasia. In 2014, the Belgian Act legalising euthanasia was amended to include requests by minors who possess the capacity of discernment. This amendment sparked great debate, and raised difficult ethical questions about when and how a minor can be deemed competent. We conducted a systematic review of argument-based literature on euthanasia in minors. The search process followed PRISMA guidelines. Thirteen publications were included. The four-principle approach of medical ethics was used to organise the ethical arguments underlying this debate. The justification for allowing euthanasia in minors is buttressed mostly by the principles of beneficence and respect for autonomy. Somewhat paradoxically, both principles are also used in the literature to argue against the extension of legislation to minors. Opponents of euthanasia generally rely on the principle of non-maleficence. CONCLUSION: The present analysis reveals that the debate surrounding euthanasia in minors is at an early stage. In order to allow a more in-depth ethical discussion, we suggest enriching the four-principle approach by including a care-ethics approach. What is Known: * The Netherlands and Belgium are the only two countries in the world with euthanasia legislation making it possible for minors to receive euthanasia. * This legislation provoked great debate globally, with ethical arguments for and against this legislation. What is New: * A systematic description of the ethical concepts and arguments grounding the debate on euthanasia in minors, as reported in the argument-based ethics literature. * A need has been identified to enrich the debate with a care-ethics approach to avoid oversimplifying the ethical decision-making process. PMID- 28573405 TI - Diagnostic accuracy of clinical dehydration scales in children. AB - : The aim of this study was to evaluate the diagnostic accuracy of the Clinical Dehydration Scale (CDS), the World Health Organization (WHO) scale, and the Gorelick scale for dehydration assessment in children. A prospective, observational study was carried out between October 2014 and December 2016. Eligible participants were children aged 1 month to 5 years with acute diarrhea. After hospital admission, each patient's weight was recorded and the degree of dehydration based on three scales was assessed. The reference standard was the percentage weight change between the discharge and admission weights. The main outcomes were the sensitivity, specificity, positive likelihood ratio (LR), and negative LR. Of 128 children enrolled in the study, complete data were available from 118 patients for analysis. Most of children presented with no or mild dehydration. Only the CDS showed limited value in confirming a diagnosis of dehydration >=6% (positive LR 3.9, 95% CI 1.1 to 9.1), with no value in ruling it out (negative LR 0.6, 95% CI 0.2 to 0.99). CONCLUSION: In our cohort, the CDS was of limited diagnostic value in ruling in severe dehydration in children with acute gastroenteritis. The WHO and Gorelick scales were not helpful in the assessment of dehydration. What is Known : * Treatment of acute gastroenteritis (AGE) is based on assessing and correcting the degree of dehydration. * Several scales combining various signs and symptoms have been developed, including the Clinical Dehydration Scale (CDS), and the World Health Organization (WHO) scale, and the Gorelick scale. None of these scales is internationally accepted for best accuracy in diagnosing dehydration in children. What is New: * The CDS was of limited diagnostic value in ruling in severe dehydration in children with AGE. * The WHO and Gorelick scales were not helpful in the assessment of dehydration. PMID- 28573406 TI - Impact of surgery for endometriomas on pregnancy outcomes following in vitro fertilization-intracytoplasmic sperm injection. Who should be the preferred laparoscopists: gynecologists or reproductive surgeons? AB - OBJECTIVE: To investigate whether laparoscopic excision of ovarian endometriomas pretreated with operation by gynecologists or reproductive surgeons exerts different effects on in vitro fertilization-intracytoplasmic sperm injection results. MATERIALS AND METHODS: Retrospective case control study. Relevant information was collected from the electronic records of women who underwent IVF/ICSI from 01/01/2013 to 30/12/2015 in our unit. The study group consisted of 35 women who previously had laparoscopic endometrioma excision by reproductive surgeons in our unit; the control group included 36 patients who underwent surgery for endometriomas by gynecologists in our hospital. RESULT(S): There were slightly higher numbers of AFC and higher pregnancy rate in the study group, although differences did not reach statistical significance. For patients over 35 years old, there were more oocyte retrieved, mature oocytes and two pronucei (2PN) in the study group than the control group although observed differences did not reach statistical significance. CONCLUSION(S): Electrocautery is more deleterious on ovarian reserve than hemostatic suture. In procedure of patients who wish to conceive, surgeons should use hemostatic suturing technique preferentially. PMID- 28573407 TI - Presentation and management of vesicovaginal fistulae after delivery at a German women's hospital. AB - Vesicovaginal fistulae are rarely seen after childbirth in developed countries. This article deals with the causes, presentation, and management of obstetric vesicovaginal fistulae in patients treated at a German women's hospital. PMID- 28573408 TI - Practical Recommendations for Transitioning Patients with Type 2 Diabetes from Hospital to Home. AB - PURPOSE OF REVIEW: The purpose of this review is to provide practical evidence based recommendations for transitioning hospitalized patients with type 2 diabetes (T2DM) to home. RECENT FINDINGS: Hospitalized patients who have newly diagnosed or poorly controlled T2DM require initiation or intensification of their outpatient diabetes regimen. Potential barriers to medication access and continuity of care should be identified early in the hospitalization. Throughout hospitalization, patients should receive diabetes education focused on basic survival skills and tailored to learning needs. Patients should leave the hospital with personalized discharge instructions that include a list of all medications and follow-up appointments with both the outpatient diabetes provider and a diabetes educator whenever possible. An approach to transitioning patients with T2DM from hospital to home that focuses on optimizing the patient's discharge diabetes regimen, anticipating patients' needs during the immediate post-discharge period, providing survival skills education, and ensuring continuation of diabetes care and education following hospital discharge has the potential to improve glycemic control and reduce emergency department visits and hospital readmissions. PMID- 28573409 TI - From iPSC towards cardiac tissue-a road under construction. AB - The possibility to generate induced pluripotent stem cells (iPSC) opens the way to generate virtually all cell types of our human body. In combination with modern gene editing techniques like CRISPR/CAS, a new set of powerful tools becomes available for life science. Scientific fields like genotype and cell type specific pharmacology, disease modeling, stem cell biology, and developmental biology have been dramatically fostered and their faces have been changed. However, as golden as the age of iPSC-derived cells and their manipulation has started, the shine begins to tarnish. Researchers face more and more practical problems intrinsic to the system. These problems are related to the specific culturing conditions which are not yet sufficient to mimic the natural environment of native stem cells differentiating towards adult cells. However, researchers work hard to uncover these factors. Here, we review a common standard approach to generate iPSCs and transduce these to iPSC cardiomyocytes. Further, we review recent achievements and discuss their current limitations and future perspectives. We are on track, but the road is still under construction. PMID- 28573412 TI - [Topical corticosteroids for treating phimosis in boys]. PMID- 28573410 TI - Depressed polymorphonuclear cell functions in periparturient cows that develop postpartum reproductive diseases. AB - The study was planned to see if there is any important and significant changes in the PMN function in cows suffering from postpartum reproductive diseases (PRD). Blood sampling was done from 41 pregnant cows on 15 days prepartum (-15d), calving day (0d), 15 days (15d) and 30 days (30d) postpartum and thorough gynaecological examination was performed on 0d, 15d, 30d and 45d for diagnosis of PRD like retained placenta (RP), clinical metritis (CM), clinical endometritis (CE) and delayed involution of uterus (DIU). The heparinised blood was used for isolation of PMN leukocytes for estimation of superoxide (SO), hydrogen peroxide (H2O2) and enzyme myeloperoxidase (MPO) activity in each group of cows. The SO production (DeltaOD) was greater for normal (0.19 +/- 0.05) than cows suffering from RP (-0.12 +/- 0.09), CM (-0.15 +/- 0.13) and CE (-0.07 +/- 0.05) at -15d. The mean value was greater for normal cows (0.12) than the cows with PRD (0.05 to 0.9) at 30d. The H2O2 production was greater for normal than cows with PRD at all sampling days and significantly greater than cows with RP and CE at 15d (p < 0.01) and 30d (P < 0.05). The MPO activity (MUmol/1 * 107) was greater for normal (18.77 +/- 1.27) than for RP (12.52 +/- 2.57) and CM (11.31 +/- 3.30) cows on 0d. The depressed capability of the PMN from the cows with PRD to produce SO, H2O2 and MPO during the periparturient period indicated their association with the development of RP, CM and CE. PMID- 28573414 TI - Primary cutaneous nocardiosis: a pitfall in the diagnosis of skin infection. PMID- 28573413 TI - [Molecular biomarkers and prognostic factors for prostate cancer]. AB - In the era of personalized medicine and precision oncology, innovative genetic biomarkers are of emerging interest to close the diagnostic and prognostic gap that is left by current clinicopathologic risk classifiers. The current review article summarizes evidence regarding prognostic and predictive genetic biomarkers that are currently in widespread clinical use at initial diagnosis as well as following definitive treatment of prostate cancer. We give a brief summary about basic principles of biomarker research studies and present current data for the Progensa PC3 test, TMPRSS2:ERG gene fusion, ConfirmMDx, Prolaris gene panel, OncotypeDX Genomic Prostate score, and Decipher classifier. Evidence regarding those genetic biomarkers has heavily increased recently. However, there is still a lack of large, multicentric and prospective clinical validation studies. Furthermore, comparative studies that investigate the prognostic value of various genetic biomarkers are needed. PMID- 28573415 TI - Published data do not support the notion that Borrelia valaisiana is human pathogenic. PMID- 28573416 TI - The budding yeast Saccharomyces cerevisiae as a model organism: possible implications for gerontological studies. AB - Experimental gerontology is based on the fundamental assumption that the aging process has a universal character and that the mechanisms of aging are well conserved among living things. The consequence of this assumption is the use of various organisms, including unicellular yeast Saccharomyces cerevisiae, as models in gerontology, and direct extrapolation of the conclusions drawn from the studies carried on these organisms to human beings. However, numerous arguments suggest that aging is not universal and its mechanisms are not conserved in a wide range of species. Instead, senescence can be treated as a side effect of the evolution of specific features for systematic group, unrelated to the passage of time. Hence, depending on the properties of the group, the senescence and proximal causes of death could have a diverse nature. We postulate that the selection of a model organism to explain the mechanism of human aging and human longevity should be preceded by the analysis of its potential to extrapolate the results to a wide group of organisms. Considering that gerontology is a human oriented discipline and that aging involves complex, systemic changes affecting the entire organism, the object of experimental studies should be animals which are closest relatives of human beings in evolutionary terms, rather than lower organisms, which do not have sufficient complexity in terms of tissues and organ structures. PMID- 28573418 TI - Rising atmospheric CO2 concentration may imply higher risk of Fusarium mycotoxin contamination of wheat grains. AB - Increasing atmospheric CO2 concentration not only has a direct impact on plants but also affects plant-pathogen interactions. Due to economic and health-related problems, special concern was given thus in the present work to the effect of elevated CO2 (750 MUmol mol-1) level on the Fusarium culmorum infection and mycotoxin contamination of wheat. Despite the fact that disease severity was found to be not or little affected by elevated CO2 in most varieties, as the spread of Fusarium increased only in one variety, spike grain number and/or grain weight decreased significantly at elevated CO2 in all the varieties, indicating that Fusarium infection generally had a more dramatic impact on the grain yield at elevated CO2 than at the ambient level. Likewise, grain deoxynivalenol (DON) content was usually considerably higher at elevated CO2 than at the ambient level in the single-floret inoculation treatment, suggesting that the toxin content is not in direct relation to the level of Fusarium infection. In the whole-spike inoculation, DON production did not change, decreased or increased depending on the variety * experiment interaction. Cooler (18 degrees C) conditions delayed rachis penetration while 20 degrees C maximum temperature caused striking increases in the mycotoxin contents, resulting in extremely high DON values and also in a dramatic triggering of the grain zearalenone contamination at elevated CO2. The results indicate that future environmental conditions, such as rising CO2 levels, may increase the threat of grain mycotoxin contamination. PMID- 28573417 TI - Convergent adaptation of cellular machineries in the evolution of large body masses and long life spans. AB - In evolutionary terms, life on the planet has taken the form of independently living cells for the majority of time. In comparison, the mammalian radiation is a relatively recent event. The common mammalian ancestor was probably small and short-lived. The "recent" acquisition of an extended longevity and large body mass of some species of mammals present on the earth today suggests the possibility that similar cellular mechanisms have been influenced by the forces of natural selection to create a convergent evolution of longevity. Many cellular mechanisms are potentially relevant for extending longevity; in this assay, we review the literature focusing primarily on two cellular features: (1) the capacity for extensive cellular proliferation of differentiated cells, while maintaining genome stability; and (2) the capacity to detect DNA damage. We have observed that longevity and body mass are both positively linked to these cellular mechanisms and then used statistical tools to evaluate their relative importance. Our analysis suggest that the capacity for extensive cellular proliferation while maintaining sufficient genome stability, correlates to species body mass while the capacity to correctly identify the presence of DNA damage seems more an attribute of long-lived species. Finally, our data are in support of the idea that a slower development, allowing for better DNA damage detection and handling, should associate with longer life span. PMID- 28573419 TI - Quantifying Cartilage Biomechanical Properties Using a Linearized Frequency Domain Method. AB - Articular cartilage function relies on its unique mechanical behavior. Cartilage mechanics have been described by several analytic models, whose parameters are usually estimated by fitting their constitutive equations to stress-relaxation data. This procedure can be long and is prone to experimental and fitting errors. Tauhis study describes a novel methodology for estimating the biomechanical properties of cartilage samples based on their linearized frequency response, derived by applying a series of small-amplitude harmonic displacements superimposed to a bias strain. The proposed methodology, denoted as linearized frequency-domain method (LFM), was demonstrated by quantifying the effects of collagenase and hyaluronidase on cartilage, where it provided robust cartilage parameter estimates that overall agreed well with estimates obtained by stress relaxation analysis. LFM was also applied to unveil the strain-dependent nature of porcine cartilage biomechanical parameters. Results showed that increasing the bias strain from 5% to 15% caused a significant decrease in cartilage permeability but did not have significant effect on the compression modulus and the Poisson's ratio. Apart from cartilage, LFM can potentially quantify the strain-dependent nature of tissues and biomaterials, thereby enhance tissue-level understanding on organ physiology and pathology, lead to better computational tissue models, and guide tissue engineering research. PMID- 28573420 TI - Identifying independent risk factors for graft loss after primary liver transplantation. AB - PURPOSE: The aim of the study is the identification of independent risk factors for re-transplantation after primary liver transplantation beyond the occurrence of hepatic artery thrombosis. METHODS: Eight hundred thirty-four adult patients undergoing primary liver transplantation were analyzed. A propensity score was developed using multivariable binary logistic regression with hepatic artery thrombosis as the dependent variable. The logit link function of the propensity score was included into multivariable Cox regression analysis for graft survival to adjust the study population. RESULTS: Graft loss was observed in 134 patients (16.1%). Independent significant risk factors for graft loss were recipient platelet count (p = 0.040; HR: 1.002; 95%-CI: 1.000-1.003), preoperative portal vein thrombosis (p = 0.032; HR: 1.797; 95%-CI: 1.054-2.925), donor age (p < 0.001; HR: 1.026; 95%-CI: 1.012-1.040), percentage of macrovesicular steatosis of the graft (p = 0.011; HR: 1.037; 95%-CI: 1.009-1.061), early complications leading to revision surgery (p < 0.001; HR: 2.734; 95%-CI: 1.897-3.956), duration of the transplant procedure (p < 0.001; HR: 1.005; 95%-CI: 1.003-1.007) as well as transplantation of a split liver graft (p = 0.003; HR: 2.637; 95%-CI: 1.420 4.728). The logit of the propensity score did not reach statistical significance in the final multivariable Cox regression model (p = 0.111) indicating good adjustment for the occurrence of hepatic artery thrombosis. CONCLUSION: Liver transplant programs might benefit from regular donor organ biopsies to assess the amount of macrovesicular steatosis. An elevated recipient platelet count can promote reperfusion injury leading to graft loss. A liver graft from an elderly donor should not be split or be transplanted in a recipient with detected portal vein thrombosis. PMID- 28573421 TI - Marijuana Liberalization, Research, and Policy: Contributions to Current Knowledge and Practice. PMID- 28573423 TI - First report of spinose ear tick, Otobius megnini (Acari, Argasidae), in Sweden. AB - A dog that had travelled to Sweden was inspected by a veterinarian. In one ear canal a tick was found. It was later identified as a spinose ear tick, Otobius megnini. In this case report we also review the previously known reports of O. megnini in Europe and the recent introduction and spread in Turkey. PMID- 28573422 TI - How to evaluate the potential occurrence of intraguild predation. AB - Intraguild predation is the combination of exploitative competition and predation among potential competitors that use similar resources. It has the potential to shape population dynamics and community structure. Although there is much empirical evidence for the occurrence of intraguild predation in natural ecosystems, the study of its effects is mainly limited to short-term microcosm experiments. There is, therefore, certain skepticism about its actual significance in nature. A relevant concern is that there is no consensus regarding criteria to evaluate the possible occurrence of intraguild predation in short-term experiments, and methodological differences may therefore underlie apparent inconsistencies among studies. Our purpose here was to evaluate existing criteria to offer guidance for the design of experiments to determine whether two species may potentially engage in intraguild predation. The criteria are based on the condition that intraguild predators need to experience immediate energetic gains when feeding on the intraguild prey. Thus, a relevant experimental design must quantify predation but also fitness benefits of feeding on the other species, i.e. increases in reproduction, somatic growth, or survival. PMID- 28573424 TI - Vitamin D inhibits the Staphylococcal enterotoxin B-induced expression of tumor necrosis factor in microglial cells. AB - Microglial cells play a crucial role in inflammatory responses in neural tissue. Vitamin D (VitD3) deficiency is associated with the pathogenesis of inflammation. Staphylococcal enterotoxin B (SEB) is a superantigen and can initiate inflammation. This study tests a hypothesis that VitD3 deficiency upregulates the expression of tumor necrosis factor (TNF) in microglial cells. Microglial cells were isolated from the mouse brain. The microglial cells were cultured in the presence or absence of VitD3 or/and SEB. The expression of TNF in the microglial cells was assessed by RT-qPCR and Western blotting. We observed that SEB increased the expression of TNF in microglial cells. The presence of calcitriol (an active form of VitD3) inhibited the SEB-induced TNF production by microglial cells in a dose-dependent manner. Exposure to SEB increased the binding of vitamin D receptor (VDR) to the TNF promoter, which was inhibited by the presence of calcitriol with the mechanism being the formation of a complex of VDR and LITAF (a transcription factor of TNF) in microglial cells; the complex prevented the binding of LITAF to the promoter of the TNF gene. Exposure to calcitriol also increased the expression of IL-10 in microglial cells; the inhibition of SEB induced TNF expression was partially due to the IL-10 induced by calcitriol (Heine G, Niesner U, Chang HD, teinmeyer A, Zugel U, Zuberbier T, et al. 1,25 dihydroxyvitamin D(3) promotes IL-10 production in human B cells. Eur J Immunol. 2008;38(8):2210-8). Hormonal vitamin D [calcitriol] can inhibit the SEB-induced TNF expression in microglial cells. PMID- 28573426 TI - Cultural Adaptations: Conceptual, Ethical, Contextual, and Methodological Issues for Working with Ethnocultural and Majority-World Populations. AB - Mayor advancements have been achieved in research on the cultural adaptation of prevention and treatment interventions that are conducted with diverse ethnocultural groups. This commentary addresses conceptual, ethical, contextual, and methodological issues related to cultural adaptations. The articles in this special issue represent a major contribution to the study of cultural adaptations in prevention science. We frame our analysis of fidelity to core intervention components using a conceptual approach that examines (a) the propositional model (theory of change), (b) the procedural model (theory of action, methods), and (c) the philosophical assumptions that undergird these models. Regarding ethics, we caution against imposing the norms, values, and world views of the Western dominant society onto vulnerable populations such as ethnocultural groups. Given that the assumption of universality in behavioral science has been questioned, and as randomized clinical trials (RCTs) seldom examine the ecological validity of evidence-based interventions and treatments (EBI/T), imposing such interventions onto ethnocultural groups is problematic since these interventions contain values, norms, beliefs, and worldviews that may be contrary to those held by many ethnocultural groups. Regarding methods, several innovative designs are discussed that serve as alternatives to the RCT and represent an important contribution to prevention science. Also, we discuss guidelines for conducting cultural adaptations. Finally, the articles in this special issue make a major contribution to the growing field of cultural adaptation of preventive interventions with ethnocultural groups and majority-world populations. PMID- 28573425 TI - Night eating syndrome and its association with weight status, physical activity, eating habits, smoking status, and sleep patterns among college students. AB - BACKGROUND: Night eating syndrome (NES) is characterized by evening hyperphagia and/or nocturnal ingestion. OBJECTIVE: The main objective of this study was to assess the percentage of students complying with symptoms and behaviors consistent with the diagnostic criteria for NES, and explore its association with body mass index (BMI), dietary habits, physical activity, smoking status, and sleep patterns, among a sample of college students. METHODS: A cross-sectional survey was conducted among a sample of 413 undergraduate students, mean age of 20.6 +/- 1.68 SD, at Central Michigan University. Students completed an online survey including demographic information and the Night Eating Diagnostic Questionnaire (NEDQ) and Pittsburgh Sleep Quality Index Questionnaire (PSQI). Participants were grouped based on self-reporting of the presence and frequency of night eating-related symptoms and behaviors related to the diagnostic criteria for NES as follows: normal, mild night eater, moderate night eater, and full syndrome night eater. Pearson's Chi-squared, Student's t test, and Wilcoxon rank sum test were used to test the association between students with and without any night eating behavior in relation to BMI, lifestyle variables, and sleep duration/quality. RESULTS: Results showed that the proportion of students complying with symptoms and behaviors consistent with full-syndrome of NES was 1.2%. There were no significant differences between students complying with symptoms and behaviors consistent with any level of NES and those without any night eating behavior regarding BMI, eating habits, physical activity, and smoking status. NES was significantly related to sleep duration (P = 0.023). Students complying with symptoms consistent with any level of NES reported shorter sleep time and had higher total PSQI score (6.73 +/- 4.06) than students without the syndrome (5.61 +/- 2.61) (P = 0.007). CONCLUSION: Although the percentage of students complying with full-syndrome NES was relatively low in our student sample, those students had shorter sleep time and poorer sleep quality than the other groups. However, it is unclear whether evening hyperphagia is a response to a lack of sleep or vice versa, and further research is needed. LEVEL OF EVIDENCE: Level III, case-control analytic study. PMID- 28573427 TI - Reliability of trauma management videos on YouTube and their compliance with ATLS(r) (9th edition) guideline. AB - OBJECTIVE: In this study, the reliability of trauma management scenario videos (in English) on YouTube and their compliance with Advanced Trauma Life Support (ATLS(r)) guidelines were investigated. METHODS: The search was conducted on February 15, 2016 by using the terms "assessment of trauma" and ''management of trauma''. All videos that were uploaded between January 2011 and June 2016 were viewed by two experienced emergency physicians. The data regarding the date of upload, the type of the uploader, duration of the video and view counts were recorded. The videos were categorized according to the video source and scores. RESULTS: The search results yielded 880 videos. Eight hundred and thirteen videos were excluded by the researchers. The distribution of videos by years was found to be balanced. The scores of videos uploaded by an institution were determined to be higher compared to other groups (p = 0.003). CONCLUSION: The findings of this study display that trauma management videos on YouTube in the majority of cases are not reliable/compliant with ATLS-guidelines and can therefore not be recommended for educational purposes. These data may only be used in public education after making necessary arrangements. PMID- 28573428 TI - A retrospective evaluation of the Modified Alvarado Score for the diagnosis of acute appendicitis in HIV-infected patients. AB - BACKGROUND: The aim of this study was to evaluate and compare the diagnostic value of a Modified Alvarado Score (MAS) >=7 for acute appendicitis in both Human Immunodeficiency Virus (HIV)-negative (HIVneg) and positive (HIVpos) patientcohorts. METHODS: This retrospective study included all HIV-tested patients undergoing appendectomy at a regional hospital from March 2010 to March 2011. The MAS was calculated for all patients, as well as for the HIVneg and HIVpos groups separately. Two subgroups were considered for each of these: MAS >=7 (high likelihood of appendicitis) and MAS <7 (low likelihood of appendicitis). These subgroups were then analysed against histopathological findings of the resected appendix. MAS specificities and sensitivities were determined by comparing Receiver Operator Characteristic (ROC) curves for the various scores. RESULTS: The study comprised 133 patients. Eighty-six (65%) were men and the median age was 20 years (range 4-64); 18 patients (14%) were HIVpos. Appendicitis was confirmed histologically in 113 patients, 100 in the HIVneg group and 13 in the HIVpos group. Specificity and sensitivity of a MAS >=7 for HIVneg patients was 73 and 85% respectively. Based on the ROC curves, HIVpos patients only showed similar sensitivities (69%) and specificities (80%) at a MAS >=8. CONCLUSION: A MAS >=7 is a reliable predictor of acute appendicitis in HIVneg patients. In HIVpos patients, the MAS threshold required to accurately predict appendicitis is 8. The use of a MAS >=7 in this group of patients will result in unnecessary surgical intervention. PMID- 28573429 TI - Predictors of outcome in 101 patients requiring emergent thoracotomy for penetrating pulmonary injuries. AB - BACKGROUND: Operative interventions are uncommonly required for penetrating pulmonary injuries. Similarly, because their incidence is low, few series appear sporadically in the literature. Objectives of this study are to identify predictors of outcome for patients requiring emergent thoracotomy for penetrating pulmonary injuries and evaluate the use of tissue sparing versus resective techniques for their management. STUDY DESIGN: This is a retrospective 169-month study of all patients with penetrating pulmonary injuries requiring thoracotomy. The main outcome measures are: physiologic parameters, AAST-OIS injury grade, surgical procedures and mortality. Statistical analysis includes univariate and stepwise logistic regression. RESULTS: 101 patients required thoracotomy for penetrating pulmonary injuries. Mechanism of injury includes: gunshot wounds (GSW)-73 (72%), stab wounds (SW)-28 (33%). Mean systolic BP 97 +/- 47, mean HR 92 +/- 47, and mean admission pH 7.22 +/- 0.17. Mean RTS 6.25 +/- 2.7, mean ISS 36 +/- 22. The mean estimated blood loss (EBL) was 5277 +/- 4955 mls. Predictors of outcome are: admission pH (p = 0.0014), admission base deficit (p < 0.0001), packed red blood cells (PRBCs) transfused (p = 0.023), whole blood transfused (p < 0.01). A total of 143 procedures were required in 101 patients: tissue sparing 114 (80%) versus resective procedures 29 (20%). Only pneumonectomy (p = 0.024) predicted outcome. Overall survival 64/101-64%. American Association for the Surgery of Trauma-Organ Injury Scale (AAST-OIS) injury grades I-III versus IV-VI predicts survival (p < 0.001). Stepwise logistic regression identified AAST-OIS injury grades IV-VI (p = 0.007; OR 6.38 [95% CI 1.64-24.78]), intraoperative dysrhythmias (p = 0.003; OR 17.38 [95% CI 2.59-116.49]) and associated cardiac injuries (p = 0.02; OR 8.74 [95% CI 1.37-55.79]) as independent predictors of outcome. CONCLUSIONS: Predictors of outcome for penetrating pulmonary injuries requiring thoracotomy are identified and must be taken into account in their operative management. Tissue sparing techniques-stapled pulmonary tractotomy is once again validated, and it remains effective as the mainstay for their management; however, only pneumonectomy predicts outcome. AAST-OIS injury grades IV-VI predict outcome with higher injury grades requiring resective procedures. PMID- 28573430 TI - Critical effects of epigenetic regulation in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is characterized by persistent pulmonary vasoconstriction and pulmonary vascular remodeling. The pathogenic mechanisms of PAH remain to be fully clarified and measures of effective prevention are lacking. Recent studies; however, have indicated that epigenetic processes may exert pivotal influences on PAH pathogenesis. In this review, we summarize the latest research findings regarding epigenetic regulation in PAH, focusing on the roles of non-coding RNAs, histone modifications, ATP-dependent chromatin remodeling and DNA methylation, and discuss the potential of epigenetic-based therapies for PAH. PMID- 28573432 TI - Comment on: Progression-Free Survival as a Surrogate for Overall Survival in Clinical Trials of Targeted Therapy in Advanced Solid Tumors. PMID- 28573433 TI - Authors' Reply to Schoenfeld: "Progression-Free Survival as a Surrogate for Overall Survival in Clinical Trials of Targeted Therapy in Advanced Solid Tumors". PMID- 28573434 TI - The Whole Price of Vancomycin: Toxicities, Troughs, and Time. AB - Vancomycin is a glycopeptide antibiotic that is active against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. Nephrotoxicity, which is usually reversible, is the most serious common adverse effect of vancomycin. Vancomycin-associated nephrotoxicity prolongs hospital stays, imposes a need for additional antibiotics and, in rare circumstances, dialysis treatment, and increases medical costs and mortality. Risk factors for nephrotoxicity include the dose and duration of vancomycin treatment, serum trough concentration, patient characteristics, and concomitant receipt of nephrotoxins. Contemporary guidelines recommend targeting vancomycin trough concentrations of >=10 mg/L to prevent resistance and trough concentrations of 15-20 mg/L to optimize outcomes. There is significant correlation between vancomycin trough serum concentrations and the incidence of vancomycin-associated nephrotoxicity; however, evidence of an association between trough concentrations and efficacy is less convincing. Routine monitoring of serum vancomycin concentrations consumes time and limited healthcare resources and may not be cost effective. The use of alternative antibacterial agents that do not require monitoring would free up pharmacy resources. This time could then be devoted to initiatives such as pharmacist-led antibiotic stewardship programs that are known to reduce antibiotic use and promote improved patient outcomes. PMID- 28573431 TI - Human heart disease: lessons from human pluripotent stem cell-derived cardiomyocytes. AB - Technical advances in generating and phenotyping cardiomyocytes from human pluripotent stem cells (hPSC-CMs) are now driving their wider acceptance as in vitro models to understand human heart disease and discover therapeutic targets that may lead to new compounds for clinical use. Current literature clearly shows that hPSC-CMs recapitulate many molecular, cellular, and functional aspects of human heart pathophysiology and their responses to cardioactive drugs. Here, we provide a comprehensive overview of hPSC-CMs models that have been described to date and highlight their most recent and remarkable contributions to research on cardiovascular diseases and disorders with cardiac traits. We conclude discussing immediate challenges, limitations, and emerging solutions. PMID- 28573435 TI - Napabucasin: An Update on the First-in-Class Cancer Stemness Inhibitor. AB - Napabucasin (BBI608) is an orally administered small molecule that blocks stem cell activity in cancer cells by targeting the signal transducer and activator of transcription 3 pathway. The signal transducer and activator of transcription 3 pathway is over-activated in many types of cancer and has been shown to be an important pathway in cancer stem cell-mediated propagation of cancer. Cancer stem cells are a subpopulation of cancer cells considered to be the primary source of tumor growth, metastasis, and resistance to conventional therapies, and thus, responsible for cancer relapse. This review describes the clinical development program of this first-in-class cancer stemness inhibitor, including preclinical discovery, early clinical trials, current phase III clinical trial evaluation, and future therapeutic combinations. The therapeutic potential of napabucasin was first reported in a preclinical study that demonstrated the potent anti-tumor and anti-metastatic activity of napabucasin in several different cancer types, both in vitro and in vivo. In mouse models, napabucasin was effective both as a monotherapy and in combination with other agents; in particular, synergy was observed with paclitaxel in vivo. Napabucasin clinical trials have demonstrated encouraging anti-tumor activity as monotherapy and in combination with conventional therapeutics, with no significant pharmacokinetic interactions when used in combination therapies. Adverse events attributed to napabucasin have been predominantly mild, although some patients have experienced grade 3 gastrointestinal adverse events. More severe adverse events required reduced or discontinued dosing of napabucasin or medication to reverse or manage symptoms. In conclusion, napabucasin may prove useful in targeting cancer stem cells, with the potential to suppress metastasis and prevent relapse in patients with varying cancer types. PMID- 28573436 TI - The Effects of Tamoxifen on Plasma Lipoprotein(a) Concentrations: Systematic Review and Meta-Analysis. AB - INTRODUCTION: Tamoxifen is a selective estrogen receptor modulator widely used in the treatment of breast cancer. Tamoxifen therapy is associated with lower circulating low-density lipoprotein cholesterol and increased triglycerides, but its effects on other lipids are less well studied. AIMS: We aimed to investigate the effect of tamoxifen on circulating concentrations of lipoprotein(a) [Lp(a)] through a meta-analysis of available randomized controlled trials (RCTs) and observational studies. METHODS: This study was registered in the PROSPERO database (CRD42016036890). Scopus, MEDLINE and EMBASE were searched from inception until 22 March 2016 to identify studies investigating the effect of tamoxifen on Lp(a) values in humans. Meta-analysis was performed using an inverse variance-weighted, random-effects model with standardized mean difference (SMD) as the effect size estimate. RESULTS: Meta-analysis of five studies with 215 participants suggested a statistically significant reduction of Lp(a) levels following tamoxifen treatment (SMD -0.41, 95% confidence interval -0.68 to -0.14, p = 0.003). This effect was robust in the sensitivity analysis. CONCLUSIONS: Meta analysis suggested a statistically significant reduction of Lp(a) levels following tamoxifen treatment. Further well-designed trials are required to validate these results. PMID- 28573437 TI - Oblique incisions in hamstring tendon harvesting reduce iatrogenic injuries to the infrapatellar branch of the saphenous nerve. AB - PURPOSE: Iatrogenic injury to the infrapatellar branch of the saphenous nerve (IPBSN) is associated with many surgical interventions to the medial aspect of the knee, such as anterior cruciate ligament (ACL) reconstruction. Different types of surgical incisions during hamstring tendon harvesting for ACL reconstruction are related to a variable risk of IPBSN injury. This study aimed to evaluate the risk of iatrogenic IPBSN injury during hamstring tendon harvesting for ACL reconstruction with different incision techniques over the pes anserinus. METHODS: This study was performed on 100 cadavers. Vertical, horizontal, or oblique incisions were simulated on each cadaveric limb to determine the incidence of iatrogenic IPBSN injury. RESULTS: The vertical incision caused the IPBSN injury during hamstring tendon harvesting in 101 (64.7%), the horizontal incision in 78 (50.0%), and the oblique incision in 43 (27.6%) examined lower limbs. The calculated odds ratios (OR) for risk of injury in vertical versus horizontal and horizontal versus oblique incisions were 2.4 (95% CI 1.5-3.6) and 1.8 (95% 1.2-2.8), respectively. CONCLUSIONS: The vertical incision technique over the pes anserinus should be avoided during hamstring tendon harvesting for ACL reconstruction. The adoption of an oblique incision, with the shortest possible length, will allow for the safest procedure possible, thus minimizing the risk of iatrogenic IPBSN injury, and improving patient outcomes and postoperative quality-of-life. PMID- 28573438 TI - The incidence and severity of errors in pharmacist-written discharge medication orders. AB - Background Errors in discharge prescriptions are problematic. When hospital pharmacists write discharge prescriptions improvements are seen in the quality and efficiency of discharge. There is limited information on the incidence of errors in pharmacists' medication orders. Objective To investigate the extent and clinical significance of errors in pharmacist-written discharge medication orders. Setting 1000-bed teaching hospital in London, UK. Method Pharmacists in this London hospital routinely write discharge medication orders as part of the clinical pharmacy service. Convenient days, based on researcher availability, between October 2013 and January 2014 were selected. Pre-registration pharmacists reviewed all discharge medication orders written by pharmacists on these days and identified discrepancies between the medication history, inpatient chart, patient records and discharge summary. A senior clinical pharmacist confirmed the presence of an error. Each error was assigned a potential clinical significance rating (based on the NCCMERP scale) by a physician and an independent senior clinical pharmacist, working separately. Main outcome measure Incidence of errors in pharmacist-written discharge medication orders. Results 509 prescriptions, written by 51 pharmacists, containing 4258 discharge medication orders were assessed (8.4 orders per prescription). Ten prescriptions (2%), contained a total of ten erroneous orders (order error rate-0.2%). The pharmacist considered that one error had the potential to cause temporary harm (0.02% of all orders). The physician did not rate any of the errors with the potential to cause harm. Conclusion The incidence of errors in pharmacists' discharge medication orders was low. The quality, safety and policy implications of pharmacists routinely writing discharge medication orders should be further explored. PMID- 28573440 TI - [Quality assurance of optical coherence tomography for diagnostics of the fundus : Positional statement of the BVA, DOG and RG]. PMID- 28573439 TI - Using pharmacy management systems for research: survival outcomes for lenalidomide in multiple myeloma in the clinical setting. AB - Background Health records can be used to measure medicine use and health outcomes. The public subsidy of lenalidomide in Australia was based on two phase III trials showing improved survival. Objective To use hospital pharmacy information management systems to determine survival outcomes for lenalidomide as a second line treatment in relapsed or refractory multiple myeloma (RRMM) patients. Setting Five public hospitals in Queensland, Australia. Method We extracted data on medicine use and survival for RRMM patients planned to start lenalidomide from pharmacy management and pathology databases. Descriptive statistical analyses (Kaplan-Meier curves) were used to calculate overall survival. Main outcome measure Overall survival. Results There were 136 patients who received at least one lenalidomide dose and 2234 cycles were ordered. The median age was 69 years and 54% were male. Two lenalidomide containing protocols were considered: 90% of patients had lenalidomide plus dexamethasone; 18% had lenalidomide plus dexamethasone with cyclophosphamide. The median starting lenalidomide dose was 20 mg (range 4.3-25 mg) on days 1-21 of a 28-day cycle. Median time on treatment 9.4 months (range 0.5-71.7 months). Median overall survival was 45.4 months (range 12.0-70.5 months). Conclusion The median survival in our study compared favourably to clinical trials. Patients and clinicians can be reassured that outcomes in this clinical setting are as good as those observed in trials. PMID- 28573441 TI - Sociodemographic and Clinical Determinants of Quality of Life of Patients with Non-small Cell Lung Cancer. AB - Non-small cell lung cancer (NSCLC) is a serious health problem. Identifying factors affecting quality of life (QoL) may help modify risk factors and improve survival. The study included 180 patients treated for NSCLC in the Lower Silesian Center of Lung Diseases between January and December 2015. QoL was assessed with QLQ-C30 and QLQ-LC13 scales. General physical functioning was measured with the ECOG Performance Status scale. The clinical and sociodemographic data were retrieved from medical records. The influence of clinical and sociodemographic factors on QoL was examined. NSCLC reduced the global QoL (47.1 +/- 23.4) and emotional functioning (57.8 +/- 28.8); cognitive functioning was affected in least (76.0 +/- 21.0). The patients reported fatigue (42.2 +/- 26.2), sleep problems (42.0 +/- 30.8), cough (49.8 +/- 24.0), and taking analgesics (50.3 +/- 37.1) as the most limiting factors. The worsening of a health condition expressed by the length of malignant disease; the presence of comorbidities, metastases, the cluster of symptoms, worse spirometric indices, and living alone had a negative influence on QoL. In conclusion, patients with NSCLC experience reduced QoL and emotional functioning. Proper treatment of comorbidities and symptom management may improve QoL in these patients. PMID- 28573442 TI - Intensity of Anxiety and Depression in Patients with Lung Cancer in Relation to Quality of Life. AB - Psychological factors, such as the anxiety and depression, which often occur in patients with lung cancer might negatively influence their quality of life. The aim of the study was to evaluate the effect of anxiety and depression in lung cancer patients on quality of life. The study included 180 lung patients of the mean age of 62.7 +/- 9.7 years. The following scales were employed in the study: Quality of Life Questionnaire QLQ-C30 and LC13 scale, and Hospital Anxiety and Depression scale (HADS). The overall score of quality of life measured by QLQ-C30 was 47.1 +/- 23.4 points on a hundred-point scale. Anxiety was diagnosed in 67 patients (37.2%) and depression in 75 patients (41.7%) by HADS. Quality of life was significantly worse in case of anxiety and depression (p < 0.05), which negatively influenced both functional and symptom intensity scales measured with QLQ-C30 and QLQ-LC13. We conclude that early identification of anxiety and depression may help in therapeutic decision-making and may be a useful predictive factor in lung cancer patients. PMID- 28573443 TI - Indoor Exposure to Volatile Organic Compounds in Children: Health Risk Assessment in the Context of Physiological Development. AB - Indoor air quality is strongly affected by the contamination of ambient air and that related to building and finishing materials and to human activity. Poor ventilation of closed spaces facilitates retention of greater quantity of pollutants. Infants and children are at particular risk of exposure to indoor air pollutants as they undergo rapid physiological and biochemical changes and demonstrate activity patterns unlike those in adults. Health risk assessment in children should be carried out with regard to children-specific factors, since these factors may constitute a source of errors. In this article we weigh up two different: Scenario 1 in which risk assessment was carried out in five age-groups (0-1, 2-3, 4-6, 7-11, and 12-16 years of age) and Scenario 2 encompassing only two age-groups (0-6 and 7-16 years of age). The findings indicate that data on carcinogenic and non-carcinogenic effects obtained by applying the second scenario were overestimated or averaged; either giving much reduced information that may lead to a false judgment on actual risk. This kind of fallacy is avoided when applying the age stratification into a greater number of groups for the health risk assessment in children. PMID- 28573444 TI - Lung Lesions During Fever of Unknown Origin. AB - Fever of unknown origin (FUO) remains one of the most difficult diagnostic challenges. The causes of FUO can be various diseases located in different organs. The aim of the study was to determine the prevalence and nature of pulmonary lesions during FUO. One hundred and sixty one patients with FUO participated in this prospective study. We performed a detailed comprehensive history, physical examination, and a wide spectrum of tests. The most common causes of FUO were infections (39%), autoimmune conditions (28%), and neoplasms (17%). Lung lesions were found in 30% of patients. In this group 35% were infections, 30% autoimmune diseases, and 4% cancer. Among patients with respiratory infections, there were cases of tuberculosis, atypical pneumonia, lung abscess, and bronchiectases. Autoimmune pulmonary lesions were observed during vasculitis and systemic lupus. The causes of FUO in the group of patients with lung lesions were also pulmonary embolism, sarcoidosis, and pulmonary fibrosis. Chest CT played an important role in the diagnosis of the causes of FUO with pulmonary manifestations. Pulmonary lesions are a common cause of FUO. Most FUO with pulmonary lesions are recognized during infections and autoimmune diseases. An important part of diagnosing FUO is a detailed evaluation of the respiratory system. PMID- 28573445 TI - Cardiac Arrhythmias in Patients with Exacerbation of COPD. AB - Supraventricular and ventricular arrhythmias are common among patients with chronic obstructive pulmonary disease (COPD). Multiple factors can contribute to the development of arrhythmias in patients with exacerbation of the disease, including: respiratory or heart failure, hypertension, coronary disease and also medications. In the present study we seek to determine the prevalence of cardiac arrhythmias and risk factors among patients with exacerbation of COPD. The study was a retrospective evaluation of 2753 24-h Holter recordings of patients hospitalized in 2004-2016. Exacerbation of COPD was diagnosed in 152 patients and the prevalence of arrhythmias in this group of patients was 97%. The commonest arrhythmia was ventricular premature beats (VPB) - 88.8%, followed by supraventricular premature beats (SPB) - 56.5%. Permanent atrial fibrillation accounted for 30.3% and paroxysmal atrial fibrillation (PAF) for 12.5%. Supraventricular tachycardia (SVT) was noted in 34.2% patients and ventricular tachycardia in 25.6%. Respiratory failure increased the risk of SPB, while heart failure increased the risk of VPB. Treatment with theophylline was associated with a higher proportion of PAF and SVT. In conclusion, COPD exacerbation is associated with a high prevalence of cardiac arrhythmias. COPD treatment and comorbidities increase the risk of arrhythmias. PMID- 28573446 TI - Echocardiographic Assessment in Patients with Granulomatosis with Polyangiitis. AB - Granulomatosis with polyangiitis (GPA) is one of the most common forms of systemic vasculitis, which usually involves the upper and lower respiratory tract, but it may affect also multiple organs. The aim of the study was an echocardiographic evaluation of cardiac involvement in GPA patients during remission. Eighty eight patients with GPA were evaluated in the study. The control group consisted of 40 age and sex-matched patients without a previous history of cardiovascular disease. We found that there were no differences between GPA and control groups regarding left atrial enlargement and interventricular septal hypertrophy. In one GPA patient, all heart chambers were enlarged. Left ventricle systolic function was decreased (LVEF <= 50%) in eight patients with GPA, and left ventricle wall motion abnormalities were observed in 12 patients. Left ventricle relaxation dysfunction, mitral valve and tricuspid valve regurgitation were observed with the same frequency in both GPA and control groups. Aortic regurgitation was the single abnormality that occurred significantly more often in the GPA group than in controls (28% vs. 7.5%; p = 0.03). Pericardial effusion was observed in three GPA patients and in none from the control group. We conclude that the most common echocardiographic manifestation in GPA patients in remission was aortic valve regurgitation. However, cardiac involvement in such patients is rather rare and in the majority of cases clinically insignificant. PMID- 28573447 TI - Identifying long-term survivors among metastatic breast cancer patients undergoing primary tumor surgery. AB - PURPOSE: The prognostic role of primary tumor surgery in women with metastatic breast cancer at diagnosis is contentious. A subset of patients who will benefit from aggressive local treatment is needed to be identified. Using a nationwide database, we developed and validated a predictive model to identify long-term survivors among patients who had undergone primary tumor surgery. METHODS: A total of 150,043 patients were enrolled in the Korean Breast Cancer Registry between January 1990 and December 2014. Of these, 2332 (1.6%) presented with distant metastasis at diagnosis. Using Cox proportional hazards regression, we developed and validated a model that predicts survival in patients who undergo primary tumor surgery, based on the clinicopathological features of the primary tumor. RESULTS: A total of 2232 metastatic breast cancer patients were reviewed. Of these, 1541 (69.0%) patients had undergone primary tumor surgery. The 3-year survival rate was 62.6% in this subgroup. Among these patients, advanced T-stage, high-grade tumor, lymphovascular invasion, negative estrogen receptor status, high Ki-67 expression, and abnormal CA 15-3 and alkaline phosphatase levels were associated with poor survival. A prediction model was developed based on these factors, which successfully identified patients with remarkable survival (score 0 3, 3-year survival rate 87.3%). The clinical significance of the model was also validated with an independent dataset. CONCLUSIONS: We have developed a predictive model to identify long-term survivors among women who undergo primary tumor surgery. This model will provide guidance to patients and physicians when considering surgery as a treatment modality for metastatic breast cancer. PMID- 28573448 TI - Breast cancer oral anti-cancer medication adherence: a systematic review of psychosocial motivators and barriers. AB - PURPOSE: In the past decade, there has been an increase in the development and use of oral anti-cancer medications (OAMs), especially for breast cancer-the most prevalent cancer in women. However, adherence rates for OAMs are often suboptimal, leading to lower survival rate, increased risk of recurrence, and higher healthcare costs. Our goal was to identify potentially modifiable psychosocial facilitators and barriers that may be targeted to increase OAM adherence for breast cancer patients. METHODS: We systematically searched PubMed for studies published in the U.S. by June 15, 2016 that addressed the following: (1) OAMs for breast cancer; (2) medication adherence; and (3) at least one psychosocial aspect of adherence. RESULTS: Of the 1752 papers screened, 21 articles were included and analyzed. The most commonly reported motivators for adherence are patient-provider relationships (n = 11 studied, 82% reported significant association) and positive views and beliefs of medication (n = 9 studied, 89% reported significant association). We also identified consistent evidence of the impact of depression and emotions, perception of illness, concern of side effects, self-efficacy in medication management and decision making, knowledge of medication, and social support on OAM adherence. CONCLUSIONS: Compared to traditional demographic, system, and clinical-related factors that have been well documented in the literature but are not easily changed, these cognitive, psychological, and interpersonal factors are more amendable via intervention and therefore could generate greater benefit in improving patient compliance and health outcomes. As OAMs shift treatment administration responsibility onto patients, continuous provider communication and education on illness and regimen are the keys to supporting patients' medication behavior. PMID- 28573449 TI - Medium Optimization for Improved Production of Dihydrolipohyl Dehydrogenase from Bacillus sphaericus PAD-91 in Escherichia coli. AB - Dihydrolipohyl dehydrogenase (DLD) is a FAD-dependent enzyme that catalyzes the reversible oxidation of dihydrolipoamide. Herein, we report medium optimization for the production of a recombinant DLD with NADH-dependent diaphorase activity from a strain of Bacillus sphaericus PAD-91. The DLD gene that consisted of 1413 bp was expressed in Escherichia coli BL21 (DE3), and its enzymatic properties were studied. The composition of production medium was optimized using one variable-at-a-time method followed by response surface methodology (RSM). B. sphaericus DLD catalyzed the reduction of lipoamide by NAD+ and exhibited diaphorase activity. The molecular weight of enzyme was about 50 kDa and determined to be a monomeric protein. Recombinant diaphorase showed its optimal activity at temperature of 30 degrees C and pH 8.5. K m and V max values with NADH were estimated to be 0.025 mM and 275.8 U/mL, respectively. Recombinant enzyme was optimally produced in fermentation medium containing 10 g/L sucrose, 25 g/L yeast extract, 5 g/L NaCl and 0.25 g/L MgSO4. At these concentrations, the actual diaphorase activity was calculated to be 345.0 +/- 4.1 U/mL. By scaling up fermentation from flask to bioreactor, enzyme activity was increased to 486.3 +/- 5.5 U/mL. Briefly, a DLD with diaphorase activity from a newly isolated B. sphaericus PAD-91 was characterized and the production of recombinant enzyme was optimized using RSM technique. PMID- 28573450 TI - Cloning, Production and Characterization of a Glycoside Hydrolase Family 7 Enzyme from the Gut Microbiota of the Termite Coptotermes curvignathus. AB - Coptotermes curvignathus is a termite that, owing to its ability to digest living trees, serves as a gold mine for robust industrial enzymes. This unique characteristic reflects the presence of very efficient hydrolytic enzyme systems including cellulases. Transcriptomic analyses of the gut of C. curvignathus revealed that carbohydrate-active enzymes (CAZy) were encoded by 3254 transcripts and that included 69 transcripts encoding glycoside hydrolase family 7 (GHF7) enzymes. Since GHF7 enzymes are useful to the biomass conversion industry, a gene encoding for a GHF7 enzyme (Gh1254) was synthesized, sub-cloned and expressed in the methylotrophic yeast Pichia pastoris. Expressed GH1254 had an apparent molecular mass of 42 kDa, but purification was hampered by its low expression levels in shaken flasks. To obtain more of the enzyme, GH1254 was produced in a bioreactor that resulted in a fourfold increase in crude enzyme levels. The purified enzyme was active towards soluble synthetic substrates such as 4 methylumbelliferyl-beta-D-cellobioside, 4-nitrophenyl-beta-D-cellobioside and 4 nitrophenyl-beta-D-lactoside but was non-hydrolytic towards Avicel or carboxymethyl cellulose. GH1254 catalyzed optimally at 35 degrees C and maintained 70% of its activity at 25 degrees C. This enzyme is thus potentially useful in food industries employing low-temperature conditions. PMID- 28573451 TI - [Quality of life in patients with vestibular schwannoma]. AB - BACKGROUND: Vestibular schwannoma (VS) is a disease which might affect health related quality of life (HR-QOL) in a negative manner. For many years, only generic quality of life instruments such as SF-36 were available to measure HR QOL. However, some years ago, the Penn Acoustic Neuroma Quality Of Life (PANQOL) tool, a disease-specific instrument, was developed and validated. It is expected that the application of this instrument will be able to better assess relevant aspects of the HR-QOL of VS patients in the future. A validated German version of the instrument does not exist yet. The disease-specific symptoms most frequently named by patients are headache and dizziness. RESULTS AND DISCUSSION: The available literature shows that the therapeutic approaches affect HR-QOL differently. In particular, radiation therapy of small and medium-sized tumors has no pronounced negative effects on HR-QOL. However, restrictions after surgery become similar to those after radiotherapy over the course of several years. For large VS with a diameter >3 cm, no guiding data on this aspect are currently available. To clarify the outstanding issues, future prospective studies with long-term follow-up of 10 years and more are desirable. PMID- 28573452 TI - Sow efficiency and early piglet mortality in two local pig breeds on smallholder farms in northern Vietnam-a longitudinal study. AB - In the recent past, pig performance and sow management on smallholder farms in the Southeast Asian Massif have been extensively researched. But the objective of this study was to investigate the lifetime efficiency of breeding sows of the local Vietnamese Ban (n = 89) and Mong Cai (n = 131) breeds in a production system context. The impact of sow longevity was considered in particular. In addition, predictors of early pre-weaning mortality in piglets were investigated. In total, nine villages of Son La province, situated in the uplands of north western Vietnam, were selected, differing in access to markets, production intensity, and pig management level. Data was collected over a period of 10 years through an on-farm performance testing system. It was shown that sows of both breeds that achieved five or more parities farrowed and weaned significantly more piglets per life year compared to sows with only one or two parities. The conception rate (Spearman's rho = 0.374) and age at first farrowing (Spearman's rho = -0.424) were significantly correlated with the number of weaned piglets per life year of stayable (>=4 parities) Mong Cai sows. The risk of early pre-weaning death of piglets born to Mong Cai sows was affected more by litter size, while for piglets born to Ban sows, the risk was influenced more by the season. Therefore, interventions to improve the sow lifetime efficiency and piglet survivability must match the sow breed and management level. PMID- 28573453 TI - Diurnal thermoregulatory responses in pregnant Yankasa ewes to the dry season in a tropical Savannah. AB - The study investigated concomitant effect of gestation and high ambient temperature under a tropical environment on rectal temperature (RT), respiratory rate (RR) and heart rate (HR) responses in Yankasa ewes. Twenty Yankasa ewes, consisting of ten pregnant and ten non-pregnant ewes, were used for the study. Ewes were synchronised and bred, such that each gestation phase coincided with different periods of the dry-seasons, early-gestation (cold/harmattan), mid gestation (peak hot-dry) and late-gestation (late hot-dry). The RT, RR and HR were recorded thrice, 2 days apart at middle of each gestation period at 06:00, 14:00 and 18:00 h, concurrently with dry- (DBT) and wet-bulb temperatures of the experimental pen. The DBT was positively correlated with RT, RR during the different gestation stages. The RT significantly (P < 0.001) increased with the hour of day, regardless of the physiological status of the ewes, with peak at 14:00 h. Values of RT and RR were higher (P < 0.05) in pregnant than non-pregnant ewes at mid- and late-gestation, respectively. Mean RT was lower (P < 0.001) at 06:00 h in pregnant than non-pregnant ewes at early-gestation (cold-dry). The HR was (P < 0.05) higher in pregnant than non-pregnant ewes during the different gestation phases. In conclusion, ambient temperature and gestation concomitantly modulate diurnal thermoregulatory responses of the ewes to hot-dry season. Adequate measures should be adopted to mitigate adverse impact of prolonged high RR on the dam and the foetus during the peak of ambient temperature prevailing in the tropical Savannah environment. PMID- 28573454 TI - Quality of life among adolescents living in residential youth care: do domain specific self-esteem and psychopathology contribute? AB - PURPOSE: Many adolescents living in residential youth care (RYC) institutions perceive their quality of life (QoL) to be low. Enhancing QoL is thus important, but little is known about the potential contributors to their QoL. Early interpersonal trauma and subsequent removal from home and repeated relocations to new placements are expected to affect mental health and self-esteem. We therefore investigated if domain-specific self-esteem contributed to QoL among adolescents living in RYC institutions over and beyond their levels of psychopathology. METHODS: All youth in Norwegian RYC institutions between the ages 12-23 years were invited to participate. Of a total of 98 RYC institutions, 86 participated, and 400 of 601 eligible youths were examined. The participants' primary contact completed the Child Behavior Checklist to assess psychopathology. The adolescents completed a revised version of the Self-Perception Profile for Adolescents and the questionnaire for measuring health-related quality of life in children and adolescents (KINDL-R). RESULTS: After adjusting for psychopathology, age, and gender, self-esteem domains uniquely explained 42% of the variance in Qol, where social acceptance (beta = 0.57) and physical appearance (beta = 0.25) domains significantly predicted concurrent QoL. CONCLUSIONS: The self-esteem domains, social acceptance and physical appearance, add substantially to the explained variance in QoL among adolescents living in RYC institutions, over and beyond the levels of psychopathology. These self-esteem domains may be targets of intervention to improve QoL, in addition to treating their psychopathology. PMID- 28573456 TI - Backbone NMR assignments of tryparedoxin, the central protein in the hydroperoxide detoxification cascade of African trypanosomes, in the oxidized and reduced form. AB - Tryparedoxin (Tpx) is a pivotal protein in the redox-metabolism of trypanosomatid parasites. Tpx has previously been identified as a potential target for drug development in the fight against human African sleeping sickness caused by Trypanosoma brucei. Tpx belongs to the thioredoxin superfamily and acts as an oxidoreductase in the parasite's cytoplasm. It contains a WCPPC active site motif, which enables the protein to undergo thiol-disulfide exchange. To promote future protein-drug interaction analyses, we report the 1H, 13C and 15N backbone chemical shift assignments for both the oxidized and reduced states of Tpx. The redox state of the protein has a significant impact on the chemical shifts of the residues at the active site of the protein, especially on the two redox active site cysteines. The NMR assignments presented here will be a prerequisite for investigating drug binding to Tpx in molecular detail and to drive further drug optimization. PMID- 28573457 TI - Oxidative damage of mitochondrial respiratory chain in different organs of a rat model of diet-induced obesity. AB - PURPOSE: Mitochondrial dysfunction plays an important role in the development of obesity and obesity-associated metabolic diseases. METHODS: In this study, we dynamically observed the characteristics of mitochondrial damage in a rat model of diet-induced obesity (DIO). From the 2nd to the 10th week, animals were killed every 2 weeks and the heart, liver, kidney, and testicular tissues were harvested. Mitochondria were isolated and the activities of respiratory chain complexes I, II, III, and IV as well as the 8-Hydroxy-2-deoxy Guanosine content were determined. Reactive oxygen species and malondialdehyde were measured. RESULTS: Mitochondrial damages were observed in the heart and liver of DIO and DR rats, and the damages occurred later in DR group than that in DIO group. The mitochondrial membrane potential of heart and liver decreased in DIO and DR groups. The activity of the heart mitochondria complexes I, III, and IV (composing NADH oxidative respiratory) was higher in the early stage of DIO and lower in the end of week 10. The higher activity of the liver complexes I, III, and IV was found until the end of week 10 in DIO and DR groups, accompanied with enhanced oxidative stress. Besides, mitochondrial DNA damages were observed in all tissues. CONCLUSION: In DIO rats, the heart mitochondrial dysfunction occurred first and the liver presented the strongest compensatory ability against oxidative stress. PMID- 28573455 TI - Toxicology of silica nanoparticles: an update. AB - Large-scale production and use of amorphous silica nanoparticles (SiNPs) have increased the risk of human exposure to SiNPs, while their health effects remain unclear. In this review, scientific papers from 2010 to 2016 were systematically selected and sorted based on in vitro and in vivo studies: to provide an update on SiNPs toxicity and to address the knowledge gaps indicated in the review of Napierska (Part Fibre Toxicol 7:39, 2010). Toxicity of SiNPs in vitro is size, dose, and cell type dependent. SiNPs synthesized by wet route exhibited noticeably different biological effects compared to thermal route-based SiNPs. Amorphous SiNPs (particularly colloidal and stober) induced toxicity via mechanisms similar to crystalline silica. In vivo, route of administration and physico-chemical properties of SiNPs influences the toxicokinetics. Adverse effects were mainly observed in acutely exposed animals, while no significant signs of toxicity were noted in chronically dosed animals. The correlation between in vitro and in vivo toxicity remains less well established mainly due to improper-unrealistic-dosing both in vitro and in vivo. In conclusion, notwithstanding the multiple studies published in recent years, unambiguous linking of physico-chemical properties of SiNPs types to toxicity, bioavailability, or human health effects is not yet possible. PMID- 28573458 TI - An in vivo whole-plant experimental system for the analysis of gene expression in extraradical mycorrhizal mycelium. AB - Arbuscular mycorrhizal fungi (AMF) establish beneficial mutualistic symbioses with land plants, receiving carbon in exchange for mineral nutrients absorbed by the extraradical mycelium (ERM). With the aim of obtaining in vivo produced ERM for gene expression analyses, a whole-plant bi-dimensional experimental system was devised and tested with three host plants and three fungal symbionts. In such a system, Funneliformis mosseae in symbiosis with Cichorium intybus var. foliosum, Lactuca sativa, and Medicago sativa produced ERM whose lengths ranged from 9.8 +/- 0.8 to 20.8 +/- 1.2 m per plant. Since ERM produced in symbiosis with C. intybus showed the highest values for the different structural parameters assessed, this host was used to test the whole-plant system with F. mosseae, Rhizoglomus irregulare, and Funneliformis coronatus. The whole-plant system yielded 1-7 mg of ERM fresh biomass per plant per harvest, and continued producing new ERM for 6 months. Variable amounts of high-quality and intact total RNA, ranging from 15 to 65 MUg RNA/mg ERM fresh weight, were extracted from the ERM of the three AMF isolates. Ammonium transporter gene expression was successfully determined in the cDNAs obtained from ERM of the three fungal symbionts by RT-qPCR using gene-specific primers designed on available (R. irregulare) and new (F. mosseae and F. coronatus) ammonium transporter gene sequences. The whole-plant experimental system represents a useful research tool for large production and easy collection of ERM for morphological, physiological, and biochemical analyses, suitable for a wide variety of AMF species, for a virtually limitless range of host plants and for studies involving diverse symbiotic interactions. PMID- 28573459 TI - Cytoskeleton-Associated Risk Modifiers Involved in Early and Rapid Progression of Sporadic Creutzfeldt-Jakob Disease. AB - A high priority in the prion field is to identify pre-symptomatic events and associated profile of molecular changes. In this study, we demonstrate the pre symptomatic dysregulation of cytoskeleton assembly and its associated cofilin-1 pathway in strain and brain region-specific manners in MM1 and VV2 subtype specific Creutzfeldt-Jakob disease at clinical and pre-clinical stage. At physiological level, PrPC interaction with cofilin-1 and phosphorylated form of cofilin (p-cofilin(Ser3)) was investigated in primary cultures of mouse cortex neurons (PCNs) of PrPC wild-type and knockout mice (PrP-/-). Short-interfering RNA downregulation of active form of cofilin-1 resulted in the redistribution/downregulation of PrPC, increase of activated form of microglia, accumulation of dense form of F-actin, and upregulation of p-cofilin(Ser3). This upregulated p-cofilin(Ser3) showed redistribution of expression predominantly in the activated form of microglia in PCNs. At pathological level, cofilin-1 expression was significantly altered in cortex and cerebellum in both humans and mice at pre-clinical stage and at early symptomatic clinical stage of the disease. Further, to better understand the possible mechanism of dysregulation of cofilin-1, we also demonstrated alterations in upstream regulators; LIM kinase isoform 1 (LIMK1), slingshot phosphatase isoform 1 (SSH1), RhoA-associated kinase (Rock2), and amyloid precursor protein (APP) in sporadic Creutzfeldt-Jakob disease MM1 mice and in human MM1 and VV2 frontal cortex and cerebellum samples. In conclusion, our findings demonstrated for the first time a key pre-clinical response of cofilin-1 and the associated pathway in prion disease. PMID- 28573461 TI - Automatic frequency and phase alignment of in vivo J-difference-edited MR spectra by frequency domain correlation. AB - OBJECTIVE: J-difference editing is often used to select resonances of compounds with coupled spins in 1H-MR spectra. Accurate phase and frequency alignment prior to subtracting J-difference-edited MR spectra is important to avoid artefactual contributions to the edited resonance. MATERIALS AND METHODS: In-vivo J difference-edited MR spectra were aligned by maximizing the normalized scalar product between two spectra (i.e., the correlation over a spectral region). The performance of our correlation method was compared with alignment by spectral registration and by alignment of the highest point in two spectra. The correlation method was tested at different SNR levels and for a broad range of phase and frequency shifts. RESULTS: In-vivo application of the proposed correlation method showed reduced subtraction errors and increased fit reliability in difference spectra as compared with conventional peak alignment. The correlation method and the spectral registration method generally performed equally well. However, better alignment using the correlation method was obtained for spectra with a low SNR (down to ~2) and for relatively large frequency shifts. CONCLUSION: Our correlation method for simultaneously phase and frequency alignment is able to correct both small and large phase and frequency drifts and also performs well at low SNR levels. PMID- 28573462 TI - Mast cell activator compound 48/40 is not an effective adjuvant for UV-attenuated Toxoplasma gondii vaccine. AB - Toxoplasma gondii (T. gondii, Tg) is a globally distributed parasitic protozoan causing different forms of toxoplasmosis in humans. Mast cells (MCs) play a role during T. gondii infection. Several studies suggest that MC activator compound 48/80 (C48/80) may be an effective vaccine adjuvant resulting in a potent and protective antigen-specific immune response against bacteria or virus infections. The present study was performed to determine whether C48/80 had adjuvant activity for ultraviolet (UV)-attenuated T. gondii vaccine to induce protective immune responses against T. gondii in mouse model. Kunming mice were divided into the following groups: naive mice, naive mice administrated with C48/80 intraperitoneal (i.p.) injection, mice infected by i.p. injection of 104 T. gondii RH strain alone (Tg group), mice infected with 104 RH tachyzoites plus C48/80 administration (Tg + C48/80), mice immunized with UV-Tg alone, and mice immunized with UV-Tg plus C48/80 administration (UV-Tg + C48/80). All the vaccinated mice were challenged with 104 tachyzoites of T. gondii RH strain at the same time as the primary infection. The survival rates, liver histopathologies, liver parasite burdens, and mRNA expression levels of Th1 and Th2 cytokines in the livers and spleens detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) were compared among the aforementioned groups after primary infection or challenge infection. The results showed that, compared to the Tg group or Tg + C48/80 group, the UV-Tg + Tg group and UV-Tg + C48/80 + Tg group had significantly prolonged survival time, lower liver histopathological scores, decreased liver parasite burdens, and increased levels of Th1 and Th2 cytokines in the livers and spleens. There was no significant difference of survival time between the UV-Tg + Tg group and the UV Tg + C48/80 + Tg group; however, the UV-Tg + C48/80 + Tg group showed higher parasite burden, more severe liver histopathology, and decreased IL-4 level compared to the UV-Tg + Tg group. These results indicate that C48/80 had no adjuvant activity for the immunization induced by UV-attenuated T. gondii vaccine. PMID- 28573464 TI - Imaging features of mammary-type myofibroblastoma of soft tissue: a case series with literature review. AB - Mammary-type myofibroblastoma (MTM) is a rare, benign neoplasm that is histologically identical to myofibroblastoma of the breast, but occurring in an extramammary site. The masses have been reported in superficial and deep soft tissue sites and visceral locations with the inguinal area and lower extremities are the most common. Most previous reports of MTMs have concentrated on clinical and pathological findings, with very limited information regarding imaging characteristics. Here, we describe three cases of MTM diagnosed at our institution, with a focus on imaging findings. We compare our findings with previously reported cases. Although MTM is rare, radiologists should be aware of this benign diagnosis as imaging characteristics can mimic those of liposarcomas and atypical lipomatous tumor/well-differentiated liposarcoma. Unlike those tumor types, MTM virtually never recurs post-resection, even when there are positive margins. Biopsy is necessary for proper diagnosis and recommended as an initial step to avoid overly aggressive treatment. PMID- 28573465 TI - From short-range repulsion to Hele-Shaw problem in a model of tumor growth. AB - We investigate the large time behavior of an agent based model describing tumor growth. The microscopic model combines short-range repulsion and cell division. As the number of cells increases exponentially in time, the microscopic model is challenging in terms of computational time. To overcome this problem, we aim at deriving the associated macroscopic dynamics leading here to a porous media type equation. As we are interested in the long time behavior of the dynamics, the macroscopic equation obtained through usual derivation method fails at providing the correct qualitative behavior (e.g. stationary states differ from the microscopic dynamics). We propose a modified version of the macroscopic equation introducing a density threshold for the repulsion. We numerically validate the new formulation by comparing the solutions of the micro- and macro- dynamics. Moreover, we study the asymptotic behavior of the dynamics as the repulsion between cells becomes singular (leading to non-overlapping constraints in the microscopic model). We manage to show formally that such asymptotic limit leads to a Hele-Shaw type problem for the macroscopic dynamics. We compare the micro- and macro- dynamics in this asymptotic limit using explicit solutions of the Hele Shaw problem (e.g. radially symmetric configuration). The numerical simulations reveal an excellent agreement between the two descriptions, validating the formal derivation of the macroscopic model. The macroscopic model derived in this paper therefore enables to overcome the problem of large computational time raised by the microscopic model, but stays closely linked to the microscopic dynamics. PMID- 28573460 TI - Brain GLP-1/IGF-1 Signaling and Autophagy Mediate Exendin-4 Protection Against Apoptosis in Type 2 Diabetic Rats. AB - Type 2 diabetes (T2D) is a modern socioeconomic burden, mostly due to its long term complications affecting nearly all tissues. One of them is the brain, whose dysfunctional intracellular quality control mechanisms (namely autophagy) may upregulate apoptosis, leading to cognitive dysfunction and Alzheimer disease (AD). Since impaired brain insulin signaling may constitute the crosslink between T2D and AD, its restoration may be potentially therapeutic herein. Accordingly, the insulinotropic anti-T2D drugs from glucagon-like peptide-1 (GLP-1) mimetics, namely, exendin-4 (Ex-4), could be a promising therapy. In line with this, we hypothesized that peripherally administered Ex-4 rescues brain intracellular signaling pathways, promoting autophagy and ultimately protecting against chronic T2D-induced apoptosis. Thus, we aimed to explore the effects of chronic, continuous, subcutaneous (s.c.) exposure to Ex-4 in brain cortical GLP 1/insulin/insulin-like growth factor-1 (IGF-1) signaling, and in autophagic and cell death mechanisms in middle-aged (8 months old), male T2D Goto-Kakizaki (GK) rats. We used brain cortical homogenates obtained from middle-aged (8 months old) male Wistar (control) and T2D GK rats. Ex-4 was continuously administered for 28 days, via s.c. implanted micro-osmotic pumps (5 MUg/kg/day; infusion rate 2.5 MUL/h). Peripheral characterization of the animal models was given by the standard biochemical analyses of blood or plasma, the intraperitoneal glucose tolerance test, and the heart rate. GLP-1, insulin, and IGF-1, their downstream signaling and autophagic markers were evaluated by specific ELISA kits and Western blotting. Caspase-like activities and other apoptotic markers were given by colorimetric methods and Western blotting. Chronic Ex-4 treatment attenuated peripheral features of T2D in GK rats, including hyperglycemia and insulin resistance. Furthermore, s.c. Ex-4 enhanced their brain cortical GLP-1 and IGF-1 levels, and subsequent signaling pathways. Specifically, Ex-4 stimulated protein kinase A (PKA) and phosphoinositide 3-kinase (PI3K)/Akt signaling, increasing cGMP and AMPK levels, and decreasing GSK3beta and JNK activation in T2D rat brains. Moreover, Ex-4 regulated several markers for autophagy in GK rat brains (as mTOR, PI3K class III, LC3 II, Atg7, p62, LAMP-1, and Parkin), ultimately protecting against apoptosis (by decreasing several caspase-like activities and mitochondrial cytochrome c, and increasing Bcl2 levels upon T2D). Altogether, this study demonstrates that peripheral Ex-4 administration may constitute a promising therapy against the chronic complications of T2D affecting the brain. PMID- 28573463 TI - Detection and identification of Leishmania spp.: application of two hsp70-based PCR-RFLP protocols to clinical samples from the New World. AB - Leishmaniasis is highly prevalent in New World countries, where several methods are available for detection and identification of Leishmania spp. Two hsp70-based PCR protocols (PCR-N and PCR-F) and their corresponding restriction fragment length polymorphisms (RFLP) were applied for detection and identification of Leishmania spp. in clinical samples recruited in Colombia, Guatemala, and Honduras. A total of 93 cases were studied. The samples were classified into positive or suspected of leishmaniasis according to parasitological criteria. Molecular amplification of two different hsp70 gene fragments and further RFLP analysis for identification of Leishmania species was done. The detection in parasitologically positive samples was higher using PCR-N than PCR-F. In the total of samples studied, the main species identified were Leishmania panamensis, Leishmania braziliensis, and Leishmania infantum (chagasi). Although RFLP-N was more efficient for the identification, RFLP-F is necessary for discrimination between L. panamensis and Leishmania guyanesis, of great importance in Colombia. Unexpectedly, one sample from this country revealed an RFLP pattern corresponding to Leishmania naiffi. Both molecular variants are applicable for the study of clinical samples originated in Colombia, Honduras, and Guatemala. Choosing the better tool for each setting depends on the species circulating. More studies are needed to confirm the presence of L. naiffi in Colombian territory. PMID- 28573466 TI - Wolbachia spreading dynamics in mosquitoes with imperfect maternal transmission. AB - Mosquitoes are primary vectors of life-threatening diseases such as dengue, malaria, and Zika. A new control method involves releasing mosquitoes carrying bacterium Wolbachia into the natural areas to infect wild mosquitoes and block disease transmission. In this work, we use differential equations to describe Wolbachia spreading dynamics, focusing on the poorly understood effect of imperfect maternal transmission. We establish two useful identities and employ them to prove that the system exhibits monomorphic, bistable, and polymorphic dynamics, and give sufficient and necessary conditions for each case. The results suggest that the largest maternal transmission leakage rate supporting Wolbachia spreading does not necessarily increase with the fitness of infected mosquitoes. The bistable dynamics is defined by the existence of two stable equilibria, whose basins of attraction are divided by the separatrix of a saddle point. By exploring the analytical property of the separatrix with some sharp estimates, we find that Wolbachia in a completely infected population could be wiped out ultimately if the initial population size is small. Surprisingly, when the infection shortens the lifespan of infected females that would impede Wolbachia spreading, such a reversion phenomenon does not occur. PMID- 28573467 TI - Branching process approach for epidemics in dynamic partnership network. AB - We study the spread of sexually transmitted infections (STIs) and other infectious diseases on a dynamic network by using a branching process approach. The nodes in the network represent the sexually active individuals, while connections represent sexual partnerships. This network is dynamic as partnerships are formed and broken over time and individuals enter and leave the sexually active population due to demography. We assume that individuals enter the sexually active network with a random number of partners, chosen according to a suitable distribution and that the maximal number of partners that an individual can have at a time is finite. We discuss two different branching process approximations for the initial stages of an outbreak of the STI. In the first approximation we ignore some dependencies between infected individuals. We compute the offspring mean of this approximating branching process and discuss its relation to the basic reproduction number [Formula: see text]. The second branching process approximation is asymptotically exact, but only defined if individuals can have at most one partner at a time. For this model we compute the probability of a minor outbreak of the epidemic starting with one or few initial cases. We illustrate complications caused by dependencies in the epidemic model by showing that if individuals have at most one partner at a time, the probabilities of extinction of the two approximating branching processes are different. This implies that ignoring dependencies in the epidemic model leads to a wrong prediction of the probability of a large outbreak. Finally, we analyse the first branching process approximation if the number of partners an individual can have at a given time is unbounded. In this model we show that the branching process approximation is asymptomatically exact as the population size goes to infinity. PMID- 28573469 TI - Geographic epidemiology of hepatocellular carcinoma, viral hepatitis, and socioeconomic position in New York City. AB - PURPOSE: Liver cancer (hepatocellular carcinoma (HCC)) incidence and mortality rates are increasing in the United States. New York City (NYC) has a high burden of liver cancer risk factors, including hepatitis C (HCV) and hepatitis B (HBV) infection, which disproportionately affect persons of low socioeconomic position. Identifying neighborhoods with HCC disparities is essential to effectively define targeted cancer control strategies. METHODS: New York State Cancer Registry data from 1 January 2001 through 31 December 2012 were matched with NYC HCV and HBV surveillance data. HCC data were aggregated to NYC Zip Code Tabulation Areas (ZCTAs). Moran's I cluster analysis, Poisson regression, and geographically weighted Poisson regression were used to identify hotspots in HCC incidence and to examine the spatial associations with viral hepatitis rates, poverty, and uninsured status. RESULTS: Among NYC residents, 8,827 HCC cases were diagnosed during 2001-2012. Significant clustering was detected in the HCC rates (Moran's I = 0.25) with the strongest clustering found in HCC patients with comorbid HCV infection (Moran's I = 0.47). Poverty and uninsured status were associated (p < 0.05) with increased rates of HCC patients with HBV or HCV infection. Neighborhoods with high rates of HCC without viral hepatitis infection had lower rates of poverty and uninsured status. CONCLUSIONS: The geographic variation in HCC highlights the need for neighborhood-targeted interventions to address risk factors and barriers to care. The clusters of HCC by viral hepatitis status may serve as a basis for healthcare policymakers and practitioners to prioritize neighborhoods for cancer screening and control efforts. PMID- 28573468 TI - Time dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response. AB - Pembrolizumab is a monoclonal antibody that targets the programmed death-1 receptor to induce immune-mediated clearance (CL) of tumor cells. Originally approved by the US Food and Drug Administration in 2014 for treating patients with unresectable or metastatic melanoma, pembrolizumab is now also used to treat patients with non-small-cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, and urothelial cancer. This paper describes the recently identified feature of pembrolizumab pharmacokinetics, the time-dependent or time-varying CL. Overall results indicate that CL decreases over the treatment period of a typical patient in a pattern well described by a sigmoidal function of time with three parameters: the maximum proportion change in CL from baseline (approximately Imax or exactly eImax - 1), the time to reach Imax/2 (TI50), and a Hill coefficient. Best overall response per response evaluation criteria in solid tumor category was found to be associated with the magnitude of Imax. PMID- 28573470 TI - External quality assessment for molecular typing of Salmonella 2013-2015: performance of the European national public health reference laboratories. AB - We report the results of three consecutive External Quality Assessments (EQAs) for molecular subtyping of Salmonella to assess the performance of the European national public health reference laboratories (NPHRLs). The EQA included the molecular typing methods used for European enhanced surveillance of human Salmonella infections: pulsed field gel electrophoresis (PFGE), including gel analysis by the use of the software BioNumerics, and 5-locus multiple locus variable number of tandem repeat analysis (MLVA) for serovar Typhimurium. The participation in the PFGE laboratory part was higher (27/35) than in the gel analysis (19/35) and MLVA (15/35), suggestive of the need for capacity building in methods requiring specialized equipment (MLVA) or software (gel analysis). The majority (25/27) of the participating NPHRLs produced inter-laboratory comparable PFGE gel(s). Two laboratories continued to produce low-quality gels and should have additional technical assistance in the future. In particular, two gel quality evaluation parameters, measuring "image acquisition and running conditions" and "bands", were identified to cause gel quality problems throughout the EQAs. Despite the high number of laboratories participating in the PFGE laboratory part, the participation in gel analysis was low, although increasing. In the MLVA part, the NPHRLs correctly assigned 96% (405/420) allelic profiles according to the nomenclature. In conclusion, the EQAs identified critical parameters for unsuccessful performance and helped to offer assistance to those laboratories that needed it most. The assessments supported the development of quality in molecular typing and promoted the harmonization of subtyping methods used for EU/EEA-wide surveillance of human Salmonella infections. PMID- 28573471 TI - Emergence of Clostridium difficile tcdC variant 078 in Marseille, France. AB - The purpose of this investigation was to evaluate the epidemiology of hypervirulent Clostridium difficile ribotypes from January 2013 to February 2017 in the Marseille area of southern France. By using the Xpert Clostridium difficile Epi polymerase chain reaction (PCR) assay and sequencing the tcdC gene, we characterised C. difficile isolates from symptomatic patients diagnosed with C. difficile infection (CDI) in Marseille university hospitals. We first tested retrospectively 278 C. difficile samples isolated from January 2013 to December 2014 and observed a high prevalence of isolates with tcdC mutations and deletions previously described in both hypervirulent ribotypes RT027 and RT078 (16.4% and 10.7%, respectively). We highlighted the co-circulation of these two hypervirulent C. difficile tcdC variants (tV) with distinct epidemiological characteristics. While an RT027 outbreak occurred mainly as healthcare-associated infection in the elderly, CDI caused by tV078 occurred mainly in a younger population as community-associated infection. From January 2016, a systematic survey of these two hypervirulent C. difficile ribotypes revealed the emergence of CDI caused by tV078, currently being more prevalent than RT027 in the Marseille area. The present study is the first report of the emergence of CDI caused by tV078 in southern France. We showed the simultaneous circulation and sequential spread of hypervirulent ribotypes, such as RT027 and tV078. This emphasises the need for an efficient surveillance system for CDI with ribotyping and an optimised management of CDI caused by hypervirulent strains. PMID- 28573473 TI - Synergistic roles of the E2 glycoprotein and 3' untranslated region in the increased genomic stability of chimeric classical swine fever virus with attenuated phenotypes. AB - The E2 glycoprotein and 3' untranslated region (UTR) of classical swine fever virus (CSFV) are virulence determinants. To investigate the synergistic roles of E2 and 3'UTR for pathogenicity and genomic stability, a series of chimeric CSFVs were constructed by replacing the E2 gene and/or 3'UTR of virulent CSFV strain Shimen with the corresponding sequence of the lapinized 'Chinese' strain (C strain) using a reverse genetic approach. The in vitro growth characterization and in vivo pathogenicity of the chimeric CSFVs were investigated. Our results demonstrated that the E2 glycoprotein mediates virus cell-to-cell spread and viral particle release and that the 3'UTR regulates viral RNA replication. The CSFV E2 and 3'UTR synergistically modulate infectious virus production, viral genomic stability in vitro, and attenuation in swine. This work contributes to our understanding of the structure and function of the CSFV genome and virus pathogenicity and will be useful for the development of a novel CSF vaccine. PMID- 28573472 TI - New nucleic acid testing devices to diagnose infectious diseases in resource limited settings. AB - Point-of-care diagnosis based on nucleic acid testing aims to incorporate all the analytical steps, from sample preparation to nucleic acid amplification and detection, in a single device. This device needs to provide a low-cost, robust, sensitive, specific, and easily readable analysis. Microfluidics has great potential for handling small volumes of fluids on a single platform. Microfluidic technology has recently been applied to paper, which is already used in low-cost lateral flow tests. Nucleic acid extraction from a biological specimen usually requires cell filtration and lysis on specific membranes, while affinity matrices, such as chitosan or polydiacetylene, are well suited to concentrating nucleic acids for subsequent amplification. Access to electricity is often difficult in resource-limited areas, so the amplification step needs to be equipment-free. Consequently, the reaction has to be isothermal to alleviate the need for a thermocycler. LAMP, NASBA, HDA, and RPA are examples of the technologies available. Nucleic acid detection techniques are currently based on fluorescence, colorimetry, or chemiluminescence. For point-of-care diagnostics, the results should be readable with the naked eye. Nowadays, interpretation and communication of results to health professionals could rely on a smartphone, used as a telemedicine device. The major challenge of creating an "all-in-one" diagnostic test involves the design of an optimal solution and a sequence for each analytical step, as well as combining the execution of all these steps on a single device. This review provides an overview of available materials and technologies which seem to be adapted to point-of-care nucleic acid-based diagnosis, in low-resource areas. PMID- 28573474 TI - Identification and Management of Eating Disorders in Integrated Primary Care: Recommendations for Psychologists in Integrated Care Settings. AB - Eating disorders are associated with deleterious health consequences, increased risk of mortality, and psychosocial impairment. Although individuals with eating disorders are likely to seek treatment in general medical settings such as primary care (PC), these conditions are often under-detected by PC providers. However, psychologists in integrated PC settings are likely to see patients with eating disorders because of the mental health comorbidities associated with these conditions. Further, due to their training in identifying risk factors associated with eating disorders (i.e., comorbid mental health and medical disorders) and opportunities for collaboration with PC providers, psychologists are well positioned to improve the detection and management of eating disorders in PC. This paper provides a brief overview of eating disorders and practical guidance for psychologists working in integrated PC settings to facilitate the identification and management of these conditions. PMID- 28573475 TI - Patient-reported symptoms during radiotherapy : Clinically relevant symptom burden in patients treated with palliative and curative intent. AB - BACKGROUND: The benefits of patient-reported symptom assessment combined with integrated palliative care are well documented. This study assessed the symptom burden of palliative and curative-intent radiation oncology patients. PATIENTS AND METHODS: Prior to first consultation and at the end of RT, all adult cancer patients planned to receive fractionated percutaneous radiotherapy (RT) were asked to answer the Edmonton Symptom Assessment Scale (ESAS; nine symptoms from 0 = no symptoms to 10 = worst possible symptoms). Mean values were used for curative vs. palliative and pre-post comparisons, and the clinical relevance was evaluated (symptom values >= 4). RESULTS: Of 163 participating patients, 151 patients (90.9%) completed both surveys (116 curative and 35 palliative patients). Before beginning RT, 88.6% of palliative and 72.3% of curative patients showed at least one clinically relevant symptom. Curative patients most frequently named decreased general wellbeing (38.6%), followed by tiredness (35.0%), anxiety (32.4%), depression (30.0%), pain (26.3%), lack of appetite (23.5%), dyspnea (17.8%), drowsiness (8.0%) and nausea (6.1%). Palliative patients most frequently named decreased general wellbeing (62.8%), followed by pain (62.8%), tiredness (60.0%), lack of appetite (40.0%), anxiety (38.0%), depression (33.3%), dyspnea (28.5%), drowsiness (25.7%) and nausea (14.2%). At the end of RT, the proportion of curative and palliative patients with a clinically relevant symptom had increased significantly to 79.8 and 91.4%, respectively; whereas the proportion of patients reporting clinically relevant pain had decreased significantly (42.8 vs. 62.8%, respectively). Palliative patients had significantly increased tiredness. Curative patients reported significant increases in pain, tiredness, nausea, drowsiness, lack of appetite and restrictions in general wellbeing. CONCLUSION: Assessment of patient-reported symptoms was successfully realized in radiation oncology routine. Overall, both groups showed a high symptom burden. The results prove the need of systematic symptom assessment and programs for early integrated supportive and palliative care in radiation oncology. PMID- 28573477 TI - Vulnerability of Forests in India: A National Scale Assessment. AB - Forests are subjected to stress from climatic and non-climatic sources. In this study, we have reported the results of inherent, as well as climate change driven vulnerability assessments for Indian forests. To assess inherent vulnerability of forests under current climate, we have used four indicators, namely biological richness, disturbance index, canopy cover, and slope. The assessment is presented as spatial profile of inherent vulnerability in low, medium, high and very high vulnerability classes. Fourty percent forest grid points in India show high or very high inherent vulnerability. Plantation forests show higher inherent vulnerability than natural forests. We assess the climate change driven vulnerability by combining the results of inherent vulnerability assessment with the climate change impact projections simulated by the Integrated Biosphere Simulator dynamic global vegetation model. While 46% forest grid points show high, very high, or extremely high vulnerability under future climate in the short term (2030s) under both representative concentration pathways 4.5 and 8.5, such grid points are 49 and 54%, respectively, in the long term (2080s). Generally, forests in the higher rainfall zones show lower vulnerability as compared to drier forests under future climate. Minimizing anthropogenic disturbance and conserving biodiversity can potentially reduce forest vulnerability under climate change. For disturbed forests and plantations, adaptive management aimed at forest restoration is necessary to build long-term resilience. PMID- 28573476 TI - Single vs. multiple fraction regimens for palliative radiotherapy treatment of multiple myeloma : A prospective randomised study. AB - PURPOSE: To compare the impact of a single fraction (8 Gy * 1 fraction) and multifraction (3 Gy * 10 fractions) radiotherapy regimens on pain relief, recalcification and the quality of life (QoL) in patients with bone destructions due to multiple myeloma (MM). PATIENTS AND METHODS: In all, 101 patients were included in a randomised prospective clinical trial: 58 patients were included in the control arm (3 Gy * 10 fractions) and 43 patients into the experimental arm (8 Gy * 1 fraction). The response rate was defined according to the International Consensus on Palliative Radiotherapy criteria. Recalcification was evaluated with radiographs. QoL questionnaires were completed before and 4 weeks after treatment. RESULTS: Pain relief was obtained in 81/101 patients (80.2%): complete response in 56 (69%) and partial in 25 patients (30.9%). No significant differences were observed in analgesic response between the groups. Significant factors for pain relief were female gender, age under 65, IgG MM type, presence of recalcification at the irradiated site. Recalcification was found in 32/101 patients (33.7%): complete in 17 (53.2%) and partial in 15 (46.2%). No significant differences were observed in recalcification between the groups. Significant factors for recalcification were Karnofsky index >= 60%, haemoglobin level <= 80 g/dl, MM stage II and analgesic response at the irradiated site. The QoL after radiotherapy was improved in the control group. CONCLUSION: The same analgesic and recalcification response was observed using two different radiotherapy regimens. Higher doses should be used to achieve a better QoL. PMID- 28573479 TI - Aspirin and the Primary Prevention of Cardiovascular Diseases: An Approach Based on Individualized, Integrated Estimation of Risk. AB - While the use of aspirin in the secondary prevention of cardiovascular (CVD) is well established, aspirin in primary prevention is not systematically recommended because the absolute CV event reduction is similar to the absolute excess in major bleedings. Recently, emerging evidence suggests the possibility that the assumption of aspirin, may also be effective in the prevention of cancer. By adding to the CV prevention benefits the potential beneficial effect of aspirin in reducing the incidence of mortality and cancer could tip the balance between risks and benefits of aspirin therapy in the primary prevention in favour of the latter and broaden the indication for treatment with in populations at average risk. While prospective and randomized study are currently investigating the effect of aspirin in prevention of both cancer and CVD, clinical efforts at the individual level to promote the use of aspirin in global (or total) primary prevention could be already based on a balanced evaluation of the benefit/risk ratio. PMID- 28573478 TI - Polycyclic Aromatic Hydrocarbons: A Critical Review of Environmental Occurrence and Bioremediation. AB - The degree of polycyclic aromatic hydrocarbon contamination of environmental matrices has increased over the last several years due to increase in industrial activities. Interest has surrounded the occurrence and distribution of polycyclic aromatic hydrocarbons for many decades because they pose a serious threat to the health of humans and ecosystems. The importance of the need for sustainable abatement strategies to alleviate contamination therefore cannot be overemphasised, as daily human activities continue to create pollution from polycyclic aromatic hydrocarbons and impact the natural environment. Globally, attempts have been made to design treatment schemes for the remediation and restoration of contaminated sites. Several techniques and technologies have been proposed and tested over time, the majority of which have significant limitations. This has necessitated research into environmentally friendly and cost-effective clean-up techniques. Bioremediation is an appealing option that has been extensively researched and adopted as it has been proven to be relatively cost-effective, environmentally friendly and is publicly accepted. In this review, the physicochemical properties of some priority polycyclic aromatic hydrocarbons, as well as the pathways and mechanisms through which they enter the soil, river systems, drinking water, groundwater and food are succinctly examined. Their effects on human health, other living organisms, the aquatic ecosystem, as well as soil microbiota are also elucidated. The persistence and bioavailability of polycyclic aromatic hydrocarbons are discussed as well, as they are important factors that influence the rate, efficiency and overall success of remediation. Bioremediation (aerobic and anaerobic), use of biosurfactants and bioreactors, as well as the roles of biofilms in the biological treatment of polycyclic aromatic hydrocarbons are also explored. PMID- 28573480 TI - Relationship of miRNA-146a to primary Sjogren's syndrome and to systemic lupus erythematosus: a meta-analysis. AB - Sjogren's syndrome (SjS) and systemic lupus erythematosus (SLE) are common systemic autoimmune diseases, which impact not only patient health but also their quality of life. miRNA-146a is a microRNA that participates in the pathophysiology of SjS and SLE. In this investigation, we conducted a meta analysis to determine the relationship of miR-146a to primary SjS (PSS) and to SLE. The following databases were interrogated; Pubmed, Cochrane Central Register of Controlled Trials, WANFANG, Chinese National Knowledge Infrastructure, and WEIPU. Standard mean difference with 95% confidence intervals (CI) were used to study the relationship between miRNA-146a expression and thee diseases by random effects model. A total of six studies, with 158 cases and 124 controls were included for the meta-analysis. The meta-analysis shows that miRNA-146a expression is associated with the risk of PSS (MD = 6.32, p = 0.005). No relationship between miR-146a expression and SLE was identified (MD = -0.86, p = 0.26). SLE subgroup analysis (peripheral blood mononuclear cells and serum) confirmed this result. The risk for PSS is related to miR-146a expression, while miRNA-146a expression is not related to SLE. As such, miRNA-146a may serve as a novel biomarker for the diagnosis of PSS, but not SLE. PMID- 28573481 TI - Copper pyrithione, a booster biocide, induces abnormal muscle and notochord architecture in zebrafish embryogenesis. AB - The metal pyrithiones, principally zinc (ZnPT) and copper (CuPT), are replacing tributyltin (TBT) as antifouling agents. Zebrafish embryos were exposed within the first hour after fertilization to 12 and 64 ug/L of CuPT for 24 h. Morphological abnormalities in notochord and muscle architecture were observed at 96 h post fertilization (hpf). TEM revealed abnormal electron dense deposits in the notochord sheath and muscle fiber degeneration in animals treated with 12 ug/L of CuPT. Embryos that were exposed to 64 ug/L of CuPT displayed severe muscle fiber degeneration including abnormal A and I band patterning and altered z disk arrangement. Abnormalities in the notochord sheath, swelling of the mitochondria and numerous lipid whorls were also noted. Total antioxidant capacity was significantly decreased in embryos exposed to 12 and 64 ug/L of CuPT. Acridine orange staining revealed an increase in apoptosis particularly in the brain, eye, heart and tail regions of both treatment groups. Apoptosis was confirmed with an increase in caspase 3/7 activity in both treatment groups. Severe alternations in primary motor neuron axon extensions, slow tonic muscle fibers and fast twitch fibers were observed in CuPT treated embryos. There was a significant upregulation in sonic hedgehog and myod1 expression at 24 hpf in the 12 ug/L treatment group. Exposed zebrafish embryos showed ultra-structural hallmarks of peroxidative injury and cell death via apoptosis. These changes question the use of copper pyrithione as an antifouling agent. PMID- 28573482 TI - Glycomyces xinjiangensis sp. nov., a novel actinomycete isolated from a hypersaline habitat. AB - A novel actinomycete strain, designated XHU 5301T, was isolated from a hypersaline habitat, China. The strain was aerobic, Gram-stain positive and the optimum NaCl concentration for growth was 7-9% (w/v). Phylogenetic analysis based on an almost-complete 16S rRNA gene sequence of strain XHU 5301T showed that the organism was most closely related to Glycomyces halotolerans TRM 40137T (96.0%). The whole-cell sugar pattern consisted of glucose and galactose. The predominant menaquinone was MK-10(H4), MK-10(H2), and MK-9(H4). The major fatty acids were anteiso-C15: 0, iso-C15: 0, iso-C16: 0, and methyl-C19: 0. The polar lipids consist of diphosphatidylglycerol, phosphatidylglycerol, and one unknown phospholipid. The G+C content of the genomic DNA was 72.5 mol %. The novel species Glycomyces xinjiangensis sp. nov. was proposed, with strain XHU 5301T (=CCTCC AA 2016043T =KCTC 39689T) as the type strain of Glycomyces xinjiangensis. PMID- 28573483 TI - The added value of combined visual and semi-quantitative assessment for 123I-FP CIT SPECT and reply to Ueda et al. PMID- 28573484 TI - Camptocormia as presenting in lower motor neuron disease with TARDBP mutation: case report. PMID- 28573485 TI - A lateral flow colloidal gold-based immunoassay for rapid detection of miroestrol in samples of White Kwao Krua, a phytoestrogen-rich plant. AB - White Kwao Krua (WKK)-derived products have been used worldwide as dietary supplements to relieve climacteric symptoms in menopausal women. Miroestrol is a unique chromene found in WKK tuberous roots that corresponds to the estrogenic activity of WKK. However, miroestrol naturally accumulates at low levels in WKK samples, which are difficult to detect. The development of a rapid and sensitive assay to detect miroestrol in numerous products derived from this plant would be a practical and useful method to guarantee the quality of raw materials. To allow rapid and easy qualitative detection of miroestrol, a lateral flow immunoassay (LFIA) using a colloidal gold-labeled monoclonal antibody (mAb) against miroestrol was developed. The qualitative LFIA was based on the competition of free miroestrol in the sample and immobilized miroestrol-conjugated proteins on the strip for a limited number of antibodies in the detection reagent. Anti miroestrol mAb was colored by colloidal gold labels and used as the detection reagent in LFIA. Anti-mouse immunoglobulin G was used to indicate the functioning of the LFIA system. The detection limit of the LFIA was 0.156 MUg of miroestrol. The LFIA was applied to determine the miroestrol content in WKK samples and products. The result was compared with the validated enzyme-linked immunosorbent assay (ELISA) and demonstrated a correlative outcome. This study shows that the developed LFIA is practical and suitable for detecting small amounts of miroestrol in WKK samples. This qualitative assay is more rapid in screening miroestrol in WKK samples (within 10 min) than conventional methods (ELISA and HPLC). PMID- 28573487 TI - Low vascularization of the nephrogenic zone of the fetal kidney suggests a major role for hypoxia in human nephrogenesis. AB - CD31 reactivity is generally utilized as a marker of endothelial cells. CD31 immunoreactivity in the developing human kidney revealed that fetal glomerular capillary endothelial cells change their immunohistochemical phenotype during maturation. The aim of this study was to analyze CD31 reactivity in the fetal human kidney in the different stages of intrauterine development: We observed different distribution of CD31-reactive vascular progenitors in the different areas of the developing kidney. In particular, the nephrogenic zone and the renal capsule were characterized by a scarcity of CD31-reactive cells at all gestational ages. These data suggest the hypothesis that nephrogenesis does not need high oxygen levels and confirms a major role of hypoxia in nephrogenesis. PMID- 28573486 TI - Feasibility of tongue strength measurements during (chemo)radiotherapy in head and neck cancer patients. AB - PURPOSE: The aim of this study was to investigate the feasibility of tongue strength measures (TSMs) and the influence of bulb location, sex, and self perceived pain and mucositis in head and neck cancer (HNC) patients during chemoradiotherapy (CRT). METHODS: Twenty-six newly diagnosed HNC patients treated with CRT performed anterior and posterior maximal isometric tongue pressures by means of the Iowa Oral Performance Instrument (IOPI). The Oral Mucositis Weekly Questionnaire (OMWQ) and a Visual Analogue Scale (VAS) for pain during swallowing were completed weekly from baseline to 1 week post CRT. RESULTS: Feasibility of TSMs during CRT declines significantly from 96 to 100% at baseline to 46% after 6 weeks of CRT. But post-hoc analyses reveal only significant differences in feasibility between baseline and measurements after 4 weeks of treatment. No effect of gender or bulb location was established, but feasibility is influenced by pain and mucositis. CONCLUSIONS: Feasibility of TSMs declines during CRT and is influenced by mucositis and pain. For the majority of subjects, TSMs were feasible within the first 4 weeks, which provides a window of scientific and clinical opportunities in this patient population. PMID- 28573488 TI - Peritoneal dialysis-related infections recommendations: 2016 update. What is new? AB - In 2016, the International Society of Peritoneal Dialysis (ISPD) published guidelines that focus on the importance of both prevention and treatment of peritonitis. For once more, the need for annual reporting of peritonitis rates and recording of peritonitis and exit-site infections, isolated microorganism and antimicrobial susceptibilities as a central component of a quality improvement program is highlighted. Data on new antibiotic regimens, techniques for microorganism isolation and peritoneal dialysis solutions are included. Training of both peritoneal dialysis nurses and patients seems to be crucial, while the modifiable risk factors for peritonitis seem to be of great interest. In this article, we record the changes in the last ISPD (2016) guidelines compared to the previous ones published in 2010. PMID- 28573489 TI - Ultrasonic evaluation of renal cortex arterial area enables differentiation between hypertensive and glomerulonephritis-related chronic kidney disease. AB - PURPOSE: Identifying the primary etiology of cardio-renal syndrome in a timely manner remains an ongoing challenge in nephrology. We hypothesized that hypertensive kidney damage can be distinguished from chronic glomerulonephritis at an early stage of chronic kidney disease (CKD) using ultrasound (US) Doppler sonography. METHODS: Fifty-six males (age 54 +/- 15, BMI 28.3 +/- 3.5 kg/m2) with hypertension and stable CKD at stages 2-4 [38 with essential hypertension (HT CKD); 18 with glomerulonephritis (GN-CKD)] were studied. Blood tests, UACR, echocardiography, ABPM, carotid IMT, and an ultrasound dynamic tissue perfusion measurement (DTPM) of the renal cortex were performed. RESULTS: HT-CKD patients had reduced proximal renal cortex perfusion as well as reduced total and proximal renal cortex arterial area. Proximal renal cortex arterial area <=0.149 cm2 identified hypertension-related CKD with a sensitivity of 71% and a specificity of 78% (AUC 0.753, p < 0.001). CONCLUSIONS: Evidence of diminished arterial vascularity or perfusion of renal proximal cortex, both derived from US Doppler, could be helpful in differentiating hypertensive nephropathy from glomerulonephritis-related CKD. PMID- 28573490 TI - Interactive association of serum uric acid and total bilirubin with renal dysfunction among community-dwelling subjects. AB - PURPOSE: Chronic kidney disease is a major public health concern. Serum uric acid (SUA) at high levels was oxidative stress agents, and total bilirubin (T-BiL) at mildly increased levels was potent antioxidants, but whether SUA and T-BiL produce an additive interaction for the risk of renal dysfunction remains unclear. METHODS: The subjects comprised 567 men aged 71 +/- 8 (mean +/- standard deviation) years and 853 women aged 70 +/- 8 years from a rural village. We examined the relationship between SUA and T-BiL, and renal function was evaluated by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease Study Group equation. RESULTS: Stepwise multiple regression analysis using eGFR as an objective variable, adjusted for risk factors as explanatory variables, showed that SUA (beta = -0.358, p < 0.001) as well as age (beta = -0.534, p < 0.001), drinking status (beta = 0.119, p < 0.001), and the presence of antihypertensive medication (beta = -0.058, p = 0.005) were significantly and independently associated with eGFR, but T-BiL was not associated with eGFR. While in the group with the highest tertile of SUA, T-BiL (beta = 0.081, p = 0.032) was significantly and independently associated with eGFR, and in the group with the lowest to middle tertile of SUA, T-BiL was not associated with eGFR. In addition, interaction between SUA and T-BiL (F = 8.512, p = 0.004) as well as age, drinking status, the presence of antihypertensive medication, SUA, and T-BiL was a significant and independent determinant for eGFR. CONCLUSIONS: Our data demonstrated that low T-BiL could be important as a potential risk factor for renal dysfunction in those with high SUA. PMID- 28573491 TI - P2X7 receptor large pore signaling in avian Muller glial cells. AB - ATP is a pleiotropic molecule that promotes extra- and intracellular signaling to regulate numerous functions. This nucleotide activates purine and pyrimidine receptors at the plasma membrane, categorized as ionotropic P2X or G-protein coupled receptor (GPCR) P2Y receptors. P2X are ligand-gated ion channel receptors, expressed in both retinal neurons and Muller cells leading to neuron glia communication, calcium waves and neurovascular coupling. However, how P2X pore is formed upon ATP activation and how signaling pathways regulates the complex is still a matter of controversy. Here we studied the properties of the P2X7 receptor (P2X7R) using electrophysiology, single cell Ca2+ imaging, and dye uptake assay in purified avian Muller glia in culture. Our data show that ATP (or benzoyl-benzoyl ATP, BzATP) evoked large inward currents in patch-clamp studies while addition of P2X7R antagonist such as brilliant Blue G (BBG), abolished these currents. Ruthenium red (RU-2), a general transient receptor potential (TRP) inhibitor, reduced currents induced by ATP. Our data also point to the involvement of mitogen activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), Ca2+-calmodulin kinase II (CAMKII), microtubules or protein kinase C (PKC) modulating ATP-induced ionic current in Muller cells. We show that ATP induced Ca2+ influx, partially inhibited by P2X7R antagonists (oxidized ATP or BBG), and totally inhibited by blockers of other pores such as transient receptor potential (TRPs) or connexin hemichannel. Additionally, MAPK, PKC, PI3K or CAMKII inhibitors also are involved in the modulation of intracellular calcium signaling. Finally, ATP induced 80-90% of dye uptake in Muller glia cells, while oxidized ATP (oATP), BBG or A740003 inhibited this effect. We conclude that large conductance channel and other P2XRs are not involved in the ATP-induced dye uptake, but signaling pathways such as MAPK, PI3-K, microtubules or PKC are involved in pore formation. PMID- 28573493 TI - Organophosphate Flame Retardants in House Dust from South China and Related Human Exposure Risks. AB - House dust associated with organic pollutants is not only a potential source of pollutants to the outdoor environment, but also a source to human exposure. The present study investigated the occurrence and concentrations of organophosphate flame retardants (OPFRs) in house dust collected from South China dwellings (n = 20). The results revealed a universal presence of most target OPFRs in house dust, with concentrations of SigmaOPFRs ranging from 2.06 to 19.95 MUg/g. The median concentration of SigmaOPFR (9.20 MUg/g) was one order of magnitude greater than that of polybrominated diphenyl ethers (0.80 MUg/g). The composition of OPFR chemicals in house dust was dominated by chlorinated OPFRs, such as tris(1,3 dichloro-2-propyl) phosphate (TDCPP) and tris(1-chloro-2-propyl) phosphate (TCPP). This compositional pattern was different from what has been reported in indoor dust from many other countries, where tris(2-butoxyethyl) phosphate (TBEP) was generally dominant. The daily intake of OPFRs by adults was estimated to be 1.6 and 4.2 ng/kg body weight/day under average and high exposure scenarios, respectively, and 31.7 and 127 ng/kg body weight/day for toddlers. PMID- 28573492 TI - Bactericidal Activity and Synergy Studies of Peptide AP-CECT7121 Against Multi resistant Bacteria Isolated from Human and Animal Soft Tissue Infections. AB - AP-CECT7121 is an antimicrobial peptide, produced by Enterococcus faecalis CECT7121, with bactericidal activity against Gram-positive bacteria. The aim of this study was to evaluate the bactericidal activity of AP-CECT7121, alone and with gentamicin, against multi-resistant bacteria isolated from human and animals with soft tissue infections. During the period 2014-2015, bacterial strains producing human and animal soft tissue infections were studied. Samples from patients attended at a general hospital and cattle from four dairies in the Province of Buenos Aires (Argentina) were included. Twenty-two methicillin resistant Staphylococcus aureus (11, human blood samples; 11, cow milk) and five vancomycin-resistant Ent. faecium strains isolated from four mastitic dairy cows were tested. AP-CECT7121 (12 mg/L) potency was assessed by time-kill curves alone or with sub-inhibitory concentrations of gentamicin. All staphylococcal strains were susceptible to gentamicin; enterococci did not show high-level gentamicin resistance. Colony counts were carried out at 0, 2, 4, 8, and 24 h of incubation. AP-CECT7121 showed bactericidal activity against all the enterococcal strains. In addition, AP-CECT7121 had a bactericidal effect on most staphylococci (16/22). Early AP-CECT7121/gentamicin synergy (4-8 h) for all staphylococci was detected. At 24 h, synergy (19/22) and indifference (3/22) were observed. Synergy with gentamicin was detected for staphylococci. AP-CECT7121 constitutes an attractive candidate for its use as a natural therapeutic tool for the treatment of infections produced by multi-resistant Staph. aureus and vancomycin-resistant Ent. faecium isolated from humans and animals. PMID- 28573494 TI - A novel TP53 germline inframe deletion identified in a Spanish series of Li fraumeni syndrome suspected families. AB - Li-Fraumeni syndrome (LFS) is an autosomal dominant, inherited tumor predisposition syndrome associated with heterozygous germline mutations in the TP53 gene. The molecular diagnosis of LFS is important to develop strategies for early detection and access to the genetic counseling. Our study evaluated germline TP53 mutations in Spanish families with a history suggestive of LFS. Germline TP53 alterations in 22 families with a history suggestive of LFS were evaluated by Sanger sequencing and multiplex ligation-dependent probe amplification. Loss of heterozygosity analysis and immunohistochemistry of the protein in the tumor were performed in order to evaluate the pathogenicity of a novel alteration detected. A total of seven TP53 mutations were detected, six point mutations (4 missense and 2 nonsense) and a novel inframe deletion. 93% of mutation carriers developed at least one malignancy (mainly breast cancer and sarcomas), with a mean age at diagnosis of the first tumor of 30.2 years. Two missense mutations acted as dominant-negative. The novel inframe mutation c.437_445del was located in the DNA-binding domain. This mutation segregated with cancer in the family, and both high expression of the protein and loss of the wild-type TP53 allele were detected in the tumor of the carrier. We have found a novel inframe deletion in TP53 that likely results in the loss of p53 function and acts in a non-dominant negative way, although further studies are necessary to clarify this issue. The identification of novel TP53 alterations is crucial for a personalized cancer-risk management of the Li-Fraumeni syndrome. PMID- 28573495 TI - RNF43 is mutated less frequently in Lynch Syndrome compared with sporadic microsatellite unstable colorectal cancers. AB - The WNT signaling pathway is commonly altered during colorectal cancer development. The E3 ubiquitin ligase, RNF43, negatively regulates the WNT signal through increased ubiquitination and subsequent degradation of the Frizzled receptor. RNF43 has recently been reported to harbor frequent truncating frameshift mutations in sporadic microsatellite unstable (MSI) colorectal cancers. This study assesses the relative frequency of RNF43 mutations in hereditary colorectal cancers arising in the setting of Lynch syndrome. The entire coding region of RNF43 was Sanger sequenced in 24 colorectal cancers from 23 patients who either (i) carried a germline mutation in one of the DNA mismatch repair genes (MLH1, MSH6, MSH2, PMS2), or (ii) showed immunohistochemical loss of expression of one or more of the DNA mismatch repair proteins, was BRAF wild type at V600E, were under 60 years of age at diagnosis, and demonstrated no promoter region methylation for MLH1 in tumor DNA. A validation cohort of 44 colorectal cancers from mismatch repair germline mutation carriers from the Australasian Colorectal Cancer Family Registry (ACCFR) were sequenced for the most common truncating mutation hotspots (X117 and X659). RNF43 mutations were found in 9 of 24 (37.5%) Lynch syndrome colorectal cancers. The majority of mutations were frameshift deletions in the G659 G7 repeat tract (29%); 2 cancers (2/24, 8%) from the one patient harbored frameshift mutations at codon R117 (C6 repeat tract) within exon 3. In the ACCFR validation cohort, RNF43 hotspot mutations were identified in 19/44 (43.2%) of samples, which was not significantly different to the initial series. The proportion of mutant RNF43 in Lynch syndrome related colorectal cancers is significantly lower than the previously reported mutation rate found in sporadic MSI colorectal cancers. These findings identify further genetic differences between sporadic and hereditary colorectal cancers. This may be because Lynch Syndrome cancers commonly arise in colorectal adenomas already bearing the APC mutation, whereas sporadic microsatellite unstable colorectal cancers arise from serrated polyps typically lacking APC mutation, decreasing the selection pressure on other WNT signaling related loci in Lynch syndrome. PMID- 28573496 TI - Patient and Caregiver Adjustment to Hematopoietic Stem Cell Transplantation: a Systematic Review of Dyad-Based Studies. AB - PURPOSE OF REVIEW: The aims of this study were to identify and systematically evaluate studies published from 2005-2017 that took a dyadic approach to assessing or intervening upon hematopoietic cell transplant (HCT) recipients and their informal caregivers. RECENT FINDINGS: Our search yielded 20 studies. Regarding sample demographic characteristics, most participants were Caucasian and most caregivers were related to the patient by marriage. Regarding design characteristics, 18 studies were quantitative and two were qualitative; five were cross-sectional, ten were longitudinal, one was experimental, and four were interventional. Most outcomes were psychosocial and the interventions were largely psycho-educational in nature. Large variation in quality of the studies emerged (six were rated as low quality, seven as adequate, and seven as high quality). Understudied populations include racial/ethnic minorities and same-sex couples. More work is needed to understand functioning during survivorship and impacts on patient medical outcomes, and to truly leverage the dyad to optimize individual- and relationship-level adjustment. PMID- 28573497 TI - Therapeutic Options for Aggressive T-Cell Lymphomas. AB - T-cell lymphomas (TCL) are a rare, heterogeneous group of non-Hodgkin lymphomas associated with very poor prognosis with standard cytotoxic chemotherapy. Epigenetic-based therapy, such as with histone deacetylase inhibitors, was initially discovered to be efficacious in TCL. In recent years, our understanding of the mechanisms driving T-cell lymphomagenesis has validated the use of epigenetic-based drugs and has also led to the development of novel agents with promising efficacy in pre-clinical and early clinical trials. These new treatments play upon the prominent existence of epigenetic and immune dysfunction present in T-cell lymphomas. With these advances, novel therapeutic regimens combining traditional chemotherapy as well as epigenetic and/or immunotherapy serve as promising future treatment options for TCL. In this review, we discuss the traditional methods of treatment for TCL as well as novel agents and combinations that will likely change the treatment paradigms resulting in better clinical outcomes. PMID- 28573500 TI - Black Hairy Tongue. PMID- 28573498 TI - Single freeze strategy with the second- generation cryballoon for atrial fibrillation: a multicenter international retrospective analysis in a large cohort of patients. AB - PURPOSE: The second-generation cryoballoon (CB-A, Arctic Front Advance, Medtronic, Minneapolis, MN, USA) has proven to be highly effective in achieving freedom from atrial fibrillation; nonetheless, the ideal number and duration of freezing cycles is still a matter of debate. We investigated the acute success, procedural complications, and clinical outcome of a single freeze strategy using the CB-A in a large, retrospective, international multicenter study. METHODS: Between January 2013 and September 2015, 818 consecutive patients (58 +/- 12 years, 68% males) with drug-resistant atrial fibrillation (AF) who underwent a CB A using a single freeze strategy were taken into consideration for our analysis. RESULTS: Paroxysmal AF was documented in 74.1% of the patients, while 25.9% presented with persistent AF. Additional freezes were needed in a mean 1.4 veins per patient. 0.2% of the patients experienced persistent PNP that was still documented at the last follow-up. After a median follow-up of 14 +/- 8 months, taking into consideration a blanking period (BP) of 3 months, 692 patients (84.6%) were free from arrhythmia recurrence. After a single procedure, AF recurrence during BP and persistent AF were identified as predictors of clinical recurrence after BP. CONCLUSIONS: Single freeze CB-A ablation is effective in treating drug-resistant AF and affords freedom from arrhythmia recurrences in 84.6% of patients during a 14-month follow-up. Persistent AF and recurrence during BP are predictors of arrhythmia recurrences. PMID- 28573499 TI - Effectiveness of Lipid-Lowering Statin Therapy in Patients With and Without Psoriasis. AB - BACKGROUND: Psoriasis is associated with dyslipidemia and metabolic syndrome, and has been linked to an increased cardiovascular risk. The aim of this study was to compare baseline characteristics and effects of statin therapy on lipid levels and cardiovascular outcomes in patients with and without psoriasis. METHODS: This post-hoc analysis assessed patients from one primary cardiovascular prevention statin trial (Collaborative AtoRvastatin Diabetes Study [CARDS]) and two secondary cardiovascular prevention statin trials (Treating to New Targets [TNT] and Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL]). Baseline characteristics, lipid changes from baseline, and cardiovascular event rates were analyzed. TNT and IDEAL data were pooled. RESULTS: Baseline characteristics and lipid profiles differed minimally in patients with and without psoriasis. In CARDS and TNT/IDEAL, similar apolipoprotein B, total cholesterol, and low-density lipoprotein cholesterol reductions occurred with statin therapy in patients with or without psoriasis. High-dose atorvastatin significantly reduced cardiovascular events vs. standard/low-dose statins in patients without psoriasis in TNT/IDEAL; similar numeric differences in event rates were observed in patients with psoriasis. CONCLUSIONS: In this post-hoc analysis, statins improved lipid levels and cardiovascular outcomes in patients with and without psoriasis, supporting statin use in patients with psoriasis. Trial registration (ClinicalTrials.gov) NCT00327418, registered 16 May, 2006; NCT00327691, registered 16 May, 2006; NCT00159835, registered 8 September, 2005. PMID- 28573501 TI - Capsule commentary on Vijn et al., Involving medical students in providing patient education for real patients: a scoping review. PMID- 28573502 TI - Re-positioning faculty development as knowledge mobilization for health professions education. AB - Faculty development as knowledge mobilization offers a particularly fruitful and novel avenue for exploring the research-practice interface in health professions education. We use this 'eye opener' to build off this assertion to envision faculty development as an enterprise that provides a formal, recognized space for the sharing of research and practical knowledge among health professions educators. Faculty development's knowledge mobilizing strategies and outcomes, which draw upon varied sources of knowledge, make it a potentially effective knowledge mobilization vehicle.First, we explain our choice of the term knowledge mobilization over translation, in an attempt to resist the false dichotomy of 'knowledge user' and 'knowledge creator'. Second, we leverage the documented strengths of faculty development against the documented critiques of knowledge mobilization in the hopes of avoiding some of the pitfalls that have befallen previous attempts at closing knowing-doing gaps.Through faculty development, faculty are indeed educated, in the traditional sense, to acquire new knowledge and skill, but they are also socialized to go on to form the systems and structures of their workplaces, as leaders and workers. Therefore, faculty development can not only mobilize knowledge, but also create knowledge mobilizers. Achieving this vision of faculty development as knowledge mobilization requires an acceptance of multiple sources of knowledge, including practice-based knowledge, and of multiple purposes for education and faculty development, including professional socialization. PMID- 28573504 TI - MicroRNA-30a functions as tumor suppressor and inhibits the proliferation and invasion of prostate cancer cells by down-regulation of SIX1. AB - Increasing reports have demonstrated that aberrant expression of microRNAs (miRNAs) is found in multiple human cancers. Many studies have shown that down regulated level of miR-30a is in a variety of cancers including prostate cancer (PCa). However, the precise mechanisms of miR-30a in PCa have not been well explored. In this study, we investigated the biological functions and molecular mechanism of miR-30a in PCa cell lines, discussing whether it could be a therapeutic biomarker of PCa in the future. We found that miR-30a is down regulated in PCa tissues and cell lines. Moreover, the low level of miR-30a was associated with increased expression of SIX1 in PCa tissues and cell lines. Up regulation of miR-30a significantly inhibited proliferation of PCa cells. In addition, invasion of PCa cells was suppressed by overexpression of miR-30a. However, down-regulation of miR-30a promoted cell growth and invasion of PCa cells. Bioinformatics analysis predicted that the SIX1 was a potential target gene of miR-30a. Next, luciferase reporter assay confirmed that miR-30a could directly target SIX1. Consistent with the effect of miR-30a, down-regulation of SIX1 by siRNA inhibited proliferation and invasion of PCa cells. Overexpression of SIX1 in PCa cells partially reversed the effect of miR-30a mimic. In conclusion, introduction of miR-30a dramatically inhibited proliferation and invasion of PCa cells by down-regulating SIX1 expression, and that down regulation of SIX1 was essential for inhibition of cell growth and invasion of PCa cells by overexpression of miR-30a. PMID- 28573503 TI - Endoplasmic Reticulum Stress, NRF2 Signalling and Cardiovascular Diseases in a Nutshell. AB - PURPOSE OF REVIEW: This short review is intended primarily to summarize the understanding of the interrelated roles of endoplasmic reticulum (ER) stress, oxidative stress and inflammation in cardiovascular diseases. RECENT FINDINGS: Insults interfering with ER function lead to the accumulation of unfolded and misfolded proteins in the ER. An excess of proteins folding in the ER is known as ER stress. This condition initiates the unfolded protein response (UPR). When the UPR fails to control the level of unfolded and misfolded proteins, ER-initiated apoptotic signalling is induced. Moreover, the role of the protective nuclear erythroid-related factor 2 (Nrf2)/antioxidant-related element (ARE) and the activation of the pro-inflammatory nuclear factor-kappa B (NF-kB) are analysed. Authors summarize evidence that oxidative stress, inflammation and ER stress are closely entwined phenomena. They are involved in the pathogenesis of different cardiovascular diseases. Current literature data are presented, focusing on three topics of related pathologies: atherosclerotic plaque, coronary artery disease and diabetes. This review will provide a basic platform for study and application to several other conditions in which oxidative stress, ER stress and inflammation are key features. Future studies in this area may identify the most promising molecules to be investigated as common targets for cardiovascular diseases. PMID- 28573505 TI - Comparative Efficacy of Ibrutinib Versus Obinutuzumab + Chlorambucil in First Line Treatment of Chronic Lymphocytic Leukemia: A Matching-Adjusted Indirect Comparison. AB - INTRODUCTION: Ibrutinib (ibr) monotherapy and the combination of obinutuzumab plus chlorambucil (obi) are approved for previously untreated chronic lymphocytic leukemia (CLL). No trials directly comparing their efficacy are available. Therefore a matching-adjusted indirect comparison (MAIC) was performed to provide insight into their relative efficacy in terms of progression-free survival (PFS) and overall survival (OS). MAIC attempts to adjust for between-trial differences in factors known or suspected to influence treatment effects, to minimize bias. METHODS: A MAIC within a Bayesian framework was conducted using individual patient data from the RESONATE-2 study of ibr versus chlorambucil and published data from the CLL11 study of obi versus chlorambucil. Both studies were conducted in patients ineligible for full-dose fludarabine-based therapy. After matching, the reweighted adjusted relative efficacy measure of ibr versus chlorambucil from RESONATE-2 [hazard ratio (HR), 95% credible interval (CrI)] was compared with that of obi versus chlorambucil from CLL11 for each endpoint, using a Bayesian indirect comparison. RESULTS: Our results suggest that in a population with similar average baseline characteristics to CLL11, ibr would improve PFS and OS outcomes compared to obi. Before matching, the HRs for ibr versus obi were 0.48 [CrI = 0.22-1.02, p(HR <1) = 97%], 0.85 [CrI = 0.44-1.63, p(HR <1) = 69%], and 0.40 [CrI = 0.10-1.54, p(HR <1) = 91%] for PFS by investigator assessment, PFS by independent review committee, and OS, respectively. After matching on all available characteristics the HRs decreased to 0.12 [CrI = 0.02-0.97, p(HR <1) = 98%], 0.24 [CrI = 0.04-1.35, p(HR <1) = 95%], and 0.21 [CrI = <0.01-8.89, p(HR <1) = 79%], respectively. There was a large variance around the treatment effect for OS due to the low number of deaths. CONCLUSION: Our analysis suggests that ibrutinib is highly likely to provide greater PFS benefit than obinutuzumab plus chlorambucil in older or less fit patients with previously untreated CLL. There is also an indication of improvement in OS, albeit with a higher uncertainty due to the low number of events. FUNDING: Janssen-Cilag Ltd. PMID- 28573506 TI - Estradiol Has Differential Effects on Acute Colonic Inflammation in the Presence and Absence of Estrogen Receptor beta Expression. AB - BACKGROUND: Inflammatory bowel disease (IBD) increases the risk of developing colon cancer. This risk is higher in men compared to women, implicating a role for female hormones in the protection against this disease. Studies from our laboratory demonstrated that estradiol (E2) protects against inflammation associated colon tumor formation when administered following chemical carcinogen and induction of chronic colitis. AIM: This study seeks to better understand the effect of E2 on acute colitis in the presence and absence of estrogen receptor beta (ERbeta). METHODS: Inflammation was induced by 2,4,6-trinitrobenzenesulfonic acid in wild-type (WT) and ERbeta knockout (ERbetaKO) mice implanted with a control or E2-containing pellet and killed 5 days later. Inflammation and injury were scored by a pathologist. Apoptosis and proliferation were assessed by immunohistochemistry. Cytokines were measured by multiplex analysis. RESULTS: E2 treatment reduced inflammation in the middle colon in WT mice and the distal colon in ERbetaKO mice compared to control mice. WT mice had reduced IL-6, IL-12, IL-17, GM-CSF, IFN-gamma, MCP-1, MIP-1alpha, and TNF-alpha, and ERbetaKO had reduced IL-6 and IFN-gamma expression in response to E2. Injury scores were lower in E2-treated ERbetaKO mice compared to control ERbetaKO mice. ERbetaKO mice had increased proliferation in the basal third of crypts in the distal colon and decreased apoptosis in the proximal colon. CONCLUSIONS: These data suggest that E2 has differential protective effects against acute colitis in the presence or absence of ERbeta and provide insight into how E2 may protect against IBD. PMID- 28573507 TI - High Center Volume Does Not Mitigate Risk Associated with Using High Donor Risk Organs in Liver Transplantation. AB - BACKGROUND: High-risk donor allografts increase access to liver transplant, but potentially reduce patient and graft survival. AIMS: It is unclear whether the risk associated with using marginal donor livers is mitigated by increasing center experience. METHODS: The United Network for Organ Sharing registry was queried for adult first-time liver transplant recipients between 2/2002 and 12/2015. High donor risk was defined as donor risk index >1.9, and 1-year patient and graft survival were compared according to donor risk index in small and large centers. Multivariable Cox regression estimated the hazard ratio (HR) associated with using high-risk donor organs, according to a continuous measure of annual center volume. RESULTS: The analysis included 51,770 patients. In 67 small and 67 large centers, high donor risk index predicted increased mortality (p = 0.001). In multivariable analysis, high-donor risk index allografts predicted greater mortality hazard at centers performing 20 liver transplants per year (HR 1.35; 95% CI 1.22, 1.49; p < 0.001) and, similarly, at centers performing 70 per year (HR 1.35; 95% CI 1.26, 1.43; p < 0.001). The interaction between high donor risk index and center volume was not statistically significant (p = 0.747), confirming that the risk associated with using marginal donor livers was comparable between smaller and larger centers. Results were consistent when examining graft loss. CONCLUSION: At both small and large centers, high-risk donor allografts were associated with reduced patient and graft survival after liver transplant. Specific strategies to mitigate the risk of liver transplant involving high-risk donors are needed, in addition to accumulation of center expertise. PMID- 28573508 TI - Crossover Subsets of CD4+ T Lymphocytes in the Intestinal Lamina Propria of Patients with Crohn's Disease and Ulcerative Colitis. AB - BACKGROUND: Hovhannisyan et al. first showed evidence of plasticity between Treg and Th17 in the inflamed intestine of Crohn's disease (CD) patients. Our previous report suggests that the inflammatory cytokine milieu generates IL-17+ Foxp3+ CD4+ T lymphocytes which is a crossover population converting Treg subset to Th17 in the peripheral blood of IBD patients. This is considered as an evidence of Treg/Th17 plasticity. AIM: The aim of this study was to characterize a variety of helper T cell crossover population, not limited to IL-17+ Foxp3+ CD4+ T lymphocytes, in the lamina propria (LP) of IBD patients. METHODS: Fresh colonoscopic biopsies were obtained from patients with CD (n = 50) and ulcerative colitis (UC, n = 32) and from healthy controls (HC, n = 25). LP mononuclear cells were assessed for intracellular cytokines and transcription factors such as IFNgamma, IL-13, IL-17, IL-22, T-bet, Gata-3, RORgammat, and Foxp3 using multicolor flow cytometry to detect subsets of LP CD4+ T lymphocytes. RESULTS: Patients with IBD demonstrated increased crossover populations in IL-17+ Foxp3+, T-bet+ Foxp3+, Gata3+ Foxp3+, RORgammat+ Foxp3+ populations compared to HC. There was an inverse correlation of Harvey-Bradshaw index with Gata3+ Foxp3+ population in CD patients, while IL-13+ Foxp3+ population was directly correlated with Mayo clinical scores in UC patients. Furthermore, total IL-22 expressing cells as well as Th22 and IL-22+ Th1 populations were decreased in UC compared to CD and HC. CONCLUSION: IBD patients exhibit the increased crossover populations in LP Treg cells toward Th2 and Th17 compared to HC. The prevalence of Treg/Th2 crossover populations is associated with clinical disease score of IBD. PMID- 28573509 TI - Temporal Changes in the Modes of Hepatitis C Virus Transmission in the USA and Northern China. AB - BACKGROUND: Predominant modes of hepatitis C virus (HCV) transmission vary between countries and over time. AIMS: To compare HCV transmission modes in the USA and northern China. METHODS: We conducted a prospective study enrolling two cohorts of chronic HCV patients in the USA, and in China at Beijing, and at Gu'an and Kuancheng counties in Hebei. Patients self-reported the most likely source and year of infection. RESULTS: A total of 1957 patients were studied (1000 USA; 957 China-428 Beijing, 387 Gu'an, 142 Kuancheng). The predominant infection sources were transfusion (23.0%) and injection drug use (IDU) (32.1%) in the USA and transfusion (64.5%) in northern China. Within China, transfusion was the most common source in Beijing (62.1%) and Gu'an (88.1%), and medical procedures (35.9%) and IDU (12.0%) in Kuancheng. Infection via transfusion decreased significantly in the USA (35.1-4.6%) and Beijing (84.2-14.3%) but remained frequent in Gu'an (90.5-72.5%) over time. Infection via IDU decreased from 32.4% in those >=61 years to 25.0% in those 41-50 years but increased to 46.5% in those <=40 years in US patients and decreased over time from 38.7 to 1.9% in Kuancheng. Infection via medical procedures increased over time in Beijing (7.0-33.3%) and remained frequent in Kuancheng (45.2-31.1%). CONCLUSIONS: There are major differences in presumed HCV infection source between the USA and northern China. Favorable as well as worrisome changes in the modes of HCV transmission in both countries were observed. PMID- 28573510 TI - B-cell lymphomas with discordance between pathological features and clinical behavior. AB - B-cell lymphomas encompass a large number of disease entities clinically ranging from indolent to aggressive. The defining pathological features usually predict clinical course, with small and large B-cell lymphomas correlating to low-grade vs high-grade features, but discordant situations may be encountered. Two sessions of the workshop of the XVIII meeting of the European Association for Haematopathology (EAHP) held in Basel in 2016 addressed this topic. One session illustrated various facets of "aggressiveness" in indolent lymphomas, either peculiar clinical manifestations, cytological variants, or unusual genetic features, as well as several examples of progression or transformation to a more aggressive disease. Another session exemplified large B-cell lymphomas with unexpected indolent behavior including cases arising in well-defined body compartments or in sanctuary sites. This paper describes the features of the cases presented in both groups, highlights the most salient points of discussion raised by the submitters and the panel, and summarizes current knowledge and recommendations relevant to diagnostic pathology practice. PMID- 28573511 TI - Early detection: the impact of genomics. AB - The field of genomics has shifted our view on disease development by providing insights in the molecular and functional processes encoded in the genome. In the case of cancer, many alterations in the DNA accumulate that enable tumor growth or even metastatic dissemination. Identification of molecular signatures that define different stages of progression towards cancer can enable early tumor detection. In this review, the impact of genomics will be addressed using early detection of colorectal cancer (CRC) as an example. Increased understanding of the adenoma-to-carcinoma progression has led to the discovery of several diagnostic biomarkers. This combined with technical advancements, has facilitated the development of molecular tests for non-invasive early CRC detection in stool and blood samples. Even though several tests have already made it to clinical practice, sensitivity and specificity for the detection of precancerous lesions still need improvement. Besides the diagnostic qualities, also the accuracy of the intermediate endpoint is an important issue on how the effectiveness of a novel test is perceived. Here, progression biomarkers may provide a more precise measure than the currently used morphologically based features. Similar developments in biomarker use for early detection have taken place in other cancer types. PMID- 28573512 TI - Prognostic impact of HER-2 Subclonal Amplification in breast cancer. AB - The presence of a limited number of cells with HER-2 amplification (Subclonal Amplification) in breast carcinomas is occasionally encountered, but its prognostic impact is poorly known. The purpose of this study is to evaluate the prognostic impact of HER-2 Subclonal Amplification in a retrospective series of breast cancers. Accordingly, 81 consecutive breast carcinomas showing HER-2 Subclonal Amplification were obtained from the histology files (case series). These cases were subdivided into two groups: (a) those cases in which the HER-2 Subclonal Amplification was consonant to the accepted criteria for amplification, showing clusters of amplified cells, and (b) those cases with rare HER-2 Subclonal Amplification that did not reflect the accepted criteria for amplification, showing scattered amplified cells only. The incidence of metastases and late recurrences of the case series was compared with a series composed of 109 consecutive cases, being HER-2 homogeneous (comprising 14 Amplified and 95 Non-Amplified cases), matched for grade and stage (control series). It appeared that cases showing Subclonal Amplification had an incidence of metastases intermediate between the cases Amplified and Non-Amplified. Specifically, Subclonal Amplification with clustered cells had a lower incidence of metastases than Amplified cases (12.9 versus 21.4%). On the contrary, Subclonal Amplification with scattered cells showed an incidence of metastases higher than Non-Amplified cases (14 versus 9.47%). In addition, patients Subclonal Amplification with clustered cells, who were treated with the specific monoclonal antibody, had a lower incidence of metastases than patients showing Subclonal Amplification with scattered cells, who did not receive target therapy. These data, together with those recently published, indicate that Subclonal Amplification has an impact on prognosis and should be taken into consideration to correctly plan the treatment of breast cancer patients. PMID- 28573513 TI - Knee joint preservation surgery in osteosarcoma using tumour-bearing bone treated with liquid nitrogen. AB - PURPOSE: To preserve the joint structure in order to maintain good limb function in patients with osteosarcoma, we perform epiphyseal or metaphyseal osteotomy and reconstruction using frozen autografts that contain a tumour treated with liquid nitrogen. There are two methods of using liquid nitrogen-treated autografts: the free-freezing method and the pedicle-freezing method. The purpose of this study was to evaluate the results of intentional joint-preserving reconstruction using the free-freezing method and the pedicle-freezing method in patients with osteosarcoma. METHODS: Between 2006 and 2014, we performed joint-preserving surgery (12 with the free-freezing method and six with the pedicle freezing method) to treat 18 cases of osteosarcoma (12 distal femurs and six proximal tibias) in patients who had achieved a good response to neoadjuvant chemotherapy. RESULTS: Among the 18 patients (nine boys and nine girls) who had a mean age of 11.6 years, 13 remained continuously disease-free, three showed no evidence of disease, one was alive with the disease, and one died from the disease. Functional outcomes were assessed as excellent in 15 patients and poor in three, with a mean follow-up period of 46.1 months. The mean Musculoskeletal Tumour Society (MSTS) score was 90.2%. Except for one patient who underwent amputation, all patients could bend their knee through >90 degrees flexion, and nine achieved full ROM. All but two patients could walk without aid, and 11 were able to run normally throughout the follow-up period. No intraoperative complications were observed, such as surrounding soft-tissue damage, neurovascular injury, or recurrence from frozen bone. CONCLUSIONS: Joint-preserving reconstruction using frozen autografts yielded excellent function in patients with osteosarcoma. PMID- 28573514 TI - Clinical and radiological outcomes after reverse shoulder arthroplasty in patients with failed deltoid or latissimus dorsi transfers. A review of ten cases. AB - PURPOSE: The purpose of this study was to report clinical and radiological results of reverse shoulder arthroplasty (RSA) after failure of either a deltoid and/or a latissimus dorsi transfer. METHODS: Between 2001 and 2011, ten patients (average age, 61 years) underwent primary RSA after a failed tendon transfer for irreparable postero-superior rotator cuff tear (five deltoid muscle transfers, four latissimus dorsi transfers and one both). Average follow-up was 48 months. Outcome measures included pain, range of motion and postoperative Constant-Murley score. RESULTS: Pain score improved significantly from a mean 8.3 to a mean 0.3. Mean shoulder elevation improved from 66 to 134 degrees , and absolute Constant Murley scores increased from 25.8 to 62.8 The mean improvement in external rotation was limited to 7.5 degrees . Subjectively, six patients rated the result as much better and three rated it as better than before surgery. CONCLUSIONS: Failure of the tendon transfer with deterioration of the functional outcomes can be salvaged with a RSA with no impact on the expected outcome. PMID- 28573515 TI - Reproducibility of a new method for measuring lowering and medialisation of the humerus after reverse shoulder arthroplasty. AB - BACKGROUND: Reverse shoulder arthroplasty (RSA) requires lowering the humerus and medialisation of the centre of rotation. Several techniques based on standard X rays are available in the literature. The aim of this study was to expose and validate a new technique for measuring these parameters. MATERIALS AND METHODS: Radiographic data of 20 patients were included. Three observers examined each X rays three times to establish the inter- and intra-reproducibility of each technique (Jobin, Renaud and our method). RESULTS: Intra-observer reproducibility was between 0.10 and 0.94. The best intra-observer intraclass correlation coefficient (ICC) was obtained using Renaud's and our techniques. The inter observer reproducibility was between 0.37 and 0.74. The best inter-observer ICC was obtained with our technique. DISCUSSION: We describe a reliable and reproducible method to evaluate lowering and medialisation of the humerus after RSA. This technique may allow determine the optimal threshold of lengthening after RSA. PMID- 28573516 TI - [Persistent organic contaminants in food : Exposure, hazard potential, and health assessment]. AB - Environmental emissions of organic contaminants are caused by man-made and natural combustion processes, industrial production facilities, and the release from products. Food represents the main source of human exposure for some of these compounds. This is the case for three groups of persistent organic contaminants: (1) per- and polyfluoroalkyl substances (PFAS), (2) polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), and for (3) polycyclic aromatic hydrocarbons (PAHs). The issues regarding PCDD/F emissions were already recognized as a problem in the 1970s and have since then been effectively regulated; the impact of PFAS as global anthropogenic environmental contaminants was identified much later.A system of toxicity equivalency factors (TEF system) was established for the assessment of the toxic potency of a mixed exposure to PCDD/F and certain PCBs. For the health assessment and regulation of PAHs and PFAS, no such system has been implemented so far. For PFAS, a re-evaluation of the present tolerable daily intake values (TDI values) is currently being discussed, as new insights into toxicology and epidemiology have been gained.The persistence in the environment of the compound groups discussed here leads to entry into the food chain over long periods of time, even if access into the environment is minimized. This requires a long-term continuation of the monitoring of food stuffs and forward-looking risk assessment approaches and regulatory measures. PMID- 28573517 TI - Video Education on Hereditary Breast and Ovarian Cancer (HBOC) for Physicians: an Interventional Study. AB - The National Comprehensive Cancer Network (NCCN) guidelines are the gold standard in hereditary cancer risk assessment, screening, and treatment. A minority of physicians follow NCCN guidelines for BRCA1 or BRCA2 mutations. This study assesses the impact of an interventional educational program on HBOC in terms of knowledge. Physicians were sent an invite to join either an intervention survey (web-training offered prior to the knowledge survey) or control survey (web training offered after the knowledge survey). Sixty-nine physicians in the intervention arm and 67 physicians in the control arm completed the survey. The interventional group regularly answered items correctly at a higher frequency than the control group. For example, 64.71% (n = 44) of physicians in the intervention group knew that multi-gene testing does not have to include only highly penetrant genes compared to 32.84% (n = 22) of the control group (p < 0.01). Similar results were seen with other specific survey items. The current study is important in that it shows web-based education to be a feasible and effective modality for training on hereditary breast cancer. This type of education may be incorporated into CME programs and can be used as a foundation for further studies as well. PMID- 28573518 TI - The Importance of Family History in Breast Cancer Patients in Primary Care Setting: a Cross-sectional Study. AB - Screening recommendations of physicians are important for women to raise awareness about their risk factors and to promote appropriate screening behaviors. However, it seems challenging for primary care physicians (PCPs) to balance disease prevention and diagnosis, treatment. The objective of this study was to describe physicians' breast cancer consultancy practice including family history, cancer prevention issues for the women they care. This cross-sectional study included 577 women aged above 45 years, free of breast cancer, during their visits to their PCPs. Nearly half of the women reported their visit to PCPs for an annual examination during the year. Among them, 36.1% had first-degree relatives with cancer and 7.3% with breast cancer. But they reported to be asked about family history of cancer and informed about cancer prevention issues 35.1 and 26.4%, respectively. Cancer still seems to be a hard issue to be discussed, even with women visiting PCPs for annual examination. Asking first-degree relative with breast cancer can give PCPs the chance of determining women with increased risk and support women's appropriate understanding of their own risk in relation to their family history. This routine can make shared-decision making for developing person-centered approach for breast cancer screening possible. Further studies are needed for better understanding of loss of consultancy leadership of physicians for breast cancer. PMID- 28573519 TI - Patterns of Care Related to Post-Operative Radiotherapy for Patients with Prostate Cancer among Canadian Radiation Oncologists and Urologists. AB - The American Society for Radiation Oncology (ASTRO) and American Urological Association (AUA) developed post-prostatectomy radiotherapy (RT) guidelines to aid patient counseling on adjuvant (ART) and salvage radiotherapy (SRT). Our study compared how aware and compliant Canadian radiation oncologists and urologists are to these guidelines. Our online survey was distributed through the Canadian Association of Radiation Oncology (CARO) and Canadian Urology Association (CUA) to radiation oncologists and urologists that treat prostate cancer. We used Wilcoxon rank-sum test and Chi-square test to compare radiation oncologists and urologists. P values for significant findings are reported. A total of 128 participants responded the survey, 52 radiation oncologists, and 76 urologists. The majority (82%) of radiation oncologists had read these guidelines, compared to only 49% of urologists (p < 0.001). Radiation oncologists were more likely to recommend ART >50% for adverse pathological findings post radical prostatectomy compared to urologists (76 vs. 51%, p = 0.011). Urologists were more likely to monitor their patient's PSA level post-prostatectomy compared to radiation oncologists (93 vs. 77%, p = 0.016). Post-thematic analysis of open ended questions revealed that urologists rarely refer patients to radiation oncologists for ART, with radiation oncologists confirming that they rarely receive referrals. This study demonstrates the low compliance to ASTRO/AUA guidelines. While radiation oncologists were more aware and compliant to guidelines, urologists were significantly more likely to monitor their patient's PSA. This study highlighted the need for better communication between urologists and radiation oncologists, especially in referrals for ART, to facilitate treatment delivery that is concordant with ASTRO/AUA guidelines. PMID- 28573520 TI - Glycotriazole-peptides derived from the peptide HSP1: synergistic effect of triazole and saccharide rings on the antifungal activity. AB - This work proposes a strategy that uses solid-phase peptide synthesis associated with copper(I)-catalyzed azide alkyne cycloaddition reaction to promote the glycosylation of an antimicrobial peptide (HSP1) containing a carboxyamidated C terminus (HSP1-NH2). Two glycotriazole-peptides, namely [p-Glc-trz-G1]HSP1-NH2 and [p-GlcNAc-trz-G1]HSP1-NH2, were prepared using per-O-acetylated azide derivatives of glucose and N-acetylglucosamine in the presence of copper(II) sulfate pentahydrate (CuSO4.5H2O) and sodium ascorbate as a reducing agent. In order to investigate the synergistic action of the carbohydrate motif linked to the triazole-peptide structure, a triazole derivative [trz-G1]HSP1-NH2 was also prepared. A set of biophysical approaches such as DLS, Zeta Potential, SPR and carboxyfluorescein leakage from phospholipid vesicles confirmed higher membrane disruption and lytic activities as well as stronger peptide-LUVs interactions for the glycotriazole-peptides when compared to HSP1-NH2 and to its triazole derivative, which is in accordance with the performed biological assays: whereas HSP1-NH2 presents relatively low and [trz-G1]HSP1-NH2 just moderate fungicidal activity, the glycotriazole-peptides are significantly more effective antifungal agents. In addition, the glycotriazole-peptides and the triazole derivative present strong inhibition effects on ergosterol biosynthesis in Candida albicans, when compared to HSP1-NH2 alone. In conclusion, the increased fungicidal activity of the glycotriazole-peptides seems to be the result of (A) more pronounced membrane-disruptive properties, which is related to the presence of a saccharide ring, together with (B) the inhibition of ergosterol biosynthesis, which seems to be related to the presence of both the monosaccharide and the triazole rings. PMID- 28573521 TI - Is centrally induced alveolar bone loss in a large animal model preventable by peripheral hormone substitution? AB - OBJECTIVES: Alveolar bone structures are mostly investigated in small animal models. The majority of these studies examined local influences on the alveolar bone, but only a few examined systemic influencing factors. The hypothalamic pituitary axis is known to be essential for a vital bone balance. The aim of this study was to analyse the effects that selective hormone treatments have on alveolar bone structure and quality in a sheep model for alveolar bone loss, induced by hypothalamic-pituitary disconnection (HPD). METHODS: Thirty sheep were randomly selected into six groups of five each: control (C), ovariectomy-OVX (O), O + HPD (OH), OH with oestrogen treatment (OHE), OH with thyroxine (T4) treatment (OHT), and OH with a combined treatment of oestrogen and thyroxine (OHTE). After OVX and HPD procedures and an additional 9-month observation/treatment period, structural bone analyses of the mandible were performed by contact radiography, micro-CT, and static histomorphometry. RESULTS: The HPD procedure caused structural alveolar bone parameters to decrease significantly compared to controls (C). Treatment with oestrogen (OHE) was protective and bone structure was maintained at baseline levels. Thyroxine treatment (OHT) promoted significant bone loss, but the combined treatment (OHTE) improved bone structure and volume parameters even above baseline levels. CONCLUSIONS: Alveolar bone homeostasis significantly underlies systemic regulatory systems. Centrally induced (HPD) bone loss can be prevented by combined peripheral treatment with oestrogen and thyroxine. CLINICAL RELEVANCE: These results demonstrate the significance of a balanced hormonal regulatory system for steady bone remodelling and maintenance of healthy alveolar bone. PMID- 28573522 TI - Embryo development after mitochondrial supplementation from induced pluripotent stem cells. AB - PURPOSE: The purpose of this study was to evaluate the effects of mitochondrial supplementation (MS) on early embryonic development and to assess the safety of MS treatments using induced pluripotent stem cells (iPSCs) as the mitochondrial donor. METHODS: In this study, we evaluated the effect of MS on early embryonic development using induced pluripotent stem cells (iPSCs) as the donor. Mouse zygotes were injected with either mitochondria from iPSCs or a vehicle solution. Several parameters were evaluated, including the rates of blastocyst formation and implantation, the weight of E13.5 embryos and placentas, the distribution of the donor mitochondrial DNA (mtDNA), and the pattern of methylation in the differentially methylated regions (DMRs) of the H19 and Snrpn genes. RESULTS: We found that neither the rates of blastocyst formation and implantation nor the weights of E13.5 embryos and placentas were significantly different between the MS and control groups. Additionally, the mtDNA from the iPSC donors could be detected in the muscle tissue of four fetuses and all placentas in the MS group. Finally, the methylation patterns of H19 and Snrpn DMRs remained unchanged by MS. CONCLUSIONS: iPSC-derived mtDNA was directly involved in the process of embryonic development after MS. No adverse effects were seen when using iPSCs as a mitochondrial donor, but it remains to be seen whether this method can improve embryonic development, especially in older mice. PMID- 28573523 TI - Selection of human blastocysts with a high implantation potential based on timely compaction. AB - PURPOSE: Recently, we established a noninvasive system for selecting human blastocysts with a high pre-transfer implantation potential based on first and second division patterns. The present study was carried out to improve the selection system. METHODS: Embryos that completed first and second divisions within 25.90 and 37.88 h after culture, respectively, were selected using a time lapse incubator. We examined the effects of compaction and blastocyst formation times on pregnancy rates after transferring these embryos at the blastocyst stage. RESULTS: The completion of compaction and blastocyst formation times (79.93 and 97.47 h after culture, respectively) of embryos resulting in pregnancies after transfer were significantly (P < 0.01) shorter than those (86.46 and 100.34 h after culture, respectively) of embryos that failed to induce pregnancies. Embryo selection based on completion of compaction time improved pregnancy rates (40.9 vs. 74.6%, P < 0.01). CONCLUSIONS: Of the embryos that formed two cells during the first division within 25.90 h after culture and four cells during the second division within 37.88 h after culture, those that completed compaction within 79.93 h after culture before reaching the blastocyst stage had a high implantation potential. PMID- 28573524 TI - Use of various gonadotropin and biosimilar formulations for in vitro fertilization cycles: results of a worldwide Web-based survey. AB - PURPOSE: The purpose of this study was to identify trends in gonadotropin therapy in patients undergoing in vitro fertilization (IVF) treatment worldwide. METHODS: Retrospective evaluation utilizing the results of a Web-based survey, IVF Worldwide ( www.IVF-worldwide.com ) was performed. RESULTS: Three hundred fourteen centers performing a total of 218,300 annual IVF cycles were evaluated. Respondents representing 62.2% of cycles (n = 135,800) did not believe there was a difference between urinary and recombinant gonadotropins in terms of efficacy and live birth rate. Of the respondents, 67.3% (n = 146,800) reported no difference between recombinant and urinary formulations in terms of short-term safety and risk of ovarian hyperstimulation syndrome. In terms of long-term safety using human urinary gonadotropins, 50.6% (n = 110,400) of respondents believe there are potential long-term risks including prion disease. For 95.3% of units (n = 208,000), the clinician was the decision maker determining which specific gonadotropins are used for IVF. Of the units, 62.6% (n = 136,700) identified efficacy as the most important factor in deciding which gonadotropin to prescribe. While most (67.3%, n = 146,800) were aware of new biosimilar recombinant FSH products entering the market, 92% (n = 201,000) reported they would like more information. A fraction of respondents (25.6%, n = 55,900) reported having experience with these new products, and of these, 80.3% (n = 46,200) reported that they were similar in efficacy as previously used gonadotropins in a similar patient group. CONCLUSIONS: Respondents representing the majority of centers do not believe a difference exists between urinary and recombinant gonadotropins with respect to efficacy and live birth rates. While many are aware of new biosimilar recombinant FSH products entering the market, over 90% desire more information on these products. PMID- 28573525 TI - Male chromosomal polymorphisms reduce cumulative live birth rate for IVF couples. AB - PURPOSE: Chromosomal polymorphisms are associated with infertility, but their effects on assisted reproductive outcomes are still quite conflicting, especially after IVF treatment. This study evaluated the role of chromosomal polymorphisms of different genders in IVF pregnancy outcomes. METHODS: Four hundred and twenty five infertile couples undergoing IVF treatment were divided into three groups: 214 couples with normal chromosomes (group A, control group), 86 couples with female polymorphisms (group B), and 125 couples with male polymorphisms (group C). The pregnancy outcomes after the first and cumulative transfer cycles were analyzed, and the main outcome measures were live birth rate (LBR) after the first transfer cycle and cumulative LBR after a complete IVF cycle. RESULTS: Comparison of pregnancy outcomes after the first transfer cycle within group A, group B, and group C demonstrated a similar LBR as well as other rates of implantation, clinical pregnancy, early miscarriage, and ongoing pregnancy (P > 0.05). However, the analysis of cumulative pregnancy outcomes indicated that compared with group A, group C had a significantly lower LBR per cycle (80.4 vs 68.00%), for a rate ratio of 1.182 (95% CI 1.030 to 1.356, P = 0.01) and a significantly higher cumulative early miscarriage rate (EMR) among clinical pregnancies (7.2 vs 14.7%), for a rate ratio of 0.489 (95% CI 0.248 to 0.963, P = 0.035). CONCLUSION: Couples with chromosomal polymorphisms in only male partners have poor pregnancy outcomes after IVF treatment manifesting as high cumulative EMR and low LBR after a complete cycle. PMID- 28573526 TI - Selecting embryos with the highest implantation potential using data mining and decision tree based on classical embryo morphology and morphokinetics. AB - PURPOSE: The objective of this work was to determine which embryonic morphokinetic parameters up to D3 of in vitro development have predictive value for implantation for the selection of embryos for transfer in clinical practice based upon information generated from embryo transfers with known implantation data (KID). METHODS: A total of 800 KID embryos (100% implantation rate (IR) per transfer and 0% IR per transfer) cultured in an incubator with Time-Lapse system were retrospectively analysed. Of them, 140 embryos implanted, whereas 660 did not. RESULTS: The analysis of morphokinetic parameters, together with the embryo morphology assessment on D3, enabled us to develop a hierarchical model that places the classical morphological score, the t4 and t8 morphokinetic values, as the variables with the best prognosis of implantation. CONCLUSION: In our decision tree, the classical morphological score is the most predictive parameter. Among embryos with better morphological scores, morphokinetics permits deselection of embryos with the lowest implantation potential. PMID- 28573527 TI - Transporting cumulus complexes using novel meiotic arresting conditions permits maintenance of oocyte developmental competence. AB - PURPOSE: The aim of this study is to evaluate the effect of a novel bovine cumulus oocyte complex (COC) shipping media designed to arrest meiotic resumption during transport on meiotic arrest, as well as meiotic resumption, subsequent embryonic development, and embryo quality. METHODS: Bovine cumulus oocyte complexes were transported overnight from the collection facility to the laboratory. COCs were placed in control in vitro maturation (IVM) or in shipping arrest medium (SAM) containing multiple meiotic inhibitors, and then shipped to our laboratory. Upon arrival, meiotic status was assessed, control COCs were inseminated, and arrested COCs were matured and inseminated the next day. Embryonic development and quality were analyzed. RESULTS: When bovine COC arrived at the laboratory after overnight shipment (21 h) in SAM, the majority of oocytes remained at the GV stage (75.6 +/- 2.9% GV). Arrested oocytes successfully resumed and completed meiosis during IVM after removal from SAM (96.8 +/- 0.5% metaphase II compared to control 88.3 +/- 5.0%). Moreover, the development of blastocysts per COC was not different from control (22.3 +/- 2.4% for control and 18.7 +/- 2.1% for SAM), nor was any difference detected in blastocyst quality as determined by cell number and allocation. CONCLUSIONS: Our study demonstrates that a physiological system incorporating cyclic adenosine monophosphate and cyclic guanosine monophosphate modulators can be used to maintain meiotic arrest followed by successful nuclear maturation and pre-implantation embryo development equal to control IVM-derived embryos. Our results offer promising insights for the development of pre-IVM media that may improve oocyte developmental competence in vitro. PMID- 28573528 TI - Inpatient hospitalizations in women with and without assisted reproductive technology live birth. AB - PURPOSE: The aim of this study is to evaluate frequency of hospitalization before, during, and after assisted reproductive technology (ART) treatment by cycle outcome. METHODS: Six thousand and one hundred thirty women residing in Massachusetts undergoing 17,135 cycles of ART reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SARTCORS) from 2004 to 2011 were linked to hospital discharges and vital records. Women were grouped according to ART treatment cycle outcome as: no pregnancy (n = 1840), one or more pregnancies but no live birth (n = 968), or one or more singleton live births (n = 3322). Hospital delivery discharges during 1998-2011 were categorized as occurring before, during, or after the ART treatment. The most prevalent ICD-9 codes for non-delivery hospital discharges were compared. Groups were compared using chi square test using SAS 9.3 software. RESULTS: The proportion of any hospitalization was 57.0, 58.3, and 91.3% for women with no pregnancy, no live birth, and ART singleton live birth, respectively; the proportion of non-delivery hospitalizations was 30.4, 31.0, and 28.3%, respectively. The non-ART delivery proportion after ART treatment did not differ by group (33.4, 36.2, and 36.9%, respectively, p = 0.17). Most frequent non-delivery diagnoses (including fibroids, obesity, ectopic pregnancy, depression, and endometriosis) also did not differ by group. A secondary analysis limited to only women with no delivery discharges before the first ART cycle showed similar results. CONCLUSIONS: All groups had live birth deliveries during the study period, suggesting an important contribution of non-ART treatment or treatment-independent conception to overall delivery and live births. Hospitalizations not associated with delivery suggested similarity in morbidity for all ART patients regardless of success with ART treatment. PMID- 28573529 TI - Temperature adaptation of lipids in diapausing Ostrinia nubilalis: an experimental study to distinguish environmental versus endogenous controls. AB - Larvae of the European corn borer (Ostrinia nubilalis Hubn.) were cold acclimated during different phases of diapause to determine if changes in the fatty acid composition lipids occur as part of a programmed diapause strategy, or as a response to low temperatures during winter. Cold acclimation of fifth instar larvae of O. nubilalis during diapause had modest effects further on the readjustments in fatty acid composition of triacylglycerols and phospholipids. Overall, FA unsaturation (UFAs/SFAs ratio) was stable, with the exception of the triacylglycerols fraction after exposure to -3 and -10 degrees C in mid-diapause (MD) when it significantly increased. Differential scanning calorimetry (DSC) was used to examine phase transitions of total body lipid of cold-acclimated larvae in diapause. Thermal analysis indicated that changes in the melt transition temperatures of whole body total lipids were subtle, but consistent with the modest changes in the level of FA unsaturation observed. We conclude that lipid rearrangements are a function of the endogenous "diapause program" rather than a direct effect of low temperatures, which proved to have limited impact on lipid changes in diapausing larvae of O. nubilalis. PMID- 28573531 TI - [Gemcitabine and capecitabine as new standard of care for adjuvant therapy in pancreatic cancer]. PMID- 28573530 TI - MeCP2 Regulates PTCH1 Expression Through DNA Methylation in Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, in which pathogenesis is not clear. Many research demonstrated that fibroblast-like synoviocytes (FLSs) play a key role in RA pathogenesis, join in the cartilage injury and hyperplasia of the synovium, and contribute to the release of inflammatory cytokines. We used adjuvant arthritis (AA) rats as RA animal models. The methyl-CpG-binding protein 2 (MeCP2) enables the suppressed chromatin structure to be selectively detected in AA FLSs. Overexpression of this protein leads to an increase of integral methylation levels. Some research has confirmed the hedgehog (Hh) signaling pathway plays an important role in RA pathogenesis; furthermore, patched 1 (PTCH1) is a negative fraction of Hh signaling pathway. We used 5-aza-2'-deoxycytidine (5-azadc) as DNA methylation inhibitor. In our research, we found MeCP2 reduced PTCH1 expression in AA FLSs; 5-azadc obstructed the loss of PTCH1 expression. 5-Azadc, treatment of AA FLSs, also blocks the release of inflammatory cytokines. In order to probe the potential molecular mechanism, we assumed the epigenetic participation in the regulation of PTCH1. Results demonstrated that PTCH1 hypermethylation is related to the persistent FLS activation and inflammation in AA rats. Knockdown of MeCP2 using small interfering RNA technique added PTCH1 expression in AA FLSs. Our results indicate that DNA methylation may offer molecule mechanisms, and the reduced PTCH1 methylation level could regulate inflammation through knockdown of MeCP2. Graphical Abstract PTCH1 is an inhibitory protein of the Hedgehog signaling pathway. Increased expression of PTCH1 can inhibit the expression of Gli1 and Shh, thereby inhibiting the activation of Hedgehog signaling pathway. Inactivated Hedgehog signaling pathway inhibits the secretion of IL-6 and TNF-alpha. MeCP2 mediates hypermethylation of PTCH1 gene and decreases the expression of PTCH1 protein, thus activating Hedgehog signaling pathway and increasing secretion of IL-6 and TNF-alpha. PMID- 28573532 TI - [Surgical strategy to save ileoanal pouch reconstruction]. AB - Restorative proctocolectomy under formation of an ileoanal/ileorectal J-pouch has become the procedure of choice in the therapy of ulcerative colitis. Although patients experience a dramatic improvement of their quality of life, surgery is not successful in about 5-10% of all treated patients. The reasons for failure are chronic pouchitis, incontinence, delayed diagnosis of Crohn's disease, fistula, surgical complications, too long remnant rectal stump, chronic abscess, and surgical technical errors. Some of the reasons do not always prevent the loss of a well-functioning ileoanal pouch. In many cases, correction, closure of fistulas or even a complete reconstruction of the ileoanal pouch are possible. Based on a review of the literature and our own experience, we show in 887 patients a success rate of 75% with acceptable pouch function. Indications, technics, and results are presented. PMID- 28573533 TI - [Neoadjuvant therapy vs. upfront resection for resectable pancreatic cancer]. PMID- 28573534 TI - The clinical characteristics and prognosis of acute zonal occult outer retinopathy. AB - PURPOSE: This prospective observational case series study aimed to observe the clinical characteristics of acute zonal occult outer retinopathy (AZOOR) and its prognosis in Chinese Han patients. METHODS: Six eyes of 5 female patients diagnosed with AZOOR were followed up for 4 months to observe the natural disease course. All enrolled subjects underwent a series of ocular examinations at the onset and each return visit, including best corrected visual acuity (BCVA), split lamp microscopy, fundus photography, optical coherence tomography (OCT), perimetry, multifocal electroretinogram and fundus fluorescein angiography. RESULTS: Over the follow-up, all enrolled patients recovered on BCVA, perimetry and OCT in different degrees. Among them, one patient recovered completely since the ocular examination results returned to normal. CONCLUSION: AZOOR is a rare ocular disorder in Chinese population. Our results demonstrated that visual functions of enrolled patients significantly improved spontaneously, indicating that Chinese female Han patients with AZOOR have good visual outcomes during the follow-up period without any specific managements. PMID- 28573535 TI - Long-Term Outcome of Bariatric Surgery in Morbidly Obese Adolescents: a Systematic Review and Meta-Analysis of 950 Patients with a Minimum of 3 years Follow-Up. AB - BACKGROUND: Obesity in pediatric and adolescent population has reached a universal pandemic. This study aimed to summarize the literature on the longest available outcome of bariatric surgery in morbidly obese adolescents. METHODS: A systematic review was conducted to pool available data on the longest available (>3 years) weight loss and comorbidity resolution outcome in adolescent bariatric surgery. RESULTS: A total of 14 studies reporting the result of bariatric surgery after 3 years in 950 morbidly obese adolescents were included. Preoperative age and BMI ranged from 12 to 19 years and from 26 to 91 kg/m2, respectively. Females were the predominant gender (72.8%). Laparoscopic roux-en-Y gastric bypass (n = 453) and adjustable gastric banding (n = 265) were the most common bariatric procedure performed. The number of patients at the latest follow-up was 677 (range from 2 to 23 years). On average, patients lost 13.3 kg/m2 of their BMI. Among comorbidities, only diabetes mellitus resolved or improved dramatically. Of 108 readmissions, 91 led to reoperation. There was a weight regain < 5 kg/m2 between 5 and 6 years of follow-up. Removal, exchange, or conversion of the previous band constituted the majority of the revisional procedures. Three deaths were reported. No long-term data was obtainable on nutritional deficiency or growth status of adolescents who underwent a bariatric procedure. CONCLUSION: Although bariatric surgery is a safe and effective procedure in the treatment of adolescent morbid obesity, long-term data is scarce regarding its nutritional and developmental complication in this growing population of patients. PMID- 28573537 TI - Derivation of new equations to estimate glomerular filtration rate in pediatric oncology patients. AB - BACKGROUND AND OBJECTIVE: Monitoring renal function is critical in treating pediatric patients, especially when dosing nephrotoxic agents. We evaluated the validity of the bedside Schwartz and Brandt equations in pediatric oncology patients and developed new equations for estimated glomerular filtration rate (eGFR) in these patients. METHODS: A retrospective analysis was conducted comparing eGFR using the bedside Schwartz and Brandt equations to measured GFR (mGFR) from technetium-99m diethylenetriamine pentaacetic acid (99mTc-DTPA) between January 2007 and August 2013. An improved equation to estimate GFR was developed, simplified, and externally validated in a cohort of patients studied from September 2013 to June 2015. Carboplatin doses calculated from 99mTc-DTPA were compared with doses calculated by GFR-estimating equations. RESULTS: Overall, the bedside Schwartz and Brandt equations did not precisely or accurately predict measured GFR (mGFR). Using a data subset, we developed a five covariate equation, which included height, serum creatinine, age, blood urea nitrogen (BUN), and gender, and a simplified version (two-covariates), which contained height and serum creatinine. These equations were used to estimate GFR in 2036 studies, resulting in precise and accurate predictors of mGFR values. Equations were validated in an external cohort of 570 studies; both new equations were more accurate in calculating carboplatin doses than either the bedside Schwartz or Brandt equation. CONCLUSIONS: Two new equations were developed to estimate GFR in pediatric oncology patients, both of which did a better job at estimating mGFR than published equations. PMID- 28573536 TI - Exploring the heat-responsive chaperones and microsatellite markers associated with terminal heat stress tolerance in developing wheat. AB - Global warming is a major threat for agriculture and food security, and in many cases the negative impacts are already apparent. Wheat is one of the most important staple food crops and is highly sensitive to the heat stress (HS) during reproductive and grain-filling stages. Here, whole transcriptome analysis of thermotolerant wheat cv. HD2985 was carried out at the post-anthesis stage under control (22 +/- 3 degrees C) and HS-treated (42 degrees C, 2 h) conditions using Illumina Hiseq and Roche GS-FLX 454 platforms. We assembled ~24 million (control) and ~23 million (HS-treated) high-quality trimmed reads using different assemblers with optimal parameters. De novo assembly yielded 52,567 (control) and 59,658 (HS-treated) unigenes. We observed 785 transcripts to be upregulated and 431 transcripts to be downregulated under HS; 78 transcripts showed >10-fold upregulation such as HSPs, metabolic pathway-related genes, etc. Maximum number of upregulated genes was observed to be associated with processes such as HS-response, protein-folding, oxidation-reduction and photosynthesis. We identified 2008 and 2483 simple sequence repeats (SSRs) markers from control and HS-treated samples; 243 SSRs were observed to be overlying on stress-associated genes. Polymorphic study validated four SSRs to be heat-responsive in nature. Expression analysis of identified differentially expressed transcripts (DETs) showed very high fold increase in the expression of catalytic chaperones (HSP26, HSP17, and Rca) in contrasting wheat cvs. HD2985 and HD2329 under HS. We observed positive correlation between RNA-seq and qRT-PCR expression data. The present study culminated in greater understanding of the heat-response of tolerant genotype and has provided good candidate genes for the marker development and screening of wheat germplasm for thermotolerance. PMID- 28573538 TI - Nutritional screening based on the controlling nutritional status (CONUT) score at the time of admission is useful for long-term prognostic prediction in patients with heart failure requiring hospitalization. AB - The objective of the study was to clarify whether controlling nutritional status (CONUT) is useful for predicting the long-term prognosis of patients hospitalized with heart failure (HF). A total of 482 (57.5%) HF patients from the Ibaraki Cardiovascular Assessment Study-HF (N = 838) were enrolled (298 men, 71.7 +/- 13.6 years). At admission, blood samples were collected and nutritional status assessed using CONUT. CONUT scores were defined as follows: 0-1, normal; 2-4, light; 5-8, moderate; and 9-12, severe undernutrition. Accordingly, 352 (73%) patients had light-to-severe nutritional disturbances. In the follow-up period [median 541.5 (range 354-786) days], 109 deaths were observed. A Kaplan-Meier analysis revealed that all-cause deaths occurred more frequently in HF patients with nutritional disturbances [n = 93 (26.4%)] than in those with normal nutrition [n = 16 (12.3%); log-rank p < 0.001]. The Cox proportional hazard analyses revealed that a per point increase in the CONUT score was associated with an increased risk of all-cause death (hazard ratio 1.142; 95% confidence interval, 1.044-1.249) after controlling simultaneously for age, sex, previous history of HF hospitalization, log brain natriuretic peptide, and use of therapeutic agents at admission (tolvaptan and aldosterone antagonists). This study suggests that nutritional screening using CONUT scores is helpful in predicting the long-term prognosis of patients hospitalized with HF in a multicenter registry setting. PMID- 28573539 TI - Enhancement of crystallinity of cellulose produced by Escherichia coli through heterologous expression of bcsD gene from Gluconacetobacter xylinus. AB - OBJECTIVES: To evaluate the crystallinity index of the cellulose produced by Escherichia coli Nissle 1917 after heterologous expression of the cellulose synthase subunit D (bcsD) gene of Gluconacetobacter xylinus BPR2001. RESULTS: The bcsD gene of G. xylinus BPR2001 was expressed in E. coli and its protein product was visualized using SDS-PAGE. FTIR analysis showed that the crystallinity index of the cellulose produced by the recombinants was 0.84, which is 17% more than that of the wild type strain. The increased crystallinity index was also confirmed by X-ray diffraction analysis. The cellulose content was not changed significantly after over-expressing the bcsD. CONCLUSION: The bcsD gene can improve the crystalline structure of the bacterial cellulose but there is not any significant difference between the amounts of cellulose produced by the recombinant and wild type E. coli Nissle 1917. PMID- 28573540 TI - Hydrolytic potential of five fungal supernatants to enhance a commercial enzyme cocktail. AB - OBJECTIVES: To evaluate the potential of enzyme cocktails produced by five filamentous fungi to supplement the industrial cellulase cocktail, Celluclast 1.5L, in order to improve the efficiency of saccharification. RESULTS: The fungi were cultivated on wheat bran and the resulting supernatants were combined with Celluclast in enzymatic hydrolysis experiments to test their ability to hydrolyze wheat bran and five cellulose-rich substrates. The supernatant showing the best performance was that from an Aspergillus niger cellulase mutant. The addition of beta-glucosidase only to the Celluclast cocktail was not as beneficial. CONCLUSION: Supplementing commercial cocktails with enzymes from carefully selected fungi may result in significantly more efficient saccharification of lignocellulosic materials. Furthermore, such an approach could lead to the identification of novel enzyme activities crucial for saccharification. PMID- 28573541 TI - miR-215 functions as an oncogene in high-grade glioma by regulating retinoblastoma 1. AB - OBJECTIVES: To investigate the roles of miR-215 in high-grade glioma and to clarify the regulation of retinoblastoma 1 (RB1) by miR-215. RESULTS: miR-215 is frequently up-regulated in high-grade glioma tissues. Increased miR-215 expression is significantly associated with World Health Organization grade (P < 0.01) tumor size (P < 0.05) and poor prognosis (P < 0.01). Over-expression of miR 215 promoted cell proliferation and knockdown of miR-215 inhibited cell proliferation in vitro. RB1 was identified as a direct and functional target of miR-215. RB1 is generally down-regulated in glioma tissues and its expression inversely correlated with miR-215, which is up-regulated in high-grade glioma tissues, and its expression was negatively correlated with miR-215. CONCLUSIONS: The new miR-215/RB1 axis provides new insights into the molecular mechanism and treatment for glioma. PMID- 28573542 TI - Erratum to: Adrenalectomy: indications and options for treatment. PMID- 28573543 TI - Transoral thyroidectomy: limitations, patients' safety, and own experiences. AB - For patients undergoing thyroidectomy, the minimally invasive aspect and the cosmetic advantage of the procedure seem to be important factors in surgery. Studies in cadaver and animals have shown that different endoscopic techniques can be performed in a safe and successful way. In the evolution of thyroid surgery, for many endocrine surgeons, the transoral approach seems to be the next step. Even if such procedures are more and more frequently applied in patients, these procedures are far from being generally implemented in routine surgery. In this study, we report on our own experience and considerations in the process of finding a sublingual endoscopic transoral way to the endoscopic transoral thyroidectomy. We describe our failures, risk assessment and compare that with the available literature on transoral sublingual and vestibular thyroid surgery. The access itself needs to be further refined, and even more suitable and better adapted instruments need to be developed, so that optimal and safe results that meet all requirements on endocrine surgery can be achieved. A learning curve at the risk of patients' lives should be avoided. Furthermore, a combination of transoral endoscopic non-transoral techniques might be a useful safer, but more traumatising alternative for implementation. The sublingual access seems to be less invasive than the vestibular access. For a sublingual single-access routine surgery, better instruments are needed. Only in highly specialized centres for endocrine and endoscopic surgery, transoral thyroidectomy should be performed. PMID- 28573544 TI - Lipocalin 2 enhances mesenchymal stem cell-based cell therapy in acute kidney injury rat model. AB - Acute kidney injury (AKI) is one of the most common health-threatening diseases in the world. There is still no effective medical treatment for AKI. Recently, Mesenchymal stem cell (MSC)-based therapy has been proposed for treatment of AKI. However, the microenvironment of damaged kidney tissue is not favorable for survival of MSCs which would be used for therapeutic intervention. In this study, we genetically manipulated MSCs to up-regulate lipocalin-2 (Lcn2) and investigated whether the engineered MSCs (MSC-Lcn2) could improve cisplatin induced AKI in a rat model. Our results revealed that up-regulation of Lcn2 in MSCs efficiently enhanced renal function. MSC Lcn2 up-regulates expression of HGF, IGF, FGF and VEGF growth factors. In addition, they reduced molecular biomarkers of kidney injury such as KIM-1 and Cystatin C, while increased the markers of proximal tubular epithelium such as AQP-1 and CK18 following cisplatin induced AKI. Overall, here we over-expressed Lcn2, a well-known cytoprotective factor against acute ischemic renal injury, in MSCs. This not only potentiated beneficial roles of MSCs for cell therapy purposes but also suggested a new modality for treatment of AKI. PMID- 28573545 TI - A software framework for real-time multi-modal detection of microsleeps. AB - A software framework is described which was designed to process EEG, video of one eye, and head movement in real time, towards achieving early detection of microsleeps for prevention of fatal accidents, particularly in transport sectors. The framework is based around a pipeline structure with user-replaceable signal processing modules. This structure can encapsulate a wide variety of feature extraction and classification techniques and can be applied to detecting a variety of aspects of cognitive state. Users of the framework can implement signal processing plugins in C++ or Python. The framework also provides a graphical user interface and the ability to save and load data to and from arbitrary file formats. Two small studies are reported which demonstrate the capabilities of the framework in typical applications: monitoring eye closure and detecting simulated microsleeps. While specifically designed for microsleep detection/prediction, the software framework can be just as appropriately applied to (i) other measures of cognitive state and (ii) development of biomedical instruments for multi-modal real-time physiological monitoring and event detection in intensive care, anaesthesiology, cardiology, neurosurgery, etc. The software framework has been made freely available for researchers to use and modify under an open source licence. PMID- 28573546 TI - Skoulekia erythrini n. sp. (Digenea: Aporocotylidae): a parasite of Pagellus erythrinus (L.) (Perciformes: Sparidae) from the western Mediterranean with an amendment of the generic diagnosis. AB - A new aporocotylid, Skoulekia erythrini n. sp., is described from the heart, cephalic kidney and gill blood vessels of the common pandora Pagellus erythrinus (L.) collected from several localities of the western Mediterranean off Spain. The new species differs from the type- and only species of the genus, S. meningialis Alama-Bermejo, Montero, Raga & Holzer, 2011 in possessing a symmetrical body (vs laterally curved), short tegumental spines (3-4 vs 7-10 um) without hooked ends, diffuse (vs conspicuous) oesophageal gland-cells, a relatively longer oesophagus, a testis that is shorter in relation to body length and a much smaller seminal vesicle (17-34 * 10-26 vs 33-101 * 27-97 MUm). Elongated ellipsoidal eggs of S. erythrini n. sp. were found trapped in gill vessels in histological sections. Phylogenetic analyses based on partial 28S rDNA and ITS2 sequences supported the placement of the new species within Skoulekia and the close relationships of this genus with Psettarium Goto & Ozaki, 1929 and Pearsonellum Overstreet & Koie, 1986. Skoulekia meningialis is described from a new sparid host, Diplodus puntazzo (Walbaum), collected off Santa Pola, Spain. The new morphological data for the two Skoulekia spp. and a re-examination of three paratypes of S. meningialis pinpointed features amending both the description of S. meningialis and the generic diagnosis of Skoulekia. PMID- 28573547 TI - Barracudia australiensis n. g., n. sp. (Nematoda: Philometridae) from the obtuse barracuda Sphyraena obtusata Cuvier (Perciformes: Sphyraenidae) off eastern Australia. AB - Based on light and scanning electron microscopical studies, a new nematode parasite, Barracudia australiensis n. sp. (Philometridae), is described from the gall-bladder of the marine fish (obtuse barracuda) Sphyraena obtusata Cuvier (Sphyraenidae, Perciformes) from off the eastern Pacific coast of Australia, for which a new genus Barracudia n. g. is established. This new genus is mainly characterised by features found in the male: sickle-shaped, ventrally curved spicules, a gubernacum with a broad, dorsally bent distal portion and a markedly dorsoventrally elongated cloacal aperture. Based on these features, Barracudia spp. conspicuously differ from representatives of all other philometrid genera with known males. Philometra philippinensis Quiazon & Yoshinaga, 2013 is transferred to Barracudia as B. philippinensis (Quiazon & Yoshinaga, 2013) n. comb. Barracudia australiensis is the third nominal species of philometrids described from the Sphyraenidae and the 19th species of the Philometridae recorded from fishes in Australian waters. PMID- 28573548 TI - Redescription of Tripaphylus musteli (van Beneden, 1851) (Copepoda: Sphyriidae) and the relegation of Paeon Wilson, 1919 to synonymy with Tripaphylus Richiardi in Anonymous, 1878. AB - Tripaphylus musteli (van Beneden, 1851) (Copepoda, Siphonostomatoida, Sphyriidae) is redescribed from an adult female collected from the branchial chamber of a starry smooth-hound, Mustelus asterias Cloquet (Carcharhiniformes, Triakidae), captured in the English Channel off Portland, UK. The new account of T. musteli is the first based on a complete adult female and highlighted the lack of a robust distinction separating Tripaphylus Richiardi, in Anonymous, 1878 and Paeon Wilson, 1919 prompting us to relegate Paeon to a junior subjective synonym of Tripaphylus. In the light of this synonymy the eight former species of Paeon are transferred to Tripaphylus as follows: T. ferox (Wilson, 1919) new combination, T. elongatus (Wilson, 1932) new combination, T. vassierei (Delamare Deboutteville & Nunes-Ruivo, 1954) new combination, T. lobatus (Kirtisinghe, 1964) new combination, T. asymboli (Turner, Kyne & Bennett, 2003) new combination, T. versicolor (Wilson, 1919) new combination, T. australis (Kabata, 1993) new combination, and T. triakis (Castro Romero, 2001) new combination. Comparisons between terminology used in this report and that in the literature indicate that all transformed adult females of Tripaphylus probably possess a full complement of cephalic appendages and maxillipeds. All limbs, with the exception of the maxillae share a general morphological similarity to the corresponding appendages of conspecific males. The maxilla of the transformed adult female of Tripaphylus is a small digitiform protuberance associated with a swelling in some species. PMID- 28573550 TI - Optimal injection method for long-range computed tomography angiography. AB - We aimed to obtain high-stable computed tomography (CT) values for CT angiography (CTA). We verified the optimal use of the new protocol for long-range scanning using a contrast material flow phantom (Ichikawa, CT imaging theory. Igaku syoin Publishing, Tokyo, 8; Awai et al., Am J Roentgenol 186(2):379-385, 1) to obtain high-stable CT values (Fig. 2). We have developed a novel contrast injection method called the stable line imaging protocol (SLIP). This method involved a gradual reduction in the rate of administration of the contrast medium, which was accompanied by simultaneous administration of saline to compensate for the resultant decrease in the rate of administration. A saline flush was further added after the contrast medium injection. The rate of administration of the saline flush was the same as that of the initial contrast medium. We injected a contrast medium from the injector into the flow phantom. The time-enhancement curve (TEC) data were obtained five times by changing the injection method, and the average CT values were determined. The maximum simulation of the aortic peak enhancement of TEC was defined as pTEC. The time required to keep the CT value more than 80% of the pTEC was defined as the time period of contrast enhancement (p80). The pTEC of a single injection was 295.7 +/- 5.3 HU, while that of SLIP was 296.5 +/- 2.3 HU; the two values did not differ significantly. The p80 of a single injection was 19.1 +/- 0.2 s, while that of SLIP was 23.2 +/- 0.4 s; p80 of SLIP was 18% longer than that of the single injection. PMID- 28573549 TI - Periprosthetic Joint Infection Is the Main Cause of Failure for Modern Knee Arthroplasty: An Analysis of 11,134 Knees. AB - BACKGROUND: Although large series from national joint registries may accurately reflect indications for revision TKAs, they may lack the granularity to detect the true incidence and relative importance of such indications, especially periprosthetic joint infections (PJI). QUESTIONS/PURPOSES: Using a combination of individual chart review supplemented with New Zealand Joint Registry data, we asked: (1) What is the cumulative incidence of revision TKA? (2) What are the common indications for revising a contemporary primary TKA? (3) Do revision TKA indications differ at various followup times after primary TKA? METHODS: We identified 11,134 primary TKAs performed between 2000 and 2015 in three tertiary referral hospitals. The New Zealand Joint Registry and individual patient chart review were used to identify 357 patients undergoing subsequent revision surgery or any reoperation for PJI. All clinical records, radiographs, and laboratory results were reviewed to identify the primary revision reason. The cumulative incidence of each revision reason was calculated using a competing risk estimator. RESULTS: The cumulative incidence for revision TKA at 15 years followup was 6.1% (95% CI, 5.1%-7.1%). The two most-common revision reasons at 15 years followup were PJI followed by aseptic loosening. The risk of revision or reoperation for PJI was 2.0% (95% CI, 1.7%-2.3%) and aseptic loosening was 1.2% (95% CI, 0.7%-1.6%). Approximately half of the revision TKAs secondary to PJI occurred within 2 years of the index TKA (95% CI, 0.8%-1.2%), whereas half of the revision TKAs secondary to aseptic loosening occurred 8 years after the index TKA (95% CI, 0.4%-0.7%). CONCLUSIONS: In this large cohort of patients with comprehensive followup of revision procedures, PJI was the dominant reason for failure during the first 15 years after primary TKA. Aseptic loosening became more important with longer followup. Efforts to improve outcome after primary TKA should focus on these areas, particularly prevention of PJI. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28573551 TI - Two-dimensional breast dosimetry improved using three-dimensional breast image data. AB - Conventional mammographic dosimetry has been developed over the past 40 years. Prior to the availability of high-resolution three-dimensional breast images, certain assumptions about breast anatomy were required. These assumptions were based on the information evident on two-dimensional mammograms; they included assumptions of thick skin, a uniform mixture of glandular and adipose tissue, and a median breast density of 50%. Recently, the availability of high-resolution breast CT studies has provided more accurate data about breast anatomy, and this, in turn, has provided the opportunity to update mammographic dosimetry. Based on hundreds of data sets on breast CT volume, a number of studies were performed and reported which have shed light on the basic breast anatomy specific to dosimetry in mammography. It was shown that the average skin thickness of the breast was approximately 1.5 mm, instead of the 4 or 5 mm in the past. In another study, 3-D breast CT data sets were used for validation of the 2-D algorithm developed at the University of Toronto, leading to data suggesting that the overall average breast density is of the order of 16-20%, rather than the previously assumed 50%. Both of these assumptions led to normalized glandular dose (DgN) coefficients which are higher than those of the past. However, a comprehensive study on hundreds of breast CT data sets confirmed the findings of other investigators that there is a more centralized average location of glandular tissue within the breast. Combined with Monte Carlo studies for dosimetry, when accurate models of the distribution of glandular tissue were used, a 30% reduction in the radiation dose (as determined by the DgN coefficient) was found as an average across typical molybdenum and tungsten spectra used clinically. The 30% average reduction was found even when the thinner skin and the lower average breast density were considered. The article reviews three specific anatomic observations made possible based on high-resolution breast CT data by several different research groups. It is noted that, periodically, previous assumptions pertaining to dosimetry can be updated when new information becomes available, so that more accurate dosimetry is achieved. Dogmatic practices typically change slowly, but it is hoped that the medical physics community will continue to evaluate changes in DgN coefficients such that they become more accurate. PMID- 28573552 TI - Autogenous bone grafts in oral implantology-is it still a "gold standard"? A consecutive review of 279 patients with 456 clinical procedures. AB - BACKGROUND: This study assessed the clinical outcomes of graft success rate and early implant survival rate after preprosthetic alveolar ridge reconstruction with autologous bone grafts. METHODS: A consecutive retrospective study was conducted on all patients who were treated at the military outpatient clinic of the Department of Oral and Plastic Maxillofacial Surgery at the military hospital in Ulm (Germany) in the years of 2009 until 2011 with autologous bone transplantation prior to secondary implant insertion. Intraoral donor sites (crista zygomatico-alveolaris, ramus mandible, symphysis mandible, and anterior sinus wall) and extraoral donor site (iliac crest) were used. A total of 279 patients underwent after a healing period of 3-5 months routinely computer tomography scans followed by virtual implant planning. The implants were inserted using guided oral implantation as described by Naziri et al. All records of all the consecutive patients were reviewed according to patient age, history of periodontitis, smoking status, jaw area and dental situation, augmentation method, intra- and postoperative surgical complications, and surgeon's qualifications. Evaluated was the augmentation surgical outcome regarding bone graft loss and early implant loss postoperatively at the time of prosthodontic restauration as well a follow-up period of 2 years after loading. RESULTS: A total of 279 patients underwent 456 autologous augmentation procedures in 546 edentulous areas. One hundred thirteen crista zygomatico-alveolaris grafts, 104 ramus mandible grafts, 11 symphysis grafts, 116 grafts from the anterior superior iliac crest, and 112 sinus lift augmentations with bone scrapes from the anterior facial wall had been performed. There was no drop out or loss of follow-up of any case that had been treated in our clinical center in this 3-year period. Four hundred thirty-six (95.6%) of the bone grafts healed successfully, and 20 grafts (4.4%) in 20 patients had been lost. Fourteen out of 20 patients with total graft failure were secondarily re-augmented, and six patients wished no further harvesting procedure. In the six patients, a partial graft resorption was detected at the time of implantation and additional simultaneous augmentation during implant insertion was necessary. No long-term nerve injury occurred. Five hundred twenty-five out of 546 initially planned implants in 259 patients could be inserted into successfully augmented areas, whereas 21 implants in 20 patients due to graft loss could not be inserted. A final rehabilitation as preplanned with dental implants was possible in 273 of the 279 patients. The early implant failure rate was 0.38% concerning two out of the 525 inserted implants which had to be removed before the prosthodontic restoration. Two implants after iliac crest augmentation were lost within a period of 2 years after loading, concerning a total implant survival rate after 2 years of occlusal loading rate of 99.6% after autologous bone augmentation prior to implant insertion. CONCLUSIONS: This review demonstrates the predictability of autologous bone material in alveolar ridge reconstructions prior to implant insertion, independent from donor and recipient site including even autologous bone chips for sinus elevation. Due to the low harvesting morbidity of autologous bone grafts, the clinical results of our study indicate that autologous bone grafts still remain the "gold standard" in alveolar ridge augmentation prior to oral implantation. PMID- 28573553 TI - Medication Use and Fall-Related Hospital Admissions from Long-Term Care Facilities: A Hospital-Based Case-Control Study. AB - BACKGROUND: Falls are a leading cause of preventable hospitalizations from long term care facilities (LTCFs). Polypharmacy and falls-risk medications are potentially modifiable risk factors for falling. OBJECTIVE: This study investigated whether polypharmacy and falls-risk medications are associated with fall-related hospital admissions from LTCFs compared with hospital admissions for other causes. METHODS: This was a hospital-based, case-control study of patients aged >=65 years hospitalized from LTCFs. Cases were patients with falls and fall related injuries, and controls were patients admitted for infections. Conditional logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between polypharmacy (defined as the use of nine or more regular pre-admission medications) and falls-risk medications (categorized as psychotropic medications and those that can cause orthostatic hypotension) with fall-related hospital admissions. RESULTS: There was no association between polypharmacy and fall-related hospital admissions (adjusted OR 0.97, 95% CI 0.63-1.48); however, the adjusted odds of fall-related hospital admissions increased by 16% (95% CI 3-30%) for each additional falls risk medication. Medications that can cause orthostatic hypotension (adjusted OR 1.25, 95% CI 1.06-1.46), but not psychotropic falls-risk medications (adjusted OR 1.02, 95% CI 0.88-1.18) were associated with fall-related hospital admissions. The association between medications that can cause orthostatic hypotension and fall-related hospital admissions was strongest among residents with polypharmacy (adjusted OR 1.44, 95% CI 1.08-1.92). CONCLUSION: Polypharmacy was not an independent risk factor for fall-related hospital admissions; however, medications that can cause orthostatic hypotension were associated with fall related hospital admissions, particularly among residents with polypharmacy. Falls-risk should be considered when prescribing medications that can cause orthostatic hypotension. PMID- 28573555 TI - [Antibiotic strategies in trauma surgery : Treatment of implant-associated infections]. AB - Implant-associated infections represent a serious complication following fracture management. Due to biofilm formation, an optimized treatment strategy is required to treat these infections. Interdisciplinary cooperation between trauma surgeon, infectious diseases specialist and microbiologist enables the deployment of a concerted surgical and antibiotic treatment concept, which significantly influences treatment success. Fracture healing and chronic osteomyelitis prevention are the primary treatment goals. In general, the eradication of infection is possible with surgical debridement, change or removal of the implant and adequate antibiotic therapy. In some cases, suppressive therapy until consolidation of fracture and later removal of the implant is an option. PMID- 28573554 TI - [Prevention of postoperative infections : Risk factors and the current WHO guidelines in musculoskeletal surgery]. AB - BACKGROUND: Despite the many scientific and technological advances postoperative infection continues to be a large problem for trauma and orthopedic surgeons. Based on a review of the current literature, this study provides a comprehensive overview of the risk factors (RF) and possible preventive measures to control surgical site infections. METHODS: Medline search and analysis from 1968-2017 (as of 01 March 2017). Selection of trauma and orthopedic relevant RFs and comparison with WHO recommendations (global guidelines for the prevention of surgical site infection, Nov. 2016). RESULTS: Identification of 858 relevant articles from the last 50 years (1968-2017). Pooled postoperative rate of infection is 0.3% (hand surgery) and 19% (3rd degree open fractures). For open fractures, there is no clear tendency towards lower infection rates during the past five decades. Identification of 115 RF from three areas (patient-dependent RF, organizational and procedural RF, trauma- and surgery-dependent RF). The five most important RFs are body mass index over 35 kg/m2, increased duration of surgery, diabetes mellitus, increased blood glucose levels in the perioperative period also in the case of nondiabetic patients, and errors in the perioperative antibiotic prophylaxis. DISCUSSION: Inconsistent definition of "infection", interaction of the RF and the different follow-up duration limit the meaningfulness of the study. CONCLUSION: In the future, considerable efforts must be made in order to achieve a noticeable reduction in the rate of infection, especially in the case of high-risk patients. PMID- 28573556 TI - The influence of bone loss on the three adult age markers of the innominate. AB - To evaluate the influence of bone loss on the three adult age markers of the innominate, 30 males and 30 females aged between 16 and 80 years coming from the British Coventry collection were analyzed. The pubic symphysis, auricular surface, and acetabulum age variables were evaluated following the descriptions of Schmitt, Buckberry-Chamberlain, and Rissech, respectively. The second metacarpal cortical index was used to evaluate bone loss. Possible sexual differences in metrical variables were explored by a Student t-test taking into account the entire sample. The possible relationships between the cortical index and the three age methods' stages were assessed by the Kruskall-Wallis test and Spearman's correlation coefficient. There were no sexual differences in the cortical index. In general, we observed no significant differences between the cortical index in the different stages of the pubic symphysis, auricular surface, or acetabulum variables in men and women. Most correlation coefficients are negatives, and their absolute values are between 0.001 and 0.44, indicating an extremely low influence of bone loss on the analyzed variables. Our findings suggest little influence of bone loss in the three ageing methods. However, further research on this topic is necessary. This is the first study to analyze the influence of bone loss in the ageing changes undergone by the variables of the three adult age indicators of the innominate taking into account both sexes. PMID- 28573557 TI - Synthesis of the DDT metabolite 2,4-dichloro-1-[2-chloro-1-(4 chlorophenyl)ethenyl]benzene (o-Cl-DDMU) and its detection in abiotic and biotic samples. AB - Technical dichlorodiphenyltrichloroethane (DDT) has been used worldwide as a pesticide since the beginning of the 1940s. Due to its persistence, DDT residues are still ubiquitously distributed in the environment. Photochemical UV degradation has been shown to be a potent degradation path for DDT and most of the resulting photoproducts have been identified up to now. Nevertheless, in 2012, a new DDT metabolite, most likely formed photochemically from DDE, was detected in ray liver samples from Brazil, an area which is highly contaminated with DDT. This study includes photochemical generation, chemical synthesis and isolation of this compound which was verified to consist of both cis- and trans 2,4-dichloro-1-[2-chloro-1-(4-chlorophenyl)ethenyl]benzene. Both stereoisomers were resolved by gas chromatography on a polar capillary column and detected in more than 60 biotic (e.g. marine mammals, birds, human milk) and abiotic samples (fat deposits in kitchen hoods) from different areas all over the world. The stereoisomer distribution and concentrations (0.3-3.9% relative to corresponding 1,1-dichloro-2,2-bis(p-chlorophenyl) ethane (p,p'-DDE) levels) were determined by means of the synthesized analytical standard, indicating the widespread occurrence of this compound as an additional minor metabolite of DDT. PMID- 28573558 TI - Short-term biochar application induced variations in C and N mineralization in a compost-amended tropical soil. AB - To mitigate food shortage due to global warming, developing sustainable management practices to stabilize soil organic matter (SOM) and sequester more carbon (C) in the cultivated soils is necessary, particularly in subtropical and tropical areas. A short-term (56 days) incubation experiment was conducted to evaluate the influences of rice husk biochar (RHB) and manure compost (MC) application on C mineralization and nitrogen (N) immobilization in a sandy loam soil. The RHB was separately incorporated into the soil at application rates of 2 and 4% (w/w) either with or without 1% (w/w) compost. Our results displayed that macroaggregates (>=2 mm) were obviously increased by 11% in soil amended with RHB + MC at the end of incubation. In addition, the experimental results presented that the C mineralization of the soil rapidly increased during the first week of incubation. However, the co-application of compost with biochar (RHB + MC) revealed that CO2 emission was significantly decreased by 13-20% compared to the soil with only MC. In addition, the mineralized N in the soil was lower in RHB + MC-amended soil simultaneously than only MC-amended soil, indicating that biochar addition induced N immobilization. The physical protection of compost by its occlusion into aggregates or adsorption on surface of RHB as proved by the micromorphological observation was the main reason for lower C and N mineralization in soil amended with RHB + MC. Overall results revealed that RHB + MC treatment can decrease the decomposition of compost and sequester more C in the tropical agricultural soils. PMID- 28573559 TI - Impact of green supply chain management practices on firms' performance: an empirical study from the perspective of Pakistan. AB - This article investigates the impact of five determinants of the green supply chain practices on organizational performance in the context of Pakistan manufacturing firms. A sample of 218 firms was collected from the manufacturing industry. The green supply chain practices were measured through five independent variables including green manufacturing, green purchasing, green information systems, cooperation with customers, and eco-design. By using exploratory factor and simultaneous regression analysis, the results indicate that except green purchasing, rests of the four independent variables have been found statistically significant to predict organizational performance. However, the eco-design of green practices followed by green information systems has revealed the greatest impact on organizational performance. Therefore, the managers of the manufacturing firms should not only implement eco-design in their supply chain but also concentrate on proper monitoring and implementation of green information systems to increase their firms' performance. A main contribution of this research from theoretical side is that it is possible to notice a negative effect of "green purchasing" towards organizational performance particularly in the scenario of Pakistan manufacturing industry. Another valuable result is that green purchasing is an important antecedent of firms economic performance in the US manufacturing firms (Green et al. 2012), although not significantly related to organizational performance in our study. In addition, we also discussed research limitations, areas for future research, and implications for practitioners. PMID- 28573560 TI - Phyto-management of Cr-contaminated soils by sunflower hybrids: physiological and biochemical response and metal extractability under Cr stress. AB - Chromium (Cr) is a biologically non-essential, carcinogenic and toxic heavy metal. The cultivation of Cr-tolerant genotypes seems the most favorable and environment friendly strategy for rehabilitation and remediation of Cr contaminated soils. To prove this hypothesis and identify the Cr tolerance, the present study was performed to assess the physiological and biochemical response of sunflower genotypes to Cr stress. The seeds of six sunflower hybrids, namely FH-425, FH-600, FH-612, FH-614, FH-619, and FH-620, were grown in spiked soil for 12 weeks under increasing concentrations of Cr (0, 5, 10, and 20 mg kg-1). A seed germination test was also run under different concentrations of Cr (0, 5, 10, 200 mM) in petri dishes. Plants were harvested after 12 weeks of germination. Different plant attributes such as growth; biomass; photosynthesis; gas exchange; activity of antioxidant enzymes, i.e., superoxide dismutase (SOD), guaiacol peroxidase (POD), ascorbate (APX), and catalases (CAT); reactive oxygen species (ROS); lipid peroxidation; electrolyte leakage; and Cr concentration as well as accumulations in all plant parts were studied for the selection of the most Cr tolerant genotype. Increasing concentration of Cr in soil triggered the reduction of all plant parameters in sunflower. Cr stress increased electrolyte leakage and production of reactive oxygen species which stimulated the activities of antioxidant enzymes and gas exchange attributes of sunflower. Chromium accumulation in the root and shoot increased gradually with increasing Cr treatments and caused reduction in overall plant growth. The accumulation of Cr was recorded in the order of FH-614 > FH-620 > FH-600 > FH-619 > FH-612 > FH-425. The differential uptake and accumulation of Cr by sunflower hybrids may be useful in selection and breeding for Cr-tolerant genotypes. PMID- 28573561 TI - Farm-level economics of innovative tillage technologies: the case of no-till in the Altai Krai in Russian Siberia. AB - In the agricultural Altai Krai in Russian Siberia, soil degradation problems are prevalent. Agronomists recommend "reduced tillage systems," especially no-till, as a sustainable way to cultivate land that is threatened by soil degradation. In the Altai Krai, less is known about the technologies in practice. In this paper, we provide information on plant cultivation technologies used in the Altai Krai and on selected factors preventing farm managers in this region from adopting no till technology based on our own quantitative survey conducted across 107 farms in 2015 and 2016. The results of the quantitative survey show that farm managers have high uncertainty regarding the use of no-till technology including its economics. To close this gap, we provide systematic analysis of factors influencing the economy of the plant production systems by using a farm optimization model (linear programming) for a real farm, together with expert estimations. The farm-specific results of the optimization model show that under optimal management and climatic conditions, the expert Modern Canadian no-till technology outperforms the farm min-till technology, but this is not the case for suboptimal conditions with lower yields. PMID- 28573562 TI - Hospital admissions in Iran for cardiovascular and respiratory diseases attributed to the Middle Eastern Dust storms. AB - The main objective of this study was to assess the possible effects of airborne particulate matter less than 10 MUm in diameter (PM10) from the Middle Eastern Dust (MED) events on human health in Khorramabad (Iran) in terms of estimated hospital admissions (morbidity) for cardiovascular diseases (HACD) and for respiratory diseases (HARD) during the period of 2015 to 2016. The AirQ program developed by the World Health Organization (WHO) was used to estimate the potential health impacts to daily PM10 exposures. The numbers of excess cases for cardiovascular/respiratory morbidity were 20/51, 72/185, and 20/53 on normal, dusty, and MED event days, respectively. The highest number of hospital admissions was estimated for PM10 concentrations in the range of 40 to 49 MUg/m3, i.e, lower than the daily (50 MUg/m3) limit value established by WHO. The results also showed that 4.7% (95% CI 3.2-6.7%) and 4.2% (95% CI 2.6-5.8%) of HARD and HACD, respectively, were attributed to PM10 concentrations above 10 MUg/m3. The study demonstrates a significant impact of air pollution on people, which is manifested primarily as respiratory and cardiovascular problems. To reduce these effects, several immediate actions should be taken by the local authorities to control the impacts of dust storms on residents' health, e.g., developing a green beltway along the Iran-Iraq border and management of water such as irrigation of dry areas that would be effective as mitigation strategies. PMID- 28573563 TI - Bioregeneration of spent mercury bearing sulfur-impregnated activated carbon adsorbent. AB - Among various adsorbents studied, sulfur-impregnated activated carbon is one of the most promising adsorbents for mercury removal from flue gas. However, a large amount of spent activated carbons containing high content of mercury are generated after adsorption. To make the adsorption a more viable option, the regeneration and reuse of the spent activated carbon should be considered. The purpose of this study is to develop a novel technique for bioregeneration of sulfur-impregnated activated carbons after adsorption of mercury from flue gases by sulfur-oxidizing bacteria. The optimal operating parameters for this bioregeneration process were studied using central composite design (CCD) and response surface methodology (RSM). Results showed that the sulfur oxidation rate was increased with increasing activated carbon dosage. Furthermore, the increase of inoculum size only caused a slight increase of sulfur oxidation rate in the bioregeneration. The maximum mercury removal efficiency of more than 50% was obtained at 10% (w/v) activated carbon dosage and 20% (v/v) inoculum size. After the bioregeneration process, Brunauer-Emmett-Teller (BET) surface area and micropore volume of spent activated carbon increased due to the bio-oxidation of mercury bearing sulfur on the surface of activated carbons. PMID- 28573564 TI - Effect of solid waste landfill organic pollutants on groundwater in three areas of Sicily (Italy) characterized by different vulnerability. AB - The aim of this study was to obtain information on the presence and levels of hazardous organic pollutants in groundwater located close to solid waste landfills. Eighty-two environmental contaminants, including 16 polycyclic aromatic hydrocarbons (PAHs), 20 volatile organic compounds (VOCs), 29 polychlorinated biphenyls (PCBs), 7 dioxins (polychlorinated dibenzo-p-dioxins, PCDDs) and 10 furans (polychlorinated dibenzofurans, PCDFs) were monitored in areas characterised by different geological environments surrounding three municipal solid waste landfills (Palermo, Siculiana and Ragusa) in Sicily (Italy) in three sampling campaigns. The total concentrations of the 16 PAHs were always below the legal threshold. Overall, the Fl/Fl + Py diagnostic ratio revealed that PAHs had a petrogenic origin. VOC levels, except for two notable exceptions near Palermo landfill, were always below the legal limit. As concerns PCB levels, several samples were found positive with levels exceeding the legal limits. It is worth noting that the % PCB distribution differs from that of commercial compositions. In parallel, some samples of groundwater containing PCDDs and PCDFs exceeding the legal threshold were also found. Among the 17 congeners monitored, the most abundant were the highest molecular weight ones. PMID- 28573565 TI - Concentration estimation of heavy metal in soils from typical sewage irrigation area of Shandong Province, China using reflectance spectroscopy. AB - Since sewage irrigation can markedly disturb the status of heavy metals in soils, a convenient and accurate technique for heavy metal concentration estimation is of utmost importance in the cropland using wastewater for irrigation. This study therefore assessed the feasibility of visible and near infrared reflectance (VINR) spectroscopy for predicting heavy metal contents including Cr, Cu, Ni, Pb, Zn, As, Cd, and Hg in the north plain of Longkou city, Shandong Province, China. A total of 70 topsoil samples were taken for in situ spectra measurement and chemical analysis. Stepwise multiple linear regression (SMLR) and principal component regression (PCR) algorithms were applied to establish the associations between heavy metals and reflectance spectral data pretreated by different transformation methods. Based on the criteria that minimal root mean square error (RMSE), maximal coefficient of determination (R 2) for calibration, and greater ratio of standard error of performance to standard deviation (RPD) is related to the optimal model, SMLR model using first deviation data (RD1) provided the best prediction for the contents of Ni, Pb, As, Cd, and Hg, calibration using SNV data for Cr and continuum removal spectra for Zn, while PCR equation employed RD1 values was fit for prediction of the contents of Cu. The determination coefficients of all the reasonable models were beyond 0.6, and RPD indicated a fair or good result. In general, first deviation preprocessing tool outperformed other methods in this study, while raw spectra reflectance performed unsatisfactory in all models. Overall, VINR reflectance spectroscopy technique could be applicable to the rapid concentration assessment of heavy metals in soils of the study area. PMID- 28573566 TI - Determination of carbamazepine and 12 degradation products in various compartments of an outdoor aquatic mesocosm by reliable analytical methods based on liquid chromatography-tandem mass spectrometry. AB - The aims of this work are to develop suitable analytical methods to determine the widely used anticonvulsant carbamazepine and 12 of its degradation/transformation products in water, sediment, fish (Gasterosteus aculeatus) and mollusc (Dreissena polymorpha). Protocols based on solid phase extraction for water, pressurized liquid extraction for sediments and QuEChERS (quick easy cheap efficient rugged and safe) extraction for both organisms followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) are developed, validated and finally applied to samples collected during a 6-month experiment in outdoor mesocosms. Very low detection limits are reached, allowing environmentally realistic doses (namely, 0.05, 0.5 and 5 MUg/L nominal concentrations) to be employed. The results indicate several metabolites and/or transformation products in each compartment investigated, with concentrations sometimes being greater than that of the parent carbamazepine. Biotic degradation of carbamazepine is demonstrated in water, leading to 10,11-dihydrocarbamazepine and 10,11-epoxycarbamazepine. In sediment, the degradation results in the formation of acridine, and 2- and 3 hydroxycarbamazepine. Finally, in both organisms, a moderate bioaccumulation is observed together with a metabolization leading to 10,11-epoxycarbamazepine in fish and 2-hydroxycarbamazepine in mollusc. Acridone is also present in fish. This study provides new and interesting data, helping to elucidate how chronic exposure to carbamazepine at relevant concentrations may affect impact freshwater ecosystems. PMID- 28573567 TI - Expression and Purification of Recombinant Proteins in Escherichia coli with a His6 or Dual His6-MBP Tag. AB - Rapid advances in bioengineering and biotechnology over the past three decades have greatly facilitated the production of recombinant proteins in Escherichia coli. Affinity-based methods that employ protein or peptide based tags for protein purification have been instrumental in this progress. Yet insolubility of recombinant proteins in E. coli remains a persistent problem. One way around this problem is to fuse an aggregation-prone protein to a highly soluble partner. E. coli maltose-binding protein (MBP) is widely acknowledged as a highly effective solubilizing agent. In this chapter, we describe how to construct either a His6- or a dual His6-MBP tagged fusion protein by Gateway(r) recombinational cloning and how to evaluate their yield and solubility. We also describe a simple and rapid procedure to test the solubility of proteins after removing their N terminal fusion tags by tobacco etch virus (TEV) protease digestion. The choice of whether to use a His6 tag or a His6-MBP tag can be made on the basis of this solubility test. PMID- 28573568 TI - Protein Crystallization. AB - Protein crystallization was discovered by chance nearly 200 years ago and was developed in the late nineteenth century as a powerful purification tool, and a demonstration of chemical purity. The crystallization of proteins, nucleic acids, and large biological complexes, such as viruses, depends on the creation of a solution that is supersaturated in the macromolecule, but exhibits conditions that do not significantly perturb its natural state. Supersaturation is produced through the addition of mild precipitating agents such as neutral salts or polymers, and by manipulation of various parameters that include temperature, ionic strength, and pH. Also important in the crystallization process are factors that can affect the structural state of the macromolecule, such as metal ions, inhibitors, cofactors, or other conventional small molecules. A variety of approaches have been developed that combine the spectrum of factors that effect and promote crystallization, and among the most widely used are vapor diffusion, dialysis, batch, and liquid-liquid diffusion. Successes in macromolecular crystallization have multiplied rapidly in recent years due to the advent of practical, easy-to-use screening kits, and the application of laboratory robotics. PMID- 28573569 TI - Advanced Methods of Protein Crystallization. AB - This chapter provides a review of different advanced methods that help to increase the success rate of a crystallization project, by producing larger and higher quality single crystals for determination of macromolecular structures by crystallographic methods. For this purpose, the chapter is divided into three parts. The first part deals with the fundamentals for understanding the crystallization process through different strategies based on physical and chemical approaches. The second part presents new approaches involved in more sophisticated methods not only for growing protein crystals but also for controlling the size and orientation of crystals through utilization of electromagnetic fields and other advanced techniques. The last section deals with three different aspects: the importance of microgravity, the use of ligands to stabilize proteins, and the use of microfluidics to obtain protein crystals. All these advanced methods will allow the readers to obtain suitable crystalline samples for high-resolution X-ray and neutron crystallography. PMID- 28573571 TI - Crystallization of Membrane Proteins: An Overview. AB - Membrane proteins are crucial components of cellular membranes and are responsible for a variety of physiological functions. The advent of new tools and technologies for structural biology of membrane proteins has led to a significant increase in the number of structures deposited to the Protein Data Bank during the past decade. This new knowledge has expanded our fundamental understanding of their mechanism of function and contributed to the drug-design efforts. In this chapter we discuss current approaches for membrane protein expression, solubilization, crystallization, and data collection. Additionally, we describe the protein quality-control assays that are often instrumental as a guideline for a shorter path toward the structure. PMID- 28573572 TI - Locating and Visualizing Crystals for X-Ray Diffraction Experiments. AB - Macromolecular crystallography has advanced from using macroscopic crystals, which might be >1 mm on a side, to crystals that are essentially invisible to the naked eye, or even under a standard laboratory microscope. As crystallography requires recognizing crystals when they are produced, and then placing them in an X-ray, electron, or neutron beam, this provides challenges, particularly in the case of advanced X-ray sources, where beams have very small cross sections and crystals may be vanishingly small. Methods for visualizing crystals are reviewed here, and examples of different types of cases are presented, including: standard crystals, crystals grown in mesophase, in situ crystallography, and crystals grown for X-ray Free Electron Laser or Micro Electron Diffraction experiments. As most techniques have limitations, it is desirable to have a range of complementary techniques available to identify and locate crystals. Ideally, a given technique should not cause sample damage, but sometimes it is necessary to use techniques where damage can only be minimized. For extreme circumstances, the act of probing location may be coincident with collecting X-ray diffraction data. Future challenges and directions are also discussed. PMID- 28573570 TI - The "Sticky Patch" Model of Crystallization and Modification of Proteins for Enhanced Crystallizability. AB - Crystallization of macromolecules has long been perceived as a stochastic process, which cannot be predicted or controlled. This is consistent with another popular notion that the interactions of molecules within the crystal, i.e., crystal contacts, are essentially random and devoid of specific physicochemical features. In contrast, functionally relevant surfaces, such as oligomerization interfaces and specific protein-protein interaction sites, are under evolutionary pressures so their amino acid composition, structure, and topology are distinct. However, current theoretical and experimental studies are significantly changing our understanding of the nature of crystallization. The increasingly popular "sticky patch" model, derived from soft matter physics, describes crystallization as a process driven by interactions between select, specific surface patches, with properties thermodynamically favorable for cohesive interactions. Independent support for this model comes from various sources including structural studies and bioinformatics. Proteins that are recalcitrant to crystallization can be modified for enhanced crystallizability through chemical or mutational modification of their surface to effectively engineer "sticky patches" which would drive crystallization. Here, we discuss the current state of knowledge of the relationship between the microscopic properties of the target macromolecule and its crystallizability, focusing on the "sticky patch" model. We discuss state-of-the-art in silico methods that evaluate the propensity of a given target protein to form crystals based on these relationships, with the objective to design variants with modified molecular surface properties and enhanced crystallization propensity. We illustrate this discussion with specific cases where these approaches allowed to generate crystals suitable for structural analysis. PMID- 28573573 TI - Collection of X-Ray Diffraction Data from Macromolecular Crystals. AB - Diffraction data acquisition is the final experimental stage of the crystal structure analysis. All subsequent steps involve mainly computer calculations. Optimally measured and accurate data make the structure solution and refinement easier and lead to more faithful interpretation of the final models. Here, the important factors in data collection from macromolecular crystals are discussed and strategies appropriate for various applications, such as molecular replacement, anomalous phasing, and atomic-resolution refinement are presented. Criteria useful for judging the diffraction data quality are also discussed. PMID- 28573574 TI - Identifying and Overcoming Crystal Pathologies: Disorder and Twinning. AB - Macromolecular crystals are prone to a number of pathologies that result from aberrant molecular packing. Two common pathologies encountered in macromolecular crystals are rigid-body disorder and twinning. When a crystal displays one of these pathologies, its diffraction pattern is altered in a way that generally complicates structure determination. The severity of the underlying abnormalities varies from case to case, and sometimes the resulting alterations to the diffraction pattern are immediately obvious, while at other times they may go entirely unnoticed. Structure determination from a crystal that suffers from disorder or twinning may or may not be possible, depending on the specific nature of the pathology, and on how the data are handled. This chapter provides an introduction to these pathologies, with an emphasis on providing guidelines for identifying and overcoming them when they pose a threat to successful structure determination. PMID- 28573575 TI - Applications of X-Ray Micro-Beam for Data Collection. AB - Micro-diffraction tools for macromolecular crystallography, first developed at the end of 1990s and now an integral part of many synchrotron beamlines, enable some of the experiments which were not feasible just a decade or so ago. These include data collection from very small samples, just a few micrometers in size; from larger, but severely inhomogeneous samples; and from samples which are optically invisible. Improved micro-diffraction tools led to improved signal-to noise ratio, to mitigation of radiation damage in some cases, and to better designed diffraction experiments. Small, micron-scale beams can be attained in different ways and knowing the details of the implementation is important in order to design the diffraction experiment properly. Similarly, precision, reproducibility and stability of the goniometry, and caveats of detection systems need to be taken into account. Lastly, to make micro-diffraction widely applicable, the sophistication, robustness, and user-friendliness of these tools are just as important as the technical capabilities. PMID- 28573576 TI - Serial Synchrotron X-Ray Crystallography (SSX). AB - Prompted by methodological advances in measurements with X-ray free electron lasers, it was realized in the last two years that traditional (or conventional) methods for data collection from crystals of macromolecular specimens can be complemented by synchrotron measurements on microcrystals that would individually not suffice for a complete data set. Measuring, processing, and merging many partial data sets of this kind requires new techniques which have since been implemented at several third-generation synchrotron facilities, and are described here. Among these, we particularly focus on the possibility of in situ measurements combined with in meso crystal preparations and data analysis with the XDS package and auxiliary programs. PMID- 28573577 TI - Time-Resolved Macromolecular Crystallography at Modern X-Ray Sources. AB - Time-resolved macromolecular crystallography unifies protein structure determination with chemical kinetics. With the advent of fourth generation X-ray sources the time-resolution can be on the order of 10-40 fs, which opens the ultrafast time scale to structure determination. Fundamental motions and transitions associated with chemical reactions in proteins can now be observed. Moreover, new experimental approaches at synchrotrons allow for the straightforward investigation of all kind of reactions in biological macromolecules. Here, recent developments in the field are reviewed. PMID- 28573578 TI - Structure Determination Using X-Ray Free-Electron Laser Pulses. AB - The intense X-ray pulses from free-electron lasers, of only femtoseconds duration, outrun most of the processes that lead to structural degradation in X ray exposures of macromolecules. Using these sources it is therefore possible to increase the dose to macromolecular crystals by several orders of magnitude higher than usually tolerable in conventional measurements, allowing crystal size to be decreased dramatically in diffraction measurements and without the need to cool the sample. Such pulses lead to the eventual vaporization of the sample, which has required a measurement approach, called serial crystallography, of consolidating snapshot diffraction patterns of many individual crystals. This in turn has further separated the connection between dose and obtainable diffraction information, with the only requirement from a single pattern being that to give enough information to place it, in three-dimensional reciprocal space, in relation to other patterns. Millions of extremely weak patterns can be collected and combined in this way, requiring methods to rapidly replenish the sample into the beam while generating the lowest possible background . The method is suited to time-resolved measurements over timescales below 1 ps to several seconds, and opens new opportunities for phasing. Some straightforward considerations of achievable signal levels are discussed and compared with a wide variety of recent experiments carried out at XFEL, synchrotron, and even laboratory sources, to discuss the capabilities of these new approaches and give some perspectives on their further development. PMID- 28573579 TI - Processing of XFEL Data. AB - The introduction of the X-ray laser to crystallography, and its impact on the types of crystallographic experiments being performed as described in the previous chapter, has meant that new data processing strategies had to be found. While some XFEL crystallography experiments approach the conventional methods quite closely, even those are not without special considerations relating to data processing. Serial femtosecond crystallography (SFX) introduces several additional problems, many of which have been solved recently, and there has been great progress towards resolving the remaining ones. Recent developments into the use of continuous scattering between the Bragg peaks will need even greater changes to the conventional data processing methods. This chapter describes the special characteristics of XFEL data and introduces the range of processing methods which are currently under development. PMID- 28573580 TI - Many Ways to Derivatize Macromolecules and Their Crystals for Phasing. AB - Due to the availability of many macromolecular models in the Protein Data Bank, the majority of crystal structures are currently solved by molecular replacement. However, truly novel structures can only be solved by one of the versions of the special-atom method. The special atoms such as sulfur, phosphorus or metals could be naturally present in the macromolecules, or could be intentionally introduced in a derivatization process. The isomorphous and/or anomalous scattering of X rays by these special atoms is then utilized for phasing. There are many ways to obtain potentially useful derivatives, ranging from the introduction of special atoms to proteins or nucleic acids by genetic engineering or by chemical synthesis, to soaking native crystals in solutions of appropriate compounds with heavy and/or anomalously scattering atoms. No approach guarantees the ultimate success and derivatization remains largely a trial-and-error process. In practice, however, there is a very good chance that one of a wide variety of the available procedures will lead to successful structure solution. PMID- 28573581 TI - Experimental Phasing: Substructure Solution and Density Modification as Implemented in SHELX. AB - This chapter describes experimental phasing methods as implemented in SHELX. After introducing fundamental concepts underlying all experimental phasing approaches, the methods used by SHELXC/D/E are described in greater detail, such as dual-space direct methods, Patterson seeding and density modification with the sphere of influence algorithm. Intensity differences from data for experimental phasing can also be used for the generation and usage of difference maps with ANODE for validation and phasing purposes. A short section describes how molecular replacement can be combined with experimental phasing methods. The second half covers practical challenges, such as prerequisites for successful experimental phasing, evaluation of potential solutions, and what to do if substructure search or density modification fails. It is also shown how auto tracing in SHELXE can improve automation and how it ties in with automatic model building after phasing. PMID- 28573583 TI - Long-Wavelength X-Ray Diffraction and Its Applications in Macromolecular Crystallography. AB - For many years, diffraction experiments in macromolecular crystallography at X ray wavelengths longer than that of Cu-K alpha (1.54 A) have been largely underappreciated. Effects caused by increased X-ray absorption result in the fact that these experiments are more difficult than the standard diffraction experiments at short wavelengths. However, due to the also increased anomalous scattering of many biologically relevant atoms, important additional structural information can be obtained. This information, in turn, can be used for phase determination, for substructure identification, in molecular replacement approaches, as well as in structure refinement. This chapter reviews the possibilities and the difficulties associated with such experiments, and it provides a short description of two macromolecular crystallography synchrotron beam lines dedicated to long-wavelength X-ray diffraction experiments. PMID- 28573584 TI - Acknowledging Errors: Advanced Molecular Replacement with Phaser. AB - Molecular replacement is a method for solving the crystallographic phase problem using an atomic model for the target structure. State-of-the-art methods have moved the field significantly from when it was first envisaged as a method for solving cases of high homology and completeness between a model and target structure. Improvements brought about by application of maximum likelihood statistics mean that various errors in the model and pathologies in the data can be accounted for, so that cases hitherto thought to be intractable are standardly solvable. As a result, molecular replacement phasing now accounts for the lion's share of structures deposited in the Protein Data Bank. However, there will always be cases at the fringes of solvability. I discuss here the approaches that will help tackle challenging molecular replacement cases. PMID- 28573582 TI - Contemporary Use of Anomalous Diffraction in Biomolecular Structure Analysis. AB - The normal elastic X-ray scattering that depends only on electron density can be modulated by an "anomalous" component due to resonance between X-rays and electronic orbitals. Anomalous scattering thereby precisely identifies atomic species, since orbitals distinguish atomic elements, which enables the multi- and single-wavelength anomalous diffraction (MAD and SAD) methods. SAD now predominates in de novo structure determination of biological macromolecules, and we focus here on the prevailing SAD method. We describe the anomalous phasing theory and the periodic table of phasing elements that are available for SAD experiments, differentiating between those readily accessible for at-resonance experiments and those that can be effective away from an edge. We describe procedures for present-day SAD phasing experiments and we discuss optimization of anomalous signals for challenging applications. We also describe methods for using anomalous signals as molecular markers for tracing and element identification. Emerging developments and perspectives are discussed in brief. PMID- 28573585 TI - Rosetta Structure Prediction as a Tool for Solving Difficult Molecular Replacement Problems. AB - Molecular replacement (MR), a method for solving the crystallographic phase problem using phases derived from a model of the target structure, has proven extremely valuable, accounting for the vast majority of structures solved by X ray crystallography. However, when the resolution of data is low, or the starting model is very dissimilar to the target protein, solving structures via molecular replacement may be very challenging. In recent years, protein structure prediction methodology has emerged as a powerful tool in model building and model refinement for difficult molecular replacement problems. This chapter describes some of the tools available in Rosetta for model building and model refinement specifically geared toward difficult molecular replacement cases. PMID- 28573586 TI - Radiation Damage in Macromolecular Crystallography. AB - Radiation damage inflicted on macromolecular crystals during X-ray diffraction experiments remains a limiting factor for structure solution, even when samples are cooled to cryotemperatures (~100 K). Efforts to establish mitigation strategies are ongoing and various approaches, summarized below, have been investigated over the last 15 years, resulting in a deeper understanding of the physical and chemical factors affecting damage rates. The recent advent of X-ray free electron lasers permits "diffraction-before-destruction" by providing highly brilliant and short (a few tens of fs) X-ray pulses. New fourth generation synchrotron sources now coming on line with higher X-ray flux densities than those available from third generation synchrotrons will bring the issue of radiation damage once more to the fore for structural biologists. PMID- 28573587 TI - Boxes of Model Building and Visualization. AB - Macromolecular crystallography and electron microscopy (single-particle and in situ tomography) are merging into a single approach used by the two coalescing scientific communities. The merger is a consequence of technical developments that enabled determination of atomic structures of macromolecules by electron microscopy. Technological progress in experimental methods of macromolecular structure determination, computer hardware, and software changed and continues to change the nature of model building and visualization of molecular structures. However, the increase in automation and availability of structure validation are reducing interactive manual model building to fiddling with details. On the other hand, interactive modeling tools increasingly rely on search and complex energy calculation procedures, which make manually driven changes in geometry increasingly powerful and at the same time less demanding. Thus, the need for accurate manual positioning of a model is decreasing. The user's push only needs to be sufficient to bring the model within the increasing convergence radius of the computing tools. It seems that we can now better than ever determine an average single structure. The tools work better, requirements for engagement of human brain are lowered, and the frontier of intellectual and scientific challenges has moved on. The quest for resolution of new challenges requires out of-the-box thinking. A few issues such as model bias and correctness of structure, ongoing developments in parameters defining geometric restraints, limitations of the ideal average single structure, and limitations of Bragg spot data are discussed here, together with the challenges that lie ahead. PMID- 28573588 TI - Structure Refinement at Atomic Resolution. AB - X-Ray diffraction data at atomic resolution, i.e., beyond 1.2 A, provide the most detailed and reliable information we have about the structure of macromolecules, which is especially important for validating new discoveries and resolving subtle issues of molecular mechanisms. Refinement at atomic resolution allows reliable interpretation of static disorder and solvent structure, as well as modeling of anisotropic atomic vibrations and even of H atoms. Stereochemical restraints can be relaxed or removed, providing unbiased information about macromolecular stereochemistry, which in turn can be used to define improved conformation dependent libraries, and the surplus of data allows estimation of least-squares uncertainties in the derived parameters. At ultrahigh resolution it is possible to study charge density distribution by multipolar refinement of electrons in non spherical orbitals. PMID- 28573589 TI - Low Resolution Refinement of Atomic Models Against Crystallographic Data. AB - This review describes some of the problems encountered during low-resolution refinement and map calculation. Refinement is considered as an application of Bayes' theorem, allowing combination of information from various sources including crystallographic experimental data and prior chemical and structural knowledge. The sources of prior knowledge relevant to macromolecules include basic chemical information such as bonds and angles, structural information from reference models of known homologs, knowledge about secondary structures, hydrogen bonding patterns, and similarity of non-crystallographically related copies of a molecule. Additionally, prior information encapsulating local conformational conservation is exploited, keeping local interatomic distances similar to those in the starting atomic model. The importance of designing an accurate likelihood function-the only link between model parameters and observed data-is emphasized. The review also reemphasizes the importance of phases, and describes how the use of raw observed amplitudes could give a better correlation between the calculated and "true" maps. It is shown that very noisy or absent observations can be replaced by calculated structure factors, weighted according to the accuracy of the atomic model. This approach helps to smoothen the map. However, such replacement should be used sparingly, as the bias toward errors in the model could be too much to avoid. It is in general recommended that, whenever a new map is calculated, map quality should be judged by inspection of the parts of the map where there is no atomic model. It is also noted that it is advisable to work with multiple blurred and sharpened maps, as different parts of a crystal may exhibit different degrees of mobility. Doing so can allow accurate building of atomic models, accounting for overall shape as well as finer structural details. Some of the results described in this review have been implemented in the programs REFMAC5, ProSMART and LORESTR, which are available as part of the CCP4 software suite. PMID- 28573590 TI - Stereochemistry and Validation of Macromolecular Structures. AB - Macromolecular structure is governed by the strict rules of stereochemistry. Several approaches to the validation of the correctness of the interpretation of crystallographic and NMR data that underlie the models deposited in the PDB are utilized in practice. The stereochemical rules applicable to macromolecular structures are discussed in this chapter. Practical, computer-based methods and tools of verification of how well the models adhere to those established structural principles to assure their quality are summarized. PMID- 28573591 TI - Validation of Protein-Ligand Crystal Structure Models: Small Molecule and Peptide Ligands. AB - Models of target proteins in complex with small molecule ligands or peptide ligands are of significant interest to the biomedical research community. Structure-guided lead discovery and structure-based drug design make extensive use of such models. The bound ligands comprise only a small fraction of the total X-ray scattering mass, and therefore particular care must be taken to properly validate the atomic model of the ligand as experimental data can often be scarce. The ligand model must be validated against both the primary experimental data and the local environment, specifically: (1) the primary evidence in the form of the electron density, (2) examined for reasonable stereochemistry, and (3) the chemical plausibility of the binding interactions must be inspected. Tools that assist the researcher in the validation process are presented. PMID- 28573592 TI - Protein Data Bank (PDB): The Single Global Macromolecular Structure Archive. AB - The Protein Data Bank (PDB)--the single global repository of experimentally determined 3D structures of biological macromolecules and their complexes--was established in 1971, becoming the first open-access digital resource in the biological sciences. The PDB archive currently houses ~130,000 entries (May 2017). It is managed by the Worldwide Protein Data Bank organization (wwPDB; wwpdb.org), which includes the RCSB Protein Data Bank (RCSB PDB; rcsb.org), the Protein Data Bank Japan (PDBj; pdbj.org), the Protein Data Bank in Europe (PDBe; pdbe.org), and BioMagResBank (BMRB; www.bmrb.wisc.edu). The four wwPDB partners operate a unified global software system that enforces community-agreed data standards and supports data Deposition, Biocuration, and Validation of ~11,000 new PDB entries annually (deposit.wwpdb.org). The RCSB PDB currently acts as the archive keeper, ensuring disaster recovery of PDB data and coordinating weekly updates. wwPDB partners disseminate the same archival data from multiple FTP sites, while operating complementary websites that provide their own views of PDB data with selected value-added information and links to related data resources. At present, the PDB archives experimental data, associated metadata, and 3D atomic level structural models derived from three well-established methods: crystallography, nuclear magnetic resonance spectroscopy (NMR), and electron microscopy (3DEM). wwPDB partners are working closely with experts in related experimental areas (small-angle scattering, chemical cross-linking/mass spectrometry, Forster energy resonance transfer or FRET, etc.) to establish a federation of data resources that will support sustainable archiving and validation of 3D structural models and experimental data derived from integrative or hybrid methods. PMID- 28573593 TI - Databases, Repositories, and Other Data Resources in Structural Biology. AB - Structural biology, like many other areas of modern science, produces an enormous amount of primary, derived, and "meta" data with a high demand on data storage and manipulations. Primary data come from various steps of sample preparation, diffraction experiments, and functional studies. These data are not only used to obtain tangible results, like macromolecular structural models, but also to enrich and guide our analysis and interpretation of various biomedical problems. Herein we define several categories of data resources, (a) Archives, (b) Repositories, (c) Databases, and (d) Advanced Information Systems, that can accommodate primary, derived, or reference data. Data resources may be used either as web portals or internally by structural biology software. To be useful, each resource must be maintained, curated, as well as integrated with other resources. Ideally, the system of interconnected resources should evolve toward comprehensive "hubs", or Advanced Information Systems. Such systems, encompassing the PDB and UniProt, are indispensable not only for structural biology, but for many related fields of science. The categories of data resources described herein are applicable well beyond our usual scientific endeavors. PMID- 28573594 TI - Transmural cellular heterogeneity in myocardial electromechanics. AB - Myocardial heterogeneity is an attribute of the normal heart. We have developed integrative models of cardiomyocytes from the subendocardial (ENDO) and subepicardial (EPI) ventricular regions that take into account experimental data on specific regional features of intracellular electromechanical coupling in the guinea pig heart. The models adequately simulate experimental data on the differences in the action potential and contraction between the ENDO and EPI cells. The modeling results predict that heterogeneity in the parameters of calcium handling and myofilament mechanics in isolated ENDO and EPI cardiomyocytes are essential to produce the differences in Ca2+ transients and contraction profiles via cooperative mechanisms of mechano-calcium-electric feedback and may further slightly modulate transmural differences in the electrical properties between the cells. Simulation results predict that ENDO cells have greater sensitivity to changes in the mechanical load than EPI cells. These data are important for understanding the behavior of cardiomyocytes in the intact heart. PMID- 28573595 TI - Developing and Evaluating an Innovative Structural Competency Curriculum for Pre Health Students. AB - The inclusion of structural competency training in pre-health undergraduate programs may offer significant benefits to future healthcare professionals. This paper presents the results of a comparative study of an interdisciplinary pre health curriculum based in structural competency with a traditional premedical curriculum. The authors describe a new evaluation tool, the Structural Foundations of Health Survey (c) (2016), developed to evaluate structural skills and sensibilities. The authors use the survey to evaluate two groups of graduating seniors at Vanderbilt University-majors in an interdisciplinary pre health curriculum titled Medicine, Health, and Society (MHS), and premed science majors-with particular attention to understanding how political, cultural, economic, and social factors shape health. Results suggest that MHS majors identified and analyzed relationships between structural factors and health outcomes at higher rates and in deeper ways than did premed science majors. MHS students also demonstrated higher understanding of structural and cultural competency in their approaches to race, intersectionality, and racial health disparities. The skills that MHS students exhibited represent proficiencies increasingly emphasized by the MCAT, the AAMC, and other educational bodies that, in an era of epigenetics and social determinants, emphasize how contextual factors shape expressions of health and illness. PMID- 28573596 TI - Advancing Pre-Health Humanities as Intensive Research Practice: Principles and Recommendations from a Cross-Divisional Baccalaureate Setting. AB - This essay argues that pre-health humanities programs should focus on intensive research practice for baccalaureate students and provides three guiding principles for implementing it. Although the interdisciplinary nature of health humanities permits baccalaureate students to use research methods from the natural sciences, social sciences, and humanities, pre-health humanities coursework tends to force students to adopt only one of many disciplinary identities. Alternatively, an intensive research approach invites students to critically select and combine methods from multiple (and seemingly opposing) disciplines to ask and answer questions about health problems more innovatively. Using the authors' experiences with implementing health humanities baccalaureate research initiatives at The University of North Carolina at Chapel Hill, the authors contend that pre-health humanities programs should teach and study multiple disciplinary research methods and their values; examine how health humanities research might transfer across disciplines; and focus on mentoring opportunities for funding, presenting, and publishing research. These recommendations have the potential to create unprecedented research experiences for baccalaureate students as they prepare to enter careers within and beyond the allied health professions. PMID- 28573597 TI - Effect of Heart Rate Variability Biofeedback on Sport Performance, a Systematic Review. AB - Aim is to determine if the training with heart rate variability biofeedback allows to improve performance in athletes of different disciplines. Methods such as database search on Web of Science, SpringerLink, EBSCO Academic Search Complete, SPORTDiscus, Pubmed/Medline, and PROQUEST Academic Research Library, as well as manual reference registration. The eligibility criteria were: (a) published scientific articles; (b) experimental studies, quasi-experimental, or case reports; (c) use of HRV BFB as main treatment; (d) sport performance as dependent variable; (e) studies published until October 2016; (f) studies published in English, Spanish, French or Portuguese. The guidelines of the PRISMA statement were followed. Out of the 451 records found, seven items were included. All studies had a small sample size (range from 1 to 30 participants). In 85.71% of the studies (n = 6) the athletes enhanced psychophysiological variables that allowed them to improve their sport performance thanks to training with heart rate variability biofeedback. Despite the limited amount of experimental studies in the field to date, the findings suggest that heart rate variability biofeedback is an effective, safe, and easy-to-learn and apply method for both athletes and coaches in order to improve sport performance. PMID- 28573598 TI - Ecological dissimilarity among land-use/land-cover types improves a heterogeneity index for predicting biodiversity in agricultural landscapes. AB - Land-use/land-cover heterogeneity is among the most important factors influencing biodiversity in agricultural landscapes and is the key to the conservation of multi-habitat dwellers that use both terrestrial and aquatic habitats. Heterogeneity indices based on land-use/land-cover maps typically do not integrate ecological dissimilarity between land-use/land-cover types. Here, we applied the concept of functional diversity to an existing land-use/land-cover diversity index (Satoyama index) to incorporate ecological dissimilarity and proposed a new index called the dissimilarity-based Satoyama index (DSI). Using Japan as a case study, we calculated the DSI for three land-use/land-cover maps with different spatial resolutions and derived similarity information from normalized difference vegetation index values. The DSI showed better performance in the prediction of Japanese damselfly species richness than that of the existing index, and a higher correlation between the index and species richness was obtained for higher resolution maps. Thus, our approach to improve the land use/land-cover diversity index holds promise for future development and can be effective for conservation and monitoring efforts. PMID- 28573599 TI - Mapping policies for surface water protection zones on forest land in the Nordic Baltic region: Large differences in prescriptiveness and zone width. AB - The forest landscape across the Nordic and Baltic regions hosts numerous lakes and watercourses, which must be included in forest management. In this study, national policy designs regarding protection zones for surface waters on forest land were reviewed and compared for the Nordic countries, Estonia and Latvia. The focus was how each country regulates protection zones, whether they are voluntary or mandatory, and the rationale behind adopting a low or high degree of prescriptiveness. Iceland and Denmark had a low degree of policy prescriptiveness, whereas Norway, Estonia and Latvia had a high degree of prescriptiveness. Sweden and Finland relied to a large extent on voluntary commitments. The prescribed zone widths within the region ranged from 1 m to 5 km. The results indicated that land-use distribution, forest ownership structure and historical and political legacies have influenced the varying degrees of prescriptiveness in the region. PMID- 28573600 TI - Vulnerability and impacts of climate change on forest and freshwater wetland ecosystems in Nepal: A review. AB - Climate change (CC) threatens ecosystems in both developed and developing countries. As the impacts of CC are pervasive, global, and mostly irreversible, it is gaining worldwide attention. Here we review vulnerability and impacts of CC on forest and freshwater wetland ecosystems. We particularly look at investigations undertaken at different geographic regions in order to identify existing knowledge gaps and possible implications from such vulnerability in the context of Nepal along with available adaptation programs and national-level policy supports. Different categories of impacts which are attributed to disrupting structure, function, and habitat of both forest and wetland ecosystems are identified and discussed. We show that though still unaccounted, many facets of forest and freshwater wetland ecosystems of Nepal are vulnerable and likely to be impacted by CC in the near future. Provisioning ecosystem services and landscape-level ecosystem conservation are anticipated to be highly threatened with future CC. Finally, the need for prioritizing CC research in Nepal is highlighted to close the existing knowledge gap along with the implementation of adaptation measures based on existing location specific traditional socio ecological system. PMID- 28573601 TI - Gallic acid and p-coumaric acid attenuate type 2 diabetes-induced neurodegeneration in rats. AB - The brain of diabetics revealed deterioration in many regions, especially the hippocampus. Hence, the present study aimed to evaluate the effects of gallic acid and p-coumaric acid against the hippocampal neurodegeneration in type 2 diabetic rats. Adult male albino rats were randomly allocated into four groups: Group 1 served as control ones and others were induced with diabetes. Group 2 considered as diabetic, and groups 3 and 4 were further orally treated with gallic acid (20 mg/kg b.wt./day) and p-coumaric acid (40 mg/kg b.wt./day) for six weeks. Diabetic rats revealed significant elevation in the levels of serum glucose, blood glycosylated hemoglobin and serum tumor necrosis factor-alpha, while the level of serum insulin was significantly declined. Furthermore, the brain of diabetic rats showed a marked increase in oxidative stress and a decrease of antioxidant parameters as well as upregulation the protein expression of Bax and downregulation the protein expression of Bcl-2 in the hippocampus. Treatment of diabetic rats with gallic acid and p-coumaric acid significantly ameliorated glucose tolerance, diminished the brain oxidative stress and improved antioxidant status, declined inflammation and inhibited apoptosis in the hippocampus. The overall results suggested that gallic acid and p-coumaric acid may inhibit hippocampal neurodegeneration via their potent antioxidant, anti inflammatory and anti-apoptotic properties. Therefore, both compounds can be recommended as hopeful adjuvant agents against brain neurodegeneration in diabetics. PMID- 28573602 TI - Cognitive reserve is a resilience factor for cognitive dysfunction in hepatic encephalopathy. AB - Cognitive Reserve (CR) modulates symptoms of brain disease. The aim of this study was: to evaluate the effect of CR on cognition in cirrhosis and on the mismatch between cognitive and neurophysiologic assessment of hepatic encephalopathy (HE). Eighty-two outpatient patients with cirrhosis without overt HE were studied [73% males; age: 62 (54-68) (median, interq. range) yrs.; education: 8 (6-13) yrs.]. The Psychometric Hepatic Encephalopathy Score (PHES) was used as cognitive measure of HE. The spectral analysis of the electroencephalogram (EEG) was used as neurophysiologic measure of HE. The CR was assessed by the CR Index (CRI), which was measured by the CRI questionnaire (CRIq) ( http://cri.psy.unipd.it ). The PHES was altered in 28% of patients and the EEG in 41%. Altered PHES was related to the severity of cirrhosis as assessed by Child-Pugh classification (R = 0.31, p < 0.005). Patients with maintained PHES had higher CRI than those with altered PHES (CRI = 100 +/- 20 vs. 88 +/- 12 vs., p < 0.01), but not the ones with normal EEG compared to those with abnormal EEG (CRI = 96 +/- 17 vs. 98 +/- 17 vs. p: n.s.).The PHES, but not the EEG, was found to be related to the CRI (r = 0.35, p < 0.01). The mismatch between cognitive and neurophysiologic evaluation of non-overt HE (the ratio between PHES and the mean dominant frequency -MDF- of the EEG i.e., cognitive performance normalized by EEG speed) was found to be correlated to the CRI (r = 0.36, p < 0.005). CR is a resilience factor for cognitive dysfunction in cirrhosis, and is easily measurable by CRIq. PMID- 28573603 TI - Influence of Culture Medium Composition and Light Conditions on the Accumulation of Bioactive Compounds in Shoot Cultures of Scutellaria lateriflora L. (American Skullcap) Grown In Vitro. AB - Methanolic extracts from in vitro grown Scutellaria lateriflora shoots cultured on five Murashige and Skoog (MS) medium variants supplemented with different combinations of 6-benzylaminopurine (BAP) and alpha-naphthaleneacetic acid (NAA) under different light conditions (monochromatic light, white light and no light) were analysed by HPLC for three groups of metabolites: flavonoids (26 compounds), phenolic acids and their precursors (19+2) and phenylethanoid glycosides (2). The analyses revealed the presence of baicalein, baicalin, wogonin, wogonoside, 3,4 dihydroxyphenylacetic acid and verbascoside. There was clear evidence of the influence of plant growth regulators and light conditions on the accumulation of the analysed groups of secondary metabolites. The amounts of the compounds changed within a wide range-for the total flavonoid content, 30.2-fold (max. 1204.3 mg.100 g-1 dry weight (DW)); for 3,4-dihydroxyphenylacetic acid, 5.5-fold (max. 33.56 mg.100 g-1 DW); and for verbascoside, 1.5-fold (169.15 max. mg.100 g 1 DW). The best medium for the production of most of the compounds was the Murashige and Skoog variant with 1 mg l-1 BAP and 1 mg l-1 NAA. For verbascoside, the best 'productive' medium was the MS variant supplemented with 0.5 mg l-1 BAP and 2 mg l-1 NAA. The accumulation of the metabolites was stimulated to the greatest extent by blue light, under which the extracts were found to contain the highest total amount of flavonoids and the highest amounts of flavonoid glucuronides, baicalin and wogonoside, as well as of verbascoside. Their amounts were, respectively, 1.54-, 1.49-, 2.05- and 1.86-fold higher than under the control white light. PMID- 28573604 TI - Dextran Utilization During Its Synthesis by Weissella cibaria RBA12 Can Be Overcome by Fed-Batch Fermentation in a Bioreactor. AB - Weissella cibaria RBA12 produced a maximum of 9 mg/ml dextran (with 90% efficiency) using shake flask culture under the optimized concentration of medium components viz. 2% (w/v) of each sucrose, yeast extract, and K2HPO4 after incubation at optimized conditions of 20 degrees C and 180 rpm for 24 h. The optimized medium and conditions were used for scale-up of dextran production from Weissella cibaria RBA12 in 2.5-l working volume under batch fermentation in a bioreactor that yielded a maximum of 9.3 mg/ml dextran (with 93% efficiency) at 14 h. After 14 h, dextran produced was utilized by the bacterium till 18 h in its stationary phase under sucrose depleted conditions. Dextran utilization was further studied by fed-batch fermentation using sucrose feed. Dextran on production under fed-batch fermentation in bioreactor gave 35.8 mg/ml after 32 h. In fed-batch mode, there was no decrease in dextran concentration as observed in the batch mode. This showed that the utilization of dextran by Weissella cibaria RBA12 is initiated when there is sucrose depletion and therefore the presence of sucrose can possibly overcome the dextran hydrolysis. This is the first report of utilization of dextran, post-sucrose depletion by Weissella sp. studied in bioreactor. PMID- 28573605 TI - Inhibitory Effect of Biosynthesized Silver Nanoparticles from Extract of Nitzschia palea Against Curli-Mediated Biofilm of Escherichia coli. AB - Extended spectrum beta lactamase (ESBL) are emerging beta-lactamases in Gram negative pathogens, causing serious problems in hospitalized patients worldwide. Biofilm mode of virulence has decreased the efficiency of antibiotics used for treatment against ESBL pathogens. Therefore, there is an urgent need for alternative agents such as nanoparticles that can prevent and inhibit the biofilm formation. The aim of the present study was to inhibit the biofilm formed by ESBL producing Escherichia coli using silver nanoparticles (AgNPs) synthesized with fresh water diatom (Nitzschia palea). AgNPs were characterized using UV-Vis spectroscopy, Fourier transform infrared (FTIR) spectroscopy, field emission scanning electron microscope (FESEM), energy-dispersive X-ray spectroscopy (EDX), and XRD. AgNPs at their biofilm inhibitory concentration (BIC) of 300 ng ml-1 significantly reduced the biofilm formed by E. coli. Interestingly, Congo red assay revealed the reduction of curli, essential for biofilm formation in the presence of AgNPs. Light and CLSM examination of the biofilm images also validated that in the presence of AgNPs, the biofilm architecture was disintegrated and the thickness was significantly reduced. Overall, the present study exemplifies the use of AgNPs as a plausible alternative for conventional coating agents on implant devices to prevent and control biofilm-associated urinary tract infections. PMID- 28573607 TI - Marburg- and Ebolaviruses: A Look Back and Lessons for the Future. AB - Since the discovery of Marburg virus 50 years ago, filoviruses have reemerged in the human population more than 40 times. Already the first episode was as dramatic as most of the subsequent ones, but none of them was as devastating as the West-African Ebola virus outbreak in 2013-2015. Although progress toward a better understanding of the viruses is impressive, there is clearly a need to improve and strengthen the measures to detect and control these deadly infections. PMID- 28573608 TI - Forty Years of Ebolavirus Molecular Biology: Understanding a Novel Disease Agent Through the Development and Application of New Technologies. AB - Molecular biology is a broad discipline that seeks to understand biological phenomena at a molecular level, and achieves this through the study of DNA, RNA, proteins, and/or other macromolecules (e.g., those involved in the modification of these substrates). Consequently, it relies on the availability of a wide variety of methods that deal with the collection, preservation, inactivation, separation, manipulation, imaging, and analysis of these molecules. As such the state of the art in the field of ebolavirus molecular biology research (and that of all other viruses) is largely intertwined with, if not driven by, advancements in the technical methodologies available for these kinds of studies. Here we review of the current state of our knowledge regarding ebolavirus biology and emphasize the associated methods that made these discoveries possible. PMID- 28573606 TI - A Phase I Study of Combination Therapy with Sorafenib and 5-Fluorouracil in Patients with Advanced Hepatocellular Carcinoma. AB - BACKGROUND AND AIMS: Sorafenib is the first molecular targeted drug approved for the treatment of advanced hepatocellular carcinoma (HCC) and is a potent small molecule inhibitor of multiple kinases. Combination therapy with sorafenib and other cytotoxic agents for HCC may result in additive anticancer activity. The purpose of this phase I study was to investigate the safety and tolerability of combination therapy with sorafenib and 5-fluorouracil (5-FU) and to determine the optimum dose of 5-FU for a phase II trial. METHODS: This phase I study used a conventional 3 + 3 dose-escalation design. The primary endpoint was to determine the maximum tolerated dose (MTD) of 5-FU in combination with sorafenib and to determine the recommended dosage (RD) for phase II. The secondary endpoints evaluated were toxicity and the tumor response rate. All patients received 800 mg of sorafenib daily and three different dosages of 5-FU (250, 350, and 450 mg/m2/day) for 20 days by intravenous infusion in 1 month as one cycle. RESULTS: Twelve patients with advanced HCC were evaluated. The MTD of 5-FU in combination with sorafenib was 450 mg/m2/day, and 350 mg/m2/day was selected as the RD for a phase II study. Thrombocytopenia, stomatitis, and hand-foot skin reaction were observed as grade 3 adverse events. Nine patients achieved stable disease (75%), and three patients (25%) were judged to have progressive disease. The disease control rate was 75%. CONCLUSIONS: Combination therapy with sorafenib and 5-FU appears to be well tolerated and may have the potential to be an option for advanced HCC. PMID- 28573609 TI - Ebolavirus: An Overview of Molecular and Clinical Pathogenesis. AB - Ebolaviruses cause severe, often fatal hemorrhagic fever in Central, East, and West Africa. Until recently, they have been viewed as rare but highly pathogenic infections with regional, but limited, global public health impact. This view has changed with the emergence of the first epidemic of Ebola hemorrhagic fever in West Africa. In this chapter we provide an introduction of the pathogenesis of ebolaviruses as well as a description of clinical disease features. We also describe the current animal models used in ebolavirus research, detailing each model's unique strengths and weaknesses. We focus on Ebola virus representing the type species Zaire ebolavirus of the genus Ebolavirus, as most work relates to this pathogen. PMID- 28573610 TI - Production of Filovirus Glycoprotein-Pseudotyped Vesicular Stomatitis Virus for Study of Filovirus Entry Mechanisms. AB - Members of the family Filoviridae are filamentous, enveloped, and nonsegmented negative-stranded RNA viruses that can cause severe hemorrhagic disease in humans and nonhuman primates with high mortality rates. Current efforts to analyze the structure and biology of these viruses as well as the development of antivirals have been hindered by the necessity of biosafety level 4 containment (BSL4). Here, we outline how to produce and work with Ebola virus glycoprotein bearing vesicular stomatitis virus (VSV) pseudovirions. These pseudovirions can be safely used to evaluate early steps of the filovirus life cycle without need for BSL4 containment. Virus gene expression in the transduced cells is easy to assess since the pseudovirions encode a reporter gene in place of the VSV G glycoprotein gene. Adoption of VSV for use as a pseudovirion system for filovirus GP has significantly expanded access for researchers to study specific aspects of the viral life cycle outside of BSL4 containment and has allowed substantial growth of filovirus research. PMID- 28573611 TI - Lentiviral Vectors Pseudotyped with Filoviral Glycoproteins. AB - Pseudotyping lentivirus-based vectors is a strategy used to study conferred vector tropism and mechanisms of envelope glycoprotein function. Lentiviruses and filoviruses both assemble at the plasma membrane and have homotrimeric structural envelope glycoproteins that mediate both receptor binding and fusion. Such similarities help foster efficient pseudotyping. Importantly, filovirus glycoprotein pseudotyping of lentiviral vectors allows investigators to study virus entry at substantially less restrictive levels of biosafety containment than that required for wild-type filovirus work (biosafety level-2 vs. biosafety level-4, respectively). Standard lentiviral vector production involves transient transfection of viral component expression plasmids into producer cells, supernatant collection, and centrifuge concentration. Because the envelope glycoprotein expression plasmid is provided in trans, wild type or variant filoviral glycoproteins from marburgvirus or ebolavirus species may be used for pseudotyping and compared side-by-side. In this chapter we discuss the manufacture of pseudotyped lentiviral vector with an emphasis on small-scale laboratory grade production. PMID- 28573612 TI - Modeling Ebola Virus Genome Replication and Transcription with Minigenome Systems. AB - In this chapter, we describe the minigenome system for Ebola virus (EBOV), which reconstitutes EBOV polymerase activity in cells and can be used to model viral genome replication and transcription. This protocol comprises all steps including cell culture, plasmid preparation, transfection, and luciferase reporter assay readout. PMID- 28573613 TI - Quantification of RNA Content in Reconstituted Ebola Virus Nucleocapsids by Immunoprecipitation. AB - Immunoprecipitations are commonly used to isolate proteins or protein complexes and assess protein-protein interactions; however, they can also be used to assess protein-RNA complexes. Here we describe an adapted RNA immunoprecipitation technique that permits the quantification of RNA content in Ebola virus nucleocapsids that have been reconstituted in vitro by transient transfection. PMID- 28573614 TI - Modeling Ebolavirus Budding with Virus Like Particles. AB - About 15 years ago, several groups initially described the release of virus like particles (VLPs) upon expression of Ebola virus VP40 in mammalian cells. Further development of the protocol later allowed for the dissection of the Ebola virus budding mechanism and for the identification of critical VP40 residues involved in this process. VLPs are now produced routinely in several laboratories as a tool to study virus entry or egress and have even been proposed as vaccine candidates against Ebola virus disease. Here we described protocols for the production and the analysis of Ebola virus VLP release. PMID- 28573615 TI - Modeling the Ebolavirus Life Cycle with Transcription and Replication-Competent Viruslike Particle Assays. AB - Ebolaviruses are the causative agent of a severe hemorrhagic fever with high case fatality rates, for which no approved specific therapy is available. As biosafety level 4 (BSL4) agents, work with live ebolaviruses is restricted to maximum containment laboratories. Transcription and replication-competent viruslike particle (trVLP) systems are reverse genetics-based life cycle modeling systems that allow researchers to model virtually the entire ebolavirus life cycle outside of a maximum containment laboratory. These systems can be used to dissect the virus life cycle, and thus increase our understanding of virus biology, as well as for more applied uses such as the screening and development of novel antivirals, and thus represent powerful tools for work on ebolaviruses. PMID- 28573616 TI - Assays to Measure Suppression of Type I Interferon Responses by Filovirus VP35 Proteins. AB - Innate immunity is the first line of defense against virus infections and is marked by production of type I interferons (IFN), a family of cytokines that includes IFN-beta and several IFN-alphas. For the filoviruses and many other RNA viruses that replicate in the cytoplasm, the RIG-I-like pattern recognition receptors (RLRs) are potential triggers of IFN production. To counteract such innate antiviral responses, many viruses encode proteins that antagonize RLR signaling. Ebola virus (EBOV) and other filoviruses produce VP35 proteins that block IFN induction via RLR signaling. We describe here cell-based reporter gene assays that quantify the IFN-antagonist function of filovirus VP35 proteins by assessing activation of the IFN-beta promoter. PMID- 28573617 TI - Nonradioactive Northern Blot Analysis to Detect Ebola Virus Minigenomic mRNA. AB - In this chapter, we describe the detection of Ebola virus minigenomic mRNA using a nonradioactive Northern hybridization. This protocol comprises all steps beginning with the synthesis of a digoxigenin-labeled riboprobe, harvest of transcribed mRNA from cells transfected with the Ebola virus minigenome system, separation of mRNA species by denaturing RNA gel electrophoresis, transfer of the mRNA to nylon membranes by vacuum blotting, and finally the detection of minigenome-specific mRNA through hybridization with a labeled riboprobe directed against the reporter gene.This method allows the direct study of cis-acting regulatory regions as well as trans-acting factors involved in Ebola virus minigenome transcription compared to the indirect measurement of reporter protein activity that additionally reflects translational effects (see Chapter 6 in this book for details). PMID- 28573618 TI - A Semi-automated High-Throughput Microtitration Assay for Filoviruses. AB - The 50% tissue culture infectious dose (TCID50) endpoint dilution assay is one of the gold standard methods for measuring filovirus infectivity. We have increased virology microtitration assay throughput at biosafety level (BSL)-4 by implementing automated liquid handling and semi-automated assay endpoint readout. Utilization of automated liquid handling for cell plating and virus dilution along with optimization of the assay endpoint readout, using a luminescent-based cell viability assay and an automated plate reader, has improved workflow efficiency, reduced operator burden and assay time, decreased assay variability, and increased data return. PMID- 28573619 TI - Generation of Recombinant Ebola Viruses Using Reverse Genetics. AB - Reverse genetics systems encompass a wide array of tools aimed at recapitulating some or all of the virus life cycle. In their most complete form, full-length clone systems allow us to use plasmid-encoded versions of the ribonucleoprotein (RNP) components to initiate the transcription and replication of a plasmid encoded version of the complete viral genome, thereby initiating the complete virus life cycle and resulting in infectious virus. As such this approach is ideal for the generation of tailor-made recombinant filoviruses, which can be used to study virus biology. In addition, the generation of tagged and particularly fluorescent or luminescent viruses can be applied as tools for both diagnostic applications and for screening to identify novel countermeasures. Here we describe the generation and basic characterization of recombinant Ebola viruses rescued from cloned cDNA using a T7-driven system. PMID- 28573620 TI - Luciferase-Expressing Ebolaviruses as Tools for Screening of Antivirals. AB - Ebolaviruses cause severe hemorrhagic fever with high case fatality rates. Despite recent progress, there is a continued need for the development of antivirals against these viruses. Reporter-expressing ebolaviruses, which can be generated using reverse genetics systems, are powerful tools for antiviral screening. While viruses expressing fluorescent reporters are amenable for this purpose and can be used for high-content imaging-type screens, as an alternative, luciferase-expressing reporter viruses have recently been developed and have the advantages of being extremely easy to use and having short assay times. Here we provide a detailed protocol for the use of such a luciferase-expressing reporter virus for antiviral screening in a 96-well format, with parallel assessment of cytotoxicity of the screened compounds. PMID- 28573621 TI - Live-Cell Imaging of Filoviruses. AB - Observation of molecular processes inside living cells is fundamental to a deeper understanding of virus-host interactions in filoviral-infected cells. These observations can provide spatiotemporal insights into protein synthesis, protein protein interaction dynamics, and transport processes of these highly pathogenic viruses. Thus, live-cell imaging provides the possibility for antiviral screening in real time and gives mechanistic insights into understanding filovirus assembly steps that are dependent on cellular factors, which then represent potential targets against this highly fatal disease. Here we describe analysis of living filovirus-infected cells under maximum biosafety (i.e., BSL4) conditions using plasmid-driven expression of fluorescently labeled viral and cellular proteins and/or viral genome-encoded expression of fluorescently labeled proteins. Such multiple-color and multidimensional time-lapse live-cell imaging analyses are a powerful method to gain a better understanding of the filovirus infection cycle. PMID- 28573622 TI - Assessment of Inhibition of Ebola Virus Progeny Production by Antiviral Compounds. AB - Assessment of small molecule compounds against filoviruses, such as Ebola virus, has identified numerous compounds that appear to have antiviral activity and should presumably be further investigated in animal efficacy trials. However, despite the many compounds that are purported to have good antiviral activity in in vitro studies, there are few instances where any efficacy has been reported in nonhuman primate models. Many of the high-throughput screening assays use reporter systems that only recapitulate a portion of the virus life cycle, while other assays only assess antiviral activity at relatively early time points. Moreover, many assays do not assess virus progeny production. A more in-depth evaluation of small numbers of test compounds is useful to economize resources and to generate higher quality antiviral hits. Assessing virus progeny production as late as 5 days post-infection allows for the elimination of compounds that have initial antiviral effects that are not sustained or where the virus rapidly develops resistance. While this eliminates many potential lead compounds that may be worthy of further structure-activity relationship (SAR) development, it also quickly excludes compounds that in their current form are unlikely to be effective in animal models. In addition, the inclusion of multiple assays that assess both cell viability and cell cytotoxicity, via different mechanisms, provides a more thorough assessment to exclude compounds that are not direct acting antivirals. PMID- 28573623 TI - Analysis of the Cellular Stress Response During Ebola Virus Infection by Immunofluorescence. AB - In this chapter, the use of immunofluorescence analysis as a tool to examine stress granule (SG) formation in Ebola virus (EBOV)-infected cells is described. The following protocol focuses on the process of inducing and analyzing the cellular stress response, including treatment of cells with inducers and inhibitors of the SG formation, and also describes EBOV infection, DNA transfection, and the usage of different cell lines. PMID- 28573624 TI - Analyzing Apoptosis Induction and Evasion in Ebola Virus-Infected Cells. AB - In this chapter, we describe a Western blot assay for the successful detection of apoptosis in Ebola virus (EBOV)-infected cells. The protocol includes all steps from cell culture, infection of cells, generation of lysates, and analysis using Western blot to detect caspase cleavage as marker of apoptosis. PMID- 28573625 TI - Electron Microscopy of Ebola Virus-Infected Cells. AB - Ebola virus (EBOV) replicates in host cells, where both viral and cellular components show morphological changes during the process of viral replication from entry to budding. These steps in the replication cycle can be studied using electron microscopy (EM), including transmission electron microscopy (TEM) and scanning electron microscopy (SEM), which is one of the most useful methods for visualizing EBOV particles and EBOV-infected cells at the ultrastructural level. This chapter describes conventional methods for EM sample preparation of cultured cells infected with EBOV. PMID- 28573626 TI - Validating the Inactivation Effectiveness of Chemicals on Ebola Virus. AB - While viruses such as Ebola virus must be handled in high-containment laboratories, there remains the need to process virus-infected samples for downstream research testing. This processing often includes removal to lower containment areas and therefore requires assurance of complete viral inactivation within the sample before removal from high-containment. Here we describe methods for the removal of chemical reagents used in inactivation procedures, allowing for validation of the effectiveness of various inactivation protocols. PMID- 28573627 TI - Visualizing Ebolavirus Particles Using Single-Particle Interferometric Reflectance Imaging Sensor (SP-IRIS). AB - This chapter describes an approach for the label-free imaging and quantification of intact Ebola virus (EBOV) and EBOV viruslike particles (VLPs) using a light microscopy technique. In this technique, individual virus particles are captured onto a silicon chip that has been printed with spots of virus-specific capture antibodies. These captured virions are then detected using an optical approach called interference reflectance imaging. This approach allows for the detection of each virus particle that is captured on an antibody spot and can resolve the filamentous structure of EBOV VLPs without the need for electron microscopy. Capture of VLPs and virions can be done from a variety of sample types ranging from tissue culture medium to blood. The technique also allows automated quantitative analysis of the number of virions captured. This can be used to identify the virus concentration in an unknown sample. In addition, this technique offers the opportunity to easily image virions captured from native solutions without the need for additional labeling approaches while offering a means of assessing the range of particle sizes and morphologies in a quantitative manner. PMID- 28573628 TI - Assessing Antiviral Countermeasures Using Mouse Models of Ebolavirus Infection. AB - Mouse models of Ebola virus (EBOV) have demonstrated their utility as important tools for screening the efficacy of candidate therapeutics and vaccines. In this chapter we explain the various mouse models that utilize either wild-type or mouse-adapted EBOV variants. PMID- 28573629 TI - Evaluation of Ebola Virus Countermeasures in Guinea Pigs. AB - Ebola virus (EBOV) pathology in humans remains incompletely understood; therefore, a number of rodent and nonhuman primate (NHP) models have been established to study the disease caused by this virus. While the macaque model most accurately recapitulates human disease, rodent models, which display only certain aspects of human disease but are more cost-effective, are widely used for initial screens during EBOV countermeasure development. In particular, mice and guinea pigs were among the first species used for the efficacy testing of EBOV vaccines and therapeutics. While mice have low predictive value, guinea pigs have proven to be a more reliable predictor for the evaluation of countermeasures in NHPs. In addition, guinea pigs are larger in size compared to mice, allowing for more frequent collection of blood samples at larger volumes. However, guinea pigs have the disadvantage that there is only a limited pool of immunological tools available to characterize host responses to vaccination, treatment and infection. In this chapter, the efficacy testing of an EBOV vaccine and a therapeutic in the guinea pig model are described. PMID- 28573630 TI - Evaluation of Medical Countermeasures Against Ebolaviruses in Nonhuman Primate Models. AB - Several ebolavirus species, with varying lethality rates, have caused sporadic outbreaks in Africa resulting in human disease. Ebolaviruses also have the potential for use as biological weapons. Currently, there are no licensed vaccines or therapeutics to respond to outbreaks or deliberate misuse of ebolaviruses. Vaccine or therapeutic efficacy testing of medical countermeasures against ebolaviruses requires an animal model of disease; in vitro testing in cell culture cannot reproduce the complicated balance between host-pathogen interactions required for the ultimate licensure of a countermeasure. Depending on the target of the countermeasure, demonstration of efficacy in the nonhuman primate ebolavirus disease models will most likely be required before licensure. Here, we describe the selection and use of nonhuman primates for vaccine and therapeutic studies against ebolaviruses. PMID- 28573631 TI - Quantification of Filovirus Glycoprotein-Specific Antibodies. AB - Serological methods such as the enzyme-linked immunosorbent assay (ELISA) and virus neutralization test are fundamental tools used in diagnosis, seroepidemiological studies of filovirus transmission/prevalence, and the evaluation of vaccine immunogenicity and potential therapeutic antibodies. Filoviruses have a single transmembrane glycoprotein (GP), which is the only known target of neutralizing antibodies. Here we describe serological methods to quantify filovirus GP-specific antibodies. PMID- 28573632 TI - Monitoring Innate Immune Gene Responses in the Hamster Model of Ebola Virus Disease by RT-PCR. AB - Ebola virus (EBOV) disease is a severe, acute human syndrome associated with high case fatality rates. Immune responses to EBOV are thought to be at least partially responsible for disease pathogenesis and must therefore be investigated to get a better understanding of underlying mechanisms of pathogenesis. Syrian hamsters are susceptible to EBOV infection and develop a disease more consistent with human EBOV disease than other rodent disease models. Quantitative RT-PCR (qRT-PCR) is ideal for monitoring immune responses during EBOV infection in low- to medium-throughput applications. A relatively straightforward protocol for monitoring immune responses, based on information gleaned from experimental EBOV infection of hamsters, is presented. PMID- 28573633 TI - Real-Time and End-Point PCR Diagnostics for Ebola Virus. AB - Reverse transcriptase polymerase chain reaction (RT-PCR)-based techniques allow for highly sensitive and specific detection of RNA viruses. Detection of the amplification products can be achieved using several methods. The following are descriptions of the detection of ebolavirus RNA using end-point RT-PCR (agarose gel visualization of amplification products) and quantitative RT-PCR (Q-RT-PCR), with fluorescent detection using an intercalating dye or detection with the use of 5' hydrolysis probe assays. All of these techniques can be used to accurately detect the presence of ebolavirus in samples. PMID- 28573634 TI - Production of Antigens for ELISA. AB - Immunologic assays such as ELISA allow detection of either virus antigens or the host's immune response to antigens associated with prior infections and offer a powerful means to approach understanding the epidemiology and epizootiology of these agents. However, the success of these assays is highly dependent on the production of high-quality materials both to establish the assays (i.e., antigen target for antibody) and to serve as controls for establishing assay parameters and sensitivity. Here we describe methods for preparing ebolavirus antigens suitable for use as either reagents or controls in a variety of ELISA formats. Considering work with filoviruses is typically restricted to maximum containment laboratories; thus, we also provide methods for inactivating and safety testing of these antigens for safe use in properly established field laboratories. PMID- 28573635 TI - ELISA Methods for the Detection of Ebolavirus Infection. AB - Ebola viruses are high-priority pathogens first discovered in rural Africa associated with sporadic outbreaks of severe hemorrhagic disease in humans and nonhuman primates. Little is known about the disease ecology or the prevalence of past exposure of human populations to any of the five species of the genus Ebolavirus. The use of immunologic means of detection for either virus antigens or the host's immune response to antigen associated with prior infections offers a powerful approach at understanding the epidemiology and epizootiology of these agents. Here we describe methods for preparing antigen detection sandwich enzyme linked immunosorbent assays (ELISAs) as well as IgG and IgM ELISAs for the detection of ebolavirus antigens or antibodies in biological samples. PMID- 28573636 TI - Ebola Virus Field Sample Collection. AB - Sampling wildlife for ebolaviruses presents the researcher with a multitude of challenges, foremost of which is safety. Throughout the methods described in this chapter, personal safety and personal protective equipment (PPE) will be reiterated for each methodology. The methods described here are those used to successfully detect and isolate marburgviruses from their natural reservoir, Rousettus aegyptiacus, and therefore should be applicable for diagnostic testing for ebolaviruses via RT-PCR, ELISA, and IHC techniques.Although an ebolavirus natural reservoir has yet to be identified, the majority of disease ecologists believe the reservoir to belong to the order Chiroptera (bats). The methods presented in this chapter are presented with bats as an example, but all of these methods would be applicable to other species of wildlife with few or no modifications. PMID- 28573638 TI - Peribiliary liver metastases MR findings. AB - We described magnetic resonance (MR) features of peribiliary metastasis and of periductal infiltrative cholangiocarcinoma. We assessed 35 patients, with peribiliary lesions, using MR 4-point confidence scale. T1-weighted (T1-W), T2 weighted (T2-W) and diffusion-weighted images (DWI) signal intensity, enhancement pattern during arterial, portal, equilibrium and hepatobiliary phase were assessed. We identified 24 patients with periductal-infiltrating cholangiocellular carcinoma. The lesions in 34 patients appeared as a single tissue, while in a single patient, the lesions appeared as multiple individual lesions. According to the confidence scale, the median value was 4 for T2-W, 4 for DWI, 3.6 for T1-W in phase, 3.6 for T1-W out phase, 3 for MRI arterial phase, 3.2 for MRI portal phase, 3.2 for MRI equilibrium phase and 3.6 for MRI hepatobiliary phase. According to Bismuth classification, all lesions were type IV. In total, 19 (54.3%) lesions were periductal, 15 (42.9%) lesions were intraperiductal, and 1 (2.8%) lesion was periductal intrahepatic. All lesions showed hypointense signal in T1-W and in ADC maps and hyperintense signal in T2-W and DWI. All lesions showed a progressive contrast enhancement. There was no significant difference in signal intensity and contrast enhancement among all metastases and among all metastases with respect to CCCs, for all imaging acquisitions (p value >0.05). MRI is the method of choice for biliary tract tumors thanks to the possibility to obtain morphological and functional evaluations. T2-W and DW sequences have highest diagnostic performance. MRI does not allow a correct differential diagnosis among different histological types of metastasis and between metastases and CCC. PMID- 28573637 TI - Clinical significance of androgen secretion disorders in men with a malignancy. AB - Cancer and its treatment can lead in men to testosterone deficiency, accompanied by somatic and mental symptoms. Germ cell tumours and their treatment may disturb the pituitary-gonadal axis, hence leading to significant clinical abnormalities. In some prostate cancer patients, castration, temporary or permanent, is a desired therapeutic condition. Yet, it is burdened with various side effects of complex intensity and significance. Last but not least, patients in the terminal stage of a malignancy present with low testosterone concentrations as a part of anorexia-cachexia syndrome. Oncological management of such patients disturbs their homeostasis, androgen metabolism included, which results in numerous complications and worsens their quality of life. In the present paper, we analysed the frequency and sequelae of testosterone deficiency in some clinical scenarios, on the basis of original papers, meta-analyses and reviews available in PubMed. Androgen secretion disorders in male cancer patients depend on a cancer type, stage and methods of treatment. Number of testicular cancer survivors is increasing, and as a consequence, more patients cope with late complications, testosterone deficiency included. Hormone therapy in prostate cancer patients significantly prolongs survival, and then numerous men experience long-term adverse effects of androgen deficiency. Those, in turn, particularly the metabolic syndrome, may contribute to increased mortality. Androgen deficiency is a part of cancer anorexia-cachexia syndrome. The role of androgen deficiency in cancer patients is still under debate, and further studies are urgently needed to establish appropriate clinical guidelines. PMID- 28573639 TI - Minimally invasive pancreatic cancer surgery: What is the current evidence? AB - Surgery remains the only option to cure pancreatic cancer. Although the use of laparoscopy in oncology is rapidly growing worldwide, its efficacy in pancreatic surgery remains controversial. A number of studies have compared outcomes of minimally invasive and open pancreatic resections. However, they are mostly non randomized trials including relatively small groups of patients. In addition, most of these studies were conducted in high-volume pancreatic centres. It seems that despite longer operative time, laparoscopy may be beneficial in terms of morbidity, blood loss and hospital stay. Thus far, very little is known about the long-term outcomes of laparoscopic surgery for pancreatic cancer. Our aim was to review current evidence for the use of minimally invasive techniques in patients with pancreatic malignancy. PMID- 28573640 TI - Expanding the search for significant EGFR mutations in NSCLC outside of the tyrosine kinase domain with next-generation sequencing. AB - While conventional organization of EGFR mutations in non-small cell lung cancer (NSCLC) includes classic lesions sensitive to tyrosine kinase inhibitors (TKI) and variants localized to the tyrosine kinase domain (TKD) in exons 18-21, next generation sequencing (NGS) raises the prospect of identifying clinically relevant variants in extra-TKD regulatory regions. NSCLC patients at our institution who received tumor profiling with NGS from 2013 to 2015 were identified. EGFR mutations were arranged based upon their distribution relative to the TKD. In silico analysis was performed to predict non-synonymous single nucleotide polymorphism (nsSNP) pathogenicity. Of 247 patients, 43 EGFR variants were seen in 39 patients (16%). While 32 had TKD lesions demonstrable through standard testing, 7 had extra-TKD nsSNPs (7/43), of which 5 were extracellular domain (ECD), 1 juxtamembrane (JM) and 1 carboxy-terminal (CT). Aside from known pathogenic ECD mutation G598V, 5/6 extra-TKD nsSNPs were predicted damaging with in silico analysis. Seven of 7 extra-TKD nsSNP+ patients smoked and were stage IV; 5/7 were adenocarcinoma. An adenocarcinoma patient with JM R675Q had erlotinib, 150 mg daily, added following progression of disease on carboplatin and paclitaxel and had a partial response for 4 months. No other extra-TKD nsSNP+ patient received EGFR-directed therapy. >2% NSCLC cases in our cohort had EGFR nsSNPs located outside of the TKD, representing >16% of all EGFR mutations. Extra TKD variants should be characterized collaboratively to determine TKI sensitivity and additional therapeutic targets. PMID- 28573641 TI - Downregulation of TRPM7 suppressed migration and invasion by regulating epithelial-mesenchymal transition in prostate cancer cells. AB - Metastasis is a leading cause of death in patients with prostate cancer (PCa). Transient receptor potential channel 7 (TRPM7) functions as a Mg2+/Ca2+-permeable channel as well as a protein kinase that regulate various cellular processes including cell adhesion, migration and survival. However, the function of TRPM7 in metastasis of PCa remains largely unknown. Microarray analysis suggested that calcium signaling pathway was significantly altered in metastatic PCa tissues, compared with benign prostatic hyperplasia tissues. Bioinformatics analysis using microarray data and database for annotation, visualization and integrated discovery database revealed altered genes involved in calcium signaling pathway were significantly upregulated in TRPM7 deficiency PCa cells, which was also confirmed by experimental verification. Therefore, we aim to investigate the role of TRPM7 in human PCa cell migration and invasion as well as the underlying mechanisms. We observed that TRPM7 was upregulated in PCa cells and tissues compared with prostate hyperplasia cells and tissues. Further investigations suggested that TRPM7 deficiency suppressed migration and invasion of distinct PCa cell lines while overexpression of TRPM7 increased migration of PCa cells. In addition, knockdown of TRPM7 in PCa cells reversed the epithelial-mesenchymal transition (EMT) status, accompanied by downregulation of MMPs and upregulation of E-cadherin. Taken together, our study indicated that downregulation of TRPM7 could inhibit migration and invasion via reversing EMT status in PCa cells. PMID- 28573642 TI - Aberrant gene promoter methylation of E-cadherin, p16 INK4a , p14 ARF , and MGMT in Epstein-Barr virus-associated oral squamous cell carcinomas. AB - The etiology of oral carcinogenesis appears to be multifactorial. There is emerging evidence of the presence of Epstein-Barr virus (EBV) in epithelial oral squamous cell carcinoma (OSCC), but an association of EBV with oral carcinogenesis has not yet been established. Although epigenetic alterations, such as aberrant DNA methylation, are known to contribute to the pathogenesis of oral cancer, the relationship of such alterations with EBV infection is little known. This study aimed to investigate the association between EBV infection and promoter methylation patterns of tumor-associated genes in OSCC tissues. A total of 165 of formalin-fixed paraffin-embedded OSCC tissues were studied (68 of EBV positive and 97 of EBV negative). The promoter methylation patterns were investigated for four tumor-associated genes, E-cadherin, p16 INK4a , p14 ARF , and MGMT, by using methylation-specific polymerase chain reaction (MSP). The frequencies of gene promoter hypermethylation in all cases were 47.3% for E cadherin, 92.7% for p16 INK4a , 74.5% for p14 ARF , and 35.8% for MGMT. Interestingly, most of the analyzed gene promoters were more frequently hypermethylated in EBV-positive than EBV-negative cases, in particular the E cadherin (56/22) and MGMT (38/21) gene promoters (p < 0.05). Concomitantly, hypermethylation of multiple gene promoters (>=3) was encountered more frequently in EBV-positive samples. Hypermethylation of the E-cadherin promoter associated with EBV was more frequently observed in moderately and poorly differentiated OSCC tissues. These results indicate that epigenetic changes frequently occur in OSCCs and may partly be induced by EBV infection, therefore, EBV may involve in development and progression of the OSCCs. PMID- 28573643 TI - Neighborhood Disadvantage, Residential Segregation, and Beyond-Lessons for Studying Structural Racism and Health. AB - A recent surge of interest in identifying the health effects of structural racism has coincided with the ongoing attention to neighborhood effects in both epidemiology and sociology. Mindful of these currents in the literature, it makes sense that we are seeing an emergent tendency in health disparities research to operationalize structural racism as either neighborhood disadvantage or racial residential segregation. This review essay synthesizes findings on the relevance of neighborhood disadvantage and residential segregation to the study of structural racism and health. It then draws on recent literature to propose four lessons for moving beyond traditional neighborhood effects approaches in the study of structural racism and health. These lessons are (1) to shift the focus of research from census tracts to theoretically meaningful units of analysis, (2) to leverage historic and geographic variation in race relations, (3) to combine data from multiple sources, and (4) to challenge normative framing that aims to explain away racial health disparities without discussing racism or racial hierarchy. The author concludes that research on the health effects of structural racism should go beyond traditional neighborhood effects approaches if it is to guide intervention to reduce racial and ethnic health disparities. PMID- 28573644 TI - Improving access to otolaryngology-head and neck surgery expert advice through eConsultations. AB - OBJECTIVES/HYPOTHESIS: Prolonged wait times have become common. Electronic consultations (eConsults) have been shown in previous studies to reduce unnecessary face-to-face consultations to specialists, but no prior study has investigated the feasibility or efficacy of eConsults in an otolaryngology-head and neck surgery (OTO-HNS) practice. STUDY DESIGN: Prospective observational study. METHODS: The Champlain BASE eConsult system is a secure web portal allowing primary care physicians (PCPs) to communicate asynchronously with specialists about a patient, without requiring a formal face-to-face consult. The data from all eConsults sent through this portal to OTO-HNS practices between July 2011 and January 2015 were collected and analyzed. RESULTS: Response time was rapid; over 40% of eConsults received a response within 24 hours, and nearly all eConsults were answered within 7 calendar days. The median response time was nearly 29 times faster than traditional face-to-face consultation. Unnecessary face-to-face referrals were avoided in 33.4% of all eConsults, and in nearly 50% of cases where the PCP initially planned a formal referral. PCPs reported adopting a new or additional course of action over 50% of the time following an eConsult. Eighty-eight percent of PCPs reported the service to be valuable for their patients, and 92% found it valuable for themselves. eConsults require only a limited time commitment from specialists, with over 75% taking less than 10 minutes to complete. CONCLUSIONS: eConsultation is a cost-effective system that can lead to decreased wait times, improved communication between PCPs and otolaryngologists, and help guide the development of targeted continuing professional development modules for PCPs. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:350-355, 2018. PMID- 28573645 TI - Effects of social identity salience on motivational orientation and conflict strategies in intergenerational conflict. AB - With the upsurge of older adults still working, the labour force is becoming increasingly diverse in age. Age diversity in an organisation can increase the likelihood of intergenerational conflict. The present study aims to integrate the dual concern model and social identity theory to explain the underlying mechanisms of intergenerational conflict by examining the effects of social identity salience on motivational orientation and conflict strategies. A 2 (subgroup identity salience: low vs. high younger/older group membership) * 2 (superordinate identity salience: low vs. high organisational group membership) factorial design with a structured questionnaire on motivational orientation and conflict strategies in relation to a hypothetical work conflict scenario was implemented among 220 postgraduate university students in Hong Kong. Results revealed that subgroup and superordinate identities had a combined influence on conflict strategies but not in motivational orientation. Subgroup and superordinate identification promoted integrating and compromising strategies, superordinate identification promoted obliging strategy, subgroup identification promoted dominating strategy and no identification promoted avoiding strategy. Age did not moderate these relationships. This study contributes to the development of the integrated model of conflict. PMID- 28573646 TI - Does endoscopic sinus surgery improve olfaction in nasal polyposis? PMID- 28573647 TI - Brazilian Capsicum peppers: capsaicinoid content and antioxidant activity. AB - BACKGROUND: Capsicum peppers are known as a source of capsaicinoids, phenolic compounds and antioxidants. Brazilian Capsicum peppers are important spices used in foods worldwide. However, little information is available on the chemical composition and antioxidant activity of these peppers. RESULTS: Capsaicin, dihydrocapsaicin, total phenolic compounds and antioxidant activity were investigated in extracts of three Brazilian peppers: Capsicum frutescens, C. chinense and C. baccatum var. pendulum, in two different harvest years and at two ripening stages. The bioactive compound content was dependent on harvest year, and changes in the concentration profiles were found for capsaicin. Mature fruits of C. chinense harvested in the first year had the highest capsaicin concentration (2.04 mg g-1 fresh pepper), and mature fruits of C. frutescens harvested in the same first year had the highest dihydrocapsaicin content (0.95 mg g-1 fresh pepper). Mature fruits of C. frutescens harvested in the first year showed the major total phenolic compound content (2.46 mg g-1 fresh pepper). The total phenolic compound content was directly related to antioxidant activity. CONCLUSION: Our results suggest that phenolic compounds significantly contribute to the antioxidant activity of the investigated peppers. Also, these data add valued novel information that enhances current knowledge of Brazilian pepper fruits. (c) 2017 Society of Chemical Industry. PMID- 28573648 TI - Current challenges and future prospects in oral anticoagulant therapy. AB - The choice for oral anticoagulant (OAC) therapy was previously limited to the vitamin K antagonists (VKAs). The advent of the direct oral anticoagulants (DOACs) brought with it the expectation that oral anticoagulation would become simpler (with the elimination of routine monitoring and introduction of a fixed dose anticoagulant), and that the use of VKAs would be slowly phased out. Although DOACs have made anticoagulation more convenient and accessible, we are now faced with what can be described as a tyranny of choice, together with many unanswered questions relating to DOAC use. These include optimal DOAC selection and dosing, use in complex 'real-world' patients, the role for monitoring and issues surrounding adherence. Warfarin remains the anticoagulant of choice in certain scenarios (e.g. metallic heart valves). The future holds much excitement: clinical studies are underway to expand the indications for DOACs and experience continues to grow outside the trials setting. PMID- 28573649 TI - Intra-individual metameric variation expressed at the enamel-dentine junction of lower post-canine dentition of South African fossil hominins and modern humans. AB - OBJECTIVES: The aim of this study is to compare the degree and patterning of inter- and intra-individual metameric variation in South African australopiths, early Homo and modern humans. Metameric variation likely reflects developmental and taxonomical issues, and could also be used to infer ecological and functional adaptations. However, its patterning along the early hominin postcanine dentition, particularly among South African fossil hominins, remains unexplored. MATERIALS AND METHODS: Using microfocus X-ray computed tomography (uXCT) and geometric morphometric tools, we studied the enamel-dentine junction (EDJ) morphology and we investigated the intra- and inter-individual EDJ metameric variation among eight australopiths and two early Homo specimens from South Africa, as well as 32 modern humans. RESULTS: Along post-canine dentition, shape changes between metameres represented by relative positions and height of dentine horns, outlines of the EDJ occlusal table are reported in modern and fossil taxa. Comparisons of EDJ mean shapes and multivariate analyses reveal substantial variation in the direction and magnitude of metameric shape changes among taxa, but some common trends can be found. In modern humans, both the direction and magnitude of metameric shape change show increased variability in M2 -M3 compared to M1 -M2 . Fossil specimens are clustered together showing similar magnitudes of shape change. Along M2 -M3 , the lengths of their metameric vectors are not as variable as those of modern humans, but they display considerable variability in the direction of shape change. CONCLUSION: The distalward increase of metameric variation along the modern human molar row is consistent with the odontogenetic models of molar row structure (inhibitory cascade model). Though much remains to be tested, the variable trends and magnitudes in metamerism in fossil hominins reported here, together with differences in the scale of shape change between modern humans and fossil hominins may provide valuable information regarding functional morphology and developmental processes in fossil species. PMID- 28573650 TI - Complete versus incomplete revascularization with drug-eluting stents for multi vessel disease in stable, unstable angina or non-ST-segment elevation myocardial infarction: A meta-analysis. AB - OBJECTIVES: To determine whether drug-eluting stent (DES) coronary complete revascularization (CR) confers clinical benefit over incomplete revascularization (IR) in patients with multivessel coronary artery disease (MVD). BACKGROUND: Clinical benefit of CR over IR in patients with MVD with angina (both stable and unstable) and non-ST-segment elevation myocardial infarction (NSTEMI) in DES has not been well studied. METHODS: We conducted a systematic online literature search of PUBMED and EMBASE. Literatures that compared the clinical outcomes between CR and IR with exclusively or majority (>80%) using DES in patients without or included only small portion (<20%) of ST-segment elevation myocardial infarction or single-vessel coronary artery disease were included. Hazards ratio (HR) with 95% confidence interval (CI) was calculated with random-effects model. RESULTS: No randomized clinical trials were identified. A total of 14 observational studies with total of 41 687 patients (CR 39.6% and IR 60.4%) were included in this meta-analysis. CR was associated with lower incident of all cause mortality (HR 0.71, P = 0.001), major adverse events (HR 0.75, P < 0.001), cardiovascular mortality (HR 0.39, P < 0.001). Meta-regression analysis showed that CR significantly reduced the risk of all-cause mortality in advanced age, triple vessel disease and male sub-groups. CONCLUSIONS: CR with DES conferred favorable outcomes compared to IR in MVD patients with stable, unstable angina or NTEMI. Further research to achieve higher CR in MVD patients may lead to improvement in prognosis in these cohorts. PMID- 28573651 TI - Periprostatic innervation: New issues based on segmental analysis of 10 human cadaver pelvic blocs. AB - BACKGROUND: The exact paths of periprostatic nerves have been under debate over the last decades. In the present study, the topographic distribution of nerves around the prostate and their relative distances from the prostatic capsule were analyzed in male cadaver visceral blocs. METHODS: The pelvic organs from ten fresh male cadavers were removed and serial sectioned en bloc for histological investigation. The macroslices was divided into four sectors. Each sector was centrally covered with a raster dividing each sector in three subsectors numbered clockwise. The prostatic capsule was identified, and distances of 2.5 and 5 mm from the prostate were demarked with lines. We quantified the number of nerve fibers present in each subsector of each slide and recorded their position relative to the prostatic capsule. RESULTS: In general, the topographic analysis revealed that the majority of nerves were identified in sectors 4 through 9, corresponding to the posterolateral and posterior surfaces of the prostate gland. At the prostate base, the majority of nerves were found at the posterolateral and posterior surfaces of the gland. Within the mid-region of the prostate, the same topographic distribution pattern was observed, but the nerve fibers were closer to the prostatic capsule. At the apical region, the percentage of nerve fibers identified in the anterior region was higher, despite their major concetration in the posterior surface. The nerves identified at the apex were mainly located up to 2.5 mm from the prostate. This proximity to the prostate was specifically observed in the anterolateral and anterior sectors. In the craniocaudal sense, the percentage of nerves identified between 2.5 and 5 mm from the prostatic capsule remained constant. CONCLUSIONS: A significant number of nerve fibers were present in the anterior and anterolateral positions, especially at the apex. The anterior nerves were closer to the prostate. This proximity suggests that the anterior nerves may participate in local physiology and that the cavernous nerves are probably formed by the posterior nerve fibers. It is likely that the safe distance of 2.5 mm from all surfaces of the prostate may be related to cavernous fiber preservation. PMID- 28573652 TI - Systematic review with meta-analysis: the impact of a depressive state on disease course in adult inflammatory bowel disease. AB - BACKGROUND: Despite a higher prevalence of psychosocial morbidity in Inflammatory Bowel Disease (IBD), the association between depressive state and disease course in IBD is poorly understood. AIM: To investigate the impact of depressive state on disease course in IBD. METHODS: We conducted a systematic review in MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and PsychINFO for prospective studies evaluating the impact of baseline depressive state on subsequent disease course in adult IBD. RESULTS: Eleven studies matched our entry criteria, representing 3194 patients with IBD. Three reported on patients with ulcerative colitis (UC), four included patients with Crohn's disease (CD) exclusively, and four studies included both UC and CD. Five studies reported an association between depressive state and disease course. None of the UC-specific studies found any association. In three of four CD-specific studies, a relationship between depressive state and worsening disease course was found. In four of five studies including patients in remission at baseline, no association between depressive state and disease course was found. Pooled analysis of IBD studies with patients in clinical remission at baseline identified no association between depressive state and disease course (HR 1.04, 95%CI: 0.97-1.12). CONCLUSION: There is limited evidence to support an association between depressive state and subsequent deterioration in disease course in IBD, but what data that exist are more supportive of an association with CD than UC. Baseline disease activity may be an important factor in this relationship. Further studies are needed to understand the relationship between mental health and outcomes in IBD. PMID- 28573653 TI - Trace elements in patients on continuous renal replacement therapy. AB - PURPOSE: Intensive care patients with acute kidney injury (AKI), treated with continuous renal replacement therapy (CRRT) are at great risk for disturbances in plasma levels of trace elements due to the underlying illness, AKI, and dialysis. This study was performed to increase our knowledge regarding eight different trace elements during CRRT. METHODS: Thirty one stable patients with AKI, treated with CRRT, were included in the study. Blood, plasma and effluent samples were taken at the start of the study and 36 +/- 12 h later. A group of 48 healthy volunteers were included as controls and exposed to one fasting blood sample. Samples were analysed for trace elements (Cr, Cu, Mn, Co, Zn, Rb, Mo, Se) and standard blood chemistry. RESULTS: Blood and plasma levels of selenium and rubidium were significantly reduced while the levels of chromium, cobalt, and molybdenum were significantly increased in the study group vs. healthy volunteers. There was an uptake of chromium, manganese, and zinc. Molybdenum mass balance was around zero. For selenium, copper, and rubidium there were a marked loss. CONCLUSIONS: The low levels of selenium and rubidium in blood and plasma from CRRT patients, together with the loss via CRRT effluent, raises the possibility of the need for selenium supplementation in this group of patients, despite the unchanged levels during the short study period. Further investigations on the effect of additional administration of trace elements to CRRT patients would be of interest. PMID- 28573654 TI - Changing practices of fluid therapy. PMID- 28573655 TI - Testosterone effects on pain and brain activation patterns. AB - BACKGROUND: This study investigated whether pain and pain-related unpleasantness ratings were altered by blood testosterone levels. We also investigated whether activation of brain regions that represent pain intensity [primary somatosensory cortex (S1)] and pain-related unpleasantness [perigenual ACC (pACC) and orbitofrontal cortex (OFC)] were affected by blood testosterone levels. METHODS: Twenty-six healthy men were recruited. Blood testosterone levels were measured before fMRI scanning. The participants were classified into two groups (high vs. low testosterone) according to their blood testosterone level (each group n = 13). The middle finger was immersed in a 50 degrees C water bath (50 degrees C, 30 s, five times) to induce identical noxious stimulation in all participants. RESULTS: The low testosterone group showed statistically significantly higher pain (P = 0.047), unpleasantness (P = 0.047), anxiety (P = 0.015), and fear ratings (P = 0.01) than the high testosterone group. Fear rating increased as pain rating rose and as testosterone level decreased (P < 0.001). When participants received noxious stimulation, the pACC and OFC were more highly activated in the low testosterone group compared to the high testosterone group. Activation of S1, a region related to pain intensity, did not differ between both groups. CONCLUSION: Compared to the high testosterone group, the low testosterone group had significant activation in the pACC and OFC, regions that represent pain related unpleasantness, but not in S1 that represents pain intensity, leading to higher pain ratings. These findings emphasize the importance of considering the effects of testosterone levels when treating patients. PMID- 28573656 TI - Objective neuromuscular monitoring of neuromuscular blockade in Denmark: an online-based survey of current practice. AB - BACKGROUND: Neuromuscular blocking agents are commonly used during general anaesthesia but can lead to postoperative residual neuromuscular blockade and associated morbidity. With appropriate objective neuromuscular monitoring (objNMM) residual blockade can be avoided. In this survey, we investigated the use of objNMM in Denmark. METHODS: We conducted an anonymous Internet-based survey distributed through e-mails to Danish public anaesthesia departments. The survey consisted of 15-17 short questions regarding the use of objNMM. RESULTS: A total of 653 (27%) anaesthetists from 90% of the hospitals answered the questionnaire. ObjNMM was always used by 58% of the anaesthetists and 86% used objNMM at least 75% of the times. Despite the frequent use, 75% of the anaesthetists experienced difficulties with objNMM in at least 25% of the cases. The likelihood of using objNMM was higher among nurse anaesthetists vs. anaesthesiologists (odds ratio (OR) 2.24 [95% confidence interval (CI): 1.62 3.08]), if the department had an employee with special interest in objNMM (OR 1.66 [95% CI: 1.12-2.47]), if the anaesthetist had < 5 years of experience (OR 1.88 [95% CI: 1.29-2.73]), or if experiencing difficulties with objNMM < 25% of the cases (OR 1.60 [95% CI: 1.00-2.57]). CONCLUSION: In this survey, Danish anaesthetists frequently, in an international perspective, use objNMM, but the use is often associated with technical difficulties. PMID- 28573657 TI - Safety assessment and global regulatory requirements for genetic toxicity evaluations of medical devices. AB - Medical devices have the potential to leach substances which, depending on the contact category of the device, can directly contact the human body. Hence, appropriate evaluation for genetic toxicity as part of the biocompatibility risk assessment is critical. The biocompatibility risk assessment of medical devices is guided by the ISO 10993 series of standards. The recently revised ISO 10993-3 (2014) provides guidance on evaluating the genotoxicity, carcinogenicity and reproductive toxicity potential of medical devices. The revised standard includes the use of risk assessments and chemical characterization in addition to traditional genetic toxicity tests. The ISO 10993-3 standard provides guidance on the selection and preparation of test samples, and the selection of tests to evaluate genetic toxicity. Although conformance to ISO 10993-3 is required by various national regulatory agencies for specific medical device categories, there are still differences in the interpretation of the requirements within the standard which may require additional testing. Environ. Mol. Mutagen. 58:375-379, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28573658 TI - An approach to understanding sleep and depressed mood in adolescents: person centred sleep classification. AB - Depressive mood in youth has been associated with distinct sleep dimensions, such as timing, duration and quality. To identify discrete sleep phenotypes, we applied person-centred analysis (latent class mixture models) based on self reported sleep patterns and quality, and examined associations between phenotypes and mood in high-school seniors. Students (n = 1451; mean age = 18.4 +/- 0.3 years; 648 M) completed a survey near the end of high-school. Indicators used for classification included school night bed- and rise-times, differences between non school night and school night bed- and rise-times, sleep-onset latency, number of awakenings, naps, and sleep quality and disturbance. Mood was measured using the total score on the Center for Epidemiologic Studies-Depression Scale. One-way anova tested differences between phenotype for mood. Fit indexes were split between 3-, 4- and 5-phenotype solutions. For all solutions, between phenotype differences were shown for all indicators: bedtime showed the largest difference; thus, classes were labelled from earliest to latest bedtime as 'A' (n = 751), 'B' (n = 428) and 'C' (n = 272) in the 3-class solution. Class B showed the lowest sleep disturbances and remained stable, whereas classes C and A each split in the 4- and 5-class solutions, respectively. Associations with mood were consistent, albeit small, with class B showing the lowest scores. Person-centred analysis identified sleep phenotypes that differed in mood, such that those with the fewest depressive symptoms had moderate sleep timing, shorter sleep-onset latencies and fewer arousals. Sleep characteristics in these groups may add to our understanding of how sleep and depressed mood associate in teens. PMID- 28573660 TI - Cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis and sample size. PMID- 28573659 TI - Cerebrospinal fluid cytotoxicity does not affect survival in amyotrophic lateral sclerosis; Methodological issues. PMID- 28573661 TI - Characterization of a PRISTANE-induced lupus-associated model in the non-human primate cynomolgus monkey. AB - BACKGROUND: Lupus is an autoimmune disease with complex syndrome. Rodent models have limitations for recapitulating the spectrum of the disease. A more powerful translational model is desirable. METHOD: Lupus-associated model in cynomolgus monkeys was induced by two intraperitoneal injections of 2, 6, 10, 14 tetramethylpentadecane (PRISTANE). Lupus-specific biomarkers and manifestations over a 246-day period were observed at multilevel. To visualize and quantify kidney function in real time, contrast-enhanced ultrasound was used. RESULTS: The indicative biomarkers and manifestations fulfilled major diagnosis criteria according to the "Criteria of Lupus" of the American College of Rheumatology. Significant changes in time-intensity curve parameters were observed, indicating impaired renal function and the method as a feasible, non-invasive diagnostic method in primate model. CONCLUSIONS: We successfully induced lupus-associated model with systemic lupus syndrome. This primate model can be a valuable translational model for further pathogenesis and symptomology studies and for exploring therapeutic candidates. PMID- 28573662 TI - Offenders with intellectual disabilities in prison: what happens when they leave? AB - BACKGROUND: People with intellectual disabilities, if convicted of offences, may be sentenced to prison, but little is known about their life when they are released. METHOD: This study followed up men with intellectual disabilities who were leaving prisons in England. RESULTS: The men were hard to contact, but 38 men were interviewed, on average 10 weeks after leaving prison. The men were living in a variety of situations and often were very under-occupied, with limited social networks. A total of 70% were above the clinical cut-off for anxiety, and 59.5% were above the clinical cut-off for depression. The men were receiving little support in the community, and many had been reinterviewed by police. CONCLUSIONS: Community teams need to provide better support to this very vulnerable group. PMID- 28573663 TI - Suppression of the Charge Density Wave State in Two-Dimensional 1T-TiSe2 by Atmospheric Oxidation. AB - Two-dimensional (2D) metallic transition-metal dichalcogenides (TMDCs), such as 1T-TiSe2 , have recently emerged as unique platforms for exploring their exciting properties of superconductivity and the charge density wave (CDW). 2D 1T-TiSe2 undergoes rapid oxidation under ambient conditions, significantly affecting its CDW phase-transition behavior. We comprehensively investigate the oxidation process of 2D TiSe2 by tracking the evolution of the chemical composition and atomic structure with various microscopic and spectroscopic techniques and reveal its unique selenium-assisting oxidation mechanism. Our findings facilitate a better understanding of the chemistry of ultrathin TMDCs crystals, introduce an effective method to passivate their surfaces with capping layers, and thus open a way to further explore the functionality of these materials toward devices. PMID- 28573664 TI - Relationship between comorbidities at diagnosis, survival and ultimate cause of death in patients with chronic lymphocytic leukaemia (CLL): a prospective cohort study. PMID- 28573665 TI - Oligomeric larvae of the pycnogonids revisited. AB - Organization and ultrastructure of the protonymphon larva were never adequately described, despite it being the common larval type of the enigmatic sea spiders and the only example of oligosegmented life stage among recent chelicerates. We have made a comprehensive examination of the newly hatched free-living protonymphons of Nymphon brevirostre using SEM, TEM, light, and confocal microscopy. Although fairly typical in their broad characters, protonymphon larvae have a number of unique and unexpected traits. Body cavity, already present at this stage, is lined with extracellular matrix and thus is conclusively identified as primary body cavity. Central nervous system includes four postocular neuromeres arranged in three ganglia: supraesophageal, subesophageal, and the first ganglion of the ventral nerve cord. Examination of the sensory organs revealed unusually organized eyes, mechanoreceptors, and chemoreceptors. We have uncovered a mixed sensory-secretory nature of chelar glands and proposed possible modalities of its receptory part. We gave first descriptions of the complex ultrastructure of three secretory organs (spinning glands, slit-like organs, proboscis glands) and hypothesized on their mode of functioning. Comparisons with another oligomeric larva, for example, nauplius, revealed discrepancies in the segmentation of these animals. Although both larvae are externally unsegmented and bear three pairs of homologous appendages, the protonymphon body includes a fourth segment of the prospective walking legs which is absent in nauplius. PMID- 28573666 TI - Detection of desmoplastic melanoma with dermoscopy and reflectance confocal microscopy. AB - BACKGROUND: Desmoplastic melanoma (DM) is frequently misdiagnosed clinically and often associated with melanoma in situ (MIS). OBJECTIVE: To improve the detection of DM using dermoscopy and reflectance confocal microscopy (RCM). METHODS: A descriptive analysis of DM dermoscopy features and a case-control study within a melanoma population for RCM feature evaluation was performed blindly, using data obtained between 2005 and 2015. After retrospectively identifying all DM cases with RCM data over the study period (n = 16), a control group of non-DM melanoma patients with RCM data, in a ratio of at least 3 : 1, was selected. The control group was matched by age and primary tumour site location, divided into non-DM invasive melanomas (n = 27) and MIS (n = 27). Invasive melanomas were selected according to the melanoma subtypes associated with the DM cases. The main outcomes were the frequency of melanoma-specific features on dermoscopy for DM; and the odds ratios of RCM features to distinguish DM from MIS and/or other invasive melanomas; or MIS from the combined invasive melanoma group. RESULTS: At least one of the 14 melanoma-specific features evaluated on dermoscopy was found in 100% of DMs (n = 15 DM with dermoscopy). Known RCM melanoma predictors were commonly found in the DMs, such as pagetoid cells (100%) and cell atypia (100%). The RCM feature of spindle cells in the superficial dermis was more common in DM compared with the entire melanoma control group (OR 3.82, 95% CI 1.01-14.90), and particularly compared to MIS (OR 5.48, 95% CI 1.11-32.36). Nucleated cells in the dermis and the RCM correlate of dermal inflammation were also significant RCM features favouring DM over MIS, as well as invasive melanoma over MIS. CONCLUSION: Dermoscopy and RCM may be useful tools for the identification of DM. Certain RCM features may help distinguish DM from MIS and other invasive melanomas. Larger studies are warranted. PMID- 28573667 TI - Low-Dimensional Organic Tin Bromide Perovskites and Their Photoinduced Structural Transformation. AB - Hybrid organic-inorganic metal halide perovskites possess exceptional structural tunability, with three- (3D), two- (2D), one- (1D), and zero-dimensional (0D) structures on the molecular level all possible. While remarkable progress has been realized in perovskite research in recent years, the focus has been mainly on 3D and 2D structures, with 1D and 0D structures significantly underexplored. The synthesis and characterization of a series of low-dimensional organic tin bromide perovskites with 1D and 0D structures is reported. Using the same organic and inorganic components, but at different ratios and reaction conditions, both 1D (C4 N2 H14 )SnBr4 and 0D (C4 N2 H14 Br)4 SnBr6 can be prepared in high yields. Moreover, photoinduced structural transformation from 1D to 0D was investigated experimentally and theoretically in which photodissociation of 1D metal halide chains followed by structural reorganization leads to the formation of a more thermodynamically stable 0D structure. PMID- 28573668 TI - Establishing a chemical genetic link between Bruton tyrosine kinase activity in malignant B cells and cell functions involved in the micro-environmental dialogue. AB - To elucidate their mechanism of action, inhibitors of Bruton tyrosine kinase (BTK) and resistant BTK mutants were employed to dissect target-dependent cellular functions. BTK-C481S and -T474I, expressed in Ramos and NALM-6 cells, maintained BTK auto-phosphorylation under treatment with ibrutinib or dasatinib, respectively, which showed only modest cytotoxicity. Retained activity of BTK T474 partially rescued cell migration from inhibition by dasatinib. Importantly, resistant BTK mutants reconstituted B cell receptor-triggered chemokine secretion in the presence of corresponding inhibitors, demonstrating that BTK activity is connected with cell-intrinsic functions of malignant B cells with importance for their dialogue with the micro-environment. PMID- 28573669 TI - Association between consistent weight gain tracking and gestational weight gain: Secondary analysis of a randomized trial. AB - OBJECTIVE: The effective components of interventions for reducing excessive gestational weight gain (GWG) remain to be identified. This study investigated the sociodemographic, physical, psychosocial, and environmental correlates of online GWG tracking and its independent association with GWG outcomes. METHODS: Eight hundred ninety-eight women in the intervention arms of a randomized trial assessing the effectiveness of an integrated online and mobile phone behavioral intervention to decrease the prevalence of excessive GWG were included in this secondary analysis. Data were analyzed using chi2 analysis and modified Poisson and linear regression approaches. RESULTS: Only 16.5% of low-income (Medicaid eligible) women consistently tracked GWG, as did 34.2% of not-low-income women. More highly educated, older, and white women were more likely to be consistent GWG trackers. Among not-low-income women, consistent GWG tracking was associated with 2.35 kg less GWG (95% CI: -3.23 to -1.46 kg; P < 0.0001) and a reduced risk of excessive GWG (RR 0.73; 95% CI: 0.59 to 0.89; P = 0.002). CONCLUSIONS: Electronic tracking of GWG is an effective component of electronic and mobile health interventions aiming to decrease the prevalence of excessive GWG in not low-income women. Income group-specific motivators are needed to increase the prevalence of GWG tracking. PMID- 28573670 TI - Successful treatment with IVIg therapy of diabetes-associated scleredema severe progressive case and review of the literature. AB - Scleredema is a deposition disorder which presents as diffuse, symmetric, non pitting skin induration from dermal deposits of glycosaminoglycans ("mucins"). It classically affects the upper back and posterior neck, often causing skin tightness and decreased range of motion. In most patients the clinical course is chronic and treatment options are limited. We report a case of a patient diagnosed with scleredema associated with longstanding insulin dependent diabetes who was treated successfully with IVIg. Additionally, we have reviewed the literature reporting other patients with scleredema treated with IVIg. PMID- 28573671 TI - Validation of reference genes for quantitative gene expression analysis in experimental epilepsy. AB - To grasp the molecular mechanisms and pathophysiology underlying epilepsy development (epileptogenesis) and epilepsy itself, it is important to understand the gene expression changes that occur during these phases. Quantitative real time polymerase chain reaction (qPCR) is a technique that rapidly and accurately determines gene expression changes. It is crucial, however, that stable reference genes are selected for each experimental condition to ensure that accurate values are obtained for genes of interest. If reference genes are unstably expressed, this can lead to inaccurate data and erroneous conclusions. To date, epilepsy studies have used mostly single, nonvalidated reference genes. This is the first study to systematically evaluate reference genes in male Sprague-Dawley rat models of epilepsy. We assessed 15 potential reference genes in hippocampal tissue obtained from 2 different models during epileptogenesis, 1 model during chronic epilepsy, and a model of noninjurious seizures. Reference gene ranking varied between models and also differed between epileptogenesis and chronic epilepsy time points. There was also some variance between the four mathematical models used to rank reference genes. Notably, we found novel reference genes to be more stably expressed than those most often used in experimental epilepsy studies. The consequence of these findings is that reference genes suitable for one epilepsy model may not be appropriate for others and that reference genes can change over time. It is, therefore, critically important to validate potential reference genes before using them as normalizing factors in expression analysis in order to ensure accurate, valid results. PMID- 28573673 TI - [n]Cyclo-3,6-phenanthrenylenes: Synthesis, Structure, and Fluorescence. AB - Five congeners of [n]cyclo-3,6-phenanthrenylene with 3, 4, 5, 7, and 8 panels were obtained from one-pot macrocyclization of dibromophenanthrene, and their crystal structures with diverse molecular shapes were revealed by X-ray crystallography. The compounds, except the four-panel congener, were highly fluorescent in solution, with quantum yields up to 85 %. The least fluorescent four-panel congener showed the smallest change in its absorption spectrum from that of monomeric phenanthrene, which provided an interesting structure-activity relationship for fluorescent macrocycles to guide future studies. PMID- 28573672 TI - MEMO: an mHealth intervention to prevent the onset of depression in adolescents: a double-blind, randomised, placebo-controlled trial. AB - BACKGROUND: Depression often starts in adolescence making it an ideal time to intervene. We developed a universal cognitive behavioural therapy-based programme (MEMO CBT) to be delivered via multimedia mobile phone messages for teens. METHODS: We conducted a prospective multicentre, randomised, placebo-controlled superiority trial in 15 high schools in Auckland, New Zealand, comparing MEMO CBT with a control programme [MEMO control] matched for intensity and type of message but with alternative content not targeting depression. The primary outcome was the change in score on the Children's Depression Rating Scale-Revised from baseline to 12 months. Secondary outcomes included the change in scores in the self-reported Reynold's Adolescent Depression Rating Scale-Second Edition, the Moods and Feelings Questionnaire, suicidal ideation using selected items from the Youth Risk Behaviour Survey, the Pediatric Quality of Life questionnaire, 12 month period prevalence of the diagnosis of depressive disorder using the Kiddie Schedule for Affective Disorders and Schizophrenia, and students' ratings of their satisfaction with the programme. RESULTS: Eight hundred and fifty-five students (13-17 years old, mean 14.3 years) were randomly assigned to MEMO CBT (426) or to MEMO Control (429). Participants (68% female) had a mean CDRS-R at baseline of 21.5 (SD: 5). Overall 394 (93%) from the intervention group and 392 (91%) from the control group were followed up at 12 months. At the end of the intervention (approximately 9 weeks) the mean CDRS-R scores were 20.8 in the intervention group versus 20.4 in the control group, and at 12 months they were 22.4 versus 22.4 (p value for difference in change from baseline = 0.3). There was no obvious association between the amount of the intervention viewed by participants and outcomes. CONCLUSIONS: There was no evidence of benefit from the mobile phone CBT intervention compared with a control programme. Universal depression prevention remains a challenge. PMID- 28573674 TI - Overexpression of alpha-synuclein in an astrocyte cell line promotes autophagy inhibition and apoptosis. AB - alpha-Synuclein is the major component of neuronal cytoplasmic aggregates called Lewy bodies, the main pathological hallmark of Parkinson disease. Although neurons are the predominant cells expressing alpha-synuclein in the brain, recent studies have demonstrated that primary astrocytes in culture also express alpha synuclein and regulate alpha-synuclein trafficking. Astrocytes have a neuroprotective role in several detrimental brain conditions; we therefore analyzed the effects of the overexpression of wild-type alpha-synuclein and its A30P and A53T mutants on autophagy and apoptosis. We observed that in immortalized astrocyte cell lines, overexpression of alpha-synuclein proteins promotes the decrease of LC3-II and the increase of p62 protein levels, suggesting the inhibition of autophagy. When these cells were treated with rotenone, there was a loss of mitochondrial membrane potential, especially in cells expressing mutant alpha-synuclein. The level of this decrease was related to the toxicity of the mutants because they show a more intense and sustained effect. The decrease in autophagy and the mitochondrial changes in conjunction with parkin expression levels may sensitize astrocytes to apoptosis. PMID- 28573675 TI - Fasciocutaneous free flaps for reconstruction of hypopharyngeal defects. AB - OBJECTIVES/HYPOTHESIS: Different reconstructive options are available for defects following total laryngectomy (TL) and circumferential (CH) or partial hypopharyngectomy (PH). We evaluated the flap success, pharyngocutaneous fistula, and pharyngoesophageal stenosis rates in two groups of patients treated by different policies. STUDY DESIGN: Comparison between two cohorts of patients treated by TL with PH/CH +/- cervical esophagectomy and reconstructed according to different strategies. METHODS: Group A (historical) was composed of 89 patients reconstructed by pectoralis major myocutaneous (PMMC), radial forearm (RF), and anterolateral thigh (ALT) flaps. A salivary bypass stent (SBPS) was not routinely applied and left in place for a maximum of 14 days. Forty-four (49%) patients received preoperative radiotherapy/chemoradiotherapy (RT/CRT). Group B (prospective) included 105 patients reconstructed by RF or ALT with long-lasting SBPS left in place for a maximum of 45 days. Sixty-one (59%) received preoperative RT/CRT. RESULTS: In group A, flap failure occurred in four (4%) cases, and all were managed by PMMC. We encountered 22 (26%) fistulas and 14 (16%) stenoses. In group B, flap failure occurred in six (6%) cases and was managed by PMMC. We encountered seven (7%) fistulas and three (3%) stenoses. Comparing complications among the two groups, we encountered a statistically significant difference in favor of group B for both fistula (P < .001) and stenosis (P = .001). We did not evidence any significant difference in terms of flap success rate. CONCLUSIONS: First-line application of RF and ALT free flaps with long-lasting SBPS in reconstruction after PH/CH allows obtaining reduced incidences of both fistula and stenosis. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2731-2737, 2017. PMID- 28573676 TI - Combined cerebral and peripheral treatments for pain: A commentary on Hazime et al. PMID- 28573677 TI - Physical properties of the chromosomes and implications for development. AB - Remarkable progress has been made in understanding chromosome structures inside the cell nucleus. Recent advances in Hi-C technologies enable the detection of genome-wide chromatin interactions, providing insight into three-dimensional (3D) genome organization. Advancements in the spatial and temporal resolutions of imaging as well as in molecular biological techniques allow the tracking of specific chromosomal loci, improving our understanding of chromosome movements. From these data, we are beginning to understand how the intra-nuclear locations of chromatin loci and the 3D genome structure change during development and differentiation. This emerging field of genome structure and dynamics research requires an interdisciplinary approach including efficient collaborations between experimental biologists and physicists, informaticians, or engineers. Quantitative and mathematical analyses based on polymer physics are becoming increasingly important for processing and interpreting experimental data on 3D chromosome structures and dynamics. In this review, we aim to provide an overview of recent research on the physical aspects of chromosome structure and dynamics oriented for biologists. These studies have mainly focused on chromosomes at the cellular level, using unicellular organisms and cultured cells. However, physical parameters that change during development, such as nuclear size, may impact genome structure and dynamics. Here, we discuss how chromatin dynamics and genome structures in early embryos change during development, which we expect will be a hot topic in the field of chromatin dynamics in the near future. We hope this review helps developmental biologists to quantitatively investigate the physical natures of chromosomes in developmental biology research. PMID- 28573678 TI - Cardiac involvements in hypereosinophilia-associated syndrome: Case reports and a little review of the literature. AB - Hypereosinophilia-associated syndrome is a rare group of systemic diseases without certain underlying causes. Hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg Strauss syndrome (CSS), are initial considerations, when underlying causes remains unexplained despite of complete evaluation of hypereosinophilia. In this study, we report two rare cases, one case of HES with Loeffler endocarditis, and the other one of EGPA with restrictive cardiomyopathy mimicking myocardial infarction, to further address differential chief cardiac manifestations between HES and EGPA. Key roles of echocardiography played in detection of cardiac involvements, diagnosis, and prognosis prediction are also highlighted. PMID- 28573679 TI - Bidirectional electric communication between the inferior occipital gyrus and the amygdala during face processing. AB - Faces contain multifaceted information that is important for human communication. Neuroimaging studies have revealed face-specific activation in multiple brain regions, including the inferior occipital gyrus (IOG) and amygdala; it is often assumed that these regions constitute the neural network responsible for the processing of faces. However, it remains unknown whether and how these brain regions transmit information during face processing. This study investigated these questions by applying dynamic causal modeling of induced responses to human intracranial electroencephalography data recorded from the IOG and amygdala during the observation of faces, mosaics, and houses in upright and inverted orientations. Model comparisons assessing the experimental effects of upright faces versus upright houses and upright faces versus upright mosaics consistently indicated that the model having face-specific bidirectional modulatory effects between the IOG and amygdala was the most probable. The experimental effect between upright versus inverted faces also favored the model with bidirectional modulatory effects between the IOG and amygdala. The spectral profiles of modulatory effects revealed both same-frequency (e.g., gamma-gamma) and cross frequency (e.g., theta-gamma) couplings. These results suggest that the IOG and amygdala communicate rapidly with each other using various types of oscillations for the efficient processing of faces. Hum Brain Mapp 38:4511-4524, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28573680 TI - The effect of age on microsurgical free flap outcomes: An analysis of 5,951 cases. AB - BACKGROUND: The growing elderly population necessitates a greater number of aging patients requiring complex reconstructive surgery involving free tissue transfer. The purpose of this study was to assess the safety, efficacy, and outcomes of microsurgical free tissue transfer in elderly patients using a national multi institutional database. METHODS: We performed a retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database to identify patients undergoing free tissue transfer. We stratified cohorts based on ages 18-49, 50-59, 60-69, 70-79, and 80+ years and analyzed primary outcomes of surgical complications, medical complications, mortality, and flap failure. RESULTS: A total of 5,951 patients were identified for inclusion in the analysis. Univariate analysis demonstrated progressively increasing surgical (P = .001) and medical (P < .001) complication rates with increasing age. After controlling for confounding variables, age was not significantly associated with rates of surgical (OR 1.00, 95% CI 0.99-1.01, P = .737) or medical (OR 1.01, 95% CI 0.99-1.03, P = .209) complications, flap failure (OR 1.00, 95% CI 1.00-1.02, P = .689), or reoperation (OR 1.01, 95% CI 1.00-1.03, P = 0.165). Factors associated with surgical complications included BMI (OR 1.03, 95% CI 1.00-1.05, P = .031), prolonged operative time (OR 1.001, 95% CI 1.000-1.002, P = .002), American Society of Anesthesiologists (ASA) classification of 3 or greater (OR 1.62, 95% CI 1.17-2.23, P = .003), and prolonged hospitalization (OR 1.03, 95% CI 1.02-1.04, P < .001). ASA classification of 3 or greater (OR 2.57, 95% CI 1.48-4.45, P = .001), renal history (OR 10.13, 95% CI 1.57-65.55, P = .015), and prolonged hospitalization (OR 1.06, 95% CI 1.04-1.08, P < .001) were associated with medical complications. Age was associated with increased mortality (OR 1.06, 95% CI 1.00-1.13, P = .048). CONCLUSION: Age alone should not be used as an absolute or even relative contraindication in patient assessment. Rather, preoperative assessment should focus on comorbidities and assessment of physiologic age instead of chronologic age. Optimization of these comorbidities is key to sustaining favorable outcomes in microsurgical free flap reconstruction in the elderly population. PMID- 28573681 TI - Projected long-term outcomes in patients with type 1 diabetes treated with fast acting insulin aspart vs conventional insulin aspart in the UK setting. AB - AIM: To assess the impact of faster aspart vs insulin aspart on long-term clinical outcomes and costs for patients with type 1 diabetes mellitus (T1DM) in the UK setting. METHODS: The QuintilesIMS CORE Diabetes Model was used to project clinical outcomes and costs over patient lifetimes in a cohort with data on baseline characteristics from the "onset 1" trial. Treatment effects were taken from the 26-week main phase of the onset 1 trial, with costs and utilities based on literature review. Future costs and clinical benefits were discounted at 3.5% annually. RESULTS: Projections indicated that faster aspart was associated with improved discounted quality-adjusted life expectancy (by 0.13 quality-adjusted life-years) vs insulin aspart. Improved clinical outcomes resulted from fewer diabetes-related complications and a delayed time to their onset with faster aspart. Faster aspart was found to be associated with reduced costs vs insulin aspart (cost savings of L1715), resulting from diabetes-related complications avoided and reduced treatment costs. CONCLUSIONS: Faster aspart was associated with improved clinical outcomes and cost savings vs insulin aspart for patients with T1DM in the UK setting. PMID- 28573682 TI - Evaluation of the extent of initial Maillard reaction during cooking some vegetables by direct measurement of the Amadori compounds. AB - BACKGROUND: During vegetable cooking, one of the most notable and common chemical reactions is the Maillard reaction, which occurs as a result of thermal treatment and dehydration. Amadori compound determination provides a very sensitive indicator for early detection of quality changes caused by the Maillard reaction, as well as to retrospectively assess the heat treatment or storage conditions to which the product has been subjected. In this paper, a hydrophilic interaction liquid chromatographic-electrospray ionization-tandem mass spectrometric method was developed for the analysis of eight Amadori compounds, and the initial steps of the Maillard reaction during cooking (steaming, frying and baking) bell pepper, red pepper, yellow onion, purple onion, tomato and carrot were also assessed by quantitative determination of these Amadori compounds. RESULTS: These culinary treatments reduced moisture and increased the total content of Amadori compounds, which was not dependent on the type of vegetable or cooking method. Moreover, the effect of steaming on Amadori compound content and water loss was less than that by baking and frying vegetables. Further studies showed that the combination of high temperature and short time may lead to lower formation of Amadori compounds when baking vegetables. CONCLUSION: Culinary methods differently affected the extent of initial Maillard reaction when vegetables were made into home-cooked products. (c) 2017 Society of Chemical Industry. PMID- 28573683 TI - Omalizumab substantially improves dermatology-related quality of life in patients with chronic spontaneous urticaria. AB - BACKGROUND: Chronic spontaneous/idiopathic urticaria (CSU/CIU) has substantial detrimental effects on health-related quality of life (HRQoL) with an effect comparable to or worse than many other skin diseases. OBJECTIVE: To assess the effect of omalizumab on CSU patients' HRQoL, measured by the Dermatology Life Quality Index (DLQI) in three phase III studies ASTERIA I, ASTERIA II and GLACIAL. METHODS: A post hoc analysis examined changes in DLQI scores, distribution of patients across DLQI bands and the proportion reaching minimal clinically important difference (MCID) following omalizumab vs. placebo. RESULTS: Omalizumab 300 mg significantly improved total DLQI scores vs. placebo, with a mean decrease from baseline to week 12 of -10.3 vs. -6.1 (P < 0.0001) in ASTERIA I, -10.2 vs. -6.1 (P = 0.0004) in ASTERIA II and -9.7 vs. -5.1 (P < 0.0001) in GLACIAL. A significant shift from high disease impact on life at baseline towards less impact at week 12 was seen with omalizumab 300 mg vs. placebo (P < 0.001; all studies). The proportion of patients where change in mean total DLQI score from baseline to week 12 reached an MCID of >=4 was 74.1%, 76.0% and 77.2% in ASTERIA I, II and GLACIAL, respectively (P < 0.01; all studies). LIMITATIONS: Maximum duration of omalizumab treatment was 24 weeks. CONCLUSION: This additional analysis assessed the impact of CSU and benefit of treatment with omalizumab by exploring different facets of DLQI data by treatment arm at multiple assessment points. The original aspects of analysis included applying the concept of the recently validated score for the MCID of the DLQI, changes in DLQI domain scores and in the distribution of subjects based on validated total DLQI score bands. It showed consistently that omalizumab provides significant and clinically relevant improvements in many aspects of HRQoL that are important to patients with CSU. These results contribute to a better understanding of the impact of CSU and its treatment on patients and can support clinical decision making in routine medical practice. PMID- 28573684 TI - LC3-association with the parasitophorous vacuole membrane of Plasmodium berghei liver stages follows a noncanonical autophagy pathway. AB - Eukaryotic cells can employ autophagy to defend themselves against invading pathogens. Upon infection by Plasmodium berghei sporozoites, the host hepatocyte targets the invader by labelling the parasitophorous vacuole membrane (PVM) with the autophagy marker protein LC3. Until now, it has not been clear whether LC3 recruitment to the PVM is mediated by fusion of autophagosomes or by direct incorporation. To distinguish between these possibilities, we knocked out genes that are essential for autophagosome formation and for direct LC3 incorporation into membranes. The CRISPR/Cas9 system was employed to generate host cell lines deficient for either FIP200, a member of the initiation complex for autophagosome formation, or ATG5, responsible for LC3 lipidation and incorporation of LC3 into membranes. Infection of these knockout cell lines with P. berghei sporozoites revealed that LC3 recruitment to the PVM indeed depends on functional ATG5 and the elongation machinery, but not on FIP200 and the initiation complex, suggesting a direct incorporation of LC3 into the PVM. Importantly, in P. berghei infected ATG5-/- host cells, lysosomes still accumulated at the PVM, indicating that the recruitment of lysosomes follows an LC3-independent pathway. PMID- 28573685 TI - Epidemiology, risk factors, and outcomes of infections in patients undergoing liver transplantation for hilar cholangiocarcinoma. AB - The epidemiology of infection after liver transplantation for hilar cholangiocarcinoma has not been systematically investigated. In this study of 124 patients, 255 infections occurred in 105 patients during the median follow-up of 4.2 years. The median time to first infection was 15.1 weeks (IQR 1.6-62.6). The most common sites were the abdomen, bloodstream, and musculoskeletal system. Risk factors for any post-transplant infection were pre-transplant VRE colonization (Hazard Ratio [HR] 1.9, P=.002), living donor transplantation (HR 6.6, P<.001), longer cold ischemia time (HR 1.05 per 10 minutes, P<.001), donor CMV seropositivity (HR 2.2, P<.001), hepatic artery thrombosis (HR 2.6, P=.005), biliary stricture (HR 3.8, P=.002), intra-abdominal fluid collection (HR 4.2, P<.001), and re-operations within 1 month after transplantation (HR 1.7, P=.020). Abdominal infections were independently associated with hemodialysis requirement within 1 month after transplantation (HR 5.6, P=.006), hepatic artery thrombosis (HR 3.3, P=.007), biliary stricture (HR 5.2, P<.001), and abdominal fluid collection (HR 3.7, P=.0002). Bloodstream infections were independently associated with allograft ischemia (HR 17.8, P<.001), biliary stricture (HR 6.5, P=.005), and recipient VRE colonization (HR 4, P<.001). Abdominal infections (HR 2.3, P=.02) and Clostridium difficile infections (HR 4.6, P=.01) were independently associated with increased mortality. PMID- 28573686 TI - Pruritus in epithelial tumours of the face. PMID- 28573687 TI - Computational insights into the S3 transfer reaction: A special case of double group transfer reaction featuring bicyclically delocalized aromatic transition state geometries. AB - An unusual pericyclic process that involves the intermolecular transfer of thiozone (S3 ) is computationally described. The process can be considered as a special case of double group transfer reaction whereby the two migrating groups are connected to the same substituent, taking place in a concerted manner via transition states featuring two five-membered C2 S3 rings fused together. Analysis of the aromaticity at the TS geometries by computing NICS values at the (3,+1) RCPS as well as ACID calculations confirms the aromatic character of each C2 S3 ring, thus resulting in bicyclically delocalized aromatic structures. The free energy barriers for the transfer of S3 are relatively similar (40-50 kcal mol-1 ) to those computed for typical double H group transfer reactions. The similarities and differences between these processes have been further analysed by applying ASM-EDA and NBO approaches to the model reactions between ethene and ethane, and ethene and 1,2,3-trithiolane. (c) 2017 Wiley Periodicals, Inc. PMID- 28573690 TI - Every vaginal delivery must count. PMID- 28573688 TI - Autoantibodies against voltage-gated potassium channel and glutamic acid decarboxylase in psychosis: A systematic review, meta-analysis, and case series. AB - Antibodies to the voltage-gated potassium channel (VGKC) complex and glutamic acid decarboxylase (GAD) have been reported in some cases of psychosis. We conducted the first systematic review and meta-analysis to investigate their prevalence in people with psychosis and report a case series of VGKC-complex antibodies in refractory psychosis. Only five studies presenting prevalence rates of VGKC seropositivity in psychosis were identified, in addition to our case series, with an overall prevalence of 1.5% (25/1720) compared to 0.7% in healthy controls (12/1753). Meta-analysis established that the pooled prevalence of GAD65 autoantibodies was 5.8% (95% confidence interval [CI]: 2.0-15.6%; I2 = 91%; nine studies) in psychotic disorders, with a prevalence of 4.6% (95%CI: 1.2-15.9%; nine studies; I2 = 89%) and 6.2% (95%CI: 1.2-27.0%; two studies; I2 = 69%) in schizophrenia and bipolar disorder, respectively. People with psychosis were more likely to have GAD65 antibodies than controls (odds ratio [OR], 2.24; 95%CI: 1.28 3.92%; P = 0.005; eight studies; I2 = 0%). Among 21 participants with treatment resistant psychosis, none had VGKC antibodies. The prevalence of VGKC antibodies is low in psychosis. Our preliminary meta-analysis suggests that GAD autoantibodies are more common in people with psychosis than in controls, although few studies accounted for the possibility of co-existing type 1 diabetes mellitus and the clinical significance of reported GAD titers remains unclear. The paucity of studies reporting thresholds for defining GAD abnormality and rates of comorbid type 1 diabetes mellitus precludes interpretations regarding the influence of GAD antibodies on the development of psychotic disorders and may have led to an overestimate of the prevalence of GAD. Our case series fails to support the hypothesis that VGKC antibodies are linked to treatment resistance in psychosis, but the literature to date is remarkably sparse. PMID- 28573691 TI - Medical abortion is fundamental to women's health care. PMID- 28573692 TI - Response to Natural childbirth ideology is endangering women and babies/Every CS must count. PMID- 28573693 TI - Term breech delivery: Is recommending vaginal birth a breach of best practice? PMID- 28573694 TI - Response to Natural childbirth ideology is endangering women and babies/Every CS must count. PMID- 28573695 TI - Natural childbirth ideology is endangering women and babies/Every CS must count. PMID- 28573696 TI - There is a place in current obstetric practice for planned vaginal breech birth. PMID- 28573697 TI - Reply to Neonatal head circumference and computed tomography pelvimetry could be useful counselling tools after caesarean section for failure to progress. PMID- 28573698 TI - Neonatal head circumference and computed tomography pelvimetry could be useful counselling tools after caesarean section for failure to progress. PMID- 28573699 TI - Painful swelling after a noxious event and the development of complex regional pain syndrome 1: A one-year prospective study. AB - BACKGROUND: The timing of diagnosis of complex regional pain syndrome (CRPS) 1 remains a challenge due to the large heterogeneity of clinical presentations. We describe the distribution and differences in outcomes and clinical manifestations between time points and patient groups with and without CRPS 1 following an initiating event. METHODS: Prospective cohort study with a consecutive registration of patients presenting with painful swelling of the affected extremity after an initiating event and follow-up visits after 3, 6 and 12 months. RESULTS: Forty-two patients were enrolled (37 females, mean age 55.1 years). At baseline, 35 participants (83%, females n = 30) fulfilled the diagnostic criteria for CRPS 1. At 3 months, 19 out of the initial 35 CRPS 1 patients (54%) did not meet the diagnostic criteria anymore. Besides our inclusion criteria of a painful swelling, early manifestations indicating a CRPS 1 primarily include an impaired quality of life (SF-35, EQ5-D), more pain (NRS, MPQ) and restricted range of motion. CONCLUSIONS: CRPS 1 develops within 8 weeks following a noxious event. Although many CRPS 1 patients reach partial remission within the first 3 months, signs and symptoms do not improve significantly at 1 year. In order to identify prognostic risk factors large prospective cohort studies are needed. SIGNIFICANCE: This prospective cohort study follows patients with complaints most suspected for complex regional pain syndrome (CRPS) 1. CRPS 1 develops within 8 weeks following a noxious event. Although many CRPS 1 patients reach partial remission within the 3 months, symptoms do not improve significantly at 1 year. PMID- 28573700 TI - Long-term follow-up of Fontan completion in adults and adolescents. AB - BACKGROUND: The Fontan procedure is rarely performed in adults and adolescents in the present era. We review our results with the Fontan procedure in adolescents and young adults. METHODS: Between 1974 and 2010, 79 consecutive patients underwent the Fontan procedure at an age >= 15 years (mean age at Fontan operation, 20.3 years +/- 4.5 years). Forty-five patients underwent atriopulmonary connection, 11 underwent the Bjork procedure, and 23 underwent total cavopulmonary connection. RESULTS: Ten hospital deaths (HDs) and/or early Fontan takedowns (TDs) occurred. The median follow-up period was 18.2 years (range, 0.6-37.6 years). The estimated freedom from death or TD rates was 79.7% at 5 years, 77.0% at 10 years, 73.9% at 15 years, and 63.9% at 20 years. Age was not a predictor of HD and/or TD. Freedom from death or TD after 1998 was 69.1% at 5 years, 69.1% at 10 years, and 69.1% at 15 years, and before 1997 was 82.3% at 5 years, 79.0% at 10 years, 75.5% at 15 years, and 65.1% at 20 years; there were no significant differences between the two groups. In 19 late-death patients, nine (47.4%) experienced sudden death. Among these patients, five had known arrhythmias before sudden death. CONCLUSIONS: In patients who were >=15 years old, the surgical results of the Fontan operation were acceptable. Approximately half of the late deaths were sudden deaths, mainly occurring 10-20 years postoperatively. PMID- 28573701 TI - Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome. AB - Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype-phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype-genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4-year-old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis. PMID- 28573702 TI - Examining coping style and the relationship between stress and subjective well being in Australia's 'sandwich generation'. AB - OBJECTIVE: The sandwich generation represents adults, often in midlife, who care for both children and ageing parents/relatives. While the stress they experience has received some attention, little research has investigated the subjective well being (SWB) of this population. This study examined the relationship between perceived stress and SWB and the moderating effect of coping style. METHODS: Ninety-three participants (80 women), aged 23-63 years, completed an online survey measuring perceived stress, coping strategies, life satisfaction and positive and negative affect. RESULTS: Stress was negatively associated with SWB. While emotion- and problem-focused coping were directly associated with SWB outcomes, the only moderating effect found was for avoidance-focused coping (AFC). Specifically, AFC was associated with higher positive affect for those reporting lower stress. CONCLUSION: This study highlights the need to recognise the distinct circumstances that exist for the sandwich generation. Limitations and suggestions for future research are discussed. PMID- 28573703 TI - TNFRSF13C (BAFFR) positive blasts persist after early treatment and at relapse in childhood B-cell precursor acute lymphoblastic leukaemia. PMID- 28573704 TI - RCT of a Video-based Intervention Program for Caregivers of Patients with an Eating Disorder. AB - OBJECTIVE: This paper presents the results of a randomized controlled trial measuring the efficacy of a video-based skills training to decrease burden and psychological distress in caregivers of inpatients treated for an eating disorder in specialized hospital units. METHOD: Two hundred eighty-five caregivers were randomized to either the video intervention (N = 147) or the control group (N = 138). Caregivers' primary outcomes were assessed via Eating Disorder Symptom Impact Scale, Accommodation and Enabling Scale and General Health Questionnaire 12 at baseline and three-months follow-up. RESULTS: Acceptability of the intervention was high. Receiving additional external professional help like psychotherapy or clinical counselling was identified as a moderator contributing to the efficacy of the intervention. Caregivers' burden (Eating Disorder Symptom Impact Scale) and psychological distress (General Health Questionnaire-12) were reduced by the intervention but not caregivers' accommodating behaviours (Accommodation and Enabling Scale). CONCLUSION: The video training is a promising approach and effective supplement for caregivers of patients with an eating disorder. Additional professional help to caregivers increases the effectiveness of the intervention. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28573705 TI - Evidence for Cognitive Remediation Therapy in Young People with Anorexia Nervosa: Systematic Review and Meta-analysis of the Literature. AB - Cognitive remediation therapy (CRT) for eating disorders has demonstrated promising findings in adult age groups, with randomised treatment trials and systematic reviews demonstrating medium to large effect sizes in improved cognitive performance. In recent years, several case series have been conducted for young people with anorexia nervosa, but these findings have not been synthesised in the form of a systematic review. This systematic review aimed to evaluate the evidence for the efficacy of CRT in child and adolescent age groups. Nine studies were identified, with a subsequent meta-analysis suggesting improvements in cognitive performance with small effect sizes. Patient feedback was positive, with low dropout rates. These findings suggest that CRT has potential as a supplementary treatment for young people with anorexia nervosa, warranting further investigation using randomised treatment trials. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28573707 TI - Teaching Tradition: Diverse Perspectives on the Pilot Urban American Indian Traditional Spirituality Program. AB - Many urban American Indian community members lack access to knowledgeable participation in indigenous spiritual practices. And yet, these sacred traditional activities remain vitally important to their reservation-based kin. In response, our research team partnered with an urban American Indian health center in Detroit for purposes of developing a structured program to facilitate more ready access to participation in indigenous spiritual knowledge and practices centered on the sweat lodge ceremony. Following years of preparation and consultation, we implemented a pilot version of the Urban American Indian Traditional Spirituality Program in the spring of 2016 for 10 urban AI community participants. Drawing on six first-person accounts about this program, we reflect on its success as a function of participant meaningfulness, staff support, mitigated sensitivities, and program structure. We believe that these observations will enable other community psychologists to undertake similar program development in service to innovative and beneficial impacts on behalf of their community partners. PMID- 28573706 TI - Diagnosis and monitoring for light chain only and oligosecretory myeloma using serum free light chain tests. AB - This study aims to guide the integration of serum free light chain (sFLC) tests into clinical practice, including a new rapid test (Seralite(r) ). Blood and urine analysis from 5573 newly diagnosed myeloma patients identified 576 light chain only (LCO) and 60 non-secretory (NS) cases. Serum was tested by Freelite(r) and Seralite(r) at diagnosis, maximum response and relapse. 20% of LCO patients had urine FLC levels below that recommended for measuring response but >97% of these had adequate sFLC levels (oligosecretory). The recommended Freelite(r) sFLC >=100 mg/l for measuring response was confirmed and the equivalent Seralite(r) FLC difference (dFLC) >20 mg/l identified. By both methods, >=38% of NS patients had measurable disease (oligosecretory). Higher sFLC levels were observed on Freelite(r) at all time points. However, good clinical concordance was observed at diagnosis and in response to therapy. Achieving at least a very good partial response according to either sFLC method was associated with better patient survival. Relapse was identified using a Freelite(r) sFLC increase >200 mg/l and found 100% concordance with a corresponding Seralite(r) dFLC increase >30 mg/l. Both Freelite(r) and Seralite(r) sensitively diagnose and monitor LCO/oligosecretory myeloma. Rapid testing by Seralite(r) could fast-track FLC screening and monitoring. Response by sFLC assessment was prognostic for survival and demonstrates the clinical value of routine sFLC testing. PMID- 28573709 TI - Cardiac cachexia causing extensive serous degeneration of bone marrow. PMID- 28573708 TI - Variability in and predictors of glycaemic responses after 24 weeks of treatment with exenatide twice daily and exenatide once weekly. AB - The range of glycated haemoglobin (HbA1c) responses and characteristics associated with above-average response to exenatide twice daily and once weekly were examined. Data were pooled from 8 exenatide-twice-daily and 5 exenatide-once weekly studies. A baseline HbA1c-corrected measure of change in HbA1c after 24 weeks identified high, average and low responses. Multiple linear regression and multivariate generalized estimating equation models identified factors associated with high response. Among 2355 participants (exenatide twice daily, n = 1414; exenatide once weekly, n = 941), baseline HbA1c correlated with change in HbA1c (P < .0001). Across baseline HbA1c levels, the 25th to 75th percentile of HbA1c change ranged from -0.3% to -3.2% with exenatide twice daily and from -0.5% to 3.6% with exenatide once weekly. Asian ethnicity and older age were significantly associated with high response to exenatide twice daily; no factors were significantly associated with response to exenatide once weekly. These data provide clinically useful information for estimating the likelihood that, depending on baseline HbA1c, an individual can achieve HbA1c goals. The association between Asian ethnicity, age and high response to exenatide twice daily may relate to the specific effects of exenatide twice daily on postprandial glucose. PMID- 28573711 TI - Corrigendum. PMID- 28573710 TI - Margins Matter: current radiation therapy practice and future directions. AB - Commentary is provided in the context of current practices for calculating radiation therapy margins and future directions that will impact on this. PMID- 28573712 TI - Cutaneous T pseudolymphoma on the red pigmented areas of a tattoo. PMID- 28573713 TI - How do reinforcers affect choice? Preference pulses after responses and reinforcers. AB - In concurrent schedules, reinforcers are often followed by a brief period of heightened preference for the just-productive alternative. Such 'preference pulses' may reflect local effects of reinforcers on choice. However, similar pulses may occur after nonreinforced responses, suggesting that pulses after reinforcers are partly unrelated to reinforcer effects. McLean, Grace, Pitts, and Hughes (2014) recommended subtracting preference pulses after responses from preference pulses after reinforcers, to construct residual pulses that represent only reinforcer effects. Thus, a reanalysis of existing choice data is necessary to determine whether changes in choice after reinforcers in previous experiments were actually related to reinforcers. In the present paper, we reanalyzed data from choice experiments in which reinforcers served different functions. We compared local choice, mean visit length, and visit-length distributions after reinforcers and after nonreinforced responses. Our reanalysis demonstrated the utility of McLean et al.'s preference-pulse correction for determining the effects of reinforcers on choice. However, visit analyses revealed that residual pulses may not accurately represent reinforcer effects, and reinforcer effects were clearer in visit analyses than in local-choice analyses. The best way to determine the effects of reinforcers on choice may be to conduct visit analyses in addition to local-choice analyses. PMID- 28573714 TI - Wide local excision vs. Mohs Tubingen technique in the treatment of dermatofibrosarcoma protuberans: a two-centre retrospective study and literature review. AB - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade mesenchymal skin tumour, characterized by slow infiltrative growth and common local recurrence, with infrequent distant metastases. OBJECTIVE: The aim of this study is to better clarify clinicopathological characteristics of this tumour and to evaluate the cure rates of Mohs Tubingen technique (MTT) and wide local excision (WLE). Eventually, we perform a literature review to compare our experience with published data. METHODS: A retrospective review was conducted on 135 patients diagnosed, treated and followed up between 1997 and 2014 at two different institutions. Sixty-two patients underwent to WLE and 73 to MTT. The primary end-points were the following: percentage of recurrences, time to progression and recurrence annual risk rate. Then, the PubMed database was searched for DFSP case series treated with standard surgical resection (SSR), WLE, Mohs' micrographic surgery (MMS) and MTT. The annual risk rate of recurrence calculated and reported for the four separate procedures was pooled to compare them. RESULTS: Five of the 62 patients with WLE (8.1%) experienced recurrences after a mean follow-up of 4.7 years; the percentage of recurred patients 9 years after MTT was 5.5%, and the annual recurrence risk rate of 0.6%. Pooling these data with those from literature, the recurrence rate varies from 26% to 60% for SSR, from 0% and 41% for WLE, from 0% and 8.3% for MMS and from 0% to 5.5% for MTT. The lowest annual recurrence risk rate was found for MTT. CONCLUSION: Significantly lower recurrence rates were recorded in patients treated with classic or Tubingen Mohs' technique. To the best of our knowledge, our case series is the widest treated with MTT ever described in the literature; these data may be useful to guide clinicians in the choice of the gold standard treatment for Dermatofibrosarcoma protuberans. PMID- 28573715 TI - Blood prime for patients with single-needle access requiring extracorporeal photopheresis: How to do and why it may be useful. PMID- 28573716 TI - Painful decisions: How classifying sensations can change the experience of pain. AB - BACKGROUND: Categorizing perceptual stimuli is a mechanism for facilitating the processing of sensory input from our environment. This facilitation of perception is achieved through generalization (assimilation) of stimulus characteristics within categories and accentuation between categories. These categorization processes have been demonstrated in visual, auditory, tactile and social perception, but never in pain perception. METHOD: We presented participants with six thermal noxious stimuli, increasing in steps of 0.5 degrees C. In an experimental group, stimuli were assigned to two categories labelled A and B containing the three lower (A1, A2, A3) and three higher (B1, B2, B3) stimuli. A control group did not receive such category information (stimuli were labelled S1 S6). In a first part of the experiment, participants simply rated pain intensity and unpleasantness for all stimuli. In a second part, we presented stimuli without labels and participants had to identify the label of each stimulus. RESULTS: We found evidence for categorization effects in both pain ratings and stimulus identification data. In particular, unpleasantness ratings within categories were more similar to each other, and ratings between categories less similar, in the experimental compared to control group. Participants in the experimental group also confused stimuli more often within than between categories, and were more confident about category membership of stimuli at the category border, compared to participants in the control group. CONCLUSIONS: Mere category information, using abstract category labels, significantly changes pain perception. Implications for our understanding of cognitive pain modulation mechanisms, as well as clinical implications of categorization effects are discussed. SIGNIFICANCE: Categorization effects in pain perception are demonstrated. Classifying and labelling painful events can modulate early perceptual processes, lead to under- or overestimation of pain symptoms and affect decision-making behaviour related to pain. PMID- 28573717 TI - Cytotoxic-mediated spontaneous regression of eruptive tufted angioma in a teenage girl. PMID- 28573718 TI - Automatic detection of end-diastolic and end-systolic frames in 2D echocardiography. AB - BACKGROUND: Correctly selecting the end-diastolic and end-systolic frames on a 2D echocardiogram is important and challenging, for both human experts and automated algorithms. Manual selection is time-consuming and subject to uncertainty, and may affect the results obtained, especially for advanced measurements such as myocardial strain. METHODS AND RESULTS: We developed and evaluated algorithms which can automatically extract global and regional cardiac velocity, and identify end-diastolic and end-systolic frames. We acquired apical four-chamber 2D echocardiographic video recordings, each at least 10 heartbeats long, acquired twice at frame rates of 52 and 79 frames/s from 19 patients, yielding 38 recordings. Five experienced echocardiographers independently marked end-systolic and end-diastolic frames for the first 10 heartbeats of each recording. The automated algorithm also did this. Using the average of time points identified by five human operators as the reference gold standard, the individual operators had a root mean square difference from that gold standard of 46.5 ms. The algorithm had a root mean square difference from the human gold standard of 40.5 ms (P<.0001). Put another way, the algorithm-identified time point was an outlier in 122/564 heartbeats (21.6%), whereas the average human operator was an outlier in 254/564 heartbeats (45%). CONCLUSION: An automated algorithm can identify the end systolic and end-diastolic frames with performance indistinguishable from that of human experts. This saves staff time, which could therefore be invested in assessing more beats, and reduces uncertainty about the reliability of the choice of frame. PMID- 28573719 TI - N-nitrosamines induced infertility and hepatotoxicity in male rabbits. AB - N-nitrosamines are widely spread environmental pollutants of well-known toxicity and carcinogenicity in various animal species. These compounds are metabolically activated by cytochrome P450 system predominantly in the liver and in other tissues into more active metabolites leading to generation of both alkylating agents that alkylate DNA and reactive oxygen species. In the current study, we investigated the influence of four types of N-nitrosamines that are commonly present in the environment [methyethylnitrosamine, (MEN), diethylnitrosamine (DEN), diphenylnitroasamine (DPN) and dimethylnitrosamine (DMN)] on both livers and testes of male rabbits through assessment of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity. The protein expression of the three cytochrome P450s (CYP11A1, CYP19A1, and CYP21A2) is involved in the steroidogenesis. The levels of testosterone (T) and estradiol (E2) were also determined in the plasma of N-nitrosamines-treated rabbits after one, four-, eight- and twelve weeks of treatment of male New Zealand rabbits with an oral dose of 0.5 mg/kg B.W/day of each compound. In addition, activities of glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT) and levels of free radicals measured as thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH) level were quantified in both livers and testes. The present study showed that levels of free radicals (TBARS) were markedly increased, whereas GSH levels were depleted in the tissues of both livers and testes after treatment of rabbits with any of N-nitrosamines. In addition, all tested N-nitrosamines inhibited the activities of antioxidant enzyme activities (GR, GST, SOD, and CAT) in hepatic and testicular tissues of rabbits after 12 weeks of treatment. Histopathological examination showed that N-nitrosamines caused lymphocytic infiltration with vascular degeneration and necrosis, congestion of central vein with RBCs hemolysis, dilated sinusoids, as well as fibrosis around portal areas were seen in hepatic tissues. In the testes, histopathological examination displayed disorganized seminiferous tubules with degeneration of germinal epithelium and Sertoli cells. Also, spermatogenic cells had pyknotic nuclei and others were detached from basement membranes of seminiferous tubules, edema was seen between seminiferous tubules. Moreover, the present data showed that MEN and DEN down-regulated the protein expression of both CYP19A1 and 21A2 in both livers and testes of male rabbits. In addition, both MEN and DEN decreased levels of testosterone and estradiol in plasma of treated rabbits. On the one hand, DMN and DPN markedly up-regulated the protein expression of CYP19A1 in both hepatic and testicular tissues of treated rabbits. These compounds potentially increased estradiol and decreased testosterone levels. On the other hand, no correlation was found between the expression of CYP11A1 and levels of both testosterone and estradiol. It is concluded that most of tested N-nitrosamines induce different changes, which could be a new mechanism of infertility due to exposure to N-nitrosamines from different environmental sources. PMID- 28573720 TI - Assessment of deep dynamic mechanical sensitivity in individuals with tension type headache: The dynamic pressure algometry. AB - BACKGROUND: To explore the validity of dynamic pressure algometry for evaluating deep dynamic mechanical sensitivity by assessing its association with headache features and widespread pressure sensitivity in tension-type headache (TTH). METHODS: One hundred and eighty-eight subjects with TTH (70% women) participated. Deep dynamic sensitivity was assessed with a dynamic pressure algometry set (Aalborg University, Denmark(c) ) consisting of 11 different rollers including fixed levels from 500 g to 5300 g. Each roller was moved at a speed of 0.5 cm/s over a 60-mm horizontal line covering the temporalis muscle. Dynamic pain threshold (DPT-level of the first painful roller) was determined and pain intensity during DPT was rated on a numerical pain rate scale (NPRS, 0-10). Headache clinical features were collected on a headache diary. As gold standard, static pressure pain thresholds (PPT) were assessed over temporalis, C5/C6 joint, second metacarpal, and tibialis anterior muscle. RESULTS: Side-to-side consistency between DPT (r = 0.843, p < 0.001) and pain evoked (r = 0.712; p < 0.001) by dynamic algometer was observed. DPT was moderately associated with widespread PPTs (0.526 > r > 0.656, all p < 0.001). Furthermore, pain during DPT was negatively associated with widespread PPTs (-0.370 < r < -0.162, all p < 0.05). DISCUSSION: Dynamic pressure algometry was a valid tool for assessing deep dynamic mechanical sensitivity in TTH. DPT was associated with widespread pressure sensitivity independently of the frequency of headaches supporting that deep dynamic pressure sensitivity within the trigeminal area is consistent with widespread pressure sensitivity. Assessing deep static and dynamic somatic tissue pain sensitivity may provide new opportunities for differentiated diagnostics and possibly a new tool for assessing treatment effects. SIGNIFICANCE: The current study found that dynamic pressure algometry in the temporalis muscle was associated with widespread pressure pain sensitivity in individuals with tension type headache. The association was independent of the frequency of headaches. Assessing deep static and dynamic somatic tissue pain sensitivity may provide new opportunities for differentiated diagnostics and possibly a tool for assessing treatment effects. PMID- 28573721 TI - GPS-identified, low-level nocturnal activity of vervets (Chlorocebus pygerythrus) and olive baboons (Papio anubis) in Laikipia, Kenya. AB - OBJECTIVES: Except for owl monkeys (Aotus spp.), all anthropoid primates are considered strictly diurnal. Recent studies leveraging new technologies have shown, however, that some diurnal anthropoids also engage in nocturnal activity. Here we examine the extent to which vervets (Chlorocebus pygerythrus) and olive baboons (Papio anubis) are active at night. MATERIALS AND METHODS: We deployed GPS collars with tri-axial accelerometer data loggers on 18 free-ranging adult females: 12 vervets spread among 5 social groups, and 6 olive baboons spread among 4 groups. Their locations were recorded every 15 min, and their activity levels, for 3 s/min over 7.5 months. We also used camera traps that were triggered by heat and movement at seven sleeping sites. RESULTS: Travel was detected on 0.4% of 2,029 vervet-nights involving 3 vervets and 1.1% of 1,109 baboon-nights involving 5 baboons. Travel was mainly arboreal for vervets but mainly terrestrial for baboons. During the night, vervets and baboons were active 13% and 15% of the time, respectively. Activity varied little throughout the night and appeared unaffected by moon phase. DISCUSSION: Our results confirm the low nocturnality of vervets and olive baboons, which we suggest is related to living near the equator with consistent 12-hr days, in contrast to other anthropoids that are more active at night. Since anthropoid primates are thought to have evolved in northern latitudes, with later dispersal to tropical latitudes, our results may have implications for understanding the evolution of anthropoid diurnality. PMID- 28573722 TI - Combined effect of pH and heating conditions on the physical properties of Alaska pollock surimi gels. AB - : Physical properties of Alaska pollock surimi paste were investigated as affected by pH (4.0 and 6.0-10.0) and heating conditions (slow and fast). The highest values of gel strength and deformability, as shown by breaking force and penetration distance, were obtained at pH 7.5-8.0, while the lowest values were at pH 10.0 followed by pH 6.0 and pH 6.5, respectively. Two-step slow heating process increased the breaking strength value nearly two times higher than one step fast heating. The effect of pH was strikingly high at pH 7.5 when gels were prepared using 2-step heating, indicating the pH dependence of endogenous transglutaminase. However, the highest gel strength was obtained at pH 8.0 when gels were prepared in fast heating. Whiteness value (L - 3b*) increased significantly (p < .05) as pH increased from 6.0 to 6.5, but thereafter decreased significantly (p < .05) as pH increased. L* value (lightness) and b* value (yellowness) continuously decreased as the pH is shifted from 6.0 to 10. Fast heated gels showed the lowest yellowness, resulting in whiter appearance, probably due to the effect of reduced browning reaction. PRACTICAL APPLICATIONS: The uniqueness of this study was to measure the combined effect of pH and heating conditions on the gel texture and color. There were various studies dealing with pH or heating conditions independently. As the primary character for surimi seafood is gel texture and color. The highest values of gel strength and deformability, as shown by breaking force and penetration distance, were obtained at pH 7.5-8.0, while the lowest values were at pH 10.0 followed by pH 6.0 and pH 6.5, respectively. Two-step slow heating process increased the breaking strength value nearly two times higher than one-step fast heating. Whiteness value (L - 3b*) increased significantly as pH increased from 6.0 to 6.5, but thereafter decreased significantly as pH increased. L* value (lightness) and b* value (yellowness) continuously decreased as the pH is shifted from 6.0 to 10. Fast heated gels showed the lowest yellowness, resulting in whiter appearance. PMID- 28573723 TI - Extruded snacks from whole wheat supplemented with textured soy flour: Effect on instrumental and sensory textural characteristics. AB - : The quality of extruded snacks can be affected not only by processing conditions, but also by some factors like the concentration and type of ingredients incorporated in their formulation and the working conditions used. Although the process conditions have been established with measurable textural properties, sensory qualities have not been correlated with these responses in expanded extruded snacks made with added functional ingredients. Therefore, in this study the effect of adding textured soy flour (TSF) and whole wheat flour (WWF) to refined wheat flour in the production of extruded snacks and expanded with hot air was evaluated. A response surface design using two levels with five central points was applied to obtain the best combinations of functional ingredients added, holding the parameters of the extrusion process and moisture of treatments. Some texture characteristics and sensory analysis were used as response variables, such as, hardness, fracturability, toughness, crispness, granularity, and chewiness. Likewise, the rate of expansion was evaluated. The results showed that the level of substitution of WWF, especially levels of 15%, had a significant effect on the hardness perceived by the panelist during sensory evaluation. The TSF at concentrations of >=15%, favored the fracturability and crispness of the samples. It was found that the best expansion index was with the combination of 5% TSF and 15% WWF. Although a correlation between instrumental and sensory tests carried out on the extruded snacks expanded was not found. PRACTICAL APPLICATIONS: The physical characteristics of the extruded snacks such as expansion, hardness, and density are important parameters in terms of consumer acceptability of the final product as well as their functional properties. In other words, the appearance and texture are two of the most important attributes that can be seen in snack foods. In particular, the texture can be measured by intrinsic tests: objective (instrumental) and subjective (sensory). That is because the instrumental analysis provides parameters such as firmness, brittleness, consistency, chewiness, among others, when subjected to different stress, strain, and strain rates at the snacks. Similarly, sensory analysis, allows us to see features that include mechanical attributes (concerning the reaction to the applied force), geometric attributes (concerning the shape, size, and orientation of the particles within the food), and attributes related to the perception of moisture or fat content. PMID- 28573724 TI - Human roughness perception and possible factors effecting roughness sensation. AB - : Surface texture sensation is significant for business success, in particular for solid surfaces for most of the materials; including foods. Mechanisms of roughness perception are still unknown, especially under different conditions such as lubricants with varying viscosities, different temperatures, or under different force loads during the observation of the surface. This work aims to determine the effect of those unknown factors, with applied sensory tests on 62 healthy participants. Roughness sensation of fingertip was tested under different lubricants including water and diluted syrup solutions at room temperature (25C) and body temperature (37C) by using simple pair-wise comparison to observe the just noticeable difference threshold and perception levels. Additionally, in this research applied force load during roughness observation was tested with pair wise ranking method to illustrate its possible effect on human sensation. Obtained results showed that human's capability of roughness discrimination reduces with increased viscosity of the lubricant, where the influence of the temperature was not found to be significant. Moreover, the increase in the applied force load showed an increase in the sensitivity of roughness discrimination. Observed effects of the applied factors were also used for estimating the oral sensation of texture during eating. These findings are significant for our fundamental understanding to texture perception, and for the development of new food products with controlled textural features. PRACTICAL APPLICATIONS: Texture discrimination ability, more specifically roughness discrimination capability, is a significant factor for preference and appreciation for a wide range of materials, including food, furniture, or fabric. To explore the mechanism of sensation capability through tactile senses, it is necessary to identify the relevant factors and define characteristics that dominate the process involved. The results that will be obtained under these principles will be helpful for the industry in the development and optimization of new products, especially for the individuals' with special needs. With this exploratory study, we illustrate differential thresholds of tactile senses under changing conditions of surface lubrication and applied force load. Also, the tests were carried out under different temperatures to understand the oral sensation capability. The results and correlations may provide useful information about texture sensitivity and also methodologies could be applied to general sensory studies. PMID- 28573726 TI - Effect of curry leaf and clove bud essential oils on textural and oxidative stability of chill stored sutchi catfish fillets. AB - : Effect of coating with curry leaf and clove essential oils (EO) on oxidative and textural stability of sutchi catfish fillets were evaluated during chilled storage. The changes in parameters associated with textural and lipid degradation was also evaluated to ascertain the interactive effect of polyphenols with muscle proteins. Further, the results were compared against vacuum and conventional polyethylene packaging practices. Prior to coating, the properties of antioxidants were evaluated in vitro based on total phenolic and flavonoid contents, 2, 2-diphenyl-1- picrylhydrazyl radical scavenging activity, inhibition of linoleic acid peroxidation, iron reducing power, and metal chelating ability. Coating with clove bud EO was found to be more effective in protecting the textural quality and retarding lipid oxidation of the fillets during chilled storage. Curry leaf EO was found to have only moderate effect. PRACTICAL APPLICATIONS: In addition to the well-studied antibacterial and antioxidant properties, plant polyphenols have become an intense focus of research for their ability to cross-link proteins that widens their applications for textural and functional modification of food and beverages. Currently, a number of carcinogenic chemicals such as ammonia and formalin are hazardously used to prevent texture deterioration in chilled fish associated with post-rigor changes and microbial reactions. This study evaluates the efficacy of polyphenols present in culinary herbs such as clove bud and curry leaf EO, in stabilising the texture of fish meat during chilled storage. From the results, it could be inferred that both the EO at 0.25% level mediated protein cross-linking/complexation and maintained textural integrity during chilled storage apart from exhibiting antioxidant activities. PMID- 28573725 TI - Effects of cellulose derivative hydrocolloids on pasting, viscoelastic, and morphological characteristics of rice starch gel. AB - : Effects of sodium carboxymethyl cellulose (CMC) and hydroxypropyl methyl cellulose (HPMC) on the pasting, viscoelastic, and morphological properties of rice starch gel were studied. The addition of CMC increased the peak and trough viscosities, while decreased the final and setback viscosities of rice starch. The peak and trough viscosities of rice starch gel were only little affected by the addition of HPMC. The dynamic viscoelastic result showed that the addition of CMC significantly increased the values of storage modulus (G') and loss modulus (G"), while reduced the value of tandelta as compared to the control sample. Only a small increase in values of G' and G" was observed in the case of HPMC. The rice starch gel with CMC addition exhibited higher resistances to the stress and produced a stronger gel network. The creep recovery data were well fitted by a four-element Burger's model. Furthermore, the morphological characteristics were in agreement with the finding of rheological results. It was concluded that the addition of CMC and HPMC modified the rheology of rice starch gel in different ways and interacted under different models based on their molecular structures. PRACTICAL APPLICATIONS: Gluten-free foods such as rice cake are essential for people who suffer from celiac disease which is a digestive disorder caused by the consumption of grains containing gluten. The use of CMC and HPMC represents the most widespread approach used to mimic gluten in the manufacture of gluten-free breads based on rice starch, due to their structure-building and water-binding properties. Therefore, it is necessary and crucial to investigate the physical chemical properties such as pasting and rheological properties of the rice starch with these hydrocolloids. In addition, a better understanding of the interactions of CMC and HPMC on the rice starch could provide additional tools for selection of gluten free recipes with improved rheological and textural properties. PMID- 28573727 TI - Characterization and bake stability of dry fruit fillings in dehydrated chiku (Manilkara zapota L. P. Royen) incorporated biscuits. AB - : Expanding the range of bakery products in terms of producing supplemented or dietetic products has been an increasingly important trend in contemporary baking. Value added products, especially products rich in fiber and phytochemicals are getting popular. Among the dry fruits used for filling, Figs were rich in ash and protein and Dates were rich in dietary fiber. Gallic acid was the dominant free phenolic acid in Fig whereas chlorogenic acid and procatechuic acid were dominant in Dates in the bound form. Farinograph water absorption, dough development time, maximum pressure (P), and extensibility (L) decreased on increase in the replacement of wheat flour with chiku powder from 0 to 30%. The dry fruit fillings in the pH range of 3.3-3.5 with 75-80 degrees Bx showed better bake stability with respect to spreadability and breaking strength. Biscuits topped with higher degrees Bx fillings had higher breaking strength values even during storage. Among the gelling agents used, addition of sodium alginate stabilized and further improved the bake stability of the fillings. The chiku incorporated biscuits sandwiched with fruit filling were rich in dietary fiber. Also significant amounts of gallic acid and chlorogenic acid in free and bound form were present in the biscuit. PRACTICAL APPLICATIONS: Bakery products can act as a vehicle for supplementation of vitamins, minerals, protein, dietary fiber, and so on, to prevent nutritive deficiencies. Among the bakery products, biscuits are shelf stable and have better consumer acceptability by all age groups. To incorporate fruits which are rich in many bioactive principles, and to add on to variety, fruit sandwiched biscuits with fruit powder in the casing too. Fillings mainly from dry fruits were prepared at varying degree brix and with different gelling agents. Biscuit sheets containing chiku powder in the formulation was topped with the fillings and looked for the bake stability with respect to texture and spreadability. Addition of fruit powder in the shells and fruit filling in between helped to increase the nutritional characteristics of the product. PMID- 28573728 TI - Substitution of modified starch with hydrogen peroxide-modified rice bran in salad dressing formulation: physicochemical, texture, rheological and sensory properties. AB - : Rice bran samples were treated under different conditions including hydrogen peroxide content (1, 4, and 7 wt%) and media pH (10.5, 11.5, and 12.5). Water holding capacity and color measurement results showed acceptable improvements compared with the untreated native bran confirmed by Fourier transform infrared analysis. Optimization of modification conditions upon characterization results suggested the introduction of 7% hydrogen peroxide at pH = 12.5. Accordingly, 1, 2 and 3 wt% of the rice bran treated under the optimized conditions, was used in salad dressing formulation; as for .3 wt% of modified starch in the formulation of blank sample, 1 wt% of treated rice bran dietary fiber was substituted. Biopolymer swelling and formation of a stable viscous gel network promoted by the chemical treatment of lignocellulosic rice bran restrict the mobility of oil droplets dispersed in the continuous phase which would consequently retard the emulsion instability phenomena. This effect was also confirmed by flow behavior and viscoelastic characterization results. Salad dressing samples containing 1 and 2 wt% treated rice bran showed acceptable physicochemical, rheological and organoleptic properties besides superior nutritional characteristics compared with the commercial modified starch traditionally used in salad dressing formulations. PRACTICAL APPLICATIONS: Despite recommended consumption of dietary fibers, addition of unprocessed lignocellulosic materials to food products usually raise negative effects in sensory, color, and texture quality. This study investigates the modification of rice bran, the byproduct of brown rice milling, to substitute modified starch traditionally used in salad dressing formulations to achieve optimum properties desirable for the final product. Optimization of modification conditions upon characterization of the formulated samples in this study would suggest new improved formulation for the commercial product. PMID- 28573729 TI - Development of protein, dietary fiber, and micronutrient enriched extruded corn snacks. AB - : The study was aimed to develop protein, dietary fiber, and micronutrient enriched corn snacks through extrusion processing. Corn snacks supplemented with chickpea, defatted soy flour (20-40/100 g) and guar gum (7/100 g) were prepared through extrusion processing. Micronutrients (iron, zinc, iodine, and vitamins A, C, and folic acid) at recommended daily values were added in all formulations. Extruded corn snacks were analyzed for physical, textural, and sensory attributes. Results showed that piece density (0.34-0.44 g/cm3 ), moisture (3.40 5.25%), water activity (0.203-0.361), hardness (64.4-133.2 N), and cohesiveness (0.25-0.44) was increased Whereas, expansion ratio (3.72-2.64), springiness (0.82 0.69), chewiness (1.63-0.42), and resilience (1.37-0.14) was decreased as supplementation with soy and chickpea flour increased from 20 to 40/100 g. Overall corn snack supplemented with 15/100 g of soy and 15/100 g of chickpea flour got the highest acceptance from the sensory panelists. PRACTICAL APPLICATIONS: The article focuses on physical, textural, and sensory attributes of extruded corn snacks enriched with protein, dietary fiber, and micronutrients Awareness about the importance of healthy snacks has grown among the consumers during the last decade. Extruded snacks developed using nutrient rich ingredients with good textural and sensory properties has always remained a challenge for the snack industry. Texture of the extruded snacks varies a lot with high levels of protein and dietary fiber. This study is helpful for the development of healthy snacks especially in developing countries lacking storage infrastructure or tropical environment. Nutrient rich extruded snacks can also be used to alleviate malnutrition by incorporating in school lunch programs. PMID- 28573730 TI - Development of a simple and objective evaluation method for thickened liquids using funnels. AB - : Some patients with dysphagia are prone to aspiration of low-viscosity liquids. Thickened liquids are often used in attempts to prevent aspiration. The patients should be given thickened liquids with suitable thickness, and the thickness should be constant at all time. While rotational and cone-and-plate viscometers are used for the evaluation of thickened liquids, they are high-precision and expensive equipment. To control the thickness of liquids, a simple and objective evaluation method is thus necessary. We developed a method to evaluate thickened liquids using funnels, and verified the appropriateness of this method. We measured the outflow times of five thickened liquids through funnels. One of the thickened liquids was a commercially available nutritional supplement, another was made with a thickening agent that contained guar gum, and all others were made with a thickening agent that contained xanthan gum. Four funnels with different stem sizes were tested. We found that the outflow time of thickened liquids through a funnel depended on their viscosities at a shear rate between 10 and 50 s-1 , when the average inner diameter of the stem was in the range of 5.3 9.0 mm, and the volume of the liquid poured into the funnel was 30 mL. The correlation coefficient between the value of the sensory evaluation and the outflow time of the funnel with an average stem ID of 5.3 mm was 0.946. Therefore, this method may be useful in hospital and nursing home kitchens for evaluating thickened liquids. PRACTICAL APPLICATIONS: The findings of this study will help develop a new method for the evaluation of thickened liquids. Funnels made from polypropylene, which are inexpensive and light, were used in this method. The process for measuring the outflow time of thickened liquids through a funnel is simple, and we can obtain quantitative data that are objective. Even though line spread test (LST) is well known as a simple measurement method, nutritional supplements and liquids thickened using a thickening agent containing guar gum have not been evaluated accurately. The funnel method was found to have a stronger correlation with sensory evaluation compared to LST. This method is useful in hospital and nursing home kitchens for evaluating thickened liquids. PMID- 28573731 TI - Application of Peleg's equation to describe creep responses of potatoes under constant and variable storage conditions. AB - : The application of Peleg's equation to characterize creep behavior of potatoes during storage was investigated. Potatoes were stored at 25, 15, 5C, and variable (fluctuating) temperature for 16 or 26 weeks. The Peleg equation adequately described the creep response of potatoes during storage at all storage conditions (R2 = .97to .99). Peleg constant k1 exhibited a significant (p < .05) decreasing trend with storage time (ts ) for samples stored under the experimental conditions whereas the constant k2 appeared to be unaffected much by ts except for samples stored at 25C. Under constant temperature storage, k1 was found to be a linear function of ts (R2 = .87 to .97). Also, the rate of change of k1 appeared to be temperature dependent described by a linear relationship between the degradation rate constant for k1 (alpha) and storage temperature (T). For the variable storage condition, a bulk mean temperature (Tbm ) was calculated to account for a series combination of storage time and temperature which the potatoes were subjected to. It was possible to describe the changes in k1 due to variable storage temperature in terms of Tbm and ts using stepwise multiple regression (R2 = . 94). PRACTICAL APPLICATIONS: Precise description of the changes in the rheological properties of raw potatoes during storage could help predict the associated effect on the texture of cooked potatoes. Easy and simple methods of describing creep responses during storage or processing will be potentially helpful to better understand the phenomenon. The model parameters from such model could be used to relate rheological properties of raw and cooked potatoes. Moreover, the model parameters could be used to establish relationship between instrumental and sensory attributes which will help in the prediction of sensory attributes from instrumental data. PMID- 28573732 TI - Error in geometric morphometric data collection: Combining data from multiple sources. AB - OBJECTIVES: This study compares two- and three-dimensional morphometric data to determine the extent to which intra- and interobserver and intermethod error influence the outcomes of statistical analyses. MATERIALS AND METHODS: Data were collected five times for each method and observer on 14 anthropoid crania using calipers, a MicroScribe, and 3D models created from NextEngine and microCT scans. ANOVA models were used to examine variance in the linear data at the level of genus, species, specimen, observer, method, and trial. Three-dimensional data were analyzed using geometric morphometric methods; principal components analysis was employed to examine how trials of all specimens were distributed in morphospace and Procrustes distances among trials were calculated and used to generate UPGMA trees to explore whether all trials of the same individual grouped together regardless of observer or method. RESULTS: Most variance in the linear data was at the genus level, with greater variance at the observer than method levels. In the 3D data, interobserver and intermethod error were similar to intraspecific distances among Callicebus cupreus individuals, with interobserver error being higher than intermethod error. Generally, taxa separate well in morphospace, with different trials of the same specimen typically grouping together. However, trials of individuals in the same species overlapped substantially with one another. CONCLUSION: Researchers should be cautious when compiling data from multiple methods and/or observers, especially if analyses are focused on intraspecific variation or closely related species, as in these cases, patterns among individuals may be obscured by interobserver and intermethod error. Conducting interobserver and intermethod reliability assessments prior to the collection of data is recommended. PMID- 28573733 TI - Low fruit and vegetable consumption is associated with low knowledge of the details of the 5-a-day fruit and vegetable message in the UK: findings from two cross-sectional questionnaire studies. AB - BACKGROUND: This project aimed to understand the details of the 5-a-day fruit and vegetable (FV) message (which foods are included, portion sizes, the need for variety, reasons for consumption) least known by UK consumers, and most associated with low FV consumption. METHODS: Study 1 assessed FV consumption, knowledge of the details of the message, and relationships between these, using a short questionnaire administered face-to-face to an opportunity sample of one large UK city. Study 2 assessed the same variables using a comprehensive postal questionnaire administered across the UK to a representative population sample. RESULTS: Five hundred and seven respondents completed Study 1 and 247 respondents completed Study 2. The majority of individuals in both studies were aware of the 5-a-day message and could recount this correctly. In both studies, however, knowledge of the details of the message was low, and lower knowledge was associated with lower FV consumption. Respondents had lowest knowledge of the details of the message related to portion sizes and the need for variety. However, FV consumption was not independently associated with knowledge of any one aspect of the message. CONCLUSIONS: These findings suggest that, although most of the UK population sampled were aware of the 5-a-day FV message and could recount this correctly, details of the 5-a-day FV message were not well known, and that FV consumption was related to this knowledge. These findings suggest that strategies to increase FV consumption will benefit from increasing UK consumers' knowledge of the details of the 5-a-day FV message. PMID- 28573734 TI - IL-17A blockade or deficiency does not affect progressive renal fibrosis following renal ischaemia reperfusion injury in mice. AB - OBJECTIVES: IL-17A contributes to acute kidney injury and fibrosis. Therefore, we asked whether IL-17A deficiency or treatment with a IL-17A blocking antibody impacts severe renal ischaemia reperfusion injury (IRI) and the progression to chronic kidney disease (CKD). METHODS: IL-17A-deficient and wild-type (WT) mice underwent transient unilateral renal pedicle clamping for 45 min to induce IRI and subsequent renal fibrosis. Furthermore, a neutralizing anti-IL-17A antibody (mAb) was injected into WT mice before induction of renal IRI intravenously. On days 1, 7 and 21, inflammation, fibrosis, leukocyte infiltration and pro inflammatory and pro-fibrotic cytokine expression were assessed in kidneys using histology, qPCR and flow cytometry. KEY FINDINGS: IL-17A was significantly increased after renal IRI in WT kidneys. Levels of pro-inflammatory (MCP-1) cytokine and pro-fibrotic (collagen 1alpha1, fibronectin) transcripts were similar in the experimental groups studied. IL-17A deficiency had no effect on renal T-cell influx or the number, inflammatory phenotype, or spatial distribution of macrophages. Similarly, administration of an IL-17A blocking antibody did not attenuate inflammation. CONCLUSIONS: Despite the effects of IL 17 in other inflammation models, neither genetic IL-17A deficiency nor treatment with an IL-17A blocking antibody attenuated IRI and progression to CKD. We conclude that in severe renal IRI IL-17A is not crucially involved in disease progression. PMID- 28573735 TI - Contraction and elongation: Mechanics underlying cell boundary deformations in epithelial tissue. AB - The cell-cell boundaries of epithelial cells form cellular frameworks at the apical side of tissues. Deformations in these boundaries, for example, boundary contraction and elongation, and the associated forces form the mechanical basis of epithelial tissue morphogenesis. In this review, using data from recent Drosophila studies on cell boundary contraction and elongation, I provide an overview of the mechanism underlying the bi-directional deformations in the epithelial cell boundary, that are sustained by biased accumulations of junctional and apico-medial non-muscle myosin II. Moreover, how the junctional tensions exist on cell boundaries in different boundary dynamics and morphologies are discussed. Finally, some future perspectives on how recent knowledge about single cell boundary-level mechanics will contribute to our understanding of epithelial tissue morphogenesis are discussed. PMID- 28573736 TI - Epilepsy as a systemic condition: Link with somatic comorbidities. AB - BACKGROUND: People with epilepsy have more concomitant medical conditions than the general population; these comorbidities play an important role in premature mortality. We sought to generate explanatory hypotheses about the co-occurrence of somatic comorbidities and epilepsy, avoiding causal and treatment-resultant biases. METHODS: We collected clinical, demographic and somatic comorbidity data for 2016 consecutive adults with epilepsy undergoing assessment at a tertiary centre and in 1278 people with epilepsy in the community. Underlying causes of epilepsy were not classed as comorbidities. RESULTS: Somatic comorbidities were more frequent in the referral centre (49%) where people more frequently had active epilepsy than in the community (36%). Consistent risk factors for comorbidities were found in both cohorts. Using multivariable ordinal regression adjusted for age, longer epilepsy duration and an underlying brain lesion were independently associated with a smaller burden of somatic conditions. The treatment burden, measured by the number of drugs to which people were exposed, was not an independent predictor. Shorter epilepsy duration was a predictor for conditions that conceivably harbour significant mortality risks. CONCLUSIONS: Somatic comorbidities do not occur randomly in relation to epilepsy; having more severe epilepsy seems to be a risk factor. Independently from age, the early period after epilepsy onset appears to be at particular risk, although it is not clear whether this relates to an early mortality or to a later decrease in the burden of comorbidities. These results suggest that, for some people, epilepsy should be considered a systemic condition not limited to the CNS. PMID- 28573737 TI - Applying a Social Justice Lens to Youth Mentoring: A Review of the Literature and Recommendations for Practice. AB - Youth mentoring interventions are often designed with the intention of promoting improved outcomes among marginalized youth. Despite their promise to reduce inequality through the provision of novel opportunities and increased social capital to marginalized youth, youth mentoring interventions hold the potential to reproduce rather than reduce inequality. In the current review, we explore literature on youth mentoring that has incorporated a social justice lens. We conclude that there is a need for greater attention to principles of social justice in the design, implementation, and evaluation of youth mentoring interventions. After reviewing the literature, we make recommendations for research and practice based on a social justice perspective and explore alternatives to traditional youth mentoring that may allow for better alignment with social justice principles. PMID- 28573738 TI - Mucosal bacterial dissemination in a rhesus macaque model of experimental brucellosis. AB - Animals were experimentally infected with Brucella melitensis via aerosol. B. melitensis was cultured from the saliva and vaginal vault of infected animals, corresponding to bacterial dissemination in other target tissues. This is the first report of bacterial dissemination to these mucosal surfaces in a non-human primate model of brucellosis. PMID- 28573739 TI - Apical hypertrophic cardiomyopathy with left ventricular apical aneurysm: Importance of multi-modality imaging. AB - Apical hypertrophic cardiomyopathy (HCM) is an uncommon variant of HCM characterized by apical hypertrophy without the septal predominance seen in the majority of HCM cases. In 2% of patients, a concomitant left ventricular apical aneurysm is observed, which increases the risk of sudden death and adverse HCM related events. Multimodality imaging is helpful for appropriate identification of this particular morphologic pattern. Herein, we present a case of apical HCM with a left ventricular apical aneurysm, exemplifying the utility of a multimodality approach from resting electrocardiogram, transthoracic echocardiogram, left ventriculography, and cardiac magnetic resonance imaging, for proper risk stratification and treatment planning. PMID- 28573740 TI - A comparison of the phenolic profile and antioxidant activity of different Cichorium spinosum L. ecotypes. AB - BACKGROUND: Wild greens are considered a rich source of phenolic compounds and antioxidants and an essential part of the so-called Mediterranean diet. In the present study, Cichorium spinosum L. ecotypes, cultivated or collected in situ from wild plants from the eastern Mediterranean, were evaluated regarding their phenolic composition and antioxidant activity. RESULTS: Significant differences were observed among the various studied ecotypes regarding their phenolic compound content and profile, especially between wild and cultivated ecotypes, as well as the phenolic acid content between commercial products and cultivated plants. The antioxidant activity also varied among the various studied ecotypes and growing conditions, with commercial products having the highest antioxidant activity, whereas wild ecotypes showed lower antioxidant activity. CONCLUSION: Cichorium spinosum leaves are a rich source of chicoric and 5-O-caffeoylquinic acid, while significant differences in total phenolic acids, flavonoids and phenolic compound content and in antioxidant activity were observed among the studied ecotypes, as well as between the tested growing conditions. According to the results of the present study, further valorization of C. spinosum species has great potential, since it could be used as a new alternative species in the food industry. (c) 2017 Society of Chemical Industry. PMID- 28573741 TI - Patterns of morphological integration between parietal and temporal areas in the human skull. AB - Modern humans have evolved bulging parietal areas and large, projecting temporal lobes. Both changes, largely due to a longitudinal expansion of these cranial and cerebral elements, were hypothesized to be the result of brain evolution and cognitive variations. Nonetheless, the independence of these two morphological characters has not been evaluated. Because of structural and functional integration among cranial elements, changes in the position of the temporal poles can be a secondary consequence of parietal bulging and reorientation of the head axis. In this study, we use geometric morphometrics to test the correlation between parietal shape and the morphology of the endocranial base in a sample of adult modern humans. Our results suggest that parietal proportions show no correlation with the relative position of the temporal poles within the spatial organization of the endocranial base. The vault and endocranial base are likely to be involved in distinct morphogenetic processes, with scarce or no integration between these two districts. Therefore, the current evidence rejects the hypothesis of reciprocal morphological influences between parietal and temporal morphology, suggesting that evolutionary spatial changes in these two areas may have been independent. However, parietal bulging exerts a visible effect on the rotation of the cranial base, influencing head position and orientation. This change can have had a major relevance in the reorganization of the head functional axis. PMID- 28573742 TI - Reductive Coupling of CO2 , Primary Amine, and Aldehyde at Room Temperature: A Versatile Approach to Unsymmetrically N,N-Disubstituted Formamides. AB - We present a simple, metal-free, and versatile route to synthesize unsymmetrically N,N-disubstituted formamides (NNFAs) from CO2 , primary amine, and aldehyde promoted by an ionic liquid (1-butyl-3-methylimidazolium chloride) at room temperature. This approach features wide scopes of amines and aldehydes, and various unsymmetrical NNFAs could be obtained in good to excellent yields. The ionic liquid can be reused for at least five runs without obvious activity loss. PMID- 28573743 TI - Impact of ixekizumab treatment on skin-related personal relationship difficulties in moderate-to-severe psoriasis patients: 12-week results from two Phase 3 trials. AB - BACKGROUND: Psoriasis symptoms may decrease quality of life for patients. Skin related personal relationship difficulties in psoriasis patients are common, under-reported and poorly understood. OBJECTIVE: To assess the effect of ixekizumab (IXE) treatment on skin-related personal relationship difficulties in patients with moderate-to-severe psoriasis. METHODS: Pooled data (N = 2570) on skin-related relationship problems were obtained from two large phase 3 trials (UNCOVER-2 and UNCOVER-3) in patients with moderate-to-severe plaque psoriasis randomized to subcutaneous placebo (PBO, N = 361), etanercept (ETN; 50 mg twice weekly, N = 740), or 80 mg IXE as one injection every 4 (IXEQ4W, N = 733) or 2 weeks (IXEQ2W, N = 736) for 12 weeks, following a 160-mg initial dose. The Dermatology Life Quality Index (DLQI) Personal Relationships Domain (PRD) (Items 8 and 9) was used to assess how much the skin caused any personal relationship difficulties at weeks 0, 2, 4 and 12. Improvement was compared for IXE vs PBO and ETN using logistic models. Factors associated with improvement were assessed using multiple linear regressions. DLQI Item 9, assessing sexual difficulties, was also analysed separately. RESULTS: PRD scores (mean +/- standard deviation) at baseline were similar across all treatment groups (PBO: 1.8 +/- 1.9; ETN: 1.7 +/- 1.8; IXEQ4W: 1.6 +/- 1.8; IXEQ2W: 1.7 +/- 1.8). Treatment with IXE rapidly and significantly improved the mean PRD score compared to PBO and ETN (P < 0.001 at all time points). Baseline PRD score was the strongest negative predictor of improvement. IXE enabled significantly more patients with moderate-to-severe plaque psoriasis to reduce their skin-related sexual difficulties at Week 12 compared to PBO (P < 0.001) or ETN (P < 0.001). CONCLUSION: Ixekizumab improves patient-reported skin-related PRD difficulties in patients with moderate-to severe psoriasis. PMID- 28573744 TI - Metabolomic analyses to evaluate the effect of drought stress on selected African Eggplant accessions. AB - BACKGROUND: Drought stress is one of the main abiotic stresses that affect crops. It leads to biochemical changes that can have adverse effects on plant growth, development and productivity. African eggplants are important vegetable and fruit crops reported to adapt and thrive well under drought stress. The diversified metabolites arising due to stress have not been well defined. A gas chromatographic-mass spectrometric metabolomic approach was applied to characterize the effect of drought stress on metabolites at different stages of growth. Nineteen accessions were selected for analysis and drought was imposed by withholding water until soil moisture reached 60% field capacity. Fresh leaf tissues were sampled before stress, 2 and 4 weeks after stress and metabolite profiling done. RESULTS: Significant changes in metabolite content were observed, and potentially important metabolites with respect to stress responses were characterized. Proline, glutamate, sucrose, fructose and tricarboxylic acid cycle metabolites were shown to be positively correlated with stress. Principal component analysis showed a clear discrimination between the different accessions, growth stages and stress/control conditions. CONCLUSION: The results illustrate that drought stress has a significant impact on the concentrations of some metabolites, such as amino acids, sugars and organic acids, which may contribute to drought stress effects and tolerance. (c) 2017 Society of Chemical Industry. PMID- 28573745 TI - Prevalence of sun-protective behaviour and intentional sun tanning in German adolescents and adults: results of a nationwide telephone survey. AB - BACKGROUND: The incidence rate of melanoma in the Caucasian population is rising worldwide. One of the major environmental risk factors for melanoma is the exposure to ultraviolet (UV) radiation. To prevent skin damage caused by UV exposure, several organizations recommend wearing protective clothing, staying in the shade, avoiding the outdoors during midday and using sunscreen. OBJECTIVE: To provide representative data on factors associated with sun-protective behaviours and intentional sun exposure during summertime in the German population. METHODS: A population-based sample of 3000 German residents aged 14-45 years (response: 32.1%) was interviewed via telephone from October to December 2015. Survey participants provided data on the use of recommended sun-protective measures on a sunny summer day and their intentional sun exposure during summertime. Data were weighted by age, sex, educational level and federal state to ensure the national representativeness of the sample. RESULTS: Wearing long-sleeved clothes was the most frequently reported protective measure (53.9%), while wearing headgear was the least common (17.9%). Significantly lower frequencies of almost all recommended sun-protective measures were identified for males, participants between 14 and 25 years, those with an immigrant background and those with low levels of education. Using sun protection was positively associated with female gender (OR = 1.62), higher levels of education (ORhigh = 1.27), sunburn during childhood (OR = 1.33) and paying attention to healthy nutrition (OR = 1.64; all P < 0.05). Sun tanning behaviour was associated with female gender (OR = 1.42), younger age, lower level of education, sunbed use (OR = 5.24) and smoking status (OR = 1.50; all P < 0.001). CONCLUSION: As individual sun-protective measures are easy to implement and provide effective protection against high-risk UV exposure, campaigns on skin cancer prevention in Germany should put a stronger focus on young adults, men, less educated individuals and those with immigration background. PMID- 28573746 TI - Beneficial effects of Rifaximin in post-infectious irritable bowel syndrome mouse model beyond gut microbiota. AB - BACKGROUND AND AIMS: Rifaximin is a minimally absorbed antibiotic, which has shown efficacy in irritable bowel syndrome (IBS) patients. However, the mechanism on how it effects in IBS is still incompletely defined. In this study, Trichinella spiralis-infected post-infectious (PI) IBS mouse model was used, to assess the action of rifaximin on visceral hypersensitivity, barrier function, gut inflammation, and microbiota. METHODS: Post-infectious IBS model was established by T. spiralis infection in mice. Rifaximin were administered to PI IBS mice for seven consecutive days. The abdominal withdrawal reflex and threshold of colorectal distention were employed to evaluate visceral sensitivity. Smooth muscle contractile response was recorded in the organ bath. Intestinal permeability was measured by Ussing chamber. Expression of tight junction protein and cytokines were measured by Western blotting. Ilumina miseq platform was used to analyze bacterial 16S ribosomal RNA. RESULTS: Post infectious IBS mice treated with rifaximin exhibited decreased abdominal withdrawal reflex score, increased threshold, reduced contractile response, and intestinal permeability. Rifaximin also suppressed the expression of interleukin 12 and interleukin-17 and promoted the expression of the major tight junction protein occludin. Furthermore, rifaximin did not change the composition and diversity, and the study reavealed that rifaximin had a tiny effect on the relative abundance of Lactobacillus and Bifidobacterium in this PI-IBS model. CONCLUSIONS: Rifaximin alleviated visceral hypersensitivity, recovered intestinal barrier function, and inhibited low-grade inflammation in colon and ileum of PI IBS mouse model. Moreover, rifaximin exerts anti-inflammatory effects with only a minimal effect on the overall composition and diversity of the gut microbiota in this model. PMID- 28573747 TI - Triploidy - variability of sonographic phenotypes. AB - OBJECTIVES: To analyze sonographic abnormalities in triploid pregnancies and assess the usefulness of the classification proposed by McFadden and Kalousek for prenatal sonographic assessment of triploid fetuses. METHODS: We conducted a retrospective analysis of the sonographic features in a series of 67 triploid fetuses evaluated between 11 and 30 weeks of gestation in a single referral center between 1997 and 2015. RESULTS: Non-specific structural fetal defects were visualized in the majority of fetuses (61.2%) regardless of the parental origin of the triploidy. A 'diandric phenotype' was identified in eight relatively well grown fetuses (11.9%) that presented with cystic placentas. A 'digynic phenotype' was identified in 47 asymmetrically growth-restricted fetuses with non-cystic placentas (70.2%). In 12 cases (17.9%), features of both phenotypes were present. CONCLUSIONS: Nearly 40% of triploid fetuses do not have any apparent structural abnormalities, and only careful assessment of fetal growth and placenta may lead to the suspicion of the diagnosis. As diandric triploidy carry a high risk for maternal complications, identification of these cases is vital for prenatal counseling. In nearly 20% of triploid pregnancies, parental origin cannot be established based on sonographic assessment. (c) 2017 John Wiley & Sons, Ltd. PMID- 28573748 TI - Conditioned pain modulation dampens the thermal grill illusion. AB - BACKGROUND: The thermal grill illusion (TGI) refers to the perception of burning heat and often pain that arises from simultaneous cutaneous application of innocuous warm and cool stimuli. This study utilized conditioned pain modulation (CPM) to help elucidate the TGI's underlying neural mechanisms, including the debated role of ascending nociceptive signals in generating the illusion. METHODS: To trigger CPM, subjects placed the left hand in noxious cold (6 degrees C) water before placing the right volar forearm onto a thermal grill. Lower pain and unpleasantness ratings of the grill in this CPM run compared to those in a control run (i.e. 33 degrees C water) were taken as evidence of CPM. To determine whether CPM reduces noxious heat pain and illusory heat pain equally, an experimental group of subjects rated pain and unpleasantness of a grill consisting of innocuous alternating warm (42 degrees C) and cool (18 degrees C) bars, while a control group rated a grill with all bars controlled to a noxious temperature (45 degrees C). RESULTS: CPM produced significant and comparable reductions in pain, unpleasantness and perceived heat of both noxious heat and the TGI. CONCLUSIONS: This result suggests that the TGI results from signals in nociceptive dorsal horn convergent neurons, since CPM involves descending inhibition with high selectivity for this neuronal population. More broadly, CPM's ability to produce a shift in perceived thermal sensation of both noxious heat and the TGI from 'hot' to 'warm' implies that nociceptive signals generated by a cutaneous stimulus can contribute to its perceived thermal intensity. SIGNIFICANCE: Conditioned pain modulation reduces the perceived painfulness, unpleasantness and heat of the thermal grill illusion and noxious heat similarly. The results have important theoretical implications for both types of pain. PMID- 28573749 TI - Obesity impedes functional improvement in youth with chronic pain: An initial investigation. AB - BACKGROUND: Youth with chronic pain are at higher risk for obesity than the general population. In youth with chronic pain, obesity exacerbates pain-specific activity limitations, and in adults with chronic pain, obesity perpetuates a cycle of disability. The current study examined whether weight status predicts functional disability outcomes over time in youth with chronic pain. METHODS: Data were obtained from a retrospective chart review of patients who consented to participate in a longitudinal outcomes study. The Child Activity Limitations Questionnaire was used to assess functional disability at intake, 1-, and 3-month follow-up. Height and weight were measured at intake. A linear mixed model was used to test whether weight status and time predicted functional disability. Trend analysis with polynomial contrasts was used to test whether improvements in functional disability showed a linear trend over time. RESULTS: The linear mixed model analysis showed a main effect of weight, suggesting that youth with higher BMI demonstrated less improvement in functional disability over time. The trend analysis suggested that improvements in functional disability were consistent with a linear trend for both healthy weight and overweight participants, but not for obese participants. CONCLUSION: These findings demonstrate that obesity impedes improvement in functioning for youth with chronic pain. Despite multidisciplinary pain treatment, youth with comorbid chronic pain and obesity demonstrate greater functional disability at follow-up and little improvement over time. These results support the need for interventions specifically tailored to the unique challenges faced by youth with comorbid chronic pain and obesity. SIGNIFICANCE: This study shows that obesity impedes improvement in functioning for youth with chronic pain. On the basis of these findings, interventions should be tailored to the unique challenges of this population. PMID- 28573750 TI - Chondrification and Character Identification in the Skull Exemplified for the Basicranial Anatomy of Early Squamate Embryos. AB - The neurocranium of vertebrates is mainly derived from early cartilaginous anlagen, the so-called chondrocranium, the base of the future skull. Two initial bar-shaped and paired chondrifications flank the notochord, the rostral trabecles and the caudal parachordals. In most reptiles, there is an additional component, the transverse acrochordal, which is placed between trabecles and parachordals. All these elements compose the base of the future chondrocranium. There are several drastically different hypotheses concerning the development and interrelationship of these elements. We reexamined the basicranial development in four squamates and found that all species show very similar conditions of early chondrocranial development. The anterior part of the notochord is not embedded into the basal plate as it was previously reported. It remains free. The medial edges of the parachordals form the lateral walls of the basicranial fenestra. Only the posterior portions of the parachordals fuse and form the basal plate. The space in-between the parachordals is filled with a thin layer of cells, which never chondrify. The anterior tips of the parachordals later fuse with the posterior edge of the acrochordal, which ultimately delimitates, as crista sellaris, the basicranial fenestra anteriorly. We consider the observed processes a common development at least in lizards and review a variety of methodological approaches and differences in data interpretation as reasons for the anatomical differences reported in the literature. Moreover, based on our data we argue that the acrochordal is of mesodermal origin, which coincides with results of fate map experimental studies. PMID- 28573752 TI - Corrigendum. PMID- 28573753 TI - Simulation of intra-ciliary diffusion suggests a novel role of primary cilia as a cell-signaling enhancer. AB - Besides the role to generate a fluid flow in the surrounding medium, eukaryotic cilia have a crucial function in sensing external signals such as chemical or mechanical stimuli. A large body of work has shown that cilia are frequently found in various types of sensory cells and are closely related to many regulatory mechanisms in differentiation and development. However, we do not yet have a definitive answer to the fundamental question, "why cilia?" It has been a long-standing mystery why cells use cilia for sensing external signals. To shed light on this, we sought to describe the kinetics of signaling with theoretical approaches. Based on the results, here we propose a new role of cilia as a cell signaling enhancer. The enhancing effect comes from restricted volume for the free intra-ciliary diffusion of molecules due to the cylindrical shape of cilia, which can facilitate quick accumulation of intracellular signaling molecules. Our simulations demonstrate that both the rate and amplitude of response in signal transduction depend on where the membrane receptors or channels are located along the ciliary shaft. In addition, the calculated transfer function of cilia regarded as a transmitter of external signals also suggests the properties of cilia as a signal enhancer. Since such unique composition of receptors and channels in cilia is found in various types of eukaryotic cells, signal enhancing is presumably one of the most essential and conserved roles of cilia. PMID- 28573751 TI - Early weaning stress induces chronic functional diarrhea, intestinal barrier defects, and increased mast cell activity in a porcine model of early life adversity. AB - BACKGROUND: Early life adversity (ELA) is a risk factor for development of gastrointestinal disorders later in life. The underlying mechanisms through which ELA and sex interact to influence disease susceptibility remains poorly understood. METHODS: Utilizing a porcine early weaning stress (EWS) model to mimic ELA, we investigated the long-term effects of EWS on functional diarrhea, ileal permeability, mast cell activity and mast cell relationship with enteric ganglia. KEY RESULTS: Juvenile and adult EWS pigs exhibited chronic, functional diarrhea (EWS 43.6% vs late wean control(LWC) 4.8%, P<.0001), increased intestinal permeability (2 fold increase EWS vs LWC, P<.0001), and mast cell numbers (at 7 weeks and 20 weeks ~1.6 fold increase EWS vs LWC, P<.05). Compared with EWS male castrates (Male-C), females EWS pigs exhibited more frequent diarrhea (58.8% vs 29.9%, P=.0016), and increased intestinal permeability (1-2 fold higher in EWS females, P<.001). Increased mast cell numbers and their enhanced co-localization with neuronal ganglia were observed in both Male-C and female EWS pigs; however, female pigs exhibited greater release of mast cell tryptase upon activation with c48/80 (~1.5 fold increase, P<.05), compared with Male-C pigs. CONCLUSIONS AND INFERENCES: These data demonstrate that pigs exposed to ELA exhibit increased vulnerability to functional diarrhea, intestinal permeability and mast cell activity. Further, these studies also showed that EWS female and Male-C pigs exhibited dimorphic responses to EWS with female piglets exhibited greater susceptibility and severity of diarrhea, intestinal permeability and mast cell tryptase release. Together, these findings mimic some of the key pathophysiologic findings in human functional GI disorders functional gastrointestinal disorders (FGIDs) suggesting that the EWS porcine model could be a valuable preclinical translational model for FGID research associated with ELA. PMID- 28573754 TI - Mitral Regurgitation Severity and Left Ventricular Systolic Dimension Predict Survival in Young Cavalier King Charles Spaniels. AB - BACKGROUND: Development and progression of myxomatous mitral valve disease (MMVD) in dogs are difficult to predict. Identification at a young age of dogs at high risk of adverse outcome in the future is desirable. HYPOTHESIS/OBJECTIVES: To study the predictive value of selected clinical and echocardiographic characteristics associated with MMVD obtained at a young age for prediction of long-term cardiac and all-cause mortality in Cavalier King Charles Spaniels (CKCS). ANIMALS: 1125 privately owned CKCS. METHODS: A retrospective study including CKCS examined at the age of 1-3 years. Long-term outcome was assessed by telephone interview with owners. The value of variables for predicting mortality was investigated by Cox proportional hazard and Kaplan-Meier analyses. RESULTS: Presence of moderate to severe mitral regurgitation (MR) (hazard ratio (HR) = 3.03, 95% confidence interval (95% CI) = 1.48-6.23, P = 0.0025) even intermittent moderate to severe MR (HR = 2.23, 95% CI = 1.48-6.23, P = 0.039) on color flow Doppler echocardiography was significantly associated with increased hazard of cardiac death. An interaction between MR and sex was significant for all-cause mortality (P = 0.035), showing that males with moderate to severe MR had a higher all-cause mortality compared to males with no MR (HR = 2.38, 95% CI = 1.27-4.49, P = 0.0071), whereas no difference was found between female MR groups. The risk of cardiac (HR = 1.37, 95% CI = 1.14-1.63, P < 0.001) and all cause (HR = 1.13, 95% CI = 1.02-1.24, P = 0.016) mortality increased with increasing left ventricular end-systolic internal dimension normalized for body weight (LVIDSN ). CONCLUSIONS AND CLINICAL IMPORTANCE: Moderate to severe MR, even if intermittent, and increased LVIDSN in dogs <3 years of age were associated with cardiac death later in life in CKCS. PMID- 28573755 TI - Whitening dentifrice and tooth surface discoloration-a systematic review and meta analysis. AB - OBJECTIVE: The aim of this systematic review was to assess the effect of a whitening dentifrice (WDF) relative to a regular dentifrice (RDF) on the reduction of natural extrinsic tooth surface discoloration (ETD). MATERIALS AND METHODS: The MEDLINE-PubMed, Cochrane-CENTRAL and EBSCO-Dentistry and Oral Sciences databases were searched, up to April 2017. The inclusion criteria were as follows:(randomized)controlled clinical trials, healthy subjects >=18 years of age, studies comparing WDF with RDF, a follow-up period of at least 6 weeks and studies scoring ETD as the stain area/extent, stain intensity or a composite score. Studies using an induced staining model were excluded. RESULTS: Independent screening of 851 unique papers resulted in 21 eligible publications, which included 32 comparisons. The descriptive analysis illustrated that the majority of comparisons showed a significant effect on ETD, in favour of WDF over RDF. The meta-analysis substantiated this observation and revealed that the difference of means (diffM) comparing WDF and RDF was a reduction for stain area of -0.44 [(95% CI: -0.55; -0.339) (P<.00001)] according to the original Lobene Stain Index; this result is in favour of the WDF. For the modified Lobene Stain Index, the diffM was -0.41 [(95% CI: -0.71; -0.10) (P=.009)]. For overall stain intensity, the diffM was -0.35 [(95% CI: -0.44; -0.25) (P<.00001)], and the composite score was -0.39 [(95% CI: -0.57; -0.21) (P<.0001)] and -0.54 [(95% CI: 0.66; -0.43) (P<.00001)]. Subgroup analysis differentiating between products that contained added chemical antidiscoloration agents showed a similar pattern. CONCLUSION: In this review, nearly all dentifrices that are specifically formulated for tooth whitening were shown to have a beneficial effect in reducing ETD, irrespective of whether or not a chemical discoloration agent was added. PMID- 28573756 TI - Improving quality of an innovative pea puree by high hydrostatic pressure. AB - BACKGROUND: The food industry is continuously innovating to fulfill consumer demand for new, healthy, ready-to-eat products. Pea purees could satisfy this trend by increasing the intake of legumes, which are an important source of nutrients. Moreover, sensorial properties like viscosity could be improved by high hydrostatic pressure (HHP). In this study the effect of a boiling treatment (10 min) followed by HHP at 550 kPa (0, 5 or 10 min) on the rheological properties, associated with enzymatic activity and particle size, as well as on the microbial and sensory quality of a pea-based puree stored for 36 days at 5 degrees C, has been assessed. RESULTS: The particle size of pea puree decreased after all processing treatments, but increased during storage in HHP-treated samples. Conversely, boiling treatment showed an increase in polygalacturonase activity at the end of the storage period, with a decrease in particle size, viscosity and stability. However, 5 min of 550 kPa HHP showed the highest mean particle size, mean surface diameter and viscosity regarding the remaining treatments. The microbial load remained low during storage. CONCLUSIONS: HHP treatment can be used by the food industry to improve the rheological properties, viscosity and stability of pea purees. (c) 2017 Society of Chemical Industry. PMID- 28573757 TI - Circuit class therapy for improving mobility after stroke. AB - BACKGROUND: Circuit class therapy (CCT) offers a supervised group forum for people after stroke to practise tasks, enabling increased practice time without increasing staffing. This is an update of the original review published in 2010. OBJECTIVES: To examine the effectiveness and safety of CCT on mobility in adults with stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched January 2017), CENTRAL (the Cochrane Library, Issue 12, 2016), MEDLINE (1950 to January 2017), Embase (1980 to January 2017), CINAHL (1982 to January 2017), and 14 other electronic databases (to January 2017). We also searched proceedings from relevant conferences, reference lists, and unpublished theses; contacted authors of published trials and other experts in the field; and searched relevant clinical trials and research registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) including people over 18 years old, diagnosed with stroke of any severity, at any stage, or in any setting, receiving CCT. DATA COLLECTION AND ANALYSIS: Review authors independently selected trials for inclusion, assessed risk of bias in all included studies, and extracted data. MAIN RESULTS: We included 17 RCTs involving 1297 participants. Participants were stroke survivors living in the community or receiving inpatient rehabilitation. Most could walk 10 metres without assistance. Ten studies (835 participants) measured walking capacity (measuring how far the participant could walk in six minutes) demonstrating that CCT was superior to the comparison intervention (Six-Minute Walk Test: mean difference (MD), fixed effect, 60.86 m, 95% confidence interval (CI) 44.55 to 77.17, GRADE: moderate). Eight studies (744 participants) measured gait speed, again finding in favour of CCT compared with other interventions (MD 0.15 m/s, 95% CI 0.10 to 0.19, GRADE: moderate). Both of these effects are considered clinically meaningful. We were able to pool other measures to demonstrate the superior effects of CCT for aspects of walking and balance (Timed Up and Go: five studies, 488 participants, MD -3.62 seconds, 95% CI -6.09 to -1.16; Activities of Balance Confidence scale: two studies, 103 participants, MD 7.76, 95% CI 0.66 to 14.87). Two other pooled balance measures failed to demonstrate superior effects (Berg Blance Scale and Step Test). Independent mobility, as measured by the Stroke Impact Scale, Functional Ambulation Classification and the Rivermead Mobility Index, also improved more in CCT interventions compared with others. Length of stay showed a non-significant effect in favour of CCT (two trials, 217 participants, MD -16.35, 95% CI -37.69 to 4.99). Eight trials (815 participants) measured adverse events (falls during therapy): there was a non-significant effect of greater risk of falls in the CCT groups (RD 0.03, 95% CI -0.02 to 0.08, GRADE: very low). Time after stroke did not make a difference to the positive outcomes, nor did the quality or size of the trials. Heterogeneity was generally low; risk of bias was variable across the studies with poor reporting of study conduct in several of the trials. AUTHORS' CONCLUSIONS: There is moderate evidence that CCT is effective in improving mobility for people after stroke - they may be able to walk further, faster, with more independence and confidence in their balance. The effects may be greater later after the stroke, and are of clinical significance. Further high-quality research is required, investigating quality of life, participation and cost-benefits, that compares CCT with standard care and that also investigates the influence of factors such as stroke severity and age. The potential risk of increased falls during CCT needs to be monitored. PMID- 28573758 TI - Orthodontic Treatment: Real Risk for Dental Age Estimation in Adults? AB - Dental age estimation becomes a challenge once the root formation is concluded. In living adults, one dental age indicator is the formation of secondary dentine, also associated with orthodontic treatment as well as root shortening. The aim of this study was to establish whether these secondary effects of orthodontic treatment could generate a statistically significant difference in dental age estimations when using Kvaal's method. The study sample included 34 pairs of pre- and postorthodontic panoramic radiographs, from different individuals with exactly the same age and sex distribution. Females 65%, median age 17.5 years, and males 35%, median age 22.5 years, were included. After data collection, dental age was estimated per tooth using formulae previously published. The risk of obtaining over-estimation of age was calculated. (RR = 1.007). The changes caused by orthodontic treatment do not have any significant effect on age estimation when Kvaal et al.'s method is applied on panoramic radiographs. PMID- 28573759 TI - Persistence of plant hormone levels in rice shoots grown under microgravity conditions in space: its relationship to maintenance of shoot growth. AB - We investigated the effects of microgravity environment on growth and plant hormone levels in dark-grown rice shoots cultivated in artificial 1 g and microgravity conditions on the International Space Station (ISS). Growth of microgravity-grown shoots was comparable to that of 1 g-grown shoots. Endogenous levels of indole-3-acetic acid (IAA) in shoots remained constant, while those of abscisic acid (ABA), jasmonic acid (JA), cytokinins (CKs) and gibberellins (GAs) decreased during the cultivation period under both conditions. The levels of auxin, ABA, JA, CKs and GAs in rice shoots grown under microgravity conditions were comparable to those under 1 g conditions. These results suggest microgravity environment in space had minimal impact on levels of these plant hormones in rice shoots, which may be the cause of the persistence of normal growth of shoots under microgravity conditions. Concerning ethylene, the expression level of a gene for 1-aminocyclopropane-1-carboxylic acid (ACC) synthase, the key enzyme in ethylene biosynthesis, was reduced under microgravity conditions, suggesting that microgravity may affect the ethylene production. Therefore, ethylene production may be responsive to alterations of the gravitational force. PMID- 28573760 TI - Oral glucose tolerance test performance in olanzapine-treated schizophrenia spectrum patients is predicted by BMI and triglycerides but not olanzapine dose or duration. AB - OBJECTIVE: Olanzapine, an atypical antipsychotic, is associated with glucoregulatory abnormalities, but the nature of this link is not fully elucidated. This is the first olanzapine oral glucose tolerance test (oGTT) study to consider treatment dose and duration, and to compare complementary indices respectively assessing insulin sensitivity (Matsuda index) and resistance (homeostasis model assessment). METHODS: Body mass index (BMI), body composition, plasma lipids, and oGTT were measured in olanzapine-treated nondiabetic patients with DSM-IV-TR diagnosis of schizophrenia or schizoaffective disorder (n = 35). RESULTS: While only one previously undiagnosed participant met diabetes criteria based on fasting plasma glucose alone (>=126 mg/dL), seven were diagnosed with oGTT (2-hr plasma glucose >=200 mg/dL). Multiple regression analyses revealed that the Matsuda index correlated with BMI (p < 0.0001) and plasma triglycerides (p = 0.01), but not with age, olanzapine dose, olanzapine treatment duration, or plasma cholesterol. Homeostasis model assessment and fasting plasma glucose correlated with triglycerides only (p < 0.0001 for both). CONCLUSIONS: Our data suggest that BMI and triglycerides may be implicated in olanzapine-related glucoregulatory abnormalities. The lack of correlation between glucoregulatory abnormalities and olanzapine dose or treatment duration suggests preexisting metabolic disturbances and/or disturbances arising early in the course of treatment. Clinicians prescribing antipsychotics should consider oGTT, especially in patients with obesity and/or hypertriglyceridemia. PMID- 28573761 TI - Sex differences in the associations between vagal reactivity and oppositional defiant disorder symptoms. AB - BACKGROUND: Vagal reactivity to stress in children has been associated with future psychiatric outcomes. However, results have been mixed possibly because these effects are in opposite direction in boys and girls. These sex differences are relevant in the context of development of psychopathology, whereby the rates of psychiatric disorders differ by sex. In this study, we aimed to examine the association between vagal reactivity, assessed as a reduction in respiratory sinus arrhythmia (RSA) in response to a challenge, and the development of future oppositional defiant disorder (ODD) symptoms in boys and girls. In addition, we examine the specific associations with ODD symptom dimensions, named irritability and headstrong. We hypothesized that increased vagal reactivity was associated with increased ODD symptoms in girls and a reduction in ODD symptoms in boys. METHODS: Participants were members of the Wirral Child Health and Development Study, a prospective epidemiological longitudinal study of 1,233 first-time mothers recruited at 20 weeks' gestation. RSA during four nonstressful and one stressful (still-face) procedures was assessed when children were aged 29 weeks in a sample stratified by adversity (n = 270). Maternal reports of ODD symptoms were collected when children were 2.5 years old (n = 253), 3.5 years old (n = 826), and 5 years old (n = 770). Structural equation modeling (SEM) was employed to test our hypotheses. RESULTS: There was a significant sex difference in the prediction of ODD symptoms due to the opposite directionality in which increasing vagal reactivity was associated with an increase in ODD symptoms in girls and a reduction of ODD symptoms in boys. This Sex by Vagal reactivity interaction was common for both ODD dimensions, with no sex by dimension-specific associations. CONCLUSIONS: Physiological reactivity to a stressful situation predicts differently ODD symptoms in boys and girls very early in life, with no difference across irritability and headstrong components. Findings are discussed in the context of the several mechanisms involved on the later development of distinct psychiatric disorders in boys and girls. PMID- 28573762 TI - In vivo measurement of vocal fold surface resistance. AB - OBJECTIVES/HYPOTHESIS: A custom-designed probe was developed to measure vocal fold surface resistance in vivo. The purpose of this study was to demonstrate proof of concept of using vocal fold surface resistance as a proxy of functional tissue integrity after acute phonotrauma using an animal model. STUDY DESIGN: Prospective animal study. METHODS: New Zealand White breeder rabbits received 120 minutes of airflow without vocal fold approximation (control) or 120 minutes of raised intensity phonation (experimental). The probe was inserted via laryngoscope and placed on the left vocal fold under endoscopic visualization. Vocal fold surface resistance of the middle one-third of the vocal fold was measured after 0 (baseline), 60, and 120 minutes of phonation. After the phonation procedure, the larynx was harvested and prepared for transmission electron microscopy. RESULTS: In the control group, vocal fold surface resistance values remained stable across time points. In the experimental group, surface resistance (X% +/- Y% relative to baseline) was significantly decreased after 120 minutes of raised intensity phonation. This was associated with structural changes using transmission electron microscopy, which revealed damage to the vocal fold epithelium after phonotrauma, including disruption of the epithelium and basement membrane, dilated paracellular spaces, and alterations to epithelial microprojections. In contrast, control vocal fold specimens showed well-preserved stratified squamous epithelia. CONCLUSIONS: These data demonstrate the feasibility of measuring vocal fold surface resistance in vivo as a means of evaluating functional vocal fold epithelial barrier integrity. Device prototypes are in development for additional testing, validation, and for clinical applications in laryngology. LEVEL OF EVIDENCE: NA Laryngoscope, 127:E364-E370, 2017. PMID- 28573763 TI - Characterizing the relationship between systemic inflammatory response syndrome and early cardiac dysfunction in traumatic brain injury. AB - Systolic dysfunction was recently described following traumatic brain injury (TBI), and systemic inflammation may be a contributing mechanism. Our aims were to 1) examine the association between the early systemic inflammatory response syndrome (SIRS) and systolic cardiac dysfunction following TBI, and 2) describe the longitudinal change in SIRS criteria, cardiac function, and hemodynamic parameters during the first week of hospitalization. We used a secondary analysis of a prospective cohort study examining cardiac function (with transthoracic echocardiography on the first day and serially over the first week of hospitalization) in 32 moderate-severe isolated TBI patients, and quantified the admission and daily SIRS response to injury. We determined the association of admission SIRS and systolic dysfunction following TBI. Admission SIRS was present in 7 (21%) patients and was associated with systolic dysfunction on multivariable analysis (relative risk 4.01; 95% 1.16-13.79, p = .028). Both SIRS criteria and systolic cardiac function improved over the first week of hospitalization. In conclusion, early SIRS is common among patients with moderate-severe TBI, and the presence of SIRS criteria on admission is associated with systolic cardiac dysfunction following TBI. PMID- 28573764 TI - Cutaneous squamous cell carcinoma of the lip: A population-based analysis. AB - OBJECTIVES/HYPOTHESIS: The role of cumulative ultraviolet (UV) radiation in cutaneous squamous cell carcinoma of the lip (CSCCL) is well understood. This study seeks to evaluate overall survival as well as incidence and demographics across geographic regions, given differences in UV exposure across the United States. STUDY DESIGN: Retrospective population-based analysis. METHODS: A total of 14,901 CSCCL cases were identified as being from the West, Midwest, South, or Northeast, utilizing the Surveillance, Epidemiology, and End Results registry from 1973 to 2013. Demographics, stage of disease, and treatment modalities were compared among regions. RESULTS: Of the CSCCL cases reported, 58.3%, 24.5%, 10.8%, and 6.4% originated from the West, Midwest, South, and Northeast, respectively. Patients most commonly presented with T1 tumors (81.3%), and nodal and distant metastasis was rare for patients from all regions (3.1% and 0.3%, respectively). Patients with American Joint Committee on Cancer stage II and higher were most likely from the Northeast or South. Overall, most patients were treated with surgery monotherapy (89.5%); however, surgical monotherapy was least commonly utilized in patients in the Northeast and South. Overall 5-year disease specific survival was measured at 94.7%. CONCLUSION: Although areas of high UV index are implicated in increased morbidity and mortality due to CSCCL, this study indicates that a variety of factors play a role in CSCCL incidence and outcomes in the United States. The elderly and non-white populations were identified as poor prognostic demographic factors. Investigation detailing differences in CSCCL detection and treatment may aid in the identification of higher-risk populations. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:84-90, 2018. PMID- 28573766 TI - Tropical Medicine & International Health. PMID- 28573767 TI - Measuring contact area in a sliding human finger-pad contact. AB - BACKGROUND/PURPOSE: The work outlined in this paper was aimed at achieving further understanding of skin frictional behaviour by investigating the contact area between human finger-pads and flat surfaces. METHODS: Both the static and the dynamic contact areas (in macro- and micro-scales) were measured using various techniques, including ink printing, optical coherence tomography (OCT) and Digital Image Correlation (DIC). RESULTS: In the studies of the static measurements using ink printing, the experimental results showed that the apparent and the real contact area increased with load following a piecewise linear correlation function for a finger-pad in contact with paper sheets. Comparisons indicated that the OCT method is a reliable and effective method to investigate the real contact area of a finger-pad and allow micro-scale analysis. The apparent contact area (from the DIC measurements) was found to reduce with time in the transition from the static phase to the dynamic phase while the real area of contact (from OCT) increased. CONCLUSIONS: The results from this study enable the interaction between finger-pads and contact object surface to be better analysed, and hence improve the understanding of skin friction. PMID- 28573765 TI - Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide. AB - The aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged >=50 years, with glycated haemoglobin (HbA1c) <=9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or >=2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world. PMID- 28573768 TI - Nodes of Ranvier in skin biopsies of patients with diabetes mellitus. AB - Paranodal demyelination has been discussed as a potential mechanism of nerve fiber damage in diabetic neuropathy (DNP). Studies on human tissue are limited, as nerve biopsies are invasive and only rarely performed in patients with confirmed DNP. Skin biopsy has recently been suggested as a tool to analyze paranodal and nodal changes of myelinated fibers. We analyzed the myelinated fibers of skin biopsies of 35 patients with DNP, 17 patients with diabetes mellitus (DM) without neuropathy, and 30 normal controls. Immunofluorescence of skin sections with antibodies against Caspr, neurofascin, sodium channels, and myelin basic protein was performed to assess paranodal/nodal architecture, segmental demyelination, and myelinated nerve fibers. Staining with antibodies against protein gene product 9.5 was used to quantify unmyelinated nerve fibers. There was an increase of elongated Ranvier nodes and a dispersion of neurofascin at the distal leg in patients with DM with and without neuropathy and at the finger in patients with DNP. An increased dispersion of Caspr was only found in biopsies of the finger in patients with DNP. Skin biopsy may be an appropriate tool to analyze nodes of Ranvier in patients with DM. Structural nodal changes are detectable in DNP and even in diabetic patients without neuropathy. PMID- 28573769 TI - Re: How to monitor pregnancies complicated by fetal growth restriction and delivery before 32 weeks: post-hoc analysis of TRUFFLE study. W. Ganzevoort, N. Mensing Van Charante, B. Thilaganathan, F. Prefumo, B. Arabin, C. M. Bilardo, et al., on behalf of the TRUFFLE Group. Ultrasound Obstet Gynecol 2017; 49: 769-777. PMID- 28573770 TI - Re: Sonographic evaluation of immobility of normal and endometriotic ovary in detection of deep endometriosis. B. Gerges, C. Lu, S. Reid, D. Chou, T. Chang and G. Condous. Ultrasound Obstet Gynecol 2017; 49: 793-798. PMID- 28573771 TI - Reply. PMID- 28573772 TI - Reply. PMID- 28573773 TI - Re: Right ventricular outflow tract obstruction in complicated monochorionic twin pregnancy. S. J. Eschbach, L. S. T. M. Boons, E. Van Zwet, J. M. Middeldorp, F. J. C. M. Klumper, E. Lopriore, A. K. K. Teunissen, M. E. Rijlaarsdam, D. Oepkes, A. D. J. Ten Harkel, M. C. Haak. Ultrasound Obstet Gynecol 2017; 49: 737-743. PMID- 28573774 TI - Percutaneous laser ablation of the feeding vessel in pulmonary sequestration or hybrid lesions. PMID- 28573775 TI - ISUOG updated consensus statement on the impact of cfDNA aneuploidy testing on screening policies and prenatal ultrasound practice. PMID- 28573776 TI - Ascertaining fetal Zika virus infection based on IgM antibody test in endemic settings. PMID- 28573778 TI - Application of Enhanced Point Estimators to a Sample of In Vivo CT-derived Facial Soft Tissue Thicknesses. AB - Facial approximations based on facial soft tissue depth measurement tables often utilize the arithmetic mean as a central tendency estimator. Stephan et al. (J Forensic Sci 2013;58:1439) suggest that the shorth and 75-shormax statistics are better suited to describe the central tendency of non-normal soft tissue depth data, while also accommodating normal distributions. The shorth, 75-shormax, arithmetic mean, and other central tendency estimators were evaluated using a CT derived facial soft tissue depth dataset. Differences between arithmetic mean and shorth mean for the tissue depths examined ranged from 0 mm to +2.3 mm (average 0.6 mm). Differences between the arithmetic mean plus one standard deviation (to approximate the same data points covered by the 75-shormax) and 75-shormax values ranged from -0.8 mm to +0.7 mm (average 0.2 mm). The results of this research suggest that few practical differences exist across the central tendency point estimators for the evaluated soft tissue depth dataset. PMID- 28573777 TI - Once-weekly administration of a long-acting fibroblast growth factor 21 analogue modulates lipids, bone turnover markers, blood pressure and body weight differently in obese people with hypertriglyceridaemia and in non-human primates. AB - AIMS: To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analogue, in obese people with hypertriglyceridaemia on atorvastatin, with or without type 2 diabetes. METHODS: Participants received PF-05231023 or placebo intravenously once weekly for 4 weeks. Safety (12-lead ECGs, vital signs, adverse events [AEs], laboratory tests) and longitudinal weight assessments were performed. Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Cardiovascular safety studies were also conducted in telemetered rats and monkeys. Blood pressure (BP; mean, systolic and diastolic) and ECGs were monitored. RESULTS: A total of 107 people were randomized. PF-05231023 significantly decreased mean placebo-adjusted fasting triglycerides (day 25, 33% 43%) and increased HDL cholesterol (day 25, 15.7%-28.6%) and adiponectin (day 25, 1574 to 3272 ng/mL) across all doses, without significant changes in body weight (day 25, -0.45% to -1.21%). Modest decreases from baseline were observed for N terminal propeptides of type 1 collagen (P1NP) on day 25, although C-telopeptide cross-linking of type 1 collagen (CTX-1) increased minimally. Systolic, diastolic BP, and pulse rate increased in a dose- and time-related manner. There were 5 serious AEs (one treatment-related) and no deaths. Three participants discontinued because of AEs. The majority of AEs were gastrointestinal. PF 05231023 increased BP and heart rate in rats, but not in monkeys. CONCLUSIONS: Once-weekly PF-05231023 lowered triglycerides markedly in the absence of weight loss, with modest changes in markers of bone homeostasis. This is the first report showing increases in BP and pulse rate in humans and rats after pharmacological administration of a long-acting FGF21 molecule. PMID- 28573779 TI - A skincare combined with combination of adapalene and benzoyl peroxide provides a significant adjunctive efficacy and local tolerance benefit in adult women with mild acne. AB - INTRODUCTION: Acne in adult women is an increasing reason for dermatological consultations. OBJECTIVE: The aim of this study was to assess in adult women with mild acne the efficacy and tolerance of a daily adjunctive application of a skincare (Normaderm(r) , Laboratoires Vichy, France) to a fixed combination of adapalene/benzoyl peroxide daily or every other evening and a standard emollient. METHODS: Subjects were randomized to receive the fixed combination applied either every evening or every other evening and a daily application of the standard emollient and the test care or a once daily application of the fixed combination and the standard emollient alone. Clinical evaluations at Day 0, Day 45 and Day 90 included the count of acne lesions, assessment of clinical improvement and local tolerance. The quantitative lipid profile of the stratum corneum of the forehead was also determined. RESULTS: After 90 days of application, acne had improved in all 299 subjects with a statistically significant difference in favour of the test care regimens (P < 0.05). Moreover, skin quality, subject satisfaction, skin discomfort and sebum composition were in favour of these regimens. CONCLUSION: In conclusion, the tested skincare combined with a fixed adapalene and benzoyl peroxide combination provides a significant adjunctive efficacy and local tolerance benefit in adult women with mild acne. PMID- 28573780 TI - Mathematical approach to nonlocal interactions using a reaction-diffusion system. AB - In recent years, spatial long range interactions during developmental processes have been introduced as a result of the integration of microscopic information, such as molecular events and signaling networks. They are often called nonlocal interactions. If the profile of a nonlocal interaction is determined by experiments, we can easily investigate how patterns generate by numerical simulations without detailed microscopic events. Thus, nonlocal interactions are useful tools to understand complex biosystems. However, nonlocal interactions are often inconvenient for observing specific mechanisms because of the integration of information. Accordingly, we proposed a new method that could convert nonlocal interactions into a reaction-diffusion system with auxiliary unknown variables. In this review, by introducing biological and mathematical studies related to nonlocal interactions, we will present the heuristic understanding of nonlocal interactions using a reaction-diffusion system. PMID- 28573781 TI - Outpatient thyroidectomy is safe in the elderly and super-elderly. AB - OBJECTIVES: 1) Determine the safety of outpatient thyroidectomy in the geriatric patient population. 2) Analyze the risk of postoperative complications from thyroid surgery in patients aged over 65 years (elderly) and aged over 80 years (super-elderly) undergoing ambulatory thyroidectomy compared to patients aged 21 through 40 years. STUDY DESIGN: A retrospective analysis of consecutive patients undergoing thyroidectomy between January 2008 and July 2015 at a tertiary academic institution. METHOD: Patients were stratified by age, and three subsets within this population were considered and analyzed further: youthful/control (aged 21-40 years), elderly (aged 65-79 years), and super-elderly (>= 80 years). Patient demographics, surgical and pathological data, admission status, complication, and readmission rates were recorded. RESULTS: A total of 1,429 thyroidectomies were accomplished; of these, 1,207 (84.5%) were outpatient operations. Among the outpatients, 85.2% were female, 14.1% were male, and the mean age was 50.3 +/- 15.2 years. The control (youthful) group was comprised of 328 patients with a mean age of 33.3 years; the elderly group of 201 patients had a mean age of 70.3 years; and 16 patients in the super-elderly group had a mean age 82.7 years. The complication rates (5.2%, 5.0%, and 6.3%, respectively; P = 0.98) and re-admission rates (1.5%, 1.5%, and 0.0%, respectively; P = 0.89) were not different among these groups. CONCLUSION: Outpatient thyroid surgery is as safe in appropriately selected elderly and super-elderly patients as it is in a control group of youthful patients. Therefore, age should not be a contraindication to conducting thyroidectomy on an ambulatory basis. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:290-294, 2018. PMID- 28573782 TI - Erratum. PMID- 28573783 TI - Towards a science and practice of resilience in the face of pain. AB - : The primary objective of this paper is to discuss how a resilience approach to (chronic) pain may advance our current understanding of (mal)adaptation to pain. Different resilience perspectives are described, and future challenges for research, prevention and treatment of (chronic) pain are discussed. Literature searches were performed in Web of Science and PubMed to identify relevant literature on risk and resilience in the context of pain. Resilience can be best defined as the ability to restore and sustain living a fulfilling life in the presence of pain. The Psychological Flexibility Model, the Broaden-and-Build Theory, and Self-Determination Theory are described as theories that may provide insight into resilience within the context of (chronic) pain. We describe how a resilience paradigm shifts the outcomes to pursue in pain research and intervention and argue the need for including positive outcomes in addition to negative outcomes. Psychological flexibility, positive affect and basic psychological needs satisfaction are described as potentially important resilience mechanisms with the potential to target both sustainability and recovery from pain. A resilience approach to chronic pain may have important implications for the prevention and treatment of chronic pain problems, as it may give specific indications on how to empower patients to continue living a fulfilling life (in the presence of pain). SIGNIFICANCE: The resilience approach put forward in this review spotlights sustainability of positive outcomes (e.g. engagement in meaningful activities) in the presence of pain as an outcome to pursue beyond recovery of negative outcomes. We illuminate the evidence-base and practical application of promising resilience mechanisms (positive emotions, psychological flexibility, needs satisfaction). For this article, a commentary is available at the Wiley Online Library. PMID- 28573784 TI - Stratification and weighting via the propensity score in estimation of causal treatment effects: a comparative study. PMID- 28573785 TI - Biomarker release after percutaneous coronary intervention in patients without established myocardial infarction as assessed by cardiac magnetic resonance with late gadolinium enhancement. AB - OBJECTIVES: This study aimed to evaluate the amount and pattern of cardiac biomarker release after elective percutaneous coronary intervention (PCI) in patients without evidence of a new myocardial infarction (MI) after the procedure as assessed by cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE). BACKGROUND: The release of myocardial necrosis biomarkers after PCI frequently occurs. However, the correlation between biomarker release and the diagnosis of procedure-related MI type 4a has been controversial. METHODS: Patients with normal baseline cardiac biomarkers who were referred for elective PCI were prospectively included. CMR with LGE was performed in all of the patients before and after the intervention. Measurements of troponin I (TnI) and creatine kinase MB fraction (CK-MB) were systematically performed before and after the procedure. Patients with a new LGE on the post-procedure CMR were excluded. RESULTS: Of the 56 patients with no evidence of a procedure-related MI as assessed by CMR after the PCI, 48 (85.1%) exhibited an elevation of TnI above the 99th percentile. In 32 patients (57.1%), the peak was greater than five times this limit. Additionally, 17 patients (30.4%) had a CK-MB peak above the 99th percentile limit, but this peak was greater than five times the 99th percentile in only two patients (3.6%). The median peak release of TnI was 0.290 (0.061 1.09) ng/mL, which was 7.25-fold higher than the 99th percentile. CONCLUSIONS: In contrast to CK-MB, an abnormal release of TnI often occurs after an elective PCI procedure, despite the absence of a new LGE on CMR. PMID- 28573786 TI - Real-life patterns of use, safety and effectiveness of sunitinib in first-line therapy of metastatic renal cell carcinoma: the SANTORIN cohort study. AB - PURPOSE: To investigate sunitinib in the real-life first-line treatment of metastatic renal cell carcinoma (mRCC). METHODS: SANTORIN is a French observational multicentre cohort. Patients initiating sunitinib in first-line mRCC therapy were included (January 2008 to April 2010) and followed for 24 months. Data were collected from medical files. The outcomes were 24-month overall survival (OS) and progression-free survival (PFS), response and safety. RESULTS: Three hundred two patients were included: median age, 64.8 years; male, 73.2%; clear cell mRCC, 83.1%; prior nephrectomy, 85.4%; >1 metastatic sites, 64.2%; brain metastases, 6.3%; ECOG-PS >= 2, 9.9%. Median duration of first-line therapy with sunitinib was 10.7 months. Initial sunitinib dose was 50 mg/day for 83.4% of patients; dose reduction occurred in 65.2%. Sunitinib was discontinued in 73.2% of the patients: for progression (61.1%), death (31.2%) or adverse events (6.8%). More than half (58.3%) had grade >=3 adverse events, mainly hypertension (12.6%) and hand-foot syndrome (12.3%). The 24-month OS and PFS rates [95%CI] were 49.5% [43.7;55.0] and 16.4% [12.5;20.9], respectively. Median OS was 23.6 months [20.2;-] and median PFS 8.4 months [7.6;9.9]. Overall best response rate was 31.1%. CONCLUSIONS: Results from this large observational study suggest that effectiveness of sunitinib in first-line mRCC as predicted by clinical trials is maintained in real-life clinical practice. The expected benefit in poor-prognosis patients that were not evaluated in the pivotal clinical trial remains; however, questionable and long-term safety monitoring is still warranted. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28573787 TI - Understanding the experience of women admitted to a psychiatric hospital in Sydney with psychosis or mania following childbirth after World War II (1945 1955). AB - In the present study, we investigated a unique set of historical health-care records of women admitted to a psychiatric hospital in Sydney, Australia with a diagnosis of psychosis or mania after childbirth in the post-World War II (WWII) period, from 1945 to 1955. This research is part of a larger project examining how the descriptions of these women documented in the health-care records from 1885 to 1975 affected their treatment and the outcome of their admission. In the present paper, we report on the findings from an intensive examination of the post WWII documents. Eighteen health-care records from a psychiatric facility (Gladesville Hospital) were identified from admission registers housed in the State Records Office of New South Wales in 2014. Although seven records had been destroyed, 11 were transcribed verbatim. The records contain demographic information; descriptions of the women's signs and symptoms on admission; and information about the women before, during, and after their admission found in letters from relatives or medical staff. A content analysis of admission information showed how the women were described by health-care professionals, but a textual analysis of the records revealed that there were other factors that could have contributed to the women's condition, which might not have been taken into consideration when treatment and care were devised. The present study demonstrates the value of investigating historical health-care records to understand how prevailing attitudes and practices might affect diagnosis and treatment. PMID- 28573789 TI - Translation-dependent mRNA cleavage by YhaV in Escherichia coli. AB - Many bacteria have toxin-antitoxin (TA) systems, where toxin gene expression inhibits their own cell growth. mRNA is one of the well-known targets of the toxins in the type II toxin-antitoxin systems. Here, we examined the ribosome dependency of the endoribonuclease activity of YhaV, one of the toxins in type II TA systems, on mRNA in vitro and in vivo. A polysome profiling assay revealed that YhaV is bound to the 70S ribosomes and 50S ribosomal subunits. Moreover, we found that while YhaV cleaves ompF and lpp mRNAs in a translation-dependent manner, they did not cleave the 5' untranslated region in primer extension experiments. From these results, we conclude that YhaV is a ribosome-dependent toxin that cleaves mRNA in a translation-dependent manner. PMID- 28573788 TI - In vitro additive antitumor effects of dimethoxycurcumin and 5-fluorouracil in colon cancer cells. AB - Dimethoxycurcumin (DMC) is a lipophilic analog of curcumin, an effective treatment for colon cancer, which has greater chemical and metabolic stability. Chemotherapy treatments, such as 5-fluorouracil (5-Fu), play a key role in the current management of colon cancer. In this study, we investigated the antitumor efficacy of DMC in combination with 5-Fu in SW480 and SW620 colon cancer cells. CCK-8 assay was used to evaluate the inhibitory effect of DMC and 5-Fu on cancer cells proliferation, and the combination index was calculated. The influence of DMC and 5-Fu on cell cycle, apoptosis, reactive oxygen species (ROS) production, and mitochondrial membrane potential in SW480 and SW620 cells was determined using flow cytometry, and the related signaling pathways were detected by western blot. Transmission electron microscopy was used to observe endoplasmic reticulum expansion. DMC- and/or 5-Fu-induced apoptosis, stimulated G0/G1 phase arrest, increased ROS levels, decreased mitochondrial membrane potential, and enhanced endoplasmic reticulum expansion. The induction of apoptosis is involved in the increasing of Bax and cytochrome c and decreasing of Bcl2 expressions. Increased production of ROS was accompanied by upregulation of CHOP and Noxa. Combination therapy of DMC and 5-Fu had increased efficacy on the above pathways compared with either drug alone. Based on the calculated IC50 , combination treatment with DMC and 5-Fu had an additive antitumor effect in both cell lines. Combined treatment with DMC and 5-Fu led to an additive antitumor effect in colon cancer cells that was related to apoptosis induction, G0/G1 phase arrest, increased ROS production, decreased mitochondrial membrane potential, and enhanced endoplasmic reticulum expansion. PMID- 28573790 TI - A comparison of programmable and nonprogrammable compression devices for treatment of lymphoedema using an administrative health outcomes dataset. AB - BACKGROUND: Patients with lymphoedema experience lifelong swelling and recurrent cellulitis despite use of complete decongestive therapy. Pneumatic compression devices (PCDs), including nonprogrammable and programmable devices that meet individual patient needs, support long-term self-care in the home. OBJECTIVES: Patients with either a nonprogrammable device (NP-PCD) or a dynamic pressure programmable device [P-PCD; Flexitouch(r) (Tactile Medical, Minneapolis, MN, U.S.A.)] were evaluated to compare associated clinical and health utilization outcomes pre-/postdevice acquisition. METHODS: Retrospective analysis of deidentified administrative claims from 2007 through 2013 of a large U.S. insurer. Outcome variables included rates of lymphoedema-related cellulitis, manual therapy use, outpatient services and inpatient hospitalizations. Multivariate regression analysis was performed to (i) compare outcomes for the 12 months pre- and postdevice acquisition and (ii) compare these two device types for their treatment-associated benefits. RESULTS: The sample consisted of 1013 NP PCD and 718 P-PCD recipients. Compared with the NP-PCD group, P-PCD patients' baseline cellulitis rate was higher, whereas their postdevice cellulitis rate was lower. In the cancer cohort, the NP-PCD group had a 53% reduction in episodes of cellulitis (from 17.9% to 8.5%), compared with a greater 79% reduction in the P PCD group (from 23.7% to 5.0%) (P < 0.001). In the noncancer cohort, the P-PCD group also experienced a larger 76% decline (from 31.0% to 7.4%) vs. 54% decline (from 22.9% to 10.6%) in cellulitis rates (P = 0.003). Outpatient service use reduced in both device groups, with greater reductions observed in the P-PCD group. Both device groups experienced reductions in manual therapy use. Inpatient hospitalizations were largely stable with reductions observed only in the noncancer cohort of the P-PCD group. CONCLUSIONS: P-PCD receipt was associated with superior lymphoedema-related health outcomes and reductions in cellulitis. PMID- 28573791 TI - Early Experiences of Contact Laser Vaporization of the Prostate using the 980 nm High Power Diode Laser for Benign Prostatic Hyperplasia. AB - OBJECTIVES: We report early experiences of contact laser vaporization of the prostate for symptomatic benign prostatic hyperplasia (BPH). METHODS: A total of 80 patients recruited at four institutions in Japan from April 2013 through September 2014 underwent contact laser vaporization of the prostate using 980 nm high power diode laser with an end-firing fiber in the contact mode. Patients were followed prospectively at 1 day, 2, 4, 8, 12, and 24 weeks, postoperatively per protocol, and at 1 and 2 years post-protocol. RESULTS: Of 76 eligible patients, 64 (84.2%) achieved more than 50% decrease in International Prostate Symptom Score at 24 weeks (95% confidence interval: 74.0-91.6%), clearing the pre fixed non-inferiority efficacy level to transurethral resection of the prostate (65%). Symptom scores, maximum flow rate, post-void residual urine, and prostate volume showed significant improvements at 12 and 24 weeks after the surgery. Perioperative complications included transient urinary retention (n = 20), retrograde ejaculation (5), bladder neck contracture (4), urethral stricture (3), stone in prostatic bed (3), bladder stone (2), bladder perforation (1), bladder deformity (1), and transient urgency incontinence (1). Urinary retention and bladder neck contracture occurred almost exclusively at one institution. Improved symptom scores, maximum flow rate, and post-void residual urine observed at 24 weeks remained virtually unchanged at 1 and 2 years. CONCLUSIONS: Early experience of contact laser vaporization in Japan showed efficacy comparable to transurethral resection of the prostate as a surgical procedure for BPH at 24 weeks. Long-term efficacy of the procedure remains uncertain. PMID- 28573793 TI - Traceability of Opuntia ficus-indica L. Miller by ICP-MS multi-element profile and chemometric approach. AB - BACKGROUND: Opuntia ficus-indica L. Miller fruits, particularly 'Ficodindia dell'Etna' of Biancavilla (POD), 'Fico d'india tradizionale di Roccapalumba' with protected brand and samples from an experimental field in Pezzolo (Sicily) were analyzed by inductively coupled plasma mass spectrometry in order to determine the multi-element profile. A multivariate chemometric approach, specifically principal component analysis (PCA), was applied to individuate how mineral elements may represent a marker of geographic origin, which would be useful for traceability. RESULTS: PCA has allowed us to verify that the geographical origin of prickly pear fruits is significantly influenced by trace element content, and the results found in Biancavilla PDO samples were linked to the geological composition of this volcanic areas. It was observed that two principal components accounted for 72.03% of the total variance in the data and, in more detail, PC1 explains 45.51% and PC2 26.52%, respectively. CONCLUSION: This study demonstrated that PCA is an integrated tool for the traceability of food products and, at the same time, a useful method of authentication of typical local fruits such as prickly pear. (c) 2017 Society of Chemical Industry. PMID- 28573794 TI - Possible Involvement of the CACNA1E Gene in Migraine: A Search for Single Nucleotide Polymorphism in Different Clinical Phenotypes. AB - OBJECTIVE: To search for differences in prevalence of a CACNA1E variant between migraine without aura, various phenotypes of migraine with aura, and healthy controls. BACKGROUND: Familial hemiplegic migraine type 1 (FHM1) is associated with mutations in the CACNA1A gene coding for the alpha 1A (Cav 2.1) pore-forming subunit of P/Q voltage-dependent Ca2+ channels. These mutations are not found in the common forms of migraine with or without aura. The alpha 1E subunit (Cav 2.3) is the counterpart of Cav 2.1 in R-type Ca2+ channels, has different functional properties, and is encoded by the CACNA1E gene. METHODS: First, we performed a total exon sequencing of the CACNA1E gene in three probands selected because they had no abnormalities in the three FHM genes. In a patient suffering from basilar type migraine, we identified a single nucleotide polymorphism (SNP) in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760; Minor Allele Frequency 0.2241) hitherto not studied in migraine. In a second step, we determined its occurrence in four groups by direct sequencing on blood genomic DNA: migraine patients without aura (N = 24), with typical aura (N = 55), complex neurological auras (N = 19; hemiplegic aura: N = 15; brain stem aura: N = 4), and healthy controls (N = 102). RESULTS: The Asp859Glu - rs35737760 SNP of the CACNA1E gene was present in 12.7% of control subjects and in 20.4% of the total migraine group. In the migraine group it was significantly over-represented in patients with complex neurological auras (42.1%), OR 4.98 (95% CI: 1.69-14.67, uncorrected P = .005, Bonferroni P = .030, 2-tailed Fisher's exact test). There was no significant difference between migraine with typical aura (10.9%) and controls. CONCLUSIONS: We identified a polymorphism in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760) that is more prevalent in hemiplegic and brain stem aura migraine. This missense variant causes a change from aspartate to glutamate at position 859 of the Cav 2.3 protein and might modulate the function of R-type Ca2+ channels. It could thus be relevant for migraine with complex neurological aura, although this remains to be proven. PMID- 28573795 TI - Digestible indispensable amino acid score (DIAAS) and protein digestibility corrected amino acid score (PDCAAS) in oat protein concentrate measured in 20- to 30-kilogram pigs. AB - BACKGROUND: Oat protein concentrate is often used in human food, but the quality of this protein has not been characterized. Therefore, the objectives of this experiment were to determine the standardized ileal digestibility (SID) of crude protein (CP) and amino acids (AA) in oat protein concentrate and to determine differences in protein quality estimates between the protein digestibility corrected AA score (PDCAAS) and the digestible indispensable AA score (DIAAS) when using growing pigs for both measurements. RESULTS: For infants, the most limiting AA in oat protein concentrate was the aromatic AA (Phe + Tyr), for which the DIAAS value was 41 and the PDCAAS was 43. For children (6 months to 3 years) and children older than 3 years, the most limiting AA in oat protein concentrate was Lys, for which the DIAAS was 56 and 67 and the PDCAAS was 58 and 69, respectively. CONCLUSION: The DIAAS value for oat protein concentrate was close to the calculated value for PDCAAS, but below the recommended intake for protein. Therefore, to satisfy the daily human AA requirement, oat protein needs to be complemented by other proteins of higher quality and specifically with greater lysine concentrations. (c) 2017 Society of Chemical Industry. PMID- 28573796 TI - Massive left atrial myxoma induced congestive heart failure. PMID- 28573797 TI - Is salivary IgA level a potential biomarker for immunosuppression in HIV-positive children? A systematic review and meta-analysis. AB - The aim of this systematic review was to determine whether or not assessment of salivary secretory immunoglobulin A (sIgA) levels could be a potential biomarker for immunosuppression in HIV-positive children. The Patient, Exposure, Comparative, Outcome question was "Is sIgA level a potential biomarker for immunosuppression in HIV-positive children?" Electronic and manual literature searches were conducted in indexed databases (MEDLINE, PubMed, EMBASE, ScienceDirect, and SCOPUS databases) up to and including June 2017. The primary outcome was total mean salivary levels of IgA among HIV seropositive and seronegative children (controls). The weighted mean differences (WMD) of outcomes and 95% confidence intervals (CI) for total mean salivary IgA levels were calculated using a random effect model. Six studies were included. Three studies showed significantly lower salivary IgA levels in HIV-infected children compared with controls. Two studies showed comparable IgA levels in HIV infected and controls. One study showed significantly higher levels of salivary IgA in HIV infected children as compared to controls. Considering the total mean salivary IgA levels among HIV seropositive and seronegative children, a high degree of heterogeneity (Q value = 254.09, P < .0001, I2 = 98.82%) was noticed among both groups. The overall WMD was not significant (WMD = -1.18, 95% CI, -1.91 to -0.44, P = .39). Whether salivary IgA level is a potential biomarker for immunosuppression in HIV-positive children remains debatable because of limited information available in the current literature. Further, high-quality case control studies with larger sample size and more solid methodological aspects are required. PMID- 28573798 TI - Pelvic osteomyelitis: Three unusual cases with predominantly abdominal symptoms. PMID- 28573799 TI - Group A streptococcal primary peritonitis in a healthy girl. PMID- 28573800 TI - No compromise on female genital mutilation. PMID- 28573802 TI - Recurrent episodes of peripheral facial nerve palsy and fissured tongue. PMID- 28573803 TI - Effect of socio-economic status on sleep. AB - AIM: Sufficient sleep is an important factor in physical and mental health. Sleep duration can be affected by socio-economic status (SES). This study aimed to examine the association between sleep duration and SES in Korean adolescents. METHODS: This study was conducted with 1608 adolescents aged 12-18 years, based on data from the 2010 to 2012 Korean National Health and Nutrition Examination Survey (KNHANES). Sleep duration was self-reported in hours and three SES indicators were used: household income, basic livelihood security programmes and type of health insurance. Confounding factors in this study were age, mental health and physical activity. RESULTS: Participants' average age was 15.6 +/- 0.05 years and average sleep duration was 7.04 +/- 0.05 h. There was a strong association between sleep duration and household income (P < 0.05) rather than other socio-economic indicators. In addition, it showed that sleep duration was significantly associated with age, body mass index (P < 0.05) and low mood is associated with short sleep and long sleep (>9 h/night). We found similar results in both genders, that is, that the highest income group had shorter sleep duration than the lowest income group. CONCLUSIONS: This study shows that the SES, particularly household income, is an important factor in short sleep duration in Korean adolescents. Our findings suggest that, in future investigations of the adolescent's sleep problem, attention should be paid to household income. PMID- 28573804 TI - Deep jaundice in a child with sickle cell disease. PMID- 28573805 TI - Recurrent episodes of peripheral facial nerve palsy and fissured tongue. PMID- 28573806 TI - Deep jaundice in a child with sickle cell disease. PMID- 28573807 TI - Jemma's diagnosis. PMID- 28573808 TI - Aboriginal staff leading partnership in remote Australia. PMID- 28573809 TI - Female genital mutilation and the role of health-care practitioners. PMID- 28573810 TI - Developmental Origins of Health and Disease: Who knows? Who cares? PMID- 28573812 TI - Oropharyngeal carriage rates of Kingella kingae in young children in New Zealand and Australia. PMID- 28573813 TI - Vitamin D in newborns. A randomised controlled trial comparing daily and single oral bolus vitamin D in infants. PMID- 28573814 TI - Retrospective review of consecutive cases of paediatric complex pain in a New South Wales tertiary children's hospital. AB - AIM: Prior to July 2013, a solo medical specialist provided a pain management service 1.5-2 days/week to children and young people aged 0-19 years, and their families at John Hunter Children's Hospital, Newcastle, NSW. A new multidisciplinary children's complex pain team now continues that service. This study aimed to identify the demographic and clinical characteristics of children, young people and their families referred to a paediatric pain specialist in the 5.5 years prior to the establishment of a multidisciplinary service and to quantify anecdotal observations, determine service priorities and identify clinical improvement opportunities. METHODS: A retrospective review of the medical records of all new patients seen between January 2008 and June 2013 was conducted. Data sets for patient demographics, clinical characteristics, service outputs and disposition at discharge were determined prior to data extraction. RESULTS: A total of 114 children and young people aged between 7 days and 18 years (mean +/- SD = 12.54 +/- 3.6 years) were consecutively referred to the service. Many demographics are consistent with those previously reported; however, the number of children who identified as being of Aboriginal origin (11%), with rare diseases (28%), new diagnoses made (47%), child protection reports submitted (14%) and psychological morbidity in children (58%) and caregivers (38%) are new findings in the context of pain management and serve as indicators of the complex service needs of these patients and their families. CONCLUSION: The complexities encountered in this small cohort provide an indication of the time investment needed to understand and manage complex paediatric pain, especially in the contexts of complex families, time-poor general practitioners and under-resourced communities. PMID- 28573815 TI - Tape Lift Sampling of Chemical Threat Agents. AB - Commercial-off-the-shelf (COTS) materials were evaluated as surface samplers for the Department of Homeland Security Chemical Forensics Program. The program helps evidence collectors identify trace chemical residues at incident scenes. COTS items are widely available, produced in large lots, and with strict controls. Chemical attribution signatures were collected from common surfaces. Eight tape lift candidates were considered, five were chosen based on performance and tested for analytical interferences and extraction efficiencies with 14 chemicals. Three products (duct tape, print lifters, command strips) were evaluated for uptake from common interior surfaces (glass, tile, ABS plastic). Duct tape provided highest recoveries across all surfaces. Even the most volatile analytes were detected in the ABS plastic samples (nondetections in others), regardless of tape lift material used. The porous plastic substrate provides better target retention than glass and tile surfaces. Forensic field operators should sample surfaces made of ABS plastic (keyboards, remotes, phones, etc.) whenever possible. PMID- 28573816 TI - Lipid Internal Dynamics Probed in Nanodiscs. AB - Nanodiscs offer a very promising tool to incorporate membrane proteins into native-like lipid bilayers and an alternative to liposomes to maintain protein functions and protein-lipid interactions in a soluble nanoscale object. The activity of the incorporated membrane protein appears to be correlated to its dynamics in the lipid bilayer and by protein-lipid interactions. These two parameters depend on the lipid internal dynamics surrounded by the lipid encircling discoidal scaffold protein that might differ from more unrestricted lipid bilayers observed in vesicles or cellular extracts. A solid-state NMR spectroscopy investigation of lipid internal dynamics and thermotropism in nanodiscs is reported. The gel-to-fluid phase transition is almost abolished for nanodiscs, which maintain lipid fluid properties for a large temperature range. The addition of cholesterol allows fine-tuning of the internal bilayer dynamics by increasing chain ordering. Increased site-specific order parameters along the acyl chain reflect a higher internal ordering in nanodiscs compared with liposomes at room temperature; this is induced by the scaffold protein, which restricts lipid diffusion in the nanodisc area. PMID- 28573817 TI - Imaging of labyrinthine fistula after repair with bone pate. AB - OBJECTIVES/HYPOTHESIS: To demonstrate imaging of labyrinthine fistula due to cholesteatoma and illustrate outcome following repair with bone pate. STUDY DESIGN: Retrospective review. METHODS: Patients with labyrinthine fistula due to cholesteatoma were identified, and pre- and postoperative imaging was assessed. Method of repair was recorded. The fistula site was examined for patency and bone density after repair. RESULTS: Twenty-nine fistulae were seen in a cohort of 375 cholesteatoma cases (8%). Preoperative computed tomography (CT) imaging for fistula detection showed sensitivity of 96% and specificity of 90%. The lateral semicircular canal was the most common site of dehiscence occurring in all cases. Facial nerve dehiscence is observed in 91% of fistula cases and stapes erosion in 69%. Severe hearing loss was present preoperatively in four (14%) cases. Bone pate was used to repair the fistula with CT-documented restoration of the otic capsule in 11/13 cases with postoperative imaging. When bone pate was not used, the otic capsule defect persisted. CONCLUSIONS: Spontaneous repair of the otic capsule following treatment of cholesteatoma is expected to be an uncommon occurrence. Repair of the fistula with bone can result in long-lasting restoration of the otic capsule. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1643 1648, 2018. PMID- 28573818 TI - The journey between brain and gut: A systematic review of psychological mechanisms of treatment effect in irritable bowel syndrome. AB - PURPOSE: Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by abdominal pain and altered bowel habits. It is estimated to affect 10-22% of the UK population. The use of psychological interventions in IBS is increasingly empirically supported, but little is known about the mechanism of psychological treatment approaches. The present systematic review aimed to investigate the mechanisms of psychological treatment approaches applied to IBS. METHODS: The systematic review included studies conducting mediation analysis in the context of psychological interventions for IBS, focusing on the outcomes of symptom severity and/or quality of life (QoL). RESULTS: Nine studies in total were included in the review. Eight of the studies assessed mediation in the context of cognitive behavioural-based interventions, and one study assessed mediation in a mindfulness-based stress reduction intervention. Results indicate that change in illness-specific cognitions is a key process by which psychological treatments may have an effect on the outcomes of symptom severity and QoL. Furthermore, results suggest that whilst GI-specific anxiety may also be a key mechanism of treatment effect, it would appear that general or state anxiety is not. Although less commonly included in mediation analysis, illness-specific behaviours may also have a mediating role. CONCLUSIONS: A mediational model amalgamating the results of studies is proposed to illustrate the findings of the review. The model depicts the process by which psychotherapy changes illness-specific cognitions, behaviours, and anxiety to achieve reduction in symptom severity. Statement of contribution What is already known on this subject? Cognitive behavioural therapy (CBT) is the predominant psychological treatment for irritable bowel syndrome (IBS), although there is some research supporting other treatments such as mindfulness and hypnotherapy. Mediation analysis in the context of psychological treatments for IBS has just begun to explore possible mechanisms of treatment effect especially within CBT studies. Some studies include anxiety in a basic mediation analysis, whilst others include cognitions with inconsistent results for each. What does this study add? Reviews mediators included in mediation analysis and the methods used for mediation analysis Proposes a mediation model informed by the results of the review for future studies to investigate Provides clinical implications for the targeting of cognitions and behaviours rather than general anxiety. PMID- 28573820 TI - Aromatherapy massage versus reflexology on female elderly with acute coronary syndrome. AB - BACKGROUND: Fatigue and abnormalities in cardiovascular parameters are recognized as major problems for patients with acute coronary syndrome. Non-pharmacological nursing interventions are useful for controlling this fatigue and reducing patients' suffering during hospitalization. AIM: The present study compared the effects of aromatherapy massage and reflexology on fatigue and cardiovascular parameters in older female patients with acute coronary syndrome. DESIGN: This study was a randomized clinical trial. METHODS: The study was conducted with 135 older female patients with acute coronary syndrome who were hospitalized in a cardiac care unit in 2014. They were invited to participate in the study and then were randomly divided into three groups: 'aromatherapy massage', 'reflexology' and 'control'. The fatigue severity and cardiovascular parameters were assessed using the Rhoten fatigue scale and a checklist. Measurements in the groups were performed before and immediately after the intervention. Data analysis was performed using descriptive and analytical statistics via the SPSS software. RESULTS: Aromatherapy massage significantly decreased fatigue, systolic blood pressure, mean arterial pressure and O2 saturation more than the reflexology intervention. However, reflexology reduced patients' heart rates more than an aromatherapy massage (P < 0.05). Moreover, no significant changes were observed in patients' diastolic blood pressures when compared to the control group (P = 0.37). CONCLUSIONS: Implementation of both aromatherapy massage and reflexology has positive effects on the fatigue and cardiovascular parameters of patients with acute coronary syndrome. However, aromatherapy massage can be more beneficial to use as a supportive approach in coronary diseases. RELEVANCE TO CLINICAL PRACTICE: The need for reducing fatigue in acute coronary syndrome (ACS) patients in a cardiac care unit is evident. The implementation of aromatherapy massage and reflexology had positive effects on patients' fatigue as related to both physical and mental health. PMID- 28573819 TI - Use of eltrombopag for secondary immune thrombocytopenia in clinical practice. AB - Eltrombopag is a second-line treatment in primary immune thrombocytopenia (ITP). However, its role in secondary ITP is unknown. We evaluated the efficacy and safety of eltrombopag in secondary ITP in daily clinical practice. Eighty-seven secondary ITP patients (46 with ITP secondary to autoimmune syndromes, 23 with ITP secondary to a neoplastic disease subtype: lymphoproliferative disorders [LPDs] and 18 with ITP secondary to viral infections) who had been treated with eltrombopag were retrospectively evaluated. Forty-four patients (38%) had a platelet response, including 40 (35%) with complete responses. Median time to platelet response was 15 days (95% confidence interval, 7-28 days), and was longer in the LPD-ITP group. Platelet response rate was significantly lower in the LPD-ITP than in other groups. However, having achieved response, there were no significant differences between the durable response of the groups. Forty three patients (49.4%) experienced adverse events (mainly grade 1-2), the commonest being hepatobiliary laboratory abnormalities. There were 10 deaths in this case series, all of which were related to pre-existing medical conditions. In routine clinical practice, eltrombopag is effective and well-tolerated in unselected patients with ITP secondary to both immune and infectious disorders. However, the response rate in LPD-ITP is low. PMID- 28573822 TI - The interview, revisited. PMID- 28573821 TI - Overexpression of the human antigen R suppresses the immediate paradoxical proliferation of melanoma cell subpopulations in response to suboptimal BRAF inhibition. AB - Tumor plasticity and the heterogeneous response of melanoma cells to targeted therapies are major limits for the long-term efficacy of this line of therapy. Targeting tumor plasticity is theoretically possible through the modulation of the expression of RNA-binding proteins which can affect many different compensatory mechanisms of the adaptive response of malignant cells to targeted therapies. Human antigen R (HuR) is a modulator of gene expression and a transacting factor in the mRNA-processing machinery used in the cell stress response, and is a potential target for reducing tumor plasticity. In this experiment, we exploit the inherent heterogeneous response of the A375 melanoma line to suboptimal BRAF inhibition as a model of immediate adaptive response. We first observe that HuR overexpression can prevent the heterogeneous response and thus the immediate paradoxical proliferation induced by low-doses vemurafenib treatment. We then use single-cell mass cytometry to characterize subpopulations, including those that paradoxically proliferate, based on their proliferation rate and the expression patterns of markers involved in the reversible adaptive resistance to BRAF inhibition and/or recognized as HuR targets involved in cell cycle regulation. Under suboptimal BRAF inhibition, HuR overexpression affects these subpopulations and their expression pattern with contrasting responses depending on their proliferation rate: faster-proliferating vemurafenib-sensitive or -resistant subpopulations showed higher death tendency and reduced size, and slower-proliferating subpopulations showed an attenuated resistant expression response and their paradoxical proliferation was inhibited. These observations pave the way to new therapeutic strategies for preventing the heterogeneous response of tumors to targeted therapies. PMID- 28573823 TI - The effect of smartphone addiction on hand joints in psoriatic patients: an ultrasound-based study. AB - BACKGROUND: Distal interphalangeal (DIP) arthritis is a frequent form of psoriatic arthritis being often linked to nail psoriasis. Modern society is characterized by overuse of smartphones. Indeed, literature has recently focalized on research into smartphone addiction and health-related problems. OBJECTIVES: As smartphone addiction is able to determine overuse and repeated movements of DIP joints and nails, the aim of this study was to evaluate the impact of smartphone use on hand joints of young psoriatic patients. METHODS: An observational study involving four different groups such as non-smartphone addicted (SA) psoriatic patients, SA psoriatic patients, non-SA controls and SA controls was performed. Each subject underwent an ultrasound examination of both hands by three independent and blinded to group assignment radiologists. A specific score was used to evaluate the inflammatory state of the analysed joints. RESULTS: The total ultrasound score was statistically significantly higher in SA controls respect to non-SA controls (3.4 vs. 1.4; P < 0.05) as well as in SA psoriasis patients compared to non-SA psoriatic subjects (15.2 vs. 6.7; P < 0.01). Higher mean of ultrasound score was found for left hand in controls (both SA or not) and for right hand in psoriatic subjects (both SA or not), however without reaching statistical significance. CONCLUSIONS: Smartphone overuse was found to be linked with higher signs of inflammation of musculoskeletal structures of hands joints in both psoriasis and controls through ultrasound examination. Therefore, smartphone overuse may be a factor which facilitate or speed up the possible development of psoriatic arthritis. PMID- 28573824 TI - Bone cement cardiac and pulmonary embolism. AB - This case describes a complication of bone cement use. A 65-year-old male patient with back spine trauma caused by a fall, underwent a percutaneous vertebroplasty. Five years later, he consulted for palpitations, and the electrocardiogram showed supraventricular arrhythmia. A transthoracic two-dimensional echocardiography showed a hyperechogenic linear structure of 7 cm length, running from the lateral wall of the right ventricle to the right atrium through the tricuspid valve. This foreign body, which was suspicious for bone cement embolism, appeared rigid and was attached at the lateral wall of the right ventricle, with its proximal end free in the right atrium. The tip of the cement embolus was inside the myocardium of the lateral wall of the right ventricle, with risk of cardiac perforation. A fluoroscopy was performed, which confirmed the presence of cement within the right heart, with great mobility in each cardiac cycle. Chest computed tomography (CT) and multidetector CT three-dimensional reconstruction confirmed the presence of cement within the right heart. Chest CT showed two pulmonary embolisms, one in the right upper lobe and one in the left lower pulmonary lobe. This case emphasizes the risk of late clinical manifestations of cardiac and pulmonary embolism of methylmethacrylate after percutaneous vertebroplasty, suggesting that the risk of such embolism might be underestimated. We propose routine chest radiography, two-dimensional echocardiography, and chest CT after every percutaneous vertebroplasty, to detect asymptomatic cardiac and pulmonary embolism and thereby prevent serious delayed cardiopulmonary failures. PMID- 28573826 TI - Relationship between parental hypertension and cardiometabolic risk factors in adolescents: Methodological issues. PMID- 28573827 TI - Does serious consequential masking exist? An update. PMID- 28573825 TI - Clinimetric properties of the Nociception Coma Scale (-Revised): A systematic review. AB - : The Nociception Coma Scale is a nociception behaviour observation tool, developed specifically for patients with disorders of consciousness (DOC) due to (acquired) brain injury. Over the years, the clinimetric properties of the NCS and its revised version (NCS-R) have been assessed, but no formal summary of these properties has been made. Therefore, we performed a systematic review on the clinimetric properties (i.e. reliability, validity, responsiveness and interpretability) of the NCS(-R). We systematically searched CENTRAL, CINAHL, Embase, PsycInfo and Web of Science until August 2015. Two reviewers independently selected the clinimetric studies and extracted data with a structured form. Included studies were appraised on quality with the COSMIN checklist. Eight studies were found eligible and were appraised with the COSMIN checklist. Although nearly all studies lacked sample size calculation, and were executed by the same group of authors, the methodological quality ranged from fair to excellent. Important aspects of reliability, construct validity and responsiveness have been studied in depth and with sufficient methodological quality. The overview of clinimetric properties in this study shows that the NCS and NCS-R are both valid and useful instruments to assess nociceptive behaviour in DOC patients. The studies provide guidance for the choice in NCS-R cut-off value for possible pain treatment and cautions awareness of interprofessional differences in NCS-R measurements. SIGNIFICANCE: This systematic review provides a structured overview of the clinimetric properties of the Nociception Coma Scale (-Revised) and provides insights for a solid evidence-based nociception behaviour assessment and treatment plan. PMID- 28573828 TI - Social support in chat sessions for adolescents and young adults living with a family member with mental illness. AB - Children from families with a mental illness are at risk of developing negative health outcomes. Online interventions are a new way to offer support to these children. The present study utilized a website that had been developed to support Dutch youth who had a family member with a mental illness. The objective was to analyse monitored and unmonitored chatroom conversations among these young people, and specifically to compare supportive messages and self-disclosures of experiences. We electronically imported session transcripts of 34 chatroom conversations into the qualitative analysis software Atlas.ti. A content analysis was performed on 4252 messages from 22 female participants. A correlational analysis was then conducted to identify significant associations between sent and received supportive statements and disclosing statements. We found supporting comments in approximately 34% of the conversations and disclosures of problems in the home in approximately 15-18% of the messages. Participants made approximately twice as many disclosing statements and approximately half as many supportive statements in the monitored sessions compared to the unmonitored sessions. The number of disclosures that were sent was positively correlated with the amount of social support that was received. The number of disclosures sent was negatively correlated with the amount of social support that was sent, but only in the unmonitored sessions. Considering the greater reach of Internet interventions, online chatroom sessions might be provided as complementary to, or as an alternative to, face-to-face groups for supporting youth with a family member who has a mental illness. PMID- 28573830 TI - Psychophysiological effects of oxytocin on parent-child interactions: A literature review on oxytocin and parent-child interactions. AB - Oxytocin (OT), often called the 'hormone of love' or 'hormone of attachment,' plays a fundamental role in the establishment and quality of parent-infant bonding. However, emerging evidence indicates that OT can also produce antisocial behavior. To clarify these effects, we review studies examining the role of endogenous and exogenous OT on several determinants of attachment: parental sensitivity, and bonding or synchrony in parent-child dyads. Contextual and individual factors moderating the effect of intranasal OT and its peripheral levels are also reviewed. Finally, potential therapeutic applications for OT and current limitations in human OT research are examined. This systematic literature review was based on the Preferred Reporting Items for Systematic reviews and Meta Analyses (PRISMA) guidelines, with two electronic databases and other bibliographic sources. We identified a total of 47 relevant studies for inclusion in our review. Most of the findings are in accordance with recent ideas that OT administration may increase parent-child prosocial interaction, showing that OT exerts beneficial effects on processes thought to promote bonding, sensitivity, and synchrony. However, we found that OT can induce antisocial behavior (e.g., anxiety) or adverse effects (modulation of maternal care recollections) that are moderated by different contextual (e.g., maltreatment level, presence of unfamiliar people) and individual (attachment style) factors. This review reinforces the importance of context- and individual-dependent factors, which must be taken into account when analyzing the psychophysiological effects of OT. PMID- 28573829 TI - Comparative proteomic profiling of the serum differentiates pancreatic cancer from chronic pancreatitis. AB - Finland ranks sixth among the countries having highest incidence rate of pancreatic cancer with mortality roughly equaling incidence. The average age of diagnosis for pancreatic cancer is 69 years in Nordic males, whereas the average age of diagnosis of chronic pancreatitis is 40-50 years, however, many cases overlap in age. By radiology, the evaluation of a pancreatic mass, that is, the differential diagnosis between chronic pancreatitis and pancreatic cancer is often difficult. Preoperative needle biopsies are difficult to obtain and are demanding to interpret. New blood based biomarkers are needed. The accuracy of the only established biomarker for pancreatic cancer, CA 19-9 is rather poor in differentiating between benign and malignant mass of the pancreas. In this study, we have performed mass spectrometry analysis (High Definition MSE ) of serum samples from patients with chronic pancreatitis (13) and pancreatic cancer (22). We have quantified 291 proteins and performed detailed statistical analysis such as principal component analysis, orthogonal partial least square discriminant analysis and receiver operating curve analysis. The proteomic signature of chronic pancreatitis versus pancreatic cancer samples was able to separate the two groups by multiple statistical techniques. Some of the enriched pathways in the proteomic dataset were LXR/RXR activation, complement and coagulation systems and inflammatory response. We propose that multiple high-confidence biomarker candidates in our pilot study including Inter-alpha-trypsin inhibitor heavy chain H2 (Area under the curve, AUC: 0.947), protein AMBP (AUC: 0.951) and prothrombin (AUC: 0.917), which should be further evaluated in larger patient series as potential new biomarkers for differential diagnosis. PMID- 28573832 TI - Effect of Preoperative Low Maximal Flow Rate on Postoperative Voiding Trials after the Midurethral Sling Procedure in Women with Stress Urinary Incontinence. AB - OBJECTIVES: To evaluate the effects of preoperative low maximal flow rate (Qmax) on voiding trials after the midurethral sling (MUS) procedure in women with stress urinary incontinence (SUI). METHODS: One hundred and sixty-eight women who underwent MUS procedure were enrolled. Preoperative free uroflowmetry was performed and patients were divided by Qmax. Low Qmax was defined as a Qmax under 15 mL/sec with voided volume at least 150 mL. Surgical results, failure of voiding trial, and postoperative uroflowmetry parameters were compared between the groups. Failure of voiding trial was defined by a PVR more than 100 mL on postoperative uroflowmetry. RESULTS: At the discharge day, there were 42 cases showing failure of voiding trial and 33 cases requiring CIC, but only one patient showed failure of voiding trial at 12 months postoperatively. Overall, 48 patients had preoperative low Qmax. Low Qmax group showed lower Qmax in all of postoperative uroflowmetry, but there were no significant differences in the rate of postoperative voiding trial failure or CIC. The low Qmax group was then divided into two groups according to the preoperative detrusor pressure at Qmax over and under 20 cmH2 O in pressure flow study. Comparing the two groups, no significant differences were observed in the cure rate, voiding trial failure or CIC. CONCLUSIONS: Our results suggest that women with preoperative low Qmax experienced no definite unfavorable voiding problem from the MUS procedure compared to those with normal voiding function. MUS procedure may be regarded as a safe and successful procedure in SUI women with low Qmax. PMID- 28573831 TI - Auditory and otologic profile of Alstrom syndrome: Comprehensive single center data on 38 patients. AB - Alstrom syndrome (AS) is a rare autosomal recessive ciliopathy caused by mutations in the ALMS1 gene. Hallmark characteristics include childhood onset of severe retinal degeneration, sensorineural hearing loss, obesity, insulin resistant diabetes, and cardiomyopathy. Here we comprehensively characterize the auditory and otologic manifestations in a prospective case series of 38 individuals, aged 1.7-37.9 years, with genetically confirmed AS. Hearing loss was preceded by retinal dystrophy in all cases, and had an average age of detection of 7.45 years (range 1.5-15). Audiometric assessments showed mean pure tone averages (0.5, 1, 2, 4 kHz) of 48.6 and 47.5 dB HL in the right and left ears, respectively. Hearing was within normal limits for only 8/74 ears (11%). For the 66 ears with hearing loss, the degree was mild (12%), moderate (54%), or severe (8%). Type of hearing loss was predominantly sensorineural (77%), while three ears had mixed loss, no ears had conductive loss, and type of hearing loss was indeterminate for the remaining 12 ears. Serial audiograms available for 33 patients showed hearing loss progression of approximately 10-15 dB/decade. Our data show that hearing loss associated with AS begins in childhood and is a predominantly symmetric, sensory hearing loss that may progress to a severe degree. Absent otoacoustic emissions, intact speech discrimination, and disproportionately normal auditory brainstem responses suggest an outer hair cell site of lesion. These findings indicate that individuals with AS would benefit from sound amplification and if necessary, cochlear implantation. PMID- 28573833 TI - Factors affecting dental fluorosis in low socioeconomic status children in Mexico. AB - OBJECTIVE: To assess the association between dental fluorosis and maternal education in schoolchildren of medium and low socioeconomic status in a low income region of Mexico. DESIGN: Cross-sectional study. SETTINGS: Public schools in the south-central region of Oaxaca, Mexico where the mean fluoride water concentration was 1.01 mg/L (SD 0.21; range 0.71-1.40). Fluoridated salt (200mgF/kg) was available in the region. PARTICIPANTS: 794 schoolchildren. METHODS: To identify the socioeconomic status of the participants, the Bronfman index was used. Dental fluorosis was assessed applying the Thysltrup-Fejerskov Index, (TF). RESULTS: The children's mean age was 10.4 (SD1.2) years. The prevalence of dental fluorosis (TF?0) was high 95.7% and 45.2% of the children showed dental fluorosis of TF>=4. The percentage of children showing TF>=4 was 48.8% where their mothers' education was ?6 years of schooling compared to 36.7% among other children (p?0.001). The multinomial logistic regression model using as base outcome category TF<=2 showed that severe forms of fluorosis (TF>=4) were associated with the consumption of boiled water, (OR= 1.65, p=0.039) of fluoridated salt (OR= 2.61 p=0.001), high brushing frequency (OR=3.12, p=0.001) and lower maternal education (OR=1.71, p=0.007). CONCLUSIONS: A high prevalence of dental fluorosis was observed in the study region. An unequal burden of fluorosis in aesthetically objectionable categories was found in children exposed to several sources of fluoride and whose mother had lower educational level. PMID- 28573834 TI - Use of Jamaican Sign language in the provision of dental health care. AB - The United Nations Development Assistance Framework for Jamaica 2012-2016 identifies as an outcome increased access to improved quality health and education services for socially excluded and at risk populations. The Deaf Jamaican population can be categorised as a socially excluded population. The communication barrier resulting from their deafness often leads to difficulties in accessing healthcare. The Faculty of Medical Sciences at The University of the West Indies, Mona Campus, implemented a programme aimed at overcoming this communication barrier and improving direct communication between Deaf patients and health professionals treating them. Competence in Jamaican Sign Language is integrated into the curricula of programmes offered by the faculty and mandated in the dentistry programme, and extends to the clinical training at the dental polyclinic where Deaf patients are seen by student dentists who can communicate with them in Jamaican sign language. This paper outlines the policies and systems employed worldwide for interacting with and treating Deaf patients at dental health care facilities, and focuses on the policies and practices governing the dental care of Deaf patients at the Mona Dental Polyclinic with a view to providing a model for government facilities locally and regionally. Public health competencies: Communication, management. PMID- 28573835 TI - Communities in action: developing a dental ambassador training programme for adults with learning disability. AB - Adults with learning disabilities may be at higher risk of poor oral health. The community outreach programme attached to Plymouth University Peninsula Dental School used established links with local agencies for this group to try out an intervention using service users as dental ambassadors. A programme was developed to meet the needs of the group and training in oral health key messages was provided along with support in presentation skills. Early evaluation shows promise in terms of feasibility, interest and improved self-care. Public health competencies being illustrated: Strategic leadership, communication, teaching and training, and collaborative working for health and oral health improvement. PMID- 28573836 TI - Improving Care for Bariatric Dental Patients in North Wales. AB - This paper presents the experiences of Betsi Cadwaladr University Health Board, North Wales, UK in improving facilities, access and quality of care for bariatric dental patients. It includes the multi-stakeholder audit of existing practice which informed those improvements. Public health competencies illustrated: needs assessment; development and implementation of oral health strategies; oral health improvement; development of clinical pathways; improving patient safety; clinical and public engagement; addressing inequalities. PMID- 28573837 TI - Public health intervention over four decades for the children in the Australian Capital Territory: Have we reached the point of diminishing returns? AB - BACKGROUND: Most of the developed world has seen some substantial improvements in the dental health of children over the past four decades owing to advances in service access, fluoride exposure, socio-economic development and improved diets, with the DMFT score of 12 year-olds dropping from well over 10 down to around one. AIM: To examine the question of advancing dental health for children even further using the same set of tools as we have to date by asking the question: Have we come to a point of diminishing returns? The study examines the long-term, near optimum settings of the known public dental health variables in the Australian Capital Territory. RESULTS: Despite having the most ideal and persistent dental health optimised situation, there remains underlying dental caries at a severity level of just below 1 DMFT (12 year olds), and over the last decade the rate of diminishing incidence and prevalence of decay has slowed and arguably stopped. CONCLUSION: This suggests that rather than toiling to eliminate dental decay completely, the focus might usefully be reoriented towards those small known pockets of society with persistent higher levels of disease and looking for new ways to address these difficult clusters, while simultaneously advancing the understanding that a small residual level of decay will always exist in society. PMID- 28573838 TI - Relationship between mental health risk factors and oral symptoms in adolescents: Korea Youth Risk Behavior Web-based Survey, 2013. AB - OBJECTIVE: To investigate the relationship between mental health risk factors and Korean adolescents' oral health. BASIC RESEARCH DESIGN: Cross-sectional study was based on the 9th Korea Youth Risk Behavior Web-based Survey (2013). PARTICIPANTS: Data were selected for 66,951 adolescents (33,777 males and 33,174 females; aged 13-18 years) out of 72,435 participants were analysed, after excluding cases with missing values. MAIN OUTCOME MEASURES: Oral health (experience of one or more of six oral symptoms), demographic characteristics (seven factors), and mental health risk (five factors). METHOD: Logistic regression analysis determined the effects of mental health risk factors on subjects' oral symptoms after adjustment for general characteristics. RESULTS: The adjusted odds ratio (AOR) was 1.52 (95%CI 1.50,1.54) for sleep satisfaction self-described as "not sufficient at all" and AOR 2.64 (95%CI 2.59,2.69) for those reporting very high stress levels. The AOR was 1.26 times (95%CI 1.24,1.27) higher for those using the internet on weekends for non-study purposes for ?6 hours than those using it for one hour. The AOR for experiencing oral symptoms was 1.44 times (95%CI 1.41,1.47) higher for those who had experienced school violence than for those who had not. CONCLUSIONS: Mental health risk factors were associated with oral symptoms. These results should inform the development of school health policies and comprehensive adolescent health promotion programs in Korea. PMID- 28573839 TI - What proportion of caries into dentine at age 5 is present at age 3? AB - OBJECTIVE: To explore the proportion of decay at age 5 in Wales presenting by and after age 3 years from geographical and deprivation perspectives. BASIC RESEARCH DESIGN: Retrospective analysis of data from independent cross-sectional studies of 3-year-olds in early 2013 and 5-year-olds in school year 2014/5. This includes novel graphical presentation of caries at age 3 and estimated 3-5 caries increment at age 5. SETTING AND PARTICIPANTS: NHS oral health surveillance programme in Wales examining children in nurseries at age 3 and in schools two years later. MAIN OUTCOME MEASURES: %d3mft?0 at ages 3 and 5 years, plus estimated 3-5 caries increments for these two indices. Data are analysed using index of deprivation and Health Board population density (as a proxy for rurality). RESULTS: In most Health Boards and all deprivation quintiles there is a larger proportion of caries into dentine presenting between ages 3-5 than by age 3. In rural Health Boards the proportion of caries present by age 3 is much smaller. In one Health Board more caries presents by age 3 than after. In rural Health Boards the current prevention activity has potential to push reported caries prevalence at age 5 below 10%. In urban Health Boards action by age 5 will be required to push caries prevalence significantly below 20%. CONCLUSIONS: Findings from this analysis suggest need for earlier prevention activity in some Health Boards in Wales. PMID- 28573840 TI - PeP-SCOT a health coaching intervention for people in prisons: the development of the intervention protocol. AB - There is a need for an alternative approach for health promotion prisons since previous work has indicated that health education, while improving health knowledge, does not result in behaviour change. Evidence has suggested that a health coaching assists in this regard. However, the question remained whether this approach would be appropriate and possible in prisons? This paper presents the public health strategies used to work in partnership with prison management to address challenges and accept opportunities as a health coaching intervention protocol was developed for oral health and wellbeing in the prison setting. PMID- 28573841 TI - Productive efficiency and its determinants in the Community Dental Service in the north-west of England. AB - OBJECTIVES: To assess the efficiency of service provision in the Community Dental Services and its determinants in the North-West of England. SETTING AND SAMPLE: 40 Community Dental Services sites operating across the North-West of England. BASIC RESEARCH DESIGN: A data envelopment analysis was undertaken of inputs (number of surgeries, hours worked by dental officers, therapists, hygienists and others) and outputs (treatments delivered, number of courses of treatment and patients seen) of the Community Dental Services to produce relative efficiency ratings by health authority. These were further analyzed in order to identify which inputs (determined within the Community Dental Services) or external factors outside the control of the Community Dental Services are associated with efficiency. MAIN OUTCOME MEASURE: Relative efficiency rankings in Community Dental Services production of dental healthcare. RESULTS: Using the quantity of treatments delivered as the measure of output, on average the Community Dental Services in England is operating at a relative efficiency of 85% (95% confidence interval 77%- 99%) compared to the best performing services. Average efficiency is lower when courses of treatment and unique patients seen are used as output measures, 82% and 68% respectively. Neither the input mix nor the patient case mix explained variations in the efficiency across Community Dental Services. CONCLUSIONS: Although large variations in performance exist across Community Dental Services, the data available was not able to explain these variations. A useful next step would be to undertake detailed case studies of several best and under-performing services to explore the factors that influence relative performance levels. PMID- 28573842 TI - Caries prevalence and treatment needs in young people in Portugal: the third national study. AB - OBJECTIVE: To evaluate caries prevalence and dental treatment needs in Portuguese children and teenagers, as well as fluorosis prevalence in 12-year-old children, in order to address public oral health program strategies. PARTICIPANTS: A representative stratified random cluster sample of 3,710 participants of 6, 12, and 18 years old was selected. A questionnaire was applied to determine sociodemographic data and some oral health determinants. The clinical examination was based on the ICDAS criteria, then adapted to DMFS index, and Dean's index for fluorosis. RESULTS: Caries prevalence at 6, 12, and 18 years old was 45.2%, 47.0%, and 67.6%, respectively. D5MFT scores were 1.18 (SD 0.06) and 2.51 (SD 0.10), respectively. Treatment needs at 12 and 18 years old were associated with 0.37 (SD 0.03) and 0.75 (SD 0.06) values in the "decayed" (D5) variable. SiC index at 12 years old was 2.68 (SD 1.68). Sealants were identified in 55% of 12 year-old children and the mean of sealants per individual was 3.61; also, moderate (2.2%) and severe (0.2%) levels of fluorosis were detected. CONCLUSIONS: The oral health situation in Portugal is favorable for young people, resulting in low treatment needs. The National Oral Health Promotion Program should be extended to include 18-year-olds. PMID- 28573843 TI - Socio-demographic and area-related factors associated with the prevalence of caries among preschool children in Greece. AB - OBJECTIVE: To assess dental caries experience in 4-6 year old children of the Athens Metropolitan Area attending public kindergartens and investigate the association of area deprivation and immigration status on dmft. BASIC RESEARCH DESIGN: A cross-sectional study of a large area-stratified sample of 683 kindergarten children was conducted during the academic years 2009-2011. Dental caries experience and oral hygiene level were assessed using dmft and the Simplified Debris index (DI-s). Area deprivation was defined using a pre established Geo-demographic System for Attica. Zero-inflated Poisson regression models were used to test associations between the dmft index and related factors; gender, age, immigrant background and area deprivation. Differences were reported in terms of predicted probabilities. RESULTS: Caries prevalence was 20.8% (95% CI17.8,24.0%). The mean dmft and DI-s scores were 0.67 (95% CI0.61,0.74) and 0.16 (95% CI0.14,0.18) respectively. The mean predicted probability of having no detectable caries experience was 79% (95% CI75, 83%), while the probability of having dmft=1 or 2 was 6% (95% CI5,8%) and 2% (95% CI1,3%) respectively. The predicted probability of having no caries experience was substantially lower for males, those from the least affluent areas and non-Greeks by 5%, 18% and 31% respectively. Regarding dmft scores, deprived children were more likely to have 1 or 2 teeth with caries experience by 9% (95% CI4,13%) and 6% (95% CI2,10%) respectively, while the corresponding differences for non-Greeks were 10% (95% CI7,14%) and 12% (95% CI7,15%). CONCLUSIONS: Socio-demographic and area-related variations in oral health exist among kindergarten children in Athens. PMID- 28573844 TI - Dental caries experience, rather than toothbrushing, influences the incidence of dental caries in young Japanese adults. AB - : A dose-response relationship between toothbrushing frequency and the incidence of dental caries has not been confirmed. Furthermore, no longitudinal study about this relationship has considered dental caries experience at baseline, which is an important factor influencing the frequency of future caries. OBJECTIVE: To elucidate the association between the incidence of dental caries and toothbrushing frequency after adjusting for dental caries experience at baseline in a Japanese population. BASIC RESEARCH DESIGN: The 92 recruits of the Japan Maritime Self-Defense Force in Kure, Japan, in 2011 were followed up for 3 years. They underwent oral examination at the annual checkups and answered questions about toothbrushing frequency. MAIN OUTCOME MEASURES: The multiple logistic regression analysis was used to analyze the incidence of dental caries and to identify independent effects of toothbrushing frequency and dental caries experience at baseline. Furthermore, the relative importance of the incidence of dental caries was investigated among other independent variables using the partial adjusted R2 score. RESULTS: Logistic regression analysis showed that toothbrushing frequency alone did not influence the increment in decayed, missing, and filled teeth (DMFT). However, DMFT at baseline alone was associated with the increment in DMFT (crude odds ratio, OR, 1.20, 95% confidence interval, CI, 1.08,1.33). In the fully adjusted model, only DMFT at baseline was associated with the increment in DMFT (adjusted OR 1.23, 95%CI 1.09,1.38). CONCLUSION: After three years, the incidence of dental caries in young adult Japanese males was influenced by DMFT at baseline, rather than toothbrushing frequency. PMID- 28573846 TI - Simultaneous Fluorescence and Chemiluminescence Turned on by Aggregation-Induced Emission for Real-Time Monitoring of Endogenous Superoxide Anion in Live Cells. AB - Biological sensors with simultaneous turn-on signals of fluorescence (FL) and chemiluminescence (CL) triggered by one single species are supposed to integrate spatiotemporally resolved FL imaging with dynamic CL sensing into one luminescent assay. Efficiently increased accuracy can be expected based on complementary information simultaneously obtained from two independent modes, which is crucial in disease detection and diagnosis. However, very few examples can be found to date because of the key challenges in the rational design of sensing structures. Herein, aggregation-induced emission (AIE) was employed to develop a novel organic platform TPE-CLA with simultaneous turn-on FL/CL signals specifically modulated by O2*- in cells, which can be attributed to the activation of AIE resulted from the decreasing solubility after recognition. Using imidazopyrazinone (CLA) as the reactive motif and tetraphenylethene (TPE) as FL/CL enhancing skeleton, TPE-CLA is sensitive enough to image native O2*- in Raw264.7 cells and lipopolysaccharide stimulated O2*- in mice. Endogenous O2*- in HL-7702 cells induced by acetaminophen (APAP) was uninterruptedly monitored for 7200 s with CL and the results were further confirmed by FL imaging. Accordingly, TPE-CLA turns out to be a reliable candidate for real-time and continuous monitoring of endogenous O2*- in live cells. The strategy utilizing AIE to accomplish the FL/CL dual detection is expected to extend the application of AIE as reaction-activated biosensors. PMID- 28573845 TI - Ethnic Disparities in Oral Health Related Quality of Life among Adults in London, England. AB - OBJECTIVE: To explore ethnic disparities in oral health related quality of life (OHQoL) among adults, and the role that socioeconomic factors play in that association. RESEARCH DESIGN: Data from 705 adults from a socially deprived, ethnically diverse metropolitan area of London (England) were analysed for this study. Ethnicity was self-assigned based on the 2001 UK Census categories. OHQoL was measured using the Oral Health Impact Profile (OHIP-14), which provides information on the prevalence, extent and intensity of oral impacts on quality of life in the previous 12 months. Ethnic disparities were assessed in logistic regression models for prevalence of oral impacts and negative binomial regression models for extent and intensity of oral impacts. RESULTS: The prevalence of oral impacts was 12.7% (95% CI: 10.2-15.1) and the mean OHIP-14 extent and severity scores were 0.27 (95% CI: 0.20-0.34) and 4.19 (95% CI: 3.74-4.64), respectively. Black adults showed greater and Asian adults lower prevalence, extent and severity of oral impacts than White adults. However, significant differences were only found for the extent of oral impacts; Black adults reporting more and Asian adults fewer OHIP-14 items affected than their White counterparts. After adjustments for socioeconomic factors, Asian adults had significantly fewer OHIP 14 items affected than White adults (rate ratio: 0.28; 95%CI: 0.08-0.94). CONCLUSION: This study found disparities in OHQoL between the three main ethnic groups in South East London. Asian adults had better and Black adults had similar OHQoL than White adults after accounting for demographic and social factors. PMID- 28573847 TI - Nickel Sequestration by the Host-Defense Protein Human Calprotectin. AB - The human innate immune protein calprotectin (CP, S100A8/S100A9 oligomer, calgranulin A/calgranulin B oligomer, MRP-8/MRP-14 oligomer) chelates a number of first-row transition metals, including Mn(II), Fe(II), and Zn(II), and can withhold these essential nutrients from microbes. Here we elucidate the Ni(II) coordination chemistry of human CP. We present a 2.6-A crystal structure of Ni(II)- and Ca(II)-bound CP, which reveals that CP binds Ni(II) ions at both its transition-metal-binding sites: the His3Asp motif (site 1) and the His6 motif (site 2). Further biochemical studies establish that coordination of Ni(II) at the hexahistidine site is thermodynamically preferred over Zn(II). We also demonstrate that CP can sequester Ni(II) from two human pathogens, Staphylococcus aureus and Klebsiella pneumoniae, that utilize this metal nutrient during infection, and inhibit the activity of the Ni(II)-dependent enzyme urease in bacterial cultures. In total, our findings expand the biological coordination chemistry of Ni(II)-chelating proteins in nature and provide a foundation for evaluating putative roles of CP in Ni(II) homeostasis at the host-microbe interface and beyond. PMID- 28573849 TI - Mass-Producible 2D-MoS2-Impregnated Screen-Printed Electrodes That Demonstrate Efficient Electrocatalysis toward the Oxygen Reduction Reaction. AB - Two-dimensional molybdenum disulfide (2D-MoS2) screen-printed electrodes (2D-MoS2 SPEs) have been designed, fabricated, and evaluated toward the electrochemical oxygen reduction reaction (ORR) within acidic aqueous media. A screen-printable ink has been developed that allows for the tailoring of the 2D-MoS2 content/mass used in the fabrication of the 2D-MoS2-SPEs, which critically affects the observed ORR performance. In comparison to the graphite SPEs (G-SPEs), the 2D MoS2-SPEs are shown to exhibit an electrocatalytic behavior toward the ORR which is found, critically, to be reliant upon the percentage mass incorporation of 2D MoS2 in the 2D-MoS2-SPEs; a greater percentage mass of 2D-MoS2 incorporated into the 2D-MoS2-SPEs results in a significantly less electronegative ORR onset potential and a greater signal output (current density). Using optimally fabricated 2D-MoS2-SPEs, an ORR onset and a peak current of approximately +0.16 V [vs saturated calomel electrode (SCE)] and -1.62 mA cm-2, respectively, are observed, which exceeds the -0.53 V (vs SCE) and -635 MUA cm-2 performance of unmodified G-SPEs, indicating an electrocatalytic response toward the ORR utilizing the 2D-MoS2-SPEs. An investigation of the underlying electrochemical reaction mechanism of the ORR within acidic aqueous solutions reveals that the reaction proceeds via a direct four-electron process for all of the 2D-MoS2-SPE variants studied herein, where oxygen is electrochemically favorably reduced to water. The fabricated 2D-MoS2-SPEs are found to exhibit no degradation in the observed achievable current over the course of 1000 repeat scans. The production of such inks and the resultant mass-producible 2D-MoS2-SPEs mitigates the need to modify post hoc an electrode via the drop-casting technique that has been previously shown to result in a loss of achievable current over the course of 1000 repeat scans. The 2D-MoS2-SPEs designed, fabricated, and tested herein could have commercial viability as electrocatalytic fuel cell electrodes because of being economical as a result of their scales of economy and inherent tailorability. The technique utilized herein to produce the 2D-MoS2-SPEs could be adapted for the incorporation of different 2D nanomaterials, resulting in SPEs with the inherent advantages identified above. PMID- 28573848 TI - Polyphenols from Lonicera caerulea L. Berry Inhibit LPS-Induced Inflammation through Dual Modulation of Inflammatory and Antioxidant Mediators. AB - Lonicera caerulea L. berry polyphenols (LCBP) are considered as major components for bioactivity. This study aimed to clarify the molecular mechanisms by monitoring inflammatory and antioxidant mediator actions in lipopolysaccharide (LPS)-induced mouse paw edema and macrophage cell model. LCBP significantly attenuated LPS-induced paw edema (3.0 +/- 0.1 to 2.8 +/- 0.1 mm, P < 0.05) and reduced (P < 0.05) serum levels of monocyte chemotactic protein-1 (MCP-1, 100.9 +/- 2.3 to 58.3 +/- 14.5 ng/mL), interleukin (IL)-10 (1596.1 +/- 424.3 to 709.7 +/- 65.7 pg/mL), macrophage inflammatory protein (MIP)-1alpha (1761.9 +/- 208.3 to 1369.1 +/- 56.4 pg/mL), IL-6 (1262.8 +/- 71.7 to 499.0 +/- 67.1 pg/mL), IL-4 (93.3 +/- 25.7 to 50.7 +/- 12.5 pg/mL), IL-12(p-70) (580.4 +/- 132.0 to 315.2 +/- 35.1 pg/mL), and tumor necrosis factor-alpha (TNF-alpha, 2045.5 +/- 264.9 to 1270.7 +/- 158.6 pg/mL). Cell signaling analysis revealed that LCBP inhibited transforming growth factor beta activated kinase-1 (TAK1)-mediated mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) pathways, and enhanced the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and manganese-dependent superoxide dismutase (MnSOD) in earlier response. Moreover, cyanidin 3-glucoside (C3G) and (-)-epicatechin (EC), two major components of LCBP, directly bound to TAK1. These data demonstrated that LCBP might inhibit LPS-induced inflammation by modulating both inflammatory and antioxidant mediators. PMID- 28573850 TI - Toward an Understanding of Thin-Film Transistor Performance in Solution-Processed Amorphous Zinc Tin Oxide (ZTO) Thin Films. AB - Amorphous zinc tin oxide (ZTO) thin films are accessible by a molecular precursor approach using mononuclear zinc(II) and tin(II) compounds with methoxyiminopropionic acid ligands. Solution processing of two precursor solutions containing a mixture of zinc and tin(II)-methoxyiminopropinato complexes results in the formation of smooth homogeneous thin films, which upon calcination are converted into the desired semiconducting amorphous ZTO thin films. ZTO films integrated within a field-effect transistor (FET) device exhibit an active semiconducting behavior in the temperature range between 250 and 400 degrees C, giving an increased performance, with mobility values between MU = 0.03 and 5.5 cm2/V s, with on/off ratios increasing from 105 to 108 when going from 250 to 400 degrees C. Herein, our main emphasis, however, was on an improved understanding of the material transformation pathway from weak to high performance of the semiconductor in a solution-processed FET as a function of the processing temperature. We have correlated this with the chemical composition and defects states within the microstructure of the obtained ZTO thin film via photoelectron spectroscopy (X-ray photoelectron spectroscopy, ultraviolet photoelectron spectroscopy), Auger electron spectroscopy, electron paramagnetic resonance spectroscopy, atomic force microscopy, and photoluminescence investigations. The critical factor observed for the improved performance within this ZTO material could be attributed to a higher tin concentration, wherein the contributions of point defects arising from the tin oxide within the final amorphous ZTO material play the dominant role in governing the transistor performance. PMID- 28573851 TI - Screening of Lipases with Unusual High Activity in the sn-2 Esterification of 1,3 Dicaprin under Mild Operating Conditions. AB - In this work, the synthesis of acylglycerides with high nutritional value was carried out by enzymatic esterification at sn-2 position of 1,3-dicaprin with palmitic acid. A comparative study of the performance of several biocatalysts according to the obtained products was carried out. The results obtained with several of the biocatalysts evaluated are very interesting, and it would be possible to use them to obtain a mixture of acylglycerides to act as a fat substitute. The final product was composed of about 90% of nutritionally attractive glycerides. These glycerides were medium-chain length triglycerides, medium-long chain triglycerides (mainly triglycerides with medium chain fatty acids at sn-1 and sn-3 positions and long chain fatty acid at sn-2 position), and 1,3-diglycerides. Pseudomonas fluorescens lipase and Burkholderia cepacia lipase immobilized on chitosan demonstrated unusual high activity in the sn-2 esterification of 1,3-dicaprin with palmitic acid at 45 degrees C and 12 h with 33% yield to 1,3-dicaproyl-2-palmitoyl glycerol. Burkholderia cepacia lipase has the advantage of being immobilized; however, BCL/chitosan has the advantages of being immobilized and therefore its easy recovery from the reaction media. PMID- 28573852 TI - Improving the Catalytic Performance of a Talaromyces leycettanus alpha-Amylase by Changing the Linker Length. AB - A novel alpha-amylase, Amy13A, that consists of these domains was identified in Talaromyces leycettanus JCM12802: catalytic TIM-barrel fold, domain B, domain C, Thr/Ser-rich linker region, and C-terminal CBM20 domain. The wild type and three mutant enzymes were then expressed in Pichia pastoris GS115 to identify the roles of linker length (Amy13A21 and Amy13A33) and CBM20 (Amy13A-CBM) in catalysis. All enzymes had similar enzymatic properties, exhibiting optimal activities at pH 4.5 5.0 and 55-60 degrees C, but varied in catalytic performance. When using soluble starch as the substrate, Amy13A21 and Amy13A33 showed specific activities (926.3 and 537.8 units/mg, respectively, vs 252.1 units/mg) and catalytic efficiencies (kcat/Km, 25.7 and 22.0 mL s-1 mg-1, respectively, vs 15.4 mL s-1 mg-1) higher than those of the wild type, while Amy13A-CBM performed worse during catalysis. This study reveals the key roles of the CBM and linker length in the catalysis of GH13 alpha-amylase. PMID- 28573853 TI - Carbon Nanoparticle Hybrid Aerogels: 3D Double-Interconnected Network Porous Microstructure, Thermoelectric, and Solvent-Removal Functions. AB - We report reduced graphene oxide (rGO)/single-walled carbon nanotube (SWCNT) hybrid aerogels with enhanced thermoelectric (TE) performance and removal of organic solvents by designing 3D double-interconnected network porous microstructures. A convenient, cost-effective, and scalable preparation procedure is proposed compared with conventional high-temperature pyrolysis and supercritical drying techniques. The obtained hybrid aerogels are systematically characterized by apparent density, scanning electron microscopy, X-ray photoemission spectroscopy, Raman spectroscopy, and porosity. An enhanced TE performance of ZT ~ ~8.03 * 10-3 has been achieved due to the 3D double interconnected network porous microstructure, the energy-filtering effect, and the phonon scattering at the abundant interfaces and joints. In addition, upon a large axial compression deformation, a high degree of retention of the Seebeck coefficient and a simultaneously significant enhancement of the electrical conductivity are observed. Finally, the hybrid aerogels display high capability for the removal of diverse organic solvents and good recyclability. These findings open a new avenue for exploiting aerogels with multifunctions and widening the applications of TE materials by judicious microstructure design. PMID- 28573854 TI - Size-Dependent Immunochromatographic Assay with Quantum Dot Nanobeads for Sensitive and Quantitative Detection of Ochratoxin A in Corn. AB - Fluorescent microspheres are a novel luminescent nanomaterial proposed as an alternative probe to improve the detection sensitivity of competitive immunochromatographic assay (ICA). Quantum dot nanobeads (QBs) possess strong luminescence and resistance to matrix interference. Theoretically, large-sized QBs exhibit stronger luminescent intensity than small-sized QBs and are beneficial to ICA sensitivity. However, oversized QBs may reduce the sensitivity of competitive ICA. Thus, the relationship between the size and luminescent intensity of QBs and the competitive ICA sensitivity must be elucidated. In this study, QBs of different sizes (58, 124, 255, 365, and 598 nm) were synthesized. Ochratoxin A (OTA) was selected as the model analyte for competitive ICA. The effects of QB size on the detection performance of competitive ICA were then evaluated. The cutoff limit of QB-ICA for naked eye detection was used for qualitative analysis, and the half-maximal inhibitory concentration (IC50) and LOD were employed for quantitative analysis. Results indicated that 124 nm QBs used as labeling probes for competitive ICA showed the optimal detection performance and the lowest cutoff value of 5 ng/mL for qualitative detection and IC50 (0.39 ng/mL) for quantitative detection. Similar to commercial ELISA, QB124 ICA displayed good accuracy, specificity, reproducibility, and practicability. In summary, 124 nm QBs can be used as a new labeling probe for competitive ICA. PMID- 28573855 TI - Nucleic Acid Amplification-Free Bioluminescent Detection of MicroRNAs with High Sensitivity and Accuracy Based on Controlled Target Degradation. AB - Accurate and sensitive detection of microRNAs is crucial to clinical diagnosis and therapy. Most of microRNA assays require target conversion in combination with nucleic acid amplification to improve the detection sensitivity, which may compromise the assay accuracy and specificity. Herein we report a sensitive bioluminescent method for microRNA assay on the basis of controlled target degradation without target conversion and nucleic acid amplification. In this assay, the target microRNA can be specifically degraded by exonuclease III after hybridization to its complementary probe, releasing adenosine monophosphate (AMP) from microRNA itself. The AMP then triggers an efficient bioluminescence generation system to produce a strong bioluminescence signal. This assay is highly sensitive with zero-background signal and a detection limit of 7.6 fM even without target amplification, and it can discriminate the single-nucleotide difference among microRNA family members with extremely high discrimination ratio. With the assistance of magnetic separation to eliminate the interference of endogenous ATP, ADP, and AMP in sample matrix, this assay can be further applied to absolute quantification of microRNAs in cancer cells and tissues from lung cancer patients, holding great potential in biomedical research and clinical diagnosis. PMID- 28573856 TI - Characterization of Aroma-Active Compounds in Italian Tomatoes with Emphasis on New Odorants. AB - An aroma distillate was prepared by solvent extraction and subsequent SAFE distillation from Italian vine-ripe tomatoes eliciting an intense overall aroma. Application of gc/olfactometry and the aroma extract dilution analysis revealed 44 odor-active compounds, 42 of which could be identified. The highest odor activity value of 2048 was established for the green, grassy (Z)-3-hexenal, the metallic smelling trans-4,5-epoxy-(E)-2-decenal, the potato-like 3 (methylthio)propanal, and the caramel-like 4-hydroxy-2,5-dimethyl-3(2H)-furanone. Of the further odorants, 13 compounds have previously not been reported as tomato odorants. Although most of these showed lower FD-factors, in particular, the coconut/dill-like smelling wine lactone ((3S,3aS,7aR)-3a,4,5,7a-tetrahydro-3,6 dimethylbenzofuran-2(3H)-one) appeared with a quite high FD factor. In addition, a fruity, almond-like odorant (6) with an FD factor of 1024 was detected. By application of high resolution mass spectrometry and polarity considerations, the structure of a methyl-2-ethoxytetrahydropyran isomer was suggested for 6. Four of the five possible isomers, the 3-methyl-, 4-methyl-, 5-methyl-, and 6-methyl-2 ethoxytetrahydropyran were synthesized and showed similar mass spectrometric patterns. However, these were excluded by their different retention indices. Although the synthesis of the remaining 2-methyl-2-ethoxytetrahydropyran resulted in only small yields, which were not sufficient for NMR measurements, this structure is very likely for 6. This compound was never reported as a food constituent before. Finally, quantitation of 23 odorants by stable isotope dilution assays allowed for the preparation of an aroma recombinate resembling the overall aroma of the tomatoes. PMID- 28573857 TI - Correction to "Asymmetric Total Synthesis and Revised Structure of Cephalezomine H". PMID- 28573858 TI - proBAMconvert: A Conversion Tool for proBAM/proBed. AB - The introduction of new standard formats, proBAM and proBed, improves the integration of genomics and proteomics information, thus aiding proteogenomics applications. These novel formats enable peptide spectrum matches (PSM) to be stored, inspected, and analyzed within the context of the genome. However, an easy-to-use and transparent tool to convert mass spectrometry identification files to these new formats is indispensable. proBAMconvert enables the conversion of common identification file formats (mzIdentML, mzTab, and pepXML) to proBAM/proBed using an intuitive interface. Furthermore, ProBAMconvert enables information to be output both at the PSM and peptide levels and has a command line interface next to the graphical user interface. Detailed documentation and a completely worked-out tutorial is available at http://probam.biobix.be . PMID- 28573860 TI - Enantioselective Iridium-Catalyzed Allylic Cyclizations. AB - A method for the enantioselective synthesis of carbo- and heterocyclic ring systems enabled through the combination of Lewis acid activation and iridium catalyzed allylic substitution is described. The reaction proceeds with branched, allylic alcohols and carbon nucleophiles as well as heteronucleophiles to give a diverse set of ring systems in good yields and with high enantioselectivities. The utility of the method is highlighted by the asymmetric syntheses of erythrococcamides A and B. PMID- 28573859 TI - Simple and Reliable Lift-Off Patterning Approach for Graphene and Graphene-Ag Nanowire Hybrid Films. AB - We present a simple, ultrasonic vibration-assisted lift-off-based patterning approach for graphene and graphene-Ag nanowire (NW) hybrid films. A 20 MUm width pattern with uniform and smooth pattern edges was neatly defined on various rigid and flexible substrates. The patterned graphene-Ag NW electrodes showed a low sheet resistance of 19 Omega/sq with a high transmittance of 93% at 550 nm, a robust stability against oxidation, and a high reliability under a bending test. The electrodes also exhibited markedly higher performance than that of commercial fluorine-doped tin oxide electrodes for dye-sensitized solar cells. Given its low cost, high throughput, and nondamaging effect, this simple and reliable patterning approach stimulates the practical applications of graphene-based flexible transparent electrodes in soft electronic and optoelectronic devices. PMID- 28573861 TI - Safety Assessment of Food and Feed from GM Crops in Europe: Evaluating EFSA's Alternative Framework for the Rat 90-day Feeding Study. AB - Regulatory-compliant rodent subchronic feeding studies are compulsory regardless of a hypothesis to test, according to recent EU legislation for the safety assessment of whole food/feed produced from genetically modified (GM) crops containing a single genetic transformation event (European Union Commission Implementing Regulation No. 503/2013). The Implementing Regulation refers to guidelines set forth by the European Food Safety Authority (EFSA) for the design, conduct, and analysis of rodent subchronic feeding studies. The set of EFSA recommendations was rigorously applied to a 90-day feeding study in Sprague Dawley rats. After study completion, the appropriateness and applicability of these recommendations were assessed using a battery of statistical analysis approaches including both retrospective and prospective statistical power analyses as well as variance-covariance decomposition. In the interest of animal welfare considerations, alternative experimental designs were investigated and evaluated in the context of informing the health risk assessment of food/feed from GM crops. PMID- 28573864 TI - Spiroannulation of Oxindoles via Aryne and Alkyne Incorporation: Substituent Diverted, Transition-Metal-Free, One-Pot Access to Spirooxindoles. AB - A "product control via substrate design" strategy has been conceptualized and implemented to harness the potential of aryne and activated alkyne insertions into oxindoles to readily and efficiently furnish pharmacophoric indano- and cyclopentannulated spirooxindole scaffolds in an operationally straightforward, one-pot, transition-metal-free protocol. PMID- 28573862 TI - Fluorinated Amine Stereotriads via Allene Amination. AB - The incorporation of fluorine into organic scaffolds often improves the bioactivity of pharmaceutically relevant compounds. C-F/C-N/C-O stereotriad motifs are prevalent in antivirals, neuraminidase inhibitors, and modulators of androgen receptors, but are challenging to install. An oxidative allene amination strategy using Selectfluor rapidly delivers triply functionalized triads of the form C-F/C-N/C-O, exhibiting good scope and diastereoselectivity for all syn products. The resulting stereotriads are readily transformed into fluorinated pyrrolidines and protected alpha-, beta-, and gamma-amino acids. PMID- 28573865 TI - Intrinsic Bond Energies from a Bonds-in-Molecules Neural Network. AB - Neural networks are being used to make new types of empirical chemical models as inexpensive as force fields, but with accuracy similar to the ab initio methods used to build them. In this work, we present a neural network that predicts the energies of molecules as a sum of intrinsic bond energies. The network learns the total energies of the popular GDB9 database to a competitive MAE of 0.94 kcal/mol on molecules outside of its training set, is naturally linearly scaling, and applicable to molecules consisting of thousands of bonds. More importantly, it gives chemical insight into the relative strengths of bonds as a function of their molecular environment, despite only being trained on total energy information. We show that the network makes predictions of relative bond strengths in good agreement with measured trends and human predictions. A Bonds in-Molecules Neural Network (BIM-NN) learns heuristic relative bond strengths like expert synthetic chemists, and compares well with ab initio bond order measures such as NBO analysis. PMID- 28573863 TI - CD38 as a PET Imaging Target in Lung Cancer. AB - Daratumumab (Darzalex, Janssen Biotech) is a clinically approved antibody targeting CD38 for the treatment of multiple myeloma. However, CD38 is also expressed by other cancer cell types, including lung cancer, where its expression or absence may offer prognostic value. We therefore developed a PET tracer based upon daratumumab for tracking CD38 expression, utilizing murine models of non small cell lung cancer to verify its specificity. Daratumumab was prepared for radiolabeling with 89Zr (t1/2 = 78.4 h) through conjugation with desferrioxamine (Df). Western blot, flow cytometry, and saturation binding assays were utilized to characterize CD38 expression and binding of daratumumab to three non-small cell lung cancer cell lines: A549, H460, and H358. Murine xenograft models of the cell lines were also generated for further in vivo studies. Longitudinal PET imaging was performed following injection of 89Zr-Df-daratumumab out to 120 h postinjection, and nonspecific uptake was also evaluated through the injection of a radiolabeled control IgG antibody in A549 mice, 89Zr-Df-IgG. Ex vivo biodistribution and histological analyses were also performed after the terminal imaging time point at 120 h postinjection. Through cellular studies, A549 cells were found to express higher levels of CD38 than the H460 or H358 cell lines. PET imaging and ex vivo biodistribution studies verified in vitro trends, with A549 tumor uptake peaking at 8.1 +/- 1.2%ID/g at 120 h postinjection according to PET analysis, and H460 and H358 at lower levels at the same time point (6.7 +/- 0.7%ID/g and 5.1 +/- 0.4%ID/g, respectively; n = 3 or 4). Injection of a nonspecific radiolabeled IgG into A549 tumor-bearing mice also demonstrated lower tracer uptake of 4.4 +/- 1.3%ID/g at 120 h. Immunofluorescent staining of tumor tissues showed higher staining levels present in A549 tissues over H460 and H358. Thus, 89Zr-Df-daratumumab is able to image CD38-expressing tissues in vivo using PET, as verified through the exploration of non-small cell lung cancer models in this study. This agent therefore holds potential to image CD38 in other malignancies and aid in patient stratification and elucidation of the biodistribution of CD38. PMID- 28573866 TI - Mid-infrared Laser-Induced Fluorescence with Nanosecond Time Resolution Using a Superconducting Nanowire Single-Photon Detector: New Technology for Molecular Science. AB - In contrast to UV photomultiplier tubes that are widely used in physical chemistry, mid-infrared detectors are notorious for poor sensitivity and slow time response. This helps explain why, despite the importance of infrared spectroscopy in molecular science, mid-infrared fluorescence is not more widely used. In recent years, several new technologies have been developed that open new experimental possibilities for research in the mid-infrared. In this Account, we present one of the more promising technologies, superconducting nanowire single photon detectors (SNSPDs) by sharing our experience with its use in a typical experiment carried out by physical chemists (laser-induced fluorescence) and comparing the SNSPD to a detector commonly used by physical chemists (InSb at LN Temperature). SNSPDs are fabricated from a thin film of superconducting metal, patterned into a meandering nanowire. The nanowire is cooled below its superconducting temperature, Tc, and held in a constant current circuit below the critical current necessary to destroy superconductivity, Ic. Upon absorption of a photon, the resulting heat is sufficient to destroy superconductivity across the entire width of the nanowire, an event that can be detected as a voltage pulse. In contrast to semiconductor-based detectors, which have a long wavelength cutoff determined by the band gap, the SNSPD exhibits single-photon sensitivity across the entire mid-IR spectrum. As these devices have not been used extensively outside the field of light detection technology research, one important goal of this Account is to provide practical details for the implementation of these devices in a physical chemistry laboratory. We provide extensive Supporting Information describing what is needed. This includes information on a liquid nitrogen cooled monochromator, the optical collection system including mid infrared fibers, as well as a closed-cycle cryogenic cooler that reaches 0.3 K. We demonstrate the advantages of these detectors in a time-resolved laser-induced infrared fluorescence experiment on the energy pooling in crystalline CO overlayers formed on a NaCl(100) surface. We present dispersed fluorescence spectra recorded from 1.9 to 7.0 MUm obtained by single-photon counting. We also estimate the sensitivity of this WSi-based detection system at 3 MUm; the system's noise equivalent power (NEP) value is ~10-3 of a conventional InSb photovoltaic device. Straightforward modifications are expected to provide another 100 000-fold improvement. We demonstrate that the temporal resolution of the experiment is limited only by the pulse duration of the laser used in this work (fwhm = 3.7 ns). The use of SNSPDs enables dramatically improved observations of energy pooling in cryogenic molecular crystals. PMID- 28573867 TI - DNA-Carbon Nanotube Complexation Affinity and Photoluminescence Modulation Are Independent. AB - Short single-stranded DNA (ssDNA) has emerged as the natural polymer of choice for noncovalently functionalizing photoluminescent single-walled carbon nanotubes. In addition, specific empirically identified DNA sequences can be used to separate single species (chiralities) of nanotubes, with an exceptionally high purity. Currently, only limited general principles exist for designing DNA nanotube hybrids amenable to separation processes, due in part to an incomplete understanding of the fundamental interactions between a DNA sequence and a specific nanotube structure, whereas even less is known in the design of nanotube based sensors with determined optical properties. We therefore developed a combined experimental and analysis platform on the basis of time-resolved near infrared fluorescence spectroscopy to extract the complete set of photoluminescence parameters that characterizes DNA-nanotube hybrids. Here, we systematically investigated the affinity of the d(GT)n oligonucleotide family for structurally defined carbon nanotubes by measuring photoluminescence response of the nanotube upon oligonucleotide displacement. We found, surprisingly, that the rate of displacement of the oligonucleotides is independent of the coverage on the nanotube, as inferred through the intrinsic optical properties of the hybrid. The kinetics of intensity modulation is essentially a single-exponential, and the time constants, which quantify the stability of DNA binding, span an order of magnitude. Surprisingly, these time constants do not depend on the intrinsic optical parameters within the hybrids, suggesting that the DNA-nanotube stability is not due to increased nanotube surface coverage by DNA. Further, a principal component analysis of the excitation and emission shifts along with intensity enhancement at equilibrium accurately identified the (8,6) nanotube as the partner chirality to (GT)6 ssDNA. When combined, the chirality-resolved equilibrium and kinetics data can guide the development of the DNA-nanotube pairs, with tunable stability and optical modulation. Additionally, this high throughput optical platform could function as a primary screen for mapping the DNA-chirality recognition phase space. PMID- 28573868 TI - Interdisciplinary Approach to Increasing Skin-to-Skin Contact Across Delivery Methods. PMID- 28573869 TI - Obiltoxaximab: Adding to the Treatment Arsenal for Bacillus anthracis Infection. AB - OBJECTIVE: To review the safety and efficacy of obiltoxaximab, a monoclonal antibody indicated for the treatment of Bacillus anthracis inhalational anthrax in adult and pediatric patients. DATA SOURCES: A MEDLINE (1946 to May, week 1, 2017) and EMBASE (1980 to 2017, week 19) search was performed using the search terms obiltoxaximab OR ETI-204 OR Anthim AND anthrax. STUDY SELECTION AND DATA EXTRACTION: All English-language clinical studies in both animal and human models assessing the safety and efficacy of obiltoxaximab were included. DATA SYNTHESIS: A total of 5 articles have been published on clinical studies examining safety and efficacy of obiltoxaximab. Efficacy studies in 2 animal models, New Zealand White rabbits and cynomolgus macaques, showed higher rates of survival post anthrax exposure when obiltoxaximab was administered. Safety studies in healthy human volunteers showed that it was tolerated, with a relatively low incidence of adverse events. CONCLUSION: Based on these clinical studies and the implausibility of conducting a trial in infected individuals, obiltoxaximab is a safe and efficacious addition to the anthrax antitoxin armamentarium to protect against and treat inhalational anthrax. PMID- 28573871 TI - The Importance of Inclusion for Cardiovascular Health Promotion Programs in Delaware. AB - Individuals with disabilities experience greater rates of cardiovascular disease than individuals without disabilities. This increase can be attributed to decreased levels of physical activity, poor eating habits, and increased levels of diabetes, smoking, and obesity. Individuals with disabilities are often excluded from surveillance, treatment, and prevention efforts. Consequently, there is little known about their participation rates in health promotion and disease prevention programs. The aims of this investigation are (1) to examine time trends in cardiovascular disease and risk factors over a 10-year period by disability status and (2) to assess the inclusiveness of health promotion programs in Delaware. The percentage of individuals with disabilities increased from 18% in 2001 to 28% in 2011. Individuals with disabilities had higher rates of cardiovascular disease (t = 80.45; degrees of freedom [df] = 198; p < .0001) and obesity (body mass index > 30 kg/m2) than individuals without disabilities (t = 33.0; df = 198; p < .0001). They also reported less physical activity (t = 44.21; df = 198; p < .0001) and worse diet quality (t = 4.70; df = 198; p < .0001). There was a consistent lack of information about inclusion and participation of individuals with disabilities in health promotion programs. Making adaptations within cardiovascular disease prevention programs in Delaware is imperative to improving the health of individuals with disabilities. Ensuring cardiovascular disease programs are accessible and provide disability-specific trained staff will reduce barriers to participation so that all individuals can benefit. PMID- 28573870 TI - Sleep and physical activity: a survey of people with inflammatory arthritis and their engagement by health professionals in rheumatology in Ireland. AB - PURPOSE: Sleep is important in maintaining the body's circadian rhythm and in maintaining health. Aim was to investigate sleep and physical activity among people who have inflammatory arthritis and their engagement with Health Professionals. MATERIALS AND METHODS: Members from a national charitable organisation for patients with arthritis and a national rheumatology health professionals society were invited to participate in separate cross-sectional surveys hosted on SurveyMonkey(R)TM. RESULTS: Ninety people responded and report an average of 5.7 (SD 1.46) hours sleep per night. A majority (61%) report their sleep quality as bad, with 31% taking medications at least once a week to help sleep. There was a statistically significant association between longer years with symptoms, taking medication at least once a week and limited in their activities, when rating their sleep quality as bad. Twenty eight (65%) health professional's responded with 53% discussing sleep with their patients. CONCLUSIONS: People with inflammatory arthritis report low sleep with those having symptoms longer, taking medications regularly and having limitations with their activities, reporting poorer sleep quality. Only half of health professionals discuss sleep. More research is needed in investigating poor sleep quality, disturbances, and physical activity in order to promote health and well being in this population. Implications for Rehabilitation People with inflammatory arthritis fall far below the National Sleep Foundations' "sleep needs spectrum", which is concerning as those who have reduced levels of sleep have been associated with decreased quality of life and physical function. Due to the importance of receiving sufficient sleep, there is a need to develop education and training for health professionals in the importance of engaging their patients in their sleep quality and disturbances. The effects of physical activity interventions on poor sleep need to be examined to show if it is a positive non-pharmacological treatment approach for the management of poor sleep in patients with inflammatory arthritis. PMID- 28573872 TI - Achieving Professionalism in Health Care Organizations. PMID- 28573873 TI - Impact of Diabetes Care by Pharmacists as Part of Health Care Team in Ambulatory Settings: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To conduct a comprehensive systematic review and meta-analyses examining the impact of pharmacist interventions as part of health care teams on diabetes therapeutic outcomes in ambulatory care settings. DATA SOURCES: PubMed/MEDLINE, EMBASE, Cochrane Library, International Pharmaceutical Abstracts, Web of Science, Scopus, WHO's Global Health Library, ClinicalTrials.gov , and Google Scholar were searched (1995 to February 2017). Search terms included pharmacist, team, and diabetes. STUDY SELECTION: Full-text articles published in English with comparative designs, including randomized controlled trials, nonrandomized controlled trials, and pretest-posttest studies evaluating hemoglobin A1C (A1C), were assessed. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened for study inclusion and extracted data. Quality of the studies was assessed using tools developed based on the framework of the Cochrane Collaboration's recommendations. DATA SYNTHESIS: A total of 1908 studies were identified from the literature and reference searches; 42 studies were included in the systematic review (n = 10 860) and 35 in the meta-analyses (n = 7417). Mean age ranged from 42 to 73 years, and 8% to 100% were male. The overall standardized mean difference (SMD) for A1C for pharmacist care versus comparison was 0.57 ( P < 0.01), a moderate effect representing a mean difference of 1.1% (95% CI = 0.88-1.27). The effects for systolic blood pressure and low-density lipoprotein cholesterol were between small and moderate (SMD = 0.31 and 0.32; P < 0.01). The heterogeneity was high for all outcomes (>83%), indicating functional differences among the studies. No publication bias was detected. CONCLUSION: Pharmacists' interventions as part of the patient's health care team improved diabetes therapeutic outcomes, substantiating the important role of pharmacists in team-based diabetes management. PMID- 28573874 TI - Role of mast cells in the induction of dry skin in a mouse model of rheumatoid arthritis. AB - PURPOSE: Rheumatoid arthritis (RA) is known to induce dry skin as an extra articular symptom. However, the mechanisms behind the induction are unclear. In this study, we utilized an arthritis mouse model to simulate RA to reveal the relationship between arthritis and dry skin. MATERIALS AND METHODS: DBA/1JJmsSlc control mice (n = 5) and DBA/1JJmsSlc collagen-induced arthritis mouse model (arthritis mice; n = 5) were used. We measured transepidermal water loss (TEWL) and capacitance to reveal the effect of arthritis on skin barrier function. In addition, we measured the expression of biomarkers of skin barrier function. RESULTS: We found that the hind limb volume of the arthritis mice was higher than that of the control mice. Our results showed that the arthritis mice had higher TEWL and lower capacitance when compared to the control mice. When compared to that of the control mice, the skin of the arthritis mice was thicker with more leukocyte infiltration. In the skin of arthritis mice, we observed lower expression of type I and IV collagens, but higher expression of matrix metalloproteinases (MMP)-1 and -9 when compared to that of the control mice. The levels of mast cells, histamine, substance P, and tryptase were higher in the arthritis mice than in the control mice. This study showed that the arthritis mice exhibited a disruption of skin barrier function (i.e. dry skin), which was improved following treatment with a mast cell inhibitor. CONCLUSIONS: Our results on mast cells suggested that an improvement of dry skin is important for RA management. PMID- 28573875 TI - Modulatory effects of l-carnitine plus l-acetyl-carnitine on neuroendocrine control of hypothalamic functions in functional hypothalamic amenorrhea (FHA). AB - Functional hypothalamic amenorrhea (FHA) is a relatively frequent disease due to the combination of metabolic, physical, or psychological stressors. It is characterized by the low endogenous GnRH-induced gonadotropin secretion, thus triggering the ovarian blockade and a hypoestrogenic condition. Up to now various therapeutical strategies have been proposed, both using hormonal treatment as well as neuroactive compounds. Since carnitine, namely l-acetyl-carnitine (LAC), has been demonstrated to be effective in the modulation of the central hypothalamic control of GnRH secretion, we aimed to evaluate whether a combined integrative treatment for 12 weeks of LAC (250 mg/die) and l-carnitine (500 mg/die) was effective in improving the endocrine and metabolic pathways in a group of patients (n = 27) with FHA. After the treatment, interval mean LH plasma levels increased while those of cortisol and amylase decreased significantly. When patients were subdivided according to baseline LH levels, only hypo-LH patients showed the significant increase of LH plasma levels and the significant decrease of both cortisol and amylase plasma levels. The increased 17OHP/cortisol ratio, as index of the adrenal activity, demonstrated the reduced stress-induced adrenal activity. In conclusion, our data sustain the hypothesis that the integrative administration of LAC plus l-carnitine reduced both the metabolic and the neuroendocrine impairment of patients with FHA. PMID- 28573876 TI - A safety assessment of biological therapies targeting the IL-23/IL-17 axis in inflammatory bowel diseases. AB - INTRODUCTION: Many different compounds targeting the interleukin 23/17 axis have been developed and successfully studied in several autoimmune diseases, including inflammatory bowel diseases. Nevertheless, interfering with key immunological pathways raises potential safety concerns. This review focuses on the safety profile of these novel biological therapies. Areas covered: A literature search until March 2017 was performed to collect safety data on different compounds targeting this pathway, with emphasis on ustekinumab and secukinumab. Firstly, the authors discuss briefly how genetics can inform about potential safety issues. Secondly, they extensively describe safety issues (common adverse events, infections, malignancies...), immunogenicity, exposure to ustekinumab in specific populations and provide advice for vaccination. Finally, they address safety profiles of secukinumab and other biological targeting the IL-23/17 axis in IBD. Expert opinion: Current evidence suggests that ustekinumab therapy overweigh the potential drug-related risks. Additional safety data beyond randomized-controlled trials, derived from statistically powered, large prospective studies with long term follow-up are urgently needed to assess the real-life ustekinumab-related risks and to establish the correct position of these novel class of biologicals in IBD treatment. Combining immunomodulators with ustekinumab seems to be safe, though prospective data specifically addressing this topic are currently missing. Similarly, the combination of different biological therapies still has to be studied. PMID- 28573877 TI - Activity restriction and risk of preterm delivery. AB - PURPOSE: We sought to determine whether activity restriction (AR) in a cohort of women at high risk for preterm delivery is associated with the risk of preterm delivery. MATERIALS AND METHODS: This is a secondary analysis of the Maternal Fetal Medicine Units MFMU's Preterm Prediction Study; a multicenter prospective cohort study designed to identify risk factors of preterm birth (PTB). The study group consisted of women with a singleton gestation that at their first study visit (23-24 weeks) had at least one of the following criteria: patient reported contractions, severe back pain, a cervical length <15 mm, spotting, protruding membranes, or positive fetal fibronectin. Women were assessed for AR at a 27- to 29-week study visit. Associations between AR and preterm delivery (<37 weeks) were examined through logistic regression models before and after adjustment for confounders. RESULTS: Of the 1086 women that met the inclusion criteria, 16.5% (n = 179) delivered preterm. In this cohort, 9.7% (n = 105) of women were recommended AR, with 37.1% (n = 39) having a PTB. In the group not recommended AR (n = 981), 14.3% (n = 140) delivered preterm. CONCLUSION: In this cohort of women at high risk for PTB, activity restriction was associated with an increased risk of PTB. The use of AR in this population should be discouraged. PMID- 28573878 TI - The effect of resistant starches on fat oxidation in healthy adults as measured by a 13CO2-breath test. AB - A resistant starch (RS) mixture (MIX) consisting of fibre of potatoes (FP) and wrinkled pea starch (WPS), and high amylose maize starch (HAMS) were supplemented in adults to evaluate their effects on fat oxidation by means of a 13CO2-breath test. Sixteen subjects received a regular diet either without or with the supplementation of MIX and HAMS in randomised order. After administration of a [U 13C]algal lipid mixture, exhaled air was collected over 14 h in 0.5- and 1-h intervals. The 13C abundances were measured by nondispersive infrared spectroscopy. In comparison to the dry run (DR), supplementation with MIX and with HAMS increased the cumulative percentage dose recovery: (DR: 16.7 %, MIX: 16.9 %, HAMS: 18.0 %), but without statistical significance. The colonic degradation of MIX and HAMS to short-chain fatty acids tends to lower the formation of carbohydrate-derived acetyl-CoA and contributes to a postprandial lipid oxidation increase by using fat-derived acetyl-CoA as a compensatory fuel source. PMID- 28573879 TI - Does Cardiovascular Comorbidity Influence the Prescribing of Bronchodilators in Chronic Obstructive Pulmonary Disease? AB - BACKGROUND: Cardiovascular disease (CVD) is the most prevalent comorbidity for chronic obstructive pulmonary disease (COPD). Potential adverse cardiovascular events of bronchodilators warrant their cautionary use in the comorbid COPD-CVD population, yet little is known about the prescribing of bronchodilators in this high-risk patient group. OBJECTIVE: To determine whether comorbid CVD is associated with reduced bronchodilator prescribing in patients with COPD. In addition, we explored how the association was modified by gender, concurrent asthma, and concomitant beta-blocker (BB) use. METHODS: A cross-sectional study was conducted using the 2010 National Ambulatory Medical Care Survey. All visits among diagnosed COPD patients 40 years and older were examined. Logistic regression on survey-weighted data was used to predict treatment with bronchodilators and determine the influence of gender, asthma, and BBs on bronchodilator prescribing. RESULTS: Among 11 627 061 ambulatory COPD visits, we found a significantly lower bronchodilator treatment rate among patients with comorbid CVD (32.3%) than among patients without CVD (57.6%). The observed effect was modified by gender, asthma, and BBs. Deprescribing was more pronounced for females than males, for nonusers of BBs than users of BBs, and for asthma patients than nonasthma patients. CVD did not affect bronchodilator prescribing in either asthmatic or nonasthmatic males taking BBs. CONCLUSIONS: Most COPD patients with concurrent CVD were less likely to be prescribed bronchodilators, with the exception of males who were also prescribed BBs. Thus, this study highlights a specific patient subgroup for whom the guidelines are less likely to be observed. PMID- 28573880 TI - Long-term outcomes of twins based on the intended mode of delivery. AB - OBJECTIVE: Recent studies have shown that for twin pregnancies with a cephalic presenting first twin, planned vaginal delivery is not associated with adverse short-term neonatal outcomes, as compared to planned cesarean delivery. Our objective was to compare long-term outcomes in twins, based on planned mode of delivery. STUDY DESIGN: This was a prospective, observational cohort of twin pregnancies delivered by a single MFM practice. All the patients with a twin pregnancy >34 weeks delivered from 2005-2014 were surveyed regarding pediatric outcomes at or after 2 years of life. The survey was mail-based, with phone follow-up for nonresponses or for clarification of answers. Using chi-square, Student's t-tests, and regression analysis we compared outcomes between women who planned a vaginal (with active management of the second stage) versus cesarean delivery. The main outcome measures were: (1) a composite of major adverse outcomes (death, cerebral palsy, necrotizing enterocolitis, chronic renal, heart, or lung disease); (2) a composite of minor adverse outcomes (learning disability, speech therapy, occupational therapy, physical therapy). RESULTS: Five hundred and thirty-two women met inclusion criteria and 354 (66.5%) responded. 178 (50.3%) women planned to have a cesarean delivery (100% of whom had a cesarean delivery) and 176 (49.7%) women planned to have a vaginal delivery (83% of whom had a vaginal delivery). The average age of the children at the time of the survey was 5.9 years. There were no differences in any pediatric outcomes between the two groups. After controlling for maternal age, IVF, obesity, and preeclampsia, the planned mode of delivery was not associated with a composite of major adverse outcomes (aOR 0.673, 95% CI 0.228, 1.985), nor a composite of minor adverse outcomes (aOR 0.767, 95% CI 0.496, 1.188). CONCLUSIONS: Planned vaginal delivery with active management of the second stage of labor in twin pregnancies >34 weeks is not associated with adverse childhood outcomes. PMID- 28573881 TI - In silico estimation of basic activity-relevant parameters for a set of drug absorption promoters. AB - Finding a balance between a desired drug's potency and its physicochemical properties that are important for its molecule pharmacokinetic or pharmacodynamics profile is still a challenging issue in rational drug discovery. Quantitative assessment of the lipophilic characteristics of potential drug molecules is indispensable for efficient development of Absorption, Distribution, Metabolism, Excretion, Toxicity-tailored structure-activity models; therefore reliable procedures for deriving log P from molecular structure are desirable. In the current work a range of various software log P predictors for estimation of the numerical lipophilic values for a set of cholic acid derivatives were employed and subsequently cross-compared with the experimental parameters. Thus, the empirical lipophilicity (RM) was compared with the corresponding log P characteristics calculated using alternative methods for deducing the lipophilic features. The mean values of the selected molecular descriptors that were averaged over the chosen calculation methods (consensus clog P) were subsequently correlated with the RM parameter. As an additional experiment, the iterative variable elimination partial least squares (IVE-PLS) methodology for an ensemble of descriptors retrieved from Dragon 6.0 software was applied for a set of drug transporters. To investigate the variations within the ensemble of cholic acid derivatives principal component analysis (PCA) and self-organizing neural network (SOM) procedures were used to visualize the major differences in the performance of drug promoters with respect to their lipophilic profile. PMID- 28573882 TI - Variation in the definition of intrauterine growth restriction in routine antenatal care: a physician survey among gynecologists in Northwest Germany. AB - OBJECTIVE: To assess how intrauterine growth restriction (IUGR) is defined by gynecologists in routine practice. MATERIALS AND METHODS: We surveyed primary care gynecologists in Bremen and Lower Saxony, Northwest Germany, between January and July 2014. Descriptive statistics were used to analyze the data; consensus was considered as 90% agreement among the respondents. Multiple logistic regression models were performed for the associations between respondents' background characteristics and choice of the small for gestational age (SGA) cutoff values. RESULTS: Overall, 185 primary care gynecologists participated in the survey. Consensus was only observed in two items: (1) an accurate determination of gestational age (91%) and (2) repeated measurement of the abdominal circumference (91%). Umbilical artery Doppler (76%) and repeated ultrasonography (76%) were the most frequently used methods to confirm suspected IUGR diagnoses, but different responses prevailed. Notably, only 46% of the respondents opted for the 10th percentile of estimated fetal weight as a cutoff for SGA classification, which is the internationally recommended value. CONCLUSIONS: The results of this survey indicate considerable practice variation regarding detection and management of IUGR pregnancies. There is a need for better agreement in terminology and definition of core aspects of IUGR in antenatal care. PMID- 28573883 TI - Longitudinal falls data in Parkinson's disease: feasibility of fall diaries and effect of attrition. AB - BACKGROUND: Identifying causes of falls for people with Parkinson's disease has met with limited success. Prospective falls measurement using the "gold standard" approach is challenging. This paper examines the process and outcomes associated with longitudinal falls reporting in this population. METHODS: Participants were recruited from ICICLE-GAIT (a collaborative study with ICICLE-PD; an incident cohort study). Monthly falls diaries were examined over 48 months for accuracy of data and rate of attrition. To further inform analysis, characteristics of participants with 36-month completed diaries were compared with those who did not complete diaries. RESULTS: One hundred and twenty-one participants were included at baseline. By 12 months, falls diary data had reduced to 107 participants; to 81 participants by 36 months; and to 59 participants by 48 months. Key reasons for diary attrition were withdrawal from ICICLE-gait (n = 16) (13.2%), and noncompliance (n = 11) (9.1%). The only significant difference between the completed and non-completed diary groups was age at 36 months, with older participants being more likely to send in diaries. CONCLUSIONS: Prospective falls data is feasible to collect over the long term. Attrition rates are high; however, participants retained in the study are overall representative of the total falls diary cohort. Implications for Rehabilitation Understanding falls evolution in Parkinson's disease through consistent, personalized monitoring of falls events is critical to inform effective management. Our study shows that it is feasible to collect longitudinal falls data using "gold standard" methodology, although significant resources are required for implementation. We anticipate that our study methodology is broadly applicable to any at-risk falls cohort including older adults and diverse neurological conditions. Researchers and clinicians collating prospective falls data must ensure that participants understand what constitutes a fall, as per the World Health Organization definition. A second key point is to ensure prompt recording of any fall event. PMID- 28573884 TI - Content and psychometric evaluations of questionnaires for assessing physical function in people with neck disorders: a systematic review of the literature. AB - PURPOSE: The purpose was to investigate how physical function is assessed in people with musculoskeletal disorders (MSD) in the neck. Specifically, we aimed to determine: (1) Which questionnaires are used to assess physical function in people with MSD in the neck? (2) What do those questionnaires measure? (3) What are the measurement properties of the questionnaires? MATERIALS AND METHODS: A systematic review was performed to identify questionnaires and psychometric evaluations. The content of the questionnaires was categorized according to the International Classification of Function, Disability and Health, and the psychometric properties were quality-rated using the COnsensus-based Standards for the selection of health Measurement INstruments checklist. RESULTS: Ten questionnaires and 32 articles evaluating measurement properties were analyzed. Most questionnaires covered only the components body functions and activity and participation, more often activity participation than body function. Internal consistency was adequate in most questionnaires, whereas responsiveness was generally low. Neck Disability Index was most evaluated, but the evaluations of all questionnaires tended to cover most properties in the checklist. CONCLUSIONS: The questionnaires differed substantially in items and extent to which their psychometric properties had been evaluated. Focus of measurement was on activities in daily life rather than physical function as such. Implications for Rehabilitation To provide early diagnostics and effective treatment for patients with neck disorders, valid and reliable instruments that measure relevant aspects of the disorders are needed. This paper presents an overview of content and quality of questionnaires used to assess physical function in neck disorders, which may facilitate informed decisions about which measurement instruments to use when evaluating the course of neck disorders. Most of the questionnaires need more testing to judge the quality, however the NDI was the most frequently tested questionnaire. The COnsensus-based Standards for the selection of health Measurement INstruments checklist is a useful tool in relation to psychometric testing of questionnaires, but clear definitions of interpretation of the quality criteria in each study would enhance comparability of results. PMID- 28573885 TI - Linking youths' mental, psychosocial, and emotional functioning to ICF-CY: lessons learned. AB - PURPOSE: Linking ready-made questionnaires to codes within the International Classification of Functioning, Disability and Health, Children and Youth Version with the intention of using the information statistically for studying mental health problems can pose several challenges. Many of the constructs measured are latent, and therefore, difficult to describe in single codes. The aim of this study was to describe and discuss challenges encountered in this coding process. MATERIALS AND METHODS: A questionnaire from a Swedish research programme was linked to the International Classification of Functioning, Disability and Health, Children and Youth Version and the agreement was assessed. RESULTS: Including the original aim of the questionnaire into the coding process was found to be very important for managing the coding of the latent constructs of the items. Items from the International Classification of Functioning, Disability and Health, Children and Youth Version chapters with narrow definitions for example mental functions, were more easily translated to meaningful concepts to code, while broadly defined chapters, such as interactions and relationships, were more difficult. CONCLUSION: This study stresses the importance of a clear, predefined coding scheme as well as the importance of not relying too heavily on common linking rules, especially in cases when it is not possible to use multiple codes for a single item. Implications for rehabilitation The International Classification of Functioning, Disability and Health, Children and Youth Version, is a useful tool for merging assessment data from several sources when documenting adolescents' mental functioning in different life domains. Measures of mental health are often based on latent constructs, often revealed in the description of the rationale/aim of a measure. The latent construct should be the primary focus in linking information. By mapping latent constructs to the International Classification of Functioning, Disability and Health, Children and Youth Version, users of the classification can capture a broad range of areas relevant to everyday functioning in adolescents with mental health problems. The subjective experience of participation, i.e., the level of subjective involvement, is not possible to code into the International Classification of Functioning, Disability and Health, Children and Youth Version. However, when linking mental health constructs to the International Classification of Functioning, Disability and Health, Children and Youth Version codes, the two dimensions of participation (the being there, and the level of involvement) need to be separated in the linking process. This can be performed by assigning codes focusing on being there as separate from items focusing on the subjective experience of involvement while being there. PMID- 28573886 TI - Effect of two high dose vitamin D by parenteral route in treating vitamin D deficiency a prospective interventional study. AB - BACKGROUND: Vitamin D deficiency is recognized as a global public health problem. Despite ample sunshine, vitamin D deficiency is very common in the Middle East (15 degrees -36 degrees N) and African (35 degrees S-37 degrees N) countries; and in South Asian countries. AIM: To find a simple, affordable and practical plan to treat vitamin-d deficiency. TYPE OF STUDY: This was a prospective interventional study. OUTCOME VARIABLE: The primary outcome was typed as vitamin-D level more than 50 nanograms/ml as 'yes' and poor response or 'no' when it was less than 50 ng/ml. PARTICIPANTS: 80 Women participated in study. Laboratory tests: Vitamin D [25-OHD]-estimations were performed with LCMSMS-liquid chromatography tandem mass spectrometry. Corrective vitamin-D doses: All participants received TWO doses of Vitamin-D injections one ml at a time [600K IU/ml or 600,000 IU/ml]. All participants received their first dose; after collecting blood samples for Vitamin-D estimations. Second dose was given about a month after the first one [range 30-37 days]. These doses were given to correct the deficiency. RESULTS: Even with this high dose treatment 60% woman had unsatisfactory Vitamin-D levels. PMID- 28573888 TI - Interrole conflict and self-efficacy to manage work and family demands mediate the relationships of job and family demands with stress in the job and family domains. AB - BACKGROUND AND OBJECTIVES: This study derives from Work-Home Resources model (ten Brummelhuis, L. L., & Bakker, A. B. (2012). A resource perspective on the work home interface: The work-home resources model. American Psychologist, 67(7), 545 556. doi: 10.1037/a0027974 ) and Social Cognitive Theory (Bandura, A. (1986). Social foundations of thought and action: A social cognitive theory. Englewood Cliffs, NJ, US: Prentice-Hall, Inc.) to investigate mechanisms responsible for the effect of job and family demands on work- and family-related perceived stress. We hypothesized that interrole conflict and self-efficacy to manage work and family demands operate either independently or sequentially transmitting the effects of demands on perceived stress. DESIGN: A sample of 100 employees of various occupations participated in the study conducted online in two waves: Time 1 (T1) and Time 2 (T2) with a three-month interval. METHOD: Regression analysis with bootstrapping was applied. RESULTS: Interrole conflict (T1) did not mediate the relationships between demands (T1) and perceived stress (T2), whereas self efficacy (T1) mediated only those between family demands (T1) and stress (T2). However, data supported the sequential mediation hypotheses: Demands (T1) were associated with increased interrole conflict (T1) which in turn decreased self efficacy (T1) and ultimately resulted in the elevated perceived stress at work and in the family (T2). CONCLUSIONS: Demands originating in one domain can impact stress both in the same and other life areas through the sequence of interrole conflict and context-specific self-efficacy. PMID- 28573887 TI - Relations between plasma oxytocin, depressive symptoms and coping strategies in response to a stressor: the impact of social support. AB - BACKGROUND: Social support can serve as a protective factor against the negative impacts of stressors and may thereby promote well-being. As well, exogenous administration of oxytocin has been tied to diminished stress responses and might also enhance the effects of social support. METHODS/RESULTS: In the current study, conducted among female undergraduate students (N = 67), higher depressive symptoms were related to lower endorsements of problem-focused coping in response to a psychosocial stressor comprising the Trier Social Stress test (TSST). However, the relation between depressive symptoms and problem-focused coping was absent among participants who had a close female friend present serving as social support prior to the stressor experience. Additionally, endogenous plasma oxytocin levels were related to certain coping strategies being favored (e.g., problem-solving, humor, cognitive distraction, self-blame and support seeking) in response to the psychosocial stressor. However, the strength of these relations varied as a function of whether individuals had social support present or not. CONCLUSION: These findings confirm the positive impact of social support in attenuating the relation between depressive symptoms and specific coping methods. The results of this study are consistent with view that oxytocin levels are accompanied by particular stress responses, possibly through the promotion of coping methods endorsed. PMID- 28573889 TI - The Subchondral Bone Is Affected by Bone Marrow Stimulation: A Systematic Review of Preclinical Animal Studies. AB - Objective Despite the mechanical and biological roles of subchondral bone (SCB) in articular cartilage health, there remains no consensus on the postoperative morphological status of SCB following bone marrow stimulation (BMS). The purpose of this systematic review was to clarify the morphology of SCB following BMS in preclinical, translational animal models. Design The MEDLINE and EMBASE databases were systematically reviewed using specific search terms on April 19, 2016 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The morphology of the SCB was assessed using of microcomputed tomography (bone density) and histology (microscopic architecture). Results Seventeen animal studies with 520 chondral lesions were included. The morphology of SCB did not recover following BMS. Compared with untreated chondral defects, BMS resulted in superior morphology of superficial SCB and cartilage but inferior morphology (specifically bone density, P < 0.05) of the deep SCB. Overall, the use of biological adjuvants during BMS resulted in the superior postoperative morphology of SCB. Conclusions Alterations in the SCB following BMS were confirmed. Biologics adjuvants may improve the postoperative morphology of both SCB and articular cartilage. Refinements of BMS techniques should incorporate consideration of SCB damage and restoration. Investigations to optimize BMS techniques incorporating both minimally invasive approaches and biologically augmented platforms are further warranted. PMID- 28573890 TI - Resorcinol-, catechol- and saligenin-based bronchodilating beta2-agonists as inhibitors of human cholinesterase activity. AB - We investigated the influence of bronchodilating beta2-agonists on the activity of human acetylcholinesterase (AChE) and usual, atypical and fluoride-resistant butyrylcholinesterase (BChE). We determined the inhibition potency of racemate and enantiomers of fenoterol as a resorcinol derivative, isoetharine and epinephrine as catechol derivatives and salbutamol and salmeterol as saligenin derivatives. All of the tested compounds reversibly inhibited cholinesterases with Ki constants ranging from 9.4 MUM to 6.4 mM and had the highest inhibition potency towards usual BChE, but generally none of the cholinesterases displayed any stereoselectivity. Kinetic and docking results revealed that the inhibition potency of the studied compounds could be related to the size of the hydroxyaminoethyl chain on the benzene ring. The additional pi-pi interaction of salmeterol's benzene ring and Trp286 and hydrogen bond with His447 probably enhanced inhibition by salmeterol which was singled out as the most potent inhibitor of all the cholinesterases. PMID- 28573891 TI - Short-term outcome of brainstem auditory function in term infants after discharge from the neonatal intensive care unit. AB - OBJECTIVES: To examine short-term outcome of brainstem auditory function in term infants after discharge from the neonatal intensive care unit (NICU). METHODS: Brainstem auditory evoked response (BAER) was recorded and analysed at various click rates at 2-4 months of age in 43 term NICU graduates. The data were compared with those in age-matched normal controls. RESULTS: The threshold of BAER in the NICU graduates was marginally elevated. The graduates also showed an increase in wave III latency at 91/s and wave V latency at all 21-91/s. The I-V interval was increased at 51 and 91/s, whereas the I-III and III-V intervals were slightly increased, with no significant differences from normal controls at any click rates. The amplitudes of waves I and V in the NICU graduates were moderately reduced at all click rates. Wave III amplitudes were reduced at 51 and 91/s. None of the slopes of BAER variables-rate functions in the NICU graduates differed significantly from normal controls. CONCLUSIONS: The BAER was moderately abnormal in the NICU graduates, suggesting that brainstem auditory function is moderately impaired at 2-4 months of age after discharge. There is a need to monitor postnatal auditory and neural development for NICU graduates. PMID- 28573892 TI - Acute myeloid leukemia in the elderly: therapeutic options and choice. AB - Acute myeloid leukemia (AML) therapies are rapidly evolving with novel targeted therapies showing high-level responses in a notoriously difficult to treat group of patients - the elderly and unfit. This review will examine the outcomes of older AML patients (>60 years old) with conventional induction strategies, and published literature on risks of pursuit of induction. Low-intensity combination therapy response rates appear to be approaching that of induction regimens, and with lower toxicity, low-intensity therapy likely represents the future standard approach in this age group. Lastly, allogeneic transplant appears to have a role in increasing durable remissions regardless of age and should be considered in patients with limited comorbidities. PMID- 28573893 TI - Identification of a novel KMT2A-SEPT14 fusion in acute myeloid leukemia. PMID- 28573894 TI - Interpersonal social responsibility model of service learning: A longitudinal study. AB - BACKGROUND: Service-learning (SL) is commonly used in Occupational Therapy (OT) programs worldwide as a community placement educational strategy. However, most SL models are not clearly defined in terms of both methodology and learning outcomes. OBJECTIVES: This longitudinal study explores a structured model of Service-Learning (Interpersonal Social Responsibility-Service Learning: ISR-SL) aimed towards the development of professional identity among OT students. Based on OT students experiences from the end of the course through later stages as mature students and professionals. MATERIAL AND METHODS: A qualitative research design was used to explore the perceptions and experiences of 150 first, second, and third-year OT students and graduates who have participated in ISR-SL during their first academic year. RESULTS: Our findings suggest that the structured, long-term relationship with a person with a disability in the natural environment, which is the core of the ISR-SL, allowed students to develop a professional identity based on seeing the person as a whole and recognizing his/her centrality in the therapeutic relationship. CONCLUSIONS AND SIGNIFICANCE: This study suggests ISR-SL as future direction or next step for implementing SL in OT and other healthcare disciplines programs. PMID- 28573896 TI - Expression of a truncated B lymphocyte-induced maturation protein-1 isoform is associated with an incomplete plasmacytic differentiation program in chronic lymphocytic leukemia. PMID- 28573895 TI - Impacts of therapeutic hypothermia on cardiovascular hemodynamics in newborns with hypoxic-ischemic encephalopathy: a case control study using echocardiography. AB - PURPOSE: The effects of therapeutic hypothermia (TH) on hemodynamics in newborns with hypoxic-ischemic encephalopathy (HIE) were evaluated. MATERIALS AND METHODS: Thirty-two neonates (gestational age, 39.4 +/- 1.3 weeks) who had TH for HIE and echocardiographic hemodynamic assessments during TH and post-TH period were studied. Gestational-age-matched 34 healthy neonates were enrolled for comparison. RESULTS: During TH, patients had significantly decreased left ventricular cardiac output (LVCO), descending aorta blood flow (DABF), and DABF/LVCO ratio, and increased resistive index of DA compared to controls. Upper body blood flow (UBBF) remained unchanged but UBBF/LVCO ratio significantly increased during TH. Urine output decreased significantly during TH and increased after rewarming, and showed significant positive correlation with DABF/LVCO ratio. Sixteen patients (50%) showed hypoxic-ischemic (HI) lesions on brain magnetic resonance imaging (MRI) and had significantly increased UBBF/LVCO ratio during TH compared to patients without HI lesions. Patients with UBBF/LVCO ratio >55% had significantly higher risk of having HI lesions on brain MRI (odds ratio 13.0; 95% CI, 2.4-70.2). CONCLUSIONS: Decrease in cardiac output and descending aorta blood flow, and preferential cerebral redistribution of cardiac output along with an increase in systemic peripheral vascular resistance may affect systemic organ perfusion and cerebral metabolism. PMID- 28573897 TI - Molecular mechanisms, current management and next generation therapy in myeloma bone disease. AB - Multiple myeloma (MM) bone disease is a major cause of morbidity and mortality in MM patients and persists even in patients in remission. This bone disease is caused by an uncoupling of bone remodeling, with increased osteoclast and decreased osteoblast activity and formation, culminating in lytic bone destruction. Bisphosphonates are the current standard of care but new therapies are needed. As the molecular mechanisms controlling MM bone disease are increasingly well understood, new therapeutic targets are extensively explored in the preclinical setting and initial clinical trials with novel compounds now show promising results. In this review, we will provide a comprehensive overview of the biology of MM bone disease, summarize its current clinical management and discuss preclinical and clinical data on next generation therapies. PMID- 28573898 TI - Effect of initial body mass index on survival outcome of patients with myelodysplastic syndrome: a single-center retrospective study. AB - Multiple studies have associated elevated body mass index (BMI) and increased incidence of hematologic malignancies, including myelodysplastic syndrome (MDS). The purpose of the present study was to evaluate the association between BMI at diagnosis and overall survival (OS) in a retrospective cohort of 92 patients with MDS. The median age at diagnosis was 63 (14-84) years. The median BMI was 22.75 (15.94-34.26) kg/m2. Eleven (12.0%) patients were underweight, 64 (69.6%) were normal weight, 17 (18.5%) were overweight or obese. Three-year OS rates differed significantly when the three BMI groups were compared (p = .0449). Multivariate Cox regression analysis indicated that normal weight (versus underweight) had a marginally significant effect on OS (hazard ratio = 0.456, p = .127), and overweight/obese (versus underweight) had a significant effect on OS (hazard ratio = 0.171, p = .015). Further investigations are required to elucidate the mechanisms responsible for this association. PMID- 28573899 TI - Exploring the Feasibility of Incorporating Sexual Education Into Routine Adolescent Office Visits. PMID- 28573900 TI - Initial therapy for acute myeloid leukemia in older patients: principles of care. AB - Older patients with acute myeloid leukemia (AML) frequently have significant comorbidities, geriatric syndromes, and high-risk leukemia that make them susceptible to high early mortality, chemotherapy-related toxicities, and poor long-term survival. The receipt of chemotherapy or hematopoietic cell transplantation is low, and the choices between intensive or low-intensity chemotherapy is often not clear. Geriatric and multidisciplinary interventions targeted to optimize functional status and improve management of comorbidities may enhance chemotherapy tolerance. Comprehensive geriatric assessment, and other integrated risk assessment models have been developed to predict the risk of chemotherapy-related toxicities and survival, and may guide therapy assignment. Development of low intensity but effective therapy is a major need. Deeper understanding of the molecular biology of AML has allowed several novel therapies to enter clinical trials in recent years. Continuation of successful collaboration between several stakeholders will be necessary to build upon the clinical and research improvements made thus far. PMID- 28573901 TI - A Case Report of Parvovirus B19 Infection in a Renal Allograft. AB - Parvovirus B19 infection is undiagnosed in recipients undergoing solid organ transplantation. It is usually responsible for unexplained acute and chronic red blood cell aplasia that does not respond to erythropoietin therapy. Cases of parvovirus B19 infection associated with pancytopenia, solid organ dysfunction, and allograft rejection have been described in the literature. The deterioration of the immune system as a result of severe immunotherapy favors the reactivation of a previous infection or the acquisition of a new one. We present a case of a 32-year-old woman with a 1-year history of renal allograft transplant and previous cytomegalovirus (CMV) infection who presented with chest pain, polyarthritis, pancytopenia, and renal dysfunction. A serum sample using polymerase chain reaction showed a parvovirus titer of 13.8 trillion IU/mL and a CMV titer of 800 IU/mL. The renal biopsy revealed nucleomegaly with focal viral inclusions, along with changes associated with immunotherapy toxicity. Electron microscopy demonstrated capillary and tubular epithelial cells with "viral factories," thereby confirming the diagnosis. Thus, screening for parvovirus B19 is advised in high-risk patients who present with refractory anemia to avoid the complications of a chronic infection associated with the fatal rejection of the transplanted organ. PMID- 28573902 TI - Cost-effectiveness of on-demand plerixafor added to chemotherapy and granulocyte colony stimulating factor for peripheral blood stem cell mobilization in multiple myeloma. AB - We here report final results of a phase II/III prospective study that evaluated in Multiple Myeloma the use of on-demand plerixafor (PLX) added to mobilizing chemotherapy for patients showing predictive signs of mobilization failure. A total of 111 patients with MM were registered, all received cyclophosphamide 4 g/m2 and granulocyte colony-stimulating factor (G-CSF). Overall, a successful CD34+ cell mobilization was achieved in 97.2% (108/111) of patients. Minimum harvest (>=2.0 * 106 CD34+ cells/kg) was achieved in 97.2% (108/111) and optimal harvest success (>=4.0 * 106 CD34+ cells/kg) was achieved in 84.6% (94/111). Multivariate analysis showed that patients who received on-demand PLX treatment had significantly higher likelihoods of successfully achieving both the minimal (p = .006) and optimal harvest (p = .05) in respect to a historical control group mobilized without any PLX. The incremental cost-effectiveness ratio, for each 1% increase in probability of achieving a successful minimal harvest, was ?40.6 per patient. PMID- 28573903 TI - A fast-growing lesion of the lower limb after medically assisted procreation. PMID- 28573904 TI - Dichloroacetonitrile induces cytotoxicity through oxidative stress-mediated and p53-dependent apoptosis pathway in LO2 cells. AB - Dichloroacetonitrile (DCAN), one of the disinfection byproducts of water chlorination, induces cell proliferation and apoptosis; however, the detailed mechanism remains unclear. Oxidative stress participates in various biological processes, including DNA damage and cytotoxicity. To explore whether oxidative stress mediated DCAN-induced cell proliferation and apoptosis, we assessed the effect of redox imbalance and apoptosis in LO2 cells. We observed increase of reactive oxygen species and malondialdehyde and increased apoptosis by 13.6% in 500 MUM DCAN compared with the control group. We also observed a decrease of antioxidant ability damage including glutathione, superoxide dismutase, and total antioxidant capacity depletion. Furthermore, DCAN might activate oxidative stress mediated apoptosis pathway via up-regulation of p53 expression and caspase-3 activity. Therefore, we conclude that DCAN may activate apoptotic signals via p53 up-regulation and oxidative stress-mediated apoptosis in LO2 cells. PMID- 28573905 TI - Regulatory T-cells drive immune dysfunction in CLL. PMID- 28573906 TI - Loss of CD3 and TCRgammadelta expression in a relapsed hepatosplenic T-cell lymphoma. PMID- 28573907 TI - Cart before the horse: use of Aspergillus PCR to increase the diagnostic yield from BAL in hematological patients at risk of invasive aspergillosis. PMID- 28573908 TI - The eIF4E inhibitor ribavirin as a potential antilymphoma therapeutic: early clinical data. PMID- 28573909 TI - Mobile gait analysis via eSHOEs instrumented shoe insoles: a pilot study for validation against the gold standard GAITRite(r). AB - Clinical gait analysis contributes massively to rehabilitation support and improvement of in-patient care. The research project eSHOE aspires to be a useful addition to the rich variety of gait analysis systems. It was designed to fill the gap of affordable, reasonably accurate and highly mobile measurement devices. With the overall goal of enabling individual home-based monitoring and training for people suffering from chronic diseases, affecting the locomotor system. Motion and pressure sensors gather movement data directly on the (users) feet, store them locally and/or transmit them wirelessly to a PC. A combination of pattern recognition and feature extraction algorithms translates the motion data into standard gait parameters. Accuracy of eSHOE were evaluated against the reference system GAITRite in a clinical pilot study. Eleven hip fracture patients (78.4 +/- 7.7 years) and twelve healthy subjects (40.8 +/- 9.1 years) were included in these trials. All subjects performed three measurements at a comfortable walking speed over 8 m, including the 6-m long GAITRite mat. Six standard gait parameters were extracted from a total of 347 gait cycles. Agreement was analysed via scatterplots, histograms and Bland-Altman plots. In the patient group, the average differences between eSHOE and GAITRite range from 0.046 to 0.045 s and in the healthy group from -0.029 to 0.029 s. Therefore, it can be concluded that eSHOE delivers adequately accurate results. Especially with the prospect as an at home supplement or follow-up to clinical gait analysis and compared to other state of the art wearable motion analysis systems. PMID- 28573911 TI - Framing the transit: expeditionary culture and identities in Lieutenant E.J.W. Noble's caricatures of the 1874 transit of Venus expedition to Honolulu. AB - Making use of a source previously unknown to historians, this article sheds new light on the British expedition to the Sandwich Islands to observe the 1874 transit of Venus. This source, a series of caricature drawings that follow the expedition from departure to return, gives insight into expeditionary culture and the experience of a previously unremarked member of this astronomical expedition, Evelyn J.W. Noble, a career officer of the Royal Marine Artillery. It also reveals overlapping military, scientific and masculine identities, developed in dialogue with, and often deliberately subverting, more public accounts. The article explores this unique source as a product of naval, imperial and expeditionary cultures; as a contribution to the wide textual and visual culture that surrounded the transit expeditions; and as a series of drawings that united the expedition members through the use of humour and irony, by differentiating the group from others they encountered, and by reflecting or rejecting ideas about the nature of scientific work and personae. The artist represented himself not as a serving officer but as part of a (mostly) united group, dedicated to but humorously self-deprecating about their contribution to the scientific effort. PMID- 28573910 TI - Haploidentical hematopoietic stem cell transplantation for adult patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. AB - To assess the efficacy of haploidentical hematopoietic stem cell transplantation (HSCT) in adult patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH), we retrospectively analyzed 30 cases that presented at our institution. At the time of HSCT, 20 patients (66.7%) had achieved a response after receiving HLH-94 or salvage therapies. All patients underwent myeloablative conditioning followed by peripheral blood HSCT from their related, haploidentical donors. Twenty-six patients (86.7%) achieved donor cell engraftment. Of these, 23 (88.5%) achieved complete chimerism and three (11.5%) demonstrated mixed chimerism. Reactivated EBV infection was found in 25 (96.2%). Acute graft-versus-host disease occurred in 18 (69.2%), with grade I-II in 11 patients and grade III-IV in seven. Chronic graft-versus-host disease occurred in six (23.1%). Nineteen patients survived until the end of follow-up. The three year overall survival rate was 63.3%. Our results indicate that haploidentical HSCT is an effective treatment for adult patients with EBV-HLH. PMID- 28573912 TI - Dissecting and customising the Childhood Obesity Prevention Advisory Council (COPAC): the development and application of a community engagement framework to improve childhood obesity prevention among migrant populations. AB - BACKGROUND: Migrant communities in Australia bear a disproportionate childhood obesity burden. They also show poor engagement in obesity prevention initiatives which may contribute to widening obesity disparities. Community engagement has been shown to be effective in reducing health disparities by improving migrant communities' participation in prevention programmes. OBJECTIVE: This study aimed to develop a community engagement framework to improve childhood obesity prevention among migrants. DESIGN: Based on the African Review Panel model and the Community-Based Participatory Research conceptual logic model, the Childhood Obesity Prevention Advisory Council (COPAC) framework was developed and established in four disadvantaged areas in Victoria, Australia. The COPAC included service providers and migrant community members from the same project's site. RESULTS: COPAC demonstrated several benefits including cross-organisational and multidisciplinary collaborations; understanding of the cultural barriers in childhood obesity prevention; enthusiasm from the COPAC members in addressing childhood obesity in their multicultural communities; equitable involvement, motivation, and empowerment of COPAC members in research development; and establishing organisational affiliations to foster long-term community involvement. This study also documented several challenges in community engagement including lack of prioritisation of migration-related childhood obesity disparities by the policymakers; staffing constraints among service providers leading to frequent disruptions in COPAC members' contributions; and lack of adequate training and skill-building of bicultural workers. CONCLUSIONS: The COPAC model adopted a flexible and dynamic community engagement process to suit the ongoing needs of the migrant community which incorporated the existing talents and resources within the community. For effective community engagement of migrant communities, it is important for policymakers to develop the knowledge, capacity and skills of the bicultural migrant workforce. Integrating both service providers and migrant community members in the COPAC has demonstrated that a multifaceted community-led approach has the potential to reduce childhood obesity related disparities in Australia. PMID- 28573913 TI - The immunogenicity and safety of GSK's recombinant hepatitis B vaccine in adults: a systematic review of 30 years of experience. AB - INTRODUCTION: Engerix B (GSK HepB, GSK, Belgium) was the first recombinant hepatitis B virus vaccine to be licensed, and marked its 30th anniversary in 2016. Vaccination of adult populations against HBV is usually implemented on a risk-based approach with varying degrees of success. Confirmation of ongoing vaccine effectiveness requires monitoring the performance of HBV immunization as reported in individual studies, using systematic methods. Areas covered: We conducted a systematic review of the literature to summarize 30 years of immunogenicity and safety data for GSK HepB in adult populations. Expert commentary: Primary 3-dose vaccination of healthy individuals is generally associated with seroprotection rates of 90% or more, although seroprotection decreases with older age. Accelerated 0, 1, 2-month or 0, 7 and 21-day schedules require the recommended booster dose to achieve similar rates of seroprotection. Lower rates of seroprotection were also observed in adults with underlying chronic disease and with a weakened immune system. GSK HepB had a clinically acceptable safety profile in all of the populations studied, including individuals with underlying co-morbidities and immunosuppression. GSK HepB will continue to contribute to global HBV control for the foreseeable future. Further investigation is needed into how to optimize seroprotection in less immune competent groups. PMID- 28573915 TI - Are Latinos Who Commit Sexual Offenses Different? A Closer Examination of Characteristics and Offense Patterns. AB - Research examining ethnic and cultural differences among individuals who commit sex offenses remains limited. Specifically, literature focusing on sex offenses committed by Latinos is scarce. Using archival data from a large sample of individuals who committed sex offenses, this study explored differences between Latino, White, and African American individuals related to their characteristics, the offenses, and the victims. Latinos in the sample were more likely to have a lower educational level, and to be living with the victim, than either their White or African American counterparts. To further understand the influence of cultural background, the study also examined differences within the Latino group based on their country of origin. Within the Latino sample, differences emerged in their educational level, criminal background, and psychiatric history. These findings are discussed as they pertain to future research and current practices related to the management and treatment of Latinos who commit sexual offenses. PMID- 28573916 TI - Peripheral T-cell lymphomas: very little good, mainly the bad and the ugly. PMID- 28573917 TI - Transplantation of allogeneic adipose-derived mesenchymal stem cells in a cerebral palsy patient (Retracted). AB - This article was retracted on 25/08/2017. PMID- 28573914 TI - Treatment strategies for DNA repair-deficient prostate cancer. AB - INTRODUCTION: Common recurrent genetic alterations have been identified in prostate cancer through comprehensive sequencing efforts, and the prevalence of mutations in DNA repair pathway genes in patients with advanced and metastatic disease approaches 20-25%. Identification of these underlying DNA repair defects may present unique treatment opportunities for patients, both in terms of standard-of-care treatments and selected investigational agents. Areas covered: We review our current understanding of the genomic landscape of prostate cancer, with special attention to alterations in DNA repair pathway genes in metastatic castration-resistant disease. For patients with tumors deficient in homologous recombination repair, potential opportunities for treatment include platinum chemotherapy, poly(ADP) ribose polymerase (PARP) inhibitors, bipolar androgen therapy, and maybe immune checkpoint blockade therapy. In addition, tumors with mismatch repair defects (i.e. microsatellite instability) may be particularly susceptible to checkpoint blockade immunotherapy. Expert commentary: We anticipate that genomic profiling of tumors will become necessary to guide treatment of advanced prostate cancer in the coming years. Work is needed to define the optimal tissue to test, and to define the natural history of tumors with specific genetic defects. The prognostic and therapeutic importance of germline vs somatic DNA repair alterations, and mono-allelic vs bi-allelic inactivation, also remains unclear. Finally, optimal strategies to sequence or combine targeted agents for these patients with 'actionable' mutations are now needed. PMID- 28573918 TI - From the Editor. PMID- 28573919 TI - Propensity score analysis with partially observed covariates: How should multiple imputation be used? AB - Inverse probability of treatment weighting is a popular propensity score-based approach to estimate marginal treatment effects in observational studies at risk of confounding bias. A major issue when estimating the propensity score is the presence of partially observed covariates. Multiple imputation is a natural approach to handle missing data on covariates: covariates are imputed and a propensity score analysis is performed in each imputed dataset to estimate the treatment effect. The treatment effect estimates from each imputed dataset are then combined to obtain an overall estimate. We call this method MIte. However, an alternative approach has been proposed, in which the propensity scores are combined across the imputed datasets (MIps). Therefore, there are remaining uncertainties about how to implement multiple imputation for propensity score analysis: (a) should we apply Rubin's rules to the inverse probability of treatment weighting treatment effect estimates or to the propensity score estimates themselves? (b) does the outcome have to be included in the imputation model? (c) how should we estimate the variance of the inverse probability of treatment weighting estimator after multiple imputation? We studied the consistency and balancing properties of the MIte and MIps estimators and performed a simulation study to empirically assess their performance for the analysis of a binary outcome. We also compared the performance of these methods to complete case analysis and the missingness pattern approach, which uses a different propensity score model for each pattern of missingness, and a third multiple imputation approach in which the propensity score parameters are combined rather than the propensity scores themselves (MIpar). Under a missing at random mechanism, complete case and missingness pattern analyses were biased in most cases for estimating the marginal treatment effect, whereas multiple imputation approaches were approximately unbiased as long as the outcome was included in the imputation model. Only MIte was unbiased in all the studied scenarios and Rubin's rules provided good variance estimates for MIte. The propensity score estimated in the MIte approach showed good balancing properties. In conclusion, when using multiple imputation in the inverse probability of treatment weighting context, MIte with the outcome included in the imputation model is the preferred approach. PMID- 28573921 TI - Sex Offender Mobility: An Application of Crime Pattern Theory Among Child Sex Offenders. AB - Sex offenders are a heterogeneous group and exhibit various offense patterns. Often the location where the offender committed the offense is different from where the offender encountered their victim. Applying crime pattern theory, this study sought to understand if the type of location, victim, and situational characteristics could predict whether an offender would commit the sexual offense in a different and more secluded location than where he first encountered the victim. Among a sample of 114 incarcerated sex offenders, the results showed that offenders who contacted their victims in locations where children are known to congregate were more than 4 times more likely to travel to a more secluded location to complete the sexual offense. Those who used noncoercive strategies (e.g., bribes, seduction) during the offense process were approximately 7 times more likely to travel to a more secluded location that those who did not. Policy implications of the findings are discussed. PMID- 28573922 TI - Determining the binding site and binding affinity of estradiol to human serum albumin and holo-transferrin: fluorescence spectroscopic, isothermal titration calorimetry and molecular modeling approaches. AB - The interactions between estradiol and two carrier proteins, i.e. human serum albumin (HSA) and holo-transferrin (HTF) in aqueous solution at pH = 7.4 were studied by three-dimensional fluorescence emission spectroscopy, isothermal titration calorimetry (ITC), zeta-potential, resonance light-scattering and molecular modeling. Extensive fluorescence quenching was observed throughout the interaction between the drug and both proteins. Moreover, conformational changes were determined by observing the rearrangement of Trp residues during binding of estradiol with HSA and HTF at different concentrations. ITC experiments revealed that, in the presence of estradiol, both van der Waals forces and hydrogen bonding became predominant. In addition, other binding parameters such as enthalpy and entropy changes were determined by the zeta potential method. Molecular modeling suggested that estradiol was situated within sub-domain IB sited in the hydrophobic cluster in Site I, whereas the drug was located in the N terminal of HTF where it was hydrogen bonded with Ala 670. PMID- 28573923 TI - Combined photothermal and photodynamic therapy by hyaluronic acid-decorated polypyrrole nanoparticles. AB - AIM: To develop a nanoparticle-based platform using polypyrrole and IR-780 for effective combined photothermal and photodynamic therapy. MATERIALS & METHODS: IR 780 was loaded in a poly(lactic-co-glycolic acid) core, decorated with polypyrrole shells and hyaluronic acid (IPPH). Physicochemical properties and in vitro and in vivo anticancer effects of these nanoparticles were evaluated. RESULTS: The resulting IPPHs were spherical, small and negatively charged. Under near-infrared laser irradiation, the IPPHs generated reactive oxygen species and heat and synergistically improved therapeutic efficacy. The antitumor effects were confirmed by in vitro cellular reactive oxygen species detection and cytotoxicity assays, and in vivo in a xenograft tumor model, with no damage to body organs. CONCLUSION: Our results indicate the potential of applying IPPH in oncology nanomedicine. PMID- 28573924 TI - The lack of association between vascular endothelial growth factor and retinopathy of prematurity in an observational study. AB - PURPOSE: The objective of this study was to investigate the association between prematurity, vascular endothelial growth factor A (VEGF-A), VEGFR-1 (soluble fms like tyrosine kinase-1 (sFLT-1)) and retinopathy of prematurity (ROP). METHODS: A cohort of 53 neonates (gestation <28 weeks) was recruited into this study and peripheral venous samples for VEGF and sFLT-1 measurement were obtained between gestational ages 320-326 weeks. RESULTS: The mean birth weight for the preterm neonates was 850 (178) g and the median gestational age was 26.4 [24.7-27.4] weeks. The median VEGF-A level was 1348 [608-2216] pg/mL and the median sFLT-1 level was 178 [103-244] pg/mL. Thirty-three neonates (33/53) developed various stages of ROP during their stay in the neonatal unit but only five neonates developed severe (stage 3) ROP needing treatment. The neonates with ROP were smaller (birth weight 801 (111) vs. 990 (175) g; p < .0001), more preterm (gestation 25.4 [24.2-26.0] vs. 27.1 [26.8-27.9] weeks; p < .0001) and received supplemental oxygen for a longer duration (1140 [218-1813] vs. 04 [40-434] hours; p= .012). There was no statistically significant difference in the VEGF-A level or sFLT-1 levels between those who developed ROP and those who did not. There was a positive correlation between VEGF and both birth weight and gestation, respectively. There was no correlation between sFLT1 and birth weight or gestation. VEGF-A/sFLT-1 ratio in babies treated for ROP was significantly lower compared to those not treated (2.8 [1.0-5.7] vs. 9.9 [5.6-13.7]; p = .04). A logistic regression model identified gestational age to be a statistically significant predictor of ROP (odds ratio 0.03 (0.001-0.550); p = .019). CONCLUSIONS: There is no direct correlation between systemic VEGF-A or sFLT-1 plasma levels and severity of ROP in extremely preterm neonates. The link between VEGF and ROP remains to be fully understood. PMID- 28573925 TI - Radiation-induced esophageal strictures treated with fluoroscopic balloon dilation: clinical outcomes and factors influencing recurrence in 62 patients. AB - Background Balloon dilation is safe and effective for the treatment of radiation induced esophageal stricture (RIES), with favorable short-term and mid-term outcomes; however, few reports of long-term outcomes exist. Few studies have evaluated factors associated with recurrence after balloon dilation. Purpose To evaluate the long-term outcome of balloon dilation in patients with RIES and to identify factors associated with stricture recurrence. Material and Methods The medical records of 62 consecutive patients who had undergone fluoroscopic balloon dilation for RIES at our institution between December 1998 and June 2016 were reviewed. Results One hundred and twenty balloon dilation sessions were performed in 62 patients (mean = 1.9 sessions per patient). Clinical success was achieved in 53 (86%) patients after single (n = 37) or multiple (n = 16) dilation sessions. Complications occurred in 27% of the dilation sessions. The primary patency rates at one, two, three, and five years were 60%, 56%, 52%, and 52%, respectively. Secondary patency rates at one, two, three, and five years were 87%, 85%, 85%, and 80%, respectively. Multivariate logistic regression analysis identified an interval from radiation therapy (RT) to stricture of >=6 months (hazard ratio [HR] = 0.205; P < 0.001), strictures located at the cervical esophagus (HR = 5.846; P < 0.001), and stricture length of >=2 cm (HR = 2.923; P = 0.006) as significant predictors of recurrence. Conclusion Despite the high incidence of ruptures and recurrences, fluoroscopic balloon dilation is valuable as an initial therapeutic option for patients with RIES. PMID- 28573926 TI - Curcumin-loaded chitosan-cholesterol micelles: evaluation in monolayers and 3D cancer spheroid model. AB - AIM: To improve the bioavailability and anticancer potential of curcumin by using a cholesterol-conjugated chitosan micelle. Methods & methods: Cholesterol was conjugated to chitosan (15 kDa) to form self-assembled micelles, which loaded curcumin. Physicochemical characterization and formulation optimization of the drug-loaded micelles (curcumin-loaded chitosan-cholesterol micelles [C-CCM]) were performed. In vitro cellular uptake and viability of C-CCM were investigated in melanoma and breast cancer cell lines. The antitumor efficacy was evaluated in 3D lung cancer spheroid model. RESULTS & CONCLUSION: The optimized C-CCM had size of approximately 162 nm with loading efficiency of approximately 36%. C-CCM was taken up efficiently by the cells, and it reduced cancer cell viability significantly compared with free curcumin. C-CCM enhanced the antitumor efficacy in spheroids, suggesting that C-CCM could be used as an effective chemotherapy in cancer. PMID- 28573927 TI - Psychometric evaluation of the Moral Distress Risk Scale: A methodological study. AB - BACKGROUND: Moral distress is a kind of suffering that nurses may experience when they act in ways that are considered inconsistent with moral values, leading to a perceived compromise of moral integrity. Consequences are mostly negative and include physical and psychological symptoms, in addition to organizational implications. OBJECTIVE: To psychometrically test the Moral Distress Risk Scale. RESEARCH DESIGN: A methodological study was realized. Data were submitted to exploratory factorial analysis through the SPSS statistical program. Participants and research context: In total, 268 nurses from hospitals and primary healthcare settings participated in this research during the period of March to June of 2016. Ethical considerations: This research has ethics committee approval. FINDINGS: The Moral Distress Risk Scale is composed of 7 factors and 30 items; it shows evidence of acceptable reliability and validity with a Cronbach's alpha = 0.913, a total variance explained of 59%, a Kaiser-Meyer-Olkin = 0.896, and a significant Bartlett <0.001. DISCUSSION: Concerns about moral distress should be beyond acute care settings, and a tool to help clarify critical points in other healthcare contexts may add value to moral distress speech. CONCLUSION: Psychometric results reveal that the Moral Distress Risk Scale can be applied in different healthcare contexts. PMID- 28573928 TI - Diversity of mitochondrial plastid DNAs (MTPTs) in seed plants. AB - Mitochondrial plastid DNAs (MTPTs) refer to plastid-derived DNA fragments in mitochondrial genomes. While the MTPTs have been described for numerous species, its overall patterns have not been examined in details. Here, we carried out a systematic analysis of MTPTs among 73 plant species, including 28 algae, 1 liverwort, 2 moss, 1 lycophyte, 1 gymnosperm, 1 magnoliid, 12 monocots, 26 eudicots and 1 relic angiosperm Amborella trichopoda. A total of 300 MTPT gene clusters were found in 39 seed plants, which represented 144 MTPT gene cluster types. The detected MTPT gene clusters were evaluated in seven aspects, and they were found to be enriched particularly in monocots and asterids of eudicots. Some MTPT gene clusters were found to be shared by closely related species. All chloroplast genes were found in MTPTs, suggesting that there is no functional relevancy for genes that were transferred. However, after calculation of the frequency of the 115 chloroplast genes, five hot spots and three cold spots were discovered in chloroplast genome. In summary, this study demonstrated the high degree of diversity in MTPTs. The discovered MTPTs would facilitate the accurate assembly of chloroplast and mitochondrial genomes as well as the understanding of organelle genome evolution. PMID- 28573930 TI - Editorial. PMID- 28573929 TI - Potential for Interfraction Motion to Increase Esophageal Toxicity in Lung SBRT. AB - PURPOSE: To characterize the effect of the relative motion of esophagus and tumor on radiation doses to the esophagus in patients treated with stereotactic body radiation therapy for central lung tumors. METHODS AND MATERIALS: Fifty fractions of stereotactic body radiation therapy in 10 patients with lung tumors within 2.5 cm of the esophagus were reviewed. The esophagus was delineated on each treatment's cone-beam computed tomography scan and compared to its position on the planning scan. Dose-volume histograms were calculated using the original treatment beams to determine the actual dose delivered to the esophagus for each fraction of stereotactic body radiation therapy. RESULTS: Median interfraction right-left shift of the esophagus was 0.9 mm (range, -5.4 to 3.3 mm) toward the left. Median interfraction anteroposterior shift was 0.7 mm (range, -3.7 to 11.5 mm) posteriorly. The median percentage increase in dose to 1 cm3, dose to 3.5 cm3, and dose to 5 cm3 was 1.7%, 5.6%, and 6.6%, respectively. Two cases of significant late esophageal toxicity were observed, with change in esophageal position relative to the planning target volume resulting in significantly higher D5cc values than anticipated. CONCLUSION: Interfraction shifts between the internal target volume and esophagus can lead to unanticipated increases in the volume of esophagus receiving high doses when treating central lung tumors with stereotactic body radiation therapy. Certain practical steps, such as considering deep breath hold for internal target volume reduction, using a planning risk volume for esophagus, and carefully visualizing and considering esophageal position at the time of stereotactic body radiation therapy, can be taken to minimize unanticipated dose increases that could cause unexpected esophageal toxicity. PMID- 28573931 TI - Third trimester growth restriction patterns: individualized assessment using a fetal growth pathology score. AB - OBJECTIVE: To qualitatively and quantitatively characterize third trimester growth patterns in fetuses/neonates with growth restriction using Individualized Growth Assessment. METHODS: Serial fetal size measurements from 73 fetuses with proven growth restriction were evaluated using a novel composite parameter, the Fetal Growth Pathology Score (FGPS1). Third trimester FGPS1 measurements plotted against fetal age were examined for patterns. Identified patterns were characterized using the four components of the FGP1 [head circumference (HC), abdominal circumference (AC), femur diaphysis length (FDL), estimated weight (EWT)]. A secondary characterization using age of onset, duration and magnitude of the growth abnormality process was also performed. Frequencies and magnitudes of abnormal values in different FGPS1 patterns were compared. RESULTS: Five growth restriction patterns were found in 70/73 (95.9%) of the cases, with progressive worsening [Pattern 1 (37.0%)] and abnormal growth identified only at last scan [Pattern 2 (27.4%)] being the most common. These two patterns were usually statistically different from each other and the other three with respect to size parameter abnormalities and abnormal growth process characteristics (MANOVA). Growth abnormalities in all parameters of the FGPS1 contributed to the five abnormality patterns although AC and EWT were most important. The age of onset, duration and magnitude were similar between patterns except for Pattern 2, which had a late onset and a short duration (GLM + contrasts). CONCLUSIONS: Our study represents the first detailed evaluation of third trimester growth restriction using methods that consider the growth potential of each fetus. Five distinctive and repetitive patterns were found, suggesting that fetal growth restriction evolves in different ways. Further research is needed to determine the relationships of these patterns to physiological/biochemical changes and adverse outcomes associated with growth restriction. PMID- 28573933 TI - Improving the Effectiveness of the Process of Postdischarge Communication Between Hospitalists and Referring Providers. PMID- 28573932 TI - Efficacy and Safety of Uninterrupted Low-Intensity Warfarin for Radiofrequency Catheter Ablation of Atrial Fibrillation in the Elderly. AB - BACKGROUND: No previous studies exist investigating the optimal intensity of uninterrupted anticoagulation with warfarin during radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) in the elderly. OBJECTIVE: Evaluate the efficacy and safety of continuous low-intensity warfarin therapy throughout the periprocedural period of RFCA for AF in the elderly. METHODS: This is a prospective randomized study. We enrolled AF patients (age >= 70 years) who underwent first-time RFCA for AF. Enrolled patients were randomized to group A and group B. The international normalized ratios before ablation were maintained at 1.5 to 2.0 and 2.0 to 2.5 in group A and B, respectively. Primary end points were periprocedural thromboembolic complications and major bleeding. Secondary end points included periprocedural asymptomatic cerebral emboli (ACE) and minor bleeding. RESULTS: A total of 101 patients were enrolled in our study (group A: 52; group B: 49). Baseline characteristics were well balanced between the 2 groups. Only 1 patient suffered from stroke in group B. No major bleeding events occurred in either group. The incidence of new ACE lesions was comparable between the 2 groups (11.5% vs 8.2%, P = 0.82). Minor bleeding occurred in 1 of 52 (1.9%) patients in group A and in 5 of 49 (10.2%) patients in group B ( P = 0.10). CONCLUSIONS: Uninterrupted low-intensity warfarin for RFCA of AF might be as effective as standard-intensity warfarin in preventing periprocedural thromboembolic complications and might be associated with fewer bleeding events in the elderly. PMID- 28573934 TI - Testicular Fibrous Hypoplasia in Cynomolgus Monkeys ( Macaca fascicularis): An Incidental, Congenital Lesion. AB - Testicular fibrous hypoplasia is an incidental lesion characterized by replacement of the testicular parenchyma by mature collagen. A retrospective survey of hematoxylin and eosin-stained testicular sections from 722 purpose-bred Asian and 90 Mauritian cynomolgus monkeys from 56 safety assessment studies conducted between 1999 and 2011 was performed. The incidence of the lesion increased markedly over time. No cases occurred between 1999 and 2004. Between 2005 and 2009, the incidence ranged between 8.1% and 11.0% of the monkeys examined and then rose to 26.1% in 2010 and 30.9% in 2011. Overall, the lesion was identified in 10.94% of Asian monkeys with the highest incidence in animals originating from China and Vietnam; severity ranged from minimal to severe and it occurred unilaterally (38.5%) and bilaterally (61.5%). In Mauritian monkeys, the lesion was predominantly minimal in severity, bilateral in distribution, and affected 6.6% of the animals examined. The lesion occurred regardless of sexual maturation status but when present in mature monkeys was often associated with cystic tubular atrophy of the seminiferous epithelium. Based on the morphological characteristics of the lesion and the unilateral/bilateral distribution, the lesion is considered to be a congenital or developmental abnormality. PMID- 28573935 TI - The NADPH Oxidase Inhibitor Apocynin Suppresses Preneoplastic Liver Foci of Rats. AB - Reactive oxygen species (ROS) have been revealed to be important factors for carcinogenesis and tumor progression. Therefore, we focused on an ROS-generating protein, nicotinamide adenine dinucleotide phosphate oxidase, and evaluated whether its inhibitor, apocynin, could suppress hepatocarcinogenesis in a medium term rat liver bioassay. The number and size of glutathione S-transferase placental form (GST-P)-positive foci were significantly reduced by apocynin in a dose-dependent manner. The reduction of ROS generation by apocynin was confirmed by dihydroethidium staining. Apocynin treatment also significantly reduced Ki-67 positivity, downregulated cyclooxygenase 2, and suppressed the activation of the c-Myc pathway. Meanwhile, ROS generation was not different between GST-P-positive foci and surrounding GST-P-negative areas of the liver. In conclusion, the present data suggest that apocynin possesses a potential antihepatocarcinogenic property. PMID- 28573936 TI - Exploring Variation in Certified Nursing Assistant Assignments From the Perspective of Nursing Home Residents: A Comparison of Adopters and Nonadopters of Consistent Assignment. AB - OBJECTIVE: To describe and compare certified nursing assistant (CNA) staffing between adopter and nonadopters of consistent assignment. DATA SOURCES: One month of preexisting CNA assignment and scheduling sheets from a purposive sample of 30 homes. STUDY DESIGN: A descriptive comparative study was conducted to calculate and compare numbers of CNAs assigned per resident across homes. DATA EXTRACTION: Resident names and CNA assignments were abstracted from assignment records and entered into the Advancing Excellence consistent assignment tool to calculate numbers of CNAs assigned per resident. PRINCIPAL FINDINGS: Both variation and overlap existed in the number of CNAs per resident within and between homes. Adopters assigned significantly fewer CNAs per resident. CONCLUSION: Research is needed to determine how assignment variations affect resident perceptions of quality. PMID- 28573938 TI - Long-term gait pattern assessment using a tri-axial accelerometer. AB - In this article, we present a pervasive solution for gait pattern classification that uses accelerometer data retrieved from a waist-mounted inertial sensor. The proposed algorithm has been conceived to operate continuously for long-term applications. With respect to traditional approaches that use a large number of features and sophisticated classifiers, our solution is able to assess four different gait patterns (standing, level walking, stair ascending and descending) by using three features and a decision tree. We assess the algorithm detection performances using data that we retrieved from a validation group composed by nine young and healthy volunteers, for a total number of 36 tests and 12.5 h of recorded acceleration data. Experimental results show that in continuous applications the proposed algorithm is able to effectively discriminate between standing (100%), level walking (~99%), stair ascending (~84%), and descending (~85%), with an average classification accuracy for the four patterns that exceeds 92% in continuous, long-lasting applications. PMID- 28573937 TI - Using the COMMVAC taxonomy to map vaccination communication interventions in Mozambique. AB - BACKGROUND: Improved communication about childhood vaccination is fundamental to increasing vaccine uptake in low-income countries. Mozambique, with 64% of children fully vaccinated, uses a range of communication interventions to promote uptake of childhood immunisation. OBJECTIVES: Using a taxonomy developed by the 'Communicate to Vaccinate' (COMMVAC) project, the study aims to identify and classify the existing communication interventions for vaccination in Mozambique and to find the gaps. METHODS: We used a qualitative research approach to identify the range of communication interventions used in Mozambique. In-depth semi-structured interviews were carried out with key purposively selected personnel at national level and relevant documents were collected and analysed. These data were complemented with observations of communication during routine vaccination and campaigns in Nampula province. We used the COMMVAC taxonomy, which organises vaccination communication intervention according to its intended purpose and the population targeted, to map both routine and campaign interventions. RESULTS: We identified interventions used in campaign and routine vaccination, or in both, fitting five of the seven taxonomy purposes, with informing or educating community members predominating. We did not identify any interventions that aimed to provide support or facilitate decision-making. There were interventions for all main target groups, although fewer for health providers. Overlap occurred: for example, interventions often targeted both parents and community members. CONCLUSIONS: We consider that the predominant focus on informing and educating community members is appropriate in the Mozambican context, where there is a high level of illiteracy and poor knowledge of the reasons for vaccination. We recommend increasing interventions for health providers, in particular training them in better communication for vaccination. The taxonomy was useful for identifying gaps, but needs to be more user-friendly if it is to be employed as a tool by health service managers. PMID- 28573939 TI - Is centre-based provision of hearing aids better than community-based provision? A cluster-randomized trial among adolescents in Bangladesh. AB - PURPOSE: In response to the need for hearing aids in low-income countries, an approach to provide hearing aids through trained community workers was developed. This study compares the effectiveness of the community-based approach with that of a centre-based approach. METHODS: One hundred and forty adolescents (56% girls; 12-18 years; mean: 15 years) from eleven sub-districts participated in a cluster-randomized trial comparing a community-based service (n = 75) with a centre-based service (n = 65) in Bangladesh. The International Outcome Inventory for Hearing Aids (IOI-HA) was administered to the participants six weeks after fitting of a hearing aid, and its scores were analyzed by Mann-Whitney U-tests and an ordinal regression model. RESULTS: The community-based approach performed as well as the centre-based approach on five out of seven outcome measures. The latter approach performed statistically significantly better on Residual participation restrictions (p = .007) and Impact on others (p = .012), but the effect sizes were small. Controlling for sex, age, hearing loss, place of living and proxy responses did not change the results. CONCLUSIONS: The community-based approach is a viable and effective option for hearing aid delivery in low resourced settings. The approach needs to be adapted to particular contexts, and possible down-sides may need to be counteracted by special interventions. Implications for Rehabilitation Hearing aid use can contribute to improved activity, participation and quality of life among adolescents in low-income countries. Community-based approaches to delivering hearing aids can be viable and effective options to centre-based services. PMID- 28573940 TI - Successful treatment of intrauterine cytomegalovirus infection with an intraventricular cyst in a dichorionic diamniotic twin gestation using cytomegalovirus immunoglobulin. AB - Congenital cytomegalovirus (CMV) infection is the leading cause of severe congenital abnormalities. CMV immunoglobulin (CMVIG) may lower risk for symptomatic disease in congenital CMV infection. In a twin pregnancy, only one fetus shows CMV infection, raising a dilemma about intervention since the uninfected fetus would be exposed to treatment unnecessarily. CMVIG (2 * 200 U/kg) was given due to high viral load and development of an intraventricular cyst. The cyst growth plateaued, no other brain damage developed, and at 8 months, the infant was symptom-free. CMVIG appears appropriate to treat intrauterine CMV infection in this setting. PMID- 28573941 TI - Neonatal outcomes following a trial of labor after Caesarean delivery: a population-based study. AB - PURPOSE: To evaluate the neonatal effects of trial of labor after Caesarean (TOLAC) births. METHODS: We conducted a retrospective population-based cohort study using the CDC's Period Linked Birth/Infant Death Public Use File (2011 2013) on women with a live singleton pregnancy and prior Caesarean delivery. Multivariate logistic regression compared neonatal outcomes between women who underwent a TOLAC with women who did not. Secondary analysis compared outcomes of birth with uterine rupture to those without. RESULTS: A total of 1,036,554 births met inclusion criteria, of which 17.5% underwent TOLAC. Women who had a TOLAC were more likely to deliver infants requiring neonatal intensive care unit (NICU) admission (odds ratios (OR) 1.12, 95%CI 1.09-1.16) and assisted ventilation (OR 1.07, 95%CI 1.03-1.12). Among women with TOLAC, 0.18% of births were in context of a uterine rupture and those neonates had an increased risk of NICU admissions (OR 5.95, 95%CI 4.56-7.76), assisted ventilation (OR 8.89, 95%CI 6.73-11.75), seizures (OR 91.66, 95%CI 42.23-198.93), and death (OR 16.28, 95%CI 5.09-52.08). CONCLUSIONS: Neonatal morbidity appears slightly increased among women with a TOLAC. However, morbidity and mortality are considerably increased in cases of uterine rupture. Appropriate selection and counseling of women for TOLAC should be undertaken as to minimize uterine rupture risk. PMID- 28573942 TI - Parents' experiences of conducting a goal-directed intervention based on children's self-identified goals, a qualitative study. AB - AIM/OBJECTIVE: To explore and describe parents' perceptions and experiences of conducting a goal-directed intervention focused on children's self-identified goals. MATERIAL AND METHODS: Individual semi-structured interviews were performed with nine parents (8 mothers, 1 father). All the parents had participated actively in conducting a goal-directed intervention addressing their children's self-identified goals. The interviews were analyzed using qualitative content analysis. RESULTS: From a parental perspective, working on children's self identified goals was a positive experience. The findings revealed three categories: Goals challenged the parents describes the parents' experiences of the complexity of goal setting. The intervention demanded an intensive and flexible parental engagement; here the parents expressed the importance of active parental engagement, which for some parents could be challenging. The child's personal goals gave more than anticipated describes the parents' experiences of how the children's personal goals positively influenced the children's self esteem, increased the children's motivation for practice, and helped the children develop more than the parents had anticipated. CONCLUSIONS AND SIGNIFICANCE: In the parents' experience, goal-directed intervention comprehensively relies on their engagement. Follow up's from the occupational therapist motivated the parents and their own child's personal goals gave them more than they could have expected. This indicates the importance of supporting parents and letting children actively participate in the goal setting process. PMID- 28573943 TI - Applying the Integrated Behavior Change Model to Understanding Physical Activity Among Older Adults: A Qualitative Study. AB - We explored older adults' experiences of physical activity (PA) and related decision-making processes underlying PA. Twenty Australians (Mage = 73.8 years) participated in semistructured interviews. Data were analyzed using thematic analysis, and identified themes were matched deductively within motivational, volitional, and implicit processes of the integrated behavior change model for PA. Motivational influences such as participants' time orientation toward health and perceptions of what PA should be like were frequently featured in participants' narratives. Volitional processes were also identified, with participants reporting different ways of coping with competing priorities. Physical surroundings and habitual PA were the identified themes within implicit processes. Together, these findings contribute to a better understanding of subjective experiences of older adults regarding PA. They also add to a more contextual understanding of multiple decision-making processes underpinning older adults' PA engagement. Identified concepts may be used in future research and PA interventions targeting older adults. PMID- 28573944 TI - Stress through the mind of the beholder: preliminary differences in child and maternal perceptions of child stress in relation to child cortisol and cardiovascular activity. AB - The present study examined associations among parent and child reports of youth's stressful life events (SLEs), perceived stress, and biological measures of stress activity (i.e. cortisol and cardiovascular activity). Examining these aspects of youth stress presents several challenges. Unlike adult studies of individual differences in which information regarding SLEs, perceptions of events, and biological activity are gathered from one individual, assessment of individual differences among children usually involves other informants (e.g. parent). However, parent and child reports of SLEs and the child's psychological response to such events are often discordant. Moreover, examinations of youth perception of stress are hampered by limitations of child cognitive processes, as well as parents' limited knowledge of their child's perception of stress. In a preliminary effort to unscramble the complex effects of youth SLEs and perceived stress in relation to biological response to acute stressors, this study examined 51 boys and girls aged 7-16, with no history of psychopathology or medical concerns. Contrary to hypotheses, findings revealed that compared to actual experiences of stress, perceived stress has greater associations with both cortisol and cardiovascular activity. That is, perceived stress is more biologically salient relative to actual stress. Results also suggest that informant differences may explain some previous inconsistent findings in studies of youth's stress reactivity. The current findings mirror the adult studies that show appraisal and perception of traumatic and stressful events may be more predictive of negative health and mental health outcomes than the severity of the events. Further studies are needed to understand the impact of youth's perceptions of stress on their biological stress reactions and later health outcomes such as clinical disorders. PMID- 28573945 TI - Resuscitation practices of low and normal birth weight infants in Nepal: an observational study using video camera recordings. AB - BACKGROUND: The global burden of stillbirth and neonatal deaths remains a challenge in low-income countries. Training in neonatal resuscitation can reduce intrapartum stillbirth and early neonatal mortality. Previous results demonstrate that infants who previously would have been registered as stillbirths are successfully resuscitated after such training, suggesting that there is a process of selection for resuscitation that needs to be explored. OBJECTIVE: To compare neonatal resuscitation of low birth weight and normal birth weight infants born at a facility in a low-income setting. METHODS: Motion-triggered video cameras were installed above the resuscitation tables at a maternity health facility during an intervention study (ISRCTN97846009) employing the Helping Babies Breathe resuscitation protocol in Kathmandu, Nepal. Recordings were analysed, noting crying, stimulation, ventilation, suctioning and oxygen administration during resuscitation. Birth weight, Apgar scores and sex of the infant were retrieved from matched hospital registers. The results were analysed by chi square and logistic regression. RESULTS: A total of 2253 resuscitation cases were recorded. Low birth weight infants in need of resuscitation had higher odds of receiving ventilation (aOR 1.73, 95% CI 1.24-2.42) and lower odds of receiving suctioning (aOR 0.53, 95% CI 0.34-0.82) after adjustment for the Helping Babies Breathe intervention, sex of the infant and place of resuscitation within the facility. The rates of stimulation and administration of oxygen were the same in both groups. CONCLUSIONS: Low birth weight was associated with more ventilation and less suctioning during neonatal resuscitation in a low-income setting. As ventilation is the most important intervention when the infant does not initiate breathing after birth, low birth weight was not a predictor for the decision to withhold resuscitation. Frequent routine use of suctioning of the lower airways continues to be a problem in the studied context, even after the introduction of the Helping Babies Breathe protocol. PMID- 28573947 TI - ? PMID- 28573946 TI - Influence of cytarabine metabolic pathway polymorphisms in acute myeloid leukemia induction treatment. AB - Cytarabine is considered the most effective chemotherapeutic option in acute myeloid leukemia (AML). The impact of 10 polymorphisms in cytarabine metabolic pathway genes were evaluated in 225 adult de novo AML patients. Variant alleles of DCK rs2306744 and CDA rs602950 showed higher complete remission (p = .024, p = .045), with lower survival rates for variant alleles of CDA rs2072671 (p = .015, p = .045, p = .032), rs3215400 (p = .033) and wild-type genotype of rs602950 (p = .039, .014). Induction death (p = .033) and lower survival rates (p = .021, p = .047) were correlated to RRM1 rs9937 variant allele. In addition, variant alleles of CDA rs532545 and rs602950 were related to skin toxicity (p = .031, p = .049) and mucositis to DCK rs2306744 minor allele (p = .046). Other toxicities associated to variant alleles were hepatotoxicity to NT5C2 rs11598702 (p = .032), lung toxicity (p = .031) and thrombocytopenia to DCK rs4694362 (p = .046). This study supports the interest of cytarabine pathway polymorphisms regarding efficacy and toxicity of AML therapy in a coherent integrated manner. PMID- 28573948 TI - ? PMID- 28573950 TI - ? PMID- 28573949 TI - ? PMID- 28573951 TI - ? PMID- 28573952 TI - ? PMID- 28573953 TI - ? PMID- 28573954 TI - ? PMID- 28573955 TI - ? PMID- 28573957 TI - ? PMID- 28573956 TI - ? PMID- 28573959 TI - ? PMID- 28573958 TI - ? PMID- 28573960 TI - Sensitive detection of rare antigen-specific T cells directed against Wilms' tumor 1 by FluoroSpot assay. PMID- 28573961 TI - Revising Working Models Across Time: Relationship Situations That Enhance Attachment Security. AB - We propose the Attachment Security Enhancement Model (ASEM) to suggest how romantic relationships can promote chronic attachment security. One part of the ASEM examines partner responses that protect relationships from the erosive effects of immediate insecurity, but such responses may not necessarily address underlying insecurities in a person's mental models. Therefore, a second part of the ASEM examines relationship situations that foster more secure mental models. Both parts may work in tandem. We posit that attachment anxiety should decline most in situations that foster greater personal confidence and more secure mental models of the self. In contrast, attachment avoidance should decline most in situations that involve positive dependence and foster more secure models of close others. The ASEM integrates research and theory, suggests novel directions for future research, and has practical implications, all of which center on the idea that adult attachment orientations are an emergent property of close relationships. PMID- 28573963 TI - Contested evidence: a Dutch reimbursement decision taken to court - CORRIGENDUM. PMID- 28573962 TI - Anatomical integration and rich-club connectivity in euthymic bipolar disorder. AB - BACKGROUND: Although repeatedly associated with white matter microstructural alterations, bipolar disorder (BD) has been relatively unexplored using complex network analysis. This method combines structural and diffusion magnetic resonance imaging (MRI) to model the brain as a network and evaluate its topological properties. A group of highly interconnected high-density structures, termed the 'rich-club', represents an important network for integration of brain functioning. This study aimed to assess structural and rich-club connectivity properties in BD through graph theory analyses. METHOD: We obtained structural and diffusion MRI scans from 42 euthymic patients with BD type I and 43 age- and gender-matched healthy volunteers. Weighted fractional anisotropy connections mapped between cortical and subcortical structures defined the neuroanatomical networks. Next, we examined between-group differences in features of graph properties and sub-networks. RESULTS: Patients exhibited significantly reduced clustering coefficient and global efficiency, compared with controls globally and regionally in frontal and occipital regions. Additionally, patients displayed weaker sub-network connectivity in distributed regions. Rich-club analysis revealed subtly reduced density in patients, which did not withstand multiple comparison correction. However, hub identification in most participants indicated differentially affected rich-club membership in the BD group, with two hubs absent when compared with controls, namely the superior frontal gyrus and thalamus. CONCLUSIONS: This graph theory analysis presents a thorough investigation of topological features of connectivity in euthymic BD. Abnormalities of global and local measures and network components provide further neuroanatomically specific evidence for distributed dysconnectivity as a trait feature of BD. PMID- 28573964 TI - A place in the sun? Healthcare rights of retired UK citizens in Spain post Brexit. AB - At least 100,000 retired UK citizens currently live in Spain. Under EU law, they are entitled to access the Spanish National Health Service (NHS) with minimum administrative difficulty. What will their legal position be under a 'no-deal Brexit'? This is a question of Spanish law. The worst case scenario is that they will have to reapply for their residence permits under the Spanish legislation applicable to non-EU/European Economic Area citizens, with all the administrative inconvenience and cost entailed. If they successfully reapply, their personal health care costs will be considerably higher than at present, should they choose to remain in Spain. Very obvious questions of capacity planning arise. The Spanish system will potentially need to gear up for a significant administrative effort. Given the distinct possibility of a 'no-deal Brexit', the UK NHS should prepare to welcome significant numbers of pensioners home. PMID- 28573965 TI - Characterization of Croatian Rape (Brassica sp.) Honey by Pollen Spectrum, Physicochemical Characteristics, and Multielement analysis by ICP-OES. AB - Rape (Brassica sp.) unifloral honey from Croatia was characterized by certain physicochemical parameters, micro- and macroelement content, and pollen spectrum, as determined in 21 honey samples. The Brassica sp. pollen type was predominant in the analyzed samples and ranged between 60 and 98%, with Trifolium spp., Robinia pseudoacacia, Rosaceae, Helianthus annuus, Salix spp., and Taraxacum officinale as the main accompanying pollen types. The electrical conductivity mean value was 0.22 +/- 0.05 mS/cm and the glucose/fructose ratio mean value was 1.1 +/- 0.07, whereas sucrose was absent in the samples. The most abundant macroelement was potassium (K) (268.49 mg/kg), followed by phosphorus (P) (60.23 mg/kg), calcium (Ca) (54.02 mg/kg), sodium (Na) (22.52 mg/kg), sulfur (S) (15.79 mg/kg), and magnesium (Mg) (12.58 mg/kg). Toxic elements were mainly bellow the LODs; only arsenic (As) concentration was detectable in higher amount (0.233 mg/kg), which may be related to the high arsenic concentration in the soil and groundwater of eastern Croatia. The differences between the two harvesting seasons observed in a large number of elements could be related to climatic and soil conditions and different nectar yields originating from the associated plant species. PMID- 28573966 TI - Learning navigation - Learning with navigation. A review. AB - The goal of this review paper is to retrieve from the existing literature relevant information (1) about the learning curve of the currently existing navigation systems and (2) about the use of navigation system for teaching orthopaedic procedures. All studies reporting on the learning curve of navigation systems support the hypothesis that computer-navigated total knee arthroplasty (TKA) involves only a short learning curve and that beginners can obtain good results from the beginning of their experience, as navigation provides continuous feedback during all phases of the knee replacement surgery and allows for correcting any bone cut errors. Interestingly, there is no comparable research on the learning curve of TKA with standard, manual instrumentation. One might postulate that this learning curve might be longer than with navigation, with potentially a higher rate of outliers. The current literature does support that navigation may be an efficient teaching tool for both experienced orthopaedic surgeons and trainees. Experienced surgeons may improve their skills with conventional techniques and learn new techniques more efficiently and more quickly. Trainees may have a better understanding of the procedure and learn standard techniques with a shorter learning curve. This is probably due to the immediate feedback of navigation systems. A shorter learning curve may be associated with improved clinical and functional results for the patient during this critical period. However, there is no evidence that training with navigation excludes trainees from the need to work in academic environments with experienced teachers. Future techniques in training may include the development of laboratory simulation procedures using navigated feedback. PMID- 28573967 TI - Dual mobility total hip arthroplasty in hemiplegic patients. AB - INTRODUCTION: The rate of cerebrovascular insults is increasing, currently leaving many patients with difficulties to maintain their balance due to muscular weakness and/or poor central control. Those patients are at risk of dislocation when total hip arthroplasty (THA) is planned. Instability remains the most significant issue after primary THA especially in such groups of patients. The risk is more pronounced when other factors are added such as, older age, femoral neck fractures, avascular necrosis and/or hip osteoarthritis. Dual mobility cup (DMC) is considered as a prosthesis with higher inherent stability that may help in such situation. In this patient series, we aimed to evaluate stability, clinical and radiological results of dual mobility THA done on the weak limb of hemiplegic patients. METHODS: Twenty-four consecutive hemiplegic patients have undergone DMC with a mean age of 68 years. The indication for surgery was hip osteoarthritis in one third of the patients and femoral neck fractures in the remaining patients. Those patients were capable of walking prior to hospital admission despite weakness. Those patients were observed postoperatively for at least one year. Clinical results and complications were recorded. RESULTS: After a minimum of one year, 91.6% of the patients have satisfactory results. No cases of hip or intraprosthetic dislocation were observed. DISCUSSION: Dual mobility THA in the hemiplegic patients provides both efficacy and stability with good functional results. PMID- 28573968 TI - Arthroscopic-assisted retrograde mosaicplasty for an osteochondral defect of the femoral head without performing surgical hip dislocation. AB - Osteochondral autograft transplantation (mosaicplasty) for the osteochondral defects of the femoral head is generally performed with safe dislocation of the hip joint. Here, we present a 27-year-old male patient who had a symptomatic osteochondral defect of the femoral head and underwent mosaicplasty applied by hip arthroscopy without surgical hip dislocation. The preoperative radiological evaluation showed a focal osteochondral defect on the weight-bearing surface of the femoral head. With the assistance of hip arthroscopy, the defect area was reconstructed with osteochondral plug, which was taken from the ipsilateral knee, inserted in a retrograde fashion, and positioned with the spherical surface of the femoral head cartilage under fluoroscopic and arthroscopic control. At the final follow-up (26 months postoperatively), he had full range of motion (ROM) without pain and radiographic evaluation showed near complete incorporation of the graft with preservation of the native joint space. Mosaicplasty can be applied in a retrograde fashion with the assistance of hip arthroscopy without using surgical hip dislocation and may be an alternative treatment option for the osteochondral defects of the femoral head in young patients. PMID- 28573969 TI - Human spiruridiasis due to Physaloptera spp. (Nematoda: Physalopteridae) in a grave of the Shahr-e Sukhteh archeological site of the Bronze Age (2800-2500 BC) in Iran. AB - Evidence of rare human helminthiasis in paleoparasitological records is scarce. we report here the finding of Physaloptera spp. eggs in a soil sample collected in the pelvic and sacrum bones area of a skeleton excavated from a grave of Shahr e Sukhteh archeological site dating back to the Bronze Age. The site is located in southeastern Iran and has attracted the attention of numerous archeological teams owing to its vast expanse and diverse archeological findings since 1997. The spirurid nematodes Physaloptera spp. are rarely the cause of human helminthiasis nowadays, but this infection might not have been so rare in ancient populations such as those in the Shahr-e Sukhteh. Out of 320 skeletons analyzed in this study, only one parasitized individual was detected. This surprising result led us to suspect the role of nematophagous fungi and other taphonomic processes in possible false-negative results. This is the first paleoparasitological study on human remains in this archeological site and the first record of ancient human physalopterosis in the Middle East. PMID- 28573970 TI - Uncertainty quantification of wall shear stress in intracranial aneurysms using a data-driven statistical model of systemic blood flow variability. AB - Adverse wall shear stress (WSS) patterns are known to play a key role in the localisation, formation, and progression of intracranial aneurysms (IAs). Complex region-specific and time-varying aneurysmal WSS patterns depend both on vascular morphology as well as on variable systemic flow conditions. Computational fluid dynamics (CFD) has been proposed for characterising WSS patterns in IAs; however, CFD simulations often rely on deterministic boundary conditions that are not representative of the actual variations in blood flow. We develop a data-driven statistical model of internal carotid artery (ICA) flow, which is used to generate a virtual population of waveforms used as inlet boundary conditions in CFD simulations. This allows the statistics of the resulting aneurysmal WSS distributions to be computed. It is observed that ICA waveform variations have limited influence on the time-averaged WSS (TAWSS) on the IA surface. In contrast, in regions where the flow is locally highly multidirectional, WSS directionality and harmonic content are strongly affected by the ICA flow waveform. As a consequence, we argue that the effect of blood flow variability should be explicitly considered in CFD-based IA rupture assessment to prevent confounding the conclusions. PMID- 28573971 TI - Relationship between increased in vivo meniscal loads and abnormal tibiofemoral surface alignment in ACL deficient sheep is varied. AB - The aim of this study was to quantify how abnormal dynamic tibiofemoral surface alignment affects the load bearing function of menisci in vivo. Using a sheep model of ACL deficiency, we tested the hypothesis that increased in vivo meniscal loads correlate with greater tibiofemoral surface alignment abnormality. Stifle kinematics were recorded using a bone-mounted instrumented spatial linkage in four sheep before, and at four and twenty weeks (w) after ACL transection. A parallel robotic manipulator was used to quantify stifle kinetics by reproducing each animal's in vivo kinematics and measuring tissue loads during gait. Meniscal resultant loads were estimated from the change in joint reaction force after sequentially removing load-bearing tissues. Tibiofemoral subchondral surfaces were then traced and modeled using thin plate splines. Proximity disturbance is a surface interaction measure used to quantify dynamic tibiofemoral surface alignment abnormality. ACL transection increased meniscal loads by 30-145% at 20w post-ACL transection, whereas the degree of dynamic tibiofemoral subchondral surface alignment varied between sheep. Positive and significant correlations between increased meniscal loads and proximity disturbance values >10mm were observed (R2=0.04-0.57; p<=0.05). Our results suggest that the proximity disturbance measure reflects abnormal meniscal loads following ACL injury; however given the range of R2 values, perturbations in dynamic tibiofemoral subchondral surface alignment do not explain abnormal joint kinetics entirely, and point to the presence of other dynamic compensatory mechanisms that may have a significant bearing on in vivo joint function and long-term joint health. PMID- 28573972 TI - The effect of in vivo rotator cuff muscle contraction on glenohumeral joint translation: An ultrasonographic and electromyographic study. AB - The proposed stabilizing mechanism of rotator cuff muscles is to limit excessive humeral head translation. However, an accurate measurement of glenohumeral joint translation in vivo has been challenging. We aimed to measure the effect of rotator cuff muscle contraction on glenohumeral joint translation using real time ultrasound (RTUS) and electromyography. Twenty healthy adults with no history of shoulder pathology were recruited. Six intramuscular electrodes were inserted in the rotator cuff muscles (supraspinatus, upper and lower infraspinatus, teres minor, upper and lower subscapularis). Anterior and posterior glenohumeral translations were measured in testing conditions (with and without translation force, with and without isometric internal and external rotation), in two positions (shoulder neutral, abduction) and views (anterior, posterior). There was reduced glenohumeral translation with rotator cuff muscle contraction in the neutral anterior (F2,38=17.8, p<0.01), neutral posterior (F1.6,31.0=44.3, p<0.01) and abducted posterior (F1.5,28.8=5.2, p<0.02) positions. There were also differences between the amount of translation limited by anterior and posterior rotator cuff muscles in response to anterior and posterior translation forces (p<0.05), indicating that their activity was, to a certain extent, direction specific. For example, in both neutral and abducted positions, contraction of the posterior rotator cuff muscles, infraspinatus and teres minor, appeared to tether anterior translation of the humeral head. Our results confirm that the rotator cuff functions as a stabilizer of the glenohumeral joint by limiting humeral head translation and this is likely to be in a direction-specific manner. PMID- 28573973 TI - Knee flexion with quadriceps cocontraction: A new therapeutic exercise for the early stage of ACL rehabilitation. AB - Quadriceps strengthening exercises designed for the early phase of anterior cruciate ligament (ACL) rehabilitation should limit the anterior tibial translation developed by quadriceps contraction near full knee extension, in order to avoid excessive strain on the healing tissue. We hypothesize that knee flexion exercises with simultaneous voluntary contraction of quadriceps (voluntary quadriceps cocontraction) can yield considerable levels of quadriceps activation while preventing the tibia from translating forward relative to the femur. Electromyographic activity in quadriceps and hamstring muscles was measured in 20 healthy males during isometric knee-flexion exercises executed near full knee extension with maximal voluntary effort of quadriceps cocontraction and external resistance (R) ranging from 0% to 60% of the 1 repetition maximum (1RM). Biomechanical modeling was applied to derive the shear (anterior/posterior) tibiofemoral force developed in each exercise condition. Isometric knee-flexion exercises with small external resistance (R=10% 1RM) and maximal voluntary effort of quadriceps cocontraction yielded a net posterior (ACL unloading) tibial pull (P=0.005) and levels of activation of 32%, 50%, and 45% of maximum voluntary isometric contraction, for the rectus femoris, vastus medialis, and vastus lateralis, respectively. This exercise might potentially rank as one of the most appropriate quadriceps strengthening interventions in the early phase of ACL rehabilitation. PMID- 28573975 TI - Benign infantile seizures followed by autistic regression in a boy with 16p11.2 deletion. AB - Benign infantile seizures (BIS) are usually a self-limiting condition, which may be associated with heterozygous mutations in the PRRT2 gene at chromosome 16p11.2. Here, we report a boy with a deletion in 16p11.2, presenting with BIS and typical neurodevelopment in the first year of life, unexpectedly followed by severe autistic regression. 16p11.2 deletions are typically associated with intellectual disability, autism, and language disorders, and only rarely with BIS. This clinical report shows that the neurodevelopmental prognosis in BIS patients may not always be benign, and suggests that array CGH screening should be considered for affected infants in order to rule out deletions at 16p11.2 and long-term clinical follow-up. PMID- 28573974 TI - Lower limb estimation from sparse landmarks using an articulated shape model. AB - Rapid generation of lower limb musculoskeletal models is essential for clinically applicable patient-specific gait modeling. Estimation of muscle and joint contact forces requires accurate representation of bone geometry and pose, as well as their muscle attachment sites, which define muscle moment arms. Motion-capture is a routine part of gait assessment but contains relatively sparse geometric information. Standard methods for creating customized models from motion-capture data scale a reference model without considering natural shape variations. We present an articulated statistical shape model of the left lower limb with embedded anatomical landmarks and muscle attachment regions. This model is used in an automatic workflow, implemented in an easy-to-use software application, that robustly and accurately estimates realistic lower limb bone geometry, pose, and muscle attachment regions from seven commonly used motion-capture landmarks. Estimated bone models were validated on noise-free marker positions to have a lower (p=0.001) surface-to-surface root-mean-squared error of 4.28mm, compared to 5.22mm using standard isotropic scaling. Errors at a variety of anatomical landmarks were also lower (8.6mm versus 10.8mm, p=0.001). We improve upon standard lower limb model scaling methods with shape model-constrained realistic bone geometries, regional muscle attachment sites, and higher accuracy. PMID- 28573976 TI - Multiband superconductivity in BiS2-based layered compounds. AB - A mean-field treatment is presented of a square lattice two-orbital-model for [Formula: see text] taking into account intra- and inter-orbital superconductivity. A rich phase diagram involving both types of superconductivity is presented as a function of the ratio between the couplings of electrons in the same and different orbitals ([Formula: see text]) and electron doping x. With the help of a quantity we call orbital-mixing ratio, denoted as [Formula: see text], the phase diagram is analyzed using a simple and intuitive picture based on how [Formula: see text] varies as electron doping increases. The predictive power of [Formula: see text] suggests that it could be a useful tool in qualitatively (or even semi-quantitatively) analyzing multiband superconductivity in BCS-like superconductors. PMID- 28573977 TI - Bioactive-glass ceramic with two crystalline phases (BioS-2P) for bone tissue engineering. AB - We aimed to evaluate the in vitro osteogenic and osteoinductive potentials of BioS-2P and its ability to promote in vivo bone repair. To investigate osteogenic potential, UMR-106 osteoblastic cells were cultured on BioS-2P and Bioglass 45S5 discs in osteogenic medium. The osteoinductive potential was evaluated using mesenchymal stem cells (MSCs) cultured on BioS-2P, Bioglass 45S5 and polystyrene in non-osteogenic medium. Rat bone calvarial defects were implanted with BioS-2P scaffolds alone or seeded with MSCs. UMR-106 proliferation was similar for both materials, while alkaline phosphatase (ALP) activity and mineralization were higher for BioS-2P. Bone sialoprotein (BSP), RUNX2 and osteopontin (OPN) gene expression and BSP, OPN, ALP and RUNX2 protein expression were higher on BioS-2P. For MSCs, ALP activity was higher on Bioglass 45S5 than on BioS-2P and was lower on polystyrene. All genes were highly expressed on bioactive glasses compared to polystyrene. BioS-2P scaffolds promoted in vivo bone formation without differences in the morphometric parameters at 4, 8 and 12 weeks. After 8 weeks, the combination of BioS-2P with MSCs did not increase the quantity of new bone compared to the BioS-2P alone. To stimulate osteoblast activity, drive MSC differentiation and promote bone formation, BioS-2P is a good choice as a scaffold for bone tissue engineering. PMID- 28573978 TI - Automatic contour propagation using deformable image registration to determine delivered dose to spinal cord in head-and-neck cancer radiotherapy. AB - To determine delivered dose to the spinal cord, a technique has been developed to propagate manual contours from kilovoltage computed-tomography (kVCT) scans for treatment planning to megavoltage computed-tomography (MVCT) guidance scans. The technique uses the Elastix software to perform intensity-based deformable image registration of each kVCT scan to the associated MVCT scans. The registration transform is then applied to contours of the spinal cord drawn manually on the kVCT scan, to obtain contour positions on the MVCT scans. Different registration strategies have been investigated, with performance evaluated by comparing the resulting auto-contours with manual contours, drawn by oncologists. The comparison metrics include the conformity index (CI), and the distance between centres (DBC). With optimised registration, auto-contours generally agree well with manual contours. Considering all 30 MVCT scans for each of three patients, the median CI is [Formula: see text], and the median DBC is ([Formula: see text]) mm. An intra-observer comparison for the same scans gives a median CI of [Formula: see text] and a DBC of ([Formula: see text]) mm. Good levels of conformity are also obtained when auto-contours are compared with manual contours from one observer for a single MVCT scan for each of 30 patients, and when they are compared with manual contours from six observers for two MVCT scans for each of three patients. Using the auto-contours to estimate organ position at treatment time, a preliminary study of 33 patients who underwent radiotherapy for head-and-neck cancers indicates good agreement between planned and delivered dose to the spinal cord. PMID- 28573979 TI - Growth factor-functionalized silk membranes support wound healing in vitro. AB - Chronic wounds represent a serious problem in daily medical routine requiring improved wound care. Silk of the domesticated silkworm (Bombyx mori) has been used to form a variety of biomaterials for medical applications. We genetically engineered B. mori to produce silk functionalized with growth factors to promote wound healing in vitro. In this study FGF-, EGF-, KGF-, PDGF- or VEGF functionalized silk membranes were compared to native B. mori silk membranes without growth factors for their ability to support wound healing in vitro. All silk membranes were cytocompatible and supported macrophage secretion of neutrophil recruiting factor CXCL1 and monocyte chemoattractant protein 1 (MCP 1). VEGF-functionalized silk significantly outperformed other growth factor functionalized silk membranes, but not native silk in angiogenesis assays. In addition, EGF- and VEGF-functionalized silk membranes slightly enhanced macrophage adhesion compared to silk without growth factors. In wound healing assays in vitro (reduction of wound lesion), dermal equivalents showed a higher wound healing capacity when covered with EGF-, FGF- or VEGF-functionalized silk membranes compared to native, KGF- or PDGF-functionalized silk membranes. Keratinocyte migration and growth is overstimulated by KGF- and VEGF functionalized silk membranes. In conclusion, growth factor-functionalized silk membranes prepared from genetically engineered silk worm glands are promising wound dressings for future wound healing therapies. PMID- 28573980 TI - 3D porous collagen scaffolds reinforced by glycation with ribose for tissue engineering application. AB - In this study, ribose was proposed as a promising, non-toxic, low-cost crosslinker to enhance the structural integrity and stiffness of type I collagen matrices. The main objective was to determine the optimal conditions of glycation by ribose to fabricate 3D porous collagen scaffolds and to verify their effectiveness for use as scaffolds for cartilage tissue engineering, by physicochemical and biological characterization. Two different crosslinking strategies were investigated including variation in the amount of ribose and the time of reaction: pre-crosslinking (PRE) and post-crosslinking (POST). All ribose glycated collagen scaffolds demonstrated good swelling properties and interconnected porous microstructure suitable for cell growth and colonization. The POST samples were superior to PRE, in terms of porosity, degree of crosslinking, fluid uptake ability, and resistance to enzymatic digestion. Moreover, the mechanical properties of the scaffolds were significantly improved upon glycation when compared to non-crosslinked collagen, manifesting the best performance for POST matrices crosslinked for 5 d and in the highest amount of sugar. In vitro studies analyzing cell-material interactions revealed scaffold cytocompatibility with higher cell viability and cell proliferation as well as higher glycosaminoglycan secretion for POST scaffolds with respect to PRE. This report demonstrated the feasibility of developing 3D collagen scaffolds by ribose glycation and highlighted the POST-crosslinking strategy as being more favorable than the PRE-crosslinking to achieve scaffolds suitable for cartilage regeneration. PMID- 28573981 TI - At what data length do cerebral autoregulation measures stabilise? AB - OBJECTIVE: Cerebral autoregulation is commonly assessed through mathematical models that use non-invasive measurements of arterial blood pressure and cerebral blood flow velocity. There is no agreement in the literature as to what is the minimum length of data needed for the cerebral autoregulation coefficients to stabilise. APPROACH: We introduce a simple empirical tool for studying the minimum length of time series needed to parameterise three popular cerebral autoregulation coefficients ARI, Mx and Phase (in the low frequency range [0.07 0.2] Hz), which can be easily applied in a more general context. We use our recently collected data, from which we select high quality (absence of non physiological artefacts), baseline ABP-CBFV time series (16 min each). The data were beat-to-beat averaged and downsampled at 10 Hz. MAIN RESULT: On average, ARI exhibits greater variability than Mx and Phase, when calculated for short intervals; however, it stabilises fastest. SIGNIFICANCE: Our results show that values of ARI, Mx and Phase calculated on intervals shorter than 3 min (1800 samples), 6 min (3600 samples) and 5 min (3000 samples), respectively, may be very sensitive to changes in the length of data interval. PMID- 28573982 TI - A silicon carbide array for electrocorticography and peripheral nerve recording. AB - OBJECTIVE: Current neural probes have a limited device lifetime of a few years. Their common failure mode is the degradation of insulating films and/or the delamination of the conductor-insulator interfaces. We sought to develop a technology that does not suffer from such limitations and would be suitable for chronic applications with very long device lifetimes. APPROACH: We developed a fabrication method that integrates polycrystalline conductive silicon carbide with insulating silicon carbide. The technology employs amorphous silicon carbide as the insulator and conductive silicon carbide at the recording sites, resulting in a seamless transition between doped and amorphous regions of the same material, eliminating heterogeneous interfaces prone to delamination. Silicon carbide has outstanding chemical stability, is biocompatible, is an excellent molecular barrier and is compatible with standard microfabrication processes. MAIN RESULTS: We have fabricated silicon carbide electrode arrays using our novel fabrication method. We conducted in vivo experiments in which electrocorticography recordings from the primary visual cortex of a rat were obtained and were of similar quality to those of polymer based electrocorticography arrays. The silicon carbide electrode arrays were also used as a cuff electrode wrapped around the sciatic nerve of a rat to record the nerve response to electrical stimulation. Finally, we demonstrated the outstanding long term stability of our insulating silicon carbide films through accelerated aging tests. SIGNIFICANCE: Clinical translation in neural engineering has been slowed in part due to the poor long term performance of current probes. Silicon carbide devices are a promising technology that may accelerate this transition by enabling truly chronic applications. PMID- 28573983 TI - Neuromorphic neural interfaces: from neurophysiological inspiration to biohybrid coupling with nervous systems. AB - OBJECTIVE: Computation in nervous systems operates with different computational primitives, and on different hardware, than traditional digital computation and is thus subjected to different constraints from its digital counterpart regarding the use of physical resources such as time, space and energy. In an effort to better understand neural computation on a physical medium with similar spatiotemporal and energetic constraints, the field of neuromorphic engineering aims to design and implement electronic systems that emulate in very large-scale integration (VLSI) hardware the organization and functions of neural systems at multiple levels of biological organization, from individual neurons up to large circuits and networks. Mixed analog/digital neuromorphic VLSI systems are compact, consume little power and operate in real time independently of the size and complexity of the model. APPROACH: This article highlights the current efforts to interface neuromorphic systems with neural systems at multiple levels of biological organization, from the synaptic to the system level, and discusses the prospects for future biohybrid systems with neuromorphic circuits of greater complexity. MAIN RESULTS: Single silicon neurons have been interfaced successfully with invertebrate and vertebrate neural networks. This approach allowed the investigation of neural properties that are inaccessible with traditional techniques while providing a realistic biological context not achievable with traditional numerical modeling methods. At the network level, populations of neurons are envisioned to communicate bidirectionally with neuromorphic processors of hundreds or thousands of silicon neurons. Recent work on brain-machine interfaces suggests that this is feasible with current neuromorphic technology. SIGNIFICANCE: Biohybrid interfaces between biological neurons and VLSI neuromorphic systems of varying complexity have started to emerge in the literature. Primarily intended as a computational tool for investigating fundamental questions related to neural dynamics, the sophistication of current neuromorphic systems now allows direct interfaces with large neuronal networks and circuits, resulting in potentially interesting clinical applications for neuroengineering systems, neuroprosthetics and neurorehabilitation. PMID- 28573985 TI - Indian Journal of Ophthalmology - New beginning, new aspirations, new trajectory. PMID- 28573984 TI - A Gaussian mixture model based adaptive classifier for fNIRS brain-computer interfaces and its testing via simulation. AB - OBJECTIVE: Functional near infra-red spectroscopy (fNIRS) is a promising brain imaging technology for brain-computer interfaces (BCI). Future clinical uses of fNIRS will likely require operation over long time spans, during which neural activation patterns may change. However, current decoders for fNIRS signals are not designed to handle changing activation patterns. The objective of this study is to test via simulations a new adaptive decoder for fNIRS signals, the Gaussian mixture model adaptive classifier (GMMAC). APPROACH: GMMAC can simultaneously classify and track activation pattern changes without the need for ground-truth labels. This adaptive classifier uses computationally efficient variational Bayesian inference to label new data points and update mixture model parameters, using the previous model parameters as priors. We test GMMAC in simulations in which neural activation patterns change over time and compare to static decoders and unsupervised adaptive linear discriminant analysis classifiers. MAIN RESULTS: Our simulation experiments show GMMAC can accurately decode under time-varying activation patterns: shifts of activation region, expansions of activation region, and combined contractions and shifts of activation region. Furthermore, the experiments show the proposed method can track the changing shape of the activation region. Compared to prior work, GMMAC performed significantly better than the other unsupervised adaptive classifiers on a difficult activation pattern change simulation: 99% versus <54% in two-choice classification accuracy. SIGNIFICANCE: We believe GMMAC will be useful for clinical fNIRS-based brain-computer interfaces, including neurofeedback training systems, where operation over long time spans is required. PMID- 28573986 TI - Ophthalmology and opportunities. PMID- 28573987 TI - Evaluating ocular blood flow. AB - Studies have shown that vascular impairment plays an important role in the etiology and pathogenesis of various ocular diseases including glaucoma, age related macular degeneration, diabetic retinopathy, and retinal venous occlusive disease. Thus, qualitative and quantitative assessment of ocular blood flow (BF) is a topic of interest for early disease detection, diagnosis, and management. Owing to the rapid improvement in technology, there are several invasive and noninvasive techniques available for evaluating ocular BF, with each of these techniques having their own limitations and advantages. This article reviews these important techniques, with a particular focus on Doppler Fourier domain optical coherence tomography (OCT) and OCT-angiography. PMID- 28573988 TI - Updates in ophthalmic pathology. AB - Ophthalmic pathology has a long history and rich heritage in the field of ophthalmology. This review article highlights updates in ophthalmic pathology that have developed significantly through the years because of the efforts of committed individuals and the confluence of technology such as molecular biology and digital pathology. This is an exciting period in the history of ocular pathology, with cutting-edge techniques paving the way for new developments in diagnostics, therapeutics, and research. Collaborations between ocular oncologists and pathologists allow for improved and comprehensive patient care. Ophthalmic pathology continues to be a relevant specialty that is important in the understanding and clinical management of ocular disease, education of eye care providers, and overall advancement of the field. PMID- 28573989 TI - Evaluation of Kayser-Fleischer ring in Wilson disease by anterior segment optical coherence tomography. AB - PURPOSE: The purpose of the study is to present anterior segment optical coherence tomography (AS-OCT) as an alternative method of evaluating Kayser Fleischer (KF) ring in Wilson disease (WD) not only by ophthalmologists but also by other clinicians dealing with WD. MATERIALS AND METHODS: This was a retrospective case series of six WD patients with KF ring. Evaluation of KF ring was done by naked eye examination using torch light, slit lamp biomicroscopy (SL), and AS-OCT. SL examination was done using a narrow slit of the superior cornea. AS-OCT was done using the Optovue RTvue PremierTM device (Fremont, CA, USA). RESULTS: AS-OCT revealed KF ring as an intense hyperreflective band at the level of Descemet membrane (DM). Color scale of AS-OCT showed KF ring as greenish/greenish yellow/orange yellow/yellowish/red band. Validation of AS-OCT findings was done by second ophthalmologist, medical gastroenterologist, surgical gastroenterologist, and neurophysician. After seeing the first observation, they could identify the AS-OCT features in all pictures with ease. CONCLUSIONS: This is the first observation of KF ring in WD on AS-OCT. On AS-OCT, KF ring is visualized as intense hyperreflectivity at the level of DM in the peripheral cornea. Further, studies are needed to evaluate the usefulness of AS-OCT in WD management. PMID- 28573990 TI - Immediate sequential bilateral cataract surgery: A 5-year retrospective analysis of 2470 eyes from a tertiary care eye center in South India. AB - PURPOSE: The purpose of this study is to evaluate the safety and benefits of immediate sequential bilateral cataract surgery. PATIENTS AND METHODS: Retrospective data analysis of patients who underwent immediate sequential bilateral phacoemulsification with foldable intraocular lens (IOL) implantation under topical anesthesia from January 2011 to September 2016 was performed. Patients with visually significant bilateral cataract within the axial length range of 21.0-26.5 mm were included in the study. Intraoperative and postoperative complications were evaluated. RESULTS: Two thousand four hundred and seventy eyes from 1235 patients with a mean age of 68.34 years (range: 4-90 years) were analyzed. Best-corrected visual acuity improved from 0.40 +/- 0.17 to 0.08 +/- 0.10 (logarithm of the minimum angle of resolution). Nearly 92.05% eyes achieved a target postoperative refraction of +/- 0.5 D spherical equivalent. Main complications observed were prolonged postoperative inflammation in 25% (n = 31), posterior capsular tears in 0.45% (n = 11), and unilateral cystoid macular edema in 0.08% (n = 2) eyes. No sight-threatening complications such as endophthalmitis, retinal detachment, corneal decompensation and intraocular hemorrhage occurred in any of the eyes. Out of the 288 (23.2%) patients who underwent bilateral multifocal IOL implantation, 23 patients (46 eyes) had femtolaser-assisted cataract surgery procedure. Two pediatric and one Downs syndrome patient underwent bilateral cataract surgery under general anesthesia and intravenous sedation, respectively. CONCLUSION: IBSCS may be considered as a preferred practice in eligible cases considering significant patient benefits such as early visual rehabilitation, time and cost-effectiveness, and better compliance with postoperative medications. In debilitated patients and special situations, such as pediatric cataract and Downs syndrome requiring general anesthesia it may be the ideal procedure. PMID- 28573991 TI - Surgical refixation of posteriorly dislocated intraocular lens with scleral-tuck technique. AB - PURPOSE: To report the outcomes of surgical refixation of posteriorly dislocated intraocular lens (IOL) using scleral-tuck method, and to compare the "scleral groove" and the "scleral flap" techniques used. STUDY DESIGN: Single-center, retrospective, interventional, comparative study. METHODS: Medical records of patients undergoing closed globe scleral refixation of posteriorly dislocated posterior chamber IOL (PCIOLs) by scleral-tuck method using two different techniques ("scleral groove" vs. "scleral flap" technique) were reviewed. This approach involved retrieving the dislocated PCIOL, externalizing the haptics through 2 sclerotomies created in paralimbal lamellar scleral grooves, or under lamellar scleral flaps and tucking the haptics into limbus-parallel scleral tunnels. No specific haptic architecture, haptic suturing, or large incisions were needed. Main outcome measures included best-corrected visual acuity (BCVA), final mean refractive error, and intra- and post-operative complications. RESULTS: Thirteen eyes of 13 patients (scleral groove, n = 6; scleral flap, n = 7 eyes) with a mean follow-up of 20.6 months were included. BCVA in all eyes was maintained or improved postoperatively, with three eyes (23%) showing >=2 line improvement. Median astigmatic error at 6-week follow-up was -1.25 D cylinder (range: -0.5 D--2.0 D) which remained stable till final follow-up. All IOLs remained stable and well centered. None of the eyes had a recurrent dislocation, retinal detachment, endophthalmitis, or glaucoma. Both techniques were comparable in terms of postoperative BCVA, and refraction. CONCLUSION: Intrascleral haptic fixation by scleral-tuck method is reliable and effective for secure IOL refixation of posteriorly dislocated IOLs, providing good IOL centration and stability with minimal surgically-induced astigmatism. Both techniques (scleral groove and scleral flap) appear to have similar outcomes in the short term. PMID- 28573992 TI - Nocardia infection following intraocular surgery: Report of seven cases from a tertiary eye hospital. AB - PURPOSE: To study the outcome of ocular nocardiosis following intraocular surgery. MATERIALS AND METHODS: A retrospective review of medical records of all postoperative cases of culture proven Nocardia infection over a period of 3 years, from October 2010 to September 2013, was performed. Microbiological analysis was performed for all cases and included smears and cultures. Fortified 2% amikacin eye drops were the mainstay of treatment. Surgical intervention was performed in case of nonresponse to medical therapy or suspected endophthalmitis. RESULTS: Seven cases of culture proven Nocardia infection were seen. All cases had been operated in a hospital surgical facility. Six followed phacoemulsification, and one followed a secondary intraocular lens implantation. Four patients were part of a cluster infection. The mean duration between the primary surgical procedure and presentation was 16.14 +/- 9.82 days. Five patients had infiltrates at the site of the surgical incision. One each had endophthalmitis and panophthalmitis. Six eyes required surgical intervention. Infection was seen to resolve in four eyes. Two eyes went into phthisis, and one was eviscerated. Only two of the six eyes, where in surgical intervention was performed early, obtained a final visual acuity of 20/60. CONCLUSION: Early surgical intervention, before the involvement of the anterior chamber, may help preserve the anatomic and functional integrity of the eye. PMID- 28573993 TI - Delayed follow-up in patients with diabetic retinopathy in South India: Social factors and impact on disease progression. AB - PURPOSE: To identify social factors associated with delayed follow-up in South Indian patients with diabetic retinopathy (DR) and to study DR progression during the delayed follow-up period. MATERIALS AND METHODS: In this cross-sectional study, 500 consecutive patients with DR returning after greater than twice the advised follow-up period were identified from a tertiary referral center in South India. A previously validated 19-item questionnaire was administered to study patients to assess causes for the follow-up delay. Patient demographics, DR status, and treatment plan were recorded at the study visit and the visit immediately before the delay. The eye with the most severe disease was included in the analysis. RESULTS: Complete data were available for 491 (98.2%) patients. Among these, 248 (50.5%) cited "my eyes were okay at the time," 201 (41.0%) cited "no attender to accompany me," and 190 (38.6%) cited "financial cost" as causes of the follow-up delay. Those with vision-threatening DR (VTDR, n = 233) predominantly reported "financial cost" (47% vs. 32%, P= 0.001), whereas those with non-VTDR more frequently reported "my eyes were okay at the time" (58% vs. 42%, P= 0.001). Evidence of disease progression from non-VTDR to VTDR was seen in 67 (26%) patients. Almost 1/3rd (29%) of patients who were previously advised regular examination required additional intervention. CONCLUSION: Many patient level factors affect poor compliance with follow-up in DR, and these factors vary by disease severity. Targeting these barriers to care through patient education and clinic procedures may promote timely follow-up and better outcomes in these patients. PMID- 28573994 TI - Microperimetric evaluation in patients with adult-onset foveomacular vitelliform dystrophy. AB - INTRODUCTION: To compare mean best-corrected visual acuity (BCVA), retinal sensitivity (RS), and bivariate contour ellipse area (BCEA) in patients with adult-onset foveomacular vitelliform dystrophy (AOFVD) and healthy subjects (HSs), reporting also functional disease-related changes in the different stages of the AOFVD disease. MATERIALS AND METHODS: In this observational cross sectional study, a total of 19 patients (30 eyes; 12 female and 7 male) with AOFVD were enrolled, and 30 patients (30 eyes; 16 female and 14 male) were recruited as age-matched control group (74.36 +/- 9.17 years vs. 71.83 +/- 6.99 years respectively, P= 0.11). All patients underwent a complete ophthalmologic examination, fundus autofluorescence and fluorescein angiography, spectral-domain optical coherence tomography and microperimetry (MP)-1 analysis. The data collection included mean BCVA, mean RS measured by means of MP-1, BCEA, and central retinal thickness. RESULTS: All the functional parameters (BCVA, RS, and BCEA) were significantly worse in AOFVD group than HS. Subgroup analysis showed that the most significant functional changes, quantified by mean BCVA, RS, and BCEA, were in the atrophic stage (P = 0.03, P= 0.01, and P= 0.001, respectively). All the functional parameters were well correlated in the different stages. CONCLUSIONS: This study further confirms the good visual prognosis in the AOFVD eyes. Fixation stability measurement using BCEA demonstrates good evaluation of visual performance integrating traditional functional parameters. It may also serve for further rehabilitative purposes in atrophic eyes. PMID- 28573995 TI - Impact of expansion of telemedicine screening for retinopathy of prematurity in India. AB - PURPOSE: The purpose of this study is to estimate the unknown burden of retinopathy of prematurity (ROP) blindness from nine states of India using demographic, incidence and treatment data from an ongoing statewide ROP program in Karnataka called the Karnataka Internet Assisted Diagnosis of ROP (KIDROP) and to calculate the fiscal quantum of preventable blindness in these states. MATERIALS AND METHODS: The KIDROP model is an ongoing tele-ROP service providing screening and treatment for ROP in Karnataka since 2008. Using this index strategy, an impact assessment in nine other states was constructed, the number of potential blind babies enumerated, the fiscal quantum of blindness prevented in blind person-years (BPYs), and the increase in burden with improving survival and institutional deliveries calculated. RESULTS: The total population in the ten study states is 681.5 million. The eligible babies for ROP screening annually are 467,664. The number of babies admitted to neonatal units is 188,561 of which 160,277 are likely to survive and require screening. Based on KIDROP data, ROP would develop in 35,886 of these infants, and 1281 babies would require treatment annually. The fiscal quantum of BPY saved in these ten states is USD 108.4 million annually, with a further increase of USD 106.8 million with improving infant survival and higher admission rates for delivery. CONCLUSION: A KIDROP like model can provide ROP screening in low-resource settings, remote centers, and regions with few ROP specialists. Expanding the model to other states with similar demographics can prevent over USD 100 million of blindness burden annually. PMID- 28573996 TI - Ridge at the medial rectus muscle insertion: A new anatomical landmark. AB - BACKGROUND AND AIM: Rectus muscle insertions are usually linear or slight curved with the anterior convexity. While operating squint surgeries, we found a presence of ridge-like structure at the medial rectus insertion. None of the other rectus muscle insertions had such structure. MATERIALS AND METHODS: Patients undergoing squint surgery were included in the study. All the patients had negative forced duction test for all the gazes and had comitant strabismus. The patients underwent surgery through the fornix route. All the squint surgeries were primary. None of the patients undergoing resurgery were included in the study. The ridge seen is actually an elevated curved structure and shows discontinuation of the actual medial rectus insertion. The measurements were taken from the superior and inferior end of the medial rectus muscle insertion. RESULTS: In a total of 76 medial rectus surgery (for recession or resection), we found the ridge was present in 68 (89.5%) of cases. The ridge was located at an average distance of 6.33 +/- 1.5 mm inferior and 3.82 +/- 0.9 mm superior to the superior and inferior point of medial rectus insertion, respectively. CONCLUSION: We describe the presence, morphology, and measurements of a ridge as an anatomical landmark at medial rectus insertion. PMID- 28573997 TI - Allergen-specific exposure associated with high immunoglobulin E and eye rubbing predisposes to progression of keratoconus. AB - We report two male children with persistent allergic eye disease (AED) and keratoconus (KC). Both presented with symptoms of vernal keratoconjunctivitis and decreased vision. In view of unrelenting AED, serum immunoglobulin E (IgE) quantification and identification of specific allergens were advised. Increased serum IgE levels were observed in both cases. Sunflower and sheep wool were identified as specific allergens for the first and second patient respectively by skin patch test. There was complete resolution of symptoms of AED in both patients following avoidance of causative allergens. However, the progression of KC in both eyes of the first patient and one eye of the second patient was observed. They were advised collagen cross-linking. Elevated serum IgE indicates the presence of systemic allergy. Avoiding implicated allergens help alleviate ocular symptoms. Using serum IgE and identifying specific allergen can guide in the treatment of AED and thus prevent progressive KC due to eye rubbing and resulting inflammation. PMID- 28573998 TI - Corneal ulcer due to a rare pleosporalean member of the genus Bipolaris following cow tail injury to the eye: A case report and review of literature. AB - Aspergillus and Fusarium are the most common fungi causing mycotic keratitis. Injury to the eye with vegetable matter, cow tail injury, long-term use of topical steroids are some of the risk factors for mycotic keratitis. There are few case reports of keratitis caused by Bipolaris. The human pathogenic species in the genus are Bipolaris spicifera, Bipolaris hawaiiensis, Bipolaris papendorfii, and Bipolaris australiensis. Most commonly reported keratitis is caused by B. hawaiiensis, followed by B. spicifera. Literature review showed only one case report of keratitis due to B. australiensis reported from Australia. We present a first case report of keratitis due to B. australiensis (currently Curvularia australienis) from India. PMID- 28573999 TI - Conjunctival leiomyosarcoma: A case report and review of literature. AB - Leiomyosarcoma is a malignant mesenchymal tumor that is very uncommon in the conjunctiva. Nevertheless, we describe here the clinical manifestations, management, and prognosis of a rare case of leiomyosarcoma in this location. An 81-year-old male presented at a tertiary hospital with a rapidly growing mass. After performing biopsy, histopathological examination revealed the existence of a conjunctival leiomyosarcoma. On this diagnosis, a thorough metastatic screening was performed showing no enlarged lymph nodes or metastatic deposits anywhere in the body. To treat the condition, we performed an evisceration with clear margins and subsequent radiotherapy. PMID- 28574000 TI - An unusual cause of recurrent bloody tear. AB - We describe a female patient who presented with watering followed by swelling in the left infraorbital area of 5 years duration. She had previously been prescribed topical antibiotics on several occasions with no improvement. On pressure over the swelling, there was blood-tinged discharge from the left eye and nostril. Magnetic resonance imaging revealed an enhancing, well-defined mass lesion in the inferomedial aspect of the left orbit, likely of nasolacrimal origin. Computed tomography dacryocystogram with three-dimensional reconstruction showed a well-circumscribed mass with an irregular surface, originating from the lacrimal sac. Gram staining and potassium hydroxide mount from the regurgitant fluid revealed thick-walled cysts with sporangia suggestive of Rhinosporidium seeberi infection. Excision biopsy of the lesion confirmed R. seeberi as the causative agent. The patient has been put on long-term dapsone therapy to prevent a recurrence and has been asked to follow-up 6 months later. PMID- 28574001 TI - Vogt-Koyanagi-Harada disease in a patient of chronic myeloid leukemia. AB - This case report describes the concurrent development of Vogt-Koyanagi-Harada (VKH) disease in a 39 year old male patient of chronic myeloid leukemia (CML). The patient being reported was a known case of CML in remission with history of painless sudden loss of vision in both eyes. Cases of leukemia can present with visual loss due to multiple ocular manifestations of leukemia itself or side effects of modern drugs used for its treatment. Clinical examination and multimodal imaging of our patient were suggestive of concurrent development of VKH. The patient was started on oral steroids, to which he showed a good response. Thus, the cases of CML may rarely develop concurrent ocular disorders not related to leukemia. These associated ocular disorders need to be distinguished from the ocular manifestations of leukemia itself. Our case highlights the concurrent development of VKH as the etiology of visual loss in a case of CML. PMID- 28574002 TI - Management of a rare presentation of Vogt-Koyanagi-Harada disease in human immunodeficiency virus/acquired immunodeficiency disease syndrome patient. AB - Vogt-Koyanagi-Harada (VKH), a multisystem autoimmune bilateral panuveitis with systemic manifestations, is uncommon in immunocompromised patients such as human immunodeficiency virus (HIV)/acquired immunodeficiency disease syndrome (AIDS). We report a rare presentation of VKH in a 45-year-old HIV-positive female on highly active antiretroviral therapy (HAART) who presented with a history of recurrent panuveitis. A diagnosis of probable VKH was made based on ocular and systemic signs and symptoms. She was treated with topical and systemic steroids with close monitoring of CD4 counts and viral loads. After inflammation control, complicated cataract was managed surgically under perioperative steroid cover. VKH in HIV/AIDS has not been reported earlier. This case shows that significant inflammation can be seen even in HIV/AIDS patients on HAART with VKH in spite of moderate CD4 counts. Management is a challenge considering the systemic risks with long-term use of steroids. PMID- 28574003 TI - Antiretinal antibody- proven autoimmune retinopathy. AB - A young female presented with bilateral subacute onset of progressive decrease in night vision and reduced peripheral field of vision. The short duration and rapid progression of symptoms along with the lack of family history of night blindness prompted a diagnosis of autoimmune retinopathy (AIR). Fundus fluorescein angiography, optical coherence tomography, visual fields, and electroretinogram were suggestive of AIR. A differential diagnosis of retinitis pigmentosa (RP) was also made. Antiretinal autoantibodies were detected in the blood sample. Treatment was with oral steroids and subsequently oral immunosuppressive agents. Visual acuity was maintained, fundus examination reverted to normal, and investigations repeated at every visit were stable with improvement in visual fields. Our case suggests that AIR, if diagnosed early and treated appropriately, may have a good outcome and should be considered in patients with an atypical presentation of RP. PMID- 28574004 TI - Surgical management of optic disc pit maculopathy with a fovea sparing internal limiting membrane flap. AB - Optic disc pit (ODP) is rare congenital cavitary anomaly of the optic disc. Serous detachment of macula is the most common complication of ODP and occurs in 25%-75% of these cases. Although various surgical techniques have been used for the treatment of ODP maculopathy; consensus still eludes as far as the optimal surgical approach is concerned. We herein report a case of ODP maculopathy in a young female treated successfully with vitrectomy, fovea sparing internal limiting membrane flap, and C3F8 tamponade. PMID- 28574005 TI - Congenital inverse Duane's retraction syndrome: A rare presentation. AB - A 12-year-old girl presented with esotropia and face turn since birth. Ocular motility examination showed restricted abduction associated with down shoot and retraction on attempted abduction characteristic of inverse Duane's retraction syndrome. To the best of our knowledge, this is one of the very few reported cases of congenital inverse Duane's retraction syndrome. PMID- 28574006 TI - Head injury, varicella vasculopathy: Differential diagnosis for pediatric retinal arterial occlusion. PMID- 28574007 TI - Interpreting data in policy & control: The case of leprosy. PMID- 28574008 TI - Celiac disease & type 1 diabetes mellitus: Connections & implications. PMID- 28574009 TI - Potential biomarkers for bipolar disorder: Where do we stand? AB - Bipolar disorder (BD) is a severe, recurrent mood disorder, associated with a significant morbidity and mortality, with high rates of suicides and medical comorbidities. There is a high risk of mood disorders among the first-degree relatives of patients with BD. In the current clinical practice, the diagnosis of BD is made by history taking, interview and behavioural observations, thereby lacking an objective, biological validation. This approach may result in underdiagnosis, misdiagnosis and eventually poorer outcomes. Due to the heterogeneity of BD, the possibility of developing a single, specific biomarker is still remote; however, there is a set of promising biomarkers which may serve as predictive, prognostic or treatment markers in the future. The review presents a critical appraisal and update on some of the most promising candidates for biomarkers, namely, neuroimaging markers, peripheral biomarkers and genetic markers, including a brief discussion on cognitive endophenotypes as indicative of genetic risk. The lessons learnt from other fields and specialties in medicine need to be applied to psychiatry to translate the knowledge from 'bench to bedside' by means of clinically useful biomarkers. Overall, the biomarkers may help in pushing the shift towards personalized medicine for psychiatric patients. PMID- 28574011 TI - Coexistence of celiac disease & type 1 diabetes mellitus in children. AB - BACKGROUND & OBJECTIVES: Type 1 diabetes mellitus (T1DM) and celiac disease (CD) tend to co-exist due to similar underlying genetic predisposition. Failure to recognize CD in patients with T1DM predisposes them to complications. The present study was aimed to assess children with T1DM for the presence of CD. METHODS: This was a retrospective analysis of the records of children with T1DM attending paediatric endocrinology clinic at a tertiary care hospital in north India from January 2006 to May 2014. All children were screened for CD at the time of diagnosis of T1DM using IgA anti-tissue transglutaminase (anti-tTG) levels in serum. Seropositive children were subjected to upper gastrointestinal endoscopy and duodenal biopsy for histopathological confirmation. The children also underwent thyroid function testing (TFT); those with deranged TFT were evaluated for thyroid-specific antibodies. RESULTS: Positive serology for CD was present in 43 of 126 children with T1DM whose records were reviewed [34.1%; 95% confidence interval (CI): 25.9-43.1]. Confirmed CD was diagnosed in 17 (13.5%; CI: 8.1-20.7) of the children screened and 17 of 40 (42.5%; CI: 27.1-59.1) seropositive participants. Four out of 17 children with coexisting CD and T1DM also had autoimmune thyroiditis with overt hypothyroidism. The children with confirmed CD were more likely to have short stature [odds ratios (OR)-3.16; 95% CI: 1.09-9.20, P<0.05] and hypothyroidism (OR-6.4; 95% CI: 1.52-26.90, P<0.05). INTERPRETATION & CONCLUSIONS: Our study showed a higher proportion of CD in children with T1DM as compared to that reported in general population. Regular screening of children with T1DM for CD is needed to improve metabolic control and prevent long-term complications. PMID- 28574010 TI - Rare cancers: Challenges & issues. AB - Rare cancers account for about 22 per cent of all cancers diagnosed worldwide, disproportionately affecting some demographic groups, with an occurrence of less than 6 per 100,000 individuals annually. Many rare cancers in adults, adolescents and children are not curable, and patients and care providers have little option to take therapeutic decisions. The epidemiology of rare cancers is a challenging area of study but is inadequately addressed. Despite efforts mainly in some European nations, a few improvements have been observed in the management of rare cancers. Reasons for this obvious stagnation are multifactorial and are mainly inherent to logistical difficulties in carrying out clinical trials in very small patient populations, hesitation of the pharmaceutical industry to spend in small markets and complexity in creating adequate information for the development of cost-effective drugs. Rare cancers also face specific challenges that include late and incorrect diagnosis, lack of clinical expertise and lack of research interest and development of new therapies. The utilization of nationally representative study findings for the patients' evaluation may possibly offer chances to find out pathogenesis and prevalence, and this will eventually lead to control and prevention. Currently, advancing targeted therapies offer a great opportunity for the better management of rare cancers. Conducting clinical trials with small patient population, innovative clinical trial approach, prevailing controlling obstacles for international cooperation and financial support for research are the present challenges for rare cancers. The International Rare Cancers Initiative functions as a main platform for achieving new international clinical trials in rare tumours. This review delineates the current challenges and issues in the interpretation, management and research scenarios of rare cancers. PMID- 28574013 TI - Identifying the risk of producing aneuploids using meiotic recombination genes as biomarkers: A copy number variation approach. AB - BACKGROUND & OBJECTIVES: Aneuploids are the most common chromosomal abnormality in liveborns and are usually the result of non-disjunction (NDJ) in meiosis. Copy number variations (CNVs) are large structural variations affecting the human genome. CNVs influence critical genes involved in causing NDJ by altering their copy number which affects the clinical outcome. In this study influence of CNVs on critical meiotic recombination was examined using new computational technologies to assess their role in causing aneuploidy. METHODS: This investigation was based on the analysis of 12 random normal populations consisting of 1714 individuals for aneuploid causing genes under CNV effect. To examine the effect of CNVs on genes causing aneuploidy, meiotic recombination genes were analyzed using EnrichR, WebGestalt and Ingenuity Pathway Analysis (IPA). RESULTS: Forty three NDJ genes were found under CNV burden; IPA (Ingenuity Pathway Analysis) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis of CNV in meiotic recombination genes revealed a significant role of breast cancer gene 1, amyloid protein precursor, mitogen-activated protein kinase and nerve growth factor as key molecular players involved in causing aneuploidy. Interaction between these genes with other CNV-overlapping genes involved in cell cycle, recombination and meiosis might lead to increased incidences of aneuploidy. INTERPRETATION & CONCLUSIONS: The findings of this study implied that the effect of CNVs on normal genome contributed in amplifying the occurrences of chromosomal aneuploidies. The normal individuals consisting of variations in the susceptible genes causing aneuploids in the population remain undetected until the disorder genes express in the succeeding generations. PMID- 28574012 TI - Association of ankyrin repeats & kinase domain containing 1 (ANKK1) gene polymorphism with co-morbid alcohol & nicotine dependence: A pilot study from a tertiary care treatment centre in north India. AB - BACKGROUND & OBJECTIVES: The frequently encountered co-morbidity of alcohol dependence (AD) with nicotine dependence (ND) increases the risk for various diseases. Ankyrin repeats and kinase domain containing 1 (ANKK1) gene polymorphism is reported to be associated with both ND and AD. This study was undertaken to investigate the possible association of alcohol and tobacco use variables with ANKK1 polymorphism in co-morbid alcohol- and nicotine-dependent treatment seekers visiting a tertiary care centre in north India. METHODS: Seventy nine male participants (18-65 yr old) fulfilling diagnostic criteria for ND and AD were included in the study. The socio-demographic data, along with alcohol and tobacco use profile, was recorded and ANKK1 profiling was carried out. Both the allele groups, A1 and A2, were compared with respect to demographic and substance dependence profile. Univariate binary logistic regression analysis was performed to determine the risk of high nicotine and alcohol consumption with genotype. RESULTS: The A1 carrier group (n=33) reported a significantly higher amount of alcohol and tobacco consumed per day. The scores on parameters of ND were found to be significantly higher in this group. The logistic regression analysis revealed that participants with A1 genotype were 2.5 times more likely to report higher amount of alcohol and nicotine consumption than A2 carriers. INTERPRETATION & CONCLUSIONS: The study provides an indication for the association of ANKK1 polymorphism in the form of higher substance consumption among alcohol dependent smokers, who are A1 carriers and thus may require higher attention of the treatment provider. PMID- 28574014 TI - Community based kangaroo mother care for low birth weight babies: A pilot study. AB - BACKGROUND & OBJECTIVES: Kangaroo mother care (KMC - early continuous skin-to skin contact between mother and infants) has been recommended as an alternative care for low birth weight infants. There is limited evidence in our country on KMC initiated at home. The present study was undertaken to study acceptability of KMC in different community settings. METHODS: A community-based pilot study was carried out at three sites in the States of Odisha, Gujarat and Maharashtra covering rural, urban and rural tribal population, respectively. Trained health workers provided IEC (information, education and communication) on KMC during antenatal period along with essential newborn care messages. These messages were reinforced during the postnatal period. Outcome measures were the proportion of women accepting KMC, duration of KMC/day and total number of days continuing KMC. Focus group discussions and in-depth interviews were also carried out. RESULTS: KMC was provided to 101 infants weighing 1500-2000 g; 57.4 per cent were preterm. Overall, 80.2 per cent mothers received health education on KMC during antenatal period, family members (68.3%) also attended KMC sessions along with pregnant women and 55.4 per cent of the women initiated KMC within 72 h of birth. KMC was provided on an average for five hours per day. Qualitative survey data indicated that the method was acceptable to mothers and family members; living in nuclear family, household work, twin pregnancy, hot weather, etc., were cited as reasons for not being able to practice KMC for a longer duration. INTERPRETATION & CONCLUSIONS: It was feasible to provide KMC using existing infrastructure, and the method was acceptable to most mothers of low birth infants. PMID- 28574015 TI - Clinical profile & complications of neurotoxic snake bite & comparison of two regimens of polyvalent anti-snake venom in its treatment. AB - BACKGROUND & OBJECTIVES: The optimal anti-snake venom (ASV) dose required to treat neurotoxic snake envenomation is not known. Low-dose ASV (national protocol: maximum dose 200 ml) may be as efficacious as the conventional regimen (100 ml six hourly till all symptoms disappear), but a direct comparison of the regimens is not available. The aim of this study was to test the efficacy of low dose ASV regimen against the conventional high-dose regimen. METHODS: The clinical profile of 51 patients with neurotoxic snake envenomation was studied. Patients were treated with either the national protocol or the conventional protocol for ASV administration. The time to complete recovery of symptoms, duration of mechanical ventilation and total dose of ASV were compared. RESULTS: More patients were females (28 vs. 23) bitten in the early morning hours (2400 0600 h). Thirty nine of 51 (76.4%) patients required mechanical ventilation. In terms of progression of neuroparalysis, time to complete resolution of ptosis and occurrence of VAP and ASV reactions, there was no difference. Duration of mechanical ventilation was less with the national protocol (24 vs. 43.5 h). Significantly less amount of ASV was used with the national protocol (224 vs. 982 ml) per patient. There were no mortality or permanent neurological sequelae with either regimen. INTERPRETATION & CONCLUSIONS: In this preliminary study, it was found that the national ASV protocol was as effective as the conventional regimen for neurotoxic snake bites. However, the findings need to be tested in a larger randomized controlled trial for definitive conclusions. PMID- 28574016 TI - Coverage & missed opportunity for Japanese encephalitis vaccine, Gorakhpur division, Uttar Pradesh, India, 2015: Implications for Japanese encephalitis control. AB - BACKGROUND & OBJECTIVES: Japanese encephalitis (JE) is an important aetiology of acute encephalitis syndrome in Gorakhpur division, Uttar Pradesh, India. Two doses of JE vaccine ( first during 9-12 months and second during 16-24 months of age) are administered under the Universal Immunization Programme. We conducted surveys to estimate the coverage of JE vaccine and magnitude of missed opportunity for vaccination (MoV) for JE in Gorakhpur division. METHODS: To estimate the JE vaccine coverage, cluster surveys were conducted in four districts of Gorakhpur division by selecting 30 clusters by probability proportional to size method in each district, seven children aged 25-36 months were selected from each cluster and their mothers were interviewed about JE vaccination. To estimate the magnitude of MoV, exit surveys were conducted in vaccination clinics in selected health facilities, mothers were interviewed about the vaccination status of their children and vaccines administered to the child on the day of interview. RESULTS: A total of 840 children were surveyed, 210 from each district. The coverages of one and two doses of JE vaccine in Gorakhpur division were 75 per cent [95% confidence interval (CI): 71.0-78.9] and 42.3 per cent (95% CI: 37.8-46.8), respectively. Facility-based exit survey indicated that 32.7 per cent of the eligible children missed JE vaccine. INTERPRETATION & CONCLUSIONS: The survey results showed that three of the four children aged 25-36 months in Gorakhpur division had received at least one dose of JE vaccine. The coverage of second dose of JE vaccine, however, was low. Failure to administer vaccination simultaneously was the most common reason for MoV for JE vaccine. Training vaccinators about correct vaccination schedule and removing their misconception about administering vaccines simultaneously would substantially improve JE vaccine coverage in Gorakhpur. PMID- 28574017 TI - Line probe assay for detection of Mycobacterium tuberculosis complex: An experience from Central India. AB - BACKGROUND & OBJECTIVES: Mycobacterium tuberculosis complex may sometimes not be detected in sputum samples of suspected multidrug-resistant tuberculosis (MDR-TB) patients by line probe assay (LPA) even though they are smear positive for acid fast bacilli (AFB). This retrospective analysis was attempted to understand and document our experience with LPA for detection of M. tuberculosis complex and diagnosis of MDR-TB under programmatic conditions. METHODS: One thousand two hundred and ninety four sputum samples of MDR-TB suspects that were smear positive for AFB, and received from February to November 2013, were tested by LPA for the presence of M. tuberculosis complex and resistance to isoniazid (INH) and rifampicin as per the diagnostic mandate of an accredited reference laboratory. As per the mandate, those samples that were negative for M. tuberculosis complex were cultured, and the growth again tested by LPA. A retrospective analysis of the results was carried out. RESULTS: M. tuberculosis complex could be detected in 1217 (94.04%) but not in 77 (5.9%) of smear-positive sputum samples. Of the 1217 positive samples, 232 (19.1%) were MDR, 130 (10.6%) were rifampicin monoresistant and 101 (8.3%) were INH monoresistant. Seven hundred and fifty four (61.9%) strains were found to be pansensitive. Overall, 5.1 per cent of the sputum samples were negative for M. tuberculosis complex by LPA and culture. In at least 10 (0.77%) sputum samples smear positive for AFB, M. tuberculosis complex could not be identified by LPA though M. tuberculosis was present, as evidenced by culture positivity. INTERPRETATION & CONCLUSIONS: LPA is a robust technique for diagnosis of drug-resistant TB that has provided the basis for rapid and effective control of drug-resistant TB in India. While the reasons for concomitantly negative LPA and culture results of smear-positive sputum samples from MDR-TB suspects may be many, the possible presence of non-tubercular mycobacteria in these samples and the likelihood of inappropriate therapy in these patients cannot be ruled out. Addition of culture to the diagnostic algorithm may enhance the diagnostic yield. PMID- 28574018 TI - Genetic diversity & drug sensitivity profiles of Mycobacterium tuberculosis isolates from two slums of Jaipur city, Rajasthan, India. AB - BACKGROUND & OBJECTIVES: Slums are considered as hotspots of tuberculosis (TB). The study of genetic diversity and drug susceptibility profile of Mycobacterium tuberculosis (MTB) will help understand the transmission dynamics and can be used for better prevention and control of the disease. The aim of this study was to determine the drug susceptibility profiles and genetic diversity using the random amplified polymorphic DNA (RAPD) and mycobacterial interspersed repetitive units variable number of tandem repeats (MIRU VNTR) of MTB isolates from sputum samples of pulmonary TB patients residing in the two slums of Jaipur city in Rajasthan, India. METHODS: Sputum samples collected from pulmonary TB patients, their contacts and suspects during 2010-2012 were processed for microscopy and mycobacterial culture. Drug susceptibility testing was done by one per cent indirect proportion method on Lowenstein-Jensen medium for first-line anti-TB drugs rifampicin, isoniazid, ethambutol and streptomycin. MTB DNA was extracted by physicochemical method, and DNA fingerprinting was done by RAPD and MIRU VNTR analysis. RESULTS: Among 175 sputum samples collected, 75 were positive (43.8%) for acid-fast bacilli, 83 for MTB culture and four were contaminated. Fifty two isolates (62.7%) were fully sensitive to four drugs, and five (6%) were multidrug resistant (MDR). RAPD analysis of 81 isolates revealed six clusters containing 23 (28.4%) isolates, and 58 (71.6%) were unique. MIRU VNTR analysis clustered 20 (24.7%) isolates, and 61 (75.3%) were unique. INTERPRETATION & CONCLUSIONS: About 62.7 per cent isolates from the sputum samples from slum areas were sensitive to four drugs; six per cent of isolates were MDR. Poly-resistance other than MDR was high (16%). About one-fourth isolates were clustered by either method. RAPD was rapid, less expensive but had low reproducibility. MIRU VNTR analysis could identify to greater extent the epidemiological link in the population studied. PMID- 28574019 TI - K time & maximum amplitude of thromboelastogram predict post-central venous cannulation bleeding in patients with cirrhosis: A pilot study. AB - BACKGROUND & OBJECTIVES: Coagulation and haemostasis are dynamic processes. The haemostatic changes in liver disease affect all aspects of coagulation. The prothrombin time (PT)/ international normalized ratio (INR) was developed to monitor oral anticoagulant therapy and the activated partial thromboplastin time to investigate inheritable single factor deficiencies. Viscoelastic tests such as thromboelastogram (TEG) give information about dynamics of clot formation (coagulation factor and anticoagulant activity), clot strength (platelets and fibrinogen) and clot stability (finbrinolysis and factor XIII). Administration of blood products before invasive procedures is still guided by INR and platelet count in patients of liver disease. This study was aimed to evaluate the validity of TEG to predict post-procedural bleed after central venous cannulation in patients with cirrhosis. METHODS: Ninety patients aged 20-70 yr diagnosed with liver cirrhosis requiring elective central venous catheter (CVC) insertion were studied. Platelet count, INR, serum creatinine, TEG and Child-Turcotte-Pugh (CTP) score were recorded before the procedure. Right-sided internal jugular vein was cannulated. On the basis of presence or absence of post-procedural bleed, patients were divided into bleeding and non-bleeding groups. The CTP score, component of TEG (R - reaction time, K - coagulation time, MA - maximum amplitude and alpha - angle) and laboratory parameters of both the groups were compared. RESULTS: Bleeding was seen more when CTP scores were >=10 (P=0.05). The K time of 3.05 min or more on thromboelastograph was a significant predictor of bleeding [area under the curve (AUC) 0.694, P=0.047]. MA of 48.8 mm or more was a significant predictor of non-bleeding. INR >=2.6 was a significant predictor of bleeding (AUC 0.765, P=0.005). K time had a low-positive predictive value of 20 per cent and the positive and negative likelihood ratios of 1.87 and 0.48, respectively. INTERPRETATION & CONCLUSIONS: Our results show that the cut-off value for INR >=2.6 and K time >=3.05 min predict bleeding and MA >=48.8 mm predicts non-bleeding in patients with cirrhosis undergoing central venous pressure catheter cannulation. PMID- 28574020 TI - Development of polymerase chain reaction-based diagnostic tests for detection of Malsoor virus & adenovirus isolated from Rousettus species of bats in Maharashtra, India. AB - BACKGROUND & OBJECTIVES: Bats are recognized as important reservoirs for emerging infectious disease and some unknown viral diseases. Two novel viruses, Malsoor virus (family Bunyaviridae, genus, Phlebovirus) and a novel adenovirus (AdV) (family, Adenoviridae genus, Mastadenovirus), were identified from Rousettus bats in the Maharashtra State of India. This study was done to develop and optimize real time reverse transcription - polymerase chain reaction (RT-PCR) assays for Malsoor virus and real time and nested PCR for adenovirus from Rousettus bats. METHODS: For rapid and accurate screening of Malsoor virus and adenovirus a nested polymerase chain reaction and TaqMan-based real-time PCR were developed. Highly conserved region of nucleoprotein gene of phleboviruses and polymerase gene sequence from the Indian bat AdV isolate polyprotein gene were selected respectively for diagnostic assay development of Malsoor virus and AdV. Sensitivity and specificity of assays were calculated and optimized assays were used to screen bat samples. RESULTS: Molecular diagnostic assays were developed for screening of Malsoor virus and AdV and those were found to be specific. Based on the experiments performed with different parameters, nested PCR was found to be more sensitive than real-time PCR; however, for rapid screening, real-time PCR can be used and further nested PCR can be used for final confirmation or in those laboratories where real-time facility/expertise is not existing. INTERPRETATION & CONCLUSIONS: This study reports the development and optimization of nested RT-PCR and a TaqMan-based real-time PCR for Malsoor virus and AdV. The diagnostic assays can be used for rapid detection of these novel viruses to understand their prevalence among bat population. PMID- 28574021 TI - Isolation of bacteria from diabetic foot ulcers with special reference to anaerobe isolation by simple two-step combustion technique in candle jar. AB - BACKGROUND & OBJECTIVES: Although polymicrobial infections involving both aerobic and anaerobic bacteria are very common in diabetic foot ulcers, in many centres of developing countries, anaerobes are rarely isolated due to technical difficulties. This can be overcome by using a new simple, innovative technique of a combination of candle combustion and use of acidified copper-coated steel wool, as reported here. METHODS: In-house developed method was used in a prospective clinico-microbiological study for anaerobes from randomly selected 43 patients with diabetic foot ulcers along with conventional method of anaerobic culture in GasPak system and aerobic culture by standard laboratory procedures. For primary isolation of anaerobes, Brucella blood agar supplemented with hemin (5 MUg/ml) and menadione (1 MUg/ml) was used. Antibiotic sensitivity tests were performed by the standard disc diffusion method for aerobes and E-test method for anaerobes. RESULTS: All the 43 samples were culture positive, of which aerobic Gram-negative bacteria (GNB) predominated, followed by Staphylococcus aureus, Enterococcus and diphtheroids. Anaerobes isolated from 21 samples were Peptostreptococcus, Bacteroides, Porphyromonas, Veillonella spp. and Clostridium perfringens by both GasPak and in-house developed and modified candle jar techniques. Imipenem and metronidazole were most sensitive while clindamycin, penicillin and cefoxitin were least sensitive drugs for anaerobes. Aerobic GNB were found to be multidrug resistant, especially to penicillin and cephalosporins. The most sensitive drug was piperacillin-tazobactam. INTERPRETATION & CONCLUSIONS: For isolation of anaerobes from clinical specimens such as diabetic foot ulcers, modified candle jar technique was found to be as reliable as GasPak system. This modified technique needs to be tested for many other clinical materials which are not yet evaluated. PMID- 28574022 TI - Multilocus sequence typing of Cryptosporidium hominis from northern India. AB - BACKGROUND & OBJECTIVES: Human cryptosporidiosis is endemic worldwide, and at least eight species have been reported in humans; the most common being Cryptosporidium hominis and C. parvum. Detailed understanding of the epidemiology of Cryptosporidium is increasingly facilitated using standardized universal technique for species differentiation and subtyping. In this study micro- and minisatellite targets in chromosome 6 were used to assess genetic diversity of C. hominis by sequence length polymorphisms along with single nucleotide polymorphisms (SNPs). METHODS: A total of 84 Cryptosporidium positive stool specimens were subjected to speciation and genotyping using small subunit (SSU) ribosomal RNA (rRNA) as the target gene. Genetic heterogeneity amongst C. hominis isolates was assessed by sequencing minisatellites, microsatellites and polymorphic markers including genes encoding the 60 kDa glycoprotein (GP60), a 47 kDa protein (CP47), a mucin-like protein (Mucin-1), a serine repeat antigen (MSC6 7) and a 56 kDa transmembrane protein (CP56). RESULTS: Of the 84 Cryptosporidium positive stool specimens, 77 (92%) were positive by SSU rRNA gene polymerase chain reaction (PCR) assay. Of these 77 isolates, 54 were identified as C. hominis and 23 as C. parvum. Of all the loci studied by multilocus sequence typing (MLST), GP60 gene could reveal the highest genetic diversity. Population substructure analysis of C. hominis performed by combined sequence length and nucleotide polymorphism showed nine multilocus subtypes, all of which were distinct groups in the study population. INTERPRETATION & CONCLUSIONS: MLST, a powerful discriminatory test, demonstrated both variations and distribution pattern of Cryptosporidium species and its subtypes. PMID- 28574023 TI - Comparison of injectable doxorubicin & its nanodrug complex chemotherapy for the treatment of 4-nitroquinoline-1-oxide induced oral squamous cell carcinoma in rats. AB - BACKGROUND & OBJECTIVES: Combination treatments of chemotherapy and nanoparticle drug delivery have shown significant promise in cancer treatment. The aim of the present study was to compare the efficacy of a nanodrug complex with its free form in the treatment of tongue squamous cell carcinoma induced by 4 nitroquinoline-1-oxide in rats. METHODS: In this study, 75 male Sprague-Dawley rats were divided into five groups. Oral squamous cell carcinoma (OSCC) was induced by using 4- nitroquinoline-1-oxide (4NQO) as a carcinogen. Newly formulated doxorubicin (DOX)-methotrexate (MTX)-loaded nanoparticles, and free DOX-MTX were administrated intravenously to rats. During the study, the animals were weighed once a week. At the end of the treatment, rats' tongues were evaluated histopathologically. RESULTS: There was significant difference between the mean weight of rats in groups A and B (P=0.001) and also groups A and K (P<0.001). No significant association was found between the mortality rate of groups. The difference between the severity of dysplasia of treated and untreated groups was significant (P<0.001). INTERPRETATION & CONCLUSIONS: Our study showed that DOX-MTX nanoparticle complex was more effective than free DOX-MTX in chemotherapy treatment of oral squamous cell carcinoma in rat models. Further investigations are necessary to clarify the advantages and disadvantages of the nanoparticle complex and its potential therapeutic application for different types of cancer. PMID- 28574024 TI - N-acetyltransferase gene polymorphisms & plasma isoniazid concentrations in patients with tuberculosis. AB - BACKGROUND & OBJECTIVES: Variations in the N-acetyltransferase (NAT2) gene among different populations could affect the metabolism and disposition of isoniazid (INH). This study was performed to genotype NAT2 gene polymorphisms in tuberculosis (TB) patients from Chennai, India, and compare plasma INH concentrations among the different genotypes. METHODS: Adult patients with TB treated in the Revised National TB Control Programme (RNTCP) in Chennai, Tamil Nadu, were genotyped for NAT2 gene polymorphism, and two-hour post-dosing INH concentrations were compared between the different genotypes. Plasma INH was determined by high-performance liquid chromatography. Genotyping of the NAT2 gene polymorphism was performed by real-time polymerase chain reaction method. RESULTS: Among the 326 patients genotyped, there were 189 (58%), 114 (35%) and 23 (7%) slow, intermediate and fast acetylators, respectively. The median two-hour INH concentrations in slow, intermediate and fast acetylators were 10.2, 8.1 and 4.1 MUg/ml, respectively. The differences in INH concentrations among the three genotypes were significant (P<0.001). INTERPRETATION & CONCLUSIONS: Genotyping of TB patients from south India for NAT2 gene polymorphism revealed that 58 per cent of the study population comprised slow acetylators. Two-hour INH concentrations differed significantly among the three genotypes. PMID- 28574025 TI - Patterns in antimicrobial susceptibility of Salmonellae isolated at a tertiary care hospital in northern India. AB - BACKGROUND & OBJECTIVES: Multidrug-resistant Salmonellae have emerged worldwide as also in India. The aim of this study was to study the antimicrobial susceptibility pattern of Salmonella enterica serovars isolated at a tertiary care hospital in northern India. METHODS: A total of 106 S. enterica serovars isolated from various clinical samples from January 2011 to June 2012 were tested for antimicrobial susceptibility by Kirby-Bauer disk diffusion method. The minimum inhibitory concentration (MIC) of ciprofloxacin, chloramphenicol and ceftriaxone was determined both by agar dilution method and E-test for all the isolates. RESULTS: Salmonella Typhi (73.6%) was the predominant isolate followed by S. Paratyphi A (15.1%), S. Typhimurium (9.4%) and S. Enteritidis (1.9%). Of these, 34 (32.1%) were resistant to ciprofloxacin (MIC >=1 MUg/ml by agar dilution) with MIC90 of ciprofloxacin for S. Typhi, S. Paratyphi A and S. Typhimurium being 32, 4 and 1 MUg/ml, respectively. All the isolates were sensitive to chloramphenicol (MIC <=8 MUg/ml) and ceftriaxone (MIC <=1 MUg/ml). Disk diffusion method showed high susceptibility rates to cefotaxime (100%), azithromycin (93.4%) and co-trimoxazole (97.2%). Nalidixic acid resistance was seen in 105 (99.1%) isolates. Of the nalidixic acid-resistant strains, only 34 (32.3%) were found to be resistant to ciprofloxacin (MIC >=1 MUg/ml). INTERPRETATION & CONCLUSIONS: This study showed an alarming increase in MIC to quinolones and re-emergence of susceptibility to conventional antibiotics among Salmonellae. PMID- 28574026 TI - Effect of moderate-intensity aerobic exercise on glycosylated haemoglobin among elderly patients with type 2 diabetes & peripheral neuropathy. AB - Aerobic exercise has been known to improve glycosylated haemoglobin (HbA1c) levels and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). The present study was undertaken to evaluate the effect of eight week moderate intensity aerobic (heart rate reserve 40-60%) exercise on glycaemic control in elderly patients with T2DM and diabetic peripheral neuropathy (DPN). The participants (n=87) were randomly assigned to an eight-week programme by a computer-generated random number table to the study or control group, respectively. There were 47 participants in the control group and 40 participants in the study group after randomization. There was a significant difference in the mean values of glycated haemoglobin (HbA1c) at baseline and 8th week between the two groups. Moderate-intensity aerobic exercise of eight weeks duration helped in achieving enhanced glycaemic control in the T2DM patients with DPN. PMID- 28574027 TI - Utility of p57 immunohistochemistry in differentiating between complete mole, partial mole & non-molar or hydropic abortus. AB - BACKGROUND & OBJECTIVES: There is considerable inter-observer variability in the diagnosis of molar pregnancies by histomorphological examination of products of conception (POC). The p57KIP2 gene is paternally imprinted and expressed from the maternal allele. On immunohistochemistry (IHC) with p57, complete mole (CM) shows absent staining whereas hydropic abortus (HA) and partial mole (PM) show positive staining. This study was undertaken to evaluate the role of p57 IHC along with histomorphology in differentiating between CM, PM and non-molar or HA. METHODS: This was a cross-sectional study over a period of three and a half years on archival material. Detailed histomorphological review along with p57 IHC was carried out in 28 diagnosed cases (23 CM, 4 PM and 1 molar pregnancy not categorized) and 25 controls of four normal placentas and 21 POC (8 non-hydropic and 13 HA). RESULTS: In 14.8 per cent (4/27) cases, there was discordance in accurate subtyping of molar pregnancy. One case of CM showed inconsistent IHC pattern. In 15.4 per cent (2/13) HA, molar pregnancy was final diagnosis. After final review, there were 25 CM, five PM, 22 non-molar controls including 10 HA and one not assigned (PM/HA). IHC with p57 was negative in 96 per cent CM and positive in 100 and 95 per cent PM and non-molar controls, respectively. INTERPRETATION & CONCLUSIONS: This study showed that negative p57KIP2 immunostaining reliably identified CM and could be used in association with the histological findings to distinguish CM from its mimics. PMID- 28574028 TI - Bacterial aetiology of neonatal meningitis: A study from north-east India. PMID- 28574030 TI - Fitz-Hugh-Curtis syndrome. PMID- 28574029 TI - Opportunistic cervical cancer screening of women visitors at a trade fair in India. PMID- 28574031 TI - An unusual vesical stone. PMID- 28574032 TI - [Calcification of atherosclerotic plaques and assessment of their stability]. AB - Presented herein is a review of the literature concerning mechanisms of calcification of atherosclerotic plaques (ASP), showing molecular mechanisms of interaction of processes of calcification with the factors inducing instability of ASPs (anti-inflammatory cytokines, neoangiogenesis, increased level of matrix metalloproteinases, etc.), also describing the effect of the value of volume of scope of calcification on stability of ASPs, followed by discussing the problems related to the role of biominerals (hydroxyapatite calcium phosphate) and Mn2+ in calcification of ASPs and their impact upon stability of the plaque. PMID- 28574033 TI - [The phenomenon of ischaemic postconditioning of the heart. Analysis of clinical data]. AB - Data concerning the effectiveness of ischaemic postconditioning (IPost) in treatment of acute ST-segment elevation myocardial infarction (STEMI) are controversial. The authors of the majority of studies have reported an anti apoptotic and infarct reducing effect of IPost. There is evidence that IPost reduces the microvascular obstruction zone, increases coronary flow reserve, and improves the pumping functions of the heart. At the same time, there are publications reporting that IPost does not influence the course of acute STEMI. It was established that IPost protects the heart from reperfusion injury occurring after cold cardioplegia in patients with tetralogy of Fallot. PMID- 28574034 TI - [Effect of actovegin and solcoseryl on microcirculation in experimental critical lower limb ischaemia]. AB - The authors examined the effect of actovegin and solcoseryl on microcirculation parameters in treatment of experimental critical lower limb ischaemia. The study included a total of 130 male Wistar albino rats divided into four groups: intact, control, first and second study groups. The intact group consisted of 10 animals used for assessment of the normal indices of microcirculation, with the remaining three groups comprising 40 rats each. All animals, except the intact ones, were subjected to modelled critical ischaemia of a hind limb. The control group animals received no treatment, with the rats of the first and second study groups given intraperitoneal actovegin and solcoseryl, respectively, at a dose of 50 MUg/kg first injected 3 hours after the operation and then once daily for five days. The level of microcirculation in the murine crural muscles was assessed by means of laser Doppler flowmetry on postoperative days 5, 10, 21 and 28. At the same time intervals, we performed histological examination of the ischaemized muscles, determining the level of microcirculation, the level of arteriovenular shunting, the area of necrosis and capillary network density. It was determined that actovegin and solcoseryl exerted a positive effect on formation of new capillaries in the ischaemized muscles, increasing density of the capillary network, decreasing arteriovenular shunting, increasing the level of microcirculation, decreasing the specific area of muscular tissue necrosis. The obtained findings showed advantages of actovegin over solcoseryl by the dynamics of the parameters of microcirculation, arteriovenular shunting, and capillary network density. PMID- 28574035 TI - [Vascular pathology in the aspect of sudden death in young adults and connective tissue dysplasia: anatomical, physiological, and morphological parallels]. AB - Vascular pathology in young adults has during the last 10 years been diagnosed more often during forensic medical examination of sudden death. Major morphological alterations are revealed in cerebral vessels, coronary vessels, and at the level of the ascending portion of the aorta. Generally, in the young age there is no stenosing atherosclerosis inducing vascular lesions and the development of complications. It was determined that connective tissue dysplasia is pathology wherein weakness of the vascular wall is genetically preconditioned, thus promoting formation of vascular aneurysms and rupture of the latter under conditions of provoking factors such as going in for sports, physical loads, and psychoemotional stress. PMID- 28574036 TI - [Stimulation of angiogenesis by bone marrow cells in experimental ischaemia of lower limb]. AB - The objective of the study was to experimentally substantiate a possibility of treating lower limb chronic ischaemia by means of administration of bone marrow cells. The study was performed on 100 laboratory 'Wistar' rats subdivided into four groups: intact, control, first and second study groups. The intact group consisted of 10 animals, with the remaining three containing 30 rats each. All animals, except the intact ones, were subjected to modelled critical ischaemia of a hind limb by means of excision of major vessels of the extremity. The rats from the first study group were given 'Myelopid' (calf bone marrow extract) at a dose of 50 MUg/kg injected into the femoral muscles 3 hours after the operation, then after 1, 2 and 3 days. The second study group rats underwent cellular therapy with the mononuclear fraction of bone marrow autologous cells. Bone marrow was procured from the femoral bone of the contralateral limb. The exfusate was subjected to double centrifugation followed by isolation of the mononuclear fraction of the bone marrow according to the Boyum technique. The obtained mononuclear fraction of autologous cells of the bone marrow amounting to 4*106 cells in a volume of 200 MUl was injected into the ischaemized limb of the animal. The control group received no treatment at all. In the first study group, the level of microcirculation as compared with the control group on day 10 increased by 48.3%, on day 21 by 50.6%, and on day 28 by 105.9%. In the second study group, the level of microcirculation as compared with the control group on day 10 increased by 67.4%, on day 21 by 85.7%, and on day 28 by 97% (the differences between the two study groups were statistically insignificant). Neither had the area of muscular necrosis statistically significant differences between the study groups, decreasing on day 10 averagely by 14.75%, on day 21 by 6.5% as compared with the control group animals, to become completely reduced on day 28. A conclusion was drawn that 'Myelopid' and the mononuclear fraction of autologous cells of bone marrow exerted a positive effect on the level of microcirculation, the scope of necrotic lesion of muscular tissue in the ischaemized extremity of laboratory animals and may potentially be used for treatment of patients suffering from obliterating diseases of lower-limb arteries. PMID- 28574037 TI - [Diagnostic significance of the color duplex scanning in estimation of the arteries state at different stages of infrainguinal reconstructions]. AB - AIM: The study was aimed at assessing diagnostic possibilities of duplex scanning (DS) of lower limb arteries, used as 'ultrasonographic angiography' in patients presenting with critical ischaemia for appropriately planning complicated infrainguinal reconstructions at stages of surgical management, including dynamic follow up in the postoperative period. PATIENTS AND METHODS: We examined a total of 30 patients. Of these, 14 patients composed the control group and 16 patients with critical ischaemia of lower limb arteries who underwent 8 external iliac tibial and 8 femorotibial bypass graftings with a relieving arteriovenous fistula and application of a venous cuff according to the type of 'St. Mary's boot'. All the 16 patients preoperatively underwent DS of lower limb arteries and CT angiography, as well as postoperative DS of the vessels of the zone of the operative intervention. We compared the possibilities of DS and CT angiography in the assessment of the state of various segments of lower limb arteries. The obtained findings were compared with the data of the 'golden standard' - X-ray contrast enhanced angiography or intraoperative revision. RESULTS: In assessing the state of the aortoiliac segment, sensitivity and specificity of the both methods amounted to 100%. In assessing patency of the femoropopliteal segment, sensitivity and specificity of DS amounted to 93.7 and 100%, with those for CT angiography equalling 87.5 and 100%. Assessing patency of arteries of the crus, sensitivity and specificity of the both methods amounted to 87.5 and 93.7%, respectively. In the postoperative period it was revealed that a prognostically favourable factor for shunt functioning is the value of the volumetric velocity of blood flow in the shunt at the level of the middle third of the femur, equalling the sum of volumetric velocities of blood flow in the donor artery distal to and in the relieving vein proximal to the anastomosis. Important prognostic parameters of shunt functioning were also the values of linear velocity of blood flow both in the shunt and donor artery. CONCLUSION: Strict compliance with the methodology and protocol of DS makes it possible to evaluate the condition of outflow pathways while planning the intervention, to assess functioning of the shunt in the postoperative period and to work out criteria for favourable functioning of the infrainguinal shunt for regular dynamic control over the state of the revascularized limb. PMID- 28574038 TI - [Prediction of ischaemic lesions of the brain in reconstructive operations on internal carotid arteries]. AB - The present study was undertaken to examine the relationship between the level of the intensity of the ultrasonic signal reflected from atherosclerotic plaques (ATP) of carotid arteries and the risk for formation of an ischaemic lesion in the brain matter, detected during diffusion-weighted magnetic resonance imaging (DW-MRI) performed 24 hours after carotid endarterectomy (CEA) or carotid angioplasty and stenting (CAS). Our prospective study included a total of 78 patients presenting with stenosis of the sinus of the interior carotid artery. Of these, 42 patients were subjected to CEA and 36 subjects endured CAS. All patients in the preoperative period underwent ultrasonographic examination with determination of the degree of heterogeneity of ATPs and registration of the values of the intensity of acoustic characteristics of the signal. The condition of the brain matter before and 24 hours after the intervention was assesses by the findings of DW-MRI. None of the patients after the reconstructive intervention during the postoperative period demonstrated any evidence of acute cerebral circulation disorders. DW-MRI carried out 24 hours after the operation revealed acute ischaemia foci (AIF) in 9 (21.4%) patients after CEA and in 18 (50%) patients after CAS (p=0.05). It was revealed that the postoperative occurrence of AIF was related to the intensity of the ultrasonographic signal prior to the operation: in the CEA group patients the postoperative ischaemic foci were associated with high-intensity ultrasonographic signals (more than 25 dB), whereas in the CAS group patients, vice versa - with low-intensity signals (less than 25dB). For CEA, sensitivity and specificity of the preoperative ultrasonographic method of predicting postoperative embolic lesions of the brain appeared to be similar, amounting to 100% each (with the cut-off point of high- and low-intensity signals equaling 25 dB), and for CAS, sensitivity of the method turned out to be 75% and specificity - 100% (with the same cut-off point of 25 dB). A conclusion was drawn that quantitative characteristics of the intensity of an ultrasonographic signal from fragments of atherosclerotic plaques of the sinus of the internal carotid artery made it possible with high probability to predict the risk for the development of AIF in the brain matter after both CEA and CAS and may therefore serve as a reliable criterion for appropriate therapeutic decision-making with the lowest risk of inflicting lesions in a particular case. The threshold cut-off points of high- and low-intensity ultrasonographic signals, as well as their clinical significance are yet to be specified and verified with the growing number of cases. PMID- 28574039 TI - [Peripheral perfusion in CAD patients with various-stage chronic heart failure undergoing coronary artery bypass grafting]. AB - Using the orthostatic test, we examined peripheral perfusion by means of laser Doppler flowmetry (LDF) and transcutaneous oximetry in a total of 104 patients presenting with coronary artery disease and functional class II-IV chronic heart failure (CHF) prior to coronary artery bypass grafting (CABG) and in the remote terms thereafter. Volumetric velocity of the microcirculatory blood flow (MCB) of the lower limbs was measured by means of LDF in perfusion units; partial oxygen pressure (TcPO2, mmHg) was registered by means of transcutaneous oximetry. The patients with CAD were subdivided into two groups as follows: Group One comprised patients with FC II CHF and Group Two included those with FC III-IV CHF. Prior to CABG according to the findings of LDF, the lowest level of MCB of the lower limbs was revealed in Group Two, being by 57.9% (42.5-61.3) less as compared with Group One (p=0.008). In Group Two patients as compared with Group One there was a larger proportion of patients with impaired reactivity of the peripheral microcirculatory bed during the orthostatic test in the form of: 1) a paradoxical reaction of the MCB both before CABG (60.6 versus 13.9%, p=0.00001) and in the remote terms after the operation (64.3 versus 16.2%, p=0.00001); 2) lack of the reaction of the MCB prior to the operation (19.7 versus 4.7%, p=0.02) and in the remote period after CABG (16.7 versus 2.7%, p=0.04). Group Two patients both before and after CABG were found to have a decrease (compared with the norm) in the TcPO2 parameters at rest, as well as lower reactivity of tissue metabolism of peripheral tissues during the orthostatic test. An initial decrease in the left ventricular output fraction of < 42% increases the chances of preserving the post CABG decreased values of TcPO2 of less than 24 mm Hg (OR=3.1; 95% CI 1.1-6.8; p=0.003). Lack of the reaction of the MCB during the orthostatic test prior to CABG increases the chances for the development of surgically significant atherosclerotic lesions of lower-limb arteries after myocardial revascularization (OR=4.2; 95% CI 1.3-2.3; p=0.01). Hence, the most pronounced impairments of the mechanisms of adaptation of the MCB in the orthostatic test prior to and in the remote terms after CABG were detected in CAD patients with FC III-IV CHF. A decrease in the microvascular tonicity during the test and, consequently, inhibition of the nutritive component in this cohort of patients were accompanied by low metabolic reactivity of peripheral tissues. PMID- 28574040 TI - [Use of a filtering protective device during angioplasty and stenting of the brachiocephalic trunk]. AB - The authors carried out a pilot study aimed at assessing the possibility and efficacy of using filtering systems for protection of cerebral arteries from distal embolism during angioplasty and stenting of the brachiocephalic trunk. A total of five patients presenting with lesions of the brachiocephalic trunk underwent 5 roentgenoendovascular interventions with the use of the filtering protective device Spider FX. Angiographic and clinical success was achieved in 100% of cases. Particles of debris were obtained from the protective device in all cases. All the five patients were found to have symptoms of vertebrobasilar insufficiency. During follow-up in the medium-term period at check examinations the implanted stents were patent, with neither major nor minor neurological complications observed. The patients turned out to be free from cerebrovascular insufficiency relapses. Presented herein are clinical case reports describing technical peculiarities of using the protective device in different variants of the anatomy and vascular lesion. PMID- 28574041 TI - [Significance of the level of implantation of the 'E-vita open plus' hybrid stent graft into the descending aorta in the development of spinal ischaemic complications]. AB - Spinal ischaemia in patients after reconstruction of the thoracic aorta is referred to the category of the most severe postoperative complications, especially in hybrid interventions. The present study was aimed at assessing the risks for the development of spinal ischaemia in patients after implantation of the 'E-vita open plus' stent graft into the descending portion of the thoracic aorta during hybrid reconstruction. The 'E-vita open plus' hybrid stent graft (Jotec, Germany) was implanted to 18 patients presenting with various pathology of the thoracic aorta (dissection, aneurysms). All operations were carried out in the conditions of moderate hypothermia, circulatory arrest and antegrade perfusion of the brain through the brachiocephalic trunk. It was determined that the distal end of the stent graft was located at the level of Th7-Th12. In 12 (66.7%) cases the 'lower' edge of the stent graft was located at the level of thoracic vertebrae Th8-Th9. Before the operation the number of open pairs of intercostal arteries amounted to 10 [9, 11]. After the operation, the number of the open pairs of the segmental arteries amounted to 3 [1; 4], they were all in the lower thoracic portion; the above-located intercostal arteries were shut by the stent graft. In 17 (94.5%) cases in the early postoperative period there were no signs of spinal ischaemia. Only one (5.5%) patient was clinically diagnosed to have developed transient spinal ischaemia noted to disappear spontaneously within the first 24 hours. A conclusion was made that using the 'E-vita open plus' stent graft in the course of hybrid reconstruction of the thoracic aorta was accompanied by the minimal risk for spinal ischaemic complications. The level of the location of the distal edge of the stent graft is not the determining factor in the risks of spinal complications in of such similar operations. PMID- 28574042 TI - [First experience with intravascular ultrasonographic examination in diagnosis of post-traumatic obstruction of deep veins]. AB - Intravascular ultrasonography (IVUS) is a highly effective method of diagnosis of post-thrombotic obstructions. Its possibilities by determining the degree and extension of obstructions of deep veins are superior to those of not only non invasive methods of examination (ultrasonography, CT and MRI) but of phlebography whose results until recently were considered fundamental in diagnosis of the disease concerned. Limited possibilities of phlebography often lead to diagnostic errors when determining the degree and extension of post-thrombotic obstructions. Intravascular ultrasonography makes it possible to obtain a maximally objective picture of the degree of intravascular alterations in post-thrombotic diseases, as well as to determine the indications for performing balloon dilatation and stenting of deep veins. First experience in using intravascular ultrasonography in the Clinic of the Institute of Experimental Medicine confirmed these provisions. A total of 15 patients diagnosed with post-thrombotic disease while examination were subjected to antegrade transfemoral phlebography in the direct and lateral projections and IVUS. Significant post-thrombotic obstruction was revealed by phlebography in 3 (20%) of the 15 patients and confirmed by the findings of IVUS. In 12 (80%) patients only carrying out IVUS made it possible to detect pronounced obstruction of veins (more than 50% of its diameter) remaining undiagnosed by phlebography. Unnoticed in phlebography turned out to be May Thurner syndrome in a female patient. Compression of the left common iliac vein by the right common iliac artery exceeding during systole 70% of the initial diameter of the vein was also revealed while performing IVUS. At the same time phlebography remains an indispensable method of examination while assessing collateral blood flow, thus making it possible to recommend its performing in combination with IVUS for obtaining the most complete notion on post-thrombotic alterations in deep veins of the inferior vena cava system. PMID- 28574044 TI - [Autotransplantation of the internal carotid artery in patients with high localization of an atherosclerotic plaque]. AB - Acute and chronic cerebral circulatory impairment is a very commonly encountered type of neurological diseases, annually affecting more than six million people worldwide. The absolute majority of all cases are associated with atherosclerosis of cerebral arteries. Surgical intervention in a stenotic lesion of the internal carotid artery (ICA) is a method of preventive treatment with confirmed efficacy. Eversion carotid endarterectomy (ECEA) is currently the most commonly used 'open' operation for this cohort of patients. It is connected with relative technical simplicity of the operative procedure, no foreign material in the wound, low risk of haemodynamic disorders in the zone of reconstruction owing to no considerable alteration in the ICA diameter, as well as favourable remote results. A disadvantage of ECEA is lack of visual control above the distal portion of the ICA and, as a consequence, limited application of the technique in cases of a highly located atherosclerotic plaque (by more than 2 cm above the bifurcation). Specialists of the Federal Centre of Cardiovascular Surgery in the city of Penza worked out a modification of the operative technique making it possible to widen the indications for using ECEA. Its essence consists in total resection of the stenosed portion of the ICA, performing eversion endarterectomy outside the wound, followed by reimplantation thereof with the help of two 'end-to-end' anastomoses, as during prosthetic repair. This technique was called autotransplantation of the ICA. Advantages of this technique are considered to include precision of removing the plaque and intimal ruptured fragments, which is easier and more convenient to achieve outside the wound; reliable fixation of the intima and non-stenosing residuals of the plaque by a distal anastomosis, as well as a possibility of using this technique in cases of high location of the plaque. The purpose of this study was to compare the immediate results_outcomes of ECEA and autotransplantation of the ICA in two groups comprising 108 and 72 patients, respectively. The measures assessed included the mean time of ICA cross-clamping during surgery, frequency of the development of perioperative strokes, haemorrhage, lesions of craniocerebral nerves, wound complications. PMID- 28574043 TI - [Von Korff questionnaire in assessment of social disadaptation and therapeutic results in women with pelvic varicose veins]. AB - AIM: The present study was conducted to examine the possibilities of the Von Korff questionnaire in assessing the impact of pelvic pain on social activity and working ability of women with pelvic varicose veins (PVV) and evaluating the results of treatment of the pathology involved. PATIENTS AND METHODS: The Von Korff questionnaire was administered in a total of 80 women presenting with PVV in order to assess the results of conservative and surgical treatment of PVV. RESULTS: Using the Von Korff questionnaire made it possible to objectively evaluate the psychosocial impact of chronic pelvic pain (CPP). It was determined that in 56 patients the presence of PVV and CPP was accompanied by a low level of social disadaptation and formation of grade I disability. 24 women were found to have moderate and high levels of social disadaptation and grade II-IV disability. Studying the outcomes of conservative and surgical treatment of PPV as assessed by means of the Von Korff questionnaire demonstrated high efficacy of the therapeutic techniques used. In patients subjected to surgical interventions, the CPP degree decreased from 7.6+/-0.9 to 1.6+/-0.9 points, the level of social disadaptation fell from 2.8+/-0.6 to 0.5+/-0.3 points, and the grade of disability decreased from 2.9+/-0.4 to 0.8+/-0.4, which may be regarded as complete restoration of social activity. DISCUSSION: The Von Korff questionnaire used in our study made it possible to objectively evaluate the impact of CPP related to pelvic varicose veins on formation of social disadaptation in women and a decrease in their working ability. In the general structure of the disease, 75% of women appeared to have a low level of social disadaptation and grade I disability, with a third having grade II, III and IV disability and a moderate-to high level of social disadaptation. In 25% of women, the determined degree of disability averagely amounted to 2.9+/-0.4, thus suggesting their significant social disadaptation. CONCLUSION: The carried out study showed that the Von Korff questionnaire is an objective and demonstrative tool of clinical determination of the severity of pelvic varicose veins, as well as the effect of CPP on both everyday and social activity of women suffering from the pathology concerned. PMID- 28574045 TI - [Surgical treatment of patients with haemodynamically significant stenosis of the internal carotid artery and contralateral occlusion]. AB - Presented herein is a review of the literature dedicated to the problem regarding surgical management of patients with haemodynamically significant stenosis of the internal carotid artery and collateral occlusion. Special consideration is given to the studies comparing perioperative and early postoperative outcomes of carotid endarterectomy in patients with the nosology concerned. The literature was retrieved by means of the following databases Scopus, Web of Science, Medline, and the Russian Science Citation Index. PMID- 28574046 TI - [Efficacy and safety of temporary bypass grafting in carotid endarterectomy]. AB - The authors analysed interrelationship between the use of temporary bypass grafting during operations of carotid endarterectomy and the frequency of the development of ischaemic complications (stroke and transitory ischaemic attacks in the early postoperative period). It was shown that in the group wherein a temporary bypass graft was established only by the criterion of decreasing retrograde pressure ischaemic complications were encountered in ten (4.4%) patients and in the group wherein temporary shunts were established by the criterion of a simultaneous decrease in cerebral oxygenation and retrograde pressure - in two (0.9%) patients (OR 5.28; 95% CI 1.22-24.38; p=0.03). It was demonstrated that using temporary bypass grafting in cases of isolated assessment of the parameters of cerebral oxygenation and retrograde pressure increased the frequency of the development of shunt-related ischaemic complications as compared with the patients in whom shunts were not used due to lack of a synchronous decrease in these parameters (13.5 vs 1.5%, respectively; OR 10.0; 95% CI 1.1 82.2; p=0.039). The findings of the carried out retrospective analysis suggested that the main predictor of the development of the outcome 'stroke + transitory ischaemic attack' was the use of a temporary internal shunt during the main stage of the operation (p<0.00001). PMID- 28574047 TI - Risk of development of neurological complications in prosthetic repair of the aortic ascending portion and arch. AB - The study comprised a total of 68 patients (presenting) with chronic dissection of the aortic ascending portion and arch, undergoing surgery and subjected to measuring at various stages of the operation the level of cerebral oxygenation (rSO2) of the right and left hemispheres by means of bilateral transcranial spectroscopy. The aim of the study was to examine the risk for the development of neurological complications in patients with chronic dissection of the aortic ascending portion and arch in various methods of cerebral protection during aortic prosthetic reconstruction. Group One consisted of thirty-one 40-to-61-year old (mean age 51 years) patients who during circulatory arrest (CA) were as cerebral protection subjected to antegrade cerebral perfusion (ACP) on the background of moderate hypothermia (23-24 degrees C). Group Two included thirty seven 40-to-58-year-old (mean age 48 years) patients who during CA were subjected to cerebral protection consisting in craniocerebral hypothermia on the background of total deep hypothermia (18 degrees C). Prior to surgery and in the immediate period thereafter, all patients underwent clinical and instrumental examination of the neurological status. During CA while aortic arch repair in Group One patients at the expense of maintaining cerebral perfusion a decrease in rSO2 registered in the right and left hemispheres amounted to only 11.8 and 8.7%, respectively, compared with the baseline values. In Group Two patients during CA a decrease in rSO2 along the right and left hemispheres amounted to 29.6 and 30.9% compared with the initial values, which was statistically significantly more than in Group One (p=0.002 and p=0.003). Thus, in Group Two patients during CA cerebral hypoperfusion resulted in a considerable decrease in oxygen supply of the brain, in spite of systemic deep hypothermia and craniocerebral hypothermia, promoting reduction of cerebral metabolism. Using ACP during CA in Group One patients maintained the oxygen status of the brain at an optimal level. In Group One patients, in the early postoperative period neurological complications were registered in 12.9% of cases. In Group Two, neurological complications were noted in 35.1% of cases. The univariate logistic regression analysis demonstrated that the risk for the development of any neurological complications depended on the degree of a decrease in rSO2 during CA while prosthetic repair of the aortic arch relative to the previous values - OR 1.25; 95% CI 1.11-1.65; p=0.02. Hence, deep hypothermia and craniocerebral hypothermia used as cerebral protection during CA turned out to be less effective compared with ACP, because despite reduction of metabolic requirements of the brain, cerebral hypoperfusion substantially of neurological status impairments in the early postoperative period. PMID- 28574048 TI - [Assessment of severity of lesions of arterial basins in patients with multifocal atherosclerosis]. AB - The present study was aimed at working out a methodology combining clinical, haemodynamic, and functional parameters of lesions of arterial basins in patients presenting with concomitant lesions of the aortic arch branches and arteries of lower extremities. The authors retrospectively investigated the results of examining a total of 181 patients operated on for concomitant atherosclerotic lesions of the aortic arch branches, terminal portion of the abdominal aorta, and lower limb arteries. In patients subjected as the first stage to interventions on the aortic arch branches (Group 1), the index of severity of the lesion of the aortic arch branches (Cs) was higher than in those from Groups 2 and 3. In Group 2 patients who as the first stage underwent reconstruction of the terminal portion of the abdominal aorta and lower-limb arteries, the index of severity of lesions of lower limb arteries (Ls) turned out to be higher as compared with patients from Groups 1 and 3. The mean value of the Ls/Cs ratio for Group 1 patients amounted to 1.07, for Group 2 patients to 2.7, and for Group 3 subjects to 1.96. The proposed methodology makes it possible to determine the degree of the lesion of arterial basins in patients suffering from multifocal atherosclerosis and may objectively reflect severity of the lesion thereof. The comparative retrospective analysis has demonstrated that with the Ls/Cs ratio equaling 1.0, the first stage consisted in carrying out an intervention on the aortic arch branches, in the Ls/Cs ratio varying from 2.5 to 3.0, the first stage performed was reconstruction of the terminal portion of the abdominal aorta and arteries of the lower limbs, and cases associated with the Ls/Cs ratio equaling 2 involved simultaneous interventions. A possibility of wide application of the method warrants further investigation. PMID- 28574049 TI - [30th Annual Meeting of the European Society for Vascular Surgery (Copenhagen, Denmark, september 28-30, 2016)]. AB - The article is a brief review of the proceedings of the 30th Annual Meeting of the European Society for Vascular Surgeons, held on September 28-30, 2016 in Copenhagen, Denmark. The papers presented reported the results of managing patients with pathology of carotid arteries, aortic aneurysms, pathology of peripheral arteries, also discussing current achievements and prospects of methods of treatment of arterial and venous diseases. PMID- 28574050 TI - [Haemangioma of the left atrium]. AB - Presented herein is a clinical case report concerning successful surgical management of a rare variety of a primary tumour of the heart, i. e., a capillary haemangioma of the left atrium, simulating by the contours and localization a myxoma. The final diagnosis was verified only by histological examination. The authors describe difficulties of diagnosis of the disease involved, underlying the necessity of plastic correction for restoration of the normal anatomical configuration of the heart. This is followed by a review of the literature, reflecting a possible course of the disease, problems of diagnosis, and therapeutic policy. PMID- 28574051 TI - [Stagewise hybrid method of treating a patient with connective tissue dysplasia, aortic aneurysm, and distal dissection]. AB - Presented herein is a clinical case report concerning the use of a hybrid technique in stagewise surgical management of a patient with distal dissection and an aneurysm of the thoracoabdominal portion of the aorta. The patient at high risk with the connective tissue dysplasia syndrome had a past medical history of prosthetic repair of the descending thoracic aorta with type-1 haemodynamic correction. Three years later, the findings of computed tomography demonstrated fenestration in the area of the distal anastomosis, a patent false channel, and an increase in the diameter of the unoperated thoracoabdominal portion of the aorta. The first stage consisted in performing prosthetic repair of the infrarenal portion of the aorta by means of the multibranched Coselli thoracoabdominal graft, followed by 'switching' the visceral branches into the formed prosthesis. 14 days later, the second stage included stenting of the dilated suprarenal portion of the aorta. The patient was discharged on day 9 after the second stage of the operation. This clinical case report demonstrates that a hybrid method of treatment may by an alternative to an open operation in high risk surgical patients presenting with severe concomitant somatic pathology. PMID- 28574052 TI - [Aneurysm of the gastroduodenal artery in a female patient with the postcholecystectomy syndrome (a clinical case report)]. AB - Aneurysms of visceral arteries appear to belong to rare and potentially lethal vascular diseases. The most important role in the aetiology of aneurysms of the gastroduodenal artery is plaid by either acute or chronic pancreatitis. The article deals with a clinical case report concerning a saccular partially thrombosed aneurysm having developed in a 77-year-old woman presenting with the postcholecystectomic syndrome and detected on ultrasonographic examination of the abdominal-cavity vessels. Timely radiodiagnosis (SCT angiography of abdominal cavity vessels), adequate and timely performed endovascular occlusion of the cavity of the aneurysm with metal spirals performed in a timely manner made it possible to attain a favourable outcome. Little is known regarding the understanding of the aetiology and lack of full clarity in therapeutic approaches to aneurysms of visceral arteries predetermine the necessity to continue collecting clinical case reports concerning this rarely encountered vascular pathology in order to generalize and work out an appropriate therapeutic-and diagnostic algorithm. PMID- 28574053 TI - [Treatment of resistant arterial hypertension in the remote period after carotid endarterectomy]. AB - The aim of the study was to determine peculiarities of the course of resistant arterial hypertension (AH) in the remote period after performing the operation of carotid endarterectomy in patients presenting with haemodynamically significant (more than 70%) stenosis of the carotid bifurcation. The study included a total of 105 patients. The course of AH was evaluated in the immediate (2-7 days) and remote (3-7 years) periods after the operation of carotid endarterectomy. Ninety two (87.6%) patients presenting prior to the operation with resistant AH were postoperatively found to have persistent stabilization of arterial pressure and its milder course. A good clinical effect (possibility of reaching the target arterial pressure) in the remote period was noted to preserve in 65.7% of patients. The proportion of patients with grade III AH decreased from 43.8% (prior to operation) to 5.8% in the remote postoperative period (p<0.001). It was also determined that the degree of the antihypertensive effect after the performed operation of carotid endarterectomy depended upon the duration of a previous medical history of arterial hypertension before surgery: the sooner the operation is performed the more pronounced its antihypertensive effect is. PMID- 28574054 TI - [First experience with total laparoscopic reconstructive operations in occlusive lesion of the aortoiliac arterial segment]. AB - According to the TASC II and the Russian National Guidelines on management of patients with lower limb arterial diseases, in patients with type C and D lesions of the arterial bed performing aortofemoral bifurcation bypass grafting is preferable. Laparoscopic technique makes it possible to combine advantages of minimally invasive surgery with well-known remote results of open reconstructive operations on the aortoiliac segment. The study included a total of 54 patients undergoing treatment at the Cardiosurgical Department of Clinic No 1 of the Volgograd State Medical University over the period from January 2012 to September 2015. The examined patients were subdivided into two groups. Group One was composed of the initial 26 patients operated on during the period from January 2012 to April 2014. Group Two comprised the remaining 28 patients operated on during the period from April 2014 to September 2015. Safety of performing the intervention was determined by prediction of the postoperative lethality and complications rates by means of the V-POSSUM scale. The predicted lethality and complications rates for both groups amounted to 2.3 and 23.5%, respectively. We carried out a comparative analysis of intraoperative data such as duration of the operative intervention, duration of mobilization of the aortoiliac segment, time of aortic cross-clamping, volume of intraoperative blood loss, intraoperative complications rate, conversion in the open access. In the early postoperative period we analysed the level of lethality, complications rate and indices of postoperative rehabilitation of the patient. For demonstrativeness of the dynamics of alterations of intraoperative indices, as well as for plotting the 'learning curve' the moving average method was used. Analysing the obtained findings revealed that implementation of total laparoscopic aortofemoral reconstructive operations was not accompanied by either high lethality or great number of complications, not exceeding the predicted indices by the V-POSSUM scale. The average duration of the operation in Group I amounted to 346+/-18.3 min, and in Group II to 316+/-13.3 min, with the time of aortic cross-clamping averaging 80+/-10.3 and 61+/-4.2 min and the volume of blood loss 898+/-23.5 ml, respectively. As experience was gained in performing laparoscopic reconstructive operations in Group Two patients the 'learning curve' demonstrated a statistically significant decrease of these intraoperative values, as well as a decrease in the complication rate and parameters of the patient's state in the postoperative period. Due to absence of extensive laparotomic or retroperitoneal accesses, the early postoperative period was characterised by rapid restoration of the passage along the intestine, early activation of patients, short length of stay in the intensive care unit and hospital stay. PMID- 28574056 TI - The DUB blade goes snicker-snack: Novel ubiquitin cleavage by a Legionella effector protein. AB - Recently, a Legionella pneumophila effector protein was shown to have an unprecedented ATP-independent ubiquitin ligase activity that couples phosphoribosylated ubiquitin (PR-Ub) to serine residues of host proteins. A new study published in Cell Research by Qiu et al. reveals that another Legionella effector protein, SidJ, catalyzes deubiquitination of PR-Ub by cleavage of the substrate-linked phosphodiester bond. PMID- 28574055 TI - Alternate binding modes of anti-CRISPR viral suppressors AcrF1/2 to Csy surveillance complex revealed by cryo-EM structures. AB - Bacteriophages encode anti-CRISPR suppressors to counteract the CRISPR/Cas immunity of their bacterial hosts, thus facilitating their survival and replication. Previous studies have shown that two phage-encoded anti-CRISPR proteins, AcrF1 and AcrF2, suppress the type I-F CRISPR/Cas system of Pseudomonas aeruginosa by preventing target DNA recognition by the Csy surveillance complex, but the precise underlying mechanism was unknown. Here we present the structure of AcrF1/2 bound to the Csy complex determined by cryo-EM single-particle reconstruction. By structural analysis, we found that AcrF1 inhibits target DNA recognition of the Csy complex by interfering with base pairing between the DNA target strand and crRNA spacer. In addition, multiple copies of AcrF1 bind to the Csy complex with different modes when working individually or cooperating with AcrF2, which might exclude target DNA binding through different mechanisms. Together with previous reports, we provide a comprehensive working scenario for the two anti-CRISPR suppressors, AcrF1 and AcrF2, which silence CRISPR/Cas immunity by targeting the Csy surveillance complex. PMID- 28574058 TI - Gut microbiota: Trust your gut - metformin and diabetes. PMID- 28574059 TI - Adipose tissue: FSH antibody prevents obesity and loss of bone. PMID- 28574060 TI - Neurodevelopmental disorders: Metformin - a therapeutic option for fragile X syndrome? PMID- 28574061 TI - Stroke: Long-term outcome of endovascular therapy for ischaemic stroke. PMID- 28574057 TI - New methods in the diagnosis of cancer and gene therapy of cancer based on nanoparticles. AB - Cancer is one of the leading cause of death in the world with the prevalence of >10 million mortalities annually. Current cancer treatments include surgical intervention, radiation, and taking chemotherapeutic drugs, which often kill the healthy cells and result in toxicity in patients. Therefore, researchers are looking for ways to be able to eliminate just cancerous cells. Intra-tumor heterogeneity of cancerous cells is the main obstacle on the way of an effective cancer treatment. However, better comprehension of molecular basis of tumor and the advent of new diagnostic technologies can help to improve the treatment of various cancers. Therefore, study of epigenetic changes, gene expression of cancerous cells and employing methods that enable us to correct or minimize these changes is critically important. In this paper, we will review the recent advanced strategies being used in the field of cancer research. PMID- 28574062 TI - Erratum to: Chikungunya: a reemerging infection spreading during 2010 dengue fever outbreak in National Capital Region of India. AB - [This corrects the article DOI: 10.1007/s13337-016-0314-z.]. PMID- 28574064 TI - Efficiency enhancement in dye-sensitized solar cells using the shape/size dependent plasmonic nanocomposite photoanodes incorporating silver nanoplates. AB - In this work, we describe the efficiency enhancement in dye-sensitized solar cells (DSSCs) by using TiO2/silver nanoplate plasmonic nanocomposite photoanodes. The nanocomposite photoanodes with tunable plasmonic properties assembled from shape/size-selected silver (Ag) nanoplates were applied to enhance the light absorption for high-performance DSSCs. It was found that the localized surface plasmon resonance can be tuned over a range from 500 to 1000 nm, which is strongly dependent on the shape and size of Ag nanoplates and the refractive index of the surrounding dielectric. The effects of the size and shape of Ag nanoplates on the surface plasmonic resonance and the efficiency of DSSCs were evaluated experimentally. Furthermore, a three-dimensional finite element method was employed to investigate the localized surface plasmon resonance (LSPR) for the shape and size effect of Ag nanoplates. PMID- 28574065 TI - Enhanced electrical conductivity and piezoresistive sensing in multi-wall carbon nanotubes/polydimethylsiloxane nanocomposites via the construction of a self segregated structure. AB - Formation of highly conductive networks is essential for achieving flexible conductive polymer composites (CPCs) with high force sensitivity and high electrical conductivity. In this study, self-segregated structures were constructed in polydimethylsiloxane/multi-wall carbon nanotube (PDMS/MWCNT) nanocomposites, which then exhibited high piezoresistive sensitivity and low percolation threshold without sacrificing their mechanical properties. First, PDMS was cured and pulverized into 40-60 mesh-sized particles (with the size range of 250-425 MUm) as an optimum self-segregated phase to improve the subsequent electrical conductivity. Then, the uncured PDMS/MWCNT base together with the curing agent was mixed with the abovementioned PDMS particles, serving as the segregated phase. Finally, the mixture was cured again to form the PDMS/MWCNT nanocomposites with self-segregated structures. The morphological evaluation indicated that MWCNTs were located in the second cured three dimensional (3D) continuous PDMS phase, resulting in an ultralow percolation threshold of 0.003 vol% MWCNTs. The nanocomposites with self-segregated structures with 0.2 vol% MWCNTs achieved a high electrical conductivity of 0.003 S m-1, whereas only 4.87 * 10-10 S m-1 was achieved for the conventional samples with 0.2 vol% MWCNTs. The gauge factor GF of the self-segregated samples was 7.4 fold that of the conventional samples at 30% compression strain. Furthermore, the self-segregated samples also showed higher compression modulus and strength as compared to the conventional samples. These enhanced properties were attributed to the construction of 3D self-segregated structures, concentrated distribution of MWCNTs, and strong interfacial interaction between the segregated phase and the continuous phase with chemical bonds formed during the second curing process. These self-segregated structures provide a new insight into the fabrication of elastomers with high electrical conductivity and piezoresistive sensitivity for flexible force-sensitive materials. PMID- 28574066 TI - Chirality-dependent growth of single-wall carbon nanotubes as revealed inside nano-test tubes. AB - Growth dynamics of single-wall carbon nanotubes (SWCNTs) have been studied with nickelocene as a precursor encapsulated in the interior of template SWCNTs. By means of multi-laser Raman spectroscopy, growth curves of nine different SWCNTs, (8,8), (12,3), (13,1), (9,6), (10,4), (11,2), (11,1), (9,3) and (9,2), have been determined upon in situ annealing at various temperatures. The data reveal that the nanotubes grow through fast and slow reaction pathways with high and low activation energies, respectively. While the activation energy of the slow growth is independent of the nanotube's chiral vector, that of the fast growth exhibits a monotonic increase as the tube diameter reduces from ~1.1 down to 0.8 nm and no dependency on the chiral angle, which can be attributed to the size-dependent properties of catalyst clusters. The chirality dependent catalytic growth properties exploited in this study provide the basis for a large-scale synthesis of single-chiral vector SWCNTs. PMID- 28574063 TI - Preschool children without 7-repeat DRD4 gene more likely to develop disorganized attachment style. AB - BACKGROUND: The current paper aimed to explore the effects of birth weight and the 7-repeat allele in Exon III of the dopamine D4 receptor (DRD4) gene on the development of disorganized attachment, a potential endophenotype of depression. Infants born with low birth weight have been shown to be at higher risk for later neurological impairments, psychological disorders or behavioural problems. The DRD4 gene is critical for the cognitive and emotional processes that are sub served by neural circuits in the prefrontal cortex. This paper examined the main effect of birth weight and DRD4 on the development of disorganized attachment. METHODS: Data was used from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) project. The sample consisted of 251 mother-child dyads with complete data. Attachment style was assessed using the modified separation reunion procedure. RESULTS: There was no main effect for birth weight on disorganized attachment, (b = -0.001, p = 0.998). There was, however, a main effect for the DRD4 7-repeat polymorphism on disorganized attachment (b = -1.120, p = 0.004). LIMITATIONS: Compared to studies of similar design, the sample size in this study was relatively small. Additionally, a significant number of subjects did not have complete data. CONCLUSIONS: Children without the DRD4 7 repeat allele were more likely to have disorganized attachment than children with the DRD4 7-repeat allele. This indicates that the 7-repeate allele of the DRD4 gene may actually serve as a protective factor against disorganized attachment. PMID- 28574068 TI - Self-assembled Co-BaZrO3 nanocomposite thin films with ultra-fine vertically aligned Co nanopillars. AB - A simple one-step pulsed laser deposition (PLD) method has been applied to grow self-assembled metal-oxide nanocomposite thin films. The as-deposited Co-BaZrO3 films show high epitaxial quality with ultra-fine vertically aligned Co nanopillars (diameter <5 nm) embedded in a BZO matrix. The diameter of the nanopillars can be further tuned by varying the deposition frequency. The metal and oxide phases grow separately without inter-diffusion or mixing. Taking advantage of this unique structure, a high saturation magnetization of ~1375 emu cm-3 in the Co-BaZrO3 nanocomposites has been achieved and further confirmed by Lorentz microscopy imaging in TEM. Furthermore, the coercivity values of this nanocomposite thin films range from 600 Oe (20 Hz) to 1020 Oe (2 Hz), which makes the nanocomposite an ideal candidate for high-density perpendicular recording media. PMID- 28574069 TI - Surface-enhanced hyper Raman hyperspectral imaging and probing in animal cells. AB - Hyper Raman scattering, that is, spontaneous, two-photon excited Raman scattering, of organic molecules becomes strong when it occurs as surface enhanced hyper Raman scattering (SEHRS), in the proximity of plasmonic nanostructures. Its advantages over one-photon excited surface-enhanced Raman scattering (SERS) include complementary vibrational information resulting from different selection rules, probing of very small focal volumes, and beneficial excitation with long wavelengths. Here, imaging of macrophage cells by SEHRS is demonstrated, using SEHRS labels consisting of silver nanoparticles and two different molecules, 2-naphthalenethiol and para-mercaptobenzoic acid, that are excited off-resonance. The vibrational signatures of the molecules are discriminated using hyperspectral analysis and provide information about the subcellular localization of the SEHRS probes. The SEHRS based hyperspectral imaging approach presented here uses principal component analysis (PCA) to localize the reporter molecules inside the cells and is augmented by hierarchical cluster analysis (HCA). The high sensitivity of SEHRS spectra with respect to small environmental changes can be utilized for mapping of physiological parameters in the endosomal system of the cells. This is illustrated by discussing the spatial distribution of endosomes of varying pH inside the cytosol. PMID- 28574070 TI - Oxalic acid as the in situ carbon monoxide generator in palladium-catalyzed hydroxycarbonylation of arylhalides. AB - An efficient palladium-catalyzed hydroxycarbonylation reaction of arylhalides using oxalic acid as a CO source has been developed. The reaction features high safety, low catalyst loading, and a broad substrate scope, and provides a safe and tractable approach to access a variety of aromatic carboxylic acid compounds. Mechanistic studies revealed the decomposition pattern of oxalic acid. PMID- 28574067 TI - Multi-responsive polypeptide hydrogels derived from N-carboxyanhydride terpolymerizations for delivery of nonsteroidal anti-inflammatory drugs. AB - A polypeptide-based hydrogel system, when prepared from a diblock polymer with a ternary copolypeptide as one block, exhibited thermo-, mechano- and enzyme responsive properties, which enabled the encapsulation of naproxen (Npx) during the sol-gel transition and its release in the gel state. Statistical terpolymerizations of l-alanine (Ala), glycine (Gly) and l-isoleucine (Ile) NCAs at a 1 : 1 : 1 feed ratio initiated by monomethoxy monoamino-terminated poly(ethylene glycol) afforded a series of methoxy poly(ethylene glycol)-block poly(l-alanine-co-glycine-co-l-isoleucine) (mPEG-b-P(A-G-I)) block polymers. beta Sheets were the dominant secondary structures within the polypeptide segments, which facilitated a heat-induced sol-to-gel transition, resulting from the supramolecular assembly of beta-sheets into nanofibrils. Deconstruction of the three-dimensional networks by mechanical force (sonication) triggered the reverse gel-to-sol transition. Certain enzymes could accelerate the breakdown of the hydrogel, as determined by in vitro gel weight loss profiles. The hydrogels were able to encapsulate and release Npx over 6 days, demonstrating the potential application of these polypeptide hydrogels as an injectable local delivery system for small molecule drugs. PMID- 28574071 TI - New selenosteroids as antiproliferative agents. AB - Starting from natural steroids (diosgenin, hecogenin, smilagenin, estrone), we have prepared a wide panel of selenoderivatives, including benzoselenazolones, selenosemicarbazones, isoselenocyanates, selenoureas, selenocyanates and diselenides, with the aim of developing new families of potential chemotherapeutic agents. The modification of the organoselenium moieties, and their position on the steroid provided valuable information concerning the antiproliferative activities. Among all the families accessed herein, the best profile was achieved for selenoureas on the A ring of estrone, which exhibited GI50 values in the range 2.0-4.1 MUM for all the tested tumor cell lines, with increased potency compared with commonly used chemotherapeutic agents, like 5 fluorouracil and cisplatin. Cell cycle analysis revealed that selenoureas induced accumulation of cells in the G1 phase of the cell cycle in the breast cancer cell lines HBL-100 and T-47D; therefore, a different mechanism than cisplatin, that induces cell cycle accumulation in the S phase as a result of DNA damage, must be involved. In the rest of the tumor cells, a slight increase of the S compartment was observed. Moreover, selenosteoids turned out to be excellent glutathione peroxidase (GPx) mimics for the catalytic removal of deleterious H2O2 (t1/2 8.0 22.5 min) and alkyl peroxides (t1/2 23.0-38.9 min) when used in substoichiometric amounts (1% molar ratio), thus providing a valuable tool for reducing the intrinsic oxidative stress in tumor progression. PMID- 28574072 TI - Dealloying assisted high-yield growth of surfactant-free <110> highly active Cu doped CeO2 nanowires for low-temperature CO oxidation. AB - CeO2 is widely used as a commercial CO oxidation catalyst, but it suffers from high-temperature (>200 degrees C) complete conversion. Despite enormous efforts made to promote its low-temperature activity by interfacing CuO and CeO2, it is still a long-standing challenge to balance the desired catalytic activity with high-yield preparation. Creating intimate synergistic interfaces between Cu and Ce species and exploring surfactant-free large-scale methods are both critical and challenging. To address these concerns, we synthesized highly active Cu doped CeO2 nanowires for low-temperature CO oxidation, relying on intentionally maneuvering precursor alloy compositions and a high-yield dealloying method. The favorable one-dimensional doping structure inherited from the nanowire bundles of the as-dealloyed precursors, clean surfaces and intimate synergistic effects between Cu and Ce contribute to excellent CO oxidation performances, with 5% room temperature conversion triggered at 35 degrees C and 100% conversion at 100 degrees C. 96% of O2 selectivity at 88 degrees C in CO preferential oxidation was also obtained. The long-term durability for 24 hours at 100% CO conversion without any decay confirms the robust characteristics of the catalysts. Moreover, this work offers some insights into the reasonable design of alloy precursors to realize property-oriented alloys to nanowires batch transformation for the study of industrial catalysts. PMID- 28574073 TI - Self-assembled artificial viral capsids bearing coiled-coils at the surface. AB - In order to construct artificial viral capsids bearing complementary dimeric coiled-coils on the surface, a beta-annulus peptide bearing a coiled-coil forming sequence at the C-terminus (beta-annulus-coiled-coil-B) was synthesized by a native chemical ligation of a beta-annulus-SBn peptide with a Cys-containing coiled-coil-B peptide. Dynamic light scattering (DLS) measurements and transmission electron microscopy (TEM) images revealed that the beta-annulus coiled-coil-B peptide self-assembled into spherical structures of about 50 nm in 10 mM Tris-HCl buffer. Circular dichroism (CD) spectra indicated the formation of the complementary coiled-coil structure on the spherical assemblies. Addition of 0.25 equivalent of the complementary coiled-coil-A peptide to the beta-annulus coiled-coil-B peptide showed the formation of spherical assemblies of 46 +/- 14 nm with grains of 5 nm at the surface, whereas addition of 1 equivalent of the complementary coiled-coil-A peptide generated fibrous assemblies. PMID- 28574074 TI - Atomic scale deposition of Pt around Au nanoparticles to achieve much enhanced electrocatalysis of Pt. AB - We report an electrochemical method to deposit atomic scale Pt on a 5 nm Au nanoparticle (NP) surface in N2-saturated 0.5 M H2SO4. Pt is provided by the Pt wire counter electrode via one-step Pt wire oxidation, dissolution, and deposition realized by controlled electrochemical scanning. Scanning from 0.6-1.0 V (vs. RHE) for 10 000 cycles gives Au98.2Pt1.8, which serves as an excellent catalyst for the formic acid oxidation reaction, showing 41 times higher specific activity (20.19 mA cm-2) and 25 times higher mass activity (10.80 A mgPt-1) with much better CO-tolerance and stability than commercial Pt. Our work demonstrates a unique strategy to minimize the use of Pt as a catalyst for electrochemical reactions. PMID- 28574075 TI - Insight into the epitaxial encapsulation of Pd catalysts in an oriented metalloporphyrin network thin film for tandem catalysis. AB - A palladium catalyst (Pd-Cs) encapsulated metalloporphyrin network PIZA-1 thin film with bifunctional properties has been developed through a modified epitaxial layer-by-layer encapsulation approach. Combining the oxidation activity of Pd-Cs and the acetalization activity of the Lewis acidic sites in the PIZA-1 thin film, this bifunctional catalyst of the Pd-Cs@PIZA-1 thin film exhibits a good catalytic activity in a one-pot tandem oxidation-acetalization reaction. Furthermore, the surface components can be controlled by ending the top layer with different precursors in the thin film preparation procedures. The catalytic performances of these thin films with different surface composites were studied under the same conditions, which showed different reaction conversions. The result revealed that the surface component can influence the catalytic performance of the thin films. This epitaxial encapsulation offers a good understanding of the tandem catalysis for thin film materials and provides useful guidance to develop new thin film materials with catalytic properties. PMID- 28574077 TI - Enzymatically activated reduction-caged SERS reporters for versatile bioassays. AB - Here we report a facile strategy for activating reduction caged Raman reporters for surface-enhanced Raman scattering (SERS) with peroxidases. After selecting suitable caged reporters, versatile bioassays were developed. First, the bioassays for bioactive small molecules were developed. Then, the immunoassay was developed for C reactive protein (CRP), a biomarker for cardiovascular diseases. PMID- 28574076 TI - Bushy sphere dendrites with husk-shaped branches axially spreading out from the core for photo-catalytic oxidation/remediation of toxins. AB - This work describes densely interlinked bushy "tree-like chains" characterized by neatly branched sphere dendrites (bushy sphere dendrites, BSD) with long fan like, husk-shaped branching paths that extend longitudinally from the core axis of the {110}-exposed plane. We confirmed that the hierarchical dendrite surfaces created bowls of swirled caves along the tree-tube in the mat-like branches. These surfaces had high-index catalytic site facets associated with the formation of ridges/defects on the dominant {110}-top-cover surface. These swirled caves along the branches were completely filled with 50-100 nm poly-CN nano-sphere fossils with orb-like appearance. Such structural features are key issues of the inherent surface reactivity of a powerful catalyst/trapper, enabling photocatalytic oxidation and trapping of extremely toxic arsenite (AsO33-) species and photo-induced recovery of arsenate (AsO43-) products from catalyst surfaces. The light-induced release of produced AsO43- from BSD indicates (i) highly controlled waste collection/management (i.e., recovery), (ii) low cost and ecofriendly photo-adsorbent, (iii) selective trapping of real sample water to produce water-free arsenite species; (iv) multiple reuse cycles of catalysts (i.e., reduced waste volume). Matrixed dendrites, covered with 3D microscopic sphere cores that capture solar-light, trap toxins, and are triggered by light, were designed. These dendrites can withstand indoor and outdoor recovery of toxins from water sources. PMID- 28574079 TI - Characterization and application studies of ProxyPhos, a chemosensor for the detection of proximally phosphorylated peptides and proteins in aqueous solutions. AB - Proximal phosphorylation on proteins appears to have functional significance and has been associated with several diseases, including Alzheimer's and cancer. While much remains to be learned about the role of proximal phosphorylation in biological systems, no simple and/or affordable technique is available for its detection. To this end, we have previously developed a ProxyPhos chemosensor, which detects proximally phosphorylated peptides and proteins over mono- and non phosphorylated motifs in aqueous solutions. In this follow-up work, we performed extensive characterization of peptide and protein ProxyPhos assay conditions to achieve enhanced detection, and further explored the selectivity of ProxyPhos, and its potential off-targets. As a result of characterization studies, selective sensing of proximally phosphorylated over mono-phosphorylated peptides and proteins was achieved. Moreover, studies demonstrated that ProxyPhos was compatible with the detection of all commonly phosphorylated residues (i.e. tyrosine, serine and threonine residues). Under optimized conditions, ProxyPhos efficiently discriminated between peptides derived from the activated (proximally phosphorylated, disease-relevant) and inactive (mono-phosphorylated) forms of JAK2, SYK and MAPK1 kinases. In addition, ProxyPhos can be used to probe phosphatase activity on peptides and proteins via detecting changes in proximal phosphorylation, demonstrating immediate utility of this chemosensing system. PMID- 28574080 TI - Electro-elastocapillary Rayleigh-plateau instability in dielectric elastomer films. AB - We demonstrate, using both finite element simulations and a linear stability analysis, the emergence of an electro-elastocapillary Rayleigh-plateau instability in dielectric elastomer (DE) films under 2D, plane strain conditions. When subject to an electric field, the DEs exhibit a buckling instability for small elastocapillary numbers. For larger elastocapillary numbers, the DEs instead exhibit the Rayleigh-plateau instability. The stability analysis demonstrates the critical effect of the electric field in causing the Rayleigh plateau instability, which cannot be induced solely by surface tension in DE films. Overall, this work demonstrates the effects of geometry, boundary conditions, and multi-physical coupling on a new example of Rayleigh-plateau instability in soft solids. PMID- 28574078 TI - Confining the spin between two metal atoms within the carbon cage: redox-active metal-metal bonds in dimetallofullerenes and their stable cation radicals. AB - Lanthanide-lanthanide bonds are exceptionally rare, and dimetallofullerenes provide a unique possibility to stabilize and study these unusual bonding patterns. The presence of metal-metal bonds and consequences thereof for the electronic properties of M2@C82 (M = Sc, Er, Lu) are addressed by electrochemistry, electron paramagnetic resonance, SQUID magnetometry and other spectroscopic techniques. A simplified non-chromatographic separation procedure is developed for the isolation of Er2@C82 (Cs(6) and C3v(8) cage isomers) and Sc2@C82 (C3v(8) isomer) from fullerene mixtures. Sulfide clusterfullerenes Er2S@C82 with Cs(6) and C3v(8) fullerene cages are synthesized for the first time. The metal-metal bonding orbital of the spd hybrid character in M2@C82 is shown to be the highest occupied molecular orbital, which undergoes reversible single-electron oxidation with a metal-dependent oxidation potential. Sulfide clusterfullerenes with a fullerene-based HOMO have more positive oxidation potentials. The metal-based oxidation of Sc2@C82-C3v is confirmed by the EPR spectrum of the cation radical [Sc2@C82-C3v]+ generated by chemical oxidation in solution. The spectrum exhibits an exceptionally large a(45Sc) hyperfine coupling constant of 199.2 G, indicating a substantial 4s contribution to the metal-metal bonding orbital. The cationic salt [Er2@C82-C3v]+SbCl6- is prepared, and its magnetization behavior is compared to that of pristine Er2@C82-C3v and Er2S@C82 C3v. The formation of the single-electron Er-Er bond in the cation dramatically changes the coupling between magnetic moments of Er ions. PMID- 28574081 TI - Depth-profiling of Yb3+ sensitizer ions in NaYF4 upconversion nanoparticles. AB - Enhancing the efficiency of upconversion nanoparticles (UCNPs) and therefore their brightness is the critical goal for this emerging material to meet growing demands in many potential applications including sensing, imaging, solar energy conversion and photonics. The distribution of the photon sensitizer and activator ions that form a network of energy transfer systems within each single UCNP is vital for understanding and optimizing their optical properties. Here we employ synchrotron-based X-ray Photoelectron Spectroscopy (XPS) to characterize the depth distribution of Yb3+ sensitizer ions in host NaYF4 nanoparticles and systematically correlate the structure with the optical properties for a range of UCNPs with different sizes and doping concentrations. We find a radial gradient distribution of Yb3+ from the core to the surface of the NaYF4 nanoparticles, regardless of their size or the sensitizer's concentration. Energy dispersive X ray Spectroscopy (EDX) was also used to further confirm the distribution of the sensitizer ions in the host matrix. These results have profound implications for the upconversion optical property variations. PMID- 28574082 TI - Ultrafast photocarrier dynamics related to defect states of Si1-xGex nanowires measured by optical pump-THz probe spectroscopy. AB - Slightly tapered Si1-xGex nanowires (NWs) (x = 0.29-0.84) were synthesized via a vapor-liquid-solid procedure using Au as a catalyst. We measured the optically excited carrier dynamics of Si1-xGex NWs as a function of Ge content using optical pump-THz probe spectroscopy. The measured -DeltaT/T0 signals of Si1-xGex NWs were converted into conductivity in the THz region. We developed a fitting formula to apply to indirect semiconductors such as Si1-xGex, which explains the temporal population of photo-excited carriers in the band structure and the relationship between the trapping time and the defect states on an ultrafast time scale. From the fitting results, we extracted intra- and inter-valley transition times and trapping times of electrons and holes of Si1-xGex NWs as a function of Ge content. On the basis of theoretical reports, we suggest a physical model to interpret the trapping times related to the species of interface defect states located at the oxide/NW: substoichiometric oxide states of Si(Ge)0+,1+,2+, but not Si(Ge)3+, could function as defect states capturing photo-excited electrons or holes and could determine the different trapping times of electrons and holes depending on negatively or neutrally charged states. PMID- 28574083 TI - Sulfinyl isobutyramide as an auxiliary for palladium(ii)-catalyzed C-H arylation and iodination of benzylamine derivatives. AB - A novel readily available bidentate 2-methylsulfinyl isobutyramide directing group has been developed for benzylamine derivatives. It promoted ortho-C-H arylation and iodination of various substrates in good to excellent yields. The auxiliary is promising to be used in organic synthesis due to its versatility and convenient preparation from inexpensive materials. PMID- 28574084 TI - Diaryliodonium salts as hydrosilylation initiators for the surface functionalization of silicon nanomaterials and their collaborative effect as ring opening polymerization initiators. AB - Diaryliodonium salts were found to initiate hydrosilylation reactions on the surface of silicon nanosheets as well as silicon nanocrystals of different sizes. A variety of different functional substrates can be used to stabilize the surface of the photoluminescent materials. Additionally, the combination of hydride terminated silicon nanomaterials with diaryliodonium salts was found to initiate cationic ring opening polymerization, demonstrating the potential of silicon based nanomaterials as coinitiators and enabling a mild, straightforward reaction method. PMID- 28574085 TI - Morphological effects on the selectivity of intramolecular versus intermolecular catalytic reaction on Au nanoparticles. AB - It is hard for metal nanoparticle catalysts to control the selectivity of a catalytic reaction in a simple process. In this work, we obtain active Au nanoparticle catalysts with high selectivity for the hydrogenation reaction of aromatic nitro compounds, by simply employing spine-like Au nanoparticles. The density functional theory (DFT) calculations further elucidate that the morphological effect on thermal selectivity control is an internal key parameter to modulate the nitro hydrogenation process on the surface of Au spines. These results show that controlled morphological effects may play an important role in catalysis reactions of noble metal NPs with high selectivity. PMID- 28574091 TI - Macrocyclic peptide inhibitors for the protein-protein interaction of Zaire Ebola virus protein 24 and karyopherin alpha 5. AB - Ebola virus infection leads to severe hemorrhagic fever in human and non-human primates with an average case fatality rate of 50%. To date, numerous potential therapies are in development, but FDA-approved drugs or vaccines are yet unavailable. Ebola viral protein 24 (VP24) is a multifunctional protein that plays critical roles in the pathogenesis of Ebola virus infection, e.g. innate immune suppression by blocking the interaction between KPNA and PY-STAT1. Here we report macrocyclic peptide inhibitors of the VP24-KPNA5 protein-protein interaction (PPI) by means of the RaPID (Random non-standard Peptides Integrated Discovery) system. These macrocyclic peptides showed remarkably high affinity to recombinant Zaire Ebola virus VP24 (eVP24), with a dissociation constant in the single digit nanomolar range, and could also successfully disrupt the eVP24-KPNA interaction. This work provides for the first time a chemical probe capable of modulating this PPI interaction and is the starting point for the development of unique anti-viral drugs against the Ebola virus. PMID- 28574092 TI - A highly controllable protein self-assembly system with morphological versatility induced by reengineered host-guest interactions. AB - Manipulating proteins to self-assemble into highly ordered nanostructures not only provides insights into the natural protein assembly process but also allows access to advanced biomaterials. Host-guest interactions have been widely used in the construction of artificial protein assemblies in recent years. CB[8] can selectively associate with two tripeptide Phe-Gly-Gly (FGG) tags with an extraordinarily high binding affinity (Kter = 1.5 * 1011 M-2). However, the FGG tags utilized before are all fixed to the N-termini via genetic fusion; this spatial limitation greatly confined the availability of the CB[8]/FGG pair in the construction of more sophisticated protein nanostructures. Here we first designed and synthesized a maleimide-functionalized Phe-Gly-Gly tag as a versatile site specific protein modification tool; this designed tag can site-selectively introduce desired guest moieties onto protein surfaces for host-guest driven protein assembly. When regulating the self-assembly process of proteins and CB[8], the constructed protein nanosystem can exhibit distinctive morphological diversities ranging from nanorings, nanospirals, nanowires to superwires. This work developed a new strategy for site-specific protein modification of the CB[8] binding tag and provides a possible direction for the construction of 'smart', dynamic self-assembly systems. PMID- 28574093 TI - In vitro degradation of polydimethylsiloxanes in breast implant applications. AB - BACKGROUND: The durability of breast implant material is associated with failure probability, increasing with time from implantation. The current study avoided the bias introduced by biological factors, to systematically investigate the degradation over time of shell materials. The same fundamental physical and chemical conditions were maintained (temperature and pH) throughout the study, to decouple biological aspects from the degradation process. METHODS: Six virgin implants of 2 brands were submitted to the in vitro degradation process, mechanical testing of shell materials, surface change analysis (via scanning electron microscopy [SEM]) and chemical composition analysis by Fourier transform infrared (FTIR) spectroscopy. RESULTS: FTIR results showed that the principal chemical bonds of the material remained intact after 12 weeks of degradation. Apparently the implants' shell structures remained unchanged. Despite this observation, there were statistically significant differences between strain at failure at different time points for the shells of both brands, translated into a stiffening of the material over time. CONCLUSIONS: Material stiffening is reported as an indicator of material degradation. This altered mechanical behavior, added to the mechanical friction from tissue-tissue and tissue-implant contact and to the external mechanical loading (physical activity), may alter the material performance in women's bodies. Ultimately these changes may affect the implants' durability. Further work is needed to understand the biological aspects of the degradation process and their impact on implant durability. PMID- 28574094 TI - Effect of storage medium and aging duration on mechanical properties of self adhesive resin-based cements. AB - BACKGROUND: The aim of this study was to investigate the effects of storage medium and aging duration on Martens hardness (HM) and indentation modulus (EIT) of self-adhesive resin-based cements (SARCs). METHODS: A total of 416 discs were fabricated from 8 SARCs (n = 52 per SARC): (i) BeautyCem (BEA), (ii) Bifix SE (BIF), (iii) Clearfil SA Cement Automix (CLE), (iv) RelyX Unicem2 Automix (RXU), (v) SeT (SET), (vi) SmartCem 2 (SMC), (vii) SoloCem (SOC) and (viii) SpeedCEM (SPC). The specimens were ground and stored in (a) physiological saliva, (b) artificial saliva, (c) sodium chloride and (d) distilled water, at 37 degrees C for 1, 7, 14, 28, 90 and 180 days. Non-aged specimens (3 hours after photo initiation) of each SARC acted as control groups. HM and EIT were assessed using a universal hardness testing machine. Data were analyzed using Kolmogorov-Smirnov and Kruskal-Wallis tests and paired t-test, and 3-, 2- and 1-way ANOVA with post hoc Scheffe test (p<0.05). RESULTS: SARC materials exerted the highest influence on HM and EIT values (p<0.001, partial eta squared [etaP2] = 0.753 and 0.433, respectively), closely followed by aging duration (p<0.001, etaP2 = 0.516 and 0.255) and storage medium (p<0.001, etaP2 = 0.043 and 0.033). The interaction effect of the combinations of the 3 independent parameters was also significant (p<0.001, etaP2 = 0.163 and 0.133). The lowest initial HM and EIT was presented by CLE, followed by SET and SPC; highest HM was for BIF, followed by RXU and SMC. SET gave a greater HM and EIT percentage decrease than SOC, SPC, BEA, SMC, RXU or CLE. CONCLUSIONS: Aging duration is a major factor affecting the micromechanical properties of SARCs, while storage medium was shown to have a significant but minor role. PMID- 28574095 TI - Characterization of an improved 1-3 piezoelectric composite by simulation and experiment. AB - INTRODUCTION: To increase electromechanical coupling factor of 1-3 piezoelectric composite and reduce its bending deformation under external stress, an improved 1 3 piezoelectric composite is developed. In the improved structure, both epoxy resin and silicone rubber are used as polymer material. METHODS: The simulation model of the improved 1-3 piezoelectric composite was established using the finite element software ANSYS. The relationship of the performance of the improved composite to the volume percentage of silicone rubber was determined by harmonic response analysis and the bending deformation under external stress was simulated by static analysis. The improved composite samples were prepared by cutting and filling methods, and the performance was tested. RESULTS: The feasibility of the improved structure was verified by finite element simulation and experiment. The electromechanical coupling factor of the improved composite can reach 0.67 and meanwhile the characteristic impedance can decline to 13 MRayl. The electromechanical coupling factor of the improved composite is higher than that of the composite with only epoxy resin as the polymer and the improved composite can reduce bending deformation. DISCUSSION: Comparison of simulation and experiment, the results of the experiment are in general agreement with those from the simulation. However, most experimental values were higher than the simulation results, and the abnormality of the test results was also more obvious than that of the simulation. These findings may be attributed to slight difference in the material parameters of simulation and experiment. PMID- 28574096 TI - Model reference adaptive control based on kp model for magnetically controlled shape memory alloy actuators. AB - INTRODUCTION: Magnetically controlled shape memory alloy (MSMA) actuators take advantages of their large deformation and high controllability. However, the intricate hysteresis nonlinearity often results in low positioning accuracy and slow actuator response. METHODS: In this paper, a modified Krasnosel'skii Pokrovskii model was adopted to describe the complicated hysteresis phenomenon in the MSMA actuators. Adaptive recursive algorithm was employed to identify the density parameters of the adopted model. Subsequently, to further eliminate the hysteresis nonlinearity and improve the positioning accuracy, the model reference adaptive control method was proposed to optimize the model and inverse model compensation. RESULTS: The simulation experiments show that the model reference adaptive control adopted in the paper significantly improves the control precision of the actuators, with a maximum tracking error of 0.0072 mm. CONCLUSIONS: The results prove that the model reference adaptive control method is efficient to eliminate hysteresis nonlinearity and achieves a higher positioning accuracy of the MSMA actuators. PMID- 28574097 TI - Functionalized biomimetic calcium phosphates for bone tissue repair. AB - The design and development of novel materials for biomineralized tissues is an extremely attractive field of research where calcium phosphates (CaPs)-based materials for biomedical applications play a leading role. The biological performance of these compounds can be enhanced through functionalization with biologically active ions and molecules. This review reports on some important recent achievements in creating functionalized biomimetic CaP materials for applications in the musculoskeletal field. Particular attention is focused on the modifications of these inorganic compounds with bioactive ions, growth factors and drugs, as well as on recent trends in some important CaP applications as biomaterials - namely, as bone cements, coatings of metallic implants and scaffolds for regenerative medicine. PMID- 28574098 TI - Physicochemical characterization of a dental eggshell powder abrasive material. AB - BACKGROUND: This study aimed to determine the physicochemical characteristics of an eggshell-based dental abrasive material. METHODS: The eggshell powder abrasive material (EPAM) was synthesized by ball milling eggshell powder and surfactants. Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), transmission electron microscopy (TEM) and a laser diffraction particle size analyzer (PSA) were used to characterize EPAM. In addition, the abrasive characteristics of EPAM were evaluated by comparison using poly(methyl methacrylate) (PMMA) resins. Surface roughness (Ra) was measured using a profilometer. RESULTS: The FTIR spectroscopy and XRD analysis confirmed that the carbonate product was primarily calcite (97.3%) with traces of graphite 2H (1.3%) and thenardite (1.4%). The TEM imagery revealed irregular particles in EPAM. The PSA analysis of the particle size distribution showed EPAM to be a superfine powder (0.3 um to 50 nm). In addition, the 50-nm EPAM (Ra = 0.04 um) measured the lowest Ra value when compared with pumice (Ra = 0.08 um). CONCLUSIONS: The salient features of this study indicate that EPAM can naturally replace calcite, which is generally mined and used as a dental abrasive material. In addition, and regarding the abrasive characteristics of EPAM in reducing the surface roughness of PMMA resin specimens, this study conclusively showed that EPAM effectively reduces the surface roughness below the threshold limit value of 0.2 um. Potentially, EPAM could reduce waste disposal problems while enabling an economic benefit from using eggshell waste material. PMID- 28574099 TI - Chemical modification of bagasse-based mesoporous carbons for chromium(III) ion adsorption. AB - AIMS: Modified bagasse-based mesoporous carbons were prepared for the efficient chromium(III) ion adsorption and removal from aqueous solutions. METHODS: Mesoporous carbons were prepared from bagasse with H3PO4 activation and subsequently oxidized with nitric acid and modified with ethylenediamine. RESULTS: The results showed that the modified carbon was rich in mesopores, oxygen and nitrogen-containing groups, and the Cr(III) adsorption capacity was greatly improved after modification, which was found to be higher than both pristine and oxidized carbons. The Cr(III) adsorption capacity on modified carbon was significantly influenced by the solution pH, and the optimum pH was 6 with the maximum Cr(III) adsorption capacity up to 24.61mg/g, which was almost 3 times higher than that for pristine carbon. Thermodynamic results manifested the adsorption was spontaneous and endothermic. Kinetic rates fitted the pseudo second-order model very well. XPS study indicated the amino group was a key factor of the high efficient adsorption. PMID- 28574100 TI - First-principles calculation of adsorption of shale gas on CaCO3 (100) surfaces. AB - BACKGROUND: To demonstrate the adsorption strength of shale gas to calcium carbonate in shale matrix, the adsorption of shale gas on CaCO3 (100) surfaces was studied using the first-principles method, which is based on the density functional theory (DFT). METHODS: The structures and electronic properties of CH4, C2H6, CO2 and N2 molecules were calculated by the generalized gradient approximation (GGA), for a coverage of 1 monolayer (ML). Under the same conditions, the density of states (DOS) of CaCO3 (100) surfaces before and after the adsorption of shale gas molecules at high-symmetry adsorption sites were compared. RESULTS: The results showed that the adsorption energies of CH4, C2H6, CO2 and N2 on CaCO3 (100) surfaces were between 0.2683 eV and -0.7388 eV. When a CH4 molecule was adsorbed at a hollow site and its 2 hydrogen atoms were parallel to the long diagonal (H3) on the CaCO3 (100) surface, it had the most stable adsorption, and the adsorption energy was only -0.4160 eV. The change of adsorption energy of CH4 was no more than 0.0535 eV. Compared with the DOS distribution of CH4 before adsorption, it shifted to the left overall after adsorption. At the same time, the partial density of states (PDOS) curves of CaCO3 (100) surfaces before and after adsorption basically overlapped. CONCLUSIONS: This work showed that the adsorption effect of shale gas on calcium carbonate is very weak, and the adsorption is physisorption at the molecular level. PMID- 28574101 TI - Bone response to porous alumina implants coated with bioactive materials, observed using different characterization techniques. AB - BACKGROUND: Implants or implantable devices should integrate into the host tissue faster than fibrous capsule formation, in which the design of the interface is one of the biggest challenges. Generally, bioactive materials are not viable for load-bearing applications, so inert biomaterials are proposed. However, the surface must be modified through techniques such as coating with bioactive materials, roughness and sized pores. The aim of this research was to validate an approach for the evaluation of the tissue growth on implants of porous alumina coated with bioactive materials. METHODS: Porous alumina implants were coated with 45S5 Bioglass(r) (BG) and hydroxyapatite (HA) and implanted in rat tibiae for a period of 28 days. Ex vivo resections were performed to analyze osseointegration, along with histological analysis, Scanning Electron Microscopy with Energy Dispersive X-Ray spectroscopy (SEM-EDX) line scanning, radiography and biomechanical testing. RESULTS: Given that the process of implant integration needs with the bone tissue to be accelerated, it was then seen that BG acted to start the rapid integration, and HA acted to sustaining the process. CONCLUSIONS: Inert materials coated with bioglass and HA present a potential for application as bone substitutes, preferably with pores of diameters between 100 MUm and 400 MUm and, restrict for smaller than 100 MUm, because it prevents pores without organized tissue formation or vacant. Designed as functional gradient material, stand out for applications in bone tissue under load, where, being the porous surface responsible for the osseointegration and the inner material to bear and to transmit the loads. PMID- 28574102 TI - A clinician's artificial organ? Instant messaging applications in medical care. AB - After the development of the first phone at the end of 19th century, communication technologies took a great leap forward in the 20th century. With the birth of the "smartphone" in the 21st century, communication technologies exponentially evolved and became an important part of our daily routine. Effective communications between clinicians is critical in medical care and miscommunications are a source of errors. Although telecommunication technologies have proliferated dramatically in the last decade, there is scarce evidence-based information on the use of this technology in medical care. For the purposes of medical communication, we can now consult each other about patients individually and within a group via instant messaging applications by using text messages, photos, audio messages and even videos. In this review, we examine the uses and drawbacks of instant messaging applications in medical communications. PMID- 28574103 TI - A microscopic view of gaseous microbubbles passing a filter screen. AB - PURPOSE: The aim of this study was to investigate the filtration efficacy of a 38 um 1-layer screen filter based on Doppler registrations and video recordings of gaseous microbubbles (GME) observed in a microscope. METHODS: The relative filtration efficacy (RFE) was calculated from 20 (n = 20) sequential bursts of air introduced into the Plasmodex(r) primed test circuit. RESULTS: The main findings indicate that the RFE decreased (p = 0.00), with increasing flow rates (100-300 mL/min) through the filter screen. This reaction was most accentuated for GME below the size of 100 um, where counts of GME paradoxically increased after filtration, indicating GME fragmentation. For GME sized between 100-250 um, the RFE was constantly >60%, independently of the flow rate level. The video recording documenting the GME interactions with the screen filter confirmed the experimental findings. CONCLUSIONS: The 38-um 1-layer screen filter investigated in this experimental setup was unable to trap gaseous microbubbles effectively, especially for GME below 100 um in size and in conjunction with high flow rates. PMID- 28574104 TI - ECMO and cytokine removal for bridging to surgery in a patient with ischemic ventricular septal defect - a case report. AB - Even in the modern era of percutaneous coronary intervention, postinfarction ventricular septal defect (VSD) remains a serious and often lethal complication. Whether or not immediate surgical repair or delaying surgery a few days aided by intra-aortic counterpulsation provides the optimal strategy remains a matter of debate. An interdisciplinary approach of intensivists and cardiac surgeons in this setting is mandatory. We report the use of veno-arterial extracorporeal membrane oxygenation and extracorporeal blood purification therapy (CytoSorb(r)) as bridging to surgical closure in a patient with an ischemic VSD leading to protracted cardiogenic shock after posterior myocardial infarction. PMID- 28574105 TI - Development of a prolonged warm ex vivo perfusion model for kidneys donated after cardiac death. AB - PURPOSE: Ex vivo perfusion of marginal kidney grafts offers the chance to expand the donor pool, but there is no current clinical standard for the prolonged warm perfusion of renal grafts. This exploratory pilot study seeks to identify a stable ex vivo kidney perfusion model that can support low intravascular resistance and preserve histologic architecture in a porcine donation after cardiac death (DCD) model. METHODS: 15 kidneys were preserved in 1 of 3 settings: normothermic whole blood (NT-WB), normothermic Steen SolutionTM (XVIVO Perfusion) with whole blood (NT-Steen/WB), or subnormothermic Steen SolutionTM at 21 degrees C (SNT-Steen). Kidneys were primarily assessed using hemodynamic parameters and histologic analysis. RESULTS: NT-WB perfusion resulted in high vascular resistance and glomerular necrosis. NT-Steen/WB and SNT-Steen resistance ranged between 0.18-0.45 mmHg/mL per minute and 0.25-0.53 mmHg/mL per minute, respectively, enabling stable perfusion for up to 24 hours. NT-Steen/WB demonstrated tubular and glomerular necrosis, while the histologic architecture of SNT-Steen was preserved with the exception of numerous proteinaceous casts. CONCLUSIONS: Our results suggest that ex vivo kidney perfusion with Steen SolutionTM at 21 degrees C supports low and stable vascular resistance and provides adequate histologic preservation during 24-hour perfusion. PMID- 28574106 TI - Biostable scaffolds of polyacrylate polymers implanted in the articular cartilage induce hyaline-like cartilage regeneration in rabbits. AB - PURPOSE: To study the influence of scaffold properties on the organization of in vivo cartilage regeneration. Our hypothesis was that stress transmission to the cells seeded inside the pores of the scaffold or surrounding it, which is highly dependent on the scaffold properties, determines the differentiation of both mesenchymal cells and dedifferentiated autologous chondrocytes. METHODS: 4 series of porous scaffolds made of different polyacrylate polymers, previously seeded with cultured rabbit chondrocytes or without cells, were implanted in cartilage defects in rabbits. Subchondral bone was injured during the surgery to allow blood to reach the implantation site and fill the scaffold pores. RESULTS: At 3 months after implantation, excellent tissue regeneration was obtained, with a well-organized layer of hyaline-like cartilage at the condylar surface in most cases of the hydrophobic or slightly hydrophilic series. The most hydrophilic material induced the poorest regeneration. However, no statistically significant difference was observed between preseeded and non-preseeded scaffolds. All of the materials used were biocompatible, biostable polymers, so, in contrast to some other studies, our results were not perturbed by possible effects attributable to material degradation products or to the loss of scaffold mechanical properties over time due to degradation. CONCLUSIONS: Cartilage regeneration depends mainly on the properties of the scaffold, such as stiffness and hydrophilicity, whereas little difference was observed between preseeded and non-preseeded scaffolds. PMID- 28574108 TI - Comparative in vivo analysis of the role of the adventitia and the endothelium on arterial mechanical function: relevance for aortic counterpulsation. AB - PURPOSE: The comparative effect of the intimal and adventitial layers on arterial biomechanics control, in basal and altered conditions, remains to be elucidated. This study aimed (1) to characterize the arterial conduit (CF) and buffering (distensibility) function of the iliac arteries in in vivo animals, in which the intimal and adventitial layers were removed; (2) to determine the effects of intra-aortic ballon pumping (IABP) on simultaneously de-adventitialized (DA) and de-endothelialized (DE) iliac arteries before and after induced heart failure. METHODS: Pressure and diameter signals were measured in the iliac arteries of sheep (n = 7) in which the adventitial and intima layer were removed. Intra aortic balloon pump (IABP) assistance was used in a control state and after heart failure induction. RESULTS: Both DE and DA determined significant changes in arterial diameter, distensibility and CF. Changes were higher after DA than after DE in terms of distensibility and CF (p<0.05). DA followed by DE (DA + DE) showed significant increases in arterial diameter and CF, accompanied by a decrease in distensibility (p<0.05) with respect to intact arteries. Heart failure induction caused significant hemodynamic changes without modifying the already impaired local biomechanical parameters. Nonsignificant improvements in the biomechanical parameters of DA + DE iliac arteries were observed during IABP before and after heart failure induction. CONCLUSIONS: Biomechanical changes caused by DA of iliac arteries were more important than those observed after DE. The DA + DE arteries showed significant differences with respect to intact arteries and with DA or DE arteries. IABP-related effects on arterial mechanics were absent in DA + DE arteries. PMID- 28574107 TI - Continuous renal replacement therapy: forty-year anniversary. AB - In 1977 Peter Kramer performed the first CAVH (continuous arteriovenous hemofiltration) treatment in Gottingen, Germany. CAVH soon became a reliable alternative to hemo- or peritoneal dialysis in critically ill patients. The limitations of CAVH spurred new research and the discovery of new treatments such as CVVH and CVVHD (continuous veno-venous hemofiltration and continuous veno venous hemodialysis). The alliance with industry led to development of new specialized equipment with improved accuracy and performance in delivering continuous renal replacement therapies (CRRTs). Machines and filters have progressively undergone a series of technological steps, reaching a high level of sophistication. The evolution of technology has continued, leading to the development and clinical application of new membranes, new techniques and new treatment modalities. With the progress of technology, the entire field of critical care nephrology moved forward, expanding the areas of application of extracorporeal therapies to cardiac, liver and pulmonary support. A great deal of research made extracorporeal therapies an interesting option for the treatment of sepsis and intoxication and the additional use of sorbents was explored. With the progress in understanding the pathophysiology of acute kidney injury (AKI), new guidelines were developed, driving indications, modalities of prescription, monitoring techniques and quality assurance programs. Information technology and precision medicine have recently contributed to further evolution of CRRT, with the possibility of collecting data in large databases and evaluating policies and practice patterns. This is likely to ultimately result in improved patient care. CRRTs are 40 years old today, but they are still young and full of potential for further evolution. PMID- 28574109 TI - A new approach combining venoarterial extracorporeal membrane oxygenation and CRRT for adults: a retrospective study. AB - PURPOSE: This study aimed to assess a new approach combining venoarterial (VA) extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) in adults, while monitoring CRRT circuit pressures. METHODS: The inlet and outlet of the CRRT circuit were connected to preoxygenator port and postoxygenator port, respectively. Then, complications and CRRT circuit pressures were evaluated. RESULTS: 7 patients underwent combined VA-ECMO and CRRT; 16 filters were used. CRRT blood flow ranged from 150 to 200 mL/min; the CRRT to ECMO blood flow ratio was <0.1. The CRRT pressures at treatment initiation were normal. No complications were reported. CONCLUSIONS: This approach combining VA ECMO and CRRT in adults did not compromise the accuracy of pressure monitoring systems for CRRT circuit function, and caused no complications. Hence, it may be a feasible method for performing combined VA-ECMO and CRRT in adults. PMID- 28574110 TI - Closed-loop helium circulation system for actuation of a continuously operating heart catheter pump. AB - BACKGROUND: Currently available, pneumatic-based medical devices are operated using closed-loop pulsatile or open continuous systems. Medical devices utilizing gases with a low atomic number in a continuous closed loop stream have not been documented to date. This work presents the construction of a portable helium circulation addressing the need for actuating a novel, pneumatically operated catheter pump. The design of its control system puts emphasis on the performance, safety and low running cost of the catheter pump. METHODS AND RESULTS: Static and dynamic characteristics of individual elements in the circulation are analyzed to ensure a proper operation of the system. The pneumatic circulation maximizes the working range of the drive unit inside the catheter pump while reducing the total size and noise production.Separate flow and pressure controllers position the turbine's working point into the stable region of the pressure creation element. A subsystem for rapid gas evacuation significantly decreases the duration of helium removal after a leak, reaching subatmospheric pressure in the intracorporeal catheter within several milliseconds. CONCLUSIONS: The system presented in the study offers an easy control of helium mass flow while ensuring stable behavior of its internal components. PMID- 28574111 TI - Isolation, characterization and cold storage of cells isolated from diseased explanted livers. AB - INTRODUCTION: Livers discarded after standard organ retrieval are commonly used as a cell source for hepatocyte transplantation. Due to the scarcity of organ donors, this leads to a shortage of suitable cells for transplantation. Here, the isolation of liver cells from diseased livers removed during liver transplantation is studied and compared to the isolation of cells from liver specimens obtained during partial liver resection. METHODS: Hepatocytes from 20 diseased explanted livers (Ex-group) were isolated, cultured and stored at 4 degrees C for up to 48 hours, and compared to hepatocytes isolated from the normal liver tissue of 14 liver lobe resections (Rx-group). The nonparenchymal cell fraction (NPC) was analyzed by flow cytometry to identify potential liver progenitor cells, and OptiPrepTM (Sigma-Aldrich) density gradient centrifugation was used to enrich the progenitor cells for immediate transplantation. RESULTS: There were no differences in viability, cell integrity and metabolic activity in cell culture and survival after cold storage when comparing the hepatocytes from the Rx-group and the Ex-group. In some cases, the latter group showed tendencies of increased resistance to isolation and storage procedures. The NPC of the Ex group livers contained considerably more EpCAM+ and significantly more CD90+ cells than the Rx-group. Progenitor cell enrichment was not sufficient for clinical application. CONCLUSIONS: Hepatocytes isolated from diseased explanted livers showed the essential characteristics of being adequate for cell transplantation. Increased numbers of liver progenitor cells can be isolated from diseased explanted livers. These results support the feasibility of using diseased explanted livers as a cell source for liver cell transplantation. PMID- 28574112 TI - Evaluation of color changes of dental luting materials in food colorant solutions. AB - BACKGROUND: The purpose of this study was to compare the color stability and water absorption of 3 commercially available resin cements in vitro by storing them in 0.15% erythrosine, dark brown and sunset yellow for 30 days. METHODS: 2 self-adhesive resin cements and 1 dual/light curing, resin-based dental luting material were evaluated (total 120 samples). The CIE L, a, b of 10 mm diameter 2.0 mm height disk shaped samples was measured using a spectrophotometer for color stability on a white background, 10 mm diameter-1.0 mm height disk shaped samples were measured for water absorption before and after storage in food colorant solutions. RESULTS: The self-adhesive resin cement-sunset yellow group caused the most severe discoloration (27.89 +/- 3.64) that is clinically unacceptable. The lowest discoloration was seen in the self-adhesive resin cement control group (3.35 +/- 1.13). The highest water absorption was observed in the self-adhesive resin cement-dark brown group (2.41 +/- 0.60) and the lowest water absorption in the dental luting material-control group (0.65 +/- 0.17). CONCLUSIONS: Storage food colorant solutions affected the color stability and water absorption of different resin cement materials. PMID- 28574113 TI - Medium cut-off membranes - closer to the natural kidney removal function. PMID- 28574115 TI - A comparative study of cone-beam computed tomography and periapical radiographs in decision-making after endodontic instrument fractures. AB - PURPOSE: This study aimed to compare the diagnostic efficacies of periapical radiographs (PRs) and cone-beam computed tomography (CBCT) scans on clinicians' decision-making in diagnosing and providing treatment of fractured instruments in root canals during glide path preparation. METHODS: 40 maxillary molar teeth were selected and randomly divided into 4 groups. In each experimental group (n = 10), Hedstroem stainless steel instruments were fractured in mesiobuccal (MB) or distobuccal (DB) root canals. In group 1 (#0.06), group 2 (#0.08), group 3 (#0.10), and group 4 (#0.15), instruments were forced to fracture. PRs and CBCT scans were evaluated and compared. Observers were asked to use the following scoring system to decide whether to: 1. remove the fragment; 2. leave the fragment in situ; 3. bypass the fragment; or 4. use a surgical approach for removing the fragment. RESULTS: CBCT observers mostly decided on removing and bypassing the fractured fragment, while radiograph observers mostly decided to leave fragments in situ. However, there was no significant difference between these parameters when CBCT scans were compared to PRs for decision-making of the fractured instruments (p>=0.05) regarding different sizes of root canal instruments. CONCLUSIONS: In decision-making regarding fractured instruments during glide path preparation, clinicians should strategize treatment options based on variables using high-resolution images that reflect accurate scenarios through PRs or CBCT scans that also take into account low radiation dosage in situ PRs have precedence for a diagnostic approach. PMID- 28574114 TI - Venlafaxine intoxication with development of takotsubo cardiomyopathy: successful use of extracorporeal life support, intravenous lipid emulsion and CytoSorb(r). AB - We describe a young patient who ingested 18 g (240 times the daily therapeutic dose) of venlafaxine in a suicide attempt. She developed severe cardiomyopathy in a takotsubo distribution causing cardiogenic shock and multi-organ dysfunction syndrome (MODS). She was successfully treated with intravenous lipid emulsion (ILE), extracorporeal life support (ECLS) and CytoSorb(r). This is remarkable as, to the best of the authors' knowledge, this is the highest amount of venlafaxine intake seen in the literature with a nonfatal outcome. PMID- 28574116 TI - The influence of acetabular morphology on prediction of proximal femur fractures types in an elderly population. AB - INTRODUCTION: The role of proximal femur morphology to the development of certain proximal femur fracture types both femoral neck and trochanteric fractures has been observed. However, the relavance of acetabular morphology to the development of proximal femur fractures is not extensively questioned. Therefore the aim of the study was to determine whether there is a correlation between acetabular morphology and pathogenesis of 2 different hip fracture types after low energy trauma. METHODS: This retrospective study includes 60 cases (41 women, 19 men) with a proximal femoral fracture after a low energy trauma between July 2012 and December 2014. Acetabular depth and acetabular index were measured on pelvic radiographs. Neck shaft angle, hip axis length and cortical index were measured on pelvic computed tomography scans. All measurements were performed on the contralateral hip. RESULTS: Mean age was 77.56 +/- 8.99 years (range 61-92 years). No statistically significant difference was found with regard to neck shaft angle, acetabular depth or cortical index measurements between patients with femoral neck fracture and patients with trochanteric femoral fractures (p>0.05). Acetabular index measurement was higher (p = 0.001) and hip axis length measurement was lower (p = 0.001) in trochanteric fracture group as compared to femoral neck fracture. CONCLUSIONS: The rate of trochanteric femur fractures is higher in patients with high acetabular index, whereas the rate of femoral neck fractures is higher in patients with increased hip axis length. PMID- 28574117 TI - Combined anteversion technique in total hip arthroplasty for Crowe IV developmental dysplasia of the hip. AB - BACKGROUND: A high rate of postoperative dislocation in total hip arthroplasty (THA) for Crowe IV developmental dysplasia of the hip (DDH) has been reported, 1 of the main reasons being higher true acetabular anteversion. If the cup is fixed with normal anteversion, the anterior rim will be excessively exposed, which reduces the contact areas of the cup and bone, affects prosthesis stability, and leads to iliopsoas tendinitis and persistent hip pain after THA. The aim of this study was to demonstrate that when cup anteversion is larger, adjusting femoral anteversion to bring the combined anteversion (CA) into the "safe zone" might prevent dislocation. METHODS: After having fixed the cup in the acetabulum according to the patients' native acetabular anteversion, we shortened and rotated the proximal femur to reduce femoral anteversion, adjusting the CA into the "safe zone". The Harris Hip Score (HHS) was used to evaluate hip joint function. Computerised tomography scanning was used to measure the anteversion angles. RESULTS: All patients were followed up without any dislocation. Preoperative and 12 months after surgery, the mean HHS were 43.3 +/- 2.6 (38-47) and 88.1 +/- 3.3 (78-92) respectively. Pre- and post-operation, the mean CA angles were 88.6 degrees +/- 9.4 degrees (80.3 degrees -119.4 degrees ) and 49.2 degrees +/- 2.6 degrees (43.4 degrees -54.4 degrees ) respectively. The bone healing time of femoral osteotomy ranged from 4 to 14 months, with a mean time of 7.5 months. CONCLUSIONS: This CA technique in THA for Crowe IV DDH can effectively prevent postoperative dislocation and provide good hip function. PMID- 28574118 TI - Wear of XLPE liner against zirconium heads in cementless total hip arthroplasty for patients under 40 years of age. AB - INTRODUCTION: Total hip arthroplasty (THA) in the young is challenging. The purpose of this study was to retrospectively determine the clinical, radiographic, and polyethylene wear rate of relatively young patients. METHODS: We evaluated the outcome of consecutive patients receiving primary THA who were under 40 years of age with a minimum 10-year follow-up. Indications for THA in these patients were osteoarthritis due to developmental dysplasia of the hip joint (9 hips), osteonecrosis of the femoral head (7 hips), juvenile idiopathic arthritis (2 hips), and osteoarthritis due to Perthes disease (1 hip). All THA were performed with a cross-linked ultra-high-molecular-weight polyethylene (XLPE) liner against zirconium heads with cementless implants. RESULTS: The average Japanese Orthopaedic Association hip score significantly improved from 42 to 93 points at the latest follow-up. The mean steady wear was 0.015 mm/year (maximum 0.033 mm/year), and the mean creep wear was 0.111 mm (maximum 0.4 mm). Osteolysis was observed around 1 acetabular component and 2 stems. 1 femoral component had subsidence over 5 mm. All of the femoral components achieved fixation with an optimal interface with spot welds at the latest follow-up. Stress shielding was observed in all hips. CONCLUSIONS: THA using an XLPE liner against zirconium heads appeared to have improved THA longevity. However, the imaging findings in some cases were suggestive of wear debris. A rigorous continual follow-up is required for relatively young patients undergoing THA. PMID- 28574119 TI - Imaging of impingement syndromes around the hip joint. AB - Impingement syndromes are increasingly recognised as significant causes of hip pain and dysfunction. A broad spectrum of intraarticular and extraarticular conditions has been implicated in their pathophysiology. Physical examination is often inconclusive as clinical findings may be unclear or misleading, often simulating other disorders. With current improvements in imaging techniques and better understanding of hip impingement related pathomechanisms, these entities can be accurately diagnosed. In addition, preoperative imaging has allowed for targeted treatment planning. This article provides an overview of the various types of hip impingement, including femoroacetabular impingement, ischiofemoral impingement, snapping hip syndrome, greater trochanteric-pelvic and subspine impingement. Current literature data regarding their pathogenesis, clinical manifestation and imaging work-up are discussed. PMID- 28574121 TI - Long-term results of total hip arthroplasty with the CementLess Spotorno (CLS) system. AB - BACKGROUND: This study presents the long-term results of the Cementless Spotorno (CLS) total hip arthroplasty system and an analysis of factors associated with clinical and radiographic outcome. METHODS: We studied a series of 120 consecutive CLS arthroplasties in a young patient group (mean age at surgery: 55.9 +/- 5.9 years). The Merle d'Aubigne-Postel score, polyethylene (PE) wear, and radiographic status were recorded during follow-up. Survival analyses, repeated-measures analysis of variance, and a nested case-control study were used for statistical evaluation. RESULTS: After a mean follow-up of 14.6 years (range 0.1-24.2 years, including revisions and lost to follow-up), 24 revisions had been performed, 16 of which for aseptic cup loosening. Kaplan-Meier survival analysis showed a 24-year survival of 72.8% (95% CI, 63.0%-82.6%) with revision for any reason as endpoint, and 80.1% (95% CI, 70.9%-89.3%) for revision for aseptic cup loosening. Mean final Merle d'Aubigne-Postel score was 16.1 points (range 7-18). Mean PE wear at final follow-up was 2.3 mm (range 0.6-6.8 mm). A higher rate of PE wear was associated with better clinical scores but also with revision for cup loosening. Factors associated with more PE wear were: younger age at surgery; 32 mm head; longer follow-up; and steeper inclination angle. CONCLUSIONS: Beyond 10 years, the CLS stem is reliable, but the high revision rate for aseptic cup loosening is concerning, specifically with better performing (cementless) alternatives available. PMID- 28574120 TI - MRI of the hip: current concepts on bone marrow oedema. AB - Bone marrow oedema (BME) is commonly found in hip MR imaging. BME is a nonspecific finding which can be related to a wide variety of diseases. However, there are cases where its existence or its pattern can narrow the differential or even point to a specific diagnosis. Therefore, deep understanding of its pathophysiology is of utmost importance for clinicians and radiologists in order to avoid diagnostic pitfalls. We hereby present currently established knowledge on BME related to adult hip pathology, aiming to raise physicians' suspicion and to highlight that it is mandatory to combine specific imaging patterns with the history, clinical and laboratory findings in order to achieve accurate diagnosis. PMID- 28574122 TI - A retained stitch in time saves 9 - but does it increase the risk of deep prosthetic infection? AB - INTRODUCTION: During the posterior approach to the hip, the short external rotators are detached and secured with stay sutures. At the time of definitive closure, some surgeons incorporate the initial sutures into their repair while others discard for fresh sutures, presumably as an infection prevention measure. We have conducted a pilot study to investigate whether the incorporation of the primary stay sutures may constitute an infection risk to the patient undergoing a total hip replacement through the posterior approach. MATERIALS AND METHODS: The pilot study was conducted between August 2014 and June 2015. A pair of suture specimens were sent from 25 patients to microbiology, 1 set of primary stay sutures and 1 set of control sutures. All operations were carried out by the senior author through a posterior approach. RESULTS: All specimens were analysed for bacterial and fungal growth, using extended cultures. 1 set of primary sutures had a positive growth, likely from skin contamination; 1 set of control sutures also had a positive growth, likely from environmental contamination. CONCLUSIONS: Our pilot study suggests that the practice of incorporating the primary stay sutures for definitive soft tissue repair of the short external rotators, rather than exchanging them for new sutures, can be deemed safe. PMID- 28574123 TI - Orthogonal plating of Vancouver B1 and C-type periprosthetic femur fracture nonunions. AB - BACKGROUND: Periprosthetic femoral shaft fractures are a significant complication after total hip arthroplasty (THA). Plate osteosynthesis has been the mainstay of treatment around well-fixed stems. Nonunions are a rare and challenging complication of this fixation method. We report the outcomes of a novel orthogonal plating surgical technique for Vancouver B1 and C-type periprosthetic fractures that previously failed open reduction internal fixation (ORIF). METHODS: A retrospective review identified all patients with Vancouver B1/C THA periprosthetic femoral nonunions from 2010 to 2015. Exclusion criteria included open fractures and periprosthetic infections. The technique utilised a mechanobiologic strategy of atraumatic exposure, resection of necrotic tissue, bone grafting with adjuvant bone morphogenetic protein (BMP) and revision open reduction internal fixation with orthogonal plate osteosynthesis. RESULTS: 6 Vancouver B1/C periprosthetic femoral nonunions were treated. 5 patients were female with an average age of 80.3 years (range 72-91 years). The fractures occurred at a mean of 5.8 years (range 1-10 years) from their initial arthroplasty procedure. No patients underwent further revision surgery; there were no perioperative complications. All patients had a minimum of 11 months follow-up (mean 18.6, range 11-36 months). All fractures achieved osseous union, defined as solid bridging callus over at least 2 cortices and pain free, independent ambulation, at an average of 24.4 weeks (range 6.1-39.7 weeks). CONCLUSIONS: This is the 1st series describing orthogonal locked compression plating using modern implants for periprosthetic femoral nonunions. This technique should be considered in periprosthetic femur fracture nonunions around a well-fixed stem. PMID- 28574124 TI - Total hip arthroplasty in young patients with post-traumatic arthritis of the hip. AB - BACKGROUND: Post-traumatic arthritis of the hip is a degenerative condition that commonly affects young patients. In this study, we evaluate long-term implant survival and patient-reported outcomes after primary total hip arthroplasty (THA) in patients aged 35 or younger with post-traumatic arthritis of the hip. METHODS: We conducted a retrospective study with follow-up. A chart review was performed to identify young patients with post-traumatic arthritis of the hip treated with primary THA. Follow-up surveys were conducted to determine implant survival and patient-reported outcomes. Implant survival was assessed using Kaplan-Meier survival analysis, and patient outcomes were determined using the hip disability and osteoarthritis outcome score (HOOS). RESULTS: We studied 42 patients (44 THAs) with a mean time to follow-up of 14 years. The 10-year implant survival rate was 87% and 20-year implant survival rate was 41%. Implant survival did not differ based on patient age, gender, implant type, bearing surface, or use of cement for implant fixation (p>0.05). The mean HOOS scores at follow-up were 87 for pain, 85 for symptoms, 89 for ADLs, and 76 for sports. HOOS scores were significantly worse in patients that had undergone revision THA (p<0.05). CONCLUSIONS: Young patients with post-traumatic arthritis of the hip have good long-term outcomes after THA. However, revision THA is predictive of worse long term outcomes. PMID- 28574125 TI - Risk factors for mid-term revision surgery in patients with articular surface replacement total hip arthroplasty. AB - INTRODUCTION: This study assessed the associations between gender and implant survival, as well as adverse local tissue reaction (ALTR), in patients with articular surface replacement (ASR) XL total hip arthroplasty (THA). Secondly, we sought to report the differences between genders in metal ion levels and patient reported outcome measures (PROMs) in these patients. METHODS: 563 unilateral ASR XL THA patients were enrolled in a multicentre follow-up study at a mean of 6.4 years after index surgery. All patients had blood metal ion levels and PROMs obtained annually, and a valid anteroposterior pelvis radiograph. A sub-set of patients from a single centre had annual MRI performed and were analysed for the presence of moderate-to-severe ALTR. RESULTS: 60 hips (11%) were revised during the study period. The only variables found to be associated with revision surgery in patients with unilateral THA were VAS pain (hazard ratio [HR], 1.35; p<0.001) and elevated cobalt metal ion levels (HR, 1.05; p<0.001). No variables assessed were found to be associated with prevalence of ALTR. Chromium concentrations were greater in female patients than males, while cobalt levels were similar between genders. Males reported higher HHS, EQ-5D and UCLA scores than females. CONCLUSIONS: Both males and females with metal-on-metal THA implants should be followed with equal vigilance as gender does not appear to be associated with poor outcomes, such as revision surgery and presence of ALTR. PMID- 28574126 TI - Radiographic outcomes of cable-plate versus cable-grip fixation in periprosthetic fractures of the proximal femur. AB - BACKGROUND: Newer generation cable-plate designs are commonly used for periprosthetic proximal femur fractures; however, comparisons relative to cable grips remain limited. The aim of this study was to compare radiographic healing rates of cable-plate versus cable-grip fixation for periprosthetic proximal femur fractures. PATIENTS AND METHODS: Consecutive patients with an acute or chronic Vancouver A, B1, or B2 periprosthetic proximal femur fracture undergoing trochanteric fixation with a cable-plate (n = 46 cases) or cable-grip (n = 24 cases) system were identified retrospectively from a single-centre hospital database (mean follow-up 28 months [range 6-89 months]). Demographics, radiographic fracture healing, and complications were compared between the 2 groups. Radiographic union rates were not different between the cable-grip versus cable-plate group (67% vs. 76% respectively; p = 0.4). Healing rates of greater trochanteric fractures alone were not different between the cable-plate versus cable-grip groups (75% vs. 71% respectively; p = 0.38). The cable-plates were used for a more diverse range of fracture patterns relative to the cable-grips. RESULTS: An increased number of cables was associated with radiographic healing (odds ratio 14 [95% confidence interval 2-64]; p = 0.01), and body mass index had a negative correlation with radiographic healing (odds ratio -0.4 [95% confidence interval 0.5-0.9]. CONCLUSIONS: Similar rates of periprosthetic fracture healing were seen using a cable-grip versus cable-plate system; however, the cable-plate system could be used for a more diverse range of fracture patterns. PMID- 28574127 TI - Influence of cigarette smoking on osteonecrosis of the femoral head (ONFH): a systematic review and meta-analysis. AB - BACKGROUND: Current studies demonstrate controversy regarding the relationship between cigarette smoking and osteonecrosis of the femoral head (ONFH). METHODS: We conducted a meta-analysis to evaluate the association between smoking and ONFH. Relevant articles published before September 2016 were identified by a systematic search of EMBASE and MEDLINE via Ovid. Summary odds ratios (OR) were calculated using random effects models, and study quality was assessed using a modified Newcastle-Ottawa scale. RESULTS: 102 citations were screened and 7 case control studies were identified and included in the review. When compared with nonsmokers, current smokers had a higher risk of developing ONFH (OR 2.53; 95% confidence interval [CI] 1.68-3.79), as did former smokers (OR 1.82; 95% CI, 1.10 3.00). Within the group of current smokers, those classified as heavy smokers (with a daily number >20 cigarettes/day) demonstrated higher risks of ONFH (OR 2.03; 95% CI, 1.29-3.19), and light smokers classified as smoking <20 cigarettes/day, also demonstrated a higher risk of ONFH when compared with nonsmokers (OR 1.73; 95% CI, 1.06-2.83). When smoking was classified by pack years, heavy smokers (>20 pack-years) were at a higher risk of ONFH (OR 2.26; 95% CI, 1.24-4.13), but no significant difference in risk was identified in light smokers (<20 pack-years) (OR 1.81; 95% CI, 0.88-3.71) when compared with nonsmokers. CONCLUSIONS: Our meta-analysis showed that current smokers were at a higher risk of ONFH, this high risk can also be found in former smokers. And heavy cigarette smoking showed a higher risk of ONFH than light smoking. PMID- 28574128 TI - Does gender influence how patients rate their patient experience after total hip arthroplasty? AB - BACKGROUND: Patient satisfaction, as measured by Press Ganey (PG) surveys, partially determines reimbursement rates. Knowing what influences these scores can lead to higher reimbursement for total hip arthroplasty (THA) surgeons. Currently, it is unknown whether gender biases exist in satisfaction surveys post THA. Therefore, we asked: (i) which PG survey factors most influence hospital ratings among men and women after THA; and (ii) is there a difference in survey element responses and overall hospital ratings between men and women post-THA? METHODS: We queried the PG database for patients who underwent THA from November 2009 to January 2015, which yielded 692 patients (277 men, 415 women). Weighted means were analysed for the scores of PG domains between men and women. A multiple regression analysis was performed for each gender, with overall hospital satisfaction as the dependent variable, in order to assess the influence (beta weight) of each PG domain. RESULTS: For men, pain management (beta = 0.317, p = 0.021) most influenced overall hospital rating. For women, staff responsiveness (beta = 0.451, p<0.001) most influenced overall hospital rating. This was followed by communication with nurses (beta = 0.373, p<0.001), and doctors (beta = 0.236, p = 0.002). There were no significant differences in mean overall hospital rating between groups. CONCLUSIONS: It is advantageous for orthopaedic surgeons to focus on the PG domains most pertinent to each patient gender post THA. Focusing efforts based on gender may allow for better patient satisfaction, optimised reimbursements, and improved hospital ratings. PMID- 28574129 TI - Smoking in Italy in 2015-2016: prevalence, trends, roll-your-own cigarettes, and attitudes towards incoming regulations. AB - PURPOSE: In 2016, a series of selective tobacco regulations, which did not affect tobacco price, came into force in Italy. To understand how Italians accepted the new norms, we analyzed data from our 2 most recent surveys among those we annually conduct on tobacco. METHODS: In 2015 and 2016, we conducted 2 representative cross-sectional studies focused on the new forthcoming tobacco legislation on a total sample of 6,046 Italians aged >=15 years. RESULTS: Overall, 21.4% of Italians (26.0% of men and 17.2% of women) were current smokers, showing a small but significant decrease in smoking prevalence since 2007 (p for trend = 0.004). No change in smoking prevalence was observed over the last decade among the young (i.e., 15-24 years; 20.1% in 2015-2016). Roll-your own cigarettes were the most frequent tobacco product for 8.3% of adult smokers and 19.7% of young smokers. According to the attitudes of Italians towards the new regulations, 91.3% supported the smoking ban in cars in presence of minors, 90.2% a more stringent enforcement of the tobacco sales-to-minors regulation, 74.3% the introduction of shocking pictorial images on tobacco packs, and 63.2% the removal from the market of small cigarette packs, usually purchased by the young. CONCLUSIONS: Smoking prevalence only marginally decreased over the last decade among adults, but did not decrease among the young. Roll-your-own tobacco is increasingly used by adults and young people. Before the entrance of the new norms, Italians largely supported them, particularly those targeting children. PMID- 28574131 TI - Surprising complete response of intramedullary spinal cord metastasis from breast cancer: a case report and literature review. AB - PURPOSE: Intramedullary spinal cord metastases (ISCM) are considered rare but their incidence is rising. Most ISCM cases are recognized to occur in patients with stage IV lung cancer or breast cancer (BC). METHODS: We report a rare case of cervical BC-ISCM in 60-year-old woman, documented by magnetic resonance imaging and positron emission tomography-computed tomography and treated with volumetric modulated arc therapy with daily image-guided radiation therapy (VMAT/IGRT). RESULTS: An unexpected clinical and radiologic complete response in absence of neurologic side effects was recorded 4 months after VMAT/IGRT. CONCLUSIONS: The present case report shows the feasibility of advanced RT and its optimal response in a case of ISCM from BC. Despite the short follow-up, in comparison with available literature data concerning the management of BC-ISCM, we found an early complete response, in contrast with other reported experiences. PMID- 28574130 TI - HPV-related vulvar diseases and perspectives of p16INK4a immunochemistry: a review of the literature. AB - INTRODUCTION: Two different types of vulvar intraepithelial neoplasia (VIN), HPV related and HPV-unrelated, should be considered as two separate entities with different management options. The incidence of HPV-related VIN is increasing worldwide and is implicated in carcinogenesis. Our objective is to investigate the use of p16INK4a immunostaining or p16INK4a/p53 double staining for the detection of HPV-related disease to overcome the problem that histological criteria often have significant overlap. METHODS: A systematic literature search was carried out in the online databases PubMed, EMBASE, Cochrane Library, Clincaltrials.gov and Scopus. The key search terms were HPV, VIN, p16INK4a immunochemistry and p53. RESULTS: We found that nuclear and cytoplasmic immunostaining for p16INK4a was intense and diffuse in HPV-associated lesions and weak and focal in normal vulvar epithelium, nondysplastic lesions, lichen sclerosus and keratinizing vulvar squamous cell carcinoma. p53 nuclear immunostaining was always negative in HPV-related disease. CONCLUSIONS: Our findings indicated that p16INK4a or p16INK4a/p53 immunoreactivity, along with histological diagnosis, could be a convenient means to adequately classify VIN and its connection to HPV infection. Therefore, the clear recognition of HPV associated VIN would lead to an appropriate strategy of treatment and follow-up. PMID- 28574132 TI - miRNA-650 exerts anti-leukemia activity by inhibiting cell proliferation through Gfi1 targeting. AB - BACKGROUND:: Acute myeloid leukemia (AML) is the most common malignancy of the bone marrow with a high mortality. Recent advances in high-throughput sequencing have led to the identification of various miRNAs implicated in the pathogenesis of AML. We found in this study that miR-650, a miRNA that was traditionally considered to participate in the onset of hepatocellular carcinoma, might play a significant role in AML development and progression. METHODS:: qRT-PCR was used to detect the expression of miR-650 and Gfi1 in AML patients and healthy controls. Next, a luciferase assay was conducted to verify the target effect of miR-650 on Gfi1. Moreover, the CCK-8 assay was performed to evaluate the effect of miR-650 on the proliferation of AML cells in the presence and absence of Gfi1. RESULTS:: miR-650 was downregulated in AML whereas Gfi1 was upregulated. miR-650 could negatively regulate Gfi1 via direct targeting of its 3'-UTR, which was confirmed by luciferase assay. In addition, overexpression of miR-650 reduced cell proliferation in K562 cells, whereas an increase in cell proliferation was observed when K562 cells were transfected with miR-650 inhibitor, which was compromised in response to the knockdown of Gfi1. CONCLUSIONS:: Our research demonstrated that miR-650 modulates cell proliferation in AML through affecting the expression of Gfi1, which occurs by direct target action. PMID- 28574133 TI - Technical feasibility of isolated Bowman layer graft preparation by femtosecond laser: a pilot study. AB - PURPOSE: To evaluate the technical feasibility of isolated Bowman layer (BL) graft preparation by femtosecond laser (FSL) and to compare the ultrastructural morphology to manually dissected grafts. METHODS: Five whole globes were placed in custom-made eye holders and debrided of epithelium. After programming a dissection depth of 20 MUm, the FSL was docked into position and 5 isolated BL grafts were created. From 5 additional globes, corneoscleral buttons were procured, mounted in artificial anterior chambers, and stripped of BL via the previously described manual technique. Three specimens from both series were randomly selected and assigned to transmission electron microscopy for ultrastructural evaluation and thickness measurements. RESULTS: All dissections were uneventful and 10 total grafts were produced: 5 by FSL and 5 by manual dissection. Mean graft thickness was 37 (+/-8.6) MUm (n = 3) for the FSL group and 11.7 (+/-1.6) MUm (n = 3) for the manually dissected group. Transmission electron microscopy revealed a thick but relatively smooth posterior cut edge in the FSL group, versus a virtually isolated BL with irregular rests of dispersed stroma in the manually dissected group. CONCLUSIONS: Femtosecond laser may have potential for harvesting intact BL and with a smooth posterior surface, but accompanied by variable amounts of anterior stroma owing to technical limitations. PMID- 28574134 TI - Assessing visual function behind cataract: preoperative predictive value of the Heine Lambda 100 retinometer. AB - PURPOSE: To analyze the accuracy of the Lambda 100 (Heine) potential visual acuity (VA) measurements in subjects undergoing cataract surgery. METHODS: The medical records of all consecutive patients who underwent clear corneal incision phacoemulsification cataract surgery by a single surgeon between 2010 and 2012 at the Department of Ophthalmology, Hadassah Medical Center, a tertiary care hospital in Jerusalem, Israel, were reviewed. Subjects age 18 or older with a follow-up time of at least 30 days were included. Subjects with previous ocular comorbidities other than glaucoma were excluded. In addition, patients with intraoperative or perioperative complications that could affect final VA were excluded. Analyses were performed to analyze the accuracy of preoperative retinometer potential VA as a predictor of postoperative best-corrected VA. RESULTS: A total of 374 operated eyes were included. There was a moderate positive correlation between Lambda estimated VA potential and postoperative achieved best-corrected VA (BCVA) (beta coefficient 0.35, p<0.0001). Overall Lambda accurately (within 2 Snellen lines) estimated postoperative BCVA results in 60% of cases. The accuracy of prediction was significantly better in moderate cataracts when compared with advanced cataracts (p<0.01) with a twofold tendency towards underestimation in advanced cataracts. A Lambda >=0.5 decimal has a calculated positive predictive value of 82% and a negative predictive value of 40% for predicting postoperative BCVA outcome >=0.5 decimal. CONCLUSIONS: Lambda may be used to relatively accurately predict postoperative BCVA in cataract patients, specifically in those with moderate cataracts. PMID- 28574135 TI - Patient-centered and visual quality outcomes of premium cataract surgery: a systematic review. AB - PURPOSE: Over 8 million cataract surgeries are performed in the United States and the European Union annually, with many patients choosing to pay out of pocket for premium options including premium intraocular lens implants (IOLs) or laser assisted cataract surgery (LACS). This report provides a systematic review evaluating patient-centered and visual quality outcomes comparing standard monofocal IOLs to premium cataract surgery options. METHODS: PubMed and EMBASE were searched for publications published between January 1, 1980, and September 18, 2016, on multifocal, accommodative, and toric IOLs, monovision, and LACS, which reported on 1) dysphotopsias, 2) contrast sensitivity, 3) spectacle independence, 4) vision-related quality of life or patient satisfaction, and 5) IOL exchange. RESULTS: Multifocal lenses achieved higher rates of spectacle independence compared to monofocal lenses but also had higher reported frequency of dysphotopsia and worse contrast sensitivity, especially with low light or glare. Accommodative lenses were not associated with reduced contrast sensitivity or more dysphotopsia but had only modest improvements in spectacle independence compared to monofocal lenses. Studies of monovision did not target a sufficiently myopic outcome in the near-vision eye to achieve the full potential for spectacle independence. Patients reported high levels of overall satisfaction regardless of implanted IOL. No studies correlated patient-reported outcomes with patient expectations. CONCLUSIONS: Studies are needed to thoroughly compare patient reported outcomes with concomitant patient expectations. In light of the substantial patient costs for premium options, patients and their surgeons will benefit from a better understanding of which surgical options best meet patients' expectations and how those expectations can be impacted by premium versus monofocal-including monovision-options. PMID- 28574136 TI - Total retinal detachment caused by a KIF11 mutation. AB - PURPOSE: This is a case report of bilateral retinal detachment associated with KIF11 mutation. METHODS: In our university hospital, an 8-week-old patient presented with a potential bilateral congenital cataract, iris atrophy, and iridocorneal contact in the left eye. An examination revealed microcephaly and edema of the dorsa of the feet. The eye examination showed a clear lens in both eyes with a dislodged anterior chamber in the left eye with vessels drawn from the iris to the lens. A retrolental white bilateral mass with vessels was also observed. The MRI and the ultrasound revealed a potential peritoneal hyperplastic glass body. Bilateral retinal detachment was diagnosed during surgery. RESULTS: Due to the external appearance of the eyes (microcephaly and edema) and the bilateral retinal detachments, a test for KIF11 mutations was requested, and the results were positive. CONCLUSIONS: There is a known association between KIF11 mutation and chorioretinopathy. The bilateral retinal detachment in the present case study has not been previously reported in the literature. PMID- 28574137 TI - Iris reconstruction using artificial iris prosthesis for management of aniridia. AB - PURPOSE: To discuss the limitations and benefits of the BrightOcular prosthetic artificial iris device in management of aniridia associated with aphakia or cataract. METHODS: This is a retrospective study including 5 eyes of 4 patients who underwent implantation of the BrightOcular iris prosthesis (Stellar Devices) for total or partial aniridia. The cases included 2 eyes of 1 patient with congenital aniridia associated with congenital cataract and 3 eyes with traumatic aniridia: 1 with subluxated cataractous lens and 2 with aphakia. In all cases, the iris prosthesis was implanted after a 3-piece acrylic intraocular lens was implanted. We evaluated the clinical course with a minimum follow-up period of 6 months, the intraoperative and postoperative complications, and the cosmetic satisfaction of patients. RESULTS: All patients had improved uncorrected distance visual acuity and best-corrected distance visual acuity. All patients had a transient corneal edema that resolved within the first postoperative week. Only the patient with congenital aniridia had a permanent increase in intraocular pressure and developed a band keratopathy throughout a 2-year follow-up period. The prosthesis was well-centered in all eyes except for one case that required scleral suture fixation after 3 months. All patients had a satisfactory cosmetic appearance. CONCLUSIONS: BrightOcular iris prosthesis is a safe and useful tool to correct aniridia associated with pseudophakia or aphakia. Being foldable, it is easy to be implanted through a small incision and placed in the ciliary sulcus without sutures when properly sized. Cosmetic results are satisfactory. Sizing methods should be improved. PMID- 28574138 TI - Detection of nonexudative choroidal neovascularization secondary to angioid streaks using optical coherence tomography angiography. AB - PURPOSE: To present a case of nonexudative choroidal neovascularization secondary to angioid streaks in a patient with pseudoxanthoma elasticum. The lesion was monitored over an 8-month period with the use of optical coherence tomography angiography. METHODS: Case report. RESULTS: The neovascular tissue area increased by 0.160 mm2 over a period of 8 months without any sign of exudation seen on optical coherence tomography or fluorescein angiography. CONCLUSIONS: To our knowledge, this is the first report of a nonexudative choroidal neovascularization secondary to angioid streaks. Given that once a patient with angioid streaks develops choroidal neovascularization in one eye there is a high risk of bilateral involvement within a short amount of time, optical coherence tomography angiography can prove a useful tool for monitoring such lesions over time. PMID- 28574140 TI - Hybrid 20/23-G pars plana vitrectomy in endophthalmitis and trauma: a strategic approach. AB - PURPOSE: To assess the safety and efficacy of hybrid vitreous surgery combining active 23-G ports with a sutured 20-G 6-mm infusion cannula for performing vitrectomy in endophthalmitis and trauma. METHODS: This is a retrospective analysis of 10 eyes with endophthalmitis and 10 eyes with trauma requiring vitreous surgery, having corneal clarity suitable for vitrectomy and best corrected visual acuity (BCVA) greater than or equal to light perception. All patients underwent hybrid 20/23-G vitrectomy. Intraoperative notes were analyzed for peroperative complications. The BCVA and retinal status at 3 months were analyzed. RESULTS: In the endophthalmitis group, patients ranged from 5 to 85 years of age and showed varied etiologies. Retinal detachment was present in 5 eyes, which received silicone oil tamponade. Mean preoperative logMAR visual acuity (VA) was 2.29 +/- 0.45, which improved to 1.10 +/- 0.72 at 3 months postoperatively (p<0.001). Trauma cases ranged from 21 to 75 years of age. Retinal detachment was present in 9 out of 10 eyes, all of which received silicone oil tamponade. Preoperative logMAR VA was 2.26 +/- 0.71, which improved to 1.33 +/- 0.50 postoperatively (p<0.001). At 3 months postsurgery, the retina was attached in all eyes in both groups. CONCLUSIONS: The longer sutured 20-G cannula was easier to visualize through fibrin, exudates, and hemorrhage and did not slip out or enter the suprachoroidal space in any of our cases. The 23-G active ports and vitrectomy cutter enhanced safety and efficacy. Hybrid vitrectomy enabled safe surgery in these difficult cases. PMID- 28574139 TI - Visual outcomes following Descemet stripping automated endothelial keratoplasty for corneal endothelial dysfunction. AB - OBJECTIVE: To assess objective and subjective visual outcomes achieved by patients with corneal endothelial dysfunction who have undergone surgical treatment with Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: A total of 40 eyes of 36 patients with corneal endothelial dysfunction underwent DSAEK. All were followed up for 1 year. Visual acuity (VA; logMAR), mean endothelial cell density (MCD; via noncontact specular microscopy), and topography assessment were performed at baseline (preoperatively). Visual acuity and topography measurement were repeated at postoperative year 1. Subjective assessment of visual quality was evaluated using the National Eye Institute Visual Function Questionnaire (NEI-VFQ). RESULTS: Preoperative best-corrected VA (BCVA) was 1.29 +/- 0.53 logMAR with mean optical correction of -0.33 +/- 1.74 D. Postoperative BCVA, assessed after a mean of 10.8 +/- 2.1 months, showed mean line gain of 7.11 +/- 4.8 logMAR, with optical correction of +1.17 +/- 1.54 D. Mean 6-month postoperative pachymetry was 598.2 +/- 72.3 um. Three patients experienced premature graft detachment, requiring repositioning via injection of a sterile air bubble. No other adverse events were observed. Significant improvement (p<.05 for all) in general, near, and far vision, ocular pain, difficulty in carrying out daily tasks, dependency, social life, and mental health were reflected by NEI-VFQ scores at 10.4 +/- 2.1 months postoperatively versus preoperatively. No significant correlation was noted between postoperative VA line gain and NEI-VFQ-25 questionnaire score (p>0.05). CONCLUSIONS: Descemet stripping automated endothelial keratoplasty treatment may restore corneal clarity, improve VA, and increase vision-related quality of life in patients with advanced endothelial dysfunction. Further large-scale study is needed to corroborate these findings. PMID- 28574141 TI - Totally implantable venous access devices in children with medical complexity: preliminary data from a tertiary care hospital. AB - INTRODUCTION: Children with special health-care needs are an emerging and consistent population. In a subset of children with medical complexity (CMC) a continuous access to the central vascular system is advisable to eliminate unnecessary pain and stress and to improve home management and palliative care. METHODS: The surgical registry of a tertiary hospital was checked in order to identify CMC who underwent totally implantable venous access device (VAD) placement. Medical records were reviewed. RESULTS: From October 2009 to August 2014, a totally implantable VAD was placed in 10 children. Seven out of 10 patients were affected by cerebral palsy while 3 presented a genetic syndrome. The median duration of the indwelling catheter was 31 months (range 5 to 77 months). Six catheters are still in place since the first placement. Infectious complications were observed in two patients, respectively, a Candida albicans and a Staphylococcus aureus colonization; in both cases the VAD was removed. In another two cases, removal was planned for reservoir dislodgment within the subcutaneous tissue. No other major complications were observed during the procedure and the follow-up period. Emergency admissions decreased from a median value of 0.4/month (range 0-1.5/month) to 0.2/month (range 0-0.6/month) after the VAD placement. CONCLUSIONS: A totally implanted VAD in CMC is safe and manageable. As expected, infection seems to be the major complication with no infection-related death. Malnutrition and musculoskeletal deformities, which are frequent comorbidities in CMC, should be considered to reduce the risk of dislodgment/migration. PMID- 28574142 TI - Ultrasound Vector Flow Imaging - could be a new tool in evaluation of arteriovenous fistulas for hemodialysis? AB - INTRODUCTION: We report the use of a new ultrasound technique to evaluate the axial and lateral components of a complex flow in the arteriovenous fistula (AVF). Vector Flow Imaging (VFI) allows to identify different components of the flow in every direction, even orthogonal to the flow streamline, represented by many single vectors. VFI could help to identify flow alterations in AVF, probably responsible for its malfunction. METHODS: From February to June 2016, 14 consecutive patients with upper-limb AVF were examined with a Resona 7 (Mindray, Shenzhen, China) ultrasound scanner equipped with VFI. An analysis of mean velocity, angular direction and mean number of vectors impacting the vessel wall was carried out. We also identified main flow patterns present in the arterial side, into the venous aneurysm and in correspondence of significant stenosis. RESULTS: A disturbed flow with the presence of vectors directed against the vessel walls was found in 9/14 patients (64.28%): in correspondence of the iuxta anastomotic venous side (4/9; 44.4%), into the venous aneurysmal tracts (3/9; 33.3%) and in concomitance of stenosis (2/9; 22.2%). The mean velocity of the vectors was around 20-25 cm/s, except in presence of stenosis, where the velocities were much higher (45-50 cm/s). The vectors directed against the vessel walls presented high angle attack (from 45 degrees to 90 degrees , with a median angular deviation 65 degrees ). CONCLUSIONS: VFI was confirmed to be an innovative and intuitive imaging technology to study the flow complexity in the arteriovenous fistulas. PMID- 28574143 TI - Multicentre experience with ZSI 375 artificial urinary sphincter for the treatment of stress urinary incontinence in men. AB - OBJECTIVES: The aim of this study was to evaluate the safety and efficacy of the artificial urinary sphincter ZSI 375 device in male patients with stress urinary incontinence (SUI) at 10 centres. METHODS: This was a retrospective, nonrandomised, multicentre study. From January 2012 to December 2014, and follow up to February 2016, men with SUI were treated with the ZSI 375 device. The primary outcome was continence. The secondary outcome was complications rate. RESULTS: A total of 147 patients with moderate-to-severe stress incontinence and mean age of 70.67 (26-85) years underwent implantation of the ZSI 375 device at 10 centres.The most common indication for placement was incontinence after radical prostatectomy (121 patients: 82.31%). The ZSI 375 device was considered successful in 86.40% of cases after 12 months follow-up, 83.52% after 24 months follow-up and 78.26% after 36 months follow-up. The infection rate was 6.12%, urethral erosion was 12.92% and mechanical failure was limited to 3.40% leading to ZSI 375 improvement. CONCLUSIONS: This study confirmed safety and efficacy of ZSI 375 device to treat moderate-to-severe SUI in men. PMID- 28574145 TI - Human epididymis: structural pattern, total length and inner surface area. AB - INTRODUCTION: The organ epididymis is secured the name considering it functioned as an appendix to the testis; earlier testis was called as didymi. Regarding the length of human epididymis, several values are attributed by different authors. The present study was aimed to find out the pattern, total length and inner surface area of human epididymis. MATERIALS AND METHODS: The study was conducted by employing microsurgical procedures on five testes from unclaimed human dead bodies. RESULTS: Caput was formed by few tubes interconnecting at three levels. These tubes led to corpus, which in turn was having more number of tubes interconnecting at different levels. Tubules were many looking like a mesh. United tubes of corpus form the single tube to form cauda. Epididymis length was 30.48 cm. Inner surface area was 818.16 mm2. CONCLUSIONS: Reported values of others seem to be a modified version from that of animals. Authors believe that organic revolutionary changes in man led to a reduction in the length of epididymis. PMID- 28574144 TI - Robot-assisted nerve-sparing radical prostatectomy using near-infrared fluorescence technology and indocyanine green: initial experience. AB - INTRODUCTION: Indocyanine green (ICG) is a fluorescent molecule that provokes detectable photon emission. The use of ICG with near-infrared (NIR) imaging system (Akorn, Lake Forest, IL) has been described during robotic partial nephrectomy (RAPN) as an adjunctive means of identifying renal artery and parenchymal perfusion. We propose the use of the ICG with NIR fluorescence during laparoscopic robot-assisted radical prostatectomy (RARP), to identify the benchmark artery improving the preservation of neurovascular bundle and to improve the visualization of the vascularization and then the hemostasis. METHODS: From April 2015 to February 2016, 62 patients underwent to RARP in our Urology Unit. In 26 consecutive patients, in the attempt to have a better visualization of neurovascular bundles, we used to inject ICG during the procedure. We evaluated the percentage of identification of neurovascular bundles using NIR fluorescence. Then, we evaluated complications related to injection of ICG and operative time differences between RARP with and without ICG injection performed by the same surgeons. RESULTS: We identified prostatic arteries and neurovascular bundles using NIR fluorescence technology in all patients (100%). There was not any increase in the operative time compared with RARP without ICG injection performed by the same surgeons. Complications related to injection of ICG did not occurred. CONCLUSIONS: In our experience, even if on a limited number of patients, the application of ICG with NIR fluorescence during RARP is helpful to identify the benchmark artery of neurovascular bundle. PMID- 28574146 TI - Niemann-Pick type C as a cause of progressive intellectual and neurological deterioration in childhood. AB - AIM: To describe the cases of Niemann-Pick type C (NP-C) disease in a United Kingdom epidemiological study of progressive intellectual and neurological deterioration in childhood. METHOD: Paediatricians notified cases via the British Paediatric Surveillance Unit between 1997 and 2015. RESULTS: Fifty-three NP-C patients were identified: 29 females, 24 males. Fifteen cases had a systemic presentation (neonatal jaundice and/or hepatosplenomegaly). Thirty-eight had a neurological onset, the commonest presenting symptom being gait disturbance/ataxia (29 cases, 76%). Forty-nine cases eventually had neurological problems, the commonest were school/cognitive difficulties (40, 82%), seizures (33, 67%), dysphagia (20, 41%), dysarthria (18, 37%), cataplexy (17, 35%), and visual deterioration (8, 16%); their commonest abnormal physical signs were vertical supranuclear gaze palsy (35, 71%), hypotonia (19, 39%) and hepatosplenomegaly (19, 39%). The median diagnostic delay in the 38 neurological onset cases was 3 years (range 0.3-12.8). Confirmatory investigations included filipin staining of skin fibroblasts (42 cases), bone marrow examination in 30 (the last in 2011), and increasingly DNA studies, mutations in NP-C1 being found in 20 cases. INTERPRETATION: NP-C should be considered in children with progressive neurological deterioration. Subtle neurological problems combined with a history of prolonged neonatal jaundice and/or hepatosplenomegaly may provide early evidence of the disease. PMID- 28574149 TI - Measurement of UV Emission from a Diffusing Optical Fiber Using Radiochromic Film. AB - Analysis of the emission pattern from optical diffuser tips is vital to their usage in biomedical applications, especially as they find growing functionality beyond established phototherapy techniques. The use of ultraviolet radiation with diffuser tips increases the need to accurately characterize these devices, both for effective application and to avoid potentially dangerous exposure conditions. This study presents a new method to capture the diffusion pattern at a high resolution through the use of radiochromic film. The film is positioned in a cylinder around the diffuser, light is emitted from the diffuser onto the film and the film expresses a color change relative to the exposure amount. The resulting emission map shows the distribution of power from the diffuser in all direction. This method, which is both quick and inexpensive, generates high resolution data much simpler than previously published works which required precise goniometric positioning. PMID- 28574150 TI - Reporting quality of case reports in international dermatology journals. PMID- 28574148 TI - How do leaf and ecosystem measures of water-use efficiency compare? AB - The terrestrial carbon and water cycles are intimately linked: the carbon cycle is driven by photosynthesis, while the water balance is dominated by transpiration, and both fluxes are controlled by plant stomatal conductance. The ratio between these fluxes, the plant water-use efficiency (WUE), is a useful indicator of vegetation function. WUE can be estimated using several techniques, including leaf gas exchange, stable isotope discrimination, and eddy covariance. Here we compare global compilations of data for each of these three techniques. We show that patterns of variation in WUE across plant functional types (PFTs) are not consistent among the three datasets. Key discrepancies include the following: leaf-scale data indicate differences between needleleaf and broadleaf forests, but ecosystem-scale data do not; leaf-scale data indicate differences between C3 and C4 species, whereas at ecosystem scale there is a difference between C3 and C4 crops but not grasslands; and isotope-based estimates of WUE are higher than estimates based on gas exchange for most PFTs. Our study quantifies the uncertainty associated with different methods of measuring WUE, indicates potential for bias when using WUE measures to parameterize or validate models, and indicates key research directions needed to reconcile alternative measures of WUE. PMID- 28574151 TI - Prey-driven control of predator assemblages: zooplankton abundance drives aquatic beetle colonization. AB - Trophic interactions are critical determinants of community structure and ecosystem function. In freshwater habitats, top predators are traditionally viewed as drivers of ecosystem structure, shaping populations of consumers and primary producers. The temporary nature of small water bodies makes them dependent on colonization by many organisms, particularly insects that form highly diverse predator assemblages. We conducted mesocosm experiments with naturally colonizing populations of aquatic beetles to assess how prey (zooplankton) abundances influenced colonization and assemblages of natural populations of aquatic beetles. We experimentally demonstrate that zooplankton populations can be proximate regulators of predator populations and assemblages via prey-density-dependent predator recruitment. Our results provide support for the importance of prey populations in structuring predator populations and the role of habitat selection in structuring communities. We indicate that traditional views of predators as drivers of ecosystem structure in many systems may not provide a comprehensive picture, particularly in the context of highly disturbed or ephemeral habitats. PMID- 28574147 TI - The p21-activated kinase 1 (Pak1) signalling pathway in cardiac disease: from mechanistic study to therapeutic exploration. AB - : p21-activated kinase 1 (Pak1) is a member of the highly conserved family of serine/threonine protein kinases regulated by Ras-related small G-proteins, Cdc42/Rac1. It has been previously demonstrated to be involved in cardiac protection. Based on recent studies, this review provides an overview of the role of Pak1 in cardiac diseases including disrupted Ca2+ homoeostasis-related cardiac arrhythmias, adrenergic stress- and pressure overload-induced hypertrophy, and ischaemia/reperfusion injury. These findings demonstrate the important role of Pak1 mediated through the phosphorylation and transcriptional modification of hypertrophy and/or arrhythmia-related genes. This review also discusses the anti arrhythmic and anti-hypertrophic, protective function of Pak1 and the beneficial effects of fingolimod (an FDA-approved sphingolipid drug), a Pak1 activator, and its ability to prevent arrhythmias and cardiac hypertrophy. These findings also highlight the therapeutic potential of Pak1 signalling in the treatment and prevention of cardiac diseases. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. PMID- 28574152 TI - Serum insulin-like growth factor-I levels are associated with improved white matter recovery after traumatic brain injury. AB - OBJECTIVE: Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin like growth factor-I (IGF-I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF-I concentrations on WM tract and neuropsychological recovery after TBI. METHODS: Thirty-nine adults after TBI (84.6% male, median age = 30.5 years, 87.2% moderate-severe, median time since TBI = 16.3 months, n = 4 with GHD) were scanned twice, 13.3 months (range = 12.1 14.9) apart, and 35 healthy controls were scanned once. Symptom and quality of life questionnaires and cognitive assessments were completed at both visits (n = 33). Our main outcome measure was fractional anisotropy (FA), a measure of WM tract integrity, in a priori regions of interest: splenium of corpus callosum (SPCC) and posterior limb of internal capsule (PLIC). RESULTS: At baseline, FA was reduced in many WM tracts including SPCC and PLIC following TBI compared to controls, indicating axonal injury, with longitudinal increases indicating axonal recovery. There was a significantly greater increase in SPCC FA over time in patients with serum IGF-I above versus below the median for age. Only the higher IGF-I group had significant improvements in immediate verbal memory recall over time. INTERPRETATION: WM recovery and memory improvements after TBI were greater in patients with higher serum IGF-I at baseline. These findings suggest that the growth hormone/IGF-I system may be a potential therapeutic target following TBI. Ann Neurol 2017;82:30-43. PMID- 28574153 TI - Effects of dietary carbohydrate on 1,5-anhydroglucitol in a population without diabetes: results from the OmniCarb trial. AB - AIMS: To determine the effects of dietary changes in amount and type of carbohydrate on 1,5-anhydroglucitol levels. METHODS: We conducted an ancillary study to a completed, randomized clinical trial in overweight and obese adults without diabetes (N=159). Using a crossover design, participants were fed each one of four diets in turn for 5 weeks, with 2-week washout periods inbetween. The four diets were: high glycaemic index (>=65) with high proportion of carbohydrate (58% kcal) (GC); low glycaemic index (GI<=45) with low proportion of carbohydrate (40% kcal) (gc); low glycaemic index with high proportion of carbohydrate (gC); and high glycaemic index with low proportion of carbohydrate (Gc). Plasma 1,5 anhydroglucitol levels were measured at baseline and after each feeding period. RESULTS: At baseline, participants had a mean age of 53 years (53% women, 52% non Hispanic black, 50% obese). Their mean fasting glucose and 1,5-anhydroglucitol levels were 97 mg/dl (5.4 mmol/l) and 18.6 MUg/mL (113.3 MUmol/l), respectively. Compared with baseline, each of the four diets reduced 1,5-anhydroglucitol by a range of -2.4 to -3.7 MUg/mL (-14.6 to -22.5 MUmol/l); all P <0.001). Reducing either glycaemic index or proportion of carbohydrate lowered 1,5-anhydroglucitol levels. These effects were additive, such that reducing both glycaemic index and proportion of carbohydrates decreased 1,5-anhydroglucitol by -1.31 MUg/mL [95% CI: -1.63, -0.99; P<0.001 or -8.0 (-9.9, -6.0) MUmol/l]. Furthermore, these effects were confirmed in a subgroup of participants with 12-h glucose monitoring and no documented hyperglycaemia (fasting glucose <160 mg/dl or 8.9 mmol/l). CONCLUSIONS: Both type and amount of dietary carbohydrate affect 1,5 anhydroglucitol plasma concentrations in adults without diabetes. This finding contradicts the long-standing notion that 1,5-anhydroglucitol remains at constant concentrations in the blood in the absence of hyperglycaemic excursions. (Clinical trials registry number: NCT00051350). PMID- 28574154 TI - What role could community pharmacists in Malaysia play in diabetes self management education and support? The views of individuals with type 2 diabetes. AB - OBJECTIVES: This study explored the experiences and views of individuals with type 2 diabetes mellitus (T2D) on their diabetes self-management and potential roles for community pharmacists in diabetes self-management education and support (DSME/S) in Malaysia. METHODS: A qualitative study, using semi-structured, face to-face interviews, was conducted with patients with T2D attending a primary care health clinic in Kuala Lumpur, Malaysia. The interviews were audio-recorded, transcribed verbatim and analysed inductively. KEY FINDINGS: Fourteen participants with T2D were interviewed. Data were coded into five main themes: experience and perception of diabetes self-management, constraints of the current healthcare system, perception of the community pharmacist and community pharmacies, perceived roles for community pharmacists in diabetes care, and challenges in utilising community pharmacies to provide DSME/S. There were misconceptions about diabetes management that may be attributed to a lack of knowledge. Although participants described potential roles for community pharmacists in education, medication review and continuity of care, these roles were mostly non-clinically oriented. Participants were not confident about community pharmacists making recommendations and changes to the prescribed treatment regimens. While participants recognised the advantages of convenience of a community pharmacy-based diabetes care service, they raised concerns over the retail nature and the community pharmacy environment for providing such services. CONCLUSION: This study highlighted the need to improve the care provision for people with T2D. Participants with T2D identified potential, but limited roles for community pharmacists in diabetes care. Participants expressed concerns that need to be addressed if effective diabetes care is to be provided from community pharmacies in Malaysia. PMID- 28574155 TI - A systematic review of neuroimaging in delirium: predictors, correlates and consequences. AB - OBJECTIVE: Neuroimaging advances our understanding of delirium pathophysiology and its consequences. A previous systematic review identified 12 studies (total participants N = 764, delirium cases N = 194; years 1989-2007) and found associations with white matter hyperintensities (WMH) and cerebral atrophy. Our objectives were to perform an updated systematic review of neuroimaging studies in delirium published since January 2006 and summarise the available literature on predictors, correlates or outcomes. METHODS: Studies were identified by keyword and MeSH-based electronic searches of EMBASE, MEDLINE and PsycINFO combining terms for neuroimaging, brain structure and delirium. We included neuroimaging studies of delirium in adults using validated delirium assessment methods. RESULTS: Thirty-two studies (total N = 3187, delirium N = 1086) met the inclusion criteria. Imaging included magnetic resonance imaging (MRI; N = 9), computed tomography (N = 4), diffusion tensor imaging (N = 3), transcranial Doppler (N = 5), near infrared spectroscopy (N = 5), functional-MRI (N = 2), single photon emission computed tomography (N = 1), proton MRI spectroscopy (N = 1), arterial spin-labelling MRI (N = 1) and 2-13 fluoro-2-deoxyglucose positron emission tomography (N = 1). Despite heterogeneity in study design, delirium was associated with WMH, lower brain volume, atrophy, dysconnectivity, impaired cerebral autoregulation, reduced blood flow and cerebral oxygenation and glucose hypometabolism. There was evidence of long-term brain changes following intensive care unit delirium. CONCLUSIONS: Neuroimaging is now used more widely in delirium research due to advances in technology. However, imaging delirious patients presents challenges leading to methodological limitations and restricted generalisability. The findings that atrophy and WMH burden predict delirium replicates findings from the original review, while advanced techniques have identified other substrates and mechanisms that warrant further investigation. PMID- 28574157 TI - Diffuse myocardial fibrosis among healthy pediatric heart transplant recipients: Correlation of histology, cardiovascular magnetic resonance, and clinical phenotype. AB - Fibrosis is commonly described in heart allografts lost late after transplantation. CMR-derived ECV is a validated measure of DMF in native adult hearts that may predict heart failure and mortality. We explored associations of ECV with histologic myocardial fibrosis and clinical features after pediatric heart transplantation. Twenty-five recipients (7.0+/-6.3 years at transplant and 10.7+/-6.5 years post-transplant) were prospectively recruited for CMR and BNP measurement at the time of surveillance biopsy. All had normal ejection fractions and lacked heart failure symptoms. Fibrosis was quantified on biopsy after picrosirius red staining as CVF. ECV was quantified using contemporaneous hematocrit on basal and mid-short-axis slices. ECV was moderately correlated with CVF (r=.47; P=.019). We found no associations of ECV with hemodynamics, ischemic time, time since transplantation, or number of prior biopsies or acute rejections. Compared to healthy non-transplant controls, there was no significant difference in ECV (25.1+/-3.0 vs 23.7+/-2.0%, P=.09). Log-transformed BNP was correlated with ECV (recipients: r=.46, P=.02; recipients and controls: r=.45, P=.006). These findings suggest ECV quantifies DMF and relates to biological indicators of cardiac function after pediatric heart transplantation. PMID- 28574156 TI - Prediction of lithium response in first-episode mania using the LITHium Intelligent Agent (LITHIA): Pilot data and proof-of-concept. AB - OBJECTIVES: Individualized treatment for bipolar disorder based on neuroimaging treatment targets remains elusive. To address this shortcoming, we developed a linguistic machine learning system based on a cascading genetic fuzzy tree (GFT) design called the LITHium Intelligent Agent (LITHIA). Using multiple objectively defined functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1 H-MRS) inputs, we tested whether LITHIA could accurately predict the lithium response in participants with first-episode bipolar mania. METHODS: We identified 20 subjects with first-episode bipolar mania who received an adequate trial of lithium over 8 weeks and both fMRI and 1 H-MRS scans at baseline pre-treatment. We trained LITHIA using 18 1 H-MRS and 90 fMRI inputs over four training runs to classify treatment response and predict symptom reductions. Each training run contained a randomly selected 80% of the total sample and was followed by a 20% validation run. Over a different randomly selected distribution of the sample, we then compared LITHIA to eight common classification methods. RESULTS: LITHIA demonstrated nearly perfect classification accuracy and was able to predict post-treatment symptom reductions at 8 weeks with at least 88% accuracy in training and 80% accuracy in validation. Moreover, LITHIA exceeded the predictive capacity of the eight comparator methods and showed little tendency towards overfitting. CONCLUSIONS: The results provided proof-of-concept that a novel GFT is capable of providing control to a multidimensional bioinformatics problem-namely, prediction of the lithium response-in a pilot data set. Future work on this, and similar machine learning systems, could help assign psychiatric treatments more efficiently, thereby optimizing outcomes and limiting unnecessary treatment. PMID- 28574158 TI - Efficacy and safety of a new microneedle patch for skin brightening: A Randomized, split-face, single-blind study. AB - BACKGROUND: Although microneedles are one of the best transdermal drug delivery systems for active compounds, few clinical trials have examined the safety and efficacy of brightening microneedle patches. AIMS: To determine the efficacy and safety of a newly developed whitening microneedle patch. PATIENTS/METHODS: A split-face study was designed for efficacy assessment with 34 Korean women applying the tested product (a whitening microneedle patch) on one cheek and a control whitening essence on the other. We objectively measured changes in melanin index values and skin brightness by mexameter and chromameter. Each participant also used global assessment to determine skin whitening. In addition, 55 participants were selected for primary skin irritation tests and repeated insult patch tests for safety assessments. RESULTS: Mean skin brightness and melanin indexes improved (P<.05) 4 weeks and 8 weeks after product use in both the whitening patch and whitening essence groups. Significant differences (P<.05) were observed between the whitening patch and whitening essence groups 8 weeks after use. Global assessment by participants showed moderate cosmetic outcomes for both the whitening patch and whitening essence groups. No adverse effects were reported, and primary irritation and human repeated insult patch tests revealed no irritation from the test product. CONCLUSIONS: A newly developed microneedle patch was effective and safe for skin brightening and would be a promising functional cosmetic product. PMID- 28574159 TI - Bladder spasm following urogenital fistula repair. AB - OBJECTIVE: To examine the occurrence of bladder spasms following surgical repair of urogenital fistula. METHODS: The present retrospective study included data from patients who underwent surgical repair of urogenital fistula at the National Obstetric Fistula Centre, Abakaliki, Nigeria, between June 1, 2015, and May 31, 2016. Patients who underwent rectovaginal fistula repair and those who experienced persistent postoperative pain requiring high doses of analgesia were excluded. Bladder spasm was defined as the sudden onset of intermittent pain in the region of the bladder lasting for short periods of time in patients who were previously comfortable with routine postoperative analgesia. The incidence of bladder spasm was calculated and the presence of an association between repair outcome and bladder spasms was investigated. RESULTS: There were 133 patients included in the present study with a mean age of 36 +/- 11 years. Bladder spasms were experienced by 60 (45.1%) patients during the study period; of these patients, failed fistula repair was recorded for 13 (22%). Good surgical outcome (closed fistula) was associated with not experiencing postsurgical bladder spasms (P=0.044). CONCLUSION: The incidence of bladder spasm following surgical repair of urogenital fistula appeared high. The occurrence of bladder spasms could influence repair outcomes. PMID- 28574160 TI - Poly(oligo(ethylene glycol) vinyl acetate)s: A Versatile Class of Thermoresponsive and Biocompatible Polymers. AB - Polymers with a thermally triggered phase transition are important in the design of materials for biological applications, where their behavior can be used to trigger release or (dis)assembly events. Despite their advantages, a system with tunable thermal response, end-group reactive sites, low toxicity, and controlled main-chain degradability has not been realized, yet this would be a significant advance. The versatile new poly(oligo(ethylene glycol) vinyl acetate)s are presented with excellent control over their molecular properties obtained through RAFT/MADIX polymerization. Furthermore, we demonstrate structure-controlled thermal transitions, conjugation to human lysozyme through the retained end group, and moreover show that this class of polymers can uniquely be copolymerized with 2-methylene-1,3-dioxepane (MDO) to generate polymers in which the degradability and cloud point can be independently tuned to create materials that display the same cloud point but degrade differently. PMID- 28574161 TI - OsIDD2, a zinc finger and INDETERMINATE DOMAIN protein, regulates secondary cell wall formation. AB - Previously, we found 123 transcription factors (TFs) as candidate regulators of secondary cell wall (SCW) formation in rice by using phylogenetic and co expression network analyses. Among them, we examined in this work the role of OsIDD2, a zinc finger and indeterminate domain (IDD) family TF. Its overexpressors showed dwarfism, fragile leaves, and decreased lignin content, which are typical phenotypes of plants defective in SCW formation, whereas its knockout plants showed slightly increased lignin content. The RNA-seq and quantitative reverse transcription polymerase chain reaction analyses confirmed that some lignin biosynthetic genes were downregulated in the OsIDD2 overexpressing plants, and revealed the same case for other genes involved in cellulose synthesis and sucrose metabolism. The transient expression assay using rice protoplasts revealed that OsIDD2 negatively regulates the transcription of genes involved in lignin biosynthesis, cinnamyl alcohol dehydrogenase 2 and 3 (CAD2 and 3), and sucrose metabolism, sucrose synthase 5 (SUS5), whereas an AlphaScreen assay, which can detect the interaction between TFs and their target DNA sequences, directly confirmed the interaction between OsIDD2 and the target sequences located in the promoter regions of CAD2 and CAD3. Based on these observations, we conclude that OsIDD2 is negatively involved in SCW formation and other biological events by downregulating its target genes. PMID- 28574162 TI - Real-world resource use and costs of haemophilia A-related bleeding. AB - INTRODUCTION: Prophylaxis treatment is recommended for haemophilia patients, but associated real-world economic costs and potential cost-savings associated with improved disease management are not fully known. This study aimed to assess haemophilia A-related resource use and cost by treatment type (prophylaxis versus non-prophylaxis) and any associated cost-savings. METHODS: Truven MarketScan Commercial claims data (2004-2012) were used to identify haemophilia A-related healthcare utilization, healthcare costs and patterns of prophylaxis and non prophylaxis treatment among 6- to 64-year-old males. We estimated bleeding related resource utilization and costs in three age groups (6-18, 19-44, 45-64) by treatment types and assessed the extent to which early initiation of prophylactic treatment can mitigate them. T-tests and ordinary least squares regressions were used to compare unadjusted and demographics-adjusted cost estimates. RESULTS: Among children, overall haemophilia- and bleeding-related non pharmacy costs were substantially lower for patients receiving prophylaxis (haemophilia-related: $15,864 vs. $53,408; P < 0.001; bleeding-related: $696 vs. $2013, respectively; P = 0.04). Among younger adults (19-44), haemophilia-related non-pharmacy costs were lower for patients receiving prophylaxis ($22,028 vs. $56,311, respectively; P = 0.001). Among children, these savings fully offset the incremental pharmacy cost due to prophylaxis. Among younger adults, the savings offset approximately 34% of the incremental pharmacy cost. No differences were found for older adults (45-64). CONCLUSION: These results suggest that initiating prophylaxis earlier in life may reduce the healthcare costs of bleeding events and their long-term complications. Future studies should strive to collect more detailed information on disease severity and treatment protocols to improve estimates of disease burden. PMID- 28574163 TI - Heavy metal ATPase 3 (HMA3) confers cadmium hypertolerance on the cadmium/zinc hyperaccumulator Sedum plumbizincicola. AB - Cadmium (Cd) is highly toxic to most organisms, but some rare plant species can hyperaccumulate Cd in aboveground tissues without suffering from toxicity. The mechanism underlying Cd detoxification by hyperaccumulators is interesting but unclear. Here, the heavy metal ATPase 3 (SpHMA3) gene responsible for Cd detoxification was isolated from the Cd/zinc (Zn) hyperaccumulator Sedum plumbizincicola. RNA interference (RNAi)-mediated silencing and overexpression of SpHMA3 were induced to investigate its physiological functions in S. plumbizincicola and a nonhyperaccumulating ecotype of Sedum alfredii. Heterologous expression of SpHMA3 in Saccharomyces cerevisiae showed Cd-specific transport activity. SpHMA3 was highly expressed in the shoots and the protein was localized to the tonoplast. The SpHMA3-RNAi lines were hypersensitive to Cd but not to Zn, with the growth of shoots and young leaves being severely inhibited by Cd. Overexpressing SpHMA3 in the nonhyperaccumulating ecotype of S. alfredii greatly increased its tolerance to and accumulation of Cd, but not Zn. These results indicate that elevated expression of the tonoplast-localized SpHMA3 in the shoots plays an essential role in Cd detoxification, which contributes to the maintenance of the normal growth of young leaves of S. plumbizincicola in Cd contaminated soils. PMID- 28574164 TI - Limited and digestive proteolysis: crosstalk between evolutionary conserved pathways. AB - Contents 958 I. 958 II. 959 III. 960 IV. 962 V. 962 962 References 963 SUMMARY: Proteases can either digest target proteins or perform the so-called 'limited proteolysis' by cleaving polypeptide chains at specific site(s). Autophagy and the ubiquitin-proteasome system (UPS) are two main mechanisms carrying out digestive proteolysis. While the net outcome of digestive proteolysis is the loss of function of protein substrates, limited proteolysis can additionally lead to gain or switch of function. Recent evidence of crosstalk between autophagy, UPS and limited proteolysis indicates that these pathways are parts of the same proteolytic nexus. Here, we focus on three emerging themes within this area: limited proteolysis as a mechanism modulating autophagy; interplay between autophagy and UPS, including autophagic degradation of proteasomes (proteophagy); and specificity of protein degradation during bulk autophagy. PMID- 28574165 TI - Synergistic chemo-enzymatic hydrolysis of poly(ethylene terephthalate) from textile waste. AB - Due to the rising global environment protection awareness, recycling strategies that comply with the circular economy principles are needed. Polyesters are among the most used materials in the textile industry; therefore, achieving a complete poly(ethylene terephthalate) (PET) hydrolysis in an environmentally friendly way is a current challenge. In this work, a chemo-enzymatic treatment was developed to recover the PET building blocks, namely terephthalic acid (TA) and ethylene glycol. To monitor the monomer and oligomer content in solid samples, a Fourier transformed Raman method was successfully developed. A shift of the free carboxylic groups (1632 cm-1 ) of TA into the deprotonated state (1604 and 1398 cm-1 ) was observed and bands at 1728 and 1398 cm-1 were used to assess purity of TA after the chemo-enzymatic PET hydrolysis. The chemical treatment, performed under neutral conditions (T = 250 degrees C, P = 40 bar), led to conversion of PET into 85% TA and small oligomers. The latter were hydrolysed in a second step using the Humicola insolens cutinase (HiC) yielding 97% pure TA, therefore comparable with the commercial synthesis-grade TA (98%). PMID- 28574166 TI - Intra- and inter-day reproducibility of low-flow mediated constriction response in young adults. AB - PURPOSE: When assessing brachial endothelial function by reactive hyperaemia, stopping blood flow creates a period of low-flow-mediated constriction (L-FMC). As little is known about how this parameter influences flow-mediated vasodilation (FMD), the purpose of this study was to better understand this relationship and to determine the intra- and interday reproducibility of brachial L-FMC. METHODS: Brachial L-FMC and FMD were measured on 26 healthy, young adults (13 males, 13 females; 24.6 +/- 2.7 years). Each participant had two assessments conducted on two separate visits, separated by a minimum of seven days. Brachial artery baseline diameter was imaged during rest. Continuous imaging of the artery was performed during the last 20 s of cuff-occlusion to 180 s postcuff release. An L FMC was considered present if the relative change from pre-occlusion baseline to L-FMC artery diameter was less than -0.1%. RESULTS: Overall, there was a strong, positive correlation between increased brachial L-FMC and blunted FMD (visit 1 test 1: r = 0.758, P<0.001; visit 1 test 2: r = 0.706, P<0.001; visit 2 test 1: r = 0.836, P<0.001; visit 2 test 2: r = 0.857, P<0.001). The reproducibility of intra- and interday L-FMC diameter was intraclass correlation coefficients (ICC) = 0.627, coefficient of variation (CV) = 54.4% and ICC = 0.734, CV = 43.5%, respectively. CONCLUSION: Vasoconstriction to low-flow conditions influences the subsequent maximal dilation during reactive hyperaemia. However, L-FMC is variable as evidenced by the weak intra- and interday reproducibility of the measure. Further research should study brachial L-FMC reproducibility among varying populations and the implications L-FMC has on the interpretation of FMD results. PMID- 28574167 TI - Predicting the prevalence of cerebral palsy by severity level in children aged 3 to 15 years across England and Wales by 2020. AB - AIM: To estimate the number of children living with cerebral palsy (CP) in England and Wales in 2013 by severity, and to extrapolate this figure to 2020. METHOD: Data from the North of England Collaborative Cerebral Palsy Survey for births during the period 1991 to 2000 were restricted to individuals aged at or above 3 years to estimate the prevalence of CP and to calculate 15-year survival by severity according to the number of severe impairments and lifestyle assessment score. The number of 3- to 15-year-olds with CP of different severity in England and Wales was estimated in 2013 and 2019 using actual and nationally projected births. RESULTS: Cumulative survival estimates up to the age of 16 years in children with CP differ significantly by severity, ranging between 97 per cent and 100 per cent for children with non-severe CP, and between 64 per cent and 67 per cent for those with the most severe CP. By the end of 2013, the estimated number of children aged 3 to 15 years living with CP in England and Wales will be about 20 500 rising to approximately 22 100 by 2020, a 7.5 per cent increase. INTERPRETATION: Owing to an increasing population, the number of children living with CP in England and Wales will increase by 2020. This will have significant implications for health and social care service planning. PMID- 28574168 TI - Mesoporous Silica Scaffolds as Precursor to Drive the Formation of Hierarchical SAPO-34 with Tunable Acid Properties. AB - Using a distinctive bottom-up approach, a hierarchical silicoaluminophosphate, SAPO-34, has been synthesized using cetyl trimethylammonium bromide (CTAB) encapsulated within ordered mesoporous silica (MCM-41) that serves as both the silicon source and mesoporogen. The structural and textural properties of the hierarchical SAPO-34 were contrasted against its microporous analogue, and the nature, strength, and accessibility of the Bronsted acid sites were studied using a range of physicochemical characterization tools; notably probe-based FTIR and solid-state magic angle spinning (SS MAS) NMR spectroscopies. Whilst CO was used to study the acid properties of hierarchical SAPO-34, bulkier molecular probes (including pyridine, 2,4,6-trimethylpyridine and 2,6-di-tert-butylpyridine) allowed particular insight into the enhanced accessibility of the acid sites. The activity of the hierarchical SAPO-34 catalyst was evaluated in the industrially relevant, acid-catalyzed Beckmann rearrangement of cyclohexanone oxime to epsilon caprolactam, under vapor-phase conditions. These catalytic investigations revealed a significant enhancement in the yield of epsilon-caprolactam using our hierarchical SAPO-34 catalyst compared to SAPO-34, MCM-41, or a mechanical mixture of these two phases. The results highlight the merits of our design strategy for facilitating enhanced mass transfer, whilst retaining favorable acid site characteristics. PMID- 28574169 TI - Dynamic Nuclear Polarization/Solid-State NMR Spectroscopy of Membrane Polypeptides: Free-Radical Optimization for Matrix-Free Lipid Bilayer Samples. AB - Dynamic nuclear polarization (DNP) boosts the sensitivity of NMR spectroscopy by orders of magnitude and makes investigations previously out of scope possible. For magic-angle-spinning (MAS) solid-state NMR spectroscopy studies, the samples are typically mixed with biradicals dissolved in a glass-forming solvent and are investigated at cryotemperatures. Herein, we present new biradical polarizing agents developed for matrix-free samples such as supported lipid bilayers, which are systems widely used for the investigation of membrane polypeptides of high biomedical importance. A series of 11 biradicals with different structures, geometries, and physicochemical properties were comprehensively tested for DNP performance in lipid bilayers, some of them developed specifically for DNP investigations of membranes. The membrane-anchored biradicals PyPol-C16, AMUPOL cholesterol, and bTurea-C16 were found to exhibit improved g-tensor alignment, inter-radical distance, and dispersion. Consequently, these biradicals show the highest signal enhancement factors so far obtained for matrix-free membranes or other matrix-free samples and may potentially shorten NMR acquisition times by three orders of magnitude. Furthermore, the optimal biradical-to-lipid ratio, sample deuteration, and membrane lipid composition were determined under static and MAS conditions. To rationalize biradical performance better, DNP enhancement was measured by using the 13 C and 15 N signals of lipids and a peptide as a function of the biradical concentration, DNP build-up time, resonance line width, quenching effect, microwave power, and MAS frequency. PMID- 28574170 TI - Rumination in breast and lung cancer patients: Preliminary data within an Italian sample. PMID- 28574172 TI - Prevention of hip displacement in children with cerebral palsy: a systematic review. AB - AIM: To conduct a systematic review and evaluate the quality of evidence for interventions to prevent hip displacement in children with cerebral palsy (CP). METHOD: A systematic review was performed using American Academy of Cerebral Palsy and Developmental Medicine (AACPDM) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. Searches were completed in seven electronic databases. Studies were included if participants had CP and the effectiveness of the intervention was reported using a radiological measure. Results of orthopaedic surgical interventions were excluded. RESULTS: Twenty-four studies fulfilled the inclusion criteria (4 botulinum neurotoxin A; 2 botulinum neurotoxin A and bracing; 1 complementary and alternative medicine; 1 intrathecal baclofen; 1 obturator nerve block; 8 positioning; 7 selective dorsal rhizotomy). There was significant variability in treatment dosages, participant characteristics, and duration of follow-up among the studies. Overall, the level of evidence was low. No intervention in this review demonstrated a large treatment effect on hip displacement. INTERPRETATION: The level and quality of evidence for all interventions aimed at slowing or preventing hip displacement is low. There is currently insufficient evidence to support or refute the use of the identified interventions to prevent hip displacement or dislocation in children and young people with CP. WHAT THIS PAPER ADDS: High-quality evidence on prevention of hip displacement is lacking. No recommendations can be made for preventing hip displacement in children with cerebral palsy because of poor-quality evidence. High-quality, prospective, longitudinal studies investigating the impact of interventions on hip displacement are required. PMID- 28574173 TI - Interaction between toothpaste abrasivity and toothbrush filament stiffness on the development of erosive/abrasive lesions in vitro. AB - OBJECTIVES: To investigate the loss of enamel and dentin surface caused by the interaction between abrasives in toothpaste and toothbrush filament stiffness. METHODS: The study followed a 2 (high-level or low-level abrasive; silica) * 3 (filament stiffness; soft, medium or hard) * 2 (cycling time; 3 or 5 days) factorial design. Polished bovine enamel and dentin specimens (n = 8 each per group) were subjected to 5 days of erosion/abrasion cycling: erosion (5 minutes, four times daily, 0.3% citric acid, pH 3.75); abrasion (15 seconds, twice daily, 45 strokes each, 150 g load, automated brushing machine); and fluoride treatment [15 seconds with abrasion and 45 seconds without abrasion; 275 p.p.m. fluoride (F ) as sodium fluoride (NaF) in abrasive slurry]. Enamel and dentin specimens were exposed to artificial saliva between erosion and abrasion/F- treatment (1 hour) and at all other times (overnight). Non-contact profilometry was used to determine surface loss (SL) after 3 and 5 days of cycling. Data were analysed using three-way analysis of variance (ANOVA) (factors: abrasive/filament stiffness/time), with separate analyses conducted for enamel and dentin. RESULTS: For enamel, only 'cycling time' was found to affect SL, with 5 days of cycling resulting in a greater SL than 3 days of cycling. Overall, there was little SL for enamel (range: 0.76-1.85 MUm). For dentin (SL range: 1.87-5.91 MUm), significantly higher SL was found for 5 days of cycling versus 3 days of cycling, with particularly large differences for hard stiffness/high-level abrasive and medium stiffness/low-level abrasive. For high-level abrasive, after 5 days of cycling hard stiffness resulted in significantly higher SL than did medium stiffness, with no other significant differences according to stiffness. Overall, high-level abrasive resulted in significantly higher SL than did low-level abrasive, with strong effects for all combinations, except medium stiffness after 5 days. CONCLUSION: The interplay between abrasivity and filament stiffness appears to be more relevant for dentin than for enamel. PMID- 28574174 TI - The evolution of vertebrate eye size across an environmental gradient: phenotype does not predict genotype in a Trinidadian killifish. AB - Vertebrates exhibit substantial variation in eye size. Eye size correlates positively with visual capacity and behaviors that enhance fitness, such as predator avoidance. This foreshadows a connection between predation and eye size evolution. Yet, the conditions that favor evolutionary shifts in eye size, besides the well-known role for light availability, are unclear. We tested the influence of predation on the evolution of eye size in Trinidadian killifish, Rivulus hartii. Rivulus are located across a series of communities where they coexist with visually oriented piscivores ("high predation" sites), and no predators ("Rivulus-only" sites). Wild-caught Rivulus from high predation sites generally exhibited a smaller relative eye size than communities that lack predators. Yet, such differences were inconsistent across rivers. Second generation common garden reared fish revealed repeatable decreases in eye size in Rivulus from high predation sites. We performed additional experiments that tested the importance of light and resources on eye size evolution. Sites that differ in light or resource availability did not differ in eye size. Our results argue that differences in predator-induced mortality underlie genetically-based shifts in vertebrate eye size. We discuss the drivers of eye size evolution in light of the nonparallel trends between the phenotypic and common garden results. PMID- 28574171 TI - Rationale for targeting the Wnt signalling modulator Dickkopf-1 for oncology. AB - : Wnt signalling is a fundamental pathway involved in embryonic development and adult tissue homeostasis. Mutations in the pathway frequently lead to developmental defects and cancer. As such, therapeutic intervention of this pathway has generated tremendous interest. Dickkopf-1 (DKK1) is a secreted inhibitor of beta-catenin-dependent Wnt signalling and was originally characterized as a tumour suppressor based on the prevailing view that Wnt signalling promotes cancer pathogenesis. However, DKK1 appears to increase tumour growth and metastasis in preclinical models and its elevated expression correlates with a poor prognosis in a range of cancers, indicating that DKK1 has more complex cellular and biological functions than originally appreciated. Here, we review current evidence for the cancer-promoting activity of DKK1 and recent insights into the effects of DKK1 on signalling pathways in both cancer and immune cells. We discuss the rationale and promise of targeting DKK1 for oncology. LINKED ARTICLES: This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc. PMID- 28574176 TI - A Photosensitizer Lanthanide Nanoparticle Formulation that Induces Singlet Oxygen with Direct Light Excitation, But Not By Photon or X-ray Energy Transfer. AB - We report the design and synthesis of europium-doped gadolinium oxysulfide nanoscintillators Gd2 O2 S:Eu3+ conjugated with two different photosensitizers (PSs): a zinc chlorin (ZnTPC) and a zinc phtalocyanine (ZnPc) by covalent bonding through a layer of N-(3-trimethoxysilylpropyl)diethylenetriamine (TPDA). These conjugates were designed to be activated under X-ray excitation to allow a photodynamic effect, although this desired outcome was not achieved in this study. The monodispersed nanoparticles of ~70 nm diameter were pegylated to be stabilized in aqueous suspension. It was shown that the PSs conserved their photophysical properties once conjugated to the nanoscintillator and efficient singlet oxygen was obtained upon photo-irradiation. However, no energy transfer was observed from the nanoscintillator to the photosensitizer neither under photo nor X-ray irradiation. PMID- 28574175 TI - Mitochondrially derived peptides as novel regulators of metabolism. AB - Mitochondrially derived peptides represent a new class of circulating signalling molecules. Humanin, the first member of this class, has been shown to have several metabolic effects such as reducing weight gain and visceral fat and increasing glucose-stimulated insulin release. The discovery of several other new members, such as MOTS-c and SHLP1-6, has further added to this group. These new peptides have also been found to affect metabolism with MOTS-c potently decreasing weight gain in mice on a high-fat diet. This review covers the basic biology of this class of peptides and discusses the relevance to organismal metabolism. PMID- 28574178 TI - Fungi: geoactive agents of metal and mineral transformations. PMID- 28574177 TI - Review of basal-plus insulin regimen options for simpler insulin intensification in people with Type 2 diabetes mellitus. AB - AIMS: To identify simple insulin regimens for people with Type 2 diabetes mellitus that can be accepted and implemented earlier in primary and specialist care, taking into consideration each individual's needs and capabilities. METHODS: Using randomized clinical trials identified by a search of the PubMed database, as well as systematic reviews, meta-analyses and proof-of-concept studies, this review addresses topics of interest related to the progressive intensification of a basal insulin regimen to a basal-plus regimen (one basal insulin injection plus stepwise addition of one to three preprandial short-acting insulin injections/day) vs a basal-bolus regimen (basal insulin plus three short acting insulin injections per day) in people with Type 2 diabetes. The review explores approaches that can be used to define the meal for first prandial injection with basal-plus regimens, differences among insulin titration algorithms, and the importance of self-motivation and autonomy in achieving optimum glycaemic control. RESULTS: A basal-plus regimen can provide glycaemic control equivalent to that obtained with a full basal-bolus regimen, with fewer injections of prandial insulin. The first critical step is to optimize basal insulin dosing to reach a fasting glucose concentration of ~6.7 mmol/l; this allows ~40% of patients with baseline HbA1c >75 mmol/mol (9%) to be controlled with only one basal insulin injection per day. CONCLUSIONS: Compared with a basal bolus regimen, a basal-plus insulin regimen is as effective but more practical, and has the best chance of acceptance and success in the real world. PMID- 28574179 TI - Episodic replacement of clotting factor concentrates does not prevent bleeding or musculoskeletal damage - the MUSFIH study. AB - PATIENTS AND METHODS: A longitudinal study was carried out in 255 children from 10 centres in nine developing countries over 5 years to assess the musculoskeletal outcome of children on episodic factor replacement. Outcome was documented by assessment of the annual joint bleeding rate (AJBR), WFH clinical and Pettersson radiological joint scores as well as the FISH score for activities. Of the 203 patients for whom data was available at the end of 5 years, 164 who had received only episodic treatment are included in this report. RESULTS: The median age at the beginning of the study was 10 years (IQR 7-12). The median clotting factor concentrate (CFC) usage was 662 IU kg-1 year-1 (IQ range: 280-1437). The median AJBR was 10 (IQ range: 5-17). The median AJBR was higher in the older children with the median being 5 for the 5 year old child, while it was 9 for the 10 year old and 11 for children older than 15. Given the episodic nature of the replacement therapy, those with a higher AJBR used significantly greater annual CFC doses (P < 0.001); The median change in WFH clinical score and Pettersson radiological score over the 5 years was 0.4/year for each, while the FISH deteriorated at a rate of 0.2/year with poor correlation of these changes with CFC dose. WFH and FISH scores were significantly worse in those with an AJBR of >3 per year (P = 0.001). The change in the Pettersson score was significantly more in those with an AJBR of >5 per year (P = 0.020). Significant changes in FISH scores were only noted after 10 years of age. CONCLUSION: Episodic CFC replacement over a large range of doses does not alter the natural course of bleeding in haemophilia or the musculoskeletal deterioration and should not be recommended as a long term option for treatment. Prophylaxis is the only way to preserve musculoskeletal function in haemophilia. PMID- 28574180 TI - Topical equol preparation improves structural and molecular skin parameters. AB - OBJECTIVE: Equol has been shown to improve skin health and regeneration, due to its antioxidative, phytoestrogenic and epigenetic characteristics. The effects of a topical intervention on skin structure, telomere length and epigenetic markers in skin cells were analysed. METHODS: Sixty-four participants were divided in four groups and three of them treated topically with the following: emulsion with Equol powder (Isoflavandiol-E-55-RS(r)); emulsion with microencapsulated Equol (Vesisorb(r) Isoflavandiol-E-55-RS(r)) and an emulsion with lecithin (Vesisorb(r) placebo). A control group of 6 volunteers did not receive any intervention. The active compound was a 0.5% equol-racemate. For 58 participants, all samples were collected. Structural analysis, molecular analysis and questionnaires were performed at the start of the study and after 8 weeks of intervention, twice a day. Structural skin parameters were analysed by Visioscan(r) VC 98 and Cutometer(r) dual MPA 580. Molecular analyses from epidermal cells collected by skin stripping of the forehead included telomere length and LINE-1 methylation, following DNA extraction, bisulfite conversion and qPCR as well as high resolution melting curve analysis. Effects of nutrition and lifestyle habits were evaluated with a standardized food and lifestyle questionnaire. RESULTS AND DISCUSSION: The surface analysis showed significant improvements in skin roughness, skin texture and skin smoothness after both interventions. Cutometer(r) dual MPA 580 measurement revealed improvement of skin firmness and elasticity parameters for both preparations. A decrease in mean LINE-1 methylation (n.s.) and telomere length (sign. P < 0.05) was observed in the sample group with age. In the treated groups, significantly longer telomeres were observed after intervention. Whether changes in telomere length reflect changes in the regulation of telomerase, epigenetic interactions or turnover of keratinocytes needs further research. Stability and availability of preparations in skin seems to be high as not many significant differences in the activity of pure or encapsulated substances were seen. CONCLUSION: The results of this study indicate that equol has beneficial effects on structural as well as molecular skin parameters and encourages further investigations to decipher the epigenetic regulation of skin ageing and interactions of equol. PMID- 28574181 TI - Increased pericarp cell length underlies a major quantitative trait locus for grain weight in hexaploid wheat. AB - Crop yields must increase to address food insecurity. Grain weight, determined by grain length and width, is an important yield component, but our understanding of the underlying genes and mechanisms is limited. We used genetic mapping and near isogenic lines (NILs) to identify, validate and fine-map a major quantitative trait locus (QTL) on wheat chromosome 5A associated with grain weight. Detailed phenotypic characterisation of developing and mature grains from the NILs was performed. We identified a stable and robust QTL associated with a 6.9% increase in grain weight. The positive interval leads to 4.0% longer grains, with differences first visible 12 d after fertilization. This grain length effect was fine-mapped to a 4.3 cM interval. The locus also has a pleiotropic effect on grain width (1.5%) during late grain development that determines the relative magnitude of the grain weight increase. Positive NILs have increased maternal pericarp cell length, an effect which is independent of absolute grain length. These results provide direct genetic evidence that pericarp cell length affects final grain size and weight in polyploid wheat. We propose that combining genes that control distinct biological mechanisms, such as cell expansion and proliferation, will enhance crop yields. PMID- 28574182 TI - Optimizing the combination insulin bolus split for a high-fat, high-protein meal in children and adolescents using insulin pump therapy. AB - AIMS: To determine the optimum combination bolus split to maintain postprandial glycaemia with a high-fat and high-protein meal in young people with Type 1 diabetes. METHODS: A total of 19 young people (mean age 12.9 +/- 6.7 years) participated in a randomized, repeated-measures trial comparing postprandial glycaemic control across six study conditions after a high-fat and high-protein meal. A standard bolus and five different combination boluses were delivered over 2 h in the following splits: 70/30 = 70% standard /30% extended bolus; 60/40=60% standard/40% extended bolus; 50/50=50% standard/50% extended bolus; 40/60=40% standard/60% extended bolus; and 30/70=30% standard/70% extended bolus. Insulin dose was determined using the participant's optimized insulin:carbohydrate ratio. Continuous glucose monitoring was used to assess glucose excursions for 6 h after the test meal. RESULTS: Standard bolus and combination boluses 70/30 and 60/40 controlled the glucose excursion up to 120 min. From 240 to 300 min after the meal, the glucose area under the curve was significantly lower for combination bolus 30/70 compared with standard bolus (P=0.004). CONCLUSIONS: High-fat and high-protein meals require a >=60% insulin:carbohydrate ratio as a standard bolus to control the initial postprandial rise. Additional insulin at an insulin:carbohydrate ratio of up to 70% is needed in the extended bolus for a high fat and protein meal to prevent delayed hyperglycaemia. PMID- 28574183 TI - Quantitative tools for implementing the new definition of significant portion of the range in the U.S. Endangered Species Act. AB - In 2014, the Fish and Wildlife Service (FWS) and National Marine Fisheries Service announced a new policy interpretation for the U.S. Endangered Species Act (ESA). According to the act, a species must be listed as threatened or endangered if it is determined to be threatened or endangered in a significant portion of its range (SPR). The 2014 policy seeks to provide consistency by establishing that a portion of the range should be considered significant if the associated individuals' "removal would cause the entire species to become endangered or threatened." We reviewed 20 quantitative techniques used to assess whether a portion of a species' range is significant according to the new guidance. Our assessments are based on the 3R criteria-redundancy (i.e., buffering from catastrophe), resiliency (i.e., ability to withstand stochasticity), and representation (i.e., ability to evolve)-that the FWS uses to determine if a species merits listing. We identified data needs for each quantitative technique and considered which methods could be implemented given the data limitations typical of rare species. We also identified proxies for the 3Rs that may be used with limited data. To assess potential data availability, we evaluated 7 example species by accessing data in their species status assessments, which document all the information used during a listing decision. In all species, an SPR could be evaluated with at least one metric for each of the 3Rs robustly or with substantial assumptions. Resiliency assessments appeared most constrained by limited data, and many species lacked information on connectivity between subpopulations, genetic variation, and spatial variability in vital rates. These data gaps will likely make SPR assessments for species with complex life histories or that cross national boundaries difficult. Although we reviewed techniques for the ESA, other countries require identification of significant areas and could benefit from this research. PMID- 28574184 TI - Land-use history as a guide for forest conservation and management. AB - Conservation efforts to protect forested landscapes are challenged by climate projections that suggest substantial restructuring of vegetation and disturbance regimes in the future. In this regard, paleoecological records that describe ecosystem responses to past variations in climate, fire, and human activity offer critical information for assessing present landscape conditions and future landscape vulnerability. We illustrate this point drawing on 8 sites in the northwestern United States, New Zealand, Patagonia, and central and southern Europe that have undergone different levels of climate and land-use change. These sites fall along a gradient of landscape conditions that range from nearly pristine (i.e., vegetation and disturbance shaped primarily by past climate and biophysical constraints) to highly altered (i.e., landscapes that have been intensely modified by past human activity). Position on this gradient has implications for understanding the role of natural and anthropogenic disturbance in shaping ecosystem dynamics and assessments of present biodiversity, including recognizing missing or overrepresented species. Dramatic vegetation reorganization occurred at all study sites as a result of postglacial climate variations. In nearly pristine landscapes, such as those in Yellowstone National Park, climate has remained the primary driver of ecosystem change up to the present day. In Europe, natural vegetation-climate-fire linkages were broken 6000 8000 years ago with the onset of Neolithic farming, and in New Zealand, natural linkages were first lost about 700 years ago with arrival of the Maori people. In the U.S. Northwest and Patagonia, the greatest landscape alteration occurred in the last 150 years with Euro-American settlement. Paleoecology is sometimes the best and only tool for evaluating the degree of landscape alteration and the extent to which landscapes retain natural components. Information on landscape level history thus helps assess current ecological change, clarify management objectives, and define conservation strategies that seek to protect both natural and cultural elements. PMID- 28574185 TI - Potential of Nonfullerene Small Molecules with High Photovoltaic Performance. AB - Over the past decades, fullerene derivatives have become the most successful electron acceptors in organic solar cells (OSCs) and have achieved great progress, with power conversion efficiencies (PCEs) of over 11 %. However, fullerenes have some drawbacks, such as weak absorption, limited energy-level tunability, and morphological instability. In addition, fullerene-based OSCs usually suffer from large energy losses of over 0.7 eV, which limits further improvements in the PCE. Recently, nonfullerene small molecules have emerged as promising electron acceptors in OSCs. Their highly tunable absorption spectra and molecular energy levels have enabled fine optimization of the resulting devices, and the highest PCE has surpassed 12 %. Furthermore, several studies have shown that OSCs based on small-molecule acceptors (SMA) have very efficient charge generation and transport efficiency at relatively low energy losses of below 0.6 eV, which suggests great potential for the further improvement of OSCs. In this focus review, we analyze the challenges and potential of SMA-based OSCs and discuss molecular design strategies for highly efficient SMAs. PMID- 28574186 TI - Oligosaccharide Sensing in Aqueous Media by Porphyrin-Curdlan Conjugates: A Pret a-Porter Rather Than Haute-Couture Approach. AB - Saccharide sensing in aqueous media is an intriguing but challenging goal in current chemistry. Herein we report the oligosaccharide-sensing behavior of newly synthesized porphyrin-curdlan conjugates, which are random coils in DMSO but become globules in aqueous solutions to induce circular dichroism (ICD) in the biologically accessible spectral region due to the conformational fixation of porphyrin reporters. The magnitude of ICD was significantly varied specifically in the presence of acarbose, a drug for type-2 diabetes, enabling us to detect the aminosaccharide at concentrations down to 200 MUm. This result demonstrates that the pret-a-porter approach, using less-defined reporter-curdlan conjugates, is more advantageous than the traditional haute-couture approach with highly sophisticated hosts in particular in oligosaccharide sensing. PMID- 28574187 TI - Menopause transition promotes distinct modulation of mRNAs and miRNAs expression in calvaria and bone marrow osteoblastic cells. AB - Investigation on functional genome research may contribute to the knowledge of functional roles of different mRNAs and miRNAs in bone cells of osteoporotic animals. Currently, few studies indicate the changes in gene modulation that osteoporosis causes in osteoblastic cells from different sites. Thus, the purpose of this investigation was to evaluate cell viability, alkaline phosphatase activity and modulation of mRNAs/miRNAs in osteoblastic cells from calvaria and bone marrow by means of microarray technology. Wistar female rats were divided in sham operated and ovariectomized groups. After 150 days of ovariectomy, cells were isolated from both sites to perform cell culture. Results showed that calvaria cells from ovariectomized rats had a decrease in viability when compared to control groups and to bone marrow cells from osteoporotic rats after 3 days. Alkaline phosphatase activity decreased in calvaria cells from ovariectomized rats whereas it was increased in bone marrow osteoblastic cells in the same group. Microarray data analysis showed 5447 differentially expressed mRNAs and 82 differentially expressed miRNAs in calvaria cells. The same way, 4399 mRNAs and 54 miRNAs were expressed in bone marrow cells. mRNAs associated with bone metabolism such as Anxa5, Sp7, Spp1, Notch1 were distinctively modulated in both sites, as well as miRNAs such as miR-350, miR-542-3p, miR-204-5p, and miR-30e-3p. The RNA species identified in this study could be further used as targets for treatment or prevention of osteoporosis. PMID- 28574188 TI - Hospital-acquired anemia due to diagnostic and therapy-related blood loss in inpatients with myasthenia gravis receiving therapeutic plasma exchange. AB - INTRODUCTION: Daily laboratory testing (DLT) is an important cause of iatrogenic anemia. Therapeutic plasma exchanges (TPE) represent another source of blood loss. This study investigated the contributions of DLT and TPE to changes in hemoglobin of inpatients with myasthenia gravis (MG) exacerbation. STUDY DESIGN AND METHODS: All admissions for MG that included TPE between 2008 and 2012 were identified. The DLT- and TPE-related blood losses per patient were estimated based on the number of laboratory tests and TPE procedures. The primary endpoint was the difference between the discharge hemoglobin (Hgb) and the admission Hgb (DeltaHgb). Univariate and multivariable analyses were used to identify clinical predictors of DeltaHgb. RESULTS: A total of 46 patients (52% male, average age of 58 years) had 90 hospitalizations and underwent 424 TPEs during the study-period. Their average length of stay (LOS) was 10.4 days, and total DLT and TPE-related blood losses were 107 and 94 mL, respectively. While 41% of patients were anemic on admission, 90% were anemic at discharge. The average DeltaHgb was -2.2 g/dL. The patient's blood volume, renal function, admission number, LOS, and combined blood losses correlated with DeltaHgb by linear regression, but only DLT was an independent predictor of DeltaHgb in the multivariable analysis. CONCLUSION: Approximately 50% of MG patients admitted for TPE developed hospital-acquired anemia, which was directly correlated with the volume of blood collected for laboratory tests. A variety of strategies to reduce DLT could circumvent this iatrogenic complication. PMID- 28574189 TI - Twenty-year progression of body mass index in a county-wide cohort of people with schizophrenia and bipolar disorder identified at their first episode of psychosis. AB - OBJECTIVE: There is an increased prevalence of obesity in schizophrenia and bipolar disorder, leading to a disproportionate risk of adverse health conditions. Prospective, long-term weight gain data, however, are scarce. METHODS: We analyzed data from the Suffolk County Mental Health Project cohort of consecutive first admissions with psychosis recruited from September 1989 to December 1995 and subsequently followed for 20 years, focusing on people with schizophrenia (n=146) and bipolar disorder (n=87). The time course of weight gain was examined using a 2 (group)*5 (time) mixed-model repeated measures ANOVA, and body mass index (BMI) scores at the first (6 months) and second (2 years) assessments were compared to examine whether early overweight predicted later obesity. RESULTS: There was a statistically significant effect of time (F(1,210)=68.06, P<.001) and diagnosis (F(1,210)=29.18, P<.001) on BMI, but not the interaction of time*diagnosis (F(1,210)=0.88, P=.48). Most participants had normal BMIs at the first two assessments. Early overweight was a predictor of eventual obesity for both groups. At the 20-year follow-ups, approximately 50% of the bipolar and 62% of the schizophrenia sample were obese, with a greater prevalence of obesity in schizophrenia at each assessment (all P<.02), except for years 4 (P=.12) and 20 (P=.27). CONCLUSIONS: Nearly two-thirds of the participants with schizophrenia and over half of those with bipolar disorder were obese 20 years after first hospitalization for psychosis, considerably higher than the rate for adults in New York State (27%). Early intervention may be required to prevent long-term consequences of obesity-related morbidity and mortality. PMID- 28574191 TI - Point of care ultrasound in haemophilia: Building a strong foundation for clinical implementation. PMID- 28574190 TI - Flow-aligned, single-shot fiber diffraction using a femtosecond X-ray free electron laser. AB - A major goal for X-ray free-electron laser (XFEL) based science is to elucidate structures of biological molecules without the need for crystals. Filament systems may provide some of the first single macromolecular structures elucidated by XFEL radiation, since they contain one-dimensional translational symmetry and thereby occupy the diffraction intensity region between the extremes of crystals and single molecules. Here, we demonstrate flow alignment of as few as 100 filaments (Escherichia coli pili, F-actin, and amyloid fibrils), which when intersected by femtosecond X-ray pulses result in diffraction patterns similar to those obtained from classical fiber diffraction studies. We also determine that F actin can be flow-aligned to a disorientation of approximately 5 degrees. Using this XFEL-based technique, we determine that gelsolin amyloids are comprised of stacked beta-strands running perpendicular to the filament axis, and that a range of order from fibrillar to crystalline is discernable for individual alpha synuclein amyloids. PMID- 28574192 TI - Feasibility study of ultrasound imaging for stereotactic body radiation therapy with active breathing coordinator in pancreatic cancer. AB - PURPOSE: Stereotactic body radiation therapy (SBRT) allows for high radiation doses to be delivered to the pancreatic tumors with limited toxicity. Nevertheless, the respiratory motion of the pancreas introduces major uncertainty during SBRT. Ultrasound imaging is a non-ionizing, non-invasive, and real-time technique for intrafraction monitoring. A configuration is not available to place the ultrasound probe during pancreas SBRT for monitoring. METHODS AND MATERIALS: An arm-bridge system was designed and built. A CT scan of the bridge-held ultrasound probe was acquired and fused to ten previously treated pancreatic SBRT patient CTs as virtual simulation CTs. Both step-and-shoot intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) planning were performed on virtual simulation CT. The accuracy of our tracking algorithm was evaluated by programmed motion phantom with simulated breath-hold 3D movement. An IRB-approved volunteer study was also performed to evaluate feasibility of system setup. Three healthy subjects underwent the same patient setup required for pancreas SBRT with active breath control (ABC). 4D ultrasound images were acquired for monitoring. Ten breath-hold cycles were monitored for both phantom and volunteers. For the phantom study, the target motion tracked by ultrasound was compared with motion tracked by the infrared camera. For the volunteer study, the reproducibility of ABC breath-hold was assessed. RESULTS: The volunteer study results showed that the arm-bridge system allows placement of an ultrasound probe. The ultrasound monitoring showed less than 2 mm reproducibility of ABC breath-hold in healthy volunteers. The phantom monitoring accuracy is 0.14 +/- 0.08 mm, 0.04 +/- 0.1 mm, and 0.25 +/- 0.09 mm in three directions. On dosimetry part, 100% of virtual simulation plans passed protocol criteria. CONCLUSIONS: Our ultrasound system can be potentially used for real time monitoring during pancreas SBRT without compromising planning quality. The phantom study showed high monitoring accuracy of the system, and the volunteer study showed feasibility of the clinical workflow. PMID- 28574193 TI - Emergency department visits for dental problems not associated with trauma in Alberta, Canada. AB - OBJECTIVES: The objective of this report was to describe the frequency of emergency department (ED) visits for dental problems not associated with trauma (DPNAT) in Alberta, Canada, over a 5-year period. METHODS: In Alberta, ED visits for DPNAT between 1 January 2011 and 30 April 2016 were identified using the codes from the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Canada (ICD-10-CA). The codes for DPNAT range from K00 to K14, described as diseases of the oral cavity, salivary glands and jaws. The data were gathered from the National Ambulatory Care Reporting System (NACRS) database and from the Alberta Real Time Syndromic Surveillance Net (ARTSSN). The information gathered on ED visits for DPNAT was related to the primary diagnosis of the discharge disposition of the visits. RESULTS: During the study period, there were a total of 147,357 ED visits for DPNAT in Alberta. The visits were made by 111,362 individuals, representing 1.3 visits per person. Among all ED visits, a prevalence of 1.2% of ED visits for DPNAT was observed. The most prevalent primary diagnosis of ED visits for DPNAT was for diseases of pulp and periapical tissues (K04), such as periapical abscess, representing 45.0% of all visits, followed by disorders of teeth and supporting structures (K08), such as toothache, representing 18.8% of all visits. The majority of the visits were made by patients from 20 to 44 years of age (52.2%). North and Calgary Alberta Health Service (AHS) Zones were those with the highest occurrence of ED visits (31.9% and 24.5%, respectively). ED visits for dental problems were more common than visits for other general health conditions, such as diabetes and asthma. CONCLUSION: The frequency of ED visits for DPNAT suggests barriers faced by the population in accessing dental care resources, especially for urgent dental needs. Policy efforts and political will are needed to provide alternative options for seeking emergency dental care. PMID- 28574194 TI - The big and intricate dreams of little organelles: Embracing complexity in the study of membrane traffic. AB - Compartmentalization of eukaryotic cells into dynamic organelles that exchange material through regulated membrane traffic governs virtually every aspect of cellular physiology including signal transduction, metabolism and transcription. Much has been revealed about the molecular mechanisms that control organelle dynamics and membrane traffic and how these processes are regulated by metabolic, physical and chemical cues. From this emerges the understanding of the integration of specific organellar phenomena within complex, multiscale and nonlinear regulatory networks. In this review, we discuss systematic approaches that revealed remarkable insight into the complexity of these phenomena, including the use of proximity-based proteomics, high-throughput imaging, transcriptomics and computational modeling. We discuss how these methods offer insights to further understand molecular versatility and organelle heterogeneity, phenomena that allow a single organelle population to serve a range of physiological functions. We also detail on how transcriptional circuits drive organelle adaptation, such that organelles may shift their function to better serve distinct differentiation and stress conditions. Thus, organelle dynamics and membrane traffic are functionally heterogeneous and adaptable processes that coordinate with higher-order system behavior to optimize cell function under a range of contexts. Obtaining a comprehensive understanding of organellar phenomena will increasingly require combined use of reductionist and system-based approaches. PMID- 28574195 TI - Pharmacoepidemiology of tacrolimus in pediatric liver transplantation. AB - AEs during immunosuppressive treatment with tacrolimus are very common. We retrospectively evaluated FK safety and efficacy in a large pediatric liver transplant cohort in Latin America. During 2-year follow-up, we analyzed data from patients who underwent liver transplantation over the period 2010-2012 and recorded FK exposure, AEs, and AR episodes. AEs were classified according causality and severity. Tacrolimus exposure before and during AE was compared using Wilcoxon matched-pairs test. Kaplan-Meier curves were used for survival analysis. In total, 46 patients (out of 72 patients) experienced 69 AEs, such as hypomagnesemia (49%), PTLD (6%), hypertension (6%), and/or nephrotoxicity (22%). 43% of AEs were classified as moderate or serious, and 89% were assigned as probable or definitive. Patients who had one or more AR episodes accounted for 65%. The 12-month acute rejection-free survival was 41% (95% CI, 30.1%-53.1%). A significant difference was observed in FK trough concentrations before and during hypomagnesemia and nephrotoxicity (P<.05). This study is the first report of FK safety in a large group of pediatric liver transplant patients in Latin America. Children experience AEs, even in protocols with low FK doses. Therapeutic monitoring is an important tool to manage immunosuppressive schemes containing tacrolimus in vulnerable populations. PMID- 28574196 TI - Wet and Functional Adhesives from One-Step Aqueous Self-Assembly of Natural Amino Acids and Polyoxometalates. AB - Sessile organisms have undergone long-term evolution to develop the unique ability by positioning themselves on wet solid surface through secreting adhesive proteins. The present study reveals that natural amino acid monomers can also exhibit similar adhesion capacity. This kind of biomimetic adhesives were created by the one-step aqueous assembly of basic amino acids with assistance of anionic polyoxometalates. The polyoxometalates not only serve as multivalent scaffold to initiate the supramolecular cross-linking of amino acid molecules, but also function as a redox component, bestowing the wet adhesives with electrochromic features. PMID- 28574197 TI - Cross-sectional study of the microbiological safety profile of reusing hyaluronic acid fillers. AB - INTRODUCTION: Facial filling with hyaluronic acid (HA) is a dermatological procedure that has been emerging today. There are not many references regarding safety of reusing the remaining product for later touch-up in the same patient. OBJECTIVE: To determine the microbiological safety of reusing hyaluronic acid that is remnant from syringes used for facial filling, stored at room temperature or cooled in a refrigerator at 4 degrees C. MATERIALS AND METHODS: In culture medium, small aliquots of leftovers from 31 hyaluronic acid fillers, previously used for facial filling, were inoculated. The fillers were stored in their original syringes at room temperature or cooled in a standard refrigerator at 4 degrees C for a period ranging from 1 week to 12 months after initial use. LIMITATIONS: The small number of samples limits extrapolation of the results obtained. RESULTS: After 42 days of inoculation in culture medium, none of the samples showed any aerobic or anaerobic bacterial or fungal growth. CONCLUSION: Hyaluronic acid fillers did not show any fungal or bacterial contamination after being opened and stored at room temperature in nonaseptic conditions. The possibility of reusing the remaining portion of the material in the syringe can be safe and economically viable. PMID- 28574198 TI - Reversible Photothermal Isomerization of Carborane-Fused Azaborole to Borirane: Synthesis and Reactivity of Carbene-Stabilized Carborane-Fused Borirane. AB - A fully reversible photothermal isomerization between carborane-fused trigonal planar azaborole (dark-purple) and tetrahedral borirane (pale-yellow) has been observed, leading to the isolation and structural characterization of the first example of carborane-fused borirane. DFT calculations indicate that the azaborole is thermodynamically more stable than the borirane by 11.2 kcal mol-1 , and the energy barrier for the thermal conversion from azaborole to borirane is 35.5 kcal mol-1 . The reactivity studies show that the B-C(cage) bond in borirane can be broken in the reaction with CuCl, HCl, or elemental sulfur. PMID- 28574199 TI - Allocation of organs to cognitively impaired patients. PMID- 28574201 TI - Standardized high-sensitivity flow cytometry testing for paroxysmal nocturnal hemoglobinuria in children with acquired bone marrow failure disorders: A single center US study. AB - BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematopoietic stem cell disorder that has not been well-documented in children, particularly those with acquired bone marrow failure disorders (ABMFD)-acquired aplastic anemia (AAA) and myelodysplastic syndrome (MDS). Therefore, we sought to determine the prevalence of PNH populations in children with ABMFD. METHODS: PNH testing was performed in children with an ABMFD diagnosis using high sensitivity (>=0.01%) fluorescent aerolysin (FLAER)-based assay according to 2010 International Clinical Cytometry Society (ICCS) PNH Consensus Guidelines and 2012 Practical PNH Guidelines. FLAER/CD64/CD15/CD24/CD14/CD45 and CD235a/CD59 panels were used for white blood cell and red blood cell testing, respectively. RESULTS: Thirty-seven patients with ABMFD (34 AAA, 3 MDS) were included (17M/20F, age 2-18 years, median 9 years). PNH populations were identified in 17 of 37 (46%) patients. Of the 17 patients with PNH populations identified, 7 were PNH clones (>1% PNH population), and 10 had minor PNH population or rare cells with PNH phenotype (<=1% PNH population). CONCLUSIONS: This is the first study to use a standardized high-sensitivity FLAER-based flow cytometry assay and the recommended cutoff of 0.01% to identify cells with PNH phenotype in pediatric patients with ABMFD in the United States. The identification of a PNH population in 46% of ABMFD supports the recommendation for high sensitivity PNH testing in children with these disorders. As a less sensitive assay using a cutoff of >= 1% PNH population would have missed 10 (27%) patients with minor PNH population or rare cells with PNH phenotype. (c) 2017 International Clinical Cytometry Society. PMID- 28574200 TI - Conversion of cis-2-carboxycyclohexylacetyl-CoA in the downstream pathway of anaerobic naphthalene degradation. AB - The cyclohexane derivative cis-2-(carboxymethyl)cyclohexane-1-carboxylic acid [(1R,2R)-/(1S,2S)-2-(carboxymethyl)cyclohexane-1-carboxylic acid] has previously been identified as metabolite in the pathway of anaerobic degradation of naphthalene by sulfate-reducing bacteria. We tested the corresponding CoA esters of isomers and analogues of this compound for conversion in cell free extracts of the anaerobic naphthalene degraders Desulfobacterium strain N47 and Deltaproteobacterium strain NaphS2. Conversion was only observed for the cis isomer, verifying that this is a true intermediate and not a dead-end product. Mass-spectrometric analyses confirmed that conversion is performed by an acyl-CoA dehydrogenase and a subsequent hydratase yielding an intermediate with a tertiary hydroxyl-group. We propose that a novel kind of ring-opening lyase is involved in the further catabolic pathway proceeding via pimeloyl-CoA. In contrast to degradation pathways of monocyclic aromatic compounds where ring-cleavage is achieved via hydratases, this lyase might represent a new ring-opening strategy for the degradation of polycyclic compounds. Conversion of the potential downstream metabolites pimeloyl-CoA and glutaryl-CoA was proved in cell free extracts, yielding 2,3-dehydropimeloyl-CoA, 3-hydroxypimeloyl-CoA, 3-oxopimeloyl CoA, glutaconyl-CoA, crotonyl-CoA, 3-hydroxybutyryl-CoA and acetyl-CoA as observable intermediates. This indicates a link to central metabolism via beta oxidation, a non-decarboxylating glutaryl-CoA dehydrogenase and a subsequent glutaconyl-CoA decarboxylase. PMID- 28574202 TI - Adaptive power priors with empirical Bayes for clinical trials. AB - Incorporating historical information into the design and analysis of a new clinical trial has been the subject of much discussion as a way to increase the feasibility of trials in situations where patients are difficult to recruit. The best method to include this data is not yet clear, especially in the case when few historical studies are available. This paper looks at the power prior technique afresh in a binomial setting and examines some previously unexamined properties, such as Box P values, bias, and coverage. Additionally, it proposes an empirical Bayes-type approach to estimating the prior weight parameter by marginal likelihood. This estimate has advantages over previously criticised methods in that it varies commensurably with differences in the historical and current data and can choose weights near 1 when the data are similar enough. Fully Bayesian approaches are also considered. An analysis of the operating characteristics shows that the adaptive methods work well and that the various approaches have different strengths and weaknesses. PMID- 28574203 TI - Microbial network, phylogenetic diversity and community membership in the active layer across a permafrost thaw gradient. AB - Biogenic production and release of methane (CH4 ) from thawing permafrost has the potential to be a strong source of radiative forcing. We investigated changes in the active layer microbial community of three sites representative of distinct permafrost thaw stages at a palsa mire in northern Sweden. The palsa site (intact permafrost and low radiative forcing signature) had a phylogenetically clustered community dominated by Acidobacteria and Proteobacteria. The bog (thawing permafrost and low radiative forcing signature) had lower alpha diversity and midrange phylogenetic clustering, characteristic of ecosystem disturbance affecting habitat filtering. Hydrogenotrophic methanogens and Acidobacteria dominated the bog shifting from palsa-like to fen-like at the waterline. The fen (no underlying permafrost, high radiative forcing signature) had the highest alpha, beta and phylogenetic diversity, was dominated by Proteobacteria and Euryarchaeota and was significantly enriched in methanogens. The Mire microbial network was modular with module cores consisting of clusters of Acidobacteria, Euryarchaeota or Xanthomonodales. Loss of underlying permafrost with associated hydrological shifts correlated to changes in microbial composition, alpha, beta and phylogenetic diversity associated with a higher radiative forcing signature. These results support the complex role of microbial interactions in mediating carbon budget changes and climate feedback in response to climate forcing. PMID- 28574204 TI - Rational clinical evaluation of suspected acute coronary syndromes: The value of more information. AB - OBJECTIVE: Many meta-analyses have provided synthesised likelihood ratio data to aid clinical decision-making. However, much less has been published on how to safely combine clinical information in practice. We aimed to explore the benefits and risks of pooling clinical information during the ED assessment of suspected acute coronary syndrome. METHODS: Clinical information on 1776 patients was collected within a randomised trial conducted across five South Australian EDs between July 2011 and March 2013. Bayes theorem was used to calculate patient specific post-test probabilities using age- and gender-specific pre-test probabilities and likelihood ratios corresponding to the presence or absence of 18 clinical factors. Model performance was assessed as the presence of adverse cardiac outcomes among patients theoretically discharged at a post-test probability less than 1%. RESULTS: Bayes theorem-based models containing high sensitivity troponin T (hs-troponin) outperformed models excluding hs-troponin, as well as models utilising TIMI and GRACE scores. In models containing hs troponin, a plateau in improving discharge safety was observed after the inclusion of four clinical factors. Models with fewer clinical factors better approximated the true event rate, tended to be safer and resulted in a smaller standard deviation in post-test probability estimates. CONCLUSIONS: We showed that there is a definable point where additional information becomes uninformative and may actually lead to less certainty. This evidence supports the concept that clinical decision-making in the assessment of suspected acute coronary syndrome should be focused on obtaining the least amount of information that provides the highest benefit for informing the decisions of admission or discharge. PMID- 28574206 TI - Genome-wide-analyses of Listeria monocytogenes from food-processing plants reveal clonal diversity and date the emergence of persisting sequence types. AB - Whole genome sequencing is increasing used in epidemiology, e.g. for tracing outbreaks of food-borne diseases. This requires in-depth understanding of pathogen emergence, persistence and genomic diversity along the food production chain including in food processing plants. We sequenced the genomes of 80 isolates of Listeria monocytogenes sampled from Danish food processing plants over a time-period of 20 years, and analysed the sequences together with 10 public available reference genomes to advance our understanding of interplant and intraplant genomic diversity of L. monocytogenes. Except for three persisting sequence types (ST) based on Multi Locus Sequence Typing being ST7, ST8 and ST121, long-term persistence of clonal groups was limited, and new clones were introduced continuously, potentially from raw materials. No particular gene could be linked to the persistence phenotype. Using time-based phylogenetic analyses of the persistent STs, we estimate the L. monocytogenes evolutionary rate to be 0.18 0.35 single nucleotide polymorphisms/year, suggesting that the persistent STs emerged approximately 100 years ago, which correlates with the onset of industrialization and globalization of the food market. PMID- 28574205 TI - First-line immune tolerance induction for children with severe haemophilia A: A protocol from the UK Haemophilia Centre Doctors' Organisation Inhibitor and Paediatric Working Parties. PMID- 28574207 TI - Human DNA helicase, RuvBL1 and its Chlamydomonas homologue, CrRuvBL1 plays an important role in ciliogenesis. AB - Several nuclear and nucleic acid-binding proteins were detected in the proteomic analyses of ciliary fractions from various organisms. Yet very little is known about the role of these proteins in ciliogenesis and ciliary signaling. In an attempt to characterize the role of these nuclear proteins, we identified a hypothetical protein from Chlamydomonas reinhardtii, CrRuvBL1, which is homologous to human DNA helicase, HsRuvBL1. CrRuvBL1 localizes to flagella and nucleus in vegetative Chlamydomonas cells. It accumulates in the nucleus specifically during initial stages of flagellar assembly and cell division indicating its role in these processes. Mammalian counterpart of this protein, HsRuvBL1, was found to be present at the basal bodies and in the primary cilium of quiescent Retinal Pigment Epithelial (RPE1) cells. In interphase cells, HsRuvBL1 is present at centrioles while the protein localizes on spindle fibers, spindle poles and midbodies, which are important structures formed during different phases of cell division. Depletion of HsRuvBL1 by using siRNAs leads to complete loss of primary cilia in RPE1 cells. Together these results suggest that nuclear proteins play an important role in ciliogenesis. PMID- 28574208 TI - Acute concomitant esotropia in children. PMID- 28574209 TI - von Willebrand disease and extra-intestinal angiodysplasia. PMID- 28574210 TI - Using the regulation of accuracy to study performance when the correct answer is not known. AB - We examined memory performance in multiple-choice questions when correct answers were not always present. How do participants answer when they are aware that the correct alternative may not be present? To answer this question we allowed participants to decide on the number of alternatives in their final answer (the plurality option), and whether they wanted to report or withhold their answer (report option). We also studied the memory benefits when both the plurality and the report options were available. In two experiments participants watched a crime and then answered questions with five alternatives. Half of the questions were presented with the correct alternative and half were not. Participants selected one alternative and rated confidence, then selected three alternatives and again rated confidence, and finally indicated whether they preferred the answer with one or with three alternatives (plurality option). Lastly, they decided whether to report or withhold the answer (report option). Results showed that participants' confidence in their selections was higher, that they chose more single answers, and that they preferred to report more often when the correct alternative was presented. We also attempted to classify a posteriori questions as either presented with or without the correct alternative from participants' selection. Classification was better than chance, and encouraging, but the forensic application of the classification technique is still limited since there was a large percentage of responses that were incorrectly classified. Our results also showed that the memory benefits of both plurality and report options overlap. PMID- 28574211 TI - Comparison of the recommendations of the AAPM TG-51 and TG-51 addendum reference dosimetry protocols. AB - This work quantified differences between recommendations of the TG-51 and TG-51 addendum reference dosimetry protocols. Reference dosimetry was performed for flattened photon beams with nominal energies of 6, 10, 15, and 23 MV, as well as flattening-filter free (FFF) beam energies of 6 and 10 MV, following the recommendations of both the TG-51 and TG-51 addendum protocols using both a Farmer(r) ionization chamber and a scanning ionization chamber with calibration coefficients traceable to absorbed dose-to-water (Dw ) standards. Differences in Dw determined by the two protocols were 0.1%-0.3% for beam energies with a flattening filter, and up to 0.2% and 0.8% for FFF beams measured with the scanning and Farmer(r) ionization chambers, respectively, due to kQ determination, volume-averaging correction, and collimator jaw setting. Combined uncertainty was between 0.91% and 1.2% (k = 1), varying by protocol and detector. PMID- 28574212 TI - Calculation algorithms alter the breath-by-breath gas exchange values when abrupt changes in ventilation occur. AB - The automatic metabolic units calculate breath-by-breath gas exchange from the expiratory data only, applying an algorithm ('expiration-only' algorithm) that neglects the changes in the lung gas stores. These last are theoretically taken into account by a recently proposed algorithm, based on an alternative view of the respiratory cycle ('alternative respiratory cycle' algorithm). The performance of the two algorithms was investigated where changes in the lung gas stores were induced by abrupt increases in ventilation above the physiological demand. Oxygen, carbon dioxide fractions and ventilatory flow were recorded at the mouth in 15 healthy subjects during quiet breathing and during 20-s hyperventilation manoeuvres performed at 5-min intervals in resting conditions. Oxygen uptakes and carbon dioxide exhalations were calculated throughout the acquisition periods by the two algorithms. Average ventilation amounted to 6.1 +/ 1.4 l min-1 during quiet breathing and increased to 41.8 +/- 27.2 l min-1 during the manoeuvres (P<0.01). During quiet breathing, the two algorithms provided overlapping gas exchange data and noise. Conversely, during hyperventilation, the 'alternative respiratory cycle' algorithm provided significantly lower gas exchange data as compared to the values yielded by the 'expiration-only' algorithm. For the first breath of hyperventilation, the average values provided by the two algorithms amounted to 0.37 +/- 0.34 l min-1 versus 0.96 +/- 0.73 l min-1 for O2 uptake and 0.45 +/- 0.36 l min-1 versus 0.80 +/- 0.58 l min-1 for exhaled CO2 (P<0.001 for both). When abrupt increases in ventilation occurred, such as those arising from a deep breath, the 'alternative respiratory cycle' algorithm was able to halve the artefactual gas exchange values as compared to the 'expiration-only' approach. PMID- 28574214 TI - Exocrine secretion spelled with a capital K+ (BK). PMID- 28574213 TI - Comparison of cardiac output estimates by bioreactance and inert gas rebreathing methods during cardiopulmonary exercise testing. AB - PURPOSE: This study assessed the agreement between cardiac output estimated by inert gas rebreathing and bioreactance methods at rest and during exercise. METHODS: Haemodynamic measurements were assessed in 20 healthy individuals (11 females, nine males; aged 32 +/- 10 years) using inert gas rebreathing and bioreactance methods. Gas exchange and haemodynamic data were measured simultaneously under rest and different stages (i.e. 30, 60, 90, 120, 150 and 180 W) of progressive graded cardiopulmonary exercise stress testing using a bicycle ergometer. RESULTS: At rest, bioreactance produced significantly higher cardiac output values than inert gas rebreathing (7.8 +/- 1.4 versus 6.5 +/- 1.7 l min-1 , P = 0.01). At low-to-moderate exercise intensities (i.e. 30-90 W), bioreactance produced significantly higher cardiac outputs compared with rebreathing method (P<0.05). At workloads of 120 W and above, there was no significant difference in cardiac outputs between the two methods (P = 0.10). There was a strong relationship between the two methods (r = 0.82, P = 0.01). Bland-Altman analysis including rest and exercise data showed that inert gas rebreathing reported 1.95 l min-1 lower cardiac output than bioreactance, with lower and upper limits of agreement of -3.1-7.07 l min-1 . Analysis of peak exercise data showed a mean difference of 0.4 l min-1 (lower and upper limits of agreement of -4.9-5.7 l min 1 ) between both devices. CONCLUSION: Bioreactance and inert gas rebreathing methods show acceptable levels of agreement for estimating cardiac output at higher levels of metabolic demand. However, they cannot be used interchangeably due to strong disparity in results at rest and low-to-moderate exercise intensity. PMID- 28574215 TI - Haemophilia care in Europe - A survey of 37 countries. AB - INTRODUCTION: The European Haemophilia Consortium (EHC) is an international non profit organization representing 45 national patients' organizations in Europe. Every 3 years, the EHC circulates a survey to its national member organizations to assess the state of haemophilia care. AIM: The purpose of this exercise is to ascertain information about the organization of haemophilia care and treatment availability at national levels. Furthermore, the survey provides a basis from which the EHC are able to monitor the unmet need and stability of care/treatment access in the individual member countries. PATIENTS AND METHODS: Surveys are distributed to EHC member organizations in English and Russian. Patient organizations are encouraged to share the survey with local clinicians to ensure accuracy of responses. The data collected are in part consistent to provide a longitudinal overview for treatment access, but topical items are included such as ageing. Subsequently, completed surveys are transposed into a database for analysis and reporting. RESULTS: Thirty-seven responses were received from the 45 countries approached, representing an 82% response rate from members. Findings suggest increased access to treatment and some improvement in certain areas of care. However, access to treatment has declined or remained largely unchanged in some countries. CONCLUSION: The survey has been a successful exercise in enabling a greater understanding of the current Haemophilia care landscape across Europe. However, there remain unmet needs in various aspects of patient care, and specific examples include psychosocial care and general preparedness for an ageing haemophilia population. PMID- 28574216 TI - Imaging of haemophilic arthropathy in growing joints: pitfalls in ultrasound and MRI. AB - The purpose of this review was to summarize the current knowledge on the utilization of magnetic resonance imaging (MRI) and ultrasound (US) for assessing arthropathy in children and adolescents with haemophilia and to recognize the limitations of each imaging modality and pitfalls in the diagnosis of soft tissue and osteochondral abnormalities. Awareness of MRI and US limitations and pitfalls in the assessment of joints in persons with haemophilia is essential for accurate diagnosis and optimal management of haemophilic arthropathy. PMID- 28574217 TI - Primary ridge augmentation with collagenated xenogenic block bone substitute in combination with collagen membrane and rhBMP-2: a pilot histological investigation. AB - OBJECTIVE: The aim of this pilot study was to test whether a porcine collagenated bone substitute block (PCBB) and collagen membrane (CM) loaded with bone morphogenetic protein-2 (BMP-2) used for horizontal ridge augmentation differ from PCBB and CM without BMP-2 regarding the osseointegration of the grafting material and the maintenance of the ridge contour. MATERIAL AND METHODS: Two semi saddle bone defects were created in each side of the mandible of six dogs. The defects were randomly allocated to receive one of the following treatments: bone augmentation using (1) PCBB, (2) PCBB loaded with BMP-2 (PCBB-BMP2), (3) PCBB + CM and (4) PCBB + CM loaded with BMP-2 (PCBB + CM-BMP2). After 12 weeks, one titanium implant was inserted into every site. After 8 weeks, one central histological section of each site was prepared. Histomorphometrical assessments were performed evaluating the augmented area (AA), the area of new bone (NB) (primary outcome), residual bone substitute (BS) and non-mineralized tissue (NMT) within AA in mm2 . In addition, the most coronal and the most buccal localizations of new bone and residual bone substitute, and the most coronal bone to-implant contact were measured in mm. RESULTS: Clinically, all PCBB were firmly integrated and permitted implant placement. All the implants osseointegrated and exhibited complete hard-tissue coverage of the buccal surface. Bone ingrowth always reached the central portions of PCBB. AA measured 10.4 +/- 4.2 mm2 for PCBB, 11.8 +/- 2.8 mm2 for PCBB-BMP2, 9.8 +/- 2.9 mm2 for PCBB + CM and 8.5 +/- 2.2 mm2 for PCBB + CM-BMP2. Only the difference between PCBB-BMP2 and PCBB + CM BMP2 was statistically significant (P = 0.031). NB reached 2.3 +/- 1.3 mm2 for PCBB, 2 +/- 0.5 mm2 for PCBB-BMP2, 2.7 +/- 1.2 mm2 for PCBB + CM and 1.8 +/- 0.7 mm2 for PCBB + CM-BMP2. There were no statistically significant differences regarding NB, the most coronal and the most buccal localizations of new bone, residual bone substitute and bone-to-implant contact (P > 0.05). CONCLUSIONS: The addition of BMP-2 to PCBB or CM used for horizontal ridge augmentation did not render a statistically significant improvement in the maintenance of the augmented ridge contour and the new bone formation. PCBB with and without CM showed pronounced bone ingrowth and capacity to maintain the augmented ridge contour. In all the regions previously augmented with PCBB, the implants successfully integrated and presented with complete hard-tissue coverage. PMID- 28574218 TI - A novel mutation in GMPPA in siblings with apparent intellectual disability, epilepsy, dysmorphism, and autonomic dysfunction. AB - GMPPA encodes the GDP-mannose pyrophosphorylase A protein (GMPPA). The function of GMPPA is not well defined, however it is a homolog of GMPPB which catalyzes the reaction that converts mannose-1-phosphate and guanosine-5'-triphosphate to GDP-mannose. Previously, biallelic mutations in GMPPA were reported to cause a disorder characterized by achalasia, alacrima, neurological deficits, and intellectual disability. In this study, we report a female proband with achalasia, alacrima, hypohydrosis, apparent intellectual disability, seizures, microcephaly, esotropia, and craniofacial dysmorphism. Exome sequencing identified a previously unreported homozygous c.853+1G>A variant in GMPPA in the proband and her affected sister. Their unaffected parents were heterozygous, and unaffected brother homozygous wild type for this variant. Lymphoblast cells from the affected sisters showed complete loss of the GMPPA protein by Western blotting, and increased levels of GDP-mannose in lymphoblasts on high performance liquid chromatography. Based on our findings and the previous report describing patients with an overlapping phenotype, we conclude that this novel variant in GMPPA, identified by exome sequencing in the proband and her affected sister, is the genetic cause of their phenotype and may expand the known phenotype of this recently described glycosylation disorder. PMID- 28574219 TI - Optimization of the dosimetric leaf gap for use in planning VMAT treatments of spine SABR cases. AB - The dosimetric leaf gap (DLG) is a beam configuration parameter used in the Varian Eclipse treatment planning system, to model the effects of rounded MLC leaf ends. Measuring the DLG using the conventional sliding-slit technique has been shown to be produce questionable results for some volumetric modulated arc therapy (VMAT) treatments. This study therefore investigated the use of radiochromic film measurements to optimize the DLG specifically for the purpose of producing accurate VMAT plans using a flattening-filter-free (FFF) beam, for use in treating vertebral targets using a stereotactic (SABR, also known as SBRT) fractionation schedule. Four test treatments were planned using a VMAT technique, to deliver a prescription of 24 Gy in 3 fractions to four different spine SABR treatment sites. Measurements of the doses delivered by these treatments were acquired using an ionization chamber and radiographic film. These measurements were compared with the doses calculated by the treatment planning system using a range of DLG values, including a DLG identified using the conventional sliding slit method (1.1 mm). An optimal DLG value was identified, as the value that produced the closest agreement between the planned and measured doses (1.9 mm). The accuracy of the dose calculations produced using the optimized DLG value was verified using additional radiochromic film measurements in a heterogeneous phantom. This study provided a specific initial DLG (1.9 mm) as well as a film based optimization method, which may be used by radiotherapy centers when attempting to commission or improve an FFF VMAT-based SABR treatment programme. PMID- 28574220 TI - Functional Mechanically Interlocked Molecules: Asymmetric Organocatalysis with a Catenated Bifunctional Bronsted Acid. AB - Interlocked molecules, such as catenanes, rotaxanes, and molecular knots, have become interesting candidates for the development of sophisticated chemical catalysts. Herein, we report the first application of a catenane-based catalyst in asymmetric organocatalysis, revealing that the catenated catalyst shows dramatically increased stereoselectivities (up to 98 % ee) in comparison to its non-interlocked analogues. A mechanistic rationale for the observed differences was developed by DFT studies, suggesting that the involvement of two catalytically active groups in the stereodetermining reaction step is responsible for the superior selectivity of the interlocked catalyst. PMID- 28574221 TI - Validation of a method for in vivo 3D dose reconstruction in SBRT using a new transmission detector. AB - Stereotactic body radiation therapy (SBRT) involves the delivery of substantially larger doses over fewer fractions than conventional therapy. Therefore, SBRT treatments will strongly benefit patients using vivo patient dose verification, because the impact of the fraction is large. For in vivo measurements, a commercially available quality assurance (QA) system is the COMPASS system (IBA Dosimetry, Germany). For measurements, the system uses a new transmission detector (Dolphin, IBA Dosimetry). In this study, we evaluated the method for in vivo 3D dose reconstruction for SBRT using this new transmission detector. We confirmed the accuracy of COMPASS with Dolphin for SBRT using multi leaf collimator (MLC) test patterns and clinical SBRT cases. We compared the results between the COMPASS, the treatment planning system, the Kodak EDR2 film, and the Monte Carlo (MC) calculations. MLC test patterns were set up to investigate various aspects of dose reconstruction for SBRT: (a) simple open fields (2 * 2-10 * 10 cm2 ), (b) a square wave chart pattern, and (c) the MLC position detectability test in which the MLCs were changed slightly. In clinical cases, we carried out 6 and 8 static IMRT beams for SBRT in the lung and liver. For MLC test patterns, the differences between COMPASS and MC were around 3%. The COMPASS with the dolphin system showed sufficient resolution in SBRT. For clinical cases, COMPASS can detect small changes for the dose profile and dose-volume histogram. COMPASS also showed good agreement with MC. We can confirm the feasibility of SBRT QA using the COMPASS system with Dolphin. This method was successfully operated using the new transmission detector and verified by measurements and MC. PMID- 28574222 TI - Transition boundaries for protistan species turnover in hypersaline waters of different biogeographic regions. AB - The identification of environmental barriers which govern species distribution is a fundamental concern in ecology. Even though salt was previously identified as a major transition boundary for micro- and macroorganisms alike, the salinities causing species turnover in protistan communities are unknown. We investigated 4.5 million high-quality protistan metabarcodes (V4 region of the SSU rDNA) obtained from 24 shallow salt ponds (salinities 4%-44%) from South America and Europe. Statistical analyses of protistan community profiles identified four salinity classes, which strongly selected for different protistan communities: 4 9%, 14-24%, 27-36% and 38-44%. The proportion of organisms unknown to science is highest in the 14-24% salinity class, showing that environments within this salinity range are an unappreciated reservoir of as yet undiscovered organisms. Distinct higher-rank taxon groups dominated in the four salinity classes in terms of diversity. As increasing salinities require different cellular responses to cope with salt, our results suggest that different evolutionary lineages of protists have evolved distinct haloadaptation strategies. Salinity appears to be a stronger selection factor for the structuring of protistan communities than geography. Yet, we find a higher degree of endemism in shallow salt ponds compared with less isolated ecosystems such as the open ocean. Thus, rules for biogeographic structuring of protistan communities are not universal, but depend on the ecosystem under consideration. PMID- 28574223 TI - Advantages of the modified double ring areolar incision over the traditional areolar incision in multicentric breast fibroadenoma surgery. AB - BACKGROUND: This study was conducted to investigate the clinical advantages of modified double ring areola incision (MDRAI) compared to ordinary areola incision (OAI) in multicentric breast fibroadenoma in women. METHODS: Sixty cases of multicentric benign breast tumor were recruited from the First Affiliated Hospital of Bengbu Medical College from January to December 2016. The cases were divided into two groups according to surgical approach: MDRAI (n = 20) and OAI (n = 40). The operation duration, intraoperative blood loss, drainage time, and postoperative recurrence rate in the first six months were compared. RESULTS: The mean age and tumor locations were not statistically different between the groups (P > 0.05). However, more lesions and larger tumor diameter were found in the MDRAI group than in the OAI group, with statistical difference (P < 0.05). The operation duration and drainage time of the two groups were not statistically different for unilateral or bilateral lesions (P > 0.05). However, the intraoperative blood loss was statistically different between the two groups (P < 0.05). All 60 cases received six months of follow-up. Eight recurrent cases were found in the OAI group, but none in the MDRAI group. The recurrence rate was significantly different (chi2 = 4.62, P < 0.05). CONCLUSION: Compared with OAI, MDRAI offers greater advantages in the aspects of blood loss and recurrence for the treatment of breast benign tumor, especially for multicentric larger lesions. PMID- 28574226 TI - Is Moderate Mitral Regurgitation Enough for Surgery or Too Much to Follow Up? PMID- 28574225 TI - Three-Stream, Bicarbonate-Based Hemodialysis Solution Delivery System Revisited: With an Emphasis on Some Aspects of Acid-Base Principles. AB - Hemodialysis patients can acquire buffer base (i.e., bicarbonate and buffer base equivalents of certain organic anions) from the acid and base concentrates of a three-stream, dual-concentrate, bicarbonate-based, dialysis solution delivery machine. The differences between dialysis fluid concentrate systems containing acetic acid versus sodium diacetate in the amount of potential buffering power were reviewed. Any organic anion such as acetate, citrate, or lactate (unless when combined with hydrogen) delivered to the body has the potential of being converted to bicarbonate. The prescribing physician aware of the role that organic anions in the concentrates can play in providing buffering power to the final dialysis fluid, will have a better knowledge of the amount of bicarbonate and bicarbonate precursors delivered to the patient. PMID- 28574227 TI - Frank A. Gotch: 1926-2017. PMID- 28574228 TI - aPKC-iota/P-Sp1/Snail signaling induces epithelial-mesenchymal transition and immunosuppression in cholangiocarcinoma. AB - : Cholangiocarcinoma (CCA) is a highly malignant bile duct cancer that tends to invade and metastasize early. The epithelial-mesenchymal transition (EMT) has been implicated in cancer cell invasion and metastasis, as well as in cancer cell evasion of host immunity. In this study, we investigated the interaction between atypical protein kinase C-iota (aPKC-iota) and Snail in the regulation of EMT and its relationship to CCA immunosuppression. Our results demonstrated that aPKC iota, Snail, and infiltrated immunosuppressive cells were significantly up regulated in CCA tumor tissues and linked to poor prognosis. aPKC-iota induced EMT and immunosuppression by regulating Snail in vitro and in vivo, although aPKC iota did not directly interact with Snail in coimmunoprecipitation experiments. To further clarify the molecular interaction between aPKC-iota and Snail in relation to EMT, quantitative iTRAQ-based phosphoproteomic analysis and liquid chromatography-tandem mass spectrometry were conducted to identify the substrates of aPKC-iota-dependent phosphorylation. Combined with coimmunoprecipitation, we showed that specificity protein 1 (Sp1) was directly phosphorylated by aPKC-iota on Ser59 (P-Sp1). Both Sp1 and P-Sp1 were up-regulated in CCA tumor tissues and associated with clinicopathological features and poor prognosis in CCA patients. Moreover, using chromatin immunoprecipitation assays, we found that P-Sp1 regulated Snail expression by increasing Sp1 binding to the Snail promoter. P-Sp1 also regulated aPKC-iota/Snail-induced EMT-like changes and immunosuppression in CCA cells. Our findings further indicated that CCA cells with EMT-like features appear to generate immunosuppressive natural T regulatory-like cluster of differentiation 4-positive (CD4+ )CD25- cells rather than to increase CD4+ CD25+ natural T regulatory cells, in part by mediating T regulatory-inducible cytokines such as transforming growth factor beta1 and interleukin 2. CONCLUSION: These results demonstrate that aPKC-iota promotes EMT and induces immunosuppression through the aPKC-iota/P-Sp1/Snail signaling pathway and may be a potential therapeutic target for CCA. (Hepatology 2017;66:1165-1182). PMID- 28574229 TI - The effects of joint disease, inhibitors and other complications on health related quality of life among males with severe haemophilia A in the United States. AB - INTRODUCTION: Health-related quality of life (HRQoL) is reduced among persons with haemophilia. Little is known about how HRQoL varies with complications of haemophilia such as inhibitors and joint disease. Estimates of preference-based HRQoL measures are needed to model the cost-effectiveness of prevention strategies. AIM: We examined the characteristics of a national sample of persons with severe haemophilia A for associations with two preference-based measures of HRQoL. METHODS: We analysed utility weights converted from EuroQol 5 Dimensions (EQ-5D) and the Short Form 6 Dimensions (SF-6D) scores from 1859 males aged >=14 years with severe haemophilia A treated at 135 US haemophilia treatment centres in 2005-2011. Bivariate and regression analyses examined age-group-specific associations of HRQoL with inhibitor status, overweight/obesity, number of bleeds, viral infections, indicators of liver and joint disease, and severe bleeding at the time of the first HRQoL measurement. RESULTS: Overall mean HRQoL utility weight values were 0.71 using the SF-6D and 0.78 using the EQ-5D. All studied patient characteristics except for overweight/obesity were significantly associated with HRQoL in bivariate analyses. In a multivariate analysis, only joint disease was significantly associated with utility weights from both HRQoL measures and across all age groups. After adjustment for joint disease and other variables, the presence of an inhibitor was not significantly associated with HRQoL scores from either of the standardized assessment tools. CONCLUSION: Clinically significant complications of haemophilia, especially joint disease, are strongly associated with HRQoL and should be accounted for in studies of preference-based health utilities for people with haemophilia. PMID- 28574230 TI - Nicotine effects on exercise performance and physiological responses in nicotine naive individuals: a systematic review. AB - The purpose of this systematic review was to evaluate the effects of smokeless forms of nicotine on physiological responses and exercise performance. Methodology and reporting were based on the PRISMA statement. The intervention was defined as any product containing nicotine that did not require smoking. Searches were conducted across two electronic databases with supplementary approaches utilized. Studies were selected following set inclusion and exclusion criteria and checked by two independent authors. A modified PEDro scale was utilized to rate study quality with studies averaging 9.3/13. Six studies assessed exercise performance with endurance-based parameters reported as significantly improved with nicotine in one study, while anaerobic parameters were unaffected or decreased compared to placebo except in one study which reported enhanced leg extensor torque but no effect on countermovement jump or Wingate anaerobic capacity. Sixteen of 28 studies investigating physiological responses reported that nicotine significantly increased heart rate compared to placebo or control. Blood pressure and blood flow were also reported as significantly increased in multiple studies. While there is strong evidence of nicotine-induced changes in physiological function that would benefit physical performance, beneficial effects have only been reported on leg extensor torque and endurance performance by one study each. Subsequently, there is need for more research with strong methodological quality to definitively evaluate nicotine's potential as an ergogenic aid. PMID- 28574231 TI - A new diagnosis of Williams-Beuren syndrome in a 49-year-old man with severe bullous emphysema. AB - Williams-Beuren syndrome (WBS) is a chromosomal microdeletion syndrome typically presenting with intellectual disability, a unique personality, a characteristic facial appearance, and cardiovascular disease. Several clinical features of WBS are thought to be due to haploinsufficiency of elastin (ELN), as the ELN locus is included within the WBS critical region at 7q11.23. Emphysema, a disease attributed to destruction of pulmonary elastic fibers, has been reported in patients without WBS who have pathogenic variants in ELN but only once (in one patient) in WBS. Here we report a second adult WBS patient with emphysema where the diagnosis of WBS was established subsequent to the discovery of severe bullous emphysema. Haploinsufficiency of ELN likely contributed to this pulmonary manifestation of WBS. This case emphasizes the contribution of rare genetic variation in cases of severe emphysema and provides further evidence that emphysema should be considered in patients with WBS who have respiratory symptoms, as it may be under-recognized in this patient population. PMID- 28574232 TI - A heritable microduplication encompassing TBL1XR1 causes a genomic sister disorder for the 3q26.32 microdeletion syndrome. AB - Recently, a new syndrome with intellectual disability (ID) and dysmorphic features due to deletions or point mutations within the TBL1XR1 gene located in the chromosomal band 3q26.32 has been described (MRD41, OMIM 616944). One recurrent point mutation in the TBL1XR1 gene has been identified as the cause of Pierpont syndrome (OMIM 602342), a distinct intellectual disability syndrome with plantar lipomatosis. In addition, different de novo point mutations in the TBL1XR1 gene have been found in patients with autism spectrum disorders (ASD) and intellectual disability. Here, we report four patients from two unrelated families in whom array-CGH analysis and real-time quantitative PCR of genomic DNA revealed a TBL1XR1-microduplication. Adjacent genes were not affected. The microduplication occurred as a de novo event in one patient, whereas the other three cases occurred in two generations of a second, unrelated family. We compare and contrast the clinical findings in TBL1XR1 microdeletion, point mutation, and microduplication cases and expand the TBL1XR1-associated phenotypic spectrum. ID, hearing loss, and ASD are common features of TBL1XR1-associated diseases. Our clinical observations add to the increasing evidence of the role of TBL1XR1 in brain development, and they simultaneously demonstrate that different genetic disease mechanisms affecting TBL1XR1 can lead to similar ID phenotypes. The TBL1XR1-microduplication syndrome is an intellectual disability/learning disability syndrome with associated incomplete penetrance ASD, hearing loss, and delay of puberty. Its phenotypic overlap indicates that it is a genomic sister disorder to the 3q26.32 microdeletion syndrome. PMID- 28574233 TI - The Impact of the ACA's Medicaid Expansion on Hospitals' Uncompensated Care Burden and the Potential Effects of Repeal. AB - ISSUE: By increasing health insurance coverage, the Affordable Care Act's Medicaid eligibility expansion was also expected to lessen the uncompensated care burden on hospitals. The expansion currently faces an uncertain future. GOAL: To compare the change in hospitals' uncompensated care burden in the 31 states (plus the District of Columbia) that chose to expand Medicaid to the changes in states that did not, and to estimate how these expenses would be affected by repeal or further expansion. METHODS: Analysis of uncompensated care data from Medicare Hospital Cost Reports from 2011 to 2015.FINDINGS AND CONCLUSIONS: Uncompensated care burdens fell sharply in expansion states between 2013 and 2015, from 3.9 percent to 2.3 percent of operating costs. Estimated savings across all hospitals in Medicaid expansion states totaled $6.2 billion. The largest reductions in uncompensated care were found for hospitals in expansion states that care for the highest proportion of low-income and uninsured patients. Legislation that scales back or eliminates Medicaid expansion is likely to expose these safety-net hospitals to large cost increases. Conversely, if the 19 states that chose not to expand Medicaid were to adopt expansion, their uncompensated care costs also would decrease by an estimated$6.2 billion. PMID- 28574234 TI - Effect of the Affordable Care Act on Health Care Access. AB - ISSUE: The Affordable Care Act's (ACA) coverage provisions have extended health insurance coverage to millions of Americans. While the effects of the Medicaid expansion and marketplace establishments on coverage have been well studied, the resulting effects of coverage on access to health care remain unclear. GOAL: To examine how the 2014 coverage expansions affected health care access following the first open enrollment period of October 2013 to March 2014. METHODS: Analysis of data from the National Health Interview Survey (NHIS) and the Behavioral Risk Factor Surveillance System (BRFSS).FINDINGS AND CONCLUSIONS: We find that gaining insurance coverage through the expansions decreased the probability of not receiving medical care by between 20.9 percent and 25 percent. Gaining insurance coverage also increased the probability of having a usual place of care by between 47.1 percent and 86.5 percent. These findings suggest that not only has the ACA decreased the number of uninsured Americans, but has substantially improved access to care for those who gained coverage. PMID- 28574235 TI - How Arizona Medicaid Accelerated the Integration of Physical and Behavioral Health Services. AB - ISSUE: In most states, one agency has responsibility for Medicaid enrollees' physical health services and at least one other agency has responsibility for their behavioral health services. Apportioning responsibility for the physical and behavioral health of Medicaid beneficiaries into different agencies inevitably leads to different--and sometimes misaligned--policy goals, program priorities, and purchasing strategies, thereby impeding the delivery of integrated care. GOAL: To describe the rationale, process, and impact of Arizona's 2015 consolidation of its physical and behavioral health services agencies into its Medicaid agency. METHOD: The study is based on published research, Arizona Medicaid agency materials, and interviews with 34 individuals, including representatives from the current Medicaid agency and previous behavioral health services agency, health plans, primary care and behavioral health providers, consumers, the justice system, and the health information exchange. FINDINGS AND CONCLUSIONS: Consolidation has led to increased attention to behavioral health services and behavioral and physical health integration, enabled more strategic purchasing and streamlined regulatory processes, and enhanced communication, collaboration, and mutual trust across sectors. Arizona's experience offers lessons to policymakers as they consider how best to integrate physical and behavioral health services and ensure that Medicaid is an efficient and effective purchaser of health care services. PMID- 28574236 TI - Improving Access to Care with School-Based Health Centers. PMID- 28574237 TI - Gastrointestinal nematodes and the deworming of mouflon (Ovis aries musimon) from Goleniowska Forest in West Pomerania province, Poland AB - Ruminants often live in environments where the natural balance has been disturbed by humans. As a result, there is a transfer of parasitosis to domestic animals and sometimes humans. The aim of the study was to determine the annual species composition and level of gastrointestinal nematode infection of mouflon (Ovis aries musimon) from the half-open breeding colonizing areas of the Goleniowska Forest, and to assess the effectiveness of deworming. The course of the parasitic infection of mouflon depends largely on geoclimatic and breeding factors. These diseases are caused by more than 17 species of nematodes with varying degrees of pathogenicity. Due to the high degree of parasitic infections in deer, both in Poland and abroad, it is necessary to develop specific preventive programs usingpreparations with a broad spectrum of action. PMID- 28574238 TI - An administrative right to be free from sexual violence? Title IX enforcement in historical and institutional perspective. AB - One of the most controversial administrative actions in recent years is the U.S. Department of Education's campaign against sexual assault on college campuses. Using its authority under Title IX of the Education Amendments of 1972 (mandating nondiscrimination on the basis of sex in all educational programs and activities receiving federal funds), the Department's Office for Civil Rights (OCR) has launched an enforcement effort that critics denounce as aggressive, manipulative, and corrosive of individual liberties. Missing from the commentary is a historically informed understanding of why this administrative campaign unfolded as it did. This Article offers crucial context by reminding readers that freedom from sexual violence was once celebrated as a national civil right--upon the enactment of the Violence Against Women Act of 1994--but then lost that status in a 5-4 decision by the U.S. Supreme Court. OCR's recent campaign reflects a legal and political landscape in which at least some potential victims of sexual violence had come to feel rightfully connected to the institutions of the federal government, and then became righteously outraged by the endurance of such violence in their communities. OCR's campaign also reflects the unique role of federal administrative agencies in this landscape. Thanks to the power of the purse and the conditions thatCongress has attached to funding streams, agencies enjoy a powerful form of jurisdiction over particular spaces and institutions. Attempts to harness this jurisdiction in service of aspirational rights claims should not surprise us; indeed, we should expect such efforts to continue. Building on this insight, the Article concludes with a research agenda for other scholars seeking to understand and evaluate OCR's handiwork. PMID- 28574239 TI - 340B Drug Pricing Program Ceiling Price and Manufacturer Civil Monetary Penalties Regulation. Final rule; further delay of effective date. AB - The Health Resources and Services Administration (HRSA) administers section 340B of the Public Health Service Act (PHSA), referred to as the "340B Drug Pricing Program" or the "340B Program." HRSA published a final rule on January 5, 2017, that set forth the calculation of the ceiling price and application of civil monetary penalties. The final rule applied to all drug manufacturers that are required to make their drugs available to covered entities under the 340B Program. In accordance with a January 20, 2017, memorandum from the Assistant to the President and Chief of Staff, entitled "Regulatory Freeze Pending Review," HRSA issued an interim final rule that delayed the effective date of the final rule published in the Federal Register (82 FR 1210, (January 5, 2017)) to May 22, 2017. HHS invited commenters to provide their views on whether a longer delay of the effective date to October 1, 2017, would be more appropriate. After consideration of the comments received on the interim final rule, HHS is delaying the effective date of the January 5, 2017 final rule, to October 1, 2017. PMID- 28574240 TI - Medicare Program; Advancing Care Coordination Through Episode Payment Models (EPMs); Cardiac Rehabilitation Incentive Payment Model; and Changes to theComprehensive Care for Joint Replacement Model (CJR); Delay of Effective Date. Final rule; delay of effective date. AB - This final rule finalizes May 20, 2017 as the effective date of the final rule titled "Advancing Care Coordination Through Episode Payment Models (EPMs); Cardiac Rehabilitation Incentive Payment Model; and Changes to the Comprehensive Care for Joint Replacement Model (CJR)" originally published in the January 3, 2017 Federal Register. This final rule also finalizes a delay of the applicability date of the regulations at 42 CFR part 512 from July 1, 2017 to January 1, 2018 and delays the effective date of the specific CJR regulations listed in the DATES section from July 1, 2017 to January 1, 2018. PMID- 28574241 TI - A High Capacity, Good Safety and Low Cost Na2FeSiO4-Based Cathode for Rechargeable Sodium-Ion Battery. AB - Rechargeable sodium-ion batteries (SIBs) are receiving intense interest because the resource abundance of sodium and its lithium-like chemistry make them low cost alternatives to the prevailing lithium-ion batteries in large-scale energy storage devices. Two typical classes of materials including transition metal oxides and polyanion compounds have been under intensive investigation as cathodes for SIBs; however, they are still limited to poor stability or low capacity of the state-of-art. Herein, we report a low cost carbon-coated Na2FeSiO4 with simultaneous high capacity and good stability, owing to the highly pure Na-rich triclinic phase and the carbon-incorporated three-dimensional network morphology. The present carbon-coated Na2FeSiO4 demonstrates the highest reversible capacity of 181.0 mAh g-1 to date with multielectron redox reaction that occurred among various polyanion-based SIBs cathodes, which achieves a close to-100% initial Coulombic efficiency and a stable cycling with 88% capacity retention up to 100 cycles. In addition, such an electrode shows excellent stability either charged at a high voltage of 4.5 V or heated up to 800 degrees C. The present work might open up the possibility for developing high capacity, good safety and low cost polyanion-based cathodes for rechargeable SIBs. PMID- 28574242 TI - Nanoengineered Stent Surface to Reduce In-Stent Restenosis in Vivo. AB - In-stent restenosis (ISR) is the leading cause of stent failure and is a direct result of a dysfunctional vascular endothelium and subsequent overgrowth of vascular smooth muscle tissue. TiO2 nanotubular (NT) arrays have been shown to affect vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) in vitro by accelerating VEC cell proliferation and migration while suppressing VSMCs. This study investigates for the first time the potentially beneficial effects of TiO2 NT arrays on vascular tissue in vivo. TiO2 NT arrays (NT diameter: 90 +/- 5 nm, height: 1800 +/- 300 nm) were grown on the surface of titanium stents and characterized in terms of surface morphology and stability. Stents were implanted into the iliofemoral artery using an overinflation model (rabbit). After 28 days, stenosis rates were determined. The data show a statistically significant reduction of stenosis by 30% compared to the control. Tissue in the presence of TiO2 NTs appears more mature, and less neointima is present between struts. In addition, the extra cellular matrix secreted by cells at the interface of the NT arrays shows complete integration into the nanostructured surface. These results document the accelerated restoration of a functional endothelium in the presence of TiO2 NT arrays and substantiate their beneficial impact on vascular tissue in vivo. Our findings suggest that TiO2 NT arrays can be used as a drug-free approach for keeping stents patent long-term and have the potential to address ISR. PMID- 28574243 TI - Facile Method to Reduce Surface Defects and Trap Densities in Perovskite Photovoltaics. AB - Owing to improvements in film morphology, crystallization process optimization, and compositional design, the power conversion efficiency of perovskite solar cells has increased from 3.8 to 22.1% in a period of 5 years. Nearly defect-free crystalline films and slow recombination rates enable polycrystalline perovskite to boast efficiencies comparable to those of multicrystalline silicon solar cells. However, volatile low melting point components and antisolvent treatments essential for the processing of dense and smooth films often lead to surface defects that hamper charge extraction. In this study, we investigate methylammonium bromide (MABr) surface treatments on perovskite films to compensate for the loss of volatile cation during the annealing process for surface defect passivation, grain growth, and a bromide-rich top layer. This facile method did not change the phase or bandgap of perovskite films yet resulted in a significant increase in the open circuit voltages of devices. The devices with 10 mM MABr treatment show 2% improvement in absolute power conversion efficiency over the control sample. PMID- 28574244 TI - Achieving Low Contact Resistance by Engineering a Metal-Graphene Interface Simply with Optical Lithography. AB - High-performance graphene-based transistors crucially depend on the creation of the high-quality graphene-metal contacts. Here we report an approach for achieving ultralow contact resistance simply with optical lithography by engineering a metal-graphene interface. Note that a significant improvement with optical lithography for the contact-treated graphene device leads to a contact resistance as low as 150 Omega.MUm. The residue-free sacrificial film impedes the photoresist from further doping graphene, and all of the source and drain contact regions defined by optical lithography remain intact. This approach, being compatible with complementary metal-oxide-semiconductor (CMOS) fabrication processes regardless of the source of graphene, would hold promise for the large scale production of graphene-based transistors with optical lithography. PMID- 28574245 TI - Synthesis and Pharmacological Profiling of the Metabolites of Synthetic Cannabinoid Drugs APICA, STS-135, ADB-PINACA, and 5F-ADB-PINACA. AB - Synthetic cannabinoids (SCs) containing a 1-pentyl-1-H substituted indole or indazole are abused around the world and are associated with an array of serious side effects. These compounds undergo extensive phase 1 metabolism after ingestion with little understanding whether these metabolites are contributing to the cannabimimetic activity of the drugs. This work presents the synthesis and pharmacological characterization of the major metabolites of two high concern SCs; APICA and ADB-PINACA. In a fluorometric assay of membrane potential, all metabolites that did not contain a carboxylic acid functionality retained potent activity at both the CB1 (EC50 = 14-787 nM) and CB2 (EC50 = 5.5-291 nM) receptors regardless of heterocyclic core or 3-carboxamide substituent. Of note were the 5 hydroxypentyl and 4-pentanone metabolites which showed significant increases in CB2 functional selectivity. These results suggest that the metabolites of SCs potentially contribute to the overall pharmacological profile of these drugs. PMID- 28574247 TI - Fabrication of Conductive Copper Films on Flexible Polymer Substrates by Low Temperature Sintering of Composite Cu Ink in Air. AB - The development of a thermal sintering method for Cu-based inks under an air atmosphere could greatly expand their application for printed electronics. However, it is well-known that Cu-based inks cannot produce conductive Cu films when sintered at low temperatures in air because Cu readily oxidizes under such conditions. In this study, we have successfully demonstrated air atmosphere sintering at low temperatures (less than 150 degrees C) via a simple hot plate heat treatment for producing conductive Cu films on flexible polymer substrates, using a novel Cu-based composite ink with sub-10 nm Cu nanoparticles protected with 1-amino-2-propanol with micrometer-sized Cu particles and submicrometer sized Cu particles; oxalic acid was also added to prevent the oxidation of the Cu during sintering. The Cu films showed a minimum resistivity of 5.5 * 10-5 Omega.cm when sintered in air at 150 degrees C for a very short period of 10 s. To the best of our knowledge, this is the first report of sintering of Cu-based inks in air at less than 150 degrees C. Another novel property of the present Cu based composite ink is the lowest reported resistivity at 80 degrees C under N2 flow (5.3 * 10-5 Omega.cm at 80 degrees C and 8.4 * 10-6 Omega.cm at 120 degrees C). This fast, efficient, and inexpensive technology for thermal sintering in ambient air using composite inks could be a commercially viable method for fabricating printed electronics on flexible substrates. PMID- 28574246 TI - Gel Electrolytes with Polyamidopyridine Dendron Modified Talc for Dye-Sensitized Solar Cells. AB - Organic-inorganic hybrid layered materials are proposed as additives in a quasi solid gel electrolyte for dye-sensitized solar cells. Talcs could provide a low cost and environmentally friendly, as well as abundant, option as gelators. Here, talcs were prepared by functionalizing an organotalc with three polyamidopyridine dendron generations, PAMPy-talc-Gn (n = 1, 2 and 3). PAMPy dendrons grow parallel to the lamellae plane and form an organized structure by intermolecular interactions. In addition, polyiodide-dendron charge-transfer complexes were prepared onto the organotalc by adsorption of iodine. In this work, the effect of the dendron generation of PAMPy-talc and the influence of polyiodide intercalation on solar cell performance and stability were investigated. The best results were reached with the use of lowest-generation PAMPy-talc (eta = 4.5 +/- 0.3%, VOC = 710 +/- 19 mV, Jsc = 10.4 +/- 0.9 mA cm-2, and FF = 61 +/- 2%): 15% higher efficiency compared to similar liquid devices. While some previously studied talcs illustrate very strong absorption of the iodide from the electrolyte, in the case of PAMPy-talc such interfering effects were absent: In a 1000 h light soaking test, the PAMPy-talc cells both with and without polyiodide intercalation demonstrated stable performances. Furthermore, the color analysis of the electrolyte indicated that the color of the electrolyte remained stable after an initial period of stabilization, which is a good indication of the compound being stable and not absorbing charge carriers from the electrolyte. The performance and stability results indicate that PAMPy-talc has potential as a gelling method for electrolytes for dye solar cells. PMID- 28574248 TI - Interfacial Reaction of Fulleropyrrolidines Affecting Organic Photovoltaic Performance. AB - : Fulleropyrrolidine derivatives are intrinsically basic owing to the amino group within the pyrrolidine structure. It can be predicted that the basicity of fulleropyrrolidine may affect the photovoltaic devices containing an acidic layer (e.g. , PEDOT: PSS). To clarify the effect of basic fulleropyrrolidine derivatives, we synthesized compounds with an N-benzyl substituent group and fabricated organic photovoltaic (OPV) cells using this N-benzyl fulleropyrrolidine. A device structure with the ITO/PEDOT:PSS/organic layer (PTB7:fulleropyrrolidine)/Ca/Al showed high series resistance, short-circuit current density (Jsc), and low fill factor (FF) values. However, OPV cells having an inverted structure, without the PEDOT:PSS layer, contributed good device performance. We were able to reproduce the high series resistance in a model experiment using aqueous ammonia vapor to treat the PEDOT:PSS layer. Our results indicated that the activity of the PEDOT:PSS layer was affected by the basicity of the fulleropyrrolidines. These results also explain why this phenomenon does not occur at the interface of OPV devices when conventional [6,6]-phenyl C61 butyric acid methyl ester is used as an acceptor material. This finding would contribute to enhancing the OPV device performances from a chemical view point of designing a new compound. PMID- 28574250 TI - Antibody Conjugated, Raman Tagged Hollow Gold-Silver Nanospheres for Specific Targeting and Multimodal Dark-Field/SERS/Two Photon-FLIM Imaging of CD19(+) B Lymphoblasts. AB - In this Research Article, we propose a new class of contrast agents for the detection and multimodal imaging of CD19(+) cancer lymphoblasts. The agents are based on NIR responsive hollow gold-silver nanospheres conjugated with antiCD19 monoclonal antibodies and marked with Nile Blue (NB) SERS active molecules (HNS NB-PEG-antiCD19). Proof of concept experiments on specificity of the complex for the investigated cells was achieved by transmission electron microscopy (TEM). The microspectroscopic investigations via dark field (DF), surface-enhanced Raman spectroscopy (SERS), and two-photon excited fluorescence lifetime imaging microscopy (TPE-FLIM) corroborate with TEM and demonstrate successful and preferential internalization of the antibody-nanocomplex. The combination of the microspectroscopic techniques enables contrast and sensitivity that competes with more invasive and time demanding cell imaging modalities, while depth sectioning images provide real time localization of the nanoparticles in the whole cytoplasm at the entire depth of the cells. Our findings prove that HNS-NB-PEG-antiCD19 represent a promising type of new contrast agents with great possibility of being detected by multiple, non invasive, rapid and accessible microspectroscopic techniques and real applicability for specific targeting of CD19(+) cancer cells. Such versatile nanocomplexes combine in one single platform the detection and imaging of cancer lymphoblasts by DF, SERS, and TPE-FLIM microspectroscopy. PMID- 28574249 TI - Synthesis and Characterization of Novel Acyl-Glycine Inhibitors of GlyT2. AB - It has been demonstrated previously that the endogenous compound N-arachidonyl glycine inhibits the glycine transporter GlyT2, stimulates glycinergic neurotransmission, and provides analgesia in animal models of neuropathic and inflammatory pain. However, it is a relatively weak inhibitor with an IC50 of 9 MUM and is subject to oxidation via cyclooxygenase, limiting its therapeutic value. In this paper we describe the synthesis and testing of a novel series of monounsaturated C18 and C16 acyl-glycine molecules as inhibitors of the glycine transporter GlyT2. We demonstrate that they are up to 28 fold more potent that N arachidonyl-glycine with no activity at the closely related GlyT1 transporter at concentrations up to 30 MUM. This novel class of compounds show considerable promise as a first generation of GlyT2 transport inhibitors. PMID- 28574252 TI - Dynamic Kinetic Resolution of Allylic Azides via Asymmetric Dihydroxylation. AB - The catalytic enantioselective preparation of densely functionalized amines is a fundamental synthetic challenge. To address this challenge, we report for the first time that the Winstein rearrangement can be enlisted as the racemization pathway in a dynamic kinetic resolution of allylic azides. Alkene functionalization by Sharpless dihydroxylation affords tertiary azides in excellent enantioselectivity (up to 99:1 er). This approach establishes the chirality of the tertiary azide, obviates the need to directly forge either a congested C-N or C-C bond at the new nitrogenous stereocenter, and establishes additional functionality. Several examples demonstrate further elaboration of this functionality. PMID- 28574251 TI - Non-Native Metal Ion Reveals the Role of Electrostatics in Synaptotagmin 1 Membrane Interactions. AB - C2 domains are independently folded modules that often target their host proteins to anionic membranes in a Ca2+-dependent manner. In these cases, membrane association is triggered by Ca2+ binding to the negatively charged loop region of the C2 domain. Here, we used a non-native metal ion, Cd2+, in lieu of Ca2+ to gain insight into the contributions made by long-range Coulombic interactions and direct metal ion-lipid bridging to membrane binding. Using X-ray crystallography, NMR, Forster resonance energy transfer, and vesicle cosedimentation assays, we demonstrate that, although Cd2+ binds to the loop region of C2A/B domains of synaptotagmin 1 with high affinity, long-range Coulombic interactions are too weak to support membrane binding of individual domains. We attribute this behavior to two factors: the stoichiometry of Cd2+ binding to the loop regions of the C2A and C2B domains and the impaired ability of Cd2+ to directly coordinate the lipids. In contrast, electron paramagnetic resonance experiments revealed that Cd2+ does support membrane binding of the C2 domains in full-length synaptotagmin 1, where the high local lipid concentrations that result from membrane tethering can partially compensate for lack of a full complement of divalent metal ions and specific lipid coordination in Cd2+-complexed C2A/B domains. Our data suggest that long-range Coulombic interactions alone can drive the initial association of C2A/B with anionic membranes and that Ca2+ further augments membrane binding by the formation of metal ion-lipid coordination bonds and additional Ca2+ ion binding to the C2 domain loop regions. PMID- 28574253 TI - Cationic, Neutral, and Anionic Hydrides of Iridium with PSiP Pincers. AB - This work describes synthetic routes from the known precursor [IrClH{kappaP,P,Si Si(Me)(C6H4-2-PiPr2)2}] (1) to new hydride and polyhydride derivatives. Substituting the chloride ligand with triflate leads to the five-coordinate complex [IrH{kappaO-O3S(CF3)}{kappaP,P,Si-Si(Me)(C6H4-2-PiPr2)2}] (2), which can undergo reversible coordination of water (H2O) or dihydrogen (H2) to generate respectively the cationic derivative [IrH{kappaP,P,Si-Si(Me)(C6H4-2 PiPr2)2}(OH2)2](CF3SO3) (3) or the neutral trans-hydride-dihydrogen [IrH{kappaO O3S(CF3)}{kappaP,P,Si-Si(Me)(C6H4-2-PiPr2)2}(eta2-H2)] (6) in equilibrium. The use of acetonitrile or carbon monoxide (CO) excess instead of water produces stable analogues of 3 (complexes 4 or 5, respectively). The reaction between 1 and NaBH4 affords the tetrahydroborate derivative [IrH{kappa2H-H2BH2}{kappaP,P,Si Si(Me)(C6H4-2-PiPr2)2}] (7), which can be protonated with triflic acid to form 2 or with HBF4 to give the dinuclear cationic derivative [(MU:kappa2H,kappa2H BH4)[IrH{kappaP,P,Si-Si(Me)(C6H4-2-PiPr2)2}]2](BF4) (8). The reactions of 7 with alcohols afford either the dihydride-carbonyl [IrH2{kappaP,P,Si-Si(Me)(C6H4-2 PiPr2)2}(CO)] (9) or the known tetrahydride [IrH4{kappaP,P,Si-Si(Me)(C6H4-2 PiPr2)2}] (10), depending on the ease of alcohol decarbonylation. NMR observations and density functional theory calculations on the fluxional behavior of 10 indicate that the spatial contour of the mer PSiP framework conditions hydride-ligand exchanges. Complex 10 reacts with NaH in tetrahydrofuran to form the anionic trihydride [IrH3{kappaP,P,Si-Si(Me)(C6H4-2-PiPr2)2}]Na (11), which exists as a mixture of fac and mer isomers in equilibrium. PMID- 28574254 TI - Direct Catalytic Desaturation of Lactams Enabled by Soft Enolization. AB - A direct catalytic method is described for the alpha,beta-desaturation of N protected lactams to their conjugated unsaturated counterparts under mildly acidic conditions. The reaction is consistently operated at room temperature and tolerates a wide range of functional groups, showing reactivity complementary to that of prior desaturation methods. Lactams with various ring sizes and substituents at different positions all reacted smoothly. The synthetic utility of this method is demonstrated in a concise synthesis of Rolipram. In addition, linear amides also prove to be competent substrates, and the phthaloyl-protected product serves as a convenient precursor to access various conjugated carboxylic acid derivatives. Strong bases are avoided in this desaturation approach, and the key is to merge soft enolization with a Pd-catalyzed oxidation process. PMID- 28574257 TI - Intramolecular Nitrofuran Diels-Alder Reactions: Extremely Substituent-Tolerant Cycloadditions via Asynchronous Transition States. AB - Nitrofurans undergo intramolecular Diels-Alder reactions with tethered electron poor dienophiles more rapidly and in higher yield than non-nitrated furans. Computational studies indicate that increased stabilization of a partial positive charge on the nitro-substituted carbon in both transition state and product is the driving force for these reactions. Frontier molecular orbital energy differences indicate a switch from normal to inverse electron demand upon nitration. There does not appear to be a contribution from any differences in aromatic stabilization energy between furans and nitrofurans. Calculations show that the nitrofuran reactions proceed via a highly asynchronous transition state allowing easier bond formation between two sterically hindered carbons. PMID- 28574255 TI - Gold Nanoparticle Size and Shape Effects on Cellular Uptake and Intracellular Distribution of siRNA Nanoconstructs. AB - Gold nanoparticles (AuNPs) show potential for transfecting target cells with small interfering RNA (siRNA), but the influence of key design parameters such as the size and shape of the particle core is incomplete. This paper describes a side-by-side comparison of the in vitro response of U87 glioblastoma cells to different formulations of siRNA-conjugated gold nanoconstructs targeting the expression of isocitrate dehydrogenase 1 (IDH1) based on 13 nm spheres, 50 nm spheres, and 40 nm stars. 50 nm spheres and 40 nm stars showed much higher uptake efficiency compared to 13 nm spheres. Confocal fluorescence microscopy showed that all three formulations were localized in the endosomes at early incubation times (2 h), but after 24 h, 50 nm spheres and 40 nm stars were neither in endosomes nor in lysosomes while 13 nm spheres remained in endosomes. Transmission electron microscopy images revealed that the 13 nm spheres were enclosed and dispersed within endocytic vesicles while 50 nm spheres and 40 nm stars were aggregated, and some of these NPs were outside of endocytic vesicles. In our comparison of nanoconstructs with different sizes and shapes, while holding siRNA surface density and nanoparticle concentration constant, we found that larger particles (50 nm spheres and 40 nm stars) showed higher potential as carriers for the delivery of siRNA. PMID- 28574258 TI - Boosting the Signal Intensity of Nanoelectrospray Ionization by Using a Polarity Reversing High-Voltage Strategy. AB - Continuous efforts have been made to further improve the performance of nano-ESI. In this work, we made use of a polarity-reversing high-voltage strategy for the generation of nano-ESI (PR-nESI). Typically, a negative high voltage of -3.0 kV was first applied to the electrode and maintained for 6 s. Then the polarity was reversed, and a positive high voltage of +1.75 kV was applied for the generation of electrospray. Compared with conventional nano-ESI, PR-nESI significantly enhanced the signal intensity of protonated protein ions. The signal-to-noise ratio (S/N) of protonated protein ions was increased by 1-2 orders of magnitude. The increase of S/N was even more remarkable at lower concentrations. Furthermore, PR-nESI also had a desalting effect. Metal ion adducts of proteins were effectively removed. No metal ion adducts were identified from the spectra, even if the concentration of salt was increased to the millimolar level. The performance of PR-nESI was confirmed in the detection of different molecules including proteins, peptides, amino acids, and other small-molecule compounds. The intact folded structure of proteins was preserved during PR-nESI. No unfolding was observed in the spectra. PR-nESI was further applied to the analysis of noncovalent protein-ligand complexes and protein digest. At last, investigations into the mechanism of PR-nESI were carried out. The enhancement of signal intensity and desalting effect were related to the electromigration of the solutes in solution. With all the advantages above, PR-nESI would be a promising method in the future analytical and bioanalytical applications. PMID- 28574259 TI - Targeting Mycolic Acid Transport by Indole-2-carboxamides for the Treatment of Mycobacterium abscessus Infections. AB - Mycobacterium abscessus is a fast-growing, multidrug-resistant organism that has emerged as a clinically significant pathogen in cystic fibrosis (CF) patients. The intrinsic resistance of M. abscessus to most commonly available antibiotics seriously restricts chemotherapeutic options. Herein, we report the potent activity of a series of indolecarboxamides against M. abscessus. The lead compounds, 6 and 12, exhibited strong activity in vitro against a wide panel of M. abscessus isolates and in infected macrophages. High resistance levels to the indolecarboxamides appear to be associated with an A309P mutation in the mycolic acid transporter MmpL3. Biochemical analyses demonstrated that while de novo mycolic acid synthesis remained unaffected, the indolecarboxamides strongly inhibited the transport of trehalose monomycolate, resulting in the loss of trehalose dimycolate production and abrogating mycolylation of arabinogalactan. Our data introduce a hereto unexploited chemical structure class active against M. abscessus infections with promising translational development possibilities for the treatment of CF patients. PMID- 28574260 TI - Mollecarbamates, Molleureas, and Molledihydroisoquinolone, o Carboxyphenethylamide Metabolites of the Ascidian Didemnum molle Collected in Madagascar. AB - The extract of a sample of the tunicate Didemnum molle (MAY13-117) collected in Mayotte afforded eight new metabolites, mollecarbamates A-D (1-4) and molleureas B-E (5-8), along with the two known natural products, N,N'-diphenylethyl urea (10) and molleurea A (11). Another sample of D. molle (MAD11-BA065) collected in Baie des Assassins, Madagascar, afforded molledihydroisoquinolone (9). Mollecarbamates 1-4 are a family of compounds that possess repeating o carboxyphenethylamide units and a carbamate moiety, while the molleureas 5-8 contain tetra- and penta-repeating carboxyphenethylamide units and a urea bridge in different positions. Molledihydroisoquinolone (9) is a cyclic form of o carboxyphenethylamide. We propose that these unique natural products are most probably produced by an unprecedented biosynthetic pathway that contains a yet unknown chorismate mutase variant. The structures of the compounds were elucidated by interpretation of the data from 1D and 2D NMR, HRESIMS, and MS/MS analyses of the positive ESIMS experiments. Compounds 1-8 were tested against pathogenic bacteria and in a cytoprotective HIV cell based assay but did not show any significant effects in these assays. PMID- 28574261 TI - Pyreniporphyrins: Porphyrin Analogues That Incorporate a Polycyclic Aromatic Hydrocarbon Subunit within the Macrocyclic Framework. AB - The first examples of porphyrin analogues incorporating pyrene units are reported. Acid-catalyzed condensation of a pyrene dialdehyde with a tripyrrane, followed by oxidation with DDQ, afforded a polycyclic aromatic hydrocarbon (PAH) porphyrin hybrid in 38% yield. Pyreniporphyrin proved to be devoid of global aromatic character, but upon protonation aromatic mono- and dicationic species were generated. In the proton NMR spectrum for the dication, the internal CH was shifted upfield to approximately +3 ppm. NICS calculations and ACID plots confirmed the diatropic nature of these structures. Pyreniporphyrin reacted with palladium(II) acetate to give excellent yields of a palladium(II) complex that showed weakly diatropic properties. Treatment of the pyrene dialdehyde with phenylmagnesium bromide generated a dicarbinol that reacted with excess pyrrole in the presence of boron trifluoride etherate to give a tripyrrane analogue. Lewis acid catalyzed ring closure with a thiophene dialcohol in 2% ethanol dichloromethane afforded a tetraphenylthiapyreniporphyrin in 31% yield. This porphyrinoid was nonaromatic in the free-base form but showed significant diatropicity upon protonation. These results demonstrate that PAH-porphyrin hybrids are easily accessible, and this strategy may allow the incorporation of even larger aromatic subunits. PMID- 28574262 TI - Beyond Immunoprecipitation: Exploring New Interaction Spaces with Proximity Biotinylation. PMID- 28574264 TI - Synergetic Determination of Thermodynamic and Kinetic Signatures Using Isothermal Titration Calorimetry: A Full-Curve-Fitting Approach. AB - Thermodynamic and kinetic signatures are pivotal information for revealing the binding mechanisms of biomolecules, and they play an indispensable role in drug discovery and optimization. While noncalorimetric methods measure only a part of these signatures, isothermal titration calorimetry (ITC) is considered to have the potential to acquire full signatures in an experiment. However, kinetic parameters are generally difficult to extract from ITC curves, as they are inevitably affected by the instrument-response function and the collateral heat of associated process during titrations. Thus, we herein report the development and validation of a full-curve-fitting method to resolve thermal power curves and to maximize the signal extraction using ITC. This method is then employed to quantify the dilution of an aqueous n-propanol solution and examine the inhibition of carbonic anhydrase by 4-carboxybenzenesulfonamide using a commercial instrument with a long apparent response time of ~13 s. PMID- 28574263 TI - Time-Resolved Investigations of Heterobimetallic Cofactor Assembly in R2lox Reveal Distinct Mn/Fe Intermediates. AB - The assembly mechanism of the Mn/Fe ligand-binding oxidases (R2lox), a family of proteins that are homologous to the nonheme diiron carboxylate enzymes, has been investigated using time-resolved techniques. Multiple heterobimetallic intermediates that exhibit unique spectral features, including visible absorption bands and exceptionally broad electron paramagnetic resonance signatures, are observed through optical and magnetic resonance spectroscopies. On the basis of comparison to known diiron species and model compounds, the spectra have been attributed to (MU-peroxo)-MnIII/FeIII and high-valent Mn/Fe species. Global spectral analysis coupled with isotopic substitution and kinetic modeling reveals elementary rate constants for the assembly of Mn/Fe R2lox under aerobic conditions. A complete reaction mechanism for cofactor maturation that is consistent with experimental data has been developed. These results suggest that the Mn/Fe cofactor can perform direct C-H bond abstraction, demonstrating the potential for potent chemical reactivity that remains unexplored. PMID- 28574265 TI - Influence of Side Chain Sizes on Dielectric and Electrorheological Responses of Poly(ionic liquid)s. AB - Poly(ionic liquid)s (PILs) show potential as new anhydrous polyelectrolyte-based smart electrorheological (ER) materials. Understanding the structure-property relationship on a molecular level is very important for guiding the design of PIL based ER materials. In this paper, a family of (p-vinylbenzyl)trialkylammonium hexafluorophosphate-based PIL particles containing different length of substituent alkyl chains attached to immobile ammonium charged site is synthesized for especially understanding the size effect of side chains on ER property. To exclude the particle shape effect, the PIL particles are controlled to be monodisperse sphere-like morphology with a similar size. The ER property of PIL particles when dispersed in insulating oil is investigated and compared by temperature-modulated rheological test under external electric fields. The dielectric spectroscopy is finally performed to study the mechanism behind the size effect of side chains on the ER property of PIL particles. We demonstrate that the size of side chains on the charged site has a significant impact on the ER effect of PIL particles and the PIL particles with shorter side chains have stronger ER property but degraded temperature dependence, and this is related to the fact that the variation of side chain size alters the transport dynamic of mobile counterions and ion motion-induced interfacial polarization. PMID- 28574266 TI - Correction to Brightly Luminescent and Color-Tunable Formamidinium Lead Halide Perovskite FAPbX3 (X = Cl, Br, I) Colloidal Nanocrystals. PMID- 28574267 TI - Copper-Catalyzed, Stereoselective Bis-trifluoromethylthiolation of Propiolic Acid Derivatives with AgSCF3. AB - A copper-catalyzed chemo- and stereoselective oxidative bis trifluoromethylthiolation of propiolic acid derivatives was achieved by using carboxylic acid as the activating group and formic acid as a cosolvent. The reaction of propiolic acid derivatives and AgSCF3 in the presence of (NH4)2S2O8 and catalytic Cu(OAc)2 in MeCN/HCO2H afforded bis-trifluoromethylthiolated acrylic acids in moderate to excellent yields with E selectivity. Further derivatization of the resultant products gave a series of polysubstituted SCF3 containing alkenes. PMID- 28574268 TI - Asymmetric Synthesis of Cyclopenta[3,4]pyrroloindolones via N-Heterocyclic Carbene-Catalyzed Michael/Aldol/Lactamization Cascade Reaction. AB - The N-heterocyclic carbene-catalyzed asymmetric Michael/aldol/lactamization cascade reaction of enals and indole-derived enones for the synthesis of functionalized cyclopenta[3,4]pyrroloindolones with four consecutive stereogenic centers has been achieved. The products were obtained in good yield with high diastereoselectivity and excellent enantioselectivity. PMID- 28574269 TI - Adsorption of Homotrifunctional 1,2,3-Benzenetriol on a Ge(100)-2 * 1 Surface. AB - The adsorption of the homotrifunctional 1,2,3-benzenetriol on Ge(100)-2 * 1 has been investigated by density functional theory calculations, Fourier transform infrared spectroscopy, and X-ray-photoelectron spectroscopy. The results show that the adsorption can occur through OH dissociation of all three hydroxyl groups, and that all three reaction pathways are kinetically and thermodynamically favorable. A coverage-dependent analysis shows that at low coverage, the molecule reacts to form a mix of trifold and dually bound adsorbates. As the coverage increases, the reactions are limited to dissociative adsorption through single and dual attachments. Calculations on the three possible dually bound configurations further reveals that the dissociative adsorption of the third hydroxyl group is limited by geometrical constraints to only two reaction channels. Finally, the proximity between OH-groups in the molecule favors intra- and intermolecular hydrogen bonding, which stabilizes singly and dually bound adsorbate configurations and limits the reactivity of the functional groups. PMID- 28574270 TI - Fluoride Anions in Self-Assembled Chiral Cage for the Enantioselective Protonation of Silyl Enol Ethers. AB - The potential of Song's chiral oligoethylene glycols (oligoEGs) as catalysts was explored in the enantioselective protonation of trimethylsilyl enol ethers in combination with alkali metal fluoride (KF and CsF) and in the presence of a proton source. Highly enantioselective protonations of various silyl enol ethers of alpha-substituted tetralones were achieved, producing chiral alpha-substituted tetralones in full conversion and with up to 99% ee. The established protocol was successfully extended to the synthesis of biologically relevant chiral alpha substituted chromanone and thiochromanone derivatives. PMID- 28574271 TI - Monomeric Octahedral Ruthenium(II) Complex Enabled meta-C-H Nitration of Arenes with Removable Auxiliaries. AB - A removable oxime-assisted meta-C-H nitration of arenes is reported. Mechanistic investigations and DFT calculations reveal a new monomeric octahedral ruthenium(II) complex is responsible for the meta-selective nitration. Dioxygen as a cooxidant is crucial for achieving high conversion and good yields. Moreover, the utility of the present reaction protocol is further showcased by the late-stage modification of the clinical CNS drugs Diazepam and Fluvoxamine. PMID- 28574272 TI - Stimulus-Responsive Supramolecular Aggregate Assembly of Auramine O Templated by Sulfated Cyclodextrin. AB - Self-aggregation of organic molecules is rarely seen with macrocyclic hosts like beta-cyclodextrin, as they preferentially involve the formation of inclusion complexes with the guest molecule. In this contribution, we report the self aggregation of a guest molecule induced by negatively charged sulfated beta cyclodextrin (SCD) to yield highly emissive aggregates of a recently projected amyloid marker dye, Auramine O (AuO). The SCD templated AuO aggregates display very different photophysics when compared to its reported behavior in a wide range of various chemical and biological environment but show a remarkable similarity with the recently reported photophysical behavior of AuO in human insulin fibrillar media, thus providing important insights into the molecular form of AuO responsible for its amyloid sensing ability. The self-assembled AuO aggregates formed in the presence of SCD display a significantly long excited state lifetime, suggesting the retardation of the torsional relaxation of dye in the aggregated state, which otherwise leads to a very short excited-state lifetime for the monomeric form of the dye in the isolated form. Detailed time resolved emission spectra (TRES) measurements show a dynamic Stokes shift suggesting excitonic migration within the AuO aggregates. The supramolecular aggregate assembly displays remarkable sensitivity to important external stimuli like temperature or ionic strength of the medium, pitching for its possible application in designing stimuli-responsive sensing schemes for important analytes. PMID- 28574273 TI - Breathable Microgel Colloidosome: Gas-Switchable Microcapsules with O2 and CO2 Tunable Shell Permeability for Hierarchical Size-Selective Control Release. AB - Microcapsules enabling precise delivery and controlled release are highly desirable. However, it is still challenging to control the release profile by regulating the microcapsule shell permeability. In this work, gas-switchable microgel colloidosome (MGC) with oxygen (O2) and carbon dioxide (CO2) dual gas tunable shell permeability has been developed and tested for control release of water-soluble cargo molecules, based on the size exclusion mechanism. The O2 and CO2 dual gas-switchable poly(2-(diethylamino)ethyl methacrylate-co-2,3,4,5,6 pentafluorostyrene), P(DEA-co-FS), microgels having surface modified with amino group (-NH2) were synthesized and used to stabilize oil-in-water (O/W) Pickering emulsions. The oil-soluble poly(propylene glycol) diglycidyl ether (PPGDGE) was added as an intermicrogel cross-linker. The cross-linking between adjacent microgel particles at the water-oil interface was achieved through the amine epoxy reaction of PPGDGE with the amine groups at the particle surface. Fluorescent-labeled dextran model cargo molecules of 10 kDa (D1) and 2000 kDa (D2) were uploaded under CO2 treatment and locked inside the MGC with N2 treatment. The O2 and CO2 dual-gas switchable properties offered the MGC with tunable shell permeability, which allowed the hierarchical release of D1 and D2 based on size exclusive mechanism. This work provides a robust method for preparation of gas-switchable microcapsules with tunable permeability and size exclusive hierarchical release profile, promising for multiple ingredient controllable release, separation, and reaction. PMID- 28574274 TI - Practical considerations for cangrelor use in patients with acute coronary syndromes. AB - Cangrelor, the first and currently only available intravenous P2Y12 receptor antagonist, has been approved and is now being used in patients with coronary artery disease requiring percutaneous coronary intervention. The rationale for cangrelor use is most robust in patients requiring an immediate, profound, and predictable level of P2Y12 inhibition - especially in patients with acute coronary syndromes. Herein we summarize the drug development program and reflect on practical considerations for clinicians on cangrelor use in the acute setting surrounding percutaneous coronary intervention, including selection of patients, concomitant administration of glycoprotein IIb/IIIa inhibitors and transition strategies from intravenous to oral P2Y12 receptor antagonists. PMID- 28574275 TI - A Novel Drug-Eluting Indwelling Pleural Catheter for the Management of Malignant Effusions. PMID- 28574277 TI - Development of the Trauma-Related Anger Scale. AB - Anger is a pervasive problem following traumatic events. Previous research has demonstrated a moderate relationship between anger and posttraumatic stress disorder (PTSD), yet findings also highlight that anger has not been rigorously measured in the context of PTSD. Thus, this study concerns the development of a complimentary measure to assess anger in the context of PTSD. Participants were 435 undergraduate students. The participants were given a battery including the proposed scale and measures of trauma exposure, PTSD, anger, depression, anxiety, and social desirability. Exploratory factor analyses revealed a hierarchical, four-factor model provided the best fit to the data. The scale appeared psychometrically sound, with excellent internal consistency, good evidence of validity, and good model fit. This scale may provide implications for clinical work, specifically for the assessment and tracking of anger symptoms connected to PTSD. Additionally, this scale may assist with research by predicting treatment outcomes, aggression, and PTSD. PMID- 28574276 TI - Intra-aortic balloon pump protects against hydrostatic pulmonary oedema during peripheral venoarterial-extracorporeal membrane oxygenation. AB - BACKGROUND: Increased left ventricular afterload during peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) support frequently causes hydrostatic pulmonary oedema. Because physiological studies demonstrated left ventricular afterload decrease during VA-ECMO assistance combined with the intra aortic balloon pump (IABP), we progressively changed our standard practice systematically to associate an IABP with VA-ECMO. This study aimed to evaluate IABP efficacy in preventing pulmonary oedema in VA-ECMO-assisted patients. METHODS: A retrospective single-centre study. RESULTS: Among 259 VA-ECMO patients included, 104 received IABP. Weinberg radiological score-assessed pulmonary oedema was significantly lower in IABP+ than IABP- patients at all times after ECMO implantation. This protection against pulmonary oedema persisted when death and switching to central ECMO were used as competing risks (subhazard ratio 0.49, 95% confidence interval (CI) 0.33-0.75; P<0.001). Multivariable analysis retained IABP as being independently associated with a lower risk of radiological pulmonary oedema (odds ratio (OR) 0.4, 95% CI 0.2-0.7; P=0.001) and a trend towards lower mortality (OR 0.54, 95% CI 0.29-1.01; P=0.06). Finally, the time on ECMO free from mechanical ventilation increased in IABP+ patients (2.2+/-4.3 vs. 0.7+/-2.0 days; P=0.0003). Less frequent pulmonary oedema and more days off mechanical ventilation were also confirmed in 126 highly comparable IABP+ and IABP- patients, propensity score matched for receiving an IABP. CONCLUSIONS: Associating an IABP with peripheral VA-ECMO was independently associated with a lower frequency of hydrostatic pulmonary oedema and more days off mechanical ventilation under ECMO. PMID- 28574278 TI - Problems of Determining the Content of Cr(VI) in Raw Materials and Materials Containing Chromite Ore. AB - Materials made with chromite ore are widely applied in the industry metallurgy as well as in the foundry industry. The oxidation number of chromium in these materials is both (III) and (VI). Currently there are no procedures allowing proper determination of chrome in chromite ores and ore-containing materials. The analytical methods applied, which are dedicated to a very narrow range of materials, e.g., cement, and cannot be applied in the case of materials which, apart from trace amounts of Cr(VI), contain mainly compounds of Cr(III), Fe(III) as well as trace compounds of Cu(II), Ni(II) and V(V). In the work particular attention has been paid to the preparation of test samples and creating measurement conditions in which interferences from Cr(III) and Fe(III) spectral lines could be minimized. Two separate instrumental measurement techniques have been applied: Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP AES) and the spectrophotometric method using diphenylcarbazide. PMID- 28574279 TI - Update on Immunohistochemical Analysis in Breast Lesions. AB - CONTEXT: - The utility of immunohistochemistry (IHC) in breast lesions needs to be updated with exceptions among these lesions. Biomarker studies with IHC in triple-negative breast carcinoma may help develop targeted therapies for this aggressive breast cancer. The distinction of metastatic lung adenocarcinoma to the breast and invasive breast carcinoma has significant prognostic and therapeutic implications. The determination can be challenging because both primary tumors can express estrogen receptor and/or HER2 by IHC, creating a diagnostic dilemma. OBJECTIVES: - To provide a practical update on the use of IHC markers in differential diagnoses in breast lesions, including benign, atypical, precancerous, and malignant tumors; to highlight recently published research findings on novel IHC markers in triple-negative breast carcinoma cases; and to reinforce the importance of IHC use as an ancillary tool in distinguishing metastatic lung adenocarcinoma to the breast from primary breast carcinoma using real case examples. DATA SOURCES: - PubMed (US National Library of Medicine, Bethesda, Maryland) literature review and authors' research data and personal experiences were used in this review. CONCLUSIONS: - Immunohistochemistry has an important role in making differential diagnoses in breast lesions in morphologically equivocal settings; recognizing IHC expression status in the exceptions among these lesions will aid in the correct diagnosis of challenging breast cases. Studies suggest that androgen receptor, p16, p53, GATA3, and PELP1 may have potential diagnostic, prognostic, and predictive value in triple negative breast carcinoma cases; these findings may provide insight and a greater understanding of the tumor biology in triple-negative breast carcinomas. In distinguishing metastatic estrogen receptor-positive or HER2+ lung adenocarcinoma to the breast from primary breast carcinoma, napsin A, TTF-1, and GATA3 comprise a useful IHC panel. PMID- 28574280 TI - Current Concepts in Diagnosis, Molecular Features, and Management of Lobular Carcinoma In Situ of the Breast With a Discussion of Morphologic Variants. AB - CONTEXT: - Lobular carcinoma in situ (LCIS) refers to a neoplastic proliferation of cells that characteristically shows loss of E-cadherin expression and has long been regarded as a risk factor for invasive breast cancer. Long-term outcome studies and molecular data have also implicated LCIS as a nonobligate precursor to invasive carcinoma. In the past few decades, pleomorphic and florid LCIS have been recognized as morphologic variants of LCIS with more-aggressive histopathologic features, less-favorable biomarker profiles, and more-complex molecular features compared with classic LCIS. There is still a lack of consensus regarding certain aspects of managing patients with LCIS. OBJECTIVES: - To review recently published literature on LCIS and to provide an overview of the current morphologic classification of LCIS, recent molecular advances, and trends in patient management. DATA SOURCES: - Sources included peer-reviewed, published journal articles in PubMed (US National Library of Medicine, Bethesda, Maryland) and published guidelines from the National Comprehensive Cancer Network (Fort Washington, Pennsylvania). CONCLUSIONS: - Lobular carcinoma in situ represents a marker for increased risk of breast cancer, as well as a nonobligate precursor to invasive carcinoma. Morphologic variants of LCIS-florid and pleomorphic LCIS-are genetically more-complex lesions and are more likely to be associated with invasive carcinoma. Further investigation into which molecular alterations in LCIS are associated with progression to invasive carcinoma is needed to help guide medical and surgical management. PMID- 28574281 TI - A Short-Wavelength Raman Optical Activity Spectrometer with Laser Source at 457 nm for the Characterization of Chiral Molecules. AB - Developing a high-sensitivity Raman optical activity (ROA) spectrometer has been regarded as one of the great challenges in chiral science and technology. Herein, we report our recent progress on the development of a short-wavelength ROA (sw ROA) spectrometer with the excitation line at 457 nm, which shows obviously improved signal-to-noise (S/N) ratio compared with the currently available 532 nm ROA spectrometer. This could be ascribed to the fifth-power of frequency dependence for ROA intensity together with the potential advantage of avoiding fluorescence for most molecules. The required laser power at the sample for being able to obtain a reliable ROA spectrum is less than 150 milliwatts (mW) for most samples. In the case of neat S-alpha-pinene sample, the ROA signal can be acquired with the laser power at sample as low as 5 mW with the total exposure time of 5 min. The concentration of S-alpha-pinene sample can be reduced to 10% (v/v) by diluting with ethanol. These results demonstrate the great potential of sw-ROA (457 nm) working with decreased laser power, shortened acquisition time, and lower sample concentration. The applicability of sw-ROA (457 nm) has also been demonstrated by measuring representative chiral samples, including carbohydrates, amino acids, protein in aqueous solution, and chiral organic molecule in organic solvents. PMID- 28574283 TI - The ultimate diagnosis of unexplained dyspnoea on exertion: Stay tuned on invasive cardiopulmonary exercise testing and beyond. PMID- 28574282 TI - Prevention of sudden death in adolescent athletes: Incremental diagnostic value and cost-effectiveness of diagnostic tests. AB - Introduction Pre-participation screening in athletes attempts to reduce the incidence of sudden death during sports by identifying susceptible individuals. The objective of this study was to evaluate the diagnostic capacity of the different pre-participation screening points in adolescent athletes and the cost effectiveness of the programme. Methods Athletes were studied between 12-18 years old. Pre-participation screening included the American Heart Association questionnaire, electrocardiogram, echocardiogram, and stress test. The cost of test was established by the Catalan public health system. Results Of 1650 athletes included, 57% were men and mean age was 15.09 +/- 1.82 years. Positive findings were identified as follows: in American Heart Association questionnaire 5.09% of subjects, in electrocardiogram 3.78%, in echocardiogram 4.96%, and in exercise test 1.75%. Six athletes (0.36%) were disqualified from participation and 10 (0.60%) were referred for interventional treatment. Diagnostic capacity was assessed by the area under the curve for detection of diseases that motivated disqualification for sport practice (American Heart Association questionnaire, 0.55; electrocardiogram, 0.72; echocardiogram, 0.88; stress test, 0.57). The cost for each athlete disqualified from the sport for a disease causing sudden death was ?45,578. Conclusion The electrocardiogram and echocardiogram were the most useful studies to detect athletes susceptible to sudden death, and the stress test best diagnosed arrhythmias with specific treatment. In our country, pre participatory screening was cost effective to detect athletes who might experience sudden death in sports. PMID- 28574284 TI - A critical review on hepatoprotective effects of bioactive food components. AB - BACKGROUND: Bioactive food components are nonessential biomolecules, which help to give beneficial effects to human being against several diseases. Natural bioactive food components derived from plants and animals, such as phytosterols, carotenoids, polyphenols and fatty acids, have been proposed as valuable substitutions for anticipation and management of hepatotoxic effects and its chronic complications based on in vitro and in vivo studies. OBJECTIVES OF THE STUDY: To summarize drugs and chemical-induced hepatotoxicity and review how various bioactive food components attenuate the hepatotoxicity via cellular mechanisms. RESULTS: Remarkable studies demonstrated that the health promoting effects of bioactive components originated from plants have been frequently attributed to their antioxidant properties and facilitate to increase cellular antioxidant defense system and thereby scavenge free radicals, inhibit lipid peroxidation, augment anti-inflammatory potential, and further protect the liver from damage. CONCLUSION: In this critical review, we summarize current progress in clarifying the molecular mechanism in hepatotoxicity and curative potential of the bioactive food components and its successive clinical outcomes in the field of drug discovery and overcome the problems of medication and chemical-induced hepatotoxic effects. PMID- 28574285 TI - Environmental Vibrio cholerae non O1/ non O139 from the Gangetic delta: a diarrhoeal disease purview. AB - Diarrhoea still remains an unsolved enigma in developing countries, a major concern for the health planners. We targeted the abundance and toxicity of Vibrio cholerae non-O1/non-O139 (NOVC) in Gangetic riverine-estuarine ecosystem. A total of 74 V. cholerae were isolated from 120 water samples (68 NOVC, 6 V. cholerae O1) from two sampling sites off river Ganges. V. cholerae showed distinct seasonality, with steady increase from summer to monsoon, steep ascent in post monsoon and an abrupt decline in winter. Highest number of NOVC was isolated form Howrah, attributed to low salinity and high anthropogenic influence. Environmental NOVC harboured hlyA (94.0 %), rtxA (81.0 %) and toxR (28.0 %) genes. About 23.4 % of the hlyA harbouring NOVC showed haemolytic activity. Accessory toxin genes (tlcR, toxT, RJ and LJ and aldA), among 3-5 % of the NOVC carry significant health implications. Haemolytic activity and biofilm formation in NOVC, during unfavourable conditions, facilitates gene transfer and emphasises the role of environmental NOVC in diarrhoeal incidence in South Bengal, India. PMID- 28574286 TI - Changes of intima-media thickness in marathon runners: A mid-term follow-up. AB - Objective Carotid intima-media thickness (IMT) is used to assess cardiovascular risk and progression of atherosclerosis. It is known that regular physical activity of moderate intensity has beneficial effects on the vasculature. However, it is still discussed controversially whether prolonged exercise, including participation in exhaustive competitive sports such as long-distance races, has also beneficial effects or might even be harmful regarding the cardiovascular system. Patients and methods Thirty-eight male marathon runners (45.8 +/- 7.3 years) were investigated twice (2009 and 2013) for their carotid IMT (using ultrasound techniques), anthropometrics and clinical chemistry. Additionally, training volume (running kilometres per year) and competition participation (half marathon, marathon and ultramarathon) within this follow-up period were assessed. Results During 3.8 +/- 0.4 years of follow-up, runners performed 1587 (850-2500) training kilometres per year and participated in a total of 7 (4-12) long distance competitions. IMT increased in total by 0.05 +/- 0.09 mm or annually by 0.013 +/- 0.023 mm, respectively. Higher increase in IMT over that period was associated with higher fasting blood glucose (beta = .355, p = .045) at baseline examination. Effects of training volume and number of competitions on the progression of IMT could not be demonstrated in our longitudinal analysis. Conclusions Higher blood glucose levels are associated with detrimental effects on vasculature in otherwise healthy male marathon runners. Regular marathon training, including competition participation over at least several years, was not associated with detrimental effects on IMT or, vice versa, seems not to provide beneficial effects on vasculature. PMID- 28574287 TI - Microbial interactions during sugar cane must fermentation for bioethanol production: does quorum sensing play a role? AB - Microbial interactions represent important modulatory role in the dynamics of biological processes. During bioethanol production from sugar cane must, the presence of lactic acid bacteria (LAB) and wild yeasts is inevitable as they originate from the raw material and industrial environment. Increasing the concentration of ethanol, organic acids, and other extracellular metabolites in the fermentation must are revealed as wise strategies for survival by certain microorganisms. Despite this, the co-existence of LAB and yeasts in the fermentation vat and production of compounds such as organic acids and other extracellular metabolites result in reduction in the final yield of the bioethanol production process. In addition to the competition for nutrients, reduction of cellular viability of yeast strain responsible for fermentation, flocculation, biofilm formation, and changes in cell morphology are listed as important factors for reductions in productivity. Although these consequences are scientifically well established, there is still a gap about the physiological and molecular mechanisms governing these interactions. This review aims to discuss the potential occurrence of quorum sensing mechanisms between bacteria (mainly LAB) and yeasts and to highlight how the understanding of such mechanisms can result in very relevant and useful tools to benefit the biofuels industry and other sectors of biotechnology in which bacteria and yeast may co-exist in fermentation processes. PMID- 28574288 TI - Chronotype and its relationship with sleep disorders in children with attention deficit hyperactivity disorder. AB - Chronotype can be classified as morningness types, people who prefer morning hours for their physical and mental activities; eveningness types, people who prefer the afternoon or evening hours; and intermediate types, those who show characteristics of both morningness and eveningness types. Attention deficit hyperactivity disorder (ADHD) has been linked with disturbances in chronotype, particularly increased eveningness. Despite the possibility of an association between chronotypes, sleep disturbances and ADHD symptoms, there is little evidence of this association considering the child population. The purpose of this study was to examine chronotype preferences in children aged between 7 and 12 years who were diagnosed as having ADHD in the context of sleep disturbances. The Schedule for Affective Disorders and Schizophrenia for School Age Children Present and Lifetime Version, Conner's Rating Scales, Children's Sleep Habit Questionnaire and Children's Chronotype Questionnaire were used for the evaluation of children with ADHD and healthy controls. The ADHD group was 73% combined-type, and the eveningness scores of the ADHD group (n = 52) were significantly higher than the control group (n = 52) (p < 0.01). There was a positive correlation between the higher scores of eveningness and total scores on resistance to sleep time (p < 0.09), respiratory problems during sleep and daytime sleepiness in the ADHD group. CSHQ total score was found to be a predictive factor for eveningness among children with ADHD (p < 0.01). These findings highlight possible reciprocal links between ADHD symptoms, sleep disturbances and chronotype in children aged 7-12 years, which might lead to individualized treatment options. PMID- 28574289 TI - MRI capture of intermittent ventriculomegaly in a patient with ventriculo peritoneal shunt. AB - Intermittent change in ventricular size in patients with ventriculo-peritoneal shunts is a recognised complication but definitive imaging evidence is rare. We report a 3 years old boy with a medullary astrocytoma and ventriculo-peritoneal shunt placement who demonstrated intermittent ventriculomegaly during a single MRI scan. PMID- 28574290 TI - Peat moss Sphagnum riparium follows a circatrigintan growth rhythm in situ: A case report. AB - In situ growth of Sphagnum riparium Angstr. shoots were monitored during the 2015 and 2016 growing seasons in Karelia, Russia. It was established that shoot growth rates fluctuated with a period of around 30 days, that is, showed a circatrigintan rhythm. Such rhythms from mosses have not been previously reported. Correlation of growth rates with the percentage of the illuminated portion of the Moon was statistically significant (p<0.01) in both years. Shoot growth rates were reliably higher around the new Moon compared to the full Moon. This phenomenon may be due either to causality or to a pure coincidence of processes with similar rhythms. PMID- 28574291 TI - Temperature-sensitive heparin-modified poloxamer hydrogel with affinity to KGF facilitate the morphologic and functional recovery of the injured rat uterus. AB - Endometrial injury usually results in intrauterine adhesion (IUA), which is an important cause of infertility and recurrent miscarriage in reproductive women. There is still lack of an effective therapeutic strategy to prevent occurrence of IUA. Keratinocyte growth factor (KGF) is a potent repair factor for epithelial tissues. Here, a temperature-sensitive heparin-modified poloxamer (HP) hydrogel with affinity to KGF (KGF-HP) was used as a support matrix to prevent IUA and deliver KGF. The rheology of KGF-HP hydrogel was carefully characterized. The cold KGF-HP solution was rapidly transited to hydrogel with suitable storage modulus (G') and loss modulus (G") for the applications of uterus cavity at temperature of 33 degrees C. In vitro release demonstrated that KGF was released from HP hydrogels in sustained release manner for a long time. In vivo bioluminescence imaging showed that KGF-HP hydrogel was able to prolong the retention of the encapsulated KGF in injured uterus of rat model. Moreover, the morphology and function of the injured uterus were significantly recovered after administration of KGF-HP hydrogel, which were evaluated by two-dimensional ultrasound imaging and receptive fertility. Not only proliferation of endometrial glandular epithelial cells and luminal epithelial cells but also angiogenesis of injured uterus were observed by Ki67 and CD31 staining after 7 d of treatment with KGF-HP hydrogel. Finally, a close relatively relationship between autophagy and proliferation of endometrial epithelial cells (EEC) and angiogenesis was firstly confirmed by detecting expression of LC3-II and P62 after KGF treatment. Overall, KGF-HP may be used as a promising candidate for IUA treatment. PMID- 28574292 TI - The benefits of a local neurosurgery careers day. PMID- 28574293 TI - Evaluation of maternal serum hypoxia inducible factor-1alpha, progranulin and syndecan-1 levels in pregnancies with early- and late-onset preeclampsia. AB - OBJECTIVE: To determine the serum levels of HIF-1 alpha, progranulin, and syndecan-1 in preeclampsia (PE) and normal pregnancy, and to compare whether these markers demonstrate any difference between early-onset PE (EO-PE) and late onset PE (LO-PE). METHODS: This cross-sectional study was conducted on 27 women with EO-PE, 27 women with LO-PE, and 26 healthy normotensive pregnant controls matched for gestational age. Maternal levels of serum HIF-1 alpha, progranulin, and syndecan-1 were measured with the use of an enzyme-linked immunosorbent assay kit. RESULTS: Statistical analysis revealed significant differences between the control and the PE groups in progranulin (p < .001) and syndecan-1 (p <.001) levels. There were no significant differences in the serum HIF-1 alpha levels between these groups (p= .069). When PE patients were evaluated by considering subgroups; statistical analysis revealed significant inter-group differences in all biomarkers. Serum progranulin levels were significantly higher in LO-PE compared with the other two groups (EO-PE versus LO-PE and LO-PE versus controls p = .000). Control group presented significantly higher syndecan-1 levels, than EO and LO-PE (p < .001). HIF-1 alpha levels positively correlated with progranulin levels (r = .439, p= .000). CONCLUSIONS: Serum progranulin may have potential to be used as a biomarker for the differentiation of EO-PE and LO-PE. The co-operative action between HIF-1 alpha and progranulin might play a key role in the pathogenesis of LO-PE. The predominant feature of LO-PE seems to be an inflammatory process, whereas in EO-PE placentation problem seems to be the main pathology. PMID- 28574296 TI - Prediction of preeclampsia in type 1 diabetes in early pregnancy by clinical predictors: a systematic review. AB - PURPOSE: The purpose of this study is to evaluate the prevalence and possible clinical predictors of preeclampsia present in early pregnancy among women with type 1 diabetes. METHODS: A systematic search of PubMed was conducted in April 2017. Inclusion criteria were largely unselected cohort, including at least 100 women with type 1 diabetes, dealing with either the prevalence of preeclampsia or possible clinical predictors of preeclampsia identified in early pregnancy. RESULTS: Based on 11,518 pregnancies in 11 articles, the prevalence of preeclampsia in women with type 1 diabetes was 17%, five to six times more than in the background population. In early pregnancy, the following clinical predictors were associated with increased prevalence of preeclampsia: diabetic nephropathy (OR 3.7-23.5), microalbuminuria (OR 3.8-11.7), diabetic retinopathy (OR 1.9-2.9) and pre-existing hypertension (OR 3.8-17.1) as well as high blood pressure within the normotensive range. HbA1C, body mass index and nulliparity were positively associated with preeclampsia, but not consistently. CONCLUSION: The prevalence of preeclampsia in women with type 1 diabetes was 17%. In early pregnancy pre-existing hypertension and high blood pressure within the normotensive range as well as presence of microangiopathy were predictors of preeclampsia. Poor glycaemic control, obesity and nulliparity probably also contribute to the increased risk. PMID- 28574295 TI - Prevalence of hepatitis C and pre-testing awareness of hepatitis C status in 1500 consecutive PWID participants at the Stockholm needle exchange program. AB - BACKGROUND: People who inject drugs (PWID) are the driving force of the hepatitis C virus (HCV) epidemic. Still, treatment is scarcely offered and the awareness of HCV status in PWID is poor. Prevention includes clean needles, syringes and other paraphernalia. HCV awareness was investigated in 1500 PWID in a needle exchange program (NEP) in Stockholm, Sweden, together with HCV prevalence, and time to HCV infection after start of injection drug use. METHODS: 1500 PWID in the Stockholm NEP were consecutively enrolled. At baseline, awareness of the individual pre test HCV status was measured followed with tests for anti-HCV and HCV RNA if anti HCV was positive. RESULTS: Mean age of participants was 39 years and the mean time of injection drug use 18 (0-51) years. The overall anti-HCV prevalence was 82% whereof 76% were HCV RNA positive. Within 4 years after start of injection drug use 50% of the participants were anti-HCV positive. Self-awareness of HCV status was low. Hence, 32% who believed that they never have encountered HCV were anti-HCV positive, and 24% were HCV RNA positive. For those who reported not being aware of their HCV status 62% were anti-HCV positive, and 47% were HCV RNA positive. CONCLUSION: The very high prevalence of chronic HCV in PWID in Stockholm indicates that both measures for prevention with increased awareness of HCV, and a higher antiviral treatment utilisation in combination need to be implemented in order to reduce the HCV prevalence and combat the HCV epidemic. PMID- 28574297 TI - Postpartum depression in adolescent mothers. AB - BACKGROUND: Postpartum depression has been extensively studied in adults but is less understood in adolescent mothers, despite a prevalence that is double that observed in adult mothers. The purpose of this review was to describe the epidemiology, risk factors, treatment and prognosis for adolescents with postpartum depression. We also sought to identify limitations of the available literature and propose areas for future study targeting postpartum depression in this vulnerable population. METHODS: A Medline literature search was conducted for articles published between 1996 and 2015. We identified relevant studies by combining the indexed search terms 'pregnancy in adolescence or teenage pregnancy' and 'depression or postpartum depression'. Additional studies were identified from references of selected articles. We limited our search results to adolescents (18 years or younger) and English language publications. Case studies/series and editorials were excluded. RESULTS: The Medline database search identified 134 articles of which 57 met inclusion criteria. Ten additional articles were identified from reference lists yielding a total of n = 67 articles for review. Among the articles selected, 10 described epidemiology, 27 identified risk factors, nine measured long-term outcome and 21 proposed treatment strategies for postpartum depression in adolescent mothers. CONCLUSIONS: There is limited literature addressing adolescent postpartum depression, but there has been a significant growth of interest in recent years. There is a need for more randomized control trials to establish gold standards for assessing postpartum depression in adolescent mothers and standards for treatment in these patients. PMID- 28574298 TI - Valuable contribution of magnetic resonance spectroscopy in differentiation of brain abscess from glioma. PMID- 28574299 TI - Quality indicators for the diagnosis and antibiotic treatment of acute respiratory tract infections in general practice: a RAND Appropriateness Method. AB - OBJECTIVE: To develop quality indicators for the diagnosis and antibiotic treatment of acute respiratory tract infections, tailored to the Danish general practice setting. DESIGN: A RAND/UCLA Appropriateness Method was used. SETTING: General practice. SUBJECTS: A panel of nine experts, mainly general practitioners, was asked to rate the relevance of 64 quality indicators for the diagnosis and antibiotic treatment of acute respiratory tract infections based on guidelines. Subsequently, a face-to-face meeting was held to resolve misinterpretations and to achieve consensus. MAIN OUTCOME MEASURES: The experts were asked to rate the indicators on a nine-point Likert scale. Consensus of appropriateness for a quality indicator was reached if the overall panel median rating was 7-9 with agreement. RESULTS: A total of 50 of the 64 proposed quality indicators attained consensus. Consensus was achieved for 12 indicators focusing on the diagnostic process and 19 indicators focusing on the decision about antibiotic treatment and choice of antibiotics, respectively. CONCLUSION: These newly developed quality indicators may be used to strengthen Danish general practitioners' focus on their management of patients with acute respiratory tract infections and to identify where there is a need for future quality improvements. PMID- 28574300 TI - Anti-CD123 antibody-modified niosomes for targeted delivery of daunorubicin against acute myeloid leukemia. AB - A novel niosomal delivery system was designed and investigated for the targeted delivery of daunorubicin (DNR) against acute myeloid leukemia (AML). Anti-CD123 antibodies conjugated to Mal-PEG2000-DSPE were incorporated into normal niosomes (NS) via a post insertion method to afford antibody-modified niosomes (CD123-NS). Next, NS was modified with varying densities of antibody (0.5 or 2%, antibody/Span 80, molar ratio), thus providing L-CD123-NS and H-CD123-NS. We studied the effect of antibody density on the uptake efficiency of niosomes in NB4 and THP-1 cells, on which CD123 express differently. Our results demonstrate CD123-NS showed significantly higher uptake efficiency than NS in AML cells, and the uptake efficiency of CD123-NS has been ligand density-dependent. Also, AML cells preincubated with anti-CD123 antibody showed significantly reduced cellular uptake of CD123-NS compared to control. Further study on the uptake mechanism confirmed a receptor-mediated endocytic process. Daunorubicin (DNR)-loaded H CD123-NS demonstrated a 2.45- and 3.22-fold higher cytotoxicity, compared to DNR loaded NS in NB4 and THP-1 cells, respectively. Prolonged survival time were observed in leukemic mice treated with DNR-H-CD123-NS. Collectively, these findings support that the CD123-NS represent a promising delivery system for the treatment of AML. PMID- 28574301 TI - Wellbeing: the challenge of 'operationalising' an holistic concept within a reductionist public health programme. AB - : Wellbeing is a concept that, while contested, recognises individual and wider social, economic, political and environmental contextual influences - and is of growing interest and relevance locally and globally. In this article, we report on one aspect of an evaluative research study conducted on a public health programme in North West England. AIMS: Within the context of a process evaluation that explored the delivery of a public health programme and sought to increase understanding of how and why different approaches worked well or not so well, this article focuses specifically on the concept of wellbeing, examining perceptions of multiple stakeholders. METHODS: Interviews and focus groups were undertaken with 52 stakeholders involved in managing and facilitating the programme and its composite projects and with 90 community members involved as project participants. Data were subjected to thematic analysis, cross-check and refining. RESULTS: Results highlight stakeholders' diverse understandings of wellbeing, the complex relationship between health and wellbeing, and the perceived dissonance between the holistic concept of wellbeing and the reductionist design of the programme. CONCLUSIONS: Wellbeing was understood to be 'more than health' and 'more than happiness', concerned with effective functioning, sense of purpose and flourishing. Essentially holistic, wellbeing offers opportunities to transcend clinical/pathogenic conceptions of 'health' and resonate with individuals, communities and local authorities. This raises concerns about how wellbeing can be meaningfully realised without compromising the concept, particularly when programmes are structured in reductionist ways requiring monitoring against discrete outcomes. Implications for practice include the following: utilising wellbeing as a driver for cross-cutting public health in challenging economic and organisational contexts, acknowledging that wellbeing is essentially social as well as individual, appreciating that wellbeing is experienced in relation to contexts and surroundings, and recognising that wellbeing defined in terms of individual happiness risks compromising the future wellbeing of societies and the planet. PMID- 28574302 TI - Clinical characteristics, molecular profile and outcomes of myeloid sarcoma: a single institution experience over 13 years. AB - BACKGROUND: Myeloid sarcoma (MS) is characterized by extramedullary infiltration by immature myeloid cells. Owing to rarity of this disease, the clinical features and overall outcomes are yet to be clarified. OBJECTIVE: To define clinical characteristics, epidemiology, pathologic findings, treatment options and outcomes in MS. METHODS: We conducted a retrospective review of 23 patients diagnosed with MS at our institute over a period of 13 years (2002-2015). RESULTS: MS presented mostly as a manifestation of relapsed acute myeloid leukemia, seen in 39% of patients. Skin and subcutaneous soft tissues were the most common sites of anatomic involvement (69.5%). Ninety five percent (n = 19) were positive for classical myeloid markers with either cytochemical staining (chloracetate-esterase, MPO), flow-cytometry (CD33, CD34, CD13 and CD117), or immunohistochemistry (CD34, CD43, CD68 and lysozyme). Of these, 52% were positive for CD33 (n = 12), 35% for CD68 (n = 8), 30% for CD34 (n = 7), and 26% for lysozyme (n = 6). Cytogenetic abnormalities were seen in 63% (n = 12/19) patients on bone-marrow aspirate, with five patients displaying a complex (n = 3) or monosomal (n = 2) karyotype. Twenty seven percent patients with a normal karyotype had presence of deleterious mutations (FLT3, ASXL, STAG and JAK2) on further testing with myeloid mutation panel. The Median overall survival (OS) of the entire cohort was 15.9 months (95% CI, 7.4-24.4 months). The OS was significantly better for patients <65 years (24.6 vs. 3.4 months, p = 0.009) of age, and for those attaining a complete remission (CR) to induction therapy (25.7 vs. 0.8 months, p < 0.001). All patients who underwent allogeneic hematopoietic stem cell transplant attained long-term remissions, with a median follow-up of 54 (range 32-120) months. CONCLUSION: Failure to achieve CR with induction therapy, and age >65 years are associated with poor outcomes in MS. Allogeneic stem-cell transplant in first remission appears to be the most effective modality for achieving long-term remissions. PMID- 28574303 TI - Technological solutions for an effective health surveillance system for road traffic crashes in Burkina Faso. AB - BACKGROUND: In the early 2000s, electronic surveillance systems began to be developed to collect and transmit data on infectious diseases in low-income countries (LICs) in real-time using mobile technologies. Such surveillance systems, however, are still very rare in Africa. Among the non-infectious epidemics to be surveilled are road traffic injuries, which constitute major health events and are the fifth leading cause of mortality in Africa. This situation also prevails in Burkina Faso, whose capital city, Ouagadougou, is much afflicted by this burden. There is no surveillance system, but there have been occasional surveys, and media reports of fatal crashes are numerous and increasing in frequency. OBJECTIVE: The objective of this article is to present the methodology and implementation of, and quality of results produced by, a prototype of a road traffic crash and trauma surveillance system in the city of Ouagadougou. METHODS: A surveillance system was deployed in partnership with the National Police over a six-month period, from February to July 2015, across the entire city of Ouagadougou. Data were collected by all seven units of the city's National Police road crash intervention service. They were equipped with geotracers that geolocalized the crash sites and sent their positions by SMS (short message service) to a surveillance platform developed using the open source tool Ushahidi. Descriptive statistical analyses and spatial analyses (kernel density) were subsequently performed on the data collected. RESULTS: The process of data collection by police officers functioned well. Researchers were able to validate the data collection on road crashes by comparing the number of entries in the platform against the number of reports completed by the crash intervention teams. In total, 873 crash scenes were recorded over 3 months. The system was accessible on the Internet for open consultation of the map of crash sites. Crash-concentration analyses were produced that identified 'hot spots' in the city. Nearly 80% of crashes involved two-wheeled vehicles. Crashes were more numerous at night and during rush hours. They occurred primarily at intersections with traffic lights. With regard to health impacts, half of the injured were under the age of 29 years, and 6 persons were killed. CONCLUSIONS: This pilot study demonstrated the feasibility of developing simple surveillance systems, based on mHealth, in LICs. PMID- 28574304 TI - Quantitative Risk Assessment of Antimicrobial-Resistant Foodborne Infections in Humans Due to Recombinant Bovine Somatotropin Usage in Dairy Cows. AB - Recombinant bovine somatotropin (rbST) is a production-enhancing technology that allows the dairy industry to produce milk more efficiently. Concern has been raised that cows supplemented with rbST are at an increased risk of developing clinical mastitis, which would potentially increase the use of antimicrobial agents and increase human illnesses associated with antimicrobial-resistant bacterial pathogens delivered through the dairy beef supply. The purpose of this study was to conduct a quantitative risk assessment to estimate the potential increased risk of human infection with antimicrobial-resistant bacteria and subsequent adverse health outcomes as a result of rbST usage in dairy cattle. The quantitative risk assessment included the following steps: (i) release of antimicrobial-resistant organisms from the farm, (ii) exposure of humans via consumption of contaminated beef products, and (iii) consequence of the antimicrobial-resistant infection. The model focused on ceftiofur (parenteral and intramammary) and oxytetracycline (parenteral) treatment of clinical mastitis in dairy cattle and tracked the bacteria Campylobacter spp., Salmonella enterica subsp. enterica, and Escherichia coli in the gastrointestinal tract of the cow. Parameter estimates were developed to be maximum risk to overestimate the risk to humans. The excess number of cows in the U.S. dairy herd that were predicted to carry resistant bacteria at slaughter due to rbST administration was negligible. The total number of excess human illnesses caused by resistant bacteria due to rbST administration was also predicted to be negligible with all risks considerably less than one event per 1 billion people at risk per year for all bacteria. The results indicate a high probability that the use of rbST according to label instructions presents a negligible risk for increasing the number of human illnesses and subsequent adverse outcomes associated with antimicrobial resistant Campylobacter, Salmonella, or E. coli . PMID- 28574305 TI - Growth Modeling of Aspergillus niger Strains Isolated from Citrus Fruit as a Function of Temperature on a Synthetic Medium from Lime (Citrus latifolia T.) Pericarp. AB - : Molds are responsible for postharvest spoilage of citrus fruits. The objective of this study was to evaluate the effect of temperature on growth rate and the time to visible growth of Aspergillus niger strains isolated from citrus fruits. The growth of these strains was studied on agar lime medium (AL) at different temperatures, and growth rate was estimated using the Baranyi and Roberts model (Int. J. Food Microbiol. 23:277-294, 1994). The Rosso et al. cardinal model with inflexion (L. Rosso, J. R. Lobry, S. Bajard, and J. P. Flandrois, J. Theor. Biol. 162:447-463, 1993) was used as a secondary model to describe the effect of temperature on growth rate and the lag phase. We hypothesized that the same model could be used to calculate the time for the mycelium to become visible (tv) by substituting the lag phase (1/lambda and 1/lambdaopt) with the time to visible colony (1/tv-opt and 1/tv), respectively, in the Rosso et al. MODEL: High variability was observed at suboptimal conditions. Extremes of temperature of growth for A. niger seem to have a normal variability. For the growth rate and time tv, the model was satisfactorily compared with results of previous studies. An external validation was performed in lime fruits; the bias and accuracy factors were 1.3 and 1.5, respectively, for growth rate and 0.24 and 3.72, respectively, for the appearance time. The discrepancy may be due to the influence of external factors. A. niger grows significantly more slowly on lime fruit than in culture medium, probably because the nutrients are more easily available in medium than in fruits, where the peel consistency may be a physical barrier. These findings will help researchers understand the postharvest behavior of mold on lime fruits, host-pathogen interactions, and environmental conditions infecting fruit and also help them develop guidelines for future work in the field of predictive mycology to improve models for control of postharvest fungi. PMID- 28574306 TI - Impact of Mannanase-Producing Bacillus spp. on the Accuracy of the 3M Petrifilm Aerobic Count Method. AB - Consistent deviations of the 3M Petrifilm aerobic counts (AC) from the standard pour plate aerobic plate count (APC) were observed with dehydrated onion and garlic products. A large study was designed to determine the relationship of these two methods and the root cause for the deviations. A total of 3,800 dehydrated onion and garlic samples were analyzed by both the Petrifilm AC and the standard pour plate APC method. Large spreader-like liquefied areas were observed on numerous Petrifilm plates. These liquefied areas made enumeration inaccurate. "Liquefier" microorganisms from Petrifilm plates were isolated and identified to species level by 16S rRNA and gyrB gene sequencing. Enzyme diffusion assay was performed to determine potential enzymatic degradation of guar gum, the gelling agent used in Petrifilm plates. The results indicated that the correlation between Petrifilm AC and standard APC is relatively low. Paired t test results suggested that the Petrifilm AC method produced significantly different results compared with standard APC. The discrepancies were attributable at least partly to a liquefier organism that hydrolyzed guar gum, leading to liquefaction. Liquefaction of Petrifilm plates seems to have two effects on accuracy: (i) liquefied areas may allow motile organisms to move and multiply in the liquefied area during the incubation period, yielding more than one colony from one cell and, as a result, leading to overestimation of the microbial load and (ii) the blurred areas obscure other colonies, leading to potential underestimation. The liquefier organism was identified as Bacillus amyloliquefaciens , a potent mannanase producer and heat-resistant spore former. Enzyme diffusion assay confirmed that mannanase contained in the cell-free supernatant of B. amyloliquefaciens can hydrolyze the 1,4-beta-mannopyranosyl bond, the backbone of guar gum. This is the first report of the role of B. amyloliquefaciens in the liquefaction of Petrifilm plates and its negative impact on accuracy. PMID- 28574307 TI - Korsakoff syndrome from retrochiasmatic suprasellar lesions: rapid reversal after relief of cerebral compression in 4 cases. AB - Korsakoff syndrome is a chronic memory disorder caused by a severe deficiency of thiamine that is most commonly observed in alcoholics. However, some have proposed that focal structural lesions disrupting memory circuits-in particular, the mammillary bodies, the mammillothalamic tract, and the anterior thalamus-can give rise to this amnestic syndrome. Here, the authors present 4 patients with reversible Korsakoff syndromes caused by suprasellar retrochiasmatic lesions compressing the mammillary bodies and adjacent caudal hypothalamic structures. Three of the patients were found to have large pituitary macroadenomas in their workup for memory deficiency and cognitive decline with minimal visual symptoms. These tumors extended superiorly into the suprasellar region in a retrochiasmatic position and caused significant mass effect in the bilateral mammillary bodies in the base of the brain. These 3 patients had complete and rapid resolution of amnestic problems shortly after initiation of treatment, consisting of resection in 1 case of nonfunctioning pituitary adenoma or cabergoline therapy in 2 cases of prolactinoma. The fourth patient presented with bizarre and hostile behavior along with significant memory deficits and was found to have a large cystic craniopharyngioma filling the third ventricle and compressing the midline diencephalic structures. This patient underwent cyst fenestration and tumor debulking, with a rapid improvement in his mental status. The rapid and dramatic memory improvement observed in all of these cases is probably due to a reduction in the pressure imposed by the lesions on structures contiguous to the third ventricle, rather than a direct destructive effect of the tumor, and highlights the essential role of the caudal diencephalic structures-mainly the mammillary bodies-in memory function. In summary, large pituitary lesions with suprasellar retrochiasmatic extension and third ventricular craniopharyngiomas can cause severe Korsakoff-like amnestic syndromes, probably because of bilateral pressure on or damage to mammillary bodies, anterior thalamic nuclei, or their major connections. Neuropsychiatric symptoms may rapidly and completely reverse shortly after initiation of therapy via surgical decompression of tumors or pharmacological treatment of prolactinomas. Early identification of these lesions with timely treatment can lead to a favorable prognosis for this severe neuropsychiatric disorder. PMID- 28574308 TI - Clinical outcomes of an endoscopic transclival and transpetrosal approach for primary skull base malignancies involving the clivus. AB - OBJECTIVE The endoscopic endonasal approach for treating primary skull base malignancies involving the clivus is a formidable task. The authors hypothesized that tumor involvement of nearby critical anatomical structures creates hurdles to endoscopic gross-total resection (GTR). The aim of this study was to retrospectively review the clinical outcomes of patients who underwent an endoscopic endonasal approach to treat primary malignancies involving the clivus and to analyze prognostic factors for GTR. METHODS Between January 2009 and November 2015, 42 patients underwent the endoscopic endonasal approach for resection of primary skull base malignancies involving the clivus at 2 independent institutions. Clinical data; tumor locations within the clivus; and anatomical involvement of the cavernous or paraclival internal carotid artery, cisternal trigeminal nerve, hypoglossal canal, and dura mater were investigated to assess the extent of resection. Possible prognostic factors affecting GTR were also analyzed. RESULTS Of the 42 patients, 37 were diagnosed with chordomas and 5 were diagnosed with chondrosarcomas. The mean (+/- SD) preoperative tumor volume was 25.2 +/- 30.5 cm3 (range 0.8-166.7 cm3). GTR was achieved in 28 patients (66.7%) and subtotal resection in 14 patients (33.3%). All tumors were classified as upper (n = 17), middle (n = 17), or lower (n = 8) clival tumors based on clival involvement, and as central (24 [57.1%]) or paramedian (18 [42.9%]) based on laterality of the tumor. Univariate analysis identified the tumor laterality (OR 6.25, 95% CI 1.51-25.86; p = 0.011) as significantly predictive of GTR. In addition, the laterality of the tumor was found to be a statistically significant predictor in multivariate analysis (OR 41.16, 95% CI 1.12-1512.65; p = 0.043). CONCLUSIONS An endoscopic endonasal approach can provide favorable clinical and surgical outcomes. However, the tumor laterality should be considered as a potential obstacle to total removal. PMID- 28574309 TI - Early low cerebral blood flow and high cerebral lactate: prediction of delayed cerebral ischemia in subarachnoid hemorrhage. AB - OBJECTIVE Delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH) is one of the major contributors to poor outcome. It is crucial to be able to detect early signs of DCI to prevent its occurrence. The objective of this study was to determine if low cerebral blood flow (CBF) measurements and pathological microdialysis parameters measured at the bedside can be observed early in patients with SAH who later developed DCI. METHODS The authors included 30 patients with severe SAH. The CBF measurements were performed at Day 0-3 after disease onset, using bedside xenon-CT. Interstitial glucose, lactate, pyruvate, glycerol, and glutamate were measured using microdialysis. RESULTS Nine of 30 patients developed DCI. Patients with DCI showed significantly lower global and regional CBF, and lactate was significantly increased in these patients. A high lactate/pyruvate ratio was also detected in patients with DCI. CONCLUSIONS Early low CBF measurements and a high lactate and lactate/pyruvate ratio may be early warning signs of the risk of developing DCI. The clinical value of these findings needs to be confirmed in larger studies. PMID- 28574311 TI - Erratum. Gamma Knife radiosurgery for recurrent or residual seizures after anterior temporal lobectomy in mesial temporal lobe epilepsy patients with hippocampal sclerosis: long-term follow-up results of more than 4 years. PMID- 28574310 TI - Exosomes as a biomarker platform for detecting epidermal growth factor receptor positive high-grade gliomas. AB - OBJECTIVE High-grade glial brain tumors are often characterized by an elevated expression of the tumorigenic epidermal growth factor receptor variant III ( EGFRvIII). The authors sought to establish a clinically adaptive protocol as a noninvasive diagnostic tool for EGFRvIII detection through serum exosomes. METHODS Purity of serum exosome/RNA was confirmed by electron microscopy and flow cytometry and through an RNA bioanalyzer profile. EGFRvIII amplification was initially established by semiquantitative polymerase chain reaction in tumor tissues and exosomes. Diagnostic performance of EGFRvIII transcript in tissue versus exosome was determined using a 2 * 2 clinical table approach. Overall survival was determined using Kaplan-Meier analysis. RESULTS The EGFRvIII transcript was detected in 39.5% of tumor tissue samples and in 44.7% of their paired serum exosome samples; 28.1% of biopsy tumors coexpressed wild-type EGFR and EGFRvIII. Tissue EGFRvIII amplification served as the reference-positive control for its paired serum expression. The overall clinical sensitivity and specificity of semiquantitative exosome EGFRvIII polymerase chain reaction detection assay in serum were 81.58% (95% CI 65.67%-92.26%) and 79.31% (95% CI 66.65%-88.83%), respectively. Age, sex, tumor location, and side of the body on which the tumor was located had no effect on the detection rate of exosomal EGFRvIII transcript. EGFRvIII expression either in exosomes or tissue correlated with poor survival. CONCLUSIONS The authors established a serum-based method for detection of EGFRvIII in high-grade brain tumors that might serve as an optimal noninvasive method for diagnosing EGFRvIII-positive high-grade gliomas. PMID- 28574313 TI - Rationale for graft selection in patients with complex internal carotid artery aneurysms treated with extracranial to intracranial high-flow bypass and therapeutic internal carotid artery occlusion. AB - OBJECTIVE After internal carotid artery (ICA) sacrifice without revascularization for complex aneurysms, ischemic complications can occur. In addition, hemodynamic alterations in the circle of Willis create conditions conducive to the formation of de novo aneurysms or the enlargement of existing untreated aneurysms. Therefore, the revascularization technique remains indispensable. Because vessel sizes and the development of collateral circulation are different in each patient, the ideal graft size to prevent low flow-related ischemic complications (LRICs) in external carotid artery (ECA)-middle cerebral artery (MCA) bypass with therapeutic ICA occlusion (ICAO) has not been well established. Authors of this study hypothesized that the adequate graft size could be calculated from the size of the sacrificed ICA and the values of MCA pressure (MCAP) and undertook an investigation in patients with complex ICA aneurysms treated with ECA-graft-MCA bypass and therapeutic ICAO. METHODS In the period between July 2006 and January 2016, 80 patients with complex ICA aneurysms were treated with ECA-MCA bypass and therapeutic ICAO. Preoperative balloon test occlusion (BTO) was performed, and the BTO pressure ratio was defined as the mean stump pressure/mean preocclusion pressure. Low flow-related ischemic complications were defined as new postoperative neurological deficits and ipsilateral cerebral blood flow reduction. Initial MCAP (iMCAP), MCAP after clamping the ICA (cMCAP), and MCAP after releasing the graft (gMCAP) were intraoperatively monitored. The MCAP ratio was defined as gMCAP/iMCAP. Based on the Hagen-Poiseuille law, the expected MCAP ratio ([expected gMCAP]/iMCAP) was hypothesized as follows: (1 - cMCAP/iMCAP)(graft radius/ICA radius)2 + (cMCAP/iMCAP). Correlations between the BTO pressure ratio and cMCAP/iMCAP, and between the actual and expected MCAP ratios, were evaluated. Risk factors for LRICs were also evaluated. RESULTS The mean BTO pressure ratio was significantly correlated with the mean cMCAP/iMCAP (r = 0.68, p < 0.0001). The actual MCAP ratio correlated with the expected MCAP ratio (r = 0.43, p < 0.0001). If the expected MCAP ratio was set up using the BTO pressure ratio instead of cMCAP/iMCAP (BTO-expected MCAP ratio), the mean BTO expected MCAP ratio significantly correlated with the expected MCAP ratio (r = 0.95, p < 0.0001). During a median follow-up period of 26.1 months, LRICs were observed in 9 patients (11%). An actual MCAP ratio < 0.80 (p = 0.003), expected MCAP ratio < 0.80 (p = 0.001), and (M2 radius/graft radius)2 < 0.49 (p = 0.002) were related to LRICs according to the Cox proportional-hazards model. CONCLUSIONS Data in the present study indicated that it was important to use an adequate graft to achieve a sufficient MCAP ratio in order to avoid LRICs and that the adequate graft size could be evaluated based on a formula in patients with complex ICA aneurysms treated with ICAO. PMID- 28574312 TI - Elevated intracranial pressure and reversible eye-tracking changes detected while viewing a film clip. AB - OBJECTIVE The precise threshold differentiating normal and elevated intracranial pressure (ICP) is variable among individuals. In the context of several pathophysiological conditions, elevated ICP leads to abnormalities in global cerebral functioning and impacts the function of cranial nerves (CNs), either or both of which may contribute to ocular dysmotility. The purpose of this study was to assess the impact of elevated ICP on eye-tracking performed while patients were watching a short film clip. METHODS Awake patients requiring placement of an ICP monitor for clinical purposes underwent eye tracking while watching a 220 second continuously playing video moving around the perimeter of a viewing monitor. Pupil position was recorded at 500 Hz and metrics associated with each eye individually and both eyes together were calculated. Linear regression with generalized estimating equations was performed to test the association of eye tracking metrics with changes in ICP. RESULTS Eye tracking was performed at ICP levels ranging from -3 to 30 mm Hg in 23 patients (12 women, 11 men, mean age 46.8 years) on 55 separate occasions. Eye-tracking measures correlating with CN function linearly decreased with increasing ICP (p < 0.001). Measures for CN VI were most prominently affected. The area under the curve (AUC) for eye-tracking metrics to discriminate between ICP < 12 and >= 12 mm Hg was 0.798. To discriminate an ICP < 15 from >= 15 mm Hg the AUC was 0.833, and to discriminate ICP < 20 from >= 20 mm Hg the AUC was 0.889. CONCLUSIONS Increasingly elevated ICP was associated with increasingly abnormal eye tracking detected while patients were watching a short film clip. These results suggest that eye tracking may be used as a noninvasive, automatable means to quantitate the physiological impact of elevated ICP, which has clinical application for assessment of shunt malfunction, pseudotumor cerebri, concussion, and prevention of second-impact syndrome. PMID- 28574314 TI - A microcontroller-based simulation of dural venous sinus injury for neurosurgical training. AB - OBJECTIVE Surgical simulation has the potential to supplement and enhance traditional resident training. However, the high cost of equipment and limited number of available scenarios have inhibited wider integration of simulation in neurosurgical education. In this study the authors provide initial validation of a novel, low-cost simulation platform that recreates the stress of surgery using a combination of hands-on, model-based, and computer elements. Trainee skill was quantified using multiple time and performance measures. The simulation was initially validated using trainees at the start of their intern year. METHODS The simulation recreates intraoperative superior sagittal sinus injury complicated by air embolism. The simulator model consists of 2 components: a reusable base and a disposable craniotomy pack. The simulator software is flexible and modular to allow adjustments in difficulty or the creation of entirely new clinical scenarios. The reusable simulator base incorporates a powerful microcomputer and multiple sensors and actuators to provide continuous feedback to the software controller, which in turn adjusts both the screen output and physical elements of the model. The disposable craniotomy pack incorporates 3D-printed sections of model skull and brain, as well as artificial dura that incorporates a model sagittal sinus. RESULTS Twelve participants at the 2015 Western Region Society of Neurological Surgeons postgraduate year 1 resident course ("boot camp") provided informed consent and enrolled in a study testing the prototype device. Each trainee was required to successfully create a bilateral parasagittal craniotomy, repair a dural sinus tear, and recognize and correct an air embolus. Participant stress was measured using a heart rate wrist monitor. After participation, each resident completed a 13-question categorical survey. CONCLUSIONS All trainee participants experienced tachycardia during the simulation, although the point in the simulation at which they experienced tachycardia varied. Survey results indicated that participants agreed the simulation was realistic, created stress, and was a useful tool in training neurosurgical residents. This simulator represents a novel, low-cost approach for hands-on training that effectively teaches and tests residents without risk of patient injury. PMID- 28574315 TI - The effect of NACHRI children's hospital designation on outcome in pediatric malignant brain tumors. AB - OBJECTIVE Although current pediatric neurosurgery guidelines encourage the treatment of pediatric malignant brain tumors at specialized centers such as pediatric hospitals, there are limited data in support of this recommendation. Previous studies suggest that children treated by higher-volume surgeons and higher-volume hospitals may have better outcomes, but the effect of treatment at dedicated children's hospitals has not been investigated. METHODS The authors analyzed the Healthcare Cost and Utilization Project Kids' Inpatient Database (KID) from 2000-2009 and included all patients undergoing a craniotomy for malignant pediatric brain tumors based on ICD-9-CM codes. They investigated the effects of patient demographics, tumor location, admission type, and hospital factors on rates of routine discharge and mortality. RESULTS From 2000 through 2009, 83.6% of patients had routine discharges, and the in-hospital mortality rate was 1.3%. In multivariate analysis, compared with children treated at an institution designated as a pediatric hospital by NACHRI (National Association of Children's Hospitals and Related Institutions), children receiving treatment at a pediatric unit within an adult hospital (OR 0.5, p < 0.01) or a general hospital without a designated pediatric unit (OR 0.4, p < 0.01) were less likely to have routine discharges. Treatment at a large hospital (> 400 beds; OR 1.8, p = 0.02) and treatment at a teaching hospital (OR 1.7, p = 0.02) were independently associated with greater likelihood of routine discharge. However, patients transferred between facilities had a significantly decreased likelihood of routine discharge (OR 0.5, p < 0.01) and an increased likelihood of mortality (OR 5.0, p < 0.01). Procedural volume was not associated with rate of routine discharge or mortality. CONCLUSIONS These findings may have implications for planning systems of care for pediatric patients with malignant brain tumors. The authors hope to motivate future research into the specific factors that may lead to improved outcomes at designated pediatric hospitals. PMID- 28574316 TI - Imaging of congenital torticollis in infants: a retrospective study of an institutional protocol. AB - OBJECTIVE The authors' objectives in this study were to evaluate their institutional protocol and create recommendations for radiographic imaging in infants with torticollis, with or without plagiocephaly, based on a retrospective clinical analysis and literature review. METHODS A retrospective analysis was conducted to identify infants with torticollis who were evaluated by the craniofacial team. The following patients were identified: those who underwent imaging in the form of radiography, CT scanning, or MRI; those who had a secondary diagnosis or additional clinical finding as the indication for imaging; and those with persistent torticollis despite completion of recommended repositioning techniques and physical therapy (PT). RESULTS A total of 683 infants between the ages of 1 day and 335 days (mean age 141.6 days) were referred for management of torticollis. Initial imaging was performed in 48 patients, of whom 44 were identified as having a diagnosis other than torticollis or a significant clinical finding as the indication for imaging. The remaining 4 patients (0.6% of the torticollis population) underwent imaging and did not have an additional diagnosis or a significant clinical finding. There were no abnormal radiological findings in these patients. Of the 639 patients diagnosed with congenital torticollis who did not have a secondary diagnosis that required initial imaging, 99.2% (634 patients) achieved resolution of torticollis with recommended repositioning techniques and completion of PT and without radiography, CT, or MRI. CONCLUSIONS Within the limits of this retrospective study and supporting literature, the authors provide the following recommendations regarding radiographic imaging of infants with congenital torticollis. 1) Clinical examination is sufficient in the diagnosis of congenital torticollis in infants. Radiography, CT scanning, and MRI are not necessary. 2) In cases in which additional clinical or neurological findings are present, imaging may be recommended. 3) PT and repositioning techniques are the recommended treatment modalities for congenital torticollis. 4) Additional evaluations should be performed throughout the duration of PT to assess progress and response to therapy. 5) Imaging should be performed to rule out nonmuscular pathologies if torticollis persists after 1 year of treatment. PMID- 28574317 TI - Reoperation after failed resective epilepsy surgery in children. AB - OBJECTIVE Although epilepsy surgery is an effective treatment option, at least 20%-40% of patients can continue to experience uncontrolled seizures resulting from incomplete resection of the lesion, epileptogenic zone, or secondary epileptogenesis. Reoperation could eliminate or improve seizures. Authors of this study evaluated outcomes following reoperation in a pediatric population. METHODS A retrospective single-center analysis of all patients who had undergone resective epilepsy surgery in the period from 2001 to 2013 was performed. After excluding children who had repeat hemispherotomy, there were 24 children who had undergone a second surgery and 2 children who had undergone a third surgery. All patients underwent MRI and video electroencephalography (VEEG) and 21 underwent magnetoencephalography (MEG) prior to reoperation. RESULTS The mean age at the first and second surgery was 7.66 (SD 4.11) and 10.67 (SD 4.02) years, respectively. The time between operations ranged from 0.03 to 9 years. At reoperation, 8 patients underwent extended cortical resection; 8, lobectomy; 5, lesionectomy; and 3, functional hemispherotomy. One year after reoperation, 58% of the children were completely seizure free (International League Against Epilepsy [ILAE] Class 1) and 75% had a reduction in seizures (ILAE Classes 1-4). Patients with MEG clustered dipoles were more likely to be seizure free than to have persistent seizures (71% vs 40%, p = 0.08). CONCLUSIONS Reoperation in children with recurrent seizures after the first epilepsy surgery could result in favorable seizure outcomes. Those with residual lesion after the first surgery should undergo complete resection of the lesion to improve seizure outcome. In addition to MRI and VEEG, MEG should be considered as part of the reevaluation prior to reoperation. PMID- 28574319 TI - Developing a training package. AB - Purpose The purpose of this paper is to outline the development of a training package for service users and carers with an interest in NHS health and social care research. It demonstrates how the developers used their unique experience and expertise as service users and carers to inform their work. Design/methodology/approach Service users and carers, NHS Research and Development Forum working group members, supported by health professionals, identified a need for research training that was tailored to other service user and carer needs. After reviewing existing provision and drawing on their training and support experience, they developed a training package. Sessions from the training package were piloted, which evaluated positively. In trying to achieve programme accreditation and training roll-out beyond the pilots, the group encountered several challenges. Findings The training package development group formed good working relationships and a co-production model that proved sustainable. However, challenges were difficult to overcome owing to external factors and financial constraints. Practical implications Lessons learnt by the team are useful for other service users and carer groups working with health service professionals. Training for service users and carers should be designed to meet their needs; quality and consistency are also important. The relationships between service user and carer groups, and professionals are important to understanding joint working. Recognising and addressing challenges at the outset can help develop strategies to overcome challenges and ensure project success. Originality/value The training package was developed by service users and carers for other service users and carers. Their unique health research experience underpinned the group's values and training development. PMID- 28574320 TI - Using flow diagrams to improve tobacco cessation programs. AB - Purpose The purpose of this paper is to understand how the Wyoming Quit Tobacco Program (WQTP) is used by its subscribers and to better understand how WQTP might be connected to WQTP outcomes. Design/methodology/approach Provider intake and program use data corresponding to the May 2010 to March 2012 enrollment period ( n=6,168) were used. All program flows were constructed using frequencies and crosstabs, based on an initial theoretical model prepared by the program provider. Data were adjusted based on analysis that explored all possible uses beyond those specified by the provider's theoretical model. Findings Although the authors could replicate the structure - the theoretical model constructed by the provider - the authors were not able to replicate all relationships between program components. The authors also found that most individuals signed up and used web-based services. Only a few individuals finished their treatment regimens in the way they were designed to be used by the program. Originality/value This is the first case study to use a program flow method to investigate an entire comprehensive tobacco cessation program structure and delivery. PMID- 28574318 TI - Pediatric abusive head trauma and stroke. AB - OBJECTIVE Despite established risk factors, abusive head trauma (AHT) continues to plague our communities. Cerebrovascular accident (CVA), depicted as areas of hypodensity on CT scans or diffusion restriction on MR images, is a well-known consequence of AHT, but its etiology remains elusive. The authors hypothesize that a CVA, in isolation or in conjunction with other intracranial injuries, compounds the severity of a child's injury, which in turn leads to greater health care utilization, including surgical services, and an increased risk of death. METHODS The authors conducted a retrospective observational study to evaluate data obtained in all children with AHT who presented to Le Bonheur Children's Hospital (LBCH) from January 2009 through August 2016. Demographic, hospital course, radiological, cost, and readmission information was collected. Children with one or more CVA were compared with those without a CVA. RESULTS The authors identified 282 children with AHT, of whom 79 (28%) had one or more CVA. Compared with individuals without a CVA, children with a stroke were of similar overall age (6 months), sex (61% male), and race (56% African-American) and had similar insurance status (81% public). Just under half of all children with a stroke (38/79, 48%) were between 1-6 months of age. Thirty-five stroke patients (44%) had a Grade II injury, and 44 (56%) had a Grade III injury. The majority of stroke cases were bilateral (78%), multifocal (85%), associated with an overlying subdural hematoma (86%), and were watershed/hypoperfusion in morphology (73%). Thirty-six children (46%) had a hemispheric stroke. There were a total of 48 neurosurgical procedures performed on 28 stroke patients. Overall median hospital length of stay (11 vs 3 days), total hospital charges ($13.8 vs $6.6 million), and mean charges per patient ($174,700 vs $32,500) were significantly higher in the stroke cohort as a whole, as well as by injury grade (II and III). Twenty children in the stroke cohort (25%) died as a direct result of their AHT, whereas only 2 children in the nonstroke cohort died (1%). There was a 30% readmission rate within the first 180-day postinjury period for patients in the stroke cohort, and of these, approximately 50% required additional neurosurgical intervention(s). CONCLUSIONS One or more strokes in a child with AHT indicate a particularly severe injury. These children have longer hospital stays, greater hospital charges, and a greater likelihood of needing a neurosurgical intervention (i.e., bedside procedure or surgery). Stroke is such an important predictor of health care utilization and outcome that it warrants a subcategory for both Grade II and Grade III injuries. It should be noted that the word "stroke" or "CVA" should not automatically imply arterial compromise in this population. PMID- 28574321 TI - Quality improvement in physiotherapy services. AB - Purpose The purpose of this paper is to evaluate a process change in physiotherapy services and to explore factors that may have influenced the outcomes. Design/methodology/approach This is a multiple case study and information was gathered from eight physiotherapy teams over 24 months. Findings The process change was successfully implemented in six teams. It had a clear, positive effect on service quality provided to patients in three teams. Whilst quality also improved in three other teams, other issues make changes difficult to assess. Factors that enabled process change to be effective are suggested. Research limitations/implications The findings are based on results achieved by only eight English teams. Practical implications This process change may be appropriate for other teams providing therapy services if attention is paid to potential enabling factors, and a learning approach is adopted to designing and introducing the change. Originality/value To the best of the authors' knowledge, no other longitudinal process change study in therapy services has been published. PMID- 28574322 TI - Volume-outcome relationship for colorectal cancer in primary care: a prospective cohort study. AB - Purpose Higher caseloads are associated with better outcomes for many conditions treated in secondary and tertiary care settings, including colorectal cancer (CRC). There is little known whether such volume-outcome relationship exist in primary care settings. The purpose of this paper is to examine general practitioner (GP) CRC-specific caseload for possible associations with referral pathways, disease stage and CRC patients' overall survival. Design/methodology/approach The paper retrospectively analyses a prospectively maintained CRC database for 2009-2014 in a single district hospital providing bowel cancer screening and tertiary rectal cancer services. Findings Of 1,145 CRC patients, 937 (81.8 per cent) were diagnosed as symptomatic cancers. In total, 210 GPs from 44 practices were stratified according to their CRC caseload over the study period into low volume (LV, 1-4); medium volume (MV, 5-7); and high volume (HV, 8-21 cases). Emergency presentation (LV: 49/287 (17.1 per cent); MV: 75/264 (28.4 per cent); HV: 105/386 (27.2 per cent); p=0.007) and advanced disease at presentation (LV: 84/287 (29.3 per cent); MV: 94/264 (35.6 per cent); HV: 144/386 (37.3 per cent); p=0.034) was more common amongst HV GPs. Three-year mortality risk was significantly higher for HV GPs (MV: (hazard ratio) HR 1.185 (confidence interval=0.897-1.566), p=0.231, and HV: HR 1.366 (CI=1.061-1.759), p=0.016), but adjustment for emergency presentation and advanced disease largely accounted for this difference. There was some evidence that HV GPs used elective cancer pathways less frequently (LV: 166/287 (57.8 per cent); MV: 130/264 (49.2 per cent); HV: 182/386 (47.2 per cent); p=0.007) and more selectively (CRC/referrals: LV: 166/2,743 (6.1 per cent); MV: 130/2,321 (5.6 per cent); HV: 182/2,508 (7.3 per cent); p=0.048). Originality/value Higher GP CRC caseload in primary care may be associated with advanced disease and poorer survival; more work is required to determine the reasons and to develop targeted intervention at local level to improve elective referral rates. PMID- 28574323 TI - Improving ICU risk management and patient safety. AB - Purpose The purpose of this paper is to describe a study which aimed to develop and validate an assessment method for the International Electrotechnical Commission (IEC) 80001-1 (IEC, 2010) standard (the Standard); raise awareness; improve medical IT-network project risk management processes; and improve intensive care unit patient safety. Design/methodology/approach An assessment method was developed and piloted. A healthcare IT-network project assessment was undertaken using a semi-structured group interview with risk management stakeholders. Participants provided feedback via a questionnaire. Descriptive statistics and thematic analysis was undertaken. Findings The assessment method was validated as fit for purpose. Participants agreed (63 per cent, n=7) that assessment questions were clear and easy to understand, and participants agreed (82 per cent, n=9) that the assessment method was appropriate. Participant's knowledge of the Standard increased and non-compliance was identified. Medical IT network project strengths, weaknesses, opportunities and threats in the risk management processes were identified. Practical implications The study raised awareness of the Standard and enhanced risk management processes that led to improved patient safety. Study participants confirmed they would use the assessment method in future projects. Originality/value Findings add to knowledge relating to IEC 80001-1 implementation. PMID- 28574324 TI - Continuous improvement projects: an authorship bibliometric analysis. AB - Purpose The purpose of this paper is to describe the current research on hospital continuous improvement projects (CIPs) from an author characteristics' perspective. This work addresses the following questions: who are the predominant research authors in hospital CIPs? To what extent are the research communities collaborating in distinct research groups? How internationalized has hospital CIPs research become with respect to author location? Design/methodology/approach A systematic literature review was conducted, identifying 302 academic publications related to hospital CIPs. Publications were analyzed using: author, quantity, diversity, collaboration, and impact. Findings Hospital CIPs are increasingly attracting new scholars each year. Based on the authors' analysis, authors publishing in this area can be described as a relatively new international community given the countries represented. Originality/value This paper describes the current hospital CIP research by assessing author characteristics. Future work should examine additional attributes to characterize maturity such as how new knowledge is being created and to what extent new knowledge is being disseminated to practitioners. PMID- 28574325 TI - Service quality, patient satisfaction and loyalty in the Bangladesh healthcare sector. AB - Purpose The purpose of this paper is to investigate service quality, patient satisfaction and loyalty in Bangladesh's healthcare sector. It identifies healthcare quality conformance, patient satisfaction and loyalty based on demographics such as gender, age and marital status. It examines the differences between public and private healthcare sectors regarding service quality, patient satisfaction and loyalty. Design/methodology/approach The authors distributed 450 self-administered questionnaires to hospital patients resulting in 204 useful responses (45.3 per cent response rate). Data were analysed based on reliability analysis, exploratory factor analysis, independent samples t-tests, ANOVA and discriminant analysis using SPSS version 23. Findings Findings indicate that single patients perceive tangibles, reliability, empathy and loyalty higher compared to married patients. Young patients (?20 years) have a higher tangibles, empathy and loyalty scores compared to other age groups. The authors observed that private hospital patients perceive healthcare service quality performance higher compared to patients in public hospitals. Research limitations/implications The authors focussed solely on the Bangladesh health sector, so the results might not be applicable to other countries. Originality/value The findings provide guidelines for enhancing service quality, patient satisfaction and loyalty in the Bangladesh healthcare sector and other countries. PMID- 28574326 TI - Healthcare quality improvement work: a professional employee perspective. AB - Purpose The purpose of this paper is to describe and analyze conditions that influence how employees engage in healthcare quality improvement (QI) work. Design/methodology/approach Qualitative case study based on interviews ( n=27) and observations ( n=10). Findings The main conditions that influence how employees engage in healthcare QI work are professions, work structures and working relationships. These conditions can both prevent and facilitate healthcare QI. Professions and work structures may cement existing institutional logics and thus prevent employees from engaging in healthcare QI work. However, attempts to align QI with professional logics, together with work structures that empower employees, can make these conditions increase employee engagement, which can be accomplished through positive working relationships that foster institutional work, which bridge different competing institutional logics, making it possible to overcome barriers that professions and work structures may constitute. Practical implications Understanding the conditions that influence how employees engage in healthcare QI work will make initiatives more likely to succeed. Originality/value Healthcare QI has mainly been studied from an implementer perspective, and employees have either been neglected or seen as passive resisters. Weak employee perspectives make healthcare QI research incomplete. In our research, healthcare QI work is studied closely at the actor level to understand healthcare QI from an employee perspective. PMID- 28574327 TI - Intrinsic LINE-1 Hypomethylation and Decreased Brca1 Expression are Associated with DNA Repair Delay in Irradiated Thyroid Cells. AB - Exposure to ionizing radiation greatly increases the risk of developing papillary thyroid carcinoma (PTC), especially during childhood, mainly due to gradual inactivation of DNA repair genes and DNA damages. Recent molecular characterization of PTC revealed DNA methylation deregulation of several promoters of DNA repair genes. Thus, epigenetic silencing might be a plausible mechanism for the activity loss of tumor suppressor genes in radiation-induced thyroid tumors. Herein, we investigated the impact of ionizing radiation on global methylation and CpG islands within promoter regions of homologous recombination (HR) and non-homologous end joining (NHEJ) genes, as well as its effects on gene expression, using two well-established normal differentiated thyroid cell lines (FRTL5 and PCCL3). Our data reveal that X-ray exposure promoted G2/M arrest in normal thyroid cell lines. The FRTL5 cells displayed a slower kinetics of double-strand breaks (DSB) repair and a lower long interspersed nuclear element-1 (LINE-1) methylation than the PCCL3 cells. Nevertheless, acute X-ray exposure does not alter the expression of genes involved in HR and NHEJ pathways, apart from the downregulation of Brca1 in thyroid cells. On the other hand, HR and NHEJ gene expressions were upregulated in radiation-induced senescent thyroid cells. Taken together, these data suggest that FRTL5 cells intrinsically have less efficient DNA DSB repair machinery than PCCL3 cells, as well as genomic instability, which could predispose the FRTL5 cells to unrepaired DSB lesions and, therefore, gene mutations. PMID- 28574328 TI - Cerebrospinal fluid outflow resistance as a diagnostic marker of spontaneous cerebrospinal fluid leakage. AB - OBJECTIVE Spinal CSF leakage causes spontaneous intracranial hypotension (SIH). The aim of this study was to characterize CSF dynamics via lumbar infusion testing in patients with and without proven spinal CSF leakage in order to explore possible discriminators for the presence of an open CSF leak. METHODS This analysis included all patients with suspected SIH who were treated at the authors' institution between January 2012 and February 2015. The gold standard for "proven" CSF leakage is considered to be extrathecal contrast accumulation after intrathecal contrast injection. To characterize CSF dynamics, the authors performed computerized lumbar infusion testing to measure lumbar pressure at baseline (opening pressure) and at plateau, as well as pulse amplitude, CSF outflow resistance (RCSF), craniospinal elastance, and pressure-volume index. RESULTS Thirty-one patients underwent clinical imaging and lumbar infusion testing and were included in the final analysis. A comparison of the 14 patients with proven CSF leakage with the 17 patients without leakage showed a statistically significantly lower lumbar opening pressure (p < 0.001), plateau pressure (p < 0.001), and RCSF (p < 0.001) in the group with leakage. Sensitivity, specificity, and positive and negative predictive values for an RCSF cutoff of <= 5 mm Hg/(ml/min) were 0.86, 1.0, 1.0, and 0.89 (area under the curve of 0.96), respectively. The median pressure-volume index was higher (p = 0.003), and baseline (p = 0.017) and plateau (p < 0.001) pulse amplitudes were lower in patients with a proven leak. CONCLUSIONS Lumbar infusion testing captures a distinct pattern of CSF dynamics associated with spinal CSF leakage. RCSF assessed by computerized lumbar infusion testing has an excellent diagnostic accuracy and is more accurate than evaluating the lumbar opening pressure. The authors suggest inclusion of RCSF in the diagnostic criteria for SIH. PMID- 28574329 TI - Spinal epidural hematomas: personal experience and literature review of more than 1000 cases. AB - OBJECTIVE The goal of this study was to identify factors that contribute to the formation of acute spinal epidural hematoma (SEH) by correlating etiology, age, site, clinical status, and treatment with immediate results and long-term outcomes. METHODS The authors reviewed their series of 15 patients who had been treated for SEH between 1996 and 2012. In addition, the authors reviewed the relevant international literature from 1869 (when SEH was first described) to 2012, collecting a total of 1010 cases. Statistical analysis was performed in 959 (95%) cases that were considered valid for assessing the incidence of age, sex, site, and clinical status at admission, correlating each of these parameters with the treatment results. Statistical analysis was also performed in 720 (71.3%) cases to study the incidence of etiological factors that favor SEH formation: coagulopathy, trauma, spinal puncture, pregnancy, and multifactorial disorders. The clinical status at admission and long-term outcome were studied for each group. Clinical status was assessed using the Neuro-Grade (NG) scale. RESULTS The mean patient age was 47.97 years (range 0-91 years), and a significant proportion of patients were male (60%, p < 0.001). A bimodal distribution has been reported for age at onset with peaks in the 2nd and 6th decades of life. The cause of the SEH was not reported in 42% of cases. The etiology concerned mainly iatrogenic factors (18%), such as coagulopathy or spinal puncture, rather than noniatrogenic factors (29%), such as genetic or metabolic coagulopathy, trauma, and pregnancy. The etiology was multifactorial in 11.1% of cases. The most common sites for SEH were C-6 (n = 293, 31%) and T-12 (n = 208, 22%), with maximum extension of 6 vertebral bodies in 720 cases (75%). At admission, 806 (84%) cases had moderate neurological impairment (NG 2 or 3), and only lumbar hematoma was associated with a good initial clinical neurological status (NG 0 or 1). Surgery was performed in 767 (80%) cases. Mortality was greater in patients older than 40 years of age (9%; p < 0.01). Sex did not influence any of these data (p > 0.05). CONCLUSIONS Factors that contribute to the formation of acute SEH are iatrogenic, not iatrogenic, or multifactorial. The treatment of choice is surgery, and the results of treatment are influenced by the patient's clinical and neurological status at admission, age, and the craniocaudal site. PMID- 28574330 TI - Role of intraoperative dynamic magnetic resonance myelogram in management of giant dorsolumbar spinal extradural arachnoid cyst: case report. AB - Giant dorsolumbar spinal arachnoid cysts are a complex, poorly understood, and difficult to manage clinical entity. Traditional CT myelography is technically difficult to use in these cases to detect the site of leakage preoperatively. The authors report a novel technique for detecting the site of the leak by using sequential, dynamic intraoperative MR myelography. To the authors' knowledge, there is no other similar report in the literature. PMID- 28574331 TI - Risk factors for 30-day reoperation and 3-month readmission: analysis from the Quality and Outcomes Database lumbar spine registry. AB - OBJECTIVE The aim of this paper was to use a prospective, longitudinal, multicenter outcome registry of patients undergoing surgery for lumbar degenerative disease in order to assess the incidence and factors associated with 30-day reoperation and 90-day readmission. METHODS Prospectively collected data from 9853 patients from the Quality and Outcomes Database (QOD; formerly known as the N2QOD [National Neurosurgery Quality and Outcomes Database]) lumbar spine registry were retrospectively analyzed. Multivariate binomial regression analysis was performed to identify factors associated with 30-day reoperation and 90-day readmission after surgery for lumbar degenerative disease. A subgroup analysis of Medicare patients stratified by age (< 65 and >= 65 years old) was also performed. Continuous variables were compared using unpaired t-tests, and proportions were compared using Fisher's exact test. RESULTS There was a 2% reoperation rate within 30 days. Multivariate analysis revealed prolonged operative time during the index case as the only independent factor associated with 30-day reoperation. Other factors such as preoperative diagnosis, body mass index (BMI), American Society of Anesthesiologists (ASA) class, diabetes, and use of spinal implants were not associated with reoperations within 30 days. Medicare patients < 65 years had a 30-day reoperation rate of 3.7%, whereas those >= 65 years had a 30-day reoperation rate of 2.2% (p = 0.026). Medicare beneficiaries younger than 65 years undergoing reoperation within 30 days were more likely to be women (p = 0.009), have a higher BMI (p = 0.008), and have higher rates of depression (p < 0.0001). The 90-day readmission rate was 6.3%. Multivariate analysis demonstrated that higher ASA class (OR 1.46 per class, 95% CI 1.25-1.70) and history of depression (OR 1.27, 95% CI 1.04-1.54) were factors associated with 90-day readmission. Medicare beneficiaries had a higher rate of 90-day readmissions compared with those who had private insurance (OR 1.43, 95% CI 1.17 1.76). Medicare patients < 65 years of age were more likely to be readmitted within 90 days after their index surgery compared with those >= 65 years (10.8% vs 7.7%, p = 0.017). Medicare patients < 65 years of age had a significantly higher BMI (p = 0.001) and higher rates of depression (p < 0.0001). CONCLUSIONS In this analysis of a large prospective, multicenter registry of patients undergoing lumbar degenerative surgery, multivariate analysis revealed that prolonged operative time was associated with 30-day reoperation. The authors found that factors associated with 90-day readmission included higher ASA class and a history of depression. The 90-day readmission rates were higher for Medicare beneficiaries than for those who had private insurance. Medicare patients < 65 years of age were more likely to undergo reoperation within 30 days and to be readmitted within 90 days after their index surgery. PMID- 28574332 TI - Incidence and risk factors for preoperative deep venous thrombosis in 314 consecutive patients undergoing surgery for spinal metastasis. AB - OBJECTIVE The authors of this study aimed to identify the incidence of and risk factors for preoperative deep venous thrombosis (DVT) in patients undergoing surgical treatment for spinal metastases. METHODS Univariate analysis of patient age, sex, ethnicity, laboratory values, comorbidities, preoperative ambulatory status, histopathological classification, spinal level, and surgical details was performed. Factors significantly associated with DVT univariately were entered into a multivariate logistic regression model. RESULTS The authors identified 314 patients, of whom 232 (73.9%) were screened preoperatively for a DVT. Of those screened, 22 (9.48%) were diagnosed with a DVT. The screened patients were older (median 62 vs 55 years, p = 0.0008), but otherwise similar in baseline characteristics. Nonambulatory status, previous history of DVT, lower partial thromboplastin time, and lower hemoglobin level were statistically significant and independent factors associated with positive results of screening for a DVT. Results of screening were positive in only 6.4% of ambulatory patients in contrast to 24.4% of nonambulatory patients, yielding an odds ratio of 4.73 (95% CI 1.88-11.90). All of the patients who had positive screening results underwent preoperative placement of an inferior vena cava filter. CONCLUSIONS Patients requiring surgery for spinal metastases represent a population with unique risks for venous thromboembolism. This study showed a 9.48% incidence of DVT in patients screened preoperatively. The highest rates of preoperative DVT were identified in nonambulatory patients, who were found to have a 4-fold increase in the likelihood of harboring a DVT. Understanding the preoperative thrombotic status may provide an opportunity for early intervention and risk stratification in this critically ill population. PMID- 28574333 TI - Depression as an independent predictor of postoperative delirium in spine deformity patients undergoing elective spine surgery. AB - OBJECTIVE Depression is the most prevalent affective disorder in the US, and patients with spinal deformity are at increased risk. Postoperative delirium has been associated with inferior surgical outcomes, including morbidity and mortality. The relationship between depression and postoperative delirium in patients undergoing spine surgery is relatively unknown. The aim of this study was to determine if depression is an independent risk factor for the development of postoperative delirium in patients undergoing decompression and fusion for deformity. METHODS The medical records of 923 adult patients (age >= 18 years) undergoing elective spine surgery at a single major academic institution from 2005 through 2015 were reviewed. Of these patients, 255 (27.6%) patients had been diagnosed with depression by a board-certified psychiatrist and constituted the Depression group; the remaining 668 patients constituted the No-Depression group. Patient demographics, comorbidities, and intra- and postoperative complication rates were collected for each patient and compared between groups. The primary outcome investigated in this study was rate of postoperative delirium, according to DSM-V criteria, during initial hospital stay after surgery. The association between depression and postoperative delirium rate was assessed via multivariate logistic regression analysis. RESULTS Patient demographics and comorbidities other than depression were similar in the 2 groups. In the Depression group, 85.1% of the patients were taking an antidepressant prior to surgery. There were no significant between-group differences in intraoperative variables and rates of complications other than delirium. Postoperative complication rates were also similar between the cohorts, including rates of urinary tract infection, fever, deep and superficial surgical site infection, pulmonary embolism, deep vein thrombosis, urinary retention, and proportion of patients transferred to the intensive care unit. In total, 66 patients (7.15%) had an episode of postoperative delirium, with depressed patients experiencing approximately a 2 fold higher rate of delirium (10.59% vs 5.84%). In a multivariate logistic regression analysis, depression was an independent predictor of postoperative delirium after spine surgery in spinal deformity patients (p = 0.01). CONCLUSIONS The results of this study suggest that depression is an independent risk factor for postoperative delirium after elective spine surgery. Further studies are necessary to understand the effects of affective disorders on postoperative delirium, in hopes to better identify patients at risk. PMID- 28574334 TI - Modified dorsal root entry zone lesioning for intractable pain relief in patients with root avulsion injury. AB - OBJECTIVE Dorsal root entry zone (DREZ) lesioning has been the most effective surgical treatment for the relief of intractable pain due to root avulsion injury, but residual pain and a decrease in pain relief in the follow-up period have been reported in 23%-70% of patients. Based on pain topography in the most recent studies on neuropathic pain, the authors modified the conventional DREZ lesioning procedure to improve clinical outcomes. The presumed rationale for this procedure is to eliminate the spontaneous discharges of neurons in the superficial spinal dorsal horn as well as wide dynamic range neurons in the deep spinal dorsal horn. METHODS Ten patients with avulsion-related pain underwent surgery between 2011 and 2015. The surgical procedure was described and postoperative pain relief was assessed as follows: excellent (residual pain never exceeded 3 on the visual analog scale [VAS] without medication), good (residual pain never exceeded 5 on the VAS with medication), and poor (residual pain was greater than 5 with medication). Specific perioperative complications were assessed. RESULTS The aim of this surgical procedure was to destroy the deeper layers of the posterior horn of spinal gray matter, which was in contrast to the procedures of Nashold and Sindou, which were to destroy the superficial layers. All patients achieved excellent (n = 7, pain relief without medication) or good (n = 3, pain relief with medication) pain relief postoperatively, and the recurrence of pain was not reported in any patients (median 29 months after surgery, range 12-64 months). Nine patients (90%) achieved complete pain relief (a score of 0 or 1 on the VAS) with or without medication. No surgical site complications such as infection or CSF leakage were noted. No motor deficit was observed in any patient. A sensory deficit was observed in 2 patients and disappeared within 1 month in 1 patient. New pain at the adjacent level of DREZ lesioning was observed in 3 patients and disappeared within 1 month in 2 patients. In the other patient, new pain persisted and required analgesics. CONCLUSIONS These preliminary results demonstrated that total and persistent global pain relief was achieved with the modified DREZ lesioning procedure in 90% of patients without major neurological deficits. The clinical improvements achieved by this modified surgical procedure support the hypothesis that not only the superficial layers, but also deeper layers of the spinal dorsal horn are associated with intractable pain due to root avulsion injury. PMID- 28574335 TI - Toxicity of orally inhaled drug formulations at the alveolar barrier: parameters for initial biological screening. AB - Oral delivery is the most common mode of systemic drug application. Inhalation is mainly used for local therapy of lung diseases but may also be a promising route for systemic delivery of drugs that have poor oral bioavailability. The thin alveolar barrier enables fast and efficient uptake of many molecules and could deliver small molecules and proteins, which are susceptible to degradation and show poor absorption by oral application. The low rate of biotransformation and proteolytic degradation increases bioavailability of drugs but accumulation of not absorbed material may impair normal lung function. This limitation is more relevant for compounds that should be systematically active because higher doses have to be applied to the lung. The review describes processes that determine absorption of orally inhaled formulations, namely dissolution in the lung lining fluid and uptake and degradation by alveolar epithelial cells and macrophages. Dissolution testing in simulated lung fluid, screening for cytotoxicity and pro inflammatory action in respiratory cells and study of macrophage morphology, and phagocytosis can help to identify adverse effects of pulmonary formulations. PMID- 28574336 TI - Early infant diagnosis of HIV in Myanmar: call for innovative interventions to improve uptake and reduce turnaround time. AB - BACKGROUND: In collaboration with the national AIDS program, early infant diagnosis (EID) is implemented by Integrated HIV Care (IHC) program through its anti-retroviral therapy (ART) centers across 10 cities in five states and regions of Myanmar. Blood samples from the ART centers are sent using public transport to a centralized PCR facility. OBJECTIVES: Among HIV-exposed babies <9 months at enrolment into IHC program (2013-15), to describe the EID cascade (enrolment, sample collection for PCR, result receipt by mother, HIV diagnosis and ART initiation) and factors associated with delayed (>8 weeks of age) or no blood sample collection for EID. METHODS: Retrospective cohort study involving record review. A predictive poisson regression model with robust variance estimates was fitted for risk factors of delayed or no sample collection. RESULTS: Of 1349 babies, 523 (39%) of the babies' mothers were on ART before pregnancy. Timely uptake of EID (<8 weeks of age) was 47% (633/1349); sample collection was delayed in 27% (367/1349) and not done in 26% (349/1349) babies. Among samples collected (n = 1000), 667 results were received by the mother; 52 (5%) were HIV-infected; among them 42 (81%) were initiated on ART. Median (IQR) turnaround time from sample collection to result receipt by mother and time to initiate ART from result receipt by mother was 7 (4,12) and 8.5 (6,16) weeks, respectively. Mothers not on ART before pregnancy and distance of ART center from PCR facility (more than 128 km) were the risk factors of delayed or no sample collection. CONCLUSIONS: Improving provision of ART to mothers (through universal 'test and treat') is urgently required, which has the potential to improve the timely uptake of EID as well. Interventions to reduce turnaround times, like point of care EID testing and/or systematic use of mobile technology to communicate results, are needed. PMID- 28574337 TI - A gut response. AB - Unexpected findings from the immune system of sea urchin larvae potentially provide insights into immune signaling in ancestral animals. PMID- 28574340 TI - Robust Nonlinear Causality Analysis of Nonstationary Multivariate Physiological Time Series. AB - GOAL: An important research area in biomedical signal processing is that of quantifying the relationship between simultaneously observed time series and to reveal interactions between the signals. Since biomedical signals are potentially nonstationary and the measurements may contain outliers and artifacts, we introduce a robust time-varying generalized partial directed coherence (rTV-gPDC) function. METHODS: The proposed method, which is based on a robust estimator of the time-varying autoregressive (TVAR) parameters, is capable of revealing directed interactions between signals. By definition, the rTV-gPDC only displays the linear relationships between the signals. We therefore suggest to approximate the residuals of the TVAR process, which potentially carry information about the nonlinear causality by a piece-wise linear time-varying moving-average model. RESULTS: The performance of the proposed method is assessed via extensive simulations. To illustrate the method's applicability to real-world problems, it is applied to a neurophysiological study that involves intracranial pressure, arterial blood pressure, and brain tissue oxygenation level (PtiO2) measurements. CONCLUSION AND SIGNIFICANCE: The rTV-gPDC reveals causal patterns that are in accordance with expected cardiosudoral meachanisms and potentially provides new insights regarding traumatic brain injuries. The rTV-gPDC is not restricted to the above problem but can be useful in revealing interactions in a broad range of applications. PMID- 28574338 TI - Synchronized HIV assembly by tunable PIP2 changes reveals PIP2 requirement for stable Gag anchoring. AB - HIV-1 assembles at the plasma membrane (PM) of infected cells. PM association of the main structural protein Gag depends on its myristoylated MA domain and PM PI(4,5)P2. Using a novel chemical biology tool that allows rapidly tunable manipulation of PI(4,5)P2 levels in living cells, we show that depletion of PI(4,5)P2 completely prevents Gag PM targeting and assembly site formation. Unexpectedly, PI(4,5)P2 depletion also caused loss of pre-assembled Gag lattices from the PM. Subsequent restoration of PM PI(4,5)P2 reinduced assembly site formation even in the absence of new protein synthesis, indicating that the dissociated Gag molecules remained assembly competent. These results reveal an important role of PI(4,5)P2 for HIV-1 morphogenesis beyond Gag recruitment to the PM and suggest a dynamic equilibrium of Gag-lipid interactions. Furthermore, they establish an experimental system that permits synchronized induction of HIV-1 assembly leading to induced production of infectious virions by targeted modulation of Gag PM targeting. PMID- 28574341 TI - Image Captioning and Visual Question Answering Based on Attributes and External Knowledge. AB - Much of the recent progress in Vision-to-Language problems has been achieved through a combination of Convolutional Neural Networks (CNNs) and Recurrent Neural Networks (RNNs). This approach does not explicitly represent high-level semantic concepts, but rather seeks to progress directly from image features to text. In this paper we first propose a method of incorporating high-level concepts into the successful CNN-RNN approach, and show that it achieves a significant improvement on the state-of-the-art in both image captioning and visual question answering. We further show that the same mechanism can be used to incorporate external knowledge, which is critically important for answering high level visual questions. Specifically, we design a visual question answering model that combines an internal representation of the content of an image with information extracted from a general knowledge base to answer a broad range of image-based questions. It particularly allows questions to be asked where the image alone does not contain the information required to select the appropriate answer. Our final model achieves the best reported results for both image captioning and visual question answering on several of the major benchmark datasets. PMID- 28574339 TI - Diverse stimuli engage different neutrophil extracellular trap pathways. AB - Neutrophils release neutrophil extracellular traps (NETs) which ensnare pathogens and have pathogenic functions in diverse diseases. We examined the NETosis pathways induced by five stimuli; PMA, the calcium ionophore A23187, nigericin, Candida albicans and Group B Streptococcus. We studied NET production in neutrophils from healthy donors with inhibitors of molecules crucial to PMA induced NETs including protein kinase C, calcium, reactive oxygen species, the enzymes myeloperoxidase (MPO) and neutrophil elastase. Additionally, neutrophils from chronic granulomatous disease patients, carrying mutations in the NADPH oxidase complex or a MPO-deficient patient were examined. We show that PMA, C. albicans and GBS use a related pathway for NET induction, whereas ionophores require an alternative pathway but that NETs produced by all stimuli are proteolytically active, kill bacteria and composed mainly of chromosomal DNA. Thus, we demonstrate that NETosis occurs through several signalling mechanisms, suggesting that extrusion of NETs is important in host defence. PMID- 28574342 TI - Robust 3D Object Tracking from Monocular Images Using Stable Parts. AB - We present an algorithm for estimating the pose of a rigid object in real-time under challenging conditions. Our method effectively handles poorly textured objects in cluttered, changing environments, even when their appearance is corrupted by large occlusions, and it relies on grayscale images to handle metallic environments on which depth cameras would fail. As a result, our method is suitable for practical Augmented Reality applications including industrial environments. At the core of our approach is a novel representation for the 3D pose of object parts: We predict the 3D pose of each part in the form of the 2D projections of a few control points. The advantages of this representation is three-fold: We can predict the 3D pose of the object even when only one part is visible; when several parts are visible, we can easily combine them to compute a better pose of the object; the 3D pose we obtain is usually very accurate, even when only few parts are visible. We show how to use this representation in a robust 3D tracking framework. In addition to extensive comparisons with the state of-the-art, we demonstrate our method on a practical Augmented Reality application for maintenance assistance in the ATLAS particle detector at CERN. PMID- 28574343 TI - Exploring Context with Deep Structured Models for Semantic Segmentation. AB - We propose an approach for exploiting contextual information in semantic image segmentation, and particularly investigate the use of patch-patch context and patch-background context in deep CNNs. We formulate deep structured models by combining CNNs and Conditional Random Fields (CRFs) for learning the patch-patch context between image regions. Specifically, we formulate CNN-based pairwise potential functions to capture semantic correlations between neighboring patches. Efficient piecewise training of the proposed deep structured model is then applied in order to avoid repeated expensive CRF inference during the course of back propagation. For capturing the patch-background context, we show that a network design with traditional multi-scale image inputs and sliding pyramid pooling is very effective for improving performance. We perform comprehensive evaluation of the proposed method. We achieve new state-of-the-art performance on a number of challenging semantic segmentation datasets. PMID- 28574344 TI - A Framework for the Generation of Realistic Synthetic Cardiac Ultrasound and Magnetic Resonance Imaging Sequences From the Same Virtual Patients. AB - The use of synthetic sequences is one of the most promising tools for advanced in silico evaluation of the quantification of cardiac deformation and strain through 3-D ultrasound (US) and magnetic resonance (MR) imaging. In this paper, we propose the first simulation framework which allows the generation of realistic 3 D synthetic cardiac US and MR (both cine and tagging) image sequences from the same virtual patient. A state-of-the-art electromechanical (E/M) model was exploited for simulating groundtruth cardiac motion fields ranging from healthy to various pathological cases, including both ventricular dyssynchrony and myocardial ischemia. The E/M groundtruth along with template MR/US images and physical simulators were combined in a unified framework for generating synthetic data. We efficiently merged several warping strategies to keep the full control of myocardial deformations while preserving realistic image texture. In total, we generated 18 virtual patients, each with synthetic 3-D US, cine MR, and tagged MR sequences. The simulated images were evaluated both qualitatively by showing realistic textures and quantitatively by observing myocardial intensity distributions similar to real data. In particular, the US simulation showed a smoother myocardium/background interface than the state-of-the-art. We also assessed the mechanical properties. The pathological subjects were discriminated from the healthy ones by both global indexes (ejection fraction and the global circumferential strain) and regional strain curves. The synthetic database is comprehensive in terms of both pathology and modality, and has a level of realism sufficient for validation purposes. All the 90 sequences are made publicly available to the research community via an open-access database. PMID- 28574345 TI - Noncontact 3-D Speckle Contrast Diffuse Correlation Tomography of Tissue Blood Flow Distribution. AB - Recent advancements in near-infrared diffuse correlation techniques and instrumentation have opened the path for versatile deep tissue microvasculature blood flow imaging systems. Despite this progress there remains a need for a completely noncontact, noninvasive device with high translatability from small/testing (animal) to large/target (human) subjects with trivial application on both. Accordingly, we discuss our newly developed setup which meets this demand, termed noncontact speckle contrast diffuse correlation tomography (nc_scDCT). The nc_scDCT provides fast, continuous, portable, noninvasive, and inexpensive acquisition of 3-D tomographic deep (up to 10 mm) tissue blood flow distributions with straightforward design and customization. The features presented include a finite-element-method implementation for incorporating complex tissue boundaries, fully noncontact hardware for avoiding tissue compression and interactions, rapid data collection with a diffuse speckle contrast method, reflectance-based design promoting experimental translation, extensibility to related techniques, and robust adjustable source and detector patterns and density for high resolution measurement with flexible regions of interest enabling unique application-specific setups. Validation is shown in the detection and characterization of both high and low contrasts in flow relative to the background using tissue phantoms with a pump-connected tube (high) and phantom spheres (low). Furthermore, in vivo validation of extracting spatiotemporal 3-D blood flow distributions and hyperemic response during forearm cuff occlusion is demonstrated. Finally, the success of instrument feasibility in clinical use is examined through the intraoperative imaging of mastectomy skin flap. PMID- 28574346 TI - Generative Adversarial Networks for Noise Reduction in Low-Dose CT. AB - Noise is inherent to low-dose CT acquisition. We propose to train a convolutional neural network (CNN) jointly with an adversarial CNN to estimate routine-dose CT images from low-dose CT images and hence reduce noise. A generator CNN was trained to transform low-dose CT images into routine-dose CT images using voxelwise loss minimization. An adversarial discriminator CNN was simultaneously trained to distinguish the output of the generator from routine-dose CT images. The performance of this discriminator was used as an adversarial loss for the generator. Experiments were performed using CT images of an anthropomorphic phantom containing calcium inserts, as well as patient non-contrast-enhanced cardiac CT images. The phantom and patients were scanned at 20% and 100% routine clinical dose. Three training strategies were compared: the first used only voxelwise loss, the second combined voxelwise loss and adversarial loss, and the third used only adversarial loss. The results showed that training with only voxelwise loss resulted in the highest peak signal-to-noise ratio with respect to reference routine-dose images. However, CNNs trained with adversarial loss captured image statistics of routine-dose images better. Noise reduction improved quantification of low-density calcified inserts in phantom CT images and allowed coronary calcium scoring in low-dose patient CT images with high noise levels. Testing took less than 10 s per CT volume. CNN-based low-dose CT noise reduction in the image domain is feasible. Training with an adversarial network improves the CNNs ability to generate images with an appearance similar to that of reference routine-dose CT images. PMID- 28574347 TI - Anisotropic Discrete Dual-Tree Wavelet Transform for Improved Classification of Trabecular Bone. AB - This paper deals with a new anisotropic discrete dual-tree wavelet transform (ADDTWT) to characterize the anisotropy of bone texture. More specifically, we propose to extend the conventional discrete dual-tree wavelet transform (DDTWT) by using the anisotropic basis functions associated with the hyperbolic wavelet transform instead of isotropic spectrum supports. A texture classification framework is adopted to assess the performance of the proposed transform. The generalized Gaussian distribution is used to model the distribution of the sub band coefficients. The estimated vector of parameters for each image is then used as input for the support vector machine classifier. Experiments were conducted on synthesized anisotropic fractional Brownian motion fields and on a real database composed of osteoporotic patients and control cases. Results show that the ADDTWT outperforms most of the competing anisotropic transforms with an area under curve rate of 93%. PMID- 28574348 TI - Direct Multitype Cardiac Indices Estimation via Joint Representation and Regression Learning. AB - Cardiac indices estimation is of great importance during identification and diagnosis of cardiac disease in clinical routine. However, estimation of multitype cardiac indices with consistently reliable and high accuracy is still a great challenge due to the high variability of cardiac structures and the complexity of temporal dynamics in cardiac MR sequences. While efforts have been devoted into cardiac volumes estimation through feature engineering followed by a independent regression model, these methods suffer from the vulnerable feature representation and incompatible regression model. In this paper, we propose a semi-automated method for multitype cardiac indices estimation. After the manual labeling of two landmarks for ROI cropping, an integrated deep neural network Indices-Net is designed to jointly learn the representation and regression models. It comprises two tightly-coupled networks, such as a deep convolution autoencoder for cardiac image representation, and a multiple output convolution neural network for indices regression. Joint learning of the two networks effectively enhances the expressiveness of image representation with respect to cardiac indices, and the compatibility between image representation and indices regression, thus leading to accurate and reliable estimations for all the cardiac indices. When applied with five-fold cross validation on MR images of 145 subjects, Indices-Net achieves consistently low estimation error for LV wall thicknesses (1.44 +/- 0.71 mm) and areas of cavity and myocardium (204 +/- 133 mm2). It outperforms, with significant error reductions, segmentation method (55.1% and 17.4%), and two-phase direct volume-only methods (12.7% and 14.6%) for wall thicknesses and areas, respectively. These advantages endow the proposed method a great potential in clinical cardiac function assessment. PMID- 28574349 TI - Specular Beamforming. AB - Acoustically hard objects, such as bones, needles, or catheters, are poorly visualized in conventional ultrasound images. These objects behave like acoustic mirrors and reflect sound in specific directions. Soft tissue and diffusive reflectors scatter sound in a broad range of directions. Conventional delay-and sum beamforming is based on the assumption of a purely scattering domain with relatively weak reflectivity. We present an adaptive beamforming technique that takes into account the physics of specular reflection. Patterns predicted by the law of reflection are detected across the pool of received data and used to enhance the visualization of specular energy. This technique can be applied to any synthetic imaging sequence. Here, it is applied to synthetic transmit aperture imaging. In vitro experiments show a clear improvement in target visibility and an increase of 30 to 60 dB in signal-to-noise ratio. PMID- 28574350 TI - Characterization of Kerfless Linear Arrays Based on PZT Thick Film. AB - Multielement transducers enabling novel cost-effective fabrication of imaging arrays for medical applications have been presented earlier. Due to the favorable low lateral coupling of the screen-printed PZT, the elements can be defined by the top electrode pattern only, leading to a kerfless design with low crosstalk between the elements. The thick-film-based linear arrays have proved to be compatible with a commercial ultrasonic scanner and to support linear array beamforming as well as phased array beamforming. The main objective of the presented work is to investigate the performance of the devices at the transducer level by extensive measurements of the test structures. The arrays have been characterized by several different measurement techniques. First, electrical impedance measurements on several elements in air and liquid have been conducted in order to support material parameter identification using the Krimholtz-Leedom Matthaei model. It has been found that electromechanical coupling is at the level of 35%. The arrays have also been characterized by a pulse-echo system. The measured sensitivity is around -60 dB, and the fractional bandwidth is close to 60%, while the center frequency is about 12 MHz over the whole array. Finally, laser interferometry measurements have been conducted indicating very good displacement level as well as pressure. The in-depth characterization of the array structure has given insight into the performance parameters for the array based on PZT thick film, and the obtained information will be used to optimize the key parameters for the next generation of cost-effective arrays based on piezoelectric thick film. PMID- 28574352 TI - A Hierarchical Approach for Rain or Snow Removing in a Single Color Image. AB - In this paper, we propose an efficient algorithm to remove rain or snow from a single color image. Our algorithm takes advantage of two popular techniques employed in image processing, namely, image decomposition and dictionary learning. At first, a combination of rain/snow detection and a guided filter is used to decompose the input image into a complementary pair: 1) the low-frequency part that is free of rain or snow almost completely and 2) the high-frequency part that contains not only the rain/snow component but also some or even many details of the image. Then, we focus on the extraction of image's details from the high-frequency part. To this end, we design a 3-layer hierarchical scheme. In the first layer, an overcomplete dictionary is trained and three classifications are carried out to classify the high-frequency part into rain/snow and non rain/snow components in which some common characteristics of rain/snow have been utilized. In the second layer, another combination of rain/snow detection and guided filtering is performed on the rain/snow component obtained in the first layer. In the third layer, the sensitivity of variance across color channels is computed to enhance the visual quality of rain/snow-removed image. The effectiveness of our algorithm is verified through both subjective (the visual quality) and objective (through rendering rain/snow on some ground-truth images) approaches, which shows a superiority over several state-of-the-art works. PMID- 28574351 TI - Fabrication and Characterization of a 20-MHz Microlinear Phased-Array Transducer for Intervention Guidance. AB - This paper describes the design and fabrication of a miniature ultrasonic phased array transducer used for intervention guidance. Currently, ultrasound probes are often placed at the body surface of the patients, leading to several drawbacks including the limitation of penetration and image quality. In order to improve the reliability of the guiding process, we propose a miniature phased-array transducer that can be placed adjacent to the intervention device during the interventional procedure. In this paper, we report the work that has been carried out on the development of this miniature phased-array transducer. It comprised 48 elements housed in a 3-mm-diameter needle. A specially designed flexible circuit was used for accommodating the transducer array in the long, thin needle housing. The center frequency and the fractional bandwidth were approximately 20 MHz and 42%, respectively, with an average crosstalk lower than -30 dB. The axial and azimuth resolutions were approximately 80 and [Formula: see text], respectively. The imaging capability of the transducer was further evaluated by acquiring the B mode images of a needle in a cow liver. The performance of the proposed phased array transducer demonstrates the feasibility of such an approach for interventional guidance. PMID- 28574353 TI - dipIQ: Blind Image Quality Assessment by Learning-to-Rank Discriminable Image Pairs. AB - Objective assessment of image quality is fundamentally important in many image processing tasks. In this paper, we focus on learning blind image quality assessment (BIQA) models, which predict the quality of a digital image with no access to its original pristine-quality counterpart as reference. One of the biggest challenges in learning BIQA models is the conflict between the gigantic image space (which is in the dimension of the number of image pixels) and the extremely limited reliable ground truth data for training. Such data are typically collected via subjective testing, which is cumbersome, slow, and expensive. Here, we first show that a vast amount of reliable training data in the form of quality-discriminable image pairs (DIPs) can be obtained automatically at low cost by exploiting large-scale databases with diverse image content. We then learn an opinion-unaware BIQA (OU-BIQA, meaning that no subjective opinions are used for training) model using RankNet, a pairwise learning-to-rank (L2R) algorithm, from millions of DIPs, each associated with a perceptual uncertainty level, leading to a DIP inferred quality (dipIQ) index. Extensive experiments on four benchmark IQA databases demonstrate that dipIQ outperforms the state-of-the-art OU-BIQA models. The robustness of dipIQ is also significantly improved as confirmed by the group MAximum Differentiation competition method. Furthermore, we extend the proposed framework by learning models with ListNet (a listwise L2R algorithm) on quality-discriminable image lists (DIL). The resulting DIL inferred quality index achieves an additional performance gain. PMID- 28574354 TI - SuperPatchMatch: An Algorithm for Robust Correspondences Using Superpixel Patches. AB - Superpixels have become very popular in many computer vision applications. Nevertheless, they remain under-exploited, since the superpixel decomposition may produce irregular and nonstable segmentation results due to the dependency to the image content. In this paper, we first introduce a novel structure, a superpixel based patch, called SuperPatch. The proposed structure, based on superpixel neighborhood, leads to a robust descriptor, since spatial information is naturally included. The generalization of the PatchMatch method to SuperPatches, named SuperPatchMatch, is introduced. Finally, we propose a framework to perform fast segmentation and labeling from an image database, and demonstrate the potential of our approach, since we outperform, in terms of computational cost and accuracy, the results of state-of-the-art methods on both face labeling and medical image segmentation. PMID- 28574355 TI - Feature Interaction Augmented Sparse Learning for Fast Kinect Motion Detection. AB - The Kinect sensing devices have been widely used in current Human-Computer Interaction entertainment. A fundamental issue involved is to detect users' motions accurately and quickly. In this paper, we tackle it by proposing a linear algorithm, which is augmented by feature interaction. The linear property guarantees its speed whereas feature interaction captures the higher order effect from the data to enhance its accuracy. The Schatten-p norm is leveraged to integrate the main linear effect and the higher order nonlinear effect by mining the correlation between them. The resulted classification model is a desirable combination of speed and accuracy. We propose a novel solution to solve our objective function. Experiments are performed on three public Kinect-based entertainment data sets related to fitness and gaming. The results show that our method has its advantage for motion detection in a real-time Kinect entertaining environment. PMID- 28574356 TI - Weakly Supervised Part Proposal Segmentation From Multiple Images. AB - Weakly supervised local part segmentation is challenging, due to the difficulty of modeling multiple local parts from image level prior. In this paper, we propose a new weakly supervised local part proposal segmentation method based on the observation that local parts will keep fixed along the object pose variations. Hence, the local part can be segmented by capturing object pose variations. Based on such observation, a new local part proposal segmentation model is proposed. Three aspects, such as shape similarity-based cosegmentation, shape matching-based part detection and segmentation, and graph matching-based part assignment are considered. A part segmentation energy function is first proposed. Four terms, such as MRF-based single image segmentation term, shape feature-based foreground consistency term, NCuts-based part segmentation term, and two-order graphs matching based part consistency term, are contained. Then, a three sub-minimization-based energy minimization method is proposed to accomplish approximation solution. Finally, we verify our method based on three image data sets (PASCAL VOC 2008 Part data set, UCB Bird data set, and Cat-Dog data set), and one video data set (UCF Sports) data set. The experimental results demonstrate a better segmentation performance compared with the existing object cosegmentation and part proposal generation methods. PMID- 28574357 TI - Single Image Rain Streak Decomposition Using Layer Priors. AB - Rain streaks impair visibility of an image and introduce undesirable interference that can severely affect the performance of computer vision and image analysis systems. Rain streak removal algorithms try to recover a rain streak free background scene. In this paper, we address the problem of rain streak removal from a single image by formulating it as a layer decomposition problem, with a rain streak layer superimposed on a background layer containing the true scene content. Existing decomposition methods that address this problem employ either sparse dictionary learning methods or impose a low rank structure on the appearance of the rain streaks. While these methods can improve the overall visibility, their performance can often be unsatisfactory, for they tend to either over-smooth the background images or generate -images that still contain noticeable rain streaks. To address the problems, we propose a method that imposes priors for both the background and rain streak layers. These priors are based on Gaussian mixture models learned on small patches that can accommodate a variety of background appearances as well as the appearance of the rain streaks. Moreover, we introduce a structure residue recovery step to further separate the background residues and improve the decomposition quality. Quantitative evaluation shows our method outperforms existing methods by a large margin. We overview our method and demonstrate its effectiveness over prior work on a number of examples. PMID- 28574358 TI - Beyond Group: Multiple Person Tracking via Minimal Topology-Energy-Variation. AB - Tracking multiple persons is a challenging task when persons move in groups and occlude each other. Existing group-based methods have extensively investigated how to make group division more accurately in a tracking-by-detection framework; however, few of them quantify the group dynamics from the perspective of targets' spatial topology or consider the group in a dynamic view. Inspired by the sociological properties of pedestrians, we propose a novel socio-topology model with a topology-energy function to factor the group dynamics of moving persons and groups. In this model, minimizing the topology-energy-variance in a two-level energy form is expected to produce smooth topology transitions, stable group tracking, and accurate target association. To search for the strong minimum in energy variation, we design the discrete group-tracklet jump moves embedded in the gradient descent method, which ensures that the moves reduce the energy variation of group and trajectory alternately in the varying topology dimension. Experimental results on both RGB and RGB-D data sets show the superiority of our proposed model for multiple person tracking in crowd scenes. PMID- 28574359 TI - Diversity-Aware Multi-Video Summarization. AB - Most video summarization approaches have focused on extracting a summary from a single video; we propose an unsupervised framework for summarizing a collection of videos. We observe that each video in the collection may contain some information that other videos do not have, and thus exploring the underlying complementarity could be beneficial in creating a diverse informative summary. We develop a novel diversity-aware sparse optimization method for multi-video summarization by exploring the complementarity within the videos. Our approach extracts a multi-video summary, which is both interesting and representative in describing the whole video collection. To efficiently solve our optimization problem, we develop an alternating minimization algorithm that minimizes the overall objective function with respect to one video at a time while fixing the other videos. Moreover, we introduce a new benchmark data set, Tour20, that contains 140 videos with multiple manually created summaries, which were acquired in a controlled experiment. Finally, by extensive experiments on the new Tour20 data set and several other multi-view data sets, we show that the proposed approach clearly outperforms the state-of-the-art methods on the two problems topic-oriented video summarization and multi-view video summarization in a camera network. PMID- 28574360 TI - Adaptive Collision Culling for Massive Simulations by a Parallel and Context Aware Sweep and Prune Algorithm. AB - We present an improved parallel Sweep and Prune algorithm that solves the dynamic box intersection problem in three dimensions. It scales up to very large datasets, which makes it suitable for broad phase collision detection in complex moving body simulations. Our algorithm gracefully handles high-density scenarios, including challenging clustering behavior, by using a double-axis sweeping approach and a cache-friendly succinct data structure. The algorithm is realized by three parallel stages for sorting, candidate generation, and object pairing. By the use of temporal coherence, our sorting stage runs with close to optimal load balancing. Furthermore, our approach is characterized by a work-division strategy that relies on adaptive partitioning, which leads to almost ideal scalability. In addition, for scenarios that involves intense clustering along several axes simultaneously, we propose an enhancement that increases the context awareness of the algorithm. By exploiting information gathered along three orthogonal axes, an efficient choice of what range query to perform can be made per object during run-time. Experimental results show high performance for up to millions of objects on modern multi-core CPUs. PMID- 28574361 TI - Electrical Impedance Myography for Evaluating Paretic Muscle Changes After Stroke. AB - Electrical impedance myography (EIM) was used to assess the paretic muscle intrinsic electrical properties post stroke. Twenty-seven subjects with chronic hemiparesis participated in this study. Muscle impedance was measured by applying high-frequency, low-intensity alternating current to biceps brachii muscles. Major EIM parameters, resistance ( ), reactance ( ), phase angle ( ), and electrical anisotropy ratios (AR) of the three parameters, were examined at 50 kHz. Statistical analysis demonstrated significant reduction of reactance, phase angle, AR of resistance, and AR of reactance in the paretic muscle compared with the contralateral side (Paretic X: , contralateral X: , and p < 0.001; Paretic : , contralateral : 14.5 +/- 0.82 degrees , and p < 0.001; Paretic AR of R: 0.969 +/- 0.013, contralateral AR of R: 1.008 +/- 0.011, and p < 0.02; and Paretic AR of X: 0.981 +/- 0.066, contralateral AR of X: 1.114 +/- 0.041, and p < 0.02). Correlation analysis, however, did not show any significant relationship between EIM parameters and clinical assessments. Findings of this paper indicated significant changes in the muscular intrinsic electrical properties after stroke, possibly related to structural modifications induced by loss of muscle fibers or fat infiltration as well as changes in the quality of cell membranes post stroke. PMID- 28574362 TI - Low-Cost Robotic Assessment of Visuo-Motor Deficits in Alzheimer's Disease. AB - A low-cost robotic interface was used to assess the visuo-motor performance of patients with Alzheimer's disease (AD). Twenty AD patients and twenty age-matched controls participated in this work. The battery of tests included simple reaction times, position tracking, and stabilization tasks performed with both hands. The regularity, velocity, visual and haptic feedback were manipulated to vary movement complexity. Reaction times and movement tracking error were analyzed. Results show a marked group effect on a subset of conditions, in particular when the patients could not rely on the visual feedback of hand movement. The visuo motor performance correlated with the measures of global cognitive functioning and with different memory-related abilities. Our results support the hypothesis that the ability to recall and use visuo-spatial associations might underlie the impairment in complex motor behavior that has been reported in AD patients. Importantly, the patients had preserved learning effects across sessions, which might relate to visuo-motor deficits being less evident in every-day life and clinical assessments. This robotic assessment, lasting less than 1 h, provides detailed information about the integrity of visuo-motor abilities. The data can aid the understanding of the complex pattern of deficits that characterizes this pervasive disease. PMID- 28574363 TI - Analysis of the Genome Sequence and Prediction of B-Cell Epitopes of the Envelope Protein of Middle East Respiratory Syndrome-Coronavirus. AB - The outbreak of Middle East respiratory syndrome-coronavirus (MERS-CoV) in South Korea in April 2015 led to 186 infections and 37 deaths by the end of October 2015. MERS-CoV was isolated from the imported patient in China. The envelope (E) protein, a small structural protein of MERS-CoV, plays an important role in host recognition and infection. To identify the conserved epitopes of the E protein, sequence analysis was performed by comparing the E proteins from 42 MERS-CoV strains that triggered severe pandemics and infected humans in the past. To predict the potential B cell epitopes of E protein, three most effective online epitope prediction programs, the ABCpred, Bepipred, and Protean programs from the LaserGene software were used. All the nucleotides and amino acids sequences were obtained from the NCBI Database. One potential epitope with a suitable length (amino acids 58-82) was confirmed and predicted to be highly antigenic. This epitope had scores of >0.80 in ABCpred and level 0.35 in Bepipred programs. Due to the lack of X-ray crystal structure of the E protein in the PDB database, the simulated 3D structure of the E protein were also predicted using PHYRE 2 and Pymol programs. In conclusion, using bioinformatics methods, we analyzed the genome sequence of MERS-CoV and identified a potential B-cell epitope of the E protein, which might significantly improve our current MERS vaccine development strategies. PMID- 28574364 TI - Genome Rearrangement with ILP. AB - The weighted Genome Sorting Problem (wGSP) is to find a minimum-weight sequence of rearrangement operations that transforms a given gene order into another given gene order using rearrangement operations that are associated with a predefined weight. This paper presents a polynomial sized Integer Linear Program -called GeRe-ILP- for solving the wGSP for the following three types of rearrangement operations: inversion , transposition, and inverse transposition. GeRe-ILP uses variables and constraints for gene orders of length . It is studied experimentally on simulated data how different weighting schemes influence the reconstructed scenarios. The influences of the length of the gene orders and of the size of the reconstructed scenarios on the runtime of GeRe-ILP are studied as well. PMID- 28574365 TI - Highly Accurate and Efficient Data-Driven Methods For Genotype Imputation. AB - High-throughput sequencing techniques have generated massive quantities of genotype data. Haplotype phasing has proven to be a useful and effective method for analyzing these data. However, the quality of phasing is undermined by the presence of missing information. Imputation provides an effective means of improving the underlying genotype information. For model organisms, imputation can rely on an available reference genotype panel and a physical or genetic map. For non-model organisms, which often do not have a genotype panel, it is important to design an imputation technique that does not rely on reference data. Here, we present ADDIT (Accurate Data-Driven Imputation Technique), which is composed of two data-driven algorithms capable of handling data generated from model and non-model organisms. The non-model variant of ADDIT (referred to as ADDIT-NM) employs statistical inference methods to impute missing genotypes, whereas the model variant (referred to as ADDIT-M) leverages a supervised learning-based approach for imputation. We demonstrate that both variants of ADDIT are more accurate, faster, and require less memory than leading state-of the-art imputation tools using model (human) and non-model (maize, apple, grape) genotype data. Software Availability: The source code of ADDIT and test data sets are available at https://github.com/NDBL/ADDIT. PMID- 28574366 TI - Wearable Microsystem for Minimally Invasive, Pseudo-Continuous Blood Glucose Monitoring: The e-Mosquito. AB - This paper presents a wearable microsystem for minimally invasive, autonomous, and pseudo-continuous blood glucose monitoring, addressing a growing demand for replacing tedious fingerpricking tests for diabetic patients. Unlike prevalent solutions which estimate blood glucose levels from interstitial fluids or tears, our design extracts a whole blood sample from a small lanced skin wound using a novel shape memory alloy (SMA)-based microactuator and directly measures the blood glucose level from the sample. In vitro characterization determined that the SMA microactuator produced penetration force of 225 gf, penetration depth of 3.55 mm, and consumed approximately 5.56 mW.h for triggering. The microactuation mechanism was also evaluated by extracting blood samples from the wrist of four human volunteers. A total of 19 out of 23 actuations successfully reached capillary vessels below the wrists producing blood droplets on the surface of the skin. The integrated potentiostat-based glucose sensing circuit of our e-Mosquito device also showed a good linear correlation (R2 = 0.9733) with measurements using standard blood glucose monitoring technology. These proof-of-concept studies demonstrate the feasibility of the e-Mosquito microsystem for autonomous intermittent blood glucose monitoring. PMID- 28574367 TI - Efficient Sample Delay Calculation for 2-D and 3-D Ultrasound Imaging. AB - Ultrasound imaging is a reference medical diagnostic technique, thanks to its blend of versatility, effectiveness, and moderate cost. The core computation of all ultrasound imaging methods is based on simple formulae, except for those required to calculate acoustic propagation delays with high precision and throughput. Unfortunately, advanced three-dimensional (3-D) systems require the calculation or storage of billions of such delay values per frame, which is a challenge. In 2-D systems, this requirement can be four orders of magnitude lower, but efficient computation is still crucial in view of low-power implementations that can be battery-operated, enabling usage in numerous additional scenarios. In this paper, we explore two smart designs of the delay generation function. To quantify their hardware cost, we implement them on FPGA and study their footprint and performance. We evaluate how these architectures scale to different ultrasound applications, from a low-power 2-D system to a next generation 3-D machine. When using numerical approximations, we demonstrate the ability to generate delay values with sufficient throughput to support 10 000 channel 3-D imaging at up to 30 fps while using 63% of a Virtex 7 FPGA, requiring 24 MB of external memory accessed at about 32 GB/s bandwidth. Alternatively, with similar FPGA occupation, we show an exact calculation method that reaches 24 fps on 1225-channel 3-D imaging and does not require external memory at all. Both designs can be scaled to use a negligible amount of resources for 2-D imaging in low-power applications and for ultrafast 2-D imaging at hundreds of frames per second. PMID- 28574368 TI - Development of a Wearable Controller for Gesture-Recognition-Based Applications Using Polyvinylidene Fluoride. AB - This paper reports on a wearable gesture-based controller fabricated using the sensing capabilities of the flexible thin-film piezoelectric polymer polyvinylidene fluoride (PVDF) which is shown to repeatedly and accurately discern, in real time, between right and left hand gestures. The PVDF is affixed to a compression sleeve worn on the forearm to create a wearable device that is flexible, adaptable, and highly shape conforming. Forearm muscle movements, which drive hand motions, are detected by the PVDF which outputs its voltage signal to a developed microcontroller-based board and processed by an artificial neural network that was trained to recognize the generated voltage profile of right and left hand gestures. The PVDF has been spatially shaded (etched) in such a way as to increase sensitivity to expected deformations caused by the specific muscles employed in making the targeted right and left gestures. The device proves to be exceptionally accurate both when positioned as intended and when rotated and translated on the forearm. PMID- 28574369 TI - A Multi-Finger Interface with MR Actuators for Haptic Applications. AB - Haptic devices with multi-finger input are highly desirable in providing realistic and natural feelings when interacting with the remote or virtual environment. Compared with the conventional actuators, MR (Magneto-rheological) actuators are preferable options in haptics because of larger passive torque and torque-volume ratios. Among the existing haptic MR actuators, most of them are still bulky and heavy. If they were smaller and lighter, they would become more suitable for haptics. In this paper, a small-scale yet powerful MR actuator was designed to build a multi-finger interface for the 6 DOF haptic device. The compact structure was achieved by adopting the multi-disc configuration. Based on this configuration, the MR actuator can generate the maximum torque of 480 N.mm with dimensions of only 36 mm diameter and 18 mm height. Performance evaluation showed that it can exhibit a relatively high dynamic range and good response characteristics when compared with some other haptic MR actuators. The multi finger interface is equipped with three MR actuators and can provide up to 8 N passive force to the thumb, index and middle fingers, respectively. An application example was used to demonstrate the effectiveness and potential of this new MR actuator based interface. PMID- 28574370 TI - Self-Powered Multiparameter Health Sensor. AB - Wearable health sensors are about to change our health system. While several technological improvements have been presented to enhance performance and energy efficiency, battery runtime is still a critical concern for practical use of wearable biomedical sensor systems. The runtime limitation is directly related to the battery size, which is another concern regarding practicality and customer acceptance. We introduced ULPSEK-Ultra-Low-Power Sensor Evaluation Kit-for evaluation of biomedical sensors and monitoring applications (http://ulpsek.com). ULPSEK includes a multiparameter sensor measuring and processing electrocardiogram, respiration, motion, body temperature, and photoplethysmography. Instead of a battery, ULPSEK is powered using an efficient body heat harvester. The harvester produced 171 W on average, which was sufficient to power the sensor below 25 C ambient temperature. We present design issues regarding the power supply and the power distribution network of the ULPSEK sensor platform. Due to the security aspect of self-powered health sensors, we suggest a hybrid solution consisting of a battery charged by a harvester. PMID- 28574371 TI - Tooth and Alveolar Bone Segmentation From Dental Computed Tomography Images. AB - Three-dimensional (3D) models of tooth-alveolar bone complex are needed in treatment planning and simulation for computer-aided orthodontics. Tooth and alveolar bone segmentation from computed tomography (CT) images is a fundamental step in reconstructing their models. Due to less application of alveolar bone in conventional orthodontic treatment which may cause undesired side effects, the previous studies mainly focused on tooth segmentation and reconstruction, and did not consider the alveolar bone. In this study, we proposed a method to implement both tooth and alveolar bone segmentation from dental CT images for reconstructing their 3D models. First, the proposed method extracted the connected region of tooth and alveolar bone from CT images using a global convex level set model. Then, individual tooth and alveolar bone are separated from the connected region based on Radon transform and a local level set model. The experimental results showed that the proposed method could successfully complete both the tooth and alveolar bone segmentation from CT images, and outperformed the state of the art tooth segmentation methods in terms of accuracy. This suggests that the proposed method can be used in reconstructing the 3D models of tooth-alveolar bone complex for precise treatment. PMID- 28574372 TI - Monitoring the Depth of Anesthesia Using a New Adaptive Neurofuzzy System. AB - Accurate and noninvasive monitoring of the depth of anesthesia (DoA) is highly desirable. Since the anesthetic drugs act mainly on the central nervous system, the analysis of brain activity using electroencephalogram (EEG) is very useful. This paper proposes a novel automated method for assessing the DoA using EEG. First, 11 features including spectral, fractal, and entropy are extracted from EEG signal and then, by applying an algorithm according to exhaustive search of all subsets of features, a combination of the best features (Beta-index, sample entropy, shannon permutation entropy, and detrended fluctuation analysis) is selected. Accordingly, we feed these extracted features to a new neurofuzzy classification algorithm, adaptive neurofuzzy inference system with linguistic hedges (ANFIS-LH). This structure can successfully model systems with nonlinear relationships between input and output, and also classify overlapped classes accurately. ANFIS-LH, which is based on modified classical fuzzy rules, reduces the effects of the insignificant features in input space, which causes overlapping and modifies the output layer structure. The presented method classifies EEG data into awake, light, general, and deep states during anesthesia with sevoflurane in 17 patients. Its accuracy is 92% compared to a commercial monitoring system (response entropy index) successfully. Moreover, this method reaches the classification accuracy of 93% to categorize EEG signal to awake and general anesthesia states by another database of propofol and volatile anesthesia in 50 patients. To sum up, this method is potentially applicable to a new real time monitoring system to help the anesthesiologist with continuous assessment of DoA quickly and accurately. PMID- 28574373 TI - RRV: A Spatiotemporal Descriptor for Rigid Body Motion Recognition. AB - The motion behaviors of a rigid body can be characterized by a six degrees of freedom motion trajectory, which contains the 3-D position vectors of a reference point on the rigid body and 3-D rotations of this rigid body over time. This paper devises a rotation and relative velocity (RRV) descriptor by exploring the local translational and rotational invariants of rigid body motion trajectories, which is insensitive to noise, invariant to rigid transformation and scale. The RRV descriptor is then applied to characterize motions of a human body skeleton modeled as articulated interconnections of multiple rigid bodies. To show the descriptive ability of our RRV descriptor, we explore its potentials and applications in different rigid body motion recognition tasks. The experimental results on benchmark datasets demonstrate that our RRV descriptor learning discriminative motion patterns can achieve superior results for various recognition tasks. PMID- 28574374 TI - Nitrophorins and nitrobindins: structure and function. AB - Classical all alpha-helical globins are present in all living organisms and are ordered in three lineages: (i) flavohemoglobins and single domain globins, (ii) protoglobins and globin coupled sensors and (iii) truncated hemoglobins, displaying the 3/3 or the 2/2 all alpha-helical fold. However, over the last two decades, all beta-barrel and mixed alpha-helical-beta-barrel heme-proteins displaying heme-based functional properties (e.g. ligand binding, transport and sensing) closely similar to those of all alpha-helical globins have been reported. Monomeric nitrophorins (NPs) and alpha1-microglobulin (alpha1-m), belonging to the lipocalin superfamily and nitrobindins (Nbs) represent prototypical heme-proteins displaying the all beta-barrel and mixed alpha-helical beta-barrel folds. NPs are confined to the Reduviidae and Cimicidae families of Heteroptera, whereas alpha1-m and Nbs constitute heme-protein families spanning bacteria to Homo sapiens. The structural organization and the reactivity of the stable ferric solvent-exposed heme-Fe atom suggest that NPs and Nbs are devoted to NO transport, storage and sensing, whereas Hs-alpha1-m participates in heme metabolism. Here, the structural and functional properties of NPs and Nbs are reviewed in parallel with those of sperm whale myoglobin, which is generally taken as the prototype of monomeric globins. PMID- 28574375 TI - One-carbon metabolism and ionizing radiation: a multifaceted interaction. AB - Ionizing radiation (IR) is a ubiquitous component of our environment and an important tool in research and medical treatment. At the same time, IR is a potent genotoxic and epigenotoxic stressor, exposure to which may lead to negative health outcomes. While the genotoxocity is well described and characterized, the epigenetic effects of exposure to IR and their mechanisms remain under-investigated. In this conceptual review, we propose the IR-induced changes to one-carbon metabolism as prerequisites to alterations in the cellular epigenome. We also provide evidence from both experimental and clinical studies describing the interactions between IR and one-carbon metabolism. We further discuss the potential for the manipulation of the one-carbon metabolism in clinical applications for the purpose of normal tissue protection and for increasing the radiosensitivity of cancerous cells. PMID- 28574376 TI - Recent advances in the mechanism of selenoamino acids toxicity in eukaryotic cells. AB - Selenium is an essential trace element due to its incorporation into selenoproteins with important biological functions. However, at high doses it is toxic. Selenium toxicity is generally attributed to the induction of oxidative stress. However, it has become apparent that the mode of action of seleno compounds varies, depending on its chemical form and speciation. Recent studies in various eukaryotic systems, in particular the model organism Saccharomyces cerevisiae, provide new insights on the cytotoxic mechanisms of selenomethionine and selenocysteine. This review first summarizes current knowledge on reactive oxygen species (ROS)-induced genotoxicity of inorganic selenium species. Then, we discuss recent advances on our understanding of the molecular mechanisms of selenocysteine and selenomethionine cytotoxicity. We present evidences indicating that both oxidative stress and ROS-independent mechanisms contribute to selenoamino acids cytotoxicity. These latter mechanisms include disruption of protein homeostasis by selenocysteine misincorporation in proteins and/or reaction of selenols with protein thiols. PMID- 28574377 TI - The chief complaint driven medical history: implications for medical education. PMID- 28574379 TI - [EFFICACY OF CYTOFLAVIN IN COMPLEX TREATMENT OF DIABETIC FOOT SYNDROME]. AB - The study involved 97 patients with severe diabetic foot syndrome (DFS) subcompensated type 2 diabetes. All patients were available mediacalcification foot and lower leg arteries of different severity. Depending on the treatment, all patients were divided into 2 groups by stratified randomization. The I group received standard therapy, which is indicated for the DFS. A II group of patients additionally received basic therapy drug Cytoflavin 10 ml 0,9% NaCl 200 ml for 10 days, followed by transfer to tablet form Cytoflavin 2 tablets 2 times per day orally for one month. We noted a positive trend of treatment of patients who, in addition to standard therapy received the drug Cytoflavin. Thus, the use of complex surgical treatment of patients with mixed form of DFS Cytoflavin reduces the severity of distal polyneuropathy, improves oxygenation of tissues and restores the enzyme activity of antioxidant system, that manifested neuroprotective, antioxidant and anti-hypoxic effects of drugs, which substantiates the indications for its use in the this pathology. PMID- 28574378 TI - [IMPACT OF ATORVASTATIN AND ROSUVASTATIN ON RESIDUAL ON-CLOPIDOGREL TREATMENT PLATELET REACTIVITY IN PATIENTS WITH ISCHEMIC HEART DISEASE AND TYPE 2 DIABETES MELLITUS AFTER ACUTE CORONARY SYNDROME]. AB - In patients with ischemic heart disease and type 2 diabetes mellitus in 4-6 weeks after acute coronary syndrome (ACS) on stable dual antiplatelet therapy (DAPT) with aspirin and clopidogrel co-adminstrated with rosuvastatin residual platelet reactivity on adenosine diphosphate was higher than in patients receiving atorvastatin. However, the rate of high residual on-clopidogrel treatment platelet reactivity (RCPR) in rosuvastatin-treated patients exceeded the rate of high RCPR in atorvastatin-treated patients insignificantly. In 6 months after ACS residual platelet reactivity did not differ between the groups. After 12 months of DAPT platelet reactivity increased as compared to baseline values both in patients receiving rosuvastatin and in patients receiving atorvastatin without switching. In patients, randomly switching from one statin type to another at 6 month of treatment, platelet reactivity did not change significantly in comparison to baseline and the prevalence of high RCPR was lower than in patients receiving statins without switching. Thus, in patients with diabetes with ACS on DAPT with acetylsalicylic acid and clopidogrel statin treatment should be started with atorvastatin and in 6 months after ACS atorvastatin should be switched to rosuvastatin. This approach will provide lower RCPR within at least first 4-6 weeks after ACS and prevent RCPR increase during 12 months of DATT use in this patients group. PMID- 28574380 TI - MTHFR GENE C677T POLYMORPHISM AND LEVELS OF DNA METHYLTRASFERASES IN SUBCLINICAL HYPOTHYROIDISM. AB - The aim of our study was to investigate the link between MTHFR gene C677T polymorphism and DNMTs levels in patients with Subclinical Hypothyroidism (SCH). In this study 19 adult patients with subclinical hypothyroidism and 19 healthy controls (mean age 31+/-5.5 and 33+/-5.1 years respectively) were recruited. All patients were diagnosed based on serum levels of TSH, FT4, anti-TG and anti-TPO antibodies. Written informed consents were obtained from all study subjects. Genomic DNA was extracted using Quick-DNA Universal Kit (Zymo Research, USA). The MTHFR C677T polymorphism was genotyped by PCR-RFLP method. Levels of DNMT1 and 3a were measured in nuclear extracts of PBMC using DNMTs assay kits (Abcam). Our data indicates that the frequency of genotypes and alleles were different among the patient and the control group. There is a significant increase in CC genotype distribution in the control group when compared to the SCH patient group, while the CT as well as TT genotype distribution were not increased significantly in SCH group versus control group. However the C allele is significantly prevalent in the control group compared to the SCH group, while T allele is prevalent in patients compared to the control group with a statically significant difference. In addition, individuals with TT and CT genotypes and hypothyroidism showed elevated amount of DNMT3a in nuclear extracts of PBMC compared with controls, while no significant difference in DNMT1 levels was observed. This study indicates the MTHFR C677T variant may contribute in alteration of epigenetic regulation such as DNA methylation mediated by DNA methyltransferases in patients with subclinical hypothyroidism and also, carriers of the T allele might have an increasing risk of developing SCH. PMID- 28574381 TI - [MEASUREMENT OF HISTONES AND CIRCULATING EXTRACELLULAR NUCLEIC ACIDS IN PATIENTS' WITH COMPLICATED FORMS OF PEPTIC ULCER]. AB - We studied 135 people (24 people, apparently healthy, 39 uncomplicated peptic ulcer disease, 42 people with complex forms peptic ulcer, 30 and after the treatment of complicated forms of peptic ulcer disease, both sexes (18-45 y.). In all patients, the diagnosis was confirmed fibrogastroduodenoscopy (EGD). Determination of histones and acid soluble fraction (ASF), RNA, DNA, in blood was performed by the method of L. Markusheva. Studies have led to the conclusion that the change in the blood concentration of extracellular nucleic acids in patients with uncomplicated disease and complex shapes can be caused by oxidative stress products and can be a signal for elimination of nucleic acids from cells. We have registered various dynamics of the studied parameters histones in the blood of patients with various forms of peptic ulcer disease, which reflects the degree of metabolic abnormalities that occur in the body, associated with changes in the structure of the nucleus. According to the results of our research in the study of the role of extracellular nucleic acids, histones to assess the extent of violations of metabolic processes at a peptic ulcer, complicated and uncomplicated form, the obtained results can be used as predictors of complications of a stomach ulcer. PMID- 28574382 TI - DERMAL ADIPOSE TISSUE IN HAIR FOLLICLE CYCLING: POSSIBLE APPLICATIONS IN ALOPECIA? AB - Cross-talk between the hair follicles (HFs) in different stages of their cycling and adjacent adipose tissue is a new important topic which is of both theoretical and practical interest. Objective - to analyze available data on possible interrelationship of dermal adipose tissue and hair follicle cycling. Experimental results obtained in rodents clearly demonstrate that HFs cycling is connected to adjacent dermal adipose tissue. Recently uncovered adipocyte myofibroblast transition can be significantly involved in miniaturization of HFs and be an important pathophysiological step in androgenetic alopecia. Improvement of adipogenic environment of HFs can be important both in treatment of alopecia and in surgical hair restoration procedures. PMID- 28574383 TI - [CARDIOREABILITATION PECULIARITIES AND CORRECTION OF VIOLATIONS OF SISTOLIC, DIASOLIC FUNCTION AND HEART RATE VARIABILITY IN PATIENTS WITH ACUTE CORONARY SYNDROME AND CORONARY ARTERY REVASCULARIZATION]. AB - In patients with acute coronary syndrome (ACS) who underwent coronary arteries revascularization, violations of hemodynamics, metabolism and heart rate variability often develop in the postoperative period, therefore, the goal of the study was to establish the features of disturbances and the effectiveness of correction of left ventricular systolic and diastolic dysfunction and heart rate variability in stages of cardiorehabilitation in patients with acute coronary syndrome who underwent coronary arteries revascularization. The experimental group included 40 patients with ACS in the postoperative period who underwent balloon angioplasty and stenting of the coronary arteries (25 patients with ST segment elevation ACS and 15 patients without ST-segment elevation ACS). The age of examined patients was 37 to 74 years, an average of 52.6+/-6.7 years. The control group consisted of 20 patients, comparable in age and clinico-laboratory manifestations of ACS, who underwent drug treatment with direct anticoagulants, double antiplatelet therapy, beta-blockers, ACE inhibitors and statins. Clinical efficacy of cardiorespiratory process in patients of both groups was assessed by the dynamics of general clinical symptoms and parameters of natriuretic propeptide, systolic and diastolic function of the left ventricle and heart rate variability. In the initial state, clinical and laboratory-instrumental signs of myocardial ischemia disappear in patients with ACS undergoing surgical revascularization of the coronary arteries, but clinical and subclinical manifestations of heart failure were diagnosed. The use of the accelerated program of cardiac rehabilitation already during the first month of studies leads to a decreasement of the signs of systolic and diastolic dysfunction, the level of NT-proBNP and improve in the variability of the heart rhythm wich significantly improves the life quality of patients with ACS. To monitor the effectiveness and safety of cardiac rehabilitation in patients with ACS who underwent coronary arteries revascularization, in addition to the generally accepted methods (determination of heart rate, blood pressure, a 6-minute test), it is advisable to diagnose the subclinical stage of heart failure by determining the level of NT-proBNP, Doppler echocardiogram, parameters of the left ventricular systolic and diastolic function and heart rate variability. PMID- 28574384 TI - [EVALUATION OF QUALITY INDICATORS OF LIFE AS A CRITERION OF THE EFFICIENCY OF TREATMENT FOR LIQUIDATORS OF THE ACCIDENT AT CHERNOBYL AEROSPHORUS, PATIENTS WITH HYPERTENSION DISEASE COMORBID WITH GASTROESOPHAGEAL REFLUX DISEASE]. AB - In order to assess the quality of life of liquidators of the accident at the Chernobyl nuclear power plant (CHPP) of patients with hypertensive comorbid disease with gastroesophageal reflux disease, 52 patients aged 46 to 71 years (mean age 57.5+/-0, 8 years old) who were on inpatient treatment in the therapeutic department of the Regional Clinical Specialized Dispensary for Radiation Protection of the Population of Kharkov from January 2016 to December 2016. The men among the examined were 44 (84.6%), women - 8 (15.4 All patients were divided into 2 groups, Group I patients received standard therapy, Group II patients, in addition to standard therapy, respectively nosology, received additionally the drug Actovegin (r) Takeda Austria GmbH. All quality of life indicators were evaluated before the treatment and after In group I patients, after the standard treatment of GB comorbid with GERD, statistically significantly reduced the limitations on the scale of body pain (BP), therefore, in points, on the contrary, to 18.8+/-2.8 points increased, indicating a decrease in pain after treatment In patients. In patients with group II GB comorbid with GERD after standard treatment with additional use of Actovegin (r), the daily activity limitations associated with the disease on the scales of physical functioning (PF), role activity (RP), physical pain (BP), Vitality (VT), emotional state (RE). PMID- 28574386 TI - [IMMUNE RESPONSE IN CHRONIC BRONCHIOLITIS OBLITERANS IN CHILDREN]. AB - The qaim of the research was to evaluate a condition of cellular and humoral immunity in 139 children with bronchiolitis obliterans in age from 2 years to 14 years of life. There was a minor immunosuppression during exacerbation followed by normalization in remission. There was a slight decrease in the level of IgA, an increased concentration of IgM and high value of the circulating immune complexes during the exacerbation with normalization as acute inflammation subsided. An analysis of interleukin dynamics revealed a significant increase in the concentration of pro- and anti-inflammatory cytokines in the acute stage of the disease with a tendency to normalization in remission. Thus, there is no place marked immunosuppression. Analyzed changes are adequate and are a response to viral and bacterial infection. PMID- 28574385 TI - [CONNECTIVE TISSUE METABOLIC FEATURES IN CLIMACTERIC SYNDROME'S PATIENTS WITH VARIOUS TYPES OF MENOPAUSE]. AB - The purpose of the study was investigation of the connective tissue metabolic features among women with menopausal syndrome (MS) and MS, in which the arthropathic syndrome is leading and comparative analysis of the connective tissue indicators exchange during menopause caused in a surgical and natural way. We examined 70 women in total, menopause duration they accounted for 1,95+/-1,1 years, it came both as natural, and as a result of a surgery. The main group included 40 women with MS with leading arthropathic syndrome. The patients' modified menopausal index was calculated (MMI), the functional condition of the joints was assessed on a scale-questionnaire with the calculation of the clinical functional index of WOMAC; the quantitative content and qualitative composition of glycosaminoglycans in the serum, the urinary excretion of hydroxyproline and uronic acids were determined. To determine the degree of deviation from the control (standard) indicators was used non-parametric Mann-Whitney criterion and factor analysis (main components method). It was revealed that all patients have an increased content of glycosaminoglycans and glycoprotein in the blood, which corresponds to the general age-related rearrangement of connective tissue metabolism, but the patients of the main group have more expressed indictors, which corresponds to more severe dystrophic changes and the severity of clinical symptoms. Redistribution of the fractional composition of glycosaminoglycans towards the increase of chondroitin-6 sulfate in patients of the main group indicates the presence of pre-emptive destruction of cartilage. The arthropathic syndrome availability also confirms the significant reduction CI-6s / CI-4s ratio and an increased content of chondroitin sulfates. Patients with a natural type of menopause showed more pronounced changes in connective tissue metabolites, in contrast to patients with surgical menopause ehat indicates a longer and more invasive pathologic course of natural menopause. PMID- 28574387 TI - [CLINICAL AND EPIDEMIOLOGICAL PECULIARITIES OF CYSTIC ECHINOCOCCOSIS IN CHILDREN]. AB - The postoperative period of cystic echinococcosis was studied in 13 children. Demographic, epidemiological, clinical diagnosis, treatment, number location, and development of cysts and serologic data were analyzed. Age of children at diagnosis range 5 to 17 years. All patients with cystic echinococcosis had abdominal cysts. The liver was the main organ involved in ten patients (76,9%) - they had cysts located in the liver, two patients (15,4%) had lung cyst, one patient had concomitant lung and liver cysts. Twelve patients had single cysts and one had more than one abdominal cysts. Surgical treatment was performed in 23,1% cases. Ultrasound studies (US) were performed during the monitoring period. Evaluation of cysts was assessed by monitoring US changes. Positive dynamics was revealed in all patients; relapse of the disease was not noticed. Proceeding from the fact that in all patients echoarchitectonics of the hepatic tissue was lumped with a non-uniform structure and uneven ultrasound distribution, it is assumed that these changes are indicative of the development of connective tissue in the liver. PMID- 28574388 TI - SPECIFICATIONS OF INTRACRANIAL SACCULAR ANEURYSMS, TREATED BY ENDOVASCULAR APPROACH USING DETACHABLE COILS. AB - The treatment of intracranial saccular aneurysms remains an actual problem due to this pathology prevalence among the human population (about 1-10%). For definition of efficiency and preventive importance of endovascular treatment, it is necessary to clear define which aneurysms are more suitable and operable for endovascular occlusion with minimal risk of complications and better final outcome. The aim of this study is to analyze anatomical features (location and structure) of intracranial saccular aneurysms and clinical data of patients who have been operated endovascular, with detachable coils in High Technology Medical Center University Clinic,Tbilisi, Georgia for the last 6 years. The study included 412 patients with 470 aneurysms who were operated from 2011 to 2016 using detachable coils. The age of patients ranged from 8 to 78 years. The largest number of patients belonged to the age group - 32-55 years. The men were 196 (47.6%), women - 216 (52.4%). In acute period 280 (68%) patients were operated, in the delayded period - 90 (21.8%), unruptured aneurysms - 42 (10.2%). Early results and outcomes (1-3 week) after endovascular treatment of SA were estimated with GOS. Full Recovery or Low disability was achieved in 313(76%) patient- GOS 5, Moderate disability in 48(11.7) patient- GOS 4 , Severe disability or Persistent vegetative state in 44(10.6%) patient- GOS 3-2 and GOS 1 death in 7(1.7%) patient. According to the study it can be concluded that endovascular treatment is a reliable, low-impact and effective way to treat the Saccular brain aneurysm. Despite the variety of aneurysm these treatments are optimistic and affirm the importance of endovascular treatment of cerebral aneurysms. PMID- 28574389 TI - [RADICAL RECONSTRUCTIVE TORACOPLASTY - A NEW METHOD OF TREATMENT OF PATIENTS WITH CHOANOID DEFORMATION OF BREAST]. AB - Objective - development of a new method of surgery correction of choanoid deformation of breast, leading to significant improvement of the treatment results of the patients with this pathotology. The new method is being developed based on the analysis of the own long experience of treatment of the patients with choanoid deformation of breast. In total, over than 70 patients have been surged, with the age ranging from 5 to 35. The surgeries have been implemented in Leningrad Pediatric Medical Institute clinic as well as clinics in Georgia. In the course of formation of conception of the new surgery, all methods of surgery treatment of the patients having the indicated disease, applied up to now, have been critically analyzed. As a result, a new method of the surgery correction of the choanoid deformation of breast has been developed and tested which enables restoration of the natural architectonics of the deformed part of the patient's thoracic wall. Meanwhile, the strut consisting of the sterno-costal-cartilage fragments according to "stone arch" type stably and strongly fixes breast bone in the correct position, not requiring application of any artificial constructions for fixation of the breast bones. The basic and general principles of treatment of the patients with the bones trauma (repositions and immobilization of the bone fragments) have been observed within the developed method, possibility of occurrence of diastalsis or tangling the bones-cartilage fragments is excluded thus guaranteeing their fastest consolidation. Our results confirmed the correctness of new conceptual approach and technical realization of the developed method. Only 5% of the patients during the surgery have been observed to have insignificant damages of the parietal and visceral pleura. All patients have been released frpm the hospital on 3-5 day after the surgery. We have observed the patients during from 1 to 13 years after the surgery. No late post-surgery complications observed. The patients have been rehabilitated in psychological and emotional point of view, the quality of life has been significantly improved, and the ability to work has been completely recovered. Therefore, the method of surgery correction of the coanoid deformation of the breast, provided that the surgery technique is completely learnt and the surgeon is of proper qualification, enables reaching the guaranteed positive result of treatment even in those patients suffering from heavier form of the diseases as well as excluded the possibility of recidivism. PMID- 28574390 TI - CLINICAL PROTOCOLS: PREPARATION, IMPRESSION AND BONDING OF ALL-CERAMIC GLASS BASED DISILICATE LITHIUM CROWNS: REVIEW AND CASE REPORT. AB - Using contemporary materials and techniques, nowadays we can offer the patients much needed restorations while achieving the desired aesthetics. The maxillary incisors are supremely important in the appearance of a smile. By establishing proper size, contours, vitality, translucency and relationship with the surrounding teeth and soft tissue, we can help create the smile of their dream. In modern dentistry, there are two major recent developments - the dentine bonding and stronger all-ceramic crown systems. Use of glass-based disilicate lithium ceramic crowns in combination with resin cements provides more desirable aesthetic solution than traditional porcelain-fused-to-metal (PFM) crowns. However, use of these materials is extremely technique sensitive. They require additional marginal precision of tooth preparation and bonding with resin cement. Consequently, protocols of tooth preparation and bonding are essential for long term success. The presented article describes the preparation, impression and bonding guidelines aided by case presentation. According to the discussed protocols, dentists who take advantage of benefits of these contemporary materials and technologies will achieve more durable and reliable bonding with improved aesthetics. PMID- 28574391 TI - NON-STEROIDAL ANTI-INFLAMMATORY DRUGS'S ANTINOCICEPTION MEDIATED BY THE OPIOID MECHANISM IN THE NUCLEUS RAPHE MAGNUS. AB - It has been established that the midbrain periaqueductal gray matter (PAG) and rostral ventro-medial medulla (RVM) are involved in the descending pain control system. The latter involves the midline nucleus raphe magnus (NRM) and adjacent reticular formation. These brain structures are is one of important parts of CNS circuit that controls nociceptive transmission at the level of spinal cord. Here we report that microinjection of commonly used non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac, ketorolac, metamizol, and xefocam into the NRM produces strong antinociception which is mediated by the opioid mechanism. The experiments were carried out on experimental and control (saline) white albino male rats. Animals were implanted with a guide cannula in the NRM and tested for antinociception following microinjection of NSAIDs into the NRM in the tail flick (TF) and hot plate (HP) tests. The analysis of variance (ANOVA) with post-hoc Tukey-Kramer multiple comparison tests were used for statistical evaluation. The obtained data show that microinjection of these NSAIDs into the NRM produced antinociception as revealed by a latency increase in the tail-flick (TF) and hot plate (HP) latencies compared to the saline control microinjected into the same nucleus. Furthermore, we definitely showed that pre-treatment with opioid antagonist naloxone in the NRM diminishes NSAID-induced antinociception expressing in significant decrease in TF and HP latencies (P<0.001). The present findings support the concept that antinociceptive effects of NSAIDs are mediated via an endogenous opioid system possibly involving the descending pain modulatory circuit. PMID- 28574392 TI - [STUDY OF HEPATOPROTECTIVE PROPERTIES OF RNA-CONTAINING DRUG "RN-13" ON THE MODEL OF ACUTE TETRAHLLORMETHANE INDUCED HEPATITIS IN RATS]. AB - The aim of the study was to assess the hepatoprotective properties of the RNA containing drug RN-13 on the model of acute CLL4 induced hepatitis in rats. To evaluate hepatoprotective properties of the RNA-containing drug RN-13 42 female rats were used. RN-13 increases the survival rate of animals with acute tetrachloromethane hepatitis. The hepatoprotective properties of RN-13 were confirmed by biochemical and morphological data. RN-13 helps to reduce the activity of alanine aminotransferase, which indicates its ability to limit cytolysis syndrome. Morphological studies confirm the ability of RN-13 to prevent destruction of liver tissue, preserve the radial structure of the hepatic lobes, and limit the development of hydropic and fatty degeneration. PMID- 28574393 TI - [RATIONAL USE APRICOT GUM (GUMMI ARMENIACAE) IN REPUBLIC OF ARMENIA]. AB - Till nowadays the sources of gums of Armenian flora are remaining unutilized because of absence of resoursological and phytochemical research as well as standards corresponding. Amongst the camed-bearing trees of the flora of Armenia (apricot, peach, plum, almond) and the other families representatives (eleagnus, tragakant) the apricot trees (Armeniaca vulgaris Lam.) became an object of our great interests, considering its being as the most important cultivating fruit bearing trees in Armenia and the fact, that they cover significant areas in the Ararat valley, Kotayk, Aragatsotn and the footings of the Vayk region. The goal of our investigation was the pharmacognostic (resoursological, commodity and analytical, phythochemical) complex evaluation encountering and the apricot tree camed's (gummi armeniacae) biological activity evaluation, as well as the natural resourses rational concepts elaboration. On the base of the investigation results got a concept of rational use of the apricot gums was developed, which assumes the local sources enlargement, as well as its wide application in medicine and in different aspects of industry. PMID- 28574394 TI - IMPACT OF SULPHUR DIOXIDE ON THE RESPIRATORY SYSTEM OF TBILISI POPULATION. AB - The possible relationship between levels of sulphur dioxide (SO2) in the air and the rate of respiratory diseases has been studied. Results of monitoring of main contaminants of outdoor air were analyzed and they are reflected in Environmental Report 2015. Information on morbidity by respiratory system diseases of Tbilisi population is has been taken from 2011-2015 reports of the National Center of Disease Control. Identified that there is no consistent correlation between sulphur dioxide concentration in the air and respiratory system disease rates in the population, including children. Obtained data demonstrated that during the study period maximum SO2 concentration was registered in 2015 - 0,14 mg/m3 (exceeding almost 3 times maximum permissible concentration - 0,5 mg/m3) and in the same year high morbidity rates are registered (incidence -18106,08), though the lowest rates are registered in 2011 (0,09 mg/m3), when incidence of respiratory system diseases in this period (13103.2) exceeds the rates registered in 2012, 2013 and 2014 (12736.4, 11336.3, 13009.0 accordingly). There is no direct correlation between the morbidity rates of 0-15 year old children and SO2 concentration. Maximum incidence rate is registered in 2015 (48487.0) and in the same year is also registered maximum concentration of SO2 (0,14 mg/m3), whereas the lowest rate is registered in 2013 (35538,70), when SO2 concentration in 2013 is lower only by 0.02 mg/m3 compared to the concentration in 2015. Direct correlation between morbidity with asthma in children and concentration of SO2 was not identified. Prevalence of asthma is minimal in 2014 (65,4), maximal in 2012 (207,1), whereas SO2 concentration in 2014 (0,13 mg/m3) exceeds the concentration in 2012 (0,12 mg/m3). It has to be considered, that besides SO2 there are many small intensity adverse factors, which are also risk factors for development of respiratory diseases. Isolated action of these factors with certain concentrations may not demonstrate any adverse effects on human health, but the combined effect of their action is stronger and obviously will affect general health and specifically - respiratory system. Implementation of urgent measures for further improvement of their ambient air quality has been recommended, which will be the basis for minimizing of many chronic diseases. PMID- 28574395 TI - [EVALUATION OF GENOMIC PARAMETERS IN DUCTAL BREAST CANCER PATIENTS AND THE ABILITY OF IT'S CORRECTION]. AB - The level of DNA single strand breaks, chromosomal abnormalities and sister chromatid exchanges and the possibility of its normalization with oligopeptide bioregulator Livagen and cobalt ions in the lymphocyte culture from patients with breast cancer have been studied. The results show that the genome of ductal breast cancer patients is characterized by the high density of DNA single strand breaks, high frequency of chromosomal abnormalities and increased levels of chromatin condensation. The usage of Livagen and cobalt in the form of modifying agents has a protective effect by all studied parameters. The obtained results allow us to conclude that research of lymphocytes of ductal breast cancer patients using the analysis conducted by us, can be useful in assessing the therapeutic effect in the treatment of breast cancer patients. PMID- 28574396 TI - COMPLEX HEAVY METAL SALTS' EFFECT ON GANGLION NUCLEI NEURONS MORPHOLOGICAL FUNCTIONS IN ADULT MALE RATS' CEREBELLAR CORTEX. AB - In order to analyze the dynamics of morphological and morphometric nuclear rearrangements of cortical cerebellar Purkinje cells under prolonged exposure (for 90 days) on the body of copper sulfate, zinc and iron experiment was conducted on 48 white adult male rats weighing 200-250g, aged 5 -8 months. We used anatomic, morphometric, statistical and common methods of micro anatomical research method. It was found that the combined effect of copper sulfate, zinc and iron on the body has nuclear device ganglion neurons in the cerebellar cortex sufficiently expressive toxicity, which affects the state of neurons. The degree of morphological rearrangements in the nuclear unit is in direct proportion to the duration of the experiment. In the nuclei of ganglion neurons develop nonspecific changes of polymorphic nature, which is reversible in the early stages of experience and irreversible, mainly necrobiotic character (chromatolysis, pycnosis and reksis) in most of the neurons within a timeline. PMID- 28574397 TI - HISTORY OF PSYCHIATRY IN GEORGIA: HIDDEN PAGES (DEDICATED TO OUR TEACHERS). AB - Psychiatry preserves a special place among the diverse medical specialties. It is noteworthy that in Europe and America the professional and scientific psychiatry gradually emerged during the second half in 1800s. Roots of psychiatry in Georgia go back to the distant past. However, the modern scientific psychiatry started developing in Georgia shortly after the foundation of the medical faculty at Tbilisi State University (1921) and is closely are associated with the name of Prof. M.Asatiani (1882-1938). This survey reflects data from all obtainable and basic psychiatric records of this period and provides brief description of significant achievements of psychiatrists, working in Georgia during 1920-1940 (M. Asatiani, A. Gotsiridze, N. Veshapeli, O. Chitava, Sh. Kipiani, G. Shengelaia, I. Menteshahvili, A. Zurabashvili, I. Bzhalava, E. Nakashidze, E. Gobronidze, V. Gudiashvili, Sh. Kvitsaridze, A. Amirgarov, N. Shubladze, I. Tavdishvili, Hovakim, Nikolava, Sulava, Shiukashvili, I. Egizarov). Finally, we would like to emphasize that Georgian psychiatrists widely presented quantitative and qualitative studies on methodology and on treatment of main mental disorders, described their views on psychology, characterology, pathophysiology, physiology, morphology, psychotherapy, classification and etc. PMID- 28574398 TI - Controllable and scalable synthesis of ordered mesoporous silica nanosheets by using acidified g-C3N4 as a lamellar surfactant. AB - Two-dimensional (2D) mesoporous nanomaterials are required in catalysis, separation, adsorption, and energy storage fields due to their outstanding mass transfer performance. However, their fabrication via the 'bottom up' strategy has been rarely reported and is limited by the difficulties in obtaining a versatile and accessible structure-directing agent. Here, ultrathin mesoporous silica nanosheets (MSN) were successfully synthesized by employing acidified g-C3N4 as a structural directing agent owing to its natural layered structure, stoichiometric solubility, and amphiphilicity. The thickness of MSN is readily adjustable by tuning the dosage of acidified g-C3N4 during the fabrication process, and when the mass ratio of silica/acidified-g-CzN4 is 10, the thickness of the MSN is 6-9 nm. TEM, SAXRD, and BET analysis demonstrated the mesoporous characteristics of MSN with a long-range ordered hexagonal arrangement symmetry, a uniform pore size distribution around 2.9 nm, and high BET surface areas of 1000-1150 m2 g-1. The superior mass-transfer performance of MSN in catalysis applications, which was derived from its special structure, was confirmed by the outstanding methane combustion activity of MSN supported Co3O4 catalysts. This work provides a controllable and scalable 'bottom up' fabrication method for 2D porous material, and also opens up an alternative application for g-C3N4. PMID- 28574399 TI - Strongly coupled CeO2/Co3O4/poly(3,4-ethylenedioxythiophene) nanofibers with enhanced nanozyme activity for highly sensitive colorimetric detection. AB - In this work, we have prepared CeO2/Co3O4 composite nanofibers via an electrospinning technique followed by a calcination process. Then core-shell structured CeO2/Co3O4/poly(3,4-ethylenedioxythiophene) (PEDOT) composite nanofibers were fabricated through a redox reaction between the 3,4 ethylenedioxythiophene (EDOT) monomer and Co3O4 on the surface of CeO2/Co3O4 composite nanofibers. The morphology and composition of the two composite nanofibers were confirmed by field-emission scanning electron microscopy, transmission electron microscopy, x-ray diffraction, Fourier transform infrared spectroscopy, and x-ray photoelectron spectra measurements. Due to the synergistic effect between CeO2 and Co3O4, the catalytic activity was enhanced compared to that of independent oxide nanofibers. After the growth of PEDOT, the catalytic activity process was further improved, having achieved a secondary synergistic effect. Application of the two prepared composite nanofibers as peroxidase-like catalysts for the colorimetric detection of H2O2 was investigated. It is anticipated that this work can inspire researchers to develop various novel functional nanocomposites for applications in biosensing and environmental monitoring. PMID- 28574400 TI - Honeycomb-like NiCo2S4 nanosheets prepared by rapid electrodeposition as a counter electrode for dye-sensitized solar cells. AB - Honeycomb-like nickel cobalt sulfide (NiCo2S4) nanosheets were directly deposited on fluorine-doped tin oxide substrate by a rapid voltammetric deposition method. The method was also controllable and feasible for preparing NiCo2S4 on flexible Ti foil without any heating processes. Compared with Pt, CoS and NiS, NiCo2S4 exhibited low charge-transfer resistances and excellent electrocatalytic activity for [Formula: see text] reduction, acting as a counter electrode for a dye sensitized solar cell. The NiCo2S4-based solar cell showed higher power conversion efficiency (7.44%) than that of Pt-based solar cell (7.09%) under simulated illumination (AM 1.5 G, 100 mW cm-2). The device based on the flexible NiCo2S4/Ti foil achieved a power conversion efficiency of 5.28% under the above illumination conditions. This work can be extended to flexible and wearable technologies due to its facile technique. PMID- 28574401 TI - Modeling elastic anisotropy in strained heteroepitaxy. AB - Using a continuum evolution equation, we model the growth and evolution of quantum dots in the heteroepitaxial Ge on Si(0 0 1) system in a molecular beam epitaxy unit. We formulate our model in terms of evolution due to deposition, and due to surface diffusion which is governed by a free energy. This free energy has contributions from surface energy, curvature, wetting effects and elastic energy due to lattice mismatch between the film and the substrate. In addition to anisotropy due to surface energy which favors facet formation, we also incorporate elastic anisotropy due to an underlying crystal lattice. The complicated elastic problem of the film-substrate system subjected to boundary conditions at the free surface, interface and the bulk substrate is solved by perturbation analysis using a small slope approximation. This permits an analysis of effects at different orders in the slope and sheds new light on the observed behavior. Linear stability analysis shows the early evolution of the instability towards dot formation. The elastic anisotropy causes a change in the alignment of dots in the linear regime, whereas the surface energy anisotropy changes the dot shapes at the nonlinear regime. Numerical simulation of the full nonlinear equations shows the evolution of the surface morphology. In particular, we show, for parameters of the [Formula: see text] [Formula: see text] on Si(0 0 1), the surface energy anisotropy dominates the shapes of the quantum dots, whereas their alignment is influenced by the elastic energy anisotropy. The anisotropy in elasticity causes a further elongation of the islands whose coarsening is interrupted due to [Formula: see text] facets on the surface. PMID- 28574402 TI - Thermal sublimation: a scalable and controllable thinning method for the fabrication of few-layer black phosphorus. AB - We report uniform layer-by-layer sublimation of black phosphorus under heating below 600 K. The uniformity and crystallinity of BP samples after thermal thinning were confirmed by Raman spectra and Raman mapping. The sublimation rate of BP was around 0.18 nm min-1 at 500 K and 1.15 nm min-1 at 550 K. Both room and high temperature Raman peak intensity ratio [Formula: see text] as functions of BP thickness were established for in situ thickness determination and control. Uniform and crystalline 2 to 4-layer BP flakes with areas from 10 to 1000 MUm2 were prepared with this method. No micron scale defects were observed. The sublimation thinning method was shown to be a controllable and scalable approach to prepare high-quality few-layer black phosphorus. PMID- 28574403 TI - Fermi energy dependence of the optical emission in core/shell InAs nanowire homostructures. AB - InAs nanowires grown by vapor-liquid-solid (VLS) method are investigated by photoluminescence. We observe that the Fermi energy of all samples is reduced by ~20 meV when the size of the Au nanoparticle used for catalysis is increased from 5 to 20 nm. Additional capping with a thin InP shell enhances the optical emission and does not affect the Fermi energy. The unexpected behavior of the Fermi energy is attributed to the differences in the residual donor (likely carbon) incorporation in the axial (low) and lateral (high incorporation) growth in the VLS and vapor-solid (VS) methods, respectively. The different impurity incorporation rate in these two regions leads to a core/shell InAs homostructure. In this case, the minority carriers (holes) diffuse to the core due to the built in electric field created by the radial impurity distribution. As a result, the optical emission is dominated by the core region rather than by the more heavily doped InAs shell. Thus, the photoluminescence spectra and the Fermi energy become sensitive to the core diameter. These results are corroborated by a theoretical model using a self-consistent method to calculate the radial carrier distribution and Fermi energy for distinct diameters of Au nanoparticles. PMID- 28574404 TI - Ultrafast spin-polarized electron dynamics in the unoccupied topological surface state of Bi2Se3. AB - The three-dimensional topological insulator Bi2Se3 presents two cone-like dispersive topological surface states centered at the [Formula: see text] point. One of them is unoccupied in equilibrium conditions and located 1.8 eV above the other one lying close to the Fermi level. In this work we employ time- and angle resolved photoemission spectroscopy with circularly polarized pump photons to selectively track the spin dynamics of the empty topological states. We observe that spin-polarized electrons flow along the topological cone and recombine towards the unpolarized bulk states on a timescale of few tens of femtoseconds. This provides direct evidence of the capability to trigger a spin current with circularly polarized light. PMID- 28574405 TI - Multi-institutional MicroCT image comparison of image-guided small animal irradiators. AB - To recommend imaging protocols and establish tolerance levels for microCT image quality assurance (QA) performed on conformal image-guided small animal irradiators. A fully automated QA software SAPA (small animal phantom analyzer) for image analysis of the commercial Shelley micro-CT MCTP 610 phantom was developed, in which quantitative analyses of CT number linearity, signal-to-noise ratio (SNR), uniformity and noise, geometric accuracy, spatial resolution by means of modulation transfer function (MTF), and CT contrast were performed. Phantom microCT scans from eleven institutions acquired with four image-guided small animal irradiator units (including the commercial PXi X-RAD SmART and Xstrahl SARRP systems) with varying parameters used for routine small animal imaging were analyzed. Multi-institutional data sets were compared using SAPA, based on which tolerance levels for each QA test were established and imaging protocols for QA were recommended. By analyzing microCT data from 11 institutions, we established image QA tolerance levels for all image quality tests. CT number linearity set to R 2 > 0.990 was acceptable in microCT data acquired at all but three institutions. Acceptable SNR > 36 and noise levels <55 HU were obtained at five of the eleven institutions, where failing scans were acquired with current-exposure time of less than 120 mAs. Acceptable spatial resolution (>1.5 lp mm-1 for MTF = 0.2) was obtained at all but four institutions due to their large image voxel size used (>0.275 mm). Ten of the eleven institutions passed the set QA tolerance for geometric accuracy (<1.5%) and nine of the eleven institutions passed the QA tolerance for contrast (>2000 HU for 30 mgI ml-1). We recommend performing imaging QA with 70 kVp, 1.5 mA, 120 s imaging time, 0.20 mm voxel size, and a frame rate of 5 fps for the PXi X-RAD SmART. For the Xstrahl SARRP, we recommend using 60 kVp, 1.0 mA, 240 s imaging time, 0.20 mm voxel size, and 6 fps. These imaging protocols should result in high quality images that pass the set tolerance levels on all systems. Average SAPA computation time for complete QA analysis for a 0.20 mm voxel, 400 slice Shelley phantom microCT data set was less than 20 s. We present image quality assurance recommendations for image-guided small animal radiotherapy systems that can aid researchers in maintaining high image quality, allowing for spatially precise conformal dose delivery to small animals. PMID- 28574406 TI - Muscle abnormalities in osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is mainly characterized by bone fragility but muscle abnormalities have been reported both in OI mouse models and in children with OI. Muscle mass is decreased in OI, even when short stature is taken into account. Dynamic muscle tests aiming at maximal eccentric force production reveal functional deficits that can not be explained by low muscle mass alone. However, it appears that diaphyseal bone mass is normally adapted to muscle force. At present the determinants of muscle mass and function in OI have not been clearly defined. Physiotherapy interventions and bisphosphonate treatment appear to have some effect on muscle function in OI. Interventions targeting muscle mass have shown encouraging results in OI animal models and are an interesting area for further research. PMID- 28574407 TI - Muscular response to the first three months of deflazacort treatment in boys with Duchenne muscular dystrophy. AB - OBJECTIVE: Duchenne muscular dystrophy (DMD) patients are often treated with glucocorticoids; yet their precise molecular action remains unknown. METHODS: We investigated muscle biopsies from nine boys with DMD (aged: 7,6+/-2,8 yrs.) collected before and after three months of deflazacort treatment and compared them to eight healthy boys (aged: 5,3+/-2,4 yrs.). mRNA transcripts involved in activation of satellite cells, myogenesis, regeneration, adipogenesis, muscle growth and tissue inflammation were assessed. Serum creatine kinase (CK) levels and muscle protein expression by immunohistochemistry of selected targets were also analysed. RESULTS: Transcript levels for ADIPOQ, CD68, CDH15, FGF2, IGF1R, MYF5, MYF6, MYH8, MYOD, PAX7, and TNFalpha were significantly different in untreated patients vs. normal muscle (p?0.05). Linear tests for trend indicated that the expression levels of treated patients were approaching normal values (p?0.05) following treatment (towards an increase; CDH15, C-MET, DLK1, FGF2, IGF1R, MYF5, MYF6, MYOD, PAX7; towards a decrease: CD68, MYH8, TNFalpha). Treatment reduced CK levels (p?0.05), but we observed no effect on muscle protein expression. CONCLUSIONS: This study provides insight into the molecular actions of glucocorticoids in DMD at the mRNA level, and we show that multiple regulatory pathways are influenced. This information can be important in the development of new treatments. PMID- 28574408 TI - Effect of whole body vibration training on quadriceps strength, bone mineral density, and functional capacity in children with hemophilia: a randomized clinical trial. AB - OBJECTIVES: The objective was to evaluate the effects of whole body vibration training on quadriceps strength, bone mineral density, and functional capacity in children with hemophilia. METHODS: Thirty children with hemophilia with age ranging from 9 to 13 years were selected and randomly assigned to either the study group that received whole body vibration training (30-40 Hz, 2-4 mm of peak to-peak vertical plate displacement for 15 minutes/day, 3 days/week/ 12 weeks) plus the conventional physical therapy program or the control group that performed a conventional physical therapy program only. Outcomes included quadriceps strength, bone mineral density, and the functional capacity. RESULTS: Children in the study group showed a significant improvement in all outcomes compared with the control group. The quadriceps peak torque after treatment was 70.26 and 56.46 Nm for the study and control group, respectively (p?0.001). The lumbar spine bone mineral density after treatment was 0.85 and 0.72 g/cm2 for the study and control group, respectively (p?0.001). The functional capacity after treatment was 325 and 290 m for the study and control group, respectively (p=0.006). CONCLUSIONS: Whole body vibration training is an effective modality in increasing quadriceps strength, bone mineral density, and functional capacity in children with hemophilia. PMID- 28574409 TI - Muscle power in children, youth and young adults who acquired HIV perinatally. AB - OBJECTIVES: To compare muscle power between youth who acquired HIV perinatally and HIV unexposed uninfected (HUU) youth. METHODS: We assessed muscle power (relative to body mass, Pmax/mass), muscle force normalized to body weight (Fmax/BW), force efficiency, jump height (Hmax) and velocity (Vmax) during a single two-legged jump with hands on waist on a force platform (Leonardo) in HIV+ youth (n=35, 9-21 y). Thirty-three and 22 participants returned at 12- and 24 months, respectively. We compared age- and sex-specific z-scores in the HIV+ youth to those in HUU controls (n=716, 9-21 y) adjusting for height and muscle cross-sectional area (MCSA, by pQCT). RESULTS: At baseline, z-scores for Pmax/mass, Fmax/BW and Vmax were less than 1 standard deviation lower than HUU after adjusting for height and MCSA (p?0.05). Pmax/mass z-score was negatively associated with level of immunosuppression (p=0.013), but this relationship was not significant after adjusting for height and MCSA (p=0.07). Z-scores for all mechanography outcomes remained stable over time in HIV+ youth. CONCLUSION: Small deficits in muscle power were apparent in children and youth who acquired HIV perinatally, and the trajectory of muscle power did not change over two years. Further study is needed to identify effective strategies to improve dynamic muscle function in this population. PMID- 28574410 TI - Changes in muscle cross-sectional area, muscle force, and jump performance during 6 weeks of progressive whole-body vibration combined with progressive, high intensity resistance training. AB - OBJECTIVES: We hypothesized that progressive whole-body vibration (WBV) superimposed to progressive high intensity resistance training has greater effects on muscle cross-sectional area (CSA), muscle force of leg muscles, and jump performance than progressive high intensity resistance training alone. METHODS: Two groups of healthy male subjects performed either 6 weeks of Resistive Vibration Exercise (RVE, squats and heel raises with WBV, n=13) or Resistive Exercise (RE, squats and heel raises without WBV, n=13). Squats under RVE required indispensable weight loading on the forefoot to damp harmful vibrations to the head. Time, intervention, and interaction effects were analyzed. RESULTS: After 6 weeks of training, knee extensor CSA, isometric knee extension force, and counter movement jump height increased equally in both groups (time effect, P?0.001, P<=0.02, and P<=0.03, respectively), whereas only in RVE ankle plantar flexor CSA and isometric ankle plantar flexion force reached significance or a tendency, respectively, (time effect, P=0.015 and P=0.069, respectively; intervention effect also for the latter, P=0.006). Drop jump contact time did significantly more improve in RVE (interaction effect, P=0.042). CONCLUSIONS: RVE showed better training effects than RE only in plantar flexor muscles. RVE seems to be suitable in professional sports with a special focus on calf muscles. PMID- 28574411 TI - Relationship between muscle performance and DXA-derived bone parameters in community-dwelling older adults. AB - OBJECTIVES: To examine association between muscle strength, jump test performance, muscle mass, bone mineral density (BMD), and bone strength in older adults. METHODS: Sixty individuals (55-75 years) participated. Leg press strength and bilateral hip abduction strength were evaluated by one repetition-maximum testing. Jump power (JPow) and jump height (JHt) were assessed by jump test performance. Relative skeletal muscle mass index (RSMI), total hip BMD, femoral neck BMD, lumbar spine BMD, section modulus (Z), cross-sectional moment of inertia (CSMI), and bone strength index (BSI) were determined by DXA. RESULTS: After adjusting for age and gender, leg press strength 1) positively correlated with the total hip BMD, femoral neck BMD, and Z (all P?0.05). Also, leg press strength predicted the total hip BMD (P=0.013) and femoral neck BMD (P=0.021), after adjusting for age, gender, and RSMI. No associations were found between jump test performance and bone density or strength. CONCLUSION: Leg press strength is positively associated with bone density and bone strength in older population. It might serve as an additional tool to identify at-risk individuals for osteoporosis. PMID- 28574412 TI - Precision of pQCT-measured total, trabecular and cortical bone area, content, density and estimated bone strength in children. AB - OBJECTIVES: To define pQCT precision errors, least-significant-changes, and identify associated factors for bone outcomes at the radius and tibia in children. METHODS: We obtained duplicate radius and tibia pQCT scans from 35 children (8-14yrs). We report root-mean-squared coefficient of variation (CV%RMS) and 95% limits-of-agreement to characterize repeatability across scan quality and least-significant-changes for bone outcomes at distal (total and trabecular area, content and density; and compressive bone strength) and shaft sites (total area and content; cortical area content, density and thickness; and torsional bone strength). We used Spearman's rho to identify associations between CV% and time between measurements, child's age or anthropometrics. RESULTS: After excluding unanalyzable scans (6-10% of scans per bone site), CV%RMS ranged from 4% (total density) to 19% (trabecular content) at the distal radius, 4% (cortical content) to 8% (cortical thickness) at the radius shaft, 2% (total density) to 14% (trabecular content) at the distal tibia and from 2% (cortical content) to 6% (bone strength) at the tibia shaft. Precision errors were within 95% limits-of agreement across scan quality. Age was associated (rho -0.4 to -0.5, p?0.05) with CV% at the tibia. CONCLUSION: Bone density outcomes and cortical bone properties appeared most precise (CV%RMS?5%) in children. PMID- 28574415 TI - A novel interpolation approach for the generation of 3D-geometric digital bone models from image stacks. AB - The authors propose a new 3D interpolation algorithm for the generation of digital geometric 3D-models of bones from existing image stacks obtained by peripheral Quantitative Computed Tomography (pQCT) or Magnetic Resonance Imaging (MRI). The technique is based on the interpolation of radial gray value profiles of the pQCT cross sections. The method has been validated by using an ex-vivo human tibia and by comparing interpolated pQCT images with images from scans taken at the same position. A diversity index of ?0.4 (1 meaning maximal diversity) even for the structurally complex region of the epiphysis, along with the good agreement of mineral-density-weighted cross-sectional moment of inertia (CSMI), demonstrate the high quality of our interpolation approach. Thus the authors demonstrate that this interpolation scheme can substantially improve the generation of 3D models from sparse scan sets, not only with respect to the outer shape but also with respect to the internal gray-value derived material property distribution. PMID- 28574413 TI - Effect of acetylcholinesterase inhibitors on post-surgical complications and mortality following a hip fracture: a cohort study. AB - There is increasing evidence suggesting that the use of acetylcholinesterase inhibitors may have beneficial effects on bone. Data on the potential post surgical effects of these medications on orthopedic interventions are very limited. This study was designed to determine whether the use of acetylcholinesterase inhibitors is associated with a decrease in post-surgical mortality and complications in hip fracture patients with Alzheimer's disease. To accomplish this objective, a retrospective cohort study was performed using data from the Clinical Practice Research Database, UK. The study included 532 Alzheimer's disease patients of age 65 years and older, who sustained a hip fracture between 1998 and 2012. During the follow-up period, 34% of the patients died (n=182), 22% sustained a second hip fracture (n=118) and 5% (n=29) required reintervention. The users of acetylcholinesterase inhibitors had a 56% reduction in all-cause mortality (HR= 0.44, 95% CI 0.30-0.63) and a 41% reduction in second hip fracture incidence during a year of post-surgical follow-up (HR= 0.59, 95% CI 0.38-0.94) after adjusting for potential confounders. Our results show that acetylcholinesterase inhibitors may have the potential to reduce all-cause mortality and the risk of suffering a second hip fracture during the first year after surgery. PMID- 28574414 TI - Impaired fracture healing with high non-union rates remains irreversible after traumatic brain injury in leptin-deficient mice. AB - Patients with traumatic brain injury (TBI) and long-bone fractures can show increased callus formation. This effect has already been reproduced in wild-type (wt) mice. However, the mechanisms remain poorly understood. Leptin is significantly increased following TBI, while its role in bone healing remains unclear. The aim of this study was to evaluate fracture healing in leptin deficient ob/ob mice and to measure any possible impact of TBI on callus formation. 138 female, 12 weeks old, ob/ob mice were divided into four groups: Control, fracture, TBI and combined trauma. Osteotomies were stabilized with an external fixator; TBI was induced with Controlled Cortical Impact Injury. Callus bridging was weekly evaluated with in vivo micro-CT. Biomechanical testing was performed ex vivo. Micro-CT showed high non-union rates after three and four weeks in the fracture and combined trauma group. No differences were observed in callus volume, density and biomechanical properties at any time point. This study shows that bony bridging is impaired in the present leptin-deficient trauma model. Furthermore, the phenomenon of increased callus formation after TBI could not be reproduced in ob/ob mice, as in wt mice. Our findings suggest that the increased callus formation after TBI may be dependent on leptin signaling. PMID- 28574416 TI - Richly innervated soft tissues covering the superficial aspect of the extensor origin in patients with chronic painful tennis elbow - Implication for treatment? AB - BACKGROUND: Tennis elbow is difficult to treat. The results of surgical treatments are not convincing. Treatment studies on Achilles and patellar tendinopathy targeting the richly innervated and vascularized soft tissues outside the tendon have shown promising outcomes. The innervation patterns in the fibrous/fatty tissues superficially to the elbow extensor origin have not been clarified. METHODS: Nine tissue specimens from the fibrous/fatty tissue covering the extensor origin was taken from seven patients (mean age: 45 years) undergoing surgical treatment for chronic painful tennis elbow. The specimens were stained for morphology (haematoxylin and eosin, H and E) and immunohistochemically for general nerve marker protein gene product 9.5 (PGP 9.5) and markers for sympathetic (tyrosine hydroxylase, TH) and sensory nerve fibres (calcitonin gene related peptide, CGRP). RESULTS: All specimens contained multiple blood vessels and nerve structures indicated by morphology and immunoreactions. There was a frequent occurrence of TH reactions, especially peri-vascularly, but also in nerve fascicles. Immunoreactions for CGRP were seen in nerve fascicles and isolated nerve fibres. CONCLUSION: The results provide new information on the innervation patterns of the superficial tissues of the extensor origin and their potential as source of tennis elbow pain. LEVEL OF EVIDENCE: IV. PMID- 28574417 TI - Study on the expression of nerve growth associated protein-43 in rat model of intervertebral disc degeneration. AB - OBJECTIVE: In the present work we studied the expression of nerve growth associated protein (GAP-43) in a rat model of intervertebral disc degeneration. METHODS: 16 healthy adult SD rats, male or female, with an average weight 220g were selected. FluoroGold was injected in L5-L6 disc as the tracer. After 7 days, Freund's adjuvant was then injected to build model of intervertebral disc degeneration. After 1, 3, 7 and 14 days of modeling immune-histochemical method was used to detect the T13-L6 dorsal root ganglion and positive expression of GAP 43, TNF-alpha and IL-1 in L5-L6 intervertebral disc; RT-PCR method was used to detect GAP-43 mRNA and Western blot method was utilized to detect the expression levels of protein. RESULTS: In the observation group, the dorsal root ganglion, positive expression rates of GAP-43, TNF-alpha and IL-1, expression levels of GAP 43 mRNA and protein in the intervertebral disc at each time point were significantly higher than those in the control group, and the differences were statistically significant (P?0.05); the positive expression rates of GAP-43, TNF alpha and IL-1, expression levels of GAP-43 mRNA and protein of the observation group reached the peak at 3d, and dropped at 7d; dorsal root ganglion reached the peak at 7d and dropped at 14d. CONCLUSION: Degenerative changes might be mediated by the abnormal high expression of GAP-43 and intervertebral disc inflammation jointly. PMID- 28574418 TI - Clinical study on the arthroscopic refreshing treatment of anterior cruciate ligament injury combined with stable medial meniscus ramp injury. AB - This study sought to investigate the clinical efficacy of arthroscopic refreshing treatment of anterior cruciate ligament (ACL) injury combined with stable medial meniscus ramp injury. Sixty-eight patients treated between January 2010 and January 2014 were included, and their clinical data were retrospectively analyzed. All patients, after being treated using ACL reconstruction, were divided into 2 groups according to meniscus injury treatment method. The observation group (31 cases) was treated by arthroscopic refreshing, which removed the tissue on both sides of the tear edge using a cutting knife, while the control group (37 cases) was treated using Fast-fix sutures. All patients were followed up for at least 24 months. Surgical duration, postoperative function recovery time, and hospital stay for patients in the observation group were significantly shorter than for those of the control group (P?0.05). Both groups showed significant post-operative improvement for Lysholm scores, IKDC scores, and average knee range of motion at 12 and 24 months post-operation (P?0.05), but no significant differences between groups were observed (P?0.05). Regarding the difference in movement range between the healthy and injured sides, both groups showed significant decrease post-operation (P?0.05). Ultimately, there was no significant difference in the recovery of ramp damage and objective symptoms between the two groups (P?0.05). Arthroscopic refreshing treatment of patients with anterior cruciate ligament injury combined with stable ramp lesion can achieve similar clinical curative effects as the Fast-fix suture, thereby providing a simple alternative for patient treatment worth popularizing. PMID- 28574419 TI - EFFECT OF INTRAVITREAL RANIBIZUMAB ON GANGLION CELL COMPLEX AND PERIPAPILLARY RETINAL NERVE FIBER LAYER IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION USING SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To analyze the changes in ganglion cell complex and peripapillary retinal nerve fiber layer thickness, in central macular thickness and choroidal thickness on spectral domain optical coherence tomography in patients with neovascular age-related macular degeneration treated with intravitreal ranibizumab injections. METHODS: All consecutive patients with untreated neovascular age-related macular degeneration received loading phase of three monthly intravitreal ranibizumab, followed by retreatments on a pro re nata protocol for 12 months. PRIMARY OUTCOME: changes in ganglion cell complex and retinal nerve fiber layer at the end of follow-up. Secondary outcome: changes in best-corrected visual acuity, central macular thickness, and choroidal thickness at the end of follow-up. Choroidal thickness was measured at 500 MUm, 1000 MUm, and 1,500 MUm intervals nasally, temporally, superiorly, and inferiorly to the fovea, respectively, on horizontal and vertical line scans centered on the fovea. RESULTS: Twenty-four eyes were included. Ganglion cell complex and peripapillary retinal nerve fiber layer thickness did not show statistically significant changes through 12 months (55.6 +/- 18.5 and 81.9 +/- 9.9 MUm at baseline, 52.7 +/- 19.3 and 84.6 +/- 15.5 MUm at month 12, P > 0.05). Central macular thickness showed progressive decrease from baseline to month 12, with maximum reduction at month 3 (P < 0.001). Statistically significant reduction in choroidal thickness was registered in the nasal 500, 1000, and 1,500 MUm from the fovea, corresponding to the papillomacular region (from 169.6 +/- 45.3 to 153.9 +/- 46.9, P < 0.001). CONCLUSION: Intravitreal ranibizumab injections did not affect retinal nerve fiber layer and ganglion cell complex thickness in 1-year follow up. Choroidal thickness in papillomacular area and central macular thickness was significantly reduced at the end of treatment. Further studies, with larger sample, longer follow-up, and greater number of injections, are warranted. PMID- 28574421 TI - Adaptable Optical Fiber Displacement-Curvature Sensor Based on a Modal Michelson Interferometer with a Tapered Single Mode Fiber. AB - A compact, highly sensitive optical fiber displacement and curvature radius sensor is presented. The device consists of an adiabatic bi-conical fused fiber taper spliced to a single-mode fiber (SMF) segment with a flat face end. The bi conical taper structure acts as a modal coupling device between core and cladding modes for the SMF segment. When the bi-conical taper is bent by an axial displacement, the symmetrical bi-conical shape of the tapered structure is stressed, causing a change in the refractive index profile which becomes asymmetric. As a result, the taper adiabaticity is lost, and interference between modes appears. As the bending increases, a small change in the fringe visibility and a wavelength shift on the periodical reflection spectrum of the in-fiber interferometer is produced. The displacement sensitivity and the spectral periodicity of the device can be adjusted by the proper selection of the SMF length. Sensitivities from around 1.93 to 3.4 nm/mm were obtained for SMF length between 7.5 and 12.5 cm. Both sensor interrogations, wavelength shift and visibility contrast, can be used to measure displacement and curvature radius magnitudes. PMID- 28574420 TI - Characterization and Temperature Dependence of Arctic Micromonas polaris Viruses. AB - Global climate change-induced warming of the Artic seas is predicted to shift the phytoplankton community towards dominance of smaller-sized species due to global warming. Yet, little is known about their viral mortality agents despite the ecological importance of viruses regulating phytoplankton host dynamics and diversity. Here we report the isolation and basic characterization of four prasinoviruses infectious to the common Arctic picophytoplankter Micromonas. We furthermore assessed how temperature influenced viral infectivity and production. Phylogenetic analysis indicated that the putative double-stranded DNA (dsDNA) Micromonas polaris viruses (MpoVs) are prasinoviruses (Phycodnaviridae) of approximately 120 nm in particle size. One MpoV showed intrinsic differences to the other three viruses, i.e., larger genome size (205 +/- 2 vs. 191 +/- 3 Kb), broader host range, and longer latent period (39 vs. 18 h). Temperature increase shortened the latent periods (up to 50%), increased the burst size (up to 40%), and affected viral infectivity. However, the variability in response to temperature was high for the different viruses and host strains assessed, likely affecting the Arctic picoeukaryote community structure both in the short term (seasonal cycles) and long term (global warming). PMID- 28574422 TI - Influence of Freeze Concentration Technique on Aromatic and Phenolic Compounds, Color Attributes, and Sensory Properties of Cabernet Sauvignon Wine. AB - Red wines produced in the Xinjiang region of China possess poor color density, and lack fruity notes and elegance. The freeze concentration technique, as a well established concentration method for liquid food systems, was applied to the Cabernet Sauvignon (Vitis vinifera L.) wine-making process, aiming to investigate its effect on wine quality improvement. Results showed that the freeze concentration treatment did not significantly alter the physicochemical properties of the wine, except for an increase of glycerol and alcoholic content. This technique increased ester contents, as well as decreasing the amount of volatile acids. Higher alcohol contents were also increased, but within an acceptable content range. All taken into consideration, the freeze concentration treated wine showed better fragrance characters according to sensory evaluation. The non-anthocyanin composition was altered by this application, however, the difference disappeared after the aging process. Fortunately, sensory evaluation showed that the treated wine possessed better mouthfeel properties. Anthocyanin contents were enhanced, and effectively stabilized the fresh wine color attributes, resulting in an improvement in appearance of the treated wine. All results considered, it can be concluded that freeze concentration treatment could be a good choice to improve wine quality. PMID- 28574423 TI - Toward a Multifactorial Conception of the Gilles de la Tourette Syndrome and Persistent Chronic Tic Disorder. AB - Despite recent giant leaps in understanding Gilles de la Tourette's syndrome (now Tourette Disorder in the DSM 5), accurate multi-modal description, rigorous assessment procedures, and the improvement of evidence-based treatment currently pose a considerable challenge. In this context, the current special edition aims to elaborate three important dimensions in Tourette Disorder. Firstly, the effective characterization and etiological basis of the disorder are reviewed, since such characterization impacts accurate assessment. Secondly, subsequent articles cover the comprehensive evaluation and assessment of tic disorders, essential for treatment planning. Thirdly, the final group of articles propose novel and innovative treatment strategies for pharmacologically and behaviorally reducing tic frequency. In the current editorial address, two main issues seem crucial to the development of interventions for Tourette disorder. Primarily, integrating new technology in treatments, while supporting cognitive and behavioral recovery through learning self-controlled strategies. Additionally, the dissemination of study results to frontline resources, needs streamlining and empirically validated treatments for tic disorders should be the subject of knowledge translation to community organizations and be more widely available to the public. PMID- 28574424 TI - A Polish Study on the Influence of Food Neophobia in Children (10-12 Years Old) on the Intake of Vegetables and Fruits. AB - Adhering to the recommended intake of fruits and vegetables is an important habit that should be inculcated in children, whereas food neophobia is indicated as one of the most important factors creating food preferences that may interfere. The aim of the presented study was to analyze the association between the food neophobia level and the intake of fruits and vegetables in children aged 10-12 years. The study was conducted among a group of 163 children (78 girls and 85 boys). The assessment of the food neophobia level was based on the Food Neophobia Scale (FNS) questionnaire and the assessment of the fruit and vegetable intake was based on the food frequency questionnaire. A negative correlation between the food neophobia level and the vegetable intake was observed both for girls (p = 0.032; R = -0.2432) and for boys (p = 0.004; R = -0.3071), whereas for girls differences in vegetable intake were observed also between various food neophobia categories (p = 0.0144). It may be concluded that children with higher food neophobia level are characterized by lower vegetable intake than children with lower food neophobia level. For fruits and juices of fruits and vegetables, associations with food neophobia level were not observed. PMID- 28574426 TI - Comparative Study of Neural Network Frameworks for the Next Generation of Adaptive Optics Systems. AB - Many of the next generation of adaptive optics systems on large and extremely large telescopes require tomographic techniques in order to correct for atmospheric turbulence over a large field of view. Multi-object adaptive optics is one such technique. In this paper, different implementations of a tomographic reconstructor based on a machine learning architecture named "CARMEN" are presented. Basic concepts of adaptive optics are introduced first, with a short explanation of three different control systems used on real telescopes and the sensors utilised. The operation of the reconstructor, along with the three neural network frameworks used, and the developed CUDA code are detailed. Changes to the size of the reconstructor influence the training and execution time of the neural network. The native CUDA code turns out to be the best choice for all the systems, although some of the other frameworks offer good performance under certain circumstances. PMID- 28574425 TI - Local Immune Responsiveness of Mice Bearing Premalignant Oral Lesions to PD-1 Antibody Treatment. AB - A carcinogen-induced premalignant oral lesion model that progresses to oral cancer was used to examine the immunological impact of a 5-week treatment regimen to block programmed cell death protein 1 (PD-1). PD-1 antibody treatment resulted in concurrent, but transient, increases in interleukin (IL)-2, IFN-gamma and IL 17, and delayed increases in IL-6 and IL-10 within the lesion-bearing tongue epithelium. In contrast, cytokine secretion by lymph node cells of PD-1 antibody treated mice was lower than for mice treated with control antibodies, with the exception of interferon (IFN)-gamma, whose secretion increased late in the treatment period. This delayed secretion of IFN-gamma coincided with an increase in CD4+ lymph node cells expressing IFN-gamma. Lymph node cells of PD-1 antibody treated mice reacted to a challenge with lysates of lesions or cancer by early production of IFN-gamma, but this rapidly subsided. There also was increased production IL-17 and tumor necrosis factor (TNF)-alpha in response to the challenge, but the response was greatest by cells of control lesion-bearing mice. Clinical assessment showed an early but transient, stabilization of disease in mice treated with PD-1 antibody. These results show an early beneficial, but time limited, response to PD-1 antibody treatment, which then fails with continued lesion progression. PMID- 28574427 TI - A Novel Anti-Hepatitis C Virus and Antiproliferative Agent Alters Metabolic Networks in HepG2 and Hep3B Cells. AB - A series of novel diflunisal hydrazide-hydrazones has been reported together with their anti-hepatitis C virus and antiproliferative activities in a number of human hepatoma cell lines. However, the mechanisms underlying the efficacy of these agents remain unclear. It was chosen to investigate the lead diflunisal hydrazide-hydrazone, 2',4'-difluoro-4-hydroxy-N'- [(pyridin-2 yl)methylidene]biphenyl-3-carbohydrazide (compound 3b), in two cultured human hepatoma cell lines-HepG2 and Hep3B-using a metabolomic protocol aimed at uncovering any effects of this agent on cellular metabolism. One sub-therapeutic concentration (2.5 MUM) and one close to the IC50 for antimitotic effect (10 MUM), after 72 h in cell culture, were chosen for both compound 3b and its inactive parent compound diflusinal as a control. A GCMS-based metabolomic investigation was performed on cell lysates after culture for 24 h. The intracellular levels of a total of 42 metabolites were found to be statistically significantly altered in either HepG2 or Hep3B cells, only eight of which were affected in both cell lines. It was concluded that compound 3b affected the following pathways-purine and pyrimidine catabolism, the glutathione cycle, and energy metabolism through glycolysis and the pentose phosphate pathway. Although the metabolomic findings occurred after 24 h in culture, significant cytotoxicity of compound 3b to both HepG2 and Hep3B cells at 10 MUM were reported not to occur until 72 h in culture. These observations show that metabolomics can provide mechanistic insights into the efficacy of novel drug candidates prior to the appearance of their pharmacological effect. PMID- 28574429 TI - Validation of Acoustic Wave Induced Traumatic Brain Injury in Rats. AB - BACKGROUND: This study looked to validate the acoustic wave technology of the Storz-D-Actor that inflicted a consistent closed-head, traumatic brain injury (TBI) in rats. We studied a range of single pulse pressures administered to the rats and observed the resulting decline in motor skills and memory. Histology was observed to measure and confirm the injury insult. METHODS: Four different acoustic wave pressures were studied using a single pulse: 0, 3.4, 4.2 and 5.0 bar (n = 10 rats per treatment group). The pulse was administered to the left frontal cortex. Rotarod tests were used to monitor the rats' motor skills while the water maze test was used to monitor memory deficits. The rats were then sacrificed ten days post-treatment for histological analysis of TBI infarct size. RESULTS: The behavioral tests showed that acoustic wave technology administered an effective insult causing significant decreases in motor abilities and memory. Histology showed dose-dependent damage to the cortex infarct areas only. CONCLUSIONS: This study illustrates that the Storz D-Actor effectively induces a repeatable TBI infarct, avoiding the invasive procedure of a craniotomy often used in TBI research. PMID- 28574428 TI - Reduced Dietary Selenium Impairs Vascular Function by Increasing Oxidative Stress in Sprague-Dawley Rat Aortas. AB - This study aimed to determine whether low dietary Se content affects the function and mechanisms mediating the vascular relaxation of rat aortas, and to test the role of oxidative stress in observed differences. Male Sprague Dawley (SD) rats were maintained for 10 weeks on low Se (low-Se group; N = 20) or normal Se content (norm-Se group; N = 20) rat chow. Dose responses to acetylcholine (ACh; 10-9-10-5M) and the response to reduced pO2 were tested in noradrenaline precontracted aortic rings in the absence/presence of the nitric oxide synthase (NOS) inhibitor nitro-l-arginine methyl ester (l-NAME), the cyclooxygenase 1 and 2 (COX-1, 2) inhibitor Indomethacin, and the antioxidative agent Tempol in tissue bath. mRNA expression of glutathione peroxidase 1 (GPx1), catalase (CAT), and Cu/Zn superoxide dismutase (SOD) was measured in rat aortas. Oxidative stress (Thiobarbituric Acid Reactive Substances; TBARS), antioxidative plasma capacity (ferric reducing ability of plasma assay; FRAP), and protein levels of GPx1 were measured in plasma and serum samples, respectively. Reduced ACh-induced relaxation (AChIR) (dominantly mediated by NO) in the low-Se group compared to the norm-Se group was restored by Tempol administration. Hypoxia-induced relaxation (HIR) (dominantly mediated by COX-1, 2), TBARS, and FRAP as well as GPx1 serum concentrations were similar between the groups. mRNA GPx1 expression in rat aortas was significantly decreased in the low-Se compared to the norm-Se group. These data suggest that low dietary Se content increases the local oxidative stress level, which subsequently affects the NO-mediated vascular response. PMID- 28574431 TI - Vitamin C Depletion and All-Cause Mortality in Renal Transplant Recipients. AB - Vitamin C may reduce inflammation and is inversely associated with mortality in the general population. We investigated the association of plasma vitamin C with all-cause mortality in renal transplant recipients (RTR); and whether this association would be mediated by inflammatory biomarkers. Vitamin C, high sensitive C-reactive protein (hs-CRP), soluble intercellular cell adhesion molecule 1 (sICAM-1), and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured in a cohort of 598 RTR. Cox regression analyses were used to analyze the association between vitamin C depletion (<=28 umol/L; 22% of RTR) and mortality. Mediation analyses were performed according to Preacher and Hayes's procedure. At a median follow-up of 7.0 (6.2-7.5) years, 131 (21%) patients died. Vitamin C depletion was univariately associated with almost two-fold higher risk of mortality (Hazard ratio (HR) 1.95; 95% confidence interval (95%CI) 1.35-2.81, p < 0.001). This association remained independent of potential confounders (HR 1.74; 95%CI 1.18-2.57, p = 0.005). Hs-CRP, sICAM-1, sVCAM-1 and a composite score of inflammatory biomarkers mediated 16, 17, 15, and 32% of the association, respectively. Vitamin C depletion is frequent and independently associated with almost two-fold higher risk of mortality in RTR. It may be hypothesized that the beneficial effect of vitamin C at least partly occurs through decreasing inflammation. PMID- 28574432 TI - Isolation, Amino Acid Sequences, and Plausible Functions of the Galacturonic Acid Binding Egg Lectin of the Sea Hare Aplysia kurodai. AB - Egg lectins occur in a variety of animals ranging from mollusks to vertebrates. A few examples of molluscan egg lectins have been reported, including that of the sea hare Aplysia kurodai; however, their biological functions in the egg remain unclarified. We report the isolation, determination of primary structure, and possible functions of A.kurodai lectin (AKL) from the egg mass of A. kurodai. We obtained AKL as an inseparable mixture of isoproteins with a relative molecular mass of approximately 32 kDa by affinity purification. The hemagglutinating activity of AKL against rabbit erythrocytes was inhibited most potently by galacturonic acid and moderately by xylose. Nucleotide sequencing of corresponding cDNA obtained by rapid amplification of cDNA ends (RACE) allowed us to deduce complete amino acid sequences. The mature polypeptides consisted of 218 or 219-amino acids with three repeated domains. The amino acid sequence had similarities to hypothetical proteins of Aplysia spp., or domain DUF3011 of uncharacterized bacterial proteins. AKL is the first member of the DUF3011 family whose function, carbohydrate recognition, was revealed. Treatment of the egg with galacturonic acid, an AKL sugar inhibitor, resulted in deformation of the veliger larvae, suggesting that AKL is involved in organogenesis in the developmental stage of A. kurodai. PMID- 28574433 TI - Aflatoxin B1 Tolerance and Accumulation in Black Soldier Fly Larvae (Hermetia illucens) and Yellow Mealworms (Tenebrio molitor). AB - Crops contaminated with fungal mycotoxins such as aflatoxin B1 (AFB1) are often downgraded or removed from the food chain. This study aimed to evaluate the tolerance and accumulation of AFB1 in two insect species to determine whether they could be used to retain condemned mycotoxin contaminated crops in the food chain. First, instar black soldier fly larvae (Hermetia illucens, BSF) and yellow mealworm (Tenebrio molitor, YMW) were fed poultry feed spiked with AFB1 and formulated to contain levels of 0.01, 0.025, 0.05, 0.10, 0.25, and up to 0.5 mg/kg dry feed. Poultry feed without any additions and feed with only the solvent added served as controls. The AFB1 in the feed did not affect survival and body weight in the BSF and YMW larvae (p > 0.10), indicating a high tolerance to aflatoxin B1 in both species. Furthermore, AFB1 and aflatoxin M1 (AFM1) were below the detection limit (0.10 ug/kg) in BSF larvae, whereas the YMW had AFB1 levels that were approximately 10% of the European Union's legal limit for feed materials and excreted AFM1. It is concluded that both BSF larvae and YMW have a high AFB1 tolerance and do not accumulate AFB1. PMID- 28574430 TI - Extracellular Vesicles in Hematological Malignancies: From Biology to Therapy. AB - Extracellular vesicles (EVs) are a heterogeneous group of particles, between 15 nanometers and 10 microns in diameter, released by almost all cell types in physiological and pathological conditions, including tumors. EVs have recently emerged as particularly interesting informative vehicles, so that they could be considered a true "cell biopsy". Indeed, EV cargo, including proteins, lipids, and nucleic acids, generally reflects the nature and status of the origin cells. In some cases, EVs are enriched of peculiar molecular cargo, thus suggesting at least a degree of specific cellular packaging. EVs are identified as important and critical players in intercellular communications in short and long distance interplays. Here, we examine the physiological role of EVs and their activity in cross-talk between bone marrow microenvironment and neoplastic cells in hematological malignancies (HMs). In these diseases, HM EVs can modify tumor and bone marrow microenvironment, making the latter "stronger" in supporting malignancy, inducing drug resistance, and suppressing the immune system. Moreover, EVs are abundant in biologic fluids and protect their molecular cargo against degradation. For these and other "natural" characteristics, EVs could be potential biomarkers in a context of HM liquid biopsy and therapeutic tools. These aspects will be also analyzed in this review. PMID- 28574435 TI - Exploring the Role of Farm Animals in Providing Care at Care Farms. AB - We explore the role of farm animals in providing care to different types of participants at care farms (e.g., youngsters with behavioural problems, people with severe mental problems and people with dementia). Care farms provide alternative and promising settings where people can interact with animals compared to a therapeutic healthcare setting. We performed a literature review, conducted focus group meetings and carried out secondary data-analysis of qualitative studies involving care farmers and different types of participants. We found that farm animals are important to many participants and have a large number of potential benefits. They can (i) provide meaningful day occupation; (ii) generate valued relationships; (iii) help people master tasks; (iv) provide opportunities for reciprocity; (v) can distract people from them problems; (vi) provide relaxation; (vii) facilitate customized care; (viii) facilitate relationships with other people; (ix) stimulate healthy behavior; (x) contribute to a welcoming environment; (xi) make it possible to experience basic elements of life; and (xii) provide opportunities for reflection and feedback. This shows the multi-facetted importance of interacting with animals on care farms. In this study the types of activities with animals and their value to different types of participants varied. Farm animals are an important element of the care farm environment that can address the care needs of different types of participants. PMID- 28574434 TI - Addressing the Immunogenicity of the Cargo and of the Targeting Antibodies with a Focus on Demmunized Bacterial Toxins and on Antibody-Targeted Human Effector Proteins. AB - Third-generation immunotoxins are composed of a human, or humanized, targeting moiety, usually a monoclonal antibody or an antibody fragment, and a non-human effector molecule. Due to the non-human origin of the cytotoxic domain, these molecules stimulate potent anti-drug immune responses, which limit treatment options. Efforts are made to deimmunize such immunotoxins or to combine treatment with immunosuppression. An alternative approach is using the so-called "human cytotoxic fusion proteins", in which antibodies are used to target human effector proteins. Here, we present three relevant approaches for reducing the immunogenicity of antibody-targeted protein therapeutics: (1) reducing the immunogenicity of the bacterial toxin, (2) fusing human cytokines to antibodies to generate immunocytokines and (3) addressing the immunogenicity of the targeting antibodies. PMID- 28574436 TI - Qualitative and Quantitative Assessment of Vascular Changes in Diabetic Macular Edema after Dexamethasone Implant Using Optical Coherence Tomography Angiography. AB - The aim of this study was to investigate retinal and choriocapillaris vessel changes in diabetic macular edema (DME) after the intravitreal dexamethasone implant (IDI) using optical coherence tomography angiography (OCTA). Moreover, a comparison between morphological and functional parameters of DME and healthy patients was performed. Twenty-five eyes of 25 type 2 diabetic retinopathy patients complicated by macular edema (DME group) and 25 healthy subjects (control group) were enrolled. Superficial capillary plexus density (SCPD) and deep capillary plexus density (DCPD) in the foveal and parafoveal areas, choricapillary density (CCD) and optic disc vessel density (ODVD) were detected using OCTA at baseline and after 7, 30, 60, 90 and 120 days post injection. Best corrected visual acuity (BCVA), retinal sensitivity, and central retinal thickness (CMT) were also evaluated in both groups of patients. A statistically significant difference between the two groups (DME and controls) was found in terms of functional (MP, p < 0.001 and BCVA, p < 0.001) and morphological (CMT, p < 0.001; SCPD in the parafoveal area, p < 0.001; DCPD in the foveal area, p < 0.05 and parafoveal area, p < 0.001; CCD, p < 0.001) parameters. After the treatment, SCPD and DCPD in the foveal and parafoveal areas did not modify significantly during the follow up. PMID- 28574438 TI - An Evaluation of the Binding Strength of Okra Gum and the Drug Release Characteristics of Tablets Prepared from It. AB - The aim of this study is to evaluate the adhesion ability of okra gum, which is gaining popularity as a tablet binder. For this purpose, gum was extracted from okra pods, and the binding strength of different concentrations (1%, 3%, and 5%) was determined quantitatively. Additionally, naproxen sodium tablets were prepared by using okra gum as a binder and were evaluated for their properties including hardness, friability, disintegration time, and dissolution rate. The binding strength values were compared with that of pre-gelatinized starch, a commonly used tablet binder. The results from universal testing machine indicate that the binding strengths of all dispersions of okra increase as the concentration increases from 1% to 5% and ranges from 2.5 to 4.5 N, which are almost twice a high as those of pre-gelatinized starch. The tablets prepared with okra gum have shown good mechanical strength with hardness values of 7-8.5 kg/cm2 and a friability <1%, comparable to tablets prepared with starch. The disintegration time was longer (7.50 min with okra gum and 5.05 min with starch paste), and the drug release from these tablets was slower than the formulations with starch. The higher binding ability of okra gum probably linked with its chemical composition as it mainly contains galactose, rhamnose, and galacturonic acid. This study concludes that okra gum is a better binder than pre-gelatinized starch, it might be explored in future for introduction as a cost-effective binder in the pharmaceutical industry. PMID- 28574437 TI - The Influence of Quercetin on Maternal Immunity, Oxidative Stress, and Inflammation in Mice with Exposure of Fine Particulate Matter during Gestation. AB - The objective is to investigate the influence of PM2.5 exposure on peripheral blood lymphocyte subsets in pregnant mice and the antagonism of quercetin on adverse effects induced by PM2.5 exposure. Pregnant mice were randomly divided into control group, PM2.5 model group and 3 quercetin intervention groups. Dams in all groups except the control group were exposed to PM2.5 suspension by intratracheal instillation on gestational day (GD) 3, 6, 9, 12 and 15. Meanwhile, each dam was given 0.15% carboxymethylcellulose sodium (CMCS) (control group & PM2.5 model group) and different doses of quercetin (quercetin intervention groups) by gavage once a day from GD0 to GD17. The percentage of lymphocyte subsets, Biomarkers of systemic inflammation injuries (IL-2, IL-6, IL-8 & TNF alpha) and oxidative stress indicators (CAT, GSH & HO-1) in peripheral blood of the dams were analyzed. The number of T cells increased, accompanied by increased level of IL-2, IL-6, IL-8 and HO-1 due to PM2.5 exposure. Less CD4+ and CD8+ T cells were counted in 100 mg/kg quercetin intervention group, compared with PM2.5 model group. Quercetin may inhibit cytokine production, especially in IL-6 and IL 8 and may upgrade the level of HO-1. Our findings indicate that PM2.5 could significantly influence the distribution of T-lymphocyte subsets, activate inflammatory reaction and elevate oxidative stress level in peripheral blood of pregnant mice. Certain dose of quercetin administration during pregnancy may protect the dams against the adverse effects through various ways. PMID- 28574439 TI - The Evolving Interplay among Abundant Adipokines in Patients with Hepatitis C during Viral Clearance. AB - How hepatatitis C virus (HCV) infection affects the interplay among abundant adipokines in the host remains unclear. A prospective study was conducted with 450 consecutive genotype 1 (G1) and G2 HCV patients who completed a course of anti-HCV therapy and underwent pre-therapy and 24-week post-therapy surveys to assess various profiles and levels of abundant adipokines, including leptin, adiponectin, and plasminogen activator inhibitor-1 (PAI-1). Before anti-HCV therapy, multivariate analyses showed gender to be associated with leptin and adiponectin levels, and BMI with leptin and PAI-1 levels. Among patients with a sustained virological response (SVR, n = 372), associations at 24 weeks post therapy were as follows: gender and BMI with all adipokine levels; hepatic steatosis and aspartate aminotransferase to platelet ratio index with adiponectin levels; and HOMA-IR and HCV genotype with PAI-1 levels. Paired t-tests revealed increased post-therapeutic PAI-1 levels in G1 SVR patients and decreased adiponectin levels in all SVR patients compared to pre-therapeutic levels. HCV infection may obscure associations between abundant adipokines and metabolic/hepatic profiles. In SVR patients, a higher hierarchical status of PAI 1 versus adiponectin in affecting glucose metabolism was noted at 24 weeks post therapy. Such genotype-non-specific adiponectin decreases and G1-specific PAI-1 increases warrant careful follow-up of HCV patients after SVR according to viral genotype. PMID- 28574442 TI - Electrophysiological Indices of Audiovisual Speech Perception in the Broader Autism Phenotype. AB - When a speaker talks, the consequences of this can both be heard (audio) and seen (visual). A novel visual phonemic restoration task was used to assess behavioral discrimination and neural signatures (event-related potentials, or ERP) of audiovisual processing in typically developing children with a range of social and communicative skills assessed using the social responsiveness scale, a measure of traits associated with autism. An auditory oddball design presented two types of stimuli to the listener, a clear exemplar of an auditory consonant vowel syllable /ba/ (the more frequently occurring standard stimulus), and a syllable in which the auditory cues for the consonant were substantially weakened, creating a stimulus which is more like /a/ (the infrequently presented deviant stimulus). All speech tokens were paired with a face producing /ba/ or a face with a pixelated mouth containing motion but no visual speech. In this paradigm, the visual /ba/ should cause the auditory /a/ to be perceived as /ba/, creating an attenuated oddball response; in contrast, a pixelated video (without articulatory information) should not have this effect. Behaviorally, participants showed visual phonemic restoration (reduced accuracy in detecting deviant /a/) in the presence of a speaking face. In addition, ERPs were observed in both an early time window (N100) and a later time window (P300) that were sensitive to speech context (/ba/ or /a/) and modulated by face context (speaking face with visible articulation or with pixelated mouth). Specifically, the oddball responses for the N100 and P300 were attenuated in the presence of a face producing /ba/ relative to a pixelated face, representing a possible neural correlate of the phonemic restoration effect. Notably, those individuals with more traits associated with autism (yet still in the non-clinical range) had smaller P300 responses overall, regardless of face context, suggesting generally reduced phonemic discrimination. PMID- 28574441 TI - Gene Expression (mRNA) Markers for Differentiating between Malignant and Benign Follicular Thyroid Tumours. AB - Distinguishing between follicular thyroid cancer (FTC) and follicular thyroid adenoma (FTA) constitutes a long-standing diagnostic problem resulting in equivocal histopathological diagnoses. There is therefore a need for additional molecular markers. To identify molecular differences between FTC and FTA, we analyzed the gene expression microarray data of 52 follicular neoplasms. We also performed a meta-analysis involving 14 studies employing high throughput methods (365 follicular neoplasms analyzed). Based on these two analyses, we selected 18 genes differentially expressed between FTA and FTC. We validated them by quantitative real-time polymerase chain reaction (qRT-PCR) in an independent set of 71 follicular neoplasms from formaldehyde-fixed paraffin embedded (FFPE) tissue material. We confirmed differential expression for 7 genes (CPQ, PLVAP, TFF3, ACVRL1, ZFYVE21, FAM189A2, and CLEC3B). Finally, we created a classifier that distinguished between FTC and FTA with an accuracy of 78%, sensitivity of 76%, and specificity of 80%, based on the expression of 4 genes (CPQ, PLVAP, TFF3, ACVRL1). In our study, we have demonstrated that meta-analysis is a valuable method for selecting possible molecular markers. Based on our results, we conclude that there might exist a plausible limit of gene classifier accuracy of approximately 80%, when follicular tumors are discriminated based on formalin fixed postoperative material. PMID- 28574440 TI - Micro-RNAs as Potential Predictors of Response to Breast Cancer Systemic Therapy: Future Clinical Implications. AB - Despite advances in diagnosis and new treatments such as targeted therapies, breast cancer (BC) is still the most prevalent tumor in women worldwide and the leading cause of death. The principal obstacle for successful BC treatment is the acquired or de novo resistance of the tumors to the systemic therapy (chemotherapy, endocrine, and targeted therapies) that patients receive. In the era of personalized treatment, several studies have focused on the search for biomarkers capable of predicting the response to this therapy; microRNAs (miRNAs) stand out among these markers due to their broad spectrum or potential clinical applications. miRNAs are conserved small non-coding RNAs that act as negative regulators of gene expression playing an important role in several cellular processes, such as cell proliferation, autophagy, genomic stability, and apoptosis. We reviewed recent data that describe the role of miRNAs as potential predictors of response to systemic treatments in BC. Furthermore, upon analyzing the collected published information, we noticed that the overexpression of miR 155, miR-222, miR-125b, and miR-21 predicts the resistance to the most common systemic treatments; nonetheless, the function of these particular miRNAs must be carefully studied and further analyses are still necessary to increase knowledge about their role and future potential clinical uses in BC. PMID- 28574443 TI - Seasonal Variation of Triacylglycerol Profile of Bovine Milk. AB - Milk contains 3-6% of fat, of which the dominant component is triacylglycerol (TAG). Over 100 TAG groups can be readily detected in any non-enriched milk sample by LC-MS; most TAG groups contain several isomers (TAG molecules with different fatty acid composition), which cannot be fully resolved chromatographically by any single stationary phase. TAG profile of mature milk from 19 cows was surveyed in this study for eight consecutive months using RP-LC Orbitrap MS. It was found that TAG profile of milk was not constant throughout the milking season and the seasonal pattern varied with TAG groups. The overall unsaturation level of TAG was stable from October 2013 to January 2014, decreased in February/March 2014 and then increased from April and peaked in May 2014. In addition to the seasonal fluctuation in TAG profile, the proportion of different isomeric species within a TAG group also changed substantially across seasons. However, the proportion of different positional isomers within a given TAG group does not seem to vary during the milking season. To our knowledge, this is the first report on the seasonal change of milk lipid at the TAG group and isomer level. PMID- 28574445 TI - Cu Nanoparticles in Hydrogels of Chitosan-PVA Affects the Characteristics of Post Harvest and Bioactive Compounds of Jalapeno Pepper. AB - Peppers are consumed all over the world due to the flavor, aroma, and color that they add to food. Additionally, they play a role in human health, as they contain a high concentration of bioactive compounds and antioxidants. The treatments used were an absolute control, Cs-PVA, and four treatments with 0.02, 0.2, 2, and 10 mg (nCu) g-1 (Cs-PVA). The application of Cu nanoparticles in chitosan-PVA hydrogels increases the content of capsaicin by up to 51% compared to the control. This application also increases the content of antioxidants ABTS [2,2' azino-bis (3-ethylbenzothiazolin-6-sulfonic acid)] and DPPH (2,2-diphenyl-1 picrylhydrazyl), total phenols and flavonoids (4%, 6.6%, 5.9%, and 12.7%, respectively) in jalapeno pepper fruits stored for 15 days at room temperature; under refrigeration, it increases DPPH antioxidants, total phenols, and flavonoids (23.9%, 1.54%, and 17.2%, respectively). The application of Cu nanoparticles in chitosan-PVA hydrogels, even when applied to the substrate, not only has an effect on the development of the jalapeno pepper crop, but also modifies the post-harvest characteristics of the jalapeno pepper fruits. PMID- 28574444 TI - Validation of the Performance of International Ovarian Tumor Analysis (IOTA) Methods in the Diagnosis of Early Stage Ovarian Cancer in a Non-Screening Population. AB - BACKGROUND: The aim of this study was to assess and compare the performance of different ultrasound-based International Ovarian Tumor Analysis (IOTA) strategies and subjective assessment for the diagnosis of early stage ovarian malignancy. METHODS: This is a secondary analysis of a prospective multicenter cross sectional diagnostic accuracy study that included 1653 patients recruited at 18 centers from 2009 to 2012. All patients underwent standardized transvaginal ultrasonography by experienced ultrasound investigators. We assessed test performance of the IOTA Simple Rules (SRs), Simple Rules Risk (SRR), the Assessment of Different NEoplasias in the adneXa (ADNEX) model and subjective assessment to discriminate between stage I-II ovarian cancer and benign disease. Reference standard was histology after surgery. RESULTS: 230 (13.9%) patients proved to have stage I-II primary invasive ovarian malignancy, and 1423 (86.1%) had benign disease. Sensitivity and specificity with respect to malignancy (95% confidence intervals) of the original SRs (classifying all inconclusive cases as malignant) were 94.3% (90.6% to 96.7%) and 73.4% (71.0% to 75.6%). Subjective assessment had a sensitivity and specificity of 90.0% (85.4% to 93.2%) and 86.7% (84.9% to 88.4%), respectively. The areas under the receiver operator characteristic curves of SRR and ADNEX were 0.917 (0.902 to 0.933) and 0.905 (0.920 to 0.934), respectively. At a 1% risk cut-off, sensitivity and specificity for SRR were 100% (98.4% to 100%) and 38.0% (35.5% to 40.6%), and for ADNEX were 100% (98.4% to 100%) and 19.4% (17.4% to 21.5%). At a 30% risk cut-off, sensitivity and specificity for SRR were 88.3% (83.5% to 91.8%) and 81.1% (79% to 83%), and for ADNEX were 84.5% (80.5% to 89.6%) and 84.5% (82.6% to 86.3%). CONCLUSION: This study shows that all three IOTA strategies have good ability to discriminate between stage I-II ovarian malignancy and benign disease. PMID- 28574447 TI - Deciphering Structural Photophysics of Fluorescent Proteins by Kinetic Crystallography. AB - Because they enable labeling of biological samples in a genetically-encoded manner, Fluorescent Proteins (FPs) have revolutionized life sciences. Photo transformable fluorescent proteins (PTFPs), in particular, recently attracted wide interest, as their fluorescence state can be actively modulated by light, a property central to the emergence of super-resolution microscopy. PTFPs, however, exhibit highly complex photophysical behaviours that are still poorly understood, hampering the rational engineering of variants with improved performances. We show that kinetic crystallography combined with in crystallo optical spectroscopy, modeling approaches and single-molecule measurements constitutes a powerful tool to decipher processes such as photoactivation, photoconversion, photoswitching, photoblinking and photobleaching. Besides potential applications for the design of enhanced PTFPs, these investigations provide fundamental insight into photoactivated protein dynamics. PMID- 28574449 TI - Reemergence of Measles in the Americas: The Genotype B3 2011-2012 Outbreak in Ecuador. AB - This study characterizes a measles outbreak which occurred in Ecuador in 2011 2012, analyzing data from 3700 suspected cases of measles reported to Ecuador's Ministry of Public Health. The study population had a large age range and included 333 confirmed cases of measles. The greatest number of cases were found in the <1 year (32.43%, n = 108) and 1-4 year (30.03%, n = 100) age-groups. Compared to Mestizos, indigenous people had the highest number of cases (68.2%, n = 227), as well as a higher risk of infection (OR 7.278 (CI 5.251-10.087)). The greatest protection from measles was observed in individuals who received two doses of the measles vaccine. Residents of Pastaza (OR 6.645 CI (3.183-13.873)) and Tungurahua (OR 8.346 CI (5.570-12.507)) had a higher risk of infection than the other provinces. Of the 17 laboratory confirmed cases, all were identified as genotype B3. Age-group, ethnicity, measles vaccinations, and residence in Tungurahua and Pastaza were correlated with rates of measles infection in the outbreak. Tungurahua and Pastaza, where the outbreak originated, have large indigenous populations. Indigenous children <1 year of age showed the highest incidence. It is likely that indigenous women do not have immunity to the virus, and so are unable to confer measles resistance to their newborns. PMID- 28574448 TI - Simultaneous Quantification of Multiple Representative Components in the Xian Ling-Gu-Bao Capsule by Ultra-Performance Liquid Chromatography Coupled with Quadrupole Time-of-Flight Tandem Mass Spectrometry. AB - Xian-Ling-Gu-Bao capsule (XLGB), a famous traditional Chinese medicine prescription, is extensively used for the treatment of osteoporosis in China. However, few studies on the holistic quality control of XLGB have been reported. In this study, a reliable method using 18 representative components in XLGB was successfully established and applied to evaluate 34 batches of XLGB samples by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS). The choice of quantitative markers mostly followed four principles, i.e., absorbed components in plasma, bioactive compounds with in vitro anti-osteoporosis activity, those derived from multiple individual medicinal herbs in XLGB with multiple representative structure types, and quantitative chemical markers in the Chinese Pharmacopoeia. The results showed chemical consistency was good except for individual batches. Multivariate statistical analysis indicated that asperosaponin VI from Radix Dipsaci, epimedin C, magnoflorine, and icariin from Herba Epimedii as well as timosaponin BII from Rhizoma Anemarrhenae varied significantly in multiple samples, which hinted an assay for these four components should be completed during all of the manufacturing processes. Taken together, this study provided a feasible method for holistic quality control of XLGB by multiple chemical markers, which could play a vital role in guaranteeing the safety, effectiveness, and controllability of administering the capsules as a medication in clinics. PMID- 28574451 TI - Effect of Montmorillonite Nanogel Composite Fillers on the Protection Performance of Epoxy Coatings on Steel Pipelines. AB - Montmorillonite (MMT) clay mineral is widely used as filler for several organic coatings. Its activity is increased by exfoliation via chemical modification to produce nanomaterials. In the present work, the modification of MMT to form nanogel composites is proposed to increase the dispersion of MMT into epoxy matrices used to fill cracks and holes produced by the curing exotherms of epoxy resins. The dispersion of MMT in epoxy improved both the mechanical and anti corrosion performance of epoxy coatings in aggressive marine environments. In this respect, the MMT surfaces were chemically modified with different types of 2 acrylamido-2-methyl propane sulfonic acid (AMPS) nanogels using a surfactant-free dispersion polymerization technique. The effect of the chemical structure, nanogel content and the interaction with MMT surfaces on the surface morphology, surface charges and dispersion in the epoxy matrix were investigated for use as nano-filler for epoxy coatings. The modified MMT nanogel epoxy composites showed excellent resistance to mechanical damage and salt spray resistance up to 1000 h. The interaction of MMT nanogel composites with the epoxy matrix and good response of AMPS nanogel to sea water improve their ability to act as self-healing materials for epoxy coatings for steel. PMID- 28574450 TI - Stable ABTS Immobilized in the MIL-100(Fe) Metal-Organic Framework as an Efficient Mediator for Laccase-Catalyzed Decolorization. AB - The successful encapsulation of 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), a well-known laccase mediator, within a mesoporous metal-organic framework sample (i.e., MIL-100(Fe)) was achieved using a one-pot hydrothermal synthetic method. The as-prepared ABTS@MIL-100(Fe) was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, nitrogen sorption, and cyclic voltammetry (CV). Our ABTS@MIL-100(Fe)-based electrode exhibited an excellent electrochemical response, indicating that MIL-100(Fe) provides an appropriate microenvironment for the immobilization and electroactivity of ABTS molecules. ABTS@MIL-100(Fe) was then evaluated as an immobilized laccase mediator for dye removal using indigo carmine (IC) as a model dye. Through the application of laccase in combination with a free (ABTS) or immobilized (ABTS@MIL-100(Fe)) mediator, decolorization yields of 95% and 94%, respectively, were obtained for IC after 50 min. In addition, following seven reuse cycles of ABTS@MIL-100(Fe) for dye treatment, a decolorization yield of 74% was obtained. Dye decolorization occurred through the breakdown of the chromophoric group by the Laccase/ABTS@MIL-100(Fe) system, and a catalytic mechanism was proposed. We therefore expect that the stability, reusability, and validity of ABTS@MIL-100(Fe) as a laccase mediator potentially render it a promising tool for dye removal, in addition to reducing the high running costs and potential toxicity associated with synthetic mediators. PMID- 28574446 TI - Activation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The "Rotation Model". AB - The epidermal growth factor receptor (EGFR) plays vital roles in cellular processes including cell proliferation, survival, motility, and differentiation. The dysregulated activation of the receptor is often implicated in human cancers. EGFR is synthesized as a single-pass transmembrane protein, which consists of an extracellular ligand-binding domain and an intracellular kinase domain separated by a single transmembrane domain. The receptor is activated by a variety of polypeptide ligands such as epidermal growth factor and transforming growth factor alpha. It has long been thought that EGFR is activated by ligand-induced dimerization of the receptor monomer, which brings intracellular kinase domains into close proximity for trans-autophosphorylation. An increasing number of diverse studies, however, demonstrate that EGFR is present as a pre-formed, yet inactive, dimer prior to ligand binding. Furthermore, recent progress in structural studies has provided insight into conformational changes during the activation of a pre-formed EGFR dimer. Upon ligand binding to the extracellular domain of EGFR, its transmembrane domains rotate or twist parallel to the plane of the cell membrane, resulting in the reorientation of the intracellular kinase domain dimer from a symmetric inactive configuration to an asymmetric active form (the "rotation model"). This model is also able to explain how oncogenic mutations activate the receptor in the absence of the ligand, without assuming that the mutations induce receptor dimerization. In this review, we discuss the mechanisms underlying the ligand-induced activation of the preformed EGFR dimer, as well as how oncogenic mutations constitutively activate the receptor dimer, based on the rotation model. PMID- 28574452 TI - Two Synechococcus genes, Two Different Effects on Cyanophage Infection. AB - Synechococcus is an abundant marine cyanobacterium that significantly contributes to primary production. Lytic phages are thought to have a major impact on cyanobacterial population dynamics and evolution. Previously, an investigation of the transcriptional response of three Synechococcus strains to infection by the T4-like cyanomyovirus, Syn9, revealed that while the transcript levels of the vast majority of host genes declined soon after infection, those for some genes increased or remained stable. In order to assess the role of two such host response genes during infection, we inactivated them in Synechococcus sp. strain WH8102. One gene, SYNW1659, encodes a domain of unknown function (DUF3387) that is associated with restriction enzymes. The second gene, SYNW1946, encodes a PIN PhoH protein, of which the PIN domain is common in bacterial toxin-antitoxin systems. Neither of the inactivation mutations impacted host growth or the length of the Syn9 lytic cycle. However, the DUF3387 mutant supported significantly lower phage DNA replication and yield of phage progeny than the wild-type, suggesting that the product of this host gene aids phage production. The PIN-PhoH mutant, on the other hand, allowed for significantly higher Syn9 genomic DNA replication and progeny production, suggesting that this host gene plays a role in restraining the infection process. Our findings indicate that host-response genes play a functional role during infection and suggest that some function in an attempt at defense against the phage, while others are exploited by the phage for improved infection. PMID- 28574453 TI - Randomized Controlled Trial of DHA Supplementation during Pregnancy: Child Adiposity Outcomes. AB - Investigating safe and effective interventions in pregnancy that lower offspring adiposity is important given the burden of obesity and subsequent metabolic derangements. Our objective was to determine if docosahexaenoic acid (DHA) given during pregnancy to obese mothers results in lower offspring adiposity. This study was a long-term follow-up of a randomized trial of mothers with gestational diabetes or obesity who were randomized to receive DHA supplementation at 800 mg/day or placebo (corn/soy oil) starting at 25-29 weeks gestation. Anthropometric measures were collected at birth and maternal erythrocyte DHA and arachidonic (AA) levels were measured at 26 and 36 weeks gestation. At two- and four-year follow-up time points, offspring adiposity measures along with a diet recall were assessed. A significant increase in erythrocyte DHA levels was observed at 36 weeks gestation in the supplemented group (p < 0.001). While no significant differences by measures of adiposity were noted at birth, two or four years by randomization group, duration of breastfeeding (p < 0.001), and DHA level at 36 weeks (p = 0.002) were associated with body mass index z-score. Our data suggest that DHA supplementation during pregnancy in obese mothers may have long-lasting effects on offspring measures of adiposity. PMID- 28574455 TI - A Lifetime Maximization Relay Selection Scheme in Wireless Body Area Networks. AB - Network Lifetime is one of the most important metrics in Wireless Body Area Networks (WBANs). In this paper, a relay selection scheme is proposed under the topology constrains specified in the IEEE 802.15.6 standard to maximize the lifetime of WBANs through formulating and solving an optimization problem where relay selection of each node acts as optimization variable. Considering the diversity of the sensor nodes in WBANs, the optimization problem takes not only energy consumption rate but also energy difference among sensor nodes into account to improve the network lifetime performance. Since it is Non deterministic Polynomial-hard (NP-hard) and intractable, a heuristic solution is then designed to rapidly address the optimization. The simulation results indicate that the proposed relay selection scheme has better performance in network lifetime compared with existing algorithms and that the heuristic solution has low time complexity with only a negligible performance degradation gap from optimal value. Furthermore, we also conduct simulations based on a general WBAN model to comprehensively illustrate the advantages of the proposed algorithm. At the end of the evaluation, we validate the feasibility of our proposed scheme via an implementation discussion. PMID- 28574456 TI - New Pinane Derivatives Found in Essential Oils of Calocedrus decurrens. AB - The main objective of this study was to determine the chemical composition of essential oils (EOs) obtained from leaf, old branches, and young branches of a coniferous species Calocedrus decurrens acclimated to Corsica. The analytical investigation was conducted by GC(RI), GC-MS, pc-GC, and NMR. C. decurrens leaf, old branches, and young branches EOs contained alpha-pinene (11.2; 56.6; 22.3%), myrcene (13.4; 8.4; 9.7%), Delta-3-carene (31.3; 5.2; 11.1%), limonene (6.4; 5.1; 5.5%), terpinolene (6.9; 1.5; 3.2%), and pin-2-en-8-ol (4.2; 4.5; 10.4%) as major components, respectively. Special attention was paid to purifying and identifying four unusual pinane derivatives: pin-2-en-8-ol, pin-2-en-8-yl Acetate, pin-2-en-8 al, and methyl pin-2-en-8-oate. The last two are reported for the first time. PMID- 28574458 TI - Computationally Efficient Direction Finding for a Mixture of Circular and Strictly Noncircular Sources with Uniform Rectangular Arrays. AB - In this paper, a novel two-dimensional (2D) direction-of-arrival (DOA) estimation algorithm for the mixed circular and strictly noncircular sources is proposed. A general array model with a mixture of signals is firstly built based on uniform rectangular arrays (URAs), and then, the approach, which uses the rank-reduction based ROOT-MUSIC, can solve 2D DOA estimation problem. Besides, the theoretical error of the proposed algorithm, a criterion of the performance for evaluation, is analyzed by the first-order Taylor expression using second-order statistics. As verified by the simulation results, a better DOA estimation performance and a lower computational complexity are achieved by the proposed algorithm than the existing methods resorting to the noncircularity of the incoming signals. PMID- 28574459 TI - Analysis and Validation of Contactless Time-Gated Interrogation Technique for Quartz Resonator Sensors. AB - A technique for contactless electromagnetic interrogation of AT-cut quartz piezoelectric resonator sensors is proposed based on a primary coil electromagnetically air-coupled to a secondary coil connected to the electrodes of the resonator. The interrogation technique periodically switches between interleaved excitation and detection phases. During the excitation phase, the resonator is set into vibration by a driving voltage applied to the primary coil, whereas in the detection phase, the excitation signal is turned off and the transient decaying response of the resonator is sensed without contact by measuring the voltage induced back across the primary coil. This approach ensures that the readout frequency of the sensor signal is to a first order approximation independent of the interrogation distance between the primary and secondary coils. A detailed theoretical analysis of the interrogation principle based on a lumped-element equivalent circuit is presented. The analysis has been experimentally validated on a 4.432 MHz AT-cut quartz crystal resonator, demonstrating the accurate readout of the series resonant frequency and quality factor over an interrogation distance of up to 2 cm. As an application, the technique has been applied to the measurement of liquid microdroplets deposited on a 4.8 MHz AT-cut quartz crystal. More generally, the proposed technique can be exploited for the measurement of any physical or chemical quantities affecting the resonant response of quartz resonator sensors. PMID- 28574460 TI - Towards Citizen Co-Created Public Service Apps. AB - WeLive project's main objective is about transforming the current e-government approach by providing a new paradigm based on a new open model oriented towards the design, production and deployment of public services and mobile apps based on the collaboration of different stakeholders. These stakeholders form the quadruple helix, i.e., citizens, private companies, research institutes and public administrations. Through the application of open innovation, open data and open services paradigms, the framework developed within the WeLive project enables the co-creation of urban apps. In this paper, we extend the description of the WeLive platform presented at , plus the preliminary results of the first pilot phase. The two-phase evaluation methodology designed and the evaluation results of first pilot sub-phase are also presented. PMID- 28574454 TI - Gene-Diet Interactions in Type 2 Diabetes: The Chicken and Egg Debate. AB - Consistent evidence from both experimental and human studies indicates that Type 2 diabetes mellitus (T2DM) is a complex disease resulting from the interaction of genetic, epigenetic, environmental, and lifestyle factors. Nutrients and dietary patterns are important environmental factors to consider in the prevention, development and treatment of this disease. Nutritional genomics focuses on the interaction between bioactive food components and the genome and includes studies of nutrigenetics, nutrigenomics and epigenetic modifications caused by nutrients. There is evidence supporting the existence of nutrient-gene and T2DM interactions coming from animal studies and family-based intervention studies. Moreover, many case-control, cohort, cross-sectional cohort studies and clinical trials have identified relationships between individual genetic load, diet and T2DM. Some of these studies were on a large scale. In addition, studies with animal models and human observational studies, in different countries over periods of time, support a causative relationship between adverse nutritional conditions during in utero development, persistent epigenetic changes and T2DM. This review provides comprehensive information on the current state of nutrient-gene interactions and their role in T2DM pathogenesis, the relationship between individual genetic load and diet, and the importance of epigenetic factors in influencing gene expression and defining the individual risk of T2DM. PMID- 28574461 TI - Innovative High-Throughput SAXS Methodologies Based on Photonic Lab-on-a-Chip Sensors: Application to Macromolecular Studies. AB - The relevance of coupling droplet-based Photonic Lab-on-a-Chip (PhLoC) platforms and Small-Angle X-Ray Scattering (SAXS) technique is here highlighted for the performance of high throughput investigations, related to the study of protein macromolecular interactions. With this configuration, minute amounts of sample are required to obtain reliable statistical data. The PhLoC platforms presented in this work are designed to allow and control an effective mixing of precise amounts of proteins, crystallization reagents and buffer in nanoliter volumes, and the subsequent generation of nanodroplets by means of a two-phase flow. Spectrophotometric sensing permits a fine control on droplet generation frequency and stability as well as on concentration conditions, and finally the droplet flow is synchronized to perform synchrotron radiation SAXS measurements in individual droplets (each one acting as an isolated microreactor) to probe protein interactions. With this configuration, droplet physic-chemical conditions can be reproducibly and finely tuned, and monitored without cross-contamination, allowing for the screening of a substantial number of saturation conditions with a small amount of biological material. The setup was tested and validated using lysozyme as a model of study. By means of SAXS experiments, the proteins gyration radius and structure envelope were calculated as a function of protein concentration. The obtained values were found to be in good agreement with previously reported data, but with a dramatic reduction of sample volume requirements compared to studies reported in the literature. PMID- 28574462 TI - A Study of 11-[3H]-Tetrodotoxin Absorption, Distribution, Metabolism and Excretion (ADME) in Adult Sprague-Dawley Rats. AB - Tetrodotoxin (TTX) is a powerful sodium channel blocker that in low doses can safely relieve severe pain. Studying the absorption, distribution, metabolism and excretion (ADME) of TTX is challenging given the extremely low lethal dose. We conducted radiolabeled ADME studies in Sprague-Dawley rats. After a single dose of 6 MUg/(16 MUCi/kg) 11-[3H]TTX, pharmacokinetics of plasma total radioactivity were similar in male and female rats. Maximum radioactivity (5.56 ng Eq./mL) was reached in 10 min. [3H]TTX was below detection in plasma after 24 h. The area under the curve from 0 to 8 h was 5.89 h.ng Eq./mL; mean residence time was 1.62 h and t1/2 was 2.31 h. Bile secretion accounted for 0.43% and approximately 51% of the dose was recovered in the urine, the predominant route of elimination. Approximately 69% was recovered, suggesting that hydrogen tritium exchange in rats produced tritiated water excreted in breath and saliva. Average total radioactivity in the stomach, lungs, kidney and intestines was higher than plasma concentrations. Metabolite analysis of plasma, urine and feces samples demonstrated oxidized TTX, the only identified metabolite. In conclusion, TTX was rapidly absorbed and excreted in rats, a standard preclinical model used to guide the design of clinical trials. PMID- 28574457 TI - Cyanobacterial Toxins of the Laurentian Great Lakes, Their Toxicological Effects, and Numerical Limits in Drinking Water. AB - Cyanobacteria are ubiquitous phototrophic bacteria that inhabit diverse environments across the planet. Seasonally, they dominate many eutrophic lakes impacted by excess nitrogen (N) and phosphorus (P) forming dense accumulations of biomass known as cyanobacterial harmful algal blooms or cyanoHABs. Their dominance in eutrophic lakes is attributed to a variety of unique adaptations including N and P concentrating mechanisms, N2 fixation, colony formation that inhibits predation, vertical movement via gas vesicles, and the production of toxic or otherwise bioactive molecules. While some of these molecules have been explored for their medicinal benefits, others are potent toxins harmful to humans, animals, and other wildlife known as cyanotoxins. In humans these cyanotoxins affect various tissues, including the liver, central and peripheral nervous system, kidneys, and reproductive organs among others. They induce acute effects at low doses in the parts-per-billion range and some are tumor promoters linked to chronic diseases such as liver and colorectal cancer. The occurrence of cyanoHABs and cyanotoxins in lakes presents challenges for maintaining safe recreational aquatic environments and the production of potable drinking water. CyanoHABs are a growing problem in the North American (Laurentian) Great Lakes basin. This review summarizes information on the occurrence of cyanoHABs in the Great Lakes, toxicological effects of cyanotoxins, and appropriate numerical limits on cyanotoxins in finished drinking water. PMID- 28574463 TI - Characterization of Aliphatic Polyesters Synthesized via Enzymatic Ring-Opening Polymerization in Ionic Liquids. AB - To evaluate the effects of ionic liquids (ILs) on the microstructural features of aliphatic polyesters for biomedical applications, a series of copolymers were synthesized by lipase ring opening polymerization of rac-lactide (rac-LA) and epsilon-caprolactone (CL). The chemical structures of resulting polymers were characterized by 1H- and 13C-NMR and the average molecular weight (Mn) and dispersity index were characterized by gel permeation chromatography. The structure of the copolymers confirms the presence of linear polymer chains with end-functional hydroxyl groups allowing covalent coupling of the therapeutic agents. Chain microstructure of copolymers indicates the presence of both random and block copolymers depending on the synthesis conditions. Moreover, it was found that CL is the most active co-monomer during copolymerization which enhances the polymerizability of rac-LA and allows to obtain higher Mn of the copolymers. The results demonstrate that ILs could be promising solvents in synthesis of aliphatic esters for biomedical applications. PMID- 28574464 TI - Interventions Aimed at the Prevention of Childhood Injuries in the Indigenous Populations in Canada, Australia and New Zealand in the Last 20 Years: A Systematic Review. AB - Globally, Indigenous children are found to be at a significantly higher risk of injury compared to non-Indigenous children. It has been suggested that mainstream injury prevention strategies are ineffective within Indigenous communities. The aim of this review is to identify existing interventions aimed at preventing injury in Indigenous children in the hope that it guides future strategies. To the best of the authors' knowledge, no prior systematic reviews exist looking at interventions specifically aimed at preventing injury in Indigenous child populations in the three chosen countries. Electronic databases were systematically searched for relevant childhood interventions aimed at the prevention of injuries in Indigenous populations based in Canada, Australia and New Zealand from 1996 to 2016. A manual search of the reference lists of relevant articles and a manual search of relevant websites were also completed. After 191 records were screened, six interventions were identified meeting the criteria for inclusion. Eligible papers underwent a quality appraisal using adapted assessment checklists and key information was extracted. Findings were then synthesized using a narrative approach. The interventions mainly promoted child safety through activities focusing on education and awareness. Only three of the six studies measured changes in injury hospitalization rates, all but one evaluation reporting a significant decrease. Studies which measured awareness all demonstrated positive changes. Results suggest that interventions delivered in a culturally appropriate manner acted as a main success factor. Barriers identified as hindering intervention success included lack of cohesion within the intervention due to staff turnover and lack of experienced staff with Indigenous knowledge. This review revealed a limited amount of evaluated interventions for the prevention of Indigenous childhood injuries. Conclusive evidence of the effectiveness of existing interventions is lacking due to the predominantly small scale evaluations of pilot interventions. Future research is needed to provide more rigorous evidence of the mechanisms driving the successful implementation, delivery and uptake of such strategies tailored to Indigenous children. PMID- 28574465 TI - Trap-Neuter-Return Activities in Urban Stray Cat Colonies in Australia. AB - Trap, neuter and return (TNR) describes a non-lethal approach to the control of urban stray cat populations. Currently, in Australia, lethal control is common, with over 85% of cats entering some municipal pounds euthanized. No research has been published describing TNR activities in Australia. Adults involved with TNR in Australia were invited to participate. Data from 53 respondents were collected via an anonymous online questionnaire. Most respondents were females 36 to 65 years of age, and slightly more participated in TNR as individuals than as part of an organization. Respondents generally self-funded at least some of their TNR activities. The median number of colonies per respondent was 1.5 (range 1 to over 100). Median colony size declined from 11.5 to 6.5 cats under TNR over a median of 2.2 years, and the median percent reduction was 31%; this was achieved by rehoming cats and kittens and reducing reproduction. A median of 69% of cats in each colony were desexed at the time of reporting. Most respondents fed cats once or twice daily, and at least 28% of respondents microchipped cats. Prophylactic healthcare was provided to adult cats and kittens, commonly for intestinal parasites (at least 49%), and fleas (at least 46%); vaccinations were less common. Time-consuming activities for respondents were feeding (median 4 h/week) and locating resources (median 1.1 h/week). These findings indicate that TNR, when involving high desexing rates within colonies, adoption of kittens and friendly adults, and ongoing oversight by volunteer caretakers, can reduce cat numbers over time, improve health and welfare of cats and kittens, and is largely funded by private individuals and organizations. PMID- 28574466 TI - A Robust 96.6-dB-SNDR 50-kHz-Bandwidth Switched-Capacitor Delta-Sigma Modulator for IR Imagers in Space Instrumentation. AB - Infrared imaging technology, used both to study deep-space bodies' radiation and environmental changes on Earth, experienced constant improvements in the last few years, pushing data converter designers to face new challenges in terms of speed, power consumption and robustness against extremely harsh operating conditions. This paper presents a 96.6-dB-SNDR (Signal-to-Noise-plus-Distortion Ratio) 50-kHz bandwidth fourth-order single-bit switched-capacitor delta-sigma modulator for ADC operating at 1.8 V and consuming 7.9 mW fit for space instrumentation. The circuit features novel Class-AB single-stage switched variable-mirror amplifiers (SVMAs) enabling low-power operation, as well as low sensitivity to both process and temperature deviations for the whole modulator. The physical implementation resulted in a 1.8-mm2 chip integrated in a standard 0.18-um 1-poly-6-metal (1P6M) CMOS technology, and it reaches a 164.6-dB Schreier figure of merit from experimental SNDR measurements without making use of any clock bootstrapping,analogcalibration,nordigitalcompensationtechnique. Whencoupledtoa2048*2048 IR imager, the current design allows more than 50 frames per minute with a resolution of 16 effective number of bits (ENOB) while consuming less than 300 mW. PMID- 28574467 TI - Research and Analysis on the Localization of a 3-D Single Source in Lossy Medium Using Uniform Circular Array. AB - In this paper, the methods and analysis for estimating the location of a three dimensional (3-D) single source buried in lossy medium are presented with uniform circular array (UCA). The mathematical model of the signal in the lossy medium is proposed. Using information in the covariance matrix obtained by the sensors' outputs, equations of the source location (azimuth angle, elevation angle, and range) are obtained. Then, the phase and amplitude of the covariance matrix function are used to process the source localization in the lossy medium. By analyzing the characteristics of the proposed methods and the multiple signal classification (MUSIC) method, the computational complexity and the valid scope of these methods are given. From the results, whether the loss is known or not, we can choose the best method for processing the issues (localization in lossless medium or lossy medium). PMID- 28574468 TI - Indoor Trajectory Tracking Scheme Based on Delaunay Triangulation and Heuristic Information in Wireless Sensor Networks. AB - Object tracking and detection is one of the most significant research areas for wireless sensor networks. Existing indoor trajectory tracking schemes in wireless sensor networks are based on continuous localization and moving object data mining. Indoor trajectory tracking based on the received signal strength indicator (RSSI) has received increased attention because it has low cost and requires no special infrastructure. However, RSSI tracking introduces uncertainty because of the inaccuracies of measurement instruments and the irregularities (unstable, multipath, diffraction) of wireless signal transmissions in indoor environments. Heuristic information includes some key factors for trajectory tracking procedures. This paper proposes a novel trajectory tracking scheme based on Delaunay triangulation and heuristic information (TTDH). In this scheme, the entire field is divided into a series of triangular regions. The common side of adjacent triangular regions is regarded as a regional boundary. Our scheme detects heuristic information related to a moving object's trajectory, including boundaries and triangular regions. Then, the trajectory is formed by means of a dynamic time-warping position-fingerprint-matching algorithm with heuristic information constraints. Field experiments show that the average error distance of our scheme is less than 1.5 m, and that error does not accumulate among the regions. PMID- 28574469 TI - Fluorometric Index for Sensing Oil in the Sea Environment. AB - Excitation-emission matrix spectroscopy (EEMS) was applied to determine the fluorometric index (FI) as a parameter indicating the presence of a source of oil pollution in a specific area of the sea. Seawater from the Polish coast (the Baltic Sea) and the same water combined with various amounts of crude oil extracted from the Baltic Sea shelf (Petrobaltic-type oil) were used in this study. The FI values were calculated for excitation and emission wavelengths found at the maximal peak, taking into account the natural seawater and the seawater artificially contaminated (for an oil-to-water ratio range of 0.5 * 10-6 - 500 * 10-6). The wavelength configurations (Ex/Em) (225/355 and 225/340) for the FI index were applied. It was found that, independent of the amount of oil, the FI achieves a higher value for natural seawater than for seawater that has had contact with oil. These results provide the basis to design a sensor signaling the appearance of oil in a defined sea area. PMID- 28574471 TI - A Map/INS/Wi-Fi Integrated System for Indoor Location-Based Service Applications. AB - In this research, a new Map/INS/Wi-Fi integrated system for indoor location-based service (LBS) applications based on a cascaded Particle/Kalman filter framework structure is proposed. Two-dimension indoor map information, together with measurements from an inertial measurement unit (IMU) and Received Signal Strength Indicator (RSSI) value, are integrated for estimating positioning information. The main challenge of this research is how to make effective use of various measurements that complement each other in order to obtain an accurate, continuous, and low-cost position solution without increasing the computational burden of the system. Therefore, to eliminate the cumulative drift caused by low cost IMU sensor errors, the ubiquitous Wi-Fi signal and non-holonomic constraints are rationally used to correct the IMU-derived navigation solution through the extended Kalman Filter (EKF). Moreover, the map-aiding method and map-matching method are innovatively combined to constrain the primary Wi-Fi/IMU-derived position through an Auxiliary Value Particle Filter (AVPF). Different sources of information are incorporated through a cascaded structure EKF/AVPF filter algorithm. Indoor tests show that the proposed method can effectively reduce the accumulation of positioning errors of a stand-alone Inertial Navigation System (INS), and provide a stable, continuous and reliable indoor location service. PMID- 28574472 TI - Investigation of Azimuth Multichannel Reconstruction for Moving Targets in High Resolution Wide Swath SAR. AB - The azimuth multichannel imaging scheme with the large receive antenna divided into multiple sub-apertures usually leads to azimuth non-uniform sampling, and echoes from all azimuth channels should be reconstructed based on the signal model before conventional SAR imaging. Unfortunately, the multichannel signal model of a moving target is different from that of a fixed target. This paper analyzes the multichannel signal model of the moving target and the effect of the target velocity on azimuth multichannel reconstruction. Based on the multichannel signal mode of the moving target, a new multichannel signal reconstruction algorithm is proposed. Furthermore, the slant range velocity is estimated by computing signal energy distribution. Simulation results on point targets validate the proposed approach. PMID- 28574470 TI - An Overview of Structurally Modified Glycyrrhetinic Acid Derivatives as Antitumor Agents. AB - Glycyrrhetinic Acid (GA), a triterpenoid aglycone component of the natural product glycyrrhizinic acid, was found to possess remarkable anti-proliferative and apoptosis-inducing activity in various cancer cell lines. Though GA was not as active as other triterpenes, such as betulinic acid and oleanolic acid, it could trigger apoptosis in tumor cells and it can be obtained easily and cheaply, which has stimulated scientific interest in using GA as a scaffold to synthesize new antitumor agents. The structural modifications of GA reported in recent decades can be divided into four groups, which include structural modifications on ring-A, ring-C, ring-E and multiple ring modifications. The lack of a comprehensive and recent review on this topic prompted us to gather more new information. This overview is dedicated to summarizing and updating the structural modification of GA to improve its antitumor activity published between 2005 and 2016. We reviewed a total of 210 GA derivatives that we encountered and compiled the most active GA derivatives along with their activity profile in different series. Furthermore, the structure activity relationships of these derivatives are briefly discussed. The included information is expected to be of benefit to further studies of structural modifications of GA to enhance its antitumor activity. PMID- 28574473 TI - Phytochemical Quantification and the In Vitro Acetylcholinesterase Inhibitory Activity of Phellodendron chinense and Its Components. AB - The dried bark of Phellodendron chinense has been used as a traditional herbal medicine to remove damp heat, relieve consumptive fever, and cure dysentery and diarrhea. In the present study, we performed quantitative analyses of the two components of P. chinense, phellodendrine and berberine, using high-performance liquid chromatography. A 70% ethanol extract of P. chinense was prepared and the two components were separated on a C-18 analytical column using a gradient solvent system of acetonitrile and 0.1% (v/v) aqueous trifluoroacetic acid. The ultraviolet wavelength used for detection was 200 nm for phellodendrine and 226 nm for berberine. The analytical method established here showed high linearity (correlation coefficient, >=0.9991). The amount of phellodendrine and berberine used was 22.255 +/- 0.123 mg/g and 269.651 +/- 1.257 mg/g, respectively. Moreover, we performed an in vitro acetylcholinesterase (AChE) activity assay and an amyloid-beta aggregation test to examine the biological properties of phellodendrine and berberine as therapeutic drugs for Alzheimer's disease. Phellodendrine and berberine inhibited AChE activity in a dose-dependent manner (IC50 = 36.51 and 0.44 MUM, respectively). In contrast, neither phellodendrine nor berberine had an effect on amyloid-beta aggregation. The P. chinense extract and phellodendrine, but not berberine, exhibited antioxidant activity by increasing radical scavenging activity. Moreover, P. chinense demonstrated a neuroprotective effect in hydrogen peroxide-treated HT22 hippocampal cells. Overall, our findings suggest that P. chinense has potential as an anti Alzheimer's agent via the suppression of the enzymatic activity of acetylcholinesterase and the stimulation of antioxidant activity. PMID- 28574474 TI - A LiDAR and IMU Integrated Indoor Navigation System for UAVs and Its Application in Real-Time Pipeline Classification. AB - Mapping the environment of a vehicle and localizing a vehicle within that unknown environment are complex issues. Although many approaches based on various types of sensory inputs and computational concepts have been successfully utilized for ground robot localization, there is difficulty in localizing an unmanned aerial vehicle (UAV) due to variation in altitude and motion dynamics. This paper proposes a robust and efficient indoor mapping and localization solution for a UAV integrated with low-cost Light Detection and Ranging (LiDAR) and Inertial Measurement Unit (IMU) sensors. Considering the advantage of the typical geometric structure of indoor environments, the planar position of UAVs can be efficiently calculated from a point-to-point scan matching algorithm using measurements from a horizontally scanning primary LiDAR. The altitude of the UAV with respect to the floor can be estimated accurately using a vertically scanning secondary LiDAR scanner, which is mounted orthogonally to the primary LiDAR. Furthermore, a Kalman filter is used to derive the 3D position by fusing primary and secondary LiDAR data. Additionally, this work presents a novel method for its application in the real-time classification of a pipeline in an indoor map by integrating the proposed navigation approach. Classification of the pipeline is based on the pipe radius estimation considering the region of interest (ROI) and the typical angle. The ROI is selected by finding the nearest neighbors of the selected seed point in the pipeline point cloud, and the typical angle is estimated with the directional histogram. Experimental results are provided to determine the feasibility of the proposed navigation system and its integration with real-time application in industrial plant engineering. PMID- 28574476 TI - Parameters for Fabricating Nano-Au Colloids through the Electric Spark Discharge Method with Micro-Electrical Discharge Machining. AB - In this study, the Electric Spark Discharge Method (ESDM) was employed with micro electrical discharge machining (m-EDM) to create an electric arc that melted two electrodes in deionized water (DW) and fabricated nano-Au colloids through pulse discharges with a controlled on-off duration (TON-TOFF) and a total fabrication time of 1 min. A total of six on-off settings were tested under normal experimental conditions and without the addition of any chemical substances. Ultraviolet-visible spectroscopy (UV-Vis), Zetasizer Nano measurements, and scanning electron microscopy-energy dispersive X-ray (SEM-EDX) analyses suggested that the nano-Au colloid fabricated at 10-10 us (10 us on, 10 us off) had higher concentration and suspension stability than products made at other TON-TOFF settings. The surface plasmon resonance (SPR) of the colloid was 549 nm on the first day of fabrication and stabilized at 532 nm on the third day. As the TON TOFF period increased, the absorbance (i.e., concentration) of all nano-Au colloids decreased. Absorbance was highest at 10-10 us. The SPR peaks stabilized at 532 nm across all TON-TOFF periods. The Zeta potential at 10-10 us was -36.6 mV, indicating that no nano-Au agglomeration occurred and that the particles had high suspension stability. PMID- 28574475 TI - Feeding a Mixture of Choline Forms to Lactating Dams Improves the Development of the Immune System in Sprague-Dawley Rat Offspring. AB - Dietary choline is essential during lactation, but few studies have examined the implications of feeding a mixture of choline forms on immune function. This study investigates the impact of feeding lactating dams different mixtures of choline forms, similar to those in human diets, on the development and later immune function of suckled offspring. Sprague-Dawley lactating dams (n = 6/diet) were randomized to consume one of three diets, containing 1 g/kg choline: Control (100% free choline (FC)), Mixed Choline (MC: 50% phosphatidylcholine (PC), 25% FC, 25% glycerophosphocholine (GPC)), or High GPC (HGPC: 75% GPC, 12.5% PC, 12.5% FC). At weaning, female pups (n = 2/dam) were fed the Control diet until 10 weeks. At 3 weeks, MC and HGPC pups were heavier and their splenocytes had a higher proportion of helper T cells expressing CD25 and CD28 and produced less interferon gamma (IFN-gamma) and tumor-necrosis factor-alpha (TNF-alpha) after Concanavalin A stimulation vs. Control pups (p < 0.05). At 10 weeks, MC and HGPC offspring had a lower proportion of macrophages and dendritic cells and produced less interleukin (IL)-1beta but more IL-10 after lipopolysaccharide stimulation vs. Control pups (p < 0.05). In summary, feeding mixed choline diets during lactation improved T cell phenotype/function at the end of suckling and programmed a less inflammatory response later in life. PMID- 28574478 TI - Toxoplasma Gondii Moderates the Association between Multiple Folate-Cycle Factors and Cognitive Function in U.S. Adults. AB - Toxoplasma gondii (T. gondii) is a microscopic, apicomplexan parasite that can infect muscle or neural tissue, including the brain, in humans. While T. gondii infection has been associated with changes in mood, behavior, and cognition, the mechanism remains unclear. Recent evidence suggests that T. gondii may harvest folate from host neural cells. Reduced folate availability is associated with an increased risk of neurodevelopmental disorders, neurodegenerative diseases, and cognitive decline. We hypothesized that impairment in cognitive functioning in subjects seropositive for T. gondii might be associated with a reduction of folate availability in neural cells. We analyzed data from the third National Health and Nutrition Examination Survey to determine the associations between T. gondii infection, multiple folate-cycle factors, and three tests of cognitive functioning in U.S. adults aged 20 to 59 years. In these analyses, T. gondii moderated the associations of folate, vitamin B-12, and homocysteine with performance on the Serial Digit Learning task, a measure of learning and memory, as well as the association of folate with reaction time. The results of this study suggest that T. gondii might affect brain levels of folate and/or vitamin B 12 enough to affect cognitive functioning. PMID- 28574479 TI - R Loops in the Regulation of Antibody Gene Diversification. AB - For nearly three decades, R loops have been closely linked with class switch recombination (CSR), the process that generates antibody isotypes and that occurs via a complex cascade initiated by transcription-coupled mutagenesis in switch recombination sequences. R loops form during transcription of switch recombination sequences in vitro and in vivo, and there is solid evidence that R loops are required for efficient class switching. The classical model of R loops posits that they boost mutation rates by generating stable and long tracts of single-stranded DNA that serve as the substrate for activation induced deaminase (AID), the enzyme that initiates the CSR reaction cascade by co-transcriptionally mutating ssDNA in switch recombination sequences. Though logical and compelling, this model has not been supported by in vivo evidence. Indeed, several reports suggest that R loops may not be involved in recruiting AID activity to switch regions, meaning that R loops probably serve other unanticipated roles in CSR. Here, I review the key findings in this field to date and propose hypotheses that could help towards elucidating the precise function of R loops in CSR. PMID- 28574480 TI - Ethnic Groups Differences in Domestic Recovery after the Catastrophe: A Case Study of the 2008 Magnitude 7.9 Earthquake in China. AB - This research examined the ethnic differences in domestic recovery after the 2008 Wenchuan Earthquake in China. In 2014, 866 valid questionnaires were collected. Han and Qiang & Zang households were analyzed using logistic regression to determine the factors influencing household recovery. It was found that the householder of the Qiang & Zang group played a more important role in household recovery. Different from the Han, females from Qiang & Zang households had negative attitudes on recovery, and Qiang & Zang households did not believe in the effectiveness of public donations for post-quake recovery. The study also showed that local workers in a household were more helpful for household recovery than were migrant workers in a household, regardless of ethnicity. Therefore, the government should create more local jobs in Han and Qiang & Zang households and pay more attention to women in Qiang households. Assistance should be established specifically for the psychological recovery of Qiang women and family recovery projects. PMID- 28574477 TI - Utilizing Zebrafish Visual Behaviors in Drug Screening for Retinal Degeneration. AB - Zebrafish are a popular vertebrate model in drug discovery. They produce a large number of small and rapidly-developing embryos. These embryos display rich visual behaviors that can be used to screen drugs for treating retinal degeneration (RD). RD comprises blinding diseases such as Retinitis Pigmentosa, which affects 1 in 4000 people. This disease has no definitive cure, emphasizing an urgency to identify new drugs. In this review, we will discuss advantages, challenges, and research developments in using zebrafish behaviors to screen drugs in vivo. We will specifically discuss a visual-motor response that can potentially expedite discovery of new RD drugs. PMID- 28574481 TI - Leucine Supplementation Differently Modulates Branched-Chain Amino Acid Catabolism, Mitochondrial Function and Metabolic Profiles at the Different Stage of Insulin Resistance in Rats on High-Fat Diet. AB - The available findings concerning the association between branched-chain amino acids (BCAAs)-particularly leucine-and insulin resistance are conflicting. BCAAs have been proposed to elicit different or even opposite effects, depending on the prevalence of catabolic and anabolic states. We tested the hypothesis that leucine supplementation may exert different effects at different stages of insulin resistance, to provide mechanistic insights into the role of leucine in the progression of insulin resistance. Male Sprague-Dawley rats were fed a normal chow diet, high-fat diet (HFD), HFD supplemented with 1.5% leucine, or HFD with a 20% calorie restriction for 24 or 32 weeks. Leucine supplementation led to abnormal catabolism of BCAA and the incompletely oxidized lipid species that contributed to mitochondrial dysfunction in skeletal muscle in HFD-fed rats in the early stage of insulin resistance (24 weeks). However, leucine supplementation induced no remarkable alternations in BCAA catabolism, but did enhance mitochondrial biogenesis with a concomitant improvement in lipid oxidation and mitochondrial function during the hyperglycaemia stage (32 weeks). These findings suggest that leucine trigger different effects on metabolic signatures at different stages of insulin resistance, and the overall metabolic status of the organisms should be carefully considered to potentiate the benefits of leucine. PMID- 28574483 TI - Expression Profiling of Strawberry Allergen Fra a during Fruit Ripening Controlled by Exogenous Auxin. AB - Strawberry fruit contain the allergenic Fra a proteins, members of the pathogenesis-related 10 protein family that causes oral allergic syndrome symptoms. Fra a proteins are involved in the flavonoid biosynthesis pathway, which might be important for color development in fruits. Auxin is an important plant hormone in strawberry fruit that controls fruit fleshiness and ripening. In this study, we treated strawberry fruits with exogenous auxin or auxin inhibitors at pre- and post-harvest stages, and analyzed Fra a transcriptional and translational expression levels during fruit development by real-time PCR and immunoblotting. Pre-harvest treatment with 1-naphthaleneacetic acid (NAA) alone did not affect Fra a expression, but applied in conjunction with achene removal NAA promoted fruit pigmentation and Fra a protein accumulation. The response was developmental stage-specific: Fra a 1 was highly expressed in immature fruit, whereas Fra a 2 was expressed in young to ripe fruit. In post-harvest treatments, auxin did not contribute to Fra a induction. Auxin inhibitors delayed fruit ripening; as a result, they seemed to influence Fra a 1 expression. Thus, Fra a expression was not directly regulated by auxin, but might be associated with the ripening process and/or external factors in a paralog-specific manner. PMID- 28574482 TI - Immunologic and Virologic Mechanisms for Partial Protection from Intravenous Challenge by an Integration-Defective SIV Vaccine. AB - The suppression of viral loads and identification of selection signatures in non human primates after challenge are indicators for effective human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) vaccines. To mimic the protective immunity elicited by attenuated SIV vaccines, we developed an integration-defective SIV (idSIV) vaccine by inactivating integrase, mutating sequence motifs critical for integration, and inserting the cytomegalovirus (CMV) promoter for more efficient expression in the SIVmac239 genome. Chinese rhesus macaques were immunized with idSIV DNA and idSIV particles, and the cellular and humoral immune responses were measured. After the intravenous SIVmac239 challenge, viral loads were monitored and selection signatures in viral genomes from vaccinated monkeys were identified by single genome sequencing. T cell responses, heterologous neutralization against tier-1 viruses, and antibody dependent cellular cytotoxicity (ADCC) were detected in idSIV-vaccinated macaques post immunization. After challenge, the median peak viral load in the vaccine group was significantly lower than that in the control group. However, this initial viral control did not last as viral set-points were similar between vaccinated and control animals. Selection signatures were identified in Nef, Gag, and Env proteins in vaccinated and control macaques, but these signatures were different, suggesting selection pressure on viruses from vaccine-induced immunity in the vaccinated animals. Our results showed that the idSIV vaccine exerted some pressure on the virus population early during the infection but future modifications are needed in order to induce more potent immune responses. PMID- 28574486 TI - Magnetoelectric Current Sensors. AB - In this work a magnetoelectric (ME) current sensor design based on a magnetoelectric effect is presented and discussed. The resonant and non-resonant type of ME current sensors are considered. Theoretical calculations of the ME current sensors by the equivalent circuit method were conducted. The application of different sensors using the new effects, for example, the ME effect, is made possible with the development of new ME composites. A large number of studies conducted in the field of new composites, allowed us to obtain a high magnetostrictive-piezoelectric laminate sensitivity. An optimal ME structure composition was matched. The characterization of a non-resonant current sensor showed that in the operation range to 5 A, the sensor had a sensitivity of 0.34 V/A, non-linearity less than 1% and for a resonant current sensor in the same operation range, the sensitivity was of 0.53 V/A, non-linearity less than 0.5%. PMID- 28574485 TI - Daucosterol Inhibits the Proliferation, Migration, and Invasion of Hepatocellular Carcinoma Cells via Wnt/beta-Catenin Signaling. AB - Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The purpose of this study was to determine the effects of daucosterol on HCC by investigating Wnt/beta-catenin signaling. In this study, HepG2 and SMMC-7721 cells were treated with varying concentrations of daucosterol, and the corresponding inhibitory effects on HCC cells were examined via CCK-8 assays. Cell migration and invasion abilities were detected via transwell assays. beta-Catenin and phospho (p)-beta-catenin levels were analyzed via western blotting. Our results showed that daucosterol reduced the proliferation, migration, and invasion capacities of HCC cells in a concentration dependent manner. In addition, daucosterol reduced the levels of beta-catenin and p-beta-catenin in HepG2 and SMMC-7721 cells. Furthermore, the Wnt signaling pathway inhibitor SB-216763 was used to treat HepG2 and SMMC-7721 cells with daucosterol. Our results showed that co-treatment with daucosterol and SB-216763 abolished the effects of daucosterol on cell inhibition ratios, cell migration, and cell invasion. These findings indicated that daucosterol inhibited cell migration and invasion in HCC cells via the Wnt/beta-catenin signaling pathway. Therefore, our study highlights the use of daucosterol as a promising therapeutic strategy for HCC treatment. PMID- 28574484 TI - Seabuckthorn Leaves Extract and Flavonoid Glycosides Extract from Seabuckthorn Leaves Ameliorates Adiposity, Hepatic Steatosis, Insulin Resistance, and Inflammation in Diet-Induced Obesity. AB - The aim of the current study was to elucidate the effect of seabuckthorn leaves (SL) extract and flavonoid glycosides extract from seabuckthorn leaves (SLG) on diet-induced obesity and related metabolic disturbances, and additionally, to identify whether flavonoid glycosides and other components in SL can exert a possible interaction for the prevention of metabolic diseases by comparing the effect of SL and SLG. C57BL/6J mice were fed a normal diet (ND, AIN-93G purified diet), high-fat diet (HFD, 60 kcal% fat), HFD + 1.8% (w/w) SL (SL), and HFD + 0.04% (w/w) SLG (SLG) for 12 weeks. In high fat-fed mice, SL and SLG decreased the adiposity by suppressing lipogenesis in adipose tissue, while increasing the energy expenditure. SL and SLG also improved hepatic steatosis by suppressing hepatic lipogenesis and lipid absorption, whilst also enhancing hepatic fatty acid oxidation, which may be linked to the improvement in dyslipidemia. Moreover, SL and SLG improved insulin sensitivity by suppressing the levels of plasma GIP that were modulated by secreted resistin and pro-inflammatory cytokine, and hepatic glucogenic enzyme activities. SL, especially its flavonoid glycosides (SLG), can protect against the deleterious effects of diet-induced obesity (DIO) and its metabolic complications such as adiposity, dyslipidemia, inflammation, hepatic steatosis, and insulin resistance. PMID- 28574487 TI - CD123 target validation and preclinical evaluation of ADCC activity of anti-CD123 antibody CSL362 in combination with NKs from AML patients in remission. AB - Despite the heterogeneity of acute myeloid leukemia (AML), overexpression of the interleukin-3 receptor-alpha (CD123) on both the more differentiated leukemic blast and leukemic stem cells (LSCs) provides a therapeutic target for antibody treatment. Here we present data on the potential clinical activity of the monoclonal antibody CSL362, which binds to CD123 with high affinity. We first validated the expression of CD123 by 100% (52/52) of patient samples and the correlation of NPM1 and FLT3-ITD mutations with the high frequency of CD123 in AML. In vitro studies demonstrated that CSL362 potently induced antibody dependent cell cytotoxicity (ADCC) of AML blasts including CD34+CD38-CD123+ LSCs by natural killer cells (NKs). Importantly, compared with healthy donor (HD) NKs, NKs drawn from AML patients in remission had a comparable ADCC activity against leukemic cells; of note, during remission, immature NKs were five times higher in AML patients than that in HDs. Significantly, we report a case where leukemic cells were resistant to autologous ADCC; however, the blasts were effectively lysed by CSL362 together with donor-derived NKs after allogeneic hematopoietic stem cell transplantation. These studies highlight CSL362 as a promising therapeutic option following chemotherapy and transplant so as to improve the outcome of AML patients. PMID- 28574489 TI - Systematic comparison of donor chimerism in peripheral blood and bone marrow after hematopoietic stem cell transplantation. PMID- 28574488 TI - Maintenance therapy with alternating azacitidine and lenalidomide in elderly fit patients with poor prognosis acute myeloid leukemia: a phase II multicentre FILO trial. PMID- 28574492 TI - Functional and anatomical outcomes of punctoplasty with Kelly punch. PMID- 28574493 TI - Agreement in central corneal thickness measurements between optical and ultrasound pachymeters in patients with primary congenital glaucoma. PMID- 28574491 TI - Atrophy of retinal inner layers is associated with poor vision after endophthalmitis: a spectral domain optical coherence tomography study. AB - PurposeTo investigate the retinal structural changes in endophthalmitis and their association with visual outcome.Patients and methodsForty-five eyes of 45 patients diagnosed with endophthalmitis were included. Spectral domain optical coherence tomography (SD-OCT) was performed after inflammation was controlled. The relationship between SD-OCT features and best-corrected visual acuity (BCVA) at the last follow-up was analyzed.ResultsThe structural changes included inner segment ellipsoid (ISe) disruption (49%), atrophy of retinal inner layers (24%), epimacular membrane (24%), and macular edema (24%). BCVA was worse in patients with ISe disruption (P=0.005) and retinal inner layers' atrophy (P=0.004) compared with those without. There was no significant difference of BCVA between the patients with and without epimacular membrane, or intraretinal cysts. Multivariate regression showed that atrophy of retinal inner layers (b=0.41+/ 0.17, P=0.022) was the only independent factor associated with BCVA.ConclusionAtrophy of retinal inner layers is associated with visual impairment in endophthalmitis, despite successful management. PMID- 28574490 TI - Capturing the genetic makeup of the active microbiome in situ. AB - More than any other technology, nucleic acid sequencing has enabled microbial ecology studies to be complemented with the data volumes necessary to capture the extent of microbial diversity and dynamics in a wide range of environments. In order to truly understand and predict environmental processes, however, the distinction between active, inactive and dead microbial cells is critical. Also, experimental designs need to be sensitive toward varying population complexity and activity, and temporal as well as spatial scales of process rates. There are a number of approaches, including single-cell techniques, which were designed to study in situ microbial activity and that have been successively coupled to nucleic acid sequencing. The exciting new discoveries regarding in situ microbial activity provide evidence that future microbial ecology studies will indispensably rely on techniques that specifically capture members of the microbiome active in the environment. Herein, we review those currently used activity-based approaches that can be directly linked to shotgun nucleic acid sequencing, evaluate their relevance to ecology studies, and discuss future directions. PMID- 28574494 TI - Aqueous humor pentraxin-3 levels in patients with diabetes mellitus. AB - PurposeTo evaluate aqueous humor (AH) pentraxin-3 (PTX3) levels in diabetic patients with and without diabetic retinopathy (DR).MethodsIn this prospective study, patients undergoing cataract surgery were enrolled. The study group was composed of 26 type-2 diabetic patients without DR (group 1), 32 diabetic patients with DR (group 2) and 29 age-matched subjects without any systemic disease (group 3). Fifteen proliferative DR (PDR) and 17 non-proliferative DR (NPDR) patients were enrolled in Group 2. HbA1c levels and duration of diabetes were noted. AH samples were obtained from anterior chamber at the beginning of cataract surgery and PTX3 levels were analyzed with Elisa kit.ResultsBaseline demographic characteristics were similar between groups. The mean duration of diabetes was 11.9+/-7.9 years in group 1 and 15.8+/-7.8 years in group 2 (P=0.11). The mean plasma HbA1c levels in group 1 was 9.1+/-2.6 and 8.2+/-2.4 in group 2 (P=0.36). PTX3 levels were 5.75+/-0.41 in group 1, 6.11+/-1.47 in group 2 and 4.93+/-0.84 ng/ml in group 3 (P=0.01). PTX3 levels in group 2 were higher than in group 1 and 3 (P=0.06 and P=0.01, respectively). There was no correlation between HbA1c and PTX3 levels (P=0.06 r=0.57, P=0.19 r=0.3, respectively). The mean PTX3 was 6.6+/-0.3 in PDR group and 5.6+/-0.5 ng/ml in NPDR group (P=0.04).ConclusionsPTX3 is an important marker especially for vascular endothelial damage. Since diabetic vascular changes are dependent on endothelial cell damage, high levels of AH PTX3 of DR patients may indicate the importance of PTX3 protein in the pathogenesis of DR. PMID- 28574495 TI - Black patients sustain vision loss while White and South Asian patients gain vision following delamination or segmentation surgery for tractional complications associated with proliferative diabetic retinopathy. AB - PurposeThis retrospective comparative case series aims to determine whether patient ethnicity (White versus South Asian versus Black) is related to the outcome of surgical treatment for traction complications of severe proliferative diabetic retinopathy (PDR).SettingMoorfields Eye Hospital London, UK.MethodsAll patients who underwent vitrectomy with, delamination and/or segmentation for PDR over a 5-year period (2009-2014) were reviewed retrospectively. Patients were divided into White, South Asian or Black groups, and their age, gender, HbA1C and type of diabetes were recorded. A total of 484 patients (253 White, 117 South Asian, 114 Black) were included. Twenty-one patients were excluded due to inadequate documentation.OutcomesLogMAR Visual acuity (converted from Snellen) (VA), was recorded pre-operatively and ~6 months post surgery (range 5-8 months). Surgical outcome was classified according to the type and duration of tamponade required post-operatively.ResultsPre-operative VA and HbA1C values were similar across all three ethnic groups (P=0.64 and 0.569, respectively). Change in VA (mean+/-SD) was 0.41+/-0.78, 0.14+/-0.76 and -0.26+/-0.57 in White, South Asian and Black patient groups respectively (P<0.001). Multiple regression analysis showed that post-op VA was significantly related to race and pre-op VA only (both P<0.001). The Black patient group were more likely to require silicone oil tamponade (P<0.001) and long-term retention of silicone oil (P<0.001) than the White and South Asian patient groups.ConclusionsThis study demonstrates that Black patients on average lose vision following delamination surgery for traction complications of PDR while White and South Asian patients gain vision. The same group is also at higher risk of retaining silicone more than 6 months after surgery. This difference remains even when corrected for glycaemic control. The higher risk of visual loss and long-term retention of silicone oil in black patients requires further investigation. If these results are confirmed, surgeons should consider their patients' ethnicity before proceeding with surgical treatment of diabetic tractional detachment. PMID- 28574497 TI - Stepping into the virtual unknown: feasibility study of a virtual reality-based test of ocular misalignment. AB - IntroductionDissociated tests of strabismus provide valuable information for diagnosis and monitoring of ocular misalignment in patients with normal retinal correspondence. However, they are vulnerable to operator error and rely on a fixed head position. Virtual reality headsets obviate the need for head fixation, while providing other clear theoretical advantages, including complete control over the illumination and targets presented for the patient's interaction.PurposeWe compared the performance of a virtual reality-based test of ocular misalignment to that of the traditional Lees screen, to establish the feasibility of using virtual reality technology in ophthalmic settings in the future.MethodsThree patients underwent a traditional Lees screen test, and a virtual reality headset-based test of ocular motility. The virtual reality headset-based programme consisted of an initial test to measure horizontal and vertical deviation, followed by a test for torsion.ResultsThe pattern of deviation obtained using the virtual reality-based test showed agreement with that obtained from the Lees screen for patients with a fourth nerve palsy, comitant esotropia, and restrictive thyroid eye disease.ConclusionsThis study reports the first use of a virtual reality headset in assessing ocular misalignment, and demonstrates that it is a feasible dissociative test of strabismus. PMID- 28574496 TI - Optical clearing of the eye using the See Deep Brain technique. AB - PurposeTissue clearing has been used in anatomy for the first time in Germany over a century ago. Neuronal tissue, like cortex, was investigated in mice using a water-based optical clearing method termed See Deep Brain (SeeDB). However, although the eye belongs to the central nervous system, this histological technique was not applied in the eye up to date. We applied SeeDB for the visualization of intraocular structures.Patients and methodsFour eyes of cornea donors (two male, two female: 73-84 years) obtained from the Cornea Bank of the Department of Ophthalmology Erlangen, four chicken eyes and two mices' optic nerve were used. Bulbi were fixed in 4% paraformaldehyde in phosphate-buffered saline and treated with increasing concentrations of aqueous fructose solution with 0.5% alpha-thioglycerol. After SeeDB, transscleral macrophotographs of the choroid were performed.ResultsComplete transparency of the sclera was obtained in enucleated human and chicken eyes after SeeDB treatment. Macroscopical anatomy of the choroid (partially transparent due to the remaining retinal pigment epithelium and melanocytes) showing vessels and other related structures was possible without preparing slides. Mice optic nerves were also transparent after SeeDB treatment.ConclusionThe SeeDB method allows visualization of intraocular structures through a completely translucent sclera. This innovative processing technique could facilitate comprehensive qualitative and quantitative topographical anatomical studies of human and animal eyes, preserving their 3D architecture. Supra- and intrachoroidal ganglionic plexus could potentially be visualized transsclerally. Finally, clinical-pathological correlations of intraocular diseases-for example, retinal tumors-will be possible in non dissected eyes. PMID- 28574498 TI - Impact of socioeconomic status on vision-related quality of life in primary open angle glaucoma. AB - PurposeTo investigate the impact of socioeconomic status (SES) on vision-related quality of life (VRQOL) in patients with primary open-angle glaucoma (POAG).Patients and methodsThis prospective cross-sectional study included consecutive patients with POAG at a tertiary hospital between March 2012 and January 2013. All patients had visual acuity no worse than 20/60 in the better eye and reliable visual field tests. VRQOL was assessed by the validated Taiwan version 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ 25). Sociodemographic characteristics, medical history, and ocular parameters were recorded. SES was evaluated based on educational attainment and monthly income, both stratified into three levels. Analysis of variance and linear regression analysis were used to evaluate the relationship between SES, VRQOL, and clinical parameters.ResultsAmong the 186 patients recruited, intergroup differences were not observed among educational or monthly income levels for binocular vision or integrated visual field defects. Patients of lower educational and monthly income levels had lower self-reported general health ratings. After adjustment for visual function, treatment complexity, and general health in the multiple linear regression model, patients with a college degree or higher reported better NEI VFQ-25 scores for the composite score (P=0.041), mental health (P=0.035), and peripheral vision (P=0.05) than did those with education below junior high school. Monthly income levels did not affect the NEI VFQ-25 scores.ConclusionEducational attainment significantly affects VRQOL in patients with POAG. Additional counseling may be provided to patients with lower educational background to help them cope with the disease. PMID- 28574499 TI - Ultra-widefield fundus fluorescein angiography in the diagnosis and management of retinal vasculitis. AB - PurposeTo quantify the additional information provided by ultra-widefield fluorescein angiography, compared with 7-field standard imaging, in patients with retinal vasculitis (RV).Patients and methodsRetrospective case series of 106 patients.ResultsRetinal vascular pathology was identified by UWF FFA, but not by standard ETDRS 7-field area, in 62 patients (58.5%) and in 79 eyes (43.4%). The pathology included active RV (47 eyes, 25.8% of eyes); retinal ischaemia, or infarction (53 eyes, 29.1%); and retinal neovascularization (7 eyes, 3.8%). A change to management was made in 36 patients (34%). Of these, 21 (20% of all patients undergoing angiography) were made after the identification of retinal vascular pathology, which was found only on UWF FFA, outside the ETDRS area.ConclusionUltra-widefield fluorescein angiography has clear advantages over standard multi-field imaging. It is currently the standard method of assessment for RV in this centre. PMID- 28574500 TI - Subconjunctival implantation of ologen Collagen Matrix to treat ocular hypotony after filtration glaucoma surgery. AB - PurposeTo report the results of subconjunctival ologen Collagen Matrix implantation to manage ocular hypotony after filtration glaucoma surgery.Patients and methodsThis retrospective observational case series included 12 consecutive implantations of ologen in nine eyes of nine Japanese subjects (five men, four women; mean age+/-SD, 72.1+/-12.7 years) who underwent subconjunctival implantation of the device to treat hypotony after glaucoma filtration surgery. Demographic data and surgical results were collected by chart review.ResultsThe subjects included six patients who underwent trabeculectomy and three who underwent an EX-PRESS shunt surgery. The duration between the last glaucoma surgery and the initial ologen implantation was longer than 2 years in seven (78%) eyes. Bleb leakage in five (56%) eyes preoperatively stopped in all cases by 8 days after the device implantation. After the initial implantation, three (33.3%) eyes required a second implantation of ologen because of insufficient efficacy. After a mean follow-up of 12.6+/-6.8 months, the mean preoperative intraocular pressure (IOP) of 3.8+/-2.7 mmHg increased significantly (P=0.0001) to 9.0+/-3.2 mmHg; no eye required glaucoma medication to control the IOP. No vision-threatening complications developed in association with the treatment.ConclusionWhen conservative management failed, subconjunctival implantation of ologen Collagen Matrix in combination with bleb revision can be a useful therapeutic option for ocular hypotony after glaucoma filtration surgery. PMID- 28574502 TI - Hepatitis B virus X protein promotes CREB-mediated activation of miR-3188 and Notch signaling in hepatocellular carcinoma. AB - Familiar clustering of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) has been frequently reported. However, limited information is available about the underlying molecular mechanisms in HBV-related HCC patients with family history of HCC. In our previous study, Agilent miRNA Base 16.0 microarray showed miRNA profiles of the plasma of HBV-related HCC patients who had a family history of HCC. This study aims to explore the expression, function, and mechanisms of miR-3188 in HCC that might provide novel insights into the role of family history on the risk of HCC. The expression levels of miR-3188 were markedly overexpressed in HCC tissues, HBV transgenic mice, and HepG2.215 cells. We knocked out miR-3188 in HCC cell lines using the CRISPR/Cas9 system, and demonstrated that miR-3188 knockout (KO) suppressed cell growth, migration, and invasion, and inhibited xenografts tumor growth in nude mice. Next, we determined that miR-3188 KO exerts antitumor functions by directly repressing ZHX2. It has been reported that HBV X protein (HBx) plays a critical role in HBV-related HCC, promoting CREB-mediated activation of miR-3188 and activation of Notch signaling through repressing ZHX2. Finally, we verified that ZHX2 functions as a transcriptional repressor to Notch1 via interaction with NF-YA. Our data demonstrate that the HBx-miR-3188-ZHX2 Notch1 signaling pathway plays an important role in the pathogenesis and progression of HBV-related HCC with family history of HCC. These findings have important implications for identifying new therapeutic targets in HBV-related HCC. PMID- 28574501 TI - RIP1 kinase activity-dependent roles in embryonic development of Fadd-deficient mice. AB - RIP1 is an essential regulator of TNF-induced signaling complexes mediating NF kappaB activation, apoptosis and necroptosis. Loss of Rip1 rescues the embryonic lethality of Fadd or Caspase-8-deficient mice, even though the double knockout mice die shortly after birth like Rip1-deficient mice. Recent studies demonstrated that mice expressing RIP1 kinase-dead mutants developed normally and resisted necroptotic stimuli in vitro and in vivo. However, the impact of RIP1 kinase activity on Fadd-/- embryonic development remains unknown. Here, we engineered two RIP1 kinase inactive mutant mouse lines, a Rip1K45A/K45A mouse line as previously reported and a novel Rip1Delta/Delta mouse line with an altered P-loop in the kinase domain. While RIP1K45A could not rescue the embryonic lethality of Fadd-deficient mice at E11.5, RIP1Delta rescued lethality of Fadd-/- mice at E11.5 and Fadd-/-Rip1Delta/Delta mice eventually died at E16.5 due to excessive death of fetal liver cells and unregulated inflammation. Under necropotosis-inducing conditions, comparing to Rip1K45A/K45A cells, Rip1Delta/Deltacells displayed reduced phosphorylation and oligomerization of RIP3 and MLKL, which lead to increased cell viability. Thus, our study provides genetic evidence that different kinase inactive mutations have distinct impacts on the embryogenesis of Fadd-deficient mice, which might attribute to their extents of protection on necroptosis signaling. PMID- 28574503 TI - Pathogen-induced ubiquitin-editing enzyme A20 bifunctionally shuts off NF-kappaB and caspase-8-dependent apoptotic cell death. AB - The human pathogen Helicobacter pylori infects more than half of the world's population and is a paradigm for persistent yet asymptomatic infection but increases the risk for chronic gastritis and gastric adenocarcinoma. For successful colonization, H. pylori needs to subvert the host cell death response, which serves to confine pathogen infection by killing infected cells and preventing malignant transformation. Infection of gastric epithelial cells by H. pylori provokes direct and fast activation of the proinflammatory and survival factor NF-kappaB, which regulates target genes, such as CXCL8, BIRC3 and TNFAIP3. However, it is not known how H. pylori exploits NF-kappaB activation and suppresses the inflammatory response and host apoptotic cell death, in order to avert the innate immune response and avoid cell loss, and thereby enhance colonization to establish long-term infection. Here we assign for the first time that H. pylori and also Campylobacter jejuni-induced ubiquitin-editing enzyme A20 bifunctionally terminates NF-kappaB activity and negatively regulates apoptotic cell death. Mechanistically, we show that the deubiquitinylase activity of A20 counteracts cullin3-mediated K63-linked ubiquitinylation of procaspase-8, therefore restricting the activity of caspase-8. Interestingly, another inducible NF-kappaB target gene, the scaffold protein p62, ameliorates the interaction of A20 with procaspase-8. In conclusion, pathogen-induced de novo synthesis of A20 regulates the shut-off of the survival factor NF-kappaB but, on the other hand, also impedes caspase-8-dependent apoptotic cell death so as to promote the persistence of pathogens. PMID- 28574504 TI - NOX2-dependent ATM kinase activation dictates pro-inflammatory macrophage phenotype and improves effectiveness to radiation therapy. AB - Although tumor-associated macrophages have been extensively studied in the control of response to radiotherapy, the molecular mechanisms involved in the ionizing radiation-mediated activation of macrophages remain elusive. Here we show that ionizing radiation induces the expression of interferon regulatory factor 5 (IRF5) promoting thus macrophage activation toward a pro-inflammatory phenotype. We reveal that the activation of the ataxia telangiectasia mutated (ATM) kinase is required for ionizing radiation-elicited macrophage activation, but also for macrophage reprogramming after treatments with gamma-interferon, lipopolysaccharide or chemotherapeutic agent (such as cisplatin), underscoring the fact that the kinase ATM plays a central role during macrophage phenotypic switching toward a pro-inflammatory phenotype through the regulation of mRNA level and post-translational modifications of IRF5. We further demonstrate that NADPH oxidase 2 (NOX2)-dependent ROS production is upstream to ATM activation and is essential during this process. We also report that the inhibition of any component of this signaling pathway (NOX2, ROS and ATM) impairs pro-inflammatory activation of macrophages and predicts a poor tumor response to preoperative radiotherapy in locally advanced rectal cancer. Altogether, our results identify a novel signaling pathway involved in macrophage activation that may enhance the effectiveness of radiotherapy through the reprogramming of tumor-infiltrating macrophages. PMID- 28574505 TI - The small molecule that packs a punch: ubiquitin-mediated regulation of RIPK1/FADD/caspase-8 complexes. AB - The mechanisms that underpin the production of small molecules and cytokines that lead to inflammation or programmed cell death are intricately intertwined. So much so that some of the proteins that contribute to the transcriptional up regulation of cytokines can switch their role in the right circumstances to generate cell death-inducing complexes. This entwinement is reflected in the fact that inflammation helps an organism fight pathogens and that therefore pathogens are under an evolutionary pressure to interfere with this process. Cell death is therefore a defensive measure that may serve to deny pathogens a host cell, expose pathogens to the immune system and also provide additional inflammatory information to the host. Clearly such a system must be tightly regulated and ubiquitylation is a post-translational protein modification that is at the heart of this regulation. In this review, we discuss the regulatory ubiquitin events that dictate the formation and activation of death-inducing complexes containing RIPK1/FADD/caspase-8, and examine how these events collectively determine cell fate. PMID- 28574506 TI - Role of Atg5-dependent cell death in the embryonic development of Bax/Bak double knockout mice. AB - Programmed cell death, which is required for the development and homeostasis of metazoans, includes mechanisms such as apoptosis, autophagic cell death, and necrotic (or type III) death. Members of the Bcl2 family regulate apoptosis, among which Bax and Bak act as a mitochondrial gateway. Although embryonic fibroblasts from Bax/Bak double-knockout (DKO) mice are resistant to apoptosis, we previously demonstrated that these cells die through an autophagy-dependent mechanism in response to various types of cellular stressors. To determine the physiological role of autophagy-dependent cell death, we generated Atg5/Bax/Bak triple-knockout (TKO) mice, in which autophagy is greatly suppressed compared with DKO mice. Embryonic fibroblasts and thymocytes from TKO mice underwent autophagy much less frequently, and their viability was much higher than DKO cells in the presence of certain cellular stressors, providing genetic evidence that DKO cells undergo Atg5-dependent death. Compared with wild-type embryos, the loss of interdigital webs was significantly delayed in DKO embryos and was even further delayed in TKO embryos. Brain malformation is a distinct feature observed in DKO embryos on the 129 genetic background, but not in those on a B6 background, whereas such malformations appeared in TKO embryos even on a B6 background. Taken together, our data suggest that Atg5-dependent cell death contributes to the embryonic development of DKO mice, implying that autophagy compensates for the deficiency in apoptosis. PMID- 28574507 TI - Exploiting tumour addiction with a serine and glycine-free diet. PMID- 28574509 TI - MYCN amplified neuroblastoma requires the mRNA translation regulator eEF2 kinase to adapt to nutrient deprivation. AB - MYC family proteins are implicated in many human cancers, but their therapeutic targeting has proven challenging. MYCN amplification in childhood neuroblastoma (NB) is associated with aggressive disease and high mortality. Novel and effective therapeutic strategies are therefore urgently needed for these tumors. MYC-driven oncogenic transformation impairs cell survival under nutrient deprivation (ND), a characteristic stress condition within the tumor microenvironment. We recently identified eukaryotic Elongation Factor 2 Kinase (eEF2K) as a pivotal mediator of the adaptive response of tumor cells to ND. We therefore hypothesized that eEF2K facilitates the adaptation of MYCN amplified NB to ND, and that inhibiting this pathway can impair MYCN-driven NB progression. To test our hypothesis, we first analyzed publicly available genomic databases and tissue microarrays for eEF2K expression in NB, and for links between eEF2K, MYCN, and clinical outcome in NB. Effects of eEF2K inhibition were evaluated on survival of MYCN amplified versus non-amplified NB cell lines under ND. Finally, NB xenograft mouse models were used to confirm in vitro observations. Our results indicate that high eEF2K expression and activity are strongly predictive of poor outcome in NB, and correlates significantly with MYCN amplification. Inhibition of eEF2K markedly decreases survival of MYCN amplified NB cell lines in vitro under ND. Growth of MYCN amplified NB xenografts is markedly impaired by eEF2K knockdown, particularly under caloric restriction. In summary, eEF2K protects MYCN overexpressing NB cells from ND in vitro and in vivo, highlighting this kinase as a critical mediator of the adaptive response of MYCN amplified NB cells to metabolic stress. PMID- 28574510 TI - RIP4 inhibits STAT3 signaling to sustain lung adenocarcinoma differentiation. AB - Loss of epithelial differentiation and extracellular matrix (ECM) remodeling are known to facilitate cancer progression and are associated with poor prognosis in patients with lung cancer. We have identified Receptor-interacting serine/threonine protein kinase 4 (RIP4) as a regulator of tumor differentiation in lung adenocarcinoma (AC). Bioinformatics analyses of human lung AC samples showed that poorly differentiated tumors express low levels of RIP4, whereas high levels are associated with better overall survival. In vitro, lung tumor cells expressing reduced RIP4 levels showed enhanced activation of STAT3 signaling and had a greater ability to invade through collagen. In contrast, overexpression of RIP4 inhibited STAT3 activation, which abrogated interleukin-6-dependent induction of lysyl oxidase, a collagen cross-linking enzyme. In an autochthonous mouse model of lung AC initiated by Kras(G12D) expression with loss of p53, Rip4 knockdown tumors progressed to a poorly differentiated state marked by an increase in Hmga2, reduced Ttf1, and enrichment of genes regulating extracellular remodeling and Jak-Stat signaling. Tail vein injections of cells overexpressing Rip4 showed a reduced potential to invade and form tumors, which was restored by co-expression of Stat3. Altogether, our work has identified that loss of RIP4 enhances STAT3 signaling in lung cancer cells, promoting the expression of ECM remodeling genes and cancer dedifferentiation. PMID- 28574508 TI - Caspase involvement in autophagy. AB - Caspases are a family of cysteine proteases widely known as the principal mediators of the apoptotic cell death response, but considerably less so as the contributors to the regulation of pathways outside cellular demise. In regards to autophagy, the modulatory roles of caspases have only recently begun to be adequately described. In contrast to apoptosis, autophagy promotes cell survival by providing energy and nutrients through the lysosomal degradation of cytoplasmic constituents. Under basal conditions autophagy and apoptosis cross regulate each other through an elaborate network of interconnections which also includes the interplay between autophagy-related proteins (ATGs) and caspases. In this review we focus on the effects of this crosstalk at the cellular level, as we aim to concentrate the main observations from research conducted so far on the fine-tuning of autophagy by caspases. Several members of this protease-family have been found to directly interact with key ATGs involved in different tiers across the autophagic cascade. Therefore, we firstly outline the core mechanism of macroautophagy in brief. In an effort to emphasize the importance of the intricate cross-regulation of ATGs and caspases, we also present examples of autophagy's contribution to apoptotic cell death during development. PMID- 28574515 TI - Erratum to: A Review of the Long-Term Oncologic Outcomes of Robotic Surgery Versus Laparoscopic Surgery for Colorectal Cancer. AB - [This corrects the article DOI: 10.1007/s12262-015-1375-8.]. PMID- 28574516 TI - Erratum to: Further Manipulations in Response Effort or Magnitude of an Aversive Consequence to Increase Self-Feeding in Children with Feeding Disorders. AB - [This corrects the article DOI: 10.1007/s40617-016-0124-1.]. PMID- 28574513 TI - Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders. AB - PURPOSE: Copy-number variation is a common source of genomic variation and an important genetic cause of disease. Microarray-based analysis of copy-number variants (CNVs) has become a first-tier diagnostic test for patients with neurodevelopmental disorders, with a diagnostic yield of 10-20%. However, for most other genetic disorders, the role of CNVs is less clear and most diagnostic genetic studies are generally limited to the study of single-nucleotide variants (SNVs) and other small variants. With the introduction of exome and genome sequencing, it is now possible to detect both SNVs and CNVs using an exome- or genome-wide approach with a single test. METHODS: We performed exome-based read depth CNV screening on data from 2,603 patients affected by a range of genetic disorders for which exome sequencing was performed in a diagnostic setting. RESULTS: In total, 123 clinically relevant CNVs ranging in size from 727 bp to 15.3 Mb were detected, which resulted in 51 conclusive diagnoses and an overall increase in diagnostic yield of ~2% (ranging from 0 to -5.8% per disorder). CONCLUSIONS: This study shows that CNVs play an important role in a broad range of genetic disorders and that detection via exome-based CNV profiling results in an increase in the diagnostic yield without additional testing, bringing us closer to single-test genomics.Genet Med advance online publication 27 October 2016. PMID- 28574511 TI - Signalome-wide RNAi screen identifies GBA1 as a positive mediator of autophagic cell death. AB - Activating alternative cell death pathways, including autophagic cell death, is a promising direction to overcome the apoptosis resistance observed in various cancers. Yet, whether autophagy acts as a death mechanism by over consumption of intracellular components is still controversial and remains undefined at the ultrastructural and the mechanistic levels. Here we identified conditions under which resveratrol-treated A549 lung cancer cells die by a mechanism that fulfills the previous definition of autophagic cell death. The cells displayed a strong and sustained induction of autophagic flux, cell death was prevented by knocking down autophagic genes and death occurred in the absence of apoptotic or necroptotic pathway activation. Detailed ultrastructural characterization revealed additional critical events, including a continuous increase over time in the number of autophagic vacuoles, in particular autolysosomes, occupying most of the cytoplasm at terminal stages. This was followed by loss of organelles, disruption of intracellular membranes including the swelling of perinuclear space and, occasionally, a unique type of nuclear shedding. A signalome-wide shRNA based viability screen was applied to identify positive mediators of this type of autophagic cell death. One top hit was GBA1, the Gaucher disease-associated gene, which encodes glucocerebrosidase, an enzyme that metabolizes glucosylceramide to ceramide and glucose. Interestingly, glucocerebrosidase expression levels and activity were elevated, concomitantly with increased intracellular ceramide levels, both of which correlated in time with the appearance of the unique death characteristics. Transfection with siGBA1 attenuated the increase in glucocerebrosidase activity and the intracellular ceramide levels. Most importantly, GBA1 knockdown prevented the strong increase in LC3 lipidation, and many of the ultrastructural changes characteristic of this type of autophagic cell death, including a significant decrease in cytoplasmic area occupied by autophagic vacuoles. Together, these findings highlight the critical role of GBA1 in mediating enhanced self-consumption of intracellular components and endomembranes, leading to autophagic cell death. PMID- 28574517 TI - Erratum to: Social Thinking(r): Science, Pseudoscience, or Antiscience? AB - [This corrects the article DOI: 10.1007/s40617-016-0108-1.]. PMID- 28574518 TI - The one thing that's missing from the health care debate. AB - If we control the cost of providing care, insurance premiums will follow suit. PMID- 28574519 TI - Stroke: A road map for subacute management. AB - Time is of the essence when a patient has signs and symptoms suggestive of a stroke or TIA. What should your initial approach and diagnostic work-up be? PMID- 28574520 TI - These 3 tools can help you streamline management of IBS. AB - A novel explanatory model, Rome IV diagnostic criteria,and evidence-based therapeutic guidelines are making it easier to care for patients with this complex disorder. PMID- 28574522 TI - Bipolar disorder: Making the Dx, selecting the right Rx. AB - A 23-year-old woman seeks medical attention at the request of her boyfriend because she's been "miserable" for 3 weeks. In the examination room, she slouches in the chair and says her mood is low, her grades have dropped, and she no longer enjoys social gatherings or her other usual activities. She has no thoughts of suicide, no weight loss, and no somatic symptoms. PMID- 28574521 TI - Post-bariatric surgery patients: Your role in their long-term care. AB - Nutritional deficiencies, decreased bone mineral density,and dumping syndrome are just some of the challenges these patients face. Here's how to optimize their care. PMID- 28574523 TI - Neuropathic pain treatment provides unexpected benefit. AB - A 57-year-old African American woman was being treated at our clinic for neurogenic urinary incontinence (UI). The UI, which occurred day and night, began 2 years earlier following a laminectomy of vertebrae C3 to C6 with spinal fusion of C3 to C7 for cervical spinal stenosis. The UI persisted despite physical therapy and trials of oxybutynin and imipramine. Since the surgery, the patient had also been experiencing chronic (debilitating) neuropathic pain in both legs, and the sensation of incomplete bladder emptying. She denied bowel incontinence or saddle anesthesia. Her prescription medications included hydrocodone acetaminophen 7.5/325 mg every 6 hours as needed for pain and lisinopril 20 mg/d for essential hypertension. The patient's body mass index was 23.3. PMID- 28574524 TI - PURLs: Oral agent offers relief from generalized hyperhidrosis AB - An inexpensive and well-tolerated anticholinergic reduces sweating in those with localized--and generalized--hyperhidrosis. PMID- 28574525 TI - Severe right hip pain. AB - While this patient had osteoporosis, she hadn't experienced any recent trauma or falls that would explain her pain. PMID- 28574526 TI - Clinical Inquiry: Do oral decongestants have a clinically significant effect on BP in patients with hypertension? AB - It is unclear. Pseudoephedrine causes an average increase of 1.2 mm Hg in systolic blood pressure (BP) in patients with controlled hypertension. However, the studies are not adequately powered to provide evidence about whether this rise in systolic BP is linked to patient-oriented outcomes (strength of recommendation: C, multiple randomized controlled trials supporting disease oriented evidence). Significant variations in BP are defined differently among studies. In addition, we do not have data on chronic use of oral decongestants; the longest time on medication in these trials was 4 weeks. PMID- 28574527 TI - Prognostic Value of Braden Activity Subscale for Mobility Status in Hospitalized Older Adults. AB - OBJECTIVE: To evaluate the predictive value of the Activity subscale of the Braden Scale for Predicting Pressure Sore Risk in assessing mobility impairment and recovery among hospitalized older adults. DESIGN: Retrospective cohort study. SETTING: UF Health Shands Hospital, University of Florida, Gainesville, Florida. PATIENTS: 19,769 older adults (>=65 years) hospitalized between January 2009 and April 2014. MEASUREMENTS: Incident mobility impairment and recovery were assessed with the Braden Activity subscale (BAS) score that nurses use to grade patients at every shift change (~3 times/d). Posthospital mortality rate and discharge disposition were used to assess the prognostic value of the BAS. RESULTS: Of the 10,717 study patients observed "walking frequently" at admission, 2218 (20.7%) developed incident mobility impairment. Of the other 9052 study patients, who were impaired at admission, 4734 (52.3%) recovered to a state of walking occasionally or frequently. Older adults who developed mobility impairment during hospitalization had an odds of death higher than that of those who remained mobile (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.08- 1.39). This effect predominately occurred within the first 6 follow-up months. Older adults who recovered from mobility impairment had an odds of death lower than that of those who did not recover mobility in the hospital (OR, 0.54; 95% CI, 0.49-0.59). This effect was slightly stronger within the first 6 months after hospitalization. CONCLUSIONS: Nurses' BAS assessment of mobility status during hospitalization provides substantial prognostic value in hospitalized older adults. The BAS could be an efficient and valuable source of information about mobility status for targeting posthospital care of older adults. Journal of Hospital Medicine 2017;12:396-401. PMID- 28574528 TI - Does Provider Self-Reporting of Etiquette Behaviors Improve Patient Experience? A Randomized Controlled Trial. AB - BACKGROUND: There is a glaring lack of published evidence-based strategies to improve the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) patient experience scores on the physician domain. Strategies that have been used are resource intensive and difficult to sustain. OBJECTIVE: We hypothesized that prompting providers to assess their own etiquette-based practices every 2 weeks over the course of 1 year would improve patient experience on the physician domain. DESIGN: Randomized controlled trial. SETTING: 4 acute care hospitals. PARTICIPANTS: Hospitalists. INTERVENTION: Hospitalists were randomized to the study or the control arm. The study arm was prompted every 2 weeks for 12 months to report how frequently they engaged in 7 best-practice bedside etiquette behaviors. Control arm participants received similarly worded questions on quality improvement behaviors. MEASUREMENT: Provider experience scores were calculated from the physician HCAHPS and Press Ganey survey provider items. RESULTS: Physicians reported high rates of etiquette-based behavior at baseline, and this changed modestly over the study period. Self-reported etiquette behaviors were not associated with experience scores. The difference in difference analysis of the baseline and postintervention physician experience scores between the intervention arm and the control arm was not statistically significant (P = 0.71). CONCLUSION: In this 12-month study, biweekly reflection and reporting of best-practice bedside etiquette behaviors did not result in significant improvement on physician domain experience scores. It is likely that hospitalists' self-assessment of their bedside etiquette may not reflect patient perception of these behaviors. Furthermore, hospitalists may be resistant to improvement in this area since they rate themselves highly at baseline. Journal of Hospital Medicine 2017;12:402-406. PMID- 28574529 TI - Prospective Cohort Study of Hospitalized Adults With Advanced Cancer: Associations Between Complications, Comorbidity, and Utilization. AB - BACKGROUND: Inpatient hospital stays account for more than a third of direct medical cancer care costs. Evidence on factors driving these costs can inform planning of services, as well as consideration of equity in access. OBJECTIVE: To measure the association between hospital costs, and demographic, clinical, and system factors, for a cohort of adults with advanced cancer. DESIGN: Prospective multisite cohort study. SETTING: Four medical and cancer centers. PATIENTS: Adults with advanced cancer admitted to a participating hospital between 2007 and 2011, excluding those with dementia. Final analytic sample included 1020 patients. METHODS: With receipt of palliative care controlled for, the associations between hospital cost and patient factors were estimated. Factors covered the domains of demographics (age, sex, race), socioeconomics and systems (education, insurance, living will, proxy), clinical care (diagnoses, complications deemed to pose a threat to life or bodily functions, comorbidities, symptom burden, activities of daily living), and prior healthcare utilization (home help, analgesic prescribing). OUTCOME MEASURE: Direct hospital costs. RESULTS: A major (markedly abnormal) complication (+$8267; P < 0.01), a minor but not a major complication (+$5289; P < 0.01), and number of comorbidities (+$852; P < 0.01) were associated with higher cost, and admitting diagnosis of electrolyte disorders (-$4759; P = 0.01) and increased age (-$53; P = 0.03) were associated with lower cost. CONCLUSIONS: Complications and comorbidity burden drive inhospital utilization for adults with advanced cancer. There is little evidence of sociodemographic associations and no apparent impact of advance directives. Attempts to control growth of hospital cancer costs require consideration of how the most resource-intensive patients are identified promptly and prioritized for cost-effective care. Journal of Hospital Medicine 2017;12:407 413. PMID- 28574530 TI - Quality of Care of Hospitalized Infective Endocarditis Patients: Report from a Tertiary Medical Center. AB - OBJECTIVE: There have been no recent studies describing the management and outcomes of patients with infective endocarditis (IE). PATIENTS AND METHODS: We conducted a retrospective cohort study of adult patients admitted to a tertiary medical center from 2007 to 2011 with a Duke criteria consistent discharge diagnosis of IE. We examined concordance with guideline recommendations. Outcomes included embolic events, inhospital and 1-year mortality, length of stay (LOS) and cardiac surgery. We used descriptive statistics to describe the cohort and Fisher exact and unpaired t tests to compare native valve endocarditis (NVE) with prosthetic valve endocarditis (PVE). RESULTS: Of 170 patients, definite IE was present in 135 (79.4%) and possible IE in 35 (20.6%); 74.7% had NVE, and 25.3% had PVE. Mean +/- standard deviation age was 60.0 +/- 17.9 years. Comparing PVE to NVE, patients with PVE were less likely to have embolic events (14.0% vs. 32.3%; P = 0.03), had shorter LOS (median 12.0 days vs. 14.0 days; P = 0.047), but they did not show a statistically significant difference in inhospital mortality (20.9% vs. 12.6%; P = 0.21). Of 170, patients 27.6% (n = 47) underwent valve surgery. Most patients received timely blood cultures and antibiotics. Guideline-recommended consults were underused, with 86.5%, 54.1%, and 47.1% of patients receiving infectious disease, cardiac surgery, and cardiology consultation, respectively. As the number of consultations increased (from 0 to 3), we observed a nonsignificant trend toward reduction in 6-month readmission and 12-month mortality. CONCLUSION: IE remains a disease with significant morbidity and mortality. There are gaps in the care of IE patients, most notably underuse of specialty consultation. Journal of Hospital Medicine 2017;12:414-420. PMID- 28574531 TI - Do HCAHPS Doctor Communication Scores Reflect the Communication Skills of the Attending on Record? A Cautionary Tale from a Tertiary-Care Medical Service. AB - BACKGROUND: Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores measure patient satisfaction with hospital care. It is not known if these reflect the communication skills of the attending physician on record. The Four Habits Coding Scheme (4HCS) is a validated instrument that measures bedside physician communication skills according to 4 habits, namely: investing in the beginning, eliciting the patient's perspective, demonstrating empathy, and investing in the end. OBJECTIVE: To investigate whether the 4HCS correlates with provider HCAHPS scores. METHODS: Using a cross-sectional design, consenting hospitalist physicians (n = 28), were observed on inpatient rounds during 3 separate encounters. We compared hospitalists' 4HCS scores with their doctor communication HCAHPS scores to assess the degree to which these correlated with inpatient physician communication skills. We performed sensitivity analysis excluding scores returned by patients cared for by more than 1 hospitalist. RESULTS: A total of 1003 HCAHPS survey responses were available. Pearson correlation between 4HCS and doctor communication scores was not significant, at 0.098 (-0.285, 0.455; P = 0.619). Also, no significant correlations were found between each habit and HCAHPS. When including only scores attributable to 1 hospitalist, Pearson correlation between the empathy habit and the HCAHPS respect score was 0.515 (0.176, 0.745; P = 0.005). Between empathy and overall doctor communication, it was 0.442 (0.082, 0.7; P = 0.019). CONCLUSION: Attending-of record HCAHPS scores do not correlate with 4HCS. After excluding patients cared for by more than 1 hospitalist, demonstrating empathy did correlate with the doctor communication and respect HCAHPS scores. Journal of Hospital Medicine 2017;12:421-427. PMID- 28574532 TI - Association Between Opioid and Benzodiazepine Use and Clinical Deterioration in Ward Patients. AB - BACKGROUND: Opioids and benzodiazepines are frequently used in hospitals, but little is known about outcomes among ward patients receiving these medications. OBJECTIVE: To determine the association between opioid and benzodiazepine administration and clinical deterioration. DESIGN: Observational cohort study. SETTING: 500-bed academic urban tertiary-care hospital. PATIENTS: All adults hospitalized on the wards from November 2008 to January 2016 were included. Patients who were "comfort care" status, had tracheostomies, sickle-cell disease, and patients at risk for alcohol withdrawal or seizures were excluded. MEASUREMENTS: The primary outcome was the composite of intensive care unit transfer or ward cardiac arrest. Discrete-time survival analysis was used to calculate the odds of this outcome during exposed time periods compared to unexposed time periods with respect to the medications of interest, with adjustment for patient demographics, comorbidities, severity of illness, and pain score. RESULTS: In total, 120,518 admissions from 67,097 patients were included, with 67% of admissions involving opioids, and 21% involving benzodiazepines. After adjustment, each equivalent of 15 mg oral morphine was associated with a 1.9% increase in the odds of the primary outcome within 6 hours (odds ratio [OR], 1.019; 95% confidence interval [CI], 1.013-1.026; P < 0.001), and each 1 mg oral lorazepam equivalent was associated with a 29% increase in the odds of the composite outcome within 6 hours (OR, 1.29; CI, 1.16- 1.45; P < 0.001). CONCLUSION: Among ward patients, opioids were associated with increased risk for clinical deterioration in the 6 hours after administration. Benzodiazepines were associated with even higher risk. These results have implications for ward monitoring strategies. Journal of Hospital Medicine 2017;12:428-434. PMID- 28574533 TI - Rates, Predictors and Variability of Interhospital Transfers: A National Evaluation. AB - IMPORTANCE: Interhospital transfer (IHT) remains a largely unstudied process of care. OBJECTIVE: To determine the nationwide frequency of, patient and hospital level predictors of, and hospital variability in IHT. DESIGN: Cross-sectional study. SETTING: Centers for Medicare and Medicaid 2013 100% Master Beneficiary Summary and Inpatient claims files merged with 2013 American Hospital Association data. PATIENTS: Beneficiaries >=65 years and older enrolled in Medicare A and B, with an acute care hospitalization claim in 2013. EXPOSURES: Patient and hospital characteristics of transferred and nontransferred patients. MEASUREMENTS: Frequency of interhospital transfers (IHT); adjusted odds of transfer of each patient and each hospital characteristic; and variability in hospital transfer rates. RESULTS: Of 6.6 million eligible beneficiaries with an acute care hospitalization, 101,507 (1.5%) underwent IHT. Selected characteristics associated with greater adjusted odds of transfer included: patient age 74-85 years (odds ratio [OR], 2.38 compared with 65-74 years; 95% confidence intervals [CI], 2.33-2.43); nonblack race (OR, 1.17; 95% CI, 1.13-1.20); higher comorbidity (OR, 1.37; 95% CI, 1.36-1.37); lower diagnosis-related group-weight (OR, 2.02; 95% CI, 1.95-2.09); fewer recent hospitalizations (OR, 1.87; 95% CI, 1.79-1.95); and hospitalization in the Northeast (OR, 1.40; 95% CI, 1.27-1.55). Higher case mix index of the hospital was associated with a lower adjusted odds of transfer (OR, 0.36; 95% CI, 0.30-0.45). Variability in hospital transfer rates remained significant after adjustment for patient and hospital characteristics (variance 0.28, P = 0.01). CONCLUSIONS: In this nationally representative evaluation, we found that a sizable number of patients undergo IHT. We identified both expected and unexpected patient and hospital-level predictors of IHT, as well as unexplained variability in hospital transfer rates, suggesting lack of standardization of this complex care transition. Our study highlights further investigative avenues to help guide best practices in IHT. Journal of Hospital Medicine 2017;12:435-442. PMID- 28574534 TI - The Shifting Landscape in Utilization of Inpatient, Observation, and Emergency Department Services Across Payers. AB - Recent policies by public and private payers have increased incentives to reduce hospital admissions. Using data from four states from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project, this study compared the payer-specific population-based rates of adults using inpatient, observation, and emergency department (ED) services for 10 common medical conditions in 2009 and in 2013. Patients had an expected primary payer of private insurance, Medicare, Medicaid, or no insurance. Across all four payer populations, inpatient admissions declined, and care shifted toward treat-and-release observation stays and ED visits. The percentage of hospitalizations that began with an observation stay increased. Implications for quality of care and costs to patients warrant further examination. Journal of Hospital Medicine 2017;12:443-446. PMID- 28574535 TI - Telemetry Monitor Watchers Reduce Bedside Nurses' Exposure to Alarms by Intercepting a High Number of Nonactionable Alarms. AB - Cardiac telemetry, designed to monitor hospitalized patients with active cardiac conditions, is highly utilized outside the intensive care unit but is also resource-intensive and produces many nonactionable alarms. In a hospital setting in which dedicated monitor watchers are set up to be the first responders to system-generated alerts, we conducted a retrospective study of the alerts produced over a continuous 2-month period to evaluate how many were intercepted before nurse notification for being nonactionable, and how many resulted in code team activations. Over the 2-month period, the system generated 20,775 alerts (5.1/patient-day, on average), of which 87% were intercepted by monitor watchers. None of the alerts for asystole, ventricular fibrillation, or ventricular tachycardia resulted in a code team activation. Our results highlight the high burden of alerts, the large majority of which are nonactionable, as well as the role of monitor watchers in decreasing the alarm burden on nurses. Measures are needed to decrease telemetry-related alerts in order to reduce alarm-related harms, such as alarm fatigue. Journal of Hospital Medicine 2017;12:447-449. PMID- 28574536 TI - Perceptions of Hospital-Dependent Patients on Their Needs for Hospitalization. AB - In the United States, older adults account for a significant proportion of hospitalizations, and a subset become hospital-dependent, for reasons that are unclear. We conducted a qualitative study to explore these individuals' perspectives on their need for hospitalizations. Twenty patients hospitalized at an academic medical center underwent semistructured qualitative interviews. Criteria for selection included age 65 and older, at least three hospitalizations over six months, admission to the medical service at the time of the study, did not meet criteria for chronic critical illness, was not comfort measures only, and did not have a conservator. Interviews were audiotaped, transcribed, and inductively analyzed. The major themes derived were the necessity and inevitability of hospitalizations ("You have to bring me in here"), feeling safe in the hospital ("It makes me feel more secure"), patients hospitalized despite having outside medical and social support ("I have everything"), and inadequate goals-of-care discussions ("It just doesn't occur to me"). Results suggested that candid discussions about health trajectories are needed to ensure hospitalization is consistent with the patient's realistic health priorities. Journal of Hospital Medicine 2017;12:450-453. PMID- 28574538 TI - Empiric Listeria monocytogenes Antibiotic Coverage for Febrile Infants (Age, 0-90 Days). PMID- 28574537 TI - Incidental Pulmonary Nodules Reported on CT Abdominal Imaging: Frequency and Factors Affecting Inclusion in the Hospital Discharge Summary. AB - Incidental imaging findings require an assessment of risk and clinical relevance, as well as consideration of further evaluation. Incidental findings are common on imaging obtained in the hospital, with pulmonary nodules being among the most frequent findings that may require additional evaluation. We conducted a retrospective study to determine the factors associated with documentation of incidental findings in the hospital discharge summary, using pulmonary nodules reported on abdominal computed tomography (CT) as an example of incidental findings with well-defined follow-up guidelines. Between January 1, 2012 and December 31, 2014, 7173 patients underwent in-patient abdominal CT without concurrent chest CT; of these patients, 62.2% were >=60 years old, 50.6% were men, and 45.5% were current or former smokers. Incidental pulmonary nodules were reported in 402 patients (5.6%; 95% confidence interval [CI], 5.1%-6.2%). Based on nodule size, reported size stability, and patients' smoking status, 208 patients (2.9%; 95% CI, 2.5%-3.3%) required follow-up surveillance, per the 2005 Fleischner Society guidelines. Of these 208 patients, 48 (23%) received discharge summaries that included documentation of the incidental findings, with 34 summaries including a recommendation for nodule follow-up and 19 summaries including a time frame for repeat CT. Three factors were positively associated with the inclusion of the pulmonary nodule in the discharge summary: mention of the pulmonary nodule in the summary headings of the radiology report (P <= 0.001), radiologist recommendations for further surveillance (P <= 0.001), and medical discharging service (P = 0.016). These findings highlight the need for a multidisciplinary systems-based approach to incidental pulmonary nodule documentation and surveillance. Journal of Hospital Medicine 2017;12:454-457. PMID- 28574539 TI - Hot in the Tropics. PMID- 28574540 TI - Postdischarge Clinics and Hospitalists: A Review of the Evidence and Existing Models. AB - Over the past 10 years, postdischarge clinics have been introduced in response to various health system pressures, including the focus on rehospitalizations and the challenges of primary care access. Often ignored in the discussion are questions of the effect of postdischarge physician visits on readmissions. In addition, little attention has been given to other clinical outcomes, such as reducing preventable harm and mortality. A review of dedicated, hospitalist-led postdischarge clinics, of the data supporting postdischarge physician visits, and of the role of hospitalists in these clinics may be instructive for hospitalists and health systems considering the postdischarge clinic environment. Journal of Hospital Medicine 2017;12:467-471. PMID- 28574541 TI - Forgotten but Not Gone: Update on Measles Infection for Hospitalists. AB - Measles (rubeola) continues to be endemic and epidemic in many regions of the world. Measles is primarily a disease of childhood, but it can also affect adult populations, and therefore it is important that both adult and pediatric hospitalist physicians be able to recognize it. Although the disease is rarely encountered in the United States, measles infection can spread rapidly across vulnerable populations. In addition, infected adults can develop complications that may require hospitalization for treatment. This review summarizes the typical clinical course and complications of measles infection, along with recommendations for diagnosis and management for both adult and pediatric hospitalists. Journal of Hospital Medicine 2017;12:472-476. PMID- 28574542 TI - Mobility Assessment in the Hospital: What Are the "Next Steps"? PMID- 28574543 TI - It's Time for a Strategic Approach to Observation Care. PMID- 28574544 TI - Monitor Watchers and Alarm Fatigue: Cautious Optimism. PMID- 28574545 TI - Ultrafast energy transfer within the photosystem II core complex. AB - We report 2D electronic spectroscopy on the photosystem II core complex (PSII CC) at 77 K under different polarization conditions. A global analysis of the high time-resolution 2D data shows rapid, sub-100 fs energy transfer within the PSII CC. It also reveals the 2D spectral signatures of slower energy equilibration processes occurring on several to hundreds of picosecond time scales that are consistent with previous work. Using a recent structure-based model of the PSII CC [Y. Shibata, S. Nishi, K. Kawakami, J. R. Shen and T. Renger, J. Am. Chem. Soc., 2013, 135, 6903], we simulate the energy transfer in the PSII CC by calculating auxiliary time-resolved fluorescence spectra. We obtain the observed sub-100 fs evolution, even though the calculated electronic energy shows almost no dynamics at early times. On the other hand, the electronic-vibrational interaction energy increases considerably over the same time period. We conclude that interactions with vibrational degrees of freedom not only induce population transfer between the excitonic states in the PSII CC, but also reshape the energy landscape of the system. We suggest that the experimentally observed ultrafast energy transfer is a signature of excitonic-polaron formation. PMID- 28574546 TI - Complexation of tetraalkyl diglycolamides with trivalent f-cations in a room temperature ionic liquid: extraction and spectroscopic investigations. AB - This paper reports the complexation of a series of tetraalkyl diglycolamides (TRDGA) with trivalent f-cations in a room temperature ionic liquid, viz., 3 octyl-1-methylimidazolium bis(trifluoromethanesulfonyl)imide ([C8mim][Tf2N]). The stability constants of TRDGA/Nd3+ complexes (where R = n-pentyl, n-hexyl, n octyl, n-decyl and 2-ethylhexl) were determined by absorbance spectroscopy. All the DGA ligands formed a 1 : 3 (Nd3+/DGA) complex as the limiting species. Solvent extraction data on Am3+ and Eu3+ were obtained with the TRDGA ligands in [C8mim][Tf2N] to arrive at a correlation between their extraction behaviour and complexation constant. The nature of the complex formed in the single phase titration (in [C8mim][Tf2N]) and those extracted in the [C8mim][Tf2N] medium from the aqueous phase were found to be identical. Fluorescence lifetime data confirmed that, in both single phase titration and biphasic solvent extraction, the complexation proceeded via replacement of water molecules from the primary coordination sphere of the metal ion. The spectroscopic data confirmed the absence of NO3- and Tf2N- ions or H2O in the extracted complexes. PMID- 28574547 TI - A substituent effect of phenylacetic acid coligand perturbed structures and magnetic properties observed in two triple-bridged azido-Cu(ii) chain compounds with ferromagnetic ordering and slow magnetic relaxation. AB - Based on two fluoro-substituted phenylacetate isomers, o-fluorophenylacetic acid (o-Hfpa) and p-fluorophenylacetic acid (p-Hfpa), two new Cu(ii)-azido compounds, [Cu(o-fpa)(N3)(C2H5OH)]n (1) and [Cu(p-fpa)(N3)(C2H5OH)]n (2), have been prepared, and structurally and magnetically characterized. Single-crystal structure analyses indicate that compounds 1 and 2 consist of 1D chain-like coordination networks in which adjacent copper cations are linked by the alternating triple-bridges of MU-1,1-azido, syn,syn-carboxylate and MU2-ethanol. For the two title compounds, the diverse charge distributions on the carboxyl groups caused by distinct substituent effects of the two phenylacetate coligands lead to the different structural parameters of intrachain Cu-Cu distances (3.218 A for 1 and 3.168 A for 2) and Cu-N-Cu angles (106.82 degrees for 1 and 104.81 degrees for 2), further resulting in the disparity of magnetic behaviors. The dominant ferromagnetic couplings between neighbouring Cu(ii) ions in the two compounds (J = 87.08 cm-1 for 1, J = 66.05 cm-1 for 2) are due to the counter complementarity of the multiple superexchange pathways, contributing to the interesting plots of a ferromagnetic order (Tc = 11.0 K for 1, 9.5 K for 2) and slow magnetic relaxation that are rarely observed in most of the reported azido Cu(ii) architectures. Heat-capacity experiments further emphasize the characteristic long-range ferromagnetic ordering in compounds 1 and 2. Magneto structural relationships of 1 and 2 are investigated as well. Moreover, DFT calculations (using different methods and basis sets) have been performed on both compounds to provide a qualitative and quantitative theoretical explanation of their magnetic behavior. PMID- 28574548 TI - Metal-organic frameworks constructed from tib and carboxylate acid ligands: selective sensing of nitro explosives and magnetic properties. AB - Four metal-organic frameworks, namely [Cd2(tib)(btb)(H2O)2].NO3.2.5DMF (1), [Cd(tib)(H2dhbqdc)0.5(NO3)].6H2O (2), [Co(tib)(1,4-ndc)].2DMF (3), and [Cu3(tib)2(2,6-ndc)2(H2O)2].2NO3.2H2O (4), were synthesized based on 1,3,5-tris(1 imidazolyl)benzene and diverse carboxylic acid ligands. They have been characterized by elemental analysis, infrared spectroscopy (IR), powder X-ray diffraction (PXRD), thermogravimetric analyses (TGA) and single crystal X-ray diffraction. Compound 1 is a 3D framework constructed from a binuclear Cd cluster with (3,3,6)-connected (63)2(69.86) topology. Compound 2 exhibits a 2D wavy layered structure with (3,4)-connected topology, and compound 3 displays a two fold interpenetrating network with (3,5)-connected topology. Compound 4 can be regarded as a three-fold interpenetrating framework. Moreover, compounds 1 and 2 can be used as fluorescent sensors sensing small molecules with high selectivity. In this context, we selected the typical toxic explosives, TNP, namely 2,4,6 trinitrophenol and NB, namely nitrobenzene, as examples to investigate the properties of sensing. Furthermore, the magnetic properties of compounds 3 and 4 are investigated. PMID- 28574549 TI - Titanium(iv)-based helicates incorporating the ortho-phenylenediamine ligand: a structural and a computational investigation. AB - The multicomponent coordination chemistry involving Ti(OPri)4, the ortho phenylenediamine ligand (opda) and 2,2'-biphenol-based proligands (L2H4 and L3H6) is described. The proligands L2H4 and L3H6 incorporate two and three 2,2' biphenol units linked with p-phenylene bridges (p-PLB) respectively. We demonstrate that this selected set of components allows the spontaneous formation of neutral double-stranded helicates. In particular, we report the X-ray crystal structure of a multicomponent helicate formed with L2, named Ti2(L2)2(opda)2. The molecular structure of the helicate shows two inequivalent L2 ligands. 1H NMR analysis at variable temperature highlights an intramolecular fluxional phenomenon for this species. An insight into this dynamic behaviour is obtained via the energy profiles of Ti2(L2)2(opda)2 resulting from the full rotation of the p-PLB rings. Additionally, the thermodynamic parameters associated with the formation of the Ti2(L2)2(opda)2 complex are modelled and discussed related to the ones linked to the formation of a related monomeric complex. PMID- 28574550 TI - Ionic liquid promotes N2 coordination to titanocene(iii) monochloride. AB - Coordination of N2 to [(Cp2TiCl)2] in a non-coordinating ionic liquid, Pyr4FAP, was studied by UV-vis/NIR and EPR spectroscopies. [(Cp2TiCl)2] is in equilibrium between monomeric [Cp2TiCl] and dimeric species [(Cp2TiCl)2]. The frozen solution EPR spectrum revealed the coordination of N2 to [Cp2TiCl], suggesting that Pyr4FAP promotes N2 coordination to the Ti(iii) center. PMID- 28574551 TI - Upper tropospheric water vapour and its interaction with cirrus clouds as seen from IAGOS long-term routine in situ observations. AB - IAGOS (In-service Aircraft for a Global Observing System) performs long-term routine in situ observations of atmospheric chemical composition (O3, CO, NOx, NOy, CO2, CH4), water vapour, aerosols, clouds, and temperature on a global scale by operating compact instruments on board of passenger aircraft. The unique characteristics of the IAGOS data set originate from the global scale sampling on air traffic routes with similar instrumentation such that the observations are truly comparable and well suited for atmospheric research on a statistical basis. Here, we present the analysis of 15 months of simultaneous observations of relative humidity with respect to ice (RHice) and ice crystal number concentration in cirrus (Nice) from July 2014 to October 2015. The joint data set of 360 hours of RHice-Nice observations in the global upper troposphere and tropopause region is analysed with respect to the in-cloud distribution of RHice and related cirrus properties. The majority of the observed cirrus is thin with Nice < 0.1 cm-3. The respective fractions of all cloud observations range from 90% over the mid-latitude North Atlantic Ocean and the Eurasian Continent to 67% over the subtropical and tropical Pacific Ocean. The in-cloud RHice distributions do not depend on the geographical region of sampling. Types of cirrus origin (in situ origin, liquid origin) are inferred for different Nice regimes and geographical regions. Most importantly, we found that in-cloud RHice shows a strong correlation to Nice with slightly supersaturated dynamic equilibrium RHice associated with higher Nice values in stronger updrafts. PMID- 28574552 TI - trans-cis C-Pd-C rearrangement in hemichelates. AB - Kinetically unstable heteroleptic trans-bispalladacycles were isolated by using hemichelation. Three structures of trans isomers and five of cis isomers were characterized by X-ray diffraction analysis. The ready trans-to-cis isomerization of such hemichelates that was monitored by variable temperature NMR experiments is facilitated dynamically because the Pd(ii) center can preserve its square planar coordination in a rather low lying transition state, which was localized by methods of the density functional theory. This process is not achievable in the isomerization of conventional homoleptic trans-bispalladacycles since it involves the preliminary partial chelate decoordination and an unfavorable high lying planar trigonal coordinated - or Y-shaped-Pd(ii) transition state according to DFT investigations. PMID- 28574553 TI - Can boron antisites of BNNTs be an efficient metal-free catalyst for nitrogen fixation? - A DFT investigation. AB - Nitrogen fixation is a challenging reaction under ambient conditions. So far, a few metal-based catalysts have been reported; however, noticeable disadvantages including high cost, gas poisoning, and them being hazardous to the environment are still to be resolved. We have carried out density functional theory based calculations with the omegaB97X-D/6-31G* level of theory to investigate the activation of dinitrogen using boron nitride based metal-free catalysts for the first time as they are environmentally friendly and corrosion resistant. The boron antisite of a boron nitride nanotube is found to be an active site for nitrogen activation. The activated N2 is characterized by the increase in bond length and the red shift in the stretching frequency of the N[triple bond, length as m-dash]N bond. The subsequent reduction mechanisms of activated N2 into ammonia through six-proton and six-electron processes have also been elucidated. The selectivity of the nitrogen reduction reaction between distal and alternating associative pathways is also rationalized. The reaction energetics highlight the distal associative mechanism as a feasible pathway under ambient conditions. The catalytic performance of BAS is further unraveled with the help of variation in the charge density. This work provides a rational model for the metal-free catalytic conversion of N2 to ammonia via an eco-friendly pathway under ambient conditions. PMID- 28574554 TI - Mesoporous titanium and niobium nitrides as conductive and stable electrocatalyst supports in acid environments. AB - The stability of carbon-based catalyst supports represents one of the biggest challenges for the commercialisation of proton-exchange membrane fuel cells (PEMFCs). Metal nitrides are an attractive alternative to carbon-based supports, owing to their high bulk conductivity and acid stability. We report the electrochemical stability evaluation of high-surface-area metal nitrides in acidic electrolytes. Three-dimensional mesoporous titanium (TiN) and niobium nitride (NbN) thin films were prepared using block copolymer self-assembly and were evaluated without using any conductive carbon additives or a carbon-based substrate. Both TiN and NbN are stable and maintain conductivity in acidic electrolytes up to at least 0.85 V (NbN) and 1.4 V (TiN) vs. reversible hydrogen electrode (RHE) after 2000 cycles. We also deposited platinum on the TiN films and demonstrate the expected cyclic voltammogram features, indicating the nitride's utility as a catalyst support. PMID- 28574555 TI - Condensed-phase biogenic-anthropogenic interactions with implications for cold cloud formation. AB - Anthropogenic and biogenic gas emissions contribute to the formation of secondary organic aerosol (SOA). When present, soot particles from fossil fuel combustion can acquire a coating of SOA. We investigate SOA-soot biogenic-anthropogenic interactions and their impact on ice nucleation in relation to the particles' organic phase state. SOA particles were generated from the OH oxidation of naphthalene, alpha-pinene, longifolene, or isoprene, with or without the presence of sulfate or soot particles. Corresponding particle glass transition (Tg) and full deliquescence relative humidity (FDRH) were estimated using a numerical diffusion model. Longifolene SOA particles are solid-like and all biogenic SOA sulfate mixtures exhibit a core-shell configuration (i.e. a sulfate-rich core coated with SOA). Biogenic SOA with or without sulfate formed ice at conditions expected for homogeneous ice nucleation, in agreement with respective Tg and FDRH. alpha-pinene SOA coated soot particles nucleated ice above the homogeneous freezing temperature with soot acting as ice nuclei (IN). At lower temperatures the alpha-pinene SOA coating can be semisolid, inducing ice nucleation. Naphthalene SOA coated soot particles acted as ice nuclei above and below the homogeneous freezing limit, which can be explained by the presence of a highly viscous SOA phase. Our results suggest that biogenic SOA does not play a significant role in mixed-phase cloud formation and the presence of sulfate renders this even less likely. However, anthropogenic SOA may have an enhancing effect on cloud glaciation under mixed-phase and cirrus cloud conditions compared to biogenic SOA that dominate during pre-industrial times or in pristine areas. PMID- 28574556 TI - The influence of polydopamine coating on gold nanorods for laser desorption/ionization time-of-flight mass spectrometric analysis. AB - This paper examines the effect of polydopamine (PD) coating of gold nanorods (GNRs) on their performance as a matrix material for laser desorption/ionization time-of-flight mass spectrometry (LDI-TOF-MS) analysis. Bare GNRs and PD-coated GNRs (PD@GNRs) were utilized for LDI-TOF-MS analyses of small molecules and synthetic polymers, and the influences of PD-coating were mechanistically studied. Based on the results, we found that the PD-coating of GNRs suppressed the generation of undesired gold cluster ions, enhanced photothermal conversion and the LDI-TOF-MS efficiency, and expanded the working molecular weight range. PMID- 28574557 TI - Enabling iron catalyzed Doyle-Kirmse rearrangement reactions with in situ generated diazo compounds. AB - Slow addition of sodium nitrite allows the in situ preparation of highly explosive diazo compounds and enables their safe and scalable application in iron catalyzed rearrangement reactions of allylic and propargylic sulfides. With catalyst loadings as low as 0.1 mol% an effective entry into alpha-mercapto nitriles, alpha-mercapto-esters and alpha-trifluoromethyl-sulfides on a gram scale is achieved. PMID- 28574558 TI - A molecular self-assembled colourimetric chemosensor array for simultaneous detection of metal ions in water. AB - We propose a novel strategy for a high-throughput sensing of metal ions using a molecular self-assembled colourimetric chemosensor array. The proposed colourimetric assay has been achieved by only using the combination of commercially available materials. Importantly, the easy-to-prepare assay can be utilised to quantitatively detect metal ions under competitive conditions. PMID- 28574559 TI - Two unusual 3D honeycomb networks based on Wells-Dawson arsenomolybdates with d10 transition-metal-pyrazole connectors. AB - Herein, two Wells -Dawson-type arsenomolybdates, formulated as [Cu(pyr)2]6[As2Mo18O62] (1) and [Ag(pyr)2]6[As2Mo18O62] (2) (pyr = pyrazole), were hydrothermally synthesized and structurally characterized via single-crystal X-ray diffraction, elemental analysis, IR and UV-vis-NIR spectroscopies, XPS, XRD, and TG analysis. The structural analysis indicated that compounds 1 and 2 were isomorphic. They are the first reported 3D honeycomb structures of Wells Dawson-type arsenomolybdates. The [M(pyr)2] (M = Cu and Ag) connected with [As2Mo18O62]6- polyoxoanions to form the {812.123}{8}3 topological structure. The contributions of organic ligands, pH value, reaction temperature, and transition metal (TM) to the construction of 3D networks were elucidated. Furthermore, compounds 1 and 2 exhibited fluorescence properties in the solid state at room temperature, highly efficient catalytic ability for the degradation of five organic dyes (MB, RhB, MO, AP, and CR) under UV irradiation, and obvious electrocatalytic activities for the reduction of H2O2. The mechanisms of photocatalysis and electrocatalysis have also been discussed in detail. PMID- 28574560 TI - Approximate quantum chemical methods for modelling carbohydrate conformation and aromatic interactions: beta-cyclodextrin and its adsorption on a single-layer graphene sheet. AB - Noncovalent functionalization of graphene by carbohydrates such as beta cyclodextrin (betaCD) has the potential to improve graphene dispersibility and its use in biomedical applications. Here we explore the ability of approximate quantum chemical methods to accurately model betaCD conformation and its interaction with graphene. We find that DFTB3, SCC-DFTB and PM3CARB-1 methods provide the best agreement with density functional theory (DFT) in calculation of relative energetics of gas-phase betaCD conformers; however, the remaining NDDO based approaches we considered underestimate the stability of the trans,gauche vicinal diol conformation. This diol orientation, corresponding to a clockwise hydrogen bonding arrangement in the glucosyl residue of betaCD, is present in the lowest energy betaCD conformer. Consequently, for adsorption on graphene of clockwise or counterclockwise hydrogen bonded forms of betaCD, calculated with respect to this unbound conformer, the DFTB3 method provides closer agreement with DFT values than PM7 and PM6-DH2 approaches. These findings suggest approximate quantum chemical methods as potentially useful tools to guide the design of carbohydrate-graphene interactions, but also highlights the specific challenge to NDDO-based methods in capturing the relative energetics of carbohydrate hydrogen bond networks. PMID- 28574561 TI - Influence of the physicochemical characteristics of reduced graphene oxides on the gas permeability of the barrier films for organic electronics. AB - The gas permeability of reduced graphene oxide (rGO) films is influenced by controlling the lateral size and void generation. Low gas permeability was achieved by the controlled synthesis of parent graphene oxide (GO). The organic device lifetime using rGO-coated barriers was prolonged by 65.9 times when compared to bare samples. PMID- 28574562 TI - One-pot preparation of a novel CO-releasing material based on a CO-releasing molecule@metal-organic framework system. AB - A novel CO releasing material has been prepared via a one-pot synthesis encapsulation strategy using the hierarchical metal organic framework [Zn2(dhtp)] (dhtp = 2,5-dihydroxyterephthalate) as a host of the photoactivable molybdenum tricarbonyl complex [Mo(CNCMe2CO2H)3(CO)3]. PMID- 28574563 TI - Reactive oxygen species formed in aqueous mixtures of secondary organic aerosols and mineral dust influencing cloud chemistry and public health in the Anthropocene. AB - Mineral dust and secondary organic aerosols (SOA) account for a major fraction of atmospheric particulate matter, affecting climate, air quality and public health. How mineral dust interacts with SOA to influence cloud chemistry and public health, however, is not well understood. Here, we investigated the formation of reactive oxygen species (ROS), which are key species of atmospheric and physiological chemistry, in aqueous mixtures of SOA and mineral dust by applying electron paramagnetic resonance (EPR) spectrometry in combination with a spin trapping technique, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a kinetic model. We found that substantial amounts of ROS including OH, superoxide as well as carbon- and oxygen-centred organic radicals can be formed in aqueous mixtures of isoprene, alpha-pinene, naphthalene SOA and various kinds of mineral dust (ripidolite, montmorillonite, kaolinite, palygorskite, and Saharan dust). The molar yields of total radicals were ~0.02-0.5% at 295 K, which showed higher values at 310 K, upon 254 nm UV exposure, and under low pH (<3) conditions. ROS formation can be explained by the decomposition of organic hydroperoxides, which are a prominent fraction of SOA, through interactions with water and Fenton-like reactions with dissolved transition metal ions. Our findings imply that the chemical reactivity and aging of SOA particles can be enhanced upon interaction with mineral dust in deliquesced particles or cloud/fog droplets. SOA decomposition could be comparably important to the classical Fenton reaction of H2O2 with Fe2+ and that SOA can be the main source of OH radicals in aqueous droplets at low concentrations of H2O2 and Fe2+. In the human respiratory tract, the inhalation and deposition of SOA and mineral dust can also lead to the release of ROS, which may contribute to oxidative stress and play an important role in the adverse health effects of atmospheric aerosols in the Anthropocene. PMID- 28574564 TI - Critical Casimir interactions between colloids around the critical point of binary solvents. AB - Critical Casimir interactions between colloidal particles arise from the confinement of fluctuations of a near-critical solvent in the liquid gap between closely-spaced particles. So far, the comparison of theoretical predictions and experimental measurements of critical Casimir forces (CCFs) has focused on the critical solvent composition, while it has been lacking for off-critical compositions. We address this issue by investigating CCFs between spherical colloidal particles around the critical point of a binary solvent through a combination of experiments, previous Ising Monte Carlo simulation results and field-theoretical methods. By measuring the correlation length of the near critical solvent and the pair potentials of the particles in terms of radial distribution functions and by determining the second virial coefficient, we test in detail theoretical predictions. Our results indicate that the critical Casimir theory gives quantitative correct predictions for the interaction potential between particles in a near critical binary mixture if weak preferential adsorption of the particle surface is taken into account. PMID- 28574565 TI - Molecular dynamics of 1-ethyl-3-methylimidazolium triflate ionic liquid studied by 1H and 19F nuclear magnetic resonances. AB - The molecular dynamics of an ionic liquid (IL) composed of a 1-ethyl-3 methylimidazolium cation and a triflate (trifluoromethanesulfonate) anion, abbreviated as [Emim][TfO], were studied by NMR spectroscopy. By measuring the temperature-dependent high-field 1H and 19F spin-lattice relaxation (SLR) rates, the frequency-dependent 1H and 19F SLR dispersion curves using fast-field-cycling relaxometry, and the temperature-dependent 1H and 19F diffusion constants, and by utilizing the fact that the primary NMR-active nucleus on the Emim cation is 1H, whereas on the TfO anion it is 19F, the cationic and anionic dynamics were studied separately. A single theoretical relaxation model successfully reproduced all the experimental data of both types of resonant nuclei by fitting all the data simultaneously with the same set of fit parameters. Upon cooling, [Emim][TfO] exhibited a supercooled liquid phase between TSL = 256 K and the crystallization temperature TCr ~ 227-222 K, as confirmed by differential scanning calorimetry (DSC) experiments. Theoretical analysis revealed that within the liquid and the supercooled liquid states of [Emim][TfO], the 1H and 19F relaxation rates are affected by both the rotational and translational diffusional processes with no discontinuous change at TSL. While the rotational diffusion is well described as an Arrhenius thermally activated process, the translational diffusion undergoes strong freezing dynamics that are well described by the Vogel-Fulcher model assuming a freezing temperature of T0 = 157 K. The existence of the supercooled liquid region in the [Emim][TfO] IL should be taken into account when using this IL for a specific application. PMID- 28574566 TI - Baseline toxicity and ion-trapping models to describe the pH-dependence of bacterial toxicity of pharmaceuticals. AB - In numerous studies on the toxicity of ionisable organic chemicals, it has been shown that the toxicity was typically higher, when larger fractions of the neutral species were present. This observation was explained in some cases by slower uptake of charged species. In other cases it was suggested that the neutral species has intrinsically higher toxicity than the charged species or is alone responsible for the toxicity. However, even permanently charged and organic chemicals with multiple acid and base functional groups and zwitterions are toxic. We set out to reconcile the divergent views and to compare the various existing models for describing the pH-dependence of toxicity with the goal to derive one model that is valid independent of the type and number of charges on the molecule. To achieve this goal we measured the cytotoxicity of 18 acidic, 15 basic and 9 multiprotic/zwitterionic pharmaceuticals at pH 5.5 to pH 9 with the bioluminescence inhibition test using Aliivibrio fischeri (Microtox assay). This assay is useful for an evaluation of various models to describe pH-dependent toxicity because the majority of chemicals act as baseline toxicants in this 30 min cytotoxicity assay. Therefore baseline toxicity with constant membrane concentrations of the sum of all chemical species of approximately 200 mmol kglip 1 served for the validation of the suitability of the various tested models. We confirmed that most tested pharmaceuticals acted as baseline toxicants in this assay at all examined pH values, when toxicity was modeled with a mixture model of concentration addition between the neutral species and all charged species. An ion trapping model, that assumes that the membrane permeability of charged species is kinetically limited, improved model predictions for some pharmaceuticals and pH values. However, neither unhindered uptake nor no uptake of the charged species were ideal models; the reality lies presumably between the two limiting cases with a slower uptake of the charged species than the neutral species. For practical applications a previously developed QSAR model with the ionisation-corrected liposome-water distribution ratio as the sole physicochemical descriptor proved to be generally applicable for all ionisable organic chemicals including those with multiple charges and zwitterions. PMID- 28574567 TI - Using advanced mass spectrometry techniques to fully characterize atmospheric organic carbon: current capabilities and remaining gaps. AB - Organic compounds in the atmosphere vary widely in their molecular composition and chemical properties, so no single instrument can reasonably measure the entire range of ambient compounds. Over the past decade, a new generation of in situ, field-deployable mass spectrometers has dramatically improved our ability to detect, identify, and quantify these organic compounds, but no systematic approach has been developed to assess the extent to which currently available tools capture the entire space of chemical identity and properties that is expected in the atmosphere. Reduced-parameter frameworks that have been developed to describe atmospheric mixtures are exploited here to characterize the range of chemical properties accessed by a suite of instruments. Multiple chemical spaces (e.g. oxidation state of carbon vs. volatility, and oxygen number vs. carbon number) were populated with ions measured by several mass spectrometers, with gas and particle-phase alpha-pinene oxidation products serving as the test mixture of organic compounds. Few gaps are observed in the coverage of the parameter spaces by the instruments employed in this work, though the full extent to which comprehensive measurement was achieved is difficult to assess due to uncertainty in the composition of the mixture. Overlaps between individual ions and regions in parameter space were identified, both between gas- and particle-phase measurements, and within each phase. These overlaps were conservatively found to account for little (<10%) of the measured mass. However, challenges in identifying overlaps and in accurately converting molecular formulas into chemical properties (such as volatility or reactivity) highlight a continued need to incorporate structural information into atmospheric measurements. PMID- 28574568 TI - Aerosol climate change effects on land ecosystem services. AB - A coupled global aerosol-carbon-climate model is applied to assess the impacts of aerosol physical climate change on the land ecosystem services gross primary productivity (GPP) and net primary productivity (NPP) in the 1996-2005 period. Aerosol impacts are quantified on an annual mean basis relative to the hypothetical aerosol-free world in 1996-2005, the global climate state in the absence of the historical rise in aerosol pollution. We examine the separate and combined roles of fast feedbacks associated with the land and slow feedbacks associated with the ocean. We consider all fossil fuel, biofuel and biomass burning aerosol emission sources as anthropogenic. The effective radiative forcing for aerosol-radiation interactions is -0.44 W m-2 and aerosol-cloud interactions is -1.64 W m-2. Aerosols cool and dry the global climate system by 0.8 degrees C and -0.08 mm per day relative to the aerosol-free world. Without aerosol pollution, human-induced global warming since the preindustrial would have already exceeded the 1.5 degrees C aspirational limit set in the Paris Agreement by the 1996-2005 decade. Aerosol climate impacts on the global average land ecosystem services are small due to large opposite sign effects in the tropical and boreal biomes. Aerosol slow feedbacks associated with the ocean strongly dominate impacts in the Amazon and North American Boreal. Aerosol cooling of the Amazon by -1.2 degrees C drives NPP increases of 8% or +0.76 +/- 0.61 PgC per year, a 5-10 times larger impact than estimates of diffuse radiation fertilization by biomass burning aerosol in this region. The North American Boreal suffers GPP and NPP decreases of 35% due to aerosol-induced cooling and drying (-1.6 degrees C, -0.14 mm per day). Aerosol-land feedbacks play a larger role in the eastern US and Central Africa. Our study identifies an eco-climate teleconnection in the polluted earth system: the rise of the northern hemisphere mid-latitude reflective aerosol pollution layer causes long range cooling that protects Amazon NPP by 8% and suppresses boreal NPP by 35%. PMID- 28574569 TI - Atmospheric protein chemistry influenced by anthropogenic air pollutants: nitration and oligomerization upon exposure to ozone and nitrogen dioxide. AB - The allergenic potential of airborne proteins may be enhanced via post translational modification induced by air pollutants like ozone (O3) and nitrogen dioxide (NO2). The molecular mechanisms and kinetics of the chemical modifications that enhance the allergenicity of proteins, however, are still not fully understood. Here, protein tyrosine nitration and oligomerization upon simultaneous exposure of O3 and NO2 were studied in coated-wall flow-tube and bulk solution experiments under varying atmospherically relevant conditions (5 200 ppb O3, 5-200 ppb NO2, 45-96% RH), using bovine serum albumin as a model protein. Generally, more tyrosine residues were found to react via the nitration pathway than via the oligomerization pathway. Depending on reaction conditions, oligomer mass fractions and nitration degrees were in the ranges of 2.5-25% and 0.5-7%, respectively. The experimental results were well reproduced by the kinetic multilayer model of aerosol surface and bulk chemistry (KM-SUB). The extent of nitration and oligomerization strongly depends on relative humidity (RH) due to moisture-induced phase transition of proteins, highlighting the importance of cloud processing conditions for accelerated protein chemistry. Dimeric and nitrated species were major products in the liquid phase, while protein oligomerization was observed to a greater extent for the solid and semi solid phase states of proteins. Our results show that the rate of both processes was sensitive towards ambient ozone concentration, but rather insensitive towards different NO2 levels. An increase of tropospheric ozone concentrations in the Anthropocene may thus promote pro-allergic protein modifications and contribute to the observed increase of allergies over the past decades. PMID- 28574570 TI - Accurate representations of the physicochemical properties of atmospheric aerosols: when are laboratory measurements of value? AB - Laboratory studies can provide important insights into the processes that occur at the scale of individual particles in ambient aerosol. We examine the accuracies of measurements of core physicochemical properties of aerosols that can be made in single particle studies and explore the impact of these properties on the microscopic processes that occur in ambient aerosol. Presenting new measurements, we examine here the refinements in our understanding of aerosol hygroscopicity, surface tension, viscosity and optical properties that can be gained from detailed laboratory measurements for complex mixtures through to surrogates for secondary organic atmospheric aerosols. PMID- 28574572 TI - Targeting the tumor microenvironment as a potential therapeutic approach in colorectal cancer: Rational and progress. AB - Colorectal cancer (CC) is often diagnosed at a late stage when tumor metastasis may have already occurred. Current treatments are often ineffective in metastatic disease, and consequently late diagnosis is often associated with poor outcomes in CC. Alternative strategies are therefore urgently required. An interaction between epithelial cancer cells and their tissue microenvironment is a contributor to metastasis, and therefore recent studies are beginning to focus on the properties of the tumor microenvironment and the mechanism by which the metastatic cells exploit the tumor microenvironment for survival, immune evasion, and growth. We have reviewed the development of the combined therapeutic approaches that have focused on targeting the microenvironment of CC. PMID- 28574573 TI - Mass media interventions for preventing smoking in young people. AB - BACKGROUND: Mass media interventions can be used as a way of delivering preventive health messages. They have the potential to reach and modify the knowledge, attitudes and behaviour of a large proportion of the community. OBJECTIVES: To assess the effects of mass media interventions on preventing smoking in young people, and whether it can reduce smoking uptake among youth (under 25 years), improve smoking attitudes, intentions and knowledge, improve self-efficacy/self-esteem, and improve perceptions about smoking, including the choice to follow positive role models. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialized Register, with additional searches of MEDLINE and Embase in June 2016. This is an update of a review first published in 1998. SELECTION CRITERIA: Randomized trials, controlled trials without randomization and interrupted time-series studies that assessed the effect of mass media campaigns (defined as channels of communication such as television, radio, newspapers, social media, billboards, posters, leaflets or booklets intended to reach large numbers of people and which are not dependent on person-to-person contact) in influencing the smoking behaviour (either objective or self-reported) of young people under the age of 25 years. We define smoking behaviour as the presence or absence of tobacco smoking or other tobacco use, or both, and the frequency of tobacco use. Eligible comparators included education or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted information relating to the characteristics and the content of media interventions, participants, outcomes, methods of the study and risks of bias. We combined studies using qualitative narrative synthesis. We assessed the risks of bias for each study using the Cochrane 'Risk of bias' tool, alongside additional domains to account for the nature of the intervention. We assessed the quality of evidence contributing to outcomes using GRADE. MAIN RESULTS: We identified eight eligible studies reporting information about mass media smoking campaigns, one of which is new for this update. Seven of the studies used a controlled trial design and one an interrupted time-series analysis. Risks of bias were high across all included studies and there was considerable heterogeneity in study design, intervention and population being assessed.Three studies (n = 17,385), one of which compared a mass media intervention to no intervention and two of which evaluated mass media interventions as adjuncts to school-based interventions, found that the mass media interventions reduced the smoking behaviour of young people. The remaining five studies (n = 72,740) did not detect a significant effect on smoking behaviour. These included three studies comparing a mass media intervention to no intervention, one study evaluating a mass media intervention as an adjunct to a school-based intervention, and one interrupted time-series study of a social media intervention. The three campaigns which found a significant effect described their theoretical basis, used formative research in designing the campaign messages, and used message broadcast of reasonable intensity over extensive periods of time. However, some of the campaigns which did not detect an effect also exhibited these characteristics. Effective campaigns tended to last longer (minimum 3 years) and were more intense (more contact time) for both school-based lessons (minimum eight lessons per grade) and media spots (minimum four weeks' duration across multiple media channels with between 167 and 350 TV and radio spots). Implementation of combined school-based components (e.g. school posters) and the use of repetitive media messages delivered by multiple channels (e.g. newspapers, radio, television) appeared to contribute to successful campaigns. AUTHORS' CONCLUSIONS: Certainty about the effects of mass media campaigns on smoking behaviour in youth is very low, due to inconsistency between studies in both design and results, and due to methodological issues amongst the included studies. It would therefore be unwise to offer firm conclusions based on the evidence in this review. Methodologically rigorous studies investigating the effect of social media and novel forms of technology as part of tobacco prevention campaigns for youth are needed. PMID- 28574571 TI - Roles of macrophage migration inhibitory factor in cartilage tissue engineering. AB - To obtain stable outcomes in regenerative medicine, understanding and controlling immunological responses in transplanted tissues are of great importance. In our previous study, auricular chondrocytes in tissue-engineered cartilage transplanted in mice were shown to express immunological factors, including macrophage migration inhibitory factor (MIF). Since MIF exerts pleiotropic functions, in this study, we examined the roles of MIF in cartilage regenerative medicine. We made tissue-engineered cartilage consisting of auricular chondrocytes of C57BL/6J mouse, atellocollagen gel and a PLLA scaffold, and transplanted the construct subcutaneously in a syngeneic manner. Localization of MIF was prominent in cartilage areas of tissue-engineered cartilage at 2 weeks after transplantation, though it became less apparent by 8 weeks. Co-culture with RAW264 significantly increased the expression of MIF in chondrocytes, suggesting that the transplanted chondrocytes in tissue-engineered cartilage could enhance the expression of MIF by stimulation of surrounding macrophages. When MIF was added in the culture of chondrocytes, the expression of type II collagen was increased, indicating that MIF could promote the maturation of chondrocytes. Meanwhile, toluidine blue staining of constructs containing wild type (Mif+/+) chondrocytes showed increased metachromasia compared to MIF-knockout (Mif-/-) constructs at 2 weeks. However, this tendency was reversed by 8 weeks, suggesting that the initial increase in cartilage maturation in Mif+/+ constructs deteriorated by 8 weeks. Since the Mif+/+ constructs included more iNOS-positive inflammatory macrophages at 2 weeks, MIF might induce an M1 macrophage-polarized environment, which may eventually worsen the maturation of tissue-engineered cartilage in the long term. PMID- 28574574 TI - Actions of quercetin, a flavonoid, on ion transporters: its physiological roles. AB - Flavonoids keep us healthy by controlling various body and cellular functions. It is well known that cations, such as Na+ , K+ , and Ca2+ , play important roles in the regulation of body and cellular functions, including generation of action potentials and the resting membrane potential of neural and muscle cells and signal transduction as intracellular second messengers. However, we have little information on the physiological roles of anions, particularly Cl- , in body and cellular functions. Quercetin, a flavonoid, stimulates Na+ -K+ -2Cl- cotransporter 1 (NKCC1), which is one of the most important ion transporters regulating the cytosolic Cl- concentration ([Cl- ]c ). Here, we introduce the molecular mechanism by which flavonoids, specifically quercetin, act through elevation of [Cl- ]c via activation of NKCC1 on important factors controlling various body and cellular functions, such as (1) antihypertensive actions controlling blood volume dependent on the amounts of renal Na+ reabsorption via expression of the epithelial Na+ channel, (2) neurite-elongating actions via polymerization of tubulin by inhibiting GTPase activity, and (3) antibacterial and antiviral infective actions through stimulation of epithelial Cl- secretion by increasing the driving force for epithelial Cl- secretion. PMID- 28574575 TI - Genomics of antibiotic-resistance prediction in Pseudomonas aeruginosa. AB - Antibiotic resistance is a worldwide health issue spreading quickly among human and animal pathogens, as well as environmental bacteria. Misuse of antibiotics has an impact on the selection of resistant bacteria, thus contributing to an increase in the occurrence of resistant genotypes that emerge via spontaneous mutation or are acquired by horizontal gene transfer. There is a specific and urgent need not only to detect antimicrobial resistance but also to predict antibiotic resistance in silico. We now have the capability to sequence hundreds of bacterial genomes per week, including assembly and annotation. Novel and forthcoming bioinformatics tools can predict the resistome and the mobilome with a level of sophistication not previously possible. Coupled with bacterial strain collections and databases containing strain metadata, prediction of antibiotic resistance and the potential for virulence are moving rapidly toward a novel approach in molecular epidemiology. Here, we present a model system in antibiotic resistance prediction, along with its promises and limitations. As it is commonly multidrug resistant, Pseudomonas aeruginosa causes infections that are often difficult to eradicate. We review novel approaches for genotype prediction of antibiotic resistance. We discuss the generation of microbial sequence data for real-time patient management and the prediction of antimicrobial resistance. PMID- 28574577 TI - PCSK9 and infection: A potentially useful or dangerous association? AB - Elevated plasma low-density lipoprotein-cholesterol (LDL-C) concentration is the most important risk factor for atherosclerotic cardiovascular diseases (CVDs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a ubiquitously expressed serine proteinase which plays a key role in cholesterol metabolism, but has been found to be implicated in some other lipid-independent physiological processes. In this review, the role of PCSK9 was evaluated not only concerning lipid metabolism but also hepatitis C virus (HCV) infection, bacterial infections/sepsis, and septic shock. Collected data from clinical trials revealed that treatment with PCSK9 inhibitors has beneficial effects in lowering LDL-C via inhibition of LDL-receptors (LDL-R), an antiviral effect on HCV infection via down-regulating the surface expression of LDL-R and CD81 on hepatic cells, and a positive association with increased inflammatory responses, as well as with septic shock by down-regulation of hepatocyte LDL-R. On the other hand, PCSK9 inhibition by therapeutic fully humanized antibodies has positive effects in reducing elevated LDL-C. However, their safety and tolerability is an important issue which has to be taken into consideration. PMID- 28574578 TI - The Fam50a positively regulates ameloblast differentiation via interacting with Runx2. AB - Differentiated ameloblasts secret enamel matrix proteins such as amelogenin, ameloblastin, and enamelin. Expression levels of these proteins are regulated by various factors. To find a new regulatory factor for ameloblast differentiation, we performed 2D-PAGE analysis using mouse ameloblast lineage cell line (mALCs) cultured with mineralizing medium. Of identified proteins, family with sequence similarity 50 member A (Fam50a) was significantly increased during differentiation of mALCs. Fam50a protein was also highly expressed in secretory ameloblasts of mouse tooth germs. In mALCs cultures, forced expression of Fam50a up-regulated the expression of enamel matrix protein genes such as amelogenin, ameloblastin, and enamelin. In addition, up-regulation of Fam50a also increased ALP activity and mineralized nodule formation in a dose-dependent manner. In contrast, knockdown of Fam50a decreased expression levels of enamel matrix protein genes, ALP activity, and mineralized nodule formation. By fluorescence microscopy, endogenous Fam50a protein was found to be localized to the nucleus of ameloblasts. In addition, Fam50a synergistically increased Ambn transactivation by Runx2. Moreover, Fam50a increased binding affinity of Runx2 to Ambn promoter by physically interacting with Runx2. Taken together, these results suggest Fam50a might be a new positive regulator of ameloblast differentiation. PMID- 28574576 TI - VEGF-A165 b protects against proteinuria in a mouse model with progressive depletion of all endogenous VEGF-A splice isoforms from the kidney. AB - KEY POINTS: Progressive depletion of all vascular endothelial growth factor A (VEGF-A) splice isoforms from the kidney results in proteinuria and increased glomerular water permeability, which are both rescued by over-expression of VEGF A165 b only. VEGF-A165 b rescues the increase in glomerular basement membrane and podocyte slit width, as well as the decrease in sub-podocyte space coverage, produced by VEGF-A depletion. VEGF-A165 b restores the expression of platelet endothelial cell adhesion molecule in glomerular endothelial cells and glomerular capillary circumference. VEGF-A165 b has opposite effects to VEGF-A165 on the expression of genes involved in endothelial cell migration and proliferation. ABSTRACT: Chronic kidney disease is strongly associated with a decrease in the expression of vascular endothelial growth factor A (VEGF-A). However, little is known about the contribution of VEGF-A splice isoforms to kidney physiology and pathology. Previous studies suggest that the splice isoform VEGF-A165 b (resulting from alternative usage of a 3' splice site in the terminal exon) is protective for kidney function. In the present study, we show, in a quad transgenic model, that over-expression of VEGF-A165 b alone is sufficient to rescue the increase in proteinuria, as well as glomerular water permeability, in the context of progressive depletion of all VEGF-A isoforms from the podocytes. Ultrastructural studies show that the glomerular basement membrane is thickened, podocyte slit width is increased and sub-podocyte space coverage is reduced when VEGF-A is depleted, all of which are rescued in VEGF-A165 b over-expressors. VEGF A165 b restores the expression of platelet endothelial cell adhesion molecule-1 in glomerular endothelial cells and glomerular capillary circumference. Mechanistically, it increases VEGF receptor 2 expression both in vivo and in vitro and down-regulates genes involved in migration and proliferation of endothelial cells, otherwise up-regulated by the canonical isoform VEGF-A165 . The results of the present study indicate that manipulation of VEGF-A splice isoforms could be a novel therapeutic avenue in chronic glomerular disease. PMID- 28574579 TI - The effect of a maternal history of childhood abuse on adrenocortical attunement in mothers and their toddlers. AB - We investigated circadian mother-child adrenocortical attunement in the context of a maternal history of childhood abuse (HoA). Mothers were screened after birth using the Childhood Trauma Questionnaire. Women reporting moderate or severe abuse formed the HoA group (n = 37; HoAG) and were compared with a non-maltreated comparison group (n = 45; CG). Three years later, cortisol awakening response (CAR) and diurnal slope (DSL) were assessed. Mother-child interaction was coded using the Emotional Availability Scales at 12 months of age. For the CAR, we found adrenocortical attunement only in the HoAG (2-way interaction: p = .004), particularly if mothers scored low on structuring (3-way interaction: p = .042) and children scored low on responsiveness (3-way interaction: p = .044). DSL attunement was dependent on maternal sensitivity (3-way interaction: p = .012) and child involvement (3-way interaction: p = .012). In the context of a maternal HoA, it seems possible for mother-child-dyads to show less optimal interactional quality but be stronger attuned to each other biologically. PMID- 28574580 TI - Echographic features and perinatal outcomes in fetuses with congenital absence of ductus venosus. AB - INTRODUCTION: The purpose of this study was to describe the echographic features and perinatal outcomes of fetuses with absence of ductus venosus. MATERIAL AND METHODS: Retrospective review of 10 cases with absence of ductus venosus diagnosed by prenatal ultrasonography between January 2014 and February 2016 at a single referral center. Prenatal findings, umbilical shunting type, perinatal outcomes, and autopsy reports were reviewed. RESULTS: A total of 11 491 fetuses underwent a first- and second-trimester screening during the study period. Ten cases of absence of ductus venosus were diagnosed. All of the fetuses presented an extrahepatic shunt: three fetuses from the umbilical vein to the right atrium and the seven remaining fetuses from the umbilical vein to the inferior vena cava. Major structural defects and fetal effusions were detected in six fetuses. There were two cases of chromosomal abnormalities. Five patients underwent legal termination of pregnancy and five decided to carry to term. In two of these, the absence of ductus venosus anomaly was isolated and had a normal outcome. In the remaining three cases, a follow up of the children showed a variety of adverse outcomes. CONCLUSIONS: The absence of ductus venosus is associated with high rates of adverse perinatal outcomes. The prognosis for this group of anomalies depends on the additional findings with targeted ultrasound. This pathology should lead to a detailed anatomical study and affected fetuses should be closely monitored for signs of congestive heart failure. PMID- 28574583 TI - The significant role of the Golgi apparatus in cardiovascular diseases. AB - The Golgi apparatus (GA) is a ribbon-like system of stacks which consist of multiple closely apposed flattened cisternae and vesicles usually localized in the juxta-nuclear area. As for the biological functions, the GA plays a major role in protein biosynthesis, post-translational modification, and sorting protein from ER to plasma membrane and other destinations. Structural changes and functional disorder of the GA is associated with various diseases. Moreover, increasing evidence revealed that swelling, poor development, and other morphological alterations of the GA are linked to cardiovascular diseases such as heart failure (HF), arrhythmia, and dilated cardiomyopathy. Furthermore, dysfunction of the GA is also related to cardiovascular diseases since the GA is extremely responsible for transport, glycosylation, biosynthesis, and subcellular distribution of cardiovascular proteins. This review gives a brief overview of the intricate relationship between the GA and cardiovascular diseases. In addition, we provide a further prospective that the GA may provide diagnosis reference for cardiovascular diseases, and changes in the ultrastructure and morphology of the GA such as swelling, poor development, and fragmentation may serve as a reliable index for cardiovascular diseases. PMID- 28574581 TI - The beta3 -adrenoceptor agonist mirabegron increases human atrial force through beta1 -adrenoceptors: an indirect mechanism? AB - BACKGROUND AND PURPOSE: Mirabegron has been classified as a beta3 -adrenoceptor agonist approved for overactive bladder syndrome. We investigated possible cardiac effects of mirabegron in the absence or presence of beta-adrenoceptor subtype antagonists. In view of its phenylethanolamine structure, we investigated whether mirabegron has indirect sympathomimetic activity by using neuronal uptake blockers. EXPERIMENTAL APPROACH: Right atrial trabeculae, from non-failing hearts, were paced and contractile force measured at 37 degrees C. Single concentrations of mirabegron were added in the absence or presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), beta3 (L 748,337), beta1 (CGP 20712A), beta2 (ICI 118,551) -adrenoceptor antagonists, neuronal uptake inhibitors desipramine or phenoxybenzamine. KEY RESULTS: Mirabegron significantly increased contractile force in human right atrium (1 MUM, 7.6 +/- 2.6%, n = 7; 10 MUM, 10.2 +/- 1.5%, n = 22 compared with (-) isoprenaline P < 0.05). In the presence of IBMX, mirabegron (10 MUM) caused a greater contraction. L-748,337 (100 nM) had no effect on the increase in contractile force caused by mirabegron (10 MUM). In contrast, mirabegron (10 MUM) reduced contractile force in the presence of CGP 20712A, which was not affected by L-748,337 (100 nM) or ICI 118,551 (50 nM). Mirabegron (10 MUM) also reduced contractile force in the presence of desipramine or phenoxybenzamine. CONCLUSIONS AND IMPLICATIONS: Mirabegron increases human atrial force through beta1 - but not beta3 -adrenoceptors. Desipramine and phenoxybenzamine block neuronal uptake and conceivably prevent mirabegron from releasing noradrenaline. A non-specific cardiodepressant effect is not mediated through beta3 (or beta2 )-adrenoceptors, consistent with lack of beta3 -adrenoceptor function on human atrial contractility. PMID- 28574584 TI - Composite marginal quantile regression analysis for longitudinal adolescent body mass index data. AB - Childhood and adolescenthood overweight or obesity, which may be quantified through the body mass index (BMI), is strongly associated with adult obesity and other health problems. Motivated by the child and adolescent behaviors in long term evolution (CABLE) study, we are interested in individual, family, and school factors associated with marginal quantiles of longitudinal adolescent BMI values. We propose a new method for composite marginal quantile regression analysis for longitudinal outcome data, which performs marginal quantile regressions at multiple quantile levels simultaneously. The proposed method extends the quantile regression coefficient modeling method introduced by Frumento and Bottai (Biometrics 2016; 72:74-84) to longitudinal data accounting suitably for the correlation structure in longitudinal observations. A goodness-of-fit test for the proposed modeling is also developed. Simulation results show that the proposed method can be much more efficient than the analysis without taking correlation into account and the analysis performing separate quantile regressions at different quantile levels. The application to the longitudinal adolescent BMI data from the CABLE study demonstrates the practical utility of our proposal. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28574582 TI - Production of G protein-coupled receptors in an insect-based cell-free system. AB - The biochemical analysis of human cell membrane proteins remains a challenging task due to the difficulties in producing sufficient quantities of functional protein. G protein-coupled receptors (GPCRs) represent a main class of membrane proteins and drug targets, which are responsible for a huge number of signaling processes regulating various physiological functions in living cells. To circumvent the current bottlenecks in GPCR studies, we propose the synthesis of GPCRs in eukaryotic cell-free systems based on extracts generated from insect (Sf21) cells. Insect cell lysates harbor the fully active translational and translocational machinery allowing posttranslational modifications, such as glycosylation and phosphorylation of de novo synthesized proteins. Here, we demonstrate the production of several GPCRs in a eukaryotic cell-free system, performed within a short time and in a cost-effective manner. We were able to synthesize a variety of GPCRs ranging from 40 to 133 kDa in an insect-based cell free system. Moreover, we have chosen the MU opioid receptor (MOR) as a model protein to analyze the ligand binding affinities of cell-free synthesized MOR in comparison to MOR expressed in a human cell line by "one-point" radioligand binding experiments. Biotechnol. Bioeng. 2017;114: 2328-2338. (c) 2017 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc. PMID- 28574585 TI - Sex-specific associations between self-reported sleep duration, depression, anxiety, fatigue and daytime sleepiness in an older community-dwelling population. AB - PURPOSE: The purpose of this study was to explore whether associations between self-reported sleep duration, depressive symptoms, anxiety, fatigue and daytime sleepiness differed in older community-dwelling men and women. DESIGN: Cross sectional. METHODS: A community-dwelling sample of 675 older men and women (mean age 77.7 years, SD 3.8 years) was used. All participants underwent a clinical examination by a cardiologist. Validated questionnaires were used to investigate sleep duration, depressive symptoms, anxiety, fatigue and daytime sleepiness. Subjects were divided into short sleepers (<=6 hours), n = 231; normal sleepers (7-8 hours), n = 338; and long sleepers (>=9 hours), n = 61. ancovas were used to explore sex-specific effects. RESULTS: Depressive symptoms were associated with short sleep in men, but not in women. Fatigue was associated with both short and long sleep duration in men. No sex-specific associations of sleep duration with daytime sleepiness or anxiety were found. CONCLUSION: Nurses investigating sleep duration and its correlates, or effects, in clinical practice need to take sex into account, as some associations may be sex specific. Depressive symptoms and fatigue can be used as indicators to identify older men with sleep complaints. PMID- 28574587 TI - Stress-responsive microRNAs are involved in re-programming of metabolic functions in hibernators. AB - Mammalian hibernation includes re-programing of metabolic capacities, partially, encouraged by microRNAs (miRNAs). Albeit much is known about the functions of miRNAs, we need learning on low temperature miRNAs target determination. As hibernators can withstand low body temperatures (TB) for a long time without anguish tissue damage, understanding the means and mechanisms that empower them to do as such are of restorative intrigue. Nonetheless, these mechanisms by which miRNAs and the hibernators react to stressful conditions are not much clear. It is evident from recent data that the gene expression and the translation of mRNA to protein are controlled by miRNAs. The miRNAs also influence regulation of major cellular processes. As the significance of miRNAs in stress conditions adaptation are getting clearer, this audit article abridges the key alterations in miRNA expression and the mechanism that facilitates stress survival. PMID- 28574586 TI - Clinical Importance of Monitoring Unbound Valproic Acid Concentration in Patients with Hypoalbuminemia. AB - STUDY OBJECTIVE: Because the pharmacokinetic evaluation of valproic acid (VPA) based on total drug concentration may be misleading in patients with hypoalbuminemia as a result of saturable protein binding and saturable metabolism, we sought to investigate the usefulness of therapeutic drug monitoring of unbound VPA concentration in a real-world clinical context, with a focus on clinically significant neurologic adverse outcomes. DESIGN: Retrospective analysis. SETTING: Large academic tertiary care hospital in Montreal, Canada. PATIENTS: Forty-one adults, hospitalized or followed as outpatients, for whom unbound VPA concentration testing was performed between January 1, 2008, and April 30, 2015. Patients were retrospectively identified by using the hospital's central laboratory database. MEASUREMENTS AND MAIN RESULTS: In the multiple linear regression analysis, the two variables that significantly predicted unbound VPA concentration were total VPA concentration (p<0.001) and albumin concentration (p<0.001). The correlation between total VPA concentration and the number of neurologic adverse symptoms was 0.187 (p=0.241), whereas the correlation between unbound VPA concentration and the number of neurologic adverse symptoms was 0.384 (p=0.013). The performance of total and unbound VPA concentrations in predicting the presence of at least one neurologic adverse symptom, as determined by the receiver operating characteristic curve, was 0.642 (95% confidence interval [CI] 0.449-0.836, p=0.167) and 0.776 (95% CI 0.629 0.923, p=0.007), respectively. CONCLUSION: This study showed that in the presence of hypoalbuminemia, high unbound VPA concentrations can be observed despite normal or low total VPA concentrations. It also demonstrated that high unbound VPA concentrations are associated with clinically significant neurologic adverse symptoms. Clinicians should be aware that unbound VPA concentration monitoring may be required in the presence of hypoalbuminemia. PMID- 28574590 TI - Pregnancy outcomes after liver transplantation in Finland. AB - INTRODUCTION: Pregnancy after liver transplantation is possible but associated with increased risk of obstetrical complications. We report here for the first time the pregnancy outcomes after liver transplantation in Finland. MATERIAL AND METHODS: All of the 25 pregnancies ending in deliveries after liver transplantation in Finland in 1998-2015 were analyzed. The data were collected from the mothers' medical records. The main outcome measures included pregnancy complications and the mode of delivery. Neonatal outcome measures were birthweight, 5-min Apgar score and umbilical artery pH. RESULTS: Twenty-six infants were born. Of all deliveries, 76% occurred at the >=37 weeks of gestation and the average birthweight was 3040 g. Apgar scores were >=7 in 25/26 (96%) of the infants and cases of birth asphyxia (umbilical artery pH <= 7.05) were not detected. Cesarean section rate was 32%. Preeclampsia occurred in 12% of the women and the preterm delivery rate was 24%. Co-morbidities (hypertension, intrahepatic cholestasis of pregnancy, Hodgkin's disease, colitis ulcerosa, epileptic attacks, cholangitis, splenic artery rupture, renal insufficiency and graft rejection) complicated 52% of pregnancies. CONCLUSION: Pregnancies after liver transplantation in Finland result in good perinatal outcome with healthy, mostly full-term, normally grown offspring; however, serious maternal complications related to underlying liver pathology, transplant surgery and immunosuppressive medication occur frequently. PMID- 28574588 TI - Protective influence of healthful nutrition on mechanisms of environmental pollutant toxicity and disease risks. AB - Human exposures to environmental contaminants around the world contribute to the global burden of disease and thus require urgent attention. Exploring preventive measures against environmental exposure and disease risk is essential. While a sedentary lifestyle and/or poor dietary habits can exacerbate the deleterious effects resulting from exposure to toxic chemicals, much emerging evidence suggests that positive lifestyle changes (e.g., healthful nutrition) can modulate and/or reduce the toxicity of environmental pollutants. Our work has shown that diets high in anti-inflammatory bioactive food components (e.g., phytochemicals or polyphenols) are possible strategies for modulating and reducing the disease risks associated with exposure to toxic pollutants in the environment. Thus, consuming healthy diets rich in plant-derived bioactive nutrients may reduce the vulnerability to diseases linked to environmental toxic insults. This nutritional paradigm in environmental toxicology requires further study in order to improve our understanding of the relationships between nutrition and other lifestyle modifications and toxicant-induced diseases. PMID- 28574589 TI - Enterovirus genotypes among patients with severe acute respiratory illness, influenza-like illness, and asymptomatic individuals in South Africa, 2012-2014. AB - Enteroviruses can cause outbreaks of severe acute respiratory illness (SARI) and EV-A, -B, -C, and -D species have different pathogenic profiles and circulation patterns. We aimed to characterize and determine the prevalence of enterovirus genotypes among South African patients with respiratory illness and controls during June 2012 to July 2014. Syndromic SARI and influenza-like illness (ILI) surveillance was performed at two sentinel sites. At each site nasopharyngeal/oropharyngeal specimens were collected from SARI and ILI patients as well as controls. Specimens were tested for enterovirus by real-time PCR. Positive specimens were further genotyped by sequencing a region of the VP1 gene. The prevalence of enterovirus was 5.8% (87/1494), 3.4% (103/3079), and 3.4% (46/1367) among SARI, ILI, and controls, respectively (SARI/controls, P = 0.002 and ILI/control, P = 0.973). Among the 101/236 (42.8%) enterovirus-positive specimens that could be genotyped, we observed a high diversity of circulating enterovirus genotypes (a total of 33 genotypes) from all four human enterovirus species with high prevalence of Enterovirus-B (60.4%; 61/101) and Enterovirus-A (21.8%; 22/101) compared to Enterovirus-C (10.9%; 11/101) and Enterovirus-D (6.9%; 7/101) (P = 0.477). Of the enterovirus genotypes identified, Echovirus 30 (9.9%, 10/101), Coxsackie virus B5 (7.9%, 8/101) and Enterovirus-D68 (6.9%, 7/101) were most prevalent. There was no difference in disease severity (SARI or ILI compared to controls) between the different enterovirus species (P = 0.167). We observed a high number of enterovirus genotypes in patients with respiratory illness and in controls from South Africa with no disease association of EV species with disease severity. PMID- 28574592 TI - Non-ignorable missingness in logistic regression. AB - Nonresponses and missing data are common in observational studies. Ignoring or inadequately handling missing data may lead to biased parameter estimation, incorrect standard errors and, as a consequence, incorrect statistical inference and conclusions. We present a strategy for modelling non-ignorable missingness where the probability of nonresponse depends on the outcome. Using a simple case of logistic regression, we quantify the bias in regression estimates and show the observed likelihood is non-identifiable under non-ignorable missing data mechanism. We then adopt a selection model factorisation of the joint distribution as the basis for a sensitivity analysis to study changes in estimated parameters and the robustness of study conclusions against different assumptions. A Bayesian framework for model estimation is used as it provides a flexible approach for incorporating different missing data assumptions and conducting sensitivity analysis. Using simulated data, we explore the performance of the Bayesian selection model in correcting for bias in a logistic regression. We then implement our strategy using survey data from the 45 and Up Study to investigate factors associated with worsening health from the baseline to follow up survey. Our findings have practical implications for the use of the 45 and Up Study data to answer important research questions relating to health and quality of-life. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28574591 TI - Bone marrow adipocytes support hematopoietic stem cell survival. AB - In bone marrow (BM), hematopoietic elements are mingled with adipocytes (BM-A), which are the most abundant stromal component in the niche. BM-A progressively increase with aging, eventually occupying up to 50% of BM cavities. In this work, the role played by BM-A was explored by studying primary human BM-A isolated from hip surgery patients at the molecular level, through microarray analysis, and at the functional level, by assessing their relationship with primary human hematopoietic stem cells (HSC) by the long-term culture initiating cell (LTC-IC) assay. Findings demonstrated that BM-A are capable of supporting HSC survival in the LTC-IC assay, since after 5 weeks of co-culture, HSC were still able to proliferate and differentiate. Furthermore, critical molecules such as C-X-C motif chemokine 12 (CXCL12), interleukin (IL)-8, colony-stimulating factor 3 (CSF3), and leukaemia inhibitory factor (LIF), were expressed at similar levels in BM-A and in primary human BM mesenchymal stromal cells (BM-MSC), whereas IL-3 was higher in BM-A. Interestingly, BM-A displayed a different gene expression profile compared with subcutaneous adipose tissue adipocytes (AT-A) collected from abdominal surgery patients, especially in terms of regulation of lipid metabolism, stemness genes, and white-to-brown differentiation pathways. Accordingly, analysis of the gene pathways involved in hematopoiesis regulation showed that BM-A are more closely related to BM-MSC than to AT-A. The present data suggest that BM-A play a supporting role in the hematopoietic niche and directly sustain HSC survival. PMID- 28574593 TI - Early versus delayed appendicectomy for appendiceal phlegmon or abscess. AB - BACKGROUND: Appendiceal phlegmon and abscess account for 2% to 10% of acute appendicitis. People with appendiceal phlegmon or abscess usually need an appendicectomy to relieve their symptoms and avoid complications. The timing of appendicectomy for appendiceal phlegmon or abscess is controversial. OBJECTIVES: To assess the effects of early versus delayed appendicectomy for appendiceal phlegmon or abscess, in terms of overall morbidity and mortality. SEARCH METHODS: We searched the Cochrane Library (CENTRAL; 2016, Issue 7), MEDLINE Ovid (1950 to 23 August 2016), Embase Ovid (1974 to 23 August 2016), Science Citation Index Expanded (1900 to 23 August 2016), and the Chinese Biomedical Literature Database (CBM) (1978 to 23 August 2016). We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform search portal (23 August 2016) and ClinicalTrials.gov (23 August 2016) for ongoing trials. SELECTION CRITERIA: We included all individual and cluster-randomised controlled trials, irrespective of language, publication status, or age of participants, comparing early versus delayed appendicectomy in people with appendiceal phlegmon or abscess. DATA COLLECTION AND ANALYSIS: Two review authors independently identified the trials for inclusion, collected the data, and assessed the risk of bias. We performed meta-analyses using Review Manager 5. We calculated the risk ratio (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: We included two randomised controlled trials with a total of 80 participants in this review. 1. Early versus delayed open appendicectomy for appendiceal phlegmonForty participants (paediatric and adults) with appendiceal phlegmon were randomised either to early appendicectomy (appendicectomy as soon as appendiceal mass resolved within the same admission) (n = 20), or to delayed appendicectomy (initial conservative treatment followed by interval appendicectomy six weeks later) (n = 20). The trial was at high risk of bias. There was no mortality in either group. There is insufficient evidence to determine the effect of using either early or delayed open appendicectomy onoverall morbidity (RR 13.00; 95% CI 0.78 to 216.39; very low-quality evidence), the proportion of participants who developed wound infection (RR 9.00; 95% CI 0.52 to 156.91; very low quality evidence) or faecal fistula (RR 3.00; 95% CI 0.13 to 69.52; very low quality evidence). The quality of evidence for increased length of hospital stay and time away from normal activities in the early appendicectomy group (MD 6.70 days; 95% CI 2.76 to 10.64, and MD 5.00 days; 95% CI 1.52 to 8.48, respectively) is very low quality evidence. The trial reported neither quality of life nor pain outcomes. 2. Early versus delayed laparoscopic appendicectomy for appendiceal abscessForty paediatric participants with appendiceal abscess were randomised either to early appendicectomy (emergent laparoscopic appendicectomy) (n = 20) or to delayed appendicectomy (initial conservative treatment followed by interval laparoscopic appendicectomy 10 weeks later) (n = 20). The trial was at high risk of bias. The trial did not report on overall morbidity or complications. There was no mortality in either group. We do not have sufficient evidence to determine the effects of using either early or delayed laparoscopic appendicectomy for outcomes relating to hospital stay between the groups (MD -0.20 days; 95% CI 3.54 to 3.14; very low quality of evidence). Health-related quality of life was measured with the Pediatric Quality of Life Scale-Version 4.0 questionnaire (a scale of 0 to 100 with higher values indicating a better quality of life). Health related quality of life score measured at 12 weeks after appendicectomy was higher in the early appendicectomy group than in the delayed appendicectomy group (MD 12.40 points; 95% CI 9.78 to 15.02) but the quality of evidence was very low. This trial reported neither the pain nor the time away from normal activities. AUTHORS' CONCLUSIONS: It is unclear whether early appendicectomy prevents complications compared to delayed appendicectomy for people with appendiceal phlegmon or abscess. The evidence indicating increased length of hospital stay and time away from normal activities in people with early open appendicectomy is of very low quality. The evidence for better health-related quality of life following early laparoscopic appendicectomy compared with delayed appendicectomy is based on very low quality evidence. For both comparisons addressed in this review, data are sparse, and we cannot rule out significant benefits or harms of early versus delayed appendicectomy.Further trials on this topic are urgently needed and should specify a set of criteria for use of antibiotics, percutaneous drainage of the appendiceal abscess prior to surgery and resolution of the appendiceal phlegmon or abscess. Future trials should include outcomes such as time away from normal activities, quality of life and the length of hospital stay. PMID- 28574594 TI - A novel protein-engineered hepatocyte growth factor analog released via a shear thinning injectable hydrogel enhances post-infarction ventricular function. AB - In the last decade, numerous growth factors and biomaterials have been explored for the treatment of myocardial infarction (MI). While pre-clinical studies have demonstrated promising results, clinical trials have been disappointing and inconsistent, likely due to poor translatability. In the present study, we investigate a potential myocardial regenerative therapy consisting of a protein engineered dimeric fragment of hepatocyte growth factor (HGFdf) encapsulated in a shear-thinning, self-healing, bioengineered hydrogel (SHIELD). We hypothesized that SHIELD would facilitate targeted, sustained intramyocardial delivery of HGFdf thereby attenuating myocardial injury and post-infarction remodeling. Adult male Wistar rats (n = 45) underwent sham surgery or induction of MI followed by injection of phosphate buffered saline (PBS), 10 MUg HGFdf alone, SHIELD alone, or SHIELD encapsulating 10 MUg HGFdf. Ventricular function, infarct size, and angiogenic response were assessed 4 weeks post-infarction. Treatment with SHIELD + HGFdf significantly reduced infarct size and increased both ejection fraction and borderzone arteriole density compared to the controls. Thus, sustained delivery of HGFdf via SHIELD limits post-infarction adverse ventricular remodeling by increasing angiogenesis and reducing fibrosis. Encapsulation of HGFdf in SHIELD improves clinical translatability by enabling minimally-invasive delivery and subsequent retention and sustained administration of this novel, potent angiogenic protein analog. Biotechnol. Bioeng. 2017;114: 2379-2389. (c) 2017 Wiley Periodicals, Inc. PMID- 28574595 TI - Influence of Hospital Type on Outcomes of Individuals Aged 80 and Older with Stroke Treated Using Intravenous Thrombolysis. AB - OBJECTIVES: The aim of the study was to confirm the safety and effectiveness of using intravenous thrombolysis (IVT) with individuals aged 80 and older in routine practice in different hospital settings. DESIGN: Observasional registry. SETTING: Prospective multicenter population-based registry of acute stroke patients treated with reperfusion therapies in Catalonia, Spain (Sistema Online d'Informacio de l'Ictus Agut). PARTICIPANTS: Individuals treated only with IVT (N = 3,231; 1,189 (36.8%) aged >=80). MEASUREMENTS: Symptomatic intracranial hemorrhage, mortality, and favorable outcome (modified Rankin Scale (mRS) score = 0-2) at 3 months were evaluated according to hospital characteristics. Treating hospitals were classified in three categories: comprehensive stroke centers (CSCs), primary stroke centers (PSCs), and community hospitals operating a telestroke system (TS). First individuals aged 80 and older were compared with those younger than 80, and then participants aged 80 and older were focused on. RESULTS: Participants aged 80 and older had significantly higher baseline National Institute of Health Stroke Scale (NIHSS) scores, longer onset to treatment times, and worse outcomes than younger participants. For participants aged 80 and older, 90-day mortality was 23.2%, with 38.7% having favorable outcomes at 3 months. Symptomatic intracranial hemorrhage (SICH; Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy definition) was observed in 4.7% of subjects. None of the risk factors differed significantly between participants treated in different types of hospitals. Basal stroke severity measured according to NIHSS score was not significantly different either. The three different types of hospitals achieved similar outcomes, although the TS and PSC hospitals had significantly higher proportions of SICH (6.3% and 6.3%, respectively) than the CSC (3.2%). CONCLUSION: Older adults with acute stroke treated with IVT had similar outcomes regardless of hospital characteristics. PMID- 28574596 TI - G protein-coupled receptor 84 controls osteoclastogenesis through inhibition of NF-kappaB and MAPK signaling pathways. AB - GPR84, a member of the G protein-coupled receptor family, is found predominantly in immune cells, such as macrophages, and functions as a pivotal modulator of inflammatory responses. In this study, we investigated the role of GPR84 in receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast differentiation. Our microarray data showed that GPR84 was significantly downregulated in osteoclasts compared to in their precursors, macrophages. The overexpression of GPR84 in bone marrow-derived macrophages suppressed the formation of multinucleated osteoclasts without affecting precursor proliferation. In addition, GPR84 overexpression attenuated the induction of c Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), which are transcription factors that are critical for osteoclastogenesis. Furthermore, knockdown of GPR84 using a small hairpin RNA promoted RANKL-mediated osteoclast differentiation and gene expression of osteoclastogenic markers. Mechanistically, GPR84 overexpression blocked RANKL-stimulated phosphorylation of IkappaBalpha and three MAPKs, JNK, ERK, and p38. GPR84 also suppressed NF-kappaB transcriptional activity mediated by RANKL. Conversely, GPR84 knockdown enhanced RANKL-induced activation of IkappaBalpha and the three MAPKs. Collectively, our results revealed that GPR84 functions as a negative regulator of osteoclastogenesis, suggesting that it may be a potential therapeutic target for osteoclast-mediated bone-destructive diseases. PMID- 28574597 TI - Mortality rates are lower in SIAD, than in hypervolaemic or hypovolaemic hyponatraemia: Results of a prospective observational study. AB - OBJECTIVE: Hyponatraemia is associated with increased mortality, but the mortality associated specifically with SIAD is not known. We hypothesized that mortality in SIAD was elevated, but that it was less than in hypervolaemic (HEN) or hypovolaemic (HON) hyponatraemia. DESIGN: Mortality rates are presented as risk ratios (RR),with 95% confidence intervals (CI), and compared to normonatraemic controls (NN). METHODS: Prospective, single centre, noninterventional study of all patients with hyponatraemia (<=130 mmol/L) admitted to hospital. RESULTS: A total of 1323 admissions with hyponatraemia were prospectively evaluated and 1136 contemporaneous NN controls. 431(32.6%) hyponatraemic patients had HON, 573(43.3%) had SIAD and 275(20.8%) patients had HEN. In patient mortality was higher in hyponatraemia than NN (9.1% vs 3.3%, P<.0001). The RRs for in-hospital mortality compared to NN were: SIAD, 1.76 (95% CI 1.08-2.8, P=.02), HON 2.77 (95% CI 1.8-4.3, P<.0001) and HEN, 4.9 (95% CI 3.2 7.4, P<.0001). The mortality rate was higher in HEN (RR 2.85; 95% CI 1.86-4.37, P<.0001) and in HON, (RR 1.6; 95% CI 1.04-2.52; P=.03), when compared to SIAD. The Charlson Comorbidity Index was lower in SIAD than in eunatraemic patients (P<.0001). 9/121(7.4%) patients died with plasma sodium <125 mmol/L and 4(3.3%) with plasma sodium <120 mmol/L. However, 69/121(57%) patients died with a plasma sodium above 133 mmol/L. CONCLUSIONS: We confirmed higher all-cause mortality in hyponatraemia than in NN. Mortality was higher in SIAD than in normonatraemia and was not explained on the basis of co-morbidities. Mortality was higher in HON and HEN than in SIAD. Mortality rates reported for all-cause hyponatraemia in the medical literature are not applicable to SIAD. PMID- 28574598 TI - Integrin-Linked Kinase Regulates Bone Formation by Controlling Cytoskeletal Organization and Modulating BMP and Wnt Signaling in Osteoprogenitors. AB - Cell-matrix interactions constitute a fundamental aspect of skeletal cell biology and play essential roles in bone homeostasis. These interactions are primarily mediated by transmembrane integrin receptors, which mediate cell adhesion and transduce signals from the extracellular matrix to intracellular responses via various downstream effectors, including integrin-linked kinase (ILK). ILK functions as adaptor protein at focal adhesion sites, linking integrins to the actin cytoskeleton, and has been reported to act as a kinase phosphorylating signaling molecules such as GSK-3beta and Akt. Thereby, ILK plays important roles in cellular attachment, motility, proliferation and survival. To assess the in vivo role of ILK signaling in osteoprogenitors and the osteoblast lineage cells descending thereof, we generated conditional knockout mice using the Osx-Cre:GFP driver strain. Mice lacking functional ILK in osterix-expressing cells and their derivatives showed no apparent developmental or growth phenotype, but by 5 weeks of age they displayed a significantly reduced trabecular bone mass, which persisted into adulthood in male mice. Histomorphometry and serum analysis indicated no alterations in osteoclast formation and activity, but provided evidence that osteoblast function was impaired, resulting in reduced bone mineralization and increased accumulation of unmineralized osteoid. In vitro analyses further substantiated that absence of ILK in osteogenic cells was associated with compromised collagen matrix production and mineralization. Mechanistically, we found evidence for both impaired cytoskeletal functioning and reduced signal transduction in osteoblasts lacking ILK. Indeed, loss of ILK in primary osteogenic cells impaired F-actin organization, cellular adhesion, spreading, and migration, indicative of defective coupling of cell-matrix interactions to the cytoskeleton. In addition, BMP/Smad and Wnt/beta-catenin signaling was reduced in the absence of ILK. Taken together, these data demonstrate the importance of integrin-mediated cell-matrix interactions and ILK signaling in osteoprogenitors in the control of osteoblast functioning during juvenile bone mass acquisition and adult bone remodeling and homeostasis. (c) 2017 American Society for Bone and Mineral Research. PMID- 28574601 TI - Explosive and maximal strength before and 6 months after total hip arthroplasty. AB - Patients with unilateral hip osteoarthritis experience impairments in lower limb muscle function due to pain and disuse of the affected limb. The influence of hip osteoarthritis and subsequent total hip arthroplasty (THA) has mostly been evaluated by maximal strength tests, yet the functionally important explosive strength capabilities of hip and knee muscles are largely unknown. We aimed to evaluate hip and knee explosive and maximal strength in hip osteoarthritis patients before and after THA. Twenty-one patients with unilateral hip osteoarthritis were evaluated before and 6 months after THA. They performed rapid maximal contractions of hip (flexor, extensor, abductor, adductor) and knee (flexor, extensor) muscles, from which explosive and maximal strength asymmetries were evaluated (involved versus uninvolved limb). Before THA, the involved limb showed significantly lower hip flexor, extensor, adductor, and knee extensor explosive and maximal strength compared to the uninvolved limb. Six months after THA surgery, hip flexor, extensor and adductor maximal and explosive strength asymmetries persisted, except for knee extensors. Explosive, but not maximal strength of hip abductors and knee extensors was lower in the involved limb before surgery and the reduced explosive strength capabilities may compromise daily living activities in hip osteoarthritis patients. After hip replacement, explosive strength asymmetries of knee extensors resolved, yet lingering asymmetries in hip flexor muscles should receive focused attention during postoperative rehabilitation. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:425-431, 2018. PMID- 28574600 TI - Diallyl trisulfides, a natural histone deacetylase inhibitor, attenuate HIF 1alpha synthesis, and decreases breast cancer metastasis. AB - Intratumoral hypoxia promotes the distant metastasis of cancer subclones. The clinical expression level of hypoxia-inducible factor-1alpha (HIF-1alpha) reflects the prognosis of a variety of cancers, especially breast cancer. Histone deacetylase (HDAC) inhibitors can target HIF-1alpha protein due to von Hippel Lindau (VHL) protein-dependent degradation. Dietary organosulfur compounds, such as those in garlic, have been reported as HDAC inhibitors. The effects of diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) on the ratio of firefly/Renilla luciferase activity in hypoxic MDA-MB-231 cells were determined. The mRNA expressions of HIF-1alpha target genes ANGPTL4, LOXL4, and LOX in hypoxic MDA-MB-231 cells were significantly down-regulated by DATS. DATS attenuated the metastatic potential of MDA-MB-231 cells in hypoxia-induced embryonic zebrafish, xenograft, and orthotopic tumors. Endothelial cell-cancer cell adhesion, wound healing, transwell, and tube formation assays showed that DATS dose-dependently inhibited the migration and angiogenesis of MDA-MB-231 cells in vitro. The expressions of L1CAM, VEGF-A, and EMT-related proteins (Slug, Snail, MMP-2) were inhibited by DATS. DATS dose-dependently inhibited HIF-1alpha transcriptional activity and hypoxia-induced hematogenous metastasis of MDA-MB 231 cells. It reduced the protein expression of HIF-1alpha, which did not involve inhibition of HIF-1alpha mRNA expression or ubiquitin proteasome degradation. Efficient inhibition of HIF-1alpha expression was required for DATS to resist breast cancer. PMID- 28574602 TI - Naive and Robust: Class-Conditional Independence in Human Classification Learning. AB - Humans excel in categorization. Yet from a computational standpoint, learning a novel probabilistic classification task involves severe computational challenges. The present paper investigates one way to address these challenges: assuming class-conditional independence of features. This feature independence assumption simplifies the inference problem, allows for informed inferences about novel feature combinations, and performs robustly across different statistical environments. We designed a new Bayesian classification learning model (the dependence-independence structure and category learning model, DISC-LM) that incorporates varying degrees of prior belief in class-conditional independence, learns whether or not independence holds, and adapts its behavior accordingly. Theoretical results from two simulation studies demonstrate that classification behavior can appear to start simple, yet adapt effectively to unexpected task structures. Two experiments-designed using optimal experimental design principles were conducted with human learners. Classification decisions of the majority of participants were best accounted for by a version of the model with very high initial prior belief in class-conditional independence, before adapting to the true environmental structure. Class-conditional independence may be a strong and useful default assumption in category learning tasks. PMID- 28574599 TI - Inhibition of glycogen synthase kinase 3 beta (GSK3beta) suppresses the progression of esophageal squamous cell carcinoma by modifying STAT3 activity. AB - Although GSK3beta has been reported to have contrasting effects on the progression of different tumors, it's possible functions in esophageal squamous cell carcinoma (ESCC) and the related molecular mechanisms remain unknown. Here, we investigated the expression, function, and molecular mechanism of GSK3beta in the development of ESCC in vitro and in vivo. Though the expression of total GSK3beta was significantly increased, the phosphorylated (inactivated) form of GSK3beta (Ser9) was concurrently decreased in the cancerous tissues of patients with ESCC compared with controls, suggesting that GSK3beta activity was enhanced in cancerous tissues. Further pathological data analysis revealed that higher GSK3beta expression was associated with poorer differentiation, higher metastasis rates, and worse prognosis of ESCC. These results were confirmed in different ESCC cell lines using a pharmacological inhibitor and specific siRNA to block GSK3beta. Using a cancer phospho-antibody array, we found that STAT3 is a target of GSK3beta. GSK3 inhibition reduced STAT3 phosphorylation, and overexpression of constitutively active GSK3beta had the opposite effect. Moreover, STAT3 inhibition mimicked the effects of GSK3beta inhibition on ESCC cell migration and viability, while overexpression of a plasmid encoding mutant STAT3 (Y705F) abrogated these effects, and these results were further substantiated by clinicopathological data. In addition, a GSK3 inhibitor (LiCl) and/or STAT3 inhibitor (WP-1066) efficiently suppressed the growth of ESCC cells in a xenograft tumor model. Altogether, these results reveal that higher GSK3beta expression promotes ESCC progression through STAT3 in vitro and in vivo, and GSK3beta-STAT3 signaling could be a potential therapeutic target for ESCC treatment. PMID- 28574603 TI - Persistence of chlorfluazuron in cabbage under different agro-climatic conditions of India and its risk assessment. AB - A multilocational field trial was conducted at 4 locations in India-Rajasthan, Gujarat, Madhya Pradesh, and West Bengal-to determine the persistence in cabbage of chlorfluazuron applied twice at 75 and 150 g active ingredient ha-1 . Cabbage head samples were collected from each replicated plot on 0 (2 h after spraying), 1, 3, 5, 7, 10, and 15 d after final insecticide application, including an untreated control. Chlorfluazuron residue in cabbage and field soil was estimated by high-performance liquid chromatography using a photo diode array detector. The limit of determination and limit of quantification of the method were recorded as 0.05 and 0.10 MUg g-1 , respectively. Results revealed that chlorfluazuron dissipated linearly with progress of time, following first-order kinetics. The mean (+/- standard deviation) half-life value of chlorfluazuron in cabbage was found to be 7.18 +/- 0.71 d, considering different locations and treatments. The residue was below the level of quantification in the harvested cabbage and soil samples. Harvesting cabbage in the experimental location, at least on day 7, after 2 applications of chlorfluazuron at the recommended dose, may not pose any ill effect for Indian adults. Environ Toxicol Chem 2017;36:3028-3033. (c) 2017 SETAC. PMID- 28574604 TI - Boosting the SNR by adding a receive-only endorectal monopole to an external antenna array for high-resolution, T2 -weighted imaging of early-stage cervical cancer with 7-T MRI. AB - The aim of this study was to investigate the signal-to-noise ratio (SNR) gain in early-stage cervical cancer at ultrahigh-field MRI (e.g. 7 T) using a combination of multiple external antennas and a single endorectal antenna. In particular, we used an endorectal monopole antenna to increase the SNR in cervical magnetic resonance imaging (MRI). This should allow high-resolution, T2 -weighted imaging and magnetic resonance spectroscopy (MRS) for metabolic staging, which could facilitate the local tumor status assessment. In a prospective feasibility study, five healthy female volunteers and six patients with histologically proven stage IB1-IIB cervical cancer were scanned at 7 T. We used seven external fractionated dipole antennas for transmit-receive (transceive) and an endorectally placed monopole antenna for reception only. A region of interest, containing both normal cervix and tumor tissue, was selected for the SNR measurement. Separated signal and noise measurements were obtained in the region of the cervix for each element and in the near field of the monopole antenna (radius < 30 mm) to calculate the SNR gain of the endorectal antenna in each patient. We obtained high-resolution, T2 -weighted images with a voxel size of 0.7 * 0.8 * 3.0 mm3 . In four cases with optimal placement of the endorectal antenna (verified on the T2 -weighted images), a mean gain of 2.2 in SNR was obtained at the overall cervix and tumor tissue area. Within a radius of 30 mm from the monopole antenna, a mean SNR gain of 3.7 was achieved in the four optimal cases. Overlap between the two different regions of the SNR calculations was around 24%. We have demonstrated that the use of an endorectal monopole antenna substantially increases the SNR of 7-T MRI at the cervical anatomy. Combined with the intrinsically high SNR of ultrahigh-field MRI, this gain may be employed to obtain metabolic information using MRS and to enhance spatial resolutions to assess tumor invasion. PMID- 28574605 TI - B Vitamins and Hip Fracture: Secondary Analyses and Extended Follow-Up of Two Large Randomized Controlled Trials. AB - Elevated plasma homocysteine levels are associated with increased risk of fractures in observational studies. However, it is unsettled whether homocysteine lowering treatment affects fracture risk. The aim of this study was to investigate the effect of an intervention with B vitamins on the risk of hip fracture in a secondary analysis of combined data from two large randomized controlled trials originally designed to study cardiovascular diseases. Both trials had identical design, intervention, and primary objective. Based on a two by-two factorial design, the intervention consisted of a daily capsule with either (1) folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg); (2) folic acid (0.8 mg) plus vitamin B12 (0.4 mg); (3) vitamin B6 alone (40 mg); or (4) placebo. The participants were followed with respect to hip fracture during the trial or during an extended follow-up (from the trial start for each patient until the end of 2012). No statistically significant association was found between folic acid plus vitamin B12 treatment and the risk of hip fracture, neither during the trial (median 3.3 years; hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.48 to 1.59) nor during the extended follow-up (median 11.1 years; HR 1.08; 95% CI, 0.84 to 1.40). Nor were there significant differences in the risk of hip fracture between groups receiving versus not receiving vitamin B6 during the trial (HR 1.42; 95% CI, 0.78 to 2.61). However, during the extended follow-up, those receiving vitamin B6 showed a significant 42% higher risk of hip fracture (HR 1.42; 95% CI, 1.09 to 1.83) compared to those not receiving vitamin B6 . In conclusion, treatment with folic acid plus vitamin B12 was not associated with the risk of hip fracture. Treatment with a high dose of vitamin B6 was associated with a slightly increased risk of hip fracture during the extended follow-up (in-trial plus post-trial follow-up). (c) 2017 American Society for Bone and Mineral Research. PMID- 28574609 TI - An Actor's Knowledge and Intent Are More Important in Evaluating Moral Transgressions Than Conventional Transgressions. AB - An actor's mental states-whether she acted knowingly and with bad intentions typically play an important role in evaluating the extent to which an action is wrong and in determining appropriate levels of punishment. In four experiments, we find that this role for knowledge and intent is significantly weaker when evaluating transgressions of conventional rules as opposed to moral rules. We also find that this attenuated role for knowledge and intent is partly due to the fact that conventional rules are judged to be more arbitrary than moral rules; whereas moral transgressions are associated with actions that are intrinsically wrong (e.g., hitting another person), conventional transgressions are associated with actions that are only contingently wrong (e.g., wearing pajamas to school, which is only wrong if it violates a dress code that could have been otherwise). Finally, we find that it is the perpetrator's belief about the arbitrary or non arbitrary basis of the rule-not the reality-that drives this differential effect of knowledge and intent across types of transgressions. PMID- 28574607 TI - Prognostic value of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression in glioblastoma excluding nontumour cells from the analysis. AB - AIMS: It is important to predict response to treatment with temozolomide (TMZ) in glioblastoma (GBM) patients. Both MGMT protein expression and MGMT promoter methylation status have been reported to predict the response to TMZ. We investigated the prognostic value of quantified MGMT protein levels in tumour cells and the prognostic importance of combining information of MGMT protein level and MGMT promoter methylation status. METHODS: MGMT protein expression was quantified in tumour cells in 171 GBMs from the population-based Region of Southern Denmark (RSD)-cohort using a double immunofluorescence approach. Pyrosequencing was performed in 157 patients. For validation we used GBM-patients from a Nordic Study (NS) investigating the effect of radiotherapy and different TMZ schedules. RESULTS: When divided at the median, patients with low expression of MGMT protein (AF-low) had the best prognosis (HR = 1.5, P = 0.01). Similar results were observed in the subgroup of patients receiving the Stupp regimen (HR = 2.0, P = 0.001). In the NS-cohort a trend towards superior survival (HR = 1.6, P = 0.08) was seen in patients with AF-low. Including MGMT promoter methylation status, we found for both cohorts that patients with methylated MGMT promoter and AF-low had the best outcome; median OS 23.1 and 20.0 months, respectively. CONCLUSION: Our data indicate that MGMT protein expression in tumour cells has an independent prognostic significance. Exclusion of nontumour cells contributed to a more exact analysis of tumour-specific MGMT protein expression. This should be incorporated in future studies evaluating MGMT status before potential integration into clinical practice. PMID- 28574608 TI - Role of Mitogen Activated Protein Kinase and Maturation Promoting Factor During the Achievement of Meiotic Competency in Mammalian Oocytes. AB - The oocyte quality remains as one of the major problems associated with poor in vitro fertilization (IVF) rate and assisted reproductive technology (ART) failure worldwide. The oocyte quality is dependent on its meiotic maturation that begins inside the follicular microenvironment and gets completed at the time of ovulation in most of the mammalian species. Follicular oocytes are arrested at diplotene stage of first meiotic prophase. The resumption of meiosis from diplotene arrest, progression through metaphase-I (M-I) and further arrest at metaphase-II (M-II) are important physiological requirements for the achievement of meiotic competency in mammalian oocytes. The achievement of meiotic competency is dependent upon cyclic stabilization/destabilization of maturation promoting factor (MPF). The mitogen-activated protein kinase3/1 (MAPK3/1) modulates stabilization/destabilization of MPF in oocyte by interacting either with signal molecules, transcription and post-transcription factors in cumulus cells or cytostatic factors (CSFs) in oocyte. MPF regulates meiotic cell cycle progression from diplotene arrest to M-II arrest and directly impacts oocyte quality. The MAPK3/1 activity is not reported during spontaneous meiotic resumption but its activity in cumulus cells is required for gonadotropin-induced oocyte meiotic resumption. Although high MAPK3/1 activity is required for the maintenance of M II arrest in several mammalian species, its cross-talk with MPF remains to be elucidated. Further studies are required to find out the MAPK3/1 activity and its impact on MPF destabilization/stabilization during achievement of meiotic competency, an important period that decides oocyte quality and directly impacts ARTs outcome in several mammalian species including human. J. Cell. Biochem. 119: 123-129, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28574606 TI - Sfp1 and Rtg3 reciprocally modulate carbon source-conditional stress adaptation in the pathogenic yeast Candida albicans. AB - The pathogenicity of the clinically important yeast, Candida albicans, is dependent on robust responses to host-imposed stresses. These stress responses have generally been dissected in vitro at 30 degrees C on artificial growth media that do not mimic host niches. Yet host inputs, such as changes in carbon source or temperature, are known to affect C. albicans stress adaptation. Therefore, we performed screens to identify novel regulators that promote stress resistance during growth on a physiologically relevant carboxylic acid and at elevated temperatures. These screens revealed that, under these 'non-standard' growth conditions, numerous uncharacterised regulators are required for stress resistance in addition to the classical Hog1, Cap1 and Cta4 stress pathways. In particular, two transcription factors (Sfp1 and Rtg3) promote stress resistance in a reciprocal, carbon source-conditional manner. SFP1 is induced in stressed glucose-grown cells, whereas RTG3 is upregulated in stressed lactate-grown cells. Rtg3 and Sfp1 regulate the expression of key stress genes such as CTA4, CAP1 and HOG1 in a carbon source-dependent manner. These mechanisms underlie the stress sensitivity of C. albicans sfp1 cells during growth on glucose, and rtg3 cells on lactate. The data suggest that C. albicans exploits environmentally contingent regulatory mechanisms to retain stress resistance during host colonisation. PMID- 28574610 TI - Costamere protein expression and tissue composition of rotator cuff muscle after tendon release in sheep. AB - Previous studies suggested that degradation of contractile tissue requires cleavage of the costamere, a structural protein complex that holds sarcomeres in place. This study examined if costamere turnover is affected by a rotator cuff tear in a previously established ovine model. We found the activity of focal adhesion kinase (FAK), a main regulator of costamere turnover, was unchanged at 2 weeks but decreased by 27% 16 weeks after surgical release of the infraspinatus tendon. This was accompanied by cleavage of the costamere protein talin into a 190 kDa fragment while full length talin remained unchanged. At 2 weeks after tendon release, muscle volume decreased by 17 cm3 from an initial 185 cm3 , the fatty tissue volume was halved, and the contractile tissue volume remained unchanged. After 16 weeks, the muscle volume decreased by 36 cm3 , contractile tissue was quantitatively lost, and the fat content increased by 184%. Nandrolone administration mitigated the loss of contractile tissue by 26% and prevented fat accumulation, alterations in FAK activity, and talin cleavage. Taken together, these findings imply that muscle remodeling after tendon release occurs in two stages. The early decrease of muscle volume is associated with reduction of fat; while, the second stage is characterized by substantial loss of contractile tissue accompanied by massive fat accumulation. Regulation of costamere turnover is associated with the loss of contractile tissue and seems to be impacted by nandrolone treatment. Clinically, the costamere may represent a potential intervention target to mitigate muscle loss after a rotator cuff tear. (c) 2017 The Authors. Journal of Orthopaedic Research(r) published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:272-281, 2018. PMID- 28574611 TI - Dithiafulvenyl-Extended N-Heterotriangulenes and Their Interaction with C60 : Cooperative Fluorescence. AB - We describe the synthesis as well as the electronic and photophysical characterization of novel N-heterotriangulene derivatives decorated with methoxycarbonyl- and methyl-sulfanyl-substituted dithiafulvenyl moieties. The association of these electron-rich compounds with fullerene C60 as electron acceptor was investigated by means of photophysical, voltammetric, and mass spectrometric methods and rationalized by DFT calculations. Importantly, light induced interactions between the dithiafulvene-substituted N-heterotriangulene bearing methoxycarbonyl substituents with C60 leads to cooperative fluorescence. Quantitative Job plot analyses by means of fluorescence spectroscopy and voltammetry confirm a 1:1 association with binding constants in the order of 104 m-1 . Supportive results for the supramolecular assembly of both N heterotriangulenes with C60 were obtained by ESI mass spectrometric investigations in the gas phase. PMID- 28574613 TI - SENP2 suppresses epithelial-mesenchymal transition of bladder cancer cells through deSUMOylation of TGF-betaRI. AB - SUMO-specific protease 2 (SENP2) is a deSUMOylation protease that plays an important role in the regulation of transforming growth factor-beta (TGF-beta) signaling. Aberrant TGF-beta signaling is common in human cancers and contributes to tumor metastasis by inducing an epithelial-mesenchymal transition (EMT). In previous studies, we demonstrated that SENP2 suppresses bladder cancer cell migration and invasion. However, little is known about whether SENP2 inhibits EMT by regulating TGF-beta signaling in bladder cancer progression. Here, we investigated the role of SENP2 in regulating TGF-beta signaling and bladder cancer metastasis in vitro and in vivo. We found that SENP2 is frequently downregulated in bladder cancer, especially in metastatic bladder cancer. SENP2 downregulation is associated with more aggressive phenotypes and poor patient outcomes. SENP2 knockdown results in a decrease of E-cadherin and an increase of N-cadherin and fibronectin at both transcript and protein levels, indicating that SENP2 negatively regulates EMT. On the contrary, SENP2 overexpression suppresses TGF-beta signaling and TGF-beta-induced EMT. We further demonstrated that SENP2 regulates TGF-beta signaling partly through deSUMOylation of TGFbeta receptor I (TGF-betaRI). Functionally, SENP2 suppresses bladder cancer cell invasion in vitro and tumor metastasis in vivo, acts as a tumor suppressor gene in bladder cancer. Our results establish a function of SENP2 in metastatic progression and suggest its candidacy as a new prognostic biomarker and target for clinical management of bladder cancer. PMID- 28574614 TI - Strontium(II) and mechanical loading additively augment bone formation in calcium phosphate scaffolds. AB - Calcium phosphate cements (CPCs) are widely used for bone-defect treatment. Current developments comprise the fabrication of porous scaffolds by three dimensional plotting and doting using biologically active substances, such as strontium. Strontium is known to increase osteoblast activity and simultaneously to decrease osteoclast resorption. This study investigated the short- and long term in vivo performances of strontium(II)-doted CPC (SrCPC) scaffolds compared to non-doted CPC scaffolds after implantation in unloaded or load-bearing trabecular bone defects in sheep. After 6 weeks, both CPC and SrCPC scaffolds exhibited good biocompatibility and osseointegration. Fluorochrome labeling revealed that both scaffolds were penetrated by newly formed bone already after 4 weeks. Neither strontium doting nor mechanical loading significantly influenced early bone formation. In contrast, after 6 months, bone formation was significantly enhanced in SrCPC compared to CPC scaffolds. Energy dispersive X ray analysis demonstrated the release of strontium from the SrCPC into the bone. Strontium addition did not significantly influence material resorption or osteoclast formation. Mechanical loading significantly stimulated bone formation in both CPC and SrCPC scaffolds after 6 months without impairing scaffold integrity. The most bone was found in SrCPC scaffolds under load-bearing conditions. Concluding, these results demonstrate that strontium doting and mechanical loading additively stimulated bone formation in CPC scaffolds and that the scaffolds exhibited mechanical stability under moderate load, implying good clinical suitability. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:106-117, 2018. PMID- 28574615 TI - Simultaneous spin-echo and gradient-echo BOLD measurements by dynamic MRS. AB - This study aimed to dissociate the intravascular and extravascular contributions to spin-echo (SE) and gradient-echo (GE) blood oxygenation level-dependent (BOLD) signals at 7 T, using dynamic diffusion-weighted MRS. We simultaneously acquired SE and GE data using a point-resolved spectroscopy sequence with diffusion weightings of 0, 600, and 1200 s/mm2 . The BOLD signals were quantified by fitting the free induction decays starting from the SE center to a mono exponential decay function. Without diffusion weighting, BOLD signals measured with SE and GE increased by 1.6 +/- 0.5% (TESE = 40 ms) and 5.2 +/- 1.4% (nominal TEGE = 40 ms) during stimulation, respectively. With diffusion weighting, the BOLD increase during stimulation measured with SE decreased from 1.6 +/- 0.5% to 1.3 +/- 0.4% (P < 0.001), whereas that measured by GE was unaffected (P > 0.05); the post-stimulation undershoots in the BOLD signal time courses were largely preserved in both SE and GE measurements. These results demonstrated the feasiblity of simultaneous SE and GE measurements of BOLD signals with and without interleaved diffusion weighting. The results also indicated a predominant extravascular contribution to the BOLD signal time courses, including post-stimulation undershoots in both SE and GE measurements at 7 T. PMID- 28574616 TI - The Therapeutic Potential of Targeting Tumor Microenvironment in Breast Cancer: Rational Strategies and Recent Progress. AB - The tumor microenvironment (TME) is cellular environment in addition to harboring carcinoma cells, consists of different components (e.g., blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, lymphocytes, signaling molecules, and the extracellular matrix) that have an essential role on drug activity and efficacy. There is growing body of evidence showing its involvement in the progression and metastasis of different cancers, including breast cancer (BC). These observations provide a proof of concept of targeting TME compartments as a novel potential therapeutic approach in treatment of this malignancy, which is the main interested for current review. J. Cell. Biochem. 119: 111-122, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28574617 TI - Confirmed identification and toxin profiling of Campylobacter jejuni using a thermostabilized multiplex PCR formulation. AB - Cytolethal distending toxin (CDT) producing Campylobacter jejuni species are one of the leading causes of human gastroenteritis worldwide. The main intent of the study was to develop a multiplex PCR assay for the confirmed identification and toxin profiling of C. jejuni. The genes targeted were rpo B as genus specific, hip O for species; cdt A, cdt B, cdt C encoding respective subunit proteins of CDT with Internal Amplification Control (IAC). To enhance its application as a pre-mixed ready-to-use format, the master mix of developed mPCR was dried by lyophilization and stability was assessed. Thermostabilized reagents showed stability of 1.5 months at room-temperature and upto six months at 4 degrees C without any loss of functionality. The assay was evaluated on a number of presumptive Campylobacter isolates along with biochemical tests. Results obtained indicated the accurate identification of C. jejuni by developed mPCR format in contrast to misconception associated with biochemical assays. The assay was also tested on spiked samples for its real-time utility. Altogether, the room temperature storable and ready-to- use mPCR format developed in this study could be preferred for rapid detection and confirmed identification of toxigenic strains of C. jejuni in place of conventional biochemical assays. PMID- 28574612 TI - Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond. AB - Basal cell carcinoma (BCC) of the skin is driven by aberrant hedgehog signaling. Thus blocking this signaling pathway by small molecules such as vismodegib inhibits tumor growth. Primary cilium in the epidermal cells plays an integral role in the processing of hedgehog signaling-related proteins. Recent genomic studies point to the involvement of additional genetic mutations that might be associated with the development of BCCs, suggesting significance of other signaling pathways, such as WNT, NOTCH, mTOR, and Hippo, aside from hedgehog in the pathogenesis of this human neoplasm. Some of these pathways could be regulated by noncoding microRNA. Altered microRNA expression profile is recognized with the progression of these lesions. Stopping treatment with Smoothened (SMO) inhibitors often leads to tumor reoccurrence in the patients with basal cell nevus syndrome, who develop 10-100 of BCCs. In addition, the initial effectiveness of these SMO inhibitors is impaired due to the onset of mutations in the drug-binding domain of SMO. These data point to a need to develop strategies to overcome tumor recurrence and resistance and to enhance efficacy by developing novel single agent-based or multiple agents-based combinatorial approaches. Immunotherapy and photodynamic therapy could be additional successful approaches particularly if developed in combination with chemotherapy for inoperable and metastatic BCCs. PMID- 28574618 TI - Effects of short-to-long term enzyme replacement therapy (ERT) on skeletal muscle tissue in late onset Pompe disease (LOPD). AB - AIMS: Pompe disease is an autosomal recessive lysosomal storage disorder resulting from deficiency of acid alpha-glucosidase (GAA) enzyme. Histopathological hallmarks in skeletal muscle tissue are fibre vacuolization and autophagy. Since 2006, enzyme replacement therapy (ERT) is the only approved treatment with human recombinant GAA alglucosidase alfa. We designed a study to examine ERT-related skeletal muscle changes in 18 modestly to moderately affected late onset Pompe disease (LOPD) patients along with the relationship between morphological/biochemical changes and clinical outcomes. Treatment duration was short-to-long term. METHODS: We examined muscle biopsies from 18 LOPD patients at both histopathological and biochemical level. All patients underwent two muscle biopsies, before and after ERT administration respectively. The study is partially retrospective because the first biopsies were taken before the study was designed, whereas the second biopsy was always performed after at least 6 months of ERT administration. RESULTS: After ERT, 15 out of 18 patients showed improved 6-min walking test (6MWT; P = 0.0007) and most of them achieved respiratory stabilization. Pretreatment muscle biopsies disclosed marked histopathological variability, ranging from an almost normal pattern to a severe vacuolar myopathy. After treatment, we detected morphological improvement in 15 patients and worsening in three patients. Post-ERT GAA enzymatic activity was mildly increased compared with pretreatment levels in all patients. Protein levels of the mature enzyme increased in 14 of the 18 patients (mean increase = +35%; P < 0.05). Additional studies demonstrated an improved autophagic flux after ERT in some patients. CONCLUSIONS: ERT positively modified skeletal muscle pathology as well as motor and respiratory outcomes in the majority of LOPD patients. PMID- 28574622 TI - Oxford medial unicompartmental knees display contact-loss during step-cycle motion and bicycle motion: A dynamic radiostereometric study. AB - The Oxford medial unicompartmental knee is designed fully congruent, with the purpose of maintaining a large contact-area throughout motion and minimize wear. No other study has investigated this design feature in-vivo. We aimed to evaluate if contact-loss was introduced between the articulating surfaces of the Oxford medial unicompartmental knee during bicycle- and step-cycle motion, and whether this correlated with essential implant parameters, such as polyethylene (PE) wear, knee-loadings, and clinical outcome. To study contact-loss, 15 patients (12 males, mean age 69 years) with an Oxford medial unicompartmental knee (7 cemented, mean follow-up 4.4 years) were examined with use of dynamic radiostereometry (RSA) (10 frames/s). PE wear was measured from static RSA and clinical outcome was evaluated with American Knee Society Score (AKSS) and Oxford Knee Score (OKS). Data on knee-loadings were acquired from the literature. Contact-loss was deteced in all patients during both exercises, and the trend of contact-loss correlated with the knee-loadings. Median contact-loss was 0.8 mm (95%PI: 0.3; 1.5) for bicycle motion and 0.3 mm (95%PI: 0.24; 0.35) for step cycle motion, and did not correlate with the PE wear rate of mean 0.06 mm/year. Possible in-congruency was seen in three patients. Clinical outcome scores correlated with contact-loss during step-cycle motion. In conclusion, contact loss was seen in all patients indicating a clinical tolerance during load. Contact-loss followed the knee-loadings, which could explain why no correlation was seen with PE wear, as an increase in load was acommadated by an increase in contact-area (contact-loss reduction). The size of contact-loss may reflect clinical outcome. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:357-364, 2018. PMID- 28574620 TI - Rescue allocation and recipient oriented extended allocation in kidney transplantation-influence of the EUROTRANSPLANT allocation system on recipient selection and graft survival for initially nonaccepted organs. AB - Nonaccepted kidneys grafts enter the rescue allocation (RA) process to avoid discards. In December 2013, recipient oriented extended allocation (REAL) was introduced to improve transparency. The aim of this study was to evaluate the influence of REAL on recipients' selection and graft function compared to the formerly existing RA as well as to identify factors that influence graft outcome. Therefore, a multicenter study of 10 transplant centers in the same region in Germany was performed. All transplantations after RA or REAL from December 1, 2012, until December 31, 2014, with a follow-up time until December 31, 2015 were analyzed. 113 of 941 kidney transplantations were performed after RA or REAL (12%). With REAL, the number of refusals before transplantation had increased (12 +/- 7.1 vs. 8.6 +/- 8.6, P = 0.036), and cold ischemia time has decreased (13.6 +/- 3.6 vs. 17.2 +/- 4.8 h, P = 0.019). Recipients after REAL needed significantly more allocation points compared to RA to receive a kidney. One-year graft survival was comparable. If kidneys from the same donor were transplanted to two recipients at one center, the greater the difference in recipient age, the greater the difference in serum creatinine after 12 months (-0.019 mg/dl per year, P = 0.011) was, that is older recipients showed lower creatinine. REAL influences selection of the recipients compared to the former RA era for successful organ receipt. Graft function is comparable and seems to be influenced by recipient age. PMID- 28574621 TI - Prospects for induction of CD8 T cell-mediated immunity to Zika virus infection by yellow fever virus vaccination. PMID- 28574623 TI - A gap in comprehensive care: Sexual health in men with haemophilia. PMID- 28574619 TI - UCP2 upregulation promotes PLCgamma-1 signaling during skin cell transformation. AB - Uncoupling protein 2 (UCP2), whose physiological role is to decrease mitochondrial membrane potential and reactive oxygen species (ROS) production, is often overexpressed in human cancers. UCP2 upregulation has recently been proposed as a novel survival mechanism for cancer cells. However, until now, how exactly UCP2 promotes tumorigenesis remains inconclusive. Based on a widely used skin cell transformation model, our data demonstrated that UCP2 differentially regulated ROS. UCP2 upregulation decreased superoxide whereas it increased hydrogen peroxide production with concomitant increase in the expression and activity of manganese superoxide dismutase (MnSOD), the primary mitochondrial antioxidant enzyme. Furthermore, hydrogen peroxide was responsible for induction of lipid peroxidation, and PLCgamma-1 activation in UCP2 overexpressed cells. Additionally, PLCgamma-1 activation enhanced skin cell transformation, and pharmacological, and siRNA mediated inhibition of PLCgamma-1, markedly reduced colony formation, and 3D cell growth. Moreover, hydrogen peroxide scavenger, catalase, suppressed lipid peroxidation, and dampened PLCgamma-1 activity. Taken together, our data suggest that (i) UCP2 is an important regulator of mitochondrial redox status and lipid signaling; (ii) hydrogen peroxide might mediate UCP2's tumor promoting activity; and (iii) pharmacological disruption of PLCgamma-1 and/or hydrogen peroxide may have clinical utility for UCP2 overexpressed cancers. PMID- 28574624 TI - Proper reprogramming of imprinted and non-imprinted genes in cloned cattle gametogenesis. AB - Epigenetic abnormalities in cloned animals are caused by incomplete reprogramming of the donor nucleus during the nuclear transfer step (first reprogramming). However, during the second reprogramming step that occurs only in the germline cells, epigenetic errors not corrected during the first step are repaired. Consequently, epigenetic abnormalities in the somatic cells of cloned animals should be erased in their spermatozoa or oocytes. This is supported by the fact that offspring from cloned animals do not exhibit defects at birth or during postnatal development. To test this hypothesis in cloned cattle, we compared the DNA methylation level of two imprinted genes (H19 and PEG3) and three non imprinted genes (XIST, OCT4 and NANOG) and two repetitive elements (Satellite I and Satellite II) in blood and sperm DNAs from cloned and non-cloned bulls. We found no differences between cloned and non-cloned bulls. We also analyzed the DNA methylation levels of four repetitive elements (Satellite I, Satellite II, Alpha-satellite and Art2) in oocytes recovered from cloned and non-cloned cows. Again, no significant differences were observed between clones and non-clones. These results suggested that imprinted and non-imprinted genes and repetitive elements were properly reprogramed during gametogenesis in cloned cattle; therefore, they contributed to the soundness of cloned cattle offspring. PMID- 28574625 TI - PNPLA3 as a liver steatosis risk factor following living-donor liver transplantation for hepatitis C. AB - AIM: Liver steatosis frequently occurs following liver transplantation (LT) and can affect patient outcome. Here, we aimed to clarify the steatosis and steatohepatitis risk factors that apply after living-donor LT for chronic hepatitis C. METHODS: We retrospectively examined 43 transplant recipients and donors, and tested for single nucleotide polymorphisms in the PNPLA3 gene. Liver biopsies taken 1 year after transplantation and yearly thereafter, or when abnormal liver enzyme levels were detected, were examined by histopathology. RESULTS: Liver steatosis (>5% steatotic hepatocytes) was evident in 13 of 43 cases (30%), and steatohepatitis in 3 (7.0%). The average time to steatosis after LT was 2.74 +/- 1.55 years. The PNPLA3 rs738409 GG genotype, a steatosis risk factor, was identified in 13 recipients and 10 donors. Steatosis prevalence did not differ according to recipient genotype. However, this condition was significantly more common among patients who received tissue from donors carrying the rs738409 GG genotype compared to those with grafts from donors of the CC or CG genotype (60, 7, and 26%, respectively; P < 0.05). All 3 steatohepatitis cases were associated with the GG donor genotype. CONCLUSION: The PNPLA3 rs738409 GG donor genotype affects liver steatosis and steatohepatitis risk following living donor LT. PMID- 28574626 TI - Assessment of phenotypic and genotypic antibiotic susceptibility of vaginal Lactobacillus sp. AB - AIM: To assess antibiotic susceptibility of vaginal lactobacilli strains and provide the data required for assessing the potential of antibiotic resistance risk of new strains selected as probiotic. METHODS AND RESULTS: Potential probiotic vaginal lactobacilli used in the study included 31 vaginal strains of Lactobacillus crispatus (n = 27), Lactobacillus gasseri (n = 3) and Lactobacillus jensenii (n = 1) obtained from the collection of Competence Centre on Health Technologies. Two commercial probiotic strains were used as controls (Lactobacillus rhamnosus GR-1 and Lactobacillus fermentum RC-14). The phenotypic and genotypic antibiotic resistances of the strains were determined by E-test and PCR methods. The location (chromosomal DNA or plasmid) of antibiotic resistance genes was also detected. All lactobacilli strains expressed high level of resistance to kanamycin, metronidazole, norfloxacin and trimethoprim/sulphamethoxazole. Some of the strains also expressed resistance to other antibiotics (chloramphenicol, vancomycin) indicating acquired resistance. I class integrons were found in 20% (6/31) of the strains. The RPP (ribosomal protection protein) gene was found to be positive in 30% (9/31) of the strains. Only one L. jensenii strain was determined with tet(M) gene. The tet(K) gene was positive in 26.7% (8/31) and erm(B) gene in 43.3% (13/31) of strains. Three RPP and both four tet(K) and erm(B) genes were located in plasmids. CONCLUSIONS: High antibiotic resistance to clinically important antibiotics was demonstrated, including metronidazole, sulphonamides, aminoglycoside and quinolones. In addition, acquired tetracycline and erythromycin resistance genes were detected in either plasmid or chromosomal DNA of certain isolates, in some of the cases for the first time in the literature. It appears that antibiotic resistance genes erm(B) and tet(K) are widely spread in vaginal lactobacilli. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides new data about antimicrobial resistance and genotypic diversity of vaginal Lactobacillus isolates. In addition, it provides data assessing the potential of antibiotic resistance risk of new strains selected as probiotic. PMID- 28574627 TI - CT versus MR Techniques in the Detection of Cervical Artery Dissection. AB - BACKGROUND: Spontaneous cervical artery dissection (sCAD) is an important etiology of juvenile stroke. The gold standard for the diagnosis of sCAD is convential angiography. However, magnetic resonance imaging (MRI)/MR angiography (MRA) and computed tomography (CT)/CT angiography (CTA) are frequently used alternatives. New developments such as multislice CT/CTA have enabled routine acquisition of thinner sections with rapid imaging times. The goal of this study was to compare the capability of recent developed 128-slice CT/CTA to MRI/MRA to detect radiologic features of sCAD. METHODS: Retrospective review of patients with suspected sCAD (n = 188) in a database of our Stroke center (2008-2014), who underwent CT/CTA and MRI/MRA on initial clinical work-up. A control group of 26 patients was added. All Images were evaluated concerning specific and sensitive radiological features for dissection by two experienced neuroradiologists. Imaging features were compared between the two modalities. RESULTS: Forty patients with 43 dissected arteries received both modalities (29 internal carotid arteries [ICAs] and 14 vertebral arteries [VAs]). All CADs were identified in CT/CTA and MRI/MRA. The features intimal flap, stenosis, and lumen irregularity appeared in both modalities. One high-grade stenosis was identified by CT/CTA that was expected occluded on MRI/MRA. Two MRI/MRA-confirmed pseudoaneurysms were missed by CT/CTA. None of the controls evidenced specific imaging signs for dissection. CONCLUSIONS: CT/CTA is a reliable and better available alternative to MRI/MRA for diagnosis of sCAD. CT/CTA should be used to complement MRI/MRA in cases where MRI/MRA suggests occlusion. PMID- 28574628 TI - A Boronic Acid Assay for the Detection of Mucin-1 Glycoprotein from Cancer Cells. AB - Cell surface glycoproteins are commonly aberrant in disease and act as biomarkers that facilitate diagnostics. Mucin-1 (MUC1) is a prominent example, exhibiting truncated glycosylation in cancer. We present herein a boronic acid microplate assay for sensitive and high-throughput detection of such glycoproteins. The immobilization of biotin-boronic acid 1 onto streptavidin plates generated a multivalent surface for glycoprotein recruitment and detection. We first validated the binding properties of 1 in solution through titrations with alizarin dye. Next, the microplate assay was explored through horseradish peroxidase (HRP) analysis as a proof-of-concept glycoprotein with chemiluminescence detection. Finally, this platform was applied for the detection of MUC1 directly from MCF-7 human breast cancer cell lysates by using an HRP tagged antibody that targets the cancerous form of this glycoprotein. Sensitive, dose-dependent detection of MUC1 was observed, showcasing the efficacy of this platform for detecting disease-associated glycoproteins. PMID- 28574631 TI - Starry Aims to Overcome Knowledge Translation Inertia: The Standards for Reporting Implementation Studies (StaRI) Guidelines. PMID- 28574629 TI - Reduction of indole-3-acetic acid methyltransferase activity compensates for high temperature male sterility in Arabidopsis. AB - High temperature is a general stress factor that causes a decrease in crop yield. It has been shown that auxin application reduces the male sterility caused by exposure to higher temperatures. However, widespread application of a hormone with vast effects on plant physiology may be discouraged in many cases. Therefore, the generation of new plant varieties that locally enhance auxin in reproductive organs may represent an alternative strategy. We have explored the possibility of increasing indole-3-acetic acid (IAA) in ovaries by reducing IAA methyltransferase1 (IAMT1) activity in Arabidopsis thaliana. The iamt1 mutant showed increased auxin signalling in funiculi, which correlated with a higher growth rate of wild-type pollen in contact with mutant ovaries and premature ovule fertilization. While the production of seeds per fruit was similar in the wild type and the mutant at 20 degrees C, exposure to 29 degrees C caused a more severe decrease in fertility in the wild type than in the mutant. Loss of IAMT1 activity was also associated with the production of more nodes after flowering and higher tolerance of the shoot apical meristem to higher temperatures. As a consequence, the productivity of the iamt1 mutant under higher temperatures was more than double of that of the wild type, with almost no apparent trade-off. PMID- 28574630 TI - High-mobility group box-1 contributes tumor angiogenesis under interleukin-8 mediation during gastric cancer progression. AB - Many soluble factors are involved in tumor angiogenesis. Thus, it is valuable to identify novel soluble factors for effective control of tumor angiogenesis in gastric cancer (GC). We investigated the role of extracellular high-mobility group box-1 (HMGB1) and its associated soluble factors in the tumor angiogenesis of GC. Clinically, we measured serum levels of HMGB1 and GC-associated cytokines/chemokines using GC serum samples (n = 120), and calculated microvessel density (MVD) by CD34 immunostaining using human GC tissues (n = 27). Then we analyzed the correlation of serum HMGB1 levels with MVD or that with cytokine/chemokine levels by linear regression. As in vitro angiogenesis assay for HMGB1, HUVEC migration and capillary tube formation assay were carried out using different histological types of human GC cells (N87 and KATOIII). CD34 positive microvessels were detected from early GC, but MVD increased according to GC stages, and were closely correlated with serum HMGB1 levels (R = 0.608, P = 0.01). The HUVECs cultured in conditioned media derived from rhHMGB1-treated or HMGB1-TF GC cells showed remarkably enhanced migration and tube formation activities. These effects were abrogated by anti-HMGB1 antibody or HMGB1 siRNA in both N87 and KATOIII cells (all P < 0.05). Among tested cytokines/chemokines, interleukin-8 (IL-8) was the most remarkable cytokine correlated with serum HMGB1 (P < 0.001), and enhanced HUVEC migration and tube formation activities by rhHMGB1 or HMGB1-TF were significantly reversed by IL-8 inhibition. These results indicate overexpressed HMGB1 contributes to tumor angiogenesis through IL-8 mediation, and combined targeting of HMGB1 and IL-8 can control tumor angiogenesis in GC. PMID- 28574632 TI - What about prophylactic surgery in BRCA1/BRCA2 mutation carriers? Observations from an Italian pilot study. PMID- 28574633 TI - A General Mechanism of Photoconversion of Green-to-Red Fluorescent Proteins Based on Blue and Infrared Light Reduces Phototoxicity in Live-Cell Single-Molecule Imaging. AB - Photoconversion of fluorescent proteins by blue and complementary near-infrared light, termed primed conversion (PC), is a mechanism recently discovered for Dendra2. We demonstrate that controlling the conformation of arginine at residue 66 by threonine at residue 69 of fluorescent proteins from Anthozoan families (Dendra2, mMaple, Eos, mKikGR, pcDronpa protein families) represents a general route to facilitate PC. Mutations of alanine 159 or serine 173, which are known to influence chromophore flexibility and allow for reversible photoswitching, prevent PC. In addition, we report enhanced photoconversion for pcDronpa variants with asparagine 116. We demonstrate live-cell single-molecule imaging with reduced phototoxicity using PC and record trajectories of RNA polymerase in Escherichia coli cells. PMID- 28574634 TI - Pinpointing clinical phenotypes - Is there evidence to support the use of a simple scoring system to define a milder bleeding phenotype in severe haemophilia A? PMID- 28574635 TI - Estradiol inhibits hepatic stellate cell area and collagen synthesis in the chicken liver. AB - Hepatic stellate cells (HSCs) are the main collagen-producing cells in the liver. The HSC area and amount of collagen fibers are different between male and female chickens. This study was performed to confirm the effect of estradiol on collagen synthesis in the growing chicken liver. Blood estradiol levels in chicks were compared at 4 and 8 weeks of age, and the collagen fibril network in liver tissue was observed at 8 weeks by scanning electron microscopy. Intraperitoneal administrations of estradiol and tamoxifen to male and female chicks, respectively, were performed daily from 5 to 8 weeks of age. The areas of HSCs and collagen contents were measured in the liver tissue. The blood estradiol level was higher in females than in males, and the collagen fibril network was denser in males than in females at 8 weeks of age. Estradiol administration in males induced decreases in the HSC area and collagen content of the liver. Conversely, tamoxifen administration in females induced an increase in the HSC area but did not facilitate collagen synthesis. Based on these results, estradiol inhibits the area and collagen synthesis of HSCs in the growing chicken liver under normal physiological conditions. PMID- 28574636 TI - Top-level sport in athletes with severe haemophilia A. PMID- 28574637 TI - Efficacy and safety of gadobutrol-enhanced MRA of the renal arteries: Results from GRAMS (Gadobutrol-enhanced renal artery MRA study), a prospective, intraindividual multicenter phase 3 blinded study. AB - PURPOSE: To compare the performance of magnetic resonance angiography (MRA) with 1M gadobutrol, a high relaxivity macrocyclic contrast agent, to 2D time-of-flight MRA (ToF-MRA) using computed tomographic angiography (CTA) as the standard of reference. Primary objectives were evaluation for superiority of structural delineation and noninferiority for detection and exclusion of clinically significant disease. MATERIALS AND METHODS: In all, 315 subjects underwent unenhanced and contrast-enhanced MRA with 1M gadobutrol (CE-MRA) and were scanned with 1.5T MRI equipped with an at least 6-element body coil. Evaluations were based on both centralized blinded read (BR) performed by six readers as well as investigator site interpretations for the 292 subjects who completed the study. Quantitative evaluations including percent stenosis and normal vessel measurements were also performed. Secondary endpoints included identification of accessory renal arteries, diagnosis of fibromuscular dysplasia (FMD), diagnostic confidence, and need for additional imaging. RESULTS: A total of 292 patients suspected of renal artery disease completed the study. CE-MRA demonstrated statistically significant improvement in assessability of vascular segments compared to ToF: 95.9% vs. 77.6% (P < 0.0001). In the BR, the sensitivity and specificity of CE-MRA were noninferior to ToF-MRA (53.4% vs. 46.6% and 95.1% vs. 85.7%, respectively). There was less error in the CE-MRA stenosis measurements (0.15 mm gadobutrol vs. 0.41 mm ToF, P < 0.05). FMD was correctly diagnosed more frequently, 10% more accessory renal arteries were identified (P < 0.01), diagnostic confidence increased (P < 0.01), and fewer additional imaging studies were recommended (P < 0.01). CONCLUSION: Gadobutrol-enhanced MRA of the renal arteries has superior visualization, more accurate vessel measurements, and may serve as a CTA alternative without any ionizing radiation. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:572-581. PMID- 28574638 TI - Amplification and quantification of cold-associated microRNAs in the Colorado potato beetle (Leptinotarsa decemlineata) agricultural pest. AB - The Colorado potato beetle [Leptinotarsa decemlineata (Say)] is an important insect pest that can inflict considerable damage to potato plants. This insect can survive extended periods of cold exposure, and yet the molecular switches underlying this phenomenon have not been fully elucidated. A better characterization of this process would highlight novel vulnerabilities associated with L. decemlineata that could serve as targets for the management of this devastating pest. Using high-throughput sequencing, the current work reveals a cold-associated signature group of microRNAs (miRNAs) in control (15 degrees C) and -5 degrees C-exposed L. decemlineata. The results show 42 differentially expressed miRNAs following cold exposure including miR-9a-3p, miR-210-3p, miR-276 5p and miR-277-3p. Functional analysis of predicted targets associated with these cold-responsive miRNAs notably linked these changes with vital metabolic and cellular processes. Overall, this study highlights the miRNAs probably responsible for facilitating cold adaptation in L. decemlineata and implicates miRNAs as a key molecular target to consider in the development of novel pest management strategies against these insects. PMID- 28574640 TI - Trigeminal Neuralgia in Pregnancy: A Management Challenge. AB - Pregnancy is known to aggravate pre-existing chronic painful conditions. Trigeminal neuralgia (TN), albeit a disease of the elderly, may afflict pregnant females, which can further complicate its management. Teratogenic effects of the commonly used drugs on the developing fetus limit pharmacological treatment. Moreover, safety of commonly performed interventional therapies is marred by their inherent fetomaternal effects and more importantly the risk for radiation effects on the fetus due to the use of fluoroscopy. This rare coexistence of TN in pregnancy has not been reported before. Here we present a case of TN in a young woman, whose pain was aggravated when she became pregnant, and she was treated successfully by conventional radiofrequency ablation of the Gasserian ganglion. PMID- 28574639 TI - DNA origami applications in cancer therapy. AB - Due to the complexity and heterogeneity of cancer, the development of cancer diagnosis and therapy is still progressing, and a complete understanding of cancer biology remains elusive. Recently, cancer nanomedicine has gained much interest as a promising diagnostic and therapeutic strategy, as a wide range of nanomaterials possess unique physical properties that can render drug delivery systems safer and more effective. Also, targeted drug delivery and precision medicine have now become a new paradigm in cancer therapy. With nanocarriers, chemotherapeutic drugs could be directly delivered into target cancer cells, resulting in enhanced efficiency with fewer side-effects. DNA, a biomolecule with molecular self-assembly properties, has emerged as a versatile nanomaterial to construct multifunctional platforms; DNA nanostructures can be modified with functional groups to improve their utilities as biosensors or drug carriers. Such applications have become possible with the advent of the scaffolded DNA origami method. This breakthrough technique in structural DNA nanotechnology provides an easier and faster way to construct DNA nanostructures with various shapes. Several experiments proved that DNA origami nanostructures possess abilities to enhance efficacies of chemotherapy, reduce adverse side-effects, and even circumvent drug resistance. Here, we highlight the principles of the DNA origami technique and its applications in cancer therapeutics and discuss current challenges and opportunities to improve cancer detection and targeted drug delivery. PMID- 28574643 TI - How far have we progressed since the Tokyo Guidelines 2013? PMID- 28574642 TI - Delivering irrigation to the anterior ethmoid region: evaluation of a lacrimal diversion device in a cadaver model. AB - BACKGROUND: Topical solutions to the sinus cavity are primarily administered via a transnasal route with inherent limitations of distribution. Here we describe an alternate method of sinus access via lacrimal sinus diversion using a novel lacrimal diversion device (LDD). METHODS: A cadaveric study was performed using 12 disarticulated fresh heads. The LDD was implanted in 23 sides meeting insertion criteria. Time to placement was recorded and patency was assessed via nasal endoscopy. Methylene blue was administered via the LDD and 16 sides underwent surgical ethmoidectomy to assess distribution of mucosal staining. Four cadavers underwent computed tomography (CT) imaging to demonstrate stent position. RESULTS: Mean time of placement was 3.66 +/- 2.37 minutes (mean +/- standard deviation [SD]). Patency rate was 100%. Six sides (37.5%) had anterior ethmoid staining, 6 sides (37.5%) had posterior ethmoid staining, and the remaining 4 sides (25%) had mixed anterior and posterior ethmoid staining. Stents placed optimally resulted in anterior ethmoid staining without complication. Malpositioned stents resulted in posterior ethmoid staining and some inadvertent ethmoid vertical lamella trauma in 2 instances. CONCLUSION: Sinus irrigation can be delivered to the ethmoid sinuses directly via a lacrimal diversion stent. Technique modification or image guidance may be helpful in ensuring optimal placement. PMID- 28574641 TI - Ectopic expression of a novel OsExtensin-like gene consistently enhances plant lodging resistance by regulating cell elongation and cell wall thickening in rice. AB - Plant lodging resistance is an important integrative agronomic trait of grain yield and quality in crops. Although extensin proteins are tightly associated with plant cell growth and cell wall construction, little has yet been reported about their impacts on plant lodging resistance. In this study, we isolated a novel extensin-like (OsEXTL) gene in rice, and selected transgenic rice plants that expressed OsEXTL under driven with two distinct promoters. Despite different OsEXTL expression levels, two-promoter-driven OsEXTL-transgenic plants, compared to a rice cultivar and an empty vector, exhibited significantly reduced cell elongation in stem internodes, leading to relatively shorter plant heights by 7% 10%. Meanwhile, the OsEXTL-transgenic plants showed remarkably thickened secondary cell walls with higher cellulose levels in the mature plants, resulting in significantly increased detectable mechanical strength (extension and pushing forces) in the mature transgenic plants. Due to reduced plant height and increased plant mechanical strength, the OsEXTL-transgenic plants were detected with largely enhanced lodging resistances in 3 years field experiments, compared to those of the rice cultivar ZH11. In addition, despite relatively short plant heights, the OsEXTL-transgenic plants maintain normal grain yields and biomass production, owing to their increased cellulose levels and thickened cell walls. Hence, this study demonstrates a largely improved lodging resistance in the OsEXTL-transgenic rice plants, and provides insights into novel extensin functions in plant cell growth and development, cell wall network construction and wall structural remodelling. PMID- 28574645 TI - Structure Mapping and Vocabularies for Thinking. AB - While extremes tend to capture attention, the ordinary is often most of the story. So it may be with the structure-mapping process. The structure-mapping process can account for such pinnacles of thinking as analogy and metaphor, which can lead to overlooking the mundane, incremental use of structure mapping. Consequently, the current discussion shifts focus to the value of close comparisons between literally similar items for the development of knowledge. The intent is to foster greater integration between process and content as well as between individuals and collectives. The payoff is identifying some undue simplifications and some promising new directions. PMID- 28574644 TI - New Prenylated ortho-Dihydroxycoumarins from the Fruits of Ficus nipponica. AB - Two new prenylated ortho-dihydroxycoumarins, designated fipsomin (1) and fipsotwin (2), were isolated from the fruits of Ficus nipponica together with a known prenylated coumarin, apigravin (3). Their structures were established by spectroscopic data and X-ray crystallographic analysis. Compound 1 exhibited antibacterial activity against Bacillus subtilis with an MIC value of 61 MUm, while 2 and 3 showed very weak activity. PMID- 28574646 TI - The measurement properties of the spence children's anxiety scale-parent version in a large international pooled sample of young people with autism spectrum disorder. AB - Anxiety-related difficulties are common in ASD, but measuring anxiety reliably and validly is challenging. Despite an increasing number of studies, there is no clear agreement on which existing anxiety measure is more psychometrically sound and what is the factor structure of anxiety in ASD. The present study examined the internal consistency, convergent, divergent, and discriminant validity, as well as the factor structure of the Spence Children's Anxiety Scale-Parent Version (SCAS-P), in a large international pooled sample of 870 caregivers of youth with ASD from 12 studies in the United Kingdom, United States, and Singapore who completed the SCAS-P. Most were community recruited, while the majority had at least one measure of ASD symptomatology and either cognitive or adaptive functioning measures completed. Existing SCAS-P total scale and subscales had excellent internal consistency and good convergent, divergent and discriminant validity similar to or better than SCAS-P properties reported in typically developing children, except for the poorer internal consistency of the physical injury subscale. Confirmatory Factor Analysis (CFA) of the existing SCAS P six-correlated factor structure was a poor fit for this pooled database. Principal component analysis using half of the pooled sample identified a 30-item five correlated factor structure, but a CFA of this PCA-derived structure in the second half of this pooled sample revealed a poor fit, although the PCA-derived SCAS-P scale and subscales had stronger validity and better internal consistency than the original SCAS-P. The study's limitations, the use of the SCAS-P to screen for DSM-derived anxiety problems in ASD and future research directions are discussed. Autism Res 2017, 10: 1629-1652. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 28574647 TI - Robust nondimensional estimators to assess the nasal airflow in health and disease. AB - There are significant variations of both human nose shapes and airflow patterns inside nasal cavities, so it is difficult to provide a comprehensive medical identification using a universal template for what otolaryngologists consider normal breathing at rest. In addition, airflow patterns present even more random characteristics in diseased nasal cavities. To give a medical assessment to differentiate the nasal cavities in health and disease, we propose 2 nondimensional estimators obtained from both medical images and computational fluid dynamics. The first mathematical estimator phi is a function of geometric features and potential asymmetries between nasal passages, while the second estimator R represents in fluid mechanics terms the total nasal resistance that corresponds to the atmosphere-choana pressure drop. These estimators only require global information such as nasal geometry and magnitudes of flow determined by simulations under laminar conditions. We find that these estimators take low and high values for healthy and diseased nasal cavities, respectively. Our study, based on 24 healthy and 25 diseased Caucasian subjects, reveals that there is an interval of values associated with healthy cavities that clusters in a small region of the plane phi-R. Therefore, these estimators can be seen as a first approximation to provide nasal airflow data to the clinician in a noninvasive method, as the computed tomography scan that provides the required images is routinely obtained as a result of the preexisting naso-sinusal condition. PMID- 28574648 TI - Block Copolymer-Templated Approach to Nanopatterned Metal-Organic Framework Films. AB - The fabrication of patterned metal-organic framework (MOF) films with precisely controlled nanoscale resolution has been a fundamental challenge in nanoscience and nanotechnology. In this study, nanopatterned MOF films were fabricated using a layer-by-layer (LBL) growth method on functional templates (such as a bicontinuous nanoporous membrane or a structure with highly long-range-ordered nanoscopic channels parallel to the underlying substrate) generated by the microphase separation of polystyrene-b-poly(2-vinylpyridine) (PS-b-P2VP) block copolymers. HKUST-1 can be directly deposited on the templates without any chemical modification because the pyridine groups in P2VP interact with metal ions via metal-BCP complexes. As a result, nanopatterned HKUST-1 films with feature sizes below 50 nm and controllable thicknesses can be fabricated by controlling the number of LBL growth cycles. The proposed fabrication method further extends the applications of MOFs in various fields. PMID- 28574649 TI - Hybrid Pharmacophoric Approach in the Design and Synthesis of Coumarin Linked Pyrazolinyl as Urease Inhibitors, Kinetic Mechanism and Molecular Docking. AB - The current research article reports the synthesis of coumarinyl pyrazolinyl thioamide derivatives and their biological activity as inhibitors of jack bean urease. The coumarinyl pyrazolinyl thioamides were synthesized by reacting thiosemicarbazide with newly synthesized chalcones to afford the products in good yields and the synthesized compounds were purified by recrystallization. Coumarinyl pyrazolinyl thioamide derivatives 5a - 5q showed significant activity against Urease enzyme and also exhibited good antioxidant potential. The compound 3-(2-oxo-2H-chromen-3-yl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbothioamide (5n) was found to be superior agent in the series with an IC50 = 0.358 +/- 0.017 MUm compared to standard thiourea with an IC50 = 4720 +/- 174 MUm. To undermine the binding mode of inhibition kinetic studies were performed for most potent derivative and it was found that compound 5n inhibits urease enzyme by non competitive mode of inhibition. Molecular docking studies were carried out to delineate the binding affinity of the synthesized derivatives. PMID- 28574650 TI - Anthropometric charts and congenital anomalies in newborns with Down syndrome. AB - The objectives of this study were to obtain updated neonatal measurements in French newborns with Down Syndrome (DS) according to their gestational age, and to assess the frequency and distribution of congenital anomalies. Data on congenital malformations, birth weight, birth length and birth occipito-frontal circumference (OFC) according to the gestational age was gathered from 1,030 babies, born between 1980 and 2010. The mean gestational age was 38 weeks from the date of the last menstrual period (LMP) (range: 29-42 weeks). Repartition of complications was found to be similar to previous studies, with no difference according to the date of birth. For girls born after 37 weeks, the mean birth weight was 3,012 +/- 430 g, the mean birth length was 47.7 +/- 2 cm, and the mean birth OFC was 33 +/- 1.4 cm. For boys born after 37 weeks, the mean birth weight was 3,103 +/- 459, the mean birth length was 48.4 +/- 2.2 cm, and the mean birth OFC was 33.2 +/- 1.4 cm. We did not find any difference in these measurements when we compared children born before 1997 and after 2007. When compared to the general population (French data and WHO charts), newborns with DS have a more pronounced difference in their birth length and their birth OFC (15-25th) than in their birth weight (25-50th). The shape of the growth curves shows that growth velocity decreases during the last weeks of gestation in all measurements, which suggests that the modal age for delivery could be earlier in DS newborns than in the general population. PMID- 28574653 TI - Cortical and Trabecular Bone Microstructure Did Not Recover at Weight-Bearing Skeletal Sites and Progressively Deteriorated at Non-Weight-Bearing Sites During the Year Following International Space Station Missions. AB - Risk for premature osteoporosis is a major health concern in astronauts and cosmonauts; the reversibility of the bone lost at the weight-bearing bone sites is not established, although it is suspected to take longer than the mission length. The bone three-dimensional structure and strength that could be uniquely affected by weightlessness is currently unknown. Our objective is to evaluate bone mass, microarchitecture, and strength of weight-bearing and non-weight bearing bone in 13 cosmonauts before and for 12 months after a 4-month to 6-month sojourn in the International Space Station (ISS). Standard and advanced evaluations of trabecular and cortical parameters were performed using high resolution peripheral quantitative computed tomography. In particular, cortical analyses involved determination of the largest common volume of each successive individual scan to improve the precision of cortical porosity and density measurements. Bone resorption and formation serum markers, and markers reflecting osteocyte activity or periosteal metabolism (sclerostin, periostin) were evaluated. At the tibia, in addition to decreased bone mineral densities at cortical and trabecular compartments, a 4% decrease in cortical thickness and a 15% increase in cortical porosity were observed at landing. Cortical size and density subsequently recovered and serum periostin changes were associated with cortical recovery during the year after landing. However, tibial cortical porosity or trabecular bone failed to recover, resulting in compromised strength. The radius, preserved at landing, unexpectedly developed postflight fragility, from 3 months post-landing onward, particularly in its cortical structure. Remodeling markers, uncoupled in favor of bone resorption at landing, returned to preflight values within 6 months, then declined farther to lower than preflight values. Our findings highlight the need for specific protective measures not only during, but also after spaceflight, because of continuing uncertainties regarding skeletal recovery long after landing. (c) 2017 American Society for Bone and Mineral Research. PMID- 28574656 TI - Nut allergy guideline. PMID- 28574651 TI - Impact of tobacco smoke on upper airway dendritic cell accumulation and regulation by sinonasal epithelial cells. AB - BACKGROUND: In these studies we examined the impact of environmental tobacco smoke (ETS) and active smoking on sinonasal dendritic cell (DC) subsets in controls or patients with chronic rhinosinusitis with nasal polyps (CRSwNP). In subsequent in-vitro investigations, we examined the influence of cigarette smoke extract (CSE) on human sinonasal epithelial cells' (HSNECs) ability to regulate DC functions. METHODS: Sinonasal tissue, blood, and hair were collected from patients undergoing sinus surgery. Smoking status and ETS exposure were determined by hair nicotine. DC subsets were examined by flow cytometric analysis. Monocyte-derived dendritic cells (moDCs) were treated with conditioned medium from non-smoked-exposed HSNECs (NS-HSNECs) or cigarette-smoke-extract exposed HSNECs (CSE-HSNECs) to assess the impact of CSE exposure on HSNEC regulation of moDC functions. RESULTS: Control subjects who were active smokers displayed increased sinonasal moDC and myeloid dendritic 1 (mDC1) cells and reduced mDC2 cells, whereas, in CRSwNP patients, only moDC and mDC2 cells were altered. ETS was found to increase only moDCs in the CRSwNP patients. In vitro, CSE stimulated HSNEC secretion of the moDC regulatory products chemokine (C-C motif) ligand 20, prostaglandin E2 , and granulocyte-macrophage colony stimulating factor. CSE exposure also promoted HSNECs to stimulate monocyte and moDC migration. moDCs treated with CSE-HSNEC media stimulated an increase in antigen uptake and expression of CD80 and CD86. Last, CSE-HSNEC-treated moDCs secreted increased levels of interleukin-10, interferon-gamma, and thymic stromal lymphopoietin. CONCLUSION: Active smoking, and to a lesser degree ETS, alters the sinonasal composition of DCs. A potential mechanism to account for this is that cigarette smoke stimulates HSNECs to induce moDC migration, maturation, and activation. PMID- 28574652 TI - Accuracy and consistency of anti-Xa activity measurement for determination of rivaroxaban plasma levels. AB - : Essentials Accurate determination of anticoagulant plasma concentration is important in clinical practice. We studied the accuracy and consistency of anti Xa assays for rivaroxaban in a multicentre study. In a range between 50 and 200 MUg L-1 , anti-Xa activity correlated well with plasma concentrations. The clinical value might be limited by overestimation and intra- and inter-individual variation. SUMMARY: Background Determining the plasma level of direct oral anticoagulants reliably is important in the work-up of complex clinical situations. Objectives To study the accuracy and consistency of anti-Xa assays for rivaroxaban plasma concentration in a prospective, multicenter evaluation study employing different reagents and analytical platforms. Methods Rivaroxaban 20 mg was administered once daily to 20 healthy volunteers and blood samples were taken at peak and trough levels (clinicaltrials.gov NCT01710267). Anti-Xa activity was determined in 10 major laboratories using different reagents and analyzers; corresponding rivaroxaban plasma concentrations were measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS). Findings Overall Pearson's correlation coefficient of anti-Xa levels and HPLC-MS results was 0.99 for Biophen(r) Heparin (95% CI, 0.99, 0.99), Biophen(r) DiXaI (95% CI, 0.99, 0.99) and STA(r) anti-Xa liquid (95% CI, 0.99, 1.00). Correlation was lower in rivaroxaban concentrations below 50 MUg L-1 and above 200 MUg L-1 . The overall bias of the Bland-Altman difference plot was 14.7 MUg L-1 for Biophen Heparin, 17.9 MUg L-1 for Biophen DiXal and 19.0 MUg L-1 for STA anti-Xa liquid. Agreement between laboratories was high at peak level but limited at trough level. Conclusions Anti-Xa activity correlated well with rivaroxaban plasma concentrations, especially in a range between 50 and 200 MUg L-1 . However, anti Xa assays systematically overestimated rivaroxaban concentration as compared with HPLC-MS, particularly at higher concentrations. This overestimation, coupled with an apparent interindividual variation, might affect the interpretation of results in some situations. PMID- 28574654 TI - Neuroprotective effects respond to cerebral ischemia without susceptibility to HB tumorigenesis in VHL heterozygous knockout mice. AB - The von Hippel-Lindau (VHL) tumor suppressor gene plays a prominent role in the development of hemangioblastomas (HBs) within specific regions of the human' central nervous system (CNS). Alterations in VHL gene are rarely observed in the more common features of human VHL-related tumors in animal models, and VHL heterozygous knockout (VHL+/-) mice do not develop HBs. We tested whether VHL heterozygous knockout mice exhibited genetic predisposition to the development of HBs and conferred a selective advantage involving growth of blood vessels to its carrier. No differences were observed between wild-type and VHL+/- mice in development ad reproduction. The heterozygous VHL+/- mice did not develop higher genetic susceptibility to CNS-HBs over their lifetime. Furthermore, this recessive VHL gene heterozygosity is relatively stable. Interestingly, we found these heterozygous VHL+/- mice gained an advantage conferring to angiogenic ability in a particular environment, compared with wild-type mice. The heterozygous VHL+/- mice obviously enhanced hypoxia inducible factor-1 (HIF) dependent and Twist1 angiogenic mechanism in response to acute cerebral ischemia, resulting in decreased cerebral tissue damage and neuroprotective response through neovascularization. Our findings provide evidence of partial loss function of VHL as a novel precise therapeutic target in acute cerebral ischemia. PMID- 28574657 TI - Time-dependent uptake and toxicity of nickel to Enchytraeus crypticus in the presence of humic acid and fulvic acid. AB - The present study aimed to investigate the influence of different fractions of dissolved organic carbon (DOC) on the uptake and toxicity of nickel (Ni) in the soil invertebrate Enchytraeus crypticus after different exposure times. The addition of DOC as humic acid or fulvic acid significantly reduced Ni uptake by E. crypticus in the soil-solution test system. Median lethal effect concentrations were calculated based on total dissolved Ni concentrations (LC50[Ni]), free Ni ion activity (LC50{Ni2+ }), and Ni body concentrations (LC50Body-Ni ). The LC50[Ni] values increased with increasing DOC levels and decreased with exposure time (4, 7, and 10 d). Humic acid exerted a greater protective effect on Ni toxicity than fulvic acid, but the protective effects decreased with prolonged exposure time. The LC50{Ni2+ } values also decreased with exposure time but were almost constant with variation in DOC levels, indicating that the protective effect of DOC is mainly through complexation with free Ni ions to reduce Ni bioavailability. The LC50Body-Ni value was independent of DOC concentration and exposure time, with an estimated overall value of 22.1 ug/g dry weight. The present study shows that body concentration could serve as an effective indicator for predicting Ni toxicity with variations in the exposure environment (e.g., DOC) and exposure time. Environ Toxicol Chem 2017;36:3019 3027. (c) 2017 SETAC. PMID- 28574658 TI - Patient-tailored colorectal cancer care: a challenge within the context of evidence based guidelines. PMID- 28574663 TI - A novel method for treatment of chronic anal fissure: adipose-derived regenerative cells - a pilot study. AB - AIM: The purpose of this study was to investigate the safety and feasibility of autologous adipose-derived regenerative cells (ADRC) in the treatment of chronic anal fissure. METHOD: A prospective pilot study was conducted in six patients with chronic anal fissures at the First Surgical Clinic, Clinical Center of Serbia and at the BelPrime Clinic, Belgrade, Serbia. All patients were candidates for surgical treatment. The average duration of symptoms was 24 months. Pain assessment was quantified using a visual analogue scale and bowel continence was assessed using the Wexner incontinence score. Both were assessed before treatment and during each postoperative outpatient visit. Liposuction was performed under local or general anaesthesia. Extraction of ADRC was achieved with a closed automated medical device. The fat and ADRC were injected subcutaneously into the edge of the fissure. The rest of the pellet was infiltrated into the internal anal sphincter. The study has been registered at ClinicalTrials.gov (NCT02628522). RESULTS: Complete healing of the anal fissure and the disappearance of symptoms was achieved in all patients. The average time to complete pain cessation was 33.7 +/- 15.0 days. All fissures healed after 3 months and remained healed 12 months after the procedure. There were no complications related to the procedure. CONCLUSION: The application of ADRC may be an alternative to lateral sphincterotomy and a reliable procedure which avoids faecal incontinence. PMID- 28574665 TI - Simultaneous Multislice-Based 5-Minute Lumbar Spine MRI Protocol: Initial Experience in a Clinical Setting. AB - BACKGROUND AND PURPOSE: Previous studies have used parallel imaging (PI) techniques to decrease spine magnetic resonance imaging (MRI) protocol acquisition times. Recently developed MRI sequences allow even faster acquisitions. Our purpose was to develop a lumbar spine MRI protocol using PI with GRAPPA (generalized autocalibrating partially parallel acquisition) and a simultaneous multislice (SMS)-based sequence and to evaluate its diagnostic performance compared to a standard lumbar spine MRI protocol. METHODS: Ten patients were scanned in a 3-Tesla scanner (MAGNETOM Skyra, Siemens Healthcare). Each patient was imaged using a standard protocol and an optimized fast protocol acquiring the same contrasts and planes. The fast protocol included sagittal T1, T2, and fat suppressed T2 sequences accelerated with GRAPPA and an SMS-based axial T2-weighted sequence using a high-density spine coil (Siemens MR, 30 channel spine). Two blinded neuroradiologists independently assessed image quality and diagnostic accuracy for clinically relevant imaging findings. RESULTS: The fast protocol acquisition time was 5:28 minutes, compared with 16:30 minutes for the standard protocol. Both protocols had a similar performance for definition of anatomical structures, diagnostic quality, and identification of clinically relevant imaging findings. There were more artifacts in the SMS Turbo Spin Echo (P = .014) sequence without compromising diagnostic performance. Artifacts in the remaining non-SMS sequences were similar in both protocols (P > .180). The sensitivity, specificity, and accuracy of the 5-minute protocol were 92.3%, 100.0%, and 99.6%, respectively, for the clinically relevant findings (P = 1.0, interrater agreement .57). CONCLUSIONS: A 5-minute SMS-based MRI protocol for lumbar spine imaging is feasible and can be achieved without significant impact in the overall diagnostic quality. PMID- 28574664 TI - Chemokine (CC motif) ligand 18 upregulates Slug expression to promote stem-cell like features by activating the mammalian target of rapamycin pathway in oral squamous cell carcinoma. AB - Chemokine (CC motif) ligand 18 (CCL18) is involved in remodeling of the tumor microenvironment and plays critical roles in oncogenesis, invasiveness, and metastasis. We previously investigated the overexpression of CCL18 in primary oral squamous cell carcinoma (OSCC) tissues and its association with advanced clinical stage in OSCC patients. However, the underlying mechanisms of this CCL18 derived activity remains unidentified. This study showed exogenous CCL18 increased cell migration and invasion and induced cell epithelial-mesenchymal transition (EMT), and that E-cadherin, an epithelial marker, decreased and N cadherin, a mesenchymal marker, increased, compared to negative control in OSCC cells. Furthermore, we detected that CCL18 induced the acquisition of cancer stem(-like) cell characteristics in oral cancer cells, but also found a significantly positive correlation between the expression of CCL18 and Bmi-1 (P < 0.001) in OSCC surgical specimens by immunohistochemistry analysis. The expression of octamer-binding transcription factor 4 and Bmi-1 were significantly upregulated, and proportions of aldehyde dehydrogenasehigh+ cells and CD133+ cells were markedly increased in CCL18-treated cells compared to untreated cells. Sphere formation ability was observably enhanced when cells were continually exposed to high levels of CCL18. Moreover, CCL18 upregulated Slug expression by stimulating the mammalian target of rapamycin (mTOR) signaling pathway in OSCC cell lines. Inhibition of the mTOR pathway by INK128, or Slug knockdown by RNA interference, reversed CCL18-induced EMT and the stemness response at both molecular and functional levels. In conclusion, our data suggested that CCL18 upregulated Slug expression to promote EMT and stem cell-like features by activating the mTOR pathway in oral cancer. These findings provide new potential targets for the early diagnosis and treatment of OSCC. PMID- 28574666 TI - Adjusting the scent ratio: using genetically modified Vitis vinifera plants to manipulate European grapevine moth behaviour. AB - Herbivorous insects use olfactory cues to locate their host plant within a complex olfactory landscape. One such example is the European grapevine moth Lobesia botrana, a key pest of the grape in the Palearctic region, which recently expanded both its geographical and host plant range. Previous studies have showed that a synthetic blend of the three terpenoids, (E)-beta-caryophyllene, (E)-beta farnesene and (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT), was as attractive for the moth as the complete grape odour profile in laboratory conditions. The same studies also showed that the specific ratio of these compounds in the grape bouquet was crucial because a percentage variation in any of the three volatiles resulted in almost complete inhibition of the blend's attractiveness. Here, we report on the creation of stable grapevine transgenic lines, with modified (E) beta-caryophyllene and (E)-beta-farnesene emission and thus with an altered ratio compared to the original plants. When headspace collections from these plants were tested in wind tunnel behavioural assays, they were less attractive than control extracts. This result was confirmed by testing synthetic blends imitating the ratio found on natural and transformed plants, as well as by testing the plants themselves. With this evidence, we suggest that a strategy based on volatile ratio modification may also interfere with the host-finding behaviour of L. botrana in the field, creating avenues for new pest control methods. PMID- 28574668 TI - Unified Asymmetric Total Syntheses of (-)-Alotaketals A-D and (-)-Phorbaketal A. AB - The novel tricyclic spiroketal alotane-type sesterterpenoids showed strikingly different biological activities and potency with subtle structural alterations. Asymmetric total syntheses of the tricyclic sesterterpenoids (-)-alotaketals A-D and (-)-phorbaketal A were accomplished [29-31 steps from (-)-malic acid] in a collective way for the first time. The key features of the strategy included 1) a new cascade cyclization of vinyl epoxy delta-keto-alcohols to forge the common tricyclic spiroketal intermediate, 2) a late-stage allylic C-H oxidation, and 3) olefin cross-metathesis to install the different side chains. PMID- 28574667 TI - High density of CD204-positive macrophages predicts worse clinical prognosis in patients with breast cancer. AB - Recent studies have indicated the clinical significance of tumor-associated macrophages (TAM) in several malignant tumors including breast cancer. Although recent studies have focused on CD68-positive or CD163-positive TAM in breast cancer, no study has investigated the significance of CD204-positive TAM in breast cancer. We found that CD204 expression on macrophages was evaluated following stimulation with the conditioned medium (CM) of breast cancer cell lines. Paraffin sections of 149 breast cancer samples which were diagnosed as invasive ductal carcinoma were immunohistochemically analyzed for CD68, CD163 and CD204 expression. The results of analyses indicated that a high number of CD204 positive TAM was associated with worse clinical prognoses, including relapse-free survival, distant relapse-free survival and breast cancer-specific survival; however, neither the numbers of CD68-positive or CD163-positive TAM were associated with clinical courses. Of the clinicopathological factors investigated, estrogen receptor, Ki-67 index, hormone subtype, and histological grade were significantly related to the increased number of CD163-positive and CD204-positive TAM. These data indicate the clinical significance of CD204 positive TAM in breast cancer progression and CD204 is a marker for predicting clinical prognosis in breast cancer. PMID- 28574669 TI - Cross-site randomized control trial of the Social ABCs caregiver-mediated intervention for toddlers with autism spectrum disorder. AB - To evaluate the efficacy of the Social ABCs parent-mediated intervention for toddlers with suspected or confirmed autism spectrum disorder (ASD), through a cross-site randomized control trial, sixty-three parent-toddler dyads (toddler age: 16-30 months) were randomized into treatment (Social ABCs) or control (service-as-usual) conditions. Video data were obtained at three key time-points: Baseline; Post-training (PT; week 12); and Follow-Up (week 24). Analyses included 62 dyads. Treatment allocation significantly accounted for PT gains, all favouring the Treatment group, in (1) child functional vocal responsiveness to parent prompts (R2 = 0.43, P < .001), (2) child vocal initiations (R2 = 0.28, P < .001), (3) parent smiling (R2 = 0.09, P = .017), and (4) fidelity of implementation (R2 = 0.71, P < .001). A trend was observed for increased social orienting (R2 = 0.06, P = 0.054); gains in parent smiling significantly predicted increases in child smiling and social orienting. Parents in the treatment condition reported significant gains in self-efficacy following the intervention (P = 0.009). No differential effects emerged for performance on standardized measures. The Social ABCs is a relatively low-resource, efficacious intervention, with potential to be a cost-effective means of intervening at the first signs of possible ASD. Autism Res 2017, 10: 1700-1711. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. Clinical Trial Title: Social ABCs for Toddlers with Signs of Autism Spectrum Disorder: RCT of a Parent-Mediated Intervention http//ClinicalTrials.gov identifier: NCT02428452. PMID- 28574670 TI - Performance of Aptima and Cobas HPV testing platforms in detecting high-grade cervical dysplasia and cancer. AB - BACKGROUND: Human papillomavirus (HPV) tests and genotyping have been used in clinical risk assessment. The purpose of this study was to analyze the performance of 2 common HPV testing platforms in detecting high-grade cervical lesions (high-grade squamous intraepithelial lesion [HSIL] or worse [>=HSIL]). METHODS: Between January 1 and December 31, 2015, 2041 Papanicolaou (Pap) tests with biopsy confirmation were analyzed along with HPV tests performed on Cobas or Aptima platforms. A biopsy diagnosis of grade 2 cervical intraepithelial neoplasia was confirmed with p16/Ki-67 immunohistochemistry. RESULTS: In total, 1866 and 175 Pap cases were tested on Cobas and Aptima platforms, respectively. Both platforms were highly sensitive (97% for both) for biopsy-confirmed >=HSIL. Cobas HPV testing had higher positive rates for the diagnosis of benign lesions (84% vs 51%) and low-grade squamous intraepithelial lesions (89% vs 63%) on biopsy compared with Aptima. Aptima testing had significantly higher specificity for >=HSIL than Cobas (41% vs 13%; P < .0001). Overall, performance of the Aptima platform was superior to that of the Cobas platform in detecting biopsy-confirmed >=HSIL, resulting from its significantly higher positive predictive value (25% vs 16%; P < .03) and overall accuracy (50% vs 26%; P < .0001). CONCLUSIONS: Although both the Cobas and Aptima platforms offer highly sensitive tests for high-grade cervical lesions, Aptima HPV testing demonstrated significantly higher specificity and positive predictive value than Cobas testing for biopsy-confirmed >=HSIL. The considerable difference may be related to the significant increase in E6/E7 expression after HPV DNA integration. The significantly higher specificity and overall accuracy of Aptima testing for >=HSIL, resulting in the identification of high-risk populations that require immediate treatment and close follow-up, may prove useful in clinical risk stratification. Cancer Cytopathol 2017;125:652-7. (c) 2017 American Cancer Society. PMID- 28574673 TI - History is Magic... Share the Magic with Your Colleagues. PMID- 28574671 TI - Interdisciplinary care in disorders/differences of sex development (DSD): The psychosocial component of the DSD-Translational research network. AB - Scientific discovery and clinical management strategies for Disorders/Differences of Sex Development (DSD) have advanced in recent years. The 2006 Consensus Statement on Management of Intersex Disorders stated that a mental health component to care is integral to promote positive adaptation, yet the parameters of this element have not been described. The objective of this paper is threefold: to describe the psychosocial screening protocol adopted by the clinical centers of the DSD-Translational Research Network; to summarize psychosocial data collected at 1 of the 10 network sites; and to suggest how systematic behavioral health screenings can be employed to tailor care in DSD that results in better health and quality of life outcomes. Steps taken in developing the largely "noncategorical" screening protocol are described. These preliminary findings suggest that DSD, as one category of pediatric chronic conditions, is not associated with marked disturbances of psychosocial adaptation, either for the family or the child; however, screening frequently uncovered "risk factors" for individual families or patients that can potentially be addressed in the context of ongoing clinical care. Administration of the DSD TRN psychosocial screening protocol was demonstrated to be feasible in the context of interdisciplinary team care and was acceptable to families on a longitudinal basis. The ultimate value of systematic screening will be demonstrated through a tailoring of psychosocial, medical and surgical services, based on this information that enhances the quality of patient and family centered care and subsequent outcomes. PMID- 28574672 TI - Safety of multidetector computed tomography pulmonary angiography to exclude pulmonary embolism in patients with a likely pretest clinical probability. AB - : Essentials Safety of computed tomography (CTPA) to exclude pulmonary embolism (PE) in all patients is debated. We analysed the outcome of PE-likely outpatients left untreated after negative CTPA alone. The 3-month venous thromboembolic risk in these patients was very low (0.6%; 95% CI 0.2-2.3). Multidetector CTPA alone safely excludes PE in patients with likely clinical probability. SUMMARY: Background In patients with suspected pulmonary embolism (PE) classified as having a likely or high pretest clinical probability, the need to perform additional testing after a negative multidetector computed tomography pulmonary angiography (CTPA) finding remains a matter of debate. Objectives To assess the safety of excluding PE by CTPA without additional imaging in patients with a likely pretest probability of PE. Patients/Methods We retrospectively analyzed patients included in two multicenter management outcome studies that assessed diagnostic algorithms for PE diagnosis. Results Two thousand five hundred and twenty-two outpatients with suspected PE were available for analysis. Of these 2522 patients, 845 had a likely clinical probability as assessed by use of the simplified revised Geneva score. Of all of these patients, 314 had the diagnosis of PE excluded by a negative CTPA finding alone without additional testing, and were left without anticoagulant treatment and followed up for 3 months. Two patients presented with a venous thromboembolism (VTE) during follow-up. Therefore, the 3-month VTE risk in likely-probability patients after a negative CTPA finding alone was 2/314 (0.6%; 95% confidence interval [CI] 0.2-2.3%). Conclusions In outpatients with suspected PE and a likely clinical probability as assessed by use of the simplified revised Geneva score, CTPA alone seems to be able to safely exclude PE, with a low 3-month VTE rate, which is similar to the VTE rate following the gold standard, i.e. pulmonary angiography. PMID- 28574674 TI - Origins of the Electronic Apex Locator - Achieving Success with Strict Adherence to Business. AB - Current history would have you believe that the evolution and development of the electronic apex locator for use during root canal procedures emanated from the work of Suzuki in 1942, which was developed as a product by Sunada in 1962. Yes, this is partly correct, however the concept of using electrical means to locate the ends of root canals was brought to the dental profession as early as 1918 by Dr. Levitt Ellsworth Custer, which was not addressed until Suzuki revisited Custer's concepts. This contribution was only one of the many that Custer proffered as he championed the use of electricity in dentistry. PMID- 28574675 TI - A Building with a Provenance: The Thomas W. Evans Building at Penn Dental Medicine. PMID- 28574676 TI - Washburn & Moen Manufacturing Company and Dr. Kazanjian. PMID- 28574678 TI - Collector's Corner: Soldering Pliers. PMID- 28574677 TI - Historical Perspectives on the Use of Microscopes in Dentistry. AB - The use of microscopes in dentistry has become quite popular since the late 1980s. However, its origin for dental applications can be traced to the early 20th century, when a microscope, invented by an American biologist named Greenough, working in the Zeiss Company, was adapted for use in dentistry. Initially it had been used in botany, metallurgy, and zoology, in addition to revolutionizing the study of coral and entomology. PMID- 28574679 TI - Depiction of a 17th-Century Tooth Extraction: A Drawing by Adriaen Pietersz van de Venne (Dutch, 1589-1662). AB - A prolific and inventive painter, draftsman, and poet, Adriaen Pietersz van de Venne was born in Delft in 1589. His wealthy parents had fled from Protestant persecution in the Southern (Spanish) Netherlands during the 1580s. Van de Venne was educated in Leiden, where he became part of the vibrant political and intellectual community around the University. He settled in Middleburg, in Zeeland, by 1614; his earliest dated paintings are also from this year. In 1625, van de Venne moved to The Hague, where he remained until his dealth. He executed several commissions for the Dutch stadholder Frederik Hendrik, was repeatedly elected dean of the guild of St. Luke, and in 1656 was one of the founding members of The Hague's painter's guild, "Pictura schilders confrerie." Van de Venne painted histories, portraits, and genre scenes; from 1618, he was also active as a printmaker and book illustrator, notably for the popular poet Jacob Cats. His literary accomplishments included satire and political propaganda, as well as several books of poetry. PMID- 28574680 TI - From the Archives: Vol. 6, Nos. 3 & 4. PMID- 28574682 TI - Increases in Drug Spending Slow. PMID- 28574683 TI - States Tackle Health Care. PMID- 28574684 TI - Stubbing Out Tobacco. PMID- 28574686 TI - The FMLA and Psychological Support: Courts Care About "Care" (and Employers Should, Too). AB - The Family and Medical Leave Act ("FMLA") recognizes an employee's right to take leave to care for a qualifying family member. In light of the Act's remedial nature, the intended scope of the care provision is broad, but its definitional details are sparse. As a result of the attendant interpretive discretion afforded to courts, the Seventh Circuit announced its rejection of the requirement-- first articulated by the Ninth Circuit--that care provided during travel be related to continuing medical treatment. A facial analysis of the resulting circuit split fails to appreciate the fundamental difference between the Seventh and Ninth Circuits' considerations: the distinction between physical and psychological care. Whereas physical care is readily measurable, psychological care is less defined and, consequently, ripe to facilitate FMLA abuse. Efforts to combat this potential lead courts to impose judicially devised limitations on psychological care, but judicial discretion still infuses some uncertainty into proceedings. For employers, the best remedy lies in the FMLA's optional certification provision, which requires medical validation of an employee's need for leave. In requiring certification, employers should distinguish between physical and psychological care, maximize the FMLA's informational requirements, and implement complete and consistent request and approval procedures. PMID- 28574685 TI - Walking a tightrope. States are balancing the rights of addicted women with the health needs of their developing babies. PMID- 28574687 TI - Miscellaneous Lasing Actions in Organo-Lead Halide Perovskite Films. AB - Lasing actions in organo-lead halide perovskite films have been heavily studied in the past few years. However, due to the disordered nature of synthesized perovskite films, the lasing actions are usually understood as random lasers that are formed by multiple scattering. Herein, we demonstrate the miscellaneous lasing actions in organo-lead halide perovskite films. In addition to the random lasers, we show that a single or a few perovskite microparticles can generate laser emissions with their internal resonances instead of multiple scattering among them. We experimentally observed and numerically confirmed whispering gallery (WG)-like microlasers in polygon shaped and other deformed microparticles. Meanwhile, owing to the nature of total internal reflection and the novel shape of the nanoparticle, the size of the perovskite WG laser can be significantly decreased to a few hundred nanometers. Thus, wavelength-scale lead halide perovskite lasers were realized for the first time. All of these laser behaviors are complementary to typical random lasers in perovskite film and will help the understanding of lasing actions in complex lead halide perovskite systems. PMID- 28574688 TI - Understanding the Enhanced Kinetics of Gradient-Chemical-Doped Lithium-Rich Cathode Material. AB - Although chemical doping has been extensively employed to improve the electrochemical performance of Li-rich layered oxide (LLO) cathodes for Li ion batteries, the correlation between the electrochemical kinetics and local structure and chemistry of these materials after chemical doping is still not fully understood. Herein, gradient surface Si/Sn-doped LLOs with improved kinetics are demonstrated. The atomic local structure and surface chemistry are determined using electron microscopy and spectroscopy techniques, and remarkably, the correlation of local structure-enhanced kinetics is clearly described in this work. The experimental results suggest that Si/Sn substitution decreases the TMO2 slab thickness and enlarges the interslab spacing, and the concentration gradient of Si/Sn affects the magnitude of these structural changes. The expanded interslab spacing accounts for the enhanced Li+ diffusivity and rate performance observed in Si/Sn-doped materials. The improved understanding of the local structure-enhanced kinetic relationship for doped LLOs demonstrates the potential for the design and development of other high-rate intercalated electrode materials. PMID- 28574689 TI - Changing Urban Carbon Metabolism over Time: Historical Trajectory and Future Pathway. AB - Cities are expected to play a major role in carbon emissions mitigation. A key step in decoupling urban economy from carbon emissions is to understand the full impact of socioeconomic development on urban metabolism over time. Herein, we establish a system-based framework for modeling the variation of urban carbon metabolism through time by integrating a metabolic flow inventory, input-output model, and network analysis. Using Beijing as a case study, we track the historical trajectory of carbon flows embodied in urban final consumption over 1985-2012. We find that while the tendency of increase in direct carbon emission continues within this time frame, consumption-based carbon footprint might have peaked around 2010. Significant transitions in emission intensity and roles sectors play in transferring carbon over the period are important signs of decoupling urban development from carbonization. Our further analysis of driving factors reveals a strong competition between efficiency gains and consumption level rise, showing a cumulative contribution of -584% and 494% to total carbon footprint, respectively. Projection into a future pathway suggests there is still a great potential for carbon mitigation for the city, but a strong mitigation plan is required to achieve such decarbonization before 2030. By bridging temporal metabolic model and socioeconomic planning, this framework fills one of the main gaps between monitoring of urban metabolism and design of a low-carbon economy. PMID- 28574690 TI - Design, Multicomponent Synthesis, and Anticancer Activity of a Focused Histone Deacetylase (HDAC) Inhibitor Library with Peptoid-Based Cap Groups. AB - In this work, we report the multicomponent synthesis of a focused histone deacetylase (HDAC) inhibitor library with peptoid-based cap groups and different zinc-binding groups. All synthesized compounds were tested in a cellular HDAC inhibition assay and an MTT assay for cytotoxicity. On the basis of their noteworthy activity in the cellular HDAC assays, four compounds were further screened for their inhibitory activity against recombinant HDAC1-3, HDAC6, and HDAC8. All four compounds showed potent inhibition of HDAC1-3 as well as significant inhibition of HDAC6 with IC50 values in the submicromolar concentration range. Compound 4j, the most potent HDAC inhibitor in the cellular HDAC assay, revealed remarkable chemosensitizing properties and enhanced the cisplatin sensitivity of the cisplatin-resistant head-neck cancer cell line Cal27CisR by almost 7-fold. Furthermore, 4j almost completely reversed the cisplatin resistance in Cal27CisR. This effect is related to a synergistic induction of apoptosis as seen in the combination of 4j with cisplatin. PMID- 28574691 TI - The Crystal Structure of a Bacterial l-Arabinonate Dehydratase Contains a [2Fe 2S] Cluster. AB - We present a novel crystal structure of the IlvD/EDD family enzyme, l-arabinonate dehydratase from Rhizobium leguminosarum bv. trifolii (RlArDHT, EC 4.2.1.25), which catalyzes the conversion of l-arabinonate to 2-dehydro-3-deoxy-l arabinonate. The enzyme is a tetramer consisting of a dimer of dimers, where each monomer is composed of two domains. The active site contains a catalytically important [2Fe-2S] cluster and Mg2+ ion and is buried between two domains, and also at the dimer interface. The active site Lys129 was found to be carbamylated. Ser480 and Thr482 were shown to be essential residues for catalysis, and the S480A mutant structure showed an unexpected open conformation in which the active site was more accessible for the substrate. This structure showed the partial binding of l-arabinonate, which allowed us to suggest that the alkoxide ion form of the Ser480 side chain functions as a base and the [2Fe-2S] cluster functions as a Lewis acid in the elimination reaction. PMID- 28574693 TI - Self-Repairing Function of Ni3S2 Layer on Ni Particles in the Na/NiCl2 Cells with the Addition of Sulfur in the Catholyte. AB - The role of the Ni3S2 layer on Ni particles in the electrochemical performance of Na/NiCl2 cells with the addition of sulfur into the cathode is studied. It was found that the Ni3S2 layer could be in situ generated on nickel particles and exhibit a self-repairing function during cycling when sulfur exists in the cathode due to the reaction between the sulfur and nickel particles. The self repairing function of the Ni3S2 layer could enhance the blocking effect and improve the battery cycle performance. The capacity of the cell with the optimum amount of sulfur (with self-repairing function) after 50 cycles is about 12% greater than that of the cell with the optimum level of Ni3S2 (without self repairing function). The effect of the self-repairing function of the Ni3S2 layer is determined by the amount of sulfur in the cathode. PMID- 28574692 TI - Cell Wall Remodeling by a Synthetic Analog Reveals Metabolic Adaptation in Vancomycin Resistant Enterococci. AB - Drug-resistant bacterial infections threaten to overburden our healthcare system and disrupt modern medicine. A large class of potent antibiotics, including vancomycin, operate by interfering with bacterial cell wall biosynthesis. Vancomycin-resistant enterococci (VRE) evade the blockage of cell wall biosynthesis by altering cell wall precursors, rendering them drug insensitive. Herein, we reveal the phenotypic plasticity and cell wall remodeling of VRE in response to vancomycin in live bacterial cells via a metabolic probe. A synthetic cell wall analog was designed and constructed to monitor cell wall structural alterations. Our results demonstrate that the biosynthetic pathway for vancomycin resistant precursors can be hijacked by synthetic analogs to track the kinetics of phenotype induction. In addition, we leveraged this probe to interrogate the response of VRE cells to vancomycin analogs and a series of cell wall-targeted antibiotics. Finally, we describe a proof-of-principle strategy to visually inspect drug resistance induction. Based on our findings, we anticipate that our metabolic probe will play an important role in further elucidating the interplay among the enzymes involved in the VRE biosynthetic rewiring. PMID- 28574694 TI - Two Barium Gold Iodates: Syntheses, Structures, and Properties of Polar BaAu(IO3)5 and Nonpolar HBa4Au(IO3)12 Materials. AB - Two new barium gold iodates, namely, BaAu(IO3)5 and HBa4Au(IO3)12, have been prepared. BaAu(IO3)5 crystallizes in the polar space group Pca21, whereas HBa4Au(IO3)12 crystallizes in the centrosymmetric space group P21/c. BaAu(IO3)5 consists of unique polar [Au(IO3)4]- anions whose four iodate groups are located at both sides of the AuO4 plane and the polarity points in the [001] direction. BaAu(IO3)5 displays strong second-harmonic-generation (SHG) effects about 0.6KTiOPO4 (KTP) and is phase-matchable. Thermal properties, optical spectra analyses, and theoretical calculations are also reported. PMID- 28574695 TI - Fabrication of Silk Scaffolds with Nanomicroscaled Structures and Tunable Stiffness. AB - Detailed control of nano- and microstructures in porous biomaterial scaffold systems is important for control of interfacial and biological functions. Self assembled silk protein nanostructured building blocks were incorporated into salt leached scaffolds to control these features. Controllable concentration and pH were used to induce the formation of amorphous silk nanofibers in solution and also to reduce beta-sheet transformation during the more traditional salt leaching process. These new scaffolds showed nanofibrous-microporous structures, reduced beta-sheet content, and tunable mechanical properties. Bone marrow mesenchymal stem cells grew better and showed differentiation behavior on these nanofibrous scaffolds, suggesting cytocompatibility and support for tunable differentiation via the scaffolds. These results suggested a new strategy of designing bioactive silk scaffolds by combining traditional scaffold formation processes with the controllable self-assembly of silk. PMID- 28574696 TI - Effect of Genetics, Environment, and Phenotype on the Metabolome of Maize Hybrids Using GC/MS and LC/MS. AB - We evaluated the variability of metabolites in various maize hybrids due to the effect of environment, genotype, phenotype as well as the interaction of the first two factors. We analyzed 480 forage and the same number of grain samples from 21 genetically diverse non-GM Pioneer brand maize hybrids, including some with drought tolerance and viral resistance phenotypes, grown at eight North American locations. As complementary platforms, both GC/MS and LC/MS were utilized to detect a wide diversity of metabolites. GC/MS revealed 166 and 137 metabolites in forage and grain samples, respectively, while LC/MS captured 1341 and 635 metabolites in forage and grain samples, respectively. Univariate and multivariate analyses were utilized to investigate the response of the maize metabolome to the environment, genotype, phenotype, and their interaction. Based on combined percentages from GC/MS and LC/MS datasets, the environment affected 36% to 84% of forage metabolites, while less than 7% were affected by genotype. The environment affected 12% to 90% of grain metabolites, whereas less than 27% were affected by genotype. Less than 10% and 11% of the metabolites were affected by phenotype in forage and grain, respectively. Unsupervised PCA and HCA analyses revealed similar trends, i.e., environmental effect was much stronger than genotype or phenotype effects. On the basis of comparisons of disease tolerant and disease susceptible hybrids, neither forage nor grain samples originating from different locations showed obvious phenotype effects. Our findings demonstrate that the combination of GC/MS and LC/MS based metabolite profiling followed by broad statistical analysis is an effective approach to identify the relative impact of environmental, genetic and phenotypic effects on the forage and grain composition of maize hybrids. PMID- 28574697 TI - Combined EXAFS Spectroscopic and Quantum Chemical Study on the Complex Formation of Am(III) with Formate. AB - The complexation of Am(III) with formate in aqueous solution is studied as a function of the pH value using a combination of extended X-ray absorption fine structure (EXAFS) spectroscopy, iterative transformation factor analysis (ITFA), and quantum chemical calculations. The Am LIII-edge EXAFS spectra are analyzed to determine the molecular structure (coordination numbers; Am-O and Am-C distances) of the formed Am(III)-formate species and to track the shift of the Am(III) speciation with increasing pH. The experimental data are compared to predictions from density functional calculations. The results indicate that formate binds to Am(III) in a monodentate fashion, in agreement with crystal structures of lanthanide formates. Furthermore, the investigations are complemented by thermodynamic speciation calculations to verify further the results obtained. PMID- 28574699 TI - Highly Enhanced Raman Scattering on Carbonized Polymer Films. AB - We have discovered a carbonized polymer film to be a reliable and durable carbon based substrate for carbon enhanced Raman scattering (CERS). Commercially available SU8 was spin coated and carbonized (c-SU8) to yield a film optimized to have a favorable Fermi level position for efficient charge transfer, which results in a significant Raman scattering enhancement under mild measurement conditions. A highly sensitive CERS (detection limit of 10-8 M) that was uniform over a large area was achieved on a patterned c-SU8 film and the Raman signal intensity has remained constant for 2 years. This approach works not only for the CMOS-compatible c-SU8 film but for any carbonized film with the correct composition and Fermi level, as demonstrated with carbonized-PVA (poly(vinyl alcohol)) and carbonized-PVP (polyvinylpyrollidone) films. Our study certainly expands the rather narrow range of Raman-active material platforms to include robust carbon-based films readily obtained from polymer precursors. As it uses broadly applicable and cheap polymers, it could offer great advantages in the development of practical devices for chemical/bio analysis and sensors. PMID- 28574700 TI - A Facile Way of Modifying Layered Double Hydroxide Nanoparticles with Targeting Ligand-Conjugated Albumin for Enhanced Delivery to Brain Tumour Cells. AB - Active targeting of nanoparticles (NPs) for cancer treatment has attracted increasing interest in the past decades. Various ligand modification strategies have been used to enhance the targeting of NPs to the tumor site. However, how to reproducibly fabricate diverse targeting NPs with narrowly changeable biophysiochemical properties remains as a major challenge. In this study, layered double hydroxide (LDH) NPs were modified as a target delivery system. Two brain tumor targeting ligands, i.e., angiopep-2 and rabies virus glycoprotein, were conjugated to the LDH NPs via an intermatrix protein moiety, bovine serum albumin (BSA), simultaneously endowing the LDHs with excellent colloidal stability and targeting capability. The ligands were first covalently linked with BSA through the heterobifunctional cross-linker sulfosuccinimidyl 4-(N maleimidomethyl)cyclohexane-1-carboxylate. Then, the ligand-linked BSA and pristine BSA were together coated onto the surface of LDHs through electrostatic interaction, followed by cross-linking with the cross-linker glutaraldehyde to immobilize these BSAs on the LDH surface. In this way, we are able to readily prepare colloidally stabilized tumor-targeted LDH NPs. The targeting efficacy of the ligand-conjugated LDH delivery system has been evidenced in the uptake by two neutral cells (U87 and N2a) compared to unmodified LDHs. This new approach provides a promising strategy for rational design and preparation of target nanoparticles as a selective and effective therapeutic treatment for brain tumors. PMID- 28574698 TI - Ozone Exposure, Cardiopulmonary Health, and Obesity: A Substantive Review. AB - From 1999-2014, obesity prevalence increased among adults and youth. Obese individuals may be uniquely susceptible to the proinflammatory effects of ozone because obese humans and animals have been shown to experience a greater decline in lung function than normal-weight subjects. Obesity is independently associated with limitations in lung mechanics with increased ozone dose. However, few epidemiologic studies have examined the interaction between excess weight and ozone exposure among adults. Using PubMed keyword searches and reference lists, we reviewed epidemiologic evidence to identify potential response-modifying factors and determine if obese or overweight adults are at increased risk of ozone-related health effects. We initially identified 170 studies, of which seven studies met the criteria of examining the interaction of excess weight and ozone exposure on cardiopulmonary outcomes in adults, including four short-term ozone exposure studies in controlled laboratory settings and three community epidemiologic studies. In the studies identified, obesity was associated with decreased lung function and increased inflammatory mediators. Results were inconclusive about the effect modification when data were stratified by sex. Obese and overweight populations should be considered as candidate at-risk groups for epidemiologic studies of cardiopulmonary health related to air pollution exposures. Air pollution is a modifiable risk factor that may decrease lung function among obese individuals with implications for environmental and occupational health policy. PMID- 28574701 TI - Discovery of Inactive Conformation-Selective Kinase Inhibitors by Utilizing Cascade Assays. AB - Achieving selectivity across the human kinome is a major hurdle in kinase inhibitor drug discovery. Targeting inactive (vs active) kinase conformations offers advantages in achieving selectivity because of their more diversified structures. Discovery of inactive conformation-selective inhibitors, however, has been hampered partly by the lack of general assay methods. Herein, we show that such inhibitors can be discovered by utilizing kinase cascade assays. This type of assay is initiated with the target kinase in its unphosphorylated, inactive conformation, which is activated during the assay. Inactive conformation selective inhibitors stabilize the inactive kinase, block activation, and yield reduced kinase activity. We investigate the properties of the assay by mathematical modeling, as well as by proof-of-concept experiments using the BRAF MEK1 cascade. This study demonstrates effective identification of inactive conformation-selective inhibitors by cascade assays, reveals key factors that impact results, and provides guidelines for successful cascade assay development. PMID- 28574702 TI - High-Throughput Platform for Synthesis of Melamine-Formaldehyde Microcapsules. AB - The synthesis of microcapsules via in situ polymerization is a labor-intensive and time-consuming process, where many composition and process factors affect the microcapsule formation and its morphology. Herein, we report a novel combinatorial technique for the preparation of melamine-formaldehyde microcapsules, using a custom-made and automated high-throughput platform (HTP). After performing validation experiments for ensuring the accuracy and reproducibility of the novel platform, a design of experiment study was performed. The influence of different encapsulation parameters was investigated, such as the effect of the surfactant, surfactant type, surfactant concentration and core/shell ratio. As a result, this HTP-platform is suitable to be used for the synthesis of different types of microcapsules in an automated and controlled way, allowing the screening of different reaction parameters in a shorter time compared to the manual synthetic techniques. PMID- 28574703 TI - Direct Formation of Carbon(sp3)-Heteroatom Bonds from RhIII To Produce Methyl Iodide, Thioethers, and Alkylamines. AB - Thermolysis of the RhIII-Me complex (DPEphos)RhMeI2 (1) results in reductive elimination of MeI. Mechanistic studies are consistent with SN2 attack by I- at the RhIII-Me group via two separate competing paths. Addition of sulfur and nitrogen nucleophiles allows effective competition and formation of C(sp3)-S and C(sp3)-N coupled products in high yields. C(sp3)-N bond formation is second-order in amine, consistent with amine substitution of iodide at the metal followed by nucleophilic attack at carbon by a second amine. PMID- 28574704 TI - How Does Recycling of Livestock Manure in Agroecosystems Affect Crop Productivity, Reactive Nitrogen Losses, and Soil Carbon Balance? AB - Recycling of livestock manure in agroecosystems to partially substitute synthetic fertilizer nitrogen (N) input is recommended to alleviate the environmental degradation associated with synthetic N fertilization, which may also affect food security and soil greenhouse gas (GHG) emissions. However, how substituting livestock manure for synthetic N fertilizer affects crop productivity (crop yield; crop N uptake; N use efficiency), reactive N (Nr) losses (ammonia (NH3) emission, N leaching and runoff), GHG (methane, CH4; and nitrous oxide, N2O; carbon dioxide) emissions and soil organic carbon (SOC) sequestration in agroecosystems is not well understood. We conducted a global meta-analysis of 141 studies and found that substituting livestock manure for synthetic N fertilizer (with equivalent N rate) significantly increased crop yield by 4.4% and significantly decreased Nr losses via NH3 emission by 26.8%, N leaching by 28.9% and N runoff by 26.2%. Moreover, annual SOC sequestration was significantly increased by 699.6 and 401.4 kg C ha-1 yr-1 in upland and paddy fields, respectively; CH4 emission from paddy field was significantly increased by 41.2%, but no significant change of that was observed from upland field; N2O emission was not significantly affected by manure substitution in upland or paddy fields. In terms of net soil carbon balance, substituting manure for fertilizer increased carbon sink in upland field, but increased carbon source in paddy field. These results suggest that recycling of livestock manure in agroecosystems improves crop productivity, reduces Nr pollution and increases SOC storage. To attenuate the enhanced carbon source in paddy field, appropriate livestock manure management practices should be adopted. PMID- 28574705 TI - Biochemical Profile of Heritage and Modern Apple Cultivars and Application of Machine Learning Methods To Predict Usage, Age, and Harvest Season. AB - The present study represents the first major attempt to characterize the biochemical profile in different tissues of a large selection of apple cultivars sourced from the United Kingdom's National Fruit Collection comprising dessert, ornamental, cider, and culinary apples. Furthermore, advanced machine learning methods were applied with the objective to identify whether the phenolic and sugar composition of an apple cultivar could be used as a biomarker fingerprint to differentiate between heritage and mainstream commercial cultivars as well as govern the separation among primary usage groups and harvest season. A prediction accuracy of >90% was achieved with the random forest method for all three models. The results highlighted the extraordinary phytochemical potency and unique profile of some heritage, cider, and ornamental apple cultivars, especially in comparison to more mainstream apple cultivars. Therefore, these findings could guide future cultivar selection on the basis of health-promoting phytochemical content. PMID- 28574706 TI - Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor. AB - Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications. PMID- 28574708 TI - Packing Defects in Fatty Amine Self-Assembled Monolayers on Mica as Revealed from AFM Techniques. AB - Self-assembled monolayers of n-octadecylamine (ODA-SAMs) on mica have been prepared and studied by contact and jumping mode atomic force microscopy (AFM). Adhesion and friction data show that the compactness of the monolayers spontaneously increases as they are allowed to ripen. Molecular packing can also be induced by the controlled mechanical perturbation exerted by the probe when getting into and out of contact intermittently. Under these conditions, defects and vacancies aggregate giving rise to detectable pinholes uniformly distributed in AFM images. Created pinhole density was found to decrease with ripening time, thus confirming the proposed spontaneous self-healing mechanism. Pinhole density is also suggested as a parameter characterizing the packing degree of ODA-SAMs, and it has been related to their tribological properties. Additionally, molecular dynamics simulations were used to corroborate the compatibility between the packing degree and the observed topography of ODA-SAMs on mica. PMID- 28574709 TI - Examining Nanoparticle Adsorption on Electrostatically "Patchy" Glycopolymer Brushes Using Real-Time zeta-Potential Measurements. AB - Biomaterial surfaces can possess chemical, topographical, or electrostatic heterogeneity, which can profoundly influence their performance. By developing experimental models that reliably simulate this nanoscale heterogeneity, we can predict how heterogeneous surfaces are transformed by their interactions with the dynamic physiological environment. In this work, we present a model surface where well-defined glycopolymer brushes are interspersed with positively charged binding sites, giving rise to an interface presenting a mixture of repulsive and adhesive cues to an approaching virus particle. We show that the density of the affinity sites relative to the glycopolymer brushes can be tuned precisely by modifying the chemical vapor deposition (CVD) copolymerization conditions. Further, we examined the effects of binding site density and glycopolymer brush architecture on the adsorption kinetics of virus-like nanoparticles through a novel approach employing time-resolved zeta-potential measurements. Most materials have charge-bearing, dynamic surfaces that are sensitive to electrostatic effects. Hence, adsorption-triggered changes in zeta-potential measurements can be captured in real time to monitor interfacial events. Real time zeta-potential measurements present an interesting platform to probe the structure and function of chemically and electrostatically heterogeneous polymer interfaces. To validate this electrokinetic method, we examined the effect of neutravidin concentration on its rate of binding to biotinylated surfaces using zeta-potential and compared our results with QCM studies. By applying electrokinetic methods to examine the roles of glycopolymer brush architecture and surface charge of these tunable glycopolymer coatings, we can enhance our understanding of the interactions of viruses with heterogeneous biomaterial interfaces. PMID- 28574707 TI - New Ustilaginoidins from Rice False Smut Balls Caused by Villosiclava virens and Their Phytotoxic and Cytotoxic Activities. AB - Ustilaginoidins are a class of bis-naphtho-gamma-pyrones, typically produced by Villosiclava virens, the pathogen of the rice false smut (RFS), which has been one of the most destructive rice fungal diseases. Previously, we found that ustilaginoidins identified from the culture of V. virens on rice medium were less polar than those reported from the RFS balls in general. In this study, we reinvestigated the high-performance liquid chromatography with diode array detection and high-resolution mass spectrometry (HPLC-DAD-HRMS) profile of the ethyl acetate (EtOAc) extract of the RFS balls and found several interesting peaks that correspond to new ustilaginoidins. As a result, eight new and polar congeners, named ustilaginoidins Q-T (1-4), 2,3-dihydroustilaginoidin T (5), and ustilaginoidins U-W (6-8), were isolated. In addition, 17 known ustilaginoidins, including ustilaginoidins K-N (9-12), ustilaginoidin P (13), ustilaginoidin E1 (14), isochaetochromin B2 (15), and ustilaginoidins A-J (16-25), were re isolated. The structures of the new compounds were elucidated by comprehensive analysis of the spectroscopic data. Ustilaginoidins Q (1) and R (2) feature an uncommon 2-hydroxypropyl-substituted skeleton and biogenetically incorporate one more acetate unit than common ustilaginoidins. Ustilaginoidin W (8) is a rare formate-containing bis-naphtho-gamma-pyrone. Ustilaginoidins R (2), U (6), B (17), and I (24) showed moderate inhibitory activities toward the radicle or germ elongation of rice seeds. Ustilaginoidins R (2), S (3), V (7), W (8), B (17), C (18), and H-J (23-25) were cytotoxic to the tested human cancer cell lines (HCT116, NCI-H1650, BGC823, Daoy, and HepG2), with IC50 values in the range of 4.06-44.1 MUM. PMID- 28574710 TI - 5-Selenocyanatouracil: A Potential Hypoxic Radiosensitizer. Electron Attachment Induced Formation of Selenium Centered Radical. AB - The propensity of 5-selenocyanatouracil (SeCNU) to decomposition induced by attachment of electron was scrutinized with the G3B3 composite quantum-chemical method and radiolytic studies. Favorable thermodynamic (Gibbs free reaction energy of -13.65 kcal/mol) and kinetic (Gibbs free activation energy of 1.22 kcal/mol) characteristics revealed by the G3B3 free energy profile suggest SeCNU to be sensitive to electron attachment. The title compound was synthesized in the reaction between uracil and selenocyanogen chloride in acetic acid. Then, an aqueous and deoxygenated solution of the HPLC purified compound containing tert butanol as a hydroxyl radical scavenger was irradiated with X-rays. SeCNU radio degradation results in two major products: the U-Se-Se-U dimer and the adduct of the ?OtBu radical to the U-Se? radical, U-Se-OtBu. The effects of radiolysis as well as the results of G3B3 calculations point to U-Se? as the primary product of dissociative electron attachment to SeCNU. The MTT test shows that SeCNU is nontoxic in vitro in concentrations equal to or lower than 10-6 M. Ionizing radiation will probably induce cytotoxic intra- and interstrand DNA cross-links as well as protein-DNA cross-links in the genomic DNA labeled with SeCNU. PMID- 28574711 TI - General Procedures for the Lithiation/Trapping of N-Boc Piperazines. AB - To provide alpha-substituted piperazines for early stage medicinal chemistry studies, a simple, general synthetic approach is required. Here, we report the development of two general and simple procedures for the racemic lithiation/trapping of N-Boc piperazines. Optimum lithiation times were determined using in situ IR spectroscopy, and the previous complicated and diverse literature procedures were simplified. Subsequent trapping with electrophiles delivered a wide range of alpha-functionalized N-Boc piperazines. The scope and limitations of the distal N-group were investigated. The selective alpha- and beta- arylation of N-Boc piperazines via lithiation/Negishi coupling is reported. PMID- 28574712 TI - Tracking Single DNA Nanodevices in Hierarchically Meso-Macroporous Antimony-Doped Tin Oxide Demonstrates Finite Confinement. AB - Housing bio-nano guest devices based on DNA nanostructures within porous, conducting, inorganic host materials promise valuable applications in solar energy conversion, chemical catalysis, and analyte sensing. Herein, we report a single-template synthetic development of hierarchically porous, transparent conductive metal oxide coatings whose pores are freely accessible by large biomacromolecules. Their hierarchal pore structure is bimodal with a larger number of closely packed open macropores (~200 nm) at the higher rank and with the remaining space being filled with a gel network of antimony-doped tin oxide (ATO) nanoparticles that is highly porous with a broad size range of textual pores mainly from 20-100 nm at the lower rank. The employed carbon black template not only creates the large open macropores but also retains the highly structured gel network as holey pore walls. Single molecule fluorescence microscopic studies with fluorophore-labeled DNA nanotweezers reveal a detailed view of multimodal diffusion dynamics of the biomacromolecules inside the hierarchically porous structure. Two diffusion constants were parsed from trajectory analyses that were attributed to free diffusion (diffusion constant D = 2.2 MUm2/s) and to diffusion within an average confinement length of 210 nm (D = 0.12 MUm2/s), consistent with the average macropore size of the coating. Despite its holey nature, the ATO gel network acts as an efficient barrier to the diffusion of the DNA nanostructures, which is strongly indicative of physical interactions between the molecules and the pore nanostructure. PMID- 28574713 TI - Structure and Dissociation Pathways of Protonated Tetralin (1,2,3,4 Tetrahydronaphthalene). AB - The infrared multiple-photon dissociation (IRMPD) spectrum of protonated tetralin (1,2,3,4-tetrahydronaphthalene, THN) has been recorded using an infrared free electron laser coupled to a Fourier transform ion cyclotron mass spectrometer. IR induced fragmentation of the protonated parent [THN + H] +, m/z 133, yielded a single fragment ion at m/z 91. No evidence for fragment ions at m/z 131 or 132 was observed, indicating that protonated THN ejects neither atomic H nor molecular H2. Comparison of the experimental spectrum with density functional calculations (B3LYP/6-311++G(d,p)) of the two possible protonated isomers identifies a preference for the position of protonation. Possible decomposition pathways starting from both [THN + H(5)]+ and [THN + H(6)]+ are investigated. The potential energy profiles computed for these decomposition routes reveal that (1) the m/z 91 ionic product resembles the benzylium ion, but with the extra hydrogen and the methylene substituents in various ortho, meta, and para conformations around the aromatic ring and that (2) the decomposition process involving the [THN + H(6)]+ isomer is predominant, while the one involving the [THN + H(5)]+ may play a smaller role. Potential energy pathways from the initial decomposition product(s) to the benzylium and tropylium ions have also been computed. Given the relatively low barriers to these ions, it is concluded that the benzylium ion and, with sufficient activation, the tropylium ion plus neutral propene are the final products. PMID- 28574714 TI - Fast Growth of GaN Epilayers via Laser-Assisted Metal-Organic Chemical Vapor Deposition for Ultraviolet Photodetector Applications. AB - In this study, we successfully developed a carbon dioxide (CO2)-laser-assisted metal-organic chemical vapor deposition (LMOCVD) approach to fast synthesis of high-quality gallium nitride (GaN) epilayers on Al2O3 [sapphire(0001)] substrates. By employing a two-step growth procedure, high crystallinity and smooth GaN epilayers with a fast growth rate of 25.8 MUm/h were obtained. The high crystallinity was confirmed by a combination of techniques, including X-ray diffraction, Raman spectroscopy, transmission electron microscopy, and atomic force microscopy. By optimizing growth parameters, the ~4.3-MUm-thick GaN films grown at 990 degrees C for 10 min showed a smooth surface with a root-mean square surface roughness of ~1.9 nm and excellent thickness uniformity with sharp GaN/substrate interfaces. The full-width at half-maximum values of the GaN(0002) X-ray rocking curve of 313 arcsec and the GaN(1012) X-ray rocking curve of 390 arcsec further confirmed the high crystallinity of the GaN epilayers. We also fabricated ultraviolet (UV) photodetectors based on the as-grown GaN layers, which exhibited a high responsivity of 0.108 A W-1 at 367 nm and a fast response time of ~125 ns, demonstrating its high optical quality with potential in optoelectronic applications. Our strategy thus provides a simple and cost effective means toward fast and high-quality GaN heteroepitaxy growth suitable for fabricating high-performance GaN-based UV detectors. PMID- 28574715 TI - Development of a Data-Independent Targeted Metabolomics Method for Relative Quantification Using Liquid Chromatography Coupled with Tandem Mass Spectrometry. AB - Quantitative metabolomics approaches can significantly improve the repeatability and reliability of metabolomics investigations but face critical technical challenges, owing to the vast number of unknown endogenous metabolites and the lack of authentic standards. The present study contributes to the development of a novel method known as "data-independent targeted quantitative metabolomics" (DITQM), which was used to investigate the label-free quantitative metabolomics of multiple known and unknown metabolites in biofluid samples. This approach initially involved the acquisition of MS/MS data for all metabolites in biosamples using a sequentially stepped targeted MS/MS (sst-MS/MS) method, in which multiple product ion scans were performed by selecting all ions in the targeted mass ranges as the precursor ions. Subsequently, scheduled multiple reaction monitoring (MRM) by LC-MS/MS of the metabolome was established for 1658 characteristic ion pairs of 1324 metabolites. For sensitive and accurate quantification of these metabolites, mixed calibration curves were generated using sequentially diluted standard reference plasma samples using established MRM methods. Relative concentrations of all metabolites in each sample were calculated without using individual authentic standards. To evaluate the reliability and applicability of this new method, the performance of DITQM was validated by comparison to absolute quantification of 12 acylcarnitines using authentic standards and traditional metabolomics analysis for lung cancer. The results proved that the DITQM protocol is more reliable and can significantly improve clustering effects and repeatability in biomarker discovery. In this study, we established a novel methodology to standardize and quantify large-scale metabolome, providing a new choice for metabolomics research and its clinical applications. PMID- 28574717 TI - Optimized Separation of Acetylene from Carbon Dioxide and Ethylene in a Microporous Material. AB - Selective separation of acetylene (C2H2) from carbon dioxide (CO2) or ethylene (C2H4) needs specific porous materials whose pores can realize sieving effects while pore surfaces can differentiate their recognitions for these molecules of similar molecular sizes and physical properties. We report a microporous material [Zn(dps)2(SiF6)] (UTSA-300, dps = 4,4'-dipyridylsulfide) with two-dimensional channels of about 3.3 A, well-matched for the molecular sizes of C2H2. After activation, the network was transformed to its closed-pore phase, UTSA-300a, with dispersed 0D cavities, accompanied by conformation change of the pyridyl ligand and rotation of SiF62- pillars. Strong C-H...F and pi-pi stacking interactions are found in closed-pore UTSA-300a, resulting in shrinkage of the structure. Interestingly, UTSA-300a takes up quite a large amounts of acetylene (76.4 cm3 g 1), while showing complete C2H4 and CO2 exclusion from C2H2 under ambient conditions. Neutron powder diffraction and molecular modeling studies clearly reveal that a C2H2 molecule primarily binds to two hexafluorosilicate F atoms in a head-on orientation, breaking the original intranetwork hydrogen bond and subsequently expanding to open-pore structure. Crystal structures, gas sorption isotherms, molecular modeling, experimental breakthrough experiment, and selectivity calculation comprehensively demonstrated this unique metal-organic framework material for highly selective C2H2/CO2 and C2H2/C2H4 separation. PMID- 28574716 TI - Development of a Clinically Viable Heroin Vaccine. AB - Heroin is a highly abused opioid and incurs a significant detriment to society worldwide. In an effort to expand the limited pharmacotherapy options for opioid use disorders, a heroin conjugate vaccine was developed through comprehensive evaluation of hapten structure, carrier protein, adjuvant and dosing. Immunization of mice with an optimized heroin-tetanus toxoid (TT) conjugate formulated with adjuvants alum and CpG oligodeoxynucleotide (ODN) generated heroin "immunoantagonism", reducing heroin potency by >15-fold. Moreover, the vaccine effects proved to be durable, persisting for over eight months. The lead vaccine was effective in rhesus monkeys, generating significant and sustained antidrug IgG titers in each subject. Characterization of both mouse and monkey antiheroin antibodies by surface plasmon resonance (SPR) revealed low nanomolar antiserum affinity for the key heroin metabolite, 6-acetylmorphine (6AM), with minimal cross reactivity to clinically used opioids. Following a series of heroin challenges over six months in vaccinated monkeys, drug-sequestering antibodies caused marked attenuation of heroin potency (>4-fold) in a schedule-controlled responding (SCR) behavioral assay. Overall, these preclinical results provide an empirical foundation supporting the further evaluation and potential clinical utility of an effective heroin vaccine in treating opioid use disorders. PMID- 28574719 TI - The Role of Online Social Identity in the Relationship Between Alcohol-Related Content on Social Networking Sites and Adolescent Alcohol Use. AB - Social networking sites (SNSs) are social platforms that facilitate communication. For adolescents, peers play a crucial role in constructing the self online through displays of group norms on SNSs. The current study investigated the role of online social identity (OSI) in the relationship between adolescent exposure to alcohol-related content posted by peers on SNSs and alcohol use. In a sample (N = 929) of Australian adolescents (Age M = 17.25, SD = 0.31) higher levels of exposure to alcohol-related content on SNSs was associated with higher levels of alcohol use. Importantly, the association was stronger when the participants reported higher OSI particularly when also reporting low or moderate amount of time spent on SNS. The findings can be explained by social identity literature that demonstrates individuals align their behaviors with other members of their social group to demonstrate, enact, and maintain social identity. The results of this study reflect the importance of considering the construction of the "self" through online and offline constructs. PMID- 28574718 TI - Calibration of 1,2,4-Triazole-3-Thione, an Original Zn-Binding Group of Metallo beta-Lactamase Inhibitors. Validation of a Polarizable MM/MD Potential by Quantum Chemistry. AB - In the context of the SIBFA polarizable molecular mechanics/dynamics (PMM/PMD) procedure, we report the calibration and a series of validation tests for the 1,2,4-triazole-3-thione (TZT) heterocycle. TZT acts as the chelating group of inhibitors of dizinc metallo-beta-lactamases (MBL), an emerging class of Zn dependent bacterial enzymes, which by cleaving the beta-lactam bond of most beta lactam antibiotics are responsible for the acquired resistance of bacteria to these drugs. Such a study is indispensable prior to performing PMD simulations of complexes of TZT-based inhibitors with MBL's, on account of the anchoring role of TZT in the dizinc MBL recognition site. Calibration was done by comparisons to energy decomposition analyses (EDA) of high-level ab initio QC computations of the TZT complexes with two probes: Zn(II), representative of "soft" dications, and water, representative of dipolar molecules. We performed distance variations of the approach of each probe to each of the two TZT atoms involved in Zn ligation, the S atom and the N atom ortho to it, so that each SIBFA contribution matches its QC counterpart. Validations were obtained by performing in- and out of-plane angular variations of Zn(II) binding in monoligated Zn(II)-TZT complexes. The most demanding part of this study was then addressed. How well does DeltaE(SIBFA) and its individual contributions compare to their QC counterparts in the dizinc binding site of one MBL, L1, whose structure is known from high-resolution X-ray crystallography? Six distinct complexes were considered, namely each separate monozinc site, and the dizinc site, whether ligated or unligated by TZT. Despite the large magnitude of the interaction energies, in all six complexes DeltaE(SIBFA) can match DeltaE(QC) with relative errors <2% and the proper balance of individual energy contributions. The computations were extended to the dizinc site of another MBL, VIM-2, and its complexes with two other TZT analogues. DeltaE(SIBFA) faithfully reproduced DeltaE(QC) in terms of magnitude, ranking of the three ligands, and trends of the separate energy contributions. A preliminary extension to correlated calculations is finally presented. All these validations should enable a secure design of a diversity of TZT-containing MBL inhibitors: a structurally and energetically correct anchoring of TZT should enable all other inhibitor groups to in turn optimize their interactions with the other target MBL residues. PMID- 28574720 TI - "Bone Development" Is an Ontology Group Upregulated in Porcine Oocytes Before In Vitro Maturation: A Microarray Approach. AB - Mammalian cumulus-oocyte complexes (COCs) reach full developmental capability during folliculogenesis and oogenesis. It is well recognized that only gametes achieving MII stage after in vivo or in vitro maturation (IVM) are successfully fertilized by a single spermatozoon. Although the process of oocyte nuclear and/or cytoplasmic maturation in pigs is well determined, there exist many differences that promote these processes in vivo and in vitro. Therefore, this study aimed to investigate the differences in RNA expression profiles between porcine oocytes before and after IVM using microarray and real-time quantitative polymerase chain reaction (RT-qPCR) assays. Experiments were performed on oocytes isolated from 55 pubertal crossbred Landrace gilts. The oocytes were analyzed both before and after IVM and only Brilliant Cresyl Blue (BCB)-positive gametes were used for subsequent microarray analysis (Affymetrix) and RT-qPCR analysis. The microarray assay, which measures expression of 12,258 transcripts, revealed 419 differentially expressed transcripts in porcine oocytes, from which 379 were downregulated and 40 were upregulated before IVM compared to those analyzed after IVM. After DAVID analysis, we found eight different transcripts, including IHH, BMP1, WWTR1, CHRDL1, KLF10, EIF2AK3, MMP14, and STC1. Their expression is related to the "bone development" ontology group and was further subjected to hierarchical clusterization. Using RT-qPCR analysis, we confirmed the results of the microarray assay, showing increased expression of the eight genes in oocytes before IVM compared to oocytes after maturation in vitro. It has been suggested that "bone development" belongs to one ontological group involving genes substantially upregulated in porcine oocytes before IVM. We suggest that the gamete mRNA expression profile before IVM may comprise stored transcripts, which are templates for protein biosynthesis following fertilization. We also hypothesize that these mRNAs may be a specific "fingerprint" of folliculogenesis and oogenesis in pigs. PMID- 28574724 TI - miR-144-3p Induces Cell Cycle Arrest and Apoptosis in Pancreatic Cancer Cells by Targeting Proline-Rich Protein 11 Expression via the Mitogen-Activated Protein Kinase Signaling Pathway. AB - microRNAs (miRNAs) have been proved to be involved in many events of tumor development and progression, including cell proliferation, cell apoptosis, and cell cycle arrest. However, the potential role of miR-144-3p in pancreatic cancer (PC) remains elusive. In this study, we demonstrated that miR-144-3p was decreased in PC tissues and PANC-1 cells, whereas proline-rich protein 11 (PRR11) was remarkably increased. miR-144-3p mimics were discovered to inhibit cell proliferation by arresting cells at the S-phase of the cell cycle, and inducing cell apoptosis in PANC-1 cells. The effects of miR-144-3p on cell proliferation and cell apoptosis were reversed after treatment with the miR-144-3p inhibitor. Furthermore, a luciferase activity assay indicated that miR-144-3p directly targeted PRR11 3'-UTR. Moreover, transfection with miR-144-3p mimics inhibited the expression of PRR11. miR-144-3p mimics also upregulated the expression of p JNK and p-p38, whereas they downregulated the expression of p-ERK. The effects of miR-144-3p on mitogen-activated protein kinase pathway proteins were reversed by the miR-144-3p inhibitor. PRR11 overexpression attenuated the effect of miR-144 3p mimics on cell apoptosis and cell cycle arrest. The expression of caspase-3 was decreased by enhanced PRR11. In summary, our findings indicated that miR-144 3p induced cell cycle arrest and apoptosis in PC by targeting PRR11. Therefore, the targeting of miR-144-3p could serve as a potential therapeutic strategy for the treatment of PC. PMID- 28574721 TI - A Multiomics Approach to Identify Genes Associated with Childhood Asthma Risk and Morbidity. AB - Childhood asthma is a complex disease. In this study, we aim to identify genes associated with childhood asthma through a multiomics "vertical" approach that integrates multiple analytical steps using linear and logistic regression models. In a case-control study of childhood asthma in Puerto Ricans (n = 1,127), we used adjusted linear or logistic regression models to evaluate associations between several analytical steps of omics data, including genome-wide (GW) genotype data, GW methylation, GW expression profiling, cytokine levels, asthma-intermediate phenotypes, and asthma status. At each point, only the top genes/single nucleotide polymorphisms/probes/cytokines were carried forward for subsequent analysis. In step 1, asthma modified the gene expression-protein level association for 1,645 genes; pathway analysis showed an enrichment of these genes in the cytokine signaling system (n = 269 genes). In steps 2-3, expression levels of 40 genes were associated with intermediate phenotypes (asthma onset age, forced expiratory volume in 1 second, exacerbations, eosinophil counts, and skin test reactivity); of those, methylation of seven genes was also associated with asthma. Of these seven candidate genes, IL5RA was also significant in analytical steps 4-8. We then measured plasma IL-5 receptor alpha levels, which were associated with asthma age of onset and moderate-severe exacerbations. In addition, in silico database analysis showed that several of our identified IL5RA single-nucleotide polymorphisms are associated with transcription factors related to asthma and atopy. This approach integrates several analytical steps and is able to identify biologically relevant asthma-related genes, such as IL5RA. It differs from other methods that rely on complex statistical models with various assumptions. PMID- 28574723 TI - Closed-Loop Insulin Delivery for Adults with Type 1 Diabetes Undertaking High Intensity Interval Exercise Versus Moderate-Intensity Exercise: A Randomized, Crossover Study. AB - BACKGROUND: We aimed to compare closed-loop glucose control for people with type 1 diabetes undertaking high-intensity interval exercise (HIIE) versus moderate intensity exercise (MIE). METHODS: Adults with type 1 diabetes established on insulin pumps undertook HIIE and MIE stages in random order during automated insulin delivery via a closed-loop system (Medtronic). Frequent venous sampling for glucose, lactate, ketones, insulin, catecholamines, cortisol, growth hormone, and glucagon levels was performed. The primary outcome was plasma glucose <4.0 mmol/L for >=15 min, from exercise commencement to 120 min postexercise. Secondary outcomes included continuous glucose monitoring and biochemical parameters. RESULTS: Twelve adults (age mean +/- standard deviation 40 +/- 13 years) were recruited; all completed the study. Plasma glucose of one participant fell to 3.4 mmol/L following MIE completion; no glucose levels were <4.0 mmol/L for HIIE (primary outcome). There were no glucose excursions >15.0 mmol/L for either stage. Mean (+/-standard error) plasma glucose did not differ between stages pre-exercise; was higher during exercise in HIIE than MIE (11.3 +/- 0.5 mmol/L vs. 9.7 +/- 0.6 mmol/L, respectively; P < 0.001); and remained higher until 60 min postexercise. There were no differences in circulating free insulin before, during, or postexercise. During HIIE compared with MIE, there were greater increases in lactate (P < 0.001), catecholamines (all P < 0.05), and cortisol (P < 0.001). Ketones increased more with HIIE than MIE postexercise (P = 0.031). CONCLUSIONS: Preliminary findings suggest that closed-loop glucose control is safe for people undertaking HIIE and MIE. However, the management of the postexercise rise in ketones secondary to counter-regulatory hormone-induced insulin resistance observed with HIIE may represent a challenge for closed-loop systems. PMID- 28574725 TI - The Diversity of Challenges in the Control of Measles Outbreaks. AB - From the Field is a semi-regular column that explores what it means to be a local health professional on the front lines of an emergency. National Association of County and City Health Officials (NACCHO) members share their stories of preparing for and responding to disasters, epidemics, and other major health issues. Through exploring the analysis of the challenges faced and the solutions developed, readers can learn how these public health champions keep their communities safe even in extreme situations. Readers may submit topics of interest to the column's editor, Meghan McGinty, PhD, MPH, MBA, at mmcginty@naccho.org . PMID- 28574722 TI - Socioeconomic Status, Amygdala Volume, and Internalizing Symptoms in Children and Adolescents. AB - The associations among socioeconomic disadvantage, amygdala volume, and internalizing symptoms in children and adolescents are unclear and understudied in the extant literature. In this study, we examined associations between socioeconomic status (SES) and amygdala volume by age across childhood and adolescence to test whether socioeconomic disadvantage would be associated with larger amygdala volume at younger ages but with smaller amygdala volume at older ages. We then examined whether SES and amygdala volume were associated with children's levels of anxiety and depression. Participants were 3- to 21-year-olds from the Pediatric Imaging, Neurocognition, and Genetics study (N = 1,196), which included structural magnetic resonance imaging. A subsample (n = 327; 7-21 years of age) completed self-report measures of anxiety and depression. Lower family income and parental education were significantly associated with smaller amygdala volume in adolescence (13-21 years) but not significantly associated with amygdala volume at younger ages (3-12 years). Lower parental education, but not family income, was significantly associated with higher levels of anxiety and depression, even after accounting for family history of anxiety/depression. Smaller amygdala volume was significantly associated with higher levels of depression, even after accounting for parental education and family history of anxiety/depression. These findings suggest that associations between SES and amygdala structure may vary by age. In addition, smaller amygdala volume may be linked with an increased risk for depression in children and adolescents. PMID- 28574726 TI - Failing States as Epidemiologic Risk Zones: Implications for Global Health Security. AB - Failed states commonly experience health and mortality crises that include outbreaks of infectious disease, violent conflict, reductions in life expectancy, and increased infant and maternal mortality. This article draws from recent research in political science, security studies, and international relations to explore how the process of state failure generates health declines and outbreaks of infectious disease. The key innovation of this model is a revised definition of "the state" as a geographically dynamic rather than static political space. This makes it easier to understand how phases of territorial contraction, collapse, and regeneration interrupt public health programs, destabilize the natural environment, reduce human security, and increase risks of epidemic infectious disease and other humanitarian crises. Better understanding of these dynamics will help international health agencies predict and prepare for future health and mortality crises created by failing states. PMID- 28574727 TI - Development of the Rheumatoid Arthritis Symptom Questionnaire (RASQ): a patient reported outcome scale for measuring symptoms of rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA), a chronic, progressive inflammatory, autoimmune disease, can substantially reduce health-related quality of life (HRQoL) and lead to severe disability and early mortality. Patient-reported outcome (PRO) instruments are used to assess the patient experience of RA symptoms and impacts, and can capture RA treatment effects. To address limitations in existing PRO instruments, this research aimed to establish the content validity of a new instrument, the Rheumatoid Arthritis Symptom Questionnaire (RASQ), to assess the signs and symptoms of RA. METHOD: The most important and relevant sign and symptom concepts for RA patients were identified through a targeted review of the published literature, expert opinion, and concept elicitation patient interviews. Cognitive interviews were conducted with patients to test the comprehensibility and comprehensiveness of the RASQ. RESULTS: Seven symptoms emerged consistently across the conceptual research: joint pain, joint swelling, joint stiffness, joint tenderness, joint warmth, muscle pain, and tiredness. Draft item content was developed to assess these symptoms, in addition to a single impact item, resulting in three RASQ versions: two utilizing a 7 day recall period (one assessing symptoms at their worst, the other on average) and a third using a 24 hour recall period assessing symptoms at their worst. Cognitive interview results demonstrated patient understanding and ability to use the instrument. CONCLUSIONS: Content validity of the RASQ was established in accordance with instrument development guidelines. The RASQ fills a measurement gap by assessing the RA signs and symptoms most important to patients. Research evaluating the RASQ's psychometric properties is underway. PMID- 28574728 TI - How Is CDC Funded to Respond to Public Health Emergencies? Federal Appropriations and Budget Execution Process for Non-Financial Experts. AB - The federal budgeting process affects a wide range of people who work in public health, including those who work for government at local, state, and federal levels; those who work with government; those who operate government-funded programs; and those who receive program services. However, many people who are affected by the federal budget are not aware of or do not understand how it is appropriated or executed. This commentary is intended to give non-financial experts an overview of the federal budget process to address public health emergencies. Using CDC as an example, we provide: (1) a brief overview of the annual budget formulation and appropriation process; (2) a description of execution and implementation of the federal budget; and (3) an overview of emergency supplemental appropriations, using as examples the 2009 H1N1 influenza pandemic, the 2014-15 Ebola outbreak, and the 2016 Zika epidemic. Public health emergencies require rapid coordinated responses among Congress, government agencies, partners, and sometimes foreign, state, and local governments. It is important to have an understanding of the appropriation process, including supplemental appropriations that might come into play during public health emergencies, as well as the constraints under which Congress and federal agencies operate throughout the federal budget formulation process and execution. PMID- 28574729 TI - Respiratory syncytial virus: prospects for new and emerging therapeutics. AB - INTRODUCTION: Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections (LRTI) in infants, the elderly, and the immunocompromised. Although the development of a RSV vaccine has been a priority for >50 years, there is still no vaccine available. Treatment of RSV LRTI has remained mostly supportive, i.e. hydration and oxygenation. Palivizumab and ribavirin are the only options currently available for prevention and treatment of RSV infection, but evidence suggests that they are not fully effective. This creates a significant unmet medical need for new therapeutics for prevention and treatment of RSV worldwide. Areas covered: This article reviews the antiviral drugs and monoclonal antibodies (mAb) for RSV that are in different stages of clinical development. Expert commentary: Over the last 10 years, new antiviral drugs and mAb have shown clinical promise against RSV, and may become available in the coming years. Although the RSV fusion protein has been the most popular target for inhibitors and mAbs, new approaches targeting other viral proteins have shown promising results. To overcome the emergence of RSV escape mutants, combination antiviral therapy may be explored in the future. PMID- 28574730 TI - Physical Activity Behavior After a Diagnosis of Lung Cancer Differs Between Countries: An Observational Cohort Study. AB - INTRODUCTION: Physical activity (PA) is important in lung cancer. OBJECTIVES: To investigate PA levels and health-related quality of life (HRQoL) of patients with lung cancer in China and compare this to a similar cohort in Australia. METHODS: Prospective cohort study. 71 patients from China (group CH) and 90 patients from Australia (group AU) with newly diagnosed lung cancer. Questionnaires assessed self-reported PA levels and HRQoL at baseline (diagnosis) and 8 weeks. RESULTS: At baseline, group CH were engaged in less overall PA than group AU (Physical Activity Scale for the Elderly [PASE] total score: median [IQR] group CH, 56 [32 59]; group AU, 66 [38-116]; P < .005), and less occupational and household activity ( P < .005). However, at baseline, group CH reported significantly more walking time than group AU (median [IQR]: group CH, 210 [150-315] min/wk; group AU, 55[0-210] min/wk; P < .0005). Global HRQoL scores were similar between groups (P = .038). Over 8 weeks, group CH increased their overall PA levels ( P < .005) and walking time ( P = .008), and HRQoL remained unchanged. The comparison group AU experienced a reduction in PA levels ( P = .02) and HRQoL ( P < .005). CONCLUSIONS: A diagnosis, patients in China were less physically active than those in Australia. Following diagnosis, patients in China increased their PA levels, whereas those in Australia reduced their PA levels. Research is required to explore potential reasons behind differences, and this may inform research/clinical services to facilitate patients with lung cancer to be more active. PMID- 28574731 TI - Why Gene Editors Like CRISPR/Cas May Be a Game-Changer for Neuroweapons. AB - This year marks the Eighth Review Conference (RevCon) of the Biological Toxins and Weapons Convention (BWC). At the same time, ongoing international efforts to further and more deeply investigate the brain's complex neuronal circuitry are creating unprecedented capabilities to both understand and control neurological processes of thought, emotion, and behavior. These advances have tremendous promise for human health, but the potential for their misuse has also been noted, with most discussions centering on research and development of agents that are addressed by existing BWC and Chemical Weapons Convention (CWC) proscriptions. In this article, we discuss the dual-use possibilities fostered by employing emergent biotechnologic techniques and tools-specifically, novel gene editors like clustered regular interspaced short palindromic repeats (CRISPR)-to produce neuroweapons. Based on our analyses, we posit the strong likelihood that development of genetically modified or created neurotropic substances will advance apace with other gene-based therapeutics, and we assert that this represents a novel-and realizable-path to creating potential neuroweapons. In light of this, we propose that it will be important to re-address current categorizations of weaponizable tools and substances, so as to better inform and generate tractable policy to enable improved surveillance and governance of novel neuroweapons. PMID- 28574732 TI - In vitro and in vivo evaluation of cubosomal in situ nasal gel containing resveratrol for brain targeting. AB - The aim of this study was to enhance the delivery of resveratrol to the brain through the transnasal route by cubosomes. Cubosomes were prepared using glycerol monooleate and Lutrol F127 by probe sonication method. A 32 full factorial design was used for optimization of cubosomes and batch containing 4% w/v glycerol monooleate and 1.5% w/v of Lutrol F 127 was optimized. The selected cubosomal batch was cubical in shape, having mean particle size 161.5 +/- 0.12 nm. Entrapment efficiency was found to be 83.08% with zeta potential of -20.9 mV. In vitro release of cubosomal batch showed controlled release of drug profile (67%) up to 24 h. The optimized cubosomal dispersion was dispersed into gelling polymer (poloxamer 407) to form in situ gel for nasal use. The optimal cubosomal gel (containing 12% w/v poloxamer 407) had been subjected to ex-vivo permeation and in vivo biodistribution studies. It showed significantly higher transnasal permeation and better distribution to brain, when compared to the drug solution (i.n.) and drug solution (oral). Finally the cubosomal gel could be considered as a promising carrier for brain targeting of Resveratrol (Res) through transnasal route. PMID- 28574733 TI - Mechanistic investigation of mixing and segregation of ordered mixtures: experiments and numerical simulations. AB - Pulmonary delivery of cohesive and micronized drugs through dry powder inhalers (DPIs) is traditionally achieved through the formation of ordered mixtures. In order to improve the mechanistic understanding of formation of ordered mixtures, the system consisting of micronized lactose (AZFL, representative of an active pharmaceutical ingredient) and a coarse particle carrier (LH100) is investigated as a function of different process and material variables in a high shear mixer (HSM) and in a low shear double cone (DCN) blender, using both experimental and numerical methods. Process insight is developed using a Discrete Element Method (DEM) based numerical model which could predict the formation of ordered mixtures in the two blenders and was verified against experimental determinations. Spatial and temporal evolution of granular flow are visualized and quantified in silico to reveal distinguishing features of both blenders to aid in rational selection of blenders and process parameters. PMID- 28574734 TI - The Recognizability and Localizability of Auditory Alarms: Setting Global Medical Device Standards. AB - Objective Four sets of eight audible alarms matching the functions specified in IEC 60601-1-8 were designed using known principles from auditory cognition with the intention that they would be more recognizable and localizable than those currently specified in the standard. Background The audible alarms associated with IEC 60601-1-8, a global medical device standard, are known to be difficult to learn and retain, and there have been many calls to update them. There are known principles of design and cognition that might form the basis of more readily recognizable alarms. There is also scope for improvement in the localizability of the existing alarms. Method Four alternative sets of alarms matched to the functions specified in IEC 60601-1-8 were tested for recognizability and localizability and compared with the alarms currently specified in the standard. Results With a single exception, all prototype sets of alarms outperformed the current IEC set on both recognizability and localizability. Within the prototype sets, auditory icons were the most easily recognized, but the other sets, using word rhythms and simple acoustic metaphors, were also more easily recognized than the current alarms. With the exception of one set, all prototype sets were also easier to localize. Conclusion Known auditory cognition and perception principles were successfully applied to an existing audible alarm problem. Application This work constitutes the first (benchmarking) phase of replacing the alarms currently specified in the standard. The design principles used for each set demonstrate the relative ease with which different alarm types can be recognized and localized. PMID- 28574735 TI - Fatal course of Saprochaete capitata fungemia in children with acute lymphoblastic leukemia. AB - Saprochaete capitata (S. capitata) is a very rare fungal pathogen that causes disseminated opportunistic infections in patients with hematologic malignancies. Fever resistant to broad-spectrum antibiotic and antifungal treatment is common in the presence of fungemia during the period of profound neutropenia. We describe three cases of leukemic children who died from S. capitata fungemia following a first febrile neutropenic episode after the induction of chemotherapy. S. capitata fungemia is an emergent infection associated with high mortality and low susceptibility to fluconazole and echinocandins. Awareness of this emergent infection is needed to ensure that it can be properly treated. PMID- 28574736 TI - Multiple functions of the E3 ubiquitin ligase CHIP in immunity. AB - The carboxyl terminal of Hsp70-interacting protein (CHIP) is an E3 ubiquitin ligase that plays a pivotal role in the protein quality control system by shifting the balance of the folding-refolding machinery toward the degradative pathway. However, the precise mechanisms by which nonnative proteins are selected for degradation by CHIP either directly or indirectly via chaperone Hsp70 or Hsp90 are still not clear. In this review, we aim to provide a comprehensive model of the mechanism by which CHIP degrades its substrate in a chaperone dependent or direct manner. In addition, through tight regulation of the protein level of its substrates, CHIP plays important roles in many physiological and pathological conditions, including cancers, neurological disorders, cardiac diseases, bone metabolism, immunity, and so on. Nonetheless, the precise mechanisms underlying the regulation of the immune system by CHIP are still poorly understood despite accumulating developments in our understanding of the regulatory roles of CHIP in both innate and adaptive immune responses. In this review, we also aim to provide a view of CHIP-mediated regulation of immune responses and the signaling pathways involved in the model described. Finally, we discuss the roles of CHIP in immune-related diseases. PMID- 28574737 TI - Preferred Place of Care and Death in Terminally Ill Patients with Lung and Heart Disease Compared to Cancer Patients. AB - OBJECTIVES: The dual aim of this study is, first, to describe preferred place of care (PPOC) and preferred place of death (PPOD) in terminally ill patients with lung and heart diseases compared with cancer patients and second, to describe differences in level of anxiety among patients with these diagnoses. BACKGROUND: Previous research on end-of-life preferences focuses on cancer patients, most of whom identify home as their PPOC and PPOD. These preferences may, however, not mirror those of patients suffering from nonmalignant fatal diseases. DESIGN: The study was designed as a cross-sectional study. SETTING: Eligible patients from the recruiting departments filled in questionnaires regarding sociodemographics, PPOC and PPOD, and level of anxiety. RESULTS: Of the 354 eligible patients, 167 patients agreed to participate in the study. Regardless of their diagnosis, most patients wished to be cared for and to die at home. Patients with cancer and heart diseases chose hospice as their second most common preference for both PPOC and PPOD, whereas patients with lung diseases chose nursing home and hospice equally frequent as their second most common preference. Regardless of their diagnosis, all patients had a higher level of anxiety than the average Danish population; patients with heart diseases had a much higher level of anxiety than patients with lung diseases and cancer. CONCLUSION: Patient preferences for PPOC and PPOD vary according to their diagnoses; tailoring palliative needs to patients' preferences is important regardless of their diagnosis. PMID- 28574739 TI - Binocular Vision and Squint, Part 2. PMID- 28574738 TI - Characteristics and Outcome of Male and Female Methadone Maintenance Patients: MMT in Tel Aviv and Las Vegas. AB - : To compare in methadone maintenance treatment (MMT) gender characteristics and outcomes, all patients ever admitted to Tel Aviv (TA) MMT clinic (N = 837) (June 1993-December 2014) and Las Vegas (LV) MMT clinic (N = 1256) (February 2000-June 2015) were prospectively followed-up (until June 2016). Drugs in urine on admission and after one year and long-term retention up to 23 and 16 years, respectively, were analyzed. Females in both clinics admitted younger than males and following shorter duration of opioid usage (TA: n = 215, 25.7%, age 35.0 +/- 7.9 vs. 40.6 +/- 9.8 years, p < .0005, duration 12.4 +/- 7.0 vs. 18.1 +/- 10 years, p < .0005; LV, n = 494, 39.3%, age 38.0 +/- 12.6 vs. 39.2 +/- 12.8, p = .08 duration 12.9 +/- 11.0 vs. 14.8 +/- 12.7 years, p = .008). On admission, higher proportion of female than male had positive urine for cocaine in TA (30.4% vs. 21.8%, p = .02) and for benzodiazepine in LVs (33.9% vs. 26.6%, p = .006). After 1 year, both genders had similar retention rate (TA: 76.1% LV: 49.8%) and opioid abstinence (TA: 67.6%, LV: 74.9%), and cumulative retention (TA: 8.2 years, 95% Confidence-Interval 7.6-8.8; LV 2.2 years, 95% confidence interval 2.0 2.4). CONCLUSIONS: Clinics differed in their characteristics and outcome, however in both clinic similar outcome between genders despite the difference in characteristics on admission was observed, as did the known women "telescoping effect." PMID- 28574740 TI - People Who Inject Drugs and Have Mood Disorders-A Brief Assessment of Health Risk Behaviors. AB - BACKGROUND: People who inject drugs have a greater risk of infectious disease and mortality than other substance abusers and nondrug users. Variation in risk behavior among people who inject drugs is likely associated with comorbid mental health disorders. OBJECTIVES: Examine the association between a history of mood disorder and recent risk behavior among people who inject drugs. METHODS: With baseline data from a behavioral HIV prevention clinical trial in a population of people who inject drugs, we used logistic regression models to compare the risk behaviors of people who report a past diagnosis of bipolar disorder (n = 113) or depression (n = 237) to a comparison group with no history of diagnosed mental illness (n = 446). We also assessed differences between groups before and after adjusting for demographic characteristics and current depressive symptoms. RESULTS: While there were no differences between groups in frequency of drug use, people who inject drugs who report a history of mood disorders reported more injection risk behaviors, drug overdoses, sex exchanges, and multiple partners than those with no history of mental illness. Adjusting the comparison for demographic characteristics and current depressive symptoms had little impact on these findings. Variation in risk between depression and bipolar disorder groups was minimal. Conclusions/Importance: People who inject drugs and have mood disorders have unique and significant social, clinical, and risk reduction needs. Despite the limited validity of self-reported mental health history, simply asking about a history of mood disorder may be effective for identifying a particularly vulnerable population of people who inject drugs. PMID- 28574741 TI - Re: Drug-Drug Interactions between Methadone and Apixaban. PMID- 28574742 TI - Working together toward vaccines and biomarkers in the real world. PMID- 28574743 TI - Invasive pneumococcal infection due to serotype 15A after the pneumococcal conjugate vaccine implementation in Turkey. AB - Invasive pneumococcal infections among children are a serious public health problem in many countries, including Turkey. Pneumococcal conjugate vaccine has been included in Turkey's National Immunization Programme since 2009. We report the first two pediatric cases of invasive pneumococcal infection due to non vaccine serotype 15A after pneumococcal conjugate vaccine implementation in Turkey. It is essential to monitor the countries' own local seroepidemiologic data for detecting selective pressure of non-vaccine serotypes of S. pneumonia. PMID- 28574744 TI - Spatial regulation of coalesced protein assemblies: Lessons from yeast to diseases. AB - Organisms rely on correctly folded proteins to carry out essential functions. Protein quality control factors guard proteostasis and prevent protein misfolding. When quality control fails and in response to diverse stresses, many proteins start to accumulate at specific deposit sites that maintain cellular organization and protect the functionality of coalescing proteins. These transitions involve dedicated proteins that promote coalescence and are facilitated by endo-membranes and cytoskeletal platforms. Moreover, several proteins make use of weak multivalent interactions or conformational templating to drive the formation of large-scale assemblies. Formation of such assemblies is often associated with a change in biochemical activity that can be used by cells to execute biochemical decisions in a localized manner during development and adaption. Since all assembly types impact cell physiology, their localization and dynamics need to be tightly regulated. Interestingly, at least some of the regulatory mechanisms are shared by functional membrane-less organelles and assemblies of terminally aggregated proteins. Furthermore, constituents of functional assemblies can aggregate and become non-functional during aging. Here we present the current knowledge as to how coalescing protein assemblies are spatially organized in cells and we postulate that failures in their spatial confinement might underscore certain aspects of aging and neurodegenerative diseases. PMID- 28574746 TI - Microbial production of mevalonate by recombinant Escherichia coli using acetic acid as a carbon source. AB - We sought to produce mevalonate, an important organic acid, by recombinant Escherichia coli, using acetic acid, a less costly alternative feedstock, as a carbon source. In this study, the mevalonate biosynthesis pathway originating with acetate was constructed in recombinant E. coli, resulting in the production of 1.06 g L-1 mevalonate with a productivity of 0.03 g L-1 h-1 in a 5-L bioreactor. The mevalonate concentration and productivity were significantly enhanced with increased cell density during 2-stage aerobic fermentation, reaching 7.85 g L-1 and 0.13 g L-1 h-1, respectively. Fed-batch fermentation was further optimized under anaerobic and microaerobic conditions, and mevalonate concentrations reached 3.05 g L-1 and 4.97 g L-1, respectively, indicating that the oxygen supply exerts a large impact on mevalonate production from acetate. This study describes a method with high potential to produce mevalonate with the engineered E. coli strain XU143 using the less costly alternative feedstock acetate as a carbon source. PMID- 28574748 TI - Ergonomic workplace design for health, wellness, and productivity. PMID- 28574747 TI - Health care utilization among young Australian women with severe tiredness: Results from the Australian Longitudinal Study on Women's Health (ALSWH). AB - In this article, we explore the use of health services and self-prescribed treatments among 8088 young Australian women with severe tiredness. Data were obtained from the Australian Longitudinal Study on Women's Health. The prevalence of severe tiredness was 49.2%. The frequency of visits to healthcare practitioners was greater among women who sought help for their severe tiredness, compared to women who did not seek help for their severe tiredness or who did not report severe tiredness. Given the impact of this health problem on Australian women, we call for further research on the optimal treatment for severe tiredness. PMID- 28574749 TI - Significance of Upper Mediastinal Lymph Node Dissection with Video-Assisted Thoracic Surgery in the Treatment of Middle Thoracic Esophageal Carcinoma. AB - BACKGROUND: The aim of this study was to explore the significance of upper mediastinal lymph node dissection performed by video-assisted thoracic surgery in the treatment of middle thoracic esophageal carcinoma. MATERIALS AND METHODS: The clinical and pathological data from 128 patients with middle thoracic esophageal carcinoma who underwent surgery from January 2013 to December 2015 using a right chest-abdomen-neck approach combined with thoracoscopy and laparoscopy in the Jieyang People's Hospital of Huangdong province were analyzed retrospectively. RESULTS: The lymph node metastasis rates of the thoracic left para-recurrent laryngeal nerve (1, 2, and 4L zones) and right para-recurrent laryngeal nerve (1R zone) were 30.47% and 28.12% in 128 cases, respectively. The metastasis rates of the 2R, 4R, and 5 zones were 4.69%, 3.91%, and 5.47%, respectively. CONCLUSIONS: The upper mediastinal region was the most common location for lymph node metastasis from middle thoracic esophageal carcinoma, and upper mediastinal lymph node dissection performed by video-assisted thoracic surgery was safe and complete. It also reduced the risk of para-recurrent laryngeal nerve injury, residual tumor, and the postoperative recurrence rate. PMID- 28574745 TI - Prion-specific Hsp40 function: The role of the auxilin homolog Swa2. AB - Yeast prions are protein-based genetic elements that propagate through cell populations via cytosolic transfer from mother to daughter cell. Molecular chaperone proteins including Hsp70, the Hsp40/J-protein Sis1, and Hsp104 are required for continued prion propagation, however the specific requirements of chaperone proteins differ for various prions. We recently reported that Swa2, the yeast homolog of the mammalian protein auxilin, is specifically required for the propagation of the prion [URE3]. 1 [URE3] propagation requires both a functional J-domain and the tetratricopeptide repeat (TPR) domain of Swa2, but does not require Swa2 clathrin binding. We concluded that the TPR domain determines the specificity of the genetic interaction between Swa2 and [URE3], and that this domain likely interacts with one or more proteins with a C-terminal EEVD motif. Here we extend that analysis to incorporate additional data that supports this hypothesis. We also present new data eliminating Hsp104 as the relevant Swa2 binding partner and discuss our findings in the context of other recent work involving Hsp90. Based on these findings, we propose a new model for Swa2's involvement in [URE3] propagation in which Swa2 and Hsp90 mediate the formation of a multi-protein complex that increases the number of sites available for Hsp104 disaggregation. PMID- 28574750 TI - Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes. AB - PURPOSE: The mechanisms involved in the reported beneficial effects of Calcium dobesilate monohydrate (CaD) for the treatment of diabetic retinopathy (DR) remain to be elucidated. The main aim of the present study is to examine whether CaD prevents early events in the pathogenesis of DR such as neurodegeneration and vascular leakage. In addition, putative mediators of both neurodegeneration (glutamate/GLAST, ET-1/ETB receptor) and early microvascular impairment (ET-1/ETA receptor, oxidative stress, VEGF, and the PKC-delta-p38 MAPK pathway) have been examined. METHODS: Diabetic (db/db) mice were randomly assigned to daily oral treatment with CaD (200 mg/Kg/day) (n = 12) or vehicle (n = 12) for 14 days. In addition, 12 non-diabetic (db/+) mice matched by age were used as the control group. Functional abnormalities were assessed by electroretinography. Neurodegeneration and microvascular abnormalities were evaluated by immunohistochemistry and Western blot. Glutamate was determined by HPLC. RESULTS: CaD significantly decreased glial activation and apoptosis and produced a significant improvement in the electroretinogram parameters. Mechanistically, CaD prevented the diabetes-induced up-regulation of ET-1 and its cognate receptors (ETA-R and ETB-R), which are involved in microvascular impairment and neurodegeneration, respectively. In addition, treatment with CaD downregulated GLAST, the main glutamate transporter, and accordingly prevented the increase in glutamate. Finally, CaD prevented oxidative stress, and the upregulation of VEGF and PKC delta-p38 MAPK pathway induced by diabetes, thus resulting in a significant reduction in vascular leakage. CONCLUSIONS: Our findings demonstrate for the first time that CaD exerts neuroprotection in an experimental model of DR. In addition, we provide first evidence that CaD prevents the overexpression of ET-1 and its receptors in the diabetic retina. These beneficial effects on the neurovascular unit could pave the way for clinical trials addressed to confirm the effectiveness of CaD in very early stages of DR. PMID- 28574751 TI - Athletic Trainers' Reasons for and Mechanics of Documenting Patient Care: A Report From the Athletic Training Practice-Based Research Network. AB - CONTEXT: Documenting patient care is an important responsibility of athletic trainers (ATs). However, little is known about ATs' reasons for documenting patient care and the mechanics of completing documentation tasks. OBJECTIVE: To understand ATs' perceptions about reasons for and the mechanics of patient care documentation. DESIGN: Qualitative study. SETTING: Individual telephone interviews with Athletic Training Practice-Based Research Network members. PATIENTS OR OTHER PARTICIPANTS: Ten ATs employed in the secondary school setting (age = 32.6 +/- 11.4 years, athletic training experience = 7.1 +/- 7.8 years) were recruited using a criterion-based sampling technique. Participants were Athletic Training Practice-Based Research Network members who used the Clinical Outcomes Research Education for Athletic Trainers electronic medical record system and practiced in 6 states. DATA COLLECTION AND ANALYSIS: We used the consensual qualitative research tradition. One investigator conducted individual telephone interviews with each participant. Data collection was considered complete after the research team determined that data saturation was reached. Interviews were transcribed verbatim and independently analyzed by 4 research team members following the process of open, axial, and selective coding. After independently categorizing interview responses into categories and themes, the members of the research team developed a consensus codebook, reanalyzed all interviews, and came to a final agreement on the findings. Trustworthiness was established through multiple-analyst triangulation and member checking. RESULTS: Participants identified 3 reasons for documenting patient care: communication, monitoring patient care, and legal implications. Four subcategories emerged from the mechanics-of-documentation theme: location, time of day, length of time, and criteria for documenting. The ATs described different criteria for documenting patient care, ranging from documenting every injury in the same manner to documenting time-loss and follow-up injuries differently. CONCLUSIONS: Whereas ATs recognized individual mechanisms that enabled them to document patient care, they may need more guidance on the appropriate criteria for documenting various patient care encounters and strategies to help them document more effectively. PMID- 28574752 TI - Athletic Trainers' Perceptions of and Barriers to Patient Care Documentation: A Report From the Athletic Training Practice-Based Research Network. AB - CONTEXT: For the practice characteristics of the services athletic trainers (ATs) provide to be identified, all ATs must complete high-quality patient care documentation. However, little is known about ATs' perceptions of patient care documentation or the potential barriers they may encounter while trying to ensure high-quality documentation. OBJECTIVE: To explore ATs' perceptions of and barriers to patient care documentation via the Clinical Outcomes Research Education for Athletic Trainers (CORE-AT) electronic medical record system in the secondary school setting. DESIGN: Qualitative study. SETTING: Individual telephone interviews. PATIENTS OR OTHER PARTICIPANTS: We interviewed 10 ATs (4 men, 6 women; age = 32.6 +/- 11.4 years, athletic training experience = 7.1 +/- 7.8 years) who were members of the Athletic Training Practice-Based Research Network (AT-PBRN) and employed in the secondary school setting. DATA COLLECTION AND ANALYSIS: We conducted an individual interview with each participant. After transcription of the interviews, the data were analyzed into common themes and categories following the consensual qualitative research tradition. Data triangulation occurred through member checking and multiple researchers to ensure accuracy during data analysis. RESULTS: Participants revealed several perceptions of patient care documentation, consisting of quality, expectations and accountability, priority, incentive, and culture of the secondary school setting. In addition, we identified barriers to quality patient care documentation: lack of time, lack of accountability for documenting patient care, inadequate facility resources, and lack of personnel. Participants discussed the volume of patients as a unique challenge in the secondary school setting. CONCLUSIONS: Whereas ATs perceived patient care documentation as important, several practical barriers may inhibit their ability to complete high-quality documentation of the services they provide. Effective strategies to improve the quality of patient care documentation among ATs are needed to ensure that their value, particularly in the secondary school setting, is accurately characterized. PMID- 28574753 TI - Diurnal and seasonal variations of odor and gas emissions from a naturally ventilated free-stall dairy barn on the Canadian prairies. AB - : This study characterized the seasonal concentration (C) and emission (E) patterns of odor, ammonia (NH3), and hydrogen sulfide (H2S) over the course of a whole year and their diurnal patterns in cold, warm, and mild seasons for a naturally ventilated free-stall dairy barn. It was found that seasonal odor and NH3 and H2S emissions varied greatly: from 17.2 to 84.4 odor units (OU) sec-1 AU 1 (AU: animal unit, 500 kg of animal body mass), from 0.27 to 0.92 mg sec-1 AU-1, and from 3 to 105 MUg sec-1 AU-1, respectively. The overall concentrations of odor and NH3 were higher in the winter, whereas the emissions were higher in the mild and warm seasons. Diurnal variation was most significant for odor emission (OE) in the mild season when the ratio of maximum (279.2 OU sec-1 AU-1) to minimum value (60.5 OU sec-1 AU-1) was up to 4.6. The indoor air quality was also evaluated by considering not only the health effect of individual gases, but also the additive effect of NH3 and H2S. Results showed that the indoor air quality was poorest in cold seasons when NH3 C could exceed the threshold limit set out in occupational health regulation, and in fact could worsen due to the additive effect of the two gases. Further, it was suggested NH3 was a good indicator for predicting odor concentration (OC) or OE. The impact of climatic parameters on odor and gases were also examined, and it was found ventilation rate (VR) negatively affected OC and NH3 C, but positively impacted OE and NH3 E. Using 70% of the total data, a multilinear model for OE was developed as a function of VR and indoor relative humidity and was validated to be acceptable using the rest of the data. IMPLICATIONS: Diurnal and seasonal variations of odor, NH3, and H2S concentrations and emissions were monitored for a naturally ventilated dairy barn in a cold region. The emission factors were calculated and indoor air quality was evaluated. The overall odor and NH3 concentrations were higher in winter, whereas emissions were higher in the mild and warm seasons. Diurnal variation was most significant for odor emission in the mild season, when the ratio of maximum to minimum value was up to 4.6. The results can be used to estimate odor and gas emissions from other dairy barns in Canada and other cold regions. PMID- 28574754 TI - Multicenter study of environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in 66 Canadian hospitals: A 2016 follow-up study. AB - PURPOSE: Oncology workers are occupationally exposed to antineoplastic drugs. This exposure can induce adverse health effects. To reduce their exposure, contamination on surfaces should be kept as low as possible. The main objective of this study was to monitor environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in oncology pharmacy and patient care areas in Canadian centers. The secondary objective was to describe the impact of some factors that may limit contamination. METHODS: This is a descriptive study. Twelve standardized sites were sampled in each participating center (six in the pharmacy and six in patient care areas). Samples were analyzed for the presence of cyclophosphamide, ifosfamide, and methotrexate by ultra-performance liquid chromatography-tandem mass spectrometry technology. Descriptive statistical analyses were done and results were compared with a Kolmogorov-Smirnov test for independent samples. RESULTS: In 2016, 66 centers participated in this study (66/202, 32.7%). Overall, 43.4% (326/752) of the samples were positive for cyclophosphamide, 13.2% (99/752) for ifosfamide and 6.9% (52/752) for methotrexate. The 75th percentile value of cyclophosphamide surface concentration was 6.8 pg/cm2 and lower than the limit of detection for ifosfamide and methotrexate. Centers who prepared more antineoplastic drugs per year (p < 0.0001), who used more cyclophosphamide per year (p < 0.0001) and who primed antineoplastic IV tubing in patient care unit by nurses (p = 0.004) showed significantly higher surface contamination to cyclophosphamide. CONCLUSION: Environmental surveillance is one part of a comprehensive approach for minimizing hazardous exposures in healthcare. This study highlights a low level of contamination of three hazardous drugs amongst 66 Canadian centers. Regular environmental monitoring is a good practice to maintain contamination as low as reasonably achievable. PMID- 28574755 TI - IH issues in natural disasters: Residents, first responders & public health. PMID- 28574756 TI - SOD2 Facilitates the Antiviral Innate Immune Response by Scavenging Reactive Oxygen Species. AB - Superoxide dismutase 2 (SOD2) is essential in radical scavenging, which balances the intracellular level of reactive oxygen species (ROS). The dysfunction of SOD2 is associated with increasing incidence of various human diseases, including cancer, neuron diseases, and myocardial defects. However, the connections between SOD2-mediated oxidative homeostasis and innate immune response remain unclear. In this study, we report that SOD2 is a crucial regulator of antiviral signaling. Depletion of SOD2 impairs RNA virus-induced type I interferon (IFN) and proinflammatory cytokine production, resulting in enhanced viral replication. Type I IFN production is highly sensitive to cellular level of ROS. SOD2 deficiency-mediated ROS accumulation potently inhibits RIG-I-like receptor (RLR) induced innate immune responses through the regulation of nuclear factor-kappa B (NF-kappaB) and interferon regulatory factor-3 activation. These findings uncover a novel role for SOD2 in regulating RLR-mediated antiviral innate immune signaling. PMID- 28574758 TI - Warburg effect-damping of electromagnetic oscillations. AB - Mitochondrial dysfunction is a central defect in cells creating the Warburg and reverse Warburg effect cancers. However, the link between mitochondrial dysfunction and cancer has not yet been clearly explained. Decrease of mitochondrial oxidative energy production to about 50 % in comparison with healthy cells may be caused by inhibition of pyruvate transfer into mitochondrial matrix and/or disturbed H+ ion transfer across inner mitochondrial membrane into cytosol. Lowering of the inner membrane potential and shifting of the working point of mitochondria to high values of pH above an intermediate point causes reorganization of the ordered water layer at the mitochondrial membrane. The reorganized ordered water layers at high pH values release electrons which are transferred to the cytosol rim of the layer. The electrons damp electromagnetic activity of Warburg effect cancer cells or fibroblasts associated with reverse Warburg effect cancer cells leading to lowered electromagnetic activity, disturbed coherence, increased frequency of oscillations and decreased level of biological functions. In reverse Warburg effect cancers, associated fibroblasts supply energy-rich metabolites to the cancer cell resulting in increased power of electromagnetic field, fluctuations due to shift of oscillations to an unstable nonlinear region, decreased frequency and loss of coherence. PMID- 28574757 TI - Effect of bit wear on hammer drill handle vibration and productivity. AB - The use of large electric hammer drills exposes construction workers to high levels of hand vibration that may lead to hand-arm vibration syndrome and other musculoskeletal disorders. The aim of this laboratory study was to investigate the effect of bit wear on drill handle vibration and drilling productivity (e.g., drilling time per hole). A laboratory test bench system was used with an 8.3 kg electric hammer drill and 1.9 cm concrete bit (a typical drill and bit used in commercial construction). The system automatically advanced the active drill into aged concrete block under feed force control to a depth of 7.6 cm while handle vibration was measured according to ISO standards (ISO 5349 and 28927). Bits were worn to 4 levels by consecutive hole drilling to 4 cumulative drilling depths: 0, 1,900, 5,700, and 7,600 cm. Z-axis handle vibration increased significantly (p<0.05) from 4.8 to 5.1 m/s2 (ISO weighted) and from 42.7-47.6 m/s2 (unweighted) when comparing a new bit to a bit worn to 1,900 cm of cumulative drilling depth. Handle vibration did not increase further with bits worn more than 1900 cm of cumulative drilling depth. Neither x- nor y-axis handle vibration was effected by bit wear. The time to drill a hole increased by 58% for the bit with 5,700 cm of cumulative drilling depth compared to a new bit. Bit wear led to a small but significant increase in both ISO weighted and unweighted z-axis handle vibration. Perhaps more important, bit wear had a large effect on productivity. The effect on productivity will influence a worker's allowable daily drilling time if exposure to drill handle vibration is near the ACGIH Threshold Limit Value. [1] Construction contractors should implement a bit replacement program based on these findings. PMID- 28574760 TI - Targeting Future Customers: An Introductory Biobanking Course for Undergraduate Students of Life Sciences. AB - INTRODUCTION: Biobanking is a relatively new concept in the Arab region. Targeting different stakeholders to introduce the concept of biobanking and develop an acceptance of it among them is important for the growth of biobanking in the region. Undergraduate students of life sciences represent an important segment of stakeholders, since they constitute potential future biobank customers. Limited funding, lack of awareness of the existence of the term "biobanking" itself among these students, and questions regarding best marketing strategies presented challenges to planning for the most effective message delivery to this target group. METHODS: A specific course was designed for undergraduate students of life sciences, which was conducted at the Faculty of Medicine, Cairo University, Egypt. The course was conducted twice in 2016 and included lectures covering biobanking, quality, ethics, information technology, and translational research. Facebook and word-of-mouth were used for marketing and advertising. RESULTS: A total number of 125 participants attended both courses cumulatively. Facebook appeared to have been an effective marketing outlet, especially when paid advertisements were used. Evaluation of knowledge, measured using a pretest and posttest, demonstrated some improvement in knowledge of participants. Evaluation forms filled after the course showed positive attitude toward content and message delivery by a majority of participants. Facebook was also used as an evaluation method through analysis of engagement with posts created after course completion. CONCLUSIONS: Biobanking education can be carried out effectively with limited resources. Understanding the needs of the target group and using appropriate methods of communication are essential prerequisites to a well-tailored curriculum and effective message delivery. Using Facebook appears to be an effective and affordable method of communication and advertising. Targeting undergraduate students of life sciences interested in research is a good investment and can be very effective in increasing awareness about biobanking inside the research community. PMID- 28574759 TI - Sedentary Behavior and Cardiometabolic Health Associations in Obese 11-13-Year Olds. AB - BACKGROUND: Improved understanding of sedentary time's impact on cardiometabolic health can help prioritize intervention targets. OBJECTIVE: We investigated cross sectional and longitudinal relations of reported screen time and objectively measured total percent of time spent sedentary with cardiometabolic health in obese youth. METHODS: Participants were 106 obese adolescents age 11-13 (N = 106, 51% girls, and 82% Hispanic) recruited from primary care clinics in southern California. Main predictor measures were child-reported screen time and objectively assessed sedentary time. Outcome measures were body mass index (BMI), waist and hip circumference, body fat, blood pressure, glucose, triglycerides, insulin, cholesterol, aspartate aminotransferase (AST), and serum alanine aminotransferase (ALT). RESULTS: Total percent sedentary time was not associated with the cardiometabolic health markers after adjusting for moderate-to-vigorous physical activity (MVPA). However, screen time was positively associated with BMI and diastolic blood pressure at baseline, and positive longitudinal associations were found with BMI, triglycerides, low-density lipoprotein, AST, and ALT. CONCLUSIONS: Reported screen time, but not total sedentary time, was related to multiple cardiometabolic health markers in obese adolescents, independent of MVPA. The findings suggest that limiting and replacing screen time, which was more than 3 hours per day on average in this sample, is likely an important behavior change strategy for interventions treating childhood obesity and comorbidities. The associations with screen time were strongest with AST and ALT, suggesting that this form of sedentary behavior may impact liver health. PMID- 28574761 TI - Lessons learned from surface wipe sampling for lead in three workplaces. AB - Surface wipe sampling in the occupational environment is a technique widely used by industrial hygienists. Although several organizations have promulgated standards for sampling lead and other metals, uncertainty still exists when trying to determine an appropriate wipe sampling strategy and how to interpret sampling results. Investigators from the National Institute for Occupational Safety and Health (NIOSH) Health Hazard Evaluation Program have used surface wipe sampling as part of their exposure assessment sampling strategies in a wide range of workplaces. This article discusses wipe sampling for measuring lead on surfaces in three facilities: (1) a battery recycling facility; (2) a firing range and gun store; and (3) an electronic scrap recycling facility. We summarize our findings from the facilities and what we learned by integrating wipe sampling into our sampling plan. Wiping sampling demonstrated lead in non-production surfaces in all three workplaces and that the potential that employees were taking lead home to their families existed. We also found that the presence of metals such as tin can interfere with the colorimetric results. We also discuss the advantages and disadvantages of colorimetric analysis of surface wipe samples and the challenges we faced when interpreting wipe sampling results. PMID- 28574762 TI - Body Image, Eating Attitudes and Breastfeeding Intention: Implications for Mental Health and Maternal Child Nurses. AB - Body image dissatisfaction and disordered eating are often overlooked as personal factors that may affect pregnancy, postpartum, and infant feeding method. The current study compared body image, eating attitudes, and breastfeeding intention of first-time breastfeeding mothers to first-time non-breastfeeding mothers. A two-group, comparative design was used to analyze data for first-time mothers recruited through a large pediatric practice with multiple offices. Although there was no significant difference in body image scores between the groups, the literature suggests that body image dissatisfaction can affect the transition to motherhood and lead to more serious mental health issues. Prevention of psychiatric disorders such as eating disorders can be addressed early with information regarding body dissatisfaction and disordered eating. Findings from this study have implications for mental health and maternal child health providers. PMID- 28574764 TI - Symbiosis of the Hydrothermal Vent Gastropod Ifremeria nautilei (Provannidae) With Endobacteria-Structural Analyses and Ecological Considerations. AB - The gastropod Ifremeria nautilei lives in high abundance around deep-sea hydrothermal vents of the Western Pacific. The filaments of its ctenidium are very long and have a rigid axis with a hemocoelic vessel and a strongly ciliated epithelium. The flattened part of each filament largely consists of bacteriocytes that are distally filled with numerous gram-negative bacteria. The bacteria lie one by one in vacuoles that seem to be part of an interconnected tubular system. Some of the apical vacuoles regularly showed what could be openings to the ambient seawater. This special topological arrangement of the bacteria suggests that in a morphological series mirroring the supposed evolutionary pathway from extra- to intracellular symbioses, I. nautilei might correspond to an intermediate stage. The high sulfur content and the low stable carbon isotope values measured in this study, combined with corresponding data from the literature, indicate that I. nautilei is the host partner in a thiotrophic chemoautotrophic bacterial symbiosis. The importance of this symbiosis for the nutrition of the gastropod is underlined by the reduced size of the host's stomach. Unlike specimens of I. nautilei from the Manus Basin (Galchenko et al., 1992), the inspected specimens from the North Fiji Basin did not contain any methanotrophic bacteria in addition to the thiotrophic type. From the disparity in results, it may be concluded that this host species can develop different patterns of symbiosis either as an adaptation to local variances of hydrothermal vent fluid chemistry or as a consequence of genetic differentiation in the host. PMID- 28574765 TI - Claw Transformation and Regeneration in Adult Snapping Shrimp: Test of the Inhibition Hypothesis for Maintaining Bilateral Asymmetry. AB - In the paired asymmetric claws of adult snapping shrimp, Alpheus heterochelis, the minor, or pincer, claw may transform into a major, or snapper, claw if the existing snapper claw is damaged or lost, implying that an intact snapper claw normally inhibits the contralateral pincer claw from advancing to a snapper. We find that the pincer-to-snapper advancement in external form occurs almost immediately after the snapper is lost even as late as the premolt stage. The transforming claw in turn inhibits the newly regenerating pincer claw from becoming a snapper, but if the dactyl of the transforming claw is cut, then snapper-based inhibition is removed and the contralateral claw may regenerate as a snapper, resulting in shrimp with paired snapper claws. However, damaging an established snapper claw will not allow another snapper claw to regenerate at the pincer site, implying that less inhibition is required to restrict a newly regenerating claw to a pincer than to arrest an existing pincer claw. Inhibition may be manifested largely in terms of quantity of innervation. Hence the greater innervation of the snapper side over the pincer side would inhibit the pincer side, accounting for the regeneration of paired claws in their previous configuration following loss of both claws. Loss of the paired claws in two consecutive molts retards their development so that both claws often appear as pincers, but in succeeding molts one usually differentiates into a snapper and bilateral asymmetry is restored. In contrast, shrimp with paired snapper claws retain this configuration over several molts unless one or both of the claws are lost; in that case, regeneration restores bilateral asymmetry. Thus, bilateral asymmetry of the paired claws of adult shrimp is governed by a strong intrinsic lateralizing mechanism in which the snapper claw inhibits the pincer from advancing to another snapper. PMID- 28574763 TI - The dark side of hippo signaling: A cancer promoter role. AB - The Hippo signaling pathway regulates organ size and tissue homeostasis. Given this role it is unsurprising that dysregulation of this pathway has implications for cancer progression. A convincing body of literature shows that the Hippo pathway serves a tumor suppressive function with its inactivation leading to massive overgrowth. However, additional studies have also shown that activation of Hippo signaling can promote tumor progression. It remains unknown how a single pathway can produce such diametrically opposed effects. This lack of knowledge is in part due to our inability to make meaningful comparisons from studies which have taken place in a variety of cell types, tissues, and organisms. Recently however, we have published 2 studies using the Drosophila wing disk to study the Hippo pathway and have found that Hippo pathway activation can promote cell migration and invasion while Hippo pathway inactivation leads to overgrowth. Thus we propose here that Drosophila can provide a research platform with which to begin addressing how the Hippo pathway can both enhance and suppress tumor progression due to published pro- and anti-tumor functionalities of the Hippo pathway in the same tissue. PMID- 28574766 TI - Limb Regeneration in the Eye Sockets of Crabs. AB - The eyestalks of crabs were removed and various tissues of the limbs were autotransplanted into the empty eye sockets to study the capacity of the limb tissue to regenerate in a heterotopic site. Autotransplantation of walking leg tissues into the eye sockets was able to regenerate complete walking legs in the new site. Autotransplantation of tissues of claw digit (dactyl and pollex) or more proximal claw segments (ischium and merus/carpus joint) could regenerate complete claws in the eye sockets. If the autotransplant of claw tissue was contralateral, claws could regenerate with host-site handedness. Sham operations or autotransplantation of frozen claw tissue did not induce regeneration in the eye sockets. These results demonstrate that complete crab claws can regenerate from the eye sockets by autotransplantation of live limb tissue and that the regeneration is not due to the traumatic effect of transplantation. The structure of the limbs regenerated in the eye sockets was determined by the source of the transplanted tissue. Complete claws resulted from autotransplantation of the tissues of the most distal claw segments (claw digits), and the most distal claw segments regenerated first, followed by the proximal claw segments in subsequent molts. Thus tissue from distal portions of crab claw can regenerate proximal portions of the claw in the eye sockets. Such a mode of regeneration is not consistent with the distalization rule of the polar coordinate model, which proposes that distal portions of the limb cannot regenerate proximal portions and that the direction of limb regeneration is always from proximal to distal. PMID- 28574767 TI - Spermiogenesis and Sperm Structure in Relation to Early Events of Fertilization in the Limpet Tectura testudinalis (Muller, 1776). AB - Spermiogenesis and fertilization in the limpet Tectura testudinalis (Mollusca: Archaeogastropoda: Patelloidea) were examined using scanning and transmission electron microscopy, as well as light microscopy. Spermiogenesis was similar to that described for other Lottiidae (Patelloidea), but some key differences were noted. We observed that the acrosomal vesicle forms on the plasma membrane from several Golgi-derived proacrosomal vesicles during the early spermatid. Evidence from anti-actin antibody staining of a related species, T. scutum, indicates that the acrosome probably contains G-actin in three different locations, but there are no preformed actin filaments. The flagellum of mature sperm tapers to a thin, filamentous end-piece. The mature egg of T. testudinalis is enclosed by a thin vitelline layer and a thick jelly coat bound by follicle cells. Where a mature sperm encounters the intact jelly coat, its acrosome tip may elongate, up to twice its original length. The acrosome reaction is not induced, but by this mechanism the acrosome bridges the jelly coat and extends down far enough to contact the vitelline layer. During the elongation of the acrosome, microfilaments are formed inside the tip. As well, new membrane required for this process is supplied by elimination of any slack in the plasma membrane and also perhaps by spontaneous formation of vesicles inside the acrosome. Once the tip of the sperm contacts and binds with the vitelline layer it undergoes the acrosome reaction, in which the plasma and acrosomal membranes fuse and roll back in a manner typical of scaphopods and some polychaetes. Sperm also may bind directly with the vitelline layer when the jelly coat is absent. Furthermore, the acrosome tip may undergo spontaneous fusion with a naked egg microvillus that formerly connected with a follicle cell process. Thus, the sperm either individually or collectively are equipped to deal with any one of several potential routes to successful fertilization of the egg. Current theories of gastropod phylogeny place the limpets as basal to the Gastropoda, but new evidence presented here supports the idea that they are a divergent group, with some unique innovations in sperm design. PMID- 28574768 TI - Are Echinoderm Egg Size Distributions Bimodal? AB - Marine invertebrates can be categorized into species that reproduce by producing either large numbers of small, energetically inexpensive eggs that become planktotrophic larvae, or fewer, larger eggs with more yolk and lecithotrophic development (1). The selective advantages of these alternative strategies were considered in a series of simple mathematical models by Vance (2, 3). These models predicted that intermediate egg sizes should have lower reproductive efficiency, and that only extreme egg sizes should be evolutionarily stable (2, 3). Specifytally, Vance's models (2, 3) and later modifications (4-7), predict that eggs of marine invertebrates should have bimodal size distributions, rejecting the contrast between small egg/feeding and large egg/nonfeeding modes of development and the selection against intermediate egg sizes. Evidence for bimodality in egg size distributions is, however, equivocal, with unimodal distributions seen in the majority of comparative studies that are appropriate tests of the hypothesis (8-13). Bimodal distributions have been described only in a few groups of molluscs (4) and asteroid and echinoid echinoderms (14). Here we test the prediction of bimodality in the holothuroid and ophiuroid echinoderms and show that although the natural log-transformed egg size distributions are visually unimodal, the holothurian egg size distribution is statistically composed of two discrete modes. Moreover, reexamination of the asteroid and echinoid egg size distributions (14) with the addition of data from more recent literature confirms that there are two statistical modes in the egg size distributions of these classes. Thus, in the phylum Echinodermata, there is a bimodal egg size distribution three of the four classes in which this prediction can tested. PMID- 28574769 TI - Oocyte Maturation in the Brachiopod Terebratalia transversa: Role of Follicle Cell-Oocyte Attachments During Ovulation and Germinal Vesicle Breakdown. AB - In the brachiopod Terebratalia transversa, each ovarian follicle consists of (i) a prophase-arrested oocyte with an enlarged nucleus (= the germinal vesicle, or GV), and (ii) a surrounding sheath of follicle cells that attach to the oocyte by means of junctional complexes. Within about 80 min after removing a follicle from the ovary, the follicular sheath undergoes a microfilament-mediated retraction, and the ovulated oocyte that emerges from the retracted sheath subsequently completes germinal vesicle breakdown (GVBD). Based on the experimental manipulations reported here, it appears that the follicle must be detached from the ovary for such ovulation and GVBD to occur. Moreover, GVBD can be prevented if the oocytes are mechanically stripped of their follicle cells up to 30 min after being isolated from the ovary. GVBD proceeds normally, however, if follicle cells are removed more than 40 min after the follicle is obtained from the ovary. The percentage of oocytes that undergo GVBD is also diminished following treatment with drugs that uncouple gap junctions. Collectively, these data suggest that removing a follicle from the ovary stimulates follicle cells to produce a maturation-inducing factor that uses the follicle cell-oocyte junctional complexes to reach the oocyte within about 30-40 min after follicular removal. The significance of these findings is discussed relative to previous reports on oocyte maturation in brachiopods and other animals. PMID- 28574770 TI - Hermaphroditic Freshwater Clams in the Genus Corbicula Produce Non-Reductional Spermatozoa With Somatic DNA Content. AB - Hermaphroditic freshwater clams in the genus Corbicula produce non-reductional spermatozoa. The DNA content of spermatozoa was almost identical with that of somatic cells in C. leana from Mie Prefecture, Japan. Hermaphroditic C. aff. fluminea from Saga Prefecture and C. fluminea from Taiwan also produce non reductional spermatozoa. On the other hand, spermatozoa of the dioecious C. sandai had half the DNA found in somatic cells. Analysis of chromosome numbers suggests that C. leana (3n = 54 in somatic cells and 18 in meiotic cells) from Mie Prefecture and C. aff. fluminea (2n = 36 in gills and 18 bivalents in meiotic cells) from Saga Prefecture are triploids and diploids, respectively. C. leana, C. aff. fluminea, and C. fluminea may lack either first or second meiosis, resulting in non-reductional spermatozoa. We assume that gynogenetic reproduction occurs in both species; maternal chromosomes are also nonreductional, and spermatozoa activate development of the eggs, but do not contribute to the offspring. PMID- 28574771 TI - Myogenic Heartbeat in the Primitive Crustacean Triops longicaudatus. AB - Pacemaker mechanisms in the heart of the primitive crustacean Triops longicaudatus were examined electrophysiologically. The heart is tubular and the heart wall consists of a single layer of myocardial cells. No nerve cells were found in the heart, either with methylene blue vital staining or by light microscopy of serial sections. The heart beats rhythmically at a frequency of 120 to 240 beats/min, and each beat is associated with a slow membrane potential change in the heart muscle. The amplitude of the slow potential varies widely and no spikes appear on it. The heart muscle cells are electrically coupled with each other and generate synchronous slow potentials. No localized portion of the heart exhibited a frequency that always preceded the others. The muscle activity could be phase-shifted by injection of a single brief current pulse and could be entrained to a lower or higher frequency by repeated brief current pulses injected into the muscle cell. The frequency of muscle activity could be changed by the injection of DC current into the muscle cell, and the change in frequency was linearly related to the intensity of the current. When the intensity of hyperpolarizing DC current exceeded a certain value, the muscle activity disappeared abruptly, and the heart stopped beating completely. These results show clearly that the heartbeat of Triops is myogenic. The heart is diffusely myogenic and should be regarded as a single muscle oscillator. PMID- 28574772 TI - Egg-Mass Gel of Melanochlamys diomedea (Bergh) Protects Embryos From Low Salinity. AB - Many opisthobranch gastropods embed their embryos in gelatinous egg masses; however, the functions of gel are not well known. We analyze the hypothesis that egg-mass gel protects embryos from salinity change. Using egg masses of Melanochlamys diomedea, we found that experimental removal of gel decreased the ability of embryos to survive osmotic stress. We evaluate several possible protective mechanisms by estimating osmotic influx of water into egg masses and by modeling salt efflux from an egg mass. On immersion in low-salinity water, egg masses lost roughly 23% of their mass, indicating that osmotic influx of water did not occur. Therefore, the principal route of salinity change within the egg mass is probably salt efflux. The model suggests that this efflux occurs quite slowly even when ambient salinity changes rapidly. Slow salinity change may be less stressful for embryos because the mechanisms that regulate cellular volume have more time to adjust. We show experimentally that slow salinity changes are less harmful to veligers than rapid ones by isolating capsules from egg-mass gel and exposing them to gradual or abrupt salinity change. The results support the hypothesis that rate of change of salinity is an important determinant of embryo survival and that egg-mass gel retards the rate of salinity change. PMID- 28574773 TI - Sexual Competition Among Male Blue Crab, Callinectes sapidus. AB - Experiments and field data on blue crab, Callinectes sapidus, from mid-Chesapeake Bay between 1991 and 1994 were used to test whether large males have advantages over small males in accessing females and in sperm competition. In the field, large males were paired more often, especially with large, more fecund females. However, the variance in the relationship between male and female size in mating pairs was high, suggesting that mating with large females may not be the primary determinant of male reproductive success. Large males had proportionately longer chelipeds, which may provide an advantage in aggressive interactions for females or in struggles to control females. Previous work indicates that sperm competition may occur in blue crabs and that ejaculate size may influence a male's ability to compete during sperm competition. Large males stored more seminal fluid and spermatophores and passed a larger volume of ejaculate to each mate than did small males. Ejaculate volume averaged 47% of a male's stored supply. However, ejaculate volume increased with the duration of copulation but decreased with successive matings, such that males needed about 15 days between matings to pass similar-sized ejaculates to successive mates. Pre-copulatory mate guarding may serve as a time to replenish ejaculate contents, and thus its duration also influences a male's performance in sperm competition. PMID- 28574775 TI - The 2017 ISBER Annual Meeting & Exhibits: "Due North: Aligning Biobanking Practice with Evolving Evidence and Innovation". PMID- 28574774 TI - Differing Experiences with Pre-Exposure Prophylaxis in Boston Among Lesbian, Gay, Bisexual, and Transgender Specialists and Generalists in Primary Care: Implications for Scale-Up. AB - The Centers for Disease Control and Prevention estimates that one in four sexually active men who have sex with men (MSM) could decrease their HIV risk by using HIV pre-exposure prophylaxis (PrEP). Because many MSM access healthcare from primary care providers (PCPs), these clinicians could play an important role in providing access to PrEP. Semistructured qualitative interviews were conducted with 31 PCPs in Boston, MA, to explore how they approach decisions about prescribing PrEP to MSM and their experiences with PrEP provision. Purposive sampling included 12 PCPs from an urban community health center specializing in the care of lesbian, gay, bisexual, and transgender persons ("LGBT specialists") and 19 PCPs from a general academic medical center ("generalists"). Analyses utilized an inductive approach to identify emergent themes. Both groups of PCPs approached prescribing decisions about PrEP as a process of informed decision making with patients. Providers would defer to patients' preferences if they were unsure about the appropriateness of PrEP. LGBT specialists and generalists were at vastly different stages of adopting PrEP into practice. For LGBT specialists, PrEP was a disruptive innovation that rapidly became normative in practice. Generalists had limited experience with PrEP; however, they desired succinct decision-support tools to help them achieve proficiency, because they considered preventive medicine to be central to their professional role. As generalists vastly outnumber LGBT specialists in the United States, interventions to support PrEP provision by generalists could accelerate the scale-up of PrEP for MSM nationally, which could in turn decrease HIV incidence for this priority population. PMID- 28574778 TI - Do the American Society of Clinical Oncology Value Framework and the European Society of Medical Oncology Magnitude of Clinical Benefit Scale Measure the Same Construct of Clinical Benefit? AB - Purpose Whether the ASCO Value Framework and the European Society for Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) measure similar constructs of clinical benefit is unclear. It is also unclear how they relate to quality-adjusted life-years (QALYs) and funding recommendations in the United Kingdom and Canada. Methods Randomized clinical trials of oncology drug approvals by the US Food and Drug Administration, European Medicines Agency, and Health Canada between 2006 and August 2015 were identified and scored using the ASCO version 1 (v1) framework, ASCO version 2 (v2) framework, and ESMO-MCBS by at least two independent reviewers. Spearman correlation coefficients were calculated to assess construct (between frameworks) and criterion validity (against QALYs from the National Institute for Health and Care Excellence [NICE] and the pan-Canadian Oncology Drug Review [pCODR]). Associations between scores and NICE/pCODR recommendations were examined. Inter-rater reliability was assessed using intraclass correlation coefficients. Results From 109 included randomized clinical trials, 108 ASCOv1, 111 ASCOv2, and 83 ESMO scores were determined. Correlation coefficients for ASCOv1 versus ESMO, ASCOv2 versus ESMO, and ASCOv1 versus ASCOv2 were 0.36 (95% CI, 0.15 to 0.54), 0.17 (95% CI, -0.06 to 0.37), and 0.50 (95% CI, 0.35 to 0.63), respectively. Compared with NICE QALYs, correlation coefficients were 0.45 (ASCOv1), 0.53 (ASCOv2), and 0.46 (ESMO); with pCODR QALYs, coefficients were 0.19 (ASCOv1), 0.20 (ASCOv2), and 0.36 (ESMO). None of the frameworks were significantly associated with NICE/pCODR recommendations. Inter-rater reliability was good for all frameworks. Conclusion The weak-to-moderate correlations of the ASCO frameworks with the ESMO-MCBS, as well as their correlations with QALYs and with NICE/pCODR funding recommendations, suggest different constructs of clinical benefit measured. Construct convergent validity with the ESMO-MCBS did not increase with the updated ASCO framework. PMID- 28574777 TI - Coping and Prognostic Awareness in Patients With Advanced Cancer. AB - Purpose Patients' understanding of their illness is key for making informed treatment decisions, yet studies suggest an association between prognostic awareness and worse quality of life (QOL) and mood among patients with advanced cancer. We sought to explore the relationships among prognostic awareness, coping, QOL, and mood in patients with newly diagnosed, incurable cancer. Methods We assessed patients' self-reported health status and treatment goal (Prognosis and Treatment Perceptions Questionnaire), coping (Brief COPE), QOL (Functional Assessment of Cancer Therapy-General), and mood (Hospital Anxiety and Depression Scale) within 8 weeks of incurable lung or GI cancer diagnosis. We used linear regression to examine associations and interaction effects among patients' health status and treatment goal, coping strategies, QOL, and mood. Results Patients who reported a terminally ill health status had worse QOL (unstandardized coefficient [B] = -6.88; P < .001), depression (B = 1.60; P < .001), and anxiety (B = 1.17; P = .007). Patients who reported their oncologist's treatment goal was "to cure my cancer" had better QOL (B = 4.33; P = .03) and less anxiety (B = -1.39; P = .007). We observed interaction effects between self-reported health status and treatment goal and certain coping strategies. Specifically, subgroup analyses showed that greater use of positive reframing was related to better QOL (B = 2.61; P < .001) and less depression (B = -0.78; P < .001) among patients who reported a terminally ill health status. Active coping was associated with better QOL (B = 3.50; P < .001) and less depression (B = -1.01; P < .001) among patients who acknowledged their oncologist's treatment goal was not "to cure my cancer." Conclusion Prognostic awareness is related to worse QOL and mood in patients with newly diagnosed, incurable cancer; however, the use of certain coping strategies may buffer these relationships. Interventions to improve patients' prognostic awareness should seek to cultivate more adaptive coping strategies in order to enhance QOL and mood. PMID- 28574780 TI - Forty Years of Engagement Research in Children's Mental Health Services: Multidimensional Measurement and Practice Elements. AB - Poor engagement in child and adolescent mental health services is a significant public health concern. The purpose of this study was to synthesize the engagement literature using a multidimensional measurement framework to identify practice elements that are associated with improved engagement. We examined 50 randomized controlled trials of interventions targeting treatment engagement in youth mental health services published between 1974 and 2016. We utilized a multidimensional measurement framework that includes five engagement domains (i.e., Relationship, Expectancy, Attendance, Clarity, Homework [REACH]). We also used a distillation method (Chorpita & Daleiden, 2009; Chorpita, Daleiden, & Weisz, 2005) to identify specific practices common to interventions that were effective at increasing engagement within each REACH domain. Engagement was most frequently operationalized in intervention studies as Attendance. Individual practices distilled from effective interventions were successful when used with participants with diverse characteristics in a wide variety of contexts. Importantly, we found unique practice patterns associated with outcomes from each REACH domain. Findings suggest that practices such as assessment, psychoeducation, accessibility promotion, barriers to treatment, and goal setting might be used with all youth and families to promote engagement and that other practices could be introduced on an as-needed basis to target specific engagement domains (e.g., modeling to promote Clarity about therapy; therapist monitoring to promote Homework/participation). A substantial evidence base demonstrates that engagement can be improved through specific interventions, and findings highlight opportunities to advance the field's understanding of engagement through multidimensional measurement in future studies. PMID- 28574779 TI - HELOISE: Phase IIIb Randomized Multicenter Study Comparing Standard-of-Care and Higher-Dose Trastuzumab Regimens Combined With Chemotherapy as First-Line Therapy in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma. AB - Purpose To compare standard-of-care (SoC) trastuzumab plus chemotherapy with higher-dose (HD) trastuzumab plus chemotherapy to investigate whether HD trastuzumab increases trastuzumab serum trough concentration (Ctrough) levels and increases overall survival (OS) in first-line human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. Patients and Methods Patients with Eastern Cooperative Oncology Group performance status 2, no prior gastrectomy, and >= two metastatic sites were randomly assigned at a one-to-one ratio to loading-dose trastuzumab 8 mg/kg followed by SoC trastuzumab maintenance 6 mg/kg every 3 weeks or loading-dose trastuzumab 8 mg/kg followed by HD trastuzumab maintenance 10 mg/kg every 3 weeks until progression; treatment in each arm was combined with cisplatin 80 mg/m2 plus capecitabine 800 mg/m2 twice per day in cycles 1 to 6. The primary objective was HD trastuzumab OS superiority (all randomly assigned patients [full-analysis set]). Final results are from an interim analysis for futility (boundary hazard ratio [HR] >= 0.95) at 125 deaths. Results At clinical cutoff, 248 patients had been randomly assigned. A marked increase in mean trastuzumab Ctrough was observed after the first HD trastuzumab cycle versus SoC trastuzumab. In the full analysis set, median OS was 12.5 months in the SoC trastuzumab arm and 10.6 months in the HD trastuzumab arm (stratified HR, 1.24; 95% CI, 0.86 to 1.78; P = .2401). Results were similar in the per-protocol set (cycle 1 trastuzumab Ctrough < 12 ug/mL). Safety was comparable between arms. Conclusion HD trastuzumab maintenance dosing was associated with higher trastuzumab concentrations, no increased efficacy, and no new safety signals. HELOISE confirms standard-dose trastuzumab (loading dose of 8 mg/kg followed by 6 mg/kg maintenance dose every 3 weeks) with chemotherapy as the SoC for first-line treatment of human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. PMID- 28574781 TI - Associations between Age, Years in Post, Years in the Profession and Personal Experience of Mental Health Problems in UK Mental Health Nurses. AB - Nurses' mental health is of paramount importance, both in terms of patient safety and the sustainability of the workforce. Age, years in the profession, in post and personal experience or exposure to mental health problems are relevant to the mental health nursing workforce crisis in the United Kingdom. This study aimed to determine the relationship between age, years in the profession and post and self reported experience of mental health problems using an online cross-sectional survey of 225 UK mental health nurses. Number of years in post was inversely correlated with overall experience of mental health problems, particularly living with someone else with mental health problems. Those with experience of living with someone with mental health problems had significantly fewer years of professional experience than those without. This article discusses possible explanations for this phenomenon and makes the case for future research on the topic. PMID- 28574783 TI - Bacterial Symbionts Colonize the Accessory Nidamental Gland of the Squid Loligo opalescens via Horizontal Transmission. AB - The accessory nidamental gland (AN gland), a reproductive organ of the mature female squid Loligo opalescens, harbors a dense culture of bacteria of unknown function. A multilayered sheath surrounding the L. opalescens egg case is similarly colonized by bacteria that presumably originate in the AN gland, as evidenced by their presence in the egg case at oviposition. This study investigates how these bacteria are transmitted to juvenile squid and examines some morphological consequences of bacterial colonization of AN gland tissues. By observing the structure of the AN gland in adults and the development and bacterial colonization of the gland in juveniles raised in captivity, we determined that the AN gland was absent in newly hatched squid and did not appear until 87 days post-hatching. At 129 days posthatching, the organ displayed tubules composed of a single layer of epithelial cells and expressing numerous cilia and microvilli. These tubules were not yet fully formed and thus were open to the mantle cavity and external seawater, possibly to aid in the acquisition of microorganisms. Since the AN gland developed a considerable time after hatching, it most likely acquires its symbionts horizontally from environmental seawater and not vertically from the egg case sheath. The switch from expression of cilia to production of microvilli on the epithelial cell surface may dictate the competence of the tissue for bacterial colonization. Electron microscopic examination of juvenile and adult AN glands revealed that an analogous process occurs during the development of the related light organ of other cephalopod species that harbor symbiotic bacteria. PMID- 28574782 TI - RNA-based ovarian cancer research from 'a gene to systems biomedicine' perspective. AB - : Ovarian cancer remains the leading cause of death from a gynecologic malignancy, and treatment of this disease is harder than any other type of female reproductive cancer. Improvements in the diagnosis and development of novel and effective treatment strategies for complex pathophysiologies, such as ovarian cancer, require a better understanding of disease emergence and mechanisms of progression through systems medicine approaches. RNA-level analyses generate new information that can help in understanding the mechanisms behind disease pathogenesis, to identify new biomarkers and therapeutic targets and in new drug discovery. Whole RNA sequencing and coding and non-coding RNA expression array datasets have shed light on the mechanisms underlying disease progression and have identified mRNAs, miRNAs, and lncRNAs involved in ovarian cancer progression. In addition, the results from these analyses indicate that various signalling pathways and biological processes are associated with ovarian cancer. Here, we present a comprehensive literature review on RNA-based ovarian cancer research and highlight the benefits of integrative approaches within the systems biomedicine concept for future ovarian cancer research. We invite the ovarian cancer and systems biomedicine research fields to join forces to achieve the interdisciplinary caliber and rigor required to find real-life solutions to common, devastating, and complex diseases such as ovarian cancer. ABBREVIATIONS: CAF: cancer-associated fibroblasts; COG: Cluster of Orthologous Groups; DEA: disease enrichment analysis; EOC: epithelial ovarian carcinoma; ESCC: oesophageal squamous cell carcinoma; GSI: gamma secretase inhibitor; GO: Gene Ontology; GSEA: gene set enrichment analyzes; HAS: Hungarian Academy of Sciences; lncRNAs: long non-coding RNAs; MAPK/ERK: mitogen-activated protein kinase/extracellular signal regulated kinases; NGS: next-generation sequencing; ncRNAs: non-coding RNAs; OvC: ovarian cancer; PI3K/Akt/mTOR: phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin; RT-PCR: real-time polymerase chain reaction; SNP: single nucleotide polymorphism; TF: transcription factor; TGF-beta: transforming growth factor-beta. PMID- 28574784 TI - Effects of Salinity on Sperm Motility, Fertilization, and Development in the Pacific Herring, Clupea pallasi. AB - We investigated the effects of salinity on fertilization and early development in a population of Pacific herring, Clupea pallasi, that migrate from oceanic waters into the San Francisco Bay estuary to spawn. The salinity range for fertilization fell between 8 and 28 ppt, with an optimal range of about 12 to 24 ppt. In comparison, the range for a population of C. harengus membras (Airisto Sound, Finland) that reside year-round in the Baltic Sea was 4 to 24 ppt. Roles for both Na+ and K+ were indicated in C. pallasi fertilization since increasing Na+ in the presence of 10 mM K+ (concentration of seawater) mimicked the effects of increased overall salinity, whereas reduced effects were obtained if [K+] was held at 5 mM (that of half-strength seawater). The initiation of C. pallasi sperm motility by components of the egg chorion, a prerequisite for fertilization, was inhibited at both elevated (28 and 32 ppt) and reduced (4 and 8 ppt) salinities. Embryonic development through larval hatching in C. pallasi exhibited a salinity tolerance similar to that of fertilization; optimum development was obtained at salinities between 8 and 24 ppt. A comparison of developmental progression in 3.5, 14, and 28 ppt seawater revealed that salinity effects became evident during the post-gastrulation stages of development and that progression to hatching was delayed in both the lower and higher salinities for those embryos that completed development. PMID- 28574785 TI - Recovery of Claw Size and Function Following Autotomy in Cancer productus (Decapoda: Brachyura). AB - We examined recovery of claw size and function following autotomy in red rock crabs Cancer productus. We also tested for costs of regeneration to growth and documented the frequency of claw injury in C. productus populations in Barkley Sound, Canada. Field and laboratory results indicated that crabs required at least three molts to recover a full-length cheliped. For injured crabs, regenerating claws were significantly less powerful than contralateral, normal (i.e., uninjured) claws even two instars after autotomy. Greater mechanical advantage in normal claws of injured (versus uninjured) crabs, however, suggests some morphological response by the remaining normal claw to increased exercise. Despite this compensatory response, our experiments indicate that injured crabs remain at a significant disadvantage while foraging. After adjusting for differences in propodus length, both regenerating and normal claws of injured crabs delivered significantly lower crushing forces than did claws of intact crabs. Energetic costs, in the form of reduced body size increase at the molt, were detected only for crabs regenerating both claws. High incidences of single claw loss in C. productus in Barkley Sound, together with our experimental data, suggest that much of the population experiences a prolonged foraging handicap following injury. PMID- 28574786 TI - Temperature and Embryonic Development in Relation to Spawning and Field Occurrence of Larvae of Three Antarctic Echinoderms. AB - The effects of temperature on development and viability were measured at 14 levels between -2{deg}C and +3{deg}C on embryos of two asteroids (Odontaster validus and Odontaster meridionalis) and an echinoid (Sterechinus neumayeri) from Signy Island, Antarctica. Development rates were 2 to 10 times slower than those for temperate or tropical echinoderms, with times to hatching up to 240 h. Development rates for the two asteroids differed by 1.15 x, and rates for both species approximately doubled over the experimental temperature range. In O. validus, embryo viability was independent of temperature, but in O. meridionalis viability declined with increasing temperature. Development rates for S. neumayeri were little affected by temperature above +0.2{deg}C, but declined rapidly at lower temperatures. Conversely, the number of nonviable eggs was low and constant below +1.7{deg}C, but rose rapidly at higher temperatures. A window of optimal temperature, between +0.2{deg}C and +1.7{deg}C, has therefore been proposed for development time and embryo viability in this population of S. neumayeri. Spawning trials and field observations of larvae indicated that the time of gamete release and periods of larval development in S. neumayeri coincided with austral summer sea temperatures in the same window. Embryos of O. meridionalis and O. validus are released in winter, when temperatures are constantly below -1.6{deg}C. Comparison of the different strategies suggests that larval food supply and predation during planktonic phases are not the dominant ecological factors for these species. PMID- 28574787 TI - Neural Control of the Lateral Abdominal Arterial Valves in the Lobster Homarus americanus. AB - A dorsal abdominal artery in Homarus americanus runs the length of the abdomen, giving rise to one pair of large lateral arteries in each segment. These lateral arteries supply hemolymph to the abdominal muscles and the swimmerets. In addition, many small vessels leave the dorsal abdominal artery ventrolaterally to supply the gut and gonads. Bicuspid muscular valves are located at the junction of each segmental lateral artery with the dorsal abdominal artery, but not at the origin of the gut vessels. Nerves originating from the ventral abdominal ganglia travel along the lateral arteries to innervate the valves, providing both inhibitory and excitatory inputs. Inhibitory input produces hyperpolarizing inhibitory junctional potentials that relax the valve muscles, and in intact in situ perfused arteries causes increases in outflow from the affected lateral artery. Excitatory input produces depolarizing excitatory junctional potentials that close the valves and reduce perfusate outflow. The valve nerves also branch to innervate valves up to two segments anterior and one segment posterior. Application of exogenous {gamma}-aminobutyric acid hyperpolarizes valve muscle fibers. This and the hyperpolarizing effect of valve nerve stimulation are reversibly abolished by the application of picrotoxin (10-5 M). Acetylcholine (10 5 M), but not glutamate, causes depolarization and contraction of valves. The role of the valves in controlling the distribution of hemolymph flow is discussed. PMID- 28574788 TI - Comparative Analysis of Escape Behavior in Male, and Gravid and Non-Gravid, Female Lobsters. AB - Few studies exist in which the parameters of a single behavior have been quantitatively compared for male and female lobsters. Here, we have examined the effects of sex and gravidity on the parameters of the escape behavior of the American lobster, Homarus americanus, elicited by a visual threat. Both non gravid females and male lobsters readily tailflipped in response to the stimulus, but gravid females failed, with one exception, to initiate a swim, even when stimulus strength was increased. Although the total distance swum by males and non-gravid females was not statistically different, males covered more ground in the initial power swim and during the subsequent swims than did non-gravid females. Males swam for a longer time, performing more tailflips, than females. Relative to their length and weight, males swam a greater distance at each stroke during the initial power swim and the subsequent swims, although, females might have compensated by swimming at a higher frequency. There were no significant differences in swimming velocity or acceleration, nor in the calculated force or work performed by the two sex classes (male and non-gravid females). Therefore, apart from egg-bearing, which severely inhibits the escape response, it remains to be seen whether the subtle physiological and anatomical sexual dimorphism that produces longer and more swim strokes in males but higher frequency tailflips in females results in the same chances of survival for the sexes. PMID- 28574789 TI - A Protein Identical to the Yolk Protein Is Stored in the Testis in Male Red Sea Urchin, Pseudocentrotus depressus. AB - Female sea urchins store the major yolk protein (MYP) in ovarian nutritive phagocytes before vitellogenesis. Using immunological procedures, we detected MYP in the testicular nutritive phagocytes of Pseudocentrotus depressus, the red sea urchin, and then compared the distribution of MYP between sexes during gametogenesis. MYP was purified from unfertilized eggs by ion exchange chromatography (Q Sepharose) and gel filtration (Superdex 200), and an antiserum (anti-MYP) was raised against MYP. Immunoblot analysis demonstrated that immature testes, as well as ovaries, contained a large quantity of MYP. Immunohistochemistry showed that MYP was distributed in the nutritive phagocytes occupying the follicular lumen in both males and females. In both sexes, as gametogenesis proceeded, the nutritive phagocytes degenerated and the gonadal lumen filled with gametes. MYP accumulated in ripe ova as a yolk protein in the mature ovary. In contrast, MYP was not detected in mature testes, because stored spermatozoa did not react with anti-MYP. We conclude that in male P. depressus, MYP is stored in the testicular nutritive phagocytes and utilized as the nutrient source for spermatogenesis. PMID- 28574790 TI - Chemical Fate of a Metamorphic Inducer in Larvae-like Buds of the Cnidarian Cassiopea andromeda. AB - Larvae-like vegetative buds of the scyphozoan Cassiopea andromeda metamorphose into polyps in the presence of oligopeptides that have a well-defined primary structure. Buds were incubated with the hexapeptide 14C-dansyl-GPGGPA, a representative inducer. Autoradiography of longitudinal sections of these buds revealed rapid internalization of peptide by the buds. Silver grain density was highest in the pre-pedal disc region (or aboral knob) of metamorphosing buds. Larvae and buds sporadically explore their habitat with this aboral knob, searching for a suitable solid substrate to which irreversible attachment will be made. Buds were incubated for 3, 8, or 16 h with 14C-dansyl-GPGGPA, then homogenized and the supernatants analyzed to determine the chemical fate of the inducer. The signal molecule was shown to be partly degraded to 14C-dansyl-GP, partly to 14C-dansyl-G, and in part still present in its original structure. These cleavage products were also found in the surrounding medium after an incubation time of 8 h with 14C-dansyl-GPGGPA, but did not induce metamorphosis. This study suggests that exposure of metamorphosis-inducing peptides to buds of Cassiopea andromeda results in signal termination. PMID- 28574791 TI - Distinctive Cytoskeletal Organization in Erythrocytes of the Cold-Seep Vesicomyid Clam, Calyptogena kilmeri. AB - Erythrocytes have long served as model cells, useful for analyzing cytoskeletal structure and function. In non-mammalian vertebrates, erythrocytes are typically highly flattened, nucleated ellipsoids in which a marginal band (MB) of microtubules interacts with the membrane skeleton (MS) to generate and maintain cell shape. Though relatively rare, erythrocytes also occur in representatives of many invertebrate phyla, including the arcid and vesicomyid molluscs, but the structure and function of these cells are not well understood. Previous work has shown arcid erythrocytes to be highly flattened ellipsoids containing the MB-MS cytoskeletal system, similar to vertebrates but with an additional interesting feature: a functional centriole-containing centrosome associated with each MB. In the present study we have examined, for the first time, erythrocyte morphology and cytoskeletal structure in a vesicomyid. Using Calyptogena kilmeri, the dominant invertebrate at many Pacific cold seeps, we have found that the erythrocytes are only slightly flattened and do not contain MBs. Rather, their cytoskeletons display a peripheral centriole-containing centrosome with radiating fibers, a distinctive type of organization not observed previously in mature erythrocytes from any species. PMID- 28574792 TI - Stimulation of Metamorphosis in the Polychaete Hydroides elegans Haswell (Serpulidae). AB - The serpulid polychaete Hydroides elegans is a common, cosmopolitan warm-water biofouling organism. Competent larvae of H. elegans metamorphose rapidly after induction by marine biofilms. Only 15 min after coming in contact with the metamorphic cue, larvae have completed secretion of the primary tube; secretion of the secondary, calcareous tube begins 1.5 h after the primary tube has been deposited. Metamorphosis is characterized by disappearance of the prototroch and differentiation of the tentacular crown in the head region, the collar and thoracic membrane in the thoracic region, and the pygidium at the tip of the abdomen. These morphogenetic events were used to gauge the responses of larvae to biofilms, as well as to the artificial inducers Cs+ and K+. A maximal metamorphic response to the two ions requires exposure to different concentrations and durations, i.e., a 3-h pulse of 10 mM CsCl, or a 24-h continuous exposure to 50 mM excess KCl. The metamorphic response to Cs+ or K+ is much slower than the response to biofilms, demonstrating that the tissues respond differently to artificial inducers. The differences in the kinetics of the responses to the natural and cationic inducers suggest that the induction mechanisms are not the same. When these artificial inducers were used, some, but not all, of the metamorphosed juveniles never attached to the substratum or secreted a primary tube, probably as a result of secondary effects of the ions on processes of tube formation. The exact mechanisms by which Cs+ and excess K+ induce metamorphosis are still unclear, although we assume, as do others, that these agents act by depolarizing the membranes of excitable sensory cells and not by interacting with specific receptors. PMID- 28574793 TI - Automated Cell Culture Systems and Their Applications to Human Pluripotent Stem Cell Studies. AB - Pluripotent stem cells are an extremely powerful tool in modeling human diseases and hold much promise for personalized regenerative or cell replacement therapies. There is an increasing need for reproducible large-scale stem cell and differentiated progeny production, with minimal variation, rendering manual approaches impracticable. Here, we provide an overview of systems currently available for automated stem cell culture, and undertake a review of their capacities, capabilities, and relative limitations. With the merging of modern technology and stem cell biology, an increased demand and implementation of automated platforms for stem cell studies is anticipated. PMID- 28574796 TI - Introduction to a special grouping of papers from the 2016 A&WMA Specialty Conference, Guideline on Air Quality Models: The New Path. PMID- 28574797 TI - What Do I Do Now? PMID- 28574794 TI - Health-care utilization and associated factors in Gauteng province, South Africa. AB - BACKGROUND: More than a billion people, mainly in low- and middle-income countries, are unable to access needed health-care services for a variety of reasons. Possible factors influencing health-care utilization include socio demographic and economic factors such as age, sex, education, employment and income. However, different studies have showed mixed results. Moreover, there are limited studies on health-care utilization. OBJECTIVE: This study aimed to determine health-care utilization and associated factors among all residents aged 18 or over in Gauteng province, South Africa. METHODS: A cross-sectional study was conducted from data collected for a Quality of Life survey which was carried out by Gauteng City-Region Observatory in 2013. Simple random sampling was used to select participants. A total of 27,490 participants have been interviewed. Data were collected via a digital data collection instrument using an open source system called Formhub. Coarsened Exact Matching (CEM) was used to improve estimation of causal effects. Stepwise multiple logistic regression was employed to identify factors associated with health-care utilization. RESULTS: Around 95.7% reported usually utilizing health-care services while the other 4.3% reported not having sought health-care services of any type. Around 75% of participants reported reduced quality of public health services as a major reason not to visit them. Higher odds of reported health-care utilization were associated with being female (OR = 2.18, 95% CI: 1.88-2.53; p < 0.001), being White compared to being African (OR = 2.28, 95% CI: 1.84-2.74; p < 0.001), and having medical insurance (OR = 5.41, 95% CI: 4.06-7.23; p < 0.001). Lower odds of seeking health-care were associated with being an immigrant (OR = 0.61, 95% CI: 0.53-0.70; p < 0.001). CONCLUSIONS: The results indicated that there is a need to improve the quality of public health-care services and perception towards them as improved health-care quality increases the choice of health-care providers. PMID- 28574798 TI - Demographic factors, mental health problems, and psychosocial resources influence women's AIDS risk. AB - The aim of this study was to examine how depressive mood, posttraumatic stress disorder (PTSD) symptoms, self-efficacy, and social support are associated with HIV risk behaviors. Participants were sexually active women (N = 1488) recruited when attending gynecological consultations in primary care settings. Standardized questionnaires were administered to assess for depressive mood, abuse/assault related PTSD, social support, self-efficacy, stress, and sexual risk behavior. The resulting association models showed that demographic factors, mental health problems, and resources are associated with sexual risk behavior. Detecting and treating mental health problems and interventions that bolster women's psychosocial resources are warranted. PMID- 28574799 TI - A novel entecavir analogue constructing with a spiro[2.4]heptane core structure in the aglycon moiety: Its synthesis and evaluation for anti-hepatitis B virus activity. AB - Synthesis of a novel 2'-deoxy-guanine carbocyclic nucleoside 4 constructed with spiro[2.4]heptane core structure in the aglycon moiety was carried out. Radical mediated 5-exo-dig mode cyclization and following cyclopropanation proceeded efficiently to furnish the spiro alcohol 10. Subsequent Mitsunobu-type glycosylation between 13 and 14, deoxygenation of the 2'-hydroxyl group of 16 and deprotection of 17 gave the title compound 4. Compound 4 demonstrated moderate anti-HBV activity (EC50 value of 0.12 +/- 0.02 uM) and no cytotoxicity against HepG2 cells was observed up to 100 uM. PMID- 28574800 TI - Nursing Staff Stress and Individual Characteristics in Relation to the Ward Atmosphere in Psychiatric In-Patient Wards. AB - This study investigated the interplay between nursing staff stress, Mastery, Moral Sensitivity, individual characteristics and the ward atmosphere in psychiatric in-patient care. Data were collected through five questionnaires from 93 nursing staff. Multivariate analysis showed that Moral Strength, Moral Burden, Internal Demands, Perceived Stress and age were related to several factors of the ward atmosphere. We conclude that efforts to reduce stress levels and create a supporting ethical climate on psychiatric wards would be beneficial for both psychiatric nursing staff and their nursing practice. PMID- 28574801 TI - Direct Gallbladder Indocyanine Green Injection Fluorescence Cholangiography During Laparoscopic Cholecystectomy. AB - BACKGROUND: Intravenous injection of indocyanine green (ICG) is used to illuminate extrahepatic biliary anatomy. Fluorescence of biliary structures may lower surgical complications that can arise due to inadvertent injury to the common bile duct. We describe a method of injecting ICG directly into the gallbladder to define the cystic duct and common bile duct anatomy. MATERIALS AND METHODS: A standard laparoscopic cholecystectomy was performed using a laparoscope with near-infrared imaging capability. Before dissection, the gallbladder was punctured with a cholangiogram catheter or a pigtail catheter to aspirate the bile within the gallbladder. The aspirated bile is mixed with ICG solution, which is reinjected into the gallbladder to fluoresce the gallbladder, cystic duct, and common bile duct structures. RESULTS: Eleven patients underwent direct gallbladder ICG injection for fluorescence cholangiography during cholecystectomy. Direct gallbladder ICG injection clearly defined the extrahepatic biliary anatomy, including the cystic duct-common bile duct junction, by fluorescence. In addition, the dissection plane between the gallbladder and the liver is highlighted with the gallbladder ICG fluorescence. CONCLUSIONS: Direct gallbladder ICG injection provides immediate visualization of extrahepatic biliary structures and clarifies the dissection plane between the gallbladder and the liver bed. PMID- 28574802 TI - Health Reform and the Substance Use Disorder Treatment System: A Time of Change. PMID- 28574803 TI - Noise characterization of oil and gas operations. AB - In cooperation with The Colorado Oil and Gas Conservation Commission, researchers at Colorado State University performed area noise monitoring at 23 oil and gas sites throughout Northern Colorado. The goals of this study were to: (1) measure and compare the noise levels for the different phases of oil and gas development sites; (2) evaluate the effectiveness of noise barriers; and (3) determine if noise levels exceeded the Colorado Oil and Gas Conservation Commission noise limits. The four phases of oil and gas development include drilling, hydraulic fracturing, completion and production. Noise measurements were collected using the A- and C-weighted sound scales. Octave band analysis was also performed to characterize the frequency spectra of the noise measurements. Noise measurements were collected using noise dosimeters and a hand-held sound-level meter at specified distances from the development sites in each cardinal direction. At 350 ft (107 m), drilling, hydraulic fracturing, and completion sites without noise barriers exceeded the maximum permissible noise levels for residential and commercial zones (55 dBA and 60 dBA, respectively). In addition, drilling and hydraulic fracturing sites with noise barriers exceeded the maximum permissible noise level for residential zones (55 dBA). However, during drilling, hydraulic fracturing, and completion operations, oil producers are allowed an exception to the noise permissible limits in that they only must comply with the industrial noise limit (80 dBA). It is stated in Rule 604.c.(2)A. that: "Operations involving pipeline or gas facility installation or maintenance, the use of a drilling rig, completion rig, workover rig, or stimulation is subject to the maximum permissible noise levels for industrial zones (80dBA)." [8] Production sites were within the Colorado Oil and Gas Conservation Commission permissible noise level criteria for all zones. At 350 ft (107 m) from the noise source, all drilling, hydraulic fracturing, and completion sites exceeded 65 dBC. Current noise wall mitigation strategies reduced noise levels in both the A- and C weighted scale measurements. However, this reduction in noise was not sufficient to reduce the noise below the residential permissible noise level (55 dBA). PMID- 28574804 TI - The Best of Times. AB - I came of age as a nutrition scientist during the best of times-years that spanned a rapidly changing world of food and nutrition science, politics, and policy that greatly broadened the specialty and its influence on public affairs. I followed the conventional route in academe, working my way up the academic ladder in Boston from a base first in a school of public health and later in a teaching hospital and medical school, interspersed with stints in Washington, DC. Thus I tell a tale of two cities. Those were the best of times because nutrition science and policy converged and led to important policies and programs that shaped the field for the next 50 years. PMID- 28574805 TI - The Development of FVIII Inhibitors in Relation to IL10 Gene Polymorphism in Hemophilia A Egyptian Pediatric Patients. AB - BACKGROUND: Development of inhibitors against Factor VIII (FVIII) in hemophilia A patients is a serious complication of therapy. Many cytokines, including interleukin-10 (IL10), may affect inhibitor development; however, literature data are not sufficient to prove this association. The aim of this study was to investigate the relation between FVIII inhibitor formation and IL10-1082A/G polymorphism among Egyptian hemophiliacs. METHODS: Patients were screened for FVIII inhibitors using the Bethesda method. IL10-1082A/G polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Six patients (12%) developed inhibitors. No statistically significant difference was found between inhibitor positive and negative patients regarding IL10-1082A/G genotypes, disease severity, or treatment-related variables (type of FVIII received, treatment regimen, age at first exposure to FVIII, and frequency of replacement therapy). CONCLUSIONS: FVIII inhibitor formation in this group of Egyptian hemophiliacs was not correlated to IL10-1082A/G polymorphism, disease severity, or any of the treatment variables. PMID- 28574806 TI - Free Fatty Acids of Newborns from Women with Gestational Diabetes Mellitus. AB - INTRODUCTION: Fetal macrosomia in gestational diabetes mellitus is contributed to by compensatory fetal mechanisms responding to alterations in maternal metabolism. OBJECTIVES: To compare FFA and blood glucose concentrations of newborns derived from healthy and hyperglycemic mothers. METHODS: Prospective study included two equal groups of term newborns (50) from GDM and healthy mothers. Blood was derived from umbilical and cubital vein of mothers immediately after birth. RESULTS: The mean FFA concentration of mothers did not differ whereas in infants of GDM mothers FFA were significantly lower. A significant correlation was found between FFA levels of healthy mothers and their newborns (p < 0.05). No such correlation was found in GDM group (p > 0.05). A significant correlation was found between mother's and newborn's glycemia (p < 0.05) in both groups. CONCLUSION: Suppression of FFA acids in newborn blood of mothers with GDM may represent the lipogenic and antilipolytic activity of the fetus. PMID- 28574807 TI - Genetic studies in a patient with X-linked retinoschisis coexisting with developmental delay and sensorineural hearing loss. AB - BACKGROUND: In this study, we present a juvenile retinoschisis patient with developmental delay, sensorineural hearing loss, and reduced axial tone. X-linked juvenile retinoschisis (XLRS) is a retinal dystrophy, most often not associated with systemic anomalies and also not showing any locus heterogeneity. Therefore it was of interest to understand the genetic basis of the condition in this patient. MATERIALS AND METHODS: RS1 gene screening for XLRS was performed by Sanger sequencing. Whole genome SNP 6.0 array analysis was carried out to investigate gross chromosomal aberrations that could result in systemic phenotype. In addition, targeted next generation sequencing (NGS) was employed to determine any possible involvement of X-linked syndromic and non-syndromic mental retardation genes. This NGS panel consisted of 550 genes implicated in several other rare inherited diseases. RESULTS: RS1 gene screening revealed a pathogenic hemizygous splice site mutation (c.78+1G>T), inherited from the mother. SNP 6.0 array analysis did not indicate any significant chromosomal aberrations that could be disease-associated. Targeted resequencing did not identify any mutations in the X-linked mental retardation genes. However, variations in three other genes (NSD1, LARGE, and POLG) were detected, which were all inherited from the patient's unaffected father. CONCLUSIONS: Taken together, RS1 mutation was found to segregate with retinoschisis phenotype while none of the other identified variations were co-segregating with the systemic defects. Hereby, we infer that the multisystemic defects harbored by the patient are a rare coexistence of XLRS, developmental delay, sensorineural hearing loss, and reduced axial tone reported for the first time in the literature. PMID- 28574808 TI - Fetal Cardiac US: Techniques and Normal Anatomy Correlated with Adult CT and MR Imaging. AB - Congenital heart disease (CHD) is an important cause of childhood mortality. Despite the widespread use of ultrasonography (US) as a screening tool, the prenatal detection rate is suboptimal. Improvement of the initial screening examination, which is performed in low-risk populations and often interpreted by community radiologists, targets a point in the screening process that is likely to have the largest population effect. If the goal of community-based screenings is to detect cases that may be abnormal and refer those to specialized centers for complete assessment, it is logical to use a checklist to confirm normal anatomy. This article presents a stepwise process to evaluate fetal cardiac anatomy using comparison with computed tomography (CT) and magnetic resonance (MR) images, which are more familiar to radiologists in busy general practices. In addition, this article presents a checklist for assessment of the four-chamber view and demonstrates the expected normal appearance of the outflow tract views as well as the additional views required for complex obstetric US. These additional views include the aortic arch and bicaval views, three-vessel view (3VV), and three-vessel trachea view (3TV). CHD may be isolated, but it may indicate aneuploidy or a syndrome that, if present, determines the prognosis. In isolated CHD, the prognosis is determined by the exact nature of the abnormalities. In particular, duct-dependent disease if undiagnosed results in circulatory collapse in the infant once the ductus closes. If the heart does not look normal, the patient should be referred for detailed evaluation. Timely diagnosis of significant CHD allows for development of a personalized pregnancy management plan. (c) RSNA, 2017. PMID- 28574810 TI - What Happens to High-Cost Patients? An Analysis of the Trajectories of Billed Charges Over Time. AB - A growing literature documents the substantial burden that a small proportion of high-cost, medically complex patients impose on health care systems. However, it is not clear whether high-cost patients remain costly over time. This study looks at the monthly distribution of billed charges for a cohort of high-cost, medically complex patients enrolled in an intensive care management program in a university health care system, and finds that the billing trajectory is heterogeneous and highly nonlinear, characterized by a substantial spike in billed charges prior to identification, followed by a considerable drop prior to enrollment and a sustained drop thereafter. The conclusion is that many high-cost patients experience costly events that resolve without intensive case management. These results also suggest that interventions should target only those high-cost patients with expected continued high cost and that pre-post study designs may overstate the impact of interventions for high-cost, medically complex patients. PMID- 28574809 TI - Testicular Seminoma and Its Mimics: From the Radiologic Pathology Archives. AB - Testicular seminoma is the most common malignant tumor of the testis. It classically manifests as a painless mass. Radiologic evaluation with high frequency ultrasonography (US) is critical for diagnosis. Seminomas are usually homogeneously hypoechoic masses at US. In challenging cases, magnetic resonance (MR) imaging may help confirm that a mass is intratesticular and provide data for local staging. Computed tomography (CT) provides valuable information for staging, including the presence and size of retroperitoneal lymph nodes. Testicular seminoma is treated with radical inguinal orchiectomy and is highly curable even at advanced stages of disease. Several neoplastic and nonneoplastic conditions may mimic testicular seminoma at imaging. Benign mimics include segmental infarction, hematoma, infection, epidermoid cyst, adrenal rests, sarcoidosis, splenogonadal fusion, and sex cord-stromal tumors. Malignant mimics include nonseminomatous germ cell tumors, lymphoma, and metastases. These conditions are individually reviewed with emphasis on features that allow differentiation from seminoma. Spermatocytic tumor, formerly known as spermatocytic seminoma, accounts for only 1% of testicular tumors. It is distinct from classic seminoma, with unique histologic, molecular, and genetic features. It affects an older patient population than classic seminoma and demonstrates indolent clinical behavior. Radiologists serve a key role in diagnosis, staging, and surveillance of patients with seminoma. A thorough knowledge of related clinical, radiologic, and pathologic findings will help the radiologist contribute to high-quality interdisciplinary care of affected patients. PMID- 28574812 TI - Associations between APOE genotype and cerebral small-vessel disease: a longitudinal study. AB - OBJECTIVE: It remains unclear if and how the interactions between APOE genotypes and cerebral small-vessel diseases (CSVD) lead to cognitive decline in the long term. Based on ADNI cohort, this longitudinal study aimed to clarify the potential relationship among APOE genotype, CSVD and cognition by integrating multi-level data. METHOD: There were 135 healthy elderly (including epsilon2, epsilon4 allele carriers and epsilon3 homozygotes) who had completed two years' follow-up. MRI markers of CSVD, including white matter hyperintensities (WMH), dilated perivascular space (dPVS), microbleeds and lacune, were assessed. Besides, neuropathological factors including Alzheimer's disease-related pathology measured by CSF and PiB-PET were assessed. Repeated measurements ANOVAs were performed to test impact of different APOE genotypes on CSVD. RESULTS: We found that APOE epsilon4 carriers had significantly more frontal WMH burden and basal ganglia dPVS at baseline and faster progression of frontal WMH burden during follow-up. Furthermore, our results showed that APOE epsilon4 carriers had significantly decreased Abeta1-42 level, and its level was negatively related with baseline and progressive total WMH burden. Then, general linear modals indicated interaction between basal frontal WMH burden and epsilon4 allele was related with declining trend of cognition. CONCLUSION: Our findings suggested APOE epsilon4 allele was associated with increased Abeta deposition, which may lead to the formation and progression of WMH, especially in frontal lobe. Besides, interaction between the increased frontal WMH burden and epsilon4 allele can exert long-term detrimental effects on individual's trajectory of cognition. PMID- 28574816 TI - Prediction of cervical cancer recurrence using textural features extracted from 18F-FDG PET images acquired with different scanners. AB - OBJECTIVES: To identify an imaging signature predicting local recurrence for locally advanced cervical cancer (LACC) treated by chemoradiation and brachytherapy from baseline 18F-FDG PET images, and to evaluate the possibility of gathering images from two different PET scanners in a radiomic study. METHODS: 118 patients were included retrospectively. Two groups (G1, G2) were defined according to the PET scanner used for image acquisition. Eleven radiomic features were extracted from delineated cervical tumors to evaluate: (i) the predictive value of features for local recurrence of LACC, (ii) their reproducibility as a function of the scanner within a hepatic reference volume, (iii) the impact of voxel size on feature values. RESULTS: Eight features were statistically significant predictors of local recurrence in G1 (p < 0.05). The multivariate signature trained in G2 was validated in G1 (AUC=0.76, p<0.001) and identified local recurrence more accurately than SUVmax (p=0.022). Four features were significantly different between G1 and G2 in the liver. Spatial resampling was not sufficient to explain the stratification effect. CONCLUSION: This study showed that radiomic features could predict local recurrence of LACC better than SUVmax. Further investigation is needed before applying a model designed using data from one PET scanner to another. PMID- 28574817 TI - Intravoxel incoherent motion diffusion-weighted MR imaging parameters predict pathological classification in thymic epithelial tumors. AB - We evaluated the performance of intravoxel incoherent motion (IVIM) parameters for preoperatively predicting the subtype and Masaoka stage of thymic epithelial tumors (TETs). Seventy-seven patients with pathologically confirmed TETs underwent a diffusion weighted imaging (DWI) sequence with 9 b values. Differences in the slow diffusion coefficient (D), fast perfusion coefficient (D*), and perfusion fraction (f) IVIM parameters, as well as the multi b-value fitted apparent diffusion coefficient (ADCmb), were compared among patients with low-risk (LRT) and high-risk thymomas (HRT) and thymic carcinomas (TC), and between early stage (stages I and II) and advanced stage (stages III and IV) TET patients. ADCmb, D, and D* values were higher in the LRT group than in the HRT or TC group, but did not differ between the HRT and TC groups. The mean ADCmb, D, and D* values were higher in the early stage TETs group than the advanced stage TETs group. The f values did not differ among the groups. These results suggest that IVIM DWI could be used to preoperatively predict subtype and Masaoka stage in TET patients. PMID- 28574818 TI - Characterization of the release and biological significance of cell-free DNA from breast cancer cell lines. AB - In breast cancer, cell-free DNA (cfDNA) has been proven to be a diagnostic and prognostic biomarker. However, there have been few studies on the origin and biological significance of cfDNA. In this study, we assessed the release pattern of cfDNA from breast cancer cell lines under different culture conditions and investigated the biological significance of cfDNA. The cfDNA concentration increased rapidly (6 h) after passage, decreased gradually, and was then maintained at a relatively stable level after 24 h. In addition, the cfDNA concentration did not correlate with the amount of apoptotic and necrotic cells. Interestingly, if more cells were in the G1 phase, more cfDNA was detected (p < 0.01) and the cfDNA concentration correlated positively with the percent of cells in the G1 phase (p < 0.05). We observed that cells could release cfDNA actively, but not exclusively, via exosomes. Furthermore, we showed that cfDNA could stimulate hormone receptor-positive breast cancer cell proliferation by activating the TLR9-NF-kappaB-cyclin D1 pathway. In conclusion, cfDNA is released from breast cancer mainly by active secretion, and cfDNA could stimulate proliferation of breast cancer cells. PMID- 28574820 TI - Differentiation capacities of skeletal muscle satellite cells in Lantang and Landrace piglets. AB - We isolated and cultured satellite cells (SCs) from the longissimus dorsi muscles of 1-day-old male Landrace and Lantang piglets to compare the SC differentiation capacity in the two breeds. Lantang piglets yielded more (P < 0.05) SCs per gram of muscle than Landrace piglets (5.2 +/- 0.9*104 vs. 2.4 +/- 0.2*104). Transcription of the differentiation markers myogenin and myosin heavy chain I (MyHC I) in the longissimus dorsi muscle was higher in Lantang than Landrace piglets (P < 0.05). Protein levels of myogenin (P < 0.05), MyHC I (P < 0.05), and myogenic regulatory factor 4 (P = 0.07) were higher in Lantang than Landrace piglet SCs after 72 h of differentiation. Creatine kinase activity was higher in Lantang than Landrace piglet SCs after 24, 48, and 72 h of differentiation (P < 0.05), and there was a greater fusion index in Landrace piglet SCs after 72 h of differentiation. In addition, phosphorylation of Akt, mTOR, S6K1, S6, and 4EBP1 was lower in Lantang than Landrace piglet SCs (P < 0.05). Thus differentiation was more extensive in Lantang than Landrace piglet SCs, but expression of the mTOR signaling pathway was lower in Lantang piglet SCs, suggesting mTOR signaling may inhibit myogenic differentiation. These findings reveal that mTOR signaling is a factor in myogenesis and imply that mTOR could potentially serve as an activator of myoblast differentiation and muscle regeneration. PMID- 28574825 TI - Dimethyl fumarate reduces the risk of mycotoxins via improving intestinal barrier and microbiota. AB - The effects of dimethyl fumarate (DMF) on mycotoxins and animal growth performance are well documented. However, its mechanism of anti-mildew effects is still unknown. The current study investigated how DMF detoxified the mycotoxin and improved the growth performance using BALB/c mice model, especially its effects on intestinal barrier function and gut micro-ecology. Our study also compared with the ultraviolet radiation (UR) treatment, a traditional anti-mildew control (TC). The results indicated that the DMF treatment had a lower contents of mycotoxin, better growth performance and improved mucosal morphology (P < 0.05), accompanied with the decreased intestinal permeability and the tighter gut barrier. Moreover, the efficiency of DMF was better than TC (P < 0.05). 16S rRNA gene sequence analysis revealed that the richness and diversity of bacteria was increased in DMF treatment. The most abundant OTUs belonged to Firmicutes and Bacteroidetes, and their changes in DMF were more moderate than the TC group, suggesting a more stable micro-ecology and the positive impact of DMF on the biodiversity of intestine. Specifically, the increased abundance of bacteria producing short-chain fatty acids (SCFAs), such as Gemella, Roseburia, Bacillus and Bacteroides in DMF group and prebiotics such as Lactobacillus in TC group, suggested a more healthier microbial composition and distribution. These findings supported that DMF had significant effects on animal's growth performance and intestinal barrier function by modulating the pathway of nutrient absorption and increasing the diversity and balance of gut microbes, which also illuminate that DMF is more efficient than traditional anti-mildew method. PMID- 28574821 TI - The effect of thermal dose on hyperthermia-mediated inhibition of DNA repair through homologous recombination. AB - Hyperthermia has a number of biological effects that sensitize tumors to radiotherapy in the range between 40-44 degrees C. One of these effects is heat induced degradation of BRCA2 that in turn causes reduced RAD51 focus formation, which results in an attenuation of DNA repair through homologous recombination. Prompted by this molecular insight into how hyperthermia attenuates homologous recombination, we now quantitatively explore time and temperature dynamics of hyperthermia on BRCA2 levels and RAD51 focus formation in cell culture models, and link this to their clonogenic survival capacity after irradiation (0-6 Gy). For treatment temperatures above 41 degrees C, we found a decrease in cell survival, an increase in sensitization towards irradiation, a decrease of BRCA2 protein levels, and altered RAD51 focus formation. When the temperatures exceeded 43 degrees C, we found that hyperthermia alone killed more cells directly, and that processes other than homologous recombination were affected by the heat. This study demonstrates that optimal inhibition of HR is achieved by subjecting cells to hyperthermia at 41-43 degrees C for 30 to 60 minutes. Our data provides a guideline for the clinical application of novel combination treatments that could exploit hyperthermia's attenuation of homologous recombination, such as the combination of hyperthermia with PARP-inhibitors for non-BRCA mutations carriers. PMID- 28574826 TI - Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)- induced lymphoproliferative disease and lytic viral replication. AB - EBV infection causes mononucleosis and is associated with specific subsets of B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced lymphoproliferative disease (LPD), which can be fatal. Leflunomide (a drug used to treat rheumatoid arthritis) and its active metabolite teriflunomide (used to treat multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation. Leflunomide also inhibits the replication of cytomegalovirus and BK virus via both "on target" and "off target" mechanisms and is increasingly used to treat these viruses in organ transplant recipients. However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown. We show that teriflunomide inhibits cellular proliferation, and promotes apoptosis, in EBV transformed B cells in vitro at a clinically relevant dose. In addition, teriflunomide prevents the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model. Furthermore, teriflunomide inhibits lytic EBV infection in vitro both by preventing the initial steps of lytic viral reactivation, and by blocking lytic viral DNA replication. Leflunomide/teriflunomide might therefore be clinically useful for preventing EBV induced LPD in patients who have high EBV loads yet require continued immunosuppression. PMID- 28574827 TI - Induction of immunoglobulin transcription factor 2 and resistance to MEK inhibitor in melanoma cells. AB - Primary or acquired resistance to MEK inhibitors has been a barrier to successful treatment with MEK inhibitors in many tumors. In this study, we analyzed genome wide gene expression profiling data from 6 sensitive and 6 resistant cell lines to identify candidate genes whose expression changes are associated with responses to a MEK inhibitor, selumetinib (AZD6244). Of 62 identified differentially expressed genes, we selected Immunoglobulin Transcription Factor 2, also known as transcription factor 4 as a potential drug resistance marker for further analysis. This was because the ITF-2 expression increase in resistant cell lines was relatively high and a previous study has suggested that ITF-2 functions as an oncogene in human colon cancers. We also established an AZD6244 resistant cell line (M14/AZD-3) from an AZD6244 sensitive M14 cell line. The expression of the ITF-2 was elevated both in primary AZD6244 resistant cell line, LOX-IMVI and acquired resistant cell line, M14/AZD-3. Targeted silencing of ITF-2 by siRNA significantly enhanced susceptibility to AZD6244 in resistant cells. Wnt/beta-catenin pathway was activated through direct interaction of p-ERK and GSK3beta. Our results suggest that up-regulation of the ITF-2 gene expression is associated with cellular resistance to MEK inhibitors, and activation of Wnt signaling pathway through interaction of p-ERK and GSK3beta seems to be a mechanism for increase of ITF-2. PMID- 28574828 TI - Targeting ERK enhances the cytotoxic effect of the novel PI3K and mTOR dual inhibitor VS-5584 in preclinical models of pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease in urgent need of newer therapeutic modalities. Majority of patients with PDAC have mutations in KRAS, which unfortunately remains an ineffectual target. Our strategy here is to target KRAS downstream effectors PI3K and mTOR. In this study, we investigated the antitumor efficacy of the novel PI3K and mTOR dual inhibitor VS-5584 in PDAC. Our data shows that PI3K/mTOR dual inhibition causes ERK activation in all tested PDAC cell lines. Although the MEK inhibitor GSK1120212 could abrogate VS-5584 induced ERK activation, it did not substantially enhance cell death in all the cell lines tested. However, combination with ERK inhibitor SCH772984 not only mitigated VS-5584-induced ERK activation but also enhanced VS-5584-induced cell death. In a xenograft model of PDAC, we observed 28% and 44% tumor inhibition for individual treatment with VS-5584 and SCH772984, respectively, while the combined treatment showed superior tumor inhibition (80%) compared to vehicle control treatment. Our findings support the clinical development of VS-5584 and ERK inhibitor combination for PDAC treatment. PMID- 28574829 TI - The impact of EpCAM expression on response to chemotherapy and clinical outcomes in patients with epithelial ovarian cancer. AB - Epithelial ovarian cancer is a highly lethal malignancy; moreover, overcoming chemoresistance is the major challenging in treating ovarian cancer patients. The cancer stem cell (CSC) hypothesis considers CSCs to be the main culprits in driving tumor initiation, metastasis, and resistance to conventional therapy. Although growing evidence suggest that CSCs are responsible for chemoresistance, the contribution of CSC marker EpCAM to resistance to chemotherapy remains unresolved.Here we have demonstrated that ovarian cancers containing high levels of EpCAM have a significantly much lower probability of achieving overall responsive rates after first-line chemotherapy. In addition, multivariate analysis revealed that EpCAM expression is an independent risk factor for chemoresistance, indicating that EpCAM expression is a predictive biomarker of chemotherapeutic response. Consistent with these clinical observations, in vitro assays, we found that the subpopulation of EpCAM-positive ovarian cancer cells shows a significantly higher viability compared with EpCAM-negative cells in response to cisplatin treatment by preventing chemotherapy-induced apoptosis, which is regulated by EpCAM-Bcl-2 axis. Furthermore, in an in vivo mouse model, platinum agents preferentially eliminated EpCAM-negative cells in comparison with EpCAM-positive cells, suggesting that the remaining subpopulation of EpCAM positive cells contributes to tumor recurrence after chemotherapy. Finally, we also found that an increased expression of EpCAM is associated with poor prognosis in ovarian cancer patients.Our findings highlight the clinical significance of EpCAM in the resistance to chemotherapy and provide a rationale for EpCAM-targeted therapy to improve chemoresistance. Targeting EpCAM should be a promising approach to effectively extirpate the CSCs as the putative root of ovarian cancer. PMID- 28574830 TI - Increased expression of long non-coding RNA CCEPR is associated with poor prognosis and promotes tumorigenesis in urothelial bladder carcinoma. AB - Recent emerging evidences have showed that long non-coding RNAs play important regulatory roles in diverse biological processes of tumor development and progression. CCEPR (cervical carcinoma expressed PCNA regulatory lncRNA) is a novel identified lncRNA that acts as a potential biomarker and involves in development and progression of cervical carcinoma. Nevertheless, we know nothing about the clinical significance and molecular mechanism of CCEPR in bladder cancer. In this study, we found that CCEPR was significantly up-regulated in bladder cancer. Furthermore, up-regulated CCEPR expression was positively correlated with advanced TNM stage and higher histological grade. Moreover, further experiments demonstrated that CCEPR promotes cell proliferation and suppresses cell apoptosis in bladder cancer. Mechanistically, we found CCEPR upregulates the expression of PCNA in mRNA and protein level to promote cancer growth. In conclusions, these findings demonstrated that CCEPR plays an important regulatory role in bladder cancer and may serve as a potential diagnostic biomarker and therapeutic target. PMID- 28574831 TI - EGF receptor lysosomal degradation is delayed in the cells stimulated with EGF Quantum dot bioconjugate but earlier key events of endocytic degradative pathway are similar to that of native EGF. AB - Quantum dots (QDs) complexed to ligands recognizing surface receptors undergoing internalization are an attractive tool for live cell imaging of ligand-receptor complexes behavior and for specific tracking of the cells of interest. However, conjugation of quasi-multivalent large QD-particle to monovalent small growth factors like EGF that bound their tyrosine-kinase receptors may affect key endocytic events tightly bound to signaling. Here, by means of confocal microscopy we have addressed the key endocytic events of lysosomal degradative pathway stimulated by native EGF or EGF-QD bioconjugate. We have demonstrated that the decrease in endosome number, increase in mean endosome integrated density and the pattern of EEA1 co-localization with EGF-EGFR complexes at early stages of endocytosis were similar for the both native and QD-conjugated ligands. In both cases enlarged hollow endosomes appeared after wortmannin treatment. This indicates that early endosomal fusions and their maturation proceed similar for both ligands. EGF-QD and native EGF similarly accumulated in juxtanuclear region, and live cell imaging of endosome motion revealed the behavior described elsewhere for microtubule-facilitated motility. Finally, EGF-QD and the receptor were found in lysosomes. However, degradation of receptor part of QD-EGF-EGFR complex was delayed compared to native EGF, but not inhibited, while QDs fluorescence was detected in lysosomes even after 24 hours. Importantly, in HeLa and A549 cells the both ligands behaved similarly. We conclude that during endocytosis EGF-QD behaves as a neutral marker for degradative pathway up to lysosomal stage and can also be used as a long-term cell marker. PMID- 28574832 TI - Impact of chronic unpredicted mild stress-induced depression on repaglinide fate via glucocorticoid signaling pathway. AB - Chronic unpredicted mild stress (CUMS)-induced depression could alter the pharmacokinetics of many drugs in rats, however, the underlying mechanism is not clear. In this work we studied the pharmacokinetics of repaglinide, and explored the role of glucocorticoid and adrenergic signaling pathway in regulating drug metabolizing enzymes (DMEs) in GK rats and BRL 3A cells. The plasma cortisol and epinephrine levels were increased, meanwhile the pharmacokinetics of repaglinide were altered significantly in depression model rats. Forty-nine genes in liver of model rats displayed significant difference comparing to control rats. The differentially expressed genes enriched in the drug metabolism and steroid hormone biosynthesis pathway significantly, and Nr1i3 matched 335 connectivity genes. CAR and Ugt1a1 protein expression were enhanced significantly in liver of model rats. The mRNA expression of Ugt1a1 and Nr1i2 were increased 2 and 4 times respectively with dexamethasone (DEX) and 8-Br-cAMP co-treatment in BRL 3A cells. The protein expression of PXR was up-regulated, too. However, RU486 reversed the up-regulated effect. The adrenergic receptor agonists had little impact on the DMEs in BRL 3A. Our data suggested that CUMS-induced depression might up-regulate DMEs expression via glucocorticoid signaling pathway, and accelerate the fate of the repaglinide in spontaneous diabetes rats. PMID- 28574833 TI - New interleukin-15 superagonist (IL-15SA) significantly enhances graft-versus tumor activity. AB - Interleukin-15 (IL-15) is a potent cytokine that increases CD8+ T and NK cell numbers and function in experimental models. However, obstacles remain in using IL-15 therapeutically, specifically its low potency and short in vivo half-life. To help overcome this, a new IL-15 superagonist complex comprised of an IL-15N72D mutation and IL-15RalphaSu/Fc fusion (IL-15SA, also known as ALT-803) was developed. IL-15SA exhibits a significantly longer serum half-life and increased in vivo activity against various tumors. Herein, we evaluated the effects of IL 15SA in recipients of allogeneic hematopoietic stem cell transplantation. Weekly administration of IL-15SA to transplant recipients significantly increased the number of CD8+ T cells (specifically CD44+ memory/activated phenotype) and NK cells. Intracellular IFN-gamma and TNF-alpha secretion by CD8+ T cells increased in the IL-15SA-treated group. IL-15SA also upregulated NKG2D expression on CD8+ T cells. Moreover, IL-15SA enhanced proliferation and cytokine secretion of adoptively transferred CFSE-labeled T cells in syngeneic and allogeneic models by specifically stimulating the slowly proliferative and nonproliferative cells into actively proliferating cells.We then evaluated IL-15SA's effects on anti-tumor activity against murine mastocytoma (P815) and murine B cell lymphoma (A20). IL 15SA enhanced graft-versus-tumor (GVT) activity in these tumors following T cell infusion. Interestingly, IL-15 SA administration provided GVT activity against A20 lymphoma cells in the murine donor leukocyte infusion (DLI) model without increasing graft versus host disease. In conclusion, IL-15SA could be a highly potent T- cell lymphoid growth factor and novel immunotherapeutic agent to complement stem cell transplantation and adoptive immunotherapy. PMID- 28574834 TI - The collagen receptor uPARAP/Endo180 as a novel target for antibody-drug conjugate mediated treatment of mesenchymal and leukemic cancers. AB - A key task in developing the field of personalized cancer therapy is the identification of novel molecular targets that enable treatment of cancers not susceptible to other means of specific therapy. The collagen receptor uPARAP/Endo180 is overexpressed by malignant cells in several non-epithelial cancers, notably including sarcomas, glioblastomas and subsets of acute myeloid leukemia. In contrast, in healthy adult individuals, expression is restricted to minor subsets of mesenchymal cells. Functionally, uPARAP/Endo180 is a rapidly recycling endocytic receptor that delivers its cargo directly into the endosomal lysosomal system, thus opening a potential route of entry into receptor-positive cells. This combination of specific expression and endocytic function appears well suited for targeting of uPARAP/Endo180-positive cancers by antibody-drug conjugate (ADC) mediated drug delivery. Therefore, we utilized a specific monoclonal antibody against uPARAP/Endo180, raised through immunization of a uPARAP/Endo180 knock-out mouse, which reacts with both the human and the murine receptor, to construct a uPARAP-directed ADC. This antibody was coupled to the highly toxic dolastatin derivative, monomethyl auristatin E, via a cathepsin labile valine-citrulline linker. With this ADC, we show strong and receptor dependent cytotoxicity in vitro in uPARAP/Endo180-positive cancer cell lines of sarcoma, glioblastoma and leukemic origin. Furthermore, we demonstrate the potency of the ADC in vivo in a xenograft mouse model with human uPARAP/Endo180 positive leukemic cells, obtaining a complete cure of all tested mice following intravenous ADC treatment with no sign of adverse effects. Our study identifies uPARAP/Endo180 as a promising target for novel therapy against several highly malignant cancer types. PMID- 28574838 TI - Histone modifications affect differential regulation of TGFbeta- induced NADPH oxidase 4 (NOX4) by wild-type and mutant p53. AB - Previously, we showed wild-type (WT) and mutant (mut) p53 differentially regulate reactive oxygen species (ROS) generation by NADPH oxidase-4 (NOX4): p53-WT suppresses TGFbeta-induced NOX4, ROS and cell migration, whereas tumor-associated mut-p53 proteins enhance NOX4 expression and cell migration. Here, we extended our findings on the effects of p53 on NOX4 in several tumors and examined the basis of NOX4 transcriptional regulation by p53 and SMAD3. Statistical analysis of expression data from primary tumors available from The Cancer Genome Atlas (TCGA) detected correlations between mut-p53 and increased NOX4 expression. Furthermore, by altering p53 levels in cell culture models we showed several common tumor-associated mutant forms support TGFbeta/SMAD3-dependent NOX4 expression. Deletion analysis revealed two critical SMAD3 binding elements (SBE) required for mut-p53-dependent NOX4 induction, whereas p53-WT caused dose dependent suppression of NOX4 transcription. ChIP analysis revealed SMAD3 and p53 WT or mut-p53 associate with SBEs and p53 response elements in a TGFbeta dependent manner. Interestingly, the repressive effects of p53-WT on NOX4 were relieved by mutation of its transactivation domain or histone deacetylase (HDAC) inhibitor treatment. Overexpression of p300, a transcriptional co-regulator and histone acetyltransferase (HAT), enhanced p53-mediated NOX4 induction, whereas HAT-inactive p300 reduced NOX4 expression. Mut-p53 augmented TGFbeta-stimulated histone acetylation within the NOX4 promoter. Finally, wound assays demonstrated NOX4 and p300 promote TGFbeta/mut-p53-mediated cell migration. Our studies provide new insight into TGFbeta/SMAD3 and mut-p53-mediated NOX4 induction involving epigenetic control of NOX4 in tumor cell migration, suggesting NOX4 is a potential therapeutic target to combat tumor progression and metastasis. PMID- 28574837 TI - 6-mercaptopurine promotes energetic failure in proliferating T cells. AB - The anticancer drug 6-mercaptopurine (6-MP) inhibits de novo purine synthesis and acts as an antiproliferative agent by interfering with protein, DNA and RNA synthesis and promoting apoptosis. Metabolic reprogramming is crucial for tumor progression to foster cancer cells growth and proliferation, and is regulated by mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) as well as the oncogenes Myc and hypoxia inducible factor 1alpha (HIF-1alpha). We hypothesized that 6-MP impacts metabolic remodeling through its action on nucleotide synthesis. The aim of our study is to provide a comprehensive characterization of the metabolic changes induced by 6-MP in leukemic T cells. Our results indicate that exposition to 6-MP rapidly reduces intracellular ATP concentration, leading to the activation of AMPK. In turn, mTOR, an AMPK target, was inhibited, and the expression of HIF-1alpha and Myc was reduced upon 6-MP incubation. As a consequence of these inhibitions, glucose and glutamine fluxes were strongly decreased. Notably, no difference was observed on glucose uptake upon exposition to 6-MP. In conclusion, our findings provide new insights into how 6-MP profoundly impacts cellular energetic metabolism by reducing ATP production and decreasing glycolytic and glutaminolytic fluxes, and how 6-MP modifies human leukemic T cells metabolism with potential antiproliferative effects. PMID- 28574840 TI - Methylation regulates HEY1 expression in glioblastoma. AB - Glioblastoma (GBM) remains one of the most lethal and difficult-to-treat cancers of the central nervous system. The poor prognosis in GBM patients is due in part to its resistance to available treatments, which calls for identifying novel molecular therapeutic targets. In this study, we identified a mediator of Notch signaling, HEY1, whose methylation status contributes to the pathogenesis of GBM. Datamining studies, immunohistochemistry and immunoblot analysis showed that HEY1 is highly expressed in GBM patient specimens. Since methylation status of HEY1 may control its expression, we conducted bisulphite sequencing on patient samples and found that the HEY1 promoter region was hypermethylated in normal brain when compared to GBM specimens. Treatment on 4910 and 5310 xenograft cell lines with sodium butyrate (NaB) significantly decreased HEY1 expression with a concomitant increase in DNMT1 expression, confirming that promoter methylation may regulate HEY1 expression in GBM. NaB treatment also induced apoptosis of GBM cells as measured by flow cytometric analysis. Further, silencing of HEY1 reduced invasion, migration and proliferation in 4910 and 5310 cells. Furthermore, immunoblot and q-PCR analysis showed the existence of a potential positive regulatory loop between HEY1 and p53. Additionally, transcription factor interaction array with HEY1 recombinant protein predicted a correlation with p53 and provided various bonafide targets of HEY1. Collectively, these studies suggest HEY1 may be an important predictive marker for GBM and potential target for future GBM therapy. PMID- 28574841 TI - Establishment of mouse neuron and microglial cell co-cultured models and its action mechanism. AB - OBJECTIVE: The objective of this study is to establish a co-culture model of mouse neurons and microglial cells, and to analyze the mechanism of action of oxygen glucose deprivation (OGD) and transient oxygen glucose deprivation (tOGD) preconditioning cell models. RESULTS: Mouse primary neurons and BV2 microglial cells were successfully cultured, and the OGD and tOGD models were also established. In the co-culture of mouse primary neurons and microglial cells, the cell number of tOGD mouse neurons and microglial cells was larger than the OGD cell number, observed by a microscope. CCK-8 assay result showed that at 1h after treatment, the OD value in the control group is lower compared to all the other three groups (P < 0.05). The treatment group exhibited the highest OD value among the four groups. The results observed at 5h were consistent with the results at 1 h. Flow cytometry results showed that at 1h after treatment the apoptosis percentages is higher in the control group compared to other three groups (P < 0.05). MATERIALS AND METHODS: Mouse brain tissues were collected and primary neurons cells were cultured. In the meantime mouse BV2 microglia cells were cultured. Two types of cells were co-cultured, and OGD and tOGD cell models were established. There were four groups in the experiment: control group (OGD), treatment group (tOGD+OGD), placebo group (tOGD+OGD+saline) and minocycline intervention group (tOGD+OGD+minocycline). CCK-8 kit was used to detect cell viability and flow cytometry was used to detect apoptosis. CONCLUSIONS: In this study, mouse primary neurons and microglial cells were co-cultured. The OGD and tOGD models were established successfully. tOGD was able to effectively protect neurons and microglial cells from damage, and inhibit the apoptosis caused by oxygen glucose deprivation. PMID- 28574842 TI - Dexmedetomidine alleviates lipopolysaccharide-induced lung injury in Wistar rats. AB - This study aimed to investigate the protective effects of dexmedetomidine on lipopolysaccharide (LPS)-induced lung injury in Wistar rats. 24 female Wistar rats were randomly assigned into 3 groups (n = 8): a control group, a LPS challenged group, and a LPS plus dexmedetomidine group. Inflammation, oxidative stress, Nrf2/Keap1, and Akt signal were determined. The results showed that LPS caused inflammation and oxidative stress via increasing pro-inflammatory cytokines and oxidative products. Dexmedetomidine treatment alleviated inflammation and oxidative stress in LPS-challenged rats. Nrf2/Keap1 was inhibited and Akt signal was activated in the lung after exposure to LPS, while dexmedetomidine activated Nrf2/Keap1, which further mediated expressions of antioxidant genes. In conclusion, dexmedetomidine alleviated inflammatory response and oxidative stress in LPS-induced lung injury in rats via influencing Nrf2/Keap1 signal. PMID- 28574845 TI - Die later with ESCRT! PMID- 28574844 TI - Socioeconomic status is associated with global diabetes prevalence. AB - The incidence of diabetes is increasing globally. We investigated the relationship between diabetes prevalence and patient socioeconomic status across multiple countries. We searched PubMed to identify population-based surveys reporting diabetes prevalence between 1990 and May 2016. Search results were filtered, and Human Development Index (HDI) values from the United Nations Development Programme were used to assess socioeconomic status for a given nation. Our analysis included 45 national surveys from 32 countries. Diabetes prevalence was positively correlated with national HDI (r = 0.421 P = 0.041) in developing countries, and negatively correlated with HDI (r = -0.442 P = 0.045) in developed countries. Diabetes prevalence trends were the same in women and men, although men were associated with increased diabetes risk in developed countries (r = 0.459 P = 0.048). Thus, diabetes prevalence rises with increasing HDI in developing countries, and this is reversed in developed countries. Ours is the first study to investigate the relationship between diabetes and socioeconomic status at global level using HDI values. These results will aid in evaluating global diabetes prevalence and risk with respect to patient socioeconomic status, and will be useful in the development of policies that help reduce disease incidence. PMID- 28574843 TI - Characterization of tumor-associated T-lymphocyte subsets and immune checkpoint molecules in head and neck squamous cell carcinoma. AB - The composition of tumor-infiltrating lymphocytes (TIL) reflects biology and immunogenicity of cancer. Here, we characterize T-cell subsets and expression of immune checkpoint molecules in head and neck squamous cell carcinoma (HNSCC). We analyzed TIL subsets in primary tumors (n = 34), blood (peripheral blood mononuclear cells (PBMC); n = 34) and non-cancerous mucosa (n = 7) of 34 treatment-naive HNSCC patients and PBMC of 15 healthy controls. Flow cytometry analyses revealed a highly variable T-cell infiltration mainly of an effector memory phenotype (CD45RA-/CCR7-). Naive T cells (CD45RA+/CCR7+) were decreased in the microenvironment compared to PBMC of patients, while regulatory T cells (CD4+/CD25+/CD127low and CD4+/CD39+) were elevated. Furthermore, we performed digital image analyses of entire cross sections of HNSCC to define the 'Immunoscore' (CD3+ and CD8+ cell infiltration in tumor core and invasive margin) and quantified MHC class I expression on tumor cells by immunohistochemistry. Immune checkpoint molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) were increased in TILs compared to peripheral T cells in flow-cytometric analysis. Human papillomavirus (HPV) positive tumors showed higher numbers of TILs, but a similar composition of T-cell subsets and checkpoint molecule expression compared to HPV negative tumors. Taken together, the tumor microenvironment of HNSCC is characterized by a strong infiltration of regulatory T cells and high checkpoint molecule expression on T-cell subsets. In view of increasingly used immunotherapies, a detailed knowledge of TILs and checkpoint molecule expression on TILs is of high translational relevance. PMID- 28574846 TI - Polymorphisms in BMP2/BMP4, with estimates of mean lung dose, predict radiation pneumonitis among patients receiving definitive radiotherapy for non-small cell lung cancer. AB - Single nucleotide polymorphisms (SNPs) in TGFbeta1 can predict the risk of radiation pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) after definitive radiotherapy. Here we investigated whether SNPs in TGFbeta superfamily members BMP2 and BMP4 are associated with RP in such patients. In total, we retrospectively analyzed 663 patients given >= 60 Gy for NSCLC. We randomly assigned 323 patients to the training cohort and 340 patients to the validation cohort. Potentially functional and tagging SNPs of BMP2 (rs170986, rs1979855, rs1980499, rs235768, rs3178250) and BMP4 (rs17563, rs4898820, rs762642) were genotyped. The median of mean lung dose (MLD) was 17.9 Gy (range, 0.15-32.74 Gy). Higher MLD was strongly associated with increased risk of grade >= 2 RP (hazard ratio [HR]=2.191, 95% confidence interval [CI] = 1.680-2.856, P < 0.001) and grade >= 3 RP (HR = 4.253, 95% CI = 2.493-7.257, P < 0.001). In multivariate analyses, BMP2 rs235768 AT/TT was associated with higher risk of grade >= 2 RP (HR = 1.866, 95% CI = 1.221-2.820, P = 0.004 vs. AA) both in training cohort and validation cohort. Similar results were observed for BMP2 rs1980499. BMP2 rs3178250 CT/TT was associated with lower risk of grade >= 3 RP (HR = 0.406, 95% CI = 0.175-0.942, P = 0.036 vs. CC) in the pooled analysis. Adding the rs235768 and rs1980499 SNPs to a model comprising age, performance status, and MLD raised the Harrell's C for predicting grade >= 2 RP from 0.6117 to 0.6235 (P = 0.0105). SNPs in BMP2 can predict grade >= 2 or 3 RP after radiotherapy for NSCLC and improve the predictive power of MLD model. Validation is underway through an ongoing prospective trial. PMID- 28574847 TI - Body mass index and persistent pain after breast cancer surgery: findings from the women's healthy eating and living study and a meta-analysis. AB - The purpose of this study is to evaluate the association between body mass index (BMI) and persistent pain after breast cancer surgery in a prospective study and synthesize available evidence through a meta-analysis. In the Women's Healthy Eating and Living (WHEL) Study, 3,088 women diagnosed of breast cancer were enrolled and assessed. After 4 years, a subgroup of 2,131 women was re-assessed for the pain information. Logistic regression models were used to assess the associations of baseline BMI and BMI change between baseline and 4 years of follow-up with general pain symptoms at 4 years of follow-up. We further synthesized all available evidence from observational studies by searching PubMed and Embase up to February 2017. In the WHEL study, baseline BMI was linearly associated with an increased risk of persistent pain at 4 years of follow-up (odds ratio (OR) (95% confidence interval (CI)): 1.07 (1.05-1.10)). After adjusting for baseline BMI, BMI change since baseline was associated with persistent pain (OR (95% CI) for every unit increase: 1.10 (1.04-1.16)). After searching the literature, additional eight studies were eligible to be included in the meta-analysis. After pooling estimates from all nine studies, there was a positive association with persistent pain development comparing obesity or overweight with normal weight. Available data suggested a linear relationship between BMI and persistent pain (OR (95% CI) for every one unit increment of BMI: 1.04 (1.02-1.07)). Overall, our analyses suggested that BMI might be positively associated with risk of persistent pain after breast cancer surgery. PMID- 28574848 TI - The significance of microRNA-148/152 family as a prognostic factor in multiple human malignancies: a meta-analysis. AB - Recent studies have demonstrated that microRNA-148/152 family emerges as a attractive biomarker for predicting tumor prognosis and progression. However, outcomes of different studies are controversial. Eligible Literature were searched through online databases: PubMed, EMBASE and Web of Science. A total of 24 eligible studies were ultimately enrolled in this meta-analysis. Results indicated that overexpression of miR-148/152 family was significantly correlated with enhanced overall/cause-specific survival (OS/CSS) (HR=0.63, 95% CI: 0.54 0.74). Stratified analysis indicated that high miR-148a and miR-148b expression predicted favorable OS/CSS (HR=0.76; 95% CI: 0.69-0.90) and (HR=0.49; 95% CI: 0.39-0.61), while miR-152 developed no significant impact (HR=0.40, 95% CI: 0.12 1.29). MiR-148/152 family was distinctly associated with superior OS/CSS in Asian (HR=0.53, 95% CI: 0.44-0.64), but not in Caucasian (HR=0.96, 95% CI: 0.82-1.13). Futhermore, miR-148/152 family expression also predicted longer disease/relapse/progression-free survival (DFS/RFS/PFS) (HR=0.37, 95% CI: 0.16 0.88). A significantly favorable DFS/RFS/PFS was observed in Asian (HR=0.21, 95% CI: 0.06-0.81) than that in Caucasian (HR=0.76, 95% CI: 0.31-1.87). miR-148/152 family overexpression also predicted longer DFS/RFS/PFS in tissues (HR=0.11, 95% CI: 0.01-0.98), but not in plasma/serum (HR=0.67, 95% CI: 0.38-1.18). Our meta analysis demonstrated that overexpression of miR-148/152 predicted enhanced OS/CSS and DFS/RFS/PFS of cancer patients. MiR-148a/b family may serve as a potential prognostic factor in multiple human malignancies. PMID- 28574851 TI - cRGD-installed docetaxel-loaded mertansine prodrug micelles: redox-triggered ratiometric dual drug release and targeted synergistic treatment of B16F10 melanoma. AB - Combinatorial chemotherapy, which has emerged as a promising treatment modality for intractable cancers, is challenged by a lack of tumor-targeting, robust and ratiometric dual drug release systems. Here, docetaxel-loaded cRGD peptide decorated redox-activable micellar mertansine prodrug (DTX-cRGD-MMP) was developed for targeted and synergistic treatment of B16F10 melanoma-bearing C57BL/6 mice. DTX-cRGD-MMP exhibited a small size of ca. 49 nm, high DTX and DM1 loading, low drug leakage under physiological conditions, with rapid release of both DTX and DM1 under a cytoplasmic reductive environment. Notably, MTT and flow cytometry assays showed that DTX-cRGD-MMP brought about a synergistic antitumor effect to B16F10 cancer cells, with a combination index of 0.37 and an IC50 over 3- and 13-fold lower than cRGD-MMP (w/o DTX) and DTX-cRGD-Ms (w/o DM1) controls, respectively. In vivo studies revealed that DTX-cRGD-MMP had a long circulation time and a markedly improved accumulation in the B16F10 tumor compared with the non-targeting DTX-MMP control (9.15 versus 3.13% ID/g at 12 h post-injection). Interestingly, mice treated with DTX-cRGD-MMP showed almost complete growth inhibition of B16F10 melanoma, with tumor inhibition efficacy following an order of DTX-cRGD-MMP > DTX-MMP (w/o cRGD) > cRGD-MMP (w/o DTX) > DTX-cRGD-Ms (w/o DM1) > free DTX. Consequently, DTX-cRGD-MMP significantly improved the survival rates of B16F10 melanoma-bearing mice. Importantly, DTX-cRGD-MMP caused little adverse effects as revealed by mice body weights and histological analyses. The combination of two mitotic inhibitors, DTX and DM1, appears to be an interesting approach for effective cancer therapy. PMID- 28574850 TI - Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients. AB - Allergy, pancreatitis and thrombosis are common side-effects of childhood acute lymphoblastic leukemia (ALL) treatment that are associated with the use of asparaginase (ASNase), a key component in most ALL treatment protocols. Starting with predicted functional germline variants obtained through whole-exome sequencing (WES) data of the Quebec childhood ALL cohort we performed exome-wide association studies with ASNase-related toxicities. A subset of top-ranking variants was further confirmed by genotyping (N=302) followed by validation in an independent replication group (N=282); except for thrombosis which was not available for that dataset. SNPs in 12 genes were associated with ASNase complications in discovery cohort including 3 that were associated with allergy, 3 with pancreatitis and 6 with thrombosis. The risk was further increased through combined SNPs effect (p<=0.002), suggesting synergistic interactions between the SNPs identified in each of the studied toxicities. Interestingly, rs3809849 in the MYBBP1A gene was associated with allergy (p= 0.0006), pancreatitis (p=0.002), thrombosis (p=0.02), event-free survival (p=0.02) and overall survival (p=0.003). Furthermore, rs11556218 in IL16 and rs34708521 in SPEF2 were both associated with thrombosis (p=0.01 and p=0.03, respectively) and pancreatitis (p=0.02). The association of SNPs in MYBBP1A, SPEF2 and IL16 geneswith pancreatitis was replicated in the validation cohort (p <=0.05) as well as in combined cohort (p=0.0003, p=0.008 and p=0.02, respectively). The synergistic effect of combining risk loci had the highest power to predict the development of pancreatitis in both cohorts and was further potentiated in the combined cohort (p=1x10-8).The present work demonstrates that using WES data is a successful "hypothesis-free" strategy for identifying significant genetic markers modulating the effect of the treatment in childhood ALL. PMID- 28574853 TI - Chemical sintering of direct-written silver nanowire flexible electrodes under room temperature. AB - Transparent and flexible electrodes on cost effective plastic substrates for wearable electronics have attract great attention recently. Due to the conductivity and flexibility in network form, metal nanowire is regarded as one of the most promising candidates for flexible electrode fabrication. Prior to application, low temperature joining of nanowire processes are required to reduce the resistance of electrodes and simultaneously maintain the dimensionality and uniformity of those nanowires. In the present work, we presented an innovative, robust and cost effective method to minimize the heat effect to plastic substrate and silver nanowires which allows silver nanowire electrodes been directly written on polycarbonate substrate and sintered by different electrolyte solutions at room temperature or near. It has been rigorously demonstrated that the resistance of silver nanowire electrodes has been reduced by 90% after chemical sintering at room temperature due to the joining of silver nanowires at junction areas. After ~1000 bending cycles, the measured resistance of silver nanowire electrode was stable during both up-bending and down-bending states. The changes of silver nanowires after sintering were characterized using x-ray photoelectron spectroscopy and transmission electron microscopy and a sintering mechanism was proposed and validated. This direct-written silver nanowire electrode with good performance has broad applications in flexible electronics fabrication and packaging. PMID- 28574852 TI - A novel 'leadless' dielectrophoresis chip with dot matrix electrodes for patterning nanowires. AB - In this paper, we present a novel 'leadless' dielectrophoresis chip with dot matrix electrodes (LDME-DEP chip) fabricated by stacking three different functional layers. Our LDME-DEP chip excels mainly in two aspects: we for the first time applied the technique of separating the lead and the electrode pattern into two different layers to patterning nanowires which achieves continuous-area manipulation of nanowires without interference from the lead; the use of dot matrix electrodes makes the manipulation more flexible. We firstly detail the fabrication and working principle of our LDME-DEP chip and propose the scheme for washing away the nanowires with unsatisfactorily positioned postures. Then, nanowire patterning applications (e.g., letter E, square and long chain) under the combination of dielectrophoretic force and hydrodynamic force are carried out and the effect of frequency of the electric signal on assembling accuracy of nanowires is discussed. PMID- 28574854 TI - Costoclavicular Space: A Reliable Gate for Continuous Regional Anesthesia Catheter Insertion. PMID- 28574855 TI - Fasting and ambulatory blood pressure monitoring. PMID- 28574856 TI - Camera-based measurement of respiratory rates is reliable. AB - OBJECTIVES: Respiratory rate (RR) is one of the most important vital signs used to detect whether a patient is in critical condition. It is part of many risk scores and its measurement is essential for triage of patients in emergency departments. It is often not recorded as measurement is cumbersome and time consuming. We intended to evaluate the accuracy of camera-based measurements as an alternative measurement to the current practice of manual counting. MATERIALS AND METHODS: We monitored the RR of healthy male volunteers with a camera-based prototype application and simultaneously by manual counting and by capnography, which was considered the gold standard. The four assessors were mutually blinded. We simulated normoventilation, hypoventilation and hyperventilation as well as deep, normal and superficial breathing depths to assess potential clinical settings. The volunteers were assessed while being undressed, wearing a T-shirt or a winter coat. RESULTS: In total, 20 volunteers were included. The results of camera-based measurements of RRs and capnography were in close agreement throughout all clothing styles and respiratory patterns (Pearson's correlation coefficient, r=0.90-1.00, except for one scenario, in which the volunteer breathed slowly dressed in a winter coat r=0.84). In the winter-coat scenarios, the camera-based prototype application was superior to human counters. CONCLUSION: In our pilot study, we found that camera-based measurements delivered accurate and reliable results. Future studies need to show that camera-based measurements are a secure alternative for measuring RRs in clinical settings as well. PMID- 28574857 TI - Effect of Growth Hormone Supplementation on Osseointegration: A Systematic Review and Meta-analyses. AB - OBJECTIVES: The aim of this study was to assess whether growth hormone (GH) replacement therapy can enhance implant osseointegration. MATERIALS AND METHODS: A systematic literature search was conducted from 1982 to March 2016. A structured search using the keywords "growth hormone," "implants," and "osseointegration" was performed to identify preclinical and clinical in vivo controlled studies and was followed by a 2-phase search strategy. Initially, 31 potentially relevant articles were identified. After removal of duplicates and screening by title and abstract, 10 potential studies were included. Studies were assessed for bias and data were synthesized using a random-effects meta-analysis model. RESULTS: All studies were preclinical animal trials, and the follow-up period ranged from 2 to 16 weeks. Seventy percent of the included studies reported an increase in bone-to-implant contact in animals receiving GH compared with controls. Meta-analysis showed a significant mean difference for bone to implant between GH groups versus controls (no GH supplementation) of 10.60% (95% confidence interval: 3.79%-17.41%) favoring GH administration. CONCLUSION: GH treatment seems to promote osseointegration around implants in preclinical studies; however, these findings must be assessed in highly controlled human clinical trials as a number of confounding factors may have influenced the outcomes of the included studies. PMID- 28574858 TI - Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy: Diagnostic Accuracy and Correlation With Electrophysiology. AB - PURPOSE: The aims of this study were to assess diagnostic accuracy of diffusion tensor imaging (DTI) in chronic inflammatory demyelinating polyneuropathy (CIDP), to correlate DTI with electrophysiological parameters, and to evaluate whether radial diffusivity (RD) and axial diffusivity (AD) might serve as specific biomarkers of demyelinating and axonal pathology. MATERIALS AND METHODS: This prospective study was approved by the institutional ethics committee, and written informed consent was obtained from all participants. Magnetic resonance neurography of upper and lower extremity nerves (median, ulnar, radial, sciatic, tibial) was performed by single-shot DTI sequences at 3.0 T in 18 patients with a diagnosis of CIDP and 18 healthy controls, matched to age and sex. The scalar readout parameters nerve fractional anisotropy (FA), mean diffusivity (MD), RD, and AD were obtained after manual segmentation and postprocessing and compared between patients and controls. Diagnostic accuracy was assessed by receiver operating characteristic analysis, and cutoff values were calculated by maximizing the Youden index. All patients underwent a complementary electroneurography and correlation of electrophysiological markers and DTI parameters was analyzed and described by Pearson and Spearman coefficients. RESULTS: Nerve FA was decreased to a mean of 0.42 +/- 0.08 in patients compared with 0.52 +/- 0.04 in healthy controls (P < 0.001). This decrease in FA was a result of an increase of RD (P = 0.02), whereas AD did not differ between the two groups. Of all DTI parameters, FA showed best diagnostic accuracy with a receiver operating characteristic area under the curve of 0.90. Optimal cutoff for an average FA of all analyzed nerves was 0.47, yielding a sensitivity of 0.83 and a specificity of 0.94. Fractional anisotropy and RD correlated strongly with electrophysiological markers of demyelination, whereas AD did not correlate with markers of axonal neuropathy. CONCLUSIONS: Diffusion tensor imaging yields valid quantitative biomarkers in CIDP and might aid in diagnosis with high diagnostic accuracy. Fractional anisotropy and RD may serve as parameters of myelin sheath integrity, but AD is unable to reflect axonal damage in CIDP. PMID- 28574859 TI - Female-to-Male Chest Reconstruction: A Review of Technique and Outcomes. AB - PURPOSE: Female-to-male transgender individuals frequently seek out chest wall masculinization as part of their gender transition and to aid with treating gender dysphoria. Critical evaluation of techniques, complications, and outcomes is important particularly as the surgery becomes more commonly performed. METHODS: A retrospective review was performed of all patients undergoing female to-male chest wall reconstruction by the senior author from 2008 to 2015. Charts were reviewed to evaluate patient demographics, intraoperative details, and postoperative outcomes. Complications were stratified into major and minor complications based on the need to return to the operating room. Inframammary fold techniques and periareolar techniques cohorts were compared for major complications, minor complications, and need for revision surgeries. RESULTS: Over 8 years, 130 patients were identified. One hundred ten patients underwent inframammary fold techniques, and 20 patients underwent periareolar incisions. Early postoperative complications occurred in 25% of patients. Hematoma was the most common complications, occurring in 14% of patients. Major complications occurred in 8% of patients. Minor complications occurred in 16% of patients, with respiratory problems found to be a significant risk factor. On long-term follow up, 9% of patients had a revision procedure performed. Patients with prior breast surgery were more likely to require revisions (P = 0.009). Of patients requiring revision, 38% had a periareolar incision, compared with only 13% of patients who did not (P = 0.03). For unplanned revisions, there was no difference in periareolar and inframammary techniques. CONCLUSIONS: Our patient cohort demonstrates that female-to-male patients who undergo chest wall contouring through a transverse inframammary fold incision with either composite or standard free nipple grafting have decreased rates of revision surgery and trend toward having lower complication rates as compared with periareolar and limited scar techniques. To best manage expectations, patients undergoing a periareolar or other limited incision technique are counseled regarding an increased risk of hematoma and an increased likelihood of revisions. PMID- 28574860 TI - Crouch gait can be an effective form of forced-use/no constraint exercise for the paretic lower limb in stroke. AB - In hemiplegic gait the paretic lower limb provides less muscle power and shows a briefer stance compared with the unaffected limb. Yet, a longer stance and a higher power can be obtained from the paretic lower limb if gait speed is increased. This supports the existence of a 'learned non-use' phenomenon, similar to that underlying some asymmetric impairments of the motion of the eyes and of the upper limbs. Crouch gait (CG) (bent-hip bent-knee, about 30 degrees minimum knee flexion) might be an effective form of 'forced-use' treatment of the paretic lower limb. It is not known whether it also stimulates a more symmetric muscle power output. Gait analysis on a force treadmill was carried out in 12 healthy adults and seven hemiplegic patients (1-127 months after stroke, median: 1.6). Speed was imposed at 0.3 m/s. Step length and single and double stance times, sagittal joint rotations, peak positive power, and work in extension of the hip, knee, and ankle (plantar flexion), and surface electromyography (sEMG) area from extensor muscles during the generation of power were measured on either side during both erect and crouch walking. Significance was set at P less than 0.05; corrections for multiplicity were applied. Patients, compared with healthy controls, adopted in both gait modalities and on both sides a shorter step length (61-84%) as well as a shorter stance (76-90%) and swing (63-83%) time. As a rule, they also provided a higher muscular work (median: 137%, range: 77-250%) paralleled by a greater sEMG area (median: 174%, range: 75-185%). In erect gait, the generation of peak extensor power across hip, knee, and ankle joints was in general lower (83-90%) from the paretic limb and higher (98-165%) from the unaffected limb compared with control values. In CG, peak power generation across the three lower limb joints was invariably higher in hemiparetic patients: 107 177% from the paretic limb and 114-231% from the unaffected limb. When gait shifted from erect to crouch, only for hemiplegic patients, at the hip, the paretic/unaffected ratio increased significantly. For peak power, work, sEMG area, and joint rotation, the paretic/unaffected ratio increased from 55 to 85%, 56 to 72%, 68 to 91%, and 67 to 93%, respectively. CG appears to be an effective form of forced-use exercise eliciting more power and work from the paretic lower limb muscles sustained by a greater neural drive. It also seems effective in forcing a more symmetric power and work from the hip extensor muscles, but neither from the knee nor the ankle. PMID- 28574862 TI - The role of microRNAs in the therapeutic action of D-cycloserine in a post traumatic stress disorder animal model: an exploratory study. AB - OBJECTIVES: Post-traumatic stress disorder is characterized by impaired fear extinction and excessive anxiety. D-Cycloserine (DCS) has previously been shown to facilitate fear extinction and decrease anxiety in animal and human studies. This study utilized a contextual fear-conditioning animal model to investigate the involvement of microRNAs (miRNAs) in fear extinction and the reduction of anxiety, as mediated by the co-administration of DCS and behavioural fear extinction. METHODS: Fear conditioning consisted of an electric foot shock; fear extinction consisted of behavioural fear extinction co-administered with either DCS or saline. The light/dark avoidance test was used to evaluate anxiety-related behaviour subsequent to fear conditioning and was used to evaluate anxiety related behaviour following fear conditioning and to subsequently group animals into well-adapted and maladapted subgroups. These subgroups also showed significant differences in terms of fear extinction. Small RNAs extracted from the left dorsal hippocampus were sequenced using next-generation sequencing to identify differentially expressed miRNAs associated with DCS-induced fear extinction and reduction of anxiety. In-silico prediction analyses identified mRNA targets (from data of the same animals) of the differentially expressed miRNAs. Two of the predicted mRNA-miRNA interactions were functionally investigated. RESULTS: Overall, 32 miRNAs were differentially expressed between rats that were fear conditioned, received DCS and were well adapted and rats that were fear conditioned, received saline and were maladapted. Nineteen of these miRNAs were predicted to target and regulate the expression of 63 genes differentially expressed between fear-conditioned, DCS-administered, well-adapted and fear-conditioned, saline-administered, and maladapted groups (several of which are associated with neuronal inflammation, learning and memory). Functional luciferase assays indicated that rno-mir-31a-5p may have regulated the expression of interleukin 1 receptor antagonist (Il1rn) and metallothionein 1a (Mt1a). CONCLUSION: These differentially expressed miRNAs may be mediators of gene expression changes that facilitated decreased neuronal inflammation, optimum learning and memory and contributed towards effective fear extinction and reduction of anxiety following the co-administration of DCS and behavioural fear extinction. PMID- 28574861 TI - Occurrence of nasal dermoid cysts in a family with a single maxillary median central incisor: extending the clinical spectrum. PMID- 28574863 TI - Mephentermine Dependence in a Young Athlete: Case Report With Review of Literature. AB - : Mephentermine is structurally related to amphetamines and is banned for its use as a performance-enhancing drug in competitive sports. Limited literature is available on management of mephentermine dependence. Here, we describe a case of mephentermine dependence followed by review of literature and a discussion about its management. A 20-year-old professional wrestler presented with high-dose intravenous mephentermine use, and rapid development of dependence, in the absence of any comorbid substance use or psychiatric disorder. The client showed improvement with bupropion and individual counseling sessions. The present report highlights the need to explore effective treatment options for individuals who have been addicted to mephentermine. PMID- 28574864 TI - Methadone Management of Withdrawal Associated With Loperamide-related Opioid Use Disorder. AB - : Loperamide hydrochloride is an over-the-counter anti-diarrheal agent, acting via mu-opioid receptor agonist effects in the intestinal myenteric plexus. Although preclinical investigations suggested that abuse liability associated with loperamide use is low, there are increasing numbers of cases reported to the US Food and Drug Administration, of abuse, dependence, and withdrawal associated with loperamide use. A case of a patient with opioid use disorder, that is, in the form of protracted loperamide excess use, requiring management of withdrawal with methadone is presented. Management of withdrawal from abrupt loperamide discontinuation has not been discussed in the literature. Long-term treatment issues are also described. PMID- 28574865 TI - The Regional Autopsy Center: The University of Alabama at Birmingham Experience. AB - Rates of autopsied deaths have decreased significantly for the last several decades. It may not be practical for some institutions to maintain the facilities and staffing required to perform autopsies. In recent years, the University of Alabama at Birmingham (UAB) has established contracts to perform autopsies for several regional institutions including the Alabama Department of Forensic Sciences (ADFS), the United States Veterans Affairs, the local prison system, local community hospitals, and with families for private autopsy services. Contracts and autopsy data from 2004 to 2015 were obtained and reviewed. Since 2004, the number of UAB hospital autopsies trended slightly downward. On average, UAB hospital cases comprised most yearly cases, and the ADFS was the second largest contributor of cases. Income generated from outside autopsies performed from 2006 to 2015 totaled just more than 2 million dollars, and most of the income was generated from referred ADFS cases. This study provides evidence that a centralized institution (regional autopsy center [RAC]) can provide regional autopsy service in a practical, feasible, and economically viable manner, and a RAC can benefit both the referring institutions as well as the RAC itself. PMID- 28574866 TI - A population-based approach to compare patient-reported outcomes of long-term Hodgkin's lymphoma survivors according to trial participation: a joint study from the Patient-Reported Outcomes Following Initial Treatment and Long-term Evaluation of Survivorship registry and European Organisation for Research and Treatment of Cancer. AB - Survival discrepancy between patients treated in a clinical trial and routine practice is well recognized. No study has assessed the health-related quality of life (HRQL) of long-term Hodgkin's lymphoma survivors (HLS) according to trial participation. We applied a population-based approach to examine the differences in HRQL, healthcare utilization, and satisfaction with healthcare among long-term HLS who had participated in a trial (tHLS) and those treated in routine care (rHLS). All HLS diagnosed during the period 1989-1998 and living in southern Netherlands were selected from the Netherlands Cancer Registry in 2004 to participate in the Patient Reported Outcomes Following Initial treatment and Long term Evaluation of Survivorship registry study. Data linkage with the European Organisation for Research and Treatment of Cancer was performed in 2015 to identify trial participation. The 65 tHLS and 67 rHLS had comparable demographic and clinical characteristics. Unadjusted and adjusted models indicated no association between trial participation and HRQL. There was no evidence of differences in healthcare satisfaction. Trial participation was associated with 48% more visits to specialists in the past year (adjusted 95% confidence interval: 10-99). No association of trial participation with cancer-related contacts was observed. tHLS and rHLS had comparable long-term HRQL. Although trial participation was associated with more specialist visits, there was no evidence of an association with healthcare satisfaction and the number of cancer related visits. Identification of trial participation in population-based cancer registry through data linkage with clinical trials enables a population-based approach to examine patient-reported outcomes differences between tHLS and rHLS. PMID- 28574867 TI - Breast cancer screening effectiveness in Portugal central Region. AB - The central region of Portugal is covered by an organized population-based breast cancer screening programme. We designed a case-referent study to investigate the association of overall mortality with mammographic screening attendance. The study population (SP) included women aged 50-69 years who received at least one invitation to the breast cancer screening programme. A case was defined as a woman from the SP diagnosed with breast cancer between 2000 and 2006 who died before 1 August 2015. Index invitation (IV) was defined as the most recent invitation before diagnosis of the case. For each case, two referents were sampled from the SP. Referents were women who did not have a breast cancer diagnosis at the IV of the case and alive at time of death of the case. Exposure to screening was defined as participation in the screening examination following the IV and/or participation in the screening round preceding the IV. To correct for self-selection bias, we used a summary correction factor on the basis of published ones. We used conditional logistic regression to estimate the odds ratio (OR) and 95% confidence interval (CI). A total of 227 cases and 454 referents were considered. The overall OR showed a mortality reduction of 47% (OR=0.53, 95% CI: 0.37-0.78). The estimated correction factor was 1.15 (95% CI: 1.06-1.25). This factor was used to correct the crude OR, resulting in a mortality reduction of 33% (OR=0.67, 95% CI: 0.45-1.00). Our results are in agreement with other case-referent studies worldwide, supporting the contribution of screening practices towards the decreasing breast cancer mortality in Portugal. PMID- 28574868 TI - Evaluation of completeness of case ascertainment in Swiss cancer registration. AB - This is the first comprehensive evaluation of completeness of case ascertainment in Swiss cancer registration. There is currently no method available that is considered to be the gold standard. Apart from simple measures such as the proportion of cases where registration was initiated by a death certificate and the proportion of diagnoses on the basis of histology or cytology/haematology, we applied two dedicated approaches: (i) the semiquantitative method of comparing the mortality to incidence rate ratio with relative survival (MI-Surv method) and (ii) the Flow method, which provides a quantitative estimate for the completeness depending on time since diagnosis. All 10 Swiss cancer registries in operation since at least 2006 and providing the required parameters were included. Simple and dedicated methods showed high completeness across all cancer registries and for most cancer types tested, with the notable exception of lymphoid leukaemia. PMID- 28574869 TI - Cancer incidence estimation method: an Apulian experience. AB - The Cancer Registry of Puglia (RTP) was instituted in 2008 as a regional population-based cancer registry. It consists of six sections (Foggia, Barletta Andria-Tran, Bari, Brindisi, Lecce, and Taranto) and covers more than 4 000 000 inhabitants. At present, four of six sections have received accreditation by AIRTUM (53% of regional population). To point out possible regional geographic variability in cancer incidence and also to support health services planning, we developed an original estimation method to ensure a complete territorial coverage. Incidence data of the four accredited RTP sections for the shared incidence period 2006-2008, the 2001-2009 hospitalization regional data, and 2006 2009 mortality data were considered. To take into account specific health features of different provinces, we performed an estimate of cancer incidence rates of nonaccredited sections using a combination of accredited sections rates and a factor that combines mortality and hospitalization ratios available for all the sections. Finally, we validated the method and we applied it to estimate regional cancer rates as the population-weighted average of accredited sections and nonaccredited sections adjusted rates. The validation process shows that estimated rates are close to real incidence data. The most frequent neoplasms in Apulia are breast (direct standardized rates 96.8 per 100 000 inhabitants), colon rectum (36.6), and thyroid cancer (25.3) in women and prostate (70.2), lung (68.4), and colon-rectum cancer (52.2) in men. This method could be useful to assess the cancer incidence when complete cancer registration data are not available, but hospitalization, mortality, and neighbouring incidence data are available. PMID- 28574871 TI - Precise Target Site of Ultrasound-Guided C5 Cervical Root Block. PMID- 28574870 TI - Dietary supplementation with fish oil prevents high fat diet-induced enhancement of sensitivity to the behavioral effects of quinpirole. AB - Eating a diet high in fat can lead to negative health consequences, including obesity and insulin resistance. Omega-3 polyunsaturated fatty acids (such as those found in fish oil) prevent high fat diet-induced obesity and insulin resistance in rats. Eating a high fat diet also enhances sensitivity of rats to the behavioral effects of drugs that act on dopamine systems (e.g. quinpirole, a dopamine D2/D3 receptor agonist). To test the hypothesis that dietary supplementation with fish oil prevents high fat diet-induced enhanced sensitivity to the behavioral effects of quinpirole (0.0032-0.32 mg/kg), male rats ate standard laboratory chow, high fat chow, standard chow with fish oil, or high fat chow with fish oil (20% w/w). After 5 weeks, rats eating high fat chow were more sensitive (e.g. leftward shift of the quinpirole dose-response curve) than rats eating standard chow to yawning induced by quinpirole. Dietary supplementation with fish oil prevented this effect. That is, quinpirole dose-response curves were not different between rats eating high fat chow supplemented with fish oil and standard chow fed controls. These data add to a growing literature showing the complex relationship between diet and dopamine systems, and the health benefits of fish oil. PMID- 28574872 TI - Comment on "Stories of an Emigrant Physician: What It Has Been Like to Practice in Canada Compared With the United States". PMID- 28574874 TI - Physical Activity and Abdominal Fat Distribution in Greenland. AB - PURPOSE: We examined how total volume of physical activity and reallocation of time spent at various objectively measured intensities of physical activity (PA) were associated with overall and abdominal fat distribution in adult Inuit in Greenland. METHODS: Data were collected as part of a countrywide cross-sectional health survey in Greenland. A combined accelerometer and HR monitor measured total physical activity energy expenditure (PAEE) and intensities of PA (N = 1536). Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were assessed by ultrasonography. Isotemporal substitution modeling was used to analyze the association between substitution of 1 h of sedentary time to light- or moderate-intensity PA and 1 h light-intensity PA to moderate- or vigorous intensity PA in relation to body mass index (BMI), waist circumference (WC), SAT, and VAT. RESULTS: A negative linear association was found for total PAEE and BMI, WC, VAT, and SAT. Exchanging 1 h of sedentary time with light-intensity PA was associated with lower WC (-0.6 cm, P = 0.01), SAT (-0.08 cm, P < 0.001), and VAT (-0.04 cm, P = 0.359). Exchanging light-intensity PA with vigorous-intensity PA resulted in -6.1-cm lower WC (P < 0.001), -0.7-cm lower VAT (P = 0.018) and -0.7 cm lower SAT (P < 0.001). When further adjusting for BMI, the associations were attenuated; however, most of them remained significant, and the directions were mostly unchanged. All 1-, 5-, and 10-min bouts of MVPA were negatively associated with overall and abdominal fat distribution. CONCLUSION: Physical activity energy expenditure is associated with lower BMI, WC, and abdominal fat among Greenland Inuit. The importance of promoting an upward shift of the whole PA intensity distribution and to spur even short bouts of MVPA to limit excessive accumulation of SAT and VAT is highlighted. PMID- 28574877 TI - Budd-Chiari Syndrome Demonstrated on PET/CT. AB - Budd-Chiari syndrome is a rare clinical condition that involves diminution or interruption of hepatic venous blood flow from the liver. We describe a case of Budd-Chiari syndrome visualized via F-FDG PET/CT in a 60-year-old woman with medical history of B-cell non-Hodgkin lymphoma who presented with abdominal pain. FDG PET/CT fusion images demonstrate increased FDG uptake with SUVmax of 2.2 along the course of the middle hepatic vein with decreased attenuation within both the middle and right hepatic veins, consistent with thrombus. PMID- 28574875 TI - Augmenting Amyloid PET Interpretations With Quantitative Information Improves Consistency of Early Amyloid Detection. AB - PURPOSE: Establishing reliable methods for interpreting elevated cerebral amyloid beta plaque on PET scans is increasingly important for radiologists, as availability of PET imaging in clinical practice increases. We examined a 3-step method to detect plaque in cognitively normal older adults, focusing on the additive value of quantitative information during the PET scan interpretation process. METHODS: Fifty-five F-florbetapir PET scans were evaluated by 3 experienced raters. Scans were first visually interpreted as having "elevated" or "nonelevated" plaque burden ("Visual Read"). Images were then processed using a standardized quantitative analysis software (MIMneuro) to generate whole brain and region of interest SUV ratios. This "Quantitative Read" was considered elevated if at least 2 of 6 regions of interest had an SUV ratio of more than 1.1. The final interpretation combined both visual and quantitative data together ("VisQ Read"). Cohen kappa values were assessed as a measure of interpretation agreement. RESULTS: Plaque was elevated in 25.5% to 29.1% of the 165 total Visual Reads. Interrater agreement was strong (kappa = 0.73-0.82) and consistent with reported values. Quantitative Reads were elevated in 45.5% of participants. Final VisQ Reads changed from initial Visual Reads in 16 interpretations (9.7%), with most changing from "nonelevated" Visual Reads to "elevated." These changed interpretations demonstrated lower plaque quantification than those initially read as "elevated" that remained unchanged. Interrater variability improved for VisQ Reads with the addition of quantitative information (kappa = 0.88-0.96). CONCLUSIONS: Inclusion of quantitative information increases consistency of PET scan interpretations for early detection of cerebral amyloid-beta plaque accumulation. PMID- 28574876 TI - Utility of Follow-up Dopamine Transporter SPECT With 123I-FP-CIT in the Diagnostic Workup of Patients With Clinically Uncertain Parkinsonian Syndrome. AB - PURPOSE: Dopamine transporter SPECT with I-FP-CIT is registered for detection (or exclusion) of nigrostriatal degeneration to support the etiologic classification of parkinsonian syndromes. In case of uncertainty in the interpretation of SPECT findings or unexpected clinical course, follow-up SPECT might be useful. However, the utility of follow-up FP-CIT SPECT has not yet been clarified. METHODS: One hundred forty-one patients (65.1 +/- 10.4 years) from 3 sites with follow-up FP CIT SPECT 22.4 +/- 13.7 months after baseline SPECT were included. Retrospective visual interpretation of FP-CIT SPECT scans was performed by 2 experienced readers according to the following 7-point score: "normal," some minor degree of uncertainty due to "mild asymmetry" or mild to moderate "uniform reduction," "Parkinson disease (PD) reduction type 1/2/3," and "atypical reduction." RESULTS: Normal FP-CIT SPECT or PD characteristic reduction was confirmed by follow-up SPECT in all cases (n = 58). Among patients with some minor degree of uncertainty at baseline (n = 65), the majority (72%) did now show abnormalities in follow-up SPECT, but 20% showed clear progression suggesting nigrostriatal degeneration. The latter was very rare at age younger than 60 years. The final categorization as normal or neurodegenerative was not affected by the time delay between baseline and follow-up SPECT. CONCLUSIONS: Follow-up FP-CIT SPECT cannot be generally recommended in case of completely normal baseline SPECT or PD characteristic reduction. It also cannot be recommended in patients younger than 60 years, even in case of some minor degree of uncertainty in the baseline SPECT. There is no evidence to delay follow-up FP-CIT SPECT longer than 12 months. PMID- 28574878 TI - 18F-FDG PET/CT Imaging of Popliteal Vasculitis Associated With Polyarteritis Nodosa. AB - We report an F-FDG linear uptake of the right popliteal artery in a 25-year-old man who underwent a PET/CT scan for unexplained chronic asthenia associated with fever symptoms, arthralgia, and subcutaneous nodes, in favor of vasculitis. The patient had a history of saphenous vein thrombosis. Thrombophilia screening finds a blood lupus anticoagulant. A biopsy of subcutaneous nodes finds an anatomopathologic lesion of polyarteritis nodosa. F-FDG PET can be useful in initial staging of polyarteritis nodosa for an early diagnosis of vasculitis, and thus, early treatment can prevent arterial complications such as occlusion or aneurysm. PMID- 28574879 TI - Possible Treatment Approach to an Extravasation of 177Lu-PSMA-617. AB - A rare accident of a subcutaneous extravasation in the elbow with 4280 MBq Lu PSMA-617 occurred in our clinic. We tried to reduce the damage by warming the elbow for 12 hours, then cooling it, and recommended the patient avoid exercises with the elbow for the next 3 days. We recognized a good resorption of the radionuclide in the scintigraphic imaging in the first 2 days. No pain, burning, or necrosis occurred. The administered therapy afterward showed an adequate decrease in the tumor marker level. PMID- 28574880 TI - A Wise Surgical Approach for Reconstruction of Postburn Axillary Contractures and Versatility of Perforator Flaps. AB - Postburn axillary adduction contractures should essentially be released for adequate shoulder function. Many methods have been described for this purpose. However, use of perforator flaps prevents harm to the underlying muscle and provides thin, pliable skin flaps. Despite the major advantages offered by perforator flaps, certain shortcomings of perforator flap surgery restrict their widespread use by inexperienced surgeons, including anatomic variations of perforator vessels. In order to rule out these shortcomings, we devised a new surgical approach with an initial incision that provides access to possible perforator systems on the dorsolateral thoracic area. The approach can easily be converted to a fasciocutaneous transposition flap when attempts for identification of a proper perforator fail. Nevertheless, a proper perforator can easily be reached through the exposure provided by this initial incision. With the intention of using perforator-based flap for reconstruction, we used this surgical approach for coverage in 14 cases of postburn axillary contractures. In 3 cases, conversions of the initial incision to local transposition flap (parascapular flap) were required. There was only 2 tip necrosis observed, which healed with secondary intention. Our current surgical approach may offer taking the advantages of using a true perforator flap for reconstruction while avoiding a second stress on the patient when an operative plan for perforator flap harvest fails. PMID- 28574881 TI - The Relationship Between Frailty and the Subjective Decision to Conduct a Goals of Care Discussion With Burned Elders. AB - Best practices are to conduct an early discussion of goals of care (GoC) after injury in the elderly, but this intervention is inconsistently applied. We hypothesized that a frail appearance was a factor in the decision to conduct a GoC discussion after thermal injury. A retrospective review was performed of all burn survivors aged >= 65 years at our American Burn Association (ABA)-verified level 1 burn center between April 02, 2009, and December 30, 2014. Demographic information included age, gender, mechanism of injury, percentage TBSA burned, revised Baux score, patient/physician racial discordance, documented GoC discussion (as defined within the electronic medical record), length of stay (LOS), and disposition. One rater retrospectively assigned clinical frailty scores to patients using the Canadian Study of Health and Aging Criteria, which ranged from 1 (very fit) to 7 (severely frail). Ordinal logistic regression was performed. Demographics for the cohort of 126 subjects were (mean +/- SD): age = 75.5 +/- 7.7 years, %TBSA burned = 11.9% +/- 7.2, revised Baux = 87.8 +/- 10.2, hospital LOS (days) = 14.9 +/- 13.7, Intensive Care Unit (ICU) LOS (days) = 6.2 +/- 1.2, frailty score = 4.1 +/- 1.1. Overall, 72% of geriatric survivors had a favorable discharge disposition. GoC discussions occurred in 25% of patients. GoC discussion (OR, 3.42; 95% CI, 1.54-7.60) and an unfavorable disposition (OR, 9.01; 95% CI, 3.91-20.78) were associated with greater predicted odds of receiving a higher ordered frailty score. Our results suggest that, even in the absence of a formal diagnosis, a frail appearance may influence a provider's decision to perform GoC discussions after severe thermal injury. PMID- 28574882 TI - Surgical Outcomes of Posterior Spinal Fusion Alone Using Cervical Pedicle Screw Constructs for Cervical Disorders Associated With Athetoid Cerebral Palsy. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: The aim of this study was to investigate clinical outcomes after posterior spinal fusion (PSF) using cervical pedicle screw (CPS) constructs for cervical disorders associated with athetoid cerebral palsy (CP). SUMMARY OF BACKGROUND DATA: Traditionally, most patients with cervical myelopathy associated with CP have required combined anterior and posterior fusion to achieve solid stability against severe involuntary movement. METHODS: Thirty-one CP patients with cervical disorders who underwent PSF alone with a minimum 2-year follow-up (mean 58 months) were analyzed. All patients were treated with PSF using CPS constructs with or without decompression procedures. The average number of fused segments was 5.1 (range, 1-10 segments), and a halo jacket was applied in 16 patients for at least 2 months after surgery. Clinical outcomes using the Japanese Orthoedic Association scoring system (JOA score) and walking ability, radiographic sagittal alignment, fusion status, and surgery related complications were evaluated. RESULTS: The JOA score improved from 8.3 points preoperatively to 10.9 points at the final follow-up (P < 0.05). Although no patients experienced deterioration in their walking ability postoperatively, 10 patients were unable to walk at the final follow-up. Sagittal alignment, including C0-2 angle, C2-7 angle, and local alignment in fused segments, was maintained postoperatively. Twenty-five patients achieved fusion at the final follow-up (fusion rate: 81%), and fivepatients with nonunion required additional surgery. With regard to complications, 5 patients encountered postoperative upper extremity palsy. CONCLUSION: The CPS construct is amenable to achieve a relatively high fusion rate without correction loss, and good clinical outcomes can be achieved with a posterior single approach for CP patients. In the future, efforts should be made to make appropriate decisions regarding the fusion area, take preventative measures against postoperative upper extremity palsy, and simplify external orthoses after surgery, especially with the use of a halo jacket. LEVEL OF EVIDENCE: 4. PMID- 28574883 TI - Long-term Radiological and Clinical Outcomes After Using Bone Marrow Mesenchymal Stem Cells Concentrate Obtained With Selective Retention Cell Technology in Posterolateral Spinal Fusion. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: The aim of this study was to evaluate the long-term clinical and radiological outcomes of the use of bone marrow mesenchymal stem cell concentrate obtained with selective cell retention technology using Cellect with a particular collagen scaffold, Healos for posterolateral spinal fusion. SUMMARY OF BACKGROUND DATA: With the increasing rate of spinal fusion, the problem of pseudarthrosis, which contributes to recurrent pain with patient disability, is considered to be the most common cause of revision lumbar spine surgery. Intensive research is being carried out to develop an alternative source of bone grafting and improve the spinal fusion rate. METHODS: A retrospective review of hospital records was performed. Identified patients were contacted to have a clinical and radiological evaluation follow-up. Clinical outcome was evaluated using visual analog scales for the back pain (VAS), Oswestry Disability Index (ODI) scores, and quality of life (EQ-5D) questionnaire. Radiological outcome was evaluated by performing dynamic flexion/extension lateral views and calculation of segmental Cobb angle. Any implant-associated complication was reported. Computed tomography (CT) scans were also performed. RESULTS: Twenty-one patients were included and all patients achieved successful fusion. The mean difference of the segmental Cobb angle was 0.48 degrees (range 0.3 degrees -0.7 degrees ). Computed tomography scans showed solid bilateral fusion with bridging bone (Grade I) in all patients, but solid unilateral fusion with bridging bone (Grade II) was detected for one patient at one level. Patients started to resume working activities within a mean period of 3.5 months. The VAS score for the residual back pain was 4.1 +/- 2.1, whereas the ODI was 10.5 +/- 5.6 points, and the mean disability index was 21.1%. CONCLUSION: The use of bone marrow mesenchymal stem cell concentrate obtained with selective cell retention technology could be considered as an effective means for augmenting spinal fusion. LEVEL OF EVIDENCE: 3. PMID- 28574885 TI - From the Editor. PMID- 28574884 TI - Comparative Analysis of Three Imaging Modalities for Evaluation of Cervical Sagittal Alignment Parameters: A Validity and Reliability Study. AB - STUDY DESIGN: This was a radiologic validity and reliability study. OBJECTIVE: We aimed to assess the validity and reliability of measurements from standing lateral cervical radiography (XR), reconstructed midsagittal images of supine cervical computerized tomography (CT) scans, and supine magnetic resonance imaging (MRI) for evaluating C2-C7 distance (C27 SVA), C2-C7 Cobb angle (CL), T1 slope (T1S), thoracic inlet angle (TIA), and neck tilt (NT). SUMMARY OF BACKGROUND DATA: XR is the criterion standard imaging modality for measuring cervical sagittal alignment parameters. However, overlapping bony structures and soft tissue often make the upper end of the manubrium and cervicothoracic junction indiscernible. CT and MRI can overcome this limitation, but their reliability and validity have not been fully elucidated. METHODS: Fifty sets of three examinations from our database have been randomly selected. Three experienced spinal surgeons independently measured C27 SVA, CL, T1S, TIA, and NT. Paired t test and Pearson correlation were used to analyze the validity of CT and MRI in comparison with that of XR. Interobserver and intraobserver reliability were assessed by using the intraclass correlation coefficient (ICC). RESULTS: The paired t test confirmed the similarities of all CT (except C27 SVA) and MR parameters (except C27 SVA and CL) to the XR parameters (all P > 0.05). All parameters except C27 SVA were correlated (Pearson correlation coefficient, 0.523 0.913). Correlation was highest between CT and MRI and lowest between CT and XR. All three imaging modalities had excellent intraobserver and interobserver reliability (ICC range: 0.770-0.999). Intraobserver and interobserver reliability were highest with MRI and lowest with XR. CONCLUSION: CT and especially MRI were more reliable than XR for evaluating cervical sagittal alignment parameters. Considering the reliability and radiation exposure, MRI is a good alternative to XR for measuring cervical sagittal alignment parameters, especially thoracic inlet alignment. LEVEL OF EVIDENCE: 4. PMID- 28574886 TI - Guest Editorial. PMID- 28574887 TI - Preserving the Wisdom: Insight From Nurses Who Chose to Lead. PMID- 28574888 TI - Carrying Skills From One C-Suite to Another: An Interview With Dr Maureen Swick. AB - This interview of Dr Maureen Swick chronicles career development and preparation for a transition into the role of CEO of the American Organization of Nurse Executives. While there are an estimated 400 000 nurses in middle management roles in the United States and 5700 in the most senior nursing positions in US hospitals, Dr Swick has assumed a role leading the leaders and highlights those experiences that have influenced her and provides insights into her vision for nursing leadership. PMID- 28574889 TI - A Spiral of Transitions Leading to Broader Influence and Action. AB - This article describes lessons learned through a reflective analysis of job transitions experienced by a registered nurse from the time of entry into the profession until the current point where the nurse is engaged in state, national, and international policy development work. The centrality and symbiotic nature of the link between policy and practice and the importance of evidence and leadership have emerged as key aspects of the expanding spiral of influence traversed as a result of various career moves. At every stage, lessons have been learned. Some of these are professional in nature, but on occasion, the lessons have been more personal. The importance of mentors cannot be underestimated in terms of the support and guidance they offer but also the challenges they bring to existing patterns of thought and behavior. PMID- 28574890 TI - Normative and Cataclysmic Career Transitions: A Nurse's Memoir. AB - Drawn from 54 years of experience as a nursing professional, this author gives a personal account of 2 types of career transitions: (1) normative transitions/stages, which include position changes, educational pursuits, and promotion; and (2) cataclysmic transitions, such as dismissal, bankruptcy, and mergers, that arise out of disruptive work situations that dramatically influence one's beliefs, actions, and perspective over time and ultimately shape a career. The importance of influencers throughout a career and lessons learned along the way are also explored. PMID- 28574891 TI - Does a CEO's Departure Trigger a Crisis for a CNO? AB - For chief nursing officers, volatility has become an expected characteristic of the professional landscape. Recent studies indicate that this volatility is likely to continue for at least the next decade. For chief nursing officers caught in an organizational crisis, the thought of leaving the leadership ranks triggers professional angst and a range of personal emotion. This article examines the most common reasons chief nursing officers leave their positions and how they can take steps to rebound. It also explores the tools and resources that can positively affect these monumental transitions, whether voluntary or involuntary. PMID- 28574892 TI - Transitional Moments: Reflections on Fulfilling the Professional Role Across a Lifetime. AB - All leaders require a plan and a template for either transition from a career to another career or retirement. Part of this plan includes receiving transition information from others. Reflections about an individual's career, observations from a career, and insights about strategies to create a rich and robust transition experience are discussed in this article. Also included are suggestions for the "transition receivers," or those benefitting from the experiences and wisdom of others, to optimize their career transitions while recognizing the value of transitioning as a 2-way process and dialogue. PMID- 28574893 TI - Personal Experience Shapes Viewpoint on Transition to Retirement. AB - Executives transitioning to retirement experience professional and personal challenges. This article provides examples of decision points for timing and potential aspects to consider when transitioning to retirement. Examples are opinion-based as a result of personal experience and observations from an expert vantage point. PMID- 28574894 TI - An Unconventional Path Leads to a Lifetime Commitment to the Nursing Profession. AB - The author shares his learnings as a nurse leader. Currently, the president and chief executive officer (CEO) of CGFNS International, Inc. (formerly known as the Commission on Graduates of Foreign Nursing Schools), he discusses job transitions; the importance of networks and colleagues, and collaboration. PMID- 28574895 TI - Job and Role Transitions: The Pathway to Career Evolution. AB - An individual's career trajectory evolves with each job and role transition. Over time, job/role experiences trigger choices as to whether to stay in a particular job setting or role. Reflective questions guide the process of deciding whether and when it is time to transition. Considerations include role fit with lifestyle expectations, need for advanced knowledge and formal education, and readiness for upward or lateral movement. Using a framework modeled after the work of Bolman and Deal, this article presents 4 lenses to guide a careerist's readiness and need for change: human resource, structural, political, and symbolic factors. Each lens is introduced to reinforce a holistic approach to key triggers and considerations in career change. The summary culminates with how to foster a joy filled career. PMID- 28574896 TI - Growing Clinical and Academic Nursing Leaders: Building the Pipeline. AB - Nursing faces a crisis because there exists a dearth of qualified nurse academicians and administrators willing to step up to high-level leadership positions such as deanships and chief nursing operators. This article critically appraises the available literature regarding succession planning in the nursing profession and offers pragmatic suggestions to the profession to engage in succession planning in a deliberate and thoughtful manner. PMID- 28574897 TI - Description of Nurse Scientists in a Large Health Care System. AB - Replicating a research study that described the work of nurse scientists in children's hospitals, the purpose of the study was to describe the role, activities, and outcomes of nurse scientists employed in a national health care organization. The characteristics of nurses filling the nurse scientist role in clinical settings and outcomes associated with the role have not been extensively described. The setting of this study is ideal since the organization includes facilities of various sizes located in rural, urban, and suburban areas in 18 states. Names and contact information of nurse scientists were obtained from nurse executives at each of the 110 affiliated organizations. Nurse scientists completed an anonymous survey. The primary role of the nurse scientists is to facilitate the work of others. Recommendations to strengthen the research infrastructure are provided. PMID- 28574898 TI - Transformational Impact on Direct Care Nurses' Supporting the Magnet Site Visit. AB - Exposure to strategic project and workforce preparation for nursing excellence throughout organizational American Nurses Credentialing Center Magnet journeys has been observed as positively impacting the escort nurse's personal goal setting and achievement beyond the site visit. This article describes a project undertaken to capture the characteristics of staff nurses serving as Magnet escorts for hospital site visits. The positive relationship of that experience on goal setting and future workplace volunteerism for projects is presented. An association with nurse confidence through perceived self-efficacy is explored. The results have significance for leader and staff involvement in nursing projects and strategic goal achievement. PMID- 28574899 TI - Letter to the Editor. PMID- 28574900 TI - Hyperdense artery sign on computed tomography in acute coronary syndrome. PMID- 28574901 TI - First-in-man demonstration of complete bioresorbable vascular scaffold resorption after treatment of in-stent restenosis. PMID- 28574902 TI - Advanced Donation Programs and Deceased Donor-Initiated Chains-2 Innovations in Kidney Paired Donation. AB - Kidney paired donation (KPD) strategies have facilitated compatible living-donor kidney transplants for end-stage renal disease patients with willing but incompatible living donors. Success has inspired further innovations that expand opportunities for kidney-paired donation. Two such innovations are the advanced donation strategy in which a donor provides a kidney before their recipient is matched, or even in need of, a kidney transplant, and deceased donor initiated chains in which chains are started with deceased donors rather than altruistic living donors. Although these innovations may expand KPD, they raise several ethical issues. Specific concerns raised by advanced donation include the management of uncertainty, the extent of donor and recipient consent, the scope of the obligation that the organization has to the kidney exchange paired recipient, the naming of alternative recipients, and the potential to unfairly advantage the recipient. Use of deceased donors for chain-initiating kidneys raises ethical issues concerning the consent process for each involved party, the prioritization of deceased donor kidneys, the allocation of chain ending kidneys, and the value of a living donor kidney versus a deceased donor kidney. We outline each ethical issue and discuss how it can be conceptualized and managed so that these KPD innovations programs are ultimately successful. PMID- 28574903 TI - HSCT-Based Approaches for Tolerance Induction in Renal Transplant. AB - Renal transplantation has become the preferred treatment for end stage kidney failure. Although short-term graft survival has significantly improved as advances in immunosuppression have occurred, long-term patient and graft survival have not. Approximately only 50% of renal transplant recipients are alive at 10 years due to the toxicities of immunosuppression and alloimmunity. Emerging research on cell-based therapies is opening a new door for patients to receive the organs they need without sacrificing quality of life and longevity because of drug-based immunosuppression. Research has focused on inducing tolerance, a state in which the body accepts the transplant and graft function is stable. Cell-based therapies to facilitate chimerism and achieve tolerance in major histocompatibility disparate recipients have been developed in mouse, swine, canine, and nonhuman primate models. These findings are now being translated into the clinic in several trials currently underway. Protocols that use a combination of traditional therapeutic agents paired with cell populations including hematopoietic stem cells, regulatory T cells, and facilitating cells are being conducted with the objective to harness the donor immune system to protect the transplanted tissue. The benefits and feasibility of the clinical application of cell-based therapy has been demonstrated, and promising results have been achieved. Here we discuss the preclinical work that has led to the clinical application of the various approaches and a summary of the most current clinical data from groups throughout the world. PMID- 28574904 TI - Randomized Clinical Trials of Corticosteroids in Septic Shock: Possibly Feasible, But Will They or Should They Change My Practice? PMID- 28574905 TI - Sepsis Subclasses: Be Careful of What You Wish for. PMID- 28574906 TI - "One Piece at a Time": The Cache of Acute Kidney Injury Data in the Electronic Medical Record. PMID- 28574907 TI - "The Times They Are A-Changin": Universal Delirium Screening in Pediatric Critical Care. PMID- 28574908 TI - Mo Money Mortality: Cost and Value in the PICU. PMID- 28574910 TI - Is Functional Status Scale a Reliable Measure of Neurologic Outcome Post Extracorporeal Membrane Oxygenation? PMID- 28574909 TI - What's the Flight Plan, Captain? PMID- 28574911 TI - Does a Medical Emergency Team Activation Define a New Paradigm of Mortality Risk? PMID- 28574912 TI - We Can Not Compartmentalize Our Patients! Overlapping Symptoms of Iatrogenic Withdrawal Syndrome, Pediatric Delirium, and Anticholinergic Toxidrome. PMID- 28574913 TI - Central Venous to Arterial CO2 Difference After Cardiac Surgery in Children: Many Unknowns. PMID- 28574914 TI - The authors reply. PMID- 28574915 TI - Effect of Sitting Pause Times on Balance After Supine to Standing Transfer in Dim Light. AB - BACKGROUND AND PURPOSE: The risk of falling for older adults increases in dimly lit environments. Longer sitting pause times, before getting out of bed and standing during the night, may improve postural stability. The purpose of this study was to measure the effect of sitting pause times on postural sway velocity immediately after a supine to standing transfer in a dimly lit room in older adult women. METHODS: Eighteen healthy women aged 65 to 75 years who were able to independently perform supine to standing transfers participated in the study. On each of 2 consecutive days, participants assumed the supine position on a mat table and closed their eyes for 45 minutes. Then, participants were instructed to open their eyes and transfer from supine to sitting, with either 2- or 30-second pause in the sitting position followed by standing. The sitting pause time order was randomized. RESULTS: A significant difference was observed in postural sway velocity between the 2- and 30-second sitting pause times. The results revealed that there was less postural sway velocity after 30-second than 2-second sitting pause time (0.61 +/- 0.19 vs 1.22 +/- 0.68, P < .001). DISCUSSION: Falls related to bathroom usage at night are the most common reported falls among older adults. In the present study, the investigators studied the effect of sitting pause times on postural sway velocity after changing position from supine to standing in a dimly lit environment. The findings showed that the mean postural sway velocity was significantly less after 30-second sitting pause time compared with 2-second sitting pause time. CONCLUSIONS: Postural sway velocity decreased when participants performed a sitting pause of 30 seconds before standing in a dimly lit environment. These results suggest that longer sitting pause times may improve adaptability to dimly lit environments, contributing to improved postural stability and reduced risk of fall in older adult women when getting out of bed at night. PMID- 28574916 TI - Functional Performance and Balance in the Oldest-Old. AB - BACKGROUND AND PURPOSE: The group of individuals 85 years and over (termed oldest old) is the fastest-growing population in the Western world. Although daily functional abilities and balance capabilities are known to decrease as an individual grows older, little is known about the balance and functional characteristics of the oldest-old population. The aims of this study were to characterize balance control, functional abilities, and balance self-efficacy in the oldest-old, to test the correlations between these constructs, and to explore differences between fallers and nonfallers in this age group. METHODS: Forty-five individuals living in an assisted living facility who ambulated independently participated in the study. The mean age was 90.3 (3.7) years. Function was tested using the Late-Life Function and Disability Instrument (LLFDI). Balance was tested with the mini-Balance Evaluation System Test (mini-BESTest) and the Timed Up and Go (TUG) test. Balance self-efficacy was tested with the Activities Specific Balance Confidence (ABC) scale. RESULTS: The mean total function LLFDI score was 63.2 (11.4). The mean mini-BESTest score was 69.8% (18.6%) and the mean TUG time was 12.6 (6.9) seconds. The mean ABC score was 80.2% (14.2%). Good correlation (r > 0.7) was observed between the ABC and the function component of the LLFDI, as well as with the lower extremity domains. Correlations between the mini-BESTest scores and the LLFDI were fair to moderate (r's range: 0.38-0.62). Age and ABC scores were significant independent explanators of LLFDI score (P = .0141 and P = .0009, respectively). Fallers and nonfallers differed significantly across all outcome measures scores, except for TUG and for the "Reactive Postural Control" and "Sensory Orientation" domains of the mini-BESTest. DISCUSSION AND CONCLUSIONS: The results of this study provide normative data regarding the balance and functional abilities of the oldest-old, and indicate a strong association between self-efficacy and function. These results emphasize the importance of incorporating strategies that maintain and improve balance self efficacy in interventions aimed at enhancing the functional level of this cohort. PMID- 28574917 TI - An Intervention to Improve Cultural Competence in Graduate Nursing Education. AB - Noting the small number of studies on the influence of an entire curriculum on graduate nursing students' cultural competence, the researchers examined the effect of a curricular intervention using a pretest-posttest design. The study, conducted from 2012 to 2014, focused solely on the Doctor of Nursing Practice program at a midwestern university. Results from a pre- and postintervention faculty curriculum survey indicated that the percentage of courses including a cultural competence objective increased from 65 percent to 81 percent. Results from the pre- and postintervention administration of the Transcultural Self Efficacy Tool showed a statistically significant improvement in students' overall score and three subscale scores. PMID- 28574919 TI - Re: Collider Bias Is Only a Partial Explanation for the Obesity Paradox. PMID- 28574920 TI - Asking Too Much of Epidemiologic Studies: The Problem of Collider Bias and the Obesity Paradox. PMID- 28574921 TI - Mediation Analysis for Censored Survival Data Under an Accelerated Failure Time Model. AB - Recent advances in causal mediation analysis have formalized conditions for estimating direct and indirect effects in various contexts. These approaches have been extended to a number of models for survival outcomes including accelerated failure time models, which are widely used in a broad range of health applications given their intuitive interpretation. In this setting, it has been suggested that under standard assumptions, the "difference" and "product" methods produce equivalent estimates of the indirect effect of exposure on the survival outcome. We formally show that these two methods may produce substantially different estimates in the presence of censoring or truncation, due to a form of model misspecification. Specifically, we establish that while the product method remains valid under standard assumptions in the presence of independent censoring, the difference method can be biased in the presence of such censoring whenever the error distribution of the accelerated failure time model fails to be collapsible upon marginalizing over the mediator. This will invariably be the case for most choices of mediator and outcome error distributions. A notable exception arises in case of normal mediator-normal outcome where we show consistency of both difference and product estimators in the presence of independent censoring. These results are confirmed in simulation studies and two data applications. PMID- 28574922 TI - Severe complicated neutropenia in two patients with metastatic non-small-cell lung cancer treated with nivolumab. AB - Checkpoint inhibitors effectively enhance the natural immune response against cancer, but they are also known to induce a unique spectrum of immune-related adverse events. Here, we report the first case of isolated neutropenia subsequent to nivolumab therapy. Prominent activated T-cells were found in the patient's serum and bone marrow alongside evidence of maturational defects in neutrophil precursors. Antineutrophil antibodies were not detected despite reliable testing techniques. A T-cell-mediated response is probable, consistent with the established mechanism for the development of other immune-related toxicities. Awareness of this rare and severe side effect reinforces the importance of early diagnosis and prompt initiation of proper treatment. PMID- 28574923 TI - EVALUATION OF PATCHY ATROPHY SECONDARY TO HIGH MYOPIA BY SEMIAUTOMATED SOFTWARE FOR FUNDUS AUTOFLUORESCENCE ANALYSIS. AB - PURPOSE: To evaluate the progression of patchy atrophy in high myopia using semiautomated software for fundus autofluorescence (FAF) analysis. METHODS: The medical records and multimodal imaging of 21 consecutive highly myopic patients with macular chorioretinal patchy atrophy (PA) were retrospectively analyzed. All patients underwent repeated fundus autofluorescence and spectral domain optical coherence tomography over at least 12 months. Color fundus photography was also performed in a subset of patients. Total atrophy area was measured on FAF images using Region Finder semiautomated software embedded in Spectralis (Heidelberg Engineering, Heidelberg, Germany) at baseline and during follow-up visits. Region Finder was compared with manually measured PA on FAF images. RESULTS: Twenty-two eyes of 21 patients (14 women, 7 men; mean age 62.8 + 13.0 years, range 32-84 years) were included. Mean PA area using Region Finder was 2.77 +/- 2.91 SD mm at baseline, 3.12 +/- 2.68 mm at Month 6, 3.43 +/- 2.68 mm at Month 12, and 3.73 +/- 2.74 mm at Month 18 (overall P < 0.005); this accounts for PA progression rate of 0.821 mm/year. Atrophy progression was significantly greater among eyes with larger PA compared with smaller baseline PA at Months 6, 12, and 18. There was no statistically significant difference between semiautomated Region Finder PA area and manually measured PA area on FAF images. CONCLUSION: Fundus autofluorescence analysis by Region Finder semiautomated software provides accurate measurements of lesion area and allows us to quantify the progression of PA in high myopia. In our series, PA enlarged significantly over at least 12 months, and its progression seemed to be related to the lesion size at baseline. PMID- 28574924 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN RETINAL VEIN OCCLUSION: Correlations Between Macular Vascular Density, Visual Acuity, and Peripheral Nonperfusion Area on Fluorescein Angiography. AB - PURPOSE: To study correlations in patients with retinal vein occlusion between the automatically quantified macular vascular densities in the superficial and deep capillary plexus (DCP) obtained using optical coherence tomography angiography (OCTA) and the data from conventional examination, particularly visual acuity and peripheral retinal nonperfusion assessed using fluorescein angiography (FA). METHODS: Retrospective, observational study of patients with retinal vein occlusion who underwent a comprehensive ophthalmic examination including FA and OCTA using the AngioVue OCTA system version 2015.100.0.35 (OptovueRTVue XR 100; AVANTI, Inc, Fremont, CA). Vascular densities in the superficial capillary plexus and DCP, as well as the area of the foveal avascular zone, were measured using the AngioAnalytics software. RESULTS: Our study of 65 eyes of 61 patients (33 men, mean age: 67 years) showed a significant correlation between peripheral nonperfusion on FA and (1) automatically quantified global vascular density in both plexus (P = 0.021 for the DCP) and (2) foveal avascular zone area (P = 0.037). We also found significant correlations between capillary dropouts in both plexus and peripheral nonperfusion (P < 0.001 for both) and between visual acuity and vascular densities (P = 0.002 for the global density in the DCP). Global density less than 46% in the DCP was associated to the presence of peripheral nonperfusion area on FA (P = 0.003) and to enlargement of the superficial foveal avascular zone (P = 0.002). CONCLUSION: Our study demonstrated a significant correlation between automatically quantified macular vascular density on OCTA and peripheral nonperfusion on FA; OCTA could help identify high risk retinal vein occlusion patients who may benefit from further evaluation using FA. PMID- 28574925 TI - The phosphodiesterase III inhibitor cilostazol protects the brain microvasculature from collagenase injury. AB - A patient's prognosis, including mortality, after intracranial hemorrhage (ICH) is strongly related to the disruption of the blood-brain barrier caused by damage to vascular endothelial cells (ECs). We reported previously that cilostazol, a phosphodiesterase III inhibitor, ameliorated collagenase-induced ICH in a mouse model. We also reported that cilostazol protected cultured ECs in a blood-brain barrier model. However, the influence of cilostazol on vascular structure and cell morphology remains unclear. Therefore, we investigated whether cilostazol exerts protective effects on vascular structures, such as the extracellular matrix (ECM). A mouse model of collagenase-induced ICH was used to observe structures of the brain vasculature in a peri-hemorrhagic lesion using transmission electron microscopy. We then evaluated the morphology of the ECM and cytoskeleton in human brain microvasculature ECs by immunostaining. The brain vasculature was changed 24 h after induction of ICH. Cilostazol (30 mg/kg, orally) suppressed the thinning of the basement membrane, which is formed by the ECM components collagen IV and laminin. Moreover, this drug also suppressed the enlargement of ECs caused by ICH. Collagenase treatment (30 U/ml) of human brain microvasculature ECs caused a decrease in collagen IV expression and an increase in the number and size of the intercellular spaces, as indicated by beta-actin immunostaining. Pretreatment of with 10 uM cilostazol suppressed these increases in the number and size of the intercellular spaces. These findings suggest that cilostazol protects the ECM of the brain microvasculature against ICH both in vivo and in vitro. PMID- 28574926 TI - Hyposmia, symptoms of rapid eye movement sleep behavior disorder, and parkinsonian motor signs suggest prodromal neurodegeneration in 22q11 deletion syndrome. AB - The 22q11 deletion syndrome (22q11DS) is one of the most common genomic disorders in humans. There is an increased risk of Parkinson's disease (PD) in individuals with 22q11DS. The characteristic motor features of PD begin when more than 50% of dopaminergic neurons in the substantia nigra have degenerated. Before this, there is a prodromal period, of up to 20 years, in which nonmotor features such as hyposmia, autonomic dysfunction, rapid eye movement sleep behavior disorder, and subtle motor dysfunction can occur. We used validated clinical tools to investigate the presence of prodromal markers of PD in 50 adults with 22q11DS and 14 matched deletion-negative controls. The median score on the University of Pennsylvania Smell Identification Test was significantly lower in the 22q11 deletion group, and 44% scored in the hyposmic range (P=0.024). Individuals with 22q11DS were significantly more likely to report autonomic symptoms (urinary dysfunction or constipation, P=0.016). Twenty-eight percent of 22q11DS participants scored above the threshold for rapid eye movement sleep behavior disorder on a screening questionnaire (P=0.022). Four 22q11DS participants had parkinsonian motor signs on examination, which did not fulfill the diagnostic criteria for PD. We report prodromal markers of PD in 22q11DS. These may help identify individuals with 22q11 deletion at risk of neurological disease. However, the significance of these signs needs to be confirmed by longitudinal studies of development of PD. PMID- 28574927 TI - Altered functional connectivity of the periaqueductal gray in chronic neck and shoulder pain. AB - Chronic neck and shoulder pain with cervical spondylotic radiculopathy (CNSP-CSR) is one of the most common clinical chronic pain diseases. This study aimed to investigate the abnormal patterns in functional connectivity (FC) pertaining to the periaqueductal gray matter (PAG) in patients with CNSP-CSR. A seed-based FC analysis was carried out for the right ventrolateral PAG and a correlation analysis was carried out with pain intensity, duration, and the extracted mean z scores. The PAG FC was significantly positively associated with the right orbital inferior frontal gyrus, supramarginal gyrus/postcentral gyrus, putamen, and the left anterior cingulate cortex, and significant negative FC was observed in the right lingual gyrus/occipital cortex in patients with CNSP-CSR. A significant negative correlation was found between the pain intensity and the mean z scores in the left anterior cingulate cortex. Our study provides evidence to show that patients with CNSP-CSR have abnormal FC in the PAG-centered pain modulation network. Knowledge of this abnormal FC might lead to a better understanding of the mechanism underlying CNSP-CSR, especially the descending pain modulation system involved in chronic pain. PMID- 28574928 TI - Clinical and Economic Burden of Peristomal Skin Complications in Patients With Recent Ostomies. AB - PURPOSE: The purpose of this study was to estimate the risk and economic burden of peristomal skin complications (PSCs) in a large integrated healthcare system in the Midwestern United States. DESIGN: Retrospective cohort study. SUBJECTS AND SETTING: The sample comprised 128 patients; 40% (n = 51) underwent colostomy, 50% (n = 64) underwent ileostomy, and 10% (n = 13) underwent urostomy. Their average age was 60.6 +/- 15.6 years at the time of ostomy surgery. METHODS: Using administrative data, we retrospectively identified all patients who underwent colostomy, ileostomy, or urostomy between January 1, 2008, and November 30, 2012. Trained medical abstractors then reviewed the clinical records of these persons to identify those with evidence of PSC within 90 days of ostomy surgery. We then examined levels of healthcare utilization and costs over a 120-day period, beginning with date of surgery, for patients with and without PSC, respectively. Our analyses were principally descriptive in nature. RESULTS: The study cohort comprised 128 patients who underwent ostomy surgery (colostomy, n = 51 [40%]; ileostomy, n = 64 [50%]; urostomy, n = 13 [10%]). Approximately one-third (36.7%) had evidence of a PSC in the 90-day period following surgery (urinary diversion, 7.7%; colostomy, 35.3%; ileostomy, 43.8%). The average time from surgery to PSC was 23.7 +/- 20.5 days (mean +/- SD). Patients with PSC had index admissions that averaged 21.5 days versus 13.9 days for those without these complications. Corresponding rates of hospital readmission within the 120-day period following surgery were 47% versus 33%, respectively. Total healthcare costs over 120 days were almost $80,000 higher for patients with PSCs. CONCLUSIONS: Approximately one third of ostomy patients over a 5-year study period had evidence of PSCs within 90 days of surgery. Costs of care were substantially higher for patients with these complications. PMID- 28574929 TI - Treatment Patterns, Outcomes, and Costs for Bowel Obstruction in Ovarian Cancer. AB - OBJECTIVE: The aim of this study was to assess treatment patterns, outcomes, and costs for bowel obstruction in ovarian cancer. METHODS/MATERIALS: All patients with stage II to IV ovarian cancer who were admitted for bowel obstruction greater than or equal to 6 months after cancer diagnosis from 2000 to 2011 were identified from the Surveillance, Epidemiology, and End Results registry-Medicare database. Management strategies and outcomes of bowel obstruction were compared. RESULTS: Among 1397 women with bowel obstruction, 562 (40%) underwent surgery, and 154 (11%) had a gastrostomy or jejunostomy (G/J) tube placed. Thirty-four percent of patients who underwent surgery subsequently received chemotherapy, compared with 8% of those managed with a G/J tube (odds ratio, 4.8; 95% confidence interval [CI], 2.7-8.8). Thirty-day complications were higher for patients in the surgery group compared with those in the tube group (69% vs 46%; odds ratio, 2.5; 95% CI, 1.8-3.7), as were mean adjusted 30-day total costs ($28,872 vs $18,528, P < 0.001). Median survival was greater for women who underwent surgery compared with those who had a G/J tube (5.3 vs 1.2 months; adjusted hazard ratio, 0.31; 95% CI, 0.25-0.38). The median survival of patients in whom surgical correction failed and required G/J tube placement during the same inpatient admission was 2.6 months. Women who received postintervention chemotherapy had improved survival compared with those who did not in both the surgery (17.0 vs 2.8 months, P < 0.001) and G/J tube (5.7 vs 1.0 months, P < 0.001) groups. CONCLUSIONS: In women with ovarian cancer who develop bowel obstruction, surgery may benefit a subset of patients, likely related to the ability to receive subsequent chemotherapy. Efforts to identify those who derive no benefit may reduce unnecessary laparotomy, along with its associated complications and costs. Given this population's limited survival, patient preferences should be evaluated in future studies assessing the management of bowel obstruction. PMID- 28574930 TI - Use of Adjuvant Chemotherapy, Radiation Therapy, or Combined Modality Therapy and the Impact on Survival for Uterine Carcinosarcoma Limited to the Pelvis. AB - OBJECTIVE: Clinical outcomes for patients with uterine carcinosarcoma are poor after surgical management alone. Adjuvant therapies including chemotherapy (CT) and/or radiation therapy (RT) have been previously investigated, but the optimal management of this disease remains controversial. The purposes of this study were to analyze the patterns of use of adjuvant CT and RT and to assess the impact on survival of each of these treatment regimens using the National Cancer Data Base. METHODS/MATERIALS: The National Cancer Data Base was queried for patients given a diagnosis of uterine carcinosarcoma confined to the pelvis who underwent total hysterectomy/bilateral salpingo-oophorectomy between 2004 and 2011. Patients were excluded if they survived less than 4 months after diagnosis. Data regarding CT and RT use were collected. Overall survival (OS) was analyzed using the Kaplan Meier method. Multivariable Cox regression analysis was performed to evaluate the effect of covariates on OS. RESULTS: A total of 4906 patients were included in this study. Median age was 67 years (interquartile range, 60-75 years). Median follow-up was 28.9 months (interquartile range, 15.4-52.9 months). There were 1777 patients (36.2%) who received no adjuvant treatment, 971 (19.8%) who received CT alone, 1060 (21.6%) who received RT alone, and 1098 (22.4%) who received both RT and CT. The 5-year OS for patients receiving no adjuvant therapy, adjuvant RT alone, adjuvant CT alone, and combined CT and RT were 44.9%, 47.1%, 47.5%, and 62.9%, respectively. On pairwise analysis, combined CT and RT was associated with improved survival compared with all other subgroups (P < 0.001). On multivariable Cox regression analysis, combined CT and RT (hazard ratio, 0.50; 95% confidence interval, 0.44-0.57; P < 0.001) and CT alone (hazard ratio, 0.78; 95% confidence interval, 0.69-0.88; P < 0.001) were significantly associated with improved OS, whereas RT alone was not. CONCLUSIONS: Combination therapy with CT and RT was associated with significantly improved 5-year OS compared with no further therapy, RT alone, or CT alone. PMID- 28574931 TI - Neoadjuvant Weekly Paclitaxel-Carboplatin Is Effective in Stage I-II Cervical Cancer. AB - OBJECTIVE: Neoadjuvant chemotherapy (NACT) followed by surgery in cervical cancer is widely studied with paclitaxel-ifosfamide-cisplatinum 3 weekly (TIP). Although the response rates with TIP are high, the toxicity is substantial. Therefore, this study evaluates dose-dense paclitaxel-carboplatin (TC) as an alternative. METHODS: In this prospective phase 2 study trial, we included 36 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB1 to IIB cervical cancer, who received 9 weeks' NACT dose-dense TC (median weekly dose paclitaxel 60 mg/m, carboplatinum area under the curve 2.7). Radiological response was evaluated by RECIST (Response Evaluation Criteria in Solid Tumors). Optimal pathologic response (OPT) was defined as complete disappearance of tumor (complete response [CR]) or residual disease with less than 3-mm stromal invasion (PR1). Suboptimal pathologic response consisted of persistent residual disease with more than 3-mm stromal invasion (PR2). RESULTS: Nine patients had a FIGO stage IB1 (25%), 7 had stage IB2(19%), 3 had stage IIA (8%), and 17 had stage IIB disease (47%). Evaluation by magnetic resonance imaging after NACT showed 32 RECIST responses (89%) (CR in 11, PR in 21). Patients who were inoperable had insufficient reduction of the tumor to be operable (4 patients), progressive disease (1 patient), or stable disease (1 patient). Thirty patients were suitable for surgery after NACT. Pathology showed OPT in 50% (CR in 10, PR1 in 5). Thirteen patients had pathologic lymph nodes on radiological evaluation before start of chemotherapy. After chemotherapy, the lymph nodes were negative in 6 (47%) of these patients (pathologic complete remission). Postoperative chemoradiotherapy was administered in 11 patients (2 because of close resection margins, 5 because of metastatic lymph node after surgery, 2 because of close resection margins and metastatic lymph nodes after surgery, and 1 tumor >4 cm after NACT). Hematologic toxicity was acceptable with no febrile neutropenia and a low nonhematologic toxicity. The estimated 5-year overall survival was 70.8%. CONCLUSIONS: Neoadjuvant TC dose-dense in cervical carcinoma has a high response rate, comparable with TIP, and an acceptable toxicity. PMID- 28574932 TI - Vascular Endothelial Growth Factor (VEGF) Polymorphisms and Serum VEGF Levels in Women With Epithelial Ovarian Cancer, Benign Tumors, and Healthy Ovaries. AB - OBJECTIVE: This study analyzed the relation of 5 single-nucleotide polymorphisms (SNPs) in the VEGF (vascular endothelial growth factor) gene in patients with epithelial ovarian cancer (EOC), compared with patients carrying benign tumors or healthy ovaries. We studied serum VEGF levels and the relation with SNPs and association between VEGF SNPs and haplotypes with progression-free survival (PFS) in patients with cancer. METHODS: The genotyping of VEGF gene polymorphisms ( 2578 C/A, -1154 G/A, -460 T/C, +405 G/C, +936 C/T) was performed in DNA isolated from blood samples of 100 women. The different genotypes were evaluated by quantitative real-time polymerase chain reaction. Vascular endothelial growth factor protein concentration was assessed in serum using solid-phase sandwich enzyme-linked immunosorbent assay. RESULTS: We found statistically significant differences in the distribution of VEGF genotypes among the 3 groups of patients: -2578 C/A between those with EOC and healthy ovary (P = 0.04), -460 T/C between those with EOC and healthy ovary (P = 0.03), and -460 T/C between those with benign tumors and healthy ovary (P = 0.02). Vascular endothelial growth factor serum levels were analyzed in patients with EOC. Higher levels were found in patients with clear cell carcinoma compared with those with serous, mucinous, or endometrioid tumors (P < 0.05). No clear association was observed between VEGF SNPs and serum VEGF levels. There was no significant correlation between VEGF SNPs and PFS. In haplotype analysis, CGTCT and CGTGT showed worse prognosis without reaching the statistical significance. CGCGC and AGTGC haplotypes had statistically significant differences among patients with EOC, benign tumors, and healthy ovaries (Ps = 0.046 and 0.041, respectively). CONCLUSIONS: The distribution of VEGF genotypes was different in patients with EOC, compared with those with benign tumors or women with healthy ovaries. Vascular endothelial growth factor serum levels were higher in patients with clear cell carcinoma. No correlation was found with improved PFS, but CGTCT and CGTGT haplotypes showed worse prognosis. PMID- 28574933 TI - Real-World Management of Trabectedin/Pegylated Liposomal Doxorubicin in Platinum Sensitive Recurrent Ovarian Cancer Patients: A National Survey. AB - BACKGROUND: Trabectedin (T) plus pegylated liposomal doxorubicin (PLD) is approved for treatment of platinum-sensitive recurrent ovarian cancer (ROC). Despite the recommendations and guidelines, variations in managing T/PLD administration in routine clinical practice cannot be excluded. We aimed at setting up an Italian survey collecting data about management of T/PLD administration in ROC patients. METHODS: We carried out the development of a questionnaire-based survey on routine clinical practice in the management of ROC patients administered T/PLD. The survey registered the physicians' approach to modification/discontinuation of treatment, type of modifications, reasons why, and so on. The survey was transmitted to medical oncologists and gynecologic oncologists practicing in national centers/institutions. RESULTS: Fifty-eight Italian centers/institutions returned the compiled questionnaire; participants practiced at community cancer centers or hospitals (56.9%), academic institutions (36.2%), and other settings (private clinics, etc) (6.9%). There was no statistically significant difference in the distribution of practice setting according to geographic areas. Most responders were medical oncologists (84.5%) and were members (82.8%) of at least 1 scientific society or cooperative group. Almost 31.5% of responders reported interruption of the whole treatment, mostly because of toxicity (41.2%), followed by patients' choice (29.4%), or achievement of clinical benefit (23.5%). Dose reduction was referred by 47.4% of responders. Reduction of dose for both drugs was referred by 88.5% of responders, and the extent of dose reduction ranged between 10% and 30%. CONCLUSIONS: This survey highlights the gaps in transposing evidence-based or consensus guidelines in the real-world management of T/PLD administration; these findings could be useful in order to focus the attention on specific knowledge and/or experience gaps and plan pertinent educational programs. PMID- 28574934 TI - PFO Closure for Cryptogenic Stroke: A Review and Clinical Treatment Algorithm. AB - With a high prevalence in the general population of approximately 25%, and a prevalence in the cryptogenic stroke population approaching 40%, the propensity of a patent foramen ovale (PFO) to precipitate or enable stroke, especially in young, otherwise healthy individuals, has been the subject of much debate. With proof of concept achieved via imaging modalities documenting thrombus-in-transit, and the development of minimally-invasive percutaneous approaches to closure, multiple observational studies and, more recently, several completed randomized controlled trials have sought to answer the question of when and in whom PFO closure should occur. We describe the historical context of PFO closure and review the observational and randomized control trial evidence in this field, culminating in the recent Food and Drug Administration approval of the first dedicated closure device for PFO. Guidelines and consensus statements are discussed, and a novel treatment algorithm is proposed. Future directions in PFO closure will include new devices, further data from completed and upcoming clinical trials, and potential expansion into other disease states associated with PFO. PMID- 28574935 TI - Genetic Insights Into Bicuspid Aortic Valve Disease. AB - Bicuspid aortic valve (BAV) is the most common valvular congenital heart defect in the general population. BAV is commonly associated with the presence of other congenital cardiovascular malformations, which leads to cardiovascular complications requiring surgery in around 27% of cases. Familial clustering of BAV is well-recognized, and international guidelines advocate that first-degree relatives of patients with BAV be screened. Studies of genetic linkage in affected families, syndromic forms of BAV, and sporadic patients led to discoveries of genetic loci harboring genes involved in the development of BAV. However, only a few of these findings have been replicated in other populations and been proven functional in animal models. This task is further complicated by the phenotypic and genetic heterogeneity of BAV disease. BAV differs in valve fusion patterns and some studies have suggested that different valve fusion patterns originate from different pathophysiological processes. We present an overview of the published work on genetic linkage and its association with BAV disease. Presented articles used different discovery strategies ranging from candidate gene association to whole exome sequencing, as well as various validation protocols. Although still very limited, our understanding of the molecular pathology of BAV disease is likely to influence current clinical practice by enabling genetic counseling, prenatal diagnosis, and risk stratification for individual patients. This task will be made possible thanks to increasing availability, as well as the reduced cost of next-generation sequencing and bioinformatic processing of data. PMID- 28574936 TI - Coronary Microcirculatory Dysfunction in Human Cardiomyopathies: A Pathologic and Pathophysiologic Review. AB - Cardiomyopathies are a heterogeneous group of diseases of the myocardium. The term cardiomyopathy involves a wide range of pathogenic mechanisms that affect the structural and functional states of cardiomyocytes, extravascular tissues, and coronary vasculature, including both epicardial coronary arteries and the microcirculation. In the developed phase, cardiomyopathies present with various clinical symptoms: dyspnea, chest pain, palpitations, swelling of the extremities, arrhythmias, and sudden cardiac death. Due to the heterogeneity of cardiomyopathic patterns and symptoms, their diagnosis and therapies are great challenges. Despite extensive research, the relation between the structural and functional abnormalities of the myocardium and the coronary circulation are still not well understood in the various forms of cardiomyopathy. The main pathological characteristics of cardiomyopathies and the coronary microcirculation develop in a progressive manner due to (1) genetic-immunologic-systemic factors; (2) comorbidities with endothelial, myogenic, metabolic, and inflammatory changes; (3) aging-induced arteriosclerosis; and (4) myocardial fibrosis. The aim of this review is to summarize the most important common pathological features and/or adaptations of the coronary microcirculation in various types of cardiomyopathies and to integrate the present understanding of the underlying pathophysiological mechanisms responsible for the development of various types of cardiomyopathies. Although microvascular dysfunction is present and contributes to cardiac dysfunction and the potential outcome of disease, the current therapeutic approaches are not specific for the given types of cardiomyopathy. PMID- 28574938 TI - Chronic Anterior Pelvic Instability: Diagnosis and Management. AB - Chronic anterior pelvic ring instability can cause pain and disability. Pain typically is localized to the suprapubic area or inner thigh; often is associated with lower back or buttock pain; and may be exacerbated by activity, direct impact, or pelvic ring compression. Known etiologies of chronic anterior pelvic ring instability include pregnancy, parturition, trauma, insufficiency fractures, athletics, prior surgery, and osteitis pubis. Diagnosis often is delayed. Physical examination may reveal an antalgic or waddling gait, tenderness over the pubic bones or symphysis pubis, and pain with provocative maneuvers. AP pelvic radiographs may demonstrate chronic degenerative changes at the pubic symphysis or nonhealing fractures. Standing single leg stance (flamingo view) radiographs can demonstrate pathologic motion at the pubic symphysis. CT may be useful in assessing posterior pelvic ring involvement. The initial management is typically nonsurgical and may include the use of an orthosis, activity modification, medication, and physical therapy. If nonsurgical modalities are unsuccessful, surgery may be warranted, although little evidence exists to guide treatment. Surgical intervention may include internal fixation alone in select patients, the addition of bone graft to fixation, or symphyseal arthrodesis. In some patients, additional stabilization or arthrodesis of the posterior pelvic ring may be indicated. PMID- 28574937 TI - Vitamin D Deficiency and Supplementation in Cardiovascular Disorders. AB - Cardiovascular disease (CVD) is the leading cause of death in developed countries. Similarly, the frequency of vitamin D deficiency is increasing, and a number of epidemiologic and clinical studies have suggested that there is an increased risk of CVD among people with depletion of this vitamin. This has raised much interest in the potential pathogenic and therapeutic role of vitamin D in CVD. However, randomized trials and meta-analyses have not shown a clear benefit of vitamin D supplementation with respect to cardiovascular events. Herein, we provide a comprehensive review of the most relevant evidence to date regarding vitamin D deficiency and supplementation, and their respective impact on CVD prevention and treatment. PMID- 28574939 TI - Management of Tarsometatarsal Joint Injuries. AB - Joint disruptions to the tarsometatarsal (TMT) joint complex, also known as the Lisfranc joint, represent a broad spectrum of pathology from subtle athletic sprains to severe crush injuries. Although injuries to the TMT joint complex are uncommon, when missed, they may lead to pain and dysfunction secondary to posttraumatic arthritis and arch collapse. An understanding of the appropriate anatomy, mechanism, physical examination, and imaging techniques is necessary to diagnose and treat injuries of the TMT joints. Nonsurgical management is indicated in select patients who maintain reduction of the TMT joints under physiologic stress. Successful surgical management of these injuries is predicated on anatomic reduction and stable fixation. Open reduction and internal fixation remains the standard treatment, although primary arthrodesis has emerged as a viable option for certain types of TMT joint injuries. PMID- 28574940 TI - Management of Lumbar Conditions in the Elite Athlete. AB - Lumbar disk herniation, degenerative disk disease, and spondylolysis are the most prevalent lumbar conditions that result in missed playing time. Lumbar disk herniation has a good prognosis. After recovery from injury, professional athletes return to play 82% of the time. Surgical management of lumbar disk herniation has been shown to be a viable option in athletes in whom nonsurgical measures have failed. Degenerative disk disease is predominately genetic but may be accelerated in athletes secondary to increased physiologic loading. Nonsurgical management is the standard of care for lumbar degenerative disk disease in the elite athlete. Spondylolysis is more common in adolescent athletes with back pain than in adult athletes. Nonsurgical management of spondylolysis is typically successful. However, if surgery is required, fusion or direct pars repair can allow the patient to return to sports. PMID- 28574941 TI - An Accurate Full-flexion Anterolateral Portal for Needle Placement in the Knee Joint With Dry Osteoarthritis. AB - INTRODUCTION: Accurate delivery of an injection into the intra-articular space of the knee is achieved in only two thirds of knees when using the standard anterolateral portal. The use of a modified full-flexion anterolateral portal provides a highly accurate, less painful, and more effective method for reproducible intra-articular injection without the need for ultrasonographic or fluoroscopic guidance in patients with dry osteoarthritis of the knee. METHODS: The accuracy of needle placement was assessed in a prospective series of 140 consecutive injections in patients with symptomatic degenerative knee arthritis without clinical knee effusion. Procedural pain was determined using the Numerical Rating Scale. The accuracy rates of needle placement were confirmed with fluoroscopic imaging to document the dispersion pattern of injected contrast material. RESULTS: Using the standard anterolateral portal, 52 of 70 injections were confirmed to have been placed in the intra-articular space on the first attempt (accuracy rate, 74.2%). Using the modified full-flexion anterolateral portal, 68 of 70 injections were placed in the intra-articular space on the first attempt (accuracy rate, 97.1%; P = 0.000). CONCLUSION: This study revealed that using the modified full-flexion anterolateral portal for injections into the knee joint resulted in more accurate and less painful injections than those performed by the same orthopaedic surgeon using the standard anterolateral portal. In addition, the technique offered therapeutic delivery into the joint without the need for fluoroscopic confirmation. LEVEL OF EVIDENCE: Therapeutic Level II. PMID- 28574942 TI - Association Between Opioid Intake and Disability After Surgical Management of Ankle Fractures. AB - BACKGROUND: Opioid-centric pain management strategies have created an epidemic of prescription opioid abuse. This study assesses whether opioid intake is associated with disability, satisfaction with treatment, and pain at the time of suture removal and at 5 to 8 months after suture removal following open reduction and internal fixation of ankle fractures. METHODS: We enrolled 102 adult patients in the study at the time of suture removal, 59 of whom were available for follow up at 5 to 8 months. At the time of suture removal, we recorded opioid use; trauma-related factors; and scores on measures of disability, pain, and treatment satisfaction. Patients who were available for follow-up completed the disability, pain, and treatment satisfaction measures at 5 to 8 months and their opioid use at that time was recorded. RESULTS: No association was found between opioid intake and disability at the time of suture removal. No association was found between opioid intake and satisfaction with treatment or satisfaction with pain management at the time of suture removal. At 5 to 8 months after suture removal, no variables were associated with opioid intake. The psychologic measures of pain anxiety and catastrophic thinking were the factors most consistently associated with disability, treatment satisfaction, satisfaction with pain management, pain at rest, and pain with activity at both of the time points. CONCLUSION: Patients with ankle fractures may be able to use fewer opioids than are currently prescribed and experience levels of disability and treatment satisfaction comparable with those of patients who take greater amounts of opioids, independent of injury characteristics. LEVEL OF EVIDENCE: Prognostic level II. PMID- 28574943 TI - The Timing and Relevance of Relapsed Deformity in Patients With Idiopathic Clubfoot. AB - BACKGROUND: The timing and relevance of relapsed deformity after correction of idiopathic clubfoot have not been well documented. METHODS: All patients with idiopathic clubfoot seen at the authors' institution during the study period who were followed for >=2 years (range, 2.0 to 9.8 years) were included (N = 191). Survival analysis and multivariate regression analysis were used to analyze the data. RESULTS: The median age at first relapse was 20 months. The probability of relapse remained approximately 30% at age 2 years and increased to 45% by 4 years and 52% by 6 years. Parent-reported adherence with bracing reduced the odds of a relapse by 15 times (P < 0.01). After an initial relapse, adherence with bracing was successful in avoiding a subsequent relapse in 68% of patients. Feet graded as very severe on the Dimeglio scale were 5.75 times more likely to relapse than those graded severe and were 7.27 times more likely than those graded as moderate. DISCUSSION: Patients whose parents reported nonadherence with bracing and patients with very severe deformities were most likely to relapse. After an initial relapse, regaining correction of the foot and resuming bracing were beneficial to avoid further relapses. These findings can be useful to clinicians in advising families regarding the prognosis of treatment. CONCLUSIONS: The development of a relapse affects the subsequent management and outcome of clubfoot deformity. The importance of bracing should be reinforced to parents. Bracing until at least age 4 years may be beneficial. For patients whose families are especially resistant to brace use and for older patients who experience a second relapse, regaining correction of the deformity via cast treatment followed by an Achilles lengthening procedure and/or tendon transfer may be the best alternative. PMID- 28574944 TI - Factors Motivating Medical Students in Selecting a Career Specialty: Relevance for a Robust Orthopaedic Pipeline. AB - INTRODUCTION: Selection of a career specialty by medical students is a complex and individualized decision. Our goals were to understand the factors that influenced medical students in selecting their career specialty, identify the stage at which this decision was made, and understand the role of demographics, mentors, and curricula in this process. METHODS: Medical students from 10 institutions participated in a web-based survey. Results were stratified by sex, race/ethnicity, and level of interest in orthopaedic surgery. RESULTS: A total of 657 students responded to the survey. Specialty content (mean rating, 8.4/10) and quality of life/lifestyle/stress level (7.5/10) were the primary motivating factors in selecting a specialty. Interest in orthopaedic surgery was lower in women than in men (2.7 versus 3.9; P < 0.01) and was equivalent among race/ethnicity groups. Although 27% of students reported moderate or extensive medical school curriculum exposure to orthopaedics, this education did not sway them toward the specialty. CONCLUSIONS: Levels of interest in orthopaedics among medical students may be lower than generally assumed. Increasing the attractiveness of the specialty will require a multifaceted approach, including recognition of lifestyle factors, adjustments in the orthopaedic clerkship to make the specialty more appealing, mentorship by orthopaedic faculty, and conversion of high levels of interest in the specialty among minority medical students into successful residency applications. LEVEL OF EVIDENCE: IV. PMID- 28574945 TI - A SERIES OF FIVE PATIENTS WITH FOVEAL HYPOPLASIA DEMONSTRATING GOOD VISUAL ACUITY. AB - BACKGROUND/PURPOSE: Foveal hypoplasia is associated with low vision in a variety of conditions. We report and show imaging studies for a series of five patients with foveal hypoplasia who had visual acuity ranging from 20/25 to 20/60. METHODS: Observational case series. PATIENTS: This series includes five patients aged 5 to 18 years who presented to the Greater Baltimore Medical Center, Hoover Low Vision Clinic. All patients showed a partial or complete absence of the fovea in both eyes on examination. RESULTS: Eight eyes exhibited absence of foveal depression on spectral domain optical coherence tomography (Cirrus high definition OCT; Carl Zeiss Meditec). Four eyes exhibited Grade 3 foveal hypoplasia, two eyes exhibited Grade 4 foveal hypoplasia, and two eyes exhibited Grade 1 foveal hypoplasia. For two eyes (one patient), the optical coherence tomography was no longer available for grading, but was interpreted as foveal hypoplasia in both eyes in the chart. Visual acuities ranged from 20/25 to 20/60. Only two of five patients showed signs of albinism. CONCLUSION: Despite the presence of foveal hypoplasia, patients can retain a high level of visual acuity, which suggests that a foveal depression is not essential for the development of good visual acuity. PMID- 28574946 TI - Free Diced Cartilage: A New Application of Diced Cartilage Grafts in Primary and Secondary Rhinoplasty. AB - BACKGROUND: Irregularities or deformities of the nasal dorsum after hump reduction account for a significant number of revision rhinoplasties. The authors therefore developed a technique of meticulously dicing and exactly placing free diced cartilage grafts, harvested from septum, rib, or ear cartilage. The cartilage paste is used for smoothening, augmentation, or camouflaging of the nasal dorsum in primary or revision rhinoplasties. METHODS: A retrospective analysis of multisurgeon consecutive open approach rhinoplasties from January to December of 2014 was conducted at a single center. The authors compared the outcome of three different techniques to augment or cover the nasal dorsum after an observation period of 7 months. In group I, 325 patients with free diced cartilage grafts as the only onlay were included. In group II, consisting of 73 patients, the dorsal onlay was either fascia alone or in combination with free diced cartilage grafts. Forty-eight patients in group III received a dorsal augmentation with the classic diced cartilage in fascia technique. RESULTS: Four hundred forty-six patients undergoing primary and secondary rhinoplasties in which one of the above-mentioned diced cartilage techniques was used were included in the study. The authors found revision rates for dorsal irregularities within the 7-month postoperative observation period of 5.2, 8.2, and 25 percent for groups I, II, and III, respectively. CONCLUSION: The authors' findings strongly support their clinical experience that the free diced cartilage graft technique presents an effective and easily reproducible method for camouflage and augmentation in aesthetic and reconstructive rhinoplasty. PMID- 28574947 TI - Dynamic Rheology for the Prediction of Surgical Outcomes in Autologous Fat Grafting. AB - BACKGROUND: Because of the abundance and biocompatibility of fat, lipotransfer has become an attractive method for treating soft-tissue deficits. However, it is limited by unpredictable graft survival and retention. Currently, little is known about the viscoelastic properties of fat after various injection methods. Here, the authors assess the effects of cannula diameter, length, and shape on the viscoelastic properties, structure, and retention of fat. METHODS: Human lipoaspirate was harvested using suction-assisted liposuction and prepared for grafting. A syringe pump was used to inject fat at a controlled flow rate through cannulas of varying gauges, lengths, and shapes. Processed samples were tested in triplicate on an oscillatory rheometer to measure their viscoelastic properties. Fat grafts from each group were placed into the scalps of immunocompromised mice. After 8 weeks, graft retention was measured using micro-computed tomography and grafts were explanted for histologic analysis. RESULTS: Lipoaspirate injected through narrower, longer, and bent cannulas exhibited more shear thinning with diminished quality. The storage modulus (G') of fat processed with 18-gauge cannulas was significantly lower than when processed with 14-gauge or larger cannulas, which also corresponded with inferior in vivo histologic structure. Similarly, the longer cannula group had a significantly lower storage modulus than the shorter cannula, and was associated with decreased graft retention. CONCLUSIONS: Discrete modifications in the methods used for fat placement can have a significant impact on immediate graft integrity, and ultimately on graft survival and quality. Respecting these biomechanical influences during the placement phase of lipotransfer may allow surgeons to optimize outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 28574948 TI - Five Operations That Give the Best Results after Brachial Plexus Injury. AB - Treatment of brachial plexus injuries has improved slowly over the past 45 years. Changes in strategy, techniques, microsurgical equipment, and technology have expanded the surgical options for reconstructing these life-altering, highly complex injuries. The surgical techniques available include neurolysis, nerve repair, nerve grafting, nerve transfers, tendon transfer, muscle transfer, and other soft- and bony-tissue procedures. In this article, the authors have selected five surgical procedures (i.e., Oberlin procedure, Leechavengvongs procedure, free functional muscle transfer, radial nerve tendon transfers, and C5 C6 nerve grafting in obstetric birth palsy) that have consistently yielded good results in patients who require surgical reconstruction. PMID- 28574949 TI - Minor Suture Fusion in Syndromic Craniosynostosis. AB - BACKGROUND: Infants with craniofacial dysostosis syndromes may present with midface abnormalities but without major (calvarial) suture synostosis and head shape anomalies. Delayed presentation of their calvarial phenotype is known as progressive postnatal craniosynostosis. Minor sutures/synchondroses are continuations of major sutures toward and within the skull base. The authors hypothesized that minor suture synostosis is present in infants with syndromic, progressive postnatal craniosynostosis, and is associated with major suture synostosis. METHODS: The authors performed a two-institution review of infants (<1 year) with syndromic craniosynostosis and available computed tomographic scans. Major (i.e., metopic, sagittal, coronal, and lambdoid) and minor suture/synchondrosis fusion was determined by two craniofacial surgeons and one radiologist using Mimics or Radiant software. RESULTS: Seventy-three patients with 84 scans were included. Those with FGFR2 mutations were more likely to lack any major suture fusion (OR, 19.0; p = 0.044). Minor suture fusion occurred more often in the posterior branch of the coronal arch (OR, 3.33; p < 0.001), squamosal arch (OR, 7.32; p < 0.001), and posterior intraoccipital synchondroses (OR, 15.84; p < 0.001), among FGFR2 versus other patients. Patients (n = 9) with multiple scans showed a pattern of minor suture fusion followed by increased minor and major suture synostosis. Over 84 percent of FGFR2 patients had minor suture fusion; however, six (13 percent) were identified with isolated major suture synostosis. CONCLUSIONS: Minor suture fusion occurs in most patients with FGFR2-related craniofacial dysostosis. Syndromic patients with patent calvarial sutures should be investigated for minor suture involvement. These data have important implications for the pathophysiology of skull growth and development in this select group of patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 28574950 TI - Prepectoral Breast Reconstruction: A Safe Alternative to Submuscular Prosthetic Reconstruction following Nipple-Sparing Mastectomy. AB - BACKGROUND: Nipple-sparing mastectomy with immediate prosthetic reconstruction is routinely performed because of excellent aesthetic results and safe oncologic outcomes. Typically, subpectoral expanders are placed, but in select patients, this can lead to significant postoperative pain and animation deformity, caused by pectoralis major muscle disinsertion and stretch. Prepectoral reconstruction is a technique that eliminates dissection of the pectoralis major by placing the prosthesis completely above the muscle with complete acellular dermal matrix coverage. METHODS: A single surgeon's experience with immediate prosthetic reconstruction following nipple-sparing mastectomy from 2012 to 2016 was reviewed. Patient demographics, adjuvant treatment, length and characteristics of the expansion, and incidence of complications during the tissue expander stage were compared between the partial submuscular/partial acellular dermal matrix (dual-plane) cohort and the prepectoral cohort. RESULTS: Fifty-one patients (84 breasts) underwent immediate prepectoral tissue expander placement, compared with 115 patients (186 breasts) undergoing immediate partial submuscular expander placement. The groups had similar comorbidities and postoperative radiation exposure. There was no significant difference in overall complication rate between the two groups (17.9 percent versus 18.8 percent; p = 0.49). CONCLUSIONS: Prepectoral breast reconstruction provides a safe and effective alternative to partial submuscular reconstruction, that yields comparable aesthetic results with less operative morbidity. In the authors' experience, the incidence of acute and chronic postoperative pain and animation deformity is significantly lower following prepectoral breast reconstruction. This technique is now considered for all patients who are safe oncologic candidates and are undergoing nipple-sparing mastectomy and prosthetic reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28574951 TI - Single-Artery Human Ear Graft Procurement: A Simplified Approach. AB - : In the field of experimental facial vascularized composite tissue allotransplantation, a human auricular subunit model, pedicled on both superficial temporal and posterior auricular arteries, was described. Clinical cases of extensive auricular replantation, however, suggested that a single artery could perfuse the entire flap. In this study, variants of this single pedicle approach have been studied, aiming to develop a more versatile replantation technique, in which the question of venous drainage has also been addressed. For arterial perfusion study, the authors harvested 11 auricular grafts, either on a single superficial temporal artery pedicle (n = 3) or a double superficial temporal and posterior auricular artery pedicle (n = 8). The authors then proceeded to selective barium injections, in the superficial temporal, posterior auricular, or both superficial temporal and posterior auricular arteries. Arteriograms were acquired with a micro-computed tomographic scan and analyzed on three-dimensionally reconstructed images. Venous drainage was investigated in eight hemifaces, carefully dissected after latex injection. Observations showed a homogenous perfusion of the whole auricle in all arterial graft variants. Venous drainage was highly variable, with either a dominant superficial temporal vein (37.5 percent), dominant posterior auricular vein (12.5 percent), or co-dominant trunks (50 percent). The authors demonstrated that auricular subunit vascularized composite tissue allotransplantation can be performed on a single artery, relying on the dynamic intraauricular anastomoses between superficial temporal artery and posterior auricular branches. Potentially, this vascular versatility is prone to simplify the subunit harvest and allows various strategies for pedicle selection. Venous drainage, however, remains inconstant and thus the major issue when considering auricular transplantation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 28574952 TI - The Hippocampus and Cortex Together Generate the Scalp EEG Ictal Discharge in Temporal Lobe Epilepsy. AB - PURPOSE: The scalp EEG ictal discharge in temporal lobe epilepsy is reportedly visible only after the intracranial discharge becomes well synchronized and present over 10 to 30 cm of cortex. We investigated the role of the hippocampal formation in the generation of the scalp EEG ictal discharge. METHODS: Intracranial EEG video monitors were recorded using simultaneous scalp, stereotaxic depth, and subdural strip electrodes in 19 subjects with temporal lobe epilepsy. The location, frequency, morphology, and timing of the initial ictal discharge, and subsequent ictal patterns, were examined in hippocampal formation, medial paleocortex, and lateral temporal neocortex electrocorticographic and scalp temporal EEG recordings. RESULTS: In every subject, a scalp ictal discharge was visible only after the intracranial ictal discharge had spread to involve the whole temporal lobe (hippocampal formation, medial paleocortex, and lateral temporal neocortex). Beta/gamma frequency and decremental electrocorticographic ictal discharges were never visualized in the EEG. The scalp EEG ictal discharge frequency was 2.4 to 10 Hz and appeared a median of 18 seconds after a faster frequency electrocorticographic initial ictal discharge, once the intracranial discharge slowed to an alpha, theta, or delta frequency. CONCLUSIONS: In temporal lobe epilepsy, an ictal pattern is not readily visible in the scalp EEG until the intracranial ictal discharge is <=10 Hz and has propagated from its site of onset to involve the hippocampus, medial paleocortex, and lateral temporal neocortex. PMID- 28574955 TI - Safety Culture in the Operating Room: Variability Among Perioperative Healthcare Workers. AB - INTRODUCTION: Safety culture is defined as the product of individual and group values, attitudes, perceptions, competencies, and patterns of behavior that determine an organization's health and safety management. There is a lack of studies assessing patient safety culture in the perioperative setting. OBJECTIVES: We examined safety culture at a single tertiary care hospital, across all types of surgery, using previously collected data from a validated survey tool. We aim to understand how safety culture varies among perioperative staff. METHODS: The Hospital Survey on Patient Safety Culture was administered at a single tertiary care hospital in 2014. We identified 431 respondents as perioperative healthcare workers: surgery attending physician, surgery trainee physician, anesthesia attending physician, anesthesia trainee physician, nurse, and technician. We calculated percent positive scores for each dimension of safety culture, as well as a composite score. Pairwise comparisons were calculated via analysis of variance. RESULTS: The average response rate was 67%. The dimensions with the highest average percent positive scores were teamwork within hospital units (69%) and organizational learning and continuous improvement (57%). The dimensions with the lowest scores were feedback and communication about error (34%) and hospital handoffs and transitions (30%). Surgery attending physicians perceived the strongest safety climate overall, whereas nurses and surgical technicians perceived significantly worse safety climate. CONCLUSIONS: We observed significant variability in perioperative safety culture, across dimensions of safety climate, professional roles, and levels of training. These variations in safety culture should be addressed when implementing culture change programs in the perioperative setting. PMID- 28574956 TI - Identifying High-alert Medications in a University Hospital by Applying Data From the Medication Error Reporting System. AB - OBJECTIVES: To facilitate safe use of high-alert medications, lists of medications posing higher risks for medication errors (MEs) and harmful effects have been compiled. These lists can be general or reflect clinical practices in specific settings. Less common has been to compile a hospital-specific list applying data from the organization's ME reporting system. Our objective was to demonstrate a method for compiling such a high-alert medication list in a university hospital. METHODS: Of the eighteen 136 MEs reported during 2007 to 2013, ME reports with medications coded as a contributing factor to the incident were included (n = 249). The involved medications were identified and compared with the hospital's drug consumption and Institute for Safe Medication Practice's List of High-Alert Medications. The report narratives of MEs with most reported and high-alert medications (120 reports) were qualitatively content analyzed. RESULTS: The included 249 reports concerned 280 medications, of which 33% were classified as high-alert medications by the Institute for Safe Medication Practice. The most common therapeutic groups were antibacterials for systemic use (13%), psycholeptics (10%), analgesics (9%), and antithrombotic agents (9%). The most common high-alert medications were oxycodone (5%), enoxaparin (3%), and noradrenaline (3%). Serious patient harm (3%) was related to cefuroxime, enoxaparin, ibuprofen, midazolam, propofol, and warfarin. A half of the MEs were related to parenteral preparations. The qualitative content analysis revealed the key process safety risks of the most reported and high-alert medications. CONCLUSIONS: The method is applicable for compiling a hospital-specific high alert medication list and related analysis of key process safety risks contributing to MEs. PMID- 28574954 TI - Short-term Variability of Repolarization Is Superior to Other Repolarization Parameters in the Evaluation of Diverse Antiarrhythmic Interventions in the Chronic Atrioventricular Block Dog. AB - Short-term variability (STV), to quantify beat-to-beat variability of repolarization, is a surrogate parameter that reliably identifies proarrhythmic risk in preclinical models. Examples include not only the use in the chronic atrioventricular block (CAVB) dog model whereby it was developed but also in vulnerable patients with heart failure or drug-induced long QT syndrome. In the CAVB dog model, STV can specifically distinguish between safe and unsafe drugs in proarrhythmic screening. Conversely, this dog model also offers the possibility to evaluate antiarrhythmic strategies in a setting of Torsades de Pointes (TdP) induction with a standard IKr inhibitor. The different antiarrhythmic interventions studied in suppression and prevention of drug-induced TdP in vivo in the CAVB dog model and in vitro in canine ventricular cardiomyocytes are described in this overview. We provide evidence that STV predicts the magnitude of antiarrhythmic effect against TdP better than other repolarization parameters in both suppression and prevention conditions. Moreover, suppression and prevention experiments revealed the same level of antiarrhythmic efficacy, whereas cellular experiments seem more sensitive in comparison with drug testing in vivo. Together, these observations suggest that STV could be used as a consistent indicator to rank efficacy of antiarrhythmic interventions in a number of conditions. PMID- 28574953 TI - Polymerase delta-interacting Protein 2: A Multifunctional Protein. AB - Polymerase delta-interacting protein 2 (Poldip2) is a multifunctional protein originally described as a binding partner of the p50 subunit of DNA polymerase delta and proliferating cell nuclear antigen. In addition to its role in DNA replication and damage repair, Poldip2 has been implicated in mitochondrial function, extracellular matrix regulation, cell cycle progression, focal adhesion turnover, and cell migration. However, Poldip2 functions are incompletely understood. In this review, we discuss recent literature on Poldip2 tissue distribution, subcellular localization, and function. We also address the putative function of Poldip2 in cardiovascular disease, neurodegenerative conditions and in renal pathophysiology. PMID- 28574957 TI - "Attention Everyone, Time Out!": Safety Attitudes and Checklist Practices in Anesthesiology in Germany. A Cross-Sectional Study. AB - BACKGROUND: The use of perioperative checklists has generated a growing body of evidence pointing toward reduction of mortality and morbidity, improved compliance with guidelines, reduction of adverse events, and improvements in human factor-related areas. Usual quality management metrics generally fall short in assessing compliance with their perioperative application. Our study assessed application attitudes and compliance with safety measures centered around the World Health Organization (WHO) "Safe Surgery Saves Lives" campaign as perceived by anesthesia professionals in Germany. METHODS: Three hundred sixteen physicians and nurses participated in our cross-sectional survey, and 304 completed all 35 questions. RESULTS: Only 59.5% of participants had knowledge of the theoretical framework behind the WHO campaign. During the "sign-in," patient ID and surgical site were checked in 99.6% and 95.1% as recommended by the WHO. Allergies were addressed by 89.2%, expected difficult airway by 65.7%, and the availability of blood products by 70.5%. A total of 84.9% of participants advocated for the time out to include all persons present in the operating room, which was the case in 57.0%. A total of 40.8% stated that the time-out was only performed between anesthetist and surgeon; in 17.0% of cases, the patient was simultaneously draped and/or surgically scrubbed. No significant differences between hospital types were observed. CONCLUSIONS: Our study paints a heterogeneous picture of the implementation, usage, and safety attitudes concerning the Safe Surgery Checklist as promoted by the WHO. The lack of standardized execution and team-mindedness can be taken as further evidence for the importance of interdisciplinary training focusing on human factors, communication, and collaboration rather than the mere implementation by decree. PMID- 28574958 TI - Re: Cell Phone Calls in the Operating Theater and Staff Distractions: An Observational Study (Avidan A, Yavobi G, Weissman C, Levin P. J Patient Saf 2017). PMID- 28574960 TI - Conference on Retroviruses and Opportunistic Infections 2017 highlights. PMID- 28574959 TI - Intravenous Smart Pump Drug Library Compliance: A Descriptive Study of 44 Hospitals. AB - BACKGROUND: Although intravenous (IV) smart pumps with built-in dose-error reduction systems (DERS) can reduce IV medication administration error, most serious adverse events still occur during IV medication administration. Sources of error include overriding DERS and manually bypassing drug libraries and the DERS. METHODS: Our purpose was to use the Regenstrief National Center for Medical Device Informatics data set to better understand IV smart pump drug library and DERS compliance. Our sample consisted of 12 months of data from 7 hospital systems, 44 individual hospitals, and descriptive data from the American Hospital Directory (AHD) for 2015. The aims of the study were (1) to determine whether there are differences in IV smart pump drug library compliance between hospital systems and (2) to provide a broad descriptive overview of relevant trends related to IV smart pump compliance. RESULTS: For aim 1, we found 3 significant relationships among the 7 hospital systems: systems 3 (P < 0.001), 6 (P = 0.003), and 7 (P = 0.002) had significantly higher IV smart compliance as compared with system 4. For aim 2, the number of drug library profiles was positively correlated (P = 0.029) with IV smart pump compliance and the IV smart pump type used was significantly correlated (P = 0.013) with IV smart pump compliance. CONCLUSIONS: Our findings support that there are differences in IV smart pump compliance both within and between hospital systems and that IV smart pump type and the number of drug library profiles may be influencing factors. Further research is required to more accurately identify the impact of these factors in this very important area of patient safety. PMID- 28574961 TI - Modifications in acute phase and complement systems predict shifts in cognitive status of HIV-infected patients. AB - BACKGROUND: The prevalence of HIV-associated neurocognitive disorders (HAND) has not changed considerably in the last two decades. Potent antiretroviral therapy has shifted the severity of HAND to milder phenotypes, but excess morbidity and mortality continue to be associated with HAND. Changes in numerous markers of immune function, inflammation, and cellular stress have been repeatedly associated with HAND, but the underlying systems that drive these changes have not been identified. METHOD: In this study, we used systems informatics to interrogate the cerebrospinal fluid proteomic content of longitudinal samples obtained from HIV-infected adults with stably unimpaired, stably impaired, worsening, or improving neurocognitive performance. RESULTS AND CONCLUSION: The patterns of change in cerebrospinal fluid protein content implicated the induction of acute phase and complement systems as important regulators of neurocognitive status. Worsening neurocognitive performance was preceded by induction of acute phase and complement systems, whereas improving neurocognitive performance was preceded by a downregulation of these systems. PMID- 28574963 TI - HIV-infection has no prognostic impact on advanced-stage Hodgkin lymphoma. AB - OBJECTIVE: Classical Hodgkin lymphoma (cHL) is a non-AIDS-defining cancer with a good response to chemotherapy in the combined antiretroviral therapy (cART) era. The aim of the present study was to compare the characteristics, the response to treatment and the survival of advanced-stage cHL treated with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) between cART-treated HIV-positive and HIV-negative patients. DESIGN AND METHODS: We retrospectively analyzed advanced-stage cHL patients from a single institution, uniformly treated with ABVD. All HIV-positive patients received cART concomitantly with ABVD. RESULTS: A total of 69 patients were included in the study: 21 were HIV-positive and 48 were HIV-negative. HIV-positive patients had more aggressive features at cHL diagnosis, such as worse performance status, more frequent bone marrow involvement and mixed cellularity histologic subtype. There were no differences in complete response rate (89% in HIV-positive vs. 91% in HIV-negative), P = 1; disease-free survival (DFS) [10-year DFS probability (95% CI) 70% (41-99%) vs. 74% (57-91%)], P = 0.907 and overall survival (OS) [10-year OS probability (95% CI) 73% (52-94%) vs. 68% (51-85%)], P = 0.904. On multivariate analysis, HIV infection did not correlate with worse OS. CONCLUSION: Although HIV-positive patients with cHL had more aggressive baseline features in this series, there were no differences in response rate or survival between HIV-positive and HIV negative patients. PMID- 28574962 TI - An increased rate of fracture occurs a decade earlier in HIV+ compared with HIV- men. AB - OBJECTIVES: To determine the incidence of fracture among aging HIV-infected (HIV+) and uninfected men (HIV-). To evaluate factors independently associated with fracture risk. DESIGN: Prospective, multicenter cohort study of men with or at risk for HIV. METHODS: Outcome measures: all fractures (excluding skull, face and digits) and fragility fractures (vertebral column, femur, wrist and humerus) were collected semiannually in 1221 HIV+ and 1408 HIV- men aged at least 40. Adjusted incident rate ratios (aIRR) with an interaction term for age (40-49, 50 59 and >=60 years) and HIV serostatus were estimated with Poisson regression models accounting for additional risk factors. RESULTS: Fracture incidence increased with age among both HIV+ and HIV- men. Although there was no significant difference in fracture incidence by HIV serostatus among men aged 40 49 years, the HIV+ men aged 50-59 years had a significantly higher incidence of all fractures [aIRR: 2.06 (1.49, 2.84)] and fragility fractures [aIRR: 2.06 (1.21, 3.50)] compared with HIV- participants of similar age. HIV modified the effect of age on all fractures (P = 0.002) but did not significantly modify the effect for fragility fractures (P = 0.135). Hypertension increased the rate of all fractures by 32% after adjustment for covariates [aIRR: 1.32 (1.04, 1.69)]. CONCLUSION: Fracture incidence increased with age among HIV+ and HIV- men but was higher among HIV+ men. A significant increase in fracture incidence was found among 50-59-year-old HIV+ men, highlighting the importance of osteoporosis screening for HIV-infected men above the age of 50. PMID- 28574964 TI - Does antiretroviral therapy change partnership dynamics and HIV risk behaviours among HIV-infected adults. AB - OBJECTIVE: We explore the impact of antiretroviral therapy (ART) on partnership acquisition and dissolution rates and changes in sexual behaviours among HIV infected adults. DESIGN: Using detailed longitudinal data from a prospective cohort of HIV-infected adults with CD4 cell count below 200 cells/MUl (ART eligible) or CD4 cell count above 500 cells/MUl (pre-ART) conducted in rural KwaZulu-Natal, South Africa, from 2009 to 2012. METHODS: Partnership acquisition and dissolution are explored through survival analysis methods, whereas generalized linear models were fitted for the sexual behaviour outcomes with interaction terms to allow the association with ART to vary over time. Throughout, the primary comparison of interest for each outcome is differences between the two ART groups. RESULTS: ART is not associated with partner acquisition or relationship dissolution. During follow-up, the two ART groups do not differ in the odds of being sexually active nor the number of sex acts, whereas the odds of unprotected sex are significantly lower for partnerships of ART-eligible participants (adjusted odds ratio 0.26, 95% confidence interval 0.15, 0.43). Relationship-level characteristics including cohabitation status and wanting more children with that partner are associated with higher odds and increased frequency of sexual activity, and increased odds of unprotected sex, whereas living with partner, higher relationship quality and longer relationship duration are associated with lower risk of partnership dissolution. CONCLUSION: Being on ART was not associated with increased sexual risk behaviours, a reassuring finding given the WHO recommends ART initiation upon HIV diagnosis. The importance of relationship-level characteristics provides evidence that HIV care services should offer routine support for HIV disclosure and sexual risk reduction, and promotion of couples-testing and positive couple relationships. PMID- 28574965 TI - Impact of comorbidity and ageing on health-related quality of life in HIV positive and HIV-negative individuals. AB - BACKGROUND: HIV-infected individuals may be at risk for the premature onset of age-associated noncommunicable comorbidities. Being HIV-positive, having comorbidities and being of higher age may adversely impact health-related quality of life (HRQL). We investigated the possible contribution of HIV infection, comorbidities and age on HRQL and depression. METHODS: HIV-infected individuals and uninfected controls from the AGEhIV Cohort Study were screened for the presence of comorbidities. They completed the Short Form 36-item Health Survey to assess HRQL and the nine-item Patient Health Questionnaire to assess depression. Linear and logistic regression were used to investigate to which extent comorbidities, aging and HIV infection were independently associated with HRQL and depression. RESULTS: HIV-infected individuals (n = 541) reported significantly worse physical and mental HRQL and had a higher prevalence of depression than HIV-uninfected individuals (n = 526). A higher number of comorbidities and HIV-positive status were each independently associated with worse physical HRQL, whereas HIV-positive status and younger age were independently associated with worse mental HRQL and more depression. The difference in physical HRQL between HIV-positive and HIV-negative individuals did not become greater with a higher number of comorbidities or with higher age. CONCLUSION: In a cohort of largely well suppressed HIV-positive participants and HIV-negative controls, HIV-positive status was significantly and independently associated with worse physical and mental HRQL and with an increased likelihood of depression. Our finding that a higher number of comorbidities was independently associated with worse physical HRQL reinforces the importance to optimize prevention and management of comorbidities as the HIV-infected population continues to age. PMID- 28574967 TI - Dolutegravir and weight gain: an unexpected bothering side effect? PMID- 28574966 TI - Moving toward test and start: learning from the experience of universal antiretroviral therapy programs for HIV-infected pregnant/ breastfeeding women. AB - : In 2015, the WHO recommended universal antiretroviral therapy (ART) for all people living with HIV after two randomized controlled trials revealed lower rates of mortality and serious illnesses among people living with HIV receiving immediate ART compared with those receiving deferred ART. Many countries in sub Saharan Africa rapidly adopted this guidance and are implementing 'test and start' programs.As this work begins, lessons learned from prevention of mother-to child transmission Option B+ programs can inform decisions for new universal HIV treatment programs. The Option B+ approach involved initiation of lifelong treatment for all HIV-infected pregnant and breastfeeding women. Since its inception in Malawi in 2011 and WHO endorsement in 2012, widespread scale-up of Option B+ prevention of mother-to-child transmission programs in most resource limited countries has resulted in a dramatic increase in ART coverage for HIV infected pregnant and breastfeeding women.Despite the overall success of the Option B+ universal lifelong treatment approach, program and operational research data highlight the need for additional focus on strategies to retain women in care. In this commentary, we highlight program considerations and lessons learned from Option B+ implementation experience in resource-limited countries, which may help guide decisions and enhance the quality of general 'test and start' programing. PMID- 28574968 TI - Evaluation of non-sexual, non-needlestick, non-occupational HIV post-exposure prophylaxis cases. PMID- 28574969 TI - Daily Experiences and Challenges Among Children and Adolescents With Celiac Disease: Focus Group Results. AB - OBJECTIVES: Maintaining a restrictive gluten-free diet is the only treatment for celiac disease (CD). Adherence among children and adolescents presents unique challenges and is often inadequate. The International Classification of Functioning, Disability and Health: Children and Youth version (ICF-CY) model encompasses all aspects of human health and daily function while dealing with a disease and interacting with the environment. The purpose was to explore everyday life experiences and challenges as perceived by children and adolescents with CD and their parents in light of the ICF-CY concepts to identify the most crucial components in management challenges. The present study was the first stage in developing a standardized questionnaire to assess these needs. METHODS: Children and adolescents diagnosed with CD for more than 6 months and their parents participated in 4 separate focus group interviews: 12 children (8-12 years) and 13 of their parents, and 10 adolescents (13-16 years) and 10 of their parents. RESULTS: The ICF-CY body functions component that includes higher-level cognitive functions, such as organization, planning, and problem solving was largely reflected. Food-related activities in and out of the home were discussed, yet thorough activity analysis was lacking in the available literature. CONCLUSIONS: The focus groups revealed a wide scope of coping issues that contribute to a deeper understanding of specific CD characteristics including daily management, participation in food-related activities, roles, strategies, and supporting or hindering factors in everyday life with CD. PMID- 28574971 TI - Peroral Endoscopic Myotomy in Children: First Experience With a New Triangular Knife. AB - OBJECTIVES: Peroral endoscopic myotomy (POEM) is a novel treatment modality for achalasia cardia. The procedure is technically challenging and time consuming. Recently, a new triangle tip knife (TTJ) has been introduced, which is equipped with water jet facility. In the present study, we analyzed the feasibility, safety, and efficacy of POEM in children with new triangle tip knife. METHODS: We retrospectively evaluated the data of children (18 years or younger) who underwent POEM using TTJ knife at our institution. All POEM procedures were performed under general anesthesia in an endoscopy suite. Technical feasibility, safety, efficacy, and procedure duration were assessed. RESULTS: Ten children (4 boys, 6 girls) with mean age of 14.2 +/- 2.74 (9-18) years, underwent POEM with TTJ knife. The subtypes of achalasia cardia were type I (4), type II (5), and type III (1). Two children had prior treatment with pneumatic balloon dilatation. POEM was performed via anterior route in majority of children (70%). Mean operating time was 47.6 +/- 19.74 (30-98) minutes with no significant difference between anterior and posterior approaches to POEM (48.57 +/- 24.01 vs 45.3 +/- 3.51; P < 0.05). Four gas-related adverse events were encountered including capnoperitoneum and retroperitoneal carbon dioxide in 2 children each. Clinical success was noticed in 9 children with significant reduction in Eckardt score at 1 month after POEM (6.7 +/- 1.49 vs 0.3 +/- 0.48; P = 0.0001). CONCLUSIONS: POEM can be efficiently performed with new triangle knife equipped with water jet technique. Integration of water jet reduces procedure duration and technical difficulty with POEM. PMID- 28574970 TI - Probiotics for the Prevention of Nosocomial Diarrhea in Children. AB - This document provides recommendations developed by the ESPGHAN Working Group on Probiotics and Prebiotics on the role of probiotics in the prevention of nosocomial diarrhea in children based on a systematic review of previously completed systematic reviews and of subsequently published randomized controlled trials. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation guidelines. Recommendations were given only if at least 2 randomized controlled trials examined the same probiotic strain. Based on currently available evidence the Working Group recommends using Lactobacillus rhamnosus GG if the use of probiotics for preventing nosocomial diarrhea in children is considered. PMID- 28574973 TI - Depressive Symptoms Moderate the Association Between Appetite and Health Status in Patients With Heart Failure. AB - BACKGROUND: Decreased appetite and depressive symptoms are clinical problems in patients with heart failure. Both may result in impaired health status. OBJECTIVE: The aims of this study were to investigate the association between appetite and health status in patients with heart failure and to explore whether depressive symptoms moderate this association. METHODS: In this cross-sectional study, patients with heart failure (n = 186; mean age, 71 years), New York Heart Association class II to IV, participated. Data on appetite (Council of Nutrition Appetite Questionnaire), depressive symptoms (Patient Health Questionnaire-9), and health status (EQ-5D 3-level scale [EQ-5D-3L] descriptive system, EQ-5D-3L index, and EQ Visual Analog Scale) were collected by self-rating questionnaires. Pearson correlation was used to investigate the association between appetite and health status. Multiple regression was performed to examine whether depressive symptoms moderate the association between appetite and health status. RESULTS: There was a significant association between appetite and health status for EQ-5D 3L descriptive system, mobility (P < .001), pain/discomfort (P < .001), and anxiety/depression (P < .001). This association was also shown in EQ-5D-3L index (P < .001) and EQ Visual Analog Scale (P < .001). Simple slope analysis showed that the association between appetite and health status was only significant for patients without depressive symptoms (B = 0.32, t = 4.66, P < .001). CONCLUSIONS: Higher level of appetite was associated with better health status. In moderation analysis, the association was presented for patients without depressive symptoms. Decreased appetite is an important sign of poor health status. To improve health status, health professionals should have greater attention on appetite, as well on signs of depressive symptoms. PMID- 28574972 TI - Heart Failure Rehospitalization and Delayed Decision Making: The Impact of Self care and Depression. AB - BACKGROUND: Rehospitalization soon after discharge can be distressing for persons with heart failure (HF) and places a heavy burden on the healthcare system. OBJECTIVE: We investigated and explored the association of self-care decision making variables with (1) rehospitalization within 30 days of discharge and (2) delay in seeking medical assistance (delayed decision making). METHODS: A cross sectional, explanatory sequential mixed methods design (quan > qual) was used to survey 127 hospitalized HF patients and interview 15 of these participants to explain their survey responses. The survey assessed rehospitalization within 30 days of discharge, delayed decision making, HF self-care, and psychosocial factors influencing self-care. RESULTS: The likelihood of delaying the decision to be hospitalized was more than 5 times higher among those with high depressive symptoms (odds ratio, 5.33; 95% confidence interval, 2.14-13.28). Those who delayed going to the hospital were uncertain about their prognosis and did not feel their symptoms were urgent. The likelihood of being rehospitalized within 30 days was more than doubled among those with high depressive symptoms (OR, 2.31; 95% confidence interval, 1.01-5.31). Those who were rehospitalized within 30 days were less likely to consult healthcare professionals in their decision making and wanted immediate relief from their symptoms. CONCLUSIONS: We recommend a patient centered approach to help HF patients identify and adequately self-manage symptoms. The strong association between high depressive symptoms and rehospitalization within 30 days as well as delayed decision making highlights the critical need for clinicians to carefully assess and address depression among HF patients. PMID- 28574974 TI - Survivors of an Acute Coronary Syndrome With Lower Patient Activation Are More Likely to Experience Declines in Health-Related Quality of Life. AB - BACKGROUND: Patient activation comprises the knowledge, skills, and confidence for self-care and may lead to better health outcomes. OBJECTIVES: We examined the relationship between patient activation and changes in health-related quality of life (HRQOL) after hospitalization for an acute coronary syndrome (ACS). METHODS: We studied patients from 6 medical centers in central Massachusetts and Georgia who had been hospitalized for an ACS between 2011 and 2013. At 1 month after hospital discharge, the patients completed the 6-item Patient Activation Measure and were categorized into 4 levels of activation. Multinomial logistic regression analyses compared activation level with clinically meaningful changes (>=3.0 points, generic; >=10.0 points, disease-specific) in generic physical (SF-36v2 Physical Component Summary [PCS]), generic mental (SF-36v2 Mental Component Summary [MCS]), and disease-specific (Seattle Angina Questionnaire [SAQ]) HRQOL from 1 to 3 and 1 to 6 months after hospitalization, adjusting for potential sociodemographic and clinical confounders. RESULTS: The patients (N = 1042) were, on average, 62 years old, 34% female, and 87% non-Hispanic white. A total of 10% were in the lowest level of activation. The patients with the lowest activation had 1.95 times (95% confidence interval, 1.05-3.62) and 2.18 times (95% confidence interval, 1.17-4.05) the odds of experiencing clinically significant declines in MCS and SAQ HRQOL, respectively, between 1 and 6 months than the most activated patients. The patient activation level was not associated with meaningful changes in PCS scores. CONCLUSIONS: Hospital survivors of an ACS with lower activation may be more likely to experience declines in mental and disease specific HRQOL than more-activated patients, identifying a group at risk of poor outcomes. PMID- 28574975 TI - A prognostic model for resectable acral melanoma patients on the basis of preoperative inflammatory markers. AB - Acral melanoma is a rare disease, but is common in Asia. Knowledge of its prognostic indicators is limited. Growing evidence indicates that inflammation plays a critical role in the development and progression of acral melanoma. We developed a novel prognostic model on the basis of preoperative inflammatory markers and examined its prognostic value in a cohort of patients. This retrospective study included 232 acral melanoma patients who underwent radical surgical resection between 2000 and 2010 at the Sun Yat-sen University Cancer Center. Significant predictive factors were identified by multivariate Cox regression analyses, and a prognostic model on the basis of these variables was constructed to predict survival. Kaplan-Meier curves were plotted to estimate overall survival. Multivariate analyses showed that C-reactive protein, albumin/globulin ratio, age, lactic dehydrogenase, and lymph node positivity were related independently to survival. After analyzing these variables, we classified patients into three risk groups. The new prognostic model identified three categories of patients with different prognoses (P<0.001) and significantly stratified patient prognosis into different tumor stages. The area under the curve of the new prognostic model was 0.684 (95% confidence interval: 0.620 0.743), which was significantly higher than that of the other variables (P<0.001). C-reactive protein and albumin/globulin ratio were independently related to survival in our study population and the prognostic model developed using inflammatory-based scores was useful in stratifying patients into different risk groups. Thus, this model will be a valuable complement to the 2009 American Joint Committee on Cancer staging for Asian patients with acral melanoma. PMID- 28574977 TI - Development of a biclonal cutaneous T-cell lymphoproliferative process during treatment with immune checkpoint inhibitors for metastatic melanoma. AB - The immune checkpoint inhibitors targeting cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and the programmed death protein 1 (PD-1)/PD-L1 pathway have recently shown promising therapeutic results in patients with metastatic melanoma. Dermatologic side effects of these agents occur in ~30-40% of cases. Here, we report the development of a biclonal cutaneous T-cell lymphoproliferative disorder in a patient being treated with ipilimumab (a CTLA-4 inhibitor) for metastatic melanoma. Nivolumab (a PD-1 inhibitor) had also been administered to him previously. An 8 mm reddish papule appeared on the skin of the left forearm. A biopsy of that lesion showed an atypical population of predominantly CD4-positive, CD30-positive T-cells that also expressed PD-1 and PD L1 immunohistochemically. PCR studies for T-cell receptor rearrangements showed the presence of two distinct clonal T-cell populations. The lesion was completely excised and the patient had no local recurrences. There was also no subsequent evidence of a systemic lymphoproliferative process. Although the development of a lymphoid skin lesion in our patient may have only been coincidentally related to his treatment, immunostimulatory drugs could theoretically cause clonal expansion of a population of lymphocytes that leads to a lymphoproliferative disorder. PMID- 28574976 TI - Single-stage excision and sentinel lymph node biopsy in cutaneous melanoma in selected patients: a retrospective case-control study. AB - Sometimes, diagnostic excision of a primary melanoma would already necessitate skin grafting or transposition skin flaps, especially in areas with an esthetic or functional importance. The utility of sentinel lymph node biopsy (SLNB) after skin reconstruction is controversial. We carried out a single-institution retrospective case-control study. In patients with a wide primary lesion at high clinical-dermatoscopic suspicion for invasive melanoma in anatomical region in which a reconstruction with a skin graft or a flap is required, we proposed the performance of a confocal microscopy examination and an incisional biopsy of the primary lesion. If these diagnostic methodologies confirmed the suspicion of melanoma, lymphatic mapping was performed before the wide excision (WE) of the primary lesion, and WE and SLNB were performed during the same operative procedure. The database evaluation showed 496 patients who had undergone a previous complete local excision and a subsequent SLNB (two-stage group), whereas 61 patients underwent WE and SLNB during the same surgical time (one-stage group). Histological results of the excisional biopsy confirmed the diagnosis of melanoma in all patients of the one-stage group. The false-negative rate was lower in the one-stage group (5.5%) than in the two-stage group (16.7%). Patients of the two groups showed a similar recurrence-free and overall survival period even when corrected for clinic-demographical variables. The concomitant execution of SLNB and WE after confocal microscopy examination and incisional biopsy appears to be a safe and accurate procedure in patients with a wide primary melanoma that requires a skin flaps or a skin graft to cover the residual defect. PMID- 28574978 TI - Adjacent Segment Degeneration Following Anterior Cervical Discectomy and Fusion Versus the Bryan Cervical Disc Arthroplasty. AB - BACKGROUND Anterior cervical discectomy and fusion (ACDF) is an established treatment for degenerative disease of the cervical disc, but adjacent segment degeneration or instability may develop long term. The aim of this study was to investigate the risk factors for adjacent segment degeneration following ACDF compared with the use of the Bryan artificial disc for cervical disc arthroplasty (CDA). MATERIAL AND METHODS A prospective comparative study included 93 patients who underwent ACDF or CDA with the Bryan artificial cervical disc between 2002 and 2004, and who had more than eight years of follow-up. There were 29 cases in the CDA group and 39 cases in ACDF group, with a follow-up rate of 73.12%. Clinical results and imaging data were assessed before and after surgery. RESULTS There was no significant difference between the two groups in radiographic parameters at each follow-up time point. There were 19 cases of adjacent segment degeneration (48.72%) in the ACDF group, and 13 cases of adjacent segment degeneration (44.83%) in the CDA group, with no statistically significant difference (P>0.05). Univariate analysis showed that advanced age (OR 1.271, 95% CI 1.005-1.607), low preoperative overall lordosis (OR 0.858, 95% CI 0.786-0.936) and low preoperative segmental lordosis (OR 1.185, 95% CI 1.086-1.193) were significantly correlated with adjacent segment degeneration. CONCLUSIONS Equally good clinical outcomes were achieved with both the ACDF and the Bryan CDA. Increasing patient age was associated with adjacent segment degeneration in both patient groups. PMID- 28574979 TI - Antenatal corticosteroids and cardiometabolic outcomes in adolescents born with very low birth weight. AB - BackgroundExposure to antenatal corticosteroids (ANCS) is associated with adverse cardiometabolic outcomes in animal models; however, long-term outcomes in clinical studies are not well characterized. We hypothesized that exposure to ANCS would be associated with markers of increased cardiometabolic risk in adolescents born with very low birth weight (VLBW).MethodsIn an observational cohort of 186 14-year-old adolescents born with VLBW, we measured resting blood pressure (BP), BP response to cold, ambulatory BP, and anthropometrics; performed dual-energy X-ray absorptiometry; and analyzed blood samples for uric acid, cholesterol, glycated hemoglobin, and high-sensitivity C-reactive protein. Multivariate analyses were used to evaluate associations with ANCS, adjusting for race, sex, and maternal hypertensive pregnancy.ResultsThere were no ANCS group differences in BP measures or blood biomarkers. Compared with adolescents unexposed to ANCS, those exposed to ANCS were taller (exposed-unexposed mean difference 3.1 cm (95% confidence interval (CI) 0.7, 5.5)) and had decreased waist-to-height ratio (exposed-unexposed mean difference -0.03 (95% CI -0.058, 0.002)). Males exposed to ANCS had lower total cholesterol (exposed-unexposed mean difference -0.54 mmol/l (95%CI -0.83, -0.06)).ConclusionAmong adolescents born with VLBW, ANCS exposure was not associated with markers of increased cardiometabolic risk. PMID- 28574982 TI - MMTF-An efficient file format for the transmission, visualization, and analysis of macromolecular structures. AB - Recent advances in experimental techniques have led to a rapid growth in complexity, size, and number of macromolecular structures that are made available through the Protein Data Bank. This creates a challenge for macromolecular visualization and analysis. Macromolecular structure files, such as PDB or PDBx/mmCIF files can be slow to transfer, parse, and hard to incorporate into third-party software tools. Here, we present a new binary and compressed data representation, the MacroMolecular Transmission Format, MMTF, as well as software implementations in several languages that have been developed around it, which address these issues. We describe the new format and its APIs and demonstrate that it is several times faster to parse, and about a quarter of the file size of the current standard format, PDBx/mmCIF. As a consequence of the new data representation, it is now possible to visualize structures with millions of atoms in a web browser, keep the whole PDB archive in memory or parse it within few minutes on average computers, which opens up a new way of thinking how to design and implement efficient algorithms in structural bioinformatics. The PDB archive is available in MMTF file format through web services and data that are updated on a weekly basis. PMID- 28574981 TI - A motor unit-based model of muscle fatigue. AB - Muscle fatigue is a temporary decline in the force and power capacity of skeletal muscle resulting from muscle activity. Because control of muscle is realized at the level of the motor unit (MU), it seems important to consider the physiological properties of motor units when attempting to understand and predict muscle fatigue. Therefore, we developed a phenomenological model of motor unit fatigue as a tractable means to predict muscle fatigue for a variety of tasks and to illustrate the individual contractile responses of MUs whose collective action determines the trajectory of changes in muscle force capacity during prolonged activity. An existing MU population model was used to simulate MU firing rates and isometric muscle forces and, to that model, we added fatigue-related changes in MU force, contraction time, and firing rate associated with sustained voluntary contractions. The model accurately estimated endurance times for sustained isometric contractions across a wide range of target levels. In addition, simulations were run for situations that have little experimental precedent to demonstrate the potential utility of the model to predict motor unit fatigue for more complicated, real-world applications. Moreover, the model provided insight into the complex orchestration of MU force contributions during fatigue, that would be unattainable with current experimental approaches. PMID- 28574980 TI - Diagnostics for neonatal sepsis: current approaches and future directions. AB - Progress has been made in the reduction of morbidity and mortality from neonatal sepsis. However, diagnosis continues to rely primarily on conventional microbiologic techniques, which can be inaccurate. The objective of this review is to provide the clinician with an overview of the current information available on diagnosing this condition. We review currently available diagnostic approaches for documenting neonatal sepsis and also describe novel approaches for diagnosing infection in neonates who are under development and investigation. Substantial progress has been made with molecular approaches and further development of non culture-based methods offer promise. The potential ability to incorporate antimicrobial resistance gene testing in addition to pathogen identification may provide a venue to incorporate a predominantly molecular platform into a larger program of neonatal care. PMID- 28574984 TI - Complexity in action: Untangling latent relationships between land quality, economic structures and socio-spatial patterns in Italy. AB - Land quality, a key economic capital supporting local development, is affected by biophysical and anthropogenic factors. Taken as a relevant attribute of economic systems, land quality has shaped the territorial organization of any given region influencing localization of agriculture, industry and settlements. In regions with long-established human-landscape interactions, such as the Mediterranean basin, land quality has determined social disparities and polarization in the use of land, reflecting the action of geographical gradients based on elevation and population density. The present study investigates latent relationships within a large set of indicators profiling local communities and land quality on a fine grained resolution scale in Italy with the aim to assess the potential impact of land quality on the regional socioeconomic structure. The importance of land quality gradients in the socioeconomic configuration of urban and rural regions was verified analyzing the distribution of 149 socioeconomic and environmental indicators organized in 5 themes and 17 research dimensions. Agriculture, income, education and labour market variables discriminate areas with high land quality from areas with low land quality. While differential land quality in peri-urban areas may reflect conflicts between competing actors, moderate (or low) quality of land in rural districts is associated with depopulation, land abandonment, subsidence agriculture, unemployment and low educational levels. We conclude that the socioeconomic profile of local communities has been influenced by land quality in a different way along urban-rural gradients. Policies integrating environmental and socioeconomic measures are required to consider land quality as a pivotal target for sustainable development. Regional planning will benefit from an in-depth understanding of place-specific relationships between local communities and the environment. PMID- 28574983 TI - Network-assisted target identification for haploinsufficiency and homozygous profiling screens. AB - Chemical genomic screens have recently emerged as a systematic approach to drug discovery on a genome-wide scale. Drug target identification and elucidation of the mechanism of action (MoA) of hits from these noisy high-throughput screens remain difficult. Here, we present GIT (Genetic Interaction Network-Assisted Target Identification), a network analysis method for drug target identification in haploinsufficiency profiling (HIP) and homozygous profiling (HOP) screens. With the drug-induced phenotypic fitness defect of the deletion of a gene, GIT also incorporates the fitness defects of the gene's neighbors in the genetic interaction network. On three genome-scale yeast chemical genomic screens, GIT substantially outperforms previous scoring methods on target identification on HIP and HOP assays, respectively. Finally, we showed that by combining HIP and HOP assays, GIT further boosts target identification and reveals potential drug's mechanism of action. PMID- 28574985 TI - Economic evaluation of multidisciplinary rehabilitation treatment versus cognitive behavioural therapy for patients with chronic fatigue syndrome: A randomized controlled trial. AB - BACKGROUND: A multi-centre RCT has shown that multidisciplinary rehabilitation treatment (MRT) is more effective in reducing fatigue over the long-term in comparison with cognitive behavioural therapy (CBT) for patients with chronic fatigue syndrome (CFS), but evidence on its cost-effectiveness is lacking. AIM: To compare the cost-effectiveness of MRT versus CBT for patients with CFS from a societal perspective. METHODS: A multi-centre randomized controlled trial comparing MRT with CBT was conducted among 122 patients with CFS diagnosed using the 1994 criteria of the Centers for Disease Control and Prevention and aged between 18 and 60 years. The societal costs (healthcare costs, patient and family costs, and costs for loss of productivity), fatigue severity, quality of life, quality-adjusted life-year (QALY), and cost-effectiveness ratios (ICERs) were measured over a follow-up period of one year. The main outcome of the cost effectiveness analysis was fatigue measured by the Checklist Individual Strength (CIS). The main outcome of the cost-utility analysis was the QALY based on the EuroQol-5D-3L utilities. Sensitivity analyses were performed, and uncertainty was calculated using the cost-effectiveness acceptability curves and cost effectiveness planes. RESULTS: The data of 109 patients (57 MRT and 52 CBT) were analyzed. MRT was significantly more effective in reducing fatigue at 52 weeks. The mean difference in QALY between the treatments was not significant (0.09, 95% CI: -0.02 to 0.19). The total societal costs were significantly higher for patients allocated to MRT (a difference of ?5,389, 95% CI: 2,488 to 8,091). MRT has a high probability of being the most cost effective, using fatigue as the primary outcome. The ICER is ?856 per unit of the CIS fatigue subscale. The results of the cost-utility analysis, using the QALY, indicate that the CBT had a higher likelihood of being more cost-effective. CONCLUSIONS: The probability of being more cost-effective is higher for MRT when using fatigue as primary outcome variable. Using QALY as the primary outcome, CBT has the highest probability of being more cost-effective. TRIAL REGISTRATION: ISRCTN77567702. PMID- 28574986 TI - An ethnobotanical survey of indigenous medicinal plants in Hafizabad district, Punjab-Pakistan. AB - Present paper offers considerable information on traditional uses of medicinal plants by the inhabitants of Hafizabad district, Punjab-Pakistan. This is the first quantitative ethnobotanical study from the area comprising popularity level of medicinal plant species intendedby using relative popularity level (RPL) and rank order priority (ROP) indices.Ethnobotanical data were collected by interviewing 166 local informants and 35 traditional health practioners (THPs) from different localities of Hafizabad district. Demographic features of informants; life form, part used, methods of preparation, modes of application and ethnomedicinal uses were documented. Ethnobotanical data were analyzed using quantitative tools, i.e. Relative frequency citation (RFC), use value (UV), informant consensus factor (ICF) fidelity level (FL), RPL and ROP indices. A total of 85 species belonging to 71 genera and 34 families were documented along with ethnomedicinal uses. Solanum surattense, Withania somnifera, Cyperus rotundus, Solanum nigrum and Melia azedarach were the most utilized medicinal plant species with highest used value. The reported ailments were classified into 11 disease categories based on ICF values and highest number of plant species was reported to treat dermatological and gastrointestinal disorders. Withania somnifera and Ranunculus sceleratus with maximum FL (100%), were used against gastrointestinal and urinary disorders, respectively. The RPL and ROP values were calculated to recognize the folk medicinal plant wealth; six out of 32 plant species (19%) were found popular, based on citation by more than half of the maximum number of informant viz. 26. Consequently, the ROP value for these species was more than 75. The comparative assessment with reported literature revealed 15% resemblance and 6% variation to previous data;however79% uses of the reported species were recorded for the first time. The diversity of medicinal plant species and associated traditional knowledge is significant in primary health care system. Medicinal plant species with high RPL values should be screened for comprehensive phytochemical and pharmacological studies. This could be useful in novel drug discovery and to validate the ethomendicinal knowledge. PMID- 28574987 TI - Reconstruction of stented coronary arteries from optical coherence tomography images: Feasibility, validation, and repeatability of a segmentation method. AB - Optical coherence tomography (OCT) is an established catheter-based imaging modality for the assessment of coronary artery disease and the guidance of stent placement during percutaneous coronary intervention. Manual analysis of large OCT datasets for vessel contours or stent struts detection is time-consuming and unsuitable for real-time applications. In this study, a fully automatic method was developed for detection of both vessel contours and stent struts. The method was applied to in vitro OCT scans of eight stented silicone bifurcation phantoms for validation purposes. The proposed algorithm comprised four main steps, namely pre-processing, lumen border detection, stent strut detection, and three dimensional point cloud creation. The algorithm was validated against manual segmentation performed by two independent image readers. Linear regression showed good agreement between automatic and manual segmentations in terms of lumen area (r>0.99). No statistically significant differences in the number of detected struts were found between the segmentations. Mean values of similarity indexes were >95% and >85% for the lumen and stent detection, respectively. Stent point clouds of two selected cases, obtained after OCT image processing, were compared to the centerline points of the corresponding stent reconstructions from micro computed tomography, used as ground-truth. Quantitative comparison between the corresponding stent points resulted in median values of ~150 MUm and ~40 MUm for the total and radial distances of both cases, respectively. The repeatability of the detection method was investigated by calculating the lumen volume and the mean number of detected struts per frame for seven repeated OCT scans of one selected case. Results showed low deviation of values from the median for both analyzed quantities. In conclusion, this study presents a robust automatic method for detection of lumen contours and stent struts from OCT as supported by focused validation against both manual segmentation and micro computed tomography and by good repeatability. PMID- 28574989 TI - Optimal classifier for imbalanced data using Matthews Correlation Coefficient metric. AB - Data imbalance is frequently encountered in biomedical applications. Resampling techniques can be used in binary classification to tackle this issue. However such solutions are not desired when the number of samples in the small class is limited. Moreover the use of inadequate performance metrics, such as accuracy, lead to poor generalization results because the classifiers tend to predict the largest size class. One of the good approaches to deal with this issue is to optimize performance metrics that are designed to handle data imbalance. Matthews Correlation Coefficient (MCC) is widely used in Bioinformatics as a performance metric. We are interested in developing a new classifier based on the MCC metric to handle imbalanced data. We derive an optimal Bayes classifier for the MCC metric using an approach based on Frechet derivative. We show that the proposed algorithm has the nice theoretical property of consistency. Using simulated data, we verify the correctness of our optimality result by searching in the space of all possible binary classifiers. The proposed classifier is evaluated on 64 datasets from a wide range data imbalance. We compare both classification performance and CPU efficiency for three classifiers: 1) the proposed algorithm (MCC-classifier), the Bayes classifier with a default threshold (MCC-base) and imbalanced SVM (SVM-imba). The experimental evaluation shows that MCC-classifier has a close performance to SVM-imba while being simpler and more efficient. PMID- 28574990 TI - The bat community of Haiti and evidence for its long-term persistence at high elevations. AB - Accurate accounts of both living and fossil mammal communities are critical for creating biodiversity inventories and understanding patterns of changing species diversity through time. We combined data from from14 new fossil localities with literature accounts and museum records to document the bat biodiversity of Haiti through time. We also report an assemblage of late-Holocene (1600-600 Cal BP) bat fossils from a montane cave (Trouing Jean Paul, ~1825m) in southern Haiti. The nearly 3000 chiropteran fossils from Trouing Jean Paul represent 15 species of bats including nine species endemic to the Caribbean islands. The fossil bat assemblage from Trouing Jean Paul is dominated by species still found on Hispaniola (15 of 15 species), much as with the fossil bird assemblage from the same locality (22 of 23 species). Thus, both groups of volant vertebrates demonstrate long-term resilience, at least at high elevations, to the past 16 centuries of human presence on the island. PMID- 28574988 TI - The differing influence of several factors on the development of fatty liver with elevation of liver enzymes between genders with metabolic syndrome: A cross sectional study. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is known to be strongly associated with obesity, visceral fat, metabolic syndrome (MS), lifestyle, and lifestyle-related diseases in both males and females. However, the prevalence of NAFLD, MS, and clinical backgrounds is different between males and females. OBJECTIVE: We conducted a cross-sectional study to examine the differing influence of lifestyle-related factors and visceral fat on fatty liver (FL) with elevation of liver enzymes between males and females with MS. METHODS: We enrolled 42,134 persons who underwent a regular health check-up, and after excluding subjects who fulfilled excluding criteria, the remaining subjects were 2,110 persons with MS. We examined the differing influence of lifestyle-related factors and visceral fat on FL with elevation of alanine aminotransferase (ALT) (ALT elevation was defined as ALT level of >=31 IU/l in the present study). RESULTS: The odds rations for FL with ALT elevation were as follows: WC, 1.83 (95% confidence interval (CI) 1.36-2.46); dyslipidemia, 1.89 (95% CI 1.34-2.68); hemoglobin A1c, 1.36 (95% CI 1.00-1.85); visceral fat type MS (V-type MS), 5.78 (95% CI 4.29-7.80); and light drinker, 0.56 (95% CI 0.41-0.78) in males with MS and BMI, 2.18 (95% CI 1.43-3.33); WC, 1.85 (95% CI 1.27-2.70); diastolic blood pressure, 1.69 (95% CI 1.16-2.45); triglyceride, 2.22 (95% CI 1.56-3.17); impaired glucose tolerance, 1.66 (95% CI 1.11-2.47); and V-type MS, 3.83 (95% CI 2.57-5.70) in females with MS. The prevalence of FL with ALT elevation and ALT was significantly higher in V-type MS than in the subcutaneous fat type MS in both males and females with MS (P < 0.001). CONCLUSION: Although V-type MS and WC is a common significant predictor of an increased prevalence of FL with ALT elevation in both males and females with MS, gender, lifestyle-related factors, and MS type in individuals with MS should be considered for the development of FL with ALT elevation. PMID- 28574991 TI - Exploring the potential of open big data from ticketing websites to characterize travel patterns within the Chinese high-speed rail system. AB - Big data have contributed to deepen our understanding in regards to many human systems, particularly human mobility patterns and the structure and functioning of transportation systems. Resonating the recent call for 'open big data,' big data from various sources on a range of scales have become increasingly accessible to the public. However, open big data relevant to travelers within public transit tools remain scarce, hindering any further in-depth study on human mobility patterns. Here, we explore ticketing-website derived data that are publically available but have been largely neglected. We demonstrate the power, potential and limitations of this open big data, using the Chinese high-speed rail (HSR) system as an example. Using an application programming interface, we automatically collected the data on the remaining tickets (RTD) for scheduled trains at the last second before departure in order to retrieve information on unused transit capacity, occupancy rate of trains, and passenger flux at stations. We show that this information is highly useful in characterizing the spatiotemporal patterns of traveling behaviors on the Chinese HSR, such as weekend traveling behavior, imbalanced commuting behavior, and station functionality. Our work facilitates the understanding of human traveling patterns along the Chinese HSR, and the functionality of the largest HSR system in the world. We expect our work to attract attention regarding this unique open big data source for the study of analogous transportation systems. PMID- 28574992 TI - A state space approach for piecewise-linear recurrent neural networks for identifying computational dynamics from neural measurements. AB - The computational and cognitive properties of neural systems are often thought to be implemented in terms of their (stochastic) network dynamics. Hence, recovering the system dynamics from experimentally observed neuronal time series, like multiple single-unit recordings or neuroimaging data, is an important step toward understanding its computations. Ideally, one would not only seek a (lower dimensional) state space representation of the dynamics, but would wish to have access to its statistical properties and their generative equations for in-depth analysis. Recurrent neural networks (RNNs) are a computationally powerful and dynamically universal formal framework which has been extensively studied from both the computational and the dynamical systems perspective. Here we develop a semi-analytical maximum-likelihood estimation scheme for piecewise-linear RNNs (PLRNNs) within the statistical framework of state space models, which accounts for noise in both the underlying latent dynamics and the observation process. The Expectation-Maximization algorithm is used to infer the latent state distribution, through a global Laplace approximation, and the PLRNN parameters iteratively. After validating the procedure on toy examples, and using inference through particle filters for comparison, the approach is applied to multiple single-unit recordings from the rodent anterior cingulate cortex (ACC) obtained during performance of a classical working memory task, delayed alternation. Models estimated from kernel-smoothed spike time data were able to capture the essential computational dynamics underlying task performance, including stimulus selective delay activity. The estimated models were rarely multi-stable, however, but rather were tuned to exhibit slow dynamics in the vicinity of a bifurcation point. In summary, the present work advances a semi-analytical (thus reasonably fast) maximum-likelihood estimation framework for PLRNNs that may enable to recover relevant aspects of the nonlinear dynamics underlying observed neuronal time series, and directly link these to computational properties. PMID- 28574993 TI - Weigh the pros and cons to ovarian reserve before stripping ovarian endometriomas prior to IVF/ICSI: A meta-analysis. AB - PURPOSE: To explore the effects of conservative surgery for endometriomas on ovarian responsiveness during assisted reproductive technology (ART) and provide reproductive and gynecological doctors with a more reliable reference program for the treatment of endometriomas. METHODS: A literature search was performed by searching the PubMed, Embase, Cochrane Library, Web of Science and Science Direct databases. Studies with inter- and intra-patient comparisons of ovarian responses and oocyte quality between operated and unoperated ovaries and that met the inclusion criteria were retrieved, and the data from the outcome measures were extracted and pooled for this meta-analysis. RESULTS: Twenty-one published studies (2649 ART cycles) were included. The total amount of gonadotropin (Gn) used (inverse variance (IV):0.48; 95% confidence interval (CI): [0.13, 1.82], P = 0.0007) was significantly increased in the women with endometriomas who had a history of cystectomy. The estrogen (E) level on the day of hCG administration (IV: -0.29; 95% CI: [-0.41, -0.17], P<0.00001), the number of mature or dominant follicles (IV: -1.17; 95% CI: [-1.51, -0.82], P<0.00001) and the total number of oocytes retrieved (IV: -1.78; 95% CI: [-2.38, -1.17], P<0.00001) were significantly decreased in the women with endometriomas who had a history of cystectomy. The duration of stimulation (IV: 0.02; 95% CI: [-0.09, 0.13], P = 0.77), the total number of formed embryos (IV: -0.06; 95% CI: [-0.17, 0.04], P = 0.25), the pregnancy rate(IV:0.98;95%CI[0.82,1.18], P = 0.83) and the live birth rate(IV:0.93;95%CI[0.70,1.23], P = 0.61)were not statistically different between the two groups. Similar intra-patient results were found in the number of mature or dominant follicles (IV: -0.88; 95% CI: [-1.25, -0.52], P<0.00001) and the total number of oocytes retrieved (IV: -3.48; 95% CI: [-4.77, -2.19], P<0.00001). CONCLUSION: ART might be a better therapeutic method for ovarian endometrioma related infertility than cystectomy. PMID- 28574994 TI - Follistatin like-1 (Fstl1) is required for the normal formation of lung airway and vascular smooth muscle at birth. AB - Fstl1, a secreted protein of the BMP antagonist class, has been implicated in the regulation of lung development and alveolar maturation. Here we generated a Fstl1 lacZ reporter mouse line as well as a Fstl1 knockout allele. We localized Fstl1 transcript in lung smooth muscle cells and identified Fstl1 as essential regulator of lung smooth muscle formation. Deletion of Fstl1 in mice led to postnatal death as a result of respiratory failure due to multiple defects in lung development. Analysis of the mutant phenotype showed impaired airway smooth muscle (SM) manifested as smaller SM line in trachea and discontinued SM surrounding bronchi, which were associated with decreased transcriptional factors myocardin/serum response factor (SRF) and impaired differentiation of SM cells. Fstl1 knockout mice also displayed abnormal vasculature SM manifested as hyperplasia SM in pulmonary artery. This study indicates a pivotal role for Fstl1 in early stage of lung airway smooth muscle development. PMID- 28574996 TI - Conversing with a devil's advocate: Interpersonal coordination in deception and disagreement. AB - This study investigates the presence of dynamical patterns of interpersonal coordination in extended deceptive conversations across multimodal channels of behavior. Using a novel "devil's advocate" paradigm, we experimentally elicited deception and truth across topics in which conversational partners either agreed or disagreed, and where one partner was surreptitiously asked to argue an opinion opposite of what he or she really believed. We focus on interpersonal coordination as an emergent behavioral signal that captures interdependencies between conversational partners, both as the coupling of head movements over the span of milliseconds, measured via a windowed lagged cross correlation (WLCC) technique, and more global temporal dependencies across speech rate, using cross recurrence quantification analysis (CRQA). Moreover, we considered how interpersonal coordination might be shaped by strategic, adaptive conversational goals associated with deception. We found that deceptive conversations displayed more structured speech rate and higher head movement coordination, the latter with a peak in deceptive disagreement conversations. Together the results allow us to posit an adaptive account, whereby interpersonal coordination is not beholden to any single functional explanation, but can strategically adapt to diverse conversational demands. PMID- 28574995 TI - Pulmonary emphysema is a predictor of pneumothorax after CT-guided transthoracic pulmonary biopsies of pulmonary nodules. AB - PURPOSE: Pneumothoraces are the most frequently occurring complications of CT guided percutaneous transthoracic pulmonary biopsies (PTPB). The aim of this study was to evaluate the influence of pre-diagnostic lung emphysema on the incidence and extent of pneumothoraces and to establish a risk stratification for the evaluation of the pre-procedure complication probability. MATERIAL AND METHODS: CT-guided PTPB of 100 pre-selected patients (mean age 67.1+/-12.8 years) were retrospectively enrolled from a single center database of 235 PTPB performed between 2012-2014. Patients were grouped according to pneumothorax appearance directly after PTPB (group I: without pneumothorax, n = 50; group II: with pneumothorax, n = 50). Group II was further divided according to post interventional treatment (group IIa: chest tube placement, n = 24; group IIb: conservative therapy, n = 26). For each patient pre-diagnostic percentage of emphysema was quantified using CT density analysis. Emphysema stages were compared between groups using bivariate analyses and multinomial logistic regression analyses. RESULTS: Emphysema percentage was significantly associated with the occurrence of post-interventional pneumothorax (p = 0.006). Adjusted for potential confounders (age, gender, lesion size and length of interventional pathway) the study yielded an OR of 1.07 (p = 0.042). Absolute risk of pneumothorax increased from 43.4% at an emphysema rate of 5% to 73.8% at 25%. No differences could be seen in patients with pneumothorax between percentage of emphysema and mode of therapy (p = 0.721). CONCLUSION: The rate of lung emphysema is proportionally related to the incidence of pneumothorax after CT-guided PTPB and allows pre-interventional risk stratification. There is no association between stage of emphysema and post-interventional requirement of chest tube placement. PMID- 28574997 TI - Attenuation of postoperative adhesions using a modeled manual therapy. AB - Postoperative adhesions are pathological attachments that develop between abdominopelvic structures following surgery. Considered unavoidable and ubiquitous, postoperative adhesions lead to bowel obstructions, infertility, pain, and reoperations. As such, they represent a substantial health care challenge. Despite over a century of research, no preventive treatment exists. We hypothesized that postoperative adhesions develop from a lack of movement of the abdominopelvic organs in the immediate postoperative period while rendered immobile by surgery and opiates, and tested whether manual therapy would prevent their development. In a modified rat cecal abrasion model, rats were allocated to receive treatment with manual therapy or not, and their resulting adhesions were quantified. We also characterized macrophage phenotype. In separate experiments we tested the safety of the treatment on a strictureplasty model, and also the efficacy of the treatment following adhesiolysis. We show that the treatment led to reduced frequency and size of cohesive adhesions, but not other types of adhesions, such as those involving intraperitoneal fatty structures. This effect was associated with a delay in the appearance of trophic macrophages. The treatment did not inhibit healing or induce undesirable complications following strictureplasty. Our results support that that maintained movements of damaged structures in the immediate postoperative period has potential to act as an effective preventive for attenuating cohesive postoperative adhesion development. Our findings lay the groundwork for further research, including mechanical and pharmacologic approaches to maintain movements during healing. PMID- 28574998 TI - Expertise with unfamiliar objects is flexible to changes in task but not changes in class. AB - Perceptual expertise is notoriously specific and bound by familiarity; generalizing to novel or unfamiliar images, objects, identities, and categories often comes at some cost to performance. In forensic and security settings, however, examiners are faced with the task of discriminating unfamiliar images of unfamiliar objects within their general domain of expertise (e.g., fingerprints, faces, or firearms). The job of a fingerprint expert, for instance, is to decide whether two unfamiliar fingerprint images were left by the same unfamiliar finger (e.g., Smith's left thumb), or two different unfamiliar fingers (e.g., Smith and Jones's left thumb). Little is known about the limits of this kind of perceptual expertise. Here, we examine fingerprint experts' and novices' ability to distinguish fingerprints compared to inverted faces in two different tasks. Inverted face images serve as an ideal comparison because they vary naturally between and within identities, as do fingerprints, and people tend to be less accurate or more novice-like at distinguishing faces when they are presented in an inverted or unfamiliar orientation. In Experiment 1, fingerprint experts outperformed novices in locating categorical fingerprint outliers (i.e., a loop pattern in an array of whorls), but not inverted face outliers (i.e., an inverted male face in an array of inverted female faces). In Experiment 2, fingerprint experts were more accurate than novices at discriminating matching and mismatching fingerprints that were presented very briefly, but not so for inverted faces. Our data show that perceptual expertise with fingerprints can be flexible to changing task demands, but there can also be abrupt limits: fingerprint expertise did not generalize to an unfamiliar class of stimuli. We interpret these findings as evidence that perceptual expertise with unfamiliar objects is highly constrained by one's experience. PMID- 28574999 TI - Predictors of renal function recovery among patients undergoing renal replacement therapy following orthotopic liver transplantation. AB - Renal dysfunction frequently occurs during the periods preceding and following orthotopic liver transplantation (OLT), and in many cases, renal replacement therapy (RRT) is required. Information regarding the duration of RRT and the rate of kidney function recovery after OLT is crucial for transplant program management. We evaluated a sample of 155 stable patients undergoing post intensive care hemodialysis (HD) from a patient population of 908 adults who underwent OLT. We investigated the average time to renal function recovery (duration of RRT required) and determined the risk factors for remaining on dialysis > 90 days after OLT. Log-rank tests were used for univariate analysis, and Cox proportional hazards models were used to identify factors associated with the risk of remaining on HD. The results of our analysis showed that of the 155 patients, 28% had pre-OLT diabetes mellitus, 21% had pre-OLT hypertension, and 40% had viral hepatitis. Among the patients, the median MELD (Model for End-Stage Liver Disease) score was 27 (interquartile range [IQR] 22-35). When they were listed for liver transplantation, 32% of the patients had serum creatinine (Scr) levels > 1.5 mg/dL or were on HD, and 50% had serum creatinine (Scr) levels > 1.5 mg/dL or were on HD at the time of OLT. Of the transplanted patients, 25% underwent pre-OLT intermittent HD, and 14% and 41% underwent continuous renal replacement therapy (CRRT) pre-OLT and post-OLT, respectively. At 90 days post OLT, 118 (76%) patients had been taken off dialysis, and 16 (10%) patients had died while undergoing HD. The median recovery time of these post-OLT patients was 33 (IQR 27-39) days. In the multivariate analysis, fulminant hepatic failure as the cause of liver disease (p<0.001), the absence of pre-OLT hypertension (p = 0.016), a lower intraoperative fresh-frozen plasma (FFP) transfusion volume (p = 0.019) and not undergoing pre-OLT intermittent HD (p = 0.032) were associated with performing RRT for less than 90 days. Therefore, a high proportion of OLT patients showed improved renal function after OLT, and those who were diagnosed with fulminant hepatic failure, had no pre-OLT hypertension, received a lower transfused volume of intraoperative FFP and did not undergo pre-OLT intermittent HD had a higher probability of recovery. PMID- 28575000 TI - Clinical and virological characteristics of dengue in Surabaya, Indonesia. AB - Dengue disease is still a major health problem in Indonesia. Surabaya, the second largest city in the country, is endemic for dengue. We report here on dengue disease in Surabaya, investigating the clinical manifestations, the distribution of dengue virus (DENV) serotypes, and the relationships between clinical manifestations and the genetic characteristics of DENV. A total of 148 patients suspected of having dengue were recruited during February-August 2012. One hundred one (68%) of them were children, and 47 (32%) were adults. Dengue fever (DF) and Dengue hemorrhagic fever (DHF) were equally manifested in all of the patients. We performed DENV serotyping on all of the samples using real-time RT PCR. Of 148, 79 (53%) samples were detected as DENV positive, with DENV-1 as the predominant serotype (73%), followed by DENV-2 (8%), DENV-4 (8%), and DENV-3 (6%), while 5% were mixed infections. Based on the Envelope gene sequences, we performed phylogenetic analyses of 24 isolates to genotype the DENV circulating in Surabaya in 2012, and the analysis revealed that DENV-1 consisted of Genotypes I and IV, DENV-2 was of the Cosmopolitan genotype, the DENV-3 viruses were of Genotype I, and DENV-4 was detected as Genotype II. We correlated the infecting DENV serotypes with clinical manifestations and laboratory parameters; however, no significant correlations were found. Amino acid analysis of Envelope protein did not find any unique mutations related to disease severity. PMID- 28575001 TI - Radiographic and magnetic resonance imaging predicts severity of cruciate ligament fiber damage and synovitis in dogs with cranial cruciate ligament rupture. AB - Cruciate ligament rupture (CR) and associated osteoarthritis (OA) is a common condition in dogs. Dogs frequently develop a second contralateral CR. This study tested the hypothesis that the degree of stifle synovitis and cranial cruciate ligament (CrCL) matrix damage in dogs with CR is correlated with non-invasive diagnostic tests, including magnetic resonance (MR) imaging. We conducted a prospective cohort study of 29 client-owned dogs with an unstable stifle due to complete CR and stable contralateral stifle with partial CR. We evaluated correlation of stifle synovitis and CrCL fiber damage with diagnostic tests including bilateral stifle radiographs, 3.0 Tesla MR imaging, and bilateral stifle arthroscopy. Histologic grading and immunohistochemical staining for CD3+ T lymphocytes, TRAP+ activated macrophages and Factor VIII+ blood vessels in bilateral stifle synovial biopsies were also performed. Serum and synovial fluid concentrations of C-reactive protein (CRP) and carboxy-terminal telopeptide of type I collagen (ICTP), and synovial total nucleated cell count were determined. Synovitis was increased in complete CR stifles relative to partial CR stifles (P<0.0001), although total nucleated cell count in synovial fluid was increased in partial CR stifles (P<0.01). In partial CR stifles, we found that 3D Fast Spin Echo Cube CrCL signal intensity was correlated with histologic synovitis (SR = 0.50, P<0.01) and that radiographic OA was correlated with CrCL fiber damage assessed arthroscopically (SR = 0.61, P<0.001). Taken together, results of this study show that clinical diagnostic tests predict severity of stifle synovitis and cruciate ligament matrix damage in stable partial CR stifles. These data support use of client-owned dogs with unilateral complete CR and contralateral partial CR as a clinical trial model for investigation of disease-modifying therapy for partial CR. PMID- 28575002 TI - Effects of early postnatal environment on hypothalamic gene expression in OLETF rats. AB - Previous reports have shown that the early postnatal environment has the ability to modify the obesity phenotype of Otsuka Long-Evans Tokushima Fatty (OLETF) rats. To determine whether this early postnatal environment affects hypothalamic signaling systems involved in energy balance, OLETF pups and lean Long-Evans Tokushima Otsuka (LETO) pups were cross-fostered to same or opposite strain Dams (designated as LdLp: LETO pups with LETO dams; LdOp: OLETF pups with LETO dams; OdLp: LETO pups with OLETF dams; and OdOp: OLETF pups with OLETF dams). Hypothalamic gene expression was examined at postnatal day 23 (PND 23) and PND 90 as OdOp rats started to gain more body weight at PND 23 and developed obesity at PND 90 relative to lean control LdLp rats. On PND 23, neuropeptide Y (Npy) gene expression was significantly increased in the dorsomedial hypothalamus (DMH) in both LdOp and OdOp pups compared to LdLp pups. Maternal environment did not affect DMH Npy expression in LETO weanlings. On PND 90, maternal environment during the cross-fostering period had a major effect on DMH Npy expression. Levels were significantly increased in both OdOp and OdLp rats relative to those in LdOp rats and LdLp controls. Reduced expression of Npy in the DMH of LdOp rats was consistent with their reduction of body weight compared to OdOp rats. In contrast to DMH Npy, gene expression for Npy and proopiomelanocortin in the arcuate nucleus appeared to appropriately respond to alterations in body weight and plasma leptin levels. Levels of oxytocin gene expression in the paraventricular nucleus were lower in offspring raised by LETO dams apparently responding to the higher DMH NPY levels. Together, our results demonstrate effects of both genotype and early postnatal environment on obesity of OLETF rats and further suggest an important role of DMH NPY in the development of obesity of OLETF rats. PMID- 28575004 TI - Comparative chloroplast genomes of eleven Schima (Theaceae) species: Insights into DNA barcoding and phylogeny. AB - Schima is an ecologically and economically important woody genus in tea family (Theaceae). Unresolved species delimitations and phylogenetic relationships within Schima limit our understanding of the genus and hinder utilization of the genus for economic purposes. In the present study, we conducted comparative analysis among the complete chloroplast (cp) genomes of 11 Schima species. Our results indicate that Schima cp genomes possess a typical quadripartite structure, with conserved genomic structure and gene order. The size of the Schima cp genome is about 157 kilo base pairs (kb). They consistently encode 114 unique genes, including 80 protein-coding genes, 30 tRNAs, and 4 rRNAs, with 17 duplicated in the inverted repeat (IR). These cp genomes are highly conserved and do not show obvious expansion or contraction of the IR region. The percent variability of the 68 coding and 93 noncoding (>150 bp) fragments is consistently less than 3%. The seven most widely touted DNA barcode regions as well as one promising barcode candidate showed low sequence divergence. Eight mutational hotspots were identified from the 11 cp genomes. These hotspots may potentially be useful as specific DNA barcodes for species identification of Schima. The 58 cpSSR loci reported here are complementary to the microsatellite markers identified from the nuclear genome, and will be leveraged for further population level studies. Phylogenetic relationships among the 11 Schima species were resolved with strong support based on the cp genome data set, which corresponds well with the species distribution pattern. The data presented here will serve as a foundation to facilitate species identification, DNA barcoding and phylogenetic reconstructions for future exploration of Schima. PMID- 28575005 TI - Various meteorological conditions exhibit both immediate and delayed influences on the risk of stroke events: The HEWS-stroke study. AB - We hypothesized that meteorological conditions on the onset day and conditions on the former days may play important roles in the modulation of physical conditions. Associations of meteorological factors and their changes in former days with stroke onset are of interest. We conducted a multicenter retrospective study to evaluate the frequency of stroke events and their interaction with meteorological conditions and their daily changes. Acute stroke patients (n = 3935, 73.5+/-12.4 years, 1610 females) who were admitted to 7 stroke hospitals in three restricted areas were enrolled in this study. Poisson regression models involving time-lag variables was used to compare daily rates of stroke events with mean thermo-hydrological index (THI), atmospheric pressure, and their daily changes. We divided onset days into quintiles based on the THI, atmospheric pressure, and their daily changes for the last 7 days. The frequencies of ischemic stroke significantly increased when THI varied either cooler or warmer from a previous day (extremely cooler, risk ratio (RR) 1.19, 95% confidence interval (CI) 1.05 to 1.34; extremely warmer, RR 1.16, 95% CI 1.03 to 1.31; r2 = 0.001 for the best regression, p = 0.001). Intracerebral hemorrhage frequencies significantly decreased on high-THI days (extremely high, RR 0.72, 95% CI 0.54 to 0.95; r2 = 0.013 for the best regression, p<0.001) and increased in high atmospheric pressure days (high, RR 1.31, 95% CI 1.04 to 1.65; r2 = 0.009 for the best regression, p<0.001). Additionally, even after adjusting for the THI on the onset day and its changes for the other days, intracerebral hemorrhage increased when THI got extremely cooler in 4 days prior (RR 1.33, 95% CI 1.03 to 1.71, r2 = 0.006 for the best regression, p<0.001). Various meteorological conditions may exhibit influences on stroke onset. And, when temperature cooled, there may be a possibility to show delayed influence on the frequency of intracerebral hemorrhage 4 days later. PMID- 28575003 TI - Establishment and transfer of classical eyeblink conditioning using electrical microstimulation of the hippocampus as the conditioned stimulus. AB - The present experiment was designed to determine whether classical eyeblink conditioning (EBC) can be established by using electrical microstimulation of the hippocampus as a conditioned stimulus (CS) paired with an air-puff unconditioned stimulus (US). We intended to examine whether EBC transfer could occur when a CS was shifted between microstimulation of the hippocampus as a CS (Hip-CS) and tone as a CS (tone-CS) and to compare the difference in transfer effectiveness between delay EBC (dEBC) and trace EBC (tEBC). Eight groups of guinea pigs, including 4 experimental groups and 4 control groups, were included in the study. First, the experimental groups received either a Hip-CS or a tone-CS paired with a US; then, these groups were exposed to a shifted CS (tone-CS or Hip-CS) paired with the US. The control groups received the corresponding Hip-CS or tone-CS, which was, however, pseudo-paired with the US. The control groups were then shifted to the tone-CS (or Hip-CS) paired with the US. The results show that EBC can be successfully established when using microstimulation of the hippocampus as a CS paired with an air-puff US, and that the acquisition rates of EBC are higher in the experimental groups than in the control groups after switching from the Hip CS to the tone-CS or vice versa, indicating the occurrence of learning transfer between EBC established with the Hip-CS and tone-CS. The present study also demonstrated that the EBC re-acquisition rates were remarkably higher in dEBC than in tEBC with both types of transfer, which suggests that the saving effect was more evident in dEBC than tEBC. These results significantly expand our knowledge of EBC transfer as well as the functional neural circuit underlying EBC transfer. PMID- 28575007 TI - Development of microsatellite markers and assembly of the plastid genome in Cistanthe longiscapa (Montiaceae) based on low-coverage whole genome sequencing. AB - Cistanthe longiscapa is an endemic annual herb and characteristic element of the Chilean Atacama Desert. Principal threats are the destruction of its seed deposits by human activities and reduced germination rates due to the decreasing occurrence of precipitation events. To enable population genetic and phylogeographic analyses in this species we performed paired-end shotgun sequencing (2x100 bp) of genomic DNA on the Illumina HiSeq platform and identified microsatellite (SSR) loci in the resulting sequences. From 29 million quality-filtered read pairs we obtained 549,174 contigs (average length 614 bp; N50 = 904). Searching for SSRs revealed 10,336 loci with microsatellite motifs. Initially, we designed primers for 96 loci, which were tested for PCR amplification on three C. longiscapa individuals. Successfully amplifying loci were further tested on eight individuals to screen for length variation in the resulting amplicons, and the alleles were exemplarily sequenced to infer the basis for the observed length variation. Finally we arrived at 26 validated SSR loci for population studies in C. longiscapa, which resulted in 146 bi-allelic SSR markers in our test sample of eight individuals. The genomic sequences were also used to assemble the plastid genome of C. longiscapa, which provides an additional set of maternally inherited genetic markers. PMID- 28575006 TI - Identification of CkSNAP33, a gene encoding synaptosomal-associated protein from Cynanchum komarovii, that enhances Arabidopsis resistance to Verticillium dahliae. AB - SNARE proteins are essential to vesicle trafficking and membrane fusion in eukaryotic cells. In addition, the SNARE-mediated secretory pathway can deliver diverse defense products to infection sites during exocytosis-associated immune responses in plants. In this study, a novel gene (CkSNAP33) encoding a synaptosomal-associated protein was isolated from Cynanchum komarovii and characterized. CkSNAP33 contains Qb- and Qc-SNARE domains in the N- and C terminal regions, respectively, and shares high sequence identity with AtSNAP33 from Arabidopsis. CkSNAP33 expression was induced by H2O2, salicylic acid (SA), Verticillium dahliae, and wounding. Arabidopsis lines overexpressing CkSNAP33 had longer primary roots and larger seedlings than the wild type (WT). Transgenic Arabidopsis lines showed significantly enhanced resistance to V. dahliae, and displayed reductions in disease index and fungal biomass, and also showed elevated expression of PR1 and PR5. The leaves of transgenic plants infected with V. dahliae showed strong callose deposition and cell death that hindered the penetration and spread of the fungus at the infection site. Taken together, these results suggest that CkSNAP33 is involved in the defense response against V. dahliae and enhanced disease resistance in Arabidopsis. PMID- 28575009 TI - A novel application of PageRank and user preference algorithms for assessing the relative performance of track athletes in competition. AB - Ranking enables coaches, sporting authorities, and pundits to determine the relative performance of individual athletes and teams in comparison to their peers. While ranking is relatively straightforward in sports that employ traditional leagues, it is more difficult in sports where competition is fragmented (e.g. athletics, boxing, etc.), with not all competitors competing against each other. In such situations, complex points systems are often employed to rank athletes. However, these systems have the inherent weakness that they frequently rely on subjective assessments in order to gauge the calibre of the competitors involved. Here we show how two Internet derived algorithms, the PageRank (PR) and user preference (UP) algorithms, when utilised with a simple 'who beat who' matrix, can be used to accurately rank track athletes, avoiding the need for subjective assessment. We applied the PR and UP algorithms to the 2015 IAAF Diamond League men's 100m competition and compared their performance with the Keener, Colley and Massey ranking algorithms. The top five places computed by the PR and UP algorithms, and the Diamond League '2016' points system were all identical, with the Kendall's tau distance between the PR standings and '2016' points system standings being just 15, indicating that only 5.9% of pairs differed in their order between these two lists. By comparison, the UP and '2016' standings displayed a less strong relationship, with a tau distance of 95, indicating that 37.6% of the pairs differed in their order. When compared with the standings produced using the Keener, Colley and Massey algorithms, the PR standings appeared to be closest to the Keener standings (tau distance = 67, 26.5% pair order disagreement), whereas the UP standings were more similar to the Colley and Massey standings, with the tau distances between these ranking lists being only 48 (19.0% pair order disagreement) and 59 (23.3% pair order disagreement) respectively. In particular, the UP algorithm ranked 'one-off' victors more highly than the PR algorithm, suggesting that the UP algorithm captures alternative characteristics to the PR algorithm, which may more suitable for predicting future performance in say knockout tournaments, rather than for use in competitions such as the Diamond League. As such, these Internet derived algorithms appear to have considerable potential for objectively assessing the relative performance of track athletes, without the need for complicated points equivalence tables. Importantly, because both algorithms utilise a 'who beat who' model, they automatically adjust for the strength of the competition, thus avoiding the need for subjective decision making. PMID- 28575008 TI - Plasma metabolome and skin proteins in Charcot-Marie-Tooth 1A patients. AB - OBJECTIVE: Charcot-Marie-Tooth 1A (CMT1A) disease is the most common inherited neuropathy that lacks of therapy and of molecular markers to assess disease severity. Herein, we have pursued the identification of potential biomarkers in plasma samples and skin biopsies that could define the phenotype of CMT1A patients at mild (Mi), moderate (Mo) and severe (Se) stages of disease as assessed by the CMT neuropathy score to contribute to the understanding of CMT pathophysiology and eventually inform of the severity of the disease. METHODS: We have used: (i) a high-throughput untargeted metabolomic approach of plasma samples in a cohort of 42 CMT1A patients and 15 healthy controls (CRL) using ultrahigh liquid chromatography coupled to mass spectrometry and (ii) reverse phase protein microarrays to quantitate the expression of some proteins of energy metabolism and of the antioxidant response in skin biopsies of a cohort of 70 CMT1A patients and 13 healthy controls. RESULTS: The metabolomic approach identified 194 metabolites with significant differences among the four groups (Mi, Mo, Se, CRL) of samples. A multivariate Linear Discriminant Analysis model using 12 metabolites afforded the correct classification of the samples. These metabolites indicate an increase in protein catabolism and the mobilization of membrane lipids involved in signaling inflammation with severity of CMT1A. A concurrent depletion of leucine, which is required for the biogenesis of the muscle, is also observed in the patients. Protein expression in skin biopsies indicates early loss of mitochondrial and antioxidant proteins in patients' biopsies. CONCLUSION: The findings indicate that CMT1A disease is associated with a metabolic state resembling inflammation and sarcopenia suggesting that it might represent a potential target to prevent the nerve and muscle wasting phenotype in these patients. The observed changes in metabolites could be useful as potential biomarkers of CMT1A disease after appropriate validation in future longitudinal studies. PMID- 28575010 TI - Effects of HIV infection on maternal and neonatal health in southern Mozambique: A prospective cohort study after a decade of antiretroviral drugs roll out. AB - INTRODUCTION: The HIV epidemic is concentrated in sub-Saharan Africa. However, limited information exists on its impact on women and infant's health since the introduction of antiretroviral drugs in this region, where health resources are often scarce. METHODS: The effect of HIV infection on maternal health, birth outcomes and infant health was analysed in two contemporary cohorts of HIV uninfected and HIV-infected pregnant women from southern Mozambique. Pregnant women attending the first antenatal care visit were followed until one month after delivery. Antiretroviral therapy was administered based on CD4+T cell count and clinical stage. Maternal and neonatal morbidity and mortality, as well as pregnancy outcomes were assessed by mother's HIV status. RESULTS: A total of 1183 HIV-uninfected and 561 HIV-infected pregnant women were enrolled. HIV-infected women were more likely to have anaemia both at the first antenatal care visit and at delivery than HIV-uninfected women (71.5% versus 54.8% and 49.4% versus 40.6%, respectively, p<0.001). Incidence of hospital admissions during pregnancy was increased among HIV-infected women (RR, 2.04, [95%CI, 1.45; 2.86]; p<0.001). At delivery, 21% of HIV-infected women reported being on antiretroviral therapy, and 70% having received antiretroviral drugs for prevention of mother to child transmission of HIV. The risk of stillbirths was doubled in HIV-infected women (RR, 2.16 [95%CI 1.17; 3.96], p = 0.013). Foetal anaemia was also increased among infants born to HIV-infected women (10.6% versus 7.3%, p = 0.022). No differences were found in mean birth weight, malaria, prematurity and maternal and neonatal deaths between groups. CONCLUSIONS: HIV infection continues to be associated with significant maternal morbidity and poor neonatal health outcomes. Efforts should urgently be made to identify the barriers that impede improvements on the devastating effects of HIV in African women and their infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00811421. PMID- 28575012 TI - Characterization of interfacial socket pressure in transhumeral prostheses: A case series. AB - One of the most important factors in successful upper limb prostheses is the socket design. Sockets must be individually fabricated to arrive at a geometry that suits the user's morphology and appropriately distributes the pressures associated with prosthetic use across the residual limb. In higher levels of amputation, such as transhumeral, this challenge is amplified as prosthetic weight and the physical demands placed on the residual limb are heightened. Yet, in the upper limb, socket fabrication is largely driven by heuristic practices. An analytical understanding of the interactions between the socket and residual limb is absent in literature. This work describes techniques, adapted from lower limb prosthetic research, to empirically characterize the pressure distribution occurring between the residual limb and well-fit transhumeral prosthetic sockets. A case series analyzing the result of four participants with transhumeral amputation is presented. A Tekscan VersaTek pressure measurement system and FaroArm Edge coordinate measurement machine were employed to capture socket residual limb interface pressures and geometrically register these values to the anatomy of participants. Participants performed two static poses with their prosthesis under two separate loading conditions. Surface pressure maps were constructed from the data, highlighting pressure distribution patterns, anatomical locations bearing maximum pressure, and the relative pressure magnitudes. Pressure distribution patterns demonstrated unique characteristics across the four participants that could be traced to individual socket design considerations. This work presents a technique that implements commercially available tools to quantitatively characterize upper limb socket-residual limb interactions. This is a fundamental first step toward improved socket designs developed through informed, analytically-based design tools. PMID- 28575011 TI - Age-dependent regulation of obesity and Alzheimer-related outcomes by hormone therapy in female 3xTg-AD mice. AB - Depletion of ovarian hormones at menopause is associated with increased Alzheimer's disease (AD) risk. Hormone loss also increases central adiposity, which promotes AD development. One strategy to improve health outcomes in postmenopausal women is estrogen-based hormone therapy (HT), though its efficacy is controversial. The window of opportunity hypothesis posits that HT is beneficial only if initiated near the onset of menopause. Here, we tested this hypothesis by assessing the efficacy of HT against diet-induced obesity and AD related pathology in female 3xTg-AD mice at early versus late middle-age. HT protected against obesity and reduced beta-amyloid burden only at early middle age. One mechanism that contributes to AD pathogenesis is microglial activation, which is increased by obesity and reduced by estrogens. In parallel to its effects on beta-amyloid accumulation, we observed that HT reduced morphological evidence of microglial activation in early but not late middle-age. These findings suggest that HT may be effective during human perimenopause in reducing indices of obesity and AD-related pathology, a conclusion consistent with the window of opportunity hypothesis. PMID- 28575013 TI - Adverse drug events-Analysis of a decade. A Portuguese case-study, from 2004 to 2013 using hospital database. AB - PURPOSE: The goal of this study was to characterise adverse drug events (ADE), including both adverse drug reaction (ADR) and accidental poisoning by drugs (AP), considering age, gender, length of stay (LOS), number of deaths and year, during the period 2004-2013. Additionally distributions of the ten's most frequent ADR and AP were characterized, considering age-group and gender. METHODS: A retrospective descriptive nationwide study was conducted, based on the hospital discharges database in Portugal from 2004 to 2013, using ICD-9. Events were identified based on the following codes: from E930 to E949.9 and from E850 to E858.9. RESULTS: A total of 9 320 076 patients were discharged within this period, with 133 688 patients (1.46%) having at least one ADE, 4% of them related with AP. The mean age of these patients was 63.79 years (SD 21.31), 54.50% were female and the mean LOS was 14.05 days (SD 22.19). Patient with AP had a mean age of 41.06 years (SD 34.05), 54.70% were female and LOS was 7.15 days (SD 19.42). We have identified 10.691 deaths that represent 8.00% from the total of patients with an ADE. The patients above 65 years were more affected by ADR and children below 18 were more affected by AP. CONCLUSION: In the last decade an increasing trend of ADR were observed and an AP pattern relatively stable. Elderly people and children were the age groups most affected. Antibiotics (in ADR) and benzodiazepine-based tranquilizers (in AP) were the major problems. This is a huge, increasing and challenging problem. Further research, using individual and contextual risk factors should be developed to understand spatiotemporal variability, promoting tailored interventions, within and across countries. PMID- 28575014 TI - The outcomes and controversies of transplant tourism-Lessons of an 11-year retrospective cohort study from Taiwan. AB - BACKGROUND: Transplant tourism has increased rapidly in the past two decades, accounting for about 10% of world organ transplants. However it is ethically controversial and discouraged by professional guidelines. We conducted this study to investigate the outcomes and trends of overseas kidney and liver transplantation in Taiwan to provide a sound basis for ethical reflection. METHODS AND FINDINGS: The Taiwanese National Health Insurance Research Database was used to identify 2381 domestic and 2518 overseas kidney transplant (KT) recipients from 1998 to 2009 and 1758 domestic and 540 overseas liver transplantation (LT) recipients from 1999 to 2009. Cox proportional hazards models were used to assess the risks of mortality and graft failure. The numbers of overseas transplantation increased after 2000, reached a peak in 2005 and decreased after 2007. Compared to their domestic counterparts, the overseas KT recipients were older, male predominant, with shorter pre-op dialysis period and more comorbidities. Similarly, the overseas LT recipients were older, male predominant and had more hepatocellular carcinoma cases. The 1-, 5-, and 10-year patient survival rates were 96.9%, 91.7% and 83.0% respectively for domestic KT and 95.8%, 87.8% and 73.1% for overseas KT (p<0.001). The 1-, 5-, and 10-year patient survival rates were 89.2%, 79.5%, 75.2% for domestic LT and 79.8%, 54.7%, 49.9% for overseas LT (p<0.001). CONCLUSION: The poorer outcomes of the overseas groups may be due to more older patients, more comorbidities (KT), or more hepatocellular carcinoma recurrences (LT). After domestic reform and international ethical challenges, the numbers of organ tourism decreased but the practice still persisted surreptitiously. Compulsory registration policies for overseas transplantation with international conventions to sanction organ trafficking and transplant tourism should be considered to stop these controversial practices. PMID- 28575015 TI - Sex initiates adaptive evolution by recombination between beneficial loci. AB - Current theory proposes that sex can increase genetic variation and produce high fitness genotypes if genetic associations between alleles at different loci are non-random. In case beneficial and deleterious alleles at different loci are in linkage disequilibrium, sex may i) recombine beneficial alleles of different loci, ii) liberate beneficial alleles from genetic backgrounds of low fitness, or iii) recombine deleterious mutations for more effective elimination. In our study, we found that the first mechanism dominated the initial phase of adaptive evolution in Brachionus calyciflorus rotifers during a natural selection experiment. We used populations that had been locally adapted to two environments previously, creating a linkage disequilibrium between beneficial and deleterious alleles at different loci in a combined environment. We observed the highest fitness increase when several beneficial alleles of different loci could be recombined, while the other mechanisms were ineffective. Our study thus provides evidence for the hypothesis that sex can speed up adaptation by recombination between beneficial alleles of different loci, in particular during early stages of adaptive evolution in our system. We also suggest that the benefits of sex might change over time and state of adaptive progress. PMID- 28575016 TI - The feline skin microbiota: The bacteria inhabiting the skin of healthy and allergic cats. AB - BACKGROUND: The skin is inhabited by a multitude of microorganisms. An imbalance of these microorganisms is associated with disease, however, the causal relationship between skin microbiota and disease remains unknown. To describe the cutaneous bacterial microbiota of cats and determine whether bacterial dysbiosis occurs on the skin of allergic cats, the skin surfaces on various regions of 11 healthy cats and 10 allergic cats were sampled. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA was extracted from skin swabs and sequenced using primers that target the V4 region of the bacterial 16S rRNA. The bacterial sequences from healthy cats revealed that there are differences in species diversity and richness between body sites and different epithelial surfaces. Bacterial communities preferred body site niches in the healthy cats, however, the bacterial communities on allergic cat skin tended to be more unique to the individual cat. Overall, the number of bacterial species was not significantly different between the two health status groups, however, the abundances of these bacterial species were different between healthy and allergic skin. Staphylococcus, in addition to other taxa, was more abundant on allergic skin. CONCLUSIONS/SIGNIFICANCE: This study reveals that there are more bacterial species inhabiting the skin of cats than previously thought and provide some evidence of an association between dysbiosis and skin disease. PMID- 28575018 TI - Computing with networks of nonlinear mechanical oscillators. AB - As it is getting increasingly difficult to achieve gains in the density and power efficiency of microelectronic computing devices because of lithographic techniques reaching fundamental physical limits, new approaches are required to maximize the benefits of distributed sensors, micro-robots or smart materials. Biologically-inspired devices, such as artificial neural networks, can process information with a high level of parallelism to efficiently solve difficult problems, even when implemented using conventional microelectronic technologies. We describe a mechanical device, which operates in a manner similar to artificial neural networks, to solve efficiently two difficult benchmark problems (computing the parity of a bit stream, and classifying spoken words). The device consists in a network of masses coupled by linear springs and attached to a substrate by non linear springs, thus forming a network of anharmonic oscillators. As the masses can directly couple to forces applied on the device, this approach combines sensing and computing functions in a single power-efficient device with compact dimensions. PMID- 28575017 TI - FOXC1 modulates MYOC secretion through regulation of the exocytic proteins RAB3GAP1, RAB3GAP2 and SNAP25. AB - The neurodegenerative disease glaucoma is one of the leading causes of blindness in the world. Glaucoma is characterized by progressive visual field loss caused by retinal ganglion cell (RGC) death. Both surgical glaucoma treatments and medications are available, however, they only halt glaucoma progression and are unable to reverse damage. Furthermore, many patients do not respond well to treatments. It is therefore important to better understand the mechanisms involved in glaucoma pathogenesis. Patients with Axenfeld-Rieger syndrome (ARS) offer important insight into glaucoma progression. ARS patients are at 50% risk of developing early onset glaucoma and respond poorly to treatments, even when surgical treatments are combined with medications. Mutations in the transcription factor FOXC1 cause ARS. Alterations in FOXC1 levels cause ocular malformations and disrupt stress response in ocular tissues, thereby contributing to glaucoma progression. In this study, using biochemical and molecular techniques, we show that FOXC1 regulates the expression of RAB3GAP1, RAB3GAP2 and SNAP25, three genes with central roles in both exocytosis and endocytosis, responsible for extracellular trafficking. FOXC1 positively regulates RAB3GAP1 and RAB3GAP2, while either increase or decrease in FOXC1 levels beyond its normal range results in decreased SNAP25. In addition, we found that FOXC1 regulation of RAB3GAP1, RAB3GAP2 and SNAP25 affects secretion of Myocilin (MYOC), a protein associated with juvenile onset glaucoma and steroid-induced glaucoma. The present work reveals that FOXC1 is an important regulator of exocytosis and establishes a new link between FOXC1 and MYOC-associated glaucoma. PMID- 28575019 TI - Clinicopathologic significance of the CXCL1-CXCR2 axis in the tumor microenvironment of gastric carcinoma. AB - PURPOSE: It was reported that the chemokine (C-X-C motif) ligand 1 (CXCL1) from cancer cells stimulated the recruitment of bone marrow-derived mesenchymal cells (BM-MCs) into tumor stroma via chemokine (C-X-C motif) receptor 2 (CXCR2) signaling. We conducted this retrospective study to determine the clinicopathologic significance of the CXCL1-CXCR2 axis in human gastric cancer. METHODS: The correlations between the clinicopathological features of 270 primary gastric carcinomas and CXCL1 in cancer cells and CXCR2 in stromal cells were analyzed in immunohistochemical studies. The effect of gastric cancer cells on the expression of CXCR2 in BM-MCs was examined using diffuse-type gastric cancer cell lines in vitro. RESULTS: The expression of CXCL1 in cancer cells was correlated with T invasion (T2-T4), lymph node metastasis, lymphatic invasion, venous invasion, peritoneal cytology, peritoneal metastasis and CXCR2 expression in stromal cells. The expression of CXCR2 in stromal cells was correlated with macroscopic type-4 cancers, histological type, T invasion (T2-T4), lymph node metastasis, lymphatic invasion, infiltration, peritoneal cytology, peritoneal metastasis and CD271 expression in stromal cells. The overall survival of patients with CXCL1 and CXCR2-positive cancer was poorer than that of the patients with negative cancer. Both CXCL1 expression in cancer cells and CXCR2 expression in stromal cells were independent prognostic factors for gastric cancer patients. CONCLUSION: The expressions of CXCL1 in cancer cells and CXCR2 in stromal cells are useful prognostic factors for gastric cancer patients. PMID- 28575020 TI - NGR-peptide-drug conjugates with dual targeting properties. AB - Peptides containing the asparagine-glycine-arginine (NGR) motif are recognized by CD13/aminopeptidase N (APN) receptor isoforms that are selectively overexpressed in tumor neovasculature. Spontaneous decomposition of NGR peptides can result in isoAsp derivatives, which are recognized by RGD-binding integrins that are essential for tumor metastasis. Peptides binding to CD13 and RGD-binding integrins provide tumor-homing, which can be exploited for dual targeted delivery of anticancer drugs. We synthesized small cyclic NGR peptide-daunomycin conjugates using NGR peptides of varying stability (c[KNGRE]-NH2, Ac-c[CNGRC]-NH2 and the thioether bond containing c[CH2-CO-NGRC]-NH2, c[CH2-CO-KNGRC]-NH2). The cytotoxic effect of the novel cyclic NGR peptide-Dau conjugates were examined in vitro on CD13 positive HT-1080 (human fibrosarcoma) and CD13 negative HT-29 (human colon adenocarcinoma) cell lines. Our results confirm the influence of structure on the antitumor activity and dual acting properties of the conjugates. Attachment of the drug through an enzyme-labile spacer to the C-terminus of cyclic NGR peptide resulted in higher antitumor activity on both CD13 positive and negative cells as compared to the branching versions. PMID- 28575021 TI - Chinook salmon and green sturgeon migrate through San Francisco Estuary despite large distortions in the local magnetic field produced by bridges. AB - Empirical evidence exists that some marine animals perceive and orient to local distortions in the earth's main static geomagnetic field. The magnetic fields produced by undersea electric power cables that carry electricity from hydrokinetic energy sources to shore-based power stations may produce similar local distortions in the earth's main field. Concerns exist that animals migrating along the continental shelves might orient to the magnetic field from the cables, and move either inshore or offshore away from their normal path. We have studied the effect of the Trans Bay Cable (TBC), an 85-km long, high voltage, direct current (DC) transmission line leading underwater from Pittsburg, CA to San Francisco, CA, on fishes migrating through the San Francisco Estuary. These included Chinook salmon smolts (Oncorhynchus tshawytscha) that migrate downstream through the San Francisco Estuary to the Pacific Ocean and adult green sturgeon (Acipenser medirostris), which migrate upstream from the ocean through the estuary to their spawning habitat in the upper Sacramento River and return to the ocean after spawning occurs. Based on a detailed gradiometer survey, we found that the distortions in the earth's main field produced by bridges across the estuary were much greater than those from the Trans Bay Cable. The former anomalies exceeded the latter by an order of magnitude or more. Significant numbers of tagged Chinook salmon smolts migrated past bridges, which produced strong magnetic anomalies, to the Golden Gate Bridge, where they were recorded by dual arrays of acoustic tag-detecting monitors moored in lines across the mouth of the bay. In addition, adult green sturgeon successfully swam upstream and downstream through the estuary on the way to and from their spawning grounds. Hence, the large anomalies produced by the bridges do not appear to present a strong barrier to the natural seasonal movement patterns of salmonid smolts and adult green sturgeon. PMID- 28575022 TI - Investigating the effect of forestry on leaf-litter arthropods (Algonquin Park, Ontario, Canada). AB - Arthropods are the most diverse taxonomic group of terrestrial eukaryotes and are sensitive to physical alterations in their environment such as those caused by forestry. With their enormous diversity and physical omnipresence, arthropods could be powerful indicators of the effects of disturbance following forestry. When arthropods have been used to measure the effects of disturbance, the total diversity of some groups is often found to increase following forestry. However, these findings are frequently derived using a coarse taxonomic grain (family or order) to accommodate for various taxonomic impediments (including cryptic diversity and poorly resourced taxonomists). Our intent with this work was to determine the diversity of arthropods in and around Algonquin Park, and how this diversity was influenced by disturbance (in this case, forestry within the past 25 years). We used DNA barcode-derived diversity estimates (Barcode Index Number (BIN) richness) to avoid taxonomic impediments and as a source of genetic information with which we could conduct phylogenetic estimates of diversity (PD). Diversity patterns elucidated with PD are often, but not always congruent with taxonomic estimates-and departures from these expectations can help clarify disturbance effects that are hidden from richness studies alone. We found that BIN richness and PD were greater in disturbed (forested) areas, however when we controlled for the expected relationship between PD and BIN richness, we found that cut sites contained less PD than expected and that this diversity was more phylogenetically clustered than would be predicted by taxonomic richness. While disturbance may cause an evident increase in diversity, this diversity may not reflect the full evolutionary history of the assemblage within that area and thus a subtle effect of disturbance can be found decades following forestry. PMID- 28575024 TI - Efficient method for site-directed mutagenesis in large plasmids without subcloning. AB - Commonly used methods for site-directed DNA mutagenesis require copying the entire target plasmid. These methods allow relatively easy modification of DNA sequences in small plasmids but become less efficient and faithful for large plasmids, necessitating full sequence verification. Introduction of mutations in larger plasmids requires subcloning, a slow and labor-intensive process, especially for multiple mutations. We have developed an efficient DNA mutagenesis technique, UnRestricted Mutagenesis and Cloning (URMAC) that replaces subcloning steps with quick biochemical reactions. URMAC does not suffer from plasmid size constraints and allows simultaneous introduction of multiple mutations. URMAC involves manipulation of only the mutagenesis target site(s), not the entire plasmid being mutagenized, therefore only partial sequence verification is required. Basic URMAC requires two PCR reactions, each followed by a ligation reaction to circularize the product, with an optional third enrichment PCR step followed by a traditional cloning step that requires two restriction sites. Here, we demonstrate URMAC's speed, accuracy, and efficiency through several examples, creating insertions, deletions or substitutions in plasmids ranging from 2.6 kb to 17 kb without subcloning. PMID- 28575023 TI - Orexin receptor agonist Yan 7874 is a weak agonist of orexin/hypocretin receptors and shows orexin receptor-independent cytotoxicity. AB - Two promising lead structures of small molecular orexin receptor agonist have been reported, but without detailed analyses of the pharmacological properties. One of them, 1-(3,4-dichlorophenyl)-2-[2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H benzo[d]imidazol-1-yl]ethan-1-ol (Yan 7874), is commercially available, and we set out to analyze its properties. As test system we utilized human OX1 and OX2 orexin receptor-expressing Chinese hamster ovary (CHO) K1 cells as well as control CHO-K1 and neuro-2a neuroblastoma cells. Gq-coupling was assessed by measurement of intracellular Ca2+ and phospholipase C activity, and the coupling to Gi and Gs by adenylyl cyclase inhibition and stimulation, respectively. At concentrations above 1 MUM, strong Ca2+ and low phospholipase C responses to Yan 7874 were observed in both OX1- and OX2-expressing cells. However, a major fraction of the response was not mediated by orexin receptors, as determined utilizing the non-selective orexin receptor antagonist N-biphenyl-2-yl-1-{[(1 methyl-1H-benzimidazol-2-yl)sulfanyl]acetyl}-L-prolinamide (TCS 1102) as well as control CHO-K1 cells. Yan 7874 did not produce any specific adenylyl cyclase response. Some experiments suggested an effect on cell viability by Yan 7874, and we thus analyzed this. Within a few hours of exposure, Yan 7874 markedly changed cell morphology (shrunken, rich in vacuoles), reduced growth, promoted cell detachment, and induced necrotic cell death. The effect was equal in cells expressing orexin receptors or not. Thus, Yan 7874 is a weak partial agonist of orexin receptors. It also displays strong off-target effects in the same concentration range, culminating in necrotic cell demise. This makes Yan 7874 unsuitable as orexin receptor agonist. PMID- 28575025 TI - Perceptions of satisfaction, usability and desirability of the DEKA Arm before and after a trial of home use. AB - OBJECTIVES: To: 1) describe perceptions of satisfaction with and usability of the DEKA Arm and preferences for the DEKA Arm or personal prosthesis; 2) compare perceptions of satisfaction and usability by DEKA Arm configuration level; and 3) evaluate satisfaction and usability for study completers and non-completers; and for those who did and did not want to receive a DEKA Arm. METHODS: The study had 2 phases: in-laboratory (Part A) and home trial (Part B). 32 participants with amputation, (50% transradial, 38% transhumeral and 13% shoulder) completed Part A and 18 completed Part B 16 (89%) of whom were prosthesis users at baseline. Measures of satisfaction, usability and user preferences were administered. Responses were compared for completers of Part A only and completers of Parts A and B. Preferences for the DEKA Arm over personal prosthesis and proportion of participants who wanted to receive a DEKA Arm were evaluated. Relationships between satisfaction, usability and desire to receive a DEKA Arm were examined. RESULTS: At end of Part A, 22 (69%) of the 32 participants who completed in laboratory training wanted to receive a DEKA Arm and 5 (16%) might want one. At end of Part B, 14 (88%) of 16 prosthesis users who completed the home trial preferred the overall function of the DEKA Arm, 13 (81%) preferred DEKA hand function and 14 (88%) preferred DEKA wrist function to their own prosthesis. In contrast, 14 (88%) preferred the weight and 13 (81%) preferred the look of their own prosthesis. Most aspects of the DEKA Arm were rated "easy" to use. No items were rated as "difficult". Users were satisfied with most aspects of the DEKA Arm, except for the weight, shoulder appearance and harnessing. There were few differences in perceived usability or satisfaction by configuration level. Findings about desire to receive a DEKA Arm pertain only to study completers. Non completers viewed the DEKA Arm less favorably than completers. Satisfaction was strongly related to participants' expressed desire to receive a DEKA Arm in the future. SIGNIFICANCE: To maximize likelihood of adoption of the DEKA Arm, findings suggest that both an in-laboratory and a home use trial may be useful prior to finalizing a recommendation for prescription. PMID- 28575026 TI - Childhood chronic conditions and health-related quality of life: Findings from a large population-based study. AB - The objective of this study was to assess the impact of health-related quality of life (HRQOL) across prevalent chronic conditions, individually and comorbid, in school-aged children in the Netherlands. 5301 children aged 4-11 years from the Dutch Health Interview Survey were included. Parents completed questionnaires regarding child and parental characteristics. HRQOL of children was measured using the Child Health Questionnaire Parent Form 28 (CHQ-PF28). Independent-t tests were used to assess differences in the mean scores of the CHQ-PF28 summary scales and profile scales between children with a prevalent chronic condition (excluding or including children with multiple chronic conditions) and children without a chronic condition. Cohen's effect sizes (d) were calculated to assess the clinical significance of difference. The mean age of children was 7.55 (SD 2.30) years; 50.0% were boys. In children without any chronic condition, the mean score of physical summary scale (PhS) was 58.53 (SD 4.28) and mean score of the psychosocial summary scale (PsS) was 53.86 (SD 5.87). Generally, PhS and/or PsS scores in children with only one condition were lower (p<0.05) than for children without chronic conditions. When children with multiple conditions were included, mean scores of CHQ-PF28 summary and profile scales were generally lower than when they were excluded. The present study shows important information regarding the impact of prevalent chronic conditions on HRQOL in a representative population based sample of school-aged children in the Netherlands. The information could be used for developing a more holistic approach to patient care and a surveillance framework for health promotion. PMID- 28575028 TI - Robust shrinking ellipsoid model predictive control for linear parameter varying system. AB - In this paper, a new off-line model predictive control strategy is presented for a kind of linear parameter varying system with polytopic uncertainty. A nest of shrinking ellipsoids is constructed by solving linear matrix inequality. By splitting the objective function into two parts, the proposed strategy moves most computations off-line. The on-line computation is only calculating the current control to assure the system shrinking into the smaller ellipsoid. With the proposed formulation, the stability of the closed system is proved, followed with two numerical examples to demonstrate the proposed method's effectiveness in the end. PMID- 28575027 TI - Linking epigenetic function to electrostatics: The DNMT2 structural model example. AB - The amino acid sequence of DNMT2 is very similar to the catalytic domains of bacterial and eukaryotic proteins. However, there is great variability in the region of recognition of the target sequence. While bacterial DNMT2 acts as a DNA methyltransferase, previous studies have indicated low DNA methylation activity in eukaryotic DNMT2, with preference by tRNA methylation. Drosophilids are known as DNMT2-only species and the DNA methylation phenomenon is a not elucidated case yet, as well as the ontogenetic and physiologic importance of DNMT2 for this species group. In addition, more recently study showed that methylation in the genome in Drosophila melanogaster is independent in relation to DNMT2. Despite these findings, Drosophilidae family has more than 4,200 species with great ecological diversity and historical evolution, thus we, therefore, aimed to examine the drosophilids DNMT2 in order to verify its conservation at the physicochemical and structural levels in a functional context. We examined the twenty-six DNMT2 models generated by molecular modelling and five crystallographic structures deposited in the Protein Data Bank (PDB) using different approaches. Our results showed that despite sequence and structural similarity between species close related, we found outstanding differences when they are analyzed in the context of surface distribution of electrostatic properties. The differences found in the electrostatic potentials may be linked with different affinities and processivity of DNMT2 for its different substrates (DNA, RNA or tRNA) and even for interactions with other proteins involved in the epigenetic mechanisms. PMID- 28575029 TI - New evidence about the "dark side" of social cohesion in promoting binge drinking among adolescents. AB - Adolescence is characterized by heightened susceptibility to peer influence, which makes adolescents vulnerable to initiating or maintaining risky habits such as heavy drinking. The aim of the study was to investigate the association of social capital with longitudinal changes in the frequency of binge drinking among adolescents at public and private high schools in the city of Diamantina, Brazil. This longitudinal study used two waves of data collected when the adolescents were 12 and 13 years old. At the baseline assessment in 2013 a classroom survey was carried out with a representative sample of 588 students. In 2014, a follow up survey was carried out with the same adolescents when they were aged 13 years. The Alcohol Use Disorder Identification Test-C (AUDIT C) was employed for the evaluation of alcohol intake. Our predictor variables included sociodemographic and economic characteristics (gender, type of school, mother's education, family income) and Social Capital. For evaluation of social capital, we used the Social Capital Questionnaire for Adolescent Students (SCQ-AS). Descriptive and bivariate analyzes were performed (p <0.05). The log-binomial model was used to calculate prevalence ratios (PR) and 95% confidence intervals. The two-tailed p value was set at <0.05. The prevalence of binge drinking in 2013 was 23.1% and in 2014 the prevalence had risen to 30.1%. Gender (PR 1.48; 95% CI 0.87-2.52) and socioeconomic status (type of school and mother's education) were not associated with the increase in the frequency of binge drinking. However, higher social capital was significantly associated with an increase in binge drinking by students. Adolescents who reported that they had an increase in social cohesion in the community/neighborhood subscale were 3.4 times more likely (95%CI 1.96 6.10) to binge drink themselves. Our results provide new evidence about the "dark side" of social cohesion in promoting binge drinking among adolescents. PMID- 28575030 TI - Method to assess the temporal persistence of potential biometric features: Application to oculomotor, gait, face and brain structure databases. AB - We introduce the intraclass correlation coefficient (ICC) to the biometric community as an index of the temporal persistence, or stability, of a single biometric feature. It requires, as input, a feature on an interval or ratio scale, and which is reasonably normally distributed, and it can only be calculated if each subject is tested on 2 or more occasions. For a biometric system, with multiple features available for selection, the ICC can be used to measure the relative stability of each feature. We show, for 14 distinct data sets (1 synthetic, 8 eye-movement-related, 2 gait-related, and 2 face-recognition related, and one brain-structure-related), that selecting the most stable features, based on the ICC, resulted in the best biometric performance generally. Analyses based on using only the most stable features produced superior Rank-1 Identification Rate (Rank-1-IR) performance in 12 of 14 databases (p = 0.0065, one-tailed), when compared to other sets of features, including the set of all features. For Equal Error Rate (EER), using a subset of only high-ICC features also produced superior performance in 12 of 14 databases (p = 0. 0065, one tailed). In general, then, for our databases, prescreening potential biometric features, and choosing only highly reliable features yields better performance than choosing lower ICC features or than choosing all features combined. We also determined that, as the ICC of a group of features increases, the median of the genuine similarity score distribution increases and the spread of this distribution decreases. There was no statistically significant similar relationships for the impostor distributions. We believe that the ICC will find many uses in biometric research. In case of the eye movement-driven biometrics, the use of reliable features, as measured by ICC, allowed to us achieve the authentication performance with EER = 2.01%, which was not possible before. PMID- 28575031 TI - Is the efficacy of antidepressants in panic disorder mediated by adverse events? A mediational analysis. AB - It has been hypothesised that the perception of adverse events in placebo controlled antidepressant clinical trials may induce patients to conclude that they have been randomized to the active arm of the trial, leading to the breaking of blind. This may enhance the expectancies for improvement and the therapeutic response. The main objective of this study is to test the hypothesis that the efficacy of antidepressants in panic disorder is mediated by the perception of adverse events. The present analysis is based on a systematic review of published and unpublished randomised trials comparing antidepressants with placebo for panic disorder. The Baron and Kenny approach was applied to investigate the mediational role of adverse events in the relationship between antidepressants treatment and efficacy. Fourteen placebo-controlled antidepressants trials were included in the analysis. We found that: (a) antidepressants treatment was significantly associated with better treatment response (beta = 0.127, 95% CI 0.04 to 0.21, p = 0.003); (b) antidepressants treatment was not associated with adverse events (beta = 0.094, 95% CI -0.05 to 0.24, p = 0.221); (c) adverse events were negatively associated with treatment response (beta = 0.035, 95% CI 0.06 to -0.05, p = 0.022). Finally, after adjustment for adverse events, the relationship between antidepressants treatment and treatment response remained statistically significant (beta = 0.122, 95% CI 0.01 to 0.23, p = 0.039). These findings do not support the hypothesis that the perception of adverse events in placebo-controlled antidepressant clinical trials may lead to the breaking of blind and to an artificial inflation of the efficacy measures. Based on these results, we argue that the moderate therapeutic effect of antidepressants in individuals with panic disorder is not an artefact, therefore reflecting a genuine effect that doctors can expect to replicate under real-world conditions. PMID- 28575032 TI - Envelope statistics of self-motion signals experienced by human subjects during everyday activities: Implications for vestibular processing. AB - There is accumulating evidence that the brain's neural coding strategies are constrained by natural stimulus statistics. Here we investigated the statistics of the time varying envelope (i.e. a second-order stimulus attribute that is related to variance) of rotational and translational self-motion signals experienced by human subjects during everyday activities. We found that envelopes can reach large values across all six motion dimensions (~450 deg/s for rotations and ~4 G for translations). Unlike results obtained in other sensory modalities, the spectral power of envelope signals decreased slowly for low (< 2 Hz) and more sharply for high (>2 Hz) temporal frequencies and thus was not well-fit by a power law. We next compared the spectral properties of envelope signals resulting from active and passive self-motion, as well as those resulting from signals obtained when the subject is absent (i.e. external stimuli). Our data suggest that different mechanisms underlie deviation from scale invariance in rotational and translational self-motion envelopes. Specifically, active self-motion and filtering by the human body cause deviation from scale invariance primarily for translational and rotational envelope signals, respectively. Finally, we used well-established models in order to predict the responses of peripheral vestibular afferents to natural envelope stimuli. We found that irregular afferents responded more strongly to envelopes than their regular counterparts. Our findings have important consequences for understanding the coding strategies used by the vestibular system to process natural second-order self-motion signals. PMID- 28575033 TI - Preoperative platelet lymphocyte ratio as independent predictors of prognosis in pancreatic cancer: A systematic review and meta-analysis. AB - BACKGROUND: Recently, the preoperative platelet to lymphocyte ratio (PLR) has been found reported to predict oncologic outcomes in multiple malignancies. However, its prognostic value in patients with pancreatic cancer (PC) remains controversial. The aim of this study was to assess the prognostic value of preoperative PLR in PC. METHODS: MEDLINE, EMBASE, and Cochrane databases were searched to identify studies evaluating the prognostic significance of preoperative PLR in PC. Pooled hazard ratios (HRs) for overall survival (OS) were calculated using fixed-effects/random-effects models. RESULTS: A total of eight studies comprising 1,904 patients with PC were included in the meta-analysis. The pooled analysis demonstrated that elevated PLR had an association with decreased OS (HR: 1.22, 95% CI: 1.04-1.43, p = 0.02). Subgroup analysis showed that a high PLR significantly predicted poor OS in Asian studies (HR: 1.25, 95% CI: 1.03 1.52, p = 0.02), patients with metastatic disease (HR: 1.34, 95% CI: 1.01-1.77, p = 0.04) and patients with PLR >150 (HR: 1.73, 95% CI: 1.21-2.49, p = 0.003). CONCLUSIONS: The preoperative PLR may be a significant independent prognostic factor in patients with PC. PMID- 28575034 TI - Ebola virus disease contact tracing activities, lessons learned and best practices during the Duport Road outbreak in Monrovia, Liberia, November 2015. AB - BACKGROUND: Contact tracing is one of the key response activities necessary for halting Ebola Virus Disease (EVD) transmission. Key elements of contact tracing include identification of persons who have been in contact with confirmed EVD cases and careful monitoring for EVD symptoms, but the details of implementation likely influence their effectiveness. In November 2015, several months after a major Ebola outbreak was controlled in Liberia, three members of a family were confirmed positive for EVD in the Duport Road area of Monrovia. The cluster provided an opportunity to implement and evaluate modified approaches to contact tracing. METHODS: The approaches employed for improved contact tracing included classification and risk-based management of identified contacts (including facility based isolation of some high risk contacts, provision of support to persons being monitored, and school-based surveillance for some persons with potential exposure but not listed as contacts), use of phone records to help locate missing contacts, and modifications to data management tools. We recorded details about the implementation of these approaches, report the overall outcomes of the contact tracing efforts and the challenges encountered, and provide recommendations for management of future outbreaks. RESULTS: 165 contacts were identified (with over 150 identified within 48 hours of confirmation of the EVD cases) and all initially missing contacts were located. Contacts were closely monitored and promptly tested if symptomatic; no contacts developed disease. Encountered challenges related to knowledge gaps among contact tracing staff, data management, and coordination of contact tracing activities with efforts to offer Ebola vaccine. CONCLUSIONS: The Duport Road EVD cluster was promptly controlled. Missing contacts were effectively identified, and identified contacts were effectively monitored and rapidly tested. There is a persistent risk of EVD reemergence in Liberia; the experience controlling each cluster can help inform future Ebola control efforts in Liberia and elsewhere. PMID- 28575035 TI - Effects of local and regional climatic fluctuations on dengue outbreaks in southern Taiwan. AB - BACKGROUND: Southern Taiwan has been a hotspot for dengue fever transmission since 1998. During 2014 and 2015, Taiwan experienced unprecedented dengue outbreaks and the causes are poorly understood. This study aims to investigate the influence of regional and local climate conditions on the incidence of dengue fever in Taiwan, as well as to develop a climate-based model for future forecasting. METHODOLOGY/PRINCIPLE FINDINGS: Historical time-series data on dengue outbreaks in southern Taiwan from 1998 to 2015 were investigated. Local climate variables were analyzed using a distributed lag non-linear model (DLNM), and the model of best fit was used to predict dengue incidence between 2013 and 2015. The cross-wavelet coherence approach was used to evaluate the regional El Nino Southern Oscillation (ENSO) and Indian Ocean Dipole (IOD) effects on dengue incidence and local climate variables. The DLNM results highlighted the important non-linear and lag effects of minimum temperature and precipitation. Minimum temperature above 23 degrees C or below 17 degrees C can increase dengue incidence rate with lag effects of 10 to 15 weeks. Moderate to high precipitation can increase dengue incidence rates with a lag of 10 or 20 weeks. The model of best fit successfully predicted dengue transmission between 2013 and 2015. The prediction accuracy ranged from 0.7 to 0.9, depending on the number of weeks ahead of the prediction. ENSO and IOD were associated with nonstationary inter annual patterns of dengue transmission. IOD had a greater impact on the seasonality of local climate conditions. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that dengue transmission can be affected by regional and local climatic fluctuations in southern Taiwan. The climate-based model developed in this study can provide important information for dengue early warning systems in Taiwan. Local climate conditions might be influenced by ENSO and IOD, to result in unusual dengue outbreaks. PMID- 28575036 TI - Vitamin D status is inversely associated with markers of risk for type 2 diabetes: A population based study in Victoria, Australia. AB - A growing body of evidence suggests a protective role of vitamin D on the risk of type 2 diabetes mellitus (T2DM). We investigated this relationship in a population sample from one Australian state. The data of 3,393 Australian adults aged 18-75 years who participated in the 2009-2010 Victorian Health Monitor survey was analyzed. Socio-demographic information, biomedical variables, and dietary intakes were collected and fasting blood samples were analyzed for 25, hydroxycholecalciferol (25OHD), HbA1c, fasting plasma glucose (FPG), and lipid profiles. Logistic regression analyses were used to evaluate the association between tertiles of serum 25OHD and categories of FPG (<5.6 mmol/L vs. 5.6-6.9 mmol/L), and HbA1c (<5.7% vs. 5.7-6.4%). After adjusting for social, dietary, biomedical and metabolic syndrome (MetS) components (waist circumference, HDL cholesterol, triglycerides, and blood pressure), every 10 nmol/L increment in serum 25OHD significantly reduced the adjusted odds ratio (AOR) of a higher FPG [AOR 0.91, (0.86, 0.97); p = 0.002] and a higher HbA1c [AOR 0.94, (0.90, 0.98); p = 0.009]. Analysis by tertiles of 25OHD indicated that after adjustment for socio demographic and dietary variables, those with high 25OHD (65-204 nmol/L) had reduced odds of a higher FPG [AOR 0.60, (0.43, 0.83); p = 0.008] as well as higher HbA1c [AOR 0.67, (0.53, 0.85); p = 0.005] compared to the lowest 25OHD (10 44 nmol/L) tertile. On final adjustment for other components of MetS, those in the highest tertile of 25OHD had significantly reduced odds of higher FPG [AOR 0.61, (0.44, 0.84); p = 0.011] and of higher HbA1c [AOR 0.74, (0.58, 0.93); p = 0.041] vs. low 25OHD tertile. Overall, the data support a direct, protective effect of higher 25OHD on FPG and HbA1c; two criteria for assessment of risk of T2DM. PMID- 28575037 TI - Elucidation of the compatible interaction between banana and Meloidogyne incognita via high-throughput proteome profiling. AB - With a diverse host range, Meloidogyne incognita (root-knot nematode) is listed as one of the most economically important obligate parasites of agriculture. This nematode species establishes permanent feeding sites in plant root systems soon after infestation. A compatible host-nematode interaction triggers a cascade of morphological and physiological process disruptions of the host, leading to pathogenesis. Such disruption is reflected by altered gene expression in affected cells, detectable using molecular approaches. We employed a high-throughput proteomics approach to elucidate the events involved in a compatible banana- M. incognita interaction. This study serves as the first crucial step in developing natural banana resistance for the purpose of biological-based nematode management programme. We successfully profiled 114 Grand naine root proteins involved in the interaction with M. incognita at the 30th- and 60th- day after inoculation (dai). The abundance of proteins involved in fundamental biological processes, cellular component organisation and stress responses were significantly altered in inoculated root samples. In addition, the abundance of proteins in pathways associated with defence and giant cell maintenance in plants such as phenylpropanoid biosynthesis, glycolysis and citrate cycle were also implicated by the infestation. PMID- 28575038 TI - Plasma brain-derived neurotrophic factor concentration is a predictor of chronic kidney disease in patients with cardiovascular risk factors - Hyogo Sleep Cardio Autonomic Atherosclerosis study. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been shown to have protective effects against cardiovascular diseases and death through neural and non-neural pathways via tropomyosin-related kinase B signaling. However, it is not known whether plasma BDNF concentration is a predictor of chronic kidney disease (CKD). DESIGN: This study was conducted as a prospective cohort study as part of the Hyogo Sleep Cardio-Autonomic Atherosclerosis. METHODS: We measured plasma BDNF concentration in 324 patients without CKD, defined as an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73m2, and with cardiovascular risk factors. As potential confounders, sleep condition, nocturnal hypertension, and autonomic function were quantitatively examined. The patients were followed for a median 37 months (range 2-59 months) and occurrence of CKD was noted. RESULTS: Plasma BDNF concentration was significantly and independently associated with CKD development, which occurred in 38 patients (11.7%). Kaplan Meier analysis revealed that patients with reduced plasma BDNF concentration exhibited a significantly (p = 0.029) greater number of CKD events as compared to those with a higher concentration. Moreover, comparisons of key subgroups showed that the risk of CKD in association with low plasma BDNF concentration was more prominent in patients with a greater reduction of nocturnal systolic blood pressure, better movement index, higher standard deviations of the NN(RR) interval or average NN(RR) interval for each 5-minute period, and without past cardiovascular disease events, smoking habit, or albuminuria. CONCLUSIONS: Plasma BDNF concentration is an independent predictor for development of CKD in patients with cardiovascular risk factors. PMID- 28575039 TI - Assessment of pathologic increase in liver stiffness enables earlier diagnosis of CFLD: Results from a prospective longitudinal cohort study. AB - About 30% of patients with Cystic Fibrosis (CF) develop CF-associated liver disease (CFLD). Recent studies have shown that transient elastography (TE), as a method to quantify liver stiffness, allows non-invasive diagnosis of CFLD in adults and children with CF. Within this study we aimed to prospectively identify patients at risk for development of CFLD by longitudinal analysis of liver stiffness and fibrosis scores in a 5-year follow-up. 36 pediatric and 16 adult patients with initial liver stiffness below the cut-off value indicative of CFLD (6.3 kPa) were examined by transient elastography for 4-5 years. TE, APRI-, and FIB-4-scores were assessed and compared by Kruskal-Wallis test and receiver operating characteristic (ROC)-analysis. Frequencies were compared by Chi2-test. Among the 36 patients participating in this study, a subgroup of 9 patients developed liver stiffness >6.3 kPa after 4-5 years with an increase of DeltaTE >0.38 kPa/a (the group with increasing liver stiffness was labelled TEinc). APRI- and FIB-4 scores confirmed the rationale for grouping. The frequency of CFLD assessed by conventional diagnosis was significantly higher in TEinc-group compared to the control group (TEnorm). None of the adult CF patients matched criteria for TEinc-group. For the first time it was shown that the non-invasive longitudinal assessment of TE allows identification of patients with progression of CFLD in a subgroup of juvenile but not in adult CF patients. Comparing TE to conventional fibrosis-scores underlined the strength of the continuous assessment of liver stiffness for the exact diagnosis of progressive CFLD. The newly described cut-off for pathologic increase of liver stiffness, DeltaTEcutoff = 0.38kPa/a, might enable to detect developing CFLD using consequent follow up TE measurements before reaching the level of stiffness indicating established CFLD. Nevertheless, the limited size of the analyzed cohort should encourage a prospective, multi-center, long term follow up study to confirm the suggested cut off for the rise in liver stiffness. PMID- 28575040 TI - Knowledge of and attitudes towards hepatitis B and its transmission from mother to child among pregnant women in Guangdong Province, China. AB - BACKGROUND: Hepatitis B virus (HBV) infection remains a serious public health problem worldwide. Mother-to-child transmission (MTCT) of HBV is the major mode of transmission in HBV-endemic areas, including China, where little is known about pregnant women's knowledge of and attitudes towards HBV infection and MTCT. METHODS: A cross-sectional survey, conducted in pregnant women in Guangdong Province, China, measured HBV knowledge and attitudes using a questionnaire, at one tertiary and two rural hospitals. RESULTS: The total response rate was 94.5% (737/780). Of the 11 knowledge questions, the mean score was 6.73 +/- 3.04 (mean +/- SD). Most pertinent to preventing MTCT, 53.3% of the respondents did not know that HBV can be transmitted through unprotected sexual intercourse and nearly 20% did not know that HBV can be transmitted from mother to infant. The results of the four attitude questions was better with 83% and 85% being willing to be screened for HBV and let their baby receive HBV vaccine and HBIg, respectively. However, only 16.5% of respondents agreed that they would be willing to take drugs that are known not to harm the fetus to prevent MTCT of HBV. In multivariable analysis, higher education level was associated with better knowledge and attitude scores. CONCLUSIONS: Knowledge about HBV among pregnant women was poor and needs to be improved to prevent MTCT of HBV. Health education needs to be directed towards pregnant mothers, particularly less educated mothers, in high HBV endemicity settings. PMID- 28575041 TI - The mutual effect of pre-pregnancy body mass index, waist circumference and gestational weight gain on obesity-related adverse pregnancy outcomes: A birth cohort study. AB - OBJECTIVE: The aim of this study was to examine the mutual effect of pre pregnancy body mass index (BMI), waist circumference (WC) and gestational weight gain (GWG) on obesity-related adverse pregnancy outcomes. METHODS: This birth cohort study was conducted in three Streets in Changsha, China, including a total of 976 mother-child pairs. All data was collected within 15 days after deliveries from a self-administered questionnaire, maternal health manual and perinatal health care information system. Multivariate logistic regression models were conducted to estimate the effects of maternal pre-pregnancy BMI, WC and GWG on obesity-related adverse pregnancy outcomes including gestational diabetes mellitus (GDM), primary cesarean section (P-CS), large for gestational age (LGA) and composite outcome (one or more adverse pregnancy outcomes). RESULTS: After controlling for all confounders, both maternal pre-pregnancy overweight/obesity and central adiposity contributed to increased risks of GDM [ORs 95% CIs = 2.19 (1.02-4.76) and 2.26 (1.11-4.60), respectively], P-CS [ORs 95% CIs = 1.66 (1.05 2.65) and 1.71 (1.11-2.63), respectively], LGA [ORs 95% CIs = 1.93 (1.07-3.50) and 2.14 (1.21-3.75), respectively] and composite outcome [ORs 95% CIs = 1.82 (1.15-2.87) and 1.98 (1.30-3.01), respectively] compared with mothers with normal pre-pregnancy weight and normal WC. Excessive GWG was found to be associated with an increased risk of LGA [OR 95% CI = 1.74 (1.05-2.89)], but was not significantly related to higher risks of GDM, P-CS and composite outcome [ORs 95% CIs = 0.90 (0.47-1.72), 1.08 (0.77-1.52), and 1.30 (0.94-1.79), respectively]. In terms of the joint effect of maternal pregestational BMI and WC on obesity related composite outcome, mothers with both pre-pregnancy overweight and central adiposity had the highest risk of composite outcome [OR 95% CI = 3.96 (2.40 6.54)], compared with mothers without pre-pregnancy overweight or central adiposity. CONCLUSIONS: The results of this study suggest that maternal pre pregnancy overweight/obesity and central adiposity may contribute to multiple obesity-related adverse pregnancy outcomes, excessive weight gain during pregnancy is associated with an increased risk of LGA. Healthcare providers should carry out health education, and guide women to keep an ideal BMI and WC prior to pregnancy and help them gain optimal weight during pregnancy based on their pre-pregnancy BMI and WC. PMID- 28575042 TI - TNF-alpha -308 A allele is associated with an increased risk of distant metastasis in rectal cancer patients from Southwestern China. AB - Tumor necrosis factor-alpha (TNF-alpha), an important factor in systematic inflammation, is reportedly involved in several cancer types. The TNF-alpha -308 G>A (rs1800629) polymorphism in the promoter region influences TNF-alpha production. The association between TNF-alpha -308 G>A polymorphism and colorectal cancer (CRC) is not fully understood, especially the connections between TNF-alpha -308 G>A polymorphism and clinical features of CRC. In this study, TNF-alpha -308 G>A polymorphism was genotyped in 1140 individuals with or without CRC from Southwestern China. In case-control studies, we found no association between TNF-alpha -308 G>A polymorphism and CRC risk. Analysis of the correlations between TNF-alpha -308 G>A polymorphism and clinical features of CRC revealed that TNF-alpha -308 A allele was associated with higher body mass index (BMI) larger tumor size, and distant tumor metastasis in all CRC patients. Notably, rectal cancer (a subtype of CRC) patients with TNF-alpha -308 A allele had a very high risk of distant tumor metastasis [odds ratio (OR) = 4.481; 95% confidence interval (CI): 2.072-9.693; P = 0.00025]. The association between TNF alpha -308 A allele and distant tumor metastasis remained even significant after adjusting all clinical characteristics (OR = 7.099; 95% CI: 2.482-20.301; P = 0.000256) in rectal cancer patients. Our results suggested that TNF-alpha -308 A allele was significantly associated with distant tumor metastasis in rectal cancer patients. PMID- 28575043 TI - Radiological evolution of porcine neurocysticercosis after combined antiparasitic treatment with praziquantel and albendazole. AB - BACKGROUND: The onset of anthelmintic treatment of neurocysticercosis (NCC) provokes an acute immune response of the host, which in human cases is associated with exacerbation of neurological symptoms. This inflammation can occur at the first days of therapy. So, changes in the brain cysts appearance may be detected by medical imaging. We evaluated radiological changes in the appearance of brain cysts (enhancement and size) on days two and five after the onset of antiparasitic treatment using naturally infected pigs as a model for human NCC. METHODS AND RESULTS: Contrast T1-weighted magnetic resonance imaging with gadolinium was performed before and after antiparasitic treatment. Eight NCC infected pigs were treated with praziquantel plus albendazole and euthanized two (n = 4) and five (n = 4) days after treatment; another group of four infected pigs served as untreated controls. For each lesion, gadolinium enhancement intensity (GEI) and cyst volume were measured at baseline and after antiparasitic treatment. Volume and GEI quantification ratios (post/pre-treatment measures) were used to appraise the effect of treatment. Cysts from untreated pigs showed little variations between their basal and post treatment measures. At days 2 and 5 there were significant increases in GEI ratio compared with the untreated group (1.32 and 1.47 vs 1.01, p = 0.021 and p = 0.021). Cyst volume ratios were significantly lower at days 2 and 5 compared with the untreated group (0.60 and 0.22 vs 0.95, p = 0.04 and p = 0.02). Cysts with lower cyst volume ratios showed more marked post-treatment inflammation, loss of vesicular fluid and cyst wall wrinkling. CONCLUSION/SIGNIFICANCE: A significant and drastic reduction of cyst size and increased pericystic enhancement occur in the initial days after antiparasitic treatment as an effect of acute perilesional immune response. These significant changes showed that early anthelmintic efficacy (day two) can be detected using magnetic resonance imaging. PMID- 28575044 TI - Evaluation of macrocyclic hydroxyisophthalamide ligands as chelators for zirconium-89. AB - The development of bifunctional chelators (BFCs) for zirconium-89 immuno-PET applications is an area of active research. Herein we report the synthesis and evaluation of octadentate hydroxyisophthalamide ligands (1 and 2) as zirconium-89 chelators. While both radiometal complexes could be prepared quantitatively and with excellent specific activity, preparation of 89Zr-1 required elevated temperature and an increased reaction time. 89Zr-1 was more stable than 89Zr-2 when challenged in vitro by excess DTPA or serum proteins and in vivo during acute biodistribution studies. Differences in radiometal complex stability arise from structural changes between the two ligand systems, and suggest further ligand optimization is necessary to enhance 89Zr chelation. PMID- 28575045 TI - The effect of alcohol on the differential expression of cluster of differentiation 14 gene, associated pathways, and genetic network. AB - Alcohol consumption affects human health in part by compromising the immune system. In this study, we examined the expression of the Cd14 (cluster of differentiation 14) gene, which is involved in the immune system through a proinflammatory cascade. Expression was evaluated in BXD mice treated with saline or acute 1.8 g/kg i.p. ethanol (12.5% v/v). Hippocampal gene expression data were generated to examine differential expression and to perform systems genetics analyses. The Cd14 gene expression showed significant changes among the BXD strains after ethanol treatment, and eQTL mapping revealed that Cd14 is a cis regulated gene. We also identified eighteen ethanol-related phenotypes correlated with Cd14 expression related to either ethanol responses or ethanol consumption. Pathway analysis was performed to identify possible biological pathways involved in the response to ethanol and Cd14. We also constructed a genetic network for Cd14 using the top 20 correlated genes and present several genes possibly involved in Cd14 and ethanol responses based on differential gene expression. In conclusion, we found Cd14, along with several other genes and pathways, to be involved in ethanol responses in the hippocampus, such as increased susceptibility to lipopolysaccharides and neuroinflammation. PMID- 28575046 TI - Habitat modification and seasonality influence avian haemosporidian parasite distributions in southeastern Brazil. AB - Habitat modification may change vertebrate and vector-borne disease distributions. However, natural forest regeneration through secondary succession may mitigate these effects. Here we tested the hypothesis that secondary succession influences the distribution of birds and their haemosporidian parasites (genera Plasmodium and Haemoproteus) in a seasonally dry tropical forest, a globally threatened ecosystem, in Brazil. Moreover, we assessed seasonal fluctuations in parasite prevalence and distribution. We sampled birds in four different successional stages at the peak and end of the rainy season, as well as in the middle and at the end of the dry season. A non-metric multidimensional scaling analysis revealed that bird communities in the pasture (i.e., highly modified) areas were different from those in the early, intermediate, and late successional areas (secondary forests). Among 461 individual birds, haemosporidian prevalence was higher in pasture areas than in the more advanced successional stages, but parasite communities were homogeneous across these areas. Parasite prevalence was higher in pasture-specialists birds (resilient species) than in forest-specialists species, suggesting that pasture specialists may increase infection risk for co-occurring hosts. We found an increase in prevalence between the middle and end of the dry season, a period associated with the beginning of the breeding season (early spring) in southeastern Brazil. We also found effects of seasonality in the relative prevalence of specific parasite lineages. Our results show that natural forest recovery through secondary succession in SDTFs is associated with compositional differences in avian communities, and that advanced successional stages are associated with lower prevalence of avian haemosporidian parasites. PMID- 28575047 TI - Utility of normalized genome quantification of Helicobacter pylori in gastric mucosa using an in-house real-time polymerase chain reaction. AB - Traditional diagnostic assays for Helicobacter pylori detection have their limitations. Molecular methods can improve both diagnosis and understanding of gastric diseases. Here we describe an in-house quantitative real-time polymerase chain reaction (q-rt-PCR) for the detection of H. pylori in gastric biopsies which has been developed and has a detection limit of 10 copies, the specificity of which was tested against other gastric colonizer bacteria. In this study, 199 gastric biopsies from adults with different clinical gastric symptoms were examined. Biopsies were obtained during endoscopy and the following tests performed: rapid urease testing (RUT), culture and q-rt-PCR. H. pylori bacterial load expressed as bacterial load per 105 cells was calculated using a standard curve. H. pylori was isolated in 41% of patients, RUT was positive in 32% and bacterial genome was detected in 45% (p = 0.010). Concordance between traditional invasive microbiological methods used together and q-rt-PCR was almost 100%. Bacterial load in patients with positive RUT was significantly higher than those where it was negative (p<0.0001). There were also significant differences between bacterial load in patients with more than one positive assay versus those where only one method was positive (p = 0.006). The in-house q-PCR developed here is quick and inexpensive, and allows accurate diagnosis of H. pylori infection. It also permits normalized bacterial load quantification, which is important to differentiate between asymptomatic colonisation and infection. PMID- 28575048 TI - Effects of a weight management program delivered by social media on weight and metabolic syndrome risk factors in overweight and obese adults: A randomised controlled trial. AB - INTRODUCTION: The aim of this project was to evaluate the effectiveness of using social media to augment the delivery of, and provide support for, a weight management program delivered to overweight and obese individuals during a twenty four week intervention. METHODS: Participants randomly divided into either one of two intervention groups or a control group. The two intervention groups were instructed to follow identical weight-management program. One group received the program within a Facebook group, along with a support network with the group, and the other intervention group received the same program in a booklet. The control group was given standard care. Participants' weight and other metabolic syndrome risk factors were measured at baseline and at weeks 6, 12, 18 and 24. RESULTS: The Facebook Group reported a 4.8% reduction in initial weight, significant compared to the CG only (p = 0.01), as well as numerically greater improvements in body mass index, waist circumference, fat mass, lean mass, and energy intake compared to the Pamphlet Group and the Control Group. CONCLUSIONS: These results demonstrate the potential of social media to assist overweight and obese individuals with respect to dietary and physical activity modifications for weight management, and justify further research into the inclusion of social media in clinical weight management programs. It is anticipated that social media will provide an invaluable resource for health professionals, as a low maintenance vehicle for communicating with patients, as well as a source of social support and information sharing for individuals undergoing lifestyle modifications. PMID- 28575049 TI - Cognitive and affective trait and state factors influencing the long-term symptom course in remitted depressed patients. AB - BACKGROUND: Major depressive disorder (MDD) is characterized by a high risk for relapses and chronic developments. Clinical characteristics such as residual symptoms have been shown to negatively affect the long-term course of MDD. However, it is unclear so far how trait repetitive negative thinking (RNT) as well as cognitive and affective momentary states, the latter experienced during daily-life, affect the long-term course of MDD. METHOD: We followed up 57 remitted depressed (rMDD) individuals six (T2) and 36 (T3) months after baseline. Clinical outcomes were time to relapse, time spent with significant symptoms as a marker of chronicity, and levels of depressive symptoms at T2 and T3. Predictors assessed at baseline included residual symptoms and trait RNT. Furthermore, momentary daily life affect and momentary rumination, and their variation over the day were assessed at baseline using ambulatory assessment (AA). RESULTS: In multiple models, residual symptoms and instability of daily-life affect at baseline independently predicted a faster time to relapse, while chronicity was significantly predicted by trait RNT. Multilevel models revealed that depressive symptom levels during follow-up were predicted by baseline residual symptom levels and by instability of daily-life rumination. Both instability features were linked to a higher number of anamnestic MDD episodes. CONCLUSIONS: Our findings indicate that trait RNT, but also affective and cognitive processes during daily life impact the longer-term course of MDD. Future longitudinal research on the role of respective AA-phenotypes as potential transdiagnostic course-modifiers is warranted. PMID- 28575050 TI - Megalin dependent urinary cystatin C excretion in ischemic kidney injury in rats. AB - BACKGROUND: Cystatin C, a marker of kidney injury, is freely filtered in the glomeruli and reabsorbed by the proximal tubules. Megalin and cubilin are endocytic receptors essential for reabsorption of most filtered proteins. This study examines the role of these receptors for the uptake and excretion of cystatin C and explores the effect of renal ischemia/reperfusion injury on renal cystatin C uptake and excretion in a rat model. METHODS: Binding of cystatin C to megalin and cubilin was analyzed by surface plasmon resonance analysis. ELISA and/or immunoblotting and immunohistochemistry were used to study the urinary excretion and tubular uptake of endogenous cystatin C in mice. Furthermore, renal uptake and urinary excretion of cystatin C was investigated in rats exposed to ischemia/reperfusion injury. RESULTS: A high affinity binding of cystatin C to megalin and cubilin was identified. Megalin deficient mice revealed an increased urinary excretion of cystatin C associated with defective uptake by endocytosis. In rats exposed to ischemia/reperfusion injury urinary cystatin C excretion was increased and associated with a focal decrease in proximal tubule endocytosis with no apparent change in megalin expression. CONCLUSIONS: Megalin is essential for the normal tubular recovery of endogenous cystatin C. The increase in urinary cystatin C excretion after ischemia/reperfusion injury is associated with decreased tubular uptake but not with reduced megalin expression. PMID- 28575051 TI - Stability of infants' preference for prosocial others: Implications for research based on single-choice paradigms. AB - Some research suggests infants display a tendency to judge others' prosocial behavior, and in particular, that infants show a strong preference for prosocial others. For example, data from one frequently cited and well-publicized study showed that, after watching a puppet show with three puppets, 74% of infants chose the puppet that "helped" rather than the puppet that "hindered" a third puppet from attaining its goal. The purpose of the current investigation was to replicate these methods and extend them by including a within-subject measure of infant puppet choice across repeated trials to assess the stability of infants' choice. In the current study, 20 infants viewed a puppet show and chose between two puppets (i.e., helper or hinderer) immediately following the puppet show. Although results were similar to previously published work on the first-choice trial (65% of infants chose the helper puppet on the first trial), infants did not consistently choose the helper across trials; several infants demonstrated a side preference, with 9 infants almost exclusively choosing puppets presented on the right or left side. The current investigation addressed limitations of previous research by including a between-subjects (replication) as well as a within-subjects (extension) repeated measure of choice that allowed for the examination of the stability of the choice measure. Our results, particularly in light of other failed replications, raise questions regarding the robustness of infants' preference for prosocial others and the reliability and validity of the single-choice paradigm. PMID- 28575053 TI - Mxi1-0 regulates the growth of human umbilical vein endothelial cells through extracellular signal-regulated kinase 1/2 (ERK1/2) and interleukin-8 (IL-8) dependent pathways. AB - Mxi1 plays an important role in the regulation of cell proliferation. Mxi1-0, a Mxi1 isoform, has a different N-terminal amino acid sequence, intracellular location and expression profile from Mxi1. However, the precise role of Mxi1-0 in cell proliferation and the molecular mechanism underlying its function remain poorly understood. Here, we showed that Mxi1-0 suppression decreased the proliferation of human umbilical vein endothelial cells (HUVECs) along with cell accumulation in the G2/M phase. Mxi1-0 suppression also significantly decreased the expression and secretion of interleukin (IL-8). Neutralizing IL-8 in conditioned medium (CM) from Mxi1-0-overexpressed HUVECs significantly eliminated CM-induced proliferation of HUVECs. In addition, Mxi1-0 suppression significantly decreased the activity of MAP kinase ERK1/2. Treatment of HUVECs with U0126, an ERK1/2 signaling inhibitor, attenuated autocrine production of IL-8 induced by Mxi1-0 overexpression. On the other hand, Mxi1-0 overexpression-induced IL-8 increased the level of phosphorylated ERK1/2 in HUVECs, and such increasing was diminished in cells incubated with CM, which neutralized with anti-IL-8 antibody. Taken together, our results suggest that Mxi1-0 regulates the growth of HUVECs via the IL-8 and ERK1/2 pathways, which apparently reciprocally activate each other. PMID- 28575052 TI - Myogenic differentiation of VCP disease-induced pluripotent stem cells: A novel platform for drug discovery. AB - Valosin Containing Protein (VCP) disease is an autosomal dominant multisystem proteinopathy caused by mutations in the VCP gene, and is primarily associated with progressive muscle weakness, including atrophy of the pelvic and shoulder girdle muscles. Currently, no treatments are available and cardiac and respiratory failures can lead to mortality at an early age. VCP is an AAA ATPase multifunction complex protein and mutations in the VCP gene resulting in disrupted autophagic clearance. Due to the rarity of the disease, the myopathic nature of the disorder, ethical and practical considerations, VCP disease muscle biopsies are difficult to obtain. Thus, disease-specific human induced pluripotent stem cells (hiPSCs) now provide a valuable resource for the research owing to their renewable and pluripotent nature. In the present study, we report the differentiation and characterization of a VCP disease-specific hiPSCs into precursors expressing myogenic markers including desmin, myogenic factor 5 (MYF5), myosin and heavy chain 2 (MYH2). VCP disease phenotype is characterized by high expression of TAR DNA Binding Protein-43 (TDP-43), ubiquitin (Ub), Light Chain 3-I/II protein (LC3-I/II), and p62/SQSTM1 (p62) protein indicating disruption of the autophagy cascade. Treatment of hiPSC precursors with autophagy stimulators Rapamycin, Perifosine, or AT101 showed reduction in VCP pathology markers TDP-43, LC3-I/II and p62/SQSTM1. Conversely, autophagy inhibitors chloroquine had no beneficial effect, and Spautin-1 or MHY1485 had modest effects. Our results illustrate that hiPSC technology provide a useful platform for a rapid drug discovery and hence constitutes a bridge between clinical and bench research in VCP and related diseases. PMID- 28575055 TI - Correction: Dual-targeting of Arabidopsis DMP1 isoforms to the tonoplast and the plasma membrane. AB - [This corrects the article DOI: 10.1371/journal.pone.0174062.]. PMID- 28575054 TI - Hemorrhagic versus ischemic stroke: Who can best benefit from blended conventional physiotherapy with robotic-assisted gait therapy? AB - BACKGROUND: Contrary to common belief of clinicians that hemorrhagic stroke survivors have better functional prognoses than ischemic, recent studies show that ischemic survivors could experience similar or even better functional improvements. However, the influence of stroke subtype on gait and posture outcomes following an intervention blending conventional physiotherapy with robotic-assisted gait therapy is missing. OBJECTIVE: This study compared gait and posture outcome measures between ambulatory hemorrhagic patients and ischemic patients, who received a similar 4 weeks' intervention blending a conventional bottom-up physiotherapy approach and an exoskeleton top-down robotic-assisted gait training (RAGT) approach with Lokomat. METHODS: Forty adult hemiparetic stroke inpatient subjects were recruited: 20 hemorrhagic and 20 ischemic, matched by age, gender, side of hemisphere lesion, stroke severity, and locomotor impairments. Functional Ambulation Category, Postural Assessment Scale for Stroke, Tinetti Performance Oriented Mobility Assessment, 6 Minutes Walk Test, Timed Up and Go and 10-Meter Walk Test were performed before and after a 4-week long intervention. Functional gains were calculated for all tests. RESULTS: Hemorrhagic and ischemic subjects showed significant improvements in Functional Ambulation Category (P<0.001 and P = 0.008, respectively), Postural Assessment Scale for Stroke (P<0.001 and P = 0.003), 6 Minutes Walk Test (P = 0.003 and P = 0.015) and 10-Meter Walk Test (P = 0.001 and P = 0.024). Ischemic patients also showed significant improvements in Timed Up and Go. Significantly greater mean Functional Ambulation Category and Tinetti Performance Oriented Mobility Assessment gains were observed for hemorrhagic compared to ischemic, with large (dz = 0.81) and medium (dz = 0.66) effect sizes, respectively. CONCLUSION: Overall, both groups exhibited quasi similar functional improvements and benefits from the same type, length and frequency of blended conventional physiotherapy and RAGT protocol. The use of intensive treatment plans blending top-down physiotherapy and bottom-up robotic approaches is promising for post-stroke rehabilitation. PMID- 28575056 TI - Inter-center comparison of EasyTube and endotracheal tube during general anesthesia in minor elective surgery. AB - BACKGROUND: The EasyTube(r) (EzT) is a supraglottic airway device (SAD) enabling ventilation irrespective of its placement into the esophagus or trachea. Data obtained on SADs from multicenter studies, performed in highly specialized centers cannot always be transferred to other sites. However, data on comparability of different sites are scarce. This study focused on inter-site variability of ventilatory and safety parameters during general anesthesia with the EzT. METHODS: 400 patients with ASA physical status I-II undergoing general anesthesia for elective surgery in four medical centers (EzT group (n = 200), ETT group (n = 200)). Mallampati classification, success of insertion, insertion time, duration of ventilation, number of insertion attempts, ease of insertion, tidal volumes, leakage, hemodynamic parameters, oxygenation, and complications rates with the EasyTube (EzT) or endotracheal tube (ETT) in comparison within the sites and in between the sites were recorded. RESULTS: Intra-site and inter-site comparison of insertion success as primary outcome did not differ significantly. The inter-site comparison of expiratory minute volumes showed that the volumes achieved over the course of anesthesia did not differ significantly, however, mean leakage at one site was significantly higher with the EzT (0.63 l/min, p = 0.02). No significant inter-site differences in heart rate, blood pressure, or oxygenation were observed. Sore throat and blood on the cuff after removal of the device were the most frequent complications with significantly more complications at one site with the EzT (p = 0.01) where insertion was also reported significantly more difficult (p = 0.02). CONCLUSION: Performance of the EzT but not the ETT varied between sites with regard to insertion difficulty, leakage, and complications but not insertion success, ventilation, hemodynamics, and oxygenation parameters in patients with ASA physical status 1-2 during general anesthesia undergoing minor elective surgery. PMID- 28575057 TI - Proteomic variation and diversity in clinical Streptococcus pneumoniae isolates from invasive and non-invasive sites. AB - Streptococcus pneumoniae is responsible for a variety of invasive and non invasive human infections. There are over 90 serotypes of S. pneumoniae differing in their ability to adapt to the different niches within the host. Two dimensional gel electrophoresis was used to discriminate clinical S. pneumoniae isolates recovered from either blood cultures (invasive site isolates) or other sites, including sputum, tracheal aspirate, ear, eye and skin swabs (non-invasive site isolates). Global protein expression profiles for five invasive site and six non-invasive site isolates representing five different serotypes (serotypes 4, 6, 9, 14 and 23) were obtained for each isolate and combined into a single data set using Progenesis SameSpotsTM software. One-hundred and eighty six protein spots (39% of the protein spots in the dataset) differed significantly (ANOVA, p<0.05) in abundance between the invasive site (101 upregulated protein spots) and non invasive site (85 upregulated protein spots) isolates. Correlations between the bacterial proteomes and their sites of isolation were determined by Principal Component Analysis (PCA) using the significantly different protein spots. Out of the 186 variable protein spots, 105 exhibited a serotype-associated pattern of variability. The expression of the remaining 81 protein spots was concluded to be uniquely linked to the site of bacterial isolation. Mass spectrometry was used to identify selected protein spots that showed either constant or differential abundance levels. The identified proteins had a diverse range of functions including, capsule biogenesis, DNA repair, protein deglycation, translation, stress response and virulence as well as amino acid, carbohydrate, lipid and nucleotide metabolism. These findings provide insight on the proteins that contribute towards the adaptation of the bacteria to different sites within the host. PMID- 28575059 TI - Distribution and diversity of aquatic macroinvertebrate assemblages in a semi arid region earmarked for shale gas exploration (Eastern Cape Karoo, South Africa). AB - This study aims to investigate macroinvertebrate assemblage structure and composition across the three major waterbody types (temporary rivers, depression wetlands and semi-permanent dams) of the Eastern Cape Karoo, and to identify important environmental and spatial correlates of macroinvertebrate assemblage composition in the region. A total of 33 waterbodies (9 dams, 13 depression wetlands and 11 rivers) were sampled. Altogether, 91 taxa were recorded in November 2014 and 82 in April 2015. Twenty-seven taxa were common to all three waterbody types (across both sampling occasions), with 17 of these observed in November and 19 in April. The ANOSIM tests revealed significant differences in assemblage composition between the depression wetlands and rivers for both sampling occasions, but dams did not differ from the other waterbody types. SIMPER analyses indicated that the notonectid Anisops varia and the corixid Micronecta scutellaris were abundant across all three waterbody types during both sampling occasions. The mayfly Cloeon africanum and the damselfly Pseudagrion sp. were abundant in river habitats during both sampling occasions, while the gastropod mollusc Bulinus tropicus and the copepod Lovenula falcifera best characterised depression wetlands on both occasions. Non-metric multidimensional scaling ordination highlighted a clear separation of assemblages between November and April, while distance-based Redundancy Analysis revealed that conductivity, altitude, turbidity and pH were the most important variables explaining the variation in macroinvertebrate assemblage patterns. These results provide baseline information which is important for future biological monitoring of impacts associated with hydraulic fracturing activities and climatic changes in the region. PMID- 28575058 TI - Timing of rehabilitation on length of stay and cost in patients with hip or knee joint arthroplasty: A systematic review with meta-analysis. AB - OBJECTIVE: To investigate the role of early initiation of rehabilitation on length of stay (LOS) and cost following total hip arthroplasty, total knee arthroplasty, or unicompartmental knee arthroplasty. DATA SOURCES: Electronic databases PubMed, CINAHL, Pedro, Embase, AMED, and the Cochrane Library were searched in July 2016. Five additional trials were identified through reference list scanning. STUDY SELECTION: Eligible studies were published in English language peer-reviewed journals; included participants that had undergone total hip arthroplasty, total knee arthroplasty, or unicompartmental knee arthroplasty reported clearly defined timing of rehabilitation onset for at least two groups; and reported at least one measure of LOS or cost. Inclusion criteria were applied by 2 independent authors, with disagreements being determined by a third author. Searching identified 1,029 potential articles, of which 17 studies with 26,614 participants met the inclusion criteria. DATA EXTRACTION: Data was extracted independently by 2 authors, with disagreements being determined by a third author. Methodological quality of each study was evaluated independently by 2 authors using the Downs and Black checklist. Pooled analyses were analyzed using a random-effects model with inverse variance methods to calculate standardized mean differences (SMD) and 95% confidence intervals for LOS. DATA SYNTHESIS: When compared with standard care, early initiation of physical therapy demonstrated a decrease in length of stay for the 4 randomized clinical trials (SMD = -1.90; 95% CI -2.76 to -1.05; I2 = 93%) and for the quasi-experimental and 5 prospective studies (SMD = -1.47; 95% CI -1.85 to -1.10; I2 = 88%). CONCLUSION: Early initiation of rehabilitation following total hip arthroplasty, total knee arthroplasty, or unicompartmental knee arthroplasty is associated with a shorter LOS, a lower overall cost, with no evidence of an increased number of adverse reactions. Additional high quality studies with standardized methodology are needed to further examine the impact of early initiation of physical therapy among patients with joint replacement procedures. PMID- 28575060 TI - Increased miltefosine tolerance in clinical isolates of Leishmania donovani is associated with reduced drug accumulation, increased infectivity and resistance to oxidative stress. AB - BACKGROUND: Miltefosine (MIL) is an oral antileishmanial drug used for treatment of visceral leishmaniasis (VL) in the Indian subcontinent. Recent reports indicate a significant decline in its efficacy with a high rate of relapse in VL as well as post kala-azar dermal leishmaniasis (PKDL). We investigated the parasitic factors apparently involved in miltefosine unresponsiveness in clinical isolates of Leishmania donovani. METHODOLOGY: L. donovani isolated from patients of VL and PKDL at pretreatment stage (LdPreTx, n = 9), patients that relapsed after MIL treatment (LdRelapse, n = 7) and parasites made experimentally resistant to MIL (LdM30) were included in this study. MIL uptake was estimated using liquid chromatography coupled mass spectrometry. Reactive oxygen species and intracellular thiol content were measured fluorometrically. Q-PCR was used to assess the differential expression of genes associated with MIL resistance. RESULTS: LdRelapse parasites exhibited higher IC50 both at promastigote level (7.92 +/- 1.30 MUM) and at intracellular amastigote level (11.35 +/- 6.48 MUM) when compared with LdPreTx parasites (3.27 +/- 1.52 MUM) and (3.85 +/- 3.11 MUM), respectively. The percent infectivity (72 hrs post infection) of LdRelapse parasites was significantly higher (80.71 +/- 5.67%, P<0.001) in comparison to LdPreTx (60.44 +/- 2.80%). MIL accumulation was significantly lower in LdRelapse parasites (1.7 fold, P<0.001) and in LdM30 parasites (2.4 fold, P<0.001) when compared with LdPreTx parasites. MIL induced ROS levels were significantly lower (p<0.05) in macrophages infected with LdRelapse while intracellular thiol content were significantly higher in LdRelapse compared to LdPreTx, indicating a better tolerance for oxidative stress in LdRelapse isolates. Genes associated with oxidative stress, metabolic processes and transporters showed modulated expression in LdRelapse and LdM30 parasites in comparison with LdPreTx parasites. CONCLUSION: The present study highlights the parasitic factors and pathways responsible for miltefosine unresponsiveness in VL and PKDL. PMID- 28575062 TI - The rs16906252:C>T SNP is not associated with increased overall survival or temozolomide response in a Han-Chinese glioma cohort. AB - The methylation status of O-6-methylguanine-DNA methyltransferase (MGMT) is associated with the prognosis in gliomas and in other cancers. Recent studies showed that rs16906252, an SNP in the MGMT promoter, is associated with promoter methylation and is a predictor of the overall survival time (OST) and the response to temozolomide (TMZ) treatment. However, these findings haven't been systematically investigated in the Han-Chinese population. We analyzed the relevance between rs16906252 polymorphisms, the MGMT methylation status, and the OST in 72 Han-Chinese gliomas patients. The MGMT promoter methylation was measured by bisulfite conversion followed by pyro-sequencing, while rs16906252 was measured by restriction endonuclease digestion. Contrary to the previous findings, we found no association between rs16906252 genotypes and promoter methylation on MGMT. The lower-grade glioma (LGGs) patients carrying the C allele with rs16906252 showed a surprisingly better OST (P = 0.04). Furthermore, the LGG patients carrying hypo-methylated MGMT promoter and rs16906252 T allele showed significantly poorer prognosis. The prognostic benefit of MGMT promoter methylation and genotypes on gliomas patients is marginal. A new molecular stratified patient grouping of LGGs is potentially associated with poorer OST. Active MGMT might have a protective role in LGG tumors, enabling evolution to severe malignancy. PMID- 28575061 TI - Dissecting structures and functions of SecA-only protein-conducting channels: ATPase, pore structure, ion channel activity, protein translocation, and interaction with SecYEG/SecDF*YajC. AB - SecA is an essential protein in the major bacterial Sec-dependent translocation pathways. E. coli SecA has 901 aminoacyl residues which form multi-functional domains that interact with various ligands to impart function. In this study, we constructed and purified tethered C-terminal deletion fragments of SecA to determine the requirements for N-terminal domains interacting with lipids to provide ATPase activity, pore structure, ion channel activity, protein translocation and interactions with SecYEG-SecDF*YajC. We found that the N terminal fragment SecAN493 (SecA1-493) has low, intrinsic ATPase activity. Larger fragments have greater activity, becoming highest around N619-N632. Lipids greatly stimulated the ATPase activities of the fragments N608-N798, reaching maximal activities around N619. Three helices in amino-acyl residues SecA619-831, which includes the "Helical Scaffold" Domain (SecA619-668) are critical for pore formation, ion channel activity, and for function with SecYEG-SecDF*YajC. In the presence of liposomes, N-terminal domain fragments of SecA form pore-ring structures at fragment-size N640, ion channel activity around N798, and protein translocation capability around N831. SecA domain fragments ranging in size between N643-N669 are critical for functional interactions with SecYEG SecDF*YajC. In the presence of liposomes, inactive C-terminal fragments complement smaller non-functional N-terminal fragments to form SecA-only pore structures with ion channel activity and protein translocation ability. Thus, SecA domain fragment interactions with liposomes defined critical structures and functional aspects of SecA-only channels. These data provide the mechanistic basis for SecA to form primitive, low-efficiency, SecA-only protein-conducting channels, as well as the minimal parameters for SecA to interact functionally with SecYEG-SecDF*YajC to form high-efficiency channels. PMID- 28575063 TI - The composition of T-cell subsets are altered in the burn wound early after injury. AB - BACKGROUND: Burn-induced inflammation leads to impaired immune responses resulting in increased morbidity and mortality. T-cells are central in the immune response and circulating CD4 and CD8 T-cells have been used to evaluate immune status; however, the role of these T-cell subsets in the burn wound is unknown. METHODS: Male C57BL/6 mice were subjected to a major 3rd degree scald burn or sham treatment. Twenty-four hours later, full thickness skin samples from sham mice and the burn wounds were collected and single cells were isolated and analyzed for alphabeta TCR, gammadelta TCR, CD3, CD4, CD8 and CD69 expressions by flow cytometry. RESULTS: The burn wound contained significantly greater numbers of T-cells than skin from sham mice, due to a profound infiltration of alphabeta T-cells. These infiltrating alphabeta T-cells were primarily suppressor T-cells with a CD8+ or CD8-CD4- phenotype. The 15-fold increase in CD8+ alphabeta T-cells caused a decrease in the CD4:CD8 ratio from 0.7 in sham skin to 0.3 in the burn wound. In contrast, the majority of the gammadelta T-cells in sham skin were CD4 CD8-, which decreased 9-fold in the burn wound. CD69 expression was suppressed on burn wound alphabeta T-cells, but increased on gammadelta T-cells in the burn wound. CONCLUSIONS: The infiltrating burn wound alphabeta T-cells likely act to quell inflammation. In contrast wound gammadelta T-cells were activated with elevated CD4 and CD69 expression. Thus, these two distinct T-cell subsets likely differentially regulate the burn wound inflammatory response. PMID- 28575064 TI - Antimicrobial resistance of Klebsiella pneumoniae stool isolates circulating in Kenya. AB - We sought to determine the genetic and phenotypic antimicrobial resistance (AMR) profiles of commensal Klebsiella spp. circulating in Kenya by testing human stool isolates of 87 K. pneumoniae and three K. oxytoca collected at eight locations. Over one-third of the isolates were resistant to >=3 categories of antimicrobials and were considered multidrug-resistant (MDR). We then compared the resistance phenotype to the presence/absence of 238 AMR genes determined by a broad-spectrum microarray and PCR. Forty-six genes/gene families were identified conferring resistance to beta-lactams (ampC/blaDHA, blaCMY/LAT, blaLEN-1, blaOKP-A/OKP-B1, blaOXA-1-like family, blaOXY-1, blaSHV, blaTEM, blaCTX-M-1 and blaCTX-M-2 families), aminoglycosides (aac(3)-III, aac(6)-Ib, aad(A1/A2), aad(A4), aph(AI), aph3/str(A), aph6/str(B), and rmtB), macrolides (mac(A), mac(B), mph(A)/mph(K)), tetracyclines (tet(A), tet(B), tet(D), tet(G)), ansamycins (arr), phenicols (catA1/cat4, floR, cmlA, cmr), fluoroquinolones (qnrS), quaternary amines (qacEDelta1), streptothricin (sat2), sulfonamides (sul1, sul2, sul3), and diaminopyrimidines (dfrA1, dfrA5, dfrA7, dfrA8, dfrA12, dfrA13/21/22/23 family, dfrA14, dfrA15, dfrA16, dfrA17). This is the first profile of genes conferring resistance to multiple categories of antimicrobial agents in western and central Kenya. The large number and wide variety of resistance genes detected suggest the presence of significant selective pressure. The presence of five or more resistance determinants in almost two-thirds of the isolates points to the need for more effective, targeted public health policies and infection control/prevention measures. PMID- 28575065 TI - Does published research on non-communicable disease (NCD) in Arab countries reflect NCD disease burden? AB - OBJECTIVES: To review trends in non-communicable (NCD) research output in the Arab region, in terms of quantity and quality, study design, setting and focus. We also examined differences by time and place, and assessed gaps between research output and NCD burden. METHODS: A scoping review of a total of 3,776 NCD related reports published between 2000 and 2013 was conducted for seven Arab countries. Countries were selected to represent diverse socio-economic development levels in the region: Regression analyses were used to assess trends in publications over time and by country. Research gaps were assessed by examining the degree of match between proportionate literature coverage of the four main NCDs (CVD, cancer, DM, and COPD) and cause-specific proportional mortality rates (PMR). RESULTS: The annual number of NCD publications rose nearly 5-fold during the study period, with higher income countries having the higher publication rates (per million populations) and the most rapid increases. The increase in the publication rate was particularly prominent for descriptive observational studies, while interventional studies and systematic reviews remained infrequent (slope coefficients = 13.484 and 0.883, respectively). Gap analysis showed a mismatch between cause-specific PMR burden and NCD research output, with a relative surplus of reports on cancer (pooled estimate +38.3%) and a relative deficit of reports on CVDs (pooled estimate -30.3%). CONCLUSION: The widening disparity between higher and lower-income countries and the discordance between research output and disease burden call for the need for ongoing collaboration among Arab academic institutions, funding agencies and researchers to guide country-specific and regional research agendas, support and conduct. PMID- 28575067 TI - Correction: An automated algorithm for the detection of cortical interruptions on high resolution peripheral quantitative computed tomography images of finger joints. AB - [This corrects the article DOI: 10.1371/journal.pone.0175829.]. PMID- 28575066 TI - Combined application of arsenic trioxide and lithium chloride augments viability reduction and apoptosis induction in human rhabdomyosarcoma cell lines. AB - Rhabdomyosarcomas (RMS) are the most prevalent soft tissue sarcomas affecting children and adolescents. Despite intensive treatment consisting of multimodal chemotherapy and surgery RMS patients diagnosed with metastatic disease expect long term survival rates of only 20%. Often multidrug resistance arises upon initial response emphasizing the need for new therapeutic drugs to improve treatment efficiency. Previously, we demonstrated the efficacy of the FDA approved drug arsenic trioxide (ATO) specifically inhibiting viability and clonal growth as well as inducing cell death in human RMS cell lines of different subtypes. In this study, we combined low dose ATO with lithium chloride (LiCl), which is approved as mood stabilizer for the treatment of bipolar disorder, but also inhibits growth and survival of different cancer cell types in pre-clinical research. Indeed, we could show additive effects of LiCl and ATO on viability reduction, decrease of colony formation as well as cell death induction. In the course of this, LiCl induced inhibitory glycogen synthase kinase-3beta (GSK 3beta) serine 9 phosphorylation, whereas glioma associated oncogene family 1 (GLI1) protein expression was particularly reduced by combined ATO and LiCl treatment in RD and RH-30 cell lines, showing high rates of apoptotic cell death. These results imply that combination of ATO with LiCl or another drug targeting GSK-3 is a promising strategy to enforce the treatment efficiency in resistant and recurrent RMS. PMID- 28575068 TI - Perception of force and stiffness in the presence of low-frequency haptic noise. AB - OBJECTIVE: This work lays the foundation for future research on quantitative modeling of human stiffness perception. Our goal was to develop a method by which a human's ability to perceive suprathreshold haptic force stimuli and haptic stiffness stimuli can be affected by adding haptic noise. METHODS: Five human participants performed a same-different task with a one-degree-of-freedom force feedback device. Participants used the right index finger to actively interact with variations of force (~5 and ~8 N) and stiffness (~290 N/m) stimuli that included one of four scaled amounts of haptically rendered noise (None, Low, Medium, High). The haptic noise was zero-mean Gaussian white noise that was low pass filtered with a 2 Hz cut-off frequency; the resulting low-frequency signal was added to the force rendered while the participant interacted with the force and stiffness stimuli. RESULTS: We found that the precision with which participants could identify the magnitude of both the force and stiffness stimuli was affected by the magnitude of the low-frequency haptically rendered noise added to the haptic stimulus, as well as the magnitude of the haptic stimulus itself. The Weber fraction strongly correlated with the standard deviation of the low-frequency haptic noise with a Pearson product-moment correlation coefficient of rho > 0.83. The mean standard deviation of the low-frequency haptic noise in the haptic stimuli ranged from 0.184 N to 1.111 N across the four haptically rendered noise levels, and the corresponding mean Weber fractions spanned between 0.042 and 0.101. CONCLUSIONS: The human ability to perceive both suprathreshold haptic force and stiffness stimuli degrades in the presence of added low frequency haptic noise. Future work can use the reported methods to investigate how force perception and stiffness perception may relate, with possible applications in haptic watermarking and in the assessment of the functionality of peripheral pathways in individuals with haptic impairments. PMID- 28575069 TI - A small molecule screen identifies in vivo modulators of peripheral nerve regeneration in zebrafish. AB - Adult vertebrates have retained the ability to regenerate peripheral nerves after injury, although regeneration is frequently incomplete, often leading to functional impairments. Small molecule screens using whole organisms have high potential to identify biologically relevant targets, yet currently available assays for in vivo peripheral nerve regeneration are either very laborious and/or require complex technology. Here we take advantage of the optical transparency of larval zebrafish to develop a simple and fast pectoral fin removal assay that measures peripheral nerve regeneration in vivo. Twenty-four hours after fin amputation we observe robust and stereotyped nerve regrowth at the fin base. Similar to laser mediated nerve transection, nerve regrowth after fin amputation requires Schwann cells and FGF signaling, confirming that the fin amputation assay identifies pathways relevant for peripheral nerve regeneration. From a library of small molecules with known targets, we identified 21 compounds that impair peripheral nerve regeneration. Several of these compounds target known regulators of nerve regeneration, further validating the fin removal assay. Twelve of the identified compounds affect targets not previously known to control peripheral nerve regeneration. Using a laser-mediated nerve transection assay we tested ten of those compounds and confirmed six of these compounds to impair peripheral nerve regeneration: an EGFR inhibitor, a glucocorticoid, prostaglandin D2, a retinoic acid agonist, an inhibitor of calcium channels and a topoisomerase I inhibitor. Thus, we established a technically simple assay to rapidly identify valuable entry points into pathways critical for vertebrate peripheral nerve regeneration. PMID- 28575071 TI - Correction: Panel of three novel serum markers predicts liver stiffness and fibrosis stages in patients with chronic liver disease. AB - [This corrects the article DOI: 10.1371/journal.pone.0173506.]. PMID- 28575070 TI - A preliminary examination of the diagnostic value of deep learning in hip osteoarthritis. AB - Hip Osteoarthritis (OA) is a common disease among the middle-aged and elderly people. Conventionally, hip OA is diagnosed by manually assessing X-ray images. This study took the hip joint as the object of observation and explored the diagnostic value of deep learning in hip osteoarthritis. A deep convolutional neural network (CNN) was trained and tested on 420 hip X-ray images to automatically diagnose hip OA. This CNN model achieved a balance of high sensitivity of 95.0% and high specificity of 90.7%, as well as an accuracy of 92.8% compared to the chief physicians. The CNN model performance is comparable to an attending physician with 10 years of experience. The results of this study indicate that deep learning has promising potential in the field of intelligent medical image diagnosis practice. PMID- 28575072 TI - Assembly, maturation and three-dimensional helical structure of the teratogenic rubella virus. AB - Viral infections during pregnancy are a significant cause of infant morbidity and mortality. Of these, rubella virus infection is a well-substantiated example that leads to miscarriages or severe fetal defects. However, structural information about the rubella virus has been lacking due to the pleomorphic nature of the virions. Here we report a helical structure of rubella virions using cryo electron tomography. Sub-tomogram averaging of the surface spikes established the relative positions of the viral glycoproteins, which differed from the earlier icosahedral models of the virus. Tomographic analyses of in vitro assembled nucleocapsids and virions provide a template for viral assembly. Comparisons of immature and mature virions show large rearrangements in the glycoproteins that may be essential for forming the infectious virions. These results present the first known example of a helical membrane-enveloped virus, while also providing a structural basis for its assembly and maturation pathway. PMID- 28575073 TI - A comprehensive retrospective study of the seroprevalence of H9N2 avian influenza viruses in occupationally exposed populations in China. AB - The H9N2 avian influenza virus circulates worldwide, predominantly in poultry. Its increasing infectivity and adaptation in poultry and mammals have enhanced the possibility of human infection. However, H9N2 human cases are difficult to detect due to their mild clinical symptoms. Serological study is valuable for risk assessment. A total of 15,700 serum samples were collected from occupationally exposed populations in 22 provinces of China and tested using hemagglutination inhibition (HI) and microneutralization (MN) assays. The sera positive rate of A/Guangzhou/333/99 (G9) was significantly higher than that of A/quail/Hong Kong/G1/97 (G1) (p<0.0001). The seroprevalences of H9N2 were significantly higher in live poultry market workers, large-scale poultry farmers and backyard farmers than in poultry slaughtering factory workers and wild bird habitant workers. The seroprevalences of A/Guangzhou/333/99 (G9) (3.42%) and A/quail/Hong Kong/G1/97 (G1) (1.37%) in Southern China were significantly higher than those in Northern China (p<0.001). The seroprevalence was highest in the elderly, followed by adults and then youths. Our results indicate that subclinical human infection with H9N2 avian influenza virus is widely distributed in China. Longer poultry exposure might contribute to the higher seroprevalence in the elderly group. The higher seroprevalence observed in Southern China than in Northern China might be caused by a higher poultry density. PMID- 28575075 TI - SeqEnrich: A tool to predict transcription factor networks from co-expressed Arabidopsis and Brassica napus gene sets. AB - Transcription factors and their associated DNA binding sites are key regulatory elements of cellular differentiation, development, and environmental response. New tools that predict transcriptional regulation of biological processes are valuable to researchers studying both model and emerging-model plant systems. SeqEnrich predicts transcription factor networks from co-expressed Arabidopsis or Brassica napus gene sets. The networks produced by SeqEnrich are supported by existing literature and predicted transcription factor-DNA interactions that can be functionally validated at the laboratory bench. The program functions with gene sets of varying sizes and derived from diverse tissues and environmental treatments. SeqEnrich presents as a powerful predictive framework for the analysis of Arabidopsis and Brassica napus co-expression data, and is designed so that researchers at all levels can easily access and interpret predicted transcriptional circuits. The program outperformed its ancestral program ChipEnrich, and produced detailed transcription factor networks from Arabidopsis and Brassica napus gene expression data. The SeqEnrich program is ideal for generating new hypotheses and distilling biological information from large-scale expression data. PMID- 28575074 TI - Lessons learnt from human papillomavirus (HPV) vaccination in 45 low- and middle income countries. AB - OBJECTIVE: To synthesise lessons learnt and determinants of success from human papillomavirus (HPV) vaccine demonstration projects and national programmes in low- and middle-income countries (LAMICs). METHODS: Interviews were conducted with 56 key informants. A systematic literature review identified 2936 abstracts from five databases; after screening 61 full texts were included. Unpublished literature, including evaluation reports, was solicited from country representatives; 188 documents were received. A data extraction tool and interview topic guide outlining key areas of inquiry were informed by World Health Organization guidelines for new vaccine introduction. Results were synthesised thematically. RESULTS: Data were analysed from 12 national programmes and 66 demonstration projects in 46 countries. Among demonstration projects, 30 were supported by the GARDASIL(r) Access Program, 20 by Gavi, four by PATH and 12 by other means. School-based vaccine delivery supplemented with health facility based delivery for out-of-school girls attained high coverage. There were limited data on facility-only strategies and little evaluation of strategies to reach out of-school girls. Early engagement of teachers as partners in social mobilisation, consent, vaccination day coordination, follow-up of non-completers and adverse events was considered invaluable. Micro-planning using school/ facility registers most effectively enumerated target populations; other estimates proved inaccurate, leading to vaccine under- or over-estimation. Refresher training on adverse events and safe injection procedures was usually necessary. CONCLUSION: Considerable experience in HPV vaccine delivery in LAMICs is available. Lessons are generally consistent across countries and dissemination of these could improve HPV vaccine introduction. PMID- 28575077 TI - A productive clash of perspectives? The interplay between articles' and authors' perspectives and their impact on Wikipedia edits in a controversial domain. AB - This study examined predictors of the development of Wikipedia articles that deal with controversial issues. We chose a corpus of articles in the German-language version of Wikipedia about alternative medicine as a representative controversial issue. We extracted edits made until March 2013 and categorized them using a supervised machine learning setup as either being pro conventional medicine, pro alternative medicine, or neutral. Based on these categories, we established relevant variables, such as the perspectives of articles and of authors at certain points in time, the (im)balance of an article's perspective, the number of non-neutral edits per article, the number of authors per article, authors' heterogeneity per article, and incongruity between authors' and articles' perspectives. The underlying objective was to predict the development of articles' perspectives with regard to the controversial topic. The empirical part of the study is embedded in theoretical considerations about editorial biases and the effectiveness of norms and rules in Wikipedia, such as the neutral point of view policy. Our findings revealed a selection bias where authors edited mainly articles with perspectives similar to their own viewpoint. Regression analyses showed that an author's perspective as well as the article's previous perspectives predicted the perspective of the resulting edits, albeit both predictors interact with each other. Further analyses indicated that articles with more non-neutral edits were altogether more balanced. We also found a positive effect of the number of authors and of the authors' heterogeneity on articles' balance. However, while the effect of the number of authors was reserved to pro-conventional medicine articles, the authors' heterogenity effect was restricted to pro-alternative medicine articles. Finally, we found a negative effect of incongruity between authors' and articles' perspectives that was pronounced for the pro-alternative medicine articles. PMID- 28575076 TI - Prevalence of colistin resistance gene (mcr-1) containing Enterobacteriaceae in feces of patients attending a tertiary care hospital and detection of a mcr-1 containing, colistin susceptible E. coli. AB - The emergence of the plasmid-mediated mcr colistin resistance gene in the community poses a potential threat for treatment of patients, especially when hospitalized. The aim of this study was to determine the prevalence of all currently known mcr mediated colistin resistance gene in fecal samples of patients attending a tertiary care hospital. From November 2014 until July 2015, fecal samples of patients attending the Leiden University Medical Center were collected and screened for presence of mcr using real-time PCR. Two of 576 patients were positive for mcr-1, resulting in a prevalence of 0.35%, whereas no mcr-2 was found. One of these samples was culture negative, the second sample contained a blaCMY-2 and mcr-1 containing E.coli. This strain belonged to Sequence Type 359 and serotype O177:H21. The mcr-1 containing E.coli was phenotypically susceptible to colistin with a MIC of <= 0.25mg/l, due to a 1329bp transposon IS10R inserted into the mcr-1 gene as identified by WGS. This prevalence study shows that mcr-1 is present in low levels patients out of the community attending a hospital. Furthermore the study underlines the importance of phenotypical confirmation of molecular detection of a mcr-1 gene. PMID- 28575078 TI - Dynamic oceanography determines fine scale foraging behavior of Masked Boobies in the Gulf of Mexico. AB - During breeding, foraging marine birds are under biological, geographic, and temporal constraints. These contraints require foraging birds to efficiently process environmental cues derived from physical habitat features that occur at nested spatial scales. Mesoscale oceanography in particular may change rapidly within and between breeding seasons, and findings from well-studied systems that relate oceanography to seabird foraging may transfer poorly to regions with substantially different oceanographic conditions. Our objective was to examine foraging behavior of a pan-tropical seabird, the Masked Booby (Sula dactylatra), in the understudied Caribbean province, a moderately productive region driven by highly dynamic currents and fronts. We tracked 135 individuals with GPS units during May 2013, November 2013, and December 2014 at a regionally important breeding colony in the southern Gulf of Mexico. We measured foraging behavior using characteristics of foraging trips and used area restricted search as a proxy for foraging events. Among individual attributes, nest stage contributed to differences in foraging behavior whereas sex did not. Birds searched for prey at nested hierarchical scales ranging from 200 m-35 km. Large-scale coastal and shelf-slope fronts shifted position between sampling periods and overlapped geographically with overall foraging locations. At small scales (at the prey patch level), the specific relationship between environmental variables and foraging behavior was highly variable among individuals but general patterns emerged. Sea surface height anomaly and velocity of water were the strongest predictors of area restricted search behavior in random forest models, a finding that is consistent with the characterization of the Gulf of Mexico as an energetic system strongly influenced by currents and eddies. Our data may be combined with tracking efforts in the Caribbean province and across tropical regions to advance understanding of seabird sensing of the environment and serve as a baseline for anthropogenic based threats such as development, pollution, and commercial fisheries. PMID- 28575079 TI - Comparison of forced-air and water-circulating warming for prevention of hypothermia during transcatheter aortic valve replacement. AB - INTRODUCTION: Transcatheter Aortic Valve Replacement (TAVR) procedures at our institution were complicated by perioperative hypothermia despite use of the standard of care forced-air convective warming device (the BairHugger, Augustine Medical Inc, Eden Prairie, MN, USA). To remedy this problem, we initiated a quality improvement process that investigated the use of a conductive warm water circulating device (the Allon ThermoWrap, Menen Medical Corporation, Trevose, PA, USA), and hypothesized that it would decrease the incidence of perioperative hypothermia. METHODS: We compared two different intraoperative warming devices using a historic control. We retrospectively reviewed intraoperative records of 80 TAVRs between 6/2013 and 6/2015, 46 and 34 of which were done with the forced air and water-circulating devices, respectively. Continuous temperature data obtained from pulmonary artery catheter, temperature upon arrival to cardiothoracic ICU (CTU), age, BSA, height, and BMI were compared. RESULTS: Patients warmed with both devices were similar in terms of demographic characteristics. First recorded intraoperative temperature (mean 36.26 +/- SD 0.61 vs. 35.95 +/- 0.46 degrees C, p = 0.02), lowest intraoperative temperature (36.01 +/- 0.58 vs. 34.89 +/- 0.76 degrees C, p<0.001), temperature at the end of the procedure (36.47 +/- 0.51 vs. 35.17 +/- 0.75 degrees C, p<0.001), and temperature upon arrival to the CTU (36.35 +/- 0.44 vs. 35.07 +/- 0.78 degrees C, p<0.001) were significantly higher in the water-circulating group as compared to the forced-air group. CONCLUSION: A quality improvement process led to selection of a new warming device that virtually eliminated perioperative hypothermia at our institution. Patients warmed with the new device were significantly less likely to experience intraoperative hypothermia and were significantly more likely to be normothermic upon arrival to the CTU. PMID- 28575081 TI - Peripatric speciation in an endemic Macaronesian plant after recent divergence from a widespread relative. AB - The Macaronesian Scrophularia lowei is hypothesized to have arisen from the widespread S. arguta on the basis of several phylogenetic studies of the genus, but sampling has been limited. Although these two annual species are morphologically distinct, the origin of S. lowei is unclear because genetic studies focused on this Macaronesian species are lacking. We studied 5 S. lowei and 25 S. arguta populations to determine the relationship of both species and to infer the geographical origin of S. lowei. The timing of S. lowei divergence and differentiation was inferred by dating analysis of the ITS region. A phylogenetic analysis of two nuclear (ITS and ETS) and two chloroplast (psbJ-petA and psbA trnH) DNA regions was performed to study the relationship between the two species, and genetic differentiation was analysed by AMOVA. Haplotype network construction and Bayesian phylogeographic analysis were conducted using chloroplast DNA regions and a spatial clustering analysis was carried out on a combined dataset of all studied regions. Our results indicate that both species constitute a well-supported clade that diverged in the Miocene and differentiated in the Late Miocene-Pleistocene. Although S. lowei constitutes a well-supported clade according to nDNA, cpDNA revealed a close relationship between S. lowei and western Canarian S. arguta, a finding supported by the spatial clustering analysis. Both species have strong population structure, with most genetic variability explained by inter-population differences. Our study therefore supports a recent peripatric speciation of S. lowei-a taxon that differs morphologically and genetically at the nDNA level from its closest relative, S. arguta, but not according to cpDNA, from the closest Macaronesian populations of that species. In addition, a recent dispersal of S. arguta to Madeira from Canary Islands or Selvagens Islands and a rapid morphological differentiation after the colonization to generate S. lowei is the most likely hypothesis to explain the origin of the last taxon. PMID- 28575080 TI - Immunization of a wild koala population with a recombinant Chlamydia pecorum Major Outer Membrane Protein (MOMP) or Polymorphic Membrane Protein (PMP) based vaccine: New insights into immune response, protection and clearance. AB - We assessed the effects of two different single-dose anti-Chlamydia pecorum (C. pecorum) vaccines (containing either Major Outer Membrane Protein (3MOMP) or Polymorphic Membrane Protein (Pmp) as antigens) on the immune response of a group of wild koalas. Both vaccines elicited a systemic humoral response as seen by the production of anti-chlamydial IgG antibodies in more than 90% of vaccinated koalas. A mucosal immune response was also observed, with an increase in Chlamydia-specific mucosal IgG and/or IgA antibodies in some koalas post vaccination. Both vaccines elicited a cell-mediated immune response as measured by the production of the cytokines IFN-gamma and IL-17 post-vaccination. To determine the level of protection provided by the vaccines under natural conditions we assessed C. pecorum infection loads and chlamydial disease status of all vaccinated koalas pre- and post-vaccination, compared to a non-vaccinated cohort from the same habitat. The MOMP vaccinated koalas that were infected on the day of vaccination showed significant clearance of their infection at 6 months post-vaccination. In contrast, the number of new infections in the PMP vaccine was similar to the control group, with some koalas progressing to disease. Genotyping of the ompA gene from the C. pecorum strains infecting the vaccinated animals, identified genetic variants of ompA-F genotype and a new genotype ompA-O. We found that those animals that were the least well protected became infected with strains of C. pecorum not covered by the vaccine. In conclusion, a single dose vaccine formulated with either recombinant PmpG or MOMP can elicit both cell-mediated and humoral (systemic and mucosal) immune responses, with the MOMP vaccine showing clearance of infection in all infected koalas. Although the capability of our vaccines to stimulate an adaptive response and be protective needs to be fully evaluated, this work illustrates the necessity to combine epitopes most relevant to a large panel of variable strains with an efficient adjuvant. PMID- 28575082 TI - The role of reactive oxygen intermediates in the intracellular fate of Leptospira interrogans in the macrophages of different hosts. AB - BACKGROUND: Pathogenic species of Leptospira cause leptospirosis, a global zoonotic disease. Our previous work showed that leptospires survive and replicate in human macrophages but are killed in murine macrophages. However, the mechanism responsible for the different intracellular fates of leptospires within the macrophages of different hosts remains unclear. RESULTS: The present study demonstrates that infection with Leptospira interrogans caused significant up regulation of reactive oxygen species (ROS) and superoxide in J774A.1 cells but did so to a lesser extent in THP-1 cells. The up-regulation of ROS and superoxide was significantly inhibited by the NADPH oxidase inhibitor apocynin. The damaged leptospires and remnants of leptospires within membrane-bound vacuoles were significantly inhibited by apocynin in J774A.1 cells but were less inhibited in THP-1 cells. In addition, apocynin significantly prevented damage to leptospires and the co-localization of L. interrogans with lysosomes in J774A.1 cells but did so to a lesser extent in THP-1 cells. Furthermore, the relative fluorescence intensity levels of intracellular leptospires and the viability of the intracellular leptospires increased in apocynin pretreated J774A.1 and THP-1 cells after 2 h of infection. CONCLUSIONS: The present study, based on our previous findings, further demonstrated that ROS contributed substantially to the bactericidal ability of mouse macrophages to kill intracellular leptospires. However, ROS did not contribute as much in human macrophages, which partially explains the different intracellular fates of L. interrogans in human and mouse macrophages. PMID- 28575083 TI - A RNAi-based therapeutic proof of concept targets salmonid whirling disease in vivo. AB - Myxobolus cerebralis is a cnidarian-myxozoan parasite that causes salmonid whirling disease. M. cerebralis alternates between two hosts: (1) a vertebrate salmonid and (2) an invertebrate oligochaete, Tubifex tubifex. There is no successful treatment for salmonid whirling disease. MyxSP-1 is a M. cerebralis serine protease implicated in whirling disease pathogenesis. We hypothesized that short-interfering RNA (siRNA)-induced RNA interference (RNAi) can silence MyxSP-1 in the invertebrate host and abrogate the M. cerebralis life cycle. This would preclude whirling disease infection in the salmonid host. To test this hypothesis, we first developed a siRNA delivery protocol in T. tubifex. Second, we determined the effective dose for siRNA treatment of M. cerebralis-infected T. tubifex. M. cerebralis-infected T. tubifex were treated with different concentrations of MyxSP-1 or negative control siRNAs (1MUM, 2MUM, 5MUM or 7MUM) at 15 degrees C for 24h, 48h, 72h and 96h, respectively. We monitored MyxSP-1 knockdown using real-time quantitative PCR (qPCR). siRNA treatment with MyxSP-1 siRNA at 2MUM concentration for 24h at 15 degrees C showed maximum significant MyxSP-1 knockdown in T. tubifex. Third, we determined the time points in the M. cerebralis life cycle in T. tubifex at which siRNA treatment was most effective. M. cerebralis-infected T. tubifex were treated with MyxSP-1 or negative control siRNAs (2MUM concentration for 24h at 15 degrees C) at 24 hours post-infection (24hpi), 48hpi, 72hpi, 96hpi, 1 month post-infection (1mpi), 2mpi and 3mpi, respectively. We observed that siRNA treatment of T. tubifex was most effective at 1mpi, 2mpi and 3mpi. Fourth, we immersed specific-pathogen-free rainbow trout fry in water inhabited by MyxSP-1 siRNA-treated T. tubifex (at 1mpi, 2mpi and 3mpi). The salmonids did not develop whirling disease and showed significant MyxSP-1 knockdown. We also observed long-term RNAi in T. tubifex. Together these results demonstrate a novel RNAi-based therapeutic proof of concept in vivo against salmonid whirling disease. PMID- 28575084 TI - Writing in the air: A visualization tool for written languages. AB - The present study investigated interactions between cognitive processes and finger actions called "kusho," meaning "air-writing" in Japanese. Kanji-culture individuals often employ kusho behavior in which they move their fingers as a substitute for a pen to write mostly done when they are trying to recall the shape of a Kanji character or the spelling of an English word. To further examine the visualization role of kusho behavior on cognitive processing, we conducted a Kanji construction task in which a stimulus (i.e., sub-parts to be constructed) was simultaneously presented. In addition, we conducted a Kanji vocabulary test to reveal the relation between the kusho benefit and vocabulary size. The experiment provided two sets of novel findings. First, executing kusho behavior improved task performance (correct responses) as long as the participants watched their finger movements while solving the task. This result supports the idea that visual feedback of kusho behavior helps cognitive processing for the task. Second, task performance was positively correlated with the vocabulary score when stimuli were presented for a relatively long time, whereas the kusho benefits and vocabulary score were not correlated regardless of stimulus-presentation time. These results imply that a longer stimulus-presentation could allow participants to utilize their lexical resources for solving the task. The current findings together support the visualization role of kusho behavior, adding experimental evidence supporting the view that there are interactions between cognition and motor behavior. PMID- 28575085 TI - Acizzia solanicola (Hemiptera: Psyllidae) probing behaviour on two Solanum spp. and implications for possible pathogen spread. AB - Piercing-sucking insects are vectors of plant pathogens, and an understanding of their feeding behaviour is crucial for studies on insect population dynamics and pathogen spread. This study examines probing behaviour of the eggplant psyllid, Acizzia solanicola (Hemiptera: Psyllidae), using the electrical penetration graph (EPG) technique, on two widespread and common hosts: eggplant (Solanum melongena) and tobacco bush (S. mauritianum). Six EPG waveforms were observed: waveform NP (non-probing phase), waveform C (pathway phase), G (feeding activities in xylem tissues), D (first contact with phloem tissues), E1 (salivation in the sieve elements) and E2 (ingestion from phloem tissues). Results showed that A. solanicola is predominantly a phloem feeder and time spent in salivation and ingestion phases (E1 and E2) differed between hosts. Feeding was enhanced on eggplant compared to tobacco bush which showed some degree of resistance, as evidenced by shorter periods of phloem ingestion, a higher propensity to return to the pathway phase once in the sieve elements and higher number of salivation events on tobacco bush. We discuss how prolonged phloem feeding could indicate the potential for A. solanicola to become an important pest of eggplant and potential pathogen vector. PMID- 28575086 TI - Lung epithelial cells have virus-specific and shared gene expression responses to infection by diverse respiratory viruses. AB - The severity of respiratory viral infections is partially determined by the cellular response mounted by infected lung epithelial cells. Disease prevention and treatment is dependent on our understanding of the shared and unique responses elicited by diverse viruses, yet few studies compare host responses to viruses from different families while controlling other experimental parameters. Murine models are commonly used to study the pathogenesis of respiratory viral infections, and in vitro studies using murine cells provide mechanistic insight into the pathogenesis observed in vivo. We used microarray analysis to compare changes in gene expression of murine lung epithelial cells infected individually by three respiratory viruses causing mild (rhinovirus, RV1B), moderate (coronavirus, MHV-1), and severe (influenza A virus, PR8) disease in mice. RV1B infection caused numerous gene expression changes, but the differential effect peaked at 12 hours post-infection. PR8 altered an intermediate number of genes whose expression continued to change through 24 hours. MHV-1 had comparatively few effects on host gene expression. The viruses elicited highly overlapping responses in antiviral genes, though MHV-1 induced a lower type I interferon response than the other two viruses. Signature genes were identified for each virus and included host defense genes for PR8, tissue remodeling genes for RV1B, and transcription factors for MHV-1. Our comparative approach identified universal and specific transcriptional signatures of virus infection that can be used to distinguish shared and virus-specific mechanisms of pathogenesis in the respiratory tract. PMID- 28575087 TI - Vowel production of Mandarin-speaking hearing aid users with different types of hearing loss. AB - In contrast with previous research focusing on cochlear implants, this study examined the speech performance of hearing aid users with conductive (n = 11), mixed (n = 10), and sensorineural hearing loss (n = 7) and compared it with the speech of hearing control. Speech intelligibility was evaluated by computing the vowel space area defined by the Mandarin Chinese corner vowels /a, u, i/. The acoustic differences between the vowels were assessed using the Euclidean distance. The results revealed that both the conductive and mixed hearing loss groups exhibited a reduced vowel working space, but no significant difference was found between the sensorineural hearing loss and normal hearing groups. An analysis using the Euclidean distance further showed that the compression of vowel space area in conductive hearing loss can be attributed to the substantial lowering of the second formant of /i/. The differences in vowel production between groups are discussed in terms of the occlusion effect and the signal transmission media of various hearing devices. PMID- 28575088 TI - Effect of blood pressure lowering medications on leg ischemia in peripheral artery disease patients: A meta-analysis of randomised controlled trials. AB - BACKGROUND: It has been suggested that anti-hypertensive medications may worsen leg ischemia in peripheral artery disease (PAD) patients. We undertook a meta analysis to assess the effect of anti-hypertensive medications on measures of leg ischemia including maximum walking distance (MWD), pain free walking distance (PFWD) and ankle brachial pressure index (ABPI). A meta-regression was performed to evaluate whether the effect of the anti-hypertensive medications on mean arterial pressure (MAP) was associated with changes in ABPI, MWD or PFWD. METHOD: A systematic literature search was performed to identify placebo controlled randomized control trials (RCT) testing anti-hypertensive medications, which reported baseline and follow-up measurements of: MAP and MWD, PFWD or ABPI in patients with intermittent claudication (IC) due to PAD. RESULT: A meta-analysis was performed on 5 RCTs comprising a total of 180 and 127 patients receiving anti hypertensive medications and placebo respectively. This analysis suggested that anti-hypertensive medication did not significantly affect MWD, PFWD or ABPI. In contrast, the meta-regression analysis showed that the reduction in MAP due to the anti-hypertensive drugs was positively correlated with increased MWD during follow-up (beta = 8.371, p = 0.035). Heterogeneity across studies, as assessed by I2, was high. The follow-up period within the included trials was generally short with 3 out of 5 studies having a follow-up period of <= 6 weeks. CONCLUSION: This study suggests that anti-hypertensive treatment does not worsen but may improve leg ischemia in PAD patients. Larger multicenter trials with longer anti hypertensive treatment periods are required to clarify the effect of anti hypertensives on leg ischemia in PAD patients. PMID- 28575089 TI - Transcriptomic analyses on muscle tissues of Litopenaeus vannamei provide the first profile insight into the response to low temperature stress. AB - The Pacific white shrimp (Litopenaeus vannamei) is an important cultured crustacean species worldwide. However, little is known about the molecular mechanism of this species involved in the response to cold stress. In this study, four separate RNA-Seq libraries of L. vannamei were generated from 13 degrees C stress and control temperature. Total 29,662 of Unigenes and overall of 19,619 annotated genes were obtained. Three comparisons were carried out among the four libraries, in which 72 of the top 20% of differentially-expressed genes were obtained, 15 GO and 5 KEGG temperature-sensitive pathways were fished out. Catalytic activity (GO: 0003824) and Metabolic pathways (ko01100) were the most annotated GO and KEGG pathways in response to cold stress, respectively. In addition, Calcium, MAPK cascade, Transcription factor and Serine/threonine protein kinase signal pathway were picked out and clustered. Serine/threonine protein kinase signal pathway might play more important roles in cold adaptation, while other three signal pathway were not widely transcribed. Our results had summarized the differentially-expressed genes and suggested the major important signaling pathways and related genes. These findings provide the first profile insight into the molecular basis of L. vannamei response to cold stress. PMID- 28575090 TI - DNA reference libraries of French Guianese mosquitoes for barcoding and metabarcoding. AB - The mosquito family (Diptera: Culicidae) constitutes the most medically important group of arthropods because certain species are vectors of human pathogens. In some parts of the world, the diversity is so high that the accurate delimitation and/or identification of species is challenging. A DNA-based identification system for all animals has been proposed, the so-called DNA barcoding approach. In this study, our objectives were (i) to establish DNA barcode libraries for the mosquitoes of French Guiana based on the COI and the 16S markers, (ii) to compare distance-based and tree-based methods of species delimitation to traditional taxonomy, and (iii) to evaluate the accuracy of each marker in identifying specimens. A total of 266 specimens belonging to 75 morphologically identified species or morphospecies were analyzed allowing us to delimit 86 DNA clusters with only 21 of them already present in the BOLD database. We thus provide a substantial contribution to the global mosquito barcoding initiative. Our results confirm that DNA barcodes can be successfully used to delimit and identify mosquito species with only a few cases where the marker could not distinguish closely related species. Our results also validate the presence of new species identified based on morphology, plus potential cases of cryptic species. We found that both COI and 16S markers performed very well, with successful identifications at the species level of up to 98% for COI and 97% for 16S when compared to traditional taxonomy. This shows great potential for the use of metabarcoding for vector monitoring and eco-epidemiological studies. PMID- 28575091 TI - Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart. AB - BACKGROUND: We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury. METHODS: Adult male and female rats received daily injections of methamphetamine (5 mg/kg) or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining. RESULTS: Hearts from methamphetamine treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C epsilon expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine. CONCLUSIONS: Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse. PMID- 28575092 TI - Exploitation of Trametes versicolor for bioremediation of endocrine disrupting chemicals in bioreactors. AB - Endocrine disrupting chemicals (EDCs) are environmental contaminants causing increasing concerns due to their toxicity, persistence and ubiquity. In the present study, degradative capabilities of Trametes versicolor, Pleurotus ostreatus and Phanerochaete chrysosporium to act on five EDCs, which represent different classes of chemicals (phenols, parabens and phthalate) and were first applied as single compounds, were assessed. T. versicolor was selected due to its efficiency against target EDCs and its potentialities were exploited against a mixture of EDCs in a cost-effective bioremediation process. A fed-batch approach as well as a starvation strategy were applied in order to reduce the need for input of 'fresh' biomass, and avoid the requirement for external nutrients. The fungus was successfully operated in two different bioreactors over one week. Semi batch cultures were carried out by daily adding a mixture of EDCs to the bioreactors in a total of five consecutive degradation cycles. T. versicolor was able to efficiently remove all compounds during each cycle converting up to 21 mg L-1 day-1 of the tested EDCs. The maintained ability of T. versicolor to remove EDCs without any additional nutrients represents the main outcome of this study, which enables to forecast its application in a water treatment process. PMID- 28575093 TI - Structure-function analysis of human stomatin: A mutation study. AB - Stomatin is an ancient, widely expressed, oligomeric, monotopic membrane protein that is associated with cholesterol-rich membranes/lipid rafts. It is part of the SPFH superfamily including stomatin-like proteins, prohibitins, flotillin/reggie proteins, bacterial HflK/C proteins and erlins. Biochemical features such as palmitoylation, oligomerization, and hydrophobic "hairpin" structure show similarity to caveolins and other integral scaffolding proteins. Recent structure analyses of the conserved PHB/SPFH domain revealed amino acid residues and subdomains that appear essential for the structure and function of stomatin. To test the significance of these residues and domains, we exchanged or deleted them, expressed respective GFP-tagged mutants, and studied their subcellular localization, molecular dynamics and biochemical properties. We show that stomatin is a cholesterol binding protein and that at least two domains are important for the association with cholesterol-rich membranes. The conserved, prominent coiled-coil domain is necessary for oligomerization, while association with cholesterol-rich membranes is also involved in oligomer formation. FRAP analyses indicate that the C-terminus is the dominant entity for lateral mobility and binding site for the cortical actin cytoskeleton. PMID- 28575094 TI - Barriers to disseminating brief CBT for voices from a lived experience and clinician perspective. AB - Access to psychological therapies continues to be poor for people experiencing psychosis. To address this problem, researchers are developing brief interventions that address the specific symptoms associated with psychosis, i.e., hearing voices. As part of the development work for a brief Cognitive Behaviour Therapy (CBT) intervention for voices we collected qualitative data from people who hear voices (study 1) and clinicians (study 2) on the potential barriers and facilitators to implementation and engagement. Thematic analysis of the responses from both groups revealed a number of anticipated barriers to implementation and engagement. Both groups believed the presenting problem (voices and psychosis symptoms) may impede engagement. Furthermore clinicians identified a lack of resources to be a barrier to implementation. The only facilitator to engagement was reported by people who hear voices who believed a compassionate, experienced and trustworthy therapist would promote engagement. The results are discussed in relation to how these barriers could be addressed in the context of a brief intervention using CBT techniques. PMID- 28575095 TI - Probiotics for prevention of radiation-induced diarrhea: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Radiotherapy is commonly used for abdominal or pelvic cancer, and patients receiving radiotherapy have a high risk developing to an acute radiation induced diarrhea. Several previous studies have discussed the effect of probiotics on prevention of radiation-induced diarrhea, but the results are still inconsistent. OBJECTIVE: We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of probiotic supplementation for prevention the radiation-induced diarrhea. METHODS: Relevant RCTs studies assessing the effect of probiotic supplementation on clinical outcomes compared with placebo were searched in PubMed, EMBASE, and the Cochrane Library databases (up to March 30 2016). Heterogeneity was assessed with I2 and H2, and publication bias was evaluated using sensitive analysis. RESULTS: Six trials, a total of 917 participants (490 participants received prophylactic probiotics and 427 participants received placebo), were included in this meta-analysis. Compared with placebo, probiotics were associated with a lower incidence of radiation induced diarrhea (RR: 0.55; 95% CI: 0.34-0.88; P = 0.01; I2: 87%; 95% CI: 75% 94%; H2: 2.8; 95% CI: 2.0-4.0). However, there is no significant difference in the anti-diarrheal medication use (RR: 0.68; 95% CI: 0.40-1.14; P = 0.14) or bristol scale on stool form (RR: 0.64; 95% CI: 0.35-1.17; P = 0.14). CONCLUSION: Probiotics may be beneficial to prevent radiation-induced diarrhea in patients who suffered from abdominal or pelvic cancers during radiotherapy period. PMID- 28575096 TI - Are social inequalities in early childhood smoking initiation explained by exposure to adult smoking? Findings from the UK Millennium Cohort Study. AB - INTRODUCTION: To assess the socio-economic gradient in early smoking initiation at age 11 years and the extent to which any inequality was explained after accounting for longitudinal exposure to adult smoking. METHODS: Analysis of the UK Millennium Cohort Study, based on 9, 609 children from ages 9 months to 11 years. The outcome was smoking initiation by age 11. Odds ratios (ORs) for smoking initiation were estimated using logistic regression, according to maternal education, whilst adjusting for baseline demographic factors. Longitudinal exposure to a regular smoker in the same room was assessed as potential mediator of the association between maternal education and early smoking, along with other socially patterned risk factors for early smoking initiation, such as parental separation and mental health. RESULTS: Overall 2.7% (95% CI: 2.3-3.1) of children had tried a cigarette by age eleven. Children of mothers with no qualifications were more than six times as likely to have tried a cigarette than children of mothers with degree level qualifications or higher (OR 6.0 [95%CI 3.5-10.1]), with clear social gradient. Controlling for potentially mediating variables, particularly exposure to a regular adult smoker reduced the OR smoking initiation in children of mothers with no qualifications by 63% (aOR 2.9 [95%CI 1.7 to 5.1]). CONCLUSIONS: Smoking initiation is more common in disadvantaged children, and this is largely explained by regular exposure to an adult smoker in the same room. Reducing adult smoking in front of children may reduce inequalities in smoking initiation in children by over a half. PMID- 28575097 TI - Influence of the definition of "metabolically healthy obesity" on the progression of coronary artery calcification. AB - OBJECTIVES: Debates whether metabolically healthy obesity (MHO) increases the cardiovascular risk might be due to the metabolic instability of MHO or the absence of a perfect definition of MHO. Therefore, we aimed to investigate the influence of the MHO phenotype on the coronary artery calcium score (CACS) progression according to definition of MHO. METHODS: We analyzed a retrospective cohort with a CACS of 0 at baseline and available serial CACS measurements taken >= 12 months apart (n = 1,218). Obesity was defined as BMI >= 25 kg/m2, and MHO was defined as obesity accompanied by <= 1 (MHO class I) or 0 (MHO class II) components of metabolic syndrome (MetS). RESULTS: During a median follow-up of 45 months, 32.2% of MHO class I and 10.2% of MHO class II subjects developed MetS. Compared to non-obese/metabolically healthy subjects (reference group), hazard ratios (HR) for development of MetS were 2.174 (95% confidence interval [CI]: 1.513-3.124) and 1.166 (95% CI: 0.434-3.129) for MHO class I and II subjects, respectively. The MHO class I subjects showed a significantly increased risk of CACS progression as compared to the reference group (HR: 1.653; 95% CI: 1.144 2.390), whereas MHO class II subjects did not (HR: 1.195; 95% CI: 0.514-2.778). Among subjects with MHO class I, no significant CACS progression was observed in the subjects who maintained metabolic health during follow-up (HR: 1.448; 95% CI: 0.921-2.278). CONCLUSIONS: The risks of metabolic deterioration and CACS progression were significant in subjects with MHO class I, but not in those with MHO class II. PMID- 28575098 TI - miR-148a-mediated estrogen-induced cholestasis in intrahepatic cholestasis of pregnancy: Role of PXR/MRP3. AB - Intrahepatic cholestasis of pregnancy (ICP) is an idiopathic liver disease while the biochemical characteristic is the elevated level of total bile acid (TBA). The present study investigated whether miR-148a mediates the induced effect of estrogen on the development of ICP and the proper mechanism: PXR/MRP3 signal pathway. mRNA expression was detected by qPCR, protein expression was detected by western blotting, the concentration of estrogen and TBA were detected by reagent kit respectively. In the cinical research, it was found that miR-148a expression was positive related with the concentration of TBA in the serum of ICP patients. In in vitro research, estradiol (500 nmol/L, 12 h) significantly upregulated miR 148a expression and LV-148a-siRNA inhibited the function of estradiol (500 nmol/L, 48 h) on TBA secretion. In addition, gene silence of miR-148a upregulated PXR expression which was inhibited by estradiol in LO2 cells. Pretreatment of rifampin (10 MUmol/L), the agonist of PXR alleviated the TBA secretion induced by estradiol (500 nmol/L, 48 h). miR-148a-siRNA and PXR had a synergistic action on TBA secretion of LO2. Both of miR-148a-siRNA and rifampin (10 MUmol/L) inhibited the upregulated effect of estradiol on MRP3 expression. This research has demonstrated that miR-148a may be involved in the induction of estrogen on ICP via PXR signal pathway, and MRP3 may be involved. PMID- 28575099 TI - Differential stability of therapeutic peptides with different proteolytic cleavage sites in blood, plasma and serum. AB - Proteolytic degradation of peptide-based drugs is often considered as major weakness limiting systemic therapeutic applications. Therefore, huge efforts are typically devoted to stabilize sequences against proteases present in serum or plasma, obtained as supernatants after complete blood coagulation or centrifugation of blood supplemented with anticoagulants, respectively. Plasma and serum are reproducibly obtained from animals and humans allowing consistent for clinical analyses and research applications. However, the spectrum of active or activated proteases appears to vary depending on the activation of proteases and cofactors during coagulation (serum) or inhibition of such enzymes by anticoagulants (plasma), such as EDTA (metallo- and Ca2+-dependent proteases) and heparin (e.g. thrombin, factor Xa). Here, we studied the presumed effects on peptide degradation by taking blood via cardiac puncture of CD-1 mice using a syringe containing a peptide solution. Due to absence of coagulation activators (e.g. glass surfaces and damaged cells), visible blood clotting was prevented allowing to study peptide degradation for one hour. The remaining peptide was quantified and the degradation products were identified using mass spectrometry. When the degradation rates (half-life times) were compared to serum derived freshly from the same animal and commercial serum and plasma samples, peptides of three different families showed indeed considerably different stabilities. Generally, peptides were faster degraded in serum than in plasma, but surprisingly all peptides were more stable in fresh blood and the order of degradation rates among the peptides varied among the six different incubation experiments. This indicates, that proteolytic degradation of peptide-based therapeutics may often be misleading stimulating efforts to stabilize peptides at degradation sites relevant only in vitro, i.e., for serum or plasma stability assays, but of lower importance in vivo. PMID- 28575100 TI - Prevalence of microalbuminuria and its associated cardiometabolic risk factors in Korean youth: Data from the Korea National Health and Nutrition Examination Survey. AB - BACKGROUND: Microalbuminuria is a known early predictive factor for renal and cardiovascular diseases, not only for patients with diabetes mellitus or hypertension but also in the general population. However, the prevalence and risk factors associated with microalbuminuria in Korean youth are unknown. OBJECTIVES: The aims of this study are to evaluate the prevalence of microalbuminuria and the association between microalbuminuria and obesity or cardiometabolic risk factors in Korean children and adolescents without diabetes. METHODS: This study examines data obtained from the Korea National Health and Nutrition Examination Survey (between 2011 and 2014). It includes a total of 1,976 participants aged between 10 and 19 years (boys 1,128 and girls 848). Microalbuminuria was defined as a urine albumin-to-creatinine ratio (UACR) of >= 30 mg/g and < 300 mg/g. Association between microalbuminuria and the risk factors for cardiometabolic diseases including insulin resistance was evaluated. RESULTS: The prevalence of microalbuminuria was found to be 3.0% in Korean children and adolescents over this time period. The mean UACR for non-obese youth was significantly greater than that found in obese youth (3.2 +/- 0.1 mg/g in the non-obese group vs. 2.1 +/- 0.2 mg/g in the obese group; P < 0.001). In multiple logistic regression analysis, microalbuminuria was associated with hyperglycemia (OR 2.62, 95% CI 1.09-6.30) and hemoglobin A1c (OR 3.34, 95% CI 1.09-10.17) in the non-obese group and hypertension (OR 14.10, 95% CI 1.12-177.98) and HbA1c (OR 6.68, 95% CI 1.87 23.95) in the obese group. CONCLUSIONS: The prevalence of microalbuminuria is not prominent in obese children and adolescents. Our findings demonstrated that the presence of hypertension and hyperglycemia was associated with microalbuminuria. Especially Hemoglobin A1c was associated with microalbuminuria in youths regardless of weight status. Microalbuminuria in pediatric population can be a helpful marker for the risk of cardiovascular disease. PMID- 28575101 TI - Efficacy of digital pupillometry for diagnosis of Horner syndrome. AB - OBJECTIVES: To evaluate the efficacy of digital pupillometry in the diagnosis of anisocoria related to Horner syndrome in adult patients. DESIGN: Retrospective, observational, case control study. METHODS: Nineteen patients with unilateral Horner syndrome (Horner group) and age-matched controls of 30 healthy individuals with normal vision and neither optic nerve dysfunction nor pupillary abnormalities were included. Pupillary light reflex (PLR) of the Horner group and controls were measured by a dynamic pupillometer (PLR-200; NeurOptics Inc., Irvine, USA). Minimal and maximal (min/max) pupil diameters, latency, constriction ratio, constriction velocity, dilation velocity, and total time taken by the pupil to recover 75% of maximal pupil diameter (T75) were noted. PLR were measured at baseline in both groups and at 30-45 minutes later after 0.5% apraclonidine (Iopidine(r); Alcon Laboratories, Fort Worth, TX, USA) instillation in the Horner group. MAIN OUTCOME MEASURES: The PLR parameters in the affected eye and inter-eye difference before and after 0.5% apraclonidine instillation. RESULTS: In the Horner group, pupil diameters and T75 showed significant difference between the affected eye and unaffected contralateral eye at baseline (all P<0.00625). Compared to controls, inter-eye difference values of pupil diameters and T75 were significantly larger in the Horner group (all P<0.001). After 0.5% apraclonidine instillation, changes in pupil diameter and constriction ratio were significantly larger in the affected eye compared to the unaffected contralateral eye (all P<0.00625). The area under the receiver operating characteristic curves for diagnosing Horner syndrome were largest for baseline inter-eye difference in min/max pupil sizes (AUC = 0.975, 0.994), T75 (AUC = 0.838), and change in min/max pupil sizes after apraclonidine instillation (AUC = 0.923, 0.929, respectively). The diagnostic criteria for Horner syndrome relying on baseline pupillary measurements was defined as one of the two major findings; 1) smaller maximal pupil diameter in the affected eye with an inter-eye difference of > 0.5 mm, or 2) T75 > 2.61 seconds in the affected eye, which showed a sensitivity of 94.7% and specificity of 93.3%. The diagnostic accuracy of apraclonidine testing showed a sensitivity of 84.6% and specificity of 92.3%. CONCLUSIONS: Digital pupillometry is an objective method for quantifying PLR. Baseline inter-eye difference in maximal pupil sizes and dilation lag measured by T75 was equally effective in the diagnosis of Horner syndrome compared to the reversal of anisocoria after apraclonidine instillation. PMID- 28575102 TI - Development of indicators for monitoring Community-Based Rehabilitation. AB - BACKGROUND: Community-Based Rehabilitation (CBR) is a multi-sectoral approach working to equalize opportunities and include people with disability in all aspects of community life. Reliable and internationally comparable data needed to monitor and evaluate CBR are scarce, partially due to the absence of standardized indicators. The objective of this manuscript is to describe the collaborative development process which led to the World Health Organization's (WHO) recently launched set of standardized CBR outcome indicators. METHODS: The WHO's CBR Guidelines recognize CBR as a comprehensive and multi-sectoral strategy, and were therefore used as the starting point for the development of the indicators, in a consensus process involving WHO and International Disability and Development Consortium. Pilot implementations in Guatemala, Egypt and China using a specifically developed mobile phone application to collect data, and an online expert survey were completed to assess validity and feasibility of the indicators and their corresponding questions. RESULTS: The indicator set includes 13 Base Indicators which are broad enough to capture the situation of people with disability in settings where CBR is carried out, independently of the specific CBR activities carried out in a community; and 27 Supplementary Indicators that provide more specific coverage and can be selected based on the specific goals of a CBR program. CONCLUSION: The indicators were suitable to assess differences in health, education, social life, livelihood and empowerment between people with disability and other community members. This comparability provides valuable information to CBR managers, donors and government agencies, to guide decision making, support advocacy and improve accountability. The CBR indicators will support WHO and its member states in their efforts towards strengthening CBR, by generating evidence on its effectiveness. PMID- 28575103 TI - Relationships of serum high-sensitivity C-reactive protein and body size with insulin resistance in a Japanese cohort. AB - BACKGROUND: Impacts of chronic systemic inflammation and body size and their interaction effect on insulin resistance in Asian populations, in whom obesity is less common, are not fully understood. This study evaluated combined relationships of systemic inflammation and body size with insulin resistance in a Japanese cohort. METHODS: We analyzed cross-sectional data from 1,074 eligible subjects (536 men and 538 women) aged 35-69 years who participated in the baseline survey of a cohort study in Tokushima Prefecture, Japan. Systemic inflammation level was assessed by serum high-sensitivity C-reactive protein (hs CRP), and the degree of insulin resistance and beta-cell function were evaluated by the homeostasis model assessment insulin resistance (HOMA-IR) and beta-cell function (HOMA-beta), respectively. Overweight and obesity were defined as a body mass index (BMI) of 23.0-24.9 kg/m2 and >=25.0 kg/m2, respectively. Associations between serum hs-CRP (assessed as quartiles and additionally continuous values after log-transformation) and indices of glucose homeostasis were analysed adjusting for probable covariates, including BMI (quartiles). Combined associations of serum hs-CRP (<=median, >median) and body size (normal, overweight, obese) with insulin resistance as well as their interaction effect on insulin resistance were also evaluated. RESULTS: Serum hs-CRP was dose dependently associated with HOMA-IR, but not HOMA-beta, after adjustment for probable covariates, including BMI. Subjects with obesity and elevated serum hs CRP (>median) showed a high multivariable-adjusted HOMA-IR value of 1.32 (95% confidence interval (CI) 1.23, 1.41) compared with subjects with normal BMI and low serum hs-CRP (<=median) whose multivariable-adjusted HOMA-IR value was 1.14 (95% CI 1.06, 1.21). The interaction effect between body size (normal, overweight, obese) and serum hs-CRP (<=median, >median) on HOMA-IR was significant (P for interaction <0.001). CONCLUSIONS: Our study suggests that elevated systemic inflammation is dose-dependently associated with increased insulin resistance, independent of the known risk factors, in a Japanese population. Concomitant obesity and elevated systemic inflammation may synergistically contribute to increased insulin resistance. PMID- 28575104 TI - Genetically diverse herpesviruses in South American Atlantic coast seabirds. AB - Different herpesviruses have been associated with respiratory and enteric disease and mortality among seabirds and waterfowl. In 2011, a respiratory disease outbreak affected 58.3% (98/168) of the Magellanic penguins undergoing rehabilitation due to an oil spill off the southern Brazilian coast. Etiology was attributed to a novel herpesvirus identified by histopathology, immunohistochemistry, electron microscopy and molecular studies with partial DNA sequencing. Since migration, rehabilitation and translocation may facilitate the spread of pathogens between populations and trigger the onset of clinical disease in animals with latent infections, investigation of herpesvirus occurrence in asymptomatic seabirds was performed. Samples from free-ranging seabirds were collected in Argentinian Patagonia (Magellanic penguins) and the Abrolhos Archipelago in Brazil (Brown boobies, Masked boobies, Red-billed tropicbirds, White-tailed tropicbirds and South American tern). Furthermore, asymptomatic seabirds housed at the facility where the outbreak occurred were also sampled. In total, 354 samples from eight seabird species were analyzed by PCR for herpesvirus. Four different sequences of herpesviruses were identified, one in Yellow-nosed Albatross, one in Boobies and Tropicbirds and two in Magellanic penguins. Magellanic penguin herpesvirus 1 was identified during the penguin outbreak at the rehabilitation facility in Brazil, while Magellanic penguin herpesvirus 2 was recovered from free-ranging penguins at four reproduction sites in Argentina. Phylogenic analysis of the herpesviruses sequences tentatively identified suggested that the one found in Suliformes and the one associated with the outbreak are related to sequences of viruses that have previously caused seabird die-offs. These findings reinforce the necessity for seabird disease surveillance programs overall, and particularly highlight the importance of quarantine, good hygiene, stress management and pre-release health exams in seabirds undergoing rehabilitation. PMID- 28575105 TI - Assessment of treatment response during chemoradiation therapy for pancreatic cancer based on quantitative radiomic analysis of daily CTs: An exploratory study. AB - PURPOSE: In an effort for early assessment of treatment response, we investigate radiation induced changes in quantitative CT features of tumor during the delivery of chemoradiation therapy (CRT) for pancreatic cancer. METHODS: Diagnostic-quality CT data acquired daily during routine CT-guided CRT using a CT on-rails for 20 pancreatic head cancer patients were analyzed. On each daily CT, the pancreatic head, the spinal cord and the aorta were delineated and the histograms of CT number (CTN) in these contours were extracted. Eight histogram based radiomic metrics including the mean CTN (MCTN), peak position, volume, standard deviation (SD), skewness, kurtosis, energy and entropy were calculated for each fraction. Paired t-test was used to check the significance of the change of specific metric at specific time. GEE model was used to test the association between changes of metrics over time for different pathology responses. RESULTS: In general, CTN histogram in the pancreatic head (but not in spinal cord) changed during the CRT delivery. Changes from the 1st to the 26th fraction in MCTN ranged from -15.8 to 3.9 HU with an average of -4.7 HU (p<0.001). Meanwhile the volume decreased, the skewness increased (less skewed), and the kurtosis decreased (less peaked). The changes of MCTN, volume, skewness, and kurtosis became significant after two weeks of treatment. Patient pathological response is associated with the changes of MCTN, SD, and skewness. In cases of good response, patients tend to have large reductions in MCTN and skewness, and large increases in SD and kurtosis. CONCLUSIONS: Significant changes in CT radiomic features, such as the MCTN, skewness, and kurtosis in tumor were observed during the course of CRT for pancreas cancer based on quantitative analysis of daily CTs. These changes may be potentially used for early assessment of treatment response and stratification for therapeutic intensification. PMID- 28575106 TI - Signal transduction pathway mediated by the novel regulator LoiA for low oxygen tension induced Salmonella Typhimurium invasion. AB - Salmonella enterica serovar Typhimurium (S. Typhimurium) is a major intestinal pathogen of both humans and animals. Salmonella pathogenicity island 1 (SPI-1) encoded virulence genes are required for S. Typhimurium invasion. While oxygen (O2) limitation is an important signal for SPI-1 induction under host conditions, how the signal is received and integrated to the central SPI-1 regulatory system in S. Typhimurium is not clear. Here, we report a signal transduction pathway that activates SPI-1 expression in response to low O2. A novel regulator encoded within SPI-14 (STM14_1008), named LoiA (low oxygen induced factor A), directly binds to the promoter and activates transcription of hilD, leading to the activation of hilA (the master activator of SPI-1). Deletion of loiA significantly decreased the transcription of hilA, hilD and other representative SPI-1 genes (sipB, spaO, invH, prgH and invF) under low O2 conditions. The response of LoiA to the low O2 signal is mediated by the ArcB/ArcA two-component system. Deletion of either arcA or arcB significantly decreased transcription of loiA under low O2 conditions. We also confirmed that SPI-14 contributes to S. Typhimurium virulence by affecting invasion, and that loiA is the virulence determinant of SPI-14. Mice infection assays showed that S. Typhimurium virulence was severely attenuated by deletion of either the entire SPI-14 region or the single loiA gene after oral infection, while the virulence was not affected by either deletion after intraperitoneal infection. The signal transduction pathway described represents an important mechanism for S. Typhimurium to sense and respond to low O2 conditions of the host intestinal tract for invasion. SPI-14 encoded loiA is an essential element of this pathway that integrates the low O2 signal into the SPI-1 regulatory system. Acquisition of SPI-14 is therefore crucial for the evolution of S. Typhimurium as an intestinal pathogen. PMID- 28575107 TI - Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling. AB - Retinoblastoma (RB) is a rare childhood malignant disorder caused by the biallelic inactivation of RB1 gene. Early diagnosis and identification of carriers of heritable RB1 mutations can improve disease outcome and management. In this study, mutational analysis was conducted on fifty-nine matched tumor and peripheral blood samples from 18 bilateral and 41 unilateral unrelated RB cases by a combinatorial approach of Multiplex Ligation-dependent Probe Amplification (MLPA) assay, deletion screening, direct sequencing, copy number gene dosage analysis and methylation assays. Screening of both blood and tumor samples yielded a mutation detection rate of 94.9% (56/59) while only 42.4% (25/59) of mutations were detected if blood samples alone were analyzed. Biallelic mutations were observed in 43/59 (72.9%) of tumors screened. There were 3 cases (5.1%) in which no mutations could be detected and germline mutations were detected in 19.5% (8/41) of unilateral cases. A total of 61 point mutations were identified, of which 10 were novel. There was a high incidence of previously reported recurrent mutations, occurring at 38.98% (23/59) of all cases. Of interest were three cases of mosaic RB1 mutations detected in the blood from patients with unilateral retinoblastoma. Additionally, two germline mutations previously reported to be associated with low-penetrance phenotypes: missense-c.1981C>T and splice variant-c.607+1G>T, were observed in a bilateral and a unilateral proband, respectively. These findings have implications for genetic counselling and risk prediction for the affected families. This is the first published report on the spectrum of mutations in RB patients from Singapore and shows that further improved mutation screening strategies are required in order to provide a definitive molecular diagnosis for every case of RB. Our findings also underscore the importance of genetic testing in supporting individualized disease management plans for patients and asymptomatic family members carrying low-penetrance, germline mosaicism or heritable unilateral mutational phenotypes. PMID- 28575108 TI - Changes in the leaf proteome profile of Withania somnifera (L.) Dunal in response to Alternaria alternata infection. AB - Withania somnifera is a high value medicinal plant which is used against large number of ailments. The medicinal properties of the plant attributes to a wide array of important secondary metabolites. The plant is predominantly infected with leaf spot pathogen Alternaria alternata, which leads to substantial biodeterioration of pharmaceutically important metabolites. To develop an effective strategy to combat this disease, proteomics based approach could be useful. Hence, in the present study, three different protein extraction methods tris-buffer based, phenol based and trichloroacetic acid-acetone (TCA-acetone) based method were comparatively evaluated for two-dimensional electrophoresis (2 DE) analysis of W. somnifera. TCA-acetone method was found to be most effective and was further used to identify differentially expressed proteins in response to fungal infection. Thirty-eight differentially expressed proteins were identified by matrix assisted laser desorption/ionization time of flight-mass spectrometry (MALDI TOF/TOF MS/MS). The known proteins were categorized into eight different groups based on their function and maximum proteins belonged to energy and metabolism, cell structure, stress and defense and RNA/DNA categories. Differential expression of some key proteins were also crosschecked at transcriptomic level by using qRT-PCR and were found to be consistent with the 2 DE data. These outcomes enable us to evaluate modifications that take place at the proteomic level during a compatible host pathogen interaction. The comparative proteome analysis conducted in this paper revealed the involvement of many key proteins in the process of pathogenesis and further investigation of these identified proteins could assist in the discovery of new strategies for the development of pathogen resistance in the plant. PMID- 28575109 TI - Computerised analysis of facial emotion expression in eating disorders. AB - BACKGROUND: Problems with social-emotional processing are known to be an important contributor to the development and maintenance of eating disorders (EDs). Diminished facial communication of emotion has been frequently reported in individuals with anorexia nervosa (AN). Less is known about facial expressivity in bulimia nervosa (BN) and in people who have recovered from AN (RecAN). This study aimed to pilot the use of computerised facial expression analysis software to investigate emotion expression across the ED spectrum and recovery in a large sample of participants. METHOD: 297 participants with AN, BN, RecAN, and healthy controls were recruited. Participants watched film clips designed to elicit happy or sad emotions, and facial expressions were then analysed using FaceReader. RESULTS: The finding mirrored those from previous work showing that healthy control and RecAN participants expressed significantly more positive emotions during the positive clip compared to the AN group. There were no differences in emotion expression during the sad film clip. DISCUSSION: These findings support the use of computerised methods to analyse emotion expression in EDs. The findings also demonstrate that reduced positive emotion expression is likely to be associated with the acute stage of AN illness, with individuals with BN showing an intermediate profile. PMID- 28575111 TI - The role of insulin resistance in experimental diabetic retinopathy-Genetic and molecular aspects. AB - BACKGROUND: Diabetic retinopathy is characterized by defects in the retinal neurovascular unit. The underlying mechanisms of impairment-including reactive intermediates and growth-factor dependent signalling pathways and their possible interplay are incompletely understood. This study aims to assess the relative role of hyperglycemia and hyperinsulinemia alone or in combination on the gene expression patterning in the retina of animal models of diabetes. MATERIAL AND METHODS: As insulinopenic, hyperglycemic model reflecting type 1 diabetes, male STZ-Wistar rats (60mg/kg BW; i.p. injection at life age week 7) were used. Male obese ZDF rats (fa/fa) were used as type-2 diabetes model characterized by persisting hyperglycemia and transient hyperinsulinemia. Male obese ZF rats (fa/fa) were used reflecting euglycemia and severe insulin resistance. All groups were kept till an age of 20 weeks on respective conditions together with appropriate age-matched controls. Unbiased gene expression analysis was performed per group using Affymetrix gene arrays. Bioinformatics analysis included analysis for clustering and differential gene expression, and pathway and upstream activator analysis. Gene expression differences were confirmed by microfluidic card PCR technology. RESULTS: The most complex genetic regulation in the retina was observed in ZDF rats with a strong overlap to STZ-Wistar rats. Surprisingly, systemic insulin resistance alone in ZF rats without concomitant hyperglycemia did not induce any significant change in retinal gene expression pattern. Pathway analysis indicate an overlap between ZDF rats and STZ-treated rats in pathways like complement system activation, acute phase response signalling, and oncostatin-M signalling. Major array gene expression changes could be confirmed by subsequent PCR. An analysis of upstream transcriptional regulators revealed interferon-gamma, interleukin-6 and oncostatin-M in STZ and ZDF rats. CONCLUSIONS: Systemic hyperinsulinaemia without hyperglycemia does not result in significant gene expression changes in retina. In contrast, persistent systemic hyperglycemia boosts much stronger expression changes with a limited number of known and new key regulators. PMID- 28575110 TI - Physical activity and risk of prostate and bladder cancer in China: The South and East China case-control study on prostate and bladder cancer. AB - BACKGROUND: Recent meta-analyses have suggested a modest protective effect of high levels of physical activity on developing both prostate and bladder cancer, but significant heterogeneity between studies included in these meta-analyses existed. To our knowledge, few Chinese studies investigated the association between physical activity and prostate cancer and none between physical activity and bladder cancer. Given the inconsistencies between previous studies and because studies on the relation between physical activity and prostate and bladder cancer in China are scarce, it remains elusive whether there is a relationship between physical activity and prostate and bladder cancer within the Chinese population. METHODS: We investigated the association between physical activity and risk of developing prostate and bladder cancer within a hospital based case-control study in the East and South of China among 260 and 438 incident prostate and bladder cancer cases, respectively, and 427 controls. A questionnaire was administered to measure physical activity as metabolic equivalents (METs). Random effects logistic regression was used to calculate odds ratios (ORs) of prostate and bladder cancer for different levels of physical activity and for the specific activities of walking and cycling. RESULTS: Increasing overall physical activity was associated with a significant reduction in prostate cancer risk (Ptrend = 0.04) with the highest activity tertile level showing a nearly 50% reduction in prostate cancer risk (OR = 0.53, 95%CI: 0.28 0.98). Overall physical activity was not significantly associated with risk of bladder cancer (Ptrend = 0.61), neither were vigorous (Ptrend = 0.60) or moderate levels of physical activity (Ptrend = 0.21). Walking and cycling were not significantly associated with either prostate (Ptrend> = 0.62) or bladder cancer risk (Ptrend> = 0.25). CONCLUSIONS: The findings of this largest ever case control study in China investigating the relationship between physical activity and prostate and bladder cancer suggest that overall physical activity is associated with a decreased risk of prostate cancer, but not with bladder cancer. PMID- 28575112 TI - Molecular epidemiology of Staphylococcus aureus bacteremia in a single large Minnesota medical center in 2015 as assessed using MLST, core genome MLST and spa typing. AB - Staphylococcus aureus is a leading cause of bacteremia in hospitalized patients. Whether or not S. aureus bacteremia (SAB) is associated with clonality, implicating potential nosocomial transmission, has not, however, been investigated. Herein, we examined the epidemiology of SAB using whole genome sequencing (WGS). 152 SAB isolates collected over the course of 2015 at a single large Minnesota medical center were studied. Staphylococcus protein A (spa) typing was performed by PCR/Sanger sequencing; multilocus sequence typing (MLST) and core genome MLST (cgMLST) were determined by WGS. Forty-eight isolates (32%) were methicillin-resistant S. aureus (MRSA). The isolates encompassed 66 spa types, clustered into 11 spa clonal complexes (CCs) and 10 singleton types. 88% of 48 MRSA isolates belonged to spa CC-002 or -008. Methicillin-susceptible S. aureus (MSSA) isolates were more genotypically diverse, with 61% distributed across four spa CCs (CC-002, CC-012, CC-008 and CC-084). By MLST, there was 31 sequence types (STs), including 18 divided into 6 CCs and 13 singleton STs. Amongst MSSA isolates, the common MLST clones were CC5 (23%), CC30 (19%), CC8 (15%) and CC15 (11%). Common MRSA clones were CC5 (67%) and CC8 (25%); there were no MRSA isolates in CC45 or CC30. By cgMLST analysis, there were 9 allelic differences between two isolates, with the remaining 150 isolates differing from each other by over 40 alleles. The two isolates were retroactively epidemiologically linked by medical record review. Overall, cgMLST analysis resulted in higher resolution epidemiological typing than did multilocus sequence or spa typing. PMID- 28575113 TI - Explaining ethnic disparities in lung function among young adults: A pilot investigation. AB - BACKGROUND: Ethnic disparities in lung function have been linked mainly to anthropometric factors but have not been fully explained. We conducted a cross sectional pilot study to investigate how best to study ethnic differences in lung function in young adults and evaluate whether these could be explained by birth weight and socio-economic factors. METHODS: We recruited 112 university students of White and South Asian British ethnicity, measured post-bronchodilator lung function, obtained information on respiratory symptoms and socio-economic factors through questionnaires, and acquired birth weight through data linkage. We regressed lung function against ethnicity and candidate predictors defined a priori using linear regression, and used penalised regression to examine a wider range of factors. We reviewed the implications of our findings for the feasibility of a larger study. RESULTS: There was a similar parental socio economic environment and no difference in birth weight between the two ethnic groups, but the ethnic difference in FVC adjusted for sex, age, height, demi span, father's occupation, birth weight, maternal educational attainment and maternal upbringing was 0.81L (95%CI: -1.01 to -0.54L). Difference in body proportions did not explain the ethnic differences although parental immigration was an important predictor of FVC independent of ethnic group. Participants were comfortable with study procedures and we were able to link birth weight data to clinical measurements. CONCLUSION: Studies of ethnic disparities in lung function among young adults are feasible. Future studies should recruit a socially more diverse sample and investigate the role of markers of acculturation in explaining such differences. PMID- 28575114 TI - Early derivation of IgM memory cells and bone marrow plasmablasts. AB - IgM memory cells are recognized as an important component of B cell memory in mice and humans. Our studies of B cells elicited in response to ehrlichial infection identified a population of CD11c-positive IgM memory cells, and an IgM bone marrow antibody-secreting cell population. The origin of these cells was unknown, although an early T-independent spleen CD11c- and T-bet-positive IgM plasmablast population precedes both, suggesting a linear relationship. A majority of the IgM memory cells detected after day 30 post-infection, also T-bet positive, had undergone somatic hypermutation, indicating they expressed activation-induced cytidine deaminase (AID). Therefore, to identify early AID expressing precursor B cells, we infected an AID-regulated tamoxifen-inducible Cre-recombinase-EYFP reporter strain. Tamoxifen administration led to the labeling of both IgM memory cells and bone marrow ASCs on day 30 and later post infection. High frequencies of labeled cells were identified on day 30 post infection, following tamoxifen administration on day 10 post-infection, although IgM memory cells were marked when tamoxifen was administered as early as day 4 post-infection. Transcription of Aicda in the early plasmablasts was not detected in the absence of CD4 T cells, but occurred independently of TLR signaling. Unlike the IgM memory cells, the bone marrow IgM ASCs were elicited independent of T cell help. Moreover, Aicda was constitutively expressed in IgM memory cells, but not in bone marrow ASCs. These studies demonstrate that two distinct long term IgM-positive B cell populations are generated early in response to infection, but are maintained via separate mechanisms. PMID- 28575115 TI - Multiplex one-step Real-time PCR by Taqman-MGB method for rapid detection of pan and H5 subtype avian influenza viruses. AB - Avian influenza virus (AIV) can infect a variety of avian species and mammals, leading to severe economic losses in poultry industry and posing a substantial threat to public health. Currently, traditional virus isolation and identification is inadequate for the early diagnosis because of its labor intensive and time-consuming features. Real-time RT-PCR (RRT-PCR) is an ideal method for the detection of AIV since it is highly specific, sensitive and rapid. In addition, as the new quencher MGB is used in RRT-PCR, it only needs shorter probe and helps the binding of target gene and probe. In this study, a pan-AIV RRT-PCR for the detection of all AIVs and H5-AIV RRT-PCR for detection of H5 AIV based on NP gene of AIV and HA gene of H5 AIV were successfully established using Taqman-MGB method. We tested 14 AIV strains in total and the results showed that the pan-AIV RRT-PCR can detect AIV of various HA subtypes and the H5-AIV RRT-PCR can detect H5 AIV circulating in poultry in China in recent three years, including H5 viruses of clade 7.2, clade 2.3.4.4 and clade 2.3.2.1. Furthermore, the multiplex detection limit for pan-AIV and H5-AIV RRT-PCR was 5 copies per reaction. When this multiplex method was applied in the detection of experimental and live poultry market samples, the detection rates of pan-AIV and H5 AIV in RRT PCR were both higher than the routine virus isolation method with embryonated chicken eggs. The multiplex RRT-PCR method established in our study showed high sensitivity, reproducibility and specificity, suggesting the promising application of our method for surveillance of both pan AIV and prevalent H5 AIV in live poultry markets and clinical samples. PMID- 28575116 TI - Molecular diagnosis and characterization of Cryptosporidium spp. in turkeys and chickens in Germany reveals evidence for previously undetected parasite species. AB - A total of 256 fecal specimens were randomly collected from farmed poultry in Germany and screened for the presence of Cryptosporidium spp. by PCR and further characterized by direct automated DNA sequencing. Using a nested PCR amplifying approximately 830 bp 18S rDNA fragment, 7.03% (n = 18) of the samples were Cryptosporidium-positive. In detail, Cryptosporidium was detected in 9.3% (8/86) of turkeys, 5.7% (9/158) of broilers and 8.3% (1/12) of layers. After DNA sequencing, Cryptosporidium parvum the most frequently observed species was identified in 5.1% (13/256) of all poultry species, including 8.1% (7/86) of turkeys, 3.2% (5/158) of broilers and 8.3% (1/12) of layers. Cryptosporidium baileyi was detected in 1.3% (2/256) of the broilers only. Three novel unclassified Cryptosporidium spp. were detected in 1.2% (1/86) of turkeys and 1.3% (2/158) of broilers. The infection rate was high in 13-20 week old turkeys, 1-6 weeks old broilers and >20 weeks old layers but differences between age groups were not significant. This is the first study in Germany uses molecular methods for the detection of Cryptosporidium in poultry. The results indicate that Cryptosporidium parasites are common among broilers and turkeys in Germany. Considering the large size of the poultry industry, the large amount of poultry meat that is consumed and the fact that C. parvum is also the most common Cryptosporidium parasite in humans, poultry might also be a source of human infections. PMID- 28575117 TI - Gene and metabolite time-course response to cigarette smoking in mouse lung and plasma. AB - Prolonged cigarette smoking (CS) causes chronic obstructive pulmonary disease (COPD), a prevalent serious condition that may persist or progress after smoking cessation. To provide insight into how CS triggers COPD, we investigated temporal patterns of lung transcriptome expression and systemic metabolome changes induced by chronic CS exposure and smoking cessation. Whole lung RNA-seq data was analyzed at transcript and exon levels from C57Bl/6 mice exposed to CS for 1- or 7 days, for 3-, 6-, or 9 months, or for 6 months followed by 3 months of cessation using age-matched littermate controls. We identified previously unreported dysregulation of pyrimidine metabolism and phosphatidylinositol signaling pathways and confirmed alterations in glutathione metabolism and circadian gene pathways. Almost all dysregulated pathways demonstrated reversibility upon smoking cessation, except the lysosome pathway. Chronic CS exposure was significantly linked with alterations in pathways encoding for energy, phagocytosis, and DNA repair and triggered differential expression of genes or exons previously unreported to associate with CS or COPD, including Lox, involved in matrix remodeling, Gp2, linked to goblet cells, and Slc22a12 and Agpat3, involved in purine and glycerolipid metabolism, respectively. CS-induced lung metabolic pathways changes were validated using metabolomic profiles of matched plasma samples, indicating that dynamic metabolic gene regulation caused by CS is reflected in the plasma metabolome. Using advanced technologies, our study uncovered novel pathways and genes altered by chronic CS exposure, including those involved in pyrimidine metabolism, phosphatidylinositol signaling and lysosome function, highlighting their potential importance in the pathogenesis or diagnosis of CS-associated conditions. PMID- 28575118 TI - Comparative analysis of genes frequently regulated by drugs based on connectivity map transcriptome data. AB - Gene expression is perturbated by drugs to different extent. Analyzing genes whose expression is frequently regulated by drugs would be useful for the screening of candidate therapeutic targets and genes implicated in side effect. Here, we obtained the differential expression number (DEN) for genes profiled in Affymetrix microarrays from the Connectivity Map project, and conducted systemic comparative computational analysis between high DEN genes and other genes. Results indicated that genes with higher down-/up-regulation number (down_h/up_h) tended to be clustered in genome, and have lower homologous gene number, higher SNP density and more disease-related SNP. Down_h and up_h were significantly enriched in cancer related pathways, while genes with lower down-/up-regulation number (down_l/up_l) were mainly involved in the development of nervous system diseases. Besides, up_h had lower interaction network degree, later developmental stage to express, higher tissue expression specificity than up_l, while down_h showed reversed tendency in comparison with down_l. Together, our analysis suggests that genes frequently regulated by drugs are more likely to be associated with disease-related functions, but the extensive activation of conserved and widely expressed genes by drugs is disfavored. PMID- 28575119 TI - Nucleolus association of chromosomal domains is largely maintained in cellular senescence despite massive nuclear reorganisation. AB - Mammalian chromosomes are organized in structural and functional domains of 0.1 10 Mb, which are characterized by high self-association frequencies in the nuclear space and different contact probabilities with nuclear sub-compartments. They exhibit distinct chromatin modification patterns, gene expression levels and replication timing. Recently, nucleolus-associated chromosomal domains (NADs) have been discovered, yet their precise genomic organization and dynamics are still largely unknown. Here, we use nucleolus genomics and single-cell experiments to address these questions in human embryonic fibroblasts during replicative senescence. Genome-wide mapping reveals 1,646 NADs in proliferating cells, which cover about 38% of the annotated human genome. They are mainly heterochromatic and correlate with late replicating loci. Using Hi-C data analysis, we show that interactions of NADs dominate interphase chromosome contacts in the 10-50 Mb distance range. Interestingly, only minute changes in nucleolar association are observed upon senescence. These spatial rearrangements in subdomains smaller than 100 kb are accompanied with local transcriptional changes. In contrast, large centromeric and pericentromeric satellite repeat clusters extensively dissociate from nucleoli in senescent cells. Accordingly, H3K9me3-marked heterochromatin gets remodelled at the perinucleolar space as revealed by immunofluorescence analyses. Collectively, this study identifies connections between the nucleolus, 3D genome structure, and cellular aging at the level of interphase chromosome organization. PMID- 28575120 TI - Structural basis for 5'-ETS recognition by Utp4 at the early stages of ribosome biogenesis. AB - Eukaryotic ribosome biogenesis begins with the co-transcriptional assembly of the 90S pre-ribosome. The 'U three protein' (UTP) complexes and snoRNP particles arrange around the nascent pre-ribosomal RNA chaperoning its folding and further maturation. The earliest event in this hierarchical process is the binding of the UTP-A complex to the 5'-end of the pre-ribosomal RNA (5'-ETS). This oligomeric complex predominantly consists of beta-propeller and alpha-solenoidal proteins. Here we present the structure of the Utp4 subunit from the thermophilic fungus Chaetomium thermophilum at 2.15 A resolution and analyze its function by UV RNA crosslinking (CRAC) and in context of a recent cryo-EM structure of the 90S pre ribosome. Utp4 consists of two orthogonal and highly basic beta-propellers that perfectly fit the EM-data. The Utp4 structure highlights an unusual Velcro closure of its C-terminal beta-propeller as relevant for protein integrity and potentially Utp8 recognition in the context of the pre-ribosome. We provide a first model of the 5'-ETS RNA from the internally hidden 5'-end up to the region that hybridizes to the 3'-hinge sequence of U3 snoRNA and validate a specific Utp4/5'-ETS interaction by CRAC analysis. PMID- 28575121 TI - Pharmacokinetics of caspofungin acetate to guide optimal dosing in cats. AB - Cats are the most common mammal to develop invasive fungal rhinosinusitis caused by cryptic species in Aspergillus section Fumigati that are resistant to azoles but susceptible to caspofungin. In this study nonlinear mixed-effects pharmacokinetic modeling and simulation was used to investigate caspofungin pharmacokinetics and explore dosing regimens in cats using caspofungin minimum effective concentrations (MECs). Plasma concentrations in healthy cats were determined using HPLC-MS/MS after administration of a single and seven consecutive daily intravenous doses of 1 mg/kg caspofungin. In the final pharmacokinetic model an optimum maximum concentration (Cmax): MEC ratio of 10-20 was used to guide caspofungin efficacy. Simulations were performed for dosing regimens (doses 0.25-2 mg/kg and 6-72 h dosing intervals) with and without inclusion of a loading dose. Using a 1 mg/kg dose Cmax first dose was 14.8 MUg/mL, Cmax at steady state was 19.8 MUg/mL, Cmin was 5 MUg/mL and Cmax: MEC was >20 in 42.6% of cats after multiple doses. An optimal Cmax: MEC ratio was achieved in caspofungin simulations using 0.75 mg/kg q 24 h or 1 mg/kg q 72h. However, at 1 mg/kg q 72h, Cmin was < MEC (<1 MUg/mL) in over 95% of the population. Using a loading dose of 1 mg/kg and a daily dose of 0.75 mg/kg thereafter, the Cmax: MEC was optimal and Cmin was > 2.5 MUg/mL for 98% of the population. Based on the modeling data this dosing regimen is likely to achieve target therapeutic concentrations, meet the proposed Cmax: MEC window and provide consistent exposure between doses. PMID- 28575122 TI - Multimodal assessment of white matter tracts in amyotrophic lateral sclerosis. AB - Several quantitative magnetic resonance imaging (MRI) techniques have been proposed to investigate microstructural tissue changes in amyotrophic lateral sclerosis (ALS) including diffusion tensor imaging (DTI), magnetization transfer imaging, and R2* mapping. Here, in this study, we compared these techniques with regard to their capability for detecting ALS related white matter (WM) changes in the brain and their association with clinical findings. We examined 27 ALS patients and 35 age-matched healthy controls. MRI was performed at 3T, after which we analyzed the diffusion properties, the magnetization transfer ratio (MTR), and the effective transversal relaxation rate R2* in 18 WM tracts that were obtained by a fully automated segmentation technique. ALS patients, especially with a bulbar onset, showed a bilateral increase in radial and mean diffusivity, as well as a reduction in fractional anisotropy of the corticospinal tract (CST), and diffusion changes in the parietal and temporal superior longitudinal fasciculus. A reduction of the MTR was found in both CSTs and an R2* reduction was seen only in the left CST. Tract-specific diffusion properties were not related to clinical status in a cross-sectional manner but demonstrated some association with disease progression over three subsequent months. DTI reveals more widespread WM tissue changes than MTR and R2*. These changes are not restricted to the CST, but affect also other WM tracts (especially in patients with bulbar onset), and are associated with the short term course of the disease. PMID- 28575123 TI - Induction of axial chirality in divanillin by interaction with bovine serum albumin. AB - Vanillin is a plant secondary metabolite and has numerous beneficial health applications. Divanillin is the homodimer of vanillin and used as a taste enhancer compound and also a promissory anticancer drug. Here, divanillin was synthesized and studied in the context of its interaction with bovine serum albumin (BSA). We found that divanillin acquires axial chirality when complexed with BSA. This chiroptical property was demonstrated by a strong induced circular dichroism (ICD) signal. In agreement with this finding, the association constant between BSA and divanillin (3.3 x 105 mol-1L) was higher compared to its precursor vanillin (7.3 x 104 mol-1L). The ICD signal was used for evaluation of the association constant, demonstration of the reversibility of the interaction and determination of the binding site, revealing that divanillin has preference for Sudlow's site I in BSA. This property was confirmed by displacement of the fluorescent markers warfarin (site I) and dansyl-L-proline (site II). Molecular docking simulation confirmed the higher affinity of divanillin to site I. The highest scored conformation obtained by docking (dihedral angle 242 degrees ) was used for calculation of the circular dichroism spectrum of divanillin using Time Dependent Density Functional Theory (TDDFT). The theoretical spectrum showed good similarity with the experimental ICD. In summary, we have demonstrated that by interacting with the chiral cavities in BSA, divanillin became a atropos biphenyl, i.e., the free rotation around the single bound that links the aromatic rings was impeded. This phenomenon can be explained considering the interactions of divanillin with amino acid residues in the binding site of the protein. This chiroptical property can be very useful for studying the effects of divanillin in biological systems. Considering the potential pharmacological application of divanillin, these findings will be helpful for researchers interested in the pharmacological properties of this compound. PMID- 28575124 TI - Seasonal variation in hemodialysis initiation: A single-center retrospective analysis. AB - The number of new dialysis patients has been increasing worldwide, particularly among elderly individuals. However, information on seasonal variation in hemodialysis initiation in recent decades is lacking, and the seasonal distribution of patients' conditions immediately prior to starting dialysis remains unclear. Having this information could help in developing a modifiable approach to improving pre-dialysis care. We retrospectively investigated the records of 297 patients who initiated hemodialysis at Hiroshima Prefectural Hospital from January 1st, 2009 to December 31st, 2013. Seasonal differences were assessed by chi2 or Kruskal-Wallis tests. Multiple comparison analysis was performed with the Steel test. The overall number of patients starting dialysis was greatest in winter (n = 85, 28.6%), followed by spring (n = 74, 24.9%), summer (n = 70, 23.6%), and autumn (n = 68, 22.9%), though the differences were not significant. However, there was a significant winter peak in dialysis initiation among patients aged >=65 years, but not in those aged <65 years. Fluid overload assessed by clinicians was the most common uremic symptom among all patients, but a winter peak was only detected in patients aged >=65 years. The body weight gain ratio showed a similar trend to fluid overload assessed by clinicians. Pulmonary edema was most pronounced in winter among patients aged >=65 years compared with other seasons. The incidences of infection were modestly increased in summer and winter, but not statistically significant. Cardiac complications were similar in all seasons. This study demonstrated the existence of seasonal variation in dialysis initiation, with a winter peak among patients aged >=65 years. The winter increment in dialysis initiation was mainly attributable to increased fluid overload. These findings suggest that elderly individuals should be monitored particularly closely during the winter. PMID- 28575125 TI - Emergence of local synchronization in neuronal networks with adaptive couplings. AB - Local synchronization, both prolonged and transient, of oscillatory neuronal behavior in cortical networks plays a fundamental role in many aspects of perception and cognition. Here we study networks of Hindmarsh-Rose neurons with a new type of adaptive coupling, and show that these networks naturally produce both permanent and transient synchronization of local clusters of neurons. These deterministic systems exhibit complex dynamics with 1/feta power spectra, which appears to be a consequence of a novel form of self-organized criticality. PMID- 28575126 TI - Gait dynamics to optimize fall risk assessment in geriatric patients admitted to an outpatient diagnostic clinic. AB - Fall prediction in geriatric patients remains challenging because the increased fall risk involves multiple, interrelated factors caused by natural aging and/or pathology. Therefore, we used a multi-factorial statistical approach to model categories of modifiable fall risk factors among geriatric patients to identify fallers with highest sensitivity and specificity with a focus on gait performance. Patients (n = 61, age = 79; 41% fallers) underwent extensive screening in three categories: (1) patient characteristics (e.g., handgrip strength, medication use, osteoporosis-related factors) (2) cognitive function (global cognition, memory, executive function), and (3) gait performance (speed related and dynamic outcomes assessed by tri-axial trunk accelerometry). Falls were registered prospectively (mean follow-up 8.6 months) and one year retrospectively. Principal Component Analysis (PCA) on 11 gait variables was performed to determine underlying gait properties. Three fall-classification models were then built using Partial Least Squares-Discriminant Analysis (PLS DA), with separate and combined analyses of the fall risk factors. PCA identified 'pace', 'variability', and 'coordination' as key properties of gait. The best PLS DA model produced a fall classification accuracy of AUC = 0.93. The specificity of the model using patient characteristics was 60% but reached 80% when cognitive and gait outcomes were added. The inclusion of cognition and gait dynamics in fall classification models reduced misclassification. We therefore recommend assessing geriatric patients' fall risk using a multi-factorial approach that incorporates patient characteristics, cognition, and gait dynamics. PMID- 28575127 TI - Thyroid peroxidase (TPO) expressed in thyroid and breast tissues shows similar antigenic properties. AB - BACKGROUND: Thyroid peroxidase (TPO) is essential for physiological function of the thyroid gland. The high prevalence of thyroid peroxidase antibodies (TPOAbs) in patients with breast cancer and their protective role had previously been demonstrated, indicating a link between breast cancer and thyroid autoimmunity. Recently, TPO was shown to be present in breast cancer tissue samples but its antigenicity has not been analyzed. METHODS: In this study, we investigated TPO expression levels in a series of fifty-six breast cancer samples paired with normal (peri-tumoral) tissue and its antigenic activity using a panel of well characterized murine anti-human TPOAbs. RESULTS: We have shown that TPO transcripts were present in both normal and cancer tissue samples, although the amounts in the latter were reduced. Additionally, we observed that TPO levels are lower in more advanced cancers. TPO protein expression was confirmed in all tissue samples, both normal and cancerous. We also found that the antigenicity of the immunodominant regions (IDRs) in breast TPO resembles that of thyroid TPO, which is crucial for effective interactions with human TPOAbs. CONCLUSIONS: Expression of TPO in breast cancer together with its antigenic activity may have beneficial effects in TPOAb-positive breast cancer patients. However, further studies are needed to confirm the beneficial role of TPOAbs and to better understand the underlying mechanism. PMID- 28575128 TI - Neurofibromatosis type 1 is not associated with subarachnoid haemorrhage. AB - BACKGROUND: The prevalence of intracranial aneurysms (IAs) has been proposed to be elevated in the patients with neurofibromatosis type 1 (NF1). Our aims were to determine the prevalence of NF1 in a large Finnish population based cohort of IA patients and, on the other hand, the occurrences of subarachnoid haemorrhage and unruptured intracranial aneurysms in a nationwide population-based cohort of NF1 patients and its matched ten-fold control cohort. METHODS: The Kuopio IA Database (www.kuopioneurosurgery.fi) includes all ruptured and unruptured IA cases admitted to the Kuopio University Hospital (KUH) from its defined Eastern Finnish catchment population since 1980. In this registry-based study, we cross-linked the Kuopio IA database with the Finnish national registry covering all hospital diagnoses. The NF1 diagnoses of the 4543 patients with either saccular of fusiform IA were identified from 1969 to 2015 and verified from patient records. Our second approach was to analyze the occurrence of aneurysmal subarachnoid haemorrhage (aSAH) and unruptured IAs in a nationwide population-based database of 1410 NF1 patients and its ten-fold matched control cohort (n = 14030) using national registry of hospital diagnoses between 1987 and 2014. RESULTS: One NF1 patient was identified among the 4543 IA patients. Three verified IA cases (one unruptured IA and two aSAH cases) were identified in the cohort of 1410 NF1 patients, with similar occurrences in the control cohort. CONCLUSIONS: We found no evidence in our population-based cohorts to support the conception that NF1 is associated with IAs. Our results indicate that the incidence of aSAH is not elevated in patients with NF1. Further studies are required to confirm that there is no association between NF1 and unruptured IAs. PMID- 28575129 TI - The involvement and possible mechanism of pro-inflammatory tumor necrosis factor alpha (TNF-alpha) in thoracic ossification of the ligamentum flavum. AB - Thoracic ossification of the ligamentum flavum (TOLF) is characterized by ectopic bone formation in the ligamentum flavum and is considered to be a leading cause of thoracic spinal canal stenosis and myelopathy. However, the underlying etiology is not well understood. An iTRAQ proteomics was used to reveal the involvement of inflammation factors in TOLF. TNF-alpha is a pro-inflammatory cytokine implicated in the pathogenesis of many human diseases. Protein profiling analysis showed that the protein level of TNF-alpha increased in the ossified ligamentum flavum of TOLF, which was confirmed by western blot. The effects of TNF-alpha on primary ligamentum flavum cells was examined. Cell proliferation assay demonstrated that primary cells from the ossified ligamentum flavum of TOLF grew faster than the control. Flow cytometry assay indicated that the proportions of cells in S phase of cell cycle of primary cells increased after TNF-alpha stimulation. To address the effect of TNF-alpha on gene expression, primary cells were derived from ligamentum flavum of TOLF patients. Culture cells were stimulated by TNF-alpha. RNA was isolated and analyzed by quantitative RT-PCR. G1/S-specific proteins cyclin D1 and c-Myc were upregulated after TNF-alpha stimulation. On the other hand, osteoblast differentiation related genes such as Bmp2 and Osterix (Osx) were upregulated in the presence of TNF-alpha. TNF-alpha activated Osx expression in a dose-dependent manner. Interestingly, a specific mitogen-activated protein kinase ERK inhibitor U0126, but not JNK kinase inhibitor SP600125, abrogated TNF-alpha activation of Osx expression. This suggests that TNF-alpha activates Osx expression through the mitogen-activated protein kinase ERK pathway. Taken together, we provide the evidence to support that TNF-alpha involves in TOLF probably through regulating cell proliferation via cyclin D1 and c-Myc, and promoting osteoblast differentiation via Osx. PMID- 28575130 TI - Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease. AB - Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin dependent defects. PMID- 28575131 TI - Bacterial co-expression of human Tau protein with protein kinase A and 14-3-3 for studies of 14-3-3/phospho-Tau interaction. AB - Abundant regulatory 14-3-3 proteins have an extremely wide interactome and coordinate multiple cellular events via interaction with specifically phosphorylated partner proteins. Notwithstanding the key role of 14-3 3/phosphotarget interactions in many physiological and pathological processes, they are dramatically underexplored. Here, we focused on the 14-3-3 interaction with human Tau protein associated with the development of several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Among many known phosphorylation sites within Tau, protein kinase A (PKA) phosphorylates several key residues of Tau and induces its tight interaction with 14-3-3 proteins. However, the stoichiometry and mechanism of 14-3-3 interaction with phosphorylated Tau (pTau) are not clearly elucidated. In this work, we describe a simple bacterial co-expression system aimed to facilitate biochemical and structural studies on the 14-3-3/pTau interaction. We show that dual co expression of human fetal Tau with PKA in Escherichia coli results in multisite Tau phosphorylation including also naturally occurring sites which were not previously considered in the context of 14-3-3 binding. Tau protein co-expressed with PKA displays tight functional interaction with 14-3-3 isoforms of a different type. Upon triple co-expression with 14-3-3 and PKA, Tau protein could be co-purified with 14-3-3 and demonstrates complex which is similar to that formed in vitro between individual 14-3-3 and pTau obtained from dual co expression. Although used in this study for the specific case of the previously known 14-3-3/pTau interaction, our co-expression system may be useful to study of other selected 14-3-3/phosphotarget interactions and for validations of 14-3-3 complexes identified by other methods. PMID- 28575132 TI - Abnormal differentiation of Sandhoff disease model mouse-derived multipotent stem cells toward a neural lineage. AB - In Sandhoff disease (SD), the activity of the lysosomal hydrolytic enzyme, beta hexosaminidase (Hex), is lost due to a Hexb gene defect, which results in the abnormal accumulation of the substrate, GM2 ganglioside (GM2), in neuronal cells, causing neuronal loss, microglial activation, and astrogliosis. We established induced pluripotent stem cells from the cells of SD mice (SD-iPSCs). In the present study, we investigated the occurrence of abnormal differentiation and development of a neural lineage in the asymptomatic phase of SD in vitro using SD mouse fetus-derived neural stem cells (NSCs) and SD-iPSCs. It was assumed that the number of SD mouse fetal brain-derived NSCs was reduced and differentiation was promoted, resulting in the inhibition of differentiation into neurons and enhancement of differentiation into astrocytes. The number of SD-iPSC-derived NSCs was also reduced, suggesting that the differentiation of NSCs was promoted, resulting in the inhibition of differentiation into neurons and enhancement of that into astrocytes. This abnormal differentiation of SD-iPSCs toward a neural lineage was reduced by the glucosylceramide synthase inhibitor, miglustat. Furthermore, abnormal differentiation toward a neural lineage was reduced in SD iPSCs with Hexb gene transfection. Therefore, differentiation ability along the time axis appears to be altered in SD mice in which the differentiation ability of NSCs is promoted and differentiation into neurons is completed earlier, while the timing of differentiation into astrocytes is accelerated. These results clarified that the abnormal differentiation of SD-iPSCs toward a neural lineage in vitro was shown to reflect the pathology of SD. PMID- 28575138 TI - Elevated Plasma Transforming Growth Factor beta1 Levels Predict the Development of Hypertension in Normotensives: The 14-Year Follow-Up Study. AB - BACKGROUND: Transforming growth factor beta1 (TGF-beta1) is a multifunctional cytokine. There is growing evidence that TGF-beta1 is involved in the pathogenesis of hypertension and the development of target organ damage in hypertensives. Although several studies have shown that TGF-beta1 induced vascular hypertrophy and remodelling in various vascular diseases, there are no longitudinal data on hypertension in the epidemiological studies. The present study tested the hypothesis whether elevated TGF-beta1 levels can predict the development of hypertension. METHODS: In 2002-2004, 528 subjects received health examinations in Uku town, southwestern Japan. We examined blood pressure (BP), body mass index, and blood test. Data on fasting plasma TGF-beta1 were obtained from 528 individuals. Of these, 149 normotensives (BP <140/90 mm Hg without antihypertensive medications) at baseline were followed-up for 14 years. RESULTS: The receiver-operating characteristic curve was used and the calculated cutoff value was 8.9 ng/ml. Of 149 normotensives at baseline, 59 subjects developed hypertension. Plasma TGF-beta1 levels were significantly associated with the development of hypertension after adjustment for confounding factors. To further examine the association between them, we performed logistic regression analysis. We divided the baseline plasma TGF-beta1 levels into 2 groups using a cutoff value. The significant high odds ratio [3.582 (95% confidence interval, 1.025 12.525)] for the development of hypertension was found in the highest group of TGF-beta1 level vs. the lowest group after adjustment for confounders. CONCLUSIONS: This is the first report demonstrating the causal relationship between them. Elevated plasma TGF-beta1 levels predicted the development of hypertension in normotensives in a population of community-dwelling Japanese. PMID- 28575139 TI - Ambulatory Blood Pressure Control in Children and Young Adults After Kidney Transplantation. AB - BACKGROUND: Ambulatory blood pressure (BP) monitoring (ABPM) is the preferred method to characterize BP status, and its use in kidney transplant recipients is increasing. Data on longitudinal ambulatory BP (ABP) trends in pediatric and young adult kidney transplant recipients are limited. METHODS: Retrospective review of a large cohort of children and young adults following kidney transplantation and evaluation of their ABP status over time and its associations with any patient and clinical characteristics. RESULTS: Two hundred and two patients had baseline ABPM available for analysis, and 123 of them had a follow up (median time 2.3 years) ABPM. At the time of follow up, more patients were treated for hypertension (80% vs. 72%, P = 0.02), and less patients had ambulatory hypertension (36% vs. 54%, P = 0.005), uncontrolled or untreated, compared with baseline, with 45% of all patients classified as having controlled hypertension (compared to 26% at baseline, P = 0.002). Prevalence of ambulatory hypertension decreased only in patients who were less than 18 years old at baseline. High baseline mean 24-hour systolic BP was independently associated with persistent hypertension. CONCLUSIONS: In young kidney transplant recipients followed by ABPM, the prevalence of ambulatory hypertension decreases over time, mainly due to the increased number of patients with controlled hypertension. PMID- 28575140 TI - Optimizing drug development in oncology by clinical trial simulation: Why and how? AB - In therapeutic research, the safety and efficacy of pharmaceutical products are necessarily tested on humans via clinical trials after an extensive and expensive preclinical development period. Methodologies such as computer modeling and clinical trial simulation (CTS) might represent a valuable option to reduce animal and human assays. The relevance of these methods is well recognized in pharmacokinetics and pharmacodynamics from the preclinical phase to postmarketing. However, they are barely used and are poorly regarded for drug approval, despite Food and Drug Administration and European Medicines Agency recommendations. The generalization of CTS could be greatly facilitated by the availability of software for modeling biological systems, by clinical trial studies and hospital databases. Data sharing and data merging raise legal, policy and technical issues that will need to be addressed. Development of future molecules will have to use CTS for faster development and thus enable better patient management. Drug activity modeling coupled with disease modeling, optimal use of medical data and increased computing speed should allow this leap forward. The realization of CTS requires not only bioinformatics tools to allow interconnection and global integration of all clinical data but also a universal legal framework to protect the privacy of every patient. While recognizing that CTS can never replace 'real-life' trials, they should be implemented in future drug development schemes to provide quantitative support for decision-making. This in silico medicine opens the way to the P4 medicine: predictive, preventive, personalized and participatory. PMID- 28575141 TI - Objectively measured physical activity and kidney function in older men; a cross sectional population-based study. AB - Background: kidney function declines in older adults and physical activity levels are low. We investigated whether higher levels of physical activity and lower levels of sedentary behaviour were associated with lower odds of low kidney function in older men. Methods: cross-sectional study of 1,352 men from the British Regional Heart Study, mean (standard deviation) age 78.5 (4.6) year. Physical activity and sedentary behaviour were measured using Actigraph GT3X accelerometers. Kidney function was measured by estimated Glomerular filtration rate (eGFR) using the chronic kidney disease-EPI creatinine-cystatin equation. Associations between physical (in)activity and kidney function were investigated using regression models. Results: higher levels of physical activity and lower levels of sedentary behaviour were associated with reduced odds ratios (ORs) for lower eGFR (<45 versus >=45 ml/min per 1.73 m2) after adjustment for covariates. Each additional 1,000 steps, 30 min of light physical activity and 10 min of moderate/vigorous physical activity per day were associated with a lower odds (95% confidence interval (CI)) of a low eGFR; OR 0.81 (0.73, 0.91), OR 0.87 (0.78, 0.97) and OR 0.84 (0.76, 0.92), respectively. Each additional 30 min of sedentary behaviour per day was associated with a higher odds of a low eGFR (1.16 95% CI 1.06, 1.27). Associations between moderate/vigorous physical activity and lower kidney function persisted after adjustment for light physical activity or sedentary behaviour. Conclusion: physical activity is associated with kidney function in older men and could be of public health importance in this group who are at increased risk of poor kidney function and low physical activity. More evidence is needed on whether the association is causal. PMID- 28575142 TI - Flow Cytometric Patterns of CD200 and CD1d Expression Distinguish CD10-Negative, CD5-Negative Mature B-Cell Lymphoproliferative Disorders. AB - Objectives: The importance of distinguishing mature B-cell lymphoproliferative disorders (B-LPDs) is highlighted by the distinct treatments used for and varying prognoses seen in association with these different diseases. Immunophenotyping allows for accurate and efficient differentiation of many B-LPDs. Recently, we showed that CD200 is highly expressed in hairy cell leukemia (HCL) but not in marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), or hairy cell leukemia-variant (HCL-v). Here, we assessed the usefulness of a flow cytometric panel combining CD200 and CD1d with CD25, CD103, and CD11c to distinguish CD10-, CD5- B-LPDs. Methods: We analyzed the expression of CD200 and CD1d by flow cytometric analysis in 79 cases of CD10-, CD5- mature B-LPDs. Results: Distinct patterns of CD200 and CD1d expression were seen in the examined B-LPDs. HCL showed bright positivity for CD200 along with positive staining for CD1d, whereas HCL-v showed low levels of expression for both markers. LPL demonstrated positive staining for CD200 in combination with dim to negative staining for CD1d. In contrast, MZL was commonly positive for CD1d and negative for CD200. Conclusions: Flow cytometric analysis of CD200 and CD1d, along with CD25, CD103, and CD11c, can aid in the diagnosis of CD10-, CD5- mature B-LPDs. PMID- 28575143 TI - Seeing the wood for the trees: a forest of methods for optimization and omic network integration in metabolic modelling. AB - Metabolic modelling has entered a mature phase with dozens of methods and software implementations available to the practitioner and the theoretician. It is not easy for a modeller to be able to see the wood (or the forest) for the trees. Driven by this analogy, we here present a 'forest' of principal methods used for constraint-based modelling in systems biology. This provides a tree based view of methods available to prospective modellers, also available in interactive version at http://modellingmetabolism.net, where it will be kept updated with new methods after the publication of the present manuscript. Our updated classification of existing methods and tools highlights the most promising in the different branches, with the aim to develop a vision of how existing methods could hybridize and become more complex. We then provide the first hands-on tutorial for multi-objective optimization of metabolic models in R. We finally discuss the implementation of multi-view machine learning approaches in poly-omic integration. Throughout this work, we demonstrate the optimization of trade-offs between multiple metabolic objectives, with a focus on omic data integration through machine learning. We anticipate that the combination of a survey, a perspective on multi-view machine learning and a step by-step R tutorial should be of interest for both the beginner and the advanced user. PMID- 28575144 TI - ceRNAs in plants: computational approaches and associated challenges for target mimic research. AB - The competing endogenous RNA hypothesis has gained increasing attention as a potential global regulatory mechanism of microRNAs (miRNAs), and as a powerful tool to predict the function of many noncoding RNAs, including miRNAs themselves. Most studies have been focused on animals, although target mimic (TMs) discovery as well as important computational and experimental advances has been developed in plants over the past decade. Thus, our contribution summarizes recent progresses in computational approaches for research of miRNA:TM interactions. We divided this article in three main contributions. First, a general overview of research on TMs in plants is presented with practical descriptions of the available literature, tools, data, databases and computational reports. Second, we describe a common protocol for the computational and experimental analyses of TM. Third, we provide a bioinformatics approach for the prediction of TM motifs potentially cross-targeting both members within the same or from different miRNA families, based on the identification of consensus miRNA-binding sites from known TMs across sequenced genomes, transcriptomes and known miRNAs. This computational approach is promising because, in contrast to animals, miRNA families in plants are large with identical or similar members, several of which are also highly conserved. From the three consensus TM motifs found with our approach: MIM166, MIM171 and MIM159/319, the last one has found strong support on the recent experimental work by Reichel and Millar [Specificity of plant microRNA TMs: cross targeting of mir159 and mir319. J Plant Physiol 2015;180:45-8]. Finally, we stress the discussion on the major computational and associated experimental challenges that have to be faced in future ceRNA studies. PMID- 28575145 TI - Is Transforming Growth Factor beta1 a Cause of Hypertension? PMID- 28575146 TI - A comprehensive evaluation of popular proteomics software workflows for label free proteome quantification and imputation. AB - Label-free mass spectrometry (MS) has developed into an important tool applied in various fields of biological and life sciences. Several software exist to process the raw MS data into quantified protein abundances, including open source and commercial solutions. Each software includes a set of unique algorithms for different tasks of the MS data processing workflow. While many of these algorithms have been compared separately, a thorough and systematic evaluation of their overall performance is missing. Moreover, systematic information is lacking about the amount of missing values produced by the different proteomics software and the capabilities of different data imputation methods to account for them.In this study, we evaluated the performance of five popular quantitative label-free proteomics software workflows using four different spike-in data sets. Our extensive testing included the number of proteins quantified and the number of missing values produced by each workflow, the accuracy of detecting differential expression and logarithmic fold change and the effect of different imputation and filtering methods on the differential expression results. We found that the Progenesis software performed consistently well in the differential expression analysis and produced few missing values. The missing values produced by the other software decreased their performance, but this difference could be mitigated using proper data filtering or imputation methods. Among the imputation methods, we found that the local least squares (lls) regression imputation consistently increased the performance of the software in the differential expression analysis, and a combination of both data filtering and local least squares imputation increased performance the most in the tested data sets. PMID- 28575148 TI - Corrigendum. PMID- 28575147 TI - Tissue-specific network-based genome wide study of amygdala imaging phenotypes to identify functional interaction modules. AB - Motivation: Network-based genome-wide association studies (GWAS) aim to identify functional modules from biological networks that are enriched by top GWAS findings. Although gene functions are relevant to tissue context, most existing methods analyze tissue-free networks without reflecting phenotypic specificity. Results: We propose a novel module identification framework for imaging genetic studies using the tissue-specific functional interaction network. Our method includes three steps: (i) re-prioritize imaging GWAS findings by applying machine learning methods to incorporate network topological information and enhance the connectivity among top genes; (ii) detect densely connected modules based on interactions among top re-prioritized genes; and (iii) identify phenotype relevant modules enriched by top GWAS findings. We demonstrate our method on the GWAS of [18F]FDG-PET measures in the amygdala region using the imaging genetic data from the Alzheimer's Disease Neuroimaging Initiative, and map the GWAS results onto the amygdala-specific functional interaction network. The proposed network-based GWAS method can effectively detect densely connected modules enriched by top GWAS findings. Tissue-specific functional network can provide precise context to help explore the collective effects of genes with biologically meaningful interactions specific to the studied phenotype. Availability and implementation: The R code and sample data are freely available at http://www.iu.edu/shenlab/tools/gwasmodule/. Contact: shenli@iu.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28575150 TI - Melatonin as a promising agent to treat ovarian cancer: molecular mechanisms. AB - Ovarian cancer (OC) has the highest mortality rate of all gynecological cancers, and most patients develop chemoresistance after first-line treatments. Despite recent advances, the 5-year relative survival is ~45% for all OC subtypes, and invasive epithelial OC has only a 17% survival rate when diagnosed at a late stage. Identification of new efficacious molecules or biomarkers represents important opportunities in the treatment of OC. The pharmacological and physiological properties of melatonin indicate this agent could be useful against OC progression and metastasis. In normal cells, melatonin has potent antioxidant and anti-apoptotic actions. Conversely, melatonin has pro-oxidant as well as anti proliferative, anti-angiogenic and immunomodulatory properties in many cancer types including hormone-dependent cancers. Although melatonin receptors have been identified in OC cells, the exact mechanism by which melatonin induces anticancer activities remains incompletely understood. Clinical studies have reported negative correlation between aggressiveness of OC and serum levels of melatonin, reinforcing the idea that melatonin may be a critical factor determining OC development. In vitro and in vivo studies suggest melatonin differentially regulates multiple signaling pathways in OC cells. This focused review explores the potential mechanisms of action of melatonin on cultured OC cells and in experimental models of OC in an attempt to clarify how melatonin modulates the signaling pathways involved in cancer cell apoptosis, survival, inflammation, proliferation and metabolic processes. Based on the evidence presented, we feel that melatonin, as an agent that controls cellular signals associated with malignancy, may be beneficial in combination with other therapeutics for OC treatment. PMID- 28575149 TI - Cerebrovascular resistance: effects on cognitive decline, cortical atrophy, and progression to dementia. AB - See Markus (doi:10.1093/awx161) for a scientific commentary on this article.Evidence for vascular contributions to Alzheimer's disease has been increasingly identified, with increased blood pressure and decreased cerebral blood flow both linked to in vivo biomarkers and clinical progression of Alzheimer's disease. We therefore hypothesized that an elevated ratio of blood pressure to cerebral blood flow, indicative of cerebrovascular resistance, would exhibit earlier and more widespread associations with Alzheimer's disease than cerebral blood flow alone. Further, we predicted that increased cerebrovascular resistance and amyloid retention would synergistically influence cognitive performance trajectories, independent of neuronal metabolism. Lastly, we anticipated associations between cerebrovascular resistance and later brain atrophy, prior to amyloid accumulation. To evaluate these hypotheses, we investigated associations between cerebrovascular resistance and amyloid retention, cognitive decline, and brain atrophy, controlling for neuronal metabolism. North American older adults (n = 232) underwent arterial spin labelling magnetic resonance imaging to measure regional cerebral blood flow in brain regions susceptible to ageing and Alzheimer's disease. An estimated cerebrovascular resistance index was then calculated as the ratio of mean arterial pressure to regional cerebral blood flow. Positron emission tomography with 18F-florbetapir and fludeoxyglucose was used to quantify amyloid retention and neuronal metabolism, respectively. Cognitive performance was evaluated via annual assessments of global cognition, memory, and executive function. Results indicated diminished inferior parietal and temporal cerebral blood flow for patients with Alzheimer's disease (n = 33) relative to both non-demented groups, but no cerebral blood flow differences between non-demented amyloid-positive (n = 87) and amyloid-negative (n = 112) cases. In contrast, the cerebrovascular resistance index was significantly elevated in amyloid-positive versus amyloid negative cases, with additional elevation in patients with Alzheimer's disease. Furthermore, cerebrovascular resistance index group differences were of greater statistical effect size and encompassed a greater number of brain regions than those for cerebral blood flow alone. Cognitive decline over 2-year follow-up was accelerated by elevated baseline cerebrovascular resistance index, particularly for amyloid-positive individuals. Increased baseline cerebrovascular resistance index also predicted greater progression to dementia, beyond that attributable to amyloid-positivity. Finally, increased cerebrovascular resistance index predicted greater regional atrophy among non-demented older adults who were amyloid negative. Findings suggest that increased cerebrovascular resistance may represent a previously unrecognized contributor to Alzheimer's disease that is independent of neuronal hypometabolism, predates changes in brain perfusion, exacerbates and works synergistically with amyloidosis to produce cognitive decline, and drives amyloid-independent brain atrophy during the earliest stage of disease. PMID- 28575151 TI - Brain inflammation accompanies amyloid in the majority of mild cognitive impairment cases due to Alzheimer's disease. AB - See Kreisl (doi:10.1093/awx151) for a scientific commentary on this article.Subjects with mild cognitive impairment associated with cortical amyloid beta have a greatly increased risk of progressing to Alzheimer's disease. We hypothesized that neuroinflammation occurs early in Alzheimer's disease and would be present in most amyloid-positive mild cognitive impairment cases. 11C Pittsburgh compound B and 11C-(R)-PK11195 positron emission tomography was used to determine the amyloid load and detect the extent of neuroinflammation (microglial activation) in 42 mild cognitive impairment cases. Twelve age-matched healthy control subjects had 11C-Pittsburgh compound B and 10 healthy control subjects had 11C-(R)-PK11195 positron emission tomography for comparison. Amyloid positivity was defined as 11C-Pittsburgh compound B target-to-cerebellar ratio above 1.5 within a composite cortical volume of interest. Supervised cluster analysis was used to generate parametric maps of 11C-(R)-PK11195 binding potential. Levels of 11C-(R)-PK11195 binding potential were measured in a selection of cortical volumes of interest and at a voxel level. Twenty-six (62%) of 42 mild cognitive impairment cases showed a raised cortical amyloid load compared to healthy controls. Twenty-two (85%) of the 26 amyloid-positive mild cognitive impairment cases showed clusters of increased cortical microglial activation accompanying the amyloid. There was a positive correlation between levels of amyloid load and 11C-(R)-PK11195 binding potentials at a voxel level within subregions of frontal, parietal and temporal cortices. 11C-(R)-PK11195 positron emission tomography reveals increased inflammation in a majority of amyloid positive mild cognitive impairment cases, its cortical distribution overlapping that of amyloid deposition. PMID- 28575152 TI - Fisetin Reduces the Impact of Aging on Behavior and Physiology in the Rapidly Aging SAMP8 Mouse. AB - Alzheimer's disease (AD) is rarely addressed in the context of aging even though there is an overlap in pathology. We previously used a phenotypic screening platform based on old age-associated brain toxicities to identify the flavonol fisetin as a potential therapeutic for AD and other age-related neurodegenerative diseases. Based on earlier results with fisetin in transgenic AD mice, we hypothesized that fisetin would be effective against brain aging and cognitive dysfunction in rapidly aging senescence-accelerated prone 8 (SAMP8) mice, a model for sporadic AD and dementia. An integrative approach was used to correlate protein expression and metabolite levels in the brain with cognition. It was found that fisetin reduced cognitive deficits in old SAMP8 mice while restoring multiple markers associated with impaired synaptic function, stress, and inflammation. These results provide further evidence for the potential benefits of fisetin for the treatment of age-related neurodegenerative diseases. PMID- 28575155 TI - Dynamic-BM: multispecies Dynamic BodyMap database from temporal RNA-seq data. AB - Biological processes, especially developmental processes, are often dynamic. Previous BodyMap projects for human and mouse have provided researchers with portals to tissue-specific gene expression, but these efforts have not included dynamic gene expression patterns. Over the past few years, substantial progress in our understanding of the molecular mechanisms of protein-coding and long noncoding RNA (lncRNA) genes in development processes has been achieved through numerous time series RNA sequencing (RNA-seq) studies. However, none of the existing databases focuses on these time series data, thus rendering the exploration of dynamic gene expression patterns inconvenient. Here, we present Dynamic BodyMap (Dynamic-BM), a database for temporal gene expression profiles, obtained from 2203 time series of RNA-seq samples, covering >25 tissues from five species. Dynamic-BM has a user-friendly Web interface designed for browsing and searching the dynamic expression pattern of genes from different sources. It is an open resource for efficient data exploration, providing dynamic expression profiles of both protein-coding genes and lncRNAs to facilitate the generation of new hypotheses in developmental biology research. Additionally, Dynamic-BM includes a literature-based knowledgebase for lncRNAs associated with tissue development and a list of manually selected lncRNA candidates that may be involved in tissue development. Dynamic-BM is available at http://bioinfo.ibp.ac.cn/Dynamic-BM. PMID- 28575153 TI - Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. AB - Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease-preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy. Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers. This evidence was validated in the hippocampus of humans who died following status epilepticus. Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms. These antioxidant drugs are already used in humans for other therapeutic indications. This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone. The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals. Treatment also decreased hippocampal neuron loss and rescued cognitive deficits. Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of disulfide high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented disulfide HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes. This intervention may be considered for patients exposed to potential epileptogenic insults. PMID- 28575154 TI - Effects of propylene glycol or elevated luteinizing hormone during follicle development on ovulation, fertilization, and early embryo development. AB - Seventeen nonlactating Holstein cows were superovulated in a Latin-square designed experiment to determine the effects of increased propylene glycol (PROP) and luteinizing hormone (LH) during antral follicle development on ovarian function, fertilization, and early embryo quality. PROP was orally drenched every 4 h for 7 days to induce hyperinsulinemia and associated metabolic changes. LH concentrations were altered by increasing LH (3-fold) during last 2 days of superovulation. Treatment groups were as follows: (1) control-oral drenching with water plus low-LH preparation; (2) high LH(HLH)-water plus HLH preparation; (3) PROP-drenching with PROP plus low LH; (4) PROP/HLH-PROP plus HLH. PROP increased glucose (P < 0.05) and insulin (P < 0.02) concentrations at all time points analyzed. Neither PROP nor LH affected numbers of follicles > 9 mm at time of gonadotropin-releasing hormone-induced LH surge, although percentage of these follicles that ovulated was decreased by both PROP (P = 0.002) and LH (P = 0.048). In addition, PROP tended (P = 0.056) to decrease total number of ovulations. PROP reduced (P = 0.028) fertilization rate, while LH tended (P = 0.092) to increase fertilization rate. There was no effect of either PROP or LH on any measure of embryo quality including percentage of embryos that were degenerate, quality 1, or quality 1 and 2 of total structures collected or fertilized structures. These results indicate that acute elevation in insulin during the preovulatory follicular wave can decrease percentage of large follicles that ovulate, particularly when combined with increased LH, and reduce fertilization of ovulated oocytes. PMID- 28575158 TI - A novel telomerase-interacting OTU protein of Eimeria tenella and its telomerase regulating activity. PMID- 28575156 TI - Consequences of endogenous and exogenous WNT signaling for development of the preimplantation bovine embryo. AB - The specific role of WNT signaling during preimplantation development remains unclear. Here, we evaluated consequences of activation and inhibition of beta catenin (CTNNB1)-dependent and -independent WNT signaling in the bovine preimplantation embryo. Activation of CTNNB1-mediated WNT signaling by the agonist 2-amino-4-(3,4-(methylenedioxy)benzylamino)-6-(3-methoxyphenyl)pyrimidine (AMBMP) and a glycogen synthase kinase 3 inhibitor reduced development to the blastocyst stage. Moreover, the antagonist of WNT signaling, dickkopf-related protein 1 (DKK1), alleviated the negative effect of AMBMP on development via reduction of CTNNB1. Based on labeling for phospho c-Jun N-terminal kinase, there was no evidence that DKK1 activated the planar cell polarity (PCP) pathway. Inhibition of secretion of endogenous WNTs did not affect development but increased number of cells in the inner cell mass (ICM). In contrast, DKK1 did not affect number of ICM or trophectoderm (TE) cells, suggesting that embryo-derived WNTs regulate ICM proliferation through a mechanism independent of CTNNB1. In addition, DKK1 did not affect the number of cells positive for the transcription factor yes-associated protein 1 (YAP1) involved in TE formation. In fact, DKK1 decreased YAP1. In contrast, exposure of embryos to WNT family member 7A (WNT7A) improved blastocyst development, inhibited the PCP pathway, and did not affect amounts of CTNNB1. Results indicate that embryo-derived WNTs are dispensable for blastocyst formation but participate in regulation of ICM proliferation, likely through a mechanism independent of CTNNB1. The response to AMBMP and WNT7A leads to the hypothesis that maternally derived WNTs can play a positive or negative role in regulation of preimplantation development. PMID- 28575159 TI - Performance of Calculated and Directly Measured Low-Density Lipoprotein Cholesterol in a Pediatric Population. AB - Objectives: An assessment of methods for the accurate measurement of low-density lipoprotein cholesterol (LDL-C) at decreased concentrations has not yet been carried out. We evaluated the performance of the Friedewald equation, a direct enzymatic assay, and a novel equation for determining LDL-C levels in a pediatric population with elevated triglycerides and reduced LDL-C levels. Methods: LDL-C concentrations of 127 pediatric patients were determined by the Friedewald equation, a direct enzymatic assay, and a novel equation. The bias of each approach was assessed at selected LDL-C cutoffs and after stratifying samples by triglyceride content. The concordance of each approach, relative to the reference method, was determined at LDL-C cut-points of less than 70, 70 to 99, and 100 to 129 mg/dL. Results: The Friedewald equation substantially underestimated pediatric LDL-C concentrations below 100 mg/dL in the presence of elevated triglycerides. The Ortho Clinical Diagnostics (Raritan, NJ) direct LDL assay was positively biased at low LDL-C levels. The novel equation most effectively reduced the bias of the Friedewald equation at all LDL-C concentrations and increased the concordance of sample classification to the reference method. Conclusions: The novel equation should be used for accurate measurement of pediatric LDL-C when the concentration is below 100 mg/dL in the presence of elevated triglycerides (150-399 mg/dL). PMID- 28575157 TI - Sex Differences in Aging: Genomic Instability. AB - Aging is characterized by decreasing physiological integration, reduced function, loss of resilience, and increased risk of death. Paradoxically, although women live longer, they suffer greater morbidity particularly late in life. These sex differences in human lifespan and healthspan are consistently observed in all countries and during every era for which reliable data exist. While these differences are ubiquitous in humans, evidence of sex differences in longevity and health for other species is more equivocal. Among fruit flies, nematodes, and mice, sex differences in lifespan vary depending on strain and treatment. In this review, we focus on sex differences in age-related alterations in DNA damage and mutation rates, telomere attrition, epigenetics, and nuclear architecture. We find that robust sex differences exist, eg, the higher incidence of DNA damage in men compared to women, but sex differences are not often conserved between species. For most mechanisms reviewed here, there are insufficient data to make a clear determination regarding the impact of sex, largely because sex differences have not been analyzed. Overall, our findings reveal an urgent need for well designed studies that explicitly examine sex differences in molecular drivers of aging. PMID- 28575161 TI - GateKeeper: a new hardware architecture for accelerating pre-alignment in DNA short read mapping. AB - Motivation: High throughput DNA sequencing (HTS) technologies generate an excessive number of small DNA segments -called short reads- that cause significant computational burden. To analyze the entire genome, each of the billions of short reads must be mapped to a reference genome based on the similarity between a read and 'candidate' locations in that reference genome. The similarity measurement, called alignment, formulated as an approximate string matching problem, is the computational bottleneck because: (i) it is implemented using quadratic-time dynamic programming algorithms and (ii) the majority of candidate locations in the reference genome do not align with a given read due to high dissimilarity. Calculating the alignment of such incorrect candidate locations consumes an overwhelming majority of a modern read mapper's execution time. Therefore, it is crucial to develop a fast and effective filter that can detect incorrect candidate locations and eliminate them before invoking computationally costly alignment algorithms. Results: We propose GateKeeper, a new hardware accelerator that functions as a pre-alignment step that quickly filters out most incorrect candidate locations. GateKeeper is the first design to accelerate pre-alignment using Field-Programmable Gate Arrays (FPGAs), which can perform pre-alignment much faster than software. When implemented on a single FPGA chip, GateKeeper maintains high accuracy (on average >96%) while providing, on average, 90-fold and 130-fold speedup over the state-of-the-art software pre alignment techniques, Adjacency Filter and Shifted Hamming Distance (SHD), respectively. The addition of GateKeeper as a pre-alignment step can reduce the verification time of the mrFAST mapper by a factor of 10. Availability and implementation: https://github.com/BilkentCompGen/GateKeeper. Contact: mohammedalser@bilkent.edu.tr or onur.mutlu@inf.ethz.ch or calkan@cs.bilkent.edu.tr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28575160 TI - Dynamic changes in methylome and transcriptome patterns in response to methyltransferase inhibitor 5-azacytidine treatment in citrus. AB - DNA methylation is known to play an important role in various developmental processes in plants. However, there is a general lack of understanding about the possible functions of DNA methylation in fruit trees. Using callus as a model, methylome, transcriptome and metabolite changes were assessed after treatment with the DNA methyltransferase inhibitor 5-azacytidine (5azaC). Genome-wide methylome analysis revealed the demethylation of a diverse of genes, including many genes encoding transcription factors (TFs), genes involved in biological processes, and the up-regulation of a wide range of transposable elements (TEs). Combined with the RNA-seq data, we observed no obvious genome-wide correlation between the changes in methylation status and expression levels. Furthermore, 5azaC treatment induced carotenoid degradation along with strong activation of carotenoid cleavage dioxygenases 1 (CpCCD1). Functional complementation analysis in bacterial system showed that CpCCD1 exhibited strong catalytic activities toward zeaxanthin, beta-carotene and lycopene. In summary, 5azaC treatments induced carotenoid degradation by CpCCD1 activation and led to a genome-wide demethylation effect. PMID- 28575162 TI - Mycoplasma hominis Infections Transmitted Through Amniotic Tissue Product. AB - Background: Mycoplasma hominis is a commensal genitourinary tract organism that can cause infections outside the genitourinary tract. We investigated a cluster of M. hominis surgical site infections in patients who underwent spine surgery, all associated with amniotic tissue linked to a common donor. Methods: Laboratory tests of tissue product from the donor, including culture, quantitative real-time polymerase chain reaction (qPCR), and whole-genome sequencing were performed. Use of this amniotic tissue product was reviewed. A multistate investigation to identify additional cases and locate any unused products was conducted. Results: Twenty-seven tissue product vials from a donor were distributed to facilities in 7 states; at least 20 vials from this donor were used in 14 patients. Of these, 4 of 14 (29%) developed surgical site infections, including 2 M. hominis infections. Mycoplasma hominis was detected by culture and qPCR in 2 unused vials from the donor. Sequencing indicated >99% similarity between patient and unopened vial isolates. For 5 of 27 (19%) vials, the final disposition could not be confirmed. Conclusions: Mycoplasma hominis was transmitted through amniotic tissue from a single donor to 2 recipients. Current routine donor screening and product testing does not detect all potential pathogens. Clinicians should be aware that M. hominis can cause surgical site infections, and may not be detected by routine clinical cultures. The lack of a standardized system to track tissue products in healthcare facilities limits the ability of public health agencies to respond to outbreaks and investigate other adverse events associated with these products. PMID- 28575163 TI - Errata. PMID- 28575164 TI - Genetic Mouse Models with Intestinal-Specific Tight Junction Deletion Resemble an Ulcerative Colitis Phenotype. AB - Background and Aims: A key pathogenetic feature of ulcerative colitis [UC] is an intrinsic low mucus phosphatidylcholine[PC] content. Recently, a paracellular transport for PC across tight junctions[TJs] was described, suggesting TJ disturbance as a cause of diminished luminal PC transport. Therefore, we aimed to generate mutant mice with TJ deletion to evaluate whether a UC phenotype developed. Methods: CL57BL/6 control wild-type mice were compared to mutant mice with tamoxifen-induced villin-Cre-dependent intestinal deletion of kindlin 1 and 2. Results: Electron microscopy of mucosal biopsies obtained from both mutants before overt inflammation following only 2 days of tamoxifen exposure revealed a defective TJ morphology with extended paracellular space and, by light microscopy, expanded mucosal crypt lumina. PC secretion into mucus was reduced by >65% and the mucus PC content dropped by >50%, causing a >50 % decrease of mucus hydrophobicity in both mutants. Consequently, the microbiota was able to penetrate the submucosa. After 3 days of tamoxifen exposure, intestinal inflammation was present in both mutants, with loose bloody stools as well as macroscopic and histological features of colitis. Oral PC supplementation was able to suppress inflammation. By analogy, colonic biopsies obtained from patients with UC in remission also showed a defective epithelium with widened intercellular clefts, and enlarged crypt luminal diameters with functionally impaired luminal PC secretion. Conclusions: Genetic mouse models with intestinal deletion of kindlin 1 and 2 resulted in TJ deletion and revealed pathophysiological features of impaired PC secretion to the mucus leading to mucosal inflammation compatible with human UC. PMID- 28575165 TI - Genome-wide profiling of Sus scrofa circular RNAs across nine organs and three developmental stages. AB - The spatio-temporal expression patterns of Circular RNA (circRNA) across organs and developmental stages are critical for its function and evolution analysis. However, they remain largely unclear in mammals. Here, we comprehensively analysed circRNAs in nine organs and three skeletal muscles of Guizhou miniature pig (S. scrofa), a widely used biomedical model animal. We identified 5,934 circRNAs and analysed their molecular properties, sequence conservation, spatio temporal expression pattern, potential function, and interaction with miRNAs. S. scrofa circRNAs show modest sequence conservation with human and mouse circRNAs, are flanked by long introns, exhibit low abundance, and are expressed dynamically in a spatio-temporally specific manner. S. scrofa circRNAs show the greatest abundance and complexity in the testis. Notably, 31% of circRNAs harbour well conserved canonical miRNA seed matches, suggesting that some circRNAs act as miRNAs sponges. We identified 149 circRNAs potentially associated with muscle growth and found that their host genes were significantly involved in muscle development, contraction, chromatin modification, cation homeostasis, and ATP hydrolysis-coupled proton transport; moreover, this set of genes was markedly enriched in genes involved in tight junctions and the calcium signalling pathway. Finally, we constructed the first public S. scrofa circRNA database, allowing researchers to query comprehensive annotation, expression, and regulatory networks of circRNAs. PMID- 28575166 TI - LTA4H regulates cell cycle and skin carcinogenesis. AB - Leukotriene A4 hydrolase (LTA4H), a bifunctional zinc metallo-enzyme, is reportedly overexpressed in several human cancers. Our group has focused on LTA4H as a potential target for cancer prevention and/or therapy. In the present study, we report that LTA4H is a key regulator of cell cycle at the G0/G1 phase acting by negatively regulating p27 expression in skin cancer. We found that LTA4H is overexpressed in human skin cancer tissue. Knocking out LTA4H significantly reduced skin cancer development in the 7,12-dimethylbenz(a)anthracene (DMBA) initiated/12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted two-stage skin cancer mouse model. LTA4H depletion dramatically decreased anchorage-dependent and -independent skin cancer cell growth by inducing cell cycle arrest at the G0/G1 phase. Moreover, our findings showed that depletion of LTA4H enhanced p27 protein stability, which was associated with decreased phosphorylation of CDK2 at Thr160 and inhibition of the CDK2/cyclin E complex, resulting in down-regulated p27 ubiquitination. These findings indicate that LTA4H is critical for skin carcinogenesis and is an important mediator of cell cycle and the data begin to clarify the mechanisms of LTA4H's role in cancer development. PMID- 28575167 TI - Evaluation of Real-World Implementation of Partitioning and Negative Pressurization for Preventing the Dispersion of Dust From Renovation Sites. AB - Objectives: The aim of this study was to assess the implementation of partitioning and the negative pressure method in limiting the dispersion of dust to areas adjacent to renovation sites. Methods: The pressure difference between the worksites and adjacent areas and PM10 concentrations in the both zones were measured in 12 renovation sites, and the factors affecting the prevention of dispersion of dust were assessed. Results: Poor implementation of partitioning and negative pressurization found in half of the renovation sites lead difficulties in achieving a proper negative pressure, causing dispersion of dust into adjacent areas. Main problems related to flimsy partitioning walls and poor air tightness of the enclosure. Dust concentrations in adjacent areas were substantially lower when natural ventilation in the renovation site was rejected and partitioning walls and their junctions to existing structures were sealed. In case of leaky enclosures, despite the high air exchange rates, a definite negative pressure could not be maintained. Instead, negative pressure minimum of 5 Pa was found to be sufficient for limiting the dispersion of dust from renovation sites. Conclusions: Improvement on implementation of dust controls is required through revising the guidance documents, education, and efficient supervision. This study revealed that the current Finnish practice to implement the negative pressurization based on the air exchange rate achieved with the portable exhaust fans alone is not reasonable to assure adequate dust containment. Continuous negative pressure minimum of -5 Pa is suggested, and it should be monitored with alarm devices throughout the renovation processes. PMID- 28575168 TI - Naked Surgeons? The Debate About What to Wear in the Operating Room. AB - There has been recent controversy regarding recommendations and regulations concerning operating room attire. We performed a nonsystematic literature search regarding operating room attire and surgical site infection (SSI) risk. Much of the literature relies on air sampling and culture of operating room equipment but does not present evidence regarding effect on SSI risk. There is no evidence regarding SSI risk related to operating room attire except for sterile gowns and the use of gloves. Naked surgeons shed fewer bacteria into the operating room environment than ones wearing scrub suits. PMID- 28575170 TI - Errata. PMID- 28575169 TI - MD-TASK: a software suite for analyzing molecular dynamics trajectories. AB - Summary: Molecular dynamics (MD) determines the physical motions of atoms of a biological macromolecule in a cell-like environment and is an important method in structural bioinformatics. Traditionally, measurements such as root mean square deviation, root mean square fluctuation, radius of gyration, and various energy measures have been used to analyze MD simulations. Here, we present MD-TASK, a novel software suite that employs graph theory techniques, perturbation response scanning, and dynamic cross-correlation to provide unique ways for analyzing MD trajectories. Availability and implementation: MD-TASK has been open-sourced and is available for download from https://github.com/RUBi-ZA/MD-TASK , implemented in Python and supported on Linux/Unix. Contact: o.tastanbishop@ru.ac.za. PMID- 28575171 TI - karyoploteR: an R/Bioconductor package to plot customizable genomes displaying arbitrary data. AB - Motivation: Data visualization is a crucial tool for data exploration, analysis and interpretation. For the visualization of genomic data there lacks a tool to create customizable non-circular plots of whole genomes from any species. Results: We have developed karyoploteR, an R/Bioconductor package to create linear chromosomal representations of any genome with genomic annotations and experimental data plotted along them. Plot creation process is inspired in R base graphics, with a main function creating karyoplots with no data and multiple additional functions, including custom functions written by the end-user, adding data and other graphical elements. This approach allows the creation of highly customizable plots from arbitrary data with complete freedom on data positioning and representation. Availability and implementation: karyoploteR is released under Artistic-2.0 License. Source code and documentation are freely available through Bioconductor (http://www.bioconductor.org/packages/karyoploteR) and at the examples and tutorial page at https://bernatgel.github.io/karyoploter_tutorial. Contact: bgel@igtp.cat. PMID- 28575172 TI - Longitudinal Changes in Excess Pressure Independently Predict Declining Renal Function Among Healthy Individuals-A Pilot Study. AB - BACKGROUND: Aortic reservoir function independently predicts end-organ damage in cross-sectional analyses. However, longitudinal associations are more important regarding causation, but this has never been examined at rest or in response to light-moderate intensity exercise. The aim of this study was to determine the association between the change in aortic reservoir characteristics, in particular excess pressure integral (Pexcess) at rest and in response to exercise and the change in kidney function among healthy individuals followed over time. METHODS: Aortic reservoir function (Pexcess and reservoir pressure), aortic stiffness, brachial and central blood pressure (BP), and renal function (estimated glomerular filtration rate [eGFR]) were recorded among 33 healthy individuals (57 +/- 9 years; 55% male) at baseline and after an average 3.0 +/- 0.3 years. RESULTS: Over the follow up period, there was a significant increase in resting brachial BP, central BP, Pexcess, and aortic stiffness (P < 0.05 all). The change over time in resting Pexcess (but not aortic stiffness) was significantly related to the change in eGFR (r = -0.38, P = 0.038) and remained independent of age at follow up, change in 24-hour ambulatory systolic BP and body mass index (beta = 0.0300, P = 0.043). There was no association between the change in aortic pulse wave velocity and the change eGFR (P = 0.46) nor were there any associations with exercising hemodynamics. CONCLUSIONS: Pexcess is independently associated with a decline in renal function among healthy people followed over 3 years. These novel findings indicate the need to determine the underlying physiological determinants of aortic reservoir function. PMID- 28575173 TI - Healthcare-Associated Mycobacterium bovis-Bacille Calmette-Guerin (BCG) Infection in Cancer Patients Without Prior BCG Instillation. AB - Background: Bacille Calmette-Guerin (BCG), an attenuated strain of Mycobacterium bovis, is widely used as adjunctive therapy for superficial bladder cancer. Intravesical administration of BCG has been associated with systemic infection. Disseminated infection due to M. bovis is otherwise uncommon. Methods: After identification of 3 patients with healthcare-associated BCG infection who had never received intravesical BCG administration, an epidemiologic study was performed. All patients with healthcare-associated BCG infection in the Barcelona tuberculosis (TB) program were reviewed from 1 January 2005 to 31 December 2015, searching for infections caused by M. bovis-BCG. Patients with healthcare associated BCG infection who had not received intravesical BCG instillation were selected and the source of infection was investigated. Results: Nine oncology patients with infection caused by M. bovis-BCG were studied. All had permanent central venous catheters. Catheter maintenance was performed at 4 different outpatient clinics in the same room in which other patients underwent BCG instillations for bladder cancer without required biological precautions. All patients developed pulmonary TB, either alone or with extrapulmonary disease. Catheter-related infection was considered the mechanism of acquisition based on the epidemiologic association and positive catheter cultures for BCG in patients in whom mycobacterial cultures were performed. Conclusions: Physicians should be alerted to the possibility of TB due to nosocomially acquired, catheter-related infections with M. bovis-BCG in patients with indwelling catheters. This problem may be more common than expected in centers providing BCG therapy for bladder cancer without adequate precautions. PMID- 28575174 TI - Effects of Endogenous Oxytocin Receptor Signaling in Nucleus Tractus Solitarius on Satiation-Mediated Feeding and Thermogenic Control in Male Rats. AB - Central oxytocin receptor (OT-R) signaling reduces food intake and increases energy expenditure, but the central sites and mechanisms mediating these effects are unresolved. We showed previously that pharmacological activation of OT-R in hindbrain/nucleus tractus solitarius (NTS) amplifies the intake-inhibitory effects of gastrointestinal (GI) satiation signals. Unexplored were the energetic effects of hindbrain OT-R agonism and the physiological relevance of NTS OT-R signaling on food intake and energy expenditure control. Using a virally mediated OT-R knockdown (KD) strategy and a range of behavioral paradigms, this study examined the role of endogenous NTS OT-R signaling on satiation-mediated food intake inhibition and thermogenic control. Results showed that, compared with controls, NTS OT-R KD rats consumed larger meals, were less responsive to the intake-inhibitory effects of a self-ingested preload, and consumed more chow following a 24-hour fast. These data indicate that NTS OT-R signaling is necessary for normal satiation control. Whereas both control and NTS OT-R KD rats increased core temperature following high-fat diet maintenance (relative to chow maintenance), the percent increase in core temperature was greater in control compared with NTS OT-R KD rats during the light cycle. Hindbrain oxytocin agonist delivery increased core temperature in both control and NTS OT-R KD rats and the percent increase relative to vehicle treatment was not significantly different between groups. Together, data reveal a critical role for endogenous NTS OT-R signaling in mediating the intake-inhibitory effects of endogenous GI satiation signals and in diet-induced thermogenesis. PMID- 28575176 TI - Global oncofertility index-data gap slows progress. AB - The number of pediatric and young adult cancer survivors is increasing globally due to earlier diagnostics and expansion of targeted chemo- and biological-based therapeutics. As a consequence, cancer-related infertility and reproductive hormone loss is of increasing concern for both male and female survivors. We attempted to estimate the reproductive loss in oncofertility-practicing countries and to develop a global oncofertility index (OFI). This would allow an accounting of the level of urgency of the issue and would provide national comparisons of fertility loss, which differ based on the prevalence and/or diagnosis frequency and treatment variables by countries or region. While the goal is laudable, an index such as this is unachievable due to the lack of the kind of information that would be necessary to calculate such a meaningful index. Without this metric, we will be unable to assess how oncofertility concerns are being addressed and what lessons can be learned from countries that improve such an index over time. PMID- 28575175 TI - Central Administration of Indomethacin Mitigates the Injury-Induced Upregulation of Aromatase Expression and Estradiol Content in the Zebra Finch Brain. AB - Injury to the vertebrate brain causes neuroinflammation, characterized in part by increases in prostaglandins. In rodents and songbirds, brain injury also induces the transcription and translation of aromatase in reactive astrocytes around the site of damage. Interestingly, this induction is more rapid in female zebra finches relative to males. Induced aromatization is neuroprotective, as inhibition of aromatase and estrogen replacement, increases and decreases the extent of damage, respectively. Although the consequences of induced astrocytic aromatization are intensely studied, little is known about what factors induce aromatase. Inflammation is sufficient to induce astrocytic aromatase suggesting that the link between inflammation and aromatase expression may be causal. To test this hypothesis, adult male and female zebra finches received bilateral mechanical injuries through which either the cyclooxygenase (COX)-1/2 inhibitor indomethacin or vehicle was administered into contralateral hemispheres. Subjects were killed either 6 or 24 hours after injury. In both sexes, an enzyme immunoassay for prostaglandin E2 (PGE2) revealed that indomethacin decreased PGE2 relative to the contralateral hemisphere at both time points, suggesting that the dose and mode of administration used were successful in affecting neuroinflammation locally. Indomethacin reduced aromatase expression and 17beta estradiol (E2) content at 6 hours but not 24 hours following injury in females. However, in males, the inhibitory effect of indomethacin on aromatase and E2 was apparent at 24 but not 6 hours after treatment. These data suggest that COX activity, perhaps via consequent prostaglandin secretion, may induce aromatase expression and central E2, an effect that is detectable in temporally distinct patterns between sexes. PMID- 28575177 TI - The Prevalence and Role of Hemoglobin Variants in Biometric Screening of a Multiethnic Population: One Large Health System's Experience. AB - Objectives: To characterize and quantitate hemoglobin (Hb) variants discovered during biometric hemoglobin A1c (HbA1c) analyses in a large multiethnic population with a focus on the effect of variants on testing method and results. Methods: In total, 13,913 individuals had their HbA1c measured via ion-exchange high-performance liquid chromatography. Samples that had a variant Hb detected or HbF fraction more than 25% underwent variant Hb characterization and confirmation by gel electrophoresis. RBC indices were also evaluated for possible concomitant thalassemia. Results: Of the 13,913 individuals evaluated, 524 (3.77%) had an Hb variant. The prevalence of each variant was as follows: HbS trait (n = 396, 2.85%), HbSS disease (n = 4, 0.03%), HbC trait (n = 85, 0.61%), HbCC disease (n = 2, 0.01%), HbSC disease (n = 5, 0.04%), HbE trait (n = 18, 0.13%), HbD or G trait (n = 9, 0.06%), HbS beta-thalassemia + disease (n = 1, 0.01%), hereditary persistence of HbF (n = 2, 0.01%), and HbMontgomery trait (n = 1, 0.01%). Concomitant alpha-thalassemia was detected in 20 (3.82%) of the 524 individuals with an Hb variant. Conclusions: This study represents one of the largest epidemiologic investigations into the prevalence of Hb variants in a North American metropolitan, multiethnic workforce and their dependents and reinforces the importance of method selection in populations with Hb variants. PMID- 28575178 TI - Predominance of CD4+ T Cells in T-Cell/Histiocyte-Rich Large B-Cell Lymphoma and Identification of a Subset of Patients With Peripheral B-Cell Lymphopenia. AB - Objectives: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a morphologic variant of large B-cell lymphoma whose flow cytometry findings are not well characterized. Methods: Nineteen cases with flow cytometric immunophenotyping were identified from the case records of four institutions between 2001 and 2016. Results: In most cases, neoplastic B cells were not detected by flow cytometry. Overall, cases showed a predominance of CD4+ T cells, which in some cases was marked. Significant coexpression of CD57 was seen on CD4+ T cells where this marker was analyzed, which correlated with PD-1 expression. Two cases also showed a profound systemic B-cell lymphopenia, which was associated in one case with hypogammaglobulinemia. Conclusions: Overall, our work challenges previous findings that cases of THRLBCL are rich in CD8+ T cells and highlights parallels between THRLBCL and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Also, an association of THRLBCL with systemic B-cell lymphopenia has not been previously reported but may represent an underrecognized manifestation. PMID- 28575179 TI - Measurement Bias of Gross Pathologic Compared With Radiologic Tumor Size of Resected Lung Adenocarcinomas: Implications for the T-Stage Revisions in the Eighth Edition of the American Joint Committee on Cancer Staging Manual. AB - Objectives: The eighth edition of the AJCC Cancer Staging Manual now stratifies the T descriptor for lung cancers by each increasing 1.0 cm increment, up to 5.0 cm, with an additional category for tumor greater than 7.0 cm. Bias in pathologic versus radiologic measurements may impact tumor staging. Methods: The gross pathologic measurements of 493 resected lung adenocarcinomas were compared with presurgical computed tomography radiologic measurements. Also, pathologic tumor measurement data from the Surveillance, Epidemiology, and End Results (SEER) program database were examined. Results: The distribution of pathologic measurements showed clustering at 0.5-cm increments, with 43.0% of pathologic measurements falling on 0.5-cm increments compared to only 20.3% of radiologic measurements. This pathologic measurement clustering was also observed for both 591,691 resected lung cancers and 3,597,685 tumors of any type from the SEER database. Conclusions: Compared to radiologic measurements, gross pathologic measurements cluster around whole- and half-cm values. This measurement bias could lead to incorrect pathologic tumor staging and influence clinical treatment plans. PMID- 28575180 TI - Performance Evaluation of Serum Free Light Chain Analysis: Nephelometry vs Turbidimetry, Monoclonal vs Polyclonal Reagents. AB - Objectives: Free light chain (FLC) measurement gained a lot of interest for diagnostic workup of monoclonal gammopathy. Methods: We evaluated the performance of turbidimetric polyclonal Freelite (The Binding Site, Birmingham, UK) assays on Cobas 6000 (Roche Diagnostics, Rotkreuz, Switzerland) and nephelometric monoclonal N Latex (Siemens Healthcare Diagnostics, Marburg, Germany) assays on BN ProSpec (Dade Behring, Deerfield, IL) vs established nephelometric Freelite assays on BN ProSpec. Results: Analytical performance was acceptable. Method comparison (n = 118) showed significant proportional FLC differences for N Latex assays. However, good correlation and clinical concordance were shown. Recovery study in the low concentration range demonstrated consistent over- and underrecovery for Freelite reagents, hampering future research on prognostic value of suppressed noninvolved FLC. Antigen excess detection was successful for kappa FLC in three-fourths of cases with Freelite reagents and in all cases with N Latex reagents. However, the latter resulted in underestimated kappa FLC concentrations. Conclusions: FLC analysis requires continuous awareness of analytical limitations. Monitoring of disease response requires FLC analysis on the same platform using the same reagents. PMID- 28575181 TI - DeepSite: protein-binding site predictor using 3D-convolutional neural networks. AB - Motivation: An important step in structure-based drug design consists in the prediction of druggable binding sites. Several algorithms for detecting binding cavities, those likely to bind to a small drug compound, have been developed over the years by clever exploitation of geometric, chemical and evolutionary features of the protein. Results: Here we present a novel knowledge-based approach that uses state-of-the-art convolutional neural networks, where the algorithm is learned by examples. In total, 7622 proteins from the scPDB database of binding sites have been evaluated using both a distance and a volumetric overlap approach. Our machine-learning based method demonstrates superior performance to two other competitive algorithmic strategies. Availability and implementation: DeepSite is freely available at www.playmolecule.org. Users can submit either a PDB ID or PDB file for pocket detection to our NVIDIA GPU-equipped servers through a WebGL graphical interface. Contact: gianni.defabritiis@upf.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28575182 TI - Erratum to: 'Proceedings from the 2nd European Clinical Consensus Conference for device-based therapies for hypertension: state of the art and considerations for the future. PMID- 28575184 TI - Corrigendum to: Risk of stroke in chronic heart failure patients with preserved ejection fraction, but without atrial fibrillation: analysis of the CHARM Preserved and I-Preserve trials. PMID- 28575183 TI - The genetic architecture of heterochrony as a quantitative trait: lessons from a computational model. AB - Heterochrony is known as a developmental change in the timing or rate of ontogenetic events across phylogenetic lineages. It is a key concept synthesizing development into ecology and evolution to explore the mechanisms of how developmental processes impact on phenotypic novelties. A number of molecular experiments using contrasting organisms in developmental timing have identified specific genes involved in heterochronic variation. Beyond these classic approaches that can only identify single genes or pathways, quantitative models derived from current next-generation sequencing data serve as a more powerful tool to precisely capture heterochronic variation and systematically map a complete set of genes that contribute to heterochronic processes. In this opinion note, we discuss a computational framework of genetic mapping that can characterize heterochronic quantitative trait loci that determine the pattern and process of development. We propose a unifying model that charts the genetic architecture of heterochrony that perceives and responds to environmental perturbations and evolves over geologic time. The new model may potentially enhance our understanding of the adaptive value of heterochrony and its evolutionary origins, providing a useful context for designing new organisms that can best use future resources. PMID- 28575185 TI - Recognition of short RP atrial tachycardia due to intra-atrial conduction delay: utility of a septal AH/HA Ratio <1. PMID- 28575186 TI - Comparing Manual Counting to Automated Image Analysis for the Assessment of Fungiform Papillae Density on Human Tongue. AB - The density of fungiform papillae (FPD) on the human tongue is currently taken as index for responsiveness to oral chemosensory stimuli. Visual analysis of digital tongue picture and manual counting by trained operators represents the most popular technique for FPD assessment. Methodological issues mainly due to operator bias are considered among factors accounting for the uncertainty about the relationships between FPD and responsiveness to chemosensory stimuli. The present study describes a novel automated method to count fungiform papillae (FP) from image analysis of tongue pictures. The method was applied to tongue pictures from 133 subjects. Taking the manual count as reference method, a partial least squares regression model was developed to predict FPD from tongue automated analysis output. FPD from manual and automated count showed the same normal distribution and comparable descriptive statistic values. Consistent subject classifications as low and high FPD were obtained according to the median values from manual and automated count. The same results on the effect of FPD variation on taste perception were obtained both using predicted and counted values. The proposed method overcomes count uncertainties due to researcher bias in manual counting and is suited for large population studies. Additional information is provided such as FP size class distribution which would help for a better understanding of the relationships between FPD variation and taste functions. PMID- 28575187 TI - High-Frequency Firing Activity of GnRH1 Neurons in Female Medaka Induces the Release of GnRH1 Peptide From Their Nerve Terminals in the Pituitary. AB - Hypothalamic gonadotropin-releasing hormone (GnRH) neurons play an important role in promoting secretion of pituitary luteinizing hormone (LH) and ovulation by releasing GnRH peptide. The release of GnRH peptide is generally assumed to be mainly modulated according to the firing activity of GnRH neurons. However, the relationship between the firing activity and the release of GnRH peptide has been elusive. We analyzed the relationship using two lines of transgenic medaka (gnrh1:enhanced green fluorescent protein and lhb:inverse-pericam) for the combined electrophysiological and Ca2+ imaging analyses. We show that a high frequency firing activity induced by an excitatory neurotransmitter, glutamate, strongly increases [Ca2+]i in the cell bodies of GnRH1 neurons, which should lead to stimulation of GnRH release. We examined whether this high-frequency firing actually leads to the release of endogenous GnRH1 peptide from the nerve terminals projecting to the pituitary LH cells using a whole brain-pituitary preparation of a fish generated by crossing the two types of transgenic fish. Ca2+ imaging analyses showed that local glutamate activation of GnRH1 cell bodies, but not their nerve terminals in the pituitary, induced a substantial Ca2+ response in LH cells that was abolished in the presence of a GnRH receptor antagonist, Analog M. These results suggest that such an evoked high-frequency firing activity of GnRH1 cell body stimulates the release of endogenous GnRH1 peptide from the axon terminals to the pituitary LH cells. Thus, the findings of the present study have clearly demonstrated the relationship between the firing activity of hypothalamic GnRH neurons and the release of GnRH peptide. PMID- 28575188 TI - Expression of OTUB1 in hepatocellular carcinoma and its effects on HCC cell migration and invasion. AB - OTUB1 (OTU domain-containing ubiquitin aldehyde binding protein 1) is a deubiquitinating enzyme (DUB) that belongs to the ovarian tumor (OTU) domain protease superfamily. Although it has been demonstrated to play important roles in the development of many kinds of cancer, the mechanism of OTUB1 in hepatocellular carcinoma (HCC) is not clear. The aim of this study was to explore the roles of OTUB1 in HCC progression using cell lines and 115 archived HCC samples. In addition, the clinical outcomes were also analyzed with a special focus on OTUB1 expression in HCC samples. In the immunohistochemical study, OTUB1 showed high expression in 60 of the 115 cases (52.2%). The OTUB1 expression level was significantly correlated with many clinicopathological parameters, including TNM stage (P = 0.002), histology stage (P = 0.002), and metastasis/recurrence (P = 0.016). Survival analysis showed that the group with OTUB1 overexpression had significantly shorter overall survival time than the group with OTUB1 downregulation (hazard ratio [HR] = 0.482; confidence interval [CI]: 0.311-0.748; P = 0.001). Multivariate analysis indicated that OTUB1 expression was a significant and independent prognostic parameter (HR = 0.214; CI: 0.126-0.364; P < 0.001) for HCC patients. The ability of HCC cells to undergo proliferation, migration, and invasion was suppressed by disruption of endogenous OTUB1 using short hairpin RNA (shRNA). OTUB1 expression appears to be a new and independent predictor for the prognosis of HCC patients. Overexpression of OTUB1 in HCC could be a novel, effective, and supplementary biomarker for HCC because it plays a vital role in the progression of HCC. PMID- 28575189 TI - Prosthetic valve endocarditis: predictors of early outcome of surgical therapy. A multicentric study. AB - OBJECTIVES: Prosthetic valve endocarditis (PVE) is an uncommon yet dreadful complication in patients with prosthetic valves that requires a distinct analysis from native valve endocarditis. The present study aims to investigate independent risk factors for early surgical outcomes in patients with PVE. METHODS: A retrospective cohort study was conducted in 8 Italian Cardiac Surgery Units from January 2000 to December 2013 by enrolling all PVE patients undergoing surgical treatment. RESULTS: A total of 209 consecutive patients were included in the study. During the study period, the global rate of surgical procedures for PVE among all operations for isolated or associated valvular disease was 0.45%. Despite its rarity this percentage increased significantly during the second time frame (2007-2013) in comparison with the previous one (2000-2006): 0.58% vs 0.31% (P < 0.001). Intraoperative and in-hospital mortality rates were 4.3% and 21.5%, respectively. Logistic regression analysis identified the following factors associated with in-hospital mortality: female gender [odds ratio (OR) = 4.62; P < 0.001], shock status (OR = 3.29; P = 0.02), previous surgical procedures within 3 months from the treatment (OR = 3.57; P = 0.009), multivalvular involvement (OR = 8.04; P = 0.003), abscess (OR = 2.48; P = 0.03) and urgent surgery (OR = 6.63; P < 0.001). CONCLUSIONS: Despite its rarity, PVE showed a significant increase over time. Up to now, in-hospital mortality after surgical treatment still remains high (>20%). Critical clinical presentation and extension of anatomical lesions are strong preoperative predictors for poor early outcome. PMID- 28575192 TI - Corrigendum. PMID- 28575191 TI - Recurrent and congenital tracheoesophageal fistula in adults. AB - OBJECTIVES: Recurrent congenital tracheoesophageal fistula (TEF) is well documented in infancy but may also present later in life. This study reviews our experience with the clinical presentation, diagnosis and management of 5 recurrent and 2 primary congenital tracheoesophageal fistulas (TEF) in adult patients. There are no literature series of late recurrence of TEF (repaired in childhood and recurring in adulthood) and relatively few reported cases of initial adult presentation of TEF. In this series, we aim to provide the first large series description of late recurrence of congenital TEF following repair in infancy or childhood. We also present management considerations for this unique group of patients. METHODS: We performed a computer-based search of the adult thoracic surgery departmental operative database at our institution from 2002 to 2014. Patients with iatrogenic TEF or malignant TEF were excluded. RESULTS: Seven patients are included in our series. Five patients (71%) had recurrent congenital TEF and 2 (29%) had initial diagnosis of congenital TEF. All presented with severe coughing symptoms, and most (86%) had a history of recurrent aspiration pneumonia. Repair technique was dictated by the location of the TEF and the specific tracheoesophageal pathology. Four patients underwent repair via cervical approach with or without a tracheal resection. Three patients with distal recurrence underwent repair via right thoracotomy with partial oesophagectomy for significant tissue compromise and cervical reconstruction. Patients were followed for at least 1 year. All 7 patients experienced full resolution of symptoms. One patient required postoperative placement of a retrievable tracheal stent for tracheomalacia. There were no mortalities. CONCLUSIONS: Adult presentation of congenital TEF is a rare but recognizable clinical entity. Recurrent TEF in adulthood is a possible late complication of TEF repair performed in childhood that has not previously been described. Adult patients experiencing symptoms of cough and recurrent aspiration pneumonia should be evaluated for congenital TEF. Surgical repair of congenital TEF in the adult is feasible and effective with acceptable morbidity. PMID- 28575190 TI - The Effects of Graded Levels of Calorie Restriction: X. Transcriptomic Responses of Epididymal Adipose Tissue. AB - Calorie restriction (CR) leads to a remarkable decrease in adipose tissue mass and increases longevity in many taxa. Since the discovery of leptin, the secretory abilities of adipose tissue have gained prominence in the responses to CR. We quantified transcripts of epididymal white adipose tissue of male C57BL/6 mice exposed to graded levels of CR (0-40% CR) for 3 months. The numbers of differentially expressed genes (DEGs) involved in NF-kappaB, HIF1-alpha, and p53 signaling increased with increasing levels of CR. These pathways were all significantly downregulated at 40% CR relative to 12 h ad libitum feeding. In addition, graded CR had a substantial impact on DEGs associated with pathways involved in angiogenesis. Of the 497 genes differentially expressed with graded CR, 155 of these genes included a signal peptide motif. These putative signaling proteins were involved in the response to ketones, TGF-beta signaling, negative regulation of insulin secretion, and inflammation. This accords with the previously established effects of graded CR on glucose homeostasis in the same mice. Overall these data suggest reduced levels of adipose tissue under CR may contribute to the protective impact of CR in multiple ways linked to changes in a large population of secreted proteins. PMID- 28575193 TI - The cost structure of routine infant immunization services: a systematic analysis of six countries. AB - Little information exists on the cost structure of routine infant immunization services in low- and middle-income settings. Using a unique dataset of routine infant immunization costs from six countries, we estimated how costs were distributed across budget categories and programmatic activities, and investigated how the cost structure of immunization sites varied by country and site characteristics. The EPIC study collected data on routine infant immunization costs from 319 sites in Benin, Ghana, Honduras, Moldova, Uganda, Zambia, using a standardized approach. For each country, we estimated the economic costs of infant immunization by administrative level, budget category, and programmatic activity from a programme perspective. We used regression models to describe how costs within each category were related to site operating characteristics and efficiency level. Site-level costs (incl. vaccines) represented 77-93% of national routine infant immunization costs. Labour and vaccine costs comprised 14-69% and 13-69% of site-level cost, respectively. The majority of site-level resources were devoted to service provision (facility based or outreach), comprising 48-78% of site-level costs across the six countries. Based on the regression analyses, sites with the highest service volume had a greater proportion of costs devoted to vaccines, with vaccine costs per dose relatively unaffected by service volume but non-vaccine costs substantially lower with higher service volume. Across all countries, more efficient sites (compared with sites with similar characteristics) had a lower cost share devoted to labour. The cost structure of immunization services varied substantially between countries and across sites within each country, and was related to site characteristics. The substantial variation observed in this sample suggests differences in operating model for otherwise similar sites, and further understanding of these differences could reveal approaches to improve efficiency and performance of immunization sites. PMID- 28575194 TI - Prohibitin 2/PHB2 in Parkin-mediated mitophagy: a potential therapeutic target for mitochondrial diseases. PMID- 28575195 TI - Prospective Associations of Local Destinations and Routes With Middle-to-Older Aged Adults' Walking. AB - Background and Objectives: To examine prospective associations of perceived attributes of local destinations and routes with middle-to-older aged adults' 4 year changes in walking for transport (WT) and walking for recreation (WR). Research Design and Methods: Data were collected from adults aged 50-64 years old, living in Adelaide, Australia. Participants (N = 454) reported weekly frequency of WT and WR at baseline (2003-2004) and follow-up (2007-2008). Attributes of local destinations and routes were based on self-reported measures at baseline and included: proximity to utilitarian and recreational destinations, the number of such destinations within 10 and 11-20 min walk from home, street connectivity, and walking paths. Generalized additive mixed models were used to examine the associations of perceived destination and route attributes with changes in frequency of WT and WR. Results: Higher levels of perceived proximity to utilitarian destinations, reporting a larger number of utilitarian destinations within 10 min walk from home and higher street connectivity were associated with more positive changes in frequency of WT. Higher levels of perceived proximity to recreational destinations and better walking paths were associated with more positive changes in frequency of WR. No curvilinear relationships were observed and baseline frequency of walking did not moderate the associations. Discussion and Implications: Proximity of utilitarian and recreational destinations, well-connected streets, and better walking paths can be supportive of long-term participation in walking among middle-to-older aged adults. Environmental and policy initiatives focusing on such destination and route attributes have the potential to support residents' aging in place. PMID- 28575196 TI - Changes in immune cell distribution and their cytokine/chemokine production during regression of the rhesus macaque corpus luteum. AB - Our previous flow cytometry results demonstrated a significant increase in neutrophils, macrophages/monocytes, and natural killer (NK) cells in dispersed rhesus monkey corpora lutea (CL) after progesterone (P4) levels had fallen below 0.3 ng/ml for >=3 days during the natural menstrual cycle. In this study, immunohistochemistry revealed the CD11b+ cells (neutrophils, macrophages/monocytes) present in the CL after luteal P4 synthesis ceased were distributed throughout the tissue. CD16+ cells (presumptive NK cells) were observed mainly near the vasculature in functional CL, until their numbers increased and they became widely distributed in regressing CL. To determine if the immune cells that enter luteal tissue during structural regression are functionally different from those that are present during peak function, CD11b+ or CD16+ populations were enriched from mid-late stage (functional) and regressing (days 1.8 +/- 0.3 postmenses) CL using antibody-conjugated magnetic microbeads. Flow cytometry analyses revealed the majority of CD11b+ cells expressed CD14, a protein mainly produced by macrophages/monocytes. The antibody enriched and depleted fractions were cultured for 24 h, and the media then analyzed for the production of 29 cytokines/chemokines. From the mid-late CL, the CD11b+-enriched fraction produced three cytokines/chemokines, whereas CD16+ enriched cells only produced the chemokine CCL2. However, CD11b +-enriched cells isolated from regressed CL produced eight cytokines/chemokines. The CD16+ enriched cells isolated from regressing CL produced significant levels of only three cytokines. Thus, the CD11b+ cells that appear in the rhesus macaque CL after functional regression produce several cytokines/chemokines that likely play a role in orchestrating structural regression. PMID- 28575197 TI - Visual recognition memory is impaired in rhesus monkeys repeatedly exposed to sevoflurane in infancy. AB - Background: Experimental studies in animals have shown that exposure to general anaesthesia in infancy can cause loss of cells in the central nervous system and long-term impairments in neurocognitive function. Some human epidemiological studies have shown increased risk of learning disability after repeated anaesthesia exposure in early childhood. Thus, we investigated in a highly translational rhesus monkey model, whether repeated exposure in infancy to the inhalation anaesthetic sevoflurane is associated with impaired visual recognition memory during the first two yr of life. Methods: Rhesus monkeys of both sexes were exposed to sevoflurane inhalation anaesthesia on approximately postnatal day 7 and then again 14 and 28 days later, for four h each time. Visual recognition memory was tested using the visual paired comparison task, which measures memory by assessing preference for looking at a new image over a previously-viewed image. Monkeys were tested at 6-10 months of age, again at 12-18 months of age, and again at 24-30 months of age. Results: No memory impairment was detected at 6 10 months old, but significant impairment (reduced time looking at the novel image) was observed at 12-18 and 24-30 months old. Conclusions: Repeated exposure of infant rhesus monkeys to sevoflurane results in visual recognition memory impairment that emerges after the first yr of life. This is consistent with epidemiological studies that show increased risk of learning disability after repeated exposure to anaesthesia in infancy/early childhood. Moreover, these deficits may emerge at later developmental stages, even when memory performance is unaffected earlier in development. PMID- 28575198 TI - Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. AB - Chronic inflammatory demyelination polyneuropathy is a heterogeneous and treatable immune-mediated disorder that lacks biomarkers to support diagnosis. Recent evidence indicates that paranodal proteins (contactin 1, contactin associated protein 1, and neurofascin-155) are the targets of autoantibodies in subsets of patients showing distinct clinical presentations. Here, we identified neurofascin-186 and neurofascin-140 as the main targets of autoantibodies in five patients presenting IgG reactivity against the nodes of Ranvier. Four patients displayed predominantly IgG4 antibodies, and one patient presented IgG3 antibodies that activated the complement pathway in vitro. These patients present distinct clinical features compared to those with anti-neurofascin-155 IgG4. Most patients had a severe phenotype associated with conduction block or decreased distal motor amplitude. Four patients had a subacute-onset and sensory ataxia. Two patients presented with nephrotic syndromes and one patient with an IgG4 related retroperitoneal fibrosis. Intravenous immunoglobulin and corticosteroids were effective in three patients, and one patient remitted following rituximab treatment. Clinical remission was associated with autoantibody depletion and with recovery of conduction block and distal motor amplitude suggesting a nodo paranodopathy. Our data demonstrate that the pathogenic mechanisms responsible for chronic inflammatory demyelination polyneuropathy are broad and may include dysfunctions at the nodes of Ranvier in a subgroup of patients. PMID- 28575199 TI - Mixotrophy in Pyroleae (Ericaceae) from Estonian boreal forests does not vary with light or tissue age. AB - Background and Aims: In temperate forests, some green plants, namely pyroloids (Pyroleae, Ericaceae) and some orchids, independently evolved a mode of nutrition mixing photosynthates and carbon gained from their mycorrhizal fungi (mixotrophy). Fungal carbon is more enriched in 13C than photosynthates, allowing estimation of the proportion of carbon acquired heterotrophically from fungi in plant biomass. Based on 13C enrichment, mixotrophic orchids have previously been shown to increase shoot autotrophy level over the growth season and with environmental light availability. But little is known about the plasticity of use of photosynthetic versus fungal carbon in pyroloids. Methods: Plasticity of mixotrophy with leaf age or light level (estimated from canopy openness) was investigated in pyroloids from three Estonian boreal forests. Bulk leaf 13C enrichment of five pyroloid species was compared with that of control autotrophic plants along temporal series (over one growth season) and environmental light gradients (n=405 samples). Key Results: Mixotrophic 13C enrichment was detected at studied sites for Pyrola chlorantha and Orthilia secunda (except at one site for the latter), but not for Chimaphila umbellata, Pyrola rotundifolia and Moneses uniflora. Enrichment with 13C did not vary over the growth season or between leaves from current and previous years. Finally, although one co occurring mixotrophic orchid showed 13C depletion with increasing light availability, as expected for mixotrophs, all pyroloids responded identically to autotrophic control plants along light gradients. Conclusions: A phylogenetic trend previously observed is further supported: mixotrophy is rarely supported by 13C enrichment in the Chimaphila + Moneses clade, whereas it is frequent in the Pyrola + Orthilia clade. Moreover, pyroloid mixotrophy does not respond plastically to ageing or to light level. This contrasts with the usual view of a convergent evolution with orchids, and casts doubt on the way pyroloids use the carbon gained from their mycorrhizal fungi, especially to replace photosynthetic carbon. PMID- 28575200 TI - The Role of Senior Housing in Hospitalizations Among Vulnerable Older Adults With Multiple Chronic Conditions: A Longitudinal Perspective. AB - Background and Objectives: This study focuses on vulnerable elders (i.e., those with moderate or low incomes who live alone) and examines to what extent a senior housing environment moderates the effects of multiple chronic conditions (MCCs) on hospitalization over time. Research Design and Methods: Data came from six waves (2002-2012) of the Health Retirement Study (N = 1,401 individuals, 3,705 observations). Mixed-effect multinomial logistic regression modeling estimated the effects of senior housing on changes in hospitalization. Results: Vulnerable elders with MCCs were more likely to be hospitalized at both moderate and heavy levels at baseline. Consistent with the environment docility hypothesis, findings show that older individuals with MCCs who live in a senior housing environment have fewer hospitalizations over time. Discussions and Implications: As one of the first efforts to build empirical knowledge on health care use among vulnerable elders in senior housing, our findings underscore the importance of continued research into these environments as a possible alternative to existing models. PMID- 28575202 TI - Evaluation of Food-Based Attractants for Drosophila suzukii (Diptera: Drosophilidae). AB - The Drosophila suzukii (Matsumura) (Diptera: Drosophilidae) is a highly invasive species attacking a wide range of ripening soft-skinned fruits. A series of laboratory choice tests were conducted to determine whether different levels of rice vinegar affected attraction of Merlot wine to D. suzukii, as well as to compare attractiveness of two common fermentation food baits: wine-vinegar and yeast-sugar water mixtures. The relative attraction of various combinations was used to develop a bait whose effectiveness was tested in the field. In laboratory choice experiments, wine-vinegar (80:20, v:v, hereafter referred to as wine) was more preferred over a yeast-sugar water mixture (hereafter referred to as yeast) by D. suzukii. Combination baits, either a mixture of wine and yeast or a mixture of wine and a supernatant from the yeast (comboS), were significantly more attractive than each product alone. The two combination baits were equally attractive to D. suzukii, so were the yeast and its supernatant, suggesting that yeast supernatant could be used as a replacement for the yeast-sugar mixture currently used for trapping D. suzukii. The additive effect between wine and yeast supernatant in the field was not as profound as observed in the laboratory. In the field trial, numerically more male and female D. suzukii were captured in traps baited with comboS than those baited with the wine or yeast alone; however, significant differences were only found between the comboS and wine or between the comboS and yeast in some weeks over the period of the experiment. PMID- 28575203 TI - Structurexplor: a platform for the exploration of structural features of RNA secondary structures. AB - Summary: Discovering function-related structural features, such as the cloverleaf shape of transfer RNA secondary structures, is essential to understand RNA function. With this aim, we have developed a platform, named Structurexplor, to facilitate the exploration of structural features in populations of RNA secondary structures. It has been designed and developed to help biologists interactively search for, evaluate and select interesting structural features that can potentially explain RNA functions. Availability and implementation: Structurxplor is a web application available at http://structurexplor.dinf.usherbrooke.ca. The source code can be found at http://jpsglouzon.github.io/structurexplor/. Contact: shengrui.wang@usherbrooke.ca. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28575204 TI - Analysis of Copy Number Variation in the Abp Gene Regions of Two House Mouse Subspecies Suggests Divergence during the Gene Family Expansions. AB - The Androgen-binding protein ( Abp ) gene region of the mouse genome contains 64 genes, some encoding pheromones that influence assortative mating between mice from different subspecies. Using CNVnator and quantitative PCR, we explored copy number variation in this gene family in natural populations of Mus musculus domesticus ( Mmd ) and Mus musculus musculus ( Mmm ), two subspecies of house mice that form a narrow hybrid zone in Central Europe. We found that copy number variation in the center of the Abp gene region is very common in wild Mmd , primarily representing the presence/absence of the final duplications described for the mouse genome. Clustering of Mmd individuals based on this variation did not reflect their geographical origin, suggesting no population divergence in the Abp gene cluster. However, copy number variation patterns differ substantially between Mmd and other mouse taxa. Large blocks of Abp genes are absent in Mmm , Mus musculus castaneus and an outgroup, Mus spretus , although with differences in variation and breakpoint locations. Our analysis calls into question the reliance on a reference genome for interpreting the detailed organization of genes in taxa more distant from the Mmd reference genome. The polymorphic nature of the gene family expansion in all four taxa suggests that the number of Abp genes, especially in the central gene region, is not critical to the survival and reproduction of the mouse. However, Abp haplotypes of variable length may serve as a source of raw genetic material for new signals influencing reproductive communication and thus speciation of mice. PMID- 28575205 TI - Relationship of Hypertension and Systolic Blood Pressure With the Risk of Stroke or Bleeding in Patients With Atrial Fibrillation: The Fushimi AF Registry. AB - BACKGROUND: Hypertension is considered a major risk factor of stroke and systemic embolism (SE) as well as bleeding in patients with atrial fibrillation (AF). The purpose of this study was to investigate the relationship of hypertension and systolic blood pressure (SBP) with the risk of stroke/SE or bleeding in AF patients. METHODS: The Fushimi AF Registry, a community-based prospective survey, was designed to enroll all of the AF patients in Fushimi-ku, Kyoto. Fushimi-ku is densely populated with a total population of 283,000. Follow-up data were available for 3,713 patients (follow-up rate 90.0%) as of August 2015, and the median follow-up period was 1,035 days. RESULTS: We compared the clinical backgrounds at baseline, and follow-up outcomes of AF patients between those with hypertension (HTN; n = 2,304, 62.1% of total) and those without (non-HTN; n = 1,409). History of hypertension was neither associated with the incidence of stroke/SE, ischemic stroke, hemorrhagic stroke nor major bleeding. However, when we divided the HTN group by baseline SBP >=150 mm Hg (HTN-high blood pressure [HBP]: n = 305, 13.3% of HTN group) or <150 mm Hg (HTN-low blood pressure [LBP]: n = 1,983), HTN-HBP group was significantly associated with a higher incidence of both stroke/SE (hazard ratio [HR]: 1.74, 95% confidence interval [CI]: 1.08-2.72) and major bleeding (HR: 2.01, 95% CI: 1.21-3.23) compared with the non-HTN group. In contrast, HTN-LBP group was not associated with the risk of stroke/SE or major bleeding, compared with the non-HTN group. CONCLUSION: The incidences of stroke/SE and bleeding were higher in AF and hypertension patients with elevated SBP. UMIN Clinical Trials Registry: UMIN000005834. PMID- 28575207 TI - Moran's I quantifies spatio-temporal pattern formation in neural imaging data. AB - Motivation: Neural activities of the brain occur through the formation of spatio temporal patterns. In recent years, macroscopic neural imaging techniques have produced a large body of data on these patterned activities, yet a numerical measure of spatio-temporal coherence has often been reduced to the global order parameter, which does not uncover the degree of spatial correlation. Here, we propose to use the spatial autocorrelation measure Moran's I, which can be applied to capture dynamic signatures of spatial organization. We demonstrate the application of this technique to collective cellular circadian clock activities measured in the small network of the suprachiasmatic nucleus (SCN) in the hypothalamus. Results: We found that Moran's I is a practical quantitative measure of the degree of spatial coherence in neural imaging data. Initially developed with a geographical context in mind, Moran's I accounts for the spatial organization of any interacting units. Moran's I can be modified in accordance with the characteristic length scale of a neural activity pattern. It allows a quantification of statistical significance levels for the observed patterns. We describe the technique applied to synthetic datasets and various experimental imaging time-series from cultured SCN explants. It is demonstrated that major characteristics of the collective state can be described by Moran's I and the traditional Kuramoto order parameter R in a complementary fashion. Availability and implementation: Python 2.7 code of illustrative examples can be found in the Supplementary Material. Contact: christoph.schmal@charite.de or grigory.bordyugov@hu-berlin.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28575201 TI - Birth Weight and Preterm Delivery Outcomes of Perinatally vs Nonperinatally Human Immunodeficiency Virus-Infected Pregnant Women in the United States: Results From the PHACS SMARTT Study and IMPAACT P1025 Protocol. AB - Background: Pregnancy outcomes of perinatally human immunodeficiency virus infected women (PHIV) are poorly defined. Methods: We compared preterm delivery and birth weight (BW) outcomes (low BW [LBW], <2500 g), small-for-gestational-age [SGA], and BW z scores [BWZ]) in HIV-exposed uninfected infants of PHIV vs nonperinatally HIV-infected (NPHIV) pregnant women in the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART Toxicities or International Maternal Pediatric Adolescent AIDS Clinical Trials P1025 studies. Mixed effects models and log binomial models were used to assess the association of maternal PHIV status with infant outcomes. Age-stratified analyses were performed. Results: From 1998 to 2013, 2270 HIV-infected pregnant women delivered 2692 newborns (270 born to PHIV and 2422 to NPHIV women). PHIV women were younger, (mean age 21 vs 25 years, P < .01) and more likely to have a pregnancy CD4 count <200 cells/mm3 (19% vs 11%, P = .01). No associations between maternal PHIV status and preterm delivery, SGA, or LBW were observed. After adjustment, BWZ was 0.12 lower in infants of PHIV vs NPHIV women (adjusted mean, -0.45 vs -0.33; P = .04). Among women aged 23 30 years (n = 1770), maternal PHIV was associated with LBW (aRR = 1.74; 95% confidence interval, 1.18, 2.58; P < .01). Conclusion: The overall lack of association between maternal PHIV status and preterm delivery or infant BW outcomes is reassuring. The higher rates of LBW observed in PHIV women aged 23-30 years warrants further mechanism-based investigations as this is a rapidly growing and aging population worldwide. Clinical Trials Registration: PHACS SMARTT study, NCT01310023. Clinical Trials Registration: IMPAACT 1025, NCT00028145. PMID- 28575208 TI - High Rate of Treatment Completion in Program Settings With 12-Dose Weekly Isoniazid and Rifapentine for Latent Mycobacterium tuberculosis Infection. AB - Background: Randomized controlled trials have demonstrated that the newest latent tuberculosis (LTBI) regimen, 12 weekly doses of directly observed isoniazid and rifapentine (3HP), is as efficacious as 9 months of isoniazid, with a greater completion rate (82% vs 69%); however, 3HP has not been assessed in routine healthcare settings. Methods: Observational cohort of LTBI patients receiving 3HP through 16 US programs was used to assess treatment completion, adverse drug reactions, and factors associated with treatment discontinuation. Results: Of 3288 patients eligible to complete 3HP, 2867 (87.2%) completed treatment. Children aged 2-17 years had the highest completion rate (94.5% [155/164]). Patients reporting homelessness had a completion rate of 81.2% (147/181). In univariable analyses, discontinuation was lowest among children (relative risk [RR], 0.44 [95% confidence interval {CI}, .23-.85]; P = .014), and highest in persons aged >=65 years (RR, 1.72 [95% CI, 1.25-2.35]; P < .001). In multivariable analyses, discontinuation was lowest among contacts of patients with tuberculosis (TB) disease (adjusted RR [ARR], 0.68 [95% CI, .52-.89]; P = .005) and students (ARR, 0.45 [95% CI, .21-.98]; P = .044), and highest with incarceration (ARR, 1.43 [95% CI, 1.08-1.89]; P = .013) and homelessness (ARR, 1.72 [95% CI, 1.25-2.39]; P = .001). Adverse drug reactions were reported by 1174 (35.7%) patients, of whom 891 (76.0%) completed treatment. Conclusions: Completion of 3HP in routine healthcare settings was greater overall than rates reported from clinical trials, and greater than historically observed using other regimens among reportedly nonadherent populations. Widespread use of 3HP for LTBI treatment could accelerate elimination of TB disease in the United States. PMID- 28575209 TI - Clinical standard for valve area after common atrioventricular valve plasty for a single ventricle. AB - OBJECTIVES: To determine a clinical standard for post-repair common atrioventricular valve orifice area based on mid- to long-term valve function in patients with a functional single ventricle. METHODS: The medical records of 19 single-ventricle patients who underwent common atrioventricular valve plasty from July 1988 to January 2013 were retrospectively reviewed. Bivalvation valvuloplasty was performed in 7 patients with relatively hypoplastic leaflets. The relationship between the orifice area of the repaired common atrioventricular valve measured intraoperatively and valve function and ventricular volume in the early postoperative period (median, 9.5 months) and at mid- to long-term follow up (median, 4 years) were analysed. RESULTS: Post-repair valve area was significantly positively correlated with valve regurgitation severity in the early postoperative period (P = 0.001, r = 0.69) and at mid- to long-term follow up (P = 0.02, r = 0.57). Patients who did not undergo bivalvation had favourable valve function at mid- to long-term follow-up and in the early postoperative period when the post-repair valve area was 96-136% of the normal mitral valve area. Bivalvation patients had significantly more valve regurgitation in the early postoperative period than patients without bivalvation, despite equivalent repaired valve area (P = 0.02). CONCLUSIONS: The post-repair orifice area of the common atrioventricular valve is significantly related to postoperative valve function. The clinical standard of post-repair valve orifice area might be 96 136% of the normal mitral valve area in patients undergoing repair without bivalvation. Patients undergoing bivalvation require greater reduction to obtain favourable mid- to long-term valve function. PMID- 28575210 TI - Triple low, double low: it's time to deal Achilles heel a single deadly blow. PMID- 28575206 TI - Heterozygote galactocerebrosidase (GALC) mutants have reduced remyelination and impaired myelin debris clearance following demyelinating injury. AB - Genome-wide association studies are identifying multiple genetic risk factors for several diseases, but the functional role of these changes remains mostly unknown. Variants in the galactocerebrosidase (GALC) gene, for example, were identified as a risk factor for Multiple Sclerosis (MS); however, the potential biological relevance of GALC variants to MS remains elusive. We found that heterozygote GALC mutant mice have reduced myelin debris clearance and diminished remyelination after a demyelinating insult. We found no histological or behavioral differences between adult wild-type and GALC +/- animals under normal conditions. Following exposure to the demyelinating agent cuprizone, however, GALC +/- animals had significantly reduced remyelination during recovery. In addition, the microglial phagocytic response and elevation of Trem2, both necessary for clearing damaged myelin, were markedly reduced in GALC +/- animals. These altered responses could be corrected in vitro by treatment with NKH-477, a compound discovered as protective in our previous studies on Krabbe disease, which is caused by mutations in both GALC alleles. Our data are the first to show remyelination defects in individuals with a single mutant GALC allele, suggesting such carriers may have increased vulnerability to myelin damage following injury or disease due to inefficient myelin debris clearance. We thus provide a potential functional link between GALC variants and increased MS susceptibility, particularly due to the failure of remyelination associated with progressive MS. Finally, this work demonstrates that genetic variants identified through genome wide association studies may contribute significantly to complex diseases, not by driving initial symptoms, but by altering repair mechanisms. PMID- 28575212 TI - Effectiveness of extraction of primary canines for interceptive management of palatally displaced permanent canines: a systematic review and meta-analysis. AB - Background: Although extraction of primary canines in the mixed dentition has been suggested as a measure to prevent impaction of palatally displaced permanent canines (PDCs), the relevant evidence has been inconclusive. Objective: To assess the effectiveness of this practice and investigate the quality of the evidence. Search methods: Search without restrictions in 15 databases and hand searching until April 2017. Selection criteria: Randomized clinical trials comparing extraction of primary canines in the mixed dentition to no treatment. Data collection and analysis: Following study retrieval and selection, data extraction, and individual study risk of bias assessment using the Cochrane Risk of Bias Tool, the random effects method of combining treatment effects was used. The overall quality of the available evidence was assessed with the Grades of Recommendation, Assessment, Development, and Evaluation approach. Results: Finally 5 studies were identified involving 214 individuals, followed for up to 48 months post-intervention. Two studies were at low and the rest at high risk of bias. Although at the 12-month evaluation, extraction of the primary canine did not result in a statistically significant difference [risk ratio (RR): 1.537; 95% confidence interval (CI): 0.656-3.601, P = 0.323; 1 study, n = 67 individuals], beyond 12 months a benefit was noted (RR: 1.784; 95% CI: 1.376-2.314, P = 0.000; 5 studies, n = 214 individuals; I2 = 0%). Analysis of the studies at low risk of bias confirmed the above-mentioned result (RR: 1.713; 95% CI: 1.226-2.394, P = 0.002; 2 studies, n = 91 individuals; I2 = 0%; moderate quality evidence). No difference was observed regarding root resorption of adjacent permanent teeth (RR: 0.602; 95% CI: 0.277-1.308, P = 0.200; 1 study; n = 67 individuals; moderate quality evidence). Conclusions: Extraction of primary canines in the mixed dentition may increase the chance of subsequent successful eruption of PDC in the long term. However, better study standardization is necessary. PMID- 28575211 TI - Clinical outcomes in patients after extracorporeal membrane oxygenation support for post-cardiotomy cardiogenic shock: a single-centre experience of 92 cases. AB - OBJECTIVES: Post-cardiotomy cardiogenic shock is a major concern in cardiac surgery. We reviewed our experience of extracorporeal membrane oxygenation (ECMO) as temporary circulatory support in post-cardiotomy cardiogenic shock. METHODS: Between January 2005 and December 2014, adult patients implanted with ECMO after cardiac surgical procedures were included. Indications for ECMO were failure to be withdrawn from cardiopulmonary bypass or refractory cardiogenic shock occurring during postoperative Days 1 and 2. Patients' characteristics and outcomes were prospectively collected in a local ECMO database. RESULTS: Ninety two patients, median age of 63 years (17-83 years), were supported by ECMO following valvular surgery (66%), acute aortic dissection (10%) and coronary artery bypass grafting (9%). A total of 37% were combined surgical procedures, 24% were redo procedures and 33% were emergent procedures. The median duration of ECMO support was 6 days (1-28 days). The weaning rate from mechanical support was 48%. Overall 1-month and 6-month survival rates were, respectively, 42% and 39%. Survivors were younger (57 vs 63 years old, P = 0.02) and had a higher preoperative left ventricular ejection fraction (52.5 vs 44.1%, P = 0.017). There was a trend for lower serum creatinine levels and total bilirubin rates in the survivors' group 24 h after initiation of ECMO (respectively, 162 vs 212 umol/l, P = 0.06; 25.3 vs 54.2 mg/dl, P = 0.08). Valvular surgery and peak lactic acid serum level were associated with poor outcomes. The mean health-related quality of life EuroQoL scale was 68 +/- 16/100 at 2 years. CONCLUSIONS: Refractory cardiogenic shock requiring ECMO was most frequently observed after redo valvular surgery in the present study. The overall 6-month survival rate was 39% after ECMO support for post-cardiotomy cardiogenic shock with acceptable health-related quality of life. Improved kidney and liver functions after 24 h of support were associated with favourable outcomes. PMID- 28575213 TI - The National Academy Report on the Elimination of Viral Hepatitis: An Infectious Disease Physician's Perspective. PMID- 28575215 TI - Comparison of the effects of selective and non-selective His bundle pacing on cardiac electrical and mechanical synchrony. AB - Aims: This study aimed to assess the acute effect of selective His bundle pacing (S-HBP), non-selective His bundle pacing (NS-HBP), and right ventricular septum pacing (RVSP) on electrical synchrony and left ventricular (LV) mechanical synchrony using electrocardiogram and phase analysis of gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). Methods and results: Totally 39 patients eligible for pacemaker were enrolled. Thirty seven patients underwent successful His bundle pacing (HBP) including S-HBP in 23 and NS-HBP in 14 patients, respectively. Thirty-one patients simultaneously underwent backup RVSP. Twenty-three patients received SPECT MPI scans under different pacing modes, including S-HBP low- and high-output, NS-HBP low- and high-output, and RVSP mode. The paced QRS duration (QRSd) in the S-HBP low- and high-output mode and in the NS-HBP high-output mode were similarly compared with the baseline intrinsic QRSd. QRS duration in the NS-HBP low-output mode was slightly longer than the baseline. QRS duration was the longest in the RVSP group. Left ventricular mechanical synchrony parameters in both the S-HBP and the NS-HBP groups were remarkably better than those in the RVSP group. Moreover, LV mechanical synchrony parameters were much better in the S-HBP groups and NS-HBP high-output group. Conclusion: Selective His bundle pacing and high-output NS-HBP could restore normal electrical and LV mechanical synchrony. PMID- 28575217 TI - Comprehensive Platelet Phenotypic Laboratory Testing and Bleeding History Scoring for Diagnosis of Suspected Hereditary Platelet Disorders: A Single-Institution Experience. AB - Objectives: Patients with hereditary/congenital platelet disorders (HPDs) have a broad range of clinical manifestations and laboratory phenotypes. We assessed the performance characteristics of the International Society on Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT) and clinically validated platelet laboratory tests for diagnosis of HPDs. Methods: The records of 61 patients with suspected HPDs were reviewed and ISTH-BAT scores calculated. Results: Nineteen (31%) patients had thrombocytopenia, and 46 (75%) had positive ISTH-BAT scores. Thirteen and 17 patients had prolonged PFA-100 (Dade Behring, Miami, FL) adenosine diphosphate and epinephrine closure times, respectively. Twenty-two had abnormal platelet light transmission aggregation. Twenty-four had platelet transmission electron microscopy (PTEM) abnormalities (10 dense granule deficiency, 14 other ultrastructural abnormalities). Positive ISTH-BAT scores were associated with thrombocytopenia (P < .0001) and abnormal PTEM (P = .002). Twenty-three patients had normal results. Conclusions: ISTH-BAT identified patients with suspected HPDs but lacked a robust association with laboratory abnormalities. Despite comprehensive laboratory testing, some patients may have normal results. PMID- 28575216 TI - Emergence of Livestock-Associated Methicillin-Resistant Staphylococcus aureus Bloodstream Infections in Denmark. AB - Background: Livestock-associated methicillin-resistant Staphylococcus aureus clonal complex 398 (LA-MRSA CC398) is causing an increasing number of skin and soft tissue infections (SSTIs) in Denmark and other European countries with industrial pig production. Yet, its impact on MRSA bloodstream infections (BSIs) has not been well studied. Methods: We investigated the clinical epidemiology of all human cases of LA-MRSA CC398 BSI during 2010-2015. Cases of LA-MRSA CC398 BSI were compared to cases of BSI caused by other types of MRSA and cases of SSTI caused by LA-MRSA CC398. Whole-genome sequence analysis was used to assess the phylogenetic relationship among LA-MRSA CC398 isolates from Danish pigs and cases of BSI and SSTI. Results: The number of LA-MRSA CC398 BSIs and SSTIs increased over the years, peaking in 2014, when LA-MRSA CC398 accounted for 16% (7/44) and 21% (211/985) of all MRSA BSIs and SSTIs, corresponding to 1.2 and 37.4 cases of BSI and SSTI per 1000000 person-years, respectively. Most patients with LA-MRSA CC398 BSI had no contact to livestock, although they tended to live in rural areas. LA-MRSA CC398 caused 24.3 BSIs per 1000 SSTIs among people with no livestock contact, which is similar to the ratio observed for other types of MRSA. Whole-genome sequence analysis showed that most of the BSI and SSTI isolates were closely related to Danish pig isolates. Conclusions: This study demonstrates that the increasing number of LA-MRSA CC398 BSIs occurred in parallel with a much larger wave of LA-MRSA CC398 SSTIs and an expanding pig reservoir. PMID- 28575218 TI - The safe volume threshold for chest drain removal following pulmonary resection. AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'In patients undergoing pulmonary resection, is there a safe drainage volume threshold for chest drain removal?' Altogether 1054 papers were found, of which 5 papers represented the best evidence. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Chest drainage threshold, where used, ranged from 250 to 500 ml/day. Both randomized controlled trials showed no significant difference in reintervention rates with a higher chest drainage volume threshold. Four studies that performed analysis on other complications showed no statistical significant difference with a higher chest drainage volume threshold. Four studies evaluating length of hospital stay showed reduced or no difference in the length of stay with a higher chest drainage volume threshold. Two cohort studies reported the mortality rate of 0-0.01% with a higher chest drainage volume threshold. We conclude that early chest drain removal after pulmonary resection, accepting a higher chest drainage volume threshold of 250-500 ml/day is safe, and may result in shorter hospital stay without increasing reintervention, morbidity or mortality. PMID- 28575219 TI - Targeted Disruption of Aromatase Reveals Dual Functions of cyp19a1a During Sex Differentiation in Zebrafish. AB - Aromatase (encoded by the cyp19a1a and cyp19a1b genes) plays a central role in sex differentiation in fish, but its precise roles during sex differentiation are still largely unknown. Here, we systematically generated cyp19a1a and cyp19a1b mutant lines as well as a cyp19a1a;cyp19a1b double mutant line in zebrafish using transcription activatorlike effector nucleases. Our results showed that cyp19a1a mutants and cyp19a1a;cyp19a1b double mutants, but not cyp19a1b mutants, had impaired sex differentiation, and all cyp19a1a mutants and cyp19a1a;cyp19a1b double mutants were males. During sex differentiation, the ovary-like gonads were not observed and the male sex differentiation program was delayed in the cyp19a1a null fish, and these phenotypes could be partially rescued by 17beta-estradiol treatment. Gene expression analysis indicated that male and female sex differentiation-related genes were significantly decreased in the cyp19a1a mutant. Collectively, our results revealed dual functions of the cyp19a1a gene during sex differentiation: cyp19a1a is not only indispensable for female sex differentiation but also required for male sex differentiation. PMID- 28575220 TI - Vancomycin Taper and Risk of Failure of Fecal Microbiota Transplantation in Patients With Recurrent Clostridium difficile Infection. AB - We retrospectively analyzed a cohort of 109 subjects treated for recurrent Clostridium difficile infection with fecal microbiota transplantation (FMT) at a tertiary referral center between 2011 and 2014 to determine risk factors for FMT failure. In a multivariate analysis, failure to use an oral vancomycin taper preceding FMT was associated with a significant risk of FMT failure (odds ratio, 0.15; 95% confidence interval, .007-.40). PMID- 28575222 TI - Corrigenda. PMID- 28575221 TI - Sudden cardiac death and Ethical issues of CRISPR technology. PMID- 28575223 TI - Repurposing of nucleoside- and nucleobase-derivative drugs as antibiotics and biofilm inhibitors. AB - There is an urgent need for new antibacterial drugs that are robust against the development of resistance. Drug repurposing is a cost-effective strategy to fast track the drug development process. Here we examine why the nucleoside and nucleobase analogue drugs in particular present an attractive class for repurposing. Some of these drugs have already been evaluated for their potential as antibacterial agents. In addition to inhibiting bacterial growth and survival, some also act synergistically with antibiotics, and as such can enhance the therapeutic spectrum of currently available antibiotics. Furthermore, nucleoside and nucleobase analogue drugs can inhibit bacterial virulence and biofilm formation. Biofilms are known to impart antibiotic tolerance and are associated with chronic infections. Targeting biofilm formation thus renders pathogens more susceptible to antibiotic treatment and host immune defences. Moreover, specific analogues have properties that make them less susceptible to the development of resistance. Thus, nucleoside and nucleobase analogue drugs ought to be considered as new weapons in our fight against pathogenic bacteria. PMID- 28575225 TI - Single-stage repair for multiple muscular septal defects: a single-centre experience across 16 years. AB - OBJECTIVES: Multiple muscular ventricular septal defects (VSDs) are surgically challenging and its management remains controversial. We present a technique of surgical repair for muscular VSDs, which includes surgical exposure and detection of these defects and has excellent clinical outcomes. METHODS: We have analysed consecutive patients who underwent surgical repair of isolated multiple muscular VSDs under cardiopulmonary bypass over a 16-year period (from January 2001 to November 2016) in a single centre from the southern part of India. These defects were accessed through the right atrium in most cases and closed directly; completeness of closure was confirmed by pressurizing the left ventricle with blood cardioplegia. There were no haemodynamically significant residual VSDs following repair. RESULTS: One hundred and two patients with an average time of follow-up of 4.1 years (1 month-12 years) were included. The mean age of our patients at the time of operation was 23.5 months (3 months-22 years) with a mean weight of 7.9 kg (2-55 kg). The mean cardiopulmonary bypass and cross-clamp time was 118.8 +/- 39.2 min (mean +/- SD) and 76.5 +/- 29.4 min (mean +/- SD), respectively. There were 10 (9.8%) hospital deaths and 3 late deaths in the entire study group. Permanent pacemaker was implanted in 2 patients. Seventy patients could be followed up after discharge. Postoperative pulmonary artery pressure was normal in 52% of the patients, mild-to-moderate hypertension in 27% and severe in 7% of the patients. The ejection fraction was >60% among the survivors, and there were no reoperations or reinterventions. CONCLUSIONS: This surgical approach to multiple muscular VSDs is safe and effective with minimal risk of complete heart block and diminution of ventricular function. PMID- 28575226 TI - Point-of-Care beta-Lactam Allergy Skin Testing by Antimicrobial Stewardship Programs: A Pragmatic Multicenter Prospective Evaluation. AB - Background: beta-lactam allergy skin testing (BLAST) is recommended by antimicrobial stewardship program (ASP) guidelines, yet few studies have systematically evaluated its impact when delivered at point of care. Methods: We conducted a pragmatic multicenter prospective evaluation of the use of point-of care BLAST by ASPs. In staggered 3-month intervals, ASP teams at 3 hospitals received training by allergists to offer BLAST for eligible patients with infectious diseases receiving nonpreferred therapy due to severity of their reported allergy. The primary outcome was the proportion of patients receiving the preferred beta-lactam therapy. Results: Of 827 patients with reported beta lactam allergy over 15 months, beta-lactam therapy was preferred among 632 (76%). During baseline periods, 50% (124/246) received preferred beta-lactam therapy based on history, compared with 60% (232/386) during the intervention periods (P = .02), which improved further to 81% (313/386) upon provision of BLAST (P < .001) without any increase in incidence of adverse drug reactions (4% vs 3%; P = .4). After adjusting for patient variables and the correlation between hospitals, the intervention period was associated with a 4.5-fold greater odds of receiving preferred beta-lactam therapy (95% confidence interval, 2.4-8.2; P < .0001). Conclusions: The use of BLAST at the point of care across 3 hospital ASPs resulted in greater use of preferred beta-lactam therapy without increasing the risk of adverse drug reactions. Longer-term studies are needed to better assess the safety and clinical impact of this ASP intervention. PMID- 28575227 TI - Relationship Between Psychophysiological Responses to Aversive Odors and Nutritional Status During Normal Aging. AB - Psychophysiological responses to disgusting and pleasant smells are one of the most important aspects of olfaction. These emotional signals can constitute an alert against toxic substances, and they may play a major role in food selection and nutritional intake. The aim of this study was to test this hypothesis by examining whether individual physiological responses to odors could predict the subject's nutritional status. Because aging is associated with changes in emotional response to smells, we also examined how aging affects the relationship between olfaction and nutrition. Twenty young and 20 old participants perceived a series of odorants while their psychophysiological responses were simultaneously measured, and completed the Mini-Nutritional Assessment (MNA) questionnaire. Regression between individual correlation coefficients (r-values between odor perceptual ratings and physiological parameters) and individual MNA scores revealed that appropriateness of the physiological responses to aversive odors predicted nutritional status (R2 = 0.22, P < 0.007): participants with higher electromyogram corrugator activity in response to aversive smells had better nutritional status. Furthermore, this relationship was significant in old (R2 = 0.45, P < 0.005) but not young participants (R2 = 0.04, P > 0.44). Taken together, preserved functioning of somatic markers in response to odors during normal aging is associated with better nutritional status, and may facilitate healthier food selection. PMID- 28575224 TI - Response to Antenatal Cholecalciferol Supplementation Is Associated With Common Vitamin D-Related Genetic Variants. AB - Context: Single-nucleotide polymorphisms (SNPs) in genes related to vitamin D metabolism have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentration, but these relationships have not been examined following antenatal cholecalciferol supplementation. Objective: To determine whether SNPs in DHCR7, CYP2R1, CYP24A1, and GC are associated with the response to gestational cholecalciferol supplementation. Design: Within-randomization group analysis of the Maternal Vitamin D Osteoporosis Study trial of antenatal cholecalciferol supplementation. Setting: Hospital antenatal clinics. Participants: In total, 682 women of white ethnicity (351 placebo, 331 cholecalciferol) were included. SNPs at rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1), and rs2282679 (GC) were genotyped. Interventions: 1000 IU/d cholecalciferol from 14 weeks of gestation until delivery. Main Outcome Measure: 25(OH)D at randomization and 34 weeks of gestation were measured in a single batch (Liaison; Diasorin, Dartford, UK). Associations between 25(OH)D and the SNPs were assessed by linear regression using an additive model [beta represents the change in 25(OH)D per additional common allele]. Results: Only rs12785878 (DHCR7) was associated with baseline 25(OH)D [beta = 3.1 nmol/L; 95% confidence interval (CI), 1.0 to 5.2 nmol/L; P < 0.004]. In contrast, rs10741657 (CYP2R1) (beta = -5.2 nmol/L; 95% CI, -8.2 to 2.2 nmol/L; P = 0.001) and rs2282679 (GC) (beta = 4.2 nmol/L; 95% CI, 0.9 to 7.5 nmol/L; P = 0.01) were associated with achieved 25(OH)D status following supplementation, whereas rs12785878 and rs6013897 (CYP24A1) were not. Conclusions: Genetic variation in DHCR7, which encodes 7-dehyrocholesterol reductase in the epidermal vitamin D biosynthesis pathway, appears to modify baseline 25(OH)D. In contrast, the response to antenatal cholecalciferol supplementation was associated with SNPs in CYP2R1, which may alter 25 hydroxylase activity, and GC, which may affect vitamin D binding protein synthesis or metabolite affinity. PMID- 28575228 TI - Right ventricular outflow tract dimensions in arrhythmogenic right ventricular cardiomyopathy/dysplasia-a multicentre study comparing echocardiography and cardiovascular magnetic resonance. AB - Aims: Right ventricular outflow tract (RVOT) dilation is one of the echocardiographic criteria in the 2010 revised Task Force Criteria (TFC) of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). However, studies comparing cardiac magnetic resonance (CMR) and transthoracic echocardiography (TTE) suggest a lower diagnostic accuracy of TTE due to its operator dependence and limited reproducibility. The goal of this study was to compare the 2010 TFC measures of RVOT dilation with three alternative measures for improving the echocardiographic assessment of RVOT in patients with ARVC/D. Methods and results: In this multicentre study, CMR and TTE were performed in 38 patients with a definite, borderline, or possible ARVC/D diagnosis and in 10 healthy controls. Besides the echocardiographic RVOT measurements listed by the 2010 TFC, we assessed three additional end-diastolic RVOT diameters. These included the RVOT diameter defined by the parasternal long axis M-mode of the aortic sinus portion (RVOT3), that defined by the parasternal long axis M-mode of the left ventricle (RVOT4), and that obtained by the parasternal short axis view of the distal RVOT proximal to the pulmonary valve (RVOT5). RVOT4 provided the best correlation between CMR and TTE (r = 0.92, [95% confidence interval (CI): 0.84-0.96; P < 0.0001]) and enhanced diagnostic accuracy for diagnosing ARVC/D (area under the curve 0.92 [95% CI, 0.78-0.98]). Conclusion: Among all RVOT diameters examined, that defined by the parasternal long axis M-mode of the left ventricle (RVOT4) provides the best agreement between CMR and TTE and exhibits the best diagnostic accuracy for ARVC/D. This novel RVOT4 measurement carries the potential for improving the echocardiographic diagnosis of ARVC/D. PMID- 28575229 TI - The Relationship Between the Score on a Simple Measure of Cognitive Function and Incident CVD in People With Diabetes: A Post Hoc Epidemiological Analysis From the ACCORD-MIND Study. AB - Context and Objective: Diabetes is associated with a greater risk for incident cardiovascular disease and cognitive dysfunction. This study aimed to investigate, in people with type 2 diabetes, the association of a simple measure of cognitive function to cardiovascular disease events and mortality. Design, Setting, Participants, Measurements, and Outcomes: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial included persons with longstanding type 2 diabetes. A substudy of 2977 (Memory in Diabetes) participants aged 55 years or older aimed to test the effect of the interventions on brain structure and function. At baseline, participants were administered a cognitive battery that included the digit symbol substitution test (DSST). The associations of the DSST and the ACCORD primary outcome (the first occurrence of nonfatal myocardial infarction or nonfatal stroke or death from cardiovascular causes) and all-cause mortality were investigated with Cox proportional hazard models adjusting for several demographic and clinical variables. Results: Median follow-up time was 4.27 years. An inverse relationship between the incidence of the ACCORD primary outcome and baseline cognitive score was demonstrated. A 1-point higher DSST score was associated with a lower incidence of the primary outcome (hazard ratio, 0.987; 95% confidence interval, 0.977 to 0.998; P = 0.019), after adjustment for demographic and clinical trial factors, additional baseline cardiovascular risk factors, and self-reported need for assistance to follow the protocol. Conclusion: Lower scores on the DSST, a simple, sensitive neuropsychological instrument, are associated with a higher incidence of cardiovascular events in persons >55 years old with longstanding diabetes. PMID- 28575230 TI - Cognitive Training for Ethnic Minority Older Adults in the United States: A Review. AB - Purpose of the Study: Interest in cognitive training for healthy older adults to reduce cognitive decline has grown considerably over the past few decades. Given the shift toward a more diverse society, the purpose of this review is to examine the extent of race/ethnic minority participation in cognitive training studies and characteristics of studies that included race/ethnic minority participants. Design and Methods: This review considered peer-reviewed studies reporting cognitive training studies for cognitively healthy, community-dwelling older adults (age 55+) in the United States published in English before December 31, 2015. A total of 31 articles published between 1986 and 2015 meeting inclusion criteria were identified and included in the review. Results: A total of 6,432 participants were recruited across all of the studies, and ranged in age from 55 to 99 years. Across all studies examined, 39% reported racial/ethnic background information. Only 3 of these studies included a substantial number of minorities (26.7% in the ACTIVE study; 28.4% in the SeniorWISE study; 22.7% in the TEAM study). Race/ethnic minority older adults were disproportionately underrepresented in cognitive training studies. Implications: Further research should aim to enroll participants representative of various race/ethnic minority populations. Strategies for recruitment and retention of ethnic minority participants in cognitive training research are discussed, which could lead to the development of more culturally appropriate and perhaps more effective cognitive interventions. PMID- 28575231 TI - Everyday Multitasking Abilities in Older HIV+ Adults: Neurobehavioral Correlates and the Mediating Role of Metacognition. AB - Objective: The prevalence of older adults living with HIV is rising, as is their risk for everyday functioning problems associated with neurocognitive dysfunction. Multitasking, the ability to maintain and carry out subgoals in support of a larger goal, is a multidimensional skill ubiquitous during most real life tasks and associated with prefrontal networks that are vulnerable in HIV. Understanding factors associated with multitasking will improve characterization of HIV-associated neurocognitive disorders. Metacognition is also associated with frontal systems, is impaired among individuals with HIV, and may contribute to multitasking. Method: Ninety-nine older (>=50 years) adults with HIV completed: the Everyday Multitasking Test (MT), a performance-based measure during which participants concurrently attempt four everyday tasks (e.g., medication management) within a time limit; a comprehensive neuropsychological battery; measures of metacognition regarding their MT performance (e.g., metacognitive knowledge and online awareness). Results: Better global neuropsychological performance (i.e., average T-score across all domains) was associated with better Everyday MT total scores (rho = 0.34; p < .001), as was global metacognition (rho = 0.37, p < .01). Bootstrapping mediation analysis revealed global metacognition was a significant partial mediator between neurocognition and Everyday MT (b = 0.09, 95% confidence interval [CI] = 0.01, 0.25). Specifically, metacognitive knowledge (but not online awareness) drove this mediation (b = 0.13, 95% CI = 0.03, 0.27). Conclusions: Consistent with findings among younger persons with HIV, neuropsychological performance is strongly associated with a complex, laboratory-based test of everyday multitasking, and metacognition of task performance was a pathway through which successful multitasking occurred. Interventions aimed at modifying metacognition to improve daily functioning may be warranted among older adults with HIV. PMID- 28575233 TI - Stem cell activity of type A spermatogonia is seasonally regulated in rainbow trout. AB - Spermatogonial stem cells (SSCs) support continuous production of sperm throughout the male's life. However, the biological characteristics of SSCs are poorly understood in animals exhibiting seasonal reproduction, even though most wild animals are seasonal breeders. During the spermiation season in rainbow trout, the lumen of the testes contains only spermatozoa and scattered type A spermatogonia (ASG) along the walls of the testicular lobules. These few remaining ASG, designated "residual ASG," are the only germ cells capable of supporting the next spermatogenesis, suggesting that the residual ASG are true SSCs. However, whether residual ASG can behave as SSCs in any teleost species is unknown. In this study, we attempted to clarify the biological characteristics of SSCs associated with seasonal reproduction in rainbow trout using spermatogonial transplantation. We found that the stem cell activity was clearly regulated seasonally during the annual reproductive cycle. Although the residual ASG exhibited moderate transplantability and colony-forming ability at the beginning of the spermiation season, these parameters decreased dramatically later and remained low until the next spermatogenesis was initiated. Furthermore, no clear correlations were observed between these qualitative changes and previously described morphologic characteristics of ASG or plasma sex steroid levels. Our results suggest that the biological properties of SSC populations in rainbow trout are seasonally regulated by a novel mechanism. PMID- 28575232 TI - Liver Safety of Statins in Prediabetes or T2DM and Nonalcoholic Steatohepatitis: Post Hoc Analysis of a Randomized Trial. AB - Context: Patients with nonalcoholic fatty liver disease have a high cardiovascular risk, but statins are rarely prescribed because of fear of hepatotoxicity. Objective: To prospectively assess the long-term safety of statins in patients with prediabetes/type 2 diabetes mellitus (T2DM) and nonalcoholic steatohepatitis (NASH). Design: Post hoc analysis of statin use during a randomized, controlled trial assessing pioglitazone vs placebo for NASH. Patients: A total of 101 patients (86 receiving statins) with biopsy-proven NASH and prediabetes/T2DM were followed for up to 36 months. Interventions: Oral glucose tolerance test and percutaneous liver biopsy (baseline, month 18, and month 36); liver magnetic resonance spectroscopy and euglycemic insulin clamp (baseline and month 18). Main Outcome Measures: Histologic and biochemical safety of statin use among patients with NASH. Results: Only 37% of patients were receiving statins at enrollment despite their high cardiovascular risk. Statin nonusers had higher plasma alanine aminotransferase levels but similar histologic severity of liver disease at baseline. In both statin users and nonusers, the same number of patients (n = 4) had a twofold or greater increase in plasma aminotransferases during follow-up. One statin nonuser was discontinued from the study because of this elevation. Values returned to normal without any active measure in all other cases. No changes on liver histology or hepatic insulin resistance were observed in patients with NASH newly started on a statin and receiving placebo during the main study. Conclusions: Statin therapy is safe in patients with prediabetes/T2DM and NASH. Given their high cardiovascular risk, statin therapy should be encouraged in this population. PMID- 28575234 TI - Assessing Grief of Family Caregivers of People with Dementia: Validation of the Chinese Version of the Marwit-Meuser Caregiver Grief Inventory. AB - Grief in dementia caregiving is underexplored in research studies in the Chinese context, yet social workers often work with caregivers of people with dementia (PWD) and who experience grief. Having a valid assessment tool can help social workers better identify the grief of caregivers and facilitate caregivers' articulation of grief. This article describes a study aimed to validate the Marwit-Meuser Caregiver Grief Inventory-Short Form (C-MM-CGI-SF) among Hong Kong Chinese caregivers of PWD. One hundred and twenty caregivers participated in this study. They were recruited from day care centers and a memory clinic. The short version of MM-CGI was translated into Chinese, and participants were asked to complete a questionnaire that included this scale and other scales validating it. Reliability and validity were examined. C-MM-CGI-SF was found to be a reliable and valid measure in the Hong Kong context. Its construct validity was demonstrated by the positive correlations with caregiving strain and depression, and negative correlations with presence of meaning and life satisfaction. The discriminant validity was supported by showing that spousal caregivers' grief level was significantly higher than that of nonspousal caregivers. Authors recommend social workers using the C-MM-CGI-SF to assess the grief of Chinese caregivers caring for people suffering from dementia. PMID- 28575238 TI - Does Disseminated Nontuberculous Mycobacterial Disease Cause False-Positive Determine TB-LAM Lateral Flow Assay Results? A Retrospective Review. AB - We retrospectively reviewed the Determine TB-LAM lateral flow assay (LF-LAM) results among human immunodeficiency virus-infected patients with disseminated nontuberculous mycobacterial (NTM) disease. LF-LAM was positive in 19 of 21 patients without evidence of tuberculosis (TB) coinfection. Although TB-NTM coinfection may have been underdiagnosed, our results suggest that disseminated NTM disease may cause false-positive LF-LAM results. PMID- 28575235 TI - Remote management of heart failure using implantable electronic devices. AB - Aims: Remote management of heart failure using implantable electronic devices (REM-HF) aimed to assess the clinical and cost-effectiveness of remote monitoring (RM) of heart failure in patients with cardiac implanted electronic devices (CIEDs). Methods and results: Between 29 September 2011 and 31 March 2014, we randomly assigned 1650 patients with heart failure and a CIED to active RM or usual care (UC). The active RM pathway included formalized remote follow-up protocols, and UC was standard practice in nine recruiting centres in England. The primary endpoint in the time to event analysis was the 1st event of death from any cause or unplanned hospitalization for cardiovascular reasons. Secondary endpoints included death from any cause, death from cardiovascular reasons, death from cardiovascular reasons and unplanned cardiovascular hospitalization, unplanned cardiovascular hospitalization, and unplanned hospitalization. REM-HF is registered with ISRCTN (96536028). The mean age of the population was 70 years (range 23-98); 86% were male. Patients were followed for a median of 2.8 years (range 0-4.3 years) completing on 31 January 2016. Patient adherence was high with a drop out of 4.3% over the course of the study. The incidence of the primary endpoint did not differ significantly between active RM and UC groups, which occurred in 42.4 and 40.8% of patients, respectively [hazard ratio 1.01; 95% confidence interval (CI) 0.87-1.18; P = 0.87]. There were no significant differences between the two groups with respect to any of the secondary endpoints or the time to the primary endpoint components. Conclusion: Among patients with heart failure and a CIED, RM using weekly downloads and a formalized follow up approach does not improve outcomes. PMID- 28575237 TI - Inside out: efflux of carbon dioxide from leaves represents more than leaf metabolism. AB - High concentrations of inorganic carbon in the xylem, produced from root, stem, and branch respiration, travel via the transpiration stream and eventually exit the plant through distant tissues as CO2. Unlike previous studies that focused on the efflux of CO2 from roots and woody tissues, we focus on efflux from leaves and the potential effect on leaf respiration measurements. We labeled transported inorganic carbon, spanning reported xylem concentrations, with 13C and then manipulated transpiration rates in the dark in order to vary the rates of inorganic carbon supply to cut leaves from Brassica napus and Populus deltoides. We used tunable diode laser absorbance spectroscopy to directly measure the rate of gross 13CO2 efflux, derived from inorganic carbon supplied from outside of the leaf, relative to gross 12CO2 efflux generated from leaf cells. These experiemnts showed that 13CO2 efflux was dependent upon the rate of inorganic carbon supply to the leaf and the rate of transpiration. Our data show that the gross leaf efflux of xylem-transported CO2 is likely small in the dark when rates of transpiration are low. However, gross leaf efflux of xylem-transported CO2 could approach half the rate of leaf respiration in the light when transpiration rates and branch inorganic carbon concentrations are high, irrespective of the grossly different petiole morphologies in our experiment. PMID- 28575236 TI - Monitoring of the spatial and temporal dynamics of BER/SSBR pathway proteins, including MYH, UNG2, MPG, NTH1 and NEIL1-3, during DNA replication. AB - Base lesions in DNA can stall the replication machinery or induce mutations if bypassed. Consequently, lesions must be repaired before replication or in a post replicative process to maintain genomic stability. Base excision repair (BER) is the main pathway for repair of base lesions and is known to be associated with DNA replication, but how BER is organized during replication is unclear. Here we coupled the iPOND (isolation of proteins on nascent DNA) technique with targeted mass-spectrometry analysis, which enabled us to detect all proteins required for BER on nascent DNA and to monitor their spatiotemporal orchestration at replication forks. We demonstrate that XRCC1 and other BER/single-strand break repair (SSBR) proteins are enriched in replisomes in unstressed cells, supporting a cellular capacity of post-replicative BER/SSBR. Importantly, we identify for the first time the DNA glycosylases MYH, UNG2, MPG, NTH1, NEIL1, 2 and 3 on nascent DNA. Our findings suggest that a broad spectrum of DNA base lesions are recognized and repaired by BER in a post-replicative process. PMID- 28575239 TI - Whole-Genome Cardiac DNA Methylation Fingerprint and Gene Expression Analysis Provide New Insights in the Pathogenesis of Chronic Chagas Disease Cardiomyopathy. AB - Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects 10 million people worldwide. Approximately 12000 deaths attributable to Chagas disease occur annually due to chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy presenting with heart failure and arrythmia; 30% of infected subjects develop CCC years after infection. Genetic mechanisms play a role in differential progression to CCC, but little is known about the role of epigenetic modifications in pathological gene expression patterns in CCC patients' myocardium. DNA methylation is the most common modification in the mammalian genome. Methods: We investigated the impact of genome-wide cardiac DNA methylation on global gene expression in myocardial samples from end-stage CCC patients, compared to control samples from organ donors. Results: In total, 4720 genes were differentially methylated between CCC patients and controls, of which 399 were also differentially expressed. Several of them were related to heart function or to the immune response and had methylation sites in their promoter region. Reporter gene and in silico transcription factor binding analyses indicated promoter methylation modified expression of key genes. Among those, we found potassium channel genes KCNA4 and KCNIP4, involved in electrical conduction and arrythmia, SMOC2, involved in matrix remodeling, as well as enkephalin and RUNX3, potentially involved in the increased T-helper 1 cytokine-mediated inflammatory damage in heart. Conclusions: Results support that DNA methylation plays a role in the regulation of expression of pathogenically relevant genes in CCC myocardium, and identify novel potential disease pathways and therapeutic targets in CCC. PMID- 28575240 TI - Epidemiology, diagnosis, and management of esophageal perforations: systematic review. AB - We performed a systematic review of epidemiological, diagnostic, and therapeutic outcomes of esophageal perforations. A systematic review was performed in PubMed database using the key-phrase 'esophageal perforation'. All studies regarding acute esophageal perforations were reviewed and parameters of epidemiology, diagnosis, and management published in the literature from 2005 up to 2015 were included in the study. Studies of postoperative esophageal leaks were excluded. Two researchers performed individually the research, while quality assessment was performed according to GRADE classification. Main outcomes and exposure were overall mortality, perforation-to-admission interval, anatomical position, cause, prevalent symptom at admission, diagnostic tests used, type of initial management (conservative or surgery), healing rate, and fistula complication. There were 1319 articles retrieved, of which 52 studies including 2,830 cases finally met inclusion criteria. Mean duration of study period was 15.2 years. Mean patient age was 58.4 years. Out of 52 studies included, there were 43 studies of very low or low quality included. The overall mortality rate according to extracted data was 13.3% (n = 214, 1,644 patients, 39 studies). Admission before 24 hours was reported in 58.1% of patients (n = 514). Position was thoracic in 72.6% of patients (n = 813, 1,120 patients, 20 studies). Mean cause of perforation was iatrogenic in 46.5% of patients (n = 899, 1,933 patients, 40 studies). Initial management was conservative in 51.3% of cases (n = 904, 1,762 patients, 41 studies) CT confirmed diagnosis in 38.7% of overall cases in which it was used as imaging diagnostic procedure (n = 266), X-ray in 36.6% (n = 231), and endoscopy in 37.4% (n = 343). Sepsis on admission was observed in 23.3% of cases (209 out of 898 patients, 16 studies). The present systematic review highlighted the significant proportion of cases diagnosed with delay over 24 hours, mortality rates ranging over 10% and no consensus regarding optimal therapeutic approach and optimal diagnostic management. As esophageal perforation represents a high risk clinical condition without consensus regarding optimal management, there should be large multicenter prospective studies or Randomized Controlled Trial (RCT)s performed in order to advance diagnostic and therapeutic approach of such challenging pathology. PMID- 28575241 TI - Reduced fitness and physical functioning are long-term sequelae after curative treatment for esophageal cancer: a matched control study. AB - Reduced physical functioning is common following resections for esophageal cancer; however, objective data on physical performance outcomes in this cohort are rare. The aim of this study was to assess the physical performance and health related quality of life (HRQOL) of disease free survivors and compare findings in a case matched noncancer control group. Twenty-five males (mean (+/-SD) aged 63 (+/-6) years) who were over 6 months postesophagectomy and disease-free were compared with 25 controls (60 +/- 6 years). Physical functioning was assessed through hand grip strength (dynamometry), exercise capacity (incremental shuttle walk test), physical activity levels (RT3 accelerometer), and body composition (bio-electrical impedance analysis). Health-related quality of life was measured using the EORTC QLQ-C30 questionnaire. Esophageal cancer survivors demonstrated significantly lower fitness (P < 0.001) and time spent in moderate (P < 0.001) and vigorous (P < 0.001) intensity physical activity compared with controls. Global health status and quality of life were similar in both groups (P = 0.245); however, physical and role functioning domains were lower in the cancer survivors (P < 0.001, and P = 0.001, respectively). These data show that disease-free survivors of curative esophageal cancer treatment demonstrate a significant compromise in physical functioning compared with controls, thus highlighting the multiple, complex rehabilitative needs of this cohort. PMID- 28575242 TI - Prognostic significance of the prognostic nutritional index in esophageal cancer patients undergoing neoadjuvant chemotherapy. AB - Nutritional status is one of the most important issues faced by cancer patients. Several studies have shown that a low preoperative nutritional status is associated with a worse prognosis in patients with various types of cancer, including esophageal cancer (EC). Recently, neoadjuvant chemotherapy (NAC) and/or radiotherapy have been accepted as the standard treatment for resectable advanced EC. However, NAC has the potential to deteriorate the nutritional status of a patient. This study aimed to evaluate the prognostic significance of the nutritional status for EC patients who underwent NAC. We retrospectively reviewed 66 squamous cell EC patients who underwent NAC consisting of docetaxel, cisplatin, and 5-fluorouracil followed by subtotal esophagectomy at Nara Medical University Hospital between January 2009 and August 2015. To assess the patients' nutritional status, the prognostic nutritional index (PNI) before commencing NAC and prior to the operation was calculated as 10 * serum albumin (g/dl) + 0.005 * total lymphocyte count in the peripheral blood (per mm3). The cutoff value of the PNI was set at 45. A multivariable analysis was performed to identify prognostic factors for overall survival (OS) and relapse-free survival (RFS). The mean pre NAC and preoperative PNI were 50.2 +/- 5.7 and 48.1 +/- 4.7, respectively (P = 0.005). The PNI decreased following NAC in 44 (66.7%) patients. Before initiating NAC, 9 (13.6%) patients had a low PNI, and 12 (18.2%) patients had a low PNI prior to the operation. The pre-NAC PNI and preoperative PNI were significantly associated with the OS (P = 0.013 and P = 0.004, respectively) and RFS (P = 0.036 and P = 0.005, respectively) rates. The multivariable analysis identified the preoperative PNI as an independent prognostic factor for poor OS and RFS, although the pre-NAC PNI was not an independent predictor. Our results suggest that the preoperative PNI is a useful marker for predicting the long-term outcomes of EC patients undergoing NAC and subsequent subtotal esophagectomy. Therefore, patients with a low preoperative nutritional status may be at a higher risk of EC recurrence. PMID- 28575243 TI - Predictive value of nodal maximum standardized uptake value of pretreatment [18F]fluorodeoxyglucose positron emission tomography imaging in patients with esophageal cancer. AB - We retrospectively reviewed 102 patients with esophageal cancer (97.1% squamous cell carcinoma, 96.1% stage III) received FDG-PET staging and were treated by chemoradiotherapy with or without resection to assess whether the pretreatment [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) maximum standardized uptake value (SUVmax) of the primary tumor and metastatic lymph nodes can predict the prognosis of patients with esophageal cancer. Receiver operating characteristic analysis was performed to find the cutoff values for primary tumor SUVmax and nodal SUVmax. The influence of clinical factors including primary tumor SUVmax and nodal SUVmax on local progression-free survival, nodal progression-free survival (NPFS), distant metastases-free survival (DMFS), and overall survival (OS) were evaluated using univariate and multivariate analyses. A total of 40 patients received esophagectomy after neoadjuvant chemoradiotherapy (trimodality), while 62 patients received definitive chemoradiotherapy (dCRT). The median follow-up was 26.4 months. The SUVmax of primary tumor had no significant predictive value on all outcomes, while the SUVmax of metastatic lymph nodes had predictive value on several outcomes. High nodal SUVmax (>=7) predicted for worse outcomes than low nodal SUVmax (<7) in the patients who received dCRT (two-year DMFS, 17% vs. 92%, P < 0.001; NPFS, 14% vs. 81%, P = 0.001; OS, 21% vs. 50%, P = 0.003), but not in those received trimodality. On multivariate analysis of patients receiving dCRT, nodal SUVmax was the strongest independent predictor on DMFS (hazard ratio [HR] 13.93, P < 0.001), NPFS (HR 3.99, P = 0.026), PFS (HR 2.90, P = 0.003), and OS (HR 3.80, P = 0.001). High pretreatment nodal SUVmax predicts worse treatment outcomes for the patients treated with dCRT. PMID- 28575244 TI - Venous superdrained gastric tube pull-up procedure for hypopharyngeal and cervical esophageal reconstruction reduces postoperative anastomotic leakage and stricture. AB - Gastric pull-up is a common procedure to reconstruct the continuity of the upper digestive tract after esophageal resection. However, this technique sometimes causes postoperative anastomotic leakage or stricture, resulting from insufficient blood flow at the distal end. To overcome this problem, additional microvascular venous anastomoses were performed. The purpose of this study was to compare the outcomes of post-surgical anastomotic leakage and stricture in patients with and without additional microvascular venous superdrainage after cervical esophageal and hypopharyngeal resection and gastric tube reconstruction. A total of 29 consecutive patients with esophageal or hypopharyngeal cancer who underwent total esophagectomy and hypopharyngectomy with gastric tube reconstruction in the National Organization Nagasaki Medical Center between April 2014 and May 2016 were analyzed in this study. Of these patients, 20 underwent additional venous anastomoses (superdrainage group), and 9 did not undergo additional procedures (standard group). We compared the frequency of post surgical stricture and leakage in the two groups retrospectively. Three of nine patients (33.3%) developed postoperative leakage in the standard group, and 1 of 20 (5.0%) did so in the superdrainage group. Six of nine patients (66.7%) showed postoperative anastomotic stricture in the standard group, but none did so in the superdrainage group. Patients who did not undergo additional venous superdrainage were significantly more likely to develop postsurgical leakage (P < 0.05, Chi square test) and anastomotic stricture (P < 0.001, Chi-square test). Our study revealed that only additional venous anastomoses could reduce the incidence of postoperative anastomotic leakage and stricture. This procedure is of merit to perform after total esophagectomy and hypopharyngectomy with gastric tube reconstruction. PMID- 28575245 TI - Peroral endoscopic myotomy versus surgical myotomy for primary achalasia: single center, retrospective analysis of 74 patients. AB - Achalasia is a neurodegenerative motility disorder of the esophagus; dysphagia, weight loss, chest pain, and regurgitation are its main symptoms. Surgical myotomy (HM) is considered the gold standard treatment. However, peroral endoscopic myotomy (POEM) seems to be a safe and effective alternative option. The aim of this study is to compare the safety and efficacy of these techniques. From March 2012 to June 2015, 74 patients with symptomatic primary achalasia underwent myotomy. The two groups were compared in terms of intraoperative and postoperative outcomes and Eckardt score at last follow-up. A morphofunctional comparison was also performed. Thirty-two myotomies were performed endoscopically (POEM group) and 42 were performed laparoscopically with a 180 degrees anterior fundoplication (surgical myotomy [SM] group). Operative time was significantly shorter for the POEM group (63 [range: 32-114] vs. 76 minutes [54-152]; P = 0.0005). Myotomy was significantly longer for the POEM group (12 [range: 10-15] vs. 9 cm [range: 7-10]; P = 0.0001). Postoperative morbidity occurred in two patients (4.7%) in the SM group; no complications (P = not significant) were recorded for the POEM group. The median Eckardt score at last follow-up decreased for each group from 6 to 1 (P < 0.001). Morphological evaluation was performed for 20 patients and functional evaluation was performed in 18 patients of each group. Lower esophageal sphincter resting and relaxation pressures were significantly reduced in both groups (P < 0.001). Eight patients in the POEM group (40%) had esophagitis at endoscopy: 4 (20%) with Los Angeles (LA) grade A, 3 (15%) with LA grade B, and 1 patient with LA grade D (5%). Five patients in POEM group (28%) had a pathologic DeMeester score. In the SM group, one patient (5%) had esophagitis (P = 0.04; 95% CI) and 4 patients (22%) presented a pathological DeMeester score. Perioperative results for POEM and SM are similar. The absence of an antireflux wrap leads to an increased risk of reflux with consequent esophagitis. SM with an antireflux wrap could be a preferred choice when a long standing gastroesophageal reflux could potentially lead to a damage as, for example, in young patients. PMID- 28575246 TI - Safety and feasibility of esophageal self- expandable metal stent placement without the aid of fluoroscopy. AB - Self-expandable metal stents (SEMSs) are used for the management of certain esophageal conditions such as strictures, perforations, and fistulae. These can be placed using fluoroscopic control, endoscopic control, or a combination of both. We evaluated our institutional experience of placing a SEMS using only endoscopy without the aid of fluoroscopy to determine safety and feasibility using this technique. A retrospective review was performed to identify all patients who underwent esophageal SEMS from January 2010 to June 2015. Placement of SEMS was accomplished under direct endoscopic visualization without the aid of fluoroscopy. Esophageal lesion was initially identified during endoscopy and a fully covered SEMS was passed over the guide wire and deployed under direct vision. Misplacement of the SEMS during the procedure that required replacement with another new SEMS was considered as a failed procedure. Other periprocedural complications caused by placement of SEMS were noted. A total of 172 patients underwent 280 procedures for SEMS placement. Mean age was 66 years. The most common indication for SEMS placement was stricture in 248 (88%) procedures. Periprocedure SEMS misplacement occurred in 12 (4%) patients. However, only 8 (3%) patients needed to have a new SEMS placed during the same procedure. A total of 64 (23%) patients had migration of SEMS. There were no other periprocedure complications leading to adverse events. Self-expandable metal stent can be placed accurately and safely under direct endoscopic visualization without the aid of fluoroscopy. PMID- 28575247 TI - Endoscopic ultrasound in diagnosis of esophageal tuberculosis: 10-year experience at a tertiary care center. AB - Definite diagnosis of esophageal tuberculosis (ET) requires isolation of tubercle bacilli, which is challenging in clinical practice. Difficulty in differentiating ET from other esophageal diseases may well result in a delay in diagnosis. The literature on utility of endoscopic ultrasound (EUS) in diagnosis of ET is insufficient. This study aims to evaluate the role of EUS morphology combined with EUS-guided tissue acquisition in the diagnosis of ET. Data of the 35 patients diagnosed with ET from January 2006 to October 2015 were retrospectively analyzed. After miniprobe and linear echoendoscopic visualization, either linear EUS-guided deep biopsy or EUS-guided fine needle aspiration was performed for tissue acquisition. Histocytopathological results showing caseous necrosis or acid fast bacilli (AFB) or epithelioid granuloma were considered diagnostic. Esophageal wall thickening or mass formation with disruption of the adventitia due to infiltration by adjacent mediastinal lymphadenopathy was typically observed under EUS. Tissue acquisition revealed epithelioid granuloma in 33 patients, caseous necrosis in 13, a positive AFB stain in 14, and nonspecific chronic inflammation in 2. Of the 35 patients, 33 (94.3%) with both characteristic EUS morphology and diagnostic histocytopathology were considered to have an EUS established diagnosis. The remaining two with only nonspecific chronic inflammation received empirical antitubercular chemotherapy based solely on EUS morphology. The two-year follow-up confirmed diagnosis of ET in all patients. While the final diagnosis of ET was based upon two-year follow-up of treatment response to antitubercular medication in addition to caseous necrosis/granuloma/positive-AFB stain revealed by EUS-guided tissue acquisition, an EUS-established diagnosis of ET and medical treatment with long-term follow-up is rational and practical compared with surgery or untreated follow-up. PMID- 28575249 TI - Esophageal distensibility measurement: impact on clinical management and procedure length. AB - Luminal distensibility measurement has demonstrated relevance to various disease processes, though its effects on clinical decision-making have been less well understood. This study aims to characterize the clinical impact of impedance planimetry measurement as well as the learning curve associated with its use in the esophagus. A single provider performed distensibility measurement in conjunction with upper endoscopy for a variety of clinical indications with the functional lumen imaging probe (FLIP) over a period of 21 months. Procedural data were prospectively collected and, along with medical records, retrospectively reviewed. Seventy-three procedures (70 patients) underwent esophageal distensibility measurement over the timeline of this study. The most common procedural indications were known or suspected achalasia (32.9%), dysphagia with connective tissue disease (13.7%), eosinophilic esophagitis (12.3%), and dysphagia with prior fundoplication (9.6%). FLIP results independently led to a change in management in 29 (39.7%) cases and supported a change in management in an additional 15 (20.5%) cases. The most common change in management was a new or amended therapeutic procedure (79.5%). Procedural time added by distensibility measurement was greater among earlier cases than among later cases. The median time added overall was 5 minutes and 46 seconds. Procedural time added varied significantly by procedural indication, but changes in management did not. Distensibility measurement added meaningful diagnostic information that impacted therapeutic decision-making in the majority of cases in which it was performed. Procedural time added by this modality is typically modest and decreases with experience. PMID- 28575248 TI - Catheter probe endoscopic ultrasonography by using cold lubricating jelly-filled method for esophageal subepithelial tumors. AB - Catheter probe endoscopic ultrasonography (C-EUS) by ultrasonographic jelly filled method has been used to evaluate esophageal subepithelial tumors (SETs). Ultrasonographic jelly is safe on the skin, but its internal safety has not been demonstrated. The jelly stored at room temperature is easily injected into the esophagus through the instrument channel of the endoscope. However, using jelly stored at room temperature remains problematic because the jelly is drained rapidly. We used cold lubricating jelly and an intravenous extension tube to resolve these problems. In this study, we evaluated the safety and efficacy of cold lubricating jelly-filled method. The medical records of patients who underwent C-EUS by using water or cold lubricating jelly-filled method for esophageal SETs from March 2013 to September 2016 in Gangneung Asan hospital were reviewed. Clinical characteristics and EUS findings were evaluated retrospectively. Image quality and procedure time between water and cold lubricating jelly-filled method were compared retrospectively. This study included 138 patients (74 males, 64 females) with esophageal SET with a mean age of 57.1 +/- 11.1 years. Thirty-four patients had lesions in the upper esophagus, 58 patients had lesions in the middle esophagus, and 46 patients had lesions in the lower esophagus. The EUS diagnoses were leiomyoma (82.6%), hemangioma (4.3%), extrinsic compressive lesion (3.6%), granulosa cell tumor (2.9%), ectopic calcification (1.4%), cyst (1.4%), lipoma (0.7%), varix (0.7%), and inconclusive lesion (2.2%). The mean image score in the cold lubricating jelly filled-method group was higher than that in the water-filled method group (3.2 +/- 0.7 vs. 2.8 +/- 0.7, P = 0.002). The procedure time in the cold lubricating jelly filled method group was shorter than that in the water-filled method group (10 minutes 27 seconds +/- 4 minutes 22 seconds versus 13 minutes 20 seconds +/- 6 minutes 20 seconds, P = 0.045). No procedure-related complication was observed. C-EUS using the cold lubricating jelly-filled method seems to provide better image quality and shorter procedure time compared with C-EUS using the water-filled method. PMID- 28575250 TI - Characterization of tissue chromogranin A (CgA) immunostaining and clinicohistopathological changes for the 125 Chinese patients with primary small cell carcinoma of the esophagus. AB - The rarity of primary small cell carcinoma of the esophagus (PSCE) has limited the clinical feature and survival analysis with large sample size. Tissue chromogranin A (CgA) protein expression has been reported to be a useful biomarker for diagnosing PSCE. Interestingly, recent studies have indicated tissue CgA as a significant prognostic marker in multiple human cancers, but without PSCE. The present study, thus, was undertaken to characterize the clinicopathological changes and to evaluate the associations of tissue CgA expression with clinical response on Chinese PSCE patients. All the 125 PSCE patients were enrolled from our 500,000 esophageal and gastric cardia carcinoma databases (1973-2015), constructed by the cooperative team from more than 700 hospitals in China and established by Henan Key Laboratory for Esophageal Cancer Research in Henan, China. Immunostaining for CgA showed that CgA was mainly located in cytoplasm of tumor cells with a positive detection rate of 44.6%. The CgA positive expression rate in PSCE at lower segment of the esophagus (72.2%) was higher than that at middle segment (41.5%) (P = 0.001). However, CgA protein expression did not correlated with lymph node metastasis (P = 0.767), TNM staging (P = 0.740), tumor invasion (P = 0.253), gender (P = 0.262), and age (P = 0.250). Multivariate survival analysis showed that the patients with higher CgA protein expression had a superior long survival than those without CgA expression (P = 0.037). The clinicopathological analysis showed that PSCE occurred predominantly in male (M:F = 1.9:1) at the middle segment (68%) of the esophagus. Histologically, 89.6% were pure PSCE and 10.4% were mixed type with either squamous cell carcinoma (8%) or adenocarcinoma (2.4%). It was noteworthy that, with the in-depth invasion from T1 to T2 and T3, the positive lymph node metastasis rate increased dramatically from 38%, 56% to 74%, respectively. The survival rates of 1-, 2-, 3-, and 5-year were 64%, 35%, 18%, and 7%, respectively. The Kaplan-Meier survival analysis showed that the young patients (<=60 years) had longer survival than the elderly (P = 0.011). Interestingly, multivariate survival analysis revealed that the patients with mixed PSCE had a significantly better survival than those with pure PSCE (P = 0.015). Furthermore, the median survival time for the patients with and without lymph node metastasis was 1.16 and 2.03 years, respectively. But, the difference was not significant (P = 0.143). Univariate analysis did not show any survival influence by gender, tumor location, tumor invasion depth, and TNM staging. It was noteworthy that, of the 13 early PSCE patients (T1N0M0), only one patient had more than 5 year survival, the others died with less than one or two year (65%). The present study indicates that the PSCE is of badly worsen prognosis, even in the pathological early stage. Tissue CgA protein expression is a promising maker not only for diagnosis and also for prognosis. Further assessment is needed to establish specific PSCE pathological staging system and to clarify the mechanisms of CgA protein in PSCE progression and prognosis. PMID- 28575251 TI - Hierarchical probabilistic models for multiple gene/variant associations based on next-generation sequencing data. AB - Motivation: The identification of genetic variants influencing gene expression (known as expression quantitative trait loci or eQTLs) is important in unravelling the genetic basis of complex traits. Detecting multiple eQTLs simultaneously in a population based on paired DNA-seq and RNA-seq assays employs two competing types of models: models which rely on appropriate transformations of RNA-seq data (and are powered by a mature mathematical theory), or count-based models, which represent digital gene expression explicitly, thus rendering such transformations unnecessary. The latter constitutes an immensely popular methodology, which is however plagued by mathematical intractability. Results: We develop tractable count-based models, which are amenable to efficient estimation through the introduction of latent variables and the appropriate application of recent statistical theory in a sparse Bayesian modelling framework. Furthermore, we examine several transformation methods for RNA-seq read counts and we introduce arcsin, logit and Laplace smoothing as preprocessing steps for transformation-based models. Using natural and carefully simulated data from the 1000 Genomes and gEUVADIS projects, we benchmark both approaches under a variety of scenarios, including the presence of noise and violation of basic model assumptions. We demonstrate that an arcsin transformation of Laplace-smoothed data is at least as good as state-of-the-art models, particularly at small samples. Furthermore, we show that an over-dispersed Poisson model is comparable to the celebrated Negative Binomial, but much easier to estimate. These results provide strong support for transformation-based versus count-based (particularly Negative-Binomial-based) models for eQTL mapping. Availability and implementation: All methods are implemented in the free software eQTLseq: https://github.com/dvav/eQTLseq. Contact: dimitris.vavoulis@well.ox.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28575252 TI - Family and Marital Conflict Among Chinese Older Adults in the United States: The Influence of Personal Coping Resources. AB - Background: Conflict in the family is a major risk factor for the well-being of older immigrants, whose lives are centered around their families. This study examined the potential linkage between personal coping resources and family and marital conflict among U.S. Chinese older adults. Methods: Data were derived from the PINE study, a population-based study of Chinese elders in Chicago (N = 3,157). Logistic regressions were carried out to predict the likelihood of having conflict with family members and with the spouse, respectively, using indicators of personal coping resources (ie, socioeconomic status, physical health, acculturation level, perceived children's filial piety, number of friends, and sense of mastery). Results: The results showed that older adults with higher education (odds ratio [OR] = 1.03, confidence interval [CI] = 1.01-1.06; OR = 1.09, CI = 1.06-1.11, respectively), lower perception of children being filial (OR = 0.95, CI = 0.93-0.97; OR = 0.96, CI = 0.94-0.98], respectively), and lower sense of mastery (OR = 0.95, CI = 0.94-0.96; OR = 0.98, CI = 0.97-0.99, respectively) were more likely to report both family and marital conflict. Older adults who had more friends were less likely to report marital conflict (OR = 0.61, CI = 0.43-0.86). Conclusions: Overall, older immigrants with greater coping resources seemed to have less family and marital conflict. Particularly important are their own sense of control and available support from children and friends in the new society. Higher education could be a risk factor for these conflicts. Future studies are needed to distinguish everyday life conflict from acculturation-related conflict in this population. PMID- 28575253 TI - Family Relationships and Depressive Symptoms Among Chinese Older Immigrants in the United States. AB - Background: Given the growth in the number of older Chinese immigrants in the United States and the importance of family support in Chinese culture, this study examines how supportive and negative relationships with family members (children and spouse) influence depressive symptom severity among this population. Methods: Using data from the Population Study of Chinese Elderly in Chicago, we carried out multivariate negative binomial regression analysis using a sample of 3,159 Chinese older immigrants. Depressive symptom severity was measured using the Patient Health Questionnaire. Intergenerational and marital relationships were characterized using self-reported measures of two supportive features (confiding and aiding) and two negative features (demanding and criticizing). Results: Confiding and aiding relationships with children (incident rate ratio [IRR] = .70, confidence interval [CI]: 0.57, 0.85; IRR = .70, CI: 0.56, 0.88, respectively) and spouses (IRR = .61, CI:0.47, 0.79; IRR = .66, CI: 0.52, 0.83, respectively) were significantly associated with lower depressive symptom severity among the older Chinese immigrants sampled. Demanding (IRR = 1.39, CI: 1.16, 1.68) and criticizing (IRR = 1.37, CI: 1.17, 1.60) intergenerational relationships significantly predicted higher depressive symptom severity, and spousal criticism (IRR = 1.41, CI: 1.24, 1.59) was related to higher depressive symptom severity. Aiding relationships with children appears to be more important for older women than men (IRR = .69, CI: 0.47, 1.01). Conclusions: The findings reveal the importance of both positive and negative interactions with spouses and children in shaping mental well-being among older Chinese immigrants. Future geriatric practice and research should consider both supportive and negative features in examining and addressing interpersonal relationships and mental health. PMID- 28575254 TI - Conscientiousness Moderates the Relationship Between Perceived Stress and Depressive Symptoms Among U.S. Chinese Older Adults. AB - Background: The present study examined whether individuals' personality traits, Neuroticism and Conscientiousness, moderated the relationship between perceived stress and depressive symptoms among U.S. Chinese older adults. Methods: Data analysis was based on the Population Study of Chinese Elderly in Chicago (PINE). Three thousand one hundred and fifty-nine Chinese adults aged 60 years and older participated in the PINE study. They completed scales that assessed their personality (ie, Neuroticism and Conscientiousness of the NEO Five-Factor Inventory), perceived stress (the Chinese Perceived Stress Scale), and depressive symptoms (the Patient Health Questionnaire). Results: Perceived stress was positively related to depressive symptoms among U.S. Chinese older adults. No moderation effects were found for Neuroticism. Conscientiousness significantly moderated the perceived stress-depressive symptom relationship. The positive relationship between perceived stress and depressive symptoms was weaker for people who were higher in Conscientiousness than those who were lower in Conscientiousness. Conclusion: Conscientiousness mitigated the stress-depressive symptom relationship among U.S. Chinese older adults. Future research is needed to identify the psychological and sociocultural profiles of individuals who show stress resilience and those who are vulnerable. Social services and psychological interventions are needed to promote health and well-being among U.S. Chinese older adults. PMID- 28575255 TI - Self-reported Discrimination and Depressive Symptoms Among Older Chinese Adults in Chicago. AB - Background: Discrimination is part of life for many Americans, especially ethnic minorities. Focusing on older Chinese Americans, this study examines the association between self-reported discrimination and depressive symptoms and identifies subgroups that are more likely to report experiencing discrimination. Methods: We conducted cross-sectional analysis of data collected from adults (age 60+ years) of Chinese origin residing in the Greater Chicago area (N = 3,004). Self-reported discrimination was assessed by the Experiences of Discrimination instrument and was dichotomized (yes vs no). Depressive symptoms were measured by the Patient Health Questionnaire (PHQ-9). Logistic regression of self-reported discrimination and negative binominal regression of depressive symptoms were conducted. Results: About 21.5% of the sample reported having experienced discrimination. The odds of reporting discrimination are higher for those who are younger, have higher education and income, are more acculturated, have been in the United States longer, live outside Chinatown, and have higher levels of neuroticism and conscientiousness. Self-reported discrimination is significantly and positively associated with depressive symptoms, independent of sociodemographic characteristics, migration-related variables, and personality factors. Conclusion: Findings suggest a robust relationship between self-reported discrimination and depressive symptoms in older Chinese Americans. They further suggest that the relatively advantaged groups-younger, higher socioeconomic status, more acculturated, and living outside Chinatown-are more likely to report experiencing discrimination. PMID- 28575256 TI - Grandparent Caregiving and Psychological Well-Being Among Chinese American Older Adults-The Roles of Caregiving Burden and Pressure. AB - Background: Though ample research on grandparent caregiving and psychological well-being outcomes exist in Western literature, little attention has been focused on Chinese American grandparents. Based on role enhancement and role strain theories, this study examined grandparent caregiving and psychological well-being among Chinese American older adults and tested whether caregiving burden or pressure from adult children moderated such association. Methods: We used the data from the Population Study of ChINese Elderly in Chicago (PINE), a population-based survey of community-dwelling Chinese older adults in the Greater Chicago area. Grandparents with grandchildren younger than 16 years old were selected for present study (N = 2,775). Negative binominal regression and logistic regression models were used to test the relationships of grandparent caregiving time and psychological well-being measured by depressive symptoms and quality of life. Results: Grandparents reported an average of 11.96 hours a week for caring for grandchildren. Caregiving time had a significantly negative association with depressive symptoms, but not with quality of life. The association between grandparent caregiving and depressive symptoms was moderated by the perception of caregiving burden. No moderating effect of caregiving pressure from adult children was found. Conclusions: More time spending on grandparent caregiving is generally beneficial to Chinese American grandparents' psychological well-being, thus supporting role enhancement theory. However, this association depends on whether this experience is a burden to the grandparents, therefore role strain theory is also supported. Policies and programs are discussed to address the grandparenting experience in the Chinese American older adults. PMID- 28575257 TI - The Relationship of Social Engagement and Social Support With Sense of Community. AB - Background: We aimed to investigate the relationship of engagement in social and cognitive activities and social support with the sense of community (SOC) and its components among older Chinese Americans. Methods: The Sense of Community Index (SCI) was used to measure SOC and its four component factors: membership, influence, needs fulfillment, and emotional connection. Social engagement was assessed with 16 questions. Social support included positive support and negative strain. Principal component analysis was used to identify the SCI components. Linear regression analysis was used to detect the contribution of social engagement and social support to SOC and its components. Results: After controlling for sociodemographics and self-rated health, social activity engagement and positive social support were positively related to SOC and its components. Conclusions: This study points to the importance of social activity engagement and positive support from family and friends in increasing the sense of community. PMID- 28575258 TI - Examination of Chronic Smoking Behavior and Eligibility for Low-Dose Computed Tomography for Lung Cancer Screening Among Older Chinese Male Smokers. AB - Background: Low-dose computed tomography lung cancer (LDCT) screening is an effective way to decrease lung cancer mortality. Both Medicare and private insurers offer coverage of LDCT screening to beneficiaries who are at high risk of developing lung cancer. In this study, we examined rates and predictors of chronic smoking behavior and eligibility for coverage of LDCT screening among older Chinese men living in the greater Chicago area. Methods: Data were obtained from the Population Study of Chinese Elderly in Chicago, a population-based survey of community-dwelling, older Chinese adults in the Chicago metropolitan area. Eligibility criteria according to Centers of Medicare and Medicaid Services (CMS) and U.S. Preventive Services Task Force (USPSTF) for LDCT screening were used. Multivariate logistic regression was conducted to determine predictors of chronic smoking behavior which was operationalized as meeting criteria for LDCT screening. Results: A quarter of the sample were current smokers and 42.5% reported a prior history of smoking. Eighteen percent and 22% of older Chinese men met the eligibility criteria for appropriateness for CMS and USPSTF LDCT screening, respectively. Furthermore, education, marital status, and number of children were significantly associated with chronic smoking behavior. Conclusion: Older Chinese men with chronic smoking behavior are at high risk of developing lung cancer and nearly one in five meet eligibility for LDCT screening. Increased outreach and education regarding early detection of lung cancer and smoking cessation are needed for this vulnerable and high-risk population. PMID- 28575259 TI - The Association Between Childhood Abuse and Elder Abuse Among Chinese Adult Children in the United States. AB - Background: The previous researchers have postulated that an abused child may abuse his or her abuser parent when the parent is getting old, also known as the intergenerational transmission of violence. However, few studies use data to support this model, and it has yet to be examined in the U.S. Chinese community. This study aims to examine the association between childhood abuse and elder abuse reported by Chinese adult children in the United States. Methods: Guided by a community-based participatory research approach, 548 Chinese adult children aged 21 years and older participated in this study. Childhood abuse was assessed by four-item Hurt-Insult-Threaten-Scream (HITS) scale. Elder abuse was assessed by a 10-item instrument derived from the Caregiver Abuse Screen (CASE). Logistic regression analysis was performed. Results: Childhood abuse was associated with caregiver abuse screen results (odds ratio = 1.92, 95% confidence interval = 1.24 2.95). Being physically hurt (r = .13, p < .01), insulted (r = .15, p < .001), threatened (r = .12, p < .01), and screamed at (r = .18, p < .001) as a child were significantly correlated with caregiver abuse screen results. Conclusion: This study suggests that childhood abuse is associated with increased risk of elder abuse among Chinese adult children in the United States. Longitudinal research should be conducted to explore the mechanisms through which childhood abuse and its subtypes links with elder abuse. PMID- 28575260 TI - Social Support, Social Strain, and Cognitive Function Among Community-Dwelling U.S. Chinese Older Adults. AB - Background: Limited research is available on the relationship between social support, social strain, and cognitive function among community-dwelling U.S. Chinese older adults. This study aims to examine the associations between social support/strain and cognitive outcomes. Methods: Data were drawn from the Population-Based Study of Chinese Elderly (N = 3,159). Cognitive function was measured by a battery of tests including the East Boston Memory Test, the Digit Span Backwards assessment, and the Symbol Digit Modalities Test. Social support and strain were measured by the scales drawn from the Health and Retirement study. Multiple regression analyses were conducted. Results: Social support was significantly associated with global cognitive function (beta = .11, SE = .02, p < .001), episodic memory (beta = .11, SE = .03, p < .001), working memory (beta = .18, SE = .08, p < .05), and executive function (beta = 1.44, SE = .37, p < .001). Social strain was significantly associated with global cognitive function (beta = .23, SE = .05, p < .001), episodic memory (beta = .27, SE = .07, p < .001), working memory (beta = .34, SE = .17, p < .05), and executive function (beta = 2.75, SE = .85, p < .01). In terms of sources of social support/strain, higher support from friends was significantly associated with higher global cognitive function (beta = .04, SE = .02, p < .05), higher episodic memory (beta = .05, SE = .02, p < .05), and higher executive function (beta = .71, SE = .29, p < .05). Higher strain from spouse was significantly associated with higher global cognitive function (beta = .10, SE = .03, p < .01), higher episodic memory (beta = .11, SE = .04, p < .01), and higher executive function (beta = 1.28, SE = .49, p < .01). Higher strain from friends was significantly associated with higher executive function (beta = 3.59, SE = 1.17, p < .01). Conclusions: Social support and strain were associated with cognitive outcomes. Future longitudinal studies should be conducted. PMID- 28575261 TI - Elder Self-neglect and Suicidal Ideation in an U.S. Chinese Aging Population: Findings From the PINE Study. AB - Background: Self-neglect and suicidal ideations are important public health issues among the aging population. This study aims to examine the association between self-neglect, its phenotypes, and suicidal ideation among U.S. Chinese older adults. Methods: Guided by a community-based participatory research approach, the Population Study of Chinese Elderly in Chicago (PINE) study is a population-based epidemiological study conducted from 2011 to 2013 among 3,159 Chinese older adults aged 60 years and older in the Greater Chicago area. Self neglect was assessed by a 27-item instrument, describing five phenotypes with hoarding, poor personal hygiene, unsanitary condition, lack of utilities, and need of home repair. Suicidal ideation was assessed by the ninth item of the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Mental State Examination Version A (GMS-A). Logistic regression is utilized to analyze the association. Results: Higher level of self-neglect was found significantly associated with increased risk of self-reported suicidal ideation within 2 weeks (odds ratio 2.97 [1.54-5.72]); 12 months (odds ratio 2.82 [1.77-4.51]); and lifetime (odds ratio 2.74 [1.89-3.95]). For phenotypes, the study found that poorer personal hygiene and severer level of unsanitary conditions were associated with increased risk of suicidal ideation at all three time periods. Conclusion: This study suggests that self-neglect and its phenotypes are significantly associated with suicidal ideation among Chinese older adults. Longitudinal studies are needed to explore the mechanisms through which self-neglect links with suicidal ideation. PMID- 28575262 TI - The Association Between Physical Function and Elder Mistreatment Among Community Dwelling Chinese Older Adults in the Greater Chicago Area. AB - Background: Physical function (PF) impairment and elder mistreatment (EM) are alarming public health issues facing by many older adults. Prior studies have not generated uniform findings on the associations between PF and EM. This study aimed to address the research gap of this association among U.S. Chinese aging population. Methods: Three thousand one hundred fifty-eight community-dwelling Chinese older adults in the Greater Chicago Area were surveyed. Independent variables included both self-reported and performance-based PF measurements. Dependent variable was EM, assessed by a 10-item instrument that has been widely used in social studies. Results: The mean age of study participants was 76.3 years (SD +/- 8.4) and 58.0% were female. After adjusting for potential covariates, higher scores of activities of daily living (odds ratio [OR] = 0.85, 95% confidence interval [CI] = 0.73-0.98), instrumental activities of daily living (OR = 0.87, 0.82-0.92), and Rosow-Breslau reversely coded (OR = 0.85, 0.75 0.96) were associated with lower risk of EM. Also, lower scores of observed PF performance measurements, including tandem stand (OR = 0.78, 0.70-0.88), measured walk (OR = 0.84, 0.77-0.91), and the overall measurement (OR = 0.93, 0.89-0.97) have significant associations with lower risk of EM. Conclusions: Findings from this study suggested that greater levels of PF impairment were associated with lower risk of EM among U.S. Chinese older adults in the Greater Chicago Area. Longitudinal studies are needed to obtain a more comprehensive understanding of the pathways between PF and EM and its subtypes among Chinese aging populations. PMID- 28575263 TI - Breast Cancer Screening Beliefs Among Older Chinese Women in Chicago's Chinatown. AB - Background: Chicago's Chinatown is home to a sizeable community of first generation Chinese American immigrants. This qualitative study seeks to describe the attitudes toward, and barriers and facilitators of, breast cancer screening among Chinese women in Chicago's Chinatown to inform strategies for future interventions. Methods: We conducted six focus groups among Chinese-speaking adult women aged 45 and older. Focus groups were transcribed, coded, and analyzed for emergent themes. Results: Forty-seven women participated in focus groups; 10 (21%) had received a breast cancer diagnosis in their lifetime, all participants were foreign-born, and 80% have resided in the United States for over 10 years. Participants expressed a range of breast cancer beliefs, attitudes toward screening, barriers encountered, and facilitators. Some differences were noted between women with cancer and those without. Barriers described include language, time, not wanting to burden their adult children, and transportation. Navigation services and physician recommendation were suggested facilitators to screening. Conclusions: Our findings have important implications for development of interventions and policies to bolster breast cancer screening among Chinese women. We highlight the need to connect Chinese older adults with resources to navigate the health care system and present opportunities for community stakeholders, researchers, health professionals, and policy makers to improve the health of Chinese Americans. PMID- 28575264 TI - Knowledge and Beliefs About Biospecimen Research Among Chinese Older Women in Chicago's Chinatown. AB - Background: Enhancing the participation of Chinese older women in biobanking efforts is important for precision medicine efforts, as underrepresented groups risk benefiting less than others from medical advancements in individualized therapies. Focusing on a sample of Chinese older women in Chicago's Chinatown, this qualitative study seeks to describe attitudes toward, and barriers and facilitators of, participation in biospecimen research. Method: We conducted six focus groups among Chinese-speaking adult women age 45 and above. Focus groups were transcribed, coded, and analyzed for emergent themes. Results: Forty-seven women participated in focus groups, the majority (66.0%) were age 66 and over and half (50.1%) had less than a high school education. Participants expressed predominantly positive attitudes toward biospecimen research, but also identified multifaceted barriers to participation that included cultural beliefs of the body, perceived physical and privacy risks, as well as perceptions related to aging. Use of minimally invasive biospecimen collection and education to promote awareness of biospecimen research were suggested facilitators to increasing biospecimen research participation. Conclusions: Culturally and linguistically isolated populations like Chinese older women are at risk of exclusion from advancements in precision medicine. Our findings provide cultural insights for tailoring interventions for Chinese older women to increase knowledge, change attitudes, and increase intention and participation in biospecimen research. We also highlight the need for individual, family, and community level interventions to promote healthy aging among Chinese older women. PMID- 28575265 TI - Change of Cognitive Function in U.S. Chinese Older Adults: A Population-Based Study. AB - Background: This study aims to assess cognitive change in a 2-year period among U.S. Chinese older adults and examine sociodemographic characteristics associated with the change. Methods: Data were from the Population Study of Chinese Elderly (PINE) in which 2,713 participants (aged 60 and older) received in-home interviews at both the baseline and 2-year follow-up. A battery of cognitive tests that assessed episodic memory, working memory, perceptual speed, and overall cognitive status were administered in both times. A composite global cognition was constructed using all tests. Mixed-effect regression was conducted. Results: Older age was associated with worse baseline cognition (ie, in all cognitive abilities) and faster decline in global cognition, episodic memory, and perceptual speed-rates of decline increased by .006, .004, and .009 standard score units, respectively, for each year older. More education was associated with better baseline cognition, but each year of additional schooling increased rates of decline in global cognition and episodic memory by .004 and .012 standard score units, respectively. Men performed better than women in most cognitive abilities at baseline but had faster rates of decline in working memory. Higher income was associated with better cognition at baseline and reduced rates of decline in working memory. Conclusions: Findings suggest differences in the rates of cognitive change by age, sex, education, and income. Those in advancing age are vulnerable to cognitive decline. The effects of education and sex on baseline performance versus change suggest a role for life experiences in cognition. PMID- 28575266 TI - Incidence of Elder Abuse in a U.S. Chinese Population: Findings From the Longitudinal Cohort PINE Study. AB - Background: Elder abuse (EA) is a global public health issue. However, no prior longitudinal research has quantified the incidence of EA, which is critical to understand risk factors and future prevention strategies. Methods: The study is based on a longitudinal cohort design. We followed 2,713 U.S. Chinese older adults who agreed to participate in the study within 2011 to 2015. A structured questionnaire was used to collect data regarding the 2-year incidence of EA and its subtypes. We employed multiple logistic regression analyses to examine the associations between the sociodemographic characteristics and incident EA. Results: The incidence of overall EA was 8.8% with 4.8% for psychological, 2.9% for financial, 0.5% for physical, 0.1% for sexual abuse, and 1.1% for caregiver neglect. Age, gender, duration of residence, language preference and health status change were associated with incident EA. Self-perceived worsened health was positively associated with overall EA (odds ratio [OR] 1.28 (1.01, 1.62). Women (OR 2.98 [1.10, 8.11]) and older individuals (OR 1.06 [1.00, 1.13]) had an increased risk of caregiver neglect. Older adults who have lived in the U.S. longer had a higher risk of financial exploitation (OR 1.02 [1.00, 1.05]). Individuals who prefer to speak Mandarin or English were more likely to experience EA (OR 2.08 [1.21, 3.58]) and sexual or physical abuse (OR 3.91 [1.01, 15.17]). No significant association was observed between education, income, marital status, number of children, country of origin, overall health, life quality, and incident EA. Conclusion: This study presents the first illustration of EA incidence in a longitudinal cohort study, the findings of which verify and challenge prior fundamental assumptions of risk factors associated with EA, and are relevant to future prevention strategies. PMID- 28575267 TI - Associations Between the Differential Definitions of Elder Mistreatment and Suicidal Ideation Outcomes in U.S. Chinese Older Adults: Do the Definitions Matter? AB - Background: Elder mistreatment (EM) prevalence varies greatly according to definitional criteria. However, little is known regarding the significance of different EM definitions with respect to health outcome. This paper explores the association between different definitions of EM and their subtypes and suicidal ideation (SI) in an U.S. Chinese aging population. Methods: The Population Study of ChINese Elderly in Chicago Study was conducted from 2011 to 2013 of 3157 community-dwelling Chinese older adults aged 60 years. Psychological, physical mistreatment (PM), caregiver neglect (CN), financial exploitation (FE), and overall EM were measured by different definitional approaches varying in the strictness. SI in the past 2 weeks and 12 months were assessed. Results: After adjusting for confounders, the least restrictive EM definition (odds ratio [OR], 2.10 [1.34-3.28]; OR, 2.43 [1.66-3.55]), moderately restrictive EM definition (OR, 2.87 [1.80-4.56]; OR, 2.71 [1.82-4.04]), and most restrictive EM definition (OR, 2.24 [1.36-3.66]; OR, 2.34 [1.54-3.56]) were associated with increased risk for 2-week and 12-month SI. For subtypes of EM, psychological mistreatment (the least and most restrictive definitions, 2-week SI: OR, 2.83 [1.71-4.68]; OR, 3.13 [1.10-8.91]; 12-month SI: OR, 2.43 [1.56-3.78]; OR, 2.88 [1.10-7.54]), PM (2-week SI: OR, 5.12 [1.83-14.29]; 12-month SI: OR, 3.45 [1.30-9.13]), and FE was not associated with 2-week SI, only the broadly defined FE (OR, 1.73 [1.01-2.96]) was associated with higher odds of reporting 12-month SI. CN was only associated with higher odds of reporting 12-month SI (OR, 2.17 [1.19-3.96]; OR, 1.94 [1.24-3.04]) but not 2-week SI. Conclusion: EM and its subtypes were significantly associated with SI; some associations varied by definitions and subtypes. PMID- 28575269 TI - The Association Between Filial Discrepancy and Depressive Symptoms: Findings From a Community-Dwelling Chinese Aging Population. AB - Background: The relationship between filial piety and depressive symptoms has been widely discussed, but limited research focused on the gap between filial expectations and filial receipt. This study aims to investigate the association between filial discrepancy and depressive symptoms. Methods: Data were derived from the Population Study of Chinese Elderly (PINE), a community-engaged, population-based epidemiological study of U.S. Chinese older adults aged 60 and older in the greater Chicago area. Depressive symptoms were measured by the Patient Health Questionnaire-9. Overall filial discrepancy was evaluated by filial receipt minus expectations. Levels of overall filial discrepancy divided older adults into four groups based on the medium value of filial expectations and receipt. Logistic regression analyses were performed. Results: Older adults with greater filial receipt than expectations were more likely to have lower risk of depressive symptoms (odds ratio [OR], 0.95 [0.92-0.97]). The group with high expectations and low receipt has the highest risk of depressive symptoms among the four groups (OR, 1.51 [1.07-2.13]). Greater receipt than expectations in care (OR, 0.83 [0.76-0.92]), make happy (OR, 0.77 [0.69-0.86]), greet (OR, 0.88 [0.79 0.97]), obey (OR, 0.76 [0.68-0.86]), and financial support (OR, 0.80 [0.71-0.89]) was associated with lower risk of depressive symptoms. Conclusions: This study goes beyond previous research by examining the association between filial discrepancy domains and depressive symptoms. Cultural relevancy of health interventions is important in the context of Chinese communities. Health care professionals are suggested to be aware of the depressive symptoms of U.S. Chinese older adults with high filial expectations and low receipt. PMID- 28575270 TI - The Decline of Directly Observed Physical Function Performance Among U.S. Chinese Older Adults. AB - Background: Physical function decline is a major public health concern and can predict later mortality. This study aims to examine the sociodemographic factors associated with physical function decline among U.S. Chinese older adults through a longitudinal population-based study. Methods: Data were derived from the Population Study of Chinese Elderly (PINE) at two time points: 2011-2013 and 2013 2015. Physical function was measured by observed physical performance testing, including chair stand, tandem stand, and timed walk. Mixed-effect models were used to analyze the demographic risk factors associated with physical function decline. Results: Of the 2,713 participants in waves 1 and 2, their average age was 72.6 years old, 58.4% were female, with 8.7 years of education average, and 85.8% had an annual individual income of less than $10,000. Our findings show subjects of older age, female sex, lower education, lower income, and a greater number of medical comorbidities had lower physical function levels at baseline. Older adults experienced a faster decline in physical function for the overall performance measure (beta = -.02, p < .001). Additionally, elderly adults with higher education have a faster decline of physical function in the overall performance measure (beta = -.03, p < .01). Discussion: As the first to examine physical function decline among U.S. Chinese older adults, our study finds older age and higher education are two factors associated with a faster rate of physical function decline. In future research, long-term follow up and multiple waves of data are needed to investigate risk or resilience factors for disability or recovering from disability. PMID- 28575271 TI - Advancing Community and Health Equity: Health and Wellbeing of U.S. Chinese Populations. PMID- 28575268 TI - Cross-Sectional and Longitudinal Association Between Trust in Physician and Depressive Symptoms Among U.S. Community-Dwelling Chinese Older Adults. AB - Background: Depression is a major public health concern among older adults and health care professionals play a vital role in screening and treatment. However, this process may be impeded by issues like lack of trust in physician (TIP). This study aims to examine the cross-sectional and longitudinal relationships between TIP and depressive symptoms among Chinese older adults in the Chicago area. Methods: Data were collected through the Population Study of Chinese Elderly (PINE), a longitudinal cohort study of Chinese older adults in the greater Chicago area. A total of 2,713 Chinese older adults completed both waves of data collection. TIP was measured through the Trust in Physician scale from Anderson and Dedrick (Anderson LA, Dedrick RF. Development of the Trust in Physician scale: a measure to assess interpersonal trust in patient-physician relationships. Psychol Rep. 1990;67(3 Pt 2):1091-1100. doi:10.2466/pr0.1990.67.3f.1091) (range: 11-55). Depressive symptoms were measured through Patient Health Questionnaire-9. Results: Every one point higher in TIP is associated with being 2% less likely to have any depressive symptoms (odds ratio [OR] 0.98, 0.97-0.99) in cross-sectional analysis. Longitudinally, every one-point increase in TIP score was associated with a 2% lower risk of depressive symptoms at Wave 2 (OR 0.98, 0.97-0.99). Improved TIP over 2 years was associated with 25% decreased risk of having any depressive symptoms at Wave 2 (OR 0.75, 0.63-0.89). Additionally, highest tertile of TIP change was associated with a 31% decreased risk of any depressive symptoms compared to lowest tertile (OR 0.68, 0.55-0.84). Discussion: Improved TIP over 2 years is associated with less risk of experiencing depressive symptoms. Future research should examine possible pathways and routes of intervention to improve mental health among older adults. PMID- 28575272 TI - Variations Between Sources of Social Support and Cancer Screen Behaviors in U.S. Chinese Older Adults. AB - Background: Social support is a key indicator of utilization of preventive health care among older adults, but we have limited knowledge on these associations in U.S. Chinese older adults. This study aims to examine the association between sources of social support and cancer screening behaviors among Chinese older adults in the greater Chicago area. Methods: Data were drawn from the Population Study of Chinese Elderly in Chicago. Social supports were measured by asking the frequency of receipt of support from spouse, non-spouse family members, and friends. Use of cancer screenings were evaluated by asking the history of utilization of colon, breast, cervical, and prostate cancer screenings. Results: After adjusting for covariates, results indicated significant association between higher social support and higher utilization of cancer screenings. Regarding to different sources of social support, higher levels of social supports from family members (odds ratio [OR], 1.15 [1.07, 1.25]) and friends (OR, 1.14 [1.06, 1.23]) were associated with higher utilization of breast cancer screening. However, higher levels of social support from family members (OR, 0.94 [0.88, 0.99]) and friends (OR, 0.94 [0.88, 1.00]) were associated with lower utilization of colon cancer screening. No associations were found between social support and prostate cancer screening. Conclusions: This study provides evidence that different types of social support were associated with variations in the utilization of cancer screenings. Future longitudinal studies are needed to explore the causal relationship between social support and cancer screening use. PMID- 28575273 TI - Positioning Ustekinumab in Crohn's Disease: From Clinical Evidence to Clinical Practice. AB - Biological medicines have revolutionised the treatment of Crohn's disease [CD]. Yet, the management of patients not responding to tumour necrosis factor [TNF] antagonists remains a clinical challenge. Ustekinumab is a human monoclonal antibody blocking the biological activity of interleukins 12 and 23, which regulate the immune system and immune-mediated inflammatory disorders. Ustekinumab has recently been approved for the treatment of adult patients with moderately to severely active CD, who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNF antagonist, or have medical contraindications to such therapies. Herein, we review the new biological drug's efficacy and safety data reported from randomised controlled trials and real-world observational studies conducted in populations with CD, in order to identify the patient groups most likely to benefit, and to appropriately place ustekinumab into treatment algorithms for CD. PMID- 28575275 TI - Erratum. PMID- 28575274 TI - Visit-to-visit variability of blood pressure and cardiovascular outcomes in patients with stable coronary heart disease. Insights from the STABILITY trial. AB - Aims: To study the relation between visit-to-visit variability of blood pressure (BP) and cardiovascular risk in patients with stable coronary heart disease. Methods and results: In 15 828 patients from the STABILITY trial (darapladib vs. placebo in patients with established coronary heart disease), BP variability was assessed by the standard deviation (SD) of systolic BP, the SD of diastolic BP, maximum BP, and minimum BP, from 5 measurements (baseline and months 1, 3, 6, and 12) during the first year after randomisation. Mean (SD) average BP during the first year of study was 131.0 (13.7) mmHg over 78.3 (8.3) mmHg. Mean (SD) of the visit-to-visit SD was 9.8 (4.8) mmHg for systolic and 6.3 (3.0) mmHg for diastolic BP. During the subsequent median follow-up of 2.6 years, 1010 patients met the primary endpoint, a composite of time to cardiovascular death, myocardial infarction, or stroke. In Cox regression models adjusted for average BP during first year of study, baseline vascular disease, treatment, renal function and cardiovascular risk factors, the primary endpoint was associated with SD of systolic BP (hazard ratio for highest vs. lowest tertile, 1.30, 95% CI 1.10-1.53, P = 0.007), and with SD of diastolic BP (hazard ratio for highest vs. lowest tertile, 1.38, 95% CI 1.18-1.62, P < 0.001). Peaks and troughs in BP were also independently associated with adverse events. Conclusion: In patients with stable coronary heart disease, higher visit-to-visit variabilities of both systolic and diastolic BP are strong predictors of increased risk of cardiovascular events, independently of mean BP. PMID- 28575277 TI - A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension. AB - Aims: Guidelines recommend a goal-oriented treatment approach in pulmonary arterial hypertension (PAH). The aim is to reach a low-risk profile, as determined by a risk assessment instrument. This strategy is incompletely validated. We aimed to investigate the bearing of such risk assessment and the benefit of reaching a low-risk profile. Methods and results: Five hundred and thirty PAH patients were included. Follow-up assessments performed after a median of 4 (interquartile range 3-5) months were available for 383 subjects. Patients were classified as 'Low', 'Intermediate', or 'High risk' and the benefit of reaching the 'Low risk' group was estimated. Survival differed (P < 0.001) between the risk groups at baseline and at follow-up. Survival was similar for patients who remained in or improved to the 'Low risk' group. Survival was similar for patients who remained in or worsened to the 'Intermediate risk' or 'High risk' groups. Irrespective of follow-up risk group, survival was better (P < 0.001) for patients with a higher proportion of variables at low risk. Results were unchanged after excluding patients with idiopathic PAH >65 years at diagnosis, and when patients with idiopathic or connective tissue disease associated PAH were analysed separately. Patients in the 'Low risk' group at follow-up exhibited a reduced mortality risk (hazard ratio 0.2, 95% confidence interval 0.1-0.4 in multivariable analysis adjusted for age, sex and PAH subset), as compared to patients in the 'Intermediate risk' or 'High risk' groups. Conclusion: These findings suggest that comprehensive risk assessments and the aim of reaching a low-risk profile are valid in PAH. PMID- 28575279 TI - Commentary: Hospital Length of Stay and Readmission Rate for Neurosurgical Patients. PMID- 28575278 TI - Pharmacokinetics of nebulized colistin methanesulfonate in critically ill patients. AB - Objectives: Optimal dosing for nebulized colistin methanesulfonate (CMS), the prodrug of colistin, is unknown. We describe the pulmonary and systemic pharmacokinetics of CMS and colistin following nebulization of 0.5 million IU (MIU) of CMS in ventilated patients. Methods: Twelve critically ill patients received 0.5 MIU of CMS administered every 8 h as 30 min nebulizations. Blood samples were collected immediately before and until 8 h after first nebulization; mini-bronchoalveolar lavage (mini-BAL) was performed at 1 and 5 h or 3 and 8 h (six patients each) post-dose. Pharmacokinetic analysis was performed for CMS and colistin plasma concentrations using a non-compartmental method. ClinicalTrials.gov: NCT01060891. Results: After nebulization, CMS concentrations in epithelial lining fluid (ELF) were much higher (100- to 1000-fold) than those in plasma. Concentrations of colistin in ELF should be considered with caution because when <6 mg/L in BAL, colistin bound to mini-BAL devices. Nevertheless, CMS and colistin concentrations in ELF were much lower than expected from previous results with a 2 MIU dose. From CMS plasma pharmacokinetics it was shown that CMS systemic bioavailability was only slightly decreased for the 0.5 MIU dose compared with 2 MIU. Conclusions: This study shows that CMS concentrations were much higher (100- to 1000-fold) in ELF than in plasma after a 0.5 MIU aerosol of CMS, but much lower (10-fold) than expected from previous results with a 2 MIU dose. Therefore, until new pharmacokinetic and pharmacodynamic assessments of the treatment of ventilator-associated pneumonia with nebulized CMS are performed, the 2 MIU dose should be preferred to the 0.5 MIU dose. PMID- 28575276 TI - Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation. AB - The catalytic activity of human cytidine deaminase APOBEC3B (A3B) has been correlated with kataegic mutational patterns within multiple cancer types. The molecular basis of how the N-terminal non-catalytic CD1 regulates the catalytic activity and consequently, biological function of A3B remains relatively unknown. Here, we report the crystal structure of a soluble human A3B-CD1 variant and delineate several structural elements of CD1 involved in molecular assembly, nucleic acid interactions and catalytic regulation of A3B. We show that (i) A3B expressed in human cells exists in hypoactive high-molecular-weight (HMW) complexes, which can be activated without apparent dissociation into low molecular-weight (LMW) species after RNase A treatment. (ii) Multiple surface hydrophobic residues of CD1 mediate the HMW complex assembly and affect the catalytic activity, including one tryptophan residue W127 that likely acts through regulating nucleic acid binding. (iii) One of the highly positively charged surfaces on CD1 is involved in RNA-dependent attenuation of A3B catalysis. (iv) Surface hydrophobic residues of CD1 are involved in heterogeneous nuclear ribonucleoproteins (hnRNPs) binding to A3B. The structural and biochemical insights described here suggest that unique structural features on CD1 regulate the molecular assembly and catalytic activity of A3B through distinct mechanisms. PMID- 28575282 TI - Mitral valve repair or replacement in hypertrophic obstructive cardiomyopathy: a prospective randomized study. AB - OBJECTIVES: The optimal surgical strategy for concomitant mitral valve intervention during myectomy remains controversial. The purpose of this study was to compare the results of mitral valve replacement versus repair in patients with hypertrophic obstructive cardiomyopathy and severe mitral regurgitation. METHODS: Between 2010 and 2013, a total of 88 patients with hypertrophic obstructive cardiomyopathy and severe mitral regurgitation were randomly assigned to undergo either mitral valve replacement or repair in addition to extended myectomy. RESULTS: Three patients from the repair group were switched to mitral valve replacement after repair failure. There was 1 early death (2.4%) in the replacement group. The resting left ventricular outflow tract gradient was reduced from 89.1 +/- 20.4 to 18.3 +/- 5.7 mmHg (P < 0.001) and from 96.6 +/- 28.1 to 14.7 +/- 5.9 mmHg (P < 0.001) in the replacement and repair groups, respectively; there was no significant difference between the groups (P = 0.458). At 2-year follow-up, overall survival was 87.2 +/- 4.9% and 96.7 +/- 3.3% (P = 0.034); freedom from sudden cardiac death was 95.6 +/- 3.1% and 96.7 +/- 3.3% (P = 0.615); and freedom from thromboembolic events was 91.2 +/- 4.2% and 100%, respectively (P = 0.026). CONCLUSIONS: Both mitral valve repair and valve replacement in addition to extended myectomy are effective methods of surgical treatment in patients with hypertrophic obstructive cardiomyopathy who have severe mitral regurgitation. The benefits of mitral valve repair are better overall survival and a lower rate of thromboembolic events. Clinical trial registration: ClinicalTrials.gov: NCT02054221. PMID- 28575283 TI - Quantification of Oral Roughness Perception and Comparison with Mechanism of Astringency Perception. AB - Texture contributes to food acceptance, but oral texture perception is incompletely understood. Presently, we quantified individual sensitivities to lingual tactile roughness and assessed the impact of age, salivary flow (SF), and fungiform papillae density (FPD) on threshold and suprathreshold perception. Additionally, we tested the hypothesis that individuals highly sensitive to tactile roughness exhibit sensitivity to astringent stimuli. Detection thresholds (DTs) were determined using the staircase method for surface roughness from stainless steel coupons (Ra; 0.177-0.465 um) and astringency elicited by epigallocatechin gallate (EGCG; 0-1.64 mM) and tannic acid (TA; 0-0.71 mM) from 30 individuals. Suprathreshold sensitivity was assessed from intensity ratings of electroforming comparator surfaces with roughnesses ranging from 0.51 to 22.8 um and astringent stimuli ranging from 0 to 5.2 mM (EGCG) and from 0 to 1.9 mM (TA). SF, FPD, and astringent food pleasantness scores were collected. Variability in threshold roughness sensitivity enabled dividing subjects into high (RHi; n = 16) and low (RLo; n = 14) sensitivity groups; however, no significant differences in age, FPD, or SF were observed across these cohorts. Interestingly, compared with RLo, the RHi group exhibited greater sensitivity to EGCG but not TA astringency and indicated greater pleasantness from astringent foods (e.g., unripe bananas and dark chocolate). When participants were allocated into high (SalivaHi; n = 15) or low SF (SalivaLo; n = 15) groups, TA-evoked astringency thresholds were significantly lower in SalivaHi whom also indicated greater pleasantness from astringent red wines. For suprathreshold assessments of surface roughness or astringency, no significant associations were identified with age, FPD, or SF. Suprathreshold roughness sensitivity was, however, associated with suprathreshold sensitivity to EGCG but not TA astringency. PMID- 28575281 TI - Knockdown and replacement therapy mediated by artificial mirtrons in spinocerebellar ataxia 7. AB - We evaluate a knockdown-replacement strategy mediated by mirtrons as an alternative to allele-specific silencing using spinocerebellar ataxia 7 (SCA7) as a model. Mirtrons are introns that form pre-microRNA hairpins after splicing, producing RNAi effectors not processed by Drosha. Mirtron mimics may therefore avoid saturation of the canonical processing pathway. This method combines gene silencing mediated by an artificial mirtron with delivery of a functional copy of the gene such that both elements of the therapy are always expressed concurrently, minimizing the potential for undesirable effects and preserving wild-type function. This mutation- and single nucleotide polymorphism-independent method could be crucial in dominant diseases that feature both gain- and loss-of function pathologies or have a heterogeneous genetic background. Here we develop mirtrons against ataxin 7 with silencing efficacy comparable to shRNAs, and introduce silent mutations into an ataxin 7 transgene such that it is resistant to their effect. We successfully express the transgene and one mirtron together from a single construct. Hence, we show that this method can be used to silence the endogenous allele of ataxin 7 and replace it with an exogenous copy of the gene, highlighting the efficacy and transferability across patient genotypes of this approach. PMID- 28575280 TI - Global position paper on cardiovascular regenerative medicine. PMID- 28575284 TI - Role of Heat Shock Factor 1 in Conserving Cholesterol Transportation in Leydig Cell Steroidogenesis via Steroidogenic Acute Regulatory Protein. AB - Testicular testosterone synthesis begins with cholesterol transport into mitochondria via steroidogenic acute regulatory (StAR) protein in Leydig cells. Acute heat stress is known to obstruct testicular steroidogenesis by transcriptional repression of StAR. In contrast, chronic heat stress such as cryptorchidism or varicocele generally does not affect testicular steroidogenesis, suggesting that Leydig cells adapt to heat stress and retain their steroid synthesis ability. However, the mechanisms of the stress response in steroid-producing cells are unclear. We examined the relationship between the heat stress response and heat shock factor 1 (HSF1), which protects cells from proteotoxic stress by inducing heat shock protein as a molecular chaperone. The influences of HSF1 deficiency on cholesterol transport by StAR and the expression of steroidogenic enzymes under chronic heat stress were studied in testes of HSF1 knockout (HSF1KO) mice with experimental cryptorchidism. StAR protein in wild type-cryptorchid mice was transiently decreased after induction of cryptorchidism and then gradually returned to basal levels. In contrast, StAR protein in HSF1KO mice continued to decrease and failed to recover, resulting in impaired serum testosterone. StAR messenger RNA was not decreased with cryptorchidism, indicating that posttranslational modification of StAR, not its transcription, was obstructed in cryptorchidism. Other steroidogenic enzymes, including CYP11A1, 3beta-HSD, and CYP17A1, were not decreased. Lipid droplets were increased in the cytosol of HSF1KO-cryptorchid mice, suggesting dysfunctional cholesterol transportation. These findings provide insight into the role of HSF1 in Leydig cell steroidogenesis, suggesting that it maintains cholesterol transport by recovering StAR under chronic heat stress. PMID- 28575285 TI - Comparison of Control of Clostridium difficile Infection in Six English Hospitals Using Whole-Genome Sequencing. AB - Background: Variation in Clostridium difficile infection (CDI) rates between healthcare institutions suggests overall incidence could be reduced if the lowest rates could be achieved more widely. Methods: We used whole-genome sequencing (WGS) of consecutive C. difficile isolates from 6 English hospitals over 1 year (2013-14) to compare infection control performance. Fecal samples with a positive initial screen for C. difficile were sequenced. Within each hospital, we estimated the proportion of cases plausibly acquired from previous cases. Results: Overall, 851/971 (87.6%) sequenced samples contained toxin genes, and 451 (46.4%) were fecal-toxin-positive. Of 652 potentially toxigenic isolates >90 days after the study started, 128 (20%, 95% confidence interval [CI] 17-23%) were genetically linked (within <=2 single nucleotide polymorphisms) to a prior patient's isolate from the previous 90 days. Hospital 2 had the fewest linked isolates, 7/105 (7%, 3-13%), hospital 1, 9/70 (13%, 6-23%), and hospitals 3-6 had similar proportions of linked isolates (22-26%) (P <= .002 comparing hospital-2 vs 3-6). Results were similar adjusting for locally circulating ribotypes. Adjusting for hospital, ribotype-027 had the highest proportion of linked isolates (57%, 95% CI 29-81%). Fecal-toxin-positive and toxin-negative patients were similarly likely to be a potential transmission donor, OR = 1.01 (0.68 1.49). There was no association between the estimated proportion of linked cases and testing rates. Conclusions: WGS can be used as a novel surveillance tool to identify varying rates of C. difficile transmission between institutions and therefore to allow targeted efforts to reduce CDI incidence. PMID- 28575287 TI - An essential domain of an early-diverged RNA polymerase II functions to accurately decode a primitive chromatin landscape. AB - A unique feature of RNA polymerase II (RNA pol II) is its long C-terminal extension, called the carboxy-terminal domain (CTD). The well-studied eukaryotes possess a tandemly repeated 7-amino-acid sequence, called the canonical CTD, which orchestrates various steps in mRNA synthesis. Many eukaryotes possess a CTD devoid of repeats, appropriately called a non-canonical CTD, which performs completely unknown functions. Trypanosoma brucei, the etiologic agent of African Sleeping Sickness, deploys an RNA pol II that contains a non-canonical CTD to accomplish an unusual transcriptional program; all protein-coding genes are transcribed as part of a polygenic precursor mRNA (pre-mRNA) that is initiated within a several-kilobase-long region, called the transcription start site (TSS), which is upstream of the first protein-coding gene in the polygenic array. In this report, we show that the non-canonical CTD of T. brucei RNA pol II is important for normal protein-coding gene expression, likely directing RNA pol II to the TSSs within the genome. Our work reveals the presence of a primordial CTD code within eukarya and indicates that proper recognition of the chromatin landscape is a central function of this RNA pol II-distinguishing domain. PMID- 28575286 TI - Efficacy of Maternal Influenza Vaccination Against All-Cause Lower Respiratory Tract Infection Hospitalizations in Young Infants: Results From a Randomized Controlled Trial. AB - Background: Influenza immunization of pregnant women protects their young infants against laboratory-confirmed influenza infection. Influenza infection might predispose to subsequent bacterial infections that cause severe pneumonia. In a secondary analysis of a randomized clinical trial (RCT), we evaluated the effect of maternal vaccination on infant hospitalizations for all-cause acute lower respiratory tract infection (ALRI). Methods: Infants born to women who participated in a double-blind placebo-controlled RCT in 2011 and 2012 on the efficacy of trivalent inactivated influenza vaccine (IIV) during pregnancy were followed during the first 6 months of life. Results: The study included 1026 infants born to IIV recipients and 1023 born to placebo recipients. There were 52 ALRI hospitalizations (median age, 72 days). The incidence (per 1000 infant months) of ALRI hospitalizations was lower in infants born to IIV recipients (3.4 [95% confidence interval {CI}, 2.2-5.4]; 19 cases) compared with placebo recipients (6.0 [95% CI, 4.3-8.5]; 33 cases) with a vaccine efficacy of 43.1% (P = .050). Thirty of the ALRI hospitalizations occurred during the first 90 days of life, 9 in the IIV group (3.0 [95% CI, 1.6-5.9]) and 21 in the placebo group (7.2 [95% CI, 4.7-11.0]) (incidence rate ratio, 0.43 [95% CI, .19-.93]) for a vaccine efficacy of 57.5% (P = .032). The incidence of ALRI hospitalizations was similar in the IIV and placebo group for infants >3 months of age. Forty-four of the hospitalized infants were tested for influenza virus infection and 1 tested positive. Conclusions: Using an RCT as a vaccine probe, influenza vaccination during pregnancy decreased all-cause ALRI hospitalization during the first 3 months of life, suggesting possible protection against subsequent bacterial infections that influenza infection might predispose to. Clinical Trial Registration: NCT01306669. PMID- 28575290 TI - Bringing the Mucosa to Heal With Vedolizumab in Patients With Inflammatory Bowel Disease. PMID- 28575288 TI - Maternal RNA regulates Aurora C kinase during mouse oocyte maturation in a translation-independent fashion. AB - During oocyte meiotic maturation, Aurora kinase C (AURKC) is required to accomplish many critical functions including destabilizing erroneous kinetochore microtubule (K-MT)attachments and regulating bipolar spindle assembly. How localized activity of AURKC is regulated in mammalian oocytes, however, is not fully understood. Female gametes from many species, including mouse, contain stores of maternal transcripts that are required for downstream developmental events. We show here that depletion of maternal RNA in mouse oocytes resulted in impaired meiotic progression, increased incidence of chromosome misalignment and abnormal spindle formation at metaphase I (Met I), and cytokinesis defects. Importantly, depletion of maternal RNA perturbed the localization and activity of AURKC within the chromosomal passenger complex (CPC). These perturbations were not observed when translation was inhibited by cycloheximide (CHX) treatment. These results demonstrate a translation-independent function of maternal RNA to regulate AURKC-CPC function in mouse oocytes. PMID- 28575291 TI - Frailty Research Moves Beyond Risk Assessment. PMID- 28575289 TI - MyoD- and FoxO3-mediated hotspot interaction orchestrates super-enhancer activity during myogenic differentiation. AB - Super-enhancers (SEs) are cis-regulatory elements enriching lineage specific key transcription factors (TFs) to form hotspots. A paucity of identification and functional dissection promoted us to investigate SEs during myoblast differentiation. ChIP-seq analysis of histone marks leads to the uncovering of SEs which remodel progressively during the course of differentiation. Further analyses of TF ChIP-seq enable the definition of SE hotspots co-bound by the master TF, MyoD and other TFs, among which we perform in-depth dissection for MyoD/FoxO3 interaction in driving the hotspots formation and SE activation. Furthermore, using Myogenin as a model locus, we elucidate the hierarchical and complex interactions among hotspots during the differentiation, demonstrating SE function is propelled by the physical and functional cooperation among hotspots. Finally, we show MyoD and FoxO3 are key in orchestrating the Myogenin hotspots interaction and activation. Altogether our results identify muscle-specific SEs and provide mechanistic insights into the functionality of SE. PMID- 28575292 TI - Durability of Response After Hepatitis B Surface Antigen Seroclearance During Nucleos(t)ide Analogue Treatment in a Multiethnic Cohort of Chronic Hepatitis B Patients: Results After Treatment Cessation. AB - In 70 chronic hepatitis B patients with hepatitis B surface antigen seroclearance during nucleos(t)ide analogue therapy, response was sustained in all 54 patients who discontinued treatment. Clinically significant relapses as indicated by high hepatitis B virus DNA and ALT levels were not observed. Anti-HBs positivity may not be required to ensure sustained off-treatment response. PMID- 28575293 TI - Clinical value of induction protocol after second generation cryoballoon ablation for paroxysmal atrial fibrillation. AB - Aims: The predictive value of induction studies after catheter ablation for atrial fibrillation (AF) is still debatable. To date, these studies have not been implemented in patients after cryoballoon (CB) ablation. Our aim was to analyse the clinical value of AF induction in patients treated by second generation CB for paroxysmal AF. Methods and results: Seventy patients underwent at first an isoproterenol challenge after pulmonary vein (PV) isolation to assess AF induction and early PV reconnections (EPVR). Patients without EPVR were evaluated for premature atrial contraction (PAC) induction; atrial ectopy was considered frequent (PAC+) if >1/10 cycles or >6/min. After restitution of baseline heart rate, rapid atrial pacing (RAP) was performed on all patients. AF induction by isoproterenol occurred only in 3/70 (4%) patients of whom 2/3 (66%) patients with an EPVR of a triggering vein. In the 62 patients without EPVR, PAC+ occurred in 17 patients (27%). RAP could induce AF in 23/70 (33%) patients. At a mean follow up of 13.5 months, there were 11/70 (16%) AF recurrences. There was no significant difference in the AF recurrence rate between RAP inducible vs. non inducible patients (log-rank P = 0.33). A 41% recurrence rate (7/17 patients) was seen in the PAC+ group with significantly different AF-free survival for PAC+ vs. PAC- patients (log rank P < 0.0001). PAC+ was the only independent determinant to predict AF recurrence after multivariate analysis. Conclusion: PAC occurrence in response to isoproterenol could predict AF recurrence after PV isolation by CB, while RAP showed no prognostic implication. PMID- 28575294 TI - Impaired coordination of nucleophile and increased hydrophobicity in the +1 subsite shift levansucrase activity towards transfructosylation. AB - Bacterial levansucrases produce beta(2,6)-linked levan-type polysaccharides using sucrose or sucrose analogues as donor/acceptor substrates. However, the dominant reaction of Bacillus megaterium levansucrase (Bm-LS) is hydrolysis. Single domain levansucrases from Gram-positive bacteria display a wide substrate-binding pocket with open access to water, challenging engineering for transfructosylation efficient enzymes. We pursued a shift in reaction specificity by either modifying the water distribution in the active site or the coordination of the catalytic acid/base (E352) and the nucleophile (D95), thus affecting the fructosyl-transfer rate and allowing acceptors other than water to occupy the active site. Two serine (173/422) and two water-binding tyrosine (421/439) residues located in the first shell of the catalytic pocket were modified. Library variants for positions 173, 421 and 422, which coordinate the position of D95 and E352, show increased transfructosylation (30-200%) and modified product spectra. Substitutions at position 422 have a higher impact on sucrose affinity, while changes at position 173 and 421 have a strong effect on the overall catalytic rate. As most retaining glycoside hydrolases (GHs) Bm-LS catalyzes hydrolysis and transglycosylation via a double displacement reaction involving two-transition states (TS1 and TS2). Hydrogen bonds of D95 with the side chains of S173 and S422 contribute a total of 2.4 kcal mol-1 to TS1 stabilization, while hydrogen bonds between invariant Y421, E352 and the glucosyl C-2 hydroxyl-group of sucrose contribute 2.15 kcal mol-1 stabilization. Changes at Y439 render predominantly hydrolytic variants synthesizing shorter oligosaccharides. PMID- 28575296 TI - Letter: Intraoperative Near-Infrared Optical Imaging Can Localize Gadolinium Enhancing Gliomas During Surgery. PMID- 28575295 TI - High-resolution crystal structures and STD NMR mapping of human ABO(H) blood group glycosyltransferases in complex with trisaccharide reaction products suggest a molecular basis for product release. AB - The human ABO(H) blood group A- and B-synthesizing glycosyltransferases GTA and GTB have been structurally characterized to high resolution in complex with their respective trisaccharide antigen products. These findings are particularly timely and relevant given the dearth of glycosyltransferase structures collected in complex with their saccharide reaction products. GTA and GTB utilize the same acceptor substrates, oligosaccharides terminating with alpha-l-Fucp-(1->2)-beta-d Galp-OR (where R is a glycolipid or glycoprotein), but use distinct UDP donor sugars, UDP-N-acetylgalactosamine and UDP-galactose, to generate the blood group A (alpha-l-Fucp-(1->2)[alpha-d-GalNAcp-(1->3)]-beta-d-Galp-OR) and blood group B (alpha-l-Fucp-(1->2)[alpha-d-Galp-(1->3)]-beta-d-Galp-OR) determinant structures, respectively. Structures of GTA and GTB in complex with their respective trisaccharide products reveal a conflict between the transferred sugar monosaccharide and the beta-phosphate of the UDP donor. Mapping of the binding epitopes by saturation transfer difference NMR measurements yielded data consistent with the X-ray structural results. Taken together these data suggest a mechanism of product release where monosaccharide transfer to the H-antigen acceptor induces active site disorder and ejection of the UDP leaving group prior to trisaccharide egress. PMID- 28575297 TI - Prognostic Factors for Satisfaction After Decompression Surgery for Lumbar Spinal Stenosis. AB - BACKGROUND: Surgical treatment for lumbar spinal stenosis is associated with both short- and long-term benefits with improvements in patient function and pain. Even though most patients are satisfied postoperatively, some studies report that up to one-third of patients are dissatisfied. OBJECTIVE: To present clinical outcome data and identify prognostic factors related to patient satisfaction 1 yr after posterior decompression surgery for lumbar spinal stenosis. METHODS: This multicenter register study included 2562 patients. Patients were treated with various types of posterior decompression. Patients with previous spine surgery or concomitant fusion were excluded. Patient satisfaction was analyzed for associations with age, sex, body mass index, smoking status, duration of pain, number of decompressed vertebral levels, comorbidities, and patient-reported outcome measures, which were used to quantify the effect of the surgical intervention. RESULTS: At 1-yr follow-up, 62.4% of patients were satisfied but 15.1% reported dissatisfaction. The satisfied patients showed significantly greater improvement in all outcome measures compared to the dissatisfied patients. The outcome scores for the dissatisfied patients were relatively unchanged or worse compared to baseline. Association was seen between dissatisfaction, duration of leg pain, smoking status, and patient comorbidities. Patients with good walking capacity at baseline were less prone to be dissatisfied compared to patients with poor walking capacity. CONCLUSION: This study found smoking, long duration of leg pain, and cancerous and neurological disease to be associated with patient dissatisfaction, whereas good walking capacity at baseline was positively associated with satisfaction after 1 yr. PMID- 28575298 TI - Chemo-enzymatic synthesis of lipid-linked GlcNAc2Man5 oligosaccharides using recombinant Alg1, Alg2 and Alg11 proteins. AB - The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum. While the purification of active Alg1 has previously been described, Alg11 and Alg2 have been mostly studied in vivo. We here describe the expression and purification of functional, full length Alg2 protein. Along with the purified soluble domains Alg1 and Alg11, we used Alg2 to chemo-enzymatically generate Dol PP-GlcNAc2Man5 analogs starting from synthetic LLOs containing a chitobiose moiety coupled to oligoprenyl carriers of distinct lengths (C10, C15, C20 and C25). We found that while the addition of the first mannose unit by Alg1 was successful with all of the LLO molecules, the Alg2-catalyzed reaction was only efficient if the acceptor LLOs contained a sufficiently long lipid tail of four or five isoprenyl units (C20 and C25). Following conversion with Alg11, the resulting C20 or C25 -containing GlcNAc2Man5 LLO analogs were successfully used as donor substrates of purified single-subunit oligosaccharyltransferase STT3A from Trypanosoma brucei. Our results provide a chemo-enzymatic method for the generation of eukaryotic LLO analogs and are the basis of subsequent mechanistic studies of the enigmatic Alg2 reaction mechanism. PMID- 28575299 TI - Mortality in Children Receiving Growth Hormone Treatment of Growth Disorders: Data From the Genetics and Neuroendocrinology of Short Stature International Study. AB - Context: Although pediatric growth hormone (GH) treatment is generally considered safe for approved indications, concerns have been raised regarding potential for increased risk of mortality in adults treated with GH during childhood. Objective: To assess mortality in children receiving GH. Design: Prospective, multinational, observational study. Setting: Eight hundred twenty-seven study sites in 30 countries. Patients: Children with growth disorders. Interventions: GH treatment during childhood. Main Outcome Measure: Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) using age- and sex-specific rates from the general population. Results: Among 9504 GH-treated patients followed for >=4 years (67,163 person-years of follow-up), 42 deaths were reported (SMR, 0.77; 95% CI, 0.56 to 1.05). SMR was significantly elevated in patients with history of malignant neoplasia (6.97; 95% CI, 3.81 to 11.69) and borderline elevated for those with other serious non-GH-deficient conditions (2.47; 95% CI, 0.99-5.09). SMRs were not elevated for children with history of benign neoplasia (1.44; 95% CI, 0.17 to 5.20), idiopathic GHD (0.11; 95% CI, 0.02 to 0.33), idiopathic short stature (0.20; 95% CI, 0.01 to 1.10), short stature associated with small for gestational age (SGA) birth (0.66; 95% CI, 0.08 to 2.37), Turner syndrome (0.51; 95% CI, 0.06 to 1.83), or short stature homeobox containing (SHOX) gene deficiency (0.83; 95% CI, 0.02 to 4.65). Conclusions: No significant increases in mortality were observed for GH-treated children with idiopathic GHD, idiopathic short stature, born SGA, Turner syndrome, SHOX deficiency, or history of benign neoplasia. Mortality was elevated for children with prior malignancy and those with underlying serious non-GH-deficient medical conditions. PMID- 28575300 TI - The Effects of Salinity on the Herbivorous Crop Pest Tetranychus urticae (Trombidiformes: Tetranychidae) on Soybean and Corn. AB - Many environmental factors, including soil characteristics, are critical for plants, herbivorous arthropods, and their interactions. Despite increasing evidence that soil salinity drastically impacts plants, little is known about how salinity affects the herbivorous arthropod pests feeding on those plants. We investigated how soil salinity affects the twospotted spider mite (Tetranychus urticae Koch) feeding on corn (Zea mays L.) and soybean (Glycine max L.). We performed two greenhouse studies, one focusing on the impact of salinity on individual mite fecundity over a period of 3 d and the other focusing on population growth of T. urticae over 7 d. Both experiments were performed across varying salinity levels; electrical conductivity values ranged from 0.84 to 8.07 dS m-1. We also performed the 3-d fecundity experiment in the field, across naturally varying saline conditions. Overall, the twospotted spider mite performed better as salinity increased; both fecundity and population growth tended to have a positive linear correlation with salinity. These studies suggest that salinity can be important for herbivores, just as it is for plants. Moreover, the negative effects of soil salinity on crop plants in agroecosystems may be further compounded by a greater risk of pest problems. Salinity may be another important environmental stressor that can directly influence crop production while also indirectly influencing herbivorous pests. PMID- 28575301 TI - Reducing Antipsychotic Medication Use in Nursing Homes: A Qualitative Study of Nursing Staff Perceptions. AB - Background and Objectives: The purpose of this study was to use qualitative methods to explore nursing home staff perceptions of antipsychotic medication use and identify both benefits and barriers to reducing inappropriate use from their perspective. Research Design and Methods: Focus groups were conducted with a total of 29 staff in three community nursing homes that served both short and long-stay resident populations. Results: The majority (69%) of the staff participants were licensed nurses. Participants expressed many potential benefits of antipsychotic medication reduction with four primary themes: (a) Improvement in quality of life, (b) Improvement in family satisfaction, (c) Reduction in falls, and (d) Improvement in the facility Quality Indicator score (regulatory compliance). Participants also highlighted important barriers they face when attempting to reduce or withdraw antipsychotic medications including: (a) Family resistance, (b) Potential for worsening or return of symptoms or behaviors, (c) Lack of effectiveness and/or lack of staff resources to consistently implement nonpharmacological management strategies, and (d) Risk aversion of staff and environmental safety concerns. Discussion and Implications: Nursing home staff recognize the value of reducing antipsychotic medications; however, they also experience multiple barriers to reduction in routine clinical practice. Achievement of further reductions in antipsychotic medication use will require significant additional efforts and adequate clinical personnel to address these barriers. PMID- 28575303 TI - Are more extensive procedures warranted at the time of aortic arch reoperation? AB - OBJECTIVES: To determine the early and late outcomes of patients undergoing aortic arch reoperations. METHODS: The follow-up of 70 patients undergoing a second arch operation (excluding univentricular physiology) between 1979 and 2015 was reviewed. Median age at initial arch operation and second operation was 9 days (interquartile range: 5-35) and 10 months (interquartile range: 3-64), respectively. The most common indication for initial arch operation was coarctation in 79% (55/70). The most common indication for a second arch operation was arch reobstruction in 90% (63/70). RESULTS: There were 2 hospital deaths (2/70, 3%) and 3 early third arch operations (3/70, 4%). Late follow-up was available in 94% (64/68) of hospital survivors. After a mean of 9 +/- 7 years, there were 5 late deaths (5/64, 8%). Fifteen-year survival was 90% (95% confidence interval: 75-96). Arch reobstruction (echocardiogram gradient >25 mmHg/third operation for reobstruction) was present in 28% (18/64) and 16% (10/64) required a third arch operation. Fifteen-year freedom from arch reobstruction and third arch operation was 63% (95% confidence interval: 43-78) and 74% (95% confidence interval: 52-87), respectively. On multivariable analysis, hypoplastic arch at initial arch repair (P = 0.03) and interposition graft at second arch operation (P < 0.0001) were risk factors for third arch operation. CONCLUSIONS: Patients undergoing a second arch operation have significant rates of arch reobstruction and reoperation. The high rates of arch reobstruction and third arch operation warrant more extensive procedures at the time of second arch operation, especially in patients with a hypoplastic arch. Regular long-term monitoring after arch reoperation is mandatory. PMID- 28575302 TI - Impact of computed tomography myocardial perfusion following computed tomography coronary angiography on downstream referral for invasive coronary angiography, revascularization and, outcome at 12 months. AB - Aims: The aim of this study was to assess the impact of adding stress computed tomography (CT) myocardial perfusion (CTP) to coronary CT angiography (CTA) on downstream referral for invasive coronary angiography (ICA), revascularization, and outcome in patients presenting with new-onset chest pain. Methods and results: Three hundred and eighty-four patients were referred for cardiac CT. Patients with lesions >=50% stenosis underwent subsequently stress CTP. Perfusion scans were considered abnormal if a defect was observed in >= 1 segment. Downstream performance of ICA, revascularization, and the occurrence of major cardiovascular events (death, non-fatal myocardial infarction, and unstable angina requiring urgent revascularization) were assessed within 12 months. In total, 119 patients showed >=50% stenosis on coronary CTA; stress CTP was normal in 61 patients, abnormal in 38 patients and was not performed in 20 patients. After normal stress CTP, 19 (31%) patients underwent ICA and 9 (15%) underwent revascularization. After abnormal stress CTP, 36 (95%) patients underwent ICA and 29 (76%) revascularizations were performed. Multivariable analyses showed a five fold reduction in likelihood of proceeding to ICA when a normal stress CTP was added to a coronary CTA showing obstructive CAD. Major cardiovascular event rates at 12 months for patients with obstructive CAD and normal stress CTP (N = 61) were low: 1 myocardial infarction, 1 urgent revascularization, and 1 non-cardiac death. Conclusion: The performance of stress CTP in patients with obstructive CAD at coronary CTA in the same setting is feasible and reduces the referral rate for ICA and revascularization. Secondly, the occurrence of major cardiovascular events at 12 months follow-up in patients with normal stress CTP is low. PMID- 28575304 TI - Impact of Rotavirus Vaccine Introduction and Postintroduction Etiology of Diarrhea Requiring Hospital Admission in Haydom, Tanzania, a Rural African Setting. AB - Background: No data are available on the etiology of diarrhea requiring hospitalization after rotavirus vaccine introduction in Africa. The monovalent rotavirus vaccine was introduced in Tanzania on 1 January 2013. We performed a vaccine impact and effectiveness study as well as a quantitative polymerase chain reaction (qPCR)-based etiology study at a rural Tanzanian hospital. Methods: We obtained data on admissions among children <5 years to Haydom Lutheran Hospital between 1 January 2010 and 31 December 2015 and estimated the impact of vaccine introduction on all-cause diarrhea admissions. We then performed a vaccine effectiveness study using the test-negative design. Finally, we tested diarrheal specimens during 2015 by qPCR for a broad range of enteropathogens and calculated pathogen-specific attributable fractions (AFs). Results: Vaccine introduction was associated with a 44.9% (95% confidence interval [CI], 17.6%-97.4%) reduction in diarrhea admissions in 2015, as well as delay of the rotavirus season. The effectiveness of 2 doses of vaccine was 74.8% (95% CI, -8.2% to 94.1%) using an enzyme immunoassay-based case definition and 85.1% (95% CI, 26.5%-97.0%) using a qPCR-based case definition. Among 146 children enrolled in 2015, rotavirus remained the leading etiology of diarrhea requiring hospitalization (AF, 25.8% [95% CI, 24.4%-26.7%]), followed by heat-stable enterotoxin-producing Escherichia coli (AF, 18.4% [95% CI, 12.9%-21.9%]), Shigella/enteroinvasive E. coli (AF, 14.5% [95% CI, 10.2%-22.8%]), and Cryptosporidium (AF, 7.9% [95% CI, 6.2%-9.3%]). Conclusions: Despite the clear impact of vaccine introduction in this setting, rotavirus remained the leading etiology of diarrhea requiring hospitalization. Further efforts to maximize vaccine coverage and improve vaccine performance in these settings are warranted. PMID- 28575305 TI - Functional Outcomes and Delayed Cerebral Ischemia Following Nonperimesencephalic Angiogram-Negative Subarachnoid Hemorrhage Similar to Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: The angiogram-negative subarachnoid hemorrhage (SAH) literature includes patients with perimesencephalic hemorrhage, which is recognized to have a much better outcome than aneurysmal SAH. OBJECTIVE: To evaluate the clinical outcomes of Nonperimesencephalic Angiogram-Negative SAH (NPAN-SAH). METHODS: A prospective, spontaneous SAH database of 1311 patients that accrued between April 2006 and December 2014 was screened. All patients with NPAN-SAH and 2 consecutive negative cerebral angiograms were included. RESULTS: We identified 191 (11%) from a total of 1311 patients with spontaneous SAH. Amongst angiogram-negative patients, 83 (4.9%) were adjudicated to have NPAN-SAH. Patient characteristics were similar across the groups, except NPAN-SAH patients were more likely to be men and had higher rates of diabetes. In a multivariable logistic regression model, NPAN-SAH patients were less likely to develop vasospasm, after adjusting for Fisher grade, sex, and diabetes (odds ratio [OR]: 0.197, 95% confidence interval [CI; 0.07-0.55], P = .002). In another adjusted model accounting for Hunt and Hess clinical grade, NPAN-SAH patients were also less likely to develop vasospasm (OR: 0.2, 95% CI [0.07-0.57], P = .002). We found no statistical significance between 2 groups for rebleed, developing hydrocephalus, seizures, or delayed cerebral ischemia. NPAN-SAH patients were equally associated with poor functional outcome (modified Rankin scale >=3; OR: 1.16, 95% CI [0.615-2.20], P = .6420), and death (OR: 1.22, 95% CI [0.362-4.132], P = .7455) compared to aneurysmal SAH. CONCLUSION: Although the risk of vasospasm may be lower, patients with NPAN-SAH are equally associated with delayed cerebral ischemia, poor outcome, and death as compared to patients with aneurysmal SAH. Furthers studies may be necessary to further clarify these findings. PMID- 28575306 TI - Job characteristics and mental health for older workers. AB - Background: Adverse job characteristics have been linked with increased incidence of depression and anxiety in working populations. However, the association between job characteristics and mental health, in an older working population while controlling for personality traits, is less well known. Aims: To examine the association between job characteristics (job demands and job control) and mental health (depression and anxiety) for older workers while controlling for personality traits. Methods: A sample of workers aged 50-69 years were recruited from a primary health care clinic in Southern Ireland. Job characteristics were measured using the Copenhagen Psychosocial Questionnaire; demands (quantitative and cognitive) and control (influence at work and possibilities for development). Personality traits were measured using the Ten-Item Personality Inventory, depression was measured using the Center for Epidemiological Studies-Depression Scale and anxiety was measured using the Hospital Anxiety and Depression Scale. Descriptive analysis, simple and multiple linear regression analyses were conducted. Results: The final sample size was 1025 with an initial 67% response rate. Multiple linear regression analysis showed job characteristics (in particular, job demands) to be significant positive predictors of symptoms of depression and anxiety. The inverse was true for job control variables and symptoms of depression. Neither possibilities for development nor influence at work were associated with symptoms of anxiety. Conclusions: Our findings indicate that despite potential confounders, higher demands at work can impact the worker's mental health negatively. Reducing job demands and encouraging role development may benefit the mental health of older workers. PMID- 28575307 TI - Identified Transmission Dynamics of Middle East Respiratory Syndrome Coronavirus Infection During an Outbreak: Implications of an Overcrowded Emergency Department. AB - A total 130 cases of Middle East respiratory syndrome coronavirus were identified during a large hospital outbreak in Saudi Arabia; 87 patients and 43 healthcare workers. The majority (80%) of transmission was healthcare-acquired (HAI) infection, with 4 generations of HAI transmission. The emergency department was the main location of exposure. PMID- 28575308 TI - Spatial-temporal transcriptional dynamics of long non-coding RNAs in human brain. AB - The functional architecture of the human brain is greatly determined by the temporal and spatial regulation of the transcription process. However, the spatial and temporal transcriptional landscape of long non-coding RNAs (lncRNAs) during human brain development remains poorly understood. Here, we report the genome-wide lncRNA transcriptional analysis in an extensive series of 1340 post mortem human brain specimens collected from 16 regions spanning the period from early embryo development to late adulthood. We discovered that lncRNA transcriptome dramatically changed during fetal development, while transited to a surprisingly relatively stable state after birth till the late adulthood. We also discovered that the transcription map of lncRNAs was spatially different, and that this spatial difference was developmentally regulated. Of the 16 brain regions explored (cerebellar cortex, thalamus, striatum, amygdala, hippocampus and 11 neocortex areas), cerebellar cortex showed the most distinct lncRNA expression features from all remaining brain regions throughout the whole developmental period, reflecting its unique developmental and functional features. Furthermore, by characterizing the functional modules and cellular processes of the spatial-temporal dynamic lncRNAs, we found that they were significantly associated with the RNA processing, neuron differentiation and synaptic signal transportation processes. Furthermore, we found that many lncRNAs associated with the neurodegenerative Alzheimer and Parkinson diseases were co expressed in the fetal development of the human brain, and affected the convergent biological processes. In summary, our study provides a comprehensive map for lncRNA transcription dynamics in human brain development, which might shed light on the understanding of the molecular underpinnings of human brain function and disease. PMID- 28575310 TI - Corrigendum. PMID- 28575309 TI - Nonhuman Primate Studies to Advance Vision Science and Prevent Blindness. AB - Most primate behavior is dependent on high acuity vision. Optimal visual performance in primates depends heavily upon frontally placed eyes, retinal specializations, and binocular vision. To see an object clearly its image must be placed on or near the fovea of each eye. The oculomotor system is responsible for maintaining precise eye alignment during fixation and generating eye movements to track moving targets. The visual system of nonhuman primates has a similar anatomical organization and functional capability to that of humans. This allows results obtained in nonhuman primates to be applied to humans. The visual and oculomotor systems of primates are immature at birth and sensitive to the quality of binocular visual and eye movement experience during the first months of life. Disruption of postnatal experience can lead to problems in eye alignment (strabismus), amblyopia, unsteady gaze (nystagmus), and defective eye movements. Recent studies in nonhuman primates have begun to discover the neural mechanisms associated with these conditions. In addition, genetic defects that target the retina can lead to blindness. A variety of approaches including gene therapy, stem cell treatment, neuroprosthetics, and optogenetics are currently being used to restore function associated with retinal diseases. Nonhuman primates often provide the best animal model for advancing fundamental knowledge and developing new treatments and cures for blinding diseases. PMID- 28575313 TI - Power calculator for instrumental variable analysis in pharmacoepidemiology. AB - Background: Instrumental variable analysis, for example with physicians' prescribing preferences as an instrument for medications issued in primary care, is an increasingly popular method in the field of pharmacoepidemiology. Existing power calculators for studies using instrumental variable analysis, such as Mendelian randomization power calculators, do not allow for the structure of research questions in this field. This is because the analysis in pharmacoepidemiology will typically have stronger instruments and detect larger causal effects than in other fields. Consequently, there is a need for dedicated power calculators for pharmacoepidemiological research. Methods and Results: The formula for calculating the power of a study using instrumental variable analysis in the context of pharmacoepidemiology is derived before being validated by a simulation study. The formula is applicable for studies using a single binary instrument to analyse the causal effect of a binary exposure on a continuous outcome. An online calculator, as well as packages in both R and Stata, are provided for the implementation of the formula by others. Conclusions: The statistical power of instrumental variable analysis in pharmacoepidemiological studies to detect a clinically meaningful treatment effect is an important consideration. Research questions in this field have distinct structures that must be accounted for when calculating power. The formula presented differs from existing instrumental variable power formulae due to its parametrization, which is designed specifically for ease of use by pharmacoepidemiologists. PMID- 28575311 TI - Pre-diagnostic copper and zinc biomarkers and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort. AB - Adequate intake of copper and zinc, two essential micronutrients, are important for antioxidant functions. Their imbalance may have implications for development of diseases like colorectal cancer (CRC), where oxidative stress is thought to be etiologically involved. As evidence from prospective epidemiologic studies is lacking, we conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to investigate the association between circulating levels of copper and zinc, and their calculated ratio, with risk of CRC development. Copper and zinc levels were measured by reflection X-ray fluorescence spectrometer in 966 cases and 966 matched controls. Multivariable adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression and are presented for the fifth versus first quintile. Higher circulating concentration of copper was associated with a raised CRC risk (OR = 1.50; 95% CI: 1.06, 2.13; P-trend = 0.02) whereas an inverse association with cancer risk was observed for higher zinc levels (OR = 0.65; 95% CI: 0.43, 0.97; P-trend = 0.07). Consequently, the ratio of copper/zinc was positively associated with CRC (OR = 1.70; 95% CI: 1.20, 2.40; P-trend = 0.0005). In subgroup analyses by follow-up time, the associations remained statistically significant only in those diagnosed within 2 years of blood collection. In conclusion, these data suggest that copper or copper levels in relation to zinc (copper to zinc ratio) become imbalanced in the process of CRC development. Mechanistic studies into the underlying mechanisms of regulation and action are required to further examine a possible role for higher copper and copper/zinc ratio levels in CRC development and progression. PMID- 28575312 TI - The contribution of tumor-associated macrophages in glioma neo-angiogenesis and implications for anti-angiogenic strategies. AB - "Tumor-associated macrophages" (TAMs) form a significant cell population in malignant tumors and contribute to tumor growth, metastasis, and neovascularization. Gliomas are characterized by extensive neo-angiogenesis, and knowledge of the role of TAMs in neovascularization is important for future anti angiogenic therapies. The phenotypes and functions of TAMs are heterogeneous and more complex than a classification into M1 and M2 inflammation response types would suggest. In this review, we provide an update on the current knowledge of the ontogeny of TAMs, focusing on diffuse gliomas. The role of TAMs in the regulation of the different processes in tumor angiogenesis is highlighted and the most recently discovered mechanisms by which TAMs mediate resistance against current antivascular therapies are mentioned. Novel compounds tested in clinical trials are discussed and brought in relation to different TAM-related angiogenesis pathways. In addition, potential therapeutic targets used to intervene in TAM-regulated tumor angiogenesis are summarized. PMID- 28575314 TI - Comment on: Increased inflammation and disease activity among current cigarette smokers with rheumatoid arthritis: a cross-sectional analysis of US veterans. PMID- 28575315 TI - Managing varicella zoster virus contact and infection in patients on anti rheumatic therapy. AB - Chickenpox and shingles can be more severe and occasionally life threatening in immunosuppressed patients. As such, some groups warrant a more detailed history, serological testing and consideration of prophylaxis following contact with the virus. Active disease may also require more aggressive treatment with antivirals. Guidance for the use of varicella zoster immunoglobulin has recently been updated by Public Health England with important implications for rheumatology patients. PMID- 28575316 TI - Oxidative Stress and Inflammation in Early Onset First Episode Psychosis: A Systematic Review and Meta-Analysis. AB - Background: People with schizophrenia and other psychosis show increased proinflammatory and prooxidative status. However, the few studies that have specifically assessed oxidative and inflammatory markers in early onset psychosis (onset before age 18) have shown contradictory results. Methods: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for systematic reviews and meta-analyses were used to conduct a systematic literature search to detect studies comparing inflammatory and oxidative markers in early onset psychosis patients and healthy controls. Results: Seven studies met criteria for the qualitative analysis. Four studies met criteria for meta analysis, comprising an overall sample of 261 early onset psychosis patients and 246 healthy controls. Six independent meta-analyses were performed for catalase, glutathione, glutathione peroxidase, superoxide dismutase, total antioxidant status, and cell/DNA oxidative damage. No significant differences were found between early onset psychosis patients and controls in any of the parameters assessed. Heterogeneity among studies was high. Qualitative analysis of individual studies showed an association of inflammatory and oxidative markers with clinical, cognitive, and neurobiological outcomes, especially in longitudinal assessments. Conclusions: Despite the lack of significant differences between early onset psychosis patients and controls in the oxidative markers assessed in the meta-analyses, results based on individual studies suggest that greater inflammation and oxidative stress might lead to poorer outcomes in patients with first episodes of early onset psychosis. PMID- 28575317 TI - Ribosomal selection of mRNAs with degenerate initiation triplets. AB - To assess the influence of degenerate initiation triplets on mRNA recruitment by ribosomes, five mRNAs identical but for their start codon (AUG, GUG, UUG, AUU and AUA) were offered to a limiting amount of ribosomes, alone or in competition with an identical AUGmRNA bearing a mutation conferring different electrophoretic mobility to the product. Translational efficiency and competitiveness of test mRNAs toward this AUGmRNA were determined quantifying the relative amounts of the electrophoretically separated wt and mutated products synthesized in vitro and found to be influenced to different extents by the nature of their initiation triplet and by parameters such as temperature and nutrient availability in the medium. The behaviors of AUAmRNA, UUGmRNA and AUGmRNA were the same between 20 and 40 degrees C whereas the GUG and AUUmRNAs were less active and competed poorly with the AUGmRNA, especially at low temperature. Nutrient limitation and preferential inhibition by ppGpp severely affected activity and competitiveness of all mRNAs bearing non-AUG starts, the UUGmRNA being the least affected. Overall, our data indicate that beyond these effects exclusively due to the degenerate start codons within an optimized translational initiation region, an important role is played by the context in which the rare start codons are present. PMID- 28575318 TI - Early versus late pulmonary valve replacement in patients with transannular patch repaired tetralogy of Fallot. AB - OBJECTIVES: Although the effects of pulmonary regurgitation after tetralogy of Fallot repair are detrimental, timing of pulmonary valve replacement (PVR) is unclear. Our goal was to evaluate the midterm efficacy and safety of early PVR. METHODS: Patients with tetralogy of Fallot who underwent repair from 1962 to 2015 were included from the local database. Statistical analyses compared patients who underwent early PVR (age <=16 years), late PVR and no PVR. The timing of the intervention was compared for efficacy-all-cause mortality and the combined end point of all-cause mortality, ventricular tachycardia and defibrillator implantation-and for safety-the combined end-point of 1-year postoperative mortality after PVR, endocarditis and reintervention. Echocardiographic and electrocardiographic data at the last follow-up examination were compared across the 3 groups. RESULTS: Two hundred seventy-three patients (age 21 +/- 5 years; 52% female) were included. The mean follow-up was 24 (95% confidence interval 22.7-26.2) years; the observed median was 21 years (interquartile range 11-31). No significant difference in survival was found between the early PVR (n = 106; 39%), the late PVR (n = 47; 17%) and the no PVR groups (n = 120; 44%) (P = 0.990). No significant difference in the combined efficacy end-point was noted between patients who underwent early PVR compared with patients who underwent late PVR (P = 0.247). Worse event-free survival for the 3-point safety end-point was observed after early PVR (P < 0.001). Right ventricular morphology (P < 0.001) and function (P < 0.001) were better preserved in the patient group that underwent PVR before the age of 16 years. CONCLUSIONS: As expected, PVR-related morbidity was higher in patients who underwent early PVR but the midterm outcome was similar. Nevertheless, better preservation of right ventricular morphology and function in the early PVR group might result in better long-term survival. PMID- 28575320 TI - High-throughput sequencing of microbial eukaryotes in Lake Baikal reveals ecologically differentiated communities and novel evolutionary radiations. AB - We performed high-throughput 18S rDNA V9 region sequencing analyses of microeukaryote (protist) communities at seven sites with depths ranging from 0 to 1450 m in the southern part of Lake Baikal. We show that microeukaryotic diversity differed according to water column depth and sediment depth. Chrysophytes and perkinsids were diverse in subsurface samples, novel radiations of petalomonads and Ichthyobodo relatives were found in benthic samples, and a broad range of divergent OTUs were detected in deep subbenthic samples. Members of clades usually associated with marine habitats were also detected, including syndineans for the first time in freshwater systems. Fungal- and cercozoan specific c. 1200 bp amplicon clone libraries also revealed many novel lineages in both planktonic and sediment samples at all depths, a novel radiation of aphelids in shallower benthic samples, and partitioning of sarcomonad lineages in shallow vs deep benthic samples. Putative parasitic lineages accounted for 12.4% of overall reads, including a novel radiation of Ichthyobodo (fish parasite) relatives. Micrometazoans were also analysed, including crustaceans, rotifers and nematodes. The deepest (>1000 m) subsurface sediment samples harboured some highly divergent sequence types, including heterotrophic flagellates, parasites, putative metazoans and sequences likely representing organisms originating from higher up in the water column. PMID- 28575319 TI - Translational Research in the Nonhuman Primate Model of Tuberculosis. AB - Infection with Mycobacterium tuberculosis predominantly establishes subclinical latent infection over the lifetime of an individual, with a fraction of infected individuals rapidly progressing to active disease. The immune control in latent infection can be perturbed by comorbidities such as diabetes mellitus, obesity, smoking, and coinfection with helminthes or HIV. Modeling the varying aspects of natural infection remains incomplete when using zebrafish and mice. However, the nonhuman primate model of tuberculosis offers a unique and accurate model to investigate host responses to infection, test novel therapeutics, and thoroughly assess preclinical vaccine candidates. Rhesus macaques and cynomolgus macaques manifest the full gamut of clinical and pathological findings in human Mycobacterium tuberculosis infection, including the ability to co-infect macaques with Simian Immunodeficiency Virus to model HIV co-infection. Here we discuss advanced techniques to assay various clinical outcomes of the natural progression of infection as well as therapeutics in development and novel preclinical vaccines. Finally, we survey the translational aspects of nonhuman primate research and argue the urgent need to thoroughly examine preclinical therapeutics and vaccines using this model prior to clinical implementation. PMID- 28575321 TI - The Validity and Sensitivity of PANSS-6 in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Study. AB - It was recently demonstrated in acutely exacerbated schizophrenia that a 6-item version (PANSS-6: P1 = delusions, P2 = conceptual disorganization, P3 = hallucinations, N1 = blunted affect, N4 = social withdrawal, N6 = lack of spontaneity/flow of conversation) of the 30-item Positive and Negative Syndrome Scale (PANSS-30) was scalable (all items provide unique information regarding syndrome severity) and able to separate the effect of antipsychotics from placebo. Here, we tested the validity and sensitivity of PANSS-6 in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) outpatient study. We examined (1) the scalability of PANSS-6 and PANSS-30; (2) the correlation between PANSS-6 and PANSS-30 total scores; (3) whether PANSS-6 could identify symptom remission (Andreasen criteria); and (4) the effect of the 5 antipsychotics studied in CATIE Phase-1, using PANSS-6 and PANSS-30 total scores as outcomes. We found that for the 577 subjects with complete PANSS ratings at baseline, month 1, 3, and 6, PANSS-6 was scalable, whereas PANSS-30 was not. In the 1432 subjects in the intention-to-treat (ITT) sample, PANSS-6 and PANSS-30 total scores were highly correlated (Spearman correlation coefficient = 0.86). Based on 5080 ITT ratings, PANSS-6 identified symptom remission with an accuracy of 0.99 (95% confidence interval = 0.99-0.99). In ITT analyses, PANSS-6 and PANSS-30 identified the same statistically significant differences in antipsychotic efficacy, ie, olanzapine was superior to risperidone (P-value PANSS-6 = 0.0003 and PANSS-30 = 0.0003) and ziprasidone (P-value PANSS-6 = 0.0018 and PANSS-30 = 0.0046). In conclusion, PANSS-6 is a brief schizophrenia rating scale that adequately measures severity, remission, and antipsychotic efficacy related to core positive and negative symptoms in clinical trials. Prospective studies of PANSS-6 in clinical practice are required. PMID- 28575323 TI - Darunavir concentrations in CSF of HIV-infected individuals when boosted with cobicistat versus ritonavir. AB - Objectives: Cobicistat and ritonavir have different inhibitory profiles for drug transporters that could impact the distribution of co-administered drugs. We compared darunavir concentrations in CSF when boosted by cobicistat versus ritonavir relative to plasma concentrations and with WT HIV-1 IC50 and IC90. Methods: An open, single-arm, sequential clinical trial (NCT02503462) where paired CSF and blood samples were taken from seven HIV-infected patients presenting with HIV-associated neurocognitive disorders (HAND) and treated with a darunavir/ritonavir (800/100 mg) once-daily regimen. Ritonavir was subsequently replaced by cobicistat and paired CSF and blood samples were obtained from the same patients after treatment with the darunavir/cobicistat (800/150 mg) once daily regimen. Darunavir concentrations at the end of the dosing interval were quantified by LC-MS/MS. Results: The median (IQR) darunavir concentrations in CSF with ritonavir and cobicistat boosting were 16.4 ng/mL (8.6-20.3) and 15.9 ng/mL (6.7-31.6), respectively (P = 0.58). The median (IQR) darunavir CSF:plasma ratios with ritonavir and cobicistat boosting were 0.007 (0.006-0.012) and 0.011 (0.007 0.015), respectively (P = 0.16). Darunavir concentrations in CSF exceeded the darunavir IC50 and IC90 by a median of 9.2- and 6.7-fold with ritonavir boosting, and by 8.9- and 6.5-fold with cobicistat boosting, respectively. All patients had darunavir CSF concentrations above the target inhibitory concentrations and remained virologically suppressed in the CSF and plasma. Conclusions: This small study shows that cobicistat and ritonavir give comparable effective darunavir concentrations in CSF, thus suggesting that these boosters can be used interchangeably in once-daily darunavir regimens. PMID- 28575322 TI - Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy. AB - The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor that plays a pivotal role in extracellular calcium homeostasis. The CaSR is also highly expressed in pancreatic islet alpha- and beta-cells that secrete glucagon and insulin, respectively. To determine whether the CaSR may influence systemic glucose homeostasis, we characterized a mouse model with a germline gain-of function CaSR mutation, Leu723Gln, referred to as Nuclear flecks (Nuf). Heterozygous- (CasrNuf/+) and homozygous-affected (CasrNuf/Nuf) mice were shown to have hypocalcemia in association with impaired glucose tolerance and insulin secretion. Oral administration of a CaSR antagonist compound, known as a calcilytic, rectified the glucose intolerance and hypoinsulinemia of CasrNuf/+ mice and ameliorated glucose intolerance in CasrNuf/Nuf mice. Ex vivo studies showed CasrNuf/+ and CasrNuf/Nuf mice to have reduced pancreatic islet mass and beta-cell proliferation. Electrophysiological analysis of isolated CasrNuf/Nuf islets showed CaSR activation to increase the basal electrical activity of beta cells independently of effects on the activity of the adenosine triphosphate (ATP)-sensitive K+ (KATP) channel. CasrNuf/Nuf mice also had impaired glucose mediated suppression of glucagon secretion, which was associated with increased numbers of alpha-cells and a higher alpha-cell proliferation rate. Moreover, CasrNuf/Nuf islet electrophysiology demonstrated an impairment of alpha-cell membrane depolarization in association with attenuated alpha-cell basal KATP channel activity. These studies indicate that the CaSR activation impairs glucose tolerance by a combination of alpha- and beta-cell defects and also influences pancreatic islet mass. Moreover, our findings highlight a potential application of targeted CaSR compounds for modulating glucose metabolism. PMID- 28575324 TI - Aortic diameter remodelling after the frozen elephant trunk technique in aortic dissection: results from an international multicentre registry. AB - OBJECTIVES: The frozen elephant trunk (FET) technique allows one-stage hybrid repair approach in aortic dissection (AoD). Even if the effect of the FET technique on promoting false lumen (FL) thrombosis has been proved in the past, the relative importance of FL thrombosis on aortic remodelling at different levels of the distal aorta and the magnitude of this effect is not well known. The aim of the study was to evaluate aortic remodelling following a FET technique for AoD. METHODS: A multicentre international registry database was searched to identify all patients who underwent a FET procedure for an AoD. A total of 383 patients with AoD were operated on between January 2005 and March 2014 with the FET technique; 137 patients (65 acute AoD and 72 chronic AoD) who survived the initial repair with at least a 1-year follow-up CT scan were included in the study. RESULTS: The rate of FL thrombosis was higher in the mid-descending thoracic aorta (99.3%) and lower in the distal abdominal aorta (13.9%) but similar between acute and chronic AoDs. The negative remodelling rate was similar between acute and chronic AoDs in the abdominal aorta, but chronic AoD exhibited a higher rate of negative remodelling in the descending thoracic aorta (33% vs 17.5%, P = 0.040). CONCLUSIONS: The FET technique provides an effective treatment for AoD, promoting FL thrombosis and remodelling in the descending thoracic aorta. Changes in the diameter of the aortic lumen depend mainly on the status of the FL and are similar between acute and chronic AoD. Changes in the diameter of true lumen are affected by both the FL status and the timing of the presentation. However, increased FL thrombosis and positive remodelling rates are not maintained at the level of the abdominal aorta, and strict follow-up is mandatory to detect early changes in the aortic dimensions, which may warrant further interventions. PMID- 28575326 TI - Two Pests Overlap: Drosophila suzukii (Diptera: Drosophilidae) Use of Fruit Exposed to Halyomorpha halys (Hemiptera: Pentatomidae). AB - Drosophila suzukii (Matsumura) (Diptera: Drosophilidae) and brown marmorated stink bug, Halyomorpha halys (Stal) (Hemiptera: Pentatomidae), are global economic pests that may co-occur on small fruits. We investigated whether fruit recently exposed to H. halys affected subsequent host use by D. suzukii. Laboratory no-choice and choice tests presented D. suzukii with H. halys-fed and unfed raspberries and blueberries immediately or 3 d after H. halys feeding. Resulting D. suzukii eggs, or larvae and pupae, were counted. The number of D. suzukii immatures among fed and unfed fruit was not significantly different in lab studies. There was no relationship between the intensity of H. halys feeding, as estimated by the number of stylet sheaths, and D. suzukii oviposition on blueberry. Lastly, field studies compared D. suzukii infestation between H. halys fed and unfed raspberries. Raspberries were previously exposed to H. halys for 3 d or simultaneously exposed to both pests for 7 d. Natural infestation by D. suzukii in the field was similar among raspberries previously or simultaneously exposed to H. halys compared to control fruit. PMID- 28575325 TI - Exclusive Enteral Nutrition Therapy in Paediatric Crohn's Disease Results in Long term Avoidance of Corticosteroids: Results of a Propensity-score Matched Cohort Analysis. AB - Background and Aims: Exclusive enteral nutrition [EEN] is recommended as a first line induction therapy for paediatric Crohn's disease [CD] although corticosteroids [CS] are still used commonly. Our aim was to compare short- and long-term disease outcomes of paediatric CD patients initially managed with either EEN or CS. Methods: Medical records of newly diagnosed paediatric CD patients treated with EEN or CS as induction therapy were retrospectively reviewed. To minimise selection bias inherent in observational cohort studies, propensity analysis was carried out. Data on anthropometrics, medical history, and presenting phenotype were collected at time of diagnosis [baseline]; outcomes of interest, including medication use, hospitalisation, surgical procedures, and disease progression were assessed up to 6 years following diagnosis. Results: Of 127 patients reviewed, a total of 111 propensity-score matched CD patients receiving EEN [n = 76] or CS [n = 35] were analysed. By 4-12 weeks of induction therapy, 86.6% of EEN-treated patients achieved remission (Paediatric Crohn's Disease Activity Index [PCDAI] <= 7.5) compared with 58.1% of patients in the CS treated group [p < 0.01]. Choice of EEN over CS for induction was associated with avoidance of corticosteroids over a 6-year follow-up period. Analysis of long term linear growth, hospitalisation, need for biologic therapy, or surgical intervention did not reveal any significant differences. Conclusions: These findings suggest that EEN induction therapy is more effective in achieving early remission and is associated with long-term steroid avoidance without increased use of biologics or need for surgery. PMID- 28575327 TI - Interpreting weightings of the peer assessment rating index and the discrepancy index across contexts on Chinese patients. AB - Objective: Determine optimal weightings of Peer Assessment Rating (PAR) index and Discrepancy Index (DI) for malocclusion severity assessment in Chinese orthodontic patients. Methods: Sixty-nine Chinese orthodontists assessed a full set of pre-treatment records from a stratified random sample of 120 subjects gathered from six university orthodontic centres. Using professional judgment as the outcome variable, multiple regression analyses were performed to derive customized weighting systems for the PAR index and DI, for all subjects and each Angle classification subgroup. Results: Professional judgment was consistent, with an Intraclass Correlation Coefficient (ICC) of 0.995. The PAR index or DI can be reliably measured, with ICC = 0.959 and 0.990, respectively. The predictive accuracy of PAR index was greatly improved by the Chinese weighting process (from r = 0.431 to r = 0.788) with almost equal distribution in each Angle classification subgroup. The Chinese-weighted DI showed a higher predictive accuracy, at P = 0.01, compared with the PAR index (r = 0.851 versus r = 0.788). A better performance was found in the Class II group (r = 0.890) when compared to Class I (r = 0.736) and III (r = 0.785) groups. Conclusions: The Chinese-weighted PAR index and DI were capable of predicting 62 per cent and 73 per cent of total variance in the professional judgment of malocclusion severity in Chinese patients. Differential prediction across Angle classifications merits attention since different weighting formulas were found. PMID- 28575329 TI - Is the Association Between Late Life Morbidity and Disability Attenuated Over Time? Exploring the Dynamic Equilibrium of Morbidity Hypothesis. AB - Objective: There is evidence suggesting that the prevalence of disability in late life has declined over time while the prevalence of chronic diseases has increased. The dynamic equilibrium of morbidity hypothesis suggests that these patterns are due to the attenuation of the morbidity-disability link over time. This study aimed to test this assumption empirically. Methods: Data were drawn from three repeated cross-sections of SWEOLD, a nationally representative survey of the Swedish population aged 77 years and older. Poisson regression models were fitted to assess the trends in the prevalence of Activities of Daily Living (ADL) disability, Instrumental ADL (IADL) disability, and selected groups of chronic conditions. The changes in the associations between chronic conditions and disabilities were examined on both multiplicative and additive scales. Results: Between 1992 and 2011, the prevalence of both ADL and IADL disabilities decreased whereas the prevalence of nearly all chronic morbidities increased. Significant attenuations of the morbidity-disability associations were found for cardiovascular diseases, metabolic disorders, poor lung function, and psychological distress. Discussion: In agreement with the dynamic equilibrium of morbidity hypothesis, this study concludes that the morbidity-disability associations among the Swedish older adults largely waned between 1992 and 2011. PMID- 28575328 TI - Identification of the amino acids inserted during suppression of CFTR nonsense mutations and determination of their functional consequences. AB - In-frame premature termination codons (PTCs) account for ~11% of all disease associated mutations. PTC suppression therapy utilizes small molecules that suppress translation termination at a PTC to restore synthesis of a full-length protein. PTC suppression is mediated by the base pairing of a near-cognate aminoacyl-tRNA with a PTC and subsequently, the amino acid becomes incorporated into the nascent polypeptide at the site of the PTC. However, little is known about the identity of the amino acid(s) inserted at a PTC during this process in mammalian cells, or how the surrounding sequence context influences amino acid incorporation. Here, we determined the amino acids inserted at the cystic fibrosis transmembrane conductance regulator (CFTR) W1282X PTC (a UGA codon) in the context of its three upstream and downstream CFTR codons during G418-mediated suppression. We found that leucine, cysteine and tryptophan are inserted during W1282X suppression. Interestingly, these amino acids (and their proportions) are significantly different from those recently identified following G418-mediated suppression of the CFTR G542X UGA mutation. These results demonstrate for the first time that local mRNA sequence context plays a key role in near-cognate aminoacyl-tRNA selection during PTC suppression. We also found that some variant CFTR proteins generated by PTC suppression exhibit reduced maturation and activity, indicating the complexity of nonsense suppression therapy. However, both a CFTR corrector and potentiator enhanced activity of protein variants generated by G418-mediated suppression. These results suggest that PTC suppression in combination with CFTR modulators may be beneficial for the treatment of CF patients with PTCs. PMID- 28575330 TI - The Utility of Gene Expression Profiling from Tissue Samples to Support Drug Safety Assessments. AB - Originally conceptualized as an integrated approach combining conventional toxicology methods with genome-wide expression profiling, toxicogenomics has promised to provide unequivocal relationships between the molecular changes elicited by a compound or a target pathway and the lesions that appear subsequently in the tissues. However, the discipline has only partially delivered on this promise, and the number of publications and submissions related to toxicogenomics is stagnating. The purpose of this article is to outline key factors contributing to a successful implementation of toxicogenomics in the drug discovery and development process. Paradigms and methods of toxicogenomics are briefly reviewed, and the prominence of biostatistics and its limitations in the particular context of nonclinical toxicology studies are discussed. We present specific approaches for pathophysiological contextualization of gene expression data derived from tissues with lesions at variable incidence and severity: "unmixing" (deconvolution) of molecular expression profiles from complex tissues, the invaluable contribution of reference data, the role of establishing causation between expression signals and pathologic changes (phenotypic anchoring), and especially molecular localization. These approaches compensate for the limitations of biostatistical analysis, which in turn, derive from tissue heterogeneity. Finally, impactful applications of toxicogenomics along the drug discovery and development process are exemplified, from the evaluation of potential target toxicities to the selection of candidate compounds and elucidation of the molecular and cellular mechanisms leading to chronic toxicity. PMID- 28575331 TI - Oesophageal Doppler guided goal-directed haemodynamic therapy in thoracic surgery - a single centre randomized parallel-arm trial. AB - Background: Postoperative pulmonary and renal complications are frequent in patients undergoing lung surgery. Hyper- and hypovolaemia may contribute to these complications. We hypothesized that goal-directed haemodynamic management based on oesophageal Doppler monitoring would reduce postoperative pulmonary complications in a randomized clinical parallel-arm trial. Methods: One hundred patients scheduled for thoracic surgery were randomly assigned to either standard haemodynamic management (control group) or goal-directed therapy (GDT group) guided by an oesophageal Doppler monitoring-based algorithm. The primary endpoint was postoperative pulmonary complications, including spirometry. Secondary endpoints included haemodynamic variables, renal, cardiac, and neurological complications, and length of hospital stay. The investigator assessing outcomes was blinded to group assignment. Results: Forty-eight subjects of each group were analysed. Compared to the control group, fewer subjects in the GDT group developed postoperative pulmonary complications (6 vs. 15 patients; P = 0.047), while spirometry did not differ between groups. Compared to the control group, patients of the GDT group showed higher cardiac index (2.9 vs. 2.1 [l min - 1 m 2 ]; P < 0.001) and stroke volume index (43 vs. 34 [ml m 2 ]; P < 0.001) during surgery. Renal, cardiac and neurological complications did not differ between groups. Length of hospital stay was shorter in the GDT compared to the control group (9 vs. 11 days; P = 0.005). Conclusions: Compared to standard haemodynamic management, oesophageal Doppler monitor-guided GDT was associated with fewer postoperative pulmonary complications and a shorter hospital stay. Clinical trial registration.: The study was registered in the German Clinical Trials Register (DRKS 00006961). https://drks-neu.uniklinik freiburg.de/drks_web/. PMID- 28575332 TI - Effects of arterial load variations on dynamic arterial elastance: an experimental study. AB - Background.: Dynamic arterial elastance (Ea dyn ), the relationship between pulse pressure variation (PPV) and stroke volume variation (SVV), has been suggested as a functional assessment of arterial load. The aim of this study was to evaluate the impact of arterial load changes during acute pharmacological changes, fluid administration, and haemorrhage on Ea dyn . Methods.: Eighteen anaesthetized, mechanically ventilated New Zealand rabbits were studied. Arterial load changes were induced by phenylephrine ( n =9) or nitroprusside ( n =9). Thereafter, animals received a fluid bolus (10 ml kg -1 ), followed by stepwise bleeding (blood loss: 15 ml kg -1 ). The influence of arterial load and cardiac variables on PPV, SVV, and Ea dyn was analysed using a linear mixed-effects model analysis. Results.: After phenylephrine infusion, mean ( sd ) Ea dyn decreased from 0.89 (0.14) to 0.49 (0.12), P <0.001; whereas after administration of nitroprusside, Ea dyn increased from 0.80 (0.23) to 1.28 (0.21), P <0.0001. Overall, the fluid bolus decreased Ea dyn [from 0.89 (0.44) to 0.73 (0.35); P <0.01], and haemorrhage increased it [from 0.78 (0.23) to 0.95 (0.26), P =0.03]. Both PPV and SVV were associated with similar arterial factors (effective arterial elastance, arterial compliance, and resistance) and heart rate. Furthermore, PPV was also related to the acceleration and peak velocity of aortic blood flow. Both arterial and cardiac factors contributed to the evolution of Ea dyn throughout the experiment. Conclusions.: Acute modifications of arterial load induced significant changes on Ea dyn ; vasodilatation increased Ea dyn , whereas vasoconstriction decreased it. The Ea dyn was associated with both arterial load and cardiac factors, suggesting that Ea dyn should be more properly considered as a ventriculo-arterial coupling index. PMID- 28575333 TI - The great fluid debate: time for Flexit? PMID- 28575334 TI - Characterization of peripheral and central sensitization after dorsal root ganglion intervention in patients with unilateral lumbosacral radicular pain: a prospective pilot study. AB - Background.: Quantitative sensory testing (QST) has been used to predict the outcome of epidural steroid injections in lumbosacral radicular pain and has the potential to be an important tool in the selection of appropriate treatment (such as epidural steroid injections vs surgery) for patients with chronic radicular pain. In addition, QST assists in identification of the pain pathways of peripheral and central sensitization in selected groups of patients. Methods.: Twenty-three patients were given dorsal root ganglion (DRG) infiltration with local anaesthesia and steroid ('DRG block'), and those who demonstrated at least 50% pain relief were offered pulsed radiofrequency (PRF) to the DRG. Questionnaires and QST scores were measured before the DRG blocks and at 1 week and 3 months after their procedure. Those who received PRF also answered questionnaires and underwent QST measurements at 1 week and 3 months after their procedure. Results.: There was a significant increase in pressure pain threshold scores after DRG blocks. A reduced conditioned pain modulation response was seen before DRG, which increased after the procedure. Ten out of 23 patients underwent PRF to the DRG, and an increase in pressure pain threshold scores after PRF was observed. The conditioned pain modulation response was maintained in this group and increased after PRF. Conclusions.: The study demonstrates that patients with unilateral radicular low back pain who receive dorsal root ganglion interventions show changes in pressure pain thresholds and conditioned pain modulation that are consistent with a 'normalization' of peripheral and central sensitization. PMID- 28575335 TI - Deep neuromuscular block to optimize surgical space conditions during laparoscopic surgery: a systematic review and meta-analysis. AB - Neuromuscular block (NMB) is frequently used in abdominal surgery to improve surgical conditions by relaxation of the abdominal wall and prevention of sudden muscle contractions. The evidence supporting routine use of deep NMB is still under debate. We aimed to provide evidence for the superiority of routine use of deep NMB during laparoscopic surgery. We performed a systematic review and meta analysis of studies comparing the influence of deep vs moderate NMB during laparoscopic procedures on surgical space conditions and clinical outcomes. Trials were identified from Medline, Embase, and Central databases from inception to December 2016. We included randomized trials, crossover studies, and cohort studies. Our search yielded 12 studies on the effect of deep NMB on the surgical space conditions. Deep NMB during laparoscopic surgeries improves the surgical space conditions when compared with moderate NMB, with a mean difference of 0.65 (95% confidence interval (CI): 0.47-0.83) on a scale of 1-5, and it facilitates the use of low-pressure pneumoperitoneum. Furthermore, deep NMB reduces postoperative pain scores in the postanaesthesia care unit, with a mean difference of - 0.52 (95% CI: -0.71 to - 0.32). Deep NMB improves surgical space conditions during laparoscopic surgery and reduces postoperative pain scores in the postanaesthesia care unit. Whether this leads to fewer intraoperative complications, an improved quality of recovery, or both after laparoscopic surgery should be pursued in future studies. The review methodology was specified in advance and registered at Prospero on July 27, 2016, registration number CRD42016042144. PMID- 28575336 TI - More or less? The Goldilocks Principle as it applies to red cell transfusions. PMID- 28575337 TI - Bank blood shortage, transfusion containment and viscoelastic point-of-care coagulation testing in cardiac surgery. PMID- 28575338 TI - Perioperative use of beta-blockers in vascular and endovascular surgery. PMID- 28575339 TI - Perioperative use of beta-blockers in vascular and endovascular surgery. PMID- 28575341 TI - 25-Hydroxyvitamin D deficiency among anaesthesiologists and anaesthesiology residents in Chile. PMID- 28575340 TI - Perioperative use of beta-blockers in vascular and endovascular surgery. PMID- 28575343 TI - Maintaining oxygenation with high-flow nasal cannula during emergent awake surgical tracheostomy. PMID- 28575342 TI - Prediction of postoperative mortality in elderly patients with hip fracture: are specific and geriatric scores better than general scores? PMID- 28575344 TI - Raw EEG characteristics, bispectral index, and suppression ratio variations during generalized seizure in electroconvulsive therapy. PMID- 28575345 TI - Hydrogen peroxide: more harm than good? PMID- 28575346 TI - Ventilation through an extraglottic tracheal tube: a technique for deep extubation and airway control. PMID- 28575348 TI - Preliminary Development of an Informational Media Use Measure for Patients with Implanted Defibrillators: Toward a Model of Social-Ecological Assessment of Patient Education and Support. AB - Social work interventions in health care, particularly those that involve working with people being treated for chronic and life-threatening conditions, frequently involve efforts to educate patients about their disease, treatment options, safety planning, medical adherence, and other associated issues. Despite an intuitive notion that patients access information about all of these issues through a variety of media-both inside and outside the clinical encounter, created by professionals and by others-there currently exists no validated means of assessing patients' use of these forms of information. To address this gap, authors first created candidate item measures with input from both physicians and a small group of diverse patients who currently have an implantable cardioverter defibrillator (ICD), a sophisticated cardiac device for which a trajectory model of social work intervention was recently outlined. Authors then surveyed a group of 205 individuals who have these devices, assessing their use of various media to learn about ICDs. They then conducted factor and item analysis to refine and remove poorly performing items while delineating forms of media use by type. The resultant preliminary measure of informational media use can be further refined and adapted for use with any clinical population. PMID- 28575349 TI - Safety and Efficacy of a Novel, Self-Adhering Dural Substitute in a Canine Supratentorial Durotomy Model. AB - BACKGROUND: Cerebrospinal fluid (CSF) leaks increase postoperative risk for complication, likelihood of reoperation, and costs. OBJECTIVE: To investigate a novel, self-adhering polyethylene glycol-coated collagen pad (PCC) as a dural substitute relative to Duragen XS (DGX; Integra LifeSciences Corporation, Plainsboro, New Jersey) and as a dural sealant relative to Tachosil (Takeda Austria GmbH, Linz, Austria), a fibrinogen and thrombin-coated collagen pad (FTC). METHODS: A canine supratentorial durotomy surgical model was used to investigate the safety and efficacy of PCC. For safety, 4 animals were bilaterally treated with DGX or PCC and recovered for 1, 8, or 16 wk; total 24 animals. Each animal underwent physical and neurological examinations weekly and 16-wk animals underwent a magnetic resonance imaging (MRI) examination at each time point. For efficacy, 9 animals were unilaterally treated with FTC or PCC and underwent a burst pressure test intraoperatively or 14 d postoperatively; total 36 animals. RESULTS: In the safety study, no abnormal clinical signs or changes were noted on physical and neurological examinations, or in clinical pathology, CSF analysis or histopathology of DGX or PCC-treated animals. No consistent signs of cerebral compression, CSF leak, hemorrhage, or hydrocephalus were noted on MRI. In the efficacy study, no significant difference was found between FTC and PCC at each time point or overall (13.9 vs 12.3 mm Hg, n = 18 per group, P = .46). CONCLUSION: PCC is safe for use as a dural substitute and effective as a dural sealant. The novel, self-adhering combination of a polyethylene glycol based sealant and a collagen pad may offer unique benefits to the advancement of duraplasty. PMID- 28575351 TI - "Enquire into All the Circumstances of the Patient Narrowly": John Rutherford's Clinical Lectures in Edinburgh, 1749-53. AB - Early eighteenth-century Edinburgh provided a unique learning environment for aspiring practitioners: one in which the unity of medicine and surgery was appreciated and clinical observations and a reasoning practitioner became the well spring of proper patient care. John Rutherford, a surgical apprentice in this environment, student on the wards of London hospitals and under Boerhaave at Leiden, became one of the original medical professors at the University of Edinburgh medical school in 1726. Rutherford taught the popular, theory-based Practice of Medicine for twenty-two years. Then at the end of 1748 he convinced Royal Infirmary of Edinburgh managers to allow him to begin a new lecture series, entitled Clinical Lectures, conducted at the patient's bedside. Pedagogically, the new lecture series integrated medical theory and its application on the ward. Pragmatically, Rutherford used the Clinical Lectures to transition students into practitioners. He oriented the student to the medical profession at large and placed him simultaneously at the patient-disease-physician interface. He taught that systematic patient observation and examination, when combined with experience and reasoning, were essential to accurate diagnoses and proper therapeutic interventions. Importantly too, Rutherford prepared his students for failure through humility, introspection, and the speculative nature of medical practice. PMID- 28575350 TI - Dipeptidyl Peptidase IV as a Prognostic Marker and Therapeutic Target in Papillary Thyroid Carcinoma. AB - Context: Dipeptidyl peptidase IV (DPP4) is overexpressed in thyroid cancer and certain malignancies. Furthermore, DPP4 has been identified as a discriminatory marker for thyroid cancer. However, it remains unclear whether DPP4 expression plays a prognostic role. Objective: The aim of this study was to investigate the expression and function of DPP4 in thyroid cancer and the mechanisms involved. Design: We determined the expression of DPP4 by immunohistochemistry in tissue microarrays of thyroid tumors. In vitro functional studies were performed after genetic and pharmacological inhibition of DPP4. Gene expression and pathway analyses were used to identify downstream targets. The therapeutic potential of DPP4 inhibition was evaluated in a mouse xenograft model. Results: High DPP4 expression was associated with extrathyroidal extension (P < 0.001), BRAF mutation (P < 0.001), and advanced tumor stage (P = 0.007) in papillary thyroid cancer. Patients in the high-DPP4 expression group were less likely to be classified as having no evidence of disease at final follow-up (P = 0.042). DPP4 silencing or treatment with DPP4 inhibitors significantly suppressed colony formation, cell migration, and invasion. Analysis of differentially expressed genes after DPP4 knockdown suggested that the transforming growth factor-beta signaling pathway is involved. In vivo experiments revealed that sitagliptin treatment reduced tumor growth and xenograft transforming growth factor-beta receptor I expression. Conclusions: Increased DPP4 expression is associated with cellular invasion and more aggressive disease in papillary thyroid cancer. Targeting DPP4 may be a therapeutic strategy for DPP4-expressing thyroid cancer. PMID- 28575352 TI - DNA methylation signatures in cord blood of ICSI children. AB - STUDY QUESTION: Does ICSI induce specific DNA methylation changes in the resulting offspring? SUMMARY ANSWER: Although several thousand analyzed CpG sites (throughout the genome) displayed significant between-group methylation differences, both ICSI and spontaneously conceived children varied within the normal range of methylation variation. WHAT IS KNOWN ALREADY: Children conceived by ART have increased risks for medical problems at birth and to the extent of present knowledge also in later life (i.e. impaired metabolic and cardiovascular functions). One plausible mechanism mediating these ART effects are epigenetic changes originating in the germ cells and/or early embryos and persisting during further development. STUDY DESIGN, SIZE, DURATION: We compared the cord blood methylomes and candidate gene methylation patterns of newborns conceived through ICSI or spontaneously. PARTICIPANTS/MATERIALS, SETTING, METHODS: Umbilical cord bloods were obtained from healthy newborn singletons conceived spontaneously (53 samples), through ICSI (89) or IVF (34). Bisulfite-converted DNA samples of 48 ICSI and 46 control pregnancies were used for genome-wide analyses with Illumina's 450K methylation arrays. Candidate genes from the methylation screen were analyzed in all three groups by bisulfite pyrosequencing. MAIN RESULTS AND THE ROLE OF CHANCE: Altogether, 4730 (0.11%) of 428 227 analyzed CpG sites exhibited significant between-group methylation differences, but all with small (beta < 10%) or very small (beta < 1%) effect size. ICSI children showed a significantly decreased DNA methylation age at birth, lagging approximately half a week behind the controls. ART-susceptible CpGs were enriched in CpG islands with low methylation values (0-20%) and in imprinting control regions (ICRs). Eighteen promoter regions (six in microRNA and SNORD RNA genes), four CpG islands (three in genes including one long non-coding RNA), and two ICRs contained multiple significant sites. Three differentially methylated regions were studied in more detail by bisulfite pyrosequencing. ATG4C and SNORD114-9 could be validated in an independent ICSI group, following adjustment for maternal age and other confounding factors. ATG4C was also significant in the IVF group. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The observed epigenetic effects are small and there are numerous potential confounding factors such as parental age and infertility. Although our study meets current standards for epigenetic screens, sample size is still two orders of magnitude below that of genome-wide association studies. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests an impact of ICSI on the offspring's epigenome(s), which may contribute to phenotypic variation and disease susceptibility in ART children. Epigenetic regulation of gene expression by different classes of non-coding RNAs may be a key mechanism for developmental programming through ART. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a research grant (no. 692185) from the European Union (ERA of ART). There are no competing interests. PMID- 28575353 TI - PERCH in Perspective: What Can It Teach Us About Pneumonia Etiology in Children? AB - The pneumonia team at the Bill & Melinda Gates Foundation congratulates the Pneumonia Etiology Research for Child Health (PERCH) study on delivering on their grant to collect high-quality data from thousands of children with World Health Organization-defined severe and very severe pneumonia and from controls in 9 diverse sites in 7 low- and middle-income countries. This supplement sets the foundation to understanding this complex study by providing an in-depth description of the study methodology, including discussion of key aspects such as antibiotic pretreatment, chest radiograph interpretation, utility of induced sputum in children, measurement of pathogen density, and use of C-reactive protein, and how these affect pneumonia etiology. PMID- 28575354 TI - Should Controls With Respiratory Symptoms Be Excluded From Case-Control Studies of Pneumonia Etiology? Reflections From the PERCH Study. AB - Many pneumonia etiology case-control studies exclude controls with respiratory illness from enrollment or analyses. Herein we argue that selecting controls regardless of respiratory symptoms provides the least biased estimates of pneumonia etiology. We review 3 reasons investigators may choose to exclude controls with respiratory symptoms in light of epidemiologic principles of control selection and present data from the Pneumonia Etiology Research for Child Health (PERCH) study where relevant to assess their validity. We conclude that exclusion of controls with respiratory symptoms will result in biased estimates of etiology. Randomly selected community controls, with or without respiratory symptoms, as long as they do not meet the criteria for case-defining pneumonia, are most representative of the general population from which cases arose and the least subject to selection bias. PMID- 28575355 TI - Standardization of Clinical Assessment and Sample Collection Across All PERCH Study Sites. AB - Background.: Variable adherence to standardized case definitions, clinical procedures, specimen collection techniques, and laboratory methods has complicated the interpretation of previous multicenter pneumonia etiology studies. To circumvent these problems, a program of clinical standardization was embedded in the Pneumonia Etiology Research for Child Health (PERCH) study. Methods.: Between March 2011 and August 2013, standardized training on the PERCH case definition, clinical procedures, and collection of laboratory specimens was delivered to 331 clinical staff at 9 study sites in 7 countries (The Gambia, Kenya, Mali, South Africa, Zambia, Thailand, and Bangladesh), through 32 on-site courses and a training website. Staff competency was assessed throughout 24 months of enrollment with multiple-choice question (MCQ) examinations, a video quiz, and checklist evaluations of practical skills. Results.: MCQ evaluation was confined to 158 clinical staff members who enrolled PERCH cases and controls, with scores obtained for >86% of eligible staff at each time-point. Median scores after baseline training were >=80%, and improved by 10 percentage points with refresher training, with no significant intersite differences. Percentage agreement with the clinical trainer on the presence or absence of clinical signs on video clips was high (>=89%), with interobserver concordance being substantial to high (AC1 statistic, 0.62-0.82) for 5 of 6 signs assessed. Staff attained median scores of >90% in checklist evaluations of practical skills. Conclusions.: Satisfactory clinical standardization was achieved within and across all PERCH sites, providing reassurance that any etiological or clinical differences observed across the study sites are true differences, and not attributable to differences in application of the clinical case definition, interpretation of clinical signs, or in techniques used for clinical measurements or specimen collection. PMID- 28575357 TI - Data Management and Data Quality in PERCH, a Large International Case-Control Study of Severe Childhood Pneumonia. AB - The Pneumonia Etiology Research for Child Health (PERCH) study is the largest multicountry etiology study of pediatric pneumonia undertaken in the past 3 decades. The study enrolled 4232 hospitalized cases and 5325 controls over 2 years across 9 research sites in 7 countries in Africa and Asia. The volume and complexity of data collection in PERCH presented considerable logistical and technical challenges. The project chose an internet-based data entry system to allow real-time access to the data, enabling the project to monitor and clean incoming data and perform preliminary analyses throughout the study. To ensure high-quality data, the project developed comprehensive quality indicator, data query, and monitoring reports. Among the approximately 9000 cases and controls, analyzable laboratory results were available for >=96% of core specimens collected. Selected approaches to data management in PERCH may be extended to the planning and organization of international studies of similar scope and complexity. PMID- 28575356 TI - Safety of Induced Sputum Collection in Children Hospitalized With Severe or Very Severe Pneumonia. AB - Background.: Induced sputum (IS) may provide diagnostic information about the etiology of pneumonia. The safety of this procedure across a heterogeneous population with severe pneumonia in low- and middle-income countries has not been described. Methods.: IS specimens were obtained as part a 7-country study of the etiology of severe and very severe pneumonia in hospitalized children <5 years of age. Rigorous clinical monitoring was done before, during, and after the procedure to record oxygen requirement, oxygen saturation, respiratory rate, consciousness level, and other evidence of clinical deterioration. Criteria for IS contraindications were predefined and serious adverse events (SAEs) were reported to ethics committees and a central safety monitor. Results.: A total of 4653 IS procedures were done among 3802 children. Thirteen SAEs were reported in relation to collection of IS, or 0.34% of children with at least 1 IS specimen collected (95% confidence interval, 0.15%-0.53%). A drop in oxygen saturation that required supplemental oxygen was the most common SAE. One child died after feeding was reinitiated 2 hours after undergoing sputum induction; this death was categorized as "possibly related" to the procedure. Conclusions.: The overall frequency of SAEs was very low, and the nature of most SAEs was manageable, demonstrating a low-risk safety profile for IS collection even among severely ill children in low-income-country settings. Healthcare providers should monitor oxygen saturation and requirements during and after IS collection, and assess patients prior to reinitiating feeding after the IS procedure, to ensure patient safety. PMID- 28575358 TI - Standardization of Laboratory Methods for the PERCH Study. AB - The Pneumonia Etiology Research for Child Health study was conducted across 7 diverse research sites and relied on standardized clinical and laboratory methods for the accurate and meaningful interpretation of pneumonia etiology data. Blood, respiratory specimens, and urine were collected from children aged 1-59 months hospitalized with severe or very severe pneumonia and community controls of the same age without severe pneumonia and were tested with an extensive array of laboratory diagnostic tests. A standardized testing algorithm and standard operating procedures were applied across all study sites. Site laboratories received uniform training, equipment, and reagents for core testing methods. Standardization was further assured by routine teleconferences, in-person meetings, site monitoring visits, and internal and external quality assurance testing. Targeted confirmatory testing and testing by specialized assays were done at a central reference laboratory. PMID- 28575359 TI - Standardized Interpretation of Chest Radiographs in Cases of Pediatric Pneumonia From the PERCH Study. AB - Background.: Chest radiographs (CXRs) are a valuable diagnostic tool in epidemiologic studies of pneumonia. The World Health Organization (WHO) methodology for the interpretation of pediatric CXRs has not been evaluated beyond its intended application as an endpoint measure for bacterial vaccine trials. Methods.: The Pneumonia Etiology Research for Child Health (PERCH) study enrolled children aged 1-59 months hospitalized with WHO-defined severe and very severe pneumonia from 7 low- and middle-income countries. An interpretation process categorized each CXR into 1 of 5 conclusions: consolidation, other infiltrate, both consolidation and other infiltrate, normal, or uninterpretable. Two members of a 14-person reading panel, who had undertaken training and standardization in CXR interpretation, interpreted each CXR. Two members of an arbitration panel provided additional independent reviews of CXRs with discordant interpretations at the primary reading, blinded to previous reports. Further discordance was resolved with consensus discussion. Results.: A total of 4172 CXRs were obtained from 4232 cases. Observed agreement for detecting consolidation (with or without other infiltrate) between primary readers was 78% (kappa = 0.50) and between arbitrators was 84% (kappa = 0.61); agreement for primary readers and arbitrators across 5 conclusion categories was 43.5% (kappa = 0.25) and 48.5% (kappa = 0.32), respectively. Disagreement was most frequent between conclusions of other infiltrate and normal for both the reading panel and the arbitration panel (32% and 30% of discordant CXRs, respectively). Conclusions.: Agreement was similar to that of previous evaluations using the WHO methodology for detecting consolidation, but poor for other infiltrates despite attempts at a rigorous standardization process. PMID- 28575360 TI - Microscopic Analysis and Quality Assessment of Induced Sputum From Children With Pneumonia in the PERCH Study. AB - Background.: It is standard practice for laboratories to assess the cellular quality of expectorated sputum specimens to check that they originated from the lower respiratory tract. The presence of low numbers of squamous epithelial cells (SECs) and high numbers of polymorphonuclear (PMN) cells are regarded as indicative of a lower respiratory tract specimen. However, these quality ratings have never been evaluated for induced sputum specimens from children with suspected pneumonia. Methods.: We evaluated induced sputum Gram stain smears and cultures from hospitalized children aged 1-59 months enrolled in a large study of community-acquired pneumonia. We hypothesized that a specimen representative of the lower respiratory tract will contain smaller quantities of oropharyngeal flora and be more likely to have a predominance of potential pathogens compared to a specimen containing mainly saliva. The prevalence of potential pathogens cultured from induced sputum specimens and quantity of oropharyngeal flora were compared for different quantities of SECs and PMNs. Results.: Of 3772 induced sputum specimens, 2608 (69%) had <10 SECs per low-power field (LPF) and 2350 (62%) had >25 PMNs per LPF, measures traditionally associated with specimens from the lower respiratory tract in adults. Using isolation of low quantities of oropharyngeal flora and higher prevalence of potential pathogens as markers of higher quality, <10 SECs per LPF (but not >25 PMNs per LPF) was the microscopic variable most associated with high quality of induced sputum. Conclusions.: Quantity of SECs may be a useful quality measure of induced sputum from young children with pneumonia. PMID- 28575361 TI - Chest Radiograph Findings in Childhood Pneumonia Cases From the Multisite PERCH Study. AB - Background.: Chest radiographs (CXRs) are frequently used to assess pneumonia cases. Variations in CXR appearances between epidemiological settings and their correlation with clinical signs are not well documented. Methods.: The Pneumonia Etiology Research for Child Health project enrolled 4232 cases of hospitalized World Health Organization (WHO)-defined severe and very severe pneumonia from 9 sites in 7 countries (Bangladesh, the Gambia, Kenya, Mali, South Africa, Thailand, and Zambia). At admission, each case underwent a standardized assessment of clinical signs and pneumonia risk factors by trained health personnel, and a CXR was taken that was interpreted using the standardized WHO methodology. CXRs were categorized as abnormal (consolidation and/or other infiltrate), normal, or uninterpretable. Results.: CXRs were interpretable in 3587 (85%) cases, of which 1935 (54%) were abnormal (site range, 35%-64%). Cases with abnormal CXRs were more likely than those with normal CXRs to have hypoxemia (45% vs 26%), crackles (69% vs 62%), tachypnea (85% vs 80%), or fever (20% vs 16%) and less likely to have wheeze (30% vs 38%; all P < .05). CXR consolidation was associated with a higher case fatality ratio at 30-day follow-up (13.5%) compared to other infiltrate (4.7%) or normal (4.9%) CXRs. Conclusions.: Clinically diagnosed pneumonia cases with abnormal CXRs were more likely to have signs typically associated with pneumonia. However, CXR-normal cases were common, and clinical signs considered indicative of pneumonia were present in substantial proportions of these cases. CXR-consolidation cases represent a group with an increased likelihood of death at 30 days post-discharge. PMID- 28575362 TI - The Diagnostic Utility of Induced Sputum Microscopy and Culture in Childhood Pneumonia. AB - Background.: Sputum microscopy and culture are commonly used for diagnosing the cause of pneumonia in adults but are rarely performed in children due to difficulties in obtaining specimens. Induced sputum is occasionally used to investigate lower respiratory infections in children but has not been widely used in pneumonia etiology studies. Methods.: We evaluated the diagnostic utility of induced sputum microscopy and culture in patients enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study, a large study of community acquired pneumonia in children aged 1-59 months. Comparisons were made between induced sputum samples from hospitalized children with radiographically confirmed pneumonia and children categorized as nonpneumonia (due to the absence of prespecified clinical and laboratory signs and absence of infiltrate on chest radiograph). Results.: One induced sputum sample was available for analysis from 3772 (89.1%) of 4232 suspected pneumonia cases enrolled in PERCH. Of these, sputum from 2608 (69.1%) met the quality criterion of <10 squamous epithelial cells per low-power field, and 1162 (44.6%) had radiographic pneumonia. Induced sputum microscopy and culture results were not associated with radiographic pneumonia, regardless of prior antibiotic use, stratification by specific bacteria, or interpretative criteria used. Conclusions.: The findings of this study do not support the culture of induced sputum specimens as a diagnostic tool for pneumonia in young children as part of routine clinical practice. PMID- 28575364 TI - The Incremental Value of Repeated Induced Sputum and Gastric Aspirate Samples for the Diagnosis of Pulmonary Tuberculosis in Young Children With Acute Community Acquired Pneumonia. AB - Background.: Mycobacterium tuberculosis (Mtb) contributes to the pathogenesis of childhood acute community-acquired pneumonia in settings with a high tuberculosis burden. The incremental value of a repeated induced sputum (IS) sample, compared with a single IS or gastric aspirate (GA) sample, is not well known. Methods.: Two IS samples were obtained for Mtb culture from children enrolled as cases in the Pneumonia Etiology Research for Child Health (PERCH) study in South Africa. Nonstudy attending physicians requested GA if pulmonary tuberculosis was clinically suspected. We compared the Mtb yield of 2 IS samples to that of 1 IS sample and GA samples. Results: . Twenty-seven (3.0%) culture-confirmed pulmonary tuberculosis cases were identified among 906 children investigated with IS and GA samples for Mtb. Results from 2 IS samples were available for 719 children (79.4%). Of 12 culture-confirmed pulmonary tuberculosis cases identified among children with >=2 IS samples, 4 (33.3%) were negative at the first IS sample. In head-to-head comparisons among children with both GA and IS samples collected, the yield of 1 GA sample (8 of 427; 1.9%) was similar to that of 1 IS sample (5 of 427, 1.2%), and the yield of 2 GA samples (10 of 300; 3.3%) was similar to that of 2 IS samples (5 of 300; 1.7%). IS samples identified 8 (42.1%) of the 19 culture-confirmed pulmonary tuberculosis cases that were identified through submission of IS and GA samples. Conclusions.: A single IS sample underestimated the presence of Mtb in children hospitalized with severe or very severe pneumonia. Detection of Mtb is enhanced by combining 2 IS with GA sample collections in young children with acute severe pneumonia. PMID- 28575363 TI - Limited Utility of Polymerase Chain Reaction in Induced Sputum Specimens for Determining the Causes of Childhood Pneumonia in Resource-Poor Settings: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study. AB - Background.: Sputum examination can be useful in diagnosing the cause of pneumonia in adults but is less well established in children. We sought to assess the diagnostic utility of polymerase chain reaction (PCR) for detection of respiratory viruses and bacteria in induced sputum (IS) specimens from children hospitalized with severe or very severe pneumonia. Methods.: Among children aged 1-59 months, we compared organism detection by multiplex PCR in IS and nasopharyngeal/oropharyngeal (NP/OP) specimens. To assess whether organism presence or density in IS specimens was associated with chest radiographic evidence of pneumonia (radiographic pneumonia), we compared prevalence and density in IS specimens from children with radiographic pneumonia and children with suspected pneumonia but without chest radiographic changes or clinical or laboratory findings suggestive of pneumonia (nonpneumonia group). Results.: Among 4232 cases with World Health Organization-defined severe or very severe pneumonia, we identified 1935 (45.7%) with radiographic pneumonia and 573 (13.5%) with nonpneumonia. The organism detection yield was marginally improved with IS specimens (96.2% vs 92.4% for NP/OP specimens for all viruses combined [P = .41]; 96.9% vs 93.3% for all bacteria combined [P = .01]). After accounting for presence in NP/OP specimens, no organism was detected more frequently in the IS specimens from the radiographic pneumonia compared with the nonpneumonia cases. Among high-quality IS specimens, there were no statistically significant differences in organism density, except with cytomegalovirus, for which there was a higher quantity in the IS specimens from cases with radiographic pneumonia compared with the nonpneumonia cases (median cycle threshold value, 27.9 vs 28.5, respectively; P = .01). Conclusions.: Using advanced molecular methods with IS specimens provided little additional diagnostic information beyond that obtained with NP/OP swab specimens. PMID- 28575368 TI - Introduction to the Epidemiologic Considerations, Analytic Methods, and Foundational Results From the Pneumonia Etiology Research for Child Health Study. PMID- 28575365 TI - Density of Upper Respiratory Colonization With Streptococcus pneumoniae and Its Role in the Diagnosis of Pneumococcal Pneumonia Among Children Aged <5 Years in the PERCH Study. AB - Background.: Previous studies suggested an association between upper airway pneumococcal colonization density and pneumococcal pneumonia, but data in children are limited. Using data from the Pneumonia Etiology Research for Child Health (PERCH) study, we assessed this potential association. Methods.: PERCH is a case-control study in 7 countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. Cases were children aged 1-59 months hospitalized with World Health Organization-defined severe or very severe pneumonia. Controls were randomly selected from the community. Microbiologically confirmed pneumococcal pneumonia (MCPP) was confirmed by detection of pneumococcus in a relevant normally sterile body fluid. Colonization density was calculated with quantitative polymerase chain reaction analysis of nasopharyngeal/oropharyngeal specimens. Results.: Median colonization density among 56 cases with MCPP (MCPP cases; 17.28 * 106 copies/mL) exceeded that of cases without MCPP (non-MCPP cases; 0.75 * 106) and controls (0.60 * 106) (each P < .001). The optimal density for discriminating MCPP cases from controls using the Youden index was >6.9 log10 copies/mL; overall, the sensitivity was 64% and the specificity 92%, with variable performance by site. The threshold was lower (>=4.4 log10 copies/mL) when MCPP cases were distinguished from controls who received antibiotics before specimen collection. Among the 4035 non-MCPP cases, 500 (12%) had pneumococcal colonization density >6.9 log10 copies/mL; above this cutoff was associated with alveolar consolidation at chest radiography, very severe pneumonia, oxygen saturation <92%, C-reactive protein >=40 mg/L, and lack of antibiotic pretreatment (all P< .001). Conclusions.: Pneumococcal colonization density >6.9 log10 copies/mL was strongly associated with MCPP and could be used to improve estimates of pneumococcal pneumonia prevalence in childhood pneumonia studies. Our findings do not support its use for individual diagnosis in a clinical setting. PMID- 28575366 TI - The Effect of Antibiotic Exposure and Specimen Volume on the Detection of Bacterial Pathogens in Children With Pneumonia. AB - Background.: Antibiotic exposure and specimen volume are known to affect pathogen detection by culture. Here we assess their effects on bacterial pathogen detection by both culture and polymerase chain reaction (PCR) in children. Methods.: PERCH (Pneumonia Etiology Research for Child Health) is a case-control study of pneumonia in children aged 1-59 months investigating pathogens in blood, nasopharyngeal/oropharyngeal (NP/OP) swabs, and induced sputum by culture and PCR. Antibiotic exposure was ascertained by serum bioassay, and for cases, by a record of antibiotic treatment prior to specimen collection. Inoculated blood culture bottles were weighed to estimate volume. Results.: Antibiotic exposure ranged by specimen type from 43.5% to 81.7% in 4223 cases and was detected in 2.3% of 4863 controls. Antibiotics were associated with a 45% reduction in blood culture yield and approximately 20% reduction in yield from induced sputum culture. Reduction in yield of Streptococcus pneumoniae from NP culture was approximately 30% in cases and approximately 32% in controls. Several bacteria had significant but marginal reductions (by 5%-7%) in detection by PCR in NP/OP swabs from both cases and controls, with the exception of S. pneumoniae in exposed controls, which was detected 25% less frequently compared to nonexposed controls. Bacterial detection in induced sputum by PCR decreased 7% for exposed compared to nonexposed cases. For every additional 1 mL of blood culture specimen collected, microbial yield increased 0.51% (95% confidence interval, 0.47% 0.54%), from 2% when volume was <=1 mL to approximately 6% for >=3 mL. Conclusions.: Antibiotic exposure and blood culture volume affect detection of bacterial pathogens in children with pneumonia and should be accounted for in studies of etiology and in clinical management. PMID- 28575370 TI - Bayesian Estimation of Pneumonia Etiology: Epidemiologic Considerations and Applications to the Pneumonia Etiology Research for Child Health Study. AB - In pneumonia, specimens are rarely obtained directly from the infection site, the lung, so the pathogen causing infection is determined indirectly from multiple tests on peripheral clinical specimens, which may have imperfect and uncertain sensitivity and specificity, so inference about the cause is complex. Analytic approaches have included expert review of case-only results, case-control logistic regression, latent class analysis, and attributable fraction, but each has serious limitations and none naturally integrate multiple test results. The Pneumonia Etiology Research for Child Health (PERCH) study required an analytic solution appropriate for a case-control design that could incorporate evidence from multiple specimens from cases and controls and that accounted for measurement error. We describe a Bayesian integrated approach we developed that combined and extended elements of attributable fraction and latent class analyses to meet some of these challenges and illustrate the advantage it confers regarding the challenges identified for other methods. PMID- 28575369 TI - The Enduring Challenge of Determining Pneumonia Etiology in Children: Considerations for Future Research Priorities. AB - Pneumonia kills more children each year worldwide than any other disease. Nonetheless, accurately determining the causes of childhood pneumonia has remained elusive. Over the past century, the focus of pneumonia etiology research has shifted from studies of lung aspirates and postmortem specimens intent on identifying pneumococcal disease to studies of multiple specimen types distant from the lung that are tested for multiple pathogens. Some major challenges facing modern pneumonia etiology studies include the use of nonspecific and variable case definitions, poor access to pathologic lung tissue and to specimens from fatal cases, poor diagnostic accuracy of assays (especially when testing nonpulmonary specimens), and the interpretation of results when multiple pathogens are detected in a given individual. The future of childhood pneumonia etiology research will likely require integrating data from complementary approaches, including applications of advanced molecular diagnostics and vaccine probe studies, as well as a renewed emphasis on lung aspirates from radiologically confirmed pneumonia and postmortem examinations. PMID- 28575367 TI - Colonization Density of the Upper Respiratory Tract as a Predictor of Pneumonia Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pneumocystis jirovecii. AB - Background.: There is limited information on the association between colonization density of upper respiratory tract colonizers and pathogen-specific pneumonia. We assessed this association for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pneumocystis jirovecii. Methods.: In 7 low- and middle income countries, nasopharyngeal/oropharyngeal swabs from children with severe pneumonia and age-frequency matched community controls were tested using quantitative polymerase chain reaction (PCR). Differences in median colonization density were evaluated using the Wilcoxon rank-sum test. Density cutoffs were determined using receiver operating characteristic curves. Cases with a pathogen identified from lung aspirate culture or PCR, pleural fluid culture or PCR, blood culture, and immunofluorescence for P. jirovecii defined microbiologically confirmed cases for the given pathogens. Results.: Higher densities of H. influenzae were observed in both microbiologically confirmed cases and chest radiograph (CXR)-positive cases compared to controls. Staphylococcus aureus and P. jirovecii had higher densities in CXR-positive cases vs controls. A 5.9 log10 copies/mL density cutoff for H. influenzae yielded 86% sensitivity and 77% specificity for detecting microbiologically confirmed cases; however, densities overlapped between cases and controls and positive predictive values were poor (<3%). Informative density cutoffs were not found for S. aureus and M. catarrhalis, and a lack of confirmed case data limited the cutoff identification for P. jirovecii. Conclusions.: There is evidence for an association between H. influenzae colonization density and H. influenzae-confirmed pneumonia in children; the association may be particularly informative in epidemiologic studies. Colonization densities of M. catarrhalis, S. aureus, and P. jirovecii are unlikely to be of diagnostic value in clinical settings. PMID- 28575372 TI - Addressing the Analytic Challenges of Cross-Sectional Pediatric Pneumonia Etiology Data. AB - Despite tremendous advances in diagnostic laboratory technology, identifying the pathogen(s) causing pneumonia remains challenging because the infected lung tissue cannot usually be sampled for testing. Consequently, to obtain information about pneumonia etiology, clinicians and researchers test specimens distant to the site of infection. These tests may lack sensitivity (eg, blood culture, which is only positive in a small proportion of children with pneumonia) and/or specificity (eg, detection of pathogens in upper respiratory tract specimens, which may indicate asymptomatic carriage or a less severe syndrome, such as upper respiratory infection). While highly sensitive nucleic acid detection methods and testing of multiple specimens improve sensitivity, multiple pathogens are often detected and this adds complexity to the interpretation as the etiologic significance of results may be unclear (ie, the pneumonia may be caused by none, one, some, or all of the pathogens detected). Some of these challenges can be addressed by adjusting positivity rates to account for poor sensitivity or incorporating test results from controls without pneumonia to account for poor specificity. However, no classical analytic methods can account for measurement error (ie, sensitivity and specificity) for multiple specimen types and integrate the results of measurements for multiple pathogens to produce an accurate understanding of etiology. We describe the major analytic challenges in determining pneumonia etiology and review how the common analytical approaches (eg, descriptive, case-control, attributable fraction, latent class analysis) address some but not all challenges. We demonstrate how these limitations necessitate a new, integrated analytical approach to pneumonia etiology data. PMID- 28575371 TI - Detection of Pneumococcal DNA in Blood by Polymerase Chain Reaction for Diagnosing Pneumococcal Pneumonia in Young Children From Low- and Middle-Income Countries. AB - Background.: We investigated the performance of polymerase chain reaction (PCR) on blood in the diagnosis of pneumococcal pneumonia among children from 7 low- and middle-income countries. Methods.: We tested blood by PCR for the pneumococcal autolysin gene in children aged 1-59 months in the Pneumonia Etiology Research for Child Health (PERCH) study. Children had World Health Organization-defined severe or very severe pneumonia or were age-frequency matched community controls. Additionally, we tested blood from general pediatric admissions in Kilifi, Kenya, a PERCH site. The proportion PCR-positive was compared among cases with microbiologically confirmed pneumococcal pneumonia (MCPP), cases without a confirmed bacterial infection (nonconfirmed), cases confirmed for nonpneumococcal bacteria, and controls. Results.: In PERCH, 7.3% (n = 291/3995) of cases and 5.5% (n = 273/4987) of controls were blood pneumococcal PCR-positive (P < .001), compared with 64.3% (n = 36/56) of MCPP cases and 6.3% (n = 243/3832) of nonconfirmed cases (P < .001). Blood pneumococcal PCR positivity was higher in children from the 5 African countries (5.5%-11.5% among cases and 5.3%-10.2% among controls) than from the 2 Asian countries (1.3% and 1.0% among cases and 0.8% and 0.8% among controls). Among Kilifi general pediatric admissions, 3.9% (n = 274/6968) were PCR-positive, including 61.7% (n = 37/60) of those with positive blood cultures for pneumococcus. Discussion.: The utility of pneumococcal PCR on blood for diagnosing childhood pneumococcal pneumonia in the 7 low- and middle-income countries studied is limited by poor specificity and by poor sensitivity among MCPP cases. PMID- 28575376 TI - Managing Person-Centered Dementia Care in an Assisted Living Facility: Staffing and Time Considerations. AB - Background and Objectives: To describe (a) the unlicensed staff time necessary to provide quality activities of daily living (ADL) care to residents receiving dementia care within an assisted living facility and (b) a staff management approach to maintain quality ADL care. Research Design and Methods: Supervisory staff used a standardized observational method to measure ADL care quality and the staff time to provide care during the morning and evening across 12 consecutive months. Staff were given individual feedback about the quality of their care provision following each observation. Results: The average staff time to provide ADL care averaged 35 (+/- 11) minutes per resident per care episode with bathing and 18 (+/- 6) minutes/resident/care episode without bathing. Morning ADL care required significantly more staff time than evening care. There was not a significant relationship between residents' levels of cognitive impairment or ADL dependency and the staff time to provide ADL care. Quality ADL care was maintained for 12 months. Discussion and Implications: This study provides novel data related to the amount of staff time necessary to provide quality ADL care for persons with dementia in an assisted living care setting. This study also describes a standardized approach to staff management that was effective in maintaining quality ADL care provision. Assisted living facilities should consider these data when determining the necessary unlicensed staffing level to provide person-centered ADL care and how to effectively manage direct care providers. PMID- 28575373 TI - Is Higher Viral Load in the Upper Respiratory Tract Associated With Severe Pneumonia? Findings From the PERCH Study. AB - Background.: The etiologic inference of identifying a pathogen in the upper respiratory tract (URT) of children with pneumonia is unclear. To determine if viral load could provide evidence of causality of pneumonia, we compared viral load in the URT of children with World Health Organization-defined severe and very severe pneumonia and age-matched community controls. Methods.: In the 9 developing country sites, nasopharyngeal/oropharyngeal swabs from children with and without pneumonia were tested using quantitative real-time polymerase chain reaction for 17 viruses. The association of viral load with case status was evaluated using logistic regression. Receiver operating characteristic (ROC) curves were constructed to determine optimal discriminatory viral load cutoffs. Viral load density distributions were plotted. Results.: The mean viral load was higher in cases than controls for 7 viruses. However, there was substantial overlap in viral load distribution of cases and controls for all viruses. ROC curves to determine the optimal viral load cutoff produced an area under the curve of <0.80 for all viruses, suggesting poor to fair discrimination between cases and controls. Fatal and very severe pneumonia cases did not have higher viral load than less severe cases for most viruses. Conclusions.: Although we found higher viral loads among pneumonia cases than controls for some viruses, the utility in using viral load of URT specimens to define viral pneumonia was equivocal. Our analysis was limited by lack of a gold standard for viral pneumonia. PMID- 28575379 TI - Efficacy of Oral Zinc Supplementation in Radiologically Confirmed Pneumonia: Secondary Analysis of a Randomized Controlled Trial. AB - Objective: To evaluate the effect of zinc as an adjuvant therapy in radiologically confirmed pneumonia in children 2-24 months of age. Patients and Methods: We analyzed data of 212 children with pneumonia for whom chest X-ray films were available at enrollment and at least two radiologists agreed on the diagnosis of pneumonia. We compared the time to recovery in the two groups (n = 121, zinc group and n = 91, placebo group) using a Cox proportional hazards regression model. Results: Time to recovery was similar in both groups [median interquartile range: zinc, 84 h (64, 140 h); placebo, 85 h (65, 140 h)]. The absolute risk reduction for treatment failure was 5.2% (95% confidence interval: 4.8, 15.1) with zinc supplementation. Conclusion: There was no significant beneficial effect of zinc on the duration of recovery or risk of treatment failure in children with radiologically confirmed pneumonia. PMID- 28575375 TI - Association of C-Reactive Protein With Bacterial and Respiratory Syncytial Virus Associated Pneumonia Among Children Aged <5 Years in the PERCH Study. AB - Background.: Lack of a gold standard for identifying bacterial and viral etiologies of pneumonia has limited evaluation of C-reactive protein (CRP) for identifying bacterial pneumonia. We evaluated the sensitivity and specificity of CRP for identifying bacterial vs respiratory syncytial virus (RSV) pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) multicenter case-control study. Methods.: We measured serum CRP levels in cases with World Health Organization-defined severe or very severe pneumonia and a subset of community controls. We evaluated the sensitivity and specificity of elevated CRP for "confirmed" bacterial pneumonia (positive blood culture or positive lung aspirate or pleural fluid culture or polymerase chain reaction [PCR]) compared to "RSV pneumonia" (nasopharyngeal/oropharyngeal or induced sputum PCR-positive without confirmed/suspected bacterial pneumonia). Receiver operating characteristic (ROC) curves were constructed to assess the performance of elevated CRP in distinguishing these cases. Results.: Among 601 human immunodeficiency virus (HIV)-negative tested controls, 3% had CRP >=40 mg/L. Among 119 HIV-negative cases with confirmed bacterial pneumonia, 77% had CRP >=40 mg/L compared with 17% of 556 RSV pneumonia cases. The ROC analysis produced an area under the curve of 0.87, indicating very good discrimination; a cut-point of 37.1 mg/L best discriminated confirmed bacterial pneumonia (sensitivity 77%) from RSV pneumonia (specificity 82%). CRP >=100 mg/L substantially improved specificity over CRP >=40 mg/L, though at a loss to sensitivity. Conclusions.: Elevated CRP was positively associated with confirmed bacterial pneumonia and negatively associated with RSV pneumonia in PERCH. CRP may be useful for distinguishing bacterial from RSV-associated pneumonia, although its role in discriminating against other respiratory viral-associated pneumonia needs further study. PMID- 28575378 TI - Long-term outcomes of different ablation strategies for ventricular tachycardia in patients with structural heart disease: systematic review and meta-analysis. AB - Aims: To compare the long-term outcomes of standard ablation of stable ventricular tachycardia (VT) vs. substrate modification, and of complete vs. incomplete substrate modification in patients with structural heart disease (SHD) presenting with VT. Methods and results: An electronic search was performed using major databases. The main outcomes were a composite of long-term ventricular arrhythmia (VA) recurrence and all-cause mortality of standard ablation of stable VT vs. substrate modification, and long-term VA recurrence in complete vs. incomplete substrate modification. Six studies were included for the comparison of standard ablation of stable VT vs. substrate modification, with a total of 396 patients (mean age 63 +/- 10 years, 87% males), and seven studies were included to assess the impact of extensive substrate modification, with a total of 391 patients (mean age 64 +/- years, 90% males). More than 70% of all the patients included had ischaemic cardiomyopathy. Substrate modification was associated with decreased composite VA recurrence/all-cause mortality compared to standard ablation of stable VTs [risk ratio (RR) 0.57, 95% confidence interval (CI) 0.40 0.81]. Complete substrate modification was associated with decreased VA recurrence as compared to incomplete substrate modification (RR 0.39, 95% CI 0.27 0.58). Conclusion: In patients with SHD who had VT related mainly to ischaemic substrates, there was a significantly lower risk of the composite primary outcome of long-term VA recurrence and all-cause mortality among those undergoing substrate modification compared to standard ablation. Long-term success is improved when performing complete substrate modification. PMID- 28575374 TI - Evaluation of Pneumococcal Load in Blood by Polymerase Chain Reaction for the Diagnosis of Pneumococcal Pneumonia in Young Children in the PERCH Study. AB - Background.: Detection of pneumococcus by lytA polymerase chain reaction (PCR) in blood had poor diagnostic accuracy for diagnosing pneumococcal pneumonia in children in 9 African and Asian sites. We assessed the value of blood lytA quantification in diagnosing pneumococcal pneumonia. Methods.: The Pneumonia Etiology Research for Child Health (PERCH) case-control study tested whole blood by PCR for pneumococcus in children aged 1-59 months hospitalized with signs of pneumonia and in age-frequency matched community controls. The distribution of load among PCR-positive participants was compared between microbiologically confirmed pneumococcal pneumonia (MCPP) cases, cases confirmed for nonpneumococcal pathogens, nonconfirmed cases, and controls. Receiver operating characteristic analyses determined the "optimal threshold" that distinguished MCPP cases from controls. Results.: Load was available for 290 of 291 cases with pneumococcal PCR detected in blood and 273 of 273 controls. Load was higher in MCPP cases than controls (median, 4.0 * 103 vs 0.19 * 103 copies/mL), but overlapped substantially (range, 0.16-989.9 * 103 copies/mL and 0.01-551.9 * 103 copies/mL, respectively). The proportion with high load (>=2.2 log10 copies/mL) was 62.5% among MCPP cases, 4.3% among nonconfirmed cases, 9.3% among cases confirmed for a nonpneumococcal pathogen, and 3.1% among controls. Pneumococcal load in blood was not associated with respiratory tract illness in controls (P = .32). High blood pneumococcal load was associated with alveolar consolidation on chest radiograph in nonconfirmed cases, and with high (>6.9 log10 copies/mL) nasopharyngeal/oropharyngeal load and C-reactive protein >=40 mg/L (both P < .01) in nonconfirmed cases but not controls. Conclusions.: Quantitative pneumococcal PCR in blood has limited diagnostic utility for identifying pneumococcal pneumonia in individual children, but may be informative in epidemiological studies. PMID- 28575380 TI - Looking Both Ways. PMID- 28575377 TI - Major hnRNP proteins act as general TDP-43 functional modifiers both in Drosophila and human neuronal cells. AB - Nuclear factor TDP-43 is known to play an important role in several neurodegenerative pathologies. In general, TDP-43 is an abundant protein within the eukaryotic nucleus that binds to many coding and non-coding RNAs and influence their processing. Using Drosophila, we have performed a functional screening to establish the ability of major hnRNP proteins to affect TDP-43 overexpression/depletion phenotypes. Interestingly, we observed that lowering hnRNP and TDP-43 expression has a generally harmful effect on flies locomotor abilities. In parallel, our study has also identified a distinct set of hnRNPs that is capable of powerfully rescuing TDP-43 toxicity in the fly eye (Hrb27c, CG42458, Glo and Syp). Most importantly, removing the human orthologs of Hrb27c (DAZAP1) in human neuronal cell lines can correct several pre-mRNA splicing events altered by TDP-43 depletion. Moreover, using RNA sequencing analysis we show that DAZAP1 and TDP-43 can co-regulate an extensive number of biological processes and molecular functions potentially important for the neuron/motor neuron pathophysiology. Our results suggest that changes in hnRNP expression levels can significantly modulate TDP-43 functions and affect pathological outcomes. PMID- 28575381 TI - Rebellious Behaviors in Adolescents With Epilepsy. AB - Objectives: The study aims are to (1) examine the prevalence of risk-taking (i.e., behaviors that can be categorized as rebellious or reckless) and (2) determine the influence of risk-taking on adherence, seizures, and health-related quality of life (HRQOL) in adolescents with epilepsy. An exploratory aim was to identify predictors of risk-taking. Methods: Fifty-four adolescents with epilepsy (M = 15.33 +/- 1.46 years) and caregivers completed questionnaires on demographics, risk-taking, parent-child relations, adolescent inattention/hyperactivity, and HRQOL at four time points across 1 year. Seizure occurrence and electronically monitored adherence were also collected. Results: Rebellious behaviors were normative and stable over 1 year in adolescents with epilepsy. Higher rebelliousness was related to poorer adolescent-reported memory HRQOL. The only significant positive predictor of rebellious behaviors was adolescent age. Conclusions: Adolescents with epilepsy endorsed normative levels of rebelliousness, which is negatively related to HRQOL. Older adolescents may warrant clinical attention. PMID- 28575383 TI - On Taking a Different Route: An Unlikely Case of Malaria by Nosocomial Transmission. AB - Vector-borne diseases can be contracted by exposure to contaminated material. This mode of transmission is not geographically restricted to the presence of a vector. Unexpected infection in regions of low incidence potentially delays diagnosis. We report a case of severe falciparum malaria following nosocomial Plasmodium falciparum transmission in nonendemic Germany. PMID- 28575382 TI - In vitro and in vivo activity of biapenem against drug-susceptible and rifampicin resistant Mycobacterium tuberculosis. AB - Background: Biapenem, a carbapenem antibiotic, has been shown to have synergistic bactericidal anti-TB activity when combined with rifampicin both in vitro and in the mouse model of TB chemotherapy. We hypothesized that this synergy would result in biapenem/rifampicin activity against rifampicin-resistant Mycobacterium tuberculosis . Objectives: Our objective was to evaluate the synergy of biapenem/rifampicin against both low- and high-level rifampicin-resistant strains of M. tuberculosis , in vitro and in the mouse model. Methods: Biapenem/rifampicin activity was evaluated using three strains of M. tuberculosis : strain 115R (low-level rifampicin resistance); strain 124R (high-level rifampicin resistance); and the drug-susceptible H37Rv parent strain. Biapenem/rifampicin synergy was evaluated in vitro by chequerboard titration. In vivo , we first conducted a dose-ranging experiment with biapenem against H37Rv in the mouse model. We then evaluated biapenem/rifampicin activity in mice infected with each M. tuberculosis strain. Results: In vitro , synergy was observed between biapenem and rifampicin against H37Rv and strain 115R. In vivo , biapenem exhibited clear dose-dependent activity against H37Rv, with all biapenem doses as active or more active than rifampicin alone. Biapenem and rifampicin had synergistic bactericidal activity against H37Rv in the mouse model; no synergy was observed in mice infected with either of the rifampicin-resistant strains. Biapenem alone was active against all three strains. Conclusions: Our preclinical experiments indicate that biapenem has potential for use as an anti-TB drug, including for use against rifampicin-resistant TB. Thus, biapenem has promise for repurposing as a 'new' - and desperately needed - drug for the treatment of drug resistant TB. PMID- 28575384 TI - Isolation of azole-resistant Aspergillus fumigatus from the environment in the south-eastern USA. AB - Background: Azole resistance in isolates of the fungus Aspergillus fumigatus has been associated with agricultural use of azole fungicides. Environmental isolation of resistant isolates has been reported in Asia, Africa, Europe and South America. Objectives: To determine whether A. fumigatus isolates containing TR34/L98H or TR46/Y121F/T289A can be found in fields in the USA treated with agricultural azoles. Methods: Crop debris was collected and screened for A. fumigatus. All A. fumigatus isolates were screened for azole resistance. The CYP51A gene of azole-resistant isolates was sequenced. The population structure of a subset of isolates was determined using microsatellite typing. Results: This article identifies azole-resistant A. fumigatus isolates containing the TR34/L98H mutation in an experimental peanut field that had been treated with azole fungicides. Conclusions: These findings suggest the development of resistance to azole antifungals in A. fumigatus may be present where agricultural azoles are used in the USA. PMID- 28575386 TI - Rare Disease in Cardiovascular Medicine I. PMID- 28575387 TI - Older Adults Without Close Kin in the United States. AB - Objectives: We document the size and characteristics of the population of older adults without close kin in the contemporary United States. Methods: Using the Health and Retirement Study, we examine the prevalence of lacking different types and combinations of living kin, examine how kinless-ness is changing across birth cohorts, and provide estimates of kinless-ness for sociodemographic and health groups. Results: In 1998-2010, 6.6% of U.S. adults aged 55 and above lacked a living spouse and biological children and 1% lacked a partner/spouse, any children, biological siblings, and biological parents. Kinless-ness, defined both ways, is becoming more common among adults in their 50s and 60s for more recent birth cohorts. Lacking close kin is more prevalent among women than men, native born than immigrants, never-married, those living alone, college-educated women, those with low levels of wealth, and those in poor health. Discussion: Kinless ness should be of interest to policy makers because it is more common among those with social, economic and health risks; those who live alone, with low levels of wealth, and disability. Aging research should address the implications of kinless ness for public health, social isolation, and the demand for institutional care. PMID- 28575385 TI - A Phylogenetic Analysis of Human Immunodeficiency Virus Type 1 Sequences in Kiev: Findings Among Key Populations. AB - Background: The human immunodeficiency virus (HIV) epidemic in Ukraine has been driven by a rapid rise among people who inject drugs, but recent studies have shown an increase through sexual transmission. Methods: Protease and reverse transcriptase sequences from 876 new HIV diagnoses (April 2013-March 2015) in Kiev were linked to demographic data. We constructed phylogenetic trees for 794 subtype A1 and 64 subtype B sequences and identified factors associated with transmission clustering. Clusters were defined as >=2 sequences, >=80% local branch support, and maximum genetic distance of all sequence pairs in the cluster <=2.5%. Recent infection was determined through the limiting antigen avidity enzyme immunoassay. Sequences were analyzed for transmitted drug resistance mutations. Results: Thirty percent of subtype A1 and 66% of subtype B sequences clustered. Large clusters (maximum 11 sequences) contained mixed risk groups. In univariate analysis, clustering was significantly associated with subtype B compared to A1 (odds ratio [OR], 4.38 [95% confidence interval {CI}, 2.56-7.50]); risk group (OR, 5.65 [95% CI, 3.27-9.75]) for men who have sex with men compared to heterosexual males; recent, compared to long-standing, infection (OR, 2.72 [95% CI, 1.64-4.52]); reported sex work contact (OR, 1.93 [95% CI, 1.07-3.47]); and younger age groups compared with age >=36 years (OR, 1.83 [95% CI, 1.10-3.05] for age <=25 years). Females were associated with lower odds of clustering than heterosexual males (OR, 0.49 [95% CI, .31-.77]). In multivariate analysis, risk group, subtype, and age group were independently associated with clustering (P < .001, P = .007, and P = .033, respectively). Eighteen sequences (2.1%) indicated evidence of transmitted drug resistance. Conclusions: Our findings suggest high levels of transmission and bridging between risk groups. PMID- 28575389 TI - Prospective, randomized, double-blind, Phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. AB - Objectives: The beta-lactamase inhibitor relebactam can restore imipenem activity against imipenem non-susceptible pathogens. Methods: To explore relebactam's safety, tolerability and efficacy, we conducted a randomized (1:1:1), controlled, Phase 2 trial comparing imipenem/cilastatin+relebactam 250 mg, imipenem/cilastatin+relebactam 125 mg and imipenem/cilastatin alone in adults with complicated urinary tract infections (cUTI) or acute pyelonephritis, regardless of baseline pathogen susceptibility. Treatment was administered intravenously every 6 h for 4-14 days, with optional step-down to oral ciprofloxacin. The primary endpoint was favourable microbiological response rate (pathogen eradication) at discontinuation of intravenous therapy (DCIV) in the microbiologically evaluable (ME) population. Non-inferiority of imipenem/cilastatin+relebactam over imipenem/cilastatin alone was defined as lower bounds of the 95% CI for treatment differences being above -15%. Results: At DCIV, 71 patients in the imipenem/cilastatin + 250 mg relebactam, 79 in the imipenem/cilastatin + 125 mg relebactam and 80 in the imipenem/cilastatin-only group were ME; 51.7% had cUTI and 48.3% acute pyelonephritis. Microbiological response rates were 95.5%, 98.6% and 98.7%, respectively, confirming non inferiority of both imipenem/cilastatin + relebactam doses to imipenem/cilastatin alone. Clinical response rates were 97.1%, 98.7% and 98.8%, respectively. All 23 ME patients with imipenem non-susceptible pathogens had favourable DCIV microbiological responses (100% in each group). Among all 298 patients treated, 28.3%, 29.3% and 30.0% of patients, respectively, had treatment-emergent adverse events. The most common treatment-related adverse events across groups (1.0% 4.0%) were diarrhoea, nausea and headache. Conclusions: Imipenem/cilastatin + relebactam (250 or 125 mg) was as effective as imipenem/cilastatin alone for treatment of cUTI. Both relebactam-containing regimens were well tolerated. (NCT01505634). PMID- 28575391 TI - Protein-Sol: a web tool for predicting protein solubility from sequence. AB - Motivation: Protein solubility is an important property in industrial and therapeutic applications. Prediction is a challenge, despite a growing understanding of the relevant physicochemical properties. Results: Protein-Sol is a web server for predicting protein solubility. Using available data for Escherichia coli protein solubility in a cell-free expression system, 35 sequence based properties are calculated. Feature weights are determined from separation of low and high solubility subsets. The model returns a predicted solubility and an indication of the features which deviate most from average values. Two other properties are profiled in windowed calculation along the sequence: fold propensity, and net segment charge. The utility of these additional features is demonstrated with the example of thioredoxin. Availability and implementation: The Protein-Sol webserver is available at http://protein-sol.manchester.ac.uk. Contact: jim.warwicker@manchester.ac.uk. PMID- 28575390 TI - Self-protective responses to norvaline-induced stress in a leucyl-tRNA synthetase editing-deficient yeast strain. AB - The editing function of aminoacyl-tRNA synthetases (aaRSs) is indispensible for formation of the correct aminoacyl-tRNAs. Editing deficiency may lead to growth inhibition and the pathogenesis of various diseases. Herein, we confirmed that norvaline (Nva) but not isoleucine or valine is the major threat to the editing function of Saccharomyces cerevisiae leucyl-tRNA synthetase (ScLeuRS), both in vitro and in vivo. Nva could be misincorporated into the proteome of the LeuRS editing-deficient yeast strain (D419A/ScDeltaleuS), potentially resulting in dysfunctional protein folding and growth delay. Furthermore, the exploration of the Nva-induced intracellular stress response mechanism in D419A/ScDeltaleuS revealed that Hsp70 chaperones were markedly upregulated in response to the potential protein misfolding. Additionally, proline (Pro), glutamate (Glu) and glutamine (Gln), which may accumulate due to the conversion of Nva, collectively contributed to the reduction of reactive oxygen species (ROS) levels in Nva treated D419A/ScDeltaleuS cells. In conclusion, our study highlights the significance of the editing function of LeuRS and provides clues for understanding the intracellular stress protective mechanisms that are triggered in aaRS editing-deficient organisms. PMID- 28575392 TI - Should limb revascularization take priority over dissection repair in type a aortic dissection presenting as isolated acute limb ischaemia. AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was should limb revascularization take priority over dissection repair in acute type A aortic dissection (ATAAD) presenting as isolated acute limb ischaemia? Altogether 133 papers were found using the reported search, of which 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Six studies showed that aortic repair alone resulted in the reperfusion of 60 100% of ischaemic lower limbs and recommended a strategy prioritizing aortic repair. In those with persistent isolated limb ischaemia post-aortic repair, expeditious peripheral revascularization procedures produced excellent patient outcomes comparable to those of ATAAD patients without malperfusion syndromes. In the remaining study, aortic repair was delayed in order to prioritize percutaneous reperfusion therapy aimed at treating the peripheral malperfusion. However, this resulted in one-third of patients not surviving to aortic surgery. We conclude that delaying aortic repair for limb reperfusion procedures results in unacceptably high mortality rates and that repair alone results in high reperfusion rates of ischaemic limbs. We therefore strongly recommend that aortic repair be the primary therapy for ATAAD patients even when limb ischaemia is the presenting feature. Limbs should be reassessed immediately after aortic repair and revascularization procedures undertaken urgently if any pulse deficits remain. PMID- 28575388 TI - Functional details of the Mycobacterium tuberculosis VapBC26 toxin-antitoxin system based on a structural study: insights into unique binding and antibiotic peptides. AB - Toxin-antitoxin (TA) systems are essential for bacterial persistence under stressful conditions. In particular, Mycobacterium tuberculosis express VapBC TA genes that encode the stable VapC toxin and the labile VapB antitoxin. Under normal conditions, these proteins interact to form a non-toxic TA complex, but the toxin is activated by release from the antitoxin in response to unfavorable conditions. Here, we present the crystal structure of the M. tuberculosis VapBC26 complex and show that the VapC26 toxin contains a pilus retraction protein (PilT) N-terminal (PIN) domain that is essential for ribonuclease activity and that, the VapB26 antitoxin folds into a ribbon-helix-helix DNA-binding motif at the N terminus. The active site of VapC26 is sterically blocked by the flexible C terminal region of VapB26. The C-terminal region of free VapB26 adopts an unfolded conformation but forms a helix upon binding to VapC26. The results of RNase activity assays show that Mg2+ and Mn2+ are essential for the ribonuclease activity of VapC26. As shown in the nuclear magnetic resonance spectra, several residues of VapB26 participate in the specific binding to the promoter region of the VapBC26 operon. In addition, toxin-mimicking peptides were designed that inhibit TA complex formation and thereby increase toxin activity, providing a novel approach to the development of new antibiotics. PMID- 28575394 TI - Sex and Age Specific Projections of Smoking Prevalence in Spain: A Bayesian Approach. AB - Objectives: To project future smoking prevalence rates in Spain by sex and age groups using Bayesian methods and to estimate the probability of a 30% relative reduction between 2010 and 2025. Methods: We used the data from the Spanish National Health Surveys (2003, 2006, and 2011) to obtain information about current and former smoking. We reconstructed annual smoking rates from 1989 through 2011 by sex and 5-year age groups. The prevalence were projected for the period 2012-2025 using a Bayesian logistic binomial model and estimated the probability to achieve the 30% relative reduction endorsed by the WHO. We calculated the 95% credible interval (CrI) of the posterior distribution, which includes a 95% of the distribution of potential smoking prevalences. Results: In men, the projections show a decline for crude (-2.64% annually, 95% CrI: -3.32; 1.97) and adjusted (-2.50%, 95% CrI:-3.14; -1.87) prevalence. In women, the projections show a decline for crude prevalence (-0.36%, 95% CrI: -1.02; -0.30)) and the age-adjusted prevalence (-1.02%, 95% CrI: -1.61, -0.47). By age groups, the decline is greater among women aged 15-39 years (-3.92%, 95% CrI: -4.92; 2.96)) while for women aged 40-64 years an increase (1.84%, 95% CrI: 1.06; 2.58) is expected. In men, the probability to achieve the WHO target is 0.728 and in women is less than 0.001. The age group 15-39 shows the highest probability to achieve the target. Conclusions: The results suggest smoking prevalence will decrease during 2012-2025 in all age groups for both sexes except for women aged 40-64. We found that the WHO target of a 30% reduction in prevalence is likely to be achieved overall and in the 15-39 years age groups for both sexes, but not achieved for older women and it is uncertain whether it will be achieved for older men. These results highlight the need to strengthen public health interventions that focus on reducing tobacco use in adult women aged 40-64 years old. Implications: We project a decrease in smoking prevalence in during 2012 2025 except for women aged 40-64. The WHO Target of a 30% relative reduction could be achieved in the population aged 15-39; but not in women and the results are inconclusive in men. These results highlight the need to strengthen public health interventions that focus on reducing tobacco use in adult women aged 40-64 years old. PMID- 28575393 TI - T7 RNA polymerase translocation is facilitated by a helix opening on the fingers domain that may also prevent backtracking. AB - Here, we studied the complete process of a viral T7 RNA polymerase (RNAP) translocation on DNA during transcription elongation by implementing extensive all-atom molecular dynamics (MD) simulations to construct a Markov state model (MSM). Our studies show that translocation proceeds in a Brownian motion, and the RNAP thermally transits among multiple metastable states. We observed non synchronized backbone movements of the nucleic acid (NA) chains with the RNA translocation accomplished first, while the template DNA lagged. Notably, both the O-helix and Y-helix on the fingers domain play key roles in facilitating NA translocation through the helix opening. The helix opening allows a key residue Tyr639 to become inserted into the active site, which pushes the RNA-DNA hybrid forward. Another key residue, Phe644, coordinates the downstream template DNA motions by stacking and un-stacking with a transition nucleotide (TN) and its adjacent nucleotide. Moreover, the O-helix opening at pre-translocation (pre trans) likely resists backtracking. To test this hypothesis, we computationally designed mutants of T7 RNAP by replacing the amino acids on the O-helix with counterpart residues from a mitochondrial RNAP that is capable of backtracking. The current experimental results support the hypothesis. PMID- 28575396 TI - BLAST-AHF: insights into biased AT1 ligands and heart failure. Beginning of the end or end of the beginning? PMID- 28575397 TI - Performance of mass spectrometry steroid profiling for diagnosis of polycystic ovary syndrome. PMID- 28575395 TI - Novel mouse models of oculopharyngeal muscular dystrophy (OPMD) reveal early onset mitochondrial defects and suggest loss of PABPN1 may contribute to pathology. AB - Oculopharyngeal muscular dystrophy (OPMD) is a late onset disease caused by polyalanine expansion in the poly(A) binding protein nuclear 1 (PABPN1). Several mouse models have been generated to study OPMD; however, most of these models have employed transgenic overexpression of alanine-expanded PABPN1. These models do not recapitulate the OPMD patient genotype and PABPN1 overexpression could confound molecular phenotypes. We have developed a knock-in mouse model of OPMD (Pabpn1+/A17) that contains one alanine-expanded Pabpn1 allele under the control of the native promoter and one wild-type Pabpn1 allele. This mouse is the closest available genocopy of OPMD patients. We show that Pabpn1+/A17 mice have a mild myopathic phenotype in adult and aged animals. We examined early molecular and biochemical phenotypes associated with expressing native levels of A17-PABPN1 and detected shorter poly(A) tails, modest changes in poly(A) signal (PAS) usage, and evidence of mitochondrial damage in these mice. Recent studies have suggested that a loss of PABPN1 function could contribute to muscle pathology in OPMD. To investigate a loss of function model of pathology, we generated a heterozygous Pabpn1 knock-out mouse model (Pabpn1+/Delta). Like the Pabpn1+/A17 mice, Pabpn1+/Delta mice have mild histologic defects, shorter poly(A) tails, and evidence of mitochondrial damage. However, the phenotypes detected in Pabpn1+/Delta mice only partially overlap with those detected in Pabpn1+/A17 mice. These results suggest that loss of PABPN1 function could contribute to but may not completely explain the pathology detected in Pabpn1+/A17 mice. PMID- 28575398 TI - Carbon dioxide insufflation and thoracoscopic ultrasonography image of pure ground-glass nodule. AB - Thoracic surgeons frequently encounter early lung cancer showing a pure ground glass nodule. Although thoracoscopic wedge resection is used extensively, it cannot be easily located for surgical procedures. Thoracoscopic ultrasonography is a real-time and less invasive technique for small lung lesion localization during thoracoscopic surgery. However, this technique has not been widely adopted because residual air in the lung results in poor ultrasound images. A 64-year-old woman was found to have pure ground-glass nodule. For intraoperative localization, we performed thoracoscopic ultrasonography. To deflate the lung, we insufflated carbon dioxide into the thoracic cavity and maintained an intrathoracic pressure of 10 mmHg for 5 min. We easily achieved complete lung collapse without any complications; pure ground-glass nodule clearly showed as a hyperechoic lesion. We performed thoracoscopic wedge resection with a pathological diagnosis of adenocarcinoma in situ. Carbon dioxide insufflation into the thoracic cavity may be effective for complete lung deflation, which is useful to detect small lung nodules. PMID- 28575399 TI - Characteristics and prognostic factors of node-negative non-small cell lung cancer larger than 5 cm. AB - OBJECTIVES: In the 7th edition of the tumour, node and metastasis staging system, a primary tumour size larger than 5 cm was shifted to Stage II. Therefore, we aimed to evaluate the characteristics and prognostic factors of node-negative non small cell lung cancer (NSCLC) larger than 5 cm. METHODS: We included 109 patients who underwent curative resection and had pathologically confirmed node negative NSCLC >5 cm (Group 1). We compared the clinicopathological characteristics and prognosis of these patients with 85 patients with node positive NSCLC >5 cm (Group 2) and 383 patients who had node-positive NSCLC <=5 cm (Group 3). RESULTS: Compared with Group 2, old age and absence of lymphovascular invasion was significantly more common in Group 1. Compared with Group 3, frequency of non-adenocarcinoma type and visceral pleural invasion were significantly higher in Group 1; however, the frequency of lymphovascular invasion was higher in Group 3. A Cox proportional hazards model showed that the maximized standardized uptake value and visceral pleural invasion was a statistically worse prognostic factor. Compared with Group 2, Group 1 showed significantly longer overall survival; however, there was no difference in recurrence-free survival. Compared with Group 3, there was no significant difference in recurrence-free survival and overall survival. In Group 1, recurrence in the contralateral lung was the most common recurrence pattern, and there was no metastasis in the mediastinal lymph nodes. CONCLUSIONS: Patients with node-negative NSCLC >5 cm had a lower incidence of lymphovascular invasion and a more common contralateral recurrence than patients with node-positive NSCLC, and visceral pleural invasion was identified as independent prognostic factors. PMID- 28575400 TI - Enhancing multiplex genome editing by natural transformation (MuGENT) via inactivation of ssDNA exonucleases. AB - Recently, we described a method for multiplex genome editing by natural transformation (MuGENT). Mutant constructs for MuGENT require large arms of homology (>2000 bp) surrounding each genome edit, which necessitates laborious in vitro DNA splicing. In Vibrio cholerae, we uncover that this requirement is due to cytoplasmic ssDNA exonucleases, which inhibit natural transformation. In ssDNA exonuclease mutants, one arm of homology can be reduced to as little as 40 bp while still promoting integration of genome edits at rates of ~50% without selection in cis. Consequently, editing constructs are generated in a single polymerase chain reaction where one homology arm is oligonucleotide encoded. To further enhance editing efficiencies, we also developed a strain for transient inactivation of the mismatch repair system. As a proof-of-concept, we used these advances to rapidly mutate 10 high-affinity binding sites for the nucleoid occlusion protein SlmA and generated a duodecuple mutant of 12 diguanylate cyclases in V. cholerae. Whole genome sequencing revealed little to no off-target mutations in these strains. Finally, we show that ssDNA exonucleases inhibit natural transformation in Acinetobacter baylyi. Thus, rational removal of ssDNA exonucleases may be broadly applicable for enhancing the efficacy and ease of MuGENT in diverse naturally transformable species. PMID- 28575402 TI - Factors influencing women's preferences for subsequent management in the event of incomplete evacuation of the uterus after misoprostol treatment for miscarriage. AB - STUDY QUESTION: What affects women's treatment preferences in the management of an incomplete evacuation of the uterus after misoprostol treatment for a first trimester miscarriage? SUMMARY ANSWER: Women's treatment preferences in the management of an incomplete evacuation of the uterus after misoprostol treatment for miscarriage are most strongly influenced by 'the risk of a reduced fertility' followed by 'the probability of success'. WHAT IS KNOWN ALREADY: Available treatment options in miscarriage are surgical, medical or expectant management. Treatment with misoprostol leads to an incomplete evacuation of the uterus and additional surgical treatment in 20-50% of women. To our knowledge, women's preferences for subsequent treatment of an incomplete evacuation of the uterus after misoprostol treatment for miscarriage have not been studied yet. STUDY DESIGN, SIZE, DURATION: Between April 2014 and January 2015, we conducted a prospective nationwide multicentre discrete-choice experiment (DCE). DCEs have become the most frequently applied approach for studying patient preferences in health care. In our DCE, which considerers five attributes, a target sample size was calculated including 20 patients per attribute for the main analysis. We intended to include 25% more patients, i.e. a total of 125 thus enabling us to assess heterogeneity of treatment choices. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women visiting the outpatient clinic with first-trimester miscarriage or incomplete miscarriage were invited to participate in the study. Women under 18 years of age, women who were unable to understand the Dutch questionnaire or women who already had received a treatment for the current miscarriage were excluded. Women's preferences were assessed using a DCE. A literature review, expert opinions and interviews with women from the general population were used to define relevant treatment characteristics. Five attributes were selected: (i) certainty about the duration of convalescence; (ii) number of days of bleeding after treatment; (iii) probability of success (empty uterus after treatment); (iv) risk of reduced fertility and (v) risk of complications requiring more time or readmission to hospital. Fourteen scenarios using these attributes were selected in the DCE. Each of these scenarios presented two treatment options, while treatment characteristics varied between the 14 scenarios. For each scenario, respondents were asked to choose the preferred treatment option. The importance of each attribute was analysed, and preference heterogeneity was investigated through latent-class analysis. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred and eighty-six women were included of whom 128 completed the DCE (69% response rate). The two attributes with the greatest effect on their preference were, probability of success and risk of reduced fertility. The latent-class analysis revealed two subgroups of patients with different preference patterns. Forty per cent of women were more influenced by treatment success and 59% were more influenced by risk. LIMITATIONS, REASONS FOR CAUTION: Most women were highly educated and were of Dutch origin, which limits the generalizability of our findings. Women with lower education levels, other cultural backgrounds and/or different previous experiences may differ from our findings. WIDER IMPLICATIONS OF THE FINDINGS: Patients preferences should be addressed when counselling patients with an incomplete miscarriage after misoprostol treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was embedded in the MisoREST trial, and funded by ZonMw, a Dutch organization for Health Research and Development, project number 80-82310-97-12066. There were no conflicts of interests. TRIAL REGISTRATION NUMBER: Dutch Trial Register NTR3310, http://www.trialregister.nl. TRIAL REGISTRATION DATE: 27 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 12 June 2012. PMID- 28575401 TI - Localization of Arabidopsis FORKED1 to a RABA-positive compartment suggests a role in secretion. AB - When FORKED1 (FKD1) is mutated, asymmetric localization of PINFORMED1 (PIN1), particularly to the apical side of cells, fails to occur properly in developing veins, resulting in an open vein pattern. FKD1 encodes a protein with a Pleckstrin homology-like (PL) domain, suggesting interaction with phosphoinositides. FKD1 has been previously found to interact with an ADP ribosylation factor GTPase-activating protein (ARF-GAP) important for vein patterning, SCARFACE/VAN3 (SFC). We find that FKD1-green fluorescent protein (GFP) localizes to the plasma membrane and to punctae labeled by SFC-yellow fluorescent protein (YFP). Supporting the idea that the FKD1 PL domain recognizes phosphatidylinositol 4-phosphate [PtdIns(4)P], FKD1-GFP co-localizes with PtdIns(4)P markers, and is more cytosolic when in a background mutant for the PtdIns(4,5)P2 hydrolases CVP2 and CVL1. Both FKD1 and SFC partially co-localize with markers for the trans-Golgi network (TGN), at which endocytic and secretory pathways merge. FKD1-labeled punctae rarely co-localize with the endocytic marker FM4-64, suggesting that FKD1 is not involved primarily in the endocytic pathway. FKD1 and SFC co-localize with members of the RABA group of RAB-GTPases, which are proposed to act in the post-Golgi secretory pathway. The compartments labeled by FKD1 and SFC do not localize to membrane compartments induced by the fungal toxin brefeldin A (BFA). Collectively, our data suggest that FKD1 and SFC act in a BFA insensitive secretory pathway. PMID- 28575403 TI - Finding a gatekeeper to coronary angiography: a step in the right direction. PMID- 28575404 TI - Evolution of the Banana Genome (Musa acuminata) Is Impacted by Large Chromosomal Translocations. AB - Most banana cultivars are triploid seedless parthenocarpic clones derived from hybridization between Musa acuminata subspecies and sometimes M. balbisiana. M. acuminata subspecies were suggested to differ by a few large chromosomal rearrangements based on chromosome pairing configurations in intersubspecies hybrids. We searched for large chromosomal rearrangements in a seedy M. acuminata ssp. malaccensis banana accession through mate-pair sequencing, BAC-FISH, targeted PCR and marker (DArTseq) segregation in its progeny. We identified a heterozygous reciprocal translocation involving two distal 3 and 10 Mb segments from chromosomes 01 and 04, respectively, and showed that it generated high segregation distortion, reduced recombination and linkage between chromosomes 01 and 04 in its progeny. The two chromosome structures were found to be mutually exclusive in gametes and the rearranged structure was preferentially transmitted to the progeny. The rearranged chromosome structure was frequently found in triploid cultivars but present only in wild malaccensis ssp. accessions, thus suggesting that this rearrangement occurred in M. acuminata ssp. malaccensis. We propose a mechanism for the spread of this rearrangement in Musa diversity and suggest that this rearrangement could have played a role in the emergence of triploid cultivars. PMID- 28575406 TI - Commentary: Incorporating a Modified Graeb Score to the Modified Fisher Scale for Improved Risk Prediction of Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage. PMID- 28575405 TI - Long-term exposure to road traffic noise, ambient air pollution, and cardiovascular risk factors in the HUNT and lifelines cohorts. AB - Aims: Blood biochemistry may provide information on associations between road traffic noise, air pollution, and cardiovascular disease risk. We evaluated this in two large European cohorts (HUNT3, Lifelines). Methods and results: Road traffic noise exposure was modelled for 2009 using a simplified version of the Common Noise Assessment Methods in Europe (CNOSSOS-EU). Annual ambient air pollution (PM10, NO2) at residence was estimated for 2007 using a Land Use Regression model. The statistical platform DataSHIELD was used to pool data from 144 082 participants aged >=20 years to enable individual-level analysis. Generalized linear models were fitted to assess cross-sectional associations between pollutants and high-sensitivity C-reactive protein (hsCRP), blood lipids and for (Lifelines only) fasting blood glucose, for samples taken during recruitment in 2006-2013. Pooling both cohorts, an inter-quartile range (IQR) higher day-time noise (5.1 dB(A)) was associated with 1.1% [95% confidence interval (95% CI: 0.02-2.2%)] higher hsCRP, 0.7% (95% CI: 0.3-1.1%) higher triglycerides, and 0.5% (95% CI: 0.3-0.7%) higher high-density lipoprotein (HDL); only the association with HDL was robust to adjustment for air pollution. An IQR higher PM10 (2.0 ug/m3) or NO2 (7.4 ug/m3) was associated with higher triglycerides (1.9%, 95% CI: 1.5-2.4% and 2.2%, 95% CI: 1.6-2.7%), independent of adjustment for noise. Additionally for NO2, a significant association with hsCRP (1.9%, 95% CI: 0.5-3.3%) was seen. In Lifelines, an IQR higher noise (4.2 dB(A)) and PM10 (2.4 ug/m3) was associated with 0.2% (95% CI: 0.1-0.3%) and 0.6% (95% CI: 0.4-0.7%) higher fasting glucose respectively, with both remaining robust to adjustment for air/noise pollution. Conclusion: Long-term exposures to road traffic noise and ambient air pollution were associated with blood biochemistry, providing a possible link between road traffic noise/air pollution and cardio metabolic disease risk. PMID- 28575407 TI - Reply to Naimi. PMID- 28575408 TI - Trends in Sales of Flavored and Menthol Tobacco Products in the United States During 2011-2015. AB - Introduction: Flavors can mask the harshness of tobacco and make it appealing to young people. This study assessed flavored and menthol tobacco product sales at the national and state levels. Methods: Universal Product Code tobacco sales data collected by Nielsen were combined for convenience stores and all-outlets combined during October 22, 2011-January 9, 2016. Products were characterized as flavored, menthol, or non-flavored/non-menthol. Total unit sales, and the proportion of flavored and menthol unit sales, were assessed nationally and by state for seven tobacco products. Joinpoint regression was used to assess trends in average monthly percentage change. Results: Nationally, the proportion of flavored and menthol sales in 2015 was as follows: cigarettes (32.5% menthol), large cigars (26.1% flavored), cigarillos (47.5% flavored, 0.2% menthol), little cigars (21.8% flavored, 19.4% menthol), chewing tobacco (1.4% flavored, 0.7% menthol), moist snuff (3.0% flavored, 57.0% menthol), and snus (88.5% menthol). From 2011 to 2015, sales increased for flavored cigarillos and chewing tobacco, as well as for menthol cigarettes, little cigars, moist snuff, and snus. Sales decreased for flavored large cigars, moist snuff, and snus, and for menthol chewing tobacco. State-level variations were observed by product; for example, flavored little cigar sales ranged from 4.4% (Maine) to 69.3% (Utah) and flavored cigarillo sales ranged from 26.6% (Maine) to 63.0% (Maryland). Conclusions: Menthol and flavored sales have increased since 2011, particularly for the products with the highest number of units sold, and significant state variation exists. Efforts to restrict flavored tobacco product sales could reduce overall U.S. tobacco consumption. Implications: Flavors in tobacco products can mask the harshness of tobacco and make these products more appealing to young people. This is the first study to assess national and state-level trends in flavored and menthol tobacco product sales. These findings underscore the importance of population-based interventions to address flavored tobacco product use at the national, state, and local levels. Additionally, further monitoring of flavored and menthol tobacco product sales can inform potential future regulatory efforts at the national, state, and local levels. PMID- 28575409 TI - Giant Reverse Transcriptase-Encoding Transposable Elements at Telomeres. AB - Transposable elements are omnipresent in eukaryotic genomes and have a profound impact on chromosome structure, function and evolution. Their structural and functional diversity is thought to be reasonably well-understood, especially in retroelements, which transpose via an RNA intermediate copied into cDNA by the element-encoded reverse transcriptase, and are characterized by a compact structure. Here, we report a novel type of expandable eukaryotic retroelements, which we call Terminons. These elements can attach to G-rich telomeric repeat overhangs at the chromosome ends, in a process apparently facilitated by complementary C-rich repeats at the 3'-end of the RNA template immediately adjacent to a hammerhead ribozyme motif. Terminon units, which can exceed 40 kb in length, display an unusually complex and diverse structure, and can form very long chains, with host genes often captured between units. As the principal polymerizing component, Terminons contain Athena reverse transcriptases previously described in bdelloid rotifers and belonging to the enigmatic group of Penelope-like elements, but can additionally accumulate multiple cooriented ORFs, including DEDDy 3'-exonucleases, GDSL esterases/lipases, GIY-YIG-like endonucleases, rolling-circle replication initiator (Rep) proteins, and putatively structural ORFs with coiled-coil motifs and transmembrane domains. The extraordinary length and complexity of Terminons and the high degree of interfamily variability in their ORF content challenge the current views on the structural organization of eukaryotic retroelements, and highlight their possible connections with the viral world and the implications for the elevated frequency of gene transfer. PMID- 28575411 TI - Operationalization of Sign Language Phonological Similarity and its Effects on Lexical Access. AB - Cognitive mechanisms for sign language lexical access are fairly unknown. This study investigated whether phonological similarity facilitates lexical retrieval in sign languages using measures from a new lexical database for American Sign Language. Additionally, it aimed to determine which similarity metric best fits the present data in order to inform theories of how phonological similarity is constructed within the lexicon and to aid in the operationalization of phonological similarity in sign language. Sign repetition latencies and accuracy were obtained when native signers were asked to reproduce a sign displayed on a computer screen. Results indicated that, as predicted, phonological similarity facilitated repetition latencies and accuracy as long as there were no strict constraints on the type of sublexical features that overlapped. The data converged to suggest that one similarity measure, MaxD, defined as the overlap of any 4 sublexical features, likely best represents mechanisms of phonological similarity in the mental lexicon. Together, these data suggest that lexical access in sign language is facilitated by phonologically similar lexical representations in memory and the optimal operationalization is defined as liberal constraints on overlap of 4 out of 5 sublexical features-similar to the majority of extant definitions in the literature. PMID- 28575410 TI - Enhanced endothelin-1/Rho-kinase signalling and coronary microvascular dysfunction in hypertensive myocardial hypertrophy. AB - Aims: Hypertensive cardiac hypertrophy is associated with reduced coronary flow reserve, but its impact on coronary flow regulation and vasomotor function remains incompletely understood and requires further investigation. Methods and results: Left ventricular hypertrophy was induced in mice by transverse aortic coarctation (TAC) for 4 weeks. The left coronary artery blood velocity (LCABV) and myocardium lactate level were measured following the metabolic activation by isoproterenol. Septal coronary arterioles were isolated and pressurized for functional studies. In TAC mice, the heart-to-body weight ratio was increased by 45%, and cardiac fractional shortening and LCABV were decreased by 51 and 14%, respectively. The resting myocardial lactate level was 43% higher in TAC mice. Isoproterenol (5 ug/g, i.p.) increased heart rate by 20% in both groups of animals, but the corresponding increase in LCABV was not observed in TAC mice. The ventricular hypertrophy was associated with elevation of myocardial endothelin-1 (ET-1), increased vascular expression of rho-kinases (ROCKs), and increased superoxide production in the myocardium and vasculature. In coronary arterioles from TAC mice, the endothelial nitric oxide (NO)-mediated dilation to acetylcholine (ACh) was reversed to vasoconstriction and the vasoconstriction to ET-1 was augmented. Inhibition of ROCK by H-1152 alleviated oxidative stress and abolished enhanced vasoconstriction to ET-1. Both H-1152 and superoxide scavenger Tempol abolished coronary arteriolar constriction to ACh in a manner sensitive to NO synthase blocker NG-nitro-L-arginine methyl ester. Conclusions: Myocardial hypertrophy induced by pressure overload leads to cardiac and coronary microvascular dysfunction and ischaemia possibly due to oxidative stress, enhanced vasoconstriction to ET-1 and compromised endothelial NO function via elevated ROCK signalling. PMID- 28575412 TI - Postpartum Changes in Mood and Smoking-Related Symptomatology: An Ecological Momentary Assessment Investigation. AB - Introduction: Postpartum smoking relapse is a highly prevalent public health problem. Mood and breast feeding are significantly associated with smoking relapse, although less is known about the temporality of these relationships. Therefore, this study utilized ecological momentary assessments (EMA) to prospectively examine changes in mood and smoking-related symptomatology in relationship to three events-childbirth, termination of breast feeding, and smoking relapse. We expected all three events to significantly alter mood and smoking-related symptomatology. Methods: We enrolled a sample of pregnant women who had recently quit smoking and intended to remain quit during the postpartum. Participants were randomized to active/placebo progesterone to prevent postpartum relapse. Participants also completed daily EMA to collect data mood and smoking related symptomatology as well as our three events of interest. Results: Participants (n = 46) were, on average, 26.5 +/- 0.8 years old and, prior to pregnancy, smoked 10.1 +/- 0.7 cigarettes/day. We noted a number of significant within- and between-subject relationships. For example, participants reported a 24% decline in negative affect after childbirth (p = .0016). Among those who relapsed to smoking (n = 23), participants randomized to placebo had a significant increase in cigarette craving after relapse (beta = 1.06, 95% confidence interval [CI] = 0.62 to 1.49, p value = .0003), whereas participants randomized to active progesterone did not (beta = 0.63, 95% CI = -0.35 to 1.62, p value = .1824). Conclusions: These observations suggest that mood and smoking related symptomatology are influenced by childbirth, breast feeding, smoking relapse, and use of exogenous progesterone. Future research should explore how these observations may inform novel postpartum smoking relapse-prevention interventions. Implications: Postpartum smoking relapse has been a persistent public health problem for more than 40 years. Although a number of significant predictors of postpartum smoking relapse have been identified (eg, depression and breast feeding), much of these analyses have relied on cross-sectional and/or self-reported retrospective data. Therefore, for the first time, we utilized ecological momentary assessment to explore the effect of childbirth, termination of breast feeding, and smoking relapse on mood and smoking-related symptomatology (eg, craving). Numerous significant relationships were observed, including a 96% increase in craving after smoking relapse. These novel observations can inform new and effective postpartum smoking relapse-prevention programs. PMID- 28575413 TI - Comprehensive protocol of traceability during IVF: the result of a multicentre failure mode and effect analysis. AB - STUDY QUESTION: Can traceability of gametes and embryos be ensured during IVF? SUMMARY ANSWER: The use of a simple and comprehensive traceability system that includes the most susceptible phases during the IVF process minimizes the risk of mismatches. WHAT IS KNOWN ALREADY: Mismatches in IVF are very rare but unfortunately possible with dramatic consequences for both patients and health care professionals. Traceability is thus a fundamental aspect of the treatment. A clear process of patient and cell identification involving witnessing protocols has to be in place in every unit. To identify potential failures in the traceability process and to develop strategies to mitigate the risk of mismatches, previously failure mode and effects analysis (FMEA) has been used effectively. The FMEA approach is however a subjective analysis, strictly related to specific protocols and thus the results are not always widely applicable. To reduce subjectivity and to obtain a widespread comprehensive protocol of traceability, a multicentre centrally coordinated FMEA was performed. STUDY DESIGN, SIZE, DURATION: Seven representative Italian centres (three public and four private) were selected. The study had a duration of 21 months (from April 2015 to December 2016) and was centrally coordinated by a team of experts: a risk analysis specialist, an expert embryologist and a specialist in human factor. Principal investigators of each centre were first instructed about proactive risk assessment and FMEA methodology. A multidisciplinary team to perform the FMEA analysis was then formed in each centre. After mapping the traceability process, each team identified the possible causes of mistakes in their protocol. A risk priority number (RPN) for each identified potential failure mode was calculated. The results of the FMEA analyses were centrally investigated and consistent corrective measures suggested. The teams performed new FMEA analyses after the recommended implementations. PARTICIPANTS/MATERIALS, SETTING, METHODS: In each centre, this study involved: the laboratory director, the Quality Control & Quality Assurance responsible, Embryologist(s), Gynaecologist(s), Nurse(s) and Administration. The FMEA analyses were performed according to the Joint Commission International. MAIN RESULTS AND THE ROLE OF CHANCE: The FMEA teams identified seven main process phases: oocyte collection, sperm collection, gamete processing, insemination, embryo culture, embryo transfer and gamete/embryo cryopreservation. A mean of 19.3 (SD +/- 5.8) associated process steps and 41.9 (SD +/- 12.4) possible failure modes were recognized per centre. A RPN >=15 was calculated in a mean of 6.4 steps (range 2-12, SD +/- 3.60). A total of 293 failure modes were centrally analysed 45 of which were considered at medium/high risk. After consistent corrective measures implementation and re-evaluation, a significant reduction in the RPNs in all centres (RPN <15 for all steps) was observed. A simple and comprehensive traceability system was designed as the result of the seven FMEA analyses. LIMITATIONS, REASONS FOR CAUTION: The validity of FMEA is in general questionable due to the subjectivity of the judgments. The design of this study has however minimized this risk by introducing external experts for the analysis of the FMEA results. Specific situations such as sperm/oocyte donation, import/export and pre-implantation genetic testing were not taken into consideration. Finally, this study is only limited to the analysis of failure modes that may lead to mismatches, other possible procedural mistakes are not accounted for. WIDER IMPLICATIONS OF THE FINDINGS: Every single IVF centre should have a clear and reliable protocol for identification of patients and traceability of cells during manipulation. The results of this study can support IVF groups in better recognizing critical steps in their protocols, understanding identification and witnessing process, and in turn enhancing safety by introducing validated corrective measures. STUDY FUNDING/COMPETING INTEREST(S): This study was designed by the Italian Society of Embryology Reproduction and Research (SIERR) and funded by the Italian National Transplant Centre (CNT) of the Italian National Institute of Health (ISS). The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A. PMID- 28575415 TI - Catastrophic healthcare expenditure and poverty related to out-of-pocket payments for healthcare in Bangladesh-an estimation of financial risk protection of universal health coverage. AB - The Sustainable Development Goals target to achieve Universal Health Coverage (UHC), including financial risk protection (FRP) among other dimensions. There are four indicators of FRP, namely incidence of catastrophic health expenditure (CHE), mean positive catastrophic overshoot, incidence of impoverishment and increase in the depth of poverty occur for high out-of-pocket (OOP) healthcare spending. OOP spending is the major payment strategy for healthcare in most low and-middle-income countries, such as Bangladesh. Large and unpredictable health payments can expose households to substantial financial risk and, at their most extreme, can result in poverty. The aim of this study was to estimate the impact of OOP spending on CHE and poverty, i.e. status of FRP for UHC in Bangladesh. A nationally representative Household Income and Expenditure Survey 2010 was used to determine household consumption expenditure and health-related spending in the last 30 days. Mean CHE headcount and its concentration indices (CI) were calculated. The propensity of facing CHE for households was predicted by demographic and socioeconomic characteristics. The poverty headcount was estimated using 'total household consumption expenditure' and such expenditure without OOP payments for health in comparison with the poverty-line measured by cost of basic need. In absolute values, a pro-rich distribution of OOP payment for healthcare was found in urban and rural Bangladesh. At the 10%-threshold level, in total 14.2% of households faced CHE with 1.9% overshoot. 16.5% of the poorest and 9.2% of the richest households faced CHE. An overall pro-poor distribution was found for CHE (CI = -0.064) in both urban and rural households, while the former had higher CHE incidences. The poverty headcount increased by 3.5% (5.1 million individuals) due to OOP payments. Reliance on OOP payments for healthcare in Bangladesh should be reduced for poverty alleviation in urban and rural Bangladesh in order to secure FRP for UHC. PMID- 28575416 TI - Toxic drug-induced liver failure during therapy of rheumatoid arthritis with tocilizumab subcutaneously: a case report. PMID- 28575414 TI - Randomized comparison of liposomal amphotericin B versus placebo to prevent invasive mycoses in acute lymphoblastic leukaemia. AB - Objectives: To prevent invasive fungal disease (IFD) in adult patients undergoing remission-induction chemotherapy for newly diagnosed acute lymphoblastic leukaemia (ALL). Patients and methods: In a double-blind multicentre Phase 3 study, patients received prophylactic liposomal amphotericin B (L-AMB) at 5 mg/kg intravenously or placebo twice weekly in a 2:1 random allocation during remission induction treatment. The primary endpoint was the development of proven or probable IFD. Secondary endpoints included those focused on the safety and tolerability of prophylactic L-AMB. Results: Three hundred and fifty-five patients from 86 centres in Europe and South America received at least one dose of L-AMB ( n = 237) or placebo ( n = 118). Rates of proven and probable IFD assessed independently were 7.9% (18/228) in the L-AMB group and 11.7% (13/111) in the placebo group ( P = 0.24). Rates of possible IFD were 4.8% (11/228) in the L-AMB and 5.4% (6/111) in the placebo group ( P = 0.82). The remission induction phase was a median of 22 days for both groups. Overall mortality was similar between the groups: 7.2% (17/237) for L-AMB and 6.8% (8/118) for placebo ( P = 1.00). Hypokalaemia and creatinine increase were significantly more frequent with L-AMB. Conclusions: The IFD rate among adult patients undergoing remission-induction chemotherapy for newly diagnosed ALL was 11.7% in the placebo group, and was not significantly different in patients receiving L-AMB, suggesting that the L-AMB regimen studied is not effective as prophylaxis against IFD. The IFD rate appears higher than previously reported, warranting further investigation. Tolerability of L-AMB was what might be expected. Further studies are needed to determine the optimal antifungal strategy during remission induction chemotherapy of ALL. PMID- 28575417 TI - Implications of electronic health record downtime: an analysis of patient safety event reports. AB - Objective: We sought to understand the types of clinical processes, such as image and medication ordering, that are disrupted during electronic health record (EHR) downtime periods by analyzing the narratives of patient safety event report data. Materials and Methods: From a database of 80 381 event reports, 76 reports were identified as explicitly describing a safety event associated with an EHR downtime period. These reports were analyzed and categorized based on a developed code book to identify the clinical processes that were impacted by downtime. We also examined whether downtime procedures were in place and followed. Results: The reports were coded into categories related to their reported clinical process: Laboratory, Medication, Imaging, Registration, Patient Handoff, Documentation, History Viewing, Delay of Procedure, and General. A majority of reports (48.7%, n = 37) were associated with lab orders and results, followed by medication ordering and administration (14.5%, n = 11). Incidents commonly involved patient identification and communication of clinical information. A majority of reports (46%, n = 35) indicated that downtime procedures either were not followed or were not in place. Only 27.6% of incidents (n = 21) indicated that downtime procedures were successfully executed. Discussion: Patient safety report data offer a lens into EHR downtime-related safety hazards. Important areas of risk during EHR downtime periods were patient identification and communication of clinical information; these should be a focus of downtime procedure planning to reduce safety hazards. Conclusion: EHR downtime events pose patient safety hazards, and we highlight critical areas for downtime procedure improvement. PMID- 28575418 TI - Sorafenib-Induced Changes in Thyroid Hormone Levels in Patients Treated for Hepatocellular Carcinoma. AB - Context: The pathogenesis of tyrosine kinase inhibitor-induced thyroid hormone (TH) alterations are still a matter of debate. Objective: The objective of this study was to determine the effects of sorafenib on TH levels in patients with hepatocellular carcinoma (HCC) and to evaluate possible mechanisms. Design: We performed a prospective cohort study between 2009 and 2016. Setting: This study was conducted at a tertiary referral center. Patients: This study included 57 consecutive patients with HCC who were treated with sorafenib. Main Outcome Measure: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels were measured every 6 weeks, and extensive thyroid function tests (TFTs) were measured before treatment (t0), after 6 weeks (t6), and at the end of therapy. The effect of sorafenib on TH transport by monocarboxylate transporter (MCT)8 or MCT10 was tested in transfected COS1 cells. Results: Four patients (7%) developed thyroiditis. Among the other patients, 30% had elevation of TSH or FT4 above the normal range. Overall, between t0 and t6, mean TSH increased from 1.28 to 1.57 mU/L (P < 0.001) and mean FT4 from 18.4 to 21.2 pmol/L (P < 0.001). Simultaneously, the serum triiodothyronine (T3)/reverse triiodothyronine ratio and the (T3/thyroxine) *100 ratio decreased. Sorafenib decreased cellular T3 uptake by MCT8 and to a lesser extent by MCT10. Conclusions: These in vivo data suggest that sorafenib affects TFTs on multiple levels. Our in vitro experiments suggest a possible role of sorafenib-induced inhibition of T3 transport into the cell by MCT8 and MCT10. PMID- 28575421 TI - Evidence of the Impact of the truth FinishIt Campaign. AB - Introduction: Over the past decade, public education mass media campaigns have been shown to be successful in changing tobacco-related attitudes, intentions, and behaviors among youth and young adults. In 2014, the national truth(r) campaign re-launched a new phase of the campaign targeted at a broad audience of youth and young adults, aged 15-21, to help end the tobacco epidemic. Methods: The study sample for this analysis is drawn from the Truth Longitudinal Cohort (TLC), a probability-based, nationally representative cohort designed to evaluate the relationship between awareness of truth media messages and changes in targeted attitudes, beliefs, and behaviors over time. The sample for this study was limited to those with data at baseline and three subsequent follow-up surveys (n = 7536). Results: Logistic regression models indicate that truth ad awareness is significantly associated with increases in targeted anti-tobacco attitudes as well as reduced intentions to smoke over time, holding constant baseline attitudes and intentions. Results also suggest a dose-response relationship in that higher levels of truth ad awareness were significantly associated with higher likelihood of reporting agreement across all five attitudinal constructs: anti-smoking imagery, anti-social smoking sentiment, anti-tobacco social movement, anti-tobacco industry sentiment, and independence. Conclusions: Longitudinal results indicate a significant dose-response relationship between awareness of the new phase of the truth campaign and campaign-targeted attitudes and intentions not to smoke among youth and young adults. Implications: Findings from this study confirm that a carefully designed anti-tobacco public education campaign aimed at youth and young adults is a key population-level intervention within the context of an expanding tobacco product landscape and a cluttered media environment. As tobacco use patterns shift and new products emerge, evidence-based public education campaigns can play a central role in helping the next generation to reject tobacco. Public education mass media campaigns are a key component to changing tobacco use attitudes and behavior, particularly among youth and young adults. PMID- 28575420 TI - Exacerbation of Endometriosis Due To Regulatory T-Cell Dysfunction. AB - Context: Endometriosis is a chronic inflammatory disease associated with altered immune response to endometrial cells facilitating the implantation and proliferation of ectopic endometrial tissues. Although regulatory T (Treg) cells play a key role in T cell-mediated immune response and development of immune disorders, their significance in endometriosis remains to be elucidated. Recently, CD4+CD45RA- forkhead box protein 3 (Foxp3)hi T cells, activated Treg cells, have been identified as a functionally true suppressive population of Treg cells. Objective: To investigate the role of Treg cells in endometriosis. Design: Three Treg cell fractions (resting Treg cells, activated Treg cells, and non-Treg cells) were examined using flow cytometry in the endometrioma, endometrium, peritoneal fluid, and peripheral blood obtained from women with (n = 27) and without (n = 28) endometriosis. A mouse model of endometriosis was made in Foxp3tm3Ayr/J (Foxp3DTR) C57BL/6 Treg cell-depleted mice (n = 28). Results: In women with endometrioma, the proportion of activated Treg cells in the endometrioma and the endometrium, but not in the peritoneal fluid or peripheral blood, was significantly decreased compared with that in women without endometriosis. In Foxp3DTR/diphtheria toxin mice, the number and weight of endometriotic lesions, inflammatory cytokine levels and angiogenetic factors were significantly increased compared with those in control mice. Conclusions: Treg cell deficiency exaggerates local inflammation and angiogenesis and simultaneously facilitates the attachment and growth of endometrial implants. The findings provide an insight into dysregulated immune response for the pathogenesis and development. PMID- 28575422 TI - Fatalities Involving Carfentanil and Furanyl Fentanyl: Two Case Reports. AB - Carfentanil is a fentanyl analog frequently used in large animal veterinary medicine. Recently, carfentanil has been discovered in postmortem and antemortem cases throughout the United States in the heroin supply either alone or mixed with heroin and/or other fentanyl analogs. The potency of carfentanil is ~10,000 times greater than morphine and 100 times greater than fentanyl. In two recent cases, carfentanil was identified and ruled to be the cause of death, either alone or in combination with other drugs. Case 1 involved a known heroin user. He was discovered slumped over in a running van blocking the bays of a carwash. Two syringes, a spoon with cotton and residue and a yellow baggie of powder were found in the van. Case 2 involved a man living in a tent in a park with his mother. He was last heard from by a sister via phone who stated he sounded very intoxicated and by his mother who noted him to be "itching all over" and upset over his girlfriend. When the mother returned from work, she discovered him unresponsive with a small baggie of brown powder next to him. Routine drug and volatile screening tests were performed on heart blood using headspace gas chromatography, immunoassay and gas chromatography mass spectrometry methods. Results from initial testing on both cases did not have any significant toxicological findings. However, due to the history, scene photos, toxicological findings in blood and urine and analysis of the drug paraphernalia on one of the cases which identified carfentanil and furanyl fentanyl, fentanyl analogues were suspected. Heart blood was sent to a reference laboratory for carfentanil and furanyl fentanyl analysis. Case 1 had a carfentanil concentration of 1.3 ng/mL and a furanyl fentanyl concentration of 0.34 ng/mL. Case 2 had a carfentanil concentration of 0.12 ng/mL. PMID- 28575423 TI - Purtscher-like retinopathy and transplant-associated thrombotic microangiopathy. PMID- 28575419 TI - Telomere shortening triggers a feedback loop to enhance end protection. AB - Telomere homeostasis is controlled by both telomerase machinery and end protection. Telomere shortening induces DNA damage sensing kinases ATM/ATR for telomerase recruitment. Yet, whether telomere shortening also governs end protection is poorly understood. Here we discover that yeast ATM/ATR controls end protection. Rap1 is phosphorylated by Tel1 and Mec1 kinases at serine 731, and this regulation is stimulated by DNA damage and telomere shortening. Compromised Rap1 phosphorylation hampers the interaction between Rap1 and its interacting partner Rif1, which thereby disturbs the end protection. As expected, reduction of Rap1-Rif1 association impairs telomere length regulation and increases telomere-telomere recombination. These results indicate that ATM/ATR DNA damage checkpoint signal contributes to telomere protection by strengthening the Rap1 Rif1 interaction at short telomeres, and the checkpoint signal oversees both telomerase recruitment and end capping pathways to maintain telomere homeostasis. PMID- 28575426 TI - Evolution of microbial communities growing with carbon monoxide, hydrogen, and carbon dioxide. AB - Microbial anaerobic conversion of carbon monoxide (CO) and syngas (mainly composed of CO, CO2 and H2) leads to the production of important industrial products, such as acetate and ethanol. The composition of CO- and syngas converting microbial communities and the microbial interactions involved are still largely unknown. The main objectives of this study were (i) to understand the effects of CO, CO2, and H2 on the structure and function of a CO-consuming microbial community, and (ii) to identify key carboxidotrophs in the mixed culture. For this, sludge was anaerobically enriched with CO as the sole carbon/energy source at incrementally increasing CO partial pressures (PCO). Phylotypes of Methanobacteriaceae and methane production were detected at PCO <= 44.1 kPa. At higher PCO, enriched phylotypes were Acetobacterium, Oscillospira and Pleomorphomonas, and acetate was the main end product. The addition of CO2/HCO3- or H2 to CO fermentation increased the acetate/ethanol ratio and species diversity, compared to growth with CO as sole substrate. Phylotypes associated with Pleomorphomonas and Acetobacterium increased in relative abundance during exponential CO utilization. The Pleomorphomonas-like isolate produced H2:CO2, whereas the Acetobacterium-like isolate produced ethanol, when CO was the only electron/carbon source. These findings shed light on the interplay between syngas components and microbial communities. PMID- 28575427 TI - Corrigendum for "Diet Polyphenol Curcumin Stimulates Hepatic Fgf21 Production and Restores Its Sensitivity in High-Fat-Fed Male Mice". PMID- 28575425 TI - Social Dominance Orientation, Language Orientation, and Deaf Identity. AB - The notion of the Deaf community as a linguistic-cultural minority has been increasingly recognized and studied over the last two decades. However, significant differences of opinion and perspective within that population typically have been neglected in the literature. Social dominance orientation (SDO), a theoretical construct, typically focusing on intergroup perceptions and relations, is one aspect that has been left unexplored and might prove particularly enlightening. The present study investigated SDO among 119 deaf and 49 hearing young adults through a standardized SDO questionnaire. SDO was examined with regard to cultural identities (deaf, hearing, bicultural, and marginal), cochlear implant use, and language orientation (sign language or spoken language). The deaf participants were found to be more egalitarian than hearing individuals overall. Deaf individuals who held the strongest deaf identities, those who were sign language oriented, and not cochlear implant users, were the most egalitarian. PMID- 28575424 TI - Association between habenula dysfunction and motivational symptoms in unmedicated major depressive disorder. AB - The lateral habenula plays a central role in reward and punishment processing and has been suggested to drive the cardinal symptom of anhedonia in depression. This hypothesis is largely based on observations of habenula hypermetabolism in animal models of depression, but the activity of habenula and its relationship with clinical symptoms in patients with depression remains unclear. High-resolution functional magnetic resonance imaging (fMRI) and computational modelling were used to investigate the activity of the habenula during a probabilistic reinforcement learning task with rewarding and punishing outcomes in 21 unmedicated patients with major depression and 17 healthy participants. High resolution anatomical scans were also acquired to assess group differences in habenula volume. Healthy individuals displayed the expected activation in the left habenula during receipt of punishment and this pattern was confirmed in the computational analysis of prediction error processing. In depressed patients, there was a trend towards attenuated left habenula activation to punishment, while greater left habenula activation was associated with more severe depressive symptoms and anhedonia. We also identified greater habenula volume in patients with depression, which was associated with anhedonic symptoms. Habenula dysfunction may contribute to abnormal response to punishment in patients with depression, and symptoms such as anhedonia. PMID- 28575428 TI - Letter to the Editor: Hypothalamic Kisspeptin in Female Rat Models of PCOS. PMID- 28575429 TI - Evidence That a Sex Difference in Neonatal DNA Methylation Organizes Two Distinct Phenotypic Characteristics of Neurons in the Murine Forebrain. PMID- 28575431 TI - Peptide Therapeutics for Weight Loss: Preventing Plasma Pancreatic Polypeptide Proteolysis. PMID- 28575430 TI - A Shot in the Dark Exposes More Trees in the Forest: Adding a Histone Demethylase (Jmjd3) and RIP-cre Neurons to the Coordination of Female Reproductive Function. PMID- 28575432 TI - Steroids, Cytokines, and Implantation. PMID- 28575433 TI - Prolactin: The Bright and the Dark Side. PMID- 28575434 TI - Incretin-Based Therapies: Revisiting Their Mode of Action. PMID- 28575435 TI - Unique ER Stress Mechanisms in beta Cells Limit the Translation Potential of Therapies Targeting eIF2alpha. PMID- 28575436 TI - Unliganded TRalpha: A "Safety Lock" to Metamorphosis. PMID- 28575438 TI - Molecular Characterization of Staphylococcus aureus Isolates From Children With Periorbital or Orbital Cellulitis. AB - Background: Periorbital and orbital cellulitis cause significant pediatric morbidity. Here, we define the clinical features of and characterize isolates from children with periorbital or orbital cellulitis caused by Staphylococcus aureus at Texas Children's Hospital in Houston. Methods: Patients were identified from a prospective S aureus study database from January 2002 to July 2015. Demographic and clinical data were collected retrospectively. Isolates were genotyped by pulsed-field gel electrophoresis, and Panton-Valentine leukocidin (lukSF-PV [pvl]) genes were detected by quantitative polymerase chain reaction. Data were analyzed with the Fisher exact or Wilcoxon rank-sum test. Results: Eighty-five patients with periorbital (n = 58) or orbital (n = 27) cellulitis were identified. We found 57 (67%) methicillin-resistant S aureus (MRSA) isolates, 72 (85%) pvl-positive (pvl+) isolates, and 66 (78%) USA300 isolates. No differences in clinical characteristics were found when we compared MRSA to methicillin-susceptible (MSSA) infections or USA300 to non-USA300 infections. Patients with orbital cellulitis were hospitalized a median of 12 days (range, 2 28 days) and received antibiotics for 21 days (range, 10-32 days). Twelve (44%) patients with orbital cellulitis received steroids. Steroid treatment did not affect the length of hospitalization or duration of antibiotic treatment. Six (7%) patients with orbital cellulitis were bacteremic. Patients with periorbital cellulitis were hospitalized for a median of 3 days (range, 0-17 days) and received antibiotics for 11 days (range, 7-32 days). According to computed tomography (CT), 19 (70%) patients with orbital cellulitis and 11 (41%) with periorbital cellulitis had sinusitis. Conclusions: The majority of periorbital and orbital S aureus infections at Texas Children's Hospital were caused by MRSA, and no change was observed over time. Empirical antibiotic treatment should include coverage for MRSA. PVL might be an important virulence factor in these presentations. S aureus is associated with sinusitis and its complications. PMID- 28575437 TI - Successful treatment of post-surgical osteomyelitis caused by XDR Pseudomonas aeruginosa with ceftolozane/tazobactam monotherapy. PMID- 28575440 TI - Impacts of Ocean Acidification on Sensory Function in Marine Organisms. AB - SYNOPSIS: Ocean acidification has been identified as a major contributor to ocean ecosystem decline, impacting the calcification, survival, and behavior of marine organisms. Numerous studies have observed altered sensory perception of chemical, auditory, and visual cues after exposure to elevated CO2. Sensory systems enable the observation of the external environment and therefore play a critical role in survival, communication, and behavior of marine organisms. This review seeks to (1) summarize the current knowledge of sensory impairment caused by ocean acidification, (2) discuss potential mechanisms behind this disruption, and (3) analyze the expected taxa differences in sensitivities to elevated CO2 conditions. Although a lack of standardized methodology makes cross-study comparisons challenging, trends and biases arise from this synthesis including a substantial focus on vertebrates, larvae or juveniles, the reef ecosystem, and chemosensory perception. Future studies must broaden the scope of the field by diversifying the taxa and ecosystems studied, incorporating ontogenetic comparisons, and focusing on cryptic sensory systems such as electroreception, magnetic sense, and the lateral line system. A discussion of possible mechanisms reveals GABAA receptor reversal as the conspicuous physiological mechanism. However, the potential remains for alternative disruption through structure or cue changes. Finally, a taxonomic comparison of physiological complexity reveals few trends in sensory sensitivities to lowered pH, but we hypothesize potential correlations relating to habitat, life history or relative use of sensory systems. Elevated CO2, in concordance with other global and local stressors, has the potential to drastically shift community composition and structure. Therefore research addressing the extent of sensory impairment, the underlying mechanisms, and the differences between taxa is vital for improved predictions of organismal response to ocean acidification. PMID- 28575441 TI - Transmembrane Motions of PglB Induced by LLO are Coupled with EL5 Loop Conformational Changes Necessary for OST Activity. AB - N-linked glycosylation is an enzymatic reaction where an oligosaccharide is transferred en bloc onto an asparagine residue of an acceptor polypeptide, catalyzed by oligosaccharyltransferase (OST). Despite the available crystal structures, the role of the external loop EL5, which is critical for the catalytic cycle, is still enigmatic as EL5 in the crystal structures is partially absent or blocks a pathway of lipid-linked oligosaccharide to the active site. Here we report the molecular origin of EL5 conformational changes through a series of molecular dynamics simulations of a bacterial OST, Campylobacter lari PglB. The simulations reveal that the isoprenoid moiety of lipid-linked oligosaccharide favorably binds to a hydrophobic groove of the PglB transmembrane domain. This binding triggers the conformational changes of the transmembrane domain and subsequently impairs the structural stability of EL5, leading to disordered EL5 with open conformations that are required for correct placement of the oligosaccharide in the active site. PMID- 28575439 TI - Mediator binds to boundaries of chromosomal interaction domains and to proteins involved in DNA looping, RNA metabolism, chromatin remodeling, and actin assembly. AB - Mediator is a multi-unit molecular complex that plays a key role in transferring signals from transcriptional regulators to RNA polymerase II in eukaryotes. We have combined biochemical purification of the Saccharomyces cerevisiae Mediator from chromatin with chromatin immunoprecipitation in order to reveal Mediator occupancy on DNA genome-wide, and to identify proteins interacting specifically with Mediator on the chromatin template. Tandem mass spectrometry of proteins in immunoprecipitates of mediator complexes revealed specific interactions between Mediator and the RSC, Arp2/Arp3, CPF, CF 1A and Lsm complexes in chromatin. These factors are primarily involved in chromatin remodeling, actin assembly, mRNA 3' end processing, gene looping and mRNA decay, but they have also been shown to enter the nucleus and participate in Pol II transcription. Moreover, we have found that Mediator, in addition to binding Pol II promoters, occupies chromosomal interacting domain (CID) boundaries and that Mediator in chromatin associates with proteins that have been shown to interact with CID boundaries, such as Sth1, Ssu72 and histone H4. This suggests that Mediator plays a significant role in higher-order genome organization. PMID- 28575442 TI - Negative Symptom Therapeutics. PMID- 28575443 TI - Accelerating Biomedical Discoveries through Rigor and Transparency. AB - Difficulties in reproducing published research findings have garnered a lot of press in recent years. As a funder of biomedical research, the National Institutes of Health (NIH) has taken measures to address underlying causes of low reproducibility. Extensive deliberations resulted in a policy, released in 2015, to enhance reproducibility through rigor and transparency. We briefly explain what led to the policy, describe its elements, provide examples and resources for the biomedical research community, and discuss the potential impact of the policy on translatability with a focus on research using animal models. Importantly, while increased attention to rigor and transparency may lead to an increase in the number of laboratory animals used in the near term, it will lead to more efficient and productive use of such resources in the long run. The translational value of animal studies will be improved through more rigorous assessment of experimental variables and data, leading to better assessments of the translational potential of animal models, for the benefit of the research community and society. PMID- 28575446 TI - Transgender Sterilisation Requirements in Europe. AB - The possibility of individuals procreating post-transition has long stalked debates on transgender rights. In 1972, Sweden became the first European jurisdiction to formally acknowledge preferred gender. Under the original Swedish law, applicants for gender recognition were explicitly required to prove an incapacity to reproduce-either through natural infertility or through a positive act of sterilisation. Across the Council of Europe, 20 countries continue to enforce a sterilisation requirement. When considering reforms to their current gender recognition rules as recently as 2015, the Polish executive and the Finnish legislature both rejected proposals to remove mandatory infertility provisions. This article critiques the rationales for transgender sterilisation in Europe. It places transgender reproduction, and non-traditional procreation, in the wider context of European equality and family law. Adopting a highly inter disciplinary framework, the article explores legal, social, medical, and moral arguments in favour of sterilisation, and exposes the weak intellectual and evidential basis for the current national laws. The article ultimately proposes a new departure for Europe's attitude towards transgender parenting, and argues that sterilisation should not be a pre-condition for legal recognition. PMID- 28575444 TI - Intrinsically disordered RGG/RG domains mediate degenerate specificity in RNA binding. AB - RGG/RG domains are the second most common RNA binding domain in the human genome, yet their RNA-binding properties remain poorly understood. Here, we report a detailed analysis of the RNA binding characteristics of intrinsically disordered RGG/RG domains from Fused in Sarcoma (FUS), FMRP and hnRNPU. For FUS, previous studies defined RNA binding as mediated by its well-folded domains; however, we show that RGG/RG domains are the primary mediators of binding. RGG/RG domains coupled to adjacent folded domains can achieve affinities approaching that of full-length FUS. Analysis of RGG/RG domains from FUS, FMRP and hnRNPU against a spectrum of contrasting RNAs reveals that each display degenerate binding specificity, while still displaying different degrees of preference for RNA. PMID- 28575447 TI - Who should we trust? PMID- 28575445 TI - Quaternary interactions and supercoiling modulate the cooperative DNA binding of AGT. AB - Human O6-alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O6 alkylguanine and O4-alkylthymine adducts in single-stranded and duplex DNAs. The search for these lesions, through a vast excess of competing, unmodified genomic DNA, is a mechanistic challenge that may limit the repair rate in vivo. Here, we examine influences of DNA secondary structure and twist on protein-protein interactions in cooperative AGT complexes formed on lesion-free DNAs that model the unmodified parts of the genome. We used a new approach to resolve nearest neighbor (nn) and long-range (lr) components from the ensemble-average cooperativity, omegaave. We found that while nearest-neighbor contacts were significant, long-range interactions dominated cooperativity and this pattern held true whether the DNA was single-stranded or duplex. Experiments with single plasmid topoisomers showed that the average cooperativity was sensitive to DNA twist, and was strongest when the DNA was slightly underwound. This suggests that AGT proteins are optimally juxtaposed when the DNA is near its torsionally relaxed state. Most striking was the decline of binding stoichiometry with linking number. As stoichiometry and affinity differences were not correlated, we interpret this as evidence that supercoiling occludes AGT binding sites. These features suggest that AGT's lesion-search distributes preferentially to sites containing torsionally-relaxed DNA, in vivo. PMID- 28575448 TI - Bacillus subtilis DNA polymerases, PolC and DnaE, are required for both leading and lagging strand synthesis in SPP1 origin-dependent DNA replication. AB - Firmicutes have two distinct replicative DNA polymerases, the PolC leading strand polymerase, and PolC and DnaE synthesizing the lagging strand. We have reconstituted in vitro Bacillus subtilis bacteriophage SPP1 theta-type DNA replication, which initiates unidirectionally at oriL. With this system we show that DnaE is not only restricted to lagging strand synthesis as previously suggested. DnaG primase and DnaE polymerase are required for initiation of DNA replication on both strands. DnaE and DnaG synthesize in concert a hybrid RNA/DNA 'initiation primer' on both leading and lagging strands at the SPP1 oriL region, as it does the eukaryotic Pol alpha complex. DnaE, as a RNA-primed DNA polymerase, extends this initial primer in a reaction modulated by DnaG and one single-strand binding protein (SSB, SsbA or G36P), and hands off the initiation primer to PolC, a DNA-primed DNA polymerase. Then, PolC, stimulated by DnaG and the SSBs, performs the bulk of DNA chain elongation at both leading and lagging strands. Overall, these modulations by the SSBs and DnaG may contribute to the mechanism of polymerase switch at Firmicutes replisomes. PMID- 28575449 TI - Efficacy of a poly-aggregated formulation of amphotericin B in treating systemic sporotrichosis caused by Sporothrix brasiliensis. AB - In severe cases of sporotrichosis, it is recommended to use amphotericin B deoxycholate (D-AMB) or its lipid formulations and/or in association with itraconazole (ITC). Our aim was to evaluate the antifungal efficacy of a poly aggregated amphotericin B (P-AMB), a nonlipid formulation, compared with D-AMB on systemic sporotrichosis caused by Sporothrix brasiliensis. In vitro assays showed that Sporothrix schenckii sensu stricto and S. brasiliensis yeast clinical isolates were susceptible to low concentrations of P-AMB and D-AMB. Although P AMB presented a higher minimal inhibitory concentration (MIC) compared to D-AMB, its cytotoxic effect on renal cells and erythrocytes was lower. For the in vivo assays, male BALB/c mice were intravenously infected with S. brasiliensis yeasts, and P-AMB or D-AMB was administered 3 days post-infection. The efficacy of five therapeutic regimens was tested: intravenous monotherapy with P-AMB or D-AMB, intravenous pulsed-therapy with P-AMB or D-AMB, and intravenous therapy with P AMB, followed by oral ITC. These treatments increased murine survival and controlled the fungal burden in the liver, spleen, lungs, and kidneys. However, only D-AMB monotherapy or the pulsed-therapies with D-AMB or P-AMB led to 100% survival of the mice 45 days post-infection; only pulsed administration of D-AMB was able to control the fungal load in all organs 45 days post-infection. Accordingly, the histopathological findings showed reductions in the fungal burden and inflammatory reactions in these treatment regimens. Together, our results suggest that the P-AMB formulation could be considered as an alternative drug to D-AMB for treating disseminated sporotrichosis. PMID- 28575450 TI - Universal attenuators and their interactions with feedback loops in gene regulatory networks. AB - Using a combination of mathematical modelling, statistical simulation and large scale data analysis we study the properties of linear regulatory chains (LRCs) within gene regulatory networks (GRNs). Our modelling indicates that downstream genes embedded within LRCs are highly insulated from the variation in expression of upstream genes, and thus LRCs act as attenuators. This observation implies a progressively weaker functionality of LRCs as their length increases. When analyzing the preponderance of LRCs in the GRNs of Escherichia coli K12 and several other organisms, we find that very long LRCs are essentially absent. In both E. coli and M. tuberculosis we find that four-gene LRCs are intimately linked to identical feedback loops that are involved in potentially chaotic stress response, indicating that the dynamics of these potentially destabilising motifs are strongly restrained under homeostatic conditions. The same relationship is observed in a human cancer cell line (K562), and we postulate that four-gene LRCs act as 'universal attenuators'. These findings suggest a role for long LRCs in dampening variation in gene expression, thereby protecting cell identity, and in controlling dramatic shifts in cell-wide gene expression through inhibiting chaos-generating motifs. PMID- 28575451 TI - Intra and Interspecific Variations of Gene Expression Levels in Yeast Are Largely Neutral: (Nei Lecture, SMBE 2016, Gold Coast). AB - It is commonly, although not universally, accepted that most intra and interspecific genome sequence variations are more or less neutral, whereas a large fraction of organism-level phenotypic variations are adaptive. Gene expression levels are molecular phenotypes that bridge the gap between genotypes and corresponding organism-level phenotypes. Yet, it is unknown whether natural variations in gene expression levels are mostly neutral or adaptive. Here we address this fundamental question by genome-wide profiling and comparison of gene expression levels in nine yeast strains belonging to three closely related Saccharomyces species and originating from five different ecological environments. We find that the transcriptome-based clustering of the nine strains approximates the genome sequence-based phylogeny irrespective of their ecological environments. Remarkably, only ~0.5% of genes exhibit similar expression levels among strains from a common ecological environment, no greater than that among strains with comparable phylogenetic relationships but different environments. These and other observations strongly suggest that most intra and interspecific variations in yeast gene expression levels result from the accumulation of random mutations rather than environmental adaptations. This finding has profound implications for understanding the driving force of gene expression evolution, genetic basis of phenotypic adaptation, and general role of stochasticity in evolution. PMID- 28575453 TI - Quantitative analysis of phagosome formation and maturation using an Escherichia coli probe expressing a tandem fluorescent protein. AB - Phagosome formation and maturation are essential innate immune mechanisms to engulf and digest foreign particles. To analyze these processes quantitatively, we established a specific Escherichia coli probe expressing a tandem fluorescent protein, comprising glutathione S-transferase fused with monomeric Cherry (mCherry) and monomeric Venus (mVenus). We demonstrated that mVenus was more susceptible to bleaching in an acidic environment than mCherry, and that the mVenus:mCherry fluorescence intensity ratio can be used to monitor phagosomal pH changes during maturation. Using this probe, we revealed that synaptosomal associated protein of 23 kDa, a plasma membrane soluble N-ethylmaleimide sensitive factor attachment protein receptor protein, actively regulated phagocytosis of E. coli and subsequent phagosome maturation in macrophages. Our results indicated that this probe has the potential to be a powerful tool in understanding the molecular mechanisms of phagosome formation and maturation. PMID- 28575452 TI - Selective disruption of an oncogenic mutant allele by CRISPR/Cas9 induces efficient tumor regression. AB - Approximately 15% of non-small cell lung cancer cases are associated with a mutation in the epidermal growth factor receptor (EGFR) gene, which plays a critical role in tumor progression. With the goal of treating mutated EGFR mediated lung cancer, we demonstrate the use of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) system to discriminate between the oncogenic mutant and wild-type EGFR alleles and eliminate the carcinogenic mutant EGFR allele with high accuracy. We targeted an EGFR oncogene harboring a single-nucleotide missense mutation (CTG > CGG) that generates a protospacer-adjacent motif sequence recognized by the CRISPR/Cas9 derived from Streptococcus pyogenes. Co-delivery of Cas9 and an EGFR mutation specific single-guide RNA via adenovirus resulted in precise disruption at the oncogenic mutation site with high specificity. Furthermore, this CRISPR/Cas9 mediated mutant allele disruption led to significantly enhanced cancer cell killing and reduced tumor size in a xenograft mouse model of human lung cancer. Taken together, these results indicate that targeting an oncogenic mutation using CRISPR/Cas9 offers a powerful surgical strategy to disrupt oncogenic mutations to treat cancers; similar strategies could be used to treat other mutation associated diseases. PMID- 28575454 TI - Comparison Between Chronic Migraine and Temporomandibular Disorders in Pain Related Disability and Fear-Avoidance Behaviors. AB - Objective: To compare patients with chronic migraine (CM) and chronic temporomandibular disorders (TMD) on disability, pain, and fear avoidance factors and to associate these variables within groups. Design: Descriptive, cross sectional study. Settings: A neurology department and a temporomandibular disorders consult in a tertiary care center. Subjects: A total of 50 patients with CM and 51 patients with chronic TMD, classified by international criteria classifications. Methods: The variables evaluated included pain intensity (visual analog scale [VAS]), neck disability (NDI), craniofacial pain and disability (CF PDI), headache impact (HIT-6), pain catastrophizing (PCS), and kinesiophobia (TSK 11). Results: Statistically significant differences were found between the CM group and the chronic TMD group in CF-PDI (P < 0.001), PCS (P = 0.03), and HIT-6 (P < 0.001); however, there were no differences between the CM group and the VAS, NDI, and TSK-11 groups (P > 0.05). For the chronic TMD group, the combination of NDI and TSK-11 was a significant covariate model of CF-PDI (adjusted R2 = 0.34). In the CM group, the regression model showed that NDI was a significant predictive factor for HIT-6 (adjusted R2 = 0.19). Conclusions: Differences between the CM group and the chronic TMD group were found in craniofacial pain and disability, pain catastrophizing, and headache impact, but they were similar for pain intensity, neck disability, and kinesiophobia. Neck disability and kinesiophobia were covariates of craniofacial pain and disability (34% of variance) for chronic TMD. In the CM group, neck disability was a predictive factor for headache impact (19.3% of variance). PMID- 28575456 TI - Letter: Washing and Irrigation: Faithful Allies of the Neurosurgeon for Endoscopy Hemostasis. PMID- 28575455 TI - Adolescent Alcohol Exposure-Induced Changes in Alpha-Melanocyte Stimulating Hormone and Neuropeptide Y Pathways via Histone Acetylation in the Brain During Adulthood. AB - Background: Adolescent intermittent ethanol exposure causes long-lasting alterations in brain epigenetic mechanisms. Melanocortin and neuropeptide Y signaling interact and are affected by ethanol exposure in the brain. Here, the persistent effects of adolescent intermittent ethanol on alpha-melanocyte stimulating hormone, melanocortin 4 receptor, and neuropeptide Y expression and their regulation by histone acetylation mechanisms were investigated in adulthood. Methods: Male rats were exposed to adolescent intermittent ethanol (2 g/kg, i.p.) or volume-matched adolescent intermittent saline from postnatal days 28 to 41 and allowed to grow to postnatal day 92. Anxiety-like behaviors were measured by the elevated plus-maze test. Brain regions from adult rats were used to examine changes in alpha-melanocyte stimulating hormone, melanocortin 4 receptor, and neuropeptide Y expression and the histone acetylation status of their promoters. Results: Adolescent intermittent ethanol-exposed adult rats displayed anxiety-like behaviors and showed increased pro-opiomelanocortin mRNA levels in the hypothalamus and increased melanocortin 4 receptor mRNA levels in both the amygdala and hypothalamus compared with adolescent intermittent saline exposed adult rats. The alpha-Melanocyte stimulating hormone and melanocortin 4 receptor protein levels were increased in the central and medial nucleus of the amygdala, paraventricular nucleus, and arcuate nucleus of the hypothalamus in adolescent intermittent ethanol-exposed compared with adolescent intermittent saline-exposed adult rats. Neuropeptide Y protein levels were decreased in the central and medial nucleus of the amygdala of adolescent intermittent ethanol exposed compared with adolescent intermittent saline-exposed adult rats. Histone H3K9/14 acetylation was decreased in the neuropeptide Y promoter in the amygdala but increased in the melanocortin 4 receptor gene promoter in the amygdala and the melanocortin 4 receptor and pro-opiomelanocortin promoters in the hypothalamus of adolescent intermittent ethanol-exposed adult rats compared with controls. Conclusions: Increased melanocortin and decreased neuropeptide Y activity due to changes in histone acetylation in emotional brain circuitry may play a role in adolescent intermittent ethanol-induced anxiety phenotypes in adulthood. PMID- 28575457 TI - Characterizing Adult Cervical Deformity and Disability Based on Existing Cervical and Adult Deformity Classification Schemes at Presentation and Following Correction. AB - BACKGROUND: Adult cervical deformity (ACD) classifications have not been implemented in a prospective ACD population and in conjunction with adult spinal deformity (ASD) classifications. OBJECTIVE: To characterize cervical deformity type and malalignment with 2 classifications (Ames-ACD and Schwab-ASD). METHODS: Retrospective review of a prospective multicenter ACD database. Inclusion: patients >=18 yr with pre- and postoperative radiographs. Patients were classified with Ames-ACD and Schwab-ASD schemes. Ames-ACD descriptors (C = cervical, CT = cervicothoracic, T = thoracic, S = coronal, CVJ = craniovertebral) and alignment modifiers (cervical sagittal vertical axis [cSVA], T1 slope minus cervical lordosis [TS-CL], modified Japanese Ortphopaedic Association [mJOA] score, horizontal gaze) were assigned. Schwab-ASD curve type stratification and modifier grades were also designated. Deformity and alignment group distributions were compared with Pearson chi2/ANOVA. RESULTS: Ames-ACD descriptors in 84 patients: C = 49 (58.3%), CT = 20 (23.8%), T = 9 (10.7%), S = 6 (7.1%). cSVA modifier grades differed in C, CT, and T deformities (P < .019). In C, TS-CL grade prevalence differed (P = .031). Among Ames-ACD modifiers, high (1+2) cSVA grades differed across deformities (C = 47.7%, CT = 89.5%, T = 77.8%, S = 50.0%, P = .013). Schwab-ASD curve type and presence (n = 74, T = 2, L = 6, D = 2) differed significantly in S deformities (P < .001). Higher Schwab-ASD pelvic incidence minus lumbar lordosis grades were less likely in Ames-ACD CT deformities (P = .027). Higher pelvic tilt grades were greater in high (1+2) cSVA (71.4% vs 36.0%, P = .015) and high (2+3) mJOA (24.0% vs 38.1%, P = .021) scores. Postoperatively, C and CT deformities had a trend toward lower cSVA grades, but only C deformities differed in TS-CL grade prevalence (0 = 31.3%, 1 = 12.2%, 2 = 56.1%, P = .007). CONCLUSION: Cervical deformities displayed higher TS-CL grades and different cSVA grade distributions. Preoperative associations with global alignment modifiers and Ames-ACD descriptors were observed, though only cervical modifiers showed postoperative differences. PMID- 28575458 TI - Letter: Genealogy of Training in Vascular Neurosurgery. PMID- 28575459 TI - Intracranial Infectious and Inflammatory Diseases Presenting as Neurosurgical Pathologies. AB - There are many infectious and inflammatory processes affecting the central nervous system that can simulate other neurosurgical pathologies (e.g. tumor) and may precipitate a brain biopsy for definitive diagnosis if not suspected a priori. The challenge for the healthcare team is to recognize imaging features that support a nonsurgical pathology to avoid unnecessary interventions. This review aims to give a general overview of some common inflammatory and infectious entities that affect the central nervous system, with illustrative examples and highlighting important pearls and pitfalls. PMID- 28575460 TI - Testing Familial Transmission of Smoking With Two Different Research Designs. AB - Introduction: Classical twin studies show that smoking is heritable. To determine if shared family environment plays a role in addition to genetic factors, and if they interact (G*E), we use a children-of-twins design. In a second sample, we measure genetic influence with polygenic risk scores (PRS) and environmental influence with a question on exposure to smoking during childhood. Methods: Data on smoking initiation were available for 723 children of 712 twins from the Netherlands Twin Register (64.9% female, median birth year 1985). Children were grouped in ascending order of risk, based on smoking status and zygosity of their twin-parent and his/her co-twin: never smoking twin-parent with a never smoking co-twin; never smoking twin-parent with a smoking dizygotic co-twin; never smoking twin-parent with a smoking monozygotic co-twin; and smoking twin-parent with a smoking or never smoking co-twin. For 4072 participants from the Netherlands Twin Register (67.3% female, median birth year 1973), PRS for smoking were computed and smoking initiation, smoking heaviness, and exposure to smoking during childhood were available. Results: Patterns of smoking initiation in the four group children-of-twins design suggested shared familial influences in addition to genetic factors. PRS for ever smoking were associated with smoking initiation in all individuals. PRS for smoking heaviness were associated with smoking heaviness in individuals exposed to smoking during childhood, but not in non-exposed individuals. Conclusions: Shared family environment influences smoking, over and above genetic factors. Genetic risk of smoking heaviness was only important for individuals exposed to smoking during childhood, versus those not exposed (G*E). Implications: This study adds to the very few existing children-of-twins (CoT) studies on smoking and combines a CoT design with a second research design that utilizes polygenic risk scores and data on exposure to smoking during childhood. The results show that shared family environment affects smoking behavior over and above genetic factors. There was also evidence for gene-environment interaction (G*E) such that genetic risk of heavy versus light smoking was only important for individuals who were also exposed to (second hand) smoking during childhood. Together, these findings give additional incentive to recommending parents not to expose their children to cigarette smoking. PMID- 28575461 TI - Adjacent Segment Degeneration After Anterior Cervical Discectomy and Fusion With an Autologous Iliac Crest Graft: A Magnetic Resonance Imaging Study of 59 Patients With a Mean Follow-up of 27 Years. AB - BACKGROUND: Anterior cervical decompression and fusion (ACDF) is a widely accepted surgical technique for the treatment of degenerative disc disease. ACDF is associated with adjacent segment degeneration (ASD). OBJECTIVE: To assess whether physiological aging of the spine would overcome ASD by comparing adjacent to adjoining segments more than 18 yr after ACDF. METHODS: Magnetic resonance imaging of 59 (36 male, 23 female) patients who underwent ACDF was performed to assess degeneration. The mean follow-up was 27 yr (18-45 yr). Besides measuring the disc height, a 5-step grading system (segmental degeneration index [SDI]) including disc signal intensity, anterior and posterior disc protrusion, narrowing of the disc space, and foraminal stenosis was used to assess the grade of adjacent and adjoining segments. RESULTS: The SDI of cranial and caudal adjacent segments was significantly higher compared to adjoining segments (P < .001). The disc height of cranial and caudal adjacent segments was significantly lower compared to adjoining segments (P < .001, P < .01). The SDI of adjacent segments in patients with repeat cervical procedure was significantly higher than in patients without repeat procedure (P = .02, P = .01). The disc height of the cranial adjacent segments in patients with repeat procedure was significantly lower than in patients without repeat procedure (P = .01). CONCLUSION: The physiological aging of the cervical spine does not overcome ASD. The disc height and the SDI in adjacent segment are significantly worse compared to adjoining segments. Patients who underwent repeat procedure had even worse findings of disc height and SDI. PMID- 28575462 TI - Sharing and helping: predictors of adolescents' willingness to share diabetes personal health information with peers. AB - Objective: Sharing personal information about type 1 diabetes (T1D) can help adolescents obtain social support, enhance social learning, and improve self care. Diabetes technologies, online communities, and health interventions increasingly feature data-sharing components. This study examines factors underlying adolescents' willingness to share personal T1D information with peers. Materials and Methods: Participants were 134 adolescents (12-17 years of age; 56% female) who completed an online survey regarding experiences helping others with T1D, perceived social resources, beliefs about the value of sharing information and helping others, and willingness to share T1D information. Hemoglobin A1c values were obtained from medical records. Results: Adolescents were more willing to share how they accomplished T1D tasks than how often they completed them, and least willing to share glucose control status. In multivariate analyses, sharing/helping beliefs (beta = 0.26, P < .01) and glucose control (HbA1c value; beta = -0.26, P < .01) were related to greater willingness to share personal health information. Glucose control moderated relationships such that adolescents with worse A1c values had stronger relationships between sharing/helping beliefs and willingness to share (beta = 0.18, P < .05) but weaker relationships between helping experience and willingness to share (beta = -0.22, P = .07). Discussion: Many adolescents with T1D are willing to share personal health information, particularly if they have better diabetes health status and a stronger belief in the benefits of sharing. Conclusion: Social learning and social media components may improve intervention participation, engagement, and outcomes by boosting adolescents' beliefs about the benefits of sharing information and helping others. PMID- 28575463 TI - Impact of working hours on sleep and mental health. AB - Background: The number of hours people are required to work has a pervasive influence on both physical and mental health. Excessive working hours can also negatively affect sleep quality. The impact at work of mental health problems can have serious consequences for individuals' as well as for organizations' productivity. Aims: To evaluate differences in sleep quality and anxiety and depression symptoms between longer working hours group (LWHG) and regular working hours group (RWHG). To examine factors influencing weekly working hours, sleep quality and anxiety and depressive symptoms. Methods: Participants were divided into two groups, RWHG and LWHG, based on working hours, with a cut-off of 48 h per week. We used the Hospital Anxiety and Depression Scale (HADS) to assess anxiety and depression symptoms and the Pittsburgh Sleep Quality Index (PSQI) to measure the quality and patterns of sleep. Results: The response rate was 23%. Among the 429 study participants, those in the LWHG group (n = 256, 53%) had significantly more depressive and anxiety symptoms and worse sleep quality than those in RWHG (n = 223, 47%). Working time was significantly positively correlated with higher corporate position and HADS scores. Moreover, HADS scores were positively correlated with PSQI scores and negatively correlated with age. Conclusions: This study suggests that longer working hours are associated with poorer mental health status and increasing levels of anxiety and depression symptoms. There was a positive correlation between these symptoms and sleep disturbances. PMID- 28575465 TI - On wagging tales about causal inference. PMID- 28575464 TI - Phase II trial of dacomitinib, a pan-human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification. AB - Background: We conducted a multicenter, 2-stage, open-label, phase II trial to assess the efficacy and safety of dacomitinib in adult patients with recurrent glioblastoma (GB) and epidermal growth factor receptor gene (EGFR) amplification with or without variant III (EGFRvIII) deletion. Methods: Patients with first recurrence were enrolled in 2 cohorts. Cohort A included patients with EGFR gene amplification without EGFRvIII mutation. Cohort B included patients with EGFR gene amplification and EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs). Primary endpoint was progression-free survival (PFS; RANO criteria) at 6 months (PFS6). Results: Thirty patients in Cohort A and 19 in Cohort B were enrolled. Median age was 59 years (range 39-81), 65.3% were male, and Eastern Cooperative Oncology Group Performance Status 0/1/2 were 10.2%/65.3%/24.5%, respectively. PFS6 was 10.6% (Cohort A: 13.3%; Cohort B: 5.9%) with a median PFS of 2.7 months (Cohort A: 2.7 mo; Cohort B: 2.6 mo). Four patients were progression free at 6 months and 3 patients were so at 12 months. Median overall survival was 7.4 months (Cohort A: 7.8 mo; Cohort B: 6.7 mo). The best overall response included 1 complete response and 2 partial responses (4.1%). Stable disease was observed in 12 patients (24.5%: eight in Cohort A and four in Cohort B). Diarrhea and rash were the most common AEs; 20 (40.8%) patients experienced grade 3-4 drug-related AEs. Conclusions: Dacomitinib has a limited single-agent activity in recurrent GB with EGFR amplification. The detailed molecular characterization of the 4 patients with response in this trial can be useful to select patients who could benefit from dacomitinib. PMID- 28575466 TI - Dose-response mutation and spectrum analyses reveal similar responses at two microsatellite loci in benzo(a)pyrene-exposed mouse spermatogonia. AB - Identifying chemical exposures that can cause germline mutations is important as these mutations can be inherited, impacting both individual and population health. However, germline mutations are extremely rare and difficult to detect. Chemically induced germline mutations can be detected through analysis of highly unstable tandem repeat DNA. We recently developed a single-molecule PCR (SM-PCR) approach to quantify mutations at a mouse microsatellite locus (Mm2.2.1) in sperm for such purposes. In this study, we refine this approach through the combined analysis of mouse microsatellites Mm2.2.1 and Mm19.2.3. Mice were exposed to 0, 25, 50 or 100 mg/kg/day benzo(a)pyrene (BaP) by oral gavage for 28 days and sperm sampled 42 days after the end of exposure to measure effects on dividing spermatogonia. DNA was diluted to a single genome per PCR well for amplification of microsatellites in singleplex and multiplex reactions, and alleles were sized to identify mutations using capillary electrophoresis. Analysis of ~300-500 molecules per animal at both microsatellite loci, when tested individually, showed a ~2-fold increase in mutations relative to the controls at both the 50 and 100 mg/kg/day BaP doses. Multiplex SM-PCR revealed similar increases in mutation frequencies in both microsatellites. Comparison with results from a previous lacZ mutation assay conducted on the same mice revealed that although microsatellite mutations are a sensitive endpoint for detecting changes in mutation frequencies at lower doses, they appear to be saturable and thus have a reduced dynamic range. These results confirm that BaP is a male germ cell mutagen that broadly impacts tandem repeat DNA. Likewise, addition of a second hypervariable microsatellite increases the sensitivity of this assay. PMID- 28575467 TI - Arousability and Fall Risk During Forced Awakenings From Nocturnal Sleep Among Healthy Males Following Administration of Zolpidem 10 mg and Doxepin 6 mg: A Randomized, Placebo-Controlled, Four-Way Crossover Trial. AB - Study Objectives: To examine and compare the arousability threshold and fall risk upon awakening of doxepin (6 mg) versus zolpidem (10 mg). Methods: A total of 52 healthy adult males were included in a double-blind, placebo-controlled, four-way crossover study. The experimental procedure included four nights with polysomnography in the lab (zolpidem, doxepin, and their respective placebo conditions). Arousability was measured using an auditory awakening threshold delivered at the peak-plasma concentration for the active hypnotics and at matched times for the respective placebo conditions. Fall risk during the night was measured following awakening using the Berg Balance Scale and the Tandem Walk Task. Results: Both arousability and fall risk were lower in the doxepin condition compared to the zolpidem condition. Furthermore, arousability and fall risk for doxepin did not differ significantly from the placebo conditions. A significantly greater proportion of participants in the zolpidem condition (63.5%) did not wake until receiving the loudest tone (110 dB) as compared to the doxepin (17.6%) and placebo conditions (17.3%, 5.8%). Conclusions: Results suggest that zolpidem has greater risks for balance and awakening threshold compared with low-dose doxepin. Future prospective studies should extend results to clinical samples with population-level risk of injury and arousability. PMID- 28575469 TI - Comment on: Increased inflammation and disease activity among current cigarette smokers with rheumatoid arthritis: a cross-sectional analysis of US veterans: reply. PMID- 28575468 TI - Evaluation of Lure Combinations Containing Essential Oils and Volatile Spiroketals for Detection of Host-Seeking Xyleborus glabratus (Coleoptera: Curculionidae: Scolytinae). AB - The invasive redbay ambrosia beetle, Xyleborus glabratus Eichhoff (Coleoptera: Curculionidae: Scolytinae), vectors the fungal pathogen (Raffaelea lauricola) that causes laurel wilt, a disease responsible for widespread mortality of trees in the Lauraceae in the southeastern United States. Early detection of incipient vector populations may allow for management practices that could successfully mitigate damage. Developing new, highly effective attractants is a priority for improving sensitivity of early detection efforts. In this study, two field tests were conducted to evaluate combinations of commercially available bark and ambrosia beetle lures for enhanced attraction of host-seeking female X. glabratus. In addition, lures were compared for capture of nontarget scolytine beetles. In the first experiment, traps baited with a combination of cubeb oil, conophthorin, chalcogran, and ethanol captured greater numbers of X. glabratus than cubeb oil alone, the current standard attractant. However, this combination lure resulted in higher nontarget scolytine captures than with the cubeb lure. In the second field test, an oil enriched in the sesquiterpene alpha-copaene caught significantly more X. glabratus than other lures currently available for monitoring this pest. There were no differences in efficacy between cubeb oil lures produced by two different manufacturers, and a combination lure containing copaiba and cubeb oils did not increase captures over the cubeb lure alone. Results of these two tests suggest that increased sensitivity for detection of X. glabratus may be achieved with a multicomponent lure that incorporates alpha copaene, spiroketals, and low release of ethanol. PMID- 28575470 TI - Liver mitochondrial dysfunction and electron transport chain defect induced by high dietary copper in broilers. AB - Copper is an important trace mineral in the diet of poultry due to its biological activity. However, limited information is available concerning the effects of high copper on mitochondrial dysfunction. In this study, 72 broilers were used to investigate the effects of high dietary copper on liver mitochondrial dysfunction and electron transport chain defect. Birds were fed with different concentrations [11, 110, 220, and 330 mg of copper/kg dry matter (DM)] of copper from tribasic copper chloride (TBCC). The experiment lasted for 60 d. Liver tissues on d 60 were subjected to histopathological observation. Additionally, liver mitochondrial function was recorded on d 12, 36, and 60. Moreover, a site specific defect in the electron transport chain in liver mitochondria was also identified by using various chemical inhibitors of mitochondrial respiration. The results showed different degrees of degeneration, mitochondrial swelling, and high-density electrons in hepatocytes. In addition, the respiratory control ratio (RCR) and oxidative phosphorylation rate (OPR) in liver mitochondria increased at first and then decreased in high-dose groups. Moreover, hydrogen peroxide (H2O2) generation velocity in treated groups was higher than that in control group, which were magnified by inhibiting electron transport at Complex IV. The results indicated that high dietary copper could decline liver mitochondrial function in broilers. The presence of a site-specific defect at Complex IV in liver mitochondria may be responsible for liver mitochondrial dysfunction caused by high dietary copper. PMID- 28575471 TI - Serum Cotinine and Hemoglobin A1c Among a National Sample of Adolescents Without Known Diabetes. AB - Introduction: National data suggest tobacco smoke is positively associated with higher glycated hemoglobin (HbA1c) among adults. Our objective was to examine the association between serum cotinine and HbA1c among adolescents without known diabetes. Methods: We assessed adolescents 12-19 years old (N = 11550) who participated in the 1999-2012 National Health and Nutrition Examination Survey. We applied sampling weights while performing multiple linear regression analyses. Results: The prevalence of serum cotinine indicative of no tobacco smoke exposure (TSE, <0.05 ng/mL) was 43.2%, passive TSE (0.05-2.99 ng/mL) was 38.9%, and active TSE (>3 ng/mL) was 17.9% in our sample. Mean (+/- standard error) HbA1c in participants with no TSE was 5.16% (+/-0.01), passive TSE was 5.16% (+/-0.01), and active TSE was 5.14% (+/-0.01). No differences in HbA1c were found between TSE groups including sex, age, race/ethnicity, education, income, and physical activity or the fully adjusted model with waist circumference. We found cotinine * sex (p = .01) and cotinine * age (p = .02) interactions. There was an association between cotinine and HbA1c for males but not females. Within males, participants with cotinine >=3 ng/mL (5.26 +/- 0.02) had higher mean HbA1c than those with cotinine 0.05-2.99 ng/mL and <0.05 ng/mL (both 5.20 +/- 0.01, p <= .02). The negative association between age and HbA1c was stronger for participants with cotinine >=3 ng/mL than participants with cotinine <0.05 ng/mL. Conclusion: No linear association was found between HbA1c and serum cotinine in adolescents overall after adjusting for potential confounders. Differences between TSE groups were found in males. Future research in adolescents should examine chronic TSE over time to examine the potential for development of type 2 diabetes. Implications: TSE has been associated with increased risk for the development of type 2 diabetes among adults. It is unclear if this relationship holds in adolescents. We examined the association between serum cotinine and HbA1c in adolescents without known diabetes who completed the 1999-2012 National Health and Nutrition Examination Survey. Although no association was found between serum cotinine and HbA1c overall while controlling for potential confounding factors, we observed interaction effects that are indicative of TSE influencing HbA1c differentially by sex and age. Reducing TSE in adolescents should be a priority for future tobacco control efforts. PMID- 28575472 TI - Population Aging and Health Trajectories at Older Ages. AB - Objective: This study examines relationships between municipal age structure and two types of self-rated health: general (SRH) and comparison with similar-aged peers (C-SRH). Methods: Using a national sample of almost 5,000 Japanese older adults over two decades, we employ hierarchical growth curve models to estimate health trajectories. For municipal age structure, we consider both the relative prevalence of elderly adults in the local population and the pace of aging over time. Results: Living in the oldest municipalities was generally associated with worse health, particularly between the ages of 70 and 80 years. For SRH, the speed of municipal population aging was also independently associated with worse health. For C-SRH, worse health in older areas was partially explained by less favorable economic conditions in those municipalities. Results also suggest that higher levels of employment and social integration among older adults living in the oldest municipalities operate in the opposite direction. That is, these attributes partially "protect" individuals from other factors that contribute to worse health. Discussion: Relative differences in municipal age structure and the pace of population aging are largely unexplored and potentially important correlates of older adult health. This line of research is increasingly salient in a world with substantial and growing regional variation in population aging. PMID- 28575473 TI - Should Rheumatology be a core discipline of a chronic pain multi-disciplinary team? PMID- 28575474 TI - Don't ignore the green light: exploring diverse roles in plant processes. AB - The pleasant green appearance of plants, caused by their reflectance of wavelengths in the 500-600 nm range, might give the impression that green light is of minor importance in biology. This view persists to an extent. However, there is strong evidence that these wavelengths are not only absorbed but that they also drive and regulate physiological responses and anatomical traits in plants. This review details the existing evidence of essential roles for green wavelengths in plant biology. Absorption of green light is used to stimulate photosynthesis deep within the leaf and canopy profile, contributing to carbon gain and likely crop yield. In addition, green light also contributes to the array of signalling information available to leaves, resulting in developmental adaptation and immediate physiological responses. Within shaded canopies this enables optimization of resource-use efficiency and acclimation of photosynthesis to available irradiance. In this review, we suggest that plants may use these wavelengths not just to optimize stomatal aperture but also to fine-tune whole canopy efficiency. We conclude that all roles for green light make a significant contribution to plant productivity and resource-use efficiency. We also outline the case for using green wavelengths in applied settings such as crop cultivation in LED-based agriculture and horticulture. PMID- 28575476 TI - Depressive Symptoms as a Predictor of Memory Complaints in the PRISM Sample. AB - Objectives : The current study investigated baseline and longitudinal relationships between memory complaints, depressive symptoms, and cognition in older adults. Method : Using the sample from the Personal Reminder Information and Social Management trial, we generated path models predicting self-rated memory complaints measured by the Memory Functioning Questionnaire (MFQ). Results : Our baseline models showed that more depressive symptoms were associated with reporting more frequent forgetting incidents and a greater decline in memory function. The baseline models also revealed that higher scores in a latent cognitive function were associated with reporting a greater decline in memory functioning and a greater use of mnemonics. However, cognitive predictors did not mediate the baseline associations between the MFQ measures and depressive symptoms. Further, these predictors were not able to directly predict the 12 month MFQ measures over and above the baseline effects. Including personality traits (neuroticism and conscientiousness) did not significantly affect the models. Discussion : Our results suggest that memory complaints about frequency of forgetting can be the most reliable indicator of depression risk among the four factors in the MFQ. We discuss theoretical implications for longitudinal relationships between memory complaints, depressive symptoms, and cognitive function in older adults. PMID- 28575477 TI - Regulation of Gene Expression in the Remobilization of Carbon Reserves in Rice Stems During Grain Filling. AB - Carbon reserves in rice straw (stem and sheath) before flowering contribute to a significant portion of grain filling. However, the molecular mechanism of carbon reserve remobilization from straw to grains remains unclear. In this study, super rice LYP9 and conventional rice 9311 showed different carbon reserve remobilization behaviors. The transcriptomic profiles of straws of LYP9 and 9311 were analyzed at three stages of grain filling. Among the differentially expressed genes (DGs), 5,733 genes were uniquely up- or down-regulated at 30 days after anthesis (DAA) between LYP9 and 9311 in comparison with 681 at 10 DAA and 495 at 20 DAA, suggesting that the gene expression profile of LYP9 was very different from that of 9311 at the late stage of grain filling. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene Ontology (GO) classification of DGs both showed that the carbohydrate catabolic pathway, plant hormone signal transduction and photosynthesis pathway were enriched in DGs, suggesting their roles in carbon reserve remobilization, which explains to a certain extent the difference in non-structural carbohydrate content, photosynthesis and ABA content between the two cultivars during grain filling. Further comparative analysis and confirmation by quantitative real-time PCR and enzyme assays suggest that genes involved in trehalose synthesis (trehalose phosphate phosphatase and trehalose 6-phosphate synthase/phosphatase), starch degradation (beta-amylase) and sucrose synthesis (sucrose-phosphate synthase and sucrose synthase) were important for carbon reserve remobilization, whereas ABA content was determined by the counteraction of NCED1 and ABA8ox1 genes. The higher expression level of all these genes and ABA content in 9311 resulted in better efficiency of carbon reserve remobilization in 9311 than in LYP9. PMID- 28575478 TI - The Preservation of Cognition 1 Year After Carotid Endarterectomy in Patients With Prior Cognitive Decline. AB - BACKGROUND: Vascular cognitive decline is critically important in the course of atherosclerosis and stroke. OBJECTIVE: To explore the hypothesis that carotid endarterectomy (CEA) by removing an unstable plaque may slow the course of vascular cognitive decline in both symptomatic and asymptomatic patients. METHODS: Patients with clinically significant (>60%) carotid stenosis were studied preop and 1 yr post-CEA for clinical symptoms, vascular cognitive decline, instability of carotid plaque-presence of microemboli, brain white matter changes, and medical risk factors. RESULTS: Forty-six percent were classically symptomatic. All patients showed vascular cognitive decline at presentation which correlated with degree of plaque instability. Significant white matter hyperintensity changes (48.7%) and cerebral emboli (25%) were also seen at baseline in both classically symptomatic and asymptomatic. One year after CEA, both groups showed no decline in cognitive function and significant improvement in 2 tests (P = .028 and P = .013). Brain white matter hyperintensities were unchanged. Microemboli were reduced but remained present (17.86%). Improvement was predicted by the presence of hypertension (P = .001), or less advanced cognitive decline preoperatively (P = .009). CONCLUSION: This study demonstrates the importance of vascular cognitive decline in atherosclerotic disease. This is a function of the degree of instability of the atherosclerotic plaque more than the presence of stroke symptoms. It further suggests that atherosclerotic vascular cognitive decline need not be inevitable, and may be modified by treating hypertension and removal of the unstable plaque. This highlights the need for continued research on the cognitive effects of cerebrovascular disease and the synergistic benefits of intensive medical and surgical therapy. PMID- 28575475 TI - Abnormal Brain Activation During Theory of Mind Tasks in Schizophrenia: A Meta Analysis. AB - Social cognition abilities are severely impaired in schizophrenia (SZ). The current meta-analysis used foci of 21 individual studies on functional abnormalities in the schizophrenic brain in order to identify regions that reveal convergent under- or over-activation during theory of mind (TOM) tasks. Studies were included in the analyses when contrasting tasks that require the processing of mental states with tasks which did not. Only studies that investigated patients with an ICD or DSM diagnosis were included. Quantitative voxel-based meta-analyses were done using Seed-based d Mapping software. Common TOM regions like medial-prefrontal cortex and temporo-parietal junction revealed abnormal activation in schizophrenic patients: Under-activation was identified in the medial prefrontal cortex, left orbito-frontal cortex, and in a small section of the left posterior temporo-parietal junction. Remarkably, robust over-activation was identified in a more dorsal, bilateral section of the temporo-parietal junction. Further abnormal activation was identified in medial occipito-parietal cortex, right premotor areas, left cingulate gyrus, and lingual gyrus. The findings of this study suggest that SZ patients simultaneously show over- and under-activation in TOM-related regions. Especially interesting, temporo-parietal junction reveals diverging activation patterns with an under-activating left posterior and an over-activating bilateral dorsal section. In conclusion, SZ patients show less specialized brain activation in regions linked to TOM and increased activation in attention-related networks suggesting compensatory effects. PMID- 28575479 TI - The Effect of Word Frequency on Phonemic Accuracy in Children With Cochlear Implants and Peers With Typical Levels of Hearing. AB - The frequency of occurrence of words and sounds has a pervasive influence on typically developing children's language acquisition. For instance, highly frequent words appear earliest in a child's lexicon, and highly frequent phonemes are produced more accurately. This study evaluates (a) whether word frequency influences word accuracy and (b) whether this is also the case for children with a history of auditory deprivation. More specifically, the influence of word frequency on phonemic accuracy is examined in deaf children with a cochlear implant (CI), and compared to age-matched children with typical hearing, between word onset and age 7. Results show that highly frequent words are produced more accurately, except for words in the highest frequency regions (i.e., predominantly closed-class words). This effect is more pronounced in children with typical hearing when compared with children with CI. Thus, children with CI are sensitive to word frequency, but to a lesser extent than peers with typical hearing. PMID- 28575480 TI - DRB4 dsRBD1 drives dsRNA recognition in Arabidopsis thaliana tasi/siRNA pathway. AB - In Arabidopsis thaliana, endogenous trans-acting and exogenous siRNA pathways are initiated by the interaction of DRB4 with trigger dsRNA. Further, DCL4:DRB4 complex cleaves the dsRNA into 21 bp siRNA. Understanding molecular determinants and mechanistic details of dsRNA recognition by DRB4 is vital for inducing long term RNAi-mediated gene regulation in plants. Here, we present solution structures of individual and concatenated DRB4 dsRBDs and demonstrate modes of dsRNA binding by employing NMR, ITC and site-specific mutagenesis. While both dsRBDs adopt the canonical alpha-beta-beta-beta-alpha fold, key structural differences and ms-MUs dynamics located at the RNA binding region were observed for dsRBD1. These features favor dsRBD1 to orient itself and make stronger tripartite contact with dsRNA, a feature missing in dsRBD2. Additionally, the inter-domain orientation induced by the linker restricts the mobility of dsRBD2, resulting in the steric hindrance of alpha1 helix in dsRBD2, and leads in further reduction of its dsRNA binding activity. Our study deciphers functional roles of DRB4 domains by showing that dsRBD1 drives the tasiRNA/siRNA pathway. Furthermore, we identify a potential role of the C-terminal region of DRB4 in protein:protein interaction as it possesses six PxxP motifs, binds to Zn2+ and contains a small structural domain. PMID- 28575482 TI - A comparison of pine and spruce in recovery from winter stress; changes in recovery kinetics, and the abundance and phosphorylation status of photosynthetic proteins during winter. AB - During winter evergreens maintain a sustained form of thermal energy dissipation that results in reduced photochemical efficiency measured using the chlorophyll fluorescence parameter Fv/Fm. Eastern white pine (Pinus strobus L.) and white spruce [Picea glauca (Moench) Voss] have been shown to differ in their rate of recovery of Fv/Fm from winter stress. The goal of this study was to monitor changes in photosynthetic protein abundance and phosphorylation status during winter recovery that accompany these functional changes. An additional goal was to determine whether light-dependent changes in light harvesting complex II (LHCII) phosphorylation occur during winter conditions. We used a combination of field measurements and recovery experiments to monitor chlorophyll fluorescence and photosynthetic protein content and phosphorylation status. We found that pine recovered three times more slowly than spruce, and that the kinetics of recovery in spruce included a rapid and slow component, while in pine there was only a rapid component to recovery. Both species retained relatively high amounts of the light harvesting protein Lhcb5 (CP26) and the PsbS protein during winter, suggesting a role for these proteins in sustained thermal dissipation. Both species maintained high phosphorylation of LHCII and the D1 protein in darkness during winter. Pine and spruce differed in the kinetics of the dephosphorylation of LHCII and D1 upon warming, suggesting the rate of dephosphorylation of LHCII and D1 may be important in the rapid component of recovery from winter stress. Finally, we demonstrated that light-dependent changes in LHII phosphorylation do not continue to occur on subzero winter days and that needles are maintained in a phosphorylation pattern consistent with the high light conditions to which those needles are exposed. Our results suggest a role for retained phosphorylation of both LHCII and D1 in maintenance of the photosynthetic machinery in a winter conformation that maximizes thermal energy dissipation. PMID- 28575484 TI - Comprehensive Analysis of Liberal and Restrictive Transfusion Strategies in Pediatric Intensive Care Unit. AB - Background: We prospectively compared restrictive and liberal transfusion strategies for critically ill children regarding hemodynamic and laboratory parameters. Methods: A total of 180 children requiring packed red blood cells (PRBCs) were randomized into two groups: the liberal transfusion strategy group (transfusion trigger < 10 g/dL, Group 1) and the restrictive transfusion strategy group (transfusion trigger <= 7 g/dL, Group 2). Basal variables including venous/arterial hemoglobin, hematocrit and lactate levels; stroke volume; and cardiac output were recorded at the beginning and end of the transfusion. Oxygen saturation, noninvasive total hemoglobin, noninvasive total oxygen content, perfusion index (PI), heart rate and systolic and diastolic blood pressures were assessed via the Radical-7 Pulse co-oximeter (Masimo, Irvine, CA, USA) with the Root monitor, initially and at 4 h. Results: In all, 160 children were eligible for final analysis. The baseline hemoglobin level for the PRBC transfusion was 7.38 +/- 0.98 g/dL for all patients. At the end of the PRBC transfusion, cardiac output decreased by 9.9% in Group 1 and by 24% in Group 2 (p < 0.001); PI increased by 10% in Group 1 and by 45% in Group 2 (p < 0.001). Lactate decreased by 9.8% in Group 1 and by 31.68% in Group 2 (p < 0.001). Conclusion: Restrictive blood transfusion strategy is better than liberal transfusion strategy with regard to the hemodynamic and laboratory values during the early period. PI also provides valuable information regarding the efficacy of PRBC transfusion in clinical practice. PMID- 28575481 TI - Occurrence of Anaemia in the First Year of Inflammatory Bowel Disease in a European Population-based Inception Cohort-An ECCO-EpiCom Study. AB - Background and aims: Anaemia is an important complication of inflammatory bowel disease [IBD]. The aim of this study was to determine the prevalence of anaemia and the practice of anaemia screening during the first year following diagnosis, in a European prospective population-based inception cohort. Methods: Newly diagnosed IBD patients were included and followed prospectively for 1 year in 29 European and one Australian centre. Clinical data including demographics, medical therapy, surgery and blood samples were collected. Anaemia was defined according to the World Health Organization criteria. Results: A total of 1871 patients (Crohn's disease [CD]: 686, 88%; ulcerative colitis [UC]: 1,021, 87%; IBD unclassified [IBDU] 164. 81%) were included in the study. The prevalence of anaemia was higher in CD than in UC patients and, overall, 49% of CD and 39% of UC patients experienced at least one instance of anaemia during the first 12 months after diagnosis. UC patients with more extensive disease and those from Eastern European countries, and CD patients with penetrating disease or colonic disease location, had higher risks of anaemia. CD and UC patients in need of none or only mild anti-inflammatory treatment had a lower risk of anaemia. In a significant proportion of patients, anaemia was not assessed until several months after diagnosis, and in almost half of all cases of anaemia a thorough work-up was not performed. Conclusions: Overall, 42% of patients had at least one instance of anaemia during the first year following diagnosis. Most patients were assessed for anaemia regularly; however, a full anaemia work-up was frequently neglected in this community setting. PMID- 28575486 TI - Leaf water maintains daytime transpiration in young Cryptomeria japonica trees. AB - Compared with stem water storage, leaf water storage is understudied although it may be important for alleviating water stress by contributing quickly and directly to transpiration demand. To quantify the relative contribution of stem versus leaf water storage to daily water deficit, we measured diurnal changes in transpiration rate, sap-flow velocity and stem radius of 10-year-old Cryptomeria japonica D. Don trees. We assumed that the duration of time lags between transpiration rate and sap-flow velocity reflected stored water in the stem and leaf, and that stem volume change represented water content of elastic tissue. The relationship between fresh mass and water potential of the whole tree indicated that the study trees had capacity to store, on average, 91.4 ml of water per kg fresh mass at turgor loss. Leaves, sapwood and elastic tissue contributed around 51%, 29% and 20% of stored water, respectively. During morning, transpiration rates were higher than sap-flow velocity suggesting depletion of stored water. During the first 2 h after onset of transpiration, stored water contributed more than 100% of whole-tree transpiration. Depletion of leaf water (PLeaf) and sapwood water (PSap) coincided with the onset of transpiration and became maximum around 15:00 h. Depletion of elastic tissue water (PElastic) lagged behind that of PLeaf and PSap by 1-2 h, indicating that replenishment of stored water occurs late in the day when low leaf water potentials resulting from daytime transpiration drive water uptake. Maximum depletion of PLeaf was about 1-3 times and 5-10 times that of PSap and PElastic, respectively. The contribution of PLeaf to total daily transpiration was 5-8%, while those of PSap and PElastic were 3-4% and 0.7-1%, respectively. Our results suggest the importance of leaf water storage in maintaining daily transpiration in young C. japonica trees. PMID- 28575483 TI - That's me in the spotlight: neural basis of individual differences in self consciousness. AB - A long-standing literature implicates activity within the default mode network (DMN) to processes linked to the self. However, contemporary work suggests that other large-scale networks networks might also be involved. For instance, goal directed autobiographical planning requires positive functional connectivity (FC) between DMN and frontoparietal control (FPCN) networks. The present study examined the inter-relationship between trait self-focus (measured via a self consciousness scale; SCS), incidental memory in a self-reference paradigm, and resting state FC of large-scale networks. Behaviourally, we found that private SCS was linked to stronger incidental memory for self-relevant information. We also examined how patterns of FC differed according to levels of self consciousness by using the SCS data to drive multiple regression analyses with seeds from the DMN, the FPCN and the limbic network. High levels of SCS was not linked to differences in the functional behaviour of the DMN, however, it was linked to stronger FC between FPCN and a cluster extending into the hippocampus, which meta analytic decoding using Neurosynth linked to episodic memory retrieval. Subsequent analysis demonstrated that trait variance in this pattern of FC was a moderator for the observed relationship between private SCS and enhanced memory for self-items. Together these findings suggest that interactions between the FPCN and hippocampus may support the memory advantage of self relevant information associated with SCS and confirm theoretical positions that argue that that self-related processing does not simply depend upon the DMN, but instead relies on complex patterns of interactions between multiple large-scale networks. PMID- 28575487 TI - Late Life Employment Histories and Their Association With Work and Family Formation During Adulthood: A Sequence Analysis Based on ELSA. AB - Objectives: To extend research on workforce participation beyond age 50 by describing entire employment histories in later life and testing their links to prior life course conditions. Methods: We use data from the English Longitudinal Study of Ageing, with retrospective information on employment histories between age 50 and 70 for 1,103 men and 1,195 women (n = 2,298). We apply sequence analysis and group respondents into eight clusters with similar histories. Using multinomial regressions, we then test their links to labor market participation, partnership, and parenthood histories during early (age 20-34) and mid-adulthood (age 35-49). Results: Three clusters include histories dominated by full-time employees but with varying age of retirement (before, at, and after age 60). One cluster is dominated by self-employment with comparatively later retirement. Remaining clusters include part-time work (retirement around age 60 or no retirement), continuous domestic work (mostly women), or other forms of nonemployment. Those who had strong attachments to the labor market during adulthood are more likely to have histories of full-time work up until and beyond age 60, especially men. Parenthood in early adulthood is related to later retirement (for men only). Continued domestic work was not linked to parenthood. Partnered women tend to work part-time or do domestic work. The findings remain consistent after adjusting for birth cohort, childhood adversity, life course health, and occupational position. Discussion: Policies aimed at increasing the proportion of older workers not only need to address later stages of the life course but also early and mid-adulthood. PMID- 28575485 TI - Adult IDH wild-type lower-grade gliomas should be further stratified. AB - Background: Astrocytoma of the isocitrate dehydrogenase (IDH) wild-type gene is described as a provisional entity within the new World Health Organization (WHO) classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be substratified prognostically. Methods: Seven hundred and eighteen adult WHO grades II and III patients with gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations. One hundred and sixty six patients with IDH wild-type cases were identified for further studies, and EGFR and MYB amplifications, mutations of histone H3F3A, TERT promoter (TERTp), and BRAF were examined. Results: EGFR amplification, BRAF, and H3F3A mutations were observed in 13.8%, 6.9%, and 9.5% of patients, respectively, in a mutually exclusive pattern in IDH wild-type lower-grade gliomas. TERTp mutations were detected in 26.8% of cases. Favorable outcome was observed in patients with young age, oligodendroglial phenotype, and grade II histology. Independent adverse prognostic values of older age, nontotal resection, grade III histology, EGFR amplification, and H3F3A mutation were confirmed by multivariable analysis. Tumors were further classified into "molecularly" high grade (harboring EGFR, H3F3A, or TERTp) (median overall survival = 1.23 y) and lower grade (lacking all of the 3) (median overall survival = 7.63 y) with independent prognostic relevance. The most favorable survival was noted in molecularly lower-grade gliomas with MYB amplification. Conclusion: Adult IDH wild-type lower-grade gliomas are prognostically heterogeneous and do not have uniformly poor prognosis. Clinical information and additional markers, including MYB, EGFR, TERTp, and H3F3A, should be examined to delineate discrete favorable and unfavorable prognostic groups. PMID- 28575489 TI - Successful Implementation of a Bundle Strategy to Prevent Ventilator-Associated Pneumonia in a Neonatal Intensive Care Unit. AB - Background: We aimed to investigate the effectiveness of evidence-based bundle that we developed to reduce ventilator-associated pneumonia (VAP) rates and to assess the degree of compliance rates to this strategy in a tertiary neonatal intensive care unit. Methods: This before-after prospective cohort trial divided into two periods was conducted. All neonates requiring ventilation were enrolled in the study. VAP incidence, compliance rates to bundle components and the contribution of each bundle component to VAP rates were compared between the periods. Results: Throughout the study period, 13 VAP episodes were observed. Full adherence to all six components of the bundle doubled in the active-bundle period (12.8 vs. 24.3%, p < 0.01). The mean VAP rate decreased from 7.33/1000 to 2.71/1000 ventilator days following intervention (p = 0.083). Conclusion: This study showed that reliable implementation of a neonate-specific VAP prevention bundle can produce sustained reductions in VAP rates. PMID- 28575488 TI - A deep boosting based approach for capturing the sequence binding preferences of RNA-binding proteins from high-throughput CLIP-seq data. AB - Characterizing the binding behaviors of RNA-binding proteins (RBPs) is important for understanding their functional roles in gene expression regulation. However, current high-throughput experimental methods for identifying RBP targets, such as CLIP-seq and RNAcompete, usually suffer from the false negative issue. Here, we develop a deep boosting based machine learning approach, called DeBooster, to accurately model the binding sequence preferences and identify the corresponding binding targets of RBPs from CLIP-seq data. Comprehensive validation tests have shown that DeBooster can outperform other state-of-the-art approaches in RBP target prediction. In addition, we have demonstrated that DeBooster may provide new insights into understanding the regulatory functions of RBPs, including the binding effects of the RNA helicase MOV10 on mRNA degradation, the potentially different ADAR1 binding behaviors related to its editing activity, as well as the antagonizing effect of RBP binding on miRNA repression. Moreover, DeBooster may provide an effective index to investigate the effect of pathogenic mutations in RBP binding sites, especially those related to splicing events. We expect that DeBooster will be widely applied to analyze large-scale CLIP-seq experimental data and can provide a practically useful tool for novel biological discoveries in understanding the regulatory mechanisms of RBPs. The source code of DeBooster can be downloaded from http://github.com/dongfanghong/deepboost. PMID- 28575491 TI - Global health promotion in the era of 'galloping populism'. PMID- 28575490 TI - Ultrasound-guided versus conventional femoral venipuncture for catheter ablation of atrial fibrillation: a multicentre randomized efficacy and safety trial (ULTRA FAST trial). AB - Aims: Complications of catheter ablation for atrial fibrillation (AF) are frequently related to vascular access. We hypothesized that ultrasound-guided (USG) venipuncture may facilitate the procedure and reduce complication rates. Methods and results: We conducted a multicentre, randomized trial in patients undergoing catheter ablation for AF on uninterrupted anticoagulation therapy. The study enrolled consecutive 320 patients (age: 63 +/- 8 years; male: 62%) and were randomized to USG or conventional venipuncture in 1:1 fashion. It was prematurely terminated due to substantially lower-than-expected complication rates, which doubled the population size needed to maintain statistical power. While the complication rates did not differ between two study arms (0.6% vs. 1.9%, P = 0.62), intra-procedural outcome measures were in favour of the USG approach (puncture time, 288 vs. 369 s, P < 0.001; first pass success, 74% vs. 20%, P < 0.001; extra puncture attempts 0.5 vs. 2.1, P < 0.001; inadvertent arterial puncture 0.07 vs. 0.25, P < 0.001; unsuccessful cannulation 0.6% vs. 14%, P < 0.001). Though these measures varied between trainees (49% of procedures) and expert operators, between-arm differences (except for unsuccessful cannulation) were comparably significant in favour of USG approach for both subgroups. Conclusions: Ultrasound-guided puncture of femoral veins was associated with preferable intra-procedural outcomes, though the major complication rates were not reduced. Both trainees and expert operators benefited from the USG strategy. (www.clinicaltrials.gov ID: NCT02834221). PMID- 28575492 TI - Smoking and Mortality in Eastern Europe: Results From the PrivMort Retrospective Cohort Study of 177 376 Individuals. AB - Background: The estimated prevalence of smoking and proportion of deaths due to tobacco in Eastern European countries are among the highest in the world. Existing estimates of mortality attributable to smoking in the region are mostly indirect. The aim of this analysis was to calculate the proportion of tobacco attributed deaths in three Eastern European countries using individual level cohort data. Methods: The PrivMort project established a cohort of relatives of participants in population sample surveys in Russia, Belarus and Hungary. Survey participants provided data on smoking habits and vital statistics of their close relatives between 1982 and 2013. Population attributable risk fractions (PARF) in men (n = 99528) and women (n = 77848) aged 40-79 years were calculated from the prevalence rates of smoking and hazard ratios of mortality for smokers versus non smokers. Trends in PARF over four 8-year time periods (1982-1989, 1990-1997, 1998 2005, and 2006-2013) were examined. Results: In men in the most recent period (2006-2013), the proportions of deaths attributable to tobacco were 23% in Russia, 22% in Belarus, and 22% in Hungary. The respective estimates in women were lower (2%, 2%, and 13%), possibly due to underestimation of smoking prevalence. PARF estimates have declined slightly since the early 1990s in men but increased in women. Conclusions: Consistently with existing indirect estimates, our results based on individual level cohort data suggest that over one fifth of all deaths in men aged 40-79 years are attributable to tobacco. While these proportions are lower in women, the increasing trend is a major concern. Implications: This is the first large scale, individual-level cohort study that estimated the mortality attributable to tobacco smoking directly in Eastern European population samples. The results confirm previous indirect estimates and show that more than 20% of all deaths in Eastern European men can be attributed to tobacco. The study also confirms the increasing trend in smoking related deaths among women. These findings emphasize the importance of targeted policy interventions in Eastern European countries. PMID- 28575495 TI - Maternal Smoking: A Life Course Blood Pressure Determinant? AB - Introduction: Exposure to maternal smoking early in life may affect blood pressure (BP) control mechanisms. We examined the association between maternal smoking (before conception, during pregnancy, and 4 years after delivery) and BP in preschool children. Methods: We evaluated 4295 of Generation XXI children, recruited at birth in 2005-2006 and reevaluated at the age of 4. At birth, information was collected by face-to-face interview and additionally abstracted from clinical records. At 4-year follow-up, interviews were performed and children's BP measured. Linear regression models were fitted to estimate the association between maternal smoking and children's BP. Results: Children of smoking mothers presented significantly higher BP levels. After adjustment for maternal education, gestational hypertensive disorders, and child's body mass index, children exposed during pregnancy to maternal smoking presented a higher systolic BP (SBP) z-score (beta = 0.08, 95% confidence interval [CI] 0.04 to 0.14). In crude models, maternal smoking was associated with higher SBP z-score at every assessed period. However, after adjustment, an attenuation of the association estimates occurred (beta = 0.08, 95% CI 0.03 to 0.13 before conception; beta = 0.07, 95%CI 0.02 to 0.12; beta = 0.04, 95%CI -0.02 to 0.10; and beta = 0.06, 95%CI 0.00 to 0.13 for the first, second, and third pregnancy trimesters, respectively; and beta = 0.07, 95%CI 0.02 to 0.12 for current maternal smoking). No significant association was observed for diastolic BP z score levels. Conclusion: Maternal smoking before, during, and after pregnancy was independently associated with systolic BP z-score in preschool children. This study provides additional evidence to the public health relevance of maternal smoking cessation programs if early cardiovascular health of children is envisaged. Implications: Using observational longitudinal data from the birth cohort Generation XXI, this study showed that exposure to maternal smoking-before pregnancy, during pregnancy, and 4 years after delivery-was associated with a systolic BP-raising effect in children at the age of 4. The findings of this study add an important insight into the need to support maternal smoke-free environments in order to provide long-term cardiovascular benefit, starting as early as possible in life. PMID- 28575493 TI - miR miR on the wall, who's the most malignant medulloblastoma miR of them all? AB - microRNAs (miRNAs) have wide-ranging effects on large-scale gene regulation. As such, they play a vital role in dictating normal development, and their aberrant expression has been implicated in cancer. There has been a large body of research on the role of miRNAs in medulloblastoma, the most common malignant brain tumor of childhood. The identification of the 4 molecular subgroups with distinct biological, genetic, and transcriptional features has revolutionized the field of medulloblastoma research over the past 5 years. Despite this, the growing body of research on miRNAs in medulloblastoma has largely focused on the clinical entity of a single disease rather than the molecular subgroups. This review begins by highlighting the role of miRNAs in development and progresses to explore their myriad of implications in cancer. Medulloblastoma is characterized by increased proliferation, inhibition of apoptosis, and maintenance of stemness programs features that are inadvertently regulated by altered expression patterns in miRNAs. This review aims to contextualize the large body of work on miRNAs within the framework of medulloblastoma subgroups. The goal of this review is to stimulate new areas of research, including potential therapeutics, within a rapidly growing field. PMID- 28575494 TI - Golgi phosphoprotein 3 promotes glioma progression via inhibiting Rab5-mediated endocytosis and degradation of epidermal growth factor receptor. AB - Background: Golgi phosphoprotein 3 (GOLPH3) is associated with worse prognosis of gliomas, but its role and mechanism in glioma progression remain largely unknown. This study aimed to explore the role and mechanism of GOLPH3 in glioma progression. Methods: The expression of GOLPH3 in glioma tissues was detected by quantitative PCR, immunoblotting, and immunohistochemistry. GOLPH3's effect on glioma progression was examined using cell growth assays and an intracranial glioma model. The effect of GOLPH3 on epidermal growth factor receptor (EGFR) stability, endocytosis, and degradation was examined by immunoblotting and immunofluorescence. The activity of Rab5 was checked by glutathione S-transferase pulldown assay. Results: GOLPH3 was upregulated in gliomas, and its downregulation inhibited glioma cell proliferation both in vitro and in vivo. Furthermore, GOLPH3 depletion dampened EGFR signaling by enhancing EGFR endocytosis, driving EGFR into late endosome and promoting lysosome-mediated degradation. Interestingly, GOLPH3 bound to Rab5 and GOLPH3 downregulation promoted the activation of Rab5. In addition, Rab5 depletion abolished the effect of GOLPH3 on EGFR endocytosis and degradation. Conclusion: Our results imply that GOLPH3 promotes glioma cell proliferation via inhibiting Rab5-mediated endocytosis and degradation of EGFR, thereby activating the phosphatidylinositol 3 kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway. We find a new mechanism by which GOLPH3 promotes tumor progression through regulating cell surface receptor trafficking. Extensive and intensive understanding of the role of GOLPH3 in glioma progression may provide an opportunity to develop a novel molecular therapeutic target for gliomas. PMID- 28575496 TI - Comparison of the Acute Effect of Radial Shock Wave Therapy and Ultrasound Therapy in the Treatment of Plantar Fasciitis: A Randomized Controlled Study. AB - Objective: This study compared the effectiveness of radial extracorporeal shock wave therapy (r-ESWT) with ultrasound (US) therapy in the treatment of plantar fasciitis (PF). Study Design: Level II, randomized controlled study. Design: A total of 54 female patients with unilateral PF were randomly assigned to two study groups and one control group. All groups performed home exercises. In addition, the first study group received three sessions of r-ESWT treatment and the second study group received seven sessions of US treatment. The Foot Function Index (FFI) and the American Orthopedic Foot and Ankle Association (AOFAS) hind foot score were determined. Static and dynamic equilibrium were evaluated with the single leg standing test and the functional reach test. Ankle proprioception sense was determined with the Biodex III isokinetic device. Patients were evaluated before and four weeks after the first treatment. Results: According to the evaluation results, there was a decrease in FFI values in all groups and these decreases were more prominent in the US group than the other groups (P < 0.05). It was observed that the hind foot AOFAS scores increased in all groups, but this increase was less in the control group (P < 0.05). Static and dynamic balance increased in all groups (P < 0.05). Ankle proprioception sense increased only in the r-ESWT group (P <0.05). Conclusions: All groups and particularly the r-ESWT and US groups' symptoms were decreased after treatment. However; FFI parameters were reduced more in the US groups than the other two groups, the ankle proprioception sense increased in the r-ESWT group, and there was no change in the other groups. PMID- 28575498 TI - Location, vocation, procreation: how choice influences life expectancy in doctors. PMID- 28575500 TI - Chronic obstructive pulmonary disease in miners with special reference to smoking. PMID- 28575499 TI - Occupational cancer: recent developments in research and legislation. PMID- 28575501 TI - Well-being apps. PMID- 28575497 TI - Loss of hepatic LRPPRC alters mitochondrial bioenergetics, regulation of permeability transition and trans-membrane ROS diffusion. AB - The French-Canadian variant of Leigh Syndrome (LSFC) is an autosomal recessive oxidative phosphorylation (OXPHOS) disorder caused by a mutation in LRPPRC, coding for a protein involved in the stability of mitochondrially-encoded mRNAs. Low levels of LRPPRC are present in all patient tissues, but result in a disproportionately severe OXPHOS defect in the brain and liver, leading to unpredictable subacute metabolic crises. To investigate the impact of the OXPHOS defect in the liver, we analyzed the mitochondrial phenotype in mice harboring an hepatocyte-specific inactivation of Lrpprc. Loss of LRPPRC in the liver caused a generalized growth delay, and typical histological features of mitochondrial hepatopathy. At the molecular level, LRPPRC deficiency caused destabilization of polyadenylated mitochondrial mRNAs, altered mitochondrial ultrastructure, and a severe complex IV (CIV) and ATP synthase (CV) assembly defect. The impact of LRPPRC deficiency was not limited to OXPHOS, but also included impairment of long chain fatty acid oxidation, a striking dysregulation of the mitochondrial permeability transition pore, and an unsuspected alteration of trans-membrane H2O2 diffusion, which was traced to the ATP synthase assembly defect, and to changes in the lipid composition of mitochondrial membranes. This study underscores the value of mitochondria phenotyping to uncover complex and unexpected mechanisms contributing to the pathophysiology of mitochondrial disorders. PMID- 28575503 TI - Reply. PMID- 28575502 TI - Charles Turner Thackrah, 1795-1833, 'The Father of Occupational Medicine'. PMID- 28575504 TI - Reply. PMID- 28575505 TI - Like mother like daughter: putamen activation as a mechanism underlying intergenerational risk for depression. AB - Having a depressed mother is one of the strongest predictors for developing depression in adolescence. Given the role of aberrant reward processing in the onset and maintenance of depression, we examined the association between mothers' and their daughters' neural response to the anticipation of reward and loss. Fifteen non-depressed mothers with a history of recurrent depression and their never-disordered daughters, and 23 mothers without past or current depression and their never-disordered daughters, underwent functional magnetic resonance imaging while performing the monetary incentive delay task. To assess mother-daughter concordance, we first identified ROIs involved in the anticipation of reward and loss across all mother-daughter pairs. Within each of these ROIs, we examined the association between mothers' and daughters' neural response, and the interaction between group status and mothers' neural response in predicting daughters' neural response. We found a significant association between mothers' and daughters' putamen response to the anticipation of loss, regardless of mother's depression history. Furthermore, pubertal stage moderated the association between mother daughter putamen concordance. Our findings suggest a unique role of the putamen in the maternal transmission of reward learning and have important implications for understanding disorders characterized by disturbances in reward learning and processing, such as major depression. PMID- 28575506 TI - Limbic Interference During Social Action Planning in Schizophrenia. AB - Schizophrenia is characterized by social interaction deficits contributing to poor functional outcome. Hand gesture use is particularly impaired, linked to frontal lobe dysfunction and frontal grey matter deficits. The functional neural correlates of impaired gesturing are currently unclear. We therefore investigated aberrant brain activity during impaired gesturing in schizophrenia. We included 22 patients with schizophrenia and 25 healthy control participants matched for age, gender, and education level. We obtained functional magnetic resonance imaging data using an event-related paradigm to assess brain activation during gesture planning and execution. Group differences in whole brain effects were calculated using factorial designs. Gesture ratings were performed by a single rater, blind to diagnoses and clinical presentation. During gesture planning and execution both groups activated brain areas of the praxis network. However, patients had reduced dorsolateral prefrontal cortex (DLPFC) and increased inferior parietal lobe (IPL) activity. Performance accuracy was associated with IPL activity in patients. Furthermore, patients activated temporal poles, amygdala and hippocampus during gesture planning, which was associated with delusion severity. Finally, patients demonstrated increased dorsomedial prefrontal cortex activity during planning of novel gestures. We demonstrate less prefrontal, but more IPL and limbic activity during gesturing in schizophrenia. IPL activity was associated with performance accuracy, whereas limbic activity was linked to delusion severity. These findings may reflect impaired social action planning and a limbic interference with gestures in schizophrenia contributing to poor gesture performance and consequently poor social functioning in schizophrenia. PMID- 28575508 TI - Effects of Duloxetine on the Toll-Like Receptor 4 Signaling Pathway in Spinal Dorsal Horn in a Rat Model of Diabetic Neuropathic Pain. AB - Objective: Although duloxetine has been approved for clinical therapy for diabetic peripheral neuropathic pain, the exact mechanism underlying the anti allodynic effects in rat models of diabetes mellitus remains obscure. We attempted to identify whether duloxetine exerts anti-allodynic effects via inhibition of the TLR4-Myd88-dependent pathway in diabetic neuropathic pain (DNP) rats. Methods: An animal model of type 1 diabetic neuropathic pain was induced by intraperitoneal streptozotocin in 108 rats randomized into four groups: control, DNP, solvent control + DNP, and DNP + duloxetine. The DNP model establishment was validated, providing the MWT and TWL measurements were less than 80% of the baseline value on d14 after streptozotocin administration. The expressions of TLR4, Myd88, and NF-kappaB in the spinal dorsal horn were determined 21 days after streptozotocin injection by immunohistochemical assay and Western blot. Results: The results revealed that MWT and TWL in DNP, SC + DNP, and DLX + DNP groups were significantly decreased 14 days after STZ administration vs control (P < 0.05), while the pain thresholds in the DLX + DNP group were partially reversed. The expressions of TLR4, Myd88, and NF-kappaB in groups C, DNP, and SC + DNP were significantly increased, whereas duloxetine administration significantly downregulated the expressions of TLR4, Myd88, and NF-kappaB (P < 0.05). Conclusions: Our findings indicated that duloxetine mitigated mechanical and thermal withdrawal thresholds in STZ-injected rats and rescued the overexpression of the TLR4-Myd88-dependent pathway in the spinal dorsal horn in these rats. Whether these changes directly contributed to the reduction of thermal and mechanical withdrawal behavior needs to be further explored. PMID- 28575507 TI - Advances in the MYB-bHLH-WD Repeat (MBW) Pigment Regulatory Model: Addition of a WRKY Factor and Co-option of an Anthocyanin MYB for Betalain Regulation. AB - Flavonoids are secondary metabolites derived from the general phenylpropanoid pathway and are widespread throughout the plant kingdom. The functions of flavonoids are diverse, including defense against phytopathogens, protection against UV light damage and oxidative stress, regulation of auxin transport and allelopathy. One of the most conspicuous functions of flavonoids has long attracted the attention of pollinators and scientist alike: the vivid shades of red, pink, orange, blue and purple on display in the flowers of angiosperms. Thus, flavonoid pigments have perhaps been the most intensely studied phenylpropanoids. From Mendel to McClintock and up to the present, studies centered on flavonoid pigments have resulted in some of the most important scientific discoveries of the last 150 years, including the first examples of transcriptional regulation in plants. Here we focus on the highly conserved MYB bHLH-WD repeat (MBW) transcriptional complex model for the regulation of the flavonoid pigment pathway. We will survey the history of the MBW model spanning the last three decades, highlighting the major findings that have contributed to our current understanding. In particular, recent discoveries regarding WRKY protein control of the flavonoid pigment pathway and its relationship to the MBW complex will be emphasized. In addition, we will discuss recent findings about the regulation of the beet betalain pigment pathway, and how a MYB member of the MBW complex was co-opted to regulate this chemically unrelated but functionally equivalent pathway. PMID- 28575509 TI - Intercentre variance in patient reported outcomes is lower than objective rheumatoid arthritis activity measures: a cross-sectional study. AB - Objective: To assess intercentre variability in the ACR core set measures, DAS28 based on three variables (DAS28v3) and Routine Assessment of Patient Index Data 3 in a multinational study. Methods: Seven thousand and twenty-three patients were recruited (84 centres; 30 countries) using a standard protocol in the Quantitative Standard Monitoring of Patients with RA study. Analysis of variance (ANOVA) and mixed-effect analysis of covariance models were used to model the relationship between study centre and different patient-reported and physician reported RA activity measures. These models were built to adjust for the remaining ACR core set measure (for each ACR core set measure or each composite index), socio-demographics and medical characteristics. ANOVA and analysis of covariance models yielded similar results, and ANOVA tables were used to present variance attributable to recruiting centre. Results: The proportion of variances attributable to recruiting centre was lower for patient reported outcomes (PROs: pain, HAQ, patient global) compared with objective measures (joint counts, ESR, physician global) in all models. In the full model, variance in PROs attributable to recruiting centre ranged from 1.53% for patient global to 3.71% for HAQ compared with objective measures that ranged from 5.92% for physician global to 9.25% for ESR; and was lower for Routine Assessment of Patient Index Data 3 (2.6%) compared with DAS28v3 (11.75%). Conclusion: Intercentre variability in PROs is lower than objective measures of RA activity demonstrating that PROs may be more comparable across centres, and the need for standardization of objective measures. PMID- 28575511 TI - Population pharmacokinetics and dosing considerations for the use of daptomycin in adult patients with haematological malignancies. AB - Objectives: To assess the population pharmacokinetics (popPK) of daptomycin at the conventional dose of 6 mg/kg/day in a cohort of oncohaematological patients. Methods: Patients underwent serial blood sampling on day 3 of therapy (before dosing and at 0, 0.5, 1, 2, 3, 5, 7, 9 and 12 h after dosing) to assess the pharmacokinetic profile of daptomycin. PopPK and Monte Carlo simulation were performed to define the probability of target attainment (PTA) with 6, 8, 10 and 12 mg/kg/day of the pharmacokinetic/pharmacodynamic target of AUC 24 /MIC >1081. Results: Thirty patients were recruited. A two-compartment open model with first order intravenous input and first-order elimination was developed. Estimated creatinine clearance (CL CR ), serum albumin concentration (Alb) and presence of AML were covariates included in the final model. Monte Carlo simulation showed that the conventional 6 mg/kg/day dose resulted in optimal PTAs (>=80%) in the presence of pathogens with an MIC up to 0.5 mg/L only in patients with CL CR 50 100 mL/min/1.73 m 2 , Alb 26-45 g/L and a haematological diagnosis other than AML. Conversely, higher dosages, up to 12 mg/kg/day, were needed to achieve this goal in the presence of pathogens with an MIC of 0.25-0.5 mg/L in all of the other tested scenarios. In patients with CL CR 101-150 mL/min/1.73 m 2 and Alb 15 25 g/L, suboptimal PTAs (<60%) were predicted even with 12 mg/kg/day dosing . Conclusions: Our study provides a strong rationale for considering daptomycin dosages of >= 8 mg/kg/day in several clinical scenarios for oncohaematological patients. In some of these scenarios therapeutic drug monitoring could be a useful adjunct for optimized care. PMID- 28575512 TI - Continuous excitation chlorophyll fluorescence parameters: a review for practitioners. AB - This review introduces, defines and critically reviews a number of chlorophyll fluorescence parameters with specific reference to those derived from continuous excitation chlorophyll fluorescence. A number of common issues and criticisms are addressed. The parameters fluorescence origin (F0) and the performance indices (PI) are discussed as examples. This review attempts to unify definitions for the wide range of parameters available for measuring plant vitality, facilitating their calculation and use. PMID- 28575510 TI - Externalizing Behaviors and Callous-Unemotional Traits: Different Associations With Sleep Quality. AB - Study Objectives: Sleep quality is associated with different aspects of psychopathology, but relatively little research has examined links between sleep quality and externalizing behaviors or callous-unemotional traits. We examined: (1) whether an association exists between sleep quality and externalizing behaviors; (2) whether anxiety mediates this association; (3) whether callous unemotional traits are associated with sleep quality. Methods: Data from two studies were used. Study 1 involved 1556 participants of the G1219 study aged 18 27 years (62% female). Questionnaire measures assessed sleep quality, anxiety, externalizing behaviors, and callous-unemotional traits. Study 2 involved 338 participants aged 18-66 years (65% female). Questionnaires measured sleep quality, externalizing behaviors, and callous-unemotional traits. In order to assess objective sleep quality, actigraphic data were also recorded for a week from a subsample of study 2 participants (n = 43). Results: In study 1, poorer sleep quality was associated with greater externalizing behaviors. This association was partially mediated by anxiety and moderated by levels of callous unemotional traits. There was no significant relationship between sleep quality and callous-unemotional traits. In study 2, poorer sleep quality, as assessed via self-reported but not objective measures, was associated with higher levels of externalizing behaviors. Furthermore, in study 2, better sleep quality (indicated in both questionnaires and actigraphy measures: lower mean activity, and greater sleep efficiency) was associated with higher levels of callous-unemotional traits. Conclusions: Self-reports of poorer sleep quality are associated with externalizing behaviors, and this association is partially mediated by anxiety. Callous-unemotional traits are not associated with poor sleep and may even be related to better sleep quality. This is an exceptional finding given that poor sleep quality appears to be a characteristic of most psychopathology. PMID- 28575514 TI - Association of Eveningness With Nonremission in Major Depressive Disorder: Reply to Knapen et al. PMID- 28575515 TI - Microscopy in this issue. PMID- 28575513 TI - Primary, Enduring Negative Symptoms: An Update on Research. AB - We previously proposed that people with schizophrenia who have primary, enduring negative symptoms have a disease-deficit schizophrenia (DS)-that is separate from that affecting people with schizophrenia without these features. Additional evidence consistent with the separate disease hypothesis has accumulated in recent years. White matter changes may be widespread in deficit compared to nondeficit patients and may relate to problems in early brain migration. These 2 patient groups also appear to differ on metabolic measures prior to antipsychotic treatment. Studies of reward and defeatist beliefs provide the basis for future treatment trials. The 2 factors or groups within negative symptoms broadly defined (both primary and secondary) have also been found in DS, and recent evidence suggests these 2 symptom groups have different correlates and reflect the existence of 2 groups with in DS. Negative symptoms are found in disorders other than schizophrenia, and excess summer birth, a deficit risk factor, has been found in a non-patient group with deficit-like features. It may be useful in future research to determine whether findings in DS extend to patients with other neuropsychiatric disorders who also have negative symptoms. PMID- 28575516 TI - Increased temperature and CO2 alleviate photoinhibition in Desmarestia anceps: from transcriptomics to carbon utilization. AB - Ocean acidification and warming are affecting polar regions with particular intensity. Rocky shores of the Antarctic Peninsula are dominated by canopy forming Desmarestiales. This study investigates the physiological and transcriptomic responses of the endemic macroalga Desmarestia anceps to a combination of different levels of temperature (2 and 7 degrees C), dissolved CO2 (380 and 1000 ppm), and irradiance (65 and 145 umol photons m-2 s-1). Growth and photosynthesis increased at high CO2 conditions, and strongly decreased at 2 degrees C plus high irradiance, in comparison to the other treatments. Photoinhibition at 2 degrees C plus high irradiance was evidenced by the photochemical performance and intensive release of dissolved organic carbon. The highest number of differentially regulated transcripts was observed in thalli exposed to 2 degrees C plus high irradiance. Algal 13C isotopic discrimination values suggested an absence of down-regulation of carbon-concentrating mechanisms at high CO2. CO2 enrichment induced few transcriptomic changes. There was high and constitutive gene expression of many photochemical and inorganic carbon utilization components, which might be related to the strong adaptation of D. anceps to the Antarctic environment. These results suggest that increased temperature and CO2 will allow D. anceps to maintain its productivity while tolerating higher irradiances than at present conditions. PMID- 28575518 TI - Outcomes of Elective Cerebral Aneurysm Treatment Performed by Attending Neurosurgeons after Night Work. AB - BACKGROUND: The association between long work hours and outcomes among attending surgeons remains an issue of debate. OBJECTIVE: To investigate whether operating emergently the night before an elective case was associated with inferior outcomes among attending neurosurgeons. METHODS: We executed a cohort study with unruptured cerebral aneurysm patients, who underwent endovascular coiling or surgical clipping from 2009 to 2013 and were registered in the Statewide Planning and Research Cooperative System database. We investigated the association of treatment by surgeons performing emergency procedures the night before with outcomes of elective cerebral aneurysm treatment using an instrumental variable analysis. RESULTS: Overall, 4700 patients underwent treatment for unruptured cerebral aneurysms. There was no difference in inpatient mortality (adjusted difference, -0.7%; 95% confidence interval [CI], -1.4% to 0.02%), discharge to a facility (adjusted difference, -0.1%; 95% CI, -1.2% to 1.2%), or length of stay (adjusted difference, -0.58; 95% CI, -1.66 to 0.50) between patients undergoing elective cerebral aneurysm treatment by surgeons who performed emergency procedures the night before, and those who did not. CONCLUSION: Using a comprehensive patient cohort in New York State for elective treatment of unruptured cerebral aneurysms, we did not identify an association of treatment by surgeons performing emergency procedures the night before, with mortality, discharge to a facility, or length of stay. Our study had 80% power to detect differences in mortality (our primary outcome), as small as 4.1%. The results of the present study do not support the argument for regulation of attending work hours. PMID- 28575519 TI - A Comparison of Daily Versus Weekly Electronic Cigarette Users in Treatment for Substance Abuse. AB - Objective: This research examined electronic cigarette (e-cigarette) use by individuals in treatment for substance abuse, a population with a high prevalence of tobacco use and poor smoking cessation outcomes. Methods: We surveyed 1127 individuals from 24 substance abuse treatment centers across the United States. Bivariate analyses and logistic regression were used to examine factors associated with daily (N = 87) versus weekly (N = 81) e-cigarette use. Results: Among the full sample, 59.8% reported any lifetime use of e-cigarettes, with 23.6% reporting past 30-day use. Daily e-cigarette users were more likely to have used second-generation, tank-type e-cigarettes, chi2(1,N = 165) = 11.54, p = .001, used more flavors overall, t(168) = 2.15, p = .03, and were more likely to report using their e-cigarette continuously throughout the day, chi2(4,N = 168) = 16.7, p = .002, compared to weekly e-cigarette users. Over half (57.7%) of the daily and weekly e-cigarette users reported having an e-cigarette device that broke. The logistic regression model adjusting for clinic type and days with poor mental health found that daily e-cigarette users were significantly more likely than weekly e-cigarette users to be from methadone clinics (adjusted odds ratio [AOR] = 2.40, p = .04), and former smokers (AOR = 6.37, p < .002). Conclusions: Daily e-cigarette users in substance abuse treatment were more likely to be from methadone clinics and former cigarette smokers. However, the majority (73.6%) of daily e-cigarette users were current cigarette smokers. E-cigarette device type reliability (eg, breakage) may be an important factor to consider among drug treatment and other populations with lower socioeconomic status. Implications: This study found several differences in the device type, flavors, and use characteristics of daily versus weekly e-cigarette users. While majority of e cigarette users in substance abuse treatment were current cigarette smokers, daily e-cigarette users were more likely to be former cigarette smokers. Administrators of substance abuse treatment programs should evaluate potential benefits and harms of e-cigarettes when developing program policies. PMID- 28575521 TI - Sex determines xylem anatomy in a dioecious conifer: hydraulic consequences in a drier world. AB - Increased drought frequency and severity may reshape tree species distribution in arid environments. Dioecious tree species may be more sensitive to climate warming if sex-related vulnerability to drought occurs, since lower performance of one sex may drive differential stress tolerance, sex-related mortality rates and biased sex ratios. We explored the effect of sex and environment on branch hydraulic (hydraulic conductivity and vulnerability to embolism) and trunk anatomical traits in both sexes of the dioecious conifer Juniperus thurifera L. at two sites with contrasting water availability. Additionally, we tested for a trade-off between hydraulic safety (vulnerability to embolism) and efficiency (hydraulic conductivity). Vulnerability to embolism and hydraulic conductivity were unaffected by sex or site at branch level. In contrast, sex played a significant role in xylem anatomy. We found a trade-off between hydraulic safety and efficiency, with larger conductivities related to higher vulnerabilities to embolism. At the anatomical level, females' trunk showed xylem anatomical traits related to greater hydraulic efficiency (higher theoretical hydraulic conductivity) over safety (thinner tracheid walls, lower Mork's Index), whereas males' trunk anatomy followed a more conservative strategy, especially in the drier site. Reconciling the discrepancy between branch hydraulic function and trunk xylem anatomy would require a thorough and integrated understanding of the tree structure-function relationship at the whole-plant level. Nevertheless, lower construction costs and higher efficiency in females' xylem anatomy at trunk level might explain the previously observed higher growth rates in mesic habitats. However, prioritizing efficiency over safety in trunk construction might make females more sensitive to drought, endangering the species' persistence in a drier world. PMID- 28575517 TI - Comprehensive classification of the PIN domain-like superfamily. AB - PIN-like domains constitute a widespread superfamily of nucleases, diverse in terms of the reaction mechanism, substrate specificity, biological function and taxonomic distribution. Proteins with PIN-like domains are involved in central cellular processes, such as DNA replication and repair, mRNA degradation, transcription regulation and ncRNA maturation. In this work, we identify and classify the most complete set of PIN-like domains to provide the first comprehensive analysis of sequence-structure-function relationships within the whole PIN domain-like superfamily. Transitive sequence searches using highly sensitive methods for remote homology detection led to the identification of several new families, including representatives of Pfam (DUF1308, DUF4935) and CDD (COG2454), and 23 other families not classified in the public domain databases. Further sequence clustering revealed relationships between individual sequence clusters and showed heterogeneity within some families, suggesting a possible functional divergence. With five structural groups, 70 defined clusters, over 100,000 proteins, and broad biological functions, the PIN domain-like superfamily constitutes one of the largest and most diverse nuclease superfamilies. Detailed analyses of sequences and structures, domain architectures, and genomic contexts allowed us to predict biological function of several new families, including new toxin-antitoxin components, proteins involved in tRNA/rRNA maturation and transcription/translation regulation. PMID- 28575520 TI - Neural dynamics underlying emotional transmissions between individuals. AB - Emotional experiences are frequently shaped by the emotional responses of co present others. Research has shown that people constantly monitor and adapt to the incoming social-emotional signals, even without face-to-face interaction. And yet, the neural processes underlying such emotional transmissions have not been directly studied. Here, we investigated how the human brain processes emotional cues which arrive from another, co-attending individual. We presented continuous emotional feedback to participants who viewed a movie in the scanner. Participants in the social group (but not in the control group) believed that the feedback was coming from another person who was co-viewing the same movie. We found that social-emotional feedback significantly affected the neural dynamics both in the core affect and in the medial pre-frontal regions. Specifically, the response time-courses in those regions exhibited increased similarity across recipients and increased neural alignment with the timeline of the feedback in the social compared with control group. Taken in conjunction with previous research, this study suggests that emotional cues from others shape the neural dynamics across the whole neural continuum of emotional processing in the brain. Moreover, it demonstrates that interpersonal neural alignment can serve as a neural mechanism through which affective information is conveyed between individuals. PMID- 28575522 TI - Identification of biomarker sets for predicting the efficacy of sublingual immunotherapy against pollen-induced allergic rhinitis. AB - Sublingual immunotherapy (SLIT) is effective against allergic rhinitis, although a substantial proportion of individuals is refractory. Herein, we describe a predictive modality to reliably identify SLIT non-responders (NRs). We conducted a 2-year clinical study in 193 adult patients with Japanese cedar pollinosis, with biweekly administration of 2000 Japanese allergy units of cedar pollen extract as the maintenance dose. After identifying high-responder (HR) patients with improved severity scores and NR patients with unchanged or exacerbated symptoms, differences in 33 HR and 34 NR patients were evaluated in terms of peripheral blood cellular profiles by flow cytometry and serum factors by ELISA and cytokine bead array, both pre- and post-SLIT. Improved clinical responses were seen in 72% of the treated patients. Pre-therapy IL-12p70 and post-therapy IgG1 serum levels were significantly different between HR and NR patients, although these parameters alone failed to distinguish NR from HR patients. However, the analysis of serum parameters in the pre-therapy samples with the Adaptive Boosting (AdaBoost) algorithm distinguished NR patients with high probability within the training data set. Cluster analysis revealed a positive correlation between serum Th1/Th2 cytokines and other cytokines/chemokines in HR patients after SLIT. Thus, processing of pre-therapy serum parameters with AdaBoost and cluster analysis can be reliably used to develop a prediction method for HR/NR patients. PMID- 28575523 TI - Safety and Pharmacokinetic Study of Fidaxomicin in Children With Clostridium difficile-Associated Diarrhea: A Phase 2a Multicenter Clinical Trial. AB - Background: Fidaxomicin is an approved therapy for Clostridium difficile associated diarrhea (CDAD) in adults. The safety of fidaxomicin in children has not been reported. Methods: In this study (ClinicalTrials.gov identifier NCT01591863), pediatric patients with CDAD received twice-daily oral fidaxomicin at a dose of 16 mg/kg per day (up to 200 mg) for 10 days in an open-label study. Plasma and fecal samples were collected for pharmacokinetic assessments. The primary outcome measure was safety, which was assessed by adverse-event (AE), laboratory, and physical examination/vital-sign monitoring. Efficacy was determined through early and sustained clinical response rates (clinical response without recurrence of CDAD). Results: The study enrolled 40 patients (11 months to 17 years of age), many with underlying comorbidity, including neoplasm (23.7%), gastrointestinal disorder (78.9%), and history of CDAD (60.5%). Plasma fidaxomicin and OP-1118 (the major fidaxomicin metabolite) 3- to 5-hour postdose concentrations were 0.6 to 87.4 and 2.4 to 882.0 ng/mL, respectively, and no age related trends were seen. Fecal fidaxomicin concentrations within 24 hours of the last dose averaged 3228 ug/g, and higher concentrations and greater variability in the youngest age group were found. AEs were reported in 73.7% of the patients; most of them were mild (44.7%) to moderate (21.1%) and were considered treatment related in 15.8% of the patients. Overall, the early clinical response rate was 92.1%. The rate of sustained clinical response (clinical response without recurrence through 28 days after treatment) was 65.8% overall. Conclusions: Fidaxomicin was well tolerated in children with CDAD and has a pharmacokinetic profile in children similar to that in adults. The clinical response rate was high. PMID- 28575525 TI - Cytochrome P450 Monooxygenase CYP716A141 is a Unique b-Amyrin C-16b Oxidase Involved in Triterpenoid Saponin Biosynthesis in Platycodon grandiflorus. PMID- 28575524 TI - Identifying transposon insertions and their effects from RNA-sequencing data. AB - Insertional mutagenesis using engineered transposons is a potent forward genetic screening technique used to identify cancer genes in mouse model systems. In the analysis of these screens, transposon insertion sites are typically identified by targeted DNA-sequencing and subsequently assigned to predicted target genes using heuristics. As such, these approaches provide no direct evidence that insertions actually affect their predicted targets or how transcripts of these genes are affected. To address this, we developed IM-Fusion, an approach that identifies insertion sites from gene-transposon fusions in standard single- and paired-end RNA-sequencing data. We demonstrate IM-Fusion on two separate transposon screens of 123 mammary tumors and 20 B-cell acute lymphoblastic leukemias, respectively. We show that IM-Fusion accurately identifies transposon insertions and their true target genes. Furthermore, by combining the identified insertion sites with expression quantification, we show that we can determine the effect of a transposon insertion on its target gene(s) and prioritize insertions that have a significant effect on expression. We expect that IM-Fusion will significantly enhance the accuracy of cancer gene discovery in forward genetic screens and provide initial insight into the biological effects of insertions on candidate cancer genes. PMID- 28575526 TI - Reconstructing the suberin pathway in poplar by chemical and transcriptomic analysis of bark tissues. AB - The tree bark periderm confers the first line of protection against pathogen invasion and abiotic stresses. The phellogen (cork cambium) externally produces cork (phellem) cells that are dead at maturity; while metabolically active, these tissues synthesize cell walls, as well as cell wall modifications, namely suberin and waxes. Suberin is a heteropolymer with aliphatic and aromatic domains, composed of acylglycerols, cross-linked polyphenolics and solvent-extractable waxes. Although suberin is essentially ubiquitous in vascular plants, the biochemical functions of many enzymes and the genetic regulation of its synthesis are poorly understood. We have studied suberin and wax composition in four developmental stages of hybrid poplar (Populus tremula x Populus alba) stem periderm. The amounts of extracellular ester-linked acyl lipids per unit area increased with tissue age, a trend not observed with waxes. We used RNA-Seq deep sequencing technology to investigate the cork transcriptome at two developmental stages. The transcript analysis yielded 455 candidates for the biosynthesis and regulation of poplar suberin, including genes with proven functions in suberin metabolism, genes highlighted as candidates in other plant species and novel candidates. Among these, a gene encoding a putative lipase/acyltransferase of the GDSL-motif family emerged as a suberin polyester synthase candidate, and specific isoforms of peroxidase and laccase genes were preferentially expressed in cork, suggesting that their corresponding proteins may be involved in cross-linking aromatics to form lignin-like polyphenolics. Many transcriptional regulators with possible roles in meristem identity, cork differentiation and acyl-lipid metabolism were also identified. Our work provides the first large-scale transcriptomic dataset on the suberin-synthesizing tissue of poplar bark, contributing to our understanding of tree bark development at the molecular level. Based on these data, we have proposed a number of hypotheses that can be used in future research leading to novel biological insights into suberin biosynthesis and its physiological function. PMID- 28575527 TI - Neighborhood Influences on Violent Reoffending Risk in Released Prisoners Diagnosed With Psychotic Disorders. AB - Released prisoners diagnosed with psychotic disorders have elevated rates of violent reoffending risk and their exposure to adverse neighborhood environments may contribute to this risk. We identified all released sentenced prisoners in Sweden between 2003 and 2013 (n = 47226) and followed them up for a median period of 4.4 years. We identified prisoners who had ever been diagnosed with a psychotic disorder (n = 3782) or prescribed antipsychotics (n = 7366). We examined 3 neighborhood characteristics: income, proportion of welfare recipients, and crime rate. By fitting generalized mixed-effects and negative binomial regression models and adopting within-individual designs that controlled for all time-invariant unmeasured confounders within each individual, we estimated neighborhood intraclass correlations (ICCs) and associations between specific neighborhood characteristics and violent reoffending. Neighborhood factors explained 13.5% (95% CI: 10.9%; 16.6%) of the violent reoffending risk among released prisoners diagnosed with psychotic disorders. This contrasted with 4.3% (95% CI: 3.7%; 4.9%) in all released prisoners. However, after controlling for unmeasured confounding, these estimates were not statistically significant (ICCpsychotic disorders = 0.9%; 95% CI: -0.8%; 2.3%; ICCall prisoners = 0.3%; 95% CI: -0.02%; 0.6%). Similarly, none of the within-individual correlations between the specific neighborhood factors and violent reoffending were significantly different from zero. We found consistent results when we investigated prisoners with other psychiatric and substance use disorders. These findings suggest that placing released prisoners with psychotic disorders in less deprived neighborhoods might not reduce their violent reoffending risk, which may also apply to other psychiatric disorders. The assessment, treatment, and community linkage of high-risk prisoners as a strategy to reduce reoffending needs further research. PMID- 28575528 TI - Increased Striatal and Reduced Prefrontal Cerebral Blood Flow in Clinical High Risk for Psychosis. AB - Increased striatal dopaminergic activity and decreased prefrontal functioning have been reported in individuals at clinical high risk (CHR) for psychosis. Abnormal metabolic rate might affect resting-state cerebral blood flow (rCBF) in the respective regions. Here, we examined if striatal and prefrontal rCBF differ between patients with CHR, first-episode psychosis (FEP), chronic schizophrenia spectrum disorder (SZ) and controls. Two cohorts with a total of 122 participants were included and analyzed separately: 32 patients with SZ and 31 healthy controls (HC) from the University Hospital of Psychiatry, and 59 patients from the Bern Early Recognition and Intervention Center (29 with CHR, 12 with FEP, and 18 clinical controls [CC]). Ultra-high risk criteria were assessed with the Structured Interview for Psychosis-Risk Syndromes, basic symptom criteria with the Schizophrenia Proneness Instrument. rCBF was measured with pseudo-continuous arterial spin labeling 3T-Magnetic Resonance Imaging. Striatal rCBF was significantly increased and prefrontal rCBF significantly decreased in the SZ group compared to HC group and in the CHR and FEP groups compared to CC group. Striatal rCBF correlated significantly with positive symptom scores in SZ and CHR. An inverse correlation between striatal and frontal rCBF was found in controls (HC, CC), but not in patient groups (SZ, FEP, CHR). This is the first study to demonstrate increased neuronal activity within the striatum, but reduced prefrontal activity in patients with CHR, FEP, and SZ compared to the respective controls. Our results indicate that alterations in striatal and prefrontal rCBF are reflecting metabolic abnormalities preceding the onset of frank psychosis. PMID- 28575529 TI - Abnormal gamma-aminobutyric acid neurotransmission in a Kcnq2 model of early onset epilepsy. AB - OBJECTIVE: Mutations of the KCNQ2 gene, which encodes the Kv 7.2 subunit of voltage-gated M-type potassium channels, have been associated with epilepsy in the neonatal period. This developmental stage is unique in that the neurotransmitter gamma aminobutyric acid (GABA), which is inhibitory in adults, triggers excitatory action due to a reversed chloride gradient. METHODS: To examine whether KCNQ2-related neuronal hyperexcitability involves neonatally excitatory GABA, we examined 1-week-old knockin mice expressing the Kv 7.2 variant p.Tyr284Cys (Y284C). RESULTS: Brain slice electrophysiology revealed elevated CA1 hippocampal GABAergic interneuron activity with respect to presynaptic firing and postsynaptic current frequency. Blockade with the GABAA receptor antagonist bicuculline decreased ictal-like bursting in brain slices with lowered divalent ion concentration, which is consistent with GABA mediating an excitatory function that contributes to the hyperexcitability observed in mutant animals. SIGNIFICANCE: We conclude that excitatory GABA contributes to the phenotype in these animals, which raises the question of whether this special type of neurotransmission has broader importance in neonatal epilepsy than is currently recognized. PMID- 28575530 TI - The skeletons in our closet: E-learning tools and what happens when one side does not fit all. AB - In the anatomical sciences, e-learning tools have become a critical component of teaching anatomy when physical space and cadaveric resources are limited. However, studies that use empirical evidence to compare their efficacy to visual kinesthetic learning modalities are scarce. The study examined how a visual kinesthetic experience, involving a physical skeleton, impacts learning when compared with virtual manipulation of a simple two-dimensional (2D) e-learning tool, A.D.A.M. Interactive Anatomy. Students from The University of Western Ontario, Canada (n = 77) participated in a dual-task study to: (1) investigate if a dual-task paradigm is an effective tool for measuring cognitive load across these different learning modalities; and (2) to assess the impact of knowledge recall and spatial ability when using them. Students were assessed using knowledge scores, Stroop task reaction times, and mental rotation test scores. Results demonstrated that the dual-task paradigm was not an effective tool for measuring cognitive load across different learning modalities with respect to kinesthetic learning. However, our study highlighted that handing physical specimens yielded major, positive impacts on performance that a simple commercial e-learning tool failed to deliver (P < 0.001). Furthermore, students with low spatial ability were significantly disadvantaged when they studied the bony joint and were tested on contralateral images (P = 0.046, R = 0.326). This suggests that, despite limbs being mirror images, students should be taught the anatomy of, as well as procedures on, both sides of the human body, enhancing the ability of all students, regardless of spatial ability, to take anatomical knowledge into the clinic and perform successfully. Anat Sci Educ 10: 570-588. (c) 2017 American Association of Anatomists. PMID- 28575531 TI - Myeloperoxidase/HLA Class II Complexes Recognized by Autoantibodies in Microscopic Polyangiitis. AB - OBJECTIVE: Autoantibodies against myeloperoxidase (MPO) that are expressed in neutrophils play an important role in the pathogenesis of microscopic polyangiitis (MPA). We recently observed that misfolded cellular proteins are transported to the cell surface by HLA class II molecules and are targeted by autoantibodies in patients with rheumatoid arthritis or antiphospholipid syndrome, suggesting that HLA class II molecules play an important role in autoantibody recognition. The aim of this study was to address the role of HLA class II molecules in the cell surface expression of MPO in patients with MPA. METHODS: The association of MPO with HLA-DR was analyzed using MPO and HLA-DR transfectants as well as neutrophils from healthy donors and patients with MPA. Autoantibody binding to the MPO/HLA-DR complex was analyzed by flow cytometry. The association of MPO with HLA-DR was assessed using the immunoprecipitation technique. The function of MPO-antineutrophil cytoplasmic antibody (ANCA) was assessed using a neutrophil-like cell line expressing HLA-DR and MPO. RESULTS: MPO protein was detected on the cell surface in the presence of HLA-DR, and the MPO/HLA-DR complex was recognized by MPO-ANCA. A competitive inhibition assay suggested that MPO associated with HLA-DR expresses cryptic autoantibody epitopes for MPO-ANCA. Autoantibody binding to the MPO/HLA-DR complex was correlated with disease susceptibility conferred by each HLA-DR allele, suggesting that the MPO/HLA-DR complex is involved in the pathogenicity of MPA. Indeed, MPO-HLA class II complexes were detected in neutrophils from a patient with MPA as well as in cytokine-stimulated neutrophils from healthy donors. Moreover, MPO-ANCA stimulated MPO/HLA-DR complex-expressing HL-60 cells. CONCLUSION: Our findings suggest that MPO complexed with HLA class II molecules is involved in the pathogenesis of MPA as a target for MPO-ANCA. PMID- 28575532 TI - Reply. PMID- 28575533 TI - Design and Synthesis of a Series of Novel Mixed Borate and Carbonate Halides. AB - Combining different functional units together has been regarded as the most ideal strategy to design and synthesize new inorganic materials. Based on numerous experiments, it was possible to assemble three kinds of anion groups together and find a series of novel mixed borate and carbonate halides, Rb9 [B4 O5 (OH)4 ]3 (CO3 )X?7 H2 O (X=Cl, Br, and I) and K9 [B4 O5 (OH)4 ]3 (CO3 )X?7 H2 O (X=OH and I). Based on the structural template of these compounds, we also obtained the NaRb6 [B4 O5 (OH)4 ]3 X (X=OH, I) crystals through replacement of the CO3 group with the NaO6 octahedron, which results in the crystal structural changes from P6? 2c to R32. In addition, it has been confirmed that the replacement of the CO3 group by the alkali cation has an influence on the band gaps, according to the experimental results and theoretical calculations. Meanwhile, millimeter-scale crystals of Rb9 [B4 O5 (OH)4 ]3 (CO3 )I?7 H2 O, K9 [B4 O5 (OH)4 ]3 (CO3 )I?7 H2 O, K9 [B4 O5 (OH)4 ]3 (CO3 )OH?7 H2 O and NaRb6 [B4 O5 (OH)4 ]3 OH were also obtained after adjusting their growing conditions. PMID- 28575534 TI - CCL2 in the Circulation Predicts Long-Term Progression of Interstitial Lung Disease in Patients With Early Systemic Sclerosis: Data From Two Independent Cohorts. AB - OBJECTIVE: There are few clinical predictors of the progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD). The purpose of this study was to examine the predictive significance of key cytokines for long-term progression of ILD and survival in 2 independent cohorts of patients with early SSc. METHODS: Plasma levels of 11 Th1/Th2 cytokines (interleukin-1beta [IL 1beta], IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, tumor necrosis factor, CCL2, interferon-inducible T cell alpha chemoattractant, and interferon-gamma-inducible 10-kd protein) were measured in 266 patients with early SSc in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) discovery cohort. Levels of CCL2, IL-10, and IL-6 were measured in 171 patients with early SSc in the Canadian Scleroderma Research Group (CSRG) replication cohort. The primary outcome measure was a decline in the forced vital capacity percent predicted (FVC%) value over time. A joint analysis of longitudinal FVC% values and survival was performed. RESULTS: After adjustment for age, sex, and ethnicity, CCL2 and IL 10 were found to be significant predictors of ILD progression in the discovery cohort. Higher CCL2 levels predicted a faster decline in FVC% values (b = -0.57, P = 0.032), while higher IL-10 levels predicted a slower decline (b = 0.26, P = 0.01). A higher CCL2 value was also predictive of poorer survival (hazard ratio 1.76, P = 0.030). In the CSRG replication cohort, higher CCL2 levels predicted a faster decline in FVC% values (b = -0.58, P = 0.038), but neither IL-10 nor IL-6 had predictive significance. A higher CCL2 level also predicted poorer survival (hazard ratio 3.89, P = 0.037). CONCLUSION: Higher CCL2 levels in the circulation were predictive of ILD progression and poorer survival in patients with early SSc, findings that support the notion that CCL2 has a role as a biomarker and potential therapeutic target. PMID- 28575536 TI - Valuing Treatment With Infliximab for Ankylosing Spondylitis Using a Willingness to-Pay Approach. AB - OBJECTIVE: To investigate willingness to pay (WTP) for treatment with infliximab by patients with ankylosing spondylitis (AS) and explore factors associated with WTP. METHODS: Data from 85 patients participating in the European AS Infliximab Cohort (EASIC) open-label extension of the AS Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT) were used. WTP was included at baseline in EASIC and comprised a hypothetical scenario exploring whether the patient would be willing to pay for beneficial effects of infliximab and, if so, what amount they would be willing to pay per administration. Factors associated with WTP were explored using zero-inflated negative binomial (ZINB) regressions. RESULTS: Of the 85 patients, 63 (74.1%) were willing to pay, and among these, the mean amount they were willing to pay per administration was ?275 (median ?100 [interquartile range ?50-200]). Multivariable ZINB analysis showed that Assessment of SpondyloArthritis international Society criteria for 20% improvement (ASAS20) response was associated with a 7-fold lower likelihood to pay 0 euros (odds ratio [OR] 0.14 [95% confidence interval (95% CI) 0.03-0.71]) and a 3-fold increase in the amount willing to pay (exp(beta) = 3.32 [95% CI 1.44 7.69]). In addition, the country of residence was associated with a lower likelihood to pay 0 euros (OR 0.07 [95% CI 0.02-0.36]), while increased age was associated with the amount willing to pay (exp(beta) = 1.05 [95% CI 1.01-1.09]). CONCLUSION: In a hypothetical scenario, three-quarters of patients with AS receiving long-term infliximab stated that they were willing to pay an out-of pocket contribution for this treatment. Treatment response contributed to the willingness as well as to the amount patients were willing to pay. PMID- 28575537 TI - Association between biochemical hyperandrogenism parameters and Ferriman-Gallwey score in patients with polycystic ovary syndrome: A systematic review and meta regression analysis. AB - BACKGROUND AND OBJECTIVE: A limited number of studies have evaluated the relationship between clinical and biochemical hyperandrogenism (HA). This study aimed to evaluate the association between biochemical hyperandrogenism parameters (BHPs) and Ferriman-Gallwey (FG) score in patients with polycystic ovary syndrome (PCOS). METHODS: We searched PubMed, Scopus, Google Scholar, ScienceDirect and Web of Sciences databases (2000-2015) to identify studies investigating clinical and biochemical parameters of HA in PCOS patients. In this meta-analysis, both fixed and random effect models were applied to estimate pooled effect size. To assess the relationships between BHPs and FG score, meta-regression analysis was used. RESULTS: Fifty-five study groups with a total of 6593 PCOS patients were analysed. Meta-regression analysis of pooled data from all eligible studies showed significant positive relationships of FG score with androstenedione (A4) (P=.034) and dehydroepiandrosterone sulphate (DHEAS) (P=.012), whereas it showed no association with total testosterone (tT), free testosterone (fT), sex hormone bonding globulin (SHBG) and free androgen index (FAI). The results did not change after adjusting for quality assessment or method of assay. Nor did the associations between A4 and FG score remain after adjusting for age and BMI, diagnostic criteria for PCOS and study design or the association between DHEAS and FG score remain after adjusting for ethnicity. CONCLUSION: This meta-analysis confirmed the associations of some BHPs, including A4 and DHEAS with FG score, indicating that measurement of these parameters can be useful for managing PCOS patients with hirsutism. PMID- 28575535 TI - Emerging Treatment Models in Rheumatology: IgG4-Related Disease: Insights Into Human Immunology and Targeted Therapies. PMID- 28575539 TI - Clinical Images: Progressive linear blaschkoid lupus erythematosus. PMID- 28575538 TI - Willingness toward organ and body donation among anatomy professors and students in Mexico. AB - Most anatomists agree that cadaver dissection serves as a superior teaching tool in human anatomy education. However, attitudes toward body donation vary widely between different individuals. A questionnaire was developed to determine the attitudes toward body and organ donation among those who learn the most from cadavers: medical students, medical student teaching assistants, medical students involved in research, and anatomy professors. A cross-sectional, prospective study was designed in which the questionnaire was distributed among first-year human anatomy students before undertaking cadaver dissection at the beginning of the semester, and then again after a commemoration service at the end of the course. The questionnaire items included demographic data, as well as questions designed to characterize participants' attitudes regarding body/organ donation from strangers, family members, and whether participants would consider such practices with their own bodies. Out of a total of 517 students enrolled in the Human Anatomy course in the Medical School at the Universidad Autonoma de Nuevo Leon, Mexico during January to June 2016, 95% responded to the first (491) and second (490) surveys. Participants' opinions on their own organ donation was similar before and after exposure to cadaver dissection, with between 87% and 81% in favor of such practices, and only 3% against it, in both surveys. Participants' willingness to donate their own bodies, as well as those of family members, increased, while reluctance regarding such practices decreased by half (P < 0.0001 and P < 0.05). Professors had the highest rates of positive opinions regarding their own body donation (74.9%), with 18.8% undecided. Low opposition toward organ and body donation remains prevalent among both anatomists and physicians in training in Mexico. Anat Sci Educ 10: 589-597. (c) 2017 American Association of Anatomists. PMID- 28575540 TI - Optimizing Antipsychotic Patient Management Using Population Pharmacokinetic Models and Point-of-Care Testing. AB - Schizophrenia is a common disease, characterized by progressive functional decline exacerbated by psychotic relapses that often result from a lack of full adherence to antipsychotic (APS) medication. Although atypical APS medications do not have clear therapeutic windows, as generally required for therapeutic drug monitoring (TDM), measuring APS plasma levels in the context of a population expected range at the point-of-care (POC) may provide valuable clinical insights for differentiating lack of efficacy from a lack of adherence to medication. PMID- 28575541 TI - Trends in the incidence of use of noninsulin glucose-lowering drugs between 2006 and 2013 in France. AB - This study aimed at describing trends in the incidence of use of noninsulin glucose-lowering drugs (NIGLDs) between 2006 and 2013 in France. Repeated cross sectional studies on NIGLD new users were performed annually from 2006 to 2013 within the Echantillon Generaliste des Beneficiaires (EGB) database, a 1/97th representative sample of the population covered by the French healthcare insurance system. NIGLD included metformin, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidylpeptidase-4 (DPP-4) inhibitors, glinides and glucagon-like peptide-1 analogues. New users were defined as patients with no delivery of any NIGLD (first-line new users) or no delivery of a NIGLD of the same class (add-on/switch new users) in the preceding year. Incidence rates of use and corresponding 95% confidence intervals (95% CI) were estimated per 1000 persons. Among the 507 043 persons included in the EGB in 2006, 2036 were identified as NIGLD first-line new users and 2192 as add on/switch new users, which corresponded to an incidence of use of 4.00/00 (95%CI 3.8-4.2) and 4.30/00 (4.1-4.5), respectively. First-line incidence increased to 5.30/00 (5.1-5.5) in 2010 and then decreased to 4.20/00 (4.0-4.4) in 2013; add on/switch incidence increased to 8.00/00 (7.8-8.2) in 2010 and then decreased to 5.30/00 (5.1-5.5) in 2013. This reduction was mainly related to DPP-4 inhibitors, whose use as add-on/switch NIGLDs was roughly halved between 2010 and 2013. Concomitantly, the use of sulfonylureas and glinides increased. In conclusion, after reaching a peak in 2010, the incidence of use of NIGLDs has markedly decreased in France. Since then, prescribers seem to have reverted to older and well-known therapies. PMID- 28575543 TI - Important Issues Concerning the Double-Blind Study of Anakinra in Familial Mediterranean Fever: Comment on the Article by Ben-Zvi et al. PMID- 28575542 TI - Rheumatoid Arthritis Patients' Motivations for Accepting or Resisting Disease Modifying Antirheumatic Drug Treatment Regimens. AB - OBJECTIVE: Patient refusal of and nonadherence to treatment with disease modifying antirheumatic drugs (DMARDs) can adversely affect disease outcomes in rheumatoid arthritis (RA). This qualitative study describes how RA patients' feelings in response to experiences and information affected their decisions to accept (agree to adopt, initiate, and implement) or resist (refuse, avoid, and discontinue) DMARD treatment regimens. METHODS: A total of 48 RA patients were interviewed about their experiences making decisions about DMARDs. The interviews were transcribed, coded, and analyzed for themes related to their internal motivations for accepting or resisting treatment regimens, using a narrative analysis approach. RESULTS: In addition to feelings about the necessity and dangers of medications, patients' feelings towards their identity as an ill person, the act of taking medication, and the decision process itself were important drivers of patient's decisions. For patients' motivations to accept treatment regimens, 2 themes emerged: a desire to return to a normal life, and fear of future disability due to RA. For motivations to resist treatment regimens, 5 themes emerged: fear of medications, maintaining control over health, denial of sick identity, disappointment with treatment, and feeling overwhelmed by the cognitive burden of deciding. CONCLUSION: Feelings in response to experiences and information played a major role in how patients weighed the benefits and costs of treatment options, suggesting that addressing patients' feelings may be important when rheumatologists counsel about therapeutic options. Further research is needed to learn how best to address patients' feelings throughout the treatment decision-making process. PMID- 28575544 TI - Improving Adherence to Exercise: Do People With Knee Osteoarthritis and Physical Therapists Agree on the Behavioral Approaches Likely to Succeed? AB - OBJECTIVE: To describe which behavior change techniques (BCTs) to promote adherence to exercise have been experienced by people with knee osteoarthritis (OA) or used by physical therapists, and to describe patient- and physical therapist-perceived effectiveness of a range of BCTs derived from behavioral theory. METHODS: Two versions of a custom-designed survey were administered in Australia and New Zealand, one completed by adults with symptomatic knee OA and the second by physical therapists who had treated people with knee OA in the past 6 months. Survey questions ascertained the frequency of receiving/prescribing exercise for knee OA, BCTs received/used targeting adherence to exercise, and perceived effectiveness of 36 BCTs to improve adherence to prescribed exercise. RESULTS: A total of 230 people with knee OA and 143 physical therapists completed the survey. Education about the benefits of exercise was the most commonly received/used technique by both groups. People with knee OA rated the perceived effectiveness of all BCTs significantly lower than the physical therapists (mean difference 1.9 [95% confidence interval 1.8-2.0]). When ranked by group mean agreement score, 2 BCTs were among the top 5 for both groups: development of specific goals related to knee pain and function; and review, supervision, and correction of exercise technique at subsequent treatment sessions. CONCLUSION: Goal-setting techniques related to outcomes were considered to be effective by both respondent groups, and testing of interventions incorporating these strategies should be a research priority. PMID- 28575545 TI - Can Patient Navigators Improve Adherence to Disease-Modifying Antirheumatic Drugs? Quantitative Findings From a Six-Month Single-Arm Pilot Intervention. AB - OBJECTIVE: Nonadherence to disease-modifying antirheumatic drugs (DMARDs) is common, worsens during the treatment course, and results in adverse outcomes. We studied whether patient navigators (laypersons trained in care coordination, motivational interviewing, basic pharmacology, and disease management) improved oral DMARD adherence. METHODS: We enrolled 107 patients ages >=18 years with systemic rheumatic diseases who initiated an oral DMARD within 6 months. Navigators interacted with patients up to 2-4 times per week for 6 months. Patients completed validated surveys (Morisky Medication Adherence Scale [MMAS 8], Mental Health Inventory [MHI-5], Beliefs about Medicines Questionnaire, and Brief Illness Perception Questionnaire) at baseline and at 6 months. We used paired t-tests to compare baseline and 6-month outcomes. We examined the association of age, race/ethnicity, insurance, and MHI-5 with change in MMAS-8 score using multivariable linear regression. RESULTS: Among 107 patients enrolled, 69 (64%) completed baseline and 6-month MMAS-8 surveys. Mean +/- SD age was 55 +/- 16 years and 93% were female. The mean +/- SD baseline MMAS-8 score was 6.7 +/- 1.3 (indicating borderline adherence), and the mean +/- SD MHI-5 score was 60.8 +/- 9.1 (<68 suggests any depressive symptoms). After 6 months, there were no significant changes in MMAS-8 (P = 0.09) or MHI-5 (P = 0.83). Patients described fewer medication concerns (P = 0.03), but a more threatening perception of illness (P = 0.01). Our multivariable model demonstrated a small change in MMAS-8 for each 5-year increase in age (beta = 0.14, P = 0.02). CONCLUSION: Our intervention resulted in no significant change in adherence from baseline. A multicenter, randomized controlled trial is needed to determine whether patient navigators are effective in maintaining adherence to DMARDs over time. PMID- 28575546 TI - Quantifying Digital Ulcers in Systemic Sclerosis: Reliability of Computer Assisted Planimetry in Measuring Lesion Size. AB - OBJECTIVE: Digital ulcers are a major problem in patients with systemic sclerosis (SSc), causing severe pain and impairment of hand function. In addition, digital ulcers heal slowly and sometimes become infected, which can lead to gangrene and necessitate amputation if appropriate intervention is not taken. A reliable, objective method for assessing digital ulcer healing or progression is needed in both the clinical and research arenas. This study was undertaken to compare 2 computer-assisted planimetry methods of measurement of digital ulcer area on photographs (ellipse and freehand regions of interest [ROIs]), and to assess the reliability of photographic calibration and the 2 methods of area measurement. METHODS: Photographs were taken of 107 digital ulcers in 36 patients with SSc spectrum disease. Three raters assessed the photographs. Custom software allowed raters to calibrate photograph dimensions and draw ellipse or freehand ROIs. The shapes and dimensions of the ROIs were saved for further analysis. RESULTS: Calibration (by a single rater performing 5 repeats per image) produced an intraclass correlation coefficient (intrarater reliability) of 0.99. The mean +/- SD areas of digital ulcers assessed using ellipse and freehand ROIs were 18.7 +/- 20.2 mm2 and 17.6 +/- 19.3 mm2 , respectively. Intrarater and interrater reliability of the ellipse ROI were 0.97 and 0.77, respectively. For the freehand ROI, the intrarater and interrater reliability were 0.98 and 0.76, respectively. CONCLUSION: Our findings indicate that computer-assisted planimetry methods applied to SSc-related digital ulcers can be extremely reliable. Further work is needed to move toward applying these methods as outcome measures for clinical trials and in clinical settings. PMID- 28575549 TI - Abstracts of the 21st International Congress of Parkinson's Disease and Movement Disorders. PMID- 28575547 TI - Implications for Drug Characterization in Glucose Tolerance Tests Without Insulin: Simulation Study of Power and Predictions Using Model-Based Analysis. AB - In antihyperglycemic drug development, drug effects are usually characterized using glucose provocations. Analyzing provocation data using pharmacometrics has shown powerful, enabling small studies. In preclinical drug development, high power is attractive due to the experiment sizes; however, insulin is not always available, which potentially impacts power and predictive performance. This simulation study was performed to investigate the implications of performing model-based drug characterization without insulin. The integrated glucose-insulin model was used to simulate and re-estimated oral glucose tolerance tests using a crossover design of placebo and study compound. Drug effects were implemented on seven different mechanisms of action (MOA); one by one or in two-drug combinations. This study showed that exclusion of insulin may severely reduce the power to distinguish the correct from competing drug effect, and to detect a primary or secondary drug effect, however, it did not affect the predictive performance of the model. PMID- 28575551 TI - PharmML in Action: an Interoperable Language for Modeling and Simulation. AB - PharmML is an XML-based exchange format created with a focus on nonlinear mixed effect (NLME) models used in pharmacometrics, but providing a very general framework that also allows describing mathematical and statistical models such as single-subject or nonlinear and multivariate regression models. This tutorial provides an overview of the structure of this language, brief suggestions on how to work with it, and use cases demonstrating its power and flexibility. PMID- 28575553 TI - Identification of robust focus measure functions for the automated capturing of focused images from Ziehl-Neelsen stained sputum smear microscopy slide. AB - Capturing of the best-focused image using focus measure function (FMF) from a stack of images acquired at different focus distances is a crucial step in automatic microscopy development. Detection of bacilli present in Ziehl-Neelsen (ZN) stained sputum smears conventional microscope (CM) images is critical to disease diagnosis. Studies have revealed that the performances of FMFs are sensitive to image contents and background noise. In this article, 24 diverse FMFs were implemented on 31 stacks of CM's field of view images acquired from three different microscopes to determine the best-focused one. Seven FMFs achieved the accuracies of greater than 90%. Accuracy, focus error, and false maxima were calculated for each FMF, and overall score and ranking were also calculated for better interpretation. Preprocessing techniques such as filtering and image distortions (noise, contrast, saturation, illumination, etc.) were performed to evaluate the robustness of every FMF. Gaussian derivative, steerable filters, Tenengrad, and Hemli and Scherer's mean FMFs were identified as the most robust and accurate functions with the accuracy >90%. These FMFs have a relatively less focus error and false maxima rate. Full widths at half maximum of these four FMFs were also computed to determine their efficacy for the optimization process. These four FMFs can be implemented for automated capturing of the image from ZN-stained sputum smear slide. Gaussian derivative FMF can also be used effectively for both CM and fluorescence microscope's field of view image stacks to determine the best-focused one from each stack. (c) 2017 International Society for Advancement of Cytometry. PMID- 28575552 TI - Supervised Machine-Learning Reveals That Old and Obese People Achieve Low Dapsone Concentrations. AB - The human species is becoming increasingly obese. Dapsone, which is extensively used across the globe for dermatological disorders, arachnid bites, and for treatment of several bacterial, fungal, and parasitic diseases, could be affected by obesity. We performed a clinical experiment, using optimal design, in volunteers weighing 44-150 kg, to identify the effect of obesity on dapsone pharmacokinetic parameters based on maximum-likelihood solution via the expectation-maximization algorithm. Artificial intelligence-based multivariate adaptive regression splines were used for covariate selection, and identified weight and/or age as predictors of absorption, systemic clearance, and volume of distribution. These relationships occurred only between certain patient weight and age ranges, delimited by multiple hinges and regions of discontinuity, not identified by standard pharmacometric approaches. Older and obese people have lower drug concentrations after standard dosing, but with complex patterns. Given that efficacy is concentration-dependent, optimal dapsone doses need to be personalized for obese patients. PMID- 28575554 TI - [A new stage of development of gerontology and geriatrics in Russia: problems of creation of a geriatric care system. Part 1. Relevance, regulatory infrastructure]. AB - This article is a 1st part of the analytical review, focused on a new step in development of geriatrics in Russia. Creation of state system geriatric care as important part of state politics in the area of enhancement of quality of life was proved. General aspects of improvement of social support of disable elderly persons in condition of restricted budget and interagency separation was presented. Establishment of unified system of medical social support and gerotechnologies for the elderly was substantiated, as a mechanism facilitated life activity and decreasing of demographic loading on economic status of regions of Russian Federation. Legislative and normative regulations of gerontology and geriatric development were observed as well. Accepted legislative and normative acts were analyzed for period since 1977 to 2014. The necessity of approaches to regulation modernization for elderly was demonstrated. Analytical review on number of legislative state documents issued after meeting of Presidium of State Council of the Russian Federation being in August 2014 was also presented. Applicability of these documents for realization new strategy of gerontology and geriatrics development in Russia was proved. PMID- 28575555 TI - [Description of aging dogs and fruit flies based on the kinetic theory]. AB - The aim of the study is to assess the adequacy of model representations, accepted in the kinetic theory of aging of living systems, the analysis of the experimental data obtained on dogs and fruit flies. The work is illustrated by applying the need to develop a mathematical model of the kinetic theory of aging to describe the probability density of death, probability of death, the average duration of life of the considered biological systems in the natural conditions of existence, as well as for dogs with limited time and chronic RA-diciannove impact, and for Drosophila - high external temperature. Op-defined kinetic equation of aging and their parameters. PMID- 28575556 TI - [Endocrinology of cancer and age: early and late stages of ontogenesis]. AB - Processes important for hormone-mediated carcinogenesis are present on different, even very early, ontogenesis stages. Early shifts in hormone-metabolic status often display opposite correlations with the risk of most common age-associated non-communicable pathologies (namely, hormone-dependent cancers and cardiovascular diseases). Additional known contradiction is the raise of reproductive system tumors incidence in the age associated with lower production of mitogenic hormones. Consequently, one should take into account production of steroids in target tissues themselves, recognize the importance of progenotoxic effect, which, apart from mitogenic function, is characteristic for estrogens and their derivatives, as well as the role of endocrine-genotoxic switchings forming so called basic triad, which is born under the influence of age-associated endocrine shifts and environmental factors. Aside from steroids-related system of increased cancer risk, attention should be paid to non-steroid ones (in particular insulin resistance- and inflammatory cytokines-associated), with their close connection to immune system functional state, low-grade chronic inflammation, obesity phenotype, and pro-/anti-inflammatory lipid factors ratio. In total, it confirms and importance of timely preventive interventions on both ontogenesis stages, early and late ones, which are often separated by several decades. PMID- 28575557 TI - [The relationship of lifespan with characteristics of life cycle and stress resistance in 12 species of Drosophila]. AB - In the present study, we investigated the relationship of lifespan with different characteristics of the life history (length of the developmental period, imago body weight, fecundity) and stress resistance (response to oxidative stress, hyperthermia, starvation, and ionizing radiation) in flies of 12 species of the Drosophila genus. It was shown, that D. virilis has the highest maximum lifespan, but the lifespan of D. kikkawai was lowest. The investigated features have a positive (length of the developmental period, imago body weight, stress resistance) or negative (fecundity) correlation with species lifespan. Apparently, the observed differences are caused by adaptations of the species to different environmental conditions of their natural habitat, and lifespan is a key indicator of integrative fitness, reflecting the viability and various characteristics of life history and stress resistance. PMID- 28575558 TI - [Model ontogenetic variability functional state of the organism in different modes of motor activity]. AB - The analysis of the study results of remote training effect of physical training and sports in the age range including the later periods of human ontogenesis, from the point of oxidative stress theory. To study the characteristics of developmental variability of the functional state of the organism, a comparative study of the functional state of the body at different modes of physical activity in different age stages of development was carried out: from sports veterans, remain actively locomotor activity after the termination of sports career; former athletes, leading a sedentary lifestyle; persons engaged in improving the forms of physical exercise; as well as persons who had not engaged in regular physical activity. Subjects contingent was formed of men of various ages, as well as former athletes and coaches teams in cycling and team sports that require endurance predominant manifestation. The results of the research allowed to develop a model that reflects the characteristics and mechanisms of developmental variability of the functional state of the organism under the influence of different modes of physical activity. PMID- 28575559 TI - [Syndrome of emotional burnout among women-physicians elderly]. AB - The article presents the results of a comparative study of clinical symptoms of syndrome of emotional burnout among 84 working in the specialty physician of older women and 48 officially ceasing operations in this specialty. The findings suggest that burnout can take place among representatives of older age and more it is continued, provided professional activities. The cessation of the work activities leads to stress, often with the subsequent development post-traumatic stress disorder and stress-induced diseases. However in this case the clinical symptoms of the syndrome of emotional burnout, does not disappear, but only happens their clinical transformation attach various psychosomatic disorders. Thus, the elderly, suffering the syndrome of emotional burnout, are at high risk group with regard to the formation and development of diseases, associated with stress and require close monitoring in the framework of the compulsory program of medical examination. PMID- 28575560 TI - [Disability in the elderly owing to cerebrovascular diseases: the leading desadaptive syndromes]. AB - The article presents data on the main desadaptive syndromes have disabilities due to cerebrovascular diseases in the elderly according to the results of analysis of medical expert documents the Bureau of medico-social examination of Saint Petersburg in the period from 2010 to 2014. The characteristics of the level, structure, dynamics and distribution according to groups of disability due to cerebrovascular diseases in retirement were shown; clinical expert in the features of the population of older people with disabilities due to cerebrovascular diseases were analyzed. We revealed a consistent decrease in the number of persons with disabilities over 5 years, increase the proportion of persons with disabilities of group III and group I disabled. We have determined the structure of the main desadaptive syndromes in the structure of the cerebrovascular diseases, causing dysfunctions of the body and disability. PMID- 28575561 TI - [Disturbance of coherence of cognitive-motor integration in elderly]. AB - Social activity of older people can be associated with deterioration as motor function (ability to stand on one leg, walk heel to toe), motor dexterity (grasping power, the tapping-test). At the same time, deterioration in motor functions is due to the fading of social activity, and as a result, deterioration of cognitive functions. Greater involvement in social life can slow the deterioration of motor functions and to maintain daily quality of life. PMID- 28575562 TI - [Seven questions for elderly in the practice of primary care physicians]. AB - Although geriatric syndromes are widespread, they often remain undiagnosed leading to the development of adverse outcomes. For the prompt detection of the most common geriatric syndromes in primary care we have created seven issues related to weight loss, vision and hearing impairments, falls, mood disorder, cognitive impairment, urinary incontinence, and the difficulties in walking. We believe that using of these questions will allow physicians to focus on addressing the important health problems associated with age and will produce the selection of patients for comprehensive geriatric assessment. PMID- 28575563 TI - [Validation of the questionnaire for screening frailty]. AB - For screening frailty in daily practice, we developed the questionnaire relating issues of weight loss, impaired vision and hearing, injuries related to falls, mood decline, cognitive impairment, urinary incontinence, and mobility difficulties. 356 outpatients from Moscow were included in the study (mean age 74,9+/-6,1 years, women - 80,4 %). Patients were interviewed using the questionnaire and underwent a comprehensive geriatric assessment. The phenotype model of frailty was determined by L. Fried criteria, the frailty index model - by K. Rockwood criteria. ROC-analysis demonstrated a satisfactory agreement between the result of the survey by the questionnaire and assessment the phenotype model of frailty and the frailty index model (AUC=0,765 and 0,731, respectively). The results statistically significantly correlated with the assessment of the phenotype model of frailty and the frailty index model (Spearman correlation = 0,4 and 0,41, p<0,001). Optimal characteristics of the questionnaire for the frailty screening were consistent to cut-off >=3 and >= 4 points. We propose to use a cut-off >= 3 point, since it corresponds to a higher value of sensitivity (85,7 and 93,3 % compared with the phenotype model of frailty and the frailty index model respectively). The proportion of patients who scored >= 3 points (58,4 %) indicates a high prevalence of geriatric syndromes among outpatients in Moscow. PMID- 28575564 TI - [Archaic stereotypies and modern approaches for understanding of ageing]. AB - In the article we discussed the processes of awareness of the place of elderly people in modern society, elaboration of adequate relation to global aging and elderly themselves are still going in social sciences. These processes are expressed in a clash of archaic stereotypes and new approaches which changed social and age structure requires. Not only elderly people are providers of archaic stereotypes, but scientific institutions and practices as well. Reorientation of science, media and social policy towards study and realization of "postponed aging" opportunities is needed. PMID- 28575565 TI - EEG-neurofeedback training and quality of life of institutionalized elderly women (a pilot study). AB - This pilot study attempted to study the applicability of neurofeedback for elderly persons living in nursing homes. We hypothesized an improve of cognitive functioning and the independence in daily life (IDL) of elderly people by using low beta (12-15HZ) EEG neurofeedback training (E-NFT). The participants (active E NFT group, n=10; control group, n=6) were community living elderly women without dementia. Neurofeedback training was adjusted ten times within 9 weeks, with a training duration of 21 minutes by use of a single electrode, which was centrally placed on the skull surface. Executive functioning (measured with the Rey and fluency tasks), memory capacity (measured with the 15 words test), and IDL (measured with the Groningen Activity Restriction Scale) were measured before and after ten E-NFT sessions in nine weeks. No effects were found for IDL nor executive functioning. Interestingly, performance on the memory test improved in the experimental group, indicating a possible positive effect of E-NFT on memory in elderly women. This study demonstrates that E-NFT is applicable to older institutionalized women. The outcome of this pilot-study justifies the investigation of possible memory effects in future studies. PMID- 28575566 TI - [Adaptation to intermittent hypoxia-hyperoxia improves cognitive performance and exercise tolerance in elderly]. AB - For improvements in exercise tolerance and cognitive function in geriatric patients Multimodal training programs (MTP) are used as combination of physiotherapy, occupational therapy and cardiovascular training. Intermittent Hypoxic-Hyperoxic Training (IHHT), a modified type of intermittent hypoxic training (IHT) is proposed to be included in MTP to elicit more pronounced beneficial effects in exercise tolerance and cognitive functions of geriatric patients likely by an additional pathway than a single MTP. Thirty four patients of the Geriatric Day Clinic aged between 64 and 92 years participated in the placebo controlled clinical trial. They were randomly assigned to receive MTP plus IHHT (experimental group - EG) or MTP plus placebo-breathing through a machine face mask (control group - CG) in a double blind fashion. Before and after the interventions course cognitive performance was assessed by the Dementia Detection-Test (DemTect) and the Clock-Drawing-Test (CDT), and functional exercise capacity - by the total distance of 6-Minute-Walk-Test (6MWT). After IHHT combined with MTP cognitive performance (DemTect) increased significantly when compared to NG (+16,7 % vs. +0,39 %, p<0,001). The CDT indicated similar results with a significant increase in the EG while the score of the CG even decreased (+10,7 % vs. -8%, p=0,031). Concerning the functional exercise capacity, both groups improved the total distance in the 6MWT but with a significantly larger increase in the EG compared to the CG (+24,1 % vs. +10,8 %, p=0,021). In addition, there was a significant relationship between the changes of the 6MWT and the DemTect Scores and the CDT. IHHT contributed significantly to improvements in cognitive performance and exercise capacity in elderly performing MTP. IHHT sessions are considered to be easily applicable to and well tolerated by geriatric patients up to 92 years. PMID- 28575567 TI - [Psychosocial characteristics of elderly people who have committed suicide attempts poisoning]. AB - The aim of this study is to identify psychosocial characteristics of older people who attempted suicide by self-poisoning. A total of 44 older people with suicide attempts by self-poisoning was examined, 12 of whom were male and 32 were female, their average age was 71,9+10,8. The comparison group consisted of 53 young people - 19 males and 34 females, their average age was 26,6+4,4. In both groups dominated deliberate self-poisoning with antiepileptic, sedative, soporific, Antiparkinson and psychotropic drugs (40,9 % vs 47,2 %, p>0,05). Amongst older people number of those who engaged in deliberate self-poisoning with drugs affecting the autonomic nervous system (25 % vs 9,4 %, p<0,05) was significantly higher. Compared with younger adults, older adults are more likely to commit a suicide attempt with serious intentions to complete suicide (62,5 % vs 24,5 %, p<0,05). There is a positive statistically significant correlation between the factor of "suicide attempt with serious intentions" and factors "loneliness" (Y=0,68), "severe physical illness" (Y=0,58) and "constant pain" (Y=0, 60). PMID- 28575568 TI - [Concentration of proinflammatory cytokines, peroxiredoxin-1 and glutathione peroxidase activity in the blood plasma of patients with coronary artery disease undergoing coronary artery bypass grafting]. AB - 76 patients with coronary heart disease (who had undergone coronary artery bypass grafting) were examined to investigate the role of pro-inflammatory cytokines and enzymes involved in redox regulation, in the mechanisms of development of systemic inflammatory response syndrome. Patients were divided into 2 groups: 1st - patients with coronary heart disease, who as a result of clinical trials has not been set postpericardiotomy syndrome; 2nd - patients with coronary heart disease who have been diagnosed postpericardiotomy syndrome. The blood plasma of both groups indicated intensification of production of interleukin-6, intrleukin 8, as well as - an imbalance in the peroxiredoxin-1 and glutathione peroxidase. These changes by patients with postpericardiotomy syndrome are observed at the earliest time and differed depth of expression. The results of this work confirm the high potential of the investigated indicators for prevention and monitoring postpericardiotomy syndrome development. PMID- 28575569 TI - [Results of troponin I testing by high sensitive method in three age groups of healthy population]. AB - Article is about troponin I testing by high sensitive method in healthy population group. 165 people (employees of hospital) were examined, 71 % - women and 29 % - men. Inclusion criteria were as follows: absence of active complaints at the time of health examination and during the previous 30 days. All the examinees were divided into three age groups: 18-34 years (middle age, I period), 35-54 years (middle age, II period), above 55 years (old age). Research of correlation between cardiac troponin I and age of healthy population group was the main aim of investigation. PMID- 28575570 TI - [Aging of the myocardium and dilated cardiomyopathy: morphological and molecular aspects]. AB - The review considers various aspects of myocardium aging in normal and dilated cardiomyopathy (DC). There is a partial fibrosis of the heart tissue due to accumulation of collagen type 1, and accumulation of amyloid during normal aging. Men myocardial aging is accompanied by loss of cardiomyocytes and increased volume of the remaining cells, whereas in women this effect is absent. There is an expression of nuclear proteins decrease (lamin A and C), the accumulation of lipofuscin, increased content of reactive oxygen species, reduction of protein synthesis Sirt1 in cardiomyocytes with aging. Sirt1 has a cardioprotective effect, supports the balance of lipid metabolism, inhibits the development of inflammation and the formation of atherosclerotic plaques. Reduction of its expression not only indicates the accelerated pace of myocardial aging, but can be a predictor of the development of DC. In DC occurs stretching of the heart cavities and systolic dysfunction, predominantly in the left ventricle. DC is characterized by the development of inflammation in the myocardium. Its markers is increased expression of ICAM-1 adhesion molecule, MMP-2, MMP-9 matrix metalloproteinases, TIMP-1 tissue inhibitor of matrix metalloproteinases and decreased expression of MMP-1 matrix metalloproteinase. PMID- 28575571 TI - [Age-related peculiarities of acute cholecystitis]. AB - In the present study the analysis of dynamics of basic laboratory parameters of patients with acute cholecystitis (AC) in the four age groups subdivided according to the WHO classification into young, middle age, elderly and senile was carried out. The most pronounced changes were found in the senile age group in which the AC was accompanied by the decreased number of erythrocytes, low hemoglobin and total protein, leukocytosis, lower percentage of lymphocytes and the highest levels of ALT, AST, bilirubin and urea. Changes in the elderly and senile groups differed and in a number of cases were opposite. In the elderly and especially in the senile group the dynamics of the studied parameters related to surgery, was poorly expressed. These findings can be used in the preparation of the elderly and senile patients for AC surgery. PMID- 28575572 TI - [Features of vertebral pain syndromes in older women depending on the duration of postmenopausal period and bone mineral density indices]. AB - We have analyzed the vertebral pain syndrome (VPS) rate in 2 844 women aged 40-89 years, divided into groups according to the period of life (reproductive, perimenopausal and postmenopausal (PMP)) and evaluated the relationship between VPS frequency and indices of bone mineral density (BMD). It was found that the frequency of VPS during different physiological periods of woman life ranges from 84,1 to 94,4 %, with significant increase when the PMP period is more than 20 years compared with women in reproductive and early postmenopausal periods. The significant increase of the VPS frequency in thoracic and lumbar spines starts from 1-3 years of PMP and is retained at higher level for all subsequent periods of PMP. In postmenopausal women, a significant increase of the relative risk of VPS in the thoracic (in 1,3-1,4 times) and the lumbar (1,2-1,3 times) spines was found. In patients with osteoporosis with duration of PMP for 1-3 years, the frequency of VPS in thoracic spine was significantly higher than the indices in women with osteopenia, while patients with duration of PMP of 7-9 years had significantly higher frequency comparing to groups with osteopenia and norms. In patients without vertebral fractures and osteoporosis VPS frequency in the thoracic spine was significantly higher during periods of 4-6 and 7-9 years of PMP compared with women in reproductive period and compared with the women with normal BMD indices. The revealed features of the VPS should be considered while planning therapeutic interventions in women of older age groups. PMID- 28575573 TI - [Contrast induced nephropathy in the older age group patients]. AB - This review devoted to actual medical problem that exists at a crossroad of cardiology, nephrology and radiology. Contrast induced nephropathy (CIN) is an important medical issue and its frequency is increasing last years. This disease may account for severe complications, including renal failure and even fatal outcome. We investigated contemporary sources to present epidemiology, pathogenesis, diagnosis, treatment and prophylaxis of CIN. PMID- 28575574 TI - Impact of Surface Charge on Cerium Oxide Nanoparticle Uptake and Translocation by Wheat (Triticum aestivum). AB - Nanoparticle (NP) physiochemical properties, including surface charge, affect cellular uptake, translocation, and tissue localization. To evaluate the influence of surface charge on NP uptake by plants, wheat seedlings were hydroponically exposed to 20 mg/L of ~4 nm CeO2 NPs functionalized with positively charged, negatively charged, and neutral dextran coatings. Fresh, hydrated roots and leaves were analyzed at various time points over 34 h using fluorescence X-ray absorption near-edge spectroscopy to provide laterally resolved spatial distribution and speciation of Ce. A 15-20% reduction from Ce(IV) to Ce(III) was observed in both roots and leaves, independent of NP surface charge. Because of its higher affinity with negatively charged cell walls, CeO2(+) NPs adhered to the plant roots the strongest. After 34 h, CeO2(-), and CeO2(0) NP exposed plants had higher Ce leaf concentrations than the plants exposed to CeO2(+) NPs. Whereas Ce was found mostly in the leaf veins of the CeO2(-) NP exposed plant, Ce was found in clusters in the nonvascular leaf tissue of the CeO2(0) NP exposed plant. These results provide important information for understanding mechanisms responsible for plant uptake, transformation, and translocation of NPs, and suggest that NP coatings can be designed to target NPs to specific parts of plants. PMID- 28575575 TI - Tunable Mechanochemistry of Lithium Battery Electrodes. AB - The interplay between mechanical strains and battery electrochemistry, or the tunable mechanochemistry of batteries, remains an emerging research area with limited experimental progress. In this report, we demonstrate how elastic strains applied to vanadium pentoxide (V2O5), a widely studied cathode material for Li ion batteries, can modulate the kinetics and energetics of lithium-ion intercalation. We utilize atomic layer deposition to coat V2O5 materials onto the surface of a shapememory superelastic NiTi alloy, which allows electrochemical assessment at a fixed and measurable level of elastic strain imposed on the V2O5, with strain state assessed through Raman spectroscopy and X-ray diffraction. Our results indicate modulation of electrochemical intercalation potentials by ~40 mV and an increase of the diffusion coefficient of lithium ions by up to 2.5-times with elastic prestrains of <2% imposed on the V2O5. These results are supported by density functional theory calculations and demonstrate how mechanics of nanomaterials can be used as a precise tool to strain engineer the electrochemical energy storage performance of battery materials. PMID- 28575576 TI - Unusual Hollow Al2O3 Nanofibers with Loofah-Like Skins: Intriguing Catalyst Supports for Thermal Stabilization of Pt Nanocrystals. AB - Recently, hollow nanofibers could be fabricated by coaxis electrospinning method or template method. However, they are limited to applications because of the hardship in actual preparation. In this work, hollow gamma-Al2O3 nanofibers with loofah-like skins were first fabricated by using a single spinneret during electrospinning. These intriguing nanofibers were explored as new Pt supports with excellently sinter-resistant performance up to 500 degrees C, attributed to the unique loofah-like surface of gamma-Al2O3 nanofibers and the strong metal support interactions between Pt and gamma-Al2O3. When applied in the catalytic reduction of p-nitrophenol, the Pt/gamma-Al2O3 calcined at 500 degrees C exhibited 4-times higher reaction rate constant (6.8 s-1.mg-1) over free Pt nanocrystals. PMID- 28575577 TI - Diphenylalanine as a Reductionist Model for the Mechanistic Characterization of beta-Amyloid Modulators. AB - The phenomenon of protein aggregation into amyloid fibrils is associated with a large number of major diseases of unrelated etiology. Unraveling the mechanism of amyloid self-assembly and identifying therapeutic directions to control this process are of utmost importance. Research in this field has been hampered by several challenges, including reproducibility, low protein purification yields, and the inherent aggregation propensity of amyloidogenic proteins, making them extremely difficult to study. Herein, on the basis of the similarity in the assembly mechanism, as well as the physical, chemical, and biological characteristics, of diphenylalanine nanostructures and aromatic amino acid containing amyloid fibrils, we report a simple, yet robust peptide-based platform that could be used for screening of small molecules potentially capable of interfering with the aggregation process and for mechanistic exploration of their mode of action. The system was validated using four small-molecule inhibitors, and the effect was examined via turbidity assay, thioflavin T fluorescence, and electron microscopy. The aggregation profile of diphenylalanine was very similar to that of beta-amyloid polypeptide in the presence of the modulators. Rosmarinic acid emerged as an extremely potent inhibitor and a destabilizer of the aggregates. The effect of stoichiometric variation of rosmarinic acid on the process of destabilization was also probed using a microfluidic technique. Finally, the formation of equimolar complexes of diphenylalanine and inhibitors was detected using mass spectrometry. This approach not only provides a system for high-throughput screening of possible inhibitor molecules from larger libraries of modulators, but is also highly useful for understanding the mechanistic aspects of the interactions leading to the process of inhibition. PMID- 28575578 TI - Chain Length Dependence of the Dielectric Constant and Polarizability in Conjugated Organic Thin Films. AB - Dielectric materials are ubiquitous in optics, electronics, and materials science. Recently, there have been new efforts to characterize the dielectric performance of thin films composed of molecular assemblies. In this context, we investigate here the relationship between the polarizability of the constituent molecules and the film dielectric constant, using periodic density functional theory (DFT) calculations, for polyyne and saturated alkane chains. In particular, we explore the implication of the superlinear chain length dependence of the polarizability, a specific feature of conjugated molecules. We show and explain from DFT calculations and a simple depolarization model that this superlinearity is attenuated by the collective polarization. However, it is not completely suppressed. This confers a very high sensitivity of the dielectric constant to the thin film thickness. This latter can increase by a factor of 3-4 at reasonable coverages, by extending the molecular length. This significantly limits the decline of the thin film capacitance with the film thickness. Therefore, the conventional fit of the capacitance versus thickness is not appropriate to determine the dielectric constant of the film. Finally, we show that the failures of semilocal approximations of the exchange-correlation functional lead to a very significant overestimation of this effect. PMID- 28575579 TI - Determination of statin drugs in hospital effluent with dispersive liquid-liquid microextraction and quantification by liquid chromatography. AB - Statins are classified as being amongst the most prescribed agents for treating hypercholesterolaemia and preventing vascular diseases. In this study, a rapid and effective liquid chromatography method, assisted by diode array detection, was designed and validated for the simultaneous quantification of atorvastatin (ATO) and simvastatin (SIM) in hospital effluent samples. The solid phase extraction (SPE) of the analytes was optimized regarding sorbent material and pH, and the dispersive liquid-liquid microextraction (DLLME), in terms of pH, ionic strength, type and volume of extractor/dispersor solvents. The performance of both extraction procedures was evaluated in terms of linearity, quantification limits, accuracy (recovery %), precision and matrix effects for each analyte. The methods proved to be linear in the concentration range considered; the quantification limits were 0.45 ug L-1 for ATO and 0.75 ug L-1 for SIM; the matrix effect was almost absent in both methods and the average recoveries remained between 81.5-90.0%; and the RSD values were <20%. The validated methods were applied to the quantification of the statins in real samples of hospital effluent; the concentrations ranged from 18.8 ug L-1 to 35.3 ug L-1 for ATO, and from 30.3 ug L-1 to 38.5 ug L-1 for SIM. Since the calculated risk quotient was <=192, the occurrence of ATO and SIM in hospital effluent poses a potential serious risk to human health and the aquatic ecosystem. PMID- 28575580 TI - Evaluation of the process performance of a down-flow hanging sponge reactor for direct treatment of domestic wastewater in Bangkok, Thailand. AB - This study assesses the performance of an aerobic trickling filter, down-flow hanging sponge (DHS) reactor, as a decentralized domestic wastewater treatment technology. Also, the characteristic eukaryotic community structure in DHS reactor was investigated. Long-term operation of a DHS reactor for direct treatment of domestic wastewater (COD = 150-170 mg/L and BOD = 60-90 mg/L) was performed under the average ambient temperature ranged from 28 degrees C to 31 degrees C in Bangkok, Thailand. Throughout the evaluation period of 550 days, the DHS reactor at a hydraulic retention time of 3 h showed better performance than the existing oxidation ditch process in the removal of organic carbon (COD removal rate = 80-83% and BOD removal rate = 91%), nitrogen compounds (total nitrogen removal rate = 45-51% and NH4+-N removal rate = 95-98%), and low excess sludge production (0.04 gTS/gCOD removed). The clone library based on the 18S ribosomal ribonucleic acid gene sequence revealed that phylogenetic diversity of 18S rRNA gene in the DHS reactor was higher than that of the present oxidation ditch process. Furthermore, the DHS reactor also demonstrated sufficient COD and NH4+-N removal efficiency under flow rate fluctuation conditions that simulates a small-scale treatment facility. The results show that a DHS reactor could be applied as a decentralized domestic wastewater treatment technology in tropical regions such as Bangkok, Thailand. PMID- 28575581 TI - Development and Validation of a New Cardio-Specific Resting Energy Expenditure Equation for Adults. AB - BACKGROUND: This study tested the accuracy of resting energy expenditure (REE) equations among patients who underwent cardiopulmonary bypass and developed/validated a more accurate cardio-specific equation (CSE). MATERIALS AND METHODS: Prospective observational cohort of 240 adults (derivation data set, 170 patients; validation data set, 70 patients). REEs were calculated with 6 equations-Penn State 2003a, Penn State 2003b, Ireton-Jones, Swinamer, Faisy, and American College of Chest Physicians-and results were compared with indirect calorimetry (IC). Multivariable linear regression analysis was used to develop the CSE. Agreement between measured and calculated REEs was assessed with Lin's concordance correlation coefficient (LCCC), Bland-Altman plot, and regression analysis. RESULTS: LCCCs present poor agreement between measured and calculated REEs: 0.24 (95% CI, 0.19-0.29), for the Faisy equation; 0.15 (95% CI, 0.1-0.19), Ireton-Jones; 0.31 (95% CI, 0.25-0.37), Swinamer; 0.17 (95% CI, 0.13-0.21), Penn State 2003a; 0.19 (95% CI, 0.14-0.23), Penn State 2003b; and 0.11 (95% CI, 0.07 0.15), American College of Chest Physicians. Based on the derivation data set, REEs are explained by the following equation: CSE = 616 - 8 * age in years + 13 * weight in kilograms + 450 if on ventilator + 159 * MV in liters + 145 if on inotropes. Based on the validation study results, the LCCC between IC and the CSE was 0.82 (95% CI, 0.73-0.88). CONCLUSION: The CSE has adequate precision and could be used for REE estimation for patients undergoing cardiopulmonary bypass if IC is unavailable. PMID- 28575582 TI - An immunoinformatics-derived DNA vaccine encoding human class II T cell epitopes of Ebola virus, Sudan virus, and Venezuelan equine encephalitis virus is immunogenic in HLA transgenic mice. AB - Immunoinformatics tools were used to predict human leukocyte antigen (HLA) class II-restricted T cell epitopes within the envelope glycoproteins and nucleocapsid proteins of Ebola virus (EBOV) and Sudan virus (SUDV) and the structural proteins of Venezuelan equine encephalitis virus (VEEV). Selected epitopes were tested for binding to soluble HLA molecules representing 5 class II alleles (DRB1*0101, DRB1*0301, DRB1*0401, DRB1*0701, and DRB1*1501). All but one of the 25 tested peptides bound to at least one of the DRB1 alleles, and 4 of the peptides bound at least moderately or weakly to all 5 DRB1 alleles. Additional algorithms were used to design a single "string-of-beads" expression construct with 44 selected epitopes arranged to avoid creation of spurious junctional epitopes. Seventeen of these 44 predicted epitopes were conserved between the major histocompatibility complex (MHC) of humans and mice, allowing initial testing in mice. BALB/c mice vaccinated with the multi-epitope construct developed statistically significant cellular immune responses to EBOV, SUDV, and VEEV peptides as measured by interferon (IFN)-gamma ELISpot assays. Significant levels of antibodies to VEEV, but not EBOV, were also detected in vaccinated BALB/c mice. To assess immunogenicity in the context of a human MHC, HLA-DR3 transgenic mice were vaccinated with the multi-epitope construct and boosted with a mixture of the 25 peptides used in the binding assays. The vaccinated HLA-DR3 mice developed significant cellular immune responses to 4 of the 25 (16%) tested individual class II peptides as measured by IFN-gamma ELISpot assays. In addition, these mice developed antibodies against EBOV and VEEV as measured by ELISA. While a low but significant level of protection was observed in vaccinated transgenic mice after aerosol exposure to VEEV, no protection was observed after intraperitoneal challenge with mouse-adapted EBOV. These studies provide proof of concept for the use of an informatics approach to design a multi-agent, multi-epitope immunogen and provide a basis for further testing aimed at focusing immune responses toward desired protective T cell epitopes. PMID- 28575584 TI - Variability in inorganic As, Sb and Tl species concentrations in waters and bottom sediments of the Klodnica River (Poland). AB - The study describes the application of new methodologies for the simultaneous determination of As(III)/As(V), Sb(III)/Sb(V) and Tl(I)/Tl(III) ions in waters and bottom sediments of the Klodnica River (Poland) with the hyphenated technique of high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) . Time and spatial correlations were determined in the changes of total and speciation concentrations of the above-mentioned analytes in Klodnica river in 2012. The developed methodologies demonstrate high selectivity and limits of quantification at the level of 0.009-0.120 ug/L. Their repeatability, precision and recovery are appropriate for trace analyses of environmental samples. Time and spatial correlations, and concentrations of inorganic As, Sb and Tl ions demonstrated high variability both in water and bottom sediments. PMID- 28575583 TI - The critical role played by endotoxin-induced liver autophagy in the maintenance of lipid metabolism during sepsis. AB - Macroautophagy/autophagy is a central mechanism by which cells maintain integrity and homeostasis, and endotoxin-induced autophagy plays important roles in innate immunity. Although TLR4 stimulation mediated by lipopolysaccharide (LPS) also upregulates autophagy in hepatocytes and liver, its physiological role remains elusive. The objective of this study was to determine the role of LPS-induced autophagy in the regulation of liver lipid metabolism. LPS treatment (5 mg/kg) increased autophagy, as detected by LC3 conversion and transmission electron microscopy (TEM) analysis in C57BL6 mouse livers. AC2F hepatocytes also showed increased autophagic flux after LPS treatment (1 MUg/ml). To investigate the role of LPS-induced autophagy further, liver lipid metabolism changes in LPS-treated mice and fasted controls were compared. Interestingly, LPS-treated mice showed less lipid accumulation in liver than fasted mice despite increased fatty acid uptake and lipid synthesis-associated genes. In vitro analysis using AC2F hepatocytes demonstrated LPS-induced autophagy influenced the degradation of lipid droplets. Inhibition of LPS-induced autophagy using bafilomycin A1 or Atg7 knockdown significantly increased lipid accumulation in AC2F hepatocytes. In addition, pretreatment with chloroquine aggravated LPS-induced lipid accumulation and inflammation in C57BL6 mouse livers. The physiological importance of autophagy was verified in LPS-treated young and aged rats. Autophagic response was diminished in LPS-treated aged rats and lipid metabolism was impaired during sepsis, indicating autophagy response is important for regulating lipid metabolism after endotoxin challenge. Our findings demonstrate endotoxin-induced autophagy is important for the regulation of lipid metabolism, and suggest that autophagy helps maintain lipid metabolism homeostasis during sepsis. PMID- 28575587 TI - Chemosensory Search Behavior in the Starfish Asterias forbesi. PMID- 28575588 TI - Far Field Chemo-orientation in the American Lobster, Homarus americanus: Effects of Unilateral Ablation and Lesioning of the Lateral Antennule. PMID- 28575586 TI - Do Tea Polyphenols Protect Dogfish Lens (Mustelus canis) Catalase Against UV Damage? PMID- 28575589 TI - Pulsatile Movement of Hermissenda. PMID- 28575590 TI - Behavioral Dynamics That Would Lead to Multiple Paternity within Egg Capsules of the Squid Loligo pealei. PMID- 28575591 TI - Nuclear Microprobe Mapping of Statoliths of Chokka Squid Loligo vulgaris reynaudii d'Orbigny, 1845. AB - Loliginid squid statoliths were broken in half and their elemental composition was assessed using the nuclear microprobe technique. Proton induced X-ray emission and proton backscattering were used simultaneously. True, quantitative maps of calcium and strontium distribution in the frontal plane were obtained using a rapid-matrix-transform method called Dynamic Analysis. These measurements were complemented by observations with scanning electron microscopy and light microscopy. In juvenile and adult statoliths, Sr was concentrated in the wing and adjacent areas, whereas the Ca concentration was highest on the edge of the lateral dome. In contrast, Sr and Ca were uniformly distributed in the statoliths of paralarval squid. Increments showed best definition in the areas anterior and adjacent to the wing, corresponding to areas of high Sr content. Although temperature, sex, maturity, and the administration of oxytetracycline may influence the quantitative distribution of Ca and Sr in the statoliths of adult squid, they do not appear to affect the general pattern described above. The finding that Sr is concentrated in regions adjacent to the macula where the clearest increments are found in loliginid statoliths supports the hypothesis linking strontium with the regulation of statolith deposition and the definition of daily increments. PMID- 28575585 TI - Transforming growth factor-beta: A therapeutic target for cancer. AB - Transforming growth factor-beta (TGF-beta) regulates cell growth and differentiation, apoptosis, cell motility, extracellular matrix production, angiogenesis, and cellular immunity. It has a paradoxical role in cancer. In the early stages it inhibits cellular transformation and prevents cancer progression. In later stages TGF-beta plays a key role in promoting tumor progression through mainly 3 mechanisms: facilitating epithelial to mesenchymal transition, stimulating angiogenesis and inducing immunosuppression. As a result of its opposing tumor promoting and tumor suppressive abilities, TGF-beta and its pathway has represented potential opportunities for drug development and several therapies targeting the TGF-beta pathway have been identified. This review focuses on identifying the mechanisms through which TGF-beta is involved in tumorigenesis and current therapeutics that are under development. PMID- 28575592 TI - Neurons Associated With a Novel Motor Pattern Expressed During Metamorphosis of the Hawkmoth, Manduca sexta. PMID- 28575593 TI - Effectiveness of Continuous Bilateral Sampling for Robot Chemotaxis in a Turbulent Odor Plume: Implications for Lobster Chemo-orientation. PMID- 28575594 TI - Can the Female American Lobster Predict the Dominant Male? PMID- 28575595 TI - Sexual Modes in the Colonial Kamptozoan Genus Barentsia. AB - Sexual mode in colonial animals is expressed at the zooid, colony, and genet level; all three must be characterized to understand sexuality in these animals. I carried out such an examination of the sexual mode of a colonial kamptozoan (entoproct), Barentsia hildegardae, at Friday Harbor, Washington. Calyces never contained both ovaries and testes, and colonies never contained both male and female calyces. Calyces and colonies (including replicate colonies from the same genet) monitored over two years did not change sex. These results suggest that B. hildegardae is comprehensively gonochoric. For comparison, I examined the sexual mode of five other species in the genus Barentsia. Barentsia benedeni, B. conferta, and B. ramosa also appear to be comprehensively gonochoric. Barentsia discreta is hermaphroditic at the colony level, with gonochoric calyces whose sex is environmentally determined, as noted by previous workers. Barentsia aggregata has simultaneously hermaphroditic calyces; this was reported by the authors who described it, but has escaped notice in subsequent reviews of kamptozoan biology. There are thus three contrasting modes of sex within the genus Barentsia. All three modes also occur in colonial cnidarians, and two of them are known in bryozoans, colonial hemichordates, and colonial urochordates. These disparate sexual modes may have evolved as adaptations to differing environmental conditions or population densities. PMID- 28575596 TI - Ciliary Feeding Assisted by Suction From the Muscular Oral Hood of Phoronid Larvae. AB - Phoronid larvae have an oral hood upstream from a postoral encircling array of ciliated tentacles. Cilia move water over the hood and between the tentacles, from anterior to posterior. When an algal cell or other particle in this current contacts a tentacle, the neighboring part of the hood lifts, and the particle is drawn toward the mouth. The correlation between movements of hood and particles indicates that the particle moves with water entering the enlarged space beneath the hood. Each lift of the hood is preceded by contact between a particle and a tentacle. A hood lift follows contact with a particle anywhere along the length of a tentacle, and clearance rates are thus proportional to the total length of tentacles deployed and the velocity of the current past the tentacles. After being detained at the ciliary bands of tentacles, particles are transported by the hood lift at speeds exceeding measured transport along the frontal ciliated surfaces of other larval forms. Faster transport may aid capture of faster prey. The larva's feeding mechanism is unique to the phylum Phoronida. Larvae of brachiopods, bryozoans, hemichordates, and echinoderms have similar ciliary bands producing feeding currents, but none are known to transport food toward the mouth by suction produced by muscle contractions. PMID- 28575597 TI - Zoogeographic Distributions of the Sibling Species Mytilus galloprovincialis and M. trossulus (Bivalvia: Mytilidae) and Their Hybrids in the North Pacific. AB - Diagnostic length differences in a PCR amplified fragment of the gene for byssal adhesive protein were used to study the zoogeographic distribution of Mytilus galloprovincialis and M. trossulus along the west coast of North America and in Japan. The distributions of M. galloprovincialis and M. trossulus are patchy, although an overall geographic pattern emerges. M. galloprovincialis was the only species found on either Kyushu or Honshu, and it was the most abundant mussel from Tomales Bay to San Diego, California. M. trossulus was the only bay mussel found on Hokkaido and in Alaska, and it was by far the most abundant mussel along the coasts of Washington and Oregon. Mytilus galloprovincialis and M. trossulus are sympatric and hybridize near Whidbey Island, Washington, in San Francisco Bay, and in San Diego Bay. A second diagnostic anonymous nuclear PCR marker was used to examine the extent of hybridization at Palo Alto, California. At this site, genotypes appeared to be a mixture of M. galloprovincialis, F1 hybrids between M. galloprovincialis and M. trossulus, and backcrosses between the F1's and M. galloprovincialis. The discontinuity between the zoogeographic distributions of these two species at about 40{deg}-41{deg}N latitude in both the eastern and western Pacific suggests that temperature is a factor in determining their present distribution and limiting their dispersal to other regions. PMID- 28575598 TI - Nearly Optimal Foraging in Patches Under Nutrient Constraints. AB - Three feeding strategies with different rules for prey selectivity were evaluated by Monte Carlo computer simulation. The predator must obtain a minimum quantity of each of three different nutrients, and it sequentially encounters one of three kinds of prey that differ in both their nutrient compositions and their relative abundances. Within patches, prey may be randomly dispersed or aggregated with Markovian transition probabilities. Overall cost is the sum of search time plus consumption cost plus emigration (between-patch traverses) risk. The predator will emigrate if it is unsuccessful in acquiring a minimum of {Gamma} units of any needed nutrient within the T most recent prey encounters. The three strategies are (1) no discrimination-with potentially high consumption costs, (2) minimal consumption-with potentially very prolonged search times, and (3) a hybrid strategy that requires a physiological monitoring of net nutrient acquisition (or the bookkeeping of highly correlated gustatory cues). Each strategy has its characteristic dynamics and optima, but collectively these simulations show that no one strategy is superior and that over a large portion of the parameter space the differences in overall cost are relatively small. PMID- 28575599 TI - Righting Response and Escape Response in Opsanus tau Are Temperature Dependent. PMID- 28575600 TI - Inhibition of Microtubule-Dependent, Minus-End Directed Transport of Axoplasmic Organelles by an Antibody Specific for the Intermediate Chain of Dynein. PMID- 28575601 TI - Comparison of a Nerve Gas Detoxifying Enzyme from Squid and from Pseudomonas diminuta. PMID- 28575602 TI - Aspects of Lead Toxicity and Habituation in Hermissenda Learning. PMID- 28575603 TI - Identification of Toadfish-Pathogenic Bacteria Based on a Comparative Molecular Approach. PMID- 28575604 TI - Photodynamic Effect of 488-nm Light on Eosin-B-stained Spisula Sperm. PMID- 28575605 TI - Physiological Stress Elevates Hemolymph Levels of Methyl Farnesoate in the Green Crab Carcinus maenas. PMID- 28575606 TI - Relationship of Methyl Transferase Activity and Methyl Farnesoate Levels in the Spider Crab, Libinia emarginata. PMID- 28575608 TI - Orientation of Motile Unicellular Algae to Oxygen: Oxytaxis in Euglena. PMID- 28575607 TI - Effect of Gossypol on the Ultrastructure of Spisula Sperm. PMID- 28575609 TI - Catecholamine-Containing Cells in Larval and Postlarval Bivalve Molluscs. AB - Previous studies have suggested an involvement of catecholamines in the control of several larval behaviors, such as feeding, locomotion, and induction of settling and metamorphosis. In the present study we employed aldehyde-induced, blue-green fluorescence to indicate catecholamines in cells within representatives of two bivalve families, the Pectinidae (Placopecten magellanicus) and the Mytilidae (Mytilus edulis). Larvae were examined at different stages of development before and also shortly after settlement. The general distribution of fluorescent cells was similar in the two species. By midveliger stage, several fluorescent cells and fibers were located along the outer rim of each velar lobe, and a pair of flask-shaped cells was located lateral to the mouth. A single fiber from near the mouth projected to a region beneath the apical tuft. In the pediveliger, the cells by the mouth were joined by an additional two to four fluorescent cells. The developing foot also contained numerous such cells, some of which had processes that penetrated the epithelium on the "sole" and bore ciliated terminals. Fluorescent somata were also located around the edge of the mantle. Centrally projecting fibers appeared to terminate in the pedal and abdominal ganglia, which also contained a few fluorescent somata. After settlement, the velar lobes and resident fluorescent somata disappeared, but fluorescent cells in the foot persisted as this latter organ grew. Fluorescent cells within the developing gill were connected with the abdominal ganglia by means of fibers. Control preparations labeled with antibodies raised against serotonin indicated that the aldehyde-induced fluorescence was not due to the presence of indoleamines. The present study not only confirms previous chromatographic evidence suggesting the presence of catecholamines in the larvae of bivalve molluscs, but also identifies putative neuronal circuits that may control various larval behaviors. PMID- 28575610 TI - Chemosensory Activation of an Antennular Grooming Behavior in the Spiny Lobster, Panulirus argus, Is Tuned Narrowly to L-Glutamate. AB - Antennular grooming behavior (AGB) is a stereotyped behavior in crustaceans in which the first pair of antennae, the major olfactory organs, are clasped and wiped repetitively by the third maxillipeds, which also serve as feeding appendages. AGB apparently functions to clear away accumulating debris on or between the antennular aesthetascs (olfactory sensilla). The purpose of this research was to determine whether AGB can be activated by chemicals commonly found in food odors. Lobsters were presented, via headset or handheld pipette, with 27 chemicals found in their food. One chemical, L-glutamate, evoked very high frequencies of wiping. Most chemicals tested were not stimulatory and only a few were weakly stimulatory (adenosine-5'-monophosphate, glycine, D-glutamate). This is surprising because previous studies have shown that other behaviors (antennular flick, search) can be evoked by a much broader array of chemicals found in food odorants. On the basis of these results, we propose that chemosensory neurons that specifically detect L-Glu activate AGB through a recently described non-olfactory pathway. Furthermore, we propose that the role of L-Glu in evoking AGB is based on its electrostatic properties. Because it has a high probability of electrostatic adherence to the antennular cuticle, L-Glu is a sensitive indicator of fouling by food-associated chemicals and thus an appropriate compound to stimulate antennular grooming. PMID- 28575611 TI - Differential Leucocyte Counts in the Toadfish, Opsanus tau: Insignificant Variation with Seasonal Temperature. PMID- 28575612 TI - Bacterial Pericarditis: A New Disease of Toadfish. PMID- 28575614 TI - Antimicrobial Activity in the Microbial Community of the Accessory Nidamental Gland and Egg Cases of Loligo pealei (Cephalopoda: Loliginidae). PMID- 28575615 TI - Coral Bleaching on Johnston Atoll, Central Pacific Ocean. PMID- 28575613 TI - Consumption of Oxygen by Isolated Skate Retinal Photoreceptors. PMID- 28575616 TI - A Hemolytic Activity Secreted by the Endotoxin-Challenged Horseshoe Crab: A Novel Immune System Operating at the Surface of the Carapace. PMID- 28575617 TI - Biosynthetic Induction of a Secondary Metabolite by a Marine Bacterium under Nutritional Stress: Potential Role of the Incomplete Oxidation of an Organic Acid. PMID- 28575618 TI - PCB Contamination Relative to Age for a Pacific Damselfish, Abudefduf sordidus (Pomacentridae). PMID- 28575619 TI - Identification of Phospholipase A2 and Phospholipase C Activities in Calcium Regulatory Endomembranes of Sand Dollar Cells. PMID- 28575620 TI - Comparison of Three Techniques for Evaluating Seasonal Gametogenesis in Spisula solidissima. PMID- 28575621 TI - Apoptosis and Tissue Regression in the Marine Sponge Microciona prolifera. PMID- 28575624 TI - Comparative Settlement Age of Damselfish Larvae (Plectroglyphidodon imparipennis, Pomacentridae) from Hawaii and Johnston Atoll. PMID- 28575622 TI - Statistical Image Analysis of Spatial and Temporal Patterns in the Pre-Nuclear Envelope Breakdown Calcium Signal. PMID- 28575623 TI - Tidal River Riffle Habitats Support High Diversity and Abundance of Gammaridean Amphipods. PMID- 28575625 TI - Control of Periphyton on Zostera marina by the Eastern Mudsnail, Ilyanassa obsoleta (Say), in a Shallow Temperate Estuary. PMID- 28575627 TI - Influence of Grazing and Nitrogen Loading on Benthic Microalgal Biomass in Estuaries of Waquoit Bay, Massachusetts. PMID- 28575626 TI - Binding of Hyaluronic Acid to Cellular Receptors of the Marine Sponge Microciona prolifera. PMID- 28575628 TI - Cell Localization of Lectin Binding in Microciona prolifera Sponge. PMID- 28575629 TI - The Importance of Access to Salt-Marsh Surface to Short-term Growth of Fundulus heteroclitus in a New England Salt Marsh. PMID- 28575631 TI - Experimental Analysis of Tentacle Formation in the Ctenophore Mnemiopsis leidyi. PMID- 28575630 TI - Growth Rates and Abundance of Fundulus heteroclitus in Estuaries Subject to Different Land-Derived Nitrogen Loads in Waquoit Bay, Massachusetts. PMID- 28575632 TI - Squids (Loligo pealei and Euprymna scolopes) Can Exhibit Polarized Light Patterns Produced by Their Skin. PMID- 28575633 TI - Photoreceptor Morphology and Visual Pigment Content in the Retina of the Common White Sucker (Catostomus commersoni). PMID- 28575635 TI - Field Verification of Predictions of the Waquoit Bay Nitrogen Loading Model. PMID- 28575634 TI - Effect of Salinity on the Fate of Inorganic Nitrogen in Sediments of the Parker River Estuary, Massachusetts. PMID- 28575636 TI - Release of N2 and N20 from Salt-Marsh Sediments Subject to Different Land-Derived Nitrogen Loads. PMID- 28575637 TI - Folic acid attenuates homocysteine and enhances antioxidative capacity in atherosclerotic rats. AB - Atherosclerosis is a chronic disease that can seriously endanger human life. Folic acid supplementation modulates several disorders, including atherosclerosis, via its antiapoptotic and antioxidative properties. This study investigated whether folic acid alleviates atherogenesis by restoring homocysteine levels and antioxidative capacity in atherosclerosis Wistar rats. To this end, 28 Wistar rats were randomly divided into 4 groups (7 rats/group) as follows: (i) wild-type group, fed only the AIN-93 semi-purified rodent diet (folic acid: 2.1 mg/kg); (ii) high-fat + folic acid-deficient group (HF+DEF) (folic acid: 0.2 mg/kg); (iii) high-fat + normal folic acid group (folic acid: 2.1 mg/kg); and (iv) high-fat + folic acid-supplemented group (folic acid: 4.2 mg/kg). After 12 weeks, histopathological changes in the atherosclerotic lesions of the aortic arch were determined. In addition, serum folate levels, plasma homocysteine levels, plasma S-adenosyl-homocysteine levels, antioxidant status, oxidant status, and lipid profiles were evaluated. The results show aggravated atherosclerotic lesions in the HF+DEF group. Folic acid supplementation increased concentrations of serum folate. Further, folic acid supplementation increased high-density lipoprotein-cholesterol, decreased plasma homocysteine levels, and improved antioxidant capacity in atherogenic rats. These findings are consistent with the hypothesis that folic acid alleviates atherogenesis by reducing plasma homocysteine levels and improving antioxidant capacity in rats fed a high-fat diet. PMID- 28575638 TI - Elbow Injuries in Professional Baseball: Epidemiological Findings From the Major League Baseball Injury Surveillance System. AB - BACKGROUND: Elbow injuries cause significant disability for the throwing athlete. Scant data are available on the distribution and characteristics of these injuries in elite baseball players. No study exists that focuses solely on the epidemiological characteristics of elbow injuries in professional baseball players using a comprehensive injury surveillance system. HYPOTHESIS: Professional baseball players have a high occurrence of elbow injuries influenced by factors including length of time playing, time period within the annual baseball season, and specific position played. STUDY DESIGN: Descriptive epidemiological study. METHODS: Data on elbow injuries occurring during the 2011 2014 seasons were collected from Major League Baseball's Health Injury and Tracking System, a comprehensive injury surveillance system. Each specific type of elbow injury was evaluated with respect to overall injury rate, years as a professional player, mechanism of injury, treatment, average time lost, and return to play. RESULTS: During the study period, 3185 elbow injuries (n = 430 Major League; n = 2755 Minor League) occurred. The mean number of days missed and percentage requiring surgery were similar between Major and Minor League players. Overall, 20.0% (650/3185) of the injuries required surgical treatment. Pitchers were the most likely to incur an elbow injury (40.0% of injured athletes were pitchers), were the most likely to require surgery (34.2% of injured pitchers required surgery), and had the greatest mean number of days missed when treated nonsurgically (33.2 days). Medial injuries composed 42.1% (1342/3185) of all elbow injuries. Of all elbow surgeries performed during the study period, the highest percentage involved ligaments (372/650; 57.2%). CONCLUSION: Elbow injuries are a considerable source of disability in professional baseball players. Pitchers are most likely to incur these injuries, are most likely to require surgery, and have the highest mean number of days missed when treated nonsurgically. The most common injuries involve the medial elbow, with ligament injuries most often requiring surgery. This study represents the only investigation to date using a comprehensive injury surveillance system to examine elbow injuries in professional baseball players. It provides a basis for injury prevention and treatment recommendations, establishes the most thorough framework for determining elbow injury risk, and focuses continued research on elbow injury prevention in the elite baseball player. PMID- 28575639 TI - Matrix Production Affects MRI Outcomes After Matrix-Associated Autologous Chondrocyte Transplantation in the Knee. AB - BACKGROUND: Matrix-associated autologous chondrocyte transplantation (MACT) has been an effective therapy for large, full-thickness cartilage lesions for years. However, little is known about how graft maturation is affected by characteristics of transplanted chondrocytes. PURPOSE: To investigate the influence of gene expression of chondrocytes at the time of transplantation on MRI outcomes up to 2 years after MACT. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This study included 25 patients with 27 symptomatic traumatic defects of articular cartilage, who had undergone MACT in the knee. Postoperative MRI examinations were conducted at 3, 6, 12, and 24 months after surgery. Biochemical graft maturation was assessed by measuring T2 relaxation time values of the transplant and healthy native cartilage areas. The MOCART (magnetic resonance observation of cartilage repair tissue) score was used to evaluate the morphological quality of regeneration tissue. Gene expression (collagen type I, collagen type II, aggrecan, versican, and interleukin-1beta) was determined by real-time polymerase chain reaction (PCR) in transplant residuals at the time point of transplantation and was correlated with MRI outcomes using Spearman's rank correlation coefficient. A Friedman test with post hoc analysis (Wilcoxon signed rank test) conducted with a Bonferroni correction was applied to compare scores at different time points. RESULTS: T2 relaxation time of regeneration tissue improved from a mean +/- SD of 74.6 +/- 20.1 milliseconds at 3 months to 47.9 +/-13.3 milliseconds at 24 months ( P < .003). These values were similar to the T2 relaxation times of the native surrounding cartilage (50.9 +/- 15 ms). The calculated T2 index (ratio of regeneration tissue to native cartilage) improved from 1.63 +/- 0.76 at 3 months to 1.0 +/- 0.4 at 24 months ( P < .011). The MOCART score increased from 51.6 +/- 15 points to 72.4 +/ 12.2 points ( P < .001). Improvement of the T2 index over time significantly correlated with aggrecan, COL1A1, COL2A1, and versican expression ( rs = 0.9, P < .001; rs = 0.674, P < .012; rs = 0.553, P < .05; and rs = 0.575, P < .04, respectively). No correlation was found for IL-1beta. CONCLUSION: These data demonstrate that matrix production in transplanted chondrocytes affects maturation of MACT grafts in MRI 2 years after surgery. PMID- 28575640 TI - The effect of subinhibitory concentrations of gentian violet on the germ tube formation by Candida albicans and its adherence to oral epithelial cells. AB - OBJECTIVE: This study investigated the effect of subinhibitory concentrations of gentian violet on the germ tube formation by Candida albicans and its adherence ability to oral epithelial cells. METHODS: Thirty strains of C. albicans isolated from denture wearers, normal healthy individuals and HIV positive patients were used in the study. The antifungal property (Minimum Fungicidal Concentration) of gentian violet was determined at various time intervals using a microdilution technique. The effect of subinhibitory concentrations of gentian violet on the adherence ability (0.000244%) and on germ tube formation ((0.000244%, 0.000122%, 0.000061% and 0.000031%) was determined. In both experiments, water was used as a control. The test results were compared using the Kruskal-Wallis test. RESULTS: At 60min a high concentration (0.0078%) of gentian violet was required to completely kill C. albicans. Subinhibitory concentrations of gentian violet significantly reduced the adherence ability of C. albicans by 57% (p<0.01) and equally inhibited germ tube formation (p<0.01) compared with the controls. The inhibition was concentration dependent, with up to 98% reduction at a concentration of 0.000244%. Germ tube reduction was significantly higher in the isolates from the HIV positive patients than in the isolates from denture wearers. CONCLUSION: At high concentrations, gentian violet killed C. albicans, whereas at subinhibitory concentrations it reduced its virulence by preventing the adherence ability and germ tube formation. This suggests that the beneficial effects of gentian violet would last beyond the fungicidal concentrations in the treatment of candidiasis. PMID- 28575641 TI - Systematic analysis of the G-box Factor 14-3-3 gene family and functional characterization of GF14a in Brachypodium distachyon. AB - The 14-3-3 proteins are highly conserved and ubiquitously found in eukaryotes. Plant 14-3-3 proteins are involved in many signaling pathways to regulate plant growth and development. Here we identified seven Brachypodium distachyon 14-3-3 genes and analyzed the evolution, gene structure and expression profiles of these genes. Several cis-elements involved in stress response and hormone pathway were found in the promoter region of 14-3-3 genes. Results of gene expression analysis showed that these genes were induced by abiotic stresses or hormone treatments. Transgenic Arabidopsis overexpressing BdGF14a exhibited increased leaf water content (LWC) and decreased electrolyte leakage (EL) and showed improved drought stress tolerance. BdGF14a transgene significantly up-regulated expression levels of DREB1A and DREB1B, but slightly elevated ABI1 expression. These results indicated that BdGF14a functioned as a positive regulator in plant response to drought stress mainly via ABA independent pathway. PMID- 28575642 TI - Position statement: Harmful effects of environmental noise exposures. PMID- 28575644 TI - Erratum. PMID- 28575643 TI - Council happenings. PMID- 28575645 TI - TESC gene-regulating genetic variant (rs7294919) affects hippocampal subfield volumes and parahippocampal cingulum white matter integrity in major depressive disorder. AB - Two recent genome-wide association studies have suggested that rs7294919 is associated with changes in hippocampal volume. rs7294919 regulates the transcriptional products of the TESC gene, which is involved in neuronal proliferation and differentiation. We investigated the interactive effect of rs7294919 and major depressive disorder (MDD) on the volume of the hippocampal subfields and the integrity of the parahippocampal cingulum (PHC). We also investigated the correlation of these structural changes with the DNA methylation status of rs7294919. A total of 105 patients with MDD and 85 healthy control subjects underwent T1-weighted structural magnetic resonance imaging and diffusion tensor imaging. The rs7294919 was genotyped and its DNA methylation status was assessed in all the participants. We analyzed the hippocampal subfield volumes and PHC integrity using FreeSurfer and the Tracts Constrained by Underlying Anatomy (TRACULA) respectively. Significant interactive effects of rs7294919 and MDD were observed in the volumes of the dentate gyrus and CA4. The patients with MDD had increased methylation in two of the three CpG loci of rs7294919, and the methylation of CpG3 was significantly correlated with right PHC integrity in the MDD group. Our results provide neurobiological evidence for the association of rs7294919 with brain structural changes in MDD. PMID- 28575646 TI - Improvement in quality of life and sexual functioning in a comorbid sample after the unified protocol transdiagnostic group treatment. AB - Patients with multiple mental disorders often experience sexual dysfunction and reduced quality of life. The unified protocol (UP) is a transdiagnostic treatment for emotional disorders that has the potential to improve quality of life and sexual functioning via improved emotion management. The present study evaluates changes in quality of life and sexual functioning in a highly comorbid sample treated with the UP in a group format. Forty-eight patients were randomly assigned to either a UP active-treatment group or a medication-only control group. Treatment was delivered in 14 sessions over the course of 4 months. Symptoms of anxiety and depression were assessed using the Beck Anxiety Inventory and Beck Depression Inventory. Sexual functioning was assessed by the Arizona Sexual Experience Scale (ASEX), and quality of life was assessed by the World Health Organization Quality of Life-BREF scale (WHOQOL-BREF). Quality of life, anxiety and depression all significantly improved among participants treated with the UP. Some improvement in sexual functioning was also noted. The results support the efficacy of the UP in improving quality of life and sexual functioning in comorbid patients. PMID- 28575648 TI - Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans. AB - Ichthyoses are a clinically and genetically heterogeneous group of genodermatoses associated with abnormal scaling of the skin over the whole body. Mutations in nine genes are known to cause non-syndromic forms of autosomal-recessive congenital ichthyosis (ARCI). However, not all genetic causes for ARCI have been discovered to date. Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member 1 (SULT2B1), showing their causative association with ARCI. Cytosolic sulfotransferases form a large family of enzymes that are involved in the synthesis and metabolism of several steroids in humans. We identified four distinct mutations including missense, nonsense, and splice site mutations. We demonstrated the loss of SULT2B1 expression at RNA and protein levels in keratinocytes from individuals with ARCI by functional analyses. Furthermore, we succeeded in reconstructing the morphologic skin alterations in a 3D organotypic tissue culture model with SULT2B1-deficient keratinocytes and fibroblasts. By thin layer chromatography (TLC) of extracts from these organotypic cultures, we could show the absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol, indicating a disturbed cholesterol metabolism of the skin upon loss of-function mutation in SULT2B1. In conclusion, our study reveals an essential role for SULT2B1 in the proper development of healthy human skin. Mutation in SULT2B1 leads to an ARCI phenotype via increased proliferation of human keratinocytes, thickening of epithelial layers, and altered epidermal cholesterol metabolism. PMID- 28575647 TI - YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction. AB - Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators. PMID- 28575649 TI - Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease. AB - Chronic kidney disease (CKD) is a complex gene-environmental disease affecting close to 10% of the US population. Genome-wide association studies (GWASs) have identified sequence variants, localized to non-coding genomic regions, associated with kidney function. Despite these robust observations, the mechanism by which variants lead to CKD remains a critical unanswered question. Expression quantitative trait loci (eQTL) analysis is a method to identify genetic variation associated with gene expression changes in specific tissue types. We hypothesized that an integrative analysis combining CKD GWAS and kidney eQTL results can identify candidate genes for CKD. We performed eQTL analysis by correlating genotype with RNA-seq-based gene expression levels in 96 human kidney samples. Applying stringent statistical criteria, we detected 1,886 genes whose expression differs with the sequence variants. Using direct overlap and Bayesian methods, we identified new potential target genes for CKD. With respect to one of the target genes, lysosomal beta A mannosidase (MANBA), we observed that genetic variants associated with MANBA expression in the kidney showed statistically significant colocalization with variants identified in CKD GWASs, indicating that MANBA is a potential target gene for CKD. The expression of MANBA was significantly lower in kidneys of subjects with risk alleles. Suppressing manba expression in zebrafish resulted in renal tubule defects and pericardial edema, phenotypes typically induced by kidney dysfunction. Our analysis shows that gene-expression changes driven by genetic variation in the kidney can highlight potential new target genes for CKD development. PMID- 28575653 TI - Dynamic Role of trans Regulation of Gene Expression in Relation to Complex Traits. PMID- 28575650 TI - Defects in the Cell Signaling Mediator beta-Catenin Cause the Retinal Vascular Condition FEVR. AB - Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder characterized by the abnormal development of the retinal vasculature. The majority of mutations identified in FEVR are found within four genes that encode the receptor complex (FZD4, LRP5, and TSPAN12) and ligand (NDP) of a molecular pathway that controls angiogenesis, the Norrin-beta-catenin signaling pathway. However, half of all FEVR-affected case subjects do not harbor mutations in these genes, indicating that further mutated genes remain to be identified. Here we report the identification of mutations in CTNNB1, the gene encoding beta-catenin, as a cause of FEVR. We describe heterozygous mutations (c.2142_2157dup [p.His720*] and c.2128C>T [p.Arg710Cys]) in two dominant FEVR-affected families and a de novo mutation (c.1434_1435insC [p.Glu479Argfs*18]) in a simplex case subject. Previous studies have reported heterozygous de novo CTNNB1 mutations as a cause of syndromic intellectual disability (ID) and autism spectrum disorder, and somatic mutations are linked to many cancers. However, in this study we show that Mendelian inherited CTNNB1 mutations can cause non-syndromic FEVR and that FEVR can be a part of the syndromic ID phenotype, further establishing the role that beta-catenin signaling plays in the development of the retinal vasculature. PMID- 28575652 TI - Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma. AB - The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation. PMID- 28575654 TI - SUMO Teams Up with a Translocase to Save TOPO. AB - In this issue of Molecular Cell, Wei et al. (2017) report how a DNA translocase uses SUMO as a cue to save Top2 from ubiquitin-mediated degradation and to minimize DNA breaks, thus providing insights into the SUMO and ubiquitin interplay in genome maintenance. PMID- 28575651 TI - Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination. AB - Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination. PMID- 28575655 TI - The ABC(E1)s of Ribosome Recycling and Reinitiation. AB - In a recent issue of Nature Structural & Molecular Biology, Heuer et al. (2017) present a 3.9-A cryo-EM structure of the 40S:ABCE1 post-splitting complex. This structure provides new insights into a dual role for ABCE1 in translation recycling and reinitiation and revisits the interpretation of Simonetti et al. (2016). PMID- 28575656 TI - Histone Mutants Separate R Loop Formation from Genome Instability Induction. AB - R loops have positive physiological roles, but they can also be deleterious by causing genome instability, and the mechanisms for this are unknown. Here we identified yeast histone H3 and H4 mutations that facilitate R loops but do not cause instability. R loops containing single-stranded DNA (ssDNA), versus RNA-DNA hybrids alone, were demonstrated using ssDNA-specific human AID and bisulfite. Notably, they are similar size regardless of whether or not they induce genome instability. Contrary to mutants causing R loop-mediated instability, these histone mutants do not accumulate H3 serine-10 phosphate (H3S10-P). We propose a two-step mechanism in which, first, an altered chromatin facilitates R loops, and second, chromatin is modified, including H3S10-P, as a requisite for compromising genome integrity. Consistently, these histone mutations suppress the high H3S10 phosphorylation and genomic instability of hpr1 and sen1 mutants. Therefore, contrary to what was previously believed, R loops do not cause genome instability by themselves. PMID- 28575657 TI - RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health. AB - Defects in the repair of DNA interstrand crosslinks (ICLs) are associated with the genome instability syndrome Fanconi anemia (FA). Here we report that cells with mutations in RFWD3, an E3 ubiquitin ligase that interacts with and ubiquitylates replication protein A (RPA), show profound defects in ICL repair. An amino acid substitution in the WD40 repeats of RFWD3 (I639K) found in a new FA subtype abolishes interaction of RFWD3 with RPA, thereby preventing RFWD3 recruitment to sites of ICL-induced replication fork stalling. Moreover, single point mutations in the RPA32 subunit of RPA that abolish interaction with RFWD3 also inhibit ICL repair, demonstrating that RPA-mediated RFWD3 recruitment to stalled replication forks is important for ICL repair. We also report that unloading of RPA from sites of ICL induction is perturbed in RFWD3-deficient cells. These data reveal important roles for RFWD3 localization in protecting genome stability and preserving human health. PMID- 28575658 TI - RFWD3-Mediated Ubiquitination Promotes Timely Removal of Both RPA and RAD51 from DNA Damage Sites to Facilitate Homologous Recombination. AB - RFWD3 is a recently identified Fanconi anemia protein FANCW whose E3 ligase activity toward RPA is essential in homologous recombination (HR) repair. However, how RPA ubiquitination promotes HR remained unknown. Here, we identified RAD51, the central HR protein, as another target of RFWD3. We show that RFWD3 polyubiquitinates both RPA and RAD51 in vitro and in vivo. Phosphorylation by ATR and ATM kinases is required for this activity in vivo. RFWD3 inhibits persistent mitomycin C (MMC)-induced RAD51 and RPA foci by promoting VCP/p97-mediated protein dynamics and subsequent degradation. Furthermore, MMC-induced chromatin loading of MCM8 and RAD54 is defective in cells with inactivated RFWD3 or expressing a ubiquitination-deficient mutant RAD51. Collectively, our data reveal a mechanism that facilitates timely removal of RPA and RAD51 from DNA damage sites, which is crucial for progression to the late-phase HR and suppression of the FA phenotype. PMID- 28575659 TI - Catch and Release of Cytokines Mediated by Tumor Phosphatidylserine Converts Transient Exposure into Long-Lived Inflammation. AB - Immune cells constantly survey the host for pathogens or tumors and secrete cytokines to alert surrounding cells of these threats. In vivo, activated immune cells secrete cytokines for several hours, yet an acute immune reaction occurs over days. Given these divergent timescales, we addressed how cytokine-responsive cells translate brief cytokine exposure into phenotypic changes that persist over long timescales. We studied melanoma cell responses to transient exposure to the cytokine interferon gamma (IFNgamma) by combining a systems-scale analysis of gene expression dynamics with computational modeling and experiments. We discovered that IFNgamma is captured by phosphatidylserine (PS) on the surface of viable cells both in vitro and in vivo then slowly released to drive long-term transcription of cytokine-response genes. This mechanism introduces an additional function for PS in dynamically regulating inflammation across diverse cancer and primary cell types and has potential to usher in new immunotherapies targeting PS and inflammatory pathways. PMID- 28575660 TI - The F-box Protein KIB1 Mediates Brassinosteroid-Induced Inactivation and Degradation of GSK3-like Kinases in Arabidopsis. AB - The glycogen synthase kinase-3 (GSK3) family kinases are central cellular regulators highly conserved in all eukaryotes. In Arabidopsis, the GSK3-like kinase BIN2 phosphorylates a range of proteins to control broad developmental processes, and BIN2 is degraded through unknown mechanism upon receptor kinase mediated brassinosteroid (BR) signaling. Here we identify KIB1 as an F-box E3 ubiquitin ligase that promotes the degradation of BIN2 while blocking its substrate access. Loss-of-function mutations of KIB1 and its homologs abolished BR-induced BIN2 degradation and caused severe BR-insensitive phenotypes. KIB1 directly interacted with BIN2 in a BR-dependent manner and promoted BIN2 ubiquitination in vitro. Expression of an F-box-truncated KIB1 caused BIN2 accumulation but dephosphorylation of its substrate BZR1 and activation of BR responses because KIB1 blocked BIN2 binding to BZR1. Our study demonstrates that KIB1 plays an essential role in BR signaling by inhibiting BIN2 through dual mechanisms of blocking substrate access and promoting degradation. PMID- 28575661 TI - RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis. AB - The MUS81-EME1 endonuclease cleaves late replication intermediates at common fragile sites (CFSs) during early mitosis to trigger DNA-repair synthesis that ensures faithful chromosome segregation. Here, we show that these DNA transactions are promoted by RECQ5 DNA helicase in a manner dependent on its Ser727 phosphorylation by CDK1. Upon replication stress, RECQ5 associates with CFSs in early mitosis through its physical interaction with MUS81 and promotes MUS81-dependent mitotic DNA synthesis. RECQ5 depletion or mutational inactivation of its ATP-binding site, RAD51-interacting domain, or phosphorylation site causes excessive binding of RAD51 to CFS loci and impairs CFS expression. This leads to defective chromosome segregation and accumulation of CFS-associated DNA damage in G1 cells. Biochemically, RECQ5 alleviates the inhibitory effect of RAD51 on 3' flap DNA cleavage by MUS81-EME1 through its RAD51 filament disruption activity. These data suggest that RECQ5 removes RAD51 filaments stabilizing stalled replication forks at CFSs and hence facilitates CFS cleavage by MUS81-EME1. PMID- 28575662 TI - HspQ Functions as a Unique Specificity-Enhancing Factor for the AAA+ Lon Protease. AB - The AAA+ Lon protease is conserved from bacteria to humans, performs crucial roles in protein homeostasis, and is implicated in bacterial pathogenesis and human disease. We investigated how Lon selectively degrades specific substrates among a diverse array of potential targets. We report the discovery of HspQ as a new Lon substrate, unique specificity-enhancing factor, and potent allosteric activator. Lon recognizes HspQ via a C-terminal degron, whose precise presentation, in synergy with multipartite contacts with the native core of HspQ, is required for allosteric Lon activation. Productive HspQ-Lon engagement enhances degradation of multiple new and known Lon substrates. Our studies reveal the existence and simultaneous utilization of two distinct substrate recognition sites on Lon, an HspQ binding site and an HspQ-modulated allosteric site. Our investigations unveil an unprecedented regulatory use of an evolutionarily conserved heat shock protein and present a distinctive mechanism for how Lon protease achieves temporally enhanced substrate selectivity. PMID- 28575663 TI - Structure and Dynamics of a 197 bp Nucleosome in Complex with Linker Histone H1. PMID- 28575664 TI - The persistent sampling bias in developmental psychology: A call to action. AB - Psychology must confront the bias in its broad literature toward the study of participants developing in environments unrepresentative of the vast majority of the world's population. Here, we focus on the implications of addressing this challenge, highlight the need to address overreliance on a narrow participant pool, and emphasize the value and necessity of conducting research with diverse populations. We show that high-impact-factor developmental journals are heavily skewed toward publishing articles with data from WEIRD (Western, educated, industrialized, rich, and democratic) populations. Most critically, despite calls for change and supposed widespread awareness of this problem, there is a habitual dependence on convenience sampling and little evidence that the discipline is making any meaningful movement toward drawing from diverse samples. Failure to confront the possibility that culturally specific findings are being misattributed as universal traits has broad implications for the construction of scientifically defensible theories and for the reliable public dissemination of study findings. PMID- 28575666 TI - The Code for Facial Identity in the Primate Brain. AB - Primates recognize complex objects such as faces with remarkable speed and reliability. Here, we reveal the brain's code for facial identity. Experiments in macaques demonstrate an extraordinarily simple transformation between faces and responses of cells in face patches. By formatting faces as points in a high dimensional linear space, we discovered that each face cell's firing rate is proportional to the projection of an incoming face stimulus onto a single axis in this space, allowing a face cell ensemble to encode the location of any face in the space. Using this code, we could precisely decode faces from neural population responses and predict neural firing rates to faces. Furthermore, this code disavows the long-standing assumption that face cells encode specific facial identities, confirmed by engineering faces with drastically different appearance that elicited identical responses in single face cells. Our work suggests that other objects could be encoded by analogous metric coordinate systems. PAPERCLIP. PMID- 28575665 TI - Senescence in Health and Disease. AB - Many cellular stresses activate senescence, a persistent hyporeplicative state characterized in part by expression of the p16INK4a cell-cycle inhibitor. Senescent cell production occurs throughout life and plays beneficial roles in a variety of physiological and pathological processes including embryogenesis, wound healing, host immunity, and tumor suppression. Meanwhile, the steady accumulation of senescent cells with age also has adverse consequences. These non proliferating cells occupy key cellular niches and elaborate pro-inflammatory cytokines, contributing to aging-related diseases and morbidity. This model suggests that the abundance of senescent cells in vivo predicts "molecular," as opposed to chronologic, age and that senescent cell clearance may mitigate aging associated pathology. PMID- 28575667 TI - Noninvasive Deep Brain Stimulation via Temporally Interfering Electric Fields. AB - We report a noninvasive strategy for electrically stimulating neurons at depth. By delivering to the brain multiple electric fields at frequencies too high to recruit neural firing, but which differ by a frequency within the dynamic range of neural firing, we can electrically stimulate neurons throughout a region where interference between the multiple fields results in a prominent electric field envelope modulated at the difference frequency. We validated this temporal interference (TI) concept via modeling and physics experiments, and verified that neurons in the living mouse brain could follow the electric field envelope. We demonstrate the utility of TI stimulation by stimulating neurons in the hippocampus of living mice without recruiting neurons of the overlying cortex. Finally, we show that by altering the currents delivered to a set of immobile electrodes, we can steerably evoke different motor patterns in living mice. PMID- 28575668 TI - Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome. AB - KCNQ1 is the pore-forming subunit of cardiac slow-delayed rectifier potassium (IKs) channels. Mutations in the kcnq1 gene are the leading cause of congenital long QT syndrome (LQTS). Here, we present the cryoelectron microscopy (cryo-EM) structure of a KCNQ1/calmodulin (CaM) complex. The conformation corresponds to an "uncoupled," PIP2-free state of KCNQ1, with activated voltage sensors and a closed pore. Unique structural features within the S4-S5 linker permit uncoupling of the voltage sensor from the pore in the absence of PIP2. CaM contacts the KCNQ1 voltage sensor through a specific interface involving a residue on CaM that is mutated in a form of inherited LQTS. Using an electrophysiological assay, we find that this mutation on CaM shifts the KCNQ1 voltage-activation curve. This study describes one physiological form of KCNQ1, depolarized voltage sensors with a closed pore in the absence of PIP2, and reveals a regulatory interaction between CaM and KCNQ1 that may explain CaM-mediated LQTS. PMID- 28575670 TI - The Centrosome Is a Selective Condensate that Nucleates Microtubules by Concentrating Tubulin. AB - Centrosomes are non-membrane-bound compartments that nucleate microtubule arrays. They consist of nanometer-scale centrioles surrounded by a micron-scale, dynamic assembly of protein called the pericentriolar material (PCM). To study how PCM forms a spherical compartment that nucleates microtubules, we reconstituted PCM dependent microtubule nucleation in vitro using recombinant C. elegans proteins. We found that macromolecular crowding drives assembly of the key PCM scaffold protein SPD-5 into spherical condensates that morphologically and dynamically resemble in vivo PCM. These SPD-5 condensates recruited the microtubule polymerase ZYG-9 (XMAP215 homolog) and the microtubule-stabilizing protein TPXL-1 (TPX2 homolog). Together, these three proteins concentrated tubulin ~4-fold over background, which was sufficient to reconstitute nucleation of microtubule asters in vitro. Our results suggest that in vivo PCM is a selective phase that organizes microtubule arrays through localized concentration of tubulin by microtubule effector proteins. PMID- 28575669 TI - The Mammalian Ribo-interactome Reveals Ribosome Functional Diversity and Heterogeneity. AB - During eukaryotic evolution, ribosomes have considerably increased in size, forming a surface-exposed ribosomal RNA (rRNA) shell of unknown function, which may create an interface for yet uncharacterized interacting proteins. To investigate such protein interactions, we establish a ribosome affinity purification method that unexpectedly identifies hundreds of ribosome-associated proteins (RAPs) from categories including metabolism and cell cycle, as well as RNA- and protein-modifying enzymes that functionally diversify mammalian ribosomes. By further characterizing RAPs, we discover the presence of ufmylation, a metazoan-specific post-translational modification (PTM), on ribosomes and define its direct substrates. Moreover, we show that the metabolic enzyme, pyruvate kinase muscle (PKM), interacts with sub-pools of endoplasmic reticulum (ER)-associated ribosomes, exerting a non-canonical function as an RNA binding protein in the translation of ER-destined mRNAs. Therefore, RAPs interconnect one of life's most ancient molecular machines with diverse cellular processes, providing an additional layer of regulatory potential to protein expression. PMID- 28575673 TI - Beyond Statins: New Therapeutic Frontiers for Cardiovascular Disease. PMID- 28575671 TI - Structural Basis for Mitotic Centrosome Assembly in Flies. AB - In flies, Centrosomin (Cnn) forms a phosphorylation-dependent scaffold that recruits proteins to the mitotic centrosome, but how Cnn assembles into a scaffold is unclear. We show that scaffold assembly requires conserved leucine zipper (LZ) and Cnn-motif 2 (CM2) domains that co-assemble into a 2:2 complex in vitro. We solve the crystal structure of the LZ:CM2 complex, revealing that both proteins form helical dimers that assemble into an unusual tetramer. A slightly longer version of the LZ can form micron-scale structures with CM2, whose assembly is stimulated by Plk1 phosphorylation in vitro. Mutating individual residues that perturb LZ:CM2 tetramer assembly perturbs the formation of these micron-scale assemblies in vitro and Cnn-scaffold assembly in vivo. Thus, Cnn molecules have an intrinsic ability to form large, LZ:CM2-interaction-dependent assemblies that are critical for mitotic centrosome assembly. These studies provide the first atomic insight into a molecular interaction required for mitotic centrosome assembly. PMID- 28575674 TI - How Do We Recognize a Face? AB - How individual faces are encoded by neurons in high-level visual areas has been a subject of active debate. An influential model is that neurons encode specific faces. However, Chang and Tsao conclusively show that, instead, these neurons encode features along specific axes, which explains why they were previously found to respond to apparently different faces. PMID- 28575675 TI - Noninvasive Neuromodulation Goes Deep. AB - Modulating deep regions of the brain with noninvasive technology has challenged researchers for decades. In a new study, Grossman et al. leverage the emergence of a slowly oscillating "beat" from intersecting high-frequency electric fields to stimulate deep brain regions, opening a frontier in the biophysics and technology of brain stimulation. PMID- 28575672 TI - A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability. AB - Mutations truncating a single copy of the tumor suppressor, BRCA2, cause cancer susceptibility. In cells bearing such heterozygous mutations, we find that a cellular metabolite and ubiquitous environmental toxin, formaldehyde, stalls and destabilizes DNA replication forks, engendering structural chromosomal aberrations. Formaldehyde selectively depletes BRCA2 via proteasomal degradation, a mechanism of toxicity that affects very few additional cellular proteins. Heterozygous BRCA2 truncations, by lowering pre-existing BRCA2 expression, sensitize to BRCA2 haploinsufficiency induced by transient exposure to natural concentrations of formaldehyde. Acetaldehyde, an alcohol catabolite detoxified by ALDH2, precipitates similar effects. Ribonuclease H1 ameliorates replication fork instability and chromosomal aberrations provoked by aldehyde-induced BRCA2 haploinsufficiency, suggesting that BRCA2 inactivation triggers spontaneous mutagenesis during DNA replication via aberrant RNA-DNA hybrids (R-loops). These findings suggest a model wherein carcinogenesis in BRCA2 mutation carriers can be incited by compounds found pervasively in the environment and generated endogenously in certain tissues with implications for public health. PMID- 28575676 TI - Aldehydes Pose a Threat to BRCA2 Mutation Carriers. AB - Humans with inherited heterozygous BRCA2 mutations have an increased risk of developing cancer; however, what triggers carcinogenesis in these individuals is unclear. Tan et al. find that environmental and metabolic aldehydes pose a threat to these individuals by promoting degradation of wild-type BRCA2 protein, thereby predisposing them to genomic instability and perhaps to cancer. PMID- 28575677 TI - Curbing Tregs' (Lack of) Enthusiasm. AB - In this issue, Overacre-Delgoffe et al. show that interferon gamma production by a subset of regulatory T cells in the tumor microenvironment triggers Treg instability locally and restores anti-tumor immunity. PMID- 28575678 TI - Genetic Control of Floral Architecture: Insights into Improving Crop Yield. AB - Selection of plants with traits that are beneficial for cultivation and consumption has been a common practice for thousands of years; however, combination of these traits can be detrimental too, for instance by leading to undesirable branching and yield loss in tomato. The findings from Soyk et al. in this issue of Cell help understand how to bypass such negative effects and improve crop productivity. PMID- 28575679 TI - Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. AB - The WNT signal transduction cascade is a main regulator of development throughout the animal kingdom. Wnts are also key drivers of most types of tissue stem cells in adult mammals. Unsurprisingly, mutated Wnt pathway components are causative to multiple growth-related pathologies and to cancer. Here, we describe the core Wnt/beta-catenin signaling pathway, how it controls stem cells, and contributes to disease. Finally, we discuss strategies for Wnt-based therapies. PMID- 28575680 TI - How does a plant orchestrate defense in time and space? Using glucosinolates in Arabidopsis as case study. AB - The sessile nature of plants has caused plants to develop means to defend themselves against attacking organisms. Multiple strategies range from physical barriers to chemical warfare including pre-formed anticipins as well as phytoalexins produced only upon attack. While phytoalexins require rapid induction, constitutive defenses can impose ecological costs if they deter pollinators or attract specialized herbivores. In the model Arabidopsis thaliana, the well-characterized glucosinolate anticipins are categorized into different classes, aliphatic and indole glucosinolates, depending on their amino acid precursor. Using glucosinolates in Arabidopsis as case study, we will discuss how plants orchestrate synthesis, storage and activation of pre-formed defense compounds spatially and temporally. PMID- 28575682 TI - Experience of harm from others' drinking and support for stricter alcohol policies: Analysis of the Australian National Drug Strategy Household Survey. AB - BACKGROUND: Previous research indicates that those who have experienced alcohol related harm from others are more likely to support stricter alcohol control policies. This study investigates the association between types of harm experienced because of others' drinking and support for stricter alcohol control policies. METHODS: Data from 20,570 Australians aged 18 and over who completed the 2013 National Drug Strategy Household Survey was used. Questions about experience of alcohol-related harm from others - being put in fear and abuse (verbal or physical) - were asked. Support for stricter alcohol control policies was quantified by a mean policy support score across 18 alcohol policy questions. RESULTS: Twenty seven percent of respondents reported harm from someone's drinking. Respondents who were put in fear had a higher level of support for stricter alcohol control policies than respondents who were not harmed (p<0.001), regardless of whether they were abused or not. Conversely, respondents who experienced abuse but were not put in fear did not significantly differ in their support for stricter policies from those who experienced no harm. CONCLUSION: It is the apprehension of harm (i.e. having been put in fear), and not the experience of harm itself (i.e. abuse), which is related to people's support for stricter alcohol policies. These findings suggest that perceiving others' intoxication as dangerous to oneself may motivate support for stricter alcohol policies. PMID- 28575681 TI - Drug use practices among people who inject drugs in a context of drug market changes: Challenges for optimal coverage of harm reduction programs. AB - BACKGROUND: Until the early 2000s, people who inject drugs (PWID) in Quebec had mainly been injecting powder cocaine and heroin. Since then, ethnographic studies have shown that the drug market has diversified, with crack and prescription opioids (PO) becoming increasingly available. This could have led to changes in drug use practices among PWID. The objectives of our study were to examine annual trends in injection of different drugs, crack smoking and frequent injection (FI), as well as relationships between injected drugs and FI. METHODS: PWID are participants in the ongoing Quebec SurvUDI surveillance system. PWID (past 6 months) were recruited in 2 urban and 6 semi-urban/rural sites. Each visit included a structured interview addressing drug use behaviours. Analyses were carried out using GEE methods. For trend analyses (2003-2014) on drugs and FI (number of injections>=upper quartile, previous month), the first annual interview was selected for PWID with multiple participations per year. Analyses on associations between FI and types of injected drugs were based on all interviews (2004-2014). RESULTS: Crack/cocaine and heroin injection declined significantly, with prevalence ratios (PR) per year of 0.983 [95% confidence interval (CI): 0.980-0.986] and 0.979 (95% CI: 0.969-0.990), while PO injection [PR=1.052 (1.045-1.059)], crack smoking [PR=1.006 (1.001-1.012)], and FI (>=120 injections, previous month) significantly increased [PR=1.015 (1.004-1.026)]. Compared to PWID who injected crack/cocaine+/-other drugs, the proportion of PWID reporting FI was higher among those who injected PO+heroin/speedball, crack/cocaine or other drugs (adjusted PR 2.29; 95% CI: 2.07-2.53) or PO only (aPR 1.72; 95%CI: 1.47-2.01). CONCLUSIONS: Changes that have occurred in the drug market are reflected in PWID's practices. The high frequency of injection observed among PO injectors is of particular concern. Drug market variations are a challenge for health authorities responsible for harm reduction programs. PMID- 28575683 TI - Lineage Tracing across 10 Years. PMID- 28575684 TI - Gli-fully Halting the Progression of Fibrosis. AB - Activating triggers, selective markers, and the residual regenerative potential of scar-forming myofibroblasts are largely determined by their origin. In this issue of Cell Stem Cell, Schneider et al. report that bone marrow myofibroblasts derive from Gli1+ mesenchymal stromal cells and that a Gli inhibitor targets them for elimination in mice and humans, ameliorating fibrosis. PMID- 28575685 TI - Surface Markers Guide the Journey toward Naive Pluripotency. AB - Several protocols have managed to reset human primed PSCs to the naive state. In this issue of Cell Stem Cell, Collier et al. (2017) report a set of surface markers that identify which cells are susceptible to resetting and suggest a potential roadmap for the acquisition of naive pluripotency. PMID- 28575686 TI - Adipocytes at the Core of Bone Function. AB - Marrow adipose tissue (MAT) is a specialized adipose tissue with endocrine function found in bone marrow. In this issue of Cell Stem Cell, Ambrosi et al. (2017) identify a stem cell population in the bone marrow that can give rise to both osteogenic and adipogenic MAT precursors and is regulated by diet and aging and affects bone functionality. PMID- 28575687 TI - Mitotic Bookmarking: Maintaining the Stem Cell Identity during Mitosis. AB - In Cell Reports, Liu et al. (2017) investigate mechanisms for how pluripotent stem cells maintain their identity during cell division. They show that the histone mark H3K27ac and pluripotency transcription factors remain associated with mitotic chromatin in ESCs and during iPSC reprogramming, demonstrating the importance of mitotic bookmarking in pluripotency. PMID- 28575688 TI - The Dynamic Identity of Intestinal Cancer Stem Cells. AB - Elimination of self-renewing cancer stem cells (CSCs) is necessary to permanently eradicate malignant tissues. In a recent article in Nature, de Sousa e Melo et al. (2017) reveal that intestinal tumors can contain dynamic pools of functionally distinct CSC populations, which seem to interconvert depending on the host tissue microenvironment. PMID- 28575690 TI - Looking Back: Cancer Stem Cells. AB - Over the past decade, our growing understanding of cancer stem cell characteristics and function continues to guide innovative new treatments to eradicate cancer. For our tenth anniversary, we asked authors who cited a selection of our most popular papers in this area about the broad influences these studies have had. PMID- 28575689 TI - Racing to Uncover the Link between Zika Virus and Microcephaly. AB - In this Backstory, Ming, Song, and Tang give a behind-the-scenes account of the collaboration leading to their 2016 paper on Zika virus infection of neural progenitor cells. It was one of the first clues into how ZIKV could be causing birth defects in babies from infected mothers. PMID- 28575691 TI - Looking Back: Epigenomics. AB - Our understanding of how changes in epigenomics facilitate reprogramming and lineage specification has grown extensively over the last decade. For our tenth anniversary, we asked authors who cited a selection of our most popular papers in this area about how these studies influenced their work and the field. PMID- 28575692 TI - Looking Back: Disease Modeling. AB - Over the past decade, the growth of stem cell-based models of human disorders has contributed to novel drug discovery and precision medicine possibilities. For our tenth anniversary, we asked authors who cited a selection of our most popular papers in this area about how these studies influenced them. PMID- 28575693 TI - Looking Back: Aging and Regeneration. AB - Developing our understanding of how stem cell decline contributes to aging and its associated diseases promotes promising approaches to enhance stem cell regenerative capacity. For our tenth anniversary, we asked authors who cited a selection of our most popular papers in this area about the broad influences these studies have had. PMID- 28575694 TI - Looking Back: Single-Cell Analysis. AB - Over the past few years, burgeoning single-cell analyses platforms have unlocked access to previously unobtainable biological information about stem cell populations. For our tenth anniversary, we asked authors that cited a selection of our most popular papers in this area about how these studies influenced their work and the field. PMID- 28575695 TI - Single-Cell RNA-Seq Analysis Maps Development of Human Germline Cells and Gonadal Niche Interactions. PMID- 28575696 TI - Regiospecific radiolabelling of Nanofitin on Ni magnetic beads with [18F]FBEM and in vivo PET studies. AB - INTRODUCTION: Nanofitins are low molecular weight, single chain and cysteine-free protein scaffolds able to selectively bind a defined biological target. They derive from Sac7d bacterial protein family and are highly stable over a wide range of pH (0-13) and temperature (Tm ~80 degrees C). Their extreme stability, low cost of production and high tolerability for chemical coupling make Nanofitins a very interesting alternative to antibodies and their fragments. Here, a hexahistidine tagged model Nanofitin (H4) directed against hen egg white lysozyme was radiolabelled and injected in mice to provide a baseline biodistribution and pharmacokinetic profiles to support future Nanofitin development programs. METHOD: A single cysteine residue has been genetically inserted in a model Nanofitin and its regioselective radiolabelling has been performed with 4-[18F]fluorobenzamido-N-ethylamino-maleimide ([18F]FBEM). The synthesis of [18F]FBEM has been completely implemented on a radiosynthesis unit (FastLab) including HPLC purification and formulation. Coupling with the [18F]FBEM has been achieved on a solid support (Ni magnetic beads) allowing rapid purification at room temperature without organic solvent. PET-MRI studies on C57BL/6 mice were conducted after injection of [18F]FBEM-Cys-H4 in order to access the biodistribution of this Nanofitin model. RESULTS: Radiochemical yield (decay corrected) of 54+/-7% (n=4) was obtained after optimization for coupling the [18F]FBEM to Nanofitin. Pharmacokinetics results of [18F]FBEM-Cys-H4 revealed a fast clearance through the liver and the kidneys. CONCLUSION: An efficient new method on Ni magnetic beads was developed to radiolabelled his-tagged biomolecules with [18F]FBEM. This procedure was applied on a Nanofitin model Cys H4 and biodistribution kinetic studies were achieved to evaluate the potential use of Nanofitin for diagnostic imaging. Fast clearance indicates that Nanofitins represent very interesting tools for diagnostic imaging. PMID- 28575697 TI - PET/CT with 18F-choline: Physiological whole bio-distribution in male and female subjects and diagnostic pitfalls on 1000 prostate cancer patients: 18F-choline PET/CT bio-distribution and pitfalls. A southern Italian experience. AB - INTRODUCTION: The 11C/18F-choline is a PET/CT radiopharmaceutical useful in detecting tumors with high lipogenesis. 11C/18F-choline uptake can occur in physiological conditions or tumors. The knowledge of its bio-distribution is essential to recognize physiologic variants or diagnostic pitfalls. Moreover, few information are available on the bio-distribution of this tracer in female patients. Our aim was to discuss some documented 18F-choline PET/CT pitfalls in prostate cancer patients. Our secondary aim was to describe the 18F-choline bio distribution in the female body. METHODS: We collected diagnostic pitfalls in three PET centers examining 1000 prostate cancer by 18F-choline PET/CT. All pitfalls were ensured by follow-up, imaging and/or histology. We also performed whole body 18F-choline PET/CT in 5 female patients. RESULTS: 169/1000 (16.9%) patients showed pitfalls not owing to prostate cancer. These findings were due to inflammation, benign tumors while, in 1% of examined patients, a concomitant neoplasm was found. In the female body, the breast showed low physiological uptake. CONCLUSIONS: The accurate knowledge of 18F-choline PET/CT bio distribution and diagnostic pitfalls is essential. Correlative imaging and histological exam are often necessary to depict pitfalls. In women, the uptake in the breast is due to the physiological gradient of 18F-choline uptake in the exocrine glands. ADVANCES IN KNOWLEDGE: Our results confirm the possibility of 18F-choline uptake in several diseases other than prostate cancer. However, our experience was acquired on a large population and shows that a conspicuous amount of 18F-choline diagnostic pitfalls are easily recognizable and attributable to inflammation. A new advance in knowledge is the minimal difference in terms of physiological tracer bio-distribution between male and female patients. IMPLICATIONS FOR PATIENT CARE: The knowledge of the physiological bio distribution and of the potential pitfalls linked of a tracer could help physicians to choose the best diagnostic and therapeutic approaches for a better patient quality of life. PMID- 28575698 TI - Corrigendum to "KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study" [Leuk. Res. 50 (Nov) (2016) 123-131. PubMed PMID: 27736729]. PMID- 28575699 TI - A novel spliced variant of the TIN2 shelterin is present in chronic lymphocytic leukemia. AB - The shelterin proteins play important roles in telomere maintenance and genome stability. These proteins have been found to be mutated in many cancers including CLL. Herein, we demonstrate here the presence of a novel spliced isoform of TIN2S in chronic lymphocytic leukemia (CLL), related to deletion of exon 2 in the TIN2 gene. The expressions of spliced TIN2S mRNA varied widely in CLL and there was an inverse relationship between the mRNA levels of full-length TIN2S and the spliced moiety. Small amounts of spliced TIN2S were also observed in normal B cells but not in T cells. Spliced TIN2S appeared dysfunctional, as immunoprecipitation studies showed the typical association of TRF2 and TIN2 in normal lymphocytes but not in CLL cells. Moreover, whereas TRF2 localized to the nucleus in normal lymphocytes, it was present in both nuclei and cytoplasm in CLL cells. The levels of spliced TIN2S increased with age and in 3 of 8 patients increased over time. The presence of the spliced variant failed to be related to telomere length in CLL suggesting other functions for this protein. Further studies are required to determine the etiology and biological significance of this unique spliced TIN2S variant. PMID- 28575700 TI - Periodic venting of MABR lumen allows high removal rates and high gas-transfer efficiencies. AB - The membrane-aerated biofilm reactor (MABR) is a novel treatment technology that employs gas-supplying membranes to deliver oxygen directly to a biofilm growing on the membrane surface. When operated with closed-end membranes, the MABR provides 100-percent oxygen transfer efficiencies (OTE), resulting in significant energy savings. However, closed-end MABRs are more sensitive to back-diffusion of inert gases, such as nitrogen. Back-diffusion reduces the average oxygen transfer rates (OTR), consequently decreasing the average contaminant removal fluxes (J). We hypothesized that venting the membrane lumen periodically would increase the OTR and J. Using an experimental flow cell and mathematical modeling, we showed that back-diffusion gas profiles developed over relatively long timescales. Thus, very short ventings could re-establish uniform gas profiles for relatively long time periods. Using modeling, we systematically explored the effect of the venting interval (time between ventings). At moderate venting intervals, opening the membrane for 20 s every 30 min, the venting significantly increased the average OTR and J without substantially impacting the OTEs. When the interval was short enough, in this case shorter than 20 min, the OTR was actually higher than for continuous open-end operation. Our results show that periodic venting is a promising strategy to combine the advantages of open-end and closed end operation, maximizing both the OTR and OTE. PMID- 28575701 TI - Detailed modeling of oxalic acid degradation by UV-TiO2 nanoparticles: Importance of light scattering and photoreactor scale-up. AB - A detailed computational fluid dynamics model is presented that integrates reactor hydrodynamics with advanced light models and UV-TiO2 advanced oxidation kinetics to yield the degradation of oxalic acid in a dispersed-phase photoreactor. Model predictions were first compared against experimental data obtained from the literature and subsequently used in a parametric study for investigating scale-up effects associated with both process and photoreactor variables. Investigated variables included: TiO2 concentration (5-400 mg L-1), initial oxalic acid concentration (0.9-32 mg L-1), lamp irradiance (100-10,000 W m-2), background fluid absorbance (0-30 m-1), reactor size (1/4-4 as relative scaling factor), lamp orientation (0-360 degrees ) and flowrate (2.5-10 m3 h-1). The analysis revealed that an optimum in oxalic acid degradation is observed when the TiO2 concentration was controlled in the 20-40 mg L-1 range (depending on lamp irradiance). While lamp orientation showed minimal impact, reactor size and flowrate emerged as key variables for photoreactor design. Moreover, an increase in initial oxalic acid concentration substantially reduced oxalic acid degradation performance observed at high loadings. Also, TiO2 activation and photoreactor degradation performance were impacted negatively by light competition with background fluid absorbance. PMID- 28575702 TI - Gene expression profiles and bioinformatics analysis of human umbilical vein endothelial cells exposed to PM2.5. AB - Cardiovascular system is demonstrated the main target of PM2.5 and the objective of this study was to explore the toxic effect and molecular mechanisms caused by PM2.5 in primary human umbilical vein endothelial cells (HUVECs) using microarray and bioinformatics analysis. The results showed that 591 genes were differentially expressed triggered by PM2.5, of which 174 genes were down regulated, while 417 genes were up-regulated. Gene ontology analysis revealed that PM2.5 caused significant changes in gene expression patterns, including response to stimuli, immune response, and cellular processes. Pathway analysis and Signal-net analysis suggested that endocytosis, chemokine signaling pathway, RNA transport, protein processing in endoplasmic reticulum (ER) and autophagy regulation were the most critical pathways in PM2.5-induced toxicity in HUVECs. Moreover, gene expression confirmation of LIF, BCL2L1, CSF3, HMOX1, RPS6, PFKFB, CAPN1, HSPBP1, MOGS, PREB, TUBB2A, GABARAP by qRT-PCR indicated that endocytosis might be involved in the cellular uptake of PM2.5 by forming phagosomes, and subsequently inflammation, hypoxia and ER stress was occurred, which finally activated autophagy after PM2.5 exposure in HUVECs. In summary, our data can serve as fundamental research clues for further studies of PM2.5-induced toxicity in HUVECs. PMID- 28575703 TI - Impact of feed water pH and membrane material on nanofiltration of perfluorohexanoic acid in aqueous solution. AB - Nanofiltration was thought to be a good option for the recovery of perfluorohexanoic acid (PFHxA) from industrial wastewater. In this study, two commercially available nanofiltration (NF) membranes (NF 270 and NTR-7450) were tested to concentrate the PFHxA in aqueous solution. Filtration test was conducted in crossflow filtration mode. Membrane flux and PFHxA rejection rate were monitored throughout the filtration test. The impact of initial feed water pH on membrane performance was investigated. Results demonstrated that the two NF membranes showed different response to the change of initial feed water pH, which was caused by the intrinsic properties of membrane material. The flux performance of NF 270 was stable, while its rejection rate of PFHxA was very sensitive to the change of initial feed water pH. Opposite result was obtained with NTR-7450. It had a very good stability on rejection rate, while its flux was very sensitive to the change of initial feed water pH. The mechanisms behind these phenomena were also discussed. The results obtained in this study should be very useful for the process design in practical engineering. PMID- 28575704 TI - Muscle function in women with systemic sclerosis: Association with fatigue and general physical function. AB - BACKGROUND: Individuals with systemic sclerosis have muscle functions with varying degrees of muscle weakness and atrophy, which in turn can have a negative impact on functional and health-related quality of life. This study aimed to evaluate peripheral muscle performance using isokinetic dynamometry of the knee in women with systemic sclerosis and to correlate peripheral muscle dysfunction with disability levels and general fatigue. METHODS: Twenty-six women with systemic sclerosis and a matched control group with an equal number of women underwent knee isokinetic dynamometry at angular speeds of 75 degrees /s and 240 degrees /s, isometric handgrip strength, the Health Assessment Questionnaire Disability Index, the Functional Assessment of Chronic Illness Therapy-Fatigue scale, and the Fatigue Impact Scale. FINDINGS: Women with systemic sclerosis showed significant reductions in almost all isokinetic parameters for the two angular velocities tested compared with the controls. An agonist/antagonist ratio with values <40% was observed in approximately one-third of the patients. These patients had lower isometric handgrip strength. These patients also performed worse on the two general fatigue scales evaluated. Significant correlations were observed between the isokinetic parameters and the measured isometric handgrip strength, and the Health Assessment Questionnaire Disability Index. INTERPRETATION: Systemic sclerosis patients have reduced strength and endurance as well as a muscle imbalance between the quadriceps and hamstrings. In these patients, lower muscle dysfunction of the knee joint is associated with lower handgrip strength and physical incapacity. PMID- 28575705 TI - Crossmodal attentional control sets between vision and audition. AB - The interplay between top-down and bottom-up factors in attentional selection has been a topic of extensive research and controversy amongst scientists over the past two decades. According to the influential contingent capture hypothesis, a visual stimulus needs to match the feature(s) implemented into the current attentional control sets in order to be automatically selected. Recently, however, evidence has been presented that attentional control sets affect not only visual but also crossmodal selection. The aim of the present study was therefore to establish contingent capture as a general principle of multisensory selection. A non-spatial interference task with bimodal (visual and auditory) distractors and bimodal targets was used. The target and the distractors were presented in close temporal succession. In order to perform the task correctly, the participants only had to process a predefined target feature in either of the two modalities (e.g., colour when vision was the primary modality). Note that the additional crossmodal stimulation (e.g., a specific sound when hearing was the secondary modality) was not relevant for the selection of the correct response. Nevertheless, larger interference effects were observed when the distractor matched both the stimulus of the primary as well as the secondary modality and this pattern was even stronger if vision was the primary modality than if audition was the primary modality. These results are therefore in line with the crossmodal contingent capture hypothesis. Both visual and auditory early processing seem to be affected by top-down control sets even beyond the spatial dimension. PMID- 28575706 TI - The impact of undergraduate clinical teaching models on the perceptions of work readiness among new graduate nurses: A cross sectional study. AB - BACKGROUND: Clinical Placements are an essential component of bridging the gap between academic theory and nursing practice. There are multiple clinical models designed to ease the transition from student to professional, yet there has been little exploration of such models and their impact on graduates' perceptions of work-readiness. OBJECTIVES: This cross sectional study examined perceptions of work-readiness of new graduate nurses who attended one of the following clinical teaching models: the University Fellowship Program (UFP), the Traditional Multi facility Clinical Model (TMCPM), and the Mixed Program (MP). METHODS: Three groups of first year graduate nurses (UFP, TMCPM, and MP) were compared using the Work-readiness Scale, a validated and reliable tool, which assessed nurses' perceptions of work-readiness in four domains: organizational acumen, personal work characteristics, social intelligence, and work competence. A multivariable Generalized Estimating Equations regression investigated socio-demographic and teaching-modelrelated factors associated with work-readiness. RESULTS: Of 43 nurses approached, 28 completed the survey (65% response rate) of whom 6 were UFP attendants, 8 attended the TMCPM and 14 the MP. Those who had attended the UFP scored higher than the other two in all four domains; however, the crude between group comparisons did not yield statistically significant results. Only after accounting for age, gender, teaching setting and prior work experience, the multivariable model showed that undertaking the UFP was likely to increase perceptions of work-readiness by 1.4 points (95% CI 0.11-2.69), P=0.03). The UFP was superior to the other two placement models. CONCLUSION: The study suggests that the UFP may enhance graduate nurses' perceptions of work readiness. PMID- 28575707 TI - Results of a study assessing teaching methods of faculty after measuring student learning style preference. AB - BACKGROUND: Learning style preference impacts how well groups of students respond to their curricula. Faculty have many choices in the methods for delivering nursing content, as well as assessing students. OBJECTIVES: The purpose was to develop knowledge around how faculty delivered curricula content, and then considering these findings in the context of the students learning style preference. DESIGN: Following an in-service on teaching and learning styles, faculty completed surveys on their methods of teaching and the proportion of time teaching, using each learning style (visual, aural, read/write and kinesthetic). SETTING: This study took place at the College of Nursing a large all-female university in Saudi Arabia. PARTICIPANTS: 24 female nursing faculty volunteered to participate in the project. METHODS: A cross-sectional design was used. RESULTS: Faculty reported teaching using mostly methods that were kinesthetic and visual, although lecture was also popular (aural). Students preferred kinesthetic and aural learning methods. Read/write was the least preferred by students and the least used method of teaching by faculty. CONCLUSIONS: Faculty used visual methods about one third of the time, although they were not preferred by the students. Students' preferred learning style (kinesthetic) was the method most used by faculty. PMID- 28575708 TI - Education of student nurses - A systematic literature review. AB - OBJECTIVE: The aim of this review was to explore the literature on the connection between teaching strategies and nursing students' learning to clarify which teaching strategies provide optimal learning experiences and outcomes. DATA SOURCES: Sources dating from January 2000 to November 2016 were systematically searched in PubMed, Cinahl, Scopus, Web of Science, ProQuest. METHODS: A systematic literature review was conducted that included quantitative and qualitative studies. Quality assessment was made in accordance with Malterud's guidelines on qualitative research and Polit and Beck's guidelines on quantitative research. The analysis was guided by Patricia Benner's organisation of teaching as teaching and learning in classroom and skills laboratory and teaching and learning in clinical practice. RESULT: In this review, 502 titles and abstracts were screened resulting in 45 read and included studies. CONCLUSION: Teaching in skills lab and simulation laboratories provides a positive learning environment and motivates student nurses to learn. It develops critical thinking and the student nurses' ability to take part in what Benner refers to as problem-based nursing. However, there is a need to transform teaching strategies so that student nurses do not experience classroom and clinical practice teaching as separate parts during their education. PMID- 28575709 TI - Explicating Filipino student nurses' preferences of clinical instructors' attributes: A conjoint analysis. AB - The role of clinical instructor in student nurses' preparation for the professional nursing practice cannot be underestimated. The extent to which such role is achieved depends highly on the instructors' ability to realize the desired qualities expected of them. While a number of empirical studies have qualitatively explored the attributes of an effective clinical instructor, no attempt has ventured yet on the power of experimental vignettes for conjoint analysis in explicating the preferences of a select group of Filipino student nurses relative to their clinical instructors' attributes. Junior and senior nursing students (n=227), recruited from one of the comprehensive universities in the Philippines, were asked to sort out orthogonal cards generated by Sawtooth Software. As shown, the full-profile conjoint analysis was considerably fit for this study: Pearson's R=0.988, (p<0.05) and Kendall's t=0.944, (p<0.05). Results indicated that the student nurses are one in terms of their most preferred clinical instructor attribute, which was clinical teaching capacity (38.14%) followed by interpersonal relationship and caring behavior (33.17%). In regard to the clinical teaching capability, a clinical instructor who parallels clinical teaching skills with the students' understanding and experience (0.089) was the highest part-worth. As for the interpersonal relationship and caring behavior, the highest part-worth was a clinical instructor who respects a student nurse as an individual and cares about him/her as a person (0.114). Findings of this study can be a basis for clinical instructors as to which qualities to cultivate best to facilitate a first-rate clinical nursing instruction. Likewise, the results of this study can inform current practices of clinical instructors by making them aware of how they can nurture a pedagogical approach consistent with the student nurses' preferences. PMID- 28575710 TI - Upper limb movement analysis during gait in multiple sclerosis patients. AB - PURPOSE: Gait disorders in multiple sclerosis (MS) are well studied; however, no previous study has described upper limb movements during gait. However, upper limb movements have an important role during locomotion and can be altered in MS patients due to direct MS lesions or mechanisms of compensation. The aim of this study was to describe the arm movements during gait in a population of MS patients with low disability compared with a healthy control group. METHODS: In this observational study we analyzed the arm movements during gait in 52 outpatients (mean age: 39.7+/-9.6years, female: 40%) with relapsing-remitting MS with low disability (mean EDSS: 2+/-1) and 25 healthy age-matched controls using a 3-dimension gait analysis. RESULTS: MS patients walked slower, with increased mean elbow flexion and decreased amplitude of elbow flexion (ROM) compared to the control group, whereas shoulder and hand movements were similar to controls. These differences were not explained by age or disability. CONCLUSION: Upper limb alterations in movement during gait in MS patients with low disability can be characterized by an increase in mean elbow flexion and a decrease in amplitude (ROM) for elbow flexion/extension. This upper limb movement pattern should be considered as a new component of gait disorders in MS and may reflect subtle motor deficits or the use of compensatory mechanisms. PMID- 28575711 TI - Microplastics in the sediments of a UK urban lake. AB - While studies on microplastics in the marine environment show their wide distribution, persistence and contamination of biota, the freshwater environment remains comparatively neglected. Where studies on freshwaters have been undertaken these have been on riverine systems or very large lakes. We present data on the distribution of microplastic particles in the sediments of Edgbaston Pool, a shallow eutrophic lake in central Birmingham, UK. These data provide, to our knowledge, the first assessment of microplastic concentrations in the sediments of either a small or an urban lake and the first for any lake in the UK. Maximum concentrations reached 25-30 particles per 100 g dried sediment (equivalent to low hundreds kg-1) and hence are comparable with reported river sediment studies. Fibres and films were the most common types of microplastic observed. Spatial distributions appear to be due to similar factors to other lake studies (i.e. location of inflow; prevailing wind directions; propensity for biofouling; distribution of macroplastic debris) and add to the growing burden of evidence for microplastic ubiquity in all environments. PMID- 28575712 TI - Effects of titanium dioxide (TiO2) nanoparticles on the photodissolution of particulate organic matter: Insights from fluorescence spectroscopy and environmental implications. AB - Widely used titanium dioxide (TiO2) nanoparticles are likely to accumulate ultimately in sediments and potentially pose a risk to water ecosystems. This study evaluated the effect of TiO2 nanoparticles on the photodissolution of particulate organic matter (POM) through fluorescence spectroscopy. Excitation emission matrices and parallel factor analyses revealed that the fluorescent characteristics of produced dissolved organic matter (DOM) during photodissolution of suspended sediment and synthetic particulate organic matter (SPOM) were primarily humic-like. SPOM particles appeared to simulate well the photodissolution of suspended sediment. Quasi-complete increases in fluorescence intensity and chromophoric DOM (CDOM) abundance were reached after 90, 60, and 50 min irradiation for TiO2 concentrations of 0, 2, and 5 mg L-1, respectively. The faster increment of fluorescence intensity and CDOM abundance indicated the photocatalytic dissolution of SPOM, as opposite charges between TiO2 and SPOM at pH = 4 favored the adsorption of TiO2 onto SPOM. For sediments, the CDOM abundance and fluorescence intensity decreased with increasing TiO2 concentration, resulting from the photocatalytic degradation of photoproduced DOM from sediments. These results demonstrated that pH plays an important role in the photocatalytic dissolution of POM by TiO2. Therefore, appropriate pH controls should be implemented when TiO2 are used to treat sediments contaminated with organic pollutants. Finally, with increasing use of TiO2, its accumulation in sediments may affect the fate of carbon, nutrients, and heavy metals in shallow water ecosystems. PMID- 28575713 TI - Characterization of the peptide fraction from digested Parmigiano Reggiano cheese and its effect on growth of lactobacilli and bifidobacteria. AB - Parmigiano Reggiano (PR) is a raw-milk, hard cooked, long-ripened cheese of high quality and nutritional value. Long ripening times allow for extensive proteolysis of milk proteins to yield a number of peptides, some of which have potential healthy bioactive properties. This study aimed to: i) determine the peptide profile of PR cheese subjected to simulated gastrointestinal transit; ii) evaluate in vitro whether the peptides could support growth of beneficial microbial groups of the gut microbiota. PR samples were subjected to in vitro digestion, simulating oral, gastric, and duodenal transit. Liquid chromatography coupled with tandem mass spectrometry revealed that digestion caused the disappearance of the serum proteins and most of the original peptides, while 71 new peptides were found, all ranging from 2 to 24 residues. The digests were given as sole nitrogen source to pure cultures of Bifidobacterium (27 strains) and Lactobacillus (30 strains), and to bioreactor batch cultures of human gut microbiota. Most of bifidobacteria and lactobacilli grew more abundantly on PR digests than on the control peptone, and exhibited strain- or species-specific peptide preferences, as evidenced by principal component analysis. Bifidobacteria generally consumed a greater amount of peptides than lactobacilli, in terms of both the mean peptide consumption and the number of peptides consumed. For bifidobacteria, peptide preferences were very diverse, but a core of 10 peptides with 4 or 5 residues were consumed by all the strains. Lactobacilli behaved more homogenously and consumed nearly only the same 6 peptides, mostly dipeptides. The peptide preferences of the different groups of bifidobacteria and lactobacilli could not be ascribed to features such as the length of the peptide or the abundance of residues with peculiar properties (hydrophobicity, polarity, charge) and likely depend on specific proteases and/or peptide transporters preferentially recognizing specific sequence motifs. The cultures of human colonic microbiota confirmed that PR digest promoted the growth of commensal bifidobacteria. This study demonstrated that peptides derived from simulated gastrointestinal digestion of PR supported the growth of most lactobacilli and bifidobacteria. PMID- 28575714 TI - Performance of people with diabetes in the labor market: An empirical approach controlling for complications. AB - This paper introduces a framework for modelling the impact that diabetes has on employment status and wages, improving the existing literature by controlling for diabetes-related complications. Using the last wave of the Spanish National Health Survey, we find that 1710 adults out of the original sample of 36,087 have diabetes, reporting higher rates of unemployment. Our empirical results suggest that persons with diabetes, compared with non-diabetic persons, have poorer labor outcomes in terms of length of unemployment and lower income. However, diabetes is not significantly associated with unemployment probabilities, suggesting that the burden of diabetes on employment is mediated by lifestyle factors and clinical and functional complications. In addition, there are mixed outcomes to this econometric approach, depending on age and gender, among other factors. This interesting finding has several implications for research and policy on strategies to get lower health inequalities. PMID- 28575715 TI - Determinants and geographical variation in the distribution of depression in the Southern cone of Latin America: A population-based survey in four cities in Argentina, Chile and Uruguay. AB - BACKGROUND: Depression is one of the major contributors to the global burden of diseases; however, population-based data in South America are limited. METHODS: We conducted a population-based cross sectional study with 7524 participants, aged 35-74 years old, recruited between February 2010 and December 2011 from randomly selected samples in 4 cities (Bariloche and Marcos Paz, Argentina; Temuco, Chile; and Pando-Barros Blancos, Uruguay). Major Depressive Episode (MDE) was assessed using the Patient Health Questionnaire (PHQ) - 9. RESULTS: The overall prevalence of MDE was 14.6% (95% CI: 13.6, 15.6). However, there was a geographical variability of up to 3.7 folds between different cities being 5.6% (95% CI: 4.6, 6.7) in Marcos Paz, Argentina; 9.5% (95% CI: 8.2, 10.9) in Bariloche, Argentina; 18.1% (95% CI: 16.3, 20.0) in Temuco, Chile, and 18.2 (95% CI: 16.3, 20.2) in Pando-Barros Blancos, Uruguay. The multivariate model showed that, adjusted by location, being female, being between 35 and 44 years old, having experienced at least one stressful life event, currently smoking, and having a history of chronic medical diseases were independently associated with an increased risk of MDE, while having higher education and being married or living with a partner reduced the risk of MDE. LIMITATIONS: These results are representative of the selected cities included in the study. As such extrapolation to the general populations of Argentina, Chile, and Uruguay should be done with caution CONCLUSIONS: This study showed a high prevalence and variability of MDE in the Southern Cone of Latin America. PMID- 28575716 TI - Structural network connectivity impairment and depressive symptoms in cerebral small vessel disease. AB - BACKGROUND: Cerebral small vessel disease (SVD) can disrupt mood regulation circuits and cause depressive symptoms which may occur prior to onset of other symptoms. However, the topological network alterations in SVD with depressive symptoms remained unclear. We aim to investigate how these changes in structural network were related to depressive symptoms in SVD. METHODS: We recruited 20 SVD with depressive symptoms (SVD+D), 20 SVD without depressive symptoms (SVD-D) and 16 healthy control (HC) individuals. Graph theory and diffusion tensor imaging (DTI) were applied to construct a structural network. We compared networks between groups, and examined the relationships between network properties, conventional measures of MRI, and depressive symptoms. RESULTS: The structural network was significantly disrupted in global and regional levels in both SVD groups. SVD+D group showed more severe impairment of global network efficiency, and lower nodal efficiency and less connections within multiple regions like hippocampus, amygdala and several cortical structures. The disruption of network connectivity was associated with depressive symptoms and MRI measures of SVD, however, no mediation effect of network efficiency was detected between MRI measures and depressive symptoms. LIMITATION: The relatively small sample size and lower spatial resolution of DTI-based network limited our power of investigation. CONCLUSIONS: The brain structural network is significantly disrupted in SVD+D and the impairment is related to severity of vascular damages and depressive symptoms. The study provides evidence for the role of structural network damage in SVD-related depressive symptoms and might be a potential novel disease marker for SVD and comorbid depression. PMID- 28575717 TI - Recurrent pulmonary emboli with characteristic histopathology. AB - We report a unique case of recurrent thromboembolism and its histological findings that were revealed in an autopsy. Although it is well known that repeating thrombosis presents organization and recanalization, we also observed rare findings of thickening of the bronchial artery and fixation of the valve of the lower extremity vein in this case. PMID- 28575718 TI - Sleep homeostasis, habits and habituation. AB - The importance of sleep for behavioural performance during waking is long established, but the underlying reasons and mechanisms remain elusive. Waking and sleep are associated with changes in the levels of GluA1 AMPAR subunit in synaptic membranes, while studies using genetically-modified mice have identified an important role for GluA1-dependent synaptic plasticity in a non-associative form of memory that underlies short-term habituation to recently experienced stimuli. Here we posit that sleep may play a role in dishabituation, which restores attentional capacity and maximises the readiness of the animal for learning and goal-directed behaviour during subsequent wakefulness. Furthermore we suggest that sleep disturbance may fundamentally change the nature of behaviour, making it more model-free and habitual as a result of reduced attentional capacity. PMID- 28575719 TI - Fast and slow Ca2+-dependent hyperpolarization mechanisms connect membrane potential and sleep homeostasis. AB - Several lines of evidence indicate that the sleep-wake state of cortical neurons is regulated not only through neuronal projections from the lower brain, but also through the cortical neurons' intrinsic ability to initiate a slow firing pattern related to the slow-wave oscillation observed in electroencephalography of the sleeping brain. Theoretical modeling and experiments with genetic and pharmacological perturbation suggest that ion channels and kinases acting downstream of calcium signaling regulate the cortical-membrane potential and sleep duration. In this review, we introduce possible Ca2+-dependent hyperpolarization mechanisms in cortical neurons, in which Ca2+ signaling associated with neuronal excitation evokes kinase cascades, and the activated kinases modify ion channels or pumps to regulate the cortical sleep/wake firing mode. PMID- 28575720 TI - Local aspects of sleep and wakefulness. AB - Slow waves, the hallmark of NREM (Non Rapid Eye Movement) sleep, are not uniformly distributed across the cortical surface, but can occur locally and asynchronously across brain regions. Their regional distribution and amplitude is affected by brain maturation and by time spent awake, mediated in part by experience-dependent changes in synaptic strength. Recent studies have shown that local low-frequency oscillations (<10Hz) can also occur in REM sleep and during wakefulness, leading to region-specific cognitive errors. Local decreases and increases of slow wave activity in posterior brain regions have been linked to the occurrence of dreaming and to unconscious sleep, respectively. Finally, the coexistence of local sleep-like and wake-like patterns in different brain areas is characteristic of several sleep disorders and may offer insights into these conditions. PMID- 28575721 TI - Synthesis of a new series of aryl/heteroarylpiperazinyl derivatives of 8-acetyl-7 hydroxy-4-methylcoumarin with low nanomolar 5-HT1A affinities. AB - We synthesized a series of aryl/heteroarylpiperazinyl derivatives of 8-acetyl-7 hydroxy-4-methylcoumarin and evaluated their antidepressant-like activity. We used a fast, microwave-assisted synthesis protocol and 1H, 13C NMR and HRMS spectrometry to confirm the structure of all compounds. We also used radioligand binding assays to determine the affinities towards 5-HT1A and 5-HT2A receptors and performed molecular docking studies to rationalize obtained results. Among the evaluated compounds seven displayed high affinity to the 5-HT1A (3a-1.3 nM, 5a-1.6 nM, 10a-1.6 nM, 11a-1.0 nM, 3b-1.0 nM, 5b-0.8 nM and 11b-1.5 nM) as well as significant 5-HT1A antagonist profiles. The equilibrium dissociation constant values of tested compounds shown differential intrinsic activity (3a-190 nM, 3b 28 nM, 5a-48 nM, 5b-23 nM, 10b-180 nM, 11a-99 nM, 11b-38 nM) of antagonist mode. Molecular docking studies using a homology model of 5-HT1A revealed that ligand 5b is stabilized mainly by hydrogen bonds to Ser190. PMID- 28575722 TI - Applications of parallel synthetic lead hopping and pharmacophore-based virtual screening in the discovery of efficient glycine receptor potentiators. AB - Glycine receptors (GlyRs) are pentameric glycine-gated chloride ion channels that are enriched in the brainstem and spinal cord where they have been demonstrated to play a role in central nervous system (CNS) inhibition. Herein we describe two novel classes of glycine receptor potentiators that have been developed using similarity- and property-guided scaffold hopping enabled by parallel synthesis and pharmacophore-based virtual screening strategies. This effort resulted in the identification of novel, efficient and modular leads having favorable in vitro ADME profiles and high CNS multi-parameter optimization (MPO) scores, exemplified by azetidine sulfonamide 19 and aminothiazole sulfone (ent2)-20. PMID- 28575723 TI - Glycoform of a newly identified pollen allergen, Cha o 3, from Chamaecyparis obtusa (Japanese cypress, Hinoki). AB - Cha o 3 is a newly found glycosylated allergen from Chamaecyparis obtusa (Japanese cypress) pollen. The deduced amino acid sequence of Cha o 3 indicates that this glycoallergen contains a cellulase domain and a number of putative N glycosylation sites. However, the structures of N -glycans linked to Cha o 3 remain to be determined. In this study, therefore, we analyzed the glycoform of Cha o 3 and found that this glycoallergen carries exclusively plant complex-type N-glycans; major structures were GlcNAc2Man3Xyl1Fuc1GlcNAc2 (39%), Gal1Fuc1GlcNAc2Man3Xyl1Fuc1GlcNAc2 (14%), and Gal2Fuc2GlcNAc2Man3Xyl1Fuc1GlcNAc2 (25%). The glycoform of Cha o 3 bearing the Lea epitope is similar to those of Cry j1, Jun a 1, or Cup a 1, major glycoallergens in cedar or cypress pollens, and the predominant occurrence of GlcNAc2Man3Xyl1Fuc1GlcNAc2 is a common structural feature of glycoallergens from Cupressaceae pollens. PMID- 28575724 TI - A mapping review of take-home naloxone for people released from correctional settings. AB - BACKGROUND: People released from correctional settings are at an elevated risk of opioid overdose death in the weeks immediately following release. However, it is not well understood how this population, as a particularly high-risk group, is included in, and benefits from take-home naloxone (THN) programs. The objective of this review is to map research into THN for people released from correctional settings in order to identify further research needs. METHOD: We searched electronic databases, grey literature, and conference abstracts for reports on THN for people in or released from correctional settings. Studies were categorised into themes defined by the study's aims and focus. Results from each study were summarised by theme. RESULTS: We identified 19 studies reporting on THN programs for people released from correctional settings. Studies have examined attitudes towards naloxone among people in custody or recently released from custody (theme 1), and among non-prisoner stakeholders such as prison staff (theme 2). Evaluations and interventional studies (theme 3) have examined process indicators and approaches to naloxone training, including for contacts of prisoners, but there are challenges in assessing health outcomes of THN in the correctional context. Case reports suggest that training in correctional settings translates to action post-release (theme 4). CONCLUSION: The feasibility of THN in the context of release from a correctional setting has been established, but there is a need for rigorous research into health outcomes and program implementation. This is an emerging field of study and ongoing assessment of the state of the literature and research needs is recommended. PMID- 28575725 TI - Regional volumetric assessment of the brain in moderately preterm infants (30-35 gestational weeks) scanned at term-equivalent age on magnetic resonance imaging. AB - BACKGROUND: Early volume analyses of the infantile brain may help predict neurodevelopmental outcome. However, brain volumes are not well understood in moderately preterm infants at term-equivalent age (TEA). AIM: This study retrospectively investigated the relationship between regional brain volumes and infant gestational age (GA) at birth in moderately preterm infants (30-35weeks' GA) on magnetic resonance imaging (MRI) at TEA. METHODS: Forty infants scanned at TEA were enrolled. Regional brain volumes were estimated by manual segmentation on MRI, and their relationship with GA at birth was assessed. RESULTS: The regional volumes of the cerebral hemispheres and deep gray matter were larger (Spearman rho=0.40, P=0.01, and Spearman rho=0.48, P<0.01, respectively), and volumes of the lateral ventricles were smaller (Spearman rho=-0.32, P=0.04) in infants born at a later GA. The volumes of the cerebral hemispheres of the infants born at 30weeks' GA were significantly smaller than those born at 33 and 35weeks' GA (P<0.05). No associations were found between the volume of the cerebellum and brainstem, and GA at birth (Spearman rho=0.24, P=0.13, and Spearman rho=0.24, P=0.14, respectively). CONCLUSIONS: The volumes of the cerebral hemispheres at TEA may be smaller in infants born at 30weeks' GA, whereas those of the cerebellum and brainstem may not be correlated with GA among moderately preterm infants. PMID- 28575726 TI - Sciadopitysin suppresses RANKL-mediated osteoclastogenesis and prevents bone loss in LPS-treated mice. AB - Previous studies reported that sciadopitysin (Sc), a type of biflavonoids, protects reactive oxygen species (ROS)-mediated osteoblast dysfunction, but its role in osteoclastogenesis remains unclear. In this study, we observed that Sc dose-dependently suppressed RANKL-induced osteoclastogenesis and bone resorption. Our results indicated that Sc treatment strongly reduced RANKL-induced osteoclast specific genes expression, including cathepsin K (CTSK), tartrate-resistant acid phosphatase (TRAP) and MMP-9. Furthermore, Sc apparently attenuated RANKL increased expressions of c-Fos and NFATc1. Meanwhile, Sc also strikingly inhibited the activation of NF-kappaB without altering the phosphorylation of MAPKs (p38, JNK and ERK1/2). Finally, our study demonstrated that Sc administration could reverse the bone loss in LPS-induced mice model. This study suggests that Sc inhibits RANKL-induced osteoclastogenesis and bone loss by inhibiting NF-kappaB activation and reducing the expression of c-Fos and NFATc1. Therefore, Sc might be benefit for RANKL-mediated osteolytic bone diseases. PMID- 28575727 TI - Association of LTBR polymorphisms with chronic hepatitis B virus infection and hepatitis B virus-related hepatocellular carcinoma. AB - Lymphotoxin-beta receptor (LTbetaR) signaling is involved in hepatitis B virus (HBV) infection, hepatitis and liver carcinogenesis. However, the potential association between LTBR polymorphisms and HBV infection remains unclear. This study investigated the associations between LTBR polymorphisms and chronic HBV infection and HBV-related hepatocellular carcinoma (HCC). The study included 409 patients with chronic HBV infection, 73 HBV infection resolvers, and 197 healthy controls. Two polymorphisms rs12354 and rs3759333 were selected and genotyped by polymerase chain reaction-ligase detection reaction method. The frequencies of rs12354 genotype GT and allele T in HBV infection resolvers were significantly higher than those in patients with chronic HBV infection and healthy controls (genotype GT: 38.4% vs. 22.2% and 38.4% vs. 20.8%, P=0.004 and P=0.004, respectively; allele T: 20.5% vs. 13.1% and 20.5% vs. 12.9%, P=0.017 and P=0.028, respectively). The frequencies of rs3759333 genotypes and alleles between HBV patients, HBV infection resolvers and healthy controls had no statistical difference. The genotype and allele frequencies of rs12354 and rs3759333 had no statistical differences between chronic hepatitis B and HBV-related HCC patients. The serum LTbetaR levels and the overall survival rate between HBV-related HCC patients carrying different rs12354 and rs3759333 genotypes had no statistical differences. These results suggest that the LTBR rs12354 polymorphism might be associated with the spontaneous resolution of HBV infection. Additional studies with large sample size are needed to confirm and extend these findings. PMID- 28575728 TI - Sustaining diabetes prevention and care interventions: A multiple case study of translational research projects. AB - BACKGROUND: This study identifies the barriers and enablers for sustainability of interventions in primary and secondary prevention of diabetes. In the context of translational research, sustainability is defined as the continued use of program components and activities for the continued achievement of desirable program and population outcomes. METHODS: In this study, eleven translational research projects, supported by the BRIDGES program of the International Diabetes Federation, were investigated. By theoretically-informed semi-structured interviews and analyses of project reports, qualitative data was collected on the sustainability outcomes and the barriers and enablers. RESULTS: The sustainability outcomes can be grouped in three main areas: (1) sustainability at the intervention site(s); (2) diffusion to the wider community; and (3) replication of the intervention at other site(s). Each of the outcomes has their own set of enablers and barriers, and thus requires consideration for a different sustainability strategy. CONCLUSIONS: This study is the first international study that relates the sustainability outcomes of translational research project to specific barriers and enablers, and develops an evidence-based framework which provides practical advice on how to ensure the sustainability of health interventions. PMID- 28575729 TI - Effects of saxagliptin on glucose homeostasis and body composition of obese patients with newly diagnosed pre-diabetes. AB - AIMS: To assess the effect of saxagliptin monotherapy on blood glucose and islet beta-cell function in obese patients with newly diagnosed pre-diabetes and abnormal fat metabolism. METHODS: A 24-week, randomized controlled trial was conducted involving 25 obese subjects with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) (mean age 45years) to receive lifestyle intervention only (control group) or combined with saxagliptin 2.5mg or 5mg daily (S2.5 or S5 group), metformin 1500mg daily (Met group). Anthropometrics, body fat and biochemical parameters were measured before and after 4, 12 and 24weeks intervention. RESULTS: S5 group and Met group showed a significant decrease in fasting plasma glucose (FPG) and HbA1c compared with the control group (all P<0.05) after 24-week intervention. However, the decrease in 2h postprandial plasma glucose levels (2hPPG) in S5 group were greater compared with control group (P<0.01). Insulin resistance (HOMA-IR) was reduced in S5 group, Met group and control group (P<0.05), and the beta-cell function (HOMA-beta) was improved in all groups (P<0.05). However, the changes in obesity-related indicators including waist circumference, hip circumference, weight, BMI, body fat, percentage of body fat and waist-to-hip fat ratio were greate in Met group (all P<0.05) compared with other groups (P>0.05). CONCLUSIONS: Saxagliptin monotherapy may prevent or delay the progression of IGT or IFG to type 2 diabetes mellitus in obese patients with newly diagnosed pre-diabetes. ClinicalTrials.gov: NCT01960205. PMID- 28575730 TI - Novel glucokinase gene mutation in the first Macedonian family tested for MODY. AB - We present a boy with mild hyperglycemia detected during an upper respiratory infection. Novel splicing mutation in the intron 1 of the GCK gene (c.45+1G>A) was detected, and was subsequently confirmed in his father. This is the first case of genetically confirmed Macedonian family with MODY. PMID- 28575731 TI - Empirical test of the performance of an acoustic-phonetic approach to forensic voice comparison under conditions similar to those of a real case. AB - In a 2012 case in New South Wales, Australia, the identity of a speaker on several audio recordings was in question. Forensic voice comparison testimony was presented based on an auditory-acoustic-phonetic-spectrographic analysis. No empirical demonstration of the validity and reliability of the analytical methodology was presented. Unlike the admissibility standards in some other jurisdictions (e.g., US Federal Rule of Evidence 702 and the Daubert criteria, or England & Wales Criminal Practice Directions 19A), Australia's Unified Evidence Acts do not require demonstration of the validity and reliability of analytical methods and their implementation before testimony based upon them is presented in court. The present paper reports on empirical tests of the performance of an acoustic-phonetic-statistical forensic voice comparison system which exploited the same features as were the focus of the auditory-acoustic-phonetic spectrographic analysis in the case, i.e., second-formant (F2) trajectories in /o/ tokens and mean fundamental frequency (f0). The tests were conducted under conditions similar to those in the case. The performance of the acoustic-phonetic statistical system was very poor compared to that of an automatic system. PMID- 28575732 TI - Extra precision docking, free energy calculation and molecular dynamics studies on glutamic acid derivatives as MurD inhibitors. AB - The binding modes of well known MurD inhibitors have been studied using molecular docking and molecular dynamics (MD) simulations. The docking results of inhibitors 1-30 revealed similar mode of interaction with Escherichia coli-MurD. Further, residues Thr36, Arg37, His183, Lys319, Lys348, Thr321, Ser415 and Phe422 are found to be important for inhibitors and E. coli-MurD interactions. Our docking procedure precisely predicted crystallographic bound inhibitor 7 as evident from root mean square deviation (0.96A). In addition inhibitors 2 and 3 have been successfully cross-docked within the MurD active site, which was pre organized for the inhibitor 7. Induced fit best docked poses of 2, 3, 7 and 15/2Y1O complexes were subjected to 10ns MD simulations to determine the stability of the predicted binding conformations. Induce fit derived docked complexes were found to be in a state of near equilibrium as evident by the low root mean square deviations between the starting complex structure and the energy minimized final average MD complex structures. The results of molecular docking and MD simulations described in this study will be useful for the development of new MurD inhibitors with high potency. PMID- 28575733 TI - Biomaterials for skeletal muscle tissue engineering. AB - Although skeletal muscle can naturally regenerate in response to minor injuries, more severe damage and myopathies can cause irreversible loss of muscle mass and function. Cell therapies, while promising, have not yet demonstrated consistent benefit, likely due to poor survival of delivered cells. Biomaterials can improve muscle regeneration by presenting chemical and physical cues to muscle cells that mimic the natural cascade of regeneration. This brief review describes strategies for muscle repair utilizing biomaterials that can provide signals to either transplanted or host muscle cells. These strategies range from approaches that utilize biomaterials alone to those that combine biomaterials with exogenous growth factors, ex vivo cultured cells, and extensive culture time. PMID- 28575735 TI - Fractional-order leaky integrate-and-fire model with long-term memory and power law dynamics. AB - Pyramidal neurons produce different spiking patterns to process information, communicate with each other and transform information. These spiking patterns have complex and multiple time scale dynamics that have been described with the fractional-order leaky integrate-and-Fire (FLIF) model. Models with fractional (non-integer) order differentiation that generalize power law dynamics can be used to describe complex temporal voltage dynamics. The main characteristic of FLIF model is that it depends on all past values of the voltage that causes long term memory. The model produces spikes with high interspike interval variability and displays several spiking properties such as upward spike-frequency adaptation and long spike latency in response to a constant stimulus. We show that the subthreshold voltage and the firing rate of the fractional-order model make transitions from exponential to power law dynamics when the fractional order alpha decreases from 1 to smaller values. The firing rate displays different types of spike timing adaptation caused by changes on initial values. We also show that the voltage-memory trace and fractional coefficient are the causes of these different types of spiking properties. The voltage-memory trace that represents the long-term memory has a feedback regulatory mechanism and affects spiking activity. The results suggest that fractional-order models might be appropriate for understanding multiple time scale neuronal dynamics. Overall, a neuron with fractional dynamics displays history dependent activities that might be very useful and powerful for effective information processing. PMID- 28575736 TI - Collective neurodynamic optimization for economic emission dispatch problem considering valve point effect in microgrid. AB - The economic emission dispatch (EED) problem aims to control generation cost and reduce the impact of waste gas on the environment. It has multiple constraints and nonconvex objectives. To solve it, the collective neurodynamic optimization (CNO) method, which combines heuristic approach and projection neural network (PNN), is attempted to optimize scheduling of an electrical microgrid with ten thermal generators and minimize the plus of generation and emission cost. As the objective function has non-derivative points considering valve point effect (VPE), differential inclusion approach is employed in the PNN model introduced to deal with them. Under certain conditions, the local optimality and convergence of the dynamic model for the optimization problem is analyzed. The capability of the algorithm is verified in a complicated situation, where transmission loss and prohibited operating zones are considered. In addition, the dynamic variation of load power at demand side is considered and the optimal scheduling of generators within 24 h is described. PMID- 28575734 TI - Equitable access to health insurance for socially excluded children? The case of the National Health Insurance Scheme (NHIS) in Ghana. AB - To help reduce child mortality and reach universal health coverage, Ghana extended free membership of the National Health Insurance Scheme (NHIS) to children (under-18s) in 2008. However, despite the introduction of premium waivers, a substantial proportion of children remain uninsured. Thus far, few studies have explored why enrolment of children in NHIS may remain low, despite the absence of significant financial barriers to membership. In this paper we therefore look beyond economic explanations of access to health insurance to explore additional wider determinants of enrolment in the NHIS. In particular, we investigate whether social exclusion, as measured through a sociocultural, political and economic lens, can explain poor enrolment rates of children. Data were collected from a cross-sectional survey of 4050 representative households conducted in Ghana in 2012. Household indices were created to measure sociocultural, political and economic exclusion, and logistic regressions were conducted to study determinants of enrolment at the individual and household levels. Our results indicate that socioculturally, economically and politically excluded children are less likely to enrol in the NHIS. Furthermore, households excluded in all dimensions were more likely to be non-enrolled or partially enrolled (i.e. not all children enrolled within the household) than fully enrolled. These results suggest that equity in access for socially excluded children has not yet been achieved. Efforts should be taken to improve coverage by removing the remaining small, annually renewable registration fee, implementing and publicising the new clause that de-links premium waivers from parental membership, establishing additional scheme administrative offices in remote areas, holding regular registration sessions in schools and conducting outreach sessions and providing registration support to female guardians of children. Ensuring equitable access to NHIS will contribute substantially to improving child health and reducing child mortality in Ghana. PMID- 28575737 TI - Bayesian geodesic path for human motor control. AB - Despite a near-infinite number of possible movement trajectories, our body movements exhibit certain invariant features across individuals; for example, when grasping a cup, individuals choose an approximately linear path from the hand to the cup. Based on these experimental findings, many researchers have proposed optimization frameworks to determine desired movement trajectories. Successful conventional frameworks include the geodesic path, which considers the geometry of our complicated body dynamics, and stochastic frameworks, which consider movement variability. The former succeed in explaining the kinematics in human reaching movements, and the latter succeed in explaining the variability in those movements. However, the conventional geodesic path framework does not consider variability, and the conventional stochastic frameworks do not consider the geometrical properties of our bodies. Thus, how to reconcile these two successful frameworks remains unclear. Here, I show that the conventional geodesic path can be interpreted as a Bayesian framework in which no uncertainty is considered. Hence, by introducing uncertainty into the framework, I propose a Bayesian geodesic path framework that can simultaneously consider the geometric properties of our bodies and movement variability. I demonstrate that the Bayesian geodesic path generates a mean movement trajectory that corresponds to the conventional geodesic path and a variability of movement trajectory, thus explaining the characteristic variability in human reaching movements. PMID- 28575738 TI - Perceived parental monitoring and adolescent internet addiction: A moderated mediation model. AB - Bronfenbrenner's (1979) ecological model focuses on the interrelation between different contexts and the interaction between individuals and their proximal contexts. Based on this theory, the present study tested a moderated mediation model of family, peer, and individual characteristics to investigate how they impact adolescent Internet addiction. Specifically, we examined whether deviant peer affiliation partially mediated the relation between perceived parental monitoring and adolescent Internet addiction, and whether this indirect relation was moderated by effortful control. A total of 747 Chinese middle school students filled out anonymous questionnaires concerning perceived parental monitoring, deviant peer affiliation, effortful control, and Internet addiction. The findings indicated that while the impact of parental monitoring on Internet addiction was partially mediated by deviant peer affiliation, effortful control moderated the first stage of the indirect relationship. For low effortful control adolescents, perceived parental monitoring negatively predicted deviant peer affiliation. Conversely, the indirect path was not significant for high effortful control adolescents. These findings highlight the need to consider family, peer and individual factors simultaneously when evaluating risks associated with adolescent Internet addiction and have important implications for the prevention and intervention of adolescent Internet addiction. PMID- 28575739 TI - Proglycosomes: A novel nano-vesicle for ocular delivery of tacrolimus. AB - Tacrolimus is an emerging candidate for the treatment of immune-mediated inflammatory ocular disorders (IIODs) however its ocular delivery remained a challenge due to its hydrophobic nature, high molecular weight and physiological and anatomical constraints of the eye. The present work describes vesicles composed of propylene glycol, phospholipid and water, proglycosomes (PNVs), as novel carriers for ocular delivery of tacrolimus. Addition of propylene glycol decreases vesicle aggregation, increases encapsulation of tacrolimus and prevented drug leakage. Developed PNVs were of nanosize (111.5+/-3.2nm) and 5 fold more elastic than conventional liposomes. PNVs showed prolonged drug release over period of 12h and higher corneal permeation, 5-fold and 13-fold, compared to conventional liposomes and tacrolimus solution, respectively. Studies in rabbits demonstrated prolonged precorneal retention (upto 8h) and manifestly improved intraocular drug levels, well above therapeutic levels, at all tested time-points following topical application of PNV formulation compared to drug solution. Further, PNVs were found to be safe for ocular use. In conclusion, the developed PNVs are prospective carriers for enhanced ocular delivery of tacrolimus. PMID- 28575741 TI - Amino-functionalized nano-vesicles for enhanced anticancer efficacy and reduced myelotoxicity of carboplatin. AB - Carboplatin is one of the few platinum-based antitumor drugs used worldwide. Unfortunately, systemic carboplatin therapy is limited by its dose-related myelosuppression. In this study, a viable way to reduce the serious myelotoxicity of carboplatin while improving its therapeutic efficacy using amino functionalized polyphosphazene vesicles is reported. First, three polyphosphazenes with different amino content were synthesized by amidating hydrophobic side groups; these polyphosphazenes could self-assemble into polymersomes with similar particle size and morphology. Based on FTIR analysis, hydrogen bonding interactions between the polymeric carriers and carboplatin were validated and shown to predominantly contribute to the significant improvement of drug loading in polymersomes. Therefore, it turned out that the amino level of polymers played a substantial role in carboplatin encapsulation. Then, PEAP-2-C polymersomes were optimized for further experimental verification to achieve depressed carboplatin-induced myelotoxicity as well as promote curative effects against CT-26 colon adenocarcinoma. These results in vitro and in vivo proved that amino-functionalized polyphosphazene vesicles have great potential for carboplatin delivery in the application of cancer therapy. PMID- 28575740 TI - Capture and separation of l-histidine through optimized zinc-decorated magnetic silica spheres. AB - Zinc-decorated magnetic silica spheres were developed, optimized and tested for the capture and separation of l-histidine. The magnetic silica spheres were prepared using a simple sol-gel method and show excellent magnetic characteristics, adsorption capacity toward metal ions, and stability in aqueous solution in a wide pH range. The binding capacity of zinc-decorated magnetic silica spheres to histidine proved to be strongly influenced by the morphology, composition and concentration of metal at the surface of the magnetic silica spheres and therefore these parameters should be carefully controlled in order to maximize the performance for protein purification purposes. Optimized zinc decorated magnetic silica spheres demonstrate a binding capacity to l-histidine of approximately 44mgg-1 at the optimum binding pH buffer. PMID- 28575742 TI - Formation of a hydrophobic and corrosion resistant coating on magnesium alloy via a one-step hydrothermal method. AB - A hydrophobic coating was fabricated on the surface of magnesium alloy using a simple one-step hydrothermal method with the use of environmentally friendly agent. Scanning electron microscopy, energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and contact angle test were used to characterize the surfaces. Corrosion behavior in a 3.5wt.% NaCl solution was evaluated using OCP time curves test, potentiodynamic polarization test and EIS analysis. The findings show that the substrate is covered by the coating of magnesium hydroxide and magnesium stearate, reaching a contact angle of around 146 degrees . Corrosion behavior show huge improvement, the progress with increase of treatment time could be related to the increased growth rate of coating. PMID- 28575745 TI - The contrasting microRNA content of a drought tolerant and a drought susceptible wheat cultivar. AB - Drought stress represents one of the most common stresses affecting the productivity of crop plants. A rather recently discovered component of the plant response to drought is the cellular population of microRNAs. Here, the microRNA content was revealed of two bread wheat cultivars contrasting strongly with respect to the ability to withstand drought stress. A total of 1813 miRNAs was identified, grouped into 106 families. Some 104 of these miRNAs were predicted to match 212 novel miRNA precursors. In the drought tolerant cultivar (SM), 105 (33 known and 72 novel) miRNAs were altered in abundance by the imposition of drought stress, while the equivalent number in the more sensitive cultivar (SW) was 51 (20 and 31). An in silico analysis predicted that these miRNAs target at least 1959 genes in SM and 1111 in SW, suggesting their broad contribution to the drought stress response. Among the target genes were several known stress-related genes, encoding, for example, superoxide dismutase, various MYB transcription factors, various ABA signaling proteins and various MADS-box transcription factors. In many cases, the more susceptible cultivar SW behaved in a contrasting manner. The suggestion is that miRNAs represent an important aspect of the drought stress response, post-transcriptionally regulating a range of stress related genes. PMID- 28575744 TI - Decreased neural precursor cell pool in NADPH oxidase 2-deficiency: From mouse brain to neural differentiation of patient derived iPSC. AB - There is emerging evidence for the involvement of reactive oxygen species (ROS) in the regulation of stem cells and cellular differentiation. Absence of the ROS generating NADPH oxidase NOX2 in chronic granulomatous disease (CGD) patients, predominantly manifests as immune deficiency, but has also been associated with decreased cognition. Here, we investigate the role of NOX enzymes in neuronal homeostasis in adult mouse brain and in neural cells derived from human induced pluripotent stem cells (iPSC). High levels of NOX2 were found in mouse adult neurogenic regions. In NOX2-deficient mice, neurogenic regions showed diminished redox modifications, as well as decrease in neuroprecursor numbers and in expression of genes involved in neural differentiation including NES, BDNF and OTX2. iPSC from healthy subjects and patients with CGD were used to study the role of NOX2 in human in vitro neuronal development. Expression of NOX2 was low in undifferentiated iPSC, upregulated upon neural induction, and disappeared during neuronal differentiation. In human neurospheres, NOX2 protein and ROS generation were polarized within the inner cell layer of rosette structures. NOX2 deficiency in CGD-iPSCs resulted in an abnormal neural induction in vitro, as revealed by a reduced expression of neuroprogenitor markers (NES, BDNF, OTX2, NRSF/REST), and a decreased generation of mature neurons. Vector-mediated NOX2 expression in NOX2-deficient iPSCs rescued neurogenesis. Taken together, our study provides novel evidence for a regulatory role of NOX2 during early stages of neurogenesis in mouse and human. PMID- 28575743 TI - IGF-II promotes neuroprotection and neuroplasticity recovery in a long-lasting model of oxidative damage induced by glucocorticoids. AB - Insulin-like growth factor-II (IGF-II) is a naturally occurring hormone that exerts neurotrophic and neuroprotective properties in a wide range of neurodegenerative diseases and ageing. Accumulating evidence suggests that the effects of IGF-II in the brain may be explained by its binding to the specific transmembrane receptor, IGFII/M6P receptor (IGF-IIR). However, relatively little is known regarding the role of IGF-II through IGF-IIR in neuroprotection. Here, using adult cortical neuronal cultures, we investigated whether IGF-II exhibits long-term antioxidant effects and neuroprotection at the synaptic level after oxidative damage induced by high and transient levels of corticosterone (CORT). Furthermore, the involvement of the IGF-IIR was also studied to elucidate its role in the neuroprotective actions of IGF-II. We found that neurons treated with IGF-II after CORT incubation showed reduced oxidative stress damage and recovered antioxidant status (normalized total antioxidant status, lipid hydroperoxides and NAD(P) H:quinone oxidoreductase activity). Similar results were obtained when mitochondria function was analysed (cytochrome c oxidase activity, mitochondrial membrane potential and subcellular mitochondrial distribution). Furthermore, neuronal impairment and degeneration were also assessed (synaptophysin and PSD-95 expression, presynaptic function and FluoroJade B(r) stain). IGF-II was also able to recover the long-lasting neuronal cell damage. Finally, the effects of IGF-II were not blocked by an IGF-IR antagonist, suggesting the involvement of IGF-IIR. Altogether these results suggest that, in or model, IGF-II through IGF-IIR is able to revert the oxidative damage induced by CORT. In accordance with the neuroprotective role of the IGF-II/IGF-IIR reported in our study, pharmacotherapy approaches targeting this pathway may be useful for the treatment of diseases associated with cognitive deficits (i.e., neurodegenerative disorders, depression, etc.). PMID- 28575747 TI - Reactive oxygen species induced by heat stress during grain filling of rice (Oryza sativa L.) are involved in occurrence of grain chalkiness. AB - Heat stress during grain filling increases rice grain chalkiness due to increased activity of alpha-amylase, which hydrolyzes starch. In rice and barley seeds, reactive oxygen species (ROS) produced after imbibition induce alpha-amylase activity via regulation of gibberellin (GA) and abscisic acid (ABA) levels during seed germination. Here, we examined whether ROS is involved in induction of grain chalkiness by alpha-amylase in developing rice grains under heat stress. To elucidate the role of ROS in grain chalkiness, we grew post-anthesis rice plants (Oryza sativa L. cv. Koshihikari) under control (25 degrees C) or heat stress (30 degrees C) conditions with or without antioxidant (dithiothreitol) treatment. The developing grains were analyzed for expression of NADPH oxidases, GA biosynthesis genes (OsGA3ox1, OsGA20ox1), ABA catabolism genes (OsABA8'OH1, OsABA8'OH2) and an alpha-amylase gene (OsAmy3E), endogenous H2O2 content and the grain quality. In grains exposed to heat stress, the expression of NADPH oxidase genes (especially, OsRbohB, OsRbohD, OsRbohF and OsRbohI) and the ROS content increased. Heat stress also increased the expression of OsGA3ox1, OsGA20ox1, OsABA8'OH1, OsABA8'OH2 and OsAmy3E. On the other hand, dithiothreitol treatment reduced the effects of heat stress on the expression of these genes and significantly reduced grain chalkiness induced by heat stress. These results suggest that, similar to cereal seed germination mechanism, ROS produced under heat stress is involved in alpha amylase induction in maturating rice grains through GA/ABA metabolism, and consequently caused grain chalkiness. PMID- 28575746 TI - The proportion of nitrate in leaf nitrogen, but not changes in root growth, are associated with decreased grain protein in wheat under elevated [CO2]. AB - The atmospheric CO2 concentration ([CO2]) is increasing and predicted to reach ~550ppm by 2050. Increasing [CO2] typically stimulates crop growth and yield, but decreases concentrations of nutrients, such as nitrogen ([N]), and therefore protein, in plant tissues and grains. Such changes in grain composition are expected to have negative implications for the nutritional and economic value of grains. This study addresses two mechanisms potentially accountable for the phenomenon of elevated [CO2]-induced decreases in [N]: N uptake per unit length of roots as well as inhibition of the assimilation of nitrate (NO3-) into protein are investigated and related to grain protein. We analysed two wheat cultivars from a similar genetic background but contrasting in agronomic features (Triticum aestivum L. cv. Scout and Yitpi). Plants were field-grown within the Australian Grains Free Air CO2 Enrichment (AGFACE) facility under two atmospheric [CO2] (ambient, ~400ppm, and elevated, ~550ppm) and two water treatments (rain-fed and well-watered). Aboveground dry weight (ADW) and root length (RL, captured by a mini-rhizotron root growth monitoring system), as well as [N] and NO3- concentrations ([NO3-]) were monitored throughout the growing season and related to grain protein at harvest. RL generally increased under e[CO2] and varied between water supply and cultivars. The ratio of total aboveground N (TN) taken up per RL was affected by CO2 treatment only later in the season and there was no significant correlation between TN/RL and grain protein concentration across cultivars and [CO2] treatments. In contrast, a greater percentage of N remained as unassimilated [NO3-] in the tissue of e[CO2] grown crops (expressed as the ratio of NO3- to total N) and this was significantly correlated with decreased grain protein. These findings suggest that e[CO2] directly affects the nitrate assimilation capacity of wheat with direct negative implications for grain quality. PMID- 28575748 TI - Effects of triclosan (TCS) on fecundity, the antioxidant system, and oxidative stress-mediated gene expression in the copepod Tigriopus japonicus. AB - Triclosan (TCS) is an antimicrobial agent that has been widely dispersed and detected in the marine environment. However, the effects of TCS in marine invertebrates are poorly understood. In this study, the effects of TCS on life cycle history (e.g. mortality and fecundity) along with cellular reactive oxygen species (ROS) levels, GSH content, antioxidant enzymatic activities, and mRNA expression levels of oxidative stress-mediated genes were measured in the copepod Tigriopus japonicus. The no observed effect concentration (NOEC) and median lethal concentration (LC50) of TCS in the adult stage were determined to be 300MUg/L and 437.476MUg/L, respectively, while in the nauplius stages the corresponding values were 20MUg/L, and 51.76MUg/L, respectively. Fecundity was significantly reduced (P<0.05) in response to TCS at 100MUg/L. Concentration- and time-dependent analysis of ROS, GSH content (%), and antioxidant enzymatic activities (e.g. GST, GPx, and SOD) were significantly increased (P<0.05) in response to TCS exposure. Additionally, mRNA expression of detoxification (e.g., CYPs) and antioxidant (e.g., glutathione S-transferase-sigma isoforms, Cu/Zn superoxide dismutase, catalase) genes was modulated in response to TCS exposure at different concentrations over a 24h period. Our results revealed that TCS can induce reduced fecundity and oxidative stress with transcriptional regulation of oxidative stress-mediated genes with activation of the antioxidant system in the copepod T. japonicus. PMID- 28575749 TI - Copper alters hypoxia sensitivity and the behavioural emersion response in the amphibious fish Kryptolebias marmoratus. AB - Elevated levels of metals have been reported in mangrove ecosystems worldwide. Mangrove fishes also routinely experience severe environmental stressors, such as hypoxia. In the amphibious fish Kryptolebias marmoratus (mangrove rivulus), a key behavioural response to avoid aquatic stress is to leave water (emersion). We hypothesized that copper (Cu) exposure would increase the sensitivity of this behavioural hypoxia avoidance response due to histopathological effects of Cu on gill structure and function. K. marmoratus were exposed to either control (no added Cu) or Cu (300MUg/L) for 96h. Following this period, fish were exposed to an acute hypoxic challenge (decline in dissolved oxygen to ~0% over 15min), and the emersion response was recorded. Gills were examined for histological changes. Fish exposed to Cu emersed at a higher dissolved oxygen level (7.5+/-0.6%), relative to the control treatment group (5.8+/-0.4%). Histological analysis showed that the gill surface area increased and the interlamellar cell mass (ILCM) was reduced following Cu exposure, contrary to our prediction. Overall, these data indicate that Cu induces hypoxia-like changes to gill morphology and increases the sensitivity of the hypoxia emersion response. PMID- 28575750 TI - Raman microspectroscopy of nucleus and cytoplasm for human colon cancer diagnosis. AB - Subcellular Raman analysis is a promising clinic tool for cancer diagnosis, but constrained by the difficulty of deciphering subcellular spectra in actual human tissues. We report a label-free subcellular Raman analysis for use in cancer diagnosis that integrates subcellular signature spectra by subtracting cytoplasm from nucleus spectra (Nuc.-Cyt.) with a partial least squares-discriminant analysis (PLS-DA) model. Raman mapping with the classical least-squares (CLS) model allowed direct visualization of the distribution of the cytoplasm and nucleus. The PLS-DA model was employed to evaluate the diagnostic performance of five types of spectral datasets, including non-selective, nucleus, cytoplasm, ratio of nucleus to cytoplasm (Nuc./Cyt.), and nucleus minus cytoplasm (Nuc. Cyt.), resulting in diagnostic sensitivity of 88.3%, 84.0%, 98.4%, 84.5%, and 98.9%, respectively. Discriminating between normal and cancerous cells of actual human tissues through subcellular Raman markers is feasible, especially when using the nucleus-cytoplasm difference spectra. The subcellular Raman approach had good stability, and had excellent diagnostic performance for rectal as well as colon tissues. The insights gained from this study shed new light on the general applicability of subcellular Raman analysis in clinical trials. PMID- 28575752 TI - Dynamic and static knee alignment at baseline predict structural abnormalities on MRI associated with medial compartment knee osteoarthritis after 2 years. AB - BACKGROUND: Dynamic and static varus alignment, both, have been reported as risk factors associated with structural progression of knee osteoarthritis. However the association of none of the static and dynamic alignment with structural, clinical, and functional progression associated with knee osteoarthritis has not been assessed yet in a longitudinal study. METHODS: Forty-seven women with early and established medial knee osteoarthritis were evaluated. Static and dynamic alignment as well as MRI detected structural features, clinical, and functional characteristics of patients were assessed at baseline and at 2 years follow-up. Associations between baseline static and dynamic alignment with structural, functional, and clinical characteristics at the time of entry, as well as the changes over 2 years were evaluated. FINDINGS: Both static and dynamic varus alignment at baseline were significantly associated with osteoarthritis related tibio-femoral joint structural abnormalities detected on MRI, at the time of entry. Only the magnitude of varus thrust at baseline was predictive of the changes in the presence of meniscal maceration over two years. None of the static or dynamic measures of knee joint alignment were associated with clinical characteristics associated with medial knee osteoarthritis. INTERPRETATION: The key finding of this study is that both frontal plane dynamic and static alignment, are associated with structural abnormalities in patients with medial knee osteoarthritis. PMID- 28575751 TI - Comparison of outcomes for cancer patients discussed and not discussed at a multidisciplinary meeting. AB - OBJECTIVES: Comparison of outcomes for cancer patients discussed and not discussed at a multidisciplinary meeting (MDM). STUDY DESIGN: Retrospective analysis of the association of MDM discussion with survival. METHODS: All newly diagnosed cancer patients from 2009 to 2012, presenting to a large regional cancer service in South West Victoria, Australia (620 colorectal, 657 breast, 593 lung and 511 haematological) were recorded and followed up to 5 years after diagnosis. Treatment patterns and survival of patients whose treatment was discussed at an MDM compared to those who were not, were explored. RESULTS: The proportion of patients presented to an MDM within 60 days after diagnosis was 56% (n = 366) for breast cancer, 59% (n = 363) for colorectal cancer, 27% (n = 137) for haematological malignancies and 60% (n = 355) for lung cancer. Seventy-three percent (n = 886) of patients discussed at an MDM had their tumour stage recorded in their medical records while only 52% (n = 604) of patients not discussed had their tumour stage recorded (P < 0.01). We found for haematological and lung cancer patients that those presented to an MDM prior to treatment had a significant reduction in mortality (lung cancer hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.50-0.76, P < 0.01) (haematological cancer HR 0.58, 95% CI 0.35-0.96, P = 0.03) compared to patients whose cases were not discussed at an MDM after adjusting for the potential cofounders of age, stage, comorbidities and treatment. This was not the case for colorectal and breast cancer patients where there was no significant difference. CONCLUSION: MDM discussion has been recommended as best practice in the management of cancer patients, however, from a public health perspective this creates potential issues around access and resources. It is likely that MDM presentation patterns and outcomes across tumour streams are linked in complex ways. We believe that our data would demonstrate that these patterns differ across tumour streams and that more detailed work is required to better allocate relatively scarce and potentially costly MDM resources to tumour streams and patient groups that may get the most benefit. PMID- 28575753 TI - Foot muscle morphology is related to center of pressure sway and control mechanisms during single-leg standing. AB - Maintaining balance is vitally important in everyday life. Investigating the effects of individual foot muscle morphology on balance may provide insights into neuromuscular balance control mechanisms. This study aimed to examine the correlation between the morphology of foot muscles and balance performance during single-leg standing. Twenty-eight recreational runners were recruited in this study. An ultrasound device was used to measure the thickness and cross-sectional area of three intrinsic foot muscles (abductor hallucis, flexor digitorum brevis and quadratus plantae) and peroneus muscles. Participants were required to perform 30s of single-leg standing for three trials on a force plate, which was used to record the center of pressure (COP). The standard deviation of the amplitude and ellipse area of the COP were calculated. In addition, stabilogram diffusion analysis (SDA) was performed on COP data. Pearson correlation coefficients were computed to examine the correlation between foot muscle morphology and traditional COP parameters as well as with SDA parameters. Our results showed that larger abductor hallucis correlated to smaller COP sway, while larger peroneus muscles correlated to larger COP sway during single-leg standing. Larger abductor hallucis also benefited open-loop dynamic stability, as well as supported a more efficient transfer from open-loop to closed loop control mechanisms. These results suggest that the morphology of foot muscles plays an important role in balance performance, and that strengthening the intrinsic foot muscles may be an effective way to improve balance. PMID- 28575754 TI - Mapping, modeling, and characterization of protein-protein interactions on a proteomic scale. AB - Proteins effect a number of biological functions, from cellular signaling, organization, mobility, and transport to catalyzing biochemical reactions and coordinating an immune response. These varied functions are often dependent upon macromolecular interactions, particularly with other proteins. Small-scale studies in the scientific literature report protein-protein interactions (PPIs), but slowly and with bias towards well-studied proteins. In an era where genomic sequence is readily available, deducing genotype-phenotype relationships requires an understanding of protein connectivity at proteome-scale. A proteome-scale map of the protein-protein interaction network provides a global view of cellular organization and function. Here, we discuss a summary of methods for building proteome-scale interactome maps and the current status and implications of mapping achievements. Not only do interactome maps serve as a reference, detailing global cellular function and organization patterns, but they can also reveal the mechanisms altered by disease alleles, highlight the patterns of interaction rewiring across evolution, and help pinpoint biologically and therapeutically relevant proteins. Despite the considerable strides made in proteome-wide mapping, several technical challenges persist. Therefore, future considerations that impact current mapping efforts are also discussed. PMID- 28575755 TI - Evaluation of an online master's programme in Somaliland. A phenomenographic study on the experience of professional and personal development among midwifery faculty. AB - To record the variation of perceptions of midwifery faculty in terms of the possibilities and challenges related to the completion of their first online master's level programme in Sexual and Reproductive Health and Rights in Somaliland. The informants included in this phenomenongraphical focus group study were those well-educated professional women and men who completed the master's program. The informant perceived that this first online master's level programme provided tools for independent use of the Internet and independent searching for evidence-based information, enhanced professional development, was challenge driven and evoked curiosity, challenged professional development, enhanced personal development and challenged context-bound career paths. Online education makes it possible for well-educated professional women to continue higher education. It furthermore increased the informants' confidence in their use of Internet, software and databases and in the use of evidence in both their teaching and their clinical practice. Programmes such as the one described in this paper could counter the difficulties ensuring best practice by having a critical mass of midwives who will be able to continually gather contemporary midwifery evidence and use it to ensure best practice. An increase of online education is suggested in South-central Somalia and in similar settings globally. PMID- 28575756 TI - Dietary fatty acids modulate adipocyte TNFa production via regulation of its DNA promoter methylation levels. AB - The factors regulating TNF alpha (TNFa) levels could be considered therapeutic targets against metabolic syndrome development. DNA methylation is a potent regulator of gene expression and may be associated with protein levels. In this study we investigate whether the effect of dietary fatty acids on TNFa released from adipocytes might be associated with modifications of the TNFa promoter DNA methylation status. A group of rats was assigned to three diets with a different composition of saturated, monounsaturated and polyunsaturated fatty acids. Samples of visceral adipose tissues were taken for adipocyte isolation, in which released TNFa levels were measured, and for methylation and expression studies. In addition, 3 T3-L1 cells were treated with palmitic, oleic and linoleic acids, with and without 5-Azacitydine (5-AZA). After treatments, cells and supernatants were included in the same analyses as rat samples. TNFa promoter methylation levels, gene expression and secretion were different according to the diets and fatty acid treatments associated with them. Cells treated with 5-AZA displayed higher TNFa levels than in the absence of 5-AZA, without differences between fatty acids. According to our results, dietary fatty acid regulation of adipocyte TNFa levels may be mediated by epigenetic modifications of the TNFa promoter DNA methylation levels. PMID- 28575758 TI - Accelerated Long Term Forgetting in patients with focal seizures: Incidence rate and contributing factors. AB - BACKGROUND: Accelerated Long Term Forgetting (ALF) is usually defined as a memory impairment that is seen only at long delays (e.g., after days or weeks) and not at shorter delays (e.g., 30min) typically used in clinical settings. Research indicates that ALF occurs in some patients with epilepsy, but the incidence rates and underlying causes have not been established. In this study, we considered these issues. METHODS: Forty-four patients with a history of focal seizures were tested at 30min and 7day delays for material from the Rey Auditory Verbal Learning Test (RAVLT) and Aggie Figures Test. Recently published norms from a matched group of 60 control subjects (Miller et al., 2015 ) were used to determine whether patients demonstrated ALF, impairment at 30min or intact memory performance. RESULTS: The incidence of ALF in the epilepsy patients (18%) was >3 times higher than normal on the RAVLT, but no different (7%) from the incidence in normal subjects on the Aggie Figures. A different, but again significantly high, proportion of patients (36%) showed shorter-term memory deficits on at least one task. ALF was found mainly in patients with temporal-lobe epilepsy, but also occurred in one patient with an extratemporal seizure focus. Presence of a hippocampal lesion was the main predicting factor of ALF. CONCLUSIONS: Many patients with a focal seizure disorder show memory deficits after longer delays that are not evident on standard assessment. The present study explored the factors associated with this ALF memory profile. These new findings will enhance clinical practice, particularly the management of patients with memory complaints. PMID- 28575757 TI - Sensorimotor experience and verb-category mapping in human sensory, motor and parietal neurons. AB - Semantic grounding is the process of relating meaning to symbols (e.g., words). It is the foundation for creating a representational symbolic system such as language. Semantic grounding for verb meaning is hypothesized to be achieved through two mechanisms: sensorimotor mapping, i.e., directly encoding the sensorimotor experiences the verb describes, and verb-category mapping, i.e., encoding the abstract category a verb belongs to. These two mechanisms were investigated by examining neuronal-level spike (i.e. neuronal action potential) activities from the motor, somatosensory and parietal areas in two human participants. Motor and a portion of somatosensory neurons were found to be involved in primarily sensorimotor mapping, while parietal and some somatosensory neurons were found to be involved in both sensorimotor and verb-category mapping. The time course of the spike activities and the selective tuning pattern of these neurons indicate that they belong to a large neural network used for semantic processing. This study is the first step towards understanding how words are processed by neurons. PMID- 28575759 TI - Development of a web-based executive functioning intervention for adolescents with epilepsy: The Epilepsy Journey. AB - INTRODUCTION: Youth with epilepsy exhibit significant deficits in executive functioning (EF), yet there are few interventions to improve EF for adolescents. The aims of the current study were to develop an individually-tailored intervention, called Epilepsy Journey, to improve aspects of EF through an iterative, patient-centered process including focus groups and usability testing. METHODS: Five adolescents and caregivers participated in focus groups. This input was used to develop ten learning modules based on subscales of the Behavioral Rating Inventory of Executive Functions and key issues that may impact EF in adolescents. Six adolescents participated in usability testing and a usability expert conducted a heuristic evaluation. Demographic information, chart reviews and measures of EF were also completed. RESULTS: Focus group participants and their parents reported difficulties with memory, attention, organization, monitoring, initiation, impulsivity, emotional control, sleep, awareness in schools and managing stress. They also identified successful strategies to address memory and organizational difficulties. Usability testing of the resultant Epilepsy Journey modules revealed problems with navigation and identified features that promoted usability, including progress bars and interactive modules. Program modifications were made after each usability trial resulting in a relatively brief, interactive and readily navigable program. Perceived utility was high with all but one participant. Participants rated the content as helpful and indicated they would recommend Epilepsy Journey to others. CONCLUSIONS: Feedback from the focus group and usability testing yielded a feasible, acceptable, relevant and user-friendly web-based intervention for adolescents with epilepsy. The Epilepsy Journey program will be further tested in an open pilot with adolescents with epilepsy and associated EF deficits. PMID- 28575760 TI - Benign childhood epilepsy with centrotemporal spikes (BECTS) and developmental co ordination disorder. AB - BACKGROUND: Benign epilepsy with centro-temporal spikes (BECTS) is a common childhood epilepsy syndrome also known as Rolandic Epilepsy (RE). Neurocognitive phenotypes have been described with greater focus on attention, reading and language domains but there have been far fewer studies focusing on motor functioning. This study included measures of motor, language and cognition in order to investigate the range, degree and pattern of difficulties associated with BECTS in a case series of children, but with a particular emphasis on motor skills. METHOD: Twenty-one children aged between 8 and 16years with a diagnosis of BECTS were asked to complete standardized assessments for language, cognition, motor functioning and handwriting. RESULTS: When measuring across language, cognitive and motor domains, 19 (90.48%) of the twenty-one children with a diagnosis of BECTS showed some difficulties on at least one area of functioning using standardized assessment tests. Of particular note nearly half (47.62%) of the children had some difficulties in one or more areas of motor functioning. DISCUSSION: Children with BECTS have a heterogeneous pattern of neurocognitive impairments. The presence of motor difficulties (DCD) should be considered in all children routinely seen in clinical settings with BECTS and included in any screening processes. PMID- 28575761 TI - Adjunctive eslicarbazepine acetate: A pooled analysis of three phase III trials. AB - OBJECTIVE: To assess the safety and efficacy of once-daily (QD) adjunctive eslicarbazepine acetate (ESL). METHODS: This post-hoc pooled analysis of three randomized, placebo-controlled trials (2093-301, -302, -304) involved adults with refractory partial-onset seizures (POS) receiving 1-3 antiepileptic drugs (AEDs). All studies included 8-week baseline, 2-week titration, and 12-week maintenance periods. Patients were randomized equally to placebo, ESL 400mg (studies 301, 302), 800mg, or 1200mg QD. The primary endpoint was standardized seizure frequency (SSF; per 4weeks); secondary endpoints included responder rates (maintenance period), and incidence of treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, serious AEs (SAEs), and deaths. RESULTS: The safety and efficacy analysis populations totaled 1447 and 1410 patients, respectively. SSF was significantly reduced versus placebo with ESL 800mg (p=0.0001) and 1200mg (p<0.0001) but not 400mg (p=0.81). There were no significant interactions between treatment effect and age, gender, race/ethnicity, geographic region, epilepsy duration, or concomitant AED use. Incidences of TEAEs and TEAEs leading to discontinuation increased with ESL dose. Incidences of the most frequent TEAEs were lower for patients who initiated dosing at 400 versus 800mg QD, regardless of titration regimen and maintenance dose. SAE incidence was <10%; there were 3 deaths (placebo, n=2; ESL 800mg, n=1). CONCLUSIONS: ESL (800 and 1200mg QD) was effective and well tolerated as adjunctive therapy for adults with refractory POS. PMID- 28575762 TI - A specific deficit of auditory processing in children with Rolandic Epilepsy and their relatives. AB - Previous research shows that children with Rolandic Epilepsy have deficits of auditory processing. We wanted to confirm the nature of this deficit and whether it aggregates in families. We compared 40 children with Rolandic Epilepsy and 32 unaffected siblings with 99 typically developing children and 71 parents of RE children with 31 healthy adults on a battery of auditory processing tests. We also examined ear advantage in children with RE, their siblings and parents using population norms and measured non-word reading performance. We found a specific deficit for competing words in patients, their siblings and their parents, suggesting that this particular impairment of auditory processing present in children with RE, is heritable and likely to be persistent. Importantly, scores on this subtest in patients and siblings were significantly correlated with non word reading performance. We saw increased rates of atypical left ear advantage in patients and siblings but no evidence of this in parents. We present these findings as evidence of familial incidence of dichotic listening and ear advantage abnormalities in relatives of children with Rolandic Epilepsy. PMID- 28575763 TI - Are physical activity levels associated with better health outcomes in people with epilepsy? AB - The aim of the study was to investigate the association of physical activity in three categories (inactive, insufficiently active and active) with health outcomes in people with epilepsy. The dependent variables and the instruments used in the study were: a) quality of life - measured by Quality of Life in Epilepsy-31 for adults and Quality of Life in Epilepsy for Adolescents, b) side effects of medication - measured by Adverse Events Profile, c) depression - measured by Neurological Disorders Depression Inventory for Epilepsy, and d) state and trait anxiety - measured by State-Trait Anxiety Inventory. Physical activity levels were analyzed using the International Physical Activity Questionnaire (IPAQ) for adults in the commuting and leisure domains and Physical Activity Questionnaire for Adolescents (PAQ-A). Simple and multiple linear regression was used in the statistical analysis. The cross-sectional study with one hundred and one individuals was conducted in Pelotas/RS, Brazil, at the Neurology Clinic of the Faculty of Medicine of the Federal University of Pelotas. In the crude analysis, physical activity was positively associated with quality of life (p<0.001) and negatively associated with depression (p=0.046), state of anxiety (p=0.014), trait of anxiety (p=0.015) and side effect of medication (p=0.01). In addition, physical activity levels explained 10% of the quality of life (R2=0.10). In the adjusted analysis, physical activity remained associated with side effect of medication (p=0.014) and was not associated with trait anxiety (p=0.066). However, quality of life showed a positive linear trend (p=0.001) while depression (p=0.033) and anxiety state (p=0.004) showed a negative trend according to physical activity levels. Physical activity was associated with health outcomes, and can be a nonpharmacological treatment in people with epilepsy for improving health and life conditions. PMID- 28575764 TI - Gaze matters! The effect of gaze direction on emotional enhancement of memory for faces in patients with mesial temporal lobe epilepsy. AB - PURPOSE: The aim of the study was to examine if gaze and emotional expression, both highly self-relevant social signals, affect the recollection accuracy of perceived faces in patients with mesial temporal lobe epilepsy (MTLE). METHODS: Forty patients with MTLE (twenty-one without surgery and nineteen after anterior temporal lobectomy) as well as twenty healthy controls (HC) took part in the study. We used a set of 64 facial stimuli: 32 neutral and 32 emotional displays (16 fearful; 16 angry) from well-established affective stimuli databases. Half of the faces in each condition had eyes directed straight and half - away from the observer. Participants performed a gender identification task, and then, after a 45-minute delay were asked to identify the previously seen stimuli, presented among a new set of photos. RESULTS: Increased automatic learning of angry and fearful compared to neutral expressions was found in HC. There was no emotional enhancement of memory in MTLE but an increased learning for faces with averted than direct gaze. CONCLUSION: Our results expand on previous research by demonstrating that emotion expression and gaze direction can affect memory of faces. The study supports the hypothesis that healthy individuals and patients with temporal lobe abnormalities present different patterns of emotional gazes processing. The potential consequences of altered emotional gaze processing and social cognition impairments need to be further investigated to improve the quality of life of patients with MTLE. PMID- 28575765 TI - The influence of levetiracetam on psychosocial and behavioral functioning in children: A case-control and follow-up study. AB - BACKGROUND: Levetiracetam, a widely used antiepileptic drug in children, has been associated with psychosocial and behavioral problems, which are also influenced by epilepsy variables, including duration or seizure frequency. PURPOSE: The objective of this study is to investigate the frequency and timing of treatment emergent psychosocial and behavioral problems in children receiving levetiracetam, irrespective of seizure variables which are possible confounders. METHODS: A prospective, case-control study with a 3-month follow-up was conducted. Consecutive children aged 6 to 16years with new-onset partial seizures were included in case of starting treatment with either levetiracetam or valproic acid. Psychosocial and behavioral functioning were assessed using a set of standardized questionnaires including Strengths and Difficulties Questionnaire (SDQ) and Children's Depression Inventory (CDI) at baseline, 1 and 3-month follow up. Patients' baseline scores were compared to healthy subjects. The difference in the follow-up SDQ and CDI scores was evaluated in patients receiving levetiracetam and valproic acid. RESULTS: A total of 101 participants were analyzed; 32 patients in levetiracetam group, 19 patients in valproic acid group and 50 healthy controls. Baseline SDQ and CDI scores were not statistically different between patients and healthy subjects (p>0.05). No statistically significant difference was observed in CDI, total and subscale SDQ scores between patients receiving levetiracetam or valproic acid during the study period (p>0.05). A girl aged 15years receiving levetiracetam had a CDI score of 18 without suicidal ideation at baseline. She developed suicidal ideation and depression, which resolved after switching of levetiracetam to valproic acid, at the 1-month follow-up. No other psychiatric or behavioral side-effects were observed in other patients. CONCLUSION: Psychosocial and behavioral side-effects of levetiracetam treatment are not frequent and they don't emerge in most of children at lower doses. At this dose, and after 3months, using these specific instruments, we did not observe any difference between the valproic acid and levetiracetam treatment groups. PMID- 28575766 TI - Increased odds and predictive rates of MMPI-2-RF scale elevations in patients with psychogenic non-epileptic seizures and observed sex differences. AB - OBJECTIVE: The Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) is a self-report instrument, previously shown to differentiate patients with epileptic seizures (ES) and psychogenic non-epileptic seizures (PNES). At present, the odds of MMPI-2-RF scale elevations in PNES patients, as well as the diagnostic predictive value of such scale elevations, remain largely unexplored. This can be of clinical utility, particularly when a diagnosis is uncertain. METHOD: After looking at mean group differences, we applied contingency table derived odds ratios to a sample of ES (n=92) and PNES (n=77) patients from a video EEG (vEEG) monitoring unit. We also looked at the positive and negative predictive values (PPV, NPV), as well as the false discovery rate (FDR) and false omission rate (FOR) for scales found to have increased odds of elevation in PNES patients. This was completed for the overall sample, as well as the sample stratified by sex. RESULTS: The odds of elevations related to somatic concerns, negative mood, and suicidal ideation in the PNES sample ranged from 2 to 5 times more likely. Female PNES patients had 3-6 times greater odds of such scale elevations, while male PNES patients had odds of 5-15 times more likely. PPV rates ranged from 53.66% to 84.62%, while NPV rates ranged from 47.52% to 90.91%. FDR across scales ranged from 15.38% to 50%, while the FOR ranged from 9.09% to 52.47%. CONCLUSIONS: Consistent with prior research, PNES patients have greater odds of MMPI-2-RF scale elevations, particularly related to somatic concerns and mood disturbance. Female PNES patients endorsed greater emotional distress, including endorsement of suicide related items. Elevations of these scales could aid in differentiating PNES from ES patients, although caution is warranted due to the possibility of both false positives and the incorrect omissions of PNES cases. PMID- 28575767 TI - Lacosamide and concomitant use of antiepileptic and other medications in a US population - A retrospective cohort study. AB - Information on the use of lacosamide and concomitant antiepileptic and non antiepileptic drugs (non-AEDs) is available from clinical trials and observational studies with small sample sizes. This retrospective cohort study was conducted to gain insight into the use of lacosamide in a large number of patients with epilepsy in real-life clinical practice with less restrictive selection criteria compared with clinical trial participants. The Truven Health MarketScan (Commercial Claims and Medicare Supplemental) database was used to identify patients with a prior diagnosis of epilepsy with at least one prescription claim for lacosamide between June 2009 and September 2013 and continuous health insurance enrolment with medical and pharmacy coverage during the 1-year pre-index baseline period. A total of 8859 eligible patients were identified, of whom, at index (lacosamide initiation), 16.8% received lacosamide as monotherapy and 54.0% as polytherapy. The median prescription duration was 196days (Interquartile range 69-476days). Levetiracetam was the most frequently prescribed concomitant AED across all age groups, followed by phenytoin among older (>65years) and lamotrigine among younger patients. Older patients who had LCM monotherapy at initiation, were prescribed fewer concomitant AEDs, but more non-AEDs. The most common non-AED medications were prescribed for pain, psychiatric conditions, hyperlipidemia and gastrointestinal diseases across all age groups. Overall, results suggest that the lacosamide use is driven predominantly by age and that there is substantial use of lacosamide monotherapy (16.8%), despite lack of indication at the time of the study. Results also reveal substantial use of concomitant non-AEDs; 90.4% among patients >65years of age and 54.3% among those <=17years, confirming the high prevalence of comorbidities among patients with epilepsy across all ages. Despite the availability of numerous newer AEDs, older AEDs are still being frequently prescribed, especially for elderly patients, notably phenytoin. This warrants careful consideration, given the strong propensity of enzyme-inducing AEDs to interact with other drugs, producing unwanted side effects. These results highlight the value of real-life prescription patterns and the potential in informing treatment decisions to ensure patients receive appropriate treatment. PMID- 28575768 TI - Early-life status epilepticus acutely impacts select quantitative and qualitative features of neonatal vocalization behavior: Spectrographic and temporal characterizations in C57BL/6 mice. AB - Early-life seizures are known to cause long-term deficits in social behavior, learning, and memory, however little is known regarding their acute impact. Ultrasonic vocalization (USV) recordings have been developed as a tool for investigating early communicative deficits in mice. Previous investigation from our lab found that postnatal day (PD) 10 seizures cause male-specific suppression of 50-kHz USVs on PD12 in 129 SvEvTac mouse pups. The present study extends these findings by spectrographic characterization of USVs following neonatal seizures. On PD10, male C57BL/6 pups were administered intraperitoneal injections of kainic acid or physiological saline. On PD12, isolation-induced recordings were captured using a broad-spectrum ultrasonic microphone. Status epilepticus significantly suppressed USV quantity (p=0.001) and total duration (p<0.05). Seizure pups also utilized fewer complex calls than controls (p<0.05). There were no changes in call latency or inter-call intervals. Spectrographic analysis revealed increased peak amplitude for complex, downward, short, two-syllable, and upward calls, as well as reduced mean duration for short and two-syllable calls in seizure mice. This investigation provides the first known spectrographic characterization of USVs following early-life seizures. These findings also enhance evidence for USVs as an indicator of select communicative impairment. PMID- 28575770 TI - People with epilepsy as partners in research. PMID- 28575769 TI - Written accounts of living with epilepsy: A thematic analysis. AB - This study examines the subjective experience of living with epilepsy by thematically analyzing participants' written accounts of their condition. Writing is seen as an individual act allowing for private exploration, reflection and expression of thoughts and feelings. Participants (n=20) were recruited from a United Kingdom hospital and from membership-led organizations for individuals living with seizures. Participants were asked to produce four pieces of writing: 1) about their thoughts and feelings about their condition; 2) a letter to their condition; 3) a letter to their younger self; and 4) about a personal value. All writings were analyzed thematically using a theory- and data-driven approach. Five main-themes and 22 sub-themes emerged from the data. Theme 1: 'seizure onset' demonstrated that the development of seizures and subsequent diagnosis was an important event that could change an individuals' identity. Theme 2: 'seizure symptoms' revealed participants externalized their seizures as an intrusive agent with a constant presence in their lives. Theme 3: 'treatment and outcome' reflected medication as an essential means to controlling seizures with subsequent side effects being perceived as a compromise. Theme 4: 'living with epilepsy' explored the consequences of the condition including restrictions and stigma. Theme 5: 'displays of coping' demonstrated that, for the most part, participants were keen to present themselves as living well with epilepsy. The results add to the growing research applying qualitative methodologies to investigate the phenomenology of epilepsy. Qualitative research can improve our understanding and awareness of the condition, as well as inform clinical practice. PMID- 28575771 TI - Moving evidence based guidelines for seizures into practice in the emergency department: What's stopping us? AB - PURPOSE: To identify barriers to implementation of an evidence based integrated care pathway (ICP) for seizure management in the Emergency Department (ED). METHODS: A site specific bespoke questionnaire was designed to solicit anonymous responses from all grades of ED medical and nursing staff to a series of questions regarding utility, feasibility, significance and implementation of a locally designed and championed ICP for seizure management and onward referral. RESULTS: While 95% of respondents agreed that the pathway ensured patients were treated according to best practice, a number of human factors were identified as barriers to use. These fell into three categories 1) environmental 2) pathway design/process and 3) user related issues. CONCLUSIONS: Most respondents understood and endorsed the evidence based utility of the pathway. Barriers to use, however, are broad with interactions involving many complex human factors. Nevertheless, solutions can be relatively easily formulated but departmental-wide effort is required to comprehensively address all issues. PMID- 28575772 TI - Atypical handedness in mesial temporal lobe epilepsy. AB - OBJECTIVE: The main aim of our study was to investigate the handedness of patients with mesial temporal lobe epilepsy (MTLE). We also sought to identify clinical variables that correlated with left-handedness in this population. METHODS: Handedness (laterality quotient) was assessed in 73 consecutive patients with MTLE associated with unilateral hippocampal sclerosis (HS) using the Edinburgh Handedness Inventory. Associations between right- and left-handedness and clinical variables were investigated. RESULTS: We found that 54 (74.0%) patients were right-handed, and 19 (26%) patients were left-handed. There were 15 (36.6%) left-handed patients with left-sided seizure onset compared to 4 (12.5%) left-handed patients with right-sided seizure onset (p=0.030). Among patients with left-sided MTLE, age at epilepsy onset was significantly correlated with handedness (8years of age [median; min-max 0.5-17] in left-handers versus 15years of age [median; min-max 3-30] in right-handers (p<0.001). CONCLUSIONS: Left-sided MTLE is associated with atypical handedness, especially when seizure onset occurs during an active period of brain development, suggesting a bi-hemispheric neuroplastic process for establishing motor dominance in patients with early onset left-sided MTLE. PMID- 28575773 TI - Glioneuronal tumors in childhood - Before and after surgery. A long-term follow up study. AB - AIM: To give a detailed description of the long-term outcome of a cohort of children with glioneuronal tumors regarding pre- and postsurgical factors, including "dual" and "double" pathology, seizure freedom, and psychosocial outcome. METHODS: During a fifteen-year period (1995-2009), all patients (age 0 17.99years) with a glioneuronal brain tumor diagnosed and treated at Uppsala University Children's Hospital were identified from the National Brain Tumor Registry and the National Epilepsy Surgery Registry. Hospital medical records were reviewed and neuroradiological and neuropathological findings were re evaluated. A cross-sectional long-term follow-up prospective evaluation, including an interview, neurologic examination, and electroencephalogram, was accomplished in patients accepting participants in the study. RESULTS: A total of 25 out of 28 (89%) eligible patients were included. The M:F ratio was 1.5:1. Mean follow-up time after surgery was 12.1years (range 5.0-19.3). Twenty patients were adults (>18years) at follow-up. Seizure freedom was achieved in 64%. Gross total resection (GTR) was the only preoperative factor significantly correlating to seizure freedom (p=0.027). Thirty-eight percent were at some time postoperatively admitted for a psychiatric evaluation. There was a trend towards both higher educational level and employment status in adults who became seizure free. CONCLUSION: Long-term outcome is good regarding seizure freedom if GTR can be achieved, but late seizure recurrence can occur. "Dual" and "double" pathology is uncommon and does not influence seizure outcome. Obtaining seizure freedom seems to be important for psychosocial outcome, but there is a risk for psychiatric comorbidities and long-term follow-up by a multi-professional team is advisable. PMID- 28575774 TI - A randomized controlled trial of a manual-based psychosocial group intervention for young people with epilepsy [PIE]. AB - : We conducted an exploratory RCT to examine feasibility and preliminary efficacy for a manual-based psychosocial group intervention aimed at improving epilepsy knowledge, self-management skills, and quality of life in young people with epilepsy. METHOD: Eighty-three participants (33:50m/f; age range 12-17years) were randomized to either the treatment or control group in seven tertiary paediatric neuroscience centres in the UK, using a wait-list control design. Participants were excluded if they reported suicidal ideation and/or scored above the cut off on mental health screening measures, or if they had a learning disability or other neurological disorder. The intervention consisted of six weekly 2-hour sessions using guided discussion, group exercises and role-plays facilitated by an epilepsy nurse and a clinical psychologist. RESULTS: At three month follow up the treatment group (n=40) was compared with a wait-list control group (n=43) on a range of standardized measures. There was a significant increase in epilepsy knowledge in the treatment group (p=0.02). Participants receiving the intervention were also significantly more confident in speaking to others about their epilepsy (p=0.04). Quality of life measures did not show significant change. Participants reported the greatest value of attending the group was: Learning about their epilepsy (46%); Learning to cope with difficult feelings (29%); and Meeting others with epilepsy (22%). Caregiver and facilitator feedback was positive, and 92% of participants would recommend the group to others. CONCLUSION: This brief psychosocial group intervention was effective in increasing participants' knowledge of epilepsy and improved confidence in discussing their epilepsy with others. We discuss the qualitative feedback, feasibility, strengths and limitations of the PIE trial. PMID- 28575775 TI - Socialization characteristics in persons with epilepsy. AB - OBJECTIVE: The purpose of this report was to describe social behaviors and preferences in adults with epilepsy, including self-reported use of various socialization media (face-to-face and indirect communication) as well as perceived social barriers. METHODS: 1320 consecutive persons with epilepsy (PWEs) confirmed through inpatient video-EEG monitoring were administered a questionnaire on the day of their first appointment. The questionnaire was designed to assess preferences in socialization practices, frequency of interpersonal contact, use of social media, and perceived barriers to socialization. The survey was developed to gain a better understanding of the socialization behaviors and preferences of our patients for the future development of customized activities in our wellness program. RESULTS: Our sample revealed higher rates of unemployment and single status as compared to the US Census of 2012. With regard socialization however, many were quite social (86% reported daily/weekly communication with friends and family via telephone, 71% saw relatives in person weekly, 68% saw friends weekly, and 65% reported using the computer daily/weekly to socialize). Facebook(r) was the preferred on-line social media. Indoor/solitary activities were most common with 63% stating they watch TV/read/use the computer followed by physical exercise and spending time outdoors (36%). The frequency of socialization with friends, relatives, and coworkers decreased with the respondents' age and the longer the respondent had carried the diagnosis of epilepsy. Respondents who were taking a greater number of AEDs or were considered refractory were less likely to consider participating in socialization-enhancing activities. The primary barriers to socialization that respondents endorsed were driving prohibition and medication side-effects. Respondents expressed the greatest interest in online support groups or educational programs (31%), office-based support groups (25%), and volunteering (19%). CONCLUSION: Although the respondents indicate that they do face barriers to socialization, a majority report frequent communication with relatives and friends via phone, in-person and social media. When designing wellness interventions with this group of patients in the future, online, as well as face to face options for support appear to be desired by a number of PWEs. PMID- 28575776 TI - A multi-objective structural optimization of an omnidirectional electromagnetic acoustic transducer. AB - In this paper an axisymmetric model of an omnidirectional electromagnetic acoustic transducer (EMAT) used to generate Lamb waves in conductive plates is introduced. Based on the EMAT model, the structural parameters of the permanent magnet were used as the design variables while other parameters were fixed. The goal of the optimization was to strengthen the generation of the A0 mode and suppress the generation of the S0 mode. The amplitudes of the displacement components at the observation point of the plate were used for calculation of the objective functions. Three approaches to obtain the amplitudes were discussed. The first approach was solving the peak values of the envelopes of the time waveforms from the time domain simulations. The second approach also involved calculation of the peaks, but the waveforms were from frequency domain model combined with the forward and inverse Fourier transforms. The third approach involved a single frequency in the frequency domain model. Single and multi objective optimizations were attempted, implemented with the genetic algorithms. In the single objective optimizations, the goal was decreasing the ratio of the amplitudes of the S0 and A0 modes, while in the multi-objective optimizations, an extra goal was strengthening the A0 mode directly. The Pareto front from the multi-objective optimizations was compared with the estimation from the data on the discrete grid of the design variables. From the analysis of the results, it could be concluded that for a linearized steel plate with a thickness of 10mm and testing frequency of 50kHz, the point with minimum S0/A0 could be selected, thus the multi-objective optimization effectively degenerated to the single objective optimization. While for an aluminum plate with a thickness of 3mm and frequency of 150kHz, without further information it would be difficult to select one particular solution from the Pareto front. PMID- 28575777 TI - Prevalence of psychological stress, depression and anxiety among medical students in Egypt. AB - Poor psychological health in medical students has been reported nationwide. This study estimated the prevalence of depression, anxiety and stress symptoms among medical students who were enrolled in a public university in Upper Egypt and determine the association of these morbidities with the students' basic socio demographic variables. This cross-sectional study included 700 students. A self administered, questionnaire for the socio-demographic characteristics, Depression Anxiety Stress Scale (DASS 21) and Pittsburgh Sleep Quality Index (PSQI) questionnaire were used for assessment. High frequencies of depression (65%), anxiety (73%) and stress (59.9%) were reported. Stress scores were significantly higher than depression and anxiety (P=0.001). 55.7% were poor sleepers. In univarate analysis, females, those living in the University campus/students' residence facility, in the preclinical years and with lower academic achievement had higher scores of DASS and PSQI compared to their comparative partners. Significant correlations were reported between stress with depression, anxiety and PQSI scores (P=0.0001). In multivariate analysis, stress scores were significantly associated with female sex, depression and anxiety scores. We conclude that depression, anxiety and stress symptoms are common in medical students of Assiut University relative to other schools and female gender was significantly correlated with these findings. PMID- 28575778 TI - Good for sewage treatment and good for agriculture: Algal based compost and biochar. AB - In this study we test a novel approach to closing the anthropogenic nutrient cycle, by using the freshwater macroalga, Oedogonium intermedium, to recover dissolved nitrogen (N) and phosphorous (P) from municipal wastewater. We then convert this cultivated algae into two types of soil ameliorant; compost and biochar. To produce compost, algae was combined with sugarcane bagasse and left to mature for 10 weeks, and to produce biochar, algae was processed through slow pyrolysis at 450 degrees C. The mature compost had a total N and P content of 2.5% and 0.6%, which was 2- to 4-times lower than the algal biochar, which had a total N and P content of 5.5% and 2.5% respectively. Composting stabilized the N and P recovered from wastewater, with 80% of the initial N and >99% of the initial P retained in the mature compost. In contrast, only 29% of the initial N and 62% of the initial P was retained in the biochar. When the mature compost was added to a low fertility soil it significantly increased the production of sweet corn (Zea mays). Treatments receiving 50 and 100% compost produced 4-9 times more corn biomass than when synthetic fertilizer alone was added to the low fertility soil. When biochar was applied in conjunction with compost there was an additional 15% increase in corn productivity, most likely due to the ability of the biochar to bind labile N and P and prevent its loss from the soil. This study demonstrates a unique model for recovering N and P from municipal wastewater and recycling these nutrients into the agricultural industry. This could be an ideal model for regional areas where agriculture and water treatment facilities are co located and could ultimately reduce the reliance of agriculture on finite mineral sources of P. PMID- 28575779 TI - A conceptualisation framework for building consensus on environmental sensitivity. AB - Examination of the intrinsic attributes of a system that render it more or less sensitive to potential stressors provides further insight into the baseline environment. In impact assessment, sensitivity of environmental receptors can be conceptualised on the basis of their: a) quality status according to statutory indicators and associated thresholds or targets; b) statutory protection; or c) inherent risk. Where none of these considerations are pertinent, subjective value judgments can be applied to determine sensitivity. This pragmatic conceptual framework formed the basis of a stakeholder consultation process for harmonising degrees of sensitivity of a number of environmental criteria. Harmonisation was sought to facilitate their comparative and combined analysis. Overall, full or wide agreement was reached on relative sensitivity values for the large majority of the reviewed criteria. Consensus was easier to reach on some themes (e.g. biodiversity, water and cultural heritage) than others (e.g. population and soils). As anticipated, existing statutory measures shaped the outcomes but, ultimately, knowledge-based values prevailed. The agreed relative sensitivities warrant extensive consultation but the conceptual framework provides a basis for increasing stakeholder consensus and objectivity of baseline assessments. This, in turn, can contribute to improving the evidence-base for characterising the significance of potential impacts. PMID- 28575780 TI - Tourism as a driver of conflicts and changes in fisheries value chains in Marine Protected Areas. AB - Although critical tools for protecting ocean habitats, Marine Protected Areas (MPAs) are sometimes challenged for social impacts and conflicts they may generate. Some conflicts have an economic base, which, once understood, can be used to resolve associated socioenvironmental problems. We addressed how the fish trade in an MPA that combines no-take zones and tourist or resident zones creates incentives for increased fisheries. We performed a value chain analysis following the fish supply and trade through interviews that assessed consumer demand and preference. The results showed a simple and closed value chain driven by tourism (70% of the consumption). Both tourists and local consumers preferred high trophic level species (predators), but the former preferred large pelagics (tuna and dolphinfish) and the latter preferred reef species (barracuda and snapper). Pelagic predators are caught with fresh sardines, which are sometimes located only in the no-take zone. Pelagic species are mainly served as fillet, and the leftover fish parts end up as waste, an issue that, if properly addressed, can help reduce fishing pressure. Whereas some of the target species may be sustainable (e.g., dolphinfish), others are more vulnerable (e.g., wahoo) and should not be intensively fished. We advise setting stricter limits to the number of tourists visiting MPAs, according to their own capacity and peculiarities, in order to avoid conflicts with conservations goals through incentives for increased resource use. PMID- 28575781 TI - Estimation of global soil respiration by accounting for land-use changes derived from remote sensing data. AB - Soil respiration is one of the largest carbon fluxes from terrestrial ecosystems. Estimating global soil respiration is difficult because of its high spatiotemporal variability and sensitivity to land-use change. Satellite monitoring provides useful data for estimating the global carbon budget, but few studies have estimated global soil respiration using satellite data. We provide preliminary insights into the estimation of global soil respiration in 2001 and 2009 using empirically derived soil temperature equations for 17 ecosystems obtained by field studies, as well as MODIS climate data and land-use maps at a 4 km resolution. The daytime surface temperature from winter to early summer based on the MODIS data tended to be higher than the field-observed soil temperatures in subarctic and temperate ecosystems. The estimated global soil respiration was 94.8 and 93.8 Pg C yr-1 in 2001 and 2009, respectively. However, the MODIS land use maps had insufficient spatial resolution to evaluate the effect of land-use change on soil respiration. The spatial variation of soil respiration (Q10) values was higher but its spatial variation was lower in high-latitude areas than in other areas. However, Q10 in tropical areas was more variable and was not accurately estimated (the values were >7.5 or <1.0) because of the low seasonal variation in soil respiration in tropical ecosystems. To solve these problems, it will be necessary to validate our results using a combination of remote sensing data at higher spatial resolution and field observations for many different ecosystems, and it will be necessary to account for the effects of more soil factors in the predictive equations. PMID- 28575782 TI - Incidence and survival of childhood cancer in the French islands of Reunion and Mayotte (2005-2011). AB - The aim of this study is to describe childhood cancer incidence and survival in the French islands of Reunion and Mayotte for the period 2005-2011. Data were taken from the population-based Cancer Registry of Reunion Island. All incident cases of malignant tumours and benign tumours of the Central Nervous System diagnosed between 2005 and 2011 in children under the age of 15 and living in Reunion or Mayotte were included. A total of 236 cases were registered (176 in Reunion, 60 in Mayotte). Age-standardised incidence rates (ASRs, world standard) for all cancers were 125.0 and 101.8 per million for Reunion and Mayotte, respectively. ASRs for the main cancer groups were lower than those described in mainland France for the same period. The 5-year overall survival rate for all patients was 78.5% (95%CI 71.9- 83.7), slightly lower than that reported in mainland France. PMID- 28575783 TI - Psychopathology and tobacco demand. AB - INTRODUCTION: Behavioral economic measurement of the relative value of tobacco (Cigarette Purchase Task; CPT) is used to examine individual differences in motivation for tobacco under certain contexts. Smokers with psychopathology, relative to those without, may demonstrate stronger demand for tobacco following a period of smoking deprivation, which could account for disparate rates of smoking and cessation among this subgroup. METHOD: Participants (n=111) were community-recruited adult daily smokers who completed the CPT after a deprivation period of approximately 60min. Presence of psychopathology was assessed via clinical interview; 40.5% (n=45) of the sample met criteria for past-year psychological diagnosis. Specifically, 31.5% (n=35) had an emotional disorder (anxiety/depressive disorder), 17.1% (n=19) had a substance use disorder, and 19.1% of the sample had more than one disorder. RESULTS: Smokers with any psychopathology showed significantly higher intensity (demand at unrestricted cost; $0) and Omax (peak expenditure for a drug) relative to smokers with no psychopathology. Intensity was significantly higher among smokers with an emotional disorder compared to those without. Smokers with a substance use disorder showed significantly higher intensity and Omax, and lower elasticity, reflecting greater insensitivity to price increases. Having>=2 disorders was associated with higher intensity relative to having 1 or no disorders. DISCUSSION: Findings suggest that presence of psychopathology may be associated with greater and more persistent motivation to smoke. Future work is needed to explore the mechanism linking psychopathology to tobacco demand. PMID- 28575784 TI - Exposure to extremely low and intermediate-frequency magnetic and electric fields among children from the INMA-Gipuzkoa cohort. AB - Detailed assessment of exposure to extremely low frequency (ELF) and intermediate frequency (IF) fields is essential in order to conduct informative epidemiological studies of the health effects from exposure to these fields. There is limited information available regarding ELF electric fields and on both magnetic and electric field exposures of children in the IF range. The aim of this study was to characterize ELF and IF exposure of children in the Spanish INMA cohort. A combination of spot and fixed measurements was carried out in 104 homes, 26 schools and their playgrounds and 105 parks. Low levels of ELF magnetic fields (ELF-MF) were observed (with the highest 24-h time-weighted average (TWA) exposure being 0.15MUT in one home). The interquartile range (IQR) of ELF electric fields (ELF-EF) ranged from 1 to 15V/m indoors and from 0.3 to 1.1V/m outdoors and a maximum value observed was 55.5V/m in one school playground. IQR ranges for IF magnetic and electric fields were between 0.02 and 0.23MUT and 0.2 and 0.5V/m respectively and maximum values were 0.03MUT and 1.51V/m in homes. Correlations between magnetic and electric fields were weak for ELF (Spearman 0.04-0.36 in different settings) and moderate for IF (between 0.28 and 0.75). Children of INMA-Gipuzkoa cohort were exposed to very low levels of ELF-MF in all settings and to similar levels of ELF-EF compared to the range of previously reported levels, although somewhat higher exposures occurred at home. Children enrolled to our study were similarly exposed to IF in all settings. PMID- 28575785 TI - Effect of season of birth on cord blood IgE and IgE at birth: A systematic review and meta-analysis. AB - BACKGROUND: Elevated cord blood IgE is important on the pathway to allergic disease. The association between season of birth and infant cord blood IgE is not well-established. Study findings differ on which birth season is associated with higher cord blood IgE risk and its magnitude. We conducted a systematic review and meta-analysis of studies on season of birth and cord blood IgE. METHODS: We searched Medline, Web of Science, Scopus and ProQuest Health databases, and reviewed reference lists of articles that met the inclusion criteria. All included studies measured IgE as a binary variable using various cut-off values. We performed multivariate-random-effects meta-analysis to handle an exposure with multiple categories of Season of Birth. RESULTS: Our search identified 275 records and 10 had sufficient data to be included in a meta-analysis. Relative to summer, winter birth had the greatest odds of high IgE (>= 0.1IU/ml), meta analysis OR = 1.24 (95%CI: 1.01-1.52). A similar OR, was found for IgE >= 0.5 IU/ml, OR = 1.30 (95%CI: 0.99-1.71). CONCLUSIONS: A winter season of birth was associated with statistically significant higher odds of elevated cord blood IgE at cut-off >= 0.1IU/ml but borderline at cut-off >= 0.5IU/ml. This winter effect is likely to be a marker for a range of other environmental exposures during specific stages of pregnancy, such as aeroallergen exposures, maternal infections and vitamin D levels. Further research is required to support our finding and to identify the exact mechanisms that lead to the winter season of birth effect on circulating IgE levels, as this may have implications for allergic disease prevention. PMID- 28575786 TI - Clinical features of IgG4-related rhinosinusitis. AB - PURPOSE: IgG4-related disease is a systemic disease that affects various organs of the body. Aim of this study is to elucidate the clinical characteristics of IgG4-related rhinosinusitis. MATERIAL AND METHODS: Clinical features, laboratory findings, radiological and endoscopic findings, associated disease, treatment and prognosis were retrospectively examined in 10 patients with IgG4-related rhinosinusitis. RESULTS: The age was 59.1+/-11.3 years old and male-to-female ratio was 1:1. The chief nasal complaints were hyposmia (n=4), nasal obstruction (n=3), and nothing (n=3). Serum IgG4 levels were elevated in all patients and the value was 740.4+/-472.4mg/dl. Other IgG4-related diseases were associated in all 10 patients, including IgG4-related sialadenitis (n=6), IgG4-related dacryoadenitis (n=5), and autoimmune pancreatitis (n=5). Imaging findings on CT/MRI were obstruction of the way of elimination (n=10), thickening of the sinus mucous membrane (n=10), and fluid in the sinus (n=6). All of the cases had bilateral findings. Nasal endoscopic findings were chiefly deviated nasal septum (n=5), polyps (n=4), edema of the mucous membrane (n=3). Histologically, abundant infiltration of IgG4 positive plasma cell and lymphocyte and an elevated IgG4+/IgG+ cell ration was detected in all 8 patients and 5 patients, respectively. Endoscopic sinus surgery was performed in 8 patients. Eight patients were treated with steroid therapy for other associated IgG4-related diseases. Symptoms improved in all 6 patients after an initial treatment (endoscopic surgery (n=5) and steroids (n=1)), but one patient suffered relapse. CONCLUSIONS: IgG4-related rhinosinusitis is a distinct entity of IgG4-related disease, and is associated in patients with multiple IgG4-related diseases. PMID- 28575787 TI - Activation of peroxymonosulfate by nitrogen-functionalized sludge carbon for efficient degradation of organic pollutants in water. AB - Nitrogen-functionalized sludge carbon (NSC) was prepared by urea-mediated pyrolysis of sewage sludge (SS) and was introduced, for the first time, as a potential metal-free catalyst to activate peroxymonosulfate (PMS) for oxidative removal of organic pollutants in water. The nitrogen functionalization of NSC catalysts significantly affected the chemical micro-environments as well as microstructures (morphology and porosity), improving the PMS activation activity towards removing various pollutants, e.g., acid orange 7, phenol and rhodamine B. On the basis of quenching studies and electron paramagnetic resonance, the formed dominant reactive oxidative species (ROS) in the NSC/PMS system was clarified to be nonradical singlet oxygen, in addition to the typical radical ROSs, sulfate and hydroxyl radicals. The incorporated pyridine N, graphite N and pristine CO in the NSC framework promoted the generation of ROS. This study provided new insights into environmentally friendly resourcing SS and exploiting novel cost effective metal-free catalyst for PMS activation. PMID- 28575788 TI - Enzyme recycle and fed-batch addition for high-productivity soybean flour processing to produce enriched soy protein and concentrated hydrolysate of fermentable sugars. AB - Despite having high protein and carbohydrate, soybean flour utilization is limited to partial replacement of animal feed to date. Enzymatic process can be exploited to increase its value by enriching protein content and separating carbohydrate for utilization as fermentation feedstock. Enzyme hydrolysis with fed-batch and recycle designs were evaluated here for achieving this goal with high productivities. Fed-batch process improved carbohydrate conversion, particularly at high substrate loadings of 250-375g/L. In recycle process, hydrolysate retained a significant portion of the limiting enzyme alpha galactosidase to accelerate carbohydrate monomerization rate. At single-pass retention time of 6h and recycle rate of 62.5%, reducing sugar concentration reached up to 120g/L using 4ml/g enzyme. When compared with batch and fed-batch processes, the recycle process increased the volumetric productivity of reducing sugar by 36% (vs. fed-batch) to 57% (vs. batch) and that of protein product by 280% (vs. fed-batch) to 300% (vs. batch). PMID- 28575789 TI - Quantitative approaches for illustrating correlations among the mechanical fragmentation scales, crystallinity and enzymatic hydrolysis glucose yield of rice straw. AB - Mechanical fragmentation is an important pretreatment in the biomass biotransformation process. Mechanical fragmentation at the tissue scale significantly reduced the particle size of rice straw but did not significantly change its crystalline properties; the increase in the glucose yield was limited from 28.75% (95.55mg/g substrate) to 35.29% (115.28mg/g substrate). Mechanical fragmentation at the cellular scale destroyed the cell wall structure and reduced its crystalline properties. Thus, the glucose yield also showed a significant increase from 35.29% (115.28mg/g substrate) to 81.71% (287.07mg/g of substrate). The quantitative equations among the particle size, crystalline properties and glucose yield (mg/g substrate) are as follows: CrI=44.14*[1-exp(-0.03658*D50)] and CP=(8.403*logD50-24.1836)/(1-4.225/D50^0.5); GY=-5.636CrI+343.7 and GY= 14.62CP+512.1; and GY=97.218+247.5*exp(-0.03824*D50). The quantitative correlations among the mechanical fragmentation scales and crystalline properties can determine the effect and mechanism of mechanical fragmentation on biomass and can further promote the construction of a cost-competitive biotransformation process for biomass. PMID- 28575790 TI - Enhanced nitrogen removal of low C/N domestic wastewater using a biochar-amended aerated vertical flow constructed wetland. AB - Recently, vertical flow constructed wetlands (VFCWs) with intermittent aeration have been proven as an efficient technology to enhance removal efficiency of organics and nitrogen for wastewater treatment. However, the low denitrification effect in VFCWs was a problem for treating low carbon source wastewater. In this study, intermittent aeration and biochar, produced by biomass pyrolysis, was used to promote the nitrogen removal in VFCWs for low C/N domestic wastewater. Four systems, including non-aerated with non-biochar VFCW, non-aerated with biochar VFCW, aerated with non-biochar VFCW and aerated with biochar VFCW, were conducted for comparing their treatment performances. The results showed that much higher removal of COD (94.9%), NH4+-N (99.1%), TN (52.7%) and lower N2O emission (60.54MUg.m-2.h-1) was obtained in aerated VFCW with biochar addition. The results suggested that adding biochar to intermittent aerated VFCWs could be an effective and appropriate strategy for low C/N wastewater treatment. PMID- 28575791 TI - Toxic effects of three crystalline phases of TiO2 nanoparticles on extracellular polymeric substances in freshwater biofilms. AB - Comparative toxicity of three typical TiO2 NPs (Anatase, Rutile, and Degussa P25, 50mg/L respectively) under UVC irradiation (An+UV, Ru+UV, and P25+UV) on production and chemical characteristics of EPS in freshwater biofilms were investigated. Rutile was more stable in lake water, yet P25 and anatase were endowed with better photo-oxidation capacity. TiO2 NPs+UV enhanced total EPS, manifesting as LB-EPS increased by 98.16% (An+UV), 143.03% (Ru+UV), and 48.21% (P25+UV), while TB-EPS increased to 1.51 (An+UV), 1.36 (Ru+UV), and 1.61 (P25+UV) times greater than control without NPs and UVC, being mainly attributed to increase of polysaccharide and proteins. Three-dimensional fluorescence spectrum revealed tyrosine (An+UV and P25+UV) and tryptophan (P25+UV) protein-like substances vanished in LB-EPS. Fourier transform infrared spectroscopy indicated PO (An+UV and P25+UV) and CO or COC (P25+UV) disappeared in EPS. P25+UV and An+UV caused more lactate dehydrogenase release, while Ru+UV induced more reactive oxygen species and malondialdehyde production, consistent with decreased in cells viability. PMID- 28575792 TI - Optimization of hydrogen and syngas production from PKS gasification by using coal bottom ash. AB - Catalytic steam gasification of palm kernel shell is investigated to optimize operating parameters for hydrogen and syngas production using TGA-MS setup. RSM is used for experimental design and evaluating the effect of temperature, particle size, CaO/biomass ratio, and coal bottom ash wt% on hydrogen and syngas. Hydrogen production appears highly sensitive to all factors, especially temperature and coal bottom ash wt%. In case of syngas, the order of parametric influence is: CaO/biomass>coal bottom ash wt%>temperature>particle size. The significant catalytic effect of coal bottom ash is due to the presence of Fe2O3, MgO, Al2O3, and CaO. A temperature of 692 degrees C, coal bottom ash wt% of 0.07, CaO/biomass of 1.42, and particle size of 0.75mm are the optimum conditions for augmented yield of hydrogen and syngas. The production of hydrogen and syngas is 1.5% higher in the pilot scale gasifier as compared to TGA-MS setup. PMID- 28575793 TI - Continuous bioethanol fermentation from wheat straw hydrolysate with high suspended solid content using an immersed flat sheet membrane bioreactor. AB - Finding a technological approach that eases the production of lignocellulosic bioethanol has long been considered as a great industrial challenge. In the current study a membrane bioreactor (MBR) set-up using integrated permeate channel (IPC) membrane panels was used to simultaneously ferment pentose and hexose sugars to ethanol in continuous fermentation of high suspended solid wheat straw hydrolysate. The MBR was optimized to flawlessly operated at high SS concentrations of up to 20% without any significant changes in the permeate flux and transmembrane pressure. By the help of the retained high cell concentration, the yeast cells were capable of tolerating and detoxifying the inhibitory medium and succeeded to co-consume all glucose and up to 83% of xylose in a continuous fermentation mode leading to up to 83% of the theoretical ethanol yield. PMID- 28575794 TI - 99mTc-labeled PSMA inhibitor: Biokinetics and radiation dosimetry in healthy subjects and imaging of prostate cancer tumors in patients. AB - : The prostate-specific membrane antigen (PSMA) is expressed in epithelial cells of the prostate and highly overexpressed in 95% of advanced prostate cancers. The aims of this study was to estimate the biokinetics and dosimetry of 99mTc EDDA/HYNIC-iPSMA (99mTc-labeled PSMA inhibitor) in eight healthy subjects and evaluate its usefulness as a tumor-imaging agent in eight prostate cancer patients. METHODS: 99mTc-EDDA/HYNIC-iPSMA was obtained from a lyophilized formulation with radiochemical purities >98%, determined by reversed-phase HPLC and ITLC-SG analyses. Whole-body images from eight healthy subjects were acquired at 20min, and at 2, 6 and 24h after 99mTc-EDDA/HYNIC-iPSMA administration. Regions of interest (ROIs) were drawn around the source organs on each time frame. Each ROI was corrected by background, attenuation, scattered radiation and physical decay. The image sequence was used to extrapolate the 99mTc-EDDA/HYNIC iPSMA time-activity curves of each organ to adjust the biokinetic model and calculate the total number of disintegrations (N) that occurred in the source regions. N data were the input for the OLINDA/EXM code to calculate internal radiation doses. In eight prostate cancer patients with histologically confirmed cancer, whole-body SPECT/CT images were obtained at 3h. RESULTS: The blood activity showed a half-life value of 4.98min for the fast component (T1/2alpha=ln2/8.34), 2.49h for the first slow component (T1/2beta=ln2/0.278), and 9.24h for the second slow component (T1/2gamma=ln2/0.076). Images from patients showed an average tumor/background ratio of 8.99+/-3.27 at 3h. The average equivalent doses calculated for a study using 740MBq were 3.80, 7.06, 9.69, 10.70, and 28.80mSv for the breast, spleen, salivary glands, liver, and kidneys respectively, with an effective dose of 3.42+/-0.78mSv. CONCLUSIONS: All the absorbed doses were comparable to those known for most of the 99mTc studies. 99mTc-EDDA/HYNIC-iPSMA obtained from kit formulations showed high tumor uptake in patients with malignant lesions, making it a promising imaging radiopharmaceutical to target site-specific prostate cancer. PMID- 28575796 TI - A comprehensive conformational space analysis of N-formyl-l-tryptophanamide system by using a genetic algorithm for multi-modal search. AB - The conformational space of protected amino acid HCO-Tryptophane-NH2 was explored by using a new optimization procedure, in order to localize the stable minima on its potential energy surface (PES). The genetic algorithm based on the Multi Niche Crowding (MNC) technique was used initially to generate a set of optimized structures for title compound. Resulting structures from the genetic algorithm technique will be used hereafter as input conformers at a hierarchy of increasingly more accurate electronic structure calculations (RHF/6-31G+(d) and DFT/B3LYP/6-31G+(d) geometry optimizations). The lowest energy conformer gammaL(g+g+) presents a folded Backbone that is stabilized by strong hydrogen bond noted C7. This links the carbonyl oxygen of the formyl group and the hydrogen of the amine group. There are further interactions from one hand between the carbonyl oxygen of the formyl group and the neighboring CH group on the pyrrole ring and from other hand between the N-terminus hydrogen and the indole ring in accordance with the experimental results. This work includes also a comparison between the theoretical calculations and the experimental results of X ray crystallography extracted from protein data bank (PDB). PMID- 28575797 TI - Prediction of crystal morphology of 3,4-Dinitro-1H-pyrazole (DNP) in different solvents. AB - Analytical grade ethyl acetate was used to recrystallize 3,4-Dinitro-1H-pyrazole (DNP), it was found that there were two different morphologies of the crystals. There is a possibility that ethyl acetate undergoes hydrolysis due to the absorption of moisture in the air. The influence of the hydrolysis products of acetic acid and ethanol on the morphology of DNP crystal was considered. In order to investigate the effect of solvents on DNP morphology, there is ongoing research to validate molecular dynamics (MD) simulation results with experiment data. The morphology of DNP in vacuum was predicted by the attachment energy (AE) model, and the growth morphology of DNP in different solvents was simulated by MD method. The modified AE model was successfully verified the phenomenon by the prediction of DNP crystals morphology in Ethyl acetate, H2O, H2O/EtOH and H2O/AcOH. The calculated results show that the two different crystal shapes are diamond and hexagon, respectively. The results are in agreement with the crystal morphology obtained by experiment. PMID- 28575795 TI - [11C]Erlotinib PET cannot detect acquired erlotinib resistance in NSCLC tumor xenografts in mice. AB - INTRODUCTION: [11C]Erlotinib PET has shown promise to distinguish non-small cell lung cancer (NSCLC) tumors harboring the activating epidermal growth factor receptor (EGFR) mutation delE746-A750 from tumors with wild-type EGFR. To assess the suitability of [11C]erlotinib PET to detect the emergence of acquired erlotinib resistance in initially erlotinib-responsive tumors, we performed in vitro binding and PET experiments in mice bearing tumor xenografts using a range of different cancer cells, which were erlotinib-sensitive or exhibited clinically relevant resistance mechanisms to erlotinib. METHODS: The following cell lines were used for in vitro binding and PET experiments: the epidermoid carcinoma cell line A-431 (erlotinib-sensitive, wild-type EGFR) and the three NSCLC cell lines HCC827 (erlotinib-sensitive, delE746-A750), HCC827EPR (erlotinib-resistant, delE746-A750 and T790M) and HCC827ERLO (erlotinib-resistant, delE746-A750 and MET amplification). BALB/c nude mice with subcutaneous tumor xenografts underwent two consecutive [11C]erlotinib PET scans, a baseline scan and a second scan in which unlabeled erlotinib (10mg/kg) was co-injected. Logan graphical analysis was used to estimate total distribution volume (VT) of [11C]erlotinib in tumors. RESULTS: In vitro experiments revealed significantly higher uptake of [11C]erlotinib (5.2 fold) in the three NSCLC cell lines as compared to A-431 cells. In all four cell lines co-incubation with unlabeled erlotinib (1MUM) led to significant reductions in [11C]erlotinib uptake (-19% to -66%). In both PET scans and for all four studied cell lines there were no significant differences in tumoral [11C]erlotinib VT values. For all three NSCLC cell lines, but not for the A-431 cell line, tumoral VT was significantly reduced following co-injection of unlabeled erlotinib (-20% to -35%). CONCLUSIONS: We found no significant differences in the in vitro and in vivo binding of [11C]erlotinib between erlotinib-sensitive and erlotinib-resistant NSCLC cells. Our findings suggest that [11C]erlotinib PET will not be suitable to distinguish erlotinib-sensitive NSCLC tumors from tumors with acquired resistance to erlotinib. PMID- 28575798 TI - Design and computational support for the binding stability of a new CCR5/CXCR4 dual tropic inhibitor: Computational design of a CCR5/CXCR4 drug. AB - The human immunodeficiency virus (HIV) infects healthy human cells by binding to the glycoprotein cluster of differentiation 4 receptors on the surface of helper T-cells, along with either of two chemokine receptors, CC chemokine receptor type 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4). Recently, a pyrazolo piperdine ligand was synthesized and the corresponding biological data showed good binding to both chemokine receptors, effectively blocking HIV-1 entry. Here, we exhaustively assess the atomistic binding interactions of this compound with both CCR5 and CXCR4, and we find that binding is driven by pi-stacking interactions between aromatic rings on the ligand and receptor residues, as well as electrostatic interactions involving the protonated piperidine nitrogen. However, these favorable binding interactions were partially offset by unfavorable desolvation of active site glutamates and aspartates, prompting our proposal of a new, synthetically-accessible derivative designed to increase the electrostatic interactions without compromising the pi-stacking features. PMID- 28575800 TI - Remediation of soil contaminated with organic and inorganic wood impregnation chemicals by soil washing. AB - The aim of this study was to evaluate the efficiency of a large scale washing/wet sieving technique for a soil contaminated with wood impregnation chemicals by 1) defining the final distribution of trace elements (As, Cu, Cr, Zn) and polycyclic aromatic hydrocarbons (PAH) in separated soil particle size fractions; and 2) defining the leaching behavior of the contaminants in these soil fractions. A soil washing experiment was implemented at waste management facility in Sweden using a full scale soil sorting and washing equipment. Five tons of soil was loaded to the equipment and wet-sieved into the following fractions: >16 mm, 8-16 mm, 2-8 mm, 0.2-2 mm, <0.2 mm and a fraction that floated on top of the slurry before the final separation phase, composed of organic matter (OM). Analysis of total concentrations of contaminants in all soil fractions indicated that wet sieving/soil washing was not efficient to reduce the total volume of soil that needs further treatment. Even the coarsest soil fractions (>8 mm) contained elevated concentrations of total As and PAH. Leaching of As from all washed soil fractions was so high, that none of the particle size fractions could be disposed of without additional treatment. PMID- 28575799 TI - Application of fish cell lines for evaluating the chromium induced cytotoxicity, genotoxicity and oxidative stress. AB - In the present study, we hypothesize that cytotoxicity, genotoxicity and oxidative stress play a key role in chromium induced toxicity in SISS, SISK, IEE, IEK, IEG, SICH and ICG cell lines after 24 h exposure. Three fish species namely Lates calcarifer, Etroplus suratensis and Catla catla were exposed to the concentrations of 0, 10, 20, 30, 40 and 50 mg/L of chromium for 96 h under static conditions for conducting acute toxicity tests. LC50 was then calculated. The percentage cell survival was assessed by multiple endpoints such as MTT, NR, AB and CB assays in the seven fish cell lines exposed to different concentrations of chromium and EC50 values of all the four endpoints were calculated. High significances were noted in the correlations between each in vitro cytotoxicity assays and in vivo mortality data. Cell shrinkage, cell detachment, vacuolations and cell swelling at the highest concentration of chromium (50 mg/L) were seen on microscopic examination of cell morphology. Comet assay and Hoechst staining were carried out to assess DNA damage and nuclear fragmentation in the seven fish lines exposed to chromium. The results of antioxidant parameters obtained indicate a significant reduction in the level of catalase, superoxide dismutase, glutathione S-transferase and Glutathione peroxidase, and increased level of lipid peroxidation in all the cell lines exposed to chromium. These results confirm that fish cell lines could be used as an alternative to whole fish for cytotoxicity, genotoxicity and oxidative stress assessment in chromium toxicity studies. PMID- 28575801 TI - Evaluation of the Parasympathetic Tone Activity (PTA) index to assess the analgesia/nociception balance in anaesthetised dogs. AB - The Parasympathetic Tone Activity (PTA) is an index based on the analysis of heart rate variability that has been recently developed to assess the analgesia/nociception balance in anaesthetised animals. The present study aimed to evaluate its performance in dogs undergoing surgery. Thirty dogs admitted for elective surgeries, were anaesthetised with a standardised protocol. PTA, heart rate (HR), systolic blood pressure (SBP) and HDR (defined as an increase by >20% in HR and/or SBP within 5min) were assessed at the following predefined time points: TStSt (steady-state, after induction of anaesthesia and before start of surgery), TClamp (clamping of surgical drapes on the skin), TCut (cutaneous incision), TPrePTA (retrospectively assessed 1min before a PTA decline of at least 20%) and TEndIso (isoflurane discontinuation). The dynamic variation of PTA over 1min (?PTA) was calculated at each predefined time-points and its performance to predict HDR was assessed by building Receiver Operating Characteristics (ROC) curves. A significant decrease of PTA (p<0.002) was detected 1min after TClamp, TCut and TPrePTA followed by a significant increase in HR and/or SBP within 5min after the time points (p<0.01). The DeltaPTA was associated with the following performance in predicting HDR: AUC ROC [95% CI]=0.80 [0.71 to 0.88] (p<0.05), with a sensitivity of 77% and a specificity of 72% for a threshold value of -18%. Although encouraging, the performance of the PTA index and its dynamic variation needs to be further evaluated, particularly in different clinical contexts. PMID- 28575803 TI - Paradigm shift of contamination risk of six heavy metals in tea (Camellia sinensis L.) growing soil: A new approach influenced by inorganic and organic amendments. AB - The present study provides several contamination and ecological risk indices for selected metals (Cd, Cr, Cu, Mn, Ni and Zn) in tea (Camellia sinensis L.; cv. S.3A/3) growing soil influenced by lower to higher doses of inorganic and organic amendments. While ecological risk indices were applied, it was observed that same treatment showed different risk levels but contamination risk status did not vary significantly. All the indices showed significant correlation with heavy metals' concentration in young shoots of tea plants. As the indices characterized experimental soils with different extents of contamination, it would be important to standardize the indices with long term experiments followed by generation of new index. Therefore, we formulated a new contamination index named as Tea Research Association Heavy Metal Contamination Index (TRAHMCI) for tea growing soils. TRAHMCI is based on the probable change of metal status in soil with progress of growth of tea plant. This could be useful to negate discrepancies arised from use of various existing metal contamination indices in tea growing soils amended with different doses of fertilizers. TRAHMCI was formulated based on individual contamination factor using statistical technique and applied to the present dataset which provided a more holistic understanding of overall tea growing soil behavior. The limitation of the developed TRAHMCI index is that, the index had not been validated for other crops in our study not to claim its effective use for crops other than tea. As already mentioned, this new index had been formulated by taking tea as the test crop with above mentioned six heavy metal contents in young shoot and made tea. PMID- 28575802 TI - Themes and variations in gene regulation by extracytoplasmic function (ECF) sigma factors. AB - The ECF sigma family was identified 23 years ago as a distinct group of sigma70 like factors. ECF sigma factors have since emerged as a major form of bacterial signal transduction that can be grouped into over 50 phylogenetically distinct subfamilies. Advances in our understanding of these sigma factors and the signaling pathways governing their activity have elucidated conserved features as well as aspects that have evolved over time. All ECF sigma factors are predicted to share a common streamlined domain structure and mode of promoter interaction. The activity of most ECF sigma factors is controlled by an anti-sigma factor. The nature of the anti-sigma factor and the activating signaling pathways appear to be conserved within ECF families, while considerable diversity exists between different families. PMID- 28575804 TI - Heteroatoms doped metal iron-polyvinylidene fluoride (PVDF) membrane for enhancing oxidation of organic contaminants. AB - Iron nanoparticles (NPs) embedded in S, N-codoped carbon were prepared by one step pyrolysis of a homogeneous mixture consisting of Fe, S, N, C precursors, and then immobilized in poly (vinylidene fluoride) membranes as a multifunctional catalytic system (NSC-Fe@PVDF) to effectively activate peroxymonosulfate (PMS) and oxidize organic compounds in water. The NSC-Fe@PVDF membranes effectively decolorized organic pollutants at a wide pH range (2.05-10.85), due to the synergistic effects between the S, N-doped carbon and iron NPs. The efficiency depended on the doping types, amount of metal, PMS dosages, reaction temperatures, solution pHs, and organic substrates. In-situ electron spin resonance spectroscopy and sacrificial-reagent incorporated catalysis indicate radical intermediates such as sulfate and hydroxyl radicals are mainly responsible for this persulfate-driven oxidation of organic compounds. Membrane's porous structure and high internal surface area not only minimize the NPs agglomeration, but also allow the facile transport of catalytic reactants to the active surface of metal catalysts. The results demonstrate the morphological and structural features of catalytic membranes enhance the overall catalytic activity. PMID- 28575805 TI - Niclosamide induces apoptosis through mitochondrial intrinsic pathway and inhibits migration and invasion in human thyroid cancer in vitro. AB - The morbidity of thyroid cancer has been rising obviously throughout the world during the past years. Classic treatment procedure is generally curable for low risk differentiated thyroid cancer, but may lead to many postoperative complications. And low-level of thyroid stimulating hormone after surgery has side effects on both cardiovascular system and skeletal system. Furthermore effective treatment approaches for more aggressive differentiated thyroid cancer, poorly differentiated thyroid cancer and anaplastic thyroid cancer are absent, thus new candidates that can inhibit tumor growth and metastasis are urgently needed. In this study, niclosamide, an FDA approved anthelminthic drug, was evaluated for its anti-thyroid cancer activity in vitro. Niclosamide potently inhibited cell proliferation and induced apoptosis in human papillary thyroid cancer cell lines TPC-1 and BCPAP, as well as anaplastic thyroid cancer cell line ACT-1. In addition, the occurrence of TPC-1 apoptosis was correlated with activation of Bax and cleaved caspases-3, and inhibition of Bcl-2 and the mitochondrial membrane potential (DeltaYm), indicating that niclosamide may induce apoptosis through a mitochondria-mediated intrinsic apoptotic pathway. Moreover, niclosamide markedly impaired TPC-1 cells and ACT-1 cells invasion. And we further found the inhibitory effect of TPC-1 was closely related with down regulating of matrix metalloproteinase (MMP)-2 and -9 and up-regulating of tissue inhibitor of metalloproteinase (TIMP)-2. Taken together, these results demonstrated that niclosamide could be a potential agent for inhibiting the growth and metastasis of thyroid cancer. PMID- 28575806 TI - Phytol induces ROS mediated apoptosis by induction of caspase 9 and 3 through activation of TRAIL, FAS and TNF receptors and inhibits tumor progression factor Glucose 6 phosphate dehydrogenase in lung carcinoma cell line (A549). AB - A number of drugs as well as lead molecules are isolated from natural sources. Phytol is one of such lead molecule belongs to terpenes group distributed widely in medicinal plants. In the present work, we investigated the cytotoxic behavior of phytol on human lung carcinoma cells (A549). Phytol was found to cause characteristic apoptotic morphological changes and generation of ROS in A549 cells. The mechanism of phytol involved the activation of TRAIL, FAS and TNF alpha receptors along with caspase 9 and 3. In silico molecular docking studies revealed that phytol has a good binding affinity with glucose-6-phosphate dehydrogenase (G6PD), which is known to promote tumor proliferation. The ability of phytol to become potential drug candidate has been revealed from the pharmacokinetic study performed in the present study. PMID- 28575807 TI - A holistic review on the autoimmune disease vitiligo with emphasis on the causal factors. AB - Vitiligo is an idiopathic systemic autoimmune disease affecting skin, hair and oral mucosa. This genetic yet acquired disease characterized by melanin loss is a cause of morbidity across all races. Though thyroid disturbance has been recognized as a key trigger of this pathology, an array of other factors plays critical role in its manifestation. Multiple hormones (corticotropin-releasing hormone, adrenocorticotropic hormone, alpha-melanocyte-stimulating hormone, melatonin, calcitriol, testosterone, estrogen), genes (Human leukocyte antigen (HLA), Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), Forkhead box D3 (FOXD3), Cluster of differentiation 117 (CD117), Estrogen receptor (ESR) 1, Cyclooxygenase-2 (COX2), Vitiligo-associated protein 1 (VIT1)), and lifestyle choices (stress, diet, cosmetic products, and medications) have been suspected as drivers of this disorder. The pathological mechanisms have been understood in recent times, with the aid of genomic studies; however a universally-effective therapy is yet to be achieved. This review discusses these under-investigated facets of vitiligo onset and progression; hence, it is expected to enrich vitiligo research. PMID- 28575808 TI - Induction of apoptosis in human colorectal cancer cell line, HCT-116 by a vanadium- Schiff base complex. AB - Vanadium compounds are well known for their therapeutic interventions against several diseases. Various biochemical attributes of vanadium complexes inspired us to evaluate the cancer cell killing efficacy of the vanadium complex, viz., vanadyl N-(2-hydroxyacetophenone) glycinate [VO(NG)2]. Previously we showed that VO(NG)2 is an effective anticancer agent in in vitro and in vivo cancer models and imposed miniscule side effects. Herein we report that VO(NG)2 is significantly cytotoxic to various cancer cell lines. Furthermore, this redox active vanadyl complex altered the redox homeostatsis of many human cancer cell lines significantly. VO(NG)2 actuates programmed cell death in human colorectal carcinoma cells(HCT-116) through mitochondrial outer membrane permeabilization but in caspase independent manner, possibly by altering cellular redox status and by inflicting DNA damage. Thus, the present work is an attempt to provide many evidences regarding the potent and selective chemotherapeutic efficacy of the novel VO(NG)2. PMID- 28575809 TI - Lutein mitigates cyclophosphamide induced lung and liver injury via NF kappaB/MAPK dependent mechanism. AB - This study targeted to test the potential protective role of lutein against lung and liver damage associated with cyclophosphamide (CP) administration. Lutein was given orally for 5days at two different doses both before and after CP injection. Results have shown that CP administration caused marked pulmonary and hepatic injurious effects in mice. Lung damage was evident through increased lung wet/dry ratio, elevated inflammatory cells infiltration into the pulmonary tissues, increased total protein content and lactate dehydrogenase (LDH) activity in the broncho-alveolar lavage fluid. Estimation of high levels of serum transaminases, alkaline phosphatase and LDH in serum revealed hepatic injury. Histopathological examination of both organs confirmed the biochemical analysis. Elevation of oxidative stress along with depressed anti-oxidant status of lung and liver were evident in CP-intoxicated animals. Furthermore, CP induced elevation of inflammatory cytokines (NOx, TNF-alpha, IL-6) contaminant with activation of nuclear factor kappa-B (NF-kappaB) and p38 mitogen activated protein kinase (p38 MAPK). On the other side, lutein treatment successfully protected the lung and the liver as indicated by improvement of the biochemical and histopathological parameters. These results suggest that lutein can ameliorate CP-induced pulmonary and hepatic oxidative injurious effects via inhibition of reactive oxygen species (ROS)/NF-kappaB/MAPK pathway. PMID- 28575810 TI - Homology modeling and molecular docking studies on Type II diabetes complications reduced PPARgamma receptor with various ligand molecules. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma), a type II nuclear receptor present in adipose tissue, colon and macrophages. It reduces the hyperglycemia associated metabolic syndromes. Particularly, type II diabetes related cardiovascular system risk in human beings. The fatty acid storage and glucose metabolism are regulated by PPARgamma activation in human body. According to recent reports commercially available PPARgamma activating drugs have been causing severe side effects. At the same time, natural products have been proved to be a promising area of drug discovery. Recently, many studies have been attempted to screen and identify a potential drug candidate to activate PPARgamma. Hence, in this study we have selected some of the bio-active molecules from traditional medicinal plants. Molecular docking studies have been carried out against the target, PPARgamma. We Results suggested that Punigluconin has a efficient docking score and it is found to have good binding affinities than other ligands. Hence, we concluded that Punigluconin is a better drug candidate for activation of PPARgamma gene expression. Further studies are necessary to confirm their efficacy and possibly it can develop as a potential drug in future. PMID- 28575811 TI - Perforation of the cecum resulting from a closed-loop obstruction in a patient with an adenocarcinoma of the sigmoid colon: a case report. AB - INTRODUCTION: Bowel obstruction is one of the principal non-traumatic causes of general surgery emergencies, both in Brazil and worldwide. This condition can be classified according to the degree (complete or incomplete), clinical course (acute or chronic) or nature (mechanical, vascular or functional) of the obstruction. CASE REPORT: ESS, a 62-year old Brazilian woman from Rio de Janeiro, was admitted to the emergency department complaining of constipation of two weeks' duration. She also reported fever and fecal vomiting in the preceding two days.A syndromic diagnosis of bowel obstruction was made, and the patient was referred for CT. The sigmoid colon, descending colon, transverse colon, ascending colon, the cecum and the terminal ileum were resected. DISCUSSION: Colorectal cancer is one of the most common forms of cancer in the elderly, perforation of the cecum occurs in only around 3-8% of cases. 15 This can be explained by the fact that patients with colorectal cancer present with wasting syndrome before the bowel lumen becomes completely obstructed. In a literature review conducted for this study, only one publication was found in which rupture of the cecum was associated with colorectal cancer. CONCLUSION: Although rupture of the cecum associated with colorectal cancer is a rare pathology, it constitutes a surgical emergency; therefore, all surgeons should be aware of the possibility. PMID- 28575812 TI - New insights into urine-based assessment of polycyclic aromatic hydrocarbon exposure from a rat model: Identification of relevant metabolites and influence of elimination kinetics. AB - A gas chromatography tandem mass-spectrometry method dedicated to the analysis of 50 metabolites of polycyclic aromatic hydrocarbons (OH-PAHs) was applied to urine specimens collected from female Long Evans rats under controlled exposure to a mixture of PAHs (at 7 doses ranging from 0.01 to 0.8 mg/kg, by gavage, 3 times per week for 90 days). On four occasions (day 1, 28, 60 and 90), urine samples were collected over a 24 h period. Among these 50 OH-PAHs, 41 were detected in urine samples. Seven additional OH-PAHs were identified for the first time: 1 corresponding to metabolite of pyrene and 3 of anthracene. Strong linear dose versus urinary concentration relationships were observed for 25 of the 41 OH-PAHs detected in rat urine, confirming their suitability for assessing exposure to their respective parent compound. In addition, some isomers (e.g. 1-OH-pyrene, 3 OH-/4-OH-chrysene, 10-OH-benz[a]anthracene, 8-OH-benzo[k]fluoranthene, 11-OH benzo[b]fluoranthene and 3-OH-benzo[a]pyrene) that were detected starting from the lowest levels of exposure or even in controls were considered particularly relevant biomarkers compared to metabolites only detected at higher levels of exposure. Finally, on the basis of the excretion profiles (on days 1, 28, 60 and 90) and urinary elimination kinetics of each OH-PAH detected at days 1 and 60, this study highlighted the fact that sampling time may influence the measurement of metabolites in urine. Taken together, these results provide interesting information on the suitability of the analysis of OH-PAHs in urine for the assessment of PAH exposure, which could be taken into consideration for the design of epidemiological studies in the future. PMID- 28575813 TI - A novel prognostic indicator for in-hospital and 4-year outcomes in patients with pulmonary embolism: TIMI risk index. AB - BACKGROUND: Thrombolysis in Myocardial Infarction (TIMI) risk index (TRI) was recently evaluated in patients with acute myocardial infarction and found as an important prognostic index. In the current study, we evaluated the prognostic value of TRI in patients with moderate-high and high risk pulmonary embolism (PE) who were treated with thrombolytic agents. METHODS: We retrospectively evaluated the in-hospital and long-term (4-year) prognostic impact of TRI in a total number of 456 patients with moderate-high and high risk PE. Patients were stratified by quartiles (Q) of admission TRI. RESULTS: In-hospital analysis revealed significantly higher rates of in-hospital death for patients with TRI in Q4. After adjustment for confounding baseline variables, TRI in Q4 was associated with 2.8-fold hazard of in-hospital death. Upon multivariate analysis, admission TRI in Q4 vs. Q1-3 was associated with 3.1 fold hazard of 4-year mortality rate. CONCLUSION: TRI in Q4, as compared to Q1-3, was significantly predictive of short term and long-term outcomes in PE patients who treated with thrombolytic agents. Our data suggest TRI to be an independent, feasible, and cost-effective tool for rapid risk stratification in moderate-high and high risk PE patients who treated with thrombolytic agents. PMID- 28575814 TI - A comparison of pre ICU admission SIRS, EWS and q SOFA scores for predicting mortality and length of stay in ICU. AB - INTRODUCTION: The 2015 sepsis definitions suggest using the quick SOFA score for risk stratification of sepsis patients among other changes in sepsis definition. Our aim was to validate the q sofa score for diagnosing sepsis and comparing it to traditional scores of pre ICU admission sepsis outcome prediction such as EWS and SIRS in our setting in order to predict mortality and length of stay. METHODS: This was a retrospective cohort study. We retrospectively calculated the q sofa, SIRS and EWS scores of all ICU patients admitted with the diagnosis of sepsis at our center in 2015. This was analysed using STATA 12. Logistic regression and ROC curves were used for analysis in addition to descriptive analysis. RESULTS: 58 patients were included in the study. Based on our one year results we have shown that although q SOFA is more sensitive in predicting LOS in ICU of sepsis patients, the EWS score is more sensitive and specific in predicting mortality in the ICU of such patients when compared to q SOFA and SIRS scores. CONCLUSION: In conclusion, we find that in our setting, EWS is better than SIRS and q SOFA for predicting mortality and perhaps length of stay as well. The q Sofa score remains validated for diagnosis of sepsis. PMID- 28575815 TI - Cardiac-disease-induced PTSD (CDI-PTSD): A systematic review. AB - The goal of the current systematic review was to provide an overview of the findings in the field of Cardiac-Disease-Induced Posttraumatic Stress Disorder (CDI-PTSD) in order to establish CDI-PTSD as a valid diagnostic entity for a wide spectrum of cardiac diseases and related medical procedures. In accordance with PRISMA guidelines, we conducted a systematic electronic literature search. Of the 3202 citations identified, 150 studies meeting the selection criteria were reviewed. Our main findings were that the prevalence of CDI-PTSD ranged between 0% and 38% (averaging at 12%) and was highly dependent on the assessment tool used. The most consistent risk factors are of a psychological nature (e.g., pre morbid distress). The consequences of CDI-PTSD range from psychosocial difficulties to lack of adherence and heightened mortality rates. Much inconsistency in the field was found with regard to patients who present with diagnoses other than acute coronary syndrome (e.g., cardiac arrest) and who undergo potentially traumatic medical procedures (e.g., defibrillator implantation). Yet the current review seems to strengthen the conceptualization of CDI-PTSD as a valid diagnostic entity, at least with regard to acute cardiac events. PMID- 28575816 TI - A naphthalene benzimidazole-based chemosensor for the colorimetric and on-off fluorescent detection of fluoride ion. AB - A novel naphthalene benzimidazole (NBI)-based chemosensor (D2) was developed for fluoride ion (F-) detection. The absorption spectrum of D2 changed dramatically from yellow to blue in the visible region accompanied with a 225nm red shift of its absorption maximum upon the addition of F- in DMSO. D2 also exhibited a fluorescence turn-off response towards the fluoride ion. The emission intensity of D2 decreased drastically along the increasing F- concentration and the detection limit for F- was as low as 3.2*10-9mol/L. 1H NMR and HRMS-ESI results indicated that the formation of NBI-O- through the desilylation reaction of F- with NBI-OSi was responsible for the spectral changes. Overall, this kind of NBI type molecules represent a new type chemosensor for the spectral detection of fluoride ion in solution. PMID- 28575817 TI - Terahertz acoustic phonon detection from a compact surface layer of spherical nanoparticles powder mixture of aluminum, alumina and multi-walled carbon nanotube. AB - We present terahertz spectroscopy study on spherical nanoparticles powder mixture of aluminum, alumina, and MWCNTs induced by surface mechanical attrition treatment (SMAT) of aluminum substrates. Surface alloying of AL, Al2O3 0.95% and MWCNTs 0.05% powder mixture was produced during SMAT process, where a compact surface layer of about 200 MUm due to ball bombardment was produced from the mixture. Al2O3 alumina powder played a significant role in MWCNTs distribution on surface, those were held in deformation surface cites of micro-cavities due to SMAT process of Al. The benefits are the effects on resulted optical properties of the surface studied at the terahertz frequency range due to electrical isolation confinement effects and electronic resonance disturbances exerted on Al electronic resonance at the same range of frequencies. THz acoustic phonon around 0.53-0.6THz (17-20cm-1) were observed at ambient conditions for the spherical nanoparticles powder mixture of Al, Al2O3 and MWCNTs. These results suggested that the presence of Al2O3 and MWCNTs during SMAT process leads to the optically detection of such acoustic phonon in the THz frequency range. PMID- 28575818 TI - In-situ studies on the micro-structure evolution of A2W2O7 (A=Li, Na, K) during melting by high temperature Raman spectroscopy and density functional theory. AB - In-situ high temperature Raman spectroscopic (HTRS) technique in combination with density functional theory (DFT) analysis has been adopted to investigate the micro-structure of solid and molten A2W2O7 (A=Li, Na, K). The [WO6] octahedra were found to be connected to each other by corner and edge sharing in the crystalline Li2W2O7 and K2W2O7 compounds. In the crystal lattice of Na2W2O7, on the other hand, the [WO4] tetrahedra and [WO6] octahedra were found to coexist and paired by corner sharing. Although the structural diversity has clearly led to distinct Raman spectra of the crystalline A2W2O7 compounds, the spectra of their melts tended to be analogous, showing the typical vibration modes of (W2O7)2- dimer. A mechanism was then proposed to explain the structure evolution occurring during the melting process of A2W2O7. The effect of A+ cation on the Raman bands of (W2O7)2- dimer in molten A2W2O7 has also been investigated. Both the wavenumber and full width at half-height (FWHH) of the characteristic band assigned to the symmetrical stretching vibration mode of WOnb (non-bridging oxygen) in (W2O7)2- were found to decrease in the sequence of Li+, Na+ and K+, indicating the cation effect on the mean bond length and its distribution range of WOnb. In addition, the relative intensity of this band was also influenced by the cation and it was increased in the order of Li2W2O7, Na2W2O7 and K2W2O7, which has been explained by the charge transfer process and confirmed by Mulliken overlap population analysis. PMID- 28575819 TI - Corrigendum to "New model for prediction binary mixture of antihistamine decongestant using artificial neural networks and least squares support vector machine by spectrophotometry method" [Spectrochim. Acta A Mol. Biomol. Spectrosc. 182 (2017) 105-115]. PMID- 28575820 TI - Effects of hydrogen bonding between pyrrole-2-carboxaldehyde and nearest polar and nonpolar environment. AB - The present paper represents dominant effects of hydrogen bonding on the existence of different molecular aggregates in one of the heterocyclic pyrrole system: pyrrole-2-carboxaldehyde (PCL). Theoretical and experimental Raman spectral evidence verifies the existence of different molecular aggregates like dimeric, monomeric, hydrated complex states in PCL. Atoms in molecules (AIMs) analysis and fluorescence decay profile provide a strong signature of intermolecular hydrogen bonding (IerHB) as the possible reason for the existence of cis form of dimeric (X) molecular aggregates. The high remnant polarization of 3.13MUCcm-2 and smaller dielectric loss in solid form of PCL arise due to in X by ordering of dipoles as a result of IerHB. A remarkable high ferroelectric response in solid phase makes PCL a desirable candidate to be used as raw material for energy storage devices. For solution phase, in presence of external hydroxylic environment, PCL reacts with external water molecules through weak IerHB and creates different hydrated PCL/(H2O)n complexes by creating water bridge with number of water molecules from 1 to n. An increasing number of water molecules helps to form stronger hydrated complex by separation of charges by lowering the transferring energy barrier. PMID- 28575821 TI - Organic and inorganic colloids impacting total iodine behavior in groundwater from the Datong Basin, China. AB - The geochemical behaviors of colloids in aquifers played an important role in determining the fate of iodine in groundwater system. To decipher the impact of colloids on iodine mobilization in aquifers, three successive pore-sized colloids filtration (0.45MUm, 30kDa and 5kDa) were conducted on in-situ during groundwater sampling. The results showed that the distribution ratios (f) of total iodine (IT) and iron in the dissolved solution (i.e., 5kDa ultrafiltered) were from 0.78 to 0.99 and from 0.56 to 0.94, respectively. Natural organic matter (NOM) in the colloidal fractions obtained the f values ranging from 0.14 to 1.00. The decreased Eh values from recharge area to discharge area indicated redox potential of groundwater system changed from oxidizing to reducing along groundwater flowpath, and interestingly, the corresponding iodine fractions in groundwater were decreasing in dissolved solution and increasing in colloidal fractions. Inverse correlation between Fe and DOC and positive correlation between iodine and DOC suggested the occurrence of reductive dissolution of iron oxyhydroxides and degradation of organic iodine in groundwater system. Iodine distribution increased in dissolved solution and decreased in colloids with pH increase. Moreover, as pH increased, f (Fe) and f (DOC) decreased in dissolved solution and increased in colloids. Relatively weak correlation of f (IT) with f (Fe) and strong relationship between f (IT) and f (DOC) in the large grain size fractions suggested the Fe-OM complexes controlled iodine distribution in groundwater, which depends on the presence of Fe bridges. Negligible association of iodine with Fe and NOM in the small grain size fractions might be attributed to the effects of abundant OH- content in groundwater. PMID- 28575822 TI - A national scale flood hazard mapping methodology: The case of Greece - Protection and adaptation policy approaches. AB - The present work introduces a national scale flood hazard assessment methodology, using multi-criteria analysis and artificial neural networks (ANNs) techniques in a GIS environment. The proposed methodology was applied in Greece, where flash floods are a relatively frequent phenomenon and it has become more intense over the last decades, causing significant damages in rural and urban sectors. In order the most prone flooding areas to be identified, seven factor-maps (that are directly related to flood generation) were combined in a GIS environment. These factor-maps are: a) the Flow accumulation (F), b) the Land use (L), c) the Altitude (A), b) the Slope (S), e) the soil Erodibility (E), f) the Rainfall intensity (R), and g) the available water Capacity (C). The name to the proposed method is "FLASERC". The flood hazard for each one of these factors is classified into five categories: Very low, low, moderate, high, and very high. The above factors are combined and processed using the appropriate ANN algorithm tool. For the ANN training process spatial distribution of historical flooded points in Greece within the five different flood hazard categories of the aforementioned seven factor-maps were combined. In this way, the overall flood hazard map for Greece was determined. The final results are verified using additional historical flood events that have occurred in Greece over the last 100years. In addition, an overview of flood protection measures and adaptation policy approaches were proposed for agricultural and urban areas located at very high flood hazard areas. PMID- 28575823 TI - Passive sampling for spatial and temporal monitoring of organic pollutants in surface water of a rural-urban river in Kenya. AB - Passive sampling is an emerging monitoring strategy for surface waters and can be applied in a range of environments including remote locations. Silicone rubber (SR) as a robust single-phase passive sampler was applied to characterize the spatial and temporal variability of organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), polyaromatic hydrocarbons (PAHs) and three phthalates, namely, dibutyl phthalate (DBP), benzyl butyl phthalate (BBP) and bis(2-ethylhexyl)phthalate (DEHP) in a tropical river traversing rural and urban catchments. OCPs and PCBs were not detected. Up to 31.8ng/L of freely dissolved concentrations of PAHs were quantified and were dominated by the lower molecular weight members. Mean concentrations of DBP, BBP and DEHP were 72.6ng/L, 3.9ng/L and 7.1ng/L respectively. However, in sampling for phthalates using SR, quality control and assurance remains the key challenge and must always be ensured. Spatial variability in concentrations was evident and could be related to land use. Temporal variability was not significant. PMID- 28575824 TI - Factors shaping alien plant species richness spatial patterns across Natura 2000 Special Areas of Conservation of Greece. AB - This paper aims to determine the main factors that shape the spatial patterns of alien plant species occurrence across Natura 2000 Special Areas of Conservation (SACs) in Greece, and quantify their influence. A series of spatial analysis techniques for the development of a spatial database of the factors involved, followed by a boosted negative binomial Generalised Additive Model for location scale and shape, were implemented. Native plant species richness, topography and hydrography, human population density, and a spatial preference to the northern western sites are the key factors that explain the variation in the occurrence of alien plant species. Native plant species richness and human population density have a positive effect on alien plant species presence, while topography aspects, such as elevation and slope, and the distance from the hydrographical network a negative one. All factors are indirectly linked to propagule pressure emphasizing the importance of human activities for the efforts on managing protected areas. PMID- 28575825 TI - Effect of biochar on the presence of nutrients and ryegrass growth in the soil from an abandoned indigenous coking site: The potential role of biochar in the revegetation of contaminated site. AB - Little is known regarding how biochars' feedstock and pyrolysis temperature affect soil function and plant growth. To address this gap in knowledge, 12 biochars (walnut shells, corn cobs, corn straws, and rice straws were separately pyrolyzed at 250, 400, and 600 degrees C for 4h) were applied to soil from an indigenous coking site with application rate of 2.5% (w/w) in a pot experiment to determine the impact of biochar types on macro-nutrients (total and available N, P, and K) and ryegrass growth in the soil from an indigenous coking site. Generally, the total N, P, and K in the soil was not significantly different from that of the control group. However, biochars decreased the available N from 21.76mg.kg-1 for the control to 14.96mg.kg-1. Corn straw and rice straw biochars increased the available P from 2.14mg.kg-1 for the control to 28.35mg.kg-1, specifically at higher pyrolysis temperature, while walnut shell and corn cob biochars had little influence on it regardless of pyrolysis temperature. Biochars increased the available K from 173.58mg.kg-1 for the control to 355.64mg.kg-1, varying as their feedstocks of corn cob>rice straw>corn straw>walnut shell and increasing with the increase of pyrolysis temperature. Correlation analysis suggests that it is responsible for the competition of soluble cations from biochars with K for adsorption sites on the soil surface. Biochars increased the ryegrass biomass from 0.07g.pot-1 for the control to 0.16g.pot-1, with the generally most effective stimulation by biochars produced at 400 degrees C. Ryegrass biomass had obviously positive correlation with available K, indicating its essential role in the growth of ryegrass in the studied soil. PMID- 28575826 TI - Polycyclic aromatic hydrocarbons (PAHs) in the settled dust of automobile workshops, health and carcinogenic risk evaluation. AB - : There are studies available on the occurrence of PAHs in indoor settled dust from residential and different occupational settings in literature but limited data is available on their occurrence and potential health risk assessment in automobile workshops. In recent decades Saudi Arabia has experienced tremendous growth in the petroleum industry and as a result, the automobile industry is booming. People working in automobile workshops are at a greater risk of exposure to chemicals releasing from the petroleum products. The main objective of this study was to report PAHs in settled dust from different automobile workshops of Jeddah, Saudi Arabia, and evaluate health risk for workers through dust exposure. Pyrene (1585-13500ng/g), Benz[a]anthracene ((NH4)2HPO4>KH2PO4>K2SO4. When levels of K2HPO4 higher than 0.75g/L were applied, the total Cd decreased from 20 to 3.8MUg/L after 12h of flocculation, i.e., the removal efficiency reached 80%. The mechanism analysis(Zeta potential, multi-element analysis) results demonstrated that the aggregation of SS and its sedimentation by K2HPO4 were due to the combined effect of the oxidation of Fe2+ to Fe3+ and cation binding behavior towards SS, as a result of charge neutralization and electric double layer compression. This method of Cd removal from irrigation water is simple and has the potential to be applied in agricultural production. PMID- 28575829 TI - Comparative study of photocatalytic activities of Zn5(OH)8Cl2.H2O and ZnO nanostructures in ciprofloxacin degradation: Response surface methodology and kinetic studies. AB - Zinc hydroxide chloride monohydrate (Zn5(OH)8Cl2.H2O) and zinc oxide (ZnO) nanostructures were synthesized by simple precipitation and pyrolysis methods, respectively and characterized by means of various instrumental methods. Their photocatalytic efficiencies as two potential photocatalysts for photodegradation of a clinical wastewater, ciprofloxacin (CIP), were probed and compared. The results indicated that in comparison with Zn5(OH)8Cl2.H2O nanoplates, the photodegradation was 1.4 times faster when using ZnO nanoparticles as well as higher removal percentage. The optimum pH obtained was 8 that it is typically found for hospital wastewater. Analysis of variance (ANOVA) exhibited high R2 values, high F-values, very low P-values, and non-significant lack of fit values demonstrating good correlation between experimental and predicted values of the response for both catalysts. Kinetic studies identified first order model as a suitable model for description of photodegradation processes for both nanosized Zn5(OH)8Cl2.H2O and ZnO. The chemical oxygen demand (COD) removal of 43.30 and 56.30% were obtained after 24h for Zn5(OH)8Cl2.H2O nanoplates and ZnO nanoparticles, respectively. Ultra-performance liquid chromatography method coupled with tandem mass spectrometry (UPLC-MS/MS) for the determination of CIP degradation products has been used. Taken together, ZnO nanoparticles were more efficient in CIP removal due to some properties as in higher surface area and lower band gap. PMID- 28575830 TI - Spatio-temporal variations in the areas suitable for the cultivation of rice and maize in China under future climate scenarios. AB - Predictions of changes in the distribution of areas suitable for the cultivation of rice and maize in China under future climate change scenarios may provide scientific support for the optimization of crop production and measures to mitigate climate change. We conducted a spatial grid-based analysis using projections of future climate generated by the National Center for Atmospheric Research Community Climate System Model version 4 for two representative concentration pathway scenarios (RCP2.6 and RCP8.5), adopted by the fifth phase of the Coupled Model Intercomparison Project to study the areas suitable for the cultivation of rice and maize in China. We investigated the migration of the centers of gravity of the cultivation areas based on climatic and hydrological factors from 2021 to 2100. The results indicated that, under RCP2.6, the areas suitable for the cultivation of rice were located throughout China, except for on the Qinghai-Tibetan Plateau, while the areas suitable for the cultivation of maize were located in northern, southwestern, central, eastern, parts of northeastern and some northern parts of western China. The distributions of both crops under RCP2.6 showed little change over time. In contrast, the areas suitable for the cultivation of rice and maize under RCP8.5 shifted northward and expanded from northwestern to northern China, as a result of greater warming in northern China and the faster warming trend under RCP8.5. This scenario would require much stronger climate mitigation policies to maintain the stable development of agriculture and to slow down the future migration of crop cultivation areas in China. The distribution of areas suitable for the cultivation of rice and maize should be studied further to design appropriate adaptation strategies for dealing with future climate change. PMID- 28575831 TI - Assessing the magnitude of potential environmental impacts related to water and toxicity in the Peruvian hyper-arid coast: A case study for the cultivation of grapes for pisco production. AB - The environmental sustainability of the cultivation of grapes for the production of alcoholic beverages has been extensively analyzed in the literature from a Life Cycle Assessment perspective, although certain impact categories have been repeatedly neglected despite their importance, such as toxic emissions or the depletion of freshwater resources. Hence, the current study provides a detailed assessment of water footprint-related impact categories, including toxicity, for the cultivation of grapes for pisco production, an alcoholic beverage produced in coastal Peru in hyper-arid areas that suffer high levels of water scarcity. Characterization factors at a sub-watershed level were used to calculate water consumption impact assessment of grape production using the AWARE method. Site specific toxic emissions were modelled using the PestLCI model, considering primary climate and soil data. The USEtox assessment method was then used to compute freshwater eco-toxicity with these data. Results demonstrate the high water footprint of irrigating vineyards in coastal Peru, especially considering the inefficient flooding irrigation process. In terms of water consumption, despite the high variability shown between sub-watersheds, the shift to other irrigation technologies must be analyzed with care due to the high competition for water existing in the area. Eutrophication potential showed particularly high values compared to the literature, whereas freshwater eco-toxicity impacts were relatively low due to the high volatilization of pesticides to air. Nevertheless, the lack of an adequate wastewater management system implies that the estimated potential toxic and eutrophying emissions may constitute a further environmental threat to water bodies. PMID- 28575832 TI - Estimates of water and solute release from a coal waste rock dump in the Elk Valley, British Columbia, Canada. AB - Long term (1999 to 2014) flow and water quality data from a rock drain located at the base of a coal waste rock dump constructed in the Elk Valley, British Columbia was used to characterize the release of three solutes (NO3-, Cl- and SO42-) from the dump and obtain whole dump estimates of net percolation (NP). The concentrations of dump derived solutes in the rock drain water were diluted by snowmelt waters from the adjacent natural watershed during the spring freshet and reached a maximum concentration during the winter baseflow period. Historical peak baseflow concentrations of conservative ions (NO3- and Cl-) increased until 2006/07 after which they decreased. This decrease was attributed to completion of the flushing of the first pore volume of water stored within the dump. The baseflow SO42- concentrations increased proportionally with NO3- and Cl- to 2007, but then continued to slowly increase as NO3- and Cl- concentrations decreased. This was attributed to ongoing production of SO42- due to oxidation of sulfide minerals within the dump. Based on partitioning of the annual volume of water discharged from the rock drain to waste rock effluent (NP) and water entering the rock drain laterally from the natural watershed, the mean NP values were estimated to be 446+/-50mm/a (area normalized net percolation/year) for the dump and 172+/-71mm/a for the natural watershed. The difference was attributed to greater rates of recharge in the dump from summer precipitation compared to the natural watershed where rainfall interception and enhanced evapotranspiration will increase water losses. These estimates included water moving through subsurface pathways. However, given the limitations in quantifying these flows the estimated NP rates for both the natural watershed and the waste rock dump are considered to be low, and could be much higher (e.g. ~450mm/a and ~800mm/a). PMID- 28575833 TI - Source apportionment and health risk assessment among specific age groups during haze and non-haze episodes in Kuala Lumpur, Malaysia. AB - This study aims to determine PM2.5 concentrations and their composition during haze and non-haze episodes in Kuala Lumpur. In order to investigate the origin of the measured air masses, the Numerical Atmospheric-dispersion Modelling Environment (NAME) and Global Fire Assimilation System (GFAS) were applied. Source apportionment of PM2.5 was determined using Positive Matrix Factorization (PMF). The carcinogenic and non-carcinogenic health risks were estimated using the United State Environmental Protection Agency (USEPA) method. PM2.5 samples were collected from the centre of the city using a high-volume air sampler (HVS). The results showed that the mean PM2.5 concentrations collected during pre-haze, haze and post-haze periods were 24.5+/-12.0MUgm-3, 72.3+/-38.0MUgm-3 and 14.3+/ 3.58MUgm-3, respectively. The highest concentration of PM2.5 during haze episode was five times higher than World Health Organisation (WHO) guidelines. Inorganic compositions of PM2.5, including trace elements and water soluble ions were determined using inductively coupled plasma-mass spectrometry (ICP-MS) and ion chromatography (IC), respectively. The major trace elements identified were K, Al, Ca, Mg and Fe which accounted for approximately 93%, 91% and 92% of the overall metals' portions recorded during pre-haze, haze and post-haze periods, respectively. For water-soluble ions, secondary inorganic aerosols (SO42-, NO3- and NH4+) contributed around 12%, 43% and 16% of the overall PM2.5 mass during pre-haze, haze and post-haze periods, respectively. During haze periods, the predominant source identified using PMF was secondary inorganic aerosol (SIA) and biomass burning where the NAME simulations indicate the importance of fires in Sumatra, Indonesia. The main source during pre-haze and post-haze were mix SIA and road dust as well as mineral dust, respectively. The highest non-carcinogenic health risk during haze episode was estimated among the infant group (HI=1.06) while the highest carcinogenic health risk was estimated among the adult group (2.27*10-5). PMID- 28575834 TI - Measuring adaptive capacity of urban wastewater infrastructure - Change impact and change propagation. AB - The ability of urban wastewater systems to adapt and transform as a response to change is an integral part of sustainable development. This requires technology and infrastructure that can be adapted to new operational challenges. In this study the adaptive capacity of urban wastewater systems is evaluated by assessing the interdependencies between system components. In interdependent and therefore tightly coupled systems, changes to one systems component will require alteration elsewhere in the system, therefore impairing the capacity of these systems to be changed. The aim of this paper is to develop a methodology to evaluate the adaptive capacity of urban wastewater systems by assessing how change drivers and innovation affect existing wastewater technology and infrastructure. The methodology comprises 7 steps and applies a change impact table and a design structure matrix that are completed by experts during workshops. Change impact tables quantify where change drivers, such as energy neutrality and resource recovery, require innovation in a system. The design structure matrix is a tool to quantify "emerging changes" that are a result of the innovation. The method is applied for the change driver of energy neutrality and shown for two innovations: a decentralised upflow anaerobic sludge blanket reactor followed by an anammox process and a conventional activated sludge treatment with enhanced chemical precipitation and high temperature-high pressure hydrolysis. The results show that the energy neutrality of wastewater systems can be address by either innovation in the decentralised or centralised treatment. The quantification of the emerging changes for both innovations indicates that the decentralised treatment is more disruptive, or in other words, the system needs to undergo more adaptation. It is concluded that the change impact and change propagation method can be used to characterise and quantify the technological or infrastructural transformations. In addition, it provides insight into the stakeholders affected by change. PMID- 28575835 TI - A review on effectiveness of best management practices in improving hydrology and water quality: Needs and opportunities. AB - Best management practices (BMPs) have been widely used to address hydrology and water quality issues in both agricultural and urban areas. Increasing numbers of BMPs have been studied in research projects and implemented in watershed management projects, but a gap remains in quantifying their effectiveness through time. In this paper, we review the current knowledge about BMP efficiencies, which indicates that most empirical studies have focused on short-term efficiencies, while few have explored long-term efficiencies. Most simulation efforts that consider BMPs assume constant performance irrespective of ages of the practices, generally based on anticipated maintenance activities or the expected performance over the life of the BMP(s). However, efficiencies of BMPs likely change over time irrespective of maintenance due to factors such as degradation of structures and accumulation of pollutants. Generally, the impacts of BMPs implemented in water quality protection programs at watershed levels have not been as rapid or large as expected, possibly due to overly high expectations for practice long-term efficiency, with BMPs even being sources of pollutants under some conditions and during some time periods. The review of available datasets reveals that current data are limited regarding both short-term and long term BMP efficiency. Based on this review, this paper provides suggestions regarding needs and opportunities. Existing practice efficiency data need to be compiled. New data on BMP efficiencies that consider important factors, such as maintenance activities, also need to be collected. Then, the existing and new data need to be analyzed. Further research is needed to create a framework, as well as modeling approaches built on the framework, to simulate changes in BMP efficiencies with time. The research community needs to work together in addressing these needs and opportunities, which will assist decision makers in formulating better decisions regarding BMP implementation in watershed management projects. PMID- 28575836 TI - Supporting local farming communities and crop production resilience to climate change through giant reed (Arundo donax L.) cultivation: An Italian case study. AB - Bioenergy crops are well known for their ability to reduce greenhouse gas emissions and increase the soil carbon stock. Although such crops are often held to be in competition with food crops and thus raise the question of current and future food security, at the same time mitigation measures are required to tackle climate change and sustain local farming communities and crop production. However, in some cases the actions envisaged for specific pedo-climatic conditions are not always economically sustainable by farmers. In this frame, energy crops with high environmental adaptability and yields, such as giant reed (Arundo donax L.), may represent an opportunity to improve farm incomes, making marginal areas not suitable for food production once again productive. In so doing, three of the 17 Sustainable Development Goals (SDGs) of the United Nations would be met, namely SDG 2 on food security and sustainable agriculture, SDG 7 on reliable, sustainable and modern energy, and SDG 13 on action to combat climate change and its impacts. In this work, the response of giant reed in the marginal areas of an agricultural district of southern Italy (Destra Sele) and expected farm incomes under climate change (2021-2050) are evaluated. The normalized water productivity index of giant reed was determined (WP; 30.1gm-2) by means of a SWAP agro-hydrological model, calibrated and validated on two years of a long-term field experiment. The model was used to estimate giant reed response (biomass yield) in marginal areas under climate change, and economic evaluation was performed to determine expected farm incomes (woodchips and chopped forage). The results show that woodchip production represents the most profitable option for farmers, yielding a gross margin 50% lower than ordinary high-input maize cultivation across the study area. PMID- 28575837 TI - Adaptation of microbial community of the anode biofilm in microbial fuel cells to temperature. AB - Temperature as an important ecological factor affects biofilm development and microbial metabolic activity. Here, the performances and microbial communities of microbial fuel cells (MFCs) at different temperature were analyzed. As the temperature decreased, the power output of MFCs declined. A maximum power density of 894.3+/-48.6mW/m2 was obtained in MFCs operating at 30 degrees C, which was 18.5% and 64.5% higher than that in MFCs at 20 degrees C and 10 degrees C, respectively. Illumina sequencing of 16S rRNA gene amplicons showed that a distinct difference in microbial community structure of the anode biofilms occurred. This resulted in different power outputs of MFCs. Species diversity analyses indicated that species evenness of the anode biofilms shifted beyond species richness at different temperatures. The predominant populations of the anode biofilm shifted from Geobacter and Azonexus (30 degrees C) to Pelobacter (20 degrees C) or Acidovorax, Zoogloea and Simplicispira, (10 degrees C). These results indicate that temperature plays an important role in shaping microbial communities of the anode biofilms in MFCs through changes in species evenness. PMID- 28575838 TI - Biofilm promoted current generation of Pseudomonas aeruginosa microbial fuel cell via improving the interfacial redox reaction of phenazines. AB - Bacteria biofilm plays a key role in current generation of microbial fuel cells (MFCs), especially for the start-up stage. However, the detailed mechanism of the biofilm promoting the power generation is not very clear so far, especially for those exoelectrogens who rely on the self-excreted electron mediators for extracellular electron transfer. In this work, a biofilm formation inhibitor sodium houttuyfonate (SH) is used to build a "non-biofilm" anode of Pseudomonas aeruginosa (P. aeruginosa) without affecting the bacteria growth during the MFC operation. According to the comparison results of the "non-biofilm" anode and biofilm-covered anode on current generation, phenazines concentration variation and anodic electrocatalysis, the biofilm on the anode not only provides plenty of bacterial cells for catalysis but also promotes the interfacial phenazine redox reaction through accumulating the self-generated mediators on anode for fast interfacial electron transfer. This work proves that the biofilm assisted electron mediator accumulation will benefit such kind of exoelectrogens to sustain sufficient electron mediators for extracellular electron transfer. PMID- 28575839 TI - Physiological and biochemical assisted screening of wheat varieties under partial rhizosphere drying. AB - Wheat is one of the major staple food of the world, which is badly affected by water deficit stress. To fulfill the dietary needs of increasing population with depleting water resources there is need to adopt technologies which result in sufficient crop yield with less water consumption. One of them is partial root zone drying (PRD). Keeping in view these conditions, a wire house experiment was conducted at University College of Agriculture and Environmental Sciences, The Islamia University Bahawalpur during 2015, to screen out the different wheat genotypes for PRD. Five approved local wheat cultivars (V1= Galaxy-2013, V2= Punjab-2011, V3 = Faisalabad-2008, V4 = Lasani-2008 and V5 = V.8200) and two irrigation levels (I1 = control irrigation and I2 = PRD irrigation) with completely randomized design having four replications were used in the experiment. Among the varieties Galaxy-2013 performed the best and attained maximum plant height, leaf area, stomatal conductance, photosynthesis, total sugars, proline contents and antioxidant enzymes activities and minimum values of all growth and physiological parameters were recorded in variety V.8200. For irrigation levels, higher values of growth, physiological and water related parameters were recorded in control treatment (I1) except leaf water potential, osmotic potential, total sugars and proline contents. However enzymes activities were higher under PRD treatment for all varieties. It was concluded that Galaxy 2013 was the most compatible and V.8200 was the most susceptible variety under PRD condition, respectively and more quality traits and enzymatic activities were recorded under PRD condition as compared to control treatment. PMID- 28575840 TI - Typing DNA profiles from previously enhanced fingerprints using direct PCR. AB - Fingermarks are a source of human identification both through the ridge patterns and DNA profiling. Typing nuclear STR DNA markers from previously enhanced fingermarks provides an alternative method of utilising the limited fingermark deposit that can be left behind during a criminal act. Dusting with fingerprint powders is a standard method used in classical fingermark enhancement and can affect DNA data. The ability to generate informative DNA profiles from powdered fingerprints using direct PCR swabs was investigated. Direct PCR was used as the opportunity to generate usable DNA profiles after performing any of the standard DNA extraction processes is minimal. Omitting the extraction step will, for many samples, be the key to success if there is limited sample DNA. DNA profiles were generated by direct PCR from 160 fingermarks after treatment with one of the following dactyloscopic fingerprint powders: white hadonite; silver aluminium; HiFi Volcano silk black; or black magnetic fingerprint powder. This was achieved by a combination of an optimised double-swabbing technique and swab media, omission of the extraction step to minimise loss of critical low-template DNA, and additional AmpliTaq Gold(r) DNA polymerase to boost the PCR. Ninety eight out of 160 samples (61%) were considered 'up-loadable' to the Australian National Criminal Investigation DNA Database (NCIDD). The method described required a minimum of working steps, equipment and reagents, and was completed within 4h. Direct PCR allows the generation of DNA profiles from enhanced prints without the need to increase PCR cycle numbers beyond manufacturer's recommendations. Particular emphasis was placed on preventing contamination by applying strict protocols and avoiding the use of previously used fingerprint brushes. Based on this extensive survey, the data provided indicate minimal effects of any of these four powders on the chance of obtaining DNA profiles from enhanced fingermarks. PMID- 28575842 TI - Correction for Barka et al., Taxonomy, Physiology, and Natural Products of Actinobacteria. PMID- 28575869 TI - The relationship between tumor markers and pulmonary embolism in lung cancer. AB - BACKGROUND: Tumor markers (TMs) and D-Dimer are both hallmarks of severity and prognosis of lung cancer. Tumor markers could be related to pulmonary embolism (PE) in lung cancer. RESULTS: The number of abnormal tumor markers of lung cancer patients with pulmonary embolism (3.9 +/- 1.1vs1.6 +/- 0.6,P 0.005) was more than that in patients without pulmonary embolism. TMs panel (P trend < 0.001), CEA (R2 0.735, P0.003) and CYFRA21-1 (R2 0.718, P0.005) were positively correlated with D Dimer in patients with pulmonary embolism. The multivariate logistic regression analysis showed that, for tumor markers, TMs panel (OR5.98, P < 0.001) had the strongest correlation with pulmonary embolism. The AUC (area under curve) of TMs panel and CEA were 0.82 [95%CI (0.71-0.95), P < 0.001] and 0.71 [95%CI (0.62 0.84), P 0.002] by ROC (receiver operating characteristic) curve analysis, respectively. MATERIALS AND METHODS: Tumor markers were compared between lung cancer patients complicated with pulmonary embolism and those without pulmonary embolism Then the correlation between each tumor marker as well as panel of combined TMs and D-Dimer as well as pulmonary embolism were analyzed for patients with pulmonary embolism. CONCLUSIONS: There is a relationship between tumor markers and pulmonary embolism in patients with lung cancer. The panel of combined tumor markers is a valuable diagnostic marker for pulmonary embolism in lung cancer. PMID- 28575877 TI - Drug-induced Nephrotoxicity and Medicinal Plants. AB - Drug-induced nephrotoxicity is one of the most common causes of acute kidney injury. There are various agents that exert nephrotoxic effects through different pathogenic mechanisms. Aminoglycoside antibiotics, chemotherapeutic agents, radiocontrast media, and nonsteroidal anti-inflammatory drugs are among common nephrotoxic agents. In recent years, natural compounds are being increasingly used in the treatment of kidney diseases. Given many reports available on the curative effects of a variety of medicinal plants against drug-associated nephrotoxicity, we aimed to review the protective effects of medicinal plants on certain nephrotoxic drugs. PMID- 28575878 TI - Kidney Calculi: Pathophysiology and as a Systemic Disorder. AB - The pathophysiology of urinary stone formation is complex, involving a combination of metabolic, genetic, and environmental factors. Over the past decades, remarkable advances have been emerged in the understanding of the pathogenesis, diagnosis, and treatment of calcium kidney calculi. For this review, both original and review articles were found via PubMed search on pathophysiology, diagnosis, and management of urinary calculi. These resources were integrated with the authors' knowledge of the field. Nephrolithiasis is suggested to be associated with systemic disorders, including chronic kidney insufficiency, hematologic malignancies, endocrine disorders, autoimmune diseases, inflammatory bowel diseases, bone loss and fractures, hypertension, type 2 diabetes mellitus, metabolic syndrome, and vascular diseases like coronary heart diseases and most recently ischemic strokes. This is changing the perspective of nephrolithiasis from an isolated disorder to a systemic disease that justifies further research in understanding the underlying mechanisms and elaborating diagnostic-therapeutic options. PMID- 28575879 TI - Changes in Kidney Function in a Population With Essential Hypertension in Real Life Settings. AB - INTRODUCTION: Hypertension has been identified as one of the commonest modifiable determinants for chronic kidney disease progression. A variety of antihypertensive drugs are available and their effect on kidney function has been investigated by a large number of randomized controlled trials. Observational studies, although scarcely been used, outpatient can reflect everyday practice, where drug exposures vary over time, and may provide an alternative for detecting longitudinal changes in kidney function. MATERIALS AND METHODS: We applied mixed model repeated measures analysis to investigate the effect of antihypertensive drug categories and their combinations on kidney function change over time in a cohort of 779 patients with essential hypertension, using the data from a Greek hypertension outpatient clinic. Antihypertensive drugs were grouped in 5 categories. Their effect was evaluated and their combinations with and without renin-angiotensin-system inhibitors (RASI) to each other. In addition, the combination of RASI with calcium channel blockers (CCBs) was studied. RESULTS: Diuretics, RASI, CCBs, and beta-blockers had a significant renoprotective and blood pressure lowering effect. Combinations with RASI had a smaller beneficial effect on kidney function compared to CCBs (0.75 mL/min/1.73 m2 per year of drug use versus 0.97 mL/min/1.73 m2). There was no additional effect when combining RASI with CCBs. However, the lowering effect on systolic blood pressure was greater (-0.83 mm Hg per year of drug use, P < .001). CONCLUSIONS: RASI were found to have a smaller, although significant, renoprotective effect. There was no additional effect on kidney function when combining RASI with CCBs. PMID- 28575880 TI - Urinary Neutrophil Gelatinase-associated Lipocalin as a Biomarker of Kidney Injury in Hematologic-Oncologic Patients Receiving Amphotericin B. AB - INTRODUCTION: The aim of the present study was to compare the changing pattern of urine neutrophil gelatinase-associated lipocalin (NGAL) with serum as well as urine creatinine during amphotericin B treatment and determine its accuracy in the early detection of amphotericin B nephrotoxicity. MATERIALS AND METHODS: A cohort study was performed during 9 months at 3 hematology-oncology services. Patients aged 15 years and greater with no documented history of acute kidney injury or chronic kidney disease, planned to receive any formulation of amphotericin B for at least 1 week, were included. Serum as well as urine creatinine and urine NGAL were determined on days zero, 3, 5, 7, 10, and 14 of amphotericin B treatment. RESULTS: Forty patients with the mean age of 38.0 +/- 14.1 years were recruited. Eleven of 40 patients (27.5%) developed amphotericin B nephrotoxicity. The overall changes in the mean values of urine NGAL were not significant during amphotericin B treatment, neither within nor between the two groups. The area under the curve of urine NGAL (0.765; 95% confidence interval, 0.588 to 0.962) on day zero was significantly higher than that of serum creatinine (0.464; 95% confidence interval, 0.268 to 0.660; P = .01) for predicting amphotericin nephrotoxicity. CONCLUSIONS: The incremental pattern of urine NGAL during amphotericin B treatment was not significant compared to baseline values. The urine level of NGAL on the first day of amphotericin B administration was more accurate than serum creatinine in predicting acute kidney injury caused by this agent. PMID- 28575881 TI - Fourier Transform Infrared Analysis of Urinary Calculi and Metabolic Studies in a Group of Sicilian Children. AB - INTRODUCTION: Prevalence of urinary calculi in children has been increasing in the past years. We performed an analysis of the chemical composition of stones formers of the pediatric population in our geographical area over the years 2005 to 2013. MATERIALS AND METHODS: Fourier transform infrared spectroscopy was employed for the determination of the calculus composition of a group of Sicilian children, and metabolic studies were performed to formulate the correct diagnosis and establish therapy. RESULTS: The prevalence of stone formation was much higher for boys than for girls, with a sex ratio of 1.9:1. The single most frequent component was found to be calcium oxalate monohydrate, and calcium oxalates (pure or mixed calculi) were the overall most frequent components. Calcium phosphates ranked 2nd for frequency, most often in mixed calculi, while urates ranked 3rd. The metabolic disorder most often associated with pure calcium oxalate monohydrate calculi was hypocitraturia, while hyperoxaluria was predominantly associated with calcium oxalate dihydrate calculi. CONCLUSIONS: Mixed calculi had the highest prevalence in our pediatric population. Our data showed that Fourier transform infrared spectroscopy was a useful tool for the determination of the calculi composition. PMID- 28575882 TI - Relationship Between Angiotensin-converting Enzyme Gene Polymorphism and QT Dispersion in Hemodialysis Patients. AB - INTRODUCTION: The angiotensin-converting enzyme (ACE) gene insertion or deletion in long-term hemodialysis patients may be associated with corrected QT interval prolongation, leading to fatal arrhythmias. The ACE D allele is known to increase the risk of malignant ventricular arrhythmias and is also associated with increased QT dispersion after myocardial infarction and hypertension. This study aimed to evaluate the relationship between ACE gene polymorphism and QT dispersion in hemodialysis patients. MATERIALS AND METHODS: In 70 hemodialysis patients, electrocardiography was performed and QT dispersion was calculated. Corrected QT interval was calculated using Bazett Formula. The ACE gene polymorphism was determined by polymerase chain reaction. RESULTS: The mean age of the patients was 60 +/- 12 years. The mean QT dispersion and corrected QT dispersion were 61.71 +/- 21.99 and 73.18 +/- 25.51, respectively. QT dispersion inversely correlated with serum calcium and potassium levels and positively correlated with ACE gene polymorphism and residual urine. Calcium level was the predictor factor for QT dispersion. The ACE genotype correlated with QT dispersion, corrected QT dispersion, hemoglobin, and residual urine, and inversely correlated with serum potassium. Corrected QT dispersion correlated with ACE gene polymorphism and residual urine. The DD genotype of ACE had significally greater QT dispersion and corrected QT dispersion than the II and ID genotypes. CONCLUSIONS: Our study showed that the most important parameter affecting corrected QT dispersion was ACE gene polymorphism on the background of D allelle. Patients carrying this allelle need special attention regarding optimal suppression of renin-angiotensin-aldosteron system activity. PMID- 28575883 TI - Effects of Erythropoiesis-stimulating Agents on Intestinal Flora in Peritoneal Fibrosis. AB - INTRODUCTION: This study aimed to investigate the effects of erythropoiesis stimulating agents (ESAs) on intestinal flora in peritoneal fibrosis. METHODS AND METHODS: Twenty-four Wistar albino rats were divided into 3 groups as the control group, which received 0.9% saline (3 mL/d) intraperitoneally; the chlorhexidine gluconate (CH) group, which received 3 mL/d injections of 0.1% CH intraperitoneally, and the ESA group, which received 3 mL/d injections of 0.1% CH intraperitoneally and epoetin beta (3 doses of 20 IU/kg/wk) subcutaneously. On the 21st day, the rats were sacrificed and the visceral peritoneum samples were obtained from left liver bowel. Blood samples were obtained from abdominal aorta and intestinal flora samples were obtained from transverse colon. RESULTS: Histopathologically, the CH, ESA, and control groups had peritoneal thickness of 135.4 +/- 22.2 um, 48.6 +/- 12.8 um, and 6.0 +/- 2.3 um, respectively. Escherichia coli was the predominant bacterium in the intestinal flora in the control group. Significant changes in microbial composition of intestinal flora towards Proteus species and Enterobacter species was seen among the groups (P < .001). There was no significant difference between the ESA and CH groups regarding the isolates from blood cultures. However, the bacterial isolates from cultures of intestinal flora among these groups were significantly different (P < .05). CONCLUSIONS: Erythropoiesis-stimulating agents change intestinal flora by a clinically significant amount in experimental peritoneal fibrosis. We consider that ESAs achieve this via regulating intestinal peristaltism. PMID- 28575884 TI - Predictors of Clinical Outcomes in Hemodialysis Patients: a Multicenter Observational Study. AB - INTRODUCTION: Cardiovascular and noncardiovascular mortality and morbidity rates of hemodialysis patients are high despite improvement in dialysis delivery. MATERIALS AND METHODS: Hemodialysis patients (n = 532) from 9 hemodialysis facilities were enrolled in this cohort study in September 2012. Causes of death, hospitalization, and hemodialysis exit were recorded during a 28-month follow-up period. A Cox proportional hazard model was used to predict death adjusting for case-mix variables, nutrition variables, bone mineral variables, Kt/V, vascular access, and Charlson comorbidities index. RESULTS: Patients were 56.0 +/- 15.4 years old (57% men). A total of 161 patients (30%) died (17 per 100 patient years), and the most common causes of death were cardiovascular diseases (42%) and infections (25%). Transplantation rate was 7 per 100 patient years and hospitalization frequency was 0.76 per patient year. Based on the multivariable Cox proportional hazard model, the mortality hazard ratio was 1.03 (95% confidence interval [CI], 1.01 to 1.05; P = .007) for age (years), 0.21 (95% CI, 0.11 to 0.40; P < .001) for serum albumin (g/dL), 1.21 (95% CI, 1.03 to 1.42; P = .02) for serum phosphorus (mg/dL), 1.001 (95% CI, 1.0005 to 1.002; P = .001) for serum intact parathyroid hormone (pg/mL), 1.58 (95% CI, 1.01 to 2.51; P = .047) for hemodialysis catheter (compared to arteriovenous fistula), and 1.75 (95% CI, 1.59 to 1.94; P < .001) for the Charlson score. CONCLUSIONS: Nutritional factors, comorbidities, vascular access, and abnormal mineral metabolism are the main determinants of mortality and morbidity in hemodialysis patients. PMID- 28575885 TI - Helicobacter pylori Eradication With Levofloxacin or Clarithromycin in Dialysis Versus Nonuremic Patients. AB - INTRODUCTION: Various medication regimens have been used to eradicate Helicobacter pylori in dialysis patients; however, optimal response to treatment is still a challenge. This study aimed to compare response to H pylori eradication in dialysis and nonuremic patients. MATERIALS AND METHODS: In a randomized controlled trial, dialysis patients with dyspepsia and confirmed positive endoscopic biopsy for H pylori were compared to nonuremic patients. Participants were randomly assigned to receive clarithromycin or levofloxacin. H pylori eradication was assessed using stool antigen test 4 weeks later. RESULTS: Forty-four dialysis and 44 nonuremic patients participated in the study. Four dialysis patients and 2 nonuremic patients did not respond to levofloxacin (P = .35). Six dialysis patients and 4 nonuremic patients did not respond to clarithromycin (P = .47). CONCLUSIONS: Response rate to H pylori eradication by clarithromycin and levofloxacin was slightly lower in dialysis patients compare to nonuremic patients. In dialysis patients, response rate to levofloxacin was slightly higher than clarithromycin, but the results were not significantly different. PMID- 28575886 TI - Role of Donors and Recipients' Glutathione S-Transferase Gene Polymorphisms in Association of Oxidative Stress With Delayed Graft Function in Kidney Allograft Recipients. AB - INTRODUCTION: Oxidative stress contributes to delayed graft function (DGF). Glutathione S-transferases (GSTs) are polymorphic genes which produce enzymes with protective effect against oxidative stress. This study aimed to investigate the association between donors' and recipients' GSTM1 and GSTT1 polymorphisms and DGF, creatinine clearance, and oxidative stress parameters in kidney allograft recipients. MATERIALS AND METHODS: One hundred and eighty-two donor-recipient pairs were studied. Lipid peroxidation and total antioxidant capacity were measured in the recipients' plasma as the parameters of oxidative stress. Delayed graft function was determined based on at least 10% increase, no change, or less than 10% decrease in the serum creatinine level in 3 consecutive days during the 1st week after transplantation. RESULTS: Lipid peroxidation was significantly greater in the recipients with DGF (P < .001). The frequency of GSTM1 null was significantly higher in the patients with DGF (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.17 to 0.86; P = .02). There was also a significant association between the donors' GSTM1 polymorphism and DGF (OR, 0.31; 95% CI, 0.14 to 0.68; P = .003). A significant association was detected between combination of recipients and donors' GSTM1 polymorphism and DGF (OR, 0.20; 95% CI, 0.07 to 0.64, P = .006). The recipients' GSTM1 polymorphism, alone and in combination with donors' GSTM1 and GSTT1, significantly affected the creatinine clearance on discharge day. CONCLUSIONS: These results suggest that the donors and recipients' GSTM1 polymorphism may be a major risk factor for oxidative stress and poor kidney allograft transplantation outcomes. PMID- 28575887 TI - Glomerulonephritis as a Type of Kidney Injury in Multiple Myeloma: a Report of 2 Cases. AB - Renal involvement in multiple myeloma has multiple etiologies. Glomerulonephritis rarely occurs in multiple myeloma and numerous case reports in the literature explain their correlation. We report 2 cases of glomerulonephritis, one membranous glomerulonephritis and the other focal segmental glomerulosclerosis, in which multiple myeloma was confirmed after several months in the first case and synchronous with the second. Glomerulonephritis can be an uncommon, but not rare, cause of proteinuria in multiple myeloma. PMID- 28575888 TI - Renal Involvement in 2 Siblings With Cockayne Syndrome. AB - Renal involvement in Cockayne syndrome is rare and its pathogenesis is yet unknown. We report herein 2 cases (siblings) with Cockayne syndrome type A confirmed by biochemical and molecular assays. The first case was a 13-year-old girl who presented with nephritic syndrome and a rapidly progressive kidney failure. Her younger sister, 7 years old, exhibited hypertension, hyperfiltration, and microalbuminuria. She had hyperreninemia and hyperaldosteronemia without kidney failure or renal arterial stenosis. Renal biopsy, performed the older sister, revealed cystic focal segmental glomerulosclerosis, arteriosclerosis, tubulointerstitial fibrosis, and tubular atrophy. The different clinical phenotypes in the two siblings support the absence of an obvious genotype-phenotype correlation in Cockayne syndrome type A patients. In the older sister, the particular focal glomerular sclerosis and senile lesions assume that kidney disease in Cockayne syndrome may be related to prematurely aging secondary to a defective nucleotide repair. PMID- 28575889 TI - A Very Unique Case of Boric Acid Intoxication With Very High-magnitude Rhabdomyolysis. PMID- 28575890 TI - Familial unilateral carpal bone dysplasia in mother and daughter. PMID- 28575891 TI - Using Simulation as an Investigational Methodology to Explore the Impact of Technology on Team Communication and Patient Management: A Pilot Evaluation of the Effect of an Automated Compression Device. AB - INTRODUCTION: This pilot study used a simulation-based platform to evaluate the effect of an automated mechanical chest compression device on team communication and patient management. METHODS: Four-member emergency department interprofessional teams were randomly assigned to perform manual chest compressions (control, n = 6) or automated chest compressions (intervention, n = 6) during a simulated cardiac arrest with 2 phases: phase 1 baseline (ventricular tachycardia), followed by phase 2 (ventricular fibrillation). Patient management was coded using an Advanced Cardiovascular Life Support-based checklist. Team communication was categorized in the following 4 areas: (1) teamwork focus; (2) huddle events, defined as statements focused on re-establishing situation awareness, reinforcing existing plans, and assessing the need to adjust the plan; (3) clinical focus; and (4) profession of team member. Statements were aggregated for each team. RESULTS: At baseline, groups were similar with respect to total communication statements and patient management. During cardiac arrest, the total number of communication statements was greater in teams performing manual compressions (median, 152.3; interquartile range [IQR], 127.6-181.0) as compared with teams using an automated compression device (median, 105; IQR, 99.5-123.9). Huddle events were more frequent in teams performing automated chest compressions (median, 4.0; IQR, 3.1-4.3 vs. 2.0; IQR, 1.4-2.6). Teams randomized to the automated compression intervention had a delay to initial defibrillation (median, 208.3 seconds; IQR, 153.3-222.1 seconds) as compared with control teams (median, 63.2 seconds; IQR, 30.1-397.2 seconds). CONCLUSIONS: Use of an automated compression device may impact both team communication and patient management. Simulation-based assessments offer important insights into the effect of technology on healthcare teams. PMID- 28575893 TI - Abstracts to be Presented at the 17th Annual International Meeting on Simulation in Healthcare: January 28th - February 1st, 2017 Orlando, FL: Erratum. PMID- 28575892 TI - Evaluation of a Vibrotactile Simulator for Dental Caries Detection. AB - INTRODUCTION: Developed to educate dental students in caries detection, the VerroTeach simulator allows dental faculty to share, record, and replay the tactile vibrations felt through a dental hand instrument. We assessed this simulation approach by asking experienced dental educators to evaluate the system's real-time and video playback modes. METHODS: VerroTeach uses an accelerometer to sense instrument vibrations and a voice coil actuator to reproduce these vibrations on another tool. Seventeen dental faculty participated in the study, first experiencing real-time mode by feeling vibrations while the experimenter touched extracted teeth. The subject then experienced vibrotactile playback of 5 prerecorded caries detection tasks and 1 prerecorded caries extraction procedure, making 10 total caries judgments and repeatedly rating the system's perceptual accuracy. RESULTS: Dental educators rated caries detection as significantly more difficult for students than experienced dentists (P < 0.0001), and they rated tactile feedback as a highly important source of information for this judgment. Subjects highly rated the realism of both real-time mode and playback mode. Experienced dentists performed well on the simulator, answering most questions correctly. Interestingly, nonpracticing dentists performed significantly worse than practicing dentists on the caries judgment questions (P = 0.003). Finally, subjects strongly recommended the system for training dental students. CONCLUSIONS: These positive results indicate that sharing, recording, and replaying instrument vibrations may be beneficial for teaching caries detection to dental students. Further research is planned to improve tactile feedback quality, integrate VerroTeach into the preclinical curriculum, and explore other possible applications for this approach to clinical simulation. PMID- 28575894 TI - Confounders, Mediators, or Colliders: What Types of Shared Covariates Does a Sibling Comparison Design Control For? AB - The sibling comparison design is an important epidemiologic tool to control for unmeasured confounding, in studies of the causal effect of an exposure on an outcome. It is routinely argued that within-family associations are automatically controlled for all measured and unmeasured covariates that are shared (constant) within sets of siblings, such as early childhood environment and parental genetic makeup. However, an important lesson from modern causal inference theory is that not all types of covariate control are desirable. In particular, it has been argued that collider control always leads to bias, and that mediator control may or may not lead to bias, depending on the research question. In this article, we use directed acyclic graphs (DAGs) to distinguish between shared confounders, shared mediators and shared colliders, and we examine which of these shared covariates the sibling comparison design really controls for. PMID- 28575895 TI - Can Collider Bias Explain Paradoxical Associations? PMID- 28575896 TI - Pirfenidone and Nintedanib for Treatment of Idiopathic Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis is one of the most common entities of the family of disorders known as the interstitial lung diseases. It is a chronic, progressive, and often-fatal disease with a median survival time of 3 to 5 years. In 2014 the US Food and Drug Administration approved pirfenidone and nintedanib, two antifibrotic agents for the treatment of idiopathic pulmonary fibrosis. Because these are the only drugs approved that can alter the course of this rare but fatal disease, this article reviews the major studies that led to the approval of these drugs and examines the indications for treatment and the expected outcomes of therapy. PMID- 28575897 TI - Effect of Diet Liberalization on Bowel Preparation. AB - OBJECTIVES: Precolonoscopy dietary regimens often are restricted to clear liquids; however, the superiority of a clear liquid diet (CLD) for bowel preparation quality is ambiguous. We performed a meta-analysis of randomized trials comparing bowel preparation outcomes between a low-residue diet (LRD) or regular diet (RD) compared with a CLD. METHODS: MEDLINE, clinicaltrials.gov, Cochrane Central Register, Scopus, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Web of Science databases were used to conduct a search for randomized controlled trials from 1976 to March 2015. Of 122 relevant references, 12 studies met our inclusion criteria, 7 studies of which were classified as being of high quality. Pooled estimates of bowel preparation quality were defined as adequate versus inadequate. Secondary outcomes included tolerability, willingness to repeat bowel preparation, adverse events, and adenoma detection rate. Pooled estimates of relative risk (RR) were used for dichotomous variables and standardized mean difference for continuous variables. RESULTS: In the high-quality studies, there were no differences in bowel preparation quality among the LRD/RD and CLD groups (RR 0.98; 95% confidence interval [CI] 0.93-1.04). Analysis of secondary outcomes included all of the studies. Tolerability (RR 1.04, 95% CI 1.01-1.08) and willingness to repeat favored the liberalized diet arm (RR 1.08, 95% CI 1.01-1.16). There was no significant difference in the adenoma detection rate, whereas hunger was more common in the CLD group. CONCLUSIONS: An LRD/RD provided no difference in bowel preparation quality as compared with a CLD. As such, it may be reasonable for patients without risk factors for poor preparation to undergo an LRD until lunch the day before their colonoscopy given that bowel preparation tolerability and willingness to repeat were greater among groups with a liberalized diet. PMID- 28575898 TI - Colon Cancer Screening in Concierge Practice. AB - OBJECTIVES: This study evaluated the effectiveness of the Center for Executive Medicine (CEM) concierge primary care practice on preventive colorectal cancer (CRC) screening rates relative to local and national comparator data. METHODS: We performed an electronic medical record search encompassing our entire patient population who are between the ages of 50 and 75 years to determine the rate of CRC screening. We compared this rate with the average rate of Medicare Advantage plans reported by our Independent Physician Association (IPA) in 2015 and national health plans reported by the National Committee for Quality Assurance in 2014. RESULTS: The CEM had a CRC screening rate of 90.2%, which was significantly higher than local IPA Medicare Advantage plans (63.3%) and National Committee for Quality Assurance national plans (57.7%-66.5%). CEM members were significantly more likely than were IPA members to undergo screening (odds ratio 1.425, 95% confidence interval 1.348-1.507, P < 0.0001). CONCLUSIONS: These results suggest that the CEM practice strategy and processes increase CRC screening rates. PMID- 28575899 TI - Effects of a 12-Month Educational Intervention on Clinicians' Attitudes/Practices Regarding the Screening Spiritual History. AB - OBJECTIVES: Patients' spiritual values, beliefs, and preferences are identified in outpatient medical settings by the taking of a screening spiritual history (SSH). We report the impact of an educational/training program on the attitudes/practices of physicians (MDs) and midlevel practitioners (MLPs). METHODS: A convenience sample of 1082 MDs or MLPs in outpatient practices was approached to participate in a 12-month educational/training program in this single-group experimental study. Of the 1082 professionals, 48% (427 physicians, 93 MLPs) agreed to complete a questionnaire assessing demographics, practice characteristics, religiosity, and attitudes/practices regarding the SSH. Changes in attitudes/practices over time were examined and baseline predictors identified using mixed-effects regression. RESULTS: Of the 520 participants completing questionnaires at baseline, 436 were assessed at 1 month (83.8%) and 432 were assessed at 12 months (83.1%). The belief that MDs should take a SSH did not significantly change over time (B = -0.022, standard error [SE] 0.028, P = 0.426). However, those who took an SSH often/always increased from 16.7% at baseline to 34.8% at 12-month follow-up (B = 0.328, SE 0.030, P < 0.0001), and perceived patient acceptance/appreciation increased from 72.1% to 80.5% (B = 0.074, SE 0.023, P = 0.001). Predictors of increased SSH taking across time among MDs were older age, female sex, family medicine specialty, prior training, and importance of religion; older age was the only predictor in MLPs. CONCLUSIONS: Although attitudes toward taking an SSH were not affected, taking an SSH increased initially and was sustained over time, as did the sense that patients accepted/appreciated this practice. Educational programs of this type may be used to increase SSH taking by outpatient MDs and MLPs. PMID- 28575900 TI - Commentary on "Effects of a 12-Month Educational Intervention on Clinicians' Attitudes/Practices Regarding the Screening Spiritual History". PMID- 28575901 TI - Dissemination Approaches to Participating Primary Care Providers in a Quality Improvement Program Addressing Opioid Use in Central Appalachia. AB - OBJECTIVES: Practice-based research networks (PBRNs) have been described as new clinical laboratories for primary care research and dissemination. PBRNs, however, have struggled to disseminate research results in a meaningful way to participating providers and clinics. METHODS: The Central Appalachia Inter Professional Pain Education Collaborative was developed to work with PBRN clinics using quality improvement methods, deliver statewide continuing education activities to address the issue of opioid use in patients with chronic pain, and develop a multimodal mechanism to disseminate project results to clinics and participating providers. RESULTS: Successful change in the delivery of chronic pain care was dependent on the clinic's commitment to a team-based, patient centered approach. Statistically significant improvements were shown in 10 of 16 process measures, and 80% of the participants agreed that the quality improvement process activity increased their knowledge and would improve their performance in managing patients with chronic pain, as well as patient outcomes in their practice. CONCLUSIONS: The Central Appalachia Inter-Professional Pain Education Collaborative project used an extensive and innovative dissemination plan under the rubric of "continual dissemination." Unlike traditional dissemination efforts that focus on summary presentations, this initiative used a continual dissemination approach that updated participants quarterly through multiple means throughout the project, which improved engagement in the project. PMID- 28575902 TI - Can Computers Be Made to Respect the Art of Medicine? PMID- 28575903 TI - Do Mixed-Flora Preoperative Urine Cultures Matter? AB - OBJECTIVES: To determine whether mixed-flora preoperative urine cultures, as compared with no-growth preoperative urine cultures, are associated with a higher prevalence of postoperative urinary tract infections (UTIs). METHODS: This was a retrospective cohort study. Women who underwent urogynecologic surgery were included if their preoperative clean-catch urine culture result was mixed flora or no growth. Women were excluded if they received postoperative antibiotics for reasons other than treatment of a UTI. Women were divided into two cohorts based on preoperative urine culture results-mixed flora or no growth; the prevalence of postoperative UTI was compared between cohorts. Baseline characteristics were compared using chi2 or Student t tests. A logistic regression analysis then was performed. RESULTS: We included 282 women who were predominantly postmenopausal, white, and overweight. There were many concomitant procedures; 46% underwent a midurethral sling procedure and 68% underwent pelvic organ prolapse surgery. Preoperative urine cultures resulted as mixed flora in 192 (68%) and no growth in 90 (32%) patients. Overall, 14% were treated for a UTI postoperatively. There was no difference in the proportion of patients treated for a postoperative UTI between the two cohorts (25 mixed flora vs 13 no growth, P = 0.77). These results remained when controlling for potentially confounding variables in a logistic regression model (adjusted odds ratio 0.92, 95% confidence interval 0.43-1.96). CONCLUSIONS: In women with mixed-flora compared with no-growth preoperative urine cultures, there were no differences in the prevalence of postoperative UTI. The clinical practice of interpreting mixed-flora cultures as negative is appropriate. PMID- 28575904 TI - Commentary on "Do Mixed-Flora Preoperative Urine Cultures Matter?" PMID- 28575905 TI - Association of White Matter Lesions, Cerebral Atrophy, Intracranial Extravascular Calcifications, and Ventricular-Communicating Hydrocephalus with Delirium Among Veterans. AB - OBJECTIVES: The literature regarding the underlying neuropathogenesis of delirium on head computed tomography (CT) is limited. The aim of this research was to investigate, using case-control retrospective chart review, the association of white matter lesions (WML), cerebral atrophy, intracranial extravascular calcifications, and ventricular-communicating hydrocephalus in older adult military veterans with and without delirium hospitalized in a Veterans Affairs Medical Center. METHODS: Head CT scans were examined for WML, atrophy, and intracranial extravascular calcifications globally in the cortex, subcortex (frontal, temporal, parietal, occipital lobes), basal ganglia (globus pallidus, caudate, putamen), and internal capsule, in addition to the presence of ventricular-communicating hydrocephalus. WML were graded as not present, <1 cm, 1 to 2 cm, or >2 cm. Atrophy, cerebral atrophy, intracranial extravascular calcifications, and ventricular-communicating hydrocephalus were graded as present or not present. RESULTS: There was a significant association of WML in the temporal lobe periventricular cortical and subcortical brain and a significant association of atrophy in the parietal lobes and the cerebellum in hospitalized older adult military veterans with delirium compared with hospitalized older adult military veterans without delirium. There were no differences between the delirium and nondelirium groups for intracranial extravascular calcifications and ventricular-communicating hydrocephalus. CONCLUSIONS: The results suggest that atrophy in the parietal lobes and the cerebellum of hospitalized older adult military veterans may be associated with an elevated risk of delirium when compared with age, race, and sex-matched control veterans. Continuing efforts are needed to clarify the role of atrophy during delirium in the veteran and nonveteran older adult population to reduce progressive frailty and decreased quality of life secondary to hospital and posthospital-discharge delirium. PMID- 28575906 TI - [Preoperative Evaluation of Adult Patients Before Elective, Non-Cardiothoracic Surgery]. AB - Evaluation of the patient's medical history and a physical examination are the cornerstones of risk assessment prior to elective surgery and may help to optimize the patient's preoperative medical condition and to guide perioperative management. Whether the performance of additional technical tests (e.g. blood chemistry, ECG, spirometry, chest x-ray) can contribute to a reduction of perioperative risk is often not very well known or controversial. Similarly, there is considerable uncertainty among anaesthesiologists, internists and surgeons with respect to the perioperative management of the patient's long-term medication. Therefore, the German Scientific Societies of Anaesthesiology and Intensive Care Medicine (DGAI), Internal Medicine (DGIM) and Surgery (DGCH) have joined to elaborate recommendations on the preoperative evaluation of adult patients prior to elective, non-cardio-thoracic surgery, which have been initially published in 2010. These recommendations have now been updated based on the current literature and existing international guidelines. In the first part the general principles of preoperative evaluation are described (part A). The current concepts for extended evaluation of patients with known or suspected major cardiovascular disease are presented in part B. Finally, the perioperative management of patients' long-term medication is discussed (part C). The concepts proposed in these interdisciplinary recommendations endorsed by the DGAI, DGIM and DGCH provide a common basis for a structured preoperative risk assessment and management. These recommendations aim to ensure that surgical patients undergo a rational preoperative assessment and at the same time to avoid unnecessary, costly and potentially dangerous testing. The joint recommendations reflect the current state-of-the-art knowledge as well as expert opinions because scientific based evidence is not always available. These recommendations will be subject to regular re-evaluation and updating when new validated evidence becomes available. PMID- 28575907 TI - Correction of Tibial Valgus Deformity. PMID- 28575908 TI - Necrotizing Enterocolitis Incidence, Characteristics, and Outcomes in Neonatal Down Syndrome Patients. PMID- 28575909 TI - Trisomy 18 Pregnancies: Is there an Increased Maternal Risk? PMID- 28575910 TI - Oropharyngeal Administration of Colostrum Increases Salivary Secretory IgA Levels in Very Low-Birth-Weight Infants. PMID- 28575912 TI - [Growth Factor Concentration in Keratocyte Supernatant after Incubation with Human Serum In Vitro]. AB - PURPOSE: Application of serum eye drops is an alternative treatment option for therapy-resistant corneal epithelial defects. In case of persisting epithelial defects, cytokines, which are secreted from stromal keratocytes, may play a role in epithelial wound healing. Our aim was to analyze fibroblast growth factor basic (FGFb), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF) and transforming growth factor beta1 (TGF-beta1) concentration in the supernatant of keratocytes, after incubation with human serum (HS). MATERIALS AND METHODS: Serum eye drops of 10 patients were prepared using the standards of the LIONS Eye Bank Saar-Lor-Lux, Trier/Westpfalz, and were stored at - 80 degrees C. Primary human keratocytes were isolated from human corneoscleral rings using collagenase A (1 mg/ml) (n = 1) and were cultured in DMEM/Ham's culture medium with 10% fetal bovine serum (FBS). Thereafter, keratocyte cultures were incubated in 15 or 30% HS (in DMEM/F14 without FBS) and FGFb, HGF, KGF and TGF-beta1 concentration was determined with an enzyme-linked immunoabsorbent assay (ELISA) from the supernatant of the culture after 24 hours. We used 15 or 30% HS without keratocytes (under the same storage conditions) as controls. RESULTS: HGF concentration was, for both HS concentrations, significantly higher in the supernatant of keratocytes, than in HS controls (without keratocytes) following 24 hours (p < 0.01). FGFb concentration was significantly increased in 30% HS with keratocytes compared to 30% HS without keratocytes after 24 hours (p < 0.01). TGF-beta1 and KGF concentrations remained unchanged through keratocytes. CONCLUSION: HGF and FGFb concentrations increase in the supernatant of keratocytes, 24 hours after incubation with human serum. These concentration changes may play a role in wound healing of epithelial defects. PMID- 28575911 TI - Rapid Transient Production of a Monoclonal Antibody Neutralizing the Porcine Epidemic Diarrhea Virus (PEDV) in Nicotiana benthamiana and Lactuca sativa. AB - Porcine epidemic diarrhea virus (PEDV) causes acute diarrhea, vomiting, dehydration, weight loss, and high mortality rate in neonatal piglets. Porcine epidemic diarrhea (PED) has been reported in Europe, America, and Asia including Thailand. The disease causes substantial losses to the swine industry in many countries. Presently, there is no effective PEDV vaccine available. In this study, we developed a plant-produced monoclonal antibody (mAb) 2C10 as a prophylactic candidate to prevent the PEDV infection. Recently, plant expression systems have gained interest as an alternative for the production of antibodies because of many advantages, such as low production cost, lack of human and animal pathogen, large scalability, etc. The 2C10 mAb was transiently expressed in Nicotiana benthamiana and lettuce using geminiviral vector. After purification by protein A affinity chromatography, the antibody was tested for the binding and neutralizing activity against PEDV. Our result showed that the plant produced 2C10 mAb can bind to the virus and also inhibit PEDV infection in vitro. These results show excellent potential for a plant-expressed 2C10 as a PEDV prophylaxis and a diagnostic for PEDV infection. PMID- 28575913 TI - [Results of Re-switch from Intravitreal Aflibercept to Ranibizumab in Patients with Exudative Age-related Macular Degeneration]. AB - BACKGROUND: The purpose of this study was to investigate the effectiveness of re switch from intravitreal aflibercept to ranibizumab in patients with exudative age-related macular degeneration. MATERIALS AND METHODS: This retrospective case series included 17 eyes of 17 patients who had previously switched from ranibizumab to aflibercept and finally back to ranibizumab. Main outcomes were change of visual acuity (VA) and assessment of central macular thickness (CMT). Secondary outcomes included predictive factors which had a beneficial effect as VA and CMT before re-switch, number of previous injections and gender. RESULTS: The mean VA was 0.64 +/- 0.36 logMAR before the switch, and 0.87 +/- 0.40 logMAR before the re-switch, and gained with a slight but not significantly improvement up to 0.85 +/- 0.58 logMAR after the re-switch (p = 0.896). The average CMT before the switch was 448.6 um +/- 181.5. This decreased to 343.8 um +/- 161.3 after the switch (p = 0.614) to 299.1 um +/- 155.8 at switchback (p = 0.133). Overall, 8 patients (47%) had an improvement of vision, whereas in 5 patients (30%) VA deteriorated. Further analysis of predictive factors revealed a mean improvement of VA in male patients after re-switch, while female patients lost VA, with statistical significance between after the switch and after the re switch to the benefit of male patients (p = 0.016). CONCLUSIONS: A re-switch from aflibercept to ranibizumab may enable improvement in morphological parameters and stabilization of VA in patients with exudative age-related macular degeneration who achieved no more benefit from the initial switch. PMID- 28575914 TI - [Critical Incident Reporting System in Risk Management at the Eye Center in Freiburg]. AB - Background With the help of reporting systems, errors that occur in medical settings can be documented and can lead to an improved workflow. We, herein, present data from our reporting system that we have used since 2012. Materials and Methods All reports since 2012 were evaluated and analyzed regarding the annual rate of reportings, who reported and what reasons were suspected to be causative for the reported errors. Results Over the last five years a mean of 33 reports were given annually. While mostly doctors reported in the first year, the following years showed almost balanced reports from medical assistant staff and doctors. Not all of these reports resulted in actions. The most often stated reason for errors or critical situations was miscommunication between the staff. Conclusion Our data show that a constant number of reports can be obtained over at least five years from doctors as well as medical assistant staff. The main reason for critical situations seems to be miscommunication. With the increased experience with reporting systems, such as CIRS, we can expect more comparative data. PMID- 28575915 TI - ["Friendly Greetings from the Eye Clinic" - The Old Eye Hospitals in Tubingen on Postcards]. PMID- 28575916 TI - ["Mystery Is in the Eye of the Beholder": The History of the "Haidinger's Brushes"]. PMID- 28575917 TI - [Surgical Options in Glaucoma Management]. AB - During the last few years, there has been a considerable capacity of innovations in glaucoma surgery owing to new micro-stents increasing the aqueous outflow via transscleral routes, via the trabecular meshwork or the suprachoroidal space. These interventions can be easily performed in combination with small-incision cataract surgery. Even the well-known filtering procedures, trabeculectomy and drainage device surgery, formerly perceived as being outdated, re-achieve better reputation owing to refinements in surgical technique and improved surgical experience. Although enthusiasm is understandable, considering the technical advances, we must wait for clinical long-term results and compare the new procedures with the established ones. PMID- 28575918 TI - [Expansion and Transplantation of Limbal Stem Cells for Corneal Surface Regeneration]. AB - In humans, regeneration of the corneal epithelium is regulated by the stem cell reservoir of the limbus. After extensive limbal damage, e.g., by inflammation, thermal burn or chemical injury, limbal stem cell deficiency leading to vascularization and opacification of the cornea and resulting in vision loss, may develop. Several techniques of autologous and allogenic stem cell transplantation have been established. The limbus can be restored by transplantation of whole limbal grafts, small limbal biopsies or by ex vivo-expanded limbal cells. In this review, the physiology of corneal epithelium, the pathophysiology of limbal stem cell deficiency and the therapeutic procedures will be presented. PMID- 28575919 TI - Zika Virus Infection in Pregnant Women and Microcephaly. AB - From the discovery of the Zika virus (ZIKV) in 1947 in Uganda (Africa), until its arrival in South America, it was not known that it would affect human reproductive life so severely. Today, damage to the central nervous system is known to be multiple, and microcephaly is considered the tip of the iceberg. Microcephaly actually represents the epilogue of this infection's devastating process on the central nervous system of embryos and fetuses. As a result of central nervous system aggression by the ZIKV, this infection brings the possibility of arthrogryposis, dysphagia, deafness and visual impairment. All of these changes of varying severity directly or indirectly compromise the future life of these children, and are already considered a congenital syndrome linked to the ZIKV. Diagnosis is one of the main difficulties in the approach of this infection. Considering the clinical part, it has manifestations common to infections by the dengue virus and the chikungunya fever, varying only in subjective intensities. The most frequent clinical variables are rash, febrile state, non-purulent conjunctivitis and arthralgia, among others. In terms of laboratory resources, there are also limitations to the subsidiary diagnosis. Molecular biology tests are based on polymerase chain reaction (PCR) with reverse transcriptase (RT) action, since the ZIKV is a ribonucleic acid (RNA) virus. The RT-PCR shows serum or plasma positivity for a short period of time, no more than five days after the onset of the signs and symptoms. The ZIKV urine test is positive for a longer period, up to 14 days. There are still no reliable techniques for the serological diagnosis of this infection. If there are no complications (meningoencephalitis or Guillain-Barre syndrome), further examination is unnecessary to assess systemic impairment. However, evidence is needed to rule out other infections that also cause rashes, such as dengue, chikungunya, syphilis, toxoplasmosis, cytomegalovirus, rubella, and herpes. There is no specific antiviral therapy against ZIKV, and the therapeutic approach to infected pregnant women is limited to the use of antipyretics and analgesics. Anti-inflammatory drugs should be avoided until the diagnosis of dengue is discarded. There is no need to modify the schedule of prenatal visits for pregnant women infected by ZIKV, but it is necessary to guarantee three ultrasound examinations during pregnancy for low-risk pregnancies, and monthly for pregnant women with confirmed ZIKV infection. Vaginal delivery and natural breastfeeding are advised. PMID- 28575920 TI - Intraoperative 1-Hour Electrical Nerve Stimulation Enhances Outcomes of Nerve Muscle-Endplate Band Grafting Technique for Muscle Reinnervation. PMID- 28575921 TI - Endurance Exercise in Hypoxia, Hyperoxia and Normoxia: Mitochondrial and Global Adaptations. AB - We hypothesized short-term endurance exercise (EN) in hypoxia (HY) to exert decreased mitochondrial adaptation, peak oxygen consumption (VO2peak) and peak power output (PPO) compared to EN in normoxia (NOR) and hyperoxia (PER). 11 male subjects performed repeated unipedal cycling EN in HY, PER, and NOR over 4 weeks in a cross-over design. VO2peak, PPO, rate of perceived exertion (RPE) and blood lactate (Bla) were determined pre- and post-intervention to assess physiological demands and adaptation. Skeletal muscle biopsies were collected to determine molecular mitochondrial signaling and adaptation. Despite reduced exercise intensity (P<0.05), increased Bla and RPE levels in HY revealed higher metabolic load compared to PER (P<0.05) and NOR (n.s.). PPO increased in all groups (P<0.05) while VO2peak and mitochondrial signaling were unchanged (P>0.05). Electron transport chain complexes tended to increase in all groups with the highest increase in HY (n.s.). EN-induced mitochondrial adaptability and exercise capacity neither decreased significantly in HY nor increased in PER compared to NOR. Despite decreased exercise intensity, short term EN under HY may not necessarily impair mitochondrial adaptation and exercise capacity while PER does not augment adaptation. HY might strengthen adaptive responses under circumstances when absolute training intensity has to be reduced. PMID- 28575922 TI - Comparison of Specific Prediction Equations to Estimate Peak Oxygen Uptake in Obese Women. AB - The aim of the current study was to compare 2 equations to predict peak oxygen uptake (VO2peak) in obese women, according to their obesity class. 92 maximal cardiopulmonary exercise testing sets (CPET with initial and subsequent increments set to achieve an exercise duration between 8-12 min) were retrospectively analysed. These CPET were divided into 3 groups according to the women body mass indexes (BMI): class 1 (30 kg.m-2<=BMI<35 kg.m-2, n=22), class 2 (35 kg.m-2<=BMI<40 kg.m-2, n=36) or class 3 (BMI>=40 kg.m-2, n=34). Each participant's VO2peak was predicted from 2 prediction equations (from Wasserman et al.'s and Debeaumont et al.'s equations) and compared with the actual VO2peak. Moreover, the correlations between these values were studied, and the accuracy of the predictions was analysed. Only predicted VO2peak from the Debeaumont et al.'s equation was not significantly different from the actual VO2peak in the women in obesity class 3 (p=0.89). Moreover, significant correlation was found between these values (p<0.001, r=0.68). The bias and the 95% limits of agreement represented -3.2+/-34.0%. In women in obesity class 3, Debeaumont et al.'s equation may be the accurate one to predict VO2peak. However, the accuracy of predictions is low. Consequently, to improve this accuracy, new prediction equations for obese women are required according to the obesity class. PMID- 28575923 TI - The Effect of a Simulated Soccer Match on Anterior Cruciate Ligament Injury Risk Factors. AB - To investigate the effect of within match fatigue on knee kinematics and jump kinetics in girls' soccer players, a quasi-experiment time series design was employed collecting data before, after and at 15-min intervals during a 90-min simulated soccer match. 15 girl players (age 13.1+/-1.4 years) performed a counter movement jump and a single-leg drop jump. Mean concentric force and flight time to contraction time ratio were derived from the counter movement jump. Knee valgus and flexion angles were calculated during the single-leg drop from 3-dimensional motion capture. Subjective ratings of perceived exertion (RPE) and readiness were collected at each time series. Small to large increases in RPE and reductions in readiness were observed throughout the match from baseline. Moderate to large improvements in mean concentric force were shown at 15, 75 and 90-min when compared to baseline. Flight time to contraction time ratio increased moderately at 15 min. Changes in kinematics were typically trivial or unclear however, small increases in knee valgus were shown after 30 min compared to baseline. Subjective measures may provide useful information to understand the physical response of young players to match play. PMID- 28575924 TI - [Positive Airway Pressure Ventilation: Theory and Practice]. PMID- 28575926 TI - Erratum. PMID- 28575925 TI - [Willingness of Students of Economics to Pay for Predictive Oncological Genetic Testing - An Empirical Analysis]. AB - Objectives: The present study aims to investigate the interest of young adults in predictive oncological genetic testing and their willingness to pay for such a test. Furthermore, major determinants of the 2 variables of interest were identified. Methods: 348 students of economics from the Leibniz University of Hanover were queried in July 2013 using an extensive questionnaire. Among other things, the participants were asked if they are interested in information about the probability to develop cancer in the future and their willingness to pay for such information. Data were analysed using descriptive statistics and ordinal probit regressions. Additionally marginal effects were calculated. Results: About 50% of the students were interested in predictive oncological genetic testing and were willing to pay for the test. Moreover, the participants who were willing to pay for the test partly attach high monetary values to the information that could so be obtained. The study shows that the interest of the students and their willingness to pay were primarily influenced by individual attitudes and perceptions. Conclusions: The study proves that young adults were interested in predictive genetic testing and appreciate information about their probability of develop cancer someday. PMID- 28575928 TI - Impact of dust and smoke mixing on column-integrated aerosol properties from observations during a severe wildfire episode over Valencia (Spain). AB - The most destructive wildfire experienced in Spain since 2004 occurred close to Valencia in summer 2012. A total of 48.500ha were affected by two wildfires, which were mostly active during 29-30 June. The fresh smoke plume was detected at the Burjassot measurement station simultaneously to a severe dust episode. We propose an empirical method to evaluate the dust and smoke mixing and its impact on the microphysical and optical properties. For this, we combine direct-sun measurements with a Cimel CE-318 sun-photometer with an inversion methodology, and the Mie theory to derive the column-integrated size distribution, single scattering albedo (SSA) and asymmetry parameter (g). The mixing of dust and smoke greatly increased the aerosol load and modified the background aerosol properties. Mineral dust increased the aerosol optical depth (AOD) up to 1, while the smoke plume caused an extreme AOD peak of 8. The size distribution of the mixture was bimodal, with a fine and coarse modes dominated by the smoke particles and mineral dust, respectively. The SSA and g for the dust-smoke mixture show a marked sensitivity on the smoke mixing-ratio, mainly at longer wavelengths. Mineral dust and smoke share a similar SSA at 440nm (~0.90), but with opposite spectral dependency. A small dust contribution to the total AOD substantially affects the SSA of the mixture, and also SSA at 1020nm increases from 0.87 to 0.95. This leads to a different spectral behaviour of SSA that changes from positive (smoke plume) to negative (dust), depending on the dust and smoke mixing-ratio. PMID- 28575927 TI - Storage induced changes in coliform, heterotrophic groups of bacteria and nutrient levels of human urine for its safe use in biological production. AB - Human urine is a potential source of various nutrients, minerals and trace elements. Its use as a fertilizer is growing popular among farmers. Here, we examined the pattern of changes in the counts of coliform, heterotrophic bacteria as well as physico-chemical characteristics of human urine during different days of storage under closed conditions at ambient temperature. We observed that after 253 days of storage under closed condition, the coliform counts were reduced significantly and remained within the safe limit to be used as fertilizer. With increase in storage period, the concentration of phosphate showed decline coupled with rise in pH, alkalinity and electrical conductance. Our study revealed that human urine can be used as safe fertilizer after 8 months of storage under closed conditions at ambient temperature ranging 25-35oC. PMID- 28575929 TI - Influence of land development on stormwater runoff from a mixed land use and land cover catchment. AB - Mitigating for the negative impacts of stormwater runoff is becoming a concern due to increased land development. Understanding how land development influences stormwater runoff is essential for sustainably managing water resources. In recent years, aggregate low impact development-best management practices (LID BMPs) have been implemented to reduce the negative impacts of stormwater runoff on receiving water bodies. This study used an integrated approach to determine the influence of land development and assess the ecological benefits of four aggregate LID-BMPs in stormwater runoff from a mixed land use and land cover (LULC) catchment with ongoing land development. It used data from 2011 to 2015 that monitored 41 storm events and monthly LULC, and a Personalized Computer Storm Water Management Model (PCSWMM). The four aggregate LID-BMPs are: ecological (S1), utilizing pervious covers (S2), and multi-control (S3) and (S4). These LID-BMPs were designed and distributed in the study area based on catchment characteristics, cost, and effectiveness. PCSWMM was used to simulate the monitored storm events from 2014 (calibration: R2 and NSE>0.5; RMSE <11) and 2015 (validation: R2 and NSE>0.5; RMSE <12). For continuous simulation and analyzing LID-BMPs scenarios, the five-year (2011 to 2015) stormwater runoff data and LULC change patterns (only 2015 for LID-BMPs) were used. Results show that the expansion of bare land and impervious cover, soil alteration, and high amount of precipitation influenced the stormwater runoff variability during different phases of land development. The four aggregate LID-BMPs reduced runoff volume (34%-61%), peak flow (6%-19%), and pollutant concentrations (53%-83%). The results of this study, in addition to supporting local LULC planning and land development activities, also could be applied to input data for empirical modeling, and designing sustainable stormwater management guidelines and monitoring strategies. PMID- 28575930 TI - Mapping cation exchange capacity using a Veris-3100 instrument and invVERIS modelling software. AB - The cation exchange capacity (CEC) is one of the most important soil properties as it influences soil's ability to hold essential nutrients. It also acts as an index of structural resilience. In this study, we demonstrate a method for 3 dimensional mapping of CEC across a study field in south-west Spain. We do this by establishing a linear regression (LR) between the calculated true electrical conductivity (sigma - mS/m) and measured CEC (cmol(+)/kg) at various depths. We estimate sigma by inverting Veris-3100 data (ECa - mS/m) collected along 47 parallel transects spaced 12m apart. We invert the ECa data acquired from both shallow (0-0.3m) and deep (0-0.9m) array configurations, using a quasi-three dimensional inversion algorithm (invVeris V1.1). The CEC data was acquired at 40 locations and from the topsoil (0-0.3m), subsurface (0.3-0.6m) and subsoil (0.6 0.9m). The best LR between sigma and CEC was achieved using S2 inversion algorithm using a damping factor (lambda)=18. The LR (CEC=1.77+0.33*sigma) had a large coefficient of determination (R2=0.89). To determine the predictive capability of the LR, we validated the model using a cross-validation. Given the high accuracy (root-mean-square-error [RMSE]=1.69 cmol(+)/kg), small bias (mean error [ME]=-0.00cmol(+)/kg) and large coefficient of determination (R2=0.88) and Lin's concordance (0.94), between measured and predicted CEC and at various depths, we conclude we were well able to predict the CEC distribution in topsoil and the subsurface. However, the predictions made in the subsoil were poor due to limited data availability in areas where ECa changed rapidly from small to large values. In this regard, improvements in prediction accuracy can be achieved by collection of ECa in more closely spaced transects, particularly in areas where ECa varies over short spatial scales. PMID- 28575931 TI - Recent forest cover changes (2002-2015) in the Southern Carpathians: A case study of the Iezer Mountains, Romania. AB - The paper explores the dynamics of the forest cover change in the Iezer Mountains, part of Southern Carpathians, in the context of the forest ownership recovery and deforestation processes, combined with the effects of biotic and abiotic disturbances. The aim of the study is to map and evaluate the typology and the spatial extension of changes in the montane forest cover between 700 and 2462m a.s.l., sampling all the representative Carpathian ecosystems, from the European beech zone up to the spruce-fir zone and the subalpine-alpine pastures. The methodology uses a change detection analysis of satellite imagery with Landsat ETM+/OLI and Sentinel-2 MSI data. The workflow started with a complete calibration of multispectral data from 2002, before the massive forest restitution to private owners, after the Law 247/2005 empowerment, and 2015, the intensification of deforestation process. For the data classification, a Maximum Likelihood supervised classification algorithm was utilized. The forest change map was developed after combining the classifications in a unitary formula using image difference. The principal outcome of the research identifies the type of forest cover change using a quantitative formula. This information can be integrated in the future decision-making strategies for forest stand management and sustainable development. PMID- 28575932 TI - Household air pollution and angiogenic factors in pregnant Nigerian women: A randomized controlled ethanol cookstove intervention. AB - BACKGROUND: Maternal exposure to ambient air pollution affects placental growth markers. OBJECTIVES: Investigate impact of household air pollution (HAP) on placental growth markers. METHODS: Two groups of pregnant women were identified: firewood/kerosene stove-users (A, n=33) and bioethanol stove-users (B, n=44) that participated in a randomized control trial in Ibadan, Nigeria. A third group of non-smoking and presumed liquefied petroleum gas-using Chicago women (C, n=19) were included in this exploratory pilot to assess for possible differences between similar racial groups. Levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) were measured in maternal and cord plasma using ELISA. RESULTS: Maternal and cord blood sFlt-1 and PlGF did not differ significantly between women of groups A and B. Nevertheless, both groups differed significantly from the Chicago group in that group A women had lower maternal sFlt-1 (1372.50 vs. 3194.19) but higher PlGF (1607.87 vs. 442.80), and higher cord blood sFlt-1 (2925.02 vs. 107.53) and PlGF (223.68 vs. 6.92), all p<=0.001. Group B showed similar trends (all p<=0.002). Maternal PlGF levels were positively correlated to minutes of HAP exposure when PM2.5 concentration was above 100MUg/m3 in Nigerian women. CONCLUSIONS: Maternal levels of PlGF and cord blood levels of sFlt-1 and PlGF in Nigerian women with varying HAP exposures were significantly higher than Chicago-based women who had no presumed HAP exposure. It suggests that in-utero exposure to HAP influenced levels of angiogenic factors involved in normal placentation and growth and could represent compensation for pollutants exposure to preserve fetal viability. PMID- 28575934 TI - DNA interaction, antioxidant and in vitro cytotoxic activities of some mononuclear metal(II) complexes of a bishydrazone ligand. AB - A tridentate ONO donor bishydrazone ligand, 3-(((3-oxoindolin-2 ylidene)hydrazono) methyl)quinoxalin-2(1H)-one (L) was synthesized. Using the ligand, mononuclear metal complexes of the type [M(L)(OAc)] (M=Co(II), Ni(II), Cu(II) and Zn(II), OAc=-OCOCH3) were synthesized. The newly synthesized compounds were thoroughly characterized by various analytical and spectral techniques. Tetrahedral geometry was proposed for Co(II), Ni(II) and Zn(II) complexes, while square planar geometry has been assigned to the Cu(II) complex. The in vitro antibacterial, antifungal and antioxidant studies reveal that the Cu(II) complex of the bishydrazone ligand possess higher activities. DNA binding studies suggest that the present compounds interact with CT DNA through intercalation. This was further supported by molecular docking. Gel electrophoresis studies substantiated the involvement of free radicals in the cleavage of pUC18 DNA. In vitro cytotoxicity of the compounds against MCF-7 cell line was also examined. The molecular modeling studies reveal that the compounds strongly interact with VEGFR 2 kinase receptor through hydrogen bonding, pi-pi, pi-cation and sigma-pi interactions. The bioavailability and bioactivity determination of the compounds suggest that the present compounds may be utilized as drug candidates. PMID- 28575933 TI - Application of surface modified nano ferrite nickel in catalytic reaction (epoxidation of alkenes) and investigation on its antibacterial and antifungal activities. AB - Newly, magnetic nanoparticles have extensively been used as alternative catalyst supports, in the view of their high surface area which results in high catalyst loading capacity, high dispersion, low toxicity, environmental preservation, distinguished stability, and suitable catalyst reusing. In the present study, the magnetite nanoparticles, NiFe2O4@Ag and NiFe2O4@Mo, were synthesized and characterized. The antimicrobial activities and catalytic properties of synthesized nanoparticles were tested afterwards. For synthetizing the nanoparticle NiFe2O4@Ag, silver ions were loaded onto the surface of the modified NiFe2O4 and reduced to silver crystal by adding NaBH4. The antibacterial effects of NiFe2O4@Ag were examined against two species of soil and plant related bacteria named Bacillus subtilis (gram positive) and Pseudomonas syringae (gram negative), respectively. The antifungal activity of this nanoparticle was evaluated against two species of plant pathogenic fungi called Alternaria solani and Fusarium oxysporum. Biological results indicated that the synthesized material has shown an excellent antibacterial and antifungal activity against all examined bacteria and fungi so that, their growth were completely inhibited 24h after treatment with NiFe2O4@Ag. For the synthesis of a heterogeneous catalyst NiFe2O4@Mo, complex Mo(CO)6 was loaded onto the surface of the modified NiFe2O4 nanoparticle. This catalyst was found as an efficient catalyst for epoxidation of cis-cyclooctene and a wide variety of alkenes, including aromatic and aliphatic terminal ones using tert-butyl hydroperoxide as oxidant. This new heterogenized catalyst could easily be recovered by using a magnetic separator and reused four consecutive and loss only 13% of its catalytic activity. PMID- 28575936 TI - Solid crystal suspension of Efavirenz using hot melt extrusion: Exploring the role of crystalline polyols in improving solubility and dissolution rate. AB - Poor aqueous solubility of drugs has emerged as a major issue for pharmaceutical scientists from many decades. The current study explores the manufacture and development of a thermodynamically stabilized solid crystal suspension (SCS) of poorly water soluble drug efavirenz via hot melt extrusion. Efavirenz is a non nucleoside reverse transcriptase inhibitor and belongs to BCS class II. The SCS was prepared using pearlitol and xylitol as a crystalline carrier. The drug excipient blend was processed by hot melt extrusion with up to 50% (w/w) drug loading. Physico-chemical characterization of the SCS conducted via a scanning electron microscopy, differential scanning calorimetry and hot stage microscopy confirmed that SCS are in crystalline state. Similarly, X-ray powder diffraction analysis revealed highly crystalline existence of pure drug, crystalline carriers and developed SCS. The FTIR chemical imaging analysis of SCS formulations showed a homogeneous drug distribution within respective crystalline carriers while an advanced chemical analysis via atomic force microscopy and Raman analysis complemented the foregoing findings. The developed SCS1 formulation showed up to 81 fold increase in the solubility and 4.1 fold increase in the dissolution rate of the drug compared to that of the bulk substance. Surprisingly, the developed SCS formulation remained stable for a period of more than one year at accelerated conditions inferred from dissolution studies. It can be concluded that the SCS approach can be used as an alternative contemporary technique to enhance the dissolution rates of many other poorly water-soluble drugs by means of thermal HME processing. PMID- 28575935 TI - Preparation of novel dual-site drug delivery system based on hydroxypropyl methyl cyclodextrin. AB - An amphipathic copolymer of poly(polyethylene glycol-b-polycaprolactone-co hydroxypropyl methyl cyclodextrin) [poly(mPEG-b-PCL-co-HPCD)] was synthesized via the free radical polymerization. The copolymer was used to prepare novel nanoparticles (NPs) by a solvent evaporation method. Curcumin (CUR) was selected as a model drug and loaded in the both sites of inner NPs and the cavities of HPCD. 1H nuclear magnetic resonance (1H NMR) study was carried out to confirm the synthesis of poly(mPEG-b-PCL-co-HPCD). The morphology and particle size distribution of the cargo-free NPs were monitored with transmission electron microscopy (TEM) and Malvern particle sizer. The distribution state of CUR in the CUR-loaded NPs was studied with differential scanning calorimetry (DSC) and X-ray diffraction (XRD) methods. The 1H NMR spectrum demonstrated the successful preparation of poly(mPEG-b-PCL-co-HPCD) copolymer. TEM photograph illustrated that the cargo-free NPs had a spherical morphology with an average diameter of 229+/-32.8nm. The cargo-free NPs had a low critical micelle concentration of 2.9*10-2mg/mL. The HepG2 cells incubated with 1.0mg/mL NPs suspension showed high cell viability. The drug release profile showed that the medicated NPs could continuously release CUR for 24h. Therefore, the poly(mPEG-b-PCL-co-HPCD) NPs had a potential application on the drug delivery. PMID- 28575937 TI - A facile way to prepare anti-fouling and blood-compatible polyethersulfone membrane via blending with heparin-mimicking polyurethanes. AB - In this study, new kinds of heparin-mimicking polyurethanes (PUs) were fabricated conveniently in the mixed solution of dimethyl sulfoxide (DMSO) and water, reducing the usage of organic solvent. Functional groups of SO3H and/or COOH were introduced into PUs with various ratios of SO3H to COOH. The PUs were then blended with polyethersulfone (PES) to fabricate heparin-mimicking modified PES membranes by a phase inversion technique. Then, the microstructures, zeta potentials, water contact angles (WCA) and protein adsorptions of the membranes were characterized. Comparing with pristine PES membrane, the modified membranes showed changed cross-sectional morphology, lowered zeta potentials and decreased water contact angles, revealing that the hydrophilicity and anti-fouling properties were improved. The modified membranes also showed prolonged clotting tines (APTTs) and suppressed platelet adhesion, revealing that the anticoagulant properties increased. The results of complement activation, contact activation and platelet activation further implied that the modified membranes had good blood compatibility. In addition, the cells on the membranes showed good morphology with the introduction of the PUs. With the increase of the ratio of SO3H to COOH, the hydrophilicity, the blood compatibility as well as the cytocompatibility increased, implying that the SO3H groups could improve the hemocompatibility of the membranes more effectively than COOH groups. While the membranes containing more COOH groups had better antifouling properties of BSA and BFG. Therefore, the hemocompatibility for the heparin-mimicking membranes could be tuned by controlling the ratios of SO3H to COOH. The PES/PU composite membranes might have great potential to be used in the field of blood purification. PMID- 28575938 TI - Tailor made alginate hydrogel for local infection prophylaxis in orthopedic applications. AB - Preventing implants associated infections is crucial in orthopedics. Local delivery of antibiotics through implants is a promising strategy to solve this issue. In this study, alginate is tailored to control its swelling, entrapment and release of ciprofloxacin (antibiotic) through the formation of interpenetrating polymer network and composite matrices using gelatin and hydroxyapatite. Developed matrices were characterized by Fourier transform infrared spectroscopy, x-ray diffraction and scanning electron microscopy. The individual tailoring approaches exerted significant influence on the swelling behavior of alginate matrix consequently enhanced the drug entrapment and extended the release period. However, the alginate matrix tailored with the combined approaches resulted in a superior matrix, which had a better control over the burst release of ciprofloxacin. Drug release prolonged from 5h to 240h for composite matrix as compared with alginate matrix showing that alginate combined with gelatin and hydroxyapatite sustained the release for longer periods. This matrix revealed excellent biocompatibility with osteoblast like MG 63 cell lines and showed good antibacterial activity against S. aureus and E. coli. PMID- 28575939 TI - Innovative surface modification of Ti6Al4V alloy by electron beam technique for biomedical application. AB - The low elastic modulus, high corrosion resistance and excellent biological response allow titanium alloys to be used for permanent orthopaedic devices. Furthermore, the design of specific multi scale surface topographies on titanium alloys can provide a fast osseointegration. This work highlights the use of electron beam as a promising technique to produce a designed surface topography and improve the tribological behaviour of Ti6Al4V alloy. The produced surface topography due to the transport of molten material is influenced by the deflection figure, the physical properties of the material and the energy input. The analysis of the surface roughness shows an increment of the area up to 26% and a canal shape in a range from 1.3MUm up to 9MUm depth and from 68.6MUm up to 119.7MUm width. The high solidification rate reached during the process affects the microstructure, provoking the formation of martensite and thus the improvement of hardness. In vitro studies with pre-osteoblastic MC3T3-E1 cells performed for several cultivation times show the cells with a polygonal shape and built connections through elongated filopodia. A notable increase of cell spreading area on surface structure with a finer canal shape is found after 48h cultivation time. PMID- 28575940 TI - Ag nanoparticle-coated zirconia for antibacterial prosthesis. AB - : Bacterial adhesion to dental materials is a major cause of caries and periodontitis, necessitating the development of compounds such as yttria stabilized zirconia (YSZ) and silver nanoparticles (AgNPs), which are widely employed in medicine due to their high antimicrobial activity and low cytotoxicity. The main goal of this study is the synthesis of the broad antimicrobial activity of AgNP-coated YSZ with facile methods. The bactericidal AgNPs were immobilized on the surface of YSZ and tested for bactericidal activity against Staphylococcus aureus, Streptococcus mutans, Escherichia coli, and Aggregatibacter actinomycetemcomitans based on ISO 22196:2007. The loading of AgNPs was optimized by culturing mouse fibroblast cells on AgNP-coated YSZ with cell viability test based on ISO 10993-5. In addition, the silver release profile of AgNP-coated YSZ in artificial saliva was determined using an accelerated aging test. Antibacterial activity, and cell viability test revealed optimum performance with no cytotoxicity at a level of 32 MUg/cm2. Accelerated aging test showed that the AgNP-coated surface was extremely stable, exhibiting a total silver leaching level of only 1% and confirming the effectiveness of this coating method for retaining AgNPs while exerting an antibacterial effect against oral pathogens. This finding also implies that the bactericidal action of AgNP-coated YSZ is not mediated by the released Ag ions, but rather corresponds to contact killing. ABBREVIATIONS: Yttria-stabilized zirconia, YSZ; silver nanoparticles, AgNPs; field emission scanning electron microscopy, FE-SEM; X-ray photoelectron spectroscopy, XPS; grazing incidence X-ray diffraction, GIXRD; ultraviolet visible, UV-vis; inductively coupled plasma atomic emission spectrometry, ICP AES. PMID- 28575941 TI - A systematic study of mechanical properties, corrosion behavior and biocompatibility of AZ31B Mg alloy after ultrasonic nanocrystal surface modification. AB - Magnesium alloys have tremendous potential for biomedical applications due to their good biocompatibility, osteoconductivity, and degradability, but can be limited by their poor mechanical properties and fast corrosion in the physiological environment. In this study, ultrasonic nanocrystal surface modification (UNSM), a recently developed surface processing technique that utilizes ultrasonic impacts to induce plastic strain on metal surfaces, was applied to an AZ31B magnesium (Mg) alloy. The mechanical properties, corrosion resistance, and biocompatibility of the alloy after UNSM treatment were studied systematically. Significant improvement in hardness, yield stress and wear resistance was achieved after the UNSM treatment. In addition, the corrosion behavior of UNSM-treated AZ31B was not compromised compared with the untreated samples, as demonstrated by the weight loss and released element concentrations of Mg and Al after immersion in alpha-minimum essential medium (alpha-MEM) for 24h. The in vitro biocompatibility of the AZ31B Mg alloys toward adipose-derived stem cells (ADSCs) before and after UNSM processing was also evaluated using a cell culture study. Comparable cell attachments were achieved between the two groups. These studies showed that UNSM could significantly improve the mechanical properties of Mg alloys without compromising their corrosion rate and biocompatibility in vitro. These findings suggest that UNSM is a promising method to treat biodegradable Mg alloys for orthopaedic applications. PMID- 28575943 TI - Ageing and degradation determines failure mode on sea urchin spines. AB - Sea urchin spines are an example of a hard natural composite with mineral and organic phases. The role of the organic phase in the response to mechanical stress was assessed by promoting the degradation of such spines by exposing them to ageing and ultraviolet (UV) irradiation. Thermal and structural characterization of the irradiated samples show that this UV irradiation treatment promotes degradation of the organic and inorganic phase of spines. Uniaxial compression tests carried out on aged and UV irradiated samples showed that both treatments affected the mechanical properties of the spines. Scanning electron microscopy (SEM) images of failed specimens were used to analyze the failure mechanisms of the compressed spines. The analysis of the fracture surfaces showed that the failure mechanisms of spines were modified as a consequence of UV irradiation, leading in the last case to mostly brittle fracture surfaces. We suggest that the proteins responsible for the formation of calcite also determine the mechanical properties and the failure mode of spines. This system can be used as a model for the study of the failure modes of other natural and synthetic hard composites. PMID- 28575942 TI - Hybrid ZnPc@TiO2 nanostructures for targeted photodynamic therapy, bioimaging and doxorubicin delivery. AB - In this study ZnPc@TiO2 hybrid nanostructures, both nanoparticles and nanotubes, as potential photosensitizers for the photodynamic therapy, fluorescent bioimaging agents, as well as anti-cancer drug nanocarriers, were prepared via zinc phthalocyanine (ZnPc) deposition on TiO2. In order to provide the selectivity of prepared hybrid nanostructures towards cancer cells they were modified with folic acid molecules (FA). The efficient attachment of both ZnPc and FA molecules was confirmed with dynamic light scattering (DLS), zeta potential measurements and X-ray photoelectron spectroscopy (XPS). It was presented that ZnPc and FA attachment has a strong effect on fluorescence emission properties of TiO2 nanostructures, which can be further used for their simultaneous visualization upon cellular uptake. ZnPc@TiO2 and FA/ZnPc@TiO2 hybrid nanotubes were then employed as doxorubicin nanocarriers. It was demonstrated that doxorubicin can be easily loaded on these hybrid nanostructures via an electrostatic interaction and then released. In vitro cytotoxicity and photo-cytotoxic activity studies showed that prepared hybrid nanostructures were selectively targeting to cancer cells. Doxorubicin loaded hybrid nanostructures were significantly more cytotoxic than un-loaded ones and their cytotoxic effect was even more severe upon irradiation. The cellular uptake of prepared hybrid nanostructures and their localization in cells was monitored in vitro in 2D cell culture and tumor-like 3D multicellular culture environment with fluorescent confocal microscopy. These hybrid nanostructures preferentially penetrated into human cervical cancer cells (HeLa) than into normal fibroblasts (MSU-1.1) and were mainly localized within the cell cytoplasm. HeLa cells spheroids were also efficiently labelled by prepared hybrid nanostructures. Fluorescent imaging of Hela cells treated with doxorubicin loaded hybrid nanostructures showed that doxorubicin was effectively delivered into cells, released and evenly distributed in the cytoplasm. In conclusion, prepared hybrid nanostructures exhibit high potential as selective bioimaging agents next to their photodynamic activity and drug delivery ability. PMID- 28575945 TI - Mechanical properties of experimental composites with different calcium phosphates fillers. AB - Calcium phosphates (CaPs)-containing composites have already shown good properties from the point of view of dental restorative materials. The purpose of this study was to examine the crucial mechanical properties of twelve hydroxyapatite- or tricalcium phosphate-filled composites. The raw and surface treated forms of both CaP fillers were applied. As a reference materials two experimental glass-containing composites and one commercial dental restorative composite were applied. Nano-hardness, elastic modulus, compressive, flexural and diametral tensile strength of all studied materials were determined. Application of statistical methods (one-way analysis of variance and cluster agglomerative analysis) allowed for assessing the similarities between examined materials according to the values of studied parameters. The obtained results show that in almost all cases the mechanical properties of experimental CaPs-composites are comparable or even better than mechanical properties of examined reference materials. PMID- 28575944 TI - Novel and facile microwave-assisted synthesis of Mo-doped hydroxyapatite nanorods: Characterization, gamma absorption coefficient, and bioactivity. AB - In the current work, the authors report the microwave-assisted synthesis Molybdenum-doped (from 0.05 to 5wt%) hydroxyapatite (HAp) for the first time. The morphology of Mo-doped HAp is nanorods of diameter in the range of 25-70nm and length in the range of 25nm to 200nm. The good crystalline nature was confirmed from X-ray diffraction patterns and also lattice parameters, grain size, strain and dislocation density were determined. The crystallite size was found to be in the range 16 to 30nm and crystallinity was found to be enhanced from 0.5 to 0.7 with doping. The field emission SEM micrographs show that the morphology of the synthesized nanostructures of pure and Mo-doped HAp are nanorods of few nanometers. The vibrational modes were identified using the FT-Raman and FT-IR spectroscopy. The dielectric properties were studied and the AC electrical conductivity was found to be increased with increasing the concentration of Mo ions doping in HAp. Moreover, antimicrobial studies were also carried out to understand the anti-bacterial and anti-fungi properties. The results suggest that it may be a good bio-ceramics material for bio-medical applications. Mo-doped HAp was subjected to the gamma irradiation produced from Cs-137 (662keV) and its related parameters such as linear absorption coefficient, the half-value layer (HVL) and the tenth value layer TVL were calculated and analyzed. PMID- 28575946 TI - Microwave assisted extraction as an efficient approach for biosynthesis of zinc oxide nanoparticles: Synthesis, characterization, and biological properties. AB - In the present study, microwave assisted extraction (MAE) was applied as an efficient, green and rapid approach to prepare the aqueous extract of Suaeda aegyptiaca (SA) plant. The obtained aqueous extracts at two different irradiation power (90 and 270W; 15min) in MAE process as well as maceration method (24h) were used in a green and eco-friendly approach for the synthesis of zinc oxide nanoparticles (ZnO NPs). The synthesized ZnO NPs have been characterized via different techniques including UV-Vis absorption; fluorescence and Fourier transform infrared (FT-IR) spectroscopices, scanning electron microscopy (SEM), and X-ray diffraction (XRD). According to the results, the average size of the prepared ZnO particles was estimated around 60nm. A broad absorption band around 382nm in UV-Vis absorption spectrum and a maximum emission at wavelength of 458nm in fluorescence spectrum clarified the successful biosynthesis of ZnO NPs. Moreover, the biological properties of the extracts and biosynthesized ZnO NPs were investigated by antimicrobial tests (i.e. Well-diffusion, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) tests), antifungal and antioxidant tests (total phenolic and flovonoid content, antioxidant activity against dipheny-picrylhydrazyl (DPPH), and ethylbenzothiazolin-6sulphonic acid (ABTS+)). Finally, DNA cleavage potential of the samples was studied, too. PMID- 28575947 TI - Platelet compatibility of magnesium alloys. AB - Lately, Mg alloys have been investigated as a new class of biomaterials owing to their excellent biodegradability and biocompatibility. It has previously been reported that the in vitro compatibility of a Mg alloy containing aluminum and zinc (AZ) alloy with the blood coagulation system is excellent due to Mg2+ ions eluting from the alloy. In this study, the compatibility of the AZ alloy with platelets was evaluated by scanning electron microscopy (SEM) and flow cytometry. In the flow cytometry analysis, the platelets were stained using PAC-1 and P selectin antibodies. SEM images and PAC-1 analyses showed no negative effects on the platelets, whereas P-selectin analysis showed marked platelet activation. To understand these contradictory results, the amount of beta-thromboglobulin (beta TG) released from the platelets was investigated. From that investigation, it was concluded that platelets are markedly activated by the alloys. In addition to clarifying divergent results depending on the analysis method used, the effects of Mg2+ ions and pH on platelet activation were studied. These results show that platelet activation is caused by an increase in pH at the alloy surface owing to the erosion of the alloy. PMID- 28575948 TI - Synthesis characterization and biological evaluation of alginate nanoparticle for the targeted delivery of curcumin. AB - Cancer continues to be a serious disaster to mankind. Chemotherapy is an efficient and effective treatment against cancer. Lack of selectivity is the main challenge faced by chemotherapy. In present study we used folic acid (FA) as a targeting ligand, which selectively targets the cancer cell lines with over expressed folate receptors (FR). We grafted polyethylene glycol (PEG) to polyethylene imine (PEI) to form PEG-b-PEI (mPPS), which is then coupled with FA to form FA- PEG-b-PEI (PPF) which is then assembled with curcumin (CUR) loaded alginate nanoparticle (AlgNP). The carrier is well characterized using FTIR, XRD, SEM and DLS. At optimum conditions DLE of 68.3% and DEE of 92.4% have been achieved and a drug release percentage higher than 80% is also obtained. The cell viability of CUR loaded carrier is found to be less than 40%. In vitro cytotoxicity studies and fluorescence images of HeLa and H9c2 cell lines confirm the selective destruction of tumor cell lines. PMID- 28575949 TI - A highly bioactive poly (amido amine)/70S30C bioactive glass hybrid with photoluminescent and antimicrobial properties for bone regeneration. AB - The field of tissue engineering constantly calls for novel biomaterials that possess intrinsically multifunctional properties such as bioactivity, bioimaging ability and antibacterial properties. In this paper, poly (amido amine) generation 5/bioactive glass inorganic-organic hybrids have been developed through direct hybridization by 3-glycidoxypropyltrimethoxysilane (GPTMS) as coupling agent. Results indicated that the degree of covalent coupling by GPTMS and the weight percent of inorganic and organic constituents highly influence hybrids properties. It was found that nanoscale integration of inorganic and organic chains by GPTMS significantly endows hybrids with high thermal stability. Furthermore, hybrids exhibited photoluminescent ability (emission 400-600nm and 700nm) without incorporating of any organic dyes or quantum dots. In addition, hydrophilicity of our hybrids indicated good cell/material interaction. The biological apatite was formed on the surface of calcium containing hybrids when soaked in simulated body fluid (SBF) for 1week. Hybrids also showed linear biodegradation behavior in SBF that could be controlled by the degree of covalent crosslinking which was indicative of their stable biodegradation ability. High inherent antibacterial properties against Staphylococcus aureus was also observed from poly (amido amine)/silica hybrids. No adverse cytotoxicity for human gingival fibroblast cell lines (HGF) was detected after 4days. It is envisaged that our novel multifunctional hybrid system will confer intriguing potential in advancing the field of tissue engineering. PMID- 28575950 TI - In vitro proliferation and differentiation of human bone marrow mesenchymal stem cells into osteoblasts on nanocomposite scaffolds based on bioactive glass (64SiO2-31CaO-5P2O5)-poly-l-lactic acid nanofibers fabricated by electrospinning method. AB - Electrospinning method was employed for fabrication of SiO2-CaO-P2O5 bioactive glass (BG) nanofibers, poly-l-lactic acid (PLLA) nanofibers and nanocomposite scaffolds fabricated from as-prepared nanofibers. Characterization of the prepared nanofibers and scaffolds by XRD, FTIR, and SEM techniques revealed the formation of nanofibers with mean diameter of about 500nm and fully fibrous scaffolds with porous structure and interconnected pores. The growth, viability and proliferation of cultured human bone marrow mesenchymal stem cells in the fabricated nanofibers and bioactive glass-poly-l-lactic acid (BG-PLLA) nanocomposite scaffolds were studied using various biological assays including MTT, ALP activity, calcium deposit content, Alizarin red staining, and RT-PCR test. Based on the obtained results, incorporation of BG nanofibers in the nanocomposite scaffolds causes the better biological behavior of the scaffolds. In addition, three-dimensional and fibrous-porous structure of the scaffolds further contributes to their improved cell behavior compared to the components. PMID- 28575951 TI - Enhanced gelation of chitosan/beta-sodium glycerophosphate thermosensitive hydrogel with sodium bicarbonate and biocompatibility evaluated. AB - The application of chitosan/beta-sodium glycerophosphate (beta-GP) thermosensitive hydrogel has been limited by the relatively slow gelation, weak mechanical resistance and poor cytocompatibility. In this study, sodium hydrogen carbonate (NaHCO3) was applied with beta-GP as gel agents to produce high strength hydrogel. The hydrogels prepared with high NaHCO3 concentration or more gel agents showed shorter gelation time, better thermostability, drastically enhanced resistance in compression. Meanwhile, the hydrogels presented obvious porous structures and excellent biocompatibility to HUVEC and NIH 3T3 cultured in vitro with higher NaHCO3 concentration and moderate concentration of beta-GP. Overall, appropriate concentration of beta-GP combined with NaHCO3 can be a good gel regent to improve properties of chitosan thermosensitive hydrogels. PMID- 28575952 TI - Biocompatibility and neurotoxicity of magnesium alloys potentially used for neural repairs. AB - Nerve injury, especially the large-size nerve damage, is a serious problem affecting millions of people. Entubulation of two ends of the injured nerve by using an implantable device, e.g., nerve guidance conduit (NGC), to guide the regeneration of nerve tissue is a promising approach for treating the large-size nerve defect. Magnesium (Mg) and its alloys are biodegradable, conductive, and own good mechanical properties. Mg2+ ion, one of the main degradation products of Mg and its alloys, was reported to promote the proliferation of neural stem cells and their neurite production. Thus, Mg and its alloys are potential materials for fabricating the nerve repair implants, such as NGC or scaffold. However, the compatibility of Mg alloys to cells, especially neurons is not clear. In this work, NZ20 (Mg-2Nd-Zn), ZN20 (Mg-2Zn-Nd) and Mg-10Li magnesium alloys were selected for study, due to the improved mechanical properties of NZ20 and ZN20 alloys and bio-function of Li+ ions from Mg-10Li to nervous system, respectively. The degradation behavior and biocompatibility were studied by in vitro degradation test and cell adhesion assay, respectively. Specifically, the cytocompatibility to dorsal root ganglion (DRG) neurons, RF/6A choroid-retina endothelial cells, and osteoblasts in the cell culture media containing Mg alloy extracts were investigated. The results showed that Mg alloys degraded at different rates in cell culture media and artificial cerebrospinal fluid. The three alloy extracts showed negligible toxic effects on the endothelial cells and osteoblasts at short term (1 day), while NZ20 extract inhibited the proliferation of these two types of cells. The effect of Mg alloy extracts on cell proliferation was also concentration-dependent. For DRG neurons, ZN20 and Mg-10Li alloy extracts showed no neural toxicity compared with control group. The results of the present work show a potential and feasibility of Mg-10Li and ZN20 for nerve repair applications. PMID- 28575953 TI - Ag-BaMoO4: Er3+/Yb3+ photocatalyst for antibacterial application. AB - Silver loaded and Er3+/Yb3+ doped BaMoO4 octahedron microcrystals were fabricated by microwave hydrothermal process. The synthesized samples were characterized by X-ray diffraction (XRD), Field emission scanning electron microscopy (FESEM), Energy dispersive X-ray spectroscopy (EDS), and Ultraviolet-visible diffuse reflection spectroscopy (UV-Vis DRS). The antibacterial application of samples were investigated by visible light irradiation and disk-diffusion method towards representative Gram-negative pathogen (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive pathogen (methicillin resistant Staphylococcus aureus). The complete inactivation of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus were observed by Ag-BaMoO4: Er3+/Yb3+ photocatalyst within 1h, 4h, and 5h, respectively, under visible light irradiation. The high killing percentage and superior zone of inhibition revealed the excellent antibacterial performance. The FESEM images were used to visualize the morphology with the extent of damage in the phospholipid layer present in the cell membrane of bacteria. The synergistic effect of loaded silver particles and doped Er3+/Yb3+ ions in BaMoO4 contributed for efficient antibacterial performance in visible light as well as in the dark. The excellent antibacterial performance of Ag-BaMoO4: Er3+/Yb3+ photocatalyst makes the material suitable for smart weapon for multidrug-resistant microorganisms and disinfectants in biomedical application. PMID- 28575955 TI - Characterisation of polyamide 11/copper antimicrobial composites for medical device applications. AB - Direct incorporation of antimicrobial additive into the polymer matrix is a cost effective approach for the development of polymer/metal antimicrobial composites. Application of these antimicrobial composite systems for manufacturing medical devices addresses the issue of device related infections. In the present study, commercially available inorganic copper based additive, Plasticopper, was incorporated into a Polyamide 11(PA 11) matrix during the polymer processing stage. These polymer composites were evaluated for their morphological, mechanical, antimicrobial and ion release properties. Isothermal crystallisation studies showed that the copper additive acted as a nucleating agent and promoted faster crystallisation. Short term mechanical studies confirmed that the incorporation of copper has reinforcing effect on the composites with 5 and 10% copper loadings and did not adversely affect the short-term mechanical performance of the polymer composites. These composite systems were shown to be active against Escherichia coli ATCC 8739 with >99.99% reduction in bacterial population. Corresponding ion release profiles for these composites indicated long term antimicrobial activity. PMID- 28575954 TI - Scaffold composed of porous vancomycin-loaded poly(lactide-co-glycolide) microspheres: A controlled-release drug delivery system with shape-memory effect. AB - Loading antibiotics in a biodegradable polymer matrix is an excellent way to control its release kinetics, which eliminates side effects caused by conventional administrations of the drug. This approach is especially beneficial for bone regeneration when using a scaffold made of a biodegradable polymer loaded with drug agents capable of controllable releases. In this case, the scaffold serves as a mechanical support to tissue formation and the drug agents may provide biomolecules to assist the tissue formation and/or provide antibiotics to prevent tissues from infections. Towards this goal, we have developed an approach to make vancomycin-loaded poly(lactide-co-glycolide) (PLGA) microspheres, from which we made scaffolds by compression molding. In this article we concentrate on characterizing the porosity and drug release profiles, as well as verifying shape-memory effect of the scaffolds. The scaffold was biodegradable and showed a much slower drug release profile than microspheres. We confirmed that our PLGA scaffolds recovered to their permanent shapes when heated to 45 degrees C. We believe that these scaffolds will find applications in bone regeneration where both the use of antibiotics against infection and accommodation to spatial restrictions may be required. PMID- 28575956 TI - Cell responses to titanium treated by a sandblast-free method for implant applications. AB - Sandblast and acid-etching (SLA) is the most prevalent treatment to titanium implants, while residual sand particles are inevitably introduced on SLA titanium surfaces. NH4OH and H2O2 mixture was used to etch titanium plates (E) and titanium bars (EB), aiming at substituting sandblast procedure. To study the effects of different scale rough structures on cell response of Human osteoblast like cells (MG63), traditional H2SO4 and HCl mixture was also used to further etch the titanium plates above (DE). Holes of 10-20MUm were obtained on E and DE surfaces, which are very close to the size of osteoblasts. Surfaces with micro/nano and micro/submicro hierarchical structures were obtained on the treated titanium. As-prepared E, DE and EB surfaces are hydrophilic, while only EB stayed hydrophilic after 5days' exposure to air. MG63 cultured on E and EB surfaces showed higher proliferation rate and attachment area than on DE and P surfaces. E and DE showed higher alkaline phosphatases (ALP) activity after 7 and 14days of osteoinduction, while EB showed the highest osteopontin (OPN) and bone sialoprotein (BSP) production after 21days of osteoinduction. These results indicate that E and EB surfaces boost the proliferation and osteogenic differentiation of MG63 without introducing sand particles. This is a promising treatment to titanium implant. PMID- 28575957 TI - Neural differentiation of human induced pluripotent stem cells on polycaprolactone/gelatin bi-electrospun nanofibers. AB - In the present study, for the first time, polycaprolactone (PCL) and gelatin (GEL) were used for neural differentiation of human induced pluripotent stem cells (hiPSCs) in the form of bi-electrospun nanofibers. The electrospun fibers were evaluated by FTIR and tensile analysis. MTT assay was used to evaluate the toxicity on the scaffolds. The hiPSCs were seeded on the fibers and after 14days in neural differentiation medium. To confirm the differentiation, real-time PCR and immunocytochemistry (ICC) analyses were performed. For morphological studies of fibers and cultured cells on them, scanning electron microscopy (SEM) and optical microscopy (OM) were used. Our results indicated that hiPSCs had differentiated to neural cells completely after incubation time. Our study demonstrates that PCL/GEL bi-electrospun nanofibers not only have the capability to support hiPSCs differentiation to neural cells, but they also are able to enhance and improve such process. Overall, PCL/GEL scaffolds seem to be a feasible, reliable and easily accessed composite for further tissue engineering experiments. PMID- 28575958 TI - Mesoporous silica nanoparticles as potential carriers for enhanced drug solubility of paclitaxel. AB - In this study, paclitaxel (PTX), a typical chemotherapeutic agent with poor water solubility, was selected as the model drug to evaluate the feasibility of mesoporous silica nanoparticles (MSN) to load a hydrophobic drug in different solvents. A sol-gel method was used to synthesize MSN. Drug loading was carried out in three different solvents: dichloromethane, ethanol and dimethyl sulfoxide (DMSO) via a solvent evaporation method, and their effects on drug loading were examined. We further studied the effects of drug loading period and mass ratio of drug to carrier on drug loading capacity of MSN, as well as the in vitro drug release was analyzed. Moreover, the cytotoxic effect of PTX loaded MSN on liver carcinoma (HepG2) cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The related materials were characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), dynamic light scattering (DLS), fourier transform infrared spectrometer (FTIR), small-angle x-ray scattering (SAXS), wide-angle x-ray diffraction (XRD) and N2 adsorption-desorption analyses. The results demonstrated a highly improved solubility of PTX by using MSN as drug carriers compared to free PTX. In addition, drug loading content increased as the solvent polarity parameter decreased or the drug/carrier mass ratio increased. Compared with the blank MSN, the PTX loaded MSN could produce a significant cytotoxicity on HepG2 cells. Our results indicated that MSN could be very potential drug delivery carriers for poorly water soluble drugs. PMID- 28575959 TI - Multifunctional inulin tethered silver-graphene quantum dots nanotheranostic module for pancreatic cancer therapy. AB - Cancer nanotechnology is an emerging area of cancer diagnosis and therapy. Although considerable progress has been made for targeted drug delivery systems to deliver anticancer agents to particular site of interest, new nanomaterials are frequently being developed and explored for better drug delivery efficiency. In the present work, we have explored a novel nanoformulation based on silver graphene quantum dots (Ag-GQDs) nanocomposite for its successful implementation for pancreatic cancer specific drug delivery in wistar rats. Carboxymethyl inulin (CMI); a modified variant of natural polysaccharide inulin is tethered with the nanocomposite via carbodiimide coupling to enhance the biocompatibility of nanoformulation. Experiments are performed to investigate the cytotoxicity reduction of silver nanoparticles after inulin tethering as well as anticancer efficacy of the system using 5-Fluorouracil (5-FU) as model drug. SEM, TEM, FT IR, UV-vis, photoluminescence and anti proliferative assays (MTT) are performed for characterisation of the nanocomposite. Hyaluronic acid (HA) is conjugated as targeting moiety for CD-44 (cancer stem cell marker) to fabricate a complete targeted drug delivery vehicle specific for pancreatic cancer. In the present work two prime objectives were achieved; mitigation the toxicity of silver nanoparticles by inulin coating and it's in vivo application for pancreatic cancer. PMID- 28575960 TI - Synthesis and characterization of MFI-type borosilicate zeolites and evaluation of their efficiency as drug delivery systems. AB - MFI-type borosilicate zeolites with different Si/B ratio were synthesized by hydrothermal method using silicic acid and sodium tetraborate decahydrate as starting materials. The prepared samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetry analysis (TGA/DTG) and Fourier transform infrared spectroscopy (FT-IR). Different characterization techniques confirmed the incorporation of boron atoms into the zeolite framework. SEM images revealed that the particle size of zeolites and their morphology can be controlled by different synthesis parameters. The effect of different parameters such as crystallization time and temperature, pH value of initial gel and Si/B ratio on the crystallinity, morphology and incorporation of boron atoms into final products was investigated and discussed in detail. The efficiency of synthesized borosilicate zeolites as drug delivery systems was examined by loading and in vitro release of anticancer drug doxorubicin (DOX). The results demonstrated that DOX-loaded borosilicate samples show a pH-sensitive drug release feature with higher drug release rate in relatively lower pH values. In vitro cytotoxicity of DOX- loaded borosilicate was evaluated by MTT assay. PMID- 28575961 TI - Strontium and strontium ranelate: Historical review of some of their functions. AB - The review covers historical and last decade's scientific literature on the biological and clinical role of strontium (Sr) and strontium ranelate (Sr RAN). It enrols the description of the main effects of Sr on supportive tissue, its proven and possible morphopathogenetical mechanisms and the interaction with the bone, and especially focuses on the Sr ability to inhibit osteoclasts and affect the programmed cell death. The main experimental and clinical experience regarding the Sr RAN influence in the treatment of osteoporosis and the search for correct doses is also highlighted. The review gives insight into the role of Sr/Sr RAN on stem cells, apoptosis, animal and clinical research. PMID- 28575962 TI - Colorimetric sensors for rapid detection of various analytes. AB - Sensor technology for the rapid detection of the analytes with high sensitivity and selectivity has several challenges. Despite the challenges, colorimetric sensors have been widely accepted for its high sensitive and selective response towards various analytes. In this review, colorimetric sensors for the detection of biomolecules like protein, DNA, pathogen and chemical compounds like heavy metal ions, toxic gases and organic compounds have been elaborately discussed. The visible sensing mechanism based on Surface Plasmon Resonance (SPR) using metal nanoparticles like Au, Ag, thin film interference using SiO2 and colorimetric array-based technique have been highlighted. The optical property of metal nanoparticles enables a visual color change during its interaction with the analytes owing to the dispersion and aggregation of nanoparticles. Recently, colorimetric changes using silica substrate for detection of protein and small molecules by thin film interference as a visible sensing mechanism has been developed without the usage of fluorescent or radioisotopes labels. Multilayer of biomaterials were used as a platform where reflection and interference of scattering light occur due to which color change happens leading to rapid sensing. Colorimetric array-based technique for the detection of organic compounds using chemoresponsive dyes has also been focused wherein the interaction of the analytes with the substrate coated with chemoresponsive dyes gives colorimetric change. PMID- 28575963 TI - Highly sensitive and selective non enzymatic electrochemical glucose sensors based on Graphene Oxide-Molecular Imprinted Polymer. AB - Graphene Oxide-Molecular Imprinted Polymer (GO-MIP) based electrochemical sensor was developed for the first time towards enzyme less determination of glucose. This GO-MIP was obtained from a series of fictionalization, polymerization and template molecule introduction/removal during the synthesizing process. The proposed GO-MIP based electrode showed excellent electrocatalytic activity towards glucose oxidation at optimized conditions and possessing detection limit of 0.1nM with a response time of ~2min. The current response of GO-MIP based glucose sensor was linearly related to the concentration of glucose. The results obtained from the real time usability of electrodes in human blood matches well with commercially available glucose monitors. Further, the reusability of the material is checked up to eight cycles and interference of glucose with ascorbic acid (AA), uric acid (UA) and dopamine (DA) were also studied. The obtained results endorse the promising application of GO-MIP towards superior glucose sensing with long term stability. PMID- 28575964 TI - Scaffolds for Bone Tissue Engineering: State of the art and new perspectives. AB - This review is intended to give a state of the art description of scaffold-based strategies utilized in Bone Tissue Engineering. Numerous scaffolds have been tested in the orthopedic field with the aim of improving cell viability, attachment, proliferation and homing, osteogenic differentiation, vascularization, host integration and load bearing. The main traits that characterize a scaffold suitable for bone regeneration concerning its biological requirements, structural features, composition, and types of fabrication are described in detail. Attention is then focused on conventional and Rapid Prototyping scaffold manufacturing techniques. Conventional manufacturing approaches are subtractive methods where parts of the material are removed from an initial block to achieve the desired shape. Rapid Prototyping techniques, introduced to overcome standard techniques limitations, are additive fabrication processes that manufacture the final three-dimensional object via deposition of overlying layers. An important improvement is the possibility to create custom made products by means of computer assisted technologies, starting from patient's medical images. As a conclusion, it is highlighted that, despite its encouraging results, the clinical approach of Bone Tissue Engineering has not taken place on a large scale yet, due to the need of more in depth studies, its high manufacturing costs and the difficulty to obtain regulatory approval. PUBMED search terms utilized to write this review were: "Bone Tissue Engineering", "regenerative medicine", "bioactive scaffolds", "biomimetic scaffolds", "3D printing", "3D bioprinting", "vascularization" and "dentistry". PMID- 28575965 TI - A review of biocompatible metal injection moulding process parameters for biomedical applications. AB - Biocompatible metals have been revolutionizing the biomedical field, predominantly in human implant applications, where these metals widely used as a substitute to or as function restoration of degenerated tissues or organs. Powder metallurgy techniques, in specific the metal injection moulding (MIM) process, have been employed for the fabrication of controlled porous structures used for dental and orthopaedic surgical implants. The porous metal implant allows bony tissue ingrowth on the implant surface, thereby enhancing fixation and recovery. This paper elaborates a systematic classification of various biocompatible metals from the aspect of MIM process as used in medical industries. In this study, three biocompatible metals are reviewed-stainless steels, cobalt alloys, and titanium alloys. The applications of MIM technology in biomedicine focusing primarily on the MIM process setting parameters discussed thoroughly. This paper should be of value to investigators who are interested in state of the art of metal powder metallurgy, particularly the MIM technology for biocompatible metal implant design and development. PMID- 28575966 TI - Naturally derived proteins and glycosaminoglycan scaffolds for tissue engineering applications. AB - Tissue engineering (TE) aims to mimic the complex environment where organogenesis takes place using advanced materials to recapitulate the tissue niche. Cells, three-dimensional scaffolds and signaling factors are the three main and essential components of TE. Over the years, materials and processes have become more and more sophisticated, allowing researchers to precisely tailor the final chemical, mechanical, structural and biological features of the designed scaffolds. In this review, we will pose the attention on two specific classes of naturally derived polymers: fibrous proteins and glycosaminoglycans (GAGs). These materials hold great promise for advances in the field of regenerative medicine as i) they generally undergo a fast remodeling in vivo favoring neovascularization and functional cells organization and ii) they elicit a negligible immune reaction preventing severe inflammatory response, both representing critical requirements for a successful integration of engineered scaffolds with the host tissue. We will discuss the recent achievements attained in the field of regenerative medicine by using proteins and GAGs, their merits and disadvantages and the ongoing challenges to move the current concepts to practical clinical application. PMID- 28575967 TI - Constructing multi-component organic/inorganic composite bacterial cellulose gelatin/hydroxyapatite double-network scaffold platform for stem cell-mediated bone tissue engineering. AB - Bacterial cellulose/hydroxyapatite (BC/HAp) composite had good bioaffinity but its poor mechanical strength limited its widespread applications in bone tissue engineering (BTE). Bacterial cellulose/gelatin (BC/GEL) double-network (DN) composite had excellent mechanical properties but was seldom used in biomedical fields. In this regard, a multi-component organic/inorganic composite BC-GEL/HAp DN composite was synthesized, which combined the advantages of BC/HAp and BC/GEL. Compared with BC/GEL, the BC-GEL/HAp exhibited rougher surface topography and higher thermal stability. Compression and tensile testing indicated that the mechanical strength of the BC-GEL/HAp was greatly reinforced compared with BC/HAp and was even higher than that of BC/GEL. In vitro cell culture demonstrated that the rat bone marrow-derived mesenchymal stem cells (rBMSCs) cultured on the BC GEL/HAp showed better adhesion and higher proliferation and differentiation potential than the cells cultured on BC/GEL. We hope the BC-GEL/HAp composite could be used as ideal bone scaffold platform or biomedical membrane in the future. PMID- 28575968 TI - Structural aspects of graphitic carbon modified SBA-15 mesoporous silica and biological interactions with red blood cells and plasma proteins. AB - Functional mesoporous materials have been worldwide studied for different applications. Mesoporous silicas are highlighted due to the synthetic possibilities for the preparation of such materials with different particle sizes and morphologies, and controlled pores sizes and structures. Moreover, the silica superficial silanol groups are explored in several chemical modifications, leading to functional materials with tuned functionalities and properties. In this work, an organo-functionalization and pyrolysis synthetic procedure is used to obtain graphitic carbon modified mesoporous SBA-15 silica. The carbon content was tuned during the functionalization step, and the graphitic nanodomains were formed in the pores surface and particles outer surface. Textural and small angle X-ray diffraction analysis accessed the presence of the carbon nanostructures inside the SBA-15 mesopores. Advanced microanalysis using electron energy loss spectroscopy coupled to a transmission electron microscope had confirmed the carbon distribution along the silica pores, which gives higher hydrophobicity and changed the interaction of the mesoporous material with biological systems. Finally, the influence of the surface modification with graphitic carbon species over the interaction with human red blood cells (hemolysis) and human blood plasma (protein corona formation) was elucidated for the very first time for this kind of functional materials. It was observed that the graphitic carbon species considerably reduced the hemolytic effect of the silica particles, and was responsible for modulating the loading and composition of the hard corona plasma proteins. This work deepness the fundamental knowledge on the interaction between such nanomaterials and biological systems, one step further the use of these modified silicas in biomedical applications. PMID- 28575969 TI - Li+ activated nanohydroxyapatite doped with Eu3+ ions enhances proliferative activity and viability of human stem progenitor cells of adipose tissue and olfactory ensheathing cells. Further perspective of nHAP:Li+, Eu3+ application in theranostics. AB - Spinal cord injuries (SCI) often require simultaneous regeneration of nerve tissue and bone. Hydroxyapatites are described as bioresorbable materials with proper biocompatibility and osteoconductivity, therefore its application for spinal surgery is considered. In this paper, we present repeatable method for developing nanocrystalline calcium hydroxyapatites structurally modified with Li+ ions (nHAP:Li+). Obtained biomaterials were profoundly characterized in terms of their physicochemical properties. Moreover, we have shown that nHAP:Li+ doped with europium (Eu3+) may serve as a theranostic agent, what additionally extend its potential usage for SCI treatment. The biocompatibility of nHAP:Li+ was determined using human olfactory ensheathing cells (hOECs) and adipose tissue derived multipotent stromal cells (hASCs). Both population of cells are eagerly applied for cell-based therapies in SCI, mainly due to their paracrine activity. The extensive in vitro studies showed that nHAP:Li+ promotes the cells proliferation, viability and cell-cell interactions. Obtained results provides encouraging approach that may have potential application in regenerative medicine and that could fulfil the promise of personalized medicine - important in SCI treatment. PMID- 28575970 TI - In situ foamable, degradable polyurethane as biomaterial for soft tissue repair. AB - Degradable foams which can be inserted endoscopically as liquid or pasty mixtures into soft tissue defects possess a promising potential for the surgical treatment of such defects. The defects can be sealed under in situ foaming and simultaneous material expansion. We developed an in situ foamable (l-lactide-co-epsilon caprolactone)-based, star-shaped prepolymer by ring opening polymerization of l lactide and epsilon-caprolactone in the presence of meso-erythritol as starter. By conversion of the terminal hydroxyl groups of the formed oligoester with lysine diisocyanate ethyl ester (LDI) an isocyanate-endcapped, reactive prepolymer has been received. Foaming can be initiated by addition of 1,4 diazabicyclo[2,2,2]octane (DABCO), water, LDI and DMSO. By varying the composition of these additives, the foaming and curing time could be varied within a clinically acceptable range. A porosity of approximately 90%, and an average tensile strength of 0.3MPa with elongations of 90% were determined for the foams. In vitro cytotoxicity on cured foams was assayed on 3T3 fibroblasts and demonstrated an excellent cytocompatibility. This was also confirmed in an in vivo study using an established rat model, where prefabricated foams and in situ hardening material were inserted into subdermal skin incisions in parallel. The feature of chronic inflammation was only weakly developed in both groups and slightly more pronounced and persisted for longer time in the group of in situ foamed material. In both groups the foreign materials were vascularized, degraded and substituted by connective tissue. The results encourage to proceed with trials where the materials are used to fill more heavily loaded defects. PMID- 28575972 TI - Photoenhanced gene transfection by a curcumin loaded CS-g-PZLL micelle. AB - The codelivery of drug and gene is a promising method for cancer treatment. In our previous works, we prepared a cationic micelles based on chitosan and poly-(N 3-carbobenzyloxylysine) (CS-g-PZLL), but transfection ratio of CS-g-PZLL to Hela cell was low. Herein, to improve the transfection efficiency of CS-g-PZLL, curcumin was loaded in the CS-g-PZLL micelle. After irradiation, the obtained curcumin loaded micelle showed a better transfection, and the p53 protein expression in Hela cells was higher. The apoptosis assay showed that the complex could induce a more significant apoptosis to Hela cells than that of curcumin or p53 used alone, and the curcumin loaded micelle inducing apoptosis was best after irradiation. Therefore, CS-g-PZLL is a safe and effective carrier for the codelivery of drug/gene, and curcumin could be used as a photosensitizer to induce a photoenhanced gene transfection, which should be encouraged in improving transfection and tumor therapy. PMID- 28575971 TI - Synthesis and biological properties of Zn-incorporated micro/nano-textured surface on Ti by high current anodization. AB - It is acknowledged that ideal implant coatings should possess micro/nano-textured surface, have good interfacial bonding, and can release bioactive elements. In this study, we fabricated a Zn-incorporated micro/nano-textured surface by one step high current anodization (HCA) in an aqueous solution with 10g/L of NaOH and different concentrations of Zn(NO3)2 (4, 7, and 12g/L). The control group of Zn free was fabricated in the electrolyte of 7g/L Zn(NO3)2. Scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), X ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and inductively coupled plasma mass spectroscopy (ICP-MS) were used to analyze the morphology, composition, microstructure, and Zn+ release kinetics of the micro/nano-textured coatings. The biological properties of the surface structure were evaluated by cytotoxicity assay, cell viability, cytoskeletal assembly and alkaline phosphatase activity. Our results show the micro/nano-textured surface is composed of TiO2 mesoporous arrays, into which the Zn is demonstrated to be incorporated in the form of ZnO. The Zn content in the surface and release level of Zn2+ can be tailored through varying Zn(NO3)2 concentration in the electrolyte. In addition, the surface oxide layers show good interfacial bonding strength to the substrate. Compared with pure Ti and anodized Zn-free samples, the Zn-incorporated surface can upregulate osteoblast functions such as proliferation and alkaline phosphatase activity, which are assayed by MTT and ALP staining experiments, respectively. Collectively, this micro/nano-textured structure combined with high interfacial bonding strength and release of Zn2+ render the material surface promising as orthopedic implant coatings. PMID- 28575973 TI - Electrochemical hydrogen peroxide sensor based on carbon supported Cu@Pt core shell nanoparticles. AB - The Cu@Pt/C nanocomposites have been synthesized via two-step reduction method. Electrochemical observations showed that the Cu@Pt/C had better electrocatalytic activity for the reduction of hydrogen peroxide than Pt/C, with a wide linear range between 0.50MUM and 32.56mM, a high sensitivity of 351.3MUAmM-1cm-2, and a low detection limit of 0.15MUM (signal/noise=3). Furthermore, the sensor based on Cu@Pt/C has potential applications due to its excellent long-time stability, good reproducibility and acceptable selectivity. PMID- 28575975 TI - Biosynthesis of reduced graphene oxide and its in-vitro cytotoxicity against cervical cancer (HeLa) cell lines. AB - The present work proposed a simple, one pot, and green approach for the deoxygenation of graphene oxide (GO) using pyrogallol as reducing and stabilizing agent. This synthetic strategy prevents the utilization of toxic reducing reagents during synthesis. The characterization results of Ultra violet visible (UV-Vis), X-ray diffraction (XRD), X-ray photo electron spectroscopy (XPS), Transmission electron microscopy (TEM) for the synthesized GO and reduced graphene oxide (RGO) indicated the strong removal of oxygen groups after reduction which followed by stabilization with oxidized form of pyrogallol. TEM analysis showed the thin transparent silk like sheets of graphene. FTIR analysis confirmed the stabilization of graphene sheets with oxidized pyrogallol molecules. XRD and XPS analysis represented the deoxygenation of GO to RGO. The in-vitro cytotoxicity of RGO towards HeLa cells is dose dependant. The prepared RGO also exhibited the percent cell viability of about 80% even at higher concentrations indicating the less toxic nature of the RGO stabilized with pyrogallol. These results have represented that this synthetic approach is effective for the preparation of bulk scale RGO in a simple, less expensive and eco-friendly method. Since this method avoids the use of chemical reagents that are toxic in nature, the produced graphene are likely to offer several potential biomedical applications. PMID- 28575974 TI - Construction of biodegradable and biocompatible AIE-active fluorescent polymeric nanoparticles by Ce(IV)/HNO3 redox polymerization in aqueous solution. AB - Aggregation-induced emission (AIE) active fluorescence polymeric nanoparticles (FPNs) have recently received increasing interests for biomedical applications such as cell imaging, drug delivery, disease diagnosis and treatment. Fabricated strategies of AIE-active FPNs with high efficiency, simplification and tenderness are still passionately pursued to promote the development of theranostic systems. In this work, we develop a facile method for the preparation of AIE-active FPNs by adopting Ce(IV)/HNO3 redox polymerization under near room temperature. Thus prepared FPNs (named as PEG-PLC-1) possess unique AIE feature, great water dispersity, excellent biocompatibility and biodegradability because of the conjugation of ultra-bright AIE dye (PhE-alc) and biodegradable PEG-PCL linear copolymers. The 1H nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, transmission electron microscopy (TEM), UV-Visible and fluorescence spectrometers were used to confirm the successful fabrication of AIE-active FPNs. Cell viability and cellular uptake behavior of PEG-PLC-1 FPNs were further investigated for their potential biomedical applications. Results demonstrated that PEG-PLC-1 FPNs are high water dispersity, intensive luminescence and low cytotoxicity, making them very attractive for biomedical applications. More importantly, the method for the fabrication of AIE active biodegradable FPNs can be occurred under rather facile conditions (e.g., low temperature, free of metal catalysts, common chain transfer agent and aqueous solution) and are specially used for fabrication of AIE-active polysaccharides with poor organic solubility. PMID- 28575976 TI - Thermosensitive hydrogel as an in situ gelling antimicrobial ocular dressing. AB - Microbial keratitis is a severe ocular condition and one of the most prevalent causes of corneal scarring and associated blindness worldwide. Risk factors include contact lens use, ocular trauma, ocular surface disease and immunosuppression. Initial clinical management mandates intensive (hourly or more frequent) topical administration of broad spectrum antimicrobial therapy for at least 48h, which may require hospital admission, followed by tailored therapy based on microbiological investigation and the institution of strategies to reduce inflammation and promote healing. In this work we report an ocular wound dressing which can encapsulate and give sustained release of different antibiotics. The use of this dressing would allow patients to have eye drops on a 4 hourly basis, thereby facilitating treatment compliance and reducing hospital admissions. PMID- 28575977 TI - Nonenzymatic glucose sensing by CuO nanoparticles decorated nitrogen-doped graphene aerogel. AB - CuO nanoparticles decorated N-doped graphene aerogel (NGA-CuO) was facilely synthesized via a mild hydrothermal method followed by freeze-drying and calcination, which was characterized by TEM, FT-IR, XPS, XRD and electrochemical impedance spectroscopy (EIS). The obtained NGA-CuO was used for the construction of a nonenzymatic sensing platform for glucose, exhibiting wide linear range, low detection limit, high sensitivity, reproducibility, selectivity and stability. The excellent analytical performances of the NGA-CuO based glucose sensor might be attributed to the synergistic effect of CuO nanoparticles and N-doped graphene aerogel (NGA). The practical applications of the proposed sensor was verified by determining glucose concentrations in five human serum samples, and the obtained results were quite comparable to those measured on the standard clinical instrument. PMID- 28575978 TI - Fabrication, optimization and characterization of electrospun poly(caprolactone)/gelatin/graphene nanofibrous mats. AB - Recently graphene-based materials have been exploited widely in graphene-polymer nanocomposites and hold notable potential for various applications. In this study novel graphene-incorporated poly(caprolactone)/gelatin nanofibrous web were produced by electrospinning technique using acetic acid as a cost-effective eco friendly solvent. Response surface methodology was used for optimizing the diameter of the electrospun nanofibrous web. To tailor electrospun nanofibers with suitable mechanical and electrical properties, the impact of affecting electrospinning parameters was studied. Our results show that, with increasing the PCL/gelatin ratio, the diameter of nanofibers increases, whereas increasing graphene concentration decreased the diameter of nanofibers up to an optimum content. With the incorporation of 1.5% graphene into PCL/gelatin matrix the tensile strength and Young modulus of nanofibrous mat considerably increased by 117 and 128% respectively. The electrical conductivity results demonstrated that nanofibrous mats own nearly 11 times higher conductivity than that of PCL/gelatin nanofibers when the graphene concentration reached the percolation threshold. Contact angle measurements confirmed that graphene-incorporated electrospun nanofibers were more hydrophilic than that of neat nanofibrous mats. Cellular toxicity results of electrospun nanofibers ascertained almost no toxicity to PC12 cells. The morphology of electrospun nanofibers was investigated by means of scanning electron microscopy (SEM). FTIR and DSC analysis revealed that there might be possible interactions between graphene and PCL/gelatin matrix. XRD analysis demonstrated that graphene-incorporated PCL/gelatin nanofibers exhibited higher crystallinity. The uniform dispersion of graphene nanosheets in nanofibrous mat was also verified through Raman spectroscopy. PMID- 28575979 TI - Live-cell biosensor for assessment of adhesion qualities of biomaterials. AB - The present study describes a live-cell biosensor, suitable for general evaluation of adhesion qualities of different substrates. It is based on NIH/3T3 fibroblast cell line stably expressing fusion fluorescently tagged proteins mCherry-vinculin and GFP-tensin as quantifiable markers for assessment not only of focal but also of fibrillar contacts. Four measurable parameters - spreading, polarization and development of focal and fibrillar adhesions were used to standardize the adhesion of biosensor cells after plating on five substrates of natural origin - fibronectin, vitronectin, laminin-111, laminin-521 and collagen type I. The obtained set of values (adhesion quality map) were utilized to describe the default biosensor behavior and as a standard for evaluation of surface biocompatibility of materials with unknown adhesive properties. To demonstrate the applicability of the biosensor we studied two PDMS-based artificial materials. The results demonstrated the superior adhesive properties of the poly(acrylic acid)-containing polymer (PDMS-PAA) over that of poly(vinyl pyrrolidone) copolymer (PDMS-PVP), and pointed out the formation of focal adhesions as a parameter for possible further improvements. PMID- 28575980 TI - Laser textured Co-Cr-Mo alloy stored chitosan/poly(ethylene glycol) composite applied on artificial joints lubrication. AB - Arthroplasty brings the wear problems because of body fluid has poor performance as lubricant. Lubricant which is used in artificial joints will rapidly degrade and be absorbed by human body after injecting. To prolong the lubricant's effectiveness, this study prepared chitosan/poly(ethylene glycol) (CS/PEG) and textures to play a role in joint lubrication and wear protection. Chitosan (CS) and poly(ethylene glycol) which have biocompatibility and biodegradability properties can be used in human body. The tribological results shown that CS/PEG sol has excellent performance when this sol was composed by 2wt% CS and 30wt% PEG, the average friction coefficient below 0.016 under the condition of 30-90N load (pressure 4.2-12.6MPa). In this study, CS/PEG was added in the texture of artificial joints, then the surfaces of the CS/PEG formed gel via NaOH solidification effect. The CS/PEG gel film could prevent the CS/PEG sol from diluting in body fluid. Meanwhile, FT-IR, XRD, UV/vis and Raman spectra revealed that CS associated with PEG via hydrogen bond effect may form a particular structure, which leaded the good tribological performance. This study provides a new, simple and green approach to enhance tribological performances of artificial joints. PMID- 28575981 TI - Pancreatic islet surface bioengineering with a heparin-incorporated starPEG nanofilm. AB - Cell surface engineering could protect implanted cells from host immune rejections while modify the cellular landscape for better post-transplantation graft function and survival. Islet transplantation is considered the most promising therapeutic option with the potential to cure diabetes. Current approach to improve clinical efficacy of pancreatic islet transplantation is alginate encapsulation. However, disappointing outcomes have been reported in clinical trials due to larger islet size resulted by encapsulation and alginate elicited host immune responses. We have developed an ultrathin nanofilm of starPEG with incorporated heparin (Hep-PEG) that binds covalently to the amine groups of islet surface membrane via its N-hydroxysuccinimide groups. The Hep-PEG nanocoating elicited minimal alteration on islet volume in culture. Hep-PEG coated islets exhibited robust islet viability accompanied by uncompromised islet insulin secretory function. Instant blood-mediated inflammatory reaction was also reduced by Hep-PEG islet coating, accompanied by enhanced intra-islet revascularization. In addition, despite its semi-permeability, Hep-PEG islet coating promoted the survival of islets exposed to pro-inflammatory cytokines. Considering that inflammation and hypoxia are primary causes of immediate cell loss for cell therapy, the Hep-PEG nanofilm represents a viable approach for cell surface engineering which would improve the clinical outcome of cell therapies. PMID- 28575982 TI - Acid-degradable carboxymethyl chitosan nanogels via an ortho ester linkage mediated improved penetration and growth inhibition of 3-D tumor spheroids in vitro. AB - This work describes an acid-degradable and tumor-targeted nanogels prepared by the copolymerization between lactobionic acid-modified methacrylated carboxymethyl chitosan and acid-labile methacrylated orthoester-based monomers. The size distribution and micromorphology of the prepared nanogels were observed by dynamic light scattering, transmission electron microscopy and scanning electron microscopy. The stability of nanogels in various environments was then investigated. Doxorubicin as a model drug was successfully encapsulated into nanogels. In vitro cellular uptake and MTT results indicate that the tumor targeting and pH-sensitive nanogels display higher cellular internalization and cytotoxicity than non-target nanogels and free DOX. The improved penetration and growth inhibition against 3-D multicellular spheroids further demonstrate that the dual-functional nanogels may be a potential nano-carrier for drug delivery in cancer therapy. PMID- 28575983 TI - Evaluation of nanohydroxyapaptite (nano-HA) coated epigallocatechin-3-gallate (EGCG) cross-linked collagen membranes. AB - Collagen is the main component of extracellular matrix (ECM) with desirable biological activities and low antigenicity. Collagen materials have been widely utilized in guided bone regeneration (GBR) surgery due to its abilities to maintain space for hard tissue growth. However, pure collagen lacks optimal mechanical properties. In our previous study, epigallocatechin-3-gallate (EGCG) cross-linked collagen membranes, with better biological activities and enhanced mechanical properties, may promote osteoblast proliferation, but their effect on osteoblast differentiation is not very significant. Nanohydroxyapatite (nano-HA) is the main component of mineral bone, which possesses exceptional bioactivity properties including good biocompatibility, high osteoconductivity and osteoinductivity, non-immunogenicity and non-inflammatory behavior. Herein, by analyzing the physical and chemical properties as well as the effects on promoting bone regeneration, we have attempted to present a novel EGCG-modified collagen membrane with nano-HA coating, and have found evidence that the novel collagen membrane may promote bone regeneration with a better surface morphology, without destroying collagen backbone. To evaluate the surface morphologies, chemical and mechanical properties of pure collagen membranes, epigallocatechin-3 gallate (EGCG) cross-linked collagen membranes, nano-HA coated collagen membranes, nano-HA coated EGCG-collagen membranes, (ii) to evaluate the bone regeneration promoted by theses membranes. In the present study, collagen membranes were divided into 4 groups: (1) untreated collagen membranes (2) EGCG cross-linked collagen membranes (3) nano-HA modified collagen membranes (4) nano HA modified EGCG-collagen membranes. Scanning electron microscope (SEM) and Fourier transform infrared spectroscopy (FTIR) were used to evaluate surface morphologies and chemical properties, respectively. Mechanical properties were determined by differential scanning calorimeter (DSC) and elastic modulus (EM) measurements. Then in 12 rats, 4 types of membranes were randomly applied to cover the rat calvarial defects. The animals were sacrificed at 8weeks. Histologic analyses were performed using Hematoxylin-eosin (H&E) staining and Masson's Trichrome stains. For statistical analysis, analysis of variance (ANOVA) followed by Tukey's multiple comparison tests was applied. HA nanoparticles were fairly well distributed nanoparticles among the collagen fibers on the nano-HA modified EGCG-collagen membranes, with smoother surface. Moreover, collagen membranes with modifications all maintained their collagen backbone and the mechanical properties were enhanced by EGCG and nano-HA treatments. In addition, EGCG cross-linked collagen membranes with nano-HA coatings promoted bone regeneration. Nano-HA modified EGCG-collagen membranes can be utilized as a barrier membrane to enhance the bone regeneration in GBR surgeries. PMID- 28575985 TI - In-vitro biodegradation and corrosion-assisted cracking of a coated magnesium alloy in modified-simulated body fluid. AB - A calcium phosphate coating was directly synthesized on AZ91D magnesium (Mg) alloy. Resistance of this coating to corrosion in a modified-simulated body fluid (m-SBF) was investigated by potentiodynamic polarization and electrochemical impedance spectroscopy (EIS). Mechanical properties of the bare and coated alloy were investigated using slow strain rate tensile (SSRT) and fatigue testing in air and m-SBF. Very little is reported in the literature on human-body-fluid assisted cracking of Mg alloys, viz., resistance to corrosion fatigue (CF) and stress corrosion cracking (SCC). This study has a particular emphasis on the effect of bio-compatible coatings on mechanical and electrochemical degradations of Mg alloys for their applications as implants. The results suggest the coating to improve the general as well as pitting corrosion resistance of the alloy. The coating also provides visible improvement in resistance to SCC, but little improvement in CF resistance. This is explained on the basis of pitting behaviour in the presence and absence of the coating. PMID- 28575984 TI - Chitosan/gamma-poly(glutamic acid) scaffolds with surface-modified albumin, elastin and poly-l-lysine for cartilage tissue engineering. AB - Cartilage has limited ability to self-repair due to the absence of blood vessels and nerves. The application of biomaterial scaffolds using biomimetic extracellular matrix (ECM)-related polymers has become an effective approach to production of engineered cartilage. Chitosan/gamma-poly(glutamic acid) (gamma PGA) scaffolds with different mass ratios were prepared using genipin as a cross linker and a freeze-drying method, and their surfaces were modified with elastin, human serum albumin (HSA) and poly-l-lysine (PLL). The scaffolds were formed through a complex between NH3+ of chitosan and COO- of gamma-PGA, confirmed by Fourier transform infrared spectroscopy, and exhibited an interconnected porous morphology in field emission scanning electron microscopy analysis. The prepared chitosan/gamma-PGA scaffolds, at a 3:1 ratio, obtained the required porosity (90%), pore size (>=100MUm), mechanical strength (compressive strength>4MPa, Young's modulus>4MPa) and biodegradation (30-60%) for articular cartilage tissue engineering applications. Surface modification of the scaffolds showed positive indications with improved activity toward cell proliferation (deoxyribonucleic acid), cell adhesion and ECM (glycoaminoglycans and type II collagen) secretion of bovine knee chondrocytes compared with unmodified scaffolds. In caspase-3 detection, elastin had a higher inhibitory effect on chondrocyte apoptosis in vitro, followed by HSA, and then PLL. We concluded that utilizing chitosan/gamma PGA scaffolds with surface active biomolecules, including elastin, HSA and PLL, can effectively promote the growth of chondrocytes, secrete ECM and improve the regenerative ability of cartilaginous tissues. PMID- 28575986 TI - Co-culturing epidermal keratinocytes and dermal fibroblasts on nano-structured titanium surfaces. AB - Long-term success of percutaneous implants depends mostly on the stable connection between the soft tissue and implant surface because bacterial invasion and infection can be prevented by a proper seal between the skin and implant. The percutaneous seal is affected by responses of keratinocytes and/or fibroblasts to the implant. Herein, the in vitro functionality of fibroblasts and keratinocytes on titania nanotubes (TNT) and polished titanium (pTi) surfaces was investigated by different culture methods. Adhesion, proliferation, morphology, and differentiation were evaluated by cell viability assay, fluorescence microscopy, real-time quantitative polymerase chain reaction (RT-PCR), and indirect immunofluorescence. Single cultured fibroblasts on the TNT surface showed increased adhesion, proliferation, and differentiation, while these cellular properties were decreased in single cultured keratinocytes. In non-contact co culture with keratinocytes, fibroblasts presented better orientation, continuous proliferation, and increased gene expression on TNT. However, decreased adhesion and proliferation were observed for keratinocytes in non-contact co-culture with fibroblasts. Furthermore, keratinocytes presented high abilities to proliferate and differentiate in contact co-culture on fibroblasts adhering on the TNT surface. The gene expression results of contact co-culture model suggested that the nano-structured titanium surface promoted the maturation of fibroblasts and the formation of dermal matrix through secreting collagen I and transforming growth factor-beta1 (TGF-beta1), and indirectly facilitated the proliferation of keratinocytes and the formation of the basement membrane by stimulating fibroblasts to secrete keratinocyte growth factor (KGF), nidogen, and collagen IValpha-1. Meanwhile, keratinocytes secreted TGF-beta1 to promote fibroblast differentiation. Moreover, the enhanced proliferation and differentiation of keratinocytes were favorable for skin-implant integration. PMID- 28575987 TI - Y-shaped methoxy poly (ethylene glycol)-block-poly (epsilon-caprolactone)-based micelles for skin delivery of ketoconazole: in vitro study and in vivo evaluation. AB - Ketoconazole is a hydrophobic broad-spectrum antifungal agent for skin infection therapy. In order to develop topical formulation of ketoconazole for improving its selective skin deposition and water-solubility, ketoconazole-loaded Y-shaped monomethoxy poly(ethylene glycol)-block-poly(E-caprolactone) micelles were prepared through thin-film hydration method with high entrapment efficiency (96.1+/-0.76%) and small particle (about 58.66nm). The drug-loaded micelles showed comparative in vitro antimicrobial activity with KET cream. In ex in vivo skin deposition and permeation study, ketoconazole-loaded micelles provided skin accumulation higher than marketed ketoconazole cream without obvious permeation in the whole period. Fluorescence microscopy study and histopathological study demonstrated the copolymeric micelles' penetrating into skin in depth due to its capability of weakening the barrier function of stratum corneum. In vivo skin deposition parameters further confirmed high skin deposition of drug-loaded micelles (AUC(0-t)=396.16MUg.h/cm2) over marketed ketoconazole cream (AUC(0 t)=250.03MUg.h/cm2). Meanwhile, in vivo pharmacokinetic parameters proved that ketoconazole-loaded micelles reduced ketoconazole's distribution in blood in comparison with the cream (AUC(0-t)=93,028.00MUg.h/L vs AUC(0 t)=151,714.00MUg.h/L), meaning lower possibility of its systemic unwanted effects in the skin fungal infection treatment. The results suggested that the copolymeric micelles can be adopted for specific delivering ketoconazole into skin for fungal infection cure. PMID- 28575988 TI - An evaluation of colloidal and crystalline properties of CaCO3 nanoparticles for biological applications. AB - Biodegradable calcium carbonate carriers are a promising and safe nanoparticle platform which might enable various applications as an engineered nanomaterial in health care, food and cosmetics. However, engineered nanoparticles can exhibit new forms of toxicity that must be carefully evaluated before being widely adopted in consumer products or novel drug delivery systems. To this end, we studied four common calcium carbonate particle systems (calcite nanoparticles, amorphous sub-micrometer and vaterite sub-micrometer and micrometer particles) and compared their behavior in biological medium and in cell culture experiments. The thermodynamically stable calcite phase is shown to maintain its morphological features as no phase transformation occurs. Size- and time-dependent phase transformation of the less stable vaterite particles are observed within 96h in cell medium. The protein serum albumin can be an effective inhibitor of phase transition and it is shown to improve colloidal stability. The impact of the biological environment goes beyond protein-corona formation, as we observed rapid dissolution of amorphous particles in high ionic strength cell medium, but not in Millipore water. Cellular responses of human osteoblasts against CaCO3 particles indicate that increased intracellular calcium ions improve viability and that particle internalization is not size-dependent. Useful insights for designing CaCO3-based delivery systems are provided and also corroborate to the idea that intrinsic material properties as well as environmental conditions are of relevance for the successful implementation of dispersed CaCO3 particles in drug delivery systems and in other applications. PMID- 28575989 TI - Highly water-soluble, pH sensitive and biocompatible PAMAM 'dendrizyme' to maintain catalytic activity in complex medium. AB - The dendrimer based synthetic mimetic enzyme has been drawing great attention. However, this mimetic enzyme is different from the natural enzymes, which are pH sensitive, biocompatible and keep their catalytic activity in biological complex medium. A single zwitterionic layer composed by primary amine and carboxyl groups may be a useful method to obtain these properties. Herein, we report a novel facile method to prepare a mimetic enzyme. The complexes of generation 5 poly(amido amine) dendrimers (G5 PAMAM) with free hemin (G5Hs) were modified by the maleic anhydride and cysteamine. Results showed that the mimetic enzymes (G5HMCs) had pH sensitivity and good stability by varying the pH from 4 to 9, while significant precipitation was observed for free hemin at pH5 after two days. The G5HMC (3:1) showed optimal catalytic activity at its isoelectric point. Furthermore, G5HMCs displayed excellent biocompatibility. The G5HMCs incubated with fibrinogen were stable for 24h, while G5Hs immediately formed large aggregates. G5HMC (3:1 2mg/mL) displayed little cytotoxicity with HeLa cells or A549 cells for 24h, while G5H (3:1) had serious cytotoxicity, which was also demonstrated by cell morphology observation. At last, G5HMCs fully preserved their catalytic activity in bovine serum albumin (BSA) solution compared with phosphate buffer saline (PBS) solution, while hemin decreased to 73.5-81.5% catalytic activity in BSA solution, which was caused by the less interaction with BSA for G5HMCs than free hemin. The surface functionalization schemes described in this report would represent a versatile method to prepare water-soluble, pH sensitive, biocompatible, and efficient artificial enzymes for biomedical related applications. PMID- 28575990 TI - Effects of curcumin-loaded PLGA nanoparticles on the RG2 rat glioma model. AB - BACKGROUND: Curcumin, the active ingredient of turmeric, has a remarkable antitumor activity against various cancers, including glioblastoma. However, it has poor absorption and low bioavailability; thus, to cross the blood-brain barrier and reach tumor tissue, it needs to be transferred to tumor site by special drug delivery systems, such as nanoparticles. OBJECTIVE: We aimed to evaluate the antitumor activity of curcumin on glioblastoma tissue in the rat glioma-2 (RG2) tumor model when it is loaded on poly(lactic-co-glycolic acid)-1,2 distearoyl-glycerol-3-phospho-ethanolamine-N-[methoxy (polyethylene glycol)-2000] ammonium salt (PLGA-DSPE-PEG) hybrid nanoparticles. METHODS: Glioblastoma was induced in 42 adult female Wistar rats (250-300g) by RG2 tumor model. The curcumin-loaded nanoparticles were injected by intravenous (n=6) or intratumoral route (n=6). There were five control groups, each containing six rats. First control group was not applied any treatment. The remaining four control groups were given empty nanoparticles or curcumin alone by intravenous or intratumoral route, respectively. The change in tumor volume was assessed by magnetic resonance imaging and histopathology before and 5days after drug injections. RESULTS: Tumor size decreased significantly after 5days of intratumoral injection of curcumin-loaded nanoparticle (from 66.6+/-44.6 to 34.9+/-21.7mm3, p=0.028), whereas it significantly increased in nontreated control group (from 33.9+/-21.3 to 123.7+/-41.1mm3, p=0.036) and did not significantly change in other groups (p>0.05 for all). CONCLUSION: In this in vivo experimental model, intratumoral administration of curcumin-loaded PLGA-DSPE-PEG hybrid nanoparticles was effective against glioblastoma. Curcumine-loaded nanoparticles may have potential application in chemotherapy of glioblastoma. PMID- 28575991 TI - Electrospun PCL/gelatin composite nanofiber structures for effective guided bone regeneration membranes. AB - Guided bone regeneration (GBR) membranes have been proved of great benefit for bone tissue engineering due to the improvement of cell attachment and proliferation. To develop GBR membranes with better biocompatibility and more proper degradation ability, here we fabricated polycaprolactone (PCL, polymer)/gelatin (protein) hybrid nanofibrous GBR membranes via electrospinning, followed by crosslinking with genipin. Acetic acid (HAc) was utilized to resolve the phase separation of PCL and gelatin, therefore homogeneous PCL/gelatin hybrid nanofibers with different ratios were successfully prepared. FTIR, XPS, TGA, DSC results proved that the proportion of PCL and gelatin in the as-spun nanofiber membranes could be simply adjusted by changing the weight ratio of PCL and gelatin in the spinning solution. SEM and AFM images demonstrated that all the nanofibers possessed uniform and smooth structures both in two dimension (2D) and three dimension (3D). The mechanical tests showed that these nanofibers exhibited appropriate tensile and strength properties, which were suitable for bone tissue engineering. CCK-8 and SEM images revealed that all the membranes were biocompatible to MC3T3-e1 cells. In addition, the in vitro osteogenesis characterizations, alizarin red in normal medium and osteogenesis medium, indicated that the nanofibers could promote bone formation. Therefore, all these results could suggest that our design of electrospun polymer/protein nanofiber membranes was effective for guided bone regeneration. PMID- 28575992 TI - Fabrication of superhydrophobic coating for preventing microleakage in a dental composite restoration. AB - Superhydrophobic coatings were successfully fabricated by photo-crosslinked polyurethane (PU) and organic fluoro group-functionalized SiO2 nanoparticles (F SiO2 NPs), and were introduced for preventing microleakage in a dental composite restoration. The F-SiO2 NPs possessed low surface energy and the PU can not only improve the mechanical stability but also promote F-SiO2 NPs to form multiscale structure, which could facilitate the properties of the as-prepared superhydrophobic coating by synergetic effect. The morphology and properties of the resulted superhydrophobic coatings with different PU/F-SiO2 ratios were studied using 1H NMR spectrum, fourier transform infrared spectra, scanning electron microscopy, atomic force microscopy and UV-vis spectrophotometry. The results showed that the superhydrophobic coatings with low PU/F-SiO2 ratio (1:3) possessed excellent hierarchical papillae structure with trapped air pockets, high contact angle (160.1 degrees ), low sliding angle (<1 degrees ) and good transparency. Additionally, MTT experiments results certified the prominent cell viability and biocompatibility for clinical application. Based on its fantastically superhydrophobic property, the as-prepared superhydrophobic coatings effectively prevented water permeation in resin composite restoration evaluation. This research may provide an effective method to solve the problem of microleakage and will efficiently increase the success rate of dental composite restorations. PMID- 28575993 TI - Graphene oxide nanoribbons as nanomaterial for bone regeneration: Effects on cytotoxicity, gene expression and bactericidal effect. AB - Graphene oxide nanoribbons (O-GNR) surges as an interesting nanomaterial for biomedical applications due to feasibility to incorporate functional groups and possible bactericidal properties. Herein, high concentrations of O-GNR were biologically evaluated using human osteoblast cells and gram positive and negative bacteria. Briefly, our goal were to evaluate: (1) synthetic pathway, (2) characterization and (3) effects of O-GNR composition and structural factors as a new approach for biomedical applications. For this, O-GNR were produced combining chemical vapor deposition and oxygen plasma treatment of multiwalled carbon nanotubes. Then, we analyzed the bioactivity, cell viability, osteogenic differentiation, matrix mineralization, mRNA levels of the five genes related direct to bone repair and bactericidal effect of high concentrations of O-GNR (10MUgmL-1, 100MUgmL-1, 200MUgmL-1 and 300MUgmL-1). Impressively, O-GNR showed no cytotoxic effects up to a concentration of 100MUgmL-1 and no gene expression alteration when used in its dose. We also observed that S. aureus and E. coli bacteria are susceptible to damage when incubated with 100MUgmL-1 of O-GNR, showing approximately 50% of bacterial death. We consider that O-GNR displays attractive properties when used at a suitable dose, displaying bactericidal effect and apparently lacking to cause damages in the bone repair process. PMID- 28575994 TI - PLLA microcapsules combined with silver nanoparticles and chlorhexidine acetate showing improved antibacterial effect. AB - In this study, composite antibacterial microcapsules combining of two antibacterial agents: chlorhexidine acetate and silver nanoparticle were prepared. The chlorhexidine acetate was encapsulated inside of the microcapsules and nano-sized silver particles were modified on the surface of microcapsules by electrostatic adsorption methods. Results show that this method decreases the silver usage dramatically, and promises a sustained antibacterial effect >30days. These microcapsules can also be modified on the surface of polymer films easily, which demonstrated the potential in functionalizing the implanted materials with antibacterial property. PMID- 28575995 TI - Improvement of adhesion and proliferation of mouse embryonic stem cells cultured on ozone/UV surface-modified substrates. AB - Culturing pluripotent stem cells effectively requires feeder cell layers or cell adhesion matrix coating. However, the feeder cell layers or animal-derived factors have to be removed to apply the pluripotent stem cells as resources for regenerative medicine. To enable xeno-free culture conditions, we focused on the UV/ozone surface treatment technique for polystyrene cell culture substrates to improve the adhesion and proliferation of pluripotent stem cells. In this study, as a fundamental research for the feeder- and matrix coating-free culture system for embryonic stem cells (ESCs), mouse ESCs were cultured on UV/ozone-modified polystyrene substrates without feeder layers. We observed that UV/ozone surface modified polystyrene substrates made it possible to culture mESCs under feeder free conditions without any chemical treatment for the substrates. PMID- 28575996 TI - A gelatin composite scaffold strengthened by drug-loaded halloysite nanotubes. AB - Mechanical properties and anti-infection are two of the most concerned issues for artificial bone grafting materials. Bone regeneration porous scaffolds with sustained drug release were developed by freeze-drying the mixture of nanosized drug-loaded halloysite nanotubes (HNTs) and gelatin. The scaffolds showed porous structure and excellent biocompatibility. The mechanical properties of the obtained composite scaffolds were enhanced significantly by HNTs to >300%, comparing to those of gelatin scaffold, and match to those of natural cancellous bones. The ibuprofen-loaded HNTs incorporated in the scaffolds allowed extended drug release over 100h, comparing to 8h when directly mixed the drug into the gelatin scaffold. The biological properties of the composite scaffolds were investigated by culturing MG63 cells on them. The HNTs/gelatin scaffolds with excellent mechanical properties and sustained drug release could be a promising artificial bone grating material. PMID- 28575997 TI - Multimodal nanoporous silica nanoparticles functionalized with aminopropyl groups for improving loading and controlled release of doxorubicin hydrochloride. AB - The purpose of this study was to develop amino modified multimodal nanoporous silica nanoparticles (M-NSNs-NH2) loaded with doxorubicin hydrochloride (DOX), intended to enhance the drug loading capacity and to achieve controlled release effect. M-NSNs were functionalized with aminopropyl groups through post synthesis. The contribution of large pore sizes and surface chemical groups on DOX loading and release were systemically studied using transmission electron microscope (TEM), nitrogen adsorption/desorption measurement, Fourier transform infrared spectroscopy (FTIR), zeta potential analysis, X-ray photoelectron spectroscopy (XPS) and ultraviolet spectrophotometer (UV). The results demonstrated that the NSNs were functionalized with aminopropyl successfully and the DOX molecules were adsorbed inside the nanopores by the hydrogen bonding. The release performance indicated that DOX loaded M-NSNs significantly controlled DOX release, furthermore DOX loaded M-NSNs-NH2 performed slower controlled release, which was mainly attributed to its stronger hydrogen bonding forces. As expected, we developed a novel carrier with high drug loading capacity and controlled release for DOX. PMID- 28575998 TI - Cellular internalisation kinetics and cytotoxic properties of statistically designed and optimised neo-geometric copper nanocrystals. AB - This study aimed to highlight a statistic design to precisely engineer homogenous geometric copper nanoparticles (CuNPs) for enhanced intracellular drug delivery as a function of geometrical structure. CuNPs with a dual functionality comprising geometric attributes for enhanced cell uptake and exerting cytotoxic activity on proliferating cells were synthesized as a novel drug delivery system. This paper investigated the defined concentrations of two key surfactants used in the reaction to mutually control and manipulate nano-shape and optimisation of the geometric nanosystems. A statistical experimental design comprising a full factorial model served as a refining factor to achieve homogenous geometric nanoparticles using a one-pot method for the systematic optimisation of the geometric CuNPs. Shapes of the nanoparticles were investigated to determine the result of the surfactant variation as the aim of the study and zeta potential was studied to ensure the stability of the system and establish a nanosystem of low aggregation potential. After optimisation of the nano-shapes, extensive cellular internalisation studies were conducted to elucidate the effect of geometric CuNPs on uptake rates, in addition to the vital toxicity assays to further understand the cellular effect of geometric CuNPs as a drug delivery system. In addition to geometry; volume, surface area, orientation to the cell membrane and colloidal stability is also addressed. The outcomes of the study demonstrated the success of homogenous geometric NP formation, in addition to a stable surface charge. The findings of the study can be utilized for the development of a drug delivery system for promoted cellular internalisation and effective drug delivery. PMID- 28575999 TI - Sterilization of silicone-based hydrogels for biomedical application using ozone gas: Comparison with conventional techniques. AB - Sterilization of hydrogels is challenging due to their often reported sensitivity to conventional methods involving heat or radiation. Although aseptic manufacturing is a possibility, terminal sterilization is safer in biological terms, leading to a higher overall efficiency, and thus should be used whenever it is possible. The main goal of this work was to study the applicability of an innovative ozone gas terminal sterilization method for silicone-based hydrogels and compare its efficacy and effects with those of traditional sterilization methods: steam heat and gamma irradiation. Ozone gas sterilization is a method with potential interest since it is reported as a low cost green method, does not leave toxic residues and can be applied to thermosensitive materials. A hydrogel intended for ophthalmological applications, based on tris(trimethylsiloxy)silyl] propyl methacrylate, was prepared and extensively characterized before and after the sterilization procedures. Alterations regarding transparency, swelling, wettability, ionic permeability, friction coefficient, mechanical properties, topography and morphology and chemical composition were monitored. Efficacy of the ozonation was accessed by performing controlled contaminations and sterility tests. In vitro cytotoxicity testes were also performed. The results show that ozonation may be applied to sterilize the studied material. A treatment with 8 pulses allowed sterilizing the material with bioburdens<=103CFU/mL, preserving all the studied properties within the required known values for contact lenses materials. However, a higher exposure (10 pulses) led to some degradation of the material and induced mild cytotoxicity. Steam heat sterilization led to an increase of swelling capacity and a decrease of the water contact angle. Regarding gamma irradiation, the increase of irradiation dose led to an increase of the friction coefficient. The higher dose (25kGy) originated surface degradation and affected the mechanical properties of the hydrogel by inducing a significant increase of the Young's modulus. Overall, the results show that ozonation may be considered as a valid and promising alternative for the sterilization of silicon-based hydrogels for biomedical applications. PMID- 28576001 TI - Doped tricalcium phosphate bone tissue engineering scaffolds using sucrose as template and microwave sintering: enhancement of mechanical and biological properties. AB - beta-tricalcium phosphate (beta-TCP) is a widely used biocompatible ceramic in orthopedic and dental applications. However, its osteoinductivity and mechanical properties still require improvements. In this study, porous beta-TCP and MgO/ZnO TCP scaffolds were prepared by the thermal decomposition of sucrose. Crack-free cylindrical scaffolds could only be prepared with the addition of MgO and ZnO due to their stabilization effects. Porous MgO/ZnO-TCP scaffolds with a density of 61.39+/-0.66%, an estimated pore size of 200MUm and a compressive strength of 24.96+/-3.07MPa were prepared by using 25wt% sucrose after conventional sintering at 1250 degrees C. Microwave sintering further increased the compressive strength to 37.94+/-6.70MPa, but it decreased the open interconnected porosity to 8.74+/ 1.38%. In addition, the incorporation of polycaprolactone (PCL) increased 22.36+/ 3.22% of toughness while maintaining its compressive strength at 25.45+/-2.21MPa. Human osteoblast cell line was seeded on scaffolds to evaluate the effects of MgO/ZnO and PCL on the biological property of beta-TCP in vitro. Both MgO/ZnO and PCL improved osteoinductivity of beta-TCP. PCL also decreased osteoblastic apoptosis due to its particular surface chemistry. This novel porous MgO/ZnO-TCP scaffold with PCL shows improved mechanical and biological properties, which has great potential in bone tissue engineering applications. PMID- 28576000 TI - The effect of solvents and hydrophilic additive on stable coating and controllable sirolimus release system for drug-eluting stent. AB - Various drug-eluting stents (DESs) have been developed to prevent restenosis after stent implantation. However, DES still needs to improve the drug-in-polymer coating stability and control of drug release for effective clinical treatment. In this study, the cobalt-chromium (CoCr) alloy surface was coated with biodegradable poly(D,L-lactide) (PDLLA) and sirolimus (SRL) mixed with hydrophilic Pluronic F127 additive by using ultrasonic spray coating system in order to achieve a stable coating surface and control SRL release. The degradation of PDLLA/SRL coating was studied under physiological solution. It was found that adding F127 reduced the degradation of PDLLA and improved the coating stability during 60days. The effects of organic solvent such as chloroform and tetrahydrofuran (THF) on the coating uniformity were also examined. It was revealed that THF produced a very smooth and uniform coating compared to chloroform. The patterns of in vitro drug release according to the type of organic solvent and hydrophilic additive proposed the possibility of controllable drug release design in DES. It was found that using F127 the drug release was sustained regardless of the organic solvent used. In addition, THF was able to get faster and controlled release profile when compared to chloroform. The structure of SRL molecules in different organic solvents was investigated using ultra-small angle neutron scattering. Furthermore, the structure of SRL is concentration-dependent in chloroform with tight nature under high concentration, but concentration-independent in THF. These results strongly demonstrated that coating stability and drug release patterns can be changed by physicochemical properties of various parameters such as organic solvents, additive, and coating strategy. PMID- 28576002 TI - A study of degradation resistance and cytocompatibility of super-hydrophobic coating on magnesium. AB - Calcium stearate based super-hydrophobic coating was deposited on plasma electrolytic oxidation (PEO) pre-treated magnesium substrate. The pre-treated magnesium and super-hydrophobic coating covered sample were characterized by scanning electron microscopy, X-ray diffraction and electrochemical corrosion measurements. The cytocompatibility and degradation resistance of magnesium, pre treated magnesium and super-hydrophobic coating were analysed in terms of cell adhesion and osteoblast differentiation. The results indicate that the calcium stearate top coating shows super-hydrophobicity and that the surface is composed of micro/nanostructure. The super-hydrophobic coating covered sample shows higher barrier properties compared with the PEO pre-treated magnesium and bare magnesium. Human osteoblast proliferation, but not differentiation is enhanced by the PEO coating. Contrary, the super-hydrophobic coating reduces proliferation, but enhances differentiation of osteoblast, observable by the formation of hydroxyapatite. The combination of corrosion protection and cell reaction indicates that this system could be interesting for biomedical applications. PMID- 28576003 TI - Correlating cytotoxicity to elution behaviors of composite resins in term of curing kinetic. AB - Cytotoxicity of photocurable composite resins is a key issue for their safe use in dental restoration. Curing kinetic and elution behaviors of the composite resin would have decisive effects on its cytotoxicity. In this study, composite resins composed of bisphenol-glycidyl dimethacrylate (Bis-GMA), triethyleneglycol dimethacrylate (TEGDMA), camphorquinone (CQ), N,N-dimethylaminoethyl methacrylate (DMAEMA) and barium glass powders were prepared by setting the photoinitiators CQ/DMAEMA at 0.5wt%, 1wt% or 3wt% of the total weight of Bis-GMA/TEGDMA. The ratio of Bis-GMA/TEGDMA was 6:4, the ratio of CQ/DMAEMA was 1:1, and the incorporated inorganic powder was 75wt%. Then, curing kinetics were studied by using real-time Fourier transform infrared spectroscopy (FTIR) and photo-DSC (differential scanning calorimeter). Elution behaviors in both ethanol solution and deionized water were monitored by using liquid chromatogram/mass spectrometry (LC/MS). Cytotoxicity was evaluated by in vitro culture of L929 fibroblasts. Finally, they were all analyzed and correlated in terms of initiator contents. It was found that the commonly used 0.5wt% of photoinitiators was somewhat insufficient in obtaining composite resin with low cytotoxicity. PMID- 28576004 TI - Preparation of poly(lactic-co-glycolic acid) and chitosan composite nanocarriers via electrostatic self assembly for oral delivery of insulin. AB - To improve insulin bioavailability and overcome multiple barriers for oral delivery of insulin, the composite nanocarriers (PLGA/FA-CS) prepared from poly(lactide-co-glycoside) (PLGA) and folic acid modified chitosan (FA-CS) were fabricated via electrostatic self-assembly method. The resultant composite nanocarriers exhibited low cytotoxicity against HT-29 cells and excellent stability against protein solution. The chemical stability of loaded insulin against digestive enzyme were established in presence of simulated gastric fluid (SGF) containing pepsin and simulated intestinal fluid (SIF) containing pancreatin, respectively. The uptake behavior of HT-29 cells was evaluated by confocal laser scanning microscope. After oral administration to the diabetic rats, an effective hypoglycemic effect was obtained compared with subcutaneous injection of insulin. This work suggests that the as-prepared composite nanocarriers may be a promising drug delivery system for oral administration of insulin and other biomacromolecules. PMID- 28576005 TI - Protein-directed gold nanoparticles with excellent catalytic activity for 4 nitrophenol reduction. AB - To explore high-performance noble metal nanomaterials for the reduction of the biotoxin 4-nitrophenol (4-NP) in medicine, we developed a green synthesis strategy of bovine serum albumin-stabilized Au nanoparticles (Au@BSA NPs). The as synthesized Au@BSA NPs were characterized by ultraviolet-visible absorption spectrum, fourier transformed infrared spectroscopy, transmission electron microscopy and dynamic light scattering. The functional bio-nanocomposites showed Au-protein core-shell structure and uniform distribution, and their sizes were dependent on the additive amount of HAuCl4. Interestingly, Au@BSA NPs showed remarkable catalytic activity for the reduction of 4-NP into 4-aminophenol in the presence of sodium borohydride. Due to the introduction of Au@BSA NPs, the reduction reaction could be conducted at ambient temperature and pressure without any additional conditions. Moreover, the reduction rate was closely related to the sizes of NPs and reaction temperature, and the catalytic mechanism was verified to follow the pseudo-first-order kinetics. Due to the environmentally friendly synthesis process and green reduction strategy of 4-NP, Au@BSA NPs would show great potential in governance of the biotoxin in medicine. PMID- 28576006 TI - The role of welding techniques in the biomechanical behavior of implant-supported prostheses. AB - This in vitro study investigated the role of welding techniques of implant supported prostheses in the 2D and 3D marginal misfits of prosthetic frameworks, strain induced on the mini abutment, and detorque of prosthetic screws. The correlations between the analyzed variables were also investigated. Frameworks were cast in commercially pure titanium (cp-Ti). A marginal misfit of 200MUm was simulated in the working models (control group) (n=20). The 2D marginal misfit was analyzed according to the single-screw test protocol using a precision optical microscope. The 3D marginal misfit was performed by X-ray microtomography. Strain gauge analysis was performed to investigate the strain induced on the mini abutment. A digital torque meter was used for analysis of the detorque and the mean value was calculated for each framework. Afterwards, the frameworks were divided into two experimental groups (n=10): Laser (L) and TIG (T). The welding techniques were performed according to the following parameters: L (390V/9ms); T (36A/60ms). The L and T groups were reevaluated according to the marginal misfit, strain, and detorque. The results were submitted to one-way ANOVA followed by Tukey's HSD test and Person correlation analysis (alpha=0.05). Welding techniques statistically reduced the 2D and 3D marginal misfits of prosthetic frameworks (p<0.001), the strain induced on the mini abutment replicas (p=0.006), and improved the screw torque maintenance (p<0.001). Similar behavior was noted between L and T groups for all dependent variables (p>0.05). Positive correlations were observed between 2D and 3D marginal misfit reading methods (r=0.943, p<0.0001) and between misfit and strain (2D r=0.844, p<0.0001 and 3D r=0.864, p<0.0001). Negative correlation was observed between misfit and detorque (2D r=-0.823, p=0.003 and 3D r=-0.811, p=0.005). In conclusion, the welding techniques improved the biomechanical behavior of the implant-supported system. TIG can be an acceptable and affordable technique to reduce the misfit of 3-unit Ti frameworks. PMID- 28576007 TI - A dual-layer macro/mesoporous structured TiO2 surface improves the initial adhesion of osteoblast-like cells. AB - A dual-layer TiO2 surface with hierarchical macro and mesoporous structure was prepared by a combinational approach of micro-arc oxidation followed by evaporation-induced self-assembly of nano-crystallites. The mesoporous layer contains pores with an average size of <10nm and consists of anatase TiO2 nanocrystallites. The dual-layer hierarchical macro/mesoporous structured TiO2 surface improves the hydrophilicity and fibronectin adsorption ability in comparison with the sole macroporous or smooth TiO2 surface. With the formation of an additional mesoporous layer on macroporous TiO2 surface, the attached number of human osteogenic sarcoma cells (SaOS-2) increases in the initial incubation of 4h but it does not show significant difference after 24h compared to that attached on the macroporous or smooth surfaces. Whereas, it was noticed that SaOS-2 cells have larger spread area and more stress fibers on the macro/mesoporous structured surface than those on the other surfaces. To understand the intracellular mechanism of the initial cell adhesion on the macro/mesoporous surface, the Rho/ROCK pathway was investigated to reveal the topography-induced biological functions by introducing the ROCK inhibitor Y-27632 during cell culture. In the presence of Y-27632, cells on the macroporous surface and macro/mesoporous surface both show stellate appearance, with poor assembly stress fibers and long cell membrane protrusions. Cells on the smooth surface have larger spread areas compared to the former two surfaces. And the attached cells significantly reduced but there are no differences among the three surfaces. It reveals that the ROCK inhibitor invalidates the promotion of initial cell adhesion on the macro/mesoporous structure. This study may shed light on the mechanism behind the enhancement effect of macro/mesoporous structure for initial cell adhesion. PMID- 28576008 TI - A novel chondroitin sulfate decorated nano platinum for the treatment of osteoarthritis. AB - The present work showed the biofabrication of platinum nanoparticles (PtNPs) using chondroitin sulfate via a facile, eco-friendly route by just heating leaf extract and H2PtCl6.6H2O (Chloroplatinic acid) solution which gave a brown colored PtNPs dispersion. The assynthesized PtNPs were analyzed by using Transmission electron microscopy (TEM), Energy dispersive spectroscopy (EDX), X ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and Selected area electron diffraction (SAED). TEM analysis showed PtNPs of irregular shape with a size existed in the range from 3 to 5nm. From zeta potential studies it is found the surface charge of the synthesized PtNPs is negative (-25.6mV). FTIR analysis and zeta potential measurements of PtNPs confirm the capping of chondroitin sulfate onto the surface of nanoparticles. XRD and SAED pattern revealed the crystalline nature of synthesized nanoparticles. Further, the in vitro cytotoxicity of PtNPs against the osteoarthritis chondrocytes showed their biocompatibility, hence the obtained nanoparticles may have future scope in the treatment of osteoarthritis. Also, the present approach is green alternative to the traditionally available chemical methods that are currently been used now a days using chemical reagents such that are hazardous to human and environment. PMID- 28576009 TI - Low toxicity superparamagnetic magnetite nanoparticles: One-pot facile green synthesis for biological applications. AB - Superparamagnetic magnetite nanoparticles have been synthesized by a highly reproducible polyvinyl alcohol (PVA)-based modified sol-gel process using water as the only solvent. The synthesis method has proven to be effective, time and cost saving and environmental friendly, resulting in PVA-coated magnetite nanoparticles as direct product from the synthesis, without any special atmosphere or further thermal treatment. X-ray diffraction and transmission electron microscopy revealed that the biocompatible PVA-coating prevents the nanoparticle agglomeration, giving rise to spherical crystals with sizes of 6.8nm (as-cast) and 9.5nm (heat treated) with great control over size and shape with narrow size distribution. Complementary compositional and magnetic characterizations were employed in order to study the surface chemistry and magnetic behavior of the samples, respectively. Cytotoxicity endpoints including no observed adverse effect concentration (NOAEC), 50% lethal concentration (LC50) and total lethal concentration (TLC) of the tested materials on cell viability were determined after 3, 24 and 48h of exposure. The PVA coating improved the biocompatibility of the synthesized magnetite nanoparticles showing good cell viability and low cytotoxicity effects on the MTT assay performed on BHK cells. Preliminary assessment of nanoparticles in vivo effects, performed after 48h on Balb/c mice, exposed to a range of different sub-lethal doses, showed their capacity to penetrate in liver and kidneys with no significant morphological alterations in both organs. PMID- 28576010 TI - Dynamic adhesive environment alters the differentiation potential of young and ageing mesenchymal stem cells. AB - Engineering dynamic stem cell niche-like environment offers opportunity to obtain better control of the fate of stem cells. We identified, for the first time, that periodic changes in the adhesive environment of human adipose derived mesenchymal stem cells (ADSCs) alters dramatically their asymmetric division but not their ability for symmetric renewal. Hereby, we used smart thermo-responsive polymer (PNIPAM) to create a dynamic adhesive environment for ADSCs by applying periodic temperature cycles to perturb adsorbed adhesive proteins to substratum interaction. Cumulative population doubling time (CPDT) curves showed insignificant decline in the symmetric cell growth studied for up to 13th passages accompanied with small changes in the overall cell morphology and moderately declined fibronectin (FN) matrix deposition probably as a functional consequence of ADSCs ageing. However, a substantial alteration in the differentiation potential of ADSCs from both early and late passages (3rd and 14th, respectively) was found when the cells were switched to osteogenic differentiation conditions. This behavior was evidenced by the significantly altered alkaline phosphatase activity and Ca deposition (Alizarin red) assayed at 3, 14 and 21day in comparison to the control samples of regular TC polystyrene processed under same temperature settings. PMID- 28576011 TI - Design and characterization of dexamethasone-loaded poly (glycerol sebacate)-poly caprolactone/gelatin scaffold by coaxial electro spinning for soft tissue engineering. AB - The aim of this research was to fabricate dexamethasone (Dex)-loaded poly (glycerol sebacate) (PGS)-poly (caprolactone) (PCL)/gelatin (Gt) (PGS-PCL/Gt-Dex) fibrous scaffolds in the form of core/shell structure which have potential application in soft tissues. In this regard, after synthesize and characterizations of PGS, PGS-PCL and gelatin fibrous scaffolds were separately developed in order to optimize the electrospinning parameters. In the next step, coaxial electrospun fibrous scaffold of PGS-PCL/Gt fibrous scaffold with PGS-PCL as core and Gt as shell was developed and its mechanical, physical and chemical properties were characterized. Moreover, degradability, hydrophilicity and biocompatibility of PGS-PCL/Gt fibrous scaffold were evaluated. In addition, Dex was encapsulated in PGS-PCL/Gt fibrous scaffold and drug release was assessed for tissue engineering application. Results demonstrated the formation of coaxial fibrous scaffold with average porosity of 79% and average fiber size of 294nm. Moreover, PGS-PCL/Gt fibrous scaffold revealed lower elastic modulus, ultimate tensile and ultimate elongation than those of PGS-PCL scaffold and more close to mechanical properties of natural tissue. Furthermore, lower contact angle of PGS PCL/Gt than that of PGS-PCL demonstrated improved surface hydrophilicity of scaffold. DEX release was sustained over a period time of 30days from the scaffolds via three steps consisting of an initial burst release, secondary linear phase release pattern with slower rate over 20days followed by an apparent zero-order release phase. MTT observations demonstrated that there was no evidence of toxicity in the samples with and without Dex. Our findings indicated that core/shell PGS-PCL/Gt-Dex fibrous could be used as a carrier for the sustained release of drugs relevant for tissue engineering which makes it appropriate for soft tissue engineering. PMID- 28576012 TI - Hyaluronic acid and carbon dots-gated hollow mesoporous silica for redox and enzyme-triggered targeted drug delivery and bioimaging. AB - In this work, a redox and enzyme dual-stimuli responsive drug delivery system (DDS) with tracking function (HMSN-SS-CDPEI@HA) based on carbon dots capped hollow mesoporous silica nanoparticles (HMSN) has been developed for targeted drug delivery. The positively charged CDPEI nanoparticles prepared by polyethylenimine (PEI) were grafted on the pore openings of HMSN through disulfide bonds and were used as "gatekeepers" to trap the drugs within the hollow cavity. The hyaluronic acid (HA), a natural polysaccharide, was further grafted on the surface of HMSN to realize targeted drug delivery, controlled drug release and improved the stability. Doxorubicin (DOX) was chosen as a model drug due to its wide clinical application. In vitro drug release profiles demonstrated that DOX-loaded HMSN-SS-CDPEI@HA exhibited redox and enzyme dual-responsive drug release property. In addition, the prepared HMSN-SS-CDPEI@HA exhibited excellent fluorescent properties and biocompatibility. Confocal laser scanning microscope (CLSM) and flow cytometry (FCM) illustrated that HMSN-SS-CDPEI@HA exhibited a higher cellular uptake via the CD44 receptor-mediated endocytosis by CD44 receptor over-expressed A549 cells than NIH-3T3 (receptor-negative) cells, leading to higher cytotoxicity against A549 cells than NIH 3T3 cells. This work suggested an exploration of dual-stimuli responsive as well as real-time imaging targeted drug delivery system based on HMSN and the prepared HMSN-SS-CDPEI@HA could be a promising platform for cancer therapy. PMID- 28576013 TI - The role of new zinc incorporated monetite cements on osteogenic differentiation of human mesenchymal stem cells. AB - beta-Tricalcium phosphate particles were sintered in the presence of different amounts (0-0.72mol) of zinc oxide (ZnO) to prepare zinc doped beta-TCP (Znbeta TCP) particles for further use in novel monetite (DCPA: CaHPO4) zinc incorporated bone cements with osteogenic differentiation potential towards human mesenchymal stem cells (hMSCs). XRD analysis of zinc incorporated cements prepared with beta TCP reagent particles doped with different amount of ZnO (i.e. 0.03, 0.09 and 0.18mol ZnO) revealed the presence of unreacted Znbeta-TCP and monetite. Furthermore, it was shown that zinc ions preferentially occupied the beta-TCP crystal lattice rather than the monetite one. Release experiments indicated a burst release of ions from the different fabricated cements during the first 24h of immersion with zinc concentrations ranging between 85 and 100% of the total concentration released over a period of 21days. Cell proliferation significantly increased (P<0.05) on zinc incorporated monetite respect to control samples (Zinc free cement) at 7 and 14days post seeding. The expression of Runx-2 was significantly up regulated (P<0.05) in the case of cells seeded on monetite prepared with beta-TCP doped with 0.03 moles of ZnO. On the other hand, the cell mineralization as well as the expression of osteogenic marker genes ALP and OSC decreased significantly (P<0.05) at 14days post cell seeding. In conclusion, these results suggest that the zinc ions released from the cements during the first 24h of culture played a critical role in regulating the osteogenic differentiation of hMSCs. PMID- 28576014 TI - Surface characteristics of bioactive Ti fabricated by chemical treatment for cartilaginous-integration. AB - Artificial hip joints are generally expected to fail due to wear after approximately 15years and then have to be replaced by revision surgery. If articular cartilage can be integrated onto the articular surfaces of artificial joints in the same way as osseo-integration of titanium dental implants, the wear of joint implants may be reduced or prevented. However, very few studies have focused on the relationship between Ti surface and cartilage. To explore the possibility of cartilaginous-integration, we fabricated chemically treated Ti surfaces with H2O2/HCl, collagen type II and SBF, respectively. Then, we evaluated surface characteristics of the prepared Ti samples and assessed the cartilage formation by culturing chondrocytes on the Ti samples. When oxidized Ti was immersed in SBF for 7days, apatite was formed on the Ti surface. The surface characteristics of Ti indicated that the wettability was increased by all chemical treatments compared to untreated Ti, and that H2O2/HCl treated surface had significantly higher roughness compared to the other three groups. Chondrocytes produced significantly more cartilage matrix on all chemically treated Ti surfaces compared to untreated Ti. Thus, to realize cartilaginous integration and to prevent wear of the implants in joints, application of bioactive Ti formed by chemical treatment would be a promising and effective strategy to improve durability of joint replacement. PMID- 28576015 TI - Porous Nb-Ti-Ta alloy scaffolds for bone tissue engineering: Fabrication, mechanical properties and in vitro/vivo biocompatibility. AB - Porous Nb-Ti-Ta (at.%) alloys with the pore size of 100-600MUm and the porosity of 50%-80% were fabricated by the combination of the sponge impregnation technique and sintering method. The results revealed that the pores were well connected with three-dimensional (3D) network structure, which showed morphological similarity to the anisotropic porous structure of human bones. The results also showed that the alloys could provide the compressive Young's modulus of 0.11+/-0.01GPa to 2.08+/-0.09GPa and the strength of 17.45+/-2.76MPa to 121.67+/-1.76MPa at different level of porosity, indicating that the mechanical properties of the alloys are similar to those of human bones. Pore structure on the compressive properties was also discussed on the basis of the deformation mode. The relationship between compressive properties and porosity was well consistent with the Gibson-Ashby model. The mechanical properties could be tailored to match different requirements of the human bones. Moreover, the alloys had good biocompatibility due to the porous structure with higher surface, which were suitable for apatite formation and cell adhesion. In conclusion, the porous Nb-Ti-Ta alloy is potentially useful in the hard tissue implants for the appropriate mechanical properties as well as the good biocompatible properties. PMID- 28576016 TI - Gold nanoparticles embedded electropolymerized thin film of pyrimidine derivative on glassy carbon electrode for highly sensitive detection of l-cysteine. AB - This paper demonstrates the fabrication of novel gold nanoparticles incorporated poly (4-amino-6-hydroxy-2-mercaptopyrimidine) (Nano-Au/Poly-AHMP) film modified glassy carbon electrode and it is employed for highly sensitive detection of l cysteine (CYS). The modified electrode was characterized by scanning electron microscope (SEM), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). SEM images of modified electrode revealed the homogeneous distribution of gold nanoparticles on poly (4-amino-6-hydroxy-2 mercaptopyrimidine) thin film modified glassy carbon electrode. The modified electrode was successfully utilized for highly selective and sensitive determination of l-cysteine at physiological pH7.0. The present electrochemical sensor successfully resolved the voltammetric signals of ascorbic acid (AA) and l cysteine with peak separation of 0.510V. To the best of our knowledge, this is the first report of larger peak separation between AA and CYS. Wide linear concentration ranges (2MUM-500MUM), low detection limit (0.020MUM), an excellent reproducibility and stability are achieved for cysteine sensing with this Nano Au/Poly-AHMP/GCE. PMID- 28576017 TI - Preparation, optimization and property of PVA-HA/PAA composite hydrogel. AB - PVA-HA/PAA composite hydrogel is prepared by freezing-thawing, PEG dehydration and annealing method. Orthogonal design method is used to choose the optimization combination. Results showed that HA and PVA have the maximum effect on water content. PVA and freezing-thawing cycles have the maximum effect on creep resistance and stress relaxation rate of hydrogel. Annealing temperature and freezing-thawing cycles have the maximum effect on compressive elastic modulus of hydrogel. Comparing with the water content and mechanical properties of 16 kinds of combination, PVA-HA/PAA composite hydrogel with freezing-thawing cycles of 3, annealing temperature of 120 degrees C, PVA of 16%, HA of 2%, PAA of 4% has the optimization comprehensive properties. PVA-HA/PAA composite hydrogel has a porous network structure. There are some interactions between PVA, HA and PAA in hydrogel and the properties of hydrogel are strengthened. The annealing treatment improves the crystalline and crosslinking of hydrogel. Therefore, the annealing PVA-HA/PAA composite hydrogel has good thermostability, strength and mechanical properties. It also has good lubrication property and its friction coefficient is relative low. PMID- 28576018 TI - Modulation of the interface between polyester and spent coffee grounds in polysaccharide membranes: Preparation, cell proliferation, antioxidant activity and tyrosinase activity. AB - The structural, antioxidant and cytocompatibility properties of membranes prepared from polyhydroxyalkanoate (PHA) and spent coffee ground (SCG) blends (PHA/SCG) were studied. Acrylic acid-grafted PHA (PHA-g-AA) was used to enhance the desirable characteristics of these membranes, which had better tensile properties than the corresponding PHA/SCG membranes. The water resistance of the PHA-g-AA/SCG membranes was greater than that of the PHA/SCG membranes, and a cytocompatibility evaluation with mouse normal tail fibroblasts (FBs) indicated that both materials were nontoxic. Cell cycle assays of FBs on PHA/SCG and PHA-g AA/SCG membrane samples were not affected by the DNA content related to damage. Moreover, SCG enhanced the saccharide and polyphenol contents, and antioxidant properties, of the PHA-g-AA/SCG and PHA/SCG membranes. Therefore, we analysed the effects of these compounds' membranes on melanogenesis in B16-F10 melanoma cells. The results demonstrated that PHA/SCG and PHA-g-AA/SCG membranes reduced cellular tyrosinase activities in vitro. PMID- 28576019 TI - Electrochemical and nonenzymatic glucose biosensor based on MDPA/MWNT/PGE nanocomposite. AB - The nonenzymatic detection of glucose has been widely investigated in a variety of fields ranging from biomedical applications to ecological approaches. Among these fields, electrochemical methods have great advantages such as high electrocatalytic ability, high sensitivity, good selectivity and low-cost for the electrooxidation of glucose. Future trends on glucose sensing are nanostructured electrodes depending upon the development of nanotechnology. In this study, an electrochemical and nonenzymatic glucose sensor based on (E)-4-((5-methylthiazole 2-yl)diazenyl)-N-phenylaniline (MDPA)/multi-walled carbon nanotube (MWNT)/pencil graphite electrode (PGE) was performed. Electrochemical measurements were obtained using cyclic voltammetry and square wave voltammetry techniques, and characterization of surfaces was carried out using scanning electron microscope and electrochemical impedance spectroscopy techniques. The modification of PGE was made using MDPA and MWNT, and 10 cycles coating was used to prepare the proposed electrode. The effects of scan rate and pH on the peak potential and the peak current were determined. The limit of detection and linear range were calculated using various concentrations of glucose. The interference study was made using coexisting substances including metal ions such as Al3+, Cu2+, Fe3+ and ascorbic acid. PMID- 28576020 TI - Polymeric micelles self-assembled from amphiphilic polymers with twin disulfides used as siRNA carriers to enhance the transfection. AB - The sequence-defined polycationic polymers with or without Cys-Arg-Cys motifs conjugated with targeting and shielding segments were synthesized as siRNA carriers via native chemical ligation (NCL) reaction. After purification, the structures and physicochemical characteristics were determined by a variety of experimental techniques. The particle size of siRNA/CRC-polymer polyplex was much smaller than that of polyplex without CRC motifs. The buffer capacity and siRNA binding ability of CRC motifs modified polymers were significantly improved, resulting from the twin disulfides and hexatomic ring formulation. The critical micelle concentrations of the polymers were <10mg/L, indicating formation of polymeric micelles and sufficient stability of the system. The CRC motifs modified polymers with folate targeted ligands exhibited a strongly enhanced cellular uptake than the negative control and the unmodified analogues. The results of gene transfection showed that the folate-PEG-ligated polymer modified with CRC motifs had much better gene transfection compared to the alanine-ended control and other analogues. Furthermore, they showed barely cytotoxicity. By the way, there was no distinctly improvement for pDNA transfection. All above results suggested that folate-PEG-ligated polymers modified with CRC motifs and their self-assembly polymeric micelles could be promising non-viral siRNA carriers. PMID- 28576021 TI - Biosynthesis and characterization of gold nanoparticles: Kinetics, in vitro and in vivo study. AB - This study reports a facile, cost effective, nontoxic and eco-friendly method for the synthesis of gold nanoparticles. In this paper, leaf extract of Mentha piperita was successfully used to reduce chloroauric acid, leading to synthesis of gold nanoparticles (AuNPs). The synthesized nanoparticles were further characterized by UV-visible spectroscopy, Fourier transform infrared spectroscopy, dynamic light scattering, transmission electron microscopy and field emission scanning electron microscopy. Kinetics studies like effect of volume of leaf extract, precursor, pH, temperature for the synthesis of AuNPs were studied spectrophotometrically. Synthesized AuNPs were found to possess hexagon structure where size of nanoparticles was ~78nm in diameter. These biologically synthesized AuNPs exhibited significant activity against cancerous cell lines MDA-MB-231 and A549 and was compared with the normal 3T3-L1 cell line. Anti-inflammatory and analgesic activities were studied on a Wistar rat model to gauge the impact of AuNPs for a probable role in these applications. AuNPs gave positive results for both these activities, although the potency was less as compared to the standard drugs. These results suggested that the leaves extract of Mentha piperita is a very good bioreductant for the synthesis of AuNPs and have potential for various biomedical and pharmaceutical applications. PMID- 28576022 TI - A biomimetic Au@BSA-DTA nanocomposites-based contrast agent for computed tomography imaging. AB - Early detection of cancer is increasingly important for being considered to increase the survival rate in the treatment process. The past decades years have witnessed the great progress in the biological detection application of gold nanoparticles. Herein, we reported a facile one-pot synthesis process to obtain gold nanoparticles (Au@BSA) with bovine serum albumin (BSA) as a biotemplate following with conjugation of diatrizoic acid (DTA) for a potential X-ray computed tomography (CT) imaging contrast agent (Au@BSA-DTA). The as-prepared biomimetic material was characterized systematically by several techniques. It was shown that the prepared biomaterial is colloid stable under the tested range of pH and temperature. The cell cytotoxicity assay, hemolytic assay and cell morphology observation showed that Au@BSA-DTA has good biocompatibility and hemocompatibility at a concentration of Au even up to 80MUg/mL. Besides, the biomimetic material Au@BSA-DTA with double radiodense elements of Au and iodine displayed much stronger CT imaging effect compared with the traditional small molecule contrast agents, which paves the potential clinical application in cancer early diagnosis. PMID- 28576023 TI - Bioengineered porous composite curcumin/silk scaffolds for cartilage regeneration. AB - Articular cartilage repair is a challenge due to its limited self-repair capacity. Cartilage tissue engineering supports to overcome following injuries or degenerative diseases. Herein, we fabricated the scaffold composed of curcumin and silk fibroin as an appropriate clinical replacement for defected cartilage. The scaffolds were designed to have adequate pore size and mechanical strength for cartilage repair. Cell proliferation, sulfated glycosaminoglycan (sGAG) content and mRNA expression analysis indicated that chondrocytes remained viable and showed its growth ability in the curcumin/silk scaffolds. Especially, in 1mg/ml curcumin/silk scaffold showed higher cell viability rate and extracellular matrix formation than other experimental groups. Furthermore, curcumin/silk scaffold showed its biocompatibility and favorable environment for cartilage repair after transplantation in vivo, as indicated in histological examination results. Overall, the functional composite curcumin/silk scaffold can be applied in cartilage tissue engineering and promising substrate for cartilage repair. PMID- 28576024 TI - Layer-by-layer assembled polyelectrolytes on honeycomb-like porous poly(epsilon caprolactone) films modulate the spatial distribution of mesenchymal stem cells. AB - Cellular behaviors can be affected by both surface chemistry and topography of biomaterials substrates. The object of the present study was to investigate how pore structure and bioactive molecules regulate the adhesion and proliferation of rabbit bone marrow-derived mesenchymal stem cells (rMSCs) in synergy. Poly(epsilon-caprolactone) (PCL) films with a honeycomb-like porous structure were fabricated via a breath-figure method, and then further coated with bioactive molecules including four combinations of polyelectrolytes (GEL/CS, GEL/HA, CHI/CS and CHI/HA) via a layer-by-layer self-assembly (LBL) process. rMSCs were seeded on these films to evaluate both adhesion and proliferation. It was shown that a uniform honeycomb-like porous structure with a pore size of 18.87+/-3.25MUm was obtained in the films. Bioactive molecules were proven to be successfully deposited on the films, the amount of which increased with the number of assembled layer. Both surface pore structure and assembled molecules play significant roles on the adhesion and proliferation of rMSCs. Notably, the spatial distribution of cells (either entrapped in pores or spreading over pores) on porous films was also dictated by the identity of the assembled molecules. These findings might be fundamental to design bioactive scaffolds for tissue engineering. PMID- 28576025 TI - Carboxylated chitosan/silver-hydroxyapatite hybrid microspheres with improved antibacterial activity and cytocompatibility. AB - The implant-associated infection remains a serious problem in clinic. A better compromise between the anti-infection property and biocompatibility of bone filling materials is still required. In this work, carboxylated chitosan/silver hydroxyapatite (CMCS/Ag-HA) hybrid microspheres were fabricated via a facile gas diffusion method. CMCS and Ag ion were evenly distributed into hybrid microspheres. CMCS regulated the morphological characteristics of the as synthesized hybrid microspheres. As the content of CMCS increased, the size of the sample increased and dispersion exacerbated. In addition, antimicrobial studies demonstrated that CMCS/Ag-HA hybrid microspheres exhibited an excellent antimicrobial activity against Staphylococcus aureus because of the synergistic effect of Ag+ and CMCS. In vitro cell tests indicated that the as-prepared CMCS/Ag-HA hybrid microspheres promoted the proliferation and adhesion of MG63 cells. CMCS/Ag-HA hybrid microspheres showed excellent bactericidal property and biocompatibility; thus, they could be used in biomedical applications, such as infection-resistant bone replacement materials. PMID- 28576026 TI - Design, characterization and in vitro evaluation of novel amphiphilic block sunflower oil-based polyol nanocarrier as a potential delivery system: Raloxifene hydrochloride as a model. AB - Presently, modern pharmaceuticals, are almost exclusively derived from the arduous refining of petroleum whose supply is inherently unsustainable. In order to address this issue bio-based materials are increasingly being used for chemical synthesis, particularly in drug delivery systems. Biodegradable and biocompatible hyper-branched polyol (an alcohol containing three or more hydroxyl groups) was synthesized via a facile method through the ring-opening and thiol ene click reactions at room temperature. Due to the bio-based content of the polyol backbone, the synthesized polyol had both excellent biodegradability and low cytotoxicity. Raloxifene hydrochloride, an oral selective estrogen receptor modulator, was used as a hydrophobic drug model to test the potential of polyol as a drug delivery system carrier. Polyol showed an amphiphilic character and could be prepared as a nanoparticle for the sustained delivery of raloxifene hydrochloride, a drug with poor bioavailability in aqueous solution. Raloxifene hydrochloride was readily encapsulated in the lipophilic core of polyol whose branched hydroxyls were on the external part of the prepared nanoparticles. The diameter of the nanoparticles was 94+/-0.43nm, their drug entrapment efficiency was 93+/-0.5% and they showed a sustained release profile (17+/-1.5% after 4weeks). The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H-tetrazolium (MTS) assay showed low toxicity towards human osteoblast MG-63 cells. Based on its good biodegradability and low cytotoxicity, polyol provides a bio-based source for the design new drug delivery systems. PMID- 28576027 TI - Methotrexate-loaded porous polymeric adsorbents as oral sustained release formulations. AB - Methotrexate as a model drug with poor aqueous solubility was adsorbed into porous polymeric adsorbents, which was used as oral sustained release formulations. In vitro release assay in simulated gastrointestinal fluids showed that the methotrexate-loaded adsorbents showed distinct sustained release performance. The release rate increased with increase in pore size of the adsorbents. In vivo pharmacokinetic study showed that the maximal plasma methotrexate concentrations after oral administration of free methotrexate and methotrexate-loaded DA201-H (a commercial porous polymeric adsorbent) to rats occurred at 40min and 5h post-dose, respectively; and the plasma concentrations decreased to 22% after 5h for free methotrexate and 44% after 24h for methotrexate-loaded DA201-H, respectively. The load of methotrexate into the porous polymeric adsorbents not only resulted in obvious sustained release, but also enhanced the oral bioavailability of methotrexate. The areas under the curve, AUC0-24 and AUC0-inf, for methotrexate-loaded DA201-H increased 3.3 and 7.7 times, respectively, compared to those for free methotrexate. PMID- 28576028 TI - Synthesis and characterization of Eu(III) complexes of modified d-glucosamine and poly(N-isopropylacrylamide). AB - A series of chain-end functional polymers composed of poly(N-isopropylacrylamide) (PNIPAM) and 2-amino-2-deoxy-d-glucopyranose(d-glucosamine, GA) was synthesized via atom transfer radical polymerization (ATRP). Novel fluorescent complexes of glucosamine-PNI- PAM/Eu(III) were then formed by chelation of the polymers and europium(III) ions. The aqueous solutions of the polymers and its Eu(III) complexes exhibited a lower critical solution temperatures (LCSTs), and which were approximately equal to body temperature. Cell viability assays suggested that these thermosensitive polymers and Eu(III) complexes showed excellent biocompatibility in vitro. PMID- 28576029 TI - Folate receptor targeted bufalin/beta-cyclodextrin supramolecular inclusion complex for enhanced solubility and anti-tumor efficiency of bufalin. AB - Bufalin (BF), a traditional Chinese medicine, exhibited inhibitory activities against a broad spectrum of tumor cells. The present study elaborates that bufalin was successfully encapsulated into the cavity of beta-cyclodextrin (beta CD), which was determined by Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance spectroscopy (1H NMR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The best reaction mole ratio of BF/beta-CD was 1:5. The solubilities of bufalin in water and phosphate buffer solution (pH=7.4) were increased up to 24 and 34 times after encapsulated into the cavity of beta-CD respectively. The inclusion efficiency (IE) and drug loading (DL) of bufalin in the inclusion complex were (94.22+/-0.85)% and (14.11+/-0.20)%, respectively. Then beta-CD conjugated with folic acid (FA) were further prepared and employed to improve the anti-tumor efficacy of inclusion complex. The in vitro dissolution and solubility study showed better values of inclusion complex and FA targeted inclusion complex than that of pure BF. Cytotoxicity experiments by using HCT116 cell line revealed that the antitumor efficiency of bufalin were enhanced more than two folds in the presence of beta CD and folate conjugated beta-CD (FA-PEI-beta-CD), which demonstrated the potential application of beta-CD (FA-PEI-beta-CD) as delivery vehicles of bufalin for antitumor therapy. PMID- 28576030 TI - Sustainable and smart keratin hydrogel with pH-sensitive swelling and enhanced mechanical properties. AB - Protein based hydrogels are a very interesting type of biomaterials with many probed strengths related to their source and chemical structure. Biocompatibility and biodegradability are accompanied by affordability when it comes to low cost sources. The main keratin source is agroindustrial waste, such as feathers, horns, hooves, hair and wool. Thus, the main cost of keratin hydrogels derives from their processing. Here is presented a new strategy for the obtaining of a keratin hydrogel with enhanced mechanical properties using low cost reagents. This keratin hydrogel is stiff enough to allow handling without special cares and also presenting a reversible pH-responsive behavior. The minimum swelling is observed at low pH due to a collapsed and disordered protein network with water tightly adsorbed to the hydrophilic sites. The swelling rises significantly above pH6 and the maximum swelling appears above pH8 where an expanded network allows water to enter to the pores. PMID- 28576031 TI - Fabrication of a three dimensional spongy scaffold using human Wharton's jelly derived extra cellular matrix for wound healing. AB - The Wharton's jelly (WJ) contains significant amounts of extracellular matrix (ECM) components and rich source of endogenous growth factors. In this study, we designed a new biomimetic spongy scaffold from decellularized WJ-derived ECM and used it as a skin substitute. Histological analysis and biochemical assays showed that bio-active molecules preserved in the fabricated scaffolds and that the scaffolds have highly interconnected porous structure. Cytotoxicity and mechanical evaluation of the scaffold indicated that it is non-toxic and has appropriate mechanical properties. MTT assay, SEM and histological analysis of human fibroblast, seeded on the scaffolds, confirmed cellular viability, attachment, penetration and proliferation. The effectiveness of WJ-derived scaffolds in the regeneration of full-thickness wound was assessed through an in vivo experiment. Our results demonstrated that the scaffolds were well integrated into the mouse tissue and absorbed the exudates after one week. Unlike the controls, in WJ group there were not only complete wound closing and disappearance of the scab, but also complete reepithelialization, newly generated epidermal layers and appendages after 12days of implantation. Taken together, our results indicate that WJ-derived scaffolds are able to improve attachment, penetration and growth of the fibroblast cells and speed up the healing processes, which would offer a proper skin graft for wound healing. PMID- 28576032 TI - Hyperbranched polyglycerol-modified graphene oxide as an efficient drug carrier with good biocompatibility. AB - As a promising drug carrier, graphene oxide (GO) has been studied widely in drug delivery due to its excellent loading ability to aromatic drugs. However, its biocompatibility, such as stability and blood compatibility, is now the biggest obstacle for its further application. Herein, the hyperbranched polyglycerol (HPG)-modified GO was prepared through the anionic ring-opening polymerization using GO as the initiator directly, and then the doxorubicin hydrochloride was loaded and showed obvious cytotoxicity to tumor cells. The obtained HPG-GO displayed good stability in the aqueous solution, as well showed low toxicity in vitro and in vivo. As an injectable drug carrier, HPG-GO showed good blood compatibility with negligible effect on the hemolysis and blood coagulation. Such a stable and blood-compatible GO derivative may be applied widely in drug delivery in the future. PMID- 28576033 TI - Insight into cytotoxicity of Mg nanocomposites using MTT assay technique. AB - In the present study, Young's modulus measurements and indirect cytotoxicity test were performed on Mg (0.97, 1.98, 2.5) vol% TiO2, Mg (0.58, 0.97, 1.98) vol% TiC, and Mg (0.58, 0.97, 1.98) vol% TiN, synthesized using the Disintegrated Melt Deposition technique to determine the cytotoxicity of low volume nano-particulate reinforcement on magnesium. The results of the indirect MTT assay on Day 3 and Day 5 indicate that 2.5vol% TiO2, TiC and TiN has little effect on the cytotoxicity when added as low volume fraction reinforcement to magnesium. While (0.97, 1.98) vol% TiO2 negatively affected the cytotoxicity when added to Mg. The Young's modulus of the materials was found to remain close to that of cortical bone which would suggest that the stress shielding effect would be reduced as the increase in Young's modulus was mitigated by the low volume addition of reinforcements. PMID- 28576034 TI - Enhancement of fluorescence brightness and stability of copper nanoclusters using Zn2+ for ratio-metric sensing of S2. AB - It is acknowledged water soluble copper nanoclusters (Cu NCs) are extremely unstable in aqueous solutions, which limit their fluorescence applications to a great extent. In this work, it is found the fluorescence intensity and stability of water soluble Cu NCs could obviously be enhanced by the introduction of Zn2+. Then, the as modified Cu NCs will be stable enough to be applied as a ratio metric sensor for S2-. This method may provide more broaden avenues for the application of fluorescent Cu NCs in the future. PMID- 28576035 TI - BMP-2 immobilized PLGA/hydroxyapatite fibrous scaffold via polydopamine stimulates osteoblast growth. AB - Combining biomaterials scaffolds with bone morphogenetic protein-2 (BMP-2) is currently used to promote the regeneration of bone tissue. However, the traditional strategies used to add BMP-2 into the polymer scaffolds directly suffer from limitations that can result in lower growth factor loading and damage the bioactivity of growth factors. In this study, we report the fabrication of poly(lactide-co-glycolide)/hydroxyapatite (PLGA/HA) composite fibrous scaffolds via melt-spinning method to mimic native extracellular matrix (ECM). In order to effectively immobilize BMP-2 on PLGA/HA composite fibrous scaffolds, the surface of the scaffold was modified with polydopamine (PDA) (PDA-PLGA/HA). PDA was chosen as an adhesive polymeric bridge-layer between PLGA/HA fibrous scaffolds and BMP-2. Analysis of the scaffold using scanning electron microscopy, Fourier transform infrared spectroscopy and X-ray photoelectron spectroscope revealed that the PDA coating was attached to the scaffold surface. Moreover, analysis of the scaffold using water contact angle demonstrated an increased hydrophilicity via PDA modification. Furthermore, the PDA coating effectively immobilized BMP-2 on the PDA-PLGA/HA fibrous scaffold and a sustained release profile of BMP-2 was achieved in the BMP-2-immobilized PLGA/HA fibrous scaffold. In vitro experiments showed that BMP-2-immobilized PLGA/HA fibrous scaffold significantly promoted the attachment and proliferation of MC3T3-E1 cells. More importantly, the ALP activity, mRNA expression of osteosis-related genes and calcium deposition in MC3T3-E1 cells cultured on BMP-2-immobilized PLGA/HA fibrous scaffold were significantly increased. These results collectively demonstrate that the BMP-2 immobilized PLGA/HA fibrous scaffold is a promising candidate for bone regeneration. PMID- 28576037 TI - Drug release profiles of modified MCM-41 with superparamagnetic behavior correlated with the employed synthesis method. AB - Mesoporous materials with superparamagnetic properties were successfully synthesized by two different methods: direct incorporation (DI) and wet impregnation (WI). The synthetized solids were evaluated as host of drugs for delivery systems and their physicochemical properties were characterized by XRD, ICP, N2 adsorption-desorption, spectroscopies of UV-Vis DR, FT-IR and their magnetic properties were measured. Indomethacin (IND) was incorporated into the materials and the kinetic of the release profiles was studied by applying the Pepas and Sahlin model. In this sense, materials modified by DI, particularly that with hydrothermal treatment, showed the higher adsorption capacity and slower release rate. This behavior could be associated to the synthesis method used that allowed a high percentage of silanol groups available in the solids surface, which can interact with the IND molecule. This feature coupled with the superparamagnetic behavior; make these materials very interesting for drug delivery systems. PMID- 28576036 TI - Cytocompatibility, biofilm assembly and corrosion behavior of Mg-HAP composites processed by extrusion. AB - In this work the cytocompatibility of pure magnesium and Mg-xHAP composites (x=5, 10 and 15wt%) fabricated by powder metallurgy routes has been investigated. The materials were produced from raw HAP powders with particle mean sizes of 6MUm (S xHAP) or 25MUm (L-xHAP). The biocompatibility study has been performed for MC3T3 cells (osteoblasts/osteoclasts) and L929 fibroblasts. The results indicate that S Mg (pure magnesium), S-10HAP and L-10HAP composites are the materials with the best biocompatibility. The ability of S. aureus bacteria to assemble biofilms was also evaluated. Biofilm formation assays showed that these materials are not particular prone to colonization and biofilm assembly is strain dependent. The corrosion resistance of S-Mg, S-10HAP and L-10HAP materials immersed in the media used for the cells culture has also been analyzed. Different trends in the corrosion resistance have been found: S-Mg and S-10HAP show a very high resistance to corrosion whereas the corrosion of L-10HAP steadily increases with time. PMID- 28576038 TI - The effect of pH, fluoride and tribocorrosion on the surface properties of dental archwires. AB - Nickel-titanium and stainless steel are the most commonly used alloys for orthodontic treatments. Even though both are known to be resistant to corrosion, there are circumstances that can lead to undesired situations, like localized types of corrosion attack, wear during sliding of an archwire though brackets and breakdowns due to iatrogenic causes. The aim of this research was to analyse the influence of environmental effects on the corrosion and tribocorrosion properties of NiTi and stainless steel dental alloys. The effects of pH and fluorides on the electrochemical properties were studied using the cyclic potentiodynamic technique. The migration of ions from the alloy into saliva during exposure to saliva with and without the presence of wear was analysed using ICP-MS analyses. Auger spectroscopy was used to study the formation of a passive oxide layer on different dental alloys. It was found that lowering the pH preferentially affects the corrosion susceptibility of NiTi alloys, whereas stainless steel dental archwires are prone to local types of corrosion. The NiTi alloy is not affected by smaller increases of fluoride ions up to 0.024M, while at 0.076M (simulating the use of toothpaste) the properties are affected. A leaching test during wear assisted corrosion showed that the concentrations of Ni ions released into the saliva exceeded the limit value of 0.5MUg/cm2/week. The oxide films on the NiTi and stainless steel alloys after the tribocorrosion experiment were thicker than those exposed to saliva only. PMID- 28576039 TI - Investigation of the mechanical and chemical characteristics of nanotubular and nano-pitted anodic films on grade 2 titanium dental implant materials. AB - OBJECTIVE: The objective of this study was to investigate the reproducibility, mechanical integrity, surface characteristics and corrosion behavior of nanotubular (NT) titanium oxide arrays in comparison with a novel nano-pitted (NP) anodic film. METHODS: Surface treatment processes were developed to grow homogenous NT and NP anodic films on the surface of grade 2 titanium discs and dental implants. The effect of process parameters on the surface characteristics and reproducibility of the anodic films was investigated and optimized. The mechanical integrity of the NT and NP anodic films were investigated by scanning electron microscopy, surface roughness measurement, scratch resistance and screwing tests, while the chemical and physicochemical properties were investigated in corrosion tests, contact angle measurement and X-ray photoelectron spectroscopy (XPS). RESULTS AND DISCUSSION: The growth of NT anodic films was highly affected by process parameters, especially by temperature, and they were apt to corrosion and exfoliation. In contrast, the anodic growth of NP film showed high reproducibility even on the surface of 3-dimensional screw dental implants and they did not show signs of corrosion and exfoliation. The underlying reason of the difference in the tendency for exfoliation of the NT and NP anodic films is unclear; however the XPS analysis revealed fluorine dopants in a magnitude larger concentration on NT anodic film than on NP surface, which was identified as a possible causative. Concerning other surface characteristics that are supposed to affect the biological behavior of titanium implants, surface roughness values were found to be similar, whereas considerable differences were revealed in the wettability of the NT and NP anodic films. CONCLUSION: Our findings suggest that the applicability of NT anodic films on the surface of titanium bone implants may be limited because of mechanical considerations. In contrast, it is worth to consider the applicability of nano-pitted anodic films over nanotubular arrays for the enhancement of the biological properties of titanium implants. PMID- 28576040 TI - Engineered 3D-scaffolds of photocrosslinked chitosan-gelatin hydrogel hybrids for chronic wound dressings and regeneration. AB - Wound repair is one of the most complex biological processes in human life. To date, no ideal biomaterial solution has been identified, which that encompasses all functions and properties of real skin tissue. Thus, this study focused on the synthesis of new biocompatible hybrid hydrogel scaffolds based on methacrylate functionalized high molecular mass chitosan with gelatin-A photocrosslinked with UV radiation to tailor matrix network properties. These hybrid hydrogels were produced via freeze-drying and were extensively characterized by swelling and degradation measurements, Fourier transform infrared spectroscopy (FTIR), UV visible spectroscopy (UV-Vis), scanning electron microscopy (SEM-EDS), and micro computed tomography (micro-CT). The results demonstrated that hydrogels were produced with broadly designed swelling degrees typically ranging from 500% to 2000%, which were significantly dependent on the relative concentration of polymers and irradiation time for crosslinking. Analogously, degradation was reduced with increased photocrosslinking of the network. Moreover, insights into the mechanism of photochemical crosslinking were suggested based on FTIR and UV Vis analyses of the characteristic functional groups involved in the reactions. SEM analysis associated with micro-CT imaging of the hybrid scaffolds showed uniformly interconnected 3D porous structures, with architectural features affected by the crosslinking of the network. These hydrogels were biocompatible, with live cell viability responses of human embryonic kidney (HEK293T) cells being above 95%. Hence, novel hybrid hydrogels were designed and produced with tunable properties through photocrosslinking and with a biocompatible response suitable for use in wound dressing and skin tissue repair applications. PMID- 28576041 TI - Electrospinning of Ag Nanowires/polyvinyl alcohol hybrid nanofibers for their antibacterial properties. AB - In order to developing a sort of flexible fibrous mats with outstanding and durable antibacterial activates, silver nanowires incorporated into polyvinyl alcohol (PVA) nanofibers were fabricated by electrospun method. Uniform Ag nanowires (NWs) were synthesized through a template-free method of solvothermal combined with polyol process, and then, they were dispersed in PVA solution. At last, Ag NWs embedded in PVA (Ag NWs/PVA) hybrid nanofibrous films were gained by electrospun of the mixed solution. The antibacterial activity of Ag NWs/PVA nanofibers against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) was investigated by the methods of absorption and turbidity. Ag NWs with a mean diameter of 86nm were demonstrated to be uniformly incorporated into PVA nanofibers, forming a core-sheath nanocable structure. The as-prepared flexible and free-standing Ag NWs/PVA nanofibrous films show outstanding antimicrobial activities against both E. coli and S. aureus. It's found that both matrix polymer of PVA and enrichment of active {111} facets present in Ag NWs are favorable for the antibacterial performance. PMID- 28576042 TI - Iron doped beta-Tricalcium phosphate: Synthesis, characterization, hyperthermia effect, biocompatibility and mechanical evaluation. AB - The ability of beta-Tricalcium phosphate [beta-TCP, beta-Ca3(PO4)2] to host iron at its structural lattice and its associated magnetic susceptibility, hyperthermia effect, biocompatibility and mechanical characteristics is investigated. The studies revealed the ability of beta-Ca3(PO4)2 to host 5.02mol% of Fe3+ at its Ca2+(5) site. Excess Fe3+ additions led to the formation of trigonal Ca9Fe(PO4)7 and moreover a minor amount of CaFe3(PO4)3O crystallization was also observed. A gradual increment in the iron content at beta-Ca3(PO4)2 results in the simultaneous effect of pronounced hyperthermia effect and mechanical stability. However, the presence of CaFe3(PO4)3O contributes for the reduced hyperthermia effect and mechanical stability of iron substituted beta Ca3(PO4)2. Haemolytic tests, cytotoxicity tests and ALP gene expression analysis confirmed the biocompatibility of the investigated systems. PMID- 28576043 TI - Insights into the rheological behaviors evolution of alginate dialdehyde crosslinked collagen solutions evaluated by numerical models. AB - The elaboration of the rheological behaviors of alginate dialdehyde (ADA) crosslinked collagen solutions, along with the quantitative analysis via numerical models contribute to the controllable design of ADA crosslinked solution system's fluid mechanics performance during manufacturing process for collagen biomaterials. In the present work, steady shear flow, dynamical viscoelasticity, creep-recovery, thixotropy tests were performed to characterize the rheological behaviors of the collagen solutions incorporating of ADA from the different aspects and fitted with corresponding numerical models. It was found that pseudoplastic properties of all samples enhanced with increasing amounts of ADA, which was confirmed by the parameters calculated from the Ostwald-de Waele model, Carreau and Cross model, for instance, the non-Newtonian index (n) decreased from 0.786 to 0.201 and a great increase by 280 times in value of viscosity index (K) was obtained from Ostwald-de Waele model. The forth-mode Leonov model was selected to fit all dynamic modulus-frequency curves due to its higher fitting precision (R2>0.99). It could be found that the values of correlation shear viscosity (etak) increased and the values of relaxation time (thetak) decreased with increasing ADA at the fixed k value, suggesting that the incorporation of ADA accelerated the transformation of the collagen solutions from liquid-like to gel-like state due to more formation of CN linkages between aldehyde groups and lysine residues. Also, the curves of creep and recovery phase of the native and crosslinked collagen solutions were simulated well using Burger model and a semi-empirical model, respectively. The ability to resist to deformation and elasticity strengthened for the samples with higher amounts of ADA, accompanied with the important fact that compliance value (J50) decreased from 56.317Pa-1 to 2.135Pa-1 and the recovery percentage (Rcreep) increased from 2.651% to 28.217%. Finally, it was found that the area of thixotropic loop increased from 8.942Pa/s to 17.823Pa/s with increasing introduction of ADA, suggesting that stronger thixotropic behavior was associated with higher amount of ADA. Furthermore, Herschel-Bulkley model was employed to describe the up and down curves of all samples and it was confirmed that all collagen solutions belonged to pseudoplastic fluid (the flow index<1) without apparent yield stress and shear-thinning behaviors were more obvious with increasing additions of ADA according to the increasing consistency coefficient K values. Overall, this work contributed a new insight into the interactions between collagen and ADA based on quantitative rheological methods reflecting the different rheological properties and the results obtained should be of great utility in the extensive application of ADA crosslinked collagen solutions into diverse collagen-based materials. PMID- 28576044 TI - Effects of DNase I coating of titanium on bacteria adhesion and biofilm formation. AB - The removal of mature biofilm from the surface of implant has been a formidable challenge in treating implant-associated infection. Prevention of biofilm formation rather than removal of existing biofilm is a more effective approach. Immobilization of biofilm-dispersing enzymes on material surfaces is regarded as one of the most promising strategies. Deoxyribonuclease I (DNase I) can degrade extracellular DNA (eDNA) and then destabilize biofilm. In this study, DNase I was immobilized on a titanium (Ti) surface by using dopamine as an intermediate. The water contact angle, SEM, EDS and XPS confirmed that DNase I was successfully coated to the bare Ti and the final coating was highly hydrophilic. The DNase I coating showed significant effects in preventing Streptococcus mutans (S. mutans) and Staphylococcus aureus (S. aureus) adhesion and biofilm formation over a time span of 24h. The favorable biocompatibility was demonstrated by cell study in vitro. In addition, cell adhesion results suggested that DNase I coating had the potential to facilitate MC3T3-E1 cell attachment. DNase I coating with anti infection ability and biocompatibility has great potential for increasing success rates of implant applications. PMID- 28576045 TI - Fabrication of high-capacity polyelectrolyte brush-grafted porous AAO-silica composite membrane via RAFT polymerization. AB - Surface-initiated reversible addition-fragmentation chain transfer (RAFT) polymerization has been utilized to fabricate high-capacity strong anion-exchange (AEX) membrane for the separation of protein. By means of RAFT polymerization, quaternized poly(3-(methacrylamidomethyl)-pyridine) brushes formed 3-dimensional nanolayers on the surface of porous anodic aluminum oxide (AAO)-silica composite membrane. The surface properties of the membranes were analyzed by SEM, water contact angle, ATR-FTIR, XPS and TGA. To investigate the adsorption performance, the new AEX membranes were applied to recover a model protein, ovalbumin (OVA). High adsorption capacities of 95.8mg/g membranes (static) and 65.3mg/g membranes (dynamic) were obtained at ambient temperature. In the further studies, up to 90% of the adsorbed OVA was efficiently eluted by using phosphate buffer-1M NaCl as elution medium. The successful separation of OVA with high purity from a mixture protein solution was also achieved by using the AEX membranes. The present study demonstrated that under mild reaction condition, RAFT polymerization can be used to fabricate ion-exchange membrane which has many remarkable features, such as high capacity and selectivity, easy elution and so on. PMID- 28576046 TI - Fabrication of self-assembled vesicle nanoparticles of poly(l-lysine)-arachidic acid conjugates for a vascular endothelial growth factor carrier. AB - Numerous growth factors account for tissue and organ development and therapeutic efficiency. Hence, the delivery of growth factors is crucial in regenerative medical practice. However, the delivery of a single factor to regenerate tissues lacks clinical utility in many current approaches. We reported the delivery of the bioactive vascular endothelial growth factor (VEGF) from novel polymeric vesicles. Polymeric vesicles were prepared from the poly(l-lysine)-g polylysine(AA) amphiphilic graft copolymer through the conjugation of arachidic acid (AA) with poly(l-lysine) for obtaining a VEGF carrier. The prepared copolymer can form a polymersome and effectively condense with VEGF without affecting its size and surface charges. The Gaussian curve fit (GCF) of amide I band were revealed that VEGF efficiently interact through the alpha-helix of the amphiphilic graft copolymer rather than beta-sheet dominated poly(l-lysine). The polymersome-VEGF complex showed a considerably higher binding affinity, transfection efficiency, and less toxicity because of the peptide-based polymer backbone. Compared with the poly(l-lysine)-VEGF complex, polymersome-VEGF revealed a high secretion of VEGF and low toxicity. These polymersomes can deliver angiogenic factors in a controlled manner in tissue regeneration and biomedical engineering. PMID- 28576047 TI - Optimally designed collagen/polycaprolactone biocomposites supplemented with controlled release of HA/TCP/rhBMP-2 and HA/TCP/PRP for hard tissue regeneration. AB - Collagen has been widely used as a very promising material to regenerate various tissues. It is a chief component of the extracellular matrix, and encourages various biological effects conducive to tissue regeneration. However, poor mechanical stability, low processability, and high level of water absorption can lead to impaired control of growth factor release and have impeded the use of collagen as a functional biomedical scaffold. Here, to overcome the shortcomings of collagen scaffolds, we have additively manufactured collagen/polycaprolactone (PCL) biocomposites supplemented with a bioceramic (hydroxyapatite (HA)/beta tricalcium-phosphate (TCP)) and two growth factors (recombinant human bone morphogenetic protein-2 [rhBMP-2] and platelet-rich plasma [PRP]). Various weight fractions of PCL in the collagen/PCL composites were manipulated to select optimal growth factor release and highly active cellular responses. After the optimal concentration of PCL in the collagen/PCL scaffold was determined, biocomposites supplemented with bioceramic/growth-factors were fabricated. Continuously released growth factors were assumed to increase the in vitro cellular activities of the osteoblast-like cells (MG63) cultured on the biocomposites. In vitro cellular responses, including osteogenic activities, were examined, and results showed that compared to the HA/TCP/rhBMP-2 supplemented scaffold the HA/TCP/PRP biocomposites provide significantly high cellular activities (cell proliferation: >1.3-fold) and mineralization (calcium deposition: >1.4-fold, osteocalcin: >2.6-fold) sufficient for regenerating bone tissue. PMID- 28576048 TI - Study on beta-cyclodextrin-complexed nanogels with improved thermal response for anticancer drug delivery. AB - For achievement of controllability in drug delivery, development of nanocarriers with thermal response is one of the most investigated stimulative strategies for oncological treatment. How to improve the thermosensitivity of the nanocarriers is an important factor for their successful drug delivery applications. In this study, a kind of complexed nanogels (PNACD) was developed by incorporating beta cyclodextrin (beta-CD) into the nanogels of copolymers of N-isopropylacrylamide (NIPAM) and acrylic acid (AA) during their polymerization via in situ crosslinking of N,N'-methylenebisacrylamide (MBA) as a crosslinker. The complexed PNACD nanogels displayed a significantly enhanced thermosensitivity near body temperature compared to the beta-CD-free nanogels (PNA), which is probably associated with the rapid volumetric transformation during heating/cooling process due to the formation of complexed (decomplexed) structure between beta-CD and PNIPAM element. The PNACD nanogels can be used for loading of an anticancer drug (doxorubicin, DOX) with an encapsulation efficiency of 54+/-5%. The DOX loaded nanogels displayed pH-/thermo-dual responsivenesses in drug release, which can be effectively internalized into KB cells (a human epithelial carcinoma cell line) to exert good anticancer bioactivity. This approach may enlighten design of novel nanocarriers for delivery of drugs beyond anticancer chemotherapeutic reagents. PMID- 28576049 TI - Improved oral bioavailability of probucol by dry media-milling. AB - The polymer/probucol co-milled mixtures were prepared to improve drug dissolution rate and oral bioavailability. Probucol, a BCS II drug, was co-milled together with Copovidone (Kollidon VA64, VA64), Soluplus, or MCC using the dry media milling process with planetary ball-milling equipment. The properties of the milled mixtures including morphology, crystal form, vitro drug dissolution and in vivo oral bioavailability in rats were evaluated. Probucol existed as an amorphous in the matrix of the co-milled mixtures containing VA64, which helped to enhance drug dissolution. The ternary mixture composed of VA64, RH40, and probucol showed increased dissolution rates in both sink and non-sink conditions. It also had a higher oral bioavailability compared to the reference formulation. Dry-media milling of binary or ternary mixtures composed of drug, polymer and surfactant possibly have wide applications to improve dissolution rate and oral bioavailability of water-insoluble drugs. PMID- 28576050 TI - Extraction and characterization of collagen from Antarctic and Sub-Antarctic squid and its potential application in hybrid scaffolds for tissue engineering. AB - Collagen is the most abundant protein found in mammals and it exhibits a low immunogenicity, high biocompatibility and biodegradability when compared with others natural polymers. For this reason, it has been explored for the development of biologically instructive biomaterials with applications for tissue substitution and regeneration. Marine origin collagen has been pursued as an alternative to the more common bovine and porcine origins. This study focused on squid (Teuthoidea: Cephalopoda), particularly the Antarctic squid Kondakovia longimana and the Sub-Antarctic squid Illex argentinus as potential collagen sources. In this study, collagen has been isolated from the skins of the squids using acid-based and pepsin-based protocols, with the higher yield being obtained from I. argentinus in the presence of pepsin. The produced collagen has been characterized in terms of physicochemical properties, evidencing an amino acid profile similar to the one of calf collagen, but exhibiting a less preserved structure, with hydrolyzed portions and a lower melting temperature. Pepsin soluble collagen isolated from I. argentinus was selected for further evaluation of biomedical potential, exploring its incorporation on poly-epsilon-caprolactone (PCL) 3D printed scaffolds for the development of hybrid scaffolds for tissue engineering, exhibiting hierarchical features. PMID- 28576051 TI - On mechanical mechanism of damage evolution in articular cartilage. AB - Superficial lesions of cartilage are the direct indication of osteoarthritis. To investigate the mechanical mechanism of cartilage with micro-defect under external loading, a new plain strain numerical model with micro-defect was proposed and damage evolution progression in cartilage over time has been simulated, the parameter were studied including load style, velocity of load and degree of damage. The new model consists of the hierarchical structure of cartilage and depth-dependent arched fibers. The numerical results have shown that not only damage of the cartilage altered the distribution of the stress but also matrix and fiber had distinct roles in affecting cartilage damage, and damage in either matrix or fiber could promote each other. It has been found that the superficial cracks in cartilage spread preferentially along the tangent direction of the fibers. It is the arched distribution form of fibers that affects the crack spread of cartilage, which has been verified by experiment. During the process of damage evolution, its extension direction and velocity varied constantly with the damage degree. The rolling load could cause larger stress and strain than sliding load. Strain values of the matrix initially increased and then decreased gradually with the increase of velocity, and velocity had a greater effect on matrix than fibers. Damage increased steadily before reaching 50%, sharply within 50 to 85%, and smoothly and slowly after 85%. The finding of the paper may help to understand the mechanical mechanism why the cracks in cartilage spread preferentially along the tangent direction of the fibers. PMID- 28576052 TI - Facile in situ formation of hybrid gels for direct-forming tissue engineering. AB - Development of bioactive hydrogel as extracellular matrix (ECM) is a very important field for cell-based therapy. In this study, we provided a facile method based on sol-gel process for fabricating bioactive composite hydrogels. The composite hydrogels were composed of sol-gel derived silica and biopolymer. Different amounts of silica solution (20-80wt%) were mixed with 2% polymer sol (alginate) followed by aging and gelation to form a network so that the alginate silica hybrid mixture could form a gel without any additional crosslinking process. The self-gelation time of the hybrid hydrogel measured by rheometer was reduced as the content of silica was increased. Such hydrogels had highly porous and interconnected structures. Their strut showed uniform surface texture. Under physiological conditions (PBS, 37 degrees C), these hybrid hydrogels exhibited long-term stability compared to alginate hydrogels as control. The mechanical properties of these hydrogels such as compressive strength, compressive modulus, and work of fracture were significantly enhanced by hybridization with sol-gel derived silica. In vitro cell tests revealed that these hybrid hydrogels exhibited improved cell adhesion and proliferation behaviors compared to pure alginate hydrogel cross-linked by CaCl2 solution. Furthermore, cell encapsulation within these hydrogels revealed that their alginate-silica composite provided suitable microenvironment for cell survival. PMID- 28576053 TI - Antibacterial SnO2 nanorods as efficient fillers of poly(propylene fumarate-co ethylene glycol) biomaterials. AB - Antibacterial and biocompatible SnO2 nanorods have been easily synthesized through a hydrothermal process with the aid of a cationic surfactant, and incorporated as nanoreinforcements in poly(propylene fumarate-co-ethylene glycol) (P(PF-co-EG)) copolymer crosslinked with N-vinyl-pyrrolidone (NVP) by sonication and thermal curing. The nanorods were randomly and individually dispersed inside the P(PF-co-EG) network, and noticeably increased the thermal stability, hydrophilicity, degree of crystallinity, protein absorption capability as well as stiffness and strength of the matrix, whilst decreased its level of porosity and biodegradation rate. More importantly, the resulting nanocomposites retained adequate rigidity and strength after immersion in a simulated body fluid (SBF) at 37 degrees C. They also exhibited biocide action against Gram-positive and Gram negative bacteria; their antibacterial effect was strong under UV-light illumination whilst in dark conditions was only moderate. Further, they did not cause toxicity on human dermal fibroblasts. The friction coefficient and wear rate strongly decreased with increasing nanorod loading under both dry and SBF conditions; the greatest drops in SBF were about 18-fold and 13-fold, respectively, compared to those of the copolymer network. These novel biomaterials are good candidates to be applied in the field of soft-tissue engineering. PMID- 28576054 TI - Functionalized graphene oxide/Fe3O4 hybrids for cellular magnetic resonance imaging and fluorescence labeling. AB - In this work, we developed a T2-weighted contrast agent based on graphene oxide (GO)/Fe3O4 hybrids for efficient cellular magnetic resonance imaging (MRI). The GO/Fe3O4 hybrids were obtained by combining with co-precipitation method and pyrolysis method. The structural, surface and magnetic characteristics of the hybrids were systematically characterized by transmission electron microscopy (TEM), vibrating sample magnetometer (VSM), AFM, Raman, FT-IR and XRD. The GO/Fe3O4 hybrids were functionalized by modifying with anionic and cationic polyelectrolyte through layer-by-layer assembling. The fluorescence probe fluorescein isothiocyanate (FITC) was further loaded on the surface of functionalized GO/Fe3O4 hybrids to trace the location of GO/Fe3O4 hybrids in cells. Functionalized GO/Fe3O4 hybrids possess good hydrophilicity, less cytotoxicity, high MRI enhancement with the relaxivity (r2) of 493mM-1s-1 as well as cellular MRI contrast effect. These obtained results indicated that the functionalized GO/Fe3O4 hybrids could have great potential to be utilized as cellular MRI contrast agents for tumor early diagnosis and monitoring. PMID- 28576055 TI - Antimicrobial property of silver, silver-zinc and silver-copper incorporated soda lime glass prepared by ion exchange. AB - Antimicrobial glasses are potential candidate as an additive in powder form for many different applications which makes them practically and scientifically important. In this context, incorporation of silver, zinc and copper into the powdered soda lime glass was carried out by ion exchange treatment using single and dual ion containing mediums. Investigating the effect of dual incorporation of silver-zinc and silver-copper on the ion release ability and antimicrobial activity of the glass was the motivation of this study. Considering the chemical analysis results, incorporation of silver, zinc and copper to the glass was realized after the treatment. The amount of released silver was observed to be higher than zinc and copper in aqueous environment. Unvarying pH values indicated that antimicrobial efficacies of the glasses were merely due to the incorporated ions. Silver release was significantly reduced in dual imparted glasses compared to the single silver imparted glasses. According to the antimicrobial test results, glasses showed sufficient and controlled level of ion release also showed antimicrobial activity. It was deduced that dual incorporation of silver zinc and silver-copper into the glass lowered the silver release which was still sufficient for effective antimicrobial activity and this contributes the long term activity. PMID- 28576056 TI - New infrared-assisted method for sol-gel derived ZnO:Ag thin films: Structural and bacterial inhibition properties. AB - A new sol-gel method, based on crystallization with Infrared heating, was developed to obtain ZnO:Ag thin films. The common sol, with zinc acetate as precursor and silver nitrate as doping source (1, 3 and 5 % molar), isopropanol and distilled water as solvents and monoethanolamine as stabilizer agent; was modified with Pluronic F127 and diethylene glycol as rheological agents, and with urea as fuel to produce enough energy to the combustion and to promote the crystallization process. Later, Corning glass-substrates were dipped into the sol at a constant speed of 3mms-1. To provide the necessary energy for obtaining the hexagonal ZnO structure of the coatings during the drying and consolidation process, instead of using the common furnace heat-treatment, the films were heated by means of an infrared (IR) ceramic lamp (800W) for 15, 30, 45, 60 and 180 minutes, and the effect of this annealing method was analyzed. The structural properties were examined by means of X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR), whereas morphology was studied by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The examination revealed a homogeneous distribution of particles with the characteristic pores of pluronic F127, and the coating roughness had an average value of 100nm by AFM. To evaluate the effect on the number of dipping cycles and the IR-treatment on the thickness, ellipsometry results for 1, 3 and 5 deposits were analyzed and showed increments of 780, 945 and 1082nm, respectively. Finally, to test of the antibacterial activity, instead of the common one microorganism approach, environmental microorganisms that grow with expose of the broth to the ambient conditions were employed (microbial consortium), which is a real environmental condition. The biological test was carried out by kinetic growth inhibition (optical density) of heterotrophic bacteria in culture liquid media under conditions of light, light-dark and darkness, to analyze the effect of light. A significance reduction in growth was obtained for doped coatings with silver in comparison with the control ZnO substrate. Furthermore, the analysis bacteria growth inhibition on a solid surface showed that the films effectively present antibacterial activity. The best result was obtained with ZnO:Ag 1% in light conditions, about 67%, but all the coatings inhibited the bacterial activity. PMID- 28576057 TI - Solvothermal synthesis of cobalt ferrite hollow spheres with chitosan. AB - Cobalt ferrite hollow spheres with chitosan (CoFe2O4/CS) were synthesized by two different approaches using the solvothermal method. The first approach involves in-situ incorporation of FeCl3:6H2O and CoNO3:6H2O in the solvothermal reaction (M1) and in second approach already prepared CoFe2O4 nanoparticles (NPs) using the thermal decomposition method was placed in the solvothermal reaction to form the hollow spheres (M2). Structural identification of the samples were characterized by Fourier transform infrared spectra (FTIR), powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetric analyses (DSC-TGA) and energy dispersive X ray spectroscopy (EDX). The magnetic properties were evaluated using a vibrating sample magnetometer (VSM). The presence of chitosan on the hollow sphere was confirmed by FTIR. The XRD analyses proved that the synthesized samples were cobalt ferrite with spinel structure. The structure of the surface and the average particle size of the spheres were observed by SEM and TEM showing the nano scale of the CoFe2O4 component. Structural characterization demonstrating that chitosan does not affect the crystallinity, chemical composition, and magnetic properties of the CoFe2O4/CS. This work demonstrates that the CoFe2O4/CS prepared using the as synthesized CoFe2O4 NPs have better structural and magnetic properties. PMID- 28576058 TI - Colloidal properties and in vitro evaluation of Hydroxy ethyl cellulose coated iron oxide particles for targeted drug delivery. AB - In this study, superparamagnetic iron oxide (Fe3O4) nanoparticles were prepared for the targeted drug delivery applications by controlling the colloidal properties with a cellulosic polymer that is Hydroxy ethyl cellulose (HEC). Fe3O4 particles were treated with HEC in a variable range of polymer concentration. Rheological, electrokinetic, magnetorheological and morphological properties of the dispersions were investigated to have stable and fully covered surfaces of Fe3O4 particles by coating with HEC and obtaining non-toxic biocompatible multifunctional magnetic particles. Fully coated HEC and iron-oxide particles were characterized thermally, magnetically and tested for toxicity in vitro. Then Doxorubicin hydrochloride (DOX), which is an anticancer drug widely used for cancer therapies, was loaded onto nanoparticles and their drug loading efficiency was determined. Finally, effects of DOX-loaded particles on the cancer cells were examined to report a nano drug system which can potentially open up new possibilities in the design of therapeutic agents. Results indicated that the synthesized nanoparticles in this study could be suitable to magnetically manipulated targeted delivery systems, imaging, magnetic hyperthermia treatments. PMID- 28576059 TI - Manufacture and property research of heparin grafted electrospinning PCU artificial vascular scaffolds. AB - PCU (polycarbonate polyurethane) is supposed to be an ideal elastomer for manufacturing artificial vessel scaffold with perfect mechanical strength and biocompatibility. Surface grafting by heparin sodium can increase its anticoagulant hemorrhagic, achieving a better application in artificial vessels. Artificial vessels were preliminarily prepared by electrostatic spinning, treated by NH3 plasma and cross-linked with the anticoagulant heparin sodium chemically. Performances of the PCU-Hep (heparin sodium grafted purethane artificial vessels) artificial vessel were calculated through the physical and chemical property tests, evaluation of blood and biocompatibility. Results manifested that heparin sodium was successfully grafted to the vascular surface, porosity, pore diameter and water permeability of the vascular prosthesis fitted the requirements of artificial vessels, the blood test results demonstrated that the vascular material had a low hemolysis, in vitro cytotoxicity experiment and animal experiments proved an excellent biocompatibility. Thus the heparin sodium grafted electrospinning vessels could reduce intravascular thrombus and had potential clinical application. PMID- 28576060 TI - Direct encapsulation of AIE-active dye with beta cyclodextrin terminated polymers: Self-assembly and biological imaging. AB - Aggregation-induced emission (AIE) phenomenon has attracted great attention recently and been extensively explored for biomedical applications. Nevertheless, the direct utilization of AIE-active dyes for biomedical applications has demonstrated to be enormous challenge owing to the hydrophobic nature of these AIE-active dyes. In this work, we reported the fabrication of amphiphilic AIE active copolymers through the specific host-guest interaction between beta cyclodextrin (beta-CD) and an adamantine terminating tetraphenylethene derivative (TPE-Ad). In this construction system, beta-CD was acted as the bridge to link TPE-Ad with PEG. The TPE-beta-CD-PEG copolymers were characterized by various equipments in detail. Cytocompatibility and cell uptake behavior of TPE-beta-CD PEG were also examined to evaluate their biomedical application potential. Results demonstrated that TPE-beta-CD-PEG copolymers were prone to self-assemble into luminescent nanoparticles, which exhibited high water dispersity, AIE feature and excellent biocompatibility. These features endowed TPE-beta-CD-PEG great potential for biomedical applications. PMID- 28576061 TI - In-vitro efficacy of different morphology zinc oxide nanopowders on Streptococcus sobrinus and Streptococcus mutans. AB - ZnO with two different morphologies were used to study the inhibition of Streptococcus sobrinus and Streptococcus mutans which are closely associated with tooth cavity. Rod-like shaped ZnO-A and plate-like shaped ZnO-B were produced using a zinc boiling furnace. The nanopowders were characterized using energy filtered transmission electron microscopy (EFTEM), X-ray diffraction (XRD), photoluminescence (PL) spectroscopy, Raman spectroscopy and dynamic light scattering (DLS) to confirm the properties of the ZnO polycrystalline wurtzite structures. XRD results show that the calculated crystallite sizes of ZnO-A and ZnO-B were 36.6 and 39.4nm, respectively, whereas DLS revealed particle size distributions of 21.82nm (ZnO-A) and 52.21nm (ZnO-B). PL spectra showed ion vacancy defects related to green and red luminescence for both ZnO particles. These defects evolved during the generation of reactive oxygen species which contributed to the antibacterial activity. Antibacterial activity was investigated using microdilution technique towards S. sobrinus and S. mutans at different nanopowder concentrations. Results showed that ZnO-A exhibited higher inhibition on both bacteria compared with ZnO-B. Moreover, S. mutans was more sensitive compared with S. sobrinus because of its higher inhibition rate. PMID- 28576062 TI - Chemical and structural analysis of gallstones from the Indian subcontinent. AB - Representative gallstones from north and southern parts of India were analyzed by a combination of physicochemical methods: X-ray diffraction (XRD), infrared spectroscopy (IR), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), CHNS analysis, thermal analysis and Nuclear Magnetic Resonance (NMR) spectroscopy (1H and 13C). The stones from north Indian were predominantly consisting of cholesterol monohydrate and anhydrous cholesterol which was confirmed by XRD analysis. FTIR spectroscopy confirmed the presence of cholesterol and calcium bilirubinate in the south Indian gallstones. EDX spectroscopy revealed the presence of carbon, nitrogen, oxygen, calcium, sulfur, sodium and magnesium and chloride in both south Indian and north Indian gallstones. FTIR and NMR spectroscopy confirmed the occurrence of cholesterol in north Indian gallstones. The respective colour of the north Indian and south Indian gallstones was yellowish and black. The morphology of the constituent crystals of the north Indian and south Indian gallstones were platy and globular respectively. The appreciable variation in colour, morphology and composition of south and north Indian gallstones may be due to different food habit and habitat. PMID- 28576063 TI - Bioresorbable beta-TCP-FeAg nanocomposites for load bearing bone implants: High pressure processing, properties and cell compatibility. AB - In this paper, the processing and properties of iron-toughened bioresorbable beta tricalcium phosphate (beta-TCP) nanocomposites are reported. beta-TCP is chemically similar to bone mineral and thus a good candidate material for bioresorbable bone healing devices; however intrinsic brittleness and low bending strength make it unsuitable for use in load-bearing sites. Near fully dense beta TCP-matrix nanocomposites containing 30vol% Fe, with and without addition of silver, were produced employing high energy attrition milling of powders followed by high pressure consolidation/cold sintering at 2.5GPa. In order to increase pure iron's corrosion rate, 10 to 30vol% silver were added to the metal phase. The degradation behavior of the developed composite materials was studied by immersion in Ringer's and saline solutions for up to 1month. The mechanical properties, before and after immersion, were tested in compression and bending. All the compositions exhibited high mechanical strength, the strength in bending being several fold higher than that of polymer toughened beta-TCP-30PLA nanocomposites prepared by the similar procedure of attrition milling and cold sintering, and of pure high-temperature sintered beta-TCP. Partial substitution of iron with silver led to an increase in both strength and ductility. Furthermore, the galvanic action of silver particles dispersed in the iron phase significantly accelerated in vitro degradation of beta-TCP-30(Fe-Ag) nanocomposites. After 1month immersion, the composites retained about 50% of their initial bending strength. In cell culture experiments, beta-TCP-27Fe3Ag nanocomposites exhibited no signs of cytotoxicity towards human osteoblasts suggesting that they can be used as an implant material. PMID- 28576064 TI - Synthesis, characterization, and sustained release property of Fe3O4@(enrofloxacin-layered double hydroxides) nanocomposite. AB - A novel magnetic nanocomposite with enrofloxacin (ENR) intercalated MgAl layered double hydroxides (LDH) coated on Fe3O4 particles, denoted as Fe3O4@(ENR-LDH), was assembled via a delamination-reassembling process. Fe3O4@(ENR-LDH) was characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, element chemical analysis, transmission electron microscopy, differential scanning calorimetry, and room-temperature magnetic measurements. Results showed the following: 1 Fe3O4@(ENR-LDH) consisted of both ENR-LDH nanocrystallite and Fe3O4 phases; 2 Fe3O4@(ENR-LDH) presented well-defined core shell structure with diameter in the range of 15-20nm; 3 the thermal stability of ENR was enhanced after intercalation; and 4 Fe3O4@(ENR-LDH) exhibited good superparamagnetism. The release kinetics of ENR was investigated in buffer solutions at pH4.6 and 7.2, and the release process fitted Bhaskar model indicating diffusion-controlled mechanism. In addition, ENR release rate from Fe3O4@(ENR-LDH) was remarkably lower than that from the corresponding physical mixture, showing that Fe3O4@(ENR-LDH) can be considered as a potential magnetic targeting drug delivery-controlled-release system. PMID- 28576066 TI - Designing of macroporous magnetic bioscaffold based on functionalized methacrylate network covered by hydroxyapatites and doped with nano-MgFe2O4 for potential cancer hyperthermia therapy. AB - In this paper, we report on synthesis and characterization of three-dimensional biocomposite based on a polymerized 3-(trimethoxysilyl)propyl methacrylate/ethylene glycol dimethacrylate (pTMSPMA/pEGDMA) framework. The resulting composite was doped with Ca2+ and PO43- or decorated by hydroxyapatite (HA) and carbonate hydroxyapatite (CHA) to aid potential bone fixation and the in vitro bioactivity was evaluated. During the construction of the macroporous scaffold, the size and shape of pores were modified depending on the type of porogens which was applied (commercially available sugar, NaCl, or NH4Cl). Delivered 3D biomaterial was next used in preparation of a magnetic scaffold containing the core/shell magnetic nanoparticles covered with silicon-rich layer creating the amorphous magnetic dead layer. Preliminary magnetic studies showed that nanocrystalline MgFe2O4@SiO2 possesses a superparamagnetic properties, narrow hysteresis loop and virgin curve. The developed magnetic scaffold fulfills the requirements of a promising biomaterial for potential cancer hyperthermia therapy. PMID- 28576065 TI - (Chitosan-g-glycidyl methacrylate)-xanthan hydrogel implant in Wistar rats for spinal cord regeneration. AB - This work reports the results of in vivo assays of an implant composed of the hydrogel Chitosan-g-Glycidyl Methacrylate-Xanthan [(CTS-g-GMA)-X] in Wistar rats. Degradation kinetics of hydrogels was assessed by lysozyme assays. Wistar rats were subjected to laminectomy by cutting the spinal cord with a scalpel. After the surgical procedure, hydrogels were implanted in the injured zone (level T8). Somatosensory evoked potentials (SEPs) obtained by electric stimulation onto periphery nerves were registered in the corresponding central nervous system (CNS) areas. Rats implanted with the biomaterials showed a successful recovery compared with the non-implanted rats after 30days. Lysozyme, derived from egg whites, was used for in vitro assays. This study serves as the basis for testing the biodegradability of the hydrogels (CTS-g-GMA)-X that is promoted by enzymatic hydrolysis. Hydrogels' hydrolysis was studied via lysozyme kinetics at two pH values, 5 and 7, under mechanical agitation at 37 degrees C. Results show that our materials' hydrolysis is slower than pure CTS possibly due to the steric hindrance imposed by the GMA grafting of functionalization. This hydrolysis helps degrade the biomaterial and at the same time it provides support for spinal cord recovery. Combination of these results may prove useful in the use of these hydrogels as scaffolds for cells proliferation and their application as implants in living organisms. PMID- 28576067 TI - pH-triggered degradable polymeric micelles for targeted anti-tumor drug delivery. AB - 2-(Octadecyloxy)-1,3-dioxan-5-amine (OD) with an acid degradable ortho ester group was synthesized, and conjugated to hyaluronic acid (HA) backbone to prepare pH-responsive and tumor-targeted hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5 amine (HOD) conjugates. 1H NMR was used to confirm the structures of the OD and HOD. The studies of pH-responsive behavior showed that HOD micelles were stable under physiological conditions while they were degraded in the tumor acidic microenvironment. Doxorubicin (DOX)-loaded HOD micelles (DOX/HOD) with a narrow size distribution were prepared and characterized. The increased release of DOX from DOX/HOD micelles was presented at low pH condition. From in vitro cytotoxicity assays against MCF-7 cells, the blank micelles exhibited low cytotoxicity, but DOX/HOD micelles had the higher cytotoxicity than pH insensitive control and free DOX. Cellular uptake experiments and confocal images demonstrated that pH-sensitive DOX/HOD micelles could be internalized efficiently by CD44 receptor mediated endocytosis, and then DOX was rapidly released due to pH-induced degradable of OD to cell nucleus compared to the non-sensitive micelles. Furthermore, endocytosis inhibition studies presented that DOX/HOD micelles were internalized into cells mainly via caveolae-mediated routes. In vivo study of micelles in tumor-bearing mice indicates that HOD micelles were more effectively accumulated into the tumor tissue than HOA micelles. These results verify that the pH-sensitive HOD micellar system is a promising nanocarrier for enhanced internalization of antitumor drugs to cancer cells. PMID- 28576068 TI - Failure of flight feathers under uniaxial compression. AB - Flight feathers are light weight engineering structures. They have a central shaft divided in two parts: the calamus and the rachis. The rachis is a thinly walled conical shell filled with foam, while the calamus is a hollow tube-like structure. Due to the fact that bending loads are produced during birds' flight, the resistance to bending of feathers has been reported in different studies. However, the analysis of bent feathers has shown that compression could induce failure by buckling. Here, we have studied the compression of feathers in order to assess the failure mechanisms involved. Axial compression tests were carried out on the rachis and the calamus of dove and pelican feathers. The failure mechanisms and folding structures that resulted from the compression tests were observed from images obtained by scanning electron microscopy (SEM). The rachis and calamus fail due to structural instability. In the case of the calamus, this instability leads to a progressive folding process. In contrast, the rachis undergoes a typical Euler column-type buckling failure. The study of failed specimens showed that delamination buckling, cell collapse and cell densification are the primary failure mechanisms of the rachis structure. The role of the foam is also discussed with regard to the mechanical response of the samples and the energy dissipated during the compression tests. Critical stress values were calculated using delamination buckling models and were found to be in very good agreement with the experimental values measured. Failure analysis and mechanical testing have confirmed that flight feathers are complex thin walled structures with mechanical adaptations that allow them to fulfil their functions. PMID- 28576069 TI - Starch, cellulose acetate and polyester biodegradable sheets: Effect of composition and processing conditions. AB - The production of biodegradable plastic materials using natural resources has aroused increased attention due to environmental concerns. This study aimed to manufacture novel, commercially feasible, biodegradable sheets by flat die extrusion-calendering process produced with thermoplastic starch/plasticized cellulose acetate (TPS/PCA) and thermoplastic starch/plasticized cellulose acetate/poly (butylene adipate-co-terephthalate) (TPS/PCA/PBAT) blends, and to investigate the effects of composition and processing conditions, morphological characteristics, and thermal properties. The results showed that TPS/PCA and TPS/PCA/PBAT biodegradable sheets properties were highly dependent upon both composition and processing temperature. The morphological characteristics and thermal properties of the sheets demonstrated the good compatibility between TPS and PCA in TPS/PCA blends, mainly at higher processing temperatures, whereas TPS/PCA/PBAT sheets present a heterogeneous structure due to the poor compatibility between the components. TPS/PCA biodegradable sheets presented suitable processability and handleability characteristics that allow them to be considered as a novel eco-friendly, economically feasible alternative to conventional plastic materials. PMID- 28576070 TI - Preparation and characterization of polymers based on PDMS and PEG-DMA as potential scaffold for cell growth. AB - This work describes a soft lithographic method for the generation of patterned both biopolymer and silver with each covered on microscope glass. Because of their biocompatible nature and permeability to gases the biopolymers are convenient for cell culture studies. The microscope glass was covered by polyethylene glycol dimethyl acrylate (PEG-DMA), as biopolymer and patterned by the UV light passing through the printed photomask for the preparation of the PDMS stamps. PDMS stamps were originally fabricated in this work for pattern transfer. Ag and polymer covered on the microscope glass were patterned by using these PDMS stamps. The patterned Ag, PDMS mold and PEG-DMA biopolymer were used as scaffolds and cell growth experiments have been performed on these materials. The degree of cell viability was measured by seeding them with L929 mouse fibroblasts and the number of the cells was measured by neutral red uptake assay. An increase in the number of cells on the material surfaces was observed. The pattern and the cell growth properties were followed by optic microscope. The results obtained from the cell growth was subjected to student's t-test. PMID- 28576073 TI - ZnO nanoflower based sensitive nano-biosensor for amyloid detection. AB - Zinc oxide (ZnO) is a semiconductor metal oxide nanoparticle with inherent optical properties. Among the different zinc oxide nanostructures, nanoflowers have greater surface area. Utilizing this property a reagentless biosensor has been developed for the detection of beta amyloids, a hallmark of neurodegenerative diseases like Alzheimer's disease, Creutzfeldt-Jakob Syndrome, insulin dependent type II diabetes etc. The poor fluorescence quantum yield and photobleaching effect of Thioflavin T (ThT) upon binding to the model insulin amyloid beta sheets in solution can be overcome by the present engineered biosensor where ThT acts as a target as well as a reporter to detect amyloids adsorbed on a solid template based on ZnO nanoflower. ThT was adsorbed on ZnO NFs grown over nano-silver thin film coated glass slide. The in vivo imaging system was used to detect and quantify the fluorescence intensity generated from the substrates upon binding with insulin amyloid. ZnO NFs have the waveguiding property which increases the local field intensity caused by a resonance between the guided fundamental mode and evanescent field associated with high- order modes. This resonance phenomenon reinforces the excitation of the fluorophores in close proximity of the NFs thereby exhibiting enhanced fluorescence like Fabry Pero't Resonator (FPR). Considering the engineering and sensitivity, the reported nanobiosensor developed on ZnO nanoflower can be treated as faster and cost effective amyloid sensor. PMID- 28576071 TI - Augmentation of the cytotoxic effects of zinc oxide nanoparticles by MTCP conjugation: Non-canonical apoptosis and autophagy induction in human adenocarcinoma breast cancer cell lines. AB - Zinc oxide nanoparticles are very toxic, but their agglomeration reduces their lethal cytotoxic effects. Here we tested the hypothesis that conjugation of ZnO nanoparticles via Meso-Tetra (4-Carboxyphenyl) Porphyrin (MTCP) could provide electrostatic or steric stabilization of ZnO nanoparticles and increase their cytotoxic effects. The cytotoxicity and cell death induction were assessed using two human breast adenocarcinoma cell lines (MCF-7 and MDA-MB-468). The MTT results indicated that the toxicity of ZnO nanoparticles was significantly increased upon MTCP conjugation. Annexin/PI and real time RT-PCR results demonstrated that the ZnO-MTCP nanoparticles induced cell death via different non canonical pathways that are under ca2+ control. Calcium signaling could regulate lysosomal dependent apoptosis and death autophagy, and killing of the two selected types of breast cancer cells. PMID- 28576072 TI - Enhanced osteogenic activity of anatase TiO2 film: Surface hydroxyl groups induce conformational changes in fibronectin. AB - In this study, with an attempt to identify the effects of TiO2 crystalline phase compositions on the osteogenic properties, the anatase and rutile TiO2 thin films with similar film thickness, surface topography and hydrophilicity were prepared on Si (100) substrates by atomic layer deposition (ALD), subsequent thermal annealing and ultraviolet irradiation. The films were studied with XRD, XPS, FE SEM, AFM, FTIR and contact angle measurements. In vitro cellular assays showed that the anatase phase led to better osteoblast compatibility in terms of adhesion, proliferation, differentiation, mineralization as well as osteogenesis related gene expression when compared with the rutile phase. We investigated the difference between the anatase and rutile TiO2 films at the biomolecular level to explain the enhanced osteogenic activity of the anatase film. It was found that the presence of more TiOH groups on anatase surface induced more cell-binding sites of fibronectin (FN) exposed on its surface, causing a more active conformation of the adsorbed FN for subsequent osteoblast behaviors. PMID- 28576074 TI - In vitro and in vivo evaluation of anti-cancer activity: Shape-dependent properties of TiO2 nanostructures. AB - Cancer is a complex and widespread disease, and it is going to be the first cause of death in the world. Chemotherapy has been used to treat cancer, but it is detrimental to immune cells and known to induce numerous side effects. Therefore it is imperative to develop new drugs for the treatment of cancer without any side effects and toxicity. TiO2 nanomaterials are human safe, cost effective, chemically stable and have numerous biomedical applications. Spherical TiO2 fine particles (TFP), TiO2 nanosquares (TNS) and TiO2 nanotubes (TNT) were developed and evaluated for anti-cancer activity in vitro and in vivo. Our data suggest that these nanostructured materials significantly inhibited proliferation of breast cancer MDAMB 231 cells in in vitro shape dependent manner. In addition, we found that TiO2 nanostructures inhibited the migration and colony formation of breast cancer MDAMB231 cells. More importantly, we found that TNS/TNT/TFP had anti-angiogenic effect in CAM assay and TNT had comparable anti-angiogenic effect with the positive control staurosporine. Additional qRT-PCR data suggest that TiO2 nanostructures induced the upregulation of tumor suppressor genes p53, MDA7, TRAIL and transcription factor STAT3, which suggests the probable mechanism for the anticancer activity of TiO2 nanostructures. Finally, analysis of TEM confirms the dispersion and interaction of nanostructures in the cells. Thus these materials could be potential therapeutic targets for the treatment of cancer. PMID- 28576076 TI - Prevention of intra-abdominal adhesion using electrospun PEG/PLGA nanofibrous membranes. AB - The use of physical barriers, such as nanofiber membranes, is a potential method to prevent adhesion formation after surgery. In this study, we fabricated electrospun composite poly(ethylene glycol) (PEG)/poly(lactic-co-glycolic) (PLGA) nanofibrous membrane to prevent abdomen adhesion; this composite acts as a barrier between cecum and the surrounding tissues without interrupting mass transfer and cecum healing. PEG/PLGA nanofibrous membranes consisting of 0% (P0), 5% (P1), 10% (P2), 15% (P3), 20% (P4), and 25% (P5) PEG were prepared, and their physicochemical properties were characterized. The P0 shows the highest thermostability, whereas P1 exhibited the most homogenous morphology, the narrowest diameter distribution, and the largest ultimate stress and strain. In vitro cell adhesion and proliferation tests using fibroblasts indicate that all nanofibrous membranes inhibited cell proliferation, with P1 showing the lowest degree of cell attachment. In vivo application of nanofibrous membranes on the repaired site of rat cecum model demonstrated that all of the membranes prevent adhesion formation to a certain extent. We concluded based on gross observation, histological analysis, and functional assays that P1 served as an effective anti adhesion membrane after cecum surgery in a clinical setting. PMID- 28576075 TI - Designing structural features of novel benznidazole-loaded cationic nanoparticles for inducing slow drug release and improvement of biological efficacy. AB - Several polymers have been investigated for producing cationic nanocarriers due to their ability to cross biological barriers. Polycations such as copolymers of polymethylmethacrylate are highlighted due to their biocompatibility and low toxicity. The purpose of this study was to produce small and narrow-sized cationic nanoparticles able to overcome cell membranes and improve the biological activity of benznidazole (BNZ) in normal and cancer cells. The effect of composition and procedure parameters of the used emulsification-solvent evaporation method were controlled for this purpose. The experimental approach included particle size, polydispersity index, zeta potential, atomic force microscopy (AFM), attenuated total reflectance Fourier transforms infrared spectroscopy (ATR- FTIR), drug loading efficiency, and physical stability assays. Spherical and stable (over six weeks) sub 150nm cationic nanoparticles were optimized, with the encapsulation efficiency >80%. The used drug/copolymer ratio modulated the slow drug release, which was adjusted by the parabolic diffusion mathematical model. In addition, the ability of the cationic nanoparticles improve the BNZ uptake in the normal kidney cells (HEK 293) and the human colorectal cancer cells (HT 29) demonstrate that this novel BNZ-loaded cationic has great potential as a chemotherapeutic application of benznidazole. PMID- 28576077 TI - Near-infrared mediated chemo/photodynamic synergistic therapy with DOX UCNPs@mSiO2/TiO2-TC nanocomposite. AB - To integrate photodynamic therapy (PDT) with chemotherapy for enhanced anticancer efficiency, near infrared (NIR) light mediated upconversion nanoparticles@mesoporous silica (UCNPs@mSiO2) nanovehicle was constructed as the nanocarrier. Based on the novel ultraviolet (UV) emission, TiO2 (3.0-3.2eV) was adopted as the photosensitiver (PS) on account of the high activity and excellent stability. Here, a simple host-assembly method was exploited to graft it onto the inner and outer surface of the mSiO2 shell. On the other hand, a UV cleavable o nitrobenzyl derivative linker (TC linker) was prepared as "gate" to encapsulate anticancer agent doxorubicin (DOX) inside mSiO2, insuring the few prematurity. Under NIR irradiation, the UV emission can excite TiO2 to produce reactive oxygen species (ROS) and also can induce the photodegradation of TC linker and drug release as well. The detailed release kinetics was studied to reveal that it is TC linker to manipulate the NIR-sensitive drug release and the amount of TC linker also can be used to adjust the release performance. The synergistic action of PDT and chemotherapy displays the improved cytotoxicity of DOX UCNPs@mSiO2/TiO2-TC to HeLa cells under NIR irradiation that makes the potential application in anticancer field due to the superior to any single means. PMID- 28576078 TI - CF2H, a Hydrogen Bond Donor. AB - The CF2H group, a potential surrogate for the OH group, can act as an unusual hydrogen bond donor, as confirmed by crystallographic, spectroscopic, and computational methods. Here, we demonstrate the bioisosterism of the OH and CF2H groups and the important roles of CF2-H...O hydrogen bonds in influencing intermolecular interactions and conformational preferences. Experimental evidence, corroborated by theory, reveals the distinctive nature of CF2H hydrogen bonding interactions relative to their normal OH hydrogen bonding counterparts. PMID- 28576079 TI - Some Theoretical and Experimental Insights on the Mechanistic Routes Leading to the Spontaneous Grafting of Gold Surfaces by Diazonium Salts. AB - The spontaneous grafting of diazonium salts on gold may involve the carbocation obtained by heterolytic dediazonation and not necessarily the radical, as usually observed on reducing surfaces. The mechanism is addressed on the basis of DFT calculations and experiments carried out under conditions where the carbocation and the radical are produced selectively. The calculations indicate that the driving force of the reaction leading from a gold cluster, used as a gold model surface, and the carbocation to the modified cluster is higher than that of the analogous reaction starting from the radical. The experiments performed under conditions of heterolytic dediazonation show the formation of thin films on the surface of gold. The grafting of a carbocation is therefore possible, but a mechanism where the cleavage of the Ar-N bond is catalyzed by the surface of gold cannot be excluded. PMID- 28576080 TI - Lysozyme orientation and conformation on MoS2 surface: Insights from molecular simulations. AB - Two-dimensional molybdenum disulfide (MoS2) has attracted intense interest owing to its unique properties and promising biosensor applications. To develop effective biocompatible platforms, it is crucial to understand the interactions between MoS2 and biological molecules such as proteins, but little knowledge exists on the orientation and conformation of proteins on the MoS2 surface at the molecular level. In this work, the lysozyme adsorption on the MoS2 surface was studied by molecular dynamics simulations, wherein six different orientations were selected based on the different faces of lysozyme. Simulation results showed that lysozyme tends to adsorb on the MoS2 surface in an "end-on" orientation, indicating that orientations within this range are favorable for stable adsorption. The end-on orientation could be further categorized into "bottom end on" and "top end-on" orientations. The driving forces responsible for the adsorption were dominated by van der Waals interactions and supplemented by electrostatic interactions. Further, the conformations of the lysozyme adsorbed on the MoS2 surface were basically preserved. This simulation study promotes the fundamental understanding of interactions between MoS2 and proteins and can guide the development of future biomedical applications of MoS2. PMID- 28576081 TI - The effects of tether placement on antibody stability on surfaces. AB - Despite their potential benefits, antibody microarrays have fallen short of performing reliably and have not found widespread use outside of the research setting. Experimental techniques have been unable to determine what is occurring on the surface of an atomic level, so molecular simulation has emerged as the primary method of investigating protein/surface interactions. Simulations of small proteins have indicated that the stability of the protein is a function of the residue on the protein where a tether is placed. The purpose of this research is to see whether these findings also apply to antibodies, with their greater size and complexity. To determine this, 24 tethering locations were selected on the antibody Protein Data Bank (PDB) ID: 1IGT. Replica exchange simulations were run on two different surfaces, one hydrophobic and one hydrophilic, to determine the degree to which these tethering sites stabilize or destabilize the antibody. Results showed that antibodies tethered to hydrophobic surfaces were in general less stable than antibodies tethered to hydrophilic surfaces. Moreover, the stability of the antibody was a function of the tether location on hydrophobic surfaces but not hydrophilic surfaces. PMID- 28576083 TI - Interpretation of x-ray absorption spectroscopy in the presence of surface hybridization. AB - X-ray absorption spectroscopy (XAS) yields direct access to the electronic and geometric structure of hybrid inorganic-organic interfaces formed upon adsorption of complex molecules at metal surfaces. The unambiguous interpretation of corresponding spectra is challenged by the intrinsic geometric flexibility of the adsorbates and the chemical interactions with the interface. Density-functional theory (DFT) calculations of the extended adsorbate-substrate system are an established tool to guide peak assignment in X-ray photoelectron spectroscopy of complex interfaces. We extend this to the simulation and interpretation of XAS data in the context of functional organic molecules on metal surfaces using dispersion-corrected DFT calculations within the transition potential approach. For the prototypical case of 2H-porphine adsorbed on Ag(111) and Cu(111) substrates, we follow the two main effects of the molecule/surface interaction onto the X-ray absorption signatures: (1) the substrate-induced chemical shift of the 1s core levels that dominates in physisorbed systems and (2) the hybridization-induced broadening and loss of distinct resonances that dominate in more chemisorbed systems. PMID- 28576082 TI - Optimization of the linear-scaling local natural orbital CCSD(T) method: Redundancy-free triples correction using Laplace transform. AB - An improved algorithm is presented for the evaluation of the (T) correction as a part of our local natural orbital (LNO) coupled-cluster singles and doubles with perturbative triples [LNO-CCSD(T)] scheme [Z. Rolik et al., J. Chem. Phys. 139, 094105 (2013)]. The new algorithm is an order of magnitude faster than our previous one and removes the bottleneck related to the calculation of the (T) contribution. First, a numerical Laplace transformed expression for the (T) fragment energy is introduced, which requires on average 3 to 4 times fewer floating point operations with negligible compromise in accuracy eliminating the redundancy among the evaluated triples amplitudes. Second, an additional speedup factor of 3 is achieved by the optimization of our canonical (T) algorithm, which is also executed in the local case. These developments can also be integrated into canonical as well as alternative fragmentation-based local CCSD(T) approaches with minor modifications. As it is demonstrated by our benchmark calculations, the evaluation of the new Laplace transformed (T) correction can always be performed if the preceding CCSD iterations are feasible, and the new scheme enables the computation of LNO-CCSD(T) correlation energies with at least triple-zeta quality basis sets for realistic three-dimensional molecules with more than 600 atoms and 12 000 basis functions in a matter of days on a single processor. PMID- 28576084 TI - Communication: Density functional theory embedding with the orthogonality constrained basis set expansion procedure. AB - Density functional theory (DFT) embedding approaches have generated considerable interest in the field of computational chemistry because they enable calculations on larger systems by treating subsystems at different levels of theory. To circumvent the calculation of the non-additive kinetic potential, various projector methods have been developed to ensure the orthogonality of molecular orbitals between subsystems. Herein the orthogonality constrained basis set expansion (OCBSE) procedure is implemented to enforce this subsystem orbital orthogonality without requiring a level shifting parameter. This scheme is a simple alternative to existing parameter-free projector-based schemes, such as the Huzinaga equation. The main advantage of the OCBSE procedure is that excellent convergence behavior is attained for DFT-in-DFT embedding without freezing any of the subsystem densities. For the three chemical systems studied, the level of accuracy is comparable to or higher than that obtained with the Huzinaga scheme with frozen subsystem densities. Allowing both the high-level and low-level DFT densities to respond to each other during DFT-in-DFT embedding calculations provides more flexibility and renders this approach more generally applicable to chemical systems. It could also be useful for future extensions to embedding approaches combining wavefunction theories and DFT. PMID- 28576085 TI - Lysozyme in water-acetonitrile mixtures: Preferential solvation at the inner edge of excess hydration. AB - Preferential solvation/hydration is an effective way for regulating the mechanism of the protein destabilization/stabilization. Organic solvent/water sorption and residual enzyme activity measurements were performed to monitor the preferential solvation/hydration of hen egg-white lysozyme at high and low water content in acetonitrile at 25 degrees C. The obtained results show that the protein destabilization/stabilization depends essentially on the initial hydration level of lysozyme and the water content in acetonitrile. There are three composition regimes for the dried lysozyme. At high water content, the lysozyme has a higher affinity for water than for acetonitrile. The residual enzyme activity values are close to 100%. At the intermediate water content, the dehydrated lysozyme has a higher affinity for acetonitrile than for water. A minimum on the residual enzyme activity curve was observed in this concentration range. At the lowest water content, the organic solvent molecules are preferentially excluded from the dried lysozyme, resulting in the preferential hydration. The residual catalytic activity is ~80%, compared with that observed after incubation in pure water. Two distinct schemes are operative for the hydrated lysozyme. At high and intermediate water content, lysozyme is preferentially hydrated. However, in contrast to the dried protein, at the intermediate water content, the initially hydrated lysozyme has the increased preferential hydration parameters. At low water content, the preferential binding of the acetonitrile molecules to the initially hydrated lysozyme was detected. No residual enzyme activity was observed in the water-poor acetonitrile. Our data clearly show that the initial hydration level of the protein macromolecules is one of the key factors that govern the stability of the protein-water-organic solvent systems. PMID- 28576086 TI - An extension of stochastic hierarchy equations of motion for the equilibrium correlation functions. AB - A traditional stochastic hierarchy equations of motion method is extended into the correlated real-time and imaginary-time propagations, in this paper, for its applications in calculating the equilibrium correlation functions. The central idea is based on a combined employment of stochastic unravelling and hierarchical techniques for the temperature-dependent and temperature-free parts of the influence functional, respectively, in the path integral formalism of the open quantum systems coupled to a harmonic bath. The feasibility and validity of the proposed method are justified in the emission spectra of homodimer compared to those obtained through the deterministic hierarchy equations of motion. Besides, it is interesting to find that the complex noises generated from a small portion of real-time and imaginary-time cross terms can be safely dropped to produce the stable and accurate position and flux correlation functions in a broad parameter regime. PMID- 28576087 TI - Self-assembly and molecular packing in cholesteryl esters at interfaces. AB - To understand the self-assembly and molecular packing in cholesteryl esters relevant to biological processes, we have studied them at the air-water and air solid interfaces. Our phase and thickness studies employing imaging ellipsometry and atomic force microscopy along with surface manometry show that the molecular packing of cholesteryl esters at interfaces can be related to Craven's model of packing, given for bulk. At the air-water interface, following Craven's model, cholesteryl nonanoate and cholesteryl laurate exhibit a fluidic bilayer phase. Interestingly, we find the fluidic bilayer phase of cholesteryl laurate to be unstable and it switches to a crystalline bilayer phase. However, according to Craven, only cholesteryl esters with longer chain lengths starting from cholesteryl tridecanoate should show the crystalline bilayer phase. The thickness behavior of different phases was also studied by transferring the films onto a silicon substrate by using the Langmuir-Blodgett technique. Texture studies show that cholesterol, cholesteryl acetate, cholesteryl nonanoate, cholesteryl laurate, and cholesteryl myristate exhibit homogeneous films with large size domains, whereas cholesteryl palmitate and cholesteryl stearate exhibit less homogeneous films with smaller size domains. We suggest that such an assembly of molecules can be related to their molecular structures. Simulation studies may confirm such a relation. PMID- 28576088 TI - Effect of nanoscale flows on the surface structure of nanoporous catalysts. AB - The surface structure and composition of a multi-component catalyst are critical factors in determining its catalytic performance. The surface composition can depend on the local pressure of the reacting species, leading to the possibility that the flow through a nanoporous catalyst can affect its structure and reactivity. Here, we explore this possibility for oxidation reactions on nanoporous gold, an AgAu bimetallic catalyst. We use microscopy and digital reconstruction to obtain the morphology of a two-dimensional slice of a nanoporous gold sample. Using lattice Boltzmann fluid dynamics simulations along with thermodynamic models based on first-principles total-energy calculations, we show that some sections of this sample have low local O2 partial pressures when exposed to reaction conditions, which leads to a pure Au surface in these regions, instead of the active bimetallic AgAu phase. We also explore the effect of temperature on the surface structure and find that moderate temperatures (~300 450 K) should result in the highest intrinsic catalytic performance, in apparent agreement with experimental results. PMID- 28576089 TI - Coarse-grained representation of the quasi adiabatic propagator path integral for the treatment of non-Markovian long-time bath memory. AB - The description of non-Markovian effects imposed by low frequency bath modes poses a persistent challenge for path integral based approaches like the iterative quasi-adiabatic propagator path integral (iQUAPI) method. We present a novel approximate method, termed mask assisted coarse graining of influence coefficients (MACGIC)-iQUAPI, that offers appealing computational savings due to substantial reduction of considered path segments for propagation. The method relies on an efficient path segment merging procedure via an intermediate coarse grained representation of Feynman-Vernon influence coefficients that exploits physical properties of system decoherence. The MACGIC-iQUAPI method allows us to access the regime of biological significant long-time bath memory on the order of hundred propagation time steps while retaining convergence to iQUAPI results. Numerical performance is demonstrated for a set of benchmark problems that cover bath assisted long range electron transfer, the transition from coherent to incoherent dynamics in a prototypical molecular dimer and excitation energy transfer in a 24-state model of the Fenna-Matthews-Olson trimer complex where in all cases excellent agreement with numerically exact reference data is obtained. PMID- 28576090 TI - On the physical interpretation of the nuclear molecular orbital energy. AB - Recently, several groups have extended and implemented molecular orbital (MO) schemes to simultaneously obtain wave functions for electrons and selected nuclei. Many of these schemes employ an extended Hartree-Fock approach as a first step to find approximate electron-nuclear wave functions and energies. Numerous studies conducted with these extended MO methodologies have explored various effects of quantum nuclei on physical and chemical properties. However, to the best of our knowledge no physical interpretation has been assigned to the nuclear molecular orbital energy (NMOE) resulting after solving extended Hartree-Fock equations. This study confirms that the NMOE is directly related to the molecular electrostatic potential at the position of the nucleus. PMID- 28576091 TI - Infrared spectroscopic and theoretical study of the HC2n+1O+ (n = 2-5) cations. AB - The carbon chain cations, HC2n+1O+ (n = 2-5), are produced via pulsed laser vaporization of a graphite target in supersonic expansions containing carbon monoxide and hydrogen. The infrared spectra are measured via mass-selected infrared photodissociation spectroscopy of the CO "tagged" [HC2n+1O.CO]+ cation complexes in the 1600-3500 cm-1 region. The geometries and electronic ground states of these cation complexes are determined by their infrared spectra compared to the predications of theoretical calculations. All of the HC2n+1O+ (n = 2-5) core cations are characterized to be linear carbon chain derivatives terminated by hydrogen and oxygen, which have the closed-shell singlet ground states with polyyne-like carbon chain structures. PMID- 28576092 TI - Searching for DFT-based methods that include dispersion interactions to calculate the physisorption of H2 on benzene and graphene. AB - Simulations of the hydrogen storage capacities of nanoporous carbons require an accurate treatment of the interaction of the hydrogen molecule with the graphite like surfaces of the carbon pores, which is dominated by the dispersion forces. These interactions are described accurately by high level quantum chemistry methods, like the Coupled Cluster method with single and double excitations and a non-iterative correction for triple excitations (CCSD(T)), but those methods are computationally very expensive for large systems and for massive simulations. Density functional theory (DFT)-based methods that include dispersion interactions at different levels of complexity are less accurate, but computationally less expensive. In order to find DFT-methods that include dispersion interactions to calculate the physisorption of H2 on benzene and graphene, with a reasonable compromise between accuracy and computational cost, CCSD(T), Moller-Plesset second-order perturbation theory method, and several DFT methods have been used to calculate the interaction energy curves of H2 on benzene and graphene. DFT calculations are compared with CCSD(T) calculations, in the case of H2 on benzene, and with experimental data, in the case of H2 on graphene. Among the DFT methods studied, the B97D, RVV10, and PBE+DCACP methods yield interaction energy curves of H2-benzene in remarkable agreement with the interaction energy curve obtained with the CCSD(T) method. With regards to graphene, the rev-vdW-DF2, PBE-XDM, PBE-D2, and RVV10 methods yield adsorption energies of the lowest level of H2 on graphene, very close to the experimental data. PMID- 28576093 TI - Diffusing diffusivity: Rotational diffusion in two and three dimensions. AB - We consider the problem of calculating the probability distribution function (pdf) of angular displacement for rotational diffusion in a crowded, rearranging medium. We use the diffusing diffusivity model and following our previous work on translational diffusion [R. Jain and K. L. Sebastian, J. Phys. Chem. B 120, 3988 (2016)], we show that the problem can be reduced to that of calculating the survival probability of a particle undergoing Brownian motion, in the presence of a sink. We use the approach to calculate the pdf for the rotational motion in two and three dimensions. We also propose new dimensionless, time dependent parameters, alpharot,2D and alpharot,3D, which can be used to analyze the experimental/simulation data to find the extent of deviation from the normal behavior, i.e., constant diffusivity, and obtain explicit analytical expressions for them, within our model. PMID- 28576094 TI - Frequency and phase synchronization in large groups: Low dimensional description of synchronized clapping, firefly flashing, and cricket chirping. AB - A common observation is that large groups of oscillatory biological units often have the ability to synchronize. A paradigmatic model of such behavior is provided by the Kuramoto model, which achieves synchronization through coupling of the phase dynamics of individual oscillators, while each oscillator maintains a different constant inherent natural frequency. Here we consider the biologically likely possibility that the oscillatory units may be capable of enhancing their synchronization ability by adaptive frequency dynamics. We propose a simple augmentation of the Kuramoto model which does this. We also show that, by the use of a previously developed technique [Ott and Antonsen, Chaos 18, 037113 (2008)], it is possible to reduce the resulting dynamics to a lower dimensional system for the macroscopic evolution of the oscillator ensemble. By employing this reduction, we investigate the dynamics of our system, finding a characteristic hysteretic behavior and enhancement of the quality of the achieved synchronization. PMID- 28576095 TI - Synchronization of moving oscillators in three dimensional space. AB - We investigate the macroscopic behavior of a dynamical network consisting of a time-evolving wiring of interactions among a group of random walkers. We assume that each walker (agent) has an oscillator and show that depending upon the nature of interaction, synchronization arises where each of the individual oscillators are allowed to move in such a random walk manner in a finite region of three dimensional space. Here, the vision range of each oscillator decides the number of oscillators with which it interacts. The live interaction between the oscillators is of intermediate type (i.e., not local as well as not global) and may or may not be bidirectional. We analytically derive the density dependent threshold of coupling strength for synchronization using linear stability analysis and numerically verify the obtained analytical results. Additionally, we explore the concept of basin stability, a nonlinear measure based on volumes of basin of attractions, to investigate how stable the synchronous state is under large perturbations. The synchronization phenomenon is analyzed taking limit cycle and chaotic oscillators for wide ranges of parameters like interaction strength k between the walkers, speed of movement v, and vision range r. PMID- 28576096 TI - An initial-boundary value problem for the integrable spin-1 Gross-Pitaevskii equations with a 4 * 4 Lax pair on the half-line. AB - We extend the idea of the Fokas unified transform to investigate the initial boundary value problem for the integrable spin-1 Gross-Pitaevskii equations with a 4 * 4 Lax pair on the half-line. The solution of this system can be expressed in terms of the solution of a 4 * 4 matrix Riemann-Hilbert (RH) problem formulated in the complex k-plane. The relevant jump matrices of the RH problem can be explicitly found using the two spectral functions s(k) and S(k), which can be defined by the initial data, the Dirichlet-Neumann boundary data at x = 0. The global relation is established between the two dependent spectral functions. The general mappings between Dirichlet and Neumann boundary values are analyzed in terms of the global relation. These results may be of the potential significance in both spinor Bose-Einstein condensates and the theory of multi-component integrable systems. PMID- 28576097 TI - Effects of partial time delays on phase synchronization in Watts-Strogatz small world neuronal networks. AB - In this paper, we study effects of partial time delays on phase synchronization in Watts-Strogatz small-world neuronal networks. Our focus is on the impact of two parameters, namely the time delay tau and the probability of partial time delay pdelay, whereby the latter determines the probability with which a connection between two neurons is delayed. Our research reveals that partial time delays significantly affect phase synchronization in this system. In particular, partial time delays can either enhance or decrease phase synchronization and induce synchronization transitions with changes in the mean firing rate of neurons, as well as induce switching between synchronized neurons with period-1 firing to synchronized neurons with period-2 firing. Moreover, in comparison to a neuronal network where all connections are delayed, we show that small partial time delay probabilities have especially different influences on phase synchronization of neuronal networks. PMID- 28576098 TI - Generation of multi-scroll attractors without equilibria via piecewise linear systems. AB - In this paper, we present a new class of dynamical system without equilibria which possesses a multiscroll attractor. It is a piecewise-linear system which is simple, stable, displays chaotic behavior and serves as a model for analogous non linear systems. We test for chaos using the 0-1 Test for Chaos from Gottwald and Melbourne [SIAM J. Appl. Dyn. Syst. 8(1), 129-145 (2009)]. PMID- 28576099 TI - Solitons and their stability in the nonlocal nonlinear Schrodinger equation with PT-symmetric potentials. AB - We report localized nonlinear modes of the self-focusing and defocusing nonlocal nonlinear Schrodinger equation with the generalized PT-symmetric Scarf-II, Rosen Morse, and periodic potentials. Parameter regions are presented for broken and unbroken PT-symmetric phases of linear bounded states and the linear stability of the obtained solitons. Moreover, we numerically explore the dynamical behaviors of solitons and find stable solitons for some given parameters. PMID- 28576100 TI - Isochronous dynamics in pulse coupled oscillator networks with delay. AB - We consider a network of identical pulse-coupled oscillators with delay and all to-all coupling. We demonstrate that the discontinuous nature of the dynamics induces the appearance of isochronous regions-subsets of the phase space filled with periodic orbits having the same period. For each fixed value of the network parameters, such an isochronous region corresponds to a subset of initial states on an appropriate surface of section with non-zero dimensions such that all periodic orbits in this set have qualitatively similar dynamical behaviour. We analytically and numerically study in detail such an isochronous region, give proof of its existence, and describe its properties. We further describe other isochronous regions that appear in the system. PMID- 28576101 TI - The stability of fixed points for a Kuramoto model with Hebbian interactions. AB - We consider a variation of the Kuramoto model with dynamic coupling, where the coupling strengths are allowed to evolve in response to the phase difference between the oscillators, a model first considered by Ha, Noh, and Park. We demonstrate that the fixed points of this model, as well as their stability, can be completely expressed in terms of the fixed points and stability of the analogous classical Kuramoto problem where the coupling strengths are fixed to a constant (the same for all edges). In particular, for the "all-to-all" network, where the underlying graph is the complete graph, the problem reduces to the problem of understanding the fixed points and stability of the all-to-all Kuramoto model with equal edge weights, a problem that is well understood. PMID- 28576102 TI - A critical comparison of Lagrangian methods for coherent structure detection. AB - We review and test twelve different approaches to the detection of finite-time coherent material structures in two-dimensional, temporally aperiodic flows. We consider both mathematical methods and diagnostic scalar fields, comparing their performance on three benchmark examples: the quasiperiodically forced Bickley jet, a two-dimensional turbulence simulation, and an observational wind velocity field from Jupiter's atmosphere. A close inspection of the results reveals that the various methods often produce very different predictions for coherent structures, once they are evaluated beyond heuristic visual assessment. As we find by passive advection of the coherent set candidates, false positives and negatives can be produced even by some of the mathematically justified methods due to the ineffectiveness of their underlying coherence principles in certain flow configurations. We summarize the inferred strengths and weaknesses of each method, and make general recommendations for minimal self-consistency requirements that any Lagrangian coherence detection technique should satisfy. PMID- 28576103 TI - Topological characterization and early detection of bifurcations and chaos in complex systems using persistent homology. AB - Early detection of bifurcations and chaos and understanding their topological characteristics are essential for safe and reliable operation of various electrical, chemical, physical, and industrial processes. However, the presence of non-linearity and high-dimensionality in system behavior makes this analysis a challenging task. The existing methods for dynamical system analysis provide useful tools for anomaly detection (e.g., Bendixson-Dulac and Poincare-Bendixson criteria can detect the presence of limit cycles); however, they do not provide a detailed topological understanding about system evolution during bifurcations and chaos, such as the changes in the number of subcycles and their positions, lifetimes, and sizes. This paper addresses this research gap by using topological data analysis as a tool to study system evolution and develop a mathematical framework for detecting the topological changes in the underlying system using persistent homology. Using the proposed technique, topological features (e.g., number of relevant k-dimensional holes, etc.) are extracted from nonlinear time series data which are useful for deeper analysis of the system behavior and early detection of bifurcations and chaos. When applied to a Logistic map, a Duffing oscillator, and a real life Op-amp based Jerk circuit, these features are shown to accurately characterize the system dynamics and detect the onset of chaos. PMID- 28576104 TI - Systematic search for wide periodic windows and bounds for the set of regular parameters for the quadratic map. AB - An efficient method to find positions of periodic windows for the quadratic map f(x)=ax(1-x) and a heuristic algorithm to locate the majority of wide periodic windows are proposed. Accurate rigorous bounds of positions of all periodic windows with periods below 37 and the majority of wide periodic windows with longer periods are found. Based on these results, we prove that the measure of the set of regular parameters in the interval [3,4] is above 0.613960137. The properties of periodic windows are studied numerically. The results of the analysis are used to estimate that the true value of the measure of the set of regular parameters is close to 0.6139603. PMID- 28576105 TI - On the influence of additive and multiplicative noise on holes in dissipative systems. AB - We investigate the influence of noise on deterministically stable holes in the cubic-quintic complex Ginzburg-Landau equation. Inspired by experimental possibilities, we specifically study two types of noise: additive noise delta correlated in space and spatially homogeneous multiplicative noise on the formation of pi-holes and 2pi-holes. Our results include the following main features. For large enough additive noise, we always find a transition to the noisy version of the spatially homogeneous finite amplitude solution, while for sufficiently large multiplicative noise, a collapse occurs to the zero amplitude solution. The latter type of behavior, while unexpected deterministically, can be traced back to a characteristic feature of multiplicative noise; the zero solution acts as the analogue of an absorbing boundary: once trapped at zero, the system cannot escape. For 2pi-holes, which exist deterministically over a fairly small range of values of subcriticality, one can induce a transition to a pi-hole (for additive noise) or to a noise-sustained pulse (for multiplicative noise). This observation opens the possibility of noise-induced switching back and forth from and to 2pi-holes. PMID- 28576107 TI - Experimental analysis of density fingering instability modified by precipitation. AB - We analyze the effect of precipitate formation on the development of density induced hydrodynamic instabilities. In this case, the precipitate is BaCO3, obtained by reaction of CO2 with aqueous BaCl2. CO2(g) dissolution increases the local density of the aqueous phase, triggering Rayleigh-Taylor instabilities and BaCO3 formation. It was observed that at first the precipitate was formed at the finger front. As the particles became bigger, they began to fall down from the front. These particles were used as tracers using PIV technique to visualize the particle streamlines and to obtain the velocity of that movement. This falling produced a downward flow that might increase the mixing zone. Contrary to expectations, it was observed that the finger length decreased, indicating that for the mixing zone development, the consumption of CO2 to form the precipitate is more important than the downward flow. The mixing zone length was recovered by increasing the availability of the reactant (higher CO2 partial pressure), compensating the CO2 used for BaCO3 formation. Mixing zone development rates reached constant values at shorter times when the precipitate is absent than when it is present. An analysis of the nonlinear regime with and without the precipitate is performed. PMID- 28576106 TI - Electrical resonance of Amphotericin B channel activity in lipidic membranes. AB - In our previous work [J. Membrane Biol. 237, 31 (2010)], we showed the dependence of the time average conductance of Nystatin channels as a function of the applied potential. Specifically, it was observed that greater potential induced enhanced channel activity. This indicates that the supramolecular structure could be stabilized by a large field, possibly by giving a preferential orientation to the monomers. In the present work, we entertain the notion that the process of pore formation in the lipidic membranes has an underlying deterministic component. To verify this hypothesis, experiments were performed under potentio-dynamic conditions, i.e., a square train of pulses of different frequencies (0.05-2 Hz) were applied to a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine membrane having 30 mol. % cholesterol and the presence of 35 MUM Amphotericin B. An emergence of a resonant frequency, in the present experiments, is tantamount to observing fingerprints of determinism in the activity of these channels in lipidic membranes. PMID- 28576108 TI - Calculation of Hamilton energy and control of dynamical systems with different types of attractors. AB - Strange attractors can be observed in chaotic and hyperchaotic systems. Most of the dynamical systems hold a finite number of attractors, while some chaotic systems can be controlled to present an infinite number of attractors by generating infinite equilibria. Chaos can also be triggered in some dynamical systems that can present hidden attractors, and the attractors in these dynamical systems find no equilibria and the basin of attraction is not connected with any equilibrium (the equilibria position meets certain restriction function). In this paper, Hamilton energy is calculated on the chaotic systems with different types of attractors, and energy modulation is used to control the chaos in these systems. The potential mechanism could be that negative feedback in energy can suppress the phase space and oscillating behaviors, and thus, the chaotic, periodical oscillators can be controlled. It could be effective to control other chaotic, hyperchaotic and even periodical oscillating systems as well. PMID- 28576109 TI - Construction of rational solutions of the real modified Korteweg-de Vries equation from its periodic solutions. AB - In this paper, we consider the real modified Korteweg-de Vries (mKdV) equation and construct a special kind of breather solution, which can be obtained by taking the limit lambdaj -> lambda1 of the Lax pair eigenvalues used in the n fold Darboux transformation that generates the order-n periodic solution from a constant seed solution. Further, this special kind of breather solution of order n can be used to generate the order-n rational solution by taking the limit lambda1 -> lambda0, where lambda0 is a special eigenvalue associated with the eigenfunction phi of the Lax pair of the mKdV equation. This eigenvalue lambda0, for which phi(lambda0)=0, corresponds to the limit of infinite period of the periodic solution. Our analytical and numerical results show the effective mechanism of generation of higher-order rational solutions of the mKdV equation from the double eigenvalue degeneration process of multi-periodic solutions. PMID- 28576110 TI - Improving the pseudo-randomness properties of chaotic maps using deep-zoom. AB - A generalized method is proposed to compose new orbits from a given chaotic map. The method provides an approach to examine discrete-time chaotic maps in a "deep zoom" manner by using k-digits to the right from the decimal separator of a given point from the underlying chaotic map. Interesting phenomena have been identified. Rapid randomization was observed, i.e., chaotic patterns tend to become indistinguishable when compared to the original orbits of the underlying chaotic map. Our results were presented using different graphical analyses (i.e., time-evolution, bifurcation diagram, Lyapunov exponent, Poincare diagram, and frequency distribution). Moreover, taking advantage of this randomization improvement, we propose a Pseudo-Random Number Generator (PRNG) based on the k logistic map. The pseudo-random qualities of the proposed PRNG passed both tests successfully, i.e., DIEHARD and NIST, and were comparable with other traditional PRNGs such as the Mersenne Twister. The results suggest that simple maps such as the logistic map can be considered as good PRNG methods. PMID- 28576111 TI - Generalized synchronization between chimera states. AB - Networks of coupled oscillators in chimera states are characterized by an intriguing interplay of synchronous and asynchronous motion. While chimera states were initially discovered in mathematical model systems, there is growing experimental and conceptual evidence that they manifest themselves also in natural and man-made networks. In real-world systems, however, synchronization and desynchronization are not only important within individual networks but also across different interacting networks. It is therefore essential to investigate if chimera states can be synchronized across networks. To address this open problem, we use the classical setting of ring networks of non-locally coupled identical phase oscillators. We apply diffusive drive-response couplings between pairs of such networks that individually show chimera states when there is no coupling between them. The drive and response networks are either identical or they differ by a variable mismatch in their phase lag parameters. In both cases, already for weak couplings, the coherent domain of the response network aligns its position to the one of the driver networks. For identical networks, a sufficiently strong coupling leads to identical synchronization between the drive and response. For non-identical networks, we use the auxiliary system approach to demonstrate that generalized synchronization is established instead. In this case, the response network continues to show a chimera dynamics which however remains distinct from the one of the driver. Hence, segregated synchronized and desynchronized domains in individual networks congregate in generalized synchronization across networks. PMID- 28576112 TI - Periodic nonlinear sliding modes for two uniformly magnetized spheres. AB - A uniformly magnetized sphere slides without friction along the surface of a second, identical sphere that is held fixed in space, subject to the magnetic force and torque of the fixed sphere and the normal force. The free sphere has two stable equilibrium positions and two unstable equilibrium positions. Two small-amplitude oscillatory modes describe the sliding motion of the free sphere near each stable equilibrium, and an unstable oscillatory mode describes the motion near each unstable equilibrium. The three oscillatory modes remain periodic at finite amplitudes, one bifurcating into mixed modes and circumnavigating the free sphere at large energies. For small energies, the free sphere is confined to one of the two discontiguous domains, each surrounding a stable equilibrium position. At large energies, these domains merge and the free sphere may visit both positions. The critical energy at which these domains merge coincides with the cumulation point of an infinite cascade of mixed-mode bifurcations. These findings exploit the equivalence of the force and torque between two uniformly magnetized spheres and the force and torque between two equivalent point dipoles, and offer clues to the rich nonlinear dynamics of this system. Online MagPhyx visualizations illustrate the dynamics. PMID- 28576113 TI - Degenerate ITS7 primer enhances oomycete community coverage and PCR sensitivity to Aphanomyces species, economically important plant pathogens. AB - Metagenomic analysis of oomycetes through deep amplicon sequencing has been conducted primarily using the ITS6-ITS7 primer set that targets the ITS1 region. While this primer set shows a perfect match to most oomycete taxa, ITS7 contains 3 mismatches to the corresponding binding site of plant pathogens within the genus Aphanomyces. Polymerase chain reaction (PCR) efficiency differs for taxa with uneven primer matching characteristics, which may explain why previous studies have detected this genus at low abundance. To overcome the impact of these mismatches on PCR sensitivity, the mismatched nucleotides were replaced with degenerate nucleotides. Oomycete communities from 35 soil samples collected from asymptomatic and root rot diseased sites in pea fields across Alberta were analyzed simultaneously using ITS6-ITS7 and ITS6-ITS7-a.e. (modified version of ITS7) primer sets on 1 Illumina MiSeq run. The number of high-quality reads obtained by ITS6-ITS7-a.e. was more than twice that of ITS6-ITS7. The relative abundance of Pythium spp. was reduced and Aphanomyces spp. increased. Aphanomyces cf. cladogamus and Aphanomyces euteiches were the second and third most abundant species, respectively, in the pea rhizosphere using the ITS7-a.e. primer, but were rare using the ITS7 primer. These results indicate that use of ITS7-a.e. provides a more accurate picture of oomycete communities than ITS7 by enhancing PCR sensitivity to Aphanomyces. PMID- 28576114 TI - A prospective cohort study on symptoms of common mental disorders among current and retired professional ice hockey players. AB - OBJECTIVES: Scientific knowledge about symptoms of common mental disorders in professional ice hockey is lacking. Consequently, the primary aims of the study were to (i) determine the prevalence, comorbidity and 6-month incidence of symptoms of common mental disorders (distress, anxiety/depression, sleep disturbance, adverse alcohol use, eating disorders) among current and retired professional ice hockey players and (ii) evaluate their potential relation with potential stressors (severe musculoskeletal injuries, surgeries, recent life events, career dissatisfaction). METHODS: A prospective cohort study with a 6 month follow-up period was conducted. Using validated questionnaires to assess symptoms of common mental disorders (thus not clinically diagnosed) as well as several stressors, an electronic questionnaire was set up and distributed by the national ice hockey players' unions from Denmark, Finland, Norway and Switzerland. RESULTS: Prevalence ranged from 8% for adverse alcohol use to 24% for anxiety/depression among current professional ice hockey players, and from 12% for distress to 29% for adverse alcohol among retired professional ice hockey players. Six-month incidence reached up to 22% for eating disorders among current players and 25% for sleep disturbance among retired players. Especially a higher number of surgeries, a higher number of recent life events and higher level of career dissatisfaction was related to symptoms of common mental disorders. CONCLUSIONS: Our findings indicate that adequate interventions should be developed to improve not only awareness and psychological resilience of both current and retired ice hockey players but also their performance and quality-of life. An interdisciplinary approach should be applied in the medical care of ice hockey players by including psychologists/psychiatrists who can provide psychotherapeutic or clinical interventions. PMID- 28576115 TI - Metagenomic analysis of oomycete communities from the rhizosphere of field pea on the Canadian prairies. AB - Oomycetes are a diverse group of microorganisms; however, little is known about their composition and biodiversity in agroecosystems. Illumina MiSeq was used to determine the type and abundance of oomycetes associated with pea root rot in the Canadian prairies. Additional objectives of the study were to identify differences in oomycete communities associated with pea root health and compare oomycete communities among the 3 prairie provinces, where field peas are commonly cultivated. Samples of soil from the rhizosphere of field pea (Pisum sativum L.) were collected from patches of asymptomatic or diseased plants from 26 commercial fields in 2013 and 2014. Oomycete communities were characterized using metagenomic analysis of the ITS1 region on Illumina MiSeq. From 105 identified operational taxonomic units (OTUs), 45 and 16 oomycete OTUs were identified at species and genus levels, respectively. Pythium was the most prevalent genus and Pythium heterothallicum the most prevalent species in all 3 provinces in both 2013 and 2014. Aphanomyces euteiches, a very important pea root rot pathogen in regions of the prairies, was detected in 57% of sites but at very low abundance (<0.2%). Multivariate analysis revealed differences in the relative abundance of species in oomycete communities between asymptomatic and diseased sites, and among years and provinces. This study demonstrated that deep amplicon sequencing can provide information on the composition and diversity of oomycete communities in agricultural soils. PMID- 28576116 TI - Endovascular treatment of thoracic aortic pseudoaneurysm due to brucellosis: a rare case report. AB - BACKGROUND: Arterial damage is a known complication of brucellosis, but the occurrence of a thoracic aortic pseudoaneurysm secondary to brucellosis has not been previously reported. CASE PRESENTATION: A 65-year-old Chinese man presented with a pseudoaneurysm in the descending segment of the thoracic aorta that caused symptoms of chest pain and intermittent fever. He was diagnosed with a thoracic aortic pseudoaneurysm secondary to brucellosis based on a positive brucella serology test (standard-tube agglutination test) and imaging examination (computed tomography angiography). Anti-brucellosis treatment and covered stent graft implantation were attempted to eliminate the brucellosis and pseudoaneurysm, respectively, and were ultimately successful, with no symptoms after 6 months of follow-up. CONCLUSION: Endovascular repair may be effective and safe for treating a thoracic aortic pseudoaneurysm resulting from brucellosis. PMID- 28576117 TI - Clinical failure with and without empiric atypical bacteria coverage in hospitalized adults with community-acquired pneumonia: a systematic review and meta-analysis. AB - BACKGROUND: Both typical and atypical bacteria can cause community-acquired pneumonia (CAP); however, the need for empiric atypical coverage remains controversial. Our objective was to evaluate the impact of antibiotic regimens with atypical coverage (a fluoroquinolone or combination of a macrolide/doxycycline with a beta-lactam) to a regimen without atypical antibiotic coverage (beta-lactam monotherapy) on rates of clinical failure (primary endpoint), mortality, bacteriologic failure, and adverse events, (secondary endpoints). METHODS: We searched the PubMed, EMBASE and Cochrane Library databases for relevant RCTs of hospitalized CAP adults. We estimated risk ratios (RRs) with 95% confidence intervals (CIs) using a fixed-effect model, but used a random-effects model if significant heterogeneity (I 2 ) was observed. RESULTS: Five RCTs with a total of 2011 patients were retained. A statistically significant lower clinical failure rate was observed with empiric atypical coverage (RR, 0.851 [95% CI, 0.732-0.99; P = 0.037]; I 2 = 0%). The secondary outcomes did not differ between the two study groups: mortality (RR = 0.549 [95% CI, 0.259-1.165, P = 0.118], I 2 = 61.434%) bacteriologic failure (RR = 0.816 [95% CI, 0.523-1.272, P = 0.369], I 2 = 0%), diarrhea (RR = 0.746 [95% CI, 0.311 1.790, P = 0.512], I 2 = 65.048%), and adverse events requiring antibiotic discontinuation (RR = 0.83 [95% CI, 0.542-1.270, P = 0.39], I 2 = 0%). CONCLUSIONS: Empiric atypical coverage was associated with a significant reduction in clinical failure in hospitalized adults with CAP. Reduction in mortality, bacterial failure, diarrhea, and discontinuation due to adverse effects were not significantly different between groups, but all estimates favored atypical coverage. Our findings provide support for the current guidelines recommendations to include empiric atypical coverage. PMID- 28576118 TI - Consultation patterns of children and adolescents with knee pain in UK general practice: analysis of medical records. AB - BACKGROUND: Knee problems are common in children and adolescents. Despite this, little is known about the epidemiology of knee problems in children and adolescents who consult in general practice. The aim of this study was to describe consultations by children and adolescents about knee problems in general practice, and examine patterns of patient presentations and consultations by age group, sex and area of socio-economic deprivation. METHODS: Consultations records specific to the knee region were extracted from a general practice consultation database (CiPCA) over a one year period. Knee consultation codes were organised into 'symptom' or 'diagnosis' (sub-categorised: 'trauma', 'non-trauma') categories. Descriptive statistics were used to describe patient presentations and number of consultations overall, and stratified analysis carried out on age group, sex, and ar ea of socio-economic deprivation. RESULTS: Out of all musculoskeletal consultations, knee problems were the fourth most common patient presentation, responsible for the second highest number of consultations. Patient presentations and consultations increased up to age 12-15 years and then stabilised. Symptoms codes e.g. 'knee pain' were used more commonly than diagnosis codes e.g. 'knee sprain' overall. However, symptom code use declined as age increased, more symptom codes were used in girls compared to boys, and more diagnosis codes were used in patients from areas of high socio-economic deprivation. CONCLUSIONS: This study provides insight into the epidemiology of knee problems in children and adolescents in general practice. Future research is needed to improve our understanding of the knee problems encountered by GPs, and the influence socio-economic deprivation has on consultations. PMID- 28576119 TI - Nicotine stimulates collagen type I expression in lung via alpha7 nicotinic acetylcholine receptors. AB - BACKGROUND: Tobacco-related chronic lung diseases are characterized by alterations in lung architecture leading to decreased lung function. Knowledge of the exact mechanisms involved in tobacco-induced tissue remodeling and inflammation remains incomplete. We hypothesize that nicotine stimulates the expression of extracellular matrix proteins, leading to relative changes in lung matrix composition, which may affect immune cells entering the lung after injury. METHODS: Pulmonary fibroblasts from wildtype and alpha7 nicotinic acetylcholine receptor knockout (alpha7KO) mice were exposed to nicotine and examined for collagen type 1 mRNA and protein expression. Testing the potential role on immune cell function, pulmonary fibroblasts were retained in culture for 120 h. The fibroblasts were eliminated by osmotic lysis and the remaining matrix-coated dishes were washed thoroughly. U937 cells were incubated on the matrix-coated dishes for 24 h followed by evaluation of IL-1beta gene expression. Wildtype or alpha7KO C57BL/6 mice (female, 8-12 weeks) were fed normal diet and exposed to nicotine in their drinking water (100 MUg/ml) for 8-12weeks. Lungs were processed for mRNA, protein, and histology. Statistical significance was determined at p <= .05 by two-tailed test or 2-way ANOVA with Bonferroni posttest. RESULTS: We found that nicotine stimulated collagen type I mRNA and protein expression in a dose dependent manner and up to 72 h in primary lung fibroblasts. The stimulatory effect of nicotine was inhibited in alpha7KO primary lung fibroblasts. Testing the potential role of these events on immune cell function, U937 monocytic cells were cultured atop matrices derived from nicotine-treated lung fibroblasts. These cells expressed more IL-1beta than those cultured atop matrices derived from untreated fibroblasts, and antibodies against the alpha2beta1 collagen integrin receptor inhibited the effect. Nicotine also stimulated fibroblast proliferation via MEK-1/ERK, unveiling a potentially amplifying pathway. In vivo, nicotine increased collagen type I expression was detected in wildtype, but not in alpha7KO mice. Wildtype mice showed increased collagen staining in lung, primarily around the airways. CONCLUSIONS: These observations suggest that nicotine stimulates fibroblast proliferation and their expression of collagen type I through alpha7 nAChRs, thereby altering the relative composition of the lung matrix without impacting the overall lung architecture; this may influence inflammatory responses after injury. PMID- 28576121 TI - Proximal spleno-renal shunt with retro-aortic left renal vein in a patient with extra-hepatic portal vein obstruction: first case report. AB - BACKGROUND: Presence of retro-aortic left renal vein poses special challenge in creating spleno-renal shunt potentially increasing the chance of shunt failure. The technical feasibility and successful outcome of splenectomy with proximal spleno-renal shunt (PSRS) with retro-aortic left renal vein is presented for the first time. The patient was treated for portal hypertension and hypersplenism due to idiopathic extra-hepatic portal vein obstruction. CASE PRESENTATION: A twenty year old male suffering from idiopathic extra-hepatic portal vein obstruction presented with bleeding esophageal varices, portal hypertensive gastropathy, asymptomatic portal biliopathy and symptomatic hypersplenism. As variceal bleeding did not respond to endoscopic and medical treatment, surgical portal decompression was planned. On preoperative contrast enhanced computed tomography retro-aortic left renal vein was detected. Splenectomy with proximal splenorenal shunt with retro-aortic left renal vein was successfully performed by using specific technical steps including adequate mobilisation of retro-aortic left renal vein and per-operative pressure studies. Perioperative course was uneventful and patient is doing well after 3 years of follow up. CONCLUSIONS: PSRS is feasible, safe and effective procedure when done with retro-aortic left renal vein for the treatment of portal hypertension related to extra-hepatic portal vein obstruction provided that attention is given to key technical considerations including pressure studies necessary to ensure effective shunt. Present case provides the first evidence that retro-aortic left renal vein can withstand the extra volume of blood flow through the proximal shunt with effective portal decompression so as to treat all the components of extra-hepatic portal vein obstruction without causing renal venous hypertension. PMID- 28576120 TI - Expression of genes associated with BMP signaling pathway in porcine oocytes before and after IVM - a microarray approach. AB - BACKGROUND: The full maturational capability of mammalian oocytes is accompanied by nuclear and cytoplasmic modifications, which are associated with proliferation and differentiation of surrounding cumulus cells. These events are regulated on molecular level by the expression of target genes involved in signal transduction pathways crucial for folliculogenesis and oogenesis. Transforming growth factor beta signaling includes several molecules that are involved in the regulation of oogenesis and embryo growth, including bone morphogenetic protein (BMP). However, the BMP-related gene expression profile in oocytes at different maturational stages requires further investigation. METHODS: Oocytes were isolated from pubertal crossbred Landrace gilts follicles, selected with a use of BCB staining test and analyzed before and after in vitro maturation. Gene expression profiles were examined using an Affymetrix microarray approach and validated by RT-qPCR. Database for Annotation, Visualization, and Integrated Discovery (DAVID) software was used for the extraction of the genes belonging to a BMP-signaling pathway ontology group. RESULTS: The assay revealed 12,258 different transcripts in porcine oocytes, among which 379 genes were down-regulated and 40 were up regulated. The DAVID database indicated a "BMP signaling pathway" ontology group, which was significantly regulated in both groups of oocytes. We discovered five up-regulated genes in oocytes before versus after in vitro maturation (IVM): chordin-like 1 (CHRDL1), follistatin (FST), transforming growth factor-beta receptor-type III (TGFbetaR3), decapentaplegic homolog 4 (SMAD4), and inhibitor of DNA binding 1 (ID1). CONCLUSIONS: Increased expression of CHRDL1, FST, TGFbetaR3, SMAD4, and ID1 transcripts before IVM suggested a subordinate role of the BMP signaling pathway in porcine oocyte maturational competence. Conversely, it is postulated that these genes are involved in early stages of folliculogenesis and oogenesis regulation in pigs, since in oocytes before IVM increased expression was observed. PMID- 28576122 TI - Impact of rural family physician program on child mortality rates in Iran: a time series study. AB - BACKGROUND: The rural family physician program and social protection scheme were started in Iran about 10 years ago, and no comprehensive study has been carried out to investigate the effects of this program on mortality-related health indicators yet. The present study aims to examine the impacts of implementation of the family physician program and rural insurance program, which was launched in June 2005, on neonatal (NMR), infant (IMR), and under-5-year (U5MR) mortality rates in rural areas of Iran between 1995 and 2011, using a time-series analysis. METHODS: Three segmented regression models were built to evaluate the effects of the program on NMR, IMR, and U5MR, and several independent variables were entered into the models, including annual incremental effect of the program (variable of interest), time effect, behvarz density, effect of the family physician and rural insurance programs, as well as socioeconomic variables including years of schooling, wealth index, sex ratio, and logarithmic scales of rural population size in each area. Data were gathered from secondary sources and other studies. Data pertaining to the year 2007 were excluded from the final analysis due to their inaccuracy. RESULTS: Our results show that the incremental effect of implementing the rural family physician program is associated with significant reductions in NMR (beta = - 0.341. p - value = 0.003) and IMR (beta = - 0.016. p value = 0.009). Although the association between this effect and reductions in U5MR were evident, they were not statistically significant (beta = - 0.003. p - value = 0.542). Moreover, wealth status of inhabitants was associated with reductions in NMR (beta = - 0.889. p - value = 0.001), IMR (beta = - 0.052. p - value < 0.001), and U5MR (beta = - 0.055. p - value < 0.001) in the time period of the study. CONCLUSIONS: In this nationally representative study, we showed that implementation of the second health system reform in Iran, known as the family physician program and social protection scheme for rural inhabitants, is associated with significant reductions in NMR and IMR. However, reported reductions in U5MR were not found to be statistically associated with the launch of the program. The advantage of this study was the ability to depict a more precise picture of the outcomes of a national-level intervention. PMID- 28576123 TI - Evaluation of strategies for increasing response rates to postal questionnaires in quality control of nasal septal surgery. AB - BACKGROUND: Postal questionnaires are often used to assess the results of nasal septoplasty, but response rates vary widely. This study assesses strategies designed to increase the response rate. METHODS: Postoperative questionnaires using visual analogue scales (VAS) for nasal obstruction were mailed to 160 consecutive patients alternately allocated to one of two groups. Group A received the questionnaire in the usual manner and group B received a modified cover letter with hand-written name and signature and a hand-stamped return envelope. RESULTS: Of the 80 patients in each group, 47 (58.8%) in group A and 54 (67.5%) in group B returned the questionnaire (p = 0.25). There were no age or gender differences between the groups, nor did the pre- and postoperative VAS scores differ between the groups. CONCLUSION: The strategies used in this study increased the response rate to postal questionnaires by 8.7% points, but this was not a statistically significant or clinically meaningful improvement. PMID- 28576124 TI - Ancylostoma ailuropodae n. sp. (Nematoda: Ancylostomatidae), a new hookworm parasite isolated from wild giant pandas in Southwest China. AB - BACKGROUND: Hookworms belonging to the genus Ancylostoma (Dubini, 1843) cause ancylostomiasis, a disease of considerable concern in humans and domestic and wild animals. Molecular and epidemiological data support evidence for the zoonotic potential among species of Ancylostoma where transmission to humans is facilitated by rapid urbanization and increased human-wildlife interactions. It is important to assess and describe these potential zoonotic parasite species in wildlife, especially in hosts that have physiological similarities to humans and share their habitat. Moreover, defining species diversity within parasite groups that can circulate among free-ranging host species and humans also provides a pathway to understanding the distribution of infection and disease. In this study, we describe a previously unrecognized species of hookworm in the genus Ancylostoma in the giant panda, including criteria for morphological and molecular characterization. METHODS: The hookworm specimens were obtained from a wild giant panda that died in the Fengtongzai Natural Reserve in Sichuan Province of China in November 2013. They were microscopically examined and then genetically analyzed by sequencing the nuclear internal transcribed spacer (ITS, ITS1-5.8S-ITS2) and mitochondrial cytochrome c oxidase subunit 1 (cox1) genes in two representative specimens (one female and one male, FTZ1 and FTZ2, respectively). RESULTS: Ancylostoma ailuropodae n. sp. is proposed for these hookworms. Morphologically the hookworm specimens differ from other congeneric species primarily based on the structure of the buccal capsule in males and females, characterized by 2 pairs of ventrolateral and 2 pairs of dorsolateral teeth; males differ in the structure and shape of the copulatory bursa, where the dorsal ray possesses 2 digitations. Pairwise nuclear and mitochondrial DNA comparisons, genetic distance analysis, and phylogenetic data strongly indicate that A. ailuropodae from giant pandas is a separate species which shared a most recent common ancestor with A. ceylanicum Looss, 1911 in the genus Ancylostoma (family Ancylostomatidae). CONCLUSION: Ancylostoma ailuropodae n. sp. is the fourth species of hookworm described from the Ursidae and the fifteenth species assigned to the genus Ancylostoma. A sister-species association with A. ceylanicum and phylogenetic distinctiveness from the monophyletic Uncinaria Frolich, 1789 among ursids and other carnivorans indicate a history of host colonization in the evolutionary radiation among ancylostomatid hookworms. Further, phylogenetic relationships among bears and a history of ecological and geographical isolation for giant pandas may be consistent with two independent events of host colonization in the diversification of Ancylostoma among ursid hosts. A history for host colonization within this assemblage and the relationship for A. ailuropodae n. sp. demonstrate the potential of this species as a zoonotic parasite and as a possible threat to human health. The cumulative morphological, molecular and phylogenetic data presented for A. ailuropodae n. sp. provides a better understanding of the taxonomy, diagnostics and evolutionary biology of the hookworms. PMID- 28576125 TI - Dissection of the internal carotid artery and stroke after mandibular fractures: a case report and review of the literature. AB - BACKGROUND: We present a report of a patient with blunt trauma and mandibular fractures who developed a significant cerebral infarction due to an initially unrecognized injury of her left internal carotid artery. We believe that increased knowledge of this association will facilitate early recognition and hence prevention of a devastating outcome. CASE PRESENTATION: A 41-year-old ethnic Norwegian woman presented to our Emergency Room after a bicycle accident that had caused a direct blow to her chin. At admittance, her Glasgow Coma Scale was 15. Initial trauma computed tomography showed triple fractures of her mandible, but no further pathology. She was placed in our Intensive Care Unit awaiting open reduction of her mandibular fractures. During the following 9 hours, she showed recurrent episodes of confusion and a progressive right-sided hemiparesis. Repeated cerebral computed tomography revealed no further pathology compared to the initial scan. She had magnetic resonance angiography 17 hours after admittance, which showed dissection and thrombus formation in her left internal carotid artery, total occlusion of her left medial cerebral artery, and left middle cerebral artery infarction was detected. CONCLUSIONS: Carotid artery dissection is a rare but life-threatening condition that can develop after trauma to the head and neck. There should be a high index of suspicion in patients with a mechanism of injury that places the internal carotid artery at risk because blunt vascular injury may show delayed onset with no initial symptoms of vascular damage. By implementing an algorithm for early detection and treatment of these injuries, serious brain damage may be avoided. PMID- 28576126 TI - Effective treatment of SIVcpz-induced immunodeficiency in a captive western chimpanzee. AB - BACKGROUND: Simian immunodeficiency virus of chimpanzees (SIVcpz), the progenitor of human immunodeficiency virus type 1 (HIV-1), is associated with increased mortality and AIDS-like immunopathology in wild-living chimpanzees (Pan troglodytes). Surprisingly, however, similar findings have not been reported for chimpanzees experimentally infected with SIVcpz in captivity, raising questions about the intrinsic pathogenicity of this lentivirus. FINDINGS: Here, we report progressive immunodeficiency and clinical disease in a captive western chimpanzee (P. t. verus) infected twenty years ago by intrarectal inoculation with an SIVcpz strain (ANT) from a wild-caught eastern chimpanzee (P. t. schweinfurthii). With sustained plasma viral loads of 105 to 106 RNA copies/ml for the past 15 years, this chimpanzee developed CD4+ T cell depletion (220 cells/MUl), thrombocytopenia (90,000 platelets/MUl), and persistent soft tissue infections refractory to antibacterial therapy. Combination antiretroviral therapy consisting of emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), and dolutegravir (DTG) decreased plasma viremia to undetectable levels (<200 copies/ml), improved CD4+ T cell counts (509 cell/MUl), and resulted in the rapid resolution of all soft tissue infections. However, initial lack of adherence and/or differences in pharmacokinetics led to low plasma drug concentrations, which resulted in transient rebound viremia and the emergence of FTC resistance mutations (M184V/I) identical to those observed in HIV-1 infected humans. CONCLUSIONS: These data demonstrate that SIVcpz can cause immunodeficiency and other hallmarks of AIDS in captive chimpanzees, including P. t. verus apes that are not naturally infected with this virus. Moreover, SIVcpz-associated immunodeficiency can be effectively treated with antiretroviral therapy, although sufficiently high plasma concentrations must be maintained to prevent the emergence of drug resistance. These findings extend a growing body of evidence documenting the immunopathogenicity of SIVcpz and suggest that experimentally infected chimpanzees may benefit from clinical monitoring and therapeutic intervention. PMID- 28576127 TI - Trials directly comparing alternative spontaneous breathing trial techniques: a systematic review and meta-analysis. AB - BACKGROUND: The effect of alternative spontaneous breathing trial (SBT) techniques on extubation success and other clinically important outcomes is uncertain. METHODS: We searched MEDLINE, EMBASE, CENTRAL, CINAHL, Evidence-Based Medicine Reviews, Ovid Health Star, proceedings of five conferences (1990-2016), and reference lists for randomized trials comparing SBT techniques in intubated adults or children. Primary outcomes were initial SBT success, extubation success, or reintubation. Two reviewers independently screened citations, assessed trial quality, and abstracted data. RESULTS: We identified 31 trials (n = 3541 patients). Moderate-quality evidence showed that patients undergoing pressure support (PS) compared with T-piece SBTs (nine trials, n = 1901) were as likely to pass an initial SBT (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.89-1.11; I 2 = 77%) but more likely to be ultimately extubated successfully (RR 1.06, 95% CI 1.02-1.10; 11 trials, n = 1904; I 2 = 0%). Exclusion of one trial with inconsistent results for SBT and extubation outcomes suggested that PS (vs T piece) SBTs also improved initial SBT success (RR 1.06, 95% CI 1.01-1.12; I 2 = 0%). Limited data suggest that automatic tube compensation plus continuous positive airway pressure (CPAP) vs CPAP alone or PS increase SBT but not extubation success. CONCLUSIONS: Patients undergoing PS (vs T-piece) SBTs appear to be 6% (95% CI 2-10%) more likely to be extubated successfully and, if the results of an outlier trial are excluded, 6% (95% CI 1-12%) more likely to pass an SBT. Future trials should investigate patients for whom SBT and extubation outcomes are uncertain and compare techniques that maximize differences in support. PMID- 28576128 TI - B cells do not have a major pathophysiologic role in acute ischemic stroke in mice. AB - BACKGROUND: Lymphocytes have been shown to play an important role in the pathophysiology of acute ischemic stroke, but the properties of B cells remain controversial. The aim of this study was to unravel the role of B cells during acute cerebral ischemia using pharmacologic B cell depletion, B cell transgenic mice, and adoptive B cell transfer experiments. METHODS: Transient middle cerebral artery occlusion (60 min) was induced in wild-type mice treated with an anti-CD20 antibody 24 h before stroke onset, JHD -/- mice and Rag1 -/- mice 24 h after adoptive B cell transfer. Stroke outcome was assessed at days 1 and 3. Infarct volumes were calculated from 2,3,5-triphenyltetrazolium chloride (TTC) stained brain sections, and neurological scores were evaluated. The local inflammatory response was determined by real-time PCR and immunohistochemistry. Apoptosis was analyzed by TUNEL staining, and astrocyte activation was revealed using immunohistochemistry and Western blot. RESULTS: Pharmacologic depletion of B cells did not influence infarct volumes and functional outcome at day 1 after stroke. Additionally, lack of circulating B cells in JHD -/- mice also failed to influence stroke outcome at days 1 and 3. Furthermore, reconstitution of Rag1 -/- mice with B cells had no influence on infarct volumes. CONCLUSION: Targeting B cells in experimental stroke did not influence lesion volume and functional outcome during the acute phase. Our findings argue against a major pathophysiologic role of B cells during acute ischemic stroke. PMID- 28576129 TI - Treatment with long-acting lanreotide autogel in early infancy in patients with severe neonatal hyperinsulinism. AB - BACKGROUND: Treatment of severe diffuse congenital hyperinsulinism (CHI) without sufficient response to diazoxide is complicated by the lack of approved drugs. Therefore, patients are often hospitalized long-term or have to undergo pancreatic surgery if episodes of severe hypoglycaemia cannot be prevented. A long-acting somatostatin analogue, octreotide, has been reported to be an effective treatment option that prevents severe hypoglycaemia in children with CHI, and its off-label use is common in CHI. However, octreotide requires continuous i.v. or s.c. infusion or multiple daily injections. Here, we report our experiences with the use of a monthly application of a long-acting somatostatin analogue, lanreotide autogel(r) (LAN-ATG), in early infancy. RESULTS: The mean blood glucose concentration within 7 days before the first LAN ATG administration were compared to 7 days after the first LAN-ATG administration and increased by 0.75 mmol/L (range 0.39-1.19 mmol/L). In the following weeks intravenous glucose infusions, octreotide, and glucagon treatment could be successfully stopped in all patients 3-20 days after the first LAN-ATG injection without substantial worsening of the hypoglycaemia rate. Increased carbohydrate requirements could be normalized with an average reduction in the carbohydrate intake of 7 g/kg body weight/d (range 1.75-12.8 g/kg body weight/d). Over a total of 52 treatment months, no serious adverse effects occurred. CONCLUSION: Long term LAN-ATG treatment improved blood glucose concentrations, lowered the frequency of hypoglycaemia or allowed for normalization of oral carbohydrate intake in infants with CHI younger than 6 months of age. No severe side effects were observed. LAN-ATG might be an alternative treatment option in infants with severe CHI who lack risk factors for necrotizing enterocolitis and are not responding to current treatment regimens as an alternative to surgery after careful individual evaluation. PMID- 28576130 TI - The Galphah-PLCdelta1 signaling axis drives metastatic progression in triple negative breast cancer. AB - BACKGROUND: Distant metastasis of triple-negative breast cancer (TNBC) to other organs, e.g., the lungs, has been correlated with poor survival rates among breast cancer patients. Therefore, the identification of useful therapeutic targets to prevent metastasis or even inhibit tumor growth of TNBC is urgently needed. Galphah is a novel GTP-binding protein and known as an inactive form of calcium-dependent tissue transglutaminase. However, the functional consequences of transamidating and G-protein activities of tissue transglutaminase in promoting cancer metastasis are still controversial. METHODS: Kaplan-Meier analyses were performed to estimate the prognostic values of Galphah and PLCdelta1 by utilizing public databases and performing immunohistochemical staining experiments. Cell-based invasion assays and in vivo lung colony-forming and orthotropic lung metastasis models were established to evaluate the effectiveness of interrupting the protein-protein interaction (PPI) between Galphah and PLCdelta1 in inhibiting the invasive ability and metastatic potential of TNBC cells. RESULTS: Here, we showed that the increased level of cytosolic, not extracellular, Galphah is a poor prognostic marker in breast cancer patients and correlates with the metastatic evolution of TNBC cells. Moreover, clinicopathological analyses revealed that the combined signature of high Galphah/PLCdelta1 levels indicates worse prognosis in patients with breast cancer and correlates with lymph node metastasis of ER-negative breast cancer. Blocking the PPI of the Galphah/PLCdelta1 complex by synthetically myristoylated PLCdelta1 peptide corresponding to the Galphah-binding interface appeared to significantly suppress cellular invasiveness in vitro and inhibit lung metastatic colonies of TNBC cells in vivo. CONCLUSIONS: This study establishes Galphah/PLCdelta1 as a poor prognostic factor for patients with estrogen receptor-negative breast cancers, including TNBCs, and provides therapeutic value by targeting the PPI of the Galphah/PLCdelta1 complex to combat the metastatic progression of TNBCs. PMID- 28576131 TI - Analysis of 31-year-old patient with SYNGAP1 gene defect points to importance of variants in broader splice regions and reveals developmental trajectory of SYNGAP1-associated phenotype: case report. AB - BACKGROUND: Whole exome sequencing is a powerful tool for the analysis of genetically heterogeneous conditions. The prioritization of variants identified often focuses on nonsense, frameshift and canonical splice site mutations, and highly deleterious missense variants, although other defects can also play a role. The definition of the phenotype range and course of rare genetic conditions requires long-term clinical follow-up of patients. CASE PRESENTATION: We report an adult female patient with severe intellectual disability, severe speech delay, epilepsy, autistic features, aggressiveness, sleep problems, broad-based clumsy gait and constipation. Whole exome sequencing identified a de novo mutation in the SYNGAP1 gene. The variant was located in the broader splice donor region of intron 10 and replaced G by A at position +5 of the splice site. The variant was predicted in silico and shown experimentally to abolish the regular splice site and to activate a cryptic donor site within exon 10, causing frameshift and premature termination. The overall clinical picture of the patient corresponded well with the characteristic SYNGAP1-associated phenotype observed in previously reported patients. However, our patient was 31 years old which contrasted with most other published SYNGAP1 cases who were much younger. Our patient had a significant growth delay and microcephaly. Both features normalised later, although the head circumference stayed only slightly above the lower limit of the norm. The patient had a delayed puberty. Her cognitive and language performance remained at the level of a one-year-old child even in adulthood and showed a slow decline. Myopathic facial features and facial dysmorphism became more pronounced with age. Although the gait of the patient was unsteady in childhood, more severe gait problems developed in her teens. While the seizures remained well controlled, her aggressive behaviour worsened with age and required extensive medication. CONCLUSIONS: The finding in our patient underscores the notion that the interpretation of variants identified using whole exome sequencing should focus not only on variants in the canonical splice dinucleotides GT and AG, but also on broader splice regions. The long-term clinical follow-up of our patient contributes to the knowledge of the developmental trajectory in individuals with SYNGAP1 gene defects. PMID- 28576132 TI - The socioeconomic context of the use of Euterpe precatoria Mart. and E. oleracea Mart. in Bolivia and Peru. AB - BACKGROUND: Traditional knowledge (TK) has enabled communities to adapt to changes in life conditions over centuries. However, this local context is being dramatically affected by recent changes through globalization and modernization of societies. In this paper we seek to identify socio-economic factors that are related to the knowledge and use of two palm species in mestizo and indigenous communities in the Amazonian of Peru and Bolivia. Both species are known in the region under the main vernacular name of Asai, and are source of two highly commercialized resources: palm-hearts and fruits. Euterpe precatoria Mart. is native to the region whereas E. oleracea Mart. is being introduced for the use of both resources. METHODS: We compare TK about the two Euterpe species in both countries in relation to 14 socioeconomic factors in seven use categories. We performed a Multivariate analysis of variance (MANOVA) to elucidate the influence of each socioeconomic factor on the overall palm knowledge or on individual use categories. RESULTS: In the two countries, we found that mestizos, speaking only Spanish, and migrants in the same ecoregion, knew more uses in all use categories for E. precatoria than for E. oleracea, even in use categories such as Medicinal and veterinary and Construction, for which indigenous participants had more uses in case of other species. In Peru, the use of E. precatoria was higher among participants with greater wealth, which could be related to the commercial importance that both the fruits and the palm-hearts have had in the markets of the region. In contrast, in Bolivia, although some income generation from Euterpe sp. was observed, the use of E. precatoria was much more homogeneously distributed. The use of E. oleracea in Bolivia is recent, and although its most important uses are related to the consumption of fruits and palm-hearts (Human food), it is now being slowly used for Medicinal and Construction purposes, similar to E. precatoria. CONCLUSIONS: The use of each of the species forms part of divergent strategies in people's livelihoods. We show that integration into a market economy does not necessarily erode TK, but can rather stimulate knowledge acquisition and transmission of knowledge, and helps to understand the role and potential of these products to contribute to the livelihoods of households. PMID- 28576133 TI - Adherence, healthcare resource utilization and Medicaid spending associated with once-monthly paliperidone palmitate versus oral atypical antipsychotic treatment among adults recently diagnosed with schizophrenia. AB - BACKGROUND: Once-monthly paliperidone palmitate (PP1M) is a long-acting injectable antipsychotic that may increase adherence rates, reduce hospitalizations, and lower medical costs compared to oral atypical antipsychotics (OAAs) among schizophrenia patients. However, the impact of PP1M in recently diagnosed patients remains unknown. The present study compared adherence, healthcare resource utilization and Medicaid spending between schizophrenia patients initiating PP1M versus OAA, among patients recently diagnosed (defined using ages 18-25 years as a proxy) and among the overall population. METHODS: Medicaid data from five states (09/2008-03/2015) were used to identify adults with schizophrenia initiated on PP1M or OAAs (index date) on or after 09/2009. Outcomes were compared between PP1M and OAA groups following inverse probability of treatment weighting (IPTW). Univariate linear and Poisson regression models with nonparametric bootstrap procedures were used to compare the 12-month healthcare resource utilization and costs using rate ratios (RRs) and mean monthly cost differences (MMCDs), respectively. RESULTS: Overall, patients initiated on PP1M (N = 2053) were younger (mean age: 41 vs. 44 years) and had more baseline antipsychotic use (88% vs. 62%) compared to OAA patients (N = 22,247). IPTW resulted in balanced baseline characteristics. Among recently diagnosed patients, PP1M was associated with better adherence (PDC >= 80%: 29% vs. 21%, P < 0.001) on the index medication as well as less use of other psychiatric medications, compared to OAAs. Adherence findings were similar for the overall cohort. Among recently diagnosed patients, lower medical costs associated with PP1M (MMCD = $-466; P = 0.028) outweighed the higher pharmacy costs (MMCD = $322; P < 0.001) resulting in similar total healthcare costs across groups (MMCD = $-144; P = 0.553). Overall, findings were similar but there was a trend toward a lower magnitude of medical cost savings (MMCD = $-286; P < 0.001). Reductions in medical costs were mainly driven by reductions in inpatient days (recently diagnosed RR = 0.85, P = 0.353; overall RR = 0.84, P = 0.004) and in home care visits (recently diagnosed RR = 0.43, P = 0.008; overall RR = 0.78, P = 0.048). CONCLUSIONS: PP1M patients demonstrated significantly lower medical costs offsetting higher pharmacy costs relative to OAA patients. Recently diagnosed patients using PP1M may have greater medical cost savings relative to OAAs than that observed in the overall population, highlighting the potential economic impact of PP1M in adults recently diagnosed with schizophrenia. PMID- 28576134 TI - Effects of infant weight gain on subsequent allergic outcomes in the first 3 years of life. AB - BACKGROUND: The association between early weight gain and later allergic outcomes has not been well studied. We examined the relation between weight gain and the subsequent development of allergic outcomes in the first 36 months of life in a Singapore birth cohort. METHODS: In repeated visits in the first 15 months, we measured infant weight and administered questionnaires ascertaining allergic outcomes. At ages 18 and 36 months, we administered skin prick tests (SPTs) to inhalant and food allergens. RESULTS: At 18 months, 13.5% had a positive SPT, 3.5% had wheeze and a positive SPT, 3.9% had rhinitis and a positive SPT, and 6.1% had eczema and a positive SPT. Higher weight gain from 6 to 9 months, 9 to 12 months and 12 to 15 months were independently associated with a reduced risk of developing a positive SPT at 18 months (p-trend <=0.03). At 36 months, 23.5% had a positive SPT, 11.9% had wheeze and a positive SPT, 12.2% rhinitis and a positive SPT, and 11.5% eczema and a positive SPT. Higher weight gain from 12 to 15 months was associated with a reduced risk of developing a positive SPT at 36 months (p-trend <0.01). No significant associations were observed between weight gain in any period and wheeze, rhinitis or eczema combined with a positive SPT at 18 or 36 months. CONCLUSION: Higher weight gain in the first 15 months of life was associated with a reduced risk of allergen sensitization, but not with combinations of allergic symptoms. TRIAL REGISTRATION: NCT01174875 Registered 1 July 2010, retrospectively registered. PMID- 28576135 TI - Epidemiology and time trends of distal forearm fractures in adults - a study of 11.2 million person-years in Sweden. AB - BACKGROUND: A distal forearm fracture is a very common injury causing both suffering and substantial health care costs. The incidence of this fracture type seemed to increase worldwide until the middle 1980's, but thereafter most reports have shown stable or decreasing rates. As few large studies have been presented lately we aimed to describe recent epidemiology and time trends of distal forearm fractures in adults. We paid special attention to fractures in working ages as they present challenges in terms of treatment and costs for sick-leave, and have not previously been thoroughly investigated. METHODS: By use of population data from Statistics Sweden and official in- and out-patient register data of men and women (>=17 years) in Sweden (Skane region), we ascertained distal forearm fractures and estimated age- and sex-specific rates and time-trends from year 1999 to 2010 (11.2 million person-years (py)). RESULTS: The total incidence rate was 278 per 100,000 py (31,233 fractures) with 23% higher annual numbers 2010 compared with 1999. An increase in the annual age standardized incidence was found in men, +0.7% per annum (95% confidence interval (CI) 0.1, 1.4), and women, +0.9% (95% CI 0.5, 1.3), driven mainly by an increasing incidence in working ages (17-64 years). Also, expected demographic changes including a 25% population increase may result in 38% more fractures until 2050, compared to 2017. CONCLUSIONS: The incidence of distal forearm fractures in adults in southern Sweden is increasing, mainly driven by an increase in working ages. In combination with expected demographic changes these findings may present substantial challenges for the future. PMID- 28576137 TI - Characteristics of patients receiving midwife-led prenatal care in Canada: results from the Maternity Experiences Survey (MES). AB - BACKGROUND: The aim of this study was to determine the characteristics of women in Canada who received care from a midwife during their prenatal period. METHODS: The findings of this study were drawn from the Maternity Experiences Survey (MES), which was a cross-sectional survey that assessed the experiences of women who gave birth between November 2005 and May 2006. The main outcome variable for this study was the prenatal care provider (i.e. midwife versus other healthcare providers). Demographic, socioeconomic, as well as health and pregnancy factors were evaluated using bivariate and multivariate models of logistic regression. RESULTS: A total of 6421 participants were included in this analysis representing a weighted total of 76,508 women. The prevalence of midwife-led prenatal care was 6.1%. The highest prevalence of midwife-led prenatal care was in British Columbia (9.8%), while the lowest prevalence of midwife-led prenatal care was 0.3% representing the cumulative prevalence in Nova Scotia, Prince Edward Island, Newfoundland and Labrador, New Brunswick, Saskatchewan, and Yukon. Factors showing significant association with midwife-led prenatal care were: Aboriginal status (OR = 2.26, 95% CI: 1.41-3.64), higher education with bachelor and graduate degree attainment having higher ORs when compared to high-school or less (OR = 2.71, 95% CI: 1.71-4.31 and OR = 3.17, 95% CI: 1.81-5.55, respectively), and alcohol use (OR = 1.63, 95% CI: 1.17-2.26). Age, marital status, immigrant status, work during pregnancy, household income, previous pregnancies, perceived health, maternal Body Mass Index (BMI), and smoking during the last 3 months of pregnancy were not significantly associated with midwife care. CONCLUSIONS: In general, women who were more educated, have aboriginal status, and/or are alcohol drinkers were more likely to receive care from midwives. Since MES is the most recent resource that includes information about national midwifery utilization, future studies can provide more up-to-date information about this important area. Moreover, future research can aim at understanding the reasons that lead women to opt for midwife-led prenatal care. PMID- 28576136 TI - Novel APC gene mutations associated with protein alteration in diffuse type gastric cancer. AB - BACKGROUND: The role of adenomatous polyposis coli (APC) gene in mitosis might be critical for regulation of genomic stability and chromosome segregation. APC gene mutations have been associated to have a role in colon cancer and since gastric and colon tumors share some common genetic lesions, it is relevant to investigate the role of APC tumor suppressor gene in gastric cancer. METHODS: We investigated for somatic mutations in the Exons 14 and 15 of APC gene from 40 diffuse type gastric cancersamples. Rabbit polyclonal anti-APC antibody was used, which detects the wild-type APC protein and was recommended for detection of the respective protein in human tissues. Cell cycle analysis was done from tumor and adjacent normal tissue. RESULTS: APC immunoreactivity showed positive expression of the protein in stages I, II, III and negative expression in Stages III and IV. Two novel deleterious variations (g.127576C > A, g.127583C > T) in exon 14 sequence were found to generate stop codon (Y622* and Q625*)in the tumor samples. Due to the generation of stop codon, the APC protein might be truncated and all the regulatory features could be lost which has led to the down-regulation of protein expression. Our results indicate that aneuploidy might occurdue to the codon 622 and 625 APC-driven gastric tumorigenesis, in agreement with our cell cycle analysis. The APC gene function in mitosis and chromosomal stability might be lost and G1 might be arrested with high quantity of DNA in the S phase. Six missense somatic mutations in tumor samples were detected in exon 15 A-B, twoof which showed pathological and disease causing effects based on SIFT, Polyphen2 and SNPs & GO score and were not previously reported in the literature or the public mutation databases. CONCLUSION: The two novel pathological somatic mutations (g.127576C > A, g.127583C > T) in exon 14 might be altering the protein expression leading to development of gastric cancer in the study population. Our study showed that mutations in the APC gene alter the protein expression and cell cycle regulation in diffuse type gastric adenocarcinoma. PMID- 28576138 TI - Changes in pancreatic histology, insulin secretion and oxidative status in diabetic rats following treatment with Ficus deltoidea and vitexin. AB - BACKGROUND: The potential application of Ficus deltoidea and vitexin for the management of symptomatologies associated with diabetes mellitus (DM) has gained much attention. However, less firm evidence comes from data to augment our understanding of the role of F. deltoidea and vitexin in protecting pancreatic beta-cells. The aim of this study was to assess histological and oxidative stress changes in the pancreas of streptozotocin (STZ)-induced diabetic rats following F. deltoidea extract and vitexin treatment. METHODS: F. deltoidea and vitexin was administrated orally to six-weeks STZ-induced diabetic rats over 8 weeks period. The glucose and insulin tolerances were assessed by intraperitoneal glucose (2 g/kg) tolerance test (IPGTT) and intraperitoneal insulin (0.65 U/kg) tolerance test (IPITT), respectively. Subsequently, insulin resistance was assessed by homeostasis assessment model of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI) and the insulin/triglyceride-derived McAuley index. The histological changes in the pancreas were then observed by hematoxylin-eosin (H&E) staining. Further, the pattern of fatty acid composition and infrared (IR) spectra of the serum and pancreas were monitored by gas chromatography (GC) method and Fourier Transform Infrared (FT-IR) spectroscopy. RESULTS: F. deltoidea and vitexin increased pancreatic antioxidant enzymes and promoted islet regeneration. However, a significant increase in insulin secretion was observed only in rats treated with F. deltoidea. More importantly, reduction of fasting blood glucose is consistent with reduced FT-IR peaks at 1200-1000 cm 1. CONCLUSIONS: These results accentuate that F. deltoidea and vitexin could be a potential agent to attenuate pancreatic oxidative damage and advocate their therapeutic potential for treating DM. PMID- 28576140 TI - RANK/RANKL/OPG system in the intervertebral disc. AB - BACKGROUND: The receptor activator of NF-kappaB ligand (RANKL), a member of the TNF ligand superfamily, is known to regulate bone metabolism. The expression of each component of the RANK/RANKL/osteoprotegerin (OPG) system in the intervertebral disc (IVD) has not been examined in detail. The purposes of this study were to examine the expression of the RANK/RANKL/OPG system and to evaluate the function of RANKL in the matrix metabolism of the rat IVD. METHODS: Sprague Dawley, 12-week-old, male rats were used in this study. Anulus fibrosus (AF), nucleus pulposus (NP) and cartilaginous endplate (CEP) cells isolated from dissected thoracolumbar discs were monolayer-cultured. RANK/RANKL/OPG expression in rat IVDs was examined using real-time polymerase chain reaction (PCR) and immunohistochemical analysis (cultured cells and IVD tissues). To examine the effect of interleukin-1beta (IL-1beta) stimulation on the mRNA levels of RANK, RANKL and OPG, the cells were cultured with or without recombinant human IL-1beta (rhIL-1beta). To evaluate the effect of RANKL on the mRNA expression of catabolic factors (IL-1beta, matrix metalloproteinase-3 (MMP-3) and MMP-13), the cells were cultured with RANKL in the presence or absence of rhIL-1beta. The immunohistochemical expression of this system was also evaluated using human IVD tissues with different grades of degeneration. RESULTS: mRNA expression levels of RANK, RANKL, and OPG were clearly identified in AF, NP and CEP cells. Immunoreactivity to RANK, RANKL and OPG was distributed in the cell membranes and/or cytoplasm of the three types of cells. The mRNA level of RANKL was significantly upregulated by treatment with rhIL-1beta of the three types of cells. Treatment with RANKL without rhIL-1beta did not induce significant effects on the mRNA expression of catabolic factors by AF, NP and CEP cells. However, the expression was significantly upregulated by stimulation with RANKL in the presence of rhIL-1beta. There was a general trend for more RANK/RANKL/OPG positive cells in human IVD tissues in an advanced stage of degeneration compared to an early stage. CONCLUSIONS: Our study showed the possibility that the RANK/RANKL/OPG system may play a part in the process of intervertebral disc degeneration. PMID- 28576139 TI - Genome-wide sequence variations between wild and cultivated tomato species revisited by whole genome sequence mapping. AB - BACKGROUND: Cultivated tomato (Solanum lycopersicum L.) is the second most important vegetable crop after potato and a member of thirteen interfertile species of Solanum genus. Domestication and continuous selection for desirable traits made cultivated tomato species susceptible to many stresses as compared to the wild species. In this study, we analyzed and compared the genomes of wild and cultivated tomato accessions to identify the genomic regions that encountered changes during domestication. RESULTS: Analysis was based on SNP and InDel mining of twentynine accessions of twelve wild tomato species and forty accessions of cultivated tomato. Percentage of common SNPs among the accessions within a species corresponded with the reproductive behavior of the species. SNP profiles of the wild tomato species within a phylogenetic subsection varied with their geographical distribution. Interestingly, the ratio of genic SNP to total SNPs increased with phylogenetic distance of the wild tomato species from the domesticated species, suggesting that variations in gene-coding region play a major role in speciation. We retrieved 2439 physical positions in 1594 genes including 32 resistance related genes where all the wild accessions possessed a common wild variant allele different from all the cultivated accessions studied. Tajima's D analysis predicted a very strong purifying selection associated with domestication in nearly 1% of its genome, half of which is contributed by chromosome 11. This genomic region with a low Tajima's D value hosts a variety of genes associated with important agronomic trait such as, fruit size, tiller number and wax deposition. CONCLUSION: Our analysis revealed a broad-spectrum genetic base in wild tomato species and erosion of that in cultivated tomato due to recurrent selection for agronomically important traits. Identification of the common wild variant alleles and the genomic regions undergoing purifying selection during cultivation would facilitate future breeding program by introgression from wild species. PMID- 28576141 TI - Adult patients' experiences of NHS specialist services for chronic fatigue syndrome (CFS/ME): a qualitative study in England. AB - BACKGROUND: Few studies have explored patients' experiences of treatment for CFS/ME. This study aims to fill this gap by capturing the perspective of patients who have been treated by NHS specialist CFS/ME services in England. METHODS: Semi structured interviews were conducted during the period June-September 2014 with 16 adults who were completing treatment at one of three outpatient NHS specialist CFS/ME services. Interviews were analysed thematically using constant comparison techniques, with particular attention paid to contrasting views. RESULTS: Three themes were identified: 'Journey to specialist services'; 'Things that help or hinder treatment'; and 'Support systems'. Within these themes nine sub-themes were identified. A wide range of factors was evident in forming participants' experiences, including personal characteristics such as perseverance and optimism, and service factors such as flexibility and positive, supportive relationships with clinicians. Participants described how specialist services played a unique role, which was related to the contested nature of the condition. Many participants had experienced a lack of validation and medical and social support before attending a specialist service. Patients' experiences of life before referral, and the concerns that they expressed about being discharged, highlighted the hardship and obstacles which people living with CFS/ME continue to experience in our society. CONCLUSIONS: The experiences of CFS/ME patients in our study showed that NHS specialist CFS/ME services played a vital role in patients' journeys towards an improved quality of life. This improvement came about through a process which included validation of patients' experiences, acceptance of change, practical advice and support, and therapeutic outcomes. PMID- 28576142 TI - Factors influencing reproductive choices of HIV positive individuals attending primary health care facilities in a South African health district. AB - BACKGROUND: There is global recognition of the reproductive health rights of people living with HIV (PLHIV). The aim of this research study was to explore the reproductive choices, and the factors influencing these choices, of HIV positive patients attending primary health care (PHC) facilities in the Ekurhuleni health district of the Gauteng Province of South Africa. METHODS: During 2013, a cross sectional survey was conducted in the Ekurhuleni health district. At each of three randomly selected community health centres, a random sample of HIV positive patients was selected. After informed consent was obtained, trained fieldworkers administered a structured questionnaire that elicited information on socio demographics, reproductive choices and knowledge of reproductive options. Survey data were analysed using STATA(r) 13. RESULTS: The majority of survey participants (n = 430) were female (70%) and unemployed (57%). The mean age of participants was 36.4 years (SD 8.6): 40.8 years (SD 8.7) for men and 34.5 years (SD7.8) for women. Among survey participants, 46% expressed a desire for children (95% CI: 41.4-50.9). In the multiple logistic regression analysis, predictors of desire for children were age less than 49 years, marriage or living together, and no biological children. The odds of wanting children was 16.48 [95% CI: 5.94 45.74] times higher for PLHIV without children, compared with those with two or more children, while for those less than 25 years, the odds of wanting children was 0.78 [95% CI: 0.23-2.59] compared with those older than 50 years. The PLHIV knowledge on the available reproductive options was limited, with the majority relying on the guidance of the health workers. CONCLUSION: Health care providers at PHC level should be educated to address the reproductive health needs of PLHIV. These aspects should be reflected in provincial and national health policies. PMID- 28576143 TI - Cervical cancer risk perceptions, sexual risk behaviors and sexually transmitted infections among Bivalent Human Papillomavirus vaccinated and non-vaccinated young women in Uganda - 5 year follow up study. AB - BACKGROUND: Previous studies were conflicting regarding the associations between HPV vaccination, cervical cancer risk perceptions, high-risk sexual behaviors and STIs. This study compared the HPV-vaccinated and non-vaccinated young women in Uganda regarding cervical cancer risk perceptions, high-risk sexual behaviors, syphilis and HIV infections 5 years after vaccine implementation. METHODS: This was a population-based comparative cross-sectional survey conducted in Uganda. The 438 participants were sexually active young women aged 15-24 years and mean age was 18.6 (SD 1.4). The majority (53.0%) were HPV-vaccinated in 2008 without assessment of sexual activity prior to HPV vaccination. Upon verbal assessment of sexual activity at the time of follow-up, data were collected using a questionnaire and laboratory testing of blood samples for syphilis and HIV infections. RESULTS: There were no significant differences between the HPV vaccinated and non-vaccinated groups regarding the prevalence of high-risk sexual behaviors, syphilis and HIV infections. Cervical cancer risk perceptions and age at sexual debut were nonetheless significantly lower among the vaccinated group compared to their non-vaccinated counterparts. However, HPV vaccination was not significantly associated to cervical cancer risk perceptions and early age at sexual debut in multivariate logistic regression analysis. CONCLUSIONS: We found no associations between HPV vaccination, cervical cancer risk perceptions, high risk sexual behaviors, syphilis and HIV infections among young women in Uganda 5 years after vaccine implementation. Young girls in the study population were found to be sexually active at a young age, affirming the importance of targeting girls of younger age for HPV vaccination. PMID- 28576144 TI - CUL4A overexpression as an independent adverse prognosticator in intrahepatic cholangiocarcinoma. AB - BACKGROUND: CUL4A has been known for its oncogenic properties in various human cancers. However, its role in intrahepatic cholangiocarcinoma (iCCA) has not been explored. METHODS: We retrospectively investigated 105 iCCA cases from a single medical institution. Tissue microarrays were used for immunohistochemical analysis of CUL4A expression. CUL4A expression vectors were introduced in cell lines. Cell migration and invasion assays were used to compare the mobility potential of iCCA cells under basal conditions and after manipulation. Then we evaluated the effects of CUL4A on the cell growth by proliferation assay, and further checked the susceptibility to cisplatin in iCCA cells with or without CUL4A overexpression. RESULTS: CUL4A overexpression was detected in 34 cases (32.4%). Patients with CUL4A-overexpressing tumors exhibited shortened disease free survival (mean, 27.7 versus 90.4 months; P = 0.011). In the multivariate analysis model, CUL4A overexpression was shown to be an independent unfavorable predictor for disease-free survival (P = 0.045). Moreover, stably transfected CUL4A-overexpressing iCCA cell lines displayed an increased mobility potential and enhanced cell growth without impact on susceptibility to cisplatin. CONCLUSIONS: Our data demonstrate that overexpression of CUL4A plays an oncogenic role in iCCA and adversely affects disease-free survival. Thus, it may prove to be a powerful prognostic factor and a potential therapeutic target. PMID- 28576146 TI - Coincidence of Persistent Mullerian duct syndrome and testicular tumors in dogs. AB - BACKGROUND: Persistent Mullerian duct syndrome (PMDS), a rare form of male pseudohermaphroditism in dogs, is an abnormal sexual phenotype in males that is characterized by the existence of a hypoplastic oviduct, uterus, and cranial part of the vagina. Dogs suffering from PMDS are often accompanied by cryptorchidism. To date, it has been mainly found in the Miniature Schnauzer breed. CASE PRESENTATION: In this report, two cases of PMDS with a malignant testicular tumor originating from cryptorchidism in breeds other than the Miniature Schnauzer breed are described. The patients were a seven-year-old male Maltese dog and a 17 year-old male mixed-breed dog weighing 3.8 kg. They also exhibited an enlarged prostate with or without abscess and an elevated serum estradiol level and were surgically treated to remove the testicular tumor and Mullerian duct derivatives. CONCLUSIONS: It is recommended that PMDS should be differentially diagnosed by ultrasonography and that orchiectomy be performed at an early age in patients suspected to have cryptorchidism to prevent the ectopic testes from becoming tumorous. PMID- 28576145 TI - The impact of a diagnostic decision support system on the consultation: perceptions of GPs and patients. AB - BACKGROUND: Clinical decision support systems (DSS) aimed at supporting diagnosis are not widely used. This is mainly due to usability issues and lack of integration into clinical work and the electronic health record (EHR). In this study we examined the usability and acceptability of a diagnostic DSS prototype integrated with the EHR and in comparison with the EHR alone. METHODS: Thirty four General Practitioners (GPs) consulted with 6 standardised patients (SPs) using only their EHR system (baseline session); on another day, they consulted with 6 different but matched for difficulty SPs, using the EHR with the integrated DSS prototype (DSS session). GPs were interviewed twice (at the end of each session), and completed the Post-Study System Usability Questionnaire at the end of the DSS session. The SPs completed the Consultation Satisfaction Questionnaire after each consultation. RESULTS: The majority of GPs (74%) found the DSS useful: it helped them consider more diagnoses and ask more targeted questions. They considered three user interface features to be the most useful: (1) integration with the EHR; (2) suggested diagnoses to consider at the start of the consultation and; (3) the checklist of symptoms and signs in relation to each suggested diagnosis. There were also criticisms: half of the GPs felt that the DSS changed their consultation style, by requiring them to code symptoms and signs while interacting with the patient. SPs sometimes commented that GPs were looking at their computer more than at them; this comment was made more often in the DSS session (15%) than in the baseline session (3%). Nevertheless, SP ratings on the satisfaction questionnaire did not differ between the two sessions. CONCLUSIONS: To use the DSS effectively, GPs would need to adapt their consultation style, so that they code more information during rather than at the end of the consultation. This presents a potential barrier to adoption. Training GPs to use the system in a patient-centred way, as well as improvement of the DSS interface itself, could facilitate coding. To enhance patient acceptability, patients should be informed about the potential of the DSS to improve diagnostic accuracy. PMID- 28576147 TI - The microbial changes in subgingival plaques of orthodontic patients: a systematic review and meta-analysis of clinical trials. AB - BACKGROUND: Orthodontic treatment was found to have an impact on the quantity and constitution of subgingival microbiota. However, contradictory findings regarding the effects of fixed appliances on microbial changes were reported. The aim of this systematic review was to investigate the microbial changes in subgingival plaques of orthodontic patients. METHODS: The PubMed, Cochrane Library, and EMBASE databases were searched up to November 20, 2016. Longitudinal studies observing microbial changes in subgingival plaques at different time points of orthodontic treatment are included. The methodological quality of the included studies was assessed by Methodological index for non-randomized studies (MINORS). The studies that reported the frequency of subgingival periodontopathogens were used for quantitative analysis. Other studies were analysed qualitatively to describe the microbial changes during orthodontic treatment. RESULTS: Thirteen studies were selected, including two controlled clinical trials, three cohort studies and eight self-controlled studies. Four periodontopathogens, including Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi) and Tannerella forsythia (Tf), were analysed. Following orthodontic appliance placement, the frequencies of Pg and Aa showed no significant change (P = 0.97 and P = 0.77), whereas the frequency of Tf significantly increased (P < 0.01) during short-term observation (0-3 months). The frequency of Pi showed a tooth-specific difference, as it presented no significant difference (P = 0.25) at the site of the first molar but was significantly increased (P = 0.01) at the incisor. During long-term observation (> = 6 months), two studies reported that the levels of subgingival periodontopathogens exhibited a transient increase but decreased to the pretreatment levels afterwards. After removal of the orthodontic appliance, the four periodontopathogens showed no significant difference compared with before removal. CONCLUSION: The levels of subgingival pathogens presented temporary increases after orthodontic appliance placement, and appeared to return to pretreatment levels several months later. This indicates that orthodontic treatment might not permanently induce periodontal disease by affecting the level of subgingival periodontal pathogen levels. Further studies of high methodological quality are required to provide more reliable evidence regarding this issue. PMID- 28576148 TI - The creation and validation of the Measure of Effective Attributes of Trainers (MEAT). AB - BACKGROUND: Training is a core component in the implementation of empirically supported treatments, especially in the case of psychosocial interventions targeting mental illness. However, common forms of training are relatively ineffective in producing behavioral changes in providers. Trainers are in a strategic position to influence the success of training, but no research, to our knowledge, has explored whether personal characteristics of trainers (e.g., enthusiasm, charisma) increase effectiveness of training empirically supported treatments in the field of mental health. To address this gap, the current study created a measure of trainer characteristics (the Measure of Effective Attributes of Trainers (MEAT)) and assessed preliminary evidence for its reliability and validity by following gold standard measure development procedures. METHODS: Measure development consisted of three steps: (1) An initial pool of items was generated based on extant literature, input from the target population, and expert input; (2) target users of the measure interacted with the initial item pool to ensure face validity as well as clarity of measure instructions, response options, and items; and (3) a convenience sample viewed training videos and completed the measure resulting from step 2 to establish preliminary evidence of reliability and validity. An exploratory factor analysis was performed on the measure to determine whether latent factors (i.e., subscales of characteristics) underlie the data. RESULTS: The final solution consisted of two factors that demonstrated preliminary evidence for structural validity of the measure. The first factor, labeled "Charisma," contained items related to characteristics that facilitate a positive personal relationship with the trainee (e.g., friendly, warm), and the second factor, labeled "Credibility," contained items related to characteristics that emphasize the qualification of the trainer (e.g., professional, experienced). There was also evidence for face validity, content validity, reliability, and known groups validity of the measure. CONCLUSIONS: The MEAT demonstrated preliminary evidence of key psychometric properties. Future research is needed to further explore and contribute to its psychometric evidence, which could be done in conjunction with measures of trainee knowledge, attitudes towards empirically supported treatments, and evaluations of trainee behavior change to delineate key characteristics of trainers to be leveraged for more effective training. PMID- 28576150 TI - The Lausanne Centre for Ultrafast Science (LACUS). PMID- 28576151 TI - Harmonium: An Ultrafast Vacuum Ultraviolet Facility. AB - Harmonium is a vacuum ultraviolet (VUV) photon source built within the Lausanne Centre for Ultrafast Science (LACUS). Utilising high harmonic generation, photons from 20-110 eV are available to conduct steady-state or ultrafast photoelectron and photoion spectroscopies (PES and PIS). A pulse preserving monochromator provides either high energy resolution (70 meV) or high temporal resolution (40 fs). Three endstations have been commissioned for: a) PES of liquids; b) angular resolved PES (ARPES) of solids and; c) coincidence PES and PIS of gas phase molecules or clusters. The source has several key advantages: high repetition rate (up to 15 kHz) and high photon flux (1011 photons per second at 38 eV). The capabilities of the facility complement the Swiss ultrafast and X-ray community (SwissFEL, SLS, NCCR MUST, etc.) helping to maintain Switzerland's leading role in ultrafast science in the world. PMID- 28576149 TI - Survival and quality of life in incident systemic sclerosis-related pulmonary arterial hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a leading cause of mortality in systemic sclerosis (SSc). We sought to determine survival, predictors of mortality, and health-related quality of life (HRQoL) related to PAH in a large SSc cohort with PAH. METHODS: We studied consecutive SSc patients with newly diagnosed (incident) World Health Organization (WHO) Group 1 PAH enrolled in a prospective cohort between 2009 and 2015. Survival methods were used to determine age and sex-adjusted standardised mortality ratio (SMR) and years of life lost (YLL), and to identify predictors of mortality. HRQoL was measured using the Short form 36 (SF-36) instrument. RESULTS: Among 132 SSc-PAH patients (112 female (85%); mean age 62 +/- 11 years), 60 (45.5%) died, with a median (+/-IQR) survival time from PAH diagnosis of 4.0 (2.2-6.2) years. Median (+/-IQR) follow up from study enrolment was 3.8 (1.6-5.8) years. The SMR for patients with SSc PAH was 5.8 (95% CI 4.3-7.8), with YLL of 15.2 years (95% CI 12.3-18.1). Combination PAH therapy had a survival advantage (p < 0.001) compared with monotherapy, as did anticoagulation compared with no anticoagulation (p < 0.003). Furthermore, combination PAH therapy together with anticoagulation had a survival benefit compared with monotherapy with or without anticoagulation and combination therapy without anticoagulation (hazard ratio 0.28, 95% CI 0.1-0.7). Older age at PAH diagnosis (p = 0.03), mild co-existent interstitial lung disease (ILD) (p = 0.01), worse WHO functional class (p = 0.03) and higher mean pulmonary arterial pressure at PAH diagnosis (p = 0.001), and digital ulcers (p = 0.01) were independent predictors of mortality. CONCLUSIONS: Despite the significant benefits conferred by advanced PAH therapies suggested in this study, the median survival in SSc PAH remains short at only 4 years. PMID- 28576152 TI - Time-resolved ARPES at LACUS: Band Structure and Ultrafast Electron Dynamics of Solids. AB - The manipulation of the electronic properties of solids by light is an exciting goal, which requires knowledge of the electronic structure with energy, momentum and temporal resolution. Time- and angle-resolved photoemission spectroscopy (tr ARPES) is the most direct probe of the effects of an optical excitation on the band structure of a material. In particular, tr-ARPES in the extreme ultraviolet (VUV) range gives access to the ultrafast dynamics over the entire Brillouin zone. VUV tr-ARPES experiments can now be performed at the ASTRA (ARPES Spectrometer for Time-Resolved Applications) end station of Harmonium, at LACUS. Its capabilities are illustrated by measurements of the ultrafast electronic response of ZrSiTe, a novel topological semimetal characterized by linearly dispersing states located at the Brillouin zone boundary. PMID- 28576153 TI - Aqueous Nanoscale Systems. AB - In the past five years the Laboratory for fundamental BioPhotonics (LBP) has worked on developing new technology that can access the molecular structure and nanoscale properties of buried aqueous interfaces and aqueous solutions. Using these methods a better understanding of the important role that water plays in (nanoscale and interfacial) processes can be obtained. These processes include the long-range interaction of ions with water, structural and charge anomalies of the hydrophobic/aqueous interface, the formation and stabilization of amphiphilic aqueous droplet interfaces, the formation and molecular properties of the electric double layer, as well as membrane structure and hydration. The result of our work on these themes is summarized for this special issue article. PMID- 28576154 TI - Several Semiclassical Approaches to Time-resolved Spectroscopy. AB - Ultrafast spectroscopy allows molecular dynamics to be resolved on the femtosecond time scale. Whereas such short time scales obviously pose many experimental challenges, they provide an opportunity for semiclassical methods, which are naturally suited for short time dynamics. Here we review several semiclassical approaches for evaluating vibrationally resolved electronic pump probe spectra, starting with the simplest, 'phase averaging' or 'dephasing representation'. We continue by discussing several methods developed in our group that allow increasing the efficiency (the cellular dephasing representation) and accuracy (cellular dephasing representation with a prefactor) and end with the Gaussian dephasing representation, which, despite its semiclassical origins, converges to the exact quantum result. The merits as well as shortcomings of the different approaches are demonstrated on time-resolved stimulated emission spectra of NCO and pyrazine. PMID- 28576155 TI - The LOUVRE Laboratory: State-of-the-Art Ultrafast Ultraviolet Spectroscopies for Molecular and Materials Science. AB - We describe the facilities for ultraviolet studies in the femtosecond to nanosecond time domain. These facilities consist of: i) a set-up for deep ultraviolet spectroscopy in the 260-380 nm range in both pump and probe pulses for transient absorption/reflectivity or two-dimensional spectroscopy studies; ii) a set-up for ultrafast fluorescence measurements with detection down to 300 nm. The capabilities of these set-ups are demonstrated by examples on molecular systems, biosystems, nanoparticles and solid materials. PMID- 28576156 TI - Ultrafast Laser to Tailor Material Properties: An Enabling Tool in Advanced Three dimensional Micromanufacturing. AB - The progress made in ultrafast laser technology towards high repetition rate systems have opened new opportunities in micromanufacturing. Non-linear absorption phenomena triggered by femtosecond pulses interacting with transparent materials allow material properties to be tailored locally and in three dimensions, with resolution beyond the diffraction limits and at rate compatible with fabrication process requirements. In this short article, we illustrate the potential of this technology for manufacturing, and more specifically micro engineering, with a few examples taken from our own research and beyond. PMID- 28576157 TI - Opportunities for Chemistry at the SwissFEL X-ray Free Electron Laser. AB - X-ray techniques have long been applied to chemical research, ranging from powder diffraction tools to analyse material structure to X-ray fluorescence measurements for sample composition. The development of high-brightness, accelerator-based X-ray sources has allowed chemists to use similar techniques but on more demanding samples and using more photon-hungry methods. X-ray Free Electron Lasers (XFELs) are the latest in the development of these large-scale user facilities, opening up new avenues of research and the possibility of more advanced applications for a range of research. The SwissFEL XFEL project at the Paul Scherrer Institute will begin user operation in the hard X-ray (2.1-12.4 keV) photon energy range in 2018 with soft X-ray (240-1930 eV) user operation to follow and here we will present the details of this project, it's operating capabilities, and some aspects of the experimental stations that will be particularly attractive for chemistry research. SwissFEL is a revolutionary new machine that will complement and extend the time-resolved chemistry efforts in the Swiss research community. PMID- 28576158 TI - Mechanistic Insights into Gold Organometallic Compounds and their Biomedical Applications. PMID- 28576162 TI - Conference Report on TEDD & 3R Workshop at ZHAW Waedenswil. AB - On April 7, 2017, TEDD (Tissue Engineering for Drug Development and Substance Testing) and the Animal Research Foundation joined forces at ZHAW Waedenswil to present their latest scientific results in the domain of the 3Rs of biomedical research: how to Refine, Reduce and Replace animal testing with alternative approaches. PMID- 28576163 TI - Report on 17th International Symposium on Solubility Phenomena and Related Equilibrium Processes (ISSP17). PMID- 28576164 TI - Swiss Chemical Society Spring Meeting, University of Bern, 21st April 2017. PMID- 28576167 TI - Imaging of Prostate-Specific Membrane Antigen Using [18F]DCFPyL. AB - Prostate-specific membrane antigen (PSMA) has been explored as a target for molecular imaging of prostate cancer and other malignancies that express PSMA in their tumor-associated neovasculature. Although several PSMA-targeted radiotracers labeled with a variety of radionuclides have been reported, positron emitting radiotracers labeled with 18F are of particular interest. One such compound, the small molecule PSMA inhibitor [18F]DCFPyL, has demonstrated initial success. This article reviews the literature on this radiotracer, including radiosynthetic approaches to the molecule, data that are available from preclinical experiments, and evidence to date of the clinical utility of this agent in prostate cancer and clear cell renal cell carcinoma. PMID- 28576166 TI - Human Epidermal Growth Factor Receptor 2-Targeted PET/Single- Photon Emission Computed Tomography Imaging of Breast Cancer: Noninvasive Measurement of a Biomarker Integral to Tumor Treatment and Prognosis. AB - Increased human epidermal growth factor receptor 2 (HER2) expression is a hallmark of aggressive breast cancer. Imaging modalities have the potential to diagnose HER2-positive breast cancer and detect distant metastases. The heterogeneity of HER2 expression between primary and metastatic disease sites limits the value of tumor biopsies. Molecular imaging is a noninvasive tool to assess HER2-positive primary lesions and metastases. Radiolabeled antibodies, antibody fragments, and affibody molecules devise a reliable and quantitative method for detecting HER2-positive cancer using PET. HER2-targeted PET imaging is a valuable clinical tool with respect to both the care and maintenance of patients with breast cancer. PMID- 28576168 TI - Theranostic Prospects of Gastrin-Releasing Peptide Receptor-Radioantagonists in Oncology. AB - Gastrin-releasing peptide receptors (GRPRs) represent attractive targets for cancer diagnosis and therapy owing to their overexpression in widespread human tumors. Bombesin (BBN) analogues coupled to suitable chelators for stable radiometal binding have been proposed for diagnostic imaging and radionuclide therapy (theranostics) of GRPR-positive tumors. Recently, interest has shifted from BBN-like receptor agonists to GRPR-radioantagonists, because radioantagonists do not induce adverse effects after injection to patients and display superior pharmacokinetic in vivo profiles. Thus, they seem more advantageous for clinical use compared to agonists. Newer developments highlighting the theranostic potential of GRPR-radioantagonists in cancer patient management are presented herein. PMID- 28576169 TI - Urokinase Plasminogen Activator Receptor-PET with 68Ga-NOTA-AE105: First Clinical Experience with a Novel PET Ligand. AB - Urokinase plasminogen activator receptor (uPAR) is a key component in proteolysis and extracellular matrix degradation during cancer invasion and metastasis. uPAR overexpression is an important biomarker for aggressiveness in several solid tumors and provides independent clinical information. A recent major breakthrough was obtained with human translation of uPAR PET using 68Ga-NOTA-AE105. Clinical results are encouraging and several large-scale clinical trials are now ongoing. This review focuses on uPAR PET with 68Ga-NOTA-AE105 as a new broadly applicable diagnostic and prognostic imaging biomarker in cancer. PMID- 28576170 TI - Magnetic Resonance-based Motion Correction for Quantitative PET in Simultaneous PET-MR Imaging. AB - Motion degrades image quality and quantitation of PET images, and is an obstacle to quantitative PET imaging. Simultaneous PET-MR offers a tool that can be used for correcting the motion in PET images by using anatomic information from MR imaging acquired concurrently. Motion correction can be performed by transforming a set of reconstructed PET images into the same frame or by incorporating the transformation into the system model and reconstructing the motion-corrected image. Several phantom and patient studies have validated that MR-based motion correction strategies have great promise for quantitative PET imaging in simultaneous PET-MR. PMID- 28576171 TI - PET Imaging for Early Detection of Alzheimer's Disease: From Pathologic to Physiologic Biomarkers. AB - This article describes the application of various PET imaging agents in the investigation and diagnosis of Alzheimer's disease (AD), including radiotracers for pathologic biomarkers of AD such as beta-amyloid deposits and tau protein aggregates, and the neuroinflammation biomarker 18 kDa translocator protein, as well as physiologic biomarkers, such as cholinergic receptors, glucose metabolism, and the synaptic density biomarker synaptic vesicle glycoprotein 2A. Potential of these biomarkers for early AD diagnosis is also assessed. PMID- 28576173 TI - Novel Phenotypes Detectable with PET in Mood Disorders: Elevated Monoamine Oxidase A and Translocator Protein Level. AB - As a result of high prevalence and high rates of treatment resistance, major depressive disorder has become the leading cause of death and disability in moderate-income to high-income nations. Poor targeting of phenotypes is a plausible reason for treatment resistance and PET imaging offers a unique role to identify phenotypes. Both increased monoamine oxidase A binding and greater translocator protein 18 kDa binding occur throughout the gray matter during major depressive episodes, including affect-modulating brain regions such as the prefrontal and anterior cingulate cortex, and are detectable with advanced radioligand technology for both of these targets. PMID- 28576174 TI - Novel PET Radiotracers with Potential Clinical Applications. PMID- 28576172 TI - Multimodal PET Imaging of Amyloid and Tau Pathology in Alzheimer Disease and Non Alzheimer Disease Dementias. AB - Biomarkers of the molecular pathology underpinning dementia syndromes are increasingly recognized as crucial for diagnosis and development of disease modifying treatments. Amyloid PET imaging is an integral part of the diagnostic assessment of Alzheimer disease. Its use has also deepened understanding of the role of amyloid pathology in Lewy body disorders and aging. Tau PET imaging is an imaging biomarker that will likely play an important role in the diagnosis, monitoring, and treatment in dementias. Using tau PET imaging to examine how tau pathology relates to amyloid and other markers of neurodegeneration will serve to better understand the pathophysiologic cascade that leads to dementia. PMID- 28576175 TI - Update on Radiotherapy for Central Nervous System Malignancies. AB - Malignancies arising from the central nervous system are rare. Brain metastases, in contrast, are perhaps the most common neurologic complication of cancer. Radiotherapy, as part of combined modality therapy, continues to evolve with the advancement of stereotactic radiosurgery indications, the addition of new technologies, such as alternating electric field therapy, and mounting advances in the complex biology of these entities. The explosion of new clinical trials combined with newly discovered molecular markers suggest the beginning of a paradigm shift in the management of these challenging malignancies that will allow for future risk-stratification strategies. PMID- 28576176 TI - Controversies in Postoperative Irradiation of Oropharyngeal Cancer After Transoral Surgery. AB - Transoral surgery (TOS) is a novel technology whose adoption is expanding in the United States and other countries. TOS offers the possibility of a minimally invasive surgical approach to head and neck cancers. Its most frequent application has been in oropharyngeal cancers (OPC), of which most are associated with human papillomavirus (HPV). For HPV-associated OPC, where high response and survival rates are expected, deintensification of standard therapy is a major area of clinical research. In HPV-OPC, traditional pathologic risk factors indicating a need for adjuvant radiation or chemoradiation may not apply as strongly. PMID- 28576177 TI - Updates in the Treatment of Breast Cancer with Radiotherapy. AB - Breast-conserving therapy is one of the most remarkable achievements of modern cancer care. The authors review the evidence supporting the role of adjuvant radiotherapy as the standard of care for breast cancer after breast-conserving surgery, consensus guidelines for margins in invasive cancer disease and ductal carcinoma in situ, the role of partial-breast irradiation and hypofractionated whole-breast irradiation, and the evolving indications for postmastectomy radiation therapy and extent of nodal coverage. Areas of research include specific methods of partial-breast irradiation, interactions between neoadjuvant chemotherapy and radiotherapy, and integration of molecular profiles with the selection of the best treatment modality and timing. PMID- 28576178 TI - Updates in Postmastectomy Radiation. AB - Although the use of postmastectomy radiation therapy (PMRT) is widely accepted in certain clinical situations, areas of controversy persist for some clinical scenarios. In addition, with significant shifts in the management of breast cancer, including omission of axillary nodal dissection in select sentinel node positive patients and increased use of neoadjuvant chemotherapy, new clinical challenges have arisen regarding the role of PMRT. This article reviews the data to support current recommendations for postmastectomy radiation and explores areas of controversy and the studies that guide clinicians in these scenarios. PMID- 28576179 TI - Management of Stage I Lung Cancer with Stereotactic Ablative Radiation Therapy. AB - Early stage non-small cell lung cancer is a growing clinical entity with evolving standards of care. With the adoption of lung screening guidelines, the incidence of early stage disease is expected to increase. Surgical resection for early stage disease has been considered standard of care; however, there is evidence that stereotactic ablative radiation therapy (SABR) may be a viable alternate to surgery. In the last decade, advances in image guidance, treatment planning systems, and improved spatial accuracy of treatment delivery have converged to result in the effective use of SABR in the treatment of early stage lung cancer. PMID- 28576180 TI - Optimal Use of Combined Modality Therapy in the Treatment of Esophageal Cancer. AB - Esophageal cancer is associated with a poor prognosis with 5-year survival rates of approximately 15% to 20%. Although patients with early stage disease may adequately be treated with a single modality, combined therapy typically consisting of neoadjuvant chemoradiation followed by esophagectomy is being adopted increasingly in patients with locally advanced disease. In patients who are not surgical candidates, definitive chemoradiation is the preferred treatment approach. All patients with newly diagnosed esophageal cancer should be evaluated in the multidisciplinary setting by a surgeon, radiation oncologist, and medical oncologist owing to the importance of each specialty in the management of these patients. PMID- 28576181 TI - The Role of Radiation Therapy for Pancreatic Cancer in the Adjuvant and Neoadjuvant Settings. AB - Pancreatic cancer is the third leading cause of cancer-related death in the United States. Although surgery remains the only curative treatment, chemotherapy and radiation therapy are frequently used. In the adjuvant setting, radiation is usually delivered with chemotherapy to eradicate residual microscopic or macroscopic disease in the resection bed. Neoadjuvant radiation therapy has become more frequently utilized. This article reviews the historical and modern literature regarding radiation therapy in the neoadjuvant and adjuvant settings, focusing on the evolution of radiation therapy techniques and clinical trials in an attempt to identify patients best suited to receiving radiation therapy. PMID- 28576182 TI - Evolving Role of Radiotherapy in the Management of Rectal Carcinoma. AB - Management of locally advanced rectal cancer has evolved over time from surgical resection alone to multimodality therapy with preoperative radiation, chemotherapy, and total mesorectal excision resulting in excellent local control rates. Refinements in neoadjuvant therapies and their sequencing have improved pathologic complete response rates such that consideration of selective radiation and nonoperative management are now active clinical trial questions. Advances in radiation treatment planning and delivery techniques may allow for further reduction in acute treatment-related toxicity in select patient populations. Collectively, therapeutic strategies remain focused on improving outcomes for patients with higher-risk disease and reducing the morbidity of treatment. PMID- 28576183 TI - Radiotherapy for Anal Cancer: Intensity-Modulated Radiotherapy and Future Directions. AB - The treatment of anal cancer has evolved remarkably in the past 30 years. Definitive chemoradiotherapy is the standard of care, allowing organ preservation and maintenance of continence for most patients. This article reviews recent advances in radiotherapy planning and delivery that have resulted in improvements in treatment-related toxicity. Most notably, the advent and wide adoption of intensity-modulated radiotherapy provides a superior toxicity profile compared with older techniques, while maintaining similar oncologic outcomes. Current areas of active research include optimizing and individualizing treatment intensity and possible integration of biologic agents and immunotherapies in the treatment of anal cancer. PMID- 28576184 TI - Radiation Oncology Management of Stage I-III Cervix Cancer. AB - Radiotherapy plays a critical role in the management of cervix carcinoma, in the adjuvant setting for patients with high-risk pathologic features and in the definitive setting for locoregionally advanced disease. External beam radiotherapy fields encompass potential areas of microscopic disease spread in addition to known areas of gross disease. In the presence of gross disease, however, escalation of dose is required that is best accomplished using a brachytherapy boost to spare surrounding normal organs from toxicity. This article addresses indications for radiotherapy in the management of nonmetastatic cervix cancer and reviews various radiotherapy techniques, with a heavy focus on brachytherapy. PMID- 28576185 TI - Brachytherapy in the Management of Prostate Cancer. AB - Brachytherapy is performed by directly inserting radioactive sources into the prostate gland and is an important treatment option for appropriately selected men with prostate adenocarcinoma. Brachytherapy provides highly conformal radiotherapy and delivers tumoricidal doses that exceed those administered with external beam radiation therapy. There is a significant body of literature supporting the excellent long-term oncologic and safety outcomes achieved when brachytherapy is used for men in all risk categories of nonmetastatic prostate cancer. This article highlights some important considerations and published outcomes that relate to brachytherapy and its role in the treatment of prostate cancer. PMID- 28576186 TI - Novel Opportunities to Use Radiation Therapy with Immune Checkpoint Inhibitors for Melanoma Management. AB - Immunotherapy has revolutionized the systemic management of numerous malignancies. Nowhere has the proven benefit of these agents in clinical practice been more evident than in the management of advanced melanoma. Numerous preclinical studies have revealed the potential benefit of immune-priming radiotherapy in stimulating tumor-specific immune responses. This signal for immune activation may lead to clinically relevant synergy with immune checkpoint inhibitors against malignant cells. In this review, the authors summarize the current data outlining the role radiation therapy may play in the management of advanced melanoma alongside immune checkpoint inhibitors. PMID- 28576187 TI - Foreword. PMID- 28576188 TI - Update of Practical Radiation Oncology Management Trends for Surgeons. PMID- 28576189 TI - Digital Arthrodesis of the Lesser Toes. AB - Foot and ankle surgeons frequently treat digital deformities of the lesser toes surgically. Arthrodesis of the proximal interphalangeal joint is the workhorse procedure for correction of hammer toe contractures. Fusion of the interphalangeal joint can be fixated with a variety of methods, including K-wire fixation, intramedullary implants, absorbable pins, and screws. Each method of fixation has advantages and disadvantages, such as variations in complication rates, cost, and fusion rates. Further research is necessary to determine the best method of fixation for digital interphalangeal joint fusion." PMID- 28576190 TI - First Metatarsal-Phalangeal Joint Arthrodesis: Primary, Revision, and Salvage of Complications. AB - Arthrodesis of the first metatarsal-phalangeal joint has been proposed for treatment of severe hallux valgus, end-stage hallux rigidus, rheumatoid arthritis, and revision of failed surgery due to the perceived safety and efficacy. This article discusses the principles of first metatarsal-phalangeal joint arthrodesis in primary and revision situations, joint preparation, configurations of osteosynthesis, and common complications, including salvage of nonunion and revision of malunion with realignment osteotomy. PMID- 28576191 TI - Tarsometatarsal Arthrodesis for Lisfranc Injuries. AB - This article discusses tarsometatarsal arthrodesis for Lisfranc injuries. Although open reduction and internal fixation has traditionally been the treatment of choice for most Lisfranc fracture-dislocations, there is a trend toward primary fusion, especially for purely ligamentous injuries. Consideration should be made for primary fusion in select fracture-dislocation cases. Primary fusion offers a single-stage alternative with potentially more stable, predictable results overtime. PMID- 28576192 TI - Subtalar Joint Arthrodesis for Elective and Posttraumatic Foot and Ankle Deformities. AB - Subtalar joint arthrodesis is a procedure used in posttraumatic arthritis, osteoarthritis, tarsal coalition management, posterior tibial tendon dysfunction, and inflammatory arthropathies, and can be used in deformity correction. The goals of the procedure are to eliminate pain, improve function, restore stability, and realign the hind foot. The procedure has high patient satisfaction with low complications while preserving motion in adjacent tarsal joints. Joint preparation is important and time should be spent preparing the joint for successful arthrodesis and the fixation construct needs to be done well and effectively to provide a solid Arbeitsgemeinschaft fur Osteosynthesefragen (AO) construct for good results. PMID- 28576193 TI - Hindfoot Arthrodesis for the Elective and Posttraumatic Foot Deformity. AB - Triple (talonavicular, subtalar, and calcaneocuboid) joint arthrodesis and most recently double (talonavicular and subtalar) joint arthrodesis have been well proposed in the literature for surgical repair of the elective, posttraumatic, and/or neuropathic hindfoot deformities. The articulation of the hindfoot with the ankle and midfoot is multiaxial, and arthrodesis of these joints can significantly alter the lower extremity biomechanical manifestations by providing anatomic correction and alignment. This article reviews the indications and preoperative planning for some of the most common procedures to address the hindfoot deformity. PMID- 28576194 TI - Operative Fixation Options for Elective and Diabetic Ankle Arthrodesis. AB - Ankle arthrodesis remains one of the most definitive treatment options for end stage arthritis, paralysis, posttraumatic and postinfectious conditions, failed total ankle arthroplasty, and severe deformities. The general aims of ankle arthrodesis are to decrease pain and instability, correct the accompanying deformity, and create a stable plantigrade foot. Several surgical approaches have been reported for ankle arthrodesis with internal fixation options. External fixation has also evolved for ankle arthrodesis in certain clinical scenarios. This article provides a comprehensive analysis of midterm to long-term outcomes for ankle arthrodesis using internal and/or external fixation each for elective and diabetic conditions. PMID- 28576195 TI - Tibiotalocalcaneal Arthrodesis for Foot and Ankle Deformities. AB - Tibiotalocalcaneal arthrodesis is a safe and viable option to treat patients with arthridities affecting ankle and subtalar joints, neuromuscular disorders, avascular necrosis of the talus, failed ankle arthrodesis, instability, and Charcot neuroarthropathy. Choice of incision and fixation is based on deformity, pathology, prior surgery and hardware, and surgeon comfort and preference. Intramedullary nails offer high primary stability, reduce sustained soft tissue damage, and may allow for earlier return to activities than traditional plate or screw constructs. Peri- and postoperative fractures, malunion, nonunion, and infections are potential complications. Postoperative recovery is a vital component for an overall successful outcome. PMID- 28576196 TI - Management of Osteomyelitis and Bone Loss in the Diabetic Charcot Foot and Ankle. AB - Bone loss and destruction due to diabetic Charcot neuroarthropathy (CN) and osteomyelitis of the foot and ankle is a challenging clinical condition when lower extremity preservation is considered. Resection and excision of osteomyelitis and associated nonviable soft tissue can lead into large osseous and soft tissue defects that will most likely need the utilization of bone grafting and subsequent arthrodesis for stability and anatomic alignment. In the diabetic population with peripheral neuropathy, osseous instability can lead to subsequent lower extremity deformity, ulceration, infection and/or amputation. This article reviews the surgical approach in the presence of diabetic CN and concomitant osteomyelitis. PMID- 28576197 TI - Soft Tissue Coverage After Revisional Foot and Ankle Surgery. AB - Unlike the traumatic "mangled" foot and ankle in which amputation could be an acceptable if not preferred option, revisional foot and ankle surgery starts with a viable foot that is then injured by the surgeon hopefully to benefit the patient. Any untoward sequela, such as inadequate wound healing, instead always requires consideration of limb salvage. Unfortunately, this may not be so simple. A proactive approach to solve this problem in a timely fashion is important. The goal must always be to get a healed wound so the final result improves the ability for independent ambulation by the patient. PMID- 28576198 TI - Current Orthobiologics for Elective Arthrodesis and Nonunions of the Foot and Ankle. AB - A fusion rate of 100% would be ideal. Despite adhering to sound surgical principles, complete compliance, and no adverse comorbidities, that 100% fusion rate goal is elusive. Orthobiologics are a special class of materials developed to enhance the fusion rates in foot and ankle arthrodesis sites. Whether orthobiologics are used for the first fusion or reserved for a nonunion is debatable, especially when considering cost. PMID- 28576199 TI - Foot and Ankle Arthrodesis. PMID- 28576200 TI - Retina area of focused competence diploma. PMID- 28576201 TI - Proposing a new scoring system in intermittent exotropia: towards a better assessment of control. AB - OBJECTIVE: There is a clinical need for a valid and reliable assessment system to quantify the severity and measure the progression of intermittent exotropia. We have developed a new scoring system (Look And Cover, then Ten seconds of Observation Scale for Exotropia [LACTOSE]) based on the examinee's potential to regain the phoria for both distance and near fixation. The test takes only 1 minute to complete. The aim of this study was to evaluate the reliability and validity of LACTOSE. METHODS: The LACTOSE was created by incorporating both distance and near score (0-4 each) into a total score ranging from 0 to 8. A total of 235 consecutive patients with intermittent exotropia were prospectively evaluated using this new scoring system. Inter-rater and test-retest reliability was assessed from a cohort of 10 patients who were video recorded while undergoing the scoring testing and then scored by 10 trained ophthalmologists independently. Construct validity was studied by comparison with clinical variables indicating disease severity. RESULTS: Inter-rater reliability was good for both distance and near (intraclass correlation coefficient [ICC] = 0.729 and 0.818). Test-retest reliability was excellent for both distance and near (ICC = 0.849 and 0.727). Median scores for distance, near, and total were 3, 1, and 4, respectively. A broad representation of the total scores was significantly linked to the age of onset and the amount of exotropia (r2 = 0.194, p = 0.003 and r2 = 0.159, p < 0.001). CONCLUSIONS: We found that our newly developed scoring system is a reliable and valid tool for assessing the severity of intermittent exotropia. This new measure can be implemented easily and efficiently across diverse clinical settings. PMID- 28576202 TI - Effect of artificial anisometropia in dominant and nondominant eyes on stereoacuity. AB - OBJECTIVE: To evaluate the effect of artificial anisometropia in dominant and nondominant eyes on stereoacuity. METHODS: In this descriptive analytic study, 60 healthy adult volunteers 18-37 years of age (mean age: 25.58 years) without any ocular disease were enrolled at Tabriz Nikookari eye hospital over a 1-year period. Anisometropia (unilateral myopia) was induced by placing trial lenses over the dominant and nondominant eyes in 1-diopter (D) increments ranging from 1 to 3 D. Stereoacuity was measured using the TNO, Randot, and Titmus stereotests and values were converted into Napierian logarithm (ln) and compared between the 2 eyes. RESULTS: Of the 60 adults (25 male and 35 female subjects), the right eye was dominant in 49 (81.7%) of the cases. Stereoacuity levels were reduced proportionately to the degree of anisometropia in all participants. Mean stereoacuity was 4.3, 5.5, and 7.4 ln for dominant eyes and 4.1, 5.4, and 7.3 ln for nondominant eyes using the TNO test by applying 1, 2, and 3 D lenses, respectively (p > 0.05). Corresponding values were 3.5, 4.6, and 6.6 ln for dominant eyes and 3.4, 4.6, and 6.5 ln for nondominant eyes by the circles subcategory of Randot test, respectively (p > 0.05). The scores were 3.8, 4.7, and 6.5 ln for dominant eyes and 3.8, 4.7, and 6.4 ln for nondominant eyes by the circles subcategory of Titmus test, respectively (p > 0.05). CONCLUSION: Artificial anisometropia could reduce stereoacuity. However, ocular dominance has no effect on the amount of stereoacuity reduction. PMID- 28576203 TI - Trends in pediatric strabismus surgery in the new millennium: influence of funding and perceived benefits of surgery. AB - OBJECTIVE: The rate of strabismus surgery was previously reported to be decreasing in the United Kingdom and Ontario. Data on the influence of government funding on surgical trends and recent population trends for surgery in pediatric patients in Canada are limited. This study aims to analyze the trend in pediatric strabismus procedures in Ontario from 2000 to 2013. DESIGN: A population based, retrospective data analysis. METHODS: An analysis of the yearly volume of strabismus procedures in the pediatric population of Ontario was performed, subdivided by number of muscles repaired and repeat procedures. The number of ophthalmologists performing strabismus surgery on the pediatric population was analyzed, subdivided by high- and low-volume surgeons and career stage. RESULTS: From 2000 to 2013, per 100,000 pediatric population, the number of total strabismus surgeries in Ontario increased 38.1%; rates of single-muscle surgery increased 12.8%, 2-muscle surgery increased 24.2%, and surgery of >=3 muscles increased 135.4%. Repeat procedures increased 263.1% from 2000 to 2013 and represented 28.5% of all surgeries in 2013.The number of high-volume surgeons increased 33.3%, whereas low-volume surgeons decreased 61.4% during the same time span. CONCLUSION: The number of pediatric strabismus procedures in Ontario has increased since 2000, and the practice has become increasingly subspecialized. This is likely due to changes in health care funding and increased parental and physician awareness of the functional and psychosocial benefits of strabismus surgery. PMID- 28576205 TI - Incision-sparing management of canaliculitis: an efficacious alternative to surgical management. AB - OBJECTIVE: The aim of this study was to describe the outcomes of conservative (punctal dilation, manual expression, microcurettage, and canalicular irrigation with antibiotics) and surgical (punctoplasty) modalities for the management of canaliculitis in an Asian population. METHODS: The medical records of 11 consecutive patients (12 eyes) presenting with canaliculitis to one surgeon from August 2010 to January 2014 were reviewed. The clinical presentation, findings, management, microbiology, and treatment outcomes were studied. RESULTS: The mean age was 70.6 years (57-91 years), 8 (72.7%) patients were females, and all 11(100%) were Chinese. The majority had unilateral canaliculitis-8 (66.7%) right eye only and 4 (33.3%) left eye only (1 patient had consecutive right canaliculitis followed by left canaliculitis)-involving the lower canaliculi (75%). Ten (83.3%) eyes had primary canaliculitis, and 2 (16.7%) eyes had secondary canaliculitis from punctal plug insertion. Common presenting symptoms included eye discharge (75%) and eyelid swelling/redness (50%). Common clinical signs included mucopurulent punctal regurgitation (75%) and pouting punctum (58.3%). Facultative anaerobes (56.3%) formed the majority of organisms, and the most common bacteria isolated were Streptococcus spp. (18.8%). Mean duration to definitive treatment was 35 days (0-126 days). Ten (83.3%) eyes were successfully treated with incision-sparing modalities, and 2 (16.7%) eyes were treated surgically. No recurrences were observed at 3, 6, and 12 months, and only 1 (10.0%) of the 10 conservatively managed eyes had a recurrence of canaliculitis after 3.8 years. CONCLUSIONS: Surgical modalities remain effective for the treatment of canaliculitis. However, they are not without disadvantages, such as scarring, discomfort, infection, and recurrence of punctal stenosis. In our experience, incision-sparing modalities are effective in the treatment of canaliculitis and have low recurrence rates. PMID- 28576204 TI - Interactive navigation-guided ophthalmic plastic surgery: the techniques and utility of 3-dimensional navigation. AB - OBJECTIVE: To demonstrate the techniques and utility of 3-dimensional reconstruction (3DR) of the target pathologies for subsequent navigation guidance in ophthalmic plastic surgery. DESIGN: Prospective interventional case series. METHODS: Stereotactic surgeries using 3D reconstruction of target lesions as the intraoperative image-guiding tool were performed in 5 patients with varied etiopathologies. All the surgeries were performed using the intraoperative image guided StealthStation system in the electromagnetic mode. 3DR was performed using StealthStation 3D model software. The utility of 3D reconstruction for extensive orbital mass lesions, large orbital fractures, intraconal foreign body, and delineation of perilesional intricate structures was studied. The intraoperative ease and usefulness for the navigation of a 3D lesion at crucial phases of the surgery were noted. RESULTS: Intraoperative geometric localization of the 3D lesions was found to be enhanced and precise. 3D reconstruction of the lesion along with the major vessels and nerves in the vicinity helped the surgeon to prevent potential injuries to these structures. The fracture defects could be navigated in a 3D plane and this helped in moderate customization of the implants intraoperatively. Foreign body located in difficult access positions could be accurately targeted for geometric localization before safe retrieval. Detailed preoperative 3D reconstruction by the surgeon was found to be beneficial for successful outcomes. CONCLUSIONS: Three-dimensional navigation is very useful in providing detailed anatomical delineation of the targets and enhances the precision in certain complex cases in ophthalmic plastic surgery. PMID- 28576206 TI - Association of orbital decompression and the characteristics of subsequent strabismus surgery in thyroid eye disease. AB - OBJECTIVE: To examine the association of orbital decompression and the characteristics and outcome of subsequent strabismus surgery in patients with thyroid eye disease (TED). METHODS: Data on patients with TED who underwent orbital decompression at the Goldschleger Eye Institute, Sheba Medical Center, Israel, between January 1990 to December 2011 were extracted. The characteristics of decompression and strabismus surgeries were recorded. The outcomes and association of both surgical procedures were analyzed. Statistical analysis included distribution, Pearson correlation, and matched paired tests. RESULTS: 145 eyes underwent orbital decompression, of which 45 eyes (31.0%) underwent strabismus surgery. Esotropia developed in 70% of the patients. Men and smokers underwent strabismus surgeries after decompression procedures more frequently than women and nonsmokers (chi2 test, p = 0.07, 0.002). Moreover, patients who complained of diplopia before the decompression surgery underwent strabismus surgery more frequently (chi2 test, p = 0.005). Seventy-seven percent of the patients who underwent medial wall decompression developed esotropia (chi2 test, p = 0.004). CONCLUSIONS: To the best of our knowledge, this is the largest series in the literature examining the association between decompression and strabismus surgeries. The patients' characteristics and the orbital walls involved in the decompression procedures are associated with the characteristics of subsequent strabismus that develops thereafter. These findings may have significant implications in planning TED management. PMID- 28576207 TI - Effect of air and sulfur hexafluoride (SF6) tamponade on visual acuity after epiretinal membrane surgery: a pilot study. AB - OBJECTIVE: The aim of this study was to compare visual acuity improvement after epiretinal membrane (ERM) surgery using air and sulfur hexafluoride (SF6) tamponade. Secondary objectives were to evaluate Visual Function Questionnaire (VFQ) scores and central retinal thickness (CRT) changes. DESIGN: This was a prospective, randomized study. PARTICIPANTS: Thirty-two patients were prospectively randomized, 19 to the air group and 13 to the SF6 group. METHODS: This study has enrolled patients with ERM from clinical practice of 4 vitreoretinal surgeons. Preoperative and postoperative data included best corrected visual acuity (BCVA) with the use of the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, VFQ scores, CRT, and cataract staging. Pars plana vitrectomy with ERM peeling was performed on all patients, either with partial air tamponade or with complete SF6 tamponade. RESULTS: Mean BCVA improved by 0.07 logMAR (3.5 ETDRS letters) in the air group and by 0.09 logMAR (4.5 ETDRS letters) in the SF6 group (p = 0.58). There was no statistically significant difference between the groups with regard to BCVA, VFQ scores, and CRT. The groups had similar rates of cataract progression and adverse events. CONCLUSIONS: ERM peeling with partial air tamponade or with complete SF6 tamponade have similar outcomes in terms of BCVA, VFQ scores, CRT, cataract development, and adverse events. PMID- 28576208 TI - Long-term in vitro functional stability of compounded ranibizumab and aflibercept. AB - OBJECTIVE: To determine the long-term in vitro functional stability of compounded ranibizumab and aflibercept. DESIGN: Laboratory study. METHODS: Ranibizumab and aflibercept were compounded into plastic syringes and stored under refrigerated conditions for up to 4 weeks. Half maximal inhibitory concentrations (IC50) from dose-response curves generated by using drugs and their respective targets in enzyme-linked immunosorbent assays were calculated. The functional activity of the drugs stored under these conditions was then compared with that of drug from a fresh glass vial obtained from the manufacturer. RESULTS: There was no statistically significant change in IC50 between ranibizumab stored in plastic syringes for 4 weeks compared with drug obtained from a fresh glass vial (p = 0.4883). Similarly, there was no statistically significant change in IC50 between aflibercept stored in plastic syringes for 4 weeks compared with drug obtained from a fresh glass vial (p = 0.6202). CONCLUSION: Compounding of ranibizumab and aflibercept in plastic syringes with storage for up to 4 weeks does not appear to have a detrimental effect on the in vitro functional activity of these medications. Because the cost of these medications can be prohibitive, compounding may be considered as a method of reducing cost. PMID- 28576209 TI - VEGF-A is increased in exogenous endophthalmitis. AB - OBJECTIVE: Exogenous endophthalmitis is an ophthalmologic emergency defined by panocular inflammation. Vascular endothelial growth factor A (VEGF-A) contributes to inflammation by promoting chemotaxis of monocytes and granulocytes and by increasing vascular permeability. The purpose of this article is to determine if VEGF-A is elevated in the vitreous samples obtained from individuals with exogenous endophthalmitis. METHODS: Vitreous samples from individuals with exogenous endophthalmitis (n = 18) were analyzed via Luminex assay and enzyme linked immunosorbent assay for the cytokines VEGF-A, tumor necrosis factor (TNF), interleukin 6 (IL-6), IL-8 (chemokine [CXCL]-8), IL-1beta, IL-10, IL-12p70, IL 33, interferon (IFN)-gamma, IFN-alpha, IFN-beta, chemokine ligand (CCL)-3, IL-2, IL-5, IL-15, CXCL-10, CCL-2, IL-1Ra, CCL-5, IL-17, and CCL-11. Vitreous samples obtained at the time of macular hole surgery served as controls (n = 8). RESULTS: Concentrations of VEGF-A were significantly elevated in vitreous samples from individuals with exogenous endophthalmitis compared with macular hole (p < 0.001). VEGF-A was significantly upregulated in individuals with exogenous endophthalmitis after cataract surgery (p = 0.001), vitrectomy (p = 0.024), and intravitreal injection (p = 0.012). VEGF-A concentrations were similar in both culture-positive and culture-negative populations (p > 0.05). In a linear regression model, levels of VEGF-A correlated significantly with the chemokine CXCL-8 (p = 0.028). CONCLUSIONS: We demonstrate that VEGF-A is potently upregulated in exogenous endophthalmitis. This observation provides a foundation for future studies of targeted VEGF-A blockade in the management of endophthalmitis. PMID- 28576210 TI - Accuracy of referral diagnosis to an emergency eye clinic. AB - OBJECTIVE: To determine the accuracy of diagnosis of ophthalmic problems from health care practitioners such as optometrists, general practitioners, and emergency physicians in and around London, Ontario, Canada. DESIGN: Retrospective review of all referrals to the Ivey Eye Institute emergency eye clinic over a period of 6 months from January to July 2011. PARTICIPANTS: During the study period, there were 1810 patient encounters, including 1134 new referrals. METHODS: For each patient encounter, information was collected regarding basic demographics, referral source, referral diagnosis, and final diagnosis. Referrals were categorized by source of referral and anatomic location of the eye problem. The accuracy of each referral was assessed by comparing the referral diagnosis to the final diagnosis. Referrals were categorized as correct, incorrect, not yet diagnosed, nonspecific, or baseline examination. RESULTS: Referral diagnoses were correct in 45% and incorrect in 28% overall. Referral diagnoses from optometrists were correct in 54%, from emergency physicians were 39% correct, and from general practitioners were 33% correct. Ophthalmologists had the highest diagnostic accuracy, with 83% of referral diagnoses being correct. Diagnoses were incorrect in 36% from optometrists, 28% from emergency physicians, and 32% from general practitioners. CONCLUSIONS: This study demonstrates the low accuracy rate of referral diagnoses of emergency eye patients from nonophthalmologists to the Ivey Eye Institute emergency eye clinic. Better training in the diagnosis of ophthalmic problems for general practitioner and emergency medicine residents would be of benefit. Optometrists may also find it helpful to have improved emergency and urgency training. Ophthalmologists should be involved in this training. PMID- 28576212 TI - Short- to long-term results of Ahmed glaucoma valve in the management of elevated intraocular pressure in patients with pediatric uveitis. AB - OBJECTIVE: The aim of this study was to evaluate the long-term outcome of Ahmed glaucoma valve (AGV) implant for elevated intraocular pressure (IOP) in pediatric patients with uveitis. DESIGN: This was a retrospective chart review. PARTICIPANTS: The study included 16 eyes (11 children) with uveitis. METHODS: Success was defined as having IOP between 6 and 21 mm Hg with (qualified success) or without (complete success) antiglaucoma medications and without the need for further glaucoma or tube extraction surgery. RESULTS: Mean age of patients at the time of AGV implantation was 14.19 +/- 3.25 years. AGV implantation was the first glaucoma surgical procedure in 12 eyes (75%). Average postoperative follow-up period was 64.46 +/- 33.56 months. Mean preoperative IOP was 33.50 +/- 7.30 mm Hg versus 12.69 +/- 3.20 mm Hg at the last follow-up visit (p < 0.001). Three eyes (18.7%) were determined as cases of "failure" because of tube removal in 2 eyes and a second AGV implantation in 1 eye. The cumulative probability of complete success was 68.8% at 6 months, 56.3% at 12 months, 49.2% at 36 months, 42.2% at 48 months, and 35.2% at 84 months, and the cumulative probability of eyes without complication was 75.0% at 6 months, 66.7% at 24 months, 58.3% at 36 months, 48.6% at 48 months and 24.3% at 108 months based on Kaplan-Meier survival analysis. CONCLUSIONS: Although AGV implant is an effective choice in the management of elevated IOP in pediatric uveitis, antiglaucoma medications are frequently needed for control of IOP. Tube exposure is an important complication in the long term. Differential diagnosis between relapse of uveitis and endophthalmitis is important in patients who received AGV implantation. PMID- 28576211 TI - Morpho-functional analysis of Stargardt Disease for reading. AB - OBJECTIVE: To analyze Stargardt disease (STGD) by morpho-functional examination and investigate the relationship between morpho-functional measures and reading performance. DESIGN: Observational case series study. PARTICIPANTS: Fifteen patients with STGD. METHODS: Twenty-six eyes of 15 patients underwent complete ophthalmic evaluation. Spectral domain optical coherence tomography, fundus autofluorescence (FAF), best corrected visual acuity (BCVA), and microperimetric examinations were performed. FAF and optical coherence tomography (OCT) overlap on microperimetric images was obtained in order to evaluate both tomographic and FAF features passing through the eccentric fixation area. Both morphologic features and functional data were correlated with magnification of prescribed device and reading rate. RESULTS: Univariable analysis showed a significant correlation between magnification power and greatest linear dimension of both OCT and FAF (r = 0.69 and r = 0.67; p < 0.05). Magnification power was related to best corrected visual acuity (r = 0.56; p < 0.05). Retinal sensitivity map (r = 0.57; p < 0.05) was considered an indicator of reading rate. Magnification levels showed a positive correlation with eccentric preferred retinal location (p = 0.03) and the degree of FAF alteration (normal, dishomogeneous, ipoautofluorescence; p < 0.0001). CONCLUSIONS: As a result of the overlapping of OCT/FAF imaging on microperimetric exam, residual activity of outer retinal layers passing through the eccentric fixation area seems to be related with required magnification and reading rate. Identification of morpho-functional parameters is helpful for designing a customized rehabilitative program. PMID- 28576213 TI - Mechanical exposure of ophthalmic surgeons: a quantitative ergonomic evaluation of indirect ophthalmoscopy and slit-lamp biomicroscopy. AB - OBJECTIVE: Vitreoretinal (VR) surgeons have high rates of spinal pain. The aim of this study was to investigate if VR surgeons adopt more complex postures in indirect ophthalmoscopy procedures compared with procedures involving the slit lamp or operating microscope. METHODS: Postures of the neck, back, and overall spine were measured by inclinometers on 13 VR surgeons. Each doctor was measured during 3 indirect examinations and 3 slit-lamp examinations (SLE), and then during 1 operating microscope procedure (phacoemulsification/vitrectomy) and 1 indirect procedure (indirect laser or cryotherapy/buckle). RESULTS: The average degree of flexion of neck/back/overall spine was significantly higher in indirect examinations compared with SLE (p < 0.01). SLE involved mainly neutral flexion, whereas indirect examinations involved significant time in moderate flexion of the neck and overall spine (42.2% and 76.2%, respectively), lateral bending of the back and overall spine (62.5% and 38%), and rotation of the neck and overall spine (76.6% and 32.1%). For indirect procedures, the neck was in moderate flexion and rotation approximately half of the time, and the overall spine was moderately flexed in >75% of the time. CONCLUSION: Based on biomechanical concepts, VR surgeons are at risk of developing spinal pain because they adopt postures that are described as ergonomically unacceptable. PMID- 28576214 TI - Surgical techniques for the treatment of conjunctivochalasis: paste-pinch-cut conjunctivoplasty versus thermal cautery conjunctivoplasty. AB - OBJECTIVE: The aim of this study was to evaluate the outcomes of paste-pinch-cut conjunctivoplasty and cautery conjunctivoplasty for the treatment of symptomatic conjunctivochalasis. DESIGN: This was a prospective cohort study. PARTICIPANTS: Sixteen patients (32 eyes) with bilateral conjunctivochalasis that was symptomatic after medical therapy were enrolled in the study. METHODS: This was a single-centre, contralateral eye, prospective study. Paste-pinch-cut conjunctivoplasty was performed in the left eye, and thermal cautery conjunctivoplasty was performed in the right eye. The outcomes of each procedure were compared preoperatively and at the 1-month follow-up by using the Canadian Dry Eye Assessment (CDEA) scoring system, standard conjunctivochalasis grading, and corneal staining. Intraoperative discomfort and immediate postoperative discomfort were assessed by using a 10-point scale. RESULTS: The mean age of patients was 72.4 +/- 8.67 years. Conjunctival redundancy was absent in 14 of 16 patients postoperatively. The mean CDEA score improved after both procedures (7.1 +/- 2.8 preoperatively versus 4.5 +/- 0.78 at the 1-month follow-up for cautery conjunctivoplasty, 7.4 +/- 2.5 versus 4.9 +/- 3.1 for paste-pinch-cut conjunctivoplasty). This improvement was statistically significant in the cautery conjunctivoplasty group (p = 0.012). Mean intraoperative discomfort was 2.6 +/- 2.1 with the use of paste-pinch-cut conjunctivoplasty and 3.5 +/- 3.2 with the use of cautery conjunctivoplasty; however, the difference was not statistically significant. No intraoperative or postoperative complications were observed with either technique. CONCLUSIONS: Paste-pinch-cut and thermal cautery conjunctivoplasty are both safe and effective surgical treatments for the repair of conjunctivochalasis, with patients reporting greater improvement in symptoms after the cautery technique. PMID- 28576215 TI - Effect of dry eye on Scheimpflug imaging of the cornea and elevation data. AB - OBJECTIVE: To evaluate the effect of dry eye on Scheimpflug imaging of the cornea and elevation data. DESIGN: Prospective observational study. PARTICIPANTS: Scheimpflug images of 50 patients with dry eye who were being tested for eligibility for corneal refractive surgery were screened. Twelve eyes of 12 patients with abnormal Belin/Ambrosio enhanced ectasia display (BAD) anterior elevation difference were included in the study. The patients had no history of contact lens wear or any other sign of ectasia. METHODS: Peak central corneal densitometry value, corneal volume, pachymetry at the thinnest point, and BAD anterior elevation difference value at the centre of the 9 mm zone were recorded before and after 4 weeks of dry eye treatment. Measurements were compared with the Wilcoxon signed rank test. RESULTS: The mean corneal peak densitometry and volume were similar before and after therapy (p = 0.465 and p = 0.441, respectively). The mean anterior elevation difference value at the centre of the 9 mm zone before treatment (6.67 +/- 1.72 um) was significantly higher than the mean post-treatment value (4.00 +/- 1.48 um) (p = 0.002). The mean pachymetry at the thinnest location after treatment (548 +/- 11.0) was significantly higher than the pretreatment value (538 +/- 8.5) (p = 0.027). CONCLUSIONS: BAD anterior elevation differences and pachymetric measurements may be affected by ocular surface or tear film abnormalities associated with dry eye disease. Repeated evaluations after treatment may reveal normal results. PMID- 28576216 TI - An unusual case of cerebral polyopia. PMID- 28576217 TI - Bilateral optic neuritis: A new twist on immune reconstitution inflammatory syndrome. PMID- 28576218 TI - Transient smartphone blindness. PMID- 28576219 TI - A late onset of choroidal metastasis from renal cell carcinoma simulating melanoma. PMID- 28576220 TI - Orbital cellular blue nevus complicated by malignant melanoma. PMID- 28576221 TI - A rare case of perfluoro-n-octane in the orbit following vitreoretinal surgery. PMID- 28576222 TI - Concurrent diagnosis of giant cell arteritis and chronic lymphocytic leukemia in a temporal artery biopsy. PMID- 28576223 TI - Detection of idiopathic intracranial hypertension, enabled by tele-ophthalmology. PMID- 28576224 TI - City Lights: corneal diseases in Hollywood movies. PMID- 28576225 TI - Widefield en face optical coherence tomography to quantify the extent of paracentral acute middle maculopathy. PMID- 28576226 TI - Corneal melt following collagen crosslinking and topography-guided customized ablation treatment for keratoconus. PMID- 28576227 TI - Late-onset diffuse lamellar keratitis 15 years after laser in situ keratomileusis. PMID- 28576228 TI - Corneal keloid with cystoid cicatrix:post-small-incision cataract surgery. PMID- 28576229 TI - Corneal edema with a systemic epidermal growth factor receptor inhibitor. PMID- 28576230 TI - Endogenous methicillin-resistant Staphylococcus aureus endophthalmitis secondary to axillary phlegmon: a case report. PMID- 28576231 TI - Blepharospasm as a masquerade of glaucomatous visual field defects. PMID- 28576232 TI - Lessons Learned from Burn Disasters in the Post-9/11 Era. AB - Although every disaster scenario is unique, certain themes have emerged repeatedly during management of burn disasters. These lessons learned are useful when planning an individual burn unit's role in future disaster response. PMID- 28576234 TI - Burn Injuries: Prevention, Advocacy, and Legislation. AB - Each year in the United States and Canada, thousands of individuals seek medical care for a burn injury. Some individuals are burned significantly enough they require treatment at specialized burn care facilities. Most of these injuries are preventable. This article presents an historical perspective related to burn prevention and elements of successful burn prevention programs and explores ways in which the plastic surgeon can promote burn prevention through education, advocacy, and the legislative process. Prevention efforts undertaken by the surgeon can increase awareness, ensure a safe environment, and reduce burn injuries. PMID- 28576233 TI - Disaster Preparedness and Response for the Burn Mass Casualty Incident in the Twenty-first Century. AB - The effective and efficient coordination of emergent patient care at the point of injury followed by the systematic resource-based triage of casualties are the most critical factors that influence patient outcomes after mass casualty incidents (MCIs). The effectiveness and appropriateness of implemented actions are largely determined by the extent and efficacy of the planning and preparation that occur before the MCI. The goal of this work was to define the essential efforts related to planning, preparation, and execution of acute and subacute medical care for disaster burn casualties. This type of MCI is frequently referred to as a burn MCI." PMID- 28576235 TI - Negligent and Inflicted Burns in Children. AB - One in 4 American children have been abused and up to 5 children die per day from abuse. Children are vulnerable and error or lag in diagnosis may lead to further injury or death. In contrast, misdiagnosis of abuse is also unacceptable. Burns are a leading cause of abuse-related fatality and determination of cause can be difficult. It is critical that clinicians distinguish between burns of abuse (inflicted) and neglect and those received accidentally (noninflicted). Discordant narratives, use of alcohol and illicit substances, characteristics of the burn wound, and concomitant injury are all red flags for inflicted and negligent burns. PMID- 28576236 TI - Burn Care in Low- and Middle-Income Countries. AB - This article examines the societal impact of thermal injury in low- and middle income countries. The authors describe the unique challenges of these health care systems in providing care for burned patients, focusing on resuscitation, excision and grafting, rehabilitation, and reconstruction. PMID- 28576237 TI - Global Burn Care: Education and Research. AB - Burns are an often-overlooked health indicator in global health literature, but account for a significant global health burden in lower middle income countries. This article provides an overview of burn injury from the global health perspective. It focuses on education and research, emphasizing the appropriate role of volunteerism. PMID- 28576238 TI - Acute Fluid Management of Large Burns: Pathophysiology, Monitoring, and Resuscitation. AB - This article reviews the pathophysiology of large burn injury and the extreme fluid shifts that occur in the hours and days after this event. The authors focus on acute fluid management, monitoring of hemodynamic status, and end points of resuscitation. Understanding the need and causes for fluid resuscitation after burn injury helps the clinician develop an effective plan to balance the competing goals of normalized tissue perfusion and limited tissue edema. Thoughtful, individualized treatment is the best answer and the most effective compromise. PMID- 28576240 TI - Management of Pulmonary Failure after Burn Injury: From VDR to ECMO. AB - This article highlights the challenges in managing pulmonary failure after burn injury. The authors review several different ventilator techniques, provide weaning parameters, and discuss complications. PMID- 28576241 TI - Rational Selection and Use of Antimicrobials in Patients with Burn Injuries. AB - Caring for patients with burn injuries is challenging secondary to the acute disease process, chronic comorbidities, and underrepresentation in evidence-based literature. Much current practice relies on extrapolation of guidance from different patient populations and wide variations in universal practices. Identifying infections or sepsis in this hypermetabolic population is imperfect and often leads to overprescribing of antimicrobials, suboptimal dosing, and multidrug resistance. An understanding of pharmacokinetics and pharmacodynamics may aid optimization of dosing regimens to better attain treatment targets. This article provides an overview of the current status of burn infection and attempts recommendations for consideration to improve universally accepted care. PMID- 28576239 TI - Inhalation Injury: Pathophysiology, Diagnosis, and Treatment. AB - The classic determinants of mortality from severe burn injury are age, size of injury, delays of resuscitation, and the presence of inhalation injury. Of the major determinants of mortality, inhalation injury remains one of the most challenging injuries for burn care providers. Patients with inhalation injury are at increased risk for pneumonia (the leading cause of death) and multisystem organ failure. There is no consensus among leading burn care centers in the management of inhalation injury. This article outlines the current treatment algorithms and the evidence of their efficacy. PMID- 28576242 TI - Sedation and Pain Management in Burn Patients. AB - Although pain management is a major challenge for clinicians, appropriate pain control is the foundation of efficacious burn care from initial injury to long term recovery. The very treatments designed to treat burn wounds may inflict more pain than the initial injury itself, making it the clinician's duty to embrace a multimodal treatment approach to burn pain. Vigilant pain assessment, meaningful understanding of the pathophysiology and pharmacologic considerations across different phases of burn injury, and compassionate attention to anxiety and other psychosocial contributors to pain will enhance the clinician's ability to provide excellent pain management. PMID- 28576243 TI - Metabolic and Endocrine Considerations After Burn Injury. AB - Severe burn injury is followed by a profound hypermetabolic response that persists up to 2 years after injury. It is mediated by up to 50-fold elevations in plasma catecholamines, cortisol, and glucagon that lead to whole-body catabolism, elevated resting energy expenditures, and multiorgan dysfunction. Modulation of the response by early excision and grafting of burn wounds, thermoregulation, control of infection, early and continuous enteral nutrition, and pharmacologic treatments aimed at mitigating physiologic derangements have markedly decreased morbidity. PMID- 28576244 TI - Clinician's Guide to Nutritional Therapy Following Major Burn Injury. AB - This article provides a clinician's guide to nutritional support of the burn patient. The authors review the assessment and management of the needs of the thermally injured patient and provide recommendations on replacement and supplementation with calories, protein, carbohydrates, lipids, fluids, and minerals. Furthermore, the authors compare and contrast enteral versus parenteral delivery of nutrition. PMID- 28576245 TI - Acalculous Cholecystitis in Burn Patients: Is There a Role for Percutaneous Cholecystostomy? AB - Although acute acalculous cholecystitis is uncommon in burn patients, this condition can be rapidly fatal due to delays in diagnosis and treatment and should always be considered in the differential diagnosis when burn patients become septic, develop abdominal pain, or have hemodynamic instability. This article reviews the use of percutaneous cholecystostomy in burn patients as both a diagnostic and therapeutic intervention. PMID- 28576246 TI - Venous Thromboembolism in Patients with Thermal Injury: A Review of Risk Assessment Tools and Current Knowledge on the Effectiveness and Risks of Mechanical and Chemical Prophylaxis. AB - Venous thromboembolism (VTE) can be a life-threatening or limb-threatening complication of thermal injury. The severity of burn injury can be used to predict VTE risk among patients with thermal injury, and a weighted risk stratification tool has been developed. This article reviews the incidence, diagnosis, and management of thromboembolic events in patients with burns. The article particularly focuses on identifying those patients who are at highest risk for VTE and provides recommendations on mechanical and chemical prophylaxis. PMID- 28576247 TI - Burn Center Care of Patients with Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. AB - Stevens-Johnson syndrome and toxic epidermal necrolysis are rare, life threatening, cutaneous drug reactions. Medications are the most common cause, although an infection may be responsible. A link between genetics and certain medications has been established. Clinical diagnosis should be confirmed with biopsy. When the area of epidermal detachment approaches 30%, burn center care is advisable. An ophthalmologist should be consulted to optimize ocular care. Pharmacologic interruption has been sought but there is little consensus on the most appropriate agent and no high-quality studies have been conducted to demonstrate if any of these agents lead to improved survival. PMID- 28576248 TI - Life-threatening Skin Disorders Treated in the Burn Center: Impact of Health care associated Infections on Length of Stay, Survival, and Hospital Charges. AB - This article reviews a single burn center experience with life-threatening skin disorders, over a 10-year period. It explores the incidence of health care associated infections and the impact on length of stay, hospital charges, and mortality. PMID- 28576249 TI - Pediatric Burn Care: Unique Considerations in Management. AB - Severe pediatric burns require a multidisciplinary team approach at a specialized pediatric burn center. Special attention must be paid to estimations of total body surface area, fluid resuscitation and metabolic demands, and adequate analgesia and sedation. Long-term effects involve scar management and psychosocial support to the child and their family. Compassionate comprehensive burn care is accomplished by a multidisciplinary team offering healing in the acute setting and preparing the child and family for long-term treatment and care. PMID- 28576250 TI - Patient Safety in Burn Care: Application of Evidence-based Medicine to Improve Outcomes. AB - This article reviews 5 areas in burn care that increasingly use evidence-based medicine to optimize quality and safety: resuscitation protocols, transfusion practices, vascular access, venous thromboembolic prophylaxis, and rational use of antibiotics. PMID- 28576251 TI - Surgical Excision of Burn Wounds: Best Practices Using Evidence-Based Medicine. AB - This article reviews guidelines for burn wound excision, regarding timing, depth, and technique. The authors collect evidence from both animal models and the clinical literature, to recommend best practices for burn wound excision. PMID- 28576252 TI - Skin Substitutes and Bioscaffolds: Temporary and Permanent Coverage. AB - Advancements in surgical wound treatment have led to skin substitutes and bioscaffolds as temporary and permanent coverage for burn wounds. Skin substitutes are used to improve wound coverage and restore the functional and aesthetic qualities of skin, and help to prevent wound infection and maintain a moist wound healing environment. Although allografts are preferred when autografts are not possible, high costs and limited availability have led to the use of xenografts and the development of skin substitutes and bioscaffolds. Despite constant evolution in the development of these skin substitutes and bioscaffolds, no single product stands out as the gold standard. PMID- 28576254 TI - Even Better Than the Real Thing? Xenografting in Pediatric Patients with Scald Injury. AB - This article reviews a single burn center experience with porcine xenografts to treat pediatric scald injuries, over a 10-year period. The authors compare xenografting to autografting, as well as wound care only, and provide outcome data on length of stay, incidence of health care-associated infections, and need for reconstructive surgery. PMID- 28576256 TI - Negative Pressure Wound Therapy for Burns. AB - Negative pressure wound therapy (NPWT) has become a widely used treatment for acute and chronic wounds. NPWT is indicated for a variety of complex wounds, and some studies validate its use for certain aspects of burn care. Although further research is needed to explore the benefits for burns, NPWT has proven beneficial in its use as a dressing that bolsters skin grafts, promotes integration of bilaminate dermal substitutes, promotes re-epithelialization of skin graft donor sites, and potentially reduces the zone of stasis. This article reviews the literature on NPWT in burns, based on indication/application, and describes our experience with the use of modified NPWT for large burns. PMID- 28576255 TI - Chemical, Electrical, and Radiation Injuries. AB - This article reviews the unique challenges presented by chemical, electrical, and radiation injuries. The authors discuss pathophysiology and diagnosis of these injuries and provide recommendations for management. PMID- 28576253 TI - Stem Cells and Tissue Engineering: Regeneration of the Skin and Its Contents. AB - In this review, the authors discuss the stages of skin wound healing, the role of stem cells in accelerating skin wound healing, and the mechanism by which these stem cells may reconstitute the skin in the context of tissue engineering. PMID- 28576258 TI - Volume 1: Rescue, Resuscitation, and Resurfacing. PMID- 28576257 TI - Management of the Chronic Burn Wound. AB - This article reviews the current evidence in using hyperbaric oxygen therapy (HBOT) in burn wounds. There is also separate consideration of diabetic foot burns and a protocol for use of HBOT in a specific case. The challenges of using HBOT in an acute burn care setting are reviewed. Next the pathophysiology of Marjolin ulcers is reviewed. The current thinking in diagnosis, treatment, and prevention of Marjolin ulcers is discussed. Finally, a background in using topical growth factors (tGF) is provided, followed by a summary of the current evidence of tGF in burn wounds. PMID- 28576259 TI - [Adolescents and young adults with acute lymphoblastic leukemia. A specific management]. AB - The acute lymphoblastic leukemia (ALL) is one of the first cancer for which emerged the particularity of the adolescent and young adult population. After decades of poorly concerted approaches, adult and pediatric haematologists found out that adolescents treated according to pediatric approaches had a better outcome than those treated in adult protocols. Therefore, pediatric-inspired therapies have been successfully implemented in the young adult population, leading to decreased criteria for allogeneic stem cell transplantation. More recently, a high prevalence of Philadelphia-like ALL has been identified in the AYA population, which opens the door to the combination of target therapy similar to Philadelphia-positive ALL. AYA patients require specific care programs including fertility counselling, adhesion evaluation, and long-term survivor follow-up. They are to be optimally treated by multidisciplinary teams, exploring their personal needs and determining the best management of the "whole patient". PMID- 28576260 TI - Regulation of bone mass by the gut microbiota is dependent on NOD1 and NOD2 signaling. AB - Germ-free (GF) mice have increased bone mass that is normalized by colonization with gut microbiota (GM) from conventionally raised (CONV-R) mice. To determine if innate immune signaling pathways mediated the effect of the GM, we studied the skeleton of GF and CONV-R mice with targeted inactivation of MYD88, NOD1 or NOD2. In contrast to WT and Myd88-/- mice, cortical bone thickness in mice lacking Nod1 or Nod2 was not increased under GF conditions. The expression of Tnfalpha and the osteoclastogenic factor Rankl in bone was reduced in GF compared to CONV-R WT mice but not in Nod1-/- or Nod2-/- mice indicating that the effect of the GM to increase Tnfalpha and Rankl in bone and to reduce bone mass is dependent on both NOD1 and NOD2 signaling. PMID- 28576261 TI - [Critical analysis of reference studies on aluminium-based adjuvants toxicokinetics]. AB - We reviewed the three reference toxicokinetic studies commonly used to suggest innocuity of aluminum (Al)-based adjuvants. A single experimental study was carried out using isotopic 26Al (Flarend et al., 1997). This study ignored adjuvant cell capture. It was conducted over a short period of time (28 days) and used only two rabbits per adjuvant. At the endpoint, Al retention was 78% for aluminum phosphate and 94% for aluminum hydroxide, both results being incompatible with quick elimination of vaccine-derived Al in urines. Tissue distribution analysis omitted three important retention sites: the injected muscle, the draining lymph node and bone. Two theoretical studies have evaluated the potential risk of vaccine Al in infants, by reference to the oral Minimal Risk Level (MRL) extrapolated from animal studies. Keith et al., 2002 used a too high MRL (2mg/kg/d), an erroneous model of 100% immediate absorption of vaccine Al, and did not consider renal and blood-brain barrier immaturity. Mitkus et al. (2011) only considered absorbed Al, with erroneous calculations of absorption duration. They ignored particulate Al captured by immune cells, which play a role in systemic diffusion and the neuro-inflammatory potential of the adjuvant. MRL they used was both inappropriate (oral Al vs injected adjuvant) and far too high (1mg/kg/d) with regard to experimental studies of Al-induced memory and behavioral changes. Both paucity and serious weaknesses of these studies strongly suggest that novel experimental studies of Al adjuvants toxicokinetics should be performed on the long-term, including post-natal and adult exposures, to ensure innocuity and restore population confidence in Al-containing vaccines. PMID- 28576262 TI - Total laparoscopic pelvic exenteration for a laterally recurrent cervical carcinoma with a vesicovaginal fistula that developed after concurrent chemoradiotherapy. AB - OBJECTIVE: For locally advanced cervical carcinoma, concurrent chemoradiotherapy (CCRT) is the standard treatment, however, CCRT can lead to development of a vesicovaginal or rectovaginal fistula [1]. Treatment options are limited for patients with laterally recurrent cervical carcinoma and fistula formation after CCRT. Chemotherapy with bevacizumab is now used for recurrent or advanced cervical carcinoma, but this treatment is associated with fistula formation [2]. When the recurrent mass is confined to the pelvic cavity, complete surgical resection with negative margins offers the most promise; however, the resectability rate is low in cases of laterally recurrent tumor [3], which may include bony structures, and survival outcomes seem to be poor in cases of a laterally recurrent vs. centrally recurrent tumor, even when the primary tumor has been resected in full [4]. Because analyses have shown that laparoscopy optimizes visualization and thus provides for meticulous dissection and that laparoscopic pelvic exenteration, in comparison to open pelvic exenteration results in minimal intraoperative blood loss and complications, fewer postoperative complications, and a shorter hospital stay [5], we perform laparoscopic pelvic exenteration in cases of laterally recurrent cervical carcinoma. METHODS: A 52-year-old woman underwent CCRT for a 10-cm stage IVA cervical carcinoma. That involved the bladder and right ureter, causing right hydronephrosis. Seven months after the CCRT, a recurrent mass at the right pelvic sidewall and vesicovaginal fistula were detected. The mass involved the right ureter and bladder and was attached to the rectum. The patient's right renal function was lost. RESULTS: Total pelvic exenteration and right nephroureterectomy were performed laparoscopically. Operation time was 566min, and the blood loss volume was 250mL. Complete tumor clearance was achieved without any complication. No adjuvant treatment has been performed, and follow-up positron emission tomography-computed tomography has revealed no sign of recurrence during the 5months that have passed since the surgery. CONCLUSION: Total laparoscopic pelvic exenteration is technically feasible for a laterally recurrent cervical carcinoma and vesicovaginal fistula that develop after CCRT. PMID- 28576263 TI - Numerical analysis of ammonia homogenization for selective catalytic reduction application. AB - Selective catalytic reduction based on urea water solution as ammonia precursor is a promising method for the NOx abatement form exhaust gasses of mobile diesel engine units. It consists of injecting the urea-water solution in the hot flue gas stream and reaction of its products with the NOx over the catalyst surface. During this process flue gas enthalpy is used for the urea-water droplet heating and for the evaporation of water content. After water evaporates, thermolysis of urea occurs, during which ammonia, a known NOx reductant, and isocyanic acid are generated. The uniformity of the ammonia before the catalyst as well as ammonia slip to the environment are important counteracting design requirements, optimization of which is crucial for development of efficient deNOx systems. The aim of this paper is to show capabilities of the developed mathematical framework implemented in the commercial CFD code AVL FIRE(r), to simulate physical processes of all relevant phenomena occurring during the SCR process including chemical reactions taking part in the catalyst. First, mathematical models for description of SCR process are presented and afterwards, models are used on the 3D geometry of a real SCR reactor in order to predict ammonia generation, NOx reduction and resulting ammonia slip. Influence of the injection direction and droplet sizes was also investigated on the same geometry. The performed study indicates importance of droplet sizes on the SCR process and shows that counterflow injection is beneficial, especially in terms of minimizing harmful ammonia slip to environment. PMID- 28576264 TI - Causes and Predictors of 30-Day Readmissions in Atrial Fibrillation (from the Nationwide Readmissions Database). AB - Atrial fibrillation (AF) is the most common cause of arrhythmia-related hospitalizations. We assessed 30-day readmissions in patients admitted with AF in a national sample of US population. Data were extracted from Nationwide Readmissions Database for the calendar year 2013. Patients with primary discharge diagnosis of AF were identified by the International Classification of Diseases, Ninth Revision, Clinical Modification, code 427.31. Patients who died during hospitalization and those <18 years were excluded. Our primary outcome was 30-day readmission rate. Causes and independent predictors of 30-day readmissions were examined. We identified 388,340 patients admitted with AF, of whom 58,634 patients (15.1%) were readmitted within 30 days. Patients who were readmitted tended to be older and have a higher burden of co-morbidities. AF and heart failure were the main causes of 30-day readmissions in our cohort. Advanced age, female gender, and multiple co-morbidities were independently associated with 30 day readmissions. In conclusion, 15% of patients admitted for AF were readmitted within 30 days. More than 1/3 of these readmissions were for AF or heart failure. PMID- 28576265 TI - Incidence and Outcomes of Heparin-Induced Thrombocytopenia in Patients Undergoing Transcatheter Aortic Valve Replacement. AB - The main objective of this study was to investigate the incidence and magnitude of impact of heparin-induced thrombocytopenia (HIT) on outcomes of patients undergoing transcatheter aortic valve placement (TAVR). The impact of HIT on procedural outcomes after cardiac surgery has been described. We sought to investigate the incidence and outcomes of HIT after TAVR using the Nationwide Inpatient Sample (NIS) database. We identified patients who underwent TAVR from 2011 to 2014. The primary outcome was the effect of HIT on inpatient mortality. Secondary outcomes included perioperative thromboembolic complications and ensuing sequelae. We also examined the length of hospital stay and hospital cost. Hierarchical mixed-effects models tested the association between HIT and main outcomes, adjusted by patient- and hospital-level characteristics. Among 33,790 patients who underwent TAVR (46.1% women and 81.4 +/- 8.5 years old), the cumulative incidence of HIT was 0.49% (95% CI 0.4% to 0.6%). After adjusting for patient- and hospital-level characteristics, in-hospital mortality was significantly higher in the TAVR group with HIT (odds ratio [OR] 5.6, 95% CI 2.0 to 15.6, p = 0.001). Venous thrombosis/pulmonary embolism (OR 6.3, 95% CI 1.4 to 28.8, p = 0.01) and acute kidney injury (OR 6.1, 95% CI 2.8 to 13.1, p <0.001) were significantly associated with HIT. Patients who developed HIT also had a longer hospital stay (p <0.001) with the median hospital cost of 68,168 USD versus 50, 494 USD for the group without HIT (p <0.001). In conclusion, among patient who underwent TAVR, HIT was associated with higher risk of in-hospital mortality, venous thrombosis/pulmonary embolism, acute kidney injury, prolonged hospital stay, and increased cost. PMID- 28576266 TI - Safety and Tolerability of Transitioning from Cangrelor to Ticagrelor in Patients Who Underwent Percutaneous Coronary Intervention. AB - The 3 phase 3 CHAMPION (Cangrelor vs Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials collectively demonstrated the safety of transitioning from cangrelor, a potent, parenteral rapidly-acting P2Y12 inhibitor, to clopidogrel in patients who underwent percutaneous coronary intervention (PCI). However, variation in timing of therapy, site-specific binding, and drug half-lives may theoretically complicate switching to other oral P2Y12 inhibitors. Since regulatory approval, limited data are available regarding the "real-world" safety and tolerability of transitioning to these more potent oral P2Y12 antagonists. From November 2015 to January 2017, we evaluated the clinical profiles and efficacy and safety outcomes in cangrelor-treated patients who underwent PCI transitioned to clopidogrel (n = 42) or ticagrelor (n = 82) at a large, tertiary care center. Most patients receiving cangrelor underwent PCI with a drug-eluting stent for acute coronary syndrome via a radial approach in the background of unfractionated heparin. Stent thrombosis within 48 hours was rare and occurred in 1 patient treated with ticagrelor. Global Use of Strategies to Open Occluded Coronary Arteries-defined bleeding occurred in 20% of patients switched to ticagrelor and 29% of patients switched to clopidogrel, but none were severe or life-threatening. In conclusion, rates of stent thrombosis and severe/life-threatening bleeding were low and comparable with those identified in the CHAMPION program, despite use of more potent oral P2Y12 inhibition. PMID- 28576267 TI - Age * Gender Interaction Effect on Resuscitation Outcomes in Patients With Out-of Hospital Cardiac Arrest. AB - Although an interaction between gender and age has been shown to influence resuscitation outcomes in patients with out-of-hospital cardiac arrest (OHCA), this interaction has not been investigated in Asian populations. In this prospective, observational study, data from all cases of OHCA in Japan between 2005 and 2012 were obtained from the Japanese National Registry. We determined the relative excess risk due to interaction and the ratio of odds ratios (ORs) to assess the interaction effect of gender and age on the incidence of return of spontaneous circulation (ROSC) before hospital arrival, 1-month survival, and neurologically intact survival 1 month after OHCA. Male gender was associated with decreased ROSC and lower 1-month survival rates in patients with OHCA of presumed cardiac origin. Older age was associated with lower 1-month and neurologically intact survival rates in male patients with OHCA of presumed cardiac and noncardiac origin and with increased ROSC in male patients with OHCA of presumed cardiac origin. The relative excess risk due to interaction for ROSC in patients with OHCA of presumed cardiac origin was statistically significant (OR 0.19, 95% confidence interval [CI] 0.06 to 0.32). The ratio of ORs for ROSC was statistically significant in patients with OHCA of presumed cardiac origin (OR 1.25, 95% CI 1.05 to 1.47) and of noncardiac origin (OR 0.40, 95% CI 0.17 to 0.92). In conclusion, the interaction effect between age and gender on ROSC was positive in OHCA cases of presumed cardiac origin and negative in those of noncardiac origin. PMID- 28576268 TI - Comparison of 1, 2, and 6-Month Readmission Rates in Patients With Acute Myocardial Infarction Directly Admitted to Hospital Versus Transferred From Another Hospital to an Academic Medical Center. AB - Patients with acute myocardial infarction (AMI) who are transferred are less likely than directly admitted patients to receive outpatient follow-up within 30 days and are more likely to be readmitted. In 2015, we launched a clinic where post-AMI patients (direct admits and transfers) are seen within 1 week of hospital discharge. We compared short- and long-term clinical outcomes of patients who were transferred to patients who were directly admitted to our institution to determine the impact of transfer status on early outpatient follow up and clinical outcomes. A total of 280 post-AMI patients, 193 direct admissions (69%), and 87 transfers (31%) were referred to the clinic. Clinic attendance was similar between the transferred and the directly admitted patients (91% vs 92%, p = 0.688, respectively). Transferred patients had similar rates of confusion regarding their medical regimen as the directly admitted patients (11% vs 8%, p = 0.393). Compared with directly admitted patients, transferred patients lived farther from the hospital (median distance of 30 vs 48 miles, p <0.0001), were predominately white (77% vs 91%, p = 0.005), and had higher rates of chronic obstructive pulmonary disease (9% vs 17%, p = 0.014). There was no difference in 30- (16% vs 13%, p = 0.562) or 60-day readmission rates (6% vs 8%, p = 0.543) between transferred patients and directly admitted patients. At 6 months, mortality rates were similar (6% vs 4%, p = 0.556). In conclusion, transferred patients who were evaluated early after hospital discharge for acute MI had similar clinical outcomes (including rates of unplanned readmissions) to their directly admitted counterparts. PMID- 28576269 TI - Canine Hip Dysplasia: Diagnostic Imaging. AB - Diagnostic imaging is the principal method used to screen for and diagnose hip dysplasia in the canine patient. Multiple techniques are available, each having advantages, disadvantages, and limitations. Hip-extended radiography is the most used method and is best used as a screening tool and for assessment for osteoarthritis. Distraction radiographic methods such as the PennHip method allow for improved detection of laxity and improved ability to predict future osteoarthritis development. More advanced techniques such as MRI, although expensive and not widely available, may improve patient screening and allow for improved assessment of cartilage health. PMID- 28576270 TI - Conservative Management of Hip Dysplasia. AB - Hip dysplasia (HD) is a common orthopedic condition seen in small animal patients that leads to osteoarthritis of the coxofemoral joint. The disease can be managed conservatively or surgically. The goals of surgical treatment in the immature patient are to either prevent the clinical signs of HD or to prevent or slow the progression of osteoarthritis. In mature patients surgery is used as a salvage procedure to treat debilitating osteoarthritis. Conservative management can be used in dogs with mild or intermittent clinical signs and includes nutritional management and weight control, exercise modification, physical rehabilitation, pain management and disease-modifying agents. PMID- 28576271 TI - Physical Rehabilitation for the Management of Canine Hip Dysplasia. AB - Hip dysplasia is among the most common orthopedic conditions affecting dogs. Joint laxity is responsible for abnormal development of the femoral head and acetabulum, leading to excessive wear of the articular cartilage. Wear leads to secondary osteoarthritis. Rehabilitation is either conservative or after surgical management. Conservative rehabilitation therapies are directed at decreasing pain, improving hip range of motion (ROM), and building or maintaining muscle mass. Postoperatively, rehabilitation focuses on decreasing postoperative pain and inflammation, improving comfort and limb use, and protecting the surgical site. Once the patient has healed, rehabilitation is directed at improving ROM and promoting muscle mass. PMID- 28576272 TI - Juvenile Pubic Symphysiodesis. AB - In properly selected dogs, juvenile pubic symphysiodesis improves joint congruity, decreases hip laxity, and can reverse or prevent progression of degenerative joint disease in the hips. To be effective, surgery must be done at a young age and in hips that are only mildly to moderately lax. Juvenile pubic symphysiodesis is best viewed more as a preemptive procedure than as a strictly therapeutic one. Dogs considered to be at risk for hip dysplasia should be screened with Ortolani testing at 12 weeks of age, with further imaging and perhaps surgery to follow for those who have a positive Ortolani sign. PMID- 28576273 TI - Femoral Head and Neck Excision. AB - Femoral head and neck excision is a surgical procedure that is commonly performed in small animal patients. It is a salvage procedure that is done to relieve pain in the coxofemoral joint and restore acceptable function of the limb. Femoral head and neck excision is most commonly used to treat severe osteoarthritis in the coxofemoral joint and can be done in dogs and cats of any size or age. The procedure should not be overused and ideally should not be done when the integrity of the coxofemoral joint can be restored. PMID- 28576274 TI - BioMedtrix Total Hip Replacement Systems: An Overview. AB - Total hip replacement for canine and feline patients affected by degenerative, traumatic, and vascular injury of the coxofemoral joint has become a highly successful orthopedic procedure. The highly effective BioMedtrix total hip replacement systems use cemented and cementless implants with unique design features to address a variety of bone conditions and surgeon expertise and preferences. There are pros and cons for both systems with common and unique complications that can occur in either system. Surgeon experience and adherence to the principles of technique will strongly influence the complication rate and outcomes. PMID- 28576275 TI - INNOPLANT Total Hip Replacement System. AB - Total hip replacement is a salvage procedure that is done to alleviate discomfort secondary to osteoarthritis in the hip, which is most often a result of hip dysplasia. Commercially available total hip replacement implants for small animal patients are classified as cemented or cementless. The INNOPLANT Total Hip Replacement system includes modular, screw-in cementless components that were developed to improve implant stability by maintaining as much normal anatomic structure, and by extension biomechanics of the coxofemoral joint, as possible. As a newer system, there are few data and no long-term studies available in the veterinary literature. PMID- 28576276 TI - Hip Dysplasia: Where Are We Now and How Do We Treat? PMID- 28576277 TI - Simulated pressure denaturation thermodynamics of ubiquitin. AB - Simulations of protein thermodynamics are generally difficult to perform and provide limited information. It is desirable to increase the degree of detail provided by simulation and thereby the potential insight into the thermodynamic properties of proteins. In this study, we outline how to analyze simulation trajectories to decompose conformation-specific, parameter free, thermodynamically defined protein volumes into residue-based contributions. The total volumes are obtained using established methods from Fluctuation Solution Theory, while the volume decomposition is new and is performed using a simple proximity method. Native and fully extended ubiquitin are used as the test conformations. Changes in the protein volumes are then followed as a function of pressure, allowing for conformation-specific protein compressibility values to also be obtained. Residue volume and compressibility values indicate significant contributions to protein denaturation thermodynamics from nonpolar and coil residues, together with a general negative compressibility exhibited by acidic residues. PMID- 28576278 TI - Spectroscopic characterization and fluorescence imaging of Helicobacter pylori endogenous porphyrins. AB - Conventional antimicrobial strategies have become increasingly ineffective due to the rapid emergence of antibiotic resistance among pathogenic bacteria. In order to overcome this problem, antimicrobial PhotoDynamic Therapy (PDT) is considered a promising alternative therapy. PDT has a broad spectrum of action and low mutagenic potential. It is particularly effective when microorganisms present endogenous photosensitizing pigments. Helicobacter pylori (Hp), a pathogen notoriously responsible of severe gastric infections (chronic gastritis, peptic ulcer, MALT lymphoma and gastric adenocarcinoma), produces and accumulates the photosensitizers protoporphyrin IX and coproporphyrin, thus it might be a suitable target of antimicrobial PDT. With the aim to design and develop an ingestible LED-based robotic pill for intragastric phototherapy, so that irradiation can be performed in situ without the use of invasive endoscopic light, photophysical studies on the Hp endogenous photosensitizers were carried out. These studies represent an important prerequisite in order to select the most effective irradiation conditions for Hp eradication. The photophysical characterization of Hp porphyrins, including their spectroscopic features in terms of absorption, steady-state and time-resolved fluorescence, was performed on bacterial extracts as well as within planktonic and biofilm growing Hp cells. PMID- 28576279 TI - [Atypical reaction to anesthesia in Duchenne/Becker muscular dystrophy]. AB - BACKGROUND AND OBJECTIVES: Duchenne/Becker muscular dystrophy affects skeletal muscles and leads to progressive muscle weakness and risk of atypical anesthetic reactions following exposure to succinylcholine or halogenated agents. The aim of this report is to describe the investigation and diagnosis of a patient with Becker muscular dystrophy and review the care required in anesthesia. CASE REPORT: Male patient, 14 years old, referred for hyperCKemia (chronic increase of serum creatine kinase levels - CK), with CK values of 7,779-29,040IU.L-1 (normal 174IU.L-1). He presented with a discrete delay in motor milestones acquisition (sitting at 9 months, walking at 18 months). He had a history of liver transplantation. In the neurological examination, the patient showed difficulty in walking on one's heels, myopathic sign (hands supported on the thighs to stand), high arched palate, calf hypertrophy, winged scapulae, global muscle hypotonia and arreflexia. Spirometry showed mild restrictive respiratory insufficiency (forced vital capacity: 77% of predicted). The in vitro muscle contracture test in response to halothane and caffeine was normal. Muscular dystrophy analysis by Western blot showed reduced dystrophin (20% of normal) for both antibodies (C and N-terminal), allowing the diagnosis of Becker muscular dystrophy. CONCLUSION: On preanesthetic assessment, the history of delayed motor development, as well as clinical and/or laboratory signs of myopathy, should encourage neurological evaluation, aiming at diagnosing subclinical myopathies and planning the necessary care to prevent anesthetic complications. Duchenne/Becker muscular dystrophy, although it does not increase susceptibility to MH, may lead to atypical fatal reactions in anesthesia. PMID- 28576280 TI - [Familial hypercholesterolemia: A largely underestimated cardiovascular risk]. AB - BACKGROUND: Familial hypercholesterolemia is a monogenic autosomal dominant dyslipidemia characterized by a permanent and isolated increase of cholesterol carried by low-density lipoproteins. The prevalence of its heterozygous form is estimated between 1/500 and 1/250, and in the absence of specific treatment, this form is responsible for an increase by a factor of 13 of the risk of premature coronary artery disease compared to patients non-affected by the disease. OBJECTIVES: To perform an inventory of the knowledge of heterozygous familial hypercholesterolemia in France for physicians involved in the management of the disease. METHODS: A survey was conducted (by phone and internet) among a representative sample of 495 physicians (cardiologists, endocrinologists/diabetologists, gynecologists, general practitioners) who, in parallel, completed 579 patient records. RESULTS: Thirty-two percent (95% CI [27.8; 36.2]) of physicians reported the difference between polygenic hypercholesterolemia and familial hypercholesterolemia. The presence of tendinous xanthomas, a key element of diagnosis, was spontaneously mentioned by 44% (95% CI [34; 54.2]) of cardiologists. Six percent (95% CI [2.2; 12.6]) of them gave a correct estimate of the prevalence of familial hypercholesterolemia. The likelihood of transmission of heterozygous familial hypercholesterolemia, when one parent is affected, was known for 59% (95% CI [48.7; 68.7]) of surveyed cardiologists. A cascade screening was performed systematically by 4% (95% CI [1.1; 9.9]) of them. Eighteen percent (95% CI [11; 26.9]) of cardiologists gave an accurate estimation of cardiovascular risk of heterozygous familial hypercholesterolemia. Fifty-seven percent (95% CI [46.7; 66.8]) of cardiologists admitted being misinformed about the heterozygous familial hypercholesterolemia and 83% (95% CI [74.1; 89.7]) expressed a need for information about this disease. CONCLUSION: The lack of knowledge of heterozygous familial hypercholesterolemia and its associated cardiovascular risk is probably the cause of a diagnostic default leading to inappropriate management of this disease. PMID- 28576281 TI - [Late discover of a coronaro-pulmonary fistula]. AB - Anomalies of the coronary arteries mainly concern a pediatric population, bringing together a wide range of defects. In adults, the evolution is linked to the hemodynamic consequences of fistula. Several therapeutic options have been proposed such as surgery or embolization. We report the case of a 55 years old patient addressed because of dyspnea secondary to aortic insufficiency. The preoperative assessment shown the coexistence of coronary abnormality corresponding to a coronaro-pulmonary fistula. This type of coronary anomaly is rarely described in the adult population, because of its consequences secondary to the closure of the foramen ovale, resulting in angina symptoms in childhood. Without treatment, mortality from this type of malformation is important (90%). PMID- 28576282 TI - [Evidence of antihypertensive effect of a land snail (Helix aspersa) by-product hydrolysate - Identification of involved peptides]. AB - The antihypertensive potential of a land snail by-product hydrolysate, obtained after an agri-food processing of the raw material, was studied in vitro and in vivo. First, the ACE inhibitory activity of hydrolysates obtained before and after an ultrafiltration step with a 10kDa membrane cutoff was assayed. The IC50 obtained were of 98.3MUg.mL-1 and 23MUg.mL-1, respectively, showing a 4.2 fold increase in ACE inhibitory capacity after the ultrafiltration step. Then, ACE inhibitory capacity of the hydrolysate was followed. No significant modification of the ACE inhibition rate was observed during an in vitro simulated human gastro intestinal digestion. Moreover, the hydrolysate was not only safe for human intestinal cells but besides that it stimulated their metabolic activity. No toxicity of the hydrolysate was observed in vivo in Wistar rats regarding to the results of the acute toxicity study. The partial purification of the hydrolysate led to the obtention of an active fraction characterized by an IC50 of 0.007MUg.mL-1. The sequences of the 17 most abundant peptides of the fraction were identified by LC/MS/MS analysis. Seven of these peptides (YG, YA, VY, FG/GF, DF, SF and VW) are known ACE inhibitory peptides. Finally, in vivo study on SHR rats showed that the hydrolysate reduced systolic blood pressure by 20mmHg after a single oral administration at both doses of 400 and 800mg.kg-1. PMID- 28576283 TI - Ketamine fails to prevent postoperative delirium. PMID- 28576284 TI - Congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia is a group of autosomal recessive disorders encompassing enzyme deficiencies in the adrenal steroidogenesis pathway that lead to impaired cortisol biosynthesis. Depending on the type and severity of steroid block, patients can have various alterations in glucocorticoid, mineralocorticoid, and sex steroid production that require hormone replacement therapy. Presentations vary from neonatal salt wasting and atypical genitalia, to adult presentation of hirsutism and irregular menses. Screening of neonates with elevated 17-hydroxyprogesterone concentrations for classic (severe) 21 hydroxylase deficiency, the most common type of congenital adrenal hyperplasia, is in place in many countries, however cosyntropin stimulation testing might be needed to confirm the diagnosis or establish non-classic (milder) subtypes. Challenges in the treatment of congenital adrenal hyperplasia include avoidance of glucocorticoid overtreatment and control of sex hormone imbalances. Long-term complications include abnormal growth and development, adverse effects on bone and the cardiovascular system, and infertility. Novel treatments aim to reduce glucocorticoid exposure, improve excess hormone control, and mimic physiological hormone patterns. PMID- 28576286 TI - A novel hybrid tobacco product that delivers a tobacco flavour note with vapour aerosol (Part 1): Product operation and preliminary aerosol chemistry assessment. AB - Vapour products have demonstrated potential to be a lower-risk alternative to cigarettes. The present study describes a novel hybrid tobacco product that combines a warm aerosol stream generated by an electronic vaporisation mechanism with tobacco top flavour from cut tobacco. During operation, the aerosol stream released from the vapour cartomiser is passed through a bed of blended cut tobacco by the puffing flow, elevating the tobacco temperature and eluting volatile tobacco flavour components. A preliminary but comprehensive analysis of the aerosol composition of the hybrid tobacco product found that emissions were dominated by the control vapour formulation. In non-targeted chemical screening, no detectable difference in GC scans was observed between the hybrid tobacco product and the control vapour product. However, a sensorially elevated tobacco flavour was confirmed by a consumer sensory panel (P < 0.05). In a targeted analysis of 113 compounds, either identified by regulatory bodies as potential toxicants in cigarette smoke or formed from electronic vapour products, only 26 were quantified. The novel action of tobacco heating and liquid aerosolisation produced classes and levels of toxicants that were similar to those of the control vapour product, but much lower than those of a Kentucky 3R4F reference cigarette. For nine toxicants mandated by the WHO Study Group on Tobacco Product Regulation for reduction in cigarette emissions, the levels were 91%-99% lower per puff in the hybrid tobacco product aerosol than in 3R4F smoke. Overall, the novel hybrid tobacco product provides a sensorially enhanced tobacco flavour, but maintains a toxicant profile similar to its parent vapour product with relatively low levels of known cigarette smoke toxicants. PMID- 28576287 TI - 2017 Keystone Symposia at the Fairmont Banff Springs: Exploring new concepts in innate immunity and interferon signaling at the haunted castle. AB - At the 2017 Keystone Symposia meeting, new research was presented in the fields of innate immunity and type I interferon regulation. Gathering experts from these research communities offered a unique opportunity to discuss new concepts and formulate novel approaches to modulate pathological mechanisms in human inflammatory diseases. PMID- 28576288 TI - Editor Note. PMID- 28576289 TI - Psychological counseling as an adjunct to stuttering treatment: Clients' experiences and perceptions. AB - PURPOSE: Stuttering can trigger anxiety and other psychological and emotional reactions, and limit participation in society. It is possible that psychological counseling could enhance stuttering treatment outcomes; however, little is known about how clients view such counseling. The purpose of this study was to gain an understanding of clients' experiences with, and perceptions of, a psychological counseling service that was offered as an optional adjunct to speech therapy for stuttering. METHOD: Nine individuals who stutter (13-38 years old) participated in semi-structured interviews. Six participants had taken part in psychological counseling; three participants did not do so. Interview data were analyzed using grounded theory as a guiding framework. RESULTS: Four thematic clusters emerged from participants' accounts: insights into personal decision-making, why others may not participate in counseling, psychological counseling as a worthwhile part of therapy, and counseling as a necessary component in a stuttering treatment program. CONCLUSION: In addition to experiencing barriers and facilitators to help-seeking that are reported in related fields, participants accounts also revealed novel facilitators (i.e., a 'why not' mentality and the importance of having a pre-existing relationship with the clinician who offered the service) and barriers (i.e., viewing the service as a 'limited resource,' and, the overwhelming nature of intensive stuttering treatment programs). Findings suggest that clients value the option to access psychological counseling with trained mental health professionals to support the stuttering treatment provided by speech-language pathologists. Participants made recommendations for the integration of psychological counseling into stuttering treatment programs. PMID- 28576285 TI - Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. AB - BACKGROUND: Delirium is a common and serious postoperative complication. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia, and some evidence suggests that ketamine prevents delirium. The primary purpose of this trial was to assess the effectiveness of ketamine for prevention of postoperative delirium in older adults. METHODS: The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] study is a multicentre, international randomised trial that enrolled adults older than 60 years undergoing major cardiac and non-cardiac surgery under general anaesthesia. Using a computer-generated randomisation sequence we randomly assigned patients to one of three groups in blocks of 15 to receive placebo (normal saline), low dose ketamine (0.5 mg/kg), or high dose ketamine (1.0 mg/kg) after induction of anaesthesia, before surgical incision. Participants, clinicians, and investigators were blinded to group assignment. Delirium was assessed twice daily in the first 3 postoperative days using the Confusion Assessment Method. We did analyses by intention-to-treat and assessed adverse events. This trial is registered with clinicaltrials.gov, number NCT01690988. FINDINGS: Between Feb 6, 2014, and June 26, 2016, 1360 patients were assessed, and 672 were randomly assigned, with 222 in the placebo group, 227 in the 0.5 mg/kg ketamine group, and 223 in the 1.0 mg/kg ketamine group. There was no difference in delirium incidence between patients in the combined ketamine groups and the placebo group (19.45% vs 19.82%, respectively; absolute difference 0.36%, 95% CI -6.07 to 7.38, p=0.92). There were more postoperative hallucinations (p=0.01) and nightmares (p=0.03) with increasing ketamine doses compared with placebo. Adverse events (cardiovascular, renal, infectious, gastrointestinal, and bleeding), whether viewed individually (p value for each >0.40) or collectively (36.9% in placebo, 39.6% in 0.5 mg/kg ketamine, and 40.8% in 1.0 mg/kg ketamine groups, p=0.69), did not differ significantly across groups. INTERPRETATION: A single subanaesthetic dose of ketamine did not decrease delirium in older adults after major surgery, and might cause harm by inducing negative experiences. FUNDING: National Institutes of Health and Cancer Center Support. PMID- 28576290 TI - Comparing acceptance and rejection in the classroom interaction of students who stutter and their peers: A social network analysis. AB - PURPOSE: Recent work has reported adverse effects of students' stuttering on their social and emotional functioning at school. Yet, few studies have provided an in-depth examination of classroom interaction of students who stutter (SWS). The current study uses a network perspective to compare acceptance and rejection in the classroom interaction between SWS and their peers in secondary education. METHODS: The sample comprised 22 SWS and 403 non-stuttering peers (22 classes) of secondary education in Flanders (Belgium). Students' nominations regarding three acceptance and three rejection criteria were combined. Social network analysis offered procedures that considered direct and indirect interaction between all classmates. RESULTS: We found few significant differences: SWS and their peers were distributed similarly across positive and negative status groups. Both considered and were considered by, on average, six or seven classmates as 'a friend', who they liked and could count on, and nominated or were nominated by one or two classmates as 'no friend', somebody who they disliked and could not count on. On average, SWS and their classmates also did not differ in terms of structural position in the class group (degree, closeness and betweenness), reciprocated rejection, and clique size. However, SWS do tend to be slightly more stringent or more careful in nominating peers, which led to fewer reciprocated friendships. CONCLUSION: Our results suggest that SWS are quite accepted by peers in secondary education in Flanders. Such positive peer interaction can create a supportive and encouraging climate for SWS to deal with specific challenges. PMID- 28576291 TI - A pilot study into a possible relationship between diet and stuttering. AB - PURPOSE: There are theoretical and empirical reasons to consider a potential role for copper metabolism in the brain in how it could influence stuttering. However, a link between stuttering and dietary intake has never been researched in a systematic way. This pilot study therefore aimed to explore a possible association between ingested amounts of copper and thiamine (vitamin B1) with stuttering frequency using a double blind cross-over longitudinal paradigm. METHODS: 19 adults who stutter between 20 and 51 years old filled out an online survey for 9 consecutive weeks. The survey consisted of self-assessed fluency and mood state scales, as well as food journals. After 4 weeks, the participants consumed either copper or thiamine supplements for 2 weeks, followed by a 1-week washout period, and another period of two weeks taking the other supplement. Formal speech assessments were done pre/post baseline and at the end of each supplement intake. Participants were not informed about the nature of the supplements during the experiment and the investigators were blinded to the order of the supplements. RESULTS: The results demonstrated that copper and thiamine had no measurable effect on the amount of stuttering (self and formal assessments) but there was a moderate, significant correlation between mood state and fluency. CONCLUSION: The findings do not support notions of dietary influences of ingested copper or thiamine on stuttering but do provide modest support for a relationship between variations in stuttering and self-perceived anxiety. PMID- 28576292 TI - A country-wide probability sample of public attitudes toward stuttering in Portugal. AB - BACKGROUND: Negative public attitudes toward stuttering have been widely reported, although differences among countries and regions exist. Clear reasons for these differences remain obscure. PURPOSE: Published research is unavailable on public attitudes toward stuttering in Portugal as well as a representative sample that explores stuttering attitudes in an entire country. This study sought to (a) determine the feasibility of a country-wide probability sampling scheme to measure public stuttering attitudes in Portugal using a standard instrument (the Public Opinion Survey of Human Attributes-Stuttering [POSHA-S]) and (b) identify demographic variables that predict Portuguese attitudes. METHODS: The POSHA-S was translated to European Portuguese through a five-step process. Thereafter, a local administrative office-based, three-stage, cluster, probability sampling scheme was carried out to obtain 311 adult respondents who filled out the questionnaire. RESULTS: The Portuguese population held stuttering attitudes that were generally within the average range of those observed from numerous previous POSHA-S samples. Demographic variables that predicted more versus less positive stuttering attitudes were respondents' age, region of the country, years of school completed, working situation, and number of languages spoken. Non predicting variables were respondents' sex, marital status, and parental status. CONCLUSION: A local administrative office-based, probability sampling scheme generated a respondent profile similar to census data and indicated that Portuguese attitudes are generally typical. PMID- 28576293 TI - The relationship between the experience of stuttering and demographic characteristics of adults who stutter. AB - PURPOSE: This study aims to examine the association between adults' experience of stuttering and their age, gender and marital status, as well as to evaluate the psychometric properties of the Hebrew version of the OASES-A. METHODS: The Hebrew version of the OASES-A was administered to 91 adults-who-stutter. The validity of the translated version was evaluated using a subset of 43 participants, who also completed three additional instruments: (a) a Perceived Stuttering Severity (PSS) self-rating scale, (b) the Situation Avoidance Behavior Checklist (SABC), (c) the Students Life Satisfaction scale (SLSS). Finally, the correlations between the participants' OASES-A scores and their age, gender and marital status were calculated. RESULTS: A negative correlation was found between the participants' OASES-A impact scores and their age (p<0.01). In addition, married participants exhibited lower OASES-A impact scores compared with unmarried participants (p<0.05). On the other hand, the speakers' gender was not associated with OASES-A impact scores. RESULTS: revealed high internal consistency of the Hebrew OASES-A, and moderate to strong correlations with the additional examined instruments. Finally, results of the Hebrew version of the questionnaire were comparable with those obtained in other languages. CONCLUSION: Our results indicated that, within our cohort, age and marital status are significantly associated with the personal experience of stuttering, whereas gender is not. In addition, the Hebrew version of the OASES-A is valid and comparable with equivalent versions in other languages. This facilitates the application of the OASES-A in future clinical and research settings. PMID- 28576294 TI - Development of quality indicators for endoscopic eradication therapies in Barrett's esophagus: the TREAT-BE (Treatment with Resection and Endoscopic Ablation Techniques for Barrett's Esophagus) Consortium. PMID- 28576295 TI - Alternative payment models lead to strategic care coordination workforce investments. AB - BACKGROUND: Care coordination is generally viewed as a key to success for health systems seeking to adapt to a range of new value-based payment policies. PURPOSE: This study explores care coordination staffing in four health systems participating in new payment models, including Medicaid payment reform and Accountable Care Organizations. METHODS: Comparative case study design is used to describe models of care coordination. Analysis of 43 semi-structured interviews with leadership, clinicians, and care coordination staff at four health systems engaged in value-based contracts. DISCUSSION: Each of the sites engaged in significant task shifting of low-complexity care coordination activities to licensed practical nurses, medical assistants, and other unlicensed personnel freeing up registered nurses and social workers for more complex patients. Few have care coordination experience, requiring a significant investment in on-the job training. CONCLUSION: Payment reform is leading to a greater investment in the care coordination workforce. However, demonstrating the return on investment remains a challenge. PMID- 28576297 TI - Preoperative 3-D MRI planning of tunnel placement in ACL reconstruction for a skeletally immature patient: A case report. PMID- 28576296 TI - Biological determinants of health: Genes, microbes, and metabolism exemplars of nursing science. AB - BACKGROUND: Increasingly, nurse scientists are incorporating "omics" measures (e.g., genomics, transcriptomics, proteomics, and metabolomics) in studies of biologic determinants of health and behavior. The role of omics in nursing science can be conceptualized in several ways: (a) as a portfolio of biological measures (biomarkers) to monitor individual risk, (b) as a set of combined data elements that can generate new knowledge based on large and complex patient data sets, (c) as baseline information that promotes health education and potentially personalized interventions, and (d) as a platform to understand how environmental parameters (e.g., diet) interact with the individual's physiology. PURPOSE: In this article, we provide exemplars of nursing scientists who use omics to better understand specific health conditions. METHODS: We highlight various ongoing nursing research investigations incorporating omics technologies to study chronic pain vulnerability, risk for a pain-related condition, cardiometabolic complications associated with pregnancy, and as biomarkers of response to a dietary intervention. DISCUSSION: Omics technologies add an important dimension to nursing science across many foci of investigation. However, there are also challenges and opportunities for nurse scientists who consider using omics in their research. CONCLUSION: The integration of omics holds promise for increasing the impact of nursing research and practice on population health outcomes. PMID- 28576299 TI - Effects of Donor Breastmilk Feeding on Growth and Early Neurodevelopmental Outcomes in Preterm Infants: An Observational Study. AB - PURPOSE: Donor breastmilk (DBM) has gained popularity as an alternative to formula when mother's own milk (MOM) is unavailable. The objective of this study was to evaluate the effects of a predominantly DBM diet on growth and subsequent neurodevelopment in preterm infants at a level 3 neonatal intensive care unit (NICU). METHODS: This single-center, observational cohort study compared data from preterm infants supplemented with predominantly (>50%) DBM to those from age and weight-matched infants fed only MOM or supplemented with predominantly (>50%) preterm formula (PF). The primary outcome was in-hospital weight gain, and the secondary outcome was neurodevelopment, as assessed by the Bayley III scale at 1 and 2 years' corrected age. Exclusion criteria were major congenital defects, death prior to discharge from the NICU, or supplementation volumes of <50% over the first month of life. We compared the outcomes among the 3 feeding groups with the chi2 test, ANOVA, and ANCOVA, with post hoc pairwise comparisons after adjustment for the following confounders: bronchopulmonary dysplasia, multiple births, and social work involvement. FINDINGS: In the entire cohort, the mean gestational age was 27.1 weeks and the mean birthweight was 914 g. The DBM (n = 27) and PF (n = 25) groups were similar with regard to socioeconomic characteristics. DBM infants regained birthweight more slowly over the first month of life compared with infants fed MOM (n = 29) or PF (mean [SD], 17.9 [5.7], 22.0 [6.8], and 20.3 [5.7] g/kg/d, respectively; P = 0.05); however, this growth difference was attenuated at later time points. In a fully adjusted model, the DBM group scored significantly lower in cognition at both 1 year (P = 0.005) and 2 years (P = 0.03) of age compared with the infants fed non-DBM diets. IMPLICATIONS: The findings from this study suggest that in this NICU, preterm infants supplemented with predominantly DBM had compromised early in-hospital weight gain and, possibly, early cognitive delays compared with infants fed only MOM or infants supplemented with predominantly PF. These findings reinforce the need for further research on the optimal use of DBM in the preterm population and a continued need for promoting breastfeeding efforts to supply MOM. PMID- 28576300 TI - Fibrin sealant (TisseelTM) for mesh fixation in repair of the deep circumflex iliac artery (DCIA) free flap donor site. PMID- 28576302 TI - Foreword. PMID- 28576301 TI - Obstetric and neonatal outcomes of pregnancies conceived after preimplantation genetic diagnosis: cohort study and meta-analysis. AB - Preimplantation genetic diagnosis (PGD) may pose risks to pregnancy outcome owing to the invasiveness of the biopsy procedure. This study compares outcome of singleton and twin clinical pregnancies conceived after fresh embryo transfers of PGD (n = 89) and matched intracytoplasmic sperm injection (ICSI) pregnancies (n = 166). The study was carried out in a single university affiliated centre. Because of the paucity of available data, a literature-based meta-analysis of studies comparing neonatal outcome of PGD and ICSI pregnancies was also conducted. In the retrospective cohort study, obstetric and neonatal outcome were available in 67 PGD and 118 ICSI pregnancies. Perinatal outcomes were comparable between PGD and ICSI pregnancies. Meta-analysis revealed similar outcomes, except for higher rate of low birth weight (<2500 g) neonates in ICSI twin pregnancies (RR 0.86, 95% CI 0.74 to 1.0). Mean birth weight, gestational age at birth, pre-term deliveries (<37 weeks) and malformations were all comparable. In this cohort study and subsequent meta-analysis, no association was found between PGD conceived pregnancies and risks of adverse neonatal or obstetrical outcomes compared with ICSI pregnancies. Hence, blastomere biopsy for PGD does not seem to increase the risk for adverse perinatal outcome compared with ICSI pregnancies. PMID- 28576304 TI - The surgical management of inflammatory bowel disease. PMID- 28576298 TI - Intracellular trafficking pathways of Cx43 gap junction channels. AB - Gap Junction (GJ) channels, including the most common Connexin 43 (Cx43), have fundamental roles in excitable tissues by facilitating rapid transmission of action potentials between adjacent cells. For instance, synchronization during each heartbeat is regulated by these ion channels at the cardiomyocyte cell-cell border. Cx43 protein has a short half-life, and rapid synthesis and timely delivery of those proteins to particular subdomains are crucial for the cellular organization of gap junctions and maintenance of intracellular coupling. Impairment in gap junction trafficking contributes to dangerous complications in diseased hearts such as the arrhythmias of sudden cardiac death. Of recent interest are the protein-protein interactions with the Cx43 carboxy-terminus. These interactions have significant impact on the full length Cx43 lifecycle and also contribute to trafficking of Cx43 as well as possibly other functions. We are learning that many of the known non-canonical roles of Cx43 can be attributed to the recently identified six endogenous Cx43 truncated isoforms which are produced by internal translation. In general, alternative translation is a new leading edge for proteome expansion and therapeutic drug development. This review highlights recent mechanisms identified in the trafficking of gap junction channels, involvement of other proteins contributing to the delivery of channels to the cell-cell border, and understanding of possible roles of the newly discovered alternatively translated isoforms in Cx43 biology. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve. PMID- 28576305 TI - Cystic Fibrosis Transmembrane Regulator Modulators: Implications for the Management of Depression and Anxiety in Cystic Fibrosis. AB - BACKGROUND: Individuals with cystic fibrosis (CF) are at high risk for depression and anxiety, which are associated with worse medical outcomes. Novel therapies for CF hold great promise for improving physical health, but the effects of these therapies on mental health remain poorly understood. OBJECTIVE: This review aims to familiarize psychiatrists with the potential effect of novel CF therapies on depression and anxiety. METHODS: We discuss novel therapies that directly target the mutant CF protein, the CF transmembrane regulator (CFTR), which are called CFTR modulators. We summarize depression and anxiety screening and treatment guidelines under implementation in accredited CF centers. Case vignettes highlight the complexities of caring for individuals with CF with comorbid depression and anxiety, including patients experiencing worsening depression and anxiety proximate to initiation of CFTR modulator therapy, and management of drug drug interactions. CONCLUSIONS: Although CFTR modulator therapies provide hope for improving clinical outcomes, worsening depression and anxiety occurs in some patients when starting these novel agents. This phenomenon may be multifactorial, with hypothesized contributions from CFTR modulator-psychotropic medication interactions, direct effects of CFTR modulators on central nervous system function, the psychologic effect of starting a potentially life-altering drug, and typical triggers of depression and anxiety such as stress, pain, and inflammation. The medical and psychiatric complexity of many individuals with CF warrants more direct involvement of mental health specialists on the multidisciplinary CF team. Inclusion of mental health variables in patients with CF registries will facilitate further examination at an epidemiologic level. PMID- 28576306 TI - Robo-Tripping: A Case of Robitussin Abuse in a Methadone Maintenance Patient. PMID- 28576308 TI - MBL2 and FCN2 gene polymorphisms in a cohort of Italian children with rheumatic fever: A case-control study. AB - BACKGROUND: Mannose-binding lectins and human ficolins are pattern-recognition proteins involved in innate immunity. A role for MBL2 and FCN2 gene polymorphisms in the pathogenesis of recurrent severe streptococcal infections and rheumatic carditis has been suggested. OBJECTIVES: The aim of this study is to evaluate the presence of MBL2 and FCN2 gene polymorphisms (SNPs) in children with a history of rheumatic fever (RF) and to investigate their possible role in RF clinical presentation and disease course. METHODS: A total of 50 Caucasian patients with RF were recruited with a control group of 52 healthy children. DNA was extracted for analysis of MBL2 gene (exon 1, codons: 52, 54, and 57) and FCN2 gene (promoter region at position -986, -602, and -4). RESULTS: The FCN2 AG genotype at the -986 position was more frequently observed in patients, as compared to healthy subjects (p = 0.006); furthermore, the A allele was identified as a possible risk factor for the development of RF (OR = 7.14, CI: 2.439-20.89). Conversely, the GG genotype at the same position was observed more frequently in the control group and can be considered a protective factor for the development of the disease (p = 0.001, OR = 8.37, 95% CI: 2.763-25.33). In addition, the FCN2 GG and AG genotypes in the -4 position were also found to be protective factors for the development of RF and for carditis respectively (OR = 3.32, CI: 1.066 10.364; OR = 0.15, 95% CI: 0.037-0.566). Finally, the AA genotype in the -602 position was associated with a late onset of RF (p = 0.006). The analysis of the MBL2 gene only resulted in a higher frequency of the AA genotype on position 57 in controls as compared to patients (p = 0.025). CONCLUSIONS: This is the first study evaluating the FCN2 gene polymorphisms in patients with RF and rheumatic carditis finding a protective effect of -986 GG and -4 GG genotypes in the development of RF and the -4 AG genotype for the development of carditis. Our data do not support a possible role for MBL2 polymorphisms in the pathogenesis and in the clinical manifestations of RF. PMID- 28576307 TI - Serological evolution in women with positive antiphospholipid antibodies. AB - OBJECTIVES: To explore the clinical and serological course of fertile women with positive antiphospholipid (aPL), and the factors and therapeutic implications associated with aPL negativization. METHODS: Retrospective study including 105 women with a positive aPL serology between 1995 and 2013 attending the obstetric autoimmune pathology clinic of a tertiary facility. Patients were classified into the following 3 groups: patients with primary antiphospholipid syndrome (pAPS, 49), patients with a positive serology for aPL, not meeting clinical criteria (42), and patients with systemic lupus erythematosus and a positive aPL serology (14). They were also classified according to the serological aPL evolution: persistently negative aPL, transiently positive serology, and persistently positive serology according to established criteria. RESULTS: After a mean follow up of 114.4 +/- 37.2 months, 59% of patients had persistently negative antibodies, while 25.7% of patients presented persistently positive aPL serology. Multivariate analysis confirmed that smoking (OR = 4; 95% CI: 1.45-11.08; p = 0.008) was an independent risk factor for positive persistence. Persistent positivity as well as a higher antibody load was associated with higher risk for further pregnancy morbidity. In 29 patients, with persistently negative serology who were asymptomatic, treatment with low-dose aspirin was discontinued. No clinical events related to APS were reported after treatment withdrawal, during the 40.95 months of follow-up. CONCLUSIONS: A significant proportion of fertile women with aPL antibodies became negative during follow-up. Tobacco use and the number of positive antibodies are associated with persistently positive serology. Patients with persistently positive aPL serology suffer more obstetric complications. Treatment withdrawal might be safe in selected patients. PMID- 28576309 TI - BNDF heterozygosity is associated with memory deficits and alterations in cortical and hippocampal EEG power. AB - Brain derived neurotrophic factor (BDNF) plays a pivotal role in structural plasticity, learning, and memory. Electroencephalogram (EEG) spectral power in the cortex and hippocampus has also been correlated with learning and memory. In this study, we investigated the effect of globally reduced BDNF levels on learning behavior and EEG power via BDNF heterozygous (KO) rats. We employed several behavioral tests that are thought to depend on cortical and hippocampal plasticity to varying degrees: novel object recognition, a test that is reliant on a variety of cognitive systems; contextual fear, which is highly hippocampal dependent; and cued fear, which has been shown to be amygdala-dependent. We also examined the effects of BDNF reduction on cortical and hippocampal EEG spectral power via chronically implanted electrodes in the motor cortex and dorsal hippocampus. We found that BDNF KO rats were impaired in novelty recognition and fear memory retention, while hippocampal EEG power was decreased in slow waves and increased in fast waves. Interestingly, our results, for the first time, show sexual dimorphism in each of our tests. These results support the hypothesis that BDNF drives both cognitive plasticity and coordinates EEG activity patterns, potentially serving as a link between the two. PMID- 28576310 TI - The paracrine effect of cobalt chloride on BMSCs during cognitive function rescue in the HIBD rat. AB - Hypoxia-ischemia (HI)-induced perinatal encephalopathy frequently causes chronic neurological morbidities and acute mortality. Bone mesenchymal stem cell (BMSC) transplantation could potentially promote functional and anatomical recovery of ischemic tissue. In vitro hypoxic preconditioning is an effective strategy to improve the survival of BMSCs in ischemic tissue. In this study, cobalt chloride (CoCl2) preconditioned medium from BMSC cultures was injected into the left lateral ventricle of HI rats using a micro-osmotic pump at a flow rate 1.0MUl/h for 7 days. The protein levels of HIF-1alpha and its target genes, vascular endothelial growth factor and erythropoietin, markedly increased after CoCl2 preconditioning in BMSCs. In 7-week-old rats that received CoCl2 preconditioned BMSC medium, results of the Morris water maze test indicated ameliorated spatial working memory function following hypoxia-ischemia damage. Neuronal loss, cellular disorganization, and shrinkage in brain tissue were also ameliorated. Extracellular field excitatory postsynaptic potentials (fEPSPs) in the brain slices of 8-week-old rats were recorded; administration of CoCl2 preconditioned BMSC culture medium induced a progressive increment of baseline and amplitude of the fEPSPs. Immunohistochemical quantification showed that GluR2 protein expression increased. In conclusion, CoCl2 activates HIF-1alpha signals in BMSCs. CoCl2 preconditioned BMSC culture medium likely effects neuroprotection by inducing long-term potentiation (LTP), which could be associated with GluR2 expression. The paracrine effects of hypoxia preconditioning on BMSCs could have applications in novel cell-based therapeutic strategies for hypoxic and ischemic brain injury. PMID- 28576312 TI - Hepatocellular carcinoma in a patient with congenital porto-systemic shunt. AB - Congenital porto-caval shunt is a rare anomaly that can result in direct shunt related complications (encephalopathy, pulmonary hypertension) or indirect complications such as the development of benign or malignant hepatic neoplasms. Treatment consists of management of the complications and occlusion of the porto caval shunt in one or two stages by either a surgical or an interventional radiology approach. PMID- 28576311 TI - Patient opinion of scarring is multidimensional: An investigation of the POSAS with confirmatory factor analysis: Statistical and methodological issues. PMID- 28576313 TI - Automated preconcentration of Fe, Zn, Cu, Ni, Cd, Pb, Co, and Mn in seawater with analysis using high-resolution sector field inductively-coupled plasma mass spectrometry. AB - A rapid, automated, high-throughput analytical method capable of simultaneous analysis of multiple elements at trace and ultratrace levels is required to investigate the biogeochemical cycle of trace metals in the ocean. Here we present an analytical approach which uses a commercially available automated preconcentration device (SeaFAST) with accurate volume loading and in-line pH buffering of the sample prior to loading onto a chelating resin (WAKO) and subsequent simultaneous analysis of iron (Fe), zinc (Zn), copper (Cu), nickel (Ni), cadmium (Cd), lead (Pb), cobalt (Co) and manganese (Mn) by high-resolution inductively-coupled plasma mass spectrometry (HR-ICP-MS). Quantification of sample concentration was undertaken using isotope dilution for Fe, Zn, Cu, Ni, Cd and Pb, and standard addition for Co and Mn. The chelating resin is shown to have a high affinity for all analyzed elements, with recoveries between 83 and 100% for all elements, except Mn (60%) and Ni (48%), and showed higher recoveries for Ni, Cd, Pb, Co and Mn in direct comparison to an alternative resin (NOBIAS Chelate-PA1). The reduced recoveries for Ni and Mn using the WAKO resin did not affect the quantification accuracy. A relatively constant retention efficiency on the resin over a broad pH range (pH 5-8) was observed for the trace metals, except for Mn. Mn quantification using standard addition required accurate sample pH adjustment with optimal recoveries at pH 7.5 +/- 0.3. UV digestion was necessary to increase recovery of Co and Cu in seawater by 15.6% and 11.4%, respectively, and achieved full break-down of spiked Co-containing vitamin B12 complexes. Low blank levels and detection limits could be achieved (e.g., 0.029 nmol L-1 for Fe and 0.028 nmol L-1 for Zn) with the use of high purity reagents. Precision and accuracy were assessed using SAFe S, D1, and D2 reference seawaters, and results were in good agreement with available consensus values. The presented method is ideal for high throughput simultaneous analysis of trace elements in coastal and oceanic seawaters. We present a successful application of the analytical method to samples collected in June 2014 in the Northeast Atlantic Ocean. PMID- 28576314 TI - Multivariate analysis of Scotch whisky by total reflection x-ray fluorescence and chemometric methods: A potential tool in the identification of counterfeits. AB - Most methods used in the identification of counterfeit whisky have focused on the profiling of volatile organic congeners determined by gas chromatography. We tested the use of total reflection x-ray fluorescence (TXRF) for trace element analysis of whisky and application of the data as a potential tool in the identification of counterfeit samples. Twenty five whiskies that were produced in different regions of Scotland or were blends, 5 counterfeit whiskies, 1 unmatured grain whisky, and 1 matured grain whisky were analysed for 11 elements (P, S, Cl, K, Ca, Mn, Fe, Cu, Zn, Br and Rb). The effect of cold plasma ashing with oxygen on whisky residues evaporated on the TXRF reflector on the instrument performance was investigated. Cold plasma ashing with oxygen reduced beam scatter and improved the limits of detection but was ultimately deemed unnecessary. The element concentration data for whisky obtained by TXRF (after log transformation) was compared with the values obtained by inductively coupled plasma spectroscopy and showed correlation values (R2) >= 0.942 for K, Mn and Cu: >= 0.800 for Ca, Fe and Rb; and >=0.535 for P, S and Zn. The range of concentration values for individual elements was variable and principal components analysis of the elemental concentrations partially differentiated the whiskies by region or type but showed clear separation of the counterfeit samples from the other samples. Using the principal component scores of the elemental concentration data, linear discriminant analysis also distinguished the counterfeits from the other samples. PMID- 28576315 TI - Electrochemical determination of cephalosporins using a bare boron-doped diamond electrode. AB - The electrochemical oxidation of seven cephalosporins (ceftriaxone, cefotaxime, ceftazidime, cefadroxil, cefuroxime, cefaclor, cefalexin) was evaluated at high potential, using a bare boron-doped diamond electrode and the influence on the analytical response of the side chains was investigated. Based on the anodic oxidation of the cephalosporin nucleus, a simple and sensitive method was developed for the electrochemical detection of cefalexin by differential pulse voltammetry. After the optimization of the experimental conditions, a linear correlation was obtained between the peak height and the molar concentration of cefalexin in the range of 0.5 MUM-700 MUM, with a limit of detection of 34.74 ng mL-1. The anodic peak for cefalexin was evaluated in the presence of other cephalosporin molecules and of other common interferents. The developed method was applied to detection of cefalexin from real environmental, biomedical and pharmaceutical samples, with good results. The electrochemical oxidation of cephalosporins was successfully adapted for flow injection analyses, with sensitive and reproducible successive analyses of cefalexin, in different concentrations. The flow analyses allowed also the determination of the total amount of cephalosporins found in the sample. PMID- 28576316 TI - Switchable hydrophilicity solvent membrane-based microextraction: HPLC-FLD determination of fluoroquinolones in shrimps. AB - A switchable hydrophilicity solvent membrane-based microextraction (SHS-MME) strategy for simple and highly-available sample pretreatment of complex matrices has been proposed. The SHS-MME procedure based on extraction of target analytes from an aqueous sample into a porous hydrophobic membrane impregnated with a switchable hydrophilicity solvent (SHS) followed by SHS ionization and back extraction of the analytes in alkaline acceptor solution. The medium-chain fatty acids were investigated as SHS for the SHS-MME of fluoroquinolones (fleroxacin, lomefloxacin, norfloxacin and ofloxacin). The SHS-MME was successfully coupled with a HPLC-FLD for the determination of fluoroquinolones in shrimp samples with no further sample pretreatment. The calibration graphs were linear over the concentration ranges of 3-1500 MUg L-1 for ofloxacin, 10-1000 MUg L-1 for norfloxacin, 15-1500 MUg L-1 for lomefloxacin and fleroxacin. The limits of detection, calculated from a blank test based on 3sigma, were 1 MUg L-1 for ofloxacin, 3 MUg L-1 for norfloxacin and 5 MUg L-1 for lomefloxacin and fleroxacin. The SHS ionization can be considered as new potential fields in analytical application of membrane-based liquid phase microextraction. PMID- 28576317 TI - A miniature optical emission spectrometric system in a lab-on-valve for sensitive determination of cadmium. AB - A miniature optical emission spectrometric (OES) system is developed by incorporating dielectric barrier discharge (DBD) microplasma as excitation source in a lab-on-valve (LOV) configuration for trace cadmium analysis. The entire system integrates bead injection (BI) sample pretreatment, post-column derivatization, in-situ nebulization and OES detection. Trace cadmium in sample solution is separated and preconcentrated by flowing through a 2-(5-Br-2 pyridylazo)-5-dethylaminophenol (5-Br-PADAP) loaded microcolumn in LOV, followed by elution with 20 MUL of 0.1 M hydrochloric acid. The eluate after online derivatization with 5 MUL of 0.2 M borate buffer solution containing 7.5% (v/v) ethanol is immediately transported into a pneumatic micronebulizer integrating DBD microplasma for cadmium excitation, and OES is recorded by using a charge coupled device (CCD) spectrometer. As a miniaturized analytical set-up, LOV provides an ideal sample-processing front-end with detection by DBD-OES, while introduction of DBD excitation source in LOV highly improves the analytical performances for trace metal species. With a sample volume of 1.0 mL, a detection limit of 0.06 MUg L-1 and a linear range of 0.2-50 MUg L-1 are achieved for cadmium, along with an enrichment factor of 38. The accuracy of the present system is confirmed by the determination of cadmium in certified reference materials, and further demonstrated by spiking recoveries of cadmium in real water samples. PMID- 28576318 TI - Automated quantification of metabolites in blood-derived samples by NMR. AB - NMR is widely applied in the field of metabolomics due to the quantitative nature of the technology and the reproducible data generated. However, because of severe spectral crowding, quantifying individual metabolites in body fluids such as serum and plasma remains a challenge. In this study, a method to automatically annotate and quantify a number of small metabolites in human serum and EDTA plasma is introduced. It combines the superior signal-to-noise ratio of the commonly applied CPMG and NOESY1D pulse sequences with the superior resolution of the 2D JRES experiment to construct a model that extracts the metabolite concentrations directly from the 1D spectra without tedious deconvolution. The performance of the method was assessed by comparing the calculated areas of the various glucose peaks with known clinical values, by comparing several peaks of the same metabolite (extracted versus non-extracted), and by comparing areas obtained from various NMR pulse sequences. Additionally, the models were tested on independent datasets. It was found that for many metabolites peaks could be assigned that show a consistent behavior, indicating a precise quantification. The same method should be applicable to other biofluids with a stable composition and pH, such as CSF fluid, cell extracts, and cell media. PMID- 28576320 TI - Self-assembled structures of N-alkylated bisbenzimidazolyl naphthalene in aqueous media for highly sensitive detection of picric acid. AB - A 2,6-dibenzimidazole-appended naphthalene derivative flanking with two N-alkyl chains (sensor 4) was designed and applied for highly sensitive detection of picric acid (PA) in aqueous media. Driven by the hydrophobicity of alkyl chain and pi-pi stacking effect of aryl, sensor 4 can undergo self-assembly to form an orderly rod-like structure in H2O/THF (v/v, 90/10) solution, as shown by the dynamic light scattering (DLS) and scanning electron microscopy (SEM) studies. Sensor 4 shows high selectivity and sensitivity toward PA over other nitroaromatic explosives. DFT calculations and 1H NMR, the time-correlated single photon counting (TCSPC) experiments confirm that the quenching mechanism is due to both electron and energy transfer from the electron-rich sensor 4 to the electron-deficient PA. Sensor 4 can detect as low as 0.57 ppb PA in aqueous media and 11.46 ag cm-2 PA by contact mode. Importantly, sensor 4 exhibits low interference against common solvents, metal ions and anions. Thus, it is practically applicable for sensing PA in real environmental samples and vapor phase. PMID- 28576319 TI - Chloroformate derivatization for tracing the fate of Amino acids in cells and tissues by multiple stable isotope resolved metabolomics (mSIRM). AB - Amino acids have crucial roles in central metabolism, both anabolic and catabolic. To elucidate these roles, steady-state concentrations of amino acids alone are insufficient, as each amino acid participates in multiple pathways and functions in a complex network, which can also be compartmentalized. Stable Isotope-Resolved Metabolomics (SIRM) is an approach that uses atom-resolved tracking of metabolites through biochemical transformations in cells, tissues, or whole organisms. Using different elemental stable isotopes to label multiple metabolite precursors makes it possible to resolve simultaneously the utilization of these precursors in a single experiment. Conversely, a single precursor labeled with two (or more) different elemental isotopes can trace the allocation of e.g. C and N atoms through the network. Such dual-label experiments however challenge the resolution of conventional mass spectrometers, which must distinguish the neutron mass differences among different elemental isotopes. This requires ultrahigh resolution Fourier transform mass spectrometry (UHR-FTMS). When combined with direct infusion nano-electrospray ion source (nano-ESI), UHR FTMS can provide rapid, global, and quantitative analysis of all possible mass isotopologues of metabolites. Unfortunately, very low mass polar metabolites such as amino acids can be difficult to analyze by current models of UHR-FTMS, plus the high salt content present in typical cell or tissue polar extracts may cause unacceptable ion suppression for sources such as nano-ESI. Here we describe a modified method of ethyl chloroformate (ECF) derivatization of amino acids to enable rapid quantitative analysis of stable isotope labeled amino acids using nano-ESI UHR-FTMS. This method showed excellent linearity with quantifiable limits in the low nanomolar range represented in microgram quantities of biological specimens, which results in extracts with total analyte abundances in the low to sub-femtomole range. We have applied this method to profile amino acids and their labeling patterns in 13C and 2H doubly labeled PC9 cell extracts, cancerous and non-cancerous tissue extracts from a lung cancer patient and their protein hydrolysates as well as plasma extracts from mice fed with a liquid diet containing 13C6-glucose (Glc). The multi-element isotopologue distributions provided key insights into amino acid metabolism and intracellular pools in human lung cancer tissues in high detail. The 13C labeling of Asp and Glu revealed de novo synthesis of these amino acids from 13C6-Glc via the Krebs cycle, specifically the elevated level of 13C3-labeled Asp and Glu in cancerous versus non-cancerous lung tissues was consistent with enhanced pyruvate carboxylation. In addition, tracking the fate of double tracers, (13C6-Glc + 2H2-Gly or 13C6-Glc + 2H3-Ser) in PC9 cells clearly resolved pools of Ser and Gly synthesized de novo from 13C6-Glc (13C3-Ser and 13C2-Gly) versus Ser and Gly derived from external sources (2H3-Ser, 2H2-Gly). Moreover the complex 2H labeling patterns of the latter were results of Ser and Gly exchange through active Ser-Gly one-carbon metabolic pathway in PC9 cells. PMID- 28576321 TI - Quantification of gene-specific DNA methylation in oesophageal cancer via electrochemistry. AB - Development of simple and inexpensive method for the analysis of gene-specific DNA methylation is important for the diagnosis and prognosis of patients with cancer. Herein, we report a relatively simple and inexpensive electrochemical method for the sensitive and selective detection of gene-specific DNA methylation in oesophageal cancer. The underlying principle of the method relies on the affinity interaction between DNA bases and unmodified gold electrode. Since the affinity trend of DNA bases towards the gold surface follows as adenine (A) > cytosine (C) > guanine (G)> thymine (T), a relatively larger amount of bisulfite treated adenine-enriched unmethylated DNA adsorbs on the screen-printed gold electrodes (SPE-Au) in comparison to the guanine-enriched methylated sample. The methylation levels were (i.e., different level of surface attached DNA molecules due to the base dependent differential adsorption pattern) quantified by measuring saturated amount of charge-compensating [Ru(NH3)6]3+ molecules in the surface-attached DNAs by chronocoulometry as redox charge of the [Ru(NH3)6]3+ molecules quantitatively reflects the amount of the adsorbed DNA confined at the electrode surface. The assay could successfully distinguish methylated and unmethylated DNA sequences at single CpG resolution and as low as 10% differences in DNA methylation. In addition, the assay showed fairly good reproducibility (% RSD= <5%) with better sensitivity and specificity by analysing various levels of methylation in two cell lines and eight fresh tissues samples from patients with oesophageal squamous cell carcinoma. Finally, the method was validated with methylation specific-high resolution melting curve analysis and Sanger sequencing methods. PMID- 28576322 TI - Accuracy in precordial ECG lead placement: Improving performance through a peer led educational intervention. AB - BACKGROUND AND OBJECTIVES: Inaccurate electrocardiography (ECG) lead placement may lead to erroneous diagnoses, such as poor R wave progression. We sought to assess the accuracy of precordial ECG lead placement amongst hospital staff members, and to re-evaluate performance after an educational intervention. METHODS AND RESULTS: 100 randomly selected eligible staff members placed sticker dots on a mannequin, their positions were recorded on a radar plot and compared to the correct precordial lead positions. The commonest errors were placing V1 and V2 leads too superiorly, and V5 and V6 leads too medially.Following an educational intervention with the aid of moderated poster presentations and volunteer patients, the study was repeated six months later. 60 subjects correctly placed all leads, compared to 10 in the pre-intervention cohort (P<0.0001) with the proportion achieving correct placement of any lead rising from 0.34 to 0.83, (p<0.0001 for all leads). CONCLUSION: Incorrect ECG lead placement is common. This may be addressed through regular training incorporated into annual induction processes for relevant health care professionals. PMID- 28576323 TI - Complement in clinical medicine: Clinical trials, case reports and therapy monitoring. AB - Research during past decades made it evident that complement is involved in more tasks than fighting infections, but has important roles in other immune surveillance and housekeeping functions. If the balance between complement activation and regulation is out of tune, however, complement can quickly turn against the host and contribute to adverse processes that result in various clinical conditions. Whereas clinical awareness was initially focused on complement deficiencies, excessive activation and insufficient regulation are frequently the dominant factors in complement-related disorders. The individual complement profile of a patient often determines the course and severity of the disease, and the pathophysiological involvement of complement may be highly diverse. As a consequence, complement assays have evolved as essential tools not only in initial diagnosis but also for following disease progression and for monitoring complement-targeted therapies, which become increasingly available in routine clinical use. We herein review the current state of complement-directed drug candidates in clinical evaluation and provide an overview of extended indications considered for the FDA-approved inhibitor eculizumab. Furthermore we review the literature describing cases reports and case series where eculizumab has been used "off-label". Finally, we give a summary of the currently available tests to measure complement profiles and discuss their suitability in diagnostics and treatment monitoring. With complement finally entering the clinical arena, there are intriguing opportunities for treating complement-mediated diseases. However, this progress also requires a new awareness about complement pathophysiology, adequate diagnostic tools and suitable treatment options among clinicians treating patients with such disorders. PMID- 28576324 TI - New concepts on the therapeutic control of complement anaphylatoxin receptors. AB - The complement system is a pivotal driver of innate immunity, coordinating the host response to protect against pathogens. At the heart of the complement response lie the active fragments, C3a and C5a, acting through their specific receptors, C3aR, C5aR1, and C5aR2, to direct the cellular response to inflammation. Their potent function however, places them at risk of damaging the host, with aberrant C3a and C5a signaling activity linked to a wide range of disorders of inflammatory, autoimmune, and neurodegenerative etiologies. As such, the therapeutic control of these receptors represents an attractive drug target, though, the realization of this clinical potential remains limited. With the success of eculizumab, and the progression of a number of novel C5a-C5aR1 targeted drugs to phase II and III clinical trials, there is great promise for complement therapeutics in future clinical practice. In contrast, the toolbox of drugs available to modulate C3aR and C5aR2 signaling remains limited, however, the emergence of new selective ligands and molecular tools, and an increased understanding of the function of these receptors in disease, has highlighted their unique potential for clinical applications. This review provides an update on the growing arsenal of drugs now available to target C5, and C5a and C3a receptor signaling, and discusses their utility in both clinical and pre-clinical development. PMID- 28576325 TI - Distinct physiological and molecular responses in Arabidopsis thaliana exposed to aluminum oxide nanoparticles and ionic aluminum. AB - Nano-aluminium oxide (nAl2O3) is one of the most widely used nanomaterials. However, nAl2O3 toxicity mechanisms and potential beneficial effects on terrestrial plant physiology remain poorly understood. Such knowledge is essential for the development of robust nAl2O3 risk assessment. In this study, we studied the influence of a 10-d exposure to a total selected concentration of 98 MUM nAl2O3 or to the equivalent molar concentration of ionic Al (AlCl3) (196 MUM) on the model plant Arabidopsis thaliana on the physiology (e.g., growth and photosynthesis, membrane damage) and the transcriptome using a high throughput state-of-the-art technology, RNA-seq. We found no evidence of nAl2O3 toxicity on photosynthesis, growth and lipid peroxidation. Rather the nAl2O3 treatment stimulated root weight and length by 48% and 39%, respectively as well as photosynthesis opening up the door to the use of nAl2O3 in biotechnology and nano agriculture. Transcriptomic analyses indicate that the beneficial effect of nAl2O3 was related to an increase in the transcription of several genes involved in root growth as well as in root nutrient uptake (e.g., up-regulation of the root hair-specific gene family and root development genes, POLARIS protein). By contrast, the ionic Al treatment decreased shoot and root weight of Arabidopsis thaliana by 57.01% and 45.15%, respectively. This toxic effect was coupled to a range of response at the gene transcription level including increase transcription of antioxidant-related genes and transcription of genes involved in plant defense response to pathogens. This work provides an integrated understanding at the molecular and physiological level of the effects of nAl2O3 and ionic Al in Arabidopsis. PMID- 28576326 TI - Examination and physical therapy management of a young gymnast with bilateral wrist pain: A case report. AB - BACKGROUND: Wrist pain associated with weight-bearing gymnastic activities may be linked to musculoskeletal impairments, faulty movement patterns, and poor training techniques. Inadequate proximal control may adversely impact the loading mechanics throughout the upper extremities and contribute to a gymnast's complaint of wrist pain. The purpose of this case report is to describe the management of a young gymnast with primary complaint of bilateral wrist pain associated with upper extremity weight-bearing activities. CASE DESCRIPTION: A 10 year-old male gymnast presented with a 6-month history of bilateral wrist pain aggravated by weight-bearing gymnastic activities. Based on the findings from a physical therapy examination, a 3-stage progressive rehabilitation program was designed using an impairment-based, multi-modal approach to treat key musculoskeletal impairments and movement deficiencies. Consistent with the principle of activity simulation, treatment targeted areas of weakness considered key to activity performance and included a progression of exercises and techniques that simulated activities reported by the gymnast to be painful. OUTCOMES: The gymnast was treated for 11 visits over 8 weeks. He demonstrated improved strength, motor control, and self-reported outcome scores that allowed pain-free return to all gymnastic activities. PMID- 28576327 TI - Issue "noninvasive molecular imaging and theranostic probes": New concepts in myocardial imaging. AB - Cardiovascular applications continue to be a driving force for new developments in radionuclide imaging. Recent years have seen an evolution of myocardial perfusion imaging systems towards optimized radiation detection sensitivity, leading to fast and low dose studies with high image quality. Additional advances in hard- and software facilitated the integration of computed tomography and nuclear imaging, and enabled absolute quantification of myocardial blood flow. Finally, non-perfusion tracers and clinical indications outside of coronary artery disease (e.g. in endocarditis, infiltrative cardiomyopathies or regenerative medicine) have resulted in a growth of molecular-targeted myocardial imaging, aiming at improved guidance of increasingly specific therapies - in a manner similar to current oncologic applications of nuclear imaging. PMID- 28576328 TI - A novel method of predicting microRNA-disease associations based on microRNA, disease, gene and environment factor networks. AB - MicroRNAs have been reported to have close relationship with diseases due to their deregulation of the expression of target mRNAs. Detecting disease-related microRNAs is helpful for disease therapies. With the development of high throughput experimental techniques, a large number of microRNAs have been sequenced. However, it is still a big challenge to identify which microRNAs are related to diseases. Recently, researchers are interesting in combining multiple biological information to identify the associations between microRNAs and diseases. In this work, we have proposed a novel method to predict the microRNA disease associations based on four biological properties. They are microRNA, disease, gene and environment factor. Compared with previous methods, our method makes predictions not only by using the prior knowledge of associations among microRNAs, disease, environment factors and genes, but also by using the internal relationship among these biological properties. We constructed four biological networks based on the similarity of microRNAs, diseases, environment factors and genes, respectively. Then random walking was implemented on the four networks unequally. In the walking course, the associations can be inferred from the neighbors in the same networks. Meanwhile the association information can be transferred from one network to another. The results of experiment showed that our method achieved better prediction performance than other existing state-of the-art methods. PMID- 28576329 TI - Incentivizing secondary raw material markets for sustainable waste management. AB - Notwithstanding several policy initiatives in many countries over a number of years, there remains a general sense that too much municipal solid waste is generated and that too much of the waste that is generated is landfilled. There is an emerging consensus that a sustainable approach to waste management requires further development of secondary raw material markets. The purpose of this paper is to propose a theoretical economic model that focuses upon this stage of a sustainable waste management program and explores policy options that could motivate efficiency in secondary raw material markets. In particular, we show how firm profit and social welfare optimizing objectives can be reconciled in a two product market of waste management processes: landfilling and material reclamation. Our results provide theoretical support for building out recent Circular Economy initiatives as well as for the relatively recent emergence of landfill mining as a means for procuring secondary raw materials. PMID- 28576330 TI - First report of two cases of cryptococcosis in Tripoli, Libya, infected with Cryptococcus neoformans isolates present in the urban area. AB - Cryptococcosis is a potentially fatal fungal disease caused by the basidiomycetes yeasts Cryptococcus neoformans and C. gattii with high predilection to invade the central nervous system mainly in immunocompromised hosts. Skin can be secondarily involved in disseminated infection or be exceptionally involved as primary cutaneous infection by inoculation with contaminated materials. We report the first two Libyan cases of cryptococcal meningitis in HIV patients, in which one of them presented a secondary cutaneous involvement due to systemic dissemination. The first patient was a 17-year-old female, had fever, cough, headache and intractable vomiting as well as itchy water bumps on her skin and upper limbs. The cutaneous eruption prompted the accurate diagnosis. Cultures were positive for C. neoformans in both cerebrospinal fluid and skin specimens, as well as cryptococcal antigen was detected in serum. The isolate was identified, by molecular analysis, as C. neoformans AD-hybrid belonging to molecular type VNIII and mating type alphaAAalpha, the same genotype found for some environmental isolates recovered from olive trees in Tripoli. The second patient was a 36-years-old male with a long history of HIV on irregular treatment. Cryptococcal antigen in serum was positive and cultures yielded the growth of C. neoformans var. grubii, molecular type VNI and mating type alphaA. Both patients did not respond adequately to treatment and died of impaired central nervous system function and respiratory failure, respectively. PMID- 28576331 TI - Rapid preparation and single-cell analysis of concentrated blood smears using a high-throughput blood cell separator and a microfabricated grid film. AB - Cytological examination of peripheral white blood cells inhomogeneously distributed on a blood smear is currently limited by the low abundance and random sampling of the target cells. To address the challenges, we present a new approach to prepare and analyze concentrated blood smears by rapidly enriching white blood cells up to 32-fold with 92% recovery on average at a high throughput (1mL/min) using a deterministic migration-based separator and by systematically analyzing a large number of the cells distributed over a blood slide using a microfabricated grid film. We anticipate that our approach will improve the clinical utility of blood smear tests, while offering the capability to detect rare cell populations. PMID- 28576332 TI - Refolding of laccase from Trametes versicolor using aqueous two phase systems: Effect of different additives. AB - Protein refolding is a strategy used to obtain active forms of proteins from inclusion bodies. On its part, laccase is an enzyme with potential for different biotechnological applications but there are few reports regarding its refolding which in many cases is considered inefficient due to the poor obtained refolding yields. Aqueous Two-Phase Systems (ATPS) have been used for the refolding of proteins getting acceptable recovery percentages since PEG presents capacity to avoid protein aggregation. In this work, 48 PEG-phosphate ATPS were analyzed to study the impact of different parameters (i.e. tie line length (TLL), volume ratio (VR) and PEG molecular weight) upon the recovery and refolding of laccase. Additionally, since laccase is a metalloprotein, the use of additives (individually and in mixture) was studied with the aim of favoring refolding. Results showed that laccase presents a high affinity for the PEG-rich phase obtaining recovery values of up to 90%. Such affinity increases with increasing TLL and decreases when PEG molecular weight and VR increase. In denatured state, this PEG-rich phase affinity decreases drastically. However, the use of additives such as l-cysteine, glutathione oxidized, cysteamine and Cu+2 was critical in improving refolding yield values up to 100%. The best conditions for the refolding of laccase were obtained using the PEG 400gmol-1, TLL 45% w/w, VR 3 ATPS and a mixture of 2.5mM cysteamine with 1mM Cu+2. To our knowledge, this is the first time that the use of additives and the behavior of the mixture of such additives to enhance refolding performance in ATPS is reported. PMID- 28576333 TI - [Hygienic-sanitary quality in abattoirs from Tucuman province, Argentina. Detection, isolation and characterization of Shiga toxin-producing Escherichia coli]. AB - Cattle are the main reservoir of Shiga toxin-producing Escherichia coli (STEC), and the strategies to prevent the transmission of these microorganisms are concentrated in the slaughtering plant. The aim of this study was to evaluate the hygienic-sanitary quality and the frequency of detection of STEC in beef carcasses in abattoirs from Tucuman province. Two hundred and seventy four beef carcass sponges were processed; the count of generic E. coli was marginal in 9 (3,3%) of them. Escherichia coli O157 was isolated in 4 (1,4%) samples; 2 of which were characterized as stx2c(vh-a)/eae/ehxA whereas the other 2 were non toxigenic strains. Non-O157 E. coli ONT:H49, stx2a/ehxA/saa was isolated from 1 sample (0,4%). In this work the quality of the analyzed product indicates that the good practices of manufacture are fulfilled in slaughtering facilities in Tucuman province. PMID- 28576334 TI - Diversity and distribution of lepidopteran-specific toxin genes in Bacillus thuringiensis strains from Argentina. AB - A total of 268 Bacillus thuringiensis strains obtained from different sources of Argentina were analyzed to determine the diversity and distribution of the cry1, cry2, cry8, cry9 and vip3A genes encoding for lepidopteran-specific insecticidal proteins. Twin strains were excluded. Ten different profiles were detected among the 80 selected B. thuringiensis strains. Two of these profiles (cry1Aa, cry1Ac, cry1Ia, cry2Aa, cry2Ab and vip3Aa (35/80), and cry1Aa, cry1Ab, cry1Ac, cry1Ia, cry2Aa, cry2Ab and vip3Aa (25/80)) pooled 75% of the strains. The existence of this low diversity is rare, since in most of the studied collections a great diversity of insecticidal toxin gene profiles has been described. In addition, the most frequently detected profile was also most frequently derived from soil (70%), stored product dust (59%) and spider webs (50%). In contrast, the cry1Aa, cry1Ab, cry1Ac, cry1Ia, cry2Aa, cry2Ab and vip3Aa profiles were mainly detected in strains isolated from leaves (40%) and dead insect larvae (50%). Six of the identified insecticidal toxin gene profiles were discovered in strains isolated from stored product dust and leaves indicating higher diversity of profiles in these kinds of sources than in others. Some strains with high insecticidal activity against Epinotia aporema (Lepidoptera) larvae were identified, which is important to explore future microbial strategies for the control of this crop pest in the region. PMID- 28576335 TI - Kuwaiti Teachers' Perceptions of Voice Handicap. AB - OBJECTIVES: The study aimed to investigate the effects of age, gender, level of education, experience, and class level taught on the perception of voice handicap by Kuwaiti teachers using the Arabic version of the Voice Handicap Index (VHI Arab). The mean VHI scores of Kuwaiti teachers were compared with those of Jordanian and Emirati teachers. METHODS: The study had a cross-sectional survey design. A total of 460 individuals (100 controls and 360 teachers) participated in this study and completed the paper copy of the VHI-Arab. We recruited 360 teachers, 180 males and 180 females (age range: 20-50 years), from 60 schools in 6 Kuwaiti districts. Teachers' VHI scores were compared with 100 nonteaching voice users (50 males and 50 females, with an age range of 18-42 years). RESULTS: Female teachers scored significantly higher than male teachers in all subscales (ie, physical: P = 0.02; emotional: P = 0.007; total: P = 0.017), except for the functional subscale (P = 0.147). Elementary school teachers scored significantly higher than teachers of other levels (middle and high school) in all VHI subscales (physical: P = 0.047; emotional: P = 0.01; total: P = 0.039), except for the functional subscale (P = 0.47). The mean score of Jordanian teachers was higher than that of Kuwaiti and Emirati teachers in all VHI subscales. CONCLUSIONS: Teachers with a more favorable teaching environment scored better on the VHI. Gender differences were found in all the Arabic nationalities studied. Female teachers of the elementary level, in particular, should be the focus of attention of efforts to prevent voice damage. PMID- 28576336 TI - Working Toward a Common Vocabulary: Reconciling the Terminology of Teachers of Singing, Voice Scientists, and Speech-Language Pathologists. PMID- 28576337 TI - Angiostrongylus cantonensis daf-2 regulates dauer, longevity and stress in Caenorhabditis elegans. AB - The insulin-like signaling (IIS) pathway is considered to be significant in regulating fat metabolism, dauer formation, stress response and longevity in Caenorhabditis elegans. "Dauer hypothesis" indicates that similar IIS transduction mechanism regulates dauer development in free-living nematode C. elegans and the development of infective third-stage larvae (iL3) in parasitic nematodes, and this is bolstered by a few researches on structures and functions of the homologous genes in the IIS pathway cloned from several parasitic nematodes. In this study, we identified the insulin-like receptor encoding gene, Acan-daf-2, from the parasitic nematode Angiostrongylus cantonensis, and determined the genomic structures, transcripts and functions far more thorough in longevity, stress resistance and dauer formation. The sequence of Acan-DAF-2, consisting of 1413 amino acids, contained all of the characteristic domains of insulin-like receptors from other taxa. The expression patterns of Acan-daf-2 in the C. elegans surrogate system showed that pAcan-daf-2:gfp was only expressed in intestine, compared with the orthologue in C. elegans, Ce-daf-2 in both intestine and neurons. In addition to the similar genomic organization to Ce-daf-2, Acan DAF-2 could also negatively regulate Ce-DAF-16A through nuclear/cytosolic translocation and partially restore the C. elegans daf-2(e1370) mutation in longevity, dauer formation and stress resistance. These findings provided further evidence of the functional conservation of DAF-2 between parasitic nematodes and the free-living nematode C. elegans, and might be significant in understanding the developmental biology of nematode parasites, particularly in the infective process and the host-specificity. PMID- 28576339 TI - The toxicity and the acaricidal mechanism against Psoroptes cuniculi of the methanol extract of Adonis coerulea Maxim. AB - SCOPE: Adonis coerulea Maxim. is a perennial herbaceous plant that grows in scrub, grassy slope areas, and as traditional medicine it has been used to treat animal acariasis for thousands of years. In this paper, we aimed to study the acute toxicity and cytotoxicity of the methanol extract of A. coerulea (MEAC) in vivo and in vitro for supporting the clinic uses. The acaricidal activity and the mechanism of action against Psoroptes cuniculi were investigated. RESULTS: The results showed that isoorientin, luteolin and apigenin were the primary compounds in MEAC. The toxicity test showed that median lethal dose (LD50) and the 50% inhibitory concentration (IC50) of MEAC were estimated to be more than 5000mg/kg in mice in vivo and more than 50mg/ml against RAW 264.7 and GM00637 cells in the 3-(4, 5-dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) test. After culturing with MEAC, the activities of superoxide dismutase (SOD), catalase (CAT), malonyldialdehyde (MDA), glutathione-S-transferase (GST), acetylcholinesterase (AChE) and Na+-K+-ATPase of mites were evaluated. Compared with the control group, SOD activity of MEAC-treated group of mites was inhibited, and CAT activity was activated at the preliminary phase but was gradually inhibited over the period of incubation. MDA content reached a peak at 6h and then gradually decreased. However, GST activity in the mites was activated in a dose- and time-dependent manner. AChE and Na+-K+-ATPase activities related to neural conduction, vital functions and the transmembrane ion gradient of the mites were inhibited. CONCLUSION: MEAC is safe in the given doses in both the in vitro and the in vivo tests, can be applied in the clinic and it had good acaricidal activity. The extension of the incubation time in the mites led to dynamic disequilibrium between the production and clearing of superoxide anions, a disruption of the energy metabolism and the transmembrane ion gradient, and the inhibition of motor function. These factors may have resulted in mite death. PMID- 28576338 TI - Susceptibility of ten Haemonchus contortus isolates from different geographical origins towards acetone:water extracts of polyphenol-rich plants. Part 2: Infective L3 larvae. AB - This study explored the variation in susceptibility to acetone:water plant extracts between infective larvae (L3) of ten Haemonchus contortus isolates from different geographical origin. The L3 of 10 different isolates were exposed either to the acetone:water extract of a temperate plant (Onobrychis viciifolia) or a tropical plant (Acacia pennatula) and were evaluated with the larval exsheathment inhibition assay (LEIA). The L3 of each isolate were incubated with different concentrations of each extract (0, 25, 50, 100, 200, 400, 600, 800, 1000 and 1200MUg/mL of phosphate buffered saline (PBS)). After incubation, the exsheathment process of L3 was induced using a solution with sodium hypochlorite (2%) and sodium chloride (16.5%). The proportion of exsheathed L3 was determined for each concentration at 0, 20, 40 and 60min. Effective concentrations 50% (EC50) and the corresponding 95% confidence intervals (95% CI) were calculated for every isolate with both extracts. Moreover, a resistance ratio (RR) was calculated for each extract to compare isolates, using the most susceptible isolate as the respective reference for each extract. To determine the role of polyphenols on the reported effect, a second set of incubations was made for each isolate and each extract, using the extracts at a concentration of 1200MUg/mL PBS with or without polyvinylpolypyrrolidone (PVPP), a polyphenol blocking agent, and controls without extract. The ten different H. contortus isolates showed variation in susceptibility for each of the 2 extracts tested (P<0.05). The EC50 values for A. pennatula extract ranged from 36 to 501MUg/mL (RR: 2.11-13.68). Meanwhile, the EC50 values for O. viciifolia extract ranged from 128 to 1003MUg/mL (RR: 1.25-7.82). The use of PVPP revealed that polyphenols were responsible for the anthelmintic activity recorded for both extracts. However, tested H. contortus isolates suggested that susceptibility to one polyphenol-rich extract did not determine the susceptibility to the other polyphenol rich extract. The latter result indicated that the different H. contortus isolates varied in their susceptibility to the polyphenols present in each extract evaluated. PMID- 28576340 TI - Utilization of composite fecal samples for detection of anthelmintic resistance in gastrointestinal nematodes of cattle. AB - Recent reports indicate that anthelmintic resistance in gastrointestinal nematodes of cattle is becoming increasingly prevalent worldwide. Presently, the fecal egg count reduction test (FECRT) is the only means available for detection of resistance to anthelmintics in cattle herds at the farm level. However, the FECRT is labor and cost intensive, and consequently is only rarely performed on cattle farms unless for research purposes. If costs could be reduced, cattle producers might be more likely to pursue drug resistance testing on their farms. One approach to reducing the cost of the FECRT, is the use of composite fecal samples for performing fecal egg counts (FEC), rather than conducting FEC on fecal samples from 15 to 20 individual animals. In this study FECRT were performed on 14 groups of cattle using both individual and composite FEC methods To measure how well the results of composite sampling reproduce those of individual sampling, Lin's Concordance Correlation Coefficient was utilized to describe both the linear relationship between methods and the slope and y intercept of the line relating the data sets. There was little difference between the approaches with 98% agreement in mean FEC found between methods Mean FEC based on individual counts ranged between 0 and 670.6 eggs per gram of feces, indicating that the results of this study are applicable to a wide range of FEC levels. Standard error of the mean FEC and range of FEC are reported for each group prior to and following treatment to describe the variability of the data set. There was greater than 95% agreement in drug efficacy between individual and composite sampling methods, demonstrating composite sampling is appropriate to evaluate drug efficacy. Notably, for all groups tested the efficacy calculated by composite sampling was within the 95% confidence interval for efficacy calculated using individual sampling. The use of composite samples was shown to reduce the number of FEC required by 79%. These data demonstrate that pooling fecal samples from a group of cattle and then performing repeated FEC on that composite sample yields results very similar to performing individual FEC on those same animals, while substantially reducing the cost of performing a FECRT as compared to individual fecal samples. Furthermore, we have developed suggested methods for using composite samples in a FECRT, provided a cost comparison for this methodology, and described potential issues associated with the use of composite samples that must be considered. PMID- 28576341 TI - Molecular confirmation of Sarcocystis fayeri in a donkey. AB - Sarcocystis fayeri is a canine protozoan parasite with an equine intermediate host. Historically classified as an incidental pathogen, recent literature has described the toxic effects of Sarcocystis fayeri in human food poisoning, and highlighted potential involvement in equine neuromuscular disease. Until now, horses were believed to be the exclusive intermediate host. This study reports the first molecular confirmation of S. fayeri in a donkey, and gives rise to the consideration of donkeys being a potential reservoir for the parasite. This finding is of particular importance in understanding the epidemiology of this disease. PMID- 28576342 TI - Development of a colloidal gold immunochromatographic strip based on HSP70 for the rapid detection of Echinococcus granulosus in sheep. AB - Echinococcus granulosus is the causative pathogen of cystic echinococcosis, a serious disease endangering human and animal health. In this study, an immunochromatographic strip was developed based on the recombinant protein Heat shock protein 70 (HSP70) for the serological detection of E. granulosus. The protocol completes within 20min requiring no specialized equipment or chemical reagents, while specificity tests confirmed no cross-reactivity with positive serum of Fasciola hepatica, Haemonchus contortus, Peste des petits ruminants virus (PPRV) and Foot-and-mouth disease virus (FMDV). The strips remained stable after storage at 4 degrees C for up to 8 months. Both immunochromatographic strip and ELISA tests were applied to detect E. granulosus antibody in a total of 728 serum samples obtained from slaughter houses in Zhejiang Province. Our data revealed positive rates of 2.61 and 1.65% by immunochromatographic strip and ELISA methods, respectively. The immunochromatographic strip test developed in this study provides a simple, specific and rapid method of E. granulosus antibody detection and infected sheep monitoring. PMID- 28576343 TI - Economic assessment of Ostertagia ostertagi and Fasciola hepatica infections in dairy cattle herds in Germany using Paracalc(r). AB - The aim of the current study was to estimate economic costs of Ostertagia ostertagi and Fasciola hepatica infections in dairy cattle herds in Germany using the online calculation programme Paracalc(r). Following a questionnaire, survey data were available from 464 farms in 14 federal states. On those farms bulk tank milk (BTM) samples and additionally up to six serum samples collected from first season grazing calves were analysed, using a commercially available ELISA (Boehringer Ingelheim SVANOVA Biotech AB, Uppsala, Sweden), an in-house ELISA (F. hepatica) and an in-house serum pepsinogen test. In total, samples obtained from 344 farms were included in the analysis since those were the only farms with complete questionnaires. Median costs per farm and year were estimated for gastrointestinal (GI) nematode infections (?721.38) and F. hepatica infection (?565.61). Decreases in milk yield in multiparous cows were the major reason for annual production losses due to GI nematodes (?13.33 per cow) and F. hepatica infections (?7.95 per cow), which was followed by annual costs for anthelmintic treatment against GI nematode infections in adult cows (?10.00 per cow) and F. hepatica infection associated annual costs due to repeated artificial insemination (?10.13 per cow) and prolonged calving intervals (?9.40 per cow). The study demonstrated that if all required information is provided, the Paracalc(r) tool can assist to identify productions losses in dairy cattle herds due to helminth infections and to optimise farm economics in Germany. PMID- 28576344 TI - Association of water handling and child feeding practice with childhood diarrhoea in rural community of Southern Nepal. AB - Diarrhoea is a major cause of childhood morbidity and mortality globally. While the childhood diarrhoea and its association with child feeding, and hygiene, hand washing and water treatment are studied elsewhere, the association of water handling and child feeding with childhood diarrhoea is an understudied area in Nepal. This study aimed to investigate the association of water handling and child feeding practice with childhood diarrhoea among children of one to five years of age in Southern, Nepal. A cross-sectional study was conducted in the Dhanusha district of Southern Nepal in 2013. A total of 284 mother-child pairs were selected using systemic random sampling. A four-week prevalence of childhood diarrhoea was reported using frequency distribution. The association of childhood diarrhoea with water handling and child feeding practices was ascertained using multiple logistic regressions after adjusting for potential confounders. The result of the study demonstrated that the four-week prevalence of childhood diarrhoea was 36.6%. Our finding showed that unsafe water handling practices were associated independently with childhood diarrhoea: untreated water (aOR 3.55; 95% CI: 1.13-11.10), uncovered water (aOR 2.14; 95% CI: 1.09-4.19). Similarly, partial breast feeding (aOR 4.35; 95% CI: 1.87-10.12) was also associated with higher odds of childhood diarrhoea. One third of children in Southern Nepal still had diarrhoea within the four weeks preceding the survey. As poor water handling and sub optimal infant feeding practice were major risk factors contributing to such a high burden of the disease, health promotion strategies such as promotion of safe water handling, improved hygiene and child feeding practices are recommended for the prevention of childhood diarrhoea in Southern Terai of Nepal. PMID- 28576345 TI - Multidirectional instability of the glenohumeral joint: Etiology, classification, assessment, and management. AB - Multidirectional instability of the shoulder is a type of glenohumeral joint shoulder instability. There are discrepancies in the definition and classification of this condition, which can make diagnosis and treatment selection challenging. Knowledge of contributing factors, the typical clinical presentation, and current best evidence for treatment options can assist in the diagnosis and appropriate treatment selection for this pathology. The purpose of this article is to present an overview of the current literature regarding the etiology, classification, assessment, and management of multidirectional instability of the glenohumeral joint. PMID- 28576346 TI - Factors influencing final outcomes in patients with shoulder pain: A retrospective review. AB - STUDY DESIGN: Retrospective cohort. INTRODUCTION: Rehabilitation interventions are commonly prescribed for patients with shoulder pain, but it is unclear what factors may help clinicians' prognosis for final outcomes. PURPOSE OF THE STUDY: The purpose of this study is to determine what factors are the best predictors of improved patient-reported outcomes at discharge in patients with shoulder pain. METHODS: Retrospective chart review of 128 patients presenting with shoulder pain to an outpatient physical therapy clinic. Chart review captured data regarding patient demographics, treatment interventions, patient history, and patient reported outcome scores. The primary dependent variable was the overall change score of the QuickDASH (initial to discharge). Thirty-eight predictor variables were entered into a forward stepwise multivariate linear regression model to determine which variables and to what degree contributed to the dependent variable. RESULTS: The linear regression model identified 5 predictor variables that yielded an R = 0.74 and adjusted R2 = 0.538 (P < .001). The 5 predictor variables identified in order of explained variance are QuickDASH change at the fifth visit, a total number of visits, initial QuickDASH score, scapular retraction exercise, and age. DISCUSSION: Early change scores, equal to minimal detectable change scores on patient-reported outcomes appear to be strong indicators that patients with shoulder pain are on a positive trajectory to benefit from rehabilitation. CONCLUSION: Using patient-reported outcomes throughout care, not just at the start and end of care, will provide therapist feedback regarding patient's progress and indicate treatment effectiveness. LEVELS OF EVIDENCE: 4. PMID- 28576347 TI - Scapular muscle dysfunction associated with subacromial pain syndrome. AB - STUDY DESIGN: Narrative Review. INTRODUCTION: One of the shoulder pain disorders in which the function of the scapula is comprised is the subacromial pain syndrome. Several rehabilitation guidelines and exercises have been proposed to improve scapulothoracic muscle dysfunction. Consideration of muscle activation patterns may help to select the most appropriate rehabilitation exercise in these patients. To date, suggesting rehabilitation exercises is often based upon the knowledge of the superficial lying scapulothoracic muscles' activity. In the assumption that the deeper lying scapulothoracic muscles' activity may hinder normal scapular movement in case of tightness or hyperactivity, exercise protocols for patients with altered pattern in scapulothoracic muscles should also integrate knowledge on the deeper lying scapulothoracic muscle activity. PURPOSE OF THE STUDY: To help clinicians choosing the most appropriate exercise in patients with subacromial pain syndrome related to scapulothoracic muscle dysfunction. METHODS: First, a summary of key alterations in scapulothoracic (muscle) function in patients with subacromial pain was accomplished. Second, promising practical rehabilitation strategies toward restoring scapulothoracic muscle dysfunction (with a focus on scapulothoracic exercises) were developed, integrating current new research evidence (including information about the deeper lying scapulothoracic muscles) with clinical practice. CONCLUSION: This review details clinical exercises and their muscular activity to guide clinicians to optimize individualized scapulothoracic training and treatment programs by selecting the most appropriate exercise, based on knowledge from the clinical examination. LEVEL OF EVIDENCE: Level 5. PMID- 28576348 TI - Editorial. PMID- 28576349 TI - Response to "Baclofen and alcohol use disorders: From miracle to mirage". PMID- 28576350 TI - Cannabinoids in attention-deficit/hyperactivity disorder: A randomised-controlled trial. AB - Adults with ADHD describe self-medicating with cannabis, with some reporting a preference for cannabis over ADHD medications. A small number of psychiatrists in the US prescribe cannabis medication for ADHD, despite there being no evidence from randomised controlled studies. The EMA-C trial (Experimental Medicine in ADHD-Cannabinoids) was a pilot randomised placebo-controlled experimental study of a cannabinoid medication, Sativex Oromucosal Spray, in 30 adults with ADHD. The primary outcome was cognitive performance and activity level using the QbTest. Secondary outcomes included ADHD and emotional lability (EL) symptoms. From 17.07.14 to 18.06.15, 30 participants were randomly assigned to the active (n=15) or placebo (n=15) group. For the primary outcome, no significant difference was found in the ITT analysis although the overall pattern of scores was such that the active group usually had scores that were better than the placebo group (Est=-0.17, 95%CI-0.40 to 0.07, p=0.16, n=15/11 active/placebo). For secondary outcomes Sativex was associated with a nominally significant improvement in hyperactivity/impulsivity (p=0.03) and a cognitive measure of inhibition (p=0.05), and a trend towards improvement for inattention (p=0.10) and EL (p=0.11). Per-protocol effects were higher. Results did not meet significance following adjustment for multiple testing. One serious (muscular seizures/spasms) and three mild adverse events occurred in the active group and one serious (cardiovascular problems) adverse event in the placebo group. Adults with ADHD may represent a subgroup of individuals who experience a reduction of symptoms and no cognitive impairments following cannabinoid use. While not definitive, this study provides preliminary evidence supporting the self-medication theory of cannabis use in ADHD and the need for further studies of the endocannabinoid system in ADHD. PMID- 28576351 TI - Publicly available software tools for decision-makers during an emergent epidemic Systematic evaluation of utility and usability. AB - Epidemics and emerging infectious diseases are becoming an increasing threat to global populations-challenging public health practitioners, decision makers and researchers to plan, prepare, identify and respond to outbreaks in near real timeframes. The aim of this research is to evaluate the range of public domain and freely available software epidemic modelling tools. Twenty freely utilisable software tools underwent assessment of software usability, utility and key functionalities. Stochastic and agent based tools were found to be highly flexible, adaptable, had high utility and many features, but low usability. Deterministic tools were highly usable with average to good levels of utility. PMID- 28576352 TI - Reprint of: Alterations of TRIM21-mRNA expression during monocyte maturation. AB - Tripartite motif-containing protein 21 (TRIM21) play a dual role in the cytoplasm of the cells where it facilitates destruction of some antibody-coated viruses and some bacteria, and initiates synthesis of proinflammatory cytokines. Macrophages and CD16+ monocyte subset can particularly participate in a proinflammatory response caused by viral infection, however, the molecular mechanisms underlying these processes are not fully understood. The aim of this study was to determine the level of TRIM21-mRNA expression in monocyte subsets including: classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++) monocytes, as well as during in vitro differentiation of the isolated monocytes towards dendritic cells or macrophages. Our results revealed that the level of TRIM21 mRNA expression was significantly lower in CD16- monocytes, when compared to CD16+ cells and the whole monocyte population, yet no significant differences were observed when CD16+ population was divided into intermediate and non classical subsets. More pronounced differences were observed in the case of monocyte-derived macrophages (MDM) and dendritic cells (DCs). TRIM21-mRNA expression level was app. 6-fold higher in DCs, and app. 16-fold higher in MDM (p<0,01), when compared to freshly isolated monocytes. Our results may suggest the new mechanism of increased proinflammatory cytokine production by CD16+ (intermediate and non-classical) monocytes and macrophages, at least in patients with acute or chronic infections, caused by enveloped viruses. We suggest that TRIM21 may be one of the factors associated with the "switching on" the proinflammatory programme in CD16+ monocytes or monocyte-derived macrophages. PMID- 28576354 TI - Does the addition of active body warming to in-line intravenous fluid warming prevent maternal hypothermia during elective caesarean section? A randomised controlled trial. AB - INTRODUCTION: Inadvertent perioperative hypothermia occurs frequently during elective caesarean section but perioperative active body warming is not widely used. There is a paucity of evidence of its use in the obstetric population, and no applicable guidelines. We set out to identify a superior active warming method for preventing inadvertent perioperative hypothermia. METHODS: Following ethical approval, 132 women presenting for uncomplicated elective caesarean section under spinal anaesthesia were recruited. All participants received in-line intravenous fluid warming and were randomised to one of three parallel groups: no active body warming; forced air warming; and conduction mattress warming. The primary outcome was the difference in mean core temperature, measured on admission to the recovery room, between study groups. Core temperature and thermal comfort were measured perioperatively at 15-min intervals. Estimated blood loss, haemoglobin change, length of hospital stay and neonatal core temperature were also recorded. RESULTS: One-hundred-and-thirty-one women completed the study. There was no significant difference in mean core temperature on admission to the recovery room (36.6 degrees C vs. 36.6 degrees C vs. 36.6 degrees C, eta2=0.005, P=0.74). Maternal hypothermia was prevented in all groups with only 0.3% hypothermic at any of the temperature measurements (3/1016). There was no difference in mean neonatal core temperature (36.3 degrees C vs. 36.3 degrees C vs. 36.3 degrees C, eta2=0.003, P=0.82); however, 59.4% (76/128) of all neonates were hypothermic. CONCLUSION: In-line intravenous fluid warming is sufficient to prevent maternal hypothermia and maintain core temperature. The addition of active body warming conferred no added benefit. PMID- 28576353 TI - Reprint of: Heme oxygenase 1 affects granulopoiesis in mice through control of myelocyte proliferation. AB - Heme oxygenase-1 (HO-1) is stress-inducible, cytoprotective enzyme degrading heme to carbon monoxide (CO), biliverdin and Fe2+. We showed that HO-1 knock-out mice (HO-1-/-) have a twofold higher level of granulocytes than wild type (WT) mice, despite decreased concentration of granulocyte colony-stimulating factor (G-CSF) in the blood and reduced surface expression of G-CSF receptor on the hematopoietic precursors. This suggests the effect of HO-1 on granulopoiesis. Here we aimed to determine the stage of granulopoiesis regulated by HO-1. The earliest stages of hematopoiesis were not biased toward myeloid differentiation in HO-1-/- mice. Within committed granulocytic compartment, in WT mice, HO-1 was up-regulated starting from myelocyte stage. This was concomitant with up regulation of miR-155, which targets Bach1, the HO-1 repressor. In HO-1-/- mice granulopoiesis was accelerated between myelocyte and metamyelocyte stage. There was a higher fraction of proliferating myelocytes, with increased nuclear expression of pro-proliferative C/EBPbeta (CCAAT/enhancer binding protein beta) protein, especially its active LAP (liver-enriched activator proteins) isoform. Also our mathematical model confirmed shortening the myelocyte cyclic-time and prolonged mitotic expansion in absence of HO-1. It seems that changes in C/EBPbeta expression and activity in HO-1-/- myelocytes can be associated with reduced level of its direct repressor miR-155 or with decreased concentration of CO, known to reduce nuclear translocation of C/EBPs. Mature HO-1-/- granulocytes were functionally competent as determined by oxidative burst capacity. In conclusion, HO-1 influences granulopoiesis through regulation of myelocyte proliferation. It is accompanied by changes in expression of transcriptionally active C/EBPbeta protein. As HO-1 expression vary in human and is up-regulated in response to chemotherapy, it can potentially influence chemotherapy-induced neutropenia. PMID- 28576355 TI - Context is king - obstetric anaesthesia management strategies in limited resource settings. PMID- 28576356 TI - Quantitative proteomics reveals new insights into calcium-mediated resistance mechanisms in Aspergillus flavus against the antifungal protein PgAFP in cheese. AB - The ability of Aspergillus flavus to produce aflatoxins in dairy products presents a potential hazard. The antifungal protein PgAFP from Penicillium chrysogenum inhibits various foodborne toxigenic fungi, including Aspergillus flavus. However, PgAFP did not inhibit A. flavus growth in cheese, which was related to the associated cation content. CaCl2 increased A. flavus permeability and prevented PgAFP-mediated inhibition in potato dextrose broth (PDB). PgAFP did not elicit any additional increase in permeability of CaCl2-incubated A. flavus. Furthermore, PgAFP did not alter metabolic capability, chitin deposition, or hyphal viability of A. flavus grown with CaCl2. Comparative proteomic analysis after PgAFP treatment of A. flavus in calcium-enriched PDB revealed increased abundance of 125 proteins, including oxidative stress-related proteins, as determined by label-free mass spectrometry (MS)-based proteomics. Seventy proteins were found at lower abundance, with most involved in metabolic pathways and biosynthesis of secondary metabolites. These changes do not support the blockage of potential PgAFP receptors in A. flavus by calcium as the main cause of the protective role. A. flavus resistance appears to be mediated by calcineurin, G-protein, and gamma-glutamyltranspeptidase that combat oxidative stress and impede apoptosis. These findings could serve to design strategies to improve PgAFP activity against aflatoxigenic moulds in dairy products. PMID- 28576357 TI - Industrial-scale application of Lactobacillus reuteri coupled with glycerol as a biopreservation system for inhibiting Clostridium tyrobutyricum in semi-hard ewe milk cheese. AB - The suitability of the biopreservation system formed by reuterin-producing L. reuteri INIA P572 and glycerol (required for reuterin production) to prevent late blowing defect (LBD) was evaluated in industrial sized semi-hard ewe milk cheese contaminated with Clostridium tyrobutyricum INIA 68, a wild strain isolated from a LBD cheese. For this purpose, six batches of cheese were made (three with and three without clostridial spores): control cheeses with lactococci starter, cheeses with L. reuteri as adjunct, and cheeses with L. reuteri and 30 mM glycerol. Spores of C. tyrobutyricum INIA 68 germinated during pressing of cheese curd, causing butyric acid fermentation in cheese after 30 d of ripening. The addition of L. reuteri, without glycerol, enhanced the symptoms and the formation of volatile compounds associated with LBD. When glycerol was added to cheese milk contaminated with C. tyrobutyricum, L. reuteri was able to produce reuterin in cheese resulting in cheeses with a uniform cheese matrix and a volatile profile similar to cheese made with L. reuteri and glycerol (without spores). Accordingly, L. reuteri INIA P572 coupled with glycerol seems a novel biopreservation system to inhibit Clostridium growth and prevent LBD by means of in situ reuterin production. PMID- 28576358 TI - Longitudinal monitoring of Listeria monocytogenes and Listeria phages in seafood processing environments in Thailand. AB - Listeria monocytogenes is a foodborne pathogen commonly found in environments of seafood processing, thus presenting a challenge for eradication from seafood processing facilities. Monitoring the prevalence and subtype diversity of L. monocytogenes together with phages that are specific to Listeria spp. ("Listeria phages") will provide knowledge on the bacteria-phage ecology in food processing plants. In this work, a total of 595 samples were collected from raw material, finished seafood products and environmental samples from different sites of a seafood processing plant during 17 sampling visits in 1.5 years of study. L. monocytogenes and Listeria spp. (non-monocytogenes) were found in 22 (3.7%) and 43 (7.2%) samples, respectively, whereas 29 Listeria phages were isolated from 9 (1.5%) phage-positive samples. DNA fingerprint analysis of L. monocytogenes isolates revealed 11 Random Amplified Polymorphic DNA (RAPD) profiles, with two subtypes were frequently observed over time. Our data reveal a presence of Listeria phages within the same seafood processing environments where a diverse set of L. monocytogenes subtypes was also found. Although serotype 4b was observed at lower frequency, data indicate that isolates from this seafood processing plant belonged to both epidemiologically important serotypes 1/2a and 4b, which may suggest a potential public health risk. Phages (all showed a unique genome size of 65 +/- 2 kb) were classified into 9 host range groups, representing both broad- and narrow-host range. While most L. monocytogenes isolates from this facility were susceptible to phages, five isolates showed resistance to 12-20 phages. Variations in phage host range among Listeria phages isolated from food processing plant may affect a presence of a diverse set of L. monocytogenes isolates derived from the same processing environment in Thailand. PMID- 28576359 TI - Survey on the phage resistance mechanisms displayed by a dairy Lactobacillus helveticus strain. AB - In this study the presence and functionality of phage defence mechanisms in Lactobacillus helveticus ATCC 10386, a strain of dairy origin which is sensitive to PhiLh56, were investigated. After exposure of ATCC 10386 to PhiLh56, the whole genome sequences of ATCC 10386 and of a phage-resistant derivative (LhM3) were compared. LhM3 showed deletions in the S-layer protein and a higher expression of the genes involved in the restriction/modification (R/M) system. Genetic data were substantiated by measurements of bacteriophage adsorption rates, efficiency of plaquing, cell wall protein size and by gene expression analysis. In LhM3 two phage resistance mechanisms, the inhibition of phage adsorption and the upregulation of Type I R/M genes, take place and explain its resistance to PhiLh56. Although present in both ATCC 10386 and LhM3 genomes, the CRISPR machinery did not seem to play a role in the phage resistance of LhM3. Overall, the natural selection of phage resistant strains resulted successful in detecting variants carrying multiple phage defence mechanisms in L. helveticus. The concurrent presence of multiple phage-resistance systems should provide starter strains with increased fitness and robustness in dairy ecosystems. PMID- 28576360 TI - Characterization of antimicrobial properties of Salmonella phage Felix O1 and Listeria phage A511 embedded in xanthan coatings on Poly(lactic acid) films. AB - Beyond simply providing a barrier between food and external contaminants, active packaging technologies aim to inhibit pathogen survival and growth within the packaged environment. Bacteriophages have a proven track record as targeted antimicrobials but have yet to be successfully integrated in active packaging without serious loss of activity. We have developed two bacteriophage based xanthan coatings on poly(lactic acid) (PLA) film which significantly inhibits Salmonella Typhimurium and Listeria monocytogenes growth in culture (P < 0.01), and significantly reduces survival and growth of diverse cocktails of Salmonella sp. and L. monocytogenes respectively on precooked sliced turkey breast over 30 days of anaerobic packaging at 4 or 10 degrees C (P < 0.05). Specifically reductions of 0.832 log at 4 degrees C and 1.30 log at 10 degrees C for Salmonella sp., and 6.31 log at 4 degrees C and 1.52 log at 10 degrees C for L. monocytogenes were observed. The coating containing Listeria phage A511 also significantly inhibited growth of L. monocytogenes over 14 days in aerobic packaging (3.79 log at 4 degrees C, 2.17 log at 10 degrees C, P < 0.05). These coatings showed 99.99% phage release within 30 min for both phages. Similar approaches could be used to develop packaging inhibitory to other significant foodborne pathogens such as Campylobacter, and Escherichia coli, as well as spoilage bacteria. PMID- 28576361 TI - Multiple microbial cell-free extracts improve the microbiological, biochemical and sensory features of ewes' milk cheese. AB - This study used cell-free enzyme (CFE) extracts from Lactobacillus casei, Hafnia alvei, Debaryomyces hansenii and Saccharomyces cerevisiae to condition or accelerate Pecorino-type cheese ripening. Compositional, microbiological, and biochemical analyses were performed, and volatile and sensory profiles were obtained. Lactobacilli and cocci increased during ripening, especially in cheeses containing CFE from L. casei, H. alvei and D. hansenii (LHD-C) and L. casei, H. alvei and S. cerevisiae (LHS-C). Compared to control cheese (CC), several enzymatic activities were higher (P < 0.05) in CFE-supplemented cheeses. Compared to the CC (1907 mg kg-1 of cheese), the free amino acid level increased (P < 0.05) in CFE-supplemented cheeses, ranging from approximately 2575 (LHS-C) to 5720 (LHD-C) mg kg-1 of cheese after 60 days of CFE-supplemented ripening. As shown by GC/MS analysis, the levels of several volatile organic compounds were significantly (P < 0.05) lower in CC than in CFE-supplemented cheeses. All cheeses manufactured by adding multiple CFEs exhibited higher scores (P < 0.05) for internal structure, acid taste and juiciness than CC samples. This study shows the possibility of producing ewes' milk cheese with standardized characteristics and improved flavor intensity in a relatively short time. PMID- 28576362 TI - Effect of different marinating conditions on the evolution of spoilage microbiota and metabolomic profile of chicken breast fillets. AB - Five different marinades were prepared containing lemon juice, apple cider vinegar, pomegranate juice and combinations of them. Three different temperatures (4, 10, and 20 degrees C) and five marinating time intervals (1, 3, 6, and 9 h) were tested. Microbial, physicochemical as well as sensory analyses were performed to assess marination. Noticeable microbial reductions and satisfactory sensory results were observed only in samples treated for short time (1 and 3 h). The marinade in which pomegranate and lemon juices were combined caused a decrease in microbial counts and led to desirable sensory attributes. Each of the marinades was characterized by a distinguishable organic acid profile, while the discrimination of the samples, based on organic acid concentration, between low (1 and 3) and high (6 and 9) marinating time was feasible. It can be concluded that marinating time affected the indigenous microbiota and the sensory characteristics of chicken meat while pomegranate could be a promising marinating ingredient from a microbiological and physicochemical perspective. PMID- 28576363 TI - Effect of green tea extract on enteric viruses and its application as natural sanitizer. AB - In this work, the effect of green tea extract (GTE) was assessed against murine norovirus (MNV) and hepatitis A virus (HAV) at different temperatures, exposure times and pH conditions. Initially, GTE at 0.5 and 5 mg/ml were individually mixed with each virus at 5 log TCID50/ml and incubated 2 h at 37 degrees C at different pHs (from 5.5 to 8.5). GTE affected both viruses depending on pH with higher reductions observed in alkaline conditions. Secondly, different concentrations of GTE (0.5 and 5 mg/ml) were mixed with viral suspensions and incubated for 2 or 16 h at 4, 25 and 37 degrees C at pH 7.2. A concentration-, temperature- and exposure time-dependent response was showed by GTE in suspension tests, where complete inactivation was achieved after overnight exposure at 37 degrees C for both viruses and also at 25 degrees C for HAV. In addition, antiviral effect of GTE proved efficient in the surface disinfection tests since 1.5 log reduction and complete inactivation were recorded for MNV and HAV on stainless steel and glass surfaces treated with 10 mg/ml GTE for 30 min, analyzed in accordance with ISO 13697:2001. GTE was also evaluated as a natural disinfectant of produce, showing 10 mg/ml GTE reduced MNV and HAV titers in lettuce and spinach by more than 1.5 log after 30 min treatment. The results show a potential of GTE as natural disinfectant able to limit enteric viral (cross )contaminations conveyed by food and food-contact surfaces. PMID- 28576364 TI - Lack of viable parasites in cured 'Parma Ham' (PDO), following experimental Toxoplasma gondii infection of pigs. AB - Twelve Large White pigs were experimentally infected with 1000 Toxoplasma gondii oocysts/each. Serology was carried out at different time points post infection (p.i.) and animals were slaughtered at four months p.i. One of two thighs was examined for T. gondii infection status by PCR and bioassay in mice. The other thigh was processed for Parma ham production. Four thighs were examined after twelve months of curing, four after fourteen months and four were examined after sixteen months. Cured hams were analyzed by PCR, bioassay and in-vitro cultivation on Vero cells followed by real-time PCR. Pigs seroconverted from day 21 p.i. Bioassays were positive for all fresh thighs, but negative for cured hams. PCR was positive for parasite DNA from most thighs both at slaughter and post curing, but parasite growth was not observed following in vitro cultivation and real-time PCR. Results indicate that the curing process of Parma Ham (PDO), when carried out according to the Parma Ham consortium regulations, can inactivate T. gondii tissue cysts. Results would suggest that food-borne transmission of T. gondii to consumers from Parma ham can be excluded. PMID- 28576365 TI - Influence of soy fortification on microbial diversity during cassava fermentation and subsequent physicochemical characteristics of garri. AB - This study investigated the influence of the addition of soy products on the microbiology, nutritional and physico-chemical characteristics of garri, a fermented cassava product. Malted soy flour (MSF) and soy protein (SP) were separately added (12% w/w) to cassava mash prior to controlled fermentation, while non-supplemented cassava mash served as a control. Identification of lactic acid bacteria (LAB) and aerobic mesophilic bacteria was accomplished by repetitive sequence based (rep)-PCR analysis and 16S rRNA gene sequencing. Physicochemical, nutritional and sensory characterisation of control and soy fortified garri was performed using conventional methods. rep-PCR allowed differentiation of 142 isolates into 41 groups corresponding to 6 species of LAB and 25 species of aerobic mesophiles. LAB isolates belonged to the genera Lactobacillus, Weissella, Leuconostoc and Lactococcus with Leuconostoc mesenteroides being the dominant species in control and MSF-cassava while Weissella cibaria dominated SP-cassava fermentation. Aerobic mesophiles included Gram positive and negative bacteria including species of the genera Bacillus, Clostridium, Staphylococcus, Serratia, Acinetobacter and Raoultella. Diversity of aerobic mesophiles varied between control, MSF- and SP- cassava mash. Protein content of soy-fortified garri increased from 0.73% to 10.17% and 10.05% in MSF and SP garri respectively with a significant decrease in total cyanide from 26 to 11 ppm. Results from physicochemical and organoleptic evaluation indicate that supplementation of cassava with soy products prior to fermentation can produce acceptable garri. Soy products can be considered a viable option for protein fortification of garri, a low protein food with the aim of combating malnutrition. PMID- 28576366 TI - Large-scale targeted metagenomics analysis of bacterial ecological changes in 88 kimchi samples during fermentation. AB - The microbial communities in kimchi vary widely, but the precise effects of differences in region of origin, ingredients, and preparation method on the microbiota are unclear. We analyzed the bacterial community composition of household (n = 69) and commercial (n = 19) kimchi samples obtained from six Korean provinces between April and August 2015. Samples were analyzed by barcoded pyrosequencing targeting the V1-V3 region of the 16S ribosomal RNA gene. The initial pH of the kimchi samples was 5.00-6.39, and the salt concentration was 1.72-4.42%. Except for sampling locality, all categorical variables, i.e., salt concentration, major ingredient, fermentation period, sampling time, and manufacturing process, influenced the bacterial community composition. Particularly, samples were highly clustered by sampling time and salt concentration in non-metric multidimensional scaling plots and an analysis of similarity. These results indicated that the microbial community differed according to fermentation conditions such as salt concentration, major ingredient, fermentation period, and sampling time. Furthermore, fermentation properties, including pH, acidity, salt concentration, and microbial abundance differed between kimchi samples from household and commercial sources. Analyses of changes in bacterial ecology during fermentation will improve our understanding of the biological properties of kimchi, as well as the relationships between these properties and the microbiota of kimchi. PMID- 28576367 TI - Factors influencing the Salmonella internalization into seedpods and whole plants of Arachis hypogaea (L.). AB - Here we investigated whether Salmonella enterica serovar Typhimurium ATCC 14028 was capable of internalizing in peanut seedpods and plants when exposed to inoculated soil and the edaphic factors that influenced uptake. Intact dry Virginia (DV) and fresh green Virginia (GV) seedpods were exposed to soil containing 6.5 Log (CFU/g) Salmonella under different soil moisture conditions. Internalization of S. Typhimurium into peanut plants germinated in inoculated soil was also examined with and without Bradyrhizobium (Arachis) sp.NC92. Salmonella counts recovered from GV seedpods were on average of 2.0 Log (CFU/pod) less than those recovered from DV seedpods. The internalization in DV pods was only observed at soil water content of 15% or greater in a loamy sand soil. S. Typhimurium was detected inside peanut plant tissues during most testing times. Cells were recovered from stem samples (3.5 Log CFU/g) at greater levels than it was observed for root (2.6 Log CFU/g) and leaf (1.7 Log CFU/g) samples. Overall, recovery of Salmonella from stem, root, and leaf samples were lower when B. NC92 was inoculated on seeds before sowing, but this trend was not significant. Our observations suggest possible routes of contamination of Salmonella into peanut products from soil. PMID- 28576368 TI - Efficacy of gaseous ozone to counteract postharvest table grape sour rot. AB - This work aims at studying the efficacy of low doses of gaseous ozone in postharvest control of the table grape sour rot, a disease generally attributed to a consortium of non-Saccharomyces yeasts (NSY) and acetic acid bacteria (AAB). Sour rot incidence of wounded berries, inoculated with 8 NSYstrains, or 7 AAB, or 56 yeast-bacterium associations, was monitored at 25 degrees C up to six days. Sour rot incidence in wounded berries inoculated with yeast-bacterium associations resulted higher than in berries inoculated with one single NSY or AAB strain. Among all NSY-AAB associations, the yeast-bacterium association composed of Candida zemplinina CBS 9494 (Cz) and Acetobacter syzygii LMG 21419 (As) showed the highest prevalence of sour rot; thus, after preliminary in vitro assays, this simplified As-Cz microbial consortium was inoculated in wounded berries that were stored at 4 degrees C for ten days under ozone (2.14 mg m-3) or in air. At the end of cold storage, no berries showed sour-rot symptoms although ozonation mainly affected As viable cell count. After additional 12 days at 25 degrees C, the sour rot index of inoculated As-Cz berries previously cold stored under ozone or in air accounted for 22.6 +/- 3.7% and 66.7 +/- 4.5%, respectively. Molecular analyses of dominant AAB and NSY populations of both sound and rotten berries during post-refrigeration period revealed the appearance of new strains mainly belonging to Gluconobacter albidus and Hanseniaspora uvarum species, respectively. Cold ozonation resulted an effective approach to extend the shelf-life of table grapes also after cold storage. PMID- 28576369 TI - Effects of heat, cold, acid and bile salt adaptations on the stress tolerance and protein expression of kefir-isolated probiotic Lactobacillus kefiranofaciens M1. AB - Lactobacillus kefiranofaciens M1 is a probiotic strain isolated from Taiwanese kefir grains. The present study evaluated the effects of heat, cold, acid and bile salt adaptations on the stress tolerance of L. kefiranofaciens M1. The regulation of protein expression of L. kefiranofaciens M1 under these adaptation conditions was also investigated. The results showed that adaptation of L. kefiranofaciens M1 to heat, cold, acid and bile salts induced homologous tolerance and cross-protection against heterologous challenge. The extent of induced tolerance varied depending on the type and condition of stress. Proteomic analysis revealed that 27 proteins exhibited differences in expression between non-adapted and stress-adapted L. kefiranofaciens M1 cells. Among these proteins, three proteins involved in carbohydrate metabolism (triosephosphate isomerase, enolase and NAD-dependent glycerol-3-phosphate dehydrogenase), two proteins involved in pH homeostasis (ATP synthase subunits AtpA and AtpB), two stress response proteins (chaperones DnaK and GroEL) and one translation-related protein (30S ribosomal protein S2) were up-regulated by three of the four adaptation treatments examined. The increased synthesis of these stress proteins might play a critical protective role in the cellular defense against heat, cold, acid and bile salt stresses. PMID- 28576370 TI - Leuconostoc strains isolated from dairy products: Response against food stress conditions. AB - A systematic study about the intrinsic resistance of 29 strains (26 autochthonous and 3 commercial ones), belonging to Leuconostoc genus, against diverse stress factors (thermal, acidic, alkaline, osmotic and oxidative) commonly present at industrial or conservation processes were evaluated. Exhaustive result processing was made by applying one-way ANOVA, Student's test (t), multivariate analysis by Principal Component Analysis (PCA) and Matrix Hierarchical Cluster Analysis. In addition, heat adaptation on 4 strains carefully selected based on previous data analysis was assayed. The strains revealed wide diversity of resistance to stress factors and, in general, a clear relationship between resistance and Leuconostoc species was established. In this sense, the highest resistance was shown by Leuconostoc lactis followed by Leuconostoc mesenteroides strains, while Leuconostoc pseudomesenteroides and Leuconostoc citreum strains revealed the lowest resistance to the stress factors applied. Heat adaptation improved thermal cell survival and resulted in a cross-resistance against the acidic factor. However, all adapted cells showed diminished their oxidative resistance. According to our knowledge, this is the first study regarding response of Leuconostoc strains against technological stress factors and could establish the basis for the selection of "more robust" strains and propose the possibility of improving their performance during industrial processes. PMID- 28576372 TI - Controlling Brochothrix thermosphacta as a spoilage risk using in-package atmospheric cold plasma. AB - Brochothrix thermosphacta is the predominant spoilage microorganism in meat and its control in processing environments is important to maintain meat product quality. Atmospheric cold plasma is of interest for control of pathogenic and spoilage microorganisms in foods. This study ascertained the potential of dielectric barrier discharge atmospheric cold plasma (DBD-ACP) for control of B. thermosphacta, taking microbial and food environment factors into consideration, and investigated the shelf-life of lamb chop after in-package plasma treatment in modified atmosphere. Community profiling was used to assess the treatment effects on the lamb microflora. ACP treatment (80 kV) for 30s inactivated B. thermosphacta populations below detection levels in PBS, while 5 min treatment achieved a 2 Log cycle reduction using a complex meat model medium and attached cells. The antimicrobial efficacy of plasma was reduced but still apparent on lamb chop surface-inoculated with high concentrations of B. thermosphacta. Lamb chop treated under modified atmosphere exhibited reduced microbial growth over the product shelf-life and community profiling showed no evident changes to the microbial populations after the treatment. The overall results indicated potential of ACP to enhance microbial control leading to meat storage life extension through adjusting the modality of treatment. PMID- 28576371 TI - Comparison of Listeria monocytogenes recoveries from spiked mung bean sprouts by the enrichment methods of three regulatory agencies. AB - Three selective enrichment methods, the United States Food and Drug Administration's (FDA method), the United States Department of Agriculture Food Safety Inspection Service's (USDA method), and the EN ISO 11290-1 standard method, were assessed for their suitability for recovery of Listeria monocytogenes from spiked mung bean sprouts. Three parameters were evaluated; the enrichment L. monocytogenes population from singly-spiked sprouts, the enrichment L. monocytogenes population from doubly-spiked (L. monocytogenes and Listeria innocua) sprouts, and the population differential resulting from the enrichment of doubly-spiked sprouts. Considerable L. monocytogenes inter-strain variation was observed. The mean enrichment L. monocytogenes populations for singly-spiked sprouts were 6.1 +/- 1.2, 4.9 +/- 1.2, and 6.9 +/- 2.3 log CFU/mL for the FDA, USDA, and EN ISO 11290-1 methods, respectively. The mean L. monocytogenes populations for doubly-spiked sprouts were 4.7 +/- 1.1, 5.5 +/- 1.3, and 4.6 +/- 1.4 log CFU/mL for the FDA, USDA, and ISO 11290-1 enrichment methods, respectively. The corresponding mean population differentials were 2.8 +/- 1.1, 3.3 +/- 1.3, and 3.6 +/- 1.4 Deltalog CFU/mL for the same three enrichment methods, respectively. The presence of L. innocua and resident microorganisms on the sprouts negatively impacted final levels of L. monocytogenes with all three enrichment methods. PMID- 28576373 TI - High relative humidity pre-harvest reduces post-harvest proliferation of Salmonella in tomatoes. AB - Outbreaks of human illness caused by enteric pathogens such as Salmonella are increasingly linked to the consumption of fruits and vegetables. Knowledge on the factors affecting Salmonella proliferation on fresh produce therefore becomes increasingly important to safeguard public health. Previous experiments showed a limited impact of pre-harvest production practices on Salmonella proliferation on tomatoes, but suggested a significant effect of harvest time. We explored the data from two previously published and one unpublished experiment using regression trees, which allowed overcoming the interpretational difficulties of classical statistical models with higher order interactions. We assessed the effect of harvest time by explicitly modeling the climatic conditions at harvest time and by performing confirmatory laboratory experiments. Across all datasets, regression trees confirmed the dominant effect of harvest time on Salmonella proliferation, with humidity-related factors emerging as the most important underlying climatic factors. High relative humidity the week prior to harvest was consistently associated with lower Salmonella proliferation. A controlled lab experiment confirmed that tomatoes containing their native epimicrobiota supported significantly lower Salmonella proliferation when incubated at higher humidity prior to inoculation. The complex interactions between environmental conditions and the native microbiota of the tomato crop remain to be fully understood. PMID- 28576374 TI - Molecular investigation of bacterial communities during the manufacturing and ripening of semi-hard Iranian Liqvan cheese. AB - Liqvan (or Lighvan) is a traditional Iranian cheese from the East Azerbaijan province of Iran, which is made of raw ewe's milk without the addition of a starter. The grazing pastures, environmental conditions and the ancient regional production methods allocate a distinctive microbial ecology to this type of cheese, and these factors are consequently associated with the quality of the product. In this study, the microbiota of the milk, curd and cheese has been investigated using culture independent approaches. Denaturing gradient gel electrophoresis (DGGE) of the bacteria, 16S rRNA based high-throughput sequencing and enumeration of the live bacterial community by means of quantitative PCR (qPCR) have been used for this purpose. The results showed that the main bacterial population in the milk belonged to both microbial contaminants and lactic acid bacteria (LAB). However, both of these populations were totally replaced by LAB during ripening. The present survey contributes by describing the microbiota of this ancient cheese in more detail during fermentation and ripening. PMID- 28576376 TI - Impact of solar radiation exposure on phyllosphere bacterial community of red pigmented baby leaf lettuce. AB - Solar radiation has been identified as a stress factor affecting phyllosphere associated bacteria colonization and survival during primary production. In the present study, the impact of different solar radiation doses on the phyllosphere microbiota of red-pigmented baby leaf lettuce cultivated in open field under commercial conditions was evaluated. Four weeks before harvest, the growing field was divided into four plots; each one was consecutively covered with one-week interval with a light-excluding plastic to reduce the sunlight exposure. Four different solar radiation treatments were generated and cumulative photosynthetically active radiation (PAR) was used to differentiate treatments as follows: 4889 +/- 428 MUmol/m2/s (uncovered), 4265 +/- 356 MUmol/m2/s (covered for 1 week), 3602 +/- 225 MUmol/m2/s (covered for 2 weeks) and 3115 +/- 313 MUmol/m2/s (covered for 3 weeks). The size and composition of the phyllosphere bacterial community were determined by cultivation-depended (plate count) and independent (qPCR) techniques. Exposure to decreased levels of cumulative PAR did not produce significant differences in total bacterial community size, regardless of the chosen quantification techniques. However, total bacteria size quantified by qPCR was around 3.5 orders of magnitude higher than those obtained by plate count. The observed differences between cultivation-depended and independent techniques could be attributed to the presence of non-viable or viable but non culturable (VBNC) bacteria. The bacterial community structure was analyzed using temperature gradient gel electrophoresis (TGGE), and significant differences were detected when the four solar treatment were compared. A qPCR approach was applied to the quantification of specific bacterial phyla and classes, previously identified in the phyllosphere of plants available literature, confirming that Proteobacteria, Bacteroidetes, Actinobacterias and Firmicutes were the most abundantly represented phyla in lettuce. Treatment comparison revealed higher proportions of Gammaproteobacteria as opposed to the Betaproteobacteria on the lettuce exposed to the lowest cumulative PAR dose (3115 +/- 313 MUmol/m2/s). The obtained results demonstrated that the solar radiation is a relevant environmental factor influencing the relative abundance of specific-groups of phyllosphere-associated bacteria in pigmented baby leaf lettuce. PMID- 28576375 TI - Testing commercial biopreservative against spoilage microorganisms in MAP packed Ricotta fresca cheese. AB - Ricotta fresca cheese is susceptible to secondary contamination and is able to support the growth of pathogens or spoilage psychotrophic bacteria during storage. The aim of the present study was to evaluate which among three commercial biopreservatives was suitable to be used to control the growth of spoilage microorganisms in sheep's milk MAP ricotta fresca cheese. 144 Ricotta fresca cheese samples were inoculated either with the bioprotective culture Lyofast FPR 2 (including Enterococcus faecium, Lactobacillus plantarum e Lactobacillus rhamnosus) or Lyofast CNBAL (Carnobacterium spp) or the fermentate MicroGARD 430. Not inoculated control and experimental ricotta were MAP packed (30% CO2 and 70% N2) and stored at 4 degrees C. Triplicate samples were analyzed after 5 h and 7, 14 and 21 days after inoculation for total bacterial count, mesophilic lactic acid bacteria, Enterobacteriaceae, Pseudomonas spp, Listeria monocytogenes, moulds and yeasts. Among the tested biopreservatives only Carnobacterium spp was able to control Pseudomonas spp and Enterobacteriaceae. The maximum reduction in the concentration of Pseudomonas spp and Enterobacteriaceae was respectively 1.93 and 2.66 log10 cfu/g, observed 14 days after production. Therefore, Carnobacterium spp was selected as the culture of choice to conduct a challenge study against Pseudomonas spp. PMID- 28576377 TI - Microbiological, biochemical, and functional aspects of sugary kefir fermentation - A review. AB - Sugary kefir beverage is produce by fermenting raw sugar solution with kefir grains, the latter consisting of polysaccharide and microorganisms. This beverage, with great consumption in countries such as USA, Japan, France, and Brazil, represents a promising market to functional cultured drinks. This paper reviews the microbial diversity and interaction, kinetics, safety, and bioactivities of sugary kefir fermentation. The literature reviewed here demonstrates that sugary kefir possesses a similar microbial association relative to traditional milk kefir fermentation, especially among lactic acid bacteria and yeast species, such as Lactobacillus, Leuconostoc, Kluyveromyces, Pichia, and Saccharomyces. However, a selective pressure at species level is generally observed, as, for example, the stimulation of Saccharomyces species metabolism, leading to a high content of alcohol in the final product. This also seems to stimulate the growth of acetic acid bacteria that benefit of increased ethanol production to acetic acid metabolism. Existing reports have suggested important bioactivities associated with sugary kefir beverage consumption, such as antimicrobial, antiedematogenic, anti-inflammatory, antioxidant, cicatrizing, and healing activities. Other alternative non-dairy substrates, such as fruits, vegetables, and molasses, have also been tested for adaptation of kefir grains and production of functional beverages with distinct sensory characteristics. This diversification is of crucial importance for the production of new probiotic products to provide people with special needs (lactose intolerance) and vegan consumers. PMID- 28576378 TI - Synergistic mixtures of chitosan and Mentha piperita L. essential oil to inhibit Colletotrichum species and anthracnose development in mango cultivar Tommy Atkins. AB - This study assessed the efficacy of chitosan (CHI) and Mentha piperita L. essential oil (MPEO) alone or in combination to control the mycelial growth of five different Colletotrichum species, C. asianum, C. dianesei, C. fructicola, C. tropicale and C. karstii, identified as potential anthracnose-causing agents in mango (Mangifera indica L.). The efficacy of coatings of CHI and MPEO mixtures in controlling the development of anthracnose in mango cultivar Tommy Atkins was evaluated. CHI (2.5, 5, 7.5 and 10 mg/mL) and MPEO (0.3, 0.6, 1.25, 2.5 and 5 MUL/mL) alone effectively inhibited mycelial growth of all tested Colletotrichum strains in synthetic media. Mixtures of CHI (5 or 7.5 mg/mL) and MPEO (0.3, 0.6 or 1.25 MUL/mL) strongly inhibited mycelial growth and showed additive or synergistic inhibitory effects on the tested Colletotrichum strains based on the Abbott index. The application of coatings of CHI (5 or 7.5 mg/mL) and MPEO (0.6 or 1.25 MUL/mL) mixtures that presented synergistic interactions decreased anthracnose lesion severity in mango artificially contaminated with either of the tested Colletotrichum strains over 15 days of storage at 25 degrees C. The anthracnose lesion severity in mango coated with the mixtures of CHI and MPEO was similar or lower than those observed in mango treated with the synthetic fungicides thiophanate-methyl (10 MUg a.i./mL) and difenoconazole (0.5 MUg a.i./mL). The application of coatings containing low doses of CHI and MPEO may be an effective alternative for controlling the postharvest development of anthracnose in mango cultivar Tommy Atkins. PMID- 28576379 TI - [Using cancer case identification algorithms in medico-administrative databases: Literature review and first results from the REDSIAM Tumors group based on breast, colon, and lung cancer]. AB - BACKGROUND: The development and use of healthcare databases accentuates the need for dedicated tools, including validated selection algorithms of cancer diseased patients. As part of the development of the French National Health Insurance System data network REDSIAM, the tumor taskforce established an inventory of national and internal published algorithms in the field of cancer. This work aims to facilitate the choice of a best-suited algorithm. METHOD: A non-systematic literature search was conducted for various cancers. Results are presented for lung, breast, colon, and rectum. Medline, Scopus, the French Database in Public Health, Google Scholar, and the summaries of the main French journals in oncology and public health were searched for publications until August 2016. An extraction grid adapted to oncology was constructed and used for the extraction process. RESULTS: A total of 18 publications were selected for lung cancer, 18 for breast cancer, and 12 for colorectal cancer. Validation studies of algorithms are scarce. When information is available, the performance and choice of an algorithm are dependent on the context, purpose, and location of the planned study. Accounting for cancer disease specificity, the proposed extraction chart is more detailed than the generic chart developed for other REDSIAM taskforces, but remains easily usable in practice. CONCLUSIONS: This study illustrates the complexity of cancer detection through sole reliance on healthcare databases and the lack of validated algorithms specifically designed for this purpose. Studies that standardize and facilitate validation of these algorithms should be developed and promoted. PMID- 28576380 TI - [Study of algorithms to identify schizophrenia in the SNIIRAM database conducted by the REDSIAM network]. AB - BACKGROUND: The aim of the REDSIAM network is to foster communication between users of French medico-administrative databases and to validate and promote analysis methods suitable for the data. Within this network, the working group "Mental and behavioral disorders" took an interest in algorithms to identify adult schizophrenia in the SNIIRAM database and inventoried identification criteria for patients with schizophrenia in these databases. METHODS: The methodology was based on interviews with nine experts in schizophrenia concerning the procedures they use to identify patients with schizophrenia disorders in databases. The interviews were based on a questionnaire and conducted by telephone. RESULTS: The synthesis of the interviews showed that the SNIIRAM contains various tables which allow coders to identify patients suffering from schizophrenia: chronic disease status, drugs and hospitalizations. Taken separately, these criteria were not sufficient to recognize patients with schizophrenia, an algorithm should be based on all of them. Apparently, only one third of people living with schizophrenia benefit from the longstanding disease status. Not all patients are hospitalized, and coding for diagnoses at the hospitalization, notably for short stays in medicine, surgery or obstetrics departments, is not exhaustive. As for treatment with antipsychotics, it is not specific enough as such treatments are also prescribed to patients with bipolar disorders, or even other disorders. It seems appropriate to combine these complementary criteria, while keeping in mind out-patient care (every year 80,000 patients are seen exclusively in an outpatient setting), even if these data are difficult to link with other information. Finally, the experts made three propositions for selection algorithms of patients with schizophrenia. CONCLUSION: Patients with schizophrenia can be relatively accurately identified using SNIIRAM data. Different combinations of the selected criteria must be used depending on the objectives and they must be related to an appropriate length of time. PMID- 28576381 TI - Agreement between hospital discharge diagnosis codes and medical records to identify metastatic colorectal cancer and associated comorbidities in elderly patients. AB - BACKGROUND: Quality of coding to identify cancers and comorbidities through the French hospital diagnosis database (Programme de medicalisation des systemes d'information, PMSI) has been little investigated. Agreement between medical records and PMSI database was evaluated regarding metastatic colorectal cancer (mCRC) and comorbidities. METHODS: From 01/01/2013 to 06/30/2014, 74 patients aged>=65years at mCRC diagnosis were identified in Bordeaux teaching hospital. Data on mCRC and comorbidities were collected from medical records. All diagnosis codes (main, related and associated) registered into the PMSI were extracted. Agreement between sources was evaluated using the percent agreement for mCRC and the kappa (kappa) statistic for comorbidities. RESULTS: Agreement for primary CRC and mCRC was higher using all types of diagnosis codes instead of the main one exclusively (respectively 95% vs. 53% for primary CRC and 91% vs. 24% for mCRC). Agreement was substantial (kappa 0.65) for cardiovascular diseases, notably atrial fibrillation (kappa 0.77) and hypertension (kappa 0.68). It was moderate for psychiatric disorders (kappa 0.49) and respiratory diseases (kappa 0.48), although chronic obstructive pulmonary disease had a good agreement (kappa 0.75). Within the class of endocrine, nutritional and metabolic diseases (kappa 0.55), agreement was substantial for diabetes (kappa 0.91), obesity (kappa 0.82) and hypothyroidism (kappa 0.72) and moderate for hypercholesterolemia (kappa 0.51) and malnutrition (kappa 0.42). CONCLUSION: These results are reassuring with regard to detection through PMSI of mCRC if all types of diagnosis codes are considered and useful to better choose comorbidities in elderly mCRC patients that could be well identified through hospital diagnosis codes. PMID- 28576382 TI - Peripheral venous catheter, a dangerous weapon. Key points to improve its use. AB - Catheter-related bacteremia is one of the most important causes of nosocomial infection. Is associated to high rates of morbidity and mortality, including an economic burden. Peripheral venous catheter bacteremia is a leading cause of nosocomial infection in internal medicine departments. In this article, we review some important key points to improve its use and avoid infections. PMID- 28576384 TI - Interaction of triterpenoids with human serum albumin: A review. AB - Triterpenoids are a large group of natural and synthetic products. This review deals with the current state of knowledge on their interaction with serum albumin. The binding of drugs to albumin may control their distribution in tissues. In literature, different techniques were used to investigate the albumin triterpenoid interaction and include fluorescence spectroscopy, Fourier transform infrared spectroscopy, circular dichroism, calorimetric techniques and molecular modeling. Changes in fluorescence intensity of albumin were observed upon triterpenoid-albumin complex formation. Thermodynamic analyses proved that hydrophobic interactions and hydrogen bonds were the mainly binding forces in triterpenoid-albumin systems. Molecular docking and site marker competitive experimental results revealed that triterpenoids bound to Sudlow's site I of albumin. Furthermore, Fourier transform infrared spectroscopy and circular dichroism spectra analysis indicated that the native conformation of the protein is affected upon binding to triterpenoids. PMID- 28576385 TI - Prognostic value of venous invasion in resected T3 pancreatic adenocarcinoma: Depth of invasion matters. AB - BACKGROUND: Incomplete evaluation of venous invasion has led to conflicting results regarding the prognosis of patients undergoing pancreatectomy with a synchronous venous resection. This study evaluates the prognostic value associated with the presence and the depth of venous invasion in T3 pancreatic adenocarcinoma. METHODS: This study evaluated retrospectively 181 consecutive pancreatoduodenectomies performed for T3N0M0 and T3N1M0 pancreatic adenocarcinomas (stages IIA and IIB) from January 2006 to December 2014. Univariate and multivariate Cox analyses were performed to assess survival prognostic factors. RESULTS: Pancreatoduodenectomies with a segmental venous resection was performed on 91 patients, while 90 other patients had a standard pancreatoduodenectomies without venous resection. Pathologic venous invasion was detected in 68 (74%) of the 91 venous resection patients. Depth of venous invasion was into the adventitia (n = 25), media (n = 28), and intima (n = 15). The overall survival rates at 1, 3, 5, and 10 years were 75%, 33%, 21%, and 6%, respectively. There were no differences in survival between patients undergoing standard pancreatoduodenectomies and pancreatoduodenectomies with venous resection (27 vs 22 months; P = .28) or between patients with and without venous invasion (20 vs 27 months; P = .08). In multivariate analysis, depth of venous invasion into the intima (hazard ratio, 2.25; 95% confidence interval, 1.16-4.34; P = .0001) and adjuvant chemotherapy (hazard ratio, 0.16; 95% confidence interval, 0.09-0.43; P <= .0001) were identified as independent prognostic factors of overall survival. CONCLUSION: Depth of venous invasion into the intima indicates poor survival in pancreatic T3 adenocarcinoma. Preoperative identification of this factor could be helpful for better selection of patients for curative operation. PMID- 28576387 TI - Role of PET/angio-CT in the Evaluation of Intracardiac Devices. PMID- 28576383 TI - Cholesterol metabolism and glaucoma: Modulation of Muller cell membrane organization by 24S-hydroxycholesterol. AB - Glaucoma is a progressive and irreversible blinding neuropathy that is characterized by the loss of retinal ganglion cells (RGCs). Muller Glial Cell (MGC) activation is induced in retinal gliosis. MGCs are the most numerous glial cells in the retina and one of their roles is to sustain cholesterol homeostasis. 24S-hydroxycholesterol (24S-OHC) is one of the form of cholesterol elimination from the retina and is overexpressed during glaucoma. The objective of this study was to determine whether 24S-OHC triggers MGC membrane dynamics involving lipid rafts and contributes to gliosis at early and late time points. A proteomic analysis was carried out by nanoLC-MS/MS in raft and non-raft fractions from MGCs after treatment with 24S-OHC (10MUM). The expression of structural and functional proteins was further analyzed by Western-blotting, as well as the levels of GM3 ganglioside by LC-MS. Cholesterol, sphingomyelin, saturated fatty acids and ganglioside GM3 are enriched in the rafts fractions in MGCs. Caveolin-1, flotillin-1, connexin-30 and -43 are localized in the MGCs rafts. Proteins implicated in adhesion or oxidative stress pathways in raft fractions were up and down-regulated by the treatment. Our data showed that 24S-OHC induced early changes in protein distribution in raft microdomains; however, further studies are needed to better characterize the surrounded mechanisms. PMID- 28576388 TI - Safety and Efficacy of Prasugrel and Ticagrelor in Acute Coronary Syndrome. Results of a "Real World" Multicenter Registry. AB - INTRODUCTION AND OBJECTIVES: The incorporation of the new antiplatelet agents (NAA) prasugrel and ticagrelor into routine clinical practice is irregular and data from the "real world" remain scarce. We aimed to assess the time trend of NAA use and the clinical safety and efficacy of these drugs compared with those of clopidogrel in a contemporary cohort of patients with acute coronary syndromes (ACS). METHODS: A multicenter retrospective observational study was conducted in patients with ACS admitted to coronary care units and prospectively included in the ARIAM-Andalusia registry between 2013 and 2015. In-hospital rates of major cardiovascular events and bleeding with NAA vs clopidogrel were analyzed using propensity score matching and multivariate regression models. RESULTS: The study included 2906 patients: 55% received clopidogrel and 45% NAA. A total of 60% had ST-segment elevation ACS. Use of NAA significantly increased throughout the study. Patients receiving clopidogrel were older and were more likely to have comorbidities. Total mortality, ischemic stroke, and stent thrombosis were lower with NAA (2% vs 9%, P < .0001; 0.1% vs 0.5%, P = .025; 0.07% vs 0.5%, P = .025, respectively). There were no differences in the rate of total bleeding (3% vs 4%; P = NS). After propensity score matching, the mortality reduction with NAA persisted (OR, 0.37; 95%CI, 0.13 to 0.60; P < .0001) with no increase in total bleeding (OR, 1.07; 95%CI, 0.18 to 2.37; P = .094). CONCLUSIONS: In a "real world" setting, NAA are selectively used in younger patients with less comorbidity and are associated with a reduction in major cardiac events, including mortality, without increasing bleeding compared with clopidogrel. PMID- 28576386 TI - [Identification of alloantibodies and their associations: Balance sheet of 3 years at the Regional Center of Blood Transfusion in Rabat/Morocco and difficult in transfusion management]. AB - : Red blood cell immunization can lead to delays or even an impasse in a transfusion. OBJECTIVES: Determine the specificities of the most common of alloantibodies and their associations to correct management of red blood cell transfused. METHODS AND MATERIALS: A retrospective study between 2013 and 2015 in immunohematology laboratories at the Blood Transfusion Center of Rabat in Morocco. The following data were studied: frequency, specificities of alloantibodies, blood group involved in alloimmunization and difficult of management of transfusion in case with association of alloantibodies. RESULTS: Five hundred of alloantibodies were identified in 425 people (372 patients/pregnant women and 53 blood donors). The alloantibodies were directed against the following antigen: RH1 (50.8 %), RH3 (11.4 %), KEL 1 (8.2 %), RH2 (7.6 %), RH4 (4.6 %), MNS1 (4 %), MNS3 (2.6 %), Jka (2.4 %) and Fya (2.2 %). Only one alloantibody was identified in 85 % of cases. In 15 %, at least, two alloantibodies were found. The most common associations were directed against: anti-(D+C) (25), anti-(E+K) (4), anti-(E+c) (3) and anti-(D+C+E) (3). The rhesus system is the most involved in alloimmunization. Frequency of specific associations of alloantibodies was identified: Fya-/Jkb- (18.23 %), Fyb-/Jkb- (11.7 %), Jka-/S- (8.70 %), Jka-/Fyb- (5.20 %), Fyb-/s- (3.40 %) and Fyb-/Jkb-/s- (0.85 %). CONCLUSIONS: Red blood cell immunization is a serious problem in transfused patients. This study proves the data of literature, the interest of using RH-Kel1 red cell units compatibles among women in age to procreate and for the transfused patients to reduce the rate of immunization. Associations of antibodies with low frequency suggest a promotion of donation. PMID- 28576389 TI - Healthcare utilization in adults with opioid dependence receiving extended release naltrexone compared to treatment as usual. AB - BACKGROUND: Opioid use disorders have reached epidemic proportions, with overdose now the leading cause of accidental death in the United States. Extended release naltrexone (XR-NTX) has emerged as a medication treatment that reduces opioid use and craving. However, the effect of XR-NTX therapy on acute healthcare utilization, including emergency department visits and inpatient hospitalizations, remains uncertain. The objective of the current study is to evaluate hospital-based healthcare resource utilization in adults involved in the criminal justice system with a history of opioid use disorder randomized to XR NTX therapy compared with treatment as usual (TAU) during a 6-month treatment phase and 12months post-treatment follow up. METHODS: This retrospective exploratory analysis uses data collected in a published randomized trial. Comparisons of the number of emergency department visits and hospital admissions (for drug detox, psychiatric care and other medical reasons) were performed using chi square tests for any admission and negative binomial models for number of admissions. RESULTS: Of the 308 participants randomized, 96% had utilization data (76% complete 6months, 67% complete follow up). No significant differences were seen in overall healthcare utilization (IRR=0.88, 95%CI 0.63-1.23, p=0.45), or substance use-related drug detox hospitalizations (IRR=0.83, 95%CI 0.32-2.16, p=0.71). Despite having more participants report chronic medical problems at baseline (43% vs. 32%, p=0.05), those receiving XR-NTX generally experienced equivalent or lower rates of healthcare utilization compared to TAU. The XR-NTX group had significantly lower medical/surgical related hospital admissions (IRR=0.55, 95%CI 0.30-1.00, p=0.05) during the course of the entire study. CONCLUSIONS: XR-NTX did not significantly increase rates of healthcare utilization compared to TAU. Provider concerns regarding healthcare utilization should not preclude the consideration of XR-NTX as therapy for opioid use disorders. PMID- 28576390 TI - Genetic basis of eugonadal and hypogonadal female reproductive disorders. AB - This review discusses the current state of our understanding regarding the genetic basis of the most important reproductive disorders in women. For clarity, these disorders have been divided into eugonadal and hypogonadal types. Hypogonadal disorders have been further subdivided according to serum gonadotropin levels. Our review focuses on historical and recent data regarding the genetics of the hypothalamic-pituitary-gonadal axis dysfunction, as well as the development and etiology of eugonadal disorders including leiomyomata, endometriosis, spontaneous ovarian hyperstimulation syndrome, polycystic ovarian syndrome, mullerian aplasia, and steroid hormone resistance syndromes. We discuss the known genes most commonly involved in hypergonadotropic hypogonadism (Turner syndrome and premature ovarian failure) and hypogonadotrophic hypogonadism (Kallmann syndrome and normosmic types). In addition, we summarize the current clinical testing approaches and their utility in practical application. PMID- 28576391 TI - Perceptions and use of the e-cigarette among university students. PMID- 28576393 TI - Diffuse gastric metastases from salivary duct carcinoma. PMID- 28576392 TI - Enzymatic tailoring of oleuropein from Olea europaea leaves and product identification by HRMS/MS spectrometry. AB - Oleuropein, a bioactive compound found in all parts of olive tree, especially in leaves and branches, presents numerous health promoting properties that increase research and market interest the last few years. In addition, oleuropein degradation products, such as hydroxytyrosol, elenolic acid, and the aglycones also exhibit biological activities with different properties compared to the starting compound. Under this view, a commercial lipase preparation Lipolase 100L and a thermophilic beta-glucosidase from Myceliophthora thermophila were used for the regioselective hydrolysis of oleuropein towards the production of the corresponding biologically active compounds. The enzymatic degradation products of oleuropein, such as hydroxytyrosol, elenolic acid and its glucoside, and oleuropein aglycones were identified by LC-HRMS/MS and NMR spectroscopy. The latter, was found as a mix of diastereomers of the monoaldehydic form of oleuropein aglycone, identified as (5S, 8R, 9S)-, (5S, 8S, 9S)- and (5S, 8R, 9R). The high substrate specificity exhibited by both lipase and beta-glucosidase allows the successful tailoring of oleuropein towards the production of different biologically active compounds with significant potential in the cosmeceutical and food industry. PMID- 28576394 TI - Cronkhite-Canada syndrome. PMID- 28576395 TI - Successful endoscopic submucosal dissection for superficial esophageal cancer on solitary esophageal varix. PMID- 28576396 TI - Hymenolepis nana infection detected by magnifying colonoscopy with narrow-band imaging (with video). PMID- 28576397 TI - The contribution of clinical and pathological predisposing factors to severe gastro-duodenal lesions in patients with long-term low-dose aspirin and proton pump inhibitor therapy. AB - BACKGROUND: Preventive strategies developed to avoid the complications of antiplatelet therapies recommend the evaluation of risk factors for gastrointestinal events and indicated gastroprotective strategies. AIM: We aimed to assess the impact of predisposing factors - histological findings, concomitant drug consumption, comorbidities, symptoms, social habits, Helicobacter pylori infection - on severe gastro-duodenal lesions in patients with low-dose aspirin and concomitant protective therapy with proton pump inhibitors (PPI). METHOD: We enrolled 237 patients with LDA and PPI therapy, referred for upper digestive endoscopy, divided into two groups according to the severity of their endoscopic lesions (172 patients with no or mild endoscopic lesions and 65 patients with severe endoscopic lesions). RESULTS: In the univariate logistic regression model, the factors associated with severe gastro-duodenal lesions were gender (OR=1.87, 95% CI: 1.04-3.41), anticoagulants (OR=2.40, 95% CI: 1.26-4.53), gastric atrophy and/or intestinal metaplasia (OR=1.85, 95% CI: 1.04-3.32), congestive heart failure (OR=2.59, 95% CI: 1.16-6.62), anaemia (OR=3.01, 95% CI: 1.67-5.47) and smoking (OR=4.29, 95% CI: 1.57-12.32). In the final model, anticoagulants (p=0.041<0.05) and anaemia (p=0.019<0.05) were risk factors for severe lesions via multivariate regression analysis, while for active/inactive chronic gastritis and smoking a positive dependency with a tendency towards statistical significance (p<0.10) was noticed for severe gastric lesions. CONCLUSIONS: In patients treated with low-dose aspirin and gastroprotective therapy with proton pump inhibitors we have enough evidence to consider co-treatment with anticoagulants and anaemia important predictors for severe endoscopic lesions, while other factors such as inflammation in gastric biopsies, congestive heart failure, co-treatment with clopidogrel and smoking tended to have a positive influence on risk for severe gastro-duodenal lesions. PMID- 28576398 TI - Characterization of circadian COPD symptoms by phenotype: Methodology of the STORICO observational study. AB - Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. The symptoms of COPD are troublesome, variable, can occur during all parts of the 24-h day and have a substantial impact on patients' health status, quality of life and healthcare resource utilization. Reducing symptoms, improving health status and increasing physical activity are major goals in the management of stable COPD. In order to provide effective, patient-oriented care, patients should be evaluated on the basis of lung function, frequency of symptoms and patient-perceived impact of symptoms on their lives and treatment decisions made on a case-by-case basis. The identification of COPD phenotypes is an evolving debate and literature data about the circadian variation of COPD symptoms according to phenotypes are nowadays lacking. The ongoing STORICO (STudio Osservazionale sulla caratteRizzazione dei sIntomi delle 24 ore nei pazienti con BPCO) study (NCT03105999) is aimed to describe by clinically defined phenotypes the frequency and 12-month evolution of early-morning, day- and night-time COPD symptoms in a cohort of 600 Italian patients with stable COPD. Secondary objectives include the description of the 12 month variation of outcomes of interest according to phenotypes and of the healthcare resources utilization (overall and by phenotype) during 12-month observation. An exploratory analysis will be conducted aimed to phenotype COPD patients in an alternative researcher-independent way based on circadian pattern of symptoms combined with measures of respiratory function, health-related quality of life and comorbidity. The present paper describes the methodology of the STORICO study. PMID- 28576400 TI - Innovation in pediatric clinical trials: The need to rethink the end-point. PMID- 28576399 TI - Weather is not significantly correlated with destination-specific transport related physical activity among adults: A large-scale temporally matched analysis. AB - Weather is an element of the natural environment that could have a significant effect on physical activity. Existing research, however, indicates only modest correlations between measures of weather and physical activity. This prior work has been limited by a failure to use time-matched weather and physical activity data, or has not adequately examined the different domains of physical activity (transport, leisure, occupational, etc.). Our objective was to identify the correlation between weather variables and destination-specific transport-related physical activity in adults. Data were sourced from the California Household Travel Survey, collected in 2012-3. Weather variables included: relative humidity, temperature, wind speed, and precipitation. Transport-related physical activity (walking) was sourced from participant-recorded travel diaries. Three part hurdle models were used to analyze the data. Results indicate statistically or substantively insignificant correlations between the weather variables and transport-related physical activity for all destination types. These results provide the strongest evidence to date that transport-related physical activity may occur relatively independently of weather conditions. The knowledge that weather conditions do not seem to be a significant barrier to this domain of activity may potentially expand the universe of geographic locations that are amenable to environmental and programmatic interventions to increase transport related walking. PMID- 28576401 TI - [Blood pressure values in adolescents in the Community of Madrid: Tables based on the MEPAFAC Study]. AB - INTRODUCTION: High blood pressure (HBP) is a modifiable cardiovascular risk factor and its detection at early ages may allow strategies to be designed to reduce cardiovascular risk in adulthood. OBJECTIVES: To provide blood pressure (BP) values in a sample of adolescents using an electronic oscillometric device. MATERIAL AND METHODS: BP was measured according the European Society of Hypertension guidelines using an oscillometric device. Height and weight were also measured. Four height groups were used in order to associate the 90, 95, and 99 percentiles with systolic BP (pSBP) and diastolic BP percentiles (pDBP) for sex and age: H150 (<= 150cm), H160(151-160cm), H170(161-170cm), and H180(>=171cm). RESULTS: Data from 2,758 students aged 12-17 years were included in the analysis. BP increases with age, with differences of up to 11mmHg in boys vs. 3mmHg in girls for SBP and 3mmHg vs. 1mmHg for DBP. In high SBP, for the younger adolescents, the difference related to height was 15mmHg in boys vs. 8mmHg in girls, with no significant increase in the older ones in either gender. The high BDP varied depending on the height, 10mmHg in younger boys and 3mmHg in older ones, while in girls the variation was 3mmHg for all ages. CONCLUSIONS: SBP/DBP in adolescents increases with age and also with height, giving similar figures in the taller ones, regardless of age. PMID- 28576402 TI - [Anterior lamellar resection with lid margin split of the upper eyelid in the treatment of trachomatous entropion]. AB - INTRODUCTION: The goal of this study is to assess functional and aesthetic results of anterior lamellar resection with lid margin splitting of the upper lid in the treatment of cicatricial trachomatous entropion. PATIENTS AND METHODS: Descriptive cross-sectional study of a series of 26 consecutive patients treated between January 2014 and December 2015. All patients were operated for cicatricial trachomatous entropion in our tertiary center using the technique of the anterior lamellar resection with lid margin splitting of the upper eyelid. All patients were followed for 6 to 12 months after surgery. The anatomical, functional and aesthetic results were evaluated six months after surgery. They were considered good if there was no recurrence of the entropion, no lashes in contact with the cornea and no associated eyelid complications. RESULTS: The mean age of the patients was 68.5+/-10 years with a male predominance (sex ratio=1.8). The average initial corrected visual acuity was 0.65+/-0.35 LogMAR, ranging from counting fingers at 1m to 6/10. Involvement was bilateral in 34.6% of cases. Correction of the cicatricial entropion was achieved in 24 patients (92.3% of cases) and full correction of misdirected lashes without any contact with the ocular surface was obtained in 23 patients (88.4% of cases). The lid margin was regular in 88.4% of cases. A significant improvement of the tear film and corneal surface was observed in 84.6% of patients. During the follow-up period, no cases of recurrent entropion were reported. DISCUSSION: Among the various surgical techniques, anterior lamellar resection with lid margin splitting is one that most respects the anatomy of the upper eyelid and allows precise intraoperative control of eyelid rotation and eversion of the misdirected lashes. Therefore, it reduces significantly the risk of recurrence and significantly enhances the aesthetic results of surgery. CONCLUSION: Anterior lamellar resection with lid margin splitting of the upper eyelid is a simple and effective technique that significantly improves the aesthetic result of cicatricial trachomatous entropion. PMID- 28576403 TI - [Phacoemulsification versus manual small incision cataract surgery: Anatomic and functional results]. AB - PURPOSE: Prospective randomised study to compare the impact of phacoemusification (PHACO) and small incision cataract surgery (SICS) on endothelial structure (cell density and morphology) and refractive results (visual acuity, induced astigmatism). METHODS: Prospective study of 57 patients (63 eyes) over 20 months (May 2012-January 2014) undergoing surgery by 2 experienced surgeons. We included patients with senile or presenile cataracts, LOCS III class 2, 3 and 4. Patients were randomized into 2 groups based on their birth month (group 1: PHACO [33]; group 2: SICS [30]). All pre- intra- and postoperative data were collected prospectively. The minimum follow-up was 6 months. We used the SPSS 18.0 for statistical analysis. Statistical tests used included the test-t Student, the Anova test, the Mann-Witney non-parametric test and the Khi2 test. A threshold of significance was set at 0.05. RESULTS: The mean preoperative endothelial cell density was 2447.5+/-225 c/mm2 with no significant difference between the two groups (P=0.207). The mean percentage of hexagonality was 55.5+/-8.2% in groups 1 and 2. The most significant cell loss was during the first immediate postoperative period for both groups. At Day 15 postoperative, the decrease in cell loss was significant (P<0.001) with a mean loss of 312.9+/-208.9 c/mm2 (P<10 2). Postoperatively, the mean best-corrected visual acuity was 0.057 log MAR for all of our patients (P=0.170); no patient had an acuity <=1/10. The mean astigmatism at the conclusion of follow-up was 1.08+/-0.42 D in group 1 and 1.51+/-0.55 D in group 2, with a significant difference (P=0.001). CONCLUSION: Both SICS and PHACO give excellent results, both anatomical and refractive. However, SICS appears to be more advantageous than PHACO in terms of speed, cost, and independence from technology, and appears to be better suited to dense cataracts and mass surgery. PMID- 28576404 TI - Attenuated diuresis and natriuresis in response to glucagon-like peptide-1 in hypertensive rats are associated with lower expression of the glucagon-like peptide-1 receptor in the renal vasculature. AB - Accumulating evidence from clinical and experimental studies indicates that the incretin glucagon-like peptide-1 (GLP-1) elicits blood-pressure lowering effects via its diuretic, natriuretic and vasodilatory properties. The present study investigated whether acute infusion of GLP-1 induces diuresis and natriuresis in spontaneously hypertensive rats (SHRs). Additionally, we examined whether GLP-1 influences the vascular reactivity of the renal arteries of normotensive and hypertensive rats and elucidated the underlying mechanisms. We found that the increase in urinary output and urinary sodium excretion in response to systemic infusion of GLP-1 for 30min in SHRs was much less pronounced than in normotensive rats. The diuretic and natriuretic actions of GLP-1 in normotensive rats were accompanied by increases in GFR and RBF and a reduction in RVR through activation of the cAMP signaling pathway. However, no changes in renal hemodynamics were observed in SHRs. Similarly, GLP-1 induced an endothelium-independent relaxation effect in the renal arteries of normotensive rats, whereas the renal vasculature of SHRs was unresponsive to this vasodilator. The absence of a GLP-1-induced renal artery vasodilator effect in SHRs was associated with lower expression of the GLP-1 receptor, blunted GLP-1-induced increases in cAMP production and higher activity and expression of the GLP-1 inactivating enzyme dipeptidyl peptidase IV relative to the renal arteries of normotensive rats. Collectively, these results demonstrate that the renal acute responses to GLP-1 are attenuated in SHRs. Thus, chronic treatment with incretin-based agents may rely upon the upregulation of GLP-1/GLP-1 receptor signaling in the kidneys of hypertensive patients and experimental models. PMID- 28576405 TI - Protective effects of Donepezil against endothelial permeability. AB - The endothelium lines the interior surface of blood vessels, and under pathophysiologic conditions, its integrity can be compromised due to a disturbance in the expression of tight junctions. Donepezil is a licensed drug used in the palliative treatment of Alzheimer's disease (AD). Increasing evidence has reported that donepezil has an anti-inflammatory activity. However, little information is available regarding the role of donepezil in vascular diseases. In this study, we found that pretreatment with donepezil significantly ameliorated endothelial permeability induced by tumor necrosis factor (TNF-alpha) by restoring the expression of the tight junction proteins vascular endothelial cadherin (VE-cadherin) and zonula occludens-1 (ZO-1) in human umbilical vein endothelial cells (HUVECs). Mechanistically, our results indicate that donepezil regulates the expression and activity of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1), but not matrix metalloproteinase-2 (MMP-2) or tissue inhibitor of metalloproteinases 2 (TIMP-2). Importantly, the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/ serine threonine kinase (AKT)/ nuclear factor kappa B (NF-kappaB) pathway was found to be involved in this process. These results suggest that donepezil may potentially play an important therapeutic role in vascular diseases. PMID- 28576406 TI - Puerarin promotes ABCA1-mediated cholesterol efflux and decreases cellular lipid accumulation in THP-1 macrophages. AB - It was reported that puerarin decreases the total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) and increases high-density lipoprotein cholesterol (HDL-C) level, but the underlying mechanism is unclear. This study was designed to determine whether puerarin decreased lipid accumulation via up-regulation of ABCA1-mediated cholesterol efflux in THP-1 macrophage-derived foam cells. Our results showed that puerarin significantly promoted the expression of ATP-binding cassette transporter A1 (ABCA1) mRNA and protein via the AMP-activated protein kinase (AMPK)-peroxisome proliferator activated receptor gamma (PPARgamma)-liver X receptor-alpha (LXR-alpha) pathway and decreased cellular lipid accumulation in human THP-1 macrophage-derived foam cells. The miR-7 directly targeted 3' untranslated region of STK11 (Serine/Threonine Kinase 11), which activated the AMPK pathway. Transfection with miR-7 mimic significantly reduced STK11 expression in puerarin-treated macrophages, decreased the phosphorylation of AMPK, down-regulated the expression of the PPARgamma-LXR-alpha-ABCA1 expression. Additionally, treatment with miR-7 decreased cholesterol efflux and increased cholesterol levels in THP-1 macrophage derived foam cells. Our study demonstrates that puerarin promotes ABCA1-mediated cholesterol efflux and decreases intracellular cholesterol levels through the pathway involving miR-7, STK11, and the AMPK-PPARgamma-LXR-alpha-ABCA1 cascade. PMID- 28576407 TI - RP5063, a novel, multimodal, serotonin receptor modulator, prevents Sugen 5416 hypoxia-induced pulmonary arterial hypertension in rats. AB - RP5063, a multimodal dopamine (DA) and serotonin (5-HT) modulator with high affinity for DA2/3/4 and 5-HT2A/2B/7 receptors and moderate affinity for SERT, is a novel therapeutic of special interest in the treatment of pulmonary arterial hypertension (PAH). Evidence indicates that therapeutics targeting the 5-HT2A/2B receptors can influence the pathogenesis of PAH. However, the therapeutic effect of RP5063 in humans has yet to be investigated. A Sugen 5416-hypoxia (SuHx) induced PAH model was used to evaluate twice-daily (b.i.d.) RP5063 at 10mg/kg (RP 10) and 20mg/kg (RP-20), as compared with positive (sildenafil 50mg/kg b.i.d.; Sil-50) and negative controls (SuHx+vehicle; SuHx+veh), in 24 adult male Wistar Kyoto rats. RP5063 showed significantly lower systolic pulmonary arterial (both doses) and systolic right ventricular (RP-10) pressures, and improvement in oxygen saturation (RP-20). It significantly reduced small-vessel wall thickness (RP-20), lowered the percentage of muscular vessels (both doses). Both doses limited arterial obliteration due to endothelial cell proliferation, prevented plexiform lesion formation, and stemmed the release of leukotriene B4. Sildenafil showed statistically greater effects on vessel structure than that seen in both RP5063 groups and improved oxygen saturation. Additionally, Sildenafil did not demonstrate any significant effect on arterial obliteration, plexiform lesion development, or pulmonary arterial or right ventricular pressure. As PAH gains in severity, the impact of RP5063 inhibition of 5HT2B increases, preventing arterial constriction and improving pulmonary hemodynamics. Due to its functional, structural, and chemokine effects, RP5063 represents a promising candidate for investigation in late-phase PAH. PMID- 28576408 TI - Browning effects of (-)-epicatechin on adipocytes and white adipose tissue. AB - In this study, we demonstrate that (-)-epicatechin (Epi), a cacao flavanol, induces the browning of fat by promoting mitochondrial biogenesis, enhancing indicators of mitochondrial structure and function, increasing fatty acid metabolism and upregulating the expression of brown adipose tissue-specific proteins in a high-fat diet mouse model of obesity and in cultured human adipocytes. Epi treatment significantly improved mitochondrial function, as measured by citrate synthase activity, and also reduced protein acetylation of total and specific regulators in both adipose tissue and human adipocytes. Browning of fat via Epi was evidenced by the increased expression of key thermogenic genes, phosphorylation of upstream regulators of fatty acid oxidation, and reduced triglyceride levels. Properly designed clinical trials are needed to explore the potential of Epi as an agent that promotes the browning of fat. PMID- 28576409 TI - Phosphoproteome and transcription factor activity profiling identify actions of the anti-inflammatory agent UTL-5g in LPS stimulated RAW 264.7 cells including disrupting actin remodeling and STAT-3 activation. AB - UTL-5g is a novel small-molecule TNF-alpha modulator. It reduces cisplatin induced side effects by protecting kidney, liver, and platelets, thereby increasing tolerance for cisplatin. UTL-5g also reduces radiation-induced acute liver toxicity. The mechanism of action for UTL-5g is not clear at the present time. A phosphoproteomic analysis to a depth of 4943 phosphopeptides and a luminescence-based transcription factor activity assay were used to provide complementary analyses of signaling events that were disrupted by UTL-5g in RAW 264.7 cells. Transcriptional activity downstream of the interferon gamma, IL-6, type 1 Interferon, TGF-beta, PKC/Ca2+ and the glucocorticoid receptor pathways were disrupted by UTL-5g. Phosphoproteomic analysis indicated that hyperphosphorylation of proteins involved in actin remodeling was suppressed by UTL-5g (gene set analysis, FDR < 1%) as was phosphorylation of Stat3, consistent with the IL-6 results in the transcription factor assay. Neither analysis indicated that LPS-induced activation of the NF-kB, cAMP/PKA and JNK signaling pathways were affected by UTL-5g. This global characterization of UTL-5g activity in a macrophage cell line discovered that it disrupts selected aspects of LPS signaling including Stat3 activation and actin remodeling providing new insight on how UTL-5g acts to reduce cisplatin-induced side effects. PMID- 28576410 TI - Phenylpyrrolidine structural mimics of pirfenidone lacking antifibrotic activity: A new tool for mechanism of action studies. AB - Pirfenidone recently received FDA approval as one of the first two drugs designed to treat idiopathic pulmonary fibrosis. While the clinical data continues to support the efficacy of pirfenidone, the specific molecular mechanism of action of this drug has not been fully defined. From a chemical perspective the comparatively simple and lipophilic structure of pirfenidone combined with its administration at high doses, both experimentally and clinically, complicates some of the basic tenants of drug action and drug design. Our objective here was to identify a commercially available structural mimic of pirfenidone which retains key aspects of its physical chemical properties but does not display any of its antifibrotic effects. We tested these molecules using lung fibroblasts derived from patients with idiopathic pulmonary fibrosis and found phenylpyrrolidine based analogs of pirfenidone that were non-toxic and lacked antifibrotic activity even when applied at millimolar concentrations. Based on our findings, these molecules represent pharmacological tools for future studies delineating pirfenidone's mechanism of action. PMID- 28576411 TI - Postnatal hyperoxia or DEHP exposure leads to growth restriction and delayed lung development in newborn rats. AB - BACKGROUND: Di-(2-ethylhexyl) phthalate (DEHP) is commonly used as a plasticizer in many medical devices. We previously showed that maternal DEHP exposure led to restricted growth and delayed lung maturation in newborn rats. As oxygen toxicity continues to be a major risk factor for bronchopulmonary dysplasia, the aim of this study was to examine the effect of hyperoxia, DEHP or DEHP combined with hyperoxia on the growth and lung maturation of newborn rats. METHODS: Newborn rats received DEHP injection, hyperoxia exposure or DEHP injection combined with hyperoxia exposure for one week or two weeks. A control group received an equal volume of vehicle and was maintained in room air. RESULTS: Hyperoxia and hyperoxia + DEHP exposure for one week led to growth failure in newborn rats. Pups in the hyperoxia group showed catch-up growth after being maintained in room air for an additional 7 days but this was not the case with the latter group, which continued to receive DEHP. Hyperoxia and DEHP both delayed lung development, as evidenced by decreased radial alveolar count. Quantitative RT-PCR showed that hyperoxia decreased the transcripts of VEGF, VEGFR-2 and eNOS on days 7 and 14, and DEHP exposure alone also led to decreased expression of VEGF gene in 14-day-old rat pups. CONCLUSION: Postnatal hyperoxia and/or DEHP exposure lead to growth restriction and delayed lung alveolar development. The VEGF gene expression was altered and may be involved as one of the possible molecular mechanisms. PMID- 28576412 TI - Test-retest reliability of the magnetic mismatch negativity response to sound duration and omission deviants. AB - Mismatch negativity (MMN) is a neurophysiological measure of auditory novelty detection that could serve as a translational biomarker of psychiatric disorders, such as schizophrenia. However, the replicability of its magnetoencephalographic (MEG) counterpart (MMNm) has been insufficiently addressed. In the current study, test-retest reliability of the MMNm response to both duration and omission deviants was evaluated over two MEG sessions in 16 healthy adults. MMNm amplitudes and latencies were obtained at both sensor- and source-level using a cortically-constrained minimum-norm approach. Intraclass correlations (ICC) were derived to assess stability of MEG responses over time. In addition, signal-to noise ratios (SNR) and within-subject statistics were obtained in order to determine MMNm detectability in individual participants. ICC revealed robust values at both sensor- and source-level for both duration and omission MMNm amplitudes (ICC = 0.81-0.90), in particular in the right hemisphere, while moderate to strong values were obtained for duration MMNm and omission MMNm peak latencies (ICC = 0.74-0.88). Duration MMNm was robustly identified in individual participants with high SNR, whereas omission MMNm responses were only observed in half of the participants. Our data indicate that MMNm to unexpected duration changes and omitted sounds are highly reproducible, providing support for the use of MEG-parameters in basic and clinical research. PMID- 28576413 TI - SISSY: An efficient and automatic algorithm for the analysis of EEG sources based on structured sparsity. AB - Over the past decades, a multitude of different brain source imaging algorithms have been developed to identify the neural generators underlying the surface electroencephalography measurements. While most of these techniques focus on determining the source positions, only a small number of recently developed algorithms provides an indication of the spatial extent of the distributed sources. In a recent comparison of brain source imaging approaches, the VB-SCCD algorithm has been shown to be one of the most promising algorithms among these methods. However, this technique suffers from several problems: it leads to amplitude-biased source estimates, it has difficulties in separating close sources, and it has a high computational complexity due to its implementation using second order cone programming. To overcome these problems, we propose to include an additional regularization term that imposes sparsity in the original source domain and to solve the resulting optimization problem using the alternating direction method of multipliers. Furthermore, we show that the algorithm yields more robust solutions by taking into account the temporal structure of the data. We also propose a new method to automatically threshold the estimated source distribution, which permits to delineate the active brain regions. The new algorithm, called Source Imaging based on Structured Sparsity (SISSY), is analyzed by means of realistic computer simulations and is validated on the clinical data of four patients. PMID- 28576414 TI - Is urodynamic evaluation a must in all operated cases of open neural tube defects. AB - BACKGROUND: Spina bifida is a common cause of pediatric neurogenic bladder. It causes renal failure in almost 100% of patients if the associated detrusor sphincter dyssynergia (DSD) is inadequately managed. Detrusor instability and high detrusor pressures (Figure) have been implicated as the major factors predictive of renal damage in these patients. Urodynamic studies provide early identification of "at risk" kidneys so that appropriate intervention can be made. However, the role in post-operative patients of spina bifida who have no clinical manifestations remains unclear. OBJECTIVE: To study the bladder dynamics in asymptomatic post-operative patients of spina bifida and to determine whether routine urodynamic study is justifiable. MATERIAL AND METHODS: Urodynamics was performed on 15 operated patients of spina bifida who did not have any neurological deficit and were asymptomatic. RESULTS: The mean age of the patients was 4.97 years. None of the patients had any urological complaints with their ultrasonography being normal. None had scars on nuclear scan. Of the 15 patients, 12 (80%) had abnormal findings on urodynamic assessment. Three patients (20%) had detrusor pressures greater than 40 cm of H2O. One patient had significant residual urine and detrusor instability. DISCUSSION: The use of urodynamic studies in asymptomatic patients of spina bifida remains controversial, with one school of thought advocating early invasive urodynamic testing. In contrast, some favor noninvasive sonological monitoring, reserving invasive tests only for patients with renal tract dilatation. In our subset of patients none had renal tract dilatation but three patients (20%) had "at risk" bladders. These patients would benefit from early intervention aimed at renal preservation. The study is limited by a small sample size because of the relative rarity of the patient profile included. A further multicenter study with a case-control design could conclusively indicate the role of urodynamic testing in these patients. CONCLUSION: Patients of spina bifida, even when asymptomatic, have a high incidence of unsafe bladders. Early identification and appropriate measures can protect kidneys from long-term damage, hence urodynamic profiling is mandatory for identification of potentially high-risk bladders. PMID- 28576415 TI - Stem cell contributions to neurological disease modeling and personalized medicine. AB - Human induced pluripotent stem cells (iPSCs) represent a revolutionary tool for disease modeling and drug discovery. The generation of tissue-relevant cell types exhibiting a patient's genetic and molecular background offers the ability to develop individual and effective therapies. In this review, we present some major achievements in the neuroscience field using iPSCs and discuss promising perspectives in personalized medicine. In addition to disease modeling, the understanding of the cellular and molecular basis of neurological disorders is explored, including the discovery of new targets and potential drugs. Ultimately, we highlight how iPSC technology, together with genome editing approaches, may bring a deep impact on pre-clinical trials by reducing costs and increasing the success of treatments in a personalized fashion. PMID- 28576416 TI - Tools for Predicting Clinical and Patient-reported Outcomes in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: A Systematic Review of Prognostic Accuracy and Validity. AB - Androgen deprivation therapy (ADT) can result in a range of adverse symptoms that reduce patients' quality of life. Careful patient counseling on the likely clinical outcomes and adverse effects is therefore vital. The present systematic review was undertaken to identify and characterize all the tools used for the prediction of clinical and patient-reported outcome measures (PROMs) in patients with prostate cancer undergoing ADT. PubMed and EMBASE were systematically searched from 2007 to 2016. Search terms related to the inclusion criteria were: prostate cancer, clinical outcomes, PROMs, ADT, and prognosis. Titles and abstracts were reviewed to find relevant studies, which were advanced to full text review. The reference lists were screened for additional studies. The Centre for Evidence Based Medicine critical appraisal of prognostic studies tool was applied. The search strategy identified 8755 studies. Of the 8755 studies, 22 on clinical outcomes were identified. However, no studies of PROMs were found. Nine tools could be used to predict clinical outcomes in treatment-naive patients and 10 in patients with recurrence. The Japan Cancer of the Prostate Risk Assessment (J-CAPRA) nomogram was the best performing and validated tool for the prediction of clinical outcomes in treatment-naive patients, and the Chi and Shamash prognostic indexes have been validated for use in patients with castration resistant disease in different clinical contexts. Using the J-CAPRA nomogram should help clinicians deliver accurate, evidence-based counseling to patients undergoing primary ADT. A strong need exists for primary studies that derive and validate tools for the prediction of PROMs in patients undergoing ADT under any circumstance because these are currently absent from the literature. PMID- 28576417 TI - Low concentrations of neutrophil extracellular traps induce proliferation in human keratinocytes via NF-kB activation. AB - INTRODUCTION: Granulocytes play a pivotal role in innate immune response, as pathogen invasion activates neutrophils, a subclass of granulocytes, inducing the production of neutrophil extracellular traps (NETs). In this study, it has been evaluated how NETs could affect human keratinocytes (HaCaT cells) behaviour. MATERIALS AND METHODS: HaCaT cells were treated with increasing NETs concentrations (0.01-200ng/ml) and the effect on cell proliferation was evaluated by MTT assay. Inhibition studies were performed by pre-treating cells with dexamethasone, chloropromazine or amiloride. NF-kB pathway activation was evaluated by western blot. RESULTS: HaCaT cells stimulation with increasing concentrations of NETs (0.01-50ng/ml) for 48h resulted in a modulation of cell proliferation with a maximum increase corresponding to 0.5-1ng/ml stimulation. NETs low concentrations not only increased cell proliferation, but were also able to induce a faster wound closure in an in vitro scratch assay. NETs scaffold, composed by histone proteins and DNA, is recognized by Toll Like Receptor 9 (TLR 9) that, in turn, activates the NF-kB pathway. In fact, NETs induced proliferation was inhibited by chloropromazine (1nM), that blocks chlatrin vesicles formation, and by amiloride (50nM) that inhibits macropinocytosis. Moreover, dexamethasone, an inhibitor of NF-kB, was able to abolish the NETs effect. DISCUSSION: This study thus demonstrates that low NETs concentrations undergo internalization finally resulting in a quick NF-kB pathway activation and HaCaT cells proliferation increase, suggesting a close relationship between first immune response and wound healing onset. PMID- 28576419 TI - Crash risk analysis during fog conditions using real-time traffic data. AB - This research investigates the changes of traffic characteristics and crash risks during fog conditions. Using real-time traffic flow and weather data at two regions in Florida, the traffic patterns at the fog duration were compared to the traffic patterns at the clear duration. It was found that the average 5-min speed and the average 5-min volume were prone to decreasing during fog. Based on previous studies, a "Crash Risk Increase Indicator (CRII)" was proposed to explore the differences of crash risk between fog and clear conditions. A binary logistic regression model was applied to link the increase of crash risks with traffic flow characteristics. The results suggested that the proposed indicator worked well in evaluating the increase of crash risk under fog condition. It was indicated that the crash risk was prone to increase at ramp vicinities in fog conditions. Also, the average 5-min volume during fog and the lane position are important factors for crash risk increase. The differences between the regions were also explored in this study. The results indicated that the locations with heavier traffic or locations at the lanes that were closest to the median in Region 2 were more likely to observe an increase in crash risks in fog conditions. It is expected that the proposed indicator can help identify the dangerous traffic status under fog conditions and then proper ITS technologies can be implemented to enhance traffic safety when the visibility declines. PMID- 28576418 TI - A Methyl-Balanced Diet Prevents CRF-Induced Prenatal Stress-Triggered Predisposition to Binge Eating-like Phenotype. AB - Binge eating (BE) is a common aberrant form of eating behavior, characterized by overconsumption of food in a brief period of time. Recurrent episodes of BE constitute the BE disorder, which mostly affects females and is associated with early-life adversities. Here, we show that corticotropin releasing factor (CRF) induced prenatal stress (PNS) in late gestation predisposes female offspring to BE-like behavior that coincides with hypomethylation of hypothalamic miR-1a and downstream dysregulation of the melanocortin system through Pax7/Pax3. Moreover, exposing the offspring to a methyl-balanced diet during adolescence prevents the dysregulation and predisposition from being triggered. We demonstrate that gestational programming, per se, will not lead to BE-like behavior, but pre existing alterations due to prenatal programming are revealed only when challenged during adolescence. We provide experimental evidence for long-term epigenetic abnormalities stemming from PNS in predisposing female offspring to BE disorder as well as a potential non-invasive prevention strategy. PMID- 28576420 TI - Effects of dietary arachidonic acid on the reproductive physiology of female Atlantic cod (Gadus morhua L.). AB - The present study was designed to investigate potential effects of arachidonic acid (ARA) on the reproductive physiology of female Atlantic cod (Gadus morhua L.). Two-year old Atlantic cod of both sexes were equally distributed into eight sea cages after completion of their first spawning in May 2005. Four experimental groups were established and fed diets with different levels of ARA corresponding to 0.5, 1, 2 and 4% of total fatty acid. Ovarian growth and development was documented every month. Fatty acid composition was analysed in ovaries, liver and plasma at the beginning of the experiment, one month prior to spawning, and in spent fish, one month after spawning was completed. Plasma concentrations of estradiol-17beta, testosterone and vitellogenin, and ovarian gene transcript levels of steroidogenic acute regulatory protein (star), P450aromatase (cyp19a1a) and 20beta-hydroxy steroid dehydrogenase (20bhsd/cbr1) were monitored every month in fish fed the experimental diets and related to oocyte stage. Potential fecundity was calculated based on ovarian samples taken one month before onset of spawning. Ovarian and plasma ARA levels were highly correlated to dietary ARA levels. There was a net accumulation of ARA compared to other essential fatty acids in ovarian tissue that was reflected in a decrease in EPA:ARA ratio. Plasma concentrations of vitellogenin, estradiol-17beta and testosterone and key gene transcript levels were affected by dietary ARA and stage of maturation. The results show that ARA has a significant influence on the reproductive physiology of female Atlantic cod. PMID- 28576421 TI - [Impact of Gleason score on biochemical recurrence free survival after radical prostatectomy with positive surgical margins]. AB - PURPOSE: Research of predictive factors of biochemical recurrence to guide the establishment of an adjuvant treatment after radical prostatectomy for cancer with positive surgical margins. METHODOLOGY: A retrospective cohort of 1577 afro caribbean patients undergoing radical prostatectomy operated between 1st January 2000 and 1st July 2013 was analyzed. In this cohort, 406 patients had positive surgical margin, we excluded 11 patients who received adjuvant therapy (radiotherapy, hormonotherapy, radio-hormonotherapy) and 2 patients for whom histological analysis of the surgical specimen was for a pT4 pathological stage. After a descriptive analysis, we used a Cox model to look for predictors of survival without biochemical recurrence then, depending on the significant variables, we separated our population into six groups: stage pT2 with Gleason score<=3+4 (group 1), stage pT2 with a score of Gleason>=4+3 (group 2), stage pT3a with a Gleason core<=3+4 (group 3), pT3a stage with a score of Gleason>=4+3 (group 4), stage pT3b with a Gleason score<=3+4 (group 5) and stage pT3b Gleason>=with a score of 4+3 (group 6) and compared survival without biochemical recurrence using a log rank test. After radical prostatectomy with surgical margins with an anatomopathological stage<=pT3b, a Gleason score>=4+3 had a pejorative survival without biochemical recurrence than pathological stage (P<0.001). RESULTS: In multivariate analysis, predictors of survival without biochemical recurrence after radical prostatectomy with positive surgical margins were the majority Gleason postoperative (P<0.0001), pathological stage (P=0.049) adjusted preoperative PSA (P=0.826), with the body mass index (BMI) (P=0.59) and tumor volume (P=0.95). CONCLUSION: A high postoperatively Gleason score (>=4+3) has a better predictive value of biochemical recurrence than pathological stage pT2 or pT3 at the patients having been treated for prostate cancer by radical prostatectomy with positive surgical margins. LEVEL OF EVIDENCE: 4. PMID- 28576422 TI - A bicentric comparative and prospective study between classic photovaporization and anatomical GreenLight laser vaporization for large-volume prostatic adenomas. AB - OBJECTIVE: Long-term outcome after prostate photovaporization (PVP) remains largely unknown, especially when performed on enlarged prostates. However, new vaporisation techniques (e.g., laser enucleation) are increasingly used. Our aim was to compare postoperative results after standard PVP to those of an anatomical technique. MATERIALS AND METHODS: This bicentric prospective study included males treated for enlarged prostate caused by benign prostatic hyperplasia using a GreenLight laser. Patients were preoperatively assessed according to prostate volume, post-void residual volume (PVR), maximum urinary-flow rate (Qmax), prostatic specific antigens, and International prostate symptom score (IPSS). Peroperative data included vaporization time, energy delivered, and operative length. Postoperative data at 1, 3, 6 and 12 months were compared with initial data; all complications were recorded. Comparisons were made between the conventional vaporization technique versus anatomical vaporization, which initially differentiated the peripheral zone of the prostate using an enucleation technique but no morcellation. RESULTS: Records from 106 surgical patients between December 2012 and December 2013 were analyzed. Operative length, vaporisation time, and energy used were greater in the anatomical PVP group. The average length of hospital stay (2.0 vs. 2.5 days), time with a catheter (1.3 vs. 1.9 days), IPSS (5.0 vs. 6.4), PVR (15.5 vs. 11.7mL), and Qmax (19.9 vs. 19.7mL/s) were comparable between the two groups. However, more complications occurred (27% vs. 37%), including stress urinary incontinence (0% vs. 8%) when using anatomic vaporization. CONCLUSION: Despite comparable groups and similar functional results, anatomical PVP caused more stress incontinence. However, the learning curve between the two techniques may explain this difference. LEVEL OF EVIDENCE: 4. PMID- 28576423 TI - [PET/CT and biochemical recurrence of prostate adenocarcinoma: Added value of 68Ga-PSMA-11 when 18F-fluorocholine is non-contributive]. AB - INTRODUCTION: Since April 201, we have introduced PET/CT using a ligand of prostate-specific membrane antigen labeled with gallium-68 (PSMA-11). We aimed to evaluate its positivity rate and impact in patients presenting biochemical recurrence of prostate cancer whose 18F-fluorocholine (FCH) PET/CT was non contributive. PATIENTS AND METHOD: Patients were prospectively included between April and December 2016. PET/CT was performed 60min after injection of 2MBq/kg of body mass of 68Ga-PSMA-11. Three anatomical areas were considered: prostatic lodge, pelvic lymph nodes and distant locations. The impact of PSMA-11 PET/CT was assessed by comparing changes in therapeutic strategy decided during multidisciplinary meeting. RESULTS: Thirty-three patients were included. The mean PSA serum level measured on the month of the PSMA-11 PET/CT was 2,8ng/mL. Twenty five (76%) PSMA-11 PET/CT were positive, 7 (21%) negative and 1 (3%) equivocal. Of 11 patients whose FCH PET/CT showed equivocal foci, PSMA-11 PET/CT confirmed those foci in 5 cases. Follow-up was available for 18 patients (55%). PSMA-11 PET/CT results led to a change in management in 12 patients (67%). CONCLUSION: 68Ga-PSMA-11 PET/CT is useful in detecting recurrence of prostate cancer, by identifying residual disease which was not detected on other imaging modalities and by changing management of 2 patients out of 3. LEVEL OF EVIDENCE: 5. PMID- 28576424 TI - [Salvage radical prostatectomy for recurrent prostate cancer. Morbidity, oncological and functional results]. AB - INTRODUCTION: Salvage radical prostatectomy (sRP) for radiorecurrent prostate cancer (PCa) is a challenging procedure. To report our experience with sRP for selected patients with local recurrence after primary treatment for localised PCa. METHODS: From 2005 to 2015, 24 patients underwent sRP for recurrent PCa in our center and were included in this retrospective study. Local recurrence was suspected by PSA increase>nadir+2ng/mL and was confirmed by biopsy. Perioperative complications according to Clavien-Dindo classification, oncological and functional results were analysed. RESULTS: Overall, 24 patients with a median age of 59 years (IQR: 55-60) were included. Median follow-up was 25 months (IQR: 9 26). Procedures were performed with open-retropubic approach in 50 % and robot assisted laparoscopic approach in 50 %. Overall, 5 (21 %) and 2 (8 %) patients experienced grade<=IIIa and grade>=IIIb postoperative complication, respectively. Surgical margins were positive in 46 % of cases. Three out of 4 patients with postoperatively detectable PSA (>0.2ng/mL) had positive surgical margins. Seven patients experienced biochemical recurrence in a median delay of 19 months (9 62). Seventy-one percent (5) of these patients experienced clinical recurrence in a median delay of 24 months (10-113). Severe urinary incontinence (>=3 pads/day) and erectile dysfunction were reported in 25 % and 63 %, respectively. CONCLUSION: sRP for patients is a feasible procedure with encouraging local control rate and acceptable morbidity. This technique should be discussed as a treatment option for locally recurrent PCa in well-selected patients. LEVEL OF EVIDENCE: 4. PMID- 28576426 TI - [Impact of pharmaceutical interventions on antibiotic therapy of urinary tract infections in rehabilitation center]. AB - BACKGROUND: The aim of this study was to assess the impact of medico pharmaceutical partnership on the quality of antibiotic treatment in urinary tract infection (UTI) within rehabilitation center. MATERIAL: All antibiotic prescriptions were validated by the pharmacist at the start of treatment and twice a week. All patients with symptomatic urinary tract infection between January 1, 2014 to December 31, 2015 were included in this study. Addition to awareness among specifiers to promoting the appropriate use of antibiotics, the pharmacist suggested pharmaceutical interventions (PI) in order to improve the quality of antibiotic treatments. At the same time, 3 quality indicators (QI) were followed: duration, dosage, antibiotic susceptibility. The compliance rates of this 3 QI allowed to assess the quality of the antibiotic treatment in urinary tract infection. RESULTS: The study population included 154 patients corresponding to 252 UTI. Sixty-eight PI were made by pharmacist about urinary tract infection treatment (overdosage or under-dosing, duration unknown, inadequate route of administration). These QI achieved 96.4% compliance with duration, 98.8% compliance with dosage and 99.2% with the antibiotic susceptibility. CONCLUSION: This study allowed showing the medico-pharmaceutical impact on the quality of antibiotic treatments in UTI. The awareness among specifiers with a daily validation of prescription by the pharmacist allowed to improve urinary tract infections care in rehabilitation center. LEVEL OF EVIDENCE: 4. PMID- 28576425 TI - [Correlation of genetic and cytogenetic alterations in pathological aggressiveness urothelial carcinoma of the bladder: Performance of BCA-1, a mini array comparative genomic hybridisation-based test]. AB - INTRODUCTION: Urothelial carcinomas are the fourth leading cause of cancer in humans. Their incidence is increasing by more than 50% in 25 years. The superficial forms (70% cases) require a close active surveillance to identify frequent recurrences and progression to invasive stage. Our main goal was to identify prognostic molecular markers for bladder cancer that could be used alone or in combination in routine clinical practice. In this aim, we evaluated the capability of the BCA-oligo test based on a CGH array to correctly classify tumoral grade/stage. METHOD: Urinary DNA was extracted from 81 patients with superficial bladder cancer and has been hybridized on the BCA-oligo array. The results from the molecular analysis were correlated with the tumoral grade and stage. RESULTS: Several chromosomal alterations were significantly more frequent in tumors of higher grade and more advanced stage. A significant association was observed between a high grade and the presence of one of these alterations: loss on 6p, gain on 8q or 13q, loss or gain on 9q or 11q, with an odds ratio of 6.91 (95% CI=2.20-21.64; P=0.0009). Moreover, a significant association was found between a more advanced stage (pT1) and the presence of one of these alterations: loss on 6p, gain on 8q, loss or gain on 5p, with an odds ratio of 15.2 (95% CI=3.71-62.58; P=0.0002). CONCLUSION: Our results showed that molecular analyses of superficial bladder cancers based on urinary DNA and the BCA-oligo test could be used as prognostic factor for the tumor evolution, allowing then a more adapted clinical management. PMID- 28576427 TI - [Food, diet and dietetic in treatment of urinary tract dysfunctions. A review]. AB - : Overactive bladder symptoms (OAB) are frequent and can impact quality of life for these patients. Numerous and various treatments could be proposed in order to improve well-being and quality of life, but all these treatments have side effects and determine for many patients, important care constraints. We present here a review of food and diet in OAB. MATERIAL AND METHODS: Literature review from PubMed Medline database and Google scholar to August 2016, without time restriction. Two hundred and ninety-six articles were screened, in English and in French, and finally, 10 were retained. HAS recommandation have been used for level of evidence. RESULTS: On the 10 studies included, only two randomised controled trial were included. The first one showed decreases on urgency (by a half) (P=0.02) and on frequency (by a third) (P=0.035), secondary to reduction of caffeine consumption by a half after education [LE2]. The second randomized trial showed significant decreases on the first need to void in urodynamic study after caffeine consumption (170mL vs. 210mL) [LE2]. Feed like bread, chicken or nutrient like vitamin C or D were assessed in cohort or observational studies and appear as protective factors of OAB onset. Instead carbonated drinks may have a negative impact on symptoms, increasing urinary incontinence (OR 1.41 [95 % CI: 1.02-1.95]) [LE2], and there are contradictory results for alcohol consumption. CONCLUSION: Diet seems to have an impact on overactive bladder syndrome and particularly caffeine consumption, which increases storage symptoms. PMID- 28576428 TI - Surgical management of corrosive-induced gastric injury in children: 10years' experience. AB - AIM: The purpose of this study was to report surgical management and outcome of corrosive-induced gastric injuries in children at our institute over the last decade. PATIENTS & METHOD: Medical records of patients admitted for corrosive induced gastric injury at the Pediatric Surgery Department of Ain Shams University between January 2007 and January 2017 were retrospectively reviewed. RESULTS: Twenty six cases (17 boys and 9 girls) were enrolled. Mean age was 3.61+/-1.29. Ingested agent was acid in all the patients. Main presenting symptom was gastric output obstruction in 22 cases. The interval between corrosive ingestion and presentation ranged from one to 135days (mean=43.9+/-34). Surgical procedure included total gastrectomy (n=2), partial gastrectomy (n=2), augmentation gastroplasty (n=1), Billroth I (n=2), antrectomy (n=2), antroplasty (n=3), gastrojejunostomy (n=2), Heineke-Mikulicz pyloroplasty (n=9), Finney pyloroplasty (n=5), and feeding jejunostomy (n=4). Anastomotic stricture requiring a second operation developed in one patient. There were three mortalities related to the associated esophageal strictures. The mean follow-up period is 3.5years. All patients are free of symptoms and gained adequate weight. CONCLUSION: Surgery is the mainstay of management for corrosive-induced gastric injuries with good long-term results. Surgical procedure should be tailored according to the patient's general condition and extent of gastric injury. LEVEL OF EVIDENCE: This is a case series with no comparison group (level IV). PMID- 28576430 TI - Gastric bypass surgery mimetic approaches. AB - Gastric bypass surgery is effectively a polypharmacological approach for treatment of obesity, type 2 diabetes and nonalcoholic steatohepatitis (NASH). The gastric bypass mimetic approaches reviewed are fixed-dose combinatorial pharmacological approaches. There are two key concepts incorporated into these gastric bypass surgery mimetic approaches. The first key concept is that the combination of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21) is essential for success of any gastric bypass surgery mimetic approach. This combination affords the potential for durable weight loss, glycemic control and reduction in liver lipids. The second key concept is that a fixed-dose combination approach is preferred over post-approval combination of the individual components because the individual components alone often lack sufficient efficacy for development. PMID- 28576429 TI - Population-level surgical outcomes for infantile hypertrophic pyloric stenosis. AB - OBJECTIVES: Determine national outcomes for pyloromyotomy; how these are affected by: (i) surgical approach (open/laparoscopic), or (ii) centre type/volume and establish potential benchmarks of quality. METHODS: Hospital Episode Statistics data were analysed for admissions 2002-2011. Data presented as median (IQR). RESULTS: 9686 infants underwent pyloromyotomy (83% male). Surgery was performed in 22 specialist (SpCen) and 39 nonspecialist centres (NonSpCen). The proportion treated in SpCen increased linearly by 0.4%/year (r=0.76, p=0.01). Annual case volume in SpCen vs. NonSpCen was 40 (24-53) vs. 1 (0-3). Time to surgery was shorter in SpCen (1day [1, 2] vs. 2 [1-3]), but total stay equal (4days [3-6]). 137 (1.4%) had complications requiring reoperation (wound problem 0.6%; repeat pyloromyotomy 0.5% and perforation, bleeding or obstruction 0.2%): pooled rates were similar between SpCen and NonSpCen (1.4% vs. 1.6%, p=0.52). Three NonSpCen had >5% reoperations (within 99.8% C.I. as small denominators). There was no relationship between reoperation and centre volume. Laparoscopic pyloromyotomy had increased risk of repeat pyloromyotomy (OR 2.28 [1.14-4.57], p=0.029). CONCLUSIONS: Pyloric stenosis surgery shifted from centres local to patients, but outcomes were unaffected by centre type/volume. Modest reported benefits of laparoscopy appear offset by increased reoperations. Quality benchmarks could be set for reoperation <4%. TYPE OF STUDY: Treatment Study. LEVEL OF EVIDENCE: Level III. PMID- 28576431 TI - Corrigendum to "Persistent organic pollutants in juvenile Magellanic Penguins (Spheniscus magellanicus) in South America" [Chemosphere 149 (2016) 391-399]. PMID- 28576432 TI - Anticeramide antibody and butyrylcholinesterase in peripheral neuropathies. AB - Ceramide is a glycosphingolipid, a component of nerve and non neuronal cell membrane and plays a role in maintaining the integrity of neuronal tissue. Butyrylcholinesterase (BChE) is a multifunctional enzyme, its involvement in neurodegenerative diseases has been well established. Anticeramide antibody (Ab Cer) and enzyme BChE have been implicated in peripheral neuropathies. The present study investigates whether there is an association between Ab-Cer and BChE activities and peripheral neuropathies. Patients included: human immunodeficiency virus associated peripheral neuropathy (HIV-PN, n=39), paucibacillary leprosy (PB L, n=36), multibacillary leprosy (MB-L, n=52), diabetic neuropathy (DN, n=22), demyelinating sensory motor polyneuropathy (DSMN, n=13) and chronic inflammatory demyelinating polyneuropathy (CIDP, n=10). Plasma Ab-Cer was measured by indirect enzyme linked immune assay (ELISA) and BChE activity in plasma was measured by colorimetric method. Ab-Cer levels were significantly elevated in MB-L and DN as compared to healthy subjects (HS). BChE levels were significantly higher in MB-L and DN as well as in HIV and HIV-PN. There is no significant difference in either Ab-Cer or BChE levels in DSMN and CIDP. Elevated plasma Ab-Cer and BChE levels may be considered significant in the pathogenesis of neuropathies. The variation in concurrent involvement of both the molecules in the neuropathies of the study, suggest their unique involvement in neurodegenerative pathways. PMID- 28576433 TI - Postictal apnea as an important mechanism for SUDEP: A near-SUDEP with continuous EEG-ECG-EMG recording. AB - Sudden unexpected death in epilepsy (SUDEP) is one of the most frequent causes of death among patients with epilepsy. Most SUDEP or near-SUDEP are unwitnessed and not observed or recorded during video-EEG recording in epilepsy monitoring units. This report describes a young woman with post ictal apnea and generalized EEG suppression (PGES) after a secondary generalized tonic-clonic seizure (sGTCS). This was accompanied by bradycardia and then ventricular tachycardia (VT). But at the end of VT, the patient's breath recovered without any intervention, such as cardio-respiratory resuscitation. This case report with continuous EEG, EKG, EMG during near SUDEP may provide insights into the mechanism of action. PMID- 28576434 TI - [Molecular epidemiology and kinetics of early Escherichia coli urinary tract infections in kidney transplant recipients]. AB - BACKGROUND: Escherichia coli strains causing Urinary Tract Infections (UTI) have a fecal origin. METHODS: A fecal sample was collected before Kidney Transplantation (KT) and concomitantly with urine at each of the 15 E. coli UTIs which occurred in 11 KT recipients. Unique E. coli strains were identified among 25 isolates per feces and 5 isolates per urinary sample by random amplification of polymorphic DNA. Phylogenetic group (which is correlated to virulence in the E. coli species) was determined for each E. coli strain by a PCR based method. RESULTS: Forty-three unique fecal strains and 14 unique urinary strains were identified among 650 fecal isolates and 75 urinary isolates. Urinary strains frequently (55% of the cases) belonged to a phylogroup usually not linked to virulence. They were detected in the feces collected concomitantly in 60% of the cases. Urinary strains belonging to a phylogroup usually linked to virulence were more frequently dominant in the feces (100%) than urinary strains belonging to a non-pathogenic phylogroup (42%; P<0.05). Vesical catheter was a facilitating factor only for urinary strains belonging to non-pathogenic phylogroups. Thirty three percent of the fecal strains were persisting in two consecutive fecal samples and 62% were detected for the first time at the UTI. Numerous pathway lead to UTIs: from a unique, virulent and persisting strain to a non-virulent recently acquired strain facilitated by a vesical catheter. CONCLUSION: Our work shows the diversity of host-microbial interactions which precede extra-intestinal virulence. PMID- 28576435 TI - [Encapsulating peritoneal sclerosis]. AB - Encapsulating peritoneal sclerosis is a rare but devastating complication of long term peritoneal dialysis with a high mortality rate. The incidence is between 0.5 and 2.5%, decreasing with time. PSE is defined as a clinical syndrome with signs of gastrointestinal obstruction, inflammation parameters, radiological and macroscopic changes. The duration of treatment and the cessation of peritoneal dialysis are the main risks. About 75% occured in patients on hemodialysis or after kidney transplantation. Morphological alterations are disappearance of mesothelial layer, submesothelial fibrosis, interstitial sclerosis and vasculopathy. Ultrafiltration failure, fast transport status of the peritoneal membrane and loss of sodium sieving, the most powerful predictor, are the functional abnormalities. Biomarkers in peritoneal effluent include cancer antigen 125, interleukin-6. The pathophysiology is probably a consequence of a multiple-hit process in which expression of growth factors and cytokines play a central role. Medical strategies (corticosteroids, tamoxifen) in association with parenteral nutrition and/or surgery (enterolysis) are discussed. Prevention is the use of physiological peritoneal dialysis solutions, icodextrine instead of high glucose concentration solutions and peritoneal lavage after peritoneal dialysis stopping. PMID- 28576436 TI - CTA in acute stroke: short intensive training intervention is highly effective in improving radiologists' performance. AB - AIM: To determine whether focussed radiology training in reporting stroke computed tomography angiography (CTA) improved diagnostic performance of general radiology specialty trainees staffing regional on call rotas. MATERIALS AND METHODS: A validated case archive (VCA) consisting of 50 hyperacute stroke CTA cases was developed for a full day course on CTA interpretation. Training days were organised ensuring all local trainees had a chance to attend. The rate of major and minor amendments by neuroradiology consultants were reviewed in 252 on call radiology trainee reports. RESULTS: Before training, radiology trainees had a total discrepancy (reporting error) rate of 37%: 12% major, 25% minor. Following CTA training, the total discrepancy rate was not significantly reduced (34%) but there was a substantial reduction in major discrepancies to 4% (p=0.037; odds ratio=3.30, 95% confidence interval [CI]: 1.08 to 10.12). CONCLUSION: An intensive training course based on a hyperacute stroke VCA significantly reduced major discrepancies in stroke CTA interpretation for radiology trainees. The ability of radiology trainees to recognise large vessel occlusions and other significant findings improved. PMID- 28576437 TI - Feasibility of high-pitch spiral dual-source CT angiography in children with complex congenital heart disease compared to retrospective-gated spiral acquisition. AB - AIM: To investigate the use of second-generation dual-source high-pitch computed tomography in obtaining confident diagnostic image quality using a low radiation dose in young patients with congenital heart disease (CHD). MATERIALS AND METHODS: From July 2014 to June 2016, 50 consecutive children <4 years with complex CHD underwent electrocardiography (ECG)-triggered dual-source computed tomography (CT). The patients were assigned randomly to two groups: high-pitch (pitch 3.4) spiral dual-source CT acquisition (group A) and retrospectively spiral dual-source CT acquisition (group B). The image quality, diagnostic accuracy, coronary artery origin, course demonstration, and radiation exposure were compared between the two groups. RESULTS: Fifty examinations were performed (group A, 25; group B, 25). There were no significant differences in image quality, diagnostic accuracy, coronary artery origin, and course demonstration between the two groups. The image quality scores were 1.3+/-0.4 in group A and 1.1+/-0.3 in group B (p=0.2). The diagnostic accuracy was 100% in both groups. The coronary arteries were traceable in 80% in group A and 84% in group B (p=0.7). A single coronary artery was identified in one case in group A and the left anterior descending (LAD) branch originated from the right coronary artery (RCA) in one case in group B. There were significant differences in the effective doses between the two groups (0.40+/-0.20 mSv in group A and 2.7+/-1.0 mSv in group B, p<0.05). CONCLUSION: Intra-cardiac and extra-cardiac malformation, coronary artery origin, and course malformation can be visualised clearly using a high-pitch ECG-triggered dual-source CT with a low radiation dose and good image quality in patients with CHD. PMID- 28576438 TI - Increase of allosensitization after a kidney graft failure: Predictors and effect on retransplantation outcomes. AB - Patients who are candidates for a second kidney transplant (SKT) frequently have a higher level of panel reactive antibodies (PRA). We assessed the allosensitisation change after a first graft failure (GF), its predictors and impact on retransplantat outcomes. We retrospectively selected 140 adult patients who received a SKT. Recipient and donor characteristics were analyzed. We defined the delta PRA (dPRA) as the difference between peak PRA before the SKT and first one (cohort median value=+10%). Logistic regression analysis was used to determine risk factors for dPRA>=10% and acute rejection (AR) in the SKT. Univariable and multivariable Cox analysis was applied to assess independent predictors of second GF. Risk factors for dPRA>=10% at SKT were AR (OR=2.57; P=0.022), first graft survival <1 year (OR=2.47; P=0.030) and ABDR HLA mismatch (OR=1.38 per each mismatch; P=0.038). AR in the SKT was associated with dPRA>=10% (OR=2.79; P=0.047). Induction with a lymphocyte-depleting agent had a protective effect (OR=0.23; P=0.010). SKT survival was lower (P=0.008) in patients with a dPRA>=10% (75.6%, 60.5% in dPRA>=10%; 88.6%, 88.6% in dPRA<10% patients at 5 and 10 years, post-transplant respectively). Multivariable Cox regression showed that dPRA>=10% (HR=2.38, P=0.042), delayed graft function (HR=2.82, P=0.006) and AR (HR=3.30, P=0.001) in the SKT were independent predictors of retransplant failure. This study shows that an increased allosensitisation at retransplant was associated with the degree of HLA mismatch and led to poorer outcomes. De emphasis of HLA matching in current allocation policies may be undesirable, particularly in patients with a higher chance of needing a SKT. PMID- 28576439 TI - Serum ICAM-1 level and ICAM-1 gene 1462A>G (K469E) polimorphism on microalbuminuria in nondiabetic, nonhypertensive and normolipidemic obese patients: Genetical background of microalbuminuria in obesity. AB - BACKGROUND: A growing body of evidence suggest that obese individuals are under risk of renal parenchymal disorders when compared to nonobese counterparts. Microalbuminuria is the early marker of renal involvement. Although most of obese patients carries multiple risk factors for microalbuminuria, some obese individuals without risk factor may progress to microalbuminuria. The present study was performed to examine the role of ICAM-1 gene 1462A>G (K469E) polymorphism on microalbuminuria in obese subjects without diabetes mellitus, hypertension, hiperlipidemia and older age. METHODS: Ninety eight obese and 96 nonobese individuals without a comorbidity enrolled into the study. Serum ICAM-1 level was measured by enzyme linked immunoabsorbent assay (ELISA) method. ICAM-1 gene 1462A>G (K469E) polymorphism was examined by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). Nepholometric method was used to examine urinary albumin loss, and microalbuminuria was measured by albumin to creatinine ratio. RESULTS: Obese individuals had significantly higher microalbuminuria and proteinuria level compared to nonobese subjects (p: 0.043 and p: 0.011; respectively). GG genotype of ICAM-1 carriers have significantly higher microalbuminuria compared to individuals with AA or AG genotype carriers (p: 0.042). Serum ICAM-1 level was significantly correlated with creatinine and microalbuminuria (p: 0.002 and p: 0.03; respectively). Logistic regression analysis indicated a 7.39 fold increased risk of microalbuminuria in individuals with GG genotype of ICAM-1 gene 1462A>G (K469E) polymorphism. CONCLUSIONS: GG genotype of ICAM-1 gene K469E polymorphism is associated with increased microalbuminuria in obese individuals without another metabolic risk factor. PMID- 28576441 TI - SPN Position Statement: Transition of Pediatric Patients Into Adult Care. PMID- 28576440 TI - Photometric assay of maltose and maltose-forming enzyme activity by using 4-alpha glucanotransferase (DPE2) from higher plants. AB - Maltose frequently occurs as intermediate of the central carbon metabolism of prokaryotic and eukaryotic cells. Various mutants possess elevated maltose levels. Maltose exists as two anomers, (alpha- and beta-form) which are rapidly interconverted without requiring enzyme-mediated catalysis. As maltose is often abundant together with other oligoglucans, selective quantification is essential. In this communication, we present a photometric maltose assay using 4-alpha glucanotransferase (AtDPE2) from Arabidopsis thaliana. Under in vitro conditions, AtDPE2 utilizes maltose as glucosyl donor and glycogen as acceptor releasing the other hexosyl unit as free glucose which is photometrically quantified following enzymatic phosphorylation and oxidation. Under the conditions used, DPE2 does not noticeably react with other di- or oligosaccharides. Selectivity compares favorably with that of maltase frequently used in maltose assays. Reducing end interconversion of the two maltose anomers is in rapid equilibrium and, therefore, the novel assay measures total maltose contents. Furthermore, an AtDPE2-based continuous photometric assay is presented which allows to quantify beta-amylase activity and was found to be superior to a conventional test. Finally, the AtDPE2-based maltose assay was used to quantify leaf maltose contents of both Arabidopsis wild type and AtDPE2-deficient plants throughout the light-dark cycle. These data are presented together with assimilatory starch levels. PMID- 28576442 TI - Comparative study of thylakoid membranes in terminal heterocysts and vegetative cells from two cyanobacteria, Rivularia M-261 and Anabaena variabilis, by fluorescence and absorption spectral microscopy. AB - Heterocyst is a nitrogen-fixing cell differentiated from a cell for oxygen evolving photosynthesis (vegetative cell) in some filamentous cyanobacteria when fixed nitrogen (e.g., ammonia and nitrate) is limited. Heterocysts appear at multiple separated positions in a single filament with an interval of 10-20 cells in some genera (including Anabaena variabilis). In other genera, a single heterocyst appears only at the basal terminal in a filament (including Rivularia M-261). Such morphological diversity may necessitate different properties of heterocysts. However, possible differences in heterocysts have largely remained unexplored due to the minority of heterocysts among major vegetative cells. Here, we have applied spectroscopic microscopy to Rivularia and A. variabilis to analyze their thylakoid membranes in individual cells. Absorption and fluorescence spectral imaging enabled us to estimate concentrations and interconnections of key photosynthetic components like photosystem I (PSI), photosystem II (PSII) and subunits of light-harvesting phycobilisome including phycocyanin (PC). The concentration of PC in heterocysts of Rivularia is far higher than that of A. variabilis. Fluorescence quantum yield of PC in Rivularia heterocysts was found to be virtually the same as those in its vegetative cells, while fluorescence quantum yield of PC in A. variabilis heterocysts was enhanced in comparison with its vegetative cells. PSI concentration in the thylakoid membranes of heterocysts seems to remain nearly the same as those of the vegetative cells in both the species. The average stoichiometric ratio between PSI monomer and PC hexamer in Rivularia heterocysts is estimated to be about 1:1. PMID- 28576443 TI - A Multicenter, Open-Label, Phase 1b Study of Carfilzomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients (CHAMPION-2). AB - INTRODUCTION: This phase 1b study evaluated the safety and efficacy of 3 dose levels of carfilzomib when provided with fixed dose oral cyclophosphamide and dexamethasone (KCyd) in patients with newly diagnosed multiple myeloma (MM). PATIENTS AND METHODS: CHAMPION-2 was a multicenter single-arm study. Patients with newly diagnosed secretory MM were enrolled and received KCyd treatment for up to 8 cycles. A 3 + 3 dose escalation scheme was used to evaluate twice-weekly carfilzomib at 36, 45, and 56 mg/m2 dose levels, followed by a dose expansion. RESULTS: No dose-limiting toxicities were observed in any of the dose evaluation cohorts. The KCyd regimen that included the maximum planned carfilzomib dose of 56 mg/m2 twice weekly was brought forward into dose expansion. A total of 16 patients were treated at this dose level. At 56 mg/m2 the overall response rate was 87.5% (95% confidence interval, 61.7-98.4), and the median time to response of 14 patients whose disease responded to therapy was 1 month. At this dose level, common adverse events of grade 3 or higher were anemia (25.0%), neutropenia (18.8%), acute kidney injury (12.5%), and decreased white blood cell count (12.5%). Ten of 16 patients who received carfilzomib at 56 mg/m2 completed all 8 cycles, 5 patients discontinued study therapy before cycle 8 as a result of adverse events, and 1 patient discontinued therapy as a result of progressive disease. CONCLUSION: Carfilzomib in combination with cyclophosphamide and dexamethasone is effective and has manageable toxicity for patients with newly diagnosed MM. PMID- 28576444 TI - Alterations in physique among young children after the Great East Japan Earthquake: Results from a nationwide survey. AB - BACKGROUND: Data for earthquake-related alterations in physique among young children in developed countries is lacking. The Great East Japan Earthquake caused severe damage in Iwate, Miyagi, and Fukushima Prefectures in northeastern Japan. METHODS: We retrospectively obtained anthropometric measurements in nursery school from 40,046 (cohort 1, historical control) and 53,492 (cohort 2) children aged 3.5-4.5 years without overweight in October 2008, and in October 2010, respectively. At the time of the earthquake in March, 2011, children in cohort 1 had already graduated from nursery school; however, children in cohort 2 were still enrolled in nursery school at this time. We compared the onset of overweight at 1 year after the baseline between children enrolled in their school located in one of the three target prefectures versus those in other prefectures using a logistic regression model, with adjustment for sex, age, history of disease, and obesity index at baseline. Overweight was defined as an obesity index of >+15%, which was calculated as (weight minus sex- and height-specific standard weight)/sex- and height-specific standard weight. RESULTS: The odds ratio (OR) for the onset of overweight in the three target prefectures was significant in cohort 2 (OR 1.25; 95% confidence interval [CI], 1.01-1.55) but not in cohort 1. When the two cohort were pooled (n = 93,538), the OR of the interaction term for school location * cohort was significant (OR 1.56; 95% CI, 1.09-2.23). CONCLUSIONS: Incident overweight in young children was significantly more common in the three prefectures affected by the Great East Japan Earthquake than in other prefectures after the disaster. PMID- 28576445 TI - Interactions between inflammatory gene polymorphisms and HTLV-I infection for total death, incidence of cancer, and atherosclerosis-related diseases among the Japanese population. AB - BACKGROUND: An increased risk of total death owing to human T-lymphotropic virus type-I (HTLV-I) infection has been reported. However, its etiology and protective factors are unclear. Various studies reported fluctuations in immune-inflammatory status among HTLV-I carriers. We conducted a matched cohort study among the general population in an HTLV-I-endemic region of Japan to investigate the interaction between inflammatory gene polymorphisms and HTLV-I infection for total death, incidence of cancer, and atherosclerosis-related diseases. METHOD: We selected 2180 sub-cohort subjects aged 35-69 years from the cohort population, after matching for age, sex, and region with HTLV-I seropositives. They were followed up for a maximum of 10 years. Inflammatory gene polymorphisms were selected from TNF-alpha, IL-10, and NF-kappaB1. A Cox proportional hazard model was used to estimate the hazard ratio (HR) and the interaction between gene polymorphisms and HTLV-I for risk of total death and incidence of cancer and atherosclerosis-related diseases. RESULTS: HTLV-I seropositivity rate was 6.4% in the cohort population. The interaction between TNF-alpha 1031T/C and HTLV-I for atherosclerosis-related disease incidence was statistically significant (p = 0.020). No significant interaction was observed between IL-10 819T/C or NF kappaB1 94ATTG ins/del and HTLV-I. An increased HR for total death was observed in the Amami island region, after adjustment of various factors with gene polymorphisms (HR 3.03; 95% confidence interval, 1.18-7.77). CONCLUSION: The present study found the interaction between TNF-alpha 1031T/C and HTLV-I to be a risk factor for atherosclerosis-related disease. Further follow-up is warranted to investigate protective factors against developing diseases among susceptible HTLV-I carriers. PMID- 28576446 TI - Prenatal and childhood exposure to phthalate diesters and sex steroid hormones in 2-, 5-, 8-, and 11-year-old children: A pilot study of the Taiwan Maternal and Infant Cohort Study. AB - BACKGROUND: Phthalate diesters are commonly used and have been well established as environmental endocrine disruptors. However, few studies have examined their effects on sex steroid hormones in children. We followed children over time to examine the association between pre- and post-natal phthalate exposure and sex steroid hormone levels at 2, 5, 8, and 11 years of age. METHODS: We recruited 430 pregnant women from central Taiwan from 2000 to 2001 and assessed their children at birth, 2, 5, 8, and 11 years of age. We studies children with at least one measurement for both phthalate and hormone levels during each any of the follow up time point (n = 193). Estradiol, free testosterone, testosterone, and progesterone were measured from venous blood. Three monoesters of di-2-ethylhexyl phthalate (DEHP), mono-benzyl phthalate, mono-n-butyl phthalate, mono-ethyl phthalate, and mono-methyl phthalate were measured in maternal urine collected during the 3rd trimester and child urine collected at each follow-up point. The sum of mono-2-ethylhexyl phthalate (?MEHP) was calculated by summing the concentrations of the three DEHP monoesters. Generalized estimating equation regression analysis with repeated measures was used to estimate associations between phthalate metabolites and hormone levels. RESULTS: After adjustment for potential confounders, maternal ?MEHP level was associated with decreased levels of progesterone in girls (beta = -0.309 p = 0.001). The child ?MEHP concentration was associated with decreased levels of progesterone for girls (beta = -0.194, p = 0.003) and with decreased levels of free testosterone for boys (beta = -0.124, p = 0.004). CONCLUSIONS: Early-life DEHP exposure may alter sex steroid hormones of children over time, which may pose potential reproductive health risks. PMID- 28576447 TI - Relationship between nutrition knowledge and dietary intake among primary school children in Japan: Combined effect of children's and their guardians' knowledge. AB - BACKGROUND: Improving the dietary habits of children is important to decrease the future burden of noncommunicable diseases. While various food education programs have been implemented worldwide, evaluation of nutrition knowledge is difficult, even at baseline. Further, the relationship between nutrition knowledge and dietary intake has not been clarified in non-western countries. METHODS: After developing nutrition knowledge questionnaires for Japanese primary school children and adults, we examined whether higher nutrition knowledge of children and their guardians was associated with better dietary intake in children. A total of 1210 children in four public primary schools and 319 guardians were included in this cross-sectional study. RESULTS: Nutrition knowledge questionnaires were developed for children in lower and higher grades and adults. Higher nutrition knowledge of the children was significantly associated with higher vegetable intake (p for trend = 0.024 for boys and <0.0001 for girls in lower grades, <0.0001 for boys and 0.020 for girls in higher grades). Higher nutrition knowledge of the guardians was also associated with higher vegetable intake, except for boys in higher grades. The relationship between guardians' nutrition knowledge and intake of staple foods and fruits in children differed by children's sex. CONCLUSIONS: We developed nutrition knowledge questionnaires for Japanese children and adults and identified a relationship between higher nutrition knowledge and healthier dietary habits. The child's own nutrition knowledge of dietary intake might be as important as that of the guardian for some foods. Sex differences in the effect of nutrition knowledge should receive greater attention in food education. PMID- 28576448 TI - Stepwise characterization of non-synonymous mutations in the HSV-1 thymidine kinase gene by different functional assays. AB - Twenty amino acid substitutions in the thymidine kinase (TK) of clinical herpes simplex virus type 1 strains were assessed for conferring acyclovir (ACV) resistance. Site-directed mutagenesis, cell-free protein synthesis and protein expression in Escherichia coli were performed to obtain recombinant TK proteins, which were authenticated by Western blotting. A modified enzyme-linked immunosorbent assay (ELISA) was carried out to determine the phosphorylation activity of the mutants towards 5-bromo-2'-deoxyuridine (BrdU). The activity against ACV and deoxythymidine (dT) was analyzed by high performance liquid chromatography/ultraviolet spectroscopy (HPLC/UV) following incubation of recombinant TK with ACV and dT. Using ELISA, seven substitutions (G61E, A93V, M121K, R163G, P173del, V238F, G264V) showing negative activity could be classified likely as resistance-related, eleven (Q15K, R20C, R32H, E43A, E43D, R89H, A156V, P269S, G271V, S276N, I326V) with high activity as natural polymorphisms, and two (N244H and N376stop) with low phosphorylation activity. Since the N244H protein did not show any activity towards ACV, but activity towards dT using HPLC/UV, it was classified as TK with altered substrate specificity. In conclusion, the ELISA determining activity towards BrdU is suitable for the characterization of substitutions regarding their significance for resistance. Ambiguous results can be re-assessed by HPLC/UV, which classifies TK with altered substrate specificity. PMID- 28576449 TI - Evaluation of the COBAS(r) AmpliPrep/COBAS(r) TaqMan(r) HCV Test v2.0 for HCV viral load monitoring using dried blood spot specimens. AB - This study evaluated the use of dried blood spot (DBS) for HCV viral load quantification using the COBAS(r) AmpliPrep/COBAS(r) Taqman(r) HCV Quantitative Test v2.0 (CAP/CTM HCV v2), and compared two different procedures for preparation of DBS samples with a Specimen Pre-Extraction (SPEX) reagent (either heated [SPEX with SH] for 10min at 56 degrees C on a thermomixer, or incubated for 1h at room temperature [SPEX at RT]) against the standard plasma input. Whole blood specimens from 48 patients with chronic HCV infection and Whatman(r) 903 Protein Saver Cards were used to prepare 35MUL DBS. An aliquot of plasma was spun and frozen from each draw. Mean DBS viral load results were compared to the corresponding results from plasma. Correlation between DBS to plasma was linear for both SPEX with SH (R2=0.96) and SPEX at RT (R2=0.97) procedures, with a constant negative offset of approximately 2.0log10IU/mL between whole blood DBS without any adjustments and plasma results. After volume corrections, the mean offset to plasma decreased to -0.39 and -0.36 for the two procedures, respectively. The study demonstrated the use of DBS for HCV viral load correlates well with plasma with a constant offset. PMID- 28576450 TI - Opioid-induced constipation: reflections on efficacy assessment. PMID- 28576451 TI - Elbasvir plus grazoprevir in patients with hepatitis C virus infection and stage 4-5 chronic kidney disease: clinical, virological, and health-related quality-of life outcomes from a phase 3, multicentre, randomised, double-blind, placebo controlled trial. AB - BACKGROUND: In the C-SURFER study, therapy with the all-oral elbasvir plus grazoprevir regimen for 12 weeks in patients with chronic hepatitis C virus (HCV) infection and stage 4-5 chronic kidney disease resulted in a high rate of virological cure compared with placebo. Here, we report sustained virological response (SVR), safety data, health-related quality-of-life (HRQOL), and virological resistance analyses in patients in C-SURFER who received immediate antiviral therapy or who received placebo before therapy. METHODS: In this phase 3, multicentre, randomised, placebo-controlled study, we randomly assigned adults with HCV genotype 1 infection and stage 4-5 chronic kidney disease enrolled at 68 centres worldwide to either elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks beginning at week 16 (deferred treatment group). The primary safety and efficacy endpoints for the immediate treatment group and placebo phase of the deferred treatment group have been reported previously. Here, we report safety and efficacy data for the treatment phase of the deferred treatment group, as well as HRQOL assessed using the 36-Item Short Form Health Survey for all groups, and baseline and treatment emergent resistance-associated substitutions (RASs). SVR at 12 weeks (SVR12) was assessed in the modified full analysis set (FAS), defined as all patients excluding those who did not receive at least one dose of study drug, who died, or who discontinued the study before the end of treatment for reasons determined to be unrelated to HCV treatment. This trial is registered with ClinicalTrials.gov, Number NCT02092350. FINDINGS: Between March 30 and Nov 28, 2014, 235 patients were enrolled and received at least one dose of study drug. The modified FAS included 116 patients assigned to immediate treatment and 99 assigned to deferred treatment. 115 (99.1%; 95% CI 95.3-100.0) of 116 assigned to immediate treatment achieved SVR12 compared with 97 (98.0%; 92.9-99.7) of 99 assigned to deferred treatment. In patients with genotype 1a infections, SVR12 was achieved by 11 (84.6%) of 13 patients with detectable baseline NS5A RASs and in 98 (100%) of 98 without. HRQOL did not differ at week 12 between immediate treatment and the placebo phase of deferred treatment. Safety was generally similar between patients receiving immediate treatment and those receiving placebo in the deferred treatment group. One serious adverse event during deferred treatment (interstitial nephritis) and one during the placebo phase of deferred treatment (raised lipase concentration) were deemed related to study drug. Four patients died, one who received immediate treatment (cardiac arrest) and three who received deferred treatment (aortic aneurysm, pneumonia, and unknown cause); all four deaths were considered unrelated to study drugs. Of the three deaths in the deferred treatment group, one occurred during placebo treatment and two occurred before starting active treatment. There were no notable differences in aminotransferase elevations in the deferred treatment group compared with the immediate treatment group, and no patients in the deferred treatment group had total bilirubin elevations. INTERPRETATION: These data add to the growing body of clinical evidence for the fixed-dose combination regimen of elbasvir plus grazoprevir for 12 weeks and support use of this therapy in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. FUNDING: Merck Sharp & Dohme. PMID- 28576453 TI - Epidemiology of infections and antimicrobial use in Australian haemodialysis outpatients: findings from a Victorian surveillance network, 2008-2015. AB - BACKGROUND: Patients with chronic renal failure who require haemodialysis are at high risk for infections. AIM: To determine the burden of bloodstream and local access-related infections and the prescribing patterns for intravenous antibiotics in Australian haemodialysis outpatients. METHODS: A surveillance network was established following stakeholder consultation, with voluntary participation by haemodialysis centres and data collation by the Victorian Healthcare Associated Infection Surveillance System Coordinating Centre. Definitions for infection and intravenous antimicrobial starts were based upon methods employed by the Centers for Disease Control and Prevention. Longitudinal mixed-effects Poisson regression was used to model time-trends for the period 2008-2015. FINDINGS: Forty-eight of 78 Victorian dialysis centres participated in the network, with 3449 events reported over 78,826 patient-months. Rates of bloodstream infection, local infection and intravenous antimicrobial starts were much higher for patients with tunnelled central lines (2.60, 1.41, and 3.37 per 100 patient-months, respectively), compared to those with arteriovenous fistulae (0.27, 0.23, and 0.73 per 100 patient-months, respectively) and arteriovenous grafts (0.76, 1.08, 1.50 per 100 patient-months, respectively). Staphylococcus aureus was the most frequent pathogen, with meticillin-resistant isolates (MRSA) responsible for 14.0%. Access-related infections diminished significantly across all vascular-access modalities over time. Vancomycin contributed nearly half of all antimicrobial starts consistently throughout the study period. CONCLUSION: Risk for bloodstream and local access-related infections is highest in Australian haemodialysis patients with tunnelled central lines. S. aureus is the most frequent cause of infection, with a low incidence of MRSA. Future programmes should evaluate infection prevention practices and appropriateness of antibiotic prescribing in this population. PMID- 28576452 TI - Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE 2): two multicentre, phase 3, double-blind, randomised, parallel-group trials. AB - BACKGROUND: Opioid-induced constipation is a frequent side-effect of opioid treatment, and standard interventions have limited or inconsistent efficacy. This study assessed the efficacy and safety of naldemedine, a peripherally acting MU opioid receptor antagonist, for the treatment of opioid-induced constipation in patients with chronic non-cancer pain. METHODS: We report two double-blind, randomised, placebo-controlled trials in adults with chronic non-cancer pain and opioid-induced constipation. The first (COMPOSE-1) was done in 68 outpatient sites in seven countries and the second (COMPOSE-2) at 69 outpatient sites in six countries; both studies were done in Europe and the USA. Eligible patients were aged 18-80 years, did not use laxatives, and had a stable opioid regimen for treatment of chronic non-cancer pain with a total daily dose averaging at least 30 mg (morphine equivalent) for at least 1 month before screening. Patients were randomly assigned (1:1) to receive either oral naldemedine 0.2 mg or matching placebo once a day for 12 weeks. Randomisation was stratified by average total daily opioid dose (30-100 mg and >100 mg equivalents of oral morphine sulphate). The primary endpoint was proportion of responders. A responder had at least three spontaneous bowel movements (SBMs) per week with an increase from baseline of at least one SBM per week for at least 9 weeks of the 12-week treatment period including at least three of the last 4 weeks. Efficacy endpoints were analysed by intention to treat and the safety population included all patients who received at least one dose of study drug. These trials have both been completed and are registered with ClinicalTrials.gov, numbers NCT01965158 and NCT01993940. FINDINGS: In COMPOSE-1, 547 patients were recruited between Aug 29, 2013, and Jan 22, 2015, and were randomly assigned to receive naldemedine (n=274) or placebo (n=273). Patients for COMPOSE-2 were recruited between Nov 4, 2013, and June 9, 2015; 553 patients were randomly assigned to receive naldemedine (n=277) or placebo (n=276). Five patients were enrolled at more than one site, so were excluded from the intention-to-treat population (COMPOSE-1: one per group; COMPOSE-2: one in the naldemedine group, two from the placebo group), with intention-to-treat group sizes of 273 in the naldemedine group and 272 in the placebo group in COMPOSE-1, and 276 in the naldemedine group and 274 in the placebo group in COMPOSE-2. The proportion of responders in both trials was significantly higher with naldemedine than with placebo in COMPOSE-1 (130 responders [47.6%] of 273 in the naldemedine group vs 94 responders [34.6%] of 272 in the placebo group, difference 13.0% [95% CI 4.8-21.3]; p=0.002) and in COMPOSE-2 (145 [52.5%] of 276 vs 92 [33.6%] of 274, difference 18.9% [10.8-27.0]; p<0.0001). Incidence of adverse events with naldemedine was similar to placebo (COMPOSE-1: 132 [49%] of 271 in the naldemedine group vs 123 [45%] of 272 in the placebo group; COMPOSE-2: 136 [50%] of 271 vs 132 [48%] of 274). Treatment related adverse events were noted in 59 (22%) of 271 patients in the naldemedine group and 45 (17%) of 272 in the placebo group in COMOPOSE-1, and in 54 (20%) of 271 patients in the naldemedine group and 31 (11%) of 274 in the placebo group of COMPOSE-2; the between-group differences were largely due to gastrointestinal disorders, which were more common with naldemedine than placebo (COMPOSE-1: 40 [15%] patients in the naldemedine group vs 18 [7%] in the placebo group; COMPOSE 2: 42 [16%] vs 20 [7%]). INTERPRETATION: Naldemedine treatment led to a significantly higher responder rate than did placebo and was generally well tolerated. These results support that naldemedine could be a new option for the treatment of opioid-induced constipation in patients with chronic non-cancer pain. FUNDING: Shionogi & Co, Ltd. PMID- 28576454 TI - Hospital effect on infections after four major surgical procedures: outlier and volume-outcome analysis using all-inclusive state data. AB - BACKGROUND: Hospital volume is known to have a direct impact on the outcomes of major surgical procedures. However, it is unclear if the evidence applies specifically to surgical site infections. AIMS: To determine if there are procedure-specific hospital outliers [with higher surgical site infection rates (SSIRs)] for four major surgical procedures, and to examine if hospital volume is associated with SSIRs in the context of outlier performance in New South Wales (NSW), Australia. METHODS: Adults who underwent one of four surgical procedures (colorectal, joint replacement, spinal and cardiac procedures) at a NSW healthcare facility between 2002 and 2013 were included. The hospital volume for each of the four surgical procedures was categorized into tertiles (low, medium and high). Multi-variable logistic regression models were built to estimate the expected SSIR for each procedure. The expected SSIRs were used to compute indirect standardized SSIRs which were then plotted in funnel plots to identify hospital outliers. FINDINGS: One hospital was identified to be an overall outlier (higher SSIRs for three of the four procedures performed in its facilities), whereas two hospitals were outliers for one specific procedure throughout the entire study period. Low-volume facilities performed the best for colorectal surgery and worst for joint replacement and cardiac surgery. One high-volume facility was an outlier for spinal surgery. CONCLUSIONS: Surgical site infections seem to be mainly a procedure-specific, as opposed to a hospital-specific, phenomenon in NSW. The association between hospital volume and SSIRs differs for different surgical procedures. PMID- 28576455 TI - Efficacy of the SENSIMED Triggerfish(r) in the postoperative follow-up of PHACO ExPRESS combined surgery. AB - OBJECTIVE: To determine the usefulness of the SENSIMED Triggerfish(r) system in the postoperative control of combined phacoemulsification and ExPRESS implant (PHACO-ExPRESS) surgery in patients with cataract and chronic open angle glaucoma (COAG) during a 2 months follow-up. METHODS: A prospective study conducted on 15 eyes that were subjected to PHACO-ExPRESS combined surgery. Using the SENSIMED Triggerfish(r) system, two records of the circadian patterns of intraocular pressure (IOP) were performed, one before and one after surgery. A record was made of the best corrected visual acuity (BCVA), comorbidities, previous IOP, and 7-30-60 days after surgery, as well as any hypotensive drugs and complications. RESULTS: The final sample was 12 eyes. The mean pre-operative BCVA (log MAR chart) before surgery was 0.5+/-0.2, and after surgery 0.14+/-0.1 (P=.02). The previous IOP was 18.7+/-3.8mmHg with 2.9+/-0.7 drugs. The mean IOP at 7, 30, and 60 days after surgery decreased to 13+/-4.1mmHg (P=.002), 13.5+/-2mmHg (P=.001), and 13.9+/-2.5mmHg (P=.001), respectively. The amplitudes of the circadian curves changed significantly after surgery (P=.007). The mean values between daytime and night-time periods decreased significantly from 146.8+/-80.9 mVeq and 61.2+/ 92.mVeq before surgery to 36.4+/-36 mVeq (P=.000), and -23,2+/-47.6mVeq (P=.014) after surgery, respectively. There were complications in one patient. CONCLUSIONS: The SENSIMED Triggerfish(r) monitoring system showed changes in the curves of the circadian patterns, as well as decreased mean amplitudes after the combined PHACO-ExPRESS technique, suggesting that it may become a useful tool for postoperative follow-up of COAG. PMID- 28576456 TI - Clinical, fundoscopic, tomographic and angiographic characteristics of dome shaped macula classified by bulge height. AB - OBJECTIVE: To classify dome shaped macula cases by their bulge height (BH). To analyse the characteristics associated with the groups formed by this classification. METHODS: Observational, descriptive and cross-sectional study on 15 selected eyes with dome shaped macula and high myopia. Using Caillaux method and optical coherence tomography images, 3groups were determined by their BH: low (50-350 MU), medium (351-650 MU), and high (>650 MU), and a study of visual acuity, axial length, presence of subfoveal serous detachment, and images by fluorescein angiography and optic coherence tomography, as main variables. The confidence interval was 95%. RESULTS: By using the chi-squared test, the study showed that a BH higher than 400 MU was associated with lower visual acuity, presence of subfoveal serous detachment, and greater atrophy of the retinal pigment epithelium measured by disc diameters (P<.05). CONCLUSIONS: The medium and high BH showed a positive correlation with the presence of foveal serous detachment and a lower visual acuity. PMID- 28576457 TI - Sugar and amino acid preference in the black garden ant Lasius niger (L.). AB - The mutualistic relationship that the garden ant Lasius niger (L.) establishes with trophobiotic homopterans makes this ant an unwelcome host in commercial crops, as ants improve the survival of homopteran pests from which they collect honeydew as a source of carbohydrates. Because the offering of alternative sugar sources can be used to disrupt this relationship, the present study explored L. niger's preference towards sugar and amino acid components that may be used in sugar solutions to increase their attractiveness. We tested the ant's preference between basic sugars (mono- and disaccharides) used as main ingredients and attractants (trisaccharides and amino acid (AA) sources) added to basic sugar in small amounts. Results showed that ants preferred disaccharides over monosaccharides, and that trisaccharides increased the attractiveness of sucrose solutions, albeit not when a protein source was added to the mix. In the case of AA sources, ants preferred components with a more diverse composition. In conclusion, trisaccharides and AA sources can be used to increase the attractiveness of sugar solutions, leading to the development of solutions that when supplied in artificial feeders can out-compete honeydew and disrupt harmful ant-homopteran mutualisms in agriculture. PMID- 28576458 TI - Understanding the complexities of traumatic brain injury: A big data approach to a big disease. PMID- 28576459 TI - Corrigendum to "TRPC3 channels critically regulate hippocampal excitability and contextual fear memory" Behav. Brain Res. 281(March) 2015, 69-77. PMID- 28576460 TI - The promising impact of molecular profiling on treatment strategies in oral cancers. AB - Oral squamous cell carcinoma (OSCC) is a major cause of cancer-associated morbidity and mortality. Although OSCC may develop from easily accessible oral preneoplastic lesions (OPLs), no intervention has been reported so far that reduces the rate of malignant transformation. A comprehensive molecular characterization of oral carcinogenesis may help refining treatment strategies both in patients with OPLs and OSCC. Herein, we review main molecular alterations occurring at different steps during oral carcinogenesis and show how molecularly based medicine and surgery may impact the outcome of OSCC in the future. PMID- 28576461 TI - Osteomyelitis of the jaw (with pathological fracture) following extraction of an impacted wisdom tooth. A case report. AB - Osteomyelitis is an infection and inflammation associated with the bone structures: bone marrow, cortical bone, periosteum, blood vessels and nerves. Although it does not have a frequent presentation, it can sometimes lead to complications such as pathological fractures or even septicemia. We present a clinical case study, to assess the relationship between osteomyelitis of the jaw and pathological fractures, after the extraction of an impacted wisdom tooth. This case highlights a rare complication following the surgical removal of mandibular third molar; a slow evolution of the pathology following an extraction should lead to close monitoring of the patient both clinically and radiographically, albeit osteomyelitis is a rare complication, it should be included as one of the differential diagnosis of persistent post-extraction pain. PMID- 28576462 TI - Platelet-rich plasma-enriched autologous fat graft in regenerative and aesthetic facial surgery: Technical note. AB - The goal of adding platelet-rich plasma (PRP) to autologous fat graft is to increase the survival rate of the graft. After their activation, platelets release some important growth factors. As a result, PRP may increase the proliferation and differentiation of Adipose-derived stem cells (ASCs) into adipocytes, improve fat graft vascularisation, and may block the apoptosis of grafted adipocytes. The other benefit expected from the addition of PRP to fat graft is the improvement of cutaneous trophicity above the grafted areas. An exhaustive review of the literature retrieved 11 clinical studies on humans and 7 on animals. A statistically significant increase of the survival rate of fat grafts has been found in 9 comparative studies. Our synthesis allowed us to set up the following protocol: addition of 20% of PRP activated with calcium hydrochloride to fat grafts. It may enhance the results of autologous facial fat graft in regenerative and aesthetic facial surgery. PMID- 28576463 TI - Prognostic implications of occult nodal tumour cells in stage I and II colon cancer: The correlation between micrometastasis and disease recurrence. AB - INTRODUCTION: Occult nodal tumour cells should be categorised as micrometastasis (MMs) and isolated tumour cells (ITCs). A recent meta-analysis demonstrated that MMs, but not ITCs, are prognostic for disease recurrence in patients with stage I/II colon cancer. AIMS & METHODS: The objective of this retrospective multicenter study was to correlate MMs and ITCs to characteristics of the primary tumour, and to determine their prognostic value in patients with stage I/II colon cancer. RESULTS: One hundred ninety two patients were included in the study with a median follow up of 46 month (IQR 33-81 months). MMs were found in eight patients (4.2%), ITCs in 37 (19.3%) and occult tumour cells were absent in 147 patients (76.6%). Between these groups, tumour differentiation and venous or lymphatic invasion was equally distributed. Advanced stage (pT3/pT4) was found in 66.0% of patients without occult tumour cells (97/147), 72.9% of patients with ITCs (27/37), and 100% in patients with MMs (8/8), although this was a non significant trend. Patients with MMs showed a significantly reduced 3 year disease free survival compared to patients with ITCs or patients without occult tumour cells (75.0% versus 88.0% and 94.8%, respectively, p = 0.005). When adjusted for T-stage, MMs independently predicted recurrence of cancer (OR 7.6 95% CI 1.5-37.4, p = 0.012). CONCLUSION: In this study, the incidence of MMs and ITCs in patients with stage I/II colon cancer was 4.2% and 19.3%, respectively. MMs were associated with an reduced 3 year disease free survival rate, but ITCs were not. PMID- 28576464 TI - Prognostic impact of macrometastasis linear size in sentinel node biopsy for breast carcinoma. AB - AIM: The aim of the present study was to evaluate the risk of axillary non sentinel lymph-node metastases (ALN) in breast cancer patients presenting macrometastasis (Mac-m) in the sentinel lymph node (SN). MATERIALS AND METHODS: A retrospective series of 1464 breast cancers from patients who underwent ALN dissection following the diagnosis of Mac-m in the sentinel node (SN) was studied. In all the cases the MAC-m linear size was evaluated and correlated with presence or absence of non-SN ALN metastases. RESULTS: Non-SN metastases were detected in 644?1464 cases (43.98%). The risk of further axillary metastases ranged from 20.2% (37/183) in cases with Mac-m between 2 and 2.9 mm, to 65.3% (262/401) in cases with Mac-m measuring > 10 mm. The risk of non-SN ALN metastases showed a 3% increase, parallel to each mm increment in SN metastasis size. The data evaluated with the receiver operating characteristic (ROC) curve showed that the Mac-m could be subdivided according to a new cut-off of 7 mm. pT1 tumours, with Mac-m < 7 mm had a risk of non-SN ALN metastases of <30%. Furthermore 109/127 of these (85.8%) had 3 or less non-SN ALN -metastases. CONCLUSIONS: The present data give a detailed description on the risk of non-SN ALN involvement, that may be useful in the evaluation of breast cancer patients. It is suggested that a Mac-m size of <7 mm is related to a low residual axillary disease burden in breast cancer patients with small (pT1) tumours. PMID- 28576465 TI - Metformin and caffeic acid regulate metabolic reprogramming in human cervical carcinoma SiHa/HTB-35 cells and augment anticancer activity of Cisplatin via cell cycle regulation. AB - Metformin shows benefits in anticancer prevention in humans. In this study, normal human fibroblasts (FB) and metastatic cervical cancer cells (SiHa) were exposed to 10 mM Metformin (Met), 100 MUM Caffeic Acid (trans-3,4 dihydroxycinnamic acid, CA) or combination of the compounds. Both drugs were selectively toxic towards cancer cells, but neither Met nor CA treatment suppressed growth of normal cells. Met and CA regulated metabolic reprogramming in SiHa tumor cells through different mechanisms: Met suppressed regulatory enzymes Glurtaminase (GLS) and Malic Enzyme 1 (ME1) and enhanced pyruvate oxidation via tricarboxylic acids (TCA) cycle, while CA acted as glycolytic inhibitor. Met/CA treatment impaired expression of Sterol Regulatory Element Binding Protein 1 (SREBP1c) which resulted in alleviation of de novo synthesis of unsaturated fatty acid. The toxic action of CisPt was supported by Met and CA not only in tumor cells, but also during co-culture of SiHa GFP+ cells with fibroblasts. Furthermore, Met and CA augmented Cisplatin (CisPt) action against quiescent tumor cells involving reprogramming of cell cycle. Our findings provide new insights into specific targeting of mitochondrial metabolism in neoplastic cells and into designing new cisplatin-based selective strategies for treating cervical cancer in humans with regard to the role of tumor microenvironment. PMID- 28576466 TI - Are additive effects of dietary surfactants on intestinal tight junction integrity an overlooked human health risk? - A mixture study on Caco-2 monolayers. AB - Surfactants may cause dysfunction of intestinal tight junctions (TJs), which is a common feature of intestinal autoimmune diseases. Effects of dietary surfactants on TJ integrity, measured as trans-epithelial resistance (TEER), were studied in Caco-2 cell monolayers. Cytotoxicity was assessed as apical LDH leakage. Monolayers were apically exposed for 60 min to the dietary surfactants solanine and chaconine (SC, potato glycoalkaloids, 0-0.25 mM), perfluorooctane sulfonic acid (PFOS, industrial contaminant, 0-0.8 mM), and sucrose monolaurate (SML, food emulsifier E 473, 0-2.0 mM) separately and as a mixture. Dose-response modelling of TEER EC50 showed that SC were 2.7- and 12-fold more potent than PFOS and SML, respectively. The mixture was composed of 1 molar unit SC, 2.7 units PFOS and 12 units SML ("SC TEER equivalent" proportions 1:1:1). Mixture exposure (0-0.05 mM SC equivalents) dose-response modelling suggested additive action on TJ integrity. Increasing SC and SML concentrations caused increased LDH leakage, but PFOS decreased LDH leakage at intermediate exposure concentrations. In the mixture PFOS appeared to protect from extensive SC- and SML-induced LDH leakage. Complex mixtures of surfactants in food may act additively on intestinal TJ integrity, which should be considered in risk assessment of emulsifier authorisation for use in food production. PMID- 28576467 TI - RIFM fragrance ingredient safety assessment, acetic acid, C7-9-branched alkyl esters, C8-rich, CAS Registry Number 108419-32-5. AB - The use of this material under current conditions is supported by existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data show that this material is not genotoxic. Data from the suitable read across analog isoamyl acetate (CAS# 123-92-2) show that this material does not have skin sensitization potential. The reproductive and local respiratory toxicity endpoints were completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (0.03 mg/kg/day and 1.4 mg/day, respectively). The repeated dose and developmental endpoint was completed using data on the target material, which provided a MOE > 100. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework. PMID- 28576468 TI - RIFM fragrance ingredient safety assessment, dihydro-alpha-terpineol, CAS Registry Number 498-81-7. PMID- 28576469 TI - The toxic influence of paraquat on hippocampal neurogenesis in adult mice. AB - Paraquat, a fast-acting non-selective contact herbicide, is considered an etiological factor related to Parkinson's disease. This study investigated its effects on hippocampal neurogenesis and cognition in adult mice as well as possible mechanisms for the effects. We administered paraquat (1.25 mg/kg, intraperitoneal injection, i.p.) and an equal volume of normal saline for 3 weeks to adult male C57BL/6J mice. The results showed that hippocampus-dependent spatial learning and memory was significantly impaired in paraquat-treated mice. Moreover, paraquat administration inhibited the proliferation of neural progenitor cells, and impaired the survival and altered the fate decision of newly generated cells in the hippocampus. The expression levels of caspase-3 and glial fibrillary acidic protein were significantly higher in paraquat-treated mice than in control mice. Interestingly, paraquat reduced the phosphorylation of Akt, but did not affect the total amount of Akt. In conclusion, our findings suggest that paraquat negatively affected adult hippocampal neurogenesis and cognition function. PMID- 28576470 TI - Toxicity of coumarins synthesized by Pechmann-Duisberg condensation against Drosophila melanogaster larvae and antibacterial effects. AB - On the background of the search of new insecticides friendly with the environment for replace those from synthesis organic origin with adverse effects on animals, soils and vegetables. It is reported in this study, the synthesis of a series of coumarins derivatives synthesized by Pechmann-Duisberg condensation assisted by microwave irradiation, their antibacterial and insecticidal activities. The most relevant results show that all compounds exhibit a mortality effect of 30-80% with doses between 10 and 100 MUg/mL. This activity is related to alkyl or aryl substituent type at position C-4 coumarin skeleton. The coumarins 5, 6, 7 and 9 showed highest insecticidal activities, and these coumarins have at 4-position a bulky and low polarity substituent. The aim of this work is to find the effects of the 4-substitued coumarins with different lipophilic and bulky substituents. Even though many researchers were worked on coumarins, there are not reports about the insecticidal effects of specifically 4-substitued coumarins. The difference of our major findings versus current knowledge is in this scope of the research. On the other hand, was possible to find that a chloride at 4-position, drew to extend the antibacterial spectra. PMID- 28576471 TI - Connection of Protein Transport and Organelle Contact Sites in Mitochondria. AB - Mitochondrial biogenesis and function depend on the intensive exchange of molecules with other cellular compartments. The mitochondrial outer membrane plays a central role in this communication process. It is equipped with a number of specific protein machineries that enable the transport of proteins and metabolites. Furthermore, the outer membrane forms molecular contact sites with other cell organelles like the endoplasmic reticulum (ER), thus integrating mitochondrial function in cellular physiology. The best-studied mitochondrial organelle contact site, the ER-mitochondria encounter structure (ERMES) has been linked to many vital processes including mitochondrial division, inheritance, mitophagy, and phospholipid transport. Strikingly, ER-mitochondria contact sites are closely connected to outer membrane protein translocases. The translocase of the outer mitochondrial membrane (TOM) represents the general mitochondrial entry gate for precursor proteins that are synthesized on cytosolic ribosomes. The outer membrane also harbors the sorting and assembly machinery (SAM) that mediates membrane insertion of beta-barrel proteins. Both of these essential protein translocases are functionally linked to ER-mitochondria contact sites. First, the SAM complex associates with an ERMES core component to promote assembly of the TOM complex. Second, several TOM components have been co-opted as ER-mitochondria tethers. We propose that protein import and organelle contact sites are linked to coordinate processes important for mitochondrial biogenesis. PMID- 28576473 TI - [The vomiting infant: When should intestinal volvulus be suspected?] PMID- 28576472 TI - Redirecting SR Protein Nuclear Trafficking through an Allosteric Platform. AB - Although phosphorylation directs serine-arginine (SR) proteins from nuclear storage speckles to the nucleoplasm for splicing function, dephosphorylation paradoxically induces similar movement, raising the question of how such chemical modifications are balanced in these essential splicing factors. In this new study, we investigated the interaction of protein phosphatase 1 (PP1) with the SR protein splicing factor (SRSF1) to understand the foundation of these opposing effects in the nucleus. We found that RNA recognition motif 1 (RRM1) in SRSF1 binds PP1 and represses its catalytic function through an allosteric mechanism. Disruption of RRM1-PP1 interactions reduces the phosphorylation status of the RS domain in vitro and in cells, redirecting SRSF1 in the nucleus. The data imply that an allosteric SR protein-phosphatase platform balances phosphorylation levels in a "goldilocks" region for the proper subnuclear storage of an SR protein splicing factor. PMID- 28576474 TI - Netrins as prophylactic targets in skeletal diseases: A double-edged sword? AB - The netrin family of proteins are involved in axon guidance during central nervous system development. In vertebrates, two membrane bound forms and five secreted forms of netrin have been reported. In addition to their critical role in neural morphogenesis, a growing number of reports suggest that netrin family proteins also play a role in inflammatory conditions, angiogenesis, and tumorigenesis. In these processes, Unc5 and DCC family proteins serve as receptors of netrin proteins. Recently, it was reported that some netrin family proteins may be involved in the pathogenesis of skeletal diseases including osteoporosis and arthritis. For example, administration of secreted netrin family proteins such as netrin 1 and netrin 4 has prophylactic potential in pathogenic bone degradation in mice. However, netrin 1 blocking antibody also protects mice from inflammatory bone destruction. Therefore, netrin family proteins are involved in the regulation of bone homeostasis, but their bona fide roles in the skeletal system remain controversial. In this review, we discuss the osteo-innate immune functions of the netrin family of proteins, and summarize their therapeutic potential. PMID- 28576475 TI - Gut microbiota and acute graft-versus-host disease. AB - Although allogeneic stem cell transplantation (allo-SCT) is a potentially curative treatment for various hematological diseases, acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality, and its management is clinically important. Advances in biological techniques have led to great progress in understanding the complex interactions between the host and the gut microbiota. The gut microbiota clearly modulates the immune response and is associated with the pathogenesis of various disorders. Also in allo-SCT, both preclinical and clinical results indicate that the gut microbiota is closely associated with the development of acute GVHD and transplant outcomes. These results led to the idea that improvement in quantitative and/or qualitative abnormalities of microbiota (dysbiosis) may be a new treatment strategy for acute GVHD. Evaluations of therapies targeting the gut microbiota such as probiotics or fecal microbiota transplantation have just begun. Furthermore, intervention in the gut microbiota with a nutritional approach including prebiotics, postbiotics, and antibiotics selection may also be another promising treatment option for acute GVHD. PMID- 28576476 TI - Mitral valve repair in dogs using an ePTFE chordal implantation device: a pilot study. AB - OBJECTIVE: Mitral valve (MV) regurgitation due to degenerative MV disease is the leading cause of cardiac death in dogs. We carried out preliminary experiments to determine the feasibility and short-term effects of beating-heart MV repair using an expanded polytetrafluorethylene (ePTFE) chordal implantation device (Harpoon TSD-5) in dogs. ANIMALS: This study involved six healthy purpose-bred Beagles (weight range 8.9-11.4 kg). MATERIAL AND METHODS: Following a mini-thoracotomy performed under general anesthesia, the TSD-5 was used to place 1 or 2 artificial ePTFE cords on the anterior MV leaflet or the posterior MV leaflet via a left ventricular transapical approach. The procedure was guided and monitored by transesophageal echocardiography. Postoperative antithrombotic treatment consisted of clopidogrel or a combination of clopidogrel and apixaban. Dogs were serially evaluated by transthoracic echocardiography at day 1, 7, 14, 21, and 30. The hearts were then examined for evaluation of tissues reactions and to detect signs of endothelialization. RESULTS: One or two chords were successfully implanted in five dogs. Four dogs completed the 30 days follow-up. One dog died intra-operatively because of aortic perforation. One dog died early post operatively from a hemorrhagic pleural effusion attributed to overly aggressive antithrombotic treatment. One dog developed a thrombus surrounding both the knot and the synthetic cord. Postmortem exam confirmed secure placement of ePTFE knots in the mitral leaflets in all dogs and the presence of endothelialization of the knots and chords. CONCLUSIONS: These preliminary results demonstrate the feasibility of artificial chordal placement using an ePTFE cordal implantation device in dogs. PMID- 28576477 TI - Perceptions of transcatheter device closure of patent ductus arteriosus in veterinary cardiology and evaluation of a canine model to simulate device placement: a preliminary study. AB - OBJECTIVES: The purpose of this study was to evaluate a canine patent ductus arteriosus (PDA) model developed for practicing device placement and to determine practices and perceptions regarding transcatheter closure of PDA from the veterinary cardiology community. METHOD: A silicone model was developed from images obtained from a dog with a PDA and device placement was performed with catheter equipment and a document camera to simulate fluoroscopy. A total of 36 individuals including 24 diplomates and 12 residents participated, and the feedback was obtained. The study included an initial questionnaire, practice with the model, observation of device placement using the model, and a follow-up questionnaire. RESULTS: A total of 92% of participants including 100% of residents indicated they did not have the opportunity to practice device placement before performing the procedure and obtained knowledge of the procedure from reading journal articles or observation. Participants indicated selecting the appropriate device size (30/36, 83%) and ensuring the device is appropriately positioned before release (18/36, 50%) as the most common areas of difficulty with device placement. Confidence level was higher after practicing with the model for residents when compared with diplomates and for participants that had performed 1-15 procedures when compared with those that had performed >15 procedures. These findings suggest those that have performed fewer procedures may benefit the most from practicing with a model. CONCLUSIONS: This preliminary study demonstrates the feasibility of a PDA model for practicing device placement and suggests that there is a potential benefit from providing additional training resources. PMID- 28576478 TI - Intracardiac echocardiography: use during transcatheter device closure of a patent ductus arteriosus in a dog. AB - Intracardiac echocardiography (ICE) is used in humans for percutaneous interventional procedures, such as transcatheter device closures. Intracardiac echocardiography provides high-resolution imaging of cardiac structures with two dimensional, M-mode, Doppler, and also three-dimensional modalities. The present report describes application of ICE during transcatheter occlusion of patent ductus arteriosus using a canine ductal occluder in a dog for which transesophageal echocardiography could not provide an optimal acoustic window. PMID- 28576479 TI - Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease. AB - INTRODUCTION: Aldosterone breakthrough (ABT) is the condition in which angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers fail to effectively suppress the activity of the renin angiotensin aldosterone system. The objective of this study was to determine if ABT occurs in dogs with naturally occurring myxomatous mitral valve disease receiving an ACEI, using the urine aldosterone to creatinine ratio (UAldo:C) as a measure of renin angiotensin aldosterone system activation. ANIMALS, MATERIALS AND METHODS: This study includes 39 dogs with myxomatous mitral valve disease. A UAldo:C cut-off definition (derived from a normal population of healthy, adult, and client-owned dogs) was used to determine the prevalence of ABT in this population. Spearman analysis and univariate logistic regression were used to evaluate the relationship between UAldo:C and ABT (yes/no) and eight variables (age, serum K+ concentration, serum creatinine concentration, ACEI therapy duration and ACEI dosage, furosemide therapy duration and furosemide dosage, and urine sample storage time). Finally, the UAldo:C in dogs receiving spironolactone, as part congestive heart failure (CHF) therapy, was compared to dogs with CHF that were not receiving spironolactone. RESULTS: The prevalence of ABT was 32% in dogs with CHF and 30% in dogs without CHF. There was no relationship between either the UAldo:C or the likelihood of ABT and the eight variables. Therapy with spironolactone lead to a significant elevation of the UAldo:C. DISCUSSION: Using the UAldo:C and a relatively stringent definition of ABT, it appears that incomplete RAAS blockade is common in dogs with MMVD receiving an ACEI. The prevalence of ABT in this canine population mirrors that reported in humans. While the mechanism of ABT is likely multifactorial and still poorly understood, the proven existence of ABT in dogs offers the potential to improve the prognosis for MMVD with the addition of a mineralocorticoid receptor blocker to current therapeutic regimens. CONCLUSIONS: Approximately 30% of dogs being treated for heart disease and CHF satisfied the definition of ABT. Identifying patient subpopulations experiencing ABT may help guide future study design and clinical decision-making. PMID- 28576480 TI - An orbital perivascular epithelioid cell tumor in a 7-year-old boy: case report and review of the literature. AB - We report the case of a 7-year-old boy who presented with a swollen right eye. Magnetic resonance imaging revealed a right intraconal orbital mass with intense contrast enhancement. Incisional biopsy led to a diagnosis of perivascular epithelioid cell tumor (PEComa). Sirolimus was initiated but discontinued at the third week of treatment because the tumor had progressed. A minor regression of the tumor was seen after six cycles of systemic chemotherapy. Previously reported cases of PEComa were benign in nature, and full remission was achieved with surgical excision. In the present case the tumor was malignant and responded only slightly to systemic chemotherapy. PMID- 28576481 TI - Ferrofluid-assisted rapid and directional harvesting of marine microalgal Chlorella sp. used for biodiesel production. AB - In this work, a novel harvesting strategy using ferrofluids coupled with flocculation as a magnetic directional harvesting system was developed, providing a fast and easy way to effectively collect microalgae with no further modifications made to the ferrofluids. With a ferrofluid dosage of 25mgL-1, a high harvesting efficiency of 95-100% was achieved within 1min. In addition, we successfully performed a wastewater recycling strategy coupled with a microalgal ferrofluid-harvesting dynamic flow-through system to harvest biomass of Chlorella sp. MTF-7 which could achieve over 80% of the maximum level after three repeated recycling cultivations. This work demonstrated the use of an integrated microalgal ferrofluid-harvesting dynamic flow-through system to develop a simple and effective strategy to enhance microalgal harvesting efficiency, along with wastewater recycling, in a marine microalgal Chlorella sp. MTF-7. PMID- 28576482 TI - Biosorption of Co (II) from aqueous solution using algal biochar: Kinetics and isotherm studies. AB - The present investigation deals with the utilization of biochar derived from the pyrolysis of microalgae Scenedesmus dimorphus as an adsorbent for the removal of cobalt (II) ion (Co) from aqueous solution. A series of experiments were conducted in a batch system to evaluate the performance of the biochar for Co removal. The effect of contact time on adsorption of Co (II) onto surface of the biochar was investigated. The equilibrium sorption data were analyzed by using Langmuir, Freundlich, Temkin, Harkins-Jura and Dubinin-Radushkevich (D-R) isotherms and were found to be adequate in describing the Co adsorption onto the biochar. Equilibrium data were well fitted for Freundlich, Temkin and D-R isotherms. The kinetic study of Co (II) adsorption on microalgae biochar were described by applying pseudo-first-order and pseudo-second-order rate equations. The surface of adsorbent before and after the removal of Co (II) was characterized by using SEM, EDX and XRD analysis. PMID- 28576483 TI - Biofilm based attached cultivation technology for microalgal biorefineries-A review. AB - The attached cultivation for microalga has many superiorities over the conventional aqua-suspend methods, which make it a promising pathway to supply feedstock for microalgae based bio-refinery attempts. In this review, the current reports on bioreactor, application, modeling, substratum material and engineering aspects were summarized and the future research and developments should be focused on the following aspects: 1) Build principles and guidelines for rational structure design by studying the relationship of physiological properties with typical structures and light regimes; 2) Set up theory foundation of substratum material selection by studying the physic-chemical properties of algal cells and substratum materials; 3) Further understanding the mass transfer behaviors of both CO2 and nutrients in biofilm for enhanced growth rate and products accumulation; 4) New equipment and machines for inoculation, harvesting and moisture keeping should be developed and integrated with bioreactor structure. PMID- 28576484 TI - Signs of subclinical atherosclerosis in asymptomatic patients at increased risk of type 2 diabetes mellitus. AB - AIMS: We aimed to study carotid intima media thickness (CIMT) in asymptomatic patients with an increased risk of type 2 diabetes mellitus (T2DM) and in a pre diabetic state. METHODS: Diabetes risk assessment was performed in 2420 participants in a voluntary screening program between 2011 and 2013. The risk of T2DM was estimated by the Findrisc scoring system (FR). A FR>=12 was considered as increased risk. HbA1c% between 5.7 and 6.4% signified a pre-diabetic state. Carotid duplex scan was performed and CIMT above 0.9 mm was regarded as pathological. Patients with T2DM or a history of cardiovascular disease were excluded. RESULTS: Overall 1475 subjects were included. Four groups were compared: "control" (normal HbA1c, FR<12), "HbA1c only" (HbA1c: 5.7-6.4%, FR<12), "Findrisc only" (normal HbA1c, FR>=12) and "combined" (HbA1c: 5.7-6.4%, FR>=12). Frequency of pathological maximal CIMT was 9.4%, 19.7%, 27.4% and 36.4% in the groups, respectively (p<0.001). Logistic regression analysis revealed that compared to control subjects, sex and risk factor-adjusted Odds Ratios for the presence of pathological maximal CIMT were 2.2 (p<0.001), 3.4 (p<0.001) and 5.1 (p<0.001) for the groups, respectively. CONCLUSIONS: Evaluation of Findrisc score and HbA1c at population level may facilitate early recognition of subclinical vascular complications even in the pre-diabetic state. PMID- 28576485 TI - Highly efficient one-step scarless protein tagging by type IIS restriction endonuclease-mediated precision cloning. AB - Protein tagging with a wide variety of epitopes and/or fusion partners is used routinely to dissect protein function molecularly. Frequently, the required DNA subcloning is inefficient, especially in cases where multiple constructs are desired for a given protein with unique tags. Additionally, the generated clones have unwanted junction sequences introduced. To add versatile tags into the extracellular domain of the transmembrane protein THSD1, we developed a protein tagging technique that utilizes non-classical type IIS restriction enzymes that recognize non-palindromic DNA sequences and cleave outside of their recognition sites. Our results demonstrate that this method is highly efficient and can precisely fuse any tag into any position of a protein in a scarless manner. Moreover, this method is cost-efficient and adaptable because it uses commercially available type IIS restriction enzymes and is compatible with the traditional cloning system used by many labs. Therefore, precision tagging technology will benefit a number of researchers by providing an alternate method to integrate an array of tags into protein expression constructs. PMID- 28576486 TI - Construction of an inducible stable cell line for efficient incorporation of unnatural amino acids in mammalian cells. AB - The genetic incorporation of unnatural amino acids (Uaas) with defined properties into proteins at designated sites represents an extremely powerful tool for protein engineering. However, the efficient incorporation of Uaas in response to the amber stop codon in mammalian cells remains a substantial challenge due to the competition from release factor 1(RF1). Addressing this challenge will greatly broaden the power and scope of this technology. Here, we chose the eRF1 mutant, which can selectively enhance Uaa incorporation in response to the amber codon without increasing the readthrough of the opal and ochre codons. Then, we developed an engineered stable cell line using a tetracycline-controlled inducible lentiviral system for the conditional expression of mutant eRF1, which can minimize the potential effect on normal translation termination. Using the eRF1-engineered cells, we provided a 2-fold improvement in the yield of protein containing a Uaa incorporated at a single site, with the protein yield approaching 90% of the wild-type control without the amber codon. Moreover, we achieved the successful incorporation of Uaas at four sites in various proteins at a measured level of 20%. PMID- 28576487 TI - MEK and PI3K catalytic activity as predictor of the response to molecularly targeted agents in triple-negative breast cancer. AB - Hyper-activation of the MAPK and PI3K-AKT pathways is linked to tumour progression in triple-negative breast cancer (TNBC). However, clinically effective predictive markers for drugs targeted against protein kinases involved in these pathways have not been identified. We investigated the ability of MEK and PI3K catalytic activity to predict sensitivity to trametinib and wortmannin in TNBC. MEK and PI3K activities correlated strongly with each other only in cell lines showing wortmannin-specific sensitivity, as shown by a linear regression curve (R = 0.951). Accordingly, we created a new parameter that distinguishes trametinib and wortmannin sensitivity in vitro and in vivo. Our findings suggest that the catalytic activities of MEK and PI3K might predict the response of TNBC to trametinib and wortmannin. PMID- 28576488 TI - Intronic miRNA-641 controls its host Gene's pathway PI3K/AKT and this relationship is dysfunctional in glioblastoma multiforme. AB - MicroRNAs have established their role as important regulators of the epigenome. A considerable number of human miRNA genes are found in intronic regions of protein coding host genes, in many cases adopting their regulatory circuitry. However, emerging evidence foreshadows an unprecedented importance for this relationship: Intronic miRNAs may protect the cell from overactivation of the respective host pathway, a setting that may trigger tumor development. AKT2 is a well-known proto oncogene central to the PI3K/AKT pathway. This pathway is known to promote tumor growth and survival, especially in glioblastoma. Its intronic miRNA, hsa-miR-641, is scarcely investigated, however. We hypothesized that miR-641 regulates its host AKT2 and that this regulation may become dysfunctional in glioblastoma. We found that indeed miR-641 expression differs significantly between GBM tissue and normal brain samples, and that transfection of glioma cells with miR-641 antagonizes the PI3K/AKT pathway. Combining clinical samples, cell cultures, and biomolecular methods, we could show that miR-641 doesn't affect AKT2's expression levels, but down-regulates kinases that are necessary for AKT2-activation, thereby affecting its functional state. We also identified NFAT5 as a miR-641 regulated central factor to trigger the expression of these kinases and subsequently activate AKT2. In summary, our study is the first that draws a connecting line between the proto-oncogene AKT2 and its intronic miRNA miR-641 with implication for glioblastoma development. PMID- 28576490 TI - Solution structure of human steroidogenic acute regulatory protein STARD1 studied by small-angle X-ray scattering. AB - Intracellular cholesterol transfer to mitochondria, a bottleneck of adrenal and gonadal steroidogenesis, relies on the functioning of the steroidogenic acute regulatory protein (StAR, STARD1), for which many disease-associated mutations have been described. Despite significant progress in the field, the exact mechanism of cholesterol binding and transfer by STARD1 still remains debatable and often considers significant structural rearrangements to achieve ligand binding. The crystal structure of STARD1, obtained recently at medium resolution, suggests that this protein has the same fold as other members of the START family. However, hydrodynamic properties and solution conformation of STARD1 are insufficiently characterized, partially due to poor solubility of this protein. Here, we used our recent protocol to obtain stable and soluble STARD1 and analyzed its hydrodynamic properties and solution conformation using a previously inapplicable small-angle X-ray scattering (SAXS). The SAXS data obtained exclusively from a monodisperse fraction of the monomeric protein suggest that, apart from movements of the flexible Omega1-loop, STARD1 unlikely undergoes significant spontaneous rearrangements proposed earlier as a gating mechanism for cholesterol binding. The consistency with the previously reported solution NMR structure of STARD6 suggests similarity of hydrodynamic behavior of other STARD containing proteins. PMID- 28576489 TI - Mitochondrial protein p32/HAPB1/gC1qR/C1qbp is required for efficient respiratory syncytial virus production. AB - Respiratory syncytial virus (RSV) is a major cause of respiratory infections in infants and the elderly, leading to more deaths than influenza each year, but there is no antiviral or efficacious vaccine currently available. Here we examine the role in infection of the host mitochondrial protein p32 (HABP/gC1qR/C1qbp) for the first time. RSV replication as well as infectious virus production was significantly reduced by p32 siRNA knockdown, consistent with an important role for p32 in RSV infection. p32 showed distinct mitochondrial localization throughout RSV infection, but immunostaining and high resolution confocal imaging for p32 as well as MitoTracker Red and cytochrome c, revealed clear changes in mitochondrial organization in RSV infection, with perinuclear mitochondrial compaction and asymmetric distribution at 8 and 18 h post-infection, respectively. The results implicate p32 as a key host factor for RSV virus production, and bring to light the potential importance of mitochondria in RSV infection. PMID- 28576492 TI - A DNA sequence obtained by replacement of the dopamine RNA aptamer bases is not an aptamer. AB - A unique specificity of the aptamer-ligand biorecognition and binding facilitates bioanalysis and biosensor development, contributing to discrimination of structurally related molecules, such as dopamine and other catecholamine neurotransmitters. The aptamer sequence capable of specific binding of dopamine is a 57 nucleotides long RNA sequence reported in 1997 (Biochemistry, 1997, 36, 9726). Later, it was suggested that the DNA homologue of the RNA aptamer retains the specificity of dopamine binding (Biochem. Biophys. Res. Commun., 2009, 388, 732). Here, we show that the DNA sequence obtained by the replacement of the RNA aptamer bases for their DNA analogues is not able of specific biorecognition of dopamine, in contrast to the original RNA aptamer sequence. This DNA sequence binds dopamine and structurally related catecholamine neurotransmitters non specifically, as any DNA sequence, and, thus, is not an aptamer and cannot be used neither for in vivo nor in situ analysis of dopamine in the presence of structurally related neurotransmitters. PMID- 28576491 TI - Blockage of glycolysis by targeting PFKFB3 alleviates sepsis-related acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells. AB - Sepsis-related acute lung injury (ALI) is characterized by excessive lung inflammation and apoptosis of alveolar epithelial cells resulting in acute hypoxemic respiratory failure. Recent studies indicated that anaerobic glycolysis play an important role in sepsis. However, whether inhibition of aerobic glycolysis exhibits beneficial effect on sepsis-induced ALI is not known. In vivo, a cecal ligation and puncture (CLP)-induced ALI mouse model was set up and mice treated with glycolytic inhibitor 3PO after CLP. The mice treated with the 3PO ameliorated the survival rate, histopathological changes, lung inflammation, lactate increased and lung apoptosis of mice with CLP-induced sepsis. In vitro, the exposure of human alveolar epithelial A549 cells to lipopolysaccharide (LPS) resulted in cell apoptosis, inflammatory cytokine production, enhanced glycolytic flux and reactive oxygen species (ROS) increased. While these changes were attenuated by 3PO treatment. Sequentially, treatment of A549 cells with lactate caused cell apoptosis and enhancement of ROS. Pretreatment with N-acetylcysteine (NAC) significantly lowered LPS and lactate-induced the generation of ROS and cell apoptosis in A549 cells. Therefore, these results indicate that anaerobic glycolysis may be an important contributor in cell apoptosis of sepsis-related ALI. Moreover, LPS specifically induces apoptotic insults to A549 cell through lactate-mediated enhancement of ROS. PMID- 28576493 TI - The suppression of innate immune response by human rhinovirus C. AB - Rhinovirus C (RV-C), a newly identified group of human rhinoviruses (RVs), is associated with exacerbation of severe asthma. The type I interferon (IFN) response induced by this virus and the mechanisms of evasion of IFN-mediated innate immunity for RV-C remain unclear. In this study, we constructed a full length cDNA clone of RV-C (LZ651) from a clinical sample. IFN-beta mRNA and protein levels were not elevated in differentiated Human bronchial epithelial (HBE) cells at the air-liquid interface infected with RV-C, except in the early stage of infection. The ability to attenuate IFN-beta activation was ascribed to 3Cpro of RV-C, and the 40-His site of 3Cpro played an important role. Furthermore, RIG-I was degraded by 3Cpro in a caspase-dependent manner and 3Cpro cleaved MAVS at 148 Q/A, which inhibited IFN signaling. Taken together, our results demonstrate the mechanism by which RV-C circumvents the production of type I IFN in infected cells. PMID- 28576495 TI - Metabolic pathway catalyzed by Vanin-1 pantetheinase plays a suppressive role in influenza virus replication in human alveolar epithelial A549 cells. AB - Our previous analysis of gene expression profiles in the peripheral blood from patients with influenza A (H1N1) pdm09 pneumonia revealed elevated transcription levels of the vanin-1 (vascular non-inflammatory molecule 1, VNN1) gene, which encodes an epithelial ectoenzyme with pantetheinase activity involved in recycling coenzyme A. Here, to elucidate the role of VNN1 in influenza A virus (IAV) H1N1 infection, we investigated the change of VNN1 expression in the context of IAV infection and the effects of its related substances, i.e., its direct substrate pantetheine and its two metabolites pantothenic acid and cysteamine on the replication of IAV in the human alveolar epithelial carcinoma cell line A549. The messenger RNA expression of VNN1 in A549 cells was significantly increased (by 4.9-fold) after IAV infection under an elevated concentration of pantetheine. Moreover, VNN1 mRNA levels were elevated by > 100 fold in response to pro-inflammatory cytokines, especially TNF-alpha and IL 1beta. Pantetheine significantly reduced the IAV replication and IAV Matrix 1 (M1) mRNA levels when it was administered prior to and during infection. In addition, cysteamine treatment during IAV infection significantly reduced the viral replication and IAV M1 mRNA levels, whereas pantothenic acid did not. These findings suggest that the metabolic pathway catalyzed by VNN1 pantetheinase plays a suppressive role in IAV infection in the respiratory tract, especially in severe conditions under hypercytokinemia. PMID- 28576496 TI - Identification of zinc finger transcription factor EGR2 as a novel acetylated protein. AB - EGR2 is a zinc finger transcription factor that regulates myelination in the peripheral nervous system and T cell anergy. The transcriptional activity of EGR2 is known to be regulated by its co-activators and/or co-repressors. Although the activity of transcription factors is generally regulated not only by interactions with co-regulators but also posttranslational modifications including acetylation, little is known about posttranslational modifications of EGR2. Here we show that EGR2 is a novel acetylated protein. Through immunoblotting analyses using an antibody that specifically recognizes the acetylated form of EGR2, CBP and p300 were identified as acetyltransferases, while HDAC6, 10 and SIRT1 were identified as deacetylases of EGR2. Although the NuRD complex containing HDAC1 and HDAC2 is known to associate with EGR2, the present study suggests that acetylation of EGR2 is regulated independently of NuRD. PMID- 28576497 TI - Regulation of osteoclast differentiation and actin ring formation by the cytolinker protein plectin. AB - Osteoclasts are cells that resorb the bone matrix and maintain bone and calcium homeostasis. An actin ring is a characteristic actin structure that is essential for bone resorption by osteoclasts. Tyrosine kinase Src deficient osteoclasts do not form actin rings; thus, Src is a key molecule for actin ring formation in osteoclasts. However, how Src regulates actin ring formation is not fully understood. We identified the cytolinker protein plectin as a Src-binding protein by immunoprecipitation and liquid chromatography tandem mass spectrometry. Plectin is a huge protein (>500 kDa) and regulates the cytoskeleton by binding to actin and tubulin. We assessed the expression and role of plectin in osteoclasts. Plectin was expressed and co-localized with Src close to the actin ring in osteoclasts. Moreover, plectin was tyrosine-phosphorylated by Src. Differentiation and actin ring formation were inhibited by downregulation of plectin. These results suggest an important role for plectin in osteoclast differentiation and actin ring formation through Src binding. PMID- 28576498 TI - Characterization of cancer stem cell drug resistance in the human colorectal cancer cell lines HCT116 and SW480. AB - BACKGROUND: Cancer stem cells (CSCs) share a number of properties with somatic stem cells including heightened protective mechanisms and the ability to self renew. CSCs are a critical subpopulation of cancer cells implicated in tumor formation, metastases and recurrence. METHODS: We used serial colonosphere culture to enrich for CSCs from two human CRC cell lines. The expression of proposed colorectal CSC markers and multi-drug resistance genes were assessed via flow cytometry and RT-qPCR. Drug resistance gene expression and self-renewal ability were also determined following treatment with the chemotherapeutic 5 fluorouracil. RESULTS: Colonosphere culture successfully enriched for a subpopulation of cells with CSC-related gene expression and heightened self renewal ability, particularly in the SW480 cell line. Chemotherapy treatment significantly reduced sphere formation however a small fraction of cells survived treatment and retained their self-renewal ability. CONCLUSIONS: Our findings support the use of the sphere formation assay to study CSCs. The ability of cells to self-renew following chemotherapy treatment highlights the importance of targeting both the bulk of tumor cells and the CSC population to prevent recurrence in colorectal cancer. PMID- 28576494 TI - Antagonism of type I interferon by flaviviruses. AB - The prompt and tightly controlled induction of type I interferon is a central event of the immune defense against viral infection. Flaviviruses comprise a large family of arthropod-borne positive-stranded RNA viruses, many of which represent a serious threat to global human health due to their high rates of morbidity and mortality. All flaviviruses studied so far have been shown to counteract the host's immune response to establish a productive infection and facilitate viral spread. Here, we review the current knowledge on the main strategies that human pathogenic flaviviruses utilize to escape both type I IFN induction and effector pathways. A better understanding of the specific mechanisms by which flaviviruses activate and evade innate immune responses is critical for the development of better therapeutics and vaccines. PMID- 28576499 TI - Retraction notice to "Multiple inflammatory pathways are involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice" [Neurobiol. Aging 33 (2012) 2661-2677]. PMID- 28576500 TI - The efficacy of conventional radiofrequency denervation in patients with chronic low back pain originating from the facet joints: a meta-analysis of randomized controlled trials. AB - BACKGROUND CONTEXT: Radiofrequency denervation is commonly used for the treatment of chronic facet joint pain that has been refractory to more conservative treatments, although the evidence supporting this treatment has been controversial. PURPOSE: We aimed to elucidate the precise effects of radiofrequency denervation in patients with low back pain originating from the facet joints relative to those obtained using control treatments, with particular attention to consistency in the denervation protocol. STUDY DESIGN/SETTING: A meta-analysis of randomized controlled trials was carried out. PATIENT SAMPLE: Adult patients undergoing radiofrequency denervation or control treatments (sham or epidural block) for facet joint disease of the lumbar spine comprised the patient sample. OUTCOME MEASURES: Visual analog scale (VAS) pain scores were measured and stratified by response of diagnostic block procedures. METHOD: We searched PubMed, Embase, Web of Science, and the Cochrane Database for randomized controlled trials regarding radiofrequency denervation and control treatments for back pain. Changes in VAS pain scores of the radiofrequency group were compared with those of the control group as well as the minimal clinically important difference (MCID) for back pain VAS. Meta-regression model was developed to evaluate the effect of radiofrequency treatment according to responses of diagnostic block while controlling for other variables. We then calculated mean differences and 95% confidence intervals (CIs) using random-effects models. RESULTS: We included data from seven trials involving 454 patients who had undergone radiofrequency denervation (231 patients) and control treatments such as sham or epidural block procedures (223 patients). The radiofrequency group exhibited significantly greater improvements in back pain score when compared with the control group for 1-year follow-up. Although the average improvement in VAS scores exceeded the MCID, the lower limit of the 95% CI encompassed the MCID. A subgroup of patients who responded very well to diagnostic block procedures demonstrated significant improvements in back pain relative to the control group at all times. When placed into our meta-regression model, the response to diagnostic block procedure was responsible for a statistically significant portion of treatment effect. Studies published over the last two decades revealed that radiofrequency denervation reduced back pain significantly in patients with facet joint disease compared with the MCID and control treatments. CONCLUSIONS: Conventional radiofrequency denervation resulted in significant reductions in low back pain originating from the facet joints in patients showing the best response to diagnostic block over the first 12 months when compared with sham procedures or epidural nerve blocks. PMID- 28576501 TI - Reporting the results of meta-analyses: a plea for incorporating clinical relevance referring to an example. AB - BACKGROUND CONTEXT: The results of meta-analyses are frequently reported, but understanding and interpreting them is difficult for both clinicians and patients. Statistical significances are presented without referring to values that imply clinical relevance. PURPOSE: This study aimed to use the minimal clinically important difference (MCID) to rate the clinical relevance of a meta analysis. STUDY DESIGN: This study is a review of the literature. PATIENT SAMPLE: This study is a review of meta-analyses relating to a specific topic, clinical results of cervical arthroplasty. OUTCOME MEASURE: The outcome measure used in the study was the MCID. METHODS: We performed an extensive literature search of a series of meta-analyses evaluating a similar subject as an example. We searched in Pubmed and Embase through August 9, 2016, and found articles concerning meta analyses of the clinical outcome of cervical arthroplasty compared with that of anterior cervical discectomy with fusion in cases of cervical degenerative disease. We evaluated the analyses for statistical significance and their relation to MCID. MCID was defined based on results in similar patient groups and a similar disease entity reported in the literature. RESULTS: We identified 21 meta-analyses, only one of which referred to MCID. However, the researchers used an inappropriate measurement scale and, therefore, an incorrect MCID. The majority of the conclusions were based on statistical results without mentioning clinical relevance. CONCLUSIONS: The majority of the articles we reviewed drew conclusions based on statistical differences instead of clinical relevance. We recommend introducing the concept of MCID while reporting the results of a meta analysis, as well as mentioning the explicit scale of the analyzed measurement. PMID- 28576502 TI - Re: Umberto Leone Roberti Maggiore, Simone Ferrero, Massimo Candiani, et al. Bladder Endometriosis: A Systematic Review of Pathogenesis, Diagnosis, Treatment, Impact on Fertility, and Risk of Malignant Transformation. Eur Urol 2017;71:790 807. PMID- 28576503 TI - Reply to Erfan Ayubi and Saeid Safiri's Letter to the Editor re: R. Jeffrey Karnes, Voleak Choeurng, Ashley E. Ross, et al. Validation of a Genomic Risk Classifier to Predict Prostate Cancer-specific Mortality in Men with Adverse Pathologic Features. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2017.03.036. Methodological Issues. PMID- 28576504 TI - Improving Quality in Renal Cell Carcinoma Care: Bridging the Gap Between Measurement and Meaning. PMID- 28576505 TI - Reply to Thorsten Derlin, Christoph-A. von Klot, and Katja Hueper's Letter to the Editor re: Sungmin Woo, Chong Hyun Suh, Sang Youn Kim, Jeong Yeon Cho, Seung Hyup Kim. Diagnostic Performance of Magnetic Resonance Imaging for the Detection of Bone Metastasis in Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2017.03.042. PMID- 28576506 TI - Re: R. Jeffrey Karnes, Voleak Choeurng, Ashley E. Ross, et al. Validation of a Genomic Risk Classifier to Predict Prostate Cancer-specific Mortality in Men with Adverse Pathologic Features. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2017.03.036. PMID- 28576507 TI - Dementia registries around the globe and their applications: A systematic review. AB - Patient registries are valuable tools helping to address significant challenges in research, care, and policy. Registries, well embedded in many fields of medicine and public health, are relatively new in dementia. This systematic review presents the current situation in regards to dementia registries worldwide. We identified 31 dementia registries operating on an international, national, or local level between 1986 and 2016. More than half of the registries aimed to conduct or facilitate research, including preclinical research registries and registries recruiting research volunteers. Other dementia registries collected epidemiological or quality of care data. We present evidence of practical and economic outcomes of registries for research, clinical practice and policy, and recommendations for future development. Global harmonization of recruitment methods and minimum data would facilitate international comparisons. Registries provide a positive return on investment; their establishment and maintenance require ongoing support by government, policy makers, research funding bodies, clinicians, and individuals with dementia and their caregivers. PMID- 28576508 TI - A review of the role of serotonin system genes in obsessive-compulsive disorder. AB - Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder that causes the patient to experience intrusive thoughts and/or to carry out repetitive, ritualized behaviors that are time consuming and impairing. OCD is familial and heritable. The genetic factors responsible for pathogenesis, however, remain largely unknown despite the numerous candidate gene studies conducted. Based on efficacy of serotonin reuptake inhibitors (SRIs) in treating OCD, serotonin system genes have been a dominant focus in OCD candidate gene studies. We review the most commonly studied candidate serotonin system gene variants (specifically in SLC6A4, HTR2A, HTR1B, and HTR2C) and their association with OCD. Although findings to date are mixed, serotonin transporter polymorphism 5-HTTLPR and HTR2A polymorphism rs6311 (or rs6313) are most consistently associated with OCD. Mixed findings may be the result of genetic complexity and phenotypic heterogeneity that future studies should account for. Homogenous patient subgroups reflecting OCD symptom dimensions, OCD subtypes, and sex should be used for gene discovery. PMID- 28576509 TI - A neuroanatomical account of mental time travelling in schizophrenia: A meta analysis of functional and structural neuroimaging data. AB - Mental time travel (MTT) abilities could be particularly compromised in schizophrenic patients due to a deficit of the cognitive processes at the basis of remembering the past and imaging the future: constructive processes, theory of mind and self-awareness. Accordingly, we assumed that the neural circuits typically associated with MTT in healthy people might be partially compromised in chronic schizophrenic patients. To quantitatively and anatomically test our hypothesis, we run two meta-analyses using the Activation Likelihood Estimate method: (i) a neurofunctional meta-analysis on MTT in healthy subjects, (ii) a morphometrical meta-analysis on chronic schizophrenia. The results of the two meta-analyses were overlapped in order to identify the candidate regions involved in MTT deficit in schizophrenia. A significant overlap was found in the vmPFC, in the precuneus, in the hippocampus and in the insular cortex. We assume that MTT deficits in schizophrenic patients may be the results of a complex dysfunctional interaction between the system underlying the creation of self-representation, the constructive system and the salience attribution network. PMID- 28576510 TI - The role of the habenula in the transition from reward to misery in substance use and mood disorders. AB - The habenula (Hb) is an evolutionary well-conserved structure located in the epithalamus. The Hb receives inputs from the septum, basal ganglia, hypothalamus, anterior cingulate and medial prefrontal cortex, and projects to several midbrain centers, most importantly the inhibitory rostromedial tegmental nucleus (RMTg) and the excitatory interpeduncular nucleus (IPN), which regulate the activity of midbrain monoaminergic nuclei. The Hb is postulated to play a key role in reward and aversion processing across species, including humans, and to be implicated in the different stages of transition from recreational drug intake to addiction and co-morbid mood disorders. The Hb is divided into two anatomically and functionally distinct nuclei, the lateral (LHb) and the medial (MHb), which are primarily involved in reward-seeking (LHb) and misery-fleeing (MHb) behavior by controlling the RMTg and IPN, respectively. This review provides a neuroanatomical description of the Hb, discusses preclinical and human findings regarding its role in the development of addiction and co-morbid mood disorders, and addresses future directions in this area. PMID- 28576512 TI - Erratum to "Impact of spillover from white matter by partial volume effect on quantification of amyloid deposition with [11C]PiB PET" [NeuroImage 143 (2016) 316-324]. PMID- 28576513 TI - miRNA expression profile in multicellular breast cancer spheroids. AB - Multicellular Tumor Spheroids develop a heterogeneous micromilieu and different cell populations, thereby constituting a cancer model with intermediate characteristics between in vitro bi-dimensional cultures and in vivo tumors. Multicellular Tumor Spheroids also acquire tumor aggressiveness features due to transcription modulation of coding and non-coding RNA. Utilizing microarray analyses, we evaluated the microRNAs expression profile in MCF-7 breast cancer cells cultured as Multicellular Tumor Spheroids. The expression data was used to predict associated cellular and molecular functions using different software tools. The biological importance of two dysregulated miRNAs (miR-221-3p and miR 187) was studied by functional assays. Finally, the clinical relevance of these dysregulated miRNAs was explored using previously reported data. Thirty-three dysregulated microRNAs were found in MCF-7 Multicellular Tumor Spheroids. miRNA expression changes were closely linked with growth, proliferation, and cell development. miRNA-221-3p and miR-187 were implicated in the acquisition of migration/invasion capacities, sensitivity to the deprivation of growth factors, cell cycle phase regulation, and cell death. A panel of 5 miRNAs, including miR 187, showed a good predictive value in discriminating between low and high-risk groups of breast cancer. PMID- 28576514 TI - Ultrasonographic assessment of tonsillar volume in children. AB - OBJECTIVES: Adenotonsillar hypertrophy in children is the most common anatomical abnormality associated with obstructive sleep apnoea. Perioperative complications associated with adenotonsillectomy are more common in children with severe obstructive sleep apnoea. An objective preoperative method to determine the size of tonsils is missing. This study assessed the validity of ultrasound as a tool for measuring tonsillar size in children. METHODS: Single-institution prospective study of twenty-six children aged 2-6 years who underwent elective bilateral tonsillectomy. Trans-cervical ultrasonographic assessment of tonsillar size prior to tonsillectomy operation was performed. We assessed correlation of ultrasonographic and actual tonsillar volume. RESULTS: A total of 52 tonsils from 26 patients were measured. Actual and ultrasonographic mean tonsillar volume (+/ SD) was 3.9 (+/-2.1) ml and 3.6 (+/-2.5) ml, respectively (P = 0.24). Ultrasonographic and actual measurements correlated well (r = 0.89). CONCLUSIONS: This is the first study to show that ultrasound is a suitable objective method for determining tonsillar volume in paediatric patients. Preoperative ultrasound assessment of tonsillar anatomy and size may be an additional and suitable, objective method in the development of a risk stratification system in children with obstructive sleep apnoea undergoing tonsillar surgery. PMID- 28576515 TI - A case report of cavernous sinus thrombosis after trauma. AB - Cavernous sinus thrombosis is a rare but well-documented complication of sinus disease, propagated by intracranial spread of infection via valveless veins of the midface, with facial cellulitis as an uncommon source of infection. We present a case of significant intracranial thromboses secondary to nasal dorsal abscess after trauma that was successfully treated with bedside drainage of the abscess in addition to broad-spectrum antibiotics, anticoagulation, and steroids, and remains asymptomatic with seven months follow-up. PMID- 28576516 TI - A novel missense mutation in the SLC26A4 gene causes nonsyndromic hearing loss and enlarged vestibular aqueduct. AB - OBJECTIVES: We aimed to investigate the genetic causes of hearing loss in a Chinese proband with nonsyndromic hearing loss and enlarged vestibular aqueduct syndrome. METHODS: We conducted clinical and genetic evaluations in a deaf proband and his normal-hearing parents. Multiplex PCR technology combined with Ion TorrentTM next-generation sequencing technology was used to detect the pathogenic mutations. As a control, a group of 1500 previously studied healthy newborns from the same ethnic background were subjected to deafness gene screening using the same method as in our previous study. RESULTS: The proband harbored two mutations in the SLC26A4 gene in the form of compound heterozygosity. He was found to be heterozygous for a novel mutation named c.1742 G > T (p.Arg581Met) in exon 13 and for the known mutation c.589 G > A (p.Gly197Arg). These variants were carried in the heterozygous state by the parents and therefore co-segregated with the genetic disease. The c.1742 G > T (p.Arg581Met) mutation was absent in 1500 healthy newborns. Protein alignment indicated high evolutionary conservation of the p.R581 residue, and this mutation was predicted by PolyPhen-2 and other online tools to be damaging. CONCLUSION: This study demonstrates that the novel mutation c.1742 G > T (p.Arg581Met) in compound heterozygosity with c.589 G > A in the SLC26A4 gene is the main cause of deafness in a family clinically diagnosed with enlarged vestibular aqueduct (EVA). Our study will provide a basic foundation for further investigations to elucidate the SLC26A4-related mechanisms of hearing loss. PMID- 28576517 TI - Retrieval of tracheobronchial foreign bodies by short flexible endoscopy in children. AB - OBJECTIVES: Flexible endoscopy (FE) is frequently used to diagnose tracheobronchial foreign bodies (TBFB). However, it is still controversial for retrieval of TBFB in pediatric field. This study aims at reporting and evaluating our experiences of using short-length FE with a non-invasive ventilation (NIV) technique and intensive care unit (ICU) support in retrieving pediatric TBFB. METHODS: A retrospective review of the hospital database and FE videos of pediatric patients aged less than 18 year-old who were diagnosed of TBFB and managed in our hospital over a 17-year period (1999-2015). The demographic data were collected and analyzed. A NIV technique of providing nasopharyngeal oxygen with intermittent nose closure and abdominal compression was routinely performed in procedural sedated patients throughout the whole FE procedures. RESULTS: Sixty six consecutive patients with 76 TBFB were enrolled. Among them, 72 (94.7%) TBFB in 64 patients were successfully retrieved at the first attempt of FE immediately after the diagnosis was made. There were 13 iatrogenic TBFB in patients who already had coexisting airway problems. The median age was 16 months (range 1.5 months-17 years) and the median body weight was 10.5 kg (range 3.5-48.5 kg). Seventy (70/72, 97.2%) TBFB were retrieved by short-length FE and among them, 55 procedures (55/72, 76.4%) used FE with no working channel. No significant acute or late adverse effects were noted. The mean retrieval procedural time was 23.6 +/- 15.1 min. CONCLUSION: Using short-length FE with this NIV technique, appropriate sedation and ICU support is a safe, simple and effective modality for the retrieval of TBFB immediately after confirming the diagnosis in pediatric patients. PMID- 28576511 TI - Elucidating opportunities and pitfalls in the treatment of experimental traumatic brain injury to optimize and facilitate clinical translation. AB - The aim of this review is to discuss the research presented in a symposium entitled "Current progress in characterizing therapeutic strategies and challenges in experimental CNS injury" which was presented at the 2016 International Behavioral Neuroscience Society annual meeting. Herein we discuss diffuse and focal traumatic brain injury (TBI) and ensuing chronic behavioral deficits as well as potential rehabilitative approaches. We also discuss the effects of stress on executive function after TBI as well as the response of the endocrine system and regulatory feedback mechanisms. The role of the endocannabinoids after CNS injury is also discussed. Finally, we conclude with a discussion of antipsychotic and antiepileptic drugs, which are provided to control TBI-induced agitation and seizures, respectively. The review consists predominantly of published data. PMID- 28576518 TI - Refractory sleep-disordered breathing due to unilateral lingual tonsillar hypertrophy in a child with Proteus Syndrome. AB - Proteus Syndrome (PS) is a rare congenital overgrowth disease affecting bones, skin, adipose and the central nervous system. The result is asymmetric, disfiguring hypertrophy which can manifest as craniofacial dysmorphia and aerodigestive tract abnormalities. We report the case of obstructive lingual tonsillar hypertrophy resulting in residual sleep disordered breathing after adenotonsillectomy in a child with PS, a previously unrecognized manifestation of the disease. Endoscopic treatment with coblation effectively and safely treated the obstructive symptoms. PMID- 28576519 TI - Pediatric post-tonsillectomy hemorrhage in the setting of post-transplantation immunosuppression. AB - INTRODUCTION: Long-term immunosuppressants form an integral part of therapy for post-transplantation patients. Immunosuppressants may also have an anticoagulant effect, and little is known about their effects on bleeding risk after adenotonsillectomy. Our objective was to investigate whether there is an increased observed rate of post-tonsillectomy hemorrhage in a population of pediatric patients on long-term immunosuppressants after solid organ transplantation, compared to healthy controls. METHODS: This was a retrospective chart review of pediatric patients with a history of renal or heart transplant undergoing adenotonsillectomy at our institution between 2000 and 2014. All patients underwent tonsillectomy with monopolar electrocautery. Retrieved data included perioperative medications, occurrence of post-operative bleeding and associated treatment. For comparison, we obtained a population of age-matched controls with no history of immunosuppression who underwent the same procedure. RESULTS: A total of 34 patients meeting criteria were identified, of which 3 (8.82%) suffered a postoperative bleed. Forty-seven controls were obtained, with a total of 2 (4.26%) postoperative hemorrhages (p = 0.65). Two of the post transplantation patients who bled postoperatively required cauterization in the operating room. None of the controls required surgical treatment. The incidences of postoperative bleeding requiring surgical treatment were 5.88% and 0%, respectively (p = 0.17). CONCLUSION: We failed to demonstrate an increased risk of bleeding after undergoing adenotonsillectomy in our cohort of post transplantation pediatric patients on chronic immunosuppression. Future research, likely requiring a multi-institutional effort, could stratify by immunosuppressive agent to elucidate bleeding risk with specific medications. PMID- 28576520 TI - Clinical characterization of novel chromosome 22q13 microdeletions. AB - INTRODUCTION: The advent of chromosome microarray analysis (CMA) for evaluation of patients with multiple congenital anomalies has made it possible to define chromosomal imbalances with greater precision and resolutions significantly smaller than possible by standard G-banded chromosome analysis. We describe two patients with novel chromosomal anomalies involving chromosome 22q13, a locus also associated with Phelan-McDermid syndrome (PMS). OBJECTIVE: We aim to characterize the novel phenotypic and genotypic findings of two patients with 22q13 microdeletions, distinct from PMS, comparing and contrasting with features of PMS. RESULTS: Case 1 is a 4-year-old boy with global developmental delay, esotropia, moderate aortic root dilation, genu valgum, and in-toeing gait. MRI brain for evaluation of neonatal hypotonia revealed a left cerebellopontine angle arachnoid cyst. He referred on newborn hearing screening, and diagnostic auditory brainstem response (ABR) showed left profound retrocochlear hearing loss. Surgical intervention for the arachnoid cyst was deferred, with spontaneous resolution at age two years without hearing recovery. CMA revealed a novel, de novo 5.1 Mb microdeletion of 22q13.31q13.33 not involving SHANK3, a gene typically deleted in PMS. Case 2 is a 6-year-old girl with some features also seen in patients with PMS but also several atypical features. She has a complex chromosomal rearrangement including a 5.3 Mb 22q13 microdeletion (not including SHANK3) and de novo 2.1 Mb gain of 22q11. CONCLUSION: As diagnostic sensitivity improves, smaller chromosomal imbalances will be detectable related to milder or different phenotypes. We present two patients with novel deletions of chromosome 22q13 associated with multiple congenital anomalies and features distinct from PMS. PMID- 28576521 TI - The effect of caffeic acid phenethyl ester (CAPE) on tympanosclerosis. AB - OBJECTIVE: To investigate the effects of caffeic acid phenethyl ester (CAPE) on tympanosclerosis. MATERIALS AND METHODS: Thirty-two male Sprague Dawley rats were separated into 4 groups as CAPE (n = 10), alcohol (n = 10), control (n = 8) and normal (n = 4) groups. All tympanic membranes except normal group were myringotomised and type 3 Streptococcus pneumoniae strains was injected into their middle ears. Myringotomies were repeated for 5 weeks. Intraperitoneal (i.p) CAPE were administrated to the CAPE group at 10 MUmol/kg/day and 10% ethyl alcohol administrated to the alcohol group for 5 weeks. The control group were left untreated. Findings of myringosclerosis were recorded by otomicroscope at sixth week. Then, all rats were sacrificed and tympanic membrane thickness and severity of middle ear mucosal inflammation evaluated histopathalogically. RESULTS: Severity of myringosclerosis was significantly higher in the alcohol and control groups compared to the CAPE group (p < 0.001), but was not significant when alcohol and control groups were compared (p = 0.17). The tympanic membrane thickness measured in the alcohol and control groups were significantly higher compared to the CAPE group (p < 0.001), but was not significant when alcohol and control groups were compared (p = 0.17). The severity of inflammation in the middle ear mucosa was significantly higher in the alcohol and control groups compared to the CAPE group (respectively, p < 0.001, p = 0.03). The severity of inflammation in the middle ear mucosa was not significant between alcohol and control groups (p = 0.30). CONCLUSION: CAPE has anti-inflammatory and antioxidant effects on the development of MS in myringotomized rats, so reduces the severity of tympanosclerosis. PMID- 28576522 TI - PD-L1 expression and CD8+ infiltration shows heterogeneity in juvenile recurrent respiratory papillomatosis. AB - INTRODUCTION: Tumor immunotherapy have broadened therapeutic options for tumor treatment. The role of immune function in juvenile recurrent respiratory papillomatosis (JRRP) has not been investigated. Applying immunoblockade inhibitors as a novel disease treatment is unclear. Our study, for the first time, evaluates immune infiltration and immuno-suppressive molecule expression in JRRP. Our study provides insights in possibly treating this disease with tumor immunotherapies. We aimed to determine expression of programmed death-ligand 1 (PD-L1), a cancer escape protein, and presence of CD8+ T cell infiltration in tumor microenvironment. MATERIAL AND METHODS: Seven patients with JRRP (mean age: 7.43; age range 3-17) in this study routinely have their tumors surgical debulked at Massachusetts Eye and Ear Infirmary. Following surgery, samples were de identified and sent to pathology where they were stained and analyzed. RESULTS: Six out of seven patients expressed PD-L1 on tumor cells to various extents. Three patients showed concurrent PD-L1 expression on tumor cells and abundant CD8+ tumor infiltrating lymphocytes as well as PD-L1+ stromal lymphocytes, while PD-L1 expression on tumor cells were not associated with CD8+ tumor infiltrating T cells nor PD-L1+ stromal lymphocytes in the other three patients. HPV 6/11 and p16 was detected in all the patients. There appeared to be no correlation between either PD-L1 expression and CD8+ infiltration and clinical severity as measured by both the number of surgeries per year or Derkay score. CONCLUSIONS: Despite a small cohort, the expression of p16 and HPV 6/11 in all of the patients confirms the tissues were HPV tumor cells. PD-L1 expression was detected in the vast majority of tumor samples, while inflammatory cell compartments showed a higher degree of variation. Expression of PD-L1 on tumor cells but not inflammatory cells raises the possibility of a tumor cell intrinsic manner of PD-L1 expression. In contrast, a group of patients showed PD-L1 positivity in both tumor and inflammatory cells along with abundant CD8+ tumor infiltrating lymphocytes, suggesting adoptive immune resistance in these tumors and potential benefits from tumor immunotherapy. PMID- 28576523 TI - Clinical symptoms that predict the presence of Obstructive Sleep Apnea. AB - OBJECTIVE: To determine if a set of clinical symptoms can help in determining the presence and severity of OSA. SETTING: Tertiary urban pediatric hospital. METHODS: Parents of children undergoing an overnight PSG answered a 56 item questionnaire based on their child's symptoms. The responses to the questionnaire were compared between patients with different severities of OSA (s determined by PSG) and those without OSA. Responses to questionnaire were also analyzed between obese and non-obese patients. RESULTS: 235 children were included (140 male and 95 female) with a mean age of 5.76 +/- 2.78 years. The mean Apnea Hypopnea Index (AHI) was 7.78 +/- 14.50 events/hour (range 0-110 events/h). 74 (31.5%) children had mild-OSA (AHI between 1 and 4.99 events/h), 31 (13.19%) had moderate-OSA (AHI between 5 and 9.99 events/h), 58 (24.7%) had severe-OSA (AHI>=10events/h) and the remaining 72 (30.64%) had No-OSA (AHI<=1event/h). 87 (37%) patients were obese. Eight clinical symptoms in non-obese and six clinical symptoms in obese patients predicted the mild to severe OSA. Sixteen symptoms in non-obese patients and nine symptoms in obese patients predicted the presence of severe OSA in these patients. CONCLUSION: Clinical symptoms reported in this study are useful to predict the presence of and the severity of OSA in children. Clinical symptoms can also predict the presence and severity of OSA in children who are obese, however, the symptoms required to make the prediction are different in obese children. PMID- 28576524 TI - Influence of nasal septum deformity on nasal obstruction, disease severity, and medical treatment response among children and adolescents with persistent allergic rhinitis. AB - OBJECTIVE: To evaluate the impact of different types of nasal septum deformity (NSD) on nasal obstruction, rhinitis severity and response to medical treatment among pediatric persistent allergic rhinitis (PER) patients. METHODS: In a prospective, real-life study, 150 children and adolescents (mean age 13 +/- 2.8 years, females 32.6%) diagnosed with PER according to ARIA guidelines were assessed by nasal endoscopy for NSD according to Mladina's classification, their response to medical treatment (intranasal steroids and antihistamines or antileucotriens), the presence of comorbidities, rhinitis severity (modified-ARIA criterion) and nasal obstruction visual analog scale score (VAS). RESULTS: Most patients (87%) had 1 of the 7 types of septal deformities. There was a high prevalence of bilateral (types 4 and 6; 46%) and anterior unilateral (types 1 and 2; 25%) NSD in patients not responding to medical treatment. Type 4 (OR = 6.4; p = 0.005) or type 6 (OR = 4.4; p = 0.03) NSD increased the risk of lack of improvement with medical treatment. Coexistence of anterior unilateral or bilateral NSD with severe turbinate enlargement increased >20-fold the risk of lack of improvement. Patients with bilateral NSD presented greater rhinitis severity. Non-responder adolescents displayed higher prevalence of bilateral NSD than children (53% vs. 23%; p = 0.02). Nasal obstruction VAS was higher for patients with anterior than posterior NSD, and greater for patients with bilateral NSD than any other type of septal morphology. CONCLUSION: Nasal endoscopy shows that bilateral and unilateral anterior nasal septum deformities are strongly associated with a poor response to medical treatment, greater rhinitis severity and higher nasal obstruction VAS. Consequently, nasal endoscopy is necessary in the PER patients to understand the disease severity as well as to plan a specific surgical treatment in order to improve nasal obstruction, disease severity, and patient's quality of life. PMID- 28576525 TI - An analysis of hearing screening test results in 2291 premature infants of Chinese population. AB - OBJECTIVE: The aim of this study was to analyze the hearing screening program among preterm infants as well as to identify risk factors associated with failing primary newborn hearing screening. METHODS: The retrospectively selected population included all preterm infants who had primary hearing screening in a neonatal ward from January 1st, 2013 to December 31st, 2015 at West China Second University Hospital, Sichuan University. The newborn hearing screening (NHS) procedure was performed in all preterm infants by automated auditory brainstem response (AABR). Infants who failed the primary hearing screening received a second screening at 42 days after birth. Infants who failed both tests were referred to a tertiary audiology center for diagnostic confirmation and management before 6 months of age. The final diagnosis for referred infants was obtained by telephone follow-up. The risk factors associated with failure to pass the primary hearing screen were evaluated and analyzed for preterm infants. RESULTS: Among 2291 preterm infants recruited, 155 infants (6.8%) failed the primary hearing screening with an abnormal AABR. Of these 155 infants, 113 (72.9%) passed the secondary screening. At the end of the follow-up, 1 infant (0.04%) was diagnosed with hearing loss, 3 infants had delayed language development, and 40 infants were lost to follow up. Multivariate regression analysis revealed that gestational age <=32 weeks (Odds ratio [OR] = 2.093, 95% confidence interval [CI] 1.370-3.196), super hyperbilirubinemia (>=25 mg/dl) (OR = 3.560, 95% CI 1.009-12.560), and respiratory failure (OR = 1.971, 95% CI 1.188 3.265) were associated with failure to pass newborn hearing screening. CONCLUSION: The prevalence of failure to pass primary hearing screening among preterm infants was 6.8% in our study, and we found a relatively low prevalence of hearing loss (0.04%). Super hyperbilirubinemia, gestational age <=32weeks, and respiratory failure were risk factors associated with failure of preterm infants to pass the primary hearing screening. Our results suggest that preterm infants with hyperbilirubinemia, gestational age <=32 weeks, and respiratory failure should be closely followed. PMID- 28576526 TI - Assessment of red blood cell distribution width and mean platelet volume in children with epistaxis. AB - OBJECTIVE: This study aimed to investigate whether there is a relationship between red blood cell distribution width, mean platelet volume and epistaxis in children. METHODS: Between January 2015 and July 2016, 105 children who were referred to our clinic with epistaxis and 100 sex- and age-matched controls were retrospectively analyzed. Red blood cell distribution width (RDW) and mean platelet volume (MPV) values were determined in both groups. RESULTS: RDW values were found significantly (P < 0.05) lower in the group with epistaxis than in the control group (11.95 +/- 1.31 vs. 12.74 +/- 1.21). MPV was 7.49 +/- 1.33 in the group with epistaxis and 7.23 +/- 1.06 in the control group, and there was no significant difference between the groups (p > 0.05). CONCLUSION: We found no difference between MPV values of both groups and significantly lower RDW values in children with epistaxis. Decreased RDW values were considered as an accompanying marker rather than a result of epistaxis. In addition, it may be thought that low RDW values may increase the bleeding tendency by disrupting the thrombotic activities. Further studies are needed to validate the relation of these parameters with epistaxis and its mechanisms. PMID- 28576527 TI - Transcervical ultrasonographic examination of palatine tonsil size and its correlation with age, gender and body-mass index in healthy children. AB - OBJECTIVE: Our aim was to assess the palatine tonsil size with transcervical ultrasonography in healthy children and to analyze whether the palatine tonsil size is correlated with age, gender and body-mass index (BMI). METHODS: This series consisted of 680 healthy children (340 females, 340 males) who underwent transcervical ultrasonography for evaluation of palatine tonsil size. A total of seventeen age groups (range: 1-17 years) comprised of 40 children (20 females, 20 males) were constituted. Demographic data including gender, height, weight and BMI were noted. Correlation between baseline descriptive data and tonsil volume was investigated. RESULTS: The average age was 102.51 +/- 59.24 months (range: 12 to 204) and body-mass index was 17.50-5.16 kg/m2 (min: 12.4-max:25.8). The average tonsil volume was 1819.5-2023.5 mm3 (min:601, max: 4007). The tonsil volume did not differ significantly between females and males (p = 0.108). However, there was a significant difference between tonsil volumes of various age groups (p < 0.001). Tonsil size seemed to be greater in parallel with advancement of age (p < 0.001) and increased BMI (p < 0.001). CONCLUSION: Transcervical ultrasonography can be an accurate, safe, cheap, non-invasive and accessible measure for evaluation of the size of tonsils objectively. There were strongly positive correlations between age, BMI and palatine tonsil size in healthy children and variability with respect to descriptive characteristics must be considered during diagnostic procedures and preoperative evaluation. ADVANCES IN KNOWLEDGE: In our study, we suggest that transcervical ultrasonography can be an accurate, safe, cheap, non-invasive and accessible measure for evaluation of the size of tonsils. There were positive correlations between age, BMI and palatine tonsil size in healthy children. PMID- 28576528 TI - Endovascular management of iatrogenic cervical internal carotid artery pseudoaneurysm in a 9-year-old child: Case report and literature review. AB - Extracranial internal carotid artery (ICA) pseudoaneurysms are uncommon in the pediatric population and are usually secondary to direct trauma to the vessel. Treatment options include surgery (ligation), anticoagulation therapy and endovascular treatment. Endovascular covered stents have shown good results in adult populations, resulting in occlusion of the aneurysm and preservation of the artery without significant complications. However, there have been only limited reports in the literature reporting endovascular carotid stent placement in the pediatric population. We report a case of a 9-year-old boy patient, who developed a cervical ICA pseudoaneurysm after a parapharyngeal tumor resection. He was successfully treated by primary endovascular covered stent placement. During a follow-up of 6 months the patient has been asymptomatic, without any adverse event. Additionally, a literature review is done. PMID- 28576529 TI - Parent educational materials regarding the newborn hearing screening process. AB - PURPOSE: Newborn hearing screening (NHS) procedures and implementation vary from state to state in the US. The purpose of this study was to evaluate the content and nature of information provided to parents about their infant's NHS across states to answer two questions: 1) what information is included in each state's parent information brochure? and 2) do the brochures include educational information requested by parents that may help reduce parental anxiety, improve satisfaction, and decrease the potential for misunderstandings? METHOD: Each state's parent brochures and educational resources provided to parents were accessed via the National Center for Hearing Assessment and Management (NCHAM) website, categorized, and reviewed for content. RESULTS: Results indicate that the information provided to parents varies considerably across states and many brochures do not contain important information that is desired by parents. CONCLUSIONS: NHS procedures may be improved by providing standardized information regarding the process to parents in all states. PMID- 28576530 TI - Maturation of auditory brainstem responses in young children with congenital monaural atresia. AB - OBJECTIVE: To date, the impact of conductive hearing loss on the auditory pathway at brainstem level has only been investigated in animal studies, which showed a species-specific delay of maturation. In this study, the functional maturation of auditory brainstem response (ABR) parameters in humans with unilateral atresia of the external auditory canal was investigated. METHODS: 42 newborns and toddlers ranging in age from 13 days to 11 months were included. The click-evoked ABR interpeak latencies (IPL) of the atretic ears and the contralateral ears with normal hearing were evaluated. The children had no comorbidities and had never been fitted with any kind of hearing aid. The absolute latencies (AL) and IPL of a matched control group were compared to the contralateral normally hearing ears of the children with unilateral atresia. RESULTS: The mean air-bone gap in the ears with atresia was 44 dB HL. Despite this partial acoustic deprivation, no significant difference between the IPLs of normal ears and ears with atresia could be detected. Both for AL and IPL, the differences between the normal ears and the control group were all within 1 standard deviation to the mean. CONCLUSION: The data showed that the monaural acoustic deprivation by a block of sound conduction does not produce any delay of functional maturation at brainstem level in this group of patients. With regard to the AL and IPL on brainstem level, no differences between the normal ears of children with unilateral atresia and children with bilateral normal hearing could be detected. PMID- 28576531 TI - The clinical efficacy of early intervention for infected preauricular sinus. AB - OBJECTIVE: The study was designed to evaluate the outcomes of early surgical intervention, and to suggest the accurate operation time and surgical strategies. METHODS: A total of 190 cases (144 patients) of PAS excision were classified into 2 groups according to their time of surgery; early intervention group (n = 53), and non-early intervention group (n = 137). Early intervention was defined as excision performed within 3 weeks from their first hospital visit, and after acute infection control, surgical removal was followed regardless of their infection status. The mean age of patients was 18.3 +/- 15.7 years old (62 male, 82 female). During surgery, a parallel incision was added when iatrogenic fistula due to incision and drainage (I &D) or additionally opened wounds caused by infection was present. RESULTS: Cases of I & D history, revision cases, use of preoperative antibiotics were significantly higher in the early intervention group compared to the non-early intervention group, however, the time of surgery did not affect the complication rate (p = 0.533). Within the infected cases, only 1 patient from the non-early intervention group showed a minor complication of keloid scar. During our follow up period of minimum of 6 months, there was no recurrence in either groups. CONCLUSION: The early intervention of PASs does not seem to increase postoperative complication or recurrence rates. A double parallel skin incision is a simple but adequate technique to treat infected PASs. PMID- 28576532 TI - Inner ear anomalies in children with isolated unilateral congenital aural atresia. AB - OBJECTIVES/HYPOTHESIS: We aim to define the frequencies of anomalies of the inner ear, oval window, and round window ipsilateral to isolated non-syndromic unilateral aural atresia. METHODS AND MATERIALS: Retrospective case series. We reviewed high resolution computed tomography scans of the temporal bones of 70 children with isolated non-syndromic unilateral congenital aural atresia. Scans were reviewed according to the Jahrsdoerfer criteria and further evaluated for anomalies of the vestibule, semi-circular canals, cochlea, internal auditory canal and vestibulocochlear nerve. RESULTS: Inner ear dysplasia was seen in two of 70 atretic ears: one with a dysmorphic lateral semicircular canal and another with a large vestibule assimilating the lateral semicircular canal. Abnormalities of the oval window and round window ipsilateral to the atresia were identified in 21% (15) and 7% (5), respectively, of the atretic ears. Oval window and round window abnormalities were associated with disproportionately lower Jahrsdoerfer scores compared to aural atresia patients without these abnormalities (P < 0.001 and P = 0.04, respectively). CONCLUSION: Compared to studies that included syndromic or bilateral atresia cases, we found inner ear and oval window abnormalities less common in children with isolated non-syndromic unilateral aural atresia. However, round window anomalies seem to occur at about the same frequency. PMID- 28576533 TI - Acoustic absorbance measurements in neonates exposed to smoking during pregnancy. AB - OBJECTIVE: To analyze acoustic absorbance using wideband tympanometry in neonates exposed to passive smoking during pregnancy. METHOD: A study comprising 54 neonates in the control group (CG - unexposed) and 19 in the study group (SG - exposed) was carried out. Subjects were submitted to the wideband tympanometry test and subsequent analysis of absorbance of 17 frequencies. RESULT: Low frequencies had a lower level of absorbance compared to high frequencies for both ambient and peak pressures, with no difference between the groups. CONCLUSION: No effect of passive smoking on acoustic absorbance measurements in neonates was observed. PMID- 28576534 TI - Using click-evoked auditory brainstem response thresholds in infants to estimate the corresponding pure-tone audiometry thresholds in children referred from UNHS. AB - OBJECTIVE: To examine whether behavioral pure-tone audiometry (PTA) thresholds in children can be accurately estimated from the corresponding infants' click-evoked auditory brainstem response (ABR) thresholds through a retrospective review of data from a universal newborn hearing screening (UNHS) program in Taiwan. METHOD: According to medical records from Mackay Memorial Hospital, Taipei Hospital District, 45,450 newborns received hearing screening during January 1999-December 2011. Among these newborns, 104 (82, both ears; 22, one ear; total, 186 ears) received regular follow-up and were recruited as subjects. The relationship between infant click-evoked ABR thresholds and the corresponding child PTA thresholds was determined through Pearson correlation coefficient and linear regression analyses. RESULTS: The correlation coefficient between click-evoked ABR thresholds and behavioral PTA thresholds at the average of frequencies of 1-4 and 2-4 kHz was 0.76 and 0.76, respectively. Linear regression analysis showed that behavioral audiometry thresholds at the average of frequencies of 1-4 and 2 4 kHz were accurately estimated from click-evoked ABR thresholds in 57% and 58% children, respectively. CONCLUSION: Click-evoked ABR testing is a reliable tool to cautiously estimate behavioral PTA thresholds at the average of frequencies of 1-4 and 2-4 kHz. For accurately performing hearing aid fitting and auditory rehabilitation in congenitally deaf infants, a combination of frequency-specific tone-burst ABR and click-evoked ABR should be used. PMID- 28576535 TI - Adherence to acute otitis media diagnosis and treatment guidelines among Israeli otolaryngologists. AB - INTRODUCTION: The recent Israeli acute otitis media (AOM) guidelines, drafted mainly by pediatricians and family physicians in 2013, addressed diagnostic and therapeutic issues, in order to reduce over-diagnosis and treatment. These guidelines are considered as the 'standard of care' for AOM management. While the adherence rate of pediatricians to previous Israeli AOM guidelines (2004) was reported to be high (>85%), the compliance of otolaryngologists has not been studied. METHODS: An anonymous 19-item questionnaire was circulated among practicing Israeli otolaryngologists (residents [n = 93], specialists [n = 283]). All the items were scored according to the number of correct answers in line with the guidelines, and summed on a 0-100 scale. RESULTS: Response rate was 34% (n = 127). Overall, scores of correct answers of residents (n = 48, 52% of all residents) and specialists (n = 79, 28% of all specialists) were similar, and showed comparable moderate adherence to both guidelines: 55.7 vs 58.3 (p = 0.26). Residents were more likely to adhere to the U.S. guidelines, when compared to specialists (score difference 6.1 vs 2.8, p = 0.008). Responders preferred the microscope for diagnosis (48%), over the recommended (pneumatic) otoscope (62%) (p = 0.05), and were more likely to start antibiotic therapy (62%), rather than the 'watchful waiting' (38%) (p = 0.03). Concerning antibiotic treatment, 50% of otolaryngologists prescribed amoxicillin as recommended, at 60-80 mg/kg/d. CONCLUSION: The moderate adherence rate suggests that the guidelines were partially adopted by otolaryngologists, who use different instrumentation than recommended, and treat more severe/complicated cases. Over-treatment with antibiotics and inaccurate dosing regimens are still common. Better implementation of the AOM guidelines among otolaryngologists should be performed in designated training platforms. PMID- 28576536 TI - Bilateral cochlear implantation in a child with Johanson Blizzard Syndrome. AB - Sensorineural hearing loss (SNHL) occurs in more than 80% of cases of Johanson Blizzard Syndrome (JBS). However, limited knowledge exists in medical literature of cochlear implantation (CI) outcomes in children with JBS. We report the case of a 5 year-old male with JBS and bilateral CI. While minimal progress in spoken language scores was noted after 4 years of bilateral CI use, substantial improvements in discrimination of speech sounds and audibility of spoken language and environmental sounds were documented. Cochlear implantation is an available treatment option of profound SNHL in children with JBS even if spoken language outcomes are marginal. PMID- 28576537 TI - Can changes in parentally measured acoustic reflectometry levels predict the middle ear status? AB - OBJECTIVE: Spectral gradient acoustic reflectometry (SG-AR) may be used to detect middle ear effusion. Our aim was to investigate whether increasing SG-AR levels between two SG-AR examinations indicate deterioration from a healthy middle ear to acute otitis media (AOM). METHODS: We enrolled 185 children (age 6-35 months) whose parents were willing to use the SG-AR at home daily. Measurement pairs of parental home SG-AR examination results were generated and analyzed. There was one SG-AR examination result obtained within +/-1 day of the reference visit and another result within +/-1 day of the subsequent visit. We defined the SG-AR level as increasing when the difference between two measurements was >=2 levels from a lower to a higher level, suggesting development of AOM. When the SG-AR level difference was <=1, we defined this no change of the SG-AR level. The middle ear diagnosis was determined by pneumatic otoscopy at the study clinic. RESULTS: 361 paired SG-AR home measurements were obtained. The reference measurement was related to a healthy middle ear as determined by pneumatic otoscopy. Increasing SG-AR levels (59/361), were 63% (95% CI 50%-74%) sensitive and 94% (91%-97%) specific for deterioration of a healthy middle ear to AOM. The positive predictive value was 71% (58%-82%) and the negative predictive value was 92% (88%-95%). When there was no SG-AR level difference between the SG-AR examinations, the corresponding figures were 88% (95% CI 84%-92%), 69% (56%-79%), 93% (89%-95%) and 57% (45%-68%), respectively. CONCLUSIONS: This study shows that increasing SG-AR levels might not be sufficiently sensitive to detect deterioration of the middle ear status from healthy middle ear to AOM in symptomatic children. Importantly, however, the development of AOM seems to be unlikely in an initially healthy middle ear when there is no difference between the SG-AR levels in two separate measurements. PMID- 28576538 TI - Do post-tonsillectomy patients who report bleeding require observation if no bleeding is present on exam? AB - OBJECTIVE: Three to ten percent of tonsillectomy patients experience post tonsillectomy hemorrhage. Examination of those patients who return to the Emergency Department (ED) with a history of hemorrhage may be found to have active bleeding, a coagulum within the fossa, or a normal post-operative exam. It is not known if those with a normal postoperative exam require inpatient observation. METHODS: This is a retrospective series from 1/1/2010 to 12/31/2014 at a tertiary pediatric hospital. We evaluated outcomes in patients who presented to our ED with a history of post tonsillectomy hemorrhage, but after a thorough inspection failed to demonstrate active bleeding or clot, and were thus deemed to have a normal postoperative exam. This cohort was then evaluated for subsequent active bleeding requiring cauterization. Demographics and clinical data were extracted from the medical record. RESULTS: In 337 visits with a history of bleeding, and a normal postoperative exam, 38 (11%) subsequently bled requiring cauterization. 32/38 (84%) bled within 24 h of admission to the ED. No demographic or clinical variables predicted an increased risk of bleeding during observation. CONCLUSIONS: Eleven percent of patients who presented to the ED with a history of bleeding at home but a normal postoperative exam subsequently bled and required cautery, usually within 24 h. Aside from the history of bleeding at home, we found no additional predictors of subsequent bleeding and recommend this group of patients should be considered for 24 hour in-hospital observation prior to discharge. PMID- 28576539 TI - Fully-covered metallic stenting in an infant with tracheoesophageal fistula due to button battery ingestion. AB - Previously, the main treatment options for tracheoesophageal fistula included surgery and conservative treatment. Herein, we report a child suffering from severe tracheoesophageal fistula due to button battery ingestion. The child relapsed soon after a repair surgery. Then, he was endotracheally implanted with a fully-covered metallic stent combined with a jejunal tube feeding. He recovered soon and the stent was removed five months later. The fistula was healed with no relapse during a 25-month follow-up. Therefore, endotracheal implantation of fully-covered metallic stent is an alternative treatment for tracheoesophageal fistula due to button battery ingestion, especially in cases with severe respiratory disorders. PMID- 28576540 TI - Refractory sleep apnea caused by tubal tonsillar hypertrophy. AB - Snoring/sleep apnea are usual symptoms of adenotonsillar hypertrophy, and adenotonsillectomy is usually recommended. In rare cases, symptoms remain after surgery, and tubal tonsil hypertrophy could be the cause. We experienced a pediatric patient whose symptoms were refratory snoring/sleep apnea although he previously underwent three times of adenotonsillectomy. We diagnosed tubal tonsil hypertrophy which was the cause of refractory symptoms, and decided to perform volume reduction with radiofrequency ablation. We suggest that tubal tonsil hypertrophy should be taken into account of the cause of refractory sleep apnea after adenotonsillectomy, and volume reduction with radiofrequency may be an effective method. PMID- 28576541 TI - A case of acute clival osteomyelitis in a 7-year-old boy secondary to infection of a Thornwaldt cyst. AB - Clival osteomyelitis is a potentially life-threatening infection that can occur in healthy children. It can be related to congenital anomalies. We report the case of a 7-year-old boy with Streptococcus intermedius and Fusobacterium clival osteomyelitis arising from a Thornwaldt cyst situated in a fossa navicularis magna of the occipital bone. Multidisciplinary management is necessary to ensure rapid improvement and complete healing. PMID- 28576542 TI - A national survey of knowledge, attitude and practices among pediatricians towards newborn hearing screening in India. AB - INTRODUCTION: Pediatricians have a key role in ensuring that infant has undergone hearing screening and required follow-up. Attempts in various countries and centers have been made at exploring their knowledge, attitude and practices towards universal newborn hearing screening. In India, such a program is at its preliminary stage, and hence a need was felt to study this aspect in pediatricians working in India. METHOD: A cross-sectional online survey was carried out among 112 pediatricians working in India. The questionnaire was framed after reviewing the existing questionnaires. Descriptive statistics was used to summarize the findings. RESULTS: A response rate of 7.99% (112/1402) was obtained of which only 20.5% reported of availability of screening program in their work set-up. The majority of the pediatricians (95%) were aware of the newborn hearing screening while 98.3% were affirmative about the importance of screening of all infants. Very few pediatricians reported of a screening program in their set-up or in their close locality. Overall the pediatricians were confident about their knowledge on this topic yet expressed a need to know more about several intricacies about hearing screening. The pediatricians also provided an input on the most preferred method of receiving more information. SUMMARY AND CONCLUSION: The success of the universal newborn hearing screening program lies in the support and cooperation of health care providers such as pediatricians. The present study draws attention to the positive attitude and practices exhibited by them. It also sheds light on the knowledge gaps that are present and need the due attention of the policy makers. Further, it highlights the need for having more continuing medical education program and awareness drives for ensuring a better implementation of UNHS. PMID- 28576543 TI - Pycnodysostosis at otorhinolaryngology. AB - AIM: Pycnodysostosis is a rare autosomal, recessive, skeletal dysplasia caused by a mutation in the cathepsin k gene. Pycnodysostosis is characterized by short stature, characteristic facial appearance (delayed closure of fontanelles and cranial sutures, mandibular hypoplasia and angle disorder, blue sclera), and acroosteolysis of the distal phalanges. Our aim was to describe the otorhinolaryngologic findings, differential diagnoses, various treatment options, and followup in eight cases of pycnodysostosis. METHOD: This retrospective clinical study used data from eight patients diagnosed with pycnodysostosis by a single pediatric endocrinologist primarily based on clinical and radiographic findings. All patients were referred to the otorhinolaryngology outpatient clinic by the pediatric endocrinology unit of the Marmara University between February 2013 and March 2015. Detailed medical histories were obtained in all cases and otorhinolaryngologic physical examination, blood assays, electrocardiogram, lateral skull X-rays, chest radiograph, cephalometric investigations, tympanograms, and audiograms were also carried out. Sleep videos of patients were recorded and those with upper airway problems were evaluated for sleep apnea by polysomnography. Informed consent form was obtained from the parents of all patients. RESULTS: Eight patients (7 females and 1 male) displaying proportionate dwarfism were included in the study. They had a mean age of 14.7 years (range: 13 16 y), the mean height of 141.3 cm (range 132-155 cm), and mean weight of 44.4 kg (range: 39.6-49.3 kg). All patients had facial dysmorphism with frontal bossing and the hands and feet had short digits with overlying cutaneous wrinkles that tapered off with large overriding nails. Midfacial hypoplasia and malocclusion were observed in seven of the eight patients (87.5%), four (50%) had micrognathia, and five (62.5%) had proptosis. Tympanograms and audiograms of all patients were type A and normal, and the mean of the pure tone audiogram was 13.3 dB (range: 10-16 dB). All patients had a narrow and grooved palate with disturbed dentition; two of them (25%) had mild markedness of the tongue base, five (62.5%) had grade 3 and three (37.5%) had grade 2 tonsillar hypertrophy, and five (62.5%) had adenoid hypertrophy. One patient (12.5%) had grade 3 Mallampati, four (50%) showed grade 2 Mallampati while three (37.5%) patients displayed grade 1 Mallampati score. Further, while six (75%) patients had no uvular pathology, one (12.5%) patient presented with uvular elongation and another patient had a bifid uvula. Cephalometric measurements such as PAS-UP (mean 5.67 mm; range: 5.0-7.6 mm) and PAS-TP (mean 9.61 mm; range: 8.5-12.2 mm) were lower than that of normal subjects. Video recordings showed that six of the eight patients (75%) had respiratory distress and four (50%) had sleep apnea. Polysomnography in these patients with sleep apnea showed that two had mild OSA (AHI: 18.2 and 20.1 events/hour) and two had severe OSA (AHI: 53.4 and 62.8 events/hour). For upper airway problems, an adenotonsillectomy was performed in two (25%) patients while two others required an adenoidectomy. Positive pressure ventilation was recommended in two patients with persistent sleep apnea after adeno/adenotonsillectomy. However, because of the parental objections, the follow up polysomnographs could not be obtained. CONCLUSION: Pycnodysostosis is a very rare form of bone dysplasia. Otorhinolaryngologically, proper follow-up of these patients and appropriate treatment of upper airway problems are important to achieve an acceptable quality of life. Adeno/adenotonsillectomy and positive pressure ventilation, used as conservative approaches in treating upper airway problems, are effective and could be used instead of an aggressive surgery such as tracheotomy or maxillomandibular advancement. This study, to the best of our knowledge, is the largest ENT case series on pycnodysostosis. PMID- 28576544 TI - Cystic cervical teratoma: A diagnostic and management challenge. AB - Cervical teratomas are relatively rare congenital tumors pathologically defined by their three germ cell layer composition. Classically they manifest as solid or mixed solid-cystic lesions. Purely cystic teratomas pose a diagnostic challenge due to their clinical and radiologic similarity to lymphatic vascular malformations. Sclerotherapy, rather than operative excision, may be offered as therapy. We present an unusual cystic neck mass to highlight this dilemma. PMID- 28576545 TI - 18F-FDG PET/CT as staging of alveolar rhabdomyosarcoma. PMID- 28576547 TI - Impact of sample size and matching on single-subject classification of schizophrenia: A meta-analysis. PMID- 28576546 TI - D2/D3 dopamine receptor binding with [F-18]fallypride correlates of executive function in medication-naive patients with schizophrenia. AB - Converging evidence indicates that the prefrontal cortex is critically involved in executive control and that executive dysfunction is implicated in schizophrenia. Reduced dopamine D2/D3 receptor binding potential has been reported in schizophrenia, and the correlations with neuropsychological test scores have been positive and negative for different tasks. The aim of this study was to examine the relation between dopamine D2/D3 receptor levels with frontal and temporal neurocognitive performance in schizophrenia. Resting-state 18F fallypride positron emission tomography was performed on 20 medication-naive and 5 previously medicated for brief earlier periods patients with schizophrenia and 19 age- and sex-matched healthy volunteers. Striatal and extra-striatal dopamine D2/D3 receptor levels were quantified as binding potential using fallypride imaging. Magnetic resonance images in standard Talairach position and segmented into gray and white matter were co-registered to the fallypride images, and the AFNI stereotaxic atlas was applied. Two neuropsychological tasks known to activate frontal and temporal lobe function were chosen, specifically the Wisconsin Card Sorting Test (WCST) and the California Verbal Learning Test (CVLT). Images of the correlation coefficient between fallypride binding and WCST and CVLT performance showed a negative correlation in contrast to positive correlations in healthy volunteers. The results of this study demonstrate that lower fallypride binding potential in patients with schizophrenia may be associated with better performance. Our findings are consistent with previous studies that failed to find cognitive improvements with typical dopamine-blocking medications. PMID- 28576548 TI - Defining the impact of childhood adversities on cognitive deficits in psychosis: An exploratory analysis. AB - BACKGROUND: Exposure to adverse childhood experiences (ACE) and cognitive deficits are both prevalent in psychosis. While it has been repeatedly demonstrated that ACE contribute to cognitive dysfunctions, the specific nature of this contribution remains elusive. Recent evidence suggests that types of adversities during critical periods have deleterious effects on brain structures that are important for cognitive functioning. The present study sought to clarify which types of adversities experienced at which time during development aggravate cognitive deficits in psychosis. METHODS: Exposure to abuse and neglect during childhood and adolescence were retrospectively assessed in N=168 adult individuals with psychotic disorder. Conditioned random forest regression was used to define the importance of type and timing of ACE for predicting domains of the MATRICS Consensus Cognitive Battery (MCCB). RESULTS: Significant importance of ACE was determined for 5 out of 7 MCCB domains. Particularly abuse at age 3 contributed to dysfunctional cognitive domains attention, learning, and working memory. Social cognition was related to neglect experienced at 11-12years, and to cumulative ACE. CONCLUSION: Abuse and neglect at periods when children spend substantial time in their families affect cognitive functioning, and hence aggravate dysfunction in psychosis. Results support the neurodevelopmental perspective on psychosis and the diagnostic value of type and timing of ACE. PMID- 28576549 TI - Computational and experimental model of transdermal iontophorethic drug delivery system. AB - The concept of iontophoresis is often applied to increase the transdermal transport of drugs and other bioactive agents into the skin or other tissues. It is a non-invasive drug delivery method which involves electromigration and electroosmosis in addition to diffusion and is shown to be a viable alternative to conventional administration routs such as oral, hypodermic and intravenous injection. In this study we investigated, experimentally and numerically, in vitro drug delivery of dexamethasone sodium phosphate to porcine skin. Different current densities, delivery durations and drug loads were investigated experimentally and introduced as boundary conditions for numerical simulations. Nernst-Planck equation was used for calculation of active substance flux through equivalent model of homogeneous hydrogel and skin layers. The obtained numerical results were in good agreement with experimental observations. A comprehensive in silico platform, which includes appropriate numerical tools for fitting, could contribute to iontophoretic drug-delivery devices design and correct dosage and drug clearance profiles as well as to perform much faster in-silico experiments to better determine parameters and performance criteria of iontophoretic drug delivery. PMID- 28576550 TI - Comparison of different zeolite framework types as carriers for the oral delivery of the poorly soluble drug indomethacin. AB - Microporous zeolites of distinct framework types, textural properties and crystal morphologies namely BEA, ZSM and NaX, have been employed as carriers to assess their effect on modulating the dissolution behavior of a BCS II model drug (indomethacin). Preparation of the loaded carriers via the incipient wetness method induced significant drug amorphization for the BEA and NaX samples, as well as high drug payloads. The stability of the amorphous drug content was retained after stressing test evaluation of the porous carriers. The dissolution profile of loaded indomethacin was evaluated in simulated gastric fluid (pH 1.2) and simulated intestinal fluids FaSSIF (fasted) and FeSSIF (fed state) conditions and was found to be dependent on the aluminosilicate ratio of the zeolites and the degree of crystalline drug content. The feasibility of the zeolitic particles as oral drug delivery systems was appraised with cytocompatibility and cellular toxicity studies in Caco-2 cultures in a time- and dose-dependent manner by means of the MTT assay and flow cytometry analysis, respectively. Intracellular accumulation of the zeolite particles was observed with no apparent cytotoxic effects at the lower concentrations tested, rendering such microporous zeolites pertinent candidates in oral drug delivery applications. PMID- 28576551 TI - Free paclitaxel-loaded E-selectin binding peptide modified micelle self-assembled from hyaluronic acid-paclitaxel conjugate inhibit breast cancer metastasis in a murine model. AB - The present work seeks to construct a nanovehicle for the efficient suppression of breast cancer metastasis through targeting E-selectin on tumor vascular endothelial cells and hyaluronic acid-receptor on tumor cells. Herein, a new ligand-PEG-lipid conjugate, E-selectin binding peptide-polyethene glycol-1 octadecylamine (Esbp-PEG-OA), was used as the targeting molecule of micelle self assembled form hyaluronic acid-paclitaxel (HA-PTX) conjugate. When loaded with free PTX, the micelles (Esbp-HA-PTX/PTX) exhibited nanoscale particle size with high drug-loading capacity (up to 31.5%). In vitro release study showed that the conjugated and entrapped PTX released simultaneously. Cellular uptake of micelles confirmed that Esbp-HA-PTX micelles could be specifically and efficiently internalized into E-selectin expressing human umbilical vein endothelial cells (HUVEC) and 4T1 breast cancer cells via receptor-meditated endocytosis. In vitro cytotoxicity assay further revealed that Esbp-HA-PTX/PTX micelles significantly improved the selectivity of PTX for killing the two cell types compared with PTX solution formulation. More importantly, Esbp-HA-PTX micelles raised the accumulation of payload in tumor through targeting two cell types in the tumor microenvironment simultaneously, resulting in marked in vivo inhibition of tumor growth, intratumoral microvessel density and metastasis, and decreased systemic toxicity over solution formulation. Overall, Esbp-HA-PTX/PTX micelle is promising in therapy of breast cancer metastasis. PMID- 28576552 TI - Poisoning in goats by the monofluoracetate-containing plant Palicourea aeneofusca (Rubiaceae). AB - The epidemiological, clinical and pathological aspects of a spontaneous outbreak of Palicourea aeneofusca poisoning in goats are reported. The main clinical signs were motor incoordination, generalized muscle tremors, broad-based posture, tachypnea, tachycardia, vocalization and respiratory distress. Two goats died 5 and 20 min after the observation of the first clinical signs. Another that was found recumbent died 80 h later. One goat with mild clinical signs recovered. Congestion and hemorrhages were observed macroscopically and histologically in most organs. Pulmonary edema was also observed. The main microscopic findings consisted of cytoplasmic vacuolization and necrosis of the renal tubular epithelium. The average concentration of monofluoroacetate obtained in sixteen samples of P. aeneofusca was 0.29 +/- 0.17%. It is concluded that P. aeneofusca is toxic to goats under natural conditions. PMID- 28576553 TI - Phosphate crosslinked pectin based dual responsive hydrogel networks and nanocomposites: Development, swelling dynamics and drug release characteristics. AB - Potential dual responsive hydrogel networks (PPAD) are fabricated from pectin, poly((2-dimethylamino)ethyl methacrylate)) and phosphate crosslinker bis[2 methacryloyloxy] ethyl phosphate (BMEP) by a simple free radical polymerization. These hydrogel networks are successfully utilized for encapsulation of an anti cancer drug, 5-fluorouracil (5-FU) and also employed as versatile platforms for production of silver nanoparticles. Fabricated hydrogel networks and silver nanocomposites were characterized by FTIR, SEM, EDX, TEM, DLS, DSC, TGA and XRD. Different polymer network parameters such as MC-, chi, xi and upsilone and diffusion constant (D) were evaluated to assess the drug release profile. The 5FU loaded PPAD hydrogels were used to perform in vitro release studies in both gastric and intestinal conditions of GIT (pH 1.2 & pH 7.4) at two different temperatures (25 and 37 degrees C). On the other hand various kinetic models (zero, first, Higuchi & Koresmeyer-Peppas) have also been employed to fit drug release profile. In addition, the antibacterial activity of PPAD silver nanocomposites were tested against four bacterial species Escherichia coli (-ve), Klebsiella pneumoniae (-ve), Bacillus cereus (+ve) and Staphylococcus aereus (+ve) using zone of inhibition test. PMID- 28576555 TI - Editorial Comment. PMID- 28576554 TI - Absence seizure susceptibility correlates with pre-ictal beta oscillations. AB - Absence seizures are generalized, cortico-thalamo-cortical (CTC) high power electroencephalographic (EEG) or electrocorticographic (ECoG) events that initiate and terminate suddenly. ECoG recordings of absence seizures in animal models of genetic absence epilepsy show a sudden spike-wave-discharge (SWD) onset that rapidly emerges from normal ECoG activity. However, given that absence seizures occur most often during periods of drowsiness or quiet wakefulness, we wondered whether SWD onset correlates with pre-ictal changes in network activity. To address this, we analyzed ECoG recordings of both spontaneous and induced SWDs in rats with genetic absence epilepsy. We discovered that the duration and intensity of spontaneous SWDs positively correlate with pre-ictal 20-40Hz (beta) spectral power and negatively correlate with 4-7Hz (O) power. In addition, the output of thalamocortical neurons decreases within the same pre-ictal window of time. In separate experiments we found that the propensity for SWD induction was correlated with pre-ictal beta power. These results argue that CTC networks undergo a pre-seizure state transition, possibly due to a functional reorganization of cortical microcircuits, which leads to the generation of absence seizures. PMID- 28576557 TI - A prospective double blind randomized controlled study on the use of ethanol locks in HPN patients. AB - BACKGROUND & AIMS: Ethanol lock therapy (ELT) has been shown to reduce the rate of catheter-related bloodstream infection (CRBSI) in high-risk home parenteral nutrition (HPN) patients. The aim of this study was to determine whether ELT therapy for all patients newly started on HPN would reduce the incidence of CRBSI. METHODS: This study was a prospective, double-blind, randomized controlled trial that was carried out from July 2014 to April 2016. The study participants were patients newly started on HPN, and they were randomly assigned to either treatment with ELT or our current standard of care with saline heparin locks. The primary outcome was occurrence of CRBSI. RESULTS: Thirty eight patients that were newly started on HPN were randomized to either treatment with ELT (n = 18) or to our current standard of care with heparin locks (n = 20). Four patients in the ELT group and one patient in the control arm had a CRBSI (p = 0.17). No significant adverse side effects were noted during the study. CONCLUSIONS: This study did not show improvement in the rate of CRBSI with ELT in all patients started on HPN. ELT therapy may be most helpful to reduce in CRBSI in high-risk HPN patients, but further studies with a randomized control trial design of high risk patients are needed to further clarify this important issue in HPN patients. The study was registered at clinicaltrials.gov prior to patient enrollment (NCT02227329). PMID- 28576556 TI - Correlative super-resolution fluorescence and electron microscopy using conventional fluorescent proteins in vacuo. AB - Super-resolution light microscopy, correlative light and electron microscopy, and volume electron microscopy are revolutionising the way in which biological samples are examined and understood. Here, we combine these approaches to deliver super-accurate correlation of fluorescent proteins to cellular structures. We show that YFP and GFP have enhanced blinking properties when embedded in acrylic resin and imaged under partial vacuum, enabling in vacuo single molecule localisation microscopy. In conventional section-based correlative microscopy experiments, the specimen must be moved between imaging systems and/or further manipulated for optimal viewing. These steps can introduce undesirable alterations in the specimen, and complicate correlation between imaging modalities. We avoided these issues by using a scanning electron microscope with integrated optical microscope to acquire both localisation and electron microscopy images, which could then be precisely correlated. Collecting data from ultrathin sections also improved the axial resolution and signal-to-noise ratio of the raw localisation microscopy data. Expanding data collection across an array of sections will allow 3-dimensional correlation over unprecedented volumes. The performance of this technique is demonstrated on vaccinia virus (with YFP) and diacylglycerol in cellular membranes (with GFP). PMID- 28576558 TI - Metabolomics of mitochondrial disease. AB - Mitochondrial disease (MD) diagnostics and disease progression investigations have traditionally relied very little on metabolic data, due to a lack of biomarker sensitivity and specificity. The recent drive to find novel, low intervention biomarkers and new therapeutic approaches have revived an interest in what metabolic data can offer, as presented in this timely review. We review how metabolomics has been applied to MD and provide an extensive overview of the reported metabolic perturbations and common mechanistic features that may provide a basis for future research. We conclude by highlighting the substantial potential of metabolomics for future diagnostics and mitochondrial medicine. PMID- 28576559 TI - The neuroprotective effect of melatonin on the hippocampus exposed to diclofenac sodium during the prenatal period. AB - Melatonin (Mel) has strong antioxidant properties since it is a direct scavenger of oxygen-based free radicals and related species. The main aim of this study is to show whether the effects of Mel can prevent the potential adverse effects of diclofenac sodium (DS), used as a non-steroidal anti-inflammatory drug (NSAID) during the prenatal period, on the newborn experimental rat brain tissues using stereological methods Twenty-four male 12-week old Wistar albino rats were used. The study involved four groups (each containing six rats), those exposed, during the prenatal period, to saline 1ml/kg (Saline group), to diclofenac sodium 3.6mg/kg (DS group), or to diclofenac sodium+melatonin 50mg/kg (DS+Mel group), and a control group (Cont group). At the end of the experiment, the brains were removed from the cranium for histological and stereological analyses. Cell loss in the hippocampus exposed to DS was observed compared to the Cont group (p<0.01), and a similar side-effect was also seen in the Saline group (p<0.01). However, there was no significant difference in cell numbers between the Cont and DS+Mel groups (p>0.05). These results suggest that exposure to DS during pregnancy causes a decrease in the number of cells in the hippocampus and dentate gyrus in the postnatal period. Using Mel, a neuroprotective agent, reduced the toxic effects of DS. PMID- 28576560 TI - The study of dental occlusion in ancient skeletal remains from Mallorca (Spain): A new approach based on dental clinical practice. AB - Occlusal characteristics, fundamental to assess the presence of malocclusion, have been often unexplored in bioarchaeological analyses. This is largely due to the fragmented condition of the skeletal remains. By applying a method that considers dental and maxillary features useful to evaluate occlusion in ancient fragmentary material, the purpose of this work is to define the occlusal features and explore the causes of malocclusion in a mediaeval population from Mallorca. The findings of this study suggest that normocclusion was present in ca. 60% of the individuals (N=31), and that some characteristics, such as molar relationship, were slightly different from those of modern populations. The analysis of the occlusal features revealed for example that open-bite was absent in 85% of the sample, posterior open-bite was completely absent and overbite and overjet were normal in around 90% of the individuals. Statistically significant correlations between canine and molar relationships and between molar relationship and dental wear of the superior and inferior canines and incisors were observed. In addition, wear could affect the curve of Spee. All these findings strengthen the hypothesis that in ancient times malocclusion was not as generalized as in modern times. Although the factors that lead to malocclusion throughout centuries could have several causes, we suggest that in this population dental wear, which is strongly associated with the diet, was the fundamental causing factor. PMID- 28576561 TI - Antimicrobial activity of polymyxin-loaded solid lipid nanoparticles (PLX-SLN): Characterization of physicochemical properties and in vitro efficacy. AB - Antimicrobial resistance is a current public health concern, limiting the available therapeutic options used for the treatment of common bacterial infections. The development of new drug entities via biotechnological processes is however expensive and time-consuming. Therefore, old antimicrobial agents have been recovered for clinical use. An example of these drugs is polymyxin, which is known for its serious adverse side effects, such as nephrotoxicity, neurotoxicity and promotion of skin pigmentation. To overcome these limitations, the use of biodegradable nanoparticles has been proposed to allow site-specific targeting, increasing the drug's bioavailability and decreasing its side effects. The aim of this work was the development of an optimized pharmaceutical formulation composed of solid lipid nanoparticles (SLN) loading polymyxin B sulphate (PLX) for the treatment of bacterial infections. The PLX-loaded SLN were produced by a double emulsion method (w/o/w), obtaining particles with a mean size of approximately 200nm, polydispersity of 0.3 and zeta potential of -30mV. The encapsulation efficiency reached values above 90% for all developed formulations. SLN remained stable for a period of 6months of storage at room temperature. The occlusive properties of the SLN was shown to be dependent on the type of lipid, while the antimicrobial properties of PLX-loaded SLN were effective against resistant strains of Pseudomonas aeruginosa. Results from the differential scanning calorimetry (DSC), wide angle X-ray diffraction (WAXD) and small angle X-ray scattering (SAXS) analyses confirmed the crystallinity of the inner SLN matrices, suggesting the capacity of these particles to modify the release profile of the loaded drug. PMID- 28576562 TI - A survey of the incidence of dyslipidemia and its components in people over 20 years old in Ahvaz: A cohort study 2009-2014. AB - INTRODUCTION: Dyslipidemia is one of the major risk factors for atherosclerosis and the main cause of death in the developing and developed countries. In this cohort study, the incidence of dyslipidemia and its components have been studied among individuals over 20 years old in Ahvaz, southwest of Iran. MATERIALS AND METHODS: The Phase 1 of this study was conducted on the prevalence of Metabolic syndrome and its related factors by Diabetes Research Center in 2009. The target population included individuals over 20 years old who were selected using cluster sampling in Ahvaz health centers. In the second phase of the study, 5 years later in 2014, subjects were again recalled by health centers. Questionnaires, anthropometric indices and measurements were repeated similar to Phase 1. The blood sample was taken from everyone after 12h of fasting and then the factors (Chol, TG, HDL) were measured. RESULTS: The cumulative incidence of dyslipidemia obtained 60.7% (males 56.7% and females 64.8%). lipid profile {HDL, Triglycerides and Cholesterol had changes in their means(a significant reduction in the mean about 10, 22.25 and 13 units respectively) between baseline and 5 years later. Waist circumference here associated with incidence of high LDL and high chol, also sex and High LDL 'educational level and daily consumption of vegetables were associated with incidence of low HDL and dyslipidemia respectively. CONCLUSION: Age, educational level and daily intake of fruits and vegetables were effective variables on incidence of dyslipidemia. According to various studies, LDL and HDL levels in different regions of Iran, seems to be influenced by factors such as climate, nutrition and activity levels. PMID- 28576563 TI - Development and validation of health related quality of life questionnaire (Indian scenario) in diabetic foot ulcer patients. AB - AIM: To develop and validate Health Related Quality of Life Questionnaire in Diabetic Foot Ulcer Patients (HRQLQDFU) for Indian scenario. MATERIALS AND METHODS: This study was conducted in two phases. First phase was Development of HRQLQDFU which included literature search and expert interview. Second phase was validation of HRQLQDFL which included face validation, content validation and construct validation. Face validation was done by ten diabetic foot ulcer patients, ten practicing nurses and ten care givers. They were asked to read and respond to questionnaire and report any difficulty in understanding the questions. Further they were asked to add any item to the questionnaire which according to them has a significant effect on quality of life. Content validation was done by six subject experts who judged the content relevance of questionnaire with score ranging from zero to four; zero being least relevant and four being most relevant. Content validity index was calculated for each question. Questions having content validity index>=0.8 were selected for the study. Reliability was tested by calculating Cronbach's alpha. RESULTS: In the development phase a questionnaire containing 37 questions with six domains was developed. None of patient had difficulty in understanding questions. After content validation a new questionnaire containing 20 questions was developed. Cronbach's alpha was 0.86 which shows good reliability. CONCLUSION: The new health related quality of life questionnaire on diabetic foot ulcer patients for an Indian scenario is validated and can be a reliably measure for quality of life in diabetic foot ulcer patients. PMID- 28576564 TI - Cognitive deficits induced by combined exposure of stress and alcohol mediated through oxidative stress-PARP pathway in the hippocampus. AB - Several studies reported that stress can enhance the consumption of alcohol in humans and animals. However, the combinatorial effect of stress and alcohol on cognitive function and neurochemical alterations is quite understudied. In the present study, we have elucidated the involvement of oxidative stress-PARP cascade in alcohol and restraint stress (RS)-exposed animals using a PARP inhibitor, 1,5-isoquinolinediol (3mg/kg for 14days). Male Swiss albino mice were given alcohol (ALC) or RS (2h per day) or both in ALC+RS group for 28days. Behavioral analysis revealed cognitive dysfunction in ALC+RS group. Furthermore, oxidative stress and raised level of pro-inflammatory cytokines were found in the hippocampus region of ALC+RS group. Semi-quantitative reverse transcriptase PCR showed overactivation of PARP-1 gene in ALC+RS group. 1,5-isoquinolinediol treatment significantly prevented cognitive deficits and aforementioned neurochemical alterations. Overall, our findings showed that ALC+RS exerted deleterious effects on the hippocampus which involves oxidative stress-PARP overactivation cascade. PMID- 28576565 TI - The expression of VDR mRNA but not NF-kappaB surprisingly decreased after vitamin D treatment in multiple sclerosis patients. AB - BACKGROUND AND PURPOSE: The aim of this study was to investigate the expression levels of vitamin D receptor (VDR) and NF-kappaB mRNAs in vitamin D (VD) supplemented multiple sclerosis (MS) patients. METHODS: RRMS patients received 50,000 IU vitamin D3/week as an intra-muscular injection for 2 months. Blood samples were obtained from 30 MS patients before and after VD supplementation and 32 healthy individuals, and then VDR and NF-kappaB mRNA levels were measured by real time PCR method and analyzed with independent and paired t-tests. Moreover, some correlations were performed between the expression levels of selected genes and some clinical features of MS and control groups. RESULTS: Surprisingly, the expression level of VDR mRNA significantly decreased after 2 months supplementation with VD in our selected patients and in contrast, the level of serum 25(OH) D increased after supplementation. Although, we didn't find any significant difference in the expression level of NF-kappaB gene before and after treatment with VD, its expression significantly decreased in untreated MS cases compared with healthy controls. CONCLUSION: In conclusion, we found some new evidences from the molecular mechanism of vitamin D effectiveness in MS treatment. Also, we need more functional studies to find the effect of VD on the expression level of VDR mRNA. PMID- 28576566 TI - Continuous theta burst stimulation facilitates the clearance efficiency of the glymphatic pathway in a mouse model of sleep deprivation. AB - Sleep deprivation (SD) is a common condition associated with a variety of nervous system diseases, and has a negative impact on emotional and cognitive function. Continuous theta burst stimulation (cTBS) is known to improve cognition and emotion function in normal situations as well as in various types of dysfunction, but the mechanism remains unknown. We used two-photon in vivo imaging to explore the effect of cTBS on glymphatic pathway clearance in normal and SD C57BL/6J mice. Aquaporin-4 (AQP4) polarization was detected by immunofluorescence. Anxiety like behaviors was measured using open field tests. We found that SD reduced influx efficiency along the peri-vascular space (PVS), disturbed AQP4 polarization and induced anxiety-like behaviors. CTBS significantly attenuated the decrease in efficiency of solute clearance usually incurred with SD, restored the loss of AQP4 polarization and improved anxiety-like behavior in SD animals. Our results implied that cTBS had the potential to protect against neuronal dysfunction induced by sleep disorders. PMID- 28576567 TI - Developing a data sharing community for spinal cord injury research. AB - The rapid growth in data sharing presents new opportunities across the spectrum of biomedical research. Global efforts are underway to develop practical guidance for implementation of data sharing and open data resources. These include the recent recommendation of 'FAIR Data Principles', which assert that if data is to have broad scientific value, then digital representations of that data should be Findable, Accessible, Interoperable and Reusable (FAIR). The spinal cord injury (SCI) research field has a long history of collaborative initiatives that include sharing of preclinical research models and outcome measures. In addition, new tools and resources are being developed by the SCI research community to enhance opportunities for data sharing and access. With this in mind, the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH) hosted a workshop on October 5-6, 2016 in Bethesda, MD, in collaboration with the Open Data Commons for Spinal Cord Injury (ODC-SCI) titled "Preclinical SCI Data: Creating a FAIR Share Community". Workshop invitees were nominated by the workshop steering committee (co-chairs: ARF and VPL; members: AC, KDA, MSB, KF, LBJ, PGP, JMS), to bring together junior and senior level experts including preclinical and basic SCI researchers from academia and industry, data science and bioinformatics experts, investigators with expertise in other neurological disease fields, clinical researchers, members of the SCI community, and program staff representing federal and private funding agencies. The workshop and ODC-SCI efforts were sponsored by the International Spinal Research Trust (ISRT), the Rick Hansen Institute, Wings for Life, the Craig H. Neilsen Foundation and NINDS. The number of attendees was limited to ensure active participation and feedback in small groups. The goals were to examine the current landscape for data sharing in SCI research and provide a path to its future. Below are highlights from the workshop, including perspectives on the value of data sharing in SCI research, workshop participant perspectives and concerns, descriptions of existing resources and actionable directions for further engaging the SCI research community in a model that may be applicable to many other areas of neuroscience. This manuscript is intended to share these initial findings with the broader research community, and to provide talking points for continued feedback from the SCI field, as it continues to move forward in the age of data sharing. PMID- 28576568 TI - Early-life exposure to caffeine affects the construction and activity of cortical networks in mice. AB - The consumption of psychoactive drugs during pregnancy can have deleterious effects on newborns. It remains unclear whether early-life exposure to caffeine, the most widely consumed psychoactive substance, alters brain development. We hypothesized that maternal caffeine ingestion during pregnancy and the early postnatal period in mice affects the construction and activity of cortical networks in offspring. To test this hypothesis, we focused on primary visual cortex (V1) as a model neocortical region. In a study design mimicking the daily consumption of approximately three cups of coffee during pregnancy in humans, caffeine was added to the drinking water of female mice and their offspring were compared to control offspring. Caffeine altered the construction of GABAergic neuronal networks in V1, as reflected by a reduced number of somatostatin containing GABA neurons at postnatal days 6-7, with the remaining ones showing poorly developed dendritic arbors. These findings were accompanied by increased synaptic activity in vitro and elevated network activity in vivo in V1. Similarly, in vivo hippocampal network activity was altered from the neonatal period until adulthood. Finally, caffeine-exposed offspring showed increased seizure susceptibility in a hyperthermia-induced seizure model. In summary, our results indicate detrimental effects of developmental caffeine exposure on mouse brain development. PMID- 28576569 TI - Top-down modulation of early print-tuned neural activity in reading. AB - Fast neural tuning to print has been found within the first 250ms of stimulus processing across different writing systems, indicated by larger N1 negativity in the ERP to words (or characters) compared to control stimuli, such as symbols. However, whether print tuning effects can be modulated by task demands at early stages of visual word recognition is still under debate. To further explore this issue, an ERP study in Chinese was conducted. Familiar, high-frequency, left/right-structured Chinese characters and unfamiliar, stroke number-matched symbols (Korean characters) were used as stimulus conditions. While viewing the characters and symbols, 20 native Chinese speakers performed three tasks: delayed naming, repetition detection, and blue color detection. Results from occipito temporal and whole map analyses suggest that the influence of task on print tuning changes throughout the N1. Accordingly in the N1 onset, a print tuning main effect was found, with a stronger N1 to words than symbols, irrespective of task. In the N1 offset, a print-by-task interaction reflected a more negative N1 to symbols than words in both delayed naming and color detection, but not in the repetition detection. After the N1 an N2 was observed with task and condition main effects at the whole map level. Taken together, the current study provides evidence that neural tuning to print is modulated by task demands already within the first 250ms, suggesting that early visual-orthographic processing may be less automatic than it was thought, and the possible top-down modulation may be much faster than it was previously assumed. PMID- 28576570 TI - Deinococcus Mn2+-peptide complex: A novel approach to alphavirus vaccine development. AB - Over the last ten years, Chikungunya virus (CHIKV), an Old World alphavirus has caused numerous outbreaks in Asian and European countries and the Americas, making it an emerging pathogen of great global health importance. Venezuelan equine encephalitis virus (VEEV), a New World alphavirus, on the other hand, has been developed as a bioweapon in the past due to its ease of preparation, aerosol dispersion and high lethality in aerosolized form. Currently, there are no FDA approved vaccines against these viruses. In this study, we used a novel approach to develop inactivated vaccines for VEEV and CHIKV by applying gamma-radiation together with a synthetic Mn-decapeptide-phosphate complex (MnDpPi), based on manganous-peptide-orthophosphate antioxidants accumulated in the extremely radiation-resistant bacterium Deinococcus radiodurans. Classical gamma-irradiated vaccine development approaches are limited by immunogenicity-loss due to oxidative damage to the surface proteins at the high doses of radiation required for complete virus-inactivation. However, addition of MnDpPi during irradiation process selectively protects proteins, but not the nucleic acids, from the radiation-induced oxidative damage, as required for safe and efficacious vaccine development. Previously, this approach was used to develop a bacterial vaccine. In the present study, we show that this approach can successfully be applied to protecting mice against viral infections. Irradiation of VEEV and CHIKV in the presence of MnDpPi resulted in substantial epitope preservation even at supra lethal doses of gamma-rays (50,000Gy). Irradiated viruses were found to be completely inactivated and safe in vivo (neonatal mice). Upon immunization, VEEV inactivated in the presence of MnDpPi resulted in drastically improved protective efficacy. Thus, the MnDpPi-based gamma-inactivation approach described here can readily be applied to developing vaccines against any pathogen of interest in a fast and cost-effective manner. PMID- 28576571 TI - Nontoxic outer membrane vesicles efficiently increase the efficacy of an influenza vaccine in mice and ferrets. AB - In this study, we developed a further-modified outer membrane vesicle (fmOMV) from the DeltamsbB/DeltapagP mutant of Escherichia coli transformed with the plasmid, pLpxF, in order to use it as an adjuvant for pandemic H1N1 (pH1N1) influenza vaccine. We evaluated the efficacy of the pH1N1 influenza vaccine containing the fmOMV in animal models as compared to the commercial adjuvants, alum or AddaVaxTM. The fmOMV-adjuvanted pH1N1 influenza vaccine induced a significant increase in the humoral immunity; however, this effect was less than that of the AddaVaxTM. The fmOMV-adjuvanted vaccine displayed pronounced an enhanced protective efficacy with increased T cell immune response and reduced the viral load in the lungs of the infected mice after challenging them with a lethal dose of the homologous virus. Moreover, it resulted in a significantly higher cross-protection against heterologous virus challenge than that of the pH1N1 vaccine with alum or with no adjuvants. In ferrets, the fmOMV-adjuvanted vaccine elicited a superior antibody response based on the HI titer and efficiently protected the animals from the lethal viral challenges. Taken together, the nontoxic fmOMV could be a promising adjuvant for inducing robust T cell priming into the pH1N1 vaccine and might be broadly applicable to the development of preventive measures against influenza virus infection. PMID- 28576572 TI - Intradermal injection of a fractional dose of an inactivated HFMD vaccine elicits similar protective immunity to intramuscular inoculation of a full dose of an Al(OH)3-adjuvanted vaccine. AB - Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) are the two major causative agents of hand, foot and mouth disease (HFMD), which erupts in the Asia-Pacific regions. A bivalent vaccine against both EV71 and CVA16 is highly desirable. In the present study, on the bases that an experimental bivalent vaccine comprising of inactivated EV71 and CVA16 induces a balanced protective immunity against both EV71 and CVA16, we compare the immunogenicity and reactogenicity of one fourth of a full dose of an intradermal vaccine administered by needle-free liquid jet injector with a full dose of an intramuscular vaccine administered by needle syringe in monkeys. The results suggest that intradermal injection of a fractional dose of an inactivated HFMD vaccine elicits similar immunogenicity and reactogenicity to intramuscular inoculation of a full dose of an Al(OH)3 adjuvanted vaccine, regardless of whether monovalent or bivalent vaccines were used. Our results support the use of an intradermal bivalent vaccine strategy for HFMD vaccination in order to satisfy the requirements and reduce the costs. PMID- 28576575 TI - Urgent care medicine and the role of the APP within this specialty. PMID- 28576573 TI - Rapid development of vaccines against emerging pathogens: The replication deficient simian adenovirus platform technology. AB - Despite the fact that there had been multiple small outbreaks of Ebola Virus Disease, when a large outbreak occurred in 2014 there were no vaccines or drugs available for use. Clinical development of multiple candidate vaccines was then initiated in parallel with attempts to contain the outbreak but only one vaccine was eventually tested in a phase III trial. In order to be better prepared for future outbreaks of known human pathogens, platform technologies to accelerate vaccine development should be employed, allowing vaccine developers to take advantage of detailed knowledge of the vaccine platform and facilitating rapid progress to clinical trials and eventually to vaccine stockpiles. This review gives an example of one such vaccine platform, replication-deficient simian adenoviruses, and describes progress in human and livestock vaccine development for three outbreak pathogens, Ebola virus, Rift Valley Fever Virus and Middle East Respiratory Syndrome Coronavirus. PMID- 28576574 TI - Physical and functional interactions between nuclear receptor LXRalpha and the forkhead box transcription factor FOXA2 regulate the response of the human lipoprotein lipase gene to oxysterols in hepatic cells. AB - Lipoprotein lipase (LPL) catalyzes the hydrolysis of triglycerides from triglyceride-rich lipoproteins such as VLDL and chylomicrons in the circulation. Mutations in LPL or its activator apolipoprotein C-II cause hypertriglyceridemia in humans and animal models. The levels of LPL in the liver are low but they can be strongly induced by a high cholesterol diet or by synthetic ligands of Liver X Receptors (LXRs). However, the mechanism by which LXRs activate the human LPL gene is unknown. In the present study we show that LXR agonists increased the mRNA and protein levels as well as the promoter activity of human LPL in HepG2 cells. A promoter deletion analysis defined the proximal -109/-28 region, which contains a functional FOXA2 element, as essential for transactivation by ligand activated LXRalpha/RXRalpha heterodimers. Silencing of endogenous FOXA2 in HepG2 cells by siRNAs or by treatment with insulin compromised the induction of the LPL gene by LXR agonists whereas mutations in the FOXA2 site abolished the synergistic transactivation of the LPL promoter by LXRalpha/RXRalpha and FOXA2. Physical and functional interactions between LXRalpha and FOXA2 were established in vitro and ex vivo. In summary, the present study revealed a novel mechanism of human LPL gene induction by oxysterols in the liver with is based on physical and functional interactions between transcription factors LXRalpha and FOXA2. This mechanism, which may not be restricted to the LPL gene, is critically important for a better understanding of the regulation of cholesterol and triglyceride metabolism in the liver under healthy or pathological states. PMID- 28576576 TI - Recent advances in measuring the kinetics of biomolecules by NMR relaxation dispersion spectroscopy. AB - Protein function can be modulated or dictated by the amplitude and timescale of biomolecular motion, therefore it is imperative to study protein dynamics. Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful technique capable of studying timescales of motion that range from those faster than molecular reorientation on the picosecond timescale to those that occur in real-time. Across this entire regime, NMR observables can report on the amplitude of atomic motion, and the kinetics of atomic motion can be ascertained with a wide variety of experimental techniques from real-time to milliseconds and several nanoseconds to picoseconds. Still a four orders of magnitude window between several nanoseconds and tens of microseconds has remained elusive. Here, we highlight new relaxation dispersion NMR techniques that serve to cover this "hidden-time" window up to hundreds of nanoseconds that achieve atomic resolution while studying the molecule under physiological conditions. PMID- 28576577 TI - Advanced technology for catheter ablation of atrial fibrillation: A double-edged sword? PMID- 28576578 TI - Understanding solid-phase HLA antibody assays and the value of MFI. AB - As the practice of medicine becomes more reliant on imaging and laboratory tests, medical decisions will be increasingly based on numbers. Accordingly, following the introduction of solid-phase testing to the HLA testing repertoire, laboratory directors and physicians have employed preset mean fluorescence intensity (MFI) thresholds as the basis for decisions in the management of transplant patients. However, what do MFI values mean? The literature is rife with reports detailing numerous factors that influence antibody assessment including (but not limited to) sensitization history of the patient, level of mismatch between donor and recipient, presence of interfering substances in the serum, whether the antigen on multiplex beads is native or denatured, day-to-day and technologist variability, and the historical performance of an assay in a given institution. How are these variables incorporated into the interpretation of MFI values? Herein, the pitfalls and complexities of single antigen bead (SAB) testing and interpretation are discussed with specific attention to what can and cannot be inferred by MFI. PMID- 28576580 TI - Quassia "biopiracy" case and the Nagoya Protocol: A researcher's perspective. AB - Biopiracy accusations are common in the world of biodiversity research. At the end of 2015, a French NGO accused researchers from the Institut de Recherche pour le Developpement (IRD) of biopiracy. These researchers had applied for a patent for a natural bioactive molecule against malaria and cancer, the Simalikalactone E, isolated from Quassia amara L. (Simaroubaceae) leaves. This biopiracy allegation triggered a huge wave of attacks from the media and social networks, and vehement recrimination from political officials in French Guiana against researchers who have been accused of ethical misconduct, by stealing the traditional knowledge of indigenous people. These accusations were made in the contentious context of the ratification of the Nagoya Protocol in the frame of implementing the French law on biodiversity, nature and landscapes. So, in an atmosphere of heightened emotions it is crucial to understand the issues behind these accusations. We describe herein the genesis of our discovery, present the detractors' arguments, and discuss the consequences of such biopiracy denunciations for scientific research. We also address our concerns about the gap between rhetoric and reality and the real impact of the Nagoya Protocol on biodiversity conservation. PMID- 28576581 TI - In vivo dosimetry for lung radiotherapy including SBRT. AB - SBRT for lung cancer is being rapidly adopted as a treatment option in modern radiotherapy centres. This treatment is one of the most complex in common clinical use, requiring significant expertise and resources. It delivers a high dose per fraction (typically ~6-30Gy/fraction) over few fractions. The complexity and high dose delivered in only a few fractions make powerful arguments for the application of in vivo dosimetry methods for these treatments to enhance patient safety. In vivo dosimetry is a group of techniques with a common objective - to estimate the dose delivered to the patient through a direct measurement of the treatment beam(s). In particular, methods employing an electronic portal imaging device have been intensely investigated over the past two decades. Treatment verification using in vivo dosimetry approaches has been shown to identify errors that would have been missed with other common quality assurance methods. With the addition of in vivo dosimetry to verify treatments, medical physicists and clinicians have a higher degree of confidence that the dose has been delivered to the patient as intended. In this review, the technical aspects and challenges of in vivo dosimetry for lung SBRT will be presented, focusing on transit dosimetry applications using electronic portal imaging devices (EPIDs). Currently available solutions will be discussed and published clinical experiences, which are very limited to date, will be highlighted. PMID- 28576579 TI - Suppression of Baeckea frutescens L. and its components on MyD88-dependent NF kappaB pathway in MALP-2-stimulated RAW264.7 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Baeckea frutescens L. is commonly used as a folk medicinal material. There are nineteen components in its volatile oil, including Pcymol which has effects of eliminating phlegm, relieving asthma and antiviral. This study was aimed to investigate the anti-infectious inflammatory activities of Baeckea frutescens L. and its conponents and analyzing the mechanisms. MATERIALS AND METHODS: The anti-infectious inflammation of Baeckea frutescens L. were studied by using macrophage activating lipopeptide-2 (MALP-2)-stimulated RAW264.7 cell model in vitro. Secretion of nitric oxide (NO), expression of inducible NO synthase (iNOS) and cytokines were detected as classic inflammatory index. Expression of Myeloid differentiation factor 88 (MyD88), degradation of inhibitory kappaBalpha (IkappaBalpha) and nuclear translocation of NF-kappaB p65 were further investigated. RESULTS: The results suggested that Baeckea frutescens L. has effect on suppression of MALP-2-mediated inflammation in RAW264.7 cells. The secretion of NO and the expression of iNOS could be inhibited. The secretion of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were also declined. Baeckea frutescens L. significantly decreased the expression of MyD88, therefore, inhibited the degradation of IkappaBalpha, reduced the level of nuclear translocation of p65. CONCLUSION: The results of this study indicated that Baeckea frutescens L. and its components could inhibit the anti-infectious inflammatory events and iNOS expression in MALP-2 stimulated RAW264.7 cells. Among them, BF-2 might play a role through the inhibition of the MyD88 and NF kappaB pathway. Our study might provide a new strategy to design and develop this kind of drug towards mycoplasma-infected inflammation. PMID- 28576583 TI - [ECG before administration of Ritalin(r): Is it useful ?] PMID- 28576582 TI - Visualization of air and metal inhomogeneities in phantoms irradiated by carbon ion beams using prompt secondary ions. AB - PURPOSE: Non-invasive methods for monitoring of the therapeutic ion beam extension in the patient are desired in order to handle deteriorations of the dose distribution related to changes of the patient geometry. In carbon ion radiotherapy, secondary light ions represent one of potential sources of information about the dose distribution in the irradiated target. The capability to detect range-changing inhomogeneities inside of an otherwise homogeneous phantom, based on single track measurements, is addressed in this paper. METHODS: Air and stainless steel inhomogeneities, with PMMA equivalent thickness of 10mm and 4.8mm respectively, were inserted into a PMMA-phantom at different positions in depth. Irradiations of the phantom with therapeutic carbon ion pencil beams were performed at the Heidelberg Ion Beam Therapy Center. Tracks of single secondary ions escaping the phantom under irradiation were detected with a pixelized semiconductor detector Timepix. The statistical relevance of the found differences between the track distributions with and without inhomogeneities was evaluated. RESULTS: Measured shifts of the distal edge and changes in the fragmentation probability make the presence of inhomogeneities inserted into the traversed medium detectable for both, 10mm air cavities and 1mm thick stainless steel. Moreover, the method was shown to be sensitive also on their position in the observed body, even when localized behind the Bragg-peak. CONCLUSIONS: The presented results demonstrate experimentally, that the method using distributions of single secondary ion tracks is sensitive to the changes of homogeneity of the traversed material for the studied geometries of the target. PMID- 28576584 TI - [Zellweger syndrome]. PMID- 28576585 TI - [Identifying pediatric victims and informing their families: An additional difficulty]. PMID- 28576586 TI - [The lung microbiota. Review]. AB - In the last 20years, culture-independent DNA-based techniques ("shotgun sequencing") demonstrated that complex microbial communities reside on most epithelial surfaces, including the lower airways. Until the amniotic sac ruptures, a fetus is considered to be essentially sterile. Many factors affect the composition of the lung microbiota: inheritance, mode of delivery, diet, and age-related changes in adults. It interacts with the digestive and oropharyngeal microbiotas. Animal models show that these interactions play a role in innate pulmonary immunity and modulation of the inflammatory response. The microbial composition of the airway microbiota differs between healthy children and those with chronic lung disease. The advances in the comprehension of microbiome changes have resulted in new approaches concerning the microbiota for treatment and prevention of disease. PMID- 28576587 TI - [Is nephron-sparing surgery relevant for unilateral Wilms tumors?] AB - BACKGROUND: Wilms tumors (WTs) are the most frequent renal tumors in children. Radical nephrectomy (RN) remains the gold-standard surgical treatment for this type of cancer. Excellent results in overall survival (>90%) make it possible to consider nephronic preservation. The objective of this systematic review is to evaluate the relevance of nephron-sparing surgery (NSS) for the treatment of nonsyndromic unilateral Wilms tumor (UWT) in children. METHODS: Articles in English related to "unilateral Wilms tumor, unilateral nephroblastoma, partial nephrectomy, nephron-sparing surgery, renal function" identified in the Medline library were screened and data were extracted to perform a qualitative systematic review. RESULTS: We identified 377 articles, 14 of which were integrated into the analysis. Data on 4288 children were included, 3994 (93.1%) underwent RN, whereas 294 (6.8%) underwent NSS. Stage I anatomopathology resulted in 55.1% RN and 79% NSS. Overall survival and event-free survival were similar: respectively 95.7% and 92.8% after RN and 96 and 90.5% after NSS. Positive margin status was higher after NSS (8.5% vs 0.5%), but tumor rupture and local tumor recurrences were similar. The rate of mild to moderate renal function was higher after RN (42% vs 10% after NSS). DISCUSSION: NSS is regularly performed for WT in case of bilateral or syndromic tumors, but the literature considering UWT does not show consensus. The superiority of NSS for renal outcomes has now been fully evaluated, but the main problem of this surgery in case of UWT is to ensure oncologic outcomes as good as outcomes after RN. WTs are usually massive tumors for which partial nephrectomy is contraindicated, but studies showed that chemotherapy before surgery could reduce tumor volume and make NSS possible. This review shows that NSS results seem to be as good as RN results and that preoperative chemotherapy should be highlighted for its participation in the reduction of the positive margin status. Although radiotherapy is used with caution because of its side effects, some studies showed that it gave excellent results for oncologic salvage after local recurrence. Constant progress in medical imaging and detection systems has led to the emergence of a new type of assistance for surgeons such as image reconstruction and vessel or urinary tract system segmentation. Virtual simulation of the operation based on a real case should help evaluate the feasibility of complex procedures in the near future. CONCLUSION: NSS for UWT seems to be a credible therapeutic alternative. New technologies such as 3D reconstruction should help surgeons define the best parameters to select ideal tumors for this surgery in the near future. For the moment, small tumors (<4cm), distant from the renal hilum (ideally on the upper pole) that respect at least 50% of the renal parenchyma (ideally superficial with exophytic development) seem to be the perfect indication for NSS. PMID- 28576588 TI - [Dystonia 12: A rare and difficult diagnosis]. AB - We report a case of dystonia 12, also called rapid-onset dystonia-parkinsonism, which occurred in a young 12-year-old boy. Type 12 dystonia is a genetic syndrome characterized by a pathogenic mutation on ATP1A3 gene encoding the subunit alpha 3 of Na-K-ATPase protein, resulting in neuronal dysfunctions. It remains a rare syndrome with less than 100 cases described in the literature. Its atypical presentation and its rarity may lead to a wandering diagnosis, even in some cases to a conversion hysteria diagnosis. Today, unfortunately, there is no effective treatment. PMID- 28576590 TI - An approach to improving heart failure management - A local contribution PMID- 28576591 TI - Large thrombus formation on an AmplatzerTM Cardiac Plug. PMID- 28576589 TI - Early changes in atrial conduction times in hypertensive patients with elevated pulse pressure. AB - OBJECTIVE: Pulse pressure (PP) is the difference between systolic and diastolic blood pressure, and is an independent predictor of atrial fibrillation (AF). In this study we investigated the relationship between PP and atrial conduction times. METHODS: The study included 157 patients with essential hypertension. PP of 60 mmHg or more was regarded as elevated (n=56). Atrial electromechanical delay (EMD) was assessed with tissue Doppler echocardiography and P-wave dispersion (Pd) was calculated from the electrocardiogram. RESULTS: Left atrial volume index (23.6+/-4.9 ml/m2 vs. 25.2+/-6.5 ml/m2, p=0.141), left ventricular mass index (77.3+/-13.5 g/m2 vs. 80.9+/-19.6 g/m2, p=0.180) and grade I diastolic dysfunction (42% vs. 53%, p=0.242) were similar between groups. Inter-atrial (33.6+/-9.2 ms vs. 41.5+/-11.3 ms, p<0.001), intra-left atrial (23.0+/-8.8 ms vs. 28.2+/-10.6 ms, p=0.001) and intra-right atrial (10.5+/-5.8 ms vs. 13.2+/-4.9 ms, p=0.004) EMD were found to be higher in patients with elevated PP. P-maximum (108+/-8 ms vs. 114+/-9 ms, p<0.001) and Pd (30+/-13 ms vs. 38+/-13 ms, p<0.001) were also prolonged in patients with elevated PP. Multivariate linear regression analysis revealed that PP was independently associated with inter-atrial EMD (beta=0.379, t=4.088, p<0.001). CONCLUSION: This study showed that elevated PP is associated with prolonged atrial EMD and Pd. Atrial conduction is disturbed in hypertensive patients with elevated PP before the development of significant structural remodeling. PMID- 28576592 TI - Evaluating the Genomic Yield of a Single Endobronchial Ultrasound-guided Transbronchial Needle Aspiration in Lung Cancer: Meeting the Challenge of Doing More With Less. AB - BACKGROUND: Minimally invasive techniques, including endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA), yield small specimens that are adequate for cytologic diagnosis of lung cancer, but also need to provide material for molecular analysis to guide treatment. The number of EBUS-TBNA passes needed for mutation testing remains unclear. We sought to assess the adequacy of a single pass for genomic profiling of actionable mutations. METHODS: In a prospective observational study, paired samples from the same lesion were obtained from patients undergoing EBUS-TBNA for lung cancer diagnosis/staging. Following tumor cell confirmation by rapid on-site evaluation, a "reference" sample comprising >= 3 passes was obtained and formalin-fixed paraffin-embedded. A "study" sample comprising a single pass was taken and snap-frozen. The primary outcome was DNA yield and quality from a single pass. The secondary outcome was diagnostic accuracy of a single pass for detecting actionable mutations. RESULTS: In 40 patients, single-pass specimens yielded a mean 3.98 MUg of highly intact DNA, well above the minimum threshold for targeted sequencing, which was performed in adenocarcinoma cases (n = 24). In 23 cases, there was 100% agreement in mutation status between reference and study samples. In 1 case, the reference sample failed to generate a molecular diagnosis owing to insufficient tumor cells; however, the study specimen identified a KRAS mutation. Tumor cell percentage in mutation-positive specimens was 1% to 70%, suggesting that single pass samples detect mutations even when tumor cell content is low. CONCLUSION: Single EBUS-TBNA passes yield DNA of high quantity and quality with high accuracy for molecular profiling, irrespective of tumor cell content. PMID- 28576593 TI - Impact of Omission of Intrapulmonary Lymph Node Retrieval on Outcome Evaluation of Lung Cancer Patients Without Lymph Node Metastasis: A Propensity Score Matching Analysis. AB - INTRODUCTION: Clinical practice of retrieval of segmental (station 13) and subsegmental (station 14) lymph nodes for pathologic examination varies during lung cancer surgery. This study aimed to evaluate whether omitting retrieval of nodes from stations 13 and 14 could affect outcome evaluation for patients with pN0 non-small-cell lung cancer (NSCLC). METHODS: This retrospective study analyzed 442 patients with NSCLC who were treated with both R0 resection and systematic mediastinal lymphadenectomy with pathologically confirmed stage pN0 NSCLC. The study group included patients in whom N1 nodes including stations 10 to 14 were investigated, and the control group included patients in whom stations 10 to 12 only were investigated. Clinical and pathologic parameters of the groups were balanced by propensity score matching, and oncologic outcomes were assessed by the log-rank test. RESULTS: A total of 435 cases were included in the final analysis (170 in the study group and 265 in the control group). In the study group, a mean +/- SD of 5.0 +/- 3.0 nodes per case were collected from nodes 13 and 14. After propensity score matching, 143 cases were included in each group. Overall and disease-free survival improved in the study group compared to the control group (P = .027 and P = .021, respectively). T staging and intrapulmonary node collection were prognostic factors for pN0 cases. CONCLUSION: Inferior oncologic outcomes of pN0 cases without intrapulmonary node retrieval suggest that the procedure of intrapulmonary lymph node retrieval may play a role in outcome evaluation for pN0 NSCLC patients. PMID- 28576594 TI - Time and Effort Required for Tissue Acquisition and Submission in Lung Cancer Clinical Trials. AB - BACKGROUND: Increasingly, analysis of tumor tissue samples for predictive and pharmacodynamic biomarkers is incorporated into lung cancer clinical trials. We determined the time and effort required for tissue acquisition and submission. PATIENTS AND METHODS: We analyzed data from patients enrolled from 2009 to 2016 at UT Southwestern onto lung cancer trials with mandatory or optional submission of tumor tissue. We collected dates of treatment-related events and staff communications; nature of tissue requirement and biomarker analysis; and location of archival tissue. Associations between case characteristics, clinical intervals, and number of staff communications were analyzed by Fisher's exact test, Wilcoxon 2-sample test, and Kruskal-Wallis test. RESULTS: We identified 129 patients enrolled onto 19 clinical trials, of whom 108 (84%) ultimately received study therapy. For cases in which tissue submission was required if available or optional, 16% and 0%, respectively, had tissue sent. The median interval between consent and treatment was 28 (interquartile range, 11-43) days if tissue was requested and 7 (interquartile range, 6-13) days if tissue was not requested (P < .001). Among cases with requested tissue, the median number of related research staff communications was 3 (range, 0-10). Over time, the number of staff communications increased (P < .001). Location of archival tissue was not associated with number of staff communications or treatment intervals. CONCLUSION: Lung cancer clinical trial requirements for tissue acquisition and submission affect the time to treatment initiation and require increasing staff effort. Improved systems to expedite these processes, as well as use of blood- or imaging-based biomarkers, may help address these issues. PMID- 28576595 TI - Prognostic Impact of Minimal Pericardial Effusion in Patients With Advanced Non small-cell Lung Cancer. AB - INTRODUCTION: Minimal (< 10 mm in thickness) pericardial effusion (PCE) can be incidentally detected by computed tomography at the time of diagnosis in patients with lung cancer. Although malignant PCE is known to be associated with poor prognosis, the impact of minimal PCE on outcome has remained unclear. We therefore examined the prognostic relevance of minimal PCE in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We retrospectively analyzed consecutive patients diagnosed with stage IV NSCLC at Kindai University Hospital between April 2009 and March 2015. The patients were classified into 3 groups on the basis of the presence and thickness of PCE: no PCE, minimal (< 10 mm) PCE, and malignant (>= 10 mm) PCE. The relation between overall survival and PCE status was examined with a Cox proportional hazards model. RESULTS: The total of 428 enrolled patients included 327 (76.4%) in the no PCE group, 61 (14.3%) in the minimal PCE group, and 40 (9.3%) in the malignant PCE group. Median overall survival was 15.0, 10.1, and 7.6 months in the no PCE, minimal PCE, and malignant PCE groups, respectively, with the survival of patients with minimal PCE thus being intermediate between that of the other 2 groups (P = .003). Multivariable analysis revealed that minimal PCE was independently associated with reduced survival (hazard ratio, 1.46; 95% confidence interval, 1.07-1.96; P = .019). CONCLUSIONS: The presence of minimal PCE was an independent prognostic factor for reduced survival in patients with advanced NSCLC. PMID- 28576597 TI - Benchmark dynamics in the environmental performance of ports. AB - This paper analyses the 2016 environmental benchmark performance of the port sector, based on a wide representation of EcoPorts members. This is the fifth time that this study has been conducted as an initiative of the European Sea Ports Organisation (ESPO). The data and results are derived from the Self Diagnosis Method (SDM), a concise checklist against which port managers can self assess the environmental management of their port in relation to the performance of the EcoPorts membership. The SDM tool was developed in the framework of the ECOPORTS project (2002-2005) and it is managed by ESPO. A total number of 91 ports from 20 different European Maritime States contributed to this evaluation. The main results are that air quality remains as the top environmental priority of the respondent ports, followed by energy consumption and noise. In terms of environmental management, the study confirms that key components are commonly implemented in the majority of European ports. 94% of contributing ports have a designated environmental manager, 92% own an environmental policy and 82% implement an environmental monitoring program. Waste is identified as the most monitored issue in ports (80%), followed by energy consumption (73%) and water quality (70%). PMID- 28576596 TI - Bronchoalveolar lavage triacetylfusarinine C (TAFC) determination for diagnosis of invasive pulmonary aspergillosis in patients with hematological malignancies. PMID- 28576598 TI - Blood cadmium and metallothionein concentrations in females of two sympatric pinnipeds species. AB - Otaria flavescens (SASL) and Arctocephalus australis (SAFS) are endemic of South America. The aims were to assess Cd concentrations in red blood cells (RBC) and plasma from free living females of both species; and to establish metallothioneins (MT) levels in blood fractions and the possible relationship between MTs and Cd. Blood of fifteen SASL and eight SAFS females from Isla de Lobos were analyzed (years 2010-2011). All animals showed Cd levels above the detection limit. Cd concentrations on SAFS were higher than those of SASL, however, no significant differences were observed on metal concentrations between cell fractions by species. Metal levels were associated with a natural presence and ecological-trophic habits of the prey items. On SASL the MT concentrations between fractions were similar; whereas, SAFS plasma concentrations were higher than RBC. The results reported constitute the first information on Cd and MT blood levels in these species. PMID- 28576599 TI - Hepatitis E virus IgG seroprevalence in HIV patients and blood donors, west central Poland. AB - OBJECTIVE: To assess hepatitis E virus (HEV) seroprevalence in HIV patients and blood donors from one region in Poland. METHODS: A group of 490 persons (244 HIV patients and 246 blood donors) aged 18-55 years were examined using the anti-HEV IgG assay (Wantai Biological Pharmacy Enterprise, Beijing, China). An analysis of the association between certain factors and the presence of this HEV exposure marker was conducted in both groups. RESULTS: An HEV seropositivity rate of 50.2% was found. There was no difference in HEV seroprevalence between blood donors (49.6%, 122/246) and HIV patients (50.8%, 124/244) (p=0.569). The anti-HEV IgG positivity rate increased with age as follows: 36.2% (59/163) in persons aged 18 30 years, 52.0% (92/177) in individuals aged 31-40 years and 63.3% (95/150) in those aged 41-55 years. HEV infection occurred in 56.4% (31/55) of people who had never travelled abroad. CONCLUSIONS: Wielkopolska Region in west-central Poland is an area hyperendemic for HEV infection. In this part of Poland, the exposure of HIV-positive persons to this virus is not greater than that of healthy blood donors. PMID- 28576600 TI - The role of nailfold capillaroscopy in the assessment of internal organ involvement in systemic sclerosis: A critical review. AB - Endothelial dysfunction and microvascular damage constitute the hallmarks of systemic sclerosis (SSc), explaining much of the pathophysiology and clinical manifestations of the disease. Nailfold videocapillaroscopy (NVC) is an established method for the assessment of the microvasculature, aiding in distinguishing different types of structural vascular abnormalities. Until recently, NVC was used in the diagnosis of SSc as well as in the assessment and follow-up of peripheral digital vasculopathy. On the top of digital ulcers, internal organ involvement such as myocardial dysfunction, pulmonary vascular and/or parenchymal lung disease characterizes severe SSc imparting a high risk of mortality. There is growing evidence suggesting that the extent of peripheral microvascular changes reflects the severity of the disease, especially in terms of life-threatening cardiopulmonary complications. The possible use of nailfold videocapillaroscopy as a useful, non-invasive modality to improve the ability to identify patients at higher risk for these devastating complications of the disease remains to be established. The aim of this review is to critically summarize and discuss current literature regarding the relationship between morphological alterations of nailfold dermal papillary vessels and several manifestations of SSc, focusing on visceral organ involvement, as well as their association with surrogate markers of macrovascular disease. PMID- 28576601 TI - Linc-ing the Noncoding Genome to Heart Function: Beating Hypertrophy. AB - The principal event of aberrant gene expression occurs in numerous disorders and syndromes, including heart failure. LncRNAs may constitute powerful treatment targets because they intensively interact with their genetic environment, as they are important regulators of genetic networks. Recent advances on the functional roles of lncRNAs in cardiac hypertrophy are expected to usher improved therapeutic strategies. PMID- 28576602 TI - Biomarkers of Human Pluripotent Stem Cell-Derived Cardiac Lineages. AB - Human pluripotent stem cells (hPSCs) offer a practical source for the de novo generation of cardiac tissues and a unique opportunity to investigate cardiovascular lineage commitment. Numerous strategies have focused on the in vitro production of cardiomyocytes, smooth muscle, and endothelium from hPSCs. However, these differentiation protocols often yield undesired cell types. Thus, establishing a set of stage-specific markers for pure cardiac subpopulations will assist in defining the hierarchy of cardiac differentiation, aid in the development of cellular therapy, and facilitate drug screening and disease modeling. The recent characterization of many such markers is enabling the isolation of major cardiac lineages and subpopulations from differentiating hPSCs. We provide here a comprehensive review detailing the suite of biomarkers used to differentiate cardiac lineages from mixed hPSC-derived populations. PMID- 28576603 TI - Association of low serum BDNF with depression in patients with Parkinson's disease. AB - OBJECTIVE: Increasing evidence shows that brain-derived neurotrophic factor (BDNF) plays a critical role in the development of depression and the mechanisms of antidepressant. Parkinson disease (PD) is associated with depression and decreased BDNF. The aim of the present study was to examine the association of BDNF with depression in PD, which has not been investigated. METHODS: We recruited 96 PD patients with (n = 46) and without depression (n = 50) and 102 healthy controls and measured the serum BDNF levels in both groups. Zung Self Rating Depression Scale (SDS) was administered for the severity of depression and Hoehn-Yahr staging scale for motor abilities in PD patients. RESULTS: Serum BDNF levels were significantly lower in PD patients than healthy controls (p < 0.01). Also serum BDNF levels were significantly decreased in PD patients with than without depression (p < 0.01). BDNF levels were negatively associated with SDS in both PD patients with and without depression (both p < 0.01). Multiple regression analysis confirmed that in either PD with or without depression group, BDNF was an independent contributor to SDS (both p < 0.05). CONCLUSIONS: Our findings suggest that decreased serum BDNF may be involved in the pathophysiology of depression in PD patients. PMID- 28576604 TI - Task-dependent variability of Essential Tremor. AB - INTRODUCTION: In Essential Tremor (ET), tremor characteristics and the impairment caused by tremor may vary from task to task. A variability of tremor frequency between postural and kinetic tasks has been proposed in ET, suggesting either multiple central oscillating networks, or peripheral or proprioceptive feedback mechanisms. This electrophysiological study aimed to assess tremor frequencies and amplitudes in tasks involving postural and kinetic tremor, and compare findings within and across tasks, to delineate physiological differences underlying individually affected manual tasks in ET. METHODS: 40 ET patients were included in the study. Tremor was characterized clinically, as well as electrophysiologically using accelerometry and digitizing tablet tasks. Tremor amplitude measures and frequencies were extracted for tasks involving kinetic (digital spiral drawing, handwriting), as well as postural tremor. Tremor was compared between and within tasks. RESULTS: Digital spiral tremor frequencies were significantly higher compared to postural tremor frequencies, as measured by accelerometry, with a mean difference of >2 Hz (p < 0.001). Within-task variability of repeated digital spirals revealed a significant amplitude reduction over time in both hands (p < 0.001), with an up to 32% reduction compared to the first spiral. CONCLUSION: ET exhibited a frequency variability, which was dependent on activation condition, suggesting neurophysiologically distinct pathways between postural and kinetic tremor. The reduction of tremor amplitudes observed in repeated digital spiral drawing may be explained by a learning effect or adaptation, and should be considered as non-random factor of variability when using spirals in ET to assess effects of interventions. PMID- 28576605 TI - Cognitive impairment is associated with Hoehn and Yahr stages in early, de novo Parkinson disease patients. AB - INTRODUCTION: The relationship between motor impairment and cognitive deterioration has long been described in Parkinson's disease (PD). The aim of the study was to compare cognitive performance of de novo PD patients in relation to the motor impairment severity according to Hoehn and Yahr (HY) stages. METHODS: Forty de novo PD patients at HY stage I and 40 patients at HY stage II completed a standardized neuropsychological battery. A multivariate analysis of covariance was used to compare cognitive performance between HY groups. Odds ratios (ORs) were employed to explore the risk of cognitive impairment between HY stages. Finally, the prevalence of mild cognitive impairment (MCI) was estimated for patients in HY stage I and II. RESULTS: Patients at HY stage I obtained better scores on neuropsychological tests than patients at HY stage II (p = 0.001). Univariate analysis of covariance revealed significant differences between HY stages on Rey's auditory verbal learning test -immediate recall (p < 0.0001), 10 points Clock Drawing Test (p = 0.002), and Rey-Osterrieth Complex Figure Test copy (p < 0.0001). ORs of having cognitive impairment were greater for HY stage II than stage I group. MCI occurred in 7.5% of patients in HY stage I, and in 42.5% of patients in HY stage II. CONCLUSION: In de novo PD patients, the severity of motor impairment at the diagnosis is associated to cognitive deficits and higher risk of MCI. PMID- 28576606 TI - Difference of achalasia subtypes based on clinical symptoms, radiographic findings, and stasis scores. AB - INTRODUCTION: Three subtypes of achalasia have been defined through high resolution esophageal manometry: subtype i shows no pressurization with swallows, subtype ii has increased isobaric panesophageal pressure, and subtype iii has distal esophageal spastic non-isobaric contractions. Studies describing the subtypes based on radiographic findings, clinical symptoms, and stasis scores are limited. AIM: To determine the differences in clinical symptoms, radiographic findings, and stasis scores for the 3 achalasia subtypes. METHODS: Patients undergoing high-resolution esophageal manometry received a questionnaire about current symptoms and previous treatments. The questions included the presence of symptoms and their severity. Barium swallow tests were performed before the high resolution esophageal manometry study to evaluate the maximum esophageal diameter. Stasis scores were calculated using the transit patterns on high resolution esophageal manometry. RESULTS: One hundred and eight patients with high-resolution esophageal manometry diagnosis of achalasia (n=8, subtype i; n=84, subtype ii; n=16, subtype iii) within the time frame of 1/2012-6/2015 were included in the study. Sex distribution was similar between the subtypes. Patient age was younger for subtype i (38+/-16 years), compared with subtypes ii (55+/-17 years) and iii (63+/-17 years) (P=.03). Esophageal symptoms did not differ between subtypes regarding the severity of nausea, chest pain, coughing, and heartburn, except for increased vomiting severity in subtype i (2.8+/-1.4 vs. 1.4+/-1.4 vs. 1.2+/-1.2, P<.01). A significant radiographic difference in esophageal dilation was seen between subtypes ii and iii (35.1+/-14.4 vs. 24.0+/ 7.2mm, P=.023). Stasis scores did not significantly differ between the subtypes. CONCLUSIONS: Achalasia subtypes had similar clinical symptoms, except for increased vomiting severity in subtype i. The maximum esophageal diameter in subtype ii was significantly greater than in subtype iii. Esophageal stasis scores were similar. Thus, high-resolution esophageal manometry remains essential in assessing achalasia subtypes. PMID- 28576607 TI - Extensiometric analysis of strain in craniofacial bones during implant-supported palatal expansion. AB - Palatal expansion has several orthodontic and orthopedic applications, such as increasing maxillary transverse dimensions and correcting maxillary atresia, oral breathing, and skeletal cross-bites. Little is known about the strain to which craniofacial bones are submitted when a palatal expander is loaded. The objectives of the present work were to propose a new palatal bone-borne titanium device (expansion screw), to determine patterns of strain distribution in craniofacial bones during palatal expansion and to show the clinical results of a new palatal expander supported by implants. For in vitro testing, the palatal expander supported by two commercially pure titanium (cp Ti) implants was inserted parallel to the median palatine suture of four dry adult human skulls. Uniaxial and triaxial strain gauges were attached to craniofacial bones and connected to a signal acquisition system. An expansion screw was turned and strain data were collected during palatal expansion. The results showed that the bone strain distribution in craniofacial bones loaded by the palatal bone-borne titanium device was complex: the strain was tensile in the palatine cortical bone and compressive in pterygopalatine processes, nasal bones, and orbital floor. The maximum compressive strain occurs in the upper portion of the pterygopalatine processes and the strain changes from compressive to tensile in the zygomatic process. The experimental results suggest that the bone strain due to the palatal expander is distributed over all craniofacial bones and that the upper portions of pterygopalatine processes are the main sites of resistance to palatal expansion. The new palatal expander supported by two cp Ti implants proposed was employed on adult patient as an illustrative report, where adequate palatal expansion was achieved. The new protocol proposed was less invasive, risky, painful and costless for the correction of moderate maxillary transverse deficiency. PMID- 28576608 TI - Response to request by journal editorship from Blood Cells, Molecules and Diseases in reference to a "Dear Editor" letter to the Pastores et al. paper, 2016. PMID- 28576609 TI - Missed opportunities. PMID- 28576610 TI - Body composition substudy of the SECOND-LINE study - Author's reply. PMID- 28576611 TI - Body composition substudy of the SECOND-LINE study. PMID- 28576613 TI - Seizing the opportunity - a salutogenic approach to public health. PMID- 28576612 TI - Evaluation of an association between long sleep duration and periodontal disease among men and women using nationally representative data. AB - OBJECTIVE: To assess the association between long sleep duration and periodontal disease among men and women using nationally representative data. METHODS: In this study, we performed a cross-sectional analysis and used multivariable logistic regression analysis models. We analysed data from 2012 through 2014 from the Korean National Health and Nutrition Examination Survey. The analysis in this study was confined to a total of 14,675 respondents over 19 years of age. We used a community periodontal index code greater than or equal to 3 to define periodontitis. RESULTS: The tendency of periodontitis increased with longer sleep duration in women. Compared with women who slept 5hours or less, women with a sleep duration of 6 to 8hours and 9hours or more had higher odds of periodontitis at 1.29 (95% confidence interval [95%CI]: 1.06-1.56) and 1.45 (95%CI: 1.07-1.96), respectively, after adjustment for age, smoking, drinking, exercise, frequency of tooth brushing, self-reported oral status, body mass index, diabetes mellitus, hypertension, white blood cell count, income, and education. A significant relationship between sleep duration and periodontitis was not found in men. CONCLUSION: Our findings suggest that long sleep duration was associated with periodontitis, after adjusting for potential confounding factors, among Korean women, especially in premenopausal women. PMID- 28576614 TI - The complexity of implementation factors in professional pharmacy services. AB - Implementation of professional pharmacy services is a complex process, in which multi-level factors interact and influence implementation process and outcomes at various levels or domains. In this paper the terms that have been used to describe the factors that influence implementation of evidence-based services and their domains are presented. The complex 'cause-and-effect' interactions by which implementation factors appear to interact throughout the implementation process are also discussed. Identifying and understanding these complex and causal relationships between different implementation factors, represents a key process in the implementation of any service, in order to assist in the development of tailored implementation strategies. Future research should be directed to gain an understanding of the nature of individual implementation factors, their cause-and effect interactions, and their relationships. Implementation strategies are less likely to succeed unless these are identified and targeted to the causes identified when designing and planning an implementation strategy. PMID- 28576615 TI - Non-regulatory related factors leading to off-label prescribing in children: A concept map. PMID- 28576616 TI - Discovery of highly reactive peptide tag by ELISA-type screening for specific cysteine conjugation. AB - We report the discovery of a highly reactive peptide tag for the specific cysteine conjugation of proteins. Screening of cysteine-containing peptides using ELISA-type screening yielded a 19-amino acid tag (DCPPPDDAADDAADDAADD), named DCP3 tag, which enabled the rapid and selective labeling of the tag-fused protein with a synthetic zinc complex on the surface of living cells. PMID- 28576617 TI - Synthesis of resveratrol derivatives as new analgesic drugs through desensitization of the TRPA1 receptor. AB - A series of 31 resveratrol derivatives was designed, synthesized and evaluated for activation and inhibition of the TRPA1 channel. Most acted as activators and desensitizers of TRPA1 channels like resveratrol or allyl isothiocyanate (AITC). Compound 4z (HUHS029) exhibited higher inhibitory activity than resveratrol with an IC50 value of 16.1MUM. The activity of 4z on TRPA1 was confirmed in TRPA1 expressing HEK293 cells, as well as in rat dorsal root ganglia neurons by a whole cell patch clamp recording. Furthermore, pretreatment with 4z exhibited an analgesic effect on AITC-evoked TRPA1-related pain behavior in vivo. PMID- 28576618 TI - Giving birth: Expectations of first time mothers in Switzerland at the mid point of pregnancy. AB - PROBLEM AND BACKGROUND: Despite a generally affluent society, the caesarean section rate in Switzerland has steadily climbed in recent years from 22.9% in 1998 to 33.7% in 2014. Speculation by the media has prompted political questions as to the reasons. However, there is no clear evidence as to why the Swiss rate should be so high especially in comparison with neighbouring countries. AIM: To describe the emerging expectations of giving birth of healthy primigravid women in the early second semester of pregnancy in four Swiss cantons. METHODS: Qualitative individual interviews with 58 healthy primigravid women, were audio recorded, transcribed and subjected to thematic analysis. Recruitment took place through public and private hospitals, birth centres, obstetricians and independent midwives. The main ethical issues were informed consent, autonomy, confidentiality and anonymity. FINDINGS: The three main themes identified were taking or avoiding decisions, experiencing a continuum of emotions and planning the care. DISCUSSION: Being pregnant was part of a project women had mapped out for their lives. Only three women in our sample expressed a wish for a caesarean section. One of the strongest emotions was that of fear but in contrast some participants expressed faith that their bodies would cope with the experience. CONCLUSION: Bringing together the three languages and cultures produced a truly "Swiss" study showing contrasts between a matter of fact approach to pregnancy and the concept of fear. Such a contrast is worthy of further and deeper exploration by a multi-disciplinary research team. PMID- 28576619 TI - Three different Hepatozoon species in domestic cats from southern Italy. AB - Three species of Hepatozoon, namely, Hepatozoon felis, Hepatozoon canis and Hepatozoon silvestris may affect domestic and/or wild felids. Although hepatozoonosis has been documented in a wide range of mammal species, data on cats are limited. To investigate the occurrence of these pathogens in cats, blood samples were collected from animals living in three provinces of southern Italy (Bari, Lecce, and Matera), and molecularly analysed by PCR amplification and sequencing of segments of the 18S rRNA gene. Out of 196 blood samples collected, Hepatozoon spp. DNA was amplified in ten cats (5.1%, CI: 3%-9%), with the majority of infected animals from Matera (8/34, 23.5%) and one each from the other two provinces. BLAST analysis revealed the highest nucleotide identity with sequences of H. canis, H. felis and H. silvestris deposited in GenBank. Results of this study indicate that these three species of Hepatozoon infect domestic cats in Italy. This is the first report of H. silvestris infection in a domestic cat. PMID- 28576620 TI - Sonographic Phenotypes of Molecular Subtypes of Invasive Ductal Cancer in Automated 3-D Breast Ultrasound. AB - Our aim was to investigate whether Breast Imaging Reporting and Data System Ultrasound (BI-RADS-US) lexicon descriptors can be used as imaging biomarkers to differentiate molecular subtypes (MS) of invasive ductal carcinoma (IDC) in automated breast ultrasound (ABUS). We included 125 IDCs diagnosed between 2010 and 2014 and imaged with ABUS at two institutes retrospectively. IDCs were classified as luminal A or B, HER2 enriched or triple negative based on reports of histopathologic analysis of surgical specimens. Two breast radiologists characterized all IDCs using the BI-RADS-US lexicon and specific ABUS features. Univariate and multivariate analyses were performed. A multinomial logistic regression model was built to predict the MSs from the imaging characteristics. BI-RADS-US descriptor margins and the retraction phenomenon are significantly associated with MSs (both p < 0.001) in both univariate and multivariate analysis. Posterior acoustic features and spiculation pattern severity were only significantly associated in univariate analysis (p < 0.001). Luminal A IDCs tend to have more prominent retraction patterns than luminal B IDCs. HER2-enriched and triple-negative IDCs present significantly less retraction than the luminal subtypes. The mean accuracy of MS prediction was 0.406. Overall, several BI-RADS US descriptors and the coronal retraction phenomenon and spiculation pattern are associated with MSs, but prediction of MSs on ABUS is limited. PMID- 28576622 TI - Haemodynamic effects of stent diameter and compaction ratio on flow-diversion treatment of intracranial aneurysms: A numerical study of a successful and an unsuccessful case. AB - BACKGROUND: Compacting a flow-diverting (FD) stent is an emerging technique to create a denser configuration of wires across the aneurysm ostium. However, quantitative analyses of post-stenting haemodynamics affected by the compaction level of different stent sizes remain inconclusive. OBJECTIVE: To compare the aneurysmal haemodynamic alterations after virtual FD treatments with different device diameters at different compaction ratios. METHODS: We virtually implanted three sizes of FD stent, with each size deployed at four compaction ratios, into two patient aneurysms previously treated with the Silk+FD-one successful case and the other unsuccessful. Wire configurations of the FD in the 24 treatment scenarios were examined, and aneurysmal haemodynamic alterations were resolved by computational fluid dynamics (CFD) simulations. We investigated the aneurysmal flow patterns, aneurysmal average velocity (AAV), mass flowrate (MF), and energy loss (EL) in each scenario. RESULTS: Compactions of the stent in the successful case resulted in a greater metal coverage rate than that achieved in the unsuccessful one. A 25% increment in compaction ratio further decreased the AAV (12%), MF (11%), and EL (9%) in both cases (average values). The averaged maximum differences attributable to device size were 10% (AAV), 8% (MF), and 9% (EL). CONCLUSIONS: Both stent size and compaction level could markedly affect the FD treatment outcomes. It is therefore important to individualise the treatment plan by selecting the optimal stent size and deployment procedure. CFD simulation can be used to investigate the treatment outcomes, thereby assisting doctors in choosing a favourable treatment plan. PMID- 28576621 TI - Chelating agents in combination with rosmarinic acid for boar sperm freeze drying. AB - The presence of DNA protective agents in the medium is necessary to maintain sperm functionality after freeze-drying procedure. The objective of this study was to investigate the effect of chelating agents, ethylene diaminetetraacetic acid (EDTA) and ethylene glycoltetraacetic acid (EGTA), in combination with rosmarinic acid (RA) on DNA integrity of freeze-dried boar sperm. We also examined the effect of these agents on the in vitro developmental ability of porcine oocytes following sperm injection (ICSI). Heterospermic mix, obtained from ejaculated sperm of three boars, was freeze-dried in two different chelating agents' media: 50mM EDTA or 50mM EGTA, and in these media supplemented with 105MUM of rosmarinic acid. Frozen-thawed sperm was used as control. After rehydration, samples were subjected to DNA damage detection using Sperm Chromatin Dispersion test. ICSI was performed to verify the ability of freeze-dried sperm to participate in embryonic development. Five replicated trials were carried out for each group. In the presence of rosmarinic acid, the percentage of spermatozoa with DNA damage decreased significantly (p=0.010), without differences between the two chelating agents combination. EDTA solution preserves more efficiently DNA integrity of boar sperm than EGTA solution (p=0.002). There were no significant differences among the studied groups related to the blastocyst formation rate. Results suggested that the addition of rosmarinic acid to the medium improves sperm DNA integrity after freeze-drying, but does not promote fertilization and blastocyst development. We also observed a similar percentage of embryos production with freeze-dried and with frozen-thawed sperm. PMID- 28576623 TI - The biomechanical model of the long finger extensor mechanism and its parametric identification. AB - The extensor mechanism of the finger is a structure transmitting the forces from several muscles to the finger joints. Force transmission in the extensor mechanism is usually modeled by equations with constant coefficients which are determined experimentally only for finger extension posture. However, the coefficient values change with finger flexion because of the extensor mechanism deformation. This induces inaccurate results for any other finger postures. We proposed a biomechanical model of the extensor mechanism represented as elastic strings. The model includes the main tendons and ligaments. The parametric identification of the model in extension posture was performed to match the distribution of the forces among the tendons to experimental data. The parametrized model was used to simulate three degrees of flexion. Furthermore, the ability of the model to reproduce how the force distribution in simulated extensor mechanism changes according to the muscle forces was also demonstrated. The proposed model could be used to simulate the extensor mechanism for any physiological finger posture for which the coefficients involved in the equations are unknown. PMID- 28576624 TI - Constrained Acetabular Components Used in Revision Total Hip Arthroplasty: A Registry Analysis. AB - BACKGROUND: Constrained acetabular components have a mechanism to lock in the femoral head. They have been developed to control postoperative dislocation, particularly in revision total hip arthroplasty (THA). Although these components may reduce dislocation, there are durability concerns: with reports of locking mechanism failures and loosening. We wanted to determine the outcome of constrained components in controlling dislocation, and if these components had a higher rate of second revision when compared with standard nonconstrained components. METHODS: Revision THA procedures from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) with a recorded primary procedure and initial diagnosis of osteoarthritis were used to compare constrained and standard nonconstrained components. Kaplan-Meier estimates of survivorship were calculated, and hazard ratios using Cox proportional hazard models were used to compare groups. RESULTS: There were 9509 THA first-revision procedures and 700 constrained components. Constrained components had a significantly higher revision rate after 3 months when large-head metal-on-metal components were included (hazard ratio = 1.37; P = .005). When large-head metal on-metal components were excluded, there was no difference in the rate of second revision between the 2 groups. When the analysis was limited to first revision for dislocation, constrained components had a higher second revision rate for further dislocation after 9 months. CONCLUSION: Constrained acetabular components had similar second-revision rates when compared with standard nonconstrained components, both for all first-revision reasons and when used to treat dislocation. Although possibly used for the more difficult unstable hips, constrained components had a higher rate of second revision for further dislocation. PMID- 28576625 TI - Detection of mechanical complications related to the potential risk of sudden cardiac death in patients with pulmonary arterial hypertension by computed tomography. AB - BACKGROUND: We explored the value of cardiac computed tomography (CT) for the detection and prediction of mechanical complications related to the risk of sudden cardiac death (SCD) in pulmonary arterial hypertension (PAH) patients. METHODS: PAH patients (n=60, mean age 47+/-15, 31.7% male) with pulmonary artery (PA) enlargement (>=40mm) by echocardiography were studied with cardiac CT. Complications explored were the presence of left main coronary artery (LM) compression, airway compression, PA dissection and PA thrombosis in relation to diameters of main PA (MPA) which were measured in (1) axial plane (MPAAx) and (2) LM oblique view (MPALMobq). RESULTS: Mechanical complications were found in 21 patients (35.0%): LM compression in 20 patients; airway compression in 3 patients; and PA thrombosis in 4 patients. Patients with complications had more dilated MPALMobq than patients without complication (59.4+/-13.0mm vs. 42.4+/ 7.0mm, p<0.001). The area under the receiver operating characteristic curve for MPALMobq was 0.889 (95% confidence interval: 0.795 to 0.983, p<0.001) with the highest discriminating sensitivity and specificity being 90.5% and 69.2%, respectively at MPALMobq of 45mm. MPAAx failed to predict the presence of mechanical complications (p>0.05). CONCLUSION: MPALMobq>=45mm was significantly associated with the presence of mechanical complications of PAH. Evaluation with CT should be considered in PAH patients with dilated MPA. PMID- 28576626 TI - Carotid artery screening at the time of coronary artery bypass - Does it influence neurological outcomes? AB - OBJECTIVE: Patients undergoing coronary artery bypass graft (CABG) are recommended to undergo carotid duplex study in presence of risk factors. Aim of the study was to quantify the relationship between risk factors and presence of carotid disease and examine if screening influenced outcomes. METHODS: Over a four year period in a single institution, 4364 consecutive patients presenting for primary isolated CABG were enrolled to undergo carotid duplex scanning. Patients were grouped as no significant carotid artery stenosis (<50%), moderate stenosis (50%-70%) and severe stenosis (>70%). Sub group analysis of patients with severe carotid stenosis was performed. Sensitivity of risk factors thought to be associated with carotid disease was also assessed. RESULTS: Of the 4364 patients, 406 patients (9.3%) had moderate or severe carotid artery stenosis. 32 (7.88%) had bilateral disease. Age>65, hypertension, left main stem stenosis, peripheral vascular disease, and previous neurological injury were all associated with carotid artery disease (p<0. 01). Diabetes (p=0.06) and smoking (p=0.79) were not significant risk factors. In patients with moderate carotid artery stenosis there was no difference in the incidence of major 4 (0.98%) vs.18 (0.45%) p=0.14 or minor 8 (1.9%) vs. 56 (1.41%); p=0.38 neurological outcomes. However, severe carotid stenosis was associated with an increase in all-cause mortality but no increase in neurological events. CONCLUSIONS: In the presence of risk factors carotid screening identifies at risk population. Severe carotid stenosis was associated with increased all-cause mortality. However, moderate stenosis did not influence neurological outcomes or mortality in patients undergoing coronary artery bypass grafting. PMID- 28576627 TI - Comparison of everolimus- and biolimus-eluting coronary stents with everolimus eluting bioresorbable vascular scaffolds: Two-year clinical outcomes of the EVERBIO II trial. AB - BACKGROUND: Data from randomized controlled trials have shown that the ABSORB BVS is non-inferior to Cobalt Chromium everolimus-eluting stents at 2years. METHODS & RESULTS: The EVERBIO II trial (Comparison of Everolimus- and Biolimus-Eluting Coronary Stents with Everolimus-Eluting Bioresorbable Vascular Scaffold) is a single-center, assessor-blind, randomized controlled trial enrolling 240 patients with an allocation ration of 1:1:1 conducted at University and Hospital Fribourg, Switzerland. The studied devices were an everolimus-eluting persistent polymer stent (EES), a biolimus-eluting stent with bioabsorbable polymer (BES) and a fully bioresorbable vascular scaffold (BVS). Clinical end points collected at 9months, 12months, and 2years, were academic research consortium defined composites, device thrombosis and target-vessel revascularization. Clinical follow-up at 2years was available in 96% (N=77) of patients in the EES group, in 100% (N=80) in the BES and 99% (N=77) in the BVS group. The device-oriented composite end point of cardiac death, target-vessel myocardial infarction and target-lesion revascularization occurred in 13 (16%) patients treated with EES, in 7 (9%) patients treated with BES and in 16 (21%) patients treated with BVS. There was no significant difference when the metallic stents were compared to the BVS (p=0.12). There was one late scaffold thrombosis throughout the trial in the BVS group, and no definite stent thrombosis in either EES or BES treated patients. CONCLUSIONS: The current analysis shows no significant differences with regard to clinical outcomes at 2years between BVS and the best-in-class metallic DES. Event rates were numerically higher in BVS-treated patients. However, when BVS were compared to BES alone, the occurrence of device related adverse events was significantly increased. PMID- 28576628 TI - Incidence of Torsade de Pointes in a tertiary hospital population. AB - BACKGROUND: Multiple risk factors play a role in the development of QTc prolongation and Torsade de Pointes (TdP). Cases of TdP are underreported and data on the incidence of TdP is scarce. The aim of this study was to investigate the incidence of TdP in a Belgian university hospital and describe the characteristics of TdP-cases using a risk score. METHODS: All cases from 2011 till 2013 coded with the ICD-9 code 427.1 in the University Hospitals of Leuven were selected. The medical files were reviewed and demographical, medical, medication and electrocardiographic data were collected. We focused on TdP-cases that were probably caused by the acquired long QT-syndrome. The RISQ-PATH score was used to quantify the risk in these cases (>=10 points as high risk for QTc prolongation/TdP). RESULTS: Over three years, 41 TdP-cases were identified of which 19 cases were secondary to the acquired long QT-syndrome (52.6% females, mean age of 74+/-12years). This corresponds with an incidence of 0.160/00/year in a hospital population. Most of the patients (N=17) were treated with at least one QTc-prolonging drug (most frequently amiodarone, sotalol and furosemide) of whom 12 patients with >=1 QTc-prolonging drug of list 1 of CredibleMeds. Fifteen patients had an electrocardiogram in a 24-hours interval before the TdP with a prolonged QTc-interval (>=450/470ms). All the patients had a RISQ-PATH score>=10. CONCLUSIONS: Although the incidence of 0.160/00/year might seem low, this means that approximately 173 possibly lethal TdP-cases can be expected in Belgian hospitals each year. All TdP-cases were associated with a high RISQ-PATH score. PMID- 28576629 TI - Robotic Resistance Treadmill Training Improves Locomotor Function in Children With Cerebral Palsy: A Randomized Controlled Pilot Study. AB - OBJECTIVE: To determine whether applying controlled resistance forces to the legs during the swing phase of gait may improve the efficacy of treadmill training as compared with applying controlled assistance forces in children with cerebral palsy (CP). DESIGN: Randomized controlled study. SETTING: Research unit of a rehabilitation hospital. PARTICIPANTS: Children with spastic CP (N=23; mean age, 10.6y; range, 6-14y; Gross Motor Function Classification System levels, I-IV). INTERVENTIONS: Participants were randomly assigned to receive controlled assistance (n=11) or resistance (n=12) loads applied to the legs at the ankle. Participants underwent robotic treadmill training 3 times a week for 6 weeks (18 sessions). A controlled swing assistance/resistance load was applied to both legs starting from the toe-off to mid-swing phase of gait during training. MAIN OUTCOME MEASURES: Outcome measures consisted of overground walking speed, 6 minute walk distance, and Gross Motor Function Measure scores and were assessed pre and post 6 weeks of training and 8 weeks after the end of training. RESULTS: After 6 weeks of treadmill training in participants from the resistance training group, fast walking speed and 6-minute walk distance significantly improved (18% and 30% increases, respectively), and 6-minute walk distance was still significantly greater than that at baseline (35% increase) 8 weeks after the end of training. In contrast, overground gait speed and 6-minute walk distance had no significant changes after robotic assistance training. CONCLUSIONS: The results of the present study indicated that robotic resistance treadmill training is more effective than assistance training in improving locomotor function in children with CP. PMID- 28576630 TI - CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis. AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is a destructive lung disease of women caused by proliferation of neoplastic-like LAM cells, with mutations in the TSC1/2 tumor suppressor genes. Based on case reports, levels of cancer antigen 125 (CA-125), an ovarian cancer biomarker, can be elevated in patients with LAM. We hypothesized that elevated serum CA-125 levels seen in some patients with LAM were due to LAM, not other malignancies, and might respond to sirolimus treatment. METHODS: Serum CA-125 levels were measured for 241 patients at each visit. Medical records were reviewed for co-morbidities, disease progression, and response to sirolimus treatment. CA-125 expression in LAM cells was determined by using immunohistochemical analysis. RESULTS: Almost 25% of patients with LAM had at least one elevated serum CA-125 measurement. Higher serum CA-125 levels correlated with lower FEV1, premenopausal status, and pleural effusion in a multivariate model (each P < .001). Serum CA-125 levels decreased following sirolimus treatment (P = .002). CA-125 and alpha-smooth muscle actin were co expressed in LAM lung nodules. CONCLUSIONS: Higher serum CA-125 levels were associated with pleural effusions and reduced pulmonary function and were decreased with sirolimus therapy. LAM cells express CA-125. Some elevated serum CA-125 levels may reflect serosal membrane involvement. PMID- 28576631 TI - Hormone Receptor-Positive Breast Cancer Has a Worse Prognosis in Male Than in Female Patients. AB - INTRODUCTION: Male breast carcinoma (MBC) is treated similarly to female breast carcinoma (FBC), and similar survival rates for both have been assumed. We analyzed prognostic and clinicopathologic features of MBC to determine whether MBC subtypes differ from FBC subtypes. PATIENTS AND METHODS: We reviewed data for 172,847 FBC and 1442 MBC patients from 2010 to 2012 from the National Cancer Institute Surveillance, Epidemiology, and End Results database. Carcinomas were subtyped according to hormone receptor (HR) and HER2 status as HR-positive (HR+)/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2-. RESULTS: The overall incidence of MBC in all breast carcinoma cases was 0.8%. MBC was more frequently HR+/HER2- than was FBC (78.3% vs. 67.4%) and less frequently HR-/HER2- (2.1% vs. 10.9%). More MBC was staged as III or IV (24.9% vs. 17.2%). MBC had significantly worse overall survival (OS) than FBC (P < .0001). After adjustment for age, ethnicity, and tumor grade, stage I and II MBC had significantly worse OS time than stage matched FBC (P = .0011 for stage I, P = .0229 for stage II). When stage- and subtype-matched patients were compared, MBC had significantly worse OS than FBC for stage I overall, for substages IA and IIB HR+/HER2- carcinoma, and for stage III HR+/HER2+ carcinoma. Furthermore, MBC patients with HR+/HER2- T1aN0 carcinomas had worse OS than did FBC patients. CONCLUSION: Patients with MBC have worse survival than patients with FBC, especially for early-stage HR+ breast cancers. More studies are needed optimize treatment for MBC. PMID- 28576632 TI - The synthesis and evaluation of triazolopyrimidines as anti-tubercular agents. AB - We identified a di-substituted triazolopyrimidine with anti-tubercular activity against Mycobacterium tuberculosis. Three segments of the scaffold were examined rationally to establish a structure-activity relationship with the goal of improving potency and maintaining good physicochemical properties. A number of compounds displayed sub-micromolar activity against Mycobacterium tuberculosis with no cytotoxicity against eukaryotic cells. Non-substituted aromatic rings at C5 and a two-carbon chain connecting a terminal aromatic at C7 were preferred features; the presence of NH at C7 and a lack of substituent at C2 were essential for potency. We identified compounds with acceptable metabolic stability in rodent and human liver microsomes. Our findings suggest that the easily synthesized triazolopyrimidines are a promising class of potent anti-tubercular agents and warrant further investigation in our search for new drugs to fight tuberculosis. PMID- 28576633 TI - Design, synthesis and biological evaluation of sulfonamide-substituted diphenylpyrimidine derivatives (Sul-DPPYs) as potent focal adhesion kinase (FAK) inhibitors with antitumor activity. AB - A class of sulfonamide-substituted diphenylpyrimidines (Sul-DPPYs) were synthesized to improve activity against the focal adhesion kinase (FAK). Most of these new Sul-DPPYs displayed moderate activity against the FAK enzyme with IC50 values of less than 100nM; regardless, they could effectively inhibit several classes of refractory cancer cell lines with IC50 values of less than 10uM, including the pancreatic cancer cell lines (AsPC-1, Panc-1 and BxPC-3), the NSCLC resistant H1975 cell line, and the B lymphocyte cell line (Ramos cells). Results of flow cytometry indicated that inhibitor 7e promoted apoptosis of pancreatic cancer cells in a dose-dependent manner. In addition, it almost completely induced the apoptosis at a concentration of 10uM. Compound 7e may be selected as a potent FAK inhibitor for the treatment of pancreatic cancer. PMID- 28576634 TI - BACE1 inhibitory activity and molecular docking analysis of meroterpenoids from Sargassum serratifolium. AB - A wide range of pharmacological properties of Sargassum spp. extracts and isolated components have been recognized. Although individual meroterpenoids of Sargassum species have been reported to possess strong activity against Alzheimer's disease (AD), the active compounds of Sargassum serratifolium have not been fully explored. Therefore, we evaluated the anti-AD activity of S. serratifolium extract through enzyme inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1). Three meroterpenoids (sargahydroquinoic acid (1), sargachromenol (2) and sargaquinoic acid (3)) were isolated from S. serratifolium. These compounds showed moderate AChE inhibitory activity, but exhibited potent inhibitory activity against BChE and BACE1 (15.1, 9.4, and 10.4uM for BChE; 4.3, 6.9, and 12.5uM for BACE1, respectively). Kinetic study and molecular docking simulation of these compounds demonstrated that 1 and 3 interacted with both catalytic aspartyl residues and allosteric sites of BACE1, whereas 2 interacted with the allosteric site of BACE1. The results of the present study demonstrate that meroterpenoids from S. serratifolium might be beneficial in the treatment of AD. PMID- 28576635 TI - [Infective endocarditis prophylaxis in congenital heart disease]. AB - Infective endocarditis can negatively impact prognosis of congenital heart disease and has a 10-15% incidence of mortality. New guidelines recommend prophylaxis of infective endocarditis only for high-risk group (cyanotic congenital heart disease, valvular prosthesis, previous endocarditis) and for some specific invasive dental procedures. New guidelines are focused mainly on oral and cutaneous hygiene. Native shunts and valvular disease are no more targets for prophylaxis. More than half of the physicians do not follow the new guidelines. High-velocity shunts like ventricular septal defect should be included in the at-risk congenital disease for infective endocarditis where prophylaxis should be applied. The new guidelines for prophylaxis of infective endocarditis did not impact on the incidence of infective endocarditis. PMID- 28576636 TI - The treatment of the pulmonary and extrapulmonary manifestations of cystic fibrosis. AB - Cystic fibrosis (CF) is a complex multisystem disease with considerable between patient variability in its manifestations and severity. In the past several decades, the range of treatments and the evidence to support their use for the pulmonary and extrapulmonary manifestations of CF have increased dramatically, contributing to the improved median survival of patients. As therapy for CF has evolved, new challenges including treatment adherence, medication intolerance and allergy, medical complications and coping with the burden of disease in the context of having a family and managing employment have arisen. While the majority of current therapy focuses primarily on improving symptoms, new therapies (CFTR modulators) target the underlying genetic defect. PMID- 28576637 TI - The diagnosis of cystic fibrosis. AB - Establishing the diagnosis of cystic fibrosis (CF) is straight forward in the majority of patients: they present with a clear clinical picture (most frequently chronic respiratory symptoms plus malabsorption), the sweat chloride value is>60mmol/L and two known disease causing CFTR mutations are identified. In less than 5% of subjects, mainly those with a milder or limited phenotype, the diagnostic process is more complex, because initial diagnostic test results are inconclusive: sweat chloride concentration in the intermediate range, less than 2 CF causing mutations identified or both. These patients should be referred to expert centers where bioassays of CFTR function like nasal potential difference measurement or intestinal current measurement can be done. Still, in some patients, despite symptoms compatible with CF and some indication of CFTR dysfunction (e.g. only intermediate sweat chloride value), diagnostic criteria are not met (e.g. only 1 CFTR mutation identified). For these subjects, the term CFTR related disorder (CFTR-RD) is used. Patients with disseminated bronchiectasis, congenital bilateral absence of the vas deferens and acute or recurrent pancreatitis may fall in this category. CF has a very wide disease spectrum and increasingly the diagnosis is being made during adult life, mainly in subjects with milder phenotypes. In many countries, nationwide CF newborn screening (NBS) has been introduced. In screen positive babies, the diagnosis of CF must be confirmed by a sweat test demonstrating a sweat chloride concentration above 60mmol/L. To achieve the benefit of NBS, every baby in whom the diagnosis of CF is confirmed must receive immediate follow-up and treatment in a CF reference center. CF NBS is not full proof: some diagnoses will be missed and in some babies the diagnosis cannot be confirmed nor ruled out with certainty. Screening algorithms that include gene sequencing will detect a high number of such babies that are screen positive with an inconclusive diagnosis (CFSPID). Even in 2016, the most reliable and widely available diagnostic test for CF is the measurement of chloride concentration in sweat. The method of choice is sweat induction by pilocarpine iontophoresis, followed by sweat collection on a gauze or filter paper or in a Macroduct coil. Since mutation specific therapies have become available, it is important to identify the mutations responsible for CF in each individual patient. PMID- 28576638 TI - Linezolid versus vancomycin in Methicillin Resistant Staphylococcus aureus nosocomial pneumonia in the elderly. PMID- 28576639 TI - When a Surgical Trainee Needs Surgery: Autonomy, Privacy, and Maintaining the Standard of Care. PMID- 28576640 TI - Tumor progression effects on drug vector access to tumor-associated capillary bed. AB - Over the last decade, the benefits of drug vectors to treat cancer have been well recognized. However, drug delivery and vector distribution differences in tumor associated capillary bed at different stages of disease progression are not well understood. To obtain further insights into drug vector distribution changes in vasculature during tumor progression, we combined intra-vital imaging of metastatic tumors in mice, microfluidics-based artificial tumor capillary models, and Computational Fluid Dynamics (CFD) modeling. Microfluidic and CFD circulation models were designed to mimic tumor progression by escalating flow complexity and chaoticity. We examined flow of 0.5 and 2MUm spherical particles, and tested the effects of hematocrit on particle local accessibility to flow area of capillary beds by co-circulating red blood cells (RBC). Results showed that tumor progression modulated drug vector distribution in tumor-associated capillaries. Both particles shared 80-90% common flow area, while 0.5 and 2MUm particles had 2 9% and 1-2% specific flow area, respectively. Interestingly, the effects of hematocrit on specific circulation area was opposite for 0.5 and 2MUm particles. Dysfunctional capillaries with no flow, a result of tumor progression, limited access to all particles, while diffusion was shown to be the only prevailing transport mechanism. In view of drug vector distribution in tumors, independent of formulation and other pharmacokinetic aspects, our results suggest that the evolution of tumor vasculature during progression may influence drug delivery efficiency. Therefore, optimized drug vectors will need to consider primary vs metastatic tumor setting, or early vs late stage metastatic disease, when undergoing vector design. PMID- 28576641 TI - A quantitative study of the intracellular fate of pH-responsive doxorubicin polypeptide nanoparticles. AB - Nanoscale carriers with an acid-labile linker between the carrier and drug are commonly used for drug delivery. However, their efficacy is potentially limited by inefficient linker cleavage, and lysosomal entrapment of drugs. To address these critical issues, we developed a new imaging method that spatially overlays the location of a nanoparticle and the released drug from the nanoparticle, on a map of the local intracellular pH that delineates individual endosomes and lysosomes, and the therapeutic intracellular target of the drug-the nucleus. We used this method to quantitatively map the intracellular fate of micelles of a recombinant polypeptide conjugated with doxorubicin via an acid-labile hydrazone linker as a function of local pH and time within live cells. We found that hydrolysis of the acid-labile linker is incomplete because the pH range of 4-7 in the endosomes and lysosomes does not provide complete cleavage of the drug from the nanoparticle, but that once cleaved, the drug escapes the acidic endo lysosomal compartment into the cytosol and traffics to its therapeutic destination-the nucleus. This study also demonstrated that unlike free drug, which enters the cytosol directly through the cell membrane and then traffics into the nucleus, the nanoparticle-loaded drug almost exclusively traffics into endosomes and lysosomes upon intracellular uptake, and only reaches the nucleus after acid-triggered drug release in the endo-lysosomes. This methodology provides a better and more quantitative understanding of the intracellular behavior of drug-loaded nanoparticles, and provides insights for the design of the next-generation of nanoscale drug delivery systems. PMID- 28576642 TI - The pathway of subarachnoid CSF moving into the spinal parenchyma and the role of astrocytic aquaporin-4 in this process. AB - AIMS: It has been proved that cerebrospinal fluid (CSF) in the subarachnoid space could reenter the brain parenchyma via the perivascular space. The present study was designed to explore the pathway of subarachnoid CSF flux into the spinal cord and the potential role of aquaporin-4 (AQP4) in this process. MAIN METHODS: Fluorescently tagged cadaverine, for the first time, was used to study CSF movement in mice. Following intracisternal infusion of CSF tracers, the cervical spinal cord was sliced and prepared for fluorescence imaging. Some sections were subject with immunostaining in order to observe tracer distribution and AQP4 expression. KEY FINDINGS: Fluorescently tagged cadaverine rapidly entered the spinal cord. Tracer influx into the spinal parenchyma was time dependent. At 10min post-infusion, cadaverine was largely distributed in the superficial tissue adjacent to the pial surface. At 70min post-infusion, cadaverine was distributed in the whole cord and especially concentrated in the gray matter. Furthermore, fluorescent tracer could enter the spinal parenchyma either along the perivascular space or across the pial surface. AQP4 was observed highly expressed in the astrocytic endfeet surrounding blood vessels and the pial surface. Blocking AQP4 by its specific inhibitor TGN-020 strikingly reduced the inflow of CSF tracers into the spinal cord. SIGNIFICANCE: Subarachnoid CSF could flow into the spinal cord along the perivascular space or across the pial surface, in which AQP4 is involved. Our observation provides a basis for the study on CSF movement in the spinal cord when some neurological diseases occur. PMID- 28576643 TI - Heel pain in psoriatic arthropathy: Analysis of a series of 291 patients. AB - OBJECTIVE: To determine the prevalence of heel pain in a series of patients with psoriatic arthritis (PsA). MATERIAL AND METHODS: Cross-sectional, observational and retrospective study of a series of 347 patients. All patients fulfilled the CASPAR criteria for PsA and 291 had a clinically significant history of heel pain. The statistical analysis was performed using chi-square test, ANOVA and binary logistic regression. RESULTS: Thirty-five percent of the patients had clinically significant heel pain. A significant association was established between an early onset of skin and joint involvement in the disease and the development of heel pain. However, no significant correlation was found between disease duration and the presence of heel pain. History of dactylitis and PsA in first-degree family members was also statistically associated with this complication. CONCLUSIONS: Clinically significant heel pain was recorded in one third of the patients in this series. There was a statistically significant association with dactylitis, PsA in first-degree family members and an earlier onset of joint and skin disease. PMID- 28576644 TI - Real-time electromagnetic tracking-based treatment platform for high-dose-rate prostate brachytherapy: Clinical workflows and end-to-end validation. AB - PURPOSE: New technologies were integrated into a novel treatment platform combining electromagnetically (EM) tracked catheters, a 3D ultrasound (3DUS) imaging device, and a new treatment planning system to provide a real-time prostate high-dose-rate (HDR) brachytherapy treatment system. This work defines workflows for offline CT and online 3DUS planning scenarios and preclinical end to-end validation of the platform. METHODS AND MATERIALS: The platform is composed of an EM-tracked stylet, a EM-tracked 3DUS probe, and an EM-tracked template guide, all used with the NDI Aurora field generator (NDI, Ontario, Canada). The treatment planning system performs continuous position and angular readings from all three EM sensors into a streamlined environment that allows for (1) contouring; (2) planning; (3) catheter insertion guidance and reconstruction; (4) QA of catheter path and tip position; and (5) exporting to an afterloader. Data were gathered on the times required for the various key steps of the 3DUS based workflow. RESULTS: The complete 3DUS-based workflow on 16-catheter implant phantoms took approximately 15 min. This time is expected to increase for actual patients. Plan generation is fast (7.6 +/- 2.5s) and the initial catheter reconstruction with updated dose distribution is obtained at no (time) cost as part of the insertion process. Subsequent catheter reconstruction takes on average 10.5 +/- 3.1s per catheter, representing less than 3 min for a 16 catheter implant. CONCLUSIONS: This preclinical study suggests that EM technology could help to significantly streamline real-time US-based high-dose-rate prostate brachytherapy. PMID- 28576645 TI - Effects of developmental conditions on glucocorticoid concentrations in adulthood depend on sex and foraging conditions. AB - Developmental conditions in early life frequently have long-term consequences on the adult phenotype, but the adult environment can modulate such long-term effects. Glucocorticoid hormones may be instrumental in mediating developmental effects, but the permanency of such endocrine changes is still debated. Here, we manipulated environmental conditions during development (small vs. large brood size, and hence sibling competition) and in adulthood (easy vs. hard foraging conditions) in a full factorial design in zebra finches, and studied effects on baseline (Bas-CORT) and stress-induced (SI-CORT) corticosterone in adulthood. Treatments affected Bas-CORT in females, but not in males. Females reared in small broods had intermediate Bas-CORT levels as adults, regardless of foraging conditions in adulthood, while females reared in large broods showed higher Bas CORT levels in hard foraging conditions and lower levels in easy foraging conditions. Female Bas-CORT was also more susceptible than male Bas-CORT to non biological variables, such as ambient temperature. In line with these results, repeatability of Bas-CORT was higher in males (up to 51%) than in females (25%). SI-CORT was not responsive to the experimental manipulations in either sex and its repeatability was high in both sexes. We conclude that Bas-CORT responsiveness to intrinsic and extrinsic conditions is higher in females than in males, and that the expression of developmental conditions may depend on the adult environment. The latter finding illustrates the critical importance of studying of causes and consequences of long-term developmental effects in other environments in addition to standard laboratory conditions. PMID- 28576646 TI - Increase in hypothalamic AMPK phosphorylation induced by prolonged exposure to LPS involves ghrelin and CB1R signaling. AB - Acute administration of lipopolysaccharide (LPS) from Gram-negative bacteria induces hypophagia. However, the repeated administration of LPS leads to desensitization of hypophagia, which is associated with increased hypothalamic p AMPK expression. Because ghrelin and endocannabinoids modulate AMPK activity in the hypothalamus, we hypothesized that these neuromodulators play a role in the reversal of tolerance to hypophagia in rats under long-term exposure to LPS. Male Wistar rats were treated with single (1 LPS, 100MUg/kg body weight, ip) or repeated injections of LPS over 6days (6 LPS). Food intake was reduced in the 1 LPS, but not in the 6 LPS group. 6 LPS rats showed an increased serum concentration of acylated ghrelin and reduced ghrelin receptor mRNA expression in the hypothalamus. Ghrelin injection (40MUg/kg body weight, ip) increased food intake, body weight gain, p-AMPK hypothalamic expression, neuropeptide Y (NPY) and Agouti related peptide (AgRP) mRNA expression in control animals (Saline). However, in 6 LPS rats, ghrelin did not alter these parameters. Central administration of a CB1R antagonist (AM251, 200ng/MUl in 5MUl/rat) induced hypophagia in 6 LPS animals, suggesting that the endocannabinoid system contributes to preserved food intake during LPS tolerance. In the presence of AM251, the ability of ghrelin to phosphorylate AMPK in the hypothalamus of 6 LPS group was restored, but not its orexigenic effect. Our data highlight that the orexigenic effects of ghrelin require CB1R signaling downstream of AMPK activation. Moreover, CB1R-mediated pathways contribute to the absence of hypophagia during repeated exposure to endotoxin. PMID- 28576647 TI - Testosterone, oxytocin, and the development of human parental care. AB - The steroid testosterone (T) and neuropeptide oxytocin (OT) have each been implicated in the development of parental care in humans and animals, yet very little research addressed the interaction between these hormones at the transition to parenthood in mothers and fathers. One hundred and sixty mothers and fathers (80 couples) were visited 1 and 6months after the birth of their first child, plasma OT and T were assayed at each time-point, and interactions between each parent and the infant were observed and micro-coded for two key parental behaviors; affectionate touch and parent-infant synchrony. T showed gender-specific effects. While paternal T was individually stable across the first six months of parenting and predicted lower father-infant synchrony, maternal T was neither stable nor predictive of maternal behavior. An interaction of OT and T showed that T has complex modulatory effects on the relations of OT and parenting. Slope analysis revealed that among fathers, only when T was high (+1SD), negative associations emerged between OT and father affectionate touch. In contrast, among mothers, the context of high T was related to a positive association between OT and maternal touch. Our findings, the first to test the interaction of OT and T in relation to observed maternal behavior, underscore the need for much further research on the complex bidirectional effects of steroid and neuropeptide systems on human mothering and fathering. PMID- 28576648 TI - Sex differences and sex hormones in anxiety-like behavior of aging rats. AB - Sex differences in the prevalence of affective disorders might be attributable to different sex hormone milieu. The effects of short-term sex hormone deficiency on behavior, especially on anxiety have been studied in numerous animal experiments, mainly on young adult rats and mice. However, sex differences in aged animals and the effects of long-term hypogonadism are understudied. The aim of our study was to analyze sex differences in anxiety-like behavior in aged rats and to prove whether they can be attributed to endogenous sex hormone production in males. A battery of tests was performed to assess anxiety-like behavior in aged female, male and gonadectomized male rats castrated before puberty. In addition, the aged gonadectomized male rats were treated with a single injection of estradiol or testosterone or supplemented with estradiol for two-weeks. Female rats displayed a less anxious behavior than male rats in most of the conducted behavioral tests except the light-dark box. Long-term androgen deficiency decreased the sex difference in anxiety either partially (open field, PhenoTyper cage) or completely (elevated plus maze). Neither single injection of sex hormones, nor two-week supplementation of estradiol in gonadectomized aged male rats significantly affected their anxiety-like behavior in the elevated plus maze. In conclusion, our results confirm sex differences in anxiety in aged rats likely mediated by endogenous testosterone production in males. Whether long-term supplementation with exogenous sex hormones could affect anxiety-like behavior in elderly individuals remains to be elucidated. PMID- 28576649 TI - Anti-androgenic effects of bisphenol-A on spatial memory and synaptic plasticity of the hippocampus in mice. AB - Bisphenol-A (BPA) is a common environmental endocrine disruptor. Our recent studies found that exposure to BPA in both adolescent and adulthood sex specifically impaired spatial memory in male mice. In this study, 11-week-old gonadectomied (GDX) male mice daily received subcutaneous injections of testosterone propionate (TP, 0.5mg/kg), TP and BPA (0.4 and 4mg/kg), or vehicle for 45days. The results of Morris water maze task showed that exposure to BPA did not affect the spatial memory of GDX mice but impaired that of sham (4mg/kg/day) and TP-treated GDX mice (0.4mg/kg/day). In addition, BPA reduced the level of testosterone (T) in the serum and brain of sham and TP-treated GDX mice. Exposure to BPA decreased the synaptic density and had an adverse effect on the synaptic interface of the hippocampus in sham and TP-treated GDX mice. The results of western blot analysis further showed that BPA (4mg/kg) reduced the levels of synaptic proteins (synapsin I and PSD-95) and NMDA receptor subunit NR2B in sham and TP-treated GDX mice. BPA decreased the phosphorylation of ERK1/2 but increased the phosphorylation of p38 in sham and TP-treated GDX mice. These results suggest that impairment of spatial memory and adverse effects on synaptic remodeling of hippocampal neurons in males after long-term BPA exposure is related to the anti-androgen effect of BPA. These effects of BPA may be associated with downregulated synaptic proteins and NMDA receptor through inhibiting ERKs and promoting the p38 pathways. PMID- 28576651 TI - Female college students' beliefs about cervical cancer screening. PMID- 28576653 TI - A G-protein-coupled chemokine receptor: A putative insertion site for a multi pathogen recombinant capripoxvirus vaccine strategy. AB - Capripoxviruses (CaPVs) have been shown to be ideal viral vectors for the development of recombinant multivalent vaccines to enable delivery of immunogenic genes from ruminant pathogens. So far, the viral thymidine kinase (TK) gene is the only gene used to generate recombinants. A putative non-essential gene encoding a G-protein-coupled chemokine receptor subfamily homologue (GPCR) was targeted as an additional insertion site. Peste des petits ruminants (PPR) was chosen as a disease model. A new recombinant CaPV expressing the viral attachment hemagglutinin (H) of the PPR virus (PPRV) in the GPCR insertion site (rKS1-HPPR GPCR) was generated in the backbone North African isolate KS1 strain of lumpy skin disease virus (LSDV). Comparison with the recombinant CaPV expressing the H of PPRV in the TK gene (rKS1-HPPR-TK) shown to induce protection against both PPR and LSD in both sheep and goats was assessed. The suitability of the GPCR gene to be a putative additional insertion site in the CaPV genome is evaluated and discussed. PMID- 28576654 TI - Mutations on M3 helix of Plutella xylostella glutamate-gated chloride channel confer unequal resistance to abamectin by two different mechanisms. AB - Abamectin is one of the most widely used avermectins for agricultural pests control, but the emergence of resistance around the world is proving a major threat to its sustained application. Abamectin acts by directly activating glutamate-gated chloride channels (GluCls) and modulating other Cys-loop ion channels. To date, three mutations occurring in the transmembrane domain of arthropod GluCls are associated with target-site resistance to abamectin: A309V in Plutella xylostella GluCl (PxGluCl), G323D in Tetranychus urticae GluCl1 (TuGluCl1) and G326E in TuGluCl3. To compare the effects of these mutations in a single system, A309V/I/G and G315E (corresponding to G323 in TuGluCl1 and G326 in TuGluCl3) substitutions were introduced individually into the PxGluCl channel. Functional analysis using Xenopus oocytes showed that the A309V and G315E mutations reduced the sensitivity to abamectin by 4.8- and 493-fold, respectively. In contrast, the substitutions A309I/G show no significant effects on the response to abamectin. Interestingly, the A309I substitution increased the channel sensitivity to glutamate by one order of magnitude (~12-fold). Analysis of PxGluCl homology models indicates that the G315E mutation interferes with abamectin binding through a steric hindrance mechanism. In contrast, the structural consequences of the A309 mutations are not so clear and an allosteric modification of the binding site is the most likely mechanism. Overall the results show that both A309V and G315E mutations may contribute to target-site resistance to abamectin and may be important for the future prediction and monitoring of abamectin resistance in P. xylostella and other arthropod pests. PMID- 28576652 TI - Platelet Function Testing in Patients with Acute Ischemic Stroke: An Observational Study. AB - BACKGROUND: The measurement of platelet reactivity in patients with stroke undergoing antiplatelet therapies is not commonly performed in clinical practice. We assessed the prevalence of therapy responsiveness in patients with stroke and further investigated differences between patients on prevention therapy at stroke onset and patients naive to antiplatelet medications. We also sought differences in responsiveness between etiological subtypes and correlations between Clopidogrel responsiveness and genetic polymorphisms. METHODS: A total of 624 stroke patients on antiplatelet therapy were included. Two different groups were identified: "non-naive patients", and "naive patients". Platelet function was measured with multiple electrode aggregometry, and genotyping assays were used to determine CYP2C19 polymorphisms. RESULTS: Aspirin (ASA) responsiveness was significantly more frequent in naive patients compared with non-naive patients (94.9% versus 82.6%, P < .0010). A better responsiveness to ASA compared with Clopidogrel or combination therapy was found in the entire population (P < .0010), in non-naive patients (P < .0253), and in naive patients (P < .0010). Multivariate analysis revealed a strong effect of Clopidogrel as a possible "risk factor" for unresponsiveness (odds ratio 3.652, P < .0001). No difference between etiological subgroups and no correlations between responsiveness and CYP2C19 polymorphisms were found. CONCLUSION: In our opinion, platelet function testing could be potentially useful in monitoring the biological effect of antiplatelet agents. A substantial proportion of patients with stroke on ASA were "resistant", and the treatment with Clopidogrel was accompanied by even higher rates of unresponsiveness. Longitudinal studies are needed to assess whether aggregometry might supply individualized prognostic information and whether it can be considered a valid tool for future prevention strategies. PMID- 28576655 TI - Intra- and extracellular domains of the Helicoverpa armigera cadherin mediate Cry1Ac cytotoxicity. AB - Diverse midgut cadherin mutations confer resistance to Cry1A toxins in at least three lepidopteran pests, including the cotton bollworm, Helicoverpa armigera. Most of these cadherin mutations are inherited as recessive alleles and result in changes within the cadherin repeat (CR) regions of the extracellular protein domain. However, the H. armigera r15 cadherin mutation results in a deletion of 55 amino acid residues within the cytoplasmic domain, and Cry1A resistance is inherited as a non-recessive trait. Here, eight recombinant H. armigera cadherin (HaCad) proteins, including seven variants containing different combinations of CRs and the cytoplasmic domain, were expressed in cultured insect cells using a baculovirus expression system and were analyzed for Cry1Ac binding and toxicity. Cells expressing either the wild-type HaCad or a mutant lacking only the region corresponding to the first nine CRs bound Cry1Ac and were equally susceptible to Cry1Ac. Cells expressing mutant HaCad proteins without the Cry1A toxin binding region (TBR) located in the CR nearest the plasma membrane did not bind Cry1Ac and were not killed by the toxin. Among the mutant proteins, loss of toxicity was observed in all cells producing HaCad variants lacking the amino acids 1422-1440, indicating that this TBR motif is important for both toxin binding and to confer susceptibility to Cry1Ac. Cells expressing the HaCad variant lacking the entire cytoplasmic domain retained Cry1Ac binding, but were significantly less susceptible to Cry1Ac than the cells producing either wild-type HaCad or HaCad lacking the first nine CRs. These results suggest that both the extracellular and the cytoplasmic domains of HaCad participate in Cry1Ac intoxication. PMID- 28576650 TI - Steroid metabolism in the brain: From bird watching to molecular biology, a personal journey. AB - Since Arnold Adolph Berthold established in 1849 the critical role of the testes in the activation of male sexual behavior, intensive research has identified many sophisticated neurochemical and molecular mechanisms mediating this action. Studies in Japanese quail demonstrated the critical role of testosterone action and of testosterone aromatization in the sexually dimorphic medial preoptic nucleus in the activation of male copulatory behavior. The development of an immunohistochemical visualization of brain aromatase in quail then allowed further refinement in the localization of the sites of neuroestrogens production. Testosterone aromatization is required for the activation of both appetitive and consummatory aspects of male sexual behavior. Brain aromatase activity is modulated by steroid-induced changes in the transcription of the corresponding gene but also more rapidly by phosphorylation processes. Sexual interactions with a female also rapidly regulate brain aromatase activity in an anatomically specific manner presumably via the release and action of endogenous glutamate. These rapid changes in estrogen production modulate sexual behavior and in particular its motivational component with latencies ranging between 15 and 30min. Brain estrogens seem to act in a manner akin to a neurotransmitter or at least a neuromodulator. More recently, assays of brain estradiol concentrations in micropunched samples or in dialysis samples obtained from behaviorally active males suggested that aromatase activity measured ex vivo might not be an accurate proxy to the rapid changes in local neuroestrogens production and concentrations. Studies of brain testosterone metabolism are thus not over and will keep scientists busy for a little longer. Elsevier SBN Keynote Address, Montreal. PMID- 28576657 TI - WISH, a novel CFEM GPCR is indispensable for surface sensing, asexual and pathogenic differentiation in rice blast fungus. AB - We have selected and characterized a unique Conserved Fungal-specific Extra cellular Membrane-spanning (CFEM) domain containing PTH11 like G-protein coupled receptor (GPCR), which is responsible for Water wettability, Infection, Surface sensing and Hyper-conidiation (WISH). The pathogenicity gene WISH is predicted to encode a novel seven transmembrane protein in the rice blast fungus, Magnaporthe oryzae, one of the deadliest pathogens of rice. We generated knockout mutants through a homologous recombination-based method to understand the function of the gene. These mutants are nonpathogenic due to a defect in sensing hydrophobic surface and appressorium differentiation. The mutant failed to undergo early events of pathogenesis, and appressorium development is diminished on inductive hydrophobic surface and was unable to penetrate susceptible rice leaves. The Deltawish mutant did not develop any appressorium, suggesting that WISH protein is required for appressorium morphogenesis and is also involved in host surface recognition. We examined various aspects of pathogenesis and the results indicated involvement of WISH in preventing autolysis of vegetative hyphae, determining surface hydrophobicity and maintenance of cell-wall integrity. WISH gene from M. oryzae strain B157 complemented the Deltawish mutant, indicating functional authenticity. Exogenous activation of cellular signaling failed to suppress the defects in Deltawish mutants. These findings suggest that WISH GPCR senses diverse extracellular signals to play multiple roles and might have effects on PTH11 and MPG1 genes especially as an upstream effector of appressorium differentiation. It is for the first time that a typical GPCR containing seven transmembrane helices involved in the early events of plant pathogenesis of M. oryzae has been functionally characterized. PMID- 28576656 TI - A double-stranded RNA degrading enzyme reduces the efficiency of oral RNA interference in migratory locust. AB - Application of RNA interference (RNAi) for insect pest management is limited by variable efficiency of RNAi in different insect species. In Locusta migratoria, RNAi is highly efficient through injection of dsRNA, but oral delivery of dsRNA is much less effective. Efforts to understand this phenomenon have shown that dsRNA is more rapidly degraded in midgut fluid than in hemolymph due to nuclease enzyme activity. In the present study, we identified and characterized two full length cDNAs of double-stranded RNA degrading enzymes (dsRNase) from midgut of L. migratoria, which were named LmdsRNase2 and LmdsRNase3. Gene expression analysis revealed that LmdsRNase2 and LmdsRNase3 were predominantly expressed in the midgut, relatively lower expression in gastric caeca, and trace expression in other tested tissues. Incubation of dsRNA in midgut fluid from LmdsRNase3 suppressed larvae or control larvae injected with dsGFP resulted in high levels of degradation; however, dsRNA incubated in midgut fluid from LmdsRNase2 suppressed larvae was more stable, indicating LmdsRNase2 is responsible for dsRNA degradation in the midgut. To verify the biological function of LmdsRNase2 in vivo, nymphs were injected with dsGFP, dsLmdsRNase2 or dsLmdsRNase3 and chitinase 10 (LmCht10) or chitin synthase 1 (LmCHS1) dsRNA were orally delivered. Mortality associated with reporter gene knockdown was observed only in locusts injected with dsLmdsRNase2 (48% and 22%, for dsLmCht10 and dsLmCHS1, respectively), implicating LmdsRNase2 in reducing RNAi efficiency. Furthermore, recombinantly expressed LmdsRNase2 fusion proteins degraded dsRNA rapidly, whereas LmdsRNase3 did not. These results suggest that rapid degradation of dsRNA by dsRNase2 in the midgut is an important factor causing low RNAi efficiency when dsRNA is orally delivered in the locust. PMID- 28576658 TI - Current Resources for Evidence-Based Practice, July/August 2017. PMID- 28576659 TI - Ceftriaxone reverses deficits of behavior and neurogenesis in an MPTP-induced rat model of Parkinson's disease dementia. AB - Hyperactivity of the glutamatergic system is involved in excitotoxicity and neurodegeneration in Parkinson's disease (PD) so that glutamatergic modulation maybe a potential therapeutic target for PD. Ceftriaxone (CEF) has been reported to increase glutamate uptake by increasing glutamate transporter expression and has been demonstrated neuroprotective effects in animal study. The aim of this study was to determine the effects of CEF on behavior and neurogenesis in the 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. MPTP was stereotaxically injected into the substantia nigra pars compacta (SNc) of male Wistar rats. Starting on the same day after MPTP lesioning (day 0), the rats were injected daily with either CEF or saline for 14days and underwent a T-maze test on days 8-10 and an object recognition test on days 12-14, then the brain was taken for histological evaluation on day 15. The results showed that MPTP lesioning resulted in decreased motor function, working memory, and object recognition and reduced neurogenesis in the substantial nigra and dentate gyrus of the hippocampus. These behavioral and neuronal changes were prevented by CEF treatment. To our knowledge, this is the first study showing that CEF prevents loss of neurogenesis in the brain of PD rats. CEF may therefore have clinical potential in the treatment of PD. PMID- 28576660 TI - Impact of light transmittance mode on polymerisation kinetics in bulk-fill resin based composites. AB - OBJECTIVES: to determine the mode of light transmission and its impact on the polymerisation kinetic in modern bulk-fill resin-based composites (B-RBC). MATERIALS AND METHODS: Four low-viscosity methacrylate-based and one high viscosity ormocer-based B-RBCs were considered. One material was available in three different shades that were all analyzed. Polymerization kinetic and light transmittance were assessed in 2 and 4mm specimen depths. Incident and transmitted irradiance and radiant exposure were measured in real-time on a laboratory-grade spectrometer. RESULTS: A progressive enhanced light transmittance during polymerisation was identified in all materials except for TetricEvoFlow BulkFill, which became progressively opaque in all shades. One-way ANOVA and multivariate analysis (alpha=0.05) were performed. The parameter material has a significant (p<0.001) effect on DC (etaP2=0.856) and light transmittance parameters (irradiance, etaP2=0.965; radiant exposure, etaP2=0.956); specimen depth influences only transmittance (etaP2=0.978; 0.980). DC variation in time was best described by an exponential sum function (R2>0.95), differentiating between the gel- and the glass-phase and revealing a faster initiation of polymerization and a slower transition into the glass-phase by lowering the filler volume. Depth retarded the transition into the glass-phase, but did not alter DC measured 300s post-irradiation. Moderate inverse correlation was identified among DC and filler volume% (-0.646) or filler weight% (-0.403), while no correlation among DC and light transmittance (p=0.141; 0.125). The maximal rate of carbon-carbon double bond conversion varied within the analyzed materials but was independent from specimen's depths. CONCLUSIONS: Light transmission changes during polymerization do not alter polymerization kinetics in modern B-RBCs. DC 300s post-irradiation was maintained with depth, while light was attenuated, the faster the more translucent the material was. DC and quality of curing cannot be related to light transmittance in B-RBCs. PMID- 28576661 TI - Knowledge and practice related to gestational diabetes among primary health care providers in Morocco: Potential for a defragmentation of care? AB - INTRODUCTION: The objective of this study was to assess knowledge and practices of general practitioners, nurses and midwives working at primary health care facilities in Morocco regarding screening and management of gestational diabetes (GDM). METHODS: Structured interviews with 100 doctors, midwives and nurses at 44 randomly selected public health care centers were conducted in Marrakech and Al Haouz. All data were descriptively analyzed. Ethical approval for the study was granted by the institutional review boards in Belgium and Morocco. RESULTS: Public primary health care providers have a basic understanding of gestational diabetes but screening and management practices are not uniform. Although 56.8% of the doctors had some pre-service training on gestational diabetes, most nurses and midwives lack such training. After diagnosing GDM, 88.5% of providers refer patients to specialists, only 11.5% treat them as outpatients. DISCUSSION: Updating knowledge and skills of providers through both pre- and in-service training needs to be supported by uniform national standards enabling first line health care workers to manage women with GDM and thus increase access and provide a continuity in care. Findings of this study will be used to pilot a model of GDM screening and initial management through the primary level of care. PMID- 28576663 TI - Impact of ranolazine on coronary microvascular dysfunction (MICRO) study. AB - BACKGROUND: Patients with angina and coronary microvascular dysfunction, without evidence of structural or epicardial coronary disease (Type I CMVD) remain without evidence based treatment options. Previous work has demonstrated that ranolazine can improve angina frequency and stability among patients with Type 1 CMVD; however, the mechanism remains unclear. Therefore, the objective of this pilot project was to assess the impact of ranolazine on Type I CMVD as measured using an invasive tool to measure global resistance (index of microcirculatory resistance (IMR)). METHODS: Patients with Type 1 CMVD diagnosed using IMR were enrolled and treated with ranolazine 1000mg BID. Coronary angiography and IMR were performed at baseline and on treatment after four weeks. The primary outcome measure was change in IMR pre- and post-treatment. Secondary outcome measures, improvement in angina and activity level, were assessed using the Seattle Angina Questionnaire (SAQ), Duke Activity Status Index (DASI) and Metabolic equivalent for Task (MET) scores. RESULTS: A total of 7 patient were enrolled and completed the study. Mean age was 57.6+/-7.5, 43% were female and 43% were Hispanic. Mean baseline IMR was 37.25+/-16.27 which decreased to 19.48+/-5.69 (p=0.02; (-48% Delta) after treatment with ranolazine. Four of the five SAQ domains improved on treatment with significant improvement in physical limitation (p=0.001), angina frequency (p=0.04), angina stability (p=0.05) and disease perception (p=0.001). Non-significant improvements in activity were also seen in both the DASI and MET scores. CONCLUSION: Among patients with Type 1 CMVD, our pilot data suggest favorable changes in IMR, anginal symptoms and activity status with ranolazine treatment. These findings support further evaluation of the effects of ranolazine on microcirculatory function and angina symptoms in a larger cohort of patients with Type 1 CMVD. PMID- 28576662 TI - Comparison of very long-term clinical and angiographic outcomes of bare metal stent implants between patients with and without type 2 diabetes. AB - BACKGROUND: Data on a large patient population regarding very long-term outcomes after bare metal stent (BMS) implantation in diabetic patients are lacking. The aim of this study was to evaluate the very long-term (8-17 years) clinical and 6 month angiographic outcomes of BMS implantations in patients with and without type 2 diabetes. METHODS AND RESULTS: A total of 2391 patients (579 with and 1812 without diabetes) who received BMS implantations between November 1995 and May 2004 were enrolled from the Cardiovascular Atherosclerosis and Percutaneous TrAnsluminal INterventions (CAPTAIN) registry into this study. During a mean follow-up period of 152+/-53months, the diabetic patients had higher rates of all cause mortality (28% vs. 15%, p<0.001), re-infarction (6% vs. 5%, p=0.284), target lesion revascularization (13% vs. 10%, p=0.049), and a lower cardiovascular event-free survival rate (42% vs. 56%, p<0.001) compared to the patients without diabetes. The diabetic patients also had a higher restenosis rate (26% vs. 18%, p<0.001) at 6-month angiographic follow-up. The multivariate analysis of risk factors for cardiac event-free survival included age (hazard ratio [HR]: 1.011; p=0.001), hypertension (HR: 1.168; p=0.011), diabetes mellitus (HR: 1.353; p<0.001), pre-existing coronary artery disease (HR: 1.341; p<0.001), and left ventricular ejection fraction (LVEF) (HR: 0.992; p=0.002) (Table 7). The Kaplan-Meier analysis showed a significant difference in cardiovascular event free survival rate between the two groups (p<0.001). CONCLUSION: The clinical and angiographic outcomes of diabetic patients with BMS implantations were worse than those of patients without diabetes after a very long-term follow-up period. PMID- 28576664 TI - Uncertainty and stress: Why it causes diseases and how it is mastered by the brain. AB - The term 'stress' - coined in 1936 - has many definitions, but until now has lacked a theoretical foundation. Here we present an information-theoretic approach - based on the 'free energy principle' - defining the essence of stress; namely, uncertainty. We address three questions: What is uncertainty? What does it do to us? What are our resources to master it? Mathematically speaking, uncertainty is entropy or 'expected surprise'. The 'free energy principle' rests upon the fact that self-organizing biological agents resist a tendency to disorder and must therefore minimize the entropy of their sensory states. Applied to our everyday life, this means that we feel uncertain, when we anticipate that outcomes will turn out to be something other than expected - and that we are unable to avoid surprise. As all cognitive systems strive to reduce their uncertainty about future outcomes, they face a critical constraint: Reducing uncertainty requires cerebral energy. The characteristic of the vertebrate brain to prioritize its own high energy is captured by the notion of the 'selfish brain'. Accordingly, in times of uncertainty, the selfish brain demands extra energy from the body. If, despite all this, the brain cannot reduce uncertainty, a persistent cerebral energy crisis may develop, burdening the individual by 'allostatic load' that contributes to systemic and brain malfunction (impaired memory, atherogenesis, diabetes and subsequent cardio- and cerebrovascular events). Based on the basic tenet that stress originates from uncertainty, we discuss the strategies our brain uses to avoid surprise and thereby resolve uncertainty. PMID- 28576665 TI - Understanding B-DNA to A-DNA transition in the right-handed DNA helix: Perspective from a local to global transition. AB - The right-handed DNA helix exhibits two major conformations, A-DNA and B-DNA, depending on the environmental conditions. The B-DNA to A-DNA (B->A) transition is sequence specific, cooperative, and reversible. The reduced water activity due to the addition of solvents like ethanol or the presence of protein or drug molecules causes B->A transition. In several biological cases, B->A transition occurs at a local level where small fragments of a long DNA sequence undergoes B >A transition. In this review, we have discussed various aspects of B->A transition such as the role of water, sequence specificity, mechanism of B->A transition, etc. The review primarily focuses on the B->A mechanism involved at a local level, and finally its connection to the global transition in theoretical and experimental studies. PMID- 28576666 TI - Itching for a diagnosis - A travel medicine perspective on delusional infestation. PMID- 28576667 TI - Bipolar Plasma Enucleation of the Prostate (B-TUEP) in Benign Prostate Hypertrophy Treatment: 3-Year Results. AB - OBJECTIVE: To investigate numerous endoscopic techniques that have been described for the treatment of benign prostate enlargement. Plasma-button enucleation of the prostate (B-TUEP) is a successful treatment option because the large surface creates a fast enucleation process, vaporization, and concomitant hemostasis. The aim of this study was to evaluate the efficacy of bipolar button electrode transurethral adenoma enucleation (B-TUEP) in saline solution. The second end point was to determine the change of International Prostate Symptom Score (IPSS), post-void residual urine, International Index of Erectile Function, transrectal ultrasound gland volume evaluation, and prostate-specific antigen. MATERIALS AND METHODS: Between July 2011 and March 2012, 50 consecutive patients underwent B TUEP in our facility, all performed by a single surgeon (R.G.). All patients were preoperatively assessed with maximum urinary flow rate, single-question quality of life assessment, IPSS and the International Index of Erectile Function questionnaires, transrectal ultrasound gland volume evaluation, prostate-specific antigen, and post-void residual urine. RESULTS: We observed a significant improvement at 12, 24, and 36 months in terms of maximum urinary flow rate (22.3 +/- 4.74 mL/s, 23.2 +/- 0.30 mL/s, and 23.6 +/- 1.26 mL/s, respectively, P <.01) and quality of life (5.28 +/- 0.97, 5.69 +/- 0.90, and 5.73 +/- 0.87). IPSS and IEEF scores improved significantly (P <.05). Gland volume evaluation and post void residue decreased (P <.001). The prostate-specific postoperative antigen levels were 0.76 +/- 0.61 ng/mL, 0.7 +/- 0.51 ng/mL, and 0.62 +/- 0.18 ng/mL, at 12, 24, and 36 months, respectively. Two patients (4%) had persistent bladder outlet obstruction requiring reoperation. CONCLUSION: After 3-year follow-up, B TUEP represents an effective, durable, and safe form of surgical intervention. B TUEP is an alternative treatment for symptomatic benign prostate enlargement. PMID- 28576668 TI - Length of Stay and Cost in Patients Undergoing Orthognathic Surgery: Does Surgeon Volume Matter? AB - PURPOSE: The relations among procedure-specific annual surgeon volume, hospital length of stay (LOS), and hospital costs for patients undergoing the 2 most common orthognathic surgical (OGS) procedures, segmental osteoplasty or osteotomy of the maxilla (SOM) or open osteoplasty or osteotomy of the mandibular ramus (SOMR), are not known. The authors hypothesized that treatment by high-volume surgeons would be associated with decreased LOS and costs. MATERIALS AND METHODS: All patients 8 to 64 years old who underwent elective SOM or SOMR were selected from the 2001 to 2009 Nationwide Inpatient Sample. Patients with missing vital status or payment mode status or who underwent more than 1 OGS procedure during the index hospitalization were excluded. Based on year- and procedure-specific annual surgeon volumes, the highest (highest quartile) and lowest (lowest quartile) procedure volume surgeon groups were compared. Multivariable logistic regression was used to study the relation between surgeon volume and extended patient LOS (defined as LOS >= 75th percentile). Generalized linear models with a log-link and gamma distribution were used to examine the association between surgeon volume and hospital costs. Models were adjusted for patient- and hospital level factors and type of procedure (SOM or SOMR). Analysis was weighted to represent national-level estimates and an alpha value of 0.05 was used for all comparisons. RESULTS: After weighting to the population level, 8,062 patients were included for study. Most were white (80.6%), female (61.4%), and privately insured (84.6%). Mean age was 26 years (standard deviation, 0.38 yr). After adjusting for potential confounders, patients treated by high-volume surgeons showed 40% lower odds of extended LOS (odds ratio = 0.60; 95% confidence interval [CI], 0.38-0.95; P = .032) and incurred substantially lower costs (-$1,484.74; 95% CI, -2,782.76 to -185.58; P = .025) compared with patients treated by low volume surgeons. CONCLUSION: These findings suggest that regionalization of patients to high-volume surgeons for OGS procedures could decrease LOS and incurred costs. PMID- 28576669 TI - Impact of Autologous Bone Marrow-Derived Stem Cells on Degenerative Changes of Articulating Surfaces Associated With the Arthritic Temporomandibular Joint: An Experimental Study in Rabbits. AB - PURPOSE: This study evaluated the effect of bone marrow-derived stem cells (BMSCs) on degenerative changes of TMJ associated with bovine collagen type II (BCII) induced-arthritis. MATERIALS AND METHODS: Fifty rabbits were divided into 3 groups. Group I (n = 10) received no treatment. Group II (n = 20) was divided into 2 subgroups according to treatment type. One subgroup (n = 10) received an intra-articular (IA) injection of phosphate buffered saline (PBS) and the other (n = 10) received an IA injection of PBS plus BMSCs. Group III (n = 20) received an injection of oil emulsion of BCII before treatment with PBS or PBS plus BMSCs as in group II. Rabbits were euthanized after the third week and the joints were processed for histology. RESULTS: Compared to TMJs of subgroup III treated with PBS, TMJs of subgroup III treated with combined therapy showed improvements in all parameters tested. Mean values in mm3 for this subgroup regarding fibrous condylar covering, cartilaginous condylar plate, subchondral bone, articular eminence, upper joint cavity, lower joint cavity and disc thickness were 4.04+/ 0.13, 5.09+/-0.08, 25.29+/-0.36, 10.54+/-0.36, 4.53+/-0.44, 3.21+/-0.27, and 24.52+/-0.41, respectively. Significant differences were found between subgroups mean values of group II and group IIII. CONCLUSIONS: BMSCs can be used safely and effectively to repair degenerative changes in rabbit TMJs associated with BCII induced arthritis. PMID- 28576671 TI - Editorial Introduction to the Special Issue on 4-Hydroxynonenal and Related Lipid Oxidation Products. PMID- 28576670 TI - Validation of the Youth Acute Pain Functional Ability Questionnaire in Children and Adolescents Undergoing Inpatient Surgery. AB - : Half of children admitted after surgery experience intense pain in hospital, and many experience continued pain and delayed functional recovery at home. However, there is a gap in tools available to measure acute functional ability in pediatric postsurgical settings. We aimed to validate the Youth Acute Pain Functional Ability Questionnaire (YAPFAQ) in a large inpatient pediatric surgical population, evaluate its responsiveness to expected functional recovery, and develop a short form for broad clinical implementation. The YAPFAQ is a self report measure assessing acute functional ability, developed in children admitted for acute sickle cell pain. We evaluated psychometric properties of the measure in 564 children ages 8 to 18 years admitted after surgery. A sample of 54 participants completed the YAPFAQ daily for 3 days after major surgery to assess responsiveness. The measure showed good reliability (Cronbach alpha = .96) and construct validity, with expected relationships with physical health-related quality of life (r = -.53, P < .001) and pain intensity (r = .42, P < .001). YAPFAQ scores decreased over time showing good responsiveness to expected recovery. A 3-item short form of the YAPFAQ showed promising psychometric properties. Early assessment of functioning after surgery may identify children at risk for poor functional outcomes and allow targeting of therapies to improve postsurgical recovery. PERSPECTIVE: The YAPFAQ showed promising psychometric properties in a pediatric postsurgical population. This study addresses a gap in tools available to monitor functional recovery during hospitalization after pediatric surgery. Early detection of problems with recovery may enable targeted therapies to improve postsurgical outcomes. PMID- 28576672 TI - Watching television for more than two hours increases the likelihood of reporting poor sleep quality among Brazilian schoolteachers. AB - Although time spent watching television and sleep problems have increased in the last few decades, it is unclear whether these conditions are associated in working adults after controlling for lifestyle, job characteristics and other individual aspects. The present study analyzed the association between time spent watching television and sleep quality among teachers from public schools in Londrina, Brazil. In this cross-sectional study, information from the Pittsburgh Sleep Quality Index (PSQI) and about time spent watching television was obtained during personal interviews. Logistic regression models adjusted by the main confounders (sociodemographic, occupational and lifestyle variables) were used in the analyses. Among the 959 studied teachers (68.2% women, median age: 42years), teachers who watched >120min/day had a higher likelihood of reporting poor sleep quality (PSQI>5) (odds ratio=1.41; 95% confidence interval=1.01; 1.98) compared with those who watched television for up to 60min/day, regardless of gender, age, work hours, leisure time physical activity and other lifestyle variables. This association did not remain significant after the adjustment for health conditions, i.e., obesity, anxiety, depression and chronic pain, which may act as confounding variables in the relationship between watching television and poor sleep quality. Watching television for >120min/day was independently associated with poorer sleep quality, which should be considered in the prevention and treatment of sleep disturbances among working population. PMID- 28576673 TI - Comparison of the immunogenicity of BM32, a recombinant hypoallergenic B cell epitope-based grass pollen allergy vaccine with allergen extract-based vaccines. PMID- 28576674 TI - Public Park Spaces as a Platform to Promote Healthy Living: Introducing a HealthPark Concept. AB - The concept of Healthy Living (HL) as a primary medical intervention continues to gain traction, and rightfully so. Being physically active, consuming a nutritious diet, not smoking and maintaining an appropriate body weight constitute the HL polypill, the foundation of HL medicine (HLM). Daily use of the HL polypill, working toward optimal dosages, portends profound health benefits, substantially reducing the risk of chronic disease [i.e., cardiovascular disease (CVD), pulmonary disease, metabolic syndromes, certain cancers, etc.] and associated adverse health consequences. To be effective and proactive, our healthcare system must rethink where its primary intervention, HLM, is delivered. Waiting for individuals to come to the traditional outpatient setting is an ineffective approach as poor lifestyle habits are typically well established by the time care is initiated. Ideally, HLM should be delivered where individuals live, work and go to school, promoting immersion in a culture of health and wellness. To this end, there is a growing interest in the use of public parks as a platform to promote the adoption of HL behaviors. The current perspectives paper provides a brief literature review on the use of public parks for HL interventions and introduces a new HealthPark model being developed in Chicago. PMID- 28576676 TI - Targeting PIK3CA-mutant advanced breast cancer in the clinical setting. PMID- 28576677 TI - Impact of different dilution techniques on boar sperm quality and sperm distribution of the extended ejaculate. AB - The dilution of ejaculates is a fundamental step for the production of liquid preserved boar semen. For a long time, it has been recommended to add the extender to the ejaculate. The aim of the present study was to first compare the effect of the position ('center' vs. 'wall') where the extender is added to the semen-mixing cylinder (height 32.5cm; diameter 12.7cm) using an automatic dispenser (n=11). In experiment 2 (n=30), we analyzed the two main dilution methods (extender to the semen ('control') vs. 'reverse'). Experiment 3 was carried out to study the dilution effect on kinematics. In Experiments 1 and 2, the sperm distribution 10min after the dilution and the sperm quality parameters during long-term storage (d1, d3, d5, and d7) were evaluated. In Experiment 3, sperm quality was assessed during short-term storage at 0, 10, 20, 30 and 60min after semen dilution ('control' vs. 'reverse'; n=6). There were no significant differences (P>0.05) between the treatments in the specific response to bicarbonate, mitochondrial activity, membrane status, thermo-resistance or sperm motility immediately after dilution or long-term storage. The sperm distribution was significantly (P=0.029) affected by the dilution method in Experiment 2. In summary, treatment with the extender first, which is used by only a few European boar studs, leads to comparable results in sperm quality during storage and better results in sperm distribution after dilution. This procedure is also less time consuming, less foam formation occurs during the semen dilution and the procedure is more hygienic. PMID- 28576678 TI - Immune therapeutic strategies using optimal controls with L1 and L2 type objectives. AB - Therapeutic strategies to correct an excessive immune response to pathogenic infection is investigated as an optimal control problem. The control problem is formulated around a four dimensional mathematical model describing the inflammatory response to a pathogenic insult with two therapeutic control inputs which have either a direct pro- or anti-inflammatory effect in the given system. We use Pontryagin's maximum principle and discuss necessary optimality conditions. We consider both an L1 type objective functional as well as an L2 type objective. For the former, the presence of singular control will be addressed. For each case, numerical simulations using a nonlinear programming optimization solver to acquire different drug treatment strategies are presented and discussed. The results provide insight for possible treatment strategies and the methods could be a relevant tool for future practice to assist in better prediction of clinical outcomes and subsequently better treatment for patients. PMID- 28576680 TI - What is the impact on the healthcare system if access to bariatric surgery is delayed? PMID- 28576679 TI - Effects of low doses of carbendazim or iprodione either separately or in mixture on the pubertal rat seminiferous epithelium: An ex vivo study. AB - It has been shown that non-cytotoxic doses of Carbendazim (CBZ), a broad-spectrum benzimidazole fungicide, possess endocrine-disrupting (androgen-like) actions, ex vivo, on the pubertal rat seminiferous epithelium. Iprodione (IPR), a dicarboximide fungicide, is also known to be an endocrine-disrupter (anti androgen). The effect of a mixture of these two pesticides was investigated in the validated rat seminiferous tubule culture model. Cultures were performed in the absence or presence of CBZ 50nM or IPR 50nM either alone or in mixture (Mix), over a 3-week period. Mix exerted a dramatic effect on two proteins (Connexin 43 and Claudin-11) of the blood-testis barrier and possessed similar effects to IPR on some germ cell populations. The presence of IPR together with CBZ (Mix) cancelled the effect of CBZ on the increase of the androgen-dependent TP1 and TP2 mRNAs and on the decrease of ERalpha, ERbeta mRNAs. Nevertheless, CBZ alone or IPR alone or Mix induced toxicity on spermatogenesis resulting in a decrease of round spermatids (the precursors of spermatozoa). These results strongly suggest that, even at these low concentrations, the effects of IPR and of CBZ are not solely dependent on their respective anti-androgenic and androgen-like effects and should involve several mechanisms of action. PMID- 28576681 TI - 30-day readmission following weight loss surgery: can psychological factors predict nonspecific indications for readmission? AB - BACKGROUND: Thirty-day readmissions occur in 5% or more of bariatric surgery patients. Some readmissions relate directly to surgical risks, whereas others relate to more nonspecific complaints or nonadherence and may reflect risks outside of the surgical procedure. OBJECTIVE: To investigate whether presurgical psychosocial factors are related to readmission. SETTING: Tertiary/quaternary academic referral center. METHODS: Bariatric surgery patients readmitted within 30 days of surgery during 2012-2015 were identified (n = 102). Patients were matched (2:1) on body mass index, age, sex, and race to 204 nonreadmitted patients. Psychiatric variables and psychological testing (Minnesota Multiphasic Personality Inventory-2-Restructured Form) at intake were compared between the 2 groups. Among those readmitted, the indication for readmission was investigated. Those with specific complications (n = 61) were delineated from those with nonspecific indications (n = 33). RESULTS: Those with nonspecific readmissions were younger and more likely to be female. These patients were also less likely to be in outpatient psychiatric care than nonreadmitted patients. Significant differences were found on the Uncommon Virtues scale of the Minnesota Multiphasic Personality Inventory-2-Restructured Form, which reflects a tendency to underreport disinhibited behaviors. Those with nonspecific readmissions had significantly higher underreporting scores compared to those with specific indications or those not readmitted. CONCLUSIONS: Readmitted patients, particularly those with nonspecific indications, were more likely to presurgically present themselves in an overly positive manner. The tendency to underreport may affect the team's ability to identify risk factors that could be ameliorated before surgery. Readmitted patients were also less likely to be receiving mental health care. Such ongoing treatment may increase monitoring and/or adherence after surgery. PMID- 28576675 TI - Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. AB - BACKGROUND: Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. METHODS: The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants. FINDINGS: Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6.9 months (95% CI 6.8-7.8) in the buparlisib group versus 5.0 months (4.0-5.2) in the placebo group (hazard ratio [HR] 0.78 [95% CI 0.67-0.89]; one-sided p=0.00021). In patients with known PI3K status (n=851), median progression-free survival was 6.8 months (95% CI 5.0-7.0) in the buparlisib group vs 4.5 months (3.3-5.0) in the placebo group (HR 0.80 [95% CI 0.68-0.94]; one-sided p=0.0033). In PI3K pathway activated patients (n=372), median progression-free survival was 6.8 months (95% CI 4.9-7.1) in the buparlisib group versus 4.0 months (3.1-5.2) in the placebo group (HR 0.76 [0.60-0.97], one-sided p=0.014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting >=2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred. INTERPRETATION: The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2 negative advanced breast cancer. Use of more selective PI3K inhibitors, such as alpha-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. FUNDING: Novartis Pharmaceuticals Corporation. PMID- 28576682 TI - Bile reflux of the remnant stomach following Roux-en-Y gastric bypass: an etiology of chronic abdominal pain treated with remnant gastrectomy. AB - BACKGROUND: Bile reflux gastritis of the remnant stomach following Roux-en-Y gastric bypass (RYGB) causing chronic abdominal pain has not been reported. We report a series of symptomatic patients with remnant gastritis treated effectively with remnant gastrectomy (RG). OBJECTIVE: The objective was to report our experience with bile reflux remnant gastritis after RYGB and our outcomes following RG. SETTING: Community teaching hospital. METHODS: All patients undergoing RG were retrospectively reviewed for presenting symptoms, diagnostic workup, pathology, complications, and symptom resolution. RESULTS: Nineteen patients underwent RG for bile reflux gastritis at a mean of 4.4 years (52.3 mo, range 8.5-124 mo) after RYGB. All patients were female and presented with pain, primarily epigastric (18/19; 95%), and described as burning (11/19; 58%), with 10 (53%) reporting nausea. Endoscopy was performed preoperatively on all patients with successful remnant inspection in 13 (68%), using push endoscopy (n = 10) or operative assist (n = 3), with 12 (of 13; 92%) biopsy-positive for reactive gastropathy. Seventeen (90%) completed a hepatobiliary scintigraphy scan with 100% positivity demonstrating bile reflux across the pylorus. Surgical approach was laparoscopic or robotic in 18 (95%) with a hospital length of stay of 2.7 days (range 0-12 d), with no major complications or readmissions. Pathology of the remnant confirmed reactive gastropathy in 90% (n = 17). Ninety percent of patients (n = 17) reported sustained symptom resolution, and 11% of patients (n = 2) remained symptomatic at last follow-up. We followed all patients for a mean of 6.6 years (1-194 mo). CONCLUSION: Bile reflux gastritis of the remnant stomach is a new consideration for chronic abdominal pain months to years following RYGB. Hepatobiliary scintigraphy imaging and endoscopic biopsy are highly suggestive. RG is safe and effective treatment. PMID- 28576683 TI - Management of acute intra-abdominal sepsis caused by leakage after one anastomosis gastric bypass. AB - BACKGROUND: Leakage after one-anastomosis gastric bypass (OAGB) is fortunately rare (<1%), but it remains the most severe complication. Few published data exist on this specific issue. OBJECTIVES: To analyze the results from patients who presented with acute intra-abdominal sepsis (AIAS) caused by leakage after OAGB. SETTING: A university public hospital in France. METHODS: Between October 2006 and February 2016, 17 consecutive patients with a diagnosis of AIAS caused by leakage after OAGB were included. Preoperative characteristics, clinical symptoms, radiologic findings, management, morbidity, and mortality were assessed. RESULTS: All 17 patients were included in the study. There were 4 men (23.5%), the median age was 48 years, and median preoperative body mass index (BMI) was 51 kg/m2. The most frequent clinical sign was tachycardia (65%). An oral contrast computed tomography scan was performed in 15 patients (88%) and showed a diagnosis of AIAS in 93% of cases. The median time between OAGB and leak diagnosis was 4 days. A gastrojejunal anastomosis (GJA) leak was the most frequent origin (41%). Sixteen patients (94%) were managed surgically (laparotomy n = 11, laparoscopy n = 5) and one medically. There were no deaths. The overall morbidity rate was 47% (major = 41%). Six patients underwent an emergency conversion into Roux-en-Y gastric bypass (RYGB) (in cases of GJA, gastric-tube, and biliary-limb leakages) and were compared to 6 patients who did not undergo conversion but who could have benefited. We observed a tendency toward a reduced overall morbidity rate (16.7% versus 83.3%, P = .08) and shorter lengths of stay in the "conversion to RYGB" group. CONCLUSION: The management of AIAS caused by leakage after OAGB was safe, effective, and mostly surgical. Emergency conversion to RYGB in cases of GJA, gastric-tube, or biliary-limb perforation was feasible and safe. PMID- 28576684 TI - Influence of oil-related environmental pollutants on female reproduction. AB - The petroleum low-weight aromatic hydrocarbons benzene, toluene, ethylbenzene, m/p-xylene, and o-xylene, also known as BTEX, are among the most common hazardous sources of environmental contamination. This paper reviews the available data concerning the effects of BTEX on different aspects of female reproduction, including the fecundity, ovaries, central nervous system (CNS), oocytes, embryos, oviducts, cytogenetics of somatic and generative cells, intracellular signaling systems, and hypothalamic, pituitary and peripheral reproductive hormones. Analysis of the available literature demonstrates that BTEX can exert negative effects on various female reproductive sites, including the CNS-pituitary-ovarian axis, their signaling molecules and receptors, ovarian follicles, corpora lutea, oocytes, embryos, oviducts, ovarian cycles, fertility, and the viability of offspring. These effects could be due to the ability of BTEX to destroy chromosomes, to affect cell metabolism, including the accumulation of free radicals, and to affect the release of hormonal regulators of reproductive processes and intracellular protein kinases. PMID- 28576685 TI - Aberrant DNA methylation patterns of human spermatozoa in current smoker males. AB - The purpose of this study was to investigate the impact of current cigarette smoking on sperm DNA methylation patterns. A total of 108 males (51 current smokers and 57 never smoked males) were included in the study. Using 450 BeadChip Arrays, the differentially methylated CpGs between current smokers (n=15) and never smoked males (n=15) were identified. Out of significantly 11 CpGs identified, 2 CpGs namely cg07869343 and cg19169023, which are located in the MAPK8IP3 and TKR genes were selected for further analysis. Using deep bisulfite sequencing in an independent cohort of current smokers (n=36) and never smoked males (n=42), 6 and 1 CpGs showed a significant difference in the MAPK8IP (CpG3, CpG5, CpG6, CpG7, CpG8, and CpG21) and in the TKR (CpG4) were identified, respectively (P<=0.05). Our results indicate that cigarette smoking causes biochemical changes in the sperm DNA methylation in many regions and could adversely affect semen parameters. PMID- 28576686 TI - Miscalculations can lead to misinterpretation of the results. PMID- 28576688 TI - Rating the blood pressure outcome after adrenalectomy for unilateral primary aldosteronism. PMID- 28576687 TI - Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. AB - BACKGROUND: Although unilateral primary aldosteronism is the most common surgically correctable cause of hypertension, no standard criteria exist to classify surgical outcomes. We aimed to create consensus criteria for clinical and biochemical outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism and apply these criteria to an international cohort to analyse the frequency of remission and identify preoperative determinants of successful outcome. METHODS: The Primary Aldosteronism Surgical Outcome (PASO) study was an international project to develop consensus criteria for outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism. An international panel of 31 experts from 28 centres, including six endocrine surgeons, used the Delphi method to reach consensus. We then retrospectively analysed follow-up data from prospective cohorts for outcome assessment of patients diagnosed with unilateral primary aldosteronism by adrenal venous sampling who had undergone a total adrenalectomy, consecutively included from 12 referral centres in nine countries. On the basis of standardised criteria, we determined the proportions of patients achieving complete, partial, or absent clinical and biochemical success in accordance with the consensus. We then used logistic regression analyses to identify preoperative factors associated with clinical and biochemical outcomes. FINDINGS: Consensus was reached for criteria for six outcomes (complete, partial, and absent success of clinical and biochemical outcomes) based on blood pressure, use of antihypertensive drugs, plasma potassium and aldosterone concentrations, and plasma renin concentrations or activities. Consensus was also reached for two recommendations for the timing of follow-up assessment. For the international cohort analysis, we analysed clinical data from 705 patients recruited between 1994 and 2015, of whom 699 also had biochemical data. Complete clinical success was achieved in 259 (37%) of 705 patients, with a wide variance (range 17-62), and partial clinical success in an additional 334 (47%, range 35-66); complete biochemical success was seen in 656 (94%, 83-100) of 699 patients. Female patients had a higher likelihood of complete clinical success (odds ratio [OR] 2.25, 95% CI 1.40-3.62; p=0.001) and clinical benefit (complete plus partial clinical success; OR 2.89, 1.49-5.59; p=0.002) than male patients. Younger patients had a higher likelihood of complete clinical success (OR 0.95 per extra year, 0.93-0.98; p<0.001) and clinical benefit (OR 0.95 per extra year, 0.92 0.98; p=0.004). Higher levels of preoperative medication were associated with lower levels of complete clinical success (OR 0.80 per unit increase, 0.70-0.90; p<0.001). INTERPRETATION: These standardised outcome criteria are relevant for the assessment of the success of surgical treatment in individual patients and will allow the comparison of outcome data in future studies. The variable baseline clinical characteristics of our international cohort contributed to wide variation in clinical outcomes. Most patients derive clinical benefit from adrenalectomy, with younger patients and female patients more likely to have a favourable surgical outcome. Screening for primary aldosteronism should nonetheless be done in every individual fulfilling US Endocrine Society guideline criteria because biochemical success without clinical success is by itself clinically important and older women and men can also derive post-operative clinical benefit. FUNDING: European Research Council; European Union's Horizon 2020; Else Kroner-Fresenius Stiftung; Netherlands Organisation for Health Research and Development-Medical Sciences; Japanese Ministry of Health, Labour and Welfare; Ministry of Health, Slovenia; US National Institutes of Health; and CONICYT-FONDECYT (Chile). PMID- 28576689 TI - Coronal alignment predicts the use of semi-constrained implants in contemporary total knee arthroplasty. AB - BACKGROUND: Semi-constrained, or varus-valgus constrained, implants are occasionally necessary to achieve stability in primary total knee arthroplasty (TKA). However, outcomes with these implants are largely unknown. Therefore, the primary goals of this study were to determine 1) can we identify preoperatively which patients might require a semi-constrained implant and 2) are there any clinical and or radiographic differences for those that require a semi constrained implant? METHODS: A multicenter retrospective study was performed to retrospectively review patients that had a Stryker Triathlon (Kalamazoo, MI) TKA with a Total Stabilized (TS) tibial insert (n=75). This TS cohort was subsequently matched 1:1 based on age, gender, and BMI to a cohort of patients with the same primary TKA design with a PS insert (n=75). Preoperative and postoperative radiographic and clinical data were compared between the two groups. RESULTS: Preoperatively, the TS cohort had significantly greater varus (9.72 vs. 3.48; p=0.0001) and valgus (14.1 vs. 7.57; p=0.0001) deformity. Post operatively, there were no statistically significant differences in revisions (p=1), reoperations (p=1), or complications (p=1). Mean clinical and radiographic follow-ups were equivalent between groups (25.5 vs. 25.8months, p=0.8851). CONCLUSION: As suspected, use of a semi-constrained insert to achieve intraoperative coronal stability was most predicted by preoperative coronal deformity (either varus or valgus). Longer follow-up and larger patient cohorts are necessary to determine. PMID- 28576691 TI - Recurrent elevated liver transaminases and acute liver failure in two siblings with novel bi-allelic mutations of NBAS. AB - BACKGROUND: Acute liver failure (ALF) in children can be life-threatening. Although many causes are known, ALF remains unexplained in about half of the cases. Recently, bi-allelic mutations in NBAS were reported to underlie recurrent episodes of elevated liver transaminases (ELT) and ALF in the context of diverse extrahepatic phenotypes. METHODS AND RESULTS: We here describe two sisters, born to non-consanguineous Portuguese parents, who had short stature and presented with recurrent episodes of severe ELT triggered by febrile respiratory viral infections since early childhood. Patient 1 had mild facial dysmorphism and died during the second ELT crisis at 3-11/12 years of age. Patient 2, currently 9 years old, had multiple episodes of ELT (>30), twice with ALF, often accompanied by extensive urticaria and facial angioedema. Whole-exome and Sanger sequencing revealed that both patients carried previously undescribed compound heterozygous mutations of NBAS (NM_015909.3): c.680A > C (p.His227Pro), affecting an evolutionarily conserved residue, and c.1749G > A (p.Trp583*), causing a premature stop codon. Both mutations are predicted to be highly damaging. The parents and two younger siblings are healthy and heterozygous for one or another mutant allele. CONCLUSION: The multiplex kindred reported herein expands the genotypic and phenotypic spectrum of this recently described clinical syndrome due to autosomal recessive NBAS deficiency. PMID- 28576692 TI - Uteroabdominal Wall Fistula After Cesarean Section in a Patient With Prior Colorectal Resection for Endometriosis: A Case Report and Systematic Review. AB - Uteroabdominal wall fistula (UAWF) is a very rare complication of cesarean section. We report an unusual case of a UAWF occurring in a 37-year-old woman 4 years after a cesarean section and previous radical surgery for deep infiltrating endometriosis with bowel resection. The patient presented with persistent purulent discharge of the Pfannenstiel scar and noted that the discharge was blood stained during menstruation. Magnetic resonance imaging confirmed the diagnosis of UAWF. Surgery was performed by laparotomy and was complicated by a postoperative rectovaginal fistula, which was successfully treated by the placement of a biological mesh via the vagina route. The postoperative course was favorable at 6 months with disappearance of painful symptoms and good quality of the colorectal anastomosis. A systematic review was conducted, and 18 case reports were found from 1939 to 2016. This case report highlights the risk of postdelivery complications in women with deep infiltrating endometriosis and colorectal involvement, especially after cesarean section. Persistent abdominal discharge in this context should suggest a diagnosis of UAWF despite its low incidence. Finally, the vaginal route for rectovaginal fistula might be considered an option for patients with prior multiple laparotomies. PMID- 28576694 TI - How Can We Increase the Percentage and Quality of Minimally Invasive Hysterectomy for Benign Disease Among Low/Intermediate-Volume Gynecologic Surgeons? A Perspective Piece From an Expert Panel Session at the 2017 Society of Gynecologic Surgeons Annual Meeting. PMID- 28576693 TI - Direct Laparoscopic Trocar Insertion: Lessons Learned from Nine Litigated Cases. AB - STUDY OBJECTIVE: To report circumstances and clinical and medicolegal outcomes of 9 litigated cases associated with direct trocar insertion (DTI) injuries to the bowel (7 cases) and major vessel (2 cases) during primary laparoscopic access. DESIGN: A case series from 1990 through 2015 (Canadian Task Force Classification II-2). PATIENTS: Nine litigated cases. INTERVENTIONS: A retrospective review of medical and legal records of litigated cases in Canada reviewed by the primary author (G.A.V.). MEASUREMENTS AND MAIN RESULTS: The average and range of age and body mass index of the women were 31 years (range, 14-65 years) and 25 kg/m2 (range, 20-35 kg/m2), respectively. Indications for laparoscopy included diagnostic (4), laparoscopically assisted vaginal hysterectomy (3), pelvic mass (1), and laparoscopic cholecystectomy (1). DTI was performed with 10-mm trocars (5 shielded, 1 reusable, and 3 unknown). Two complications were experienced by patients of the same male surgeon (cases 2 and 9). Injuries included the small bowel (4 cases), colon (3 cases), and major vessel (2 cases). Vascular injuries resulted in permanent brain damage in 1 and near loss of limb in the other; litigation was favorable to the plaintiff in both cases. All bowel injuries presented with signs and symptoms of peritonitis within 3 postoperative days (PODs) (5 patients on POD 1, 1 patient on POD 2, and 1 patient on POD 3); however, only 2 cases were acted upon and remedied with favorable clinical and medicolegal outcomes. A delayed exploratory laparotomy resulted in significant adverse clinical outcomes (ileostomy/colostomy in 4 patients, multiple surgeries in 7 patients, and 1 death), and in all delayed actions, the medicolegal outcomes were favorable to the plaintiff. CONCLUSION: During laparoscopic primary peritoneal access using the DTI technique, inadvertent intra-abdominal injury may be significant when major vessels are involved and when intervention is delayed in bowel injuries. These result in significant adverse clinical complications and may provoke higher litigation with more favorable outcomes for the plaintiff. PMID- 28576690 TI - Complement component C3aR constitutes a novel regulator for chick eye morphogenesis. AB - Complement components have been implicated in a wide variety of functions including neurogenesis, proliferation, cell migration, differentiation, cancer, and more recently early development and regeneration. Following our initial observations indicating that C3a/C3aR signaling induces chick retina regeneration, we analyzed its role in chick eye morphogenesis. During eye development, the optic vesicle (OV) invaginates to generate a bilayer optic cup (OC) that gives rise to the retinal pigmented epithelium (RPE) and neural retina. We show by immunofluorescence staining that C3 and the receptor for C3a (the cleaved and active form of C3), C3aR, are present in chick embryos during eye morphogenesis in the OV and OC. Interestingly, C3aR is mainly localized in the nuclear compartment at the OC stage. Loss of function studies at the OV stage using morpholinos or a blocking antibody targeting the C3aR (anti-C3aR Ab), causes eye defects such as microphthalmia and defects in the ventral portion of the eye that result in coloboma. Such defects were not observed when C3aR was disrupted at the OC stage. Histological analysis demonstrated that microphthalmic eyes were unable to generate a normal optic stalk or a closed OC. The dorsal/ventral patterning defects were accompanied by an expansion of the ventral markers Pax2, cVax and retinoic acid synthesizing enzyme raldh-3 (aldh1a3) domains, an absence of the dorsal expression of Tbx5 and raldh-1 (aldh1a1) and a re-specification of the ventral RPE to neuroepithelium. In addition, the eyes showed overall decreased expression of Gli1 and a change in distribution of nuclear beta-catenin, suggesting that Shh and Wnt pathways have been affected. Finally, we observed prominent cell death along with a decrease in proliferating cells, indicating that both processes contribute to the microphthalmic phenotype. Together our results show that C3aR is necessary for the proper morphogenesis of the OC. This is the first report implicating C3aR in eye development, revealing an unsuspected hitherto regulator for proper chick eye morphogenesis. PMID- 28576695 TI - Perspectives on Subcutaneous Route of Administration as an Immunogenicity Risk Factor for Therapeutic Proteins. AB - An increasing number of therapeutic proteins are being developed for delivery through the subcutaneous (SC) route of administration. Relative to intravenous (IV) administration, the SC route offers more convenience to patients, flexibility in dosing, and potential to reduce health care costs. There is a perception that SC administration can pose a higher immunogenicity risk than IV administration for a given protein. To evaluate whether there is a difference in therapeutic protein immunogenicity associated with administration routes, a more detailed understanding of the interactions with the immune system by each route is needed. Few approved therapeutic proteins have available clinical immunogenicity data sets in the public domain that represent both IV and SC administration routes. This has prevented a direct comparison of the 2 routes of administration across a large sample size. Of the 6 marketed products where SC and IV route-related incidences of anti-drug antibody (ADA) were available, 4 were associated with higher immunogenicity incidence with SC. In other cases, there was no apparent difference between the SC and IV routes. Overall, the ADA incidence was low (<15%) with no impact on safety or efficacy. The challenges associated with identifying specific risk factors unique to SC administration are discussed. PMID- 28576696 TI - Anti-interleukin 5 therapies in severe asthma. PMID- 28576697 TI - Sequencing viral siRNAs to identify previously undescribed viruses and viroids in a panel of ornamental plant samples structured as a matrix of pools. AB - Ornamental plants constitute a largely unknown and potentially important source of pathogens affecting not only ornamental plants, but also major crop species. We have carried out studies using high-throughput sequencing of 21-24 nt RNAs from potentially virus-infected ornamental plants, followed by assembly of sequence scaffolds, to identify the virus and viroid genomes present in a panel of 67 plant samples representing 46 species belonging to the main sectors of the ornamental plant industry (cut flowers, pot plants, bulbs). A pilot study demonstrated that samples could be pooled (5 samples per pool), and the overall process simplified without loss of detection of important known pathogens. In a full-scale study, pools of 5 samples were organized in a 5*5 matrix to facilitate attribution of a sequence to a precise sample directly from analysis of the matrix. In the total of 67 samples analyzed in the two studies, partial sequences suggesting the presence of 25 previously unknown viruses and viroids were detected, including all types of virus and viroid genomes, and also showed four cases of known viruses infecting previously undescribed hosts. Furthermore, two types of potential mis-assembly were analyzed, and were shown to not affect the conclusions regarding the presence of the pathogens identified, but show that mis assembly can affect the results when the objective is determining complete bona fide viral genome sequences. These results clearly confirm that ornamental plants constitute a potential source of unknown viruses and viroids that could have a major impact on agriculture, and that sequencing siRNAs of potentially virus- or viroid-infected ornamental plants is an effective means for screening for the presence of potentially important pathogens. PMID- 28576698 TI - Impact of shoulder rotation on neck-shaft angle: A clinical study. AB - BACKGROUND: Two recent experimental studies evaluated the influence of shoulder rotation on neck-shaft angle, with conflicting results. However, there have been no clinical studies of whether this angle varies in different shoulder positions. The present study aimed to determine whether shoulder rotation affects neck-shaft angle on standard radiographs in patients with complaints of shoulder pain. HYPOTHESIS: Shoulder rotation does not affect neck-shaft angle. MATERIALS AND METHODS: A prospective study was conducted in selected patients with shoulder pain. Three true anterior-posterior radiographic views were obtained: in neutral rotation, 30 degrees external rotation, and internal rotation with patient's arm in a sling. The X-rays were evaluated by three shoulder and elbow surgeons. Inter and intra-observer reliability was evaluated by intraclass correlation coefficient (ICC). RESULTS: Neck-shaft angle on true AP view did not differ between neutral rotation and 30 degrees external rotation: 132+/-6 degrees and 130+/-9 degrees , respectively (P>0.999). In internal rotation with the hand resting on the abdomen, neck-shaft angle was 145+/-6 degrees : i.e., significantly different (P<0.001) to the other two positions. Intra- and inter observer correlation demonstrated excellent reliability. CONCLUSIONS: Radiographic neck-shaft angle was significantly different in internal rotation with the patient's arm in a sling, compared with views in neutral or 30 degrees external rotation. Intra- and inter-observer correlation showed excellent reliability. LEVEL OF EVIDENCE: II, comparative prospective study. PMID- 28576699 TI - Chronic instability of the thumb metacarpo-phalangeal joint: Seven-year outcomes of three surgical techniques. AB - BACKGROUND: Severe sprain of the thumb metacarpo-phalangeal joint (TMCPJ) is a common injury whose functional outcome is good when repair is performed at the acute stage. The diagnosis is often missed, however, leading to chronic instability. The optimal treatment of chronic TMCPJ instability is controversial. The objective of this study was to compare the clinical outcomes of the three main surgical techniques used to treat chronic TMCPJ instability. HYPOTHESIS: Arthrodesis is the best surgical option when ligament repair is not feasible. MATERIAL AND METHODS: This single-centre retrospective study included all patients managed surgically between 2000 and 2012 for chronic post-traumatic TMCPJ instability using any of the three following techniques: primary repair, ligament reconstruction, and arthrodesis. Subjective and objective outcomes and complication rates at last follow-up were compared across these three techniques. RESULTS: Of 67 included patients, 55 were re-evaluated, after a mean follow-up of 84 months (range: 24-164 months). Among them, 48 (87.3%) were satisfied or very satisfied with the outcome. Pain relief was significantly better in the arthrodesis group. Mean Quick-DASH scores were 17.4 (range: 0.0-89.5) with primary repair, 25.7 (range: 0.0-58.3) with ligament reconstruction, and 17.8 (range: 0.0-50.0) with arthrodesis. Mean pinch-test strength compared to the normal side was 89% with primary repair, 84% with ligament reconstruction, and 94% with arthrodesis. In the ligament reconstruction group, 6 of the 10 patients had instability at last follow-up and the proportion of patients describing themselves as fully recovered was significantly smaller than in the other groups. Four failures were recorded at last follow-up. CONCLUSION: Surgery to treat chronic TMCPJ instability produces good outcomes. Primary repair deserves preference whenever possible. In contrast to previous reports, outcomes after ligament reconstruction were not better compared to arthrodesis. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 28576700 TI - Tumoral calcinosis: Diffuse multifocal form in hemodialysis patients. Two case reports. AB - Orthopedic surgeons are often consulted for diagnosis of MASS syndrome, imaging showing periarticular calcification, or joint stiffness. Such presentations in a dialyzed patient should suggest tumoral calcinosis, which is a rare complication of dialysis, often diagnosed wrongly or late. It is often associated with calcium phosphate balance disorder, in which treatment is difficult and must take account of known contributing factors: severe hyperparathyroidism, increased phosphocalcic product, therapeutic calcium and vitamin D overload, and bone turnover slowed for varying reasons. We report a clinical, radiological and therapeutic description of two cases of tumoral calcinosis, which consists in deposits of hydroxyapatite, the crystalline form of calcium phosphate, in diffuse multifocal periarticular locations, inducing both esthetic and functional damage. PMID- 28576701 TI - Relevance of MRI for management of non-displaced lateral humeral condyle fractures in children. AB - INTRODUCTION: The treatment for non-displaced (<2 mm displacement) fractures of the lateral humeral condyle in children is controversial. Most studies recommend non-surgical treatment. However, plain radiographs are not sufficient to evaluate extension of the fracture line through the articular cartilage. This explains the high frequency of secondary displacements and non-unions, despite well-conducted conservative treatment. We hypothesized that MRI could be used to analyse whether the fracture is complete or incomplete. This could help to determine whether surgical or conservative treatment is indicated. MATERIAL AND METHODS: This prospective study enrolled children being treated for a non-displaced (< 2 mm gap) fracture of the lateral humeral condyle. All patients were treated with a long-arm cast in the emergency room. An MRI was done later on without sedation. A specific protocol was used to reduce the duration of the examination. T2-weighted and proton density fat-saturated sequences were used. RESULTS: Twenty-seven patients were enrolled: 16 boys and 11 girls with a mean age of 5 years (2-10). The MRI was performed an average of 7 days (1-23) after the fracture. The MRI could not be interpreted in two cases because the child had moved during the examination. In the other 25 patients, the fracture was incomplete in 17 patients and complete in 8 patients. Two children had secondary displacement diagnosed 7 and 11 days after the fracture event. These two patients underwent open reduction and internal fixation. There was no correlation between patient age and the fracture being complete or incomplete. There were no cases of non-union. CONCLUSION: MRI appears to be a reliable method for determining whether the fracture line is complete or incomplete. It can be performed without sedation, even in children as young as 2 years of age. Use of an injury-specific MRI protocol reduces the length of the examination, thereby improving its performance. We recommend that it be used to analyse non-displaced fractures of the lateral humeral condyle in children. LEVEL OF EVIDENCE: 3 Prospective study. PMID- 28576702 TI - Operative management of supracondylar humeral fractures in children: Comparison of five fixation methods. AB - BACKGROUND: The best method for stabilising supracondylar humeral fractures (SHFs) in children remains unclear. The objective of this study was to compare the outcomes of five different fixation methods for SHFs in children. HYPOTHESIS: Differences in intra-operative and short-term post-operative parameters can be demonstrated across different fixation methods for SHFs in children. PATIENTS AND METHODS: We reviewed the medical files of paediatric patients managed at our centre between 2006 and 2016 for SHF with major displacement (type 3 or 4 in the Lagrange-Rigault classification). Clinical and radiological parameters collected post-operatively and at last follow-up included Baumann's angle, anteversion of the distal humeral epiphysis, and operative time. Over the 11-year study period, 251 patients were included; mean age was 6.4 years and mean follow-up 4.7 months. The five fixation methods used were elastic stable intra-medullary nailing (ESIN, n=16), two pins in an X configuration (n=33), two lateral pins and one medial pin (n=144), two lateral pins (n=33), and three lateral pins (n=25). A minimally invasive 2-cm approach was used to insert the medial pins. Immediate instability of the fixation was considered in patients with an at least 15 degrees deficit in Baumann's angle or anteversion, or with rotational malalignment, on the radiographs taken on day 1. Outcomes were analysed in each of the five internal fixation groups. RESULTS: Immediate instability showed no significant differences across the five groups. Operative time was significantly shorter with two lateral pins (33min, P=0.046). Time to hardware removal was longer in the ESIN group (54 days, P=0.03). Use of a medial pin was associated with a lower risk of secondary displacement (2.0% vs. 8.6%, P=0.04) but did not affect the risk of nerve injury (4% vs. 3%, P=0.86). DISCUSSION: This is one of the largest retrospective cohort studies of outcomes according to the fixation technique used to treat SHFs in children. Adding a medial pin through a minimally invasive approach is associated with a longer operative time but limits the risk of secondary displacement without increasing the frequency of iatrogenic nerve injury and improves fracture site stability. Use of a medial pin therefore deserves to be considered in paediatric SHFs. LEVEL OF EVIDENCE: IV, retrospective cohort study. PMID- 28576703 TI - Porin flexibility in Providencia stuartii: cell-surface-exposed loops L5 and L7 are markers of Providencia porin OmpPst1. AB - Epidemiologically unrelated Providencia stuartii strains isolated in hospitals in the south of France were investigated for their porin sequences and profiles. Noticeable resistance to beta-lactams was found to be associated with production of extended spectrum beta-lactamases or AmpC overproduction, but not metallo-beta lactamases. At the same time, the expression level of outer membrane porins was unmodified in these isolates. The identity of the amino acid sequences of the major porin OmpPst1 was less than 90% in the tested clinical strains, whereas sequences of the second major porin OmpPst2 were found to be identical in all isolates. Sequence diversity identified in the OmpPst1 porins was mainly located in two cell-surface-exposed loops (L5 and L7): these loops were found to be responsible for 80% of the main movements of the protein. Parallel tempering MD simulations indicated possible coordinated movement of these loops that might affect the electrostatic interaction of the porin with membrane components (e.g. LPS) or with external molecules/surfaces. This suggests that such flexibility of surface-exposed domains of OmpPst1 may participate in bacterial adaptation to the environment. PMID- 28576705 TI - The pathogenic LRRK2 R1441C mutation induces specific deficits modeling the prodromal phase of Parkinson's disease in the mouse. AB - The aim of the present study was to further explore the in vivo function of the Leucine-rich repeat kinase 2 (LRRK2)-gene, which is mutated in certain familial forms of Parkinson's disease (PD). We generated a mouse model harboring the disease-associated point mutation R1441C in the GTPase domain of the endogenous murine LRRK2 gene (LRRK2 R1441C line) and performed a comprehensive analysis of these animals throughout lifespan in comparison with an existing knockdown line of LRRK2 (LRRK2 knockdown line). Animals of both lines do not exhibit severe motor dysfunction or pathological signs of neurodegeneration neither at young nor old age. However, at old age the homozygous LRRK2 R1441C animals exhibit clear phenotypes related to the prodromal phase of PD such as impairments in fine motor tasks, gait, and olfaction. These phenotypes are only marginally observable in the LRRK2 knockdown animals, possibly due to activation of compensatory mechanisms as suggested by in vitro studies of synaptic transmission. Thus, at the organismal level the LRRK2 R1441C mutation does not emerge as a loss of function of the protein, but induces mutation specific deficits. Furthermore, judged by the phenotypes presented, the LRRK2-R1441C knock-in line is a valid preclinical model for the prodromal phase of PD. PMID- 28576704 TI - alpha-Synuclein fibril-induced inclusion spread in rats and mice correlates with dopaminergic Neurodegeneration. AB - Proteinaceous inclusions in neurons, composed primarily of alpha-synuclein, define the pathology in several neurodegenerative disorders. Neurons can internalize alpha-synuclein fibrils that can seed new inclusions from endogenously expressed alpha-synuclein. The factors contributing to the spread of pathology and subsequent neurodegeneration are not fully understood, and different compositions and concentrations of fibrils have been used in different hosts. Here, we systematically vary the concentration and length of well characterized alpha-synuclein fibrils and determine their relative ability to induce inclusions and neurodegeneration in different hosts (primary neurons, C57BL/6J and C3H/HeJ mice, and Sprague Dawley rats). Using dynamic-light scattering profiles and other measurements to determine fibril length and concentration, we find that femptomolar concentrations of fibrils are sufficient to induce robust inclusions in primary neurons. However, a narrow and non-linear dynamic range characterizes fibril-mediated inclusion induction in axons and the soma. In mice, the C3H/HeJ strain is more sensitive to fibril exposures than C57BL/6J counterparts, with more inclusions and dopaminergic neurodegeneration. In rats, injection of fibrils into the substantia nigra pars compacta (SNpc) results in similar inclusion spread and dopaminergic neurodegeneration as injection of the fibrils into the dorsal striatum, with prominent inclusion spread to the amygdala and several other brain areas. Inclusion spread, particularly from the SNpc to the striatum, positively correlates with dopaminergic neurodegeneration. These results define biophysical characteristics of alpha-synuclein fibrils that induce inclusions and neurodegeneration both in vitro and in vivo, and suggest that inclusion spread in the brain may be promoted by a loss of neurons. PMID- 28576706 TI - rHIgM22 enhances remyelination in the brain of the cuprizone mouse model of demyelination. AB - Failure of oligodendrocyte precursor cells (OPCs) to differentiate and remyelinate axons is thought to be a major cause of the limited ability of the central nervous system to repair plaques of immune-mediated demyelination in multiple sclerosis (MS). Current therapies for MS aim to lessen the immune response in order to reduce the frequency and severity of attacks, but these existing therapies do not target remyelination or stimulate repair of the damaged tissue. Thus, the promotion of OPC differentiation and remyelination is potentially an important therapeutic goal. Previous studies have shown that a recombinant human-derived monoclonal IgM antibody, designated rHIgM22, promotes remyelination, particularly of the spinal cord in rodent models of demyelination. Here, we examined the effects of rHIgM22 in remyelination in the brain using the mouse model of cuprizone-induced demyelination, which is characterized by spontaneous remyelination. The myelination state of the corpus callosum of cuprizone-fed mice treated with rHIgM22 was examined immediately after the end of the cuprizone diet as well as at different time points during the recovery period with regular food, and compared with that of cuprizone-fed animals treated with either vehicle or human IgM isotype control antibody. Mice fed only regular food were used as controls. We demonstrate that treatment with rHIgM22 accelerated remyelination of the demyelinated corpus callosum. The remyelination-enhancing effects of rHIgM22 were found across different, anatomically distinct regions of the corpus callosum, and followed a spatiotemporal pattern that was similar to that of the spontaneous remyelination process. These enhancing effects were also accompanied by increased differentiation of OPCs into mature oligodendrocytes. Our data indicate strong remyelination-promoting capabilities of rHIgM22 and further support its therapeutic potential in MS. PMID- 28576708 TI - A systems level analysis of epileptogenesis-associated proteome alterations. AB - Despite intense research efforts, the knowledge about the mechanisms of epileptogenesis and epilepsy is still considered incomplete and limited. However, an in-depth understanding of molecular pathophysiological processes is crucial for the rational selection of innovative biomarkers and target candidates. Here, we subjected proteomic data from different phases of a chronic rat epileptogenesis model to a comprehensive systems level analysis. Weighted Gene Co expression Network analysis identified several modules of interconnected protein groups reflecting distinct molecular aspects of epileptogenesis in the hippocampus and the parahippocampal cortex. Characterization of these modules did not only further validate the data but also revealed regulation of molecular processes not described previously in the context of epilepsy development. The data sets also provide valuable information about temporal patterns, which should be taken into account for development of preventive strategies in particular when it comes to multi-targeting network pharmacology approaches. In addition, principal component analysis suggests candidate biomarkers, which might inform the design of novel molecular imaging approaches aiming to predict epileptogenesis during different phases or confirm epilepsy manifestation. Further studies are necessary to distinguish between molecular alterations, which correlate with epileptogenesis versus those reflecting a mere consequence of the status epilepticus. PMID- 28576707 TI - Development of transcripts regulating dendritic spines in layer 3 pyramidal cells of the monkey prefrontal cortex: Implications for the pathogenesis of schizophrenia. AB - Certain cognitive deficits in schizophrenia appear to emerge from altered postnatal development of the dorsolateral prefrontal cortex (DLPFC). Dendritic spines on DLPFC layer 3 pyramidal cells are essential for certain cognitive functions, change in density over development, and are reduced in number in schizophrenia. Altered expression of molecular regulators of actin filament assembly and stability, which are essential for spine formation and maintenance, is thought to contribute to the pathogenesis of spine deficits in the disease. However, the normal developmental expression patterns of these molecular regulators of dendritic spines, which might provide insight into the timing of spine deficits in schizophrenia, are unknown. Therefore, we quantified the expression from birth to adulthood of key transcripts regulating dendritic spine density in monkey DLPFC. Layer 3 pyramidal cells, and tissue samples containing layers 3 or 6, were captured by laser microdissection and selected transcripts were quantified using PCR. In layer 3 pyramidal cells, the expression levels of most of the transcripts studied changed early, and not late, in postnatal development. These developmental shifts in expression were generally not detected in tissue homogenates of layers 3 or 6, suggesting that the changes may be enriched in layer 3 pyramidal cells. The timing of these shifts in expression suggests that early, rather than later, postnatal development may be a vulnerable period for layer 3 pyramidal neurons. Disruption of the normal developmental trajectories of these transcripts may contribute to layer 3 pyramidal neuron spine deficits in individuals who are later diagnosed with schizophrenia. PMID- 28576709 TI - Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndrome. AB - Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe intellectual and developmental disabilities. The disease is caused by the loss of function of maternally inherited UBE3A, a gene that exhibits paternal-specific imprinting in neuronal tissues. Ube3a-maternal deficient mice (AS mice) display many classical features of AS, although, the underlying mechanism of these behavioural deficits is poorly understood. Here we report that the absence of Ube3a in AS mice brain caused aberrant increase in HDAC1/2 along with decreased acetylation of histone H3/H4. Partial knockdown of Ube3a in cultured neuronal cells also lead to significant up-regulation of HDAC1/2 and consequent down regulation of histones H3/H4 acetylation. Treatment of HDAC inhibitor, sodium valproate, to AS mice showed significant improvement in social, cognitive and motor impairment along with restoration of various proteins linked with synaptic function and plasticity. Interestingly, HDAC inhibitor also significantly increased the expression of Ube3a in cultured neuronal cells and in the brain of wild type mice but not in AS mice. These results indicate that anomalous HDAC1/2 activity might be linked with synaptic dysfunction and behavioural deficits in AS mice and suggests that HDAC inhibitors could be potential therapeutic molecule for the treatment of the disease. PMID- 28576710 TI - Evaluation of Screw Placement Accuracy in Circumferential Lumbar Arthrodesis Using Robotic Assistance and Intraoperative Flat-Panel Computed Tomography. AB - BACKGROUND: Neuronavigation has become a common means of placing pedicle screws in vertebral arthrodesis, because it reduces the incidence of complications related to poor screw positioning. OBJECTIVE: The To evaluate the accuracy of pedicle screw placement during lumbar arthrodesis performed with the new ROSA Spine robot and intraoperative flat-panel computed tomography (fpCT) guidance. METHODS: We performed a descriptive, observational, retrospective, single-center study of patients having undergone transforaminal lumbar interbody fusion (TLIF) for degenerative pathologies with the ROSA Spine robot and intraoperative fpCT guidance. The primary endpoint was the presence or absence of pedicle wall breach, as assessed from the fpCT scan. Screw placement was graded according to Ravi's classification. RESULTS: Twenty-five patients were operated on between November 2014 and July 2016; 21 underwent minimally invasive TLIF, and 4 underwent open TLIF. The mean +/- standard deviation operating time was 241 +/- 49.8 minutes. Of the 110 screws placed, 101 (91.8%) were completely within the pedicle (Ravi grade A), 5 (4.5%) had a pedicle wall breach <2 mm (grade B), 2 (1.8%) had a pedicle wall breach of 2-4 mm (grade C), and 2 had pedicle wall breach >4 mm (grade D) (1.8%). One screw (a grade D) was replaced during surgery. None of the breaches were symptomatic. CONCLUSIONS: When coupled with fpCT, the ROSA Spine robot is a reliable, accurate means of performing lumbar pedicle screwing. PMID- 28576711 TI - Safety and Efficacy of Antibacterial Prophylaxis After Craniotomy: A Decision Model Analysis. AB - BACKGROUND: Antibiotic prophylaxis has revolutionized the safety of neurosurgical procedures in the last century. Today, the clinician's drug of choice before surgery often is based on the antibiotic's resistance profile and drug-induced complications. METHODS: A decision tree model was developed to compare cefazolin (cephalosporin), vancomycin, or their combination on 90-day mortality postcraniotomy. We modeled the infection type (methicillin-sensitive, methicillin resistant, or other organisms), antibiotic-related complications that could affect mortality (e.g., renal injury), and Clostridium difficile infections. Parameters' values were extracted from published sources. One-way sensitivity analysis was used to examine results' robustness to plausible variations in input parameter values. RESULTS: The expected value (EV) of 90-day survival was the greatest among patients on cefazolin (EV = 0.9145), followed by patients on vancomycin (EV = 0.8898), and patients on the combination (EV = 0.8886). Cefazolin was the preferred strategy in most one-way sensitivity analyses, except for a few cases in which other options could be preferred based on expected survival. Vancomycin was preferred if kidney injury risk was <=0.056 conditional on vancomycin intake or >=12% conditional on cefazolin intake. The combination was preferred if kidney injury conditional risk was <=0.083 or that for kidney injury-mortality was <=4.7%. Varying other risks (e.g., postsurgical-site infections (methicillin-resistant Staphylococcus aureus, methicillin-sensitive Staphylococcus aureus, or other); Clostridium difficile infections' risks conditional on each antibiotic) did not change the preferred strategy. CONCLUSIONS: According to this decision analysis, patients undergoing a craniotomy who had cefazolin as prophylaxis had a slightly greater expected survival compared with other strategies. These results were sensitive to changes in kidney injury development risk and kidney failure-associated death. PMID- 28576712 TI - Preserving the Facial Nerve During Orbitozygomatic Craniotomy: Surgical Anatomy Assessment and Stepwise Illustration. AB - OBJECTIVE: Surgical safety and efficiency during an orbitozygomatic (OZ) osteotomy rely on thorough knowledge of the surgical anatomy of the facial nerve. Although the anatomy of the facial nerve and its relation to the pterional craniotomy are described, a thorough assessment of facial nerve preservation techniques during the OZ approach and its variations is lacking. We assessed the surgical anatomy of the facial nerve related to the OZ approach and provided a thorough stepwise description on how to preserve it. METHODS: The OZ approach was performed bilaterally in 15 cadaveric heads. The interfascial and subfascial techniques were performed to study their nuances in preserving the facial nerve. We compared the 2 techniques and provided a thorough description on how to preserve the facial nerve during each step of the OZ approach. RESULTS: At the zygomatic arch, the facial nerve was found between the galea and the superficial temporal fascia. A cut in the fascia at the posterior end of the zygomatic arch did not cross any facial nerve branches. The subfascial technique was simpler, more efficient, and provided more structural protection of the facial nerve branches than the interfascial technique. CONCLUSIONS: The frontal division of the facial nerve is related directly to dissection over the zygomatic bone and may be injured during fascial dissection or osteotomies. Both interfascial and subfascial techniques are feasible to use during the OZ craniotomy and provide ample exposure of the OZ unit. Regarding the preservation of the facial nerve branches, we favor the subfascial method. PMID- 28576713 TI - Adaptation of continuous biogas reactors operating under wet fermentation conditions to dry conditions with corn stover as substrate. AB - Corn stover (CS) is the agricultural by-product of maize cultivation. Due to its high abundance and high energy content it is a promising substrate for the bioenergy sector. However, it is currently neglected in industrial scale biogas plants, because of its slow decomposition and hydrophobic character. To assess the maximum biomethane potential of CS, long-term batch fermentations were carried out with various substrate concentrations and particle sizes for 72 days. In separate experiments we adapted the biogas producing microbial community in wet fermentation arrangement first to the lignocellulosic substrate, in Continuous Stirred Tank Reactor (CSTR), then subsequently, by continuously elevating the feed-in concentration, to dry conditions in solid state fermenters (SS-AD). In the batch tests, the <10 mm fraction of the grinded and sieved CS was amenable for biogasification, but it required 10% more time to produce 90% of the total biomethane yield than the <2 mm sized fraction, although in the total yields there was no significant difference between the two size ranges. We also observed that increasing amount of substrate added to the fermentation lowered the specific methane yield. In the CSTR experiment, the daily substrate loading was gradually increased from 1 to 2 gvs/L/day until the system produced signs of overloading. Then the biomass was transferred to SS-AD reactors and the adaptation process was studied. Although the specific methane yields were lower in the SS-AD arrangement (177 mL CH4/gvs in CSTR vs. 105 mL in SS-AD), the benefits of process operational parameters, i.e. lower energy consumption, smaller reactor volume, digestate amount generated and simpler configuration, may compensate the somewhat lower yield. PMID- 28576715 TI - Thermo-sensitive polypeptide hydrogel for locally sequential delivery of two pronged antitumor drugs. AB - : In the synergistic treatment with cytotoxic drug and vascular disrupting agent, the order of drug release shows great importance to enhance the antitumor efficacy. When vascular disrupting agent is firstly administrated, the reduced blood supply and overexpressed hypoxia-inducible factor-1alpha greatly limit the efficiency of chemotherapy. In this work, an injectable thermo-sensitive polypeptide hydrogel was firstly developed for the locally sequential delivery of hydrophilic doxorubicin (DOX, a cytotoxic agent) and hydrophobic combretastatin A4 (CA4, a vascular disrupting drug). The aqueous solution of polypeptide at low temperature transformed into hydrogel under the body temperature after subcutaneous injection and completely degraded after four weeks with excellent biocompatibility. DOX and CA4 were co-loaded into the hydrogel, and the release of DOX showed much faster than that of CA4 due to their difference in water solubility. The superior inhibition of tumor volume after treatment with DOX and CA4 co-loaded hydrogel occurred in the treatment of grafted mouse U14 cervical tumor compared with both free drugs and single drug-loaded hydrogels. In addition, the co-loaded hydrogel obtained enhanced apoptosis of tumor cells, significant shutdown of blood vessels, and wholly regional tumor apoptosis, which indicated the eradication of solid tumor. Moreover, treatments with the drug loaded hydrogels showed negligible damage to normal tissues, suggesting their low systemic toxicity. The locally sequential delivery system had great potential for in situ synergistic chemotherapy. STATEMENT OF SIGNIFICANCE: The release order makes great difference in the synergistic efficacies of cytotoxic drug and vascular disrupting agent. When cytotoxic drug is administrated before vascular disrupting agent, an eradication of tumor might be obtained. On the contrary, the antitumor efficiency will be greatly hindered by limited penetration of later cytotoxic drug and drug resistant induced by vascular disrupting agent. Therefore, the adjustment of the delivery behaviors of such two-pronged agents in one platform was significant for their efficiently synergistic chemotherapy. The present study originally provides a convenient strategy and an advanced sample for sequential administration of cytotoxic drug and vascular disrupting agent in one platform based on their water solubility to achieve upregulated efficacy and safety. PMID- 28576716 TI - Enhanced targeting of invasive glioblastoma cells by peptide-functionalized gold nanorods in hydrogel-based 3D cultures. AB - : Cancer stem cells (CSCs) are responsible for drug resistance, tumor recurrence, and metastasis in several cancer types, making their eradication a primary objective in cancer therapy. Glioblastoma Multiforme (GBM) tumors are usually composed of a highly infiltrating CSC subpopulation, which has Nestin as a putative marker. Since the majority of these infiltrating cells are able to elude conventional therapies, we have developed gold nanorods (AuNRs) functionalized with an engineered peptide capable of specific recognition and selective eradication of Nestin positive infiltrating GBM-CSCs. These AuNRs generate heat when irradiated by a near-infrared laser, and cause localized cell damage. Nanoparticle internalization assays performed with GBM-CSCs or Nestin negative cells cultured as two-dimensional (2D) monolayers or embedded in three dimensional (3D) biodegradable-hydrogels of tunable mechanical properties, revealed that the AuNRs were mainly internalized by GBM-CSCs, and not by Nestin negative cells. The AuNRs were taken up via energy-dependent and caveolae mediated endocytic mechanisms, and were localized inside endosomes. Photothermal treatments resulted in the selective elimination of GBM-CSCs through cell apoptosis, while Nestin negative cells remained viable. Results also indicated that GBM-CSCs embedded in hydrogels were more resistant to AuNR photothermal treatments than when cultured as 2D monolayers. In summary, the combination of our engineered AuNRs with our tunable hydrogel system has shown the potential to provide an in vitro platform for the evaluation and screening of AuNR-based cancer therapeutics, leading to a substantial advancement in the application of AuNRs for targeted GBM-CSC therapy. STATEMENT OF SIGNIFICANCE: There is an urgent need for reliable and efficient therapies for the treatment of Glioblastoma Multiforme (GBM), which is currently an untreatable brain tumor form with a very poor patient survival rate. GBM tumors are mostly comprised of cancer stem cells (CSCs), which are responsible for tumor reoccurrence and therapy resistance. We have developed gold nanorods functionalized with an engineered peptide capable of selective recognition and eradication of GBM-CSCs via heat generation by nanorods upon NIR irradiation. An in vitro evaluation of nanorod therapeutic activities was performed in 3D synthetic-biodegradable hydrogel models with distinct biomechanical cues, and compared to 2D cultures. Results indicated that cells cultured in 3D were more resistant to photothermolysis than in 2D systems. PMID- 28576717 TI - Transient phase behavior of an elastomeric biomaterial applied to abdominal laparotomy closure. AB - : Secure closure of the fascial layers after entry into the peritoneal cavity is crucial to prevent incisional hernia, yet appropriate purchase of the tissue can be challenging due to the proximity of the underlying protuberant bowel which may become punctured by the surgical needle or strangulated by the suture itself. Devices currently employed to provide visceral protection during abdominal closure, such as the metal malleable retractor and Glassman Visceral Retainer, are unable to provide complete protection as they must be removed prior to complete closure. A puncture resistant, biocompatible, and degradable matrix that can be left in place without need for removal would facilitate rapid and safe abdominal closure. We describe a novel elastomer (CC-DHA) that undergoes a rapid but controlled solid-to-liquid phase transition through the application of a destabilized carbonate cross-linked network. The elastomer is comprised of a polycarbonate cross-linked network of dihydroxyacetone, glycerol ethoxylate, and tri(ethylene glycol). The ketone functionality of the dihydroxyacetone facilitates hydrolytic cleavage of the carbonate linkages resulting in a rapidly degrading barrier that can be left in situ to facilitate abdominal fascial closure. Using a murine laparotomy model we demonstrated rapid dissolution and metabolism of the elastomer without evidence of toxicity or intraabdominal scarring. Furthermore, needle puncture and mechanical properties demonstrated the material to be both compliant and sufficiently puncture resistant. These unique characteristics make the biomaterial extraordinarily useful as a physical barrier to prevent inadvertent bowel injury during fascial closure, with the potential for wider application across a variety of medical and surgical applications. STATEMENT OF SIGNIFICANCE: Fascial closure after abdominal surgery requires delicate maneuvers to prevent incisional hernia while minimizing risk for inadvertent bowel injury. We describe a novel biocompatible and biodegradable polycarbonate elastomer (CC-DHA) comprised of dihydroxyacetone, glycerol ethoxylate, and tri(ethylene glycol), for use as a rapidly degrading protective visceral barrier to aid in abdominal closure. Rapid polymer dissolution and metabolism was demonstrated using a murine laparotomy model without evidence of toxicity or intraabdominal scarring. Furthermore, mechanical studies showed the material to be sufficiently puncture resistant and compliant. Overall, this new biomaterial is extraordinary useful as a physical barrier to prevent inadvertent bowel injury during fascial closure, with the potential for wider application across a variety of medical and surgical applications. PMID- 28576714 TI - Alginate microbeads are coagulation compatible, while alginate microcapsules activate coagulation secondary to complement or directly through FXII. AB - : Alginate microspheres are presently under evaluation for future cell-based therapy. Their ability to induce harmful host reactions needs to be identified for developing the most suitable devices and efficient prevention strategies. We used a lepirudin based human whole blood model to investigate the coagulation potentials of alginate-based microspheres: alginate microbeads (Ca/Ba Beads), alginate poly-l-lysine microcapsules (APA and AP microcapsules) and sodium alginate-sodium cellulose sulfate-poly(methylene-co-cyanoguanidine) microcapsules (PMCG microcapsules). Coagulation activation measured by prothrombin fragments 1+2 (PTF1.2) was rapidly and markedly induced by the PMCG microcapsules, delayed and lower induced by the APA and AP microcapsules, and not induced by the Ca/Ba Beads. Monocytes tissue factor (TF) expression was similarly activated by the microcapsules, whereas not by the Ca/Ba Beads. PMCG microcapsules-induced PTF1.2 was abolished by FXII inhibition (corn trypsin inhibitor), thus pointing to activation through the contact pathway. PTF1.2 induced by the AP and APA microcapsules was inhibited by anti-TF antibody, pointing to a TF driven coagulation. The TF induced coagulation was inhibited by the complement inhibitors compstatin (C3 inhibition) and eculizumab (C5 inhibition), revealing a complement-coagulation cross-talk. This is the first study on the coagulation potentials of alginate microspheres, and identifies differences in activation potential, pathways and possible intervention points. STATEMENT OF SIGNIFICANCE: Alginate microcapsules are prospective candidate materials for cell encapsulation therapy. The material surface must be free of host cell adhesion to ensure free diffusion of nutrition and oxygen to the encapsulated cells. Coagulation activation is one gateway to cellular overgrowth through deposition of fibrin. Herein we used a physiologically relevant whole blood model to investigate the coagulation potential of alginate microcapsules and microbeads. The coagulation potentials and the pathways of activation were depending on the surface properties of the materials. Activation of the complement system could also be involved, thus emphasizing a complement-coagulation cross-talk. Our findings points to complement and coagulation inhibition as intervention point for preventing host reactions, and enhance functional cell-encapsulation devices. PMID- 28576719 TI - Phenolic derivatives from Blaps japanensis and their biological evaluation. AB - This study was designed to characterize compounds from two thousands of insects of Blaps japanensis. With this purpose, pipajiains A-C (1-3), three novel phenolic derivatives, pipajiains D (4) and E (5), two new natural occurring compounds, and four known substances were isolated thereof. Their structures were identified by spectroscopic methods. Biological activities of all these compounds towards EV71, tuberculosis, COX-2, ROCK1/2, and JAK3 kinases were evaluated. PMID- 28576718 TI - Effect of altered haemodynamics on the developing mitral valve in chick embryonic heart. AB - Intracardiac haemodynamics is crucial for normal cardiogenesis, with recent evidence showing valvulogenesis is haemodynamically dependent and inextricably linked with shear stress. Although valve anomalies have been associated with genetic mutations, often the cause is unknown. However, altered haemodynamics have been suggested as a pathogenic contributor to bicuspid aortic valve disease. Conversely, how abnormal haemodynamics impacts mitral valve development is still poorly understood. In order to analyse altered blood flow, the outflow tract of the chick heart was constricted using a ligature to increase cardiac pressure overload. Outflow tract-banding was performed at HH21, with harvesting at crucial valve development stages (HH26, HH29 and HH35). Although normal valve morphology was found in HH26 outflow tract banded hearts, smaller and dysmorphic mitral valve primordia were seen upon altered haemodynamics in histological and stereological analysis at HH29 and HH35. A decrease in apoptosis, and aberrant expression of a shear stress responsive gene and extracellular matrix markers in the endocardial cushions were seen in the chick HH29 outflow tract banded hearts. In addition, dysregulation of extracellular matrix (ECM) proteins fibrillin-2, type III collagen and tenascin were further demonstrated in more mature primordial mitral valve leaflets at HH35, with a concomitant decrease of ECM cross-linking enzyme, transglutaminase-2. These data provide compelling evidence that normal haemodynamics are a prerequisite for normal mitral valve morphogenesis, and abnormal blood flow could be a contributing factor in mitral valve defects, with differentiation as a possible underlying mechanism. PMID- 28576720 TI - Pocahemiketals A and B, two new hemiketals with unprecedented sesquiterpenoid skeletons from Pogostemon cablin. AB - Pocahemiketals A and B (1 and 2), two novel hemiketal sesquiterpenoids with unprecedented skeletons, were isolated from the essential oil of the aerial parts of Pogostemon cablin. In addition to a bicyclo[3.2.1]-carbon core, 1 and 2 possessed a hemiketal alpha,beta-unsaturated-gamma-lactone moiety. Their structures were determined by extensive spectroscopic analysis, electronic circular dichroism calculation, and single-crystal X-ray diffraction. Compound 2 exhibited significant vasorelaxant activity against phenylephrine-induced contraction of a rat aorta ring with the EC50 value of 16.32MUM. PMID- 28576721 TI - Novel hybrids of natural beta-elemene bearing isopropanolamine moieties: Synthesis, enhanced anticancer profile, and improved aqueous solubility. AB - A series of novel beta-elemene isopropanolamine derivatives were synthesized and evaluated for their antitumor activity. The results indicated that all of the compounds showed stronger antiproliferative activities than beta-elemene as well as improved aqueous solubility. In particular dimer 6q showed the strongest cytotoxicity against four tumor cell lines (SGC-7901, HeLa, U87 and A549) with IC50 values ranging from 4.37 to 10.20MUM. Moreover, combination of 6q with cisplatin exhibited a synergistic effect on these cell lines with IC50 values ranging from 1.21 to 2.94MUM, and reversed the resistance of A549/DPP cells with an IC50 value of 2.52MUM. The mechanism study revealed that 6q caused cell cycle arrest at the G2 phase and induced apoptosis of SGC-7901 cells through a mitochondrial-dependent apoptotic pathway. Further in vivo study in H22 liver cancer xenograft mouse model validated the antitumor activity of 6q with a tumor inhibitory ratio (TIR) of 60.3%, which was higher than that of beta-elemene (TIR, 49.1%) at a dose of 60mg/kg. Altogether, the potent antitumor activity of 6qin vitro and in vivo warranted further preclinical investigation for potential anticancer chemotherapy. PMID- 28576722 TI - A novel dihydroxylated derivative of artemisinin from microbial transformation. AB - Microbial transformation of artemisinin (1) by Cunninghamella elegans was investigated. Four isolated products were identified as 6beta-hydroxyartemisinin (2), 7alpha-hydroxyartemisinin (3), 7beta-hydroxyartemisinin (4), and 6beta,7alpha-dihydroxyartemisinin (5). The structures were elucidated by spectroscopic and X-ray crystallographic analysis. Product 5 is a novel compound and being reported here for the first time. It features two hydroxyl groups in its structure, and this is the first report on dihydroxylation of the artemisinin skeleton. Quantitative structure-activity relationship and molecular modeling studies indicate the modification of artemisinin skeleton will increase antimalarial activity and water solubility. The chemical syntheses of artemisinin derivatives at C6 or C7 position are impossible due to the lack of functional groups. 6beta,7alpha-Dihydroxyartemisinin is hydroxylated at both 6beta- and 7alpha-positions of artemisinin skeleton at the same time. Therefore, this new compound would be a good scaffold for further structural modification in the search for more potent antimalarial drugs. PMID- 28576723 TI - Four new bi-phenylethylchromones from artificial agarwood. AB - Four new bi-phenylethylchromones (1-4) were isolated from the EtOAc extract of artificial agarwood induced by holing method originating from Aquilaria sinensis (Lour.) Gilg. The structures of new compounds were unambiguously elucidated by one- and two-dimensional NMR and HRESIMS measurements, and the absolute configuration was determined by analysis of circular dichroism (CD) spectra. All compounds were tested for acetylcholinesterase (AChE) inhibitory activity using modified Ellman's colorimetric method and alpha-glucosidase inhibitory activity using PNPG method. Compounds 2-4 exhibited different levels of inhibitory activity against AChE with the inhibition ratios in the range of 10-45%. However, none of the compounds was active against the alpha-glucosidase. PMID- 28576724 TI - Interaction of GABA and norepinephrine in the lateral division of the bed nucleus of the stria terminals in anesthetized rat, correlating single-unit and cardiovascular responses. AB - The bed nucleus of the stria terminalis (BST) consists of multiple anatomically distinct nuclei. The lateral division, which receives dense noradrenergic innervation, has been implicated in cardiovascular regulation and modulation of responses to stress. This study is performed to identify the cardiovascular and single-unit responses of the lateral BST to norepinephrine (NE), involved adrenoceptors, and possible interaction with GABAergic system of the BST in urethane-anesthetized rats. NE, adrenoreceptor antagonists, and GABAA antagonist were microinjected into the lateral division of BST, while arterial pressure (AP), heart rate (HR), and single-unit responses were simultaneously recorded. NE microinjected into the lateral division of BST produced depressor and bradycardic responses. The decrease in AP and HR to NE was blocked by prazosin, an alpha1 adrenoreceptor antagonist, but not by yohimbine, an alpha2 antagonist. Furthermore, injections of the GABAA receptor antagonist, bicuculline methiodide (BMI), into the lateral BST abolished the NE-induced depressor and bradycardic responses. We also observed single-unit responses consisting of excitatory and inhibitory responses correlated with cardiovascular function to the microinjection of NE. In conclusion, these data provide the first evidence that microinjection of NE in the lateral division of BST produces depressor and bradycardic responses in urethane-anesthetized rat. The depressor and bradycardiac response are mediated by local alpha1- but not alpha2-adrenoceptors. alpha1-AR activates the GABAergic system within the BST, which in turn produces depressor and bradycardic responses. PMID- 28576725 TI - Imaging of glial cell morphology, SOD1 distribution and elemental composition in the brainstem and hippocampus of the ALS hSOD1G93A rat. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor and cognitive domains of the CNS. Mutations in the Cu,Zn-superoxide dismutase (SOD1) cause 20% of familial ALS and provoke formation of intracellular aggregates and copper and zinc unbinding, leading to glial activation and neurodegeneration. Therefore, we investigated glial cell morphology, intracellular SOD1 distribution, and elemental composition in the brainstem and hippocampus of the hSOD1G93A transgenic rat model of ALS. Immunostaining for astrocytes, microglia and SOD1 revealed glial proliferation and progressive tissue accumulation of SOD1 in both brain regions of ALS rats starting already at the presymptomatic stage. Glial cell morphology analysis in the brainstem of ALS rats revealed astrocyte activation occurring before disease symptoms onset, followed by activation of microglia. Hippocampal ALS astrocytes exhibited an identical reactive profile, while microglial morphology was unchanged. Additionally, ALS brainstem astrocytes demonstrated progressive SOD1 accumulation in the cell body and processes, while microglial SOD1 levels were reduced and its distribution limited to distal cell processes. In the hippocampus both glial cell types exhibited SOD1 accumulation in the cell body. X-ray fluorescence imaging revealed decreased P and increased Ca, Cl, K, Ni, Cu and Zn in the brainstem, and higher levels of Cl, Ni and Cu, but lower levels of Zn in the hippocampus of symptomatic ALS rats. These results bring new insights into the glial response during disease development and progression in motor as well as in non-motor CNS structures, and indicate disturbed tissue elemental homeostasis as a prominent hallmark of disease pathology. PMID- 28576726 TI - Nicotine-induced and D1-receptor-dependent dendritic remodeling in a subset of dorsolateral striatum medium spiny neurons. AB - Nicotine is one of the most addictive substances known, targeting multiple memory systems, including the ventral and dorsal striatum. One form of neuroplasticity commonly associated with nicotine is dendrite remodeling. Nicotine-induced dendritic remodeling of ventral striatal medium spiny neurons (MSNs) is well documented. Whether MSN dendrites in the dorsal striatum undergo a similar pattern of nicotine-induced structural remodeling is unknown. A morphometric analysis of Golgi-stained MSNs in rat revealed a natural asymmetry in dendritic morphology across the mediolateral axis, with larger, more complex MSNs found in the dorsolateral striatum (DLS). Chronic nicotine produced a lasting (at least 21day) expansion in the dendritic complexity of MSNs in the DLS, but not dorsomedial striatum (DMS). Given prior evidence that MSN subtypes can be distinguished based on dendritic morphology, MSNs were segregated into morphological subpopulations based on the number of primary dendrites. Analysis of these subpopulations revealed that DLS MSNs with more primary dendrites were selectively remodeled by chronic nicotine exposure and remodeling was specific to the distal-most portions of the dendritic arbor. Co-administration of the dopamine D1 receptor (D1R) antagonist SCH23390 completely reversed the selective effects of nicotine on DLS MSN dendrite morphology, supporting a causal role for dopamine signaling at D1 receptors in nicotine-induced dendrite restructuring. Considering the functional importance of the DLS in shaping and expressing habitual behavior, these data support a model in which nicotine induces persistent and selective changes in the circuit connectivity of the DLS that may promote and sustain addiction-related behavior. PMID- 28576727 TI - Reconfiguration of dominant coupling modes in mild traumatic brain injury mediated by delta-band activity: A resting state MEG study. AB - During the last few years, rich-club (RC) organization has been studied as a possible brain-connectivity organization model for large-scale brain networks. At the same time, empirical and simulated data of neurophysiological models have demonstrated the significant role of intra-frequency and inter-frequency coupling among distinct brain areas. The current study investigates further the importance of these couplings using recordings of resting-state magnetoencephalographic activity obtained from 30 mild traumatic brain injury (mTBI) subjects and 50 healthy controls. Intra-frequency and inter-frequency coupling modes are incorporated in a single graph to detect group differences within individual rich club subnetworks (type I networks) and networks connecting RC nodes with the rest of the nodes (type II networks). Our results show a higher probability of inter frequency coupling for (delta-gamma1), (delta-gamma2), (theta-beta), (theta gamma2), (alpha-gamma2), (gamma1-gamma2) and intra-frequency coupling for (gamma1 gamma1) and (delta-delta) for both type I and type II networks in the mTBI group. Additionally, mTBI and control subjects can be correctly classified with high accuracy (98.6%), whereas a general linear regression model can effectively predict the subject group using the ratio of type I and type II coupling in the (delta, theta), (delta, beta), (delta, gamma1), and (delta, gamma2) frequency pairs. These findings support the presence of an RC organization simultaneously with dominant frequency interactions within a single functional graph. Our results demonstrate a hyperactivation of intrinsic RC networks in mTBI subjects compared to controls, which can be seen as a plausible compensatory mechanism for alternative frequency-dependent routes of information flow in mTBI subjects. PMID- 28576728 TI - Cellular circadian oscillators in the suprachiasmatic nucleus remain coupled in the absence of connexin-36. AB - In mammals, the master circadian clock resides in the suprachiasmatic nucleus (SCN). The SCN is characterized by robust circadian oscillations of clock gene expression and neuronal firing. The synchronization of circadian oscillations among individual cells in the SCN is attributed to intercellular coupling. Previous studies have shown that gap junctions, specifically those composed of connexin-36 (Cx36) subunits, are required for coupling of electrical firing among SCN neurons at a time scale of milliseconds. However, it remains unknown whether Cx36 gap junctions also contribute to coupling of circadian (~24h) rhythms of clock gene expression. Here, we investigated circadian expression patterns of the clock gene Period 2 (Per2) in the SCN of Cx36-deficient mice using luminometry and single-cell bioluminescence imaging. Surprisingly, we found that synchronization of circadian PER2 expression rhythms is maintained in SCN explants from Cx36-deficient mice. Since Cx36 expression levels change with age, we also tested circadian running-wheel behavior of juvenile (3-4weeks old) and adult (9-30weeks old) Cx36-deficient mice. We found that impact of connexin-36 expression on circadian behavior changes greatly during postnatal development. However, consistent with the intact synchrony among SCN cells in cultured explants, Cx36-deficient mice had intact locomotor circadian rhythms, although adults displayed a lengthened period in constant darkness. Our data indicate that even though Cx36 may be required for electrical coupling of SCN cells, it does not affect coupling of molecular clock gene rhythms. Thus, electrical coupling of neurons and coupling of circadian clock gene oscillations can be regulated independently in the SCN. PMID- 28576729 TI - Afferent synaptogenesis between ectopic hair-cell-like cells and neurites of spiral ganglion induced by Atoh1 in mammals in vitro. AB - Newly formed ectopic hair-cell-like cells (EHCLCs) induced by overexpression of atonal homolog 1 (Atoh1) in vitro were found to possess features of endogenous hair cells (HCs) in previous reports and in the present study. However, limited information is available regarding whether EHCLCs and native spiral ganglion neurons (SGNs) form afferent synapses, which are important for the restoration of hearing. In the current study, we focused on the afferent synaptogenesis between EHCLCs and SGN-derived dendrites. Cochlear explants of auditory epithelia with native SGNs retained were cultured in vitro, and human adenovirus serotype 5 (Ad5) vectors encoding Atoh1 were used to overexpress Atoh1 and induce EHCLCs. We observed that the neurites of the original SGNs extended toward the lesser epithelial ridge (LER) and innervated the EHCLCs. Immunohistochemical analyses revealed the expression of presynaptic ribbon C-terminal-binding protein 2 (CtBP2) and postsynaptic density protein (PSD)-95 in the nerve endings of SGN derived neurons adjacent to EHCLCs. PSD-95 was located directly opposite CtBP2 positive puncta in the terminals of branches of SGNs, demonstrating that the neurites of SGNs formed afferent-like synaptic connections with EHCLCs. However, the expression of glutamate receptor type 2 (GluR2) could not be detected in the terminals of branches of SGNs surrounding EHCLCs. In addition, we found that the presynaptic ribbon (CtBP2) formation in EHCLCs preceded neural innervation. Furthermore, CtBP2-positive puncta increased and then decreased in EHCLCs, similar to the changes observed in endogenous HCs in terms of their number and distribution. Our finding of the generation of cochlear afferent synapses between EHCLCs and original SGNs will lay the foundation for regenerative approaches to restoring hearing after hair cell loss. PMID- 28576730 TI - Short-term deep brain stimulation of the thalamic reticular nucleus modifies aberrant oscillatory activity in a neurodevelopment model of schizophrenia. AB - Dysfunction of thalamo-cortical networks involving particularly the thalamic reticular nucleus (TRN) is implicated in schizophrenia. In the neonatal ventral hippocampal lesion (NVHL), a heuristic animal model of schizophrenia, brain oscillation changes similar to those of schizophrenic patients have been reported. The aim of this study was to analyze the effects of short-term deep brain stimulation (DBS) in the thalamic reticular nucleus on electroencephalographic (EEG) activity in the NVHL. Male and female Sprague Dawley rats were used and the model was prepared by excitotoxicity damage of the ventral hippocampus on postnatal day 7 (PD-7). Chronic bilateral stainless steel electrodes were implanted in the TRN, thalamic dorsomedial nucleus and prelimbic area at PD-90. Rats were classified as follows: sham and NVHL groups, both groups received bilateral DBS in the TRN for one hour (100Hz, 100us pulses, 200uA). All animals showed a sudden behavioral arrest accompanied by widespread symmetric bilateral spike-wave discharges, this activity was affected by DBS-TRN. Additionally, the power spectra of 0.5-100Hz and the coherence of 0.5-4.5 and 35 55Hz frequencies were modified by DBS-TRN. Our results suggest that DBS in the TRN may modify functional connectivity between different parts of the thalamo cortical network. Additionally, our findings may suggest a beneficial effect of DBS-TRN on some preclinical aberrant oscillatory activities in a neurodevelopmental model of schizophrenia. PMID- 28576731 TI - Quantify neuromagnetic network changes from pre-ictal to ictal activities in absence seizures. AB - OBJECTIVE: The cortico-thalamo-cortical network plays a key role in childhood absence epilepsy (CAE). However, the exact interaction between the cortex and the thalamus remains incompletely understood. This study aimed to investigate the dynamic changes of frequency-dependent neural networks during the initialization of absence seizures. METHODS: Magnetoencephalography data from 14 patients with CAE were recorded during and between seizures at a sampling rate of 6000Hz and analyzed in seven frequency bands. Neuromagnetic sources were volumetrically scanned with accumulated source imaging. Effective connectivity networks of the entire brain, including the cortico-thalamo-cortical network, were evaluated at the source level through Granger causality analysis. RESULTS: The low-frequency (1-80Hz) activities showed significant frontal cortical and parieto-occipito temporal junction source localization around seizures. The high-frequency (80 250Hz) oscillations showed predominant activities consistently localized in deep brain areas and medial frontal cortex. The increased cortico-thalamic effective connectivity was observed around seizures in both low- and high-frequency ranges. The direction was predominantly from the cortex to the thalamus at the early time, although the cortex that drove connectivity varied among subjects. CONCLUSIONS: The cerebral cortex plays a key role in driving the cortico-thalamic connections at the early portion of the initialization of absence seizures. The oscillatory activities in the thalamus could be triggered by networks from various regions in the cortex. SIGNIFICANCE: The dynamic changes of neural network provide evidences that absence seizures are probably resulted from cortical initialized cortico-thalamic network. PMID- 28576732 TI - Forskolin and protein kinase inhibitors differentially affect hair cell potassium currents and transmitter release at the cytoneural junction in the isolated frog labyrinth. AB - The post-transductional elaboration of sensory input at the frog semicircular canal has been studied by correlating the effects of drugs that interfere with phosphorylation processes on: (i) potassium conductances in isolated hair cell and (ii) transmitter release at the cytoneural junction in the intact labyrinth. At hair cells, delayed potassium currents (IKD) undergo voltage- and time dependent inactivation; inactivation removal requires ATP, is sensitive to kinase blockade, but is unaffected by exogenous application of cyclic nucleotides. We report here that forskolin, an activator of endogenous adenylyl cyclase, enhances IKD inactivation removal in isolated hair cells, but produces an overall decrease in IKD amplitude consistent with the direct blocking action of the drug on several families of K channels. In the intact labyrinth, forskolin enhances transmitter release, consistent with such depression of K conductances. Kinase blockers - H-89 and KT5823 - have been shown to reduce IKD inactivation removal and IKD amplitude at isolated hair cells. In the labyrinth, the effects of these drugs on junctional activity are quite variable, with predominant inhibition of transmitter release, rather than the enhancement expected from the impairment of K currents. The overall action of forskolin and kinase inhibitors on K conductances is similar (depression), but they have opposite effects on transmitter release: this indicates that some intermediate steps between the bioelectric control of hair cell membrane potential and transmitter release are affected in opposite ways and therefore are presumably regulated by protein phosphorylation. PMID- 28576733 TI - Neuronal zinc-alpha2-glycoprotein is decreased in temporal lobe epilepsy in patients and rats. AB - Zinc-alpha2-glycoprotein (ZAG) is a 42-kDa protein encoded by the AZGP1 gene that is known as a lipid mobilizing factor and is highly homologous to major histocompatibility complex class I family molecules. Recently, transcriptomic research has shown that AZGP1 expression is reduced in the brain tissue of epilepsy patients. However, the cellular distribution and biological role of ZAG in the brain and epilepsy are unclear. Patients with refractory temporal lobe epilepsy (TLE) and brain trauma were included in this study, and pentylenetetrazole (PTZ)-kindled rats were also used. The existence and level of ZAG in the brain were identified using immunohistochemistry, double-labeled immunofluorescence and western blot, and the expression level of AZGP1 mRNA was determined with quantitative real-time polymerase chain reaction (qrt-PCR). To explore the potential biological role of ZAG in the brain, co-immunoprecipitation (Co-IP) of phosphorylated ERK (p-ERK), TGF-beta1 and ZAG was also performed. ZAG was found in the cytoplasm of neurons in brain tissue from both patients and rats. The levels of AZGP1 mRNA and ZAG were lower in refractory TLE patients and PTZ-kindled rats than in controls. In addition, the ZAG level decreased as PTZ kindling continued. Co-IP identified direct binding between p-ERK, TGF-beta1 and ZAG. ZAG was found to be synthesized in neurons, and both the AZGP1 mRNA and ZAG protein levels were decreased in epilepsy patients and rat models. The reduction in ZAG may participate in the pathogenesis and pathophysiology of epilepsy by interacting with p-ERK and TGF-beta1, promoting inflammation, regulating the metabolism of ketone bodies, or affecting other epilepsy-related molecules. PMID- 28576735 TI - The Syk Tyrosine Kinase Is Required for Skin Inflammation in an In Vivo Mouse Model of Epidermolysis Bullosa Acquisita. AB - The inflammatory form of epidermolysis bullosa acquisita is caused by autoantibodies against type VII collagen (C7), a component of the dermal epidermal junction. We have previously shown that myeloid Src family kinases mediate skin inflammation triggered by anti-C7 antibodies. Here we identify the Syk tyrosine kinase as a critical component of autoantibody-induced skin inflammation downstream of Src family kinases. Immobilized C7-anti-C7 immune complexes triggered neutrophil activation and Syk phosphorylation in a Src family kinase-dependent manner. Bone marrow chimeric mice lacking Syk in their hematopoietic compartment were completely protected from skin inflammation triggered by anti-C7 antibodies despite normal circulating anti-C7 levels. Syk deficiency abrogated the accumulation of CXCL2, IL-1beta, and leukotriene B4 at the site of inflammation and resulted in defective in vivo neutrophil recruitment. Syk-/- neutrophils had a normal intrinsic migratory capacity but failed to release CXCL2 or leukotriene B4 upon activation by immobilized C7-anti C7 immune complexes, indicating a role for Syk in the amplification of the inflammation process. These results identify Syk as a critical component of skin inflammation in a mouse model of epidermolysis bullosa acquisita and as a potential therapeutic target in epidermolysis bullosa acquisita and other mechanistically related inflammatory skin diseases such as bullous pemphigoid. PMID- 28576734 TI - Protocol for the MATCH study (Mindfulness and Tai Chi for cancer health): A preference-based multi-site randomized comparative effectiveness trial (CET) of Mindfulness-Based Cancer Recovery (MBCR) vs. Tai Chi/Qigong (TCQ) for cancer survivors. AB - PURPOSE: A growing number of cancer survivors suffer high levels of distress, depression and stress, as well as sleep disturbance, pain and fatigue. Two different mind-body interventions helpful for treating these problems are Mindfulness-Based Cancer Recovery (MBCR) and Tai Chi/Qigong (TCQ). However, while both interventions show efficacy compared to usual care, they have never been evaluated in the same study or directly compared. This study will be the first to incorporate innovative design features including patient choice while evaluating two interventions to treat distressed cancer survivors. It will also allow for secondary analyses of which program best targets specific symptoms in particular groups of survivors, based on preferences and baseline characteristics. METHODS AND SIGNIFICANCE: The design is a preference-based multi-site randomized comparative effectiveness trial. Participants (N=600) with a preference for either MBCR or TCQ will receive their preferred intervention; while those without a preference will be randomized into either intervention. Further, within the preference and non-preference groups, participants will be randomized into immediate intervention or wait-list control. Total mood disturbance on the Profile of mood states (POMS) post-intervention is the primary outcome. Other measures taken pre- and post-intervention and at 6-month follow-up include quality of life, psychological functioning, cancer-related symptoms and physical functioning. Exploratory analyses investigate biomarkers (cortisol, cytokines, blood pressure/Heart Rate Variability, telomere length, gene expression), which may uncover potentially important effects on key biological regulatory and antineoplastic functions. Health economic measures will determine potential savings to the health system. PMID- 28576737 TI - Nrf2 Promotes Keratinocyte Proliferation in Psoriasis through Up-Regulation of Keratin 6, Keratin 16, and Keratin 17. AB - Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation of epidermis. Although hyperproliferation-associated keratins K6, K16, and K17 are considered to be the hallmarks of psoriasis, the molecular basis underlying the overexpression of these keratins remains unclear. Nrf2 regulates cell proliferation. Therefore, we investigated whether Nrf2 regulates keratinocyte proliferation via promoting expression of K6, K16, and K17 in psoriasis. We initially found that psoriatic epidermis exhibited elevated expression of Nrf2. Furthermore, Nrf2 promoted expression of K6, K16, and K17 in both HaCaT cells and primary human keratinocytes by binding to the ARE domains located in the promoter of these genes. Additionally, upon stimulation with IL-17 or IL-22, Nrf2 translocated to the nucleus and initiated expression of targeted keratins. In mice of imiquimod-induced psoriasis-like dermatitis, topical application of Nrf2 small interfering RNA alleviated the epidermal hyperplasia with reduced expression of these keratins. More importantly, Nrf2 promoted the proliferation of human keratinocytes through up-regulation of K6, K16, or K17. These data suggested that inflammatory cytokines promoted Nrf2 nuclear translocation in psoriatic epidermis, which led to elevated expression of K6, K16, and K17, thus promoting keratinocyte proliferation and contributing to the pathogenesis of psoriasis. PMID- 28576736 TI - Oral Vitamin D Rapidly Attenuates Inflammation from Sunburn: An Interventional Study. AB - The diverse immunomodulatory effects of vitamin D are increasingly being recognized. However, the ability of oral vitamin D to modulate acute inflammation in vivo has not been established in humans. In a double-blinded, placebo controlled interventional trial, 20 healthy adults were randomized to receive either placebo or a high dose of vitamin D3 (cholecalciferol) one hour after experimental sunburn induced by an erythemogenic dose of UVR. Compared with placebo, participants receiving vitamin D3 (200,000 international units) demonstrated reduced expression of proinflammatory mediators tumor necrosis factor-alpha (P = 0.04) and inducible nitric oxide synthase (P = 0.02) in skin biopsy specimens 48 hours after experimental sunburn. A blinded, unsupervised hierarchical clustering of participants based on global gene expression profiles revealed that participants with significantly higher serum vitamin D3 levels after treatment (P = 0.007) demonstrated increased skin expression of the anti inflammatory mediator arginase-1 (P = 0.005), and a sustained reduction in skin redness (P = 0.02), correlating with significant expression of genes related to skin barrier repair. In contrast, participants with lower serum vitamin D3 levels had significant expression of proinflammatory genes. Together the data may have broad implications for the immunotherapeutic properties of vitamin D in skin homeostasis, and implicate arginase-1 upregulation as a previously unreported mechanism by which vitamin D exerts anti-inflammatory effects in humans. PMID- 28576739 TI - mcr-1 plasmid-mediated colistin resistance gene detection in an Enterobacter cloacae clinical isolate in France. PMID- 28576738 TI - Monoallelic Large Intragenic KRT5 Deletions Account for Genetically Unsolved Cases of Epidermolysis Bullosa Simplex. PMID- 28576740 TI - Draft genome sequence of a Kluyvera intermedia isolate from a patient with a pancreatic abscess. AB - The genus Kluyvera comprises potential pathogens that can cause many infections. This study reports a Kluyvera intermedia strain (FOSA7093) from a pancreatic cyst specimen from a long-term hospitalised patient. Whole-genome sequencing (WGS) of the K. intermedia isolate was performed and the strain was reported as sensitive to Danish-registered antibiotics although it had a fosA-like gene in the genome. There were nine contigs that aligned to a plasmid, and these contigs contained several heavy metal resistance gene homologues. Furthermore, a prophage was discovered in the genome. WGS represents an efficient tool for monitoring Kluyvera spp. and its role as a reservoir of multidrug resistance. Therefore, this susceptible K. intermedia genome has many characteristics that allow comparison of resistant K. intermedia that might be discovered in the future. PMID- 28576741 TI - Multilocus sequence typing of carbapenemase-producing Enterobacter cloacae bloodstream isolates between 2002 and 2013 in a Taiwanese university hospital. PMID- 28576742 TI - Draft genome sequence of a CTX-M-15-producing endophytic Klebsiella pneumoniae ST198 isolate from commercial lettuce. AB - CTX-M-15-producing Klebsiella pneumoniae is one of the leading causes of hospital acquired infections globally. In this study, we present the draft genome sequence of the first CTX-M-15-producing endophytic K. pneumoniae strain, belonging to sequence type 198 (ST198) and isolated from commercial lettuce, which can be used as a reference sequence for comparative analysis with clinical and environmental strains of K. pneumoniae. PMID- 28576743 TI - Internalization and localization of basal insulin peglispro in cells. AB - BACKGROUND: Basal insulin peglispro (BIL) is a novel, PEGylated insulin lispro that has a large hydrodynamic size compared with insulin lispro. It has a prolonged duration of action, which is related to a delay in insulin absorption and a reduction in clearance. Given the different physical properties of BIL compared with native insulin and insulin lispro, it is important to assess the cellular internalization characteristics of the molecule. METHODS AND MATERIALS: Using immunofluorescent confocal imaging, we compared the cellular internalization and localization patterns of BIL, biosynthetic human insulin, and insulin lispro. We assessed the effects of BIL on internalization of the insulin receptor (IR) and studied cellular clearance of BIL. RESULTS: Co-localization studies using antibodies to either insulin or PEG, and the early endosomal marker EEA1 showed that the overall internalization and subcellular localization pattern of BIL was similar to that of human insulin and insulin lispro; all were rapidly internalized and co-localized with EEA1. During ligand washout for 4 h, concomitant loss of insulin, PEG methoxy group, and PEG backbone immunostaining was observed for BIL, similar to the loss of insulin immunostaining observed for insulin lispro and human insulin. Co-localization studies using an antibody to the lysosomal marker LAMP1 did not reveal evidence of lysosomal localization for insulin lispro, human insulin, BIL, or PEG using either insulin or PEG immunostaining reagents. BIL and human insulin both induced rapid phosphorylation and internalization of human IR. CONCLUSIONS: Our findings show that treatment of cells with BIL stimulates internalization and localization of IR to early endosomes. Both the insulin and PEG moieties of BIL undergo a dynamic cellular process of rapid internalization and transport to early endosomes followed by loss of cellular immunostaining in a manner similar to that of insulin lispro and human insulin. The rate of clearance for the insulin lispro portion of BIL was slower than the rate of clearance for human insulin. In contrast, the PEG moiety of BIL can recycle out of cells. PMID- 28576744 TI - Jak Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition. AB - The effects of Jak Stat signaling and the persistent activation of Stat3 and Stat5 on tumor cell survival, proliferation and invasion have made the Jak Stat pathway a favorite target for drug development and cancer therapy. This notion was strengthened when additional biological functions of Stat signaling in cancer and their roles in the regulation of cytokine dependent inflammation and immunity in the tumor microenvironment were discovered. Stats act not only as transcriptional inducers, but affect gene expression via epigenetic modifications, induce epithelial mesenchymal transition, generate a pro tumorigenic microenvironment, promote cancer stem cell self-renewal and differentiation, and help to establish the pre-metastatic niche formation. The effects of Jak Stat inhibition on the suppression of pro-inflammatory responses appears most promising and could become a strategy in the prevention of tumor progression. The direct and mediated mechanisms of Jak Stat signaling in and on tumors cells, the interactions with other signaling pathways and transcription factors and the targeting of the functionally crucial secondary modifications of Stat molecules suggest novel approaches to the future development of Jak Stat based cancer therapeutics. PMID- 28576745 TI - Lung Adenocarcinoma Manifesting as Pure Ground-Glass Nodules: Correlating CT Size, Volume, Density, and Roundness with Histopathologic Invasion and Size. AB - OBJECTIVES: The aims of this study were to quantify the relationship between computed tomography (CT) size, volume, density, and roundness of lung adenocarcinomas (ACs) manifesting as pure ground-glass nodules (pGGNs) on CT images and to correlate these parameters with histologic features of invasiveness. METHODS: From 2005 to 2015, 63 ACs manifesting as pGGNs on CT images were surgically resected at our institution. CT size was measured, and roundness, volumes and densities were computed. CT parameters were correlated to age and sex, as well as to size and number of invasive foci and histologic AC subcategories. Correlations were quantified with Spearman rank correlation coefficients. RESULTS: Of 63 ACs, 28 (44%) were AC in situ, 25 (40%) were minimally invasive AC, and 10 (16%) were invasive AC. Six of 35 nodules with invasive foci (17%) were smaller than 10 mm. Correlations between age and CT size, volume, density, and roundness were not significant (range r = -0.061 to 0.144, p = 0.285 to 0.902). Correlations between size and number of invasive foci with CT size (r = 0.417, p < 0.001 and r = 0.389, p = 0.003, respectively) were similar to the correlations with volume (r = 0.401, p = 0.001 and r = 0.350, p = 0.005, respectively) and stronger than the correlation with density (r = 0.237, p = 0.062 and r = 0.222, p = 0.081, respectively) and roundness (r = 0.059, p = 0.648 and r = -0.030, p = 0.831, respectively). CONCLUSIONS: In ACs manifesting as pGGNs on CT images, nodule size is positively related to size and number of histologically invasive foci. However, invasive foci can be found in pGGNs smaller than 10 mm. Measuring volume and density of pGGNs provides no advantage over two-dimensional size measurements, which appear sufficient for risk estimation in clinical practice. PMID- 28576746 TI - A Higher Proportion of the EGFR T790M Mutation May Contribute to the Better Survival of Patients with Exon 19 Deletions Compared with Those with L858R. AB - INTRODUCTION: Increasing evidence has demonstrated that exon 19 deletions (Del19) and L858R mutation in EGFR have different prognostic and predictive roles in NSCLC. We aimed to investigate whether these two mutations produced differences in mechanisms of resistance to EGFR tyrosine kinase inhibitors. METHODS: Consecutive patients with advanced EGFR-mutant NSCLC who acquired resistance to EGFR tyrosine kinase inhibitors and underwent postprogression biopsy were enrolled. Mechanisms including T790M mutation, mesenchymal-epithelial transition proto-oncogene (MET) amplification, and histological transformation, as well as KRAS, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation, and anaplastic lymphoma receptor tyrosine kinase gene (ALK) fusion, were analyzed. RESULTS: The prevalence of T790M mutation was significantly higher in the Del19 subgroup than that in L858R subgroup (50.4% versus 36.5%, p = 0.043). Apart from this, there was no difference in other mechanisms including MET amplification and histological transformation. The median overall survival (OS) of patients with T790M mutation was 36.0 months (95% confidence interval [CI]: 30.9-41.2), which was significantly longer than the 26.5 months (95% CI: 24.0-29.0) in MET-positive patients, 19.7 months (95% CI: 18.2-21.2) in patients with histological transformation, and 23.0 months (95% CI: 17.4-28.6) in the KRAS/PIK3CA/ALK-altered population (p = 0.021). The hazard ratios of the MET-amplification subgroup and subgroup with histological transformation were 1.809-fold and 2.370-fold higher than that in T790M-positive subgroup. The median OS times were months 33.3 (95% CI: 28.9-37.7) in the Del19 subgroup and 26.4 months (95% CI: 23.2-29.6) in the L858R subgroup (p = 0.028). However, in multivariable analysis adjusted for T790M genotype, the EGFR mutation subtype was no longer found to be significant. CONCLUSIONS: Significant OS benefit was observed in patients with T790M mutation, suggesting that a larger proportion of T790M mutation might contribute to the better survival of patients with Del19. PMID- 28576747 TI - Long-term Outcome of Surgery or Stereotactic Radiotherapy for Lung Oligometastases. AB - Local treatment for pulmonary oligometastases (one to five lesions) using metastasectomy or stereotactic ablative radiotherapy (SABR) was investigated in a cohort that received multidisciplinary tumor board-based treatment decisions. The first choice of treatment was surgery; SABR was recommended in cases of adverse clinical factors. Propensity score-adjusted and unadjusted overall survival was the primary end point; local control and time to failure of a local-only treatment strategy were also analyzed. With a minimum follow-up time of 5.8 years, the 5-year overall survival rate was 41% for surgery (n = 68) and 45% for SABR (n = 42). Again not different for the two modalities, 40% of patients were free from failure of a local-only treatment strategy, and 20% were free from any progression at 5 years. The 5-year local control rate was 83% for SABR and 81% for surgery. Despite treatment selection clearly disadvantaging SABR against surgery, even unadjusted outcome was not better when pulmonary oligometastases were surgically removed rather than irradiated. PMID- 28576748 TI - Automatic recognition of symptom severity from psychiatric evaluation records. AB - This paper presents a novel method for automatically recognizing symptom severity by using natural language processing of psychiatric evaluation records to extract features that are processed by machine learning techniques to assign a severity score to each record evaluated in the 2016 RDoC for Psychiatry Challenge from CEGS/N-GRID. The natural language processing techniques focused on (a) discerning the discourse information expressed in questions and answers; (b) identifying medical concepts that relate to mental disorders; and (c) accounting for the role of negation. The machine learning techniques rely on the assumptions that (1) the severity of a patient's positive valence symptoms exists on a latent continuous spectrum and (2) all the patient's answers and narratives documented in the psychological evaluation records are informed by the patient's latent severity score along this spectrum. These assumptions motivated our two-step machine learning framework for automatically recognizing psychological symptom severity. In the first step, the latent continuous severity score is inferred from each record; in the second step, the severity score is mapped to one of the four discrete severity levels used in the CEGS/N-GRID challenge. We evaluated three methods for inferring the latent severity score associated with each record: (i) pointwise ridge regression; (ii) pairwise comparison-based classification; and (iii) a hybrid approach combining pointwise regression and the pairwise classifier. The second step was implemented using a tree of cascading support vector machine (SVM) classifiers. While the official evaluation results indicate that all three methods are promising, the hybrid approach not only outperformed the pairwise and pointwise methods, but also produced the second highest performance of all submissions to the CEGS/N-GRID challenge with a normalized MAE score of 84.093% (where higher numbers indicate better performance). These evaluation results enabled us to observe that, for this task, considering pairwise information can produce more accurate severity scores than pointwise regression - an approach widely used in other systems for assigning severity scores. Moreover, our analysis indicates that using a cascading SVM tree outperforms traditional SVM classification methods for the purpose of determining discrete severity levels. PMID- 28576749 TI - A combinatorial strategy using YAP and pan-RAF inhibitors for treating KRAS mutant pancreatic cancer. AB - KRAS mutation is the most common genetic event in pancreatic cancer. Whereas KRAS itself has proven difficult to inhibit, agents that target key downstream signals of KRAS, such as RAF, are possibly effective for pancreatic cancer treatment. Because selective BRAF inhibitors paradoxically induce downstream signaling activation, a pan-RAF inhibitor, LY3009120 is a better alternate for KRAS-mutant tumor treatment. Here we explored a new combinational strategy using a YAP inhibitor and LY3009120 in pancreatic cancer treatment. We found that reduced YAP expression closely correlates with longer relapse-free and overall survival of patients. Stable knockdown of YAP significantly inhibited pancreatic cancer cell proliferation and tumor growth. In addition, LY3009120 exhibited a dramatically enhanced antitumor effect in combination with YAP knockdown. YAP depletion blocks the activation of a parallel AKT signal pathway after LY3009120 treatment. Finally, combination with a YAP inhibitor, verteporfin, significantly enhanced the antitumor efficacy of LY3009120. Collectively, our results demonstrate that genetic or pharmacological inhibition of YAP can increase sensitivity to LY3009120 in pancreatic cancer through blocking compensatory activation of a parallel AKT signal pathway, thereby validating a combinatorial approach for treating KRAS-mutant pancreatic cancer. PMID- 28576750 TI - BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe. AB - Multidrug resistance (MDR) interferes with the efficiency of chemotherapy. Therefore, developing novel anti-cancer agents that can overcome MDR is necessary. Here, we screened a series of colchicine binding site inhibitors (CBSIs) and found that 5-(3, 4, 5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) displayed potent cytotoxic activity against both A549 and A549/Taxol cells. We further explored the underlying mechanisms and found that BZML caused mitosis phase arrest by inhibiting tubulin polymerization in A549 and A549/Taxol cells. Importantly, BZML was a poor substrate for P-glycoprotein (P gp) and inhibited P-gp function by decreasing P-gp expression at the protein and mRNA levels. Cell morphology changes and the expression of cycle- or apoptosis related proteins indicated that BZML mainly drove A549/Taxol cells to die by mitotic catastrophe (MC), a p53-independent apoptotic-like cell death, whereas induced A549 cells to die by apoptosis. Taken together, our data suggest that BZML is a novel colchicine binding site inhibitor and overcomes MDR in A549/Taxol cells by inhibiting P-gp function and inducing MC. Our study also offers a new strategy to solve the problem of apoptosis-resistance. PMID- 28576751 TI - Targeting of super-enhancers and mutant BRAF can suppress growth of BRAF-mutant colon cancer cells via repression of MAPK signaling pathway. AB - Bromodomain and extra-terminal (BET) inhibitors suppress super-enhancers and show cytotoxicity against multiple types of tumors. However, early clinical trials with BET inhibitors showed severe hematopoietic toxicities, highlighting the need for sensitive tumors and rational combination strategies to enhance their therapeutic potential. Here, we identified colon cancer-specific super-enhancers that were associated with multiple oncogenic pathways, including the mitogen activated protein kinase (MAPK) signaling pathway. Among the 14 colon cancer cell lines tested, their sensitivity to JQ1, a BET inhibitor, was not correlated with c-MYC expression. Three of four BRAFV600E-mutant cell lines were sensitive. Addition of JQ1 to vemurafenib, a specific mutant BRAF inhibitor, suppressed cell growth by arresting cell cycle progression and inducing apoptosis in the BRAFV600E-mutant cells. Mechanistically, the feedback activation of MAPK signaling pathway by vemurafenib was repressed by JQ1. Further, the addition of JQ1 to a BRAF inhibitor enhanced the in vivo anti-tumor effect. Thus, this study indicates the therapeutic potential of targeting of super-enhancers and mutant BRAF in patients with BRAFV600E-mutant colorectal cancer. PMID- 28576752 TI - Response to "Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer," Cancer Lett. 2017 Mar 1; 388(2017): 208 219. PMID- 28576754 TI - Stroke Avoidance for Children in REpublica Dominicana (SACRED): Protocol for a Prospective Study of Stroke Risk and Hydroxyurea Treatment in Sickle Cell Anemia. AB - BACKGROUND: In the Dominican Republic, where the burden of sickle cell anemia (SCA) is high, many children lack access to routine screening and preventative care. Children with SCA are at risk for stroke, an event that leads to significant morbidity and mortality. In the United States, screening via transcranial Doppler (TCD) identifies children with SCA at highest stroke risk, allowing early intervention with blood transfusions. The need for indefinite transfusions for primary stroke prevention limits their practicality in limited resource countries. Hydroxyurea has been shown to lower TCD velocities and to prevent conversion from conditional (170 to 199 cm/sec) to abnormal (greater than or equal to 200 cm/sec) velocities. In resource-limited settings, implementation of a TCD screening program, coupled with hydroxyurea therapy, could reduce the burden of SCA and stroke. OBJECTIVE: The aims of the Stroke Avoidance for Children in REpublica Dominicana (SACRED) trial are (1) to screen children with SCA for stroke risk using TCD and to determine the prevalence of elevated velocities in a cross-sectional sample; (2) to identify clinical and laboratory correlates of elevated velocities; and (3) to obtain longitudinal data on the natural history of TCD velocities and to measure therapeutic effects of hydroxyurea. METHODS: This prospective trial, designed and conducted by Cincinnati Children's Hospital Medical Center (CCHMC) and Hospital Infantil Robert Reid Cabral (HIRRC) with Centro de Obstetricia y Ginecologia, includes a baseline cross-sectional epidemiological survey of the distribution of TCD velocities across a large cohort of children with SCA in the Dominican Republic. Children with conditional velocities are eligible to begin protocol-directed hydroxyurea if laboratory criteria are met. The treatment schedule begins with a fixed-dose of approximately 20 mg/kg/day for 6 months, after which it escalates to maximum tolerated dose (MTD). All participants undergo longitudinal annual TCD evaluation, while those on hydroxyurea have semi-annual evaluations during the 3 year study period. Data are collected using an Internet-based Research Electronic Data Capture (REDCap) system with forms translated into Spanish; both remote and on-site monitoring are used. RESULTS: To date, 122 children with SCA have enrolled in SACRED including 85 (69.7%, 85/122) with normal, 29 (23.8%, 29/122) with conditional, 5 (4.1%, 5/122) with abnormal, and 3 (2.5%, 3/122) with inadequate TCD velocities. Of the 29 children with conditional TCD velocities, 17 (59%, 17/29) have initiated hydroxyurea per protocol, with plans for escalation to MTD. CONCLUSIONS: The SACRED trial will provide novel epidemiologic data about the prevalence of children with SCA and increased stroke risk in the Dominican Republic. The study also includes an investigation of the impact of hydroxyurea at MTD on elevated TCD velocities, as well as clinical and laboratory parameters. The design and implementation of SACRED reflect a successful international institutional partnership, one that features local capacity building and training in research methods and clinical care. The trial's results have important implications for screening and prevention of primary stroke in children with SCA living in resource-limited settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT02769845; https://www.clinicaltrials.gov/ct2/show/NCT02769845 (Archived by WebCite at http://www.webcitation.org/6qf6n0Egh). PMID- 28576753 TI - Review: The function of regulatory T cells at the ocular surface. AB - Regulatory T cells (Tregs) are critical modulators of immune homeostasis. Tregs maintain peripheral tolerance to self-antigens, thereby preventing autoimmune disease. Furthermore, Tregs suppress excessive immune responses deleterious to the host. Recent research has deepened our understanding of how Tregs function at the ocular surface. This manuscript describes the classification, the immunosuppressive mechanisms, and the phenotypic plasticity of Tregs. We review the contribution of Tregs to ocular surface autoimmune disease, as well as the function of Tregs in allergy and infection at the ocular surface. Finally, we review the role of Tregs in promoting allotolerance in corneal transplantation. PMID- 28576756 TI - The Research Topic Defines "Noise" in Social Media Data - a Response from the Authors. PMID- 28576757 TI - Using Feedback to Promote Physical Activity: The Role of the Feedback Sign. AB - BACKGROUND: Providing feedback is a technique to promote health behavior that is emphasized by behavior change theories. However, these theories make contradicting predictions regarding the effect of the feedback sign-that is, whether the feedback signals success or failure. Thus, it is unclear whether positive or negative feedback leads to more favorable behavior change in a health behavior intervention. OBJECTIVE: The aim of this study was to examine the effect of the feedback sign in a health behavior change intervention. METHODS: Data from participants (N=1623) of a 6-month physical activity intervention was used. Participants received a feedback email at the beginning of each month. Feedback was either positive or negative depending on the participants' physical activity in the previous month. In an exploratory analysis, change in monthly step count averages was used to evaluate the feedback effect. RESULTS: The feedback sign did not predict the change in monthly step count averages over the course of the intervention (b=-84.28, P=.28). Descriptive differences between positive and negative feedback can be explained by regression to the mean. CONCLUSIONS: The feedback sign might not influence the effect of monthly feedback emails sent out to participants of a large-scale physical activity intervention. However, randomized studies are needed to further support this conclusion. Limitations as well as opportunities for future research are discussed. PMID- 28576755 TI - Access to Electronic Personal Health Records Among Patients With Multiple Chronic Conditions: A Secondary Data Analysis. AB - BACKGROUND: In the United States, national incentives for offering access to electronic personal health records (ePHRs) through electronic means are geared toward creating a culture of patient engagement. One group of patients who stand to benefit from online access to ePHRs is the growing population with multiple chronic conditions (MCC). However, little is known about the current availability and use of ePHRs and patient portals among those managing MCC. OBJECTIVE: The aim was to determine the associations between number of chronic conditions and sociodemographic characteristics and usage of ePHRs, and to assess how the public's use of ePHRs varies across subpopulations, including those with MCC. METHODS: This study used data collected from the 2014 Health Information National Trends Survey (HINTS), and assessed differences in use of ePHRs between those with and without MCC (N=3497) using multiple logistic regression techniques. Variables associated with health care systems (insurance status, having a regular provider) and patient-reported self-efficacy were included in the statistical models. RESULTS: Those with MCC (n=1555) had significantly higher odds of accessing their records three or more times in the past year compared to those reporting no chronic conditions (n=1050; OR 2.46, 95% CI 1.37-4.45), but the overall percentage of those with MCC using ePHRs remained low (371 of 1529 item respondents, 25.63% weighted). No difference in odds of accessing their records was found between those reporting one chronic condition (n=892) and those reporting none (n=1050; OR 1.02, 95% CI 0.66-1.58). Significant differences in odds of accessing ePHRs were seen between income and age groups (P<.001 and P=.05, respectively), and by whether respondents had a regular provider (P=.03). CONCLUSIONS: We conclude that ePHRs provide a unique opportunity to enhance MCC patient self-management, but additional effort is needed to ensure that these patients are able to access their ePHRs. An increase in availability of patient access to their ePHRs may provide an opportunity to increase patient engagement and support self-management for all patients and especially those with MCC. PMID- 28576758 TI - Recruiting Young Gay and Bisexual Men for a Human Papillomavirus Vaccination Intervention Through Social Media: The Effects of Advertisement Content. AB - BACKGROUND: Web-based approaches, specifically social media sites, represent a promising approach for recruiting young gay and bisexual men for research studies. Little is known, however, about how the performance of social media advertisements (ads) used to recruit this population is affected by ad content (ie, image and text). OBJECTIVE: The aim of this study was to evaluate the effects of different images and text included in social media ads used to recruit young gay and bisexual men for the pilot test of a Web-based human papillomavirus (HPV) vaccination intervention. METHODS: In July and September 2016, we used paid Facebook advertisements to recruit men who were aged 18-25 years, self-identified as gay or bisexual, US resident, and had not received HPV vaccine. A 4x2x2 factorial experiment varied ad image (a single young adult male, a young adult male couple, a group of young adult men, or a young adult male talking to a doctor), content focus (text mentioning HPV or HPV vaccine), and disease framing (text mentioning cancer or a sexually transmitted disease [STD]). Poisson regression determined whether these experimental factors affected ad performance. RESULTS: The recruitment campaign reached a total of 35,646 users who viewed ads for 36,395 times. This resulted in an overall unique click-through rate of 2.01% (717/35,646) and an overall conversion rate of 0.66% (241/36,395). Reach was higher for ads that included an image of a couple (incidence rate ratio, IRR=4.91, 95% CI 2.68-8.97, P<.001) or a group (IRR=2.65, 95% CI 1.08-6.50, P=.03) compared with those that included an image of a single person. Ads that included an image of a couple also had a higher conversion rate (IRR=2.56, 95% CI 1.13-5.77, P=.02) than ads that included an image of a single person. Ads with text mentioning an STD had a higher unique click-through rate compared with ads with text mentioning cancer (IRR=1.34, 95% CI 1.06-1.69, P=.01). The campaign cost a total of US $413.72 and resulted in 150 eligible and enrolled individuals (US $2.76 per enrolled participant). CONCLUSIONS: Facebook ads are a convenient and cost-efficient strategy for reaching and recruiting young gay and bisexual men for a Web-based HPV vaccination intervention. To help optimize ad performance among this population, researchers should consider the importance of the text and image included in the social media recruitment ads. PMID- 28576759 TI - Competitive Dominance within Biofilm Consortia Regulates the Relative Distribution of Pneumococcal Nasopharyngeal Density. AB - Streptococcus pneumoniae is a main cause of child mortality worldwide, but strains also asymptomatically colonize the upper airways of most children and form biofilms. Recent studies have demonstrated that ~50% of colonized children carry at least two different serotypes (i.e., strains) in the nasopharynx; however, studies of how strains coexist are limited. In this work, we investigated the physiological, genetic, and ecological requirements for the relative distribution of densities, and spatial localization, of pneumococcal strains within biofilm consortia. Biofilm consortia were prepared with vaccine type strains (i.e., serotype 6B [S6B], S19F, or S23F) and strain TIGR4 (S4). Experiments first revealed that the relative densities of S6B and S23F were similar in biofilm consortia. The density of S19F strains, however, was reduced to ~10% in biofilm consortia, including either S6B, S23F, or TIGR4, in comparison to S19F monostrain biofilms. Reduction of S19F density within biofilm consortia was also observed in a simulated nasopharyngeal environment. Reduction of relative density was not related to growth rates, since the Malthusian parameter demonstrated similar rates of change of density for most strains. To investigate whether quorum sensing (QS) regulates relative densities in biofilm consortia, two different mutants were prepared: a TIGR4DeltaluxS mutant and a TIGR4DeltacomC mutant. The density of S19F strains, however, was similarly reduced when consortia included TIGR4, TIGR4DeltaluxS, or TIGR4DeltacomC Moreover, production of a different competence-stimulating peptide (CSP), CSP1 or CSP2, was not a factor that affected dominance. Finally, a mathematical model, confocal experiments, and experiments using Transwell devices demonstrated physical contact-mediated control of pneumococcal density within biofilm consortia.IMPORTANCEStreptococcus pneumoniae kills nearly half a million children every year, but it also produces nasopharyngeal biofilm consortia in a proportion of asymptomatic children, and these biofilms often contain two strains (i.e., serotypes). In our study, we investigated how strains coexist within pneumococcal consortia produced by vaccine serotypes S4, S6B, S19F, and S23F. Whereas S6B and S23F shared the biofilm consortium, our studies demonstrated reduction of the relative density of S19F strains, to ~10% of what it would otherwise be if alone, in consortial biofilms formed with S4, S6B, or S23F. This dominance was not related to increased fitness when competing for nutrients, nor was it regulated by quorum-sensing LuxS/AI-2 or Com systems. It was demonstrated, however, to be enhanced by physical contact rather than by a product(s) secreted into the supernatant, as would naturally occur in the semidry nasopharyngeal environment. Competitive interactions within pneumococcal biofilm consortia regulate nasopharyngeal density, a risk factor for pneumococcal disease. PMID- 28576760 TI - Mathermycin, a Lantibiotic from the Marine Actinomycete Marinactinospora thermotolerans SCSIO 00652. AB - Lantibiotics are antimicrobial peptides belonging to the family of ribosomally synthesized and posttranslationally modified peptides (RiPPs) and feature thioether linkages in their structures. In this study, we identified the biosynthetic gene cluster of a cinnamycin analog, named mathermycin, from Marinactinospora thermotolerans SCSIO 00652 and reconstituted its biosynthesis in Streptomyces lividans and Escherichia coli Key posttranslational modification enzymes of mathermycin were characterized. Mathermycin exhibited antimicrobial activity and therefore represents an example of cinnamycin-like lantibiotics from Marinactinospora species.IMPORTANCE The discovery of new antimicrobial compounds that can be used as potential drugs is in urgent need due to increasing bacterial resistance to current antibiotics. Lantibiotics are important antimicrobial compounds that have found applications in both the clinic setting and food industry. We report here the discovery of a new lantibiotic, mathermycin, from a marine-derived Marinactinospora thermotolerans strain and elucidation of its biosynthesis. We also demonstrate that mathermycin possesses antimicrobial activity toward a Bacillus strain. PMID- 28576761 TI - A natural Vibrio parahaemolyticus PirvpA-B+ mutant kills shrimp but produces no Pirvp toxins or AHPND lesions. AB - Acute hepatopancreatic necrosis disease (AHPND) of shrimp is caused by Vibrio parahaemolyticus (VP) isolates that harbor a pVA plasmid encoding toxins PirvpA and PirvpB (VPAHPND). These are released from VPAHPND that colonize the shrimp stomach and produce pathognomonic AHPND lesions (massive sloughing of hepatopancreatic tubule epithelial cells). PCR results indicated that VP isolate XN87 lacked PirvpA but carried PirvpB Unexpectedly, western blot analysis of proteins from culture broth of XN87 revealed absence of both toxins and the lack of PirvpB was further confirmed by ELISA assay. However, shrimp immersion challenge with XN87 resulted in 47% mortality without AHPND lesions. Instead, lesions consisted of collapsed hepatopancreatic tubule epithelia. By contrast, control shrimp challenged with typical VPAHPND isolate 5HP gave 90% mortality, accompanied by AHPND lesions. Sequence analysis revealed that pVA plasmid of XN87 contained a mutated PirvpA gene interrupted by out-of-frame insertion of a transposon gene fragment. The upstream region and beginning of the original PirvpA gene remained intact, but the insertion caused a 2-base reading-frame shift in the remainder of the PirvpA gene sequence and in the downstream PirvpB gene sequence. RT-PCR and sequencing of 5HP revealed a bi-cystronic PirvpAB mRNA transcript that was not produced by XN87, explaining the absence of both toxins in its culture broth. However, the virulence of XN87 revealed some VP isolates carrying mutant pVA plasmids that produce no Pirvp toxins can cause mortality in EMS outbreak ponds but may not have been previously recognized as AHPND-related because they do not cause pathognomonic AHPND lesions.IMPORTANCE Shrimp acute hepatopancreatic necrosis disease (AHPND) is caused by Vibrio parahaemolyticus isolates that harbor pVA1 plasmid encoding toxins PirvpA and PirvpB (VPAHPND). The toxins are produced in the shrimp stomach but cause death by massive sloughing of hepatopancreatic tubule epithelial cells (pathognomonic AHPND lesions). VP isolate XN87 harbors a mutant pVA plasmid that produces no Pir toxins and does not cause AHPND lesions but still causes ~50% shrimp mortality. Such isolates may cause a portion of the mortality in EMS ponds that is not ascribed to VPAHPND Thus, they pose an additional threat to shrimp farmers that would be missed by current testing for VPAHPND Moribund shrimp from EMS ponds that exhibit collapsed hepatopancreatic tubule epithelial cells can serve as indicators for the possible presence of such isolates that can then be confirmed by additional PCR tests for presence of a pVA plasmid. PMID- 28576762 TI - Anaerobic Copper Toxicity and Iron-Sulfur Cluster Biogenesis in Escherichia coli. AB - While copper is an essential trace element in biology, pollution of groundwater from copper has become a threat to all living organisms. Cellular mechanisms underlying copper toxicity, however, are still not fully understood. Previous studies have shown that iron-sulfur proteins are among the primary targets of copper toxicity in Escherichia coli under aerobic conditions. Here, we report that, under anaerobic conditions, iron-sulfur proteins in E. coli cells are even more susceptible to copper in medium. Whereas addition of 0.2 mM copper(II) chloride to LB (Luria-Bertani) medium has very little or no effect on iron-sulfur proteins in wild-type E. coli cells under aerobic conditions, the same copper treatment largely inactivates iron-sulfur proteins by blocking iron-sulfur cluster biogenesis in the cells under anaerobic conditions. Importantly, proteins that do not have iron-sulfur clusters (e.g., fumarase C and cysteine desulfurase) in E. coli cells are not significantly affected by copper treatment under aerobic or anaerobic conditions, indicating that copper may specifically target iron sulfur proteins in cells. Additional studies revealed that E. coli cells accumulate more intracellular copper under anaerobic conditions than under aerobic conditions and that the elevated copper content binds to the iron-sulfur cluster assembly proteins IscU and IscA, which effectively inhibits iron-sulfur cluster biogenesis. The results suggest that the copper-mediated inhibition of iron-sulfur proteins does not require oxygen and that iron-sulfur cluster biogenesis is the primary target of anaerobic copper toxicity in cells.IMPORTANCE Copper contamination in groundwater has become a threat to all living organisms. However, cellular mechanisms underlying copper toxicity have not been fully understood up to now. The work described here reveals that iron-sulfur proteins in Escherichia coli cells are much more susceptible to copper in medium under anaerobic conditions than they are under aerobic conditions. Under anaerobic conditions, E. coli cells accumulate excess intracellular copper, which specifically targets iron-sulfur proteins by blocking iron-sulfur cluster biogenesis. Since iron-sulfur proteins are involved in diverse and vital physiological processes, inhibition of iron-sulfur cluster biogenesis by copper disrupts multiple cellular functions and ultimately inhibits cell growth. The results from this study illustrate a new interplay between intracellular copper toxicity and iron-sulfur cluster biogenesis in bacterial cells under anaerobic conditions. PMID- 28576765 TI - Citizens' juries for health policy. PMID- 28576763 TI - Phylogenetic and Functional Diversity of Total (DNA) and Expressed (RNA) Bacterial Communities in Urban Green Infrastructure Bioswale Soils. AB - New York City (NYC) is pioneering green infrastructure with the use of bioswales and other engineered soil-based habitats to provide stormwater infiltration and other ecosystem functions. In addition to avoiding the environmental and financial costs of expanding traditional built infrastructure, green infrastructure is thought to generate cobenefits in the form of diverse ecological processes performed by its plant and microbial communities. Yet, although plant communities in these habitats are closely managed, we lack basic knowledge about how engineered ecosystems impact the distribution and functioning of soil bacteria. We sequenced amplicons of the 16S ribosomal subunit, as well as seven genes associated with functional pathways, generated from both total (DNA based) and expressed (RNA) soil communities in the Bronx, NYC, NY, in order to test whether bioswale soils host characteristic bacterial communities with evidence for enriched microbial functioning, compared to nonengineered soils in park lawns and tree pits. Bioswales had distinct, phylogenetically diverse bacterial communities, including taxa associated with nutrient cycling and metabolism of hydrocarbons and other pollutants. Bioswale soils also had a significantly greater diversity of genes involved in several functional pathways, including carbon fixation (cbbL-R [cbbL gene, red-like subunit] and apsA), nitrogen cycling (noxZ and amoA), and contaminant degradation (bphA); conversely, no functional genes were significantly more abundant in nonengineered soils. These results provide preliminary evidence that urban land management can shape the diversity and activity of soil communities, with positive consequences for genetic resources underlying valuable ecological functions, including biogeochemical cycling and degradation of common urban pollutants.IMPORTANCE Management of urban soil biodiversity by favoring taxa associated with decontamination or other microbial metabolic processes is a powerful prospect, but it first requires an understanding of how engineered soil habitats shape patterns of microbial diversity. This research adds to our understanding of urban microbial biogeography by providing data on soil bacteria in bioswales, which had relatively diverse and compositionally distinct communities compared to park and tree pit soils. Bioswales also contained comparatively diverse pools of genes related to carbon sequestration, nitrogen cycling, and contaminant degradation, suggesting that engineered soils may serve as effective reservoirs of functional microbial biodiversity. We also examined both total (DNA-based) and expressed (RNA) communities, revealing that total bacterial communities (the exclusive targets in the vast majority of soil studies) were poor predictors of expressed community diversity, pointing to the value of quantifying RNA, especially when ecological functioning is considered. PMID- 28576764 TI - Early postnatal hyperglycaemia is a risk factor for treatment-demanding retinopathy of prematurity. AB - BACKGROUND: To investigate whether neonatal hyperglycaemia in the first postnatal week is associated with treatment-demanding retinopathy of prematurity (ROP). METHODS: This is a Danish national, retrospective, case-control study of premature infants (birth period 2003-2006). Three national registers were searched, and data were linked through a unique civil registration number. The study sample consisted of 106 cases each matched with two comparison infants. Matching criteria were gestational age (GA) at birth, ROP not registered and born at the same neonatal intensive care unit. Potential 'new' risk factors were analysed in a multivariate logistic regression model, while adjusted for previously recognised risk factors (ie, GA at birth, small for gestational age, multiple birth and male sex). RESULTS: Hospital records of 310 preterm infants (106 treated; 204 comparison infants) were available. Nutrition in terms of energy (kcal/kg/week) and protein (g/kg/week) given to the preterm infants during the first postnatal week were statistically insignificant between the study groups (Mann-Whitney U test; p=0.165/p=0.163). Early postnatal weight gain between the two study groups was borderline significant (t-test; p=0.047). Hyperglycaemic events (indexed value) were statistically significantly different between the two study groups (Mann-Whitney U test; p<0.001). Hyperglycaemia was a statistically independent risk factor (OR: 1.022; 95% CI 1.002 to 1.042; p=0.031). CONCLUSION: An independent association was found between the occurrence of hyperglycaemic events during the first postnatal week and later development of treatment-demanding ROP, when adjusted for known risk factors. PMID- 28576766 TI - Comparative Evaluation of Plasma Bile Acids, Dehydroepiandrosterone Sulfate, Hexadecanedioate, and Tetradecanedioate with Coproporphyrins I and III as Markers of OATP Inhibition in Healthy Subjects. AB - Multiple endogenous compounds have been proposed as candidate biomarkers to monitor organic anion transporting polypeptide (OATP) function in preclinical species or humans. Previously, we demonstrated that coproporphyrins (CPs) I and III are appropriate clinical markers to evaluate OATP inhibition and recapitulate clinical drug-drug interactions (DDIs). In the present study, we investigated bile acids (BAs) dehydroepiandrosterone sulfate (DHEAS), hexadecanedioate (HDA), and tetradecanedioate (TDA) in plasma as endogenous probes for OATP inhibition and compared these candidate probes to CPs. All probes were determined in samples from a single study that examined their behavior and their association with rosuvastatin (RSV) pharmacokinetics after administration of an OATP inhibitor rifampin (RIF) in healthy subjects. Among endogenous probes examined, RIF significantly increased maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC)(0-24h) of fatty acids HDA and TDA by 2.2- to 3.2 fold. For the 13 bile acids in plasma examined, no statistically significant changes were detected between treatments. Changes in plasma DHEAS did not correlate with OATP1B inhibition by RIF. On the basis of the magnitude of effects for the endogenous compounds that demonstrated significant changes from baseline over interindividual variations, the overall rank order for the AUC change was found to be CP I > CP III > HDA ~ TDA ~ RSV > > BAs. Collectively, these results reconfirmed that CPs are novel biomarkers suitable for clinical use. In addition, HDA and TDA are useful for OATP functional assessment. Since these endogenous markers can be monitored in conjunction with pharmacokinetics analysis, the CPs and fatty acid dicarboxylates, either alone or in combination, offer promise of earlier diagnosis and risk stratification for OATP-mediated DDIs. PMID- 28576767 TI - Risk factors for human-directed canine aggression in a referral level clinical population. AB - Risk factors for human-directed aggression were investigated using retrospective analysis ofdata from a referral-level clinical behaviour population in the UK. A sample of 200 casesinvolving human-directed canine aggression and 200 control cases involving no instance ofhuman-directed aggression were selected at random from a population of 746 cases. Thefinal model suggested that clinical cases with human-directed aggression were significantlyyounger than those presenting with other undesired behaviours (P=0.008) and that maledogs were 1.4 times more likely to be aggressive towards human beings than female dogs(P=0.019). Dogs were 1.7 times more likely to be aggressive towards people if they hadattended more than five puppy classes than if they had never attended puppy class(P=0.015) and that dogs were 2.8 times more likely to be aggressive towards human beingsif there was another dog between 0 months and 24 months of age in the home (P=0.004).These factors only account for 7 per cent to 10 per cent of the variance between the human-directedaggression population and the control population, but factors such as attendance atpuppy classes and numbers of dogs in the household suggest the need for longitudinalstudies to investigate temporal relationships. PMID- 28576769 TI - Defective Hand1 phosphoregulation uncovers essential roles for Hand1 in limb morphogenesis. AB - The morphogenesis of the vertebrate limbs is a complex process in which cell signaling and transcriptional regulation coordinate diverse structural adaptations in diverse species. In this study, we examine the consequences of altering Hand1 dimer choice regulation within developing vertebrate limbs. Although Hand1 deletion via the limb-specific Prrx1-Cre reveals a non-essential role for Hand1 in mouse limb morphogenesis, altering Hand1 phosphoregulation, and consequently Hand1 dimerization affinities, results in a severe truncation of proximal-anterior limb elements. Molecular analysis reveals a non-cell-autonomous mechanism that causes widespread cell death within the embryonic limb bud. In addition, we observe changes in proximal-anterior gene regulation, including a reduction in the expression of Irx3, Irx5, Gli3 and Alx4, all of which are upregulated in Hand2 limb conditional knockouts. A reduction of Hand2 and Shh gene dosage improves the integrity of anterior limb structures, validating the importance of the Twist-family bHLH dimer pool in limb morphogenesis. PMID- 28576768 TI - Defining epithelial cell dynamics and lineage relationships in the developing lacrimal gland. AB - The tear-producing lacrimal gland is a tubular organ that protects and lubricates the ocular surface. The lacrimal gland possesses many features that make it an excellent model in which to investigate tubulogenesis, but the cell types and lineage relationships that drive lacrimal gland formation are unclear. Using single-cell sequencing and other molecular tools, we reveal novel cell identities and epithelial lineage dynamics that underlie lacrimal gland development. We show that the lacrimal gland from its earliest developmental stages is composed of multiple subpopulations of immune, epithelial and mesenchymal cell lineages. The epithelial lineage exhibits the most substantial cellular changes, transitioning through a series of unique transcriptional states to become terminally differentiated acinar, ductal and myoepithelial cells. Furthermore, lineage tracing in postnatal and adult glands provides the first direct evidence of unipotent KRT5+ epithelial cells in the lacrimal gland. Finally, we show conservation of developmental markers between the developing mouse and human lacrimal gland, supporting the use of mice to understand human development. Together, our data reveal crucial features of lacrimal gland development that have broad implications for understanding epithelial organogenesis. PMID- 28576770 TI - Placental labyrinth formation in mice requires endothelial FLRT2/UNC5B signaling. AB - The placental labyrinth is the interface for gas and nutrient exchange between the embryo and the mother; hence its proper development is essential for embryogenesis. However, the molecular mechanism underlying development of the placental labyrinth, particularly in terms of its endothelial organization, is not well understood. Here, we determined that fibronectin leucine-rich transmembrane protein 2 (FLRT2), a repulsive ligand of the UNC5 receptor family for neurons, is unexpectedly expressed in endothelial cells specifically in the placental labyrinth. Mice lacking FLRT2 in endothelial cells exhibited embryonic lethality at mid-gestation, with systemic congestion and hypoxia. Although they lacked apparent deformities in the embryonic vasculature and heart, the placental labyrinths of these embryos exhibited aberrant alignment of endothelial cells, which disturbed the feto-maternal circulation. Interestingly, this vascular deformity was related to endothelial repulsion through binding to the UNC5B receptor. Our results suggest that the proper organization of the placental labyrinth depends on coordinated inter-endothelial repulsion, which prevents uncontrolled layering of the endothelium. PMID- 28576771 TI - BMP signaling orchestrates a transcriptional network to control the fate of mesenchymal stem cells in mice. AB - Signaling pathways are used reiteratively in different developmental processes yet produce distinct cell fates through specific downstream transcription factors. In this study, we used tooth root development as a model with which to investigate how the BMP signaling pathway regulates transcriptional complexes to direct the fate determination of multipotent mesenchymal stem cells (MSCs). We first identified the MSC population supporting mouse molar root growth as Gli1+ cells. Using a Gli1-driven Cre-mediated recombination system, our results provide the first in vivo evidence that BMP signaling activity is required for the odontogenic differentiation of MSCs. Specifically, we identified the transcription factors Pax9, Klf4, Satb2 and Lhx8 as being downstream of BMP signaling and expressed in a spatially restricted pattern that is potentially involved in determining distinct cellular identities within the dental mesenchyme. Finally, we found that overactivation of one key transcription factor, Klf4, which is associated with the odontogenic region, promotes odontogenic differentiation of MSCs. Collectively, our results demonstrate the functional significance of BMP signaling in regulating MSC fate during root development and shed light on how BMP signaling can achieve functional specificity in regulating diverse organ development. PMID- 28576774 TI - The fusogen AFF-1 can rejuvenate the regenerative potential of adult dendritic trees by self-fusion. AB - The aging brain undergoes structural changes that affect brain homeostasis, neuronal function and consequently cognition. The complex architecture of dendritic arbors poses a challenge to understanding age-dependent morphological alterations, behavioral plasticity and remodeling following brain injury. Here, we use the PVD polymodal neurons of C. elegans as a model to study how aging affects neuronal plasticity. Using confocal live imaging of C. elegans PVD neurons, we demonstrate age-related progressive morphological alterations of intricate dendritic arbors. We show that mutations in daf-2, which encodes an insulin-like growth factor receptor ortholog, fail to inhibit the progressive morphological aging of dendrites and do not prevent the minor decline in response to harsh touch during aging. We uncovered that PVD aging is characterized by a major decline in the regenerative potential of dendrites following experimental laser dendrotomy. Furthermore, the remodeling of transected dendritic trees by AFF-1-mediated self-fusion can be restored in old animals by daf-2 mutations, and can be differentially re-established by ectopic expression of the fusion protein AFF-1. Thus, ectopic expression of the fusogen AFF-1 in the PVD and mutations in daf-2 differentially rejuvenate some aspects of dendritic regeneration following injury. PMID- 28576773 TI - Distinct roles for the mTOR pathway in postnatal morphogenesis, maturation and function of pancreatic islets. AB - While much is known about the molecular pathways that regulate embryonic development and adult homeostasis of the endocrine pancreas, little is known about what regulates early postnatal development and maturation of islets. Given that birth marks the first exposure to enteral nutrition, we investigated how nutrient-regulated signaling pathways influence postnatal islet development in mice. We performed loss-of-function studies of mechanistic target of rapamycin (mTOR), a highly conserved kinase within a nutrient-sensing pathway known to regulate cellular growth, morphogenesis and metabolism. Deletion of Mtor in pancreatic endocrine cells had no significant effect on their embryonic development. However, within the first 2 weeks after birth, mTOR-deficient islets became dysmorphic, beta-cell maturation and function were impaired, and animals lost islet mass. Moreover, we discovered that these distinct functions of mTOR are mediated by separate downstream branches of the pathway, in that mTORC1 (with adaptor protein Raptor) is the main complex mediating the maturation and function of islets, whereas mTORC2 (with adaptor protein Rictor) impacts islet mass and architecture. Taken together, these findings suggest that nutrient sensing may be an essential trigger for postnatal beta-cell maturation and islet development. PMID- 28576772 TI - Incompatibility between mitochondrial and nuclear genomes during oogenesis results in ovarian failure and embryonic lethality. AB - Mitochondrial dysfunction can cause female infertility. An important unresolved issue is the extent to which incompatibility between mitochondrial and nuclear genomes contributes to female infertility. It has previously been shown that a mitochondrial haplotype from D. simulans (simw501 ) is incompatible with a nuclear genome from the D. melanogaster strain Oregon-R (OreR), resulting in impaired development, which was enhanced at higher temperature. This mito-nuclear incompatibility is between alleles of the nuclear-encoded mitochondrial tyrosyl tRNA synthetase (Aatm) and the mitochondrial-encoded tyrosyl-tRNA that it aminoacylates. Here, we show that this mito-nuclear incompatibility causes a severe temperature-sensitive female infertility. The OreR nuclear genome contributed to death of ovarian germline stem cells and reduced egg production, which was further enhanced by the incompatibility with simw501 mitochondria. Mito-nuclear incompatibility also resulted in aberrant egg morphology and a maternal-effect on embryonic chromosome segregation and survival, which was completely dependent on the temperature and mito-nuclear genotype of the mother. Our findings show that maternal mito-nuclear incompatibility during Drosophila oogenesis has severe consequences for egg production and embryonic survival, with important broader relevance to human female infertility and mitochondrial replacement therapy. PMID- 28576775 TI - Cold Fusion: Massive Karyotype Evolution in the Antarctic Bullhead Notothen Notothenia coriiceps. AB - Half of all vertebrate species share a series of chromosome fusions that preceded the teleost genome duplication (TGD), but we do not understand the causative evolutionary mechanisms. The "Robertsonian-translocation hypothesis" suggests a regular fusion of each ancestral acro- or telocentric chromosome to just one other by centromere fusions, thus halving the karyotype. An alternative "genome stirring hypothesis" posits haphazard and repeated fusions, inversions, and reciprocal and nonreciprocal translocations. To study large-scale karyotype reduction, we investigated the decrease of chromosome numbers in Antarctic notothenioid fish. Most notothenioids have 24 haploid chromosomes, but bullhead notothen (Notothenia coriiceps) has 11. To understand mechanisms, we made a RAD tag meiotic map with ~10,000 polymorphic markers. Comparative genomics aligned about a thousand orthologs of platyfish and stickleback genes along bullhead chromosomes. Results revealed that 9 of 11 bullhead chromosomes arose by fusion of just two ancestral chromosomes and two others by fusion of three ancestral chromosomes. All markers from each ancestral chromosome remained contiguous, implying no inversions across fusion borders. Karyotype comparisons support a history of: (1) Robertsonian fusions of 22 ancestral chromosomes in pairs to yield 11 fused plus two small unfused chromosomes, like N. angustata; (2) fusion of one of the remaining two ancestral chromosomes to a preexisting fused pair, giving 12 chromosomes like N. rossii; and (3) fusion of the remaining ancestral chromosome to another fused pair, giving 11 chromosomes in N. coriiceps These results raise the question of what selective forces promoted the systematic fusion of chromosomes in pairs and the suppression of pericentric inversions in this lineage, and provide a model for chromosome fusions in stem teleosts. PMID- 28576779 TI - Trump's decision to leave climate pact threatens public health, US doctors warn. PMID- 28576776 TI - RNA Binding Protein Vigilin Collaborates with miRNAs To Regulate Gene Expression for Caenorhabditis elegans Larval Development. AB - Extensive studies have suggested that most miRNA functions are executed through complex miRNA-target interaction networks, and such networks function semiredundantly with other regulatory systems to shape gene expression dynamics for proper physiological functions. We found that knocking down vgln-1, which encodes a conserved RNA-binding protein associated with diverse functions, causes severe larval arrest at the early L1 stage in animals with compromised miRISC functions (an ain-2/GW182 mutant). Through an enhancer screen, we identified five specific miRNAs, and miRNA families, that act semiredundantly with VGLN-1 to regulate larval development. By RIP-Seq analysis, we identified mRNAs that are directly bound by VGLN-1, and highly enriched for miRNA binding sites, leading to a hypothesis that VGLN-1 may share common targets with miRNAs to regulate gene expression dynamics for development. PMID- 28576780 TI - Outcomes of Ventricular Tachycardia Ablation Using Percutaneous Left Ventricular Assist Devices. AB - BACKGROUND: Although percutaneous left ventricular assist devices (pLVADs) facilitate mapping and ablation of hemodynamically unstable ventricular tachycardia (VT), there is limited data whether clinical outcomes are improved. We sought to retrospectively compare the outcomes of patients undergoing scar related VT ablation with and without pLVAD support. METHODS AND RESULTS: The study population comprised 194 patients (109 pLVAD and 85 non-pLVAD). The pLVAD group more often had dilated cardiomyopathy (33% versus 13%; P=0.001), New York Heart Association heart failure class >=III (51% versus 25%; P<0.001), lower left ventricular ejection fractions (26+/-10% versus 39+/-16%; P<0.001), and electrical storm (49% versus 34%; P=0.04). Procedure times (422+/-112 versus 330+/-92 minutes; P<0.001), postablation VT inducibility (20% versus 7%; P=0.02), and length of subsequent hospitalization (median 6 versus 4 days; P=0.001) were all higher in the pLVAD group. During median follow-up of 215 days, the primary end point (recurrent VT, heart transplantation, or death) occurred in 36% of the pLVAD versus 26% of the non-pLVAD groups (P=0.14). After propensity matching for differences between groups, no differences were seen between groups for both acute procedural outcomes and the primary end point. CONCLUSIONS: In this large single-center scar-related VT ablation experience, despite the worse clinical status of the patients selected for pLVAD support, clinical outcomes were better than expected and were similar to healthier patients not receiving hemodynamic support. Patients with dilated cardiomyopathy presenting with electrical storm, advanced heart failure, and severe left ventricular dysfunction most frequently received hemodynamic support during VT ablation. PMID- 28576781 TI - Electrocardiographic Preexcitation and Risk of Cardiovascular Morbidity and Mortality: Results From the Copenhagen ECG Study. AB - BACKGROUND: The majority of available data on the clinical course of patients with ventricular preexcitation in the ECG originates from tertiary centers. We aimed to investigate long-term outcomes in individuals from a primary care population with electrocardiographic preexcitation. METHODS AND RESULTS: Digital ECGs from 328 638 primary care patients were collected during 2001 to 2011. We identified 310 individuals with preexcitation (age range, 8-85 years). Data on medication, comorbidity, and outcomes were collected from Danish nationwide registries. The median follow-up time was 7.4 years (quartiles, 4.6-10.3 years). Compared with the remainder of the population, patients with preexcitation had higher adjusted hazards of atrial fibrillation (hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.07-4.70) and heart failure (HR, 2.11; 95% CI, 1.27 3.50). Subgroup analysis on accessory pathway location revealed a higher adjusted hazard of heart failure for a right anteroseptal accessory pathway (HR, 5.88; 95% CI, 2.63-13.1). There was no evidence of a higher hazard of death among individuals with preexcitation when looking across all age groups (HR, 1.07; 95% CI, 0.68-1.68). However, a statistically significant (P=0.01) interaction analysis (<65 versus >=65 years) indicated a higher hazard of death for patients with preexcitation >=65 years (HR, 1.85; 95% CI, 1.07-3.18). CONCLUSIONS: In this large ECG study, individuals with preexcitation had higher hazards of atrial fibrillation and heart failure. The higher hazard of heart failure seemed to be driven by a right anteroseptal accessory pathway. Among elderly people, we found a statistically significant association between preexcitation and a higher hazard of death. PMID- 28576782 TI - Tenecteplase in ischemic stroke offers improved recanalization: Analysis of 2 trials. AB - OBJECTIVE: To test whether patients with complete vessel occlusion show greater recanalization at 24 hours and have improved clinical outcomes at 24 hours and 90 days when treated with tenecteplase compared to alteplase. METHODS: Pooled clinical and imaging data from 2 phase 2 randomized trials comparing tenecteplase with alteplase allowed CT angiography (CTA) scans to be assessed centrally for occlusion status at baseline and at 24 hours post thrombolysis using the modified thrombolysis in cerebral infarction (TICI) scale. Twenty-four-hour poststroke NIH Stroke Scale (NIHSS) and 90-day modified Rankin Scale (mRS) scores were also compared between treatment groups using linear regression to generate odds ratios (ORs). RESULTS: From 146 pooled patients, 69 had a TICI 0/1 occlusion overall at baseline. Tenecteplase-treated patients with a complete vessel occlusion had greater complete recanalization rates at 24 hours (71% for tenecteplase vs 43% for alteplase, p < 0.001). Patients with a TICI 0/1 occlusion who were treated with tenecteplase also showed greater early clinical improvement (median NIHSS change with tenecteplase was 9, interquartile range [IQR] 6, alteplase 1, IQR 1, p = 0.001) and higher rates of favorable 90-day outcomes (mRS 0-1 of tenecteplase compared with alteplase, OR 4.82, 95% confidence interval 1.02-7.84, p = 0.05). CONCLUSIONS: Tenecteplase may offer greater recanalization efficacy compared to alteplase, possibly exaggerated in patients with complete vessel occlusions on baseline CTA. PMID- 28576785 TI - Chlamydia trachomatis-induced reactive arthritis in India: frequency and clinical presentation. PMID- 28576783 TI - Survival and Left Ventricular Function Changes in Fulminant Versus Nonfulminant Acute Myocarditis. AB - BACKGROUND: Previous reports have suggested that despite their dramatic presentation, patients with fulminant myocarditis (FM) might have better outcome than those with acute nonfulminant myocarditis (NFM). In this retrospective study, we report outcome and changes in left ventricular ejection fraction (LVEF) in a large cohort of patients with FM compared with patients with NFM. METHODS: The study population consists of 187 consecutive patients admitted between May 2001 and November 2016 with a diagnosis of acute myocarditis (onset of symptoms <1 month) of whom 55 required inotropes and/or mechanical circulatory support (FM) and the remaining 132 were hemodynamically stable (NFM). We also performed a subanalysis in 130 adult patients with acute viral myocarditis and viral prodrome within 2 weeks from the onset, which includes 34 with FM and 96 with NFM. Patients with giant-cell myocarditis, eosinophilic myocarditis, or cardiac sarcoidosis and those <15 years of age were excluded from the subanalysis. RESULTS: In the whole population (n=187), the rate of in-hospital death or heart transplantation was 25.5% versus 0% in FM versus NFM, respectively (P<0.0001). Long-term heart transplantation-free survival at 9 years was lower in FM than NFM (64.5% versus 100%, log-rank P<0.0001). Despite greater improvement in LVEF during hospitalization in FM versus NFM forms (median, 32% [interquartile range, 20%-40%] versus 3% [0%-10%], respectively; P<0.0001), the proportion of patients with LVEF <55% at last follow-up was higher in FM versus NFM (29% versus 9%; relative risk, 3.32; 95% confidence interval, 1.45-7.64, P=0.003). Similar results for survival and changes in LVEF in FM versus NFM were observed in the subgroup (n=130) with viral myocarditis. None of the patients with NFM and LVEF >=55% at discharge had a significant decrease in LVEF at follow-up. CONCLUSIONS: Patients with FM have an increased mortality and need for heart transplantation compared with those with NFM. From a functional viewpoint, patients with FM have a more severely impaired LVEF at admission that, despite steep improvement during hospitalization, remains lower than that in patients with NFM at long-term follow up. These findings also hold true when only the viral forms are considered and are different from previous studies showing better prognosis in FM. PMID- 28576786 TI - Pilot study for the 'Test n Treat' trial of on-site rapid chlamydia/gonorrhoea tests and same day treatment. PMID- 28576787 TI - Use of Multimodality Imaging in Diagnosing Invasive Fungal Diseases of the Heart. PMID- 28576819 TI - Time to put health at the heart of all policy making. PMID- 28576788 TI - Pigs, Unlike Mice, Have Two Distinct Colonic Stem Cell Populations Similar to Humans That Respond to High-Calorie Diet prior to Insulin Resistance. AB - Basal colonic crypt stem cells are long lived and play a role in colon homeostasis. Previous evidence has shown that high-calorie diet (HCD) enhances colonic stem cell numbers and expansion of the proliferative zone, an important biomarker for colon cancer. However, it is not clear how HCD drives dysregulation of colon stem cell/colonocyte proliferative kinetics. We used a human-relevant pig model and developed an immunofluorescence technique to detect and quantify colonic stem cells. Pigs (n = 8/group) were provided either standard diet (SD; 5% fat) or HCD (23% fat) for 13 weeks. HCD- and SD-consuming pigs had similar total calorie intake, serum iron, insulin, and glucose levels. However, HCD elevated both colonic proliferative zone (KI-67) and stem cell zone (ASCL-2 and BMI-1). Proliferative zone correlated with elevated innate colonic inflammatory markers TLR-4, NF-kappaB, IL6, and lipocalin-2 (r >= 0.62, P = 0.02). Elevated gut bacterial phyla proteobacteria and firmicutes in HCD-consuming pigs correlated with proliferative and stem cell zone. Colonic proteome data revealed the upregulation of proteins involved in cell migration and proliferation and correlated with proliferative and stem cell zone expansion. Our study suggests that pig colon, unlike mice, has two distinct stem cells (ASCL-2 and BMI-1) similar to humans, and HCD increases expansion of colonic proliferative and stem cell zone. Thus, pig model can aid in the development of preventive strategies against gut bacterial dysbiosis and inflammation-promoted diseases, such as colon cancer. Cancer Prev Res; 10(8); 442-50. (c)2017 AACR. PMID- 28576820 TI - miR-210 expression is associated with methionine-induced differentiation of trout satellite cells. AB - In fish, data on microRNAs (miRNAs) involved in myogenesis are scarce. In order to identify miRNAs involved in satellite cell differentiation, we used a methionine depletion/replenishment protocol to synchronize myogenic cell differentiation. Our results validated that methionine removal (72 h) from the medium strongly decreased myoD1 and myogenin expression, indicating differentiation arrest. In contrast, methionine replenishment rescued expression of myoD1 and myogenin, showing a resumption of differentiation. We performed a miRNA array analysis of myogenic cells under three conditions: presence of methionine for 72 h (control), absence of methionine for 72 h (Meth-) and absence of methionine for 48 h followed by 24 h of methionine replenishment (Meth-/+). A clustering analysis identified three clusters: cluster I corresponds to miRNA upregulated only in Meth-/+ conditions; cluster II corresponds to miRNA downregulated only in Meth-/+ conditions; cluster III corresponds to miRNAs with high expression in control, low expression in Meth- conditions and intermediate expression after methionine replenishment (Meth-/+). Cluster III was very interesting because it fitted with the data obtained for myoD1 and myogenin (supporting an involvement in differentiation) and contained seven miRNAs with muscle-related function (e.g. miR-133a) and one (miR-210) with unknown function. Based on our previously published miRNA repertoire ( Juanchich et al., 2016), we confirmed miR-133a was expressed only in white muscle and showed that miR-210 had strong expression in white muscle. We also showed that miR-210 expression was upregulated during differentiation of satellite cells, suggesting that miR-210 was potentially involved in the differentiation of satellite cells. PMID- 28576821 TI - Contraction-induced enhancement of relaxation during high force contractions of mouse lumbrical muscle at 37 degrees C. AB - Repeated stimulation of unfatigued rodent fast-twitch skeletal muscle accelerates the kinetics of tension relaxation through an unknown mechanism. This effect varies with muscle type and stimulation parameters, and has been observed at physiological temperatures for submaximal but not maximal contractions. The purpose of this study was to compare relaxation kinetics of C57BL/6 mouse lumbrical muscles ex vivo from maximal isometric force (500 Hz for 20 ms) when evoked before (pre) and after (post) an intervening tetanic contraction at 37 degrees C. During post contractions, we noted significant increases in the rate of tension decline during both the slow linear phase and the fast exponential phase of relaxation, as well as a reduced duration of the slow phase of relaxation compared with pre contractions (all P<0.05). This is the first demonstration of enhanced slow and fast relaxation phases from maximal isometric tension induced by prior stimulation in intact muscle at a physiological temperature. PMID- 28576823 TI - Heart rate dynamics in a marsupial hibernator. AB - The eastern pygmy possum (Cercartetus nanus) is a small marsupial that can express spontaneous short bouts of torpor, as well as multi-day bouts of deep hibernation. To examine heart rate (fH) control at various stages of torpor in a marsupial hibernator, and to see whether fH variability differs from that of deep placental hibernators, we used radiotelemetry to measure ECG and body temperature (Tb) while measuring the rate of O2 consumption and ventilation. fH and O2 consumption rate during euthermia were at a minimum (321+/-34 beats min-1, 0.705+/-0.048 ml O2 g-1 h-1) at an ambient temperature (Ta) of 31 degrees C. fH had an inverse linear relationship with Ta to a maximum of 630+/-19 beats min-1 at a Ta of 20 degrees C. During entry into torpor at a Ta of 20 degrees C, fH slowed primarily as a result of episodic periods of cardiac activity where electrical activity of the heart occurred in groups of 3 or 4 heart beats. When Tb was stable at 24 degrees C in these torpor bouts, the episodic nature of fH had disappeared (i.e. no asystoles) with a rate of 34+/-3 beats min-1 For multi day bouts of deep torpor, Ta was lowered to 6.6+/-0.8 degrees C. During these deep bouts of torpor, Tb reached a minimum of 8.0+/-1.0 degrees C, with a minimum fH of 8 beats min-1 and a minimum O2 consumption rate of 0.029+/-0.07 ml O2 g-1 h 1 Shivering bouts occurred in deep torpor about every 8 min, during which ventilation occurred, and fH was elevated to 40 beats min-1 The duration of the QRS complex increased from 12 ms during euthermia to 69 ms at a Tb of 8 degrees C. These findings demonstrate the dynamic functioning range of fH to be about 600 beats min-1 (~80-fold), one of the largest known ranges in mammals. Our study shows that despite a separation of ~160 million years, the control and function of the cardiac system seems indistinguishable in marsupial and placental hibernating mammals. PMID- 28576822 TI - Ammonia exposure affects the mRNA and protein expression levels of certain Rhesus glycoproteins in the gills of climbing perch. AB - The freshwater climbing perch, Anabas testudineus, is an obligate air-breathing and euryhaline teleost capable of active ammonia excretion and tolerant of high concentrations of environmental ammonia. As Rhesus glycoproteins (RhGP/Rhgp) are known to transport ammonia, this study aimed to obtain the complete cDNA coding sequences of various rhgp isoforms from the gills of A. testudineus, and to determine their mRNA and protein expression levels during 6 days of exposure to 100 mmol l-1 NH4Cl. The subcellular localization of Rhgp isoforms in the branchial epithelium was also examined in order to elucidate the type of ionocyte involved in active ammonia excretion. Four rhgp (rhag, rhbg, rhcg1 and rhcg2) had been identified from the gills of A. testudineus They had conserved amino acid residues for NH4+ binding, NH4+ deprotonation, channel gating and lining of the vestibules. Despite inwardly directed NH3 and NH4+ gradients, there were significant increases in the mRNA expression levels of the four branchial rhgp in A. testudineus at certain time points during 6 days of ammonia exposure, with significant increases in the protein abundances of Rhag and Rhcg2 on day 6. Immunofluorescence microscopy revealed a type of ammonia-inducible Na+/K+-ATPase alpha1c-immunoreactive ionocyte with apical Rhag and basolateral Rhcg2 in the gills of fish exposed to ammonia for 6 days. Hence, active ammonia excretion may involve NH4+ entering the ionocyte through the basolateral Rhcg2 and being excreted through the apical Rhag, driven by a transapical membrane electrical potential generated by the apical cystic fibrosis transmembrane conductance regulator Cl- channel, as suggested previously. PMID- 28576824 TI - Pre-settlement coral-reef fish larvae respond to magnetic field changes during the day. AB - Observations of coral-reef fish larvae have revealed remarkably consistent orientation behaviour while swimming offshore, requiring large-scale orientation cues. However, the mechanisms underlying this behaviour are still being investigated. One potential large-scale cue for orientation is the Earth's geomagnetic field. Here, we examined the effect of magnetic field manipulations on the orientation behaviour of coral-reef fish during the pelagic larval phase. In the absence of visual cues, individual larvae responded to a 90 deg shift of the horizontal component of the magnetic field within a Helmholtz coil with a comparable shift in orientation, demonstrating that they use a magnetic compass for orientation. Our findings suggest that geomagnetic field information guides swimming behaviour of larval fish in the pre-settlement phase. The ability to use large-scale sensory cues allows location-independent orientation of swimming, a behaviour that influences dispersal and connectivity of fish populations, which has important ecological implications for anthropogenic development of marine areas. PMID- 28576825 TI - Identification of an optimized 2'-O-methylated trinucleotide RNA motif inhibiting Toll-like receptors 7 and 8. AB - Bacterial RNA serves an important function as activator of the innate immune system. In humans bacterial RNA is sensed by the endosomal receptors TLR7 and TLR8. Differences in the posttranscriptional modification profile of prokaryotic when compared with eukaryotic RNA allow innate immune cells to discriminate between "host" and "foreign" RNA. Ribose 2'-O-methylation is of particular importance and has been reported to antagonize TLR7/8 activation. Yet, the exact sequence context in which 2'-O-methylation has to occur to mediate its inhibitory activity remains largely undefined. On the basis of a naturally occurring 2'-O methylated RNA sequence, we performed a systematic permutation of the methylated nucleotide as well as adjacent bases and hereby identify two minimal trinucleotide motifs within a 9-mer oligoribonucleotide that are necessary and sufficient to antagonize TLR7 and TLR8 activation, respectively. Given the growing interest in the development of inhibitors of nucleic acid-sensing TLRs for therapeutic purposes, these results will facilitate the rational design of such antagonists in the future. PMID- 28576826 TI - Archaeal fibrillarin-Nop5 heterodimer 2'-O-methylates RNA independently of the C/D guide RNP particle. AB - Archaeal fibrillarin (aFib) is a well-characterized S-adenosyl methionine (SAM) dependent RNA 2'-O-methyltransferase that is known to act in a large C/D ribonucleoprotein (RNP) complex together with Nop5 and L7Ae proteins and a box C/D guide RNA. In the reaction, the guide RNA serves to direct the methylation reaction to a specific site in tRNA or rRNA by sequence complementarity. Here we show that a Pyrococcus abyssi aFib-Nop5 heterodimer can alone perform SAM dependent 2'-O-methylation of 16S and 23S ribosomal RNAs in vitro independently of L7Ae and C/D guide RNAs. Using tritium-labeling, mass spectrometry, and reverse transcription analysis, we identified three in vitro 2'-O-methylated positions in the 16S rRNA of P. abyssi, positions lying outside of previously reported pyrococcal C/D RNP methylation sites. This newly discovered stand-alone activity of aFib-Nop5 may provide an example of an ancestral activity retained in enzymes that were recruited to larger complexes during evolution. PMID- 28576827 TI - The transcriptional repressor GATAD2B mediates progesterone receptor suppression of myometrial contractile gene expression. AB - The mechanisms whereby progesterone (P4), acting via the progesterone receptor (PR), inhibits proinflammatory/contractile gene expression during pregnancy are incompletely defined. Using immortalized human myometrial (hTERT-HM) cells stably expressing wild-type PR-A or PR-B (PRWT), we found that P4 significantly inhibited IL-1beta induction of the NF-kappaB target genes, COX-2 and IL-8 P4 PRWT transrepression occurred at the level of transcription initiation and was mediated by decreased recruitment of NF-kappaB p65 and RNA polymerase II to COX-2 and IL-8 promoters. However, in cells stably expressing a PR-A or PR-B DNA binding domain mutant (PRmDBD), P4-mediated transrepression was significantly reduced, suggesting a critical role of the PR DBD. ChIP analysis of hTERT-HM cells stably expressing PRWT or PRmDBD revealed that P4 treatment caused equivalent recruitment of PRWT and PRmDBD to COX-2 and IL-8 promoters, suggesting that PR inhibitory effects were not mediated by its direct DNA binding. Using immunoprecipitation, followed by MS, we identified a transcriptional repressor, GATA zinc finger domain-containing 2B (GATAD2B), that interacted strongly with PRWT but poorly with PRmDBD P4 treatment of PRWT hTERT-HM cells caused enhanced recruitment of endogenous GATAD2B to COX-2 and IL-8 promoters. Further, siRNA knockdown of endogenous GATAD2B significantly reduced P4-PRWT transrepression of COX-2 and IL-8 Notably, GATAD2B expression was significantly decreased in pregnant mouse and human myometrium during labor. Our findings suggest that GATAD2B serves as an important mediator of P4-PR suppression of proinflammatory and contractile genes during pregnancy. Decreased GATAD2B expression near term may contribute to the decline in PR function, leading to labor. PMID- 28576828 TI - The intracellular chloride channel proteins CLIC1 and CLIC4 induce IL-1beta transcription and activate the NLRP3 inflammasome. AB - The NLRP3 inflammasome is a multiprotein complex that regulates the activation of caspase-1 leading to the maturation of the proinflammatory cytokines IL-1beta and IL-18 and promoting pyroptosis. Classically, the NLRP3 inflammasome in murine macrophages is activated by the recognition of pathogen-associated molecular patterns and by many structurally unrelated factors. Understanding the precise mechanism of NLRP3 activation by such a wide array of stimuli remains elusive, but several signaling events, including cytosolic efflux and influx of select ions, have been suggested. Accordingly, several studies have indicated a role of anion channels in NLRP3 inflammasome assembly, but their direct involvement has not been shown. Here, we report that the chloride intracellular channel proteins CLIC1 and CLIC4 participate in the regulation of the NLRP3 inflammasome. Confocal microscopy and cell fractionation experiments revealed that upon LPS stimulation of macrophages, CLIC1 and CLIC4 translocated into the nucleus and cellular membrane. In LPS/ATP-stimulated bone marrow-derived macrophages (BMDMs), CLIC1 or CLIC4 siRNA transfection impaired transcription of IL-1beta, ASC speck formation, and secretion of mature IL-1beta. Collectively, our results demonstrate that CLIC1 and CLIC4 participate both in the priming signal for IL-1beta and in NLRP3 activation. PMID- 28576829 TI - Differential effects of the dynein-regulatory factor Lissencephaly-1 on processive dynein-dynactin motility. AB - Cytoplasmic dynein is the primary minus-end-directed microtubule motor protein in animal cells, performing a wide range of motile activities, including transport of vesicular cargos, mRNAs, viruses, and proteins. Lissencephaly-1 (LIS1) is a highly conserved dynein-regulatory factor that binds directly to the dynein motor domain, uncoupling the enzymatic and mechanical cycles of the motor and stalling dynein on the microtubule track. Dynactin, another ubiquitous dynein-regulatory factor, releases dynein from an autoinhibited state, leading to a dramatic increase in fast, processive dynein motility. How these opposing activities are integrated to control dynein motility is unknown. Here, we used fluorescence single-molecule microscopy to study the interaction of LIS1 with the processive dynein-dynactin-BicD2N (DDB) complex. Surprisingly, in contrast to the prevailing model for LIS1 function established in the context of dynein alone, we found that binding of LIS1 to DDB does not strongly disrupt processive motility. Motile DDB complexes bound up to two LIS1 dimers, and mutational analysis suggested that LIS1 binds directly to the dynein motor domains during DDB movement. Interestingly, LIS1 enhanced DDB velocity in a concentration-dependent manner, in contrast to observations of the effect of LIS1 on the motility of isolated dynein. Thus, LIS1 exerts concentration-dependent effects on dynein motility and can synergize with dynactin to enhance processive dynein movement. Our results suggest that the effect of LIS1 on dynein motility depends on both LIS1 concentration and the presence of other regulatory factors such as dynactin and may provide new insights into the mechanism of LIS1 haploinsufficiency in the neurodevelopmental disorder lissencephaly. PMID- 28576831 TI - Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAFV600E Melanoma Lines with Vemurafenib. AB - Over 60% of human melanoma tumors bear a mutation in the BRAF gene. The most frequent mutation is a substitution at codon 600 (V600E), leading to a constitutively active BRAF and overactivation of the MAPK pathway. Patients harboring mutated BRAF respond to kinase inhibitors such as vemurafenib. However, these responses are transient, and relapses are frequent. Melanoma cells are efficiently lysed by activated natural killer (NK) cells. Melanoma cells express several stress-induced ligands that are recognized by activating NK-cell receptors. We have investigated the effect of vemurafenib on the immunogenicity of seven BRAF-mutated melanoma cells to NK cells and on their growth and sensitivity to NK-cell-mediated lysis. We showed that vemurafenib treatment modulated expression of ligands for two activating NK receptors, increasing expression of B7-H6, a ligand for NKp30, and decreasing expression of MICA and ULBP2, ligands for NKG2D. Vemurafenib also increased expression of HLA class I and HLA-E molecules, likely leading to higher engagement of inhibitory receptors (KIRs and NKG2A, respectively), and decreased lysis of vemurafenib-treated melanoma cell lines by cytokine-activated NK cells. Finally, we showed that whereas batimastat (a broad-spectrum matrix metalloprotease inhibitor) increased cell surface ULBP2 by reducing its shedding, vemurafenib lowered soluble ULBP2, indicating that BRAF signal inhibition diminished expression of both cell-surface and soluble forms of NKG2D ligands. Vemurafenib, inhibiting BRAF signaling, shifted the balance of activatory and inhibitory NK ligands on melanoma cells and displayed immunoregulatory effects on NK-cell functional activities. Cancer Immunol Res; 5(7); 582-93. (c)2017 AACR. PMID- 28576830 TI - GTPase Sar1 regulates the trafficking and secretion of the virulence factor gp63 in Leishmania. AB - Metalloprotease gp63 (Leishmania donovani gp63 (Ldgp63)) is a critical virulence factor secreted by Leishmania However, how newly synthesized Ldgp63 exits the endoplasmic reticulum (ER) and is secreted by this parasite is unknown. Here, we cloned, expressed, and characterized the GTPase LdSar1 and other COPII components like LdSec23, LdSec24, LdSec13, and LdSec31 from Leishmania to understand their role in ER exit of Ldgp63. Using dominant-positive (LdSar1:H74L) and dominant negative (LdSar1:T34N) mutants of LdSar1, we found that GTP-bound LdSar1 specifically binds to LdSec23, which binds, in turn, with LdSec24(1-702) to form a prebudding complex. Moreover, LdSec13 specifically interacted with His6 LdSec31(1-603), and LdSec31 bound the prebudding complex via LdSec23. Interestingly, dileucine 594/595 and valine 597 residues present in the Ldgp63 C terminal domain were critical for binding with LdSec24(703-966), and GFP Ldgp63L594A/L595A or GFP-Ldgp63V597S mutants failed to exit from the ER. Moreover, Ldgp63-containing COPII vesicle budding from the ER was inhibited by LdSar1:T34N in an in vitro budding assay, indicating that GTP-bound LdSar1 is required for budding of Ldgp63-containing COPII vesicles. To directly demonstrate the function of LdSar1 in Ldgp63 trafficking, we coexpressed RFP-Ldgp63 along with LdSar1:WT-GFP or LdSar1:T34N-GFP and found that LdSar1:T34N overexpression blocks Ldgp63 trafficking and secretion in Leishmania Finally, we noted significantly compromised survival of LdSar1:T34N-GFP-overexpressing transgenic parasites in macrophages. Taken together, these results indicated that Ldgp63 interacts with the COPII complex via LdSec24 for Ldgp63 ER exit and subsequent secretion. PMID- 28576832 TI - EET intervention on Wnt1, NOV, and HO-1 signaling prevents obesity-induced cardiomyopathy in obese mice. AB - We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on vascular function; in addition to its antiapoptotic action, it increases insulin sensitivity and inhibits inflammation. To uncover the signaling mechanisms by which EET reduces cardiomyopathy, we hypothesized that EET infusion might ameliorate obesity-induced cardiomyopathy by improving heme oxygenase (HO)-1, Wnt1, thermogenic gene levels, and mitochondrial integrity in cardiac tissues and improved pericardial fat phenotype. EET reduced levels of fasting blood glucose and proinflammatory adipokines, including nephroblastoma overexpressed (NOV) signaling, while increasing echocardiographic fractional shortening and O2 consumption. Of interest, we also noted a marked improvement in mitochondrial integrity, thermogenic genes, and Wnt 1 and HO-1 signaling mechanisms. Knockout of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) in EET-treated mice resulted in a reversal of these beneficial effects including a decrease in myocardial Wnt1 and HO-1 expression and an increase in NOV. To further elucidate the effects of EET on pericardial adipose tissues, we observed EET treatment increases in adiponectin, PGC-1alpha, phospho-AMP-activated protein kinase, insulin receptor phosphorylation, and thermogenic genes, resulting in a "browning" pericardial adipose phenotype under high-fat diets. Collectively, these experiments demonstrate that an EET agonist increased Wnt1 and HO-1 signaling while decreasing NOV pathways and the progression of cardiomyopathy. Furthermore, this report presents a portal into potential therapeutic approaches for the treatment of heart failure and metabolic syndrome.NEW & NOTEWORTHY The mechanism by which EET acts on obesity-induced cardiomyopathy is unknown. Here, we describe a previously unrecognized function of EET infusion that inhibits nephroblastoma overexpressed (NOV) levels and activates Wnt1, hence identifying NOV inhibition and enhanced Wnt1 expression as novel pharmacological targets for the prevention and treatment of cardiomyopathy and heart failure.Listen to this article's corresponding podcast at http://ajpheart.physiology.org/content/early/2017/05/31/ajpheart.00093.2017. PMID- 28576833 TI - Spinal cord stimulation reduces ventricular arrhythmias during acute ischemia by attenuation of regional myocardial excitability. AB - Myocardial ischemia creates autonomic nervous system imbalance and can trigger cardiac arrhythmias. We hypothesized that neuromodulation by spinal cord stimulation (SCS) will attenuate local cardiac sympathoexcitation from ischemia induced increases in afferent signaling, reduce ventricular arrhythmias, and improve myocardial function during acute ischemia. Yorkshire pigs (n = 20) were randomized to SCS (50 Hz at 200-MUs duration, current 90% motor threshold) or sham operation (sham) for 30 min before ischemia. A four-pole SCS lead was placed percutaneously in the epidural space (T1-T4), and a 56-electrode mesh was placed over the heart for high-resolution electrophysiological recordings, including activation recovery intervals (ARIs), activation time, repolarization time, and dispersion of repolarization. Electrophysiological and hemodynamic measures were recorded at baseline, after SCS/sham, during acute ischemia (300-s coronary artery ligation), and throughout reperfusion. SCS 1) reduced sympathoexcitation induced ARI and repolarization time shortening in the ischemic myocardium; 2) attenuated increases in the dispersion of repolarization; 3) reduced ventricular tachyarrythmias [nonsustained ventricular tachycardias: 24 events (3 sham animals) vs. 1 event (1 SCS animal), P < 0.001]; and 4) improved myocardial function (dP/dt from baseline to ischemia: 1,814 +/- 213 to 1,596 +/- 282 mmHg/s in sham vs. 1,422 +/- 299 to 1,380 +/- 299 mmHg/s in SCS, P < 0.01). There was no change in ventricular electrophysiology during baseline conditions without myocardial stress or in the nonischemic myocardium. In conclusion, in a porcine model of acute ventricular ischemia, SCS reduced regional myocardial sympathoexcitation, decreased ventricular arrhythmias, and improved myocardial function. SCS decreased sympathetic nerve activation locally in the ischemic myocardium with no effect observed in the normal myocardium, thus providing mechanistic insights into the antiarrhythmic and myocardial protective effects of SCS.NEW & NOTEWORTHY In a porcine model of ventricular ischemia, spinal cord stimulation decreased sympathetic nerve activation regionally in ischemic myocardium with no effect on normal myocardium, demonstrating that the antiarrhythmic effects of spinal cord stimulation are likely due to attenuation of local sympathoexcitation in the ischemic myocardium and not changes in global myocardial electrophysiology. PMID- 28576835 TI - Relative contributions from the ventricle and arterial tree to arterial pressure and its amplification: an experimental study. AB - Arterial pressure is an important diagnostic parameter for cardiovascular disease. However, relative contributions of individual ventricular and arterial parameters in generating and augmenting pressure are not understood. Using a novel experimental arterial model, our aim was to characterize individual parameter contributions to arterial pressure and its amplification. A piston driven ventricle provided programmable stroke profiles into various silicone arterial trees and a bovine aorta. Inotropy was varied in the ventricle, and arterial parameters modulated included wall thickness, taper and diameter, the presence of bifurcation, and a native aorta (bovine) versus silicone. Wave reflection at bifurcations was measured and compared with theory, varying parent to-child tube diameter ratios, and branch angles. Intravascular pressure-tip wires and ultrasonic flow probes measured pressure and flow. Increasing ventricular inotropy independently augmented pressure amplification from 17% to 61% between the lower and higher systolic gradient stroke profiles in the silicone arterial network and from 10% to 32% in the bovine aorta. Amplification increased with presence of a bifurcation, decreasing wall thickness and vessel taper. Pulse pressure increased with increasing wall thickness (stiffness) and taper angle and decreasing diameter. Theoretical predictions of wave transmission through bifurcations werre similar to measurements (correlation: 0.91, R2 = 0.94) but underestimated wave reflection (correlation: 0.75, R2 = 0.94), indicating energy losses during mechanical wave reflection. This study offers the first comprehensive investigation of contributors to hypertensive pressure and its propagation throughout the arterial tree. Importantly, ventricular inotropy plays a crucial role in the amplification of peripheral pressure wave, which offers opportunity for noninvasive assessment of ventricular health.NEW & NOTEWORTHY The present study distinguishes contributions from cardiac and arterial parameters to elevated blood pressure and pressure amplification. Most importantly, it offers the first evidence that ventricular inotropy, an indicator of ventricular function, is an independent determinant of pressure amplification and could be measured with such established devices such as the SphygmoCor. PMID- 28576834 TI - Autophagy modulation: a potential therapeutic approach in cardiac hypertrophy. AB - Autophagy is an evolutionarily conserved process used by the cell to degrade cytoplasmic contents for quality control, survival for temporal energy crisis, and catabolism and recycling. Rapidly increasing evidence has revealed an important pathogenic role of altered activity of the autophagosome-lysosome pathway (ALP) in cardiac hypertrophy and heart failure. Although an early study suggested that cardiac autophagy is increased and that this increase is maladaptive to the heart subject to pressure overload, more recent reports have overwhelmingly supported that myocardial ALP insufficiency results from chronic pressure overload and contributes to maladaptive cardiac remodeling and heart failure. This review examines multiple lines of preclinical evidence derived from recent studies regarding the role of autophagic dysfunction in pressure overloaded hearts, attempts to reconcile the discrepancies, and proposes that resuming or improving ALP flux through coordinated enhancement of both the formation and the removal of autophagosomes would benefit the treatment of cardiac hypertrophy and heart failure resulting from chronic pressure overload. PMID- 28576837 TI - Hypothalamic Inflammation in Human Obesity Is Mediated by Environmental and Genetic Factors. AB - Obesity is associated with hypothalamic inflammation (HI) in animal models. In the current study, we examined the mediobasal hypothalamus (MBH) of 57 obese human subjects and 54 age- and sex- matched nonobese control subjects by MRI and analyzed the T2 hyperintensity as a measure of HI. Obese subjects exhibited T2 hyperintensity in the left but not the right MBH, which was strongly associated with systemic low-grade inflammation. MRS revealed the number of neurons in the left hypothalamic region to be similar in obese versus control subjects, suggesting functional but not structural impairment due to the inflammatory process. To gain mechanistic insights, we performed nutritional analysis and 16S rDNA microbiome sequencing, which showed that high-fat diet induces reduction of Parasutterella sp. in the gut, which is significantly correlated with MBH T2 hyperintensity. In addition to these environmental factors, we found subjects carrying common polymorphisms in the JNK or the MC4R gene to be more susceptible to HI. Finally, in a subgroup analysis, bariatric surgery had no effect on MBH T2 hyperintensity despite inducing significant weight loss and improvement of peripheral insulin sensitivity. In conclusion, obesity in humans is associated with HI and disturbances in the gut-brain axis, which are influenced by both environmental and genetic factors. PMID- 28576841 TI - Quantifying the Benefits of Genome-Driven Oncology. AB - The excitement surrounding genomically selected cancer therapy has led many to question whether this treatment paradigm is living up to its initial promise. The MOSCATO study suggests that a genome-driven strategy for cancer therapy improves outcomes in a significant minority of patients who undergo molecular screening. Cancer Discov; 7(6); 552-4. (c)2017 AACR.See related article by Massard et al., p. 586. PMID- 28576842 TI - Toward Molecularly Driven Precision Medicine in Lung Adenocarcinoma. AB - Assessing the benefit of routine panel-based genomic sequencing of tumor tissue remains a critical need in clinical oncology. Jordan and coauthors report on 860 patients with metastatic or recurrent lung adenocarcinoma from a single institution with prospectively sequenced tumors using a targeted gene panel of >300 genes to guide therapy. Their results suggest that early prospective tumor sequencing, including non-standard-of-care predictive biomarkers combined with careful clinical annotation, can guide therapy, improve clinical outcomes, and accelerate the development of biomarkers and drugs. Cancer Discov; 7(6); 555-7. (c)2017 AACRSee related article by Jordan et al., p. 596. PMID- 28576843 TI - Targeting BRAF-Mutant Colorectal Cancer: Progress in Combination Strategies. AB - BRAF mutations in colorectal cancer portend a poor prognosis, with first line treatment often involving triplet or quadruplet chemotherapy, and single agent targeted therapy with BRAF inhibitors failing to demonstrate clinical activity. Blockade of multiple critical nodes along the MAPK and other pathways may be necessary to improve response rates and survival. Cancer Discov; 7(6); 558 60. (c)2017 AACR.See related article by van Geel et al., p. 610. PMID- 28576844 TI - The Sequences of 1504 Mutants in the Model Rice Variety Kitaake Facilitate Rapid Functional Genomic Studies. AB - The availability of a whole-genome sequenced mutant population and the cataloging of mutations of each line at a single-nucleotide resolution facilitate functional genomic analysis. To this end, we generated and sequenced a fast-neutron-induced mutant population in the model rice cultivar Kitaake (Oryza sativa ssp japonica), which completes its life cycle in 9 weeks. We sequenced 1504 mutant lines at 45 fold coverage and identified 91,513 mutations affecting 32,307 genes, i.e., 58% of all rice genes. We detected an average of 61 mutations per line. Mutation types include single-base substitutions, deletions, insertions, inversions, translocations, and tandem duplications. We observed a high proportion of loss-of function mutations. We identified an inversion affecting a single gene as the causative mutation for the short-grain phenotype in one mutant line. This result reveals the usefulness of the resource for efficient, cost-effective identification of genes conferring specific phenotypes. To facilitate public access to this genetic resource, we established an open access database called KitBase that provides access to sequence data and seed stocks. This population complements other available mutant collections and gene-editing technologies. This work demonstrates how inexpensive next-generation sequencing can be applied to generate a high-density catalog of mutations. PMID- 28576845 TI - Cytokinin Signaling Activates WUSCHEL Expression during Axillary Meristem Initiation. AB - The homeodomain transcription factor WUSCHEL (WUS) defines the shoot stem cell niche, but the mechanisms underlying the establishment of WUS expression remain unclear. Here, we show that cytokinin signaling precedes WUS expression in leaf axils and activates WUS expression de novo in the leaf axil to promote axillary meristem initiation. Furthermore, type-B Arabidopsis response regulator proteins, which are transcriptional activators in the cytokinin signaling pathway, directly bind to the WUS promoter and activate its expression. Finally, we show that cytokinin activation of WUS in the leaf axil correlates with increased histone acetylation and methylation markers associated with transcriptional activation, supporting the fact that WUS expression requires a permissive epigenetic environment to restrict it to highly defined meristematic tissues. Taken together, these findings explain how cytokinin regulates axillary meristem initiation and establish a mechanistic framework for the postembryonic establishment of the shoot stem cell niche. PMID- 28576846 TI - Type-B ARABIDOPSIS RESPONSE REGULATORs Specify the Shoot Stem Cell Niche by Dual Regulation of WUSCHEL. AB - Plants are known for their capacity to regenerate the whole body through de novo formation of apical meristems from a mass of proliferating cells named callus. Exogenous cytokinin and auxin determine cell fate for the establishment of the stem cell niche, which is the vital step of shoot regeneration, but the underlying mechanisms remain unclear. Here, we show that type-B ARABIDOPSIS RESPONSE REGULATORs (ARRs), critical components of cytokinin signaling, activate the transcription of WUSCHEL (WUS), which encodes a key regulator for maintaining stem cells. In parallel, type-B ARRs inhibit auxin accumulation by repressing the expression of YUCCAs, which encode a key enzyme for auxin biosynthesis, indirectly promoting WUS induction. Both pathways are essential for de novo regeneration of the shoot stem cell niche. In addition, the dual regulation of type-B ARRs on WUS transcription is required for the maintenance of the shoot apical meristem in planta. Thus, our results reveal a long-standing missing link between cytokinin signaling and WUS regulator, and the findings provide critical information for understanding cell fate specification. PMID- 28576847 TI - Arabidopsis WRKY46, WRKY54, and WRKY70 Transcription Factors Are Involved in Brassinosteroid-Regulated Plant Growth and Drought Responses. AB - Plant steroid hormones, brassinosteroids (BRs), play important roles in growth and development. BR signaling controls the activities of BRASSINOSTERIOD INSENSITIVE1-EMS-SUPPRESSOR1/BRASSINAZOLE-RESISTANT1 (BES1/BZR1) family transcription factors. Besides the role in promoting growth, BRs are also implicated in plant responses to drought stress. However, the molecular mechanisms by which BRs regulate drought response have just begun to be revealed. The functions of WRKY transcription factors in BR-regulated plant growth have not been established, although their roles in stress responses are well documented. Here, we found that three Arabidopsis thaliana group III WRKY transcription factors, WRKY46, WRKY54, and WRKY70, are involved in both BR-regulated plant growth and drought response as the wrky46 wrky54 wrky70 triple mutant has defects in BR-regulated growth and is more tolerant to drought stress. RNA-sequencing analysis revealed global roles of WRKY46, WRKY54, and WRKY70 in promoting BR mediated gene expression and inhibiting drought responsive genes. WRKY54 directly interacts with BES1 to cooperatively regulate the expression of target genes. In addition, WRKY54 is phosphorylated and destabilized by GSK3-like kinase BR INSENSITIVE2, a negative regulator in the BR pathway. Our results therefore establish WRKY46/54/70 as important signaling components that are positively involved in BR-regulated growth and negatively involved in drought responses. PMID- 28576848 TI - Identification of Fc Gamma Receptor Glycoforms That Produce Differential Binding Kinetics for Rituximab. AB - Fc gamma receptors (FcgammaR) bind the Fc region of antibodies and therefore play a prominent role in antibody-dependent cell-based immune responses such as ADCC, CDC and ADCP. The immune effector cell activity is directly linked to a productive molecular engagement of FcgammaRs where both the protein and glycan moiety of antibody and receptor can affect the interaction and in the present study we focus on the role of the FcgammaR glycans in this interaction. We provide a complete description of the glycan composition of Chinese hamster ovary (CHO) expressed human Fcgamma receptors RI (CD64), RIIaArg131/His131 (CD32a), RIIb (CD32b) and RIIIaPhe158/Val158 (CD16a) and analyze the role of the glycans in the binding mechanism with IgG. The interactions of the monoclonal antibody rituximab with each FcgammaR were characterized and we discuss the CHO FcgammaRIIIaPhe158/Val158 and CHO-FcgammaRI interactions and compare them to the equivalent interactions with human (HEK293) and murine (NS0) produced receptors. Our results reveal clear differences in the binding profiles of rituximab, which we attribute in each case to the differences in host cell-dependent FcgammaR glycosylation. The glycan profiles of CHO expressed FcgammaRI and FcgammaRIIIaPhe158/Val158 were compared with the glycan profiles of the receptors expressed in NS0 and HEK293 cells and we show that the glycan type and abundance differs significantly between the receptors and that these glycan differences lead to the observed differences in the respective FcgammaR binding patterns with rituximab. Oligomannose structures are prevalent on FcgammaRI from each source and likely contribute to the high affinity rituximab interaction through a stabilization effect. On FcgammaRI and FcgammaRIIIa large and sialylated glycans have a negative impact on rituximab binding, likely through destabilization of the interaction. In conclusion, the data show that the IgG1-FcgammaR binding kinetics differ depending on the glycosylation of the FcgammaR and further support a stabilizing role of FcgammaR glycans in the antibody binding interaction. PMID- 28576851 TI - Urinary Tamm-Horsfall protein, albumin, vitamin D-binding protein, and retinol binding protein as early biomarkers of chronic kidney disease in dogs. AB - Proteinuria is a marker and mediator of chronic kidney disease (CKD). In clinical practice, the urinary protein-to-creatinine ratio (UP/C) is of limited usefulness, because it indicates only the magnitude of proteinuria and not the origin of the loss (glomerular or tubular). The complete assessment of proteinuria includes quantitative and qualitative evaluations, both of which are required in order to optimize the therapy. In addition to measuring the UP/C, we performed SDS-PAGE and western blotting to determine the expression of albumin, vitamin D-binding protein (VDBP), retinol-binding protein (RBP), and Tamm Horsfall protein (THP) in urine samples of 49 dogs: healthy (control) dogs (n = 9); and dogs with CKD (n = 40), stratified by stage. In the dogs with stage 3 or 4 CKD, there was a predominance of tubular proteins. Neither VDBP nor RBP was observed in the urine of the control dogs. Among the dogs with stage 1 or 2 CKD, VDBP and RBP were detected in those without proteinuria or with borderline proteinuria. The expression of urinary albumin was significantly higher in the stage 4 group than in any other group (P <= 0.01). In the stage 4 group, urinary THP was either undetectable or lower than in the control group (P <= 0.01). In conclusion, urinary VDBP and RBP might act as early markers of kidney injury, and a decrease in urinary THP could be an indicator of CKD progression. PMID- 28576849 TI - Proteome-wide Identification of Glycosylation-dependent Interactors of Galectin-1 and Galectin-3 on Mesenchymal Retinal Pigment Epithelial (RPE) Cells. AB - Identification of interactors is a major goal in cell biology. Not only protein protein but also protein-carbohydrate interactions are of high relevance for signal transduction in biological systems. Here, we aim to identify novel interacting binding partners for the beta-galactoside-binding proteins galectin-1 (Gal-1) and galectin-3 (Gal-3) relevant in the context of the eye disease proliferative vitreoretinopathy (PVR). PVR is one of the most common failures after retinal detachment surgeries and is characterized by the migration, adhesion, and epithelial-to-mesenchymal transition of retinal pigment epithelial cells (RPE) and the subsequent formation of sub- and epiretinal fibrocellular membranes. Gal-1 and Gal-3 bind in a dose- and carbohydrate-dependent manner to mesenchymal RPE cells and inhibit cellular processes like attachment and spreading. Yet knowledge about glycan-dependent interactors of Gal-1 and Gal-3 on RPE cells is very limited, although this is a prerequisite for unraveling the influence of galectins on distinct cellular processes in RPE cells. We identify here 131 Gal-3 and 15 Gal-1 interactors by galectin pulldown experiments combined with quantitative proteomics. They mainly play a role in multiple binding processes and are mostly membrane proteins. We focused on two novel identified interactors of Gal-1 and Gal-3 in the context of PVR: the low-density lipoprotein receptor LRP1 and the platelet-derived growth factor receptor beta PDGFRB. Addition of exogenous Gal-1 and Gal-3 induced cross-linking with LRP1/PDGFRB and integrin-beta1 (ITGB1) on the cell surface of human RPE cells and induced ERK/MAPK and Akt signaling. Treatment with kifunensine, an inhibitor of complex type N-glycosylation, weakened the binding of Gal-1 and Gal-3 to these interactors and prevented lattice formation. In conclusion, the identified specific glycoprotein ligands shed light into the highly specific binding of galectins to dedifferentiated RPE cells and the resulting prevention of PVR associated cellular events. PMID- 28576852 TI - Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease. AB - Cardiovascular dysautonomia as well as the deterioration of circadian rhythms are among the earliest detectable pathophysiological changes in individuals with Huntington's disease (HD). Preclinical research requires mouse models that recapitulate disease symptoms and the Q175 knock-in model offers a number of advantages but potential autonomic dysfunction has not been explored. In this study, we sought to test the dual hypotheses that cardiovascular dysautonomia can be detected early in disease progression in the Q175 model and that this dysfunction varies with the daily cycle. Using radiotelemetry implants, we observed a significant reduction in the diurnal and circadian activity rhythms in the Q175 mutants at the youngest ages. By middle age, the autonomically driven rhythms in core body temperature were highly compromised, and the Q175 mutants exhibited striking episodes of hypothermia that increased in frequency with mutant huntingtin gene dosage. In addition, Q175 mutants showed higher resting heart rate (HR) during sleep and greatly reduced correlation between activity and HR HR variability was reduced in the mutants in both time and frequency domains, providing more evidence of autonomic dysfunction. Measurement of the baroreceptor reflex revealed that the Q175 mutant could not appropriately increase HR in response to a pharmacologically induced decrease in blood pressure. Echocardiograms showed reduced ventricular mass and ejection fraction in mutant hearts. Finally, cardiac histopathology revealed localized points of fibrosis resembling those caused by myocardial infarction. Thus, the Q175 mouse model of HD exhibits cardiovascular dysautonomia similar to that seen in HD patients with prominent sympathetic dysfunction during the resting phase of the activity rhythm. PMID- 28576853 TI - Myocardial apoptosis and mesenchymal stem cells with acute exercise. AB - Aerobic exercise confers many health benefits. However, numerous reports have shown that acute aerobic exercise can injure the heart. We tested the general hypothesis that acute moderate-intensity exercise in rodents induces cardiomyocyte damage and stimulates mesenchymal stem cells (MSCs) to increase paracrine-mediated protective effects on cardiomyocytes. A single session of treadmill running (13 m/min, 0% grade, for 45 min) in untrained C57BL/6 male mice (n = 18) increased cleaved poly ADP-ribose polymerase (PARP), a marker of apoptosis, in the myocardium 24 h postexercise. Microarray analysis of mouse myocardium identified 11 relevant apoptotic genes and several shifts in matrix remodeling transcripts over the postexercise window. Postexercise cardiomyocyte death was recapitulated in neonatal rat cardiomyocytes (NRCMs) by culturing cells in 2% plasma harvested from exercised rats. The increased cell death observed in exercise-treated NRCMs was attenuated by beta-adrenergic blockade, but not antioxidant treatment. MSC survival, proliferation, and chemotaxis showed no significant differences between sedentary and exercise plasma conditions, despite increased IL-6, TNF-alpha, IL-1beta, and IFN-gamma secretions from MSCs treated with exercise plasma. NRCM survival was increased nearly 500% when cocultured with MSCs, but this effect was not altered under exercise plasma culture conditions. Our results suggest acute moderate-intensity aerobic treadmill running in exercise-naive rodents induces temporal cardiomyocyte death due to plasma-borne factors, namely, catecholaminergic stress. Even though exercise conditions prompt an inflammatory response in MSCs, the exercise milieu does not alter the MSC-protective phenotype on cardiomyocytes. PMID- 28576854 TI - Mdivi-1 induced acute changes in the angiogenic profile after ischemia reperfusion injury in female mice. AB - The aim of this study is to determine the effects of mitochondrial division inhibitor 1 (Mdivi-1), the mitochondrial fission inhibitor, on the angiogenic profiles after the ischemia reperfusion injury (IR injury) in female mice. Female mice were treated with Mdivi-1 inhibitor, 2 days prior, on the day of IR injury and 2 days after IR injury, for a period of 5 days. Both control and treatment groups underwent 30 min of ischemia and 72 h of reperfusion. On the day 3, mice were sacrificed and the ischemic and nonischemic portions of heart tissue were collected. Relative levels of 53 angiogenesis-related proteins were quantified simultaneously using Angiogenic arrays. Heart function was evaluated before and after 72 h of IR injury. Mdivi-1 treatment ameliorated IR induced functional deterioration with positive angiogenic profile. The seminal changes include suppression of Matrix metalloproteinase (MMP3), tissue inhibitor of metalloproteases (TIMP1) and chemokine (C-X-C motif) ligand 10 (CXCL10) levels and prevention of connexin 43 (Cx43) loss and downregulation in the antioxidant enzyme levels. These changes are correlated with enhanced endothelial progenitor cell marker (cluster of differentiation (CD31), endothelial-specific receptor tyrosine kinase (Tek), fMS-like tyrosine kinase 4 (Flt4) and kinase insert domain protein receptor (Kdr)) presence. Our study is the first to report the role of mitochondrial dynamics in regulation of myocardial IR-induced angiogenic responses. Inhibition of excessive mitochondrial fission after IR injury ameliorated heart dysfunction and conferred positive angiogenic response. In addition, there were improvements in the preservation of Cx43 levels and oxidative stress handling along with suppression of apoptosis activation. The findings will aid in shaping the rational drug development process for the prevention of ischemic heart disease, especially in females. PMID- 28576856 TI - Oncology Drug Approvals: Evaluating Endpoints and Evidence in an Era of Breakthrough Therapies. PMID- 28576855 TI - Sodium balance, circadian BP rhythm, heart rate variability, and intrarenal renin angiotensin-aldosterone and dopaminergic systems in acute phase of ARB therapy. AB - We have revealed that even in humans, activated intrarenal renin-angiotensin aldosterone system (RAAS) enhances tubular sodium reabsorption to facilitate salt sensitivity and nondipper rhythm of blood pressure (BP), and that angiotensin receptor blocker (ARB) could increase daytime urinary sodium excretion rate (UNaV) to produce lower sodium balance and restore nondipper rhythm. However, the sympathetic nervous system and intrarenal dopaminergic system can also contribute to renal sodium handling. A total of 20 patients with chronic kidney disease (61 +/- 15 years) underwent 24-h ambulatory BP monitoring before and during two-day treatment with ARB, azilsartan. Urinary angiotensinogen excretion rate (UAGTV, MUg/gCre) was measured as intrarenal RAAS; urinary dopamine excretion rate (UDAV, pg/gCre) as intrarenal dopaminergic system; heart rate variabilities (HRV, calculated from 24-h Holter-ECG) of non-Gaussianity index lambda25s as sympathetic nerve activity; and power of high-frequency (HF) component or deceleration capacity (DC) as parasympathetic nerve activity. At baseline, glomerular filtration rate correlated inversely with UAGTV (r = -0.47, P = 0.04) and positively with UDAV (r = 0.58, P = 0.009). HF was a determinant of night/day BP ratio (beta = -0.50, F = 5.8), rather than DC or lambda25s During the acute phase of ARB treatment, a lower steady sodium balance was not achieved. Increase in daytime UNaV preceded restoration of BP rhythm, accompanied by decreased UAGTV (r = -0.88, P = 0.05) and increased UDAV (r = 0.87, P = 0.05), but with no changes in HRVs. Diminished sodium excretion can cause nondipper BP rhythm. This was attributable to intrarenal RAAS and dopaminergic system and impaired parasympathetic nerve activity. During the acute phase of ARB treatment, cooperative effects of ARB and intrarenal dopaminergic system exert natriuresis to restore circadian BP rhythm. PMID- 28576857 TI - BRAF Mutations as Predictive Biomarker for Response to Anti-EGFR Monoclonal Antibodies. AB - : Recently, the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) recommended that patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer could be treated with anti-EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab only in absence of Rat-Sarcoma (RAS) mutations. In addition to the previously established biomarker Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2, cumulative evidence also shows that patients whose tumors harbor KRAS exons 3 or 4 and neuroblastoma rat-sarcoma viral oncogene homolog (NRAS) exons 2, 3, and 4 mutations are found unlikely to benefit from anti-EGFR treatment.In line with the resistance of RAS mutated (mt) tumors, treatment response in BRAFmt tumors may also be altered given their important role in the EGFR signaling pathway. However, BRAF is not recommended as predictive biomarker yet because the evidence for the impact of BRAF mutations on treatment outcome is considered insufficient.This article summarizes the evidence for the impact of BRAF mutations on treatment outcome of anti-EGFR mAbs. Based on a review of literature, eight meta-analyses were included that consistently show that patients with BRAF mutations have a lack of treatment benefit of anti-EGFR mAbs. After discussing the quality and quantity of available evidence, we conclude that evidence is stronger than suggested by ESMO and ASCO. Additionally, we highlight that the quality of evidence for BRAF is even higher than for extended RAS as a biomarker. We therefore advise ESMO and ASCO to reconsider BRAF status as a predictive biomarker for response. IMPLICATIONS FOR PRACTICE: In metastatic colorectal cancer (mCRC), therapy with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab is indicated in absence of RAS mutations. Cumulative evidence shows that patients with BRAF mutations, who comprise 10% of the mCRC population, do not benefit from anti-EGFR-antibody treatment. Although guidelines state that evidence for BRAF as a predictive marker is insufficient, we highlight that the quality and quantity of evidence is higher than suggested. We therefore encourage the use of BRAF as a predictive marker in order to exclude patients from therapy for whom limited treatment benefit is expected. PMID- 28576859 TI - Regarding "Oncology Drug Approvals: Evaluating Endpoints and Evidence in an Era of Breakthrough Therapies". PMID- 28576858 TI - Inflammatory Arthritis: A Newly Recognized Adverse Event of Immune Checkpoint Blockade. PMID- 28576860 TI - Coordination of Heparan Sulfate Proteoglycans with Wnt Signaling To Control Cellular Migrations and Positioning in Caenorhabditis elegans. AB - Heparan sulfates (HS) are linear polysaccharides with complex modification patterns, which are covalently bound via conserved attachment sites to core proteins to form heparan sulfate proteoglycans (HSPGs). HSPGs regulate many aspects of the development and function of the nervous system, including cell migration, morphology, and network connectivity. HSPGs function as cofactors for multiple signaling pathways, including the Wnt-signaling molecules and their Frizzled receptors. To investigate the functional interactions among the HSPG and Wnt networks, we conducted genetic analyses of each, and also between these networks using five cellular migrations in the nematode Caenorhabditis elegans We find that HSPG core proteins act genetically in a combinatorial fashion dependent on the cellular contexts. Double mutant analyses reveal distinct redundancies among HSPGs for different migration events, and different cellular migrations require distinct heparan sulfate modification patterns. Our studies reveal that the transmembrane HSPG SDN-1/Syndecan functions within the migrating cell to promote cellular migrations, while the GPI-linked LON-2/Glypican functions cell nonautonomously to establish the final cellular position. Genetic analyses with the Wnt-signaling system show that (1) a given HSPG can act with different Wnts and Frizzled receptors, and that (2) a given Wnt/Frizzled pair acts with different HSPGs in a context-dependent manner. Lastly, we find that distinct HSPG and Wnt/Frizzled combinations serve separate functions to promote cellular migration and establish position of specific neurons. Our studies suggest that HSPGs use structurally diverse glycans in coordination with Wnt-signaling pathways to control multiple cellular behaviors, including cellular and axonal migrations and, cellular positioning. PMID- 28576861 TI - Pharmacological Inhibition of the DNA Damage Checkpoint Prevents Radiation Induced Oocyte Death. AB - Ovarian function is directly correlated with survival of the primordial follicle reserve. Women diagnosed with cancer have a primary imperative of treating the cancer, but since the resting oocytes are hypersensitive to the DNA-damaging modalities of certain chemo- and radiotherapeutic regimens, such patients face the collateral outcome of premature loss of fertility and ovarian endocrine function. Current options for fertility preservation primarily include the collection and cryopreservation of oocytes or in vitro-fertilized oocytes, but this necessitates a delay in cancer treatment and additional assisted reproductive technology procedures. Here, we evaluated the potential of pharmacological preservation of ovarian function by inhibiting a key element of the oocyte DNA damage checkpoint response, checkpoint kinase 2 (CHK2; CHEK2). Whereas nonlethal doses of ionizing radiation (IR) eradicate immature oocytes in wild-type mice, irradiated Chk2-/- mice retain their oocytes and, thus, fertility. Using an ovarian culture system, we show that transient administration of the CHK2 inhibitor 2-(4-(4-chlorophenoxy)phenyl)-1H-benzimidazole-5 carboxamide-hydrate ("CHK2iII") blocked activation of the CHK2 targets TRP53 and TRP63 in response to sterilizing doses of IR, and preserved oocyte viability. After transfer into sterilized host females, these ovaries proved functional and readily yielded normal offspring. These results provide experimental evidence that chemical inhibition of CHK2 is a potentially effective treatment for preserving the fertility and ovarian endocrine function of women exposed to DNA damaging cancer therapies such as IR. PMID- 28576862 TI - Genetics of Genome-Wide Recombination Rate Evolution in Mice from an Isolated Island. AB - Recombination rate is a heritable quantitative trait that evolves despite the fundamentally conserved role that recombination plays in meiosis. Differences in recombination rate can alter the landscape of the genome and the genetic diversity of populations. Yet our understanding of the genetic basis of recombination rate evolution in nature remains limited. We used wild house mice (Mus musculus domesticus) from Gough Island (GI), which diverged recently from their mainland counterparts, to characterize the genetics of recombination rate evolution. We quantified genome-wide autosomal recombination rates by immunofluorescence cytology in spermatocytes from 240 F2 males generated from intercrosses between GI-derived mice and the wild-derived inbred strain WSB/EiJ. We identified four quantitative trait loci (QTL) responsible for inter-F2 variation in this trait, the strongest of which had effects that opposed the direction of the parental trait differences. Candidate genes and mutations for these QTL were identified by overlapping the detected intervals with whole-genome sequencing data and publicly available transcriptomic profiles from spermatocytes. Combined with existing studies, our findings suggest that genome wide recombination rate divergence is not directional and its evolution within and between subspecies proceeds from distinct genetic loci. PMID- 28576863 TI - Evolving Mistranslating tRNAs Through a Phenotypically Ambivalent Intermediate in Saccharomyces cerevisiae. AB - The genetic code converts information from nucleic acid into protein. The genetic code was thought to be immutable, yet many examples in nature indicate that variations to the code provide a selective advantage. We used a sensitive selection system involving suppression of a deleterious allele (tti2-L187P) in Saccharomyces cerevisiae to detect mistranslation and identify mechanisms that allow genetic code evolution. Though tRNASer containing a proline anticodon (UGG) is toxic, using our selection system we identified four tRNASerUGG variants, each with a single mutation, that mistranslate at a tolerable level. Mistranslating tRNALeuUGG variants were also obtained, demonstrating the generality of the approach. We characterized two of the tRNASerUGG variants. One contained a G26A mutation, which reduced cell growth to 70% of the wild-type rate, induced a heat shock response, and was lost in the absence of selection. The reduced toxicity of tRNASerUGG-G26A is likely through increased turnover of the tRNA, as lack of methylation at G26 leads to degradation via the rapid tRNA decay pathway. The second tRNASerUGG variant, with a G9A mutation, had minimal effect on cell growth, was relatively stable in cells, and gave rise to less of a heat shock response. In vitro, the G9A mutation decreases aminoacylation and affects folding of the tRNA. Notably, the G26A and G9A mutations were phenotypically neutral in the context of an otherwise wild-type tRNASer These experiments reveal a model for genetic code evolution in which tRNA anticodon mutations and mistranslation evolve through phenotypically ambivalent intermediates that reduce tRNA function. PMID- 28576865 TI - Canalization by Selection of de Novo Induced Mutations. AB - One of the most fascinating scientific problems, and a subject of intense debate, is that of the mechanisms of biological evolution. In this context, Waddington elaborated the concepts of "canalization and assimilation" to explain how an apparently somatic variant induced by stress could become heritable through the germline in Drosophila He resolved this seemingly Lamarckian phenomenon by positing the existence of cryptic mutations that can be expressed and selected under stress. To investigate the relevance of such mechanisms, we performed experiments following the Waddington procedure, then isolated and fixed three phenotypic variants along with another induced mutation that was not preceded by any phenocopy. All the fixed mutations we looked at were actually generated de novo by DNA deletions or transposon insertions, highlighting a novel mechanism for the assimilation process. Our study shows that heat-shock stress produces both phenotypic variants and germline mutations, and suggests an alternative explanation to that of Waddington for the apparent assimilation of an acquired character. The selection of the variants, under stress, for a number of generations allows for the coselection of newly induced corresponding germline mutations, making the phenotypic variants appear heritable. PMID- 28576867 TI - Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study). AB - Purpose: Markers of chemotherapy efficacy in metastatic colorectal cancer (mCRC) are essential for optimization of treatment strategies. We evaluated the applicability of early changes in circulating tumor DNA (ctDNA) as a marker of therapeutic efficacy.Experimental Design: This prospective study enrolled consecutive patients with mCRC receiving a first- or second-line chemotherapy. CtDNA was assessed in plasma collected before the first (C0), second (C1) and/or third (C2) chemotherapy cycle, using picodroplet-digital PCR assays based either on detection of gene mutation (KRAS, BRAF, TP53) or hypermethylation (WIF1, NPY). CT scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyses were adjusted on age, gender, ECOG performance status (PS), metastatic synchronicity, and treatment line.Results: Eighty-two patients with mCRC treated in first- (82.9%) or second- (17.1%) line chemotherapy were included. Patients with a high (>10 ng/mL) versus low (<=0.1 ng/mL) ctDNA concentration at C0 had a shorter overall survival (OS; 6.8 vs. 33.4 months: adjusted HR, 5.64; 95% CI, 2.5 12.6; P < 0.0001). By analyzing the evolution of the ctDNA concentration between C0 and C2 or C1 (C2or1), we classified the patients in two groups (named "good" or "bad ctDNA responders"). In multivariate analysis, patients belonging to the group called "good ctDNA responder" (n = 58) versus "bad ctDNA responder" (n = 15) had a better objective response rate (P < 0.001), and a longer median progression-free survival (8.5 vs. 2.4 months: HR, 0.19; 95% CI, 0.09-0.40; P < 0.0001) and OS (27.1 vs. 11.2 months: HR, 0.25; 95% CI, 0.11-0.57; P < 0.001).Conclusions: This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in patients with mCRC. Clin Cancer Res; 23(18); 5416-25. (c)2017 AACR. PMID- 28576869 TI - Triiodothyroacetic acid in health and disease. AB - Thyroid hormone (TH) is crucial for development and metabolism of many tissues. The physiological relevance and therapeutic potential of TH analogs have gained attention in the field for many years. In particular, the relevance and use of 3,3',5-triiodothyroacetic acid (Triac, TA3) has been explored over the last decades. Although TA3 closely resembles the bioactive hormone T3, differences in transmembrane transport and receptor isoform-specific transcriptional activation potency exist. For these reasons, the application of TA3 as a treatment for resistance to TH (RTH) syndromes, especially MCT8 deficiency, is topic of ongoing research. This review is a summary of all currently available literature about the formation, metabolism, action and therapeutic applications of TA3. PMID- 28576870 TI - Role of miR-383 and miR-146b in different propensities to obesity in male mice. AB - The study was designed to investigate the possible mechanisms of hepatic microRNAs (miRs) in regulating local thyroid hormone (TH) action and ultimately different propensities to high-fat diet (HFD)-induced obesity. When obesity-prone (OP) and obesity-resistant (OR) mice were fed HFD for 7 weeks, OP mice showed apparent hepatic steatosis, with significantly higher body weight and lower hepatic TH receptor b (TRb) expression and type 1 deiodinase (DIO1) activity than OR mice. Next-generation sequencing technology revealed that 13 miRs in liver were dysregulated between the two phenotypes, of which 8 miRs were predicted to target on Dio1 or TRb When mice were fed for 17 weeks, OR mice had mild hepatic steatosis and increased Dio1 and TRb expression than OP mice, with downregulation of T3 target genes (including Srebp1c, Acc1, Scd1 and Fasn) and upregulation of Cpt1alpha, Atp5c1, Cox7c and Cyp7a1 A stem-loop qRT-PCR analysis confirmed that the levels of miR-383, miR-34a and miR-146b were inversely correlated with those of DIO1 or TRb. Down-regulated expression of miR-383 or miR-146b by miR-383 inhibitor (anti-miR-383) or miR-146b inhibitor (anti-miR-146b) in free fatty acid treated primary mouse hepatocytes led to increased DIO1 and TRb expressions, respectively, and subsequently decreased cellular lipid accumulation, while miR 34a inhibitor (anti-miR-34a) transfection had on effects on TRb expression. Luciferase reporter assay illustrated that miR-146b could directly target TRb 3'untranslated region (3'UTR). These findings suggested that miR-383 and miR-146b might play critical roles in different propensities to diet-induced obesity via targeting on Dio1 and TRb, respectively. PMID- 28576864 TI - LIN-41 and OMA Ribonucleoprotein Complexes Mediate a Translational Repression-to Activation Switch Controlling Oocyte Meiotic Maturation and the Oocyte-to-Embryo Transition in Caenorhabditis elegans. AB - An extended meiotic prophase is a hallmark of oogenesis. Hormonal signaling activates the CDK1/cyclin B kinase to promote oocyte meiotic maturation, which involves nuclear and cytoplasmic events. Nuclear maturation encompasses nuclear envelope breakdown, meiotic spindle assembly, and chromosome segregation. Cytoplasmic maturation involves major changes in oocyte protein translation and cytoplasmic organelles and is poorly understood. In the nematode Caenorhabditis elegans, sperm release the major sperm protein (MSP) hormone to promote oocyte growth and meiotic maturation. Large translational regulatory ribonucleoprotein (RNP) complexes containing the RNA-binding proteins OMA-1, OMA-2, and LIN-41 regulate meiotic maturation downstream of MSP signaling. To understand the control of translation during meiotic maturation, we purified LIN-41-containing RNPs and characterized their protein and RNA components. Protein constituents of LIN-41 RNPs include essential RNA-binding proteins, the GLD-2 cytoplasmic poly(A) polymerase, the CCR4-NOT deadenylase complex, and translation initiation factors. RNA sequencing defined messenger RNAs (mRNAs) associated with both LIN-41 and OMA 1, as well as sets of mRNAs associated with either LIN-41 or OMA-1 Genetic and genomic evidence suggests that GLD-2, which is a component of LIN-41 RNPs, stimulates the efficient translation of many LIN-41-associated transcripts. We analyzed the translational regulation of two transcripts specifically associated with LIN-41 which encode the RNA regulators SPN-4 and MEG-1 We found that LIN-41 represses translation of spn-4 and meg-1, whereas OMA-1 and OMA-2 promote their expression. Upon their synthesis, SPN-4 and MEG-1 assemble into LIN-41 RNPs prior to their functions in the embryo. This study defines a translational repression to-activation switch as a key element of cytoplasmic maturation. PMID- 28576866 TI - Heat-Induced Calcium Leakage Causes Mitochondrial Damage in Caenorhabditis elegans Body-Wall Muscles. AB - Acute onset of organ failure in heatstroke is triggered by rhabdomyolysis of skeletal muscle. Here, we showed that elevated temperature increases free cytosolic Ca2+ [Ca2+]f from RYR (ryanodine receptor)/UNC-68 in vivo in the muscles of an experimental model animal, the nematode Caenorhabditis elegans This subsequently leads to mitochondrial fragmentation and dysfunction, and breakdown of myofilaments similar to rhabdomyolysis. In addition, treatment with an inhibitor of RYR (dantrolene) or activation of FoxO (Forkhead box O)/DAF-16 is effective against heat-induced muscle damage. Acute onset of organ failure in heatstroke is triggered by rhabdomyolysis of skeletal muscle. To gain insight into heat-induced muscle breakdown, we investigated alterations of Ca2+ homeostasis and mitochondrial morphology in vivo in body-wall muscles of C. elegans exposed to elevated temperature. Heat stress for 3 hr at 35 degrees increased the concentration of [Ca2+]f, and led to mitochondrial fragmentation and subsequent dysfunction in the muscle cells. A similar mitochondrial fragmentation phenotype is induced in the absence of heat stress by treatment with a calcium ionophore, ionomycin. Mutation of the unc-68 gene, which encodes the ryanodine receptor that is linked to Ca2+ release from the sarcoplasmic reticulum, could suppress the mitochondrial dysfunction, muscle degeneration, and reduced mobility and life span induced by heat stress. In addition, in a daf-2 mutant, in which the DAF-16/FoxO transcription factor is activated, resistance to calcium overload, mitochondrial fragmentation, and dysfunction was observed. These findings reveal that heat-induced Ca2+ accumulation causes mitochondrial damage and consequently induces muscle breakdown. PMID- 28576873 TI - Patient experience should be recorded in health records. PMID- 28576871 TI - STEAP4: its emerging role in metabolism and homeostasis of cellular iron and copper. AB - Preserving energy homeostasis in the presence of stressors such as proinflammatory cytokines and nutrient overload is crucial to maintaining normal cellular function. Six transmembrane epithelial antigen of the prostate 4 (STEAP4), a metalloreductase involved in iron and copper homeostasis, is thought to play a potentially important role in the cellular response to inflammatory stress. Genome-wide association studies have linked various mutations in STEAP4 with the development of metabolic disorders such as obesity, metabolic syndrome and type 2 diabetes. Several studies have shown that expression of Steap4 is modulated by inflammatory cytokines, hormones and other indicators of cellular stress and that STEAP4 may protect cells from damage, helping to maintain normal metabolic function. STEAP4 appears to be particularly relevant in metabolically oriented cells, such as adipocytes, hepatocytes and pancreatic islet cells. These cells struggle to maintain their function in iron or copper overloaded states, presumably due to increased oxidative stress, suggesting STEAP4's role in metal homeostasis is critical to the maintenance of cellular homeostasis in general, and in preventing the onset of metabolic disease. In this review, we explore genetic associations of STEAP4 with metabolic disorders, and we examine STEAP4 tissue expression, subcellular localization, regulation, structure and function as it relates to metabolic diseases. We then examine how STEAP4's role as a regulator of cellular iron and copper may relate to type 2 diabetes. PMID- 28576872 TI - Origin of a rapidly evolving homeostatic control system programming testis function. AB - Mammals share common strategies for regulating reproduction, including a conserved hypothalamic-pituitary-gonadal axis; yet, individual species exhibit differences in reproductive performance. In this report, we describe the discovery of a species-restricted homeostatic control system programming testis growth and function. Prl3c1 is a member of the prolactin gene family and its protein product (PLP-J) was discovered as a uterine cytokine contributing to the establishment of pregnancy. We utilized mouse mutagenesis of Prl3c1 and revealed its involvement in the regulation of the male reproductive axis. The Prl3c1-null male reproductive phenotype was characterized by testiculomegaly and hyperandrogenism. The larger testes in the Prl3c1-null mice were associated with an expansion of the Leydig cell compartment. Prl3c1 locus is a template for two transcripts (Prl3c1-v1 and Prl3c1-v2) expressed in a tissue-specific pattern. Prl3c1-v1 is expressed in uterine decidua, while Prl3c1-v2 is expressed in Leydig cells of the testis. 5'RACE, chromatin immunoprecipitation and DNA methylation analyses were used to define cell-specific promoter usage and alternative transcript expression. We examined the Prl3c1 locus in five murid rodents and showed that the testicular transcript and encoded protein are the result of a recent retrotransposition event at the Mus musculus Prl3c1 locus. Prl3c1-v1 encodes PLP-J V1 and Prl3c1-v2 encodes PLP-J V2. Each protein exhibits distinct intracellular targeting and actions. PLP-J V2 possesses Leydig cell-static actions consistent with the Prl3c1-null testicular phenotype. Analysis of the biology of the Prl3c1 gene has provided insight into a previously unappreciated homeostatic setpoint control system programming testicular growth and function. PMID- 28576874 TI - BLOC-1 is required for selective membrane protein trafficking from endosomes to primary cilia. AB - Primary cilia perceive the extracellular environment through receptors localized in the ciliary membrane, but mechanisms directing specific proteins to this domain are poorly understood. To address this question, we knocked down proteins potentially important for ciliary membrane targeting and determined how this affects the ciliary trafficking of fibrocystin, polycystin-2, and smoothened. Our analysis showed that fibrocystin and polycystin-2 are dependent on IFT20, GMAP210, and the exocyst complex, while smoothened delivery is largely independent of these components. In addition, we found that polycystin-2, but not smoothened or fibrocystin, requires the biogenesis of lysosome-related organelles complex-1 (BLOC-1) for ciliary delivery. Consistent with the role of BLOC-1 in sorting from the endosome, we find that disrupting the recycling endosome reduces ciliary polycystin-2 and causes its accumulation in the recycling endosome. This is the first demonstration of a role for BLOC-1 in ciliary assembly and highlights the complexity of pathways taken to the cilium. PMID- 28576875 TI - Genome editing of factor X in zebrafish reveals unexpected tolerance of severe defects in the common pathway. AB - Deficiency of factor X (F10) in humans is a rare bleeding disorder with a heterogeneous phenotype and limited therapeutic options. Targeted disruption of F10 and other common pathway factors in mice results in embryonic/neonatal lethality with rapid resorption of homozygous mutants, hampering additional studies. Several of these mutants also display yolk sac vascular defects, suggesting a role for thrombin signaling in vessel development. The zebrafish is a vertebrate model that demonstrates conservation of the mammalian hemostatic and vascular systems. We have leveraged these advantages for in-depth study of the role of the coagulation cascade in the developmental regulation of hemostasis and vasculogenesis. In this article, we show that ablation of zebrafish f10 by using genome editing with transcription activator-like effector nucleases results in a major embryonic hemostatic defect. However, widespread hemorrhage and subsequent lethality does not occur until later stages, with absence of any detectable defect in vascular development. We also use f10-/- zebrafish to confirm 5 novel human F10 variants as causative mutations in affected patients, providing a rapid and reliable in vivo model for testing the severity of F10 variants. These findings as well as the prolonged survival of f10-/- mutants will enable us to expand our understanding of the molecular mechanisms of hemostasis, including a platform for screening variants of uncertain significance in patients with F10 deficiency and other coagulation disorders. Further study as to how fish tolerate what is an early lethal mutation in mammals could facilitate improvement of diagnostics and therapeutics for affected patients with bleeding disorders. PMID- 28576876 TI - Targeting chronic myeloid leukemia stem cells with the hypoxia-inducible factor inhibitor acriflavine. AB - Chronic myeloid leukemia (CML) is a hematopoietic stem cell (HSC)-driven neoplasia characterized by expression of the constitutively active tyrosine kinase BCR/Abl. CML therapy based on tyrosine kinase inhibitors (TKIs) is highly effective in inducing remission but not in targeting leukemia stem cells (LSCs), which sustain minimal residual disease and are responsible for CML relapse following discontinuation of treatment. The identification of molecules capable of targeting LSCs appears therefore of primary importance to aim at CML eradication. LSCs home in bone marrow areas at low oxygen tension, where HSCs are physiologically hosted. This study addresses the effects of pharmacological inhibition of hypoxia-inducible factor-1 (HIF-1), a critical regulator of LSC survival, on the maintenance of CML stem cell potential. We found that the HIF-1 inhibitor acriflavine (ACF) decreased survival and growth of CML cells. These effects were paralleled by decreased expression of c-Myc and stemness-related genes. Using different in vitro stem cell assays, we showed that ACF, but not TKIs, targets the stem cell potential of CML cells, including primary cells explanted from 12 CML patients. Moreover, in a murine CML model, ACF decreased leukemia development and reduced LSC maintenance. Importantly, ACF exhibited significantly less-severe effects on non-CML hematopoietic cells in vitro and in vivo. Thus, we propose ACF, a US Food and Drug Administration (FDA)-approved drug for nononcological use in humans, as a novel therapeutic approach to prevent CML relapse and, in combination with TKIs, enhance induction of remission. PMID- 28576877 TI - Presenting ADAMTS13 antibody and antigen levels predict prognosis in immune mediated thrombotic thrombocytopenic purpura. AB - Immune-mediated thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder caused by antibodies against ADAMTS13. From the United Kingdom TTP registry, we undertook a prospective study investigating the impact of the presenting anti-ADAMTS13 IgG antibody and ADAMTS13 antigen on mortality. A total of 312 episodes involving 292 patients over 87 months were included; 68% were female, median age 46 (range, 11-88 years), and median presenting ADAMTS13 of <5% (range, <5%-18%). The mortality rate was 10.3% (n = 32); 68% of patients had a raised troponin at presentation conferring a sixfold increase in mortality compared with those with normal troponin levels (12.1% vs 2.0%, P = .04). Twenty four percent had a reduced Glasgow Coma Score (GCS) at presentation with a ninefold increase in mortality (20% vs 2.2% for normal GCS at presentation, P < .0001). Mortality increased with higher anti-ADAMTS13 antibody levels and lower ADAMTS13 antigen levels. Those with antibody levels in the upper quartile (antibody >77%) had a mortality of 16.9% compared with 5.0% for the lowest quartile (antibody <20%) (P = .004). Those with an antigen level in the lowest quartile (antigen <1.5%) had a mortality of 18% compared with 3.8% for the highest quartile (antigen >11%) (P = .005). The synergistic effect of anti ADAMTS13 IgG antibody in the upper quartile and ADAMTS13 antigen in the lowest quartile had the highest mortality of 27.3%. We conclude that both anti-ADAMTS13 IgG antibody and ADAMTS13 antigen levels correlate with outcome in TTP with increased cardiac and neurological involvement and increased mortality. PMID- 28576878 TI - The disulfide isomerase ERp72 supports arterial thrombosis in mice. AB - Several CGHC motif-containing disulfide isomerases support thrombosis. We here report that endoplasmic reticulum protein 72 (ERp72), with 3 CGHC redox-active sites (ao, a, and a'), supports thrombosis. We generated a new conditional knockout mouse model and found that Tie2-Cre/ERp72fl/fl mice with blood and endothelial cells lacking ERp72 had prolonged tail bleeding times and decreased platelet accumulation in laser-induced cremaster arteriole injury and FeCl3 induced mesenteric arterial injury. Fibrin deposition was decreased in the laser injury model. Both platelet and fibrin accumulation defects were fully rescued by infusion of recombinant ERp72 containing functional a and a' CGHC motifs (ERp72(oo-ss-ss)). Infusion of ERp72 containing inactivated a and a' CGHC motifs (ERp72(ss-oo-oo)) inhibited platelet accumulation and fibrin deposition in wild type mice. Infusion of ERp72(oo-ss-ss) into beta3-null mice increased fibrin deposition in the absence of platelets. ERp72-null platelets had defective aggregation, JON/A binding, P-selectin expression, and adenosine triphosphate (ATP) secretion. The aggregation and ATP secretion defects were fully rescued by ERp72(oo-ss-ss) but partially rescued by ERp72(ss-oo-ss) and ERp72(ss-ss-oo). Aggregation and ATP secretion of human platelets was potentiated by ERp72(oo-ss ss) but inhibited by ERp72(ss-oo-ss) and ERp72(ss-ss-oo). These data suggest that both the a and a' active sites are required for platelet function. ERp72 bound poorly to beta3-null mouse platelets, and the addition of ERp72(oo-ss-ss) to human platelets generated thiols in alphaIIbbeta3, suggesting a direct interaction of ERp72 with alphaIIbbeta3. Defective aggregation of ERp72-null platelets was recovered by ERp72, but not other thiol isomerases. In summary, ERp72 plays a critical role in platelet function and coagulation through the a and a' CGHC motifs. PMID- 28576880 TI - Differential regulation of monocarboxylate transporter 8 expression in thyroid cancer and hyperthyroidism. AB - OBJECTIVE: Thyroid hormone (TH) transporters are expressed in thyrocytes and most play a role in TH release. We asked whether expression of the monocarboxylate transporter 8 (MCT8) and the L-type amino acid transporters LAT2 and LAT4 is changed with thyrocyte dedifferentiation and in hyperfunctioning thyroid tissues. DESIGN AND METHODS: Protein expression and localization of transporters was determined by immunohistochemistry in human thyroid specimen including normal thyroid tissue (NT, n = 19), follicular adenoma (FA, n = 44), follicular thyroid carcinoma (FTC, n = 45), papillary thyroid carcinoma (PTC, n = 40), anaplastic thyroid carcinoma (ATC, n = 40) and Graves' disease (GD, n = 50) by calculating the 'hybrid' (H) score. Regulation of transporter expression was investigated in the rat follicular thyroid cell line PCCL3 under basal and thyroid stimulating hormone (TSH) conditions. RESULTS: MCT8 and LAT4 were localized at the plasma membrane, while LAT2 transporter showed cytoplasmic localization. MCT8 expression was downregulated in benign and malignant thyroid tumours as compared to NT. In contrast, significant upregulation of MCT8, LAT2 and LAT4 was found in GD. Furthermore, a stronger expression of MCT8 was demonstrated in PCCL3 cells after TSH stimulation. CONCLUSIONS: Downregulation of MCT8 in thyroid cancers qualifies MCT8 as a marker of thyroid differentiation. The more variable expression of LATs in distinct thyroid malignancies may be linked with other transporter properties relevant to altered metabolism in cancer cells, i.e. amino acid transport. Consistent upregulation of MCT8 in GD is in line with increased TH release in hyperthyroidism, an assumption supported by our in vitro results showing TSH dependent upregulation of MCT8. PMID- 28576881 TI - Assessing elements of an extended evolutionary synthesis for plant domestication and agricultural origin research. AB - The development of agricultural societies, one of the most transformative events in human and ecological history, was made possible by plant and animal domestication. Plant domestication began 12,000-10,000 y ago in a number of major world areas, including the New World tropics, Southwest Asia, and China, during a period of profound global environmental perturbations as the Pleistocene epoch ended and transitioned into the Holocene. Domestication is at its heart an evolutionary process, and for many prehistorians evolutionary theory has been foundational in investigating agricultural origins. Similarly, geneticists working largely with modern crops and their living wild progenitors have documented some of the mechanisms that underwrote phenotypic transformations from wild to domesticated species. Ever-improving analytic methods for retrieval of empirical data from archaeological sites, together with advances in genetic, genomic, epigenetic, and experimental research on living crop plants and wild progenitors, suggest that three fields of study currently little applied to plant domestication processes may be necessary to understand these transformations across a range of species important in early prehistoric agriculture. These fields are phenotypic (developmental) plasticity, niche construction theory, and epigenetics with transgenerational epigenetic inheritance. All are central in a controversy about whether an Extended Evolutionary Synthesis is needed to reconceptualize how evolutionary change occurs. An exploration of their present and potential utility in domestication study shows that all three fields have considerable promise in elucidating important issues in plant domestication and in agricultural origin and dispersal research and should be increasingly applied to these issues. PMID- 28576882 TI - Modeling gene regulation from paired expression and chromatin accessibility data. AB - The rapid increase of genome-wide datasets on gene expression, chromatin states, and transcription factor (TF) binding locations offers an exciting opportunity to interpret the information encoded in genomes and epigenomes. This task can be challenging as it requires joint modeling of context-specific activation of cis regulatory elements (REs) and the effects on transcription of associated regulatory factors. To meet this challenge, we propose a statistical approach based on paired expression and chromatin accessibility (PECA) data across diverse cellular contexts. In our approach, we model (i) the localization to REs of chromatin regulators (CRs) based on their interaction with sequence-specific TFs, (ii) the activation of REs due to CRs that are localized to them, and (iii) the effect of TFs bound to activated REs on the transcription of target genes (TGs). The transcriptional regulatory network inferred by PECA provides a detailed view of how trans- and cis-regulatory elements work together to affect gene expression in a context-specific manner. We illustrate the feasibility of this approach by analyzing paired expression and accessibility data from the mouse Encyclopedia of DNA Elements (ENCODE) and explore various applications of the resulting model. PMID- 28576879 TI - Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML. AB - Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID IL2Rgammanull background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD34+ cells (n = 8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n = 10) resulted in robust engraftment of CMML in BM, spleen, liver, and lung of recipients (n = 82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD34+ cells in secondary NSGS recipients (2/5 patients, 6/11 mice), demonstrating the durability of CMML grafts and functionally validating CD34+ cells as harboring the disease-initiating compartment in vivo. Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n = 4 patients, n = 12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically accurate preclinical models of these disorders. PMID- 28576883 TI - Crystal structure of tubulin tyrosine ligase-like 3 reveals essential architectural elements unique to tubulin monoglycylases. AB - Glycylation and glutamylation, the posttranslational addition of glycines and glutamates to genetically encoded glutamates in the intrinsically disordered tubulin C-terminal tails, are crucial for the biogenesis and stability of cilia and flagella and play important roles in metazoan development. Members of the diverse family of tubulin tyrosine ligase-like (TTLL) enzymes catalyze these modifications, which are part of an evolutionarily conserved and complex tubulin code that regulates microtubule interactions with cellular effectors. The site specificity of TTLL enzymes and their biochemical interplay remain largely unknown. Here, we report an in vitro characterization of a tubulin glycylase. We show that TTLL3 glycylates the beta-tubulin tail at four sites in a hierarchical order and that TTLL3 and the glutamylase TTLL7 compete for overlapping sites on the tubulin tail, providing a molecular basis for the anticorrelation between glutamylation and glycylation observed in axonemes. This anticorrelation demonstrates how a combinatorial tubulin code written in two different posttranslational modifications can arise through the activities of related but distinct TTLL enzymes. To elucidate what structural elements differentiate TTLL glycylases from glutamylases, with which they share the common TTL scaffold, we determined the TTLL3 X-ray structure at 2.3-A resolution. This structure reveals two architectural elements unique to glycyl initiases and critical for their activity. Thus, our work sheds light on the structural and functional diversification of TTLL enzymes, and constitutes an initial important step toward understanding how the tubulin code is written through the intersection of activities of multiple TTLL enzymes. PMID- 28576884 TI - Mdm2 Is Required for Survival and Growth of p53-Deficient Cancer Cells. AB - p53 deletion prevents the embryonic lethality of normal tissues lacking Mdm2, suggesting that cells can survive without Mdm2 if p53 is also absent. Here we report evidence challenging this view, with implications for therapeutically targeting Mdm2. Deletion of Mdm2 in T-cell lymphomas or sarcomas lacking p53 induced apoptosis and G2 cell-cycle arrest, prolonging survival of mice with these tumors. p53-/- fibroblasts showed similar results, indicating that the effects of Mdm2 loss extend to premalignant cells. Mdm2 deletion in p53-/- cells upregulated p53 transcriptional target genes that induce apoptosis and cell-cycle arrest. Mdm2 deletion also increased levels of p73, a p53 family member. RNAi mediated attenuation of p73 rescued the transcriptional and biological effects of Mdm2 loss, indicating that p73 mediates the consequences of Mdm2 deletion. In addition, Mdm2 deletion differed from blocking Mdm2 interaction with p53 family members, as Nutlin-3 induced G1 arrest but did not activate apoptosis in p53-/- sarcoma cells. Our results indicate that, in contrast to current dogma, Mdm2 expression is required for cell survival even in the absence of p53. Moreover, our results suggest that p73 compensates for loss of p53 and that targeting Mdm2 in p53-deficient cancers has therapeutic potential. Cancer Res; 77(14); 3823-33. (c)2017 AACR. PMID- 28576886 TI - Regulation of sphingolipid biosynthesis by the morphogenesis checkpoint kinase Swe1. PMID- 28576885 TI - Osteoporosis and ageing affects the migration of stem cells and this is ameliorated by transfection with CXCR4. AB - OBJECTIVES: Cellular movement and relocalisation are important for many physiologic properties. Local mesenchymal stem cells (MSCs) from injured tissues and circulating MSCs aid in fracture healing. Cytokines and chemokines such as Stromal cell-derived factor 1(SDF-1) and its receptor chemokine receptor type 4 (CXCR4) play important roles in maintaining mobilisation, trafficking and homing of stem cells from bone marrow to the site of injury. We investigated the differences in migration of MSCs from the femurs of young, adult and ovariectomised (OVX) rats and the effect of CXCR4 over-expression on their migration. METHODS: MSCs from young, adult and OVX rats were put in a Boyden chamber to establish their migration towards SDF-1. This was compared with MSCs transfected with CXCR4, as well as MSCs differentiated to osteoblasts. RESULTS: MSCs from OVX rats migrate significantly (p < 0.05) less towards SDF-1 (9%, sd 5%) compared with MSCs from adult (15%, sd 3%) and young rats (25%, sd 4%). Cells transfected with CXCR4 migrated significantly more towards SDF-1 compared with non-transfected cells, irrespective of whether these cells were from OVX (26.5%, sd 4%), young (47%, sd 17%) or adult (21%, sd 4%) rats. Transfected MSCs differentiated to osteoblasts express CXCR4 but do not migrate towards SDF-1. CONCLUSIONS: MSC migration is impaired by age and osteoporosis in rats, and this may be associated with a significant reduction in bone formation in osteoporotic patients. The migration of stem cells can be ameliorated by upregulating CXCR4 levels which could possibly enhance fracture healing in osteoporotic patients.Cite this article: A. Sanghani-Kerai, M. Coathup, S. Samazideh, P. Kalia, L. Di Silvio, B. Idowu, G. Blunn. Osteoporosis and ageing affects the migration of stem cells and this is ameliorated by transfection with CXCR4. Bone Joint Res 2017;6:-365. DOI: 10.1302/2046-3758.66.BJR-2016-0259.R1. PMID- 28576888 TI - Correction: New Perspectives of Curcumin in Cancer Prevention. PMID- 28576887 TI - Astrocytes take the stage in a tale of signaling-metabolism coupling. AB - Astrocytes are crucial cells in the brain that are intimately coupled with neuronal metabolism. A new paper from San Martin et al. provides evidence that physiological levels of the gaseous signal molecule NO can rapidly and reversibly increase astrocyte metabolism of glucose and production of lactate. A proposed neurological coupling-from the potential source of NO, endothelial cells, to the potential beneficiary from the lactate, neurons-prompts new questions regarding the controversial role of lactate in the brain. PMID- 28576889 TI - Blood coagulation system in patients with chronic kidney disease: a prospective observational study. AB - OBJECTIVES: Thromboembolic events are the major factor affecting the prognosis of patients with chronic kidney disease (CKD). Haemostatic alterations are possible causes of these complications, but their roles remain poorly characterised. In the prospective observational study, we investigated the entire coagulation process in patients with CKD to elucidate the mechanisms of their high thromboembolic risk. METHODS: A total of 95 patients with CKD and 20 healthy controls who met the inclusion criteria were consecutively recruited from September 2015 to March 2016. The platelet count, platelet aggregation, von Willebrand factor antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCo), fibrinogen, factor V (FV), FVII, FVIII, antithrombin III, protein C, protein S, D dimer, standard coagulation tests and thromboelastography were measured in patients with CKD and controls. Associations between the estimated glomerular filtration rate (eGFR) and haemostatic biomarkers were tested using multivariable linear regression. RESULTS: The adjusted and unadjusted levels of vWF:Ag, vWF:RCo, fibrinogen, FVII, FVIII and D-dimer were significantly higher in patients with CKD than that in the healthy controls, and were elevated with CKD progression. However, after adjustment for baseline differences, platelet aggregation and thromboelastography parameters showed no significant differences between patients with CKD and healthy controls. In the correlation analysis, vWF:Ag, vWF:RCo and FVIII were inversely associated with eGFR (r=-0.359, p<0.001; r=-0.391, p<0.001; r=-0.327, p<0.001, respectively). During the 1-year of follow up, one cardiovascular event occurred in patients with CKD 5 stage, whereas no thromboembolic event occurred in the CKD 3 and 4 and control groups. CONCLUSIONS: Patients with CKD are characterised by endothelial dysfunction and increased coagulation, especially FVIII activity. The abnormal haemostatic profiles may contribute to the elevated risk of thrombotic events but further longer-term study with large samples is still required to more precisely determine the relationship between the elevation of procoagulant factors and clinical outcomes. PMID- 28576890 TI - Perceived challenges to achieving universal health coverage: a cross-sectional survey of social health insurance managers/administrators in China. AB - OBJECTIVE: China has achieved over 96% health insurance coverage. However, universal health coverage (UHC) entails population coverage and the range of services covered and the extent to which health service costs are covered. This study aimed to determine the performance of the health insurance system in China in terms of its role in UHC and to identify challenges in the progress of UHC as perceived by health insurance managers/administrators. METHODS: A cross-sectional questionnaire survey was conducted in Beijing, Ningbo, Harbin and Chongqing over the period of 2014 and 2015. A stratified cluster random sampling strategy was adopted to select study participants. A total of 1277 (64.8%) respondents who reported familiarity with the current health insurance system and the requirements of UHC provided valid data for analyses. They gave a rating on the role of the current health insurance system in achieving UHC. A multivariate logistic regression model was developed to determine the associations between the rating and the features of insurance arrangements. RESULTS: There was consensus among the respondents on the performance of the current health insurance system in terms of its role in UHC, regardless who they were and what responsibility they held in their organisation (ie, policy development, managing fund transactions, and so on). Overall, about 45% of the respondents believed that there is a long way to go to achieve UHC. The low rating was found to be associated with limited financial protection (OR=1.656, 95% CI 1.279 to 2.146), healthcare inequity (OR=1.607, 95% CI 1.268 to 2.037), poor portability (OR=1.347, 95% CI 1.065 to 1.703) and ineffective supervision and administration of funds (OR=1.339, 95% CI 1.061 to 1.692) as perceived by the respondents. CONCLUSION: Health insurance managers/administrators in China are pessimistic about the achievements of the current health insurance system. They are concerned about the overall lack of benefit that insurance programmes bring to members, including low levels of entitlements, large healthcare inequity, limited financial protection and poor portability. A singular amendment of the structural design of the existing funds may not be enough to offer a satisfactory solution to these identified barriers. There is a need to increase funding capacities, to develop unified and consistent policies and to increase the level of fund pooling. PMID- 28576891 TI - The effect of life course socioeconomic position on crystallised cognitive ability in two large UK cohort studies: a structured modelling approach. AB - OBJECTIVES: This study systematically compared accumulation, sensitive period, critical period and social mobility models relating life course socioeconomic position (SEP) and adult crystallised cognitive ability, which has not been comprehensively investigated. DESIGN: Two prospective cohort studies. PARTICIPANTS: Five thousand three hundred and sixty-two participants in the Medical Research Council National Survey of Health and Development (NSHD) Birth Cohort Study and 10 308 participants in the Whitehall II Occupational Cohort Study. MEASURES: Childhood SEP was measured by father's occupational SEP, early adulthood SEP by educational qualifications and adult SEP by own occupational SEP. Each life course model was compared with a saturated model. RESULTS: Using multiple imputation to account for missing data, the sensitive period model, which contained childhood, early adulthood and adult SEP terms, with different coefficients, provided the best fit for both men and women in the NSHD and Whitehall II cohorts. Early adulthood SEP had the largest coefficient in NSHD women, whereas for NSHD men early adulthood and adult SEP had similar coefficients. In Whitehall II adult SEP had the largest effect size for both men and women. CONCLUSIONS: Sensitive period with all three time periods was the most appropriate life course models for adult crystallised cognitive ability in both cohorts, including an effect of childhood SEP. It is important to directly compare the life course models to determine which is the most appropriate. PMID- 28576892 TI - Study protocol of a pragmatic, randomised controlled pilot trial: clinical effectiveness on smoking cessation of traditional and complementary medicine interventions, including acupuncture and aromatherapy, in combination with nicotine replacement therapy. AB - INTRODUCTION: Nicotine dependence is a disease, and tobacco use is related to 6 million deaths annually worldwide. Recently, in many countries, there has been growing interest in the use of traditional and complementary medicine (T&CM) methods, especially acupuncture, as therapeutic interventions for smoking cessation. The aim of this pilot study is to investigate the effectiveness of T&CM interventions on smoking cessation. METHODS AND ANALYSIS: The STOP (Stop Tobacco Programme using traditional Korean medicine) study is designed to be a pragmatic, open-label, randomised pilot trial. This trial will evaluate whether adding T&CM methods (ie, ear and body acupuncture, aromatherapy) to conventional cessation methods (ie, nicotine replacement therapy (NRT), counselling) increases smoking cessation rates. Forty participants over 19 years old who are capable of communicating in Korean will be recruited. They will be current smokers who meet one of the following criteria: (1) smoke more than 10 cigarettes a day, (2) smoke less than 10 cigarettes a day and previously failed to cease smoking, or (3) smoke fewer than 10 cigarettes a day and have a nicotine dependence score (Fagerstrom Test for Nicotine Dependence) of 4 points or more. The trial will consist of 4 weeks of treatment and a 20 week follow-up period. A statistician will perform the statistical analyses for both the intention-to-treat (all randomly assigned participants) and per-protocol (participants who completed the trial without any protocol deviations) data using SAS 9.1.3. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board (IRB) of the Dunsan Korean Medicine Hospital of Daejeon University (IRB reference no: DJDSKH-15-BM-11-1, Protocol No. version 4.1.).The protocol will be reapproved by IRB if it requires amendment. The trial will be conducted according to the Declaration of Helsinki, 7th version (2013). This study is designed to minimise the risk to participants, and the investigators will explain the study to the participants in detail. As an ethical clinical trial, the control group will also be given conventional cessation treatments, including NRT and counselling. Participants will be screened and provided with a registration number to protect their personal information. Informed consent will be obtained from the participants prior to enrolling them in the trial. Participants will be allowed to withdraw at anytime without penalty. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT02768025); pre-results. PMID- 28576893 TI - Motivation of Dutch high school students from various backgrounds for applying to study medicine: a qualitative study. AB - OBJECTIVE: To explore high school students' motivation for applying to study medicine and the factors that influence this. To find explanations for under representation of minority students in medical education, descriptions of motivation of students with different background characteristics were compared. DESIGN: Qualitative phenomenological study using semistructured one-on-one interviews. SETTING: One predominantly white and one mixed high school in a large multicultural city in the Netherlands. The study was conducted in March-December 2015. PARTICIPANTS: Twenty-four high school students, purposively sampled for demographic characteristics. METHODS: The analysis consisted of the coding of data using a template based on the motivation types (autonomous and controlled motivation) described by self-determination theory and open coding for factors that influence motivation. RESULTS: The main reasons for pursuing a medical career pertained to autonomous motivation (interest in science and helping people), but controlled motivation (eg, parental pressure, prestige) was also mentioned. Experiences with healthcare and patients positively influenced students' autonomous motivation and served as a reality check for students' expectations. Having to go through a selection process was an important demotivating factor, but did not prevent most students from applying. Having medical professionals in their network also sparked students' interest, while facilitating easier access to healthcare experiences. CONCLUSIONS: The findings showed a complex interplay between healthcare experiences, growing up in a medical family, selection processes and motivation. Healthcare experiences, often one of the selection criteria, help students to form autonomous motivation for studying medicine. However, such experiences as well as support in the selection process seem unequally accessible to students. As a result, under-represented students' motivation decreases. Medical schools should be aware of this and could create opportunities to acquire healthcare experiences. High schools could incorporate internships as part of their study counselling programmes and offer tailor-made guidance to each individual student. PMID- 28576895 TI - Has the NHS 111 urgent care telephone service been a success? Case study and secondary data analysis in England. AB - OBJECTIVES: To explore the success of the introduction of the National Health Service (NHS) 111 urgent care service and describe service activity in the period 2014-2016. DESIGN: Comparative mixed method case study of five NHS 111 service providers and analysis of national level routine data on activity and service use. SETTINGS AND DATA: Our primary research involved five NHS 111 sites in England. We conducted 356 hours of non-participant observation in NHS 111 call centres and the urgent care centres and, linked to these observations, held 6 focus group interviews with 47 call advisors, clinical and managerial staff. This primary research is augmented by a secondary analysis of routine data about the 44 NHS 111 sites in England contained in the NHS 111 Minimum Data Set made available by NHS England. RESULTS: Opinions vary depending on the criteria used to judge the success of NHS 111. The service has been rolled out across 44 sites. The 111 phone number is operational and the service has replaced its predecessor NHS Direct. This new service has led to changes in who does the work of managing urgent care demand, achieving significant labour substitution. Judged against internal performance criteria, the service appears not to meet some targets such as call answering times, but it has seen a steady increase in use over time. Patients appear largely satisfied with NHS 111, but the view from some stakeholders is more mixed. The impact of NHS 111 on other health services is difficult to assess and cost-effectiveness has not been established. CONCLUSION: The new urgent care service NHS 111 has been brought into use but its success against some key criteria has not been comprehensively proven. PMID- 28576894 TI - Use of a geographic information system to identify differences in automated external defibrillator installation in urban areas with similar incidence of public out-of-hospital cardiac arrest: a retrospective registry-based study. AB - OBJECTIVES: Early defibrillation in out-of-hospital cardiac arrest (OHCA) is of importance to improve survival. In many countries the number of automated external defibrillators (AEDs) is increasing, but the use is low. Guidelines suggest that AEDs should be installed in densely populated areas and in locations with many visitors. Attempts have been made to identify optimal AED locations based on the incidence of OHCA using geographical information systems (GIS), but often on small datasets and the studies are seldom reproduced. The aim of this paper is to investigate if the distribution of public AEDs follows the incident locations of public OHCAs in urban areas of Stockholm County, Sweden. METHOD: OHCA data were obtained from the Swedish Register for Cardiopulmonary Resuscitation and AED data were obtained from the Swedish AED Register. Urban areas in Stockholm County were objectively classified according to the pan European digital mapping tool, Urban Atlas (UA). Furthermore, we reclassified and divided the UA land cover data into three classes (residential, non-residential and other areas). GIS software was used to spatially join and relate public AED and OHCA data and perform computations on relations and distance. RESULTS: Between 1 January 2012 and 31 December 2014 a total of 804 OHCAs occurred in public locations in Stockholm County and by December 2013 there were 1828 AEDs available. The incidence of public OHCAs was similar in residential (47.3%) and non-residential areas (43.4%). Fewer AEDs were present in residential areas than in non-residential areas (29.4% vs 68.8%). In residential areas the median distance between OHCAs and AEDs was significantly greater than in non-residential areas (288 m vs 188 m, p<0.001). CONCLUSION: The majority of public OHCAs occurred in areas classified in UA as 'residential areas' with limited AED accessibility. These areas need to be targeted for AED installation and international guidelines need to take geographical location into account when suggesting locations for AED installation. PMID- 28576896 TI - Barriers and facilitators to recruitment of South Asians to health research: a scoping review. AB - OBJECTIVES: People of South Asian ethnicity are under-represented in health research studies. The objectives of this scoping review were to examine the barriers and facilitators to recruitment of South Asians to health research studies and to describe strategies for improving recruitment. DESIGN: Scoping review METHODS: Using the Arksey and O'Malley framework for scoping reviews, we comprehensively searched electronic databases (MEDLINE via PubMed, Cochrane Library, CINAHL and PsycINFO). Studies that identified barriers and facilitators to recruitment, or recruitment strategies for South Asian populations were included. Recruitment barriers, facilitators and strategies were grouped thematically and summarised narratively. SYNTHESIS: Of 1846 potentially relevant articles, 15 met the inclusion criteria and were included in the thematic synthesis. Multiple facilitators and barriers to enrolment of South Asians in health research studies were identified; these most commonly related to logistical challenges, language and cultural barriers, concerns about adverse consequences of participating and mistrust of research. Several actionable strategies were discussed, the most common being engagement of South Asian communities, demonstration of cultural competency, provision of incentives and benefits, language sensitivity through the use of translators and translated materials and the development of trust and personal relationships. CONCLUSION: There is a growing awareness of the barriers and facilitators to recruitment of South Asian participants to health research studies. Knowledge of effective recruitment strategies and implementation during the grant funding stages may reduce the risk of poor recruitment and representation of South Asians. PMID- 28576897 TI - Anticipatory guidance to prevent infant sleep problems within a randomised controlled trial: infant, maternal and partner outcomes at 6 months of age. AB - OBJECTIVE: To evaluate the effectiveness of sleep education delivered antenatally and at 3 weeks postpartum to prevent infant sleep problems at 6 months of age. DESIGN: Sleep intervention within a randomised controlled trial for the Prevention of Overweight in Infancy (POI) study. PARTICIPANTS: 802 families were randomly allocated to one of four groups: usual care (control), sleep intervention (sleep), food, activity and breastfeeding intervention (FAB), and combined group receiving both interventions (combination). INTERVENTIONS: All groups received standard Well Child care. The sleep intervention groups (sleep and combination) received an antenatal group education session (all mothers and most partners) emphasising infant self-settling and safe sleeping, and a home visit at 3 weeks reinforcing the antenatal sleep education. FAB and combination groups received four contacts providing education and support on breast feeding, food and activity up to 4 months postpartum. OUTCOME MEASURES: Here we report secondary sleep outcomes from the POI study: the prevalence of parent-reported infant sleep problems and night waking, and differences in sleep duration. Additional outcomes reported include differences in infant self-settling, safe sleep practices, and maternal and partner reports of their own sleep, fatigue and depression symptoms. RESULTS: Linear or mixed linear regression models found no significant intervention effects on sleep outcomes, with 19.1% of mothers and 16.6% of partners reporting their infant's sleep a problem at 6 months. Actigraphy estimated the number of night wakings to be significantly reduced (8%) and the duration of daytime sleep increased (6 min) in those groups receiving the sleep intervention compared with those who did not. However, these small differences were not clinically significant and not observed in 24 hours infant sleep diary data. No other differences were observed. CONCLUSION: A strategy delivering infant sleep education antenatally and at 3 weeks postpartum was not effective in preventing the development of parent-reported infant sleep problems. PMID- 28576898 TI - Sex differences in auditory verbal hallucinations in early, middle and late adolescence: results from a survey of 17 451 Japanese students aged 12-18 years. AB - OBJECTIVES: Women have higher rates of auditory verbal hallucinations (AVH) than men; however, less is known about sex differences in the prevalence of AVH in early, middle and late adolescence. We sought to elucidate the differences in the prevalence of AVH and to examine the degree to which these differences could be explained by differences in levels of depressive symptoms. DESIGN: We used a cross-sectional design and a self-reported questionnaire. SETTING: Participants were recruited from public junior and senior high schools in Tsu, Mie Prefecture and Kochi Prefecture, Japan. PARTICIPANTS: In total, 19 436 students were contacted and 18 250 participated. Responses from 17 451 students with no missing data were analysed (aged 12-18 years, Mage=15.2 years (SD=1.7), 50.6% girls). MEASURES: AVH were assessed through one of four items adopted from the schizophrenia section of the Japanese version of the Diagnostic Interview Schedule for Children. Depressive symptoms were assessed using the 12-item General Health Questionnaire. RESULTS: The prevalence of AVH was 7.0% among early adolescents (aged 12-13 years), 6.2% among middle adolescents (aged 14-15 years) and 4.8% among late adolescents (aged 16-18 years). Being female was significantly associated with a higher prevalence of AVH through adolescence (OR=1.71, 95% CI 1.31 to 2.23 in early adolescence; OR=1.42, 95% CI 1.14 to 1.76 in middle adolescence; OR=1.52, 95% CI 1.23 to 1.87 in late adolescence); however, these differences became non-significant after adjusting for depressive symptoms (OR=1.21, 95% CI 0.92 to 1.60; OR=1.00, 95% CI 0.80 to 1.25; OR=1.16, 95% CI 0.93 to 1.44, respectively). CONCLUSIONS: Sex differences in auditory hallucinations are seen in both adult and youth populations. The higher rates of auditory verbal hallucinations seen in girls may be secondary to the differences in the rate of depressive symptoms. PMID- 28576899 TI - Association between exposure to the Chinese famine during infancy and the risk of self-reported chronic lung diseases in adulthood: a cross-sectional study. AB - OBJECTIVE: To examine the association between early-life exposure to the Chinese famine and the risk of chronic lung diseases in adulthood. DESIGN: Data analysis from a cross-sectional survey. SETTING AND PARTICIPANTS: 4135 subjects were enrolled into the study from the China Health and Retirement Longitudinal Study (CHARLS) 2011-2012 baseline survey to analyse the associations between prenatal and early postnatal famine exposure and the risk of chronic lung diseases in adulthood. MAIN OUTCOME MEASURES: Chronic lung diseases were defined based on self-reported information. RESULTS: The prevalence of self-reported chronic lung diseases in fetus-exposed, infant-exposed, preschool-exposed, and non-exposed groups was 6.5%, 7.9%, 6.8%, and 6.1%, respectively. The risk of chronic lung diseases in the infant-exposed group was significantly higher (OR 1.95, 95% CI 1.10 to 3.44) than the non-exposed group in severely affected areas, even after adjusting for gender, smoking, and drinking, family economic status, and the highest educational attainment of the parents (OR 2.57, 95% CI 1.26 to 5.25). In addition, after stratification by gender and famine severity, we found that only infant exposure to the severe famine was associated with the elevated risk of chronic lung diseases among male adults (OR 3.16, 95% CI 1.17 to 8.51). CONCLUSIONS: Severe famine exposure during the period of infancy might increase the risk of chronic lung diseases in male adults. PMID- 28576900 TI - Hepatitis B vaccination coverage, knowledge and sociodemographic determinants of uptake in high risk public safety workers in Kaduna State, Nigeria: a cross sectional survey. AB - OBJECTIVES: To estimate hepatitis B vaccination (HBVc) coverage, and knowledge and sociodemographic determinants of full dose uptake in Federal Road Safety Corps (FRSC) members, Kaduna State, Nigeria, to inform relevant targeted vaccination policies. DESIGN: A cross sectional survey of FRSC members, Kaduna Sector Command. SETTINGS: Six randomly selected unit commands under Kaduna Sector Command, Kaduna State, Nigeria. PARTICIPANTS: A pilot tested, structured, self administered questionnaire was administered to 341 participants aged >=18 years with >=6 months of service between 17 June and 22 July 2015. Excluded were FRSC members in road safety 1 zonal command headquarters as the zonal command includes other states beyond the study scope. PRIMARY OUTCOME: HBVc status of participants categorised as 'not vaccinated' for uptake of <3 doses and 'vaccinated' for uptake of >=3 doses. ANALYSIS: Descriptive analysis estimated HBVc coverage while logistic regression ascertained associations. RESULTS: Most participants were men, aged 30-39 years, with 3-10 years of service and of marshal cadre. HBVc coverage was 60.9% for >=1 dose and 30.5% for >=3 doses. Less than 47% of participants scored above the mean knowledge score for hepatitis B virus (HBV) and HBVc. Female sex (AOR 2.28, 95% CI 1.15 to 4.52, p<0.05), perceiving there to be an occupational risk of exposure to HBV (AOR 2.86, 95% CI 1.06 to 7.70, p<0.001) and increasing HBVc knowledge (AOR 2.68, 95% CI 1.83 to 3.92, p<0.001) were independent predictors of full dose HBVc in FRSC members, Kaduna Sector Command. CONCLUSIONS: HBVc coverage and knowledge were poor among FRSC members, Kaduna Sector Command. Educational intervention, geared towards improving FRSC members' knowledge of HBVc and perception of risk of occupational exposure to HBV, is recommended for these vulnerable public safety workers. Such enlightenment could be a cheap and easy way of improving HBVc coverage in the study population. PMID- 28576901 TI - AnAnkle Trial study protocol: a randomised trial comparing pain profiles after peripheral nerve block or spinal anaesthesia for ankle fracture surgery. AB - INTRODUCTION: Ankle fracture surgery is a common procedure, but the influence of anaesthesia choice on postoperative pain and quality of recovery is poorly understood. Some authors suggest a benefit of peripheral nerve block (PNB) in elective procedures, but the different pain profile following acute fracture surgery and the rebound pain on cessation of the PNB both remain unexplored. We present an ongoing randomised study aiming to compare primary PNB anaesthesia with spinal anaesthesia for ankle fracture surgery regarding postoperative pain profiles and quality of recovery. METHODS AND ANALYSIS: AnAnkle Trial is a randomised, dual-centre, open-label, blinded analysis trial of 150 adult patients undergoing primary internal fixation of an ankle fracture. Main exclusion criteria are habitual opioid use, impaired pain sensation, other painful injuries or cognitive impairment. The intervention is ultrasound-guided popliteal sciatic (20 mL) and saphenal nerve (8 mL) PNB with ropivacaine 7.5 mg/mL, and controls receive spinal anaesthesia (2 mL) with hyperbaric bupivacaine 5 mg/mL. Postoperatively all receive paracetamol, ibuprofen and patient-controlled intravenous morphine on demand. Morphine consumption and pain scores are registered in the first 27 hours and reported as an integrated pain score as the primary endpoint. Pain score intervals are 3 hours and we will use the area under curve to get a longitudinal measure of pain. Secondary outcomes include rebound pain on cessation of anaesthesia, opioid side effects (Opioid-Related Symptom Distress Scale), quality of recovery (Danish Quality of Recovery-15 score) and pain scores and medication days 1-7 (diary). ETHICS AND DISSEMINATION: The study has been approved by the Regional Ethics Committees in the Capital Region of Denmark, the Danish Data Protection Agency and the Danish Health and Medical Authority. We will publish the results in international peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: AnAnkle Trial is registered in the European Clinical Trials Database (EudraCT 2015-001108-76). PMID- 28576902 TI - Application of pharmacogenomics to investigate adverse drug reactions to the disease-modifying treatments for multiple sclerosis: a case-control study protocol for dimethyl fumarate-induced lymphopenia. AB - INTRODUCTION: Adverse drug reactions (ADRs) are a global public health issue. The potential for pharmacogenomic biomarkers has been demonstrated in several therapeutical areas, including HIV infection and oncology. Dimethyl fumarate (DMF) is a licensed disease-modifying therapy for the treatment of multiple sclerosis (MS). The use of DMF in MS has been associated with a severe reduction in lymphocyte counts and reports of progressive multifocal leukoencephalopathy. Here, we outline the protocol for a case-control study designed to discover genomic variants associated with DMF-induced lymphopenia. The ultimate goal is to replicate these findings and create an efficient and adaptable approach towards the identification of genomic markers that could assist in mitigating adverse drug reactions in MS. METHODS AND ANALYSIS: The population sample will comprise DMF-exposed patients with MS, with cases representing those who developed lymphopenia and controls who did not. DNA genotyping will take place using a high throughput genome-wide array. Fine mapping and imputation will be performed to focus in on the potentially causal variants associated with lymphopenia. Multivariable logistic regression will be used to compare genotype and allele frequencies between the cases and the controls, with consideration of potential confounders. The association threshold will be set at p<1.0*10-5 for the discovery of genomic association analyses to select variants for replication. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the respective research ethics board, which includes written informed consent. Findings will be disseminated widely, including at scientific conferences, via podcasts (targeted at both healthcare professionals as well as patients and the wider community), through patient engagement and other outreach community events, written lay summaries for all participants and formal publication in peer-reviewed scientific journals. PMID- 28576903 TI - The Taking Charge After Stroke (TaCAS) study protocol: a multicentre, investigator-blinded, randomised controlled trial comparing the effect of a single Take Charge session, two Take Charge sessions and control intervention on health-related quality of life 12 months after stroke for non-Maori, non-Pacific adult New Zealanders discharged to community living. AB - INTRODUCTION: Stroke is one of the leading causes of disability worldwide. Recent data support the possibility that person-centred, self-management interventions can reduce dependence after stroke. However, there is limited information on the generalisability and optimum dose of these interventions. METHODS: The Taking Charge After Stroke (TaCAS) study is a multicentre, investigator-blinded, randomised controlled trial recruiting 400 participants following acute stroke from seven hospitals in New Zealand. All patients discharged to community living who have ongoing symptoms at time of discharge (modified Rankin scale>0) will be eligible. Participants will be randomly assigned to one Take Charge session, two Take Charge sessions 6 weeks apart or control. OUTCOMES: The primary outcome will be the Physical Component Summary score of the Short-Form 36 at 12 months post stroke. Secondary outcomes will include dependence (modified Rankin scale), performance in activities of daily living (Barthel Index) and carer strain (Caregiver Strain Index), at 6 and 12 months post stroke. All analyses will be conducted on an intention-to-treat basis. ETHICS AND DISSEMINATION: The TaCAS study is funded by a Health Research Council of New Zealand grant. It has been approved by the Central Health and Disability Ethics Committee (15/CEN/115). Results will be published and presented at relevant stroke meetings within New Zealand and internationally, informing the use of a self-management intervention after stroke. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry ACTRN12615001163594. Date registered 02-11-2015. Medical Research Institute of New Zealand Registry TCS01. Universal trial number U1111-1171-4127. PMID- 28576905 TI - CMV and BKPyV Infections in Renal Transplant Recipients Receiving an mTOR Inhibitor-Based Regimen Versus a CNI-Based Regimen: A Systematic Review and Meta Analysis of Randomized, Controlled Trials. AB - BACKGROUND AND OBJECTIVES: The objective of this meta-analysis is to compare the incidences of cytomegalovirus and BK polyoma virus infections in renal transplant recipients receiving a mammalian target of rapamycin inhibitor (mTOR)-based regimen compared with a calcineurin inhibitor-based regimen. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a comprehensive search for randomized, controlled trials up to January of 2016 addressing our objective. Other outcomes included acute rejection, graft loss, serious adverse events, proteinuria, wound healing complications, and eGFR. Two review authors selected eligible studies, abstracted data, and assessed risk of bias. We assessed quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology. RESULTS: We included 28 randomized, controlled trials with 6211 participants classified into comparison 1: mTOR inhibitor versus calcineurin inhibitor and comparison 2: mTOR inhibitor plus reduced dose of calcineurin inhibitor versus regular dose of calcineurin inhibitor. Results showed decreased incidence of cytomegalovirus infection in mTOR inhibitor-based group in both comparison 1 (risk ratio, 0.54; 95% confidence interval, 0.41 to 0.72), with high quality of evidence, and comparison 2 (risk ratio, 0.43; 95% confidence interval, 0.24 to 0.80), with moderate quality of evidence. The available evidence neither confirmed nor ruled out a reduction of BK polyoma virus infection in mTOR inhibitor-based group in both comparisons. Secondary outcomes revealed more serious adverse events and acute rejections in mTOR inhibitor-based group in comparison 1 and no difference in comparison 2. There was no difference in graft loss in both comparisons. eGFR was higher in the mTOR inhibitor-based group in comparison 1 (mean difference =4.07 ml/min per 1.73 m2; 95% confidence interval, 1.34 to 6.80) and similar to the calcineurin inhibitor-based group in comparison 2. More proteinuria and wound-healing complications occurred in the mTOR inhibitor-based groups. CONCLUSIONS: We found moderate- to high-quality evidence of reduced risk of cytomegalovirus infection in renal transplant recipients in the mTOR inhibitor-based compared with the calcineurin inhibitor-based regimen. Our review also suggested that a combination of a mTOR inhibitor and a reduced dose of calcineurin inhibitor may be associated with similar eGFR and rates of acute rejections and serious adverse events compared with a standard calcineurin inhibitor-based regimen at the expense of higher incidence of proteinuria and wound-healing complications. PMID- 28576908 TI - Increase body weight to treat superior mesenteric artery syndrome. AB - INTRODUCTION: Superior mesenteric artery (SMA) syndrome is a rare cause of duodenal obstruction resulting from vascular compression of the third part of the duodenum in the angle between the abdominal aorta and SMA. CASE PRESENTATION: A 19-year-old woman with anorexia nervosa with upper gastrointestinal obstruction symptoms resorted to the emergency department. A diagnosis of SMA syndrome was made. Symptoms were solved with conservative treatment aimed at increase body weight. DISCUSSION: SMA syndrome is most commonly associated with debilitating illnesses. Patients present with acute or insidious upper gastrointestinal obstruction symptoms. Aortomesenteric artery angle of <=25 degrees is the most sensitive measure of diagnosis. Advances in both enteral and parenteral nutrition led to a shift towards conservative treatment. CONCLUSIONS: Low threshold of suspicion is important to make a timely diagnosis and treatment. A conservative treatment aimed at increasing body weight is the first-line approach, leaving surgical intervention for failure cases. PMID- 28576906 TI - Factors Associated with Frailty and Its Trajectory among Patients on Hemodialysis. AB - BACKGROUND AND OBJECTIVES: Frailty is common among patients on hemodialysis and associated with adverse outcomes. However, little is known about changes in frailty over time and the factors associated with those changes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To address these questions, we examined 762 participants in the A Cohort to Investigate the Value of Exercise/Analyses Designed to Investigate the Paradox of Obesity and Survival in ESRD cohort study, among whom frailty was assessed at baseline and 12 and 24 months. We used ordinal generalized estimating equations analyses and modeled frailty (on a scale from zero to five possible components) and death during follow-up. RESULTS: The mean frailty score at baseline was 1.9, and the distribution of frailty scores was similar at each evaluation. However, most participants' scores changed, with patients improving almost as often as worsening (overall change, 0.2 points per year; 95% confidence interval, 0.1 to 0.3). Hispanic ethnicity (0.6 points per year; 95% confidence interval, 0.0 to 1.1) and diabetes (0.7 points per year; 95% confidence interval, 0.3 to 1.0) were associated with higher frailty scores and higher serum albumin concentration with lower frailty scores (-1.1 points per g/dl; 95% confidence interval, -1.5 to -0.7). In addition, patients whose serum albumin increased over time were less likely to become frail, with each 1-g/dl increase in albumin associated with a 0.4-point reduction in frailty score (95% confidence interval, -0.80 to -0.05). To examine the underpinnings of the association between serum albumin and frailty, we included serum IL-6, normalized protein catabolic rate, and patient self-report of hospitalization within the last year in a second model. Higher IL-6 and hospitalization were statistically significantly associated with worse frailty at any point and worsening frailty over time, whereas normalized protein catabolic rate was not independently associated with frailty. CONCLUSIONS: There was substantial year to year variability in frailty scores, with approximately equal numbers of patients improving and worsening. Markers of inflammation and hospitalization were independently associated with worsening frailty. Studies should examine whether interventions to address inflammation or posthospitalization rehabilitation can improve the trajectory of frailty. PMID- 28576909 TI - Abciximab-induced delayed profound thrombocytopaenia. AB - Abciximab, the first approved glycoprotein (GP IIb/IIIa) inhibitor, is being widely used during acute coronary syndromes and offers the promising approach to antithrombotic therapy. We present a case of a young woman who initially received abciximab infusion for undergoing percutaneous coronary intervention of left anterior descending artery and was eventually diagnosed with abciximab-induced delayed thrombocytopaenia. This case outlines the importance of close follow-up of these patients to prevent serious adverse events. PMID- 28576907 TI - Low Bone Density and Bisphosphonate Use and the Risk of Kidney Stones. AB - BACKGROUND AND OBJECTIVES: Previous studies have demonstrated lower bone density in patients with kidney stones, but no longitudinal studies have evaluated kidney stone risk in individuals with low bone density. Small studies with short follow up reported reduced 24-hour urine calcium excretion with bisphosphonate use. We examined history of low bone density and bisphosphonate use and the risk of incident kidney stone as well as the association with 24-hour calcium excretion. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a prospective analysis of 96,092 women in the Nurses' Health Study II. We used Cox proportional hazards models to adjust for age, body mass index, thiazide use, fluid intake, supplemental calcium use, and dietary factors. We also conducted a cross sectional analysis of 2294 participants using multivariable linear regression to compare 24-hour urinary calcium excretion between participants with and without a history of low bone density, and among 458 participants with low bone density, with and without bisphosphonate use. RESULTS: We identified 2564 incident stones during 1,179,860 person-years of follow-up. The multivariable adjusted relative risk for an incident kidney stone for participants with history of low bone density compared with participants without was 1.39 (95% confidence interval [95% CI], 1.20 to 1.62). Among participants with low bone density, the multivariable adjusted relative risk for an incident kidney stone for bisphosphonate users was 0.68 (95% CI, 0.48 to 0.98). In the cross-sectional analysis of 24-hour urine calcium excretion, the multivariable adjusted mean difference in 24-hour calcium was 10 mg/d (95% CI, 1 to 19) higher for participants with history of low bone density. However, among participants with history of low bone density, there was no association between bisphosphonate use and 24-hour calcium with multivariable adjusted mean difference in 24-hour calcium of -2 mg/d (95% CI, -25 to 20). CONCLUSIONS: Low bone density is an independent risk factor for incident kidney stone and is associated with higher 24-hour urine calcium excretion. Among participants with low bone density, bisphosphonate use was associated with lower risk of incident kidney stone but was not independently associated with 24-hour urine calcium excretion. PMID- 28576910 TI - Large bilateral seminal vesicle calculi presenting with spermolithiasis. AB - A 34-year-old male presented with an 8-month history of passing increasingly painful 'grit' in his ejaculate. Semen analysis was normal as were urinary and blood tests. T1-weighted MRI revealed several bilateral high-signal areas measuring up to 1 cm in diameter, located in the seminal vesicles. These were confirmed as calculi on T2-weighted imaging and a seminal vesiculogram, with no drainage from the left ejaculatory duct and only minimal from the right duct. He is currently awaiting a robot-assisted laparoscopic vesiculotomy after completion of family. PMID- 28576911 TI - High-grade myxofibrosarcoma of the abdominal wall. AB - The authors present a case of a 57-year-old man, who presented to the surgical clinic with a mass in the suprapubic region. A CT scan revealed a well circumscribed lobular, heterogeneous soft tissue mass measuring 12*8.6*7.8 cm. The final histopathological diagnosis from the resection of the lesion was a myxofibrosarcoma (MFS), grade 3. The management of MFS includes surgical and oncological options which are reviewed here. These are aimed at complete excision and reducing the risk of local occurrence. PMID- 28576913 TI - Peptoniphilus asaccharolyticus-associated septic arthritis and osteomyelitis in a woman with osteoarthritis and diabetes mellitus. AB - Peptoniphilus asaccharolyticus, a Gram-positive obligatory anaerobic coccus, is a commensal of the human vagina and gut and can be an opportunistic pathogen in immunocompromised patients. It is usually part of polymicrobial anaerobic infections such as skin and soft tissue infections in diabetics, bone and joint infections and surgical site infections; however, infections caused by P. asaccharolyticus in pure culture have been reported as well. Herein, we describe a case of septic arthritis and osteomyelitis caused by P. asaccharolyticus in a woman with osteoarthritis and diabetes mellitus. PMID- 28576912 TI - Insular carcinoma arising on a background of follicular carcinoma, thyrolipomatosis and amyloid goitre. AB - A 67-year-old man was referred with a history of a right-sided neck lump and dysphonia, secondary to a lesion in the thyroid gland. After undergoing a total thyroidectomy, he was found to have an exceedingly rare combination of follicular carcinoma, insular carcinoma, thyrolipomatosis and an amyloid goitre in his thyroid gland. He subsequently underwent further radioactive iodine ablation and has been in remission. He was also later incidentally diagnosed with systemic amyloidosis, which explained the amyloid deposition in his thyroid gland. PMID- 28576914 TI - Do not treat the numbers: lithium toxicity. AB - We describe the case of a 62-year-old man with a history of bipolar disorder, previously stable on lithium for over 20 years, who presented with a manic relapse and signs of lithium toxicity in the form of a coarse tremor. Serum lithium levels were in the normal range, and the patient had stage 3 chronic kidney disease. He was admitted for treatment under Section 2 of the Mental Health Act, and after stopping lithium was started on olanzapine. Signs of lithium toxicity improved after withdrawal of lithium. This case highlights the need to treat normal serum lithium levels with caution in patients showing signs of clinical lithium toxicity. PMID- 28576915 TI - Transanal removal of a broken drinking glass self-inserted and retained in the rectum. AB - Retained rectal foreign bodies are increasingly reported in current clinical practice, and there is no clear consensus in the literature as to whether transanal extraction should be performed in the emergency or in the operating room. A 47-year-old presented to the hospital for a retained drinking glass in the rectum that was broken after an attempt at self-extraction. Physical examination showed no evidence of abdominal guarding nor bleeding from the rectum; abdominal and pelvic X-rays confirmed the presence of a broken glass, 8*6 cm in size and no signs of perforation. Initial anoscopy performed in the emergency room confirmed the partial fracture of the glass. The patient was transferred to the operating room and transanal extraction was carried out under general anaesthesia without complications. PMID- 28576916 TI - Fabry heterozygote mimicking multiple sclerosis. AB - Fabry's disease (FD) is a recognised mimic of multiple sclerosis (MS). It is an X linked storage lysosomal disorder with deficiency of alpha-galactosidase A and enzyme replacement therapy is available. Patients with FD may satisfy modified McDonald criteria if the diagnosis of FD has not been pursued. We present a case of FD in a 65-year-old woman masquerading as benign MS for 40 years. She has recurrent posterior circulation stroke-like symptoms, hearing loss and acroparaesthesia, but typical radiological features of MS on MRI brain. Later she developed an ischaemic stroke, infiltrative cardiomyopathy and chronic renal failure. There was a missense mutation at p.R342Q in the galactodisdase alpha (GLA) gene. Neurologists need to consider FD and look for red flags in atypical MS cases and should not be over-reliant on MRI findings. Missed diagnosis of FD could lead to unnecessary immunosuppression, inappropriate disease counselling and missed treatment opportunity. PMID- 28576917 TI - Consider the vulnerable patient given full access to health records. PMID- 28576918 TI - An unusual cause of neonatal ascites. PMID- 28576919 TI - Trivial role for NSMCE2 during in vitro proliferation and differentiation of male germline stem cells. AB - Spermatogenesis, starting with spermatogonial differentiation, is characterized by ongoing and dramatic alterations in composition and function of chromatin. Failure to maintain proper chromatin dynamics during spermatogenesis may lead to mutations, chromosomal aberrations or aneuploidies. When transmitted to the offspring, these can cause infertility or congenital malformations. The structural maintenance of chromosomes (SMC) 5/6 protein complex has recently been described to function in chromatin modeling and genomic integrity maintenance during spermatogonial differentiation and meiosis. Among the subunits of the SMC5/6 complex, non-SMC element 2 (NSMCE2) is an important small ubiquitin related modifier (SUMO) ligase. NSMCE2 has been reported to be essential for mouse development, prevention of cancer and aging in adult mice and topological stress relief in human somatic cells. By using in vitro cultured primary mouse spermatogonial stem cells (SSCs), referred to as male germline stem (GS) cells, we investigated the function of NSMCE2 during spermatogonial proliferation and differentiation. We first optimized a protocol to generate genetically modified GS cell lines using CRISPR-Cas9 and generated an Nsmce2-/- GS cell line. Using this Nsmce2-/- GS cell line, we found that NSMCE2 was dispensable for proliferation, differentiation and topological stress relief in mouse GS cells. Moreover, RNA sequencing analysis demonstrated that the transcriptome was only minimally affected by the absence of NSMCE2. Only differential expression of Sgsm1 appeared highly significant, but with SGSM1 protein levels being unaffected without NSMCE2. Hence, despite the essential roles of NSMCE2 in somatic cells, chromatin integrity maintenance seems differentially regulated in the germline. PMID- 28576922 TI - Cancer Immunology and Immunotherapy: Taking a Place in Mainstream Oncology Keystone Symposia Meeting Summary. AB - The Keystone Symposia conference on Cancer Immunology and Immunotherapy: Taking a Place in Mainstream Oncology was held at the Fairmont Chateau in Whistler, British Columbia, Canada, on March 19-23, 2017. The conference brought together a sold-out audience of 654 scientists, clinicians, and others from both academia and industry to discuss the latest developments in cancer immunology and immunotherapy. This meeting report summarizes the main themes that emerged during the four-day conference. Cancer Immunol Res; 5(6); 434-8. (c)2017 AACR. PMID- 28576921 TI - Novel "Elements" of Immune Suppression within the Tumor Microenvironment. AB - Adaptive evolution has prompted immune cells to use a wide variety of inhibitory signals, many of which are usurped by tumor cells to evade immune surveillance. Although tumor immunologists often focus on genes and proteins as mediators of immune function, here we highlight two elements from the periodic table-oxygen and potassium-that suppress the immune system in previously unappreciated ways. While both are key to the maintenance of T-cell function and tissue homeostasis, they are exploited by tumors to suppress immuno-surveillance and promote metastatic spread. We discuss the temporal and spatial roles of these elements within the tumor microenvironment and explore possible therapeutic interventions for effective and promising anticancer therapies. Cancer Immunol Res; 5(6); 426 33. (c)2017 AACR. PMID- 28576928 TI - Half of CCGs plan treatment cutbacks to meet financial targets. PMID- 28576930 TI - Robert C Gray. PMID- 28576932 TI - Advancing Our Profession in Exciting and Challenging Times. PMID- 28576931 TI - Erratum. PMID- 28576933 TI - The Value of Experience: Lessons Learned and Pearls of Wisdom Gathered. PMID- 28576927 TI - Overcoming the Immunosuppressive Tumor Microenvironment of Hodgkin Lymphoma Using Chimeric Antigen Receptor T Cells. AB - Patients with otherwise treatment-resistant Hodgkin lymphoma could benefit from chimeric antigen receptor T-cell (CART) therapy. However, Hodgkin lymphoma lacks CD19 and contains a highly immunosuppressive tumor microenvironment (TME). We hypothesized that in Hodgkin lymphoma, CART should target both malignant cells and the TME. We demonstrated CD123 on both Hodgkin lymphoma cells and TME, including tumor-associated macrophages (TAM). In vitro, Hodgkin lymphoma cells convert macrophages toward immunosuppressive TAMs that inhibit T-cell proliferation. In contrast, anti-CD123 CART recognized and killed TAMs, thus overcoming immunosuppression. Finally, we showed in immunodeficient mouse models that CART123 eradicated Hodgkin lymphoma and established long-term immune memory. A novel platform that targets malignant cells and the microenvironment may be needed to successfully treat malignancies with an immunosuppressive milieu.Significance: Anti-CD123 chimeric antigen receptor T cells target both the malignant cells and TAMs in Hodgkin lymphoma, thereby eliminating an important immunosuppressive component of the tumor microenvironment. Cancer Discov; 7(10); 1154-67. (c)2017 AACR.This article is highlighted in the In This Issue feature, p. 1047. PMID- 28576934 TI - Cholesteryl esters of omega-(O-acyl)-hydroxy fatty acids in vernix caseosa. AB - Cholesteryl esters of omega-(O-acyl)-hydroxy FAs (Chl-omegaOAHFAs) were identified for the first time in vernix caseosa and characterized using chromatography and MS. Chl-omegaOAHFAs were isolated using adsorption chromatography on silica gel and magnesium hydroxide. Their general structure was established using high-resolution and tandem MS of intact lipids, and products of their transesterification and derivatizations. Individual molecular species were characterized using nonaqueous reversed-phase HPLC coupled to atmospheric pressure chemical ionization. The analytes were detected as protonated molecules, and their structures were elucidated in the negative ion mode using controlled thermal decomposition and data-dependent fragmentation. About three hundred molecular species of Chl-omegaOAHFAs were identified in this way. The most abundant Chl-omegaOAHFAs contained 32:1 omega-hydroxy FA (omega-HFA) and 14:0, 15:0, 16:0, 16:1, and 18:1 FAs. The double bond in the 32:1 omega-HFA was in the n-7 and n-9 positions. Chl-omegaOAHFAs are estimated to account for approximately 1-2% of vernix caseosa lipids. PMID- 28576936 TI - betaIII Spectrin Is Necessary for Formation of the Constricted Neck of Dendritic Spines and Regulation of Synaptic Activity in Neurons. AB - Dendritic spines are postsynaptic structures in neurons often having a mushroom like shape. Physiological significance and cytoskeletal mechanisms that maintain this shape are poorly understood. The spectrin-based membrane skeleton maintains the biconcave shape of erythrocytes, but whether spectrins also determine the shape of nonerythroid cells is less clear. We show that betaIII spectrin in hippocampal and cortical neurons from rodent embryos of both sexes is distributed throughout the somatodendritic compartment but is particularly enriched in the neck and base of dendritic spines and largely absent from spine heads. Electron microscopy revealed that betaIII spectrin forms a detergent-resistant cytoskeletal network at these sites. Knockdown of betaIII spectrin results in a significant decrease in the density of dendritic spines. Surprisingly, the density of presynaptic terminals is not affected by betaIII spectrin knockdown. However, instead of making normal spiny synapses, the presynaptic structures in betaIII spectrin-depleted neurons make shaft synapses that exhibit increased amplitudes of miniature EPSCs indicative of excessive postsynaptic excitation. Thus, betaIII spectrin is necessary for formation of the constricted shape of the spine neck, which in turn controls communication between the synapse and the parent dendrite to prevent excessive excitation. Notably, mutations of SPTNB2 encoding betaIII spectrin are associated with neurodegenerative syndromes, spinocerebellar ataxia Type 5, and spectrin-associated autosomal recessive cerebellar ataxia Type 1, but molecular mechanisms linking betaIII spectrin functions to neuronal pathologies remain unresolved. Our data suggest that spinocerebellar ataxia Type 5 and spectrin-associated autosomal recessive cerebellar ataxia Type 1 pathology likely arises from poorly controlled synaptic activity that leads to excitotoxicity and neurodegeneration.SIGNIFICANCE STATEMENT Dendritic spines are small protrusions from neuronal dendrites that make synapses with axons of other neurons in the brain. Dendritic spines usually have a mushroom-like shape, which is essential for brain functions, because aberrant spine morphology is associated with many neuropsychiatric disorders. The bulbous head of a mushroom-shaped spine makes the synapse, whereas the narrow neck transmits the incoming signals to the dendrite and supposedly controls the signal propagation. We show that a cytoskeletal protein betaIII spectrin plays a key role for the formation of narrow spine necks. In the absence of betaIII spectrin, dendritic spines collapse onto dendrites. As a result, synaptic strength exceeds acceptable levels and damages neurons, explaining pathology of human syndromes caused by betaIII spectrin mutations. PMID- 28576937 TI - Binocular Disparity Selectivity Weakened after Monocular Deprivation in Mouse V1. AB - Experiences during the critical period sculpt the circuitry within the neocortex, leading to changes in the functional responses of sensory neurons. Monocular deprivation (MD) during the visual critical period causes shifts in ocular preference, or dominance, toward the open eye in primary visual cortex (V1) and disrupts the normal development of acuity. In carnivores and primates, MD also disrupts the emergence of binocular disparity selectivity, a cue resulting from integrating ocular inputs. This disruption may be a result of the increase in neurons driven exclusively by the open eye that follows deprivation or a result of a mismatch in the convergence of ocular inputs. To distinguish between these possibilities, we measured the ocular dominance (OD) and disparity selectivity of neurons from male and female mouse V1 following MD. Normal mouse V1 neurons are dominated by contralateral eye input and contralateral eye deprivation shifts mouse V1 neurons toward more balanced responses between the eyes. This shift toward binocularity, as assayed by OD, decreased disparity sensitivity. MD did not alter the initial maturation of binocularity, as disparity selectivity before the MD was indistinguishable from normal mature animals. Decreased disparity tuning was most pronounced in binocular and ipsilaterally biased neurons, which are the populations that have undergone the largest shifts in OD. In concert with the decline in disparity selectivity, we observed a shift toward lower spatial frequency selectivity for the ipsilateral eye following MD. These results suggest an emergence of novel synaptic inputs during MD that disrupt the representation of disparity selectivity.SIGNIFICANCE STATEMENT We demonstrate that monocular deprivation during the developmental critical period impairs binocular integration in mouse primary visual cortex. This impairment occurs despite an increase in the degree to which neurons become more binocular. We further demonstrate that our deprivation did not impair the maturation of disparity selectivity. Disparity selectivity has already reached a matured level before the monocular deprivation. The loss of disparity tuning is primarily observed in neurons dominated by the open eye, suggesting a link between altered inputs and loss of disparity sensitivity. These results suggest that new inputs following deprivation may not maintain the precise spatial relationship between the two eye inputs required for disparity selectivity. PMID- 28576935 TI - Inflammatory Pain Reduces C Fiber Activity-Dependent Slowing in a Sex-Dependent Manner, Amplifying Nociceptive Input to the Spinal Cord. AB - C fibers display activity-dependent slowing (ADS), whereby repetitive stimulation (>=1 Hz) results in a progressive slowing of action potential conduction velocity, which manifests as a progressive increase in response latency. However, the impact of ADS on spinal pain processing has not been explored, nor whether ADS is altered in inflammatory pain conditions. To investigate, compound action potentials were made, from dorsal roots isolated from rats with or without complete Freund's adjuvant (CFA) hindpaw inflammation, in response to electrical stimulus trains. CFA inflammation significantly reduced C fiber ADS at 1 and 2 Hz stimulation rates. Whole-cell patch-clamp recordings in the spinal cord slice preparation with attached dorsal roots also demonstrated that CFA inflammation reduced ADS in the monosynaptic C fiber input to lamina I neurokinin 1 receptor expressing neurons (1-10 Hz stimulus trains) without altering the incidence of synaptic response failures. When analyzed by sex, it was revealed that females display a more pronounced ADS that is reduced by CFA inflammation to a level comparable with males. Cumulative ventral root potentials evoked by long and short dorsal root stimulation lengths, to maximize and minimize the impact of ADS, respectively, demonstrated that reducing ADS facilitates spinal summation, and this was also sex dependent. This finding correlated with the behavioral observation of increased noxious thermal thresholds and enhanced inflammatory thermal hypersensitivity in females. We propose that sex/inflammation-dependent regulation of C fiber ADS can, by controlling the temporal relay of nociceptive inputs, influence the spinal summation of nociceptive signals contributing to sex/inflammation-dependent differences in pain sensitivity.SIGNIFICANCE STATEMENT The intensity of a noxious stimulus is encoded by the frequency of action potentials relayed by nociceptive C fibers to the spinal cord. C fibers conduct successive action potentials at progressively slower speeds, but the impact of this activity-dependent slowing (ADS) is unknown. Here we demonstrate that ADS is more prevalent in females than males and is reduced in an inflammatory pain model in females only. We also demonstrate a progressive delay of C fiber monosynaptic transmission to the spinal cord that is similarly sex and inflammation dependent. Experimentally manipulating ADS strongly influences spinal summation consistent with sex differences in behavioral pain thresholds. This suggests that ADS provides a peripheral mechanism that can regulate spinal nociceptive processing and pain sensation. PMID- 28576938 TI - Neuroimmune-Glia Interactions in the Sensory Ganglia Account for the Development of Acute Herpetic Neuralgia. AB - Herpetic neuralgia is the most important symptom of herpes zoster disease, which is caused by Varicella zoster Nevertheless, the pathophysiological mechanisms involved in herpetic neuralgia are not totally elucidated. Here, we examined the neuroimmune interactions at the sensory ganglia that account for the genesis of herpetic neuralgia using a murine model of Herpes Simplex Virus Type-1 (HSV-1) infection. The cutaneous HSV-1 infection of mice results in the development of a zosteriform-like skin lesion followed by a time-dependent increase in pain-like responses (mechanical allodynia). Leukocytes composed mainly of macrophages and neutrophils infiltrate infected DRGs and account for the development of herpetic neuralgia. Infiltrating leukocytes are responsible for driving the production of TNF, which in turn mediates the development of herpetic neuralgia through downregulation of the inwardly rectifying K+ channel Kir4.1 in satellite glial cells. These results revealed that neuroimmune-glia interactions at the sensory ganglia play a critical role in the genesis of herpetic neuralgia. In conclusion, the present study elucidates novel mechanisms involved in the genesis of acute herpetic pain and open new avenues for its control.SIGNIFICANCE STATEMENT Acute herpetic neuralgia is the most important symptom of herpes zoster disease and it is very difficult to treat. Using a model of peripheral infection of mice with HSV-1, we have characterized for the first time the neuroimmune-glia interactions in the sensory ganglia that account for the development of acute herpetic neuralgia. Among these mechanisms, leukocytes composed mainly of macrophages and neutrophils infiltrate infected sensory ganglia and are responsible for driving the production of TNF. TNF, via TNFR1, mediates herpetic neuralgia development through downregulation of the inwardly rectifying K+ channel Kir4.1 in satellite glial cells. This study elucidates novel mechanisms involved in the genesis of acute herpetic neuralgia and open new avenues for its control. PMID- 28576939 TI - The X-Linked Intellectual Disability Protein IL1RAPL1 Regulates Dendrite Complexity. AB - Mutations and deletions of the interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene, located on the X chromosome, are associated with intellectual disability (ID) and autism spectrum disorder (ASD). IL1RAPL1 protein is located at the postsynaptic compartment of excitatory synapses and plays a role in synapse formation and stabilization. Here, using primary neuronal cultures and Il1rapl1-KO mice, we characterized the role of IL1RAPL1 in regulating dendrite morphology. In Il1rapl1-KO mice we identified an increased number of dendrite branching points in CA1 and CA2 hippocampal neurons associated to hippocampal cognitive impairment. Similarly, induced pluripotent stem cell-derived neurons from a patient carrying a null mutation of the IL1RAPL1 gene had more dendrites. In hippocampal neurons, the overexpression of full-length IL1RAPL1 and mutants lacking part of C-terminal domains leads to simplified neuronal arborization. This effect is abolished when we overexpressed mutants lacking part of N-terminal domains, indicating that the IL1RAPL1 extracellular domain is required for regulating dendrite development. We also demonstrate that PTPdelta interaction is not required for this activity, while IL1RAPL1 mediates the activity of IL-1beta on dendrite morphology. Our data reveal a novel specific function for IL1RAPL1 in regulating dendrite morphology that can help clarify how changes in IL1RAPL1 regulated pathways can lead to cognitive disorders in humans.SIGNIFICANCE STATEMENT Abnormalities in the architecture of dendrites have been observed in a variety of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. Here we show that the X-linked intellectual disability protein interleukin-1 receptor accessory protein like 1 (IL1RAPL1) regulates dendrite morphology of mice hippocampal neurons and induced pluripotent stem cell-derived neurons from a patient carrying a null mutation of IL1RAPL1 gene. We also found that the extracellular domain of IL1RAPL1 is required for this effect, independently of the interaction with PTPdelta, but IL1RAPL1 mediates the activity of IL-1beta on dendrite morphology. Our data reveal a novel specific function for IL1RAPL1 in regulating dendrite morphology that can help clarify how changes in IL1RAPL1 regulated pathways can lead to cognitive disorders in humans. PMID- 28576940 TI - Descending Systems Direct Development of Key Spinal Motor Circuits. AB - The formation of mature spinal motor circuits is dependent on both activity dependent and independent mechanisms during postnatal development. During this time, reorganization and refinement of spinal sensorimotor circuits occurs as supraspinal projections are integrated. However, specific features of postnatal spinal circuit development remain poorly understood. This study provides the first detailed characterization of rat spinal sensorimotor circuit development in the presence and absence of descending systems. We show that the development of proprioceptive afferent input to motoneurons (MNs) and Renshaw cells (RCs) is disrupted by thoracic spinal cord transection at postnatal day 5 (P5TX). P5TX also led to malformation of GABApre neuron axo-axonic contacts on Ia afferents and of the recurrent inhibitory circuit between MNs and RCs. Using a novel in situ perfused preparation for studying motor control, we show that malformation of these spinal circuits leads to hyperexcitability of the monosynaptic reflex. Our results demonstrate that removing descending input severely disrupts the development of spinal circuits and identifies key mechanisms contributing to motor dysfunction in conditions such as cerebral palsy and spinal cord injury.SIGNIFICANCE STATEMENT Acquisition of mature behavior during postnatal development correlates with the arrival and maturation of supraspinal projections to the spinal cord. However, we know little about the role that descending systems play in the maturation of spinal circuits. Here, we characterize postnatal development of key spinal microcircuits in the presence and absence of descending systems. We show that formation of these circuits is abnormal after early (postnatal day 5) removal of descending systems, inducing hyperexcitability of the monosynaptic reflex. The study is a detailed characterization of spinal circuit development elucidating how these mechanisms contribute to motor dysfunction in conditions such as cerebral palsy and spinal cord injury. Understanding these circuits is crucial to developing new therapeutics and improving existing ones in such conditions. PMID- 28576941 TI - Reduced Slc6a15 in Nucleus Accumbens D2-Neurons Underlies Stress Susceptibility. AB - Previous research demonstrates that Slc6a15, a neutral amino acid transporter, is associated with depression susceptibility. However, no study examined Slc6a15 in the ventral striatum [nucleus accumbens (NAc)] in depression. Given our previous characterization of Slc6a15 as a striatal dopamine receptor 2 (D2)-neuron enriched gene, we examined the role of Slc6a15 in NAc D2-neurons in mediating susceptibility to stress in male mice. First, we showed that Slc6a15 mRNA was reduced in NAc of mice susceptible to chronic social defeat stress (CSDS), a paradigm that produces behavioral and molecular adaptations that resemble clinical depression. Consistent with our preclinical data, we observed Slc6a15 mRNA reduction in NAc of individuals with major depressive disorder (MDD). The Slc6a15 reduction in NAc occurred selectively in D2-neurons. Next, we used Cre inducible viruses combined with D2-Cre mice to reduce or overexpress Slc6a15 in NAc D2-neurons. Slc6a15 reduction in D2-neurons caused enhanced susceptibility to a subthreshold social defeat stress (SSDS) as observed by reduced social interaction, while a reduction in social interaction following CSDS was not observed when Slc6a15 expression in D2-neurons was restored. Finally, since both D2-medium spiny neurons (MSNs) and D2-expressing choline acetyltransferase (ChAT) interneurons express Slc6a15, we examined Slc6a15 protein in these interneurons after CSDS. Slc6a15 protein was unaltered in ChAT interneurons. Consistent with this, reducing Slc5a15 selectively in NAc D2-MSNs, using A2A-Cre mice that express Cre selectively in D2-MSNs, caused enhanced susceptibility to SSDS. Collectively, our data demonstrate that reduced Slc6a15 in NAc occurs in MDD individuals and that Slc6a15 reduction in NAc D2-neurons underlies stress susceptibility.SIGNIFICANCE STATEMENT Our study demonstrates a role for reduced Slc6a15, a neutral amino acid transporter, in nucleus accumbens (NAc) in depression and stress susceptibility. The reduction of Slc6a15 occurs selectively in the NAc D2-neurons. Genetic reduction of Slc6a15 induces susceptibility to a subthreshold stress, while genetic overexpression in D2-neurons prevents social avoidance after chronic social defeat stress. PMID- 28576942 TI - Wild-Type Monomeric alpha-Synuclein Can Impair Vesicle Endocytosis and Synaptic Fidelity via Tubulin Polymerization at the Calyx of Held. AB - alpha-Synuclein is a presynaptic protein the function of which has yet to be identified, but its neuronal content increases in patients of synucleinopathies including Parkinson's disease. Chronic overexpression of alpha-synuclein reportedly expresses various phenotypes of synaptic dysfunction, but the primary target of its toxicity has not been determined. To investigate this, we acutely loaded human recombinant alpha-synuclein or its pathological mutants in their monomeric forms into the calyces of Held presynaptic terminals in slices from auditorily mature and immature rats of either sex. Membrane capacitance measurements revealed significant and specific inhibitory effects of WT monomeric alpha-synuclein on vesicle endocytosis throughout development. However, the alpha synuclein A53T mutant affected vesicle endocytosis only at immature calyces, whereas the A30P mutant had no effect throughout. The endocytic impairment by WT alpha-synuclein was rescued by intraterminal coloading of the microtubule (MT) polymerization blocker nocodazole. Furthermore, it was reversibly rescued by presynaptically loaded photostatin-1, a photoswitcheable inhibitor of MT polymerization, in a light-wavelength-dependent manner. In contrast, endocytic inhibition by the A53T mutant at immature calyces was not rescued by nocodazole. Functionally, presynaptically loaded WT alpha-synuclein had no effect on basal synaptic transmission evoked at a low frequency, but significantly attenuated exocytosis and impaired the fidelity of neurotransmission during prolonged high frequency stimulation. We conclude that monomeric WT alpha-synuclein primarily inhibits vesicle endocytosis via MT overassembly, thereby impairing high frequency neurotransmission.SIGNIFICANCE STATEMENT Abnormal alpha-synuclein abundance is associated with synucleinopathies including Parkinson's disease, but neither the primary target of alpha-synuclein toxicity nor its mechanism is identified. Here, we loaded monomeric alpha-synuclein directly into mammalian glutamatergic nerve terminals and found that it primarily inhibits vesicle endocytosis and subsequently impairs exocytosis and neurotransmission fidelity during prolonged high-frequency stimulation. Such alpha-synuclein toxicity could be rescued by blocking microtubule polymerization, suggesting that microtubule overassembly underlies the toxicity of acutely elevated alpha-synuclein in the nerve terminal. PMID- 28576943 TI - Polysialic Acid Regulates Sympathetic Outflow by Facilitating Information Transfer within the Nucleus of the Solitary Tract. AB - Expression of the large extracellular glycan, polysialic acid (polySia), is restricted in the adult, to brain regions exhibiting high levels of plasticity or remodeling, including the hippocampus, prefrontal cortex, and the nucleus of the solitary tract (NTS). The NTS, located in the dorsal brainstem, receives constant viscerosensory afferent traffic as well as input from central regions controlling sympathetic nerve activity, respiration, gastrointestinal functions, hormonal release, and behavior. Our aims were to determine the ultrastructural location of polySia in the NTS and the functional effects of enzymatic removal of polySia, both in vitro and in vivo polySia immunoreactivity was found throughout the adult rat NTS. Electron microscopy demonstrated polySia at sites that influence neurotransmission: the extracellular space, fine astrocytic processes, and neuronal terminals. Removing polySia from the NTS had functional consequences. Whole-cell electrophysiological recordings revealed altered intrinsic membrane properties, enhancing voltage-gated K+ currents and increasing intracellular Ca2+ Viscerosensory afferent processing was also disrupted, dampening low-frequency excitatory input and potentiating high-frequency sustained currents at second order neurons. Removal of polySia in the NTS of anesthetized rats increased sympathetic nerve activity, whereas functionally related enzymes that do not alter polySia expression had little effect. These data indicate that polySia is required for the normal transmission of information through the NTS and that changes in its expression alter sympathetic outflow. polySia is abundant in multiple but discrete brain regions, including sensory nuclei, in both the adult rat and human, where it may regulate neuronal function by mechanisms identified here.SIGNIFICANCE STATEMENT All cells are coated in glycans (sugars) existing predominantly as glycolipids, proteoglycans, or glycoproteins formed by the most complex form of posttranslational modification, glycosylation. How these glycans influence brain function is only now beginning to be elucidated. The adult nucleus of the solitary tract has abundant polysialic acid (polySia) and is a major site of integration, receiving viscerosensory information which controls critical homeostatic functions. Our data reveal that polySia is a determinant of neuronal behavior and excitatory transmission in the nucleus of the solitary tract, regulating sympathetic nerve activity. polySia is abundantly expressed at distinct brain sites in adult, including major sensory nuclei, suggesting that sensory transmission may also be influenced via mechanisms described here. These findings hint at the importance of elucidating how other glycans influence neural function. PMID- 28576947 TI - The Slow Cycling Phenotype: A Growing Problem for Treatment Resistance in Melanoma. AB - Treatment resistance in metastatic melanoma is a longstanding issue. Current targeted therapy regimes in melanoma largely target the proliferating cancer population, leaving slow-cycling cancer cells undamaged. Consequently, slow cycling cells are enriched upon drug therapy and can remain in the body for years until acquiring proliferative potential that triggers cancer relapse. Here we overview the molecular mechanisms of slow-cycling cells that underlie treatment resistance in melanoma. Three main areas of molecular reprogramming are discussed that mediate slow cycling and treatment resistance. First, a low microphthalmia associated transcription factor (MITF) dedifferentiated state activates various signaling pathways. This includes WNT5A, EGFR, as well as other signaling activators, such as AXL and NF-kappaB. Second, the chromatin-remodeling factor Jumonji/ARID domain-containing protein 1B (JARID1B, KDM5B) orchestrates and maintains slow cycling and treatment resistance in a small subpopulation of melanoma cells. Finally, a shift in metabolic state toward oxidative phosphorylation has been demonstrated to regulate treatment resistance in slow cycling cells. Elucidation of the underlying processes of slow cycling and its utilization by melanoma cells may reveal new vulnerable characteristics as therapeutic targets. Moreover, combining current therapies with targeting slow cycling subpopulations of melanoma cells may allow for more durable and greater treatment responses. Mol Cancer Ther; 16(6); 1002-9. (c)2017 AACR. PMID- 28576946 TI - FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions. AB - The receptor tyrosine kinase fms-like tyrosine kinase 3 (FLT3), involved in regulating survival, proliferation, and differentiation of hematopoietic stem/progenitor cells, is expressed on acute myeloid leukemia (AML) cells in most patients. Mutations of FLT3 resulting in constitutive signaling are common in AML, including internal tandem duplication (ITD) in the juxtamembrane domain in 25% of patients and point mutations in the tyrosine kinase domain in 5%. Patients with AML with FLT3-ITD have a high relapse rate and short relapse-free and overall survival after chemotherapy and after transplant. A number of inhibitors of FLT3 signaling have been identified and are in clinical trials, both alone and with chemotherapy, with the goal of improving clinical outcomes in patients with AML with FLT3 mutations. While inhibitor monotherapy produces clinical responses, they are usually incomplete and transient, and resistance develops rapidly. Diverse combination therapies have been suggested to potentiate the efficacy of FLT3 inhibitors and to prevent development of resistance or overcome resistance. Combinations with epigenetic therapies, proteasome inhibitors, downstream kinase inhibitors, phosphatase activators, and other drugs that alter signaling are being explored. This review summarizes the current status of translational and clinical research on FLT3 inhibitors in AML, and discusses novel combination approaches. Mol Cancer Ther; 16(6); 991-1001. (c)2017 AACR. PMID- 28576948 TI - Correction: Dedifferentiation of Glioma Cells to Glioma Stem-like Cells By Therapeutic Stress-induced HIF Signaling in the Recurrent GBM Model. PMID- 28576945 TI - The Role of CtBP1 in Oncogenic Processes and Its Potential as a Therapeutic Target. AB - Transcriptional corepressor proteins have emerged as an important facet of cancer etiology. These corepressor proteins are often altered by loss- or gain-of function mutations, leading to transcriptional imbalance. Thus, research directed at expanding our current understanding of transcriptional corepressors could impact the future development of new cancer diagnostics, prognostics, and therapies. In this review, our current understanding of the CtBP corepressors, and their role in both development and disease, is discussed in detail. Importantly, the role of CtBP1 overexpression in adult tissues in promoting the progression of multiple cancer types through their ability to modulate the transcription of developmental genes ectopically is explored. CtBP1 overexpression is known to be protumorigenic and affects the regulation of gene networks associated with "cancer hallmarks" and malignant behavior, including increased cell survival, proliferation, migration, invasion, and the epithelial mesenchymal transition. As a transcriptional regulator of broad developmental processes capable of promoting malignant growth in adult tissues, therapeutically targeting the CtBP1 corepressor has the potential to be an effective method for the treatment of diverse tumor types. Although efforts to develop CtBP1 inhibitors are still in the early stages, the current progress and the future perspectives of therapeutically targeting this transcriptional corepressor are also discussed. Mol Cancer Ther; 16(6); 981-90. (c)2017 AACR. PMID- 28576950 TI - Retrospective Case Reports of Two Central North Carolina Residents: Frequency of Tick Bites and Associated Illnesses, 2001-2014. AB - BACKGROUND Tick bites are a source of illness and disease agents that may lead to morbidity and occasional fatalities in North Carolina. Public health interest in tick-borne illness and disease has increased due to continuing discoveries of tick-borne diseases and their increasing geographic spread and disease incidence. There are no data published on lay individuals with cumulative tick bites and associated illnesses over a period of years.METHODS We learned of a married couple living on a central North Carolina property who had used reasonable bite prevention methods, kept attached ticks after removal, and recorded dates and related illness records from 2001-2014. We obtained permission to analyze their records. Ticks were identified by an entomologist.RESULTS The male subject had a total of 219 bites from identifiable ticks comprising 213 Amblyomma americanum, 4 Dermacentor variabilis, and 2 Ixodes scapularis He was treated for possible Rocky Mountain spotted fever once and presumed Southern Tick Associated Rash Illness once. The female subject had 193 bites comprising 168 A. americanum, 23 D. variabilis, and 2 I. scapularis She was treated for 4 episodes of presumed Southern Tick Associated Rash Illness and one possible case of a tick-borne infection. Several years of data were missing for both subjects.LIMITATIONS This retrospective report relied on the subjects' own records for much of the data. The experience of these individuals cannot be generalized. Diagnoses of these tick-related illnesses are inexact due to lack of tests for the Southern Tick Associated Rash Illness and cross-reactivity in tests for spotted fever rickettsiosis.CONCLUSIONS This report demonstrates that tick-associated illnesses, including episodes fitting the Center for Disease Control and Prevention's definition of the Southern Tick Associated Rash Illness, may be more common than realized. Use of personal tick protection measures for tick bite illness and disease prevention may not be sufficiently protective. Further subject-based research on tick and disease burden on selected populations would be informative, and could aid in planning appropriate actions to mitigate the effects of tick-borne disease in North Carolina. PMID- 28576951 TI - Not Your Father's Pharmacist. PMID- 28576952 TI - The Role of the Pharmacist in Health Care: Expanding and Evolving. PMID- 28576949 TI - Trends and Correlates of Hookah Use Among High School Students in North Carolina. AB - OBJECTIVES Although youth cigarette smoking has declined in the United States, use of alternative tobacco products, such as hookah, has increased. This study assesses changes in prevalence of use from 2011 to 2013, and examines factors associated with current hookah use among North Carolina high school students in 2013.METHODS Data came from the North Carolina Youth Tobacco Survey in 2011 (n = 4,791) and 2013 (n = 4,092). STATA (StataCorp LLC) logistic regression survey procedures account for the complex survey design and sampling weights.RESULTS Prevalence of reported current hookah use significantly increased from 3.6% (95% CI: 2.8-4.5) in 2011 to 6.1% (95% CI: 4.9-7.5) in 2013 while reported lifetime hookah use increased from 9.8% (95% CI: 8.0-12.0) in 2011 to 12.6% (95% CI: 11.0 14.4) in 2013. Correlates of current hookah use included having a weekly disposable income over $50 (adjusted odds ratio (AOR) = 2.05, 95% CI: 1.25-3.35), currently smoking cigarettes (AOR = 4.57, 95% CI: 1.80-11.62), and living with hookah users (AOR = 6.45, 95% CI: 3.21-12.93). Participant self-reports of "liking" or positively commenting on tobacco products on social media were associated with current hookah use (AOR = 1.83, 95% CI: 1.84-4.52). Frequent exposure to online tobacco advertisements (AOR = 1.61, 95% CI: 1.13-2.28) were also associated with current hookah use.CONCLUSIONS Comprehensive product specific communication and policy interventions are needed to educate youth about the dangers of hookah use and reduce social acceptability among youth. To decrease hookah use in North Carolina, policymakers should consider restoring funding for comprehensive tobacco prevention and control programs, and equalizing tobacco tax rates for all tobacco product types. PMID- 28576953 TI - The Medication Optimization Value Proposition: Aligning Teams and Education to Improve Care. AB - United States health care lags behind other countries in quality and cost. The present health care system is unsustainable, and there is now a quick movement toward value-based care. This article lays out essential care delivery elements, and makes the case for medication optimization to enable new value-based models. Success factors include enhancing team-based care and interdisciplinary education to achieve patient-centered care. PMID- 28576954 TI - Payment Reform Meets Pharmacy Practice and Education Transformation. AB - The pharmacy profession has for the greater part of four decades been associated with dispensing activities and product reimbursement. This has hindered the ability of pharmacists to evolve their roles in their respective sites of care. Payment reform efforts that create an outcomes marketplace offer an opportunity for professional transformation. PMID- 28576955 TI - Health Care Systems and Transitions of Care: Implication on Interdisciplinary Pharmacy Services. AB - Effective medication management is critical to successful patient outcomes. Pharmacists and pharmacy technicians working within North Carolina Health Systems provide a variety of services that aid in those successful outcomes. By leveraging the North Carolina Clinical Pharmacist Practitioner designation along with integrated health records, health system pharmacists are uniquely positioned to provide expert clinical support to patients. Services such as medication history collection, discharge medication dispensing and counseling, post discharge clinic engagement, and drug therapy management are all components of an even larger number of strategic health system pharmacy assets that aid in the care of patients whether they are admitted to hospitals, seen in clinics, or cared for in the community. PMID- 28576956 TI - The Integral Role of the Clinical Pharmacist Practitioner in Primary Care. AB - Clinical pharmacist practitioners serve as integral team members in primary care clinics. They extend the care provided for patients with chronic illnesses, improve health and wellness, and positively impact quality metrics in patient centered medical homes and accountable care organizations. PMID- 28576957 TI - A Clinical Pharmacist in Telehealth Team Care for Rural Patients with Diabetes. PMID- 28576958 TI - The North Carolina Experiment: Active Research in the Development and Assessment of New Practice Models. AB - Improving the quality of health care requires innovative approaches to addressing the misuse, overuse, and underuse of medication in the United States. Strategies must be patient-centered, collaborative, and aligned with the move toward value based care. We highlight research in North Carolina aimed at achieving these goals. PMID- 28576959 TI - Achieving Better Quality and Lower Costs in Medicaid Through Enhanced Pharmacy Services. PMID- 28576960 TI - Compounding Pharmacists Provide Customized Care. AB - Compounding is the creation of a pharmaceutical preparation by a licensed pharmacist to meet the unique needs of an individual patient when commercially available drugs do not meet those needs. For hundreds of years, compounding was the traditional practice of pharmacy. Today's advanced practice of compounding provides health care practitioners customized options for unique patients or for hard to treat conditions. PMID- 28576961 TI - Disaster Relief: A Look Into the Pharmacist's Role. AB - After hurricane Matthew devastated southeastern North Carolina on October 8, 2016, health care providers and medical volunteers from various regions in North Carolina and from other surrounding states pulled together to initiate emergency medical services. Along with other healthcare providers, pharmacists played a key role in relief efforts. By using their broad knowledge of medicine and healthcare to efficiently utilize limited resources, pharmacists were vital in providing patient care. Their skills and knowledge make them a valuable resource in disaster relief. PMID- 28576963 TI - The Role of Pharmacists in the Opioid Epidemic: An Examination of Pharmacist Focused Initiatives Across the United States and North Carolina. AB - A pharmacy presence on national, state, and local levels is helping to address the opioid epidemic. This article will comment on and examine how pharmacists are working together with the health care team and community to address the opioid crisis. PMID- 28576962 TI - Innovative Community Pharmacy Practice Models in North Carolina. AB - There are several different types and sizes of community pharmacies ranging from large chains to small individually owned pharmacies. Community pharmacies are located in supermarkets, drugstores, big box stores, and even shopping malls in neighborhoods across North Carolina. Pharmacists are the most accessible health professionals and the ones that many patients see most frequently. Many pharmacists provide services long after other health care professionals' offices have closed. The traditional role of the pharmacist-the health care professional who dispenses prescriptions written by doctors-is changing. In recent years many pharmacists have developed services to help manage highly complex patient populations and improve health care outcomes. The profiles below highlight four innovative community pharmacies in North Carolina that show the potential community pharmacies have to improve quality, outcomes, and cost of care. PMID- 28576964 TI - The Role of Pharmacists as Immunizers in North Carolina. AB - Pharmacists are well-equipped to provide information to other health care providers on immunizations that may benefit patients, and can administer these immunizations in the pharmacy setting. Pharmacists have positively impacted vaccination rates, especially among patients who infrequently visit other health care providers or have reduced access to care. North Carolina has expanded the list of vaccinations pharmacists can provide, which helps to promote disease prevention and improve population health. PMID- 28576965 TI - Running the Numbers: Drug Expenditure Trends in North Carolina Medicaid. PMID- 28576966 TI - Spotlight on the Safety Net: Dispensing Hope: North Carolina's Only Statewide Free Pharmacy Program for the Uninsured. PMID- 28576967 TI - North Carolina Child Health Report Card 2017. PMID- 28576968 TI - Localisation of Nup153 and SENP1 to nuclear pore complexes is required for 53BP1 mediated DNA double-strand break repair. AB - The nuclear basket of nuclear pore complexes (NPCs) is composed of three nucleoporins: Nup153, Nup50 and Tpr. Nup153 has a role in DNA double-strand break (DSB) repair by promoting nuclear import of 53BP1 (also known as TP53BP1), a mediator of the DNA damage response. Here, we provide evidence that loss of Nup153 compromises 53BP1 sumoylation, a prerequisite for efficient accumulation of 53BP1 at DSBs. Depletion of Nup153 resulted in reduced SUMO1 modification of 53BP1 and the displacement of the SUMO protease SENP1 from NPCs. Artificial tethering of SENP1 to NPCs restored non-homologous end joining (NHEJ) in the absence of Nup153 and re-established 53BP1 sumoylation. Furthermore, Nup50 and Tpr, the two other nuclear basket nucleoporins, also contribute to proper DSB repair, in a manner distinct from Nup153. Similar to the role of Nup153, Tpr is implicated in NHEJ and homologous recombination (HR), whereas loss of Nup50 only affects NHEJ. Despite the requirement of all three nucleoporins for accurate NHEJ, only Nup153 is needed for proper nuclear import of 53BP1 and SENP1 dependent sumoylation of 53BP1. Our data support the role of Nup153 as an important regulator of 53BP1 activity and efficient NHEJ. PMID- 28576969 TI - Redox regulation of the yeast voltage-gated Ca2+ channel homolog Cch1p by glutathionylation of specific cysteine residues. AB - Cch1p, the yeast homolog of the pore-forming subunit alpha1 of the mammalian voltage-gated Ca2+ channel (VGCC), is located on the plasma membrane and mediates the redox-dependent influx of Ca2+ Cch1p is known to undergo both rapid activation (after oxidative stress and or a change to high pH) and slow activation (after ER stress and mating pheromone activation), but the mechanism of activation is not known. We demonstrate here that both the fast activation (exposure to pH 8-8.5 or treatment with H2O2) and the slow activation (treatment with tunicamycin or alpha-factor) are mediated through a common redox-dependent mechanism. Furthermore, through mutational analysis of all 18 exposed cysteine residues in the Cch1p protein, we show that the four mutants C587A, C606A, C636A and C642A, which are clustered together in a common cytoplasmic loop region, were functionally defective for both fast and slow activations, and also showed reduced glutathionylation. These four cysteine residues are also conserved across phyla, suggesting a conserved mechanism of activation. Investigations into the enzymes involved in the activation reveal that the yeast glutathione S transferase Gtt1p is involved in the glutathionylation of Cch1p, while the thioredoxin Trx2p plays a role in the Cch1p deglutathionylation. PMID- 28576971 TI - Substrate stiffness-dependent regulation of the SRF-Mkl1 co-activator complex requires the inner nuclear membrane protein Emerin. AB - The complex comprising serum response factor (SRF) and megakaryoblastic leukemia 1 protein (Mkl1) promotes myofibroblast differentiation during wound healing. SRF Mkl1 is sensitive to the mechanical properties of the extracellular environment; but how cells sense and transduce mechanical cues to modulate SRF-Mkl1-dependent gene expression is not well understood. Here, we demonstrate that the nuclear lamina-associated inner nuclear membrane protein Emerin stimulates SRF-Mkl1 dependent gene activity in a substrate stiffness-dependent manner. Specifically, Emerin was required for Mkl1 nuclear accumulation and maximal SRF-Mkl1-dependent gene expression in response to serum stimulation of cells grown on stiff substrates but was dispensable on more compliant substrates. Focal adhesion area was also reduced in cells lacking Emerin, consistent with a role for Emerin in sensing substrate stiffness. Expression of a constitutively active form of Mkl1 bypassed the requirement for Emerin in SRF-Mkl1-dependent gene expression and reversed the focal adhesion defects evident in EmdKO fibroblasts. Together, these data indicate that Emerin, a conserved nuclear lamina protein, couples extracellular matrix mechanics and SRF-Mkl1-dependent transcription. PMID- 28576970 TI - Low-intensity pulsed ultrasound promotes cell motility through vinculin controlled Rac1 GTPase activity. AB - Low-intensity pulsed ultrasound (LIPUS) is a therapy used clinically to promote healing. Using live-cell imaging we show that LIPUS stimulation, acting through integrin-mediated cell-matrix adhesions, rapidly induces Rac1 activation associated with dramatic actin cytoskeleton rearrangements. Our study demonstrates that the mechanosensitive focal adhesion (FA) protein vinculin, and both focal adhesion kinase (FAK, also known as PTK2) and Rab5 (both the Rab5a and Rab5b isoforms) have key roles in regulating these effects. Inhibiting the link of vinculin to the actin-cytoskeleton abolished LIPUS sensing. We show that this vinculin-mediated link was not only critical for Rac1 induction and actin rearrangements, but was also important for the induction of a Rab5-dependent increase in the number of early endosomes. Expression of dominant-negative Rab5, or inhibition of endocytosis with dynasore, also blocked LIPUS-induced Rac1 signalling events. Taken together, our data show that LIPUS is sensed by cell matrix adhesions through vinculin, which in turn modulates a Rab5-Rac1 pathway to control ultrasound-mediated endocytosis and cell motility. Finally, we demonstrate that a similar FAK-Rab5-Rac1 pathway acts to control cell spreading upon fibronectin. PMID- 28576972 TI - Secreted tissue inhibitor of matrix metalloproteinase restricts trans-synaptic signaling to coordinate synaptogenesis. AB - Synaptogenesis is coordinated by trans-synaptic signals that traverse the specialized synaptomatrix between presynaptic and postsynaptic cells. Matrix metalloproteinase (Mmp) activity sculpts this environment, balanced by secreted tissue inhibitors of Mmp (Timp). Here, we use the simplified Drosophila melanogaster matrix metalloproteome to test the consequences of eliminating all Timp regulatory control of Mmp activity at the neuromuscular junction (NMJ). Using in situ zymography, we find Timp limits Mmp activity at the NMJ terminal and shapes extracellular proteolytic dynamics surrounding individual synaptic boutons. In newly generated timp null mutants, NMJs exhibit architectural overelaboration with supernumerary synaptic boutons. With cell-targeted RNAi and rescue studies, we find that postsynaptic Timp limits presynaptic architecture. Functionally, timp null mutants exhibit compromised synaptic vesicle cycling, with activity that is lower in amplitude and fidelity. NMJ defects manifest in impaired locomotor function. Mechanistically, we find that Timp limits BMP trans synaptic signaling and the downstream synapse-to-nucleus signal transduction. Pharmacologically restoring Mmp inhibition in timp null mutants corrects bone morphogenetic protein (BMP) signaling and synaptic properties. Genetically restoring BMP signaling in timp null mutants corrects NMJ structure and motor function. Thus, Timp inhibition of Mmp proteolytic activity restricts BMP trans synaptic signaling to coordinate synaptogenesis. PMID- 28576973 TI - Caspase-9 has a nonapoptotic function in Xenopus embryonic primitive blood formation. AB - Caspases constitute a family of cysteine proteases centrally involved in programmed cell death, which is an integral part of normal embryonic and fetal development. However, it has become clear that specific caspases also have functions independent of cell death. In order to identify novel apoptotic and nonapoptotic developmental caspase functions, we designed and transgenically integrated novel fluorescent caspase reporter constructs in developing Xenopus embryos and tadpoles. This model organism has an external development, allowing direct and continuous monitoring. These studies uncovered a nonapoptotic role for the initiator caspase-9 in primitive blood formation. Functional experiments further corroborated that caspase-9, but possibly not the executioners caspase-3 and caspase-7, are required for primitive erythropoiesis in the early embryo. These data reveal a novel nonapoptotic function for the initiator caspase-9 and, for the first time, implicate nonapoptotic caspase activity in primitive blood formation. PMID- 28576974 TI - Lecithin:Cholesterol Acyltransferase Activation by Sulfhydryl-Reactive Small Molecules: Role of Cysteine-31. AB - Lecithin:cholesterol acyltransferase (LCAT) catalyzes plasma cholesteryl ester formation and is defective in familial lecithin:cholesterol acyltransferase deficiency (FLD), an autosomal recessive disorder characterized by low high density lipoprotein, anemia, and renal disease. This study aimed to investigate the mechanism by which compound A [3-(5-(ethylthio)-1,3,4-thiadiazol-2 ylthio)pyrazine-2-carbonitrile], a small heterocyclic amine, activates LCAT. The effect of compound A on LCAT was tested in human plasma and with recombinant LCAT. Mass spectrometry and nuclear magnetic resonance were used to determine compound A adduct formation with LCAT. Molecular modeling was performed to gain insight into the effects of compound A on LCAT structure and activity. Compound A increased LCAT activity in a subset (three of nine) of LCAT mutations to levels comparable to FLD heterozygotes. The site-directed mutation LCAT-Cys31Gly prevented activation by compound A. Substitution of Cys31 with charged residues (Glu, Arg, and Lys) decreased LCAT activity, whereas bulky hydrophobic groups (Trp, Leu, Phe, and Met) increased activity up to 3-fold (P < 0.005). Mass spectrometry of a tryptic digestion of LCAT incubated with compound A revealed a +103.017 m/z adduct on Cys31, consistent with the addition of a single hydrophobic cyanopyrazine ring. Molecular modeling identified potential interactions of compound A near Cys31 and structural changes correlating with enhanced activity. Functional groups important for LCAT activation by compound A were identified by testing compound A derivatives. Finally, sulfhydryl-reactive beta-lactams were developed as a new class of LCAT activators. In conclusion, compound A activates LCAT, including some FLD mutations, by forming a hydrophobic adduct with Cys31, thus providing a mechanistic rationale for the design of future LCAT activators. PMID- 28576975 TI - Route of Administration Affects Corticosteroid Sensitivity of a Combined Ovalbumin and Lipopolysaccharide Model of Asthma Exacerbation in Guinea Pigs. AB - Lipopolysaccharide (LPS) contributes to asthma exacerbations and development of inhaled corticosteroid insensitivity. Complete resistance to systemic corticosteroids is rare, and most patients lie on a continuum of steroid responsiveness. This study aimed to examine the sensitivity of combined ovalbumin (Ova) and LPS-induced functional and inflammatory responses to inhaled and systemic corticosteroid in conscious guinea pigs to test the hypothesis that the route of administration affects sensitivity. Guinea pigs were sensitized to Ova and challenged with inhaled Ova alone or combined with LPS. Airway function was determined by measuring specific airway conductance via whole-body plethysmography. Airway hyper-responsiveness to histamine was determined before and 24 hours post-Ova challenge. Airway inflammation and underlying mechanisms were determined from bronchoalveolar lavage cell counts and lung tissue cytokines. Vehicle or dexamethasone was administered by once-daily i.p. injection (5, 10, or 20 mg/kg) or twice-daily inhalation (4 or 20 mg/ml) for 6 days before Ova challenge or Ova with LPS. LPS exacerbated Ova-induced responses, elongating early asthmatic responses (EAR), prolonging histamine bronchoconstriction, and further elevating airway inflammation. Intraperitoneal dexamethasone (20 mg/kg) significantly reduced the elongated EAR and airway inflammation but not the increased bronchoconstriction to histamine. In contrast, inhaled dexamethasone (20 mg/ml), which inhibited responses to Ova alone, did not significantly reduce functional and inflammatory responses to combined Ova and LPS. Combined Ova and LPS-induced functional and inflammatory responses are insensitive to inhaled, but they are only partially sensitive to systemic, dexamethasone. This finding suggests that the route of corticosteroid administration may be important in determining corticosteroid sensitivity of asthmatic responses. PMID- 28576976 TI - Pleiotropic and Adverse Effects of Statins-Do Epigenetics Play a Role? AB - Statins are widely used to prevent major cardiovascular events by lowering serum cholesterol. There is evidence that statins have pleiotropic effects-that is, cholesterol-independent effects-that may also confer protection from cardiovascular disease and potentially numerous other pathologies, including cancer. Statins also have a number of well described adverse effects, including myopathy, rhabdomyolysis, liver damage, and type 2 diabetes. This paper examines the evidence of epigenetic modifications as a contributory factor to the pleiotropic and adverse effects of statins. In vitro and animal studies have shown that statins can inhibit histone deacetylase activity and increase histone acetylation. Similarly, there is evidence that statins may inhibit both histone and DNA methyltransferases and subsequently demethylate histone residues and DNA, respectively. These changes have been shown to alter expression of various genes, including tumor suppressor genes and genes thought to have anti-atherosclerotic actions. Statins have also been shown to influence the expression of numerous microRNAs that suppress the translation of proteins involved in tumorigenesis and vascular function. Whether the adverse effects of statins may also have an epigenetic component has been less widely studied, although there is evidence that microRNA expression may be altered in statin-induced muscle and liver damage. As epigenetics and microRNAs influence gene expression, these changes could contribute to the pleiotropic and adverse effects of statins and have long lasting effects on the health of statin users. PMID- 28576977 TI - Monoclonal Invariant NKT (iNKT) Cell Mice Reveal a Role for Both Tissue of Origin and the TCR in Development of iNKT Functional Subsets. AB - Invariant NKT (iNKT) cell functional subsets are defined by key transcription factors and output of cytokines, such as IL-4, IFN-gamma, IL-17, and IL-10. To examine how TCR specificity determines iNKT function, we used somatic cell nuclear transfer to generate three lines of mice cloned from iNKT nuclei. Each line uses the invariant Valpha14Jalpha18 TCRalpha paired with unique Vbeta7 or Vbeta8.2 subunits. We examined tissue homing, expression of PLZF, T-bet, and RORgammat, and cytokine profiles and found that, although monoclonal iNKT cells differentiated into all functional subsets, the NKT17 lineage was reduced or expanded depending on the TCR expressed. We examined iNKT thymic development in limited-dilution bone marrow chimeras and show that higher TCR avidity correlates with higher PLZF and reduced T-bet expression. iNKT functional subsets showed distinct tissue distribution patterns. Although each individual monoclonal TCR showed an inherent subset distribution preference that was evident across all tissues examined, the iNKT cytokine profile differed more by tissue of origin than by TCR specificity. PMID- 28576978 TI - Hox5 Paralogous Genes Modulate Th2 Cell Function during Chronic Allergic Inflammation via Regulation of Gata3. AB - Allergic asthma is a significant health burden in western countries, and continues to increase in prevalence. Th2 cells contribute to the development of disease through release of the cytokines IL-4, IL-5, and IL-13, resulting in increased airway eosinophils and mucus hypersecretion. The molecular mechanisms behind the disease pathology remain largely unknown. In this study we investigated a potential regulatory role for the Hox5 gene family, Hoxa5, Hoxb5, and Hoxc5, genes known to be important in lung development within mesenchymal cell populations. We found that Hox5-mutant mice show exacerbated pathology compared with wild-type controls in a chronic allergen model, with an increased Th2 response and exacerbated lung tissue pathology. Bone marrow chimera experiments indicated that the observed enhanced pathology was mediated by immune cell function independent of mesenchymal cell Hox5 family function. Examination of T cells grown in Th2 polarizing conditions showed increased proliferation, enhanced Gata3 expression, and elevated production of IL-4, IL-5, and IL-13 in Hox5-deficient T cells compared with wild-type controls. Overexpression of FLAG tagged HOX5 proteins in Jurkat cells demonstrated HOX5 binding to the Gata3 locus and decreased Gata3 and IL-4 expression, supporting a role for HOX5 proteins in direct transcriptional control of Th2 development. These results reveal a novel role for Hox5 genes as developmental regulators of Th2 immune cell function that demonstrates a redeployment of mesenchyme-associated developmental genes. PMID- 28576980 TI - TLR9 Regulates the NF-kappaB-NLRP3-IL-1beta Pathway Negatively in Salmonella Induced NKG2D-Mediated Intestinal Inflammation. AB - TLRs are key sensors for conserved bacterial molecules and play a critical role in host defense against invading pathogens. Although the roles of TLRs in defense against pathogen infection and in maintaining gut immune homeostasis have been studied, the precise functions of different TLRs in response to pathogen infection in the gut remain elusive. The present study investigated the role of TLR signaling in defense against the Gram-negative bacterial pathogen Salmonella typhimurium The results indicated that TLR9-deficient mice were more susceptible to S. typhimurium infection compared with wild-type and TLR2- or TLR4-deficient mice, as indicated by more severe intestinal damage and the highest bacterial load. TLR9 deficiency in intestinal epithelial cells (IECs) augmented the activation of NF-kappaB and NLRP3 inflammasomes significantly, resulting in increased secretion of IL-1beta. IL-1beta increased the expression of NKG2D on intestinal intraepithelial lymphocytes and NKG2D ligands on IECs, resulting in higher susceptibility of IECs to cytotoxicity of intestinal intraepithelial lymphocytes and damage to the epithelial barrier. We proposed that TLR9 regulates the NF-kappaB-NLRP3-IL-1beta pathway negatively in Salmonella-induced NKG2D mediated intestinal inflammation and plays a critical role in defense against S. typhimurium infection and in the protection of intestinal integrity. PMID- 28576984 TI - Pets at risk as vaccinations decline. PMID- 28576985 TI - Who will get your vote next week? AB - How do the political parties compare on Brexit and animal welfare issues? PMID- 28576979 TI - Controlled Human Malaria Infection Leads to Long-Lasting Changes in Innate and Innate-like Lymphocyte Populations. AB - Animal model studies highlight the role of innate-like lymphocyte populations in the early inflammatory response and subsequent parasite control following Plasmodium infection. IFN-gamma production by these lymphocytes likely plays a key role in the early control of the parasite and disease severity. Analyzing human innate-like T cell and NK cell responses following infection with Plasmodium has been challenging because the early stages of infection are clinically silent. To overcome this limitation, we examined blood samples from a controlled human malaria infection (CHMI) study in a Tanzanian cohort, in which volunteers underwent CHMI with a low or high dose of Plasmodium falciparum sporozoites. The CHMI differentially affected NK, NKT (invariant NKT), and mucosal-associated invariant T cell populations in a dose-dependent manner, resulting in an altered composition of this innate-like lymphocyte compartment. Although these innate-like responses are typically thought of as short-lived, we found that changes persisted for months after the infection was cleared, leading to significantly increased frequencies of mucosal-associated invariant T cells 6 mo postinfection. We used single-cell RNA sequencing and TCR alphabeta-chain usage analysis to define potential mechanisms for this expansion. These single cell data suggest that this increase was mediated by homeostatic expansion-like mechanisms. Together, these data demonstrate that CHMI leads to previously unappreciated long-lasting alterations in the human innate-like lymphocyte compartment. We discuss the consequences of these changes for recurrent parasite infection and infection-associated pathologies and highlight the importance of considering host immunity and infection history for vaccine design. PMID- 28576989 TI - Targeted control measures to reduce bovine TB 'are working' in Wales. PMID- 28576993 TI - Owners of brachycephalic dogs pay more attention to looks than health. PMID- 28576995 TI - Disease surveillance in England and Wales, May 2017. AB - Current and emerging issues: potentially toxic blue-green algal blooms Highlights from the scanning surveillance network Update on international disease threats Focus on topical issues and recent cases relating to wildlifeThese are among matters discussed in the Animal and Plant Health Agency's (APHA's) disease surveillance report for May 2017. PMID- 28576981 TI - STAT1 Represses Cytokine-Producing Group 2 and Group 3 Innate Lymphoid Cells during Viral Infection. AB - The appropriate orchestration of different arms of the immune response is critical during viral infection to promote efficient viral clearance while limiting immunopathology. However, the signals and mechanisms that guide this coordination are not fully understood. IFNs are produced at high levels during viral infection and have convergent signaling through STAT1. We hypothesized that STAT1 signaling during viral infection regulates the balance of innate lymphoid cells (ILC), a diverse class of lymphocytes that are poised to respond to environmental insults including viral infections with the potential for both antiviral or immunopathologic functions. During infection with respiratory syncytial virus (RSV), STAT1-deficient mice had reduced numbers of antiviral IFN gamma+ ILC1 and increased numbers of immunopathologic IL-5+ and IL-13+ ILC2 and IL-17A+ ILC3 compared with RSV-infected wild-type mice. Using bone marrow chimeric mice, we found that both ILC-intrinsic and ILC-extrinsic factors were responsible for this ILC dysregulation during viral infection in STAT1-deficient mice. Regarding ILC-extrinsic mechanisms, we found that STAT1-deficient mice had significantly increased expression of IL-33 and IL-23, cytokines that promote ILC2 and ILC3, respectively, compared with wild-type mice during RSV infection. Moreover, disruption of IL-33 or IL-23 signaling attenuated cytokine-producing ILC2 and ILC3 responses in STAT1-deficient mice during RSV infection. Collectively, these data demonstrate that STAT1 is a key orchestrator of cytokine producing ILC responses during viral infection via ILC-extrinsic regulation of IL 33 and IL-23. PMID- 28576996 TI - Wildlife: topical issues, recent cases. AB - This focus article was prepared by Paul Duff, Paul Holmes and Alex Barlow of the APHA Wildlife Expert Group. PMID- 28576997 TI - What is causing acute haemorrhagic diarrhoea syndrome in dogs? PMID- 28576999 TI - Can zoo licensing be improved? PMID- 28577000 TI - Hunting with hounds. PMID- 28577001 TI - Transfusion medicine across the species. PMID- 28577002 TI - Transfusion medicine across the species. PMID- 28577004 TI - No action likely on slaughter without stunning. PMID- 28577003 TI - Holly leaf ingestion causing pharyngeal obstruction in lambs. PMID- 28577005 TI - Duncan McMartin. AB - A veterinarian whose contributions to avian health and food safety were recognised nationally and internationally. He enthusiastically and readily shared his knowledge about poultry care and health. PMID- 28577006 TI - General Election 2017: influencing the party manifestos. AB - Amy Waddell, BVA head of media and public affairs, says that following the announcement of a snap General Election, BVA has produced a manifesto for 2017, highlighting 20 key recommendations for the next Government to consider in terms of domestic policy setting as well as throughout Brexit discussions. PMID- 28577007 TI - Helping clients understand pets' needs. AB - During National Pet Month in April the Veterinary Animal Welfare Coalition launched its second public-facing campaign to improve pet owners' understanding of their animals' welfare, writes Felicity Quick, BVA media officer. PMID- 28577009 TI - Championing the profession in Scotland. AB - Hayley Atkin, BVA Policy Officer, gives a roundup of highlights from BVA Scottish Branch. PMID- 28577008 TI - Great value BVA In Practice CPD for 2017. AB - BVA has 16 CPD courses coming up for the second half of the year. They are aimed at vets working in general and mixed practice. Zoe Davies, marketing manager, outlines some of the highlights. PMID- 28577010 TI - Hop to it to help rabbits. AB - Rabbit Awareness Week promotes the welfare needs of rabbits; it takes place from June 17 to 25. PMID- 28577011 TI - Outback is put through its paces. AB - Ashley Rubens, winner of the competition to find the BVA member facing the toughest driving conditions in the UK, has spent the past few months putting a Subaru Outback through its paces. PMID- 28577013 TI - How I found my career. AB - Kenny Hall was unaware of the veterinary nursing profession until his vet student girlfriend suggested it would be the perfect career for him. As a male nurse he got used to being a 'rarity' and now encourages other men to consider veterinary nursing as a great career choice. PMID- 28577012 TI - Help build a network that's right for you. AB - Becky Richardson, Young Vet Network representative on BVA Council, explains how young vets can get involved. PMID- 28577014 TI - My week: Greta Manfrin. AB - Greta Manfrin joined Vets Now through its Cutting Edge programme. Here, she describes a recent working week as the principal vet at an out-of-hours pet emergency clinic in Gillingham, Kent. PMID- 28577015 TI - PROSPECTIVE OBSERVATIONAL COHORT STUDY OF PREDICTORS OF THE EFFECTIVENESS OF PEGYLATED INTERFERON IN PATIENTS WITH HEPATITIS C IN GEORGIA. AB - The main objective of the study was to evaluate the predictive values of virological response at 4th and 12th weeks after treatment initiation on sustained virological response by HCV genotype in patients with hepatitis C in Georgia. Local, non-interventional, prospective, cohort study was conducted in 2011-2016. A cohort of adult peginterferon treatment naive patients with chronic hepatitis C were observed during the complete active treatment period with PEGASYS(r)/COPEGUS(r) and 24 weeks after the end of treatment. HCV RNA titers were assessed prior to treatment, after 4, 12 weeks of treatment, at the end of treatment and 24 weeks after the end of treatment.530 men and women aged >=18 years with serologically proven CHC (all genotypes) were enrolled in this study. Enrolles study subjects were treated with PEGASYS(r) 180mkg (peginterferon alfa 2a) in combination with COPEGUS(r) 200mg (ribavirin) according to the current standard of care and in line with current summary of product characteristics. All clinical information for this cohort study was collected from the patient's medical records. All laboratory parameters which were collected for this observational study according to the protocol were performed in study centers. All data were analyzed with descriptive and analytical statistics. Our analysis demonstrated that the early achievement of viral response predicts the higher probability of achieving sustainvirul response. The viral response itself was strongly associated with baseline liver fibrosis quantitive HCV RNA level. Early starting of treatment determines the probability of achievement higher osustain viral response. PMID- 28577016 TI - CLINICAL AND EPIDEMIOLOGICAL CHARACTERIZATION OF INFLUENZA A/H1N1PDM AND B AMONG HOSPITALIZED CHILDREN, GEORGIA, SEASON 2010-2011. AB - The aim of the study was to describe, analyze and compare clinical and epidemiological characteristics of laboratory confirmed influenza A(H1N1)pdm and B cases in hospitalized children during post pandemic season. Between 1st January and 1st May, 2011 retrospective observational study was conducted in M. Iashvili Children's Central Hospital. From 1028 patients with influenza like illness hospitalized at Children's Hospital 871 specimens were collected and 360 tested positive for influenza: A(H1N1)pdm - 139 and B - 221. Data were obtained for 290 cases: A(H1N1)pdm - 122 and B - 168. At the time of hospital admission, influenza A(H1N1)pdm and B cases had similar median age of 2 years. The median length of hospital stay was 5 days for both influenza types. Predominant clinical symptoms were fever (98.3%), cough (82.4%) and running nose (68.6%). 39.7% (115/290) of patients suffered with lower respiratory tract infection: A(H1N1)pdm - 41% (50/122) and B - 38.7% (65/168). 19% (55/290) developed pneumonia of which 12 with primary diagnosis of acute respiratory failure were admitted to ICU: A(H1N1)pdm - 4.9% (6/122) and B - 3.6% (6/168). Median length in ICU stay was 6 days. Only two patients with A(H1N1)pdm required artificial ventilation with one fatal outcome. Almost equally (31%) patients with influenza A or B viruses suffered with at least one pre-existing condition. Statistically significant association was revealed between neurological pre-existing conditions and developing pneumonia (OR=5.6; p=0.00) and ICU requirement (OR=17.5, p=0.00). Congenital malformations were also associated with sever course of disease (OR=9.1; p=0.01). Treatment with antiviral oseltamivir was prescribed to 29.5% (36/122) A(H1N1)pdm and 8.3% (14/168) B cases among whom only 24% cases received antiviral within 48 hours after symptoms onset. None of the patients was vaccinated against influenza. Our study revealed no significant difference between influenza A(H1N1)pdm and influenza B in terms of age distribution, clinical manifestation, hospital stay or complications in hospitalized children during post pandemic season. Pre-existing conditions such as neurological disorders and congenital malformations represented risk factors for severe course of influenza, therefore timely antiviral treatment and annual influenza vaccination is recommended to avoid complications. PMID- 28577017 TI - Effect of CYP2C19 Gene Polymorphisms on Proton Pump Inhibitor, Amoxicillin, and Levofloxacin Triple Therapy for Eradication of Helicobacter Pylori. AB - BACKGROUND The effects of PPI are variable owing to the CYP2C19 polymorphisms. However, whether the polymorphisms could affect the Hp eradication efficacy of triple therapy is still not clear. The present study aimed to assess the effects of CYP2C19 gene polymorphisms on proton pump inhibitor (PPI), amoxicillin, and levofloxacin triple therapy for Helicobacter pylori (Hp) eradication. MATERIAL AND METHODS We randomly assigned 160 Hp-positive patients with chronic gastritis to 2 groups to receive either 20 mg bid omeprazole (OAL group, n=80) or 10 mg bid rabeprazole (RAL group, n=80), combined with 1000 mg bid amoxicillin and 500 mg qd levofloxacin. The 2 groups were treated for 10 days. The CYP2C19 genotypes included wild-type, M1 mutant gene (*2, the mutation of exon 5), and M2 mutant gene (*3, the mutation of exon 4) identified by polymerase chain reaction restriction fragment length polymorphism (PCR-RFIP). According to CYP2C19 genotype combinations, the patients were divided into extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) subgroups. The eradication efficacy of Hp was evaluated by 14C-UBT at 28 days after treatment. RESULTS The trial was completed by 155 patients. Hp eradication rates in OAL and RAL groups were 78.2% and 88.3%, respectively, on per-protocol (PP) analysis, indicating no significant difference (P>0.05). Regarding CYP2C19 genotypes, eradication rates of 60.7%, 84.2%, and 100% were obtained for EM, IM, and PM subgroups, respectively, of the OAL group. EM group eradication rates were significantly lower than IM and PM group values (P<0.05). In the RAL group, no such difference was observed (P>0.05). Hp eradication rates were significantly lower in the EM subgroup of the OAL group compared with that of the RAL group. CONCLUSIONS Hp eradication rates were higher in the RAL group than in OAL-treated patients. Interestingly, omeprazole-based therapy was significantly affected by the CYP2C19 genotype, unlike the rabeprazole-based therapy. PMID- 28577018 TI - A Case of Kidney Involvement in Primary Sjogren's Syndrome. AB - BACKGROUND Sjogren's syndrome is an autoimmune disorder caused by the infiltration of monocytes in epithelial glandular and extra-glandular tissues. Hallmark presentations include mouth and eye dryness. Although renal involvement is uncommon in primary Sjogren's syndrome (pSS), patients may experience renal tubular acidosis type I (RTA I), tubulointerstitial nephritis, diabetes insipidus (DI), nephrolithiasis, and Fanconi syndrome. However, it is atypical to see more than 1 of these manifestations in a single patient. CASE REPORT We present the case of a 24-year-old woman with polyuria and polydipsia, who was initially diagnosed with nephrogenic diabetes insipidus. She also had chronic hypokalemia and nephrolithiasis. Based on clinical presentation and work up, she was diagnosed with pSS and treated accordingly. CONCLUSIONS This was a pSS patient with tubulointerstitial nephritis, diabetes insipidus, renal tubular acidosis, hypokalemia, and nephrolithiasis, who was receiving symptomatic treatment for diabetes insipidus. Diagnosis and treatment of pSS led to significant improvement in systemic and renal presentations of the patient. pSS should be considered as one of the differential diagnoses in patients with diabetes insipidus and renal tubular acidosis. PMID- 28577019 TI - RNA-sequencing Identifies Novel Pathways in Sarcoidosis Monocytes. AB - Sarcoidosis is a complex systemic granulomatous disorder of unknown etiology. Genome-wide association studies have not been able to explain a causative role for nucleotide variation in its pathogenesis. The goal of the present study was to identify the gene expression profile and the cellular pathways altered in sarcoidosis monocytes via RNA-sequencing. Peripheral blood monocytes play a role in sarcoidosis inflammation. Therefore, we determined and compared the transcriptional signature of monocytes from peripheral blood from sarcoidosis patients and healthy controls via RNA-sequencing. We found 2,446 differentially expressed (DE) genes between sarcoidosis and healthy control monocytes. Analysis of these DE genes showed enrichment for ribosome, phagocytosis, lysosome, proteasome, oxidative phosphorylation and metabolic pathways. RNA-sequencing identified upregulation of genes involved in phagocytosis and lysosomal pathway in sarcoidosis monocytes, whereas genes involved in proteasome degradation and ribosomal pathways were downregulated. Further studies are needed to investigate the role of specific genes involved in the identified pathways and their possible interaction leading to sarcoidosis pathology. PMID- 28577020 TI - Assessment of the diagnostic value of different biomarkers in relation to various stages of diabetic nephropathy in type 2 diabetic patients. AB - Albuminuria is widely used to indicate early phases of diabetic nephropathy although it is limited by the fact that structural damage might precede albumin excretion. This necessitates identifying better biomarkers that diagnose or predict diabetic nephropathy. This is a cross-sectional hospital based study recruiting type 2 diabetic patients cohort aged 35-75 years with diabetes duration of >=10 years. Out of total eligible 467 patients, 200 patients were with normal albumin excretion, 184 patients with microalbuminuria and 83 patients with macroalbuminuria. All the patients were tested for the 22 selected biomarkers including serum, plasma and urinary markers. Sensitivity, specificity, and area under the curve (AUC) were calculated as measures of diagnostic accuracy. Out of the tested biomarkers, urinary transferrin, urinary Retinol binding protein (RBP) and serum osteopontin had the best diagnostic value for diabetic nephropathy presence based on the AUC value. The rest of the biomarkers had comparatively less or even no discriminative power. The urinary transferrin and RBP and serum osteopontin, had the best diagnostic value in type 2 diabetic patients at different stages of diabetic nephropathy. Further longitudinal prospective studies are needed to evaluate the predictive power of those markers for detecting diabetic nephropathy before any structural damage occurs. PMID- 28577022 TI - Liquid-liquid extraction intensification by micro-droplet rotation in a hydrocyclone. AB - The previous literature reports that using a hydrocyclone as an extractor intensifies the mass transfer and largely reduces the consumption of extractant from 1800-2000 kg h-1 to 30-90 kg h-1. However, the intensification mechanism has not been clear. This paper presents experimental and numerical methods to study the multi-scale motion of particles in hydrocyclones. In addition to the usually considered translational behavior, the high-speed rotation of dispersed micro spheres caused by the anisotropic swirling shear flow is determined. The rotation speeds of the tested micro-spheres are above 1000 rad s-1, which are much larger than the instantaneous rotation speed in isotropic turbulence. Due to the conical structure of a hydrocyclone, the rotation speed maintains stability along the axial direction. Numerical results show that the particle Reynolds number of micro-droplets in a hydrocyclone is equal to that in conventional extractors, but the particles have high rotation speeds of up to 10,000 rad s-1 and long mixing lengths of more than 1000 mm. Both the rotation of micro-droplets along the spiral trajectories and the intense eddy diffusion in a hydrocyclone contribute to the extraction intensification. PMID- 28577021 TI - Segmental Duplication of Chromosome 11 and its Implications for Cell Division and Genome-wide Expression in Rice. AB - Segmental duplication is a major structural variation that occurs in chromosomes. Duplication leads to the production of gene copies with increased numbers of related repeat segments, causing the global genome to be in a state of imbalance. In addition, if the added segment contains a centromeric specific DNA, the duplicated chromosome will have structural multiple centromeres. We identified a segmental duplication containing structurally tricentric regions derived from the short arm of chromosome 11 (11L? + 11L? + 11S?11S?11S?11S, "?" represents the centromeric DNA repeat loci), and analyzed its implications for cell division and genome-wide expression. In the variant, only the middle centromere of 11S?11S?11S?11S is functionally active. As a result, the structurally tricentric chromosome was stable in mitosis, because it is actually a functional monocentric chromosome. However, the structurally tricentric chromosome, which usually formed a bivalent, was either arranged on the equatorial plane or was lagging, which affected its separation during meiosis. Furthermore, RNA-seq and RT-qPCR analysis showed that the segmental duplication affected genome-wide expression patterns. 34.60% of genes in repeat region showed positive dosage effect. Thus, the genes on chromosome arm 11S-2 didn't exhibit obviously dosage compensation, as illustrated by no peak around a ratio of 1.00. However, the gene dosage effect will reduce after sexual reproduction of a generation. PMID- 28577023 TI - Palaeoclimatic conditions in the Mediterranean explain genetic diversity of Posidonia oceanica seagrass meadows. AB - Past environmental conditions in the Mediterranean Sea have been proposed as main drivers of the current patterns of distribution of genetic structure of the seagrass Posidonia oceanica, the foundation species of one of the most important ecosystems in the Mediterranean Sea. Yet, the location of cold climate refugia (persistence regions) for this species during the Last Glacial Maximum (LGM) is not clear, precluding the understanding of its biogeographical history. We used Ecological Niche Modelling together with existing phylogeographic data to locate Pleistocene refugia in the Mediterranean Sea and to develop a hypothetical past biogeographical distribution able to explain the genetic diversity presently found in P. oceanica meadows. To do that, we used an ensemble approach of six predictive algorithms and two Ocean General Circulation Models. The minimum SST in winter and the maximum SST in summer allowed us to hindcast the species range during the LGM. We found separate glacial refugia in each Mediterranean basin and in the Central region. Altogether, the results suggest that the Central region of the Mediterranean Sea was the most relevant cold climate refugium, supporting the hypothesis that long-term persistence there allowed the region to develop and retain its presently high proportion of the global genetic diversity of P. oceanica. PMID- 28577024 TI - Voluntary movement reverses the effect of cathodal transcranial direct current stimulation (tDCS) on corticomotor excitability. AB - Motor cortex activity level is a critical part of the effect of transcranial direct current stimulation (tDCS) on corticomotor excitability. Based on homeostatic plasticity, the state of the stimulated cortical area influences the direction of neuroplastic changes induced by stimuli. Owing to homeostatic plasticity, cathodal tDCS (c-tDCS) would likely have a pronounced inhibitory effect on corticomotor excitability during a motor task, compared with the resting state. To test this hypothesis, we detected motor evoked potential (MEP) amplitude changes before and during c-tDCS with voluntary movement. Twelve healthy right-handed volunteers (9 males, 27-48 years) were enrolled in the study. Subjects performed little finger abduction motor task. Passive (APB) and active (ADM) muscles were studied. MEP amplitudes were measured during resting (baseline) and movement stages, and subsequently with the contralateral M1 modulated by c-tDCS. c-tDCS caused reduced baseline MEP amplitude in the ADM (p < 0.05) and APB (p < 0.001) muscles. Sham stimulation had no effect on the baseline MEP amplitudes. MEP amplitude ratio (MEP amplitude triggered by movement/baseline MEP amplitude) was higher during c-tDCS than before c-tDCS (p < 0.01). Our results suggested that during voluntary contraction, c-tDCS has an opposite effect on corticospinal excitability compared with resting state modulation effect. This contrast effect could be related to modulation of movement preparation and execution. PMID- 28577025 TI - SUV driving "masculinizes" risk behavior in females: a public health challenge. AB - Involvement of sport utility vehicles (SUV) in accidents especially with children is of increasing importance. Studies have indicated a more risky behavior in SUV drivers. We conducted an observational study focusing on traffic violations, car type, and the gender of the driver in Vienna. The study was conducted on five weekdays at the beginning of school term. Three busy intersections were selected.Drivers of 43,168 normal cars and 5653 SUVs were counted at the intersections during the observation period. In total 13.8% drivers were unbelted, 3.1% were using a handheld mobile phone, and 2.5% violated traffic lights. These frequencies were significantly higher in SUV drivers than in normal passenger car drivers. This "SUV effect" also occurred in women for all violations, although male drivers violated traffic laws more often than female drivers. However, for driving unbelted the difference between males and females was smaller in SUV drivers. PMID- 28577026 TI - Low temperature, autotrophic microbial denitrification using thiosulfate or thiocyanate as electron donor. AB - Wastewaters generated during mining and processing of metal sulfide ores are often acidic (pH < 3) and can contain significant concentrations of nitrate, nitrite, and ammonium from nitrogen based explosives. In addition, wastewaters from sulfide ore treatment plants and tailings ponds typically contain large amounts of inorganic sulfur compounds, such as thiosulfate and tetrathionate. Release of these wastewaters can lead to environmental acidification as well as an increase in nutrients (eutrophication) and compounds that are potentially toxic to humans and animals. Waters from cyanidation plants for gold extraction will often conjointly include toxic, sulfur containing thiocyanate. More stringent regulatory limits on the release of mining wastes containing compounds such as inorganic sulfur compounds, nitrate, and thiocyanate, along the need to increase production from sulfide mineral mining calls for low cost techniques to remove these pollutants under ambient temperatures (approximately 8 degrees C). In this study, we used both aerobic and anaerobic continuous cultures to successfully couple inorganic sulfur compound (i.e. thiosulfate and thiocyanate) oxidation for the removal of nitrogenous compounds under neutral to acidic pH at the low temperatures typical for boreal climates. Furthermore, the development of the respective microbial communities was identified over time by DNA sequencing, and found to contain a consortium including populations aligning within Flavobacterium, Thiobacillus, and Comamonadaceae lineages. This is the first study to remediate mining waste waters by coupling autotrophic thiocyanate oxidation to nitrate reduction at low temperatures and acidic pH by means of an identified microbial community. PMID- 28577027 TI - Heavy metal accumulation by Saccharomyces cerevisiae cells armed with metal binding hexapeptides targeted to the inner face of the plasma membrane. AB - Accumulation of heavy metals without developing toxicity symptoms is a phenotype restricted to a small group of plants called hyperaccumulators, whose metal related characteristics suggested the high potential in biotechnologies such as bioremediation and bioextraction. In an attempt to extrapolate the heavy metal hyperaccumulating phenotype to yeast, we obtained Saccharomyces cerevisiae cells armed with non-natural metal-binding hexapeptides targeted to the inner face of the plasma membrane, expected to sequester the metal ions once they penetrated the cell. We describe the construction of S. cerevisiae strains overexpressing metal-binding hexapeptides (MeBHxP) fused to the carboxy-terminus of a myristoylated green fluorescent protein (myrGFP). Three non-toxic myrGFP-MeBHxP (myrGFP-H6, myrGFP-C6, and myrGFP-(DE)3) were investigated against an array of heavy metals in terms of their effect on S. cerevisiae growth, heavy metal (hyper) accumulation, and capacity to remove heavy metal from contaminated environments. PMID- 28577029 TI - [Osteoarthritis of the upper ankle joint]. AB - The majority of cases of upper ankle joint (UAJ) osteoarthritis are due to secondary causes. Clinically, osteoarthritis is usually characterized by an increasing limitation in dorsal extension of the UAJ with often relatively mild symptoms. In the course of time the full scale of the typical symptoms and the progressive restriction of the global function of the joint develop. Conservative therapy is often able to provide long-term improvement of the symptoms for the majority of patients by means of intermittent analgesics and orthoses as well as shoe modifications. Operative treatment strategies for initial stages are based on joint-sparing methods. The most frequently used therapy for progressive destruction of the UAJ is still arthrodesis. Total ankle replacement is becoming an increasingly more competitive procedure. Total ankle replacement provides a valuable extension of therapeutic possibilities for UAJ osteoarthritis. PMID- 28577028 TI - Ketones 2-heptanone, 2-nonanone, and 2-undecanone inhibit DnaK-dependent refolding of heat-inactivated bacterial luciferases in Escherichia coli cells lacking small chaperon IbpB. AB - Many bacteria, fungi, and plants produce volatile organic compounds (VOCs) emitted to the environment. Bacterial VOCs play an important role in interactions between microorganisms and in bacterial-plant interactions. Here, we show that such VOCs as ketones 2-heptanone, 2-nonanone, and 2-undecanone inhibit the DnaKJE ClpB bichaperone dependent refolding of heat-inactivated bacterial luciferases. The inhibitory activity of ketones had highest effect in Escherichia coli ibpB::kan cells lacking small chaperone IbpB. Effect of ketones activity increased in the series: 2-pentanone, 2-undecanone, 2-heptanone, and 2-nonanone. These observations can be explained by the interaction of ketones with hydrophobic segments of heat-inactivated substrates and the competition with the chaperones IbpAB. If the small chaperone IbpB is absent in E. coli cells, the ketones block the hydrophobic segments of the polypeptides and inhibit the action of the bichaperone system. These results are consistent with the data on inhibitory effects of VOCs on survival of bacteria. It can be suggested that the inhibitory activity of the ketones indicated is associated with different ability of these substances to interact with hydrophobic segments in proteins. PMID- 28577030 TI - Stereotactic radiosurgery for small brain metastases and implications regarding management with systemic therapy alone. AB - While stereotactic radiosurgery (SRS) has been shown effective in the management of brain metastases, small brain metastases (<=10 mm) can pose unique challenges. Our aim was to investigate the efficacy of SRS in the treatment of small brain metastases, as well as elucidate clinically relevant factors impacting local failure (LF). We utilized a large, single-institution cohort to perform a retrospective analysis of patients with brain metastases up to 1 cm in maximal dimension. Clinical and radiosurgical parameters were investigated for an association with LF and compared using a competing risk model to calculate cumulative incidence functions, with death and whole brain radiotherapy serving as competing risks. 1596 small brain metastases treated with SRS among 424 patients were included. Among these tumors, 33 developed LF during the follow-up period (2.4% at 12 months following SRS). Competing risk analysis demonstrated that LF was dependent on tumor size (0.7% if <=2 mm and 3.0% if 2-10 mm at 12 months, p = 0.016). Other factors associated with increasing risk of LF were the decreasing margin dose, increasing maximal tumor diameter, volume, and radioresistant tumors (each p < 0.01). 22 tumors (0.78%) developed radiographic radiation necrosis following SRS, and this incidence did not differ by tumor size (<=2 mm and 2-10 mm, p = 0.200). This large analysis confirms that SRS remains an effective modality in treatment of small brain metastases. In light of the excellent local control and relatively low risk of toxicity, patients with small brain metastases who otherwise have a reasonable expected survival should be considered for radiosurgical management. PMID- 28577031 TI - Natural history of optic pathway gliomas in a cohort of unselected patients affected by Neurofibromatosis 1. AB - Optic pathway glioma (OPG) represents the most common central nervous system tumor in children with Neurofibromatosis type-1 (NF1). Although overall survival is usually good, no clear prognostic factors have been identified so far. We assessed the natural history of OPG in a cohort of unselected patients affected by NF1. We retrospectively evaluated 414 consecutive patients affected by NF1 and referred to our NF1 clinic before age 6. Average follow-up was 11.9 years: 52 out of 414 patients had OPG with a total cumulative incidence of 15.4% at age 15 (Kaplan-Meier estimate) and a statistically significant difference according to sex. Brain and orbit MRI was performed in 44.7% of patients: 34.6% for screening purposes and 65.4% because of the presence of neurological, ocular or other symptoms. OPG was diagnosed in 12.5% of cases in the first group, whereas in 36.4% in the latter group (p = 0.001). Clinical management was conservative in most patients, while 8 of them underwent therapy mainly because of visual deterioration. OPG was diagnosed earlier in treated patients, but the difference was not statistically significant. Conversely, all patients who underwent screening MRI had normal visual outcome. In conclusion, OPG location does not correlate with need for treatment; female patients were more frequently affected by OPG but not more frequently treated. OPG diagnosis by screening MRI does not affect the natural history of the tumor. PMID- 28577032 TI - Advancements in the study of miRNA regulation during the cell cycle in human pituitary adenomas. AB - Pituitary adenomas (PAs), single-clone adenomas arising from pituitary gland cells, comprise one of the most frequent tumors found in the sella region. The prevalence of PAs is approximately 15%, third only after gliomas and meningioma among intracranial tumors. Autopsy and radiological analysis found that the incidence of PAs is approximately 22.5%. Most PAs are benign, although a few are malignant. Just 0.1% of patients with PAs develop pituitary carcinoma. However, owing to mass effects and unregulated secretion of pituitary hormones, PAs also lead to serious morbidity. The low rate of diagnosis at onset and the lack of effective treatments for patients with recurrent disease increase the morbidity rates. Therefore, there is an urgent need to ascertain the pathological mechanism of PAs for improved diagnosis and development of specific therapies. At present, the pathogenesis of PAs is poorly understood; however, disruption of the cell cycle is known to play an important role. MicroRNAs are short noncoding RNAs that regulate gene expression at the post-transcriptional level and play a role in regulating genes involved in carcinogenesis or tumor suppression. Previous studies have demonstrated a strong connection between dysregulation of microRNAs and dysregulation of the cell cycle in PAs. In this review, we summarize the recent progress in the study of microRNA dysregulation resulting in disruption of the cell cycle in PAs. PMID- 28577033 TI - Impact of acute hematological toxicity on treatment interruptions during cranio spinal irradiation in medulloblastoma: a tertiary care institute experience. AB - To analyze treatment interruptions due to acute hematological toxicity in patients of medulloblastoma receiving cranio-spinal irradiation (CSI). Prospectively collected data from case records of 52 patients of medulloblastoma treated between 2011 and 2014 was evaluated. Blood counts were monitored twice a week during CSI. Spinal irradiation was interrupted for patients with >=grade 2 hematological toxicity and resumed after recovery to grade 1 level (TLC >3000; platelet count >75,000). Treatment interruptions and hematological toxicity were analyzed. Median age was 11 years. All patients received adjuvant CSI of 36 Gy, followed by boost of 18 Gy to posterior fossa, at 1.8 Gy per fraction. Concurrent chemotherapy was not given. Adjuvant chemotherapy was given after CSI for high risk patients. Spinal fields were interrupted in 73.1% of patients. Cause of first interruption was leucopenia in 92.1%, thrombocytopenia in 2.6%, and both in 5.3%. Median number of fractions at first interruption was 8, with 25% of interruptions in first week. Median duration for hematological recovery after nadir was 5 days for leucopenia and 3 days for thrombocytopenia. Half of the patients had at least 2 interruptions, and 19% subsequently developed grade 3 toxicity. On multivariate analysis, significant correlation with duration of delay was observed for pre-treatment haemoglobin, number of fractions at first interruption, grade and duration of recovery of leucopenia. Acute hematological toxicity with CSI is frequently under-reported. Patients with low pre-treatment hemoglobin, early onset leucopenia, profound leucopenia and prolonged recovery times are at a higher risk of having protracted courses of irradiation. Frequent monitoring of blood counts and timely interruption of spinal fields of irradiation at grade 2 level of hematological toxicity minimizes the risk of grade 3 and grade 4 toxicity, while reducing the interruptions in irradiation of the gross tumour bed. PMID- 28577034 TI - Antero-lateral minimally invasive plate osteosynthesis (MIPO) with the radial nerve exploration for extra-articular distal-third diaphyseal fractures of the humerus. AB - INTRODUCTION: Traditional open reduction and internal fixation (ORIF) of extra articular distal humerus fractures has a risk of iatrogenic radial nerve injury, extensive soft tissue stripping, and long incision scar. We performed an antero lateral minimally invasive plate osteosynthesis (MIPO) technique with the radial nerve exploration for distal-third diaphyseal fractures of the humerus and evaluated clinical and radiographic outcomes through this respective study. METHODS: From April 2010 to June 2016, 28 cases of extra-articular distal-third diaphyseal fractures were treated with an antero-lateral MIPO procedure. Patient demographics, Disabilities of the Arm, Shoulder and Hand (DASH) Score, Mayo Elbow Performance (MEP) Score, elbow range of motion, scars and post-operative complications were recorded and analyzed. RESULTS: All fractures were united with a mean time of 3.5 months. One patient exhibited delayed union (3.6%). The mean DASH Score was 6.6, and all patients had excellent or good MEP Score values. The average scar length was 6.8 cm, and the shortest was 4.5 cm. CONCLUSIONS: The MIPO technique via an antero-lateral approach for extra-articular distal-third diaphyseal fractures of the humerus results in satisfactory clinical outcomes. LEVEL OF EVIDENCE: Level IV, case series, treatment study. PMID- 28577035 TI - Survivorship of medial opening wedge high tibial osteotomy in the elderly: two to ten years of follow up. AB - BACKGROUND AND PURPOSE: Medial opening wedge high tibial osteotomy (MOWHTO) is a well-accepted procedure, which has been widely used for pain relief and varus deformity correction in the osteoarthritic (OA) knee, especially in the young patient. However, in the elderly patient, the efficacy of this procedure is still unknown. Therefore, this study aims to evaluate the survivorship of MOWHTO in elderly patients as the primary outcome. The secondary outcome is to evaluate the loss of correction angle that is the common complication after MOWTHO. MATERIALS AND METHOD: A retrospective study of 50 elderly patients (>= 60 years) was conducted to track survivorship of MOWHTO. All patients were diagnosed with varus OA knee and underwent MOWHTO at our institute. The patients who had previous knee surgery or incomplete data were excluded. Medical records and radiographs of eligible patients were reviewed for recruiting the data. Survivorship of MOWHTO was analyzed using Kaplan-Meier curves. The starting point was the time of operation and the end point was the time of subsequent TKA. The loss of correction angle was defined as the change of medial proximal tibial angle (MPTA) between three months and one year post-operatively. RESULTS: The mean age of patients was 66 +/- 5.0 years. The majority of patients were female (74%). The mean correction angle was 10.6 +/- 3.6 degrees. The union rate of osteotomy site was 100%. In survival analysis, the median follow-up time was 6.0 +/- 3.0 years. Two patients required subsequent conversions to TKA. The survivorship of MOWHTO at four years was 95.5% (95%CI, 96.0 to 98.0). For radiographic assessment, the loss of correction angle was 1.0 +/- 0.5 degrees at one year post-operatively. CONCLUSION: This study proved that MOWHTO in patient >=60 years had good mid-term survivorship with acceptable complications. This procedure can be the alternative option for the treatment of varus OA knee in the elderly. PMID- 28577036 TI - Long-term wear of dual mobility total hip replacement cups: explant study. AB - PURPOSE: Dual mobility THA implantations are increasing. THA survival of more than 15 years is considered long-term survival based on the Charnley prosthesis, which has a median wear rate of 39 to 98 mm3/year. What is the median wear rate of dual mobility THA cups and its repartition on the liner volume? What are the factors influencing dual mobility wear? METHODS: Thirty-five explants were analysed. The liners were entirely mapped with a fully automatic stripe light scanner that uses green LED light. RESULTS: The liners had a median wear rate of 38 mm3/year. The distribution of the wear between the two bearings varied greatly. No factor was found influencing wear volumes. CONCLUSIONS: The median annual wear of dual mobility liners is at least as low as the wear of cemented polyethylene liners and lower than equivalent cementless liners. The two articulations of the dual mobility THA do not cause more wear. LEVEL OF EVIDENCE: Level IV - case series. PMID- 28577037 TI - Metabolic Impact of Rapamycin (Sirolimus) and B-Estradiol Using Mouse Embryonic Fibroblasts as a Model for Lymphangioleiomyomatosis. AB - INTRODUCTION: Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease that predominantly affects women of childbearing age. Exogenous rapamycin (sirolimus) has been shown to improve clinical outcomes and was recently approved to treat LAM, whereas estrogen (E2) is implicated in disease progression. No consistent metabolic model currently exists for LAM, therefore wild-type mouse embryonic fibroblasts (MEF +/+) and TSC2 knockout cells (MEF -/-) were used in this study as a model for LAM. METHODS: Oxygen consumption rates (OCR) and redox potential were measured to determine metabolic state across control cells, MEF +/+ and -/- cells treated with rapamycin (Rapa), and MEF +/+ and -/- cells treated with E2. An XF96 extracellular flux analyzer from Seahorse Bioscience(r) was used to measure OCR, and a RedoxSYSTM ORP was used to measure redox potential. RESULTS: OCR of MEF -/- cells treated with rapamycin (MEF -/- Rapa) versus MEF -/- control were significantly lower across all conditions. The static oxidation reduction potential of the MEF -/- Rapa group was also lower, approaching significance. The coupling efficiency and ratio of ATP-linked respiration to maximum respiration were statistically lower in MEF -/- Rapa compared to MEF +/+ Rapa. There were no significant metabolic findings across any of the MEF cells treated with E2. MEF -/- control cells versus MEF +/+ control cells were not found to significantly differ. CONCLUSION: MEF cells are thought to be a feasible metabolic model for LAM, which has implications for future pharmacologic and biologic testing. PMID- 28577039 TI - How I do it? Cranial setup for cranial settling. AB - BACKGROUND: Expanded endonasal endoscopic techniques allow us to treat several pathologies related to the odontoid process and craniocervical junction. Cases such as giant basilar invagination represent a surgical challenge. METHODS: The authors provide technical nuances and describe how to complete an endoscopic endonasal odontoidectomy and release the craniocervical junction with the aim of restoring a correct sagittal balance in cases with giant basilar invagination. The study of cadaveric specimens adds clarifying dissections. CONCLUSIONS: Endonasal endoscopic odontoidectomy and craniocervical junction joint release allow the treatment of irreducible basilar invagination and restoration of better sagittal balance before posterior cervical occipitocervical fusion. PMID- 28577038 TI - A Swine Model of Percutaneous Intracoronary Ethanol Induced Acute Myocardial Infarction and Ischemic Mitral Regurgitation. AB - Ischemic mitral regurgitation (IMR) is a frequent complication after a myocardial infarction (MI), which doubles mortality. Transcatheter mitral repairs are emerging as alternative treatment options to open heart surgery for IMR, but animal models to test them are lacking. We report a percutaneous swine model of IMR. Seventeen swine were randomized to (group 1, n = 12) MI causing IMR, and (group 2, n = 5) controls. In group 1, MI was induced via percutaneous ethanol injection into the obtuse marginal branches of the left circumflex artery, resulting in ST elevating myocardial infarction. Nine animals were survived to 8 10 weeks with weekly echocardiograms and three swine were survived to 16-20 weeks with MRI at termination. In group 1 animals, average IMR fraction at termination was 26.6 +/- 2.3% in the echo group, and 24.51 +/- 0.41% in the MRI group. None of the animals in group 2 had IMR. Left ventricular dysfunction and significant dilatation were evident in group 1 animals, compared to the controls. In conclusion, a reproducible model of IMR is reported for use in pre-clinical testing of new mitral technologies. PMID- 28577040 TI - Highlight report: N-acetyltransferase 2 and urinary bladder cancer risk. PMID- 28577041 TI - Determining skeletal muscle architecture with Laplacian simulations: a comparison with diffusion tensor imaging. AB - Determination of skeletal muscle architecture is important for accurately modeling muscle behavior. Current methods for 3D muscle architecture determination can be costly and time-consuming, making them prohibitive for clinical or modeling applications. Computational approaches such as Laplacian flow simulations can estimate muscle fascicle orientation based on muscle shape and aponeurosis location. The accuracy of this approach is unknown, however, since it has not been validated against other standards for muscle architecture determination. In this study, muscle architectures from the Laplacian approach were compared to those determined from diffusion tensor imaging in eight adult medial gastrocnemius muscles. The datasets were subdivided into training and validation sets, and computational fluid dynamics software was used to conduct Laplacian simulations. In training sets, inputs of muscle geometry, aponeurosis location, and geometric flow guides resulted in good agreement between methods. Application of the method to validation sets showed no significant differences in pennation angle (mean difference [Formula: see text] or fascicle length (mean difference 0.9 mm). Laplacian simulation was thus effective at predicting gastrocnemius muscle architectures in healthy volunteers using imaging-derived muscle shape and aponeurosis locations. This method may serve as a tool for determining muscle architecture in silico and as a complement to other approaches. PMID- 28577042 TI - Intra-Suprasellar Schwannoma Presumably Originating from the Internal Carotid Artery Wall : Case Report and Review of the Literature. AB - Intracranial schwannomas are common but intra-suprasellar schwannomas are extremely rare. We represent the case of a 57-year-old woman with an intra suprasellar tumor that was presurgically diagnosed as an anterior clinoidal meningioma. Intraoperatively it adhered tightly to the internal carotid artery wall and could not easily be dissected, possibly leading to profuse hemorrhage and sacrifice of the carotid artery with coil embolization. Histopathology demonstrated a schwannoma. We reviewed and summarized the clinical, imaging, and intraoperative findings of previously reported intra-suprasellar schwannomas. PMID- 28577043 TI - Anti-CD138 chimeric antigen receptor-modified T cell therapy for multiple myeloma with extensive extramedullary involvement. PMID- 28577044 TI - Successful treatment with azacitidine for the simultaneous occurrence of multiple myeloma and acute myeloid leukemia with concomitant del(5q) and the JAK2 V617F mutation. PMID- 28577045 TI - Prevalence and Risk Factors of Drug-Associated Corrected QT Prolongation in Elderly Hospitalized Patients: Results of a Retrospective Analysis of Data Obtained Over 6 Months. AB - OBJECTIVES: Little information exists on the frequency and determinants of drug associated long QT syndrome in older adults. The objectives of this study were to assess the prevalence and identify risk factors of drug-associated long QT syndrome in a population of elderly hospitalized patients. METHODS: This was a retrospective study performed over 6 months in hospital geriatric medicine. Various QT-correction equations were fitted to the individual QT-RR data to evaluate the most appropriate equation. Long QT syndrome was defined as corrected QT >=450 ms. Available data were compared in patients with and without long QT syndrome. Logistic regression and classification and regression tree analysis were performed to identify determinants of long QT syndrome. RESULTS: Thirty three of 152 patients (22%) exhibited corrected QT >=450 ms. The different QT correction equations provided similar results, except the Bazett equation. In patients with long QT syndrome, there was a higher proportion of male subjects (58 vs. 33%, p = 0.009) and a higher number of QT-prolonging drugs than in patients without long QT syndrome. Male sex (odds ratio, 3.25) and the number of prescribed QT-prolonging agents (odds ratio, 1.77) were significantly associated with the probability of long QT syndrome. The number of QT-prolonging drugs had a stronger influence on the risk of long QT syndrome in men than in women. CONCLUSION: Male sex was found to be a significant risk factor of corrected QT prolongation in elderly hospitalized patients. The risk also increased with the number of QT-prolonging agents, especially in men. Those findings may help to mitigate the risk of long QT syndrome in elderly patients in clinical practice. PMID- 28577047 TI - Erratum to: The Effect of Losses Disguised as Wins and Near Misses in Electronic Gaming Machines: A Systematic Review. PMID- 28577048 TI - Impact of Pluronic(r) F68 on hollow fiber filter-based perfusion culture performance. AB - High cell density is an important factor in achieving high bioreactor productivity. To meet the oxygen demand with density at >100 * 106 cells/mL, a frit sparger is often used. In this study, the impact of Pluronic(r) F68 on a perfusion process using a frit sparger was studied. The perfusion process was developed using an alternating tangential flow device with a 0.2 um PES hollow fiber filter. Pluronic(r) F68 at 2 g/L was sufficient in preventing cell damage at gas flow rate of ~0.20 vvm from a drilled hole sparger (0.5 mm) but inadequate at ~0.025 vvm from a frit sparger (20 um). Increase of Pluronic(r) F68 concentration to 5 g/L prevented cell death at up to ~0.10 vvm from the frit sparger and was able to maintain high cell density at high viability in the range of 60-80 * 106 cells/mL. Such positive effect was demonstrated in both 3- and 200 L bioreactors. Supplementing additional Pluronic(r) F68 was also effective in restoring cell growth/viability from low viability cultures. Increased Pluronic(r) F68 concentration had no adverse impact on target antibody, HCP, and Pluronic(r) F68 transmissions. PMID- 28577046 TI - Fractional flow reserve: a clinical perspective. AB - Fractional flow reserve (FFR) is a reference invasive diagnostic test to assess the physiological significance of an epicardial coronary artery stenosis. FFR guided percutaneous coronary intervention in stable coronary artery disease has been assessed in three seminal clinical trials and the indications for FFR assessment are expanding into other clinical scenarios. In this article we review the theoretical, experimental and clinical basis for FFR measurement. We place FFR measurement in the context of the comprehensive invasive assessment of coronary physiology in patients presenting with known or suspected angina pectoris in daily clinical practice, and review the recent developments in FFR assessment. PMID- 28577049 TI - Eburicoic acid from Laetiporus sulphureus (Bull.:Fr.) Murrill attenuates inflammatory responses through inhibiting LPS-induced activation of PI3K/Akt/mTOR/NF-kappaB pathways in RAW264.7 cells. AB - Excessive activation of macrophages has been implicated in various types of inflammatory injury. Suppression of macrophage activation would have therapeutic benefits, leading to the alleviation of the progression of inflammatory diseases. Eburicoic acid (EA) is one of main bioactive components isolated from Laetiporus sulphureus (Bull.:Fr.) Murrill. In our previous study, we found that EA possessed anti-inflammatory activities. However, the cellular and molecular mechanisms underlying its anti-inflammatory activities remain to be poorly understood. The present study aimed to further evaluate its effect on lipopolysaccharide (LPS) induced inflammatory responses in RAW264.7 macrophage cells. We investigated the anti-inflammatory effect by modulating LPS-induced activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/nuclear transcription factor-kappaB (NF-kappaB) pathway in RAW264.7 cells. The results showed that EA caused no obvious cytotoxicity, and its suitable concentrations on RAW264.7 cells were in the range from 0.02 to 0.08 MUM. EA significantly inhibited the releases of inflammatory mediators, nitrite oxide (NO) and prostaglandin E2 (PGE2); suppressed mRNA and protein expression levels of inducible nitrite oxide synthase (iNOS) and cyclooxygenase-2 COX-2 and pro-inflammatory cytokine TNF-alpha, IL-6, and IL-1beta; and reduced levels of phosphorylated PI3K, Akt, mTOR, and NF-kappaBp65 in LPS-induced RAW264.7 cells in dose- and time-dependent manners. These aforementioned results indicated that EA executed anti-inflammatory effect on LPS-induced RAW264.7 cells, and this effect might be achieved via suppressing the PI3K/Akt/mTOR/NF-kappaB signaling pathway and inhibiting the LPS-induced productions of inflammatory mediators and pro inflammatory cytokines. PMID- 28577050 TI - Anticonvulsive activity of (1S)-(-)-verbenone involving RNA expression of BDNF, COX-2, and c-fos. AB - (1S)-(-)-verbenone (VRB) is a monoterpene present in the essential oils of many plants which has shown therapeutic effect; however, its anticonvulsant activity has not yet been evaluated. The present work sought to investigate the anticonvulsant activity of VRB using pilocarpine and pentylenetetrazole-induced seizure testing; seeking also probable mechanisms of action. VRB caused no significant changes in motor coordination. Also, no significant data was observed in the pilocarpine-induced seizure tests. In the PTZ-induced seizures test, VRB showed anticonvulsant activity at doses of 200 mg/kg i.p. (733 +/- 109.4 s) and 250 mg/kg i.p. (648.8 +/- 124.5 s) significantly increasing the latency to onset of first seizure as compared with the vehicle group (51.8 +/- 2.84 s). Pretreatment with flumazenil (FLU) did not reverse the anticonvulsive effect of VRB; however, it was able to upregulate BDNF and COX-2 genes and downregulate c fos. The findings suggest that the anticonvulsant effects of VRB may be related to RNA expression modulations of COX-2, BDNF, and c-fos. PMID- 28577051 TI - Riparian Meadow Response to Modern Conservation Grazing Management. AB - Riparian meadows occupy a small proportion of the public lands in the western United States but they provide numerous ecosystem services, including the production of high-quality forage for livestock grazing. Modern conservation management strategies (e.g., reductions in livestock stocking rates and adoption of new riparian grazing standards) have been implemented to better balance riparian conservation and livestock production objectives on publicly managed lands. We examined potential relationships between long-term changes in plant community, livestock grazing pressure and environmental conditions at two spatial scales in meadows grazed under conservation management strategies. Changes in plant community were not associated with either livestock stocking rate or precipitation at the grazing allotment (i.e., administrative) scale. Alternatively, both grazing pressure and precipitation had significant, albeit modest, associations with changes in plant community at the meadow (i.e., ecological site) scale. These results suggest that reductions in stocking rate have improved the balance between riparian conservation and livestock production goals. However, associations between elevation, site wetness, precipitation, and changes in plant community suggest that changing climate conditions (e.g., reduced snowpack and changes in timing of snowmelt) could trigger shifts in plant communities, potentially impacting both conservation and agricultural services (e.g., livestock and forage production). Therefore, adaptive, site-specific management strategies are required to meet grazing pressure limits and safeguard ecosystem services within individual meadows, especially under more variable climate conditions. PMID- 28577052 TI - [Analysis of therapy-relevant receptors in bone marrow carcinosis : Comparison of pathological and clinical parameters]. AB - BACKGROUND: Bone marrow carcinosis is a sign of advanced tumor stage with nonspecific clinical and hematological symptoms. Diagnosis is based on bone marrow biopsy and histopathology, but biopsies are not part of the standard work up in oncological diseases and data on the correlation between clinical presentation and pathological findings are sparse. MATERIAL AND METHODS: In a retrospective single-center study, data from 20 tumor patients with bone marrow carcinosis were analyzed. Bone marrow biopsies were re-evaluated regarding quantity of tumor cells, fibrosis/necrosis, and bone changes. Immunohistochemistry of potential therapy-relevant receptors and PD-L1 was performed. RESULTS: The median age in these 20 patients (13 women, 7 men) was 65 years. The most frequent diagnoses were breast (n = 8) and lung cancer (n = 5). Anemia (94% of patients), thrombocytopenia (72%), and elevated LDH (83%) were frequent findings. The degree of bone marrow infiltration was highly variable and accounted for between 1 and 95% of biopsy space. Significant bone remodeling was present in 14/20 biopsies. No correlation could be found between histological and radiological findings. Treated patients showed some clinical and biochemical improvement, but the overall survival was poor (median 4.5 months, range < 0.5 to 21.5 months). DISCUSSION: Anemia and thrombocytopenia are frequently associated with bone marrow carcinosis, but are nonspecific. The extent of tumor cell infiltration and osteolytic/osteoblastic changes did not correlate with radiological findings. Therapy-relevant target factors should be evaluated, but therapeutic options are often limited and the prognosis is bad. PMID- 28577054 TI - [What is a granuloma?] AB - The histogenesis of granulomata is dependent on various cell types. The typical composition is a center of macrophages/histiocytes with lymphocytes at the border. The sequence of events leading to granuloma formation is regulated by various cell types and cytokines: While Th1-associated mechanisms promote granuloma development, it appears that regulatory T cells as well as M2 macrophages together with interleukin (IL)-10 and IL-13 lead to their dissociation and tissue healing. There is a strong correlation between structure and function of granulomas. Chronic inflammatory granulomatous skin diseases are primarily based on dysfunctional downmodulation of inflammatory processes that lead to and maintain granuloma formation. PMID- 28577055 TI - [Evidence of compression therapy]. AB - BACKGROUND: Medical compression therapy is widely used to treat phlebologic diseases. Compression bandages as well as compression stockings are used. Compression has been identified to be an effective conservative therapy for the healing of venous ulcers and other indications. Thus, the evidence for the use of medical compression therapy and for which indications is presented. MATERIALS AND METHODS: Review and systematic presentation of the evidence-based use of compression. The current literature, guidelines, and consensus statements were searched and the indications for compression therapy are presented. RESULTS: There is a high level of evidence that compression therapy is effective to heal venous ulcers and to prevent recurrent ulcers. The use of compression bandages and hosiery after interventional and surgical procedures for varicose veins is based on experience but not on randomized controlled trials. According to clinical experience, the healing of inflammatory skin diseases (e.g., erythema nodosum, pyoderma gangrenosum, necrobiosis lipoidica, cutaneous leukocytoclastic vasculitis, and psoriasis of the extremities) is supported by compression therapy. Compression therapy in patients suffering from venous ulcers is highly recommended. PMID- 28577053 TI - Regenerative properties of collagenated porcine bone grafts in human maxilla: demonstrative study of the kinetics by synchrotron radiation microtomography and light microscopy. AB - OBJECTIVES: Recently, it has been reported that heterologous biomaterials, where the collagen matrix is preserved, seem to facilitate blood clotting and the subsequent invasion of repairing and regenerative cells. This study aimed at evaluating the healing of human extraction sockets grafted with a collagenated cortico-cancellous porcine bone (mp3(r), OsteoBiol(r), Tecnoss(r), Giaveno, Italy) by synchrotron radiation X-ray microtomography (microCT) and histology in order to have a 3D quantitative characterization over time. MATERIALS AND METHODS: Ridge preservation with porcine bone and collagen membrane was performed on 21 patients using a flapless approach and a secondary soft tissue closure. At the time of implant placement, six bone samples were harvested, two in the 3 month group, two in the 6-month group, one in the 12-month group post-surgery, and one spontaneously healed control, and evaluated by microCT and histology. RESULTS: MicroCT revealed that in the grafted sites there were a greater number of trabeculae, although they appeared thinner than in the control sites; these trabeculae homogenously filled the defects, suggesting an improved strength of the socket. Histology showed that over time, the amount of biomaterial decreased and the newly formed bone increased, while less dense bone with wider marrow spaces was detected in the control sample, supporting synchrotron findings. CONCLUSIONS: The morphometric data converge to indicate the suitability of porcine bone for the preservation of post-extraction sockets. CLINICAL RELEVANCE: The use of mp3 is encouraged to preserve and heal sockets. PMID- 28577056 TI - [Specific indications for foam sclerotherapy]. AB - BACKGROUND: Foam sclerotherapy is well established in the treatment of varicose veins of different sizes. METHODS: A literature review was performed to determine which specific indications for foam sclerotherapy exist. RESULTS: Treatment of venous leg ulcers, varices that might rupture, varicose veins in geriatric patients, pudendal veins and seroma could be determined as specific indications for foam sclerotherapy. CONCLUSION: In some indications, foam sclerotherapy is the treatment option of first choice. It is an effective and safe treatment option. PMID- 28577057 TI - Case reports e-online in Supplement 1, 2017. PMID- 28577058 TI - Type B and A monoamine oxidase and their inhibitors regulate the gene expression of Bcl-2 and neurotrophic factors in human glioblastoma U118MG cells: different signal pathways for neuroprotection by selegiline and rasagiline. AB - Type B monoamine oxidase (MAO-B) in glial cells has been considered to be associated with neuronal death in Parkinson's disease. MAO-B inhibitors, rasagiline and selegiline [(-)deprenyl], protect neurons in animal and cellular models of neurodegeneration. However, the role of MAO-B itself in the regulation of cell death processing remains elusive, whereas type A MAO (MAO-A) mediates the induction of anti-apoptotic Bcl-2 genes by rasagiline and selegiline. In this paper, the involvement of MAOs in the induction of neuroprotective genes by MAO inhibitors was investigated in human glioblastoma U118MG cells expressing mainly MAO-B. Selegiline significantly increased Mao-B, which was suppressed by Mao-A knockdown with short interfering (si)RNA, whereas rasagiline less markedly increased Mao-B, which was not affected by Mao-A knockdown. Mao-A mRNA was also markedly increased by rasagiline and selegiline, and Mao-B knockdown significantly enhanced the induction by selegiline, but not by rasagiline. Mao-B knockdown also significantly increased mRNA levels of Bcl-2, brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Selegiline synergistically enhanced the expression of these genes in Mao B knockdown cells, but Mao-A knockdown suppressed the increase. Rasagiline increased BDNF and GDNF, which Mao-B and Mao-A knockdown inhibited. These results show that MAO-B might function as a repressor and MAO-A as a mediator in the constitutional expression of pro-survival genes, and that MAO-B and MAO-A might regulate different signal pathways for rasagiline and selegiline to induce neuroprotective genes. The novel role of glial MAOs in the regulation of gene expression is discussed. PMID- 28577060 TI - Is sedation administration strategy and analysis during drug-induced sedation endoscopy objective and systematic? PMID- 28577059 TI - Totally laparoscopic right colectomy versus laparoscopically assisted right colectomy: a propensity score analysis. AB - INTRODUCTION: The aim of this study is to compare short- and long-term outcomes of totally laparoscopic right colectomy (TLRC) and laparoscopically assisted right colectomy (LARC), using propensity score matching (PSM) analysis. MATERIALS AND METHODS: A retrospective analysis of patients who underwent laparoscopic right colectomy between January 2006 and July 2016 was conducted. PSM analysis was performed to overcome patient selection bias between the two surgical techniques. RESULTS: A total of 116 patients were reviewed. After PSM, 54 patients for the TLRC group and 54 patients for the LARC group were compared. TLRC was associated with shorter post-operative hospital stay (6.81 vs. 4.79 days; p < 0.001) with no difference in 30-day morbidity and mortality. A lower incidence of long-term incisional hernia was observed in the TLRC group (1.9 vs. 21.2%; p = 0.002). TLRC showed better oncological accuracy as demonstrated by a greater number of lymph node achieved (19.21 vs. 15.19; p = 0.001) and higher vascular pedicle length (131.81 vs. 114.76 mm; p = 0.014). DISCUSSION: TLRC is a safe and feasible technique with similar results of LARC in terms of short-term morbidity and mortality. Major advantages related to TLRC are represented by shorter post-operative hospital stay and lower incidence of long-term incisional hernias. Further investigations are needed to assess the oncological outcomes for this technique. PMID- 28577061 TI - Chronology of mineralization of the permanent mandibular second molar teeth and forensic age estimation. AB - Forensic age estimation frequently relies upon the chronology of mineralization of the third molar teeth. However, even when present, third molar teeth cannot always be used for estimating age in people who are classified as minors. Seconds molars develop earlier and in a more predictable way, and therefore are often more reliable for age estimation in this age group. This study aims to contribute to forensic age estimation using an age threshold of 14-years, studying the stages of development of permanent mandibular second molar teeth mineralization. 367 orthopantograms of a Portuguese population group, aged between 3 and 19 years, were studied. The stages of mineralization of mandibular permanent second molar teeth were studied following the classification stages proposed by Demirjian et al. Stage descriptive analysis was performed, and associations between age and stage were studied. A logistic regression to determine age over 14 years, using maturation stages and sex as a predictive variables, was made. A second sample was used for testing the model. The significance level was set at 5%. The model correctly classified 92.0% of cases overall. The equation was tested in the second sample, and the results showed that there were no statistical significant differences between the binary real age (i.e. age < 14 and age >= 14 years) and the estimated age (p = 0.109). The developed model is useful for age estimation using 14-years as a threshold. However, stage maturation analyses showed that stage F, in males, and stages G and H, in both sexes, lead to an estimated age with significant statistical differences from chronological age. PMID- 28577062 TI - Hepatic progenitor cell expansion in early-stage nonalcoholic steatohepatitis: evidence from immunohistochemistry and immunoelectron microscopy of matrix metalloproteinase-1. PMID- 28577063 TI - Indoor and outdoor radon measurements at lung cancer patients' homes in the dwellings of Rize Province in Turkey. AB - In this study, indoor and outdoor radon (222Rn) surveys were carried out in the summer and winter seasons in homes of one hundred lung cancer patients in the year 2013-2014. The aim was to investigate the relationship between radon and cancer patients. Lung cancer patients completed a questionnaire concerning their living environment, various physical parameters and living habits. Pearson correlation and t tests revealed no meaningful results between radon concentrations, on one hand, and environmental and personal living habits, on the other hand. Consequently, the BEIR VI model was adapted and 222Rn exposure was estimated to be responsible for about 12% of the lung cancer incidences in the winter season and around 5% in the summer season in the Rize Province. However, due to the limited number of data and numerous parameters that could lead to lung cancer, the estimations done with the model should be taken very lightly. The annual effective doses due to inhalation of indoor and outdoor 222Rn were estimated to be, respectively, 1.43 and 0.94 mSv y-1. The indoor and outdoor annual effective doses were, respectively, close and below the world annual effective dose (1.3 mSv y-1). At the district level, the indoor annual effective dose equivalent in the Iyidere district was 4.52 mSv y-1, which was 3.5 times greater than the world average. The number of patients in the majority of the houses in this district was more than one. PMID- 28577065 TI - Treatment of talus osteochondral defects in chronic lateral unstable ankles: small-sized lateral chondral lesions had good clinical outcomes. AB - PURPOSE: To assess and compare the clinical and MRI outcomes of patients with talus osteochondral defect (OCD) and patients without OCD in a cohort with chronic lateral ankle instability. METHODS: All patients who underwent open or arthroscopic anterior talofibular ligament repair of the lateral ligament complex by a single surgeon were included in this study. Ankle arthroscopic surgery was initially performed to manage any intra-articular OCD, including debridement and microfracture. Functional scores (AOFAS, Karlsson score) and Tegner activity level scores were determined. An MRI scan was performed at follow-up to assess talus OCD after treatment. Spearman's correlation coefficients were calculated between functional scores and various factors. RESULTS: A total of 104 patients with chronic ankle instability were included in this study. Among them, 33 patients had cartilage injury on the talus (OCD group), and the other 71 patients had no cartilage injury (control group). After surgery, there was a significant increase in the AOFAS scores (p < 0.001), the Karlsson scores (p < 0.001), and the Tegner activity scores (p < 0.001) in both the OCD group and the control group. However, there was no significant difference in the AOFAS scores (90.7 +/- 6.6 vs. 92.5 +/- 8.5; n.s.), the Karlsson scores (89.7 +/- 9.3 vs. 91.2 +/- 9.1; n.s.), or the Tegner activity scores (5 vs. 6; n.s.) between the OCD group and the control group postoperatively. In the OCD group, there was a significant negative association between the functional scores (AOFAS, Karlsson score, or Tegner score) and the number of intra-articular lesions. For the lateral OCD, the mean lesion area significantly decreased from 49.0 +/- 10.7 mm2 preoperatively to 18.3 +/- 13.1 mm2 at the final follow-up (p < 0.001). CONCLUSION: No significant difference in functional outcomes was found between the OCD group and the control group postoperatively. Arthroscopic microfracture is a good option for the long term treatment of lateral talus OCD. LEVEL OF EVIDENCE: III. PMID- 28577064 TI - No benefit of autologous transfusion drains in total knee arthroplasty. AB - PURPOSE AND HYPOTHESIS: Autologous blood transfusion drains are commonly used to reduce allogeneic blood transfusion rate after total knee arthroplasty. There is conflicting evidence as to whether autologous transfusion drains (ABT drains) were effective when restrictive transfusion triggers were used. The aim of our study was to ascertain where, as a part of a blood management protocol, autologous blood transfusion drains reduce the allogeneic blood transfusion rate after total knee arthroplasty. METHODS: Two-hundred total knee arthroplasty patients were included in the prospective randomized controlled study. After implantation, a Redon drain without vacuum assistance (control, n = 100) or an autologous blood transfusion drain (ABT group, n = 100) was used. Demographic and operative data were collected. The blood loss, total blood loss, blood values and transfusion rate were documented. RESULTS: The blood loss in the drains was significantly increased for the ABT group (409 vs. 297 ml, p < 0.001). There was a non-significant trend towards a higher total blood loss for ABT patients (1844 vs. 1685 ml, n.s.). The allogeneic blood transfusion rate was similar for both groups (8 vs. 9%, n.s.). Similarly, the number of transfused blood units was comparable between both groups (0.2U/patient vs. 0.17U/patient n.s.). CONCLUSION: In combination with restrictive blood transfusion triggers, ABT drains had no positive effect on the allogeneic blood transfusion rate. The blood loss in ABT drains was higher. As a consequence, the use of ABT drains was discontinued. LEVEL OF EVIDENCE: I. PMID- 28577068 TI - Intensive care medicine in 2050: statistical tools for development of prognostic models (why clinicians should not be ignored). PMID- 28577066 TI - Comparison of the Psychopharmacological Effects of Tiletamine and Ketamine in Rodents. AB - The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine (KET) produces rapid and sustained antidepressant effects in patients. Tiletamine (TIL; 2-ethylamino-2-thiophen-2-yl-cyclohexan-1-one) is another uncompetitive NMDA receptor antagonist, used in a medical (veterinary) setting as an anesthetic tranquilizer. Here, we compared the behavioral actions of KET and TIL in a variety of tests, focusing on antidepressant-like and dissociative-like effects in mice and rats. The minimum effective doses of KET and TIL were 10 mg/kg to reduce mouse forced swim test immobility and 15 mg/kg to reduce marble-burying behavior. However, at similar doses, both compounds diminished locomotor activity and disturbed learning processes in the mouse passive avoidance test and the rat novel object recognition test. KET and TIL also reduced social behavior and accompanying 50-kHz "happy" ultrasonic vocalizations (USVs) in rats. TIL (5-15 mg/kg) displayed additional anxiolytic-like effects in the four-plate test. Neither KET nor TIL affected pain response in the hot plate test. Examination of the "side effects" revealed that only at the highest doses investigated did both compounds produce motor deficits in the rotarod test in mice. While KET produced behavioral effects at doses comparable between species, in the rats, TIL was ~10 times more potent than in the mice. In summary, antidepressant-like properties of both KET and TIL are similar, as are their adverse effect liabilities. We suggest that TIL could be an alternative to KET as an antidepressant with an additional anxiolytic-like profile. PMID- 28577070 TI - Heparan sulfate proteoglycans as key regulators of the mesenchymal niche of hematopoietic stem cells. AB - The complex microenvironment that surrounds hematopoietic stem cells (HSCs) in the bone marrow niche involves different coordinated signaling pathways. The stem cells establish permanent interactions with distinct cell types such as mesenchymal stromal cells, osteoblasts, osteoclasts or endothelial cells and with secreted regulators such as growth factors, cytokines, chemokines and their receptors. These interactions are mediated through adhesion to extracellular matrix compounds also. All these signaling pathways are important for stem cell fates such as self-renewal, proliferation or differentiation, homing and mobilization, as well as for remodeling of the niche. Among these complex molecular cues, this review focuses on heparan sulfate (HS) structures and functions and on the role of enzymes involved in their biosynthesis and turnover. HS associated to core protein, constitute the superfamily of heparan sulfate proteoglycans (HSPGs) present on the cell surface and in the extracellular matrix of all tissues. The key regulatory effects of major medullar HSPGs are described, focusing on their roles in the interactions between hematopoietic stem cells and their endosteal niche, and on their ability to interact with Heparin Binding Proteins (HBPs). Finally, according to the relevance of HS moieties effects on this complex medullar niche, we describe recent data that identify HS mimetics or sulfated HS signatures as new glycanic tools and targets, respectively, for hematopoietic and mesenchymal stem cell based therapeutic applications. PMID- 28577071 TI - Isolation of a methylated mannose-binding protein from terrestrial worm Enchytraeus japonensis. AB - To elucidate a biological role of the methylated mannose residues found in N glycans of terrestrial worm Enchytraeus japonensis, we first synthesized 3-O methyl mannose- and 4-O-methyl mannose-derivatives and immobilized them to Sepharose 4B beads in order to isolate the sugar-binding protein. When whole protein extracts from the worms was applied to a series of the columns immobilized with the modified and unmodified mannose-derivatives, respectively, a protein with a molecular weight of 25,000 was isolated by 4-O-methyl mannose immobilized column chromatography, and termed as a methylated mannose-binding protein (mMBP). mMBP bound weakly to a mannose-immobilized column and moderately to a 3-O-methyl mannose-immobilized column. The N-terminal amino acid sequences of mMBP and its endoprotease-digested peptides were determined. Using the degenerate first primers synthesized based on the primary sequence, a genomic DNA fragment was isolated. Then, the second primers were synthesized based on the genomic DNA fragment, and with use of them two cDNA fragments were obtained by the 3'- and 5'-RACE methods. Finally, the third primers were synthesized based on the sequences of the two cDNA fragments and one genomic DNA fragment, and with use of them a full-length cDNA of mMBP was isolated and shown to comprise a putative 633 bp open reading frame encoding 210 amino acid residues. BLAST analysis revealed that mMBP has identities by 26 ~ 55% to several proteins including the regeneration-upregulated protein 3 from the same species. Whether mMBP is involved in the regeneration of the worm is under investigation. PMID- 28577073 TI - Size-exclusion chromatography of xylan derivatives-the critical evaluation of macromolecular data. AB - Hydroxypropyl xylans with varying degrees of substitution were characterized by size-exclusion chromatography. Molar masses of the samples were determined using two approaches: by conventional calibration with molar mass standards and by a multi-detection method that utilizes the combination of static light scattering, viscometry, and differential refractive index detection. The molar mass results obtained by the multi-detection method were accurate, but required the determination of separate refractive index increments for each structurally different sample. The column calibration approach with standard pullulan samples gave biased results due to the differences in hydrodynamic volumes between pullulans and hydroxypropyl xylans with similar molar masses. The degree of hydroxypropylation affected the chain conformation and compactness of the polymer chains. Mark-Houwink parameters and persistence length values suggested that the hydroxypropyl substituents reduced the flexibility of the xylan chain and made the polymer chain more extended. PMID- 28577072 TI - Regulation of renal Na-(K)-Cl cotransporters by vasopressin. AB - Vasopressin (AVP) induces antidiuresis, thus playing an essential role in body water and electrolyte homeostasis. Its antidiuretic effects are mediated chiefly by V2 vasopressin receptors (V2R) expressed along the distal nephron and collecting duct epithelia. NaCl reabsorption in the distal nephron, which includes the thick ascending limb (TAL) and distal convoluted tubule (DCT), largely depends on the activity of two structurally related Na-(K)-Cl cotransporters, NKCC2 in TAL and NCC in DCT. AVP-induced activation of these transporters contributes to urine concentration and renal electrolyte reabsorption. Previous work has specified molecular pathways mediating the effects of V2R activation in TAL and DCT, and protein networks involved in intracellular trafficking and phosphoregulation of the two transporters have been identified. This review summarizes recent progress in understanding AVP signalling mechanisms that are responsible for the activation of NKCC2 and NCC. Implications in the pathophysiology of diseases such as nephrogenic diabetes insipidus, diabetes mellitus and salt-sensitive hypertension are discussed in this context. PMID- 28577074 TI - Laboratory and field studies on a new sensor for dissolved N2O. AB - Nitrous oxide (N2O) is a strong greenhouse gas, whose atmospheric concentration has been continuously increasing for more than 200 years. One major source is wastewater treatment plants (WWTPs), where N2O emissions should either be minimized or pushed to levels where exploitation in biogas combustion engines becomes efficient. Both these strategies require online control of the N2O concentrations in the liquid as well as in the gas phase. For this purpose, we propose a system for membrane extraction of the gas from the liquid phase, which then allows for a subsequent gas-phase analysis, which we perform by photoacoustic spectroscopy. We compare different theoretical calculations of the extraction efficiency, based either on a straightforward mathematical model or on a finite element simulation. The comparison of results with measurements produced on a well-defined model system shows good accordance. Based on the outcome, a field probe was developed and tested on a WWTP, yielding results comparable to the one achieved by GC reference analysis. Graphical abstract Gas extraction from liquids, e.g. from a wastewater treatment plant, for online gas monitoring. PMID- 28577075 TI - The holocaust of the disabled. AB - The Holocaust is commonly known as the genocide perpetrated by the Nazi regime which killed six million European Jews. Not many people know, however, that another holocaust took place at the same time: the holocaust of the disabled. As Hitler pursued a strategic vision of a dominant, pure Aryan race, any inferior and weak human being was exterminated. A brief consideration is called for in order to not forget the horrifying events that took place at the beginning of the last century and in order to re-shape our concept of normality. PMID- 28577076 TI - 68Ga-PSMA-11 PET/CT: the rising star of nuclear medicine in prostate cancer imaging? AB - Ever since the introduction of 68Ga-prostate-specific membrane antigen 11 positron-emission tomography/computed tomography (68Ga-PSMA-11 PET/CT) a few years ago, it has rapidly achieved great success in the field of prostate cancer imaging. A large number of studies have been published to date, indicating a high potential of 68Ga-PSMA-11 PET/CT in the work-up of prostate cancer patients, including primary diagnosis, staging and biochemical recurrence. The aim of this review is to present the most important data on this novel, highly promising imaging technique, and to formulate recommendations for possible applications of 68Ga-PSMA-11 PET/CT in clinical routine. PMID- 28577069 TI - Prevention of acute kidney injury and protection of renal function in the intensive care unit: update 2017 : Expert opinion of the Working Group on Prevention, AKI section, European Society of Intensive Care Medicine. AB - BACKGROUND: Acute kidney injury (AKI) in the intensive care unit is associated with significant mortality and morbidity. OBJECTIVES: To determine and update previous recommendations for the prevention of AKI, specifically the role of fluids, diuretics, inotropes, vasopressors/vasodilators, hormonal and nutritional interventions, sedatives, statins, remote ischaemic preconditioning and care bundles. METHOD: A systematic search of the literature was performed for studies published between 1966 and March 2017 using these potential protective strategies in adult patients at risk of AKI. The following clinical conditions were considered: major surgery, critical illness, sepsis, shock, exposure to potentially nephrotoxic drugs and radiocontrast. Clinical endpoints included incidence or grade of AKI, the need for renal replacement therapy and mortality. Studies were graded according to the international GRADE system. RESULTS: We formulated 12 recommendations, 13 suggestions and seven best practice statements. The few strong recommendations with high-level evidence are mostly against the intervention in question (starches, low-dose dopamine, statins in cardiac surgery). Strong recommendations with lower-level evidence include controlled fluid resuscitation with crystalloids, avoiding fluid overload, titration of norepinephrine to a target MAP of 65-70 mmHg (unless chronic hypertension) and not using diuretics or levosimendan for kidney protection solely. CONCLUSION: The results of recent randomised controlled trials have allowed the formulation of new recommendations and/or increase the strength of previous recommendations. On the other hand, in many domains the available evidence remains insufficient, resulting from the limited quality of the clinical trials and the poor reporting of kidney outcomes. PMID- 28577077 TI - [Pain therapy during labour]. AB - To date the gold standard of treating labour pain is regional analgesia by application of epidural analgesia. When offering epidural analgesia, the programmed intermittent epidural bolus (PIEB) is more effective in terms of pain reduction, less motor blocks and higher satisfaction of the parturient compared to continuous application via perfusor pump. An upcoming alternative to epidural analgesia is remifentanil, a short acting and potent opioid. Remifentanil, however, requires haemodynamic monitoring as cardiac and respiratory impairment has been described. Nitrous oxide has been used for decades in the Anglosphere but it is a greenhouse gas, and interactions with Vitamin B12 are possible. Using novel extraction systems, nitrous oxide has become more attractive for treatment of the initial phase of labour pain in Central Europe. In order to provide the parturient with the best possible and with a tailored pain concept an interdisciplinary approach with obstetricians, midwives and anaesthesiologists is required. PMID- 28577078 TI - Comparison of residual cancer burden, American Joint Committee on Cancer staging and pathologic complete response in breast cancer after neoadjuvant chemotherapy: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). AB - PURPOSE: Several pathologic staging systems characterize residual tumor in patients undergoing neoadjuvant chemotherapy for breast cancer. Pathologic complete response (pCR) is now accepted by the Food and Drug Administration as an endpoint for granting accelerated drug approval. Two other systems of post neoadjuvant pathologic tumor staging-residual cancer burden (RCB) and the American Joint Committee on Cancer post-neoadjuvant therapy staging system (yAJCC)-have been developed to characterize residual tumors when patients do not achieve pCR. The optimal system and the ways in which these systems complement each other have not been fully determined. METHODS: Using data from the I-SPY 1 TRIAL, we compared pCR, RCB, and yAJCC as predictors of early recurrence-free survival (RFS) to identify ways to improve post-neoadjuvant pathologic evaluation. RESULTS: Among 162 patients assessed, pCR identified patients at lowest risk of recurrence, while RCB and yAJCC identified patients at highest risk. Hormone-receptor (HR) and HER2 subtypes further improved risk prediction. Recursive partitioning indicated that triple-negative or HER2+ patients with yAJCC III or RCB 3 have the highest recurrence risk, with an RFS of 27%. Our analysis also highlighted discrepancies between RCB and yAJCC stratification: 31% of patients had discrepant RCB and yAJCC scores. We identified differential treatment of lymph node involvement and tumor cellularity as drivers of these discrepancies. CONCLUSIONS: These data indicate that there is benefit to reporting both RCB and yAJCC for patients in order to identify those at highest risk of relapse. PMID- 28577079 TI - Unenhanced magnetic resonance screening using fused diffusion-weighted imaging and maximum-intensity projection in patients with a personal history of breast cancer: role of fused DWI for postoperative screening. AB - PURPOSE: To assess the diagnostic performance of unenhanced abbreviated protocol (AP) comprising fused diffusion-weighted imaging (DWI) using T1-weighted imaging (T1WI) with DWI maximum-intensity projections (DWI MIPs) for screening patients with a personal history of breast cancer (PHBC). METHODS: This institutional review board-approved retrospective observational study included 343 patients with PHBC who underwent 3T breast magnetic resonance imaging (MRI) between November 2013 and September 2015. Three breast radiologists reviewed the DWI MIPs of the AP to identify lesions, and the remaining axial AP images to characterize the detected lesions and establish the breast imaging reporting and data system final assessment. The conventional protocol (CP) images were also evaluated in the same way. The decision-making times were recorded. RESULTS: MRI acquisition time was approximately 5 min for AP. The mean times to read MIPs and remaining images were shorter in AP than in CP (5.5 and 22.1 s vs. 7.8 and 29.6 s). On DWI MIPs, the readers detected 9, 8, and 9 of 9 pathologically proven cancers, with negative predictive values (NPVs) of 100.0, 99.6, and 100.0%. Complete AP showed sensitivities of 88.9, 100.0, and 88.9% and specificities of 94.8, 93.4, and 95.1%. Complete CP showed sensitivities of 100.0, 100.0, and 88.9% and specificities of 93.4, 94.0, and 96.3%. CONCLUSIONS: An unenhanced AP had a short acquisition time of 5 min, and DWI MIPs showed NPVs greater than 99% across readers. The diagnostic performance of complete AP was equivalent to that of CP for screening patients with PHBC. PMID- 28577080 TI - Receptor activator of nuclear factor kappa B (RANK) expression in primary breast cancer correlates with recurrence-free survival and development of bone metastases in I-SPY1 (CALGB 150007/150012; ACRIN 6657). AB - PURPOSE: The receptor activator of nuclear factor kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) axis may contribute to the development of bone metastases (BM). We studied gene expression in this pathway in primary breast cancer (BC) to determine correlations with clinical characteristics and outcomes in the neoadjuvant I-SPY1 study. METHODS: We evaluated RANK/RANKL/OPG expression using expression microarrays in I-SPY1 (n = 149). Associations with clinical features were determined using t test and ANOVA. Associations between biomarker high versus low groups (dichotomized at an optimal cutpoint) and recurrence-free survival (RFS) were evaluated using the log-rank test and in a multivariate Cox proportional hazard model. A pooled external neoadjuvant cohort with gene expression data (GSE25066) (Hatzis et al. in JAMA 305(18):1873-1881, 30) (n = 425) was used for validation. Associations with site-specific relapse were evaluated using the t-test and multivariate logistic regression adjusting for hormone receptor (HR) status. RESULTS: RANK was significantly higher in HR negative versus HR positive (p = 0.027), in basal versus non-basal disease (p = 0.004), and in those achieving pathologic complete response (p = 0.038); the associations with HR negative and basal BC were also significant in GSE25066. In both datasets, higher RANK associated with significantly worse RFS (I-SPY1: p = 0.045, GSE25066: p = 0.044). However, this association did not remain significant after adjusting for HR status. In I-SPY1 patients with recurrence, higher RANK correlated with BM versus non-BM (p = 0.045), even after adjusting for HR status (p = 0.035). CONCLUSIONS: RANK is increased in HR negative and basal BC, and correlates with worse RFS and risk of BM. The RANK pathway is a potential therapeutic target in BC. PMID- 28577082 TI - [Psychological interventions for pain reduction]. PMID- 28577081 TI - The 21-gene recurrence score in special histologic subtypes of breast cancer with favorable prognosis. AB - BACKGROUND/PURPOSE: The 21-gene recurrence score (RS) assay predicts the likelihood of distant recurrence and chemotherapy benefit in early-stage, estrogen receptor (ER)-positive, HER2-negative breast cancer. Data on the RS of special histologic subtypes of invasive breast carcinoma with favorable prognosis are limited. METHODS: We reviewed our institutional database to identify patients with special histologic subtypes of breast cancer associated with favorable prognosis and available RS results. Our cohort consists of fifty-seven women: thirty-three patients with pure mucinous carcinoma (MC), ten with tubular carcinoma (TC), nine with encapsulated papillary carcinoma (EPC), and five with solid papillary carcinoma (SPC). RESULTS: Most (44/57, 77.2%) carcinomas had low RS (<=17), and none had high RS (>=31). All EPCs had low RS, but other subtypes had RS 18-30. Higher RS was associated with lower progesterone receptor (PR) expression by immunohistochemistry and lower PR mRNA scores (P <= 0.007). No morphologic feature (tumor grade, biopsy site changes, cellular stroma, inflammatory cells) was associated with RS >= 18. At a median follow-up of 40 months, the distant recurrence-free survival was 100%. One patient with SPC developed locoregional recurrence at 22 months. CONCLUSIONS: As the largest series to date, our study raises the question of whether the RS assay is necessary for breast cancers with favorable histology. Reflex testing of node negative, ER+/HER2- breast cancers may be deferred for these special histologic subtypes, emphasizing the need for multidisciplinary discussions between breast pathologists and other members of the breast cancer team. PMID- 28577084 TI - Integrated analysis of leaf morphological and color traits in different populations of Chinese cabbage (Brassica rapa ssp. pekinensis). AB - KEY MESSAGE: QTLs and candidate gene markers associated with leaf morphological and color traits were identified in two immortalized populations of Brassica rapa, which will provide genetic information for marker-assisted breeding. Brassica rapa is an important leafy vegetable consumed worldwide and morphology is a key character for its breeding. To enhance genetic control, quantitative trait loci (QTLs) for leaf color and plant architecture were identified using two immortalized populations with replications of 2 and 4 years. Overall, 158 and 80 QTLs associated with 23 and 14 traits were detected in the DH and RIL populations, respectively. Among them, 23 common robust-QTLs belonging to 12 traits were detected in common loci over the replications. Through comparative analysis, five crucifer genetic blocks corresponding to morphology trait (R, J&U, F and E) and color trait (F, E) were identified in three major linkage groups (A2, A3 and A7). These might be key conserved genomic regions involved with the respective traits. Through synteny analysis with Arabidopsis, 64 candidate genes involved in chlorophyll biosynthesis, cell proliferation and elongation were co localized within QTL intervals. Among them, SCO3, ABI3, FLU, HCF153, HEMB1, CAB3 were mapped within QTLs for leaf color; and CYCD3;1, CYCB2;4, AN3, ULT1 and ANT were co-localized in QTL regions for leaf size. These robust QTLs and their candidate genes provide useful information for further research into leaf architecture with crop breeding. PMID- 28577083 TI - Genome-wide association study for agronomic and physiological traits in spring wheat evaluated in a range of heat prone environments. AB - KEY MESSAGE: We identified 27 stable loci associated with agronomic traits in spring wheat using genome-wide association analysis, some of which confirmed previously reported studies. GWAS peaks identified in regions where no QTL for grain yield per se has been mapped to date, provide new opportunities for gene discovery and creation of new cultivars with desirable alleles for improving yield and yield stability in wheat. We undertook large-scale genetic analysis to determine marker-trait associations (MTAs) underlying agronomic and physiological performance in spring wheat using genome-wide association studies (GWAS). Field trials were conducted at seven sites in three countries (Sudan, Egypt, and Syria) over 2-3 years in each country. Twenty-five agronomic and physiological traits were measured on 188 wheat genotypes. After correcting for population structure and relatedness, a total of 245 MTAs distributed over 66 loci were associated with agronomic traits in individual and mean performance across environments respectively; some of which confirmed previously reported loci. Of these, 27 loci were significantly associated with days to heading, thousand kernel weight, grain yield, spike length, and leaf rolling for mean performance across environments. Despite strong QTL by environment interactions, eight of the loci on chromosomes 1A, 1D, 5A, 5D, 6B, 7A, and 7B had pleiotropic effects on days to heading and yield components (TKW, SM-2, and SNS). The winter-type alleles at the homoeologous VRN1 loci significantly increased days to heading and grain yield in optimal environments, but decreased grain yield in heat prone environments. Top 20 high-yielding genotypes, ranked by additive main effects and multiplicative interaction (AMMI), had low kinship relationship and possessed 4-5 favorable alleles for GY MTAs except two genotypes, Shadi-4 and Qafzah-11/Bashiq-1-2. This indicated different yield stability mechanisms due to potentially favorable rare alleles that are uncharacterized. Our results will enable wheat breeders to effectively introgress several desirable alleles into locally adapted germplasm in developing wheat varieties with high yield stability and enhanced heat tolerance. PMID- 28577087 TI - Ritual Participation, Sense of Community, and Social Well-Being: A Study of Seva in the Sikh Community. AB - The study examined the impact of frequency of ritual participation on sense of community and social well-being of a minority community in India, the Sikhs. We looked at a unique ritualistic practice of the Sikhs, seva. Rituals are known to contribute toward social solidarity and cohesion as well as physical and mental well-being. In particular for a minority community, rituals help group members establish and maintain strong community networks and a unique group identity. A total of 156 members of the Sikh community (85 males; 71 females) participated in the study. Frequency of ritual participation was positively related with social well-being and sense of community. Furthermore, sense of community was found to mediate the effect of frequency of ritual participation on social well-being. Results are discussed in the light of the importance of studying rituals in minority groups, the frequency of participation in a ritual activity and the importance of addressing social well-being in ritual research. PMID- 28577085 TI - Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy. AB - The endoplasmic reticulum (ER) stress is a cellular process that occurs as a consequence of several stress circumstances, such as the accumulation of unfolded proteins in the lumen of the ER or distinct insults that disturb the ER normal function. Different conditions in the tumor microenvironment (TME), including hypoxia, nutrient deprivation, and the elevated production of reactive oxygen and nitrogen species destabilize the loading and dispatching of the newly synthesized proteins, triggering ER stress in cancer cells and tumor-infiltrating leukocytes. In order to cope with TME-induced ER stress, tumor and stromal cells initiate an adaptive response process that aims to resolve ER stress and to restore cellular homeostasis, which is referred as the unfolded protein responses (UPR). Paradoxically, the UPR can also induce cell death under severe and/or permanent ER stress. The UPR is started through three mediators, the activation of the inositol-requiring enzyme-1alpha, the pancreatic ER kinase-like ER kinase, and the activating transcription factor 6. In this minireview, we will discuss the pro- and anti-tumorigenic role of the UPR in cancer cells. In addition, we will describe the effects of the TME-induced ER stress in the immunosuppressive activity of tumor-infiltrating myeloid cells. Also, we will review the results of emerging therapeutic interventions that target ER stress and the UPR mediators in cancer. We postulate that the inhibition of ER stress or the UPR-related elements could represent a significant approach to increase the efficacy of various forms of cancer immunotherapy. PMID- 28577088 TI - Role of ATP-Sensitive K+ Channels in Myocardial Infarct Size-Limiting Effect of Chronic Continuous Normobaric Hypoxia. AB - The role of KATP channels in myocardial infarct size-limiting effect of chronic continuous normobaric hypoxia was examined in a rat model based on a 20-min coronary occlusion and subsequent 3-h reperfusion. Rats were adapted to normobaric hypoxia (12% O2) for 21 days. This hypoxia produced a pronounced infarct size-limiting effect, which had been prevented by 0.3 mg/kg glibenclamide, a non-selective inhibitor of entire pool of KATP channels, or 5 mg/kg 5-hydroxydecanoate, an inhibitor of mitochondrial KATP channels. The study highlighted the important role of mitochondrial KATP channels in myocardial infarct size-limiting effect of chronic normobaric hypoxia. PMID- 28577089 TI - Effects of Bone Marrow Multipotent Mesenchymal Stromal Cells and Their Secretory Products on Microcirculation in the Broad Ligament of the Uterus of Wistar Rats during Experimental Chronic Genital Inflammation. AB - Effects of bone marrow multipotent mesenchymal stromal cells and their secretory products released into the conditioned medium on microcirculatory bed in the broad ligament of the uterus were studied in Wistar rats with chronic genital inflammation. Opposite changes in the parameters of microcirculation and lymphatic drainage in the broad ligament of the uterus were observed after administration of cells and conditioned medium via different routes, which should be taken into account during the treatment of inflammatory and degenerative processes in the pelvic organs. PMID- 28577090 TI - Circulating Proteasomes in the Pathogenesis of Head and Neck Squamous Cell Carcinoma. AB - Increased proteasome activity was revealed in blood serum of patients with stage T1N0M0 head and neck squamous cell carcinoma in comparison with patients with chronic diseases of the larynx and laryngopharynx. This opens prospects of using chymotrypsin-like activity measurement for differential diagnosis of squamous cell carcinoma, screening for high-risk groups, and evaluation of the degree of tumor differentiation. PMID- 28577091 TI - Characteristics of 4-Day Infradian Biorhythms in Mature Male Wistar Rats after Pinealectomy. AB - We studied the effect of pinealectomy on the parameters of 4-day infradian biorhythms in mature male Wistar rats. It was shown that pinealectomy did not change the period and phase of infradian biorhythm of total locomotor activity, serum concentrations corticosterone and testosterone, and mitotic index of esophageal epithelium. No significant changes in the number of nucleated cells in the spleen of pinealectomized animals in comparison with intact animals were found. The amplitude of biorhythms of locomotor activity and corticosterone and testosterone concentrations did not significantly change in pinealectomized animals. Despite the important role of the epiphysis in the regulation of circadian biorhythms in mammals, this organ is not the main synchronizer of infradian biorhythms of glucocorticoid and sex hormones in male Wistar rats. PMID- 28577092 TI - Response of the Hypothalamic-Pituitary-Adrenal System to Repeated Moderate Psychoemotional Stress Exposure Is Associated with Behavioral Parameters. AB - Individual features of the response of the hypothalamic-pituitary-adrenal axis (HPAA) to repeated moderate stress exposure (daily 2-h restraint stress for 10 days) was studied in young female rhesus monkeys with healthy normal behavior and combined group of female rhesus monkeys with abnormal depression-like and anxious behavior. No between-group differences in the response of ACTH and cortisol were found on day 1. On day 10, a rapid and less pronounced increase in ACTH secretion was observed in all animals in comparison with day 1. Analysis of between-group differences in HPAA response showed higher increase in ACTH level and lower increase in cortisol concentration in animals with depression-like and anxious behavior. These changes were similar to the previously described differences in the response of the adenohypophysis and adrenal cortex to acute restraint stress in old monkeys with similar behavior. Thus, individuals with depression-like and anxious behavior demonstrate impaired stress-induced reactivity of HPAA as early as in young age. PMID- 28577093 TI - Structure of Rat Lungs after Administration of Magnetomicelles Based on the Carbon-Coated Iron Nanoparticles. AB - We studied the effects of single administration of a suspension of magnetomicelles based on carbon-coated iron nanoparticles on the structure of rat lungs within 40 days. Histological analysis revealed a complex of hemodynamic alterations in the lungs. Described changes persisted in the lung stroma from day 1 until day 40, but their intensity decreased by the end of the experiment. Using immunohistochemical Perls reaction we identified cells morphologically corresponding to alveolar and interstitial lung macrophages. The number of Perls+ cells decreased by day 40 of the experiment. Ultrastructural analysis showed endocytosis of modified iron nanoparticles and their accumulation in intracellular digestionorganelles (endo- and lysosomes) of mononuclear phagocyte system cells. Accumulation of magnetomicelles in the lungs was not associated with damage to pneumocytes, macrophages, and blood-air barrier. PMID- 28577094 TI - Local and Systemic Functional Responses of Mouse Macrophages to Intravaginal Infection with Type 2 Herpes Simplex Virus and Vaccination. AB - Activity of cathepsin D and phagocytosis of macrophages from vaginal lavage fluid, peritoneal exudation, and spleen were studied in mice of sensitive (DBA/2) and resistant (BALB/c) lines after intravaginal infection with type 2 herpes simplex virus and vaccination. Activity of cathepsin D and intensity of phagocytosis (irrespective of the macrophage source) and their ratio in BALB/c mice in early terms after infection were close to the control levels taken as a unit. In DBA/2 mice, these parameters and their balance were shifted and changes in cathepsin D activity depended on the time after challenge. Activities of cellular and extracellular cathepsin D increased sharply on day 1 postinfection under conditions of local virus interaction with the vaginal mucosa and activation of the pathological process. Later, after generalization of the infection, activity of cathepsin D decreased, while phagocytosis increased in all the studied macrophage populations. Vaccination corrected the cathepsin D/phagocytosis imbalance and created conditions for rapid elimination of the virus. PMID- 28577095 TI - Initial Stages of Angiogenesis after Acute Experimental Local Venous Outflow Disturbances and Application of Cell Technologies. AB - The initial stages of angiogenesis in rats after transcutaneous injection of autologous bone marrow multipotent mesenchymal stromal cells transfected with GFP gene and stained cell membranes in the projection of ligated femoral vein were studied by fluorescent light and confocal laser microscopy. Large clusters of brightly fluorescing elongated fibroblast-like cells were seen in the paravasal tissue and in the postoperative scar and signs of angiogenesis were noted as soon as in 4 days. The injected cells not only formed new vessels, but also integrated into vessels formed by host cells. Some injected cells were phagocytizied by macrophages and the latter started to fluoresce due to the presence of the membrane dye. These macrophages within the specified period appeared in the regional inguinal lymph nodes where they formed clusters in the lymphoid parenchyma of the cortical substance. PMID- 28577097 TI - Influence of ACTG4-7-PGP (Semax) on Morphofunctional State of Hepatocytes in Chronic Emotional and Painful Stress. AB - We studied the effect of intraperitoneal administration of peptide ACTG4-7-PGP to male Wistar rats in doses of 5, 50, 150, and 450 MUg/kg on the morphofunctional state of hepatocytes in chronic emotional and painful stress. A dose-dependent stress-limiting effect of the peptide was observed: it normalized the protein synthesis function of the liver and serum activity of ALT. The anticytolytic effect of the peptide increased with increasing its dose against the background of the increase in the relative number of multinucleated and multinucleolated cells and deceleration of the recovery of serum protein concentration. The decrease of hepatocyte cytolysis against the background of more intense morphological signs of protein synthesis processes attests to activation of reparative processes in the liver parenchyma via enhanced constitutional synthesis of protein. PMID- 28577096 TI - Association of Polymorphism in SCN5A, GJA5, and KCNN3 Gene with Sudden Cardiac Death. AB - We studied association of single-nucleotide SCN5A (rs1805124), GJA5 (rs35594137), and KCNN3 (rs13376333) polymorphisms and sudden cardiac death. Humans died suddenly from cardiac causes (N=379) and unrelated sex- and age-matched control subjects were genotyped. No significant intergroup differences were found in the frequency of rs1805124 and rs13376333 genotypes and alleles. In women under 50 years, enhanced risk of sudden cardiac death was associated with rs35594137 GG genotype (OR=3.6; 95%CI=1.2-10.4; p=0.022), while in older women it was associated with rs35594137 AA genotype (OR=3.0; 95%CI=2.3-3.9; p=0.041). In women under 50 years, GA rs35594137 genotype was associated with a protective effect against sudden cardiac death (OR=0.3; 95%CI=0.1-0.8; p=0.036). Thus, GJA5 gene rs35594137 polymorphism is significantly associated with sudden cardiac death in the examined group. PMID- 28577098 TI - Effect of Cytokines on the Formation Tube-Like Structures by Endothelial Cells in the Presence of Trophoblast Cells. AB - Despite ample data on cytokine secretion in the uteroplacental interface, the influence of microenvironment cells, in particular, trophoblast cells on angiogenesis and the role of cytokines in this process remain poorly studied. We studied the influence of cytokines on the formation of tube-like structures by endothelial cells in the presence of trophoblast cells and showed that trophoblast cells suppressed the angiogenic potential of endothelial cells. Antiangiogenic cytokines IFN-gamma, IL-10, TNF-alpha, and TGFbeta via modulation of trophoblast cells stimulated the formation of tube-like structures by endothelial cells. In the co-culture of endothelial and trophoblast cells, the effects of cytokines changed and they gained additional regulatory functions. PMID- 28577099 TI - Toxic Effects of Nanostructured Silicon Dioxide on Multipotent Mesenchymal Stromal Cells. AB - We studied the effect of nanostructured silicon dioxide particles on functional activity and ultrastructure of rat multipotent mesenchymal stem cells. A dose dependent decrease in cell adhesion to plastics and their proliferative potential, accumulation of apoptotic cells, a decrease in the electron density of cell cytoplasm due to swelling and degenerative changes of organelles, and intracellular accumulation of nanostructured of silicon dioxide particles were observed. PMID- 28577100 TI - The Content of Multipotent Stromal Cells in 3-4.5-Month Heterotopic Bone Marrow Transplants of CBA Mice Subjected to a Single Exposure to Osteogenic Stimuli (Curettage, BMP-2) or Antigens (S. typhimurium antigenic complex, LPS). AB - At the early stages of development (3 months), transplants from bone marrow donors subjected to single in vivo stimulation (curettage, administration of BMP 2 or antigenic complex of S. typhimurium) 1 day before transplantation were characterized by significantly elevated content of nucleated cells (by 1.4, 1.9 and 2.9 times, respectively), efficiency of cloning of multipotent stromal cells (by 3.8, 3.8 and 7.2 times), and total number of multipotent stromal cells (by 5, 7 and 21 times) and osteogenic multipotent stromal cells (by 5, 9 and 15 times) in comparison with the control (intact donors); more rapid increase in the weight of bone capsules was also noted. At later terms, the difference by these parameters between the control and experimental groups became less pronounced, but even in 4.5 months, the total number of multipotent stromal cells in the transplant in experimental groups exceeded the control values by 1.4-1.7 times and osteogenic multipotent stromal cells by 2 times. In donors exposed to the specified stimulations, the content of multipotent stromal cells in the femoral bone marrow in 1 day increased by 2.1 times (curettage), 2.6 times (administration of S. typhimurium antigens), and 3.3 times (LPS); administration of BMP-2 reduced this value by 50%. The content of osteogenic bone marrow multipotent stromal cells at this term increased by 1.7 times (BMP-2) and 5.5 times (curettage), after administration of S. typhimurium antigens, this parameter corresponded to the control. The concentration of osteogenic multipotent stromal cells in the bone marrow of intact donors was 22%; the maximum values were observed after curettage (57%) and BMP-2 administration (74%) and minimum after treatment with S. typhimurium antigens (8%). However, this parameter in all groups of transplants little differed and leveled as soon as by 3-4 months, which can be due to regulatory influences of the recipient body. The initial advantage in the content of bone marrow multipotent stromal cells in donors exposed to osteogenic stimuli and administration of antigens ensured considerably more rapid growth of the transplants in comparison with the control. These results can be useful for the development of optimal protocols of tissue grafting. PMID- 28577101 TI - High Potassium Concentration during Culturing of Early Mammalian Embryos: Normal or Extreme Situation? AB - Analysis of the element composition of oviduct and uterine fluid in mammals showed high potassium concentrations in the early embryo microenvironment in vivo. The results of early embryogenesis of mammals in vitro in the presence of high potassium concentrations are discussed. The data are summarized in accordance with the conditions of experimentally modeled pre-implantation development. Comparative assessment of the quality of embryo development until the blastocyst stage in vitro proved the embryos more successfully developed at potassium concentrations close to those registered in the oviductal fluid. PMID- 28577102 TI - Dihydroquercetin Improves Microvascularization and Microcirculation in the Brain Cortex of SHR Rats during the Development of Arterial Hypertension. AB - The effects of dihydroquercetin (50 mg/kg intragastrically daily for 6 weeks) on the density of capillary network (mean number of capillaries per mm2), mean capillary diameter, structure of capillary network, capillary diameter distribution (<3, 3-5, 5-7, and 7-9 MU), and local cerebral blood flow (by laser Doppler) in the visual cortex were studied in SHR rats during the development of arterial hypertension (from the 6th to the 12th week of life). Normally, the systolic and diastolic BP progressively increased in SHR rats during this period. Dihydroquercetin did not affect the development of arterial hypertension. At the same time, the drug significantly increased the mean diameter of capillaries (by 11%), capillary network density (by 23%), and in the percentage of capillaries with a diameter of 3-9 MU (passable for erythrocytes; by 42%). Positive effects of dihydroquercetin on the structure of microcirculatory bed improved microcirculation: local cerebral blood flow in the visual cortex of SHR rats was significantly higher (by 36%) than in rats receiving no flavonoid and close to the value in Wistar-Kyoto rats. Dihydroquercetin improved microvascularization and microcirculation in the cerebral cortex of SHR rats during the formation of arterial hypertension. PMID- 28577103 TI - Neuromotor Activity, Anxiety and Cognitive Function in the In Vivo Model of Alimentary Hyperlipidemia and Obesity. AB - Behavioral indicators characterizing specific features of the pathological process of alimentary-dependent diseases were studied using in vivo model of alimentary hyperlipidemia in rats and mice. Rats and mice of the control groups received balanced semisynthetic diet for 63 days; animals of the experimental groups received a diet with high fat content (30% dry weight), balanced or high fat diet with fructose solution instead of water, balanced cholesterol-enriched diet (0.5% dry weight), or balanced cholesterol-enriched diet with fructose solution. During the experiment, the mass of food, consumed by the animals, was monitored daily. Muscle tone was assessed by the front paw grip strength on days 33 and 54 of the experiment. Anxiety was tested in the elevated plus maze on days 36 and 57. Behavior and memory were assessed by conditioned passive avoidance reflex on days 39, 40, and 61. A significant increase in muscle tone was revealed on day 54 in rats fed with a balanced diet with fructose, and in mice, that received a similar diet, supplemented with fructose and cholesterol. Anxiety in the second test (day 57) was significantly decreased in rats fed high-fat diet and increased in mice fed high fat diet and high fat diet with fructose. In the second test, additional amount of cholesterol in the diet was the factor that significantly improved both short-term and long-term memory in both species. In mice, in contrast to rats, addition of fructose, including combination with high fat diet, significantly worsened short-term and long-term memory. Thus, dietary factors, contributing to alimentary dyslipidemia development in rats and mice, can significantly affect the indices of neuromotor activity, anxiety level and cognitive functions, and the nature and direction of these changes are largely species-specific. PMID- 28577104 TI - Level of Interleukins IL-6 and IL-15 in Blood Plasma of Mice after Forced Swimming Test. AB - We measured the concentrations of IL-6 and IL-15 in blood plasma of mice at different terms after forced swimming, taking into account exercise intensity and preliminary training. It was shown that training was an important factor affecting blood plasma level of IL both at rest and after single forced swimming: in trained animals, the concentration of both myokines increased immediately after swimming, while in untrained animals, this increase was observed only after 5 h. Changes in cytokine production against the background of training can be associated with various factors, including neuroendocrine mechanisms, stress, modification of intracellular signaling, as well as reorganization of transcriptional mechanisms in muscle fibers. The most important factor is shift in the ratio of monovalent cations (sodium and potassium) in the cytoplasm. PMID- 28577106 TI - Effect of Stimulation of Neurotransmitter Systems on Heart Rate Variability and beta-Adrenergic Responsiveness of Erythrocytes in Outbred Rats. AB - We studied heart rate variability and beta-adrenergic responsiveness of erythrocytes and changes in these parameters in response to single administration of beta-adrenoblocker propranolol (2 mg/kg) in outbred male rats against the background of activation of the noradrenergic, serotonergic, and dopaminergic neurotransmitter systems achieved by 4-fold injections maprotiline (10 mg/kg), 5 hydroxytryptophan (50 mg/kg) combined with fluoxetine (3 mg/kg), and L-DOPA (20 mg/kg) with amantadine (20 mg/kg), respectively. Stimulation of the noradrenergic system moderately enhanced the heart rhythm rigidity and beta-adrenergic responsiveness of erythrocytes. In addition, it markedly augmented the moderating effect of subsequently administered propranolol on LF and VLF components in the heart rate variability and reversed the effect of propranolol on beta-adrenergic responsiveness of erythrocytes. Stimulation of the serotonergic system dramatically decreased all components in the heart rate variability and pronouncedly enhanced beta-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol slightly restored all components in the heart rate variability and decreased beta-adrenergic responsiveness of erythrocytes to the control level. Stimulation of the dopaminergic system made the heart rate more rigid due to decrease of all components in the heart rate variability; in addition, it slightly but significantly enhanced beta-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol produced no significant effects on all components in the heart rate variability and on beta-adrenergic responsiveness of erythrocytes. Stimulation of noradrenergic, serotonergic, and dopaminergic neurotransmitter systems produced unidirectional and consorted effects on heart rate variability and beta-adrenergic responsiveness of erythrocytes, although the magnitudes of these effects were different. Probably, the changes in the heart rate variability in rats with stimulated neurotransmitter systems results from modification of the cellular sensitivity in peripheral organs to adrenergic influences. However, the differences in the reactions to beta-adrenoblocker attest to specificity of the mechanisms underlying the changes in membrane reception and adrenergic pathways in every experimental model employed in this study. PMID- 28577105 TI - Effect of Atorvastatin Therapy on the Level of CD34+CD133+CD309+ Endothelial Progenitor Cells in Patients with Coronary Heart Disease. AB - In 58 patients with coronary heart disease, the count of CD34+CD133+CD309+ endothelial progenitor cells in the blood was determined and the dynamics of the content of endothelial progenitor cells, angiogenic growth factors, and lipid parameters over 3 months of atorvastatin therapy was analyzed. Atorvastatin was administered in daily doses of 10 mg (26 patients) and 40 mg (32 patients). Control group comprised 15 healthy volunteers. In patients with coronary heart disease, the count of endothelial progenitor cells was lower by 4 times, the level of VEGF was higher by 52%, and the level of endostatin was lower by 13% than in healthy volunteers. Atorvastatin therapy significantly reduced the levels of VEGF (by 11%), C-reactive protein (by 26%), total cholesterol (by 30%), LDL cholesterol (by 35%), and triglycerides (by 18%); the levels of endostatin, MCP 1, and HDL cholesterol remained unchanged. The count of endothelial progenitor cells increased significantly by 72% irrespectively on the statin dose, but the changes were more pronounced in patients with lower initial endothelial progenitor cell counts and in patients with more drastic decrease in LDL cholesterol. PMID- 28577107 TI - Interaction of Constitutive Nitric Oxide Synthases with Cyclooxygenases in Regulation of Bicarbonate Secretion in the Gastric Mucosa. AB - Neuronal NO synthase blocker 7-nitroindazole suppressed bicarbonate secretion in rat gastric mucosa induced by mild local irritation with 1 M NaCl (pH 2.0). Non selective blocker of neuronal and endothelial synthases, Nomega-nitro-L-arginine (L-NNA), did not affect HCO3- production, but inhibited secretion after pretreatment with omeprazole. Non-selective cyclooxygenase blocker indomethacin inhibited HCO3- production under conditions of normal synthase activity and in the presence of L-NNA, but was ineffective when co-administered with 7 nitroindazole. It was concluded that neuronal and endothelial synthases are involved in different mechanisms of regulation of HCO3- secretion in the gastric mucosa induced by mild irritation. Activation of neuronal synthase stimulated HCO3- production, which is mediated mainly through activation of cyclooxygenase. Theoretically, activation of endothelial synthase should suppress HCO3- production. The effect of endothelial synthase depends on acid secretion in the stomach and bicarbonate concentration in the submucosa, as it was demonstrated in experiments with intravenous NaHCO3 infusion. PMID- 28577108 TI - [Intracranial hemorrhage secondary to vitamin K deficiency in an infant despite oral vitamin K prophylaxis : Also a challenge for the anesthesiologist]. AB - This article presents the case of a 6-week-old infant who, despite oral vitamin K prophylaxis and otherwise normal developmental progress, suffered a severe intracerebral and subdural hemorrhage, which required surgical evacuation. The interdisciplinary approach is described with emphasis on the management of hemostasis. Furthermore, the clinical picture of intracranial bleeding due to vitamin K deficiency, which is nowadays rare in the Western World, is described in the anesthesiology literature for the first time. The usual recommendations regarding prophylaxis as well as certain risk factors are presented. PMID- 28577110 TI - Daily chronomics of proteomic profile in aging and rotenone-induced Parkinson's disease model in male Wistar rat and its modulation by melatonin. AB - Aging is associated with changes in several basic parameters of circadian timing system (CTS) in mammals leading to circadian dysfunction. We had reported earlier that upon aging and in rotenone induced Parkinson's disease (RIPD) rat model there were significant alterations in the core clock genes expression levels and daily pulses. To identify biomarkers of aging and PD chronomics of proteomic day night profiles in suprachiasmatic nucleus (SCN), pineal and substantia nigra (SN) in 3 month (m), 12, 24 m and RIPD rat model were studied at two time points i.e. Zeitgeber Time (ZT)-6 (mid-day) and ZT-18 (mid-night). Proteome analysis was done by using two dimensional (2-D) electrophoresis and the spots showing robust day night variations were identified by using MALDI TOF/TOF analysis. In 3 m rats the number of proteins showing day-night variations were relatively more than 12, 24 m and RIPD rat model in SCN and SN. But in pineal there was increase in number of protein spots showing day-night variations in 24 m. Mass spectroscopy of the protein spots showing robust day night variation in aging and RIPD rats were identified. As melatonin, a multitasking molecule, an endogenous synchronizer of rhythm, an antioxidant and an antiaging drug, declines with aging, the effects of melatonin administration on differential alterations in chronomics of 2-D protein profiles in aging and RIPD male Wistar rats were studied. We report here that the melatonin could be playing an important role in modulating the chronomics of 2-D protein profiles. Additionally, various proteins were identified for the first time in this study showing significant day night variation in SCN, pineal and SN may prove useful towards targeting novel treatments for circadian dysfunction, good health and longevity. PMID- 28577109 TI - Phosgene-induced acute lung injury (ALI): differences from chlorine-induced ALI and attempts to translate toxicology to clinical medicine. AB - BACKGROUND: Phosgene (carbonyl dichloride) gas is an indispensable chemical inter mediate used in numerous industrial processes. There is no clear consensus as to its time- and inhaled-dose-dependent etiopathologies and associated preventive or therapeutic treatment strategies. METHODS: Cardiopulmonary function was examined in rats exposed by inhalation to the alveolar irritant phosgene or to the airway irritant chlorine during and following exposure. Terminal measurements focused on hematology, protein extravasation in bronchoalveolar lavage (BAL), and increased lung weight. Noninvasive diagnostic and prognostic endpoints in exhaled breath (carbon dioxide and nitric oxide) were used to detect the clinically occult stage of pulmonary edema. RESULTS: The first event observed in rats following high but sublethal acute exposure to phosgene was the stimulation of alveolar nociceptive vagal receptors. This afferent stimulation resulted in dramatic changes in cardiopulmonary functions, ventilation: perfusion imbalances, and progressive pulmonary edema and phospholipoproteinosis. Hematology revealed hemoconcentration to be an early marker of pulmonary edema and fibrin as a discriminating endpoint that was positive for the airway irritant chlorine and negative for the alveolar irritant phosgene. CONCLUSIONS: The application of each gas produced typical ALI/ARDS (acute lung injury/acute respiratory distress syndrome) characteristics. Phosgene-induced ALI showed evidence of persistent apnea periods, bradycardia, and shifts of vascular fluid from the peripheral to the pulmonary circulation. Carbon dioxide in expired gas was suggestive of increased ventilation dead space and appeared to be a harbinger of progressively developing lung edema. Treatment with the iNOS inhibitor aminoguanidine aerosol by inhalation reduced the severity of phosgene-induced ALI when applied at low dose-rates. Symptomatic treatment regimens were considered inferior to causal modes of treatment. PMID- 28577111 TI - Family Life and Social Medicine: Discourses and Discontents Surrounding Puebla's Psychiatric Care. AB - Drawing on clinical data from 15 months of on-site participant observation in the only public psychiatric hospital in the state of Puebla, Mexico, this article advances our understanding of globalization in relation to psychiatry. I challenge the construction of psychiatry as only treating the individual patient and provide grounded doctor-patient-family member interaction in a Mexican psychiatric clinic in order to review what happens when doctors cannot interact with patients as atomized individuals even though in theory they are trained to think of patients that way. Challenged by severe structural constraints and bolstered by lessons from other nations' efforts at deinstitutionalization, psychiatrists in Puebla push to keep patients out of the inpatient wards and in their respective communities. To this end, psychiatrists call upon co-present kin who are identified both as the customer and part of the caretaking system outside the clinic. This modification to the visit structure changes the dynamic and content of clinical visits while doctors seamlessly respond to unspoken beliefs and values that are central to local life, ultimately showing that efforts to define a "global psychiatry" informed by global policy will fail because it cannot exist in a uniform way-interpersonal interaction and personal experience matters. PMID- 28577112 TI - 3D-QSAR, molecular dynamics simulations, and molecular docking studies on pyridoaminotropanes and tetrahydroquinazoline as mTOR inhibitors. AB - Cancer is a second major disease after metabolic disorders where the number of cases of death is increasing gradually. Mammalian target of rapamycin (mTOR) is one of the most important targets for treatment of cancer, specifically for breast and lung cancer. In the present research work, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) studies were performed on 50 compounds reported as mTOR inhibitors. Three different alignment methods were used, and among them, distill method was found to be the best method. In CoMFA, leave-one-out cross-validated coefficients [Formula: see text], conventional coefficient [Formula: see text], and predicted correlation coefficient [Formula: see text] values were found to be 0.664, 0.992, and 0.652, respectively. CoMSIA study was performed in 25 different combinations of features, such as steric, electrostatic, hydrogen bond donor, hydrogen bond acceptor, and hydrophobic. From this, a combination of steric, electrostatic, hydrophobic (SEH), and a combination of steric, electrostatic, hydrophobic, donor, and acceptor (SEHDA) were found as best combinations. In CoMSIA (SEHDA), [Formula: see text], [Formula: see text] and [Formula: see text] were found to be 0.646, 0.977, and 0.682, respectively, while in the case of CoMSIA (SEH), the values were 0.739, 0.976, and 0.779, respectively. Contour maps were generated and validated by molecular dynamics simulation-assisted molecular docking study. Highest active compound 19, moderate active compound 15, and lowest active compound 42 were docked on mTOR protein to validate the results of our molecular docking study. The result of the molecular docking study of highest active compound 19 is in line with the outcomes generated by contour maps. Based on the features obtained through this study, six novel mTOR inhibitors were designed and docked. This study could be useful for designing novel molecules with increased anticancer activity. PMID- 28577113 TI - Support for Military Medical Students-One School's Experience. PMID- 28577114 TI - Building Beautiful Minds: Teaching Through Movies to Tackle Stigma in Psychology Students in the UAE. AB - OBJECTIVE: The use of movie-based educational interventions has been used widely and is considered an effective method aiming at changing the stigmatizing attitudes of future mental health professionals. The purpose of this study was to examine the effectiveness of a 10-week intervention that combined movies and related discussions in a sample of 26 psychology students in the United Arab Emirates, where the opportunities for real contact with patients with mental illness are limited. METHODS: By means of mixed methods approach, students were assessed at two time points by the Opening Minds Stigma Scale for Health Care Providers [OMS-HC] (T1-T2) and by qualitative questions only at the end of the intervention (T2). RESULTS: The results corroborated changes to some of the students' attitudes, namely agency, compassion, and proximity, but did not prove a general attitudinal change. Additionally, students acknowledged the benefit obtained by their participation with regard to their learning experience, pointing out the importance of combining theory with practical examples of mental illness for spreading awareness and tackling stigma. CONCLUSION: The results are discussed in the light of their importance for the United Arab Emirates educational context. PMID- 28577115 TI - The Psychiatry Major: A Curricular Innovation to Improve Undergraduate Psychiatry Education in China. AB - OBJECTIVE: In China, a psychiatry major curriculum (PMC) has been implemented in select medical schools to improve the quality of undergraduate psychiatry education (UPE). Our aim was to describe this PMC and compare it with UPE in the standard Chinese clinical medicine curriculum (CMC). We also benchmarked PMC to UPE programs in the Hong Kong Special Administrative Region of China and the United States of America (USA) to determine how well it met standards of well established programs and to highlight areas for improvement. METHODS: Based on archival information, relevant literature, and communication with key informants, we described PMC and CMC in a Chinese school with both curriculums. We then compared PMC to UPE curriculums in Hong Kong and the USA. RESULTS: PMC provides substantially more comprehensive exposure to psychiatry than CMC, with more preclinical experiences and psychiatry clerkship course hours, greater diversity of clinical sites, and exploration of subspecialties. PMC employs a variety of teaching methods and offers mentoring for students. PMC has similar UPE preclinical content and course hours as programs in Hong Kong and the USA. PMC also provides more clinical exposure than programs in Hong Kong or the USA, although there is less variety in clinical settings. CONCLUSION: We recommend implementation of concrete measures to improve UPE in Chinese medical schools, using the PMC curriculum as a model that has been successfully implemented in China. We also recommend improvements to PMC based on comparisons with existing programs outside Mainland China. PMID- 28577116 TI - The Community Value of Academic Psychiatry: The Development of a Psychiatry Residency Program in a Federally Qualified Health Center. PMID- 28577117 TI - Teaching Psychological Assessments to Forensic Psychiatry Fellows: A Practical Guide. PMID- 28577118 TI - Comparing and Contrasting the Use of Problem-Based Learning in Child and Adolescent Psychiatry Programs. AB - OBJECTIVE: Problem-based learning (PBL) is one of the core components of medical education. To facilitate the spread and use of PBL in child and adolescent psychiatry (CAP) fellowship training, a special interest study group (SISG) was formed at the American Academy of Child and Adolescent Psychiatry (AACAP). Different approaches to the implementation of PBL between programs represented at the SISG are compared in this report. METHODS: The authors distributed a survey to SISG participants after the 2015 annual AACAP meeting, which gathered information about the different approaches programs use to implement PBL in graduate medical education. RESULTS: Six CAP training programs responded to the survey, providing descriptions of the structure and content of PBL seminars. Programs chose to include a wide variety of topics in PBL courses and approach course organization in a number of ways. To the degree that PBL draws from identified reference texts, programs were similar in selecting definitive textbooks, practice parameters, and seminal articles. CONCLUSIONS: This small pilot study is intended to provide a snapshot of the state of PBL implementation in CAP fellowship programs. It reflects that programs can incorporate PBL in a variety of ways, tailored to the needs of the institution. Future directions of research include assessment of resident satisfaction with PBL, impact on resident education, and identifying successful methods of implementation of PBL. PMID- 28577119 TI - Gene networks for total number born in pigs across divergent environments. AB - For reproductive traits such as total number born (TNB), variance due to different environments is highly relevant in animal breeding. In this study, we aimed to perform a gene-network analysis for TNB in pigs across different environments using genomic reaction norm models. Thus, based on relevant single nucleotide polymorphisms and linkage disequilibrium blocks across environments obtained from GWAS, different sets of candidate genes having biological roles linked to TNB were identified. Network analysis across environment levels resulted in gene interactions consistent with known mammal's fertility biology, captured relevant transcription factors for TNB biology and pointing out different sets of candidate genes for TNB in different environments. These findings may have important implication for animal production, as optimal breeding may vary depending on later environments. Based on these results, genomic diversity was identified and inferred across environments highlighting differential genetic control in each scenario. PMID- 28577121 TI - Recent Advances in Musculoskeletal Tissue Regeneration. PMID- 28577120 TI - Large-Scale Prediction of Drug-Target Interaction: a Data-Centric Review. AB - The prediction of drug-target interactions (DTIs) is of extraordinary significance to modern drug discovery in terms of suggesting new drug candidates and repositioning old drugs. Despite technological advances, large-scale experimental determination of DTIs is still expensive and laborious. Effective and low-cost computational alternatives remain in strong need. Meanwhile, open access resources have been rapidly growing with massive amount of bioactivity data becoming available, creating unprecedented opportunities for the development of novel in silico models for large-scale DTI prediction. In this work, we review the state-of-the-art computational approaches for identifying DTIs from a data centric perspective: what the underlying data are and how they are utilized in each study. We also summarize popular public data resources and online tools for DTI prediction. It is found that various types of data were employed including properties of chemical structures, drug therapeutic effects and side effects, drug-target binding, drug-drug interactions, bioactivity data of drug molecules across multiple biological targets, and drug-induced gene expressions. More often, the heterogeneous data were integrated to offer better performance. However, challenges remain such as handling data imbalance, incorporating negative samples and quantitative bioactivity data, as well as maintaining cross links among different data sources, which are essential for large-scale and automated information integration. PMID- 28577122 TI - Successful Treatment of Pulmonary Mucormycosis Caused by Cunninghamella bertholletiae with High-Dose Liposomal Amphotericin B (10 mg/kg/day) Followed by a Lobectomy in Cord Blood Transplant Recipients. AB - Infection caused by Cunninghamella bertholletiae carries one of the highest mortality rates among mucormycosis, and there are no reported cases that survived from the infection in allogeneic hematopoietic stem cell transplantation recipients occurring before neutrophil engraftment. Here, we present two cases of pulmonary mucormycosis caused by C. bertholletiae occurring before neutrophil engraftment after cord blood transplantation. Both were successfully treated with high-dose liposomal amphotericin B (10 mg/kg/day) combined with micafungin, which was then followed by neutrophil recovery, reduction in immunosuppressive agents, and a subsequent lobectomy. The intensive antifungal therapy immediately administered upon suspicion of mucormycosis greatly suppressed the infection in its early stage and was well tolerated despite its prolonged administration and simultaneous use of nephrotoxic agents after transplantation. Although the synergic effect of micafungin remains unclear, these cases highlight the importance of prompt administration of high-dose lipid polyene when suspecting mucormycosis in highly immunocompromised patients, which enables subsequent diagnostic and therapeutic interventions, resulting in a favorable outcome. PMID- 28577123 TI - Hepatic Disease with Portal Hypertension and Acute Juvenile Paracoccidioidomycosis: A Report of Two Cases and Literature Review. AB - Paracoccidioidomycosis (PCM) is a neglected systemic mycosis endemic to Latin America caused by dimorphic fungi of the genus Paracoccidioides. The acute juvenile PCM is a severe type of presentation that usually affects young vulnerable patients and rarely progresses to portal hypertension. Here, two cases of liver disease and portal hypertension as complications of acute juvenile PCM are reported. Diagnosis of PCM was performed by isolation of the fungus and molecular identification of the strains provided through partial sequencing of two protein encoding genes, arf and gp43. Genotypic analysis revealed that Paracoccidioides brasiliensis S1 was the phylogenic species involved in both cases. Patients presented a good clinical response to amphotericin B and sulfamethoxazole-trimethoprim. These results highlight the importance of the interdisciplinary approach in patients with severe forms of PCM to avoid and treat complications, and the necessity of further investigations focusing on host pathogen interaction in order to explain the broad clinical spectrum in PCM as well as the severity and poor outcome in some clinical cases. PMID- 28577125 TI - Preparation of Nano- and Microstructures For Drug Delivery. PMID- 28577124 TI - Association mapping to discover significant marker-trait associations for resistance against fusarium wilt variant 2 in pigeonpea [Cajanus cajan (L.) Millspaugh] using SSR markers. AB - Pigeonpea production is severely constrained by wilt disease caused by Fusarium udum. In the current study, we discover the putative genomic regions that control resistance response to variant 2 of fusarium wilt using association mapping approach. The association panel comprised of 89 diverse pigeonpea genotypes including seven varieties, three landraces and 79 germplasm lines. The panel was screened rigorously for 3 consecutive years (2013-14, 2014-15 and 2015-2016) against variant 2 in a wilt-sick field. A total of 65 pigeonpea specific hypervariable SSR markers (HASSRs) were screened representing seven linkage groups and 29 scaffolds of the pigeonpea genome. A total of 181 alleles were detected, with average values of gene diversity and polymorphism information content (PIC) of 0.55 and 0.47, respectively. Further analysis using model based (STRUCTURE) and distance based (clustering) approaches separated the entire pigeonpea collection into two distinct subgroups (K = 2). The marker trait associations (MTAs) were established based on three-year wilt incidence data and SSR dataset using a unified mixed linear model. Consequently, six SSR markers were identified, which were significantly associated with wilt resistance and explained up to 6% phenotypic variance (PV) across the years. Among these SSRs, HASSR18 was found to be the most stable and significant, accounting for 5-6% PV across the years. To the best of our knowledge, this is the first report of identification of favourable alleles for resistance to variant 2 of Fusarium udum in pigeonpea using association mapping. The SSR markers identified here will greatly facilitate marker assisted resistance breeding against fusarium wilt in pigeonpea. PMID- 28577126 TI - Nanoencapsulation Improves Scavenging Capacity and Decreases Cytotoxicity of Silibinin and Pomegranate Oil Association. AB - Silibinin (SB) and pomegranate oil (PO) present therapeutic potential due to antioxidant activity, but the biological performance of both bioactives is limited by their low aqueous solubility. To overcome this issue, the aim of the present investigation was to develop nanocapsule suspensions with PO as oil core for SB encapsulation, as well as assess their toxicity in vitro and radical scavenging activity. The nanocapsule suspensions were prepared by interfacial deposition of preformed polymer method. SB-loaded PO-based nanocapsules (SBNC) showed an average diameter of 157 +/- 3 nm, homogenous size distribution, zeta potential of -14.1 +/- 1.7 mV, pH of 5.6 +/- 0.4 and SB content close to 100%. Similar results were obtained for the unloaded formulation (PONC). The nanocapsules controlled SB release at least 10 times as compared with free SB in methanolic solution. The SBNC scavenging capacity in vitro was statistically higher than free SB (p < 0.05). Cell viability in monocytes and lymphocytes was kept around 100% in the treatments with SBNC and PONC, while the SB and the PO caused a decrease around 30% at 50 MUM (SB) and 724 MUg/mL (PO). Protein carbonyls and DNA damage were minimized by SB and PO nanoencapsulation. Lipid peroxidation occurred in nanocapsule treatments regardless of the SB presence, which may be attributed to PO acting as substrate in reaction. The free compounds also caused lipid peroxidation. The results show that SBNC and PONC presented adequate physicochemical characteristics and low toxicity against human blood cells. Thereby, this novel nanocarrier may be a promising formulation for therapeutic applications. PMID- 28577128 TI - Letter to the editor. PMID- 28577127 TI - Utility of intraoperative nerve monitoring in thyroid surgery: 20-year experience with 1418 cases. AB - PURPOSE: The efficacy of intraoperative nerve monitoring is controversial in the literature. This study of a single surgeon's experience seeks to determine if the use of intraoperative nerve monitoring influences recurrent laryngeal nerve injury during thyroid surgery. METHODS: Six hundred fifty-seven patients with normal pre-operative vocal fold function underwent thyroid surgery without the use of intraoperative nerve monitoring from September 1997 to January 2007, while 761 patients underwent thyroid surgery from February 2007 to February 2016 with routine use of nerve monitoring. Patients were followed for a minimum of 6 months after surgery, and postoperative nerve function was determined by fiberoptic laryngoscopy. A Fisher test was used to determine if nerve injury was statistically different between both groups. RESULTS: In patients operated on without nerve monitoring, 21 patients were found to have postoperative vocal fold paralysis with nine regaining functioning. In patients operated on with nerve monitoring, 27 were found to have vocal fold dysfunction with 17 regaining function. Fisher test analysis, both with and without patients regaining function, showed no difference in nerve injury between groups (p > 0.05, p > 0.05). CONCLUSION: Intraoperative monitoring during thyroidectomy may not prevent injury to the recurrent laryngeal nerve. PMID- 28577129 TI - Effects of Mild to Severe Hepatic Impairment on the Pharmacokinetics of Sonidegib: A Multicenter, Open-Label, Parallel-Group Study. AB - BACKGROUND AND OBJECTIVE: Sonidegib is a potent, selective and orally bioavailable inhibitor of the Hedgehog signaling pathway, primarily metabolized by the liver. In order to make dose recommendations for patients with hepatic impairment, we have assessed here the pharmacokinetics (PKs) and safety of sonidegib in subjects with varying degrees of hepatic function. METHODS: The primary objective of this phase I, multicenter, open-label study was to evaluate the PKs of a single oral 800 mg dose of sonidegib in subjects with impaired hepatic function compared with healthy subjects. PK parameters (e.g. area under the concentration-time curve from time zero to infinity [AUCinf], area under the concentration-time curve from time zero to the last measurable concentration [AUClast], maximum concentration [C max], apparent clearance [CL/F], and terminal half-life [t 1/2]) for parent drug and the metabolite were compared with the normal group, as the reference. Metabolite ratio, unbound PK parameters, and the relationship between specific PK parameters and liver function parameters were assessed. RESULTS: In total, 33 subjects entered the study and received sonidegib. Plasma concentrations peaked at approximately 2-3 h in all groups after dosing. Compared with the normal group, AUClast decreased by 35 and 23% and increased by 14% in the mild, severe, and moderate hepatic impairment groups, respectively. The C max values were lower in all groups with respect to the normal group (decreases of 20, 21 and 60% in the mild, moderate and severe hepatic impairment groups, respectively). Protein binding was independent of hepatic function, and similar trends in the PK parameters were observed for unbound sonidegib and the metabolite. Protein binding was similar across all groups. Weak to no correlation between specific PK and hepatic function parameters was found. CONCLUSIONS: Overall, sonidegib exposures were similar or decreased in the hepatic impairment groups compared with the normal group, and sonidegib was generally well-tolerated in all subjects. Dose adjustment is not considered necessary for subjects with mild, moderate, or severe hepatic impairment. PMID- 28577130 TI - Gemcitabine/Cisplatin Treatment Induces Concomitant SERTAD1, CDKN2B and GADD45A Modulation and Cellular Changes in Bladder Cancer Cells Regardless of the Site of TP53 Mutation. AB - Simultaneous use of cisplatin (CIS) and gemcitabine (GEN) for treating bladder cancer has increased because of their complementary effects. However, the molecular mechanisms underlying the activities of these two antineoplastic drugs are not fully known. Here, molecular biology techniques and microscopy were used to investigate transcriptomic and morphological changes in low and high-grade urinary bladder transitional carcinoma cell lines [RT4 - wild type TP53; 5637 - two TP53 mutations, one in codon 72 (Arg-Pro) and other in codon 280 (Arg-Thr) and T24 - in-frame deletion of tyrosine 126 in the TP53 allele] simultaneously treated with CIS/GEN. Gene expression profile was evaluated by PCR arrays; cell morphology by scanning and transmission electron microscopy, and apoptosis was analyzed using fluorescent dye. Results showed concomitantly upregulation of CDKN2B (G1/S transition), GADD45A (DNA repair and apoptosis) and SERTAD1 (regulation of transcription) gene, increased number of nuclear chamfers and apoptotic cells, and reduced number of microfilaments, organelles and in the size of the nucleus in 5637 and T24 cells after simultaneous treatment with CIS/GEN. In conclusion, independently of the TP53 mutation status and tumor grade, CIS/GEN induced gene modulation accompanied by changes in cell morphologies, which confirm the antiproliferative activity of the treatment protocol. These findings help to understand the pathways modulated by these antineoplastic agents and may provide insights for anti-cancer chemotherapy. PMID- 28577131 TI - Deep Learning for Brain MRI Segmentation: State of the Art and Future Directions. AB - Quantitative analysis of brain MRI is routine for many neurological diseases and conditions and relies on accurate segmentation of structures of interest. Deep learning-based segmentation approaches for brain MRI are gaining interest due to their self-learning and generalization ability over large amounts of data. As the deep learning architectures are becoming more mature, they gradually outperform previous state-of-the-art classical machine learning algorithms. This review aims to provide an overview of current deep learning-based segmentation approaches for quantitative brain MRI. First we review the current deep learning architectures used for segmentation of anatomical brain structures and brain lesions. Next, the performance, speed, and properties of deep learning approaches are summarized and discussed. Finally, we provide a critical assessment of the current state and identify likely future developments and trends. PMID- 28577132 TI - Tangeretin inhibits neurodegeneration and attenuates inflammatory responses and behavioural deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinson's disease dementia in rats. AB - Our aim was to investigate whether tangeretin, a citrus flavonoid, was able to prevent neuroinflammation and improve dementia in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced rodent model of Parkinson's disease (PD). MPTP HCl was infused into the substantia nigra pars compacta of male Sprague-Dawley rats. Tangeretin (50, 100 or 200 mg/kg body weight) was administered orally starting 3 days prior to MPTP injection and was continued for 20 days following injection. MPTP-lesioned rats revealed motor dysfunction in bar test and rota rod tests. Deficits in working memory and object recognition function were also observed following MPTP induction. Tangeretin treatment significantly attenuated the memory deficits and improved motor functions and cognition. Immunohistochemical analysis reveals the protective effects of tangeretin against MPTP lesion-induced dopaminergic degeneration and hippocampal neuronal loss. Tangeretin reduced expression of inflammatory mediators-COX-2, iNOS-as well reduced the levels of cytokines-interleukins (IL)-IL-1beta, IL-6 and IL-2. The experimental data suggest tangeretin as an effective candidate drug with potential for prevention and treatment of neuroinflammation and dementia associated with PD. PMID- 28577133 TI - Protective effect of gallic acid in experimental model of ketamine-induced psychosis: possible behaviour, biochemical, neurochemical and cellular alterations. AB - Gallic acid has been reported to possess a number of psychopharmacological activities. These activities are attributed to the antioxidant potential due to the presence of phenolic moeity. The present study was carried out to investigate the protective effects of gallic acid in an experimental model of ketamine induced psychosis in mice. Ketamine (50 mg/kg, i.p.) was used to induce stereotyped psychotic behavioural symptoms in mice. Behavioural studies (locomotor activity, stereotype behaviour, immobility duration and memory retention) were carried out to investigate the protective of gallic acid on ketamine-induced psychotic symptoms, followed by biochemical and neurochemical changes and cellular alterations in the brain. Chronic treatment with gallic acid for 15 consecutive days significantly attenuated stereotyped behavioural symptoms in mice. Biochemical estimations revealed that gallic acid reduced the lipid peroxidation and restored the total brain proteins. Furthermore, gallic acid remarkably reduced the dopamine levels, AChE activity and inflammatory surge (serum TNF-alpha), and increased the levels of GABA and increased glutathione in mice. The study revealed that gallic acid could ameliorate psychotic symptoms and biochemical changes in mice, indicating protective effects in psychosis. PMID- 28577134 TI - Role of Oxidative Stress in the Suppression of Immune Responses in Peripheral Blood Mononuclear Cells Exposed to Combustible Tobacco Product Preparation. AB - Cigarette smoking is a major risk factor for several human diseases. Chronic inflammation, resulting from increased oxidative stress, has been suggested as a mechanism that contributes to the increased susceptibility of smokers to cancer and microbial infections. We have previously shown that whole-smoke conditioned medium (WS-CM) and total particulate matter (TPM) prepared from Kentucky 3R4F reference cigarettes [collectively called as combustible tobacco product preparations (TPPs)] potently suppressed agonist-stimulated cytokine secretion and target cell killing in peripheral blood mononuclear cells (PBMCs). Here we have investigated the role of oxidative stress from TPPs, which alters inflammatory responses in vitro. Particularly, we investigated the mechanisms of WS-CM-induced suppression of select cytokine secretions in Toll-like receptor (TLR) agonist-stimulated cells and target cell killing by effector cells in PBMCs. Pretreatment with N-acetyl cysteine (NAC), a precursor of reduced glutathione and an established anti-oxidant, protected against DNA damage and cytotoxicity caused by exposure to WS-CM. Similarly, secretion of tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 in response to TLR-4 stimulation was restored by pretreatment with NAC. Target cell killing, a functional measure of cytolytic cells in PBMCs, is suppressed by WS-CM. Pretreatment with NAC restored the target cell killing in WS-CM treated PBMCs. This was accompanied by higher perforin levels in the effector cell populations. Collectively, these data suggest that reducing oxidative stress caused by cigarette smoke components restores select immune responses in this ex vivo model. PMID- 28577135 TI - A Review of Adjunctive CNS Medications Used for the Treatment of Post-Surgical Pain. AB - Inadequate post-operative pain management can have significant impacts on patients' quality of life. Effective management of acute pain after surgery is important for early mobilization and discharge from hospital, patient satisfaction, and overall well-being. Utilizing multimodal analgesic strategies has become the mainstay of acute post-operative pain management. A comprehensive search was performed, assessing the published or otherwise publically available literature on different central nervous system (CNS) drugs [excluding opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and acetaminophen] and their uses to treat acute post-surgical pain. Included among the drugs evaluated in this review are anticonvulsants, N-methyl-D-aspartic acid (NMDA) agonists, local anesthetics, alpha2-agonists, cannabinoids, serotonin-noradrenaline reuptake inhibitors (SNRIs), and serotonin-noradrenaline-dopamine reuptake inhibitors (SNDRIs). Timing, dosing, routes of administration, as well as mechanisms of action are discussed for these CNS drugs. PMID- 28577136 TI - Genome-wide gene expression profiling reveals that CD274 is up-regulated new onset type 1 diabetes mellitus. AB - AIMS: Early studies have identified type 1 diabetes mellitus (T1DM) as a disease that is caused by the autoimmune destruction of the insulin-producing pancreatic beta-cells. Genetics, environment and the immune pathogenesis of T1DM are three major pillars of T1DM research. We try to understand the changes in the gene expression profile during the pathogenesis of T1DM. METHODS: We performed a systematic search in the Gene Expression Omnibus (GEO) database for microarray studies of T1DM with samples taken at or before the T1DM onset. RESULTS: The results of an integrated analysis of different GEO datasets and a comparison of the gene expression level in T1DM samples taken at the time of appearance of the islet autoantibodies, 1 year before T1DM onset, and at the time of T1DM onset showed that CD274, which encodes PD-L1, was up-regulated in the newly onset T1DM samples. CD274 had a stable expression level in the control samples but showed a gradual up-regulation from the appearance of autoantibodies to the onset of T1DM. CONCLUSIONS: These results indicate that CD274 up-regulation in T1DM is correlated with disease pathogenesis. PD-L1 might play a protective role in preventing the pancreatic islets from autoimmune destruction, which may help researchers find strategies for preventing the destruction process of pancreas beta-cells in T1DM. PMID- 28577137 TI - Ischemic index changes in diabetic retinopathy after intravitreal dexamethasone implant using ultra-widefield fluorescein angiography: a pilot study. AB - AIMS: To investigate the effect of dexamethasone intravitreal implant on peripheral ischemia in patients affected by diabetic macular edema (DME). METHODS: Patients with treatment-naive diabetic retinopathy (DR) undergoing intravitreal dexamethasone implant for DME between October 2015 and March 2017 were enrolled. Patients underwent a comprehensive ocular examination at baseline (<2 weeks before treatment) and 10 +/- 2 weeks after dexamethasone implant including best-corrected visual acuity (BCVA), intraocular pressure, optical coherence tomography, ultra-widefield (UWF) retinography and UWF fluorescein angiography (UWFA). RESULTS: Nine eyes of seven consecutive patients (five males; mean age 66.4 +/- 6.7 years) were enrolled. Mean duration of DR was 12.3 +/- 8.4 years. Mean interval between UWFA acquisitions was 12.1 +/- 2.1 weeks, and the mean interval between intravitreal injection and UWFA acquisition was 11.0 +/- 1.6 weeks. Mean pre- and post-injection BCVA was 0.30 +/- 0.20 and 0.21 +/- 0.14 logMAR (p = 0.06), respectively. Mean pre- and post-injection central macular thickness was 449.8 +/- 92.5 and 356.3 +/- 52.4 MUm (p = 0.03), respectively. Mean pre- and post-injection ischemic index was 24.0 +/- 25.0 and 9.8 +/- 12.1% (p = 0.0427), respectively. CONCLUSIONS: Intravitreal dexamethasone implant reduces peripheral retina ischemia in patients with DR. PMID- 28577138 TI - Elevated 1-h post-challenge plasma glucose levels in subjects with normal glucose tolerance or impaired glucose tolerance are associated with whole blood viscosity. AB - AIM: It has been suggested that glucose levels >=155 mg/dl at 1-h during an oral glucose tolerance test (OGTT) may predict development of type 2 diabetes and cardiovascular events among adults with normal glucose tolerance (NGT 1 h-high). Studies showed a link between increased blood viscosity and type 2 diabetes. However, whether blood viscosity is associated with dysglycemic conditions such as NGT 1 h-high, impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) is unsettled. METHODS: 1723 non-diabetic adults underwent biochemical evaluation and OGTT. A validated formula based on hematocrit and total plasma proteins was employed to estimate whole blood viscosity. Subjects were categorized into NGT with 1 h glucose <155 mg/dL (NGT-1 h-low), NGT-1 h-high, IFG and/or IGT. RESULTS: Hematocrit and blood viscosity values appeared significantly higher in individuals with NGT 1 h-high, IFG and/or IGT as compared to NGT 1 h low subjects. Blood viscosity was significantly correlated with age, waist circumference, blood pressure, HbA1c, fasting, 1- and 2-h post-challenge insulin levels, total cholesterol and low-density lipoprotein, triglycerides, fibrinogen, white blood cell, and inversely correlated with high-density lipoprotein and insulin sensitivity. Of the four glycemic parameters, 1-h post-challenge glucose showed the strongest correlation with blood viscosity (beta = 0.158, P < 0.0001) in a multivariate regression analysis model including several atherosclerosis risk factors. CONCLUSIONS: Our results demonstrate a positive relationship between blood viscosity and 1-h post-challenge plasma glucose. They also suggest that a subgroup of NGT individuals with 1-h post-challenge plasma >155 mg/dl have increased blood viscosity comparable to that observed in subjects with IFG and/or IGT. PMID- 28577139 TI - Temporal comparison of global inventories of CO2 emissions from biomass burning during 2002-2011 derived from remotely sensed data. AB - Biomass burning is a large important source of greenhouse gases and atmospheric aerosols, and can contribute greatly to the temporal variations of CO2 emissions at regional and global scales. In this study, we compared four globally gridded CO2 emission inventories from biomass burning during the period of 2002-2011, highlighting the similarities and differences in seasonality and interannual variability of the CO2 emissions both at regional and global scales. The four datasets included Global Fire Emissions Database 4s with small fires (GFED4s), Global Fire Assimilation System 1.0 (GFAS1.0), Fire INventory from NCAR 1.0 (FINN1.0), and Global Inventory for Chemistry-Climate studies-GFED4s (G-G). The results showed that in general, the four inventories presented consistent temporal trend but with large differences as well. Globally, CO2 emissions of GFED4s, GFAS1.0, and G-G all peaked in August with the exception in FINN1.0, which recorded another peak in annual March. The interannual trend of all datasets displayed an overall decrease in CO2 emissions during 2002-2011, except for the inconsistent FINN1.0, which showed a tendency to increase during the considered period. Meanwhile, GFED4s and GFAS1.0 noted consistent agreement from 2002 to 2011 at both global (R 2 > 0.8) and continental levels (R 2 > 0.7). FINN1.0 was found to have the poorest temporal correlations with the other three inventories globally (R 2 < 0.6). The lower estimation in savanna CO2 emissions and higher calculation in cropland CO2 emissions by FINN1.0 from 2002 to 2011 was the primary reason for the temporal differences of the four inventories. Besides, the contributions of the three land covers (forest, savanna, and cropland) on CO2 emissions in each region varied greatly within the year (>80%) but showed small variations through the years (<40%). PMID- 28577140 TI - Malondialdehyde concentrations in the intestine and gills of Vardar chub (Squalius vardarensis Karaman) as indicator of lipid peroxidation. AB - A lipid peroxidation product, malondialdehyde (MDA), was studied in Vardar chub (Squalius vardarensis Karaman) as an indicator of oxidative stress, using native fish from three rivers in northern Macedonia: the mining-impacted Zletovska and Kriva rivers and the agriculturally impacted Bregalnica River. MDA concentrations were measured in the intestine in the spring and autumn of 2012 and in the gills in autumn. The aims of the study were to establish the type of contamination which provokes a more pronounced MDA increase, as well as the organ which more reliably reflects the occurrence of oxidative stress. MDA levels in the intestine in spring amounted to 3.29-155.8 nmol g-1 and in autumn to 4.85-111.1 nmol g-1, whereas MDA concentrations in the gills in autumn were 7.69-147.5 nmol g-1. Stronger influence of organic contamination on development of oxidative stress was observed in both organs, as seen from higher median MDA concentrations in autumn in fish from the highly pesticide-contaminated Bregalnica River (gills 78.4 nmol g-1; intestine 23.5 nmol g-1) compared to the highly metal-contaminated Zletovska River (gills 15.9 nmol g-1; intestine 17.4 nmol g-1). The response of the gills to contamination was twice stronger than that of the intestine. The majority of fish from the pesticide-polluted river had increased MDA in the gills, in contrast to only sporadically increased MDA in the intestine. Our results indicated that development of oxidative stress strongly depends on the selected fish organ and that the gills seem to be a better choice for monitoring oxidative stress than the intestine, due to their continuous and direct exposure to polluted river water. PMID- 28577141 TI - Detection of typhoid fever by diatom-based optical biosensor. AB - Surface-modified diatom substrates are employed for the development of immunocomplex-based optical biosensor for diagnosis of typhoid. Biosensor has been prepared by covalent immobilization of Salmonella typhi antibody onto the crosslinked diatom substrates via glutaraldehyde. Photoluminescent (PL) studies revealed good specificity and ability of conjugated diatom substrates to distinguish complementary (S. typhi) and non-complementary (Escherichia coli) antigens. The immunocomplexed biosensor showed detection limit of 10 pg. The excellent performance of biosensor is associated to its large surface-to-volume ratio, good photoluminescent property, and biocompatibility of diatom frustules, which enhances the antibody immobilization and facilitates the nucleophilic electron transfer between antibody and conjugated diatom surface. Hence, immunocomplexed diatom substrates are considered to be a suitable platform for the environmental monitoring of water-borne pathogen S. typhi. PMID- 28577142 TI - Acute toxic effect of sewage effluent on the early life phase of an estuarine crab Scylla serrata. AB - The biological quality of secondary treated sewage effluent was evaluated using a toolbox approach, which combined a larval developmental bioassay and measurement of fecal indicator organisms. The zoea developmental toxicity of Scylla serrata from stage I to stage II was determined by exposing to a range of secondary treated sewage concentrations. Results indicated that the relative progress of zoea stage I to zoea stage II negatively correlated with increasing sewage concentrations. Data was analyzed statistically to determine lethal, median lethal, sublethal, low observed effect, and no observed effect concentrations. Water samples collected along the Buckingham canal discharge zone were also analyzed for its toxicity to the larval development. Fecal indicator organisms chosen to determine the water quality were E. coli, enterococci, C. perfrigens, and F+ coliphages. Concentrations of these fecal markers were determined in the raw influent, primary treated effluent, secondary treated effluent, and in four discharge zone sites. Data showed that this biological toolbox is helpful for providing baseline information on the effectiveness of the wastewater treatment and environmental health of the discharge zone. PMID- 28577143 TI - Spectroscopic and molecular characterization of humic substances (HS) from soils and sediments in a watershed: comparative study of HS chemical fractions and the origins. AB - Optical properties and molecular composition of humic substances (HS) can provide valuable information on the sources and the history of the associated biogeochemical processes. In this study, many well-known spectral and molecular characteristics were examined in eight different HS samples, which were extracted from soils and sediments located in a forested watershed, via two advanced tools including fluorescence excitation emission matrix-parallel factor analysis (EEM PARAFAC) and high-resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Two humic-like (C1 and C2) and one protein-like (C3) components were identified from EEM-PARAFAC. Irrespective of the origins, humic acid (HA) fractions were distinguished from fulvic acid (FA) fractions by the HS characteristics of specific UV absorbance (SUVA), the number of formulas, maximum fluorescence intensities of C1 and C2, condensed aromatics, tannins, and CHON, CHOS, and CHONS classes. In contrast, only five HS indices, including C3 intensity, H%, modified aromatic index (AImod), the percentages of carbohydrates, and unsaturated hydrocarbons, were found to be significant factors in discriminating between the two HS origins (i.e., soils and sediments). The ordination of the Bray-Curtis dissimilarity matrix further confirmed that the HS chemical fraction (i.e., HA or FA) was the more important factor to determine the measured HS characteristics than the HS origin. Our results provided an in-depth insight into the chemical and structural heterogeneity of bulk HS, which could be even beyond the differences observed along the two HS origins. This study also delivers a cautious message that the two operationally defined HS chemical fractions should be carefully considered in tracking the origins of different HS samples. PMID- 28577145 TI - The pesticide chlordecone is trapped in the tortuous mesoporosity of allophane clays. AB - Some volcanic soils like andosols contain short-range order nanoclays (allophane) which build aggregates with a tortuous and fractal microstructure. The aim of the work was to study the influence of the microstructure and mesoporosity of the allophane aggregates on the pesticide chlordecone retention in soils. Our study shows that the allophane microstructure favors pollutants accumulation and sequestration in soils. We put forth the importance of the mesoporous microstructure of the allophane aggregates for pollutant trapping in andosols. We show that the soil contamination increases with the allophane content but also with the mesopore volume, the tortuosity, and the size of the fractal aggregate. Moreover, the pore structure of the allophane aggregates at nanoscale favors the pesticide retention. The fractal and tortuous aggregates of nanoparticles play the role of nanolabyrinths. It is suggested that chlordecone storage in allophanic soils could be the result of the low transport properties (permeability and diffusion) in the allophane aggregates. The poor accessibility to the pesticide trapped in the mesopore of allophane aggregates could explain the lower pollutant release in the environment. PMID- 28577144 TI - Resource recovery of food waste through continuous thermophilic in-vessel composting. AB - In the Kingdom of Saudi Arabia (KSA) and Gulf region, a very small amount of municipal solid waste (MSW) is treated for compost production. The produced compost through traditional methods of compost piles and trenches does not coincide with the international standards of compost quality. Therefore, in this study, a continuous thermophilic composting (CTC) method is introduced as a novel and efficient technique for treating food waste into a quality compost in a short period of time. The quality of the compost was examined by degradation rates of organic matter (OM), changes in total carbon (TC), ash contents, pH, dynamics in ammonium nitrogen (NH4-N) and nitrate nitrogen (NO3-N), and nitrification index (NI). The results showed that thermophilic treatment at 60 degrees C increased the pH of the substrate and promoted degradation and mineralization process. After 30 days of composting, the degree of OM degradation was increased by 43.26 and 19.66%, NH4-N by 65.22 and 25.23%, and NO3-N by 44.76 and 40.05% as compared to runs treated at 25 and 40 degrees C, respectively. The stability of the compost was attained after 30 to 45 days with quality better than the compost that was stabilized after 60 days of the experiment under mesophilic treatment (25 degrees C). The final compost also showed stability at room temperature, confirming the rapid degradation and maturation of food waste after thermophilic treatment. Moreover, the quality of produced compost is in line with the compost quality standard of United States (US), California, Germany, and Austria. Hence, CTC can be implemented as a novel method for rapid decomposition of food waste into a stable organic fertilizer in the given hot climatic conditions of KSA and other Gulf countries with a total net saving of around US $70.72 million per year. PMID- 28577146 TI - Historical and future emission of hazardous air pollutants (HAPs) from gas-fired combustion in Beijing, China. AB - The consumption of natural gas in Beijing has increased in the past decade due to energy structure adjustments and air pollution abatement. In this study, an integrated emission inventory of hazardous air pollutants (HAPs) emitted from gas fired combustion in Beijing was developed for the period from 2000 to 2014 using a technology-based approach. Future emission trends were projected through 2030 based on current energy-related and emission control policies. We found that emissions of primary HAPs exhibited an increasing trend with the rapid increase in natural gas consumption. Our estimates indicated that the total emissions of NO X , particulate matter (PM)10, PM2.5, CO, VOCs, SO2, black carbon, Pb, Cd, Hg, As, Cr, Cu, Ni, Zn, polychlorinated dibenzo-p-dioxins and dibenzofurans, and benzo[a]pyrene from gas-fired combustion in Beijing were approximately 22,422 t, 1042 t, 781 t, 19,097 t, 653 t, 82 t, 19 t, 0.6 kg, 0.1 kg, 43 kg, 52 kg, 0.3 kg, 0.03 kg, 4.3 kg, 0.6 kg, 216 MUg, and 242 g, respectively, in 2014. To mitigate the associated air pollution and health risks caused by gas-fired combustion, stricter emission standards must be established. Additionally, combustion optimization and flue gas purification system could be used for lowering NO X emissions from gas-fired combustion, and gas-fired facilities should be continuously monitored based on emission limits. Graphical abstract Spatial distribution and typical live photos of gas-fired boiler in Beijing. PMID- 28577147 TI - Enhancement of sorption capacity of cocoa shell biomass modified with non-thermal plasma for removal of both cationic and anionic dyes from aqueous solution. AB - Removal of cationic dye, Azur II, and anionic dye, Reactive Red 2 (RR-2) from aqueous solutions, has been successfully achieved by using a modified agricultural biomaterial waste: cocoa shell husk (Theobroma cacao) treated by gliding arc plasma (CPHP). The biomass in its natural form CPHN and modified form CPHP was characterized by infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and point of zero charge (pHpzc). Experimental variables such as initial pH, contact time, and temperature were optimized for adsorptive characteristics of CPHN and CPHP. The results show that the removal of the Azur II dye was favorable in the basic pH region (pH 10) while the Reactive Red 2 dye was favorable in the acidic pH region (pH 2). The minimum equilibrium time for Azur II and RR-2 dye was obtained after 40 and 240 min, respectively. The adsorption kinetics and isotherm data obtained were best described by a pseudo-second-order kinetic rate model and a combination of Langmuir-Freundlich isotherm models. This work indicates that the plasma-treated raw materials are good alternative multi-purpose sorbents for the removal of many coexisting pollutants from aqueous solutions. PMID- 28577148 TI - Assessing energy efficiencies, economy, and global warming potential (GWP) effects of major crop production systems in Iran: a case study in East Azerbaijan province. AB - Efficient use of energy in farming systems is one of the most important implications for decreasing greenhouse gas (GHG) emissions and mitigating global warming (GW). This paper describes the energy use patterns, analyze the economics, and report global warming potential effects of major crop production systems in East Azerbaijan province, Iran. For this purpose, 110 farmers whose main activity was major crop production in the region, including wheat, barley, carrot, tomato, onion, potato, alfalfa, corn silage, canola, and saffron, were surveyed. Some other data was obtained from the Ministry of Agriculture Jihad of Iran. Results showed that, in terms of total energy input, onion (87,556 Mj ha-1) and potato (80,869 Mj ha-1) production systems were more energy-intensive than other crops. Among the studied crops, the highest values of net return (6563.8 $ ha-1) and benefit/cost ratio (1.95) were related to carrot and corn silage production systems, respectively. Studies have also shown that onion and saffron production systems emit the highest (5332.6 kg CO2eq ha-1) and lowest (646.24 kg CO2eq ha-1) CO2 eq. emission, respectively. When it was averaged across crops, diesel fuel accounted for the greatest GHG contribution with 43% of the total, followed by electric power (28%) and nitrogen fertilizer (21%). In the present study, eco-efficiency was calculated as a ratio of the gross production value and global warming potential effect for the studied crops. Out of all the studied crops, the highest values of eco-efficiency were calculated to be 8.65 $ kg CO2eq 1 for the saffron production system followed by the carrot (3.65 $ kg CO2eq-1) production. Generally, from the aspect of energy balance and use efficiency, the alfalfa production system was the best; however, from an economical point of view, the carrot production system was better than the other crops. PMID- 28577149 TI - An unusual case of neck pain in Hashimoto's thyroiditis. PMID- 28577150 TI - Yogurt consumption, body composition, and metabolic health in the Quebec Family Study. AB - PURPOSE: The aim was to compare the anthropometric and metabolic profiles and lifestyle behaviours of yogurt consumers and non-consumers and to determine if the observed differences persisted after adjustment for diet quality and related variables. METHODS: Using cross-sectional and follow-up data from the Quebec Family Study, men and women were classified into yogurt consumers (n = 269; 96 men and 173 women) and non-consumers (n = 570; 279 men and 291 women), and their anthropometric measurements, metabolic profiles, and lifestyle factors were compared. RESULTS: Men yogurt consumers had a lower body weight, BMI, % body fat, waist circumference and lower plasma insulin, and C-peptide concentrations in response to oral glucose, while women yogurt consumers had lower waist circumference, BMI, % body fat, plasma glucose, insulin, and C-peptide compared with non-consumers (P < 0.05). After adjustment for the Nutrient-Rich Foods (NRF) index, a marker of diet quality, these differences persisted in men and only for glycemic variables in women. Additional adjustment for physical activity participation and % body fat did not abolish the significant differences observed between yogurt consumers and non-consumers for plasma glucose, insulin, and C peptide responses to oral glucose in women only (P < 0.05). Analyses of data after a 6-year follow-up reinforced these observations, since both men and women yogurt consumers maintained a better metabolic profile compared with non consumers after adjustments for age and NRF (P < 0.05). In addition, an interaction between group and time for % body fat in men suggests a benefit of yogurt consumption over time on body composition. CONCLUSION: Yogurt consumption is associated with body composition and metabolic health benefits that are not entirely explained by a global effect of diet quality. PMID- 28577151 TI - Haemoglobin monitoring in endometrial cancer patients undergoing radiotherapy. AB - PURPOSE: To evaluate the level of anaemia monitoring and to determine the prevalence of anaemia in patients with endometrial carcinoma (EC) undergoing postoperative pelvic radiotherapy (RT). METHODS: We evaluated 233 consecutive patients diagnosed with EC receiving RT in our institution between January 2011 and December 2015. One hundred and fifty-two patients (65.2%) received a combination of external beam radiotherapy (EBRT) and high dose rate brachytherapy (HDR-BT) (mean dose 53.4 Gy, range 21-75), and 71 patients (30.5%) were exclusively treated with HDR-BT (mean dose 10.2 Gy, range 7-20). Blood test results with haemoglobin (Hb) levels were collected at three specific time points were: pre-RT (Hb1), during RT (Hb2) and post-RT (Hb3). Anaemia was defined as Hb <12 g/dL. RESULTS: Anaemia was detected in 54% of patients (67 patients) in the pre-RT analysis. Only 53.7% (n = 36) of the patients with anaemia detected pre-RT underwent subsequent Hb controls (during or post-RT). Blood tests were performed in 124 patients (53.20%) pre-RT, in 51 (17.59%) during RT and in 90 patients (38.62%) post-RT. Significant differences were observed between the mean Hb levels at Hb1-Hb3 (p = 0.001) and Hb2-Hb3 (p = 0.004). Patients with a pre-RT Hb level <12 g/dL presented a worse overall survival (OS) (p = 0.021, chi 2 5.3) with a mean OS of 53.39 months (range 45.5-61.3) vs. 61.4 (range 58.4-64.4) in patients with Hb >=12 g/dL. CONCLUSION: Although the presence of anaemia is frequent in patients with EC (53.2% of patients affected at cancer diagnosis) and influences the OS, Hb monitoring in patients receiving RT remains suboptimal (no controls during RT in 46.3%). There is a strong need to pay attention to blood test prescription for all the patients during and after RT. PMID- 28577152 TI - Cost minimization analysis of treatment with intravenous or subcutaneous trastuzumab in patients with HER2-positive breast cancer in Spain. AB - PURPOSE: To describe healthcare professional (HCP) and patient time and related costs associated with trastuzumab intravenous infusion (IV) and trastuzumab subcutaneous (SC) formulations in patients with HER2-positive early breast cancer. METHODS: This prospective, observational time, and motion study in three Spanish centers was run as a substudy of the PrefHer trial. We recorded active HCP time for trastuzumab SC and IV-related tasks and calculated HCP time as the mean sum of task times over 154 administrations (80 IV, 74 SC). We calculated mean patient infusion chair time and treatment room time. Staff costs were calculated using fully loaded salary costs based on Spanish salaries (? 2012). RESULTS: The transition from trastuzumab IV to SC led to a 50% reduction in active HCP time [27.2 min (95% CI 21.8-32.6) vs. 13.2 min (95% CI 8.9-17.5) per cycle]. Time savings resulted from avoiding IV catheter installation and removal, line flushing, and drug reconstitution. SC administration led to a fivefold reduction (78-85%) in chair time and a fourfold reduction (59-81%) in patient treatment room time, resulting in 24 h free-up time in the total treatment course (18 cycles). Total estimated direct costs were ? 29,431.75 and ? 28,452.12 for IV and SC, respectively, a saving of ? 979.60 over a full treatment course. CONCLUSIONS: Trastuzumab SC provided substantial time savings for HCP and patients, and reduced staff costs vs. trastuzumab IV. Reducing the use of hospital facilities may result in further savings and improved quality of medical care. PMID- 28577154 TI - Association of endometrial hyperplasia and cancer with a history of gestational diabetes. AB - PURPOSE: Excess circulating insulin may contribute to endometrial cancer (EC) development; studies suggest increased risk of EC associated with type 2 diabetes. We investigated whether gestational diabetes is associated with increased risk of EC and its precursor, endometrial hyperplasia (EH). METHODS: We conducted a population-based, case-control study of women in Washington State. Cases were women with a hospital discharge record indicating the presence of EH/EC who could be linked to a prior delivery hospitalization or birth record from 1987 to 2013 (n = 593). Controls were randomly selected from remaining deliveries, frequency matched 10:1 on delivery year and maternal age at delivery (n = 5,743). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: After adjustment for race/ethnicity, maternal age at delivery, and delivery year, EH/EC was associated with a history of gestational diabetes (OR 1.73, 95% CI 1.27-2.35). This association was present for both EH and EC (OR 1.61, 95% CI 1.00-2.60 and OR 1.80, 95% CI 1.22-2.65, respectively). After adjustment for prepregnancy body mass index, the OR for EH/EC was attenuated and became statistically non-significant (OR 1.22, 95% CI 0.87-1.72), except in women <50 years old at the time of case ascertainment (OR 1.49, 95% CI 1.00-2.20). Associations were slightly stronger for EC than EH. CONCLUSIONS: We observed an association between EH/EC and a history of gestational diabetes specific to younger women. Future studies focusing on the relationships between gestational diabetes, obesity, and EC, including age at diagnosis, are warranted. PMID- 28577153 TI - Tumor infiltrating lymphocytes in acral lentiginous melanoma: a study of a large cohort of cases from Latin America. AB - PURPOSE: Acral lentiginous melanoma (ALM) is a poor prognosis subtype and is the most prevalent in non-Caucasian populations. The presence of tumor infiltrating lymphocytes (TILs) has been associated with poor prognosis in melanoma. A large cohort of ALM cases was studied to determine status of TIL and its association with outcome. METHODS: All patients with cutaneous melanoma presenting from 2005 to 2012 at Instituto Nacional de Enfermedades Neoplasicas in Peru were retrospectively identified. Clinicopathological information was obtained from the medical charts. A prospective evaluation of TIL was performed. Analysis of association between ALM and clinicopathological features including TIL as well as survival analysis compared the outcome of ALM to whole group and extremity NALM was performed. RESULTS: 537 ALM from a total of 824 cutaneous melanoma cases were studied. Older age (p = 0.022), higher Breslow (p = 0.008) and ulceration (p < 0.001) were found to be more frequent in ALM. Acral had worse overall survival (OS) compared with the whole group (p = 0.04). Clinical stage (CS) I-II patients had a median OS of 5.3 (95% CI 4.3-6.2) for ALM and 9.2 (95% CI 5.0-7.0) for extremity NALM (p = 0.016). Grade 0 (absence of TIL), I, II and III were found in 7.5, 34.5, 32.1, and 25.9%, respectively. Lower TIL grade was associated with larger tumor size (p = 0.003), higher Breslow (p = 0.001), higher Clark level (p = 0.007), higher CS (p = 0.002), extremity location (p = 0.048), histological subtype ALM (p = 0.024) and better OS (p = 0.001). CONCLUSIONS: ALM is highly prevalent in Peru and carries poor outcome. Lower TIL levels were associated with poor outcome and ALM. PMID- 28577156 TI - Recanalization of TIPSS via transsplenic puncture. AB - Transjugular intrahepatic portosystemic shunt (TIPSS) has important role in the management of Budd-Chiari syndrome (BCS). Stent dysfunction rate up to 80% at 2 years limits the use of TIPSS. Reintervention is required if shunt develops occlusion or stenosis. Different techniques have been reported for the catheterization of TIPSS in cases of an occluded stent. In those failing a standard transvenous approach, the Colapinto needle technique, a combined transvenous transhepatic approach or transplenic approaches have been described. Here, we report our experience in a challenging TIPSS recanalization using a transsplenic approach. PMID- 28577155 TI - RBM20, a potential target for treatment of cardiomyopathy via titin isoform switching. AB - Cardiomyopathy, also known as heart muscle disease, is an unfavorable condition leading to alterations in myocardial contraction and/or impaired ability of ventricular filling. The onset and development of cardiomyopathy have not currently been well defined. Titin is a giant multifunctional sarcomeric filament protein that provides passive stiffness to cardiomyocytes and has been implicated to play an important role in the origin and development of cardiomyopathy and heart failure. Titin-based passive stiffness can be mainly adjusted by isoform switching and post-translational modifications in the spring regions. Recently, genetic mutations of TTN have been identified that can also contribute to variable passive stiffness, though the detailed mechanisms remain unclear. In this review, we will discuss titin isoform switching as it relates to alternative splicing during development stages and differences between species and muscle types. We provide an update on the regulatory mechanisms of TTN splicing controlled by RBM20 and cover the roles of TTN splicing in adjusting the diastolic stiffness and systolic compliance of the healthy and the failing heart. Finally, this review attempts to provide future directions for RBM20 as a potential target for pharmacological intervention in cardiomyopathy and heart failure. PMID- 28577157 TI - Analysis of the incidence and risk factors of male urinary tract infection following urodynamic study. AB - The purpose of this study was to investigate the incidence and risk factors of male urinary tract infection (UTI) after urodynamic study (UDS). A total of 854 consecutive male patients, who underwent UDS at Peking Union Medical College Hospital from January 2010 to March 2016, were recruited in this study. Two to four weeks before the examination, urinalysis with bacterial culture was performed. Patients with negative results were selected for UDS. Immediately before the examination, urinalysis was repeated to rule out any preoperative UTI. Between 48 and 72 h after the exam, urine culture was performed again to determine the incidence of UTI. The incidence of UTI and patients' baseline characteristics, including age, medical history, urodynamic parameters, current diagnosis and pathogen type, were analyzed. Among the 854 patients undergoing UDS, urinary infection was found in 84 cases after the examination, the incidence was 9.83%. Comorbidity with diabetes, post void residual (PVR), volume of prostate (Vp), and two urodynamic parameters, maximal flow rate (Qmax) and average flow rate (Qav) were found to be the independent risk factors for UTI after UDS. The most common pathogens were Escherichia coli (54.76%) and Enterococcus faecalis (19.05%). The incidence of UTI after UDS in male patients was 9.83%. Patients who suffered from comorbidity of diabetes, high PVR, high Vp, low Qmax or Qav may need to be treated with prophylactic antibiotics to prevent postoperative UTI. PMID- 28577158 TI - Adherence to clinical practice guidelines for the management of Clostridium difficile infection in Japan: a multicenter retrospective study. AB - This study was conducted to investigate the adherence to clinical practice guidelines (CPGs) for Clostridium difficile infection (CDI). A retrospective multicenter observational study was conducted via chart review at four teaching hospitals in Japan from April 2012 through September 2013. CDI was diagnosed based on positive identification of CD toxin by enzyme immunoassay testing. CDI patients were divided into non-severe and severe groups according to the severity criteria of four published guidelines (SHEA/IDSA 2010, ACG 2013, ESCMID 2009, HPA/DH 2008). Three parameters were assessed in association with disease severity: adherence to treatment guidelines, prognosis, and relapse rate. In total, 170 patients were diagnosed with CDI (1.04 cases per 10,000 patient-days). The 30-day all-cause mortality and recurrence rates were 13% and 14%, respectively. CPGs adherence ranged from 52% to 70% in the non-severe group and from 8.5 to 23% in the severe group (P < 0.01). Among severe CDI patients, no significant difference in mortality or recurrence was found between the patients whose treatments adhered and did not adhere to the CPGs. CPGs adherence was low, especially for patients with severe CDI. Improved guideline adherence and more accurate definitions of severity based on prognosis are needed for appropriate CDI management. PMID- 28577159 TI - Biventricular thrombosis in biventricular stress(takotsubo)-cardiomyopathy. AB - Endo-ventricular thrombosis represents a possible clinical complication of stress(takotsubo)-cardiomyopathy (SC). Depressed ventricular systolic ventricular function, localized left ventricular (LV) dyskinesis, but also an increased pro thrombotic state induced by catecholamine surge may facilitate the occurrence of endovascular thrombosis in SC. SC, however, may also present as right ventricular (RV) dysfunction or even as biventricular ballooning. Ventricular thrombosis may therefore theoretically occur in either ventricles or both. We report the case of an 88-year old woman, with vascular dementia and depression, admitted for abdominal pain, diarrhea, and rectal bleeding. Unexpectedly, electrocardiogram showed induced QT-prolongation with diffuse negative T-waves, while echocardiogram severe LV dysfunction (ejection fraction 35%), but also RV dysfunction and biventricular thrombosis. The diagnosis was therefore biventricular SC complicated by biventricular thrombosis; LV recovered after 10 days. When SC presents with a biventricular involvement, a careful assessment of either ventricular cavities should be therefore recommended to exclude the presence of (bi)ventricular thrombosis. It remains unresolved whether biventricular SC may represent a condition at higher risk of ventricular thrombosis. PMID- 28577160 TI - Fascial reinforcement fixing the bronchi to the heart: its anatomy and clinical significance. AB - PURPOSE: The details of the mediastinal fascia have been scarcely described and the bronchopericardial membrane is the only known structure that is present between the bronchi and the pericardium. However, the anatomical description of this structure is unclear. This study aimed to investigate the fascial structures between the bronchi and the pericardium based on surgical findings. METHODS: The connective tissues in the mid-mediastinum were observed surgically when lung lobectomy, including mediastinal lymph node dissection for lung cancer, was performed at our institute from April 2011 to March 2016. RESULTS: In total, 96 lobectomies were performed in 94 patients. A firm fibrous structure connecting the tracheobronchus and the fibrous pericardium was observed. It fixes the central bronchi to the pericardium and is composed of three parts. The largest part exists in front of the carina, its appearance is membranous, and runs behind the pulmonary artery. The other parts run over the right pulmonary artery and diverge at its superior trunk. The location at which all these structures fuse to the pericardium is the venous part of the hilum cordis (VHC). CONCLUSIONS: The results showed that connections of the dense fibrous tissues existed between the tracheobronchus and VHC. The structure not only works as a ligament that fixes the bronchi to the mid-mediastinum, but also divides the mid-mediastinum into two compartments: the Barety and subcarinal spaces. The anatomy of the structure observed in this study differs from the previous description of the bronchopericardial membrane. PMID- 28577163 TI - Expanding the circle of care: Can children find a perioperative surgical home? PMID- 28577161 TI - Morphological and qualitative characteristics of the quadriceps muscle of community-dwelling older adults based on ultrasound imaging: classification using latent class analysis. AB - BACKGROUND: Muscle thickness and echo intensity measured using ultrasound imaging represent both increased muscle volume and connective tissue accumulation. In combination, these ultrasound measurements can be utilized for assessing sarcopenia in community-dwelling older adults. AIMS: This study aimed to determine whether morphological and qualitative characteristics classified by quadriceps muscle thickness and echo intensity measured using ultrasound are associated with muscle strength, physical function, and sarcopenia in community dwelling older adults. METHODS: Quadriceps muscle thickness and echo intensity were measured using ultrasound imaging in 1239 community-dwelling older adults. Latent class analyses were conducted to classify participants based on similarity in the subcutaneous fat thickness (FT), quadriceps muscle thickness (MT), subcutaneous fat echo intensity (FEI), and muscle echo intensity (MEI), which were assessed using ultrasound imaging. RESULTS AND DISCUSSION: Morphological and qualitative characteristics were classified into four types as follows: (A) normal, (B) sarcopenic obesity, (C) obesity, and (D) sarcopenia type. Knee extension strength was significantly greater in A than in B and D. FT and percent body fat were greater in C than in the other types. The correlation between the ultrasound measures and knee extension strength differed among the classification types. The classification types were significantly associated with sarcopenia prevalence. CONCLUSIONS: Classification of the morphological and qualitative characteristics obtained from ultrasound imaging may be useful for assessing sarcopenia in community-dwelling older adults. PMID- 28577164 TI - Internal jugular vein blood flow in the upright position during external compression and increased central venous pressure: an ultrasound study in healthy volunteers. AB - BACKGROUND: External compression of the jugular veins is an effective method to increase intracranial blood volume and brain stiffness in rats and healthy volunteers. It has been reported that, on assuming an upright posture, cerebral venous drainage is distributed away from the internal jugular veins (IJVs) to the cervical venous plexus, causing complete collapse of the IJV. If so, it is not clear why external IJV compression would increase intracranial blood volume, but the latter is frequently observed in neurosurgery in the sitting position. The aim of this study was to observe the effect of external IJV compression and the Valsalva maneuver on the change in IJV cross-sectional area and IJV flow in volunteers in the upright posture. METHODS: After Research Ethics Board approval, we used ultrasound to evaluate both IJV cross-sectional areas and peak velocities in ten healthy volunteers in the sitting position. With the volunteers breathing normally at rest, we applied the Valsalva maneuver along with circumferential supraclavicular compression of 15 mmHg. Imaging was performed at the level of the cricoid cartilage and at the most superior level under the mandible. The IJV flow was calculated using the product of Doppler velocity and IJV cross-sectional area. RESULTS: Flow was detected in both IJVs of all subjects. The median [interquartile range] cross-sectional area for the right IJV at the level of the cricoid was 0.04 [0.03-0.08] cm2 (baseline), with collar 0.4 [0.2-0.6] cm2 (P = 0.003 compared with baseline). There were no significant changes in the median blood flow. CONCLUSIONS: Compression of the internal jugular veins or an increase in intrathoracic pressure does not reduce venous drainage but actually may increase intracranial venous volume. PMID- 28577165 TI - Situational awareness: a tacit yet viable concept. PMID- 28577166 TI - 8th Asian Biological Inorganic Chemistry Conference. PMID- 28577169 TI - Anesthesia research in Japan: seeds of recovery and the role of the Journal of Anesthesia. PMID- 28577167 TI - Bacterial Rhizoplane Colonization Patterns of Buchloe dactyloides Growing in Metalliferous Mine Tailings Reflect Plant Status and Biogeochemical Conditions. AB - Plant establishment during phytostabilization of legacy mine tailings in semiarid regions is challenging due to low pH, low organic carbon, low nutrients, and high toxic metal(loid) concentrations. Plant-associated bacterial communities are particularly important under these harsh conditions because of their beneficial services to plants. We hypothesize that bacterial colonization profiles on rhizoplane surfaces reflect deterministic processes that are governed by plant health and the root environment. The aim of this study was to identify associations between bacterial colonization patterns on buffalo grass (Buchloe dactyloides) rhizoplanes and both plant status (leaf chlorophyll and plant cover) and substrate biogeochemistry (pH, electrical conductivity, total organic carbon, total nitrogen, and rhizosphere microbial community). Buffalo grass plants from mesocosm- and field-scale phytostabilization trials conducted with tailings from the Iron King Mine and Humboldt Smelter Superfund Site in Dewey-Humboldt, Arizona, were analyzed. These tailings are extremely acidic and have arsenic and lead concentrations of 2-4 g kg-1 substrate. Bacterial communities on rhizoplanes and in rhizosphere-associated substrate were characterized using fluorescence in situ hybridization and 16S rRNA gene amplicon sequencing, respectively. The results indicated that the metabolic status of rhizoplane bacterial colonizers is significantly related to plant health. Principal component analysis revealed that root-surface Alphaproteobacteria relative abundance was associated most strongly with substrate pH and Gammaproteobacteria relative abundance associated strongly with substrate pH and plant cover. These factors also affected the phylogenetic profiles of the associated rhizosphere communities. In summary, rhizoplane bacterial colonization patterns are plant specific and influenced by plant status and rhizosphere biogeochemical conditions. PMID- 28577168 TI - Behavioural effects of the neonicotinoid insecticide thiamethoxam on the predatory insect Platynus assimilis. AB - Little information is available regarding sublethal effects of neonicotinoids on insect predators, many of which perform important roles in ecosystem functioning and biocontrol. In this study, dose-dependent sublethal effects of a dietary administered neonicotinoid insecticide thiamethoxam on two basic behaviours, locomotion and feeding, were quantified in the carabid Platynus assimilis (Coleoptera, Carabidae) using automated video-tracking and weighing of consumed food, respectively. Acute toxicity tests showed that, when orally administered, the LD50 of thiamethoxam for P. assimilis beetles was 114.5 ng/g. Thiamethoxam at 108.1 ng/g caused a short-term locomotor hyperactivity within several hours of treatment. Next day after exposure to the insecticide, all the beetles were in a state of locomotor hypoactivity independent of the administered dose ranging from 1.1 to 108.1 ng/g. Reduction in clean food consumption rate (CFCR) is another altered behavioural endpoint of poisoned insect predators as first demonstrated in this study. On the first day of thiamethoxam administration, a remarkable reduction in feeding only occurred in beetles treated at 108.1 ng/g but on the next day, this negative effect appeared even at doses ten to a hundred-fold lower. Recovery from locomotion abnormalities and reduced feeding took several days. Both locomotor activity and CFCR are sensitive and valuable ecotoxicological biomarkers of carabids which should be taken into account in Integrated Pest Management programs where optimal combination of reduced insecticide use and biological control by predatory insects is crucial to achieve best results. PMID- 28577170 TI - Laparoscopic ventral mesh rectopexy for obstructive defecation syndrome: still the way to go? AB - Laparoscopic ventral mesh rectopexy (VMR) has become a popular surgical technique for treating women with full-thickness rectal prolapse with a low recurrence rate, as demonstrated by several studies. In addition, it is increasingly applied to female patients with obstructive defecation syndrome (ODS) caused by intussusception +/- rectocele. Functional improvement can be achieved in a high number of patients with ODS, but expectations need to be discussed carefully, as a few patients may not benefit at all. In particular, long-term data on functional outcome and complications following laparoscopic VMR for ODS are still lacking in the literature. Notably, laparoscopic VMR appears to be better than alternative operations for prolapse, intussusception, and rectocele in terms of efficacy, recurrence rates, and adverse effects, but there is a lack of evidence directly comparing techniques through randomized controlled trials; thus, its exact role stills needs to be defined in the future. PMID- 28577171 TI - A randomized, nonblinded extension study of single-incision versus transobturator midurethral sling in women with stress urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: Midurethral sling procedures are the first surgical option in women undergoing surgery for stress urinary incontinence (SUI). Single incision midurethral-slings (SIMS) were designed to provide similar efficacy to traditional midurethral slings but with reduced morbidity. In this international trial we compared the efficacy of a SIMS (MiniArc) and a transobturator standard midurethral sling (SMUS; Monarc) in the treatment of SUI in terms of subjective and objective cure rates and morbidity over a long-term follow-up. METHODS: This was a randomized controlled nonblinded extended trial with a follow-up period of 36 months. Women with symptomatic SUI were eligible. The primary outcome was subjective cure, defined as an improvement in the Patient Global Impression of Improvement (PGI-I) score. Secondary outcomes were objective cure (negative cough stress test), disease-specific quality of life, surgical parameters and morbidity. An intention to treat analysis was performed. Differences in dichotomous variables were tested using the chi-squared test. Differences in continuous variables were tested using Student's t test or the Mann-Whitney U test. We hypothesized that MiniArc would be noninferior to Monarc concerning subjective cure. RESULTS: We randomized 97 women to the MiniArc group and 96 to the Monarc group. The attrition rate was 23% in the MiniArc group and 22% in the Monarc group after 3 years. At 36 months, the subjective cure rates were 86% in the MiniArc group and 87% in the Monarc group (risk difference -0.6%, 95% CI -12 to 11%). The objective cure rates were 89% and 88%, respectively (risk difference 1.3%, 95% CI -9 to 11%). Both procedures were associated with low complication rates. CONCLUSIONS: After a follow-up of 36 months, MiniArc (SIMS) is non inferior to Monarc (SMUS) with respect to subjective and objective cure. PMID- 28577173 TI - Surgery for recurrent stress urinary incontinence: the views of surgeons and women. AB - INTRODUCTION AND HYPOTHESIS: The objectives were to explore the views of women with recurrent stress incontinence (SUI) with regard to treatment preferences and the acceptability of randomisation to a future trial, and to survey the views of UK specialists on treatment preferences and equipoise regarding different treatment alternatives. METHODS: An online survey of the British Society of Urogynaecology (BSUG) and British Society of Urological Surgeons (BAUS) was carried out. Qualitative semi-structured interviews with a purposive sample of surgeons and women suffering from recurrent SUI from three UK centres. RESULTS: Two hundred fifty-six survey replies were received (176 gynaecology; 80 urology). Comparing the treatments offered, urogynaecologists were more likely to offer pelvic floor exercises (p < 0.05), and repeat midurethral tape (MUT) (p < 0.001). From the Surgical Equipoise Scale (SES) responses, "no preference" was rarely the commonest response. Marked differences for several options existed; midurethral tape dominated responses whenever it appeared. Twenty-one clinicians were interviewed. Treatment preferences were complex, influenced by a range of factors (reason for failure, patient comorbidity, investigations, personal experience, training). A future trial was regarded as important. Eleven women were interviewed. Most had considered more than one option, but felt that decision making was more a process of elimination rather than a positive process. Randomisation to a study was regarded as unacceptable by most. CONCLUSIONS: No consensus exists among surgeons about preferred treatment options for recurrent SUI, and personal experience and training dominate decision-making. For patients, choices were usually based on an elimination of options, including that of a repeat failed procedure. This contrasts with surgeons, who mostly preferred a repeat MUT above other options. Any future comparative study will be challenging. PMID- 28577172 TI - Impact of surgeon experience on routine prolapse operations. AB - INTRODUCTION AND HYPOTHESIS: Surgical work encompasses important aspects of personal and manual skills. In major surgery, there is a positive correlation between surgical experience and results. For pelvic organ prolapse (POP), this relationship has to our knowledge never been examined. In any clinical practice, there is always a certain proportion of inexperienced surgeons. In Sweden, most prolapse surgeons have little experience in performing prolapse operations, 74% conducting the procedure once a month or less. Simultaneously, surgery for POP globally has failure rates of 25-30%. In other words, for most surgeons, the operation is a low-frequency procedure, and outcomes are unsatisfactory. The aim of this study was to clarify the acceptability of having a high proportion of low volume surgeons in the management of POP. METHODS: A group of 14,676 exclusively primary anterior or posterior repair patients was assessed. Data were analyzed by logistic regression and as a group analysis. RESULTS: Experienced surgeons had shorter operation times and hospital stays. Surgical experience did not affect surgical or patient-reported complication rates, organ damage, reoperation, rehospitalization, or patient satisfaction, nor did it improve patient-reported failure rates 1 year after surgery. Assistant experience, similarly, had no effect on the outcome of the operation. CONCLUSIONS: A management model for isolated anterior or posterior POP surgery that includes a high proportion of low volume surgeons does not have a negative impact on the quality or outcome of anterior or posterior colporrhaphy. Consequently, the high recurrence rate was not due to insufficient experience of the surgeons performing the operation. PMID- 28577174 TI - An image retrieval framework for real-time endoscopic image retargeting. AB - PURPOSE: Serial endoscopic examinations of a patient are important for early diagnosis of malignancies in the gastrointestinal tract. However, retargeting for optical biopsy is challenging due to extensive tissue variations between examinations, requiring the method to be tolerant to these changes whilst enabling real-time retargeting. METHOD: This work presents an image retrieval framework for inter-examination retargeting. We propose both a novel image descriptor tolerant of long-term tissue changes and a novel descriptor matching method in real time. The descriptor is based on histograms generated from regional intensity comparisons over multiple scales, offering stability over long term appearance changes at the higher levels, whilst remaining discriminative at the lower levels. The matching method then learns a hashing function using random forests, to compress the string and allow for fast image comparison by a simple Hamming distance metric. RESULTS: A dataset that contains 13 in vivo gastrointestinal videos was collected from six patients, representing serial examinations of each patient, which includes videos captured with significant time intervals. Precision-recall for retargeting shows that our new descriptor outperforms a number of alternative descriptors, whilst our hashing method outperforms a number of alternative hashing approaches. CONCLUSION: We have proposed a novel framework for optical biopsy in serial endoscopic examinations. A new descriptor, combined with a novel hashing method, achieves state-of-the-art retargeting, with validation on in vivo videos from six patients. Real-time performance also allows for practical integration without disturbing the existing clinical workflow. PMID- 28577175 TI - Multi-level deep supervised networks for retinal vessel segmentation. AB - PURPOSE: Changes in the appearance of retinal blood vessels are an important indicator for various ophthalmologic and cardiovascular diseases, including diabetes, hypertension, arteriosclerosis, and choroidal neovascularization. Vessel segmentation from retinal images is very challenging because of low blood vessel contrast, intricate vessel topology, and the presence of pathologies such as microaneurysms and hemorrhages. To overcome these challenges, we propose a neural network-based method for vessel segmentation. METHODS: A deep supervised fully convolutional network is developed by leveraging multi-level hierarchical features of the deep networks. To improve the discriminative capability of features in lower layers of the deep network and guide the gradient back propagation to overcome gradient vanishing, deep supervision with auxiliary classifiers is incorporated in some intermediate layers of the network. Moreover, the transferred knowledge learned from other domains is used to alleviate the issue of insufficient medical training data. The proposed approach does not rely on hand-crafted features and needs no problem-specific preprocessing or postprocessing, which reduces the impact of subjective factors. RESULTS: We evaluate the proposed method on three publicly available databases, the DRIVE, STARE, and CHASE_DB1 databases. Extensive experiments demonstrate that our approach achieves better or comparable performance to state-of-the-art methods with a much faster processing speed, making it suitable for real-world clinical applications. The results of cross-training experiments demonstrate its robustness with respect to the training set. CONCLUSIONS: The proposed approach segments retinal vessels accurately with a much faster processing speed and can be easily applied to other biomedical segmentation tasks. PMID- 28577176 TI - Complement C5a induces mesenchymal stem cell apoptosis during the progression of chronic diabetic complications. AB - AIMS/HYPOTHESIS: Regeneration and repair mediated by mesenchymal stem cells (MSCs) are key self-protection mechanisms against diabetic complications, a reflection of diabetes-related cell/tissue damage and dysfunction. MSC abnormalities have been reported during the progression of diabetic complications, but little is known about whether a deficiency in these cells plays a role in the pathogenesis of this disease. In addition to MSC resident sites, peripheral circulation is a major source of MSCs that participate in the regeneration and repair of damaged tissue. Therefore, we investigated whether there is a deficiency of circulating MSC-like cells in people with diabetes and explored the underlying mechanisms. METHODS: The abundance of MSC-like cells in peripheral blood was evaluated by FACS. Selected diabetic and non-diabetic serum (DS and NDS, respectively) samples were used to mimic diabetic and non-diabetic microenvironments, respectively. The proliferation and survival of MSCs under different serum conditions were analysed using several detection methods. The survival of MSCs in diabetic microenvironments was also investigated in vivo using leptin receptor mutant (Lepr db/db ) mice. RESULTS: Our data showed a significant decrease in the abundance of circulating MSC-like cells, which was correlated with complications in individuals with type 2 diabetes. DS strongly impaired the proliferation and survival of culture-expanded MSCs through the complement system but not through exposure to high glucose levels. DS-induced MSC apoptosis was mediated, at least in part, by the complement C5a-dependent upregulation of Fas-associated protein with death domain (FADD) and the Bcl-2 associated X protein (BAX)/B cell lymphoma 2 (Bcl-2) ratio, which was significantly inhibited by neutralising C5a or by the pharmacological or genetic inhibition of the C5a receptor (C5aR) on MSCs. Moreover, blockade of the C5a/C5aR pathway significantly inhibited the apoptosis of transplanted MSCs in Lepr db/db recipient mice. CONCLUSIONS/INTERPRETATION: C5a-dependent apoptotic death is probably involved in MSC deficiency and in the progression of complications in individuals with type 2 diabetes. Therefore, anticomplement therapy may be a novel intervention for diabetic complications. PMID- 28577177 TI - The epigenetic memory of temperature during embryogenesis modifies the expression of bud burst-related genes in Norway spruce epitypes. AB - MAIN CONCLUSION: Epigenetic memory affects the timing of bud burst phenology and the expression of bud burst-related genes in genetically identical Norway spruce epitypes in a manner usually associated with ecotypes. In Norway spruce, a temperature-dependent epigenetic memory established during embryogenesis affects the timing of bud burst and bud set in a reproducible and predictable manner. We hypothesize that the clinal variation in these phenological traits, which is associated with adaptation to growth under frost-free conditions, has an epigenetic component. In Norway spruce, dehydrins (DHNs) have been associated with extreme frost tolerance. DHN transcript levels decrease gradually prior to flushing, a time when trees are highly sensitive to frost. Furthermore, EARLY BUD BREAK 1 genes (EBB1) and the FT-TFL1-LIKE 2-gene (PaFTL2) were previously suggested to be implied in control of bud phenology. Here we report an analysis of transcript levels of 12 DHNs, 3 EBB1 genes and FTL2 in epitypes of the same genotype generated at different epitype-inducing temperatures, before and during spring bud burst. Earlier flushing of epitypes originating from embryos developed at 18 degrees C as compared to 28 degrees C, was associated with differential expression of these genes between epitypes and between buds and last year's needles. The majority of these genes showed significantly different expressions between epitypes in at least one time point. The general trend in DHN expression pattern in buds showed the expected reduction in transcript levels when approaching flushing, whereas, surprisingly, transcript levels peaked later in needles, mainly at the moment of bud burst. Collectively, our results demonstrate that the epigenetic memory of temperature during embryogenesis affects bud burst phenology and expression of the bud burst-related DHN, EBB1 and FTL2 genes in genetically identical Norway spruce epitypes. PMID- 28577178 TI - Population Pharmacokinetic Analysis of Bisoprolol in Patients with Stable Coronary Artery Disease. AB - BACKGROUND AND OBJECTIVES: Bisoprolol is a selective beta adrenergic antagonist commonly used in treatment of coronary artery disease (CAD). The aim of our analysis was to estimate and identify different factors that could affect bisoprolol clearance (CL) and develop a population pharmacokinetic model in patients with stable coronary artery disease (CAD). METHODS: Population pharmacokinetic analysis was performed by using sixty-six plasma concentrations from the same number of patients (mean age 60.26 +/- 9.68 years; mean total body weight 80.37 +/- 12.93 kg) with CAD. We examined the effects of various clinical and demographic parameters using nonlinear mixed-effect modeling (NONMEM) with ADVAN1 with TRANS2 subroutine. The pharmacokinetics of bisoprolol in patients with CAD were suitably defined by an oral one-compartment model. RESULTS: The typical mean value for bisoprolol CL, estimated by the base model, in the target population was 6.76 l/h. The only demographic covariate which affected bisoprolol pharmacokinetic variability was creatinine clearance (CLcr). The final model of bisoprolol clearance was described by following equation: CL (l/h) = 2.83 + 0.0385 * CLcr (ml/min). Validation of the final model was performed in a group of 17 patients using the validation set and bootstrapping analysis. CONCLUSIONS: These findings suggest that one of the causes of clearance of bisoprolol variability in patients with CAD is the difference in renal function. PMID- 28577179 TI - Good isometric and isokinetic power restoration after distal biceps tendon repair with anchors. AB - INTRODUCTION: Distal biceps brachii tendon rupture can lead to 30-40% power loss of elbow flexion and up to 50% of forearm supination. Re-fixation of the distal biceps brachii tendon is recommended to warrant an adequate quality of the patient's life. This study reports the isometric and isokinetic results after anchor re-fixation 2.5 years after surgery. PATIENTS AND METHODS: Between 2007 and 2010, 69 patients with distal biceps brachii tendon tear underwent a suture anchor reattachment. During the follow-up examination, a questionnaire and DASH score were filled in, the circumferences of the arm were measured, range of motion was collected, and different trials were conducted at the BTE Primus RSTM (Baltimore Therapeutic Equipment) on both arms. RESULTS: 49 patients (71%) were reinvestigated with a follow-up of 32 months (11-58 months). A significant difference was found in the ability of elbow flexion between the affected arm and the opposite side as well as in pronation and supination. In elbow flexion and extension as well as in pronation and supination of the forearm, the strength was significantly diminished. CONCLUSIONS: 32 months after surgical re-fixation of the distal biceps brachii tendon rupture, strength in all exercises is marginally reduced in comparison to the opposite arm. Re-fixation of the distal biceps brachii tendon is an adequate method to return the range of motion and the strength in the elbow joint to an almost normal level and that gives rise to a high level of patient satisfaction. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 28577180 TI - Olivibacter flavus sp. nov., a novel endophytic bacterium isolated from the root of Camellia sinensis. AB - A novel Gram-negative rod, endophytic bacterium, designated strain TMCC 8258T, was isolated from the root of Camellia sinensis collected from Puer, south-west China. Comparative 16S rRNA gene sequence analysis showed that the strain belongs to the family Sphingobacteriaceae and a neighbour-joining phylogenetic tree suggested that strain TMCC 8258T formed a cluster with the type strain of Olivibacter ginsengisoli (showed the highest 16S rRNA gene sequence similarity of 95.8%). Chemotaxonomic data [major fatty acid iso-C15:0, summed feature 3 (C16:1 omega7c and/or C16:1 omega6c), iso-C17:0 3-OH and major respiratory quinone MK-7] confirmed the affiliation of strain TMCC 8258T to the genus Olivibacter. The G + C content was 39.1 mol %. The results of the phylogenetic analysis, together with the physiological, morphological and biochemical tests, suggested that strain TMCC 8258T should be classified as representing a novel species of the genus Olivibacter, for which the name Olivibacter flavus is proposed. The type strain is TMCC 8258T (=CGMCC 1.16141 = KCTC 42683). PMID- 28577181 TI - Clinical Outcomes in pT4 Tongue Carcinoma are Worse than in pT3 Disease: How Extrinsic Muscle Invasion Should be Considered? AB - BACKGROUND: The identification of extrinsic tongue muscle invasion in oral cavity cancer remains challenging. Notably, the most recent American Joint Committee on Cancer (AJCC 2017, 8th edition) staging manual indicates that extrinsic muscle invasion does not lead to the diagnosis of a T4 tumor. Because this approach carries the risk of tumor downstaging, we compared the clinical outcomes of patients with oral tongue squamous cell carcinoma (SCC) staged as pT3 vs. pT4 according to the AJCC 2010, 7th edition criteria. METHODS: We retrospectively examined the records of consecutive patients with pT3 (n = 135) and pT4 (n = 68) tongue SCC who underwent radical surgery. Of the 68 pT4 tongue SCC, 63 (93%) had extrinsic muscle involvement alone. The 5-year locoregional control (LRC), distant metastasis (DM), and disease-free survival (DFS) rates served as outcome measures. RESULTS: Compared with pT3 tongue SCC, pT4 patients presented significantly more frequently with pN2 disease, extranodal extension, poor tumor differentiation, tumor depth >15 and >20 mm, margin status <=4 mm, perineural invasion, vascular invasion, and were more frequently treated with surgery plus concurrent chemoradiotherapy. Less favorable 5-year outcomes were observed in patients with pT4 than pT3 tumors (LRC 50 vs. 75%, p < 0.001; DM 27 vs. 14%, p = 0.013; DFS 43 vs. 69%, respectively, p < 0.001). We identified pT4 disease (vs. pT3) as an independent adverse prognostic factor for LRC and DFS. CONCLUSIONS: We suggest classifying patients with tongue SCC and extrinsic muscle invasion as having pT4 disease. PMID- 28577182 TI - Economic burden of cancer among patients with surgical resections of the lung, rectum, liver and uterus: results from a US hospital database claims analysis. AB - OBJECTIVES: To determine hospital resource utilization, associated costs and the risk of complications during hospitalization for four types of surgical resections and to estimate the incremental burden among patients with cancer compared to those without cancer. METHODS: Patients (>=18 years old) were identified from the Premier Research Database of US hospitals if they had any of the following types of elective surgical resections between 1/2008 and 12/2014: lung lobectomy, lower anterior resection of the rectum (LAR), liver wedge resection, or total hysterectomy. Cancer status was determined based on ICD-9-CM diagnosis codes. Operating room time (ORT), length of stay (LOS), and total hospital costs, as well as frequency of bleeding and infections during hospitalization were evaluated. The impact of cancer status on outcomes (from a hospital perspective) was evaluated using multivariable generalized estimating equation models; analyses were conducted separately for each resection type. RESULTS: Among the identified patients who underwent surgical resection, 23 858 (87.9% with cancer) underwent lung lobectomy, 13 522 (63.8% with cancer) underwent LAR, 2916 (30.0% with cancer) underwent liver wedge resection and 225 075 (11.3% with cancer) underwent total hysterectomy. After adjusting for patient, procedural, and hospital characteristics, mean ORT, LOS, and hospital cost were statistically higher by 3.2%, 8.2%, and 9.2%, respectively for patients with cancer vs. no cancer who underwent lung lobectomy; statistically higher by 6.9%, 9.4%, and 9.6%, respectively for patients with cancer vs. no cancer who underwent LAR; statistically higher by 4.9%, 14.8%, and 15.7%, respectively for patients with cancer vs. no cancer who underwent liver wedge resection; and statistically higher by 16.0%, 27.4%, and 31.3%, respectively for patients with cancer vs. no cancer who underwent total hysterectomy. Among patients who underwent each type of resection, risks for bleeding and infection were generally higher among patients with cancer as compared to those without cancer. CONCLUSIONS: In this analysis, we found that patients who underwent lung lobectomy, lower anterior resection of the rectum (LAR), liver wedge resection or total hysterectomy for a cancer indication have significantly increased hospital resource utilization compared to these same surgeries for benign indications. PMID- 28577183 TI - Evaluation of comprehensive chromosome screening platforms for the detection of mosaic segmental aneuploidy. AB - PURPOSE: A subset of preimplantation embryos identified as euploid may in fact possess both whole and sub-chromosomal mosaicism, raising concerns regarding the predictive value of current comprehensive chromosome screening (CCS) methods utilizing a single biopsy. Current CCS methods may be capable of detecting sub chromosomal mosaicism in a trophectoderm biopsy by examining intermediate levels of segmental aneuploidy within a biopsy. This study evaluates the sensitivity and specificity of segmental aneuploidy detection by three commercially available CCS platforms utilizing a cell line mixture model of segmental mosaicism in a six cell trophectoderm biopsy. METHODS: Two cell lines with known karyotypes were obtained and mixed together at specific ratios of six total cells (0:6, 1:5, 2:4, 3:3, 4:2, 5:1, and 6:0). A female cell line containing a 16.2 Mb deletion on chromosome 5 and a male cell line containing a 25.5 Mb deletion on chromosome 4 were used to create mixtures at each level. Six replicates of each mixture were prepared, randomized, and blinded for analysis by one of the three CCS platforms (SNP-array, VeriSeq NGS, or NexCCS). Sensitivity and specificity of segmental aneuploidy at each level of mosaicism was determined and compared between each platform. Additionally, an alternative VeriSeq NGS analysis method utilizing previously published criteria was evaluated. RESULTS: Examination of the default settings of each platform revealed that the sensitivity was significantly different between NexCCS and SNP up to 50% mosaicism, custom VeriSeq, and SNP array up to 66% mosaicism, and between NexCCS and custom VeriSeq up to 50% mosaicism. However, no statistical difference was observed in mixtures with >50% mosaicism with any platform. No comparison was made between default VeriSeq, as it does not report segmental imbalances. Furthermore, while the use of previously published criteria for VeriSeq NGS significantly increased sensitivity at low levels of mosaicism, a significant decrease in specificity was observed (66% false positive prediction of segmental aneuploidy). CONCLUSION: These results demonstrate the potential of NGS-based detection methods to detect segmental mosaicism within a biopsy. However, these data also demonstrate that a balance between sensitivity and specificity should be more carefully considered. These results emphasize the importance of vigorous preclinical evaluation of new testing criteria prior to clinical implementation providing a point of departure for further algorithm development and improved detection of mosaicism within preimplantation embryos. PMID- 28577184 TI - Is employer coverage of elective egg freezing coercive?: a survey of medical students' knowledge, intentions, and attitudes towards elective egg freezing and employer coverage. AB - PURPOSE: The purpose of this study was to understand medical students' knowledge, intentions, and attitudes towards oocyte cryopreservation and employer coverage of such treatment. METHODS: This cross-sectional study was performed via an online cross-sectional survey distributed to 280 female medical students from March through August 2016. Demographics, attitudes towards employer coverage, and factors influencing decision-making were assessed via a self-reported multiple choice questionnaire. The relationship between respondents' attitudes towards employer coverage and other parameters was analyzed. RESULTS: A total of 99 responses were obtained out of 280 female medical students. Most respondents (71%) would consider oocyte cryopreservation (potential freezers), although 8% would not consider the procedure and 21% were unsure. Seventy-six percent of respondents felt pressure to delay childbearing. Potential freezers were more likely to be single (p = 0.001), to report feeling pressure to delay childbearing (p = 0.016), and to consider egg freezing if offered by an employer (p < 0.001). Importantly, 71% percent did not view employer coverage as coercive and 77% of respondents would not delay childbearing due to employer coverage. Factors influencing decision-making in potential freezers were absence of a suitable partner (83%), likelihood of success (95%), and health of offspring (94%), among others. Knowledge about the low chance of pregnancy per oocyte (6-10%) would influence decision-making in 42% of potential freezers. CONCLUSION: Oocyte freezing is an acceptable strategy for the majority of young women surveyed. Pressure to delay childbearing was related to openness to freeze eggs. The majority of respondents did not find employer coverage for egg freezing coercive although further research is needed with larger, representative samples to ascertain the relationship between pressure to delay childbearing due to work demands and employer coverage for egg freezing. PMID- 28577185 TI - Light-emitting diode modulates carbohydrate metabolism by pancreatic duct regeneration. AB - Pancreatic lesions can produce metabolic disorders. Light-emitting diode (LED) has been used as a safe and effective phototherapy for cell proliferation and regeneration. We investigate the effects of phototherapy using LED irradiation on the pancreas after the injection of streptozotocin (STZ) to induce experimental diabetes and evaluate that the beta cells can regenerate in the pancreas in an in vivo model and observe its implications on the control of carbohydrate metabolism. Twenty Wistar rats were randomized into three groups: non-diabetic control, diabetic control, and diabetic treated with LED. Except for the non diabetic control group, all were induced to diabetes type I by streptozotocin injection. Treated groups were irradiated by LED: lambda = 805 nm; 40 mW, 22 s; spot diameter 5 mm, spot area 0.196 cm2, 0.88 J that it was applied on pancreas projection area for 5 consecutive days and monitored for 30 days. Diabetic group treated with LED showed regeneration of islets and ducts (p = 0.001) on the pancreas. Intraperitoneal insulin tolerance test showed differences between the diabetic control and diabetic treated groups (p = 0.03). In diabetic control group, the hepatic glycogen content was 296% lower when compared with diabetic treated with LED. Furthermore, in the diabetic control group, the glycogen content of the gastrocnemius muscle was 706% smaller when compared with diabetic treated with LED. This study shows that LED was able to modify morphological and metabolic features and also altered carbohydrate metabolism on irradiated pancreas in experimental model of diabetes. PMID- 28577186 TI - Multiple laser pulses in conjunction with an optical clearing agent to improve the curative effect of cutaneous vascular lesions. AB - Port-wine stains (PWSs) usually respond poorly to pulsed dye laser treatment because of the shallow penetration and light absorption of melanin in the epidermis. Multiple laser pulses (MLPs) Nd:YAG laser in conjunction with an optical clearing agent can help to reduce the total laser energy required for blood coagulation. The quantitative optical clearing effect (OCE) of glycerol was investigated by using a tissue-like phantom. Thereafter, an in vitro capillary tube experimental system and an in vivo hamster dorsal skin chamber experiment for the laser treatment of PWSs were established to visually obtain the quantitative relationship between the OCE and the blood coagulation properties under the irradiation of 1064 nm MLPs. Diffuse reflection coefficient decreases by 36.69% and transmission coefficient increases by 38.73% at 1064 nm, after applying 0.5 mL anhydrous glycerol for 10 min on the surface of the tissue-like phantom. The number of laser pulses required for blood coagulation decreases by 25% after the application of 0.5 mL anhydrous glycerol for 4 min, thrombosis appears after 10 min, and the 0.0854 clotting area completely blocks the capillary tubes in 6 pulses. For 10 min, the incident energy can be reduced by 35.09 and 29.82%. When the 0.3-mm vessel's buried depths are 1 and 0.5 mm, the pulse number can be reduced from 11 to 8 and from 6 to 4, respectively. Adding anhydrous glycerol directly on the hamster dorsal skin is an effective way to reduce the number of laser pulses from 4~5 to 2~3 for similar capillary tube diameter. Therefore, the MLPs of 1064 nm Nd:YAG demonstrates a substantial curative effect for large capillary tubes. In conjunction with glycerol, this approach may treat deeply buried cutaneous capillary tubes and prevent the unwanted thermal damage of normal dermal tissue. PMID- 28577187 TI - Autofluorescence imaging for improved visualization of joint structures during arthroscopic surgery. AB - BACKGROUND: The purpose of our study is to develop the arthroscopic autofluorescence imaging (AFI) system to improve the visualization during arthroscopic surgery by real-time enhancing the contrast between joint structures with autofluorescence imaging. Its validity was evaluated around the arthroscopic anterior cruciate ligament (ACL) reconstruction, specifically improving the contrast between the femoral insertion site and its background. The feasibility of the AFI system was validated with bovine and human knees. The spectral responses of the femoral insertion site and its surrounding bone and cartilage were measured with a fluorospectrometer. A prototype of the AFI system was developed based on the spectral responses (SR) and test images of the insertion site. The accuracy was validated by evaluating the overlap between manually segmented insertion sites on the white light color images and on the corresponding spectral unmixed autofluorescence images. The final prototype of the AFI system was tested during arthroscopy in cadaveric knees. RESULTS: The results showed that the joint structures have different SRs. Spectral unmixing enabled separation of the SRs and improved the contrast between the joint structures. The agreement between visible light and autofluorescence ligament insertions had a mean Dice coefficient of 0.84 and the mean Dice coefficient of the interobserver variability for visible light imaging was 0.85. CONCLUSIONS: We have shown that the femoral insertion site can be accurately visualized with autofluorescence imaging combined with spectral unmixing. The AFI system demonstrates the feasibility of real-time and subject-specific visualization of the femoral insertion site which can facilitate anatomic ACL reconstruction. In addition, the AFI system can facilitate arthroscopic procedures in other joints and can also be used as a diagnostic tool. PMID- 28577188 TI - From genetics to personalized nephrology: kidney research at a tipping point. PMID- 28577189 TI - The use of tucuma oil (Astrocaryum vulgare) in alloxan-induced diabetic mice: effects on behavior, oxidant/antioxidant status, and enzymes involved in brain neurotransmission. AB - The aim of this study was to investigate the effects of tucuma oil (Astrocaryum vulgare) on memory, enzymatic activities of sodium-potassium pump (Na+, K+ ATPase) and acetylcholinesterase (AChE) in the brain of alloxan-induced diabetic mice. The animals were divided into four groups (n = 6 each): the group A (non diabetic/water), the group B (non-diabetic/tucuma oil), the group C (diabetic/water), and the group D (diabetic/tucuma oil) treated 14 days with 5.0 mL kg-1 via oral gavage. Untreated diabetic mice (the group C) showed memory deficit, increased levels of thiobarbituric acid reactive species (TBARS) and protein carbonylation (PC), and decreased (p < 0.05) catalase (CAT), superoxide dismutase (SOD), and the Na+, K+-ATPase activities, while acetylcholinesterase (AChE) activity showed a significant increase (p < 0.05) compared to non-diabetic mice (the group A). Tucuma oil prevented these alterations in diabetic mice treated with tucuma oil (the group D) compared to diabetic mice (the group C). Our findings suggest that tucuma oil can modulate cholinergic neurotransmission resting membrane potential of neurons by modulating enzymatic antioxidant defenses. In conclusion, the present data showed that treatment with tucuma oil is beneficial to diabetic mice, demonstrating that this oil can modulate cholinergic neurotransmission and consequently improve or avoid memory deficits. PMID- 28577191 TI - Deletion Analysis of GH7 Endoglucanase Gene (cel7B) Promoter Region in a Talaromyces cellulolyticus ligD-Disrupted Strain. AB - Talaromyces cellulolyticus is expected to become an industrial cellulase producer. In this study, we performed deletion analysis of the promoter region of the GH7 endoglucanase gene (cel7B), which encodes one of the major cellulases, using a beta-glucuronidase reporter system. To obtain strains that harbor each gene cassette at the same locus, we had to improve the homologous recombination frequency. Hence, the ligD gene, encoding DNA ligase IV, was disrupted by homologous recombination. After that, the introduced pyrF marker gene, encoding orotate phosphoribosyl transferase, was deleted by a marker recycling system. The resultant strain, YDLP, exhibits high homologous recombination frequency. These data suggest that this approach will drastically improve the genetic modification tools of T. cellulolyticus. We obtained 7 strains for reporter analysis using YDLP as the host strain. Reporter analysis revealed that the promoter region between -812 and -612 is important for expression of cel7B. These results imply a relationship between this region and novel transcriptional factors. PMID- 28577192 TI - Cloning, Site-Directed Mutagenesis, and Functional Analysis of Active Residues in Lymantria dispar Chitinase. AB - Chitinases are glycosyl hydrolases that catalyze the hydrolysis of beta-(1,4) glycosidic bonds in chitin, the major structural polysaccharide presented in the cuticle and gut peritrophic matrix of insects. Two aspartate residues (D143, D145) and one tryptophan (W146) in the Lymantria dispar chitinase are highly conserved residues observed within the second conserved motif of the family 18 chitinase catalytic region. In this study, a chitinase cDNA, LdCht5, was cloned from L. dispar, and the roles of the three residues were investigated using site directed mutagenesis and substituting them with three other amino acids. Seven mutant proteins, D143E, D145E, W146G, D143E/D145E, D143E/W146G, D145E/W146G, and D143E/D145E/W146G, as well as the wild-type enzyme, were produced using the baculovirus-insect cell line expression system. The enzymatic and kinetic properties of these mutant enzymes were measured using the oligosaccharide substrate MU-(GlcNAc)3. Among the seven mutants, the D145E, D143E/D145E, and D145E/W146G mutations kept some extant catalytic activity toward MU-(GlcNAc)3, while the D143E, W146G, D143E/W146G, and D143E/D145E/W146G mutant enzymes were inactivated. Compared with the mutant enzymes, the wild-type enzyme had higher values of k cat and k cat / K m . A study of the multiple point mutations in the second conserved catalytic region would help to elucidate the role of the critical residues and their relationships. PMID- 28577190 TI - 17beta-Estradiol and/or estrogen receptor alpha blocks isoproterenol-induced calcium accumulation and hypertrophy via GSK3beta/PP2A/NFAT3/ANP pathway. AB - The present study was aimed to investigate the protective effects of 17beta estradiol (E2) and estrogen receptor alpha (ERalpha) on isoproterenol (ISO) treated H9c2 cardiomyoblast cells. In the present study, we treated H9c2 cells with ISO, a beta-adrenergic receptor agonist, to induce myocardiac hypertrophy. Pre-administration of E2 or ERalpha (induced by doxycycline) and E2 plus ERalpha significantly prevented ISO-induced increase of cell size and cytosolic calcium accumulation, accompanied with increased mRNA of atrial natriuretic peptide and brain natriuretic peptide. However, ICI-ERs antagonist, and melatonin, a specific inhibitor for ERalpha, reversed the cardioprotective effects, suggesting that E2 action was mediated through ERalpha. Further evidences showed that E2 and ERalpha increased the protein level of GSK3beta and protein phosphatase 2a inhibitor 2 (I2-PP2A), which subsequently enhanced the activation of I2-PP2A by disrupting PP2A activity and maintains normal calcium outflow. Collectively, E2 and ERalpha inhibited hypertrophy by preventing cytosol calcium accumulation and by inhibiting the association between PP2A with Na+-Ca2+ exchanger via GSK3beta and I2-PP2A activation. PMID- 28577193 TI - The effects of local variation in light availability on pollinator visitation, pollen and resource limitation of female reproduction in Hosta ventricosa. AB - BACKGROUND: Light availability may have direct effects on reproduction through resource availability, and indirect effects on female reproduction by influencing plant-pollinator interactions. Floral display size, pollinator visitation per flower, resource and pollen limitation of fruit and seed production were quantified in a forested patch and an adjacent open patch of two populations of the perennial herb Hosta ventricosa. RESULTS: Plants in the open patch produced significantly larger floral displays than those in the forested patch in both populations. Floral display size had a positive effect on pollinator visitation rate per flower in one population, but no effect in the other. Plants in the open patch received approximately 8-11 times more visitation rates and produced significantly more fruit and seeds per flower than those in the forested patch. However, supplemental pollination resulted in significantly more fruit and seed production per flower compared to natural pollination in the forested patch but not in the open patch in one population, and did not enhance fruit and seed production in either the forested or the open patch in the other. In both populations, supplementally pollinated plants in the open patch produced significantly more fruit and seeds per flower than supplementally pollinated plants in the forested patch. CONCLUSIONS: In H. ventricosa, local variation in light conditions could affect pollinator activity and influence female reproduction through resource availability; however differences in the degree of pollen limitation between local habitats were found to be population-specific. PMID- 28577194 TI - Genome-wide characterization of the Rab gene family in Gossypium by comparative analysis. AB - BACKGROUND: Rab protein family is the largest subfamily of small G protein family. As one of the most important families in plant, Rab family plays an important role in the process of plant growth and development. So far, the identification of 57 members of the Rab family in Arabidopsis has been completed. In cotton, the relevant family has not been reported. RESULTS: Here, we identified 87, 169, 136, 80 Rabs in the four sequenced cotton species, G. raimondii (D5), G. hirsutum acc. TM-1 (AD1), G. barbadense acc. 3-79 (AD2) and G. arboreum (A2), respectively. Biological information analysis showed that the number of amino acid is 200-300 aa among Rab family members in G. raimondii and the protein molecular weight is between 20 and 30 kDa, which is consistent with the characterization of the Rab protein itself. 87 GrRabs in G. raimondii are divided into eight groups. In each group, intron numbers and subcellular localization of Rab protein are basically the same. We mapped the distribution of GrRab genes on 13 chromosomes of G. raimondii except two genes. Among the 87 GrRabs in G. raimondii, we identified 60 pairs of GrRabs formed in whole genome duplication. Among all the gene pairs, the Ka/Ks values were less than 1. This indicates that it is the results of the purification selection and will help maintain the conservation of gene in structure and function. Further, 4 of the 87 GrRabs showed tandem duplication. They were GrRabA2a vs GrRabD1a and GrRabA2h vs GrRabD1b respectively. Expression patterns analysis of 169 GhRabs in G. hirsutum acc. TM-1 indicates that most Rab family members play a certain role in different tissues/organs and different growth stages of cotton, implying their potential function in the polar growth of pollen tube, root hair and fiber cell, as well as improving stress and disease tolerance. CONCLUSION: The systematic investigation of Rab genes in cotton will lay a foundation for understanding the functional roles of different Rab members in the polar growth and stress tolerance. PMID- 28577195 TI - Identification among morphologically similar Argyreia (Convolvulaceae) based on leaf anatomy and phenetic analyses. AB - BACKGROUND: The genus Argyreia Lour. is one of the species-rich Asian genera in the family Convolvulaceae. Several species complexes were recognized in which taxon delimitation was imprecise, especially when examining herbarium materials without fully developed open flowers. The main goal of this study is to investigate and describe leaf anatomy for some morphologically similar Argyreia using epidermal peeling, leaf and petiole transverse sections, and scanning electron microscopy. Phenetic analyses including cluster analysis and principal component analysis were used to investigate the similarity of these morpho-types. RESULTS: Anatomical differences observed between the morpho-types include epidermal cell walls and the trichome types on the leaf epidermis. Additional differences in the leaf and petiole transverse sections include the epidermal cell shape of the adaxial leaf blade, the leaf margins, and the petiole transverse sectional outline. The phenogram from cluster analysis using the UPGMA method represented four groups with an R value of 0.87. Moreover, the important quantitative and qualitative leaf anatomical traits of the four groups were confirmed by the principal component analysis of the first two components. The results from phenetic analyses confirmed the anatomical differentiation between the morpho-types. CONCLUSIONS: Leaf anatomical features regarded as particularly informative for morpho-type differentiation can be used to supplement macro morphological identification. PMID- 28577196 TI - Role of a novel benzoxazine derivative in the chemosensitization of colon cancer. AB - The concept to fight against tumour resistance is to use chemosensitizers that selectively sensitize tumour cells to chemotherapeutic drugs without affecting normal tissue. In this study, the chemosensitizing potential of a novel benzoxazine derivative in combination with Doxorubicin, a DNA damaging chemotherapeutic drug was evaluated. The results of this study showed that the compound LTUR6 is a potent chemosensitizer of Doxorubicin in colon cancer cell lines, HCT116 and HT29. It was also observed that LTUR6 delayed the resolution of Doxorubicin-induced gammaH2AX, a specific marker of unrepaired DNA DSB, and prolonged cell cycle arrest in both cell lines. This eventually led to DNA fragmentation, caspase activation and ultimately apoptosis in LTUR6 treated cell lines. Results of western blot analysis revealed that LTUR6 significantly inhibited the phosphorylation of DSB repair enzyme AKT, in response to Doxorubicin-induced DSB. We propose that the chemosensitization observed following inhibition of PI3K is likely due to the involvement of a number of downstream targets of AKT. PMID- 28577197 TI - Health promotion in the poly-tobacco market. PMID- 28577198 TI - Heart disease versus cancer: understanding perceptions of population prevalence and personal risk. AB - Although the gap is narrowing, Americans are more likely to be diagnosed with and die from heart disease than cancer, and yet many believe cancer is more common and their personal risk of cancer is higher than their heart disease risk. Using nationally representative 2013 Health Information National Trends Survey data, we assessed such beliefs and examined sociodemographic and psychological factors and health behaviors associated with these beliefs. 42.8% of participants rated cancer as more common and 78.5% rated their own cancer risk as equal to or exceeding their heart disease risk. These misperceptions were only modestly correlated. Beliefs about relative population risk were associated with various psychological factors, whereas beliefs about relative personal risk were not. Both beliefs were inconsistently associated with health behaviors. Accuracy in beliefs about cancer and heart disease relative risk and prevalence is low and future research should explore antecedents and consequences of these beliefs. PMID- 28577199 TI - Urine Incontinence Induced by Valproic Acid. PMID- 28577200 TI - ANCA-associated Vasculitis Presenting as Severe Pulmonary Hypertension and Right Heart Failure. AB - Microscopic polyangiitis (MPA) is a small vessel multisystemic disorder characterised by necrotising small vessel vasculitis without any immune deposits. Kidney and lung are the predominant organs affected in MPA. Skin, gastrointestinal and neurological findings are also described. Isolated pulmonary manifestations are rare. The authors describe a two-year girl who presented with right heart failure and was subsequently diagnosed as ANCA-associated vasculitis. This case report is intended to sensitise pediatricians to consider systemic vasculitis with pulmonary hemorrhage in children with pulmonary hypertension even in the absence of severe pallor. PMID- 28577201 TI - Lung Ultrasound in Childhood Pneumonia: The Emerging New Era. PMID- 28577202 TI - Symposium "Brain plasticity in epilepsy", Leuven, Belgium, 13-16 May 2017. PMID- 28577203 TI - The Non-Union Scoring System: an interobserver reliability study. AB - PURPOSE: The Non-Union Scoring System (NUSS) aims to classify non-unions according to their severity and relate them to four treatment categories. The main purpose of this study was to evaluate the reliability of the NUSS. In addition we assessed its clinical validity. METHODS: Forty-four Patients with a tibia non-union between 2005 and 2015 were included in this study. Data from all included patients were scored independently by three observers according to the NUSS criteria. The interobserver agreement was evaluated using the intraclass correlation coefficient (ICC). The interobserver agreement of the Weber-Cech system was assessed using Fleiss' kappa. Finally, the clinical validity of the NUSS was analysed by comparing outcomes of the actual treatment groups to the proposed treatment groups following from the NUSS scores. RESULTS: Forty-four patients were included. The comparison of NUSS scores between observers showed substantial agreement [ICC; 0.78 (0.67-0.86)]. The comparison of the Weber-Cech classification between observers showed only fair agreement [Fleiss kappa; 0.30 (0.17-0.42)]. The chi 2 test for the treatment groups according to the NUSS and the treatments at index procedure showed an independent relation (chi 2 = 5.794, 6 degrees of freedom, p: 0.447). In contrast, the proposed treatment strategy corresponds well to the definitive treatment (chi 2 = 29.963, 9 degrees of freedom, p < 0.001). CONCLUSION: We conclude that the NUSS is both a reliable and valid system to classify non-unions. PMID- 28577204 TI - The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression. AB - Juvenile and adult GM1-gangliosidosis are invariably characterized by progressive neurological deterioration. To date only symptomatic therapies are available. We report for the first time the positive results of Miglustat (OGT 918, N-butyl deoxynojirimycin) treatment on three Italian GM1-gangliosidosis patients. The first two patients had a juvenile form (enzyme activity <=5%, GLB1 genotype p.R201H/c.1068 + 1G > T; p.R201H/p.I51N), while the third patient had an adult form (enzyme activity about 7%, p.T329A/p.R442Q). Treatment with Miglustat at the dose of 600 mg/day was started at the age of 10, 17 and 28 years; age at last evaluation was 21, 20 and 38 respectively. Response to treatment was evaluated using neurological examinations in all three patients every 4-6 months, the assessment of Movement Disorder-Childhood Rating Scale (MD-CRS) in the second patient, and the 6-Minute Walking Test (6-MWT) in the third patient. The baseline neurological status was severely impaired, with loss of autonomous ambulation and speech in the first two patients, and gait and language difficulties in the third patient. All three patients showed gradual improvement while being treated; both juvenile patients regained the ability to walk without assistance for few meters, and increased alertness and vocalization. The MD-CRS class score in the second patient decreased from 4 to 2. The third patient improved in movement and speech control, the distance covered during the 6-MWT increased from 338 to 475 m. These results suggest that Miglustat may help slow down or reverse the disease progression in juvenile/adult GM1-gangliosidosis. PMID- 28577206 TI - Comment on: "Measuring the Volume-Outcome Relation for Complex Hospital Surgery". PMID- 28577205 TI - A Preliminary Study: PS1 Increases U1 snRNA Expression Associated with AD. AB - U1 small nuclear RNA (snRNA) is selectively enriched in 100% of familial Alzheimer's disease (AD) resulting from presenilin1 (PS1) and amyloid precursor protein (APP) mutations. However, it remains unknown what gene or protein cause the U1 snRNA overexpression and then resulted in AD. Using SH-SY5Y cells, we discovered that PS1 induced the overexpression of U1 snRNA, which increased the production of Abeta. Moreover, the U1 snRNA overexpression induced the upregulation of apoe and clu transcripts. In addition, the levels of phosphorylation of tau protein at Thr212 were significantly elevated in U1 snRNA overexpression cells. Immunofluorescence using antibodies reactive with the phosphorylation of tau at Thr212 site demonstrated the hyperphosphorylated tau localization with alpha-tubulin, the main component of cytoskeleton. Importantly, the increased levels of Bax, Bcl2, and Bax/Bcl2 ratio showed that the overexpression of U1 snRNA could cause cell apoptosis. Conclusively, these findings suggest that PS1 considerably increases the level of U1snRNA accompanied with the adverse change of Abeta level, AD-related tau cytoskeletal pathology, and cell apoptosis. PMID- 28577207 TI - Vitiligo: An Update on Pathophysiology and Treatment Options. AB - The pathophysiology of vitiligo is becoming increasingly clarified. In non segmental vitiligo, early factors include activation of innate immunity, inflammasome activation, oxidative stress, and loss of melanocyte adhesion. Nonetheless, the main mechanism leading to non-segmental vitiligo involves an immune-mediated destruction of melanocytes. Anti-melanocyte-specific cytotoxic T cells exert a central role in the final effector stage. Genetic research revealed a multi-genetic inheritance displaying an overlap with other autoimmune disorders. However, some melanocyte-specific genes were also affected. Segmental vitiligo carries a different pathogenesis with most evidence indicating a mosaic skin disorder. Current management includes topical corticosteroids and immunomodulators. Narrow-band ultraviolet B can be used in patients not responding to topical treatment or in patients with extensive disease. Pigment cell transplantation offers an alternative for the treatment of segmental vitiligo or stable non-segmental lesions. Recent findings have revealed new targets for treatment that could lead to more efficient therapies. Targeted immunotherapy may halt the active immune pathways, although combination therapy may still be required to induce satisfying repigmentation. A recently established core set of outcome measures, new measurement instruments, and biomarker research pave the way for future standardized clinical trials. PMID- 28577208 TI - Erratum to: Primary fungal prophylaxis in acute leukemia patients with different risk factors: retrospective analysis from the CAESAR study. PMID- 28577209 TI - Improved diagnosis and prognostication of patients with pleural malignant mesothelioma using biomarkers in pleural effusions and peripheral blood samples - a short report. AB - PURPOSE: There is a lack of robust and clinically utilizable markers for the diagnosis and prognostication of malignant pleural mesothelioma (MPM). This research was aimed at optimizing and exploring novel approaches to improve the diagnosis and prognostication of MPM in pleural effusions and peripheral blood samples. METHODS: CellSearch-based and flow cytometry-based assays using melanoma cell adhesion molecule (MCAM) to identify circulating tumor cells (CTCs) in pleural effusions and peripheral blood samples of MPM patients were optimized, validated, explored clinically and, in case of pleural effusions, compared with cytological analyses. Additionally, tumor-associated circulating endothelial cells (CECs) were measured in peripheral blood samples. The assays were performed on a MPM cohort encompassing patients with histology-confirmed MPM (n=27) and in a control cohort of patients with alternative diagnoses (n=22). Exploratory analyses on the prognostic value of all assays were also performed. RESULTS: The malignancy of MCAM-positive cells in pleural effusions from MPM patients was confirmed. The detection of MPM CTCs in pleural effusions by CellSearch showed a poor specificity. The detection of MPM CTCs in pleural effusions by flow cytometry showed a superior sensitivity (48%) to standard cytological analysis (15%) (p = 0.03). In peripheral blood, CTCs were detected in 26% of the MPN patients, whereas in 42% of the MPM patients tumor-associated CECs were detected above the upper limit of normal (ULN). In exploratory analyses the absence of CTCs in pleural effusions, and tumor-associated CECs in peripheral blood samples above the ULN, appeared to be associated with a worse overall survival. CONCLUSION: MCAM-based flow cytometric analysis of pleural effusions is more sensitive than routine cytological analysis. Flow cytometric analysis of pleural effusions and tumor-associated CECs in peripheral blood may serve as a promising approach for the prognostication of MPM patients and, therefore, warrants further study. PMID- 28577210 TI - [Distal femoral osteotomy using a lateral opening wedge technique]. AB - OBJECTIVE: To shift the weight-bearing axis of the lower limb medially by opening a lateral-based metaphyseal osteotomy at the distal femur. INDICATIONS: Femoral based valgus malalignment and symptomatic lateral unicompartimental osteoarthritis, lateral hyperpression syndrome, cartilage therapy of the lateral compartment, lateral meniscal replacement/transplantation, medial instability with valgus thrust, reconstruction of the medial collateral ligament, patellar instability and/or maltracking. CONTRAINDICATIONS: Advanced cartilage damage (>grade 2) or subtotal meniscal loss of the medial compartment, age >65 years (relative), nicotine abuse, body mass index >30, flexion contracture >25 degrees , corrections with a wedge base >10 mm in case of congenital deformities, inflammatory or septic arthritis, severe osteoporosis. SURGICAL TECHNIQUE: Lateral approach to the distal femur; biplanar osteotomy (frontal + axial osteotomy), gradual opening of the osteotomy, osteotomy fixation with a locking plate. POSTOPERATIVE MANAGEMENT: Free range of motion. Partial weight bearing with 20 kg for 2 weeks, followed by progressive weight bearing thereafter. RESULTS: Mean improvement of knee scores from 20-30 points and mean 10-year survival rate of 80% in patients with lateral unicompartimental osteoarthritis. Mean complication rate of 9%. PMID- 28577211 TI - Prognostic factors for return to work of employees with common mental disorders: a meta-analysis of cohort studies. AB - PURPOSE: To examine prognostic factors for return to work (RTW) of employees with common mental disorders (CMDs). METHODS: A systematic review and meta-analysis were performed using data from 18 published cohort studies with 24,579 participants. The studies were identified from MEDLINE/PubMed, PsycINFO, EMBASE, SocINDEX, and Human resource management databases from 1995 to 2016. Two authors independently screened selected studies and assessed the quality of the studies as well as the extracted data. RESULTS: We screened 7755 abstracts, from which 211 full text articles were reviewed. Eighteen cohort studies met the inclusion criteria and were included in the analysis. Significant prognostic factors for RTW included age, contact with medical specialists, RTW-self-efficacy, and work ability. The pooled hazard ratios and 95% confidence interval (CI) for age, RTW SE, contact with medical specialists, and high work ability/low work demands in relation to RTW were 0.77 (95% CI 0.65-0.88), 1.79 (95% CI 1.24-2.33), 0.64 (95% CI 0.49-0.80) and 1.08 (95% CI 1.06-1.11), respectively. CONCLUSIONS: Self efficacy (SE) is a key factor in the enhancement of work ability and RTW. Improving employee's SE and collaborating with employers to enhance work ability may help to facilitate RTW. As the RTW process is complex, exploring theoretical frameworks for RTW in individuals with a CMD is also needed. PMID- 28577212 TI - Salivirus infection in children with diarrhea, Thailand. AB - A new member of the Picornaviridae family named salivirus, and also known as klassevirus, was identified recently from the feces of children with gastroenteritis. At present, it remains unclear whether salivirus is associated with gastroenteritis in humans and epidemiological data are very limited. To investigate the prevalence of salivirus in Thailand, we performed molecular screening of fecal samples from children hospitalized with acute gastroenteritis in Chiang Mai, Thailand during 2015-2016 through the application of RT-nested PCR. Salivirus was detected in 1 out of 229 (0.44%) fecal samples tested and it belonged to genotype A1, based on nucleotide sequences of the 5'UTR, VP1, and 3D regions. This is the first report of salivirus infection in young children with acute diarrhea in Thailand. PMID- 28577214 TI - Monitoring of Newcastle disease virus in environmental samples. AB - Newcastle disease virus (NDV) is an important pathogen in poultry. Waterfowl and a number of other avian species serve as the host for NDV. Severity of the disease is variable and infected animals mainly develop respiratory and neurological symptoms. Outbreaks of NDV in poultry are recorded regularly in the Republic of Kazakhstan despite the widespread use of vaccines. Here we present evidence that nucleic acid found in open water bodies in Kazakhstan can be detected by means of next-generation sequencing and belongs to at least three distinct genotypes of NDV. PMID- 28577213 TI - Evaluation of the impact of ul54 gene-deletion on the global transcription and DNA replication of pseudorabies virus. AB - Pseudorabies virus (PRV) is an animal alphaherpesvirus with a wide host range. PRV has 67 protein-coding genes and several non-coding RNA molecules, which can be classified into three temporal groups, immediate early, early and late classes. The ul54 gene of PRV and its homolog icp27 of herpes simplex virus have a multitude of functions, including the regulation of viral DNA synthesis and the control of the gene expression. Therefore, abrogation of PRV ul54 function was expected to exert a significant effect on the global transcriptome and on DNA replication. Real-time PCR and real-time RT-PCR platforms were used to investigate these presumed effects. Our analyses revealed a drastic impact of the ul54 mutation on the genome-wide expression of PRV genes, especially on the transcription of the true late genes. A more than two hour delay was observed in the onset of DNA replication, and the amount of synthesized DNA molecules was significantly decreased in comparison to the wild-type virus. Furthermore, in this work, we were able to successfully demonstrate the utility of long-read SMRT sequencing for genotyping of mutant viruses. PMID- 28577215 TI - Sequence analysis of double-strand RNA6 and RNA9 from the fungus Sclerotium hydrophilum. AB - We have recently reported the identification of 10 double-strand RNA segments from Sclerotium hydrophilum [HZ11] mycelia and of virus-like particles isolated from the mycelia, as well as the sequences of dsRNA2 and dsRNA7. Phylogenetic analysis revealed that dsRNA2 and dsRNA7 belong to a group of unclassified viruses. In this report, we cloned and sequenced dsRNA6 and dsRNA9 from the 10 dsRNAs. We tentatively named the putative virus "Sclerotium hydrophilum virus 1", with isolates being abbreviated to ShV1, with dsRNA6 and dsRNA9 corresponding to dsRNA1 and dsRNA2, respectively, of ShV1. dsRNA1 was 1975 bp in length and encoded a putative RNA-dependent RNA polymerase (RdRp). dsRNA2 was 1728 bp and encoded a putative coat protein (CP). Phylogenetic analysis showed that the proteins encoded by dsRNA1 and dsRNA2 were highly related to known viral RdRps and CP, respectively, of viruses classified within the genus Alphapartitivirus of the family Partitiviridae. These members include Rhizoctonia solani dsRNA virus 2, Diuris pendunculata cryptic virus, and Heterobasidion partitivirus. The 5'- and 3'-untranslated regions (UTRs) of the two dsRNAs showed a high sequence identity. The 5'-UTR contained conserved sequences 5'-GAAGCAUCACUU(/G) G(/U)AGU(/A)UCGC(/U)CCA(/G) CAAUAACGAA-3' and 5'-AAAUUGAUCUUACCUCUCAC-3'. The 3' UTR contained the conserved sequence 5'-UUGUUUU-3' and 5'-UUUA(/U)A(/C) UUAU-3'. These results indicate that dsRNA1 and dsRNA2 are phylogenetically related to members of the genus Alphapartitivirus of family Partitiviridae. We therefore propose that dsRNA1 and dsRNA2 are the genome sequences of a new partitivirus, ShV1. PMID- 28577216 TI - Concentration-based self-assembly of phycocyanin. AB - Cyanobacteria light-harvesting complexes can change their structure to cope with fluctuating environmental conditions. Studying in vivo structural changes is difficult owing to complexities imposed by the cellular environment. Mimicking this system in vitro is challenging, as well. The in vivo system is highly concentrated, and handling similar in vitro concentrated samples optically is difficult because of high absorption. In this research, we mapped the cyanobacteria antennas self-assembly pathways using highly concentrated solutions of phycocyanin (PC) that mimic the in vivo condition. PC was isolated from the thermophilic cyanobacterium Thermosynechococcus vulcanus and measured by several methods. PC has three oligomeric states: hexamer, trimer, and monomer. We showed that the oligomeric state was changed upon increase of PC solution concentration. This oligomerization mechanism may enable photosynthetic organisms to adapt their light-harvesting system to a wide range of environmental conditions. PMID- 28577217 TI - Assessment of Heavy Metal Pollution in the Groundwater of the Northern Develi Closed Basin, Kayseri, Turkey. AB - This study was carried out to assess the groundwater pollution in the northern Develi Closed Basin by using the heavy metal pollution index (HPI). Samples from 10 wells and 5 springs were collected in dry and wet seasons and concentrations of Pb, Zn, Cr, Mn, Fe, Cu, Cd, As and B were determined. In both seasons, for more than half of the samples, As, B and Fe concentrations exceeded the Turkish drinking water guideline values. Due to the occurrence of these metals in high concentrations in some samples HPI values are up to 1740. The source of these metals is geogenic and attributed to the interaction of these waters with highly altered volcanic and pyroclastic rocks. The overall HPI for wet and dry periods are reported as 360 and 440, respectively. Accordingly, the pollution level in the groundwater of this area is unacceptable. PMID- 28577218 TI - Total Mercury, Methylmercury, Inorganic Arsenic and Other Elements in Meat from Minke Whale (Balaenoptera acutorostrata) from the North East Atlantic Ocean. AB - Meat samples of 84 minke whales (Balaenoptera acutorostrata) mainly from the Barents Sea, collected between 1 May and 16 August 2011, were analyzed for total mercury, methylmercury, cadmium, lead, total arsenic, inorganic arsenic and selenium. The average total mercury concentration found was 0.15 +/- 0.09 mg/kg, with a range from 0.05 to 0.49 mg/kg. The molar ratio of selenium to mercury varied between 1.0 and 10.3. Cadmium content ranged from 0.002 to 0.036 mg/kg, while the content of lead in whale meat ranged from <0.01 to 0.09 mg/kg. None of the whale samples exceeded established EU maximum levels for metals in fish muscle, but 4.8% and 6.8% of the samples exceeded Japanese maximum levels for total mercury and methylmercury, respectively, in whale meat. There was only minor variations in element concentrations between whales from different geographical areas, and cadmium was the only element were the concentration increased with increasing length. PMID- 28577220 TI - Response to Sharma et al.: Long Pulmonary Residence Time and Plasma Half-Life of Tiotropium: Implications for Pharmacokinetic Bioequivalence Studies. PMID- 28577219 TI - Spo0M: structure and function beyond regulation of sporulation. AB - In this mini-review, we present a perspective on the recent findings relating Spo0M structure and function that will stimulate and guide further studies in the characterization of this interesting protein. Cell division and sporulation constitute two of the best studied processes in the model organism Bacillus subtilis; however, there are many missing pieces in the giant regulatory puzzle that governs the independent and shared networks between them. Spo0M is a little studied protein that has been related to both, cell division and sporulation, but its biochemical function and its direct interactions have not been yet defined. Structural analysis of Spo0M revealed the presence of an arrestin-like domain and an FP domain (a dimerization domain present in proteasome elements), motifs more commonly found in eukaryotic proteins. The aim of this perspective is to present open questions regarding the functional and structural features of Spo0M that make this protein a good candidate for the ancestor of arrestins in bacteria and an important element in developmental and differentiation processes of Bacillus subtilis. PMID- 28577221 TI - Concentration-dependent effects of PM2.5 mass on expressions of adhesion molecules and inflammatory cytokines in nasal mucosa of rats with allergic rhinitis. AB - Allergic rhinitis (AR) represents a clinical health issue affecting approximately 500 million people worldwide. This study aimed to explore the effects of airborne fine particulate matter (PM2.5) on the nasal mucosa of rats with AR. Seventy-five healthy male SD rats were included and randomly divided into the normal, model, low-concentration, middle-concentration, and high-concentration groups (15 rats each group). AR rat models were established using sensitized mixture and were stimulated using different concentrations of PM2.5. Sneeze and nose-scratching events were observed. Automatic hematology analyzer was utilized to count white blood cells (WBCs). The serum IgE, ICAM-1, and VCAM-1 expressions, eosinophil (EOS) infiltration, and IFN-gamma, IL-4, IL-5, IL-33, and TSLP expressions were detected by ELISA, HE staining, and qRT-PCR. Greater numbers of WBCs, increased IgE level, elevated levels of ICAM-1, VCAM-1, EOS, IFN-gamma, IL-4, IL-5, IL-33, and TSLP in the model, low-concentration, middle-concentration, and high concentration groups than the normal group. The same trend also exhibited in rats of the middle-concentration and high-concentration groups than that of the model and low-concentration groups. Comparisons between normal rats and AR rats indicated that AR rats exhibit remarkably higher cytokine expression levels of IFN-gamma, IL-4, IL-5, TSLP, and IL-33. The study revealed that as stimulation is triggered by PM2.5, AR rats result in increased levels of adhesion molecules and inflammatory cytokine expressions in a concentration-dependent manner. Analyses of PM2.5 as well as, its effects on AR are crucial in the continued drive for both prevention and management of the disease. PMID- 28577222 TI - Relationship Between the Relative Age Effect and Lengths of Professional Careers in Male Japanese Baseball Players: a Retrospective Analysis. AB - BACKGROUND: The mechanisms underlying the relative age effect in sport events have been investigated for more than two decades. The present study focused on the relationship between the relative age effect and lengths of professional careers among professional male Japanese baseball players. METHODS: The birth dates of players and lengths of professional careers were collected from an official publication, and data were divided into four quarters (Q1: April-June; Q2: July-September; Q3: October-December; Q4: January-March of the following year) grouped by 3 years. Based on the data for Q4, the expected numbers for the lengths of professional careers were calculated for Q1, Q2, and Q3. RESULTS: The number of players with professional careers of more than 19 years was significantly smaller in Q4 than in Q1, Q2, and Q3. CONCLUSIONS: The relative age effect among professional male Japanese baseball players was associated with the lengths of professional careers. Relative age appears to be a very important factor for the development of expertise among male Japanese baseball players and involves long-term disadvantages after becoming professional players. PMID- 28577223 TI - Correspondence between negative symptoms and potential sources of secondary negative symptoms over time. AB - There has been a debate in the literature about the distinction between primary and secondary negative symptoms of schizophrenia. Our aim was to study the associations between negative symptoms and potential sources of secondary negative symptoms over time. A sample of 275 participants with at least mid moderate negative symptoms was randomized into body psychotherapy or Pilates class in a previous study. No significant differences were found between groups over time and changes in the symptom domains were modest. The present investigation considers the longitudinal correlation between variables of interest at baseline, 3 and 9 months follow-up. Measures were the Clinical Assessment Interview for Negative Symptoms (CAINS), the Positive and Negative Symptom Scale (PANSS), the Calgary Depression Scale (CDSS) and the Simpson-Angus Extrapyramidal side-effects Scale (SAS). Mixed models were computed to test the longitudinal association between these variables. In a sensitivity analysis, the dosages of antipsychotic, illness duration and allocated intervention were taken into account. Overall, the course of extrapyramidal side-effects, depressive and positive symptoms was significantly related to the course of negative symptoms. Only extrapyramidal effects were longitudinally correlated to expressive negative symptoms. The sensitivity analyses showed unaltered results for positive symptoms and depression but a lack of association between extrapyramidal effects and the CAINS outcomes. In conclusion, the unambiguous interpretation between primary and secondary negative symptoms may lead to refined treatment approaches for schizophrenia and to increased effects of the interventions. PMID- 28577225 TI - High opioids tolerance due to transmucosal fentanyl abuse. PMID- 28577224 TI - Long-term use of proton pump inhibitors among community-dwelling persons with and without Alzheimer's disease. AB - PURPOSE: The aim of this study is to determine the prevalence of use and long term use (>=180 days) of proton pump inhibitors (PPIs) and associated factors among community-dwellers with and without Alzheimer's disease (AD). METHODS: MEDALZ cohort encompassed all persons who received a verified diagnosis of AD in Finland during the years 2005-2011 and their age-, sex-, and region of residence matched comparison persons, including 69,353 persons with and 69,353 persons without AD. Data was derived from several Finnish administrative registers. A mathematical modelling method, PRE2DUP, was used for converting dispensing data to drug use periods (when regular PPI use started and ended). Morbid conditions and concomitant drugs associated with use and long-term use of PPIs were assessed with logistic regression models. RESULTS: Use of PPIs was more common among comparison persons than persons with AD (39.0 and 35.8%, respectively, p < 0.001), whereas long-term use of PPIs was more frequent among persons with than without AD (20.3 and 17.9%, respectively, p < 0.001). Factors related to long term use of PPIs were female sex, history of gastrointestinal bleedings, AD, rheumatoid arthritis, cardiovascular disease, asthma/COPD and use of bisphosphonates, SSRIs and antithrombotic agents. Median follow-up time was 2.6 years among persons with AD and 3.5 years among persons without AD. Median duration of the first long-term PPI use was similar in both groups (1.4 years). CONCLUSION: Long-term use of PPIs was common among persons with and without AD. Due to possible adverse events associated with the long-term use of PPIs, need for PPIs should be assessed regularly. PMID- 28577226 TI - PET measurements of myocardial blood flow post myocardial infarction: Relationship to invasive and cardiac magnetic resonance studies and potential clinical applications. AB - This review focuses on clinical studies concerning assessment of coronary microvascular and conduit vessel function primarily in the context of acute and sub acute myocardial infarction (MI). The ability of quantitative PET measurements of myocardial blood flow (MBF) to delineate underlying pathophysiology and assist in clinical decision making in this setting is discussed. Likewise, considered are physiological metrics fractional flow reserve, coronary flow reserve, index of microvascular resistance (FFR, CFR, IMR) obtained from invasive studies performed in the cardiac catheterization laboratory, typically at the time of PCI for MI. The role both of invasive studies and cardiac magnetic resonance (CMR) imaging in assessing microvascular function, a key determinant of prognosis, is reviewed. The interface between quantitative PET MBF measurements and underlying pathophysiology, as demonstrated both by invasive and CMR methodology, is discussed in the context of optimal interpretation of the quantitative PET MBF exam and its potential clinical applications. PMID- 28577227 TI - [Search for risk genes in Alzheimer's disease]. AB - Alzheimer's disease (AD) is the most common form of neurodegenerative dementia. The susceptibility to AD is determined by a complex interaction between genetic, epigenetic, and environmental factors. Herein, the risk that can be attributed to genetic factors is high (up to 80%). While most AD patients are sporadic, in rare families Mendelian mode of inheritance can be observed. In these rare familial cases, full penetrant mutations have been identified in APP, PSEN1, and PSEN2. Mutations in these three genes are however rarely found in sporadic AD. For over 20 years, the only known genetic risk factor in sporadic AD cases was the APOE epsilon4 allele, which increases susceptibility to AD by approximately threefold. Unfortunately, none of these genes explain the frequency of AD. Identification of additional genetic factors was propelled by the advent of genomic approaches such as genome-wide association studies, which has already led to the characterization of 26 novel genetic risk factors. Interestingly, several of these genetic signals cluster in biological pathways including cholesterol, lipid metabolism, immune response, and endocytic trafficking. An additional impulse in genetic research came from the development of novel sequencing technologies. For example, the whole exome sequencing approach has identified an association between the risk of AD and rare coding variants (minor allele frequency <1%) located in genes such as TREM2, SORL1, and ABCA7. Thus, progress from genetic research has significantly increased our understanding of the disease mechanisms operating in AD. However, even though our knowledge of the genetics of sporadic forms of AD has progressed markedly over the last years, it is still far from complete. Additional research is needed to complete the genetic architecture of AD. PMID- 28577228 TI - Role of hepatectomy in gastric cancer with multiple liver-limited metastases. AB - BACKGROUND: Several studies have demonstrated the benefit of hepatectomy for treating gastric cancer (GC) with liver-limited metastases (LLM). The survival benefit of hepatectomy compared with that of systemic chemotherapy is unknown, particularly in patients with multiple LLM. This study investigated the survival benefit of hepatectomy compared with that of systemic chemotherapy administered to patients with GC with multiple LLM. METHODS: We retrospectively reviewed the data of consecutive patients with GC with two or three LLM who underwent hepatectomy or received systemic chemotherapy as initial treatment at the Shizuoka Cancer Center between December 2004 and December 2015. RESULTS: Nine of 24 patients who met the inclusion criteria underwent hepatectomy, and 15 received chemotherapy. In the hepatectomy group, all patients achieved R0 resection and none died during hospitalization. Three patients received adjuvant chemotherapy. Disease recurred in eight patients (88.9%). In the chemotherapy group, three patients underwent hepatectomy following initial chemotherapy and did not experience recurrence or death during follow-up. Median follow-up was 47.9 months and median overall survival (OS) was 38.1 and 24.8 months in the chemotherapy and hepatectomy groups, respectively. Multivariate analysis of OS, including initial treatment, revealed that unilobar liver metastasis was the only independent favorable prognostic factor. CONCLUSIONS: Although hepatectomy for patients with GC with multiple LLM is not recommended as the initial therapy, it prolonged the survival of patients with tumors controlled using systemic chemotherapy. PMID- 28577230 TI - The financial performance of the health care industry: a global, regional and industry specific empirical investigation. AB - This article analyzes the financial (out-) performance of all listed health care companies. The health care sector outperformed the market in the period from 2000 to June 2015. The performance was driven by companies from Americas, and Asia as well as companies from the pharmaceuticals sub-segment. Additionally, bull periods appear to be the main driver for the outperformance. Euro-based investors can expect different outcomes of their investments to those of USD investors. However, the main trends remain unchanged. PMID- 28577229 TI - Automated histological classification of whole-slide images of gastric biopsy specimens. AB - BACKGROUND: Automated image analysis has been developed currently in the field of surgical pathology. The aim of the present study was to evaluate the classification accuracy of the e-Pathologist image analysis software. METHODS: A total of 3062 gastric biopsy specimens were consecutively obtained and stained. The specimen slides were anonymized and digitized. At least two experienced gastrointestinal pathologists evaluated each slide for pathological diagnosis. We compared the three-tier (positive for carcinoma or suspicion of carcinoma; caution for adenoma or suspicion of a neoplastic lesion; or negative for a neoplastic lesion) or two-tier (negative or non-negative) classification results of human pathologists and of the e-Pathologist. RESULTS: Of 3062 cases, 33.4% showed an abnormal finding. For the three-tier classification, the overall concordance rate was 55.6% (1702/3062). The kappa coefficient was 0.28 (95% CI, 0.26-0.30; fair agreement). For the negative biopsy specimens, the concordance rate was 90.6% (1033/1140), but for the positive biopsy specimens, the concordance rate was less than 50%. For the two-tier classification, the sensitivity, specificity, positive predictive value, and negative predictive value were 89.5% (95% CI, 87.5-91.4%), 50.7% (95% CI, 48.5-52.9%), 47.7% (95% CI, 45.4-49.9%), and 90.6% (95% CI, 88.8-92.2%), respectively. CONCLUSIONS: Although there are limitations and requirements for applying automated histopathological classification of gastric biopsy specimens in the clinical setting, the results of the present study are promising. PMID- 28577232 TI - Impact of sleep disorders in cognitive function of thyroid cancer survivors. PMID- 28577231 TI - Electronic versus paper-pencil methods for assessing chemotherapy-induced peripheral neuropathy. AB - PURPOSE: The aim of this study is to examine and compare with the validated, paper/pencil European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy Scale (QLQ CIPN20), the psychometric properties of three electronically administered patient reported outcome (PRO) measures of chemotherapy-induced peripheral neuropathy (CIPN): (1) the two neuropathy items from the National Cancer Institute's Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), (2) the QLQ-CIPN20, and (3) the 0-10 Neuropathy Screening Question (NSQ). METHODS: We employed a descriptive, cross-sectional design and recruited 25 women with breast cancer who were receiving neurotoxic chemotherapy at an academic hospital. Participants completed the paper/pencil QLQ-CIPN20 and electronic versions of the QLQ-CIPN20, PRO-CTCAE, and NSQ. Internal consistency reliability, intraclass correlation, and concurrent and discriminant validity analyses were conducted. RESULTS: The alpha coefficients for the electronic QLQ CIPN20 sensory and motor subscales were 0.76 and 0.75. Comparison of the electronic and paper/pencil QLQ-CIPN20 subscales supported mode equivalence (intraclass correlation range >0.91). Participants who reported the presence of numbness/tingling via the single-item NSQ reported higher mean QLQ-CIPN20 sensory subscale scores (p < 0.001). PRO-CTCAE neuropathy severity and interference items correlated well with the QLQ-CIPN20 electronic and paper/pencil sensory (r = 0.76; r = 0.70) and motor (r = 0.55; r = 0.62) subscales, and with the NSQ (r = 0.72; r = 0.44). CONCLUSION: These data support the validity of the electronically administered PRO-CTCAE neuropathy items, NSQ, and QLQ-CIPN20 for neuropathy screening in clinical practice. The electronic and paper/pencil versions of the QLQ-CIPN can be used interchangeably based on evidence of mode equivalence. PMID- 28577233 TI - Zinc and Selenium Co-supplementation Reduces Some Lipid Peroxidation and Angiogenesis Markers in a Rat Model of NAFLD-Fed High Fat Diet. AB - Studies have shown that non-alcoholic fatty liver disease (NAFLD) patients are more prone to cardiovascular disease (CVD). Zinc and selenium deficiency are common in NAFLD. But the effects of zinc and selenium co-supplementation before and/or after disease progression on CVD markers are not clear in NAFLD patients. This study aimed to compare the effects of zinc and selenium co-supplementation before and/or after disease progression on some of the CVD markers in an experimental model of NAFLD. Forty male Sprague Dawley rats (197 +/- 4 g) were randomly assigned into four dietary groups: control group (C; received 9% of calorie as fat), model group (M; received 82% of calorie as fat), and supplementation before (BS) or after (AS) disease progression. Animals were fed diets for 20 weeks in all groups. Fasting plasma glucose (FPG), insulin, HOMA-IR, ALT, AST, lipid profile, malondialdehyde (MDA) and vascular endothelial growth factor (VEGF) levels were measured as CVD indices. Serum ALT, AST, FPG, insulin, MDA, VEGF and HOMA-IR were significantly higher in the M than C group. Co supplementation reduced serum ALT and AST levels in the BS and AS groups compared with the M group. FPG, insulin, HOMA-IR, VEGF, MDA, LDL/HDL-c and TC/HDL-c ratio were significantly reduced in the AS compared with the M group. TG/HDL-c ratio was significantly reduced in the BS and AS compared with the M group. Serum MDA, VEGF, Insulin and HOMA-IR were significantly lowered in the AS than BS group (p < 0.05). Zinc and selenium co-supplementation after NAFLD progression reduced CVD risk indices in an experimental model. PMID- 28577234 TI - Antagonistic Effect of Laver, Pyropia yezonensis and P. haitanensis, on Subchronic Lead Poisoning in Rats. AB - Lead, one of the most harmful heavy metals, can cause various hazardous effects on living organisms. This study was undertaken to evaluate the antagonistic and protective effects of two economically important laver species, Pyropia yezoensis and P. haitanensis, against subchronic lead poisoning in rats by a 30-day feeding test. Sixty-four healthy Wistar rats were randomly divided into eight groups with eight rats (4? + 4?) per group, among which, one group was served as the control, the others were respectively treated with lead acetate (5 mg/kg b w), and a combination of lead acetate and P. yezoensis or P. haitanensis at different dosages. Weight gain of rats was observed and recorded. Changes in antioxidant indexes, and liver and renal function markers were determined to evaluate the antagonistic effect. Lead content in rats was determined to investigate lead excretion effect of laver. The results showed that exposure to lead caused lead accumulation in kidney and liver, thus leading to significant oxidative damage and impaired liver and renal function compared to the control group. The co treatment of laver slightly increased body weight compared to the lead-treated group. The co-administration of laver restored liver and renal function of rats by preventing the increment in the activities of alanine transaminase (ALT), alkaline phosphatase (ALP), and aspartate transaminase (AST), and the levels of blood urea nitrogen (BUN) and creatinine (Cr). The increasing of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities, and lowering of the enhanced malondialdehyde (MDA) contents of rats were observed in the laver co treated groups, which indicated that laver enhanced the antioxidative capacity of rats. The laver also enhanced lead content in feces and reduced it in liver and kidney. The results indicated that P. yezoensis and P. haitanensis could maintain or promote the normal physiological and biochemical function of lead-induced subchronic poisoning of rats, probably owing to their enhancements of antioxidant capacity and lead excretion. PMID- 28577235 TI - Dietary Iodine Affected the GSH-Px to Regulate the Thyroid Hormones in Thyroid Gland of Rex Rabbits. AB - Iodine (I) is an essential trace element that can influence animal health and productivity. In this study, we investigated the effects of dietary iodine on the antioxidant indices of organ (liver and thyroid gland) and messenger RNA (mRNA) expression of glutathione peroxidase (GSH-Px) in Rex rabbits. A total of 120 4 month-old Rex rabbits (2235.4 +/- 13.04 g BW) were divided into four equal groups, and their diets were supplemented with iodine (0, 0.2, 2, or 4 mg/kg dry matter (DM)). The iodine concentration in basal diet (control group) was 0.36 mg/kg DM. In most of measured parameters, supplemental iodine exerted no significant effect. Growth and slaughter performance and organ weight were not influenced significantly by iodine supplementation. Serum T3 was significantly lower in 2-mg I group than in 0.2 and 4-mg I groups (P < 0.05). Superoxide dismutase (SOD), GSH-Px, methane dicarboxylic aldehyde (MDA), and thyroperoxidase (TPO) in the serum and liver were not influenced (P > 0.05). Conversely, serum catalase (CAT) was significantly reduced (P < 0.05). In the thyroid, GSH-Px was higher in the 2-mg I group than in the 0.2- and 4-mg I groups (P < 0.05). RT-PCR results showed that the mRNA expression level of GSH-Px in the liver was not significantly influenced (P > 0.05). In the thyroid gland, the mRNA expression level of GSH-Px was higher in the 2-mg I group than in the 4-mg I group (P < 0.05), which agreed with the activity of GSH-Px. In conclusion, iodine supplementation exerted no effect on the performance and antioxidant capacity of the body, but dietary iodine influenced serum T3 or GSH-Px in the thyroid gland. Thus, on the basis of serum T3 and GSH-Px levels in the thyroid gland, we hypothesized that GSH-Px secretion was increased by adding dietary iodine in the thyroid, which may inhibit the H2O2 generation and further influence the thyroid hormone synthesis. PMID- 28577236 TI - Glutathione S-transferase related detoxification processes are correlated with receptor-mediated vacuolar sorting mechanisms. AB - KEY MESSAGE: Triticum durum Glutathione S-transferase Z1 is specifically responsive to glyphosate. Its expression influences the receptor-mediated vacuolar sorting mechanisms involved in tolerance mechanisms. A zeta subfamily glutathione S-transferase gene from Triticum durum (cv Cappelli) (TdGSTZ1) was characterized as part of a complex detoxification mechanism. The effect of different abiotic stresses on TdGSTZ1 revealed that the gene is unexpectedly responsive to glyphosate (GLY) herbicide despite it should not be part of tolerance mechanisms. Its role in the non-target-site mechanism of GLY resistance was then investigated. To analyze the GLY and the TdGSTZ1 overexpression effects on vacuolar sorting mechanisms, we performed transient transformation experiments in Nicotiana tabacum protoplasts using two vacuolar markers, AleuGFPgl133 and GFPgl133Chi, labeling the Sar1 dependent or independent sorting, respectively. We observed that the adaptive reaction of tobacco protoplasts vacuolar system to the treatment with GLY could be partially mimicked by the overexpression of TdGSTZ1 gene. To confirm the influence of GLY on the two vacuolar markers accumulation and the potential involvement of the secretion pathway activity in detoxification events, Arabidopsis thaliana transgenic plants overexpressing the non glycosylated versions of the two markers were analyzed. The results suggested that GLY treatment specifically altered different vacuolar sorting characteristics, suggesting an involvement of the receptor-mediated AleuGFP sorting mechanism in GLY resistance. Finally, the expression analysis of selected genes confirmed that the non-target-site GLY resistance mechanisms are related to vacuolar sorting. PMID- 28577237 TI - Insertion of a solo LTR retrotransposon associates with spur mutations in 'Red Delicious' apple (Malus * domestica). AB - KEY MESSAGE: Insertion of a solo LTR, which possesses strong bidirectional, stem specific promoter activities, is associated with the evolution of a dwarfing apple spur mutation. Spur mutations in apple scions revolutionized global apple production. Since long terminal repeat (LTR) retrotransposons are tightly related to natural mutations, inter-retrotransposon-amplified polymorphism technique and genome walking were used to find sequences in the apple genome based on these LTRs. In 'Red Delicious' spur mutants, a novel, 2190-bp insertion was identified as a spur-specific, solo LTR (sLTR) located at the 1038th nucleotide of another sLTR, which was 1536 bp in length. This insertion-within-an-insertion was localized within a preexisting Gypsy-50 retrotransposon at position 3,762,767 on chromosome 4. The analysis of transcriptional activity of the two sLTRs (the 2190 and 1536-bp inserts) indicated that the 2190-bp sLTR is a promoter, capable of bidirectional transcription. GUS expression in the 2190-bp-sense and 2190-bp antisense transgenic lines was prominent in stems. In contrast, no promoter activity from either the sense or the antisense strand of the 1536-bp sLTR was detected. From ~150 kb of DNA on each side of the 2190 bp, sLTR insertion site, corresponding to 300 kb of the 'Golden Delicious' genome, 23 genes were predicted. Ten genes had predicted functions that could affect shoot development. This first report, of a sLTR insertion associated with the evolution of apple spur mutation, will facilitate apple breeding, cloning of spur-related genes, and discovery of mechanisms behind dwarf habit. PMID- 28577239 TI - Population pharmacokinetic analyses of the effect of carboplatin pretreatment on olaparib in recurrent or refractory women's cancers. AB - PURPOSE: Combining olaparib with carboplatin was recently shown to be active in both BRCA and non-BRCA mutant cancers in a recent phase I/Ib combination trial. The optimal drug sequence recommended was carboplatin 1-day before olaparib. However, carboplatin pre-treatment induced a ~50% faster olaparib clearance. METHODS: To further explore this drug interaction, a population pharmacokinetic (PK) model was designed that included a lag time parameter, a second absorption compartment from tablet formulation, a single distribution/elimination compartment, and covariance among the clearance and volume parameters. RESULTS: Clearance (6.8 L/h) and volume (33 L) estimates were comparable with literature. The only significant covariate was the presence of carboplatin on olaparib clearance, consistent with published noncompartmental PK and in vitro data. CONCLUSIONS: Simulations predicted lower steady-state peak/trough olaparib exposure through 24-36 h post carboplatin pre-treatment, but this effect was lost by day 2 and thus no dose adjustment is recommended. PMID- 28577238 TI - Dihedral angle preferences of amino acid residues forming various non-local interactions in proteins. AB - In theory, a polypeptide chain can adopt a vast number of conformations, each corresponding to a set of backbone rotation angles. Many of these conformations are excluded due to steric overlaps. Ramachandran and coworkers were the first to look into this problem by plotting backbone dihedral angles in a two-dimensional plot. The conformational space in the Ramachandran map is further refined by considering the energetic contributions of various non-bonded interactions. Alternatively, the conformation adopted by a polypeptide chain may also be examined by investigating interactions between the residues. Since the Ramachandran map essentially focuses on local interactions (residues closer in sequence), out of interest, we have analyzed the dihedral angle preferences of residues that make non-local interactions (residues far away in sequence and closer in space) in the folded structures of proteins. The non-local interactions have been grouped into different types such as hydrogen bond, van der Waals interactions between hydrophobic groups, ion pairs (salt bridges), and pipi stacking interactions. The results show the propensity of amino acid residues in proteins forming local and non-local interactions. Our results point to the vital role of different types of non-local interactions and their effect on dihedral angles in forming secondary and tertiary structural elements to adopt their native fold. PMID- 28577240 TI - A Rhodamine-Based Fluorescent Chemosensor for the Detection of Pb2+, Hg2+ and Cd2. AB - A new rhodamine-based fluorescent chemosensor (1) has been designed and synthesized by linking rhodamine 6G hydrazide with N-methylisatin via an imine linkage. The receptor can selectively recognize and sense Pb2+, Hg2+ and Cd2+ by showing different fluorescence characteristics. In ethanol/HEPES buffer medium, the addition of Cd2+ caused a yellowish-green fluorescence, while the presence of Pb2+ or Hg2+ gave rise to an orange fluorescence. Additionally, the sensor shows an irreversible fluorescence response to Pb2+ and reversible fluorescence responses to Hg2+ and Cd2+. PMID- 28577242 TI - Divergence in the approach to tumor necrosis factor alpha-inhibitor recipients with coccidioidomycosis. AB - BACKGROUND: Tumor necrosis factor alpha-inhibitors (TNFIs) have been associated with increased risk of certain fungal infections, including coccidioidomycosis. The optimal treatment approach to coccidioidomycosis in TNFI recipients is unknown. METHODS: We constructed an anonymous, voluntary survey for practicing pulmonary and infectious disease physicians in the state of Arizona regarding approach to TNFI patients with coccidioidomycosis. RESULTS: There is no current consensus on managing these patients. CONCLUSIONS: Further research is necessary to determine the optimal approach to TNFI recipients with coccidioidomycosis. PMID- 28577243 TI - Review on the Biological Mechanisms Associated with Depo-Provera and HIV-1 Risk Acquisition in Women. AB - Women constitute more than 50% out of millions of individuals infected with HIV 1, the major causative agent of acquired immune deficiency syndrome. About 40% of HIV-1 infections have been reported to initiate in the female reproductive tract. However, the mechanisms through which these infections are spread are poorly understood; hence, there is now a major concern in women who use long acting injectable hormonal contraceptives, particularly Depo-Provera and an increase of HIV-1 risk acquisition. Based on literature, Depo-Provera has an affinity for both the glucocorticoid receptor and the progesterone receptor in the female reproductive tract. Therefore, investigating HIV-1 pathogenesis in the female reproductive tract via the glucocorticoid receptor and the progesterone receptor mechanisms in response to the effect of Depo-Provera is of great importance. PMID- 28577241 TI - Human infectious diseases and risk of preeclampsia: an updated review of the literature. AB - BACKGROUND: Preeclampsia (PE) is one of the major causes of maternal and perinatal morbidity and mortality, especially in low- and middle-income countries. In recent years, a growing body of literatures suggests that infections by bacteria, viruses, and parasites and their related inflammations play an important role in the pathogenesis of PE. METHODS: We searched PubMed, Google scholar, and Cochrane databases using the following search words: "infection and preeclampsia," "bacterial infection and preeclampsia," "viral infection and preeclampsia" and "parasitic infection and preeclampsia." RESULTS: The literature review revealed that many bacteria including Helicobacter pylori, Chlamydia pneumonia, and those are involved in periodontal disease or urinary tract infections (UTIs) and some viral agents such as Cytomegalovirus, herpes simplex virus type-2, human immunodeficiency virus, and some parasites especially Plasmodium spp. and Toxoplasma gondii can be effective in development of PE. Inflammation responses against infections has major role in the inducement of PE. The shift of immunological cytokine profile of Th2 toward Th1 and high levels of pro-inflammatory cytokines (TNF-alpha, IL-12, IFN-gamma, etc.), increase of oxidative stress, increase of anti-angiogenic proteins, increase of vascular endothelial growth factor receptor 1 (sVEGFR1), and complement C5a are the main potential mechanisms related to infections and enhanced development of PE. CONCLUSION: Thus, early diagnosis and treatment of bacterial, viral, and parasitic infections could be an effective strategy to reduce the incidence of PE. PMID- 28577246 TI - Gestational Weight Gain: A New Factor Influencing Pregnancy Outcomes in Women with Inflammatory Bowel Disease. PMID- 28577244 TI - Furazolidone, an Underutilized Drug for H. pylori Eradication: Lessons from Iran. AB - BACKGROUND: Treatment success of H. pylori eradication therapy has declined worldwide largely because of increased antimicrobial resistance. New therapeutic approaches are needed, especially for countries like Iran, where resistance to commonly used drugs is already widespread and traditional H. pylori therapies produce poor cure rates. AIM: To review the results of quadruple therapy trials containing bismuth and furazolidone in Iran. METHODS: We searched PubMed, Google scholar as well as the references of all published papers for studies conducted in Iran, utilizing furazolidone in the treatment of H. pylori infections. The target population was four drug studies that utilized a combination of bismuth, furazolidone, amoxicillin, or tetracycline plus a proton pump inhibitor. RESULTS: Eighteen studies with 22 arms including 1713 subjects were found. The weighted mean cure rate for 14-day studies (six studies) using 200 mg b.i.d. furazolidone was 80% intention to treat (ITT) and 87% per protocol (PP). Studies using 100 mg b.i.d. (three studies) were less effective (weighted mean ITT cure rate = 67%). One small 14-day study with furazolidone 100 mg q.i.d. achieved cure rates of 94.5% ITT and PP. CONCLUSIONS: Although furazolidone-bismuth quadruple therapy proved relatively effective in Iran, furazolidone-containing regimens remain to be optimized. Based on these data and results from China, it appears likely that 14-day therapy containing furazolidone 100 mg t.i.d. or q.i.d. is likely to provide the highest cure rates with lowest side effects; this remains to be experimentally tested. Detailed suggestions for further development of furazolidone-containing regimens are provided. PMID- 28577245 TI - From Harmful Treatment to Secondary Gain: Adverse Event Reporting in Dyspepsia and Gastroparesis. AB - INTRODUCTION: Medical management of gastroparesis and functional dyspepsia remains difficult with several recent trials showing limited or no benefit. If treatment comes with only marginal improvements, concerns about adverse events become more relevant. We therefore examined the type and outcomes of side effects submitted to a public repository. METHODS: We searched the Federal Adverse Event Reporting System for reports associated with the treatment of dyspepsia or gastroparesis. Demographic data, medications used and implicated, side effects, and outcomes were abstracted for the years 2004-2015. RESULTS: Acid-suppressive agents and prokinetics were the most commonly listed medications with a stronger emphasis on prokinetics in gastroparesis. Submissions related to metoclopramide by far exceeded reports about other agents and mostly described tardive dyskinesia or other neurological concerns. They peaked around 2012, driven by submissions through legal workers. Most reports about metoclopramide described short-term use to prevent or treat nausea and vomiting. Concerns about acid suppressive medications increased over time and spanned a wide spectrum of potential problems, including osteoporosis, worsening renal function, or cardiac events. CONCLUSION: Despite biasing factors, such as pending legal action, the voluntary repository of adverse events provides insight into current medical practice and its associated risk. Knowing about common and uncommon, but potentially serious risks may enable patients and providers to decide on effective and safe management strategies. PMID- 28577247 TI - Controlled Attenuation Parameter (CAP) with the XL Probe of the Fibroscan(r): A Comparative Study with the M Probe and Liver Biopsy. AB - INTRODUCTION: Controlled attenuation parameter (CAP) is a new method for the diagnosis of steatosis. Until now, CAP was available only with the M probe of the Fibroscan. The aim of this study was to evaluate the diagnostic performance of CAP with the XL probe versus CAP with the M probe, using liver biopsy (LB) as gold standard. PATIENTS AND METHODS: A total of 236 patients with chronic liver disease undergoing LB had CAP measurement with M and XL probes the same day. All LB were analyzed independently by two experienced pathologists. RESULTS: Median CAP was 240.5 and 239.5 dB/m with the M and XL probes, respectively. For the detection of steatosis grade with the M and XL probes, AUROCs were 0.82/0.83 for S >= 1, 0.89/0.88 for S >= 2, and 0.92/0.93 for S3, respectively. Cutoffs were (M and XL probes) 246/242 for S >= 1, 269/267 for S >= 2, and 285/286 dB/m for S3, respectively. The factor significantly associated with CAP with the M and XL probes was steatosis grade. In multivariate analysis, a low CAP value with XL probe was negatively associated with waist circumference, triglycerides, albumin, and the alcohol consumption, and positively with alkaline phosphatases. In multivariate analysis, a high CAP value with the XL probe was positively associated with waist circumference and triglycerides. CONCLUSION: CAP with the XL probe is a new tool for the diagnosis of steatosis. This parameter could be useful for the diagnosis and the follow-up of obese patients. PMID- 28577249 TI - Progeny production in the periplasm of Thermosipho globiformans. AB - Thermotogales are rod-shaped, Gram-negative, anaerobic, (hyper) thermophiles distinguished by an outer sheath-like toga, which comprises an outer membrane (OM) and an amorphous layer (AL). Thermosipho globiformans bacteria can transform into spheroids with multiple cells concurrently with AL disintegration during early growth; the cell is defined as the cytoplasmic membrane (CM) plus the entity surrounded by the CM. Spheroids eventually produce rapidly moving periplasmic 'progenies' through an unknown mechanism. Here, we used high temperature microscopy (HTM) to directly observe spheroid generation and growth. Rod OMs abruptly inflated to form ~2 MUm-diameter balloons. Concurrently, multiple globular cells emerged in the balloons, suggesting their translocation and transformation from the rod state. During spheroid growth, the cells elongated and acquired a large dish shape by possible fusion. Spheroids with dish shaped cells further enlarged to ~12 MUm in diameter. HTM and epifluorescence microscopy results collectively indicated that the nucleoids of dish-shaped cells transformed to form a ring shape, which then distorted to form a lip shape as the spheroid enlarged. HTM showed that 'progenies' were produced in the spheroid periplasm. Transmission electron microscopy results suggested that the 'progenies' represented immature progenies lacking togas, which were acquired subsequently. PMID- 28577248 TI - Pathological Findings of the Antral and Pyloric Smooth Muscle in Patients with Gastroparesis-Like Syndrome Compared to Gastroparesis: Similarities and Differences. AB - BACKGROUND: Gastroparesis (GP)-like syndrome presents with the symptoms of GP but without delayed gastric emptying (GE). Whether GP-like syndrome is part of a spectrum of GP is not clear. This study aimed to compare the histopathological features of antral and pyloric smooth muscle tissue in GP and GP-like syndrome. METHODS: Full-thickness antral and/or pyloric biopsies were obtained from 37 GP and 18 GP-like syndrome patients who underwent abdominal surgery to place a gastric electrical stimulator or jejunal feeding tube and/or pyloroplasty. The tissues were stained with H&E, C-Kit, and trichrome. Based on previous control data, an interstitial cells of Cajal (ICC) count of <10 per high power field in the antrum and/or pylorus was considered depletion. Baseline total symptom score (TSS) was recorded. RESULTS: Twenty-four GP and 7 GP-like patients had pyloric biopsies. Pyloric ICC loss was observed in 20/24 (83.3%) GP and 2/7 (28.6%) GP like patients (p < 0.01). Fibrosis was detected in the pyloric tissue of 20/24 (83.3%) GP and 2/7 (28.6%) GP-like patients who had pyloric trichrome staining (p < 0.01). Seventeen out of 24 (70.8%) GP patients with pyloric biopsies had concomitant pyloric ICC loss and fibrosis, while only one GP-like patient had ICC loss and simultaneous pyloric fibrosis. GP patients had a greater TSS compared to GP-like patients. In GP patients, those with pyloric ICC loss had a greater TSS compared to those with normal ICC. GP patients with pyloric fibrosis had a higher TSS compared to those without pyloric fibrosis. CONCLUSIONS: Compared to GP-like patients, the pyloric histopathological findings of ICC loss and fibrosis are common in GP and predict a greater symptom score. These pathological findings might be considered as markers of "pyloric dysfunction" and explain delayed GE in GP. PMID- 28577250 TI - Bone mineral density in older patients with never-treated congenital hypogonadotropic hypogonadism. PMID- 28577251 TI - [Anti-infective strategies in trauma surgery Part 1]. PMID- 28577252 TI - ? PMID- 28577253 TI - Am I ready for it? Students' perceptions of meaningful feedback on entrustable professional activities. AB - BACKGROUND: Receiving feedback while in the clinical workplace is probably the most frequently voiced desire of students. In clinical learning environments, providing and seeking performance-relevant information is often difficult for both supervisors and students. The use of entrustable professional activities (EPAs) can help to improve student assessment within competency-based education. This study aimed to illustrate what students' perceptions are of meaningful feedback viewed as conducive in preparing for performing EPA unsupervised. METHODS: In a qualitative multicentre study we explored students' perceptions on meaningful feedback related to EPAs in the clinical workplace. Focus groups were conducted in three different healthcare institutes. Based on concepts from the literature, the transcripts were coded, iteratively reduced and displayed. RESULTS: Participants' preferences regarding meaningful feedback on EPAs were quite similar, irrespective of their institution or type of clerkship. Participants explicitly mentioned that feedback on EPAs could come from a variety of sources. Feedback must come from a credible, trustworthy supervisor who knows the student well, be delivered in a safe environment and stress both strengths and points for improvement. The feedback should be provided immediately after the observed activity and include instructions for follow-up. Students would appreciate feedback that refers to their ability to act unsupervised. CONCLUSION: There is abundant literature on how feedback should be provided, and what factors influence how feedback is sought by students. This study showed that students who are training to perform an EPA unsupervised have clear ideas about how, when and from whom feedback should be delivered. PMID- 28577255 TI - Erratum to: Intra-procedural determination of viability by myocardial deformation imaging: a randomized prospective study in the cardiac catheter laboratory. PMID- 28577254 TI - The value of whole-brain CT perfusion imaging and CT angiography using a 320 slice CT scanner in the diagnosis of MCI and AD patients. AB - OBJECTIVES: To validate the value of whole-brain computed tomography perfusion (CTP) and CT angiography (CTA) in the diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: Whole-brain CTP and four-dimensional CT angiography (4D-CTA) images were acquired in 30 MCI, 35 mild AD patients, 35 moderate AD patients, 30 severe AD patients and 50 normal controls (NC). Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and correlation between CTP and 4D-CTA were analysed. RESULTS: Elevated CBF in the left frontal and temporal cortex was found in MCI compared with the NC group. However, TTP was increased in the left hippocampus in mild AD patients compared with NC. In moderate and severe AD patients, hypoperfusion was found in multiple brain areas compared with NC. Finally, we found that the extent of arterial stenosis was negatively correlated with CBF in partial cerebral cortex and hippocampus, and positively correlated with TTP in these areas of AD and MCI patients. CONCLUSIONS: Our findings suggest that whole-brain CTP and 4D CTA could serve as a diagnostic modality in distinguishing MCI and AD, and predicting conversion from MCI based on TTP of left hippocampus. KEY POINTS: * Whole-brain perfusion using the full 160-mm width of 320 detector rows * Provide clinical experience of 320-row CT in cerebrovascular disorders of Alzheimer's disease * Initial combined 4D CTA-CTP data analysed perfusion and correlated with CT angiography * Whole-brain CTP and 4D-CTA have high value for monitoring MCI to AD progression * TTP in the left hippocampus may predict the transition from MCI to AD. PMID- 28577256 TI - Dominance and social information use in a lizard. AB - There is mounting evidence that social learning is not just restricted to group living animals, but also occurs in species with a wide range of social systems. However, we still have a poor understanding of the factors driving individual differences in social information use. We investigated the effects of relative dominance on social information use in the eastern water skink (Eulamprus quoyii), a species with age-dependent social learning. We used staged contests to establish dominant-subordinate relationships in pairs of lizards and tested whether observers use social information to more quickly solve both an association and reversal learning task in situations where the demonstrator was either dominant or subordinate. Surprisingly, we found no evidence of social information use, irrespective of relative dominance between observer and demonstrator. However, dominant lizards learnt at a faster rate than subordinate lizards in the associative learning task, although there were no significant differences in the reversal task. In light of previous work in this species, we suggest that age may be a more important driver of social information use because demonstrators and observers in our study were closely size-matched and were likely to be of similar age. PMID- 28577257 TI - Effects of Vitamin D Supplementation on Serum 25-Hydroxyvitamin D Concentrations and Physical Performance in Athletes: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: There is currently no systematic review examining the effects of vitamin D supplementation among athletes. A rigorous systematic review and meta analysis is important to provide a balanced view of current knowledge on the effect of vitamin D on serum 25-hydroxyvitamin D [25(OH)D] concentrations and physical performance. OBJECTIVES: This systematic review of randomized controlled trials (RCTs) evaluated the effects of oral vitamin D supplementation on serum 25(OH)D concentrations and physical performance in athletes. METHODS: Multiple electronic databases were searched, and study eligibility, methodological quality assessment, and data extraction were completed independently and in duplicate. Studies were stratified by baseline vitamin D sufficiency, season, and latitude. A cut-off of 30 ng/ml (75 nmol/l) of 25(OH)D was used for sufficiency. Absolute mean differences (AMDs) between vitamin D and placebo using random effects analysis, and heterogeneity using Q statistic and I 2 index, were calculated. AMD with 95% confidence interval (CI), p value, and I 2 are reported. RESULTS: In total, 13 RCTs (2005-2016) with 532 athletes (vitamin D 311, placebo 221) were eligible. A total of 433 athletes (vitamin D 244, placebo 189) had complete outcome data. Among athletes with baseline values suggesting insufficiency, vitamin D supplementation led to significant increases from 3000 IU (AMD 15.2 ng/ml; 95% CI 10.7-19.7, p < 0.0001, I 2 = 0%) and 5000 IU (AMD 27.8 ng/ml; 95% CI 16.9-38.8, p < 0.0001, I 2 = 78%) per day at >45 degrees latitudes. Both doses led to sufficiency concentrations during winter months. Among athletes with baseline vitamin D suggesting sufficiency, serum 25(OH)D sufficiency was maintained from different doses at both latitudes. Of 13 included trials, only seven measured different physical performances and none demonstrated a significant effect of vitamin D supplementation during 12 weeks of follow-up. CONCLUSION: Despite achieving sufficiency in vitamin D concentrations from >=3000 IU supplementation, physical performance did not significantly improve. Between study heterogeneity was large, and well-designed RCTs examining the effect of vitamin D supplementation on serum 25(OH)D concentrations, physical performance, and injuries in different sports, latitudes, ethnicities, and vitamin D status are needed. PMID- 28577259 TI - ? PMID- 28577263 TI - Modelling for the proposed roll-out of the '111' service in Wales: a case study. AB - NHS Direct Wales provides a single point of access where members of the public can telephone and seek medical support and/or advice. The service is provided for all the Health Boards in Wales by a single virtual call centre run from a main location in Swansea with 2 satellite locations. Patients in Wales can also access a local General Practitioner service during the evenings and at weekends, by phoning their Out of Hours service. The introduction of a '111' service is intended to combine these two operations on a pan-Wales basis using the existing NHS Direct Wales call centre and staff, with the existing Health Board Out of Hours 'hubs'. The merger of the two services is intended to improve the overall performance of both services. This paper focuses on the planned introduction of '111' in Cwm Taf and Hywel Dda University Health Boards. The purpose of the case study was to support the merger of the two telephony systems from both an organisational and service delivery perspective, by developing a Discrete Event Simulation to model the impact on service levels and staffing. In particular, to examine the percentage increase / decrease in the staffing requirements needed under partial or full integration of the two services. The results from the scenario analysis highlight that extra staffing resources would be required in certain groups (nurses and call handlers) whilst savings could be achieved in others, provided that there wasn't an increase in call volume after implementation of the new service. PMID- 28577262 TI - Altered EEG spectral power during rest and cognitive performance: a comparison of preterm-born adolescents to adolescents with ADHD. AB - Preterm birth has been associated with an increased risk for ADHD-like behavioural symptoms and cognitive impairments. However, direct comparisons across ADHD and preterm-born samples on neurophysiological measures are limited. The aim of this analysis was to test whether quantitative EEG (QEEG) measures identify differences or similarities in preterm-born adolescents, compared to term-born adolescents with and without ADHD, during resting-state and cognitive task conditions. We directly compared QEEG activity between 186 preterm-born adolescents, 69 term-born adolescents with ADHD and 135 term-born control adolescents during an eyes-open resting-state condition (EO), which previously discriminated between the adolescents with ADHD and controls, and during a cued continuous performance task (CPT-OX). Absolute delta power was the only frequency range to demonstrate a significant group-by-condition interaction. The preterm group, like the ADHD group, displayed significantly higher delta power during EO, compared to the control group. In line with these findings, parent-rated ADHD symptoms in the preterm group were significantly correlated with delta power during rest. While the preterm and control groups did not differ with regard to absolute delta power during CPT-OX, the ADHD group showed significantly higher absolute delta power compared to both groups. Our results provide evidence for overlapping excess in the absolute delta range in preterm-born adolescents and term-born adolescents with ADHD during rest. During CPT-OX, preterm-born adolescents resembled controls. Increased delta power during rest may be a potential general marker of brain trauma, pathology or neurotransmitter disturbances. PMID- 28577264 TI - Negative and Positive Emotion Responses to Daily School Problems: Links to Internalizing and Externalizing Symptoms. AB - Examining emotion reactivity and recovery following minor problems in daily life can deepen our understanding of how stress affects child mental health. This study assessed children's immediate and delayed emotion responses to daily problems at school, and examined their correlations with psychological symptoms. On 5 consecutive weekdays, 83 fifth graders (M = 10.91 years, SD = 0.53, 51% female) completed brief diary forms 5 times per day, providing repeated ratings of school problems and emotions. They also completed a one-time questionnaire about symptoms of depression, and parents and teachers rated child internalizing and externalizing problems. Using multilevel modeling techniques, we assessed within-person daily associations between school problems and negative and positive emotion at school and again at bedtime. On days when children experienced more school problems, they reported more negative emotion and less positive emotion at school, and at bedtime. There were reliable individual differences in emotion reactivity and recovery. Individual-level indices of emotion responses derived from multilevel models were correlated with child psychological symptoms. Children who showed more negative emotion reactivity reported more depressive symptoms. Multiple informants described fewer internalizing problems among children who showed better recovery by bedtime, even after controlling for children's average levels of exposure to school problems. Diary methods can extend our understanding of the links between daily stress, emotions and child mental health. Recovery following stressful events may be an important target of research and intervention for child internalizing problems. PMID- 28577265 TI - On the injectability of free-standing magnetic nanofilms. AB - Free-standing films with sub-micrometric thickness, composed of soft polymers and functional nanostructures are promising candidates for many potential applications in the biomedical field, such as reduced port abdominal surgery. In this work, freely suspended poly(L-lactic acid) nanofilms with controlled morphology embedding superparamagnetic iron oxide nanoparticles were fabricated by spin-coating deposition. The mechanical properties of magnetic nanofilms were investigated by Strain-Induced Elastic Buckling Instability for Mechanical Measurements (SIEBIMM) test. Our results show that these freely suspended nanocomposite nanofilms are highly flexible and deformable, with Young's moduli of few GPa. Since they can be handled in liquid with syringes, a quantitative description of the nanofilms behavior during the manipulation with clinically applicable needles has been also provided. These magnetic nanofilms, remotely controllable by external electromagnetic fields, have potential applications in minimally invasive surgery as injectable nanopatches on inner organs wall. Graphical abstract ?. PMID- 28577258 TI - "Beet-ing" the Mountain: A Review of the Physiological and Performance Effects of Dietary Nitrate Supplementation at Simulated and Terrestrial Altitude. AB - Exposure to altitude results in multiple physiological consequences. These include, but are not limited to, a reduced maximal oxygen consumption, drop in arterial oxygen saturation, and increase in muscle metabolic perturbations at a fixed sub-maximal work rate. Exercise capacity during fixed work rate or incremental exercise and time-trial performance are also impaired at altitude relative to sea level. Recently, dietary nitrate (NO3-) supplementation has attracted considerable interest as a nutritional aid during altitude exposure. In this review, we summarise and critically evaluate the physiological and performance effects of dietary NO3- supplementation during exposure to simulated and terrestrial altitude. Previous investigations at simulated altitude indicate that NO3- supplementation may reduce the oxygen cost of exercise, elevate arterial and tissue oxygen saturation, improve muscle metabolic function, and enhance exercise capacity/performance. Conversely, current evidence suggests that NO3- supplementation does not augment the training response at simulated altitude. Few studies have evaluated the effects of NO3- at terrestrial altitude. Current evidence indicates potential improvements in endothelial function at terrestrial altitude following NO3- supplementation. No effects of NO3- supplementation have been observed on oxygen consumption or arterial oxygen saturation at terrestrial altitude, although further research is warranted. Limitations of the present body of literature are discussed, and directions for future research are provided. PMID- 28577266 TI - Reimagining Childhood: Responding to the Challenge Presented by Severe Developmental Disability. AB - Through an exploration of the experience of severe and profound intellectual disability, this essay will attempt to expose the predominant, yet usually obscured, medical anthropology of the child and examine its effects on pediatric bioethics. I will argue that both modern western society and modern western medicine do, actually, have a robust notion of the child, a notion which can find its roots in three influential thinkers: Aristotle, Immanuel Kant and Jean Piaget. Together, these philosophers offer us a compelling vision: the child is primarily a future rational, autonomous adult. While this tacit understanding has arguably widespread effects on such things as our concept of good parenting, of proper schooling, and so on, I will focus on the effect is has on the treatment of children with severe developmental disabilities. When examined in light of this population, the dominant medical anthropology of the child will be shown to be deficient. Instead, I argue for an expansion-indeed, a full reimagining-of our notions of childhood, not only to re-infuse dignity into the lives of children with SDD, but to better represent the goods of childhood, generally. PMID- 28577267 TI - Cognitive training in Alzheimer's disease: a controlled randomized study. AB - This controlled randomized single-blind study evaluated the effects of cognitive training (CT), compared to active music therapy (AMT) and neuroeducation (NE), on initiative in patients with mild to moderate Alzheimer's disease (AD). Secondarily, we explored the effects of CT on episodic memory, mood, and social relationships. Thirty-nine AD patients were randomly assigned to CT, AMT, or NE. Each treatment lasted 3 months. Before, at the end, and 3 months after treatment, neuropsychological tests and self-rated scales assessed initiative, episodic memory, depression, anxiety, and social relationships. At the end of the CT, initiative significantly improved, whereas, at the end of AMT and NE, it was unchanged. Episodic memory showed no changes at the end of CT or AMT and a worsening after NE. The rates of the patients with clinically significant improvement of initiative were greater after CT (about 62%) than after AMT (about 8%) or NE (none). At the 3-month follow-up, initiative and episodic memory declined in all patients. Mood and social relationships improved in the three groups, with greater changes after AMT or NE. In patients with mild to moderate AD, CT can improve initiative and stabilize memory, while the non-cognitive treatments can ameliorate the psychosocial aspects. The combining of CT and non cognitive treatments may have useful clinical implications. PMID- 28577268 TI - The predictive accuracy of the black hole sign and the spot sign for hematoma expansion in patients with spontaneous intracerebral hemorrhage. AB - In patients with spontaneous intracerebral hemorrhage (sICH), hematoma expansion (HE) is associated with poor outcome. Spot sign and black hole sign are neuroimaging predictors for HE. This study was aimed to compare the predictive value of two signs for HE. Within 6 h after onset of sICH, patients were screened for the computed tomography angiography spot sign and the non-contrast computed tomography black hole sign. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of two signs for HE prediction were calculated. The accuracy of two signs in predicting HE was analyzed by receiver-operator analysis. A total of 129 patients were included in this study. Spot sign was identified in 30 (23.3%) patients and black hole sign in 29 (22.5%) patients, respectively. Of 32 patients with HE, spot sign was observed in 19 (59.4%) and black hole sign was found in 14 (43.8%). The occurrence of black hole sign was significantly associated with spot sign (P < 0.001). The sensitivity, specificity, PPV, and NPV of spot sign for predicting HE were 59.38, 88.66, 63.33, and 86.87% respectively. In contrast, the sensitivity, specificity, PPV, and NPV of black hole sign for predicting HE were 43.75, 84.54, 48.28, and 82.00%, respectively. The area under the curve was 0.740 for spot sign and 0.641 for black hole sign. (P = 0.228) Both spot sign and black hole sign appeared to have good predictive value for HE, and spot sign seemed to be a better predictor. PMID- 28577269 TI - Catheterization via direct cannulation of superior vena cava for a hemodialysis patient with an original dysfunctional catheter on the left internal jugular vein. AB - Establishing a long-term vascular access in patients exhibiting vascular access exhaustion is challenging. In this study, we reported a case of a direct catheterization in the superior vena cava of a hemodialysis patient with vascular access exhaustion and original dysfunctional catheter inserted via the left internal jugular vein. The direct catheterization was performed with cuffed tunnel catheter (CUFF) and guided by digital subtraction angiography (DSA) and multidetector computed tomography venography (MDCTV). The DSA and MDCTV results revealed an occlusion in the right innominate vein and thromboses in the left innominate, right internal jugular, subclavian, and femoral veins. The distal end of the superior vena cava was localized clearly by the original CUFF under DSA. Directed at the distal end of the superior vena cava, a 0.5-cm secondary puncture was introduced below the lateral head of the sternocleidomastoid muscle via the right neck area. This study is one of the few reports regarding direct catheterization of CUFF via the superior vena cava of a patient with vascular access exhaustion and CUFF dysfunction on the left internal jugular vein.We believe that our study can provide a new alternative for inserting central venous catheter for such patient. PMID- 28577270 TI - Hidden Causes of Anaphylaxis. AB - PURPOSE OF REVIEW: This study aimed to review important hidden causes of anaphylaxis in ingestants, non-ingestants, and uncommon settings. RECENT FINDINGS: Multiple new and elusive causes of anaphylaxis have been described over the past 35 years. Further research is required to identify the epidemiology, pathophysiology, and clinical impact of these hidden causes. Although these culprits should be considered in the appropriate clinical scenarios, many remain exceedingly rare. PMID- 28577271 TI - Genotoxicity of two heavy metal compounds: lead nitrate and cobalt chloride in Polychaete Perinereis cultrifera. AB - The present study explores the in vivo and in vitro genotoxic effects of lead nitrate, [Pb(NO3)2] a recognized environmental pollutant and cobalt chloride (CoCl2), an emerging environmental pollutant in polychaete Perinereis cultrifera using comet assay. Despite widespread occurrence and extensive industrial applications, no previous published reports on genotoxicity of these compounds are available in polychaete as detected by comet assay. Polychaetes were exposed in vivo to Pb(NO3)2 (0, 100, 500, and 1000 MUg/l) and CoCl2 (0, 100, 300, and 500 MUg/l) for 5 days. At 100 MUg/l Pb(NO3)2 concentration, tail DNA (TDNA) values in coelomocytes were increase by 1.16, 1.43, and 1.55-fold after day 1, day 3, and day 5, whereas, OTM showed 1.12, 2.33, and 2.10-fold increase in in vivo. Pb(NO3)2 showed a concentration and time-dependent genotoxicity whereas CoCl2 showed a concentration-dependent genotoxicity in in vivo. A concentration dependent increase in DNA damage was observed in in vitro studies for Pb(NO3)2 and CoCl2. DNA damage at 500 MUg/L showed almost threefold increase in TDNA and approximately fourfold increase in OTM as compared to control in in vitro. Our studies suggest that Pb(NO3)2 and CoCl2 have potential to cause genotoxic damage, with Pb(NO3)2 being more genotoxic in polychaete and should be used more carefully in industrial and other activities. Graphical abstract. PMID- 28577273 TI - Reply to Comment on "The Impact of Psychological Support on Weight Loss Post Weight Loss Surgery: a Randomised Control Trial" Ratcliffe et al. PMID- 28577272 TI - A Two-way Randomized Cross-over Pharmacokinetic and Pharmacodynamic Study of an Innovative Oral Solution of Midazolam (ADV6209). AB - PURPOSE: The objective of this study was to assess the bioavailability and the sedative effect of a single-dose administration of an innovative oral solution of midazolam containing gamma-cyclodextrins (ADV6209). METHODS: A bioavailability study with a standard two-sequences, two-periods, and crossover design was conducted. Subjects randomly received 15 mg of ADV6209 by oral route followed by 5 mg of the reference drug (midazolam hydrochloride intravenous solution (Hypnovel(r), Roche) by intravenous route or vice versa. Blood samples were drawn at different time points to measure midazolam and its metabolite alpha hydroxymidazolam concentrations. Non-compartmental pharmacokinetic methods were used to calculate main pharmacokinetic parameters and absolute bioavailability. RESULTS: Caucasian healthy subjects (n = 12) were included in the study. ADV6209 had a bioavailability of 39.6%. The oral elimination half-life with ADV6209 was slightly shorter than with the reference i.v. form (2.66 h versus 2.99 h). The sedative effect was observed 27.5 +/- 15.5 min after oral administration for a duration of 48.5 +/- 35.4 min. Double peak phenomenon was observed in 5 patients. CONCLUSIONS: Cyclodextrins have little impact on midazolam oral bioavailability and the pharmacokinetics parameters of midazolam formulation ADV6209 are close to those reported previously. PMID- 28577274 TI - Unexpected events disrupt visuomotor working memory and increase guessing. AB - When an unexpected event, such as a car horn honking, occurs in daily life, it often disrupts our train of thought. In the lab, this effect was recently modeled with a task in which verbal working memory (WM) was disrupted by unexpected auditory events (Wessel et al. in Nature Communications, 7, 11195, 2016). Here we tested whether this effect extends to a different type of WM-namely, visuomotor. We found that unexpected auditory events similarly decremented visuomotor WM. Moreover, this effect persisted for many more trials than had previously been shown for verbal WM, and the effect occurred for two different types of unexpected auditory events. Furthermore, we found that unexpected events decremented WM by decreasing the quantity, but not necessarily the quality, of items stored. These results showed an impact of unexpected events on visuomotor WM that was statistically robust and endured across time. They also showed that the effect was based on an increase in guessing, consistent with a neuroscience inspired theory that unexpected events "wipe out" WM by stopping the ongoing maintenance of the trace. This new task paradigm is an excellent vehicle for further explorations of distractibility. PMID- 28577275 TI - Are you mind-wandering, or is your mind on task? The effect of probe framing on mind-wandering reports. AB - The last decade has seen a dramatic rise in the number of studies that utilize the probe-caught method of collecting mind-wandering reports. This method involves stopping participants during a task, presenting them with a thought probe, and asking them to choose the appropriate report option to describe their thought-state. In this experiment we manipulated the framing of this probe, and demonstrated a substantial difference in mind-wandering reports as a function of whether the probe was presented in a mind-wandering frame compared with an on task frame. This framing effect has implications both for interpretations of existing data and for methodological choices made by researchers who use the probe-caught mind-wandering paradigm. PMID- 28577276 TI - Examining an Executive Function Battery for Use with Preschool Children with Disabilities. AB - Performance-based assessments of EF for use with young children who have or are at risk for disabilities are lacking. The current study investigates the use of a computerized battery for children with subclinical behaviors (N = 846) across a variety of developmental disabilities and evaluates practical information about feasibility of task administration. Results reveal that children with disabilities performed similarly to their typically developing peers across a variety of metrics for evaluating the battery, ranging from percent correct scores to administrator quality ratings. Thus, the battery may be considered an easy-to-administer, performance-based assessment tool in which children with disabilities do not perform systemically worse than typically developing peers. PMID- 28577277 TI - In vitro production of insulin-responsive skeletal muscle tissue from mouse embryonic stem cells by spermine-induced differentiation method. AB - The treatment of an embryoid body with spermine for a short duration can trigger the generation of a 3-dimensional multilayer myotube sheet (MMTS) that shows pulsatile activity. MMTS was previously characterized as a model of skeletal muscle tissue. In the present work, the insulin responsiveness of MMTS was investigated because it is an essential function for a model of skeletal muscle. The glucose uptake activity of MMTS was analyzed by confocal microscopy using fluorescent glucose analogs, namely 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4 yl)amino]-2-deoxy-D-glucose (2-NBDG) and its L-glucose counterpart, 2-NBDLG. The specific uptake rate of glucose was estimated from the difference between the fluorescent signals of 2-NBDG and 2-NBDLG. It was enhanced by insulin stimulation to 3.6 times higher than the control without insulin, and this insulin responsiveness was maintained for 5 days. The advantages of the 3-dimensional structure of MMTS are discussed in the contexts of its potential in vivo and in vitro uses. PMID- 28577278 TI - ARENA 2.0: The next generation automated remote environmental navigation apparatus to facilitate cross-species comparisons in behavior and cognition. AB - A series of experiments illustrated the effectiveness and flexibility of a newly developed Automated Remote Environmental Navigation Apparatus (ARENA) as an alternative to traditional operant and open-field procedures. This system improves the concept developed by Badelt and Blaisdell (Behavior Research Methods, 40, 613-621, 2008; see also Leising, Garlick, Parenteau, & Blaisdell in Behavioural Processes, 81, 105-113, 2009), with significant upgrades in flexibility and reliability, as well as a reduction in cost. ARENA is particularly well adapted for open-field studies and eliminates many confounding factors associated with traditional procedures, such as handling effects and physical cues left by the subject. The original system was based on wireless modules with a small stimulus-response well. Nosepokes or pecks within the aperture of the well could be detected and recorded by a computer. ARENA 2.0 increases the flexibility of this system by replacing the modules with stimulus presentation through a data projector mounted on the ceiling and response detection and recording through a video camera system. We report the specifics of this system as well as behavioral tests using rats and pigeons. We demonstrated the feasibility of ARENA 2.0 for the acquisition of conditional approach to a visual target, followed by tests showing generalization of performance to novel locations and visual properties of the target. These experiments support the use of this technology for automated tasks traditionally studied through open-field preparations or using touchscreen-equipped operant chambers. The advantages of ARENA 2.0 over the original system are a significant reduction in cost and increased reliability, ease of use, and flexibility in both stimulus configuration and subject response measures. PMID- 28577279 TI - Role of PET to evaluate coronary microvascular dysfunction in non-ischemic cardiomyopathies. AB - Coronary microvascular dysfunction (CMD) can result from structural and functional abnormalities at the intramural and small coronary vessel level affecting coronary blood flow autoregulation and consequently leading to impaired coronary flow reserve. CMD often co-exists with epicardial coronary artery disease but is also commonly seen in patients with various forms of heart disease, including dilated, hypertrophic, and infiltrative cardiomyopathies. CMD can go unnoticed without any symptoms, or manifest as angina, and/or dyspnea, and contribute to the development of heart failure, and even sudden death especially when co-existing with myocardial fibrosis. However, whether CMD in non-ischemic cardiomyopathy is a cause or an effect of the underlying cardiomyopathic process, or whether it can be potentially modifiable with specific therapies, remains incompletely understood. PMID- 28577281 TI - Acquired Tamoxifen Resistance in MCF-7 Breast Cancer Cells Requires Hyperactivation of eIF4F-Mediated Translation. AB - While selective estrogen receptor modulators, such as tamoxifen, have contributed to increased survival in patients with hormone receptor-positive breast cancer, the development of resistance to these therapies has led to the need to investigate other targetable pathways involved in oncogenic signaling. Approval of the mTOR inhibitor everolimus in the therapy of secondary endocrine resistance demonstrates the validity of this approach. Importantly, mTOR activation regulates eukaryotic messenger RNA translation. Eukaryotic translation initiation factor 4E (eIF4E), a component of the cap-dependent translation complex eIF4F, confers resistance to drug-induced apoptosis when overexpressed in multiple cell types. The eIF4F complex is downstream of multiple oncogenic pathways, including mTOR, making it an appealing drug target. Here, we show that the eIF4F translation pathway was hyperactive in tamoxifen-resistant (TamR) MCF-7L breast cancer cells. While overexpression of eIF4E was not sufficient to confer resistance to tamoxifen in MCF-7L cells, its function was necessary to maintain resistance in TamR cells. Targeting the eIF4E subunit of the eIF4F complex through its degradation using an antisense oligonucleotide (ASO) or via sequestration using a mutant 4E-BP1 inhibited the proliferation and colony formation of TamR cells and partially restored sensitivity to tamoxifen. Further, the use of these agents also resulted in cell cycle arrest and induction of apoptosis in TamR cells. Finally, the use of a pharmacologic agent which inhibited the eIF4E-eIF4G interaction also decreased the proliferation and anchorage-dependent colony formation in TamR cells. These results highlight the eIF4F complex as a promising target for patients with acquired resistance to tamoxifen and, potentially, other endocrine therapies. PMID- 28577283 TI - A giant pararectal cyst successfully treated by robotic surgery. AB - A 50 year-old patient was referred to our department with severe obstructive lower urinary tract symptoms, suprapubic pain and rectal fullness that started after a perianal fistula operation performed one year ago. Radiologic evaluation showed a large pararectal cystic lesion with septa formation on the right side compressing the bladder and prostate. Aspiration of the cystic fluid attempted initially but was not successful. A robotic transperitoneal approach was applied and the cyst was excised completely. On 1-year follow-up, patient did not have any symptoms and cyst was completely disappeared on radiology. PMID- 28577280 TI - The role of myocardial viability in contemporary cardiac practice. AB - Ischemic heart disease (IHD) remains the single most common cause of death worldwide. Ischemic cardiomyopathy is a major sequel of coronary artery disease. The economic health burden of IHD is substantial. In patients with old myocardial infarction (OMI), the extent of viable myocardium (VM) directly affects the short and long-term outcome. There is a considerable collection of observational data showing substantial improvement in patients with significant left ventricular dysfunction when the need for revascularization is guided by preoperative assessment of viability and hibernation. However, a major challenge for present cardiovascular imaging is to identify better ways to assess viable but inadequately perfused myocardium and thus optimize selection of patients for coronary revascularization. Several non-invasive techniques have been developed to detect signs of viability. Hence, our aim is to provide the reader a state-of the art review for the assessment of myocardial viability. PMID- 28577282 TI - Estrogen Receptor-beta Modulation of the ERalpha-p53 Loop Regulating Gene Expression, Proliferation, and Apoptosis in Breast Cancer. AB - Estrogen receptor alpha (ERalpha) is a crucial transcriptional regulator in breast cancer, but estrogens mediate their effects through two estrogen receptors, ERalpha and ERbeta, subtypes that have contrasting regulatory actions on gene expression and the survival and growth of breast cancer cells. Here, we examine the impact of ERbeta on the ERalpha-p53 loop in breast cancer. We found that ERbeta attenuates ERalpha-induced cell proliferation, increases apoptosis, and reverses transcriptional activation and repression by ERalpha. Further, ERbeta physically interacts with p53, reduces ERalpha-p53 binding, and antagonizes ERalpha-p53-mediated transcriptional regulation. ERalpha directs SUV39H1/H2 and histone H3 lys9 trimethylation (H3K9me3) heterochromatin assembly at estrogen-repressed genes to silence p53-activated transcription. The copresence of ERbeta in ERalpha-positive cells abrogates the H3K9me3 repressive heterochromatin conformation by downregulating SUV39H1 and SUV39H2, thereby releasing the ERalpha-induced transcriptional block. Furthermore, the presence of ERbeta stimulates accumulation of histone H3 lys4 trimethylation (H3K4me3) and RNA polymerase II (RNA Pol II) on ERalpha-repressed genes, inducing H3K4me3 associated epigenetic activation of the transcription of these repressed genes that can promote p53-based tumor suppression. ERbeta also reduced corepressor N CoR and SMRT recruitment by ERalpha that could attenuate the crosstalk between ERalpha and p53. Overall, our data reveal a novel mechanism for ERbeta's anti proliferative and pro-apoptotic effects in breast cancer cells involving p53 and epigenetic changes in histone methylation that underlie gene regulation of these cellular activities. PMID- 28577284 TI - Overexpression of Rice Auxilin-Like Protein, XB21, Induces Necrotic Lesions, up Regulates Endocytosis-Related Genes, and Confers Enhanced Resistance to Xanthomonas oryzae pv. oryzae. AB - BACKGROUND: The rice immune receptor XA21 confers resistance to the bacterial pathogen, Xanthomonas oryzae pv. oryzae (Xoo). To elucidate the mechanism of XA21 mediated immunity, we previously performed a yeast two-hybrid screening for XA21 interactors and identified XA21 binding protein 21 (XB21). RESULTS: Here, we report that XB21 is an auxilin-like protein predicted to function in clathrin mediated endocytosis. We demonstrate an XA21/XB21 in vivo interaction using co immunoprecipitation in rice. Overexpression of XB21 in rice variety Kitaake and a Kitaake transgenic line expressing XA21 confers a necrotic lesion phenotype and enhances resistance to Xoo. RNA sequencing reveals that XB21 overexpression results in the differential expression of 8735 genes (4939 genes up- and 3846 genes down-regulated) (>=2-folds, FDR <=0.01). The up-regulated genes include those predicted to be involved in 'cell death' and 'vesicle-mediated transport'. CONCLUSION: These results indicate that XB21 plays a role in the plant immune response and in regulation of cell death. The up-regulation of genes controlling 'vesicle-mediated transport' in XB21 overexpression lines is consistent with a functional role for XB21 as an auxilin. PMID- 28577287 TI - Lipemic Serum in Hypertriglyceridemia-Induced Pancreatitis. PMID- 28577285 TI - The influence of birth weight and length on bone mineral density and content in adolescence: The Tromso Study, Fit Futures. AB - : The influence of birth weight and length on bone mineral parameters in adolescence is unclear. We found a positive association between birth size and bone mineral content, attenuated by lifestyle factors. This highlights the impact of environmental stimuli and lifestyle during growth. PURPOSE: The influence of birth weight and length on bone mineral density and content later in life is unclear, especially in adolescence. This study evaluated the impact of birth weight and length on bone mineral density and content among adolescents. METHODS: We included 961 participants from the population-based Fit Futures study (2010 2011). Dual-energy X-ray absorptiometry (DXA) was used to measure bone mineral density (BMD) and bone mineral content (BMC) at femoral neck (FN), total hip (TH) and total body (TB). BMD and BMC measures were linked with birth weight and length ascertained from the Medical Birth Registry of Norway. Linear regression models were used to investigate the influence of birth parameters on BMD and BMC. RESULTS: Birth weight was positively associated with BMD-TB and BMC at all sites among girls; standardized beta coefficients [95% CI] were 0.11 [0.01, 0.20] for BMD-TB and 0.15 [0.06, 0.24], 0.18 [0.09, 0.28] and 0.29 [0.20, 0.38] for BMC-FN, TH and TB, respectively. In boys, birth weight was positively associated with BMC at all sites with estimates of 0.10 [0.01, 0.19], 0.12 [0.03, 0.21] and 0.15 [0.07, 0.24] for FN, TH and TB, respectively. Corresponding analyses using birth length as exposure gave significantly positive associations with BMC at all sites in both sexes. The significant positive association between birth weight and BMC TB in girls, and birth length and BMC-TB in boys remained after multivariable adjustment. CONCLUSIONS: We found a positive association between birth size and BMC in adolescence. However, this association was attenuated after adjustment for weight, height and physical activity during adolescence. PMID- 28577286 TI - Management of older adults with hip fractures in India: a mixed methods study of current practice, barriers and facilitators, with recommendations to improve care pathways. AB - : Evidence-based management can reduce deaths and suffering of older adults with hip fractures. This study investigates the evidence-practice gaps in hip fracture care in three major hospitals in Delhi, potential barriers and facilitators to improving care, and consequently, identifies contextually appropriate interventions for implementing best practice for management of older adults with hip fractures in India. PURPOSE: Hip fracture in older adults is a significant public health issue in India. The current study sought to document current practices, identify barriers and facilitators to adopting best practice guidelines and recommend improvements in the management of older adults with hip fractures in Delhi, India. METHODS: This mixed methods observational study collected data from healthcare providers, patients, carers and medical records from three major public tertiary care hospitals in Delhi, India. All patients aged >=50 years with an X-ray confirmed hip fracture that were admitted to these hospitals over a 10-week period were recruited. Patients' data were collected at admission, discharge and 30 days post-injury. Eleven key informant interviews and four focus group discussions were conducted with healthcare providers. Descriptive data for key quantitative variables were computed. The qualitative data were analysed and interpreted using a behaviour change wheel framework. RESULTS: A total of 136 patients, 74 (54%) men and 62 women, with hip fracture were identified in the three participating hospitals during the recruitment period and only 85 (63%) were admitted for treatment with a mean age of 66.5 years (SD 11.9). Of these, 30% received surgery within 48 h of hospital admission, 95% received surgery within 39 days of hospital admission and two (3%) had died by 30 days of injury. According to the healthcare providers, inadequate resources and overcrowding prevent adequate caring of the hip fracture patients. They unanimously felt the need for protocol-based management of hip fracture in India. CONCLUSION: The development and implementation of national guidelines and standardized protocols of care for older people with hip fractures in India has the potential to improve both care and patient-related outcomes. PMID- 28577288 TI - Single Analyzer Precursor Ion Scans in a Linear Quadrupole Ion Trap Using Orthogonal Double Resonance Excitation. AB - Reported herein is a simple method of performing single analyzer precursor ion scans in a linear quadrupole ion trap using orthogonal double resonance excitation. A first supplementary AC signal applied to the y electrodes is scanned through ion secular frequencies in order to mass-selectively excite precursor ions while, simultaneously, a second fixed-frequency AC signal is applied orthogonally on the x electrodes in order to eject product ions of selected mass-to-charge ratios towards the detector. The two AC signals are applied orthogonally so as to preclude the possibility of (1) inadvertently ejecting precursor ions into the detector, which results in artifact peaks, and (2) prevent beat frequencies on the x electrodes from ejecting ions off resonance. Precursor ion scans are implemented while using the inverse Mathieu q scan for easier mass calibration. The orthogonal double resonance experiment results in single ion trap precursor scans with far less intense artifact peaks than when both AC signals are applied to the same electrodes, paving the way for implementation of neutral loss scanning in single ion trap mass spectrometers. Graphical Abstract ?. PMID- 28577290 TI - In silico Discovery of Novel FXa Inhibitors by Pharmacophore Modeling and Molecular Docking. AB - Coagulation Factor Xa (FXa) is the crucial enzyme at the convergent point of the intrinsic and extrinsic coagulation pathways. The inhibition of FXa is an effective approach against thrombotic diseases. In the present study, a specific strategy is reported to discover 10 novel FXa inhibitors based on ligand-based (pharmacophore) virtual screening and molecular docking analysis from a dataset of specs(containing 220000 molecules). The binding modes analysis provide insights into the contribution of particular structural moieties of the compounds towards their activity against FXa, and 10 novel structural compounds were discovered as potent candidate molecules. This work could be helpful in further design and development of FXa inhibitors. PMID- 28577289 TI - Immunoglobulin-responsive chikungunya encephalitis: two case reports. AB - Chikungunya virus is an alphavirus transmitted by the mosquito Aedes, mainly Aedes aegypti and Aedes albopictus, that can cause acute illness, mostly self limited, characterized by fever, maculopapular rash, and disabling polyarthritis/arthralgia, with an incubation period of 1 to 12 days. Chikungunya was largely regarded as a non-fatal and self-limited disease, but recently, serious cases have been reported including some with severe involvement of the nervous system, such as meningoencephalitis, myelitis, polyradiculitis, and polyradiculoneuropathy. In this report, we describe the clinical and laboratory findings of two patients with encephalitis associated with chikungunya in a northeastern city in Brazil, who exhibited a good outcome, with improvement after treatment with i.v. immunoglobulin (IVIg). PMID- 28577291 TI - A CZT-based blood counter for quantitative molecular imaging. AB - BACKGROUND: Robust quantitative analysis in positron emission tomography (PET) and in single-photon emission computed tomography (SPECT) typically requires the time-activity curve as an input function for the pharmacokinetic modeling of tracer uptake. For this purpose, a new automated tool for the determination of blood activity as a function of time is presented. The device, compact enough to be used on the patient bed, relies on a peristaltic pump for continuous blood withdrawal at user-defined rates. Gamma detection is based on a 20 * 20 * 15 mm3 cadmium zinc telluride (CZT) detector, read by custom-made electronics and a field-programmable gate array-based signal processing unit. A graphical user interface (GUI) allows users to select parameters and easily perform acquisitions. RESULTS: This paper presents the overall design of the device as well as the results related to the detector performance in terms of stability, sensitivity and energy resolution. Results from a patient study are also reported. The device achieved a sensitivity of 7.1 cps/(kBq/mL) and a minimum detectable activity of 2.5 kBq/ml for 18F. The gamma counter also demonstrated an excellent stability with a deviation in count rates inferior to 0.05% over 6 h. An energy resolution of 8% was achieved at 662 keV. CONCLUSIONS: The patient study was conclusive and demonstrated that the compact gamma blood counter developed has the sensitivity and the stability required to conduct quantitative molecular imaging studies in PET and SPECT. PMID- 28577292 TI - A Dipeptidyl Peptidase-4 Inhibitor, Teneligliptin, Decreases Plasma Triglyceride Rich Lipoprotein Remnants in Diabetic Patients with Chronic Kidney Disease Undergoing Hemodialysis. AB - OBJECTIVE: A high plasma level of remnant-like particle cholesterol (RLP-C), which is equivalent to triglyceride-rich lipoprotein remnant, is an important coronary risk marker. RLP-C level is high, independent of other plasma lipids, in patients with chronic kidney disease (CKD) undergoing hemodialysis. The effect of teneligliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, on plasma levels of RLP C in patients with diabetes mellitus and CKD under hemodialysis was studied. METHODS: Teneligliptin 20 mg/day was administered to 15 patients with diabetes and CKD undergoing hemodialysis for 12 weeks. Ten patients with diabetes and CKD undergoing hemodialysis were allocated to the control group. Blood was sampled following a 12-h fast. Fasting plasma glucose (FPG), C-peptide, triglyceride, low density lipoprotein (LDL)-cholesterol (C), high-density lipoprotein (HDL)-C, RLP C, apolipoprotein (apo) B, oxidized LDL, lipoprotein lipase, and glycated hemoglobin (HbA1c) were measured. RESULTS: HbA1c decreased in the teneligliptin group but significantly increased in the control group. FPG and RLP-C significantly decreased in the teneligliptin group. Plasma lipoprotein-related parameters except RLP-C were not affected by teneligliptin treatment. CONCLUSION: Teneligliptin treatment significantly reduced plasma levels of RLP-C, FPG, and HbA1c in patients with diabetes with CKD who are undergoing hemodialysis. PMID- 28577293 TI - Pharmacokinetics of Bevacizumab in Three Patients Under the Age of 3 Years with CNS Malignancies. AB - BACKGROUND: Bevacizumab is a recombinant antibody that is increasingly used in pediatric malignancies. The pharmacokinetics of bevacizumab in pediatric patients have been shown to be influenced by tumor localization and body weight. In this report, we present data on the pharmacokinetics and safety of bevacizumab in children under the age of 3 years with central nervous system (CNS) malignancies. METHODS: Three patients (mean age 22 months) were treated with intravenous bevacizumab 10 mg/kg every 2 weeks. In total, 20 trough and peak bevacizumab concentrations of 10 treatment cycles were obtained at steady state. RESULTS: Bevacizumab was generally well-tolerated in this age group. The mean trough concentration was 127 +/- 29 ug/ml (range 77-155), and the mean peak concentration was 149 +/- 13 ug/ml (range 113-157). Trough and peak levels were stable upon repeated treatment cycles in the same patient. In contrast, we determined strong interindividual variations in trough levels. Whereas the plasma concentration of the oldest patient matched the prediction of a previously published model, younger patients showed markedly higher trough levels. CONCLUSIONS: Serum peak concentrations of bevacizumab in children under the age of 3 years with CNS malignancies are in a similar magnitude to that found in older children and adults. Thus, a dosing schedule of bevacizumab 10 mg/kg every 2 weeks can be considered sufficient and safe, even in very young children. We further show that very young children with CNS malignancies show a markedly reduced plasma clearance, possibly related to lower body weight or differences in clearance mechanisms of antibodies. PMID- 28577294 TI - Comparison of Generic Drug Reviews for Marketing Authorization between Japan and Canada. AB - PURPOSE: Generic drugs are assuming an increasingly important role in sustaining modern healthcare systems, as the cost of healthcare, including drug usage, is gradually expanding around the world. To date, published articles comparing generic drug reviews between different countries are scarce. OBJECTIVE: The objective of this study was to examine generic drug reviews in Japan and Canada. METHODS: We surveyed generic drug reviews from Japan and Canada and compared the following points: general matter (application types, type of partial change or Supplement to an Abbreviated New Drug Submission, application and approval numbers, review period, application format, review report, responsibility for review), bioequivalence studies for solid oral dosage forms, and bioequivalence guidelines, guidance, or basic principles regarding various dosage forms. RESULTS: This survey described the many similarities and differences in generic drug reviews between the two countries and points that should be improved to promote better generic drug reviews. In particular, regulations for the definition of the same or different active pharmaceutical ingredients (APIs) are similar for both authorities. CONCLUSIONS: The results clarified the future challenges of generic drug reviews, and the differences highlighted by this survey will be important considerations for the future. This is the first article to present and discuss the details of generic drug reviews between Japan and Canada. PMID- 28577295 TI - Response assessment with the CXCR4-directed positron emission tomography tracer [68Ga]Pentixafor in a patient with extranodal marginal zone lymphoma of the orbital cavities. AB - CXCR4 belongs to the family of chemokine receptors. Together with its sole known ligand CXCL12 (SDF-1alpha), it has a pivotal role during organogenesis and for homing of hematopoietic stem cells. CXCR4 is overexpressed in various malignancies, and this is often associated with poor prognosis. Therefore, molecular imaging of CXCR4 bears a great potential for diagnostics and selecting patients for CXCR4-directed therapies. The CXCR4-directed positron emission tomography (PET) tracer [68Ga]Pentixafor has been shown to visualize CXCR4 expression in various malignancies in vivo. Whereas this tracer has limitations compared to 18F-Fluorodeoxyglucose ([18F]FDG) in diagnostic PET imaging in peripheral tumour lesions, it might add valuable information in routine diagnostics and response assessment of tumours in close proximity to the central nervous system (CNS) and malignancies within this organ. As a proof-of-concept, we performed [68Ga]Pentixafor PET imaging in a patient with extranodal marginal zone lymphoma (MZL) of the orbital cavities at diagnosis and for post-therapy response assessment. Compared to routinely conducted [18F]FDG PET, the lymphoma lesions determined by magnetic resonance imaging (MRI) showed high tracer accumulation at diagnosis, which decreased upon treatment. We therefore propose that imaging of CXCR4 with [68Ga]Pentixafor is a potential diagnostic tool for tumours close to or within the CNS and suggest this being studied in clinical trials. PMID- 28577297 TI - Prevalence and type distribution of human papillomavirus in squamous cell carcinoma and intraepithelial neoplasia of the vulva. AB - In this updated systematic review and meta-analysis, we estimate the pooled prevalence of human papillomavirus (HPV) DNA and HPV type distribution in squamous cell carcinoma of the vulva (vulvar cancer) and vulvar intraepithelial neoplasia (VIN). PubMed, Embase and Cochrane Library databases were used to identify studies published between 1990 and 2015 and using a PCR-based or hybrid capture test to evaluate the presence of HPV DNA in vulvar cancer or VIN. Pooled estimates of the HPV prevalence with corresponding 95% confidence intervals (CI) were calculated based on a random effects model. The I2 statistic was used to describe the amount of heterogeneity. In meta-regression analyses, potential sources of heterogeneity were evaluated. We identified 92 eligible papers, comprising altogether 5,015 cases of vulvar cancer (64 papers) and 2,764 cases of VIN (48 papers). The pooled prevalence of HPV in vulvar cancer was 39.7% (95% CI: 35.1-44.4%). Overall, 76.3% (95% CI: 70.1-82.1%) of VIN lesions tested HPV positive, while the HPV prevalence in new subcategories of VIN, uVIN and dVIN, was 86.2% (95% CI: 73.5-95.5%) and 2.0% (95% CI: 0-10.0%), respectively. Substantial between-study heterogeneity was observed (vulvar cancer: I2 = 88.4%; VIN: I2 = 90.7%) with the largest variation between geographical regions. Among HPV-positive cases, the predominant high-risk HPV type was HPV16, followed by HPV33 and HPV18. HPV6 was detected as a single infection in a small subset of VIN and vulvar cancer samples. Thus, HPV vaccination targeting these HPV types may prevent a substantial number of vulvar lesions. PMID- 28577296 TI - Concise Review: Criteria for Chamber-Specific Categorization of Human Cardiac Myocytes Derived from Pluripotent Stem Cells. AB - Human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) have great potential application in almost all areas of cardiovascular research. A current major goal of the field is to build on the past success of differentiation strategies to produce CMs with the properties of those originating from the different chambers of the adult human heart. With no anatomical origin or developmental pathway to draw on, the question of how to judge the success of such approaches and assess the chamber specificity of PSC-CMs has become increasingly important; commonly used methods have substantial limitations and are based on limited evidence to form such an assessment. In this article, we discuss the need for chamber specific PSC-CMs in a number of areas as well as current approaches used to assess these cells on their likeness to those from different chambers of the heart. Furthermore, describing in detail the structural and functional features that distinguish the different chamber-specific human adult cardiac myocytes, we propose an evidence-based tool to aid investigators in the phenotypic characterization of differentiated PSC-CMs. Stem Cells 2017;35:1881-1897. PMID- 28577298 TI - Cx43 suppresses evx1 expression to regulate joint initiation in the regenerating fin. AB - BACKGROUND: How joints are correctly positioned in the vertebrate skeleton remains poorly understood. From our studies on the regenerating fin, we have evidence that the gap junction protein Cx43 suppresses joint formation by suppressing the expression of the evx1 transcription factor. Joint morphogenesis proceeds through at least two discrete stages. First, cells that will produce the joint condense in a single row on the bone matrix ("initiation"). Second, these cells separate coincident with articulation of the bone matrix. We propose that Cx43 activity is transiently reduced prior to joint initiation. RESULTS: We first define the timing of joint initiation with respect to regeneration. We next correlate reduced cx43 expression and increased evx1 expression with initiation. Through manipulation of cx43 expression, we demonstrate that Cx43 negatively influences evx1 expression and joint formation. We further demonstrate that Cx43 activity in the dermal fibroblasts is required to rescue joint formation in the cx43 mutant, short finb123 . CONCLUSIONS: We conclude that Cx43 activity in the dermal fibroblasts influences the expression of evx1, and therefore the differentiation of the precursor cells that give rise to the joint-forming osteoblasts. Developmental Dynamics 246:691-699, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28577299 TI - uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells. AB - In this manuscript, we show the involvement of the uPA/uPAR system in the regulation of aerobic glycolysis of melanoma cells. uPAR over-expression in human melanoma cells controls an invasive and glycolytic phenotype in normoxic conditions. uPAR down-regulation by siRNA or its uncoupling from integrins, and hence from integrin-linked tyrosine kinase receptors (IL-TKRs), by an antagonist peptide induced a striking inhibition of the PI3K/AKT/mTOR/HIF1alpha pathway, resulting into impairment of glucose uptake, decrease of several glycolytic enzymes and of PKM2, a checkpoint that controls metabolism of cancer cells. Further, binding of uPA to uPAR regulates expression of molecules that govern cell invasion, including extracellular matrix metallo-proteinases inducer (EMPPRIN) and enolase, a glycolytyc enzyme that also serves as a plasminogen receptor, thus providing a common denominator between tumor metabolism and phenotypic invasive features. Such effects depend on the alpha5beta1-integrin mediated uPAR connection with EGFR in melanoma cells with engagement of the PI3K mTOR-HIFalpha pathway. HIF-1alpha trans-activates genes whose products mediate tumor invasion and glycolysis, thus providing the common denominator between melanoma metabolism and its invasive features. These findings unveil a unrecognized interaction between the invasion-related uPAR and IL-TKRs in the control of glycolysis and disclose a new pharmacological target (i.e., uPAR/IL TKRs axis) for the therapy of melanoma. PMID- 28577300 TI - Application of higher energy collisional dissociation (HCD) to the fragmentation of new DOTA-based labels and N-termini DOTA-labeled peptides. AB - 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives are applied in quantitative proteomics owing to their ability to react with different functional groups, to harbor lanthanoides and hence their compatibility with molecular and elemental mass spectrometry. The new DOTA derivatives, namely Ln MeCAT-Click and Ln-DOTA-Dimedone, allow efficient thiol labeling and targeting sulfenation as an important post-translational modification, respectively. Quantitative applications require the investigation of fragmentation behavior of these reagents. Therefore, the fragmentation behavior of Ln-MeCAT-Click and Ln DOTA-Dimedone was studied using collision-induced dissociation (CID), infrared multiphoton dissociation (IRMPD) and higher-energy collision dissociation (HCD) using different energy levels, and the efficiency of reporter ion production was estimated. The efficiency of characteristic fragment formation was in the order IRMPD > HCD (normal energy level) > CID. On the other hand, the application of HCD at high energy levels (HCD@HE; NCE > 250%) resulted in a significant increase in reporter ion production (33-54%). This new strategy was successfully applied to generate label-specific reporter ions for DOTA amino labeling at the N-termini and in a quantitative fashion for the estimation of amino:thiol ratio in peptides. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28577301 TI - Neural organization of afferent pathways from the stomatopod compound eye. AB - Crustaceans and insects share many similarities of brain organization suggesting that their common ancestor possessed some components of those shared features. Stomatopods (mantis shrimps) are basal eumalacostracan crustaceans famous for their elaborate visual system, the most complex of which possesses 12 types of color photoreceptors and the ability to detect both linearly and circularly polarized light. Here, using a palette of histological methods we describe neurons and their neuropils most immediately associated with the stomatopod retina. We first provide a general overview of the major neuropil structures in the eyestalks lateral protocerebrum, with respect to the optical pathways originating from the six rows of specialized ommatidia in the stomatopod's eye, termed the midband. We then focus on the structure and neuronal types of the lamina, the first optic neuropil in the stomatopod visual system. Using Golgi impregnations to resolve single neurons we identify cells in different parts of the lamina corresponding to the three different regions of the stomatopod eye (midband and the upper and lower eye halves). While the optic cartridges relating to the spectral and polarization sensitive midband ommatidia show some specializations not found in the lamina serving the upper and lower eye halves, the general morphology of the midband lamina reflects cell types elsewhere in the lamina and cell types described for other species of Eumalacostraca. PMID- 28577303 TI - Hhex Regulates Hematopoietic Stem Cell Self-Renewal and Stress Hematopoiesis via Repression of Cdkn2a. AB - The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin- Sca+ Kit+ cells showed that Hhex deletion leads to derepression of polycomb repressive complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16Ink 4a and p19Arf . Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress. Stem Cells 2017;35:1948-1957. PMID- 28577302 TI - IP6K1 Reduces Mesenchymal Stem/Stromal Cell Fitness and Potentiates High Fat Diet Induced Skeletal Involution. AB - Mesenchymal stem/stromal cells (MSCs) are the predominant source of bone and adipose tissue in adult bone marrow and play a critical role in skeletal homeostasis. Age-induced changes in bone marrow favor adipogenesis over osteogenesis leading to skeletal involution and increased marrow adiposity so pathways that prevent MSC aging are potential therapeutic targets for treating age-related bone diseases. Here, we show that inositol hexakisphosphate kinase 1 (Ip6k1) deletion in mice increases MSC yields from marrow and enhances cell growth and survival ex vivo. In response to the appropriate stimuli, Ip6k1-/- versus Ip6k1+/+ MSCs also exhibit enhanced osteogenesis and hematopoiesis supporting activity and reduced adipogenic differentiation. Mechanistic-based studies revealed that Ip6k1-/- MSCs express higher MDM2 and lower p53 protein levels resulting in lower intrinsic mitochondrial reactive oxygen species (ROS) levels as compared to Ip6k1+/+ MSCs, but both populations upregulate mitochondrial ROS to similar extents in response to oxygen-induced stress. Finally, we show that mice fed a high fat diet exhibit reduced trabecular bone volume, and that pharmacological inhibition of IP6K1 using a pan-IP6K inhibitor largely reversed this phenotype while increasing MSC yields from bone marrow. Together, these findings reveal an important role for IP6K1 in regulating MSC fitness and differentiation fate. Unlike therapeutic interventions that target peroxisome proliferator-activated receptor gamma and leptin receptor activity, which yield detrimental side effects including increased fracture risk and altered feeding behavior, respectively, inhibition of IP6K1 maintains insulin sensitivity and prevents obesity while preserving bone integrity. Therefore, IP6K1 inhibitors may represent more effective insulin sensitizers due to their bone sparing properties. Stem Cells 2017;35:1973-1983. PMID- 28577304 TI - The association between individual metabolic syndrome components, primary liver cancer and cirrhosis: A study in the Swedish AMORIS cohort. AB - Metabolic syndrome (MetS) is associated with non-alcoholic fatty liver disease, which may progress to cirrhosis, a significant risk factor of hepatocellular carcinoma (HCC), the commonest malignant primary liver cancer (PLC). We investigated the association between the individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity), PLC and cirrhosis. A total of 509,436 participants from the Swedish AMORIS cohort, recruited between January 1985 and December 1996 (end-date December 2011), aged >=20 with baseline triglycerides (TG), total cholesterol (TC), glucose and liver enzymes were included. Those with baseline benign liver tumours, PLC or cirrhosis were excluded. Multivariate Cox regression, adjusted for age, gender, socio-economic status, liver disease (excluding cirrhosis) and MetS factors were used to estimate the association with PLC and cirrhosis. There were 766 PLC and 2,775 cirrhosis cases over 13 years. Raised TG, low TC, raised glucose, diabetes and low HDL were associated with an increased risk of developing PLC and cirrhosis. ApoB/ApoA-I ratio were also associated with PLC, whilst low LDL, raised TG/HDL, low ApoA-I and low ApoB were associated with cirrhosis. Obesity was significantly associated with PLC but not cirrhosis. Raised TG, low TC, raised glucose and diabetes showed stronger associations with PLC in participants with cirrhosis but many participants developed PLC without cirrhosis. Individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity) were associated with an increased risk of developing PLC or cirrhosis. MetS components were more strongly associated with PLC with preceding cirrhosis history but many participants developed PLC without cirrhosis. PMID- 28577306 TI - Cetuximab or nimotuzumab plus intensity-modulated radiotherapy versus cisplatin plus intensity-modulated radiotherapy for stage II-IVb nasopharyngeal carcinoma. AB - To compare intensity-modulated radiotherapy (IMRT) with cisplatin (CDDP) versus cetuximab (CTX) and nimotuzumab (NTZ) for Stage II-IVb Nasopharyngeal Carcinoma (NPC). A total of 1,837 patients with stage II-IVb NPC who received IMRT plus CTX or NTZ, or CDDP between January 2009 and December 2013 were included in the current analysis. Using propensity scores to adjust for potential prognostic factors, a well-balanced cohort of 715 patients was created by matching each patient who underwent IMRT plus concomitant NTZ/CTX with four patients who underwent IMRT plus concomitant CDDP (1:4). Efficacy and safety were compared between the CTX/NTZ and CDDP groups of this well-balanced cohort. Furthermore, we conducted multivariate analysis and subgroup analysis based on all the 1,837 eligible cases. There was no significant difference between CTX/NTZ group and CDDP group in terms of DFS (3-year, 86.7% vs. 86.2%, p > 0.05), LRRFS (96.2% vs. 96.3%, p > 0.05), DMFS (91.1% vs. 92.3%, p > 0.05) and OS (91.7% vs. 91.9%, p > 0.05). Subgroup analysis demonstrated a significant interaction effect between patients with IMRT plus CTX/NTZ and N3 node stage on LRRFS with the highest risk of loco-regional relapse (HR 8.85, p = 0.001). Significantly increased hematologic toxicities, gastrointestinal reactions were observed in the CDDP group (p < 0.05). Patients of 3.4-4.7% experienced severe hematologic toxicities during the treatment with concomitant CTX and NTZ. Increased rate of CTX related skin reaction and mucositis was observed in the CTX group. CTX/NTZ used concurrently with IMRT may be comparable to those of the standard CDDP-IMRT combination for maximizing survival for patients with stage II-IVb NPC. PMID- 28577305 TI - Phenotyping of nNOS neurons in the postnatal and adult female mouse hypothalamus. AB - Neurons expressing nitric oxide (NO) synthase (nNOS) and thus capable of synthesizing NO play major roles in many aspects of brain function. While the heterogeneity of nNOS-expressing neurons has been studied in various brain regions, their phenotype in the hypothalamus remains largely unknown. Here we examined the distribution of cells expressing nNOS in the postnatal and adult female mouse hypothalamus using immunohistochemistry. In both adults and neonates, nNOS was largely restricted to regions of the hypothalamus involved in the control of bodily functions, such as energy balance and reproduction. Labeled cells were found in the paraventricular, ventromedial, and dorsomedial nuclei as well as in the lateral area of the hypothalamus. Intriguingly, nNOS was seen only after the second week of life in the arcuate nucleus of the hypothalamus (ARH). The most dense and heavily labeled population of cells was found in the organum vasculosum laminae terminalis (OV) and the median preoptic nucleus (MEPO), where most of the somata of the neuroendocrine neurons releasing GnRH and controlling reproduction are located. A great proportion of nNOS-immunoreactive neurons in the OV/MEPO and ARH were seen to express estrogen receptor (ER) alpha. Notably, almost all ERalpha-immunoreactive cells of the OV/MEPO also expressed nNOS. Moreover, the use of EYFPVglut2 , EYFPVgat , and GFPGad67 transgenic mouse lines revealed that, like GnRH neurons, most hypothalamic nNOS neurons have a glutamatergic phenotype, except for nNOS neurons of the ARH, which are GABAergic. Altogether, these observations are consistent with the proposed role of nNOS neurons in physiological processes. PMID- 28577307 TI - Disrupting Interactions Between beta-Catenin and Activating TCFs Reconstitutes Ground State Pluripotency in Mouse Embryonic Stem Cells. AB - The 2i-media, composed of two small molecule inhibitors (PD0325901 and CHIR99021) against MEK and GSK3-kinases, respectively, is known to establish naive ground state pluripotency in mouse embryonic stem cells (mESCs). These inhibitors block MEK-mediated differentiation, while driving beta-catenin dependent de-repression of pluripotency promoting targets. However, accumulating evidence suggest that beta-catenin's association with activating TCFs (TCF7 and TCF7L2) can induce expression of several lineage-specific prodifferentiation genes. We posited that CHIR-induced upregulation of beta-catenin levels could therefore compromise the stability of the naive state in long-term cultures. Here, we investigated whether replacing CHIR with iCRT3, a small molecule that abrogates beta-catenin-TCF interaction, can still retain ground state pluripotency in mESCs. Our data suggests that iCRT3 + PD mediated coinhibition of MEK and beta-catenin/TCF dependent transcriptional activity over multiple passages significantly reduces expression of differentiation markers, as compared to 2i. Furthermore, the ability to efficiently contribute toward chimera generation and germline transmission suggests that the inhibition of beta-catenin's TCF-dependent transcriptional activity, independent of its protein expression level, retains the naive ground state pluripotency in mESCs. Additionally, growth medium containing iCRT3 + PD can provide an alternative to 2i as a stable culture method. Stem Cells 2017;35:1924-1933. PMID- 28577308 TI - Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer. AB - BACKGROUND: The pattern of infections among neutropenic patients with cancer has shifted in the last decades to a predominance of gram-positive infections. Some of these gram-positive bacteria are increasingly resistant to beta-lactams and necessitate specific antibiotic treatment. OBJECTIVES: To assess the effectiveness of empirical anti-gram-positive (antiGP) antibiotic treatment for febrile neutropenic patients with cancer in terms of mortality and treatment failure. To assess the rate of resistance development, further infections and adverse events associated with additional antiGP treatment. SEARCH METHODS: For the review update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (May 2012 to 2017), Embase (May 2012 to 2017), LILACS (2012 to 2017), conference proceedings, ClinicalTrials.gov trial registry, and the references of the included studies. We contacted the first authors of all included and potentially relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing one antibiotic regimen versus the same regimen with the addition of an antiGP antibiotic for the treatment of febrile neutropenic patients with cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and extracted all data. Risk ratios (RR) with 95% confidence intervals (CIs) were calculated. A random-effects model was used for all comparisons showing substantial heterogeneity (I2 > 50%). Outcomes were extracted by intention-to-treat and the analysis was patient-based whenever possible. MAIN RESULTS: Fourteen trials and 2782 patients or episodes were included. Empirical antiGP antibiotics were tested at the onset of treatment in 12 studies, and for persistent fever in two studies. The antiGP treatment was a glycopeptide in nine trials. Eight studies were assessed in the overall mortality comparison and no significant difference was seen between the comparator arms, RR of 0.90 (95% CI 0.64 to 1.25; 8 studies, 1242 patients; moderate-quality data). Eleven trials assessed failure, including modifications as failures, while seven assessed overall failure disregarding treatment modifications. Failure with modifications was reduced, RR of 0.72 (95% CI 0.65 to 0.79; 11 studies, 2169 patients; very low-quality data), while overall failure was the same, RR of 1.00 (95% CI 0.79 to 1.27; 7 studies, 943 patients; low-quality data). Sensitivity analysis for allocation concealment and incomplete outcome data did not change the results. Failure among patients with gram positive infections was reduced with antiGP treatment, RR of 0.56 (95% CI 0.38 to 0.84, 5 studies, 175 patients), although, mortality among these patients was not changed.Data regarding other patient subgroups likely to benefit from antiGP treatment were not available. Glycopeptides did not increase fungal superinfection rates and were associated with a reduction in documented gram positive superinfections. Resistant colonisation was not documented in the studies. AUTHORS' CONCLUSIONS: Based on very low- or low-quality evidence using the GRADE approach and overall low risk of bias, the current evidence shows that the empirical routine addition of antiGP treatment, namely glycopeptides, does not improve the outcomes of febrile neutropenic patients with cancer. PMID- 28577309 TI - 1 H-19 F REDOR-filtered NMR spin diffusion measurements of domain size in heterogeneous polymers. AB - Solid state NMR spectroscopy is inherently sensitive to chemical structure and composition and thus makes an ideal method to probe the heterogeneity of multicomponent polymers. Specifically, NMR spin diffusion experiments can be used to extract reliable information about spatial domain sizes on multiple length scales, provided that magnetization selection of one domain can be achieved. In this paper, we demonstrate the preferential filtering of protons in fluorinated domains during NMR spin diffusion experiments using 1 H-19 F heteronuclear dipolar dephasing based on rotational echo double resonance (REDOR) MAS NMR techniques. Three pulse sequence variations are demonstrated based on the different nuclei detected: direct 1 H detection, plus both 1 H?13 C cross polarization and 1 H?19 F cross polarization detection schemes. This 1 H-19 F REDOR-filtered spin diffusion method was used to measure fluorinated domain sizes for a complex polymer blend. The efficacy of the REDOR-based spin filter does not rely on spin relaxation behavior or chemical shift differences and thus is applicable for performing NMR spin diffusion experiments in samples where traditional magnetization filters may prove unsuccessful. This REDOR-filtered NMR spin diffusion method can also be extended to other samples where a heteronuclear spin pair exists that is unique to the domain of interest. PMID- 28577311 TI - Acclimation of 2-chlorophenol Biodegrading Activated Sludge and Microbial Community Analysis. AB - Taking glucose as co-substrate, the activated sludge which could effectively biodegrade 2-chlorophenol (2-CP) of 40 mg/L was successfully domesticated after acclimation for 49 days in sequencing batch reactors. High-throughput sequencing (HTS) analysis revealed that the community richness initially increased for 5 days and then decreased after another 20 days with the increase of 2-CP. The original sludge obtained from water resource recovery facility had the highest diversity. At the beginning of acclimation, the community diversity decreased. With the acclimation going on, both richness and diversity of community increased, but decreased significantly when the concentration of 2-CP was increased to 40 mg/L. Saccharibacteria_norank, Bacillus, Saprospiraceae_uncultured and Lactococcus were the dominant bacteria detected in this study. Bacillus and Pseudomonas were the main chlorophenol-degrading bacteria. WCHB1-60_norank, Tetrasphaera, Comamonadaceae_unclassified and Haliangium had lower tolerance to 2-CP. Higher bacterial tolerance to CPs does not mean higher degrading capability. The degradation of CPs was not positively correlated with the abundance of known 2-CP degrading bacteria detected in this study. PMID- 28577310 TI - Elucidating the molecular basis of MSH2-deficient tumors by combined germline and somatic analysis. AB - In a proportion of patients presenting mismatch repair (MMR)-deficient tumors, no germline MMR mutations are identified, the so-called Lynch-like syndrome (LLS). Recently, MMR-deficient tumors have been associated with germline mutations in POLE and MUTYH or double somatic MMR events. Our aim was to elucidate the molecular basis of MSH2-deficient LS-suspected cases using a comprehensive analysis of colorectal cancer (CRC)-associated genes at germline and somatic level. Fifty-eight probands harboring MSH2-deficient tumors were included. Germline mutational analysis of MSH2 (including EPCAM deletions) and MSH6 was performed. Pathogenicity of MSH2 variants was assessed by RNA analysis and multifactorial likelihood calculations. MSH2 cDNA and methylation of MSH2 and MSH6 promoters were studied. Matched blood and tumor DNA were analyzed using a customized next generation sequencing panel. Thirty-five individuals were carriers of pathogenic or probably pathogenic variants in MSH2 and EPCAM. Five patients harbored 4 different MSH2 variants of unknown significance (VUS) and one had 2 novel MSH6 promoter VUS. Pathogenicity assessment allowed the reclassification of the 4 MSH2 VUS and 6 probably pathogenic variants as pathogenic mutations, enabling a total of 40 LS diagnostics. Predicted pathogenic germline variants in BUB1, SETD2, FAN1 and MUTYH were identified in 5 cases. Three patients had double somatic hits in MSH2 or MSH6, and another 2 had somatic alterations in other MMR genes and/or proofreading polymerases. In conclusion, our comprehensive strategy combining germline and somatic mutational status of CRC-associated genes by means of a subexome panel allows the elucidation of up to 86% of MSH2-deficient suspected LS tumors. PMID- 28577312 TI - Biodegradation of Laundry Wastewater Under Aerobic and Anaerobic Conditions: A Kinetic Evaluation. AB - This research was conducted in a batch mode in a laboratory-scale setup to study (1) the biodegradation of laundry wastewater under aerobic and anaerobic conditions and to quantify the degradation at steady-state in terms of kinetic parameters and (2) the inhibition caused by laundry wastewater on growth substrate utilization by un-acclimated ethanol-enriched aerobic and anaerobic microbial cultures. The chemical oxygen demand (COD) removal was above 95% under aerobic condition; however, the COD removal varied between 70 and 88% under anaerobic condition. The steady-state kinetic parameters k, Ks, Y, MUm, and kd were 1.75 d-1, 21.67 mg COD/L, 0.4 mg volatile suspended solids (VSS)/mg COD, 0.7 d-1, and 0.06 d-1 respectively under aerobic condition; corresponding values under anaerobic condition were 4.7 d-1, 173.67 mg COD/L, 0.06 mg VSS/mg COD, 0.3 d-1, and 0.04 d-1. Laundry wastewater caused a competitive inhibition at doses above 200 mg/L under aerobic and anaerobic conditions. PMID- 28577313 TI - A Nanofiltration Decision Tool for Potable Reuse: A New Rejection Model for Recalcitrant CECs. AB - Effluent samples from three water resource recovery facilities (WRRFs) were individually characterized for presence and concentration of 94 different chemicals of emerging concern (CECs), using analytical methods with reporting limits in the low-parts-per-trillion. Following CEC analysis, each sample was subjected to dead-end, pressurized membrane filtration with either a nanofiltration (NF) or reverse osmosis (RO) membrane. The majority of the measured CECs were rejected by both membranes by 1-log removal (90%) or greater. However, nine of the 94 CECs had average rejection rates by the NF membrane less than 90%. A multilevel, multivariable model was developed to predict the probable rejection coefficients of CECs with the studied NF membrane. The resulting Quantitative Molecular Properties Model (QMPM) predicted the NF rejection of CECs based on size, ionic charge, and hydrophobicity. The model parameters that successfully predicted NF rejection in bench testing were log (Kow/Kaw) and the polar surface area of the CEC molecule. PMID- 28577315 TI - Multiscale regeneration scaffold in vitro and in vivo. AB - Biocompatible scaffolds play an important role in modulating tissue growth. A gelatin and sodium alginate scaffold with a unique structure produced by a combination of 3-D printing, electrospinning, and vacuum freeze-drying has been developed for tissue engineering. The scaffold is composed of a macrostructure, a honeycomb microporous surface morphology, and nanofibers. This structure meets the design criteria for an ideal tissue engineering scaffold. The scaffold degrades and has low cytotoxicity. The biocompatibility of the scaffold is improved by the favorable cell-matrix interaction; cells attach to the scaffold well and secrete large amounts of extracellular matrix in vitro. Rats with the scaffold implanted survived without signs of complications and the host cells infiltrated the interior of the scaffold. After 2 months in vivo, the scaffold was vascularized and contained collagen fibers. This multiscale regeneration scaffold may be suitable for tissue engineering because of its unique structure, degradation, mechanical properties, and lower cytotoxicity, which support cell infiltration and growth, and promote vascularization and generation of granulation tissue in vivo. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1218-1225, 2018. PMID- 28577316 TI - Seroprevalence and risk factors of hepatitis E virus infection among the Korean, Manchu, Mongol, and Han ethnic groups in Eastern and Northeastern China. AB - Hepatitis E virus (HEV) infection is a serious public health concern in developing countries. China is regarded as an HEV-endemic area, but epidemiological data for HEV among different nationalities is limited. This study was conducted to estimate the seroprevalence and risk factors of HEV infection in Koreans (n = 520), Manchus (n = 303), Mongols (n = 217), and Hans (n = 802) in Eastern and Northeastern China between 2013 and 2015. A total of 366 (19.87%) out of 1842 samples were seropositive for IgG or IgM HEV-antibodies detected by enzyme-linked immunoassays. Among these groups, the Mongols had the highest seroprevalence of HEV infection (25.35%, 55/217), followed by the Koreans (23.65%, 123/520), the Manchus (19.80%, 60/303), and the Hans (15.96%, 128/802). Multiple analysis showed that the gender, consumption of raw/undercooked meat, source of drinking water, residence area, and age were significantly associated with HEV infection in four ethnic groups. The present results indicated that HEV infection was prevalent in Mongols, Koreans, Manchus, and Hans in the surveyed regions, which demonstrated the higher risk of transmitting HEV in multiple nationalities in Eastern and Northeastern China. PMID- 28577314 TI - Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts. AB - Although most nephron segments contain one type of epithelial cell, the collecting ducts consists of at least two: intercalated (IC) and principal (PC) cells, which regulate acid-base and salt-water homeostasis, respectively. In adult kidneys, these cells are organized in rosettes suggesting functional interactions. Genetic studies in mouse revealed that transcription factor Tfcp2l1 coordinates IC and PC development. Tfcp2l1 induces the expression of IC specific genes, including specific H+-ATPase subunits and Jag1. Jag1 in turn, initiates Notch signaling in PCs but inhibits Notch signaling in ICs. Tfcp2l1 inactivation deletes ICs, whereas Jag1 inactivation results in the forfeiture of discrete IC and PC identities. Thus, Tfcp2l1 is a critical regulator of IC-PC patterning, acting cell-autonomously in ICs, and non-cell-autonomously in PCs. As a result, Tfcp2l1 regulates the diversification of cell types which is the central characteristic of 'salt and pepper' epithelia and distinguishes the collecting duct from all other nephron segments. PMID- 28577318 TI - Persistence of acetochlor, atrazine, and S-metolachlor in surface and subsurface horizons of 2 typic argiudolls under no-tillage. AB - Variations in soil properties with depth strongly influence the degradation and persistence of herbicides, underlining the importance of studying these processes in soil horizons with distinctively different properties. The persistence of the herbicides acetochlor, atrazine, and S-metolachlor was measured in samples of the A, B, and C horizons of 2 Typic Argiudolls from Argentina under no-till management. The soils studied differed in soil organic carbon (OC) content, pH, particle size distribution, and structure. Quantification of herbicides in soil was done through high-performance liquid chromatography with diode array detector. There were interactions of herbicide * horizon (p < 0.01) that resulted in degradation rates (k) of all herbicides decreasing, and their corresponding dissipation half-life (DT50) values increasing, with soil depth. Herbicide persistence across all soils and horizons ranged from 15 to 73 d for acetochlor, 13 to 29 d for atrazine, and 82 to 141 d for S-metolachlor, which had significantly (p < 0.01) greater persistence than atrazine and acetochlor. The DT50 values of herbicides were negatively correlated with the contents of OC (correlation coefficients ranging from -0.496 to -0.773), phosphorus (-0.427 to 0.564), and nitrogen-nitrate (-0.507 to -0.662), and with microbial activity ( 0.454 to -0.687) and the adsorption coefficient (-0.530 to -0.595); DT50s were positively correlated with pH (0.366 to 0.648). Adsorption was likely the most influential process in determining persistence of these herbicides in surface and subsurface horizons. The present study can potentially improve the prediction of the fate of acetochlor, atrazine, and S-metolachlor in soils because it includes much needed information on the degradation of the herbicides in subsurface horizons. Environ Toxicol Chem 2017;36:3065-3073. (c) 2017 SETAC. PMID- 28577319 TI - Diffusion kurtosis MRI versus conventional diffusion-weighted imaging for evaluating inflammatory activity in Crohn's disease. AB - PURPOSE: To assess the efficacy of diffusion kurtosis imaging (DKI) and to compare DKI-derived parameters with that of conventional diffusion-weighted imaging (DWI) for grading the inflammatory activity of Crohn's disease (CD). MATERIALS AND METHODS: In all, 38 patients with CD underwent 3T magnetic resonance enterography (MRE) with DKI (b values of 0-2000 s/mm2 ). The inflammatory activity of the bowel segments was graded by magnetic resonance index of activity (MaRIA) as inactive (<7), mild (>=7 and <11), or moderate severe (>=11). Apparent diffusion for non-Gaussian distribution (Dapp ) and apparent kurtosis coefficient (Kapp ) on DKI as well as apparent diffusion coefficient (ADC) on DWI were compared. RESULTS: In all, 86 bowel segments including inactive (20), mild (19), and moderate-severe (47) CD were analyzed. The differences in Kapp , Dapp , and ADC among inactive, mild, and moderate severe CD were significant (all P < 0.05). Kapp (r = 0.862), Dapp (r = -0.755), and ADC (r = -0.713) correlated well with MaRIA in all segments. Stronger correlation with MaRIA in moderate-severe CD was found for Kapp (r = 0.647) than that of Dapp (r = -0.414) and ADC (r = -0.580). Receiver operating characteristic (ROC) curve analysis showed high accuracy of Kapp , Dapp , and ADC for differentiating active from inactive CD (AUC: 0.953 for Kapp , 0.944 for Dapp , 0.907 for ADC) as well as differentiating inactive-mild from moderate-severe CD (AUC: 0.946 for Kapp , 0.887 for Dapp , 0.846 for ADC). The threshold Kapp of 0.731 allowed differentiation of active from inactive CD with 89.4% sensitivity and 95% specificity. CONCLUSION: DKI of CD is clinically feasible and might be superior to conventional DWI for grading the inflammatory activity of CD. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:702 709. PMID- 28577320 TI - Life of Martha Entwistle: Australia's first convict mental health nurse. AB - The present position paper provides an account of the life of Martha Entwistle, the earliest recorded convict nurse who worked within the Castle Hill Asylum. In our review of primary historical sources, Australia's first convict mental health nurse was found to be a resilient woman who endured several traumatic life experiences. Her nursing within Australia's first mental health asylum was highly valued by the superintendent of the service. She nursed in a harsh colonial environment, short of adequate resources, during an era of fast-paced industrial and technological a change. Martha Entwistle's experiences provide a historical account of the role of the early convict mental health nurse. Her life story enables modern-day nurses to reflect on the advances made in mental health nursing and contexts of care for nurses today. PMID- 28577321 TI - Chlorophyll-Based Organic-Inorganic Heterojunction Solar Cells. AB - Solid-state chlorophyll solar cells (CSCs) employing a carboxylated chlorophyll derivative, methyl trans-32 -carboxypyropheophorbide a, as a light-harvesting dye sensitizer chlorophyll (DSC) deposited on mesoporous TiO2 , on which four zinc hydroxylated chlorophyll derivatives were spin-coated for hole transporter chlorophylls (HTCs), are described. Key parameters, including the effective carrier mobility of the HTC films, as determined by the space charge-limited current method, and the frontier molecular orbitals of these DSCs and HTCs, as estimated from cyclic voltammetry and electronic absorption spectra, suggest that both charge separation and carrier transport are favorable. The power conversion efficiencies (PCEs) of the present CSCs with fluorine-doped tin oxide (FTO)/TiO2 /DSC/HTCs/Ag were determined to follow the order of HTC-1>HTC-2>HTC-3>HTC-4, which coincided perfectly with the order of their hole mobilities. The maximum PCE achieved was 0.86 % with HTC-1. The photovoltaic devices studied herein with two types of chlorophyll derivatives as dye sensitizers and hole transporters provide a unique solution for the utilization of solar energy with a view to truly realizing "green energy". PMID- 28577322 TI - Programmed Synthesis of Molecular Wires with Fixed Insulation and Defined Length Based on Oligo(phenylene ethynylene) and Permethylated alpha-Cyclodextrins. AB - The development of new tuning methods for pi-conjugated insulated molecular wires with strictly defined axle lengths as well as positions and degrees of macrocycle coverage would provide unprecedented insight into insulation effects in functionalized materials. Herein, iterative reactions of oligo(phenylene ethynylene) (OPE) linked with permethylated alpha-cyclodextrins were carried out to fabricate insulated molecular wires with a defined length and insulation in desired areas. Insulated OPEs were elongated in a stepwise manner by performing sequential coupling/deprotection reactions. The insulated areas on the OPE units in each expansion step were selectively controlled by means of programmed solvent conditions (high/low polarity). Moreover, a completely insulated OPE (up to a linked [11]rotaxane) with high structural regularity and high covering ratio was synthesized by appropriate tuning of the Pd catalyst and an extension unit bearing a traceless capping unit based on a tert-butyldimethylsilyl group. This strategy may guide the development of the selective synthesis of fully insulated, partially insulated, and uninsulated molecular wires with well-defined lengths and covered/uncovered areas. PMID- 28577323 TI - Na+ Ions Induce the Pirouetting Motion and Catalytic Activity of [2]Rotaxanes. AB - We have prepared [2]rotaxanes, the behavior of which as switchable catalysts depends on their pirouetting motion, which can be controlled through the addition and removal of Na+ ions. At least three sequential on/off cycles of a Michael reaction can be performed in situ when using the NaTFPB/[2.2.2]cryptand reagent pair to switch "on" and "off" the catalytic ability of the [2]rotaxanes. PMID- 28577324 TI - Soluble Two-Dimensional Covalent Organometallic Polymers by (Arene)Ruthenium Sulfur Chemistry. AB - A class of two-dimensional (2D) covalent organometallic polymers, with nanometer scale crosslinking, was obtained by arene(ruthenium) sulfur chemistry. Their ambivalent nature, with positively charged crosslinks and lypophylic branches is the key to the often sought-for and usually hard-to-achieve solubility of 2D polymers in various kinds of solvents. Solubility is here controlled by the planarity of the polymer, which in turn controls Coulomb interactions between the polymer layers. High planarity is achieved for high symmetry crosslinks and short, rigid branches. Owing to their solubility, the polymers are easily processable, and can be handled as powder, deposited on surfaces by mere spin coating, or suspended across membranes by drop-casting. The novel 2D materials are potential candidates as flexible membranes for catalysis, cancer therapy, and electronics. PMID- 28577325 TI - Borylenes: An Emerging Class of Compounds. AB - Free borylenes (R-B:) have only been spectroscopically characterized in the gas phase or in matrices at very low temperatures. However, in recent years, a few mono- and bis(Lewis base)-stabilized borylenes have been isolated. In both of these compounds the boron atom is in the formal oxidation state +I which contrasts with classical organoboron derivatives wherein the element is in the +III oxidation state. Mono(Lewis base)-stabilized borylenes are isoelectronic with singlet carbenes, and their reactivity mimics to some extent that of transition metals. They can activate small molecules, such as H2 , and coordinate an additional ligand; in other words, they are boron metallomimics. Bis(Lewis base)borylene adducts are isoelectronic with amines and phosphines. In contrast to boranes, which act as electron acceptors and thus Lewis acids, they are electron-rich and act as ligands for transition metals. PMID- 28577326 TI - Trivalent chromium induces autophagy by activating sphingomyelin phosphodiesterase 2 and increasing cellular ceramide levels in renal HK2 cells. AB - In this study, we examined the role of autophagy in the initiation of lipid increases in renal epithelial HK2 cells. We found that trivalent chromium [Cr(III)] induced autophagy by activating sphingomyelin phosphodiesterase 2 (SMPD2). SMPD2 increases levels of ceramide and other lipids. Confocal immunofluorescence microscopy showed that signals of ceramide overlapped with LC3, suggesting that ceramide might play an important role in the formation of autophagosome. In conclusion, our data indicate that Cr(III) induces autophagy via structural aberration of organelle membrane, in particular by the increase of lipid compositions in addition to autophagy-associated proteins. PMID- 28577328 TI - Human embryonic stem cell dispersion in electrospun PCL fiber scaffolds by coating with laminin-521 and E-cadherin-Fc. AB - Advances in human pluripotent cell cultivation and differentiation protocols have led to production of stem cell-derived progenitors as a promising cell source for replacement therapy. Three-dimensional (3-D) culture is a better mimic of the natural niche for stem cells and is widely used for disease modeling. Here, we describe a nonaggregate culture system of human embryonic stem cells inside electrospun polycaprolactone (PCL) fiber scaffolds combined with defined extracellular proteins naturally occurring in the stem cell niche. PCL fiber scaffolds coated with recombinant human laminin-521 readily supported initial stem cell attachment and growth from a single-cell suspension. The combination of recombinant E-cadherin-Fc and laminin-521 further improved cell dispersion rendering a uniform cell population. Finally, we showed that the cells cultured in E-cadherin-Fc- and laminin-521-coated PCL scaffolds could differentiate into all three germ layers. Importantly, we provided a chemically defined 3-D system in which pluripotent stem cells grown and differentiated avoiding the formation of cell aggregates. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1226-1236, 2018. PMID- 28577327 TI - Merging Photoredox with Bronsted Acid Catalysis: The Cross-Dehydrogenative C-O Coupling for sp3 C-H Bond Peroxidation. AB - A photoredox and Bronsted acid synergistically catalyzed cross-dehydrogenative C O coupling reaction is developed in which isochroman peroxyacetals are formed through sp3 C-H bond peroxidation. The reported method is characterized by its extremely mild reaction conditions, excellent yields, and broad substrate scope. An oxocarbenium ion p-chlorobenzenesulfonate was speculated to be the reactive intermediate. The role of hemiacetals and oxygenated dimers on the effective stabilization of the oxocarbenium ion was investigated; the presence of acid appeared to establish equilibrium between hemiacetals and oxygenated dimers with the oxocarbenium ion pairs. The broad applicability of the method highlights the potential of the protocol for molecule synthesis. PMID- 28577329 TI - Automated image quality evaluation of T2 -weighted liver MRI utilizing deep learning architecture. AB - PURPOSE: To develop and test a deep learning approach named Convolutional Neural Network (CNN) for automated screening of T2 -weighted (T2 WI) liver acquisitions for nondiagnostic images, and compare this automated approach to evaluation by two radiologists. MATERIALS AND METHODS: We evaluated 522 liver magnetic resonance imaging (MRI) exams performed at 1.5T and 3T at our institution between November 2014 and May 2016 for CNN training and validation. The CNN consisted of an input layer, convolutional layer, fully connected layer, and output layer. 351 T2 WI were anonymized for training. Each case was annotated with a label of being diagnostic or nondiagnostic for detecting lesions and assessing liver morphology. Another independently collected 171 cases were sequestered for a blind test. These 171 T2 WI were assessed independently by two radiologists and annotated as being diagnostic or nondiagnostic. These 171 T2 WI were presented to the CNN algorithm and image quality (IQ) output of the algorithm was compared to that of two radiologists. RESULTS: There was concordance in IQ label between Reader 1 and CNN in 79% of cases and between Reader 2 and CNN in 73%. The sensitivity and the specificity of the CNN algorithm in identifying nondiagnostic IQ was 67% and 81% with respect to Reader 1 and 47% and 80% with respect to Reader 2. The negative predictive value of the algorithm for identifying nondiagnostic IQ was 94% and 86% (relative to Readers 1 and 2). CONCLUSION: We demonstrate a CNN algorithm that yields a high negative predictive value when screening for nondiagnostic T2 WI of the liver. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:723-728. PMID- 28577330 TI - Treated wastewater effluent as a source of pyrethroids and fipronil at todos santos bay, Mexico: Its impact on sediments and organisms. AB - Pyrethroids are insecticides widely used to control pests and disease vectors in residential areas and agricultural lands. Pyrethroids are emerging pollutants, and their use is a growing concern because of their toxicity potential to aquatic organisms. Todos Santos Bay and the Punta Banda estuary, 2 coastal bodies located to the south of the Southern California Bight, were studied to establish a baseline of the current conditions of pollution by pyrethroids and fipronil. Eight pyrethroids, along with fipronil and its 2 metabolites, were determined in effluents from wastewater-treatment plants (n = 3), surface sediments (n = 32), and 3 locations with mussels (Mytilus californianus, n = 9). Bifenthrin, permethrin, and cypermethrin were the most common pyrethroids found in the study areas and were widespread in sediments, mussels, and wastewater-treated effluents. Fipronil and its metabolites were detected in mussels and wastewater treated effluents only. Total pyrethroid concentrations in sediments ranged from 0.04 to 1.95 ng/g dry weight in the Punta Banda estuary (n = 13) and from 0.07 to 6.62 ng/g dry weight in Todos Santos Bay (n = 19). Moreover, total pyrethroids in mussels ranged from 1.19 to 6.15 ng/g wet weight. Based on the toxic unit data calculated for pyrethroids and fipronil for Eohaustorius estuarius and Hyalella azteca, little to no impact is expected to the benthic population structure. Environ Toxicol Chem 2017;36:3057-3064. (c) 2017 SETAC. PMID- 28577331 TI - Risk-based prioritization method for the classification of groundwater pesticide pollution from agricultural regions. AB - Agricultural regions are a significant source of groundwater pesticide pollution. To ensure that agricultural regions with a significantly high risk of groundwater pesticide contamination are properly managed, a risk-based ranking method related to groundwater pesticide contamination is needed. In the present paper, a risk based prioritization method for the classification of groundwater pesticide pollution from agricultural regions was established. The method encompasses 3 phases, including indicator selection, characterization, and classification. In the risk ranking index system employed here, 17 indicators involving the physicochemical properties, environmental behavior characteristics, pesticide application methods, and inherent vulnerability of groundwater in the agricultural region were selected. The boundary of each indicator was determined using K-means cluster analysis based on a survey of a typical agricultural region and the physical and chemical properties of 300 typical pesticides. The total risk characterization was calculated by multiplying the risk value of each indicator, which could effectively avoid the subjectivity of index weight calculation and identify the main factors associated with the risk. The results indicated that the risk for groundwater pesticide contamination from agriculture in a region could be ranked into 4 classes from low to high risk. This method was applied to an agricultural region in Jiangsu Province, China, and it showed that this region had a relatively high risk for groundwater contamination from pesticides, and that the pesticide application method was the primary factor contributing to the relatively high risk. The risk ranking method was determined to be feasible, valid, and able to provide reference data related to the risk management of groundwater pesticide pollution from agricultural regions. Integr Environ Assess Manag 2017;13:1052-1059. (c) 2017 SETAC. PMID- 28577333 TI - MRI-based assessment of acute effect of head-down tilt position on intracranial hemodynamics and hydrodynamics. AB - PURPOSE: To quantify the acute effect of the head-down tilt (HDT) posture on intracranial hemodynamics and hydrodynamics. MATERIALS AND METHODS: We evaluated the intracranial physiological parameters, blood flow-related parameters, and brain morphology in the HDT (-6 degrees and -12 degrees ) and the horizontal supine (HS) positions. Seven and 15 healthy subjects were scanned for each position using 3.0 T magnetic resonance imaging system. The peak-to-peak intracranial volume change, the peak-to-peak cerebrospinal fluid (CSF) pressure gradient (PGp-p ), and the intracranial compliance index were calculated from the blood and CSF flow determined using a cine phase-contrast technique. The brain volumetry was conducted using SPM12. The measurements were compared using the Wilcoxon signed-rank test or a paired t-test. RESULTS: No measurements changed in the -6 degrees HDT. The PGp-p and venous outflow of the internal jugular veins (IJVs) in the -12 degrees HDT were significantly increased compared to the HS (P < 0.001 and P = 0.025, respectively). The cross-sectional areas of the IJVs were significantly larger (P < 0.001), and the maximum, minimum, and mean blood flow velocity of the IJVs were significantly decreased (P = 0.003, < 0.001, and = 0.001, respectively) in the -12 degrees HDT. The mean blood flow velocities of the internal carotid arteries were decreased (P = 0.023). Neither position affected the brain volume. CONCLUSION: Pressure gradient and venous outflow were increased in accordance with the elevation of the intracranial pressure as an acute effect of the HDT. However, the CSF was not constantly shifted from the spinal canal to the cranium. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:565-571. PMID- 28577332 TI - Hippocampal fractional amplitude of low-frequency fluctuation and functional connectivity changes in premenstrual syndrome. AB - PURPOSE: To investigate differences in hippocampal activity between premenstrual syndrome (PMS) patients and healthy controls, to elucidate the neural mechanisms of PMS. MATERIALS AND METHODS: Twenty female patients with PMS (PMS group) and 21 healthy controls (HC group) underwent a single-shot gradient-recalled echo planar imaging (EPI) sequence scan during the luteal phase in 3.0 Tesla MRI. Spontaneous neural activity in hippocampus (HIPP) was measured by fractional amplitude of low frequency fluctuation (fALFF). Functional connectivity (FC) was used to examine the neural networks of PMS patients by selecting the abnormal HIPP as the seed region. All participants completed a daily record of severity of problems (DRSP) questionnaire to measure the severity of clinical symptoms. RESULTS: Results from a two-sample t-test showed increased left HIPP fALFF in the PMS group compared with the HC group (P = 0.042), while there was no between-group difference of fALFF in the right HIPP (P = 0.1011). A secondary analysis using a two-sample t test with the left HIPP as the seed region, the results revealed that the PMS group exhibited increased FC between the left HIPP and left medial prefrontal cortex (mPFC), left posterior cingulate cortex (PCC), right middle cingulate cortex (MCC), and bilateral precentral cortex (PC), while decreased FC between the left HIPP and right orbitofrontal cortex (OFC). Moreover, the PMS group exhibited higher DRSP scores, which were positively correlated (r = 0.64, P = 0.003) with FC between the left HIPP and mPFC during the luteal phase. CONCLUSION: Altered spontaneous neural activity and connectivity of left HIPP may be involved in PMS. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:545-553. PMID- 28577334 TI - Catalytic Oxygenative Allylic Transposition of Alkenes into Enones with an Azaadamantane-Type Oxoammonium Salt Catalyst. AB - The first catalytic oxygenative allylic transposition of unactivated alkenes into enones has been developed using an oxoammonium salt as the catalyst. This reaction converts various tri- and trans-disubstituted alkenes into their corresponding enones with transposition of their double bonds at ambient temperature in good yields. The use of a less-hindered azaadamantane-type oxoammonium salt as the catalyst and a combination of two distinct stoichiometric oxidants, namely, iodobenzene diacetate and magnesium monoperoxyphthalate hexahydrate (MMPP?6 H2 O) are essential to facilitate the enone formation efficiently. PMID- 28577335 TI - Application of whole-lesion histogram analysis of pharmacokinetic parameters in dynamic contrast-enhanced MRI of breast lesions with the CAIPIRINHA-Dixon-TWIST VIBE technique. AB - PURPOSE: To investigate the application of whole-lesion histogram analysis of pharmacokinetic parameters for differentiating malignant from benign breast lesions on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: In all, 92 women with 97 breast lesions (26 benign and 71 malignant lesions) were enrolled in this study. Patients underwent dynamic breast MRI at 3T using a prototypical CAIPIRINHA-Dixon-TWIST-VIBE (CDT-VIBE) sequence and a subsequent surgery or biopsy. Inflow rate of the agent between plasma and interstitium (Ktrans ), outflow rate of agent between interstitium and plasma (Kep ), extravascular space volume per unit volume of tissue (ve ) including mean value, 25th/50th/75th/90th percentiles, skewness, and kurtosis were then calculated based on the whole lesion. A single-sample Kolmogorov-Smirnov test, paired t-test, and receiver operating characteristic curve (ROC) analysis were used for statistical analysis. RESULTS: Malignant breast lesions had significantly higher Ktrans , Kep , and lower ve in mean values, 25th/50th/75th/90th percentiles, and significantly higher skewness of ve than benign breast lesions (all P < 0.05). There was no significant difference in kurtosis values between malignant and benign breast lesions (all P > 0.05). The 90th percentile of Ktrans , the 90th percentile of Kep , and the 50th percentile of ve showed the greatest areas under the ROC curve (AUC) for each pharmacokinetic parameter derived from DCE-MRI. The 90th percentile of Kep achieved the highest AUC value (0.927) among all histogram-derived values. CONCLUSION: The whole-lesion histogram analysis of pharmacokinetic parameters can improve the diagnostic accuracy of breast DCE-MRI with the CDT-VIBE technique. The 90th percentile of Kep may be the best indicator in differentiation between malignant and benign breast lesions. LEVEL OF EVIDENCE: 4 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2018;47:91-96. PMID- 28577337 TI - Confounding factors of ultrafiltration and protein analysis in extracellular vesicle research. AB - Identification and validation of extracellular vesicle (EV)-associated biomarkers requires robust isolation and characterization protocols. We assessed the impact of some commonly implemented pre-analytical, analytical and post-analytical variables in EV research. Centrifugal filters with different membrane types and pore sizes are used to reduce large volume biofluids prior to EV isolation or to concentrate EVs. We compared five commonly reported filters for their efficiency when using plasma, urine and EV-spiked PBS. Regenerated cellulose membranes with pore size of 10 kDa recovered EVs the most efficient. Less than 40% recovery was achieved with other filters. Next, we analyzed the effect of the type of protein assays to measure EV protein in colorimetric and fluorometric kits. The fluorometric assay Qubit measured low concentration EV and BSA samples the most accurately with the lowest variation among technical and biological replicates. Lastly, we quantified Optiprep remnants in EV samples from density gradient ultracentrifugation and demonstrate that size-exclusion chromatography efficiently removes Optiprep from EVs. In conclusion, choice of centrifugal filters and protein assays confound EV analysis and should be carefully considered to increase efficiency towards biomarker discovery. SEC-based removal of Optiprep remnants from EVs can be considered for downstream applications. PMID- 28577339 TI - A new method to reduce the number of time delays in a network. AB - Time delays may cause dramatic changes to the dynamics of interacting oscillators. Coupled networks of interacting dynamical systems can have unexpected behaviours when the signal between the vertices are time delayed. It has been shown for a very general class of systems that the time delays can be rearranged as long as the total time delay over the constitutive loops of the network is conserved. This fact allows to reduce the number of time delays of the problem without loss of information. There is a theoretical lower bound for this number that can be numerically improved if the time delays are commensurable. Here we propose a formulation of the problem and a numerical method to even further reduce the number of time delays in a network. PMID- 28577338 TI - Specific brain activation patterns associated with two neuromuscular electrical stimulation protocols. AB - The influence of neuromuscular electrical stimulation (NMES) parameters on brain activation has been scarcely investigated. We aimed at comparing two frequently used NMES protocols - designed to vary in the extent of sensory input. Whole brain functional magnetic resonance imaging was performed in sixteen healthy subjects during wide-pulse high-frequency (WPHF, 100 Hz-1 ms) and conventional (CONV, 25 Hz-0.05 ms) NMES applied over the triceps surae. Each protocol included 20 isometric contractions performed at 10% of maximal force. Voluntary plantar flexions (VOL) were performed as control trial. Mean force was not different among the three protocols, however, total current charge was higher for WPHF than for CONV. All protocols elicited significant activations of the sensorimotor network, cerebellum and thalamus. WPHF resulted in lower deactivation in the secondary somatosensory cortex and precuneus. Bilateral thalami and caudate nuclei were hyperactivated for CONV. The modulation of the NMES parameters resulted in differently activated/deactivated regions related to total current charge of the stimulation but not to mean force. By targeting different cerebral brain regions, the two NMES protocols might allow for individually-designed rehabilitation training in patients who can no longer execute voluntary movements. PMID- 28577340 TI - Abnormal Growth and Feeding Behavior Persist After Removal of Upper Airway Obstruction in Juvenile Rats. AB - Pediatric obstructive sleep-disordered breathing is associated with growth retardation, but also with obesity that has a tendency to persist following treatment. We investigated the effect of upper airways obstruction (AO) and of obstruction removal (OR) in juvenile rats on gut-derived ghrelin and related hypothalamic factors, feeding, and growth hormone (GH) homeostasis. Here, we show that after seven weeks of AO, animals gained less weight compared to controls, despite an increase in food intake due to elevated ghrelin and hypothalamic feeding factors. OR rats who had complete restoration of tracheal diameter, consumed more food due to increased ghrelin and exhibited growth retardation due to deregulation of GH homeostasis. This study is the first to show dysregulation of the hormonal axes controlling feeding behavior and growth that are not fully restored following OR. Thus, surgical treatment by itself may not be sufficient to prevent post-surgical increased food intake and growth retardation. PMID- 28577341 TI - The malate sensing two-component system MaeKR is a non-canonical class of sensory complex for C4-dicarboxylates. AB - Microbial colonization of different environments is enabled to a great extent by the plasticity of their sensory mechanisms, among them, the two-component signal transduction systems (TCS). Here, an example of TCS plasticity is presented: the regulation of L-malate catabolism via malic enzyme by MaeRK in Lactobacillales. MaeKR belongs to the citrate family of TCS as the Escherichia coli DcuSR system. We show that the Lactobacillus casei histidine-kinase MaeK is defective in autophosphorylation activity as it lacks a functional catalytic and ATP binding domain. The cognate response regulator MaeR was poorly phosphorylated at its phosphoacceptor Asp in vitro. This phosphorylation, however, enhanced MaeR binding in vitro to its target sites and it was required for induction of regulated genes in vivo. Elucidation of the MaeR structure revealed that response regulator dimerization is accomplished by the swapping of alpha4-beta5-alpha5 elements between two monomers, generating a phosphoacceptor competent conformation. Sequence and phylogenetic analyses showed that the MaeKR peculiarities are not exclusive to L. casei as they are shared by the rest of orthologous systems of Lactobacillales. Our results reveal MaeKR as a non canonical TCS displaying distinctive features: a swapped response regulator and a sensor histidine kinase lacking ATP-dependent kinase activity. PMID- 28577342 TI - Lower SHBG level is associated with higher leptin and lower adiponectin levels as well as metabolic syndrome, independent of testosterone. AB - In addition to testosterone (T), the emerging role of sex hormone-binding globulin (SHBG) in pathogenesis of metabolic syndrome (MetS) has been noted recently. However, reports of associations with serum adipocytokine levels are still limited. Therefore, we conducted this study to evaluate whether serum T and SHBG levels are independent predictors for the risk of MetS that are associated with adiponectin and leptin levels in 614 Taiwanese men over 40 years old collected from a free health screening. Subjects in the lowest quartile of TT and SHBG levels are exposed to a 1.58 and 3.22 times risk of developing MetS, as compared to those in the highest quartile of TT and SHBG levels. However, SHBG retains its significance independent of TT as a MetS risk predictor, but not vice versa. In addition, SHBG was significantly correlated with both adiponectin and leptin levels even after adjusting for TT levels. In conclusion, SHBG served as a major predictor for the risk of MetS and was correlated with serum adiponectin and leptin levels that are independent of T. Further studies are needed to elucidate the true role of SHBG in the pathogenesis of MetS and possible mechanisms associated with serum adiponectin and leptin levels. PMID- 28577344 TI - Associated anomalies in cases with esophageal atresia. AB - Esophageal atresia (EA) is a common type of congenital anomaly. The etiology of esophageal atresia is unclear and its pathogenesis is controversial. Infants with esophageal atresia often have other non-EA associated congenital anomalies. The purpose of this investigation was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in cases with EA were collected in all livebirths, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 116 cases with esophageal atresia, representing a prevalence of 2.99 per 10,000, 54 (46.6%) had associated anomalies. There were 9 (7.8%) cases with chromosomal abnormalities including 6 trisomies 18, and 20 (17.2%) nonchromosomal recognized dysmorphic conditions including 12 cases with VACTERL association and 2 cases with CHARGE syndrome. Twenty five (21.6%) of the cases had multiple congenital anomalies (MCA). Anomalies in the cardiovascular, the digestive, the urogenital, the musculoskeletal, and the central nervous systems were the most common other anomalies. The anomalies associated with esophageal atresia could be classified into a recognizable malformation syndrome or pattern in 29 out of 54 cases (53.7%). This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion the overall prevalence of associated anomalies, which was close to one in two cases, emphasizes the need for a thorough investigation of cases with EA. A routine screening for other anomalies may be considered in infants and in fetuses with EA. PMID- 28577343 TI - De novo RNA synthesis catalyzed by the Zika Virus RNA polymerase domain. AB - Mosquito- and tick-borne pathogens including Chikungunya, Dengue, Japanese encephalitis, West Nile, Yellow fever and Zika virus, represent a new economic and public health challenge. In the absence of effective vaccines and specific therapies, only supportive regimens are administrated for most of these infections. Thus, the development of a targeted therapy is mandatory to stop the rapid progression of these pathogens and preoccupant associated burdens such as Guillain-Barre syndrome, microcephaly. For this, it is essential to develop biochemical tools to help study and target key viral enzymes involved in replication such as helicase complexes, methyl-transferases and RNA-dependent RNA polymerases. Here, we show that a highly purified ZIKV polymerase domain is active in vitro. Importantly, we show that this isolated domain is capable of de novo synthesis of the viral genome and efficient elongation without terminal nucleotide transferase activity. Altogether, this isolated polymerase domain will be a precious tool to screen and optimize specific nucleoside and non-nucleoside inhibitors to fight against Zika infections. PMID- 28577345 TI - Coexistence of Strong Second Harmonic Generation Response and Wide Band Gap in AZn4 Ga5 S12 (A=K, Rb, Cs) with 3D Diamond-like Frameworks. AB - Mid-infrared (MIR, 2-20 MUm) second-order nonlinear optical (NLO) materials with outstanding performances are of great importance in laser science and technology. However, the enormous challenge to design and synthesize an excellent MIR NLO material lies in achieving simultaneously a strong second harmonic generation (SHG) response [dij >0.6 * AgGaS2 (AGS)] and wide band gap (Eg >3.5 eV). Herein three new MIR NLO materials, AZn4 Ga5 S12 (A=K, Rb, Cs) are reported, which crystallize in the KCd4 Ga5 S12 -type structure and adopt a 3D diamond-like framework (DLF) consisting of MS4 (M=Zn/Ga) tetrahedra; achieving the desired balance with strong powder SHG response (1.2-1.4 * AGS) and wide band gap (Eg ~3.65 eV). Moreover, they also show large laser induced damage thresholds (LIDTs, 36 * AGS), a wide range of optical transparency (0.4-25 MUm) and ultrahigh thermal stability (up to 1400 K). Upon analyzing the structure-property relationship of AXII4 XIII5 Q12 family, these 3D DLF structures can be used as a highly versatile and tunable platform for designing excellent MIR NLO materials. PMID- 28577346 TI - Scanning of own- versus other-race faces in infants from racially diverse or homogenous communities. AB - We examined the role of community face experience on 6- and 8-month-old Caucasian infants' scanning of own- and other-race face scanning. We measured infants' proportional fixation time and scan path amplitudes as indices of face processing. Proportional fixation time to informationally rich face regions varied as a function of age and face race for infants living in a racially homogeneous community, whereas scan path amplitudes varied as a function of age and face race for infants living in a racially diverse community. In both communities 6-month-old infants did not show different responding to own- and other-race faces, whereas 8-month-old infants responded differently to own- and other-race faces. However, 8-month-old infants from the two communities showed different patterns of cross-race face scanning. Therefore, experience in the community beyond the home appears to contribute to the development of differential scanning of own- versus other-race faces between 6 and 8 months of age. PMID- 28577348 TI - Chirality Induction from a Chiral Guest to the Hydrogen-Bonding Network of Its Hexameric Resorcinarene Host Capsule. AB - The hexameric capsule of resorcin[4]arene 1 is capable of encapsulating tertiary amines, which has recently been used in the application of [(1)6 (H2 O)8 ] as (co )catalyst in various asymmetric reactions. However, not much is known about the highly asymmetric but conformationally very dynamic structure of the capsule after uptake of chiral molecules. Therefore, in this contribution, we utilize electronic circular dichroism and vibrational circular dichroism spectroscopy to investigate how several chiral guest molecules affect the structural preferences of the capsule [(1)6 (H2 O)8 ]. In particular, we show that one small chiral amine encapsulated in [(1)6 (H2 O)8 ] is sufficient to control and dictate the stereochemical preferences of the entire capsule. Furthermore, neither strong pi pi interactions nor a significant steric bulk are required for this induction. The observation of such a chiral imprint of the guest's stereochemistry onto its host molecule is expected to have implications also for other supramolecular capsules. PMID- 28577347 TI - Neuroradiographic findings in 22q11.2 deletion syndrome. AB - 22q11.2 deletion syndrome (22q11.2DS) is a common genetic disorder with enormous phenotypic heterogeneity. Despite the established prevalence of developmental and neuropsychiatric issues in this syndrome, its neuroanatomical correlates are not as well understood. A retrospective chart review was performed on 111 patients diagnosed with 22q11.2DS. Of the 111 patients, 24 with genetically confirmed 22q11.2 deletion and brain MRI or MRA were included in this study. The most common indications for imaging were unexplained developmental delay (6/24), seizures of unknown etiology (5/24), and unilateral weakness (3/24). More than half (13/24) of the patients had significant radiographic findings, including persistent cavum septi pellucidi and/or cavum vergae (8/24), aberrant cortical veins (6/24), polymicrogyria or cortical dysplasia (4/24), inner ear deformities (3/24), hypoplastic internal carotid artery (2/24), and hypoplastic cerebellum (1/24). These findings reveal the types and frequencies of brain malformations in this case series, and suggest that the prevalence of neuroanatomical abnormalities in 22q11.2DS may be underestimated. Understanding indications for imaging and frequently encountered brain malformations will result in early diagnosis and intervention in an effort to optimize patient outcomes. PMID- 28577349 TI - Emerging issues in disorders/differences of sex development (DSD). AB - Disorders/Differences of Sex Development (DSD), as defined by the 2006 Consensus Statement, are "congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical." They represent a spectrum of chronic medical conditions collectively affecting about 1% of the population and are associated with increased risk of infertility, cancer, and psychosocial distress. Clinical management in DSD is subject to multiple controversies about gender assignment, the timing and appropriateness of genital surgery and the approach to disclosure. There is dissent within and between stakeholders (healthcare providers, advocacy groups, families) regarding what constitutes optimal care. This special issue investigates the progress made as well as the uncertainties remaining a decade after the consensus statement and the gaps to be filled by future research and improved clinical practice. It discusses the increasing intricacy of genetic variant interpretation in the era of next-generation sequencing and the associated complexity of phenotypic variability. The issue tackles ethical dilemmas and the complicated decision-making process of assignment of sex of rearing at birth in cases of 5-alpha reductase type 2 deficiency, surveys delivery of clinical services in the United States, discusses challenges of interdisciplinary care and of educating patients and parents about DSD,and reviews the factors predisposing to gonadal tumor and their consequences on clinical management. PMID- 28577350 TI - Treatment of fifth metacarpal neck fractures with antegrade single elastic intramedullary nailing. AB - BACKGROUND: The aim of this study was to investigate clinical outcomes of fifth metacarpal neck fractures using antegrade single elastic nail and to explore ideal puncture point to avoid iatrogenic ulnar nerve injury. METHODS: A single elastic nail with suitable diameter was used in 27 cases of fifth metacarpal neck fractures with dorsal angulation over 45 degrees . An initial entry point was perforated at the ulnar-dorsal base of the metacarpal. The nail was inserted in an antegrade approach. The nail was usually removed at about 5 weeks postoperatively. RESULTS: At final follow up, all fractures proceeded to bony union. The mean total passive motion was 285 degrees and the mean total active motion (TAM) was 270 degrees . The mean angulation decreased from 50.2 +/- 6.3 degrees preoperatively to 7.4 +/- 2.3 degrees postoperatively (p < 0.001). The mean DASH-Score was 2.1 +/- 3.6 points after surgery. Two cases of skin irritation and one case of the dorsal cutaneous branch of the ulnar nerve (DCBUN) injury were observed. Superficial wound infections were not observed. CONCLUSIONS: Collectively, antegrade single elastic intramedullary nailing was a minimally invasive and reliable fixation technique for fifth metacarpal neck fractures with dorsal angulation over 45 degrees . Appropriate puncture position helped to reduce nerve damage. PMID- 28577351 TI - After accounting for competing causes of death and more advanced stage, do Aboriginal and Torres Strait Islander peoples with cancer still have worse survival? A population-based cohort study in New South Wales. AB - BACKGROUND: Aboriginal and Torres Strait Islander peoples in Australia have been found to have poorer cancer survival than non-Aboriginal people. However, use of conventional relative survival analyses is limited due to a lack of life tables. This cohort study examined whether poorer survival persist after accounting for competing risks of death from other causes and disparities in cancer stage at diagnosis, for all cancers collectively and by cancer site. METHODS: People diagnosed in 2000-2008 were extracted from the population-based New South Wales Cancer Registry. Aboriginal status was multiply imputed for people with missing information (12.9%). Logistic regression models were used to compute odds ratios (ORs) with 95% confidence intervals (CIs) for 'advanced stage' at diagnosis (separately for distant and distant/regional stage). Survival was examined using competing risk regression to compute subhazard ratios (SHRs) with 95%CIs. RESULTS: Of the 301,356 cases, 2517 (0.84%) identified as Aboriginal (0.94% after imputation). After adjusting for age, sex, year of diagnosis, socio-economic status, remoteness, and cancer site Aboriginal peoples were more likely to be diagnosed with distant (OR 1.30, 95%CI 1.17-1.44) or distant/regional stage (OR 1.29, 95%CI 1.18-1.40) for all cancers collectively. This applied to cancers of the female breast, uterus, prostate, kidney, others (those not included in other categories) and cervix (when analyses were restricted to cases with known stages/known Aboriginal status). Aboriginal peoples had a higher hazard of death than non-Aboriginal people after accounting for competing risks from other causes of death, socio-demographic factors, stage and cancer site (SHR 1.40, 95%CI 1.31 1.50 for all cancers collectively). Consistent results applied to colorectal, lung, breast, prostate and other cancers. CONCLUSIONS: Aboriginal peoples with cancer have an elevated hazard of cancer death compared with non-Aboriginal people, after accounting for more advanced stage and competing causes of death. Further research is needed to determine reasons, including any contribution of co morbidity, lifestyle factors and differentials in service access to help explain disparities. PMID- 28577352 TI - Increased postpartum haemorrhage, the possible relation with serotonergic and other psychopharmacological drugs: a matched cohort study. AB - BACKGROUND: Postpartum haemorrhage is a major obstetric risk worldwide. Therefore risk factors need to be investigated to control for this serious complication. A recent systematic review and meta-analysis revealed that the use of both serotonergic and non-serotonergic antidepressants in pregnancy are associated with a higher risk of postpartum haemorrhage. However, use of antidepressants in pregnancy is often necessary because untreated depression in pregnancy is associated with adverse maternal and neonatal outcome, such as postpartum depression, preterm birth and dysmaturity. Therefore it is of utmost importance to unravel the possible association between postpartum haemorrhage and the use of serotonergic and other psychopharmacological medication during pregnancy. METHODS: We performed a matched cohort observational study consecutively including all pregnant women using serotonergic medication (n = 578) or other psychopharmacological medication (n = 50) visiting two teaching hospitals in Amsterdam between 2010 and 2014. The incidence of postpartum haemorrhage in women using serotonergic medication or other psychopharmacological medication was compared with the incidence of postpartum haemorrhage in 641,364 pregnant women not using psychiatric medication selected from the database of the Netherlands Perinatal Registry foundation (Perined). Matching took place 1:5 for nine factors, i.e., parity, maternal age, ethnicity, socioeconomic status, macrosomia, gestational duration, history of postpartum haemorrhage, labour induction and hypertensive disorder. RESULTS: Postpartum haemorrhage occurred in 9.7% of the women using serotonergic medication. In the matched controls this was 6.6% (p = 0.01). The adjusted odds ratio (aOR) before matching was 1.6 (95% CI 1.2-2.1) and after matching 1.5 (95% CI 1.1-2.1). Among the women using other psychopharmacological medication, the incidence of postpartum haemorrhage before matching was 12.0% versus 6.1% (p = 0.08) with OR 2.1 (95% CI 0.9-4.9), and after matching 12.1% versus 4.4% (p = 0.03) with aOR of 3.3 (95% CI 1.1-9.8). CONCLUSIONS: Pregnant women using serotonergic medication have an increased risk of postpartum haemorrhage, but this high risk is also seen in pregnant women using other psychopharmacological medication. We suggest that this higher risk of postpartum haemorrhage could not only be explained by serotonin, but also by other mechanisms. An additional explanation could be the underlying psychiatric disorder. PMID- 28577353 TI - Simeprevir with peginterferon alpha-2a/ribavirin for chronic hepatitis C virus genotype 1 infection in treatment-experienced patients: an open-label, rollover study. AB - BACKGROUND: This Phase 3, open-label, rollover study (NCT01323244) investigated the efficacy and safety of simeprevir plus peginterferon alpha-2a (PegIFNalpha 2a) and ribavirin (RBV) in a well-characterized population of HCV genotype 1 (GT1)-infected treatment-experienced patients. METHODS: Patients who had failed PegIFNalpha/RBV treatment in the placebo arm of a previous Phase 2/3 simeprevir study (Phase 2/3 group, n = 125), or had been exposed to HCV direct-acting antivirals (simeprevir or other) for up to 14 days in a selected Phase 1 study (Phase 1 group, n = 16), were eligible. Phase 2/3 group patients were classified according to prior relapse, breakthrough, or non-response (null response, partial response, non-classifiable non-response) to PegIFNalpha/RBV. Eight patients in the Phase 1 group received short-term (<=14 days) simeprevir. Treatment comprised simeprevir 150 mg once daily (QD) plus PegIFNalpha-2a/RBV for 12 weeks followed by PegIFNalpha-2a/RBV for 12 or 36 weeks (using response-guided therapy [RGT] to determine total treatment duration in Phase 2/3 prior relapsers or breakthrough) or 36 weeks fixed (Phase 2/3 group non-responders and Phase 1 group). The primary endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12). RESULTS: Phase 2/3 group: SVR12 rate was 69.6% (87/125) overall; 92.7% (51/55), 60.0% (6/10), 64.3% (18/28), and 36.7% (11/30) in patients with prior relapse, viral breakthrough, partial response, or null response, respectively. SVR12 rates were similar for patients with HCV GT1a (66.0% [33/50]) and GT1b infection (72.0% [54/75]) and among HCV GT1a-infected patients with/without a baseline Q80K polymorphism (66.7% [8/12] and 65.8% [25/38], respectively). The majority of RGT-eligible patients (prior viral relapse or breakthrough) met RGT criteria (89.2% [58/65]); of these, 89.7% (52/58) achieved SVR12. Overall, 16.0% (20/125) of patients experienced on-treatment failure and 14.4% (18/125) experienced post-treatment failure (15 relapses, 3 missing data). Phase 1 group (simeprevir-naive and -experienced patients combined): SVR12 rate was 37.5% (6/16). Safety and tolerability findings were comparable to those of the feeder studies. CONCLUSIONS: The majority of RGT-eligible patients met criteria for shortening treatment to 24 weeks in total. Simeprevir 150 mg QD with PegIFNalpha 2a/RBV led to a high SVR rate among prior relapsers with HCV GT1 infection. No new safety signals were noted. TRIAL REGISTRATION: NCT01323244 . (date of registration: March 24, 2011). PMID- 28577354 TI - Clinical outcomes of arthroscopic surgery for external snapping hip. AB - BACKGROUND: Studies have reported on the arthroscopic technique for release of external snapping hip syndrome. However, no study with large sample size has been reported for arthroscopic surgery. METHODS: Patients with 229 bilateral and 19 unilateral external snapping hips were treated from January 2012 to June 2013. After locating the contracture position, arthroscopic surgery was performed accordingly. Preoperative and postoperative angles were compared. RESULTS: Comparing range of motion, all patients obtained higher adduction and flexion angles. At postoperative follow-up of 24 months, the adduction angle was improved from -14.4 +/- 5.14 to 35.7 +/- 4.21 for type I, from -31.2 +/- 5.22 to 31.7 +/- 2.84 for type II, from -49.0 +/- 3.47 to 21.6 +/- 3.43 for type III, and from 64.5 +/- 4.65 to 18.3 +/- 3.10 for type IV (P < 0.001). Similarly, the flexion angle was also significantly improved for all the four types (P < 0.001). Excellent ratio and satisfaction rate were good in types I and II. All the clinical features were cured after arthroscopic surgery. CONCLUSIONS: Arthroscopic surgery could be an effective procedure for external snapping hip, due to less operating time, small scar, fast postoperative recovery, and complete contracture release. PMID- 28577355 TI - Frailty assessment in older adults using upper-extremity function: index development. AB - BACKGROUND: Numerous multidimensional assessment tools have been developed to measure frailty; however, the clinical feasibility of these tools is limited. We previously developed and validated an upper-extremity function (UEF) assessment method that incorporates wearable motion sensors. The purpose of the current study was to: 1) cross-sectionally validate the UEF method in a larger sample in comparison with the Fried index; 2) develop a UEF frailty index to predict frailty categories including non-frail, pre-frail, and frail based on UEF parameters and demographic information, using the Fried index as the gold standard; and 3) develop a UEF continuous score (points scores for each UEF parameter and a total frailty score) based on UEF parameters and demographic information, using the Fried index as the gold standard. METHODS: We performed a cross-sectional validation and index development study within the Banner Medical Center, Tucson, and Banner Sun Health Research Institute, Sun City, Arizona. Community-dwelling and outpatient older adults (>=60 years; n = 352; 132 non frail, 175 pre-frail, and 45 frail based on Fried criteria) were recruited. For the UEF test, each participant performed a 20-s elbow flexion, within which they repetitively and rapidly flexed and extended their dominant elbow. Using elbow motion outcomes two UEF indexes were developed (categorical and score). The Fried index was measured as the gold standard. RESULTS: For the categorical index, speed of elbow flexion, elbow range of motion, elbow moment, number of flexion, speed variability and reduction within 20 s, as well as body mass index (BMI) were included as the pre-frailty/frailty predictor parameters. Results from 10 fold cross-validation showed receiver operator characteristic area under the curve of 0.77 +/- 0.07 and 0.80 +/- 0.12 for predicting Fried pre-frailty and frailty, respectively. UEF score (0.1 to 1.0) was developed using similar UEF parameters. CONCLUSIONS: We present an objective, sensor-based frailty assessment tool based on physical frailty features including slowness, weakness, exhaustion (muscle fatigue), and flexibility of upper-extremity movements. Within the current study, the method was validated cross-sectionally using the Fried index as the gold standard and the UEF categorical index and UEF frailty score were developed for research purposes and potentially for future clinical use. PMID- 28577356 TI - BMI is a poor predictor of adiposity in young overweight and obese children. AB - BACKGROUND: The body mass index (BMI) is a simple and widely utilized screening tool for obesity in children and adults. The purpose of this investigation was to evaluate if BMI could predict total fat mass (TFM) and percent body fat (%FAT) in a sample of overweight and obese children. METHODS: In this observational study, body composition was measured by dual energy x-ray absorptiometry (DXA) in 663 male and female overweight and obese children at baseline within a multidisciplinary, pediatric fitness clinic at an academic medical center. Univariate and multivariate regression analyses were conducted to evaluate whether BMI z-score (BMIz) predicts TFM or %FAT. RESULTS: The BMIz, sex and age of subjects were identified as significant predictors for both TFM and %FAT. In subjects younger than 9 years, the BMIz was a weak to moderate predictor for both TFM (R2 = 0.03 for males and 0.26 for females) and %FAT (R2 = 0.22 for males and 0.38 for females). For subjects between 9 and 18 years, the BMIz was a strong predictor for TFM (R2 between 0.57 and 0.73) while BMIz remained only moderately predictive for %FAT (R2 between 0.22 and 0.42). CONCLUSIONS: These findings advance the understanding of the utility and limitations of BMI in children and adolescents. In youth (9-18y), BMIz is a strong predictor for TFM, but a weaker predictor of relative body fat (%FAT). In children younger than 9y, BMIz is only a weak to moderate predictor for both TFM and %FAT. This study cautions the use of BMIz as a predictor of %FAT in children younger than 9 years. PMID- 28577357 TI - Assessing the effect of patient screening and isolation on curtailing Clostridium difficile infection in hospital settings. AB - BACKGROUND: Patient screening at the time of hospital admission is not recommended as a routine practice, but may be an important strategy for containment of Clostridium difficile infection (CDI) in hospital settings. We sought to investigate the effect of patient screening in the presence of asymptomatic carriers and in the context of imperfect patient isolation. METHODS: We developed and parameterized a stochastic simulation model for the transmission dynamics of CDI in a hospital ward. RESULTS: We found that the transmission of CDI in the hospital, either through asymptomatic carriers or as a results of ineffective implementation of infection control practices, at the time of hospital admission. The results show that, for a sufficiently high reproduction number of CDI, the disease can persist within a hospital setting in the presence of in-ward transmission, even when there are no asymptomatically colonized patients at the time of hospital admission. CONCLUSIONS: Our findings have significant public health and clinical implications, especially in light of the emergence and community spread of hypervirulent CDI strains with enhanced transmission rates and toxin production. Rapid detection of colonized patients remains an important component of CDI control, especially in the context of asymptomatic transmission. Screening of in-hospital patients with potential exposure to colonized patients or contaminated environment and equipment can help reduce the rates of silent transmission of CDI through asymptomatic carriers. PMID- 28577358 TI - Sensitivity of alternative measures of functioning and wellbeing for adults with sickle cell disease: comparison of PROMIS(r) to ASCQ-MeSM. AB - BACKGROUND: Sickle Cell Disease (SCD) causes profound suffering and decrements in daily functioning. Demand is growing for valid and reliable measures to systematically document these effects, particularly in adults. The Adult Sickle Cell Quality of Life Measurement System, ASCQ-MeSM, was developed for this purpose. ASCQ-MeSM is one of four measurement systems housed within the Person Centered Assessment Resource (PCAR), funded by the National Institutes of Health, to support clinical research. To help users select the best of these measures for adults with SCD, we evaluated and compared two PCAR systems: one designed to be "universally applicable" (the Patient-Reported Outcome Measurement Information System, PROMIS(r)) and one designed specifically for SCD (ASCQ-MeSM). METHODS: Respondents to PROMIS and ASCQ-Me questions were 490 adults with SCD from seven geographically-disbursed clinics within the US. Data were collected for six ASCQ Me measures (Emotional Impact, Sleep Impact, Social Impact, Stiffness Impact, Pain Impact, SCD Pain Episode Frequency and Severity) and ten PROMIS measures (Pain Impact, Pain Behavior, Physical Functioning, Anxiety, Depression, Fatigue, Satisfaction with Discretionary Social Activities, Satisfaction with Social Roles, Sleep Disturbance, and Sleep-Related Impairment). Statistical analyses, including analysis of variance and multiple linear regression, were conducted to determine the sensitivity of measures to SCD severity. SCD severity was assessed via a checklist of associated treatments and conditions. RESULTS: For those with the most severe SCD, PROMIS scores showed worse health compared to the general population for nine of ten health domains: the magnitude of the difference ranged 0.5 to 1.1 standard deviation units. The PROMIS domains most severely affected were Physical Functioning and Pain (Impact and Behavior). Significant differences by tertile of the SCD-MHC were shown for most PROMIS short forms and all ASCQ-Me short and fixed forms. In most models, ASCQ-Me measures explained statistically significant unique variance in SCD-MHC scores complementary to that explained by corresponding PROMIS measures. CONCLUSIONS: Study results supported the validity of both PROMIS and ASCQ-Me measures for use in adults with SCD. Compared to comparable PROMIS scores, most ASCQ-Me scores were better predictors of SCD disease severity, as measured by a medical history checklist. The clinical implications of these results require further investigation. PMID- 28577359 TI - A nationwide multi-institutional retrospective study to identify prognostic factors and develop a graded prognostic assessment system for patients with brain metastases from uterine corpus and cervical cancer. AB - BACKGROUND: The prevalence of brain metastases (BM) from uterine cancer has recently increased because of the improvement of overall survival (OS) of patients with uterine cancer due to its early detection and improved local control as a result of new effective treatments. However, little information is available regarding their clinical characteristics and prognosis, because oncologists have encountered BM from uterine cancer on rare occasions. METHODS: Records from 81 patients with uterine BM were collected from 10 institutes in Japan. These were used in a multi-institutional study to identify prognostic factors and develop a graded prognostic assessment (GPA) for patients with BM from uterine cancer. RESULTS: Median OS after the development of BM was 7 months (95% confidence interval, 4 to 10 months). Multivariate analysis revealed that there were survival differences according to the existence of extracranial metastases and number of BM. In the present uterine-GPA, a score of 0 was assigned to those patients with >=5 BM and extracranial metastasis, a score of 2 was assigned to those patients with one to four BM or without extracranial metastasis, and a score of 4 was assigned to those patients with one to four BM and without extracranial metastasis. The median OS for patients with a uterine GPA scores of 0, 2, and 4 was 3, 7, and 22 months, respectively. A survival analysis confirmed the presence of statistically significant differences between these groups (p < 0.05). The results were validated by data obtained from the National Report of Brain Tumor Registry of Japan. CONCLUSION: Uterine GPA incorporates two simple clinical parameters of high prognostic significance and can be used to predict the expected survival times in patients with BM from uterine cancer. Its use may help in determining an appropriate treatment for individual patients with BM. PMID- 28577360 TI - Aeroembolism in left atrium during catheter ablation of atrial fibrillation in a patient with dextrocardia: a case report and review of the literature. AB - BACKGROUND: Air embolus penetrating into heart chamber as a complication during percutaneous radiofrequency catheter ablation has been infrequently reported. CASE PRESENTATION: A 55-year-old man with dextrocardia who suffered from abdominal pain was suspected to have multiple arterial thromboembolisms, which might have originated from left atrium thrombosis since he had atrial fibrillation. He received oral anticoagulant therapy and catheter ablation of the arrhythmia. During the ablation procedure, an iatrogenic aeroembolism penetrated into the left atrium due to improper operation. Ultimately, the entire air embolus was extracted from the patient, who was free of any aeroembolism events thereafter. CONCLUSIONS: It is essential for an operator to pay full attention to all details of the procedure to avoid an aeroembolism during catheter ablation. In case of aeroembolism, removal by aspiration is an optimal and effective treatment. PMID- 28577361 TI - 'It is a difficult topic' - a qualitative study of midwives' experiences with routine antenatal enquiry for intimate partner violence. AB - BACKGROUND: Intimate partner violence (IPV) during pregnancy may jeopardize maternal and fetal health (IJFWM 49:159-164, 2004; IJGO 133:269-276, 2016). In recognition of the significant public health impact of IPV, the Norwegian Directorate of Health issued new guidelines in 2014, which recommend that health professionals routinely ask all women in antenatal care about their exposure to violence. The objective of this study was to gain an in-depth understanding of midwives' experiences with routine enquiry for intimate partner violence during the antenatal period. METHODS: The study had a qualitative design. Individual semi-structured interviews with eight midwives providing antenatal care at eight Mother and Child Health Centres (MCHC) in Norway were conducted. Graneheim and Lundmans method of content analysis inspired the analysis. RESULTS: Three main themes emerged: Midwives do ask about violence; It can be a challenge; and Factors that make it easier to ask. All midwives enquired, but not on a regular basis, about violence. The midwives' personal interest in the topic was an important factor that made it easier for them to ask about violence. Lack of time, fear of not knowing how to deal with a positive answer and lack of organizational support were barriers to asking pregnant women about their experiences of violence. CONCLUSION: Midwives were aware of the guidelines and made some efforts to implement them. However, further education and organisational support is needed to enable midwives to routinely ask all pregnant women about IVP. PMID- 28577362 TI - Serum uric acid concentration is associated with hypertensive retinopathy in hypertensive chinese adults. AB - BACKGROUND: This cross sectional investigation included 12,966 subjects with hypertension, a cohort of the China Stroke Primary Prevention Trial (CSPPT), a randomized, multicenter clinical trial. This study aimed to explore the correlation between serum uric acid (SUA) concentration and hypertensive retinopathy in hypertensive adults. METHODS: Diagnosis of hypertensive retinopathy was determined by non-mydriatic fundus photography and classified with Keith-Wagener-Barker (KWB) system. The correlation of SUA levels with hypertensive retinopathy prevalence and severity was assessed by statistical analysis. RESULTS: 9848 (75.95%) subjects were diagnosed with hypertensive retinopathy with the following retinopathy grade distribution: grade 1: 58.80%, grade 2: 14.81%, and grade 3-4: 2.34%. SUA levels were significantly associated with hypertensive retinopathy prevalence. Patients with hypertensive retinopathy had higher SUA levels than those without hypertensive retinopathy. Patients in the highest uric acid quartile had an odds ratio for hypertensive retinopathy of 1.21 compared to patients in the lowest uric acid quartile (OR = 1.21, 95% CI: 1.05-1.40, P = 0.008). When compared to the non-hyperuricemia group, those in the hyperuricemia group had an odds ratio for hypertensive retinopathy of 1.18(OR = 1.18, 95% CI: 1.05-1.33, P = 0.004). Every 1 mg/dl increase in uric acid concentration was significantly associated with a 6% higher odds of hypertensive retinopathy (OR = 1.06, 95% CI: 1.02-1.10, P = 0.002). CONCLUSIONS: The prevalence of hypertensive retinopathy was high (75.95%) among hypertensives in our patients cohort. In addition, SUA concentration was significantly associated with hypertensive retinopathy. PMID- 28577364 TI - Factors associated with impaired color vision without retinopathy amongst people with type 2 diabetes mellitus: a cross-sectional study. AB - BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) may develop color vision impairment. This study aimed to determine the prevalence and factors associated with impaired color vision in patients with T2DM but without diabetic retinopathy. METHODS: Enrolment criteria included multi-ethnic Asian participants, age 21 to 80 years, with known T2DM for a minimum of 2 years. Their diagnoses were affirmed from oral glucose tolerance test results and they were screened for impaired color vision using the Farnsworth D-15 instrument. Demographic characteristics were described and clinical data for the preceding 2 years were analyzed using logistic regression. RESULTS: Twenty-two percent of 849 eligible participants had impaired color vision with higher involvement of the right eye. Impaired blue-yellow color-vision(Tritanomaly) was the commonest impaired color vision. Participants with impaired color vision were significantly associated with age and lower education; longer duration of T2DM (median 6 years vs 4 years); higher HbA1c level and HDL-Cholesterol in 2nd year; lower mean total cholesterol, mean LDL-Cholesterol and mean triglyceride in 2nd year. They also have poorer vision beyond 6/12 in the affected eye. Logistic regression showed that impaired color vision was associated with older patients (OR=1.04), increased duration of T2DM (OR=1.07); prescription of Tolbutamide (OR=3.79) and lower mean systolic blood pressure (OR=0.98). CONCLUSION: Almost one in four participants with T2DM had impaired color vision, largely with tritanomaly. Color vision screening may be considered for participants who develop T2DM for 6 years or longer, but this requires further cost-effectiveness evaluation. PMID- 28577363 TI - International workshop on insecticide resistance in vectors of arboviruses, December 2016, Rio de Janeiro, Brazil. AB - Vector-borne diseases transmitted by insect vectors such as mosquitoes occur in over 100 countries and affect almost half of the world's population. Dengue is currently the most prevalent arboviral disease but chikungunya, Zika and yellow fever show increasing prevalence and severity. Vector control, mainly by the use of insecticides, play a key role in disease prevention but the use of the same chemicals for more than 40 years, together with the dissemination of mosquitoes by trade and environmental changes, resulted in the global spread of insecticide resistance. In this context, innovative tools and strategies for vector control, including the management of resistance, are urgently needed. This report summarizes the main outputs of the first international workshop on Insecticide resistance in vectors of arboviruses held in Rio de Janeiro, Brazil, 5-8 December 2016. The primary aims of this workshop were to identify strategies for the development and implementation of standardized insecticide resistance management, also to allow comparisons across nations and across time, and to define research priorities for control of vectors of arboviruses. The workshop brought together 163 participants from 28 nationalities and was accessible, live, through the web (> 70,000 web-accesses over 3 days). PMID- 28577365 TI - Prevalence of methicillin resistant Staphylococcus aureus in Lumbini Medical College and Teaching Hospital, Palpa, Western Nepal. AB - BACKGROUND: Multidrug resistant Staphylococcus aureus is common in both tertiary and primary health care settings. Emergence of methicillin resistance in S. aureus (MRSA) along with macrolide, lincosamide, streptogramin B (MLSB) has made treatment of Staphylococcal infection more challenging. The main objective of this study was to detect MRSA, MLSB (inducible; MLSBi and constitutive; MLSBc) resistant S. aureus using phenotypic methods and to determine their antibiogram. METHODS: Various samples were collected from 1981 patients who attended Lumbini Medical College and Teaching Hospital (LMCTH) during the period of 6 months from September 2015 to February 2016. Out of a total of 1981 samples, 133 S. aureus were isolated. Cefoxitin was used to detect MRSA by the disk diffusion test. Inducible clindamycin resistance (MLSBi) was detected by the D-zone test. The antibiotic profile of all isolates was tested by a modified Kirby Bauer disk diffusion method. RESULTS: Among 133 S. aureus, there were 58 (43.6%) MRSA, 34 (25.6%) MLSBi and 30 (22.6%) MLSBc. Of a total of 64 MLSB, a significant proportion (62.5%) was MRSA (p < 0.001). Among 11 different antibiotics that were tested for S. aureus, MRSA showed significant resistance to 9 (p < 0.05) with the exception of vancomycin and linezolid. All the isolates were 100% sensitive to linezolid. MLSBi organisms were 100% sensitive to vancomycin and linezolid. Both MLSBi and MLSBc showed a higher degree of resistance to multiple antibiotics (p < 0.05). CONCLUSIONS: Isolation of MRSA, MLSBi and MLSBc were remarkably high. Routine use of simple and cost effective methods such as the disk diffusion test by cefoxitin for MRSA and the D-zone test for MLSBi organisms can easily identify these isolates. Antibiotic resistance profiles from this study can optimize the treatment of multi-drug resistant S. aureus. PMID- 28577366 TI - Accuracy of four intraoral scanners in oral implantology: a comparative in vitro study. AB - BACKGROUND: Until now, only a few studies have compared the ability of different intraoral scanners (IOS) to capture high-quality impressions in patients with dental implants. Hence, the aim of this study was to compare the trueness and precision of four IOS in a partially edentulous model (PEM) with three implants and in a fully edentulous model (FEM) with six implants. METHODS: Two gypsum models were prepared with respectively three and six implant analogues, and polyether-ether-ketone cylinders screwed on. These models were scanned with a reference scanner (ScanRider(r)), and with four IOS (CS3600(r), Trios3(r), Omnicam(r), TrueDefinition(r)); five scans were taken for each model, using each IOS. All IOS datasets were loaded into reverse-engineering software, where they were superimposed on the reference model, to evaluate trueness, and superimposed on each other within groups, to determine precision. A detailed statistical analysis was carried out. RESULTS: In the PEM, CS3600(r) had the best trueness (45.8 +/- 1.6MUm), followed by Trios3(r) (50.2 +/- 2.5MUm), Omnicam(r) (58.8 +/- 1.6MUm) and TrueDefinition(r) (61.4 +/- 3.0MUm). Significant differences were found between CS3600(r) and Trios3(r), CS3600(r) and Omnicam(r), CS3600(r) and TrueDefinition(r), Trios3(r) and Omnicam(r), Trios3(r) and TrueDefinition(r). In the FEM, CS3600(r) had the best trueness (60.6 +/- 11.7MUm), followed by Omnicam(r) (66.4 +/- 3.9MUm), Trios3(r) (67.2 +/- 6.9MUm) and TrueDefinition(r) (106.4 +/- 23.1MUm). Significant differences were found between CS3600(r) and TrueDefinition(r), Trios3(r) and TrueDefinition(r), Omnicam(r) and TrueDefinition(r). For all scanners, the trueness values obtained in the PEM were significantly better than those obtained in the FEM. In the PEM, TrueDefinition(r) had the best precision (19.5 +/- 3.1MUm), followed by Trios3(r) (24.5 +/- 3.7MUm), CS3600(r) (24.8 +/- 4.6MUm) and Omnicam(r) (26.3 +/- 1.5MUm); no statistically significant differences were found among different IOS. In the FEM, Trios3(r) had the best precision (31.5 +/- 9.8MUm), followed by Omnicam(r) (57.2 +/- 9.1MUm), CS3600(r) (65.5 +/- 16.7MUm) and TrueDefinition(r) (75.3 +/- 43.8MUm); no statistically significant differences were found among different IOS. For CS3600(r), For CS3600(r), Omnicam(r) and TrueDefinition(r), the values obtained in the PEM were significantly better than those obtained in the FEM; no significant differences were found for Trios3(r). CONCLUSIONS: Significant differences in trueness were found among different IOS; for each scanner, the trueness was higher in the PEM than in the FEM. Conversely, the IOS did not significantly differ in precision; for CS3600(r), Omnicam(r) and TrueDefinition(r), the precision was higher in the PEM than in the FEM. These findings may have important clinical implications. PMID- 28577367 TI - Occurence of dentinal defects after root canal preparation with R-phase, M-Wire and Gold Wire instruments: a micro-CT analysis. AB - BACKGROUND: This study aims to evaluate the frequency of dentinal defects after root canal preparation with the ProTaper NEXT, K3XF and WaveOne GOLD systems using microcomputed tomography. METHODS: Sixty permanent mandibular incisors with a single canal were selected. Inspection of the teeth was performed under a stereomicroscope (15x) to observe the presence of pre-existing cracks and fractures lines. Samples were divided into three experimental groups (n = 20): ProTaper NEXT (PTN), K3XF (K3XF) and WaveOne GOLD (WOG). Specimens were scanned through high-resolution microcomputed tomography before and after the preparation of the root canal. Subsequently, all the axial images were examined by two different methods to find possible dentinal defects. Furthermore, an analysis of each millimeter of ten apical millimeters was also performed. The absence or presence of dentinal defects was screened by 3 pre-calibrated blinded examiners. RESULTS: After analysing all 45,720 slices, dentinal defects were observed in 48,33% (22096 slices). PTN, K3XF and WOG groups represented 11,11% (5079 slices), 17,22% (7873 slices) and 20% (n = 9144) of the cross-sectional images, respectively. At 10 apical millimeters (600 slices), 33,33% (200 slices) presented some dentinal defects, representing 7,22% (43 slices), 13,33% (80 slices) and 12,77% (77 slices) of the cross-sectional images in the PTN, K3XF and WOG groups, respectively. All the dentinal defects presented in the postoperative images existed in the images prior to instrumentation. CONCLUSIONS: There was no correlation between the preparation of a root canal using the PTN, K3XF and WOG systems and the formation of new dentinal defects. PMID- 28577368 TI - Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads. AB - BACKGROUND: Protein ubiquitylation is an important post-translational regulation, which has been shown to be necessary for life cycle progression and survival of Plasmodium falciparum. Ubiquitin is a highly conserved 76 amino acid polypeptide, which attaches covalently to target proteins through combined action of three classes of enzymes namely, the ubiquitin-activating enzyme (E1), ubiquitin conjugating enzyme (E2) and ubiquitin-protein ligase (E3). Ubiquitin E1 and E2 are highly conserved within eukaryotes. However, the P. falciparum E3 ligase is substantially variable and divergent compared to the homologs from other eukaryotes, which make the E3 ligase a parasite-specific target. METHODS: A set of selected E3 ubiquitin ligase inhibitors was tested in vitro against a chloroquine-sensitive P. falciparum D6 strain (PfD6) and a chloroquine-resistant P. falciparum W2 strain (PfW2). The inhibitors were also tested against Vero and transformed THP1 cells for cytotoxicity. The lead antimalarial E3 ubiquitin ligase inhibitors were further evaluated for the stage-specific antimalarial action and effects on cellular development of P. falciparum in vitro. Statistics analysis was done by two-way ANOVA followed by Tukey and Sidak multiple comparison test using GraphPad Prism 6. RESULTS: E3 ligase inhibitors namely, JNJ 26854165, HLI 373 and Nutlin 3 showed prominent antimalarial activity against PfD6 and PfW2. These inhibitors were considerably less cytotoxic to mammalian Vero cells. JNJ 26854165, HLI 373 and Nutlin 3 blocked the development of P. falciparum parasite at the trophozoite and schizont stages, resulting in accumulation of distorted trophozoites and immature schizonts. CONCLUSIONS: Interruption of trophozoites and schizont maturation by the antimalarial E3 ligase inhibitors suggest the role of ubiquitin/proteasome functions in the intraerythrocytic development of malaria parasite. The ubiquitin/proteasome functions may be critical for schizont maturation. Further investigations on the lead E3 ligase inhibitors shall provide better understanding regarding the importance of E3 ligase functions in the malaria parasite as a potential new antimalarial drug target and a new class of antimalarial drug leads. PMID- 28577370 TI - Viruses vector control proposal: genus Aedes emphasis. AB - The dengue fever is a major public health problem in the world. In Brazil, in 2015, there were 1,534,932 cases, being 20,320 cases of severe form, and 811 deaths related to this disease. The distribution of Aedes aegypti, the vector, is extensive. Recently, Zika and Chikungunya viruses had arisen, sharing the same vector as dengue and became a huge public health issue. Without specific treatment, it is urgently required as an effective vector control. This article is focused on reviewing vector control strategies, their effectiveness, viability and economical impact. Among all, the Sterile Insect Technique is highlighted as the best option to be adopted in Brazil, once it is largely effectively used in the USA and Mexico for plagues related to agribusiness. PMID- 28577369 TI - Efficacy of a Four-Hour Drainage Clamping Technique in the Reduction of Blood Loss Following Total Hip Arthroplasty: A Prospective Cohort Study. AB - BACKGROUND During total hip arthroplasty (THA) drainage is used by most surgeons. However, the optimal drainage strategy remains controversial. The aim of this prospective cohort study was to determine the safety and efficacy of a four-hour drainage clamping technique in patients undergoing THA. MATERIAL AND METHODS There were 64 patients who underwent THA from March 2012 to December 2015 who were enrolled in the study; 32 patients were randomly assigned to four hours of a drainage clamping technique (clamping group); 32 patients were treated with a non clamping drainage technique (non-clamping group). All perioperative clinical details were recorded for comparative analysis. RESULTS The postoperative drainage volume and calculated blood loss were significantly greater in the drainage non-clamping group, p<0.001 and p=0.028, respectively. Significantly more patients in the drainage non-clamping group required a blood transfusion, seven cases versus one case (p=0.023). Significantly more units of blood were transfused in the drainage non-clamping group (p=0.001). No significant differences were found for all other clinical outcome factors. CONCLUSIONS The four-hour drainage clamping technique following THA, compared with drainage non clamping technique reduced blood loss and requirement for blood transfusion. There was no increase in adverse clinical events using the four-hour drainage clamping method. Therefore, four-hour drainage clamping has the potential for routine use in THA. PMID- 28577371 TI - Prevalence of Torus Mandibularis in Young Healthy Dentate Adults. AB - PURPOSE: There have been only a few reports on the prevalence of torus mandibularis (TM) in young adult patients, and TM can have various adverse effects on oral and occlusal states in middle-age patients. This study was designed to determine the association between TM status and oral and occlusal states in young healthy dentate adults. MATERIALS AND METHODS: This was a cross sectional study; the sample population included students at Hiroshima University (Hiroshima, Japan) who participated for practical education. The predictor variables in this study included oral symptoms (temporomandibular joint noise, tooth clenching and grinding, buccal mucosa ridging, dental attrition, and tongue habit), oral anatomy (occlusal vertical dimension), and oral function (average occlusal pressure, occlusal contact area, and maximum voluntary tongue pressure). The outcome variable was TM status (present or absent). Additional variables were demographic in nature and included age, number of residual teeth, body weight, and gender. These variables were compared among participants with and without TM using univariate analysis and multiple logistic regression analysis. Statistical analyses were carried out using SPSS Statistics 19 for Windows (IBM Corp, Armonk, NY); a P value less than .05 was considered significant. RESULTS: Of 204 participants included in the study, 50% were men and 50% were women. The mean age was 22.4 +/- 2.7 years. TM was present in 119 (58.3%). Multiple logistic regression analysis showed that TM status was associated with dental attrition and occlusal contact area (P < .05). CONCLUSIONS: This study showed that TM was present in more than half the young healthy dentate participants and was closely associated with dental attrition and occlusal contact area. This study will provide readers with useful information to help prevent the development of TM before middle age. PMID- 28577373 TI - Using Q Methodology in Quality Improvement Projects. AB - Q methodology consists of a philosophical framework and procedures to identify subjective viewpoints that may not be well understood, but its use in nursing is still quite limited. We describe how Q methodology can be used in quality improvement projects to better understand local viewpoints that act as facilitators or barriers to the implementation of evidence-based practice. We describe the use of Q methodology to identify nurses' attitudes about the provision of skin-to-skin care after cesarean birth. PMID- 28577372 TI - Effects of Objective 3-Dimensional Measures of Facial Shape and Symmetry on Perceptions of Facial Attractiveness. AB - PURPOSE: Meeting patient desires for enhanced facial esthetics requires that providers have standardized and objective methods to measure esthetics. The authors evaluated the effects of objective 3-dimensional (3D) facial shape and asymmetry measurements derived from 3D facial images on perceptions of facial attractiveness. MATERIALS AND METHODS: The 3D facial images of 313 adults in Iowa were digitized with 32 landmarks, and objective 3D facial measurements capturing symmetric and asymmetric components of shape variation, centroid size, and fluctuating asymmetry were obtained from the 3D coordinate data using geo morphometric analyses. Frontal and profile images of study participants were rated for facial attractiveness by 10 volunteers (5 women and 5 men) on a 5-point Likert scale and a visual analog scale. Multivariate regression was used to identify the effects of the objective 3D facial measurements on attractiveness ratings. RESULTS: Several objective 3D facial measurements had marked effects on attractiveness ratings. Shorter facial heights with protrusive chins, midface retrusion, faces with protrusive noses and thin lips, flat mandibular planes with deep labiomental folds, any cants of the lip commissures and floor of the nose, larger faces overall, and increased fluctuating asymmetry were rated as significantly (P < .001) less attractive. CONCLUSION: Perceptions of facial attractiveness can be explained by specific 3D measurements of facial shapes and fluctuating asymmetry, which have important implications for clinical practice and research. PMID- 28577374 TI - Evaluation of lipid oxidation of Chinese-style sausage during processing and storage based on electronic nose. AB - A portable electronic nose was used for extracting flavour fingerprint map of Chinese-style sausage during processing and storage, in parallel with detection of acid value (AV) and peroxide value (POV) for evaluating lipid oxidation. Sausage samples during processing and storage were divided into three and five quality phases, respectively. After comparison of sensors response to lipid oxidation, optimal sensor array was determined. Several classification and regression models were developed to classify samples into their respective quality phase and predict lipid oxidation using full and optimal sensor array. Results indicated classification accuracy for sausage samples were, respectively, above 95% and 82% during the processing and storage. For support vector machine (SVM) and artificial neural networks (ANN) regression models, good performance in predicting AV and POV were obtained, with the coefficients of determination (R2s) >0.914 and 0.814 during processing and storage, respectively. Thus, E-nose demonstrated acceptable feasibility in evaluating the degree of lipid oxidation of Chinese-style sausage during processing and storage. PMID- 28577376 TI - Editorial Comment. PMID- 28577375 TI - Moisture migration, microstructure damage and protein structure changes in porcine longissimus muscle as influenced by multiple freeze-thaw cycles. AB - This study investigated the effects of multiple freeze-thaw (F-T) cycles on water mobility, microstructure damage and protein structure changes in porcine longissimus muscle. The transverse relaxation time T2 increased significantly when muscles were subjected to multiple F-T cycles (P<0.05), which means that immobile water shifted to free water and the free water mobility increased. Multiple F-T cycles caused sarcomere shortening, Z line fractures, and I band weakening and also led to microstructural destruction of muscle tissue. The decreased free amino group content and increased dityrosine in myofibrillar protein (MP) revealed that multiple F-T cycles caused protein cross-linking and oxidation. In addition, the results of size exclusion chromatography, circular dichroism spectra, UV absorption spectra, and intrinsic fluorescence spectroscopy indirectly proved that multiple F-T cycles could cause protein aggregation and degradation, alpha-helix structure disruption, hydrophobic domain exposure, and conformational changes of MP. Overall, repeated F-T cycles changed the protein structure and water distribution within meat. PMID- 28577377 TI - Reply by Authors. PMID- 28577378 TI - Re: Extended Duration Enoxaparin Decreases the Rate of Venous Thromboembolic Events after Radical Cystectomy Compared to Inpatient Only Subcutaneous Heparin: J. J. Pariser, S. M. Pearce, B. B. Anderson, V. T. Packiam, V. N. Prachand, N. D. Smith and G. D. Steinberg J Urol 2017;197:302-307. PMID- 28577379 TI - Re: Magnetic Resonance Imaging Underestimation of Prostate Cancer Geometry: Use of Patient Specific Molds to Correlate Images with Whole Mount Pathology: A. Priester, S. Natarajan, P. Khoshnoodi, D. J. Margolis, S. S. Raman, R. E. Reiter, J. Huang, W. Grundfest and L. S. Marks J Urol 2017;197:320-326. PMID- 28577380 TI - Season, molt, and body size influence mercury concentrations in grebes. AB - We studied seasonal and physiological influences on mercury concentrations in western grebes (Aechmophorus occidentalis) and Clark's grebes (A. occidentalis) across 29 lakes and reservoirs in California, USA. Additionally, at three of these lakes, we conducted a time series study, in which we repeatedly sampled grebe blood mercury concentrations during the spring, summer, and early fall. Grebe blood mercury concentrations were higher among males (0.61 +/- 0.12 MUg/g ww) than females (0.52 +/- 0.10 MUg/g ww), higher among Clark's grebes (0.58 +/- 0.12 MUg/g ww) than western grebes (0.51 +/- 0.10 MUg/g ww), and exhibited a strong seasonal pattern (decreasing by 60% from spring to fall). Grebe blood THg concentrations exhibited a shallow, inverse U-shaped pattern with body size, and was lowest among the smallest and largest grebes. Further, the relationship between grebe blood mercury concentrations and wing primary feather molt exhibited a shallow U-shaped pattern, where mercury concentrations were highest among birds that had not yet begun molting, decreased approximately 24% between pre-molt and late molt, and increased approximately 19% from late molt to post molt. Because grebes did not begin molting until mid-summer, lower grebe blood mercury concentrations observed in late summer and early fall were consistent with the onset of primary feather molt. However, because sampling date was a much stronger predictor of grebe mercury concentrations than molt, other seasonally changing environmental factors likely played a larger role than molt in the seasonal variation in grebe mercury concentrations. In the time series study, we found that seasonal trends in grebe mercury concentrations were not consistent among lakes, indicating that lake-specific variation in mercury dynamics influence the overall seasonal decline in grebe blood mercury concentrations. These results highlight the importance of accounting for sampling date, as well as ecological processes that may influence mercury concentrations, when developing monitoring programs to assess site-specific exposure risk of mercury to wildlife. PMID- 28577381 TI - Neurotoxicity of low bisphenol A (BPA) exposure for young male mice: Implications for children exposed to environmental levels of BPA. AB - To investigate the neuron toxicities of low-dose exposure to bisphenol A (BPA) in children, mice were used as an animal model. We examined brain cell damage and the effects of learning and memory ability after BPA exposure in male mice (4 weeks of age) that were divided into four groups and chronically received different BPA treatments for 8 weeks. The comet assay and hippocampal neuron counting were used to detect the brain cell damage. The Y-maze test was applied to test alterations in learning and memory ability. Long term potentiation induction by BPA exposure was performed to study the potential mechanism of performance. The percentages of tail DNA, tail length and tail moment in brain cells increased with increasing BPA exposure concentrations. Significant differences in DNA damage were observed among the groups, including between the low-dose and control groups. In the Y-maze test, the other three groups qualified for the learned standard one day earlier than the high-exposed group. Furthermore, the ratio of qualified mice in the high-exposed group was always the lowest among the groups, indicating that high BPA treatment significantly altered the spatial memory performance of mice. Different BPA treatments exerted different effects on the neuron numbers of different regions in the hippocampus. In the CA1 region, the high-exposed group had a significant decrease in neuron numbers. A non-monotonic relationship was observed between the exposure concentrations and neuron quantity in the CA3 region. The hippocampal slices in the control and medium-exposed groups generated long-term potentiation after induction by theta burst stimulation, but the low-exposed group did not. A significant difference was observed between the control and low-exposed groups. In conclusion, chronic exposure to a low level of BPA had adverse effects on brain cells and altered the learning and memory ability of adolescent mice. PMID- 28577382 TI - Transport, retention, and long-term release behavior of polymer-coated silver nanoparticles in saturated quartz sand: The impact of natural organic matters and electrolyte. AB - This study investigated the transport and long-term release of stabilized silver nanoparticles (AgNPs), including polyvinylpyrrolidone-coated AgNPs (PVP-AgNPs) and bare AgNPs (Bare-AgNPs), in the presence of natural organic matters (NOMs; both humic acids (HA) and alginate (Alg)) and an electrolyte (Ca2+) in a sand packed column. Very low breakthrough rate (C/C0) of AgNPs (below 0.04) occurred in the absence of NOM and the electrolyte. Increasing the concentration of NOM and decreasing the influent NOM solution's ionic strength (IS) reduced the retention of AgNPs. The reduced NP retention at high NOM and low IS was mainly attributed to the increased energy barrier between the AgNPs and the sand grain surface. Notably, the retention of PVP-AgNPs was enhanced at high Alg concentration and low IS, which mainly resulted from the improved hydrophobicity that could increase the interaction between the PVP-AgNPs and the collector. The total release amount of PVP-AgNPs (10.03%, 9.50%, 28.42%, 6.37%) and Bare-AgNPs (3.28%, 2.58%, 10.36%, 1.54%) were gained when exposed to four kinds of NOM solutions, including deionized water, an electrolyte solution (1 mM Ca2+), HA with an electrolyte (1 mM Ca2+), and a Alg (40 mg/L) solution with an electrolyte (1 mM Ca2+). The long-term release of retained silver nanoparticles in the quartz sand was mostly through the form of released Ag NPs. The factors that increased the mobility of AgNPs in quartz sand could improve the release of the AgNPs. The release of AgNPs had no significant change in the presence Ca2+ but were increased in the presence of HA. The Alg slightly decreased the release of AgNPs by increasing the hydrophobicity of AgNPs. The results of the study indicated that all the tested NOM and Ca2+ have prominent influence on the transport and long-term release behavior of silver nanoparticles in saturated quartz sand. PMID- 28577383 TI - Transport of terrigenous polycyclic aromatic hydrocarbons affected by the coastal upwelling in the northwestern coast of South China Sea. AB - Coastal upwelling prevails in the coast of Hainan Island, the northern South China Sea (SCS) during summer. We studied the influences of the upwelling on the horizontal and vertical transport of terrigenous polycyclic aromatic hydrocarbons (PAHs). PAHs in dissolved and suspended particulate phase of water samples were determined in the upper (depth < 1 m) and water column (depth > 10 m). PAH levels decreased sharply from inshore to offshore to open sea. The results showed that terrestrial input was the main source of coastal PAHs. Perylene, an important indicator of land plant-derived PAH, showed the significant correlation with PAHs (p < 0.005). This implied that fluvial transport was the primary pathway of terrigenous PAHs into the coast of northern SCS. Variations of the concentrations, compositions and diagnostic ratios of PAHs, accompanied the partition equilibrium in the water column, could indicate the selective degradation of PAHs by the plankton affected by upwelling. Different from the "traditional" transport pathway of PAHs in the water column (surface enrichment depth depletion distribution), the upwelling could provide the original driver to elevate the upward diffusion of sediment entrained contaminants towards the intermediate even the upper waters. It could also enhance the outward diffusion of terrigenous PAHs accompanied by the offshore transport of the upper waters. Therefore, the transport pathway of PAHs can be summarized by the coastal upwelling rising PAHs with their subsequent transport offshore and settling in the adjacent open sea. PMID- 28577384 TI - Elemental mercury: Its unique properties affect its behavior and fate in the environment. AB - Elemental mercury (Hg0) has different behavior in the environment compared to other pollutants due to its unique properties. It can remain in the atmosphere for long periods of time and so can travel long distances. Through air-surface (e.g., vegetation or ocean) exchange (dry deposition), Hg0 can enter terrestrial and aquatic systems where it can be converted into other Hg species. Despite being ubiquitous and playing a key role in Hg biogeochemical cycling, Hg0 behavior in the environment is not well understood. The objective of this review is to provide a better understanding of how the unique physicochemical properties of Hg0 affects its cycling and chemical transformations in different environmental compartments. The first part focuses on the fundamental chemistry of Hg0, addressing why Hg0 is liquid at room temperature and the formation of amalgam, Hg halide, and Hg chalcogenides. The following sections discuss the long range transport of Hg0 as well as its redistribution in the atmosphere, aquatic and terrestrial systems, in particular, on the sorption/desorption processes that occur in each environmental compartment as well as the involvement of Hg0 in chemical transformation processes driven by photochemical, abiotic, and biotic reactions. PMID- 28577385 TI - Mercury levels of yellowfin tuna (Thunnus albacares) are associated with capture location. AB - Mercury is a toxic compound to which humans are exposed by consumption of fish. Current fish consumption advisories focus on minimizing the risk posed by the species that are most likely to have high levels of mercury. Less accounted for is the variation within species, and the potential role of the geographic origin of a fish in determining its mercury level. Here we surveyed the mercury levels in 117 yellowfin tuna caught from 12 different locations worldwide. Our results indicated significant variation in yellowfin tuna methylmercury load, with levels that ranged from 0.03 to 0.82 MUg/g wet weight across individual fish. Mean mercury levels were only weakly associated with fish size (R2 < 0.1461) or lipid content (R2 < 0.00007) but varied significantly, by a factor of 8, between sites. The results indicate that the geographic origin of fish can govern mercury load, and argue for better traceability of fish to improve the accuracy of exposure risk predictions. PMID- 28577386 TI - Hydraulics and gas exchange recover more rapidly from severe drought stress in small pot-grown grapevines than in field-grown plants. AB - Modifications of plant hydraulics and shoot resistances (Rshoot) induced by water withholding followed by rewatering, and their relationships with plant water status, leaf gas exchange and water use efficiency at the leaf level, were investigated in pot-grown and field-grown, own-rooted Syrah grapevines in an arid climate. Water stress induced anisohydric behavior, gradually reducing stomatal conductance (gs) and leaf photosynthesis (A) in response to decreasing midday stem water potential (Psis). Water stress also rapidly increased intrinsic water use efficiency (A/gs); this effect persisted for many days after rewatering. Whole-plant (Kplant), canopy (Kcanopy), shoot (Kshoot) and leaf (Kleaf) hydraulic conductances decreased during water stress, in tune with the gradual decrease in Psis, leaf gas exchange and whole plant water use. Water-stressed vines also had a lower Psi gradient between stem and leaf (DeltaPsil), which was correlated with lower leaf transpiration rate (E). E and DeltaPsil increased with increasing vapour pressure deficit (VPD) in non-stressed control vines but not in stressed vines. Perfusion of xylem-mobile dye showed that water flow to petioles and leaves was substantially reduced or even stopped under moderate and severe drought stress. Leaf blade hydraulic resistance accounted for most of the total shoot resistance. However, hydraulic conductance of the whole root system (Kroot) was not significantly reduced until water stress became very severe in pot-grown vines. Significant correlations between Kplant, Kcanopy and Psis, Kcanopy and leaf gas exchange, Kleaf and Psis, and Kleaf and A support a link between water supply, leaf water status and gas exchange. Upon re-watering, Psis recovered faster than gas exchange and leaf-shoot hydraulics. A gradual recovery of hydraulic functionality of plant organs was also observed, the leaves being the last to recover after rewatering. In pot-grown vines, Kcanopy recovered rather quickly following restoration of Psis, although gas exchange recovery did not directly depend on recovery of Kcanopy. In field-grown vines, recovery of water status, gas exchange and hydraulic functionality was slower than in pot-grown plants, and low gs after rewatering was related to sustained decreased Kplant, Kcanopy and Kshoot and lower water transport to leaves. These results suggest that caution should be exercised when scaling up conclusions from experiments with small pot-grown plants to field conditions. PMID- 28577387 TI - A double knockout mutant of acyl-glucose-dependent anthocyanin glucosyltransferase genes in Delphinium grandiflorum. AB - Blue coloration in delphinium flowers arises from 7-polyacylated anthocyanins which are modified alternately with acyl and glucosyl residues at the 7 position of the aglycone. Previously, we identified two independent genes for acyl-glucose dependent anthocyanin 7-(6-(p-hydroxybenzoyl)-glucoside) glucosyltransferases (AA7BG-GT); recombinant proteins from the two cDNAs were produced in Escherichia coli and showed AA7BG-GT activity in vitro. Here, a double knockout mutant of both genes was found to lack modification of the second glucosyl residue following further acyl and glucosyl modifications. Both genes in the double mutant had nucleotide sequence changes and deletions that disrupted their transcripts and caused loss of AA7BG-GT activity in sepals. These results provide genetic confirmation that both genes are responsible for AA7BG-GT enzyme activity. PMID- 28577388 TI - Recurrence of venous thromboembolism among adults acute leukemia patients treated at the University of Texas MD Anderson Cancer Center: Incidence and risk factors. AB - The purpose was to determine the incidence and risk factors for venous thromboembolism (VTE) recurrence among adult acute leukemia patients. We performed a retrospective study of adult acute leukemia patients who were treated at our institution between November 1999 and May 2005. Medical records of 139 patients with an initial VTE were reviewed and followed up to May 2010 for VTE recurrence. Of these 139 patients [86 with acute myelogenous leukemia (AML), 53 with acute lymphocytic leukemia (ALL)], 27 (19.4%, 16 AML and 11 ALL) had VTE recurrence. The overall incidence rate of VTE was 8.6 per 100 person-years (median follow-up time: 0.9years). It was 5.9 and 12.4 per 100 person-years among ALL and AML patients, respectively. The cumulative proportion of recurrent VTE was 2.16%, 10.9%, 16.6%, 25.9%, 30.6%, and 34.2% at 1month, 6months, 1year, 3years, 5years, and 7years, respectively. In a multivariate Cox hazards model, significant predictors for VTE recurrence included catheter thrombosis [adjusted hazard ratio (aHR)]:6.3, 95%CI:1.17-34.0), prior history of hematologic cancer (aHR:4.2, 95%CI:1.5-11.2), chronic lung disease (aHR: 3.4, 95%CI:0.92-12.5), psychological disorder (aHR: 4.3, 95%CI:1.5-12.2), and liver disease (aHR: 3.8, 95%CI: 1.04-14.3). VTE recurrence is common among adult acute leukemia patients and it continues up to 7years after the initial episode. Catheter thrombosis, a history of hematologic malignancy antecedent to acute leukemia, and lung, liver and psychiatric co-morbidities increase the patient risk for VTE recurrence. Further studies should be conducted to improve the prevention of VTE recurrence in leukemia patients. PMID- 28577389 TI - Factor V Leiden paradox and the occurrence of distal vein thrombosis in a large cohort of thrombotic patients. PMID- 28577390 TI - Feasibility of the Von Willebrand disease PREVENT trial. AB - BACKGROUND: Despite treatment, women with von Willebrand disease (VWD) have lower von Willebrand factor (VWF) levels and greater blood loss at delivery than controls. Current weight-based dosing does not account for the ~1.5-fold increase in blood volume in pregnancy. METHODS: To evaluate the feasibility of a trial to prevent postpartum hemorrhage (PPH), we reviewed pre-pregnancy and 8th month VWF levels in women with VWD with and without PPH following vaginal delivery, assessed VWF concentrate use at delivery by U.S. hemophilia treatment center physician survey, and reviewed thrombosis risk with VWF concentrate by literature review. We determined trial interest and acceptability by structured interviews of physicians and patients. Analysis was by Student's t-test for continuous data, and chi-square or Fisher's exact test for discrete data. RESULTS: PPH was associated with lower pre-pregnancy VWF:RCo, p<0.005; higher pre-pregnancy, 8th and 9th-month weight, each p<0.001; a family bleeding history, p=0.036; and VWF concentrate treatment, p=0.005. Surveyed physicians reported first-line therapy at delivery was VWF concentrate, at a mean dose 50IU/kg. A trial of a 1.5-fold volume-based dose increase was acceptable to physicians and patients, if it is safe and if costs and visits are minimized. A literature review determined thrombosis risk with VWF concentrate is low, 0.4%. CONCLUSIONS: This study suggests pre-pregnancy VWF:RCo may predict PPH, but 50-80IU/kg VWF concentrate dosing may not prevent PPH. If pharmacokinetic modeling confirms volume-based dosing achieves VWF levels comparable to pregnant controls, it may be possible to determine if volume-modified VWF concentrate dosing will reduce PPH in VWD. PMID- 28577391 TI - Shrimp TAB1 interacts with TAK1 and p38 and activates the host innate immune response to bacterial infection. AB - Mammalian TAB1 has been previously identified as transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1) binding protein, which functions as the activator of TAK1 and p38. This report, for the first time, identified and characterized the homolog of TAB1 in shrimp, to be specific, the homolog gene from Litopenaeus vannamei, containing a 1560-bp open reading frame (ORF) that encoded a putative protein of 519 amino acids with the conserved PP2Cc (Serine/threonine phosphatases, family 2C, catalytic) domain in N-terminal and a TAK1 binding motif in C-terminus, has been cloned and named LvTAB1. LvTAB1 was most abundant in gills and its expression could respond significantly to a series of stimuli, including LPS, Vibrio parahemolyticus and Staphylococcus aureus. Moreover, Co-immunoprecipitation (Co-IP) experiments showed that LvTAB1 could combine with LvTAK1 as well as Lvp38, two members of IMD-NF-kappaB/MAPK pathway, which meant LvTAB1 could have a role in regulating the activities of these kinases. Over-expression of LvTAB1 in drosophila S2 cells could improve the transcriptional levels of antimicrobial peptide genes (AMPs) such as Diptericin (Dpt), the hallmark of drosophila NF-kappaB activated genes, indicating its activation effect on NF-kappaB pathway. Furthermore, suppression of LvTAB1 expression in vivo by RNA-interference increased the sensibility of shrimps to V. parahaemolyticus infection, implying its protective role against bacterial infection. In conclusion, these results provide some insight into the function of LvTAB1 during bacterial infection. PMID- 28577392 TI - Impact of in-vehicle navigation information on lane-change behavior in urban expressway diverge segments. AB - Lane-changing behaviors frequently occur at upstream of the urban expressway off ramp, which possibly cause bottleneck or accident. This paper studies how in vehicle navigation information impacts lane-changing behavior at this urban expressway diverge segments with comparison to the traditional road signs by conducting a series of driving simulator experiments, in consideration of variation of the first provision time point and traffic flow density. Firstly, the driving simulator is validated by comparing data of lane-changing position and merging gap from both field survey and simulator. Then comparison study was performed for twelve scenarios which comprise four information provision design schemes under three different traffic flow density status. Lane-changing characteristics are analyzed by selecting six indicators, which are lane-changing merging gap, lane-changing position, lane change delay, lane-changing steering angle, lane-changing deceleration, and the safe distance of lane-changing. The results show that the impact of in-vehicle navigation information on lane changing behavior varies with traffic flow density and the time point of the first navigation information provided. The in-vehicle navigation information had significant positive impact on lane-changing safety under medium to high density condition. However, the effect is not significant under light density condition. Moreover, more improvement in operational safety and smooth could be gained when the in-vehicle navigation information is provided earlier within range of 2km upstream of the exit gore. PMID- 28577393 TI - Vaporised nicotine and tobacco harm reduction for addressing smoking among people living with HIV: A cross-sectional survey of Australian HIV health practitioners' attitudes. AB - BACKGROUND: Tobacco smoking is a major cause of morbidity and mortality among people living with HIV (PLHIV). Due to the limited success of standard abstinence focused smoking cessation strategies in this population, there is growing interest in tobacco harm reduction (THR) approaches as an additional strategy to address these high smoking rates. This study explored the attitudes of health practitioners who provide healthcare to PLHIV towards THR. METHODS: 179 Australian health practitioners who provide healthcare to PLHIV completed an online survey that measured their attitudes towards THR approaches, including switching from cigarettes to e-cigarettes or vaporised nicotine products (VNPs). RESULTS: Respondents supported the concept of THR but were undecided on the role of VNPs. Respondents most commonly reported 'don't know' or 'undecided' responses to statements regarding VNPs. More respondents, however, agreed than disagreed that switching from smoking to long-term vaping could reduce risk (36% and 22% respectively) and be an effective strategy to help PLHIV to quit smoking (37% agree and 17% disagree). Only a minority of respondents (20%) agreed that VNPs are too harmful to recommend to patients, however around half (53%) were undecided. CONCLUSIONS: Despite supporting the principle of THR, health practitioners may require more evidence and knowledge about VNPs before being willing to consider them as a suitable intervention strategy. PMID- 28577394 TI - Combining lead isotopes and cluster analysis to distinguish the Guarani and Serra Geral Aquifer Systems and contaminated waters in a highly industrialized area in Southern Brazil. AB - The Rio dos Sinos Watershed area is located at the Middle-West region of the Rio Grande do Sul State, Southern Brazil, along thirty two municipalities and affecting 1.5 million inhabitants and many important industrial centers. Three main aquifers are recognized in the study area: the unconfined-fractured Serra Geral Aquifer System, the porous Guarani Aquifer System, and the Permian Aquitard. This study aims to understand groundwater, surface water and human activity interactions in the Rio dos Sinos Watershed, evaluating the application of stable lead isotopic ratios analyzed for this propose. Thirty six groundwater samples, 8 surface water samples and 5 liquid effluents of tanneries and landfills samples were measured using a Thermal Ionization Mass Spectrometer Thermo-Finnigan and a Neptune Multi-Collector Inductively Coupled Plasma Mass Spectrometer. Groundwater isotopic ratios have a wider range compared to the surface water, with less radiogenic averages 208Pb/204Pb = 38.1837 vs 38.4050 (standard deviation = 0.2921 vs 0.1343) and 206Pb/204Pb = 18.2947 vs 18.4766 (standard deviation = 0.2215 vs 0.1059), respectively. Industrial liquid effluents (tanneries and industrial landfill) have averages 208Pb/204Pb = 38.1956 and 206Pb/204Pb = 18.3169, distinct from effluent samples of domestic sanitary landfill (averages 208Pb/204Pb = 38.2353 and 206Pb/204Pb = 18.6607). Hierarchical cluster analysis led to distinguish six groups of groundwater, representing the three aquifers that occur in the area, two clusters suggesting groundwater mixtures and one demonstrating a highly contaminated groundwater. By analyzing the cluster results and wells' stratigraphic profiles it was possible to distinguish the different aquifers in the area. The Serra Geral Aquifer System has 206Pb/204Pb ratios between 18.4718 and 18.7089; 207Pb/204Pb between 15.6692 and 15.6777; 208Pb/204Pb between 38.6826 and 38.7616; 207Pb/206Pb between 0.8372 and 0.8623; 208Pb/206Pb between 2.0671 and 2.0964 and the Guarani Aquifer System has a wider range (208Pb/204Pb ranged from 37.9393 to 38.1279 and 206Pb/204Pb ranged from 18.0892 to 18.3217). Water mixing of these two aquifer systems is reflected by transitional results. The results confirm that the hierarchical cluster analysis of lead isotopes is a useful tool to discriminate different aquifer conditions, reflecting mostly the influence of the natural lead isotopic composition of the aquifers instead of the anthropogenic activities (urban and industrial), except when the groundwater is highly contaminated by human activity. PMID- 28577396 TI - Hydrogeological characteristics influencing the occurrence of pesticides and pesticide metabolites in groundwater across the Republic of Ireland. AB - Pesticide contamination of water is a potential environmental issue which may impact the quality of drinking water. The full extent of pesticide contamination is not fully understood due to complex fate pathways in the subsurface. Groundwater pesticide occurrence was investigated at seven agricultural sites in different hydrogeological settings to identify where pesticide occurrence dominated in temperate maritime climatic conditions. In Ireland, six cereal dominated sites in the South East and one grassland site in the West were investigated. Soil and subsoils varied from acid brown earths with high permeability to clay and silt rich tills with lower permeability. Over a 2year monitoring period, 730 samples were collected from a network of dedicated wells and springs across the seven sites. Multi-nested piezometers were installed in intergranular, fissured and karstic type aquifers to target shallow, transition and deeper groundwaters. Several springs were also sampled and the network included a confined aquifer. Groundwater was analysed for nine pesticide active ingredients and eight metabolites. Mecoprop and 2,4-D were the most frequently detected active ingredients above the instrument detection limit, accounting for 36% and 26% of the 730 samples collected and analysed. Phenoxyacetic acid was the most frequently detected and widespread metabolite found in 39% of samples collected at all seven sites. Where the European Union drinking water standard of 0.1MUg/L was exceeded, metabolites accounted for the majority of exceedances with 3,5-dichlorobenzoic acid (DBA) and phenoxyacetic acid (PAC) dominating. Highest detections were encountered in sites with well drained soils underlain by gravel and limestone aquifers and within gravel lenses in lower permeability subsoil. Across the seven sites pesticide detections were mostly associated with metabolites and the environmental impact of many of these is unknown as they have received little attention in groundwater previously. PMID- 28577395 TI - Investigating the social behavioral dynamics and differentiation of skill in a martial arts technique. AB - Coordinating interpersonal motor activity is crucial in martial arts, where managing spatiotemporal parameters is emphasized to produce effective techniques. Modeling arm movements in an Aikido technique as coupled oscillators, we investigated whether more-skilled participants would adapt to the perturbation of weighted arms in different and predictable ways compared to less-skilled participants. Thirty-four participants ranging from complete novice to veterans of more than twenty years were asked to perform an Aikido exercise with a repeated attack and response, resulting in a period of steady-state coordination, followed by a take down. We used mean relative phase and its variability to measure the steady-state dynamics of both the inter- and intrapersonal coordination. Our findings suggest that interpersonal coordination of less skilled participants is disrupted in highly predictable ways based on oscillatory dynamics; however, more-skilled participants overcome these natural dynamics to maintain critical performance variables. Interestingly, the more-skilled participants exhibited more variability in their intrapersonal dynamics while meeting these interpersonal demands. This work lends insight to the development of skill in competitive social motor activities. PMID- 28577397 TI - Efficiency and acceptance of new water allocation rules - The case of an agricultural water users association. AB - Water scarcity is one of the major environmental problems in Southern Europe. High levels of water stress and increasing frequency of droughts, along with a greater environmental protection, make it necessary to design water management strategies that are allocative efficient and balance supply and demand. When functioning markets cannot be developed, the allocation rules proposed in the literature of social choice have been recognized as a suitable alternative. However, the application of new water allocation rules can be impaired by a lack of acceptance and implementation problems. This paper examines these obstacles for the case of an agricultural water users association (WUA), situated in the basin of the River Ebro, in relation to the governance structure and collective decision rule of the WUA. It analyzes the extent to which the gains and losses of the farmers affect their acceptance, and examines conditions for building agreements with side payments that provide incentives for the majority of the farmers to form part of a possible agreement. The results show that the uniform and sequential rules improve the allocative efficiency under normal conditions compared to the status quo and the sequential rule even in the case of droughts. In the presence of side payments this rule is likely to be accepted and has only an insignificant impact on distributional inequality. PMID- 28577398 TI - Evaluation of synergy and bacterial regrowth in photocatalytic ozonation disinfection of municipal wastewater. AB - The use of solar and ultraviolet titanium dioxide photocatalytic ozonation processes to inactivate waterborne pathogens (Escherichia coli, Salmonella species, Shigella species and Vibrio cholerae) in synthetic water and secondary municipal wastewater effluent is presented. The performance indicators were bacterial inactivation efficiency, post-disinfection regrowth and synergy effects (collaboration) between ozonation and photocatalysis (photocatalytic ozonation). Photocatalytic ozonation effectively inactivated the target bacteria and positive synergistic interactions were observed, leading to synergy indices (SI) of up to 1.86 indicating a performance much higher than that of ozonation and photocatalysis individually (SI<=1, no synergy; SI>1 shows synergy between the two processes). Furthermore, there was a substantial reduction in contact time required for complete bacterial inactivation by 50-75% compared to the individual unit processes of ozonation and photocatalysis. Moreover, no post-treatment bacterial regrowth after 24 and 48h in the dark was observed. Therefore, the combined processes overcame the limitations of the individual unit processes in terms of the suppression of bacterial reactivation and regrowth owing to the fact that bacterial cells were irreparably damaged. The treated wastewater satisfied the bacteriological requirements in treated wastewater for South Africa. PMID- 28577399 TI - A parsimonious approach to estimate PAH concentrations in river sediments of anthropogenically impacted watersheds. AB - The contamination of riverine sediments and suspended matter with hydrophobic pollutants is typically associated with urban land use. However, it is rarely related to the sediment supply of the watershed, because sediment yield data are often missing. We show for a suite of watersheds in two regions of Germany with contrasting land use and geology that the contamination of suspended particles with polycyclic aromatic hydrocarbons (PAH) can be explained by the ratio of inhabitants residing within the watershed and the watershed's sediment yield. The modeling of sediment yields is based on the Revised Universal Soil Loss Equation (RUSLE2015, Panagos et al., 2015) and the sediment delivery ratio (SDR). The applicability of this approach is demonstrated for watersheds ranging in size from 1.4 to 3000km2. The approach implies that the loading of particles with PAH can be assumed as time invariant. This is indicated by additional long-term measurements from sub-watersheds of the upper River Neckar basin, Germany. The parsimonious conceptual approach allows for reasonable predictions of the PAH loading of suspended sediments especially at larger scales. Our findings may easily be used to estimate the vulnerability of river systems to particle associated urban pollutants with similar input pathways as the PAH or to indicate if contaminant point sources such as sites of legacy pollution exist in a river basin. PMID- 28577400 TI - Integral microalgae-bacteria model (BIO_ALGAE): Application to wastewater high rate algal ponds. AB - An integral mechanistic model describing the complex interactions in mixed algal bacterial systems was developed. The model includes crucial physical, chemical and biokinetic processes of microalgae as well as bacteria in wastewater. Carbon limited microalgae and autotrophic bacteria growth, light attenuation, photorespiration, temperature and pH dependency are some of the new features included. The model named BIO_ALGAE was built using the general formulation and structure of activated sludge models (ASM), and it was implemented in COMSOL MultiphysicsTM platform. Calibration and validation were conducted with experimental data from two identical pilot HRAPs receiving real wastewater. The model was able to simulate the dynamics of different components in the ponds, and to predict the relative proportion of microalgae (58-68% in average of total suspended solids (TSS) and bacteria (30-20% in average of TSS). Microalgae growth resulted strongly influenced by the light factor fL(I), decreasing microalgae concentrations from 40 to 60%. Furthermore, reducing the influent organic matter concentration of 50% and 70%, model predictions indicated that microalgae production increased from (8.7gTSSm-2d-1 to 13.5gTSSm-2d-1) due to the new distribution of particulate components. The proposed model could be an efficient tool for industry to predict the production of microalgae, as well as to design and optimize HRAPs. PMID- 28577401 TI - Enhanced protection of PDMS-embedded palladium catalysts by co-embedding of sulphide-scavengers. AB - For Pd-containing hydrodechlorination catalysts, coating with poly(dimethyl siloxane) (PDMS) was proposed earlier as promising protection scheme against poisoning. The PDMS coating can effectively repel non-permeating poisons (such as SO32-) retaining the hydrodechlorination Pd activity. In the present study, the previously achieved protection efficiency was enhanced by incorporation of sulphide scavengers into the polymer. The embedded scavengers were able to bind permeating non-ionic poisons (such as H2S) during their passage through PDMS prior to Pd contact which ensured an extended catalyst lifetime. Three scavenger types forming non-permeable sulphur species from H2S - alkaline, oxidative or iron-based compounds - were either incorporated into single-layer coats around individual Pd/Al2O3 particles or into a second layer above Pd-containing PDMS films (Pd-PDMS). Hydrodechlorination and hydrogenation were chosen as model reactions, carried out in batch and continuous-flow reactors. Batch tests with all scavenger-containing catalysts showed extended Pd protection compared to scavenger-free catalysts. Solid alkaline compounds (Ca(OH)2, NaOH, CaO) and MnO2 showed the highest instantaneous scavenger efficiencies (retained Pd activity=30 60%), while iron-based catalysts, such as nano zero-valent iron (nZVI) or ferrocene (FeCp2), proved less efficient (1-10%). When stepwise poisoning was applied, the protection efficiency of iron-based and oxidizing compounds was higher in the long term than that of alkaline solids. Long-term experiments in mixed-flow reactors were performed with selected scavengers, revealing the following trend of protection efficiency: CaO2>Ca(OH)2>FeCp2. Under field simulating conditions using a fixed-bed reactor, the combination of sulphide pre oxidation in the water phase by H2O2 and local scavenger-enhanced Pd protection was successful. The oxidizing agent H2O2 does not disturb the Pd-catalysed reduction, while the PDMS-incorporated scavenger considerably extends the catalyst life in the presence of H2S. This work demonstrates that the scavenger based protection strategy is an effective means to increase the resistance of PDMS-embedded Pd against permeating poisons. PMID- 28577402 TI - Comparative effects of sulfuric and nitric acid rain on litter decomposition and soil microbial community in subtropical plantation of Yangtze River Delta region. AB - Acid rain is mainly caused by dissolution of sulfur dioxide and nitrogen oxides in the atmosphere, and has a significant negative effect on ecosystems. The relative composition of acid rain is changing gradually from sulfuric acid rain (SAR) to nitric acid rain (NAR) with the rapidly growing amount of nitrogen deposition. In this study, we investigated the impact of simulated SAR and NAR on litter decomposition and the soil microbial community over four seasons since March 2015. Results first showed that the effects of acid rain on litter decomposition and soil microbial were positive in the early period of the experiment, except for SAR on soil microbes. Second, soil pH with NAR decreased more rapidly with the amount of acid rain increased in summer than with SAR treatments. Only strongly acid rain (both SAR and NAR) was capable of depressing litter decomposition and its inhibitory effect was stronger on leaf than on fine root litter. Meanwhile, NAR had a higher inhibitory effect on litter decomposition than SAR. Third, in summer, autumn and winter, PLFAs were negatively impacted by the increased acidity level resulting from both SAR and NAR. However, higher acidity level of NAR (pH=2.5) had the strongest inhibitory impact on soil microbial activity, especially in summer. In addition, Gram negative bacteria (cy19:0) and fungi (18:1omega9) were more sensitive to both SAR and NAR, and actinomycetes was more sensitive to SAR intensity. Finally, soil total carbon, total nitrogen and pH were the most important soil property factors affecting soil microbial activity, and high microbial indices (fungi/bacteria) with high soil pH. Our results suggest that the ratio of SO42- to NO3- in acid rain is an important factor which could affect litter decomposition and soil microbial in subtropical forest of China. PMID- 28577403 TI - Temporal changes in radiological and chemical composition of Cambrian-Vendian groundwater in conditions of intensive water consumption. AB - Intensive groundwater uptake is a process at the intersection of the anthroposphere, hydrosphere, and lithosphere. In this study, groundwater uptake on a peninsula where only one aquifer system - the Cambrian-Vendian (CmV) - is available for drinking water uptake is observed for a period of four years for relevant radionuclides and chemical parameters (Cl, Mn, Fe, delta18O). Intensive groundwater uptake from the CmV aquifer system may lead to water inflow either from the sea, through ancient buried valleys or from the under-laying crystalline basement rock which is rich in natural radionuclides. Changes in the geochemical conditions in the aquifer may in turn bring about desorption of Ra from sediment surface. Knowing the hydrogeological background of the wells helps to predict possible changes in water quality which in turn are important for sustainable groundwater management and optimization of water treatment processes. Changes in Cl and Ra concentrations are critical parameters to monitor for sustainable management of the CmV groundwater. Radionuclide activity concentrations in groundwater are often considered rather stable, minimum monitoring frequency of the total indicative dose from drinking water is set at once every ten years. The present study demonstrates that this is not sufficient for ensuring stable drinking water quality in case of aquifer systems as sensitive as the CmV aquifer system. Changes in Cl concentrations can be used as a tool to predict Ra activity concentrations and distribute the production between different wells opening to the same aquifer system. PMID- 28577404 TI - Sources of groundwater salinity and potential impact on arsenic mobility in the western Hetao Basin, Inner Mongolia. AB - The quality of groundwater used for human consumption and irrigation in the Hetao Basin of Inner Mongolia, China is affected by elevated salinity as well as high arsenic (As) concentrations. However, the origin of high salinity and its potential impact on As mobility in the Basin remain unclear. This study explores both issues using stable isotopic compositions and Cl/Br ratios of groundwater as well as the major ions of both groundwater and leachable salts in aquifer sediments. Limited variations in delta18O and delta2H (-11.13 to -8.10, -82.23 to -65.67) with the wide range of Total Dissolved Solid (TDS, 351-6734mg/L) suggest less contribution of direct evaporation to major salinity in groundwater. Deuterium excess shows that non-direct evaporation (capillary evaporation, transpiration) and mineral/evaporite dissolution contribute to >60% salinity in groundwater with TDS>1000mg/L. Non-direct evaporation, like capillary evaporation and transpiration, is proposed as important processes contributing to groundwater salinity based on Cl/Br ratio and halite dissolution line. The chemical weathering of Ca, Mg minerals and evaporites (Na2SO4 and CaSO4) input salts into groundwater as well. This is evidenced by the fact that lacustrine environment and the arid climate prevails in Pleistocene period. Dissolution of sulfate salts not only promotes groundwater salinity but affects As mobilization. Due to the dissolution of sulfate salts and non-direct evaporation, groundwater SO42- prevails and its reduction may enhance As enrichment. The higher As concentrations (300-553MUg/L) are found at the stronger SO42- reduction stage, indicating that reduction of Fe oxide minerals possibly results from HS- produced by SO42- reduction. This would have a profound impact on As mobilization since sulfate is abundant in groundwater and sediments. The evolution of groundwater As and salinity in the future should be further studied in order to ensure sustainable utilization of water resource in this water scarce area. PMID- 28577405 TI - Meteorological factors had more impact on airborne bacterial communities than air pollutants. AB - Airborne bacteria have gained increasing attention because they affect ecological balance and pose potential risks on human health. Recently, some studies have focused on the abundance and composition of airborne bacteria under heavy, hazy polluted weather in China, but they reached different conclusions about the comparisons with non-polluted days. In this study, we tested the hypothesis that meteorological factors could have a higher impact on shaping airborne bacterial communities than air pollutants by systematically monitoring the communities for 1year. Total suspended particles in Beijing were sampled for 20 consecutive days in each season of 2015. Bacterial abundance varied from 8.71*103 to 2.14*107 ribosomal operons per cubic meter according to the quantitative PCR analysis. There were relatively higher bacterial counts in spring and in autumn than in winter and summer. Airborne bacterial communities displayed a strong seasonality, according to the hierarchical cluster analysis. Only two exceptions overtook the seasonal trend, and both occurred in or after violent meteorological changes (sandstorm or rain). Aggregated boosted tree analysis performed on bacterial abundance showed that the dominant factors shaping bacterial communities were meteorological. They were air pressure in winter, air temperature and relative humidity in spring, RH in summer, and vapor pressure in autumn. Variation partition analysis on community structure showed that meteorological factors explained more variations than air pollutants. Therefore, both of the two models verified our hypothesis that the differences in airborne bacterial communities in polluted days or non-polluted days were mainly driven by the discrepancies of meteorological factors rather than by the presence of air pollutants. PMID- 28577406 TI - The removal efficiency and insight into the mechanism of para arsanilic acid adsorption on Fe-Mn framework. AB - Para arsanilic acid (p-ASA) is extensively used as feed additives in poultry industry, resulting contaminates soil and natural water sources through the use of poultry litter as a fertilizer in croplands. Thus, removal of p-ASA prior to its entering environments is significant to control their environmental risk. Herein, we studied Fe-Mn framework and cubic Fe(OH)3 as promising novel adsorbents for the removal of p-ASA from aqueous solution. The chemical and micro structural properties of Fe-Mn framework and cubic Fe(OH)3 materials were characterized by X-ray diffraction patterns (XRD), nitrogen adsorption (SBET), zeta (zeta-) potential, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectra (XPS). The maximum adsorption capacity for p-ASA on Fe-Mn framework and cubic Fe(OH)3 was determined to be 1.3mmolg-1 and 0.72mmolg-1 at pH4.0, respectively. Adsorption of p-ASA decreased gradually with increasing pH indicated that adsorption was strongly pH dependent. Azophenylarsonic acid was identified as an oxidation intermediate product of p-ASA after adsorption on Fe-Mn framework. Plausible removal mechanism for p-ASA by Fe-Mn framework was proposed. The obtained results gain insight into the potential applicability of Fe-Mn framework, which can be potentially important for the removal of p-ASA from water. PMID- 28577407 TI - Time-resolved immunoassay based on magnetic particles for the detection of diethyl phthalate in environmental water samples. AB - Diethyl phthalate (DEP) is an extensively used phthalic acid diester (PAEs) with estrogenic activity and the potential for carcinogenic and teratogenic effects. To monitor trace DEP in environmental waters, a sensitive direct competitive time resolved fluoroimmunoassay based on magnetic particles (MPs) as solid support was established. For the assay system, the anti-DEP antibody was oriented on the surface of the MPs using goat anti-rabbit antibody as linkers, and DEP-OVA was labeled using Eu3+. Several physicochemical factors that potentially influence the assay performance of the proposed method were investigated in detail, including concentration of MPs, dilution of DEP-OVA-Eu3+ and incubation time. Under the optimized conditions, the method showed: (i) low limit of detection (LOD) of 5.92ng/L; (ii) satisfactory accuracy (recoveries, 91.97-134.54%) with good reproducibility (inter-CV, 4.17-9.17%; intra-CV, 7.41-14.72%). All of which indicated that the newly established method had much higher efficiency and great potential for use in environmental water analysis for DEP. In addition, the proposed immunoassay was applied for investigation of DEP in aquatic environments at Zhenjiang City. Our results showed that DEP was detected at the concentration of 2.98-65.18ng/mL in river samples and 46.95-306.19ng/mL in wastewater treatment plants (WWTPs), which showed rather high concentrations compared with reported data. Our study provides background data important for risk assessment and contamination control of DEP in the aquatic environment of this area. PMID- 28577408 TI - Dendrimer-functionalized electrospun nanofibres as dual-action water treatment membranes. AB - This work reports the preparation of composite electrospun membranes combining antimicrobial action with the capacity of retaining low-molecular weight non polar pollutants. The membranes were electrospun blends of polyvinyl alcohol (PVA) and poly(acrylic acid) (PAA) stabilized using heat curing. The membranes were functionalized by grafting amino-terminated poly(amidoamine) (PAMAM) G3 dendrimers. The antimicrobial effect was assessed using strains of Escherichia coli and Staphylococcus aureus by tracking their capacity to form new colonies and their metabolic impairment upon contact with membranes. The antimicrobial activity was particularly high to the gram-positive bacterium S. aureus with a 3 log reduction in their capacity to colonize dendrimer-functionalized membranes with respect to neat PVA/PAA fibers. The effect to gram-positive bacteria was attributed to the interaction of dendrimers with the negatively charged bacterial membranes and resulted in membranes essentially free of bacterial colonization after 20h in contact with cultures at 36 degrees C. The adsorption of toluene on PAA/PVA fibers and on dendrimer-functionalized membranes was assayed using toluene over a broad concentration range. The host-guest encapsulation of toluene inside dendrimer molecules was computed through docking studies, which allowed calculating a maximum capacity of 14 molecules of toluene per molecule of PAMAM G3. The theoretical prediction was in good agreement with the experimental capacity at the higher concentrations assayed. PMID- 28577409 TI - The role of cadmium in obesity and diabetes. AB - Multiple studies have shown an association between environmental exposure to hazardous chemicals including toxic metals and obesity, diabetes, and metabolic syndrome. At the same time, the existing data on the impact of cadmium exposure on obesity and diabetes are contradictory. Therefore, the aim of the present work was to review the impact of cadmium exposure and status on the risk and potential etiologic mechanisms of obesity and diabetes. In addition, since an effect of cadmium exposure on incidence of diabetes mellitus and insulin resistance was suggested by several epidemiologic studies, we carried out a meta-analysis of all studies assessing risk of prevalence and incidence of diabetes. By comparing the highest versus the lowest cadmium exposure category, we found a high risk of diabetes incidence (odds ratio=1.38, 95% confidence interval 1.12-1.71), which was higher for studies using urine as exposure assessment. On the converse, results of epidemiologic studies linking cadmium exposure and overweight or obesity are far less consistent and even conflicting, also depending on differences in exposure levels and the specific marker of exposure (blood, urine, hair, nails). In turn, laboratory studies demonstrated that cadmium adversely affects adipose tissue physiopathology through several mechanisms, thus contributing to increased insulin resistance and enhancing diabetes. However, intimate biological mechanisms linking Cd exposure with obesity and diabetes are still to be adequately investigated. PMID- 28577410 TI - Human health implications, risk assessment and remediation of As-contaminated water: A critical review. AB - Arsenic (As) is a naturally occurring metalloid and Class-A human carcinogen. Exposure to As via direct intake of As-contaminated water or ingestion of As contaminated edible crops is considered a life threatening problem around the globe. Arsenic-laced drinking water has affected the lives of over 200 million people in 105 countries worldwide. Limited data are available on various health risk assessment models/frameworks used to predict carcinogenic and non carcinogenic health effects caused by As-contaminated water. Therefore, this discussion highlights the need for future research focusing on human health risk assessment of individual As species (both organic and inorganic) present in As contaminated water. Various conventional and latest technologies for remediation of As-contaminated water are also reviewed along with a discussion of the fate of As-loaded waste and sludge. PMID- 28577412 TI - Postmortem computed tomography evaluation of fatal gas embolism due to connection of an intravenous cannula to an oxygen supply. AB - An 84-year-old man who had suffered from chronic obstructive pulmonary disease accompanied by moderate pneumonia as well as gastric cancer with liver metastasis was found dead by a nurse, who noticed that the patient's intravenous catheter in the left forearm had been erroneously connected to an oxygen supply in his hospital room, leading to infusion of oxygen into a vein. Postmortem CT scanning demonstrated multiple accumulations of gas in the pulmonary artery, the right atrium and ventricle, as well as the left subclavian and brachiocephalic veins, corresponding to the route that the infused gas would have taken to the heart and pulmonary artery. Conventional autopsy revealed the presence of gas in the right ventricle. These findings suggested that the immediate cause of death was a gas embolus due to oxygen that had entered the cardiopulmonary circulation via the intravenous catheter. This case highlights the usefulness of postmortem imaging as an aid to conventional autopsy for demonstrating gas embolism. PMID- 28577413 TI - Contact analysis and experimental investigation of a linear ultrasonic motor. AB - The effects of surface roughness are not considered in the traditional motor model which fails to reflect the actual contact mechanism between the stator and slider. An analytical model for calculating the tangential force of linear ultrasonic motor is proposed in this article. The presented model differs from the previous spring contact model, the asperities in contact between stator and slider are considered. The influences of preload and exciting voltage on tangential force in moving direction are analyzed. An experiment is performed to verify the feasibility of this proposed model by comparing the simulation results with the measured data. Moreover, the proposed model and spring model are compared. The results reveal that the proposed model is more accurate than spring model. The discussion is helpful for designing and modeling of linear ultrasonic motors. PMID- 28577411 TI - Tau pathology and cognitive reserve in Alzheimer's disease. AB - Cognitive reserve (CR) is defined as the ability to maintain functionality despite accumulating pathology. Education has been used as a proxy for CR. For example, by using positron emission tomography imaging, higher educated Alzheimer's disease (AD) patients presented increased amyloid beta pathology than lower educated patients despite equal symptomatology. Whether similar associations exist for in vivo tau pathology remains elusive. We utilized [18F]AV 1451 positron emission tomography imaging to examine whether high-educated AD patients (n = 12) present more severe tau pathology compared with low-educated patients (n = 12) despite equal clinical severity in regions of interest corresponding to the pathologic disease stages defined by Braak & Braak. We report tau pathology in advanced Braak stages associated with parietal and frontal regions in high-educated AD patients, whereas in low-educated AD patients tau accumulation is still confined to lower Braak stages associated with temporal and cingulate regions. Highly educated AD patients seem to be able to tolerate more tau tangle pathology than lower educated patients with comparable cognitive impairment supporting the cognitive reserve hypothesis. PMID- 28577414 TI - Dynamic measurement of speed of sound in n-Heptane by ultrasonics during fuel injections. AB - The paper presents a technique to measure the speed of sound in fuels based on pulse-echo ultrasound. The method is applied inside the test chamber of a Zeuch type instrument used for indirect measurement of the injection rate (Mexus). The paper outlines the pulse-echo method, considering probe installation, ultrasound beam propagation inside the test chamber, typical signals obtained, as well as different processing algorithms. The method is validated in static conditions by comparing the experimental results to the NIST database both for water and n Heptane. The ultrasonic system is synchronized to the injector so that time resolved samples of speed of sound can be successfully acquired during a series of injections. Results at different operating conditions in n-Heptane are shown. An uncertainty analysis supports the analysis of results and allows to validate the method. Experimental results show that the speed of sound variation during an injection event is less than 1%, so the Mexus model assumption to consider it constant during the injection is valid. PMID- 28577415 TI - Maternal emotion regulation during child distress, child anxiety accommodation, and links between maternal and child anxiety. AB - Environmental contributions are thought to play a primary role in the familial aggregation of anxiety, but parenting influences remain poorly understood. We examined dynamic relations between maternal anxiety, maternal emotion regulation (ER) during child distress, maternal accommodation of child distress, and child anxiety. Mothers (N=45) of youth ages 3-8 years (M=4.8) participated in an experimental task during which they listened to a standardized audio recording of a child in anxious distress pleading for parental intervention. Measures of maternal and child anxiety, mothers' affective states, mothers' ER strategies during the child distress, and maternal accommodation of child anxiety were collected. Mothers' resting respiratory sinus arrhythmia (RSA) reactivity during the recording was also acquired. Higher maternal negative affect and greater maternal ER switching (i.e., using multiple ER strategies in a short time without positive regulatory results) during child distress were associated with child anxiety. Sequential mediation modeling showed that maternal anxiety predicted ineffective maternal ER during child distress exposure, which in turn predicted greater maternal accommodation, which in turn predicted higher child anxiety. Findings support the mediating roles of maternal ER and accommodation in linking maternal and child anxiety, and suggest that ineffective maternal ER and subsequent attempts to accommodate child distress may act as mechanisms underlying the familial aggregation of anxiety. PMID- 28577416 TI - The impact of attentional and emotional demands on memory performance in obsessive-compulsive disorder. AB - Lower performance on memory tests in obsessive-compulsive disorder (OCD) has been repeatedly observed. However, the origins of these performance deficits are not sufficiently explained. In this study we tested if OCD-related extensive focus of attention on thoughts (heightened self-consciousness) could be an explanatory mechanism for lower memory performance. Heightened situational self-consciousness was manipulated by instructing participants to either monitor neutral thoughts or to monitor OCD-related thoughts. We included a Behavioral Avoidance Task based on individual obsessions and compulsions to induce OCD-related thoughts. Participants were asked to perform these monitoring tasks in parallel to a taxing verbal memory task, resulting in learning under divided attention. The two conditions of learning under divided attention were compared to a single-task condition. Twenty-four participants with OCD and 24 healthy controls took part in these three learning conditions. The results indicate that in both groups memory performance deteriorated in the two conditions with divided attention compared to the single task condition. In the OCD-related thought monitoring condition (OTM) self-consciousness and Behavioral Avoidance Task-induced stress and fear were particularly increased and memory performance further deteriorated in the OCD group. This finding highlights an important and underestimated mechanism (personal involvement) which might serve to better understand lower memory performance in OCD. PMID- 28577417 TI - Structured debriefing: What difference does it make? AB - Debriefing in simulation is a cornerstone of learning. However, in-depth studies examining simulation debriefing are scarce. This study explored four key debriefing attributes-feedback, reflection, knowledge development, and psychological safety-prior and subsequent to the implementation of a new pedagogical intervention in a pre-clinical scenario simulation course. The scenarios focused on patients with deteriorating conditions and took place at bachelor's nursing degree level. The new intervention for the debriefing sessions contained a detailed observation tool describing specific, correct nursing actions for deteriorating patients; video playback watched only by students acting as nurses, and debriefing organized into two sections. The study design was explorative. To generate data, 12 debriefing sessions were audio and video recorded in 2013 and 11 in 2014. Two student groups participated each year, comprising 16 and 10 students, respectively. Qualitative analysis was performed to examine the transcribed audio and video recordings. Relative to the 2013 cohort, the reflections of observers and the students acting as nurses were more assertive, and students' feedback was more specific and comprehensive in the 2014 cohort. Conducting in-depth studies examining debriefing is important to increase knowledge regarding the impact of pedagogical underpinnings on debriefing content and processes. PMID- 28577418 TI - Macro- and microstructural tracking of ageing-related changes of papaverine hydrochloride-loaded electrospun nanofibrous buccal sheets. AB - Electrospun papaverine hydrochloride-loaded nanofibrous sheets consist of hydroxypropyl cellulose/poly(vinyl alcohol) composite were prepared for buccal administration for cerebral ischemia. The nanofibrous drug delivery system was subjected to accelerated stability test for four weeks in order to scrutinize the solid state changes relating to the stress induced (40+/-2 degrees C/75+/-5% relative humidity) physical ageing. Micro- and macrostructural alterations were detected using scanning electron microscopy (SEM), Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR) and positron annihilation lifetime spectroscopy (PALS). Significant changes were revealed at both supramolecular and macroscopic levels. Microscopic morphology uncovered major morphological transitions. Subtle variations of Raman and FTIR spectra indicated that the local chemical environment of papaverine was altered suggesting a partial phase transition of the active. Discrete o-Ps lifetimes and lifetime-distributions unveiled a two-step ageing process of the drug carrier. In addition to the tracking of the glassy-to-rubbery transition of the fiber forming polymers, the Raman spectroscopy enabled monitoring the kinetics of the phase transition observed. PMID- 28577419 TI - A simplified guide for charged aerosol detection of non-chromophoric compounds Analytical method development and validation for the HPLC assay of aerosol particle size distribution for amikacin. AB - Amikacin, an aminoglycoside antibiotic lacking a UV chromophore, was developed into a drug product for delivery by inhalation. A robust method for amikacin assay analysis and aerosol particle size distribution (aPSD) determination, with comparable performance to the conventional UV detector was developed using a charged aerosol detector (CAD). The CAD approach involved more parameters for optimization than UV detection due to its sensitivity to trace impurities, non linear response and narrow dynamic range of signal versus concentration. Through careful selection of the power transformation function value and evaporation temperature, a wider linear dynamic range, improved signal-to-noise ratio and high repeatability were obtained. The influences of mobile phase grade and glassware binding of amikacin during sample preparation were addressed. A weighed (1/X2) least square regression was used for the calibration curve. The limit of quantitation (LOQ) and limit of detection (LOD) for this method were determined to be 5MUg/mL and 2MUg/mL, respectively. The method was validated over a concentration range of 0.05-2mg/mL. The correlation coefficient for the peak area versus concentration was 1.00 and the y-intercept was 0.2%. The recovery accuracies of triplicate preparations at 0.05, 1.0, and 2.0mg/mL were in the range of 100-101%. The relative standard deviation (Srel) of six replicates at 1.0mg/mL was 1%, and Srel of five injections at the limit of quantitation was 4%. A robust HPLC-CAD method was developed and validated for the determination of the aPSD for amikacin. The CAD method development produced a simplified procedure with minimal variability in results during: routine operation, transfer from one instrument to another, and between different analysts. PMID- 28577420 TI - Reliability of point-of-collection testing devices for drugs of abuse in oral fluid: A systematic review and meta-analysis. AB - Point-of-collection testing (POCT) devices for drugs of abuse are used to screen for the presence of psychoactive substances (PAS) in different types of settings and environments. However, these quick and advantageous tools also present disadvantages, including low-reliability measures in comparison to chromatographic assays. Therefore, this article presents a systematic review and meta-analysis of studies evaluating the reliability of measurements of PAS detection in oral fluid using POCT devices. The reliability measures for detection of the five most important drug classes - cocaine, amphetamines, benzodiazepines, cannabinoids and opioids, are reported. The article also presents a subgroup analysis considering the reliability estimates for the different POCT devices that were evaluated by the studies contemplated in the review. A discussion considering the strengths and limitations of POCT techniques was performed in order to guide policymakers, traffic agents and other professionals who also conduct such tests. The use of POCT devices often involves legal and moral aspects of the subjects tested, which demands critical evaluation of these devices before they are implemented in different settings. PMID- 28577421 TI - Season-dependent effects of photoperiod and temperature on circadian rhythm of arylalkylamine N-acetyltransferase2 gene expression in pineal organ of an air breathing catfish, Clarias gariepinus. AB - Arylalkylamine N-acetyltransferase (AANAT) activity, aanat gene expression and melatonin production have been reported to exhibit prominent circadian rhythm in the pineal organ of most species of fish. Three types of aanat genes are expressed in fish, but the fish pineal organ predominantly expresses aanat2 gene. Increase and decrease in daylength is invariably associated with increase and decrease in temperature, respectively. But so far no attempt has been made to delineate the role of photoperiod and temperature in regulation of the circadian rhythm of aanat2 gene expression in the pineal organ of any fish with special reference to seasons. Therefore, we studied effects of various lighting regimes (12L-12D, 16L-8D, 8L-16D, LL and DD) at a constant temperature (25 degrees C) and effects of different temperatures (15 degrees , 25 degrees and 35 degrees C) under a common photoperiod 12L-12D on circadian rhythm of aanat2 gene expression in the pineal organ of Clarias gariepinus during summer and winter seasons. Aanat2 gene expression in fish pineal organ was studied by measuring aanat2 mRNA levels using Real-Time PCR. Our findings indicate that the pineal organ of C. gariepinus exhibits a prominent circadian rhythm of aanat2 gene expression irrespective of photoperiods, temperatures and seasons, and the circadian rhythm of aanat2 gene expression responds differently to different photoperiods and temperatures in a season-dependent manner. Existence of circadian rhythm of aanat2 gene expression in pineal organs maintained in vitro under 12L-12D and DD conditions as well as a free running rhythm of the gene expression in pineal organ of the fish maintained under LL and DD conditions suggest that the fish pineal organ possesses an endogenous circadian oscillator, which is entrained by light-dark cycle. PMID- 28577422 TI - Midwifery continuity: The use of social media. AB - BACKGROUND: Continuity models of midwifery care improve women's experiences of care and clinical outcomes, but organisationally driven working practices do not facilitate a continuity model and the midwifery care received by most women is fragmented (Sandall et al., 2016, NHS England, 2016). Little is known about the potential for continuity of midwifery care to be achieved using an electronic platform. This paper examines the experiences of women accessing known midwives through a social media platform and their experiences and perception of continuity of care. METHODS: The study forms part of a larger research project aiming to increase understanding about online social learning within professionally moderated social media based communities. This paper reports specifically the concept of midwifery continuity within the online communities. Two secret Facebook groups consisting of 31 mothers and 4 midwife moderators were created (17 mothers & 2 midwives / 14 mothers & 2 midwives). Primary data included 8 online and face to face focus groups, conducted at approximately 10 week intervals, and 28 individual one to one interviews with members of the online community within six weeks of giving birth. DATA ANALYSIS: A thematic analysis using a priori themes was undertaken. This involved coding data which evidenced relational, informational and management continuity across the entire dataset (28 interviews and 8 focus groups). The analysis was undertaken broadly following the six stages described by Braun and Clarke (2006). FINDINGS: Relational and informational continuity were identified across the data. Relational continuity was evident for both the participants and the midwife moderators; informational continuity was described by the participants. Management continuity was not identified. Continuity through social media use was valued by both the mothers and the midwives. CONCLUSION: Information and relational continuity needs of women can be met using professionally moderated, social media based groups. They may provide an alternative means of facilitating the continuity that is so often lacking in traditional models of care. PMID- 28577423 TI - Severe hand, foot and mouth disease associated with Coxsackievirus A10 infections in Xiamen, China in 2015. AB - BACKGROUND: Coxsackievirus A10 (CV-A10) is one of the etiological agents associated with hand, foot and mouth disease (HFMD) and usually causes mild cases. During 2009-2014, no severe cases caused by CV-A10 was reported in Xiamen, China, however, an increase in cases was seen in 2015. OBJECTIVES: We aimed to perform a retrospective molecular epidemiological analysis of HFMD associated with CV-A10 infections in Xiamen. STUDY DESIGN: CV-A10 VP1 (n=41) capsid and full length or near full-length genomes (n=14) were sequenced. Phylogenetic trees were constructed based on these sequences and other reference sequences and nucleotide and amino acid changes were characterized. RESULTS: From 2009-2014, no laboratory confirmed CV-A10 infections associated with severe cases were identified, however, in 2015, 39% (7/18) of severe HFMD cases were CV-A10 infections. Sequence analysis of severe and non-severe CV-A10 HFMD cases determined that severe cases predominantly clustered with an emerging clade E lineage A strain which contained 4 nucleotide changes in 5' UTR and 5 amino acid substitutions in structural and non-structural proteins. CONCLUSIONS: The results indicate CV-A10 infection may be emerging as a new and major cause of severe HFMD and CV-A10 surveillance should be increased and considered in HFMD prevention and control strategies. PMID- 28577424 TI - Specific needs of families of young adults with profound intellectual disability during and after transition to adulthood: What are we missing? AB - INTRODUCTION: At the age of 21, the trajectory of services offered to youth with profound intellectual disability (ID) change significantly since access to specialised services is more limited. Despite the desire of parents to avoid any impact on their child, several factors can influence the course of this transition. However, there is little research on facilitators and obstacles to the transition to adulthood, and impacts on people with a profound ID. It is therefore difficult to provide solutions that meet their specific needs. OBJECTIVE: The study aimed to document the needs of parents and young adults with profound ID during and after the transition to adulthood by exploring their transitioning experience and factors that influenced it. METHOD: Using a descriptive qualitative design, two individual semi-structured interviews were conducted with fourteen (14) parents of young adults aged between 18 and 26 with a profound ID. RESULTS: At this point, many material, informative, cognitive and emotional needs of young adults and their parents are not met. Obstacles, mainly organisational, persist and result in a particularly difficult transition to adulthood experience. CONCLUSION: By knowing the specific needs of these families, it is possible to develop and implement solutions tailored to their reality. WHAT THE PAPERS ADDS?: The transition to adulthood is a critical period for families with young adults with an intellectual disability (ID), a reality observed internationally. Current literature on all levels of ID suggests some barriers to transition that lead to negative impacts on both parents and young adults with ID. However, presently, very little research exists on the reality of families of young adults with profound ID and factors influencing transition to adult life. Most of studies target people with mild to moderate ID. Considering the significant disabilities of people with profound ID, it is possible to imagine that their experience of transition will be even more difficult and they will present specific needs. The lack of understanding of these needs makes it difficult to introduce solutions tailored to their reality. The results of this current study suggest that many needs of young adults with profound ID and their parents are not met despite existent transition planning services. Transition to adulthood seems particularly difficult for these families who face many challenges. Parents in this study proposed different obstacles during transition to adulthood that could be improved for creation of future solutions adapted to their reality. PMID- 28577425 TI - Denaturing gradient gel electrophoresis profiles of bacteria from the saliva of twenty four different individuals form clusters that showed no relationship to the yeasts present. AB - OBJECTIVES: The aim was to investigate the relationship between groups of bacteria identified by cluster analysis of the DGGE fingerprints and the amounts and diversity of yeast present. METHODS: Bacterial and yeast populations in saliva samples from 24 adults were analysed using denaturing gradient gel electrophoresis (DGGE) of the bacteria present and by yeast culture. RESULTS: Eubacterial DGGE banding patterns showed considerable variation between individuals. Seventy one different amplicon bands were detected, the band number per saliva sample ranged from 21 to 39 (mean+/-SD=29.3+/-4.9). Cluster and principal component analysis of the bacterial DGGE patterns yielded three major clusters containing 20 of the samples. Seventeen of the 24 (71%) saliva samples were yeast positive with concentrations up to 103cfu/mL. Candida albicans was the predominant species in saliva samples although six other yeast species, including Candida dubliniensis, Candida tropicalis, Candida krusei, Candida guilliermondii, Candida rugosa and Saccharomyces cerevisiae, were identified. The presence, concentration, and species of yeast in samples showed no clear relationship to the bacterial clusters. CONCLUSION: Despite indications of in vitro bacteria yeast interactions, there was a lack of association between the presence, identity and diversity of yeasts and the bacterial DGGE fingerprint clusters in saliva. This suggests significant ecological individual-specificity of these associations in highly complex in vivo oral biofilm systems under normal oral conditions. PMID- 28577426 TI - Trajectories of traumatic stress symptoms during conflict: A latent class growth analysis. AB - BACKGROUND: The ways in which traumatic stress symptoms unfold under situations of ongoing threat and trauma exposure are poorly understood. The current study aims to identify traumatic stress symptom trajectories during conflict, as well as potential risk factors. METHODS: Experience sampling methods were used to study traumatic stress symptoms during the 2014 Israel-Gaza conflict in 100 Israeli civilians exposed to rocket fire. Summary reports of traumatic symptoms were made twice-daily for 30 days via mobile phone. RESULTS: Latent class growth analysis revealed four distinct classes (low, reducing, moderate, and high) characterised by their trajectory of traumatic stress symptoms during the conflict. Female gender, not being in a relationship, and higher prior trauma exposure were identified as potential risk factors. LIMITATIONS: Data were not collected in the early phase of the conflict, the sample was relatively small, and only traumatic stress symptoms were investigated as outcomes. CONCLUSIONS: This study identified heterogeneous traumatic stress symptom trajectories among civilians during a conflict, with different subgroups showing distinct response patterns over time, associated with various risk factors. Investigating responses to ongoing trauma, and identifying predictors of different stress symptom trajectories has clinical implications for the targeted delivery of interventions. Further exploration of heterogeneous trajectories could potentially elucidate mechanisms that drive resilience and recovery, including in situations of ongoing exposure such as during conflict. PMID- 28577427 TI - Fruit and vegetable intake, physical activity, and depressive symptoms in the African American Health (AAH) study. AB - BACKGROUND: Healthy diet and physical activity (PA) have been associated with reduced depressive symptoms, but few studies have examined them simultaneously in African Americans. AIMS: To investigate fruit and vegetable intake (FVI) and PA as predictors of clinically-relevant levels of depressive symptoms (CRLDS) in African Americans. METHODS: African American Health (AAH) is a population-based longitudinal study of African Americans in St. Louis, MO, who were born in 1936 1950 (inclusive) and empaneled in 2000-01 (wave 1). At wave 8, participants self reported fruit and vegetable intake (FVI) and completed the Yale Physical Activity Scale. At both waves 8 and 10, the CES-D 11-item scale was used to identify those who met criteria for CRLDS. Sequential logistic regression modeling was used to examine the associations of components of FVI/PA with CRLDS, both cross-sectionally (n = 680, including imputed values) and longitudinally (n = 582, including imputed values). Modeling employed gender, age, perceived income adequacy, and education as potential confounders. RESULTS: Cross-sectionally, vigorous PA, and leisurely walking PA, were independently associated with lower odds of CRLDS in all but the fifth model and green vegetables in all models. Longitudinally, green vegetables and interactions between the FVI summary score, the PA summary score, and other factors at wave 8 were most consistently associated with CRLDS at wave 10. In both cross-sectional and longitudinal models, the socioeconomic variables showed the strongest association as risk factors for CRLDS. LIMITATIONS: Both FVI and PA were self-reported rather than observed, our cohort had limited geographic- and age-ranges, and confidence intervals for some results were broad. CONCLUSIONS: Green vegetables, total FVI, and various aspects of PA showed protective effects regarding CRLDS. Therefore, the promotion of such lifestyles is likely to help prevent CRLDS in this population. PMID- 28577428 TI - VPAC1 Targeted 64Cu-TP3805 kit preparation and its evaluation. AB - INTRODUCTION: Previously, our laboratory has shown that 64Cu-TP3805 can specifically target VPAC1 receptors and be used for positron emission tomography (PET) imaging of breast (BC) and prostate cancer (PC) in humans. Present work is aimed at the formulation of a freeze-dried diaminedithiol-peptide (N2S2-TP3805) kit and it's evaluation for the preparation of 64Cu labeled TP3805. Parameters such as pH, temperature and incubation time were examined that influenced the radiolabeling efficiency and stability of the product. METHODS: Kits were prepared under different conditions and radiolabeling efficiency of TP3805 kit was evaluated for a range of pH3.5-8.5, after addition of 64Cu in 30MUl, 0.1M HCl. Incubation temperature (37-90 degrees C) and time (30-120min.) were also investigated. Kits were stored at -10 degrees C and their long term stability was determined as a function of their radiolabeling efficiency. Further, stability of 64Cu-TP3805 complex was evaluated in presence of fetal bovine serum and bovine serum albumin by using SDS polyacrylamide gel electrophoresis. Kits were then used for PET imaging of BC and PC following eIND (101550) and institutional approvals. Specificity of 64Cu-TP3805 for VPAC1 was examined with digital autoradiography (DAR) of prostate tissues obtained after prostatectomy, benign prostatic hyperplasia (BPH) tissue, and benign and malignant lymph nodes. Results were compared with corresponding tissue histology. RESULTS: Radiolabeling efficiency was >=95% at final pH ~7.2 when incubated at 50 degrees C for 90min. Kits were stable up to 18months when stored at -10 degrees C, and 64Cu-TP3805 complex exhibited excellent stability for up to 4h at room temperature. 64Cu TP3805 complex did not show any transchelation even after 2h incubation at 37 degrees C in 10% FBS as well as in BSA as determined by SDS PAGE analysis. DAR identified >=95% of malignant lesions 11 new PC lesions, 20 high grade prostatic intraepithelial neoplasia, 2/2 ejaculatory ducts and 5/5 urethra verumontanum not previously identified The malignant lymph nodes were correctly identified by DAR and for 3/3 BPH patients, and 5/5 cysts, DAR was negative. In human BC (n=19) and PC (n=26) were imaged with 100% sensitivity. CONCLUSION: Availability of ready to use N2S2-peptide kits for 64Cu labeling is convenient and eliminates possible day to day variation during its routine preparation for clinical use. PMID- 28577429 TI - Genetic strategies to access activated neurons. AB - A major goal of modern neuroscience is to understand how ensembles of neurons participate in neural circuits underlying behavior. The recent explosion of genetically-encoded circuit analysis tools has allowed neuroscientists to characterize molecularly-defined neuronal types with unprecedented detail. However, since neurons defined by molecular expression can be functionally heterogeneous, targeting circuit analysis tools to neurons based on their activity is critical to elucidating the neural basis of behavior. Here we review genetic strategies to access activated neurons and characterize their functional properties, molecular profiles, connectivity, and causal roles in sensory-coding, memory, and valence-encoding. We also discuss future possibilities for improving these strategies and using them to screen brain-wide activity patterns underlying adaptive and maladaptive behaviors. PMID- 28577430 TI - Posttranslational modifications of neuroligins regulate neuronal and glial signaling. AB - This review covers the dynamic regulation of neuroligin isoforms, focusing on posttranslational events including phosphorylation, glycosylation and activity dependent cleavage. There is a growing literature on how phosphorylation confers an isoform-specific level of modulation affecting a variety of protein interactions. In addition, recent studies describe activity-dependent proteolytic cleavage of neuroligins, revealing a broader role for neuroligins than just synaptic 'glue'. Interesting new research implicates the cleaved extracellular fragments of neuroligins in promoting glioma. These reports on cell signaling mediated by the cleavage products of neuroligins suggest novel and important roles for neuroligins in neuro-glial signaling. PMID- 28577431 TI - Supramolecular organization of NMDA receptors and the postsynaptic density. AB - The postsynaptic density (PSD) of all vertebrate species share a highly complex proteome with ~1000 conserved proteins that function as sophisticated molecular computational devices. Here, we review recent studies showing that this complexity can be understood in terms of the supramolecular organization of proteins, which self-assemble within a hierarchy of different length scales, including complexes, supercomplexes and nanodomains. We highlight how genetic and biochemical approaches in mice are being used to uncover the native molecular architecture of the synapse, revealing hitherto unknown molecular structures, including highly selective mechanisms for specifying the assembly of NMDAR-MAGUK supercomplexes. We propose there exists a logical framework that precisely dictates the subunit composition of synaptic complexes, supercomplexes, and nanodomains in vivo. PMID- 28577432 TI - Psychophysical assessment of koniocellular pathway in patients with schizophrenia versus healthy controls. AB - This study was designed to perform psychophysical assessment of koniocellular pathway in patients with schizophrenia versus healthy controls. A total of 26 patients diagnosed with schizophrenia and 15 healthy controls were included. Snellen Visual Acuity Chart scores and Short Wavelength Automated Perimetry (SWAP) visual field testing including global visual field indices [mean deviation (MD), pattern standard deviation (PSD), test time (min)], reliability parameters [false negative responses (%), false positive responses (%) and fixed losses (%)] and average threshold sensitivity [central (parafovea), peripheral area, and four quadrants] were recorded in both groups. Significantly lower MD scores, higher PSD scores and lower average threshold sensitivity at each location across the visual field were noted in schizophrenia relative to control group. In conclusion, our findings revealed a deficit in koniocellular pathway with impaired SWAP global indices and lower threshold sensitivity at each location across the visual field among chronic schizophrenic patients as compared with control subjects. Our findings emphasize potential application of SWAP outside its original intended purpose as a glaucoma test, to provide deeper understanding of the specific contribution of lateral geniculate nucleus to the visual and cognitive disturbances of schizophrenia. PMID- 28577434 TI - Simulation, identification and statistical variation in cardiovascular analysis (SISCA) - A software framework for multi-compartment lumped modeling. AB - It has not yet been possible to obtain modeling approaches suitable for covering a wide range of real world scenarios in cardiovascular physiology because many of the system parameters are uncertain or even unknown. Natural variability and statistical variation of cardiovascular system parameters in healthy and diseased conditions are characteristic features for understanding cardiovascular diseases in more detail. This paper presents SISCA, a novel software framework for cardiovascular system modeling and its MATLAB implementation. The framework defines a multi-model statistical ensemble approach for dimension reduced, multi compartment models and focuses on statistical variation, system identification and patient-specific simulation based on clinical data. We also discuss a data driven modeling scenario as a use case example. The regarded dataset originated from routine clinical examinations and comprised typical pre and post surgery clinical data from a patient diagnosed with coarctation of aorta. We conducted patient and disease specific pre/post surgery modeling by adapting a validated nominal multi-compartment model with respect to structure and parametrization using metadata and MRI geometry. In both models, the simulation reproduced measured pressures and flows fairly well with respect to stenosis and stent treatment and by pre-treatment cross stenosis phase shift of the pulse wave. However, with post-treatment data showing unrealistic phase shifts and other more obvious inconsistencies within the dataset, the methods and results we present suggest that conditioning and uncertainty management of routine clinical data sets needs significantly more attention to obtain reasonable results in patient specific cardiovascular modeling. PMID- 28577433 TI - Reduced fronto-amygdalar connectivity in adolescence is associated with increased depression symptoms over time. AB - Depression is common among adolescents, affecting greater than 12% of youth in a given year. Studies have shown aberrant amygdala connectivity in depressed adolescents, compared with controls; however, no studies have examined whether these abnormalities precede and heighten risk for depressive symptom expression. This study used resting state functional connectivity (RSFC) magnetic resonance imaging to examine neurobiological markers of escalating depression symptoms in adolescents (ages 12-16 years; free from psychopathology at baseline). Of a large sample of adolescents, 18 showed >= 1 S.D. increase in depression scale t-scores over time ("escalators"; time to escalation ranging from 6 to 54 months in follow up) and were matched and compared to 19 youth showing stable CDI scores over time ("controls"). Whole-brain analyses on baseline RSFC data using an amygdala seed region-of-interest (ROI) showed that controls had greater RSFC, relative to escalators, between the right amygdala and left inferior frontal and supramarginal gyrus and right mid-cingulate cortex. Additionally, relative to escalators, control youth had less RSFC between the left amygdala and cerebellum. Findings suggest a possible neurobiological marker of increasing depressive symptoms during adolescence, characterized in part by reduced fronto-limbic connectivity, suggesting a premorbid deficiency in top-down emotional regulation. PMID- 28577435 TI - Aryl benzofuran derivatives from the stem bark of Calpocalyx dinklagei attenuate inflammation. AB - Calpocalyx dinklagei Harms (Fabaceae) is a tropical medicinal tree, which is indigenous to Western Africa. A phytochemical study of this local plant species from its stem bark has led to the isolation of two previously undescribed aryl benzofuran derivatives, named dinklagein A and B, together with eight known compounds. Their chemical structures were elucidated by use of extensive spectroscopic methods (IR, HREI-MS and 1D and 2D NMR). Among all isolates, dinklagein A displayed remarkably potent inhibitory activity against the production of nitric oxide (NO) in the lipopolysaccharide (LPS) induced RAW264.7 macrophages. SAR and molecular docking investigations on iNOS and previously undescribed compounds (dinklagein A and B) supported experimental data. Furthermore, dinklagein A dose dependently suppressed the LPS-stimulated iNOS expression at both mRNA and protein level. It also attenuated IL-1beta release, mRNA expressions of IL-1beta and COX-2 at low doses. These results suggest that dinklagein A can be developed as natural, multi-target agent against several inflammatory diseases. PMID- 28577436 TI - Anti-inflammatory effects of ursolic acid-3-acetate on human synovial fibroblasts and a murine model of rheumatoid arthritis. AB - Ursolic acid (UA), a pentacyclic triterpenoid, is a common natural substance known to be effective in the treatment of inflammation, oxidative stress, and ulcers in arthritis. This study examined the effects of ursolic acid-3-acetate (UAA), a derivative of UA, on rheumatoid arthritis (RA) and verified the underlying mechanism of action by using a type-II collagen-induced arthritis (CIA) mice model and tumor necrosis factor (TNF)-alpha-stimulated RA synovial fibroblasts. The oral administration of UAA showed a decrease in clinical arthritis symptoms, paw thickness, histologic and radiologic changes, and serum IgG1 and IgG2a levels. UAA administration reduced Th1/Th17 phenotype CD4+ T lymphocyte expansion and inflammatory cytokine production in draining lymph nodes. In addition, UAA effectively reduced the expression and production of inflammatory mediators, including cytokines and matrix metalloproteinase-1/3 in the knee joint tissue and RA synovial fibroblasts, through the downregulation of IKKalpha/beta, IotakappaBalpha, and nuclear factor-kappaB. Our findings showed that UAA modulated helper T cell immune responses and matrix-degrading enzymes. The effects of UAA were comparable with those of the positive control drug, dexamethasone. In summary, all the evidence presented in this paper suggest that UAA could be a therapeutic candidate for the treatment of RA. PMID- 28577437 TI - Rutin exhibits hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease by reducing hepatic lipid levels and mitigating lipid-induced oxidative injuries. AB - Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic lipids and oxidative injury of hepatocytes. Rutin is a natural flavonoid with significant roles in combating cellular oxidative stress and regulating lipid metabolism. The current study aims to investigate the molecular mechanisms underlying rutin's hypolipidemic and hepatoprotective effects in nonalcoholic fatty liver disease. Rutin treatment was applied to male C57BL/6 mice maintained on a high-fat diet and HepG2 cells challenged with oleic acid. Hepatic lipid accumulation was evaluated by triglyceride assay and Oil Red O staining. Oxidative hepatic injury was assessed by malondialdehyde assay, superoxide dismutase assay and reactive oxygen species assay. The expression levels of various lipogenic and lipolytic genes were determined by quantitative real-time polymerase chain reactions. In addition, liver autophagy was investigated by enzyme-linked immunosorbent assay. In both fat-challenged murine liver tissues and HepG2 cells, rutin treatment was shown to significantly lower triglyceride content and the abundance of lipid droplets. Rutin was also found to reduce cellular malondialdehyde level and restore superoxide dismutase activity in hepatocytes. Among the various lipid-related genes, rutin treatment was able to restore the expression of peroxisome proliferator-activated receptor alpha (PPAR-alpha) and its downstream targets, carnitine palmitoyltransferase 1 and 2 (CPT-1 and CPT-2), while suppressing those of sterol regulatory element-binding protein 1c (SREBP-1c), diglyceride acyltransfase 1 and 2 (DGAT-1 and 2), as well as acyl-CoA carboxylase (ACC). In addition, rutin was shown to repress the autophagic function of liver tissues by down-regulating key autophagy biomarkers, including tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1beta). The experimental data demonstrated that rutin could reduce triglyceride content and mitigate oxidative injuries in fat-enriched hepatocytes. The hypolipidemic properties of rutin could be attributed to its ability to simultaneously facilitate fatty acid metabolism and inhibit lipogenesis. PMID- 28577438 TI - Schisandrin B inhibits LPS-induced inflammatory response in human umbilical vein endothelial cells by activating Nrf2. AB - Schisandrin B (SchB), an active ingredient extracted from Schisandra chinensis (Turcz.) Baill, has been known to have anti-oxidant and anti-inflammatory activities. In this study, we investigated the anti-inflammatory effects and mechanism of SchB in LPS-stimulated human umbilical vein endothelial cells (HUVECs). The effects of SchB on VCAM-1, ICAM-1, NF-kappaB and Nrf2 expression were detected by western blot analysis. The effects of SchB on TNF-alpha and IL-8 production were detected by ELISA. The results showed that SchB strongly suppressed the production of TNF-alpha and IL-8 in HUVECs stimulated with LPS. SchB also inhibited LPS-induced VCAM-1 and ICAM-1 expression. Furthermore, SchB blocked the activation of NF-kappaB induced by LPS. In addition, SchB increased the expression of Nrf2 and HO-1 in a concentration-dependent manner. And the inhibition of TNF-alpha and IL-8 production by SchB was blocked by transfection with Nrf2 siRNA. Our findings showed that SchB inhibited LPS-induced inflammation in HUVECs by activating Nrf2 signaling pathway. PMID- 28577440 TI - Effects of unstable footwear on gait characteristic: A systematic review. AB - BACKGROUND: Over the last three decades, several designs of unstable footwear have been developed in the forms of shoes, sandals and boots. There are marketing claims related to the positive effects of these shoes on the training of lower limb muscles and improving gait. Many studies have been performed on the effects of unstable footwear on muscle activity, balance, posture, energy expenditure, lower extremity disorders, and biomechanical changes. The analysis of the kinetics and kinematics characteristics of gait would provide objective representation of body movement. OBJECTIVE: To systematically review available evidence on the use of unstable footwear on kinetic and kinematic parameters to make specific recommendation for practice and future studies. METHOD: A computer based search was undertaken through PubMed, Cochrane Library, Embase, PEDro, Web of Science and Google Scholar from 2005 to 2015. The included studies were appraised using McMaster Critical Review Form for Quantitative Studies. RESULT: Ten studies (quasi-experimental design) were included. CONCLUSION: Considering kinetic and kinematic interaction of variables in the included studies revealed that confounding factors may have high impact on biomechanical findings of unstable footwear. Then, more homogeneous studies, considering these factors, should be implemented in future studies to inform the best clinical practice. PMID- 28577439 TI - Targeted alpha-Particle Radiation Therapy of HER1-Positive Disseminated Intraperitoneal Disease: An Investigation of the Human Anti-EGFR Monoclonal Antibody, Panitumumab. AB - Identifying molecular targets and an appropriate targeting vehicle, i.e., monoclonal antibodies (mAb) and their various forms, for radioimmunotherapy (RIT) remains an active area of research. Panitumumab, a fully human and less immunogenic mAb that binds to the epidermal growth factor receptor (Erb1; HER1), was evaluated for targeted alpha-particle radiation therapy using 212Pb, an in vivo alpha generator. A single dose of 212Pb-panitumumab administered to athymic mice bearing LS-174T intraperitoneal (i.p.) tumor xenografts was found to have greater therapeutic efficacy when directly compared with 212Pb-trastuzumab, which binds to HER2. A dose escalation study determined a maximum effective working dose of 212Pb-panitumumab to be 20MUCi with a median survival of 35 days versus 25 days for the untreated controls. Pretreatment of tumor-bearing mice with paclitaxel and gemcitabine 24hours prior to injection of 212Pb-pantiumumab at 10 or 20MUCi resulted in the greatest enhanced therapeutic response at the higher dose with median survivals of 106 versus 192 days, respectively. The greatest therapeutic impact, however, was observed in the animals that were treated with topotecan 24hours prior to RIT and then again 24hours after RIT; the best response from this combination was also obtained with the lower 10-MUCi dose of 212Pb-panitumumab (median survival >280 days). In summary, 212Pb-panitumumab is an excellent candidate for the treatment of HER1-positive disseminated i.p. disease. Furthermore, the potentiation of the therapeutic impact of 212Pb pantiumumab by chemotherapeutics confirms and validates the importance of developing a multimodal therapy regimen. PMID- 28577442 TI - The environmental impact of obesity: longitudinal evidence from the United States. AB - OBJECTIVE: This paper examines the relationship between obesity and greenhouse gas (GHG) emissions while accounting for the environmental impact of growth in transportation output and in crop and animal farming. STUDY DESIGN: The study makes use of US state-level longitudinal data over the 1997-2011 period. METHODS: Random effects and fixed effects estimators are employed within a multiple regression analysis framework. RESULTS: After controlling for other sources of emissions, there is evidence that the effect of transportation output on CO2 emissions worsens at obesity rates exceeding 33.7% and the effect on N2O emissions worsens at obesity rates exceeding 22.5%. In addition, the impact of crop and animal farming on N2O emissions worsens at obesity rates exceeding 20.2%. CONCLUSION: This paper provides significant and new insight about the causal link between obesity and environmental emissions and highlights the importance of addressing the obesity epidemic on public health and environmental grounds. Thus, mitigating GHG emissions connected to obesity requires joint effort between policymakers, public health officials, and parties from concerned economic sectors in pursuing remedial actions to reverse the current obesity trend. Various policy measures are discussed. PMID- 28577441 TI - Exploring disparities in incidence and mortality rates of breast and gynecologic cancers according to the Human Development Index in the Pan-American region. AB - OBJECTIVE: To evaluate whether a country's Human Development Index (HDI) can help explain the differences in the country's breast cancer and gynecological cancer incidence and mortality rates in the Pan-American region. STUDY DESIGN: Ecological analysis. METHODS: Pan-American region countries with publicly available data both in GLOBOCAN 2012 and the United Nations Development Report 2012 were included (n = 28). Incidence and mortality rates age-standardized per 100,000 were natural log-transformed for breast cancer, ovarian cancer, corpus uteri cancer, and cervical cancer. The mortality-to-incidence ratio (MIR) was calculated for each site. Pearson's correlation test and a simple linear regression were performed. RESULTS: The HDI showed a positive correlation with breast cancer and ovarian cancer incidence and mortality rates, respectively, and a negative correlation with cervical cancer incidence and mortality rates. The HDI and corpus uteri cancer showed no association. MIR and the HDI showed a negative correlation for all tumor types except ovarian cancer. An increment in 1 HDI unit leads to changes in cancer rates: in breast cancer incidence beta = 4.03 (95% confidence interval [CI] 2.61; 5.45) P < 0.001, breast cancer mortality beta = 1.76 (95% CI 0.32; 3.21) P = 0.019, and breast cancer-MIR beta = -0.705 (95% CI 0.704; 0.706) P < 0.001; in cervical cancer incidence beta = -3.28 (95% CI -4.78; -1.78) P < 0.001, cervical cancer mortality beta = -4.63 (95% CI -6.10; -3.17) P < 0.001, and cervical cancer-MIR beta = -1.35 (95% CI -1.83; -0.87) P < 0.001; in ovarian cancer incidence beta = 3.26 (95% CI 1.78; 4.75) P < 0.001, ovarian cancer mortality beta = 1.82 (95% CI 0.44; 3.20) P = 0.012, and ovarian cancer MIR beta = 5.10 (95% CI 3.22; 6.97) P < 0.001; in corpus uteri cancer incidence beta = 2.37 (95% CI -0.33; 5.06) P = 0.83, corpus uteri cancer mortality beta = 0.68 (95% CI -2.68; 2.82) P = 0.96, and corpus uteri cancer-MIR beta = -2.30 (95% CI -3.19; -1.40) P < 0.001. CONCLUSIONS: A country's HDI should be considered to understand disparities in breast cancer and gynecological cancer in the Pan American region. PMID- 28577443 TI - Re-working biographies: Women's narratives of pregnancy whilst living with epilepsy. AB - This paper explores the multiple ways experiences of pregnancy and early motherhood come to 'rework' the biographies of women living with epilepsy. Pregnancy is explored as a temporarily concurrent status alongside the long-term condition of epilepsy. Narrative interviews were conducted with 32 women from across the UK. Analysis of these narratives suggests that biographical disruption and continuity are both useful in the conceptualisation of women's diverse experiences of pregnancy and epilepsy. Such findings challenge the notion that the presence of a condition over a long period of time leads to the normalisation of illness. Participants' narratives demonstrate that, for some, pregnancy and early motherhood may be disruptive and can raise concerns regarding an ever present condition that may previously have been taken for granted. Findings also indicate the need for a greater consideration of gender and care responsibilities, as well explorations of concomitant conditions, in the theorising of biographies and chronic illness. PMID- 28577444 TI - Auditory processing deficits are sometimes necessary and sometimes sufficient for language difficulties in children: Evidence from mild to moderate sensorineural hearing loss. AB - There is a general consensus that many children and adults with dyslexia and/or specific language impairment display deficits in auditory processing. However, how these deficits are related to developmental disorders of language is uncertain, and at least four categories of model have been proposed: single distal cause models, risk factor models, association models, and consequence models. This study used children with mild to moderate sensorineural hearing loss (MMHL) to investigate the link between auditory processing deficits and language disorders. We examined the auditory processing and language skills of 46, 8 16year-old children with MMHL and 44 age-matched typically developing controls. Auditory processing abilities were assessed using child-friendly psychophysical techniques in order to obtain discrimination thresholds. Stimuli incorporated three different timescales (us, ms, s) and three different levels of complexity (simple nonspeech tones, complex nonspeech sounds, speech sounds), and tasks required discrimination of frequency or amplitude cues. Language abilities were assessed using a battery of standardised assessments of phonological processing, reading, vocabulary, and grammar. We found evidence that three different auditory processing abilities showed different relationships with language: Deficits in a general auditory processing component were necessary but not sufficient for language difficulties, and were consistent with a risk factor model; Deficits in slow-rate amplitude modulation (envelope) detection were sufficient but not necessary for language difficulties, and were consistent with either a single distal cause or a consequence model; And deficits in the discrimination of a single speech contrast (/balpha/ vs /dalpha/) were neither necessary nor sufficient for language difficulties, and were consistent with an association model. Our findings suggest that different auditory processing deficits may constitute distinct and independent routes to the development of language difficulties in children. PMID- 28577445 TI - Wormholes in virtual space: From cognitive maps to cognitive graphs. AB - Humans and other animals build up spatial knowledge of the environment on the basis of visual information and path integration. We compare three hypotheses about the geometry of this knowledge of navigation space: (a) 'cognitive map' with metric Euclidean structure and a consistent coordinate system, (b) 'topological graph' or network of paths between places, and (c) 'labelled graph' incorporating local metric information about path lengths and junction angles. In two experiments, participants walked in a non-Euclidean environment, a virtual hedge maze containing two 'wormholes' that visually rotated and teleported them between locations. During training, they learned the metric locations of eight target objects from a 'home' location, which were visible individually. During testing, shorter wormhole routes to a target were preferred, and novel shortcuts were directional, contrary to the topological hypothesis. Shortcuts were strongly biased by the wormholes, with mean constant errors of 37 degrees and 41 degrees (45 degrees expected), revealing violations of the metric postulates in spatial knowledge. In addition, shortcuts to targets near wormholes shifted relative to flanking targets, revealing 'rips' (86% of cases), 'folds' (91%), and ordinal reversals (66%) in spatial knowledge. Moreover, participants were completely unaware of these geometric inconsistencies, reflecting a surprising insensitivity to Euclidean structure. The probability of the shortcut data under the Euclidean map model and labelled graph model indicated decisive support for the latter (BFGM>100). We conclude that knowledge of navigation space is best characterized by a labelled graph, in which local metric information is approximate, geometrically inconsistent, and not embedded in a common coordinate system. This class of 'cognitive graph' models supports route finding, novel detours, and rough shortcuts, and has the potential to unify a range of data on spatial navigation. PMID- 28577446 TI - That's my hand! Therefore, that's my willed action: How body ownership acts upon conscious awareness of willed actions. AB - Whether and how body ownership ("this body is mine") contributes to human conscious experience of voluntary action is still unclear. In order to answer this question, here we incorporated two signatures (i.e., an ad hoc questionnaire and the sensory attenuation paradigm) of human's sense of agency ("this action is due to my own will") within a well-known experimental manipulation of body ownership (i.e., the rubber hand illusion paradigm). In two different experiments, we showed that the illusory ownership over a fake hand (induced by the rubber hand illusion) triggered also an illusory agency over its movements at both explicit and implicit level. Specifically, when the fake (embodied) hand pressed a button delivering an electrical stimulus to the participant's body, the movement was misattributed to participant's will (explicit level) and the stimulus intensity was attenuated (implicit level) exactly as it happened when the own hand actually delivered the stimulus. Our findings suggest that body ownership per se entails also motor representations of one's own movements. Whenever required by the context, this information would act upon agency attribution even prospectively (i.e., prior to action execution). PMID- 28577447 TI - Unconscious integration of multisensory bodily inputs in the peripersonal space shapes bodily self-consciousness. AB - Recent studies have highlighted the role of multisensory integration as a key mechanism of self-consciousness. In particular, integration of bodily signals within the peripersonal space (PPS) underlies the experience of the self in a body we own (self-identification) and that is experienced as occupying a specific location in space (self-location), two main components of bodily self consciousness (BSC). Experiments investigating the effects of multisensory integration on BSC have typically employed supra-threshold sensory stimuli, neglecting the role of unconscious sensory signals in BSC, as tested in other consciousness research. Here, we used psychophysical techniques to test whether multisensory integration of bodily stimuli underlying BSC also occurs for multisensory inputs presented below the threshold of conscious perception. Our results indicate that visual stimuli rendered invisible through continuous flash suppression boost processing of tactile stimuli on the body (Exp. 1), and enhance the perception of near-threshold tactile stimuli (Exp. 2), only once they entered PPS. We then employed unconscious multisensory stimulation to manipulate BSC. Participants were presented with tactile stimulation on their body and with visual stimuli on a virtual body, seen at a distance, which were either visible or rendered invisible. We found that participants reported higher self identification with the virtual body in the synchronous visuo-tactile stimulation (as compared to asynchronous stimulation; Exp. 3), and shifted their self location toward the virtual body (Exp.4), even if stimuli were fully invisible. Our results indicate that multisensory inputs, even outside of awareness, are integrated and affect the phenomenological content of self-consciousness, grounding BSC firmly in the field of psychophysical consciousness studies. PMID- 28577448 TI - Wettability alteration of oil-wet limestone using surfactant-nanoparticle formulation. AB - Wettability remains a prime factor that controls fluid displacement at pore-scale with substantial impact on multi-phase flow in the subsurface. As the rock surface becomes hydrophobic, any oleic phase present is tightly stored in the rock matrix and produced (hydrocarbon recovery) or cleaned up (soil decontamination) by standard waterflooding methods. Although surface active agents such as surfactants have been used for several decades for changing the wetting states of such rocks, an aspect that has been barely premeditated is the simultaneous blends of surfactants and nanoparticles. This study thus, systematically reports the behaviour of surfactants augmented nanoparticles on wettability alteration. Contact angle, spontaneous imbibition, and mechanistic approaches were adopted to assess the technical feasibility of the newly formulated wetting agents, tested over wide-ranging conditions to ascertain efficient wetting propensities. The contact angle measurement is in good agreement with the morphological and topographical studies and spontaneous imbibition. The wetting trends for the formulated systems indicate advancing and receding water contact angle decreased with increase in nanoparticle concentration and temperature, and the spontaneous water imbibition test also showed faster water-imbibing tendencies for nanoparticle-surfactant exposed cores. Thus, the new formulated nanoparticle-surfactant systems were considered suitable for enhancing oil recovery and soil-decontamination, particularly in fractured hydrophobic reservoirs. PMID- 28577449 TI - Thoracic spinal osteochondroma: A rare presentation of spinal cord compression. AB - Osteochondromas are the most common benign bone tumor typically seen in the appendicular skeleton and are rarely found in the spine. We present a case of an osteochondroma of the spine presenting with spinal cord compression. 27-year-old male presented with lower extremity weakness and paresthesia, decreased lower extremity sensation, and decreased proprioception. MRI showed a heterogeneous mass with minimal peripheral enhancement and without restricted diffusion. CT demonstrated a calcified mass extending from the left facet joint of T11-T12 with medial extension, resulting in severe central canal stenosis and cord compression. The patient underwent surgical resection with pathology demonstrating an osteochondroma. PMID- 28577451 TI - Optimization of the operation of packed bed bioreactor to improve the sulfate and metal removal from acid mine drainage. AB - The present study discusses the potentiality of using anaerobic Packed Bed Bioreactor (PBR) for the treatment of acid mine drainage (AMD). The multiple process parameters such as pH, hydraulic retention time (HRT), concentration of marine waste extract (MWE), total organic carbon (TOC) and sulfate were optimized together using Taguchi design. The order of influence of the parameters towards biological sulfate reduction was found to be pH > MWE > sulfate > HRT > TOC. At optimized conditions (pH - 7, 20% (v/v) MWE, 1500 mg/L sulfate, 48 h HRT and 2300 mg/L TOC), 98.3% and 95% sulfate at a rate of 769.7 mg/L/d. and 732.1 mg/L/d. was removed from the AMD collected from coal and metal mine, respectively. Efficiency of metal removal (Fe, Cu, Zn, Mg and Ni) was in the range of 94-98%. The levels of contaminants in the treated effluent were below the minimum permissible limits of industrial discharge as proposed by Bureau of Indian Standards (IS 2490:1981). The present study establishes the optimized conditions for PBR operation to completely remove sulfate and metal removal from AMD at high rate. The study also creates the future scope to develop an efficient treatment process for sulfate and metal-rich mine wastewater in a large scale. PMID- 28577450 TI - N-Acetylcysteine-induced vasodilatation is modulated by KATP channels, Na+/K+ ATPase activity and intracellular calcium concentration: An in vitro study. AB - BACKGROUND: In this study, we aimed to investigate the role of ATP-sensitive potassium (KATP) channel, Na+/K+-ATPase activity, and intracellular calcium levels on the vasodilatory effect of N-acetylcysteine (NAC) in thoracic aorta by using electrophysiological and molecular techniques. METHODS: Rat thoracic aorta ring preparations and cultured thoracic aorta cells were divided into four groups as control, 2mM NAC, 5mM NAC, and 10mM NAC. Thoracic aorta rings were isolated from rats for measurements of relaxation responses and Na+/K+-ATPase activity. In the cultured thoracic aorta cells, we measured the currents of KATP channel, the concentration of intracellular calcium and mRNA expression level of KATP channel subunits (KCNJ8, KCNJ11, ABCC8 and ABCC9). RESULTS: The relaxation rate significantly increased in all NAC groups compared to control. Similarly, Na+/K+- ATPase activity also significantly decreased in NAC groups. Outward KATP channel current significantly increased in all NAC groups compared to the control group. Intracellular calcium concentration decreased significantly in all groups with compared control. mRNA expression level of ABCC8 subunit significantly increased in all NAC groups compared to the control group. Pearson correlation analysis showed that relaxation rate was significantly associated with KATP current, intracellular calcium concentration, Na+/K+-ATPase activity and mRNA expression level of ABCC8 subunit. CONCLUSION: Our findings suggest that NAC relaxes vascular smooth muscle cells through a direct effect on KATP channels, by increasing outward K+ flux, partly by increasing mRNA expression of KATP subunit ABCC8, by decreasing in intracellular calcium and by decreasing in Na+/K+-ATPase activity. PMID- 28577452 TI - Green and efficient biosorptive removal of methylene blue by Abelmoschus esculentus seed: Process optimization and multi-variate modeling. AB - The present work explores, for the first time, the adsorptive removal of methylene blue (MB) dye from aqueous solution using different parts of abundantly available agricultural product, Abelmoschus esculentus (lady's finger), and the processed seed powder (designated as LFSP) was found as the best. The aforesaid biosorbent was characterized using field emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FTIR) and pHZPC analyses. The biosorption performance was evaluated using batch studies at 303 K, at varying operating conditions such as solution pH, biosorbent dosage, initial dye concentration and contact time. The pseudo-second order kinetic model was followed during the adsorption, and it was also found that intra-particle diffusion played a prominent role in the rate-controlling step. Langmuir and Temkin isotherms were followed the best, as was evident from the lower % non linear error values and higher degree of determination coefficients. Thermodynamic investigations revealed that the biosorption processes were spontaneous and endothermic. Using the response surface methodology (RSM), a central composite design was developed, and subsequently applied as an input for the artificial neural network (ANN) approach in order to further analyze the interactive term effects between the significant process parameters, on the maximum biosorption capacity for MB dye removal by LFSP. The non-linear error functions and linear regression coefficients on the RSM model showed its dominance behaviour over ANN model for both data fitting and estimation capabilities. Using the statistical optimization, the maximum uptake capacity was found to be 205.656 mg/g. Experiments were conducted to regenerate the adsorbent and to recover the adsorbed dye using the eluent 0.5 M HCl. Cost analysis showed that, LFSP was 7 times cheaper than commercially available activated carbons. PMID- 28577453 TI - Stabilization of arsenic and fluoride bearing spent adsorbent in clay bricks: Preparation, characterization and leaching studies. AB - The presence of arsenic and fluoride in groundwater has been observed throughout the world. Many technologies have been developed by various research groups in order to tackle this problem. Adsorption has emerged as one of the best possible technique for the removal of arsenic, fluoride and many other pollutants from drinking water. Although a considerable amount of work has been published on the adsorptive removal of arsenic and fluoride, the area related to the management of spent adsorbent is not well explored. Present paper deals with the adsorptive removal of arsenic and fluoride from aqueous solution by three different types of adsorbents, namely, thermally treated laterite (TTL), acid-base treated laterite (ABTL) and aluminum oxide/hydroxide nanoparticles (AHNP). Under the experimental conditions in batch operation, the adsorption capacities of TTL, ABLT and AHNP for arsenic are found to be 6.43 MUg/g, 9.25 MUg/g and 48.5 MUg/g respectively, whereas for fluoride, these values are found as 0.21 mg/g, 0.85 mg/g and 4.65 mg/g respectively. After adsorption, the spent adsorbents have been stabilized in the form of clay bricks. The effects of spent adsorbent concentration on the properties of bricks and their leaching properties are investigated. The bricks have been tested for various properties like density, percentage water absorption, shrinkage, compressive strength and efflorescence. The maximum values of density and shrinkage of the bricks formed are found as 2.3 g/cm3 and 10.2%, whereas the percentage water absorption and compressive strength of the bricks are found between 11 and 14% and 35 to 150 kgf/cm2 respectively. All the test results are in accordance with the criteria set by Indian Standards. The leaching test of arsenic and fluoride from the bricks reveals that their maximum values in leachate are 510 MUg/L and 2.1 mg/L respectively, which are below the permissible limits of USEPA standards. PMID- 28577454 TI - Evaluation of waste biomasses and their biochars for removal of polycyclic aromatic hydrocarbons. AB - This work evaluates the use of biomasses and their biochars as adsorbents to remove polycyclic aromatic hydrocarbons from water. Coconut waste (CW) and orange waste (OW) were pyrolyzed at 350 degrees C to produce the corresponding biochars (BCW and BOW). Adsorption tests using a mixed solution of benzo(a)anthracene, benzo(b)fluoranthene, benzo(k)fluoranthene, benzo(a)pyrene, and dibenzo(a,h)anthracene showed removal percentages of 30.33-83.43% (CW), 47.09 83.02% (BCW), 24.20-74.25% (OW), and 23.84-84.02% (BOW). The adsorption mechanisms appeared to involve pi-pi interactions of similar groups of the adsorbate and adsorbent, together with hydrophobic effects. There was no indication of competition between the PAHs for the adsorption sites, and there was evidence of cooperative adsorption. The PAHs could be desorbed from the adsorbents with efficiencies in the range 34.88-72.32%, and the reuse of the adsorbents in two further cycles demonstrated their potential for use in the removal of PAHs from water. PMID- 28577456 TI - DNA decontamination of fingerprint brushes. AB - Genetic profiling of DNA collected from fingerprints that have been exposed to various enhancement techniques is routine in many forensic laboratories. As a result of direct contact with fingermark residues during treatment, there is concern around the DNA contamination risk of dusting fingermarks with fingerprint brushes. Previous studies have demonstrated the potential for cross-contamination between evidentiary items through various mechanisms, highlighting the risk of using the same fingerprint brush to powder multiple surfaces within and between crime-scenes. Experiments were performed to assess the contamination risk of reused fingerprint brushes through the transfer of dried saliva and skin deposits from and to glass surfaces with new unused squirrel hair and fiberglass brushes. Additional new unused brushes and brushes previously used in casework were also tested for their ability to contaminate samples. In addition, the ability to eradicate DNA from used squirrel hair and fiberglass fingerprint brushes was assessed using a 1% sodium hypochlorite solution and a 5% solution of a commercially available alternative, Virkon. DNA profiling results from surfaces contacted by treated and untreated brushes were compared to determine the effectiveness of the devised cleaning protocol. Brush durability was also assessed over multiple wash/rinse/dry cycles with both agents. Varying amounts of DNA-containing material were collected and transferred by squirrel hair and fiberglass brushes, with detectability on the secondary surface dependent on the biological nature of the material being transferred. The impact of DNA contamination from dirty fingerprint brushes was most apparent in simulations involving the transfer of dried saliva and brushes previously used in casework, while minimal transfer of touch DNA was observed. Alarmingly, large quantities of DNA were found to reside on new unused squirrel hair brushes, while no DNA was detected on new unused fiberglass brushes or brushes sold as DNA-free. Squirrel hair brushes were easily and effectively cleaned with both hypochlorite and Virkon, with no evidence of DNA transfer between exhibits by treated brushes. Brushes were still deemed useable after multiple cleaning cycles with either agent. In contrast, fiberglass bristles became tangled and matted when wet and could not be cleaned effectively using either method. It is recommended they are disposed of following use. Each laboratory should consider their current circumstances before adapting a cleaning method. The implementation of a program to monitor the effectiveness of the cleaning regime is also advised. PMID- 28577455 TI - The treatment of chromium containing wastewater using electrocoagulation and the production of ceramic pigments from the resulting sludge. AB - This research experimentally investigates the treatment of authentic electroplating wastewater with high Cr(VI) content by electrocoagulation with the obtained sludge being reused as a raw material to produce inorganic pigments. A zero waste process is introduced to help conserve resources and to minimize environmental effects. The effects of operational parameters on electrocoagulation are determined in a batch stirred reactor using an iron electrode. The best performance was observed when a current density 20 mA/cm2, pH 2.4 and 0.05 M NaCl electrolyte were maintained. The initial Cr(VI) concentration of 1000 mg/L was almost completely abated (~100%) at an energy cost of 2.68 kWh/m3, fulfilling the EPA guideline of 2.77 mg/L within a single step process. The sludge was characterized using XRD and XRF showing that the sludge is a rich source of iron and chromium and can be reused to produce value added ceramic pigments. Pigments prepared in this way appeared to be reddish brown and black color in transparent glaze and were also characterized using XRD and XRF. In this study, a zero waste process is successfully introduced with ~100% Cr(VI) removal, with subsequent reuse of the resulting sludge. PMID- 28577457 TI - A qualitative study on feedback provided by students in nurse education. AB - BACKGROUND: This study aims to help nurse educators/academics understand the perspectives and expectations of students providing their feedback to educators about teaching performance and subject quality. AIM: The aim of this study is to reveal students' voices regarding their feedback in nurse education in order to shed light on how the current student feedback practice may be modified. DESIGN: A qualitative study using focus group inquiry. METHODS: Convenience sampling was adopted and participants recruited from one school of nursing in Hong Kong. A total of 66 nursing students from two pre-registration programs were recruited for seven focus group interviews: one group of Year 1 students (n=21), two groups of Year 3 students (n=27), and four groups of Final Year students (n=18). The interviews were guided by a semi-structured interview guideline and the interview narratives were processed through content analysis. The trustworthiness of this study was guaranteed through peer checking, research meetings, and an audit trail. The participants' privacy was protected throughout the study. RESULTS: Four core themes were discerned based on the narratives of the focus group interviews: (1) "timing of collecting feedback at more than one time point"; (2) "modify the questions being asked in collecting student feedback"; (3) "are electronic means of collecting feedback good enough?; and (4) "what will be next for student feedback?". CONCLUSIONS: This study is significant in the following three domains: 1) it contributed to student feedback because it examined the issue from a student's perspective; 2) it explored the timing and channels for collecting feedback from the students' point of view; and 3) it showed the preferred uses of student feedback. PMID- 28577458 TI - The "Hispanic mortality paradox" revisited: Meta-analysis and meta-regression of life-course differentials in Latin American and Caribbean immigrants' mortality. AB - The literature on immigrant health has repeatedly reported the paradoxical finding, where immigrants from Latin American countries to OECD countries appear to enjoy better health and greater longevity, compared with the local population in the host country. However, no previous meta-analysis has examined this effect focusing specifically on immigrants from Latin America (rather than Hispanic ethnicity) and we still do not know enough about the factors that may moderate the relationship between immigration and mortality. We conducted meta-analyses and meta-regressions to examine 123 all-cause mortality risk estimates and 54 cardiovascular mortality risk estimates from 28 publications, providing data on almost 800 million people. The overall results showed that the mean rate ratio (RR) for immigrants vs. controls was 0.92 (95% CI, 0.84-1.01) for all-cause mortality and 0.73 (CI, 0.67-0.80) for cardiovascular mortality. While the overall results suggest no immigrant mortality advantage, studies that used only native born persons as controls did find a significant all-cause mortality advantage (RR, 0.86; 95% CI, 0.76-0.97). Furthermore, we found that the relative risk of mortality largely depends on life course stages. While the mortality advantage is apparent for working-age immigrants, it is not significant for older age immigrants and the effect is reversed for children and adolescents. PMID- 28577459 TI - Nurse practitioners as primary care providers with their own patient panels and organizational structures: A cross-sectional study. AB - BACKGROUND: Health care systems globally are facing challenges of meeting the growing demand for primary care services due to a shortage of primary care physicians. Policy makers and administrators are searching for solutions to increase the primary care capacity. The effective utilization of nurse practitioners (NPs) has been proposed as a solution. However, organizations utilize NPs in variable capacities. In some settings, NPs serve as primary care providers delivering ongoing continuous care to their patients, referred to as patient panels, whereas in other settings they deliver episodic care. Little is known about why organizations deploy NPs differently. OBJECTIVES: Investigate the NP role in care delivery-primary care providers with the own patient panels or delivering episodic care-within their organizations and understand how work environments affect their role. DESIGN: A cross-sectional survey design was used to collect data from primary care NPs. SETTINGS: The study was conducted in one state in the United States (Massachusetts). Data from 163 primary care organizations was obtained, which employed between one to 12 NPs. PARTICIPANTS: 807 NPs recruited from the Massachusetts Provider Database received mail surveys; 314 completed and returned the survey, yielding a response rate of 40%. METHODS: The survey contained measures of NP role in care delivery and work environment. NP role was measured by an item asking NPs to report if they deliver ongoing continuous care to their patient panel or if they do not have patient panel. The work environment was measured with the Nurse Practitioner Primary Care Organizational Climate Questionnaire (NP-PCOCQ). The multilevel Cox regression models investigated the influence of organization-level work environment on NP role in care delivery. RESULTS: About 45% of NPs served as primary care providers with their own patient panel. Organization-level Independent Practice and Support subscale, an NP-PCOCQ subscale, had a significant positive effect on NP role (risk ratio=2.33; 95% CI: 1.06-5.13); with a one unit increase on this subscale, the incidence of the NPs serving as primary care providers with their own patient panel doubled. CONCLUSIONS: NPs can help meet the increasing demand for primary care by taking responsibilities as primary care providers, and organizations can assign NPs their own patient panels. Supporting NP independent practice within organizations promotes NP role as primary care providers. Policy and organizational change focused on promoting NP work environments so NPs can practice as primary care providers can be an effective strategy to increase the primary care capacity. PMID- 28577460 TI - Fabrication of alpha-FeOOH decorated graphene oxide-carbon nanotubes aerogel and its application in adsorption of arsenic species. AB - Arsenic pollution has caused worldwide attention due to its mandatory toxicity. Chemical structures of the adsorbent and arsenic species greatly influence the arsenic adsorption efficiency. The goethite impregnated graphene oxide (GO) carbon nanotubes (CNTs) aerogel (alpha-FeOOH@GCA) was prepared via a facile self assembly method of GO-CNTs induced by in-situ Fe2+ reduction. alpha-FeOOH@GCA showed excellent adsorption capacities of 56.43, 24.43 and 102.11mgg-1 for As(V), DMA and p-ASA comparing with that of 25.71, 8.03 and 14.52mgg-1 of pristine alpha FeOOH, respectively. The incorporation of GO-CNTs not only hinders the aggregation of GO-CNTs but also inhibits the growth of alpha-FeOOH nanoparticles greatly facilitating the diffusion and adsorption capacity of arsenic species. alpha-FeOOH@GCA shows wide favorable application pH for arsenic species adsorption, high adsorption kinetics and excellent reusability. The phosphate and silicate anions compete with the arsenic species for active adsorption sites due to the similar anionic structure. Based on FTIR spectra, arsenic species were proven to form inner sphere complex on the surface of alpha-FeOOH@GCA through different ligand exchanging mechanism greatly dependent on the molecular structures of arsenic species. The results show that alpha-FeOOH@GCA could be used as promising adsorbent for arsenic purification in water system. PMID- 28577461 TI - Gold nanoparticle and graphene oxide incorporated strontium crosslinked alginate/carboxymethyl cellulose composites for o-nitroaniline reduction and Suzuki-Miyaura cross-coupling reactions. AB - Self-organized strontium ion crosslinked alginate/carboxymethyl cellulose composite materials with gold nanoparticles (Au-NPs) and graphene oxide (GO) were effectively fabricated using dissipative convective procedures followed by the freeze-drying method. Composite gels were characterized by using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscopy with Energy dispersive X-ray analysis (SEM-EDAX) and transmission electron microscopy (TEM) analysis. Moreover, thermal, mechanical and rheological properties were also performed to identify their strength and stability. The results revealed that Sr/Alg/CMC/Au and Sr/Alg/CMC/GO/Au composites showed remarkably porous structures with ordered capillaries; rheologically gel-like structures with high mechanical strength. Moreover, composites were tested for the reduction of o-nitroaniline and Suzuki-Miyaura cross-coupling reaction. The Sr/Alg/CMC/GO/Au composite competently reduced the o nitroaniline within 2min (k=4.86*10-2s-1) with recyclability up to 7 consecutive cycles and also displayed 98% isolated yield (TOF value is 4900h-1) for Suzuki Miyaura cross-coupling reaction with 6cycles recyclability. This approach of using nanoparticles incorporated composite systems as reusable catalysts opens a door of new materials for various catalytic applications. PMID- 28577463 TI - Stabilisation of water-in-water emulsions by montmorillonite platelets. AB - The formation of water-in-water emulsions from the aqueous two phase system containing polyethylene oxide and pullulan, stabilised by montmorillonite platelets, was investigated. A novel approach of preparing the emulsions at non equilibrium polymer concentrations was successfully utilised to control viscosity during mixing and allow the use of low energy emulsification methods. Polyethylene oxide adsorbed to the platelets much more strongly than pullulan favouring the formation of pullulan-in-polyethylene oxide emulsions which remained stable for a period of weeks. Polarising microscopy and small angle light scattering were used to show that droplets were most likely stabilised against coalescence by the adsorption of randomly oriented aggregates of platelets and against creaming by the formation of chains of droplets bridged by the adsorbed aggregates. Montmorillonite platelets were therefore shown to stabilise water-in-water emulsions and their preference for emulsion type was driven by the adsorption of the polymers to the particle surface. PMID- 28577462 TI - One-pot preparation of ternary reduced graphene oxide nanosheets/Fe2O3/polypyrrole hydrogels as efficient Fenton catalysts. AB - Ternary reduced graphene oxide nanosheets (rGSs)/Fe2O3/polypyrrole (PPy) hydrogels with Fe2O3 nanoparticles (NPs) embedded between rGSs and PPy layer were prepared in one-pot. The ternary hydrogels exhibited an interconnected and porous three-dimensional network with co-existence of macropores and mesopores. Fe2O3 NPs uniformly dispersed on rGS surface with the diameter of 8.8nm. Control experiments were carried out to investigate the roles of components in formation of ternary hydrogels. During heterogeneous Fenton degradation of methylene blue (MB) dyes, the ternary hydrogels exhibited much better removal efficiency than the reference samples, not only because rGSs and PPy layer altered the adsorption, dispersity and diameter of Fe2O3 NPs; but also owing to the structural merits of ternary hydrogels. The effects of operating conditions, such as initial MB concentrations, dosages of catalysts and H2O2, were carefully investigated. With the help of Fe2O3 NPs, ternary rGSs/Fe2O3/PPy hydrogels could be easily separated via a magnet. In recycling experiments, they showed superior reusability. PMID- 28577464 TI - Ag filament induced nonvolatile resistive switching memory behaviour in hexagonal MoSe2 nanosheets. AB - In this work, hexagonal MoSe2 nanosheets were prepared by hydrothermal process. Next, the resistive switching memory behaviour of single MoSe2 nanosheets was further investigated. We observed that MoSe2 nanosheets based memory device show reproducible and stable bipolar resistive switching memory characteristics. Through the analysis for conductive mechanism, the formation and rupture of nanoscale Ag filament inside the MoSe2 nanosheets is suggested to explain the memory behaviour. PMID- 28577465 TI - Nanocomposites based on banana starch reinforced with cellulose nanofibers isolated from banana peels. AB - Cellulose nanofibers were isolated from banana peel using a combination of chemical and mechanical treatments with different number of passages through the high-pressure homogenizer (0, 3, 5, and 7 passages). New nanocomposites were then prepared from a mixed suspension of banana starch and cellulose nanofibers using the casting method and the effect of the addition of these nanofibers on the properties of the resulting nanocomposites was investigated. The cellulose nanofibers homogeneously dispersed in the starch matrix increased the glass transition temperature, due to the strong intermolecular interactions occurring between the starch and cellulose. The nanocomposites exhibited significantly increased the tensile strength, Young's modulus, water-resistance, opacity, and crystallinity as the number of passages through the homogenizer augmented. However, a more drastic mechanical treatment (seven passages) caused defects in nanofibers, deteriorating the nanocomposite properties. The most suitable mechanical treatment condition for the preparation of cellulose nanofibers and the corresponding nanocomposite was five passages through the high-pressure homogenizer. In general, the cellulose nanofibers improved the features of the starch-based material and are potentially applicable as reinforcing elements in a variety of polymer composites. PMID- 28577466 TI - Synthesis of functionalized MgAl-layered double hydroxides via modified mussel inspired chemistry and their application in organic dye adsorption. AB - In this paper, a novel strategy for the preparation of poly(levodopa) functionalized MgAl-layered double hydroxide (PDOPA-f-LDH) was developed based on the modified mussel inspired chemistry. The utilization of PDOPA-f-LDH for the removal of methylene blue (MB) from aqueous solution was also examined. Taken advantage of the self-polymerization of levodopa (DOPA) in alkaline solution and the strong affinity of catechol groups to the substrate surface, the LDH was covered homogeneously by a layer of polymer coating of DOPA, leading to the functionalization toward LDH. The structure, surface morphology, thermostability and elemental composition of as-prepared PDOPA-f-LDH were investigated by the transmission electron microscope, scanning electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and X-ray photoelectron spectroscopy. Besides, the surface charge of the PDOPA-f-LDH was also investigated using zeta potential. The effects of various parameters, including contact time, initial MB concentration, solution pH and temperature, on the adsorption of MB onto PDOPA-f-LDH were systematically investigated. Results show that the adsorption capacity of functionalized LDH at 25 degrees C could reach up to 102mg/g, which is much higher than that of pure LDH in the same experimental conditions. The adsorption kinetics and isotherm of MB adsorption were studied in batch experiments. The pseudo-second-order model is found to be the best to describe the adsorption kinetics. The isotherm result shows that the Freundlich isotherm is the better-fit-isotherm model to represent the equilibrium data. The values of thermodynamic parameters, including enthalpy change DeltaH0, entropy change DeltaS0 and Gibbs free energy change DeltaG0, were also determined. All the DeltaG0 values are negative; the DeltaH0 and DeltaS0 values of PDOPA-f-LDH were -7.824kJmol-1 and -0.01562kJmol-1K-1, respectively. And the activation energy of system (Ea) is calculated as 24.69kJmol-1. The fact suggests that the MB adsorption on PDOPA-f-LDH is a spontaneous and exothermic process. These obtained results indicate that the prepared PDOPA-f-LDH could be used as an interesting adsorbent with great potential to adsorb the cationic dyeing pollutants from aqueous media. PMID- 28577467 TI - Ag/AgCl nanoparticles-modified CdSnO3.3H2O nanocubes photocatalyst for the degradation of methyl orange and antibiotics under visible light irradiation. AB - CdSnO3.3H2O (CSH) nanocubes modified with Ag/AgCl nanoparticles were constructed via the ultrasonic-assisted precipitation-photoreduction method. The obtained samples were characterized using various analytical techniques. Methyl orange (MO), tetracycline (TC), and oxytetracycline hydrochloride (OTC-HCl) were degraded as target pollutants under visible light irradiation to evaluate the photocatalytic activity of the as-prepared samples. Compared with pure CSH and Ag/AgCl nanoparticles, the developed composite of which 5mL of AgNO3 was added on the synthesis, labelled as 5-Ag/AgCl/CSH, occupied the best photocatalytic activity. The corresponding degradation rate for MO was 94% within 40min. 94% of TC and 90% of OTC-HCl were also degraded by 5-Ag/AgCl/CSH catalyst within 60min, respectively. The enhanced photocatalytic activity might arise from the surface plasmon resonance effect of Ag/AgCl nanoparticles and efficient separation of photogenerated electron-hole pairs. Meanwhile, a possible photocatalytic mechanism over 5-Ag/AgCl/CSH sample was proposed based on the experiment and theoretical analysis. PMID- 28577468 TI - Wake-sleep circuitry: an overview. AB - Although earlier models of brain circuitry controlling wake-sleep focused on monaminergic and cholinergic arousal systems, recent evidence indicates that these play mainly a modulatory role, and that the backbone of the wake-sleep regulatory system depends upon fast neurotransmitters, such as glutmate and GABA. We review here recent advances in understanding the role these systems play in controlling sleep and wakefulness. PMID- 28577470 TI - Ankle-foot orthosis bending axis influences running mechanics. AB - Passive-dynamic ankle-foot orthoses (AFOs) are commonly prescribed to improve locomotion for people with lower limb musculoskeletal weakness. The clinical prescription and design process are typically qualitative and based on observational assessment and experience. Prior work examining the effect of AFO design characteristics generally excludes higher impact activities such as running, providing clinicians and researchers limited information to guide the development of objective prescription guidelines. The proximal location of the bending axis may directly influence energy storage and return and resulting running mechanics. The purpose of this study was to determine if the location of an AFO's bending axis influences running mechanics. Marker and force data were recorded as 12 participants with lower extremity weakness ran overground while wearing a passive-dynamic AFO with posterior struts manufactured with central (middle) and off-centered (high and low) bending axes. Lower extremity joint angles, moments, powers, and ground reaction forces were calculated and compared between limbs and across bending axis conditions. Bending axis produced relatively small but significant changes. Ankle range of motion increased as the bending axis shifted distally (p<0.003). Peak ankle power absorption was greater in the low axis than high (p=0.013), and peak power generation was greater in the low condition than middle or high conditions (p<0.009). Half of the participants preferred the middle bending axis, four preferred low and two preferred high. Overall, if greater ankle range of motion is tolerated, a low bending axis provides power and propulsive benefits during running, although individual preference and physical ability should also be considered. PMID- 28577469 TI - The interaction between HIV-1 Nef and adaptor protein-2 reduces Nef-mediated CD4+ T cell apoptosis. AB - Acquired Immune Deficiency Syndrome is characterized by a decline in CD4+ T cells. Here, we elucidated the mechanism underlying apoptosis in Human Immunodeficiency Virus-1 (HIV-1) infection by examining host apoptotic pathways hijacked by the HIV-1 Nef protein in the CD4+ T-cell line Sup-T1. Using a panel of Nef mutants unable to bind specific host proteins we uncovered that Nef generates pro- and anti-apoptotic signals. Apoptosis increased upon mutating the motifs involved in the interaction of Nef:AP-1 (NefM20A or NefEEEE62-65AAAA) or Nef:AP-2 (NefLL164/165AA), implying these interactions limit Nef-mediated apoptosis. In contrast, disrupting the Nef:PAK2 interaction motifs (NefH89A or NefF191A) reduced apoptosis. To validate further, apoptosis was measured after short-hairpin RNA knock-down of AP-1, AP-2 and PAK2. AP-2alpha depletion enhanced apoptosis, demonstrating that disrupting the Nef:AP-2alpha interaction limits Nef mediated apoptosis. Collectively, we describe a mechanism by which HIV-1 regulates cell survival and demonstrate the consequence of interfering with Nef:host protein interactions. PMID- 28577471 TI - Men and women show similar survival outcome in stage IV breast cancer. AB - PURPOSE: To evaluate the clinicopathological features, patterns of distant metastases, and survival outcome between stage IV male breast cancer (MBC) and female breast cancer (FBC). METHODS: Patients diagnosed with stage IV MBC and FBC between 2010 and 2013 were included using the Surveillance, Epidemiology, and End Results program. Univariate and multivariate Cox regression analyses were used to analyze risk factors for overall survival (OS). RESULTS: A total of 4997 patients were identified, including 60 MBC and 4937 FBC. Compared with FBC, patients with MBC were associated with a significantly higher rate of estrogen receptor positive, progesterone receptor-positive, unmarried, lung metastases, and a lower frequency of liver metastases. Univariate and multivariate analyses showed no significant difference in OS between MBC and FBC. In the propensity score-matched population, there was also no difference in survival between MBC and FBC. Multivariate analysis of MBC showed that OS was longer for patients aged 50-69 years and with estrogen receptor-positive disease. CONCLUSIONS: There was no significant difference in survival outcome between stage IV MBC and FBC, but significant differences in clinicopathological features and patterns of metastases between the genders. PMID- 28577472 TI - General movement trajectories and neurodevelopment at 3months of age following neonatal surgery. AB - BACKGROUND: Neonates who undergo major surgery are at risk of neurodevelopmental disability. The General Movements Assessment (GMA) is a valid and reliable method to predict neurodevelopment, however, there are minimal data on the applicability among infants post-surgery. AIM: To describe GMs trajectories following neonatal surgery. STUDY DESIGN: Prospective cohort study. SUBJECTS: 217 infants following major cardiac and non-cardiac neonatal surgery. OUTCOME MEASURES: Infants were assessed following surgery at term age (mean 40weeks, SD 2.3), and at 3months of age (mean 12weeks, SD 1.6) using the GMA and the Bayley Scales of Infant and Toddler Development III. GMA videos were independently scored by three advanced trained assessors, two blinded to infant details. RESULTS: The most common result in the writhing period was 'poor repertoire' (n=117, 54%), however, 99 (84%) of these infants had normal fidgety movements. For infants with normal writhing (n=75, 34%), only four had absent fidgety movements. Cramped synchronised movements were seen in 10 infants, and three of these were rated as absent fidgety. There was no significant difference between the surgical groups. In total, 24 infants (11%) had absent fidgety movements and lower scores on average in all subtests of the BSID-III than those with normal fidgety movements. CONCLUSIONS: This is the first report describing GMs trajectories in infants who have undergone neonatal surgery. Similar to other high risk infant populations, this group showed a high proportion of poor repertoire writhing movements, however, most infants demonstrated normal fidgety movements and development at 3months of age. PMID- 28577473 TI - Alexithymia and depression in patients with fibromyalgia: When the whole is greater than the sum of its parts. AB - This study investigated the link between alexithymia and depressive symptoms in Fibromyalgia (FM). 181 FM women and 181 healthy controls (HC) were compared using the Hospital Anxiety and Depression Scale and the Toronto Alexithymia Scale. A moderation analysis was performed to examine the moderation effect of the group (FM vs. HC) on the relationship between alexithymia and depression. Group was a significant moderator, highlighting a stronger relationship between alexithymia and depressive symptoms in the FM compared to HC. The study highlighted that the association between alexithymia and depression is different when we consider FM patients rather than the healthy population. PMID- 28577474 TI - Promiscuous viruses-how do viruses survive multiple unrelated hosts? AB - Arthropod-borne viruses (arboviruses) require efficient replication in taxonomically divergent hosts in order to perpetuate in nature. This review discusses recent advances in our understanding of the phylogenetic position of arthropod-borne viruses relative to insect-specific viruses, which appear to be more common and ecological requirements for successful adoption of the 'arbovirus phenotype.' Several molecular and other mechanisms that permit replication in divergent hosts are also discussed. PMID- 28577475 TI - Needle-guided ultrasound technique for axillary artery catheter placement in critically ill patients: A case series and technique description. AB - PURPOSE: Axillary arterial cannulation for blood pressure monitoring has been reported in adults since 1973. Reported failure rates using palpation landmarks are high. This report describes a needle-guided ultrasound technique for axillary arterial line placement in critically ill patients. METHODS: A retrospective review of all patients requiring axillary arterial cannulation attempts with ultrasound-assisted needle guidance for hemodynamic monitoring was performed from July 2010 to June 2016 at a single institution. RESULTS: One hundred fifty nine (159) cannulation attempts were performed in 155 patients. The overall success rate was 97%, with a first pass success rate of 84%. Inexperienced operators performed 49% of procedures under direct faculty supervision, and had a 99% success rate, which was not different from experienced operators. Almost 20% of patients had moderate-to-severe coagulopathy (platelets<50k/uL, INR>2.0 or PTT>60s). Complications reported included the following: nonfunctioning of catheter (6%) and hematoma (6%). Ischemia was noted in 2 patients (1%), but only one was attributed to the arterial catheter. CONCLUSIONS: Use of the needle guided ultrasound assisted approach for axillary arterial line placement is easily teachable and can be used to promote safe and successful placement of axillary arterial lines for novice learners. PMID- 28577476 TI - Concurrent intravenous drug administration to critically ill children: Evaluation of frequency and compatibility. AB - PURPOSE: To evaluate the frequency of concurrent drug administration and drug drug incompatibility of concurrently administered drugs in critically ill children based on available references. MATERIALS AND METHODS: We retrospectively evaluated concurrent intravenous drug administration in children admitted to a single centre. Eligible patients included those admitted to the critical care unit for at least 6-hours in the ten-year period ending 30 July 2015 and received two or more IV drug administrations. Compatibilities were classified using local reference documents. RESULTS: The 16,863 eligible patients were admitted to ICU for 2,212,326h and received 3,664,667 concurrent administrations. Concurrent infusions ran for 6,263,600h. There were 2,284,066 (62%) concurrent administrations; 334,144 (9%) were compatible, 293,856 (8%) were incompatible, 293,856 (8%) required pharmacist consultation, and 752,601 (21%) had 'unknown' compatibility. Individual patients received a median (IQR) of 33 (10-132) concurrent administrations, comprised of 7 (1-30) concurrent injections 1 (0-5) concurrent infusions and 13 (0-74) concurrently administered injections and infusions. CONCLUSIONS: Concurrent IV-drug administration is frequent in critically ill children. Known incompatible concurrent administration occurs, however the compatibilities of many drug-drug pairs were unknown - adding complexity to routine bedside management and identifying information gaps for future research. PMID- 28577477 TI - Is 'gut feeling' by medical staff better than validated scores in estimation of mortality in a medical intensive care unit? - The prospective FEELING-ON-ICU study. AB - PURPOSE: The aim of the FEELING-ON-ICU study was to compare mortality estimations of critically ill patients based on 'gut feeling' of medical staff and by Acute Physiology And Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS) II and Sequential Organ Failure Assessment (SOFA). MATERIALS AND METHODS: Medical staff estimated patients' mortality risks via questionnaires. APACHE II, SAPS II and SOFA were calculated retrospectively from records. Estimations were compared with actual in-hospital mortality using receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC). RESULTS: 66 critically ill patients (60.6% male, mean age 63+/-15years (range 30 86)) were evaluated each by a nurse (n=66, male 32.4%) and a physician (n=66, male 67.6%). 15 (22.7%) patients died on the intensive care unit. AUC was largest for estimations by physicians (AUC 0.814 (95% CI 0.705-0.923)), followed by SOFA (AUC 0.749 (95% CI 0.629-0.868)), SAPS II (AUC 0.723 (95% CI 0.597-0.849)), APACHE II (AUC 0.721 (95% CI 0.595-0.847)) and nursing staff (AUC 0.669 (95% CI 0.529-0.810)) (p<0.05 for all results). CONCLUSIONS: The concept of physicians' 'gut feeling' was comparable to classical objective scores in mortality estimations of critically ill patients. Concerning practicability physicians' evaluations were advantageous to complex score calculation. PMID- 28577478 TI - Association between advanced practice nursing and 30-day mortality in mechanically ventilated critically ill patients: A retrospective cohort study. AB - PURPOSE: Little is known about the association between advanced practice nursing and mortality. The aim of this study was to evaluate whether the presence of advanced practice nurses (APN), that is, certified nurse (CN) and certified nurse specialist (CNS) in intensive care, is associated with 30-day mortality for mechanically ventilated critically ill patients. MATERIALS AND METHODS: Using a Japanese national in-patient database, we identified 45,620 patients who were admitted to an intensive care unit (ICU) and received mechanical ventilation within 2 days of hospital admission between 1 April 2014 and 31 March 2015. We assessed the association between the number of CN/CNSs per 10 adult ICU beds and 30-day mortality. RESULTS: We examined 8955 patients in 134 hospitals without CN/CNSs and 36,665 in 284 hospitals with CN/CNSs. Overall, the number of CN/CNSs per 10 adult ICU beds ranged from 0 to 7.5. In the multivariable analysis, the number of CN/CNSs per 10 adult ICU beds was significantly associated with a reduction in 30-day mortality (adjusted odds ratio 0.97; 95% confidence interval, 0.94-1.00; P=0.023). CONCLUSIONS: Our findings show that APNs may play an important role in improving patient outcome in the adult ICU. PMID- 28577479 TI - Characterization of a beta-glucosidase from Paenibacillus species and its application for succinic acid production from sugarcane bagasse hydrolysate. AB - In this study, a beta-glucosidase from Paenibacillus sp. M1 was expressed in E. coli BL21(DE3), purified and characterized. The specific activity of purified BglA was 137.64U.mg-1 protein with optimal temperature and pH of 50 degrees C and 6.0. Furthermore, BglA shows excellent adaption to various environmental factors such as temperature, pH and metal ions. Engineered E. coli Suc260 was further reconstructed by overexpressing the beta-glucosidase for achieving direct cellobiose utilization, which could efficiently utilize the pretreated sugarcane bagasses hydrolysate (SBH) consisting of 25.30g.L-1 cellobiose, 9.70g.L-1 glucose, 5.90g.L-1 arabinose and 7.10g.L-1 xylose. As a result, 26.50g.L-1 and 24.30g.L-1 succinic acid were produced by strain Suc260(pTbglA) from cellobiose and SBH with corresponding yields of 88.30% and 89.20% using dual-phase fermentation, respectively. This study indicated that incomplete enzymatic hydrolysate of SCB will be a potential feedstock for succinic acid production. PMID- 28577480 TI - A novel glycosylated solution from Dioscorea zingiberensis C.H. Wright significantly improves the solvent productivity of Clostridium beijerinckii. AB - The economics of bio-solvent production are largely dependent on the cost of the fermentation substrate. Dioscorea zingiberensis C.H. Wright (DZW), the main raw material used to produce saponin, contains 13-18% starch which can be directly saccharified to a saccharification liquid of DZW starch (SLDS) that contains abundant nutrients. In this study, the water-soluble micromolecule compounds in SLDS were quantified through 1H NMR. Using SLDS as the substrate to conduct ABE fermentation by Clostridium beijerinckii, the fermentation cycle was shortened 24h, the maximum biomass and consumption rate of the glucose significantly increased, and the productivity of total solvents were increased by 0.244+/ 0.010g/L/h compared to standard P2 medium. Expression analysis of genes encoding key enzymes involved in acetone and butanol production and glucose consumption showed that they were induced by SLDS. Taken together, SLDS is a useful and renewable glycosylated solution for ABE fermentation. PMID- 28577481 TI - A simple method for preparing a binder-free paper-based air cathode for microbial fuel cells. AB - In this paper, we proposed a simple method for preparing a binder-free air cathode using carbonized kraft paper as the support and iron (II) phthalocyanine (FePc) as the catalyst. The results indicated that the oxygen reduction reaction (ORR) performance of the air-cathodes was dependent on the fabrication steps. A cathode (KP-HT-FePc-HT) fabricated by pyrolyzing kraft paper at 1000 degrees C followed by FePc heat treatment at 700 degrees C showed the highest Pmax of 830+/ 31mWm-2 compared to FePc/KP-HT (363+/-48mWm-2) prepared by direct pyrolysis. X ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Raman spectroscopy and electrochemical tests showed that the superior electrocatalytic activity of KP-HT-FePc-HT was attributable to its higher content of pyridinic-N. This study demonstrated that the FePc/KP-based binder-free air-cathode had the advantages of low cost, easy fabrication, environmental benefits, and good scalability and therefore could serve as a good alternative for the air-cathode of MFCs. PMID- 28577482 TI - Microbial monitoring of ammonia removal in a UASB reactor treating pre-digested chicken manure with anaerobic granular inoculum. AB - Performance and microbial community dynamics in an upflow anaerobic sludge bed (UASB) reactor coupled with anaerobic ammonium oxidizing (Anammox) treating diluted chicken manure digestate (Total ammonia nitrogen; TAN=123+/-10mg/L) were investigated for a 120-d operating period in the presence of anaerobic granular inoculum. Maximum TAN removal efficiency reached to above 80% with as low as 20mg/L TAN concentrations in the effluent. Moreover, total COD (tCOD) with 807+/ 215mg/L in the influent was removed by 60-80%. High-throughput sequencing revealed that Proteobacteria, Actinobacteria, and Firmicutes were dominant phyla followed by Euryarchaeota and Bacteroidetes. The relative abundance of Planctomycetes significantly increased from 4% to 8-9% during the late days of the operation with decreased tCOD concentration, which indicated a more optimum condition to favor ammonia removal through anammox route. There was also significant association between the hzsA gene and ammonia removal in the UASB reactor. PMID- 28577483 TI - Evaluation of agricultural residues pyrolysis under non-isothermal conditions: Thermal behaviors, kinetics, and thermodynamics. AB - The thermal conversion characteristics, kinetics, and thermodynamics of agricultural residues, rape straw (RS) and wheat bran (WB), were investigated under non-isothermal conditions. TGA experiments showed that the pyrolysis characteristics of RS were quite different from those of WB. As reflected by the comprehensive devolatilization index, when the heating rate increased from 10 to 30Kmin-1, the pyrolysis performance of RS and WB were improved 5.27 and 5.96 times, respectively. The kinetic triplets of the main pyrolysis process of agricultural residues were calculated by the Starink method and the integral master-plots method. Kinetic analysis results indicated that the most potential kinetic models for the pyrolysis of RS and WB were D2 and F2.7, respectively. The thermodynamic parameters (DeltaH, DeltaG, and DeltaS) were determined by the activated complex theory. The positive DeltaH, positive DeltaG, and negative DeltaS at characteristic temperatures validated that the pyrolysis of agricultural residues was endothermic and non-spontaneous. PMID- 28577484 TI - Effect of ensiling and silage additives on biogas production and microbial community dynamics during anaerobic digestion of switchgrass. AB - Silage processing has a crucial positive impact on the methane yield of anaerobic treated substrates. Changes in the characteristics of switchgrass after ensiling with different additives and their effects on methane production and microbial community changes during anaerobic digestion were investigated. After ensiling (CK), methane yield was increased by 33.59% relative to that of fresh switchgrass (FS). In comparison with the CK treatment, methane production was improved by 17.41%, 13.08% and 8.72% in response to ensiling with LBr+X, LBr and X, respectively. A modified Gompertz model predicted that the optimum treatment was LBr+X, with a potential cumulative methane yield of 178.31mL/g total solids (TS) and a maximum biogas production rate of 44.39mL/g TS.d. Firmicutes and Bacteroidetes were the predominant bacteria in FS and silage switchgrass; however, the switchgrass treated with LBr+X was rich in Synergistetes, which was crucial for methane production. PMID- 28577485 TI - Polishing of anaerobic secondary effluent by Chlorella vulgaris under low light intensity. AB - To investigate anaerobic secondary effluent polishing by microalgae (Chlorella vulgaris) under low light intensity (14MUmol/m2/s), bubbling column reactors were operated in batches of 8 d with initial ammonium nitrogen 10-50mg/L, initial phosphate phosphorus 2-10mg/L and microalgal seed 40mg/L. Maximum microalgal biomass and minimum generation time were 370.9mg/L and 2.5d, respectively. Nitrogen removal (maximum 99.6%) was mainly attributed to microalgal growth rate, while phosphorus removal (maximum 49.8%) was related to microalgal growth rate, cell phosphorus content (maximum 1.5%) and initial nutrients ratio. Dissolved microalgal organics release in terms of chemical oxygen demand (maximum 63.2mg/L) and hexane extractable material (i.e., oil and grease, maximum 8.5mg/L) was firstly reported and mainly affected by nitrogen deficiency and deteriorated effluent quality. Ultrafiltration critical flux (16.6-39.5L/m2/h) showed negative linear correlation to microalgal biomass. Anaerobic membrane bioreactor effluent polishing showed similar results with slight inhibition to synthetic effluent. PMID- 28577486 TI - An accurate and robust LC-MS/MS method for the quantification of chlorfenvinphos, ethion and linuron in liver samples. AB - A method for the determination of chlorfenvinphos, ethion and linuron in liver samples by LC-MS/MS is described. Sample treatment was performed by using SolaTM polymeric reverse phase SPE cartridges after protein precipitation. Gradient elution using 10 mM ammonium formate in methanol (A) and 10 mM ammonium formate in water (B) was used for chromatographic separation of analytes on a HypersilTM end-capped Gold PFP reverse phase column (100 mm * 2.1 mm, 3 MUm). All analytes were quantified without interference, in positive ionization mode using multiple reaction monitoring (MRM) with chlorfenvinphos-d10 as internal standard. The whole procedure was validated according to the FDA guidelines for bioanalytical methods. The calibration curves for chlorfenvinphos, linuron and ethion compounds were linear over the concentration range of 0.005-2 MUM (i.e. 0.0018-0.720 MUg/mL, 0.0019-0.770 MUg/mL and 0.0012-0.500 MUg/mL respectively) with coefficients of determination higher than 0.998. A Lower limit of quantification of 0.005 MUM was achieved for all analytes, i.e. 5.76, 6.08 and 3.84 MUg/kg of liver for chlorfenvinphos, ethion and linuron respectively. Compounds extraction recovery rates ranged from 92.9 to 99.5% with a RSD of 2.3%. Intra- and inter-day accuracies were within 90.9 and 100%, and imprecision varied from 0.8 to 8.2%. Stability tests proved all analytes were stable in liver extracts during instrumental analysis (+12 degrees C in autosampler tray for 72 h) at the end of three successive freeze-thaw cycles and at -20 degrees C for up to 9 months. This accurate and robust analytical method is therefore suitable for contamination or metabolism studies. PMID- 28577487 TI - Modeling pesticide diuron loading from the San Joaquin watershed into the Sacramento-San Joaquin Delta using SWAT. AB - Quantifying pesticide loading into the Sacramento-San Joaquin Delta of northern California is critical for water quality management in the region, and potentially useful for biological weed control planning. In this study, the Soil and Water Assessment Tool (SWAT) was applied to model streamflow, sediment, and pesticide diuron loading in the San Joaquin watershed, a major contributing area to the elevated pesticide levels in the downstream Delta. The Sequential Uncertainty Fitting version 2 (SUFI-2) algorithm was employed to perform calibration and uncertainty analysis. A combination of performance measures (PMs) and standardized performance evaluation criteria (PEC) was applied to evaluate model performance, while prediction uncertainty was quantified by 95% prediction uncertainty band (95PPU). Results showed that streamflow simulation was at least "satisfactory" at most stations, with more than 50% of the observed data bracketed by the 95PPU. Sediment simulation was rated as at least "satisfactory" based on two PMs, and diuron simulation was judged as "good" by all PMs. The 95PPU of sediment and diuron bracketed about 40% and 30% of the observed data, respectively. Significant correlations were observed between the diuron loads, and precipitation, streamflow, and the current and antecedent pesticide use. Results also showed that the majority (>70%) of agricultural diuron was transported during winter months, when direct exposure of biocontrol agents to diuron runoff is limited. However, exposure in the dry season could be a concern because diuron is relatively persistent in aquatic system. This study not only provides valuable information for the development of biological weed control plan in the Delta, but also serves as a foundation for the continued research on calibration, evaluation, and uncertainty analysis of spatially distributed, physically based hydrologic models. PMID- 28577488 TI - Motor imagery-based implicit sequence learning depends on the formation of stimulus-response associations. AB - Implicit sequence learning (ISL) occurs without conscious awareness and is critical for skill acquisition. The extent to which ISL occurs is a function of exposure (i.e., total training time and/or sequence to noise ratio) to a repeated sequence, and thus the cognitive mechanism underlying ISL is the formation of stimulus-response associations. As the majority of ISL studies employ paradigms whereby individuals unknowingly physically practice a repeated sequence, the cognitive mechanism underlying ISL through motor imagery (MI), the mental rehearsal of movement, remains unknown. This study examined the cognitive mechanisms of MI-based ISL by probing the link between exposure and the resultant ISL. Seventy-two participants underwent MI-based practice of an ISL task following randomization to one of four conditions: 4 training blocks with a high (4-High) or low (4-Low) sequence to noise ratio, or 2 training blocks with a high (2-High) or low (2-Low) sequence to noise ratio. Reaction time differences (dRT) and effect sizes between repeated and random sequences assessed the extent of learning. All groups showed a degree of ISL, yet effect sizes indicated a greater degree of learning in groups with higher exposure (4-Low and 4-High). Findings indicate that the extent to which ISL occurs through MI is impacted by manipulations to total training time and the sequence to noise ratio. Overall, we show that the extent of ISL occurring through MI is a function of exposure, indicating that like physical practice, the cognitive mechanisms of MI-based ISL rely on the formation of stimulus response associations. PMID- 28577490 TI - Quantitative biomonitoring of nitrogen deposition with TONIS (Total N Input Biomonitoring System). AB - Monitoring of air pollutants is an important instrument to detect threats and to observe temporal trends of emissions. Determining the spatial distribution of oxidized and reduced N species via modelling requires sufficient knowledge about innumerous small sources from traffic, settlements and agriculture. Empirical studies are required to validate the model data but measurements of the total N deposition (e.g. micrometeorological measurements) are very expensive. Against this background, the TONIS, a new suitable technique which combines a biomonitoring with plants and technical measurements was developed. During 6 exposures between 2012 and 2016 at different polluted sites in Northwest Germany, TONIS accumulated between 17 and 25 kg N ha-1 yr-1t. The results are feasible compared to simultaneously measured NH3 and NO2 concentration and bulk N deposition. At one site within a peat bog the accumulated N in TONIS was found to be in the range of total N deposition derived from a micrometeorological approach. PMID- 28577491 TI - Bluetongue outbreaks: Looking for effective control strategies against Culicoides vectors. AB - Several arthropod-borne diseases are now rising with increasing impact and risks for public health, due to environmental changes and resistance to pesticides currently marketed. In addition to community surveillance programs and a careful management of herds, a next-generation of effective products is urgently needed to control the spread of these diseases, with special reference to arboviral ones. Natural product research can afford alternative solutions. Recently, a re emerging of bluetongue disease is ongoing in Italy. Bluetongue is a viral disease that affects ruminants and is spread through the bite of bloodsucking insects, especially Culicoides species. In this review, we focused on the importance of vector control programs for prevention or bluetongue outbreaks, outlining the lack of effective tools in the fight against Culicoides vectors. Then, we analyzed a field case study in Sardinia (Italy) concerning the utilization of the neem cake (Azadirachta indica), to control young instar populations of Culicoides biting midges, the vectors of bluetongue virus. Neem cake is a cheap and eco friendly by-product obtained from the extraction of neem oil. Overall, we propose that the employ of neem extraction by-products as aqueous formulations in muddy sites close to livestock grazing areas may represent an effective tool in the fight against the spread of bluetongue virus in the Mediterranean areas. PMID- 28577493 TI - Inhibition of PI3K/AKt/mTOR signaling pathway protects against d galactosamine/lipopolysaccharide-induced acute liver failure by chaperone mediated autophagy in rats. AB - OBJECTIVE: This study aims to investigate the effects of PI3K/AKt/mTOR signaling pathway on the proliferation and apoptosis in acute liver failure (ALF) by chaperone mediated autophagy (CMA). METHODS: The hepatocytes extracted from both normal rats and rats with ALF were assigned to control, acute injury, P13K agonist, and P13K inhibitor groups. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used as part of this investigation to detect the expression of PI3K/AKt/mTOR signaling pathway related-proteins (PI3K, AKt, mTOR), apoptosis related-proteins (Fas, Bax, Bcl-2), chaperone mediated autophagy (CMA) marker proteins (LAMP-2A, HSC 70), p-PI3K, p-AKt, p-4E BPI, and p-S6K. An MTT assay was used for analysis of cell proliferation after transfection. Flow cytometry is performed to detect the cell apoptosis. RESULTS: In comparison to the normal group, the model group showed enhanced positive rate of PI3K, AKt, mTOR, increased expression levels of PI3K, AKt, mTOR, Fas, Bax, p PI3K, p-AKt, p-4E-BPI and p-S6K, reduced expression levels of Bcl-2, LAMP-2A and HSC 70. The results in vitro experiment: compared with the acute injury group, the PI3K agonist group showed elevated expression levels of PI3K, AKt, mTOR, Fas, Bax, p-PI3K, p-AKt, p-4E-BPI and p-S6K, decreased expression levels of Bcl-2, LAMP-2A and HSC 70, inhibited cell proliferation, more arrested cells in G1 stage, and promoted cell apoptosis. Opposing this, the P13K inhibitor group exhibited an opposite trend. CONCLUSION: In conclusion, inhibition of the PI3K/AKt/mTOR signaling pathway plays a protective role in ALF by promoting CMA expression, which could arrest cell proliferation and promote cell apoptosis. PMID- 28577492 TI - rhBMP2-loaded calcium phosphate cements combined with allogenic bone marrow mesenchymal stem cells for bone formation. AB - OBJECTIVE: The osteogenesis effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) and osteogenic differentiation potential of bone marrow mesenchymal stem cells (BMSCs) has been generally acknowledged. However, human bone formation effect of rhBMP-2 loaded calcium phosphate cememts (CPC) combined with allogenic BMSCs is still undefined. This study aimed to investigate how composite osteogenic bone marrow mesenchymal stem cells (BMSCs) and osteoinductive bone morphogenetic protein-2 (BMP-2) influenced the process of bone formation. METHODS: We chose calcium phosphate cements (cancellous bone granules; cancellous bone granules contained rhBMP-2) to facilitate osteogenesis. The composites of CPC+BMSC and CPC/rhBMP-2+BMSC were implanted respectively into nude mice via subcutaneous implantation and the tooth socket after maxillary canine teeth extraction. MAR analysis, Micro-CT analysis and immunohistochemistry assay were performed in this study to observe and compare by the schedule. RESULTS: It was showed that combined with CPC+BMSC or CPC/rhBMP-2+BMSC induced stronger ability of the proliferation of allogenic BMSCs observed by scanning electron microscopy (SEM). Picric acid-fuchsin staining and immunohistochemical analysis illustrated the stronger new bone forming ability of CPC+BMSC group and CPC/rhBMP-2+BMSC group than those of controlled group. CONCLUSION: The combinations of rhBMP2-loaded CPC with allogeneic BMSCs promote new bone tissue formation. PMID- 28577494 TI - Antibacterial, modulatory activity of antibiotics and toxicity from Rhinella jimi (Stevaux, 2002) (Anura: Bufonidae) glandular secretions. AB - The increase in microorganisms with resistance to medications has caused a strong preoccupation within the medical and scientific community. Animal toxins studies, such as parotoid glandular secretions from amphibians, possesses a great potential in the development of drugs, such as antimicrobials, as these possess bioactive compounds. It was evaluated Rhinella jimi (Stevaux, 2002) glandular secretions against standard and multi-resistant bacterial strains; the effect of secretions combined with drugs; and determined the toxicity using two biologic in vivo models, and a in vitro model with mice livers. Standard strains were used for the determination of the Minimum Inhibitory Concentration (MIC), while for the modulatory activity of antibiotics, the clinical isolates Escherichia coli 06, Pseudomonas aeruginosa 03 and Staphylococcus aureus 10 were used. Modulatory activity was evaluated by the broth microdilution method with aminoglycosides and beta-lactams as target antibiotics. The secretions in association with the antibiotics have a significant reduction in MIC, both the aminoglycosides and beta-lactams. The toxicity and cytotoxicity results were lower than the values used in the modulation. R. jimi glandular secretions demonstrated clinically relevant results regarding the modulation of the tested antimicrobials. PMID- 28577495 TI - Knockdown of long noncoding RNA GHET1 inhibits cell activation of gastric cancer. AB - OBJECTION: The aim of this study was to evaluate the effects of lncRNA GHET1 in developing of Gastric Cancer. METHODS: Collecting the 20 gastric cancer patients and evaluated the pathological of adjacent and tumor tissues by HE stating. We analyzed the protein expression of Numb in gastric cancer (GC) tissues by using IHC and the gene expression of Numb and GHET1 in adjacent and GC tissues by RT PCR. The AGS cells were divided into 3 groups: Control (Co), NC and shRNA groups. Measuring the cell proliferation, apoptosis, cell cycle, invasion and migration abilities by MTT, flow cytometry, transwell and wound healing assays. We analyzed the relative signaling pathway by WB assay. RESULTS: In the clinical analyzing, compared with adjacent tissues, the pathological was significantly changed in tumor tissues, the GHET1 gene and protein expressions were significantly increased in the GC tissues. In the cell experiment, down-regulation of GHET1 had suppressed the cell proliferation, invasion and migration activities and enhanced the cell apoptosis and G1 phase. We found that knockdown of GHET1 dramatically increased E-cadherin, while reducing fibronectin and vimentin. CONCLUSION: lncRNA GHET1 promoted AGS cells activations, and the results were shown that GHET1 dysregulation might be involved in the occurrence and development of gastric cancer. These results suggested that GHET1 might be a molecular marker for the progression of gastric cancer and a molecular target for targeted therapy. PMID- 28577496 TI - Hepatoprotective and antioxidant activity of quercetin loaded chitosan/alginate particles in vitro and in vivo in a model of paracetamol-induced toxicity. AB - The toxic liver impairment caused by free radical injury or excessive reactive oxigen species (ROS) formation could be effectivelly attenuated by natural antioxidants. The present study aimed to explore and compare the hepatoprotective and antioxidant effects of free and encapsulated quercetin in in vitro and in vivo models of hepatotoxicity. Thus, quercetin was encapsulated in chitosan/alginate nanoparticles by gelation method. Both empty and quercetin loaded nanoparticles revealed good safety profile in vitro, determined by the lack of cytotoxicity in human hepatoma HepG2 cells. The pretreatment of HepG2 cells with encapsulated quercetin (10MUg/ml) significantly attenuated the decrease in cell viability in H2O2-induced oxidative stress (0.1mM H2O2), thus showing an effective in vitro protection. In vivo evaluation of the antioxidant and hepatoprotective potential of free and encapsulated quercetin was performed in a model of paracetamol - induced liver injury in male Wistar rats. The oral pretreatment with encapsulated quercetin (0.18mg/kg b.w., 7days) significantly diminished the increased levels of serum transaminases ALT and AST, attenuated the lipid peroxidation and restored the levels of gluthation (a marker of cell antioxidant defence system). The protective effects of quercetin encapsulated in chitosan-based nanoformulation were superior to those of free quercetin. The results of the study suggest that the encapsulation of quercetin in chitosan/alginate nanoformulations might represent an effective therapeutic approach against oxidative stress induced liver injury. PMID- 28577497 TI - MicroRNA-505 predicts prognosis and acts as tumor inhibitor in cervical carcinoma with inverse association with FZD4. AB - PURPOSE: We investigated the expression and mechanisms of microRNA-505 (miR-505) and its downstream target gene Frizzled-4 (FZD4) in cervical cancer. METHODS: miR 505 expression was evaluated by qRT-PCR in cervical cancer cell lines and human carcinomas. Cancer patients' clinicopathological factors and survival were analyzed based on their tumorous miR-505 levels. Ca-Ski and HeLa cells were transduced with lentivirus to upregulate or downregulate miR-505. Their impacts on cervical cancer were evaluated by in vitro proliferation, invasion and in vivo tumorigenicity assays, respectively. Target gene of miR-505, FZD4, was evaluated by dual-luciferase reporter assay. Its expression in cervical cancer cell was evaluated by qRT-PCR. FZD4 was either upregulated or downregulated in cervical cancer cells to further assess its impact on modulating cervical cancer development in vitro. RESULTS: MiR-505 is lowly expressed in cervical cancer cell lines and human carcinomas. Low tumorous miR-505 expression was associated with patients' advanced tumor stage and short survival. In Ca-Ski and HeLa cells, lentivirus-mediated miR-505 upregulation suppressed cancer proliferation and invasion in vitro, and tumorigenicity in vivo, whereas miR-505 downregulation had no functional effects. FZD4 was confirmed to be a downstream target of miR-505, and found to be upregulated in cervical cancer. Genetic modification of FZD4 in cervical cancer cells yielded a significant change in cancer growth, as FZD4 upregulation suppressed whereas FZD4 downregulation promoted cervical cancer proliferation and invasion In vitro. CONCLUSION: MiR-505 may act as a cancer inhibitor and prognostic factor in cervical cancer. FDZ4 is reversely expressed as miR-505, and has dramatic regulatory function in cervical cancer. PMID- 28577498 TI - Telomerase reverse transcriptase genetically modified adipose tissue derived stem cells improves erectile dysfunction by inhibiting oxidative stress and enhancing proliferation in rat model. AB - Erectile dysfunction (ED) is considered to be incapable of obtaining or/and keeping a sufficient erection function to receive the satisfactory during the sexual intercourse. This study aims to investigate the effects of telomerase reverse transcriptase (hTERT) modified adipose tissue derived stem cells (ADSCs) autologously injected into cavernosa of the ED rats on erectile function. The ADSCs were isolated form the rat subcutaneous adipose tissue sample, and identified by examining the CD29 and CD44 molecule. The ED model was established by using 100MUg/kg apomorphine (APO). The adenovirus expressing rat hTERT (Ade hTERT vector) was established, and transfected into ADSCs and injected into ED rat model, respectively. Telomerase activity, cell growth, cell apoptosis were analyzed by using TRAP ELISA assay, CCK8 assay and flow cytometry assay, respectively. The trophic growth factors were examined by using enzyme-linked immunosorbent assay (ELISA). The mRNA and proteins were detected by using semi quantitative PCR and western blot assay, respectively. Ade-hTERT vector was highly expressed in both ADSCs and ED rat mode. The hTERT expression enhanced the telomerase activity, inhibits cell apoptosis and enhances proliferation of ADSCs (P<0.05). hTERT expression triggers the secretory function of ADSCs and induces differentiative potential of ADSCs. hTERT expression inhibits apoptosis and increases eNOS and nNOS levels in older ED rats compared to the Ade-vector injected ED rats (P<0.05). In conclusion, the hTERT modification could enhance the ADSCs proliferation, and hTERT modified ADSCs could increase the anti oxidative stress capacity in the ED rat model. PMID- 28577499 TI - Leukocyte trafficking in tumor microenvironment. AB - The tumor microenvironment consists of both malignant and non-malignant cells and a plethora of soluble mediators. Different types of tumors have specific tumor microenvironments characterized by distinct chemokines and chemotactic factors that influence leukocyte recruitment. The immune cell infiltrate continuously interacts with stroma cells and influence tumor growth. Emerging evidence suggests that the regulation of the composition and the metabolic state of tumor associated leukocytes may represent a new promising intervention strategy. Here we summarize the current knowledge on the role of tumor-associated immune cells in tumor growth and dissemination, with a specific focus on the nature of the chemotactic factors responsible for their accumulation and activation in tumors. PMID- 28577500 TI - A genosensor for detection of consensus DNA sequence of Dengue virus using ZnO/Pt Pd nanocomposites. AB - An electrochemical genosensor based on Zinc oxide/platinum-palladium (ZnO/Pt-Pd) modified fluorine doped tin oxide (FTO) glass plate was fabricated for detection of consensus DNA sequence of Dengue virus (DENV) using methylene blue (MB) as an intercalating agent. To achieve it, probe DNA (PDNA) was immobilized on the surface of ZnO/Pt-Pd nanocomposites modified FTO electrode. The synthesized nano composites were characterized by high resolution transmission electron microscopy (HRTEM), energy dispersive X-ray analysis (EDX), atomic force microscopy (AFM), scanning electron microscopy (SEM), UV-Vis spectroscopy, X-ray diffraction (XRD) analysis and Fourier transform infra-red (FTIR) spectroscopy. This PDNA modified electrode (PDNA/ZnO/Pt-Pd/FTO) served as a signal amplification platform for the detection of the target hybridized DNA (TDNA). The hybridization between PDNA and TDNA was detected by reduction in current, generated by interaction of anionic mediator, i.e., methylene blue (MB) with free guanine (3'G) of ssDNA. The sensor showed a dynamic linear range of 1 * 10-6M to 100 * 10-6M with LOD as 4.3 * 10-5 M and LOQ as 9.5 * 10-5 M. Till date, majorly serotype specific biosensors for dengue detection have been developed. The genosensor reported here eliminates the possibility of false result as in case of serotype specific DNA sensor. This is the report where conserved sequences present in all the serotypes of Dengue virus has been employed for fabrication of a genosensor. PMID- 28577501 TI - Advances in developing rapid, reliable and portable detection systems for alcohol. AB - Development of portable, reliable, sensitive, simple, and inexpensive detection system for alcohol has been an instinctive demand not only in traditional brewing, pharmaceutical, food and clinical industries but also in rapidly growing alcohol based fuel industries. Highly sensitive, selective, and reliable alcohol detections are currently amenable typically through the sophisticated instrument based analyses confined mostly to the state-of-art analytical laboratory facilities. With the growing demand of rapid and reliable alcohol detection systems, an all-round attempt has been made over the past decade encompassing various disciplines from basic and engineering sciences. Of late, the research for developing small-scale portable alcohol detection system has been accelerated with the advent of emerging miniaturization techniques, advanced materials and sensing platforms such as lab-on-chip, lab-on-CD, lab-on-paper etc. With these new inter-disciplinary approaches along with the support from the parallel knowledge growth on rapid detection systems being pursued for various targets, the progress on translating the proof-of-concepts to commercially viable and environment friendly portable alcohol detection systems is gaining pace. Here, we summarize the progress made over the years on the alcohol detection systems, with a focus on recent advancement towards developing portable, simple and efficient alcohol sensors. PMID- 28577502 TI - Influence of the environmental tonicity perturbations on the release of model compounds from large unilamellar vesicles (LUVs): A mechanistic investigation. AB - In this work, the influence of environmental tonicity perturbations on the size and release kinetics of model markers from liposomes (calcein and rhodamine) was investigated. Large unilamellar vesicles (LUVs) were prepared from a mixture composed of organic solvents containing dissolved phosphatidylcholine and phosphate buffered saline (PBS, pH 7.4). Organic phase was removed by rotary evaporation and the obtained liposomal dispersions were extruded to reduce the liposomal sizes to approx. 400 nm. The LUVs were exposed to PBS of different tonicity to induce water migration, and consequently, generate an osmotic pressure on the vesicle membranes. The markers release kinetics were studied by the dialysis method employing Franz diffusion cells. LUVs appeared to be more susceptible to the osmotic swelling than the shrinking and the size changes were significantly more pronounced for calcein-loaded LUVs in comparison to rhodamine loaded LUVs. The calcein release from LUVs was highly affected by the water influx/efflux, whereas rhodamine release was less affected by the tonicity perturbations. Mechanistically, it appeared that hydrophilic molecules (calcein) followed the water flux, whereas lipophilic molecules (rhodamine) seemed to be more affected by the changes in LUVs size and consequent alteration of the tightness of the phospholipid bilayer (where the lipophilic marker was imbedded in). These results demonstrate that the different tonicity (within the inner core and external environment of vesicles) can enhance/hamper the diffusion of a marker from LUVs and that osmotically active liposomes could be used as a novel controlled drug delivery system. PMID- 28577503 TI - pH triggered controlled drug delivery from contact lenses: Addressing the challenges of drug leaching during sterilization and storage. AB - In the present work a novel cyclosporine-loaded Eudragit S100 (pH-sensitive) nanoparticles-laden contact lenses were designed to provide sustained release of cyclosporine at therapeutic rates, without leaching of drug during sterilization and storage period (shelf life). The nanoparticles were prepared by Quasi emulsion solvent diffusion technique using different weight ratios of cyclosporine to Eudragit S100. The contact lenses with direct drug entrapment were also fabricated (DL-50) for comparison. The percentage swelling and optical transparency of nanoparticles-laden contact lenses were improved in comparison to DL-50 lenses. The nanoparticles-laden contact lenses showed sustained drug release profiles, with inverse relationship to the amount of nanoparticles loaded in the contact lenses. It was interesting to note that nanoparticles form nanochannels/cavities after dissolution of Eudragit S 100 in tear fluid pH=7.4 (in vitro release study). This followed the precipitation of drug in hydrogel matrix of contact lenses. As the amount of nanoparticles loading increased, more number of cavities were formed, which caused the formation of large cavities in contact lens matrix. This in turn precipitated the drug. The nanoparticles-laden contact lenses with 1:1 (drug: Eudragit) weight ratio showed the most promising results of sustaining the drug release up to 156h, without affecting optical and physical properties of contact lenses. Packaging study confirmed that the drug was not leached in packaging solution (buffer, pH=6.5) from nanoparticles-laden lenses during shelf life period. In-vivo study in rabbit tear fluid showed sustained release up to 14days. The study revealed the application of pH sensitive nanoparticles-laden contact lenses for controlled release of cyclosporine without altering the optical and physical properties of lens material. PMID- 28577504 TI - Isolation and characterization of Cepa2, a natural alliospiroside A, from shallot (Allium cepa L. Aggregatum group) with anticancer activity. AB - Exploration of new and promising anticancer compounds continues to be one of the main tasks of cancer research because of the drug resistance, high cytotoxicity and limitations of tumor selectivity. Natural products represent a better choice for cancer treatment in comparison with synthetic compounds because of their pharmacokinetic properties and lower side effects. In the current study, we isolated a steroidal saponin, named Cepa2, from the dry roots of shallot (Allium cepa L. Aggregatum group), and determined its structure by using two-dimensional nuclear manganic resonance (2D NMR). The 1H NMR and 13C NMR data revealed that the newly isolated Cepa2 compound is identical to alliospiroside A (C38H60O12) [(25S)-3beta-hydroxyspirost-5-en-1beta-yl-2-O-(6-deoxy-alpha-L-mannopyranosyl) alpha-L-arabinopyranoside], whose anticancer activity remains elusive. Our in vitro examination of the cytotoxic activity of the identified Cepa2 against P3U1 myeloma cancer cell line showed its high efficiency as an anticancer with 91.13% reduction in P3U1 cell viability 12 h post-treatment. The reduction of cell viability was correlated with the increase in reactive oxygen species levels in Cepa2-treated P3U1 cells, as compared with untreated cells. Moreover, scanning electron microscope results demonstrated apoptosis of the Cepa2-treated P3U1 cells in a time course-dependent manner. The results of our study provide evidence for the anticancer properties of the natural Cepa2/alliospiroside A extracted from shallot plants, and a strong foundation for in-depth investigations to build theoretical bases for cell apoptosis and development of novel anticancer drugs. PMID- 28577505 TI - Transdiagnostic treatment of bipolar disorder and comorbid anxiety using the Unified Protocol for Emotional Disorders: A pilot feasibility and acceptability trial. AB - BACKGROUND: Comorbid anxiety in bipolar disorder (BD) is associated with greater illness severity, reduced treatment response, and greater impairment. Treating anxiety in the context of BD is crucial for improving illness course and outcomes. The current study examined the feasibility, acceptability and preliminary efficacy of the Unified Protocol (UP), a transdiagnostic cognitive behavioral therapy, as an adjunctive treatment to pharmacotherapy for BD and comorbid anxiety disorders. METHODS: Twenty-nine patients with BD and at least one comorbid anxiety disorder were randomized to pharmacotherapy treatment-as usual (TAU) or TAU with 18 sessions of the UP (UP+TAU). All patients completed assessments every four weeks to track symptoms, functioning, emotion regulation and temperament. Linear mixed-model regressions were conducted to track symptom changes over time and to examine the relationship between emotion-related variables and treatment response. RESULTS: Satisfaction ratings were equivalent for both treatment groups. Patients in the UP+TAU group evidenced significantly greater reductions over time in anxiety and depression symptoms (Cohen's d's>0.80). Baseline levels of neuroticism, perceived affective control, and emotion regulation ability predicted magnitude of symptom change for the UP+TAU group only. Greater change in perceived control of emotions and emotion regulation skills predicted greater change in anxiety related symptoms. LIMITATIONS: This was a pilot feasibility and acceptability trial; results should be interpreted with caution. CONCLUSIONS: Treatment with the UP+TAU was rated high in patient satisfaction, and resulted in significantly greater improvement on indices of anxiety and depression relative to TAU. This suggests that the UP may be a feasible treatment approach for BD with comorbid anxiety. PMID- 28577508 TI - Change in gait after high tibial osteotomy: A systematic review and meta analysis. AB - We conducted a meta-analysis to analyze how high tibial osteotomy (HTO) changes gait and focused on the following questions: (1) How does HTO change basic gait variables? (2) How does HTO change the gait variables in the knee joint? Twelve articles were included in the final analysis. A total of 383 knees was evaluated. There were 237 open wedge (OW) and 143 closed wedge (CW) HTOs. There were 4 level II studies and 8 level III studies. All studies included gait analysis and compared pre- and postoperative values. One study compared CWHTO and unicompartmental knee arthroplasty (UKA), and another study compared CWHTO and OWHTO. Five studies compared gait variables with those of healthy controls. One study compared operated limb gait variables with those in the non-operated limb. Gait speed, stride length, knee adduction moment, and lateral thrust were major variables assessed in 2 or more studies. Walking speed increased and stride length was increased or similar after HTO compared to the preoperative value in basic gait variables. Knee adduction moment and lateral thrust were decreased after HTO compared to the preoperative knee joint gait variables. Change in co contraction of the medial side muscle after surgery differed depending on the degree of frontal plane alignment. The relationship between change in knee adduction moment and change in mechanical axis angle was controversial. Based on our systematic review and meta-analysis, walking speed and stride length increased after HTO. Knee adduction moment and lateral thrust decreased after HTO compared to the preoperative values of gait variables in the knee joint. PMID- 28577507 TI - Design, synthesis and antimycobacterial activity of novel imidazo[1,2-a]pyridine 3-carboxamide derivatives. AB - We report herein the design and synthesis of "novel imidazo [1,2-a]pyridine-3 carboxamides (IPAs)" bearing a variety of different linkers, based on the structure of IMB-1402 discovered in our lab. Results reveal that 2,6-dimethyl-N [2-(phenylamino)ethyl] IPAs with an electron-donating group on the benzene ring as a potent scaffold. Compounds 26g and 26h have considerable activity (MIC: 0.041-2.64 MUM) against drug-sensitive/resistant MTB strains, and they have acceptable safety indices against MTB H37Rv with the SI values of 4395 and 1405, respectively. Moreover, N-[2-(piperazin-1-yl)ethyl] moiety was also identified as a potentially alternative linker (compound 31), opening a new direction for further SAR studies. PMID- 28577506 TI - High enhancer, downer, withdrawal helper: Multifunctional nonmedical benzodiazepine use among young adult opioid users in New York City. AB - BACKGROUND: Benzodiazepines are a widely prescribed psychoactive drug; in the U.S., both medical and nonmedical use of benzodiazepines has increased markedly in the past 15 years. Long-term use can lead to tolerance and dependence, and abrupt withdrawal can cause seizures or other life-threatening symptoms. Benzodiazepines are often used nonmedically in conjunction with other drugs, and with opioids in particular-a combination that can increase the risk for fatal and non-fatal overdose. This mixed-methods study examines nonmedical use of benzodiazepines among young adults in New York City and its relationship with opioid use. METHODS: For qualitative analysis, 46 90-minute semi-structured interviews were conducted with young adult opioid users (ages 18-32). Interviews were transcribed and coded for key themes. For quantitative analysis, 464 young adult opioid users (ages 18-29) were recruited using Respondent-Driven Sampling and completed structured interviews. Benzodiazepine use was assessed via a self report questionnaire that included measures related to nonmedical benzodiazepine and opioid use. RESULTS: Participants reported using benzodiazepines nonmedically for a wide variety of reasons, including: to increase the high of other drugs; to lessen withdrawal symptoms; and to come down from other drugs. Benzodiazepines were described as readily available and cheap. There was a high prevalence (93%) of nonmedical benzodiazepine use among nonmedical opioid users, with 57% reporting regular nonmedical use. In bivariate analyses, drug-related risk behaviours such as polysubstance use, drug binging, heroin injection and overdose were strongly associated with regular nonmedical benzodiazepine use. In multivariate analysis, growing up in a middle-income household (earning between $51,000 and $100,000 annually), lifetime overdose experience, having ever used cocaine regularly, having ever been prescribed benzodiazepines, recent drug binging, and encouraging fellow drug users to use benzodiazepines to cope with opioid withdrawal were consistently strong predictors of regular nonmedical benzodiazepine use. CONCLUSION: Nonmedical benzodiazepine use may be common among nonmedical opioid users due to its drug-related multi-functionality. Harm reduction messages should account for the multiple functions benzodiazepines serve in a drug-using context, and encourage drug users to tailor their endorsement of benzodiazepines to peers to include safer alternatives. PMID- 28577509 TI - Nuclear bodies: news insights into structure and function. AB - The cell nucleus contains a number of different dynamic bodies that are variously composed of proteins and generally, but not always, specific RNA molecules. Recent studies have revealed new understanding about nuclear body formation and function in different aspects of nuclear metabolism. Here, we focus on findings describing the role of nuclear bodies in the biogenesis of specific ribonucleoprotein complexes, processing of key mRNAs, and subnuclear sequestration of protein factors. We highlight how nuclear bodies are involved in stress responses, innate immunity and tumorigenesis. We further review organization of nuclear bodies and principles that govern their assembly, highlighting the pivotal role of scaffolding noncoding RNAs, and liquid-liquid phase separation, which are transforming our picture of nuclear body formation. PMID- 28577510 TI - Drop coating deposition Raman spectroscopy of proteinogenic amino acids compared with their solution and crystalline state. AB - The Raman spectra of 20 proteinogenic amino acids were recorded in the solution, glass phase (as drop coating deposition Raman (DCDR) samples) and crystalline forms in the wide spectral range of 200-3200cm-1. The most apparent spectral differences between the Raman spectra of the crystalline forms, glass phases and aqueous solutions of amino acids were briefly discussed and described in the frame of published works. The possible density dependencies of spectral bands were noted. In some cases, a strong influence of the sample density, as well as of the organization of the water envelope, was observed. The most apparent changes were observed for Ser and Thr. Nevertheless, for the majority of amino acids, the DCDR sample form is an intermediate between the solution and crystalline forms. In contrast, aromatic amino acids have only a small sensitivity to the form of the sample. Our reference set of Raman spectra is useful for revealing discrepancies between the SERS and solid/solution spectra of amino acids. We also found that some previously published Raman spectra of polycrystalline samples resemble glassy state rather than crystalline spectra. Therefore, this reference set of spectra will find application in every branch of Raman spectroscopy where the spectra of biomolecules are collected from coatings. PMID- 28577511 TI - Therapies for castration-resistant prostate cancer in a new era: The indication of vintage hormonal therapy, chemotherapy and the new medicines. AB - When advanced prostate cancer recurred during hormonal therapy and became the castration-resistant prostate cancer, "vintage hormonal therapy," such as antiandrogen alternating therapy or estrogen-related hormonal therapy, was widely carried out in Japan until 2013. This vintage hormonal therapy controlled the progression of castration-resistant prostate cancer. When castration-resistant prostate cancer relapses during these therapies, chemotherapy using docetaxel has been carried out subsequently. Since new hormonal therapies using abiraterone acetate and enzalutamide, which improve the prognosis of castration-resistant prostate cancer, became available in Japan from 2014, therapeutic options for castration-resistant prostate cancer have increased. Furthermore, the improvement of the further prognosis is promising by using cabazitaxel for docetaxel resistant castration-resistant prostate cancer and radium-223 for castration resistant prostate cancer with bone metastasis. An increase in therapeutic options gives rise to many questions, including best timing to use them and the indication. Furthermore, physicians have to consider the treatment for the recurrence after having carried out chemotherapy. We want to argue the difference in hormonal therapy between Japan and Western countries, and problems when carrying out new treatments, and the importance of imaging in the present review article. PMID- 28577512 TI - Possible radioprotective effect of folic acid supplementation on low dose ionizing radiation-induced genomic instability in vitro. AB - Ionizing radiation (IR) induces DNA damage through production of single and double-strand breaks and reactive oxygen species (ROS). Folic acid (FA) prevents radiation-induced DNA damage by modification of DNA synthesis and/or repair and as a radical scavenger. We hypothesized that in vitro supplementation with FA will decrease the sensitivity of cells to genetic damage induced by low dose of ionizing radiation. Annexin V, comet and micronucleus assays were performed in cultured CHO cells. After 7 days of pre-treatment with 0, 100, 200 or 300 nM FA, cultures were exposed to radiation (100 mSv). Two un-irradiated controls were executed (0 and 100 nM FA). Data were statistically analyzed with X2-test and linear regression analysis (P ?0.05). We observed a significantly decreased frequency of apoptotic cells with the increasing FA concentration (P <0.05). The same trend was observed when analyzing DNA damage and chromosomal instability (P <0.05 for 300 nM). Only micronuclei frequencies showed significant differences for linear regression analysis (R2=94.04; P <0.01). Our results have demonstrated the radioprotective effect of folic acid supplementation on low dose ionizing radiation-induced genomic instability in vitro; folate status should be taken into account when studying the effect of low dose radiation in environmental or occupational exposure. PMID- 28577513 TI - Synergistic protective effect of picrorhiza with honey in acetaminophen induced hepatic injury. AB - Rhizome of picrorhiza along with honey prevents hepatic damage and cure the acetaminophen (paracetamol) induced hepatotoxicity by modulating the activity of hepatic enzymes. Here, we studied the in vivo effects of Picrorhiza kurroa and honey on acetaminophen induced hepatotoxicity Balb/c mice model. Hepatic histopathological observations of acetaminophen fed (day-6) group showed more congestion, hemorrhage, necrosis, distorted hepatic architecture and nuclear inclusion. Such damages were recompensed to normal by picrorhiza or honey alone or both in combinations. We observed increased activity of SGPT and SGOT in injured liver tissues, and that too was compensated to normal with picrorhiza or honey alone or both in combinations. We observed 1.27 and 1.23-fold enhanced activity of SGPT in serum and liver lysate, respectively while SGOT showed 1.66 and 1.11 fold enhanced activity. These two enzymes are signature enzymes of liver damage. Thus, our results support that honey may be used with drug picrorhiza due to its synergistic role to enhance hepatoprotective and hepatoregenerative ability along with allopathic drugs to mitigate the hepatotoxic effects. PMID- 28577514 TI - Ethanol production from Rice (Oryza sativa) straw by simultaneous saccharification and cofermentation. AB - Ethanol production from alkali treated rice straw was investigated by simultaneous saccharification and cofermentation (SSCF) using commercial cellulase and 3 different yeast strains viz., Saccharomyces cerevisiae HAU-1, Pachysolen tannophilus and Candida sp. individually as well as in combination at varied fermentation temperature and incubation time. Dilute alkali (2%) pretreatment of straw resulted in efficient delignification as observed by low residual lignin (12.52%) with 90.6% cellulose and 28.15% hemicellulose recovery. All the 3 yeast strains were able to produce ethanol form alkali treated rice straw and overall ethanol concentration varied from 5.30 to 24.94 g/L based on different fermentation time and temperature. Comparative analysis of ethanol production from different yeast strains combinations revealed maximum ethanol concentration of 23.48 g/L after 96 h incubation at 35oC with P. tannophilus individually and 24.94 g/L when used as co-culture with Saccharomyces cerevisiae. PMID- 28577515 TI - Glycoside hydrolase production by Aspergillus terreus CM20 using mixture design approach for enhanced enzymatic saccharification of alkali pretreated paddy straw. AB - A successful lignocellulosic ethanol production process needs to address the technological impediments such as cost-competitiveness and sustainability of the process. Effective biomass utilization requires a repertoire of enzymes including various accessory enzymes. Developing an enzyme preparation with defined hydrolytic activities can circumvent the need for supplementing cellulases with accessory enzymes for enhanced hydrolysis. With this objective, mixture design approach was used in the present study to enhance glycoside hydrolase production of a fungal isolate, Aspergillus terreus CM20, by determining the proportion of different lignocellulosic components as enzyme inducers in the culture medium. A mixture of paddy straw and wheat straw (1.42:1.58) resulted in improved cellulolytic activities. The precipitated crude enzyme showed higher CMCase (365.03 18 IU g-1), FPase (161.48 IU g-1), avicelase (15.46 IU g-1), beta glucosidase (920.92 IU g-1) and xylanase (9627.79 IU g-1) activities. The potential of the crude enzyme for saccharification of alkali pretreated paddy straw was also tested. Under optimum conditions, saccharification released 25.0 g L-1 of fermentable sugars. This indicates the superiority of the crude enzyme produced with respect to its hydrolytic enzyme components. PMID- 28577516 TI - Improvement of Bacillus strains by mutation for overproduction of exopolygalacturonases. AB - Pectinases, produced by microorganisms, have wide range application in food industry, textile processing, paper making, coffee and tea fermentation, etc. It accounts for 10% of the global industrial enzymes produced. The most important and widely used commercial pectinase polygalacturonase is produced by alkalophilic strains of Bacillus sp. and Streptomyces sp. Here, we explored 29 bacterial strains isolated from rotten mango samples for polygalacturonase production and selected 16 strains through preliminary screening by well-plate method for enzyme activity. The maximum zone of inhibition of pectin was observed up to 28 mm in diameter but one strain ZM11 was exhibiting no activity. Quantitative dinitrisalicylic acid (DNS) assay for polygalacturonase enzyme was also performed for the selected bacterial isolates. All the strains bestowed significant enzyme activity with the highest activity of 2.4 U/uL exhibited by strain ZM3 (P <=0.05). Characterization of the isolates was performed using different biochemical tests which also confirmed the isolates as members of the genus Bacillus. Mutation was induced to the selected strains by UV light and acridine orange for different periods of time. Qualitative and quantitative assays of the mutant bacterial isolates showed that the enzyme activity increased to 4.62 U/uL which clearly indicated that induced mutation enhanced the ability of Bacillus strains to produce more polygalacturonase enzyme up to 3-fold as compared to the wild strains (P <=0.05). Molecular characterization by 16S rRNA sequences further confirmed that the bacterial isolates belong to Bacillus subtilis and B. amyloliquefaciens. PMID- 28577517 TI - Genotoxicity in lead treated human lymphocytes evaluated by micronucleus and comet assays. AB - Lead (Pb) which plays a significant role in modern industry is related to a broad range of physiological, biochemical, behavioural and genetical dysfunctions. Its exposure leads to an increased frequency of genetic aberrations in humans. Hence, this study was designed to assess the genotoxic effect of lead acetate at three dosage levels (10, 25 and 50 ug/mL) by employing: the Cytokinesis Block Micronucleus (CBMN) assay and the Comet assay in Peripheral Blood Lymphocyte Cultures. The results of this study revealed an increased level of DNA damage among treated groups. A significant increase in the tail length of comets and other indices was observed at 25 and 50 ug/mL concentrations comparatively. Thus, lead acetate induced single-strand breaks (SSB) and double strand breaks (DSB) in DNA, alkali-labile sites (ALS), oxidative DNA damage as well as DNA-DNA/DNA protein/DNA-metal cross linking as evidenced by the Comet assay. The chromosome breakage, DNA misrepair, chromosome loss and telomere end fusion were determined by the Micronucleus assay. Micronucleus frequency in treated lymphocytes was significantly higher as compared to controls. Nucleoplasmic bridges increased significantly and Nuclear buds increased at higher two doses only in exposed cultures. Thus, these assays are better indices for lead induced genotoxicity and metal-nucleus interactions. PMID- 28577518 TI - Development of transgenic pigeonpea (Cajanus cajan. L Millsp) overexpressing citrate synthase gene for high phosphorus uptake. AB - Plants have developed several adaptive strategies to enhance the availability and uptake of phosphorus (P) from the soil under conditions of P deficiency. Exudation of organic acids like citrate is one of the important strategies. In this study, we developed transgenic pigeonpea (Cajanus cajan) over-expressing Dacus carota citrate synthase (DcCs) gene to increase the synthesis and exudation of citrate. Transgenic plants were generated through agro bacterium mediated in planta transformation technique. Integration and expression of the transgene was confirmed by genomic Southern and RT-PCR analysis. We observed that the transgenic lines had more tissue P and chlorophyll content, and also citrate synthase content higher in the roots. Further, transgenic lines had more vigorous root system both under P sufficient and deficient conditions with more lateral roots and root hairs under P deficient conditions. We conclude that the transgenic pigeonpea plants have the capacity to acquire more P under P deficient conditions. PMID- 28577519 TI - Drug allergy evaluation for betalactam hypersensitivity: Cross-reactivity with cephalosporines, carbapenems and negative predictive value. AB - BACKGROUND: There are no studies on cross-reactivity of betalactams among patients allergic to penicillin, or on the negative predictive value (NPV) of penicillin allergy evaluation from Arabian Gulf countries. OBJECTIVE: We aimed to assess the role and NPV of drug provocation test (DPT) for betalactam hypersensitivity reactions in patients referred for allergy evaluation in Kuwait. METHODS: Skin test (ST) was performed for all patients with a history of betalactam hypersensitivity, other than anaphylaxis. Patients with a negative ST were challenged with a DPT containing phenoxymethyl penicillin or the culprit drug. Patients with anaphylaxis or who tested positive to betalactams were then challenged with a DPT containing cefuroxime, meropenem or ceftriaxone. Patients who tested negative were contacted by phone to evaluate subsequent betalactam intake. RESULTS: A total of 214 patients were tested for betalactam hypersensitivity. We had 91(42.5%) positive cases. Among positives, there were 78 (85.7%) patients with an initial reaction to penicillin and 13 (14.3%) who reacted to cephalosporin. DPT with alternative betalactam was performed in fifty who tested positive for betalactam hypersensitivity and 45 (90%) tolerated alternative antibiotics. Phone calls to 113 (59.8%) patients with negative betalactam testing showed that among 40(35.4%) patients who were successfully contacted; 17 (15%) took betalactams and 23 (20%) did not. Among the 17 patients who took betalactams, our calculated NPV for penicillin testing range from 88.2 to 100%, as the 2 patients who reported a reaction refused confirmatory retesting. CONCLUSION: Carbapenems and cephalosporines can be safely given to penicillin allergic patients by means of skin testing and if negative, proceeding with a graded challenge. Our calculated NPV for penicillin testing is similar to other studies. PMID- 28577520 TI - Duration of neutralizing antibody persisting in Thai individuals after childhood vaccination against smallpox. AB - BACKGROUND: Although smallpox was completely eliminated by 1980, it remains possible that variola virus could be intentionally released in an act of bioterrorism. Thus, several studies have been performed to detect antibody levels after smallpox vaccination of the current population in various countries to indicate the duration of maintenance of immunological memory. Our study endeavored to investigate the level of neutralizing (Nt) antibody responses of Thai individuals who had been immunized with smallpox vaccine during childhood. METHODS: The plaque reduction neutralization test (PRNT) was used to study vaccinia Nt antibody responses in sera of individuals ranging in age from 35-4, 45-54, 55-64, 65-74, 75-84 and > 84 years old, referred to as groups 1-6, respectively. Each group included 200 sera: 100 male sera and 100 female sera. RESULTS: An incubation time of 15 hours for sera and vaccinia virus was confirmed to be the optimal incubation period for PRNT. Positive Nt antibody titers (>=32) were detected in 135 (11.25%) of 1,200 sera: 81 (6.75%) male sera and 54 (4.5%) female sera. There were 4 (2%), 11 (5.5%), 19 (9.5%), 16 (8%), 33 (16.5%), and 52 (26%) positive sera in groups 1-6, respectively. Interestingly, the oldest individual with positive Nt antibody was a 98-year-old female. Two males aged 96 and 91 years old had the highest Nt antibody titers. CONCLUSIONS: Our data suggests that the vaccinia-specific Nt antibody response in the current Thai population could be maintained for more than 90 years after vaccination. However, the majority of the Thai population aged >=35-74 years old is still highly susceptible to infection. PMID- 28577521 TI - Seven chronic granulomatous disease cases in a single-center experience and a review of the literature. AB - BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme system. This disease causes the disordered functioning of phagocytic cells. It is characterized by life-threatening and/or recurrent infections by bacteria and fungi. CGD has both an X-linked recessive (X CGD) and autosomal recessive (AR-CGD) phenotypes. AR form have four subtypes including defects with one of these NADPH oxidase components (p22, p40, p47 and p67phox). OBJECTIVES: To report the clinical and laboratory characteristics of seven CGD patients based on their genetic characteristics. METHODS: Seven boys with CGD were reviewed based on clinical findings and genetic results. Dihydrorhodamine-1,2,3 (DHR) assay was used as a diagnostic test. Genetic analysis was conducted to establish moleculer diagnoses in all patients. RESULTS: The age of diagnosis varied between 1.5 years and 15 years. The most frequent clinical presentation was pneumonia, and two patients had BCG-itis. Four patients had the AR-CGD phenotype, and three patients had the X-CGD phenotype. Severe invasive infections due to Aspergillus, Staphylococcus, and Serratia species were reported. Frequent lung and lymph node involvement was observed during follow-up of the cases. CONCLUSIONS: CGD is life-threatening disease that involves deep seated infection. In our patients, the most commonly affected organs were the lungs and lymph nodes. Phagocytic disorders should be considered in cases of recurrent infectious diseases, invasive fungal diseases, BCG complications that are not self-limiting, unexplained lymphadenitis or osteomyelitis, and chronic inflammatory disorders. PMID- 28577522 TI - Rosai-Dorfman disease with features of IgG4-related disease in the breast: Cases report and literature review. AB - BACKGROUND: A proportion of cases of Rosai-Dorfman disease exhibit some histological features consistent with IgG4-related disease (IgG4RD). Several investigators have discussed whether Rosai-Dorfman disease belongs to the spectrum of IgG4RD or is concurrent with it by coincidence. OBJECTIVE: To elucidate the relationship between the two diseases, we report key features, including IgG4 and amyloid levels, of four cases of Rosai-Dorfman disease in the breast. METHODS: The histological features of the four cases were analyzed and the numbers of IgG4+ plasma cells and IgG4/IgG ratios were evaluated. Serum IgG4 concentrations were also measured in two recent cases. A literature review was also performed. RESULTS: Two cases (case 1 and 2) showed features of IgG4RD, including lymphoid follicle formation with regressive changes, obliterative phlebitis, increased number of IgG4+ plasma cells, and increased IgG4/IgG ratio; one of the two had an elevated serum IgG4 level. Amyloidosis was detected in these cases, with amyloid in the stroma and the vessel walls of the lesion. The other two cases (case 3 and 4) only had mild increases in the numbers of IgG4+ plasma cells, while amyloid was deposited in the stroma only. CONCLUSIONS: A subset of Rosai-Dorfman disease may overlap with IgG4RD in the breast. When Rosai Dorfman disease has features of IgG4RD, amyloidosis could be induced in the lesion. PMID- 28577523 TI - Quantification of Fel d 1 in house dust samples of cat allergic patients by using monoclonal antibody specific to a novel IgE-binding epitope. AB - BACKGROUND: Avoidance of allergen exposure is an effective measure for preventing naIve and allergic individuals from sensitization (primary intervention) and disease aggravation (secondary intervention), respectively. Regular monitoring of the allergens in the environment is required for the effective intervention. Thus, there is a need for cost-effective test kits for environmental allergen quantifications. OBJECTIVE: To invent a test kit for quantification of cat major allergen, Fel d 1. METHODS: A mouse monoclonal antibody (MAb) specific to the newly identified IgE-binding conformational epitope of the cat major allergen (Fel d 1) and rabbit polyclonal IgG to recombinant Fel d 1 were used as allergen capture and detection reagents, respectively. Native Fel d 1 was used in constructing a standard curve. RESULTS AND CONCLUSION: Sixteen of 36 dust samples collected from houses of cat allergic subjects in Bangkok contained Fel d 1 above 0.29 MUg/gram of dust which is considered as a novel threshold level for causing cat allergy sensitization or symptoms. Among them, 7 samples contained the allergen exceeding 2.35 MUg/gram of dust which is the level that would aggravate asthma. Results of the allergen quantification using the locally made test kit showed strong correlation (r = 0.923) with the allergen quantification using commercialized reagents. The assay using MAb to Fel d 1 IgE-binding epitope of this study has potential application as an economic and practical tool for cat allergy intervention measure especially in localities where health resources are relatively limited. PMID- 28577524 TI - Childhood asthma control in Japan: A nationwide, cross-sectional, web-based survey. AB - BACKGROUND: Recent surveys have shown that many patients with asthma experience uncontrolled symptoms and decreased quality of life due to their disease. However, few large population-based studies have evaluated asthma control in Japanese children. OBJECTIVE: To show the reality of asthma control and the pattern of asthma controller medication use among Japanese children. METHODS: In 2012, a web-based survey was conducted to identify children aged 6 to 11 years with asthma in Japan. Among children with current asthma, we collected information regarding their asthma controller medication use and evaluated the control level of asthma using the Childhood Asthma Control Test (C-ACT). In this study, a C-ACT score of 19 or less, 20 to 22 and over 22 were classified as uncontrolled asthma, well-controlled asthma, and optimally controlled asthma, respectively. RESULTS: Among the 3,033 children with current asthma, 442 (14.6%), 635 (20.9%), and 1,956 (64.5%) children had uncontrolled, well-controlled, and optimally controlled disease, respectively. In the past 1 month, 1,387 (45.7%) reported receiving at least 1 asthma controller medication with 638 (21.0%) reported receiving inhaled corticosteroid. Among the children with uncontrolled asthma, 67 (15.2%) were not receiving any asthma controller mediations. Among children receiving asthma controller medication, 27.0%, 31.4% and 41.5% had uncontrolled, well-controlled, and optimally controlled asthma, respectively. CONCLUSIONS: Although more than half of children with current asthma had optimally controlled disease, some children without any controller medications and more than a quarter of the children receiving asthma controller medications had uncontrolled disease. PMID- 28577525 TI - Unstimulated salivary flow, pH, proteins and oral health in patients with Juvenile Idiopathic Arthritis. AB - BACKGROUND: There have been inconsistent conclusions regarding salivary abnormalities and their effect on oral health of Juvenile Idiopathic Arthritis (JIA) patients. The purpose of the study was to evaluate the flow rate and selected biochemical parameters of unstimulated whole saliva in correlation to oral health in JIA children. METHODS: Thirty-four JIA patients and 34 age- and sex-matched controls not affected by JIA (C) were divided into two groups: with mixed and permanent dentition. DMFT/dmft, gingival and simplified oral hygiene indices were evaluated. Salivary flow rate, pH, lysozyme, lactoferrin, salivary protein concentrations and peroxidase activity were assessed. RESULTS: The salivary flow rate was significantly lower in the total JIA group (0.41 ml/min) as compared with the C (0.51 ml/min) and in the permanent dentition of JIA children (0.43 ml/min) as compared with the C (0.61 ml/min). A significantly lower pH was observed in total (6.74), mixed (6.7) and permanent (6.76) dentition of JIA groups in comparison to the C (7.25, 7.21, 7.28 respectively). The specific activity of peroxidase was significantly higher in JIA patients (total 112.72 IU/l, mixed dentition 112.98 IU/l, permanent dentition 112.5 IU/l) than in the C group (total 70.03 IU/l, mixed dentition 71.83 IU/l, permanent dentition 68.61 IU/l). The lysozyme concentration in JIA patients (total and permanent dentition groups) was significantly higher than in the C group. There were no significant differences in lactoferrin and salivary protein concentrations. There were no statistically significant differences in oral status between JIA patients and C, respectively: DMFT = 5.71, dmft = 3.73, OHI-S = 0.95, GI = 0.25 and DMFT 5.71, dmft = 3.73, OHI-S = 0.85, GI = 0.24. The specific activity of peroxidase in the unstimulated whole saliva was inversely correlated with the GI index, whereas the salivary lysozyme concentration was inversely correlated with the dmft index in JIA patients. CONCLUSION: In the course of JIA occur a reduction of the resting salivary flow rate and a decrease of saliva pH. In spite of this, no differences in the clinical oral status between the JIA children population and the control group were found. The mobilisation of salivary peroxidase and lysozyme contributes to the maintenance of healthy oral tissues. PMID- 28577526 TI - Unplanned pregnancy-risks and use of emergency contraception: a survey of two Nigerian Universities. AB - BACKGROUND: The vulnerabilities of young women of low socio-economic status and those with little or no formal education tend to dominate the discourse on unplanned pregnancy, unsafe abortion and emergency contraception (EC) in sub Saharan Africa. This article draws on a survey conducted among female undergraduate students to shed light on sexual behaviour and the dynamics of emergency contraceptive use among this cohort. METHODS: The survey involved 420 female undergraduate students drawn using a multistage sampling technique, while a self-administered questionnaire was used for data collection. Univariate and bivariate analyses were applied to examine the factors associated with the use of emergency contraception. RESULTS: Of the 176 female students who reported being sexually active in the year preceding the survey, only 38.6% reported the use of condom during the entire year. Of those who reported unplanned pregnancy anxiety n = 94, about 30.1% used EC, 20.4% used non-EC pills as EC, while others reported having used no EC. A few respondents (n = 3) had terminated a pregnancy under unsafe conditions. Awareness of EC (p < 0.001), knowledge of timing of EC (p = 0.001), perceived risk of unplanned pregnancy (p < 0.001), and level of study (p = 0.013), were significantly correlated with the use of EC. CONCLUSION: The study revealed that educated youths engaged in high-risk sexual activities and also, sought recourse to unproven and unsafe contraceptive methods. Poor knowledge of EC methods and timing of use, as well as wrong perception about EC side effects, are barriers to the utilisation of EC for the prevention of unplanned pregnancy among the study participants. PMID- 28577527 TI - Misdiagnosis of HIV treatment failure based on clinical and immunological criteria in Eastern and Central Kenya. AB - BACKGROUND: Routine laboratory monitoring is part of the basic care package offered to people living with the Human Immunodeficiency Virus (PLHIV). This paper aims to identify the proportion of PLHIVs with clinical and immunological failure who are virologically suppressed and risk being misclassified as treatment failures. METHODS: A retrospective analysis of patient viral load data collected between January 2013 and June 2014 was conducted. Of the patients classified as experiencing either clinical or immunological failure, we evaluated the proportion of true (virological) failure, and estimated the sensitivity and specificity of the immunological and clinical criteria in diagnosing true treatment failure. RESULTS: Of the 27,418 PLHIVs aged 2-80 years on ART in the study period, 6.8% (n = 1859) were suspected of treatment failure and their viral loads analysed. 40% (n = 737) demonstrated viral suppression (VL < 1000 copies/ml). The median viral load (VL) was 3317 copies/ml (IQR 0-47,547). Among the 799 (2.9%) PLHIVs on ART classified as having clinical failure, 41.1% (n = 328) of them had confirmed viral suppression. Of the 463 (1.7%) classified as having immunological failure, 36.9% (n = 171) had confirmed viral suppression. The sensitivity of the clinical criteria in diagnosing true failure was 61% (CI 58%-65%) while that of the immunological criteria 38% (CI 35%-42%). The specificity of the clinical criteria was 34% (CI 30%-39%) while that of the immunological criteria 66% (61%-70%). Age below 20 years was associated with a high viral load (p < .001). Sex and ART regimen were not associated with the viral load. CONCLUSION: Clinical and immunological criteria alone are not sufficient to identify true treatment failure. There is need for accurate treatment failure diagnosis through viral load testing to avoid incorrect early or delayed switching of patients to second-line regimens. This study recommends increased viral load testing in line with the Kenya's ART guidelines. PMID- 28577489 TI - European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS). AB - The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed. PMID- 28577528 TI - Factors associated with the occurrence of injuries requiring hospital transfer among older and working-age pedestrians in Kurume, Japan. AB - BACKGROUND: Pedestrian injuries among older people tend to occur near their residence. However, knowledge regarding whether distance travelled from home to the injury site or road environmental/socioeconomic factors affect injury severity remains limited. METHODS: A cross-sectional study was performed using injury registry data from the Kurume City Fire Department, Japan. Distance travelled from home was determined with geographic information system (GIS) software. Data were analyzed for potential association with injury occurrence and severity, with stratification by age. Signal detection analysis using 10 variables was applied to identify factors associated with the occurrence of severe pedestrian injuries. RESULTS: Among the 545 adult pedestrian injuries reviewed, the factors associated with the occurrence of severe pedestrian injuries for older people and working-age people were evaluated, focusing on the effect of the network distance travelled from home to injury site. Network distance travelled from home to injury site was not associated with the occurrence of severe pedestrian injuries among older people. By applying signal detection analysis, for older people, higher socioeconomic status, wider road width per lane, and higher aging rate in the residential area were significant factors, and for working-age pedestrians, longer network distance travelled between injury place and their residential area and a higher aging rate in the residential area were significantly associated. CONCLUSIONS: To reduce severe pedestrian injuries among older people, improvement of road infrastructure in areas with wider roads, higher socioeconomic status and higher aging rates is required. PMID- 28577529 TI - The effect of immunoregulation of Streptococcus lactis L16 strain upon Staphylococcus aureus infection. AB - BACKGROUND: Staphylococcus aureus is an important pathogen that causes various infections in medical facilities. However, resistance to multiple drugs has made this infection difficult to manage. Thus, new therapeutic strategies are urgently needed to solve this worldwide public health problem. The Streptococcus lactis L16 strain was isolated from the fermented hot chili sauce. To explore whether it can be used as a protective agent against S. aureus infection, we designed a mouse model of S. aureus infection to evaluate the therapeutic potency of S. lactis. Mice were grouped into pre-(P) and post-(T) S. aureus infection groups following oral administration of S. lactis L16. The protection and treatment effects were assessed by examining body weight, internal organ weight, serum cytokines and intestinal secretory IgA alternations. RESULT: Oral administration of the S. lactis L16 strain reduced the loss of body weight in mice post infection and alleviated infection-induced hepatomegaly. In particular, the PL16 group (protection with L16) showed more effective resistance to S. aureus than the TL16 group (treatment with L16). The level of serum cytokine interferon gamma following oral administration of the L16 strain was remarkably increased during infection, as were interleukin-4 levels during convalescence. The probiotic L16 strain induced more sIgA production than S. aureus. CONCLUSION: Our data suggest that S. lactis L16 is an effective strain with anti-Staphylococcus activity. By regulating the Th1/Th2 response, S. lactis can effectively reduce lesions from infection, indicating its therapeutic potential in overcoming antibiotic resistance in this mouse infection model that mimics infections observed in humans. PMID- 28577531 TI - Ideal T1 laminar screw fixation based on computed tomography morphometry. AB - BACKGROUND: The application of laminar screws is an alternative fixation for the first thoracic vertebra (T1). This paper is to determine the anatomical characteristics for adequate laminar screw fixation, and present a modified method of sagittal reconstruction of T1 to provide more accurate measurements. METHODS: Computed tomography (CT) images of 62 patients (32 males, 30 females) were used for the analysis. The following parameters of the T-1 lamina were measured using Mimics software: lamina length, axis angle, minimal outer cortical width, cancellous width, minimal outer cortical height, cancellous height, and spinous process height. Right or left modified sagittal reconstructions (parallel to right or left screws) were innovatively used for measurement. RESULTS: There were no significant differences between the left and right sides for each measurement performed (P > 0.05), but significant differences were detected between males and females (P < 0.05). The mean length of the T1 lamina was 32.8 mm of the T1 minimal outer cortical width was 7.4 mm, and 3.8% of males had a minimal outer cortical width < 5 mm, while 8.6% of females had a minimal outer cortical width < 5 mm. The mean minimal outer cortical height was 10.8 mm, and 1.9% of males had a minimal outer cortical height < 9 mm, while 7.7% of females had a minimal outer cortical height < 9 mm. CONCLUSION: This study suggests there are no anatomical limitations for T1 laminar screw placement in most people. The modified sagittal reconstruction method described allows for easy and precise measurement to aid in the insertion of laminar screws in T1, and gives good visualization of laminar screw insertion direction. PMID- 28577532 TI - Parasitic outbreak of the copepod Balaenophilus manatorum in neonate loggerhead sea turtles (Caretta caretta) from a head-starting program. AB - BACKGROUND: Diseases associated to external parasitosis are scarcely reported in sea turtles. During the last decades several organism have been documented as a part of normal epibiont community connected to sea turtles. The copepod Balaenophilus manatorum has been cited as a part of epibiont fauna with some concern about its parasitic capacity. This study serves three purposes, i.e. (i) it sheds light on the type of life style that B. manatorum has developed with its hosts, particularly turtles; (ii) it makes a cautionary note of the potential health risks associated with B. manatorum in sea turtles under captivity conditions and in the wild, and (iii) it provides data on effective treatments against B. manatorum. RESULTS: We report for the first time a massive infestation of the copepod B. manatorum and subsequent acute mortality in a group of loggerhead sea turtle hatchlings. Four-month-old turtles from a head-starting program started exhibiting excitatory and fin rubbing behavior preceding an acute onset of lethargy, skin ulceration and death in some animals. All the individuals (n = 57) were affected by severe copepod load and presented different degrees of external macroscopic skin lesions. The ventral area of front flippers, axillar and pericloacal skin were mostly affected, and were the main parasite distribution regions. Copepods were also detected on plastron and carapace sutures. The gut contents of B. manatorum reacted positively for cytokeratin, indicating consumption of turtle skin. Severe ulcerative necrotic dermatitis and large amount of bacteria presence were the major histopathological findings. CONCLUSIONS: Individual fresh water immersion for 10 min and lufenuron administration (0.1 ppm) to the water system every 2 weeks proved effective for removing turtle parasites and to control re-infestation, respectively. The results from our study clearly indicated that B. manatorum individuals consume turtle skin. The pathological effects of this agent and the potential implications in sea turtle conservation and management are discussed. PMID- 28577530 TI - Implementation fidelity of a nurse-led falls prevention program in acute hospitals during the 6-PACK trial. AB - BACKGROUND: When tested in a randomized controlled trial (RCT) of 31,411 patients, the nurse-led 6-PACK falls prevention program did not reduce falls. Poor implementation fidelity (i.e., program not implemented as intended) may explain this result. Despite repeated calls for the examination of implementation fidelity as an essential component of evaluating interventions designed to improve the delivery of care, it has been neglected in prior falls prevention studies. This study examined implementation fidelity of the 6-PACK program during a large multi-site RCT. METHODS: Based on the 6-PACK implementation framework and intervention description, implementation fidelity was examined by quantifying adherence to program components and organizational support. Adherence indicators were: 1) falls-risk tool completion; and for patients classified as high-risk, provision of 2) a 'Falls alert' sign; and 3) at least one additional 6-PACK intervention. Organizational support indicators were: 1) provision of resources (executive sponsorship, site clinical leaders and equipment); 2) implementation activities (modification of patient care plans; training; implementation tailoring; audits, reminders and feedback; and provision of data); and 3) program acceptability. Data were collected from daily bedside observation, medical records, resource utilization diaries and nurse surveys. RESULTS: All seven intervention components were delivered on the 12 intervention wards. Program adherence data were collected from 103,398 observations and medical record audits. The falls-risk tool was completed each day for 75% of patients. Of the 38% of patients classified as high-risk, 79% had a 'Falls alert' sign and 63% were provided with at least one additional 6-PACK intervention, as recommended. All hospitals provided the recommended resources and undertook the nine outlined program implementation activities. Most of the nurses surveyed considered program components important for falls prevention. CONCLUSIONS: While implementation fidelity was variable across wards, overall it was found to be acceptable during the RCT. Implementation failure is unlikely to be a key factor for the observed lack of program effectiveness in the 6-PACK trial. TRIAL REGISTRATION: The 6-PACK cluster RCT is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000332921 (29 March 2011). PMID- 28577534 TI - A novel variation of the recurrent laryngeal nerve. AB - BACKGROUND: Injury to the recurrent laryngeal nerve is one of the most severe complications of thyroid surgery. Several anatomic variations of the nerve increase the likelihood of iatrogenic damage. CASE PRESENTATION: A 50-year-old woman was presented to our department with a nodule in the right thyroid lobe, and she reported no voice changes. She had no history of surgery or radiation to the head or neck. Fine-needle aspiration was recorded as papillary thyroid carcinoma. The preoperative laryngoscopy revealed left vocal cord paralysis. Right thyroid lobectomy was performed. A scarce course of the left recurrent laryngeal nerve was found during the operation that ascended along the medial edge of the superior thyroid pole and finally disappeared beneath the superior cornu of the thyroid cartilage without any tracheal, esophageal, or laryngeal branches. The patient was discharged on the third postoperative day with the diagnoses of papillary thyroid carcinoma and congenital left vocal cord paralysis. CONCLUSIONS: The novel variation of the recurrent laryngeal nerve may challenge the current concept of the anatomy of the nerve. The vocal folds mobility should be examined routinely before surgery in patients undergoing thyroid operation. PMID- 28577533 TI - An agent-based model simulation of influenza interactions at the host level: insight into the influenza-related burden of pneumococcal infections. AB - BACKGROUND: Host-level influenza virus-respiratory pathogen interactions are often reported. Although the exact biological mechanisms involved remain unelucidated, secondary bacterial infections are known to account for a large part of the influenza-associated burden, during seasonal and pandemic outbreaks. Those interactions probably impact the microorganisms' transmission dynamics and the influenza public health toll. Mathematical models have been widely used to examine influenza epidemics and the public health impact of control measures. However, most influenza models overlooked interaction phenomena and ignored other co-circulating pathogens. METHODS: Herein, we describe a novel agent-based model (ABM) of influenza transmission during interaction with another respiratory pathogen. The interacting microorganism can persist in the population year round (endemic type, e.g. respiratory bacteria) or cause short-term annual outbreaks (epidemic type, e.g. winter respiratory viruses). The agent-based framework enables precise formalization of the pathogens' natural histories and complex within-host phenomena. As a case study, this ABM is applied to the well-known influenza virus-pneumococcus interaction, for which several biological mechanisms have been proposed. Different mechanistic hypotheses of interaction are simulated and the resulting virus-induced pneumococcal infection (PI) burden is assessed. RESULTS: This ABM generates realistic data for both pathogens in terms of weekly incidences of PI cases, carriage rates, epidemic size and epidemic timing. Notably, distinct interaction hypotheses resulted in different transmission patterns and led to wide variations of the associated PI burden. Interaction strength was also of paramount importance: when influenza increased pneumococcus acquisition, 4-27% of the PI burden during the influenza season was attributable to influenza depending on the interaction strength. CONCLUSIONS: This open-source ABM provides new opportunities to investigate influenza interactions from a theoretical point of view and could easily be extended to other pathogens. It provides a unique framework to generate in silico data for different scenarios and thereby test mechanistic hypotheses. PMID- 28577535 TI - Tuberculosis screening among persons with diabetes mellitus in Pune, India. AB - BACKGROUND: Diabetes mellitus (DM) increases tuberculosis (TB) risk, and there is increasing concern over the public health implications of the convergence of these two epidemics. Screening for TB among people with DM is now recommended in India. METHODS: People with DM seeking care at a large public sector tertiary care hospital clinic in Pune, India, were screened for TB from June 2015 to May 2016. All consenting people with DM were screened for TB at each clinic visit using a five-item, WHO-recommended questionnaire and those with TB symptoms and/or risk factors were tested for active TB using sputum smear microscopty, Xpert(r) MTB/RIF and TB culture. Categorical data and continuous variables were summarized using descriptive statistics. The x 2 test or Wilcoxon rank-sum test was used to ascertain significant associations between categorical and continuous variables, respectively. RESULTS: Among 630 adults approached for screening, median age was 60 (interquartile range (IQR), 57-64) years and 350 (56%) were females. Median hemoglobin A1c (HbA1c) was 8.7% (IQR, 6.7-9.9) and 444 (70.5%) were poorly controlled DM (HbA1c > 7). Forty-four (7%) had prior history of TB but the proportion with TB risk factors at screening was low (<5%). While 18% of participants reported any TB symptoms, none of these patients were diagnosed with culture confirmed TB. CONCLUSIONS: Our study failed to yield any active TB cases using a WHO-recommended questionnaire among people with DM. High TB risk populations among people with DM must be identified if TB screening is to be feasible in settings such as India where the DM epidemic continues to rise. PMID- 28577536 TI - How changing quality management influenced PGME accreditation: a focus on decentralization and quality improvement. AB - BACKGROUND: Evaluating the quality of postgraduate medical education (PGME) programs through accreditation is common practice worldwide. Accreditation is shaped by educational quality and quality management. An appropriate accreditation design is important, as it may drive improvements in training. Moreover, accreditors determine whether a PGME program passes the assessment, which may have major consequences, such as starting, continuing or discontinuing PGME. However, there is limited evidence for the benefits of different choices in accreditation design. Therefore, this study aims to explain how changing views on educational quality and quality management have impacted the design of the PGME accreditation system in the Netherlands. METHODS: To determine the historical development of the Dutch PGME accreditation system, we conducted a document analysis of accreditation documents spanning the past 50 years and a vision document outlining the future system. A template analysis technique was used to identify the main elements of the system. RESULTS: Four themes in the Dutch PGME accreditation system were identified: (1) objectives of accreditation, (2) PGME quality domains, (3) quality management approaches and (4) actors' responsibilities. Major shifts have taken place regarding decentralization, residency performance and physician practice outcomes, and quality improvement. Decentralization of the responsibilities of the accreditor was absent in 1966, but this has been slowly changing since 1999. In the future system, there will be nearly a maximum degree of decentralization. A focus on outcomes and quality improvement has been introduced in the current system. The number of formal documents striving for quality assurance has increased enormously over the past 50 years, which has led to increased bureaucracy. The future system needs to decrease the number of standards to focus on measurable outcomes and to strive for quality improvement. CONCLUSION: The challenge for accreditors is to find the right balance between trusting and controlling medical professionals. Their choices will be reflected in the accreditation design. The four themes could enhance international comparisons and encourage better choices in the design of accreditation systems. PMID- 28577537 TI - Large-scale mitochondrial DNA analysis of native honey bee Apis mellifera populations reveals a new African subgroup private to the South West Indian Ocean islands. AB - BACKGROUND: The South West Indian Ocean (SWIO) archipelagos and Madagascar constitute a hotspot of biodiversity with a high rate of endemism. In this area, the endemic subspecies A. m. unicolor has been described in Madagascar. It belongs to the African lineage, one of the four described evolutionary lineages in honey bees. Despite a long beekeeping tradition and several recorded European introductions, few studies have been carried out on the diversity and proportion of honey bee subspecies. In order to identify and define which evolutionary lineages and potential sub-lineages are present in the SWIO, the COI-COII intergenic region and the ND2 gene of the mtDNA were sequenced in honey bee colonies from three archipelagos. An extensive sampling (n = 1184 colonies) was done in the Mascarene (La Reunion, Mauritius, Rodrigues), Seychelles (Mahe, Praslin, La Digue) and Comoros (Grande Comore, Moheli, Anjouan, Mayotte) archipelagos. Islands genetic diversity was compared to newly sampled populations from Madagascar, continental African and European populations. RESULTS: African lineage haplotypes were found in all islands (except for Rodrigues). Madagascar, Comoros and Seychelles had 100% of A lineage, 95.5% in La Reunion and 56.1% in Mauritius. Among all African colonies detected in the SWIO, 98.1% (n = 633) of COI-COII haplotypes described the presence of the subspecies A. M. unicolor. Both genetic markers revealed i) a new private AI mitochondrial group shared by the SWIO archipelagos and Madagascar distant from continental populations; ii) the private African haplotypes for each island suggested diversity radiation in the archipelagos; iii) the detection of the Comoros archipelago as a possible contact area between insular and continental African populations. The exotic European C and M lineages were only detected in the Mascarene archipelago, but striking differences of proportion were observed among islands. Merely 4.6% of European colonies were found in La Reunion whereas Mauritius cumulated 44%. Here, among the 84 observed COI-COII haplotypes, 50 were newly described including 13 which were private to the SWIO archipelagos and Madagascar. Similarly, 24 of the 34 found ND2 haplotypes were novel which included six haplotypes particular to the SWIO populations. CONCLUSION: A new African subgroup was described in the SWIO region with mitochondrial genetic evidence that A. m. unicolor is the indigenous subspecies of the archipelagos surrounding Madagascar. PMID- 28577538 TI - Dai-Huang-Fu-Zi-Tang alleviates pulmonary and intestinal injury with severe acute pancreatitis via regulating aquaporins in rats. AB - BACKGROUND: Dai-Huang-Fu-Zi-Tang (DHFZT) is a famous traditional Chinese prescription with intestinal obstruction, acute pancreatitis and cholecystalgia for thousands of years. Our previous work found that DHFZT could act against pulmonary and intestinal pathological injury in rats with severe acute pancreatitis (SAP). But the underlying mechanism has not been fully elucidated. The aim of present study was to investigate whether DHFZT could relieve pulmonary and intestinal injury by regulating aquaporins after SAP induced by sodium taurocholate in rats. METHODS: Forty of SD rats were used for dose dependant experiments of DHFZT.Accurate-mass Time-of-flight liquid chromatography-mass spectrometry was used for qualitative screening of chemical compositions of DHFZT. Twenty-four rats were randomly divided into 3 groups: sham group (n = 8), model group (SAP, n = 8), DHFZT group (SAP with DHFZT treatment, n = 8). SAP models were established by retrograde injections of 5% sodium taurocholate solutions into rat pancreaticobiliary ducts. Blood samples were taken at 0, 12, 24, 48 h post-operation for detecting serum amylase, lipase, endotoxin, TNF alpha, IL-6 and IL-10. Protein expression and location of aquaporin (AQP)1, 5, 8 and 9 were assessed by immunohistochemistry, western blot and immunofluorescence respectively. RESULTS: The study showed that 27 kinds of chemical composition were identified, including 10 kinds in positive ion mode and 17 kinds in negative ion mode. The results showed that AQP1, AQP5 of lung, and AQP1, AQP5, AQP8 of intestine in model group were significantly lower than that of sham group (P < 0.05), and which were obviously reversed by treatment with DHFZT. In addition, protein levels of pro-inflammatory cytokines such as TNF-alpha, IL-6 and endotoxin in peripheral blood were significantly suppressed by DHFZT, and that anti-inflammatory cytokine like IL-10 was just opposite. Finally, we also noted that DHFZT reduced serum levels of amylase, lipase and endotoxin, and also improved edema and pathological scores of lung and intestine after SAP. CONCLUSIONS: DHFZT ameliorated the pulmonary and intestinal edema and injury induced by SAP via the upregulation of different AQPs in lung and intestine, and suppressed TNF-alpha, IL-6 expression and enhanced IL-10 expression. PMID- 28577540 TI - Overview of systematic reviews of therapeutic ranges: methodologies and recommendations for practice. AB - BACKGROUND: Many medicines are dosed to achieve a particular therapeutic range, and monitored using therapeutic drug monitoring (TDM). The evidence base for a therapeutic range can be evaluated using systematic reviews, to ensure it continues to reflect current indications, doses, routes and formulations, as well as updated adverse effect data. There is no consensus on the optimal methodology for systematic reviews of therapeutic ranges. METHODS: An overview of systematic reviews of therapeutic ranges was undertaken. The following databases were used: Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts and Reviews of Effects (DARE) and MEDLINE. The published methodologies used when systematically reviewing the therapeutic range of a drug were analyzed. Step by step recommendations to optimize such systematic reviews are proposed. RESULTS: Ten systematic reviews that investigated the correlation between serum concentrations and clinical outcomes encompassing a variety of medicines and indications were assessed. There were significant variations in the methodologies used (including the search terms used, data extraction methods, assessment of bias, and statistical analyses undertaken). Therapeutic ranges should be population and indication specific and based on clinically relevant outcomes. Recommendations for future systematic reviews based on these findings have been developed. CONCLUSION: Evidence based therapeutic ranges have the potential to improve TDM practice. Current systematic reviews investigating therapeutic ranges have highly variable methodologies and there is no consensus of best practice when undertaking systematic reviews in this field. These recommendations meet a need not addressed by standard protocols. PMID- 28577539 TI - Inguinal and anorectal Lymphogranuloma Venereum: a case series from a sexually transmitted disease center in Rome, Italy. AB - BACKGROUND: Lymphogranuloma venereum (LGV) is a sexually transmitted infection caused by L1, L2, L3 serovars of C. trachomatis (CT). Since 2003, LGV cases have been increasing in Europe. Aim of this report is to describe the LGV cases diagnosed in the largest STI center in Rome, Italy, from 2000 to 2016. This report shows that two clinically and epidemiologically different series of cases exist, and that, at present, the ano-rectal LGV represents the clinical variant occurring more frequently among men having sex with men (MSM), particularly those HIV-infected. CASE PRESENTATION: Ten cases of LGV were observed. Three were diagnosed in 2009 in HIV-negative heterosexuals patients that presented the classical genito-ulcerative form with lymphadenopathy. Seven cases were observed in 2015-2016 in HIV-infected MSM, that presented the rectal variant and L2b serovar infection; 4 of these had been misclassified as a chronic bowel disease. Chlamydia infection was confirmed by CT-specific PCR (ompA gene nested PCR), followed by sequence analysis to identify the serovar. All the patients were treated with doxycycline for 3 weeks, obtaining a complete response with healing of both clinical symptoms and dermatological lesions. CONCLUSIONS: Our findings suggest that, in case of persistent rectal symptoms in HIV-infected MSM, LGV should be taken into account and investigated through molecular analyses, in order to achieve a correct diagnosis and management of the patients. PMID- 28577541 TI - Phytomedical assessment of two Cymbopogon species found in Nkonkobe Municipality: toxicological effect on human Chang liver cell line. AB - BACKGROUND: Cymbopogon species are widely used as herbal remedies by the traditional healers living in Nkonkobe Municipality for the treatment and management of skin and respiratory infections. According to our survey, the plants seem to be very important because of the higher demands. METHODS: The leaves of C. validis and C. plurinodis were hydro-distilled and the resulted extracted oils were analyzed by GC/MS. Minimum inhibitory concentrations (MICs) ranging from 7.8 to 500.0 MUg/ml of the extracted oils were tested against eight bacterial strains, using micro-well dilution method. The human Chang liver cell viability was determined using the CellTiter-Blue cell assay. RESULTS: GC-MS analysis of the C. validis essential oil amounted to 87.03%, major components identified were Linalyl alcohol (18.9%), 2-Nephthalenemethanol (6.67%), Longifolene (6.53%), Cubedol (6.08%). Total oil percentage of C. plurinodis was 81.47% and the main components were characterized as 3-Cyclohexane-1-ol (13.58%), Nerolidol (13.6%) and 2-Carene (12.6%). The essential oils from both plants were found to be active against the growth of Gram positive than the Gram negative bacterial tested. Lethal dose at 50 (LD50) of both plants showed 74.87 +/- 1.41 and 81.66 +/- 1.40 degree of toxicity at 24 h. CONCLUSION: Both plants extracts were toxic to human Chang liver cell lines. PMID- 28577542 TI - The effectiveness of creatine treatment for Parkinson's disease: an updated meta analysis of randomized controlled trials. AB - BACKGROUND: The effectiveness of creatine in treating Parkinson's disease (PD) has not been conclusively determined. Therefore, we performed a meta-analysis to address this issue. METHODS: The Cochrane Central Register of Controlled Trials, PUBMED, EMBASE, and other databases were searched, and outcomes measured by the Total Unified Parkinson's Disease Rating Scale (UPDRS) and the Schwab & England Scale were analyzed. RESULTS: Five randomized controlled trials (RCTs) were selected, and 1339 participants were included in the analysis. There were no significant differences between the control and treatment groups in the total, mental, activities of daily living (ADL), or motor UPDRS scores, but an improvement in Schwab & England Scale scores was observed. CONCLUSIONS: Creatine has no observed benefit in PD patients, although more correlated studies are still needed. PMID- 28577543 TI - Implementation of eMental Health care: viewpoints from key informants from organizations and agencies with eHealth mandates. AB - BACKGROUND: The use of technology such as computers, tablets, and smartphones to improve access to and the delivery of mental health care (eMental Health care) is growing worldwide. However, despite the rapidly expanding evidence base demonstrating the efficacy of eMental Health care, its implementation in clinical practice and health care systems remains fragmented. To date, no peer-reviewed, key-informant studies have reported on the perspectives of decision-makers concerned with whether and how to implement eMental Health care. METHODS: From September to November 2015, we conducted 31 interviews with key informants responsible for leadership, policy, research, and/ or information technology in organizations influential in the adoption of technology for eMental Health care. Deductive and inductive thematic analyses of transcripts were conducted using the Behavior Change Wheel as an organizing framework. Frequency and intensity effect sizes were calculated for emerging themes to further explore patterns within the data. RESULTS: Key informant responses (n = 31) representing 6 developed countries and multiple organizations showed consensus on common factors impacting implementation: individual and organizational capacities (e.g., computer literacy skills [patients and providers], knowledge gaps about cyber security, limited knowledge of available services); motivational drivers of technology-based care (e.g., extending care, data analytics); and opportunities for health systems to advance eMental Health care implementation (e.g., intersectoral research, rapid testing cycles, sustainable funding). Frequency effect sizes showed strong associations between implementation and credibility, knowledge, workflow, patient empowerment, electronic medical record (EMR) integration, sustained funding and intersectoral networks. Intensity effect sizes showed the highest concentration of statements (>10% of all comments) related to funding, credibility, knowledge gaps, and patient empowerment. CONCLUSION: This study provides previously unavailable information about key informant perspectives on eMental Health care implementation. The themes that emerged, namely the need to intensify intersectoral research, measure/monitor readiness to implement, define cost utility benchmarks, raise awareness about available technologies, and test assumptions that 'proven' technologies will be easily integrated can inform the design and evaluation of eMental Health care implementation models. PMID- 28577544 TI - Deactivation vs. asynchronous pacing - prospective evaluation of a protocol for rhythm management in patients with magnetic resonance conditional pacemakers undergoing adenosine stress cardiovascular magnetic resonance imaging. AB - BACKGROUND: Cardiovascular Magnetic Resonance (CMR) imaging with adenosine stress is an important diagnostic tool in patients with known or suspected coronary artery disease (CAD). However, the method is not yet established for CAD patients with pacemakers (PM) in clinical practice. A possible reason is that no recommendations exist for PM setting (paused pacing or asynchronous mode) during adenosine stress. We elaborated a protocol for rhythm management in clinical routine for PM patients that considers heart rate changes under adenosine using a test infusion of adenosine in selected patients. METHODS: 47 consecutive patients (mean age 72.3 +/- 10,0 years) with MR conditional PM and known or suspected CAD who underwent CMR in clinical routine were studied in this prospective observational study. PM indications were sinus node dysfunction (SND, n = 19; 40,4%), atrioventricular (AV) block (n = 26; 55.3%) and bradyarrhythmia in permanent atrial fibrillation (AF, n = 2; 4.3%). In patients with SND, normal AV conduction and resting HR >45 bpm at the time of CMR and in AF the PM was deactivated for the scan. In intermittent AV-block a test infusion of adenosine was given prior to the scan. All patients with permanent higher degree sinuatrial or AV-block or deterioration of AV-conduction in the adenosine test were paced asynchronously during CMR, in patients with preserved AV-conduction under adenosine the pacemaker was deactivated. CMR protocol included cine imaging, adenosine stress perfusion and late gadolinium enhancement. RESULTS: The adenosine test was able to differentiate between mandatory PM stimulation during CMR and safe deactivation of the device. In patients with permanent sinuatrial or AV-block (n = 11; 23.4%) or deterioration of AV conduction in the adenosine test (n = 5, 10.6%) asynchronous pacing above resting heart rate did not interfere with intrinsic rhythm, no competitive stimulation was seen during the scan. 10 of 15 (66,7%) patients with intermittent AV-block showed preserved AV-conduction under adenosine. As in SND and AF deactivation of the PM showed to be safe during CMR, no bradycardia was observed. CONCLUSION: Our protocol for rhythm management during adenosine stress CMR showed to be feasible and safe and may be recommended for pacemaker patients undergoing routine CMR. PMID- 28577545 TI - The effect of a prenatal lifestyle intervention on glucose metabolism: results of the Norwegian Fit for Delivery randomized controlled trial. AB - BACKGROUND: The effectiveness of prenatal lifestyle intervention to prevent gestational diabetes and improve maternal glucose metabolism remains to be established. The Norwegian Fit for Delivery (NFFD) randomized, controlled trial studied the effect of a combined lifestyle intervention provided to a general population, and found significantly lower gestational weight gain among intervention participants but no improvement in obstetrical outcomes or the proportion of large infants. The aim of the present study is to examine the effect of the NFFD intervention on glucose metabolism, including an assessment of the subgroups of normal-weight and overweight/obese participants. METHODS: Healthy, non-diabetic women expecting their first child, with pre-pregnancy body mass index (BMI) >=19 kg/m2, age >= 18 years and a singleton pregnancy of <=20 gestational-weeks were enrolled from healthcare clinics in southern Norway. Gestational weight gain was the primary endpoint. Participants (n = 606) were individually randomized to intervention (two dietary consultations and access to twice-weekly exercise groups) or control group (routine prenatal care). The effect of intervention on glucose metabolism was a secondary endpoint, measuring glucose (fasting and 2-h following 75-g glucose load), insulin, homeostatic assessment of insulin resistance (HOMA-IR) and leptin levels at gestational-week 30. RESULTS: Blood samples from 557 (91.9%) women were analyzed. For the total group, intervention resulted in reduced insulin (adj. Mean diff -0.91 mU/l, p = 0.045) and leptin levels (adj. Mean diff -207 pmol/l, p = 0.021) compared to routine care, while glucose levels were unchanged. However, the effect of intervention on both fasting and 2-h glucose was modified by pre-pregnancy BMI (interaction p = 0.030 and p = 0.039, respectively). For overweight/obese women (n = 158), intervention was associated with increased risk of at least one glucose measurement exceeding International Association of Pregnancy and Diabetes Study Group thresholds (33.7% vs. 13.9%, adj. OR 3.89, p = 0.004). CONCLUSIONS: The Norwegian Fit for Delivery intervention lowered neither glucose levels nor GDM incidence, despite reductions in insulin and leptin. Prenatal combined lifestyle interventions designed for a general population may be unsuited to reduce GDM risk, particularly among overweight/obese women, who may require earlier and more targeted interventions. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT01001689 , registered July 2, 2009, confirmed completed October 26, 2009 (retrospectively registered). PMID- 28577546 TI - High maternal mortality in Jigawa State, Northern Nigeria estimated using the sisterhood method. AB - BACKGROUND: Maternal mortality is extremely high in Nigeria. Accurate estimation of maternal mortality is challenging in low-income settings such as Nigeria where vital registration is incomplete. The objective of this study was to estimate the lifetime risk (LTR) of maternal death and the maternal mortality ratio (MMR) in Jigawa State, Northern Nigeria using the Sisterhood Method. METHODS: Interviews with 7,069 women aged 15-49 in 96 randomly selected clusters of communities in 24 Local Government Areas (LGAs) across Jigawa state were conducted. A retrospective cohort of their sisters of reproductive age was constructed to calculate the lifetime risk of maternal mortality. Using most recent estimates of total fertility for the state, the MMR was estimated. RESULTS: The 7,069 respondents reported 10,957 sisters who reached reproductive age. Of the 1,026 deaths in these sisters, 300 (29.2%) occurred during pregnancy, childbirth or within 42 days after delivery. This corresponds to a LTR of 6.6% and an estimated MMR for the study areas of 1,012 maternal deaths per 100,000 live births (95% CI: 898 1,126) with a time reference of 2001. CONCLUSIONS: Jigawa State has an extremely high maternal mortality ratio underscoring the urgent need for health systems improvement and interventions to accelerate reductions in MMR. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov ( NCT01487707 ). Initially registered on December 6, 2011. PMID- 28577547 TI - Validity of self-reported weight and height: a cross-sectional study among Malaysian adolescents. AB - BACKGROUND: Self-reported weight and height are commonly used in lieu of direct measurements of weight and height in large epidemiological surveys due to inevitable constraints such as budget and human resource. However, the validity of self-reported weight and height, particularly among adolescents, needs to be verified as misreporting could lead to misclassification of body mass index and therefore overestimation or underestimation of the burden of BMI-related diseases. The objective of this study was to determine the validity of self reported weight and height among Malaysian secondary school children. METHODS: Both self-reported and directly measured weight and height of a subgroup of 663 apparently healthy schoolchildren from the Malaysian Adolescent Health Risk Behaviour (MyAHRB) survey 2013/2014 were analysed. Respondents were required to report their current body weight and height via a self-administrative questionnaire before they were measured by investigators. The validity of self reported against directly measured weight and height was examined using intraclass correlation coefficient (ICC), the Bland-Altman plot and weighted Kappa statistics. RESULTS: There was very good intraclass correlation between self-reported and directly measured weight [r = 0.96, 95% confidence interval (CI): 0.93, 0.97] and height (r = 0.94, 95% CI: 0.90, 0.96). In addition the Bland-Altman plots indicated that the mean difference between self-reported and direct measurement was relatively small. The mean difference (self-reported minus direct measurements) was, for boys: weight, -2.1 kg; height, -1.6 cm; BMI, -0.44 kg/m2 and girls: weight, -1.2 kg; height, -0.9 cm; BMI, -0.3 kg/m2. However, 95% limits of agreement were wide which indicated substantial discrepancies between self-reported and direct measurements method at the individual level. Nonetheless, the weighted Kappa statistics demonstrated a substantial agreement between BMI status categorised based on self-reported weight and height and the direct measurements (kappa = 0.76, 95% CI: 0.67, 0.84). CONCLUSION: Our results show that the self-reported weight and height were consistent with direct measurements and therefore can be used in assessing the nutritional status of Malaysian school children from the age of 13 to 17 years old in epidemiological studies and for surveillance purposes when direct measurements are not feasible, but not for assessing nutritional status at the individual level. PMID- 28577548 TI - Depression, suicidality, and alcohol use disorder among people living with HIV/AIDS in Nigeria. AB - BACKGROUND: People Living with HIV/AIDS (PLHIV) face various day-to-day and long term personal, interpersonal, social, physical and psychological challenges as a result of, and in addition to the health conditions they are susceptible to due to their HIV status. There is a dearth of large-scale research to provide robust prevalence estimates of mental health problems among PLHIV, especially in Nigeria. This study aimed to ascertain the prevalence and factors associated with major depressive episodes, suicidality, and alcohol use disorder among people living with HIV/AIDS in Nigeria. METHODS: A survey of 1187 participants aged 18 years and above was conducted within three HIV treatment centres in Abuja, Nigeria. Depression, suicidality, and alcohol use disorder modules of the WHO World Mental Health Composite International Diagnostic Interview questionnaire were used for this study. A socio-demographic questionnaire was also used to collect other health and demographic data. Descriptive statistics (frequency distribution, percentage, mean, median, mode, and standard deviation) and regression analyses were conducted to explore associations between mental health problems and demographic and other health-related factors. RESULTS: Twelve-month prevalence rates were 28.2% for major depressive episodes, 2.9% for suicidal ideation, 2.3% for suicide attempts, 7.8% for harmful alcohol use, 7.0% for alcohol abuse, and 2.2% for alcohol dependence. Major depressive episodes were significantly associated with having planned suicide and marital status. Suicidal ideation was significantly associated with major depressive episodes, marital status, and religion. Females were less likely to be diagnosed with alcohol disorders. CONCLUSIONS: Some people living with HIV/AIDS also tend to suffer from depression, suicidality, and alcohol use disorders. These findings highlight the need for the integration of mental health services into HIV/AIDS care in Nigeria. PMID- 28577549 TI - Whole exome sequencing of an asbestos-induced wild-type murine model of malignant mesothelioma. AB - BACKGROUND: Malignant mesothelioma (MM) is an aggressive cancer of the pleural and peritoneal cavities caused by exposure to asbestos. Asbestos-induced mesotheliomas in wild-type mice have been used extensively as a preclinical model because they are phenotypically identical to their human counterpart. However, it is not known if the genetic lesions in these mice tumours are similar to in the human disease, a prerequisite for any new preclinical studies that target genetic abnormalities. METHODS: We performed whole exome sequencing of fifteen asbestos induced murine MM tumour cell lines from BALB/c, CBA and C57BL/6 mouse strains and compared the somatic mutations and copy number variations with those recurrently reported in human MM. We then catalogued and characterised the mutational landscape of the wild-type murine MM tumours. Quantitative RT-PCR was used to interrogate the expression of key MM genes of interest in the mRNA. RESULTS: Consistent with human MM tumours, we identified homozygous loss of the tumour suppressor Cdkn2a in 14/15 tumours. One tumour retained the first exon of both of the p16INK4a and p19ARF isoforms though this tumour also contained genetic amplification of Myc resulting in increased expression of the c-Myc proto oncogene in the mRNA. There were no chromosomal losses in either the Bap1 or Nf2 regions. One tumour harbored homozygous loss of Trp53 in the DNA. Mutation rates were similar in tumours generated in the CBA and C57BL/6 strains when compared to human MM. Interestingly, all BALB/c tumour lines displayed high mutational loads, consistent with the known mutator phenotype of the host strain. The Wnt, MAPK and Jak-STAT signaling pathways were found to be the most commonly affected biological pathways. Mutations and copy number deletions also occurred in the Hedgehog and Hippo pathways. CONCLUSIONS: These data suggest that in the wild type murine model asbestos causes mesotheliomas in a similar way to in human MM. This further supports the notion that the murine model of MM represents a genuine homologue of the human disease, something uncommon in cancer, and is thus a valuable tool to provide insight into MM tumour development and to aide the search for novel therapeutic strategies. PMID- 28577550 TI - Study protocol of the ASD-Net, the German research consortium for the study of Autism Spectrum Disorder across the lifespan: from a better etiological understanding, through valid diagnosis, to more effective health care. AB - BACKGROUND: Autism Spectrum Disorder (ASD) is a severe, lifelong neurodevelopmental disorder with early onset that places a heavy burden on affected individuals and their families. Due to the need for highly specialized health, educational and vocational services, ASD is a cost-intensive disorder, and strain on health care systems increases with increasing age of the affected individual. METHODS: The ASD-Net will study Germany's largest cohort of patients with ASD over the lifespan. By combining methodological expertise from all levels of clinical research, the ASD-Net will follow a translational approach necessary to identify neurobiological pathways of different phenotypes and their appropriate identification and treatment. The work of the ASD-Net will be organized into three clusters concentrating on diagnostics, therapy and health economics. In the diagnostic cluster, data from a large, well-characterized sample (N = 2568) will be analyzed to improve the efficiency of diagnostic procedures. Pattern classification methods (machine learning) will be used to identify algorithms for screening purposes. In a second step, the developed algorithm will be tested in an independent sample. In the therapy cluster, we will unravel how an ASD-specific social skills training with concomitant oxytocin administration can modulate behavior through neurobiological pathways. For the first time, we will characterize long-term effects of a social skills training combined with oxytocin treatment on behavioral and neurobiological phenotypes. Also acute effects of oxytocin will be investigated to delineate general and specific effects of additional oxytocin treatment in order to develop biologically plausible models for symptoms and successful therapeutic interventions in ASD. Finally, in the health economics cluster, we will assess service utilization and ASD-related costs in order to identify potential needs and cost savings specifically tailored to Germany. The ASD-Net has been established as part of the German Research Network for Mental Disorders, funded by the BMBF (German Federal Ministry of Education and Research). DISCUSSION: The highly integrated structure of the ASD-Net guarantees sustained collaboration of clinicians and researchers to alleviate individual distress, harm, and social disability of patients with ASD and reduce costs to the German health care system. TRIAL REGISTRATION: Both clinical trials of the ASD-Net are registered in the German Clinical Trials Register: DRKS00008952 (registered on August 4, 2015) and DRKS00010053 (registered on April 8, 2016). PMID- 28577551 TI - Clinical diagnostic exome evaluation for an infant with a lethal disorder: genetic diagnosis of TARP syndrome and expansion of the phenotype in a patient with a newly reported RBM10 alteration. AB - BACKGROUND: Diagnostic Exome Sequencing (DES) has been shown to be an effective tool for diagnosis individuals with suspected genetic conditions. CASE PRESENTATION: We report a male infant born with multiple anomalies including bilateral dysplastic kidneys, cleft palate, bilateral talipes, and bilateral absence of thumbs and first toes. Prenatal testing including chromosome analysis and microarray did not identify a cause for the multiple congenital anomalies. Postnatal diagnostic exome studies (DES) were utilized to find a molecular diagnosis for the patient. Exome sequencing of the proband, mother, and father showed a previously unreported maternally inherited RNA binding motif protein 10 (RBM10) c.1352_1353delAG (p.E451Vfs*66) alteration. Mutations in RBM10 are associated with TARP syndrome, an X-linked recessive disorder originally described with cardinal features of talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava. CONCLUSION: DES established a molecular genetic diagnosis of TARP syndrome for a neonatal patient with a poor prognosis in whom traditional testing methods were uninformative and allowed for efficient diagnosis and future reproductive options for the parents. Other reported cases of TARP syndrome demonstrate significant variability in clinical phenotype. The reported features in this infant including multiple hemivertebrae, imperforate anus, aplasia of thumbs and first toes have not been reported in previous patients, thus expanding the clinical phenotype for this rare disorder. PMID- 28577552 TI - Determining the amount of training needed for competency of anesthesia trainees in ultrasonographic identification of the cricothyroid membrane. AB - BACKGROUND: Airway guidelines recommend the use of ultrasound to localize the cricothyroid membrane prior to airway manipulation in difficult airways. In this study, we aimed to determine the amount of training anesthesia trainees would need to achieve competence in bedside ultrasound to identify the cricothyroid membrane. METHODS: This is a prospective non-randomized cohort study in the Department of Anesthesia at Mount Sinai Hospital (Toronto, Ontario, Canada). Following institutional ethics approval, six anesthesia trainees consisting of four residents and two fellows underwent a 2-h training session on neck ultrasound to identify neck landmarks and the cricothyroid membrane. The trainees had no previous airway ultrasound experience. One-two weeks later, each trainee performed consecutive neck ultrasound scans on 20 healthy volunteers to identify the cricothyroid membrane. Cumulative sum (CUSUM) learning curves were constructed for each trainee. Primary outcome was the number of ultrasound examinations required to achieve competence, defined as 90% success rate in a series of 20 ultrasound scans. Secondary outcomes were the overall success rate, the time (sec.) required to perform the task, and 3-month skills assessment. RESULTS: CUSUM analysis showed four trainees achieved competence with a mean [range] success rate of 94.0% [90-100%] and a median [range] number of attempts of 14 [9-18]. Two trainees did not achieve competence, but obtained a success rate of 75.0 and 80.0% each. Overall (number of attempts) success rate was 88.3% (106/120) with a mean (SD) time of 36.9 (9.0) sec. Three months after training, ultrasound of five consecutive neck scans showed a mean success rate of 86.7% (26/30) and mean (SD) time of 47.7 (16.0) sec. CONCLUSIONS: After a short 2-h training session, most anesthesia trainees (n = 4/6) achieved competence in ultrasound-identification of the cricothyroid membrane with less than 20 scans in a mean time less than 60 s., and that they remain reasonably competent 3 months later. The learning curve for ultrasound identification of the cricothyroid membrane seems to be short even without prior airway ultrasound experience. PMID- 28577553 TI - The refractive state of the eye in Icelandic horses with the Silver mutation. AB - BACKGROUND: The syndrome Multiple Congenital Ocular Anomalies (MCOA) is a congenital eye disorder in horses. Both the MCOA syndrome and the Silver coat colour in horses are caused by the same missense mutation in the premelanosome protein (PMEL) gene. Horses homozygous for the Silver mutation (TT) are affected by multiple ocular defects causing visual impairment or blindness. Horses heterozygous for the Silver mutation (CT) have less severe clinical signs, usually cysts arising from the ciliary body iris or retina temporally. It is still unknown if the vision is impaired in horses heterozygous for the Silver mutation. A recent study reported that Comtois horses carrying the Silver mutation had significantly deeper anterior chambers of the eye compared to wild type horses. This could potentially cause refractive errors. The purpose of the present study was to investigate if Icelandic horses with the Silver mutation have refractive errors compared to wild-type horses. One hundred and fifty-two Icelandic horses were included in the study, 71 CT horses and five TT horses. All horses were genotyped for the missense mutation in PMEL. Each CT and TT horse was matched by a wild-type (CC) horse of the same age +/- 1 year. Skiascopy and a brief ophthalmic examination were performed in all horses. Association between refraction and age, eye, genotype and sex was tested by linear mixed-effect model analysis. TT horses with controls were not included in the statistical analyses as they were too few. RESULTS: The interaction between age and genotype had a significant impact on the refractive state (P = 0.0001). CT horses older than 16 years were on average more myopic than wild-type horses of the same age. No difference in the refractive state could be observed between genotypes (CT and CC) in horses younger than 16 years. TT horses were myopic (-2 D or more) in one or both eyes regardless of age. CONCLUSION: Our results indicate that an elderly Icelandic horse (older than 16 years) carrying the Silver mutation is more likely to be myopic than a wild-type horse of the same age. PMID- 28577554 TI - Fermentation of lactose to ethanol in cheese whey permeate and concentrated permeate by engineered Escherichia coli. AB - BACKGROUND: Whey permeate is a lactose-rich effluent remaining after protein extraction from milk-resulting cheese whey, an abundant dairy waste. The lactose to ethanol fermentation can complete whey valorization chain by decreasing dairy waste polluting potential, due to its nutritional load, and producing a biofuel from renewable source at the same time. Wild type and engineered microorganisms have been proposed as fermentation biocatalysts. However, they present different drawbacks (e.g., nutritional supplements requirement, high transcriptional demand of recombinant genes, precise oxygen level, and substrate inhibition) which limit the industrial attractiveness of such conversion process. In this work, we aim to engineer a new bacterial biocatalyst, specific for dairy waste fermentation. RESULTS: We metabolically engineered eight Escherichia coli strains via a new expression plasmid with the pyruvate-to-ethanol conversion genes, and we carried out the selection of the best strain among the candidates, in terms of growth in permeate, lactose consumption and ethanol formation. We finally showed that the selected engineered microbe (W strain) is able to efficiently ferment permeate and concentrated permeate, without nutritional supplements, in pH-controlled bioreactor. In the conditions tested in this work, the selected biocatalyst could complete the fermentation of permeate and concentrated permeate in about 50 and 85 h on average, producing up to 17 and 40 g/l of ethanol, respectively. CONCLUSIONS: To our knowledge, this is the first report showing efficient ethanol production from the lactose contained in whey permeate with engineered E. coli. The selected strain is amenable to further metabolic optimization and represents an advance towards efficient biofuel production from industrial waste stream. PMID- 28577555 TI - Intake of Boron, Cadmium, and Molybdenum enhances rat thyroid cell transformation. AB - BACKGROUND: Epidemiologic data in volcanic areas suggest that environmental factors might be involved in the increase of thyroid cancer (TC) incidence. Recent reports indicate that several heavy metals and metalloids are increased in volcanic areas. This study aims to evaluate the combined effect of three of these elements Boron (B), Cadmium (Cd), and Molybdenum (Mo) - all increased in the volcanic area of Mt. Etna, in Italy - on thyroid tumorigenesis in the rat. METHODS: Female Wistar rats prone to develop thyroid tumors by low-iodine diet and methimazole treatment received ad libitum drinking water supplemented with B, Cd, and Mo at concentrations in the range found in the urine samples of residents of the volcanic area. At 5 and 10 months animals were euthanized, and their thyroid analysed. Statistical analysis was performed with a 2-way unpaired t test. RESULTS: No toxic effect of the three elements on the growth of the animals was observed. A significant increase of histological features of transformation was observed in thyroid follicular cells of rats treated with B, Cd, and Mo compared with those of control group. These abnormalities were associated with decreased iodine content in the thyroid. CONCLUSIONS: This study provides the evidence that slightly increased environmental concentrations of B, Cd, and Mo can accelerate the appearance of transformation marks in the thyroid gland of hypothyroid rats. PMID- 28577556 TI - Mobile phone use, school electromagnetic field levels and related symptoms: a cross-sectional survey among 2150 high school students in Izmir. AB - BACKGROUND: Health outcomes of electromagnetic fields (EMF) from mobile phones and their base stations are of concern. Conducting multidisciplinary research, targeting children and exploring dose-response are recommended. Our objectives were to describe the mobile phone usage characteristics of high school students and to explore the association between mobile phone usage characteristics, high school EMF levels and self-reported symptoms. METHODS: This cross-sectional study's data were collected by a survey questionnaire and by measuring school EMF levels between November 2009 and April 2011. A sample size of 2530 was calculated from a total of 20,493 students in 26 high schools and 2150 (85.0%) were included in the analysis. The frequencies of 23 symptoms were questioned and analysed according to 16 different aspects of mobile phone use and school EMF levels, exploring also dose-response. School EMF levels were measured with Aaronia Spectran HF-4060 device. Chi square and trend tests were used for univariate and logistic regression was used for multivariate analyses. RESULTS: Among participants, 2021 (94.0%) were using mobile phones and 129 (6.0%) were not. Among users, 49.4% were speaking <10 min and 52.2% were sending/receiving 75 or more messages per day. Headache, fatigue and sleep disturbances were observed respectively 1.90 (95% CI 1.30-2.77), 1.78 (1.21-2.63) and 1.53 (1.05-2.21) times more among mobile phone users. Dose-response relationships were observed especially for the number of calls per day, total duration of calls per day, total number of text messages per day, position and status of mobile phone at night and making calls while charging as exposures and headache, concentration difficulties, fatigue and sleep disturbances as general symptoms and warming of the ear and flushing as local symptoms. CONCLUSIONS: We found an association between mobile phone use and especially headache, concentration difficulties, fatigue, sleep disturbances and warming of the ear showing also dose-response. We have found limited associations between vicinity to base stations and some general symptoms; however, we did not find any association with school EMF levels. Decreasing the numbers of calls and messages, decreasing the duration of calls, using earphones, keeping the phone away from the head and body and similar precautions might decrease the frequencies or prevalence of the symptoms. PMID- 28577557 TI - Unusual neoplasm on the hard palate of a child: a case report. AB - BACKGROUND: Myoepitheliomas account for less than 1% of salivary gland tumors. They mostly affect the parotid glands of adults during the third to fifth decades. CASE PRESENTATION: A 10-year-old Indian boy reported a small swelling in the roof of his mouth of 10 days' duration. History revealed that the lesion was painless and not associated with bleeding or pus discharge. On examination, a purplish well-circumscribed growth was noted on his posterior hard palate. Magnetic resonance imaging was suggestive of a well-encapsulated hemangioma. An excisional biopsy was performed and histopathology along with immunohistochemistry analysis showed that the lesion was a spindle cell variant of benign myoepithelioma. CONCLUSION: Palatal myoepitheliomas are rare and their occurrence in young individuals is rarer. PMID- 28577558 TI - Epidemiology of pertussis in Alberta, Canada 2004-2015. AB - BACKGROUND: We describe the epidemiology of pertussis in Alberta, Canada by person, place, and time between 2004 and 2015, identify outbreak years, and examine vaccination coverage and vaccination timeliness. METHODS: We used health data from Alberta's Communicable Disease Registry System for the period of January 1, 2004 through August 31, 2015 to identify unique cases of pertussis. Unique cases were deterministically linked to data in Alberta's immunization repository and health care insurance plan registry. Population estimates and vaccination coverage were extracted from Alberta's online Interactive Health Data Application. We estimated pertussis incidence rates per 100,000 persons by year, age group, gender, and health zone. Outbreak years were identified using a one sided cumulative sum (CUSUM) analysis by comparing annual incidence rates to baseline rates. RESULTS: Over the period, 3510 cases of pertussis were confirmed by laboratory testing or epidemiological linkage. Incidence rates per 100,000 persons were highest in 2004 (20.5), 2005 (13.6), and 2015 (10.4) for all age groups. Incidence rates were highest among the youngest age groups and decreased as age groups increased. Based on CUSUM analysis, 2008 and 2012 met the criteria for outbreak years. Vaccination coverage was over 90% among the general population, however only 61% of cases received at least one dose. About 60% of cases were diagnosed 5+ years after receiving the vaccine. Approximately 87-91% of vaccinated cases did not receive the first three vaccine doses in a timely manner. CONCLUSION: Pertussis incidence rates fluctuated over the period across all age groups. The majority of cases had no record of vaccination or were delayed in receiving vaccines. CUSUM analysis was an effective method for identifying outbreaks. PMID- 28577560 TI - Research dissemination workshops: observations and implications based on an experience in Burkina Faso. AB - BACKGROUND: In Burkina Faso, malaria remains the primary cause of healthcare use, morbidity and child mortality. Therefore, efforts are needed to support the knowledge transfer and application of the results of numerous studies to better formulate and implement programs in the fight against the malaria pandemic. To this end, a 2-day dissemination workshop was held to share the most recent results produced by a multidisciplinary research team. The objective of the present study was to evaluate the workshop and the policy briefs distributed there, the effects these produced on research results use and the processes that facilitated, or not, the application of the knowledge transmitted. METHODS: A mixed-methods design was used. The data were drawn from a quantitative evaluation questionnaire completed after the workshop (n = 25/31) and qualitative interviews conducted with the researchers and various actors who attended the workshop (n = 11) and with participants in working groups (n = 40) that later analysed the policy briefs distributed at the workshop. RESULTS: The participants recognised the quality of the research results presented, but felt that more needed to be done to adapt the researchers' language and improve the functioning of the workshop. The potential effects of the workshop were rather limited. Effects were mainly at two levels: individual (e.g. acquisition of new knowledge, personal awareness raising) and local (e.g. change of practice in a local non-governmental organisation). Most participants perceived the utility of the research results, but several reported that their narrow decisional power limited their ability to apply this knowledge. CONCLUSIONS: This study showed the importance of workshops to inform key actors of research results and the need to undertake several different activities to increase the chances that the knowledge will be applied. Several recommendations are proposed to improve knowledge translation approaches in the West African context, including organising working and discussion groups, developing an action plan at the end of the workshop and offering support to participants after the workshop, among others. PMID- 28577559 TI - Ectopic germinal center and megalin defect in primary Sjogren syndrome with renal Fanconi syndrome. AB - BACKGROUND: This study reports the clinical and pathological features of 12 cases of primary Sjogren syndrome (pSS) with renal involvement presenting with proximal tubular dysfunction in a single center, and investigates the possible correlation of ectopic germinal center formation and megalin/cubilin down-expression. METHOD: Clinical and pathological records were reviewed. Immunohistochemistry was carried out to detect megalin, cubilin, CD21 and IL-17 expression. RESULTS: Patients presented with different degrees of proximal renal tubule lesion and decreased estimated glomerular filtration rate (eGFR). Renal biopsy revealed tubulointerstitial nephritis, with tubular epithelial cell degeneration, tubular atrophy, interstitial inflammation and focal fibrosis. Immunohistochemistry revealed decreased expression of megalin and cubilin, two important multiligand protein receptors on the brush border of proximal tubular epithelial cells. IL-17 secreted by Th17 subtype effector T cells was diffusely detected in the renal proximal tubule, with a negative correlation of IL-17 and megalin expression. In addition, ectopic germinal centers characterized by CD21+ follicular dendritic cells were present in the renal interstitium. In patients with a decreased eGFR, treatment with 4 weeks of glucocorticoid therapy resulted in an improved eGFR in 75% of patients. CONCLUSION: We report 12 cases of pSS characterized by Fanconi syndrome. The decreased megalin and cubilin expression may contribute to the proximal tubular reabsorption defect, possibly secondary to Th17 infiltration and formation of ectopic germinal centers. PMID- 28577561 TI - Cameroonian professional soccer players and risk of atherosclerosis. AB - BACKGROUND: Elevated titers of antibodies against oxidized low-density lipoproteins-cholesterol (ox-LDL-Ab) have been reported among professional athletes, paradoxically reflecting an increased risk of developing atherogenic and/or cardiovascular events. This study aimed to determine titers of ox-LDL-Ab in a group of Cameroonian professional soccer players, and evaluate their evolution during part of a competition season as well as the plasmatic antioxidant status to find out if this latter correlates with ox-LDL-Ab . METHODS: We conducted a descriptive cohort study in 2012 including 18 healthy male soccer players. Three samplings were performed in March (T1), May (T2), and July 2012 (T3) to assess the lipid profile, titers of ox-LDL-Ab, and plasmatic concentrations of four antioxidants: the ferric reducing antioxidant power (FRAP), reduced glutathione (GSH), superoxide dismutase (SOD), and uric acid. RESULTS: Ages ranged from 16 to 28 years with a median (interquartile range) of 19.5 (19-23) years. Total cholesterol, high-density lipoproteins-cholesterol (HDL C), low-density lipoproteins-cholesterol (LDL-C) and triglycerides varied within normal ranges throughout the three samplings. While total cholesterol and LDL-C titers increased significantly (p = 0.003 and p = 0.006, respectively), triglycerides and HDL-C values varied non-significantly throughout the measurements (p = 0.061 and p = 0.192, respectively). The median ox-LDL-Ab titers were respectively: 653.3 (468.2-838.8) mIU/ml at T1, 777.7 (553.7-1150.7) mIU/ml at T2, and 1037.7 (901.7-1481.5) mIU/ml at T3. Overall, ox-LDL-Ab titers increased significantly from T1 to T3 (p = 0.006). Concomitantly, uric acid and FRAP concentrations decreased significantly (p = 0.001 and p = 0.003, respectively); on the contrary, GSH and SOD values increased, but insignificantly (p = 0.115 and p = 0.110, respectively). There was a positive and significant correlation between ox-LDL-Ab and HDL-C (rho = 0.519, p = 0.027), and between ox LDL-Ab and SOD (rho = 0.504, p = 0.033) at T2. Ox-LDL-Ab values were expected to increase with each new visit (beta = 201.1; p = 0.041) and each IU/ml of SOD titers (beta = 23.6; p = 0.019). CONCLUSION: These Cameroonian professional soccer players exhibited high levels of ox-LDL-Ab reflecting elevated levels of oxidatively-modified LDL-C particles with an increment over time, this being insufficiently counterbalanced by the antioxidant defense mechanisms. As a consequence, they may be at increased atherogenic and cardiovascular risks. PMID- 28577563 TI - Endoscopic ultrasonography compared with multidetector computed tomography for the preoperative staging of gastric cancer: a meta-analysis. AB - BACKGROUND: The current study sought to perform a meta-analysis to compare the preoperative staging of endoscopic ultrasonography (EUS) and multidetector computed tomography (MDCT) in gastric carcinoma. METHODS: Articles published between January 1, 2000, and April 1, 2016, that compared EUS with MDCT were included, and data were presented as 2 * 2 tables. The sensitivities, specificities and summary receiver operating characteristic (ROC) curves for T and N staging were calculated using a bivariate mixed effects model. Data were weighted by generic variance and then pooled by random-effects modeling. RESULTS: Eight studies comprising 1736 patients were included in this meta-analysis. For T1 staging, the sensitivity value for EUS (82%) was significantly higher than that for MDCT (41%) (relative risk (RR): 2.06, 95% confidence interval (CI) 1.07 3.94; P = 0.030). For lymph node involvement, the sensitivity value for EUS (91%) was also significantly higher than that for MDCT (77%) (RR 1.14, 95% CI 1.05 1.23; P = 0.001). However, the specificity values of both EUS and MDCT were quite low, at 49 and 63%, respectively. No significant differences in T2-4 staging between EUS and MDCT were noted. CONCLUSION: This meta-analysis indicates that EUS may be superior to MDCT in preoperative T1 and N staging. Additionally, the low specificity values of EUS and MDCT for N staging merits attention. PMID- 28577562 TI - Current role of perampanel in pediatric epilepsy. AB - Perampanel is among the latest AEDs approved, indicated for the treatment of partial-onset seizures with or without secondary generalization, and for primary generalized tonic-clonic seizures, in patients aged 12 years and older. This paper summarizes the clinical recommendations on the current role of perampanel in the treatment of pediatric epilepsies and future directions for research. The optimal dosage should be comprised between 4 and 12 mg/day, with 8 mg/day being the most common dosage used. The rate and severity of adverse events, including psychiatric symptoms, can be decreased by starting at low doses, and titrating slowly. Overall, perampanel presents an acceptable risk/benefit ratio, but special caution should be made to the risk of seizure aggravation and behavioral problems. The favorable cognitive profile, the ease of use of the titration scheme and the once-daily formulation offer advantage over other AEDs and make this drug particularly suitable for adolescent population. Perampanel is a welcome addition to the armamentarium of the existing AEDs, as it represents a new approach in the management of epilepsy, with a novel mechanism of action and a potential to have a considerable impact on the treatment of adolescents with epilepsy. PMID- 28577565 TI - The sound of tumor cell-microenvironment communication - composed by the Cancer Cluster Salzburg research network. PMID- 28577564 TI - High frequency of the recurrent c.1310_1313delAAGA BRCA2 mutation in the North East of Morocco and implication for hereditary breast-ovarian cancer prevention and control. AB - BACKGROUND: To date, a limited number of BRCA1/2 germline mutations have been reported in hereditary breast and/or ovarian cancer in the Moroccan population. Less than 20 different mutations of these two genes have been identified in Moroccan patients, and recently we reported a further BRCA2 mutation (c.1310_1313delAAGA; p.Lys437IlefsX22) in three unrelated patients, all from the North-East of the country. We aimed in this study to evaluate the frequency and geographic distribution of this BRCA2 frameshift mutation, in order to access its use as the first-line BRCA genetic testing strategy for Moroccan patients. We enrolled in this study 122 patients from different regions of Morocco, with suggestive inherited predisposition to breast and ovarian cancers. All subjects gave written informed consent to BRCA1/2 genetic testing. According to available resources of our lab and enrolled families, 51 patients were analyzed by the conventional individual exon-by-exon Sanger sequencing, 23 patients were able to benefit from a BRCA next generation sequencing and a target screening for exon 10 of BRCA2 gene was performed in 48 patients. RESULTS: Overall, and among the 122 patients analyzed for at least the exon 10 of the BRCA2 gene, the c.1310_1313delAAGA frameshift mutation was found in 14 patients. Genealogic investigation revealed that all carriers of this mutation shared the same geographic origin and were descendants of the North-East of Morocco. DISCUSSION: In this study, we highlighted that c.1310_1313delAAGA mutation of BRCA2 gene is recurrent with high frequency in patients from the North-East region of Morocco. Therefore, we propose to use, in public health strategies, the detection of this mutation as the first-line screening tests in patients with breast and ovarian cancer originated from this region. PMID- 28577566 TI - Erratum to: The progressive fragmentation of the KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GIST). PMID- 28577567 TI - Erratum to: Telomere shortening and accelerated aging in COPD: findings from the BODE cohort. PMID- 28577569 TI - Overexpression of apolipoprotein A-I alleviates endoplasmic reticulum stress in hepatocytes. AB - BACKGROUND: Abnormal lipid metabolism may contribute to an increase in endoplasmic reticulum (ER) stress, resulting in the pathogenesis of non-alcoholic steatohepatitis. Apolipoprotein A-I (apoA-I) accepts cellular free cholesterol and phospholipids transported by ATP-binding cassette transporter A1 to generate nascent high density lipoprotein particles. Previous studies have revealed that the overexpression of apoA-I alleviated hepatic lipid levels by modifying lipid transport. Here, we examined the effects of apoA-I overexpression on ER stress and genes involved in lipogenesis in both HepG2 cells and mouse hepatocytes. METHODS: Human apoA-I was overexpressed in HepG2 hepatocytes, which were then treated with 2 MUg/mL tunicamycin or 500 MUM palmitic acid. Eight-week-old male apoA-I transgenic or C57BL/6 wild-type mice were intraperitoneally injected with 1 mg/kg body weight tunicamycin or with saline. At 48 h after injecting, blood and liver samples were collected. RESULTS: The overexpression of apoA-I in the models above resulted in decreased protein levels of ER stress makers and lipogenic gene products, including sterol regulatory element binding protein 1, fatty acid synthase, and acetyl-CoA carboxylase 1. In addition, the cellular levels of triglycerides and free cholesterol also decreased. Some of gene products which are related to ER stress-associated apoptosis were also affected by apoA-I overexpression. These results suggested that apoA-I overexpression could reduce steatosis by decreasing lipid levels and by suppressing ER stress and lipogenesis in hepatocytes. CONCLUSION: ApoA-I expression could significantly reduce hepatic ER stress and lipogenesis in hepatocytes. PMID- 28577568 TI - Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy. AB - BACKGROUND: Pirfenidone (PFD) is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis (IPF), but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species (ROS)-mediated platelet-derived growth factor receptor (PDGFR) activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts (LF) was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy. METHODS: Transforming growth factor-beta (TGF-beta) induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin (BLM)-induced lung fibrosis model using PARK2 knockout (KO) mice. RESULTS: We found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-beta. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of lung fibrosis and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD. CONCLUSIONS: These results suggest that PFD induces PARK2-mediated mitophagy and also inhibits lung fibrosis development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment. PMID- 28577570 TI - Post-traumatic stress disorder in parturients delivering by caesarean section and the implication of anaesthesia: a prospective cohort study. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) occurs in 1-7% of women following childbirth. While having a caesarean section (C-section) is known to be a significant risk factor for postpartum PTSD, it is currently unknown whether coexisting anaesthesia-related factors are also associated to the disorder. The aim of this study was to assess anaesthesia-linked factors in the development of acute postpartum PTSD. METHODS: We performed a prospective cohort study on women having a C-section in a tertiary hospital in Switzerland. Patients were followed up six weeks postpartum. Patient and procedure characteristics, past morbidity or traumatic events, psychosocial status and stressful perinatal events were measured. Outcome was divided into two categories: full PTSD disease and PTSD profile. This was based on the number of DSM-IV criteria of the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) present. The PTSD Checklist Scale and the Clinician Administered PTSD Scale were used for measurement. RESULTS: Of the 280 patients included, 217 (77.5%) answered the questionnaires and 175 (62.5%) answered to an additional phone interview. Twenty (9.2%) had a PTSD profile and six (2.7%) a PTSD. When a full predictive model of risk factors for PTSD profile was built using logistic regression, maternal prepartum and intrapartum complications, anaesthetic complications and dissociative experiences during C-section were found to be the significant predictors for PTSD profile. CONCLUSION: This is the first study to show in parturients having a C-section that an anaesthesia complication is an independent risk factor for postpartum PTSD and PTSD profile development, in addition to known perinatal and maternal risk factors. PMID- 28577572 TI - Using Ellenberg-Pignatti values to estimate habitat preferences of wild food and medicinal plants: an example from northeastern Istria (Croatia). AB - BACKGROUND: The paper presents the first ethnobotanical application of Ellenberg indicator values, which are widely used in European plant ecology. The aim of the study was to find out if Ellenberg values (indicating habitat preferences) differ for wild food and medicinal plants used in north-eastern Istria (Croatia). We used Ellenberg-Pignatti values (the version of Ellenberg values used in this part of Europe). METHODS: Fifty semi-structured interviews were carried out among local key informants, asking which wild food and medicinal plants they used. RESULTS: The mean number of food and medicinal plants mentioned per interview was 30. Altogether, 121 species were recorded as food or medicine used or previously used in the study area. Thirty-one species are used exclusively as food or everyday drink, 50 species are used exclusively as medicine and 40 species are used for both food and medicine. There were no significant differences between Ellenberg values for food and medicinal plants, apart from the Nitrogen indicator value - the plants used exclusively as food had a significantly higher index than those used in medicine. This probably stems from the fact that plants with soft fleshy shoots are attractive as food and they are more likely to come from nitrogen-rich ruderal habitats. CONCLUSIONS: Food plants and medicinal plants are collected from a variety of habitats and no clear difference between the two categories of plants was detected, however further testing of Ellenberg values in ethnobotanical studies could be interesting. PMID- 28577573 TI - Differences in placement of calcium phosphate-hybridized tendon grafts within the femoral bone tunnel during ACL reconstruction do not influence tendon-to-bone healing. AB - BACKGROUND: Calcium phosphate (CaP)-hybridization of tendon grafts has been shown to improve tendon-to-bone healing. The purpose of this study was to clarify the influence of different tendon graft placement methods on tendon-to-bone healing using CaP-hybridized tendon grafts in anterior cruciate ligament (ACL) reconstructions in rabbits. METHODS: We compared two methods of tendon graft placement within the femoral bone tunnel: suspension of the tendon graft within the bone tunnel (suspension group) and implantation of the tendon graft coherent with the bone socket (coherence group). CaP-hybridized tendon grafts were used in both groups. Fifty-six male Japanese white rabbits were used for this study. The results of biomechanical tests (n = 9) and histological analyses (n = 5) were evaluated at 2 and 4 weeks after surgery. RESULTS: The ultimate failure load, stiffness, stress, soft tissue remaining in bone tunnel after biomechanical testing, and direct bonding area at tendon-bone interface did not differ significantly between the suspension and coherence groups at either 2 or 4 weeks after surgery (p > 0.05). In both groups, the ultimate failure load, stress, soft tissue remaining in the bone tunnel, and direct bonding area at interface at 4 weeks after surgery were significantly greater than those at 2 weeks after surgery (p < 0.05). CONCLUSIONS: Tendon-to-bone healing in both groups progressed until the endpoint of 4 weeks. There was no influence of the CaP-hybridized tendon graft placement method on tendon-to-bone healing at 4 weeks after ACL reconstruction in rabbits. Thus, the CaP-hybridized tendon grafts were unaffected by differences in their placement within the bone tunnel and became equally anchored to the bone tunnel during the early postoperative period. The tendon graft placement method may not influence tendon-to-bone healing in ACL reconstruction when CaP-hybridized tendon grafts are used. PMID- 28577574 TI - Activating transcription factor 3 promotes embryo attachment via up-regulation of leukemia inhibitory factor in vitro. AB - BACKGROUND: A receptive endometrium is essential for maternal-embryonic molecular communication during implantation. However, the specific molecular regulatory mechanisms of the endometrial capacity remain poorly understood. Here, we examined activating transcription factor 3 (ATF3) expression in human endometria and the functional effect of ATF3 on embryo attachment in vitro. METHODS: Immunohistochemistry (IHC) was used to assess the ATF3 expression patterns in human endometria. Quantitative real-time PCR (qRT-PCR), western blotting and immunofluorescence (IF) studies were applied to explore ATF3 expression in Ishikawa cells upon estrogen (E2) and medroxyprogesterone acetate (MPA) treatment. qRT-PCR and western blotting were performed to inspect LIF (leukemia inhibitory factor) expression after enhancement or inhibition of ATF3, and a luciferase reporter assay and ChIP-PCR were used to confirm the regulatory mechanism of ATF3 to LIF. Endometrial epithelial capacity was assessed by an in vitro model of attachment of BeWo spheroids to Ishikawa cells. Western blotting was performed to compare the expression of ATF3 in endometrial samples of recurrent implantation failure (RIF) patients with that in samples from fertile women (FER) who had undergone no less than one successful embryo transplantation. RESULTS: ATF3 was located in human endometrial epithelial cells and stromal cells and was significantly induced by E2 and MPA in Ishikawa cells. Adenovirus mediated overexpression of ATF3 in Ishikawa cells activated LIF promoter activity and enhanced its expression. Accordingly, the stimulation of BeWo spheroid adhesion promoted by ATF3 was inhibited by pretreatment with a specific antibody against LIF via the antibody-blocking assay. Moreover, ATF3 was aberrantly decreased in the endometria of RIF patients. CONCLUSIONS: Our findings suggest that ATF3 plays a significant role in regulating human endometrial receptivity and embryo attachment in vitro via up-regulation of leukemia inhibitory factor. TRIAL REGISTRATION: Construction and management of the Nanjing multi-center biobank. No. 2013-081-01 . Registered 10 Dec. 2013. PMID- 28577571 TI - Genetic determinants of inherited susceptibility to hypercholesterolemia - a comprehensive literature review. AB - Hypercholesterolemia is a strong determinant of mortality and morbidity associated with cardiovascular diseases and a major contributor to the global disease burden. Mutations in four genes (LDLR, APOB, PCSK9 and LDLRAP1) account for the majority of cases with familial hypercholesterolemia. However, a substantial proportion of adults with hypercholesterolemia do not have a mutation in any of these four genes. This indicates the probability of having other genes with a causative or contributory role in the pathogenesis of hypercholesterolemia and suggests a polygenic inheritance of this condition. Here in, we review the recent evidence of association of the genetic variants with hypercholesterolemia and the three lipid traits; total cholesterol (TC), HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C), their biological pathways and the associated pathogenetic mechanisms. Nearly 80 genes involved in lipid metabolism (encoding structural components of lipoproteins, lipoprotein receptors and related proteins, enzymes, lipid transporters, lipid transfer proteins, and activators or inhibitors of protein function and gene transcription) with single nucleotide variants (SNVs) that are recognized to be associated with hypercholesterolemia and serum lipid traits in genome-wide association studies and candidate gene studies were identified. In addition, genome-wide association studies in different populations have identified SNVs associated with TC, HDL-C and LDL-C in nearly 120 genes within or in the vicinity of the genes that are not known to be involved in lipid metabolism. Over 90% of the SNVs in both these groups are located outside the coding regions of the genes. These findings indicates that there might be a considerable number of unrecognized processes and mechanisms of lipid homeostasis, which when disrupted, would lead to hypercholesterolemia. Knowledge of these molecular pathways will enable the discovery of novel treatment and preventive methods as well as identify the biochemical and molecular markers for the risk prediction and early detection of this common, yet potentially debilitating condition. PMID- 28577575 TI - Identification of sympatric cryptic species of Aedes albopictus subgroup in Vietnam: new perspectives in phylosymbiosis of insect vector. AB - BACKGROUND: The Aedes (Stegomyia) albopictus subgroup includes 11 cryptic species of which Ae. albopictus is the most widely distributed. Its global expansion associated with a documented vector competence for several emerging arboviruses raise obvious concerns in the recently colonized regions. While several studies have provided important insights regarding medical importance of Ae. albopicus, the investigations of the other sibling species are scarce. In Asia, indigenous populations within the Ae. albopictus subgroup can be found in sympatry. In the present study, we aimed to describe and compare molecular, morphological and bacterial symbionts composition among sympatric individuals from the Ae. albopictus subgroup inhabiting a Vietnamese protected area. RESULTS: Based on morphological structure of the cibarial armarture, we identified a cryptic species in the forest park at Bu Gia Map in the south-eastern region of Vietnam. Analysis of nuclear (ITS1-5.8S-ITS2) and mitochondrial (cox1, nad5) markers confirmed the divergence between the cryptic species and Ae. albopictus. Analysis of midgut bacterial microbiota revealed a strong similarity among the two species with a notable difference; contrary to Ae. albopictus, the cryptic species did not harbour any Wolbachia infection. CONCLUSIONS: These results could reflect either a recent invasion of Wolbachia in Ae. albopictus or alternatively a loss of this symbiont in the cryptic species. We argue that neglected species of the Ae. albopictus subgroup are of main importance in order to estimate variation of host-symbionts interactions across evolution. PMID- 28577578 TI - Retraction Note: Robust method for TALEN-edited correction of pF508del in patient specific induced pluripotent stem cells. PMID- 28577577 TI - Serum thyroid-stimulating hormone and interleukin-8 levels in boys with autism spectrum disorder. AB - BACKGROUND: Autism spectrum disorder (ASD) affects approximately 1 in 68 children in the USA. An ASD blood biomarker may enable early diagnosis and/or identification of new therapeutic targets. Serum samples from ASD and typically developing (TD) boys (n = 30/group) were screened for differences in 110 proteins using a multiplex immunoassay. RESULTS: Eleven proteins were found that together could confirm ASD with modest accuracy using multiple training and test sets. Two of the 11 proteins identified here were further tested using a different detection platform and with a larger sample of ASD and TD boys. The two proteins, thyroid-stimulating hormone (TSH) and interleukin-8 (IL-8), have been previously identified as putative biomarkers for ASD. TSH levels were significantly lower in ASD boys, whereas IL-8 levels were significantly elevated. The diagnostic accuracy for ASD based upon TSH or IL-8 levels alone varied from 74 to 76%, but using both proteins together, the diagnostic accuracy increased to 82%. In addition, TSH levels were negatively correlated with the Autism Diagnostic Observation Schedule subdomain scores. CONCLUSIONS: These data suggest that a panel of proteins may be useful as a putative blood biomarker for ASD. PMID- 28577576 TI - Sphingosine 1-phosphate receptor 3 and RhoA signaling mediate inflammatory gene expression in astrocytes. AB - BACKGROUND: Sphingosine 1-phosphate (S1P) signals through G protein-coupled receptors to elicit a wide range of cellular responses. In CNS injury and disease, the blood-brain barrier is compromised, causing leakage of S1P from blood into the brain. S1P can also be locally generated through the enzyme sphingosine kinase-1 (Sphk1). Our previous studies demonstrated that S1P activates inflammation in murine astrocytes. The S1P1 receptor subtype has been most associated with CNS disease, particularly multiple sclerosis. S1P3 is most highly expressed and upregulated on astrocytes, however, thus we explored the involvement of this receptor in inflammatory astrocytic responses. METHODS: Astrocytes isolated from wild-type (WT) or S1P3 knockout (KO) mice were treated with S1P3 selective drugs or transfected with short interfering RNA to determine which receptor subtypes mediate S1P-stimulated inflammatory responses. Interleukin-6 (IL-6), and vascular endothelial growth factor A (VEGFa) messenger RNA (mRNA) and cyclooxygenase-2 (COX-2) mRNA and protein were assessed by q-PCR and Western blotting. Activation of RhoA was measured using SRE.L luciferase and RhoA implicated in S1P signaling by knockdown of Galpha12/13 proteins or by inhibiting RhoA activation with C3 exoenzyme. Inflammation was simulated by in vitro scratch injury of cultured astrocytes. RESULTS: S1P3 was highly expressed in astrocytes and further upregulated in response to simulated inflammation. Studies using S1P3 knockdown and S1P3 KO astrocytes demonstrated that S1P3 mediates activation of RhoA and induction of COX-2, IL-6, and VEGFa mRNA, with some contribution from S1P2. S1P induces expression of all of these genes through coupling to the Galpha12/13 proteins which activate RhoA. Studies using S1P3 selective agonists/antagonists as well as Fingolimod (FTY720) confirmed that stimulation of S1P3 induces COX-2 expression in astrocytes. Simulated inflammation increased expression of Sphk1 and consequently activated S1P3, demonstrating an autocrine pathway through which S1P is formed and released from astrocytes to regulate COX-2 expression. CONCLUSIONS: S1P3, through its ability to activate RhoA and its upregulation in astrocytes, plays a unique role in inducing inflammatory responses and should be considered as a potentially important therapeutic target for CNS disease progression. PMID- 28577580 TI - The Role of Threat Level and Intolerance of Uncertainty (IU) in Anxiety: An Experimental Test of IU Theory. AB - Intolerance of uncertainty (IU) has been proposed as an important transdiagnostic variable within mood- and anxiety-related disorders. The extant literature has suggested that individuals high in IU interpret uncertainty more negatively. Furthermore, theoretical models of IU posit that those elevated in IU may experience an uncertain threat as more anxiety provoking than a certain threat. However, no research to date has experimentally manipulated the certainty of an impending threat while utilizing an in vivo stressor. In the current study, undergraduate participants (N = 79) were randomized to one of two conditions: certain threat (participants were told that later on in the study they would give a 3-minute speech) or uncertain threat (participants were told that later on in the study they would flip a coin to determine whether or not they would give a 3 minute speech). Participants also completed self-report questionnaires measuring their baseline state anxiety, baseline trait IU, and prespeech state anxiety. Results indicated that trait IU was associated with greater state anticipatory anxiety when the prospect of giving a speech was made uncertain (i.e., uncertain condition). Further, findings indicated no significant difference in anticipatory state anxiety among individuals high in IU when comparing an uncertain versus certain threat (i.e., uncertain and certain threat conditions, respectively). Furthermore, results found no significant interaction between condition and trait IU when predicting state anticipatory anxiety. This investigation is the first to test a crucial component of IU theory while utilizing an ecologically valid paradigm. Results of the present study are discussed in terms of theoretical models of IU and directions for future work. PMID- 28577579 TI - Patterns of relapse in primary central nervous system lymphoma: inferences regarding the role of the neuro-vascular unit and monoclonal antibodies in treating occult CNS disease. AB - BACKGROUND AND PURPOSE: The radiologic features and patterns of primary central nervous system lymphoma (PCNSL) at initial presentation are well described. High response rates can be achieved with first-line high-dose methotrexate (HD-MTX) based regimens, yet many relapse within 2 years of diagnosis. We describe the pattern of relapse and review the potential mechanisms involved in relapse. METHODS: We identified 78 consecutive patients who attained complete radiographic response (CR) during or after first-line treatment for newly diagnosed PCNSL (CD20+, diffuse large B cell type). Patients were treated with HD-MTX based regimen in conjunction with blood-brain barrier disruption (HD-MTX/BBBD); 44 subsequently relapsed. Images and medical records of these 44 consecutive patients were retrospectively reviewed. The anatomical location of enhancing lesions at initial diagnosis and at the time of relapse were identified and compared. RESULTS: 37/44 patients fulfilled inclusion criteria and had new measureable enhancing lesions at relapse; the pattern and location of relapse of these 37 patients were identified. At relapse, the new enhancement was at a spatially distinct site in 30 of 37 patients. Local relapse was found only in seven patients. DISCUSSION: Unlike gliomas, the majority of PCNSL had radiographic relapse at spatially distinct anatomical locations within the brain behind a previously intact neurovascular unit (NVU), and in few cases outside, the central nervous system (CNS). This may suggest either (1) reactivation of occult reservoirs behind an intact NVU in the CNS (or ocular) or (2) seeding from bone marrow or other extra CNS sites. CONCLUSION: Recognizing patterns of relapse is key for early detection and may provide insight into potential mechanisms of relapse as well as help develop strategies to extend duration of complete response. PMID- 28577581 TI - Trait Affect, Emotion Regulation, and the Generation of Negative and Positive Interpersonal Events. AB - Positive and negative trait affect and emotion regulatory strategies have received considerable attention in the literature as predictors of psychopathology. However, it remains unclear whether individuals' trait affect is associated with responses to state positive affect (positive rumination and dampening) or negative affect (ruminative brooding), or whether these affective experiences contribute to negative or positive interpersonal event generation. Among 304 late adolescents, path analyses indicated that individuals with higher trait negative affect utilized dampening and brooding rumination responses, whereas those with higher trait positive affect engaged in rumination on positive affect. Further, there were indirect relationships between trait negative affect and fewer positive and negative interpersonal events via dampening, and between trait positive affect and greater positive and negative interpersonal events via positive rumination. These findings suggest that individuals' trait negative and positive affect may be associated with increased utilization of emotion regulation strategies for managing these affects, which may contribute to the occurrence of positive and negative events in interpersonal relationships. PMID- 28577582 TI - The Role of Patient Characteristics in the Concordance of Daily and Retrospective Reports of PTSD. AB - Research has documented discrepancies between daily and retrospective reports of psychological symptoms in a variety of conditions. A limited number of studies have assessed these discrepancies in samples of individuals with posttraumatic stress disorder (PTSD), with even less research addressing potential covariates that may influence such discrepancies. In the current study, 65 individuals with co-occurring PTSD and alcohol use disorder (AUD) completed daily assessments of their PTSD symptoms for 1 month, followed by a standard retrospective report of PTSD over the same month. Initial analyses explored the mean levels of daily and retrospective PTSD symptoms, while multilevel models assessed the level of agreement between daily and retrospective reports and the role of demographic variables and comorbid psychopathology (e.g., depression) or substance use (e.g., alcohol use) in moderating the association of daily and retrospective reports. Results showed that retrospective reports of arousal and avoidance symptoms were weakly related to daily reports of these symptoms, while reports of reexperiencing and numbing symptoms showed better agreement. Intra-individual alcohol consumption also moderated associations of reexperiencing and avoidance symptoms, such that on days individuals drank more, their daily reports resembled their retrospective reports less well. Future research should explore the degree to which these results generalize to nondually diagnosed samples, as well as the role such reporting discrepancies may play in PTSD treatment. PMID- 28577583 TI - Long-Term Outcomes of Cognitive-Behavioral Therapy for Adolescent Body Dysmorphic Disorder. AB - Emerging evidence suggests that cognitive-behavioral therapy (CBT) is an efficacious treatment for adolescent body dysmorphic disorder (BDD) in the short term, but longer-term outcomes remain unknown. The current study aimed to follow up a group of adolescents who had originally participated in a randomized controlled trial of CBT for BDD to determine whether treatment gains were maintained. Twenty-six adolescents (mean age = 16.2, SD = 1.6) with a primary diagnosis of BDD received a course of developmentally tailored CBT and were followed up over 12 months. Participants were assessed at baseline, midtreatment, posttreatment, 2-, 6-, and 12-month follow-up. The primary outcome measure was the clinician-rated Yale-Brown Obsessive-Compulsive Scale Modified for BDD. Secondary outcomes included measures of insight, depression, quality of life, and global functioning. BDD symptoms decreased significantly from pre- to posttreatment and remained stable over the 12-month follow-up. At this time point, 50% of participants were classified as responders and 23% as remitters. Participants remained significantly improved on all secondary outcomes at 12 month follow-up. Neither baseline insight nor baseline depression predicted long term outcomes. The positive effects of CBT appear to be durable up to 12-month follow-up. However, the majority of patients remained symptomatic and vulnerable to a range of risks at 12-month follow-up, indicating that longer-term monitoring is advisable in this population. Future research should focus on enhancing the efficacy of CBT in order to improve long-term outcomes. PMID- 28577584 TI - Computer Informed and Flexible Family-Based Treatment for Adolescents: A Randomized Clinical Trial for at-Risk Racial/Ethnic Minority Adolescents. AB - Family interventions have been shown to be effective for adolescents with behavior problems. Current literature supports both adaptive treatments and technology-assisted interventions as highly promising innovations for treating at risk adolescents. The purpose of this investigation was to develop and test the efficacy of a computer-assisted version of an established office-based multicomponent family therapy. Eighty Hispanic and Black Non-Hispanic adolescents and their families participated in the study and were randomized to either Immediate Computer-Assisted CIFFTA or Delayed Computer-Assisted CIFFTA. Significant between-groups effects were found from baseline to posttreatment showing the superiority of the Immediate CA CIFFTA condition on both the Conduct Disorder (B = -5.17, SE = 1.73, p < .01, CI [-8.55, -1.79]) and Socialized Aggression (B = -2.04, SE = .83, p < .05, CI [-3.67, -.41]) subscales of the Revised Behavior Problem Checklist, on the Youth Self Report Externalizing scale (B = -4.22, SE = 1.40, p < .01, CI [-6.95, -1.48]), and on both the parent (B = 1.34, SE = .50, p < .01, CI [.36, 2.32]) and adolescent (B = 1.31, SE = .46, p < .01, CI [.41, 2.21]) reports of the Family Environment Scale's family cohesion subscale. Baseline to 6-weeks posttreatment (T1-T3) analyses showed that these significant within-subjects effects were sustained for the treatment group. Results highlight that adolescent behavior problems can be significantly impacted by a computer-assisted intervention that replaces psychoeducational face-to-face meetings with computer-delivered modules. PMID- 28577585 TI - Advancing Personalized Medicine: Application of a Novel Statistical Method to Identify Treatment Moderators in the Coordinated Anxiety Learning and Management Study. AB - There has been increasing recognition of the value of personalized medicine where the most effective treatment is selected based on individual characteristics. This study used a new method to identify a composite moderator of response to evidence-based anxiety treatment (CALM) compared to Usual Care. Eight hundred seventy-six patients diagnosed with one or multiple anxiety disorders were assigned to CALM or Usual Care. Using the method proposed by Kraemer (2013), 35 possible moderators were examined for individual effect sizes then entered into a forward-stepwise regression model predicting differential treatment response. K fold cross validation was used to identify the number of variables to include in the final moderator. Ten variables were selected for a final composite moderator. The composite moderator effect size (r = .20) was twice as large as the strongest individual moderator effect size (r = .10). Although on average patients benefitted more from CALM, 19% of patients had equal or greater treatment response in Usual Care. The effect size for the CALM intervention increased from d = .34 to d = .54 when accounting for the moderator. Findings support the utility of composite moderators. Results were used to develop a program that allows mental health professionals to prescribe treatment for anxiety based on baseline characteristics (http://anxiety.psych.ucla.edu/treatmatch.html). PMID- 28577587 TI - Criticism in the Romantic Relationships of Individuals With Social Anxiety. AB - Social anxiety is associated with difficulties in intimate relationships. Because fear of negative evaluation is a cardinal feature of social anxiety disorder, perceived criticism and upset due to criticism from partners may play a significant role in socially anxious individuals' intimate relationships. In the present study, we examine associations between social anxiety and perceived, observed, and expressed criticism in interactions with romantic partners. In Study 1, we collected self-report data from 343 undergraduates and their romantic partners on social anxiety symptoms, perceived and expressed criticism, and upset due to criticism. One year later couples reported whether they were still in this relationship. Results showed that social anxiety was associated with being more critical of one's partner, and among women, being more upset by criticism from a partner. Social anxiety was not related to perceived criticism, nor did criticism variables predict relationship status at Time 2. In Study 2, undergraduate couples with a partner high (n = 26) or low (n = 26) in social anxiety completed a 10-minute, video-recorded problem-solving task. Both partners rated their perceived and expressed criticism and upset due to criticism following the interaction, and observers coded interactions for criticism. Results indicated that social anxiety was not significantly related to any of the criticism variables, but post hoc analyses cast doubts upon the external validity of the problem-solving task. Results are discussed in light of known difficulties with intimacy among individuals with social anxiety. PMID- 28577586 TI - Does the Delivery of CBT for Youth Anxiety Differ Across Research and Practice Settings? AB - Does delivery of the same manual-based individual cognitive-behavioral treatment (ICBT) program for youth anxiety differ across research and practice settings? We examined this question in a sample of 89 youths (M age = 10.56, SD = 1.99; 63.70% Caucasian; 52.80% male) diagnosed with a primary anxiety disorder. The youths received (a) ICBT in a research setting, (b) ICBT in practice settings, or (c) non-manual-based usual care (UC) in practice settings. Treatment delivery was assessed using four theory-based subscales (Cognitive-behavioral, Psychodynamic, Client-Centered, Family) from the Therapy Process Observational Coding System for Child Psychotherapy-Revised Strategies scale (TPOCS-RS). Reliable independent coders, using the TPOCS-RS, rated 954 treatment sessions from two randomized controlled trials (1 efficacy and 1 effectiveness trial). In both settings, therapists trained and supervised in ICBT delivered comparable levels of cognitive-behavioral interventions at the beginning of treatment. However, therapists trained in ICBT in the research setting increased their use of cognitive-behavioral interventions as treatment progressed whereas their practice setting counterparts waned over time. Relative to the two ICBT groups, the UC therapists delivered a significantly higher dose of psychodynamic and family interventions and a significantly lower dose of cognitive-behavioral interventions. Overall, results indicate that there were more similarities than differences in manual-based ICBT delivery across research and practice settings. Future research should explore why the delivery of cognitive-behavioral interventions in the ICBT program changed over time and across settings, and whether the answers to these questions could inform implementation of ICBT programs. PMID- 28577588 TI - Social Anxiety and Biased Recall of Positive Information: It's Not the Content, It's the Valence. AB - Cognitive theorists hypothesize that individuals with social anxiety are prone to memory biases such that event recall becomes more negative over time. With few exceptions, studies have focused primarily on changes in negative self-judgments. The current study examined whether memory for positive social events is also subject to recall bias. Undergraduate participants (N = 138) engaged in an unexpected public speaking task and received standardized positive or neutral feedback on their performance. They rated their memory of the received feedback following a 5-minute delay and again 1 week later. Results revealed that higher scores on social anxiety symptoms predicted significant reductions in the recalled valence of positive feedback over time, whereas no changes were observed for neutral feedback. The results suggest that social anxiety may lead to erosion in memory of positive events. PMID- 28577589 TI - Prospective Investigation of the Contrast Avoidance Model of Generalized Anxiety and Worry. AB - The factors that maintain generalized anxiety disorder (GAD) symptoms and worry over time are not entirely clear. The Contrast Avoidance Model (CAM) postulates that individuals at risk for pathological worry and GAD symptoms uniquely fear emotional shifts from neutral or positive emotions into negative emotional states, and consequently use worry to maintain negative emotion in order to avoid shifts or blunt the effect of negative contrasts. This model has received support in laboratory experiments, but has not been investigated prospectively in the naturalistic context of daily life. The present study tested the CAM in a longitudinal experience sampling study with a subclinical sample. Participants selected to represent a broad range of symptoms (N = 92) completed baseline measures of GAD and depression symptoms, and eight weekly assessments of worry, experiences of negative emotional contrasts during their worst event of the week, and situation-specific negative emotion. Consistent with the CAM, GAD symptoms prospectively predicted higher endorsement of negative contrast experiences as worst events, independent of depression symptoms. Unsurprisingly, higher negative contrasts predicted higher negative emotion. However, both higher baseline GAD symptoms and weekly worry uniquely moderated (reduced) this relationship, providing consistent support for the idea that worry may blunt the emotional effects of contrasts. Depression symptoms did not have the same moderating effect. These findings support the CAM in an ecologically valid context. PMID- 28577590 TI - Dialectical Behavior Therapy Group Skills Training for Bipolar Disorder. AB - There is growing evidence that the capacity for emotion regulation is compromised in individuals with bipolar disorder. Dialectical behavior therapy (DBT), an empirically supported treatment that specifically targets emotion dysregulation, may be an effective adjunct treatment for improving emotion regulation and residual mood symptoms in patients with bipolar disorder. In this open, proof-of concept pilot study, 37 participants engaged in a 12-week DBT group skills training program, learning mindfulness, emotion regulation, and distress tolerance skills. Repeated measures mixed models revealed skill acquisition in the areas of mindfulness, emotion regulation and distress tolerance, as well as improved psychological well-being and decreased emotion reactivity. The results of this study support a burgeoning literature that DBT is a feasible adjunct intervention for patients with bipolar disorder. PMID- 28577593 TI - Chemical generation of volatile species of copper - Optimization, efficiency and investigation of volatile species nature. AB - This work is a comprehensive study on chemical generation of volatile species (VSG) of copper for analytical atomic spectrometry. VSG was carried out in a flow injection mode in a special arrangement of the generator. Atomization in a diffusion flame atomizer (DF) with atomic absorption spectrometry detection was mostly used for VSG optimization. Inductively coupled plasma mass spectrometry (ICP-MS) was utilized to investigate generation efficiencies and feasibility of VSG system for ultratrace analysis. Concentration of individual reagents, namely of nitric acid, sodium tetrahydroborate and various reaction modifiers, was optimized with respect to generation efficiency. Triton X-100 and Antifoam B were chosen as the best combination of the modifiers owing to sixfold increase in sensitivity, decrease of tailing of measured signals and long-term repeatability. The addition of 500 MUg L-1 of Ag was found crucial to maintain identical generation efficiency at low concentrations of Cu. This phenomenon was ascribed to the change in the size of generated species. The release and generation efficiency were accurately determined as 56-58 and 31-32%, respectively. The contribution of co-generated aerosol to release and generation efficiency measured by means of Cs and Ba was found negligible, only 0.40 and 0.13%, respectively, which underlines highly efficient VSG of Cu. The nature of volatile species was investigated by various approaches. The results cannot provide the decisive evidence. However, experiments with the DF, ICP-MS and transmission electron microscopy (TEM) indicate that the generated species are not volatile in the true sense but that they are strongly associated with fine aerosol co generated during VSG. Cu clusters or nanoparticles of very small size (< 10 nm) are presumed but the formation of metastable copper hydride cannot be conclusively excluded. PMID- 28577592 TI - Electrosynthesized molecularly imprinted polyscopoletin nanofilms for human serum albumin detection. AB - Molecularly imprinted polymers (MIPs) rendered selective solely by the imprinting with protein templates lacking of distinctive properties to facilitate strong target-MIP interaction are likely to exhibit medium to low template binding affinities. While this prohibits the use of such MIPs for applications requiring the assessment of very low template concentrations, their implementation for the quantification of high-abundance proteins seems to have a clear niche in the analytical practice. We investigated this opportunity by developing a polyscopoletin-based MIP nanofilm for the electrochemical determination of elevated human serum albumin (HSA) in urine. As reference for a low abundance protein ferritin-MIPs were also prepared by the same procedure. Under optimal conditions, the imprinted sensors gave a linear response to HSA in the concentration range of 20-100 mg/dm3, and to ferritin in the range of 120-360 mg/dm3. While as expected the obtained limit of detection was not sufficient to determine endogenous ferritin in plasma, the HSA-sensor was successfully employed to analyse urine samples of patients with albuminuria. The results suggest that MIP-based sensors may be applicable for quantifying high abundance proteins in a clinical setting. PMID- 28577591 TI - Implementing Clinical Research Using Factorial Designs: A Primer. AB - Factorial experiments have rarely been used in the development or evaluation of clinical interventions. However, factorial designs offer advantages over randomized controlled trial designs, the latter being much more frequently used in such research. Factorial designs are highly efficient (permitting evaluation of multiple intervention components with good statistical power) and present the opportunity to detect interactions amongst intervention components. Such advantages have led methodologists to advocate for the greater use of factorial designs in research on clinical interventions (Collins, Dziak, & Li, 2009). However, researchers considering the use of such designs in clinical research face a series of choices that have consequential implications for the interpretability and value of the experimental results. These choices include: whether to use a factorial design, selection of the number and type of factors to include, how to address the compatibility of the different factors included, whether and how to avoid confounds between the type and number of interventions a participant receives, and how to interpret interactions. The use of factorial designs in clinical intervention research poses choices that differ from those typically considered in randomized clinical trial designs. However, the great information yield of the former encourages clinical researchers' increased and careful execution of such designs. PMID- 28577594 TI - Errors in alkylated polycyclic aromatic hydrocarbon and sulfur heterocycle concentrations caused by currently employed standardized methods. AB - Alkylated polycyclic aromatic hydrocarbon (PAH) and polycyclic aromatic sulfur heterocycle (PASH) standardized methods often rely on gas chromatography/mass spectrometry operated in the selected ion monitoring mode (GC/MS-SIM). The objective of this study is to develop a method that produces accurate data while minimizing sample preparation and achieving low levels of detection. Most standardized methods are based on acquiring a given homologue's molecular ion (1 ion). Some methods include a second, confirming ion (2-ion) in the hopes of excluding non-target ion signals from the total homologue peak area. Although all methods use homologue-specific retention windows, these windows differ greatly among the methods. In this paper we evaluate, for the first time, errors in quantitation caused by using different windows as well as common ion effects when target and/or matrix compounds coelute. Two NIST-certified Standard Reference Materials (SRMs), crude oil SRM 1582 and marine sediment SRM 1941b, were analyzed by five standardized methods and by the new method we developed, which relies on spectral deconvolution of three to five ions per PAH/PASH and as many fragmentation patterns as needed to correctly identify the C1 to C4 homologues (MFPPH). All of the standardized methods overestimated the concentrations of the majority of alkylated homologues whereas MFPPH obtained values much closer to NIST-certified concentrations. Rather than straight-line integration of all peaks in the retention window or recognizing peak patterns, the MFPPH data analysis software integrates only those peaks that meet the compound identity criteria. PMID- 28577595 TI - A strategy to identify and quantify closely related adulterant herbal materials by mass spectrometry-based partial least squares regression. AB - In this study, a new strategy combining mass spectrometric (MS) techniques with partial least squares regression (PLSR) was proposed to identify and quantify closely related adulterant herbal materials. This strategy involved preparation of adulterated samples, data acquisition and establishment of PLSR model. The approach was accurate, sensitive, durable and universal, and validation of the model was done by detecting the presence of Fritillaria Ussuriensis Bulbus in the adulteration of the bulbs of Fritillaria unibracteata. Herein, three different MS techniques, namely wooden-tip electrospray ionization mass spectrometry (wooden tip ESI/MS), ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) and UPLC-triple quadrupole tandem mass spectrometry (UPLC-TQ/MS), were applied to obtain MS profiles for establishing PLSR models. All three models afforded good linearity and good accuracy of prediction, with correlation coefficient of prediction (rp2) of 0.9072, 0.9922 and 0.9904, respectively, and root mean square error of prediction (RMSEP) of 0.1004, 0.0290 and 0.0323, respectively. Thus, this strategy is very promising in tracking the supply chain of herb-based pharmaceutical industry, especially for identifying adulteration of medicinal materials from their closely related herbal species. PMID- 28577596 TI - Novel electrochemical immune sensor based on Hep-PGA-PPy nanoparticles for detection of alpha-Fetoprotein in whole blood. AB - A simple and accurate immune sensor for quantitative detection of alpha Fetoprotein (AFP) was developed based on the immobilization of antigen on the surface of Hep-PGA-PPy nanoparticles modified glassy carbon electrodes (GCE). The obtained Hep-PGA-PPy nanoparticles were characterized by fourier transform infrared (FT-IR) spectra and transmission electron microscopy (TEM). And the blood compatibility of Hep-PGA-PPy nanoparticles was investigated by in vitro coagulation tests, hemolysis assay and whole blood adhesion tests. Combining the conductive property of polypyrrole (PPy) and the biocompatibility of heparin (Hep), the Hep-PGA-PPy nanoparticles could improve not only the anti-biofouling effect the electrode, but also improved the electrochemical properties of the immune sensor. Under optimal conditions, the proposed immune sensor could detect AFP in a linear range from 0.1 to 100 ng mL-1 with a detection limit of 0.099 ng mL-1 at the signal-to-noise ratio of 3, and it also possessed good reproducibility and storage stability. Furthermore, the detection of AFP in five human blood samples also showed satisfactory accuracy with low relative errors. Thus, the developed immune sensor which showed acceptable reproducibility, selectivity, stability and accuracy could be potentially used for the detection of whole blood samples directly. PMID- 28577597 TI - Enhanced DNA sensitized Tb3+ luminescence in organic solvents for more sensitive detection. AB - DNA-sensitized Tb3+ luminescence spectroscopy is a powerful method for probing nucleic acids and developing biosensors. Its performance in organic solvents has yet to be explored. In this study, Tb3+ luminescence with nucleosides, nucleotides and DNA oligonucleotides in various organic solvents is studied. Tb3+ emission with single nucleotides is quenched up to 88% in dimethyl formamide (DMF), while its emission with nucleosides is enhanced. For the four 15-mer DNA homopolymers, the strongest absolute emission enhancement was achieved with C15. Similar emission properties are observed in other solvents including DMF, DMSO, acetonitrile methanol, ethanol, isopropanol and ethylene glycol. A few DNAzymes are tested as random DNA sequences all showing 1.4-6.9-fold emission enhancement in ethanol. A previously reported optimized sequence in water (G3T)5 is further enhanced by the solvents. Using this sequence, a detection limit of 5.5 nm Hg2+ is achieved in 25% ethanol solution. A similar Hg2+ sensitivity is also observed in a lake water mixed with ethanol. Luminescence lifetime is longer in DMF than in water. This study indicates that DNA-sensitized Tb3+ luminescence can be measured in water miscible solvents and most likely, with even stronger emission than that in water. PMID- 28577598 TI - Microwave-assisted, grafting polymerization preparation of strong cation exchange nylon 6 capillary-channeled polymer fibers and their chromatographic properties. AB - Native nylon 6 C-CP fibers were modified with 2-acrylamido-2 methylpropanesulfonic acid (AMPS) via the microwave-assisted grafting polymerization to affect a strong cation exchange stationary phase. Various concentrations of AMPS and the initiator potassium persulfate (KPS) were used in the modifications. The resultant nylon-SO3H fibers were characterized by Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM) and acid-base titrations. The chromatographic properties, including column permeability, protein separation quality, and protein binding capacity, of the nylon-SO3H fiber columns were also studied. The cation exchange ligand densities on the modified fibers (SO3H) were determined to be 50-317 MUmol g-1, in comparison to the cation (COOH) density of 28 MUmol g-1 of native nylon 6 fibers. The modified fiber phase showed increased lysozyme dynamic loading capacities (up to ~13 mg mL-1 bed volume) at a linear velocity of ~90 cm min-1, while native nylon 6 showed only ~1 mg mL-1 lysozyme loading capacity. Fast (30 s-3 min) gradient separations of myoglobin, alpha chymotrypsinogen A, and lysozyme were achieved on nylon-SO3H columns, with the separation resolution and peak capacity characterized. The efficiency of surface re-equilibration was probed with an eye toward using the phase as the second dimension in comprehensive two-dimensional liquid chromatography (2D-LC). The results indicate that this nylon-SO3H fiber phase has a good deal of potential for use in high-throughput analytical and preparative protein separations. PMID- 28577599 TI - Molecular inversion probes equipped with discontinuous rolling cycle amplification for targeting nucleotide variants: Determining SMN1 and SMN2 genes in diagnosis of spinal muscular atrophy. AB - The novel techniques of molecular inversion probes (MIPs) combined with discontinuous rolling cycle amplification (DRCA) was developed for determination of the multi-nucleotide variants at single base. The different-length MIPs, a padlock-probe based technology, are designed to simultaneously recognize the identical nucleotide variants. After ligation and DRCA, the different-length genetic products representing the certain genotypes could be simply determined by the short-end capillary electrophoresis (CE) method. By using MIPs-DRCA method, the various gene dosages of SMN1 and SMN2 genes in homologous or heterologous subjects were successfully quantified for diagnosis of spinal muscular atrophy (SMA). The length of the MIP for SMN1 gene was 106 bp, and for SMN2 gene was 86 bp. After method optimization, the MIP products of SMN1 and SMN2 were well separated with the resolution of 1.13 +/- 0.17 (n = 3) within 10 min. There were total of 56 DNA blind samples analyzed by this strategy, including 38 wild types, 12 carriers and 6 SMA patients, and the data of gene dosages was corresponding to those analyzed by conformation sensitive CE and denatured high performance liquid chromatography (DHPLC) methods. This MIPs-DRCA method which could be applied to simultaneously genotype multi nucleotide variants at single base, such as K-ras gene, was very feasible for determination of genetic diseases in clinical. PMID- 28577600 TI - Early Childhood Mental Health: Starting Early with the Pregnant Mother. AB - Perinatal mental health has important implications for maternal and child outcomes. Most women with psychiatric disorders during pregnancy go undiagnosed and untreated, despite widespread initiatives for early identification. Universal screening for psychiatric disorders, particularly depression and anxiety, has been implemented in obstetric and primary care settings. However, there is little evidence regarding the effectiveness on psychiatric symptom reduction or prevention of adverse outcomes in children. Recently, comprehensive screening and follow-up programs integrated within obstetric or primary care settings have shown promising results in improving maternal mental health outcomes. Further work is needed to determine best clinical and most cost-effective practices. PMID- 28577602 TI - Clinical Assessment of Young Children. AB - Mental health assessment of young children provides valuable information to shape a formulation and guide treatment. Early childhood mental health assessment can occur in an increasing number of settings beyond traditional mental health practices, including childcare settings, primary care settings, and other settings where children and family are regularly seen. Although many of the components of an early childhood mental health assessment are included in the assessment of older children, assessment of very young children requires some specific developmental adjustments and additional considerations including attention to the parent-child relationship and caregiving context and rapid development. PMID- 28577601 TI - Assessment: The Newborn. AB - Neonatal neurobehavioral assessment has become a standardized component of clinical care provided to newborn infants, guiding neonatal clinical care and subsequent access to early interventions and services. Links between neonatal assessment and neurosensory and motor impairments in high-risk infants have been relatively well established. In contrast, the extent to which newborn neurobehavioral assessment might also facilitate the early identification of infants susceptible to socioemotional impairments in early childhood is less well documented. This review examines longitudinal links between the neonatal neurobehavioral assessment, temperament, and socioemotional outcomes in early childhood. PMID- 28577603 TI - Beyond Reactive Attachment Disorder: How Might Attachment Research Inform Child Psychiatry Practice? AB - This article provides an updated review of attachment research with a focus on how comprehensive clinical assessment and intervention informs the care of young children. Child psychiatrists can serve as an important part of care coordination teams working with young children who have histories of early maltreatment and/or disruption in caregiving whether or not the children they are seeing meet criteria for an attachment disorder. Child psychiatrists should be familiar with both comprehensive assessment and the recent attachment-based interventions and appreciate how pharmacotherapy can be a useful adjunctive intervention when intensive therapy alone is ineffective. PMID- 28577604 TI - Trauma and Very Young Children. AB - This article examines the intersection of early childhood mental health and trauma. Working definitions, incidence, and prevalence of trauma events for this population are outlined with an emphasis on children younger than age 4 years. Trauma impacts on early childhood development are reviewed, with attention to clinical consequences, protective factors, and resilience. Best practices for assessment, screening tools, and treatment methods are presented based on the current research. Future implications include clinician and researcher partnerships to increase the number of effective screening and intervention tools for addressing trauma in very young children. PMID- 28577605 TI - Disruptive Behavior Disorders in Children 0 to 6 Years Old. AB - Disruptive behavior disorders (DBDs), specifically oppositional defiant disorder and conduct disorder, are common, serious, and treatable conditions among preschoolers. DBDs are marked by frequent aggression, deceitfulness, and defiance, and often persist through the lifespan. Exposure to harsh or inconsistent parenting, as frequently seen with parental depression and stress, increases DBD risk. Candidate genes that may increase DBD risk in the presence of childhood adversity have also been identified, but more research is needed. Neurophysiologic and structural correlates with DBD also exist. Parent management training programs, focusing on increasing parenting competence and confidence, are the gold standard treatment of preschool DBDs. PMID- 28577607 TI - Attention Deficit Hyperactivity Disorder in Preschool-Age Children. AB - Attention deficit hyperactivity disorder is a neurodevelopmental disorder marked by age-inappropriate deficits in attention or hyperactivity/impulsivity that interfere with functioning or development. It is highly correlated with other disorders, such as oppositional defiant disorder, conduct disorder, and mood symptoms. The etiology is multifactorial, and neuroimaging findings are nonspecific. Although assessment tools exist, there is variability among them, and historically, parent-teacher agreement has not been consistent. Treatment algorithm for attention deficit hyperactivity disorder in preschoolers includes behavioral interventions first followed by psychopharmacologic treatment when behavioral therapies fail. Other nonpharmacologic and nonbehavioral interventions are discussed including the role of exercise and nutrition. PMID- 28577609 TI - The Early Origins of Autism. AB - Autism spectrum disorders (ASDs) are neurodevelopmental disorders whose core features of impaired social communication and atypical repetitive behaviors and/or restrictions in range of interests emerge in toddlerhood and carry significant implications at successive stages of development. The ability to reliably identify most cases of the condition far earlier than the average age of diagnosis presents a novel opportunity for early intervention, but the availability of such an intervention is disparate across US communities, and its impact is imperfectly understood. New research may transform the clinical approach to these conditions in early childhood. PMID- 28577610 TI - Feeding Disorders. AB - Feeding disorders often present in children with complex medical histories as well as those with neurodevelopmental disabilities. If untreated, feeding problems will likely persist and may lead to additional developmental and medical complications. Treatment of pediatric feeding disorders should involve an interdisciplinary team, but the core intervention should include behavioral feeding techniques as they are the only empirically supported therapy for feeding disorders. PMID- 28577606 TI - Depression and Anxiety in Preschoolers: A Review of the Past 7 Years. AB - This article reviews recent empirical literature on the prevalence, correlates, assessment, and treatment of preschool-onset internalizing disorders. Major advances in the acceptance and recognition of both preschool-onset depression and anxiety have occurred over the past decade. This work has been greatly enhanced by the discovery of genetic, neural, and physiologic indicators, which further validate these constellations of symptoms in young children. Despite this growth in research, much work still needs to be done to further elucidate the cause, risk, treatment, and protective factors for preschool-onset internalizing disorders. PMID- 28577611 TI - Sleep Disorders: Assessment and Treatment in Preschool-Aged Children. AB - Sleep issues are common in preschoolers, defined in this article as ages 3 to 5 years. Sleep deprivation can cause behavioral and cognitive issues. Sleep issues seen in the preschool years include insomnia, obstructive sleep apnea, parasomnias, and restless legs syndrome. Sleep issues seem to exacerbate mood and attention disturbances. Conversely, children with psychiatric disorders are likely to have sleep problems. Treatment of sleep issues is important for long term mental health and optimization of functioning. PMID- 28577608 TI - Intellectual Disability and Language Disorder. AB - Intellectual disability (ID) and language disorders are neurodevelopmental conditions arising in early childhood. Child psychiatrists are likely to encounter children with ID and language disorders because both are strongly associated with challenging behaviors and mental disorder. Because early intervention is associated with optimal outcomes, child psychiatrists must be aware of their signs and symptoms, particularly as related to delays in cognitive and adaptive function. Optimal management of both ID and language disorders requires a multidisciplinary, team-based, and family centered approach. Child psychiatrists play an important role on this team, given their expertise with contextualizing and treating challenging behaviors. PMID- 28577612 TI - Partnerships with Primary Care for the Treatment of Preschoolers. AB - This article reviews mental health access issues relevant to preschool children and data on this population obtained through the Michigan Child Collaborative Care Program (MC3). The MC3 program provides telephonic consultation to primary care physicians (PCPs) in 40 counties in Michigan and video telepsychiatric consultation to patients and families. Attention-deficit/hyperactivity disorder and disruptive behavioral disorders are frequent initial presenting diagnoses, but autism spectrum disorders, parent-child relational issues, trauma, and posttraumatic stress disorder should also be considered. Collaborative care programs provide promising ways to promote access to child psychiatric services when these services are distant to local PCP offices. PMID- 28577614 TI - Early Childhood Mental Health: Empirical Assessment and Intervention from Conception Through Preschool. PMID- 28577613 TI - The Future of Preschool Prevention, Assessment, and Intervention. AB - Preschoolers are in the most rapid period of brain development. Environment shapes the structure and function of the developing brain. Promoting brain health requires cultivation of healthy environments at home, school, and in the community. This improves the emotional-behavioral and physical health of all children, can prevent problems in children at risk, and can alter the trajectory of children already suffering. For clinicians, this starts with assessing and treating the entire family, equipping parents with the principles of parent management training, and incorporating wellness prescriptions for nutrition, physical activity, music, and mindfulness. PMID- 28577615 TI - Maternal allo-recognition of the fetus. AB - Immunological adjustments are needed to accommodate the close contact between two genetically different individuals, the mother and her baby, during mammalian pregnancy. Contact occurs between fetal somatic or placental cells that enter the maternal systemic circulation or between uterine immune cells and the invading extravillous trophoblast. Here we discuss two main types of maternal allo recognition of the fetus. One depends on avoidance of maternal T cells recognizing and responding to paternally-derived non-self human leukocyte antigens class I and class I allotypes. The other is natural killer allo recognition where maternally-inherited variable killer immunoglobulin-like receptors expressed by uterine natural killer cells bind to polymorphic fetal human leukocyte antigens-C molecules displayed by extravillous trophoblast. Genetic studies indicate that natural killer cell allo-recognition regulates placentation and the allocation of resources to the fetus. PMID- 28577616 TI - DNAH1 gene mutations and their potential association with dysplasia of the sperm fibrous sheath and infertility in the Han Chinese population. AB - OBJECTIVE: To investigate dynein, axonemal, heavy chain 1 (DNAH1) gene mutations that may be associated with dysplasia of the sperm fibrous sheath (DFS) and infertility in the Han Chinese population. DESIGN: Dysfunction of DNAH1 is known to cause multiple morphologic abnormalities of the flagella (MMAF), DFS, and infertility. Whole-exome sequencing was performed in DFS subjects and the healthy control subjects. SETTING: Not applicable. PATIENT(S): Twenty-one patients of Han ethnicity with primary infertility and diagnosed with asthenozoospermia and MMAF, but without primary ciliary dyskinesia. Fifty healthy men with normal fertility served as control subjects. MAIN OUTCOME MEASURE(S): Whole-exome sequencing, polymerase chain reaction and sequencing, pedigree analysis, Western blotting, and immunofluorescence assay. INTERVENTIONS(S): None. RESULT(S): A total of 17 mutations in the DNAH1 gene were identified in 12 of the 21 patients. These included one homozygous mutation at the splice site and 16 complex heterozygous mutations at the splice sites and exons. These mutations may cause deletion, replacement of amino acids in the peptide, or introduction of a stop codon in the coding sequence according to bioinformatic prediction. Of note, 52430998CCT>C deletion at exon 73, which may result in c.11726_11727del:p.P3909fs, was found in six patients, which suggests that this mutation may be an etiologic factor for MMAF. Although these DNAH1 gene mutations were found in Exome Aggregation Consortium (ExAC) databases, none were found in the Han healthy control subjects. The expression of DNAH1 protein in the sperm of patient P10, with 52409336C>T in exon 45 and 52430998CCT>C in exon 73 mutations, and patient P12, with 52402755A>G in exon 37 and 52428484G>T in exon 67 mutations, was missing or very weak compared with the sperm of healthy control subjects. The peptide phenotypes of 52409336C>T, 52402755A>G, and 52428484G>T were R2356W, nonsense, and E3544X, respectively. The sperm tails were short or coiled in P10 and P12 compared with healthy control subjects. Pedigree analysis supported the notion that the combination of DNAH1 gene mutations 52430998CCT>C and 52409336C>T and 52428484G>T alone were associated with MMAF. CONCLUSION(S): These DNAH1 gene mutations may be associated with DFS and infertility in the Han population. PMID- 28577617 TI - Novel zona pellucida gene variants identified in patients with oocyte anomalies. AB - OBJECTIVE: To detect ZP (zona pellucida) gene (ZP1-ZP4) mutations in patients with oocyte anomalies. DESIGN: Case-control genetic study. SETTING: University based reproductive medicine center. PATIENT(S): A total of 92 infertile patients with repeated cycles of oocyte maturation arrest (group I, n = 49) or oocyte morphologic defect (group II, n = 43) as well as 373 healthy controls. INTERVENTION(S): Genomic DNA extracted from peripheral blood and coding regions of ZP genes amplified by polymerase chain reaction and sequenced by a DNA analyzer. MAIN OUTCOME MEASURE(S): Variant prediction of ZP genes with software. RESULT(S): In group I with oocyte maturation arrest, no novel variants were found. In group II with oocyte morphologic defects, four novel variants, two in the ZP1 gene [c.247T>C (p.W83R) and c.1413G>A (p.W471X)] and two in the ZP2 gene [c.1599G>T (p.R533S) and c.1696T>C (p.C566R)] were detected in 4 of 43 patients (approximately 9%) but were absent from the controls. Protein alignments showed that the four variants were highly conserved among different species, and all four variants were predicted to be deleterious by gene software predictions. CONCLUSION(S): ZP gene variants may account for patients with oocyte morphologic abnormalities but not for those with oocyte maturation arrest. PMID- 28577618 TI - Hysteroscopic management of a stenotic cervix. AB - OBJECTIVE: To demonstrate an approach to the hysteroscopic management of a stenotic cervix. DESIGN: Step-by-step explanation of the techniques using video and animation (educational video). SETTING: Academic tertiary level referral center. PATIENT(S): Patients with cervical stenosis, inclusive of both reproductive age and postmenopausal women. Gynecologists require intrauterine access for many procedures, but a stenotic cervix can obstruct surgery. Blind dilation of a stenotic cervix can lead to a cervical laceration or uterine perforation, with concomitant complications. INTERVENTION(S): The hysteroscopic management of a stenotic cervix includes optimizing the surgical environment, performing vaginoscopy and "no-touch" hysteroscopy, and revision of the cervical canal. Revision can be performed using microscissors, micrograspers, or a cutting loop electrode. Partial cervical canal excision to aid in hysteroscopy access should be reserved in women who are not interested in future pregnancy or those who are postmenopausal. Outpatient hysteroscopy uses smaller instruments and shows operative success with patient satisfaction. Although these techniques are demonstrated in an outpatient hysteroscopy setting, they can be adapted for use in an operating theater. MAIN OUTCOME MEASURE(S): The individual steps and approach are emphasized. RESULT(S): Intrauterine access can be achieved with various techniques. CONCLUSION(S): The "see-and-treat" approach demonstrated in this video can allow access into the uterine cavity despite a stenotic cervix. PMID- 28577619 TI - Cardiovascular Risk Assessment. AB - Cardiovascular risk assessment is fundamental to prevention of cardiovascular disease, because it helps determine the size of the potential benefits that might accrue to individual patients from use of statins, aspirin, and other preventive interventions. Current guidelines recommend specific algorithms for cardiovascular risk assessment that combine information from traditional risk factors including blood pressure, lipids, and smoking, along with age and sex and other factors. These algorithms are the subject of active research and controversy. This article addresses the rationale, current guidelines and use, and potential future directions of cardiovascular risk assessment. PMID- 28577621 TI - Screening for Hypertension and Lowering Blood Pressure for Prevention of Cardiovascular Disease Events. AB - Hypertension affects 1 in 3 American adults. Blood pressure (BP)-lowering therapy reduces the risk of cardiovascular disease. The United States Preventive Services Task Force recommends all adults be screened for hypertension. Most patients whose office BP is elevated should have out-of-office monitoring to confirm the diagnosis. Ambulatory BP monitoring is preferred for out-of-office measurement, but home BP monitoring is a reasonable alternative. Guidelines for treatment are stratified by age (<60 vs >60 years) and include cutoffs for recommended treatment BPs and target BP goals. Quality of hypertension care is improved by incorporating population health management using registries and medication titration. PMID- 28577620 TI - Statins for Primary Prevention of Cardiovascular Disease: Review of Evidence and Recommendations for Clinical Practice. AB - Numerous large randomized clinical trials have shown that statin therapy is effective and safe for primary prevention of atherosclerotic cardiovascular disease (CVD) for adults aged 40 to 75 years and support the use of 10-year CVD risk as a means to identify individuals for treatment. Uncertainty exists in those older than 75 years who may be more likely to benefit because of their underlying CVD risk, but also face uncertain harms. Several high-quality mathematical simulation models have shown that statin therapy is cost-effective for primary prevention of atherosclerotic CVD. Despite effectiveness and safety, statins are underutilized for primary prevention. PMID- 28577622 TI - Aspirin for Primary Prevention. AB - Aspirin reduces the risk of nonfatal myocardial infarction and stroke, and the risk of colorectal cancer. Aspirin increases the risk of gastrointestinal and intracranial bleeding. The best available evidence supports initiating aspirin in select populations. In 2016, the US Preventive Services Task Force recommended initiating aspirin for the primary prevention of both cardiovascular disease and colorectal cancer among adults ages 50 to 59 who are at increased risk for cardiovascular disease. Adults 60 to 69 who are at increased cardiovascular disease risk may also benefit. There remains considerable uncertainty about whether younger and older patients may benefit. PMID- 28577624 TI - Cervical Cancer Screening. AB - Cervical cancer screening in the United States has accompanied profound decreases in cancer incidence and mortality over the last half century. Two screening strategies are currently endorsed by US-based guideline groups: (1) triennial cytology for women aged 21 to 65 years, and (2) triennial cytology for women aged 21 to 29 years followed by cytology plus testing for high-risk human papillomavirus types every 5 years for women aged 30 years and older. Providing women with affordable, easily accessible screening, follow-up of abnormal tests, and timely treatment will result in the greatest impact of screening on cervical cancer incidence and mortality. PMID- 28577623 TI - Risk-based Breast Cancer Screening: Implications of Breast Density. AB - The approach to breast cancer screening has changed over time from a general approach to a more personalized, risk-based approach. Women with dense breasts, one of the most prevalent risk factors, are now being informed that they are at increased risk of developing breast cancer and should consider supplemental screening beyond mammography. This article reviews the current evidence regarding the impact of breast density relative to other known risk factors, the evidence regarding supplemental screening for women with dense breasts, supplemental screening options, and recommendations for physicians having shared decision making discussions with women who have dense breasts. PMID- 28577625 TI - Colorectal Cancer Screening in Average Risk Patients. AB - Colorectal cancer (CRC) contributes a major burden of cancer mortality in the United States. There are multiple effective screening approaches that can reduce CRC mortality. These approaches are supported by different levels of evidence, and each has its own advantages and disadvantages. Implementing a systematic approach to screening that addresses the multiple steps involved in the screening process is essential to improving population-level CRC screening. Offering patients stool-based screening is important for increasing screening uptake. However, programs that offer stool testing must support the population health infrastructure needed to promote adherence to repeat testing and follow-up of abnormal tests. PMID- 28577626 TI - Lung Cancer Screening. AB - Lung cancer is the leading cause of cancer death in the United States. More than 80% of these deaths are attributed to tobacco use, and primary prevention can effectively reduce the cancer burden. The National Lung Screening Trial showed that low-dose computed tomography (LDCT) screening could reduce lung cancer mortality in high-risk patients by 20% compared with chest radiography. The US Preventive Services Task Force recommends annual LDCT screening for persons aged 55 to 80 years with a 30-pack-year smoking history, either currently smoking or having quit within 15 years. PMID- 28577627 TI - Prevention of Prostate Cancer Morbidity and Mortality: Primary Prevention and Early Detection. AB - More than any other cancer, prostate cancer screening with the prostate-specific antigen (PSA) tests increases the risk a man will have to face a diagnosis of prostate cancer. The best evidence from screening trials suggests a small but finite benefit from prostate cancer screening in terms of prostate cancer specific mortality, about 1 fewer prostate cancer death per 1000 men screened over 10 years. The more serious harms of prostate cancer screening, such as erectile dysfunction and incontinence, result from cancer treatment with surgery or radiation, particularly for men whose PSA-detected cancers were never destined to cause morbidity or mortality. PMID- 28577628 TI - Screening Adults for Depression in Primary Care. AB - The burden of depression in the United States is substantial. Evidence supports the benefits of screening for depression in all adults, including older patients and pregnant and postpartum women, when coupled with appropriate resources for management of disease. Developing, implementing, and sustaining a high-fidelity screening process is an important first step for improving the care of patients with depression in primary care. Initial treatment for depression should include psychotherapy, pharmacotherapy, or a combination of both. Collaborative care models are evidence-based approaches to depression treatment and follow-up that can be feasibly initiated in the primary care setting. PMID- 28577630 TI - An Ounce of Prevention? PMID- 28577629 TI - Screening and Counseling for Unhealthy Alcohol Use in Primary Care Settings. AB - Unhealthy alcohol use is a leading causes of preventable death in the United States. Reducing unhealthy alcohol use should be a high priority for health care providers. Well-validated screening instruments are available, and behavioral counseling interventions delivered in primary care can reduce risky drinking. For people with alcohol use disorder, treatment programs with or without medication can reduce consumption and promote abstinence. To overcome barriers to implementation of screening for alcohol use and subsequent delivery of appropriate interventions in primary care settings, support systems, changes in staffing or roles, formal protocols, and additional provider and staff training may be required. PMID- 28577631 TI - Update on Key Clinical Preventive Services for Adults. PMID- 28577632 TI - Oral Health Interventions During Pregnancy. AB - Oral health is a fundamental component of health and physical and mental well being. Oral health is influenced by an individual's physiologic and psychosocial attributes and cumulative oral health experiences. The perinatal period is a critical time when health and oral health determinants set in and thus an important time for intervention. Recognition of the importance of oral health intervention during pregnancy and oral health infrastructures have substantially grown over the last several years. This article reviews the current state of knowledge and practice of oral health intervention during pregnancy with a focus on individual- and population-based strategies, and summarizes key agendas for advancing prenatal oral health. PMID- 28577633 TI - Prenatal Maternal Factors, Intergenerational Transmission of Disease, and Child Oral Health Outcomes. AB - This article reviews maternal prenatal risk factors for caries in children and intergenerational transmission of caries, emphasizing early interventions for pregnant women and mother-infant pairs. A growing body of evidence focuses on maternal interventions. Studies suggest that early prenatal clinical and educational interventions are effective at reducing mother-child mutans streptococci (MS) transmission and delaying colonization and caries in young children. Dental screenings and anticipatory guidance about maternal and infant oral health should be included in prenatal care and pediatric well visits. Dental care during pregnancy is safe and recommended and can reduce maternal MS levels. Infants should visit a dentist by age 1. PMID- 28577634 TI - Social Determinants of Pediatric Oral Health. AB - Social determinants of health are defined as conditions in which people are born and live and the role these conditions play on health outcomes. Research indicates that risk factors and their interactions are far more complex than originally thought. This article outlines social determinant constructs and their role in understanding oral health promotion. Due to the complex interactions, oral health must be promoted using a multilevel chronic disease model or common risk factor approach. An understanding of social determinants is particularly important for the pediatric population because optimum oral health and general health in adulthood are heavily influenced by childhood. PMID- 28577637 TI - Interventions Focusing on Children with Special Health Care Needs. AB - The term children with special health care needs encompasses a wide variety of conditions. When considering interventions, a broad definition of children with special needs is suggested in this article along with a focus on developing specific treatment recommendations based on a thorough data-gathering process and developing customized recommendations for children based on their unique circumstances. An area for future research is increasing the understanding of the relationship between customized recommendations and the underlying special health care needs. PMID- 28577635 TI - Intergenerational and Social Interventions to Improve Children's Oral Health. AB - Dental caries and gingival and periodontal diseases are commonly occurring, preventable chronic conditions in children. These diseases are more common in disadvantaged communities and marginalized populations. Thus, public health approaches that stress prevention are key to improving oral health equity. There is currently limited evidence on which community-based, population-level interventions are most effective and equitable in promoting children's oral health. More rigorous measurement and reporting of study findings are needed to improve the quality of available evidence. Improved understanding of the multilevel influences of children's oral health may lead to the design of more effective and equitable social interventions. PMID- 28577638 TI - Pediatric Workforce Issues. AB - Untreated dental disease remains one of the most prevalent health conditions for children, driven in part by disparities in access to care. This article examines evidence-based workforce strategies being used to facilitate better access to pediatric health services and to improve oral health status and outcomes for children. The workforce strategies described in this article include promising new models in the dental field, with new and existing providers as well as emerging workforce models outside of the dental field. Case studies for some of these workforce strategies are also presented. Future directions and health policy implications are considered. PMID- 28577636 TI - Acculturation and Pediatric Minority Oral Health Interventions. AB - Immigrant populations are growing at a fast pace in the United States. Cultural variations can have implications on oral health of children from immigrant households. Length of stay in the United States and language spoken at home, proxies for measuring acculturation, are some of the crucial factors determining the level of acculturation in families. Higher acculturation generally has a positive impact on oral health utilization. Improving cultural competency of dental teams and involving the stakeholders in intervention design and implementation are some strategies that may increase the trust of ethnic minority patients and reduce barriers to access to care. PMID- 28577639 TI - Pediatric Dental-Focused Interprofessional Interventions: Rethinking Early Childhood Oral Health Management. AB - Evidence of effectiveness for prevention of early childhood caries suggests that parent engagement needs to occur perinatally and that unconventional providers, helping professionals like social workers and dietitians and lay health workers like community health workers, are most effective. This finding, coupled with the emergence of population-based accountable care, value-based purchasing with global payments, understanding of common risk factors for multiple conditions, and social determinants of health behaviors, calls for a rethinking of early childhood oral health care. A population-based model that incorporates unconventional providers is suggested together with research needed to achieve caries reductions in at-risk families. PMID- 28577640 TI - Parent Refusal of Topical Fluoride for Their Children: Clinical Strategies and Future Research Priorities to Improve Evidence-Based Pediatric Dental Practice. AB - A growing number of parents are refusing topical fluoride for their children during preventive dental and medical visits. This nascent clinical and public health problem warrants attention from dental professionals and the scientific community. Clinical and community-based strategies are available to improve fluoride-related communications with parents and the public. In terms of future research priorities, there is a need to develop screening tools to identify parents who are likely to refuse topical fluoride and diagnostic instruments to uncover the reasons for topical fluoride refusal. This knowledge will lead to evidence-based strategies that can be widely disseminated into clinical practice. PMID- 28577641 TI - Precision Dentistry in Early Childhood: The Central Role of Genomics. AB - Pediatric oral health is determined by the interaction of environmental factors and genetic influences. This is the case for early childhood caries, the most common disease of childhood. The complexity of exogenous-environmental factors interacting with innate biological predispositions results in a continuum of normal variation, as well as oral health and disease outcomes. Optimal oral health and care or precision dentistry warrants comprehensive understanding of these influences and tools enabling intervention on modifiable factors. This article reviews the current knowledge of the genomic basis of pediatric oral health and highlights known and postulated mechanistic pathways of action relevant to early childhood caries. PMID- 28577643 TI - The Science and Art of Evidence-Based Pediatric Dentistry. PMID- 28577642 TI - Research Evidence Use in Early and Periodic Screening, Diagnostic, and Treatment Dental Medicaid Class Action Lawsuits. AB - Little is known about research evidence use in dental Medicaid class action lawsuits. This qualitative study develops a conceptual model to understand the role of dentists and how research evidence was used. Archival analyses were conducted and 15 key informants interviewed. Dentists had key roles requiring scientific expertise or clinical experience serving vulnerable populations. Most evidence was newly generated, not based on existing sources. Dentists were involved in all phases of the lawsuits. Future research should identify conditions fostering research evidence use in dental Medicaid lawsuits and whether high-quality research evidence use improves child health outcomes. PMID- 28577644 TI - Tides within ourselves: how posture can affect blood volume, blood cells and clinical reasoning. PMID- 28577645 TI - Seroprevalence, cost per donation and reduction in blood supply due to positive and indeterminate results for infectious markers in a blood bank in Lima, Peru. AB - INTRODUCTION: Safety in Transfusion Medicine is subject to regulations and government legislation within a total quality framework. The aim of this study was to evaluate the impact of seroprevalence and indeterminate results on lost units and cost per donation. METHODS: A prospective cross-sectional study was performed in the Blood Bank and Transfusion Therapy Department of the Hospital Central de la Policia Nacional del Peru in Lima, Peru. All completed donations (replacement/voluntary) without complications were included in this study. Every donation met the institutional requirements and quality criteria of Programa Nacional de Hemoterapia y Bancos de Sangre (PRONAHEBAS). Data analysis was achieved using the Statistical Package for the Social Sciences. RESULTS: A total of 7723 donations were evaluated during 2014 and 2015 with 493 being seropositive (overall prevalence 5.25%) and 502 having indeterminate results (overall prevalence 5.35%). Thus total loss was 995units, 437.8L of blood and 49,750 US dollars. The most common seropositive infectious markers were the core antibody of hepatitis B virus (2.82%) and syphilis (1.02%), and the most common indeterminate results were Chagas disease (1.27%) and the core antibody of hepatitis B virus (1.26%). There was no significant change in the prevalence of seropositivity (p-value=0.243) or indeterminate results (p-value=0.227) over the two-year period of the study. A statistical correlation was found between the cost per lost donation and the most prevalent markers (rho=0.848; p value=<0.001). CONCLUSION: Seroprevalence was lower than the regional mean, but the prevalence of indeterminate results was elevated causing a great impact on blood supply and economic losses to this institution. PMID- 28577646 TI - Interleukin-10 haplotypes are not associated with acute cerebral ischemia or high risk transcranial Doppler in a newborn cohort of 395 children with sickle cell anemia. AB - BACKGROUND: The etiology of stroke, a severe complication of sickle cell anemia, involves inflammatory processes. However, the pathogenetic mechanisms are unknown. The aim of this study was to evaluate the influence of interleukin-10 polymorphisms and haplotypes on the risk of acute cerebral ischemia and high-risk transcranial Doppler in 395 children with sickle cell anemia from the state of Minas Gerais, Brazil. METHODS: Interleukin-10 haplotypes were determined by polymerase chain reaction-restriction fragment length polymorphism and sequencing. The outcomes studied were acute cerebral ischemia and high-risk transcranial Doppler. Clinical data were retrieved from the children's records. RESULTS: There was no statistically significant difference in the frequencies of polymorphisms and haplotypes between children with and without acute cerebral ischemia or children with or without high-risk transcranial Doppler. These data are consistent with a previous report that showed an absence of association between interleukin-10 plasma levels and high-risk transcranial Doppler velocity in children with sickle cell anemia. CONCLUSION: Interleukin-10 haplotypes were not associated with the risk of acute cerebral ischemia or high-risk transcranial Doppler velocity in children with sickle cell anemia from the state of Minas Gerais, Brazil. PMID- 28577647 TI - Foxo3 gene expression and oxidative status in beta-thalassemia minor subjects. AB - BACKGROUND: Oxidative stress may aggravate symptoms of hemolytic anemias such as beta-thalassemia. FoxO3 activation results in resistance to oxidative stress in fibroblasts and neuronal cell cultures. OBJECTIVE: The purpose of this research was to study FoxO3 gene expression and oxidative status in beta-thalassemia minor individuals. METHODS: Sixty-three subjects (42 apparently healthy individuals and 21 with beta-thalassemia minor) were analyzed at the Universidad Nacional de Tucuman, Argentina, between September 2013 and June 2014. A complete blood count, hemoglobin electrophoresis in alkaline pH and hemoglobin A2 levels were quantified. Moreover, thiobarbituric acid reactive species, erythrocyte catalase activity and iron status were evaluated. Beta-thalassemia mutations were determined by real-time polymerase chain reaction. FoxO3 gene expression was investigated by real-time reverse transcription-polymerase chain reaction using mononuclear cells from peripheral blood. RESULTS: Subjects were grouped as children (<=12 years), and adult women and men. The analysis of erythrocyte catalase activity/hemoglobin ratio revealed a significant difference (p-value <0.05) between healthy and beta-thalassemia minor adults, but no significant difference was observed in the thiobarbituric acid reactive species levels and FoxO3 gene expression (p-value >0.05). Thiobarbituric acid reactive species and the erythrocyte catalase activity/hemoglobin ratio were not significantly different on comparing the type of beta-thalassemia mutation (beta0 or beta+) present in carriers. CONCLUSIONS: The lack of systemic oxidative imbalance demonstrated by thiobarbituric acid reactive species is correlated to the observation of normal FoxO3 gene expression in mononuclear cells of peripheral blood. However, an imbalanced antioxidant state was shown by the erythrocyte catalase activity/hemoglobin ratio in beta-thalassemia minor carriers. It would be necessary to study FoxO3 gene expression in reticulocytes to elucidate the role of FoxO3 in this pathology. PMID- 28577648 TI - Molecular typing of human platelet antigens in immune thrombocytopenia patients in northern Brazil. AB - BACKGROUND: Immune thrombocytopenia is an immune disease characterized by thrombocytopenia and bleeding due to platelet antibodies against platelet membrane glycoproteins. Human platelet antigens are derived from polymorphisms of these glycoproteins. The aim of this study was to investigate human platelet antigen frequencies in immune thrombocytopenia patients from the state of Amazonas, Brazil and investigate the potential association between specific antigens and risk for immune thrombocytopenia. METHOD: Human platelet antigen typing was performed by BeadChip technology to determine allelic variants of 11 systems (HPA-1 to HPA-9, HPA-11 and HPA-15). Thirty-six patients (8 male and 28 female) with a median age of 34 years (range: 9-69 years) were evaluated and compared with data from Amazonas blood donors. RESULTS: Platelet counts varied from 3 to 98*109/L. The allele frequencies were 0.944 for HPA-1a, 0.056 for HPA 1b, 0.847 for HPA-2a, 0.153 for HPA-2b, 0.555 for HPA-3a, 0.444 for HPA-3b, 0.805 for HPA-5a, 0.222 for HPA-5b, 0.9975 for HPA-9a, 0.025 for HPA-9b, 0.486 for HPA 15a and 0.513 for HPA-15b. Among immune thrombocytopenia individuals, no b allele of the HPA-4, -6, -7, -8 and -11 were found. CONCLUSIONS: The results suggest HPA 1a, HPA-3b and HPA-5b are immune thrombocytopenia-specific autoepitopes. PMID- 28577649 TI - Patient posture for blood collection by venipuncture: recall for standardization after 28 years. AB - BACKGROUND: Although data about the effect of posture on routine hematological testing were published 28 years ago, this pre-analytical issue has not been standardized so far. This study was planned to evaluate whether postural changes influence the results of hematology testing. METHODS: A complete blood count was performed in 19 healthy volunteers after 25min in the supine position, 20min in a sitting position and 20min stationary standing in an upright position. RESULTS: The change from supine to sitting position caused clinically significant increases in the hemoglobin, hematocrit and red blood cell count. Furthermore, the change from supine to standing caused clinically significant increases in the hemoglobin, hematocrit, red blood cell, leukocyte, neutrophil, lymphocyte, basophil and platelet counts, and mean platelet volume, and that from sitting to standing caused clinically significant increases in hemoglobin, hematocrit, and red blood cell, leukocyte, neutrophil and lymphocyte counts. CONCLUSION: The results of this investigation provide further support to the notion that effort should be made to achieve widespread standardization in the practice of phlebotomy, including patient posture. PMID- 28577650 TI - Physical activity level and performance in the six-minute walk test of children and adolescents with sickle cell anemia. AB - BACKGROUND: To establish determinants of maximum walking distance in the 6-minute walk test of children and adolescents with sickle cell anemia, and to compare the performance in this test with physical activity level between patients and healthy controls. METHODS: A cross-sectional study was performed in which the participants answered the Physical Activity Questionnaire for Older Children and Adolescents, and completed the 6-minute walk test. MAIN RESULTS: Fifty-seven patients and 58 controls were studied. By univariate analysis of the patients, age (p<0.0001) and indirect bilirubin (p=0.008) were associated with maximum walking distance in the 6-minute walk test. In multivariate analysis, age was positively associated (p<0.0001; beta: 0.75), while body mass index was inversely associated with distance walked (p=0.047; beta: -0.32). This yields the following equation: maximum distance walked=487.7 (age*18.3)-(12*body mass index) meters. Patients reported a lower physical activity level however there was no significant difference in the distance walked in six minutes between patients (500.6+/-88.7m) and controls (536.3+/-94m). CONCLUSION: The determinants for the 6-minute walk test in children and adolescents with sickle cell anemia were age and body mass index. There was no significant difference in the 6-minute walk test but patients with sickle cell anemia had a lower physical activity level compared to healthy controls. PMID- 28577651 TI - Telomere length correlates with disease severity and inflammation in sickle cell disease. AB - BACKGROUND: Telomeres, the ends of linear chromosomes, shorten during mitotic cell division and erosion may be aggravated by inflammation or proliferative and oxidative stress. As the bone marrow is under hyperproliferative pressure in sickle cell disease and several tissues are submitted to chronic inflammation, this study sought to determine the telomere length of patients with sickle cell disease. METHODS: The mean telomere length was measured in peripheral blood leukocytes by quantitative polymerase chain reaction. The age-adjusted telomere to single copy gene ratio was compared between 91 adult sickle cell disease patients and 188 controls. RESULTS: Sickle cell disease patients had significantly shorter telomeres than the controls (p-value<0.0001). Moreover, among sickle cell disease genotypes, Hb SS patients had significantly shorter telomeres compared to Hb SC and Hb Sbeta patients (p-value<0.0001). Patients on hydroxyurea also had shorter telomeres in comparison to those off the drug (p value=0.02). A positive correlation was observed between telomere length and hemoglobin level (r=0.3; p-value=0.004), whereas negative correlations were detected between telomere length and lymphocyte count (r=-0.3; p-value=0.005) and interleukin-8 serum levels (r=-0.4; p-value=0.02). CONCLUSIONS: The findings of this study indicate that telomeres are short in sickle cell disease patients and that telomere erosion directly correlates with disease genotype, inflammation markers, and the use of hydroxyurea. PMID- 28577652 TI - Splenic marginal zone lymphoma: a literature review of diagnostic and therapeutic challenges. AB - Splenic marginal zone lymphoma (SMZL) is a low-grade B-cell non-Hodgkin's lymphoma characterized by massive splenomegaly, moderate lymphocytosis with or without villous lymphocytes, rare involvement of peripheral lymph nodes and indolent clinical course. As a rare disease, with no randomized prospective trials, there is no standard of care for SMZL so far. Splenectomy has been done for many years as an attempt to control disease, but nowadays it has not been encouraged as first line because of new advances in therapy as rituximab, that are as effective with minimal toxicity. Facing these controversies, this review highlights advances in the literature regarding diagnosis, prognostic factors, treatment indications and therapeutic options. PMID- 28577653 TI - Nutritional status and hyperglycemia in the peritransplant period: a review of associations with parenteral nutrition and clinical outcomes. AB - Hematopoietic stem cell transplantation is an established treatment option for various hematological diseases. This therapy involves complex procedures and is associated with several systemic complications. Due to the toxic effects of the conditioning regimen used in allogeneic transplantations, patients frequently suffer from severe gastrointestinal complications and are unable to feed themselves properly. This complex clinical scenario often requires specialized nutritional support, and despite the increasing number of studies available, many questions remain regarding the best way to feed these patients. Parenteral nutrition has been traditionally indicated when the effects on gastrointestinal mucosa are significant; however, the true benefits of this type of nutrition in reducing clinical complications have been questioned. Hyperglycemia is a common consequence of parenteral nutrition that seems to be correlated to poor transplantation outcomes and a higher risk of infections. Additionally, nutrition related pre-transplantation risk factors are being studied, such as impaired nutritional status, poorly controlled diabetes mellitus and obesity. This review aims to discuss some of these recent issues. A real case of allogeneic transplant was used to illustrate the scenario and to highlight the most important topics that motivated this literature review. PMID- 28577654 TI - Sickle cell intrahepatic cholestasis unresponsive to exchange blood transfusion: a case report. PMID- 28577655 TI - Concomitant chronic myeloid leukemia and monoclonal B cell lymphocytosis - a very rare condition. PMID- 28577656 TI - Idiopathic hypereosinophilic syndrome with 20 years of diagnostic delay. PMID- 28577657 TI - Oral lesions associated with Fanconi anemia. PMID- 28577658 TI - Bone marrow transplant donor recruitment strategies to maximize, optimize, and equalize recipient chances of an acceptable match. PMID- 28577659 TI - Presence of atypical beta globin (HBB) gene cluster haplotypes in sickle cell anemia patients of India. PMID- 28577660 TI - Stathmin 1 expression in plasma cell neoplasms. PMID- 28577661 TI - Erratum to "Alloimmunization screening after transfusion of red blood cells in a prospective study" [Rev Bras Hematol Hemoter. 2012;34(3):206-211]. PMID- 28577662 TI - Human platelet antigens and primary immune thrombocytopenia. PMID- 28577663 TI - Stressed ends: telomere attrition in chronic diseases. PMID- 28577664 TI - Feasibility of exercise stress echocardiography and myocardial response in patients with repaired congenital heart disease. AB - BACKGROUND: Exercise stress echocardiography (ESE) can unmask ventricular dysfunction in asymptomatic patients with congenital heart disease (CHD), but its acquisition and interpretation is often challenging, and the method has not been validated in CHD. This study aimed to evaluate the feasibility of ESE using Doppler imaging and to assess myocardial response to exercise in patients with biventricular (BiV) and univentricular (UniV) circulation after CHD repair. METHODS: In this single-center prospective study, we recruited 55 participants (17 females), median age 14 years (8-22 years). Our analysis categorized participants in these three groups: with structurally normal hearts as controls (n=21), with BiV circulation (n=20) and with UniV circulation (n=14). We acquired ESE images of the systemic ventricle including pulsed-wave flow and spectral tissue Doppler imaging (TDI) of lateral free wall before and immediately after standard, symptom-limited exercise tests on an electronically braked cycle ergometer. RESULTS: During ESE we obtained inflow E-wave and TDI systolic (S') and early diastolic (E') velocities in 93% to 100% of participants at rest and in 90% to 100% of participants post exercise. Feasibility to obtain Doppler imaging parameter was the same across study groups. The myocardial response to exercise was increase in heart rate (HR), S' and inflow E-wave velocity in all participants. Patients with BiV circulation had preserved ventricular function at rest. While patients with UniV circulation had low S', E', and E-wave velocities at rest in comparison to controls and to BiV group (all P<.001), both patients with BiV and UniV circulation showed significant increases in HR, S' velocity and inflow E-wave velocity post exercise, with magnitudes of these increases higher in controls than in the BiV and UniV group. The S' and E' velocities were strongly associated with lower percent predicted peak oxygen consumption VO2 (rs=0.614 and rs=0.64, respectively, both P<.001). CONCLUSION: ESE with Doppler imaging is a practical noninvasive diagnostic method and sufficiently robust for the assessment of morphologic LV/systemic ventricles under exercise in patients after biventricular and univentricular CHD repair. Although patients with BiV and UniV circulation had both preserved myocardial response to exercise, the magnitude of this response was the lowest in patients with UniV circulation. PMID- 28577665 TI - Rationale, design, and baseline characteristics of the Salt Substitute and Stroke Study (SSaSS)-A large-scale cluster randomized controlled trial. AB - Lowering sodium intake with a reduced-sodium, added potassium salt substitute has been proved to lower blood pressure levels. Whether the same strategy will also reduce the risks of vascular outcomes is uncertain and controversial. The SSaSS has been designed to test whether sodium reduction achieved with a salt substitute can reduce the risk of vascular disease. The study is a large-scale, open, cluster-randomized controlled trial done in 600 villages across 5 provinces in China. Participants have either a history of stroke or an elevated risk of stroke based on age and blood pressure level at entry. Villages were randomized in a 1:1 ratio to intervention or continued usual care. Salt substitute is provided free of charge to participants in villages assigned to the intervention group. Follow-up is scheduled every 6months for 5years, and all potential endpoints are reviewed by a masked adjudication committee. The primary end point is fatal and nonfatal stroke, and the 2 secondary endpoints are total major cardiovascular events and total mortality. The study has been designed to provide 90% statistical power (with 2-sided alpha = .05) to detect a 13% or greater relative risk reduction for stroke. The power estimate assumes a primary outcome event rate of 3.5% per year and a systolic blood pressure difference of 3.0mm Hg between randomized groups. Recruitment is complete and there are 20,996 participants (about 35 per village) that have been enrolled. Mean age is 65years and 49% are female. There were 73% enrolled on the basis of a history of stroke. The trial is well placed to describe the effects of salt substitution on the risks of vascular disease and death and will provide important policy-relevant data. PMID- 28577666 TI - A prospective, randomized, open-label trial of 6-month versus 12-month dual antiplatelet therapy after drug-eluting stent implantation in ST-elevation myocardial infarction: Rationale and design of the "DAPT-STEMI trial". AB - BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with second-generation drug eluting stents (DESs) is unclear. Because prolonged DAPT is associated with higher bleeding risk and health care costs, establishing optimal DAPT duration is of paramount importance. No other randomized controlled trials have evaluated the safety of shorter DAPT duration in ST-elevation myocardial infarction (STEMI) patients treated with second-generation DESs and latest P2Y12 platelet receptor inhibitors. HYPOTHESIS: Six months of DAPT after Resolute Integrity stent implantation in STEMI patients is not inferior to 12 months of DAPT in clinical outcomes. STUDY DESIGN: The Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation In ST-elevation Myocardial Infarction (DAPT-STEMI) trial is a randomized, multicenter, international, open-label trial designed to examine the safety (noninferiority) of 6-month DAPT after Resolute Integrity stent implantation in STEMI patients compared with 12-month DAPT. Event-free patients on DAPT at 6month will be randomized (1:1 fashion) between single (aspirin only) versus DAPT for an additional 6 months and followed until 2 years after primary percutaneous coronary intervention. The primary end point is a patient-oriented composite endpoint of all-cause mortality, any myocardial infarction, any revascularization, stroke, and major bleeding (net adverse clinical events [NACE]) at 18 months after randomization. To achieve a power of 85% for a noninferiority limit of 1.66, a total of 1100 enrolled patients are required. SUMMARY: The DAPT-STEMI trial aims to assess in STEMI patients treated with second-generation DESs whether discontinuation of DAPT after 6 months of event free survival is noninferior to routine 12-month DAPT. PMID- 28577667 TI - Clinical SYNTAX score predicts outcomes of patients undergoing coronary artery bypass grafting. AB - BACKGROUND: The SYNTAX score (SS) is a determinant of outcome in patients undergoing percutaneous coronary intervention. In addition, it has been recently shown that the clinical SYNTAX score (cSS), obtained by adding clinical variables to the SS, improves the predictive power of the resulting risk model. We assessed the hypothesis that the use of the cSS may predict outcomes of patients undergoing coronary artery bypass grafting (CABG). METHODS: We measured the SYNTAX score in 874 patients undergoing isolated first time on-pump CABG. The clinical SYNTAX score was calculated at the time of the study using age, creatinine clearance and ejection fraction, the modified ACEF score, and analyses performed for major adverse cardiac and cerebrovascular events (MACCE) and all cause mortality at 3-year follow-up. RESULTS: The mean age of the study population was 70.9 +/- 8.1 years, and the median cSS 14.2 (range 2.1-286.5). The ROC curve analysis showed that a cSS >14.5 (81.4% sensitivity and 67.8% specificity) was a reliable tool in discrimination of patients for the occurrence of MACCE (AUC 0.78) and all-cause mortality (AUC 0.74). Kaplan-Meier survival analysis confirmed that patients belonging to higher cSS quartiles have poorer 3 year survival (P = .0001) and MACCE-free survival (P = .0001), with respect to those with lower cSS. CONCLUSIONS: This observational study has shown that the clinical SYNTAX score, incorporating the lesion-based SS and clinical-based ACEF score, predicted mid-term adverse outcomes of patients undergoing CABG and may play an important role in the risk stratification of this population. Further studies are needed to confirm these findings. PMID- 28577668 TI - Characterization of hemodynamically stable acute heart failure patients requiring a critical care unit admission: Derivation, validation, and refinement of a risk score. AB - BACKGROUND: Most patients with acute heart failure (AHF) admitted to critical care units (CCUs) are low acuity and do not require CCU-specific therapies, suggesting that they could be managed in a lower-cost ward environment. This study identified the predictors of clinical events and the need for CCU-specific therapies in patients with AHF. METHODS: Model derivation was performed using data from patients in the ASCEND-HF trial cohort (n=7,141), and the Acute Heart Failure Emergency Management community-based registry (n=666) was used to externally validate the model and to test the incremental prognostic utility of 4 variables (heart failure etiology, troponin, B-type natriuretic peptide [BNP], ejection fraction) using net reclassification index and integrated discrimination improvement. The primary outcome was an in-hospital composite of the requirement for CCU-specific therapies or clinical events. RESULTS: The primary composite outcome occurred in 545 (11.4%) derivation cohort participants (n=4,767) and 7 variables were predictors of the primary composite outcome: body mass index, chronic respiratory disease, respiratory rate, resting dyspnea, hemoglobin, sodium, and blood urea nitrogen (c index=0.633, Hosmer-Lemeshow P=.823). In the validation cohort (n=666), 87 (13.1%) events occurred (c index=0.629, Hosmer Lemeshow P=.386) and adding ischemic heart failure, troponin, and B-type natriuretic peptide improved model performance (net reclassification index 0.79, 95% CI 0.046-0.512; integrated discrimination improvement 0.014, 95% CI 0.005 0.0238). The final 10-variable clinical prediction model demonstrated modest discrimination (c index=0.702) and good calibration (Hosmer-Lemeshow P=.547). CONCLUSIONS: We derived, validated, and improved upon a clinical prediction model in an international trial and a community-based cohort of AHF. The model has modest discrimination; however, these findings deserve further exploration because they may provide a more accurate means of triaging level of care for patients with AHF who need admission. PMID- 28577669 TI - Diastolic dysfunction revisited: A new, feasible, and unambiguous echocardiographic classification predicts major cardiovascular events. AB - BACKGROUND: Echocardiographic classification of DDF has been widely discussed. The aim of this study was to investigate the independent prognostic value of established echocardiographic measures in a community-based population and create a new classification of DDF. METHODS: Within the Copenhagen City Heart Study, a prospective, community-based study, 1851 participants were examined by echocardiography including Tissue Doppler Imaging (TDI) in 2001 to 2003 and followed with regard to MACE (median, 10.9 years). RESULTS: We found that persons with impaired myocardial relaxation as defined by low peak early diastolic mitral annular velocity e' by TDI had higher incidence of clinical and echocardiographic markers of cardiac dysfunction and increased risk of MACE. Among persons with impaired relaxation, only echocardiographic indices of increased filling pressures such as LAVi>=34 mL/m2 (HR 1.97 (1.13-3.45, P=.017), E/e' >= 17 (HR 1.89 (1.34-2.65), P<.001), and E/A>2 (HR 5.24 (1.91-14.42), P=.001) provided additional and independent prognostic information on MACE. Based on these findings, we created a new classification of DDF where all grades were significant predictors of MACE independently of age, sex, and cardiac clinical risk markers (Mild DDF: HR 1.99 (1.23-3.21), P=.005; Moderate DDF: HR 3.11 (1.81 5.34), P<.001; Severe DDF: HR 4.20 (1.81-9.73), P<.001). Increasing severity of DDF was linearly associated with increasing plasma proBNP concentrations. CONCLUSIONS: In the general population, the presence of echocardiographic markers of elevated filling pressures in persons with impaired relaxation increased the risk of MACE significantly. Based on this, we present a new, feasible, and unambiguous classification of DDF capable of accurate risk prediction in the community. PMID- 28577670 TI - Cangrelor reduces the risk of ischemic complications in patients with single vessel and multi-vessel disease undergoing percutaneous coronary intervention: Insights from the CHAMPION PHOENIX trial. AB - OBJECTIVE: To examine the safety and efficacy of cangrelor in patients with single-vessel disease (SVD) and multi-vessel disease (MVD). BACKGROUND: Cangrelor, an intravenous, rapidly acting P2Y12 inhibitor, is superior to clopidogrel in reducing ischemic events among patients receiving percutaneous coronary intervention (PCI). METHODS: We studied a modified intention to treat population of patients with SVD and MVD from the CHAMPION PHOENIX trial. The primary efficacy outcome was the composite of death, myocardial infarction (MI), ischemia-driven revascularization (IDR), and stent thrombosis (ST) at 48hours. The key safety outcome was non-coronary artery bypass grafting GUSTO severe bleeding at 48hours. RESULTS: Among 10,921 patients, 5,220 (48%) had SVD and 5,701 (52%) had MVD. MVD patients were older and more often had diabetes, hyperlipidemia, hypertension, prior stroke, and prior MI. After adjustment, MVD patients had similar rates of 48-hour death/MI/IDR/ST (6.3% vs 4.2%, adjusted odds ratio [OR] 1.6 [95% CI 0.42-6.06]) and GUSTO severe bleeding (0.1% vs 0.2%, P=.67) compared with SVD patients. Consistent with overall trial findings, cangrelor use reduced ischemic complications in patients with both SVD (3.9% vs 4.5%; OR 0.86, 95% CI 0.65-1.12) and MVD (5.5% vs 7.2%; OR 0.74, 95% CI 0.6-0.92, P-interaction=.43). GUSTO severe bleeding outcomes were not significantly increased with cangrelor or clopidogrel in either SVD or MVD patients. CONCLUSION: In the CHAMPION PHOENIX trial, MVD and SVD patients had similar ischemic outcomes at 48hours and 30days. Cangrelor consistently reduced ischemic complications in both SVD and MVD patients without a significant increase in GUSTO severe bleeding. CLINICAL PERSPECTIVES. PMID- 28577671 TI - Dual antiplatelet therapy in patients with diabetes and acute coronary syndromes managed without revascularization. AB - OBJECTIVE: Patients with diabetes mellitus (DM) presenting with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI) derived enhanced benefit with dual antiplatelet therapy (DAPT) with prasugrel vs. clopidogrel. The risk profile and treatment response to DAPT for medically managed ACS patients with DM remains uncertain. METHODS: The TRILOGY ACS trial compared aspirin + prasugrel vs. aspirin + clopidogrel for up to 30months in non ST-segment elevation (NSTE) ACS patients managed medically without revascularization. We compared treatment-related outcomes among 3539 patients with DM vs. 5767 patients without DM. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. RESULTS: Patients with vs. without DM were younger, more commonly female, heavier, and more often had revascularization prior to the index ACS event. The frequency of the primary endpoint through 30months was higher among patients with vs. without DM (24.8% vs. 16.3%), with a higher risk for those patients with DM treated with insulin vs. those treated without insulin (35.3% vs. 19.9%). There was no significant difference in the frequency of the primary endpoint by treatment with prasugrel vs. clopiodgrel in those with or without DM (Pint=0.82) and with or without insulin treatment among those with DM (Pint=0.304). CONCLUSIONS: Among NSTE ACS patients managed medically without revascularization, patients with DM had a higher risk of ischemic events that was amplified among those treated with insulin. There was no differential treatment effect with a more potent DAPT regimen of aspirin + prasugrel vs. aspirin + clopidogrel. PMID- 28577672 TI - A randomized double-blind trial of an interventional device treatment of functional mitral regurgitation in patients with symptomatic congestive heart failure-Trial design of the REDUCE FMR study. AB - The Carillon Mitral Contour System has been studied in 3 nonrandomized trials in patients with symptomatic congestive heart failure and functional mitral regurgitation. The REDUCE FMR study is a uniquely designed, double-blind trial evaluating the impact of the Carillon device on reducing regurgitant volume, as well as assessing the safety and clinical efficacy of this device. Carillon is a coronary sinus-based indirect annuloplasty device. Eligible patients undergo an invasive venogram to assess coronary sinus vein suitability for the Carillon device. If the venous dimensions are suitable, they are randomized on a 3:1 basis to receive a device or not. Patients and assessors are blinded to the treatment assignment. The primary end point is the difference in regurgitant volume at 1 year between the implanted and nonimplanted groups. Other comparisons include clinical parameters such as heart failure hospitalizations, 6-minute walk test, Kansas City Cardiomyopathy Questionnaire (KCCQ), and other echocardiographic parameters. An exercise echo substudy will also be included. PMID- 28577675 TI - Prognostication on the spot! The evolving importance of urinary creatinine in heart failure. PMID- 28577674 TI - Relationship between therapeutic effects on infarct size in acute myocardial infarction and therapeutic effects on 1-year outcomes: A patient-level analysis of randomized clinical trials. AB - BACKGROUND: While infarct size in patients with ST-segment elevation myocardial infarction (STEMI) has been generally associated with long-term prognosis, whether a therapeutic effect on infarct size has a corresponding therapeutic effect on long-term outcomes is unknown. METHODS: Using combined patient-level data from 10 randomized trials of primary percutaneous coronary intervention (PCI) for STEMI, we created multivariable Cox proportional hazard models for one year heart failure hospitalization and all-cause mortality, which included clinical features and a variable representing treatment effect on infarct size. The trials included 2679 participants; infarct size was measured at a median 4 days post infarction. RESULTS: Mean infarct size among the control groups ranged from 16% to 35% of the left ventricle, and from 12% to 36% among treatment groups. There was a significant relationship between treatment effect on infarct size and treatment effect on 1-year heart failure hospitalization (HR 0.85, 95% CI 0.77-0.93, P=.0006), but not on one-year mortality (HR 0.97, 95% CI 0.89 1.06). The treatment effect between infarct size and heart failure hospitalization was stable in sensitivity analyses adjusting for time from STEMI onset to infarct size assessment, and when considering heart failure as the main outcome and death as a competing risk. CONCLUSIONS: We conclude that early treatment-induced effects on infarct size are related in direction and magnitude to treatment effects on heart failure hospitalizations. This finding enables consideration of using infarct size as a valid surrogate outcome measure in assessing new STEMI treatments. PMID- 28577673 TI - Bridging Income Generation with Group Integrated Care for cardiovascular risk reduction: Rationale and design of the BIGPIC study. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality worldwide, with >80% of CVD deaths occurring in low and middle income countries (LMICs). Diabetes mellitus and pre-diabetes are risk factors for CVD, and CVD is the major cause of morbidity and mortality among individuals with DM. There is a critical period now during which reducing CVD risk among individuals with diabetes and pre-diabetes may have a major impact. Cost-effective, culturally appropriate, and context-specific approaches are required. Two promising strategies to improve health outcomes are group medical visits and microfinance. METHODS/DESIGN: This study tests whether group medical visits integrated into microfinance groups are effective and cost-effective in reducing CVD risk among individuals with diabetes or at increased risk for diabetes in western Kenya. An initial phase of qualitative inquiry will assess contextual factors, facilitators, and barriers that may impact integration of group medical visits and microfinance for CVD risk reduction. Subsequently, we will conduct a four-arm cluster randomized trial comparing: (1) usual clinical care, (2) usual clinical care plus microfinance groups only, (3) group medical visits only, and (4) group medical visits integrated into microfinance groups. The primary outcome measure will be 1-year change in systolic blood pressure, and a key secondary outcome measure is 1-year change in overall CVD risk as measured by the QRISK2 score. We will conduct mediation analysis to evaluate the influence of changes in social network characteristics on intervention outcomes, as well as moderation analysis to evaluate the influence of baseline social network characteristics on effectiveness of the interventions. Cost-effectiveness analysis will be conducted in terms of cost per unit change in systolic blood pressure, percent change in CVD risk score, and per disability-adjusted life year saved. DISCUSSION: This study will provide evidence regarding effectiveness and cost-effectiveness of interventions to reduce CVD risk. We aim to produce generalizable methods and results that can provide a model for adoption in low-resource settings worldwide. PMID- 28577677 TI - Corrigendum to 'Association of Standard Clinical and Laboratory Variables with Red Blood Cell Distribution Width (RDW)'[Am. Heart J. (2016) 22-28]. PMID- 28577676 TI - Clinical and prognostic value of spot urinary creatinine in chronic heart failure An analysis from GISSI-HF. AB - OBJECTIVES: This study aimed to identify patient characteristics associated with low urinary creatinine in morning spot urine and investigate its association with clinical outcome. BACKGROUND: Twenty-four-hour creatinine excretion is an established marker of muscle mass in heart failure and other populations. Spot urine creatinine might be an easy obtainable, cheap marker of muscle wasting and prognosis in heart failure (HF) patients. METHODS: Spot urine creatinine concentration was measured in 2130 patients included in the GISSI-HF trial. We evaluated the prognostic value of urinary creatinine and its relation with clinical variables. RESULTS: Median spot urinary creatinine was 0.80 (IQR 0.50 1.10) g/L. Lower spot urinary creatinine was associated with older age, smaller height and weight, higher NYHA class, worse renal function and more frequent spironolactone and diuretic use (all P<.02). During a median follow-up of 2.8 years, 655 patients (31%) experienced the combined endpoint of all-cause mortality or HF hospitalization. Lower urinary creatinine was independently associated with an increased risk of all-cause mortality or HF hospitalization (HR, 1.59 [1.21-2.08] per log decrease, P=.001), and all-cause mortality (HR, 1.75 [1.25-2.45] per log decrease, P=.001). CONCLUSION: Lower urinary creatinine, measured in morning spot urine in patients with chronic HF, is associated with worse renal function, smaller body size, more severe HF and is independently associated with an increased risk of all-cause death and HF hospitalization. PMID- 28577678 TI - Does perceived stress increase the risk of atrial fibrillation? A population based cohort study in Denmark. AB - BACKGROUND: Psychological stress is associated with increased risk of acute cardiovascular diseases, as myocardial infarction. We recently found a higher risk of atrial fibrillation following an acute stressful life event, but it remains unknown whether this also applies to common and less acute stress exposures. METHODS: We investigated the risk of incident atrial fibrillation in people with high levels of perceived stress by following a population-based cohort of 114,337 participants from the Danish National Health Survey from 2010 to 2014. The survey holds information on lifestyle factors and perceived stress measured by Cohen's 10-item Perceived Stress Scale (PSS). We obtained information on atrial fibrillation, comorbidities and socioeconomic status from Danish nationwide registers. We identified 2172 persons with a first episode of atrial fibrillation during 424,839 person-years of follow-up. The hazard ratio (HR) of atrial fibrillation with 95% confidence interval (CI) was calculated with Cox proportional hazard model. RESULTS: The risk of atrial fibrillation increased with increasing PSS score; persons in the highest perceived stress quintile had 28% (95% CI, 12%-46%) higher risk of atrial fibrillation compared with persons in the lowest perceived stress quintile. However, the association disappeared when adjusting for comorbidities, socioeconomic status and lifestyle factors; HR was 1.01 (95% CI, 0.88-1.16) when comparing persons in the highest and the lowest perceived stress quintile. CONCLUSIONS: This large population-based cohort study did not reveal a higher risk of atrial fibrillation among persons with a high degree of perceived stress after adjustment for participants' baseline characteristics. PMID- 28577679 TI - The effects of sacubitril/valsartan on coronary outcomes in PARADIGM-HF. AB - BACKGROUND: Angiotensin converting enzyme inhibitors (ACE-I), are beneficial both in heart failure with reduced ejection fraction (HF-REF) and after myocardial infarction (MI). We examined the effects of the angiotensin-receptor neprilysin inhibitor sacubitril/valsartan, compared with the ACE-I enalapril, on coronary outcomes in PARADIGM-HF. METHODS AND RESULTS: We examined the effect of sacubitril/valsartan compared with enalapril on the following outcomes: i) the primary composite endpoint of cardiovascular (CV) death or HF hospitalization, ii) a pre-defined broader composite including, in addition, MI, stroke, and resuscitated sudden death, and iii) a post hoc coronary composite of CV-death, non-fatal MI, angina hospitalization or coronary revascularization. At baseline, of 8399 patients, 3634 (43.3%) had a prior MI and 4796 (57.1%) had a history of any coronary artery disease. Among all patients, compared with enalapril, sacubitril/valsartan reduced the risk of the primary outcome (HR 0.80 [0.73 0.87], P<.001), the broader composite (HR 0.83 [0.76-0.90], P<.001) and the coronary composite (HR 0.83 [0.75-0.92], P<.001). Although each of the components of the coronary composite occurred less frequently in the sacubitril/valsartan group, compared with the enalapril group, only CV death was reduced significantly. CONCLUSIONS: Compared with enalapril, sacubitril/valsartan reduced the risk of both the primary endpoint and a coronary composite outcome in PARADIGM-HF. Additional studies on the effect of sacubitril/valsartan on atherothrombotic outcomes in high-risk patients are merited. PMID- 28577681 TI - A laboratory association between hemoglobin and VerifyNow P2Y12 reaction unit: A systematic review and meta-analysis. AB - BACKGROUND: VerifyNow P2Y12 assay is used widely to evaluate residual platelet reactivity in patients taking P2Y12 receptor antagonists. However, a laboratory association between VerifyNow P2Y12 reaction unit (PRU) and hemoglobin, which might lead to wrong interpretation of the data, is reported. We performed these systematic review and meta-analysis to clearly define the relationship between PRU and hemoglobin and to elucidate whether the relationship, if any, is a true biological association or is just a laboratory error. METHODS: Through a comprehensive electronic and manual search, 10 studies were selected for the cohort level meta-analysis. Among 10 studies, we were able to retrieve the raw data of 5 studies, and a patient-level meta-analysis was performed. Potential publication bias was searched by funnel plot analysis and was actively adjusted, if present, by trim and fill method. RESULTS: The pooled analysis revealed a significant inverse correlation between PRU and hemoglobin (r=-0.349; P<.001; 10 studies with 4,793 patients). VerifyNow P2Y12 base unit, which reflects off-drug platelet reactivity, was also inversely correlated with hemoglobin (r=-0.526; P<.001; 8 studies with 4,395 patients). % Inhibition (r=0.081; P=.059; 6 studies with 3,832 patients) and DeltaPRU (r=-0.037; P=.188; 5 studies with 3,521 patients) were not associated with hemoglobin. A significant inverse association between PRU and hemoglobin was also observed in the patient-level meta-analysis (3,533 patients pooled from 5 studies; r=-0.335; P<.001). Light transmission aggregometry (r=0.160; P=.072; 4 studies with 1,144 patients) and multiple electrode platelet aggregometry (r=-0.029; P=.394; 3 studies with 7,645 patients) showed no significant association with hemoglobin. CONCLUSIONS: A significant inverse association was observed between PRU and hemoglobin which is likely to be a laboratory error. Clinicians should be aware that this association might lead to wrong interpretation of the data. PMID- 28577680 TI - Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation. AB - BACKGROUND: The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes. OBJECTIVES: This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan. METHODS: A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five. RESULTS: The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts. CONCLUSIONS: Udenafil was well tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial. PMID- 28577682 TI - Digital health intervention during cardiac rehabilitation: A randomized controlled trial. AB - BACKGROUND: Digital health interventions (DHI) have been shown to improve intermediates of cardiovascular health, but their impact on cardiovascular (CV) outcomes has not been fully explored. The aim of this study was to determine whether DHI administered during cardiac rehabilitation (CR) would reduce CV related emergency department (ED) visits and rehospitalizations in patients after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). METHODS: We randomized patients undergoing CR following ACS and PCI to standard CR (n=40) or CR+DHI (n=40) for 3 months with 3 patients withdrawing from CR prior to initiation in the treatment arm and 6 in the control group. The DHI incorporated an online and smartphone-based CR platform asking the patients to report of dietary and exercise habits throughout CR as well as educational information toward patients' healthy lifestyles. We obtained data regarding ED visits and rehospitalizations at 180 days, as well as other metrics of secondary CV prevention at baseline and 90 days. RESULTS: Baseline demographics were similar between the groups. The DHI+CR group had improved weight loss compared to the control group (-5.1+/-6.5 kg vs. -0.8+/-3.8 kg, respectively, P=.02). Those in the DHI+CR group also showed a non-significant reduction in CV-related rehospitalizations plus ED visits compared to the control group at 180 days (8.1% vs 26.6%; RR 0.30, 95% CI 0.08-1.10, P=.054). CONCLUSIONS: The current study demonstrated that complementary DHI significantly improves weight loss, and might offer a method to reduce CV-related ED visits plus rehospitalizations in patients after ACS undergoing CR. The study suggests a role for DHI as an adjunct to CR to improve secondary prevention of CV disease. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov (NCT01883050). PMID- 28577683 TI - Use of prasugrel vs clopidogrel and outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention in contemporary clinical practice: Results from the PROMETHEUS study. AB - BACKGROUND AND OBJECTIVES: We sought to determine the frequency of use and association between prasugrel and outcomes in acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI) in clinical practice. METHODS: PROMETHEUS was a multicenter observational registry of acute coronary syndrome patients undergoing PCI from 8 centers in the United States that maintained a prospective PCI registry for patient outcomes. The primary end points were major adverse cardiovascular events at 90days, a composite of all cause death, nonfatal myocardial infarction, stroke, or unplanned revascularization. Major bleeding was defined as any bleeding requiring hospitalization or blood transfusion. Hazard ratios (HRs) were generated using multivariable Cox regression and stratified by the propensity to treat with prasugrel. RESULTS: Of 19,914 patients (mean age 64.4years, 32% female), 4,058 received prasugrel (20%) and 15,856 received clopidogrel (80%). Prasugrel-treated patients were younger with fewer comorbid risk factors compared with their counterparts receiving clopidogrel. At 90days, there was a significant association between prasugrel use and lower major adverse cardiovascular event (5.7% vs 9.6%, HR 0.58, 95% CI 0.50-0.67, P<.0001) and bleeding (1.9% vs 2.9%, HR 0.65, 95% CI 0.51-0.83, P<.001). After propensity stratification, associations were attenuated and no longer significant for either outcome. Results remained consistent using different approaches to adjusting for potential confounders. CONCLUSIONS: In contemporary clinical practice, patients receiving prasugrel tend to have a lower-risk profile compared with those receiving clopidogrel. The lower ischemic and bleeding events associated with prasugrel use were no longer evident after accounting for these baseline differences. PMID- 28577684 TI - Electronically self-assessed functional capacity and exercise testing: A comparison of the Duke Activity Status Index and Patient-Reported Outcomes Measurement Information System tools. AB - PURPOSE: Electronic screening tools, such as Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short-Form 12a (PF SF12a), may aid in the assessment of functional capacity. However, PROMIS PF SF12a has not been validated against exercise capacity, or compared with established questionnaires, including the Duke Activity Status Index (DASI). We compared the DASI and PROMIS PF-SF12a to the maximum metabolic equivalents (METs) achieved during exercise stress testing. METHODS: DASI and PROMIS PF-SF12a were electronically administered to 100 adult patients (median age 56years, 61% male) immediately before exercise stress testing. DASI-predicted METs and PROMIS T score were calculated. Correlations with exercise METs with and without age adjustment were examined. Linear regression lines were derived and adjusted r2 statistic was calculated. We compared models with the Davidson-Mackinnon J test. RESULTS: The median (interquartile range) DASI-predicted METs, PROMIS Tscore, and exercise METs were 8.97 (7.61-9.89), 47.90 (43.33-52.40), and 10.10 (10.10 12.80), respectively. In unadjusted correlation analyses, PROMIS accounted for 26% of the variance in exercise METs compared with 38% with DASI. With age adjustment, the r2values increased to 0.36 (PROMIS) and 0.46 (DASI). In both unadjusted and age-adjusted analyses, inclusion of DASI improved prediction of exercise METs beyond PROMIS T score (P<.0001). In contrast, PROMIS T score did not improve exercise MET prediction compared with DASI alone (P>.10). CONCLUSION: Among patients undergoing clinically indicated exercise stress testing, DASI outperformed PROMIS PF-SF12a as a predictor of exercise METs. PMID- 28577686 TI - Atrial fibrillation incrementally increases dementia risk across all CHADS2 and CHA2DS2VASc strata in patients receiving long-term warfarin. AB - BACKGROUND: Patients with atrial fibrillation (AF) are at higher risk for developing dementia. Warfarin is a common therapy for the prevention of thromboembolism in AF, valve replacement, and thrombosis patients. The extent to which AF itself increases dementia risk remains unknown. METHODS: A total 6030 patients with no history of dementia and chronically anticoagulated with warfarin were studied. Warfarin management was provided through a Clinical Pharmacy Anticoagulation Service. Patients were stratified by warfarin indication of AF (n=3015) and non-AF (n=3015) and matched by propensity score (+/-0.01). Patients were stratified by the congestive heart failure, hypertension, age >75 years, diabetes, stroke (CHADS2) score calculated at the time of warfarin initiation and followed for incident dementia. RESULTS: The average age of the AF cohort was 69.3+/-11.2 years, and 52.7% were male; average age of non-AF cohort was 69.3+/ 10.9 years, and 51.5% were male. Increasing CHADS2 score was associated with increased dementia incidence, P trend=.004. When stratified by warfarin indication, AF patients had an increased risk of dementia incidence. After multivariable adjustment, AF patients continued to display a significantly increased risk of dementia when compared with non-AF patients across all CHADS2 scores strata. CONCLUSIONS: In patients receiving long-term warfarin therapy, dementia risk increased with increasing CHADS2 scores. However, the presence of AF was associated with higher rates of dementia across all CHADS2 score strata. These data suggest that AF contributes to the risk of dementia and that this risk is not solely attributable to anticoagulant use. Dementia may be an end manifestation of a systemic disease state, and AF likely contributes to its progression. PMID- 28577685 TI - Lisinopril or Coreg CR in reducing cardiotoxicity in women with breast cancer receiving trastuzumab: A rationale and design of a randomized clinical trial. AB - BACKGROUND: Trastuzumab (TZB) is an established therapy for HER2-positive breast cancer. The use of TZB is commonly associated with cardiotoxicity manifesting as asymptomatic decrease in left ventricular ejection fraction (LVEF) or overt heart failure. Several studies demonstrated favorable effects of angiotensin-converting enzyme (ACE) inhibitors and beta-blockers (BBs) in the prevention of chemotherapy induced cardiotoxicity. We hypothesize that patients, randomized to receive an ACE inhibitor or a BB during trastuzumab therapy for breast cancer, will maintain a higher LVEF than patients randomized to placebo. METHODS AND RESULTS: We designed a prospective, multicenter, randomized, phase II placebo-controlled clinical trial to evaluate the effects of an ACE inhibitor (lisinopril) and a BB (carvedilol phosphate-extended release) on cardiotoxicity in patients with breast cancer who are receiving adjuvant or neoadjuvant TZB therapy. The primary objectives include (1) comparison of incidence of cardiotoxicity and (2) comparison of LVEF as a continuous variable in between the arms. Cardiotoxicity was defined as an absolute decrease in LVEF from baseline of >=10% at follow-up or an absolute decrease of >=5% in LVEF from baseline for individuals with <50% LVEF at follow-up. The target accrual is 468 participants, representing patients both with and without anthracycline exposure. The enrollment is completed. The trial is co-sponsored by University of South Florida and National Cancer Institute. The LVEF is being evaluated by echocardiography or multigated acquisition scan. CONCLUSIONS: If we can demonstrate that the use of an ACE inhibitor or a BB can reduce the degree of TZB-induced cardiotoxicity, it is hoped that patients will receive complete and uninterrupted TZB therapy for breast cancer without compromising cardiac function. PMID- 28577687 TI - True rate of mineralocorticoid receptor antagonists-related hyperkalemia in placebo-controlled trials: A meta-analysis. AB - BACKGROUND: Mineralocorticoid receptor antagonists (MRA) improve survival in heart failure with reduced ejection fraction but are often underused, mostly due to concerns of hyperkalemia. Because hyperkalemia occurs also on placebo, we aimed to determine the truly MRA-related rate of hyperkalemia. METHODS: We performed a meta-analysis including randomized, placebo-controlled trials reporting hyperkalemia on MRAs in patients after myocardial infarction or with chronic heart failure. We evaluated the truly MRA-related rate of hyperkalemia that represents hyperkalemia on MRA, corrected for hyperkalemia on placebo (Pla), according to the equation: True MRA (%)=(MRA (%) - Pla (%))/MRA (%). RESULTS: A total number of 16,065 patients from 7 trials were analyzed. Hyperkalemia was more frequently observed on MRA (9.3%) vs placebo (4.3%) (risk ratio 2.17, 95% CI 1.92-2.45, P<.0001). Truly MRA-related hyperkalemia was 54%, whereas 46% were non MRA related. In trials using eplerenone, hyperkalemia was documented in 5.0% on eplerenone and in 2.6% on placebo (P<.0001). In spironolactone trials, hyperkalemia was documented in 17.5% and in 7.5% of patients on placebo (P=.0001). Hypokalemia occurred less frequently in patients on MRA (9.3%) compared with placebo (14.8%) (risk ratio 0.58, CI 0.47-0.72, P<.0001). CONCLUSION: This meta-analysis shows that in clinical trials, 54% of hyperkalemia cases were specifically related to the MRA treatment and 46% to other reasons. Therefore, non-MRA-related rises in potassium levels might be underestimated and should be rigorously explored before cessation of the evidence-based therapy with MRAs. PMID- 28577689 TI - The Association between Depression and Medication Nonpersistence in New Users of Antidiabetic Drugs. AB - OBJECTIVES: To measure the association between depression and nonpersistence with antidiabetic drugs (ADs) among new users of oral ADs and to estimate factors associated with nonpersistence among these new users with depression. METHODS: We used administrative claims data to identify an adult cohort (>=18 years) of new oral AD users who were free of depression. We followed the patients from AD initiation until either discontinuation, ineligibility for the public drug plan, death, or the end of the study. A proportional hazard Cox regression model with depression as a time-dependent variable was used to compute the adjusted hazard ratio of nonpersistence. A proportional hazard Cox regression model was also used to identify factors associated with nonpersistence in the subcohort of patients with depression. RESULTS: We identified 114,366 new oral AD users, of whom 4,808 were diagnosed with depression during the follow-up. A greater proportion (55.4%) of patients with depression (vs. 42.5% without depression) discontinued their treatment during the follow-up. The adjusted hazard ratio of nonpersistence with ADs was 1.52 (95% confidence interval 1.41-1.63). Among patients with depression, independent factors associated with nonpersistence included younger age at oral AD initiation (<45 years) and starting treatment with drugs other than metformin (especially polytherapy with insulin). CONCLUSIONS: Patients with depression are more likely to discontinue their treatment. Health care professionals should pay attention to patients on AD therapy who also suffer from depression, especially if the patients are young or are using insulin because these patients are at an increased risk of nonpersistence. PMID- 28577690 TI - Value of Comprehensive HCV Treatment among Vulnerable, High-Risk Populations. AB - OBJECTIVES: The objective of this study was to explore the trade-offs society and payers make when expanding treatment access to patients with chronic hepatitis C virus (HCV) infection in early stages of disease as well as to vulnerable, high risk populations, such as people who inject drugs (PWID) and HIV-infected men who have sex with men (MSM-HIV). METHODS: A discrete time Markov model simulated HCV progression and treatment over 20 years. Population cohorts were defined by behaviors that influence the risk of HCV exposure: PWID, MSM-HIV, an overlap cohort of individuals who are both PWID and MSM-HIV, and all other adults. Six different treatment scenarios were modeled, with varying degrees of access to treatment at different fibrosis stages and to different risk cohorts. Benefits were measured as quality-adjusted life-years and a $150,000/quality-adjusted life year valuation was used to assess social benefits. RESULTS: Compared with limiting treatment to METAVIR fibrosis stages F3 or F4 and excluding PWID, expanding treatment to patients in all fibrosis stages and including PWID reduces cumulative new infections by 55% over a 20-year horizon and reduces the prevalence of HCV by 93%. We find that treating all HCV-infected individuals is cost saving and net social benefits are over $500 billion greater compared with limiting treatment. Including PWID in treatment access saves 12,900 to 41,200 lives. CONCLUSIONS: Increased access to treatment brings substantial value to society and over the long-term reduces costs for payers, as the benefits accrued from long-term reduction in prevalent and incident cases, mortality, and medical costs outweigh the cost of treatment. PMID- 28577691 TI - Economic Evaluation of Complete Revascularization for Patients with Multivessel Disease Undergoing Primary Percutaneous Coronary Intervention. AB - OBJECTIVES: To determine the cost-effectiveness of complete revascularization at index admission compared with infarct-related artery (IRA) treatment only, in patients with multivessel disease undergoing primary percutaneous coronary intervention (P-PCI) for ST-segment elevation myocardial infarction. METHODS: An economic evaluation of a multicenter randomized trial was conducted, comparing complete revascularization at index admission to IRA-only P-PCI in patients with multivessel disease (12-month follow-up). Overall hospital costs (costs for P-PCI procedure(s), hospital length of stay, and any subsequent re-admissions) were estimated. Outcomes were major adverse cardiac events (MACEs, a composite of all cause death, recurrent myocardial infarction, heart failure, and ischemia-driven revascularization) and quality-adjusted life-years (QALYs) derived from the three level EuroQol five-dimensional questionnaire. Multiple imputation was undertaken. The mean incremental cost and effect, with associated 95% confidence intervals, the incremental cost-effectiveness ratio, and the cost-effectiveness acceptability curve were estimated. RESULTS: On the basis of 296 patients, the mean incremental overall hospital cost for complete revascularization was estimated to be -L215.96 (-L1390.20 to L958.29), compared with IRA-only, with a per-patient mean reduction in MACEs of 0.170 (0.044 to 0.296) and a QALY gain of 0.011 (-0.019 to 0.041). According to the cost-effectiveness acceptability curve, the probability of complete revascularization being cost-effective was estimated to be 72.0% at a willingness-to-pay threshold value of L20,000 per QALY. CONCLUSIONS: Complete revascularization at index admission was estimated to be more effective (in terms of MACEs and QALYs) and cost-effective (overall costs were estimated to be lower and complete revascularization thereby dominated IRA only). There was, however, some uncertainty associated with this decision. PMID- 28577692 TI - Ulcerative Colitis Treatment Patterns and Cost of Care. AB - OBJECTIVES: To examine treatment patterns, dosing, health care resource utilization, and cost of tumor necrosis factor inhibitors (TNFi), adalimumab (ADA) and infliximab (IFX), among patients enrolled in US Humana insurance plans who have been diagnosed with ulcerative colitis (UC). METHODS: This retrospective cohort study identified the first pharmacy or medical claim for ADA or IFX (from January 1, 2007, to December 31, 2014) in patients with continuous enrollment for 6 months or more preindex and 12 months or more postindex, with one or more UC diagnosis claim 6 months pre- or postindex. TNFi discontinuation was defined as a therapy gap of 56 days or more for ADA and 112 days or more for IFX. TNFi switch was defined as nonindex TNFi initiation. Health care resource utilization and costs were characterized quarterly according to treatment patterns. RESULTS: The study population comprised 295 patients: mean age 50.9 years, 50.5% females, and 61.7% in southern United States. At the index date, 17% of patients received ADA and 83% received IFX. Treatment discontinuation was observed in 52% of ADA and 45% of IFX users through 12 months postindex (mean time 19 and 22 weeks, respectively). Among discontinuers, 46% of ADA and 68% of IFX users did not restart/switch TNFi. ADA and IFX showed mean times to switch of 18 and 30 weeks, respectively. TNFi discontinuers had the lowest mean quarterly total health care cost ($3,935) versus patients who initiated/switched TNFi ($15,004). Nevertheless, discontinuers had higher UC-related hospitalization versus patients receiving therapy. CONCLUSIONS: Approximately half of ADA and IFX users discontinued, with approximately half of discontinuers not restarting/switching therapies. Further investigation of treatment patterns and outcomes after TNFi discontinuation is required. PMID- 28577693 TI - Economic Consequences and Potentially Preventable Costs Related to Osteoporosis in the Netherlands. AB - BACKGROUND: Osteoporosis often does not involve symptoms, and so the actual number of patients with osteoporosis is higher than the number of diagnosed individuals. This underdiagnosis results in a treatment gap. OBJECTIVES: To estimate the total health care resource use and costs related to osteoporosis in the Netherlands, explicitly including fractures, and to estimate the proportion of fracture costs that are linked to the treatment gap and might therefore be potentially preventable; to also formulate, on the basis of these findings, strategies to optimize osteoporosis care and treatment and reduce its related costs. METHODS: In this retrospective study, data of the Achmea Health Database representing 4.2 million Dutch inhabitants were used to investigate the economic consequence of osteoporosis in the Netherlands in 2010. Specific cohorts were created to identify osteoporosis-related fractures and their costs. Besides, costs of pharmaceutical treatment regarding osteoporosis were included. Using data from the literature, the treatment gap was estimated. Sensitivity analysis was performed on the base-case results. RESULTS: A total of 108,013 individuals with a history of fractures were included in this study. In this population, 59,193 patients were using anti-osteoporotic medication and 86,776 patients were using preventive supplements. A total number of 3,039 osteoporosis-related fractures occurred. The estimated total costs were ?465 million. On the basis of data presented in the literature, the treatment gap in our study population was estimated to vary from 60% to 72%. CONCLUSIONS: The estimated total costs corrected for treatment gap were ?1.15 to ?1.64 billion. These results indicate room for improvement in the health care policy against osteoporosis. PMID- 28577694 TI - Manual Compression versus Vascular Closing Device for Closing Access Puncture Site in Femoral Left-Heart Catheterization and Percutaneous Coronary Interventions: A Retrospective Cross-Sectional Comparison of Costs and Effects in Inpatient Care. AB - OBJECTIVES: To compare complication rates, length of hospital stay, and resulting costs between the use of manual compression and a vascular closing device (VCD) in both diagnostic and interventional catheterization in a German university hospital setting. METHODS: A stratified analysis according to risk profiles was used to compare the risk of complications in a retrospective cross-sectional single-center study. Differences in costs and length of hospital stay were calculated using the recycled predictions method, based on regression coefficients from generalized linear models with gamma distribution. All models were adjusted for propensity score and possible confounders, such as age, sex, and comorbidities. The analysis was performed separately for diagnostic and interventional catheterization. RESULTS: The unadjusted relative risk (RR) of complications was not significantly different in diagnostic catheterization when a VCD was used (RR = 0.70; 95% confidence interval [CI] 0.22-2.16) but significantly lower in interventional catheterization (RR = 0.44; 95% CI 0.21 0.93). Costs were on average ?275 lower in the diagnostic group (95% CI -?478.0 to -?64.9; P = 0.006) and around ?373 lower in the interventional group (95% CI ?630.0 to -?104.2; P = 0.014) when a VCD was used. The adjusted estimated average length of stay did not differ significantly between the use of a VCD and manual compression in both types of catheterization. CONCLUSIONS: In interventional catheterization, VCDs significantly reduced unadjusted complication rates, as well as costs. A significant reduction in costs also supports their usage in diagnostic catheterization on a larger scale. PMID- 28577695 TI - Mind the Gap: Hospitalizations from Multiple Sources in a Longitudinal Study. AB - BACKGROUND: Medicare claims and prospective studies with self-reported utilization are important sources of hospitalization data for epidemiologic and outcomes research. OBJECTIVES: To assess the concordance of Medicare claims merged with interview-based surveillance data to determine factors associated with source completeness. METHODS: The Atherosclerosis Risk in Communities (ARIC) study recruited 15,792 cohort participants aged 45 to 64 years in the period 1987 to 1989 from four communities. Hospitalization records obtained through cohort report and hospital record abstraction were matched to Medicare inpatient records (MedPAR) from 2006 to 2011. Factors associated with concordance were assessed graphically and using multinomial logit regression. RESULTS: Among fee-for service enrollees, MedPAR and ARIC hospitalizations matched approximately 67% of the time. For Medicare Advantage enrollees, completeness increased after initiation of hospital financial incentives in 2008 to submit shadow bills for Medicare Advantage enrollees. Concordance varied by geographic site, age, veteran status, proximity to death, study attrition, and whether hospitalizations were within ARIC catchment areas. CONCLUSIONS: ARIC and MedPAR records had good concordance among fee-for-service enrollees, but many hospitalizations were available from only one source. MedPAR hospital records may be missing for veterans or observation stays. Maintaining study participation increases stay completeness, but new sources such as electronic health records may be more efficient than surveillance for mobile elderly populations. PMID- 28577697 TI - Economic Impacts of the Generic Drug User Fee Act Fee Structure. AB - BACKGROUND: A Food and Drug Administration (FDA) Generic Drug User system, Generic Drug User Fee Amendment of 2012 (GDUFA), started October 1, 2012, and has been in place for over 3 years. There is controversy about the GDUFA fee structure but no analysis of GDUFA data that we could find. OBJECTIVE: To look at the economic impact of the GDUFA fee structure. METHODS: We compared the structure of GDUFA with that of other FDA Human Drug User fees. We then, using FDA-published information, analyzed where GDUFA facility and Drug Master File fees are coming from. We used the Orange Book to identify the sponsors of all approved Abbreviated New Drug Applications (ANDAs) and the S&P Capital IQ database to find the ultimate parent companies of sponsors of approved ANDAs. RESULTS: The key differences between the previous structure for Human Drug User fees and the GDUFA are as follows: GDUFA has no approved product fee and no first time or small business fee exemptions and GDUFA charges facility fees from the time of filing and charges a foreign facility levy. Most GDUFA fees are paid by or on behalf of foreign entities. The top 10 companies hold nearly 50% of all approved ANDAs but pay about 14% of GDUFA facility fees. CONCLUSIONS: We conclude that the regressive nature of the GDUFA fee structure penalizes small, new, and foreign firms while benefiting the large established firms. A progressive fee structure in line with other human drug user fees is needed to ensure a healthy generic drug industry. PMID- 28577696 TI - The Type and Impact of Evidence Review Group Exploratory Analyses in the NICE Single Technology Appraisal Process. AB - BACKGROUND: As part of the UK National Institute for Health and Care Excellence (NICE) single technology appraisal process, independent evidence review groups (ERGs) critically appraise a company's submission relating to a specific technology and indication. OBJECTIVES: To explore the type of additional exploratory analyses conducted by ERGs and their impact on the recommendations made by NICE. METHODS: The 100 most recently completed single technology appraisals with published guidance were selected for inclusion. A content analysis of relevant documents was undertaken to identify and extract relevant data, and narrative synthesis was used to rationalize and present these data. RESULTS: The types of exploratory analysis conducted in relation to companies' models were fixing errors, addressing violations, addressing matters of judgment, and the provision of a new, ERG-preferred base case. Ninety-three of the 100 ERG reports contained at least one of these analyses. The most frequently reported type of analysis in these 93 ERG reports related to the category "Matters of judgment," which was reported in 83 reports (89%). At least one of the exploratory analyses conducted and reported by an ERG is mentioned in 97% of NICE appraisal consultation documents and 94% of NICE final appraisal determinations, and had a clear influence on recommendations in 72% of appraisal consultation documents and 47% of final appraisal determinations. CONCLUSIONS: These results suggest that the additional analyses undertaken by ERGs in the appraisal of company submissions are highly influential in the policy-making and decision making process. PMID- 28577698 TI - Eliciting Preferences for Clinical Follow-Up in Patients with Head and Neck Cancer Using Best-Worst Scaling. AB - OBJECTIVES: There are no commonly accepted standards for monitoring patients treated for head and neck cancer. The aim of this study was to assess patients' preferences for different aspects of follow-up. METHODS: A best-worst survey was conducted in a sample of head and neck cancer patients in clinical follow-up at the National Cancer Institute (Milan, Italy). Conditional logit regression with choice as the dependent variable was run to analyse the data. A covariate adjusted analysis was performed in order to identify socio-demographic and clinical factors related to the selection of best-worst items. The participants were asked to report any difficulties encountered during the survey. RESULTS: A total of 143 patients, predominantly male (74%) and with a mean age of 58 years were enrolled in the survey. The strongest positive preference was expressed for a hospital-based program of physical examinations with frequency decreasing over time. Conversely, the lowest valued item was not performing any positron emission tomography (PET) scan during follow-up. Patients with high educational levels were more likely to value attending a primary care-based program and undergoing intensive radiological investigations. Other patient-specific variables significantly associated with the choice of items were employment and living status, time already spent in follow-up and number of treatments received. CONCLUSIONS: Overall, patients were more likely to choose an intensive follow-up scheme broadly consistent with the program currently administered by the hospital. There is little evidence of preference heterogeneity that might justify customized programs based on demographics. The best-worst scaling task appeared feasible for most participants. PMID- 28577699 TI - Budget Impact Analysis of Against Colorectal Cancer In Our Neighborhoods (ACCION): A Successful Community-Based Colorectal Cancer Screening Program for a Medically Underserved Minority Population. AB - OBJECTIVES: Given the uncertain cost of delivering community-based cancer screening programs, we developed a Markov simulation model to project the budget impact of implementing a comprehensive colorectal cancer (CRC) prevention program compared with the status quo. METHODS: The study modeled the impacts on the costs of clinical services, materials, and staff expenditures for recruitment, education, fecal immunochemical testing (FIT), colonoscopy, follow-up, navigation, and initial treatment. We used data from the Against Colorectal Cancer In Our Neighborhoods comprehensive CRC prevention program implemented in El Paso, Texas, since 2012. We projected the 3-year financial consequences of the presence and absence of the CRC prevention program for a hypothetical population cohort of 10,000 Hispanic medically underserved individuals. RESULTS: The intervention cohort experienced a 23.4% higher test completion rate for CRC prevention, 8 additional CRC diagnoses, and 84 adenomas. The incremental 3-year cost was $1.74 million compared with the status quo. The program cost per person was $261 compared with $86 for the status quo. The costs were sensitive to the proportion of high-risk participants and the frequency of colonoscopy screening and diagnostic procedures. CONCLUSIONS: The budget impact mainly derived from colonoscopy-related costs incurred for the high-risk group. The effectiveness of FIT to detect CRC was critically dependent on follow-up after positive FIT. Community cancer prevention programs need reliable estimates of the cost of CRC screening promotion and the added budget impact of screening with colonoscopy. PMID- 28577700 TI - Value for Money in H1N1 Influenza: A Systematic Review of the Cost-Effectiveness of Pandemic Interventions. AB - BACKGROUND: The 2009 A/H1N1 influenza pandemic generated additional data and triggered new studies that opened debate over the optimal strategy for handling a pandemic. The lessons-learned documents from the World Health Organization show the need for a cost estimation of the pandemic response during the risk assessment phase. Several years after the crisis, what conclusions can we draw from this field of research? OBJECTIVE: The main objective of this article was to provide an analysis of the studies that present cost-effectiveness or cost benefit analyses for A/H1N1 pandemic interventions since 2009 and to identify which measures seem most cost-effective. METHODS: We reviewed 18 academic articles that provide cost-effectiveness or cost-benefit analyses for A/H1N1 pandemic interventions since 2009. Our review converts the studies' results into a cost-utility measure (cost per disability-adjusted life-year or quality adjusted life-year) and presents the contexts of severity and fatality. RESULTS: The existing studies suggest that hospital quarantine, vaccination, and usage of the antiviral stockpile are highly cost-effective, even for mild pandemics. However, school closures, antiviral treatments, and social distancing may not qualify as efficient measures, for a virus like 2009's H1N1 and a willingness-to pay threshold of $45,000 per disability-adjusted life-year. Such interventions may become cost-effective for severe crises. CONCLUSIONS: This study helps to shed light on the cost-utility of various interventions, and may support decision making, among other criteria, for future pandemics. Nonetheless, one should consider these results carefully, considering these may not apply to a specific crisis or country, and a dedicated cost-effectiveness assessment should be conducted at the time. PMID- 28577701 TI - Challenges of Developing an Observable Parent-Reported Measure: A Qualitative Study of Functional Impact of ADHD in Children. AB - BACKGROUND: Informant-reported outcome measures, usually completed by parents, are often administered in pediatric clinical trials with the intention of collecting data to support claims in a medical product label. Recently, there has been an emphasis on limiting these measures to observable content, as recommended in the US Food and Drug Administration guidance on patient-reported outcomes. This qualitative study explores the concept of observability using the example of childhood attention deficit/hyperactivity disorder (ADHD). METHODS: Concept elicitation interviews were conducted with children (aged 6-12 years) diagnosed with ADHD and parents of children with ADHD to identify concepts for a potential parent-reported measure of functional impact of childhood ADHD. The observability of each concept was considered. RESULTS: Of the 30 parents (90% females; mean age = 42.0 years), 24 had a child who was also interviewed (87.5% males; mean age = 9.6 years). Areas of functional impact reported by parents and/or children included the following: 1) functioning within the home/family, 2) academic performance, 3) school behavior, 4) social functioning, 5) emotional functioning, and 6) decreased self-efficacy. Parents cited many examples of direct observation at home, but opportunities for observation of some important areas of impact (e.g., school behavior and peer relationships) were limited. CONCLUSIONS: Findings illustrate the substantial functional impairment associated with childhood ADHD while highlighting the challenges of developing informant-reported outcome measures limited to observable content. Because ADHD has an impact on children's functioning in a wide range of contexts, a parent-report measure that includes only observable content may fail to capture important aspects of functional impairment. Approaches for addressing this observability challenge are discussed. PMID- 28577702 TI - The Role of Patient-Reported Outcome Measures in Value-Based Payment Reform. AB - The U.S. health care system is currently experiencing profound change. Pressure to improve the quality of patient care and control costs have caused a rapid shift from traditional volume-driven fee-for-service reimbursement to value-based payment models. Under the 2015 Medicare Access and Children's Health Insurance Program Reauthorization Act, providers will be evaluated on the basis of quality and cost efficiency and ultimately receive adjusted reimbursement as per their performance. Although current performance metrics do not incorporate patient reported outcome measures (PROMs), many wonder whether and how PROMs will eventually fit into value-based payment reform. On November 17, 2016, the second annual Patient-Reported Outcomes in Healthcare Conference brought together international stakeholders across all health care disciplines to discuss the potential role of PROs in value-based health care reform. The purpose of this article was to summarize the findings from this conference in the context of recent literature and guidelines to inform implementation of PROs in value-based payment models. Recommendations for evaluating key perspectives and measurement goals are made to facilitate appropriate use of PROMs to best benefit and amplify the voice of our patients. PMID- 28577704 TI - Imaging of Cartilage in the Athlete. AB - MRI remains the optimal imaging modality to evaluate cartilage injuries in the athlete. As these injuries have no intrinsic healing capacity, early and accurate noninvasive diagnosis remains integral to determining the most appropriate treatment option in this class of patients. Although surgical success depends primarily on clinical outcomes, MRI evaluation can provide pertinent information regarding the status of the surgical repair and the progression of cartilage disease. PMID- 28577703 TI - Basic Science of Articular Cartilage. AB - The most challenging aspects in treating articular cartilage injury include identifying the cellular and molecular mechanism(s) that lead to matrix changes and the differentiation and dedifferentiation behavior of chondrocytes, and understanding how they affect the structural integrity of the articular cartilage and tissue remodeling. Several treatment strategies have been proposed. A better understanding of the signaling pathways and growth and transcription factors for genes responsible for chondrogenesis is an important component in the development of new therapies to prevent cartilage degeneration or promote repair to replicate the physiologic and functional properties of the original cartilage. PMID- 28577705 TI - Nonoperative Options for Management of Articular Cartilage Disease. AB - Nonoperative options for articular cartilage injury are pervasive but have not shown to be curative. Recommendations for low-impact exercise and weight loss provide benefit and are a foundation for the treatment of osteoarthritis. Judicious use of NSAIDs and acetaminophen can be appropriate for pain management. Topical NSAIDs may be a treatment option with fewer side effects than its oral counterpart. Additionally, viscosupplementation injections are useful for mild to moderate knee osteoarthritis, whereas short-term pain relief is provided by intra articular corticosteroid injections. Future studies to individualize treatment options based on patient phenotype and genotype may hold promise. PMID- 28577707 TI - Management of Osteochondritis Dissecans Lesions of the Knee, Elbow and Ankle. AB - Although osteochondritis dissecans (OCD) has been a recognized condition for more than 100 years, our understanding of the etiology, natural history, and treatment remains poorly characterized. OCD most commonly affects the knee, followed by the elbow and ankle. Adolescents and young adults are most commonly affected. Patients present with vague, often intermittent symptoms and generally have no history of acute injury. Although diagnosis can be made with plain radiographs, treatment decisions are generally based on MRI. Skeletal maturity and stability of the OCD lesion determine treatment. Treatments range from immobilization and activity restriction to operative therapies. Clinical indications are discussed. PMID- 28577706 TI - Biologic Options for Articular Cartilage Wear (Platelet-Rich Plasma, Stem Cells, Bone Marrow Aspirate Concentrate). AB - Biological treatments for articular cartilage repair have gained in popularity in the past decade. Advantages of these therapies include minimal invasiveness, improved healing time, and faster recovery. Biological therapies for cartilage repair include platelet-rich plasma, bone marrow aspirate concentrate, and cell based therapies. These methods have the added benefit of containing growth factors and/or stem cells that aid in recovery and regeneration. The purpose of this article is to review the current cartilage treatment options and the existing literature on outcomes, complications, and safety profile of these products for use in the knee and hip joints. PMID- 28577709 TI - Microfracture and Microfracture Plus. AB - Articular cartilage damage remains a significant cause for early osteoarthritis in adolescents and young adults. After chondroplasty alone, the mainstay procedure for cartilage injuries is microfracture. Although in small lesions this may be successful long-term, positive results of treating larger lesions this way are less certain. This inconsistency in outcomes has led to augmentation of these defects with scaffolding for autograft regeneration or for allograft cartilage to fill the defect with a hyaline cartilage. This discussion includes current techniques for the addition of scaffolding to the microfracture defect for larger lesions, the rationale, and preliminary results. PMID- 28577708 TI - Osteochondral Autologous Transplantation. AB - Osteochondral autologous transplantation (OAT) is a treatment strategy for small and medium sized focal articular cartilage defects in the knee. This article reviews the indications, surgical techniques, outcomes, and limitations of OAT for the management of symptomatic chondral and osteochondral lesions in the knee joint. PMID- 28577710 TI - Allografts: Osteochondral, Shell, and Paste. AB - There is an increasing need for articular cartilage restoration procedures. Hyaline cartilage lacks intrinsic healing capacity. Persistent osteochondral defects can lead to early and rapid degenerative changes. Microfracture and autologous chondrocyte implantation provide reasonable outcomes for smaller defects without bone loss. However, these techniques have limited effectiveness for lesions greater than 4 cm2 or with significant bony involvement. Ostochondral allografts provide an option for these lesions. This article reviews osteochondral allografts for articular defects. Emerging options provide different approaches to difficult cartilage defects. We discuss current screening, procurement, and storage methods, surgical techniques, outcomes, and bacterial/viral transmission. PMID- 28577711 TI - Autologous Chondrocytes and Next-Generation Matrix-Based Autologous Chondrocyte Implantation. AB - Focal chondral defects of the knee are common and can significantly impair quality of life. The autologous chondrocyte implantation technique has evolved over the past 20 years; the newest third-generation technique is matrix-induced autologous chondrocyte implantation. Physical examination is important to characterize location and source of pain and identify associated injuries. Imaging studies allow characterization of the lesions, identification of associated lesions, and alignment. Conservative measures should be exhausted before proceeding with surgical treatment. Steps of surgical treatment are diagnostic arthroscopy and biopsy, chondrocyte culture, and chondrocyte implantation. The techniques and their outcomes are discussed in this article. PMID- 28577712 TI - Management and Surgical Options for Articular Defects in the Shoulder. AB - Isolated, full-thickness chondral lesions of the glenohumeral joint are a significant pathology encountered by laborers, athletes, and the elderly. A thorough history should be obtained in any patient presenting to the office with shoulder pain and concern for the etiology being an articular cartilage defect. The first-line imaging should include plain radiographs of the glenohumeral joint; MRI and CT can be ordered as necessary to provide greater detail. Typically, the initial treatment of glenohumeral chondral disease is nonsurgical; however, many surgical treatment options have been refined to provide pain relief, create reparative tissue, or restore the articular surface. PMID- 28577713 TI - A Critical Review: Management and Surgical Options for Articular Defects in the Hip. AB - Patients with articular cartilage lesions of the hip may present with pain and symptoms that may be vague in nature and onset. Therefore, a thorough history and physical examination should be performed for every patient presenting with hip pain and/or disability. The management may be operative or nonoperative. Nonoperative management includes a trial of rest and/or activity modification, along with anti-inflammatory medications, physical therapy, and biologic injections. Operative treatment in the form of arthroscopic techniques continues to decrease morbidity and offer innovative solutions and new applications for microfracture, ACT, and AMIC. PMID- 28577714 TI - The Early Osteoarthritic Knee: Implications for Cartilage Repair. AB - Patients with early osteoarthritis (OA) have been reported to have inferior outcomes with an increased prevalence of early failure after cartilage procedures. The underlying reasons for this failure are likely multifactorial, including a chronic synovial and chondrogenic process, which is confounded by persistent muscle weakness and altered pain processing for those with increased preoperative symptom duration. Pain, radiographic changes, patient-reported outcomes, and macroscopic changes on arthroscopic evaluation or MRI can assist clinicians in identifying the early OA knee to both aid in clinical decision making and create realistic postoperative expectations for patients. PMID- 28577715 TI - Articular Cartilage. PMID- 28577716 TI - Articular Cartilage: The Search for the Holy Grail of Treatment and Restoration. PMID- 28577717 TI - Contemporary reappraisal of the efficacy of adjuvant chemotherapy in resected retroperitoneal sarcoma: Evidence from a nationwide clinical oncology database and review of the literature. AB - BACKGROUND: While margin-negative resection remains the cornerstone of therapy for retroperitoneal sarcoma (RPS), the impact of adjuvant chemotherapy (AC) on overall survival (OS) remains poorly understood. METHODS: The National Cancer Data Base was queried for patients undergoing curative-intent resection of primary non-metastatic RPS (2004-2013). Multivariable modeling identified factors associated with AC receipt. Cox regression identified covariates associated with OS, and AC and surgery alone (SA) cohorts were matched 1:1 by propensity scores based on these covariates. In the propensity-score matched cohort, OS was compared by Kaplan-Meier estimates. Results from this analysis were presented in the context of a review of the existing literature on the impact of AC in resected RPS. RESULTS: Of 3892 resected RPS patients, 90.0% and 10.0% received SA and AC, respectively. Predictors of AC receipt included younger age, non Caucasian race, hospital location, histologic grade, adjacent organ invasion, and histologic subtype. The propensity score-matched cohort comprised 767 patients (SA n = 377; AC n = 390); at a median follow-up of 59.2 (IQR 35.0-85.3) months, median OS of the propensity-matched cohort was 53.6 (IQR 22.4-119.5) months. Utilization of AC was associated with significantly worse long-term survival (median OS: 47.8 vs. 68.9 months, p = 0.017; HR 1.30, 95% CI 1.05-1.61). AC was not associated with improved OS in margin-positive (R1/R2) resection, high-grade (G2/G3) and larger (>10 cm) tumors, or in any histologic subtype. Albeit not statistically significant, there was a trend toward improved OS with AC in spindle cell (HR 0.37, 95% CI 0.10-1.38), giant cell (HR 0.82, 95% CI 0.32-2.13), and synovial (HR 0.26, 95% CI 0.05-1.33) sarcoma. CONCLUSIONS: Data from a large nationwide oncology database and review of the existing literature do not support adjuvant chemotherapy regimens following curative-intent resection of RPS, even in subgroups at high risk of failure (e.g., R1/R2 resection, high-grade or large tumors). The possible benefit of conventional adjuvant regimens in spindle cell, giant cell, and synovial sarcoma should be explored in prospective studies. PMID- 28577718 TI - Intrahepatic cholangiocarcinoma: Molecular markers for diagnosis and prognosis. AB - Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver tumor with increasing incidence worldwide. The outcome of patients with iCCA is dismal owing to tumor's aggressiveness, late diagnosis and lack of effective treatment options. Detection of the tumor at early stages may make surgical resection, as only potential curative treatment, more feasible. Unfortunately, despite recent developments in imaging modalities and laboratory tests, the diagnosis of iCCA remains challenging and patients often present in advanced stages when surgery cannot be offered. Moreover, accurate assessment of disease burden is critical to optimize management strategy, including the use of adjuvant therapies and clinical trials. Identifying iCCA specific diagnostic and prognostic biomarkers has been a focus of interest among many investigators with a progressive increase in data on iCCA related to advances in "omics" technologies. We herein summarize iCCA biomarkers and define the molecular mechanisms underlying iCCA carcinogenesis, as well as highlight potential diagnostic and prognostic application of molecular biomarkers. PMID- 28577719 TI - Personalized therapy in hepatocellular carcinoma: Molecular markers of prognosis and therapeutic response. AB - Hepatocellular carcinoma (HCC) represents a growing worldwide health crisis with rising incidence, limited effective therapies and persistently poor prognosis. Five-year survival remains less than 20% despite decades of research. One byproduct of research efforts is the identification of numerous biomarkers of disease. From prognosis to therapeutic response, biomarker identification parallels a deeper molecular understanding of the disease that to date has generated limited gain in clinical outcomes. As one example, the classical prognostic biomarkers of tumor Ki-67 protein expression and TP53 gene mutation have been repeatedly demonstrated to correlate with poor prognosis. There have been several studies throughout the past two decades identifying other gene-based biomarkers of prognosis. Critically, translation into the clinic has been slow and focus has shifted to a search for markers of therapeutic response in hopes of generating novel approaches to the disease. With this focus, many of the correlates are based on retrospective review of sorafenib effectiveness. Sorafenib, an oral targeted multi-kinase inhibitor, is currently the standard of care systemic agent for non-resectable disease. The Wnt-pathway, particularly when activated, is the most commonly cited molecular marker of sorafenib responsiveness. Additional work has identified a profile of genes involved in drug absorption, processing, and elimination that also appears to increase responsiveness. Overall, despite promising clinical data the use of biomarkers in the clinic for HCC is limited. In this piece, progress and opportunities for future work "beyond the genome" are highlighted, including metabolomic, epigenetic, and non-coding RNA studies. Additionally, barriers to the implementation of personalized therapeutic selection in HCC are reviewed. PMID- 28577720 TI - Multidisciplinary management of intrahepatic cholangiocarcinoma: Current approaches. AB - Intrahepatic cholangiocarcinoma (ICC) is a common primary hepatic tumor. However, its outcomes are usually worse than those of hepatocellular carcinoma owing to its non-specific presentation and detection at an advanced stage. The most widely used serum marker, carbohydrate antigen 19-9, is non-specific. Furthermore, imaging studies rarely identify any pathognomonic features. Surgery is the only treatment option that offers a chance of long-term survival. However, the resectability rate is low owing to the high frequencies of intrahepatic metastases, peritoneal carcinomatosis, or extrahepatic metastases. Surgical treatment should be tailored according to the macroscopic classification of ICC (e.g. mass-forming, periductal infiltrating, and intraductal growth types) because it reflects the tumor's dissemination pattern. Although lymph node metastasis is a negative prognostic factor, the importance and extent of lymph node dissection is still controversial. To improve patient survival, liver transplantation is considered in some patients with unresectable ICC, especially in those with an insufficient remnant liver volume. Minimally invasive procedures, including laparoscopic and robotic liver resection, have been tested and achieved comparable outcomes to conventional surgery in preliminary studies. No randomized trials have confirmed the efficacy of adjuvant chemotherapy in ICC, and several trials have evaluated molecular-targeted agents as monotherapy or in combination with cytotoxic chemotherapy. Multidisciplinary approaches are necessary to improve the outcomes of ICC. PMID- 28577721 TI - SGM-101: An innovative near-infrared dye-antibody conjugate that targets CEA for fluorescence-guided surgery. AB - PURPOSE: Fluorescence-guided surgery (FGS) provides surgeons with new opportunities to improve real-time cancer nodule detection and tumor margin visualization. Currently, the most important challenge in this field is the development of fluorescent dyes that specifically target tumors. We developed, characterized and evaluated SGM-101, an innovative antibody-dye conjugate in which the fluorochrome BM104, which has an absorbance band centered at 700 nm, is coupled to a chimeric monoclonal antibody (mAb) against carcinoembryonic antigen (CEA). METHODS: The dye to mAb ratio, binding to CEA and photobleaching of SGM 101 were determined. FGS was performed and results analyzed using different mouse models of human digestive tumors. RESULTS: SGM-101 allowed the detection of tumor nodules in three different colon cancer models: LS174T human colorectal adenocarcinoma cell-induced peritoneal carcinomatosis (PC) and liver metastases, and orthotopic grafts of HT29 human colorectal adenocarcinoma cells. In the PC model, submillimeter-sized nodules were detected during SGM-101-based FGS and SGM 101 predictive positive values ranged from 99.04% to 90.24% for tumor nodules >10 mg and nodules <1 mg, respectively. Similarly, in the orthotopic model of pancreatic cancer using BxPC3 (pancreas adenocarcinoma) cells, SGM-101 could clearly delineate tumors in vivo with a tumor-to-background ratio of 3.5, and penetrated in tumor nodules, as demonstrated by histological analysis. Free BM105 dye (BM104 with an activated ester for conjugation to the antibody) and an irrelevant conjugate did not induce any NIR fluorescence. CONCLUSION: These preclinical data indicate that SGM-101 is an attractive candidate for FGS of CEA expressing tumors and is currently assessed in clinical trials. PMID- 28577723 TI - Postoperative infections after limb-sparing surgery for primary bone tumors of the pelvis: Incidence, characterization and functional impact. AB - INTRODUCTION: Surgical site infections (SSI) represent the most common postoperative complication after limb sparing surgery for primary malignant bone tumors, with incidence ranging from 10 to 47%. There is no consensus concerning about the optimal surgical strategy, or the adequate antibiotic prophylaxis in pelvic resections. A greater knowledge of these infections and their surgical trajectories seem essential to obtain. MATERIALS AND METHODS: We retrospectively studied 45 cases of pelvic resection, including at least the periacetabular zone 2 of Enneking, performed between 1989 and 2013 in the same center. Infection rate, risk factors and surgical trajectories were analyzed. The impact of a postoperative infection on the quality of life and functional recovery was evaluated by the Musculoskeletal Tumor Society scoring system (MSTS). RESULTS: Sixteen patients presented a SSI in the first post-operative year (35.6%). We found as risk factors the pre-operative ASA score, the age at surgery and the number of packed red cells transfused during surgery. In case of failure of an initial washout, an iterative procedure is responsible for a high failure rate of 88.9%. Irrespective of the type of reconstruction, our functional results show that this surgery is often a source of handicap with a MSTS score of 13.77 in infected patients versus 17.70 in non-infected patients, at two-year follow-up. DISCUSSION: In case of failure of an initial wash, prosthetic material must be removed and a hip transposition procedure should be preferred to a second-look surgery. Concerning prophylactic antibiotherapy, a dual therapy for at least 48 h after surgery should probably be preferred. PMID- 28577722 TI - Minimal impact of postmastectomy radiation therapy on locoregional recurrence for breast cancer patients with 1 to 3 positive lymph nodes in the modern treatment era. AB - INTRODUCTION: Given modern treatment strategies, controversy remains regarding whether postmastectomy radiation therapy (PMRT) is necessary for breast cancer patients with 1-3 positive axillary lymph nodes (ALN). Our aim was to assess the significance of PMRT in the modern treatment era for these patients. MATERIAL AND METHODS: We have conducted the retrospective multicenter study and identified 658 patients with 1-3 positive ALN who were treated with mastectomy and ALN dissection between 1999 and 2012. Propensity score weighting was used to minimize the influence of confounding factors between the PMRT and no-PMRT groups. The variables including tumor size, lymph nodes status, skin and/or muscle invasion, histological grade, lymphovascular invasion and ER positivity which were statistically unbalanced between the groups were used to define the propensity scores. RESULTS: The median follow-up time was 7.3 years. In the modern era (2006 2012), no significant difference in locoregional recurrence (LRR)-free survival was noted between the PMRT and no-PMRT groups (P = 0.3625). The 8-year LRR-free survival rates of the PMRT and no-PMRT groups were 98.2% and 95.3%, respectively. After matching patients by propensity scores, the PMRT group, compared to the no PMRT group, exhibited significantly better locoregional control (P = 0.0366) in the entire cohort. The 10-year LRR-free survival rates were 97.8% and 88.4% in the PMRT and no-PMRT groups, respectively. In contrast, no significant difference in LRR-free survival was noted between the PMRT and no-PMRT groups in the modern era (P = 0.5298). The 8-year LRR-free survival rates of patients treated in the modern era were approximately the same between the groups (98.0% and 95.7% in the PMRT and no-PMRT groups, respectively). Particularly, LRR-free survival of HER2 positive breast cancer significantly improved in the modern treatment era, compared with that of the old treatment era (P = 0.0349). CONCLUSION: PMRT had minimal impact on LRR for breast cancer patients with 1-3 positive ALN in the modern treatment era. PMID- 28577724 TI - Identification of the resection severity index as a significant independent prognostic factor for early mortality and observed survival >5 and >10 years after liver resection for hepatocellular carcinoma. AB - BACKGROUND AND OBJECTIVES: This study evaluates predictive factors for observed long-term survival of more than 5 and 10 years for patients after liver resection for hepatocellular carcinoma and compares their life expectancy to the normal national population matched for sex, year of birth and age at resection. METHODS: 230 patients after primary liver resection for HCC (01.01.1995-31.12.2004) were analyzed. Multivariable logistic regression models were determined based on Cox regression results and their prognostic capability evaluated with areas under the receiver operating characteristic curve (AUROCs). RESULTS: Life years after surgery in deceased patients compared to the normal national population matched for sex, year of birth and age at resection was reduced by median 21.7 years. Independent predictive factors for 10-year survival were age at resection (p < 0.001; OR = 0.898; 95%-CI: 0.846-0.954), UICC 7 tumor staging (p = 0.003; OR = 0.344; 95%-CI: 0.126-0.941) and ASAT (GOT) in U/l divided by Quick in percent multiplied by the extent of liver resection graded in points labelled as the resection severity index (p < 0.001; OR = 0.136; 95%-CI: 0.022-0.843) enabling prediction of 10-year survival with an AUROC of 0.884. The same factors plus revision surgery (yes/no) predict 5-year survival (AUROC 0.736). CONCLUSIONS: Liver resection enables predictable long-term survival >5 and > 10 years. The proposed resection severity index quantifies the prognostic relevance of liver cellular damage, synthesis and loss of parenchyma for long-term survival. PMID- 28577725 TI - Postoperative liver volume was accurately predicted by a medical image three dimensional visualization system in hepatectomy for liver cancer. AB - BACKGROUND: Liver cancer is the second most common cause of cancer death worldwide. The hepatectomy is the most effective and the only potentially curative treatment for patients with resectable neoplasm. Precisely preoperative assessment of remnant liver volume is essential in preventing postoperative liver failure. The aim of our study is to report our experience of using a medical image three dimensional (3D) visualization system (MI-3DVS), which was developed by our team, in assisting hepatectomy for patients with liver cancer. METHODS: Between January 2010 and June 2016, 69 patients with liver cancer underwent hepatic resection based on the MI-3DVS were enrolled in this study. All patients underwent CT scan 5 days before the surgery and within 5 days after resection. CT images were reconstructed with the MI-3DVS to assist to perform hepatectomy. Simple linear regression, intra-class correlation coefficient (ICC) and Bland Altman analysis were used to evaluate the relationship and agreement between actual excisional liver volume (AELV) and predicted excisional liver volume (PELV). RESULTS: Among 69 patients in this study, 62(89.85%) of them were diagnosed with hepatocellular carcinoma by histopathologic examination, and 41(59.42%) underwent major hepatectomy. The average AELV was 330.13 cm3 and the average PELV was 287.67 cm3. The simple regression equation is AELV = 1.016 * PELV+30.39(r = 0.966; p < 0.0003). PELV (ICC = 0.964) achieved an excellent agreement with AELV with statistical significance (p < 0.001). 65 of 69 dots are in the range of 95% confidence interval in Bland-Altman analyses. CONCLUSIONS: The MI-3DVS has advantages of simple usage and convenient hold. It is accurate in assessment of postoperative liver volume and improve safety in liver resection. PMID- 28577726 TI - Updates in hepatic oncology imaging. AB - The utilization of advanced imaging modalities play an important role in the detection and differentiation of benign and malignant hepatic lesions. Imaging characteristics of hepatic tumors can sometimes be atypical, often leading to diagnostic challenges. Recent technical improvements in contrast enhanced ultrasound (CEUS), computed tomography (CT), and magnetic resonance imaging (MRI) have helped to better characterize hepatic lesions. For example, contrast agents used in US can now better delineate liver lesions, while the ability to reliably produce multiplanar and 3-D reconstructions through the use of MDCT provides an additional advantage in the context of therapeutic decision making for patients with hepatic lesions. In addition, modern MR that includes the use of biliary excreted contrast material, various post-processing techniques like multiplanar reformation (MPR), as well as volume rendering (VR) allow detailed evaluation of the biliary tract, hepatic vasculature, and better characterization of hepatic tumors. As the imaging technologies available continue to evolve and advance, understanding how to effectively utilize these modalities is key to clinical practice. We herein provide a review of the various hepatic oncologic imaging modalities with a focus on how advancements and novel techniques within the different fields may be utilized in the diagnosis, treatment and management of different benign and malignant hepatic lesions. PMID- 28577727 TI - Spleen-preserving lymphadenectomy versus splenectomy in laparoscopic total gastrectomy for advanced gastric cancer. AB - BACKGROUND: To investigate the optimal approach for laparoscopic splenic hilum lymph node dissection in proximal advanced gastric cancer, we compared the operative outcomes between laparoscopic spleen-preserving total gastrectomy (sp LTG) and laparoscopic total gastrectomy with splenectomy (sr-LTG). METHODS: A retrospective case-cohort study was conducted between February 2006 and December 2012. The operative outcomes, the number of retrieved splenic hilum lymph node, complication, and patients' survivals were analyzed. RESULTS: 112 patients who underwent laparoscopic total gastrectomy with or without splenectomy for advanced gastric cancer were enrolled (68 sp-LTGs and 44 sr-LTGs). The mean operation time (227 min vs. 224 min, p = 0.762), estimated blood loss (157 ml vs. 164 ml, p = 0.817), and complication rate (17.6% vs. 13.6%, p = 0.572) were not different between two groups. Regarding splenic lymph node dissection, there were significantly differences in the mean number of retrieved lymph nodes between sp LTG and sr-LTG (LN no.10; 1.78 vs. 3.21, p = 0.033, LN no.11d; 1.41 vs. 2.76, p = 0.004). The 5-year survivals were 77.3% in sp-LTG and 65.9% in sr-LTG (p = 0.240). The hazard ratio of splenectomy was 1.139 (95% confidence interval 0.514 2.526, p = 0.748). CONCLUSION: In laparoscopic total gastrectomy for proximal advanced gastric cancer, spleen-preserving hilar dissection showed comparable short-term and long-term outcomes. PMID- 28577728 TI - Socioeconomic and gender disparities in anal cancer diagnosis and treatment. AB - BACKGROUND AND OBJECTIVES: We investigated whether receipt of radiation in patients with anal carcinoma is related to income level and other demographic factors. METHODS: The SEER database (1988-2011) was queried and linked to the Area Health Resources File (AHRF). We used logistic regression and Kaplan-Meier analyses to correlate receipt of radiation and overall and cancer-specific survival with tumor stage, age, gender, and income. RESULTS: Of 28,028 patients with anal cancer, 14,783 (53%) received radiation. Patients in the lowest quartile for median household income were significantly more likely to present at higher stages, were 1.87 times more likely to receive radiation (95% CI 1.74 2.00, p < 0.001), and 1.27 times more likely to die of anal cancer (95% CI 1.18 1.33, p < 0.001) than those in the highest income quartile. Within most stages, however, the wealthiest patients were more likely to receive radiation therapy than the poorest patients. Additionally, we found that women presented at higher stages (p < 0.001), were 2.67 times more likely to receive radiation (95% CI 2.55 2.81, p < 0.001), and were 1.25 times more likely to die of anal cancer than men (95% CI 1.17-1.32, p < 0.001). CONCLUSIONS: Women and poorer patients present with more advanced stages of anal cancer, more commonly receive radiation, and are more likely to die of anal cancer than men and wealthier patients, respectively. PMID- 28577729 TI - [Acute obstructive nephropathy: A pathophysiological view]. AB - Obstructive acute renal failure is a heterogeneous entity as the pathophysiology of intratubular obstruction is quite different from upper tract obstruction. In the former case, tubules are dilated due to a high hydrostatic pressure whereas pressures are normal in urinary upper tract. In the latter case, a high pressure above the ureteral obstacle is responsible for dilated renal cavities leading to extrinsic compression with no or only few dilated tubules though high hydrostatic pressure are recorded within tubules. Obstruction within tubules may be related to crystal formation, exfoliated cells, cellular debris and/or protein gels altogether with cell proliferation, proliferating cells, and recruitment of inflammatory cells. Though fibrosis may develop, the occurrence of atubular glomeruli in several nephrons due to an initial loss of tubular patency highlights the critical importance of maintaining a fluid flow within tubules in order to avoid uncontrolled tubular cell proliferation. The onset of tubular obstruction in few tubules, especially in crystal nephropathy is underestimated especially in chronic kidney disease patients, thus suggesting that some macromolecular solubilizing factors may be potential relevant therapy to prevent (and/or reverse) chronic kidney disease progression or decrease acute renal failure sequelae. PMID- 28577730 TI - [Sucroferric oxyhydroxide, a novel iron-based phosphate binder. Which current use in dialysis patients?] AB - International guidelines suggest lowering elevated phosphorus level to the normal range in patients on dialysis. Among the phosphate-lowering strategies, phosphate binder is frequently used in addition to dietary phosphate restriction and an adequate dialysis strategy. However, serum phosphate concentration higher than 1.78mmol/L is observed in more than 40% of patients justifying the quest for new drugs. Sucroferric oxyhydroxide is one of the new iron-based agents and is available in France since May 2016. A recent international multicentre study showed this new drug to be as efficacious and non-inferior to sevelamer carbonate in magnitude of serum phosphate control. The serum phosphorus-lowering effect was maintained over 1year. When compared to carbonate sevelamer, the pill-burden was half with sucroferric oxyhydroxide because of its high phosphate binding capacity. As previously shown by experimental studies, no risk of iron accumulation was observed since iron absorption is negligible. Discolored feces and diarrhea were fairly frequent side effects. When diarrhea subsides, the tolerability of this new phosphate binder is excellent on a long-term basis. PMID- 28577731 TI - Thrombotic microangiopathies and antineoplastic agents. AB - Thrombotic microangiopathy is a well-described complication of cancer treatment. Its incidence has increased these last decades, as a result of a better awareness of this complication in cancer patients in one hand, but also of a larger array of therapeutic compounds including anti-vascular endothelium growth factor (VEGF) drugs. It is therefore mandatory to recognize these conditions since they have a significant impact in thrombotic microangiopathies management and prognosis. Practitioners should be aware of the more classical antineoplastic agents associated with thrombotic microangiopathies, the mechanisms by which they induce them, and the resulting management and prognosis. Since malignancy itself can induce thrombotic microangiopathies, it is also mandatory to know how to distinguish rapidly those caused by antineoplastic agents from those associated with cancer, for an adapted management. Thrombotic microangiopathies associated with chemotherapy remain of dismal prognosis. A better understanding of pathophysiology in these forms of thrombotic microangiopathies, in association with a more empirical approach through the use of new therapeutic agents that can also help in the understanding on new mechanisms a posteriori, should improve their prognosis. The preliminary encouraging results reported with complement blockers in this field could represent a convincing example. PMID- 28577732 TI - [Prospective: How will renal, prostatic and urothelial tumours be treated in 10 years?] AB - Forward thinking does not seek to predict the future, to unveil it as if it were already in existence, rather, its aim is to help us to construct it. Although today's epidemiological and therapeutic situations for urogenital tumours can evolve over the next 10 years, diagnostic and therapeutic methods, as well as the treatment and implementation of innovations, are already rapidly changing. Rather than reducing our prospective thinking to the therapeutic treatment of cancer only, we will aim at proposing a global sanitary vision that includes diagnosis, therapies, prevention, routine utilisation of technomedicine, genomics and even nanomedicine. This journey into the near future of tomorrow's cancerology holds the promise of being better adapted to the evolution of the medical thinking process. Imagining the way we will be treating renal, prostatic and urothelial tumours in 10 years' time is as much an introspection into our present day treatment system as a projection into its hoped for future evolution. PMID- 28577733 TI - [Transplant tolerance through mixed chimerism]. AB - Three pilot studies have offered proof-of-concept that operational tolerance can be induced through mixed chimerism in recipients of combined kidney and hematopoietic cell transplants from the same donor. In two studies, sustained mixed chimerism was induced allowing safe and rejection-free immunosuppression withdrawal. However, this success came at heavy toll, requiring harsh cytoreductive regimen and a balance tipped toward graft-versus-host reactivity. Hence, achievement of durable chimerism in humans is not devoid of a significant risk of graft-versus-host disease. In contrast, transient mixed chimerism can be induced with non-myeloablative and a less cytotoxic regimen, leading to transplant tolerance, whose underpinning mechanisms are more complex, involving T cell exhaustion, peripheral deletion and suppression. PMID- 28577734 TI - [Renal replacement therapy for acute kidney injury in the intensive care unit]. AB - Renal replacement therapy for acute kidney injury has been used for more than 60 years. Except when life-threatening metabolic complications such as severe hyperkalaemia are present, renal replacement therapy initiation criteria are the subject of intense debate. Significant progress has been made with the publication of the AKIKI multicenter trial, which showed that a delayed renal replacement therapy initiation strategy (in the absence of life-threatening metabolic complications) was not associated with a difference in mortality compared to an early renal replacement therapy initiation strategy. In addition, this delayed strategy obviated the need for renal replacement therapy in almost 50% of cases was associated with a more rapid renal function recovery and with a lower incidence of catheter-bloodstream related infections. Research on renal replacement therapy modalities (continuous vs. intermittent renal replacement therapy, citrate vs. heparin anticoagulation, jugular vs. femoral catheterization) did not show any obvious superiority of one modality over another. Thus, the choice depends mainly on local considerations (patient recruitment, availability of modalities, staff experience). The criteria for renal replacement therapy discontinuation are still unclear due to difficulties in assessing renal function recovery. Urine output remains the main criteria in the decision to wean from renal replacement therapy. Pending the confirmation of AKIKI trial by similar studies in progress, it seems reasonable to choose a delayed renal replacement therapy initiation strategy under watchful surveillance in case of severe acute kidney injury in the absence of life-threatening metabolic complications. PMID- 28577735 TI - [New scores in renal transplantation: How can we use them?] AB - In renal transplant medicine, several scores have been recently developed in order to help decision-making in clinical practice. The aim of this update is to focus on these new scores that allow to better estimate the quality of the renal transplant, to refine the allocation policy, to help registration of old recipients on the waiting list, or to evaluate the risk to develop end-stage renal failure after living donation. PMID- 28577736 TI - [Post-transplantation diabetes mellitus in kidney recipients]. AB - Post-transplantation diabetes mellitus is defined as diabetes that is diagnosed in grafted patients. It affects 20 to 30 % of kidney transplant recipients, with a high incidence in the first year. The increasing age at transplantation and the rising incidence of obesity may increase its prevalence in the next years. Post transplantation diabetes mellitus is associated with poor outcomes, such as mortality, cardiovascular events or graft dysfunction. Its occurrence is mainly related to immunosuppressive agents, affecting both insulin secretion and sensibility. Immunosuppressants may be iatrogenic, and as such, induce an early and transient diabetes. They may also precociously determine a permanent diabetes, acting here as a promoting factor in patients proned to the development of type 2 diabetes. Lastly, they may behave, far from transplantation, as an additional risk factor for type 2 diabetes. The screening, management and prognosis of these different subtypes of post-transplantation diabetes mellitus will be different. PMID- 28577737 TI - [Screening and management of intracranial aneurisms in patients with autosomal dominant polycystic kidney disease]. AB - Autosomal dominant polycystic kidney disease is the most frequent hereditary kidney disease. Intracranial aneurysm prevalence in this population is four to five times higher than the prevalence in the general population. The most frequent complication of intracranial aneurysms is rupture with subarachnoidal hemorrhage, which is associated with a high morbidity and mortality. The only identified risk factor for unruptured intracranial aneurysm is a family history of intracranial aneurysm. However, most cases of aneurysm rupture occur without any family history of intracranial aneurysm. Magnetic resonance angiography without contrast medium injection facilitates screening, and progress have been made in preventive (endovascular or neurosurgical) treatment of intracranial aneurysm. Recommendations have recently been published concerning intracranial aneurysm screening, and suggest screening patients with autosomal dominant polycystic kidney disease and a family history of intracranial aneurysm, those who have an at-risk activity and those who request screening despite adequate information. Conflicting opinions exist, however, in the literature. Furthermore, a study of practice was conducted among French-speaking nephrologists in Europe and showed that approximately a third of the participants were in favor of systematic screening for intracranial aneurysm in all patients with autosomal dominant polycystic kidney disease. Beyond intracranial aneurysm prevalence, it is necessary to better define rupture rates in the autosomal dominant polycystic kidney disease population, with and without familial history of intracranial aneurysm. This would allow optimizing intracranial aneurysm screening practices in autosomal dominant polycystic kidney disease. PMID- 28577738 TI - [PIK3CA-related overgrowth syndrome (PROS)]. AB - This review presents an overview of a recently characterized spectrum of overgrowth syndrome: phosphoinositide-3 kinase (PI3K)-related overgrowth spectrum (PROS). This spectrum encompasses overgrowth syndromes associated with somatic mosaic activating PIK3CA mutations such as megalencephaly-capillary malformation (MCAP) syndrome, dysplatic megalencephaly (DMEG), congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome, hemihyperplasia-multiple lipomatosis (HHML), fibroadipose overgrowth and Klippel-Trenaunay syndrome. Mosaic gain of function mutation in PIK3CA gene leads to abnormal AKT-mTOR pathway activation and is responsible of the clinical manifestations. Here, we summarize the current knowledge on this disorder. PMID- 28577739 TI - Mitochondrial cytopathies and the kidney. AB - Mitochondrial cytopathies include a heterogeneous group of diseases that are characterized by impaired oxidative phosphorylation. Current evidence suggests that renal involvement is probably more frequent than originally suspected but remains subclinical in a significant number of patients or is underestimated due to the severity of other clinical manifestations. Until recently, these diseases were thought to develop primarily in pediatric patients but patients that become symptomatic only in adulthood are now well recognized. From a renal standpoint, many patients with severe systemic disease and several patients with oligo symptomatic clinical pictures have tubular defects, ranging from isolated tubular wasting of electrolytes to complete forms of renal Fanconi syndrome. Aside from rare cases of tubulo-interstitial and cystic diseases, other patients present with glomerular diseases that correspond in the majority of cases to focal segmental glomerulosclerosis lesions. Two specific entities should be singled out, namely the 3243 A>G mutation in the gene encoding for the mitochondrial leucine tRNA because it represents the most frequent form of mitochondrial glomerulopathy, and defects in the biosynthesis of coenzyme Q10 because they represent one of the few treatable forms of mitochondrial cytopathies. PMID- 28577740 TI - Oxygen sensors as therapeutic targets in kidney disease. AB - Hypoxia is a common clinical problem that has profound effects on renal homeostasis. Prolyl-4-hydroxylases PHD1, 2 and 3 function as oxygen sensors and control the activity of hypoxia-inducible factor (HIF), an oxygen-sensitive transcription factor that regulates a multitude of hypoxia responses, which help cells and tissues to adapt to low oxygen environments. This review provides an overview of the molecular mechanisms that govern these hypoxia responses and discusses clinical experience with compounds that inhibit prolyl-4-hydroxylases to harness HIF responses for therapy in nephrology. PMID- 28577741 TI - [Role of the kidneys in glucose homeostasis. Implication of sodium-glucose cotransporter 2 (SGLT2) in diabetes mellitus treatment]. AB - Kidney plays an important role in glucose homeostasis, both in the post absorptive and postprandial period. Kidney produces glucose by gluconeogenesis in the renal cortex and uses glucose for covering energy needs of the medulla. Kidney participates also to the reabsorption of filtered glucose in order the terminal urine was devoided of glucose, as long as blood glucose did not exceed 180mg/dL. Reabsorption of glucose is mediated by sodium-glucose cotransporters (SGLT1 et SGLT2) expressed in S1 and S3 segments of proximal tubule. SGLT2 is the main sodium-glucose cotransporter responsible for 90% of glucose reabsorption. In type 2 diabetics, renal gluconeogenesis and glucose utilisation are increased by 30%. Surprisingly, renal glucose reabsorption is increased, participating to worsening of hyperglycemia. This results from the increase in the renal threshhold of glucose reabsorption (220mg/dL) and from an overexpression of SGLT2 in response to hyperglycemia and of cytokine secretion. The administration of SGLT2 inhibitors to type 2 diabetic patients induced a decreased in the renal threshhold of glucose reabsorption (80mg/dL) and strongly reduced kidney glucose reabsorption. The inhibitors of SGLT2 are the only antidiabetic molecules able to correct the excessive renal glucose reabsorption in type 2 diabetics and thus to contribute, by an original mechanism, to the lowering of blood glucose level. PMID- 28577742 TI - Dual renin-angiotensin system blockade for nephroprotection. AB - In experimental diabetic and nondiabetic chronic kidney disease, angiotensin converting enzyme (ACE) inhibitor and angiotensin receptor blockers (ARB) combination therapy reduce proteinuria and prevent structural lesions more effectively than either drug alone. Consistently, in humans, a multidrug individually tailored antiproteinuric treatment based on combination therapy with maximum tolerated doses of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers ("Remission Clinic") reduced proteinuria and prevented end-stage renal disease more effectively than angiotensin-converting enzyme/angiotensin receptor blockers monotherapy, in particular in subjects with nondiabetic chronic kidney disease. Fixed doses of an angiotensin-converting enzyme inhibitor or renin inhibitor added-on losartan failed to exert any additional renoprotective effect as compared with losartan monotherapy in patients with type 2 diabetes and overt nephropathy. However, the VA NEPHRON D study found that losartan and lisinopril combination therapy reduced by 34 % the risk of pre-defined reductions in estimated glomerular filtration rate, end-stage renal disease or death as compared to losartan in 1448 type 2 diabetes patients with overt nephropathy. Unfortunately, treatment effect failed to achieve the nominal significance (P=0.07) because of premature trial interruption. Thus, the Remission Clinic protocol is the most powerful tool to prevent progression to end stage renal disease in nondiabetic proteinuric chronic kidney disease. Results of the ongoing VALID trial will show whether this approach can be safely extended to type 2 diabetes patients. PMID- 28577743 TI - Renin-angiotensin system blockade: Finerenone. AB - Finerenone is a novel selective nonsteroidal mineralocorticoid receptor antagonist. Results in preclinical studies showed that lower doses of finerenone were needed to achieve similar cardiorenal protective effects compared to both spironolactone and eplerenone and phase II studies in finerenone in patients with heart failure, type-2 diabetes mellitus and/or chronic kidney disease are encouraging as the drug is effective and safe in patients on renin-angiotensin system inhibitors (significant reduction in albuminuria and a low rate of hyperkalemia), but the primary end points were "soft" end points (serum potassium, estimated glomerular filtration rate, albuminuria, N-terminal prohormone B-type natriuretic peptide levels). Thus, further, large-scale, long term phase III trials are needed to confirm whether the greater affinity and selectivity is translated into improved clinical outcomes. PMID- 28577744 TI - Orthostatic hypotension: A review. AB - Orthostatic hypotension, defined by a drop in blood pressure of at least 20mmHg for systolic blood pressure and at least 10mmHg for diastolic blood pressure within 3minutes of standing up, is a frequent finding, particularly in elderly patients. It is associated with a significant increase in morbidity and mortality. Although it is often multifactorial, the first favoring factor is medications. Other etiologies are divided in neurogenic orthostatic hypotension, characterized by autonomic failure due to central or peripheral nervous system disorders, and non-neurogenic orthostatic hypotension, mainly favoured by hypovolemia. Treatment always requires education of the patient regarding triggering situations and physiological countermanoeuvers. Pharmacological treatment may sometimes be necessary and mainly relies on volume expansion by fludrocortisone and/or a vasopressor agents such as midodrine. There is no predefined blood pressure target, the goal of therapy being the relief of symptoms and fall prevention. PMID- 28577745 TI - [Blood pressure targets in nephrology in 2017]. AB - Epidemiological data clearly show that high blood pressure is associated with cardiovascular mortality and progression of chronic kidney disease. Although several randomized controlled trials performed over the last decades have demonstrated a cardiovascular benefit of reducing blood pressure in hypertensive patients, solid evidence for general and specific blood pressure targets, especially in the population with chronic kidney disease, is lacking. In this context, recently published trials have provided novel insights in the management of hypertension. Here, we review and discuss the existing evidence and the current guidelines on blood pressure targets in both the general and the population with chronic kidney disease. PMID- 28577746 TI - [Non-dialytic treatment of acute kidney injury]. AB - Acute kidney injury is frequently encountered in patients in intensive care units and is associated with higher risk of mortality and chronic renal failure. Even small increases in serum creatinine are associated with adverse outcomes. Many interventions have been proposed to prevent or treat acute kidney injury in patients in intensive care units. However, no intervention has proved its efficacy in large randomized control trials. This review presents the various attempts aiming at acute kidney injury improvement in patients in intensive care units published over the recent years: hemodynamic interventions, "usual" drugs used in intensive care units, modulation of inflammation and hemostasis, remote ischemic conditioning, drugs specifically dedicated for acute kidney injury, and stimulation of renal recovery. PMID- 28577747 TI - [Membranous nephropathy: Pathophysiology and natural history]. AB - Membranous nephropathy is a major cause of nephrotic syndrome in adults, with various etiologies and outcomes. One third of patients enter spontaneous remission with blockade of the renin-angiotensin system, one third develop a persistent nephrotic syndrome, while another third of patients develop end-stage kidney disease and 40% of them relapse after kidney transplantation. Treatment of membranous nephropathy remains controversial. Immunosuppressive therapy is only recommended in case of renal function deterioration or persistent nephrotic syndrome after 6months of renin-angiotensin system blockade. Therefore, delayed immunosuppressive treatments may lead to significant and potentially irreversible complications. For long, no biological markers could predict clinical outcome and guide therapy. The discovery of autoantibodies to the phospholipase A2 receptor (PLA2R1) in 2009, and to the thrombospondin type 1 domain containing 7A (THSD7A) in 2014 in respectively 70 and 5% of patients with membranous nephropathy were major breakthroughs. The passive infusion of human anti-THSD7A antibodies in mouse induces proteinuria and membranous nephropathy. The identification of these antigens has allowed developing diagnostic and prognostic tests. High anti-PLA2R1 titers at time of diagnosis predict a poor renal outcome. Anti-PLA2R1 antibodies can bind at least three different domains of PLA2R1. Epitope spreading with binding of two or three of these antigenic domains is associated with active membranous nephropathy and poor renal survival. These new tools could help us to monitor disease severity and to predict renal prognosis for a better selection of patients that should benefit of early immunosuppressive therapy. PMID- 28577748 TI - [Membranous nephropathy: New insights in therapeutic approach]. AB - Membranous nephropathy is one of the leading causes of nephrotic syndrome in adults, evolving to 30 % end-stage renal disease after 10 years, in the absence of specific treatment. In 2009, the M-type phospholipase A2 receptor (PLA2R), a podocyte membrane glycoprotein, was identified as the first autoantigen involved in more than 70 % of primitive membranous nephropathy. Many studies have reported that high titers of PLA2R antibodies are correlated with a lower risk of spontaneous or immunosuppressant-induced remission, a higher risk of nephrotic syndrome and of progression to end-stage renal disease. Treatment is still challenging and controversial because of potential toxicity and lack of a reliable prognosis marker. In the past, the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines recommended immunosuppressive therapies as steroids and alkylating agents or cyclosporine in patients with persistent nephrotic syndrome or impaired renal function. Recent studies and one multicentric randomised controlled trial brought clear evidence to support the use of rituximab in these patients: rituximab regimen induces immunological and clinical remission in patients with membranous nephropathy, with a high safety profile. However, they have provided important data on the impact of PLA2R antibodies assessment as a prognostic biomarker in patients with membranous nephropathy. The next step will be the integration of this biomarker in KDIGO guidelines and the recommendation of rituximab as a first line immunosuppressive therapy in patient with persistent nephrotic syndrome due to membranous nephropathy. PMID- 28577749 TI - [Modelling of phosphorus transfers during haemodialysis]. AB - Chronic kidney disease causes hyperphosphatemia, which is associated with increased cardiovascular risk and mortality. In patients with end-stage renal disease, haemodialysis allows the control of hyperphosphatemia. During a 4-h haemodialysis session, between 600 and 700mg of phosphate are extracted from the plasma, whereas the latter contains only 90mg of inorganic phosphate. The precise origin of phosphates remains unknown. The modelling of phosphorus transfers allows to predict the outcome after changes in dialysis prescription (duration, frequency) with simple two-compartment models and to describe the transfers between the different body compartments with more complex models. Work using 31P nuclear magnetic resonance spectroscopy performed in animals showed an increase in intracellular phosphate concentration and a decrease in intracellular ATP during a haemodialysis session suggesting an intracellular origin of phosphates. PMID- 28577750 TI - [Strategies aiming to control hyperphosphatemia in chronic kidney disease]. AB - Chronic kidney disease is known to be associated with phosphate retention. The mechanisms are complex and the early increase in serum phosphate levels in chronic kidney disease is not strictly related to the dietary phosphate load or to the degree of phosphate retention. It also implicates the activity of intestinal sodium-phosphate cotransporters, the degree of bone turnover and the retention and/or phosphate release from the skeleton, and the feedback mechanisms regulating the phosphaturia. Indeed, the increase in serum phosphate levels is only a reflection of underlying complex mechanisms, and many important factors play a role including parathyroid hormone, vitamin D, fibroblast growth factor 23 (FGF23), and others. Hyperphosphatemia increases the risk of cardiovascular morbidity and mortality in chronic kidney disease as well as in subjects with normal renal function. Oral phosphate binders are prescribed in patients with chronic kidney disease and in those treated by dialysis, to prevent intestinal absorption of dietary phosphate and reduce serum phosphate. In prospective observational studies, they have been shown to decrease all-cause and cardiovascular mortality risk. However, different problems have been associated with currently available phosphate binders including the induction of a positive calcium balance and impaired outcomes with calcium-based phosphate binders or increased costs with non-calcium-based phosphate binders. Iron-based phosphate binders represent a new class of phosphate binders. The aim of this article is to provide an update review of the pathophysiological mechanisms leading and maintaining elevated serum phosphate levels in patients with chronic kidney disease and patients in dialysis, and the educational, nutritional, and therapeutic strategies that can be undertaken to control the hyperphosphatemia. PMID- 28577751 TI - Association Between Local Bipolar Voltage and Conduction Gap Along the Left Atrial Linear Ablation Lesion in Patients With Atrial Fibrillation. AB - A bipolar voltage reflects a thick musculature where formation of a transmural lesion may be hard to achieve. The purpose of this study was to explore the association between local bipolar voltage and conduction gap in patients with persistent atrial fibrillation (AF) who underwent atrial roof or septal linear ablation. This prospective observational study included 42 and 36 consecutive patients with persistent AF who underwent roof or septal linear ablations, respectively. After pulmonary vein isolation, left atrial linear ablations were performed, and conduction gap sites were identified and ablated after first-touch radiofrequency application. Conduction gap(s) after the first-touch roof and septal linear ablation were observed in 13 (32%) and 19 patients (53%), respectively. Roof and septal area voltages were higher in patients with conduction gap(s) than in those without (roof, 1.23 +/- 0.77 vs 0.73 +/- 0.42 mV, p = 0.010; septal, 0.96 +/- 0.43 vs 0.54 +/- 0.18 mV, p = 0.001). Trisected regional analyses revealed that the voltage was higher at the region with a conduction gap than at the region without. Complete conduction block across the roof and septal lines was not achieved in 3 (7%) and 6 patients (17%), respectively. Patients in whom a linear conduction block could not be achieved demonstrated higher ablation area voltage than those with a successful conduction block (roof, 1.91 +/- 0.74 vs 0.81 +/- 0.51 mV, p = 0.001; septal, 1.15 +/- 0.56 vs 0.69 +/- 0.31 mV, p = 0.006). In conclusion, a high regional bipolar voltage predicts failure to achieve conduction block after left atrial roof or septal linear ablation. In addition, the conduction gap was located at the preserved voltage area. PMID- 28577752 TI - Usefulness of a Gentle and Short Hemostasis Using the Transradial Band Device after Transradial Access for Percutaneous Coronary Angiography and Interventions to Reduce the Radial Artery Occlusion Rate (from the Prospective and Randomized CRASOC I, II, and III Studies). AB - The study sought to evaluate the benefit of the reduction in intensity and duration of the hemostasis obtained with the transradial (TR) Band compression device on the radial artery occlusion (RAO) rate. RAO is the most frequent complication of TR access for cardiac catheterization and limits future use of this safe route. Its occurrence must be minimized. Between 2009 and 2016, 3,616 TR accesses were randomized to TR Band hemostasis during 3 consecutive protocols: CRASOC I (Compression of Radial ArterieS without Occlusion): 13 versus 10 cc of air into the TR Band and for 4 hours of continuous compression; CRASOC II: 10 cc of air for 3 hours versus 2 hours of compression; and CRASOC III: 10 cc of air for 2 hours versus 1.5 hours of compression and virtual 4F introducer as default sheath (both arms). Radial artery patency was assessed by plethysmography at 24 hours, using Doppler for doubtful or negative plethysmography. The primary end point, 24 hours of RAO, was markedly reduced when hemostasis was soft (10 cc of air) and short (1.5 hours) and resulted in a 2.3% rate of RAO versus 9.4% for 13 cc, 4 hours. Hemostasis was obtained in 89% of patients with only 10 cc of air and in 97% of patients with less than the recommended 13 cc. About 8% of patients required more than the 1.5 hours of hemostasis time. In conclusion, short and soft hemostasis with the TR Band device leads to a low RAO rate. PMID- 28577754 TI - A review on the mechanical and thermodynamic robustness of superhydrophobic surfaces. AB - Advancements in the fabrication and study of superhydrophobic surfaces have been significant over the past 10years, and some 20years after the discovery of the lotus effect, the study of special wettability surfaces can be considered mainstream. While the fabrication of superhydrophobic surfaces is well advanced and the physical properties of superhydrophobic surfaces well-understood, the robustness of these surfaces, both in terms of mechanical and thermodynamic properties, are only recently getting attention in the literature. In this review we cover publications that appeared over the past ten years on the thermodynamic and mechanical robustness of superhydrophobic surfaces, by which we mean the long term stability under conditions of wear, shear and pressure. The review is divided into two parts, the first dedicated to thermodynamic robustness and the second dedicated to mechanical robustness of these complex surfaces. Our work is intended as an introductory review for researchers interested in addressing longevity and stability of superhydrophobic surfaces, and provides an outlook on outstanding aspects of investigation. PMID- 28577755 TI - Regeneration of Photoreceptor Outer Segments After Scleral Buckling Surgery for Rhegmatogenous Retinal Detachment. PMID- 28577756 TI - Reply. PMID- 28577753 TI - Cocaine-Induced Chromatin Modifications Associate With Increased Expression and Three-Dimensional Looping of Auts2. AB - BACKGROUND: Exposure to drugs of abuse alters the epigenetic landscape of the brain's reward regions, such as the nucleus accumbens. We investigated how combinations of chromatin modifications affect genes that regulate responses to cocaine. We focused on Auts2, a gene linked to human evolution and cognitive disorders, which displays strong clustering of cocaine-induced chromatin modifications in this brain region. METHODS: We combined chromosome conformation capture, circularized chromosome conformation capture, and related approaches with behavioral paradigms relevant to cocaine phenotypes. Cell type-specific functions were assessed by fluorescence-activated cell sorting and viral-mediated overexpression in Cre-dependent mouse lines. RESULTS: We observed that Auts2 gene expression is increased by repeated cocaine administration specifically in D2 type medium spiny neurons in the nucleus accumbens, an effect seen in male but not female mice. Auts2 messenger RNA expression was also upregulated postmortem in the nucleus accumbens of male human cocaine addicts. We obtained evidence that chromosomal looping, bypassing 1524 kb of linear genome, connects Auts2 to the Caln1 gene locus under baseline conditions. This looping was disrupted after repeated cocaine exposure, resulting in increased expression of both genes in D2 type medium spiny neurons. Cocaine exposure reduces binding of CCCTC-binding factor, a chromosomal scaffolding protein, and increases histone and DNA methylation at the Auts-Caln1 loop base in the nucleus accumbens. Cell type specific overexpression of Auts2 or Caln1 in D2-type medium spiny neurons demonstrated that both genes promote cocaine reward. CONCLUSIONS: These findings suggest that cocaine-induced alterations of neuronal three-dimensional genome organization destabilize higher order chromatin at specific loci that regulate responses to the drug. PMID- 28577757 TI - Robust statistical methods: A primer for clinical psychology and experimental psychopathology researchers. AB - This paper reviews and offers tutorials on robust statistical methods relevant to clinical and experimental psychopathology researchers. We review the assumptions of one of the most commonly applied models in this journal (the general linear model, GLM) and the effects of violating them. We then present evidence that psychological data are more likely than not to violate these assumptions. Next, we overview some methods for correcting for violations of model assumptions. The final part of the paper presents 8 tutorials of robust statistical methods using R that cover a range of variants of the GLM (t-tests, ANOVA, multiple regression, multilevel models, latent growth models). We conclude with recommendations that set the expectations for what methods researchers submitting to the journal should apply and what they should report. PMID- 28577758 TI - Diagnosis of recurrent venous thromboembolism. AB - The diagnostic management of suspected recurrent venous thromboembolism (VTE) is challenging for four main reasons. First, clinical decision rules are less useful to identity patients with a low pre-test probability. Second, the diagnostic performance of D-dimer tests is decreased. Together, these two point lead to a clearly lower proportion of patients in whom recurrent VTE can be ruled out without performing imaging tests. Third, recurrent thrombi may be difficult to differentiate from residual thrombi, which may be often identified in patients with a history of VTE. Fourth and lastly, the prevalence of VTE in patients with suspected recurrent disease is higher than in patients with suspected first VTE. As a consequence, the failure rates of the algorithms in patients with suspected recurrent VTE are higher as well, underling the relevance of accurate diagnostic management of this specific patient population. There is a lack of large well designed diagnostic studies that focus mainly on patients with prior VTE. Even so, available evidence suggests that diagnostic algorithms validated for first VTE are also largely applicable to suspected recurrent VTE. Emerging imaging techniques such as magnetic resonance direct thrombus imaging (MRDTI) are likely to improve the accuracy of the algorithms in the near future. PMID- 28577759 TI - pIP40a, a type 1 IncC plasmid from 1969 carries the integrative element GIsul2 and a novel class II mercury resistance transposon. AB - The 167.5kb sequence of the conjugative IncC plasmid pIP40a, isolated from a Pseudomonas aeruginosa in 1969, was analysed. pIP40a confers resistance to kanamycin, neomycin, ampicillin, sulphonamides and mercuric ions, and several insertions in a type 1 IncC backbone were found, including copies of IS3, Tn1000 and a novel mercury resistance transposon, Tn6182. The antibiotic resistance genes were in two locations. Tn6023, containing the aphA1 kanamycin and neomycin resistance gene, is in a partial copy of Tn1/Tn2/Tn3 (blaTEM, ampicillin resistance) in the kfrA gene, and the sul2 sulphonamide resistance gene is in the integrative element GIsul2 in the position of ARI-B islands. The 11.5kb class II transposon Tn6182 is only distantly related to other class II transposons, with at most 33% identity between the TnpA of Tn6182 and TnpA of other group members. In addition, the inverted repeats are 37bp rather than 38bp, and the likely resolution enzyme is a tyrosine recombinase (TnpI). Re-annotation of GIsul2 revealed genes predicted to confer resistance to arsenate and arsenite, but resistance was not detected. The location of GIsul2 confirms it as the progenitor of the ARI-B configurations seen in many IncC plasmids isolated more recently. However, GIsul2 has integrated at the same site in type 1 and type 2 IncC plasmids, indicating that it targets this site. Analysis of the distribution of GIsul2 revealed that it in addition to its chromosomal integration site at the 3' end of the guaA gene, it has also integrated into other plasmids, increasing its mobility. PMID- 28577761 TI - The Troublesome Epidemiology of Barrett's Esophagus and Esophageal Adenocarcinoma. AB - Barrett's esophagus and esophageal adenocarcinoma diagnoses have increased markedly in recent decades. Recent research with patients diagnosed with Barrett's esophagus (the only known precursor for esophageal adenocarcinoma) and esophageal adenocarcinoma has identified several modifiable and nonmodifiable potential risk factors. Consistent risk factors for both disorders include increasing age, male sex, white non-Hispanic race/ethnicity, gastroesophageal reflux disease, lack of infection with Helicobacter pylori, smoking, abdominal obesity, and a Western diet. The authors present detailed discussions of these risk factors along with possible explanations for some apparent discrepancies and ideas for future study. PMID- 28577760 TI - The occurrence of three D-J-C clusters within the dromedary TRB locus highlights a shared evolution in Tylopoda, Ruminantia and Suina. AB - The alphabeta T cells are important components of the adaptive immune system and can recognize a vast array of peptides presented by MHC molecules. The ability of these T cells to recognize the complex depends on the diversity of the alphabeta TR, which is generated by a recombination of specific Variable, Diversity and Joining genes for the beta chain, and Variable and Joining genes for the alpha chain. In this study, we analysed the genomic structure and the gene content of the TRB locus in Camelus dromedarius, which is a species belonging to the Tylopoda suborder. The most noteworthy result is the presence of three in tandem TRBD-J-C clusters in the dromedary TRB locus, which is similar to clusters found in sheep, cattle and pigs and suggests a common duplication event occurred prior to the Tylopoda/Ruminantia/Suina divergence. Conversely, a significant contraction of the dromedary TRBV genes, which was previously found in the TRG and TRD loci, was observed with respect to the other artiodactyl species. PMID- 28577762 TI - Who Deserves Endoscopic Screening for Esophageal Neoplasia? AB - Despite the availability of safe and effective endoscopic treatment of Barrett's esophagus (BE)-related dysplasia and neoplasia, the incidence and mortality from esophageal adenocarcinoma (EAC) have continued to increase. This likely stems from the large population of patients that develop EAC outside of a BE screening and surveillance program. Identification of BE with screening followed by enrollment in an appropriate surveillance/risk stratification program could be a strategy to address both the incidence of and mortality from EAC. This article summarizes the rationale and challenges for BE screening, the risk factors for BE, and the currently described BE risk assessment tools. PMID- 28577764 TI - Effectiveness and Cost-Effectiveness of Endoscopic Screening and Surveillance. AB - Guidelines for the screening and surveillance of Barrett's esophagus continue to evolve as the incidence of esophageal adenocarcinoma increases, identification of individuals at highest risk for cancer improves, and management of dysplasia evolves. This article reviews related studies and economic analyses. Advances in diagnosis offer promising strategies to help focus screening efforts on those individuals who are most likely to develop esophageal adenocarcinoma. PMID- 28577763 TI - Alternatives to Traditional Per-Oral Endoscopy for Screening. AB - Barrett's esophagus (BE) predisposes patients to esophageal adenocarcinoma. 3 to 6% of individuals with gastro-esophageal reflux disease are estimated to have BE but only 20 to 25% of BE patients are currently diagnosed. The current gold standard for diagnosis of BE is per-oral upper GI endoscopy. As this is not suitable for large-scale screening, a number of alternative methods are currently being investigated: transnasal and video capsule endoscopy, endomicroscopy, cell collection devices like the cytosponge and biomarkers. Some of these are promising, however, well powered studies carried out in relevant screening populations are needed. PMID- 28577765 TI - The Role of Adjunct Imaging in Endoscopic Detection of Dysplasia in Barrett's Esophagus. AB - Advances in imaging technologies have demonstrated promise in early detection of dysplasia and cancer in Barrett's esophagus (BE). Optical chromoendoscopy, dye based chromoendoscopy, and novel technologies have provided the opportunity to visualize the cellular and subcellular structures. Only narrow-band imaging and acetic acid chromoendoscopy have reached benchmarks for clinical use. Volumetric laser endomicroscopy and molecular imaging are not established for routine use. Best practice in management of BE should be focused on careful endoscopic examination, resection, or ablation of the entire abnormal lesion, as well as the use of available imaging technique that has good diagnostic accuracy. PMID- 28577767 TI - Management of Nodular Neoplasia in Barrett's Esophagus: Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection. AB - Endoscopic resection has proven highly effective and safe in the removal of focal early neoplastic lesions in Barrett's esophagus and is considered the cornerstone of endoscopic treatment. Several techniques are available for endoscopic resection in Barrett's esophagus. The most widely used technique for piecemeal resection of early Barrett's neoplasia is the ligate-and-cut technique. Newer techniques such as endoscopic submucosal dissection may also play a role in the treatment of neoplastic Barrett's esophagus. Treatment of early Barrett's neoplasia should be centralized and limited to expert centers with a high-volume load and sufficient expertise in the detection and treatment of esophageal neoplasia. PMID- 28577766 TI - Beyond Dysplasia Grade: The Role of Biomarkers in Stratifying Risk. AB - Gastroenterology society guidelines recommend endoscopic surveillance as a means to detect early stage cancer in Barrett's esophagus. However, the incidence of esophageal adenocarcinoma in Western countries continues to increase, suggesting that this strategy may be inadequate. Current surveillance methods rely on the endoscopist's ability to identify suspicious areas of Barrett's esophagus to biopsy, random biopsies, and on the histopathologic diagnosis of dysplasia. This review highlights the challenges of using dysplasia to stratify cancer risk and addresses the development and use of molecular biomarkers and in vivo molecular imaging to detect early neoplasia in Barrett's esophagus. PMID- 28577768 TI - The Role of Endoscopic Ultrasound in the Management of Patients with Barrett's Esophagus and Superficial Neoplasia. AB - Endoscopic ultrasound (EUS) is a minimally invasive advanced imaging procedure using high-frequency sound waves to produce detailed images of the esophageal wall with fine-needle aspiration to biopsy adjacent lymph nodes. The role of EUS is well established in patients with locally advanced Barrett esophagus neoplasia. The utility of EUS in the evaluation of Barrett esophagus patients is controversial. This is a review of the evidence using EUS in BE patients. The assessment is that EUS may be a powerful tool in managing patients with BE neoplasia. PMID- 28577769 TI - Radiofrequency Ablation of Barrett's Esophagus: Patient Selection, Preparation, and Performance. AB - Radiofrequency ablation (RFA) is a safe and effective thermal ablative therapy for dysplastic Barrett's esophagus (BE) and, to a lesser extent, nondysplastic BE. Before the utilization of RFA, there must be an appropriate indication, assessment of potential contraindications, discussion of risks and benefits with patients, and careful endoscopic planning. The ease of performance of the procedure along with its efficacy and low rate of adverse events have established RFA as a reliable technique for endoscopic management of dysplastic BE. PMID- 28577770 TI - Radiofrequency Ablation of Barrett's Esophagus: Efficacy, Complications, and Durability. AB - In the last decade, radiofrequency ablation in combination with endoscopic mucosal resection has simplified and improved the treatment of Barrett's esophagus. These treatments not only reduced the progression of dysplastic Barrett's esophagus to esophageal adenocarcinoma but also decreased treatment related complications. More recent data from larger series with extended follow up periods are emerging to refine expectations in patients treated with radiofrequency ablation. Although most patients achieve eradication of neoplasia and intestinal metaplasia, in the long-term a substantial portion of patients develop recurrent disease. This article provides an updated review of radiofrequency ablation efficacy, complications, and durability. PMID- 28577771 TI - Cryotherapy for Barrett's Esophagus. AB - Cryotherapy or cryoablation involves the freezing of tissues to destroy unwanted tissue or to control bleeding. Endoscopic cryotherapy has been developed for gastrointestinal application by through-the-scope noncontact delivery of compressed carbon dioxide gas or liquid nitrogen (cryospray) or contact balloon cryoablation. The mechanism of cryotherapy ablative effects includes immediate injury as well as coagulation necrosis occurring over several hours and days, unlike heat-based thermal ablation. This article reviews the basis, technique, safety, efficacy, and durability for the use of endoscopic cryotherapy in Barrett's esophagus and esophageal adenocarcinoma. PMID- 28577772 TI - Care of the Postablation Patient: Surveillance, Acid Suppression, and Treatment of Recurrence. AB - Endoscopic eradication therapy is effective and durable for the treatment of Barrett's esophagus (BE), with low rates of recurrence of dysplasia but significant rates of recurrence of intestinal metaplasia. Identified risk factors for recurrence include age and length of BE before treatment and may also include presence of a large hiatal hernia, higher grade of dysplasia before treatment, and history of smoking. Current guidelines for surveillance following ablation are limited, with recommendations based on low-quality evidence and expert opinion. New modalities including optical coherence tomography and wide-area tissue sampling with computer-assisted analysis show promise as adjunctive surveillance modalities. PMID- 28577773 TI - Esophagectomy for Superficial Esophageal Neoplasia. AB - Endoscopic therapies have become the standard of care for most cases of Barrett's esophagus with high-grade dysplasia or intramucosal adenocarcinoma. Despite a rapid and dramatic evolution in treatment paradigms, esophagectomy continues to occupy a place in the therapeutic armamentarium for superficial esophageal neoplasia. The managing physician must remain cognizant of the limitations of endoscopic approaches and consider surgical resection when they are exceeded. Esophagectomy, performed at experienced centers for appropriately selected patients with early-stage disease can be undertaken with the expectation of cure as well as low mortality, acceptable morbidity, and good long-term quality of life. PMID- 28577774 TI - Barrett's Esophagus and the Prevention of Esophageal Adenocarcinoma. PMID- 28577775 TI - New Directions in Barrett's Esophagus. PMID- 28577776 TI - Does Prior Cartilage Restoration Impact Outcomes Following Knee Arthroplasty? AB - This study compared patients who failed a cartilage restoration procedure and underwent ipsilateral knee arthroplasty with matched control subjects undergoing knee arthroplasty without prior cartilage restoration. Although patients with a failed cartilage procedure derived benefit from knee arthroplasty, their magnitude of improvement and final outcomes scores were lower than the matched control subjects. In this cohort, the cartilage patients also experienced little to no benefit from cartilage restoration, suggesting that unmeasured shared patient characteristics may play a role. This information can be used to counsel this difficult patient population on expected outcomes following arthroplasty procedures. Further research identifying characteristics of responders to treatment remains critical to refine clinical decision-making for this difficult patient group. PMID- 28577777 TI - Applications of Tissue Engineering in Joint Arthroplasty: Current Concepts Update. AB - Research in tissue engineering has undoubtedly achieved significant milestones in recent years. Although it is being applied in several disciplines, tissue engineering's application is particularly advanced in orthopedic surgery and in degenerative joint diseases. The literature is full of remarkable findings and trials using tissue engineering in articular cartilage disease. With the vast and expanding knowledge, and with the variety of techniques available at hand, the authors aimed to review the current concepts and advances in the use of cell sources in articular cartilage tissue engineering. PMID- 28577778 TI - Bone Substitute Materials and Minimally Invasive Surgery: A Convergence of Fracture Treatment for Compromised Bone. AB - This article focuses on the understanding of the biochemistry and surgical application of bone substitute materials (BSMs) and particularly the newer calcium phosphate materials that can form a structural orthobiologic matrix within the metaphyseal components of the periarticular bone. Six characteristics of BSMs are detailed that can be used as a guide for the proper selection and application of the optimal BSM type for periarticular fracture repair. These 6 characteristics of BSMs are divided into 2 pillars. One pillar details the 3 biochemical features of BSMs and the other pillar details the 3 surgical application properties. PMID- 28577779 TI - Bone Morphogenetic Protein: Is There Still a Role in Orthopedic Trauma in 2017? AB - Approximately 10 years ago bone morphogenic protein (BMP) was seen as a miraculous adjuvant to assist with bone growth. However, in the face of an increasing number of complications and a lack of understanding its long-term effects, it is unclear what role BMP has in the current treatment of orthopedic trauma patients. This article reviews the current recommendations, trends, and associated complications of BMP use in fracture care. PMID- 28577780 TI - Role of Bone Marrow Aspirate in Orthopedic Trauma. AB - Bone marrow aspirate grafting entails mesenchymal stem cell-containing bone marrow harvesting and injection into a fracture site to promote bone formation. Although the use of bone marrow aspirate in orthopedic trauma is not widespread, an increasing number of studies are reporting clinical success. Advantages of using bone marrow aspirate are that it is readily obtainable, has low harvest morbidity, and can be easily and quickly injected. However, no universally accepted role for its use exists. Future studies directly comparing bone marrow aspirate with conventional techniques are needed to define its role in the treatment of orthopedic trauma patients. PMID- 28577781 TI - Orthobiologics in Pediatric Orthopedics. AB - Orthobiologics are biologic devices or products used in orthopedic surgery to augment or enhance bone formation. The use of orthobiologics in pediatric orthopedics is less frequent than in other orthopedic subspecialties, mainly due to the naturally abundant healing potential and bone formation in children compared with adults. However, orthobiologics are used in certain situations in pediatric orthopedics, particularly in spine and foot surgery. Other uses have been reported in conjunction with specific procedures involving the tibia and pelvis. The use of bioabsorable implants to stabilize children's fractures is an emerging concept but has limited supporting data. PMID- 28577782 TI - Orthobiologics in Pediatric Sports Medicine. AB - Orthobiologics are biological substances that allow injured muscles, tendons, ligaments, and bone to heal more quickly. They are found naturally in the body; at higher concentrations they can aid in the healing process. These substances include autograft bone, allograft bone, demineralized bone matrix, bone morphogenic proteins, growth factors, stem cells, plasma-rich protein, and ceramic grafts. Their use in sports medicine has exploded in efforts to increase graft incorporation, stimulate healing, and get athletes back to sport with problems including anterior cruciate ligament ruptures, tendon ruptures, cartilage injuries, and fractures. This article reviews orthobiologics and their applications in pediatric sports medicine. PMID- 28577784 TI - Autologous Blood and Platelet-Rich Plasma Injections for Treatment of Lateral Epicondylitis. AB - Lateral epicondylitis (tennis elbow) is a frequent cause of elbow pain; most patients (80%-90%) are successfully treated with standard nonoperative methods (rest, nonsteroidal anti-inflammatory drugs, bracing, and physical therapy). Autologous blood injections and platelet-rich plasma injections are the two most frequently used orthobiologic techniques in the treatment of lateral epicondylitis. Studies of the effectiveness of autologous blood injections and platelet-rich plasma report varying outcomes, some citing significant clinical relief and others reporting no beneficial effect. More research is needed to determine how to best use orthobiologics in the treatment of lateral epicondylitis. PMID- 28577783 TI - Biologic Approaches to Problems of the Hand and Wrist. AB - Orthobiologics are not used as frequently in the hand and wrist as in other sites. The most frequently reported is the use of bone morphogenetic protein for the treatment of Kienbock disease. Animal studies have described improved tendon healing with the use of platelet-rich plasma (PRP), but no clinical studies have confirmed these results. PRP has been reported to produce improvements in the outcomes of distal radial fractures and osteoarthritis of the trapeziometacarpal in small numbers of patients. The use of orthobiologics in the hand and wrist are promising, but clinical trials are necessary to establish efficacy and safety. PMID- 28577785 TI - Osseous Healing in Foot and Ankle Surgery with Autograft, Allograft, and Other Orthobiologics. AB - In the surgical treatment of foot and ankle abnormality, many problems require bone grafting for successful osseous union. Nonunion, reconstruction, and arthrodesis procedures pose specific challenges due to bony defects secondary to trauma, malunions, or previous surgery. Nonunion in foot and ankle arthrodesis is a significant risk and is well documented in recent literature. This article is a review of the recent literature regarding the use of bone graft and orthobiologics in foot and ankle surgery. PMID- 28577787 TI - Orthobiologics. PMID- 28577786 TI - Restorative Tissue Transplantation Options for Osteochondral Lesions of the Talus: A Review. AB - Symptomatic osteochondral lesions of the talus remain a challenging problem due to inability for cartilage lesions to heal. Numerous treatment options exist, including nonoperative management, marrow stimulating techniques, and autograft allograft. Arthroscopic marrow stimulation forms fibrocartilage that has been shown to be biomechanically weaker than hyaline cartilage. Restorative tissue transplantation options are being used more for larger and cystic lesions. Newer biologics and particulated juvenile cartilage are currently under investigation for possible clinical efficacy. This article provides an evidenced-based summary of available literature on the use of biologics for treatment of osteochondral lesions of the talus. PMID- 28577788 TI - A posteriori healthy dietary patterns may decrease the risk of central obesity: findings from a systematic review and meta-analysis. AB - Central obesity is a pivotal component of metabolic syndrome, and several studies have investigated the association of dietary patterns and central obesity. However, findings of studies are inconclusive. Therefore, we aimed to conduct the present study to summarize the available data regarding the association of a posteriori dietary patterns and central obesity in adults to test the hypothesis of whether a highly healthy dietary pattern is associated with decreased risk of central obesity. We searched all published English studies to identify related articles in MEDLINE, EMBASE, and Google Scholar databases up to December 2015. The meta-analysis was conducted on 13 studies including 12 cross-sectional studies and 1 case-control study that reported odds ratios (ORs), relative risks, or hazard ratios for risk of central obesity. The between-study variance was assessed using Cochran Q test and I2. Subgroup analysis was applied to define possible sources of heterogeneity. The highest category of healthy/prudent patterns compared with those in the lowest category resulted in significant decrease in the risk of central obesity (pooled OR was 0.81 [95% confidence interval 0.66-0.96]). Pooled results indicated a higher nonsignificant increase in the risk of central obesity (OR was 1.16 [95% confidence interval 0.96-1.35]) in the highest category of Unhealthy/Western pattern compared with those in the lowest category. There was also a significant heterogeneity in the observed associations. We found that sex, country, and continent were the potential sources of heterogeneity. The results of the present meta-analysis showed that a posteriori healthy dietary patterns may decrease the risk of central obesity, whereas no significant association was found between unhealthy dietary patterns and central obesity. Together, the results highlight the need for well-designed and carefully carried out clinical trials based on dietary patterns in future research. PMID- 28577789 TI - Nutritional modulation of age-related changes in the immune system and risk of infection. AB - The immune system undergoes some adverse alterations during aging, many of which have been implicated in the increased morbidity and mortality associated with infection in the elderly. In addition to intrinsic changes to the immune system with aging, the elderly are more likely to have poor nutritional status, which further impacts the already impaired immune function. Although the elderly often have low zinc serum levels, several manifestations commonly observed during zinc deficiency are similar to the changes in immune function with aging. In the case of vitamin E, although its deficiency is rare, the intake above recommended levels is shown to enhance immune functions in the elderly and to reduce the risk of acquiring upper respiratory infections in nursing home residents. Vitamin D is a critical vitamin in bone metabolism, and its deficiency is far more common, which has been linked to increased risk of infection as demonstrated in a number of observational studies including those in the elderly. In this review, we focus on zinc, vitamin E, and vitamin D, the 3 nutrients which are relatively well documented for their roles in impacting immune function and infection in the elderly, to discuss the findings in this context reported in both the observational studies and interventional clinical trials. A perspective will be provided based on the analysis of information under review. PMID- 28577790 TI - Impact of Provider Characteristics on Outcomes of Carotid Endarterectomy for Asymptomatic Carotid Stenosis in New York State. AB - BACKGROUND: The purpose of this study is to explore the impact of surgeon characteristics (including annual volume, specialty, and years in practice) on outcomes of carotid endarterectomy (CEA) for asymptomatic carotid atherosclerosis in New York State. METHODS: The New York Statewide Planning and Cooperation System database was utilized to identify patients undergoing CEA from 2004 to 2011. Provider characteristics were determined by linkage to the New York Office of Professions and National Provider Identification databases. Provider-level factors were characterized by defining 5 quintiles of equal size for each factor. Hierarchical logistic regression models were created to evaluate the impact of provider characteristics on outcome. RESULTS: In total, 36,495 patients underwent CEA for asymptomatic disease performed by vascular (75.7%), general (16.1%), cardiac (6%), and neuro (2.1%) surgeons. Outcomes of interest included in hospital mortality (0.26%), stroke (0.45%), and the composite end point of mortality, stroke, or cardiac complication (2.2%). Unadjusted outcomes improved with increasing surgeon annual CEA volume. Mid-career surgeons had lower mortality and stroke rates than early or late-career surgeons. Odds of mortality were increased when surgery was performed by the lowest volume providers (quintile 1; 0-11 CEA/year) (odds ratio [OR] 2.62, 95% confidence interval [CI] 1.3-5.28) or a nonspecialty trained (general) surgeon (OR 1.64, 95% 1.01-2.67). After adjustment for all patient-level factors, provider volume remained an independent predictor of outcome, with significantly increased odds of mortality for volume quintile 1 (OR 2.57, 95% CI 1.27-5.23) and quintile 2 (12-22 CEA/year) (0.30%; OR 2.07, 95% CI 1-4.27) surgeons. CONCLUSIONS: Adverse events after CEA for asymptomatic disease are comparatively rare. However, surgeon characteristics impact outcome, with the best results offered by high-volume, mid-career, specialty-trained surgeons. Efforts to define the optimal treatment of asymptomatic carotid atherosclerosis must account for the impact of surgeon characteristics on patient outcomes. PMID- 28577791 TI - PlanTEnrichment: A tool for enrichment analysis of transposable elements in plants. AB - Transposable elements (TEs) are mobile DNA sequences that play roles in gene regulation, and have a potential to influence the expression of nearby genes by functioning as cis-regulatory sequences. However, bioinformatics tools facilitating analysis of the associations between TEs and nearby genes in plants are still lacking. We therefore reanalyzed the comprehensive annotation data of gene models and TEs of 11 plant species available in Ensembl Plants database, and built an up-to-date, unique tool called PlanTEnrichment, enabling enrichment analysis of TEs located within the upstream regions of a given gene list. PlanTEnrichment takes, for example, a group of differentially expressed genes under a particular biological condition as input and returns the list of TEs associated with those genes, along with their calculated enrichment scores and statistical significances. PlanTEnrichment is freely available at http://tools.ibg.deu.edu.tr/plantenrichment/ and is likely to substantially enhance our understanding of the role of TEs in diverse biological processes. PMID- 28577792 TI - Genome-wide analysis of gene expression of EMS-induced short fiber mutant Ligon lintless-y (liy) in cotton (Gossypium hirsutum L.). AB - In this work we describe a chemically-induced short fiber mutant cotton line, Ligon-lintless-y (liy), which is controlled by a single recessive locus and affects multiple traits, including height of the plant, and length and maturity of fiber. An RNAseq analysis was used to evaluate global transcriptional changes during cotton fiber development at 3, 8 and 16days post anthesis. We found that 613, 2629 and 3397 genes were significantly down-regulated, while 2700, 477 and 3260 were significantly up-regulated in liy at 3, 8 and 16 DPA. Gene set enrichment analysis revealed that many metabolic pathways, including carbohydrate, cell wall, hormone metabolism and transport were substantially altered in liy developing fibers. We discuss perturbed expression of genes involved in signal transduction and biosynthesis of phytohormones, such as auxin, abscisic acid, gibberellin and ethylene. The results of this study provide new insights into transcriptional regulation of cotton fiber development. PMID- 28577793 TI - If Only the Doctor Will Let Me Go Home: Same Day Discharge after PCI. PMID- 28577794 TI - CRT 2017 late-breaking trials. PMID- 28577795 TI - FDA Town Hall at CRT 2017: Current status and future endeavors in cardiovascular devices. PMID- 28577796 TI - How to Define Atopic Dermatitis? AB - Although atopic dermatitis (AD) is the most common skin disorder, there remains an ongoing debate on this denomination, its definition and the binary view based on immunoglobulin E measurement. The wide spectrum of the clinical phenotype of AD reflects the complex genetic and pathophysiologic mechanisms underlying the disease. The diagnostic criteria have to be reconsidered and adapted to different ethnic populations. There is an urgent need for biomarker discovery further supporting the clinical diagnostic criteria as well as the precision medicine approach on a global level. PMID- 28577797 TI - Public Health Burden and Epidemiology of Atopic Dermatitis. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disorder with significant morbidity and quality-of-life impairment. The epidemiology of AD is complex and challenging to study. The 1-year US prevalence of AD was 12.98% in children in 2007-2008 and 7.2%-10.2% in adults in 2010-2012. There is considerable statewide and countrywide variation of AD prevalence and severity. The prevalence of childhood AD dramatically increased over the past few decades but may be leveling off in developed nations. AD is associated with increased direct and indirect costs to payers and patients, thereby contributing toward a considerable public health burden. PMID- 28577799 TI - Adult-Onset Atopic Dermatitis: Fact or Fancy? AB - Atopic dermatitis therapy can be a challenge in many cases. Persistence into adulthood often reflects the more severe cases and such patients have the added problems of hand eczema and thick nummular lesions that resist topical medications. Within this group are patients labeled as having adult-onset atopic dermatitis, a designation that is hard to define and probably represents those whose childhood eczema was simply forgotten. Management is difficult for most adult cases and should not be diverted by questionable labels. PMID- 28577798 TI - The Long-Term Course of Atopic Dermatitis. AB - Atopic dermatitis (AD) is a chronic, relapsing condition, meaning that the intensity of symptoms usually fluctuates over time. Changes in skin physiology may be evident from birth, suggesting that AD may be a lifelong condition marked by intermittent symptoms/disease activity. Methodological considerations for studying the long-term course of AD are reviewed in detail. Improved measurement of the frequency and duration of active disease periods can help to elucidate more about the clinical course AD and the role of treatment in long-term outcomes. PMID- 28577800 TI - Patient Burden of Atopic Dermatitis. AB - Atopic dermatitis is associated with significant patient burden, with impacts from symptoms and visible physical manifestations of the disease. Consequences include detrimental effects on quality of life (QoL), sleep, self-esteem, interpersonal relationships, participation in leisure and sports, and attendance or performance at school or work. Patients also spend a significant amount of time on treatments and care. Worsening severity of disease appears to be associated with a higher risk of impaired QoL, and pharmacologic and educational interventions that improve disease severity appear to, for the most part, simultaneously improve QoL. PMID- 28577801 TI - An Update on the Pathophysiology of Atopic Dermatitis. AB - Atopic dermatitis (AD) is increasingly recognized as a complex, inflammatory skin disease involving interplay of multiple elements. This article notes key advances in understanding of immune dysregulation, skin barrier dysfunction, environmental, genetic, and microbial influences orchestrating disease pathogenesis, and the relevance of therapeutic interventions in each area. Accumulating evidence and the discovery of new T-cell subsets has matured AD as a multiple-cytokine-axes-driven disorder, evolved from the widely held belief of it being a biphasic Th1/Th2 disease. These new insights have led to active trials testing multiple, targeted therapeutics with better efficacy and safety-profiles. PMID- 28577802 TI - The Role of Interleukins 4 and/or 13 in the Pathophysiology and Treatment of Atopic Dermatitis. AB - Moderate to severe atopic dermatitis (AD) can be debilitating and often requires use of systemic immunosuppressant therapy to achieve adequate disease control. There are currently no US Food and Drug Administration-approved systemic agents for the long-term treatment of AD. Recent insight has identified the T helper 2 cytokines, interleukins 4 and 13, as playing a major role in the pathogenesis of AD. There are multiple novel biologic agents in development that target interleukins 4 and/or 13 for the treatment of moderate to severe AD. The age of targeted biologics for AD has arrived. PMID- 28577803 TI - Long-Term Treatment of Atopic Dermatitis. AB - Many patients with mild to moderate atopic dermatitis (AD) are managed by identifying and avoiding allergens and irritants, ensuring skin moisturization, and graded use of topical corticosteroids and/or calcineurin inhibitors. There is little consensus on the next step. Most systemic therapies are "off label" in the United States and include phototherapy, cyclosporine, mycophenolic acid precursors, azathioprine, and methotrexate. The decision to use these therapies should be based on efficacy and safety readouts from well designed, long-term trials. This article reviews the long-term randomized, controlled trials examining safety and/or efficacy of interventions recommended for patients with mild to severe AD. PMID- 28577804 TI - Special Considerations for Therapy of Pediatric Atopic Dermatitis. AB - Atopic dermatitis is the leading cause of pediatric dermatology visits in developed nations. Recurrent, itchy rashes in typical locations and a family/personal history of atopy helps to identify children with disease. Most cases (85%) are diagnosed by age 5 years. Some comorbidities are age-based and may affect disease course. Topical corticosteroids are the mainstay of therapy; corticosteroidphobia and side effects complicate use. Topical calcineurin inhibitors are alternatives to corticosteroids, especially in sensitive locations. Systemic therapies include antihistamines, immune suppressive agents, and phototherapy, with specific pediatric modifications. This article reviews the nuances and caveats of pediatric atopic dermatitis diagnosis and management. PMID- 28577805 TI - Management of Atopic Hand Dermatitis. AB - This article provides an overview of clinical aspects of hand eczema in patients with atopic dermatitis. Hand eczema can be a part of atopic dermatitis itself or a comorbidity, for example, as irritant or allergic contact dermatitis. When managing hand eczema, it is important to first categorize the subtype and identify potential culprit allergens or irritants. First-line therapy should be a combination of emollients and topical corticosteroids; possible alternatives include topical calcineurin inhibitors or coal tar. Second-line therapy includes UV therapy and systemic therapy, including azathioprine, cyclosporine, methotrexate, and mycophenolate. Prednisolone should only be very infrequently used. PMID- 28577806 TI - Adjunctive Management of Itch in Atopic Dermatitis. AB - Itch, or pruritus, is a hallmark feature of atopic dermatitis (AD). The impact of AD-related pruritus can range from mildly distressing or distracting to completely disabling. Traditionally, management of itch in AD patients has focused on restoring the altered skin barrier with topical emollients and/or reducing inflammation. A growing emphasis has been placed on directly targeting the neural transmission pathways that mediate itch signaling. Off-label use of neuromodulatory agents has helped reduce this aggravating symptom in atopic patients. This article reviews the current literature on the use of neuromodulatory agents and nonpharmacologic alternative therapies used to treat AD-related pruritus. PMID- 28577807 TI - Atopic Dermatitis: Racial and Ethnic Differences. AB - Atopic dermatitis (AD) is a common, chronic inflammatory skin condition affecting up to 20% of children and 3% of adults worldwide. There is wide variation in the prevalence of AD among different countries. Although the frequency of AD is increasing in developing countries, it seems to have stabilized in developed countries, affecting approximately 1 in 5 schoolchildren. Adult-onset AD is not uncommon and is significantly higher, affecting between 11% and 13% of adults in some countries, for example, Singapore, Malaysia, and Sweden. AD is thus associated with significant health care economic burden in all age groups. PMID- 28577809 TI - The Wisdom of a Legend Lives On. PMID- 28577808 TI - Atopic Dermatitis: A Heterogeneous Disorder. PMID- 28577810 TI - Findings From the INANE Survey on Student Papers Submitted to Nursing Journals. AB - Nursing students are often encouraged or required to submit scholarly work for consideration for publication but most manuscripts or course assignment papers do not meet journal standards and consume valuable resources from editors and peer reviewers. The International Academy of Nursing Editors (INANE) is a group of nurse editors and publishers dedicated to promoting best practices in publishing in the nursing literature. In August 2014, editors at INANE's annual meeting voiced frustrations over multiple queries, poorly written student papers, and lack of proper behavior in following through. This article describes the findings of a survey distributed to INANE members to seek feedback about submissions by students. Fifty-three (53) members responded to an online anonymous survey developed by the INANE Student Papers Work Group. Data were analyzed using descriptive statistics for Likert-type questions and content analysis of open ended questions. Quantitative data revealed that most editors reported problems with student papers across all levels of graduate programs. Six themes emerged from the qualitative data: submissions fail to follow author guidelines; characteristics of student submissions; lack of professional behavior from students; lack of professional behavior from faculty; editor responses to student submissions; and faculty as mentors. These themes formed the basis for recommendations and strategies to improve student scholarly writing. Overall, editors endorsed supporting new scholars in the publication process but faculty engagement was integral to student success. PMID- 28577811 TI - Lessons Learned: Answering the Call to Increase the BSN Workforce. AB - Academic institutions across the United States are responding to the national call to action to raise the educational preparation of the nursing workforce. North Carolina has responded with the Regionally Increasing Baccalaureate Nurses program, which provides a seamless, economically sound pathway for attainment of a baccalaureate degree in nursing by using an academic partnership model between community colleges and a collaborating university. This article describes the accomplishments made and the lessons learned over the first 5 years of implementation of this educational pathway. Implications for research and educational practice are discussed. PMID- 28577812 TI - Re-Envisioning a DNP Program for Quality and Sustainability. AB - When the University of Washington, School of Nursing determined that its post-BSN DNP degree program, with multiple specialty tracks and programs of study, was not sustainable, the curriculum was re-envisioned. The revised program is consistent with the American Association of Colleges of Nursing (AACN) Essentials of Doctoral Education for Advanced Nursing Practice and the national Licensure Accreditation, Certification, and Education (LACE) model. The re-envisioned program was conceptualized as a single degree in which students preparing for any specialty would have the same number of required credits with the majority of courses (DNP core) required for all students. Two major pathways, 1) advanced practice registered nursing and 2) advanced systems and population health were identified. The model allows for specialties to be added or discontinued without major disruption to the core curriculum. The consolidated curriculum reduced instructional costs to the school by approximately 26% and reduced and made more equitable the tuition costs for the majority of students. The revised consolidated program is innovative, maintains quality, attracts students, and aligns with resources. This article discusses how we achieved revision and consolidation of a post-BSN DNP program with multiple specialty tracks that is innovative, high quality, sustainable, and replicable by other schools of nursing. PMID- 28577813 TI - A Power Experience: A Phenomenological Study of Interprofessional Education. AB - The purpose of this supplementary analysis of a hermeneutic phenomenological study of the experience of interprofessional collaboration for nursing and medical students was to explore the experience of power that was threaded throughout the original study. Seventeen students participated in guided, face-to face conversations in the original study (Prentice, Engel, Taplay, & Stobbe, 2014). Through the processes of deductive analysis and inductive reasoning, 2 themes of power emerged from these research conversations: (a) complicated knowledge is power and (b) the power and silence of intimidation. These themes suggest that power and power differentials are significant factors in student interactions in interprofessional learning and have the potential to adversely affect these interactions. Students' perceptions of power need to be taken into account and addressed when planning and implementing interprofessional education events. PMID- 28577814 TI - A Scoping Review Examining Nursing Student Peer Mentorship. AB - This paper outlines a scoping review and thematic analysis which was conducted on the topic of nursing student peer mentorship programs. This paper outlines the reasons for conducting a scoping review, includes a description of the scoping review model used for this review, documents the actual scoping review process undertaken, and details the results of the scoping review and thematic analysis on the topic of nursing student peer mentorship. The results of this scoping review and thematic analysis review revealed the following themes related to nursing student peer mentorship: support, dialog, connections, meanings, and a process of socialized learning. Finally, this paper outlines limitations of this scoping review and thematic analysis and offers suggestions for future research. PMID- 28577815 TI - Standardized Testing Practices: Effect on Graduation and NCLEX(r) Pass Rates. AB - The use standardized testing in pre-licensure nursing programs has been accompanied by conflicting reports of effective practices. The purpose of this project was to describe standardized testing practices in one states' nursing programs and discover if the use of a cut score or oversight of remediation had any effect on (a) first time NCLEX(r) pass rates, (b) on-time graduation (OTG) or (c) the combination of (a) and (b). Administrators of 38 nursing programs in one Southwest state were sent surveys; surveys were returned by 34 programs (89%). Survey responses were compared to each program's NCLEX pass rate and on-time graduation rate; t-tests were conducted for significant differences associated with a required minimum score (cut score) and oversight of remediation. There were no significant differences in NCLEX pass or on-time graduation rates related to establishment of a cut score. There was a significant difference when the NCLEX pass rate and on-time graduation rate were combined (Outcome Index "OI") with significantly higher program outcomes (P=.02.) for programs without cut scores. There were no differences associated with faculty oversight of remediation. The results of this study do not support establishment of a cut score when implementing a standardized testing. PMID- 28577816 TI - Academic and Demographic Predictors of NCLEX-RN Pass Rates in First- and Second Degree Accelerated BSN Programs. AB - Relatively few studies have addressed predictors of first-attempt outcomes (pass fail) on the National Council Licensure Examination-Registered Nurses (NCLEX-RN) for accelerated BSN programs. The purpose of this study was to compare potential predictors of NCLEX outcomes in graduates of first-degree accelerated (FDA; n=62) and second-degree accelerated (SDA; n=173) BSN programs sharing a common nursing curriculum. In this retrospective study, bivariate analyses and multiple logistic regression assessed significance of selected demographic and academic characteristics as predictors of NCLEX-RN outcomes. FDA graduates were more likely than SDA graduates to fail the NCLEX-RN (P=.0013). FDA graduates were more likely to speak English as a second or additional language (P<.0001), have lower end-of-program GPA and HESI Exit Exam scores (both P<.0001), and have a higher proportions of grades <= C (P=.0023). All four variables were significant predictors of NCLEX-RN outcomes within both FDA and SDA programs. The only significant predictors in adjusted logistic regression of NCLEX-RN outcome for the pooled FDA+SDA graduate sample were proportion of grades <= C (a predictor of NCLEX-RN failure) and HESI Exit Exam score (a predictor of passing NCLEX-RN). Grades of C or lower on any course may indicate inadequate mastery of critical NCLEX-RN content and increased risk of NCLEX-RN failure. PMID- 28577817 TI - Iranian Nursing Students' Experiences of Case-Based Learning: A Qualitative Study. AB - The purpose of this study was to explore the experiences of undergraduate nursing students of the implementation of case-based learning in an emergency nursing course. The present qualitative study was conducted using the qualitative content analysis method. Participants consisted of 18 third year undergraduate nursing students selected through purposive sampling, which continued until the saturation of the data. Data were collected using semistructured interviews and were analyzed concurrently with their collection through the constant comparison method. The process of data analysis led to the emergence of 4 main themes, including "the continuum of knowledge from production to transfer competence," "a positive atmosphere of interaction," "the process of stress relieving," "the sense of role-playing in professional life," and the emergence of 12 subthemes signifying participants' experiences and perceptions with regard to the implementation of case-based learning (CBL) in teaching the emergency nursing course. The results of the present study showed that CBL is a stressful but pleasant and empowering experience for Iranian nursing students that develops critical thinking and stress management skills, reinforces peers' potentials, improves diagnostic abilities, and helps acquire professional competencies for use in future practices through the creation of a positive environment. PMID- 28577819 TI - Nutritional support for critically ill children: A Cochrane review summary. PMID- 28577818 TI - Iranian Nursing Students' Experience of Stressors in Their First Clinical Experience. AB - The first clinical experience is a turning point in the educational journey of nursing students as it marks the beginning of their professional development. This experience is often stressful for students. This study was conducted mainly to research, describe and interpret nursing students' perceptions of stressors in the clinical environment in their first clinical experience. The present phenomenological study selected seven nursing students through purposive and snow balling sampling and questioned them in semi-structured interviews. The data acquired were analyzed by Colaizzi's method. The following themes emerged in this study: 1- the sense of inadequacy, 2- being ignored, 3- ineffective communication, 4- prevailing sadness and 5- ambiguity. The results of the present study showed that nursing students experience several sources of stress in their first clinical experiences. Hence nursing administrators should diligently evaluate and rectify nursing students' clinical stressors. PMID- 28577820 TI - Cognitive rehabilitation for memory deficits after stroke: A Cochrane review summary. PMID- 28577821 TI - Vitamin D for the management of asthma: A Cochrane Review Summary. PMID- 28577823 TI - The effectiveness of Penumbra 400 micro-coils in the embolization of large cerebral aneurysms. AB - BACKGROUND: The objective of this work is to analyze the effectiveness of Penumbra 400 micro-coils in the embolization of large cerebral aneurysms. MATERIAL AND METHODS: A retrospective analysis has been conducted in a group of 32 patients at the average age of 54.5 years (30-84) for whose embolization the P400 micro-coils (P400) have been used. A control group consisted of 44 patients at the average age of 52.7 years (24-82) in whose aneurysm embolization the 18 micro-coils (MC) have been utilized. RESULTS: The respective percentages of micro coil packing density in aneurysm sacs were 31.5% for P400 and 29% for MC. The average P400 fluoroscopy time was 21min, and 34min in case of MC. The average number of used micro-coils was 3.9 for P400 and 5.6 for MC. The radiation dose received by a patient was 1.7Gy/2.2Gy, respectively. The recanalization of P400 has occurred in 14/31 cases (45%), and for MC it has occurred in 23/44 (52%) patients. One patient died due to early recanalization after P400 aneurysm embolization. CONCLUSION: Procedures with use of the P400 demonstrate minimally higher effectiveness of large aneurysms embolization in comparison with the MS with a not much shorter duration and reduction of a radiation dose that a patient receives. PMID- 28577824 TI - [False positive results or what's the probability that a significant P-value indicates a true effect?] AB - The use of statistical test is central in the clinical trial. At the statistical level, obtaining a P<0.05 allows to claim the effectiveness of the new studied treatment. However, given its underlying mathematical logic the concept of "P value" is often misinterpreted. It is often assimilated, mistakenly, to the likelihood that treatment is ineffective. Actually the "P value" gives an indirect information about the plausibility of the existence of treatment effect. With "P<0.05", the probability that the treatment is effective may vary depending on other statistical parameters which are the alpha level of risk, the power of the study and especially the a priori probability of the existence of treatment effect. A "P<0.05" does not always produce the same degree of certainty. Thus there exist situations where the risk of a result "P<0.05" is in reality a false positive is very high. This is the case if the power is low, if there is an inflation of the alpha risk or if the result is exploratory or chance discoveries. This possibility is important to take into consideration when interpreting the results of clinical trials in order to avoid pushing ahead significant results in appearance, but which are likely to be actually false positive results. PMID- 28577825 TI - Introduction. PMID- 28577826 TI - Safety Considerations in Stereotactic Body Radiation Therapy. AB - Although many error pathways are common to both stereotactic body radiation therapy (SBRT) and conventional radiation therapy, SBRT presents a special set of challenges including short treatment courses and high-doses, an enhanced reliance on imaging, technical challenges associated with commissioning, special resource requirements for staff and training, and workflow differences. Emerging data also suggest that errors occur at a higher rate in SBRT treatments. Furthermore, when errors do occur they often have a greater effect on SBRT treatments. Given these challenges, it is important to understand and employ systematic approaches to ensure the quality and safety of SBRT treatment. Here, we outline the pathways by which error can occur in SBRT, illustrated through a series of case studies, and highlight 9 specific well-established tools to either reduce error or minimize its effect to the patient or both. PMID- 28577822 TI - Genome-wide association study of language performance in Alzheimer's disease. AB - Language impairment is common in prodromal stages of Alzheimer's disease (AD) and progresses over time. However, the genetic architecture underlying language performance is poorly understood. To identify novel genetic variants associated with language performance, we analyzed brain MRI and performed a genome-wide association study (GWAS) using a composite measure of language performance from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=1560). The language composite score was associated with brain atrophy on MRI in language and semantic areas. GWAS identified GLI3 (GLI family zinc finger 3) as significantly associated with language performance (p<5*10-8). Enrichment of GWAS association was identified in pathways related to nervous system development and glutamate receptor function and trafficking. Our results, which warrant further investigation in independent and larger cohorts, implicate GLI3, a developmental transcription factor involved in patterning brain structures, as a putative gene associated with language dysfunction in AD. PMID- 28577827 TI - Normal Tissue Constraints for Abdominal and Thoracic Stereotactic Body Radiotherapy. AB - Although stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy has become an established standard of care for the treatment of a variety of malignancies, our understanding of normal tissue dose tolerance with extreme hypofractionation remains immature. Since Timmerman initially proposed normal tissue dose constraints for SBRT in the 2008 issue of Seminars of Radiation Oncology, experience with SBRT has grown, and more long-term clinical outcome data have been reported. This article reviews the modern toxicity literature and provides updated clinically practical and useful recommendations of SBRT dose constraints for extracranial sites. We focus on the major organs of the thoracic and upper abdomen, specifically the liver and the lung. PMID- 28577828 TI - Stereotactic Body Radiotherapy in the Treatment of Spinal Metastases. AB - Patients with metastatic disease including polymetastatic, oligometastatic, and oligorecurrent spinal lesions have extended life expectancy secondary to improvements in systemic agents, and thus require durable local control of spine metastases. Stereotactic body radiotherapy (SBRT), which uses highly conformal treatment planning techniques coupled with image-guided technology, has enabled the safe delivery of tumor-ablative doses of radiotherapy. The NOMS decision framework has been developed as a tool to aid in the determination of the optimal treatment of spinal metastases, incorporating radiosurgery, separation surgery, stabilization techniques, and conventional radiation. Tumor radiosensitivity is critical in determining appropriateness of radiosurgery. In general, higher radiation doses provide significant, more durable tumor control, whether single fraction or hypofractionated regimens are used. Spine SBRT can provide a high likelihood of durable tumor control with very low rates of serious toxicity, and careful attention should be given to dose constraints of organs at risk. Here, we review the indications for spine SBRT via the NOMS decision framework and provide practical information to the radiation oncologist regarding spine radiosurgery. PMID- 28577829 TI - Stereotactic Ablative Radiotherapy for Early-Stage Lung Cancer. AB - The rising incidence of early-stage lung cancer, particularly in medically inoperable patients, is anticipated because of the implementation of early detection strategies and population aging in the United States and worldwide. This mandates the development of noninvasive curative treatment approaches for this disease. Stereotactic ablative radiotherapy (SABR) has recently emerged as a standard of care for early-stage lung cancer in medically inoperable patients who cannot safely tolerate surgical lobectomy, the established standard for operable patients. Further experience has demonstrated key principles with this highly conformal and dose-intensive radiation technique, including the need for sufficiently high biologically effective dose to achieve optimal local control, dose-fractionation modifications needed to treat centrally located tumors safely, and individualization of treatment based on tumor size, location, and other factors. SABR requires particular technical expertise including a nuanced understanding of dose prescription and calculation and appropriate management of tumor and organ motion. Progress continues as increasing experience with and data on SABR in selected cohorts of medically operable patients suggest comparable oncologic outcomes and a more favorable toxicity profile that challenges the historical standard of care for broader patient populations. PMID- 28577830 TI - Stereotactic Ablative Body Radiotherapy for Lung Metastases: Where is the Evidence and What are We Doing With It? AB - This review provides an overview of the use of stereotactic ablative body radiotherapy (SABR) for pulmonary metastases. The local control rates after SABR are generally >90%. Whether this also translates into a significant improvement in overall survival is the subject of ongoing studies. New exciting opportunities including the integration of SABR with targeted and immune therapies as well as some competing treatment strategies are discussed. PMID- 28577831 TI - Stereotactic Body Radiotherapy for Liver Metastases. AB - Many cancers can spread to the liver, often as the sole site of metastatic disease. For properly selected patients with limited hepatic disease and good performance status, an aggressive strategy involving radical local therapy to the site(s) of metastasis offers a chance for extended disease-free survivorship. The development of stereotactic body radiotherapy has inserted radiation therapy into the arsenal of valuable treatment options in this clinical setting. This article summarizes the latest advancements in the use of stereotactic body radiotherapy to treat liver metastases. PMID- 28577832 TI - Advances in Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma. AB - Stereotactic Body Radiation Therapy (SBRT) is an emerging effective treatment for hepatocellular carcinoma (HCC) associated with acceptable rates of toxicity in appropriately selected patients. Despite often being reserved for patients unsuitable for other local treatments, prospective and retrospective studies have demonstrated excellent long-term control. SBRT may be used as a stand-alone treatment, or as an adjunct to other HCC therapies. Based on available data, SBRT appears to complement existing local liver therapies. Randomized and nonrandomized comparative studies are required to better determine the optimal role of SBRT in HCC treatment. PMID- 28577833 TI - Integration of Stereotactic Body Radiation Therapy into the Multidisciplinary Management of Pancreatic Cancer. AB - Although most patients with pancreatic cancer die of metastatic disease, an autopsy study showed that up to one-third of patients die of predominantly local disease. This patient population stands to benefit the most from radiation, surgery, or both. Unfortunately, however, single-agent chemotherapy has had minimal benefit in pancreatic cancer, and most patients progress distantly before receiving radiation therapy (RT). With the addition of multiagent chemotherapy, patients are living longer, and RT has emerged as an important modality in preventing local progression. Standard chemoradiation delivered over 5-6 weeks has been shown to improve local control, but this approach delays full-dose systemic therapy and increases toxicity when compared to chemotherapy alone. Stereotactic body RT (SBRT) delivered in 3-5 fractions can be used to accurately target the pancreatic tumor with small margins and limited acute treatment related toxicity. Given the favorable toxicity profile, SBRT can easily be integrated with other therapies in all stages of pancreatic cancer. However, future studies are necessary to determine optimal dose or fractionation regimens and sequencing with targeted therapies and immunotherapy. The purpose of this review is to discuss our current understanding of SBRT in the multidisciplinary management of patients with pancreatic cancer and future implications. PMID- 28577834 TI - Stereotactic Body Radiotherapy for Low- and Intermediate-Risk Prostate Cancer. AB - With over a decade's worth of clinical experience to guide stereotactic body radiotherapy (SBRT) for the treatment of clinically localized prostate cancer (PCa), sufficient data exist for robust conclusions to be made regarding its efficacy and the toxicities associated with this treatment. We briefly review the fundamental radiobiological basis of SBRT for PCa and provide a comprehensive synthesis of the medical literature to date, focusing on clinical outcomes and toxicities. When possible, we draw comparisons to comparable data for conventionally fractionated radiotherapy. Finally, a brief overview of technical considerations is presented. Although randomized clinical trials comparing SBRT with conventionally fractionated radiotherapy are underway, the current body of evidence supports the efficacy and safety of SBRT for PCa. PMID- 28577835 TI - New Techniques for Irradiating Early Stage Breast Cancer: Stereotactic Partial Breast Irradiation. AB - Several improvements in breast cancer radiation delivery have been realized using new techniques over the past several decades. As an example, for early stage disease, there has been active investigation of partial breast irradiation (PBI) vs whole breast irradiation. Although still investigational, PBI reduces the treatment volumes, doses to organs at risk, and may improve cosmesis. Over the past 2 decades PBI has been delivered via interstitial brachytherapy, intracavitary brachytherapy, intraoperative radiation therapy, or 3-dimensional external beam radiation therapy. More recently, there has been growing evidence that supports stereotactic body radiation therapy as a safe and effective new treatment for early stage breast cancer. This article describes this new treatment opportunity and reviews the emerging data of stereotactic partial breast irradiation. PMID- 28577836 TI - Radiation and Immune Checkpoint Blockade: From Bench to Clinic. AB - Immune escape of malignant cells is an important hallmark of cancer, necessary for tumor formation and progression. Accordingly, in recent years, therapies that enhance the immune system have had remarkable success in treating a myriad of malignancies. Particularly successful has been immune checkpoint blockade (ICB), which is a therapy that targets T-cell inhibitory receptors, or immune checkpoints. Despite these encouraging clinical results, most patients do not respond to such agents. Therefore, determining methods to better target and enhance the therapeutic efficacy of ICB is of paramount importance. One appealing approach is to use standard anticancer therapies, such as radiation, chemotherapy, and targeted biologics, to favorably modulate the immune system and enhance the anticancer immune response. For example, although radiation therapy has classically been thought of as a local therapy, there is significant potential for combining radiation therapy with ICB to both optimize local control and to treat metastatic disease. This concept is supported by numerous preclinical studies and clinical case reports and has since led to many early and ongoing clinical trials. However, it is still unclear how to optimally combine radiation and ICB to maximize the therapeutic effect. In this review, we highlight relevant preclinical and clinical studies in the field of radiation and ICB and discuss optimal strategies for combination therapies moving forward. PMID- 28577837 TI - MiR-375 delivered by lipid-coated doxorubicin-calcium carbonate nanoparticles overcomes chemoresistance in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a prevalent and lethal disease that is characterized by drug resistance. Doxorubicin (DOX) is a widely used chemotherapeutic drug and miR-375 has been shown to be a tumor suppressor in HCC. Here, we reported that miR-375 and DOX co-loaded into lipid-coated calcium carbonate nanoparticles (LCC-DOX/miR-375 NPs), enhanced the anti-tumor effects through combination therapy, and were highly effective in reversing drug resistance in HCC. LCC-DOX/miR-375 NPs were prepared by a reverse microemulsions method. In vitro, LCC-DOX/miR-375 NPs exhibited enhanced intracellular accumulation, pH-sensitive DOX release and potent cytotoxicity. In vivo, LCC DOX/miR-375 NPs showed efficient antitumor effect both in xenograft and primary HCC murine models. Our results showed that the LCC-DOX/miR-375 nanoparticles provide a novel strategy to overcome the drug resistance and promote addictive effect between miR-375 and DOX in HCC. PMID- 28577838 TI - Reply to the Editor - High-Degree Atrioventricular Block in a 77-Year-Old Man. PMID- 28577839 TI - Letter to the Editor- High-degree atrioventricular block in a 77-year-old man. PMID- 28577840 TI - Efficacy and safety of left atrial appendage closure with WATCHMAN in patients with or without contraindication to oral anticoagulation: 1-Year follow-up outcome data of the EWOLUTION trial. AB - BACKGROUND: Left atrial appendage (LAA) occlusion with WATCHMAN has emerged as viable alternative to vitamin K antagonists in randomized controlled trials. OBJECTIVE: EWOLUTION was designed to provide data in routine practice from a prospective multicenter registry. METHODS: A total of 1025 patients scheduled for a WATCHMAN implant were prospectively and sequentially enrolled at 47 centers. Indication for LAA closure was based on European Society of Cardiology guidelines. Follow-up and transesophageal echocardiography (TEE) were performed per local practice. RESULTS: The baseline CHA2DS2-VASc score was 4.5 +/- 1.6; the mean age was 73.4 +/- 9 years; previous transient ischemic attack/ischemic stroke was present in 312 (30.5%), 155 (15.1%) had previous hemorrhagic stroke, and 320 (31.3%) had a history of major bleeding; and 750 (73%) were deemed unsuitable for oral anticoagulation therapy. WATCHMAN implant succeeded in 1005 (98.5%) of patients, without leaks >5 mm in 1002 (99.7%) with at least 1 TEE follow-up in 875 patients (87%). Antiplatelet therapy was used in 784 (83%), while vitamin K antagonists were used in only 75 (8%). At 1 year, mortality was 98 (9.8%), reflecting the advanced age and comorbidities in this population. Device thrombus was observed in 28 patients at routine TEE (3.7%) and was not correlated with the drug regimen (P = .14). Ischemic stroke rate was 1.1% (relative risk 84% vs estimated historical data); the major bleeding rate was 2.6% and was predominantly (2.3%) nonprocedure/device related. CONCLUSION: LAA closure with the WATCHMAN device has a high implant and sealing success. This method of stroke risk reduction appears to be safe and effective with an ischemic stroke rate as low as 1.1%, even though 73% of patients had a contraindication to and were not using oral anticoagulation. PMID- 28577841 TI - Aortic Atheroma Increases the Risk of Long-Term Mortality in 20,000 Patients. AB - BACKGROUND: The association between long-term survival and aortic atheroma in cardiac surgical patients has not been comprehensively investigated. In this study we determine the relation between grade of atheroma and the risk of long term mortality in a retrospective cohort of more than 20,000 patients undergoing cardiac operation during a 20-year period. METHODS: We included 22,304 consecutive intraoperative transesophageal and epiaortic ultrasound examinations performed at Brigham and Women's Hospital between 1995 and 2014, with long-term follow-up. The extent of atheromatous disease recorded in each examination was used for analysis. Mortality data were obtained from our institution's data registry. Mortality analyses were done using Cox proportional hazard regression models with follow-up as a time scale. We repeated the analysis in a subgroup of 14,728 patients with more detailed demographic characteristics, including postoperative stroke, queried from the institutional Society of Thoracic Surgeons database. RESULTS: A total of 7,722 mortality events and 872 stroke events occurred. Patients with atheromatous disease demonstrated a significant increase in mortality across all grades of severity, both for the ascending and descending aorta. This relation remained unchanged after adjusting for additional covariates. Adjustments for postoperative stroke resulted in only minimal attenuation in the risk of postoperative mortality related to aortic atheroma. CONCLUSIONS: Aortic atheromatous disease of any grade in the ascending and descending aorta is a significant long-term risk of long-term, all-cause mortality in cardiac operation patients. This association remains independent of other conventional risk factors and is not related to postoperative cerebrovascular accidents. PMID- 28577842 TI - A Nationwide Rise in the Use of Stents for Benign Esophageal Perforation. AB - BACKGROUND: Surgical repair or drainage is the standard treatment for benign esophageal perforation. The United States Food and Drug Administration has approved the use of esophageal stents for the management of malignant esophageal stricture or fistula, or both. We hypothesize that increasing enthusiasm and experience with esophageal stents has led to greater use of stents for the management of benign esophageal perforation. METHODS: We performed a retrospective cohort study (2007 to 2014) of patients with benign esophageal perforation using MarketScan (Thomson Reuters, New York, NY), a commercial claims database. Patients had 6 months of follow-up. Regression was used for risk adjustment. RESULTS: Benign esophageal perforation was treated in 659 patients (mean age, 49 years; 41% women), comprising surgical repair in 449 (69%), surgical drainage in 110 (17%), and stent in 100 (15%). Stent use increased from 7% in 2007 to 30% in 2014 (p < 0.001 for trend). Over the same period, surgical repair decreased from 71% to 53% (p = 0.001 for trend), but surgical drainage did not change (p = 0.24). After adjustment for other factors that could vary over time, stent use increased by 28% per year (incidence rate ratio, 1.28; 95% confidence interval, 1.17 to 1.39). Changes in risk-adjusted deaths, discharges home, readmissions, or costs over the same period were not significant (all p > 0.05 for trend). CONCLUSIONS: The use of stents for the management of benign esophageal perforation has increased by over fourfold in just 8 years, but short term outcomes have not changed over time for this population of patients. A national registry for off-label use of esophageal stents may clarify the indications for and risks and benefits of stenting benign esophageal perforations. PMID- 28577843 TI - Glutaraldehyde Treatment of Allografts and Aortic Outcomes Post-Norwood: Challenging Surgical Decision. AB - BACKGROUND: Glutaraldehyde (GA) treatment of allografts used for arch reconstruction prevents the immunologic sensitization that occurs with untreated allografts, but its use may cause tissue changes that predispose to recurrent obstruction. The objective was to determine whether GA treatment of allografts used in Norwood procedures increases the risk of recurrent aortic obstruction. METHODS: All infants who underwent a Norwood procedure between 2000 and 2015 were included. Cryopreserved pulmonary allografts were used for all arch reconstructions; starting in 2005 all were treated with GA before use. Complete follow-up was obtained, including survival, transplantation, and all repeat procedures. Competing risks analyses were used to assess for differences in aortic reintervention over time. RESULTS: Two hundred six infants (132 male) were included. There were 60 deaths and 14 transplantations; 5-year transplantation free survival was 71.9%. GA treatment of patches (n = 142, 68.9%) was not predictive of death (hazard ratio [HR] 1.38, 95% confidence interval [CI]: 0.61 to 3.08). Fifty-five patients had at least one aortic reintervention and 31 patients (15.0%) required surgical aortic reintervention. At 1-year, freedom from all aortic reintervention was similar between patients with and without treated patches, but freedom from surgical aortic reintervention was lower in the treated group (87.6% versus 95.3%, p = 0.0256). GA treatment was not associated with the combined end point of catheter-based or surgical reintervention but was associated with specific need for surgical reintervention (HR 4.05, 95% CI: 1.19 to 13.77). CONCLUSIONS: GA treatment is associated with increased late surgical aortic reintervention. The advantages of decreased sensitization with GA treatment need to be balanced against the risk of aortic reobstruction. PMID- 28577844 TI - Preoperative Staphylococcus Aureus Screening and Targeted Decolonization in Cardiac Surgery. AB - BACKGROUND: We assessed the impact of preoperative Staphylococcus aureus screening and targeted decolonization on the incidence of postoperative methicillin-resistant S aureus (MRSA) colonization, intensive care unit MRSA transmission, and surgical site infections in cardiac surgery patients. METHODS: We reviewed medical records for all adult patients during two periods: preintervention (January 2007 to April 2010) and intervention (January 2011 to December 2014). In the intervention period, we performed nasal screening for methicillin-sensitive S aureus and MRSA using polymerase chain reaction within 30 days of the operation. Colonized patients received intranasal mupirocin twice daily and chlorhexidine baths daily for 5 days; patients colonized with MRSA also received prophylactic vancomycin plus cefazolin with contact isolation precautions. Nasal surveillance for MRSA was performed on intensive care unit admission and weekly thereafter. Multivariable logistic regression models were constructed to determine risk factors for postoperative MRSA colonization, and surgical site infections and the impact of our screening program was assessed in these models. Poisson regression was used to assess MRSA transmission. RESULTS: Comparing 2,826 preintervention and 4,038 intervention patients, cases differed in age, diabetes mellitus, preoperative infection, preoperative length of stay, and bypass time (all p <= 0.03). Intervention patients had risk-adjusted reductions in MRSA colonization (odds ratio 0.53, 95% confidence interval [CI]: 0.37 to 0.76, p < 0.001), transmission (incidence rate ratio 0.29, 95% CI: 0.13 to 0.65, p = 0.002), and surgical site infections (odds ratio 0.58, 95% CI: 0.40 to 0.86, p = 0.007). Increased duration of preoperative decolonization therapy was associated with decreased postoperative MRSA colonization (odds ratio 0.73, 95% CI: 0.53 to 1.00, p = 0.05). CONCLUSIONS: Preoperative S aureus screening with targeted decolonization was associated with reduced MRSA colonization, transmission, and surgical site infections. Duration of preoperative therapy correlated with decreased frequency of postoperative MRSA colonization. PMID- 28577845 TI - Ninety-Day Mortality After Video-Assisted Thoracoscopic Lobectomy: Incidence and Risk Factors. AB - BACKGROUND: We evaluated the incidence and risk factors of 90-day mortality rate after video-assisted thoracoscopic (VATS) lobectomy. METHODS: Retrospective analysis on 733 VATS lobectomies or segmentectomies (January 2012 to February 2016), including 66 operations converted to open operation. Several patient related and surgical variables were tested to verify their association with 90 day mortality using univariable and logistic regression analyses. A score was assigned to each variable in the final model by proportionally weighting the regression odds ratios (ORs) and assigning 1 point to the smallest one. A total score was generated for each patient by adding the individual points. The patients were finally grouped into classes of risk. RESULTS: In-hospital/30-day mortality rate was 1.9% (14 patients). Additionally, 4 patients died after discharge between 30 and 90 days. Total 90-day mortality rate was 2.5% (18 patients). Regression analysis showed that factors significantly associated with 90-day mortality were male sex (OR 12, p = 0.001), carbon monoxide lung diffusion capacity (Dlco) less than 60% (OR 4.8, p =0.001), and operative time longer than 150 minutes (OR 4.2, p = 0.03). A score was developed assigning 1 point to the variables Dlco and operative time and 3 points to the variable male sex. The total score ranged from 0 (155 patients) to 5 points (32 patients). Patients were grouped into five risk classes showing an incremental 90-day mortality rate (class A, 0; class B, 0.38%; class C, 0.93%; class D, 5.65%; class E, 18.75%, p < 0.0001). CONCLUSIONS: Our results represent important information to be shared with the patients during surgical counseling. It can also assist multidisciplinary tumor board discussion about treatment selection. PMID- 28577846 TI - Surgical Outcome and Prognostic Stratification for Pulmonary Metastasis From Colorectal Cancer. AB - BACKGROUND: This study investigated recent clinical outcomes and prognostic factors of metastasectomy for pulmonary metastasis (PM) from colorectal cancer. METHODS: Data for 785 patients with PM from colorectal cancer who underwent curative resection, including 376 patients treated with postmetastasectomy adjuvant chemotherapy, between 2004 and 2008, were collected from 46 Japanese hospitals. Disease-free and overall survival was analyzed. Potential prognostic factors were assessed. RESULTS: The 5-year disease-free and overall survival rates (95% confidence interval) of all patients were 37.1% (33.7% to 40.9%) and 68.1% (64.6% to 71.8%), respectively, over a median follow-up of 65 months. On multivariable analysis, no survival benefit for postmetastasectomy adjuvant chemotherapy was observed (hazard ratio, 0.85; 95% confidence interval, 0.65 to 1.12; p = 0.25), and the independent poor prognostic factors for overall survival (hazard ratio, 95% confidence interval) were age 70 years and older (1.50, 1.15 to 1.97), disease-free interval of less than 2 years (1.76, 1.31 to 2.35), extrathoracic metastatic lesion treated curatively before PM resection (1.35, 1.01 to 1.79), abnormal carcinoembryonic antigen level (1.99, 1.53 to 2.58), and three or more PMs (1.72, 1.20 to 2.45). The 5-year overall survival rates (95% confidence interval) of the low-risk (no prognostic factor, n = 87), moderate risk (1 to 2 factors, n = 539), and high-risk (>=3 factors, n = 159) groups were 89.4% (82.2% to 98.2%), 72.5% (68.3% to 76.8%), and 48.9% (41.7% to 57.3%), respectively. CONCLUSIONS: Metastasectomy of PM from colorectal cancer was associated with a favorable prognosis. Patients could be classified into three risk groups using five prognostic factors. This grouping may be useful for identifying an optimal treatment strategy according to risk in future studies. PMID- 28577847 TI - Short-Term and Midterm Follow-Up of Transthoracic Device Closure of Atrial Septal Defect in Infants. AB - BACKGROUND: The purpose of this study was to outline the safety and feasibility of transthoracic device closure of an atrial septal defect (ASD) with a domestic occluder in infants. METHODS: Sixty-eight infants underwent transthoracic device closure of an ASD at Union Hospital, Fujian Medical University, Fuzhou, China from January 2010 to January 2015. All relevant clinical data were recorded and analyzed. All patients were invited to undergo contrast transthoracic echocardiography for 12 to 60 months after ASD closure, and telephone interviews were conducted with the infants' parents to evaluate the patients' clinical status further. RESULTS: All patients had successful ASD occlusion using this approach. The most frequent complication was transient cardiac arrhythmia, which was easily treated or automatically recovered during the perioperative period. During the follow-up period, no recurrence, thrombosis, device embolization, valve damage, device failure, or death was reported. The total occlusion rate was 100% in the 12 months of follow-up, and all patients showed significant improvement in their clinical status. From transthoracic echocardiographic data, intracardiac structure and cardiac function were significantly improved at follow up. CONCLUSIONS: Transthoracic device closure of an ASD with a domestic occluder in infants is a safe and feasible technique. The short- and medium-term follow-up results were satisfactory, but long-term follow-up is required to assess the safety and feasibility of this method in infants more accurately. PMID- 28577848 TI - Does Surgical Ablation Energy Source Affect Long-Term Success of the Concomitant Cox Maze Procedure? AB - BACKGROUND: The Cox maze (CM) procedure is routinely performed using surgical ablation technology. Reports are scarce on long-term outcomes of CM, especially for a large series of patients. This study examined the potential impact of surgical ablation energy source on safety and long-term efficacy of concomitant CM procedures. METHODS: The study sample consisted of 709 concomitant CM-treated patients operated on with cryothermal energy only (group 1; n = 386) or combination of cryothermal and bipolar radiofrequency (group 2; n = 323). Data were collected prospectively on perioperative outcomes, rhythm status, survival, and clinical events. Propensity score matching conducted by energy source resulted in 298 patients per group. RESULTS: Perioperative outcomes included stroke (n = 4), reoperation for bleeding (n = 23), renal failure requiring temporary dialysis (n = 18), readmissions before 30 days (n = 86), and operative death before 30 days (n = 16; ratio of observed to expected mortality [O/E ratio], 0.50). Independent predictors for 1-year and 5-year rhythm success were a shorter history of atrial fibrillation (1-year odds ratio [OR], 0.93, p = 0.001; 5-year OR, 0.93, p = 0.042) and cryothermia alone (1-year OR=1.77, p = 0.020; 5 year OR = 2.29, p = 0.009). After matching, group 1 had significantly higher sinus rhythm without antiarrhythmic drugs at 6 months (79% vs 70%; p = 0.016), 36 months (81% vs 69%; p = 0.010), and 60 months (75% vs 57%; p = 0.008). Stroke incidence was lower for group 1 (0.7% vs 3%; p = 0.033), with no difference in major bleeding (10% vs 11%; p = 0.597). Groups had similar survival rates (log rank, 0.6; p = 0.452). CONCLUSIONS: Concomitant CM procedures performed with cryothermal energy alone or combined with bipolar radiofrequency ablation are safe and exceedingly effective. The association of cryothermal energy alone with higher rates of sinus rhythm and stroke reduction should be investigated further. PMID- 28577849 TI - The Society of Thoracic Surgeons Adult Cardiac Surgery Database: 2017 Update on Research. AB - Containing more than 6 million cumulative operative records and accounting for 90% to 95% of adult cardiac surgery performed in the United States, The Society of Thoracic Surgeons Adult Cardiac Surgery Database is an invaluable resource for performance assessment, quality improvement, and clinical research. This article reviews the seven major research efforts published in 2016 that utilized the Adult Cardiac Surgery Database. Two studies evaluated national trends in clinical practice, three assessed the effect of several risk factors on postoperative morbidity and mortality, and two developed new models to evaluate quality of care. The findings of these studies have enhanced clinical practice and delineated areas for future quality improvement research. PMID- 28577850 TI - Chronic Myocardial Ischemia Leads to Loss of Maximal Oxygen Consumption and Complex I Dysfunction. AB - BACKGROUND: Cardiomyocytes rely heavily on mitochondrial energy production through oxidative phosphorylation. Chronic myocardial ischemia may cause mitochondrial dysfunction and affect ATP formation. Metabolic changes due to ischemia alters cardiac bioenergetics and hence myocardial function and overall bioenergetic state. Here, we evaluate differences in functional status of respiratory complexes in mitochondrial isolates extracted from left atrial appendage tissue (LAA) from patients undergoing cardiac surgery, with and without chronic ischemia. METHODS: Mitochondrial isolates were extracted from LAA in ischemic coronary artery bypass grafting patients (n = 8) and non-ischemic control patients (n = 6) undergoing other cardiac surgery (valve repair/replacement). Coupling and electron transport chain assays were performed using Seahorse XFe 96 (Agilent Technologies, Santa Clara, CA) analyzer. Oxygen consumption rates were measured to calculate respiration states. RESULTS: Respiratory control rate (RCR) in ischemic patients was significantly lower than control patients (6.17 +/- 0.27 vs 7.11 +/- 0.31, respectively; p < 0.05). This is the result of minimal, non-significant state 3ADP and state 4O changes in chronic ischemia. Complex I respiration is diminished in ischemic tissue (99.1 +/ 14.9 vs 257.8 +/- 65.2 in control; p < 0.01). Maximal complex I/II respiration ratio was significantly lower in ischemic patients (58.9% +/- 5.5% vs 90.9% +/- 8.8%; p < 0.05), a difference that was also seen in complex I/IV ratios (p < 0.05). There was no significant difference in complex II/IV ratios between groups. CONCLUSIONS: Ischemic patients have aberrant mitochondrial function, highlighted by a lowered RCR. All ratios involving complex I were affected, suggesting that the insufficient ATP formation is predominantly due to complex I dysfunction. Complex II and IV respiration may be impaired as well, but to a lesser extent. PMID- 28577851 TI - Impact of Liver Indicators on Clinical Outcome in Patients Undergoing Transcatheter Aortic Valve Implantation. AB - BACKGROUND: Liver dysfunction increases death and morbidity after cardiac operations. There are currently no data evaluating liver function in patients undergoing transcatheter aortic valve replacement (TAVR). We aimed therefore to evaluate our TAVR results in regard to liver function. METHODS: A total of 640 consecutive TAVR patients were evaluated. Of those, 11 patients presented with chronic liver disease before TAVR. The Model for End-Stage Liver Disease score was used to measure liver function in these patients. The primary study end point was 30-day mortality in patients presenting with liver dysfunction. Secondary study end point was liver enzymes after TAVR. RESULTS: The mean Model for End Stage Liver Disease score in patients with chronic liver disease was 16.8 +/- 6.2 (median, 18; range, 7 to 26). The 30-day mortality was 9.1% (57 of 629) in patients presenting without liver disease and 9.1% (1 of 11) in patients with liver disease (p = 1.00). Patients with chronic liver disease showed significantly higher preoperative levels of gamma-glutamyl transpeptidase (p < 0.001). After TAVR, we observed a significant increase in alanine aminotransferase on postoperative day 3 compared with preoperative values (p < 0.001), accompanied by a decrease in albumin (p < 0.001). CONCLUSIONS: Liver cirrhosis per se is not considered as a contraindication for cardiac operations. In the present study, we did not observe a higher 30-day mortality rate in liver cirrhotic patients undergoing TAVR, suggesting TAVR as a feasible alternative with acceptable outcomes in patients with chronic liver disease. Moreover, the present study is the first to evaluate liver variables in patients undergoing TAVR. PMID- 28577852 TI - Fascia Temporalis Free Flap for Cricotracheal Reconstruction: A Novel Approach. AB - BACKGROUND: The aim of tracheal reconstruction is to provide an airtight and noncollapsible airway covered with a suitable epithelial lining. To date, no ideal treatment is available for large tracheal defects. METHODS: We report 4 patients who underwent one-stage reconstruction for a cricotracheal stenosis with a free temporoparietal fascia flap and costal cartilage grafts. RESULTS: Closure of tracheostoma was achieved for all patients. The main advantage of this flap compared with the free radial forearm flap is that it supplies a more suitable lining allowing the reepithelialization process with respiratory epithelium. CONCLUSIONS: This one-stage procedure provides a reliable construct to substitute for large tracheal defects, even in areas previously exposed to an operation or radiotherapy. PMID- 28577854 TI - Diabetes with early kidney involvement may shorten life expectancy by 16 years. AB - This study aimed to identify the excess risks associated with diabetic patients with early kidney involvement (early diabetic kidney disease). The mortality risks of early diabetic kidney disease, defined as diabetes in early stages 1-3 chronic kidney disease (CKD), were assessed from a cohort of 512,700 adults in Taiwan participating in a health surveillance program from 1994-2008. Three related groups were identified and compared: diabetes without CKD, early diabetic kidney disease, and early CKD without diabetes. Deaths were ascertained through the National Death Registry. One-third of diabetics had early kidney disease, and approximately two-thirds of patients were classified with early CKD due to proteinuria. Patients with early diabetic kidney disease had more lifestyle risks such as inactivity or obesity, which characteristically amplified excess mortality by up to five times. The three-fold increase in all-cause mortality (hazard ratio 3.16) and a 16-year loss in life expectancy made early diabetic kidney disease a serious and yet often overlooked disease, with most patients unaware of their kidney involvement. Mortality for early diabetic kidney disease was nearly twice as high as that for early CKD (hazard ratio 2.01) or diabetes without CKD (hazard ratio 1.79). The 16-year life span loss is much worse than individually from early CKD (six years) or diabetes (ten years). Thus, identifying early proteinuria among diabetic patients and realizing the importance of reducing lifestyle risks like inactivity is a clinical challenge, but can save lives. PMID- 28577853 TI - Loss of transcriptional activation of the potassium channel Kir5.1 by HNF1beta drives autosomal dominant tubulointerstitial kidney disease. AB - Hepatocyte nuclear factor 1 homeobox B (HNF1beta) is an essential transcription factor for the development and functioning of the kidney. Mutations in HNF1beta cause autosomal dominant tubulointerstitial kidney disease characterized by renal cysts and maturity-onset diabetes of the young (MODY). Moreover, these patients suffer from a severe electrolyte phenotype consisting of hypomagnesemia and hypokalemia. Until now, genes that are regulated by HNF1beta are only partially known and do not fully explain the phenotype of the patients. Therefore, we performed chIP-seq in the immortalized mouse kidney cell line mpkDCT to identify HNF1beta binding sites on a genome-wide scale. In total 7,421 HNF1beta-binding sites were identified, including several genes involved in electrolyte transport and diabetes. A highly specific and conserved HNF1beta site was identified in the promoter of Kcnj16 that encodes the potassium channel Kir5.1. Luciferase-promoter assays showed a 2.2-fold increase in Kcnj16 expression when HNF1beta was present. Expression of the Hnf1beta p.Lys156Glu mutant, previously identified in a patient with autosomal dominant tubulointerstitial kidney disease, did not activate Kcnj16 expression. Knockdown of Hnf1beta in mpkDCT cells significantly reduced the appearance of Kcnj16 (Kir5.1) and Kcnj10 (Kir4.1) by 38% and 37%, respectively. These results were confirmed in a HNF1beta renal knockout mouse which exhibited downregulation of Kcnj16, Kcnj10 and Slc12a3 transcripts in the kidney by 78%, 83% and 76%, respectively, compared to HNF1beta wild-type mice. Thus, HNF1beta is a transcriptional activator of Kcnj16. Hence, patients with HNF1beta mutations may have reduced Kir5.1 activity in the kidney, resulting in hypokalemia and hypomagnesemia. PMID- 28577855 TI - Quantitative analyses reveal distinct sensitivities of the capture of HIV-1 primary viruses and pseudoviruses to broadly neutralizing antibodies. AB - Development of vaccines capable of eliciting broadly neutralizing antibodies (bNAbs) is a key goal to controlling the global AIDS epidemic. To be effective, bNAbs must block the capture of HIV-1 to prevent viral acquisition and establishment of reservoirs. However, the role of bNAbs, particularly during initial exposure of primary viruses to host cells, has not been fully examined. Using a sensitive, quantitative, and high-throughput qRT-PCR assay, we found that primary viruses were captured by host cells and converted into a trypsin resistant form in less than five minutes. We discovered, unexpectedly, that bNAbs did not block primary virus capture, although they inhibited the capture of pseudoviruses/IMCs and production of progeny viruses at 48h. Further, viruses escaped bNAb inhibition unless the bNAbs were present in the initial minutes of exposure of virus to host cells. These findings will have important implications for HIV-1 vaccine design and determination of vaccine efficacy. PMID- 28577857 TI - A wrong electrode placement. PMID- 28577858 TI - Effectiveness of Surgical and Postsurgical Interventions for Carpal Tunnel Syndrome-A Systematic Review. AB - OBJECTIVE: To present an evidence-based overview of the effectiveness of surgical and postsurgical interventions for carpal tunnel syndrome (CTS). DATA SOURCES: The Cochrane Library, PubMed, EMBASE, CINAHL, and PEDro were searched for relevant systematic reviews and randomized controlled trials (RCTs) up to April 8, 2016. STUDY SELECTION: Two reviewers independently applied the inclusion criteria to select potential studies. DATA EXTRACTION: Two reviewers independently extracted the data and assessed the methodologic quality. DATA SYNTHESIS: A best-evidence synthesis was performed to summarize the results. Four systematic reviews and 33 RCTs were included. Surgery versus nonsurgical interventions, timing of surgery, and various surgical techniques and postoperative interventions were studied. Corticosteroid injection was more effective than surgery (strong evidence, short-term). Surgery was more effective than splinting or anti-inflammatory drugs plus hand therapy (moderate evidence, midterm and long-term). Manual therapy was more effective than surgical treatment (moderate evidence, short-term and midterm). Within surgery, corticosteroid irrigation of the median nerve before skin closure as additive to CTS release or the direct vision plus tunneling technique was more effective than standard open CTS release (moderate evidence, short-term). Furthermore, short was more effective than long bulky dressings, and a sensory retraining program was more effective than no program after surgery (moderate evidence, short-term). For all other interventions only conflicting, limited, or no evidence was found. CONCLUSIONS: Surgical treatment seems to be more effective than splinting or anti inflammatory drugs plus hand therapy in the short-term, midterm, and/or long-term to treat CTS. However there is strong evidence that a local corticosteroid injection is more effective than surgery in the short-term, and moderate evidence that manual therapy is more effective than surgery in the short-term and midterm. There is no unequivocal evidence that suggests one surgical treatment is more effective than the other. Postsurgical, a short- (2-3 days) favored a long duration (9-14 days) bulky dressing and a sensory retraining program seems to be more effective than no program in short-term. More research regarding the optimal timing of surgery for CTS is needed. PMID- 28577859 TI - Fenethylline-Induced Psychosis, Fenethylline-Themed Paranoid Delusions, or Both? PMID- 28577856 TI - Glycosylation and oligomeric state of envelope protein might influence HIV-1 virion capture by alpha4beta7 integrin. AB - The alpha4beta7 integrin present on host cells recognizes the V1V2 domain of the HIV-1 envelope protein. This interaction might be involved in virus transmission. Administration of alpha4beta7-specific antibodies inhibit acquisition of SIV in a macaque challenge model. But the molecular details of V1V2: alpha4beta7 interaction are unknown and its importance in HIV-1 infection remains controversial. Our biochemical and mutational analyses show that glycosylation is a key modulator of V1V2 conformation and binding to alpha4beta7. Partially glycosylated, but not fully glycosylated, envelope proteins are preferred substrates for alpha4beta7 binding. Surprisingly, monomers of the envelope protein bound strongly to alpha4beta7 whereas trimers bound poorly. Our results suggest that a conformationally flexible V1V2 domain allows binding of the HIV-1 virion to the alpha4beta7 integrin, which might impart selectivity for the poorly glycosylated HIV-1 envelope containing monomers to be more efficiently captured by alpha4beta7 integrin present on mucosal cells at the time of HIV-1 transmission. PMID- 28577860 TI - Glaucoma. AB - Glaucoma is a heterogeneous group of diseases characterised by cupping of the optic nerve head and visual-field damage. It is the most frequent cause of irreversible blindness worldwide. Progression usually stops if the intraocular pressure is lowered by 30-50% from baseline. Its worldwide age-standardised prevalence in the population aged 40 years or older is about 3.5%. Chronic forms of glaucoma are painless and symptomatic visual-field defects occur late. Early detection by ophthalmological examination is mandatory. Risk factors for primary open-angle glaucoma-the most common form of glaucoma-include older age, elevated intraocular pressure, sub-Saharan African ethnic origin, positive family history, and high myopia. Older age, hyperopia, and east Asian ethnic origin are the main risk factors for primary angle-closure glaucoma. Glaucoma is diagnosed using ophthalmoscopy, tonometry, and perimetry. Treatment to lower intraocular pressure is based on topical drugs, laser therapy, and surgical intervention if other therapeutic modalities fail to prevent progression. PMID- 28577861 TI - Diagnostic preparedness for infectious disease outbreaks. AB - Diagnostics are crucial in mitigating the effect of disease outbreaks. Because diagnostic development and validation are time consuming, they should be carried out in anticipation of epidemics rather than in response to them. The diagnostic response to the 2014-15 Ebola epidemic, although ultimately effective, was slow and expensive. If a focused mechanism had existed with the technical and financial resources to drive its development ahead of the outbreak, point-of-care Ebola tests supporting a less costly and more mobile response could have been available early on in the diagnosis process. A new partnering model could drive rapid development of tests and surveillance strategies for novel pathogens that emerge in future outbreaks. We look at lessons learned from the Ebola outbreak and propose specific solutions to improve the speed of new assay development and ensure their effective deployment. PMID- 28577862 TI - Role of Adaptive Immunity in the Development and Progression of Heart Failure: New Evidence. AB - Heart failure (HF) is considered the endpoint of a variety of cardiac diseases, which are the leading cause of death in adults and considered a growing pandemic worldwide. Independent of the initial form of cardiac injury, there is evidence linking the involvement of the immune system. In HF there is evidence of the participation of TH1, and TH17 cells, which account for sustained pathological chronic inflammation, cell migration, and the induction of specific pathological phenotypes of mononuclear cells. Of equal or even higher relevance are the B lymphocyte activation mechanisms that include production of pro-inflammatory cytokines, chemokines, and cardiac autoantibodies with or without activation of the complement proteins. Both of these unbalanced T- and B-cell pathways of the adaptive immune system are associated with cardiomyocyte death and tissue remodeling by fibrosis leading to a dysfunctional heart. At this time, therapy with neutralizing antibodies and the use of anti-cytokine immunomodulators to counteract the immune system effects have reached a plateau of mixed results in clinical trials. Nevertheless, recent evidence showed promising results in animal models that suggest that modulation of the adaptive immune system cells more than some of their effector molecules could have benefits in HF patients. This review summarizes the role of the adaptive immunity cells in HF, considering the sustained activation of adaptive immune system as a potential contributor to disease progression in humans and experimental models where its regulation provides a new therapeutic target. PMID- 28577863 TI - Association Study of MMP-9 -1562C/T Gene Polymorphism with Susceptibility to Multiple Autoimmune Diseases: A Meta-analysis. AB - BACKGROUND AND AIMS: Matrix metalloproteinase-9 (MMP-9) -1562 C/T gene polymorphism has been identified as a susceptible gene for multiple autoimmune diseases (ADs), but studies are inconsistent. The aim of this study was to assess the overall association between MMP-9 gene polymorphism and multiple ADs using a meta-analysis. METHODS: Databases of Pubmed, Embase and Web of Science updated to March 1, 2016 were retrieved. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) as effect size were calculated by fixed-effect or random effect model on the basis of heterogeneity. RESULTS: A total of 12 relevant studies containing 2,034 cases and 1,861 controls were included in this meta analysis. A significant association between MMP-9 -1562 T allele and AD susceptibility was found in the overall population (OR = 1.269, 95% CI = 1.114 1.444, p <0.001) and the Caucasian populations (OR = 1.222, 95% CI = 1.051-1.422, p = 0.009), but not in the Asian populations (OR = 1.337, 95% CI = 0.989-0.808, p = 0.059). Stratified by disease type, we detected a significant association in other ADs (OR = 1.501, 95% CI = 1.212-1.859, p <0.001), but not in patients with multiple sclerosis (OR = 1.150, 95% CI = 0.977-1.354, p = 0.092). No publication bias was detected in the current meta-analysis. CONCLUSIONS: Data from the present study suggest that the MMP-9 -1562 C/T polymorphism may be associated with multiple AD susceptibility, especially in the Caucasian populations and other ADs. Further epidemiological studies with a larger sample size are needed to confirm these findings. PMID- 28577864 TI - Cigarette Smoking, Alcohol Consumption and Overweight in Multiple Sclerosis: Disability Progression. AB - BACKGROUND: The rate at which disability progresses in multiple sclerosis (MS), and its severity, have been associated with modifiable lifestyle habits. OBJECTIVE: To investigate the risk of disability progression in MS patients according to tobacco and alcohol consumption and to the presence of overweight. METHODS: This was a follow-up of MS cases from a concluded case-control study (National Institute of Neurology and Neurosurgery, Mexico 2010-2013). The evolution in EDSS (Expanded Disability Scale Score) units was followed through a medical record review. Kaplan Meier statistics and multivariate Cox regression analysis were performed. RESULTS: Of 181 cases, 63.5% were women and 82.5% had relapsing remitting MS. Study duration was 19.95 +/- 15.24 months. The disease progressed faster in daily smokers than in non-smokers (p = 0.0168). In overweight patients, disability progressed faster than in normal weight patients (p = 0.0249). Ex-consumers of alcohol had lower risk of progression than current consumers (HR = 0.33 CI 95% = 0.14-0.83, p = 0.019) and both daily and ex-smokers presented higher risk of progression than non-smokers (HR = 2.32 CI 95% = 1.14 4.72, p = 0.020 and HR = 3.56, CI 95% = 1.21-10.46, p = 0.021). Stratifying by gender, the effects of smoking and overweight were only found in men. CONCLUSIONS: Smoking is associated with rapid disability progression in MS. Our results suggest that cessation of tobacco and alcohol consumption could be clinically beneficial. Although there is association between overweight and disability progression in men, a further exploration of gender differences is necessary to corroborate this finding. PMID- 28577865 TI - Atherosclerosis and Cancer; A Resemblance with Far-reaching Implications. AB - Atherosclerosis and cancer are chronic diseases considered two of the main causes of death all over the world. Taking into account that both diseases are multifactorial, they share not only several important molecular pathways but also many ethiological and mechanistical processes from the very early stages of development up to the advanced forms in both pathologies. Factors involved in their progression comprise genetic alterations, inflammatory processes, uncontrolled cell proliferation and oxidative stress, as the most important ones. The fact that external effectors such as an infective process or a chemical insult have been proposed to initiate the transformation of cells in the artery wall and the process of atherogenesis, emphasizes many similarities with the progression of the neoplastic process in cancer. Deregulation of cell proliferation and therefore cell cycle progression, changes in the synthesis of important transcription factors as well as adhesion molecules, an alteration in the control of angiogenesis and the molecular similarities that follow chronic inflammation, are just a few of the processes that become part of the phenomena that closely correlates atherosclerosis and cancer. The aim of the present study is therefore, to provide new evidence as well as to discuss new approaches that might promote the identification of closer molecular ties between these two pathologies that would permit the recognition of atherosclerosis as a pathological process with a very close resemblance to the way a neoplastic process develops, that might eventually lead to novel ways of treatment. PMID- 28577866 TI - Multimorbidity Patterns in Older Adults: An Approach to the Complex Interrelationships Among Chronic Diseases. AB - BACKGROUND AND AIMS: There is a growing need for evidence based answers to multimorbidity, especially in primary care settings. The aim was estimate the prevalence and patterns of multimorbidity in a Mexican population of public health institution users >=60 years old. METHODS: Observational and multicenter study was carried out in four family medicine units in Mexico City; included older men and women who attended at least one consultation with their family doctor during 2013. The most common diseases were grouped into 11 domains. The observed and expected rates, as well as the prevalence ratios, were calculated for the pairs of the more common domains. Logistic regression models were developed to estimate the magnitude of the association. Cluster and principal components analyses were performed to identify multimorbidity patterns. RESULTS: Half of all of the patients who were >=60 years old and treated by a family doctor had multimorbidity. The most common disease domains were hypertensive and endocrine diseases. The highest prevalence of multimorbidity concerned the renal domain. The domain pairs with the strongest associations were endocrine + renal and hypertension + cardiac. The cluster and principal components analyses revealed five consistent patterns of multimorbidity. CONCLUSIONS: The domains grouped into five patterns could establish the framework for developing treatment guides, deepen the knowledge of multimorbidity, develop strategies to prevent it, decrease its burden, and align health services to the care needs that doctors face in daily practice. PMID- 28577867 TI - Effects of miR-29a and miR-101a Expression on Myocardial Interstitial Collagen Generation After Aerobic Exercise in Myocardial-infarcted Rats. AB - BACKGROUND AND AIMS: Myocardial infarction (MI) is accompanied by increased collagen deposition, cell necrosis and angiogenesis in cardiac tissue, which results in reduced ventricular compliance. Both microRNA-29a (miR-29a) and microRNA-101a (miR-101a) target the mRNAs encoding collagens and other proteins involved in fibrosis. METHODS: We assessed the effects of intermittent aerobic exercise on the expression of cardiac miR-29a and miR-101a and following effects on the TGFbeta, fos, Smad2/3, COL1A1 and COL3A1 in MI model of rats. Intermittent aerobic exercise for MI rats was begun from the second week and ended at the ninth week postsurgery. Expressions of microRNAs (miRNAs) and fibrosis-associated genes were detected from the infarction adjacent region located in the left ventricle. The heart coefficient (HC = heart weight/body weight) and hemodynamics assay were used to evaluate cardiac function level. RESULTS: Intermittent aerobic exercise inhibited myocardial interstitial collagen deposition and significantly improved cardiac function of MI rats. The results of real-time PCR and Western blot indicate that intermittent aerobic exercise enhanced the expression of miR 29a and miR-101a and inhibited TGFbeta pathway in the MI rats. CONCLUSIONS: Our results suggest that controlled intermittent aerobic exercise can inhibit TGFbeta pathway via up-regulation to the expression of miR-29a and miR-101a and finally cause a reduced fibrosis and scar formation in cardiac tissue. We believe that controlled intermittent aerobic exercise is beneficial to the healing and discovery of damaged cardiac tissues and their function after MI. PMID- 28577868 TI - Prenatal Food Restriction with Postweaning High-fat Diet Alters Glucose Metabolic Function in Adult Rat Offspring. AB - BACKGROUND AND AIMS: The present study was designed to investigate the effects of prenatal food restriction (PFR) with postweaning high-fat diet (HFD) on glucose metabolic function in adult offspring. METHODS: Pregnant Wistar rats were given PFR treatment from gestational day 11 to spontaneous delivery. All pups were fed by HFD after weaning. Oral glucose tolerance test (OGTT) was conducted at postnatal week (PW) 20. Rats were decapitated in PW24 to collect liver and pancreas, and expression of hepatic insulin signaling genes were then quantified. RESULTS: Body weight from PW4 to PW24 in PFR males was lower than those in control males, whereas there was no distinct difference between females. However, body weight gain rates were higher from PW16 to PW24 in PFR males and females. Fasting serum glucose presented no changes, whereas fasting serum insulin decreased in PW20 in PFR pups. Moreover, glucose intolerance only appeared in PFR males, whereas no changes were shown in PFR females in relative values. Serum insulin increased in both PFR groups after OGTT. Remarkable pathological changes were also found in islets from PFR rats. There was an increase in the hepatic mRNA expression of IR in PFR females and of Glut2 in PFR males. CONCLUSION: PFR with postweaning HFD induced a catch-up growth in body weight, especially in PFR females. Serum insulin decreased in both PFR groups in fasting status. Insulin resistance after OGTT only existed in PFR males, whereas PFR females showed no obvious changes in glucose metabolism. PMID- 28577869 TI - Polyunsaturated Fatty Acids Differentially Modulate Cell Proliferation and Endocannabinoid System in Two Human Cancer Lines. AB - BACKGROUND AND AIMS: Evidence suggests that quantity and quality of dietary polyunsaturated fatty acids (PUFAs) play a role in the development of cancer. However, the mechanisms involved in this interaction(s) are not clear. Endocannabinoids are lipid metabolites known to have growth modulatory actions. We studied the effect of supplementation with PUFAs omega-6 and omega-3 (essential fatty acids, EFAs), saturated and monounsaturated fatty acids (non EFAs) on the growth of tumor cells and modifications in their endocannabinoid content. METHODS: Cell cultures of human glioblastoma (T98G) and breast cancer (MCF7) were supplemented with 50 or 100 mmol EFAs and non-EFAs for 72 h. Cell proliferation was then determined by MTT, anandamide (AEA) levels by HPLC, total fatty acids profiles by GLC, CB1 receptor expression by WB and FAAH activity by spectrophotometric method. RESULTS: Fatty acids profile reflected the incorporation of the lipids supplemented in each assay. Arachidonic acid (EFA omega-6) supplementation increased AEA levels and inhibited the growth of T98G, whereas palmitic acid (non-EFA) enhanced their proliferation. In breast cancer (MCF7) cells, eicosapentaenoic acid (EFA omega-3) reduced and oleic acid (non EFA) enhanced their proliferation. CB1 expression was higher in T98G and no differences were observed in FAAH activity. CONCLUSIONS: The growth of tumor cells can be differentially modulated by fatty acids and, at least in part, can be attributed to their ability to act on the components of the endocannabinoid system. PMID- 28577870 TI - Mitochondria As the Target for the Modulatory Effect of Curcumin in Oxaliplatin induced Toxicity in Isolated Rat Liver Mitochondria. AB - BACKGROUND AND AIMS: To explore hepatoprotective action of curcumin (CMN, a bioflavonoid) on oxaliplatin (Oxa)-triggered mitochondrial oxidative stress and respiratory chain complexes in liver of rats. Oxa is a ubiquitously utilized platinum-based chemotherapeutic agent commonly used for the treatment of colorectal cancer. Mitochondria have recently emerged as targets for anticancer drugs in several kinds of toxicity including hepatotoxicity that can lead to neoplastic disease. There is a dearth of evidence involving the role of mitochondria in mediating Oxa-evoked hepatotoxicity and its underlying mechanism is still debatable. METHODS: The study was performed in mitochondria isolated from liver of Wistar rats. Oxa (200 MUg/mL) and CMN (5 MUmol) were incubated under in vitro conditions. RESULTS: Oxa evoked a significant increase in the membrane lipid peroxidation (LPO) levels, protein carbonyl (PC) contents, decrease in reduced glutathione (GSH) and nonprotein thiol (NP-SH) levels. Oxa also caused a marked decline in the activities of enzymatic antioxidants and respiratory chain enzymes (I, II, III and V) in liver mitochondria. CMN pre treatment significantly prevented the activities of enzymatic antioxidants and mitochondrial respiratory chain enzymes. CMN also restored the LPO and PC contents, GSH and NP-SH levels in liver mitochondria. CONCLUSION: CMN intake might be effective in regulation of Oxa-evoked mitotoxicity during chemotherapy. Moreover, it is included in the armamentarium for anticancer agent-induced oxidative stress. PMID- 28577871 TI - Loperamide-induced Cardiac Depression Is Enhanced by Hyperglycemia: Evidence Relevant to Loperamide Abuse. AB - BACKGROUND AND AIMS: Cardiac dysryhthmias and death are reported after loperamide abuse. The mechanism of death is not clear and cardiac depression may play a role in this mechanism. Loperamide is widely used as an agonist of the MU-opioid receptor (MOR) in clinical practice. In skeletal muscle, an increase in MOR in response to hyperglycemia is largely attributable to higher expression of the transducer and activator of transcription 3 (STAT3), which binds to the promoter of the MOR genes. Therefore, we investigated the changes in cardiac MOR caused by hyperglycemia both in vivo and in vitro. METHODS: Streptozotocin-induced type 1 like diabetic rats (STZ rats) were used to estimate cardiac performance and changes in cardiac MOR under the influence of loperamide. STAT3 was measured in cultured cardiomyocytes under high glucose (HG) to mimic the in vivo changes. RESULTS: Loperamide-induced reduction of cardiac performance was more marked in STZ rats than in normal rats. The increased MOR in the hearts of STZ rats was reversed by the reduction of hyperglycemia. Higher MOR expression paralleled the increase in STAT3 in cardiomyocytes under HG and was reversed by siRNA of STAT3. Stattic at a dose sufficient to inhibit STAT3 reduced MOR both in vivo and in vitro. CONCLUSION: Cardiac depression induced by loperamide is enhanced by hyperglycemia due to higher MOR expression, which is associated with higher expression of STAT3 in the heart. These results suggest that loperamide abuse is particularly dangerous for individuals with hyperglycemia. PMID- 28577872 TI - Association of Adiponectin with Subclinical Atherosclerosis in a Mexican-Mestizo Population. AB - BACKGROUND AND AIMS: Adiponectin (ADPN) is a cardioprotective adipocytokine, and its association with atherosclerosis development is controversial. The aim of the present study was to assess the association of low ADPN plasma levels with the presence of subclinical atherosclerosis in a Mexican-Mestizo population without history of diabetes or coronary artery disease (CAD). METHODS: In 818 subjects (53.4 +/- 9 years; 49.9% women) anthropometry, subcutaneous and visceral adipose tissue, lipids, glucose, C-reactive protein (CRP), insulin, and ADPN levels were determined. Carotid artery intima-media thickness (CIMT) was measured with ultrasound in B mode and the sex-age specific value higher than 75th percentile defined the presence of subclinical atherosclerosis. Low ADPN was considered when plasma concentrations were lower than 25th percentile (8.67 MUg/mL in women, 5.30 MUg/mL in men). RESULTS: Prevalence of low ADPN was 43.6% (42.9% in women and 44.4% in men; p = 0.66) and elevated CIMT (eCIMT) was 23.8% (25.8% in women and 21.9% in men; p = 0.184). In addition to their higher prevalence of low ADPN, subjects with eCIMT had higher values of body mass index, blood pressure, total cholesterol, triglycerides, glucose, insulin, and CRP. Multivariate analysis revealed that independent of these factors, low ADPN was associated with eCIMT (OR [95% CI]: 1.505 [1.051-2.153]). CONCLUSIONS: In the studied population, low adiponectin concentrations are associated with a higher prevalence of subclinical atherosclerosis, independent of traditional cardiovascular risk factors. PMID- 28577873 TI - Increased Circulating Autoantibodies Levels of IgG, IgA, IgM Against Cytokeratin 18 and Cytokeratin 19 in Chronic Obstructive Pulmonary Disease. AB - BACKGROUND AND AIMS: Autoimmune processes are involved in the progression of chronic obstructive pulmonary disease (COPD). Autoantibodies against cytokeratin 18 (CK18) and cytokeratin 19 (CK19) could be associated with lung injury. We undertook this study to investigate the role of these autoantibodies against CK18 and CK19 in the development of COPD. METHODS AND RESULTS: We used blood samples from 228 COPD patients or 136 healthy controls and male C57BL/6j mice as experimental subjects to analyze the serum autoantibody levels against CK18 or CK19 autoantigen by enzyme-linked immunosorbent assay (ELISA). We found that the circulating autoantibody levels of IgG, IgA, IgM against CK18 and CK19 were elevated in patients with COPD compared with healthy controls, which were increased gradually as the severity of the disease increases, especially in GOLD III and GOLD IV with the exception of anti-CK19 IgG and anti-CK18 IgA autoantibodies. Moreover, we observed that the serum levels of anti-CK18 and anti CK19 IgG autoantibodies were higher in mice exposed to cigarette smoke compared with mice exposed to room air for 6 months and 9 months. Additionally, we identified the distribution of antibodies and the presence of autoantibodies (IgG) against CK18 and CK19 in the damaged lung tissues of mice. CONCLUSIONS: Increased circulating autoantibodies against CK18 and CK19 are closely related to the progression of COPD, which play an important role in the process of lung injury in COPD, suggesting that it is promising for anti-CK18 and anti-CK19 autoantibodies to serve as a tool to monitor lung damage and guide treatment. PMID- 28577874 TI - RAS Genetic Variants in Interaction with ACE Inhibitors Drugs Influences Essential Hypertension Control. AB - BACKGROUNDS AND AIMS: Essential Hypertension (EH) is a common disorder associated with increased cardiovascular morbidity and mortality in Malaysia. To investigate how genetic polymorphisms of the renin-angiotensin-aldosterone system (RAS) influence EH control with angiotensin-converting enzyme inhibitor drugs (ACEI). METHODS: A case-control, cross-sectional population-based nested study (n = 142) included hypertensive subjects treated with ACEI drugs, either lisinopril or enalapril (20 mg, once daily) as monotherapy for 24 weeks. In total seven possible polymorphisms of RAS genes were genotyped. The association between those polymorphisms and the changes in blood pressure were observed in the 24 week treatment. RESULTS: Statistically significant associations of I, G, T, M and G alleles of ACE (I/D, G2350A), AGT (M235T, T175M and G-6A) respectively were observed in essential hypertensive subjects. The decrease in systolic blood pressure and diastolic blood pressure after 24 weeks of treatment of the patients carrying II, GG, and TT genotypes were greater than the groups carrying DD, AA, MM, MM and GG of I/D, G2350A, M235T, T174M and G-6A genotypes respectively. In contrast, No significant difference was observed between renin gene polymorphisms (Bg/I and MboI) and hypertensives. CONCLUSIONS: Although this study shows a possible association of polymorphisms of RAS genes with the risk of non-control of HT in ACEI-treated patients and indicates the importance of all this system's components in regulating HT, it needs to be replicated in other data sources. PMID- 28577875 TI - Circulating miR-150, miR-192, miR-200b, and miR-423-3p as Non-invasive Biomarkers of Chronic Allograft Dysfunction. AB - BACKGROUND AND AIMS: Chronic allograft dysfunction (CAD) is the major cause of renal allograft loss and can only be diagnosed by invasive histological examinations. The current study aimed to determine whether or not the circulating miR-125a, miR-150, miR-192, miR-200b, miR-423-3p and miR-433 could serve as predictors of graft outcome in the renal transplant recipients with CAD. METHODS: To evaluate the expression levels of miRNAs, we used quantitative real-time PCR (qPCR) and analyzed the plasma samples of 53 renal transplant recipients, including: 27 recipients with stable graft function (SGF), 26 recipients with biopsy-proven interstitial fibrosis and tubular atrophy (IFTA) and 15 healthy controls. Possible correlation between the clinicopathological parameters and the studied circulating miRNAs was also evaluated. RESULTS: miR-150 (p <0.001), miR 192 (p = 0.003), miR-200b (p = 0.048) and miR-423-3p (p <0.001) were differentially expressed between IFTA and SGF plasma samples. Creatinine correlated with miR-192 (r = 0.414, p = 0.036) and miR-423-3p (r = -0.431, p = 0.028). Moreover, the estimated glomerular filtration rate (eGFR) significantly correlated with the circulating miR-192 (r = -0.390, p = 0.049) and miR-423 (r = 0.432, p = 0.028). Receiver operating characteristic (ROC) analysis indicated that four miRNAs possessed the best diagnostic value for discriminating IFTA from SGF recipients with the areas under the curve (AUC) of 0.87 and high sensitivity and specificity values of 78% and 91%, respectively. CONCLUSIONS: The results suggest that aberrant plasma levels of these miRNAs are associated with the renal allograft dysfunction. Therefore, they are proposed to be considered as potential diagnostic biomarkers for monitoring of renal graft function. PMID- 28577876 TI - A preliminary study on the neural oscillatory characteristics of motor preparation prior to dysfluent and fluent utterances in adults who stutter. AB - PURPOSE: Recent literature on speech production in adults who stutter (AWS) has begun to investigate the neural mechanisms characterizing speech-motor preparation prior to speech onset. Compelling evidence has suggested that stuttering is associated with atypical processing within cortical and sub cortical motor networks, particularly in the beta frequency range, that is effective before speech production even begins. Due to low stuttering frequency in experimental settings, however, the literature has so far predominantly reported on fluent speech production in AWS. Consequently, we have limited understanding of the way in which fluent speech processing in AWS is disturbed leading to a dysfluency. This preliminary study aims to characterize neural motor preparation prior to stuttered utterances in AWS. METHODS: Eight AWS participated in the study. A total of 336 stuttered utterances were compared to the participants' own fluent utterance productions. Beta oscillatory activity was analyzed with magnetoencephalography (MEG) and localized using minimum-variance beamforming. RESULTS: Preparation for speech production induced beta suppression in the bilateral premotor and motor cortex prior to speech onset. Although the data revealed some interesting trends, no significant differences between fluent and stuttered utterances were present. This may be due to a relatively low and variable number of stuttered trials analyzed in individual subjects. CONCLUSION: While the lack of significant differences may have resulted from the relatively low numbers of stuttered utterances across subjects, the observed trends demonstrated that the proposed methodology and experimental paradigm is a promising approach for future studies aiming to characterize differences between stuttered and fluent speech. PMID- 28577877 TI - Hardiness Mediates Stress and Impact Level in ED Nurses Who Experienced a Violent Event. AB - INTRODUCTION: This secondary analysis examined the mediating effect of hardiness between stress and impact level in ED nurses who experienced a violent event. METHOD: This correlational study was conducted from June to August 2014. We used the visual analog scale to measure stress level, the Impact of Event Scale Revised to measure impact level after the violent event, and the Dispositional Resilience Scale to measure hardiness. We then analyzed mediating effects with the Sobel test. Data were collected in 31 emergency medical centers located in B city in Korea. Data from 321 ED nurses who experienced a violent event were analyzed. Most nurses (91.9%) were women, with a mean age of 28.73 years. The main outcome measure was the mediating effect of hardiness between stress and impact level after ED nurses experienced violence. RESULTS: We found that both violence-related stress (B = 0.22, P < .001) and hardiness (B = -0.33, P = .037) were significant predictors of impact level from a violent event. Based on results of a Sobel test, hardiness partially mediated the relationship between violence-related stress and impact level from a violent event (Z = 2.03, P = .044). DISCUSSION: Hardiness had an effect on reducing the impact level of ED nurses who had experienced a violent event and had a mediating role in mitigating their stress. Therefore, we recommend the development of an intervention program that emphasizes the improvement of hardiness in ED nurses. PMID- 28577878 TI - Nurses leading change to advance health. AB - BACKGROUND: The article includes a review of selected past and current leadership initiatives as well as a summary of three leadership meetings convened by The Center to Champion Nursing in America, a partnership of the Robert Wood Johnson Foundation (RWJF), AARP and the AARP Foundation. PURPOSE: These "Leadership in Action" meetings were designed to address the Campaign for Action's (CFA) goal to increase the number of nurse leaders in health- and health care-related boardrooms at the local, state and national levels. METHODS: RWJF supported key nursing organizations in initial discussions around integrating state and national efforts to get more nurses onto boards leading to a active vibrant coalition making significant progress. CONCLUSION: This article concludes with a call to action encouraging all nurses to consider board service as an essential component of improving health and health care and to do their part to help build a Culture of Health in the United States. PMID- 28577880 TI - Shadows in the light of reason. PMID- 28577881 TI - Gene-enriched draft genome of the cattle tick Rhipicephalus microplus: assembly by the hybrid Pacific Biosciences/Illumina approach enabled analysis of the highly repetitive genome. AB - The genome of the cattle tick Rhipicephalus microplus, an ectoparasite with global distribution, is estimated to be 7.1Gbp in length and consists of approximately 70% repetitive DNA. We report the draft assembly of a tick genome that utilized a hybrid sequencing and assembly approach to capture the repetitive fractions of the genome. Our hybrid approach produced an assembly consisting of 2.0Gbp represented in 195,170 scaffolds with a N50 of 60,284bp. The Rmi v2.0 assembly is 51.46% repetitive with a large fraction of unclassified repeats, short interspersed elements, long interspersed elements and long terminal repeats. We identified 38,827 putative R. microplus gene loci, of which 24,758 were protein coding genes (>=100 amino acids). OrthoMCL comparative analysis against 11 selected species including insects and vertebrates identified 10,835 and 3,423 protein coding gene loci that are unique to R. microplus or common to both R. microplus and Ixodes scapularis ticks, respectively. We identified 191 microRNA loci, of which 168 have similarity to known miRNAs and 23 represent novel miRNA families. We identified the genomic loci of several highly divergent R. microplus esterases with sequence similarity to acetylcholinesterase. Additionally we report the finding of a novel cytochrome P450 CYP41 homolog that shows similar protein folding structures to known CYP41 proteins known to be involved in acaricide resistance. PMID- 28577883 TI - Corrigendum to "comparison of outcomes for MR-guided versus CT-guided high-dose rate interstitial brachytherapy in women with locally advanced carcinoma of the cervix" [Gynecol. Oncol. 145 (2017) 284-290]. PMID- 28577882 TI - Heritable genetic transformation of Strongyloides stercoralis by microinjection of plasmid DNA constructs into the male germline. AB - Heretofore, transgenesis in the parasitic nematode genus Strongyloides has relied on microinjecting transgene constructs into gonadal syncytia of free-living females. We now report transgenesis in Strongyloides stercoralis by microinjecting constructs into the syncytial testes of free-living males. Crosses of individual males microinjected with a construct encoding GFP with cohorts of 12 non-injected females produced a mean of 7.28+/-2.09 transgenic progeny. Progeny of males and females microinjected with distinct reporter constructs comprised 2.6%+/-0.7% of individuals expressing both paternal and maternal transgenes. Implications of this finding for deployment of CRISPR/Cas9 mutagenesis in Strongyloides spp. are discussed. PMID- 28577884 TI - Cost-effectiveness of opportunistic salpingectomy for ovarian cancer prevention. AB - OBJECTIVES: Data suggesting a link between the fallopian tube and ovarian cancer have led to an increase in rates of salpingectomy at the time of pelvic surgery, a practice known as opportunistic salpingectomy (OS). However, the potential benefits, risks and costs for this new practice are not well established. Our objective was to assess the cost-effectiveness of opportunistic salpingectomy at the time of laparoscopic permanent contraception or hysterectomy for benign indications. METHODS: We created two models to compare the cost-effectiveness of salpingectomy versus usual care. The hypothetical study population is 50,000 women aged 45 undergoing laparoscopic hysterectomy with ovarian preservation for benign indications, and 300,000 women aged 35 undergoing laparoscopic permanent contraception. SEER data were used for probabilities of ovarian cancer cases and deaths. The ovarian cancer risk reduction, complication rates, utilities and associated costs were obtained from published literature. Sensitivity analyses and Monte Carlo simulation were performed, and incremental cost-effectiveness ratios (ICERs) were calculated to determine the cost per quality adjusted life year (QALY) gained. RESULTS: In the laparoscopic hysterectomy cohort, OS is cost saving and would yield $23.9 million in health care dollars saved. In the laparoscopic permanent contraception cohort, OS is cost-effective with an ICER of $31,432/QALY compared to tubal ligation, and remains cost-effective as long as it reduces ovarian cancer risk by 54%. Monte Carlo simulation demonstrated cost effectiveness with hysterectomy and permanent contraception in 62.3% and 55% of trials, respectively. CONCLUSIONS: Opportunistic salpingectomy for low-risk women undergoing pelvic surgery may be a cost-effective strategy for decreasing ovarian cancer risk at time of hysterectomy or permanent contraception. In our model, salpingectomy was cost-effective with both procedures, but the advantage greater at time of hysterectomy. PMID- 28577885 TI - Isolated tumor cells identified by sentinel lymph node mapping in endometrial cancer: Does adjuvant treatment matter? AB - OBJECTIVE: To evaluate the outcome and the role of adjuvant treatment in the management of patients with endometrial cancer and isolated tumor cells (ITCs) identified by SLN mapping. METHODS: This single center study identified all patients undergoing hysterectomy, salpingo-oophorectomy, lymphadenectomy and SLN mapping for endometrial cancer between November 2010 and December 2015. Data was prospectively collected. Progression-free survival was analyzed according to the Kaplan-Meier method and compared using the log-rank test. RESULTS: A total of 519 patients were included. Overall, 85 patients (16.4%) were found to have SLN metastases of which 43 (51%) were macrometastasis, 11 (13%) micrometastasis (MM) and 31 (36%) ITC. Eleven (35%) of patients with ITCs received adjuvant chemotherapy+/-whole pelvic radiation therapy (WPRT), 10 (32%) received WPRT, and 10 (32%) received either no adjuvant treatment or vault brachytherapy (VBT) only. ITC patients received significantly less chemotherapy (p=0.0001) and WPRT (p=0.007) compared to patients with macrometastasis. Of note, ITC were not considered node positive in our study. With a median follow-up of 29months (range: 0-67), the progression free survival (PFS) at 3-years for the ITC patients was 95.5%, similar to node negative (87.6%) and micrometastasis patients (85.5%), but statistically better than patients with macrometastasis (58.5%) (p=0.0012). Only 1/31 patient with ITC recurred (IB, 7cm carcinosarcoma) despite adjuvant treatments. None of the ITC patients with endometrioid histology recurred (0/28) and none of the ITC patients who did not receive adjuvant treatment or VBT recurred (0/10). CONCLUSIONS: Patients with endometrial cancer found to have SLN ITCs have an excellent outcome. The use of adjuvant treatment should be tailored to uterine factors and histology and not solely based on the presence of ITCs. Patients with ITCs and otherwise low-risk uterine disease probably derive little benefit from receiving additional treatments. More studies are needed to confirm our results. PMID- 28577879 TI - Developmental psychoneuroendocrine and psychoneuroimmune pathways from childhood adversity to disease. AB - Childhood adversity has been repeatedly and robustly linked to physical and mental illness across the lifespan. Yet, the biological pathways through which this occurs remain unclear. Functioning of the inflammatory arm of the immune system and the hypothalamic-pituitary-adrenal (HPA)-axis are both hypothesized pathways through which childhood adversity leads to disease. This review provides a novel developmental framework for examining the role of adversity type and timing in inflammatory and HPA-axis functioning. In particular, we identify elements of childhood adversity that are salient to the developing organism: physical threat, disrupted caregiving, and unpredictable environmental conditions. We propose that existing, well-characterized animal models may be useful in differentiating the effects of these adversity elements and review both the animal and human literature that supports these ideas. To support these hypotheses, we also provide a detailed description of the development and structure of both the HPA-axis and the inflammatory arm of the immune system, as well as recent methodological advances in their measurement. Recommendations for future basic, developmental, translational, and clinical research are discussed. PMID- 28577887 TI - The contribution of coping related variables and cardiac vagal activity on the performance of a dart throwing task under pressure. AB - The aims of this study were 1) to assess the predictive role of coping related variables (CRV) on cardiac vagal activity (derived from heart rate variability), and 2) to investigate the influence of CRV (including cardiac vagal activity) on a dart throwing task under low pressure (LP) and high pressure (HP) conditions. Participants (n=51) completed trait CRV questionnaires: Decision Specific Reinvestment Scale, Movement Specific Reinvestment Scale and Trait Emotional Intelligence Questionnaire. They competed in a dart throwing task under LP and HP conditions. Cardiac vagal activity measurements were taken at resting, task and during recovery for 5min. Self-reported ratings of stress were recorded at three time points via a visual analogue scale. Upon completion of the task, self-report measures of motivation, stress appraisal, attention, perceived pressure and dart throwing experience were completed. Results indicated that resting cardiac vagal activity had no predictors. Task cardiac vagal activity was predicted by resting cardiac vagal activity in both pressure conditions with the addition of a trait CRV in HP. Post task cardiac vagal activity was predicted by resting cardiac vagal activity in both conditions with the addition of a trait CRV in HP. Cardiac vagal reactivity (difference from resting to task) was predicted by a trait CRV in HP conditions. Cardiac vagal recovery (difference from task to post task) was predicted by a state CRV only in LP. Dart throwing task performance was predicted by a combination of both CRV and cardiac vagal activity. The current research suggests that coping related variables and cardiac vagal activity influence dart throwing task performance differently dependent on pressure condition. PMID- 28577886 TI - Investigating physiological glucose excursions before, during, and after Ramadan in adults without diabetes mellitus. AB - AIM: The study aimed to investigate physiological effects of Ramadan fasting on continuously monitored glucose levels in relation to Ramadan in young non diabetic adults. METHODS: Continuous glucose monitoring was employed to measure interstitial glucose for several days 1-2weeks before Ramadan, in the middle of Ramadan, and 4-6weeks after Ramadan to assess glucose exposure and glucose variability. RESULTS: A total of 34,182 accurate glucose sensor readings and 438 capillary blood glucose values [mean absolute difference median (interquartile range) 8.5 (6.9-11.1)%] were obtained from 18 non-diabetic adults [13 females; aged 24 (21-27) years; baseline body mass index 23.9 (20.6-28.9) kg/m2]. The continuous glucose monitoring profiles showed an increase in the hyperglycemic (above 140mg/dL) area under the curve after Ramadan compared to both before (P=0.004) and during Ramadan (P=0.003), along with an increased glucose variability after Ramadan (P=0.014). Both the area under the interstitial glucose concentration curve for the entire day and the average glucose were positively associated with body mass index during (P=0.004 and P=0.005, respectively) and after Ramadan (P=0.013 and P=0.01, respectively). Atypical continuous glucose patterns were recognized in 11% of subjects, distinguished by a prolonged increased glucose exposure, particularly in response to a meal. CONCLUSION: The time-point 4-6weeks after Ramadan was distinguished by greater glucose exposure and wider glucose variability that may reflect ongoing changes in insulin sensitivity in response to altering lifestyle patterns in non-diabetic young adults across the spectrum of body weight. PMID- 28577889 TI - Nitric oxide associated protein 1 is associated with chloroplast perturbation and disease symptoms in Nicotiana benthamiana infected with South African cassava mosaic virus. AB - Nitric oxide associated 1 (NOA1) in plants is a cyclic GTPase involved in protein translation in the chloroplast and has been indirectly linked to nitric oxide (NO) accumulation and response to biotic stress. The association between NOA1 and NO accumulation in Arabidopsis noa1 mutants has been linked to the inability of noa1 mutants to accumulate carbon reserves such as fumarate, leading to chloroplast dysfunction and a pale green leaf phenotype. To understand the role played by NOA1 in response to South African cassava mosaic virus infection in Nicotiana benthamiana, the expression of NbNOA1 and the accumulation of NO in leaf samples was compared between south african cassava mosaic (SACMV)-infected and mock-infected plants at 14 and 28 dpi. Real-time qPCR was used to measure SACMV viral load which increased significantly by 20% from 14 to 28 dpi as chlorosis and symptom severity progressed. At 14 and 28 dpi, NbNOA1 expression was significantly lower than mock inoculated plants (2-fold lower at 14 dpi, p value=0.01 and 5-fold lower at 28, p-value=0.00). At 14 dpi, NO accumulation remained unchanged in infected leaf tissue compared to mock inoculated, while at 28 dpi, NO accumulation was 40% lower (p-value=0.01). At 28 dpi, the decrease in NbNOA1 expression and NO accumulation was accompanied by chloroplast dysfunction, evident from the significant reduction in chlorophylls a and b and carotenoids in SACMV-infected leaves. Furthermore, the expression of chloroplast translation factors (chloroplast RNA binding, chloroplast elongation factor G, translation elongation factor Tu, translation initiation factor 3-2, plastid-specific ribosomal protein 6 and plastid ribosome recycling factor) were found to be repressed in infected N. benthamiana. GC-MS analysis showed a decrease in fumarate and an increase in glucose in SACMV-infected N. benthamiana in comparison to mock samples suggesting a decrease in carbon stores. Collectively, these results provide evidence that in response to SACMV infection, a decrease in photopigments and carbon stores, accompanied by an increase in glucose and decrease in fumarate, leads to a decline in NbNOA1expression and NO levels. This is manifested by suppressed translation factors and disruption of chloroplast function, thereby contributing to chlorotic disease symptoms. PMID- 28577890 TI - Exercise training protects against aging-induced mitochondrial fragmentation in mouse skeletal muscle in a PGC-1alpha dependent manner. AB - Aging is associated with impaired mitochondrial function, whereas exercise training enhances mitochondrial content and function in part through activation of PGC-1alpha. Mitochondria form dynamic networks regulated by fission and fusion with profound effects on mitochondrial functions, yet the effects of aging and exercise training on mitochondrial network structure remain unclear. This study examined the effects of aging and exercise training on mitochondrial network structure using confocal microscopy on mitochondria-specific stains in single muscle fibers from PGC-1alpha KO and WT mice. Hyperfragmentation of mitochondrial networks was observed in aged relative to young animals while exercise training normalized mitochondrial network structure in WT, but not in PGC-1alpha KO. Mitochondrial fission protein content (FIS1 and DRP1) relative to mitochondrial content was increased with aging in both WT and PGC-1alpha KO mice, while exercise training lowered mitochondrial fission protein content relative to mitochondrial content only in WT. Mitochondrial fusion protein content (MFN1/2 and OPA1) was unaffected by aging and lifelong exercise training in both PGC 1alpha KO and WT mice. The present results provide evidence that exercise training rescues aging-induced mitochondrial fragmentation in skeletal muscle by suppressing mitochondrial fission protein expression in a PGC-1alpha dependent manner. PMID- 28577891 TI - Treatment of posterior cruciate ligament tibial avulsion by a minimally-invasive open posterior approach. AB - OBJECTIVE: To assess the surgical technique and report the outcomes following fixation of PCL bony avulsions through mini-invasive posterior knee approach as described by Burks and Schaffer. METHODS: From June 2012 to July 2015, 27 patients enrolled in the study (21 males and 6 females). Fixation of tibial PCL avulsion fractures was done with one or two cannulated screws, or sutures through Burks and Schaffer's approach. The mean interval before surgery was 16days (1-70) .Patients was followed up for an average of 51 weeks. The outcome measures evaluated at final follow-up were (1) clinical stability as assessed by posterior drawer test, (2) radiologic union, (3) functional assessment by Lysholm score, and (4) gastrocnemius muscle strength as a measure of morbidity. RESULTS: Average operative time was 43min. Improvement of both subjective Lysholm score (mean 93) and objective stability testing by posterior drawer test (returns to normal in 81.1% of patients) at the final follow-up. Good radiographic union at average of 5.6 weeks. No morbidity of the gastrocnemius with few complications. CONCLUSIONS: The approach was fast and safe with excellent visualization. It allows surgeons to address other injuries in the same setting. It can be considered as a minimally-invasive open surgery without surgery-related morbidity. It is a reproducible technique that can be done at any trauma centre by surgeons with average experience. The subjective and objective results of the technique are excellent and comparable to the arthroscopic procedures that needs more specific centres with well-trained surgeons. PMID- 28577892 TI - Effects of EDC crosslinking on the stiffness of dentin hybrid layers evaluated by nanoDMA over time. AB - : Application of collagen cross-linkers to demineralized dentin improves bond durability. While the benefits of cross-linking treatments to bond strength and fatigue resistance have been explored, changes in hybrid layer stiffness with aging have not been examined. OBJECTIVE: To examine the influence of a cross linking treatment using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) on hybrid layer stiffness of resin-dentin adhesive bonds, using spatially-resolved nanoscopic Dynamic Mechanical Analysis (nanoDMA). METHODS: Bonded interface specimens were prepared using a two-step (SB) or three-step (SBMP) etch-and-rinse adhesive. Adhesive bonding of the treated groups was preceded by a 1min application of an experimental EDC conditioner to the acid-etched dentin. Control specimens did not receive EDC treatment. The bonded interfaces were evaluated using nanoDMA to determine the dynamic mechanical properties after storage in artificial saliva at 37 degrees C for 0, 3 and 6 months. RESULTS: The EDC treatment had no influence on the dynamic mechanical properties of the hybrid layer immediately after bonding. There was also no reduction in the hybrid layer stiffness after 3 and 6 months aging as defined by the complex modulus and storage modulus. However, there was a significant reduction in the loss modulus and tandelta components (i.e. viscous behavior) of the hybrid layers with aging. Degradation occurred to both adhesive systems with storage, but was greatest for SB. Without EDC treatment, the reduction in tandelta of the hybrid layer prepared with SB exceeded 80% in 6 months. SIGNIFICANCE: The application of EDC to acid etched dentin helps maintain the viscoelasticity of hybrid layers. PMID- 28577893 TI - Academy of Dental Materials guidance-Resin composites: Part I-Mechanical properties. AB - OBJECTIVE: The objective of this project, which was initiated from the Academy of Dental Materials, was to review and critically appraise methods to determine fracture, deformation and wear resistance of dental resin composites, in an attempt to provide guidance for investigators endeavoring to study these properties for these materials. METHODS: Test methods have been ranked in the priority of the specific property being tested, as well as of the specific test methods for evaluating that property. Focus was placed on the tests that are considered to be of the highest priority in terms of being the most useful, applicable, supported by the literature, and which show a correlation with clinical findings. Others are mentioned briefly for the purpose of being inclusive. When a standard test method exists, including those used in other fields, these have been identified in the beginning of each section. Also, some examples from the resin composite literature are included for each test method. RESULTS: The properties for evaluating resin composites were ranked in the priority of measurement as following: (1) Strength, Elastic Modulus, Fracture toughness, Fatigue, Indentation Hardness, Wear-abrasion (third body) and Wear attrition (contact/two body), (2) Toughness, Edge strength (chipping) and (3) Wear determined by toothbrush. SIGNIFICANCE: The following guidance is meant to aid the researcher in choosing the proper method to assess key properties of dental resin composites with regard to their fracture, deformation and wear resistance. PMID- 28577894 TI - Proteolytic control of regulated necrosis. AB - Proteases control most of the physiological processes that occur in a cell. This particularly applies to apoptosis, the most well-studied form of cell death, where proteolysis by cysteine-aspartic proteases (caspases) is the primary mechanism for both initiation and execution of cell suicide. In contrast, the impact of proteolysis on other, non-apoptotic cell death pathways (summarized under the term "regulated necrosis", RN) has long been enigmatic, but has clearly been confirmed by a number of recent groundbreaking discoveries. Here, we review these discoveries and provide an overview on the role of proteolysis in known forms of RN, with a particular focus on necroptosis and pyroptosis, and their regulation by deubiquitinases, apoptotic and inflammatory caspases. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John. PMID- 28577896 TI - Review of TCE cardiac defects data by Makris et al. is not systematic. PMID- 28577895 TI - Sox2 regulates Muller glia reprogramming and proliferation in the regenerating zebrafish retina via Lin28 and Ascl1a. AB - Sox2 is a well-established neuronal stem cell-associated transcription factor that regulates neural development and adult neurogenesis in vertebrates, and is one of the critical genes used to reprogram differentiated cells into induced pluripotent stem cells. We examined if Sox2 was involved in the early reprogramming-like events that Muller glia undergo as they upregulate many pluripotency- and neural stem cell-associated genes required for proliferation in light-damaged adult zebrafish retinas. In the undamaged adult zebrafish retina, Sox2 is expressed in Muller glia and a subset of amacrine cells, similar to other vertebrates. Following 31 h of light damage, Sox2 expression significantly increased in proliferating Muller glia. Morpholino-mediated knockdown of Sox2 expression resulted in decreased numbers of proliferating Muller glia, while induced overexpression of Sox2 stimulated Muller glia proliferation in the absence of retinal damage. Thus, Sox2 is necessary and sufficient for Muller glia proliferation. We investigated the role of Wnt/beta-catenin signaling, which is a known regulator of sox2 expression during vertebrate retinal development. While beta-catenin 2, but not beta-catenin 1, was necessary for Muller glia proliferation, neither beta-catenin paralog was required for sox2 expression following retinal damage. Sox2 expression was also necessary for ascl1a (neurogenic) and lin28a (reprogramming) expression, but not stat3 expression following retinal damage. Furthermore, Sox2 was required for Muller glial-derived neuronal progenitor cell amplification and expression of the pro-neural marker Tg(atoh7:EGFP). Finally, loss of Sox2 expression prevented complete regeneration of cone photoreceptors. This study is the first to identify a functional role for Sox2 during Muller glial-based regeneration of the vertebrate retina. PMID- 28577897 TI - Time as tyrant: The minute, hour and day make a difference for corticosterone concentrations in wild nestlings. AB - The hypothalamic-pituitary-adrenal (HPA) axis has been studied extensively in adults, but the HPA axis in early life is not well characterized, and there is an immense amount of unexplained variation in glucocorticoid levels during early life, especially in wild animals. To characterize population-wide natural variation in early-life HPA axis function, we compared plasma corticosterone levels (at baseline and after 30min acute restraint-stress) from seven-day-old nestlings (n=123) from a free-living, marked population of Savannah sparrows (Passerculus sandwichensis). We found a surprising sensitivity of the HPA axis to timing of sample collection across time scales. Even within the accepted 3-min framework to collect baseline samples, time to collect blood had a significant effect on baseline corticosterone concentrations. Daily rhythms also influenced baseline levels, which increased significantly during the relatively short window of sample collection (1100 and 1600). On a broader timeframe, there was a strong effect of hatch date (over a 2month period) on HPA axis responsiveness, where nestlings hatched later in the breeding season had lower stress-induced corticosterone levels than those hatched earlier. The ecophysiological mechanisms and implications of these patterns warrant future investigation; meanwhile this study highlights the critical need to consider, and potentially restrict, time across scales when collecting blood samples from wild birds to assess stress physiology. PMID- 28577898 TI - The nexus of hair corticosterone level, immunocompetence, metabolic rates and overwinter survival in the root vole, Microtus oeconomus. AB - Although corticosterone (CORT) regulates many physiological mechanisms, the associations between CORT levels, immunocompetence, energy expenditures and overwinter survival have not been examined. Here, we studied individual variation in CORT level extracted from hair, immunocompetence quantified as the neutrophil to-lymphocyte (N/L) ratio, total white blood cells (WBC) and natural antibody levels (NAbs), along with the resting (RMR) and peak metabolic rates (PMR) and mortality during three consecutive winter seasons in a natural population of the root vole, Microtus oeconomus. In early winter, hair CORT level was strongly positively associated with body mass and inversely related to voles' ability to survive. We suggest that the observed association between hair CORT level and body mass may be the key component of the physiological nexus driving the survivorship of individual rodents. Additionally, hair CORT was a significant predictor of variation of the whole body RMR, which in turn enhanced overwinter survival in the studied population. On the other hand, hair CORT was not significantly associated with changes in the blood indices. Interestingly, the analysis carried out only during the first year of study (2008), which was characterized by a high population density and prevalence of infestation with a blood protozoan, Babesia spp., showed that the intensity of the infestation was negatively correlated with both the hair CORT level and the N/L ratio. Because CORT is often considered immunosuppressive, we expected a positive association between its level and the N/L ratio. However, hair CORT did not significantly correlate with the N/L ratio. We suggest that the lack of an association between hair CORT and the N/L ratio resulted from a small inter-individual variation in the N/L ratio in 2008, which was much higher and less variable than in the other years of our study. PMID- 28577899 TI - Development of a novel and highly efficient method of isolating bacteriophages from water. AB - Bacteriophages are widely used to the treatment of drug-resistant bacteria and the improvement of food safety through bacterial lysis. However, the limited investigations on bacteriophage restrict their further application. In this study, a novel and highly efficient method was developed for isolating bacteriophage from water based on the electropositive silica gel particles (ESPs) method. To optimize the ESPs method, we evaluated the eluent type, flow rate, pH, temperature, and inoculation concentration of bacteriophage using bacteriophage f2. The quantitative detection reported that the recovery of the ESPs method reached over 90%. The qualitative detection demonstrated that the ESPs method effectively isolated 70% of extremely low-concentration bacteriophage (100 PFU/100L). Based on the host bacteria composed of 33 standard strains and 10 isolated strains, the bacteriophages in 18 water samples collected from the three sites in the Tianjin Haihe River Basin were isolated by the ESPs and traditional methods. Results showed that the ESPs method was significantly superior to the traditional method. The ESPs method isolated 32 strains of bacteriophage, whereas the traditional method isolated 15 strains. The sample isolation efficiency and bacteriophage isolation efficiency of the ESPs method were 3.28 and 2.13 times higher than those of the traditional method. The developed ESPs method was characterized by high isolation efficiency, efficient handling of large water sample size and low requirement on water quality. PMID- 28577900 TI - A novel prophylaxis with C1-inhibitor concentrate in hereditary angioedema during erythema marginatum. AB - BACKGROUND: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is a rare, autosomal dominant disorder. The characteristic episodes of subcutaneous/submucosal edema formation may be preceded by erythema marginatum (EM) - the occurrence of a 'map-like' pattern on the skin. EM can occur as an isolated finding or accompanying a hereditary angiooedema (HAE) attack as well. Nevertheless, it is unknown whether a HAE attack can be prevented by the proper prophylactic treatment during EM. OBJECTIVES: Our aim was to assess the prevalence of EM in the Hungarian C1-INH-HAE population and to introduce a safe and effective novel prophylactic treatment during EM in patients who's HAE attacks are preceded by EM in a considerable proportion of the cases. RESULTS: Based on the data of the Hungarian HAE Registry, 49 among 173 C1-INH-HAE patients (28.3%) from 32 families had EM in their life. According to the clinical data and the patient's HAE diaries, two patients (Patient #1, Patient #2) were selected who frequently had EM as a prodromal symptom. Both patients were instructed to administer plasma-derived C1-inhibitor concentrate (pdC1-INH) as soon as possible after the onset of EM, in order to prevent the development of HAE attack. Interestingly, HAE attacks never developed if pdC1-INH was administered within 6h from the occurrence of EM in both patients. In contrast, without pdC1-INH treatment, in Patient 1 and Patient 2, 97.0% and 44.3% of the EM were followed by a HAE attack, respectively (p<0.0001, Fisher's exact test). CONCLUSIONS: As a novel prophylaxis in C1-INH-HAE, intravenous administration of pdC1-INH concentrate during EM might be an effective, individual therapeutic strategy in those patients who's HAE attacks are often preceded by EM. Besides it can improve the quality of life of these selected patients, pdC1-INH administration during EM provides the lowest effective dose for the prophylaxis of their HAE attacks. PMID- 28577901 TI - Functional studies of chronic lymphocytic leukemia B cells expressing beta2 integrin type complement receptors CR3 and CR4. AB - The expression and role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in B cells are not yet explored in contrast to myeloid cells, where these beta2-integrin type receptors are known to participate in various cellular functions, including phagocytosis, adherence and migration. Here we aimed to reveal the expression and role of CR3 and CR4 in human B cells. In B cells of healthy donors CR3 and CR4 are scarcely expressed. However, two patients with chronic lymphocytic leukemia (CLL) characterized by a peculiar immune-phenotype containing both CD5-positive and CD5-negative B cell populations made possible to study these molecules in distinct B cell subsets. We found that CD11b and CD11c were expressed on both CD5 positive and CD5-negative B cells, albeit to different extents. Our data suggest that these receptors are involved in spreading, since this activity of CpG activated B cells on fibrinogen could be partially blocked by monoclonal antibodies specific for CD11b or CD11c. CpG-stimulation lead to proliferation of both CD5-positive and CD5-negative B cells of the patients with a less pronounced effect on the CD5-positive cells. In contrast to normal B cells, CLL B cells of both patients reacted to CpG-stimulation with robust IL-10 production. The concomitant, suboptimal stimulus via the BCR and TLR9 exerted either a synergistic enhancing effect or resulted in inhibition of proliferation and IL-10 production of patients' B cells. Our data obtained studying B cells of leukemic patients point to the role of CR3 and probably CR4 in the interaction of tumor cells with the microenvironment and suggest the involvement of IL-10 producing B cells in the pathologic process. PMID- 28577902 TI - Directional sensitivity of anomalous diffusion in human brain assessed by tensorial fractional motion model. AB - Anisotropic diffusion in the nervous system is most commonly modeled by apparent diffusion tensor, which is based on regular diffusion theory. However, the departure of diffusion-induced signal attenuation from a mono-exponential form implies that there is anomalous diffusion. Recently, a novel diffusion NMR theory based on the fractional motion (FM) model, which is an anomalous diffusion model, has been proposed. While the FM model has been applied to both healthy subjects and tumor patients, its anisotropy in the nervous system remains elusive. In this study, this issue was addressed by measuring the FM-related parameters in 12 non collinear directions. A metric to quantify the directional deviation was derived. Furthermore, the FM-related parameters were modeled as tensors and analyzed in analogy with the conventional diffusion tensor imaging (DTI). Experimental results, which were obtained for 15 healthy subjects at 3T, exhibited pronounced anisotropy of the FM-related parameters, although the effects were smaller than the apparent diffusion coefficient (ADC). The tensorial nature for alpha, which is the Noah exponent in the FM model, showed behavior similar to the ADC, especially the principal eigenvector for alpha aligned with the dominant white matter fiber directions. The Hurst exponent H in the FM model, however, showed no correlation with the major fiber directions. The anisotropy of the FM model may provide complementary information to DTI and may have potential for tractography and detecting brain abnormalities. PMID- 28577903 TI - The role of adhesion junctions in the biomechanical behaviour and osteogenic differentiation of 3D mesenchymal stem cell spheroids. AB - Osteogenesis of mesenchymal stem cells (MSC) can be regulated by the mechanical environment. MSCs grown in 3D spheroids (mesenspheres) have preserved multi lineage potential, improved differentiation efficiency, and exhibit enhanced osteogenic gene expression and matrix composition in comparison to MSCs grown in 2D culture. Within 3D mesenspheres, mechanical cues are primarily in the form of cell-cell contraction, mediated by adhesion junctions, and as such adhesion junctions are likely to play an important role in the osteogenic differentiation of mesenspheres. However the precise role of N- and OB-cadherin on the biomechanical behaviour of mesenspheres remains unknown. Here we have mechanically tested mesenspheres cultured in suspension using parallel plate compression to assess the influence of N-cadherin and OB-cadherin adhesion junctions on the viscoelastic properties of the mesenspheres during osteogenesis. Our results demonstrate that N-cadherin and OB-cadherin have different effects on mesensphere viscoelastic behaviour and osteogenesis. When OB-cadherin was silenced, the viscosity, initial and long term Young's moduli and actin stress fibre formation of the mesenspheres increased in comparison to N-cadherin silenced mesenspheres and mesenspheres treated with a scrambled siRNA (Scram) at day 2. Additionally, the increased viscoelastic material properties correlate with evidence of calcification at an earlier time point (day 7) of OB-cadherin silenced mesenspheres but not Scram. Interestingly, both N-cadherin and OB cadherin silenced mesenspheres had higher BSP2 expression than Scram at day 14. Taken together, these results indicate that N-cadherin and OB-cadherin both influence mesensphere biomechanics and osteogenesis, but play different roles. PMID- 28577905 TI - Influence of rapidly successive head impacts on brain strain in the vicinity of bridging veins. AB - Acute subdural hematoma due to a bridging vein rupture is a devastating but rare injury. There has to date been no satisfactory biomechanical explanation for this infrequent but costly injury. We surmise that it may be associated with multiple head impacts. Though numerical models have been used to estimate vein strains in single impact events, none to date have examined the influence on localized brain strain of rapidly consecutive impacts. Using the Simulated Injury Monitor, we investigated the hypothesis that such double impacts can increase strain beyond that created by any single impact. Input to our parametric study comprised hypothetical biphasic rotational head accelerations producing a maximum angular velocity of 40rad./s. In each of 19 simulations, two identical angular inputs are applied at right angles to each other but with time separations varying from 0 to 40ms. For these double impacts, it has been generally found that strain in the region of the bridging veins is different, than what would be associated with any corresponding single impact. In some cases, the effect is to actually reduce the tissue strain. In others, the strain in the region of the bridging veins is increased markedly. The mechanistic explanation for the strain increase is that the tissue strain from the first impact has not diminished fully when strain from the second impact is initiated. Rapidly consecutive impacts could be a potential mechanism leading to vein rupture that warrants further investigation. PMID- 28577904 TI - Merging computational fluid dynamics and 4D Flow MRI using proper orthogonal decomposition and ridge regression. AB - Time resolved phase-contrast magnetic resonance imaging 4D-PCMR (also called 4D Flow MRI) data while capable of non-invasively measuring blood velocities, can be affected by acquisition noise, flow artifacts, and resolution limits. In this paper, we present a novel method for merging 4D Flow MRI with computational fluid dynamics (CFD) to address these limitations and to reconstruct de-noised, divergence-free high-resolution flow-fields. Proper orthogonal decomposition (POD) is used to construct the orthonormal basis of the local sampling of the space of all possible solutions to the flow equations both at the low-resolution level of the 4D Flow MRI grid and the high-level resolution of the CFD mesh. Low resolution, de-noised flow is obtained by projecting in vivo 4D Flow MRI data onto the low-resolution basis vectors. Ridge regression is then used to reconstruct high-resolution de-noised divergence-free solution. The effects of 4D Flow MRI grid resolution, and noise levels on the resulting velocity fields are further investigated. A numerical phantom of the flow through a cerebral aneurysm was used to compare the results obtained using the POD method with those obtained with the state-of-the-art de-noising methods. At the 4D Flow MRI grid resolution, the POD method was shown to preserve the small flow structures better than the other methods, while eliminating noise. Furthermore, the method was shown to successfully reconstruct details at the CFD mesh resolution not discernible at the 4D Flow MRI grid resolution. This method will improve the accuracy of the clinically relevant flow-derived parameters, such as pressure gradients and wall shear stresses, computed from in vivo 4D Flow MRI data. PMID- 28577906 TI - Dynamic head-neck stabilization and modulation with perturbation bandwidth investigated using a multisegment neuromuscular model. AB - The human head-neck system requires continuous stabilization in the presence of gravity and trunk motion. We investigated contributions of the vestibulocollic reflex (VCR), the cervicocollic reflex (CCR), and neck muscle co-contraction to head-in-space and head-on-trunk stabilization, and investigated modulation of the stabilization strategy with the frequency content of trunk perturbations and the presence of visual feedback. We developed a multisegment cervical spine model where reflex gains (VCR and CCR) and neck muscle co-contraction were estimated by fitting the model to the response of young healthy subjects, seated and exposed to anterior-posterior trunk motion, with frequency content from 0.3 up to 1, 2, 4 and 8Hz, with and without visual feedback. The VCR contributed to head-in-space stabilization with a strong reduction of head rotation (<8Hz) and a moderate reduction of head translation (>1Hz). The CCR contributed to head-on-trunk stabilization with a reduction of head rotation and head translation relative to the trunk (<2Hz). The CCR also proved essential to stabilize the individual intervertebral joints and prevent neck buckling. Co-contraction was estimated to be of minor relevance. Control strategies employed during low bandwidth perturbations most effectively reduced head rotation and head relative displacement up to 3Hz while control strategies employed during high bandwidth perturbations reduced head global translation between 1 and 4Hz. This indicates a shift from minimizing head-on-trunk rotation and translation during low bandwidth perturbations to minimizing head-in-space translation during high bandwidth perturbations. Presence of visual feedback had limited effects suggesting increased usage of vestibular feedback. PMID- 28577907 TI - Assessment of the lower limb soft tissue artefact at marker-cluster level with a high-density marker set during walking. AB - The estimation of joint kinematics from skin markers is hindered by the soft tissue artefact (STA), a well-known phenomenon although not fully characterized. While most assessments of the STA have been performed based on the individual skin markers displacements, recent assessments were based on the marker-cluster geometrical transformations using, e.g., principal component or modal analysis. However, these marker-clusters were generally made of 4-6 markers and the current findings on the STA could have been biased by the limited number of skin makers analysed. The objective of the present study was therefore to confirm them with a high-density marker set, i.e. 40 markers placed on the segments. A larger number of modes than found in the literature was required to describe the STA. Nevertheless, translations and rotations of the marker-cluster remained the main STA modes, archetypally the translation along the proximal-distal and anterior posterior axes for the shank and the translation along the proximal-distal axis and the rotation about the medial-lateral axis for the thigh. High correlations were also found between the knee flexion angle and the amplitude of these modes for the thigh whereas moderate ones were found for the shank. These findings support the current re-orientation of the STA compensation methods, from bone pose estimators which typically address the non-rigid components of the marker cluster to kinematic-driven rigid-component STA models. PMID- 28577908 TI - New phenalenone derivatives from Pinellia ternata tubers derived Aspergillus sp. AB - Nine new phenalenone derivatives (1-9), along with two known analogues (10-11) have been isolated from the solid cultures of an endophytic fungus Aspergillus sp. which was obtained from Pinellia ternate. Their structures were established through interpretations of spectroscopic evidence, and some of their absolute configurations were determined by electronic circular dichroism (ECD) and Mo2(OCOCH3)4 induced ECD. All of the phenalenones are unusual acyclic diterpenoid adducts, which are diversely oxidized and partly epoxidized to form different heterocycles. In addition, compound 10 exhibited significant antimicrobial activity against Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis with MIC50 values of 1.87, 2.77, and 4.80MUg/mL, respectively. PMID- 28577909 TI - SOX7 expression is critically required in FLK1-expressing cells for vasculogenesis and angiogenesis during mouse embryonic development. AB - The transcriptional program that regulates the differentiation of endothelial precursor cells into a highly organized vascular network is still poorly understood. Here we explore the role of SOX7 during this process, performing a detailed analysis of the vascular defects resulting from either a complete deficiency in Sox7 expression or from the conditional deletion of Sox7 in FLK1 expressing cells. We analysed the consequence of Sox7 deficiency from E7.5 onward to determine from which stage of development the effect of Sox7 deficiency can be observed. We show that while Sox7 is expressed at the onset of endothelial specification from mesoderm, Sox7 deficiency does not impact the emergence of the first endothelial progenitors. However, by E8.5, clear signs of defective vascular development are already observed with the presence of highly unorganised endothelial cords rather than distinct paired dorsal aorta. By E10.5, both Sox7 complete knockout and FLK1-specific deletion of Sox7 lead to widespread vascular defects. In contrast, while SOX7 is expressed in the earliest specified blood progenitors, the VAV-specific deletion of Sox7 does not affect the hematopoietic system. Together, our data reveal the unique role of SOX7 in vasculogenesis and angiogenesis during embryonic development. PMID- 28577911 TI - A singular mutation in the hemagglutinin of the 1918 pandemic virus. AB - The influenza pandemic of 1918-1919 killed at least 50 million people. The reasons why this pandemic was so deadly remain largely unknown [9]. However, It has been shown that the 1918 viral hemagglutinin allows to reproduce the hallmarks of the illness observed during the original pandemic [11]. Thanks to the wealth of hemagglutinin sequences accumulated over the last decades, amino acid substitutions that are found in the 1918-1919 sequences but rare otherwise can be identified with high confidence. Noteworthy, Gly 188, which is located within a key motif of the receptor binding site, has never been observed again in sequences of human viruses of subtype H1. Monitoring this singular mutation in viral sequences may help prevent another dramatic pandemic. PMID- 28577910 TI - The type II isopentenyl Diphosphate:Dimethylallyl diphosphate isomerase (IDI-2): A model for acid/base chemistry in flavoenzyme catalysis. AB - The chemical versatility of the flavin coenzyme is nearly unparalleled in enzyme catalysis. An interesting illustration of this versatility can be found in the reaction catalyzed by the type II isopentenyl diphosphate:dimethylallyl diphosphate isomerase (IDI-2) - an enzyme that interconverts the two essential isoprene units (isopentenyl pyrophosphate and dimethylallyl pyrophosphate) that are needed to initiate the biosynthesis of all isoprenoids. Over the past decade, a variety of biochemical, spectroscopic, structural and mechanistic studies of IDI-2 have provided mounting evidence that the flavin coenzyme of IDI-2 acts in a most unusual manner - as an acid/base catalyst to mediate a 1,3-proton addition/elimination reaction. While not entirely without precedent, IDI-2 is by far the most extensively studied flavoenzyme that employs flavin-mediated acid/base catalysis. Thus, IDI-2 serves as an important mechanistic model for understanding this often overlooked, but potentially widespread reactivity of flavin coenzymes. This review details the most pertinent studies that have contributed to the development of mechanistic proposals for this highly unusual flavoenzyme, and discusses future experiments that may be able to clarify remaining uncertainties in the chemical mechanism of IDI-2. PMID- 28577912 TI - Targeting survivin for therapeutic discovery: past, present, and future promises. AB - Survivin, the smallest member of the inhibitor of apoptosis protein (IAP) family, is overexpressed in cells of almost all cancers but not in most normal tissues in adults. Survivin expression is required for cancer cell survival and knocking down its expression or inhibiting its function using molecular approaches results in spontaneous apoptosis. Thus, survivin is an attractive and perhaps ideal target for cancer drug discovery. However, a US Food and Drug Administration (FDA)-approved drug targeting survivin has yet to emerge. In this Foundation Review, we examine and evaluate various strategies that have been used to target survivin and the stages of each survivin inhibitor to help understand this lack of success. We also provide future perspectives moving forward in targeting survivin for drug discovery. PMID- 28577913 TI - Anticonvulsant activity of resveratrol-loaded liposomes in vivo. AB - Resveratrol (3,5,4'-stilbenetriol), a natural polyphenol produced by various plants, has attracted attention over the past decade because of its multiple beneficial properties, including anti-inflammatory, anti-oxidant and chemopreventive, yet, there is limited information about its antiepileptic effects. Moreover, its poor solubility in water and low bioavailability are the challenging issues. In the present study, we aimed to investigate effects of free resveratrol and resveratrol delivered in amphipathic liposomal delivery system, which has a high blood-brain barrier crossing potential, on penicillin-induced epileptic seizure model. For this purpose, adult male Sprague-Dawley rats were divided into four groups as saline (Control), liposome (LIP), free resveratrol (RES) and resveratrol+liposome (RES+LIP). Penicillin-induced epileptic activity was recorded for 120 min by electrocorticography. Glutathione S-transferase (GST), Glutathione (GSH), Superoxide dismutase (SOD) and Malondialdehyde (MDA) assays were performed in brain tissues collected. Our results showed that RES+LIP was the most effective anticonvulsant treatment on penicillin-induced epileptic seizures when compared to control, as RES+LIP immediately decreased the number of spikes per minute. GST and SOD activity, as well as the GSH levels, were significantly increased in the RES+LIP group as compared with the control group. Also, the MDA levels were significantly higher in the RES+LIP compared to RES and control groups. In conclusion, RES+LIP treatment was more effective on the decrease in spike frequency and spike amplitudes than other treatments. Our results suggest that the RES+LIP is more effective than RES on penicillin-induced epileptiform activity. PMID- 28577914 TI - Genetic characterization of enterovirus strains identified in Hand, Foot and Mouth Disease (HFMD): Emergence of B1c, C1 subgenotypes, E2 sublineage of CVA16, EV71 and CVA6 strains in India. AB - Hand, Foot and Mouth disease (HFMD) is a common childhood disease and caused due to Enterovirus-A (EV-A), EV-B and EV-C species worldwide. Cases of HFMD were reported from, Ahmedabad (Gujarat, 2012) and Pune (Maharashtra, 2013-2014) in India. The present study highlights the identification of EV strains (CVA16, CVA6, CVA4 and Echo12), characterization of subgenotypes of CVA16, CVA6 strains during 2012-14 and CVA16, CVA6, EV71 strains reported from the earlier study (2009-10) in HFMD cases from India. A total 158 clinical specimens collected from 64 HFMD cases (2012-2014) were included in the study. EV detection was carried out by 5'NCR based RT-PCR, molecular typing and subgenotyping was by VP1/2A junction or VP1, full VP1 gene amplification respectively followed by phylogenetic analysis. The present study reports 63.92% (101/158) EV positivity by RT-PCR. Ninety four of the 101 (93.06%) EV positive strains were amplified by VP1/2A junction or VP1 regions. Sequence analysis revealed the presence of CVA16 (61.7%), CVA6 (34.04%), CVA4 and Echo12 (4.3%). A total of 114 EV positive strains were genotyped using full and partial VP1 region. All CVA16 Indian strains (n=70) clustered with rarely reported B1c subgenotype, CVA6 (n=43) and EV71 (n=1) strains clustered with sub-lineage E2 and C1 subgenotypes respectively. In summary, the study reports genetic characterization of CVA16, CVA6, CVA4 and Echo12 strains in HFMD cases from India. Circulation of B1c subgenotype of CVA16, E2 sub-lineage of CVA6 and C1 subgenotype of EV 71 strains in HFMD cases were reported for the first time from India. This study helps to understand the genotype distribution, genetic diversity of EV strains associated with HFMD from Eastern, Western and Southern regions in India. PMID- 28577916 TI - Complete genome sequence of Bacillus sp. 275, producing extracellular cellulolytic, xylanolytic and ligninolytic enzymes. AB - Technologies for degradation of three major components of lignocellulose (e.g. cellulose, hemicellulose and lignin) are needed to efficiently utilize lignocellulose. Here, we report Bacillus sp. 275 isolated from a mudflat exhibiting various lignocellulolytic activities including cellulase, xylanase, laccase and peroxidase in the cell culture supernatant. The complete genome of Bacillus sp. 275 strain contains 3832 protein cording sequences and an average G+C content of 46.32% on one chromosome (4045,581bp) and one plasmid (6389bp). The genes encoding enzymes related to the degradation of cellulose, xylan and lignin were detected in the Bacillus sp. 275 genome. In addition, the genes encoding glucosidases that hydrolyze starch, mannan, galactoside and arabinan were also found in the genome, implying that Bacillus sp. 275 has potentially a wide range of uses in the degradation of polysaccharide in lignocellulosic biomasses. PMID- 28577917 TI - Sequential congenital and acquired presentation of bilateral Brown syndrome. PMID- 28577915 TI - Histo-blood group carbohydrates as facilitators for infection by Helicobacter pylori. AB - Helicobacter pylori infect millions of people around the world. It occupies a niche in the human gastrointestinal tract characterized by high expression of a repertoire of carbohydrates. ABO and Lewis histo-blood group systems are controlled by genes coding for functional glycosyltransferases which synthesize great diversity of related fucosylated carbohydrate in different tissues, including gastrointestinal mucosa, and exocrine secretions. The structural diversity of histo-blood group carbohydrates is highly complex and depends on epistatic interactions among gene-encoding glycosyltransferases. The histo-blood group glycosyltransferases act in the glycosylation of proteins and lipids in the human gastrointestinal tract allowing the expression of a variety of potential receptors in which H. pylori can adhere. These oligosaccharide molecules are part of the gastrointestinal repertoire of carbohydrates which act as potential receptors for microorganisms, including H. pylori. This Gram-negative bacillus is one of the main causes of the gastrointestinal diseases such as chronic active gastritis, peptic ulcer, and cancer of stomach. Previous reports showed that some H. pylori strains use carbohydrates as receptors to adhere to the gastric and duodenal mucosa. Since some histo-blood group carbohydrates are highly expressed in one but not in others histo-blood group phenotypes it has pointed out that quantitative differences among them influence the susceptibility to diseases caused by H. pylori. Additionally, some experiments using animal model are helping us to understand how this bacillus explore histo-blood group carbohydrates as potential receptors, offering possibility to explore new strategies of management of infection, disease treatment, and prevention. This text highlights the importance of structural diversity of ABO and Lewis histo blood group carbohydrates as facilitators for H. pylori infection. PMID- 28577918 TI - The neuropeptidome of the Crown-of-Thorns Starfish, Acanthaster planci. AB - : Outbreaks of Crown-of-Thorns Starfish (COTS; Acanthaster planci) are a major cause of destruction of coral communities on the Australian Great Barrier Reef. While factors relating to population explosions and the social interactions of COTS have been well studied, little is known about the neural mechanisms underlying COTS physiology and behaviour. One of the major classes of chemical messengers that regulate physiological and behavioural processes in animals is the neuropeptides. Here, we have analysed COTS genome and transcriptome sequence data to identify neuropeptide precursor proteins in this species. A total of 48 neuropeptide precursors were identified, including homologs of neuropeptides that are evolutionarily conserved throughout the Bilateria, and others that are novel. Proteomic mass spectrometry was employed to confirm the presence of neuropeptides in extracts of radial nerve cords. These transcriptomic and proteomic resources provide a foundation for functional studies that will enable a better understanding of COTS physiology and behaviour, and may facilitate development of novel population biocontrol methods. SIGNIFICANCE: The Crown-of-Thorns Starfish (COTS) is one of the primary factors leading to coral loss on the Great Barrier Reef, Australia. Our combined gene and proteomic findings of this study reveal the COTS neuropeptidome, including both echinoderm-like neuropeptides and novel putative neuropeptides. This represents the most comprehensive neuropeptidome for an echinoderm, contributing to the evolving knowledge of the COTS molecular neurobiology that may assist towards the development of biocontrol methods. PMID- 28577919 TI - Immunization of Tg-APPswe/PSEN1dE9 mice with Abeta3-10-KLH vaccine prevents synaptic deficits of Alzheimer's disease. AB - The amyloid cascade hypothesis is widely accepted by researchers as the mechanism of Alzheimer's disease. Active immunization to eliminate Abeta depositions has been used in preclinical and clinical studies. Abeta3-10-KLH is a vaccine of the Abeta3-10 peptide combined with keyhole limpet hemocyanin (KLH). We immunized 2.5 month-old Tg-APPswe/PSEN1dE9 mice with Abeta3-10-KLH peptide and Abeta1-42 peptide to eliminate Abeta deposits in the brains of these transgenic mice. The results of immunohistochemical staining and transmission electron microscopy detection indicated that our new vaccine was more advantageous in protecting synaptic function and structure than the Abeta1-42 peptide. Abeta3-10-KLH peptide is an effective vaccine in the treatment of Alzheimer's disease. PMID- 28577920 TI - The MAM-E17 schizophrenia rat model: Comprehensive behavioral analysis of pre pubertal, pubertal and adult rats. AB - The MAM-E17 model is one of the most accepted schizophrenia rat models, which follows the neurodevelopmental theory of the disease. While symptoms of MAM-E17 rats were studied extensively, their examinations were usually restricted to adulthood and in a few cases to prepuberty. It is well known, however, that schizophrenia symptoms often start at puberty or early adulthood. Therefore the purpose of this study was to investigate the behavioral characteristics of MAM E17 rats in various tests throughout three different age-periods, namely in prepuberty, late puberty and adulthood. In open field test, MAM-E17 rats displayed increased locomotor activity, elevated sniffing frequency and, as tendency, enhanced rearing activity. The elevated activity turned up in late puberty and remained there in adulthood, too. There was also a deficient prepulse inhibition (PPI) of startle response in late puberty and adulthood, but not before puberty. In rotarod task, MAM-treated rats performed better than control rats. The enhanced performance on rotarod was only present in late puberty and adulthood. In elevated plus maze test MAM-treated rats displayed diminished anxiety mostly in prepuberty. Histological analysis revealed reduced volume and cell disarray in the dorsal hippocampus. This is the first comprehensive study about symptoms of MAM-E17 rats manifested in behavioral tests carried out in prepuberty, late puberty and adulthood. Results display the age-dependent appearance of schizophrenia symptoms in the same rats. The present findings provide basic information to accomplish the schizophrenia related animal research, as well as can also confer further data to develop preventive treatment for human patients. PMID- 28577921 TI - Parent-of-origin effects on schizophrenia-relevant behaviours of type III neuregulin 1 mutant mice. AB - A robust, disease-relevant phenotype is paramount to the validity of genetic mouse models, which are an important tool in understanding complex diseases. Recent evidence from genome-wide association studies suggests the genetic contribution of parents to offspring is not equivalent. Despite this, few studies to date have examined the potential impact of parent genotype (i.e. origin of mutation) on the offspring of disease-relevant genetic mouse models. To elucidate the potential impact of the sex of the mutant parent on offspring phenotype, we characterized male and female offspring of an established schizophrenia mouse model, which had been generated using two different breeding schemes, in a range of disease-relevant behaviours. We compared heterozygous type III neuregulin 1 mutant (type III Nrg1+/-) and wild type-like control (WT) offspring from mutant father x WT mother pairings with offspring from mutant mother x WT father pairings. Offspring were tested in schizophrenia-relevant paradigms including the elevated plus maze (EPM), fear conditioning (FC), prepulse inhibition (PPI), social interaction (SI), and open field (OF). We found type III Nrg1+/- males from mutant fathers, but not mutant mothers, showed deficits in contextual fear associated memory and exhibited increased social interaction, compared to their WT littermates. Type III Nrg1+/- females across breeding colonies only exhibited a subtle change to their acoustic startle response and sensorimotor gating. These results suggest a paternal-dependent transmission of genetically induced behavioural characteristics. Though the mechanisms governing this phenomenon are unclear, our results show that parental origin of mutation can alter the behavioural phenotype of genetic mouse models. Thus, researchers should carefully consider their breeding scheme when dealing with genetic mouse models of diseases such as schizophrenia. PMID- 28577922 TI - Role of silver nitrate in the efficacy of hydrogen peroxide aerial decontamination systems. PMID- 28577923 TI - Adenosine triphosphate bioluminescence to validate decontamination of endoscopes. AB - The reports of outbreaks involving carbapenemase-resistant Enterobacteriaceae (CRE) associated with gastrointestinal endoscopy prompted a review and study of a novel method of assessing cleaning. This study assessed adenosine triphosphate (ATP) bioluminescence to demonstrate cleanliness prior to endoscopy. ATP testing was compared with microbiological monitoring for 127 endoscopes. Samples were taken after cleaning, reprocessing and storage, but immediately before the endoscopy procedure. We recommend implementing ATP testing prior to endoscopy procedures as an alternative to microbiological testing at periodic intervals. ATP testing provides a convenient assessment of endoscopy hygiene to demonstrate safety and quality assurance. PMID- 28577924 TI - Forceful patterning in mouse preimplantation embryos. AB - The generation of a functional organism from a single, fertilized ovum requires the spatially coordinated regulation of diverse cell identities. The establishment and precise arrangement of differentiated cells in developing embryos has, historically, been extensively studied by geneticists and developmental biologists. While chemical gradients and genetic regulatory networks are widely acknowledged to play significant roles in embryo patterning, recent studies have highlighted that mechanical forces generated by, and exerted on, embryos are also crucial for the proper control of cell differentiation and morphogenesis. Here we review the most recent findings in murine preimplantation embryogenesis on the roles of cortical tension in the coupling of cell-fate determination and cell positioning in 8-16-cell-stage embryos. These basic principles of mechanochemical coupling in mouse embryos can be applied to other pattern formation phenomena that rely on localized modifications of cell polarity proteins and actin cytoskeletal components and activities. PMID- 28577926 TI - MACF1, versatility in tissue-specific function and in human disease. AB - Spectraplakins are a family of evolutionarily conserved gigantic proteins and play critical roles in many cytoskeleton-related processes. Microtubule actin crosslinking factor 1 (MACF1) is one of the most versatile spectraplakin with multiple isoforms. As a broadly expressed mammalian spectraplakin, MACF1 is important in maintaining normal functions of many tissues. The loss-of-function studies using knockout mouse models reveal the pivotal roles of MACF1 in embryo development, skin integrity maintenance, neural development, bone formation, and colonic paracellular permeability. Mutation in the human MACF1 gene causes a novel myopathy genetic disease. In addition, abnormal expression of MACF1 is associated with schizophrenia, Parkinson's disease, cancer and osteoporosis. This demonstrates the crucial roles of MACF1 in physiology and pathology. Here, we review the research advances of MACF1's roles in specific tissue and in human diseases, providing the perspectives of MACF1 for future studies. PMID- 28577927 TI - Deletion of the Bombyx mori odorant receptor co-receptor (BmOrco) impairs olfactory sensitivity in silkworms. AB - Olfaction plays an essential role in many important insect behaviors such as feeding and reproduction. To detect olfactory stimuli, an odorant receptor co receptor (Orco) is required. In this study, we deleted the Orco gene in the Lepidopteran model insect, Bombyx mori, using a binary transgene-based clustered regulatory interspaced short palindromic repeats (CRISPR)/Cas9 system. We initially generated somatic mutations in two targeted sites, from which we obtained homozygous mutants with deletion of a 866 base pair sequence. Because of the flight inability of B. mori, we developed a novel method to examine the adult mating behavior. Considering the specialization in larval feeding, we examined food selection behavior in Orco somatic mutants by the walking trail analysis of silkworm position over time. Single sensillum recordings indicated that the antenna of the homozygous mutant was unable to respond to either of the two sex pheromones, bombykol or bombykal. An adult mating behavior assay revealed that the Orco mutant displayed a significantly impaired mating selection behavior in response to natural pheromone released by a wild-type female moth as well as an 11:1 mixture of bombykol/bombykal. The mutants also exhibited a decreased response to bombykol and, similar to wild-type moths, they displayed no response to bombykal. A larval feeding behavior assay revealed that the Orco mutant displayed defective selection for mulberry leaves and different concentrations of the volatile compound cis-jasmone found in mulberry leaves. Deletion of BmOrco severely disrupts the olfactory system, suggesting that BmOrco is indispensable in the olfactory pathway. The approach used for generating somatic and homozygous mutations also highlights a novel method for mutagenesis. This study on BmOrco function provides insights into the insect olfactory system and also provides a paradigm for agroforestry pest control. PMID- 28577925 TI - Molecular and cytoskeletal regulations in epidermal development. AB - At the surface of the body, the epidermis covers great depth in its developmental regulation. While many genes have been shown to be important for skin development through their associations with disease phenotypes in mice and human, it is in the past decade that the intricate interplay between various molecules become gradually revealed through sophisticated genetic models and imaging analyses. In particular, there is increasing evidence suggesting that cytoskeleton-associated proteins, including adhesion proteins and the crosslinker proteins may play critical roles in regulating epidermis development. We here provide a broad overview of the various molecules involved in epidermal development with special emphasis on the cytoskeletal components. PMID- 28577928 TI - Renal Tuberculosis Following Intravesical Bacillus Calmette-Guerin for High-grade Non-muscle-invasive Bladder Cancer. AB - A 47-year-old man presented to the urology department with visible hematuria. He was found to have a high-grade non-muscle-invasive transitional cell carcinoma of the bladder and was subsequently treated with intravesical Bacillus Calmette Guerin instillations. On routine surveillance computed tomography scan following treatment, he was found to have multiple rounded areas of low density in the right kidney, suspicious for renal malignancy. He underwent renal biopsy that revealed necrotizing granulomatous inflammation suggestive of mycobacterial infection. He was successfully treated with antituberculosis therapy. PMID- 28577929 TI - MRP-1 and BCRP Promote the Externalization of Phosphatidylserine in Oxalate treated Renal Epithelial Cells: Implications for Calcium Oxalate Urolithiasis. AB - OBJECTIVE: To investigate the possible involvement of multidrug resistance associated protein 1 (MRP-1) and breast cancer resistance protein (BCRP) in the oxalate-induced redistribution of phosphatidylserine (PS) in renal epithelial cell membranes. METHODS: A western blot analysis was used to examine the MRP-1 and BCRP expression levels. Surface-expressed PS was detected by the annexin V binding assay. The cell-permeable fluorogenic probe 2,7-dichlorofluorescein diacetate was used to measure the intracellular reactive oxygen species (ROS) level. A rat model of hyperoxaluria was obtained using 0.5% ethylene glycol and 1.0% ammonium chloride. In addition, certain animals received verapamil (50 mg/kg body weight), which is a common inhibitor of MRP-1 and BCRP. The degree of nephrolithiasis was assessed histomorphometrically using sections stained by Pizzolato method and by measuring the calcium oxalate crystal content in the renal tissue. RESULTS: Oxalate produced a concentration-dependent increase in the synthesis of MRP-1 and BCRP. Treatment with MK571 and Ko143 (MRP-1- and BCRP specific inhibitors, respectively) significantly attenuated the oxalate-induced PS externalization. Adding the antioxidant N-acetyl-l-cysteine significantly reduced MRP-1 and BCRP expression. In vivo, markedly decreased nephrocalcinosis was observed compared with that in the rat model of hyperoxaluria without verapamil treatment. CONCLUSION: Oxalate induces the upregulation of MRP-1 and BCRP, which act as phospholipid floppases causing PS externalization in the renal epithelial cell membrane. The process is mediated by intracellular ROS production. The ROS-mediated increase in the synthesis of MRP-1 and BCRP can play an important role in hyperoxaluria-promoted calcium oxalate urolithiasis by facilitating phosphatidylserine redistribution in renal epithelial cells. PMID- 28577931 TI - When the Gold Standard Proves to Be Fool's Gold-Blue-light Cystoscopy in a Case of High-risk Non-muscle-invasive Bladder Cancer. PMID- 28577930 TI - Lower Urinary Tract Symptoms and Benign Prostate Hyperplasia Features Among Male BRCA Mutation Carriers. AB - OBJECTIVE: To analyze lower urinary tract symptoms and benign prostate hyperplasia features among male BRCA1 and 2 carriers and an age-matched control group. METHODS: Male BRCA carriers and noncarriers aged 40-70 years were enrolled in our cross-sectional study. Relevant clinical data were collected, and patients filled the International Prostate Symptom Score. Patients also underwent prostate specific antigen (PSA) blood testing, digital rectal examination, uroflowmetry, and post-void residual ultrasound examination. As part of their routine follow up, BRCA carriers underwent prostate magnetic resonance imaging. RESULTS: Overall, 87 carriers and 30 noncarriers were enrolled. The median age, mean body mass index, and comorbidities in both groups were similar. Maximal flow (QMAX) was higher in the noncarrier group (16.9 mL/s vs 12 mL/s, P = .01). Mean prostate volume among all BRCA carriers was 38.8 cc (19.7), but BRCA1 patients had larger glands with higher mean PSA and PSA density than BRCA2 patients (41.8 cc vs 33.1 cc, P = .047, 1.84 ng/mL vs 1.07 ng/mL, P = .006, and .044 vs .032, P = .042, respectively). Multivariate analysis demonstrated age being the sole significant predictor of PSA density in BRCA2 patients. CONCLUSION: Male carrying BRCA mutations have significantly lower QMAX than healthy men. BRCA1 patients have on average larger prostate glands and higher PSA than BRCA2 patients. Further research is required to decipher the association of lower urinary tract symptoms or benign prostate hyperplasia with BRCA carriers. PMID- 28577932 TI - In-vitro activity of several antimicrobial agents against methicillin-resistant Staphylococcus aureus (MRSA) isolates expressing aminoglycoside-modifying enzymes: potency of plazomicin alone and in combination with other agents. AB - This study investigated the in-vitro activity of clinically relevant aminoglycosides and new antimicrobial agents-plazomicin, ceftobiprole and dalbavancin-against 55 methicillin-resistant Staphylococcus aureus (MRSA) isolates producing aminoglycoside-modifying enzymes (AMEs). The checkerboard method was used to assess synergism between plazomicin and four antibiotics (fosfomycin, ceftobiprole, cefoxitin and meropenem), and time-kill assays were performed for the most active combinations. Among the aminoglycosides tested, plazomicin was the most active agent against MRSA, with >90% of isolates being inhibited at a minimum inhibitory concentration (MIC) of <=1 mg/L. MIC50 and MIC90 values for ceftobiprole and dalbavancin were 2 and 4 mg/L, and 0.125 and 0.125 mg/L, respectively. The most prevalent AME gene was aac(6')Ie-aph(2")Ia (87.3%), followed by ant(4')Ia (52.7%) and aph(3')IIIa (52.7%). Plazomicin activity was not affected by the type or number of enzymes detected. In checkerboard and time-kill assays, indifference was the most common result achieved for the antibiotic combinations. Notably, no antagonism was observed with any combination tested. Overall, plazomicin in combination with meropenem had the highest synergistic effect, demonstrating synergy against seven isolates in the checkerboard assay and three isolates in time-kill curves. In conclusion, plazomicin showed potent activity against aminoglycoside-resistant MRSA isolates, regardless of the number and type of AMEs present. These findings indicate the potential utility of plazomicin in combination with meropenem for the treatment of MRSA infections. PMID- 28577933 TI - Impact of selective reporting of antibiotic susceptibility test results on the appropriateness of antibiotics chosen by French general practitioners in urinary tract infections: a randomised controlled case-vignette study. AB - Selective reporting of antibiotic susceptibility test (AST) results is a potential intervention for laboratory-based antibiotic stewardship. The aim of this study was to assess the impact of AST reporting on the appropriateness of antibiotics selected by French general practitioners for urinary tract infections (UTIs). A randomised controlled case-vignette study in a region of northeast France surveyed general practitioners between July and October 2015 on treatment of four clinical cases of community-acquired Escherichia coli UTIs (two cases of complicated cystitis, one of acute pyelonephritis and one male UTI). In Group A, selective reporting of AST results was used for the first two cases and complete reporting for the other two cases; these were reversed in Group B. The overall participation rate was 131/198 (66.2%). Provision of selective AST results significantly increased the rate of adherence to national guidelines for first line antibiotic treatment in Cases 1, 3 and 4 by 22.4% (55.2% vs. 32.8%, P = 0.01), 67.5% (75.0% vs. 7.5%, P <0.001) and 36.3% (45.3% vs. 9.0%, P <0.001), respectively. The improvement in compliance was not significant for Case 2. Prescriptions of amoxicillin-clavulanic acid, fluoroquinolones and cephalosporins decreased by 25.0% to 45.0%, depending on the clinical vignette. Most (106/131, 81.0%) participants favoured the routine use of selective reporting of AST results. In conclusion, selective reporting of AST results seems to improve antibiotic prescribing practices in primary care, and may be considered a key element of antimicrobial stewardship programmes. PMID- 28577934 TI - Assessing mRNA nuclear export in mammalian cells by microinjection. AB - The nuclear export of mRNAs is an important yet little understood part of eukaryotic gene expression. One of the easiest methods for monitoring mRNA export in mammalian tissue culture cells is through the microinjection of DNA plasmids into the nucleus and monitoring the distribution of the transcribed product over time. Here we describe how to setup a microscope equipped with a micromanipulator used in cell microinjections, and we explain how to perform a nuclear mRNA export assay and obtain the nuclear export rate for any given mRNA. PMID- 28577935 TI - Co-expression analysis among microRNAs, long non-coding RNAs, and messenger RNAs to understand the pathogenesis and progression of diabetic kidney disease at the genetic level. AB - Diabetic kidney disease (DKD) is a serious disease that presents a major health problem worldwide. There is a desperate need to explore novel biomarkers to further facilitate the early diagnosis and effective treatment in DKD patients, thus preventing them from developing end-stage renal disease (ESRD). However, most regulation mechanisms at the genetic level in DKD still remain unclear. In this paper, we describe our innovative methodologies that integrate biological, computational, and statistical approaches to investigate important roles performed by regulations among microRNAs (miRs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs) in DKD. We conducted fully transparent, rigorously designed experiments. Our robust and reproducible results identified hsa-miR-223 3p as a candidate novel biomarker performing important roles in DKD disease process. PMID- 28577936 TI - Association between DNA methylation and coronary heart disease or other atherosclerotic events: A systematic review. AB - BACKGROUND AND AIMS: The aim of this study was to perform a systematic review of the association between DNA methylation and coronary heart disease (CHD) or related atherosclerotic traits. METHODS: A systematic review was designed. The condition of interest was DNA methylation, and the outcome was CHD or other atherosclerosis-related traits. Three DNA methylation approaches were considered: global methylation, candidate-gene, and epigenome-wide association studies (EWAS). A functional analysis was undertaken using the Ingenuity Pathway Analysis software. RESULTS: In total, 51 articles were included in the analysis: 12 global methylation, 34 candidate-gene and 11 EWAS, with six studies using more than one approach. The results of the global methylation studies were inconsistent. The candidate-gene results were consistent for some genes, suggesting that hypermethylation in ESRalpha, ABCG1 and FOXP3 and hypomethylation in IL-6 were associated with CHD. The EWAS identified 84 genes showing differential methylation associated with CHD in more than one study. The probability of these findings was <1.37.10-5. One third of these genes have been related to obesity in genome-wide association studies. The functional analysis identified several diseases and functions related to these set of genes: inflammatory, metabolic and cardiovascular disease. CONCLUSIONS: Global DNA methylation seems to be not associated with CHD. The evidence from candidate-gene studies was limited. The EWAS identified a set of 84 genes highlighting the relevance of obesity, inflammation, lipid and carbohydrate metabolism in CHD. This set of genes could be prioritized in future studies assessing the role of DNA methylation in CHD. PMID- 28577937 TI - Therapy-induced E-cadherin downregulation alters expression of programmed death ligand-1 in lung cancer cells. AB - OBJECTIVES: Immunotherapy that targets the programmed death-1/programmed death ligand 1 (PD-L1) axis has been approved for treatment of non-small cell lung cancer (NSCLC) patients in many countries. However, our current understanding of the role of immunotherapies on NSCLC patients with epidermal growth factor receptor (EGFR) mutation, following acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs), is so far unclear. Especially, there is little data on if each acquired resistance mechanism to EGFR-TKIs alters PD-L1 expression status which is employed as an important predictive biomarker for PD-1/PD-L1 targeting agents. MATERIALS AND METHODS: Lung cancer cell lines (HCC827, HCC4006, PC9, H1975, H358, SW900, and H647) and their daughter cells that acquired resistance to EGFR-TKIs or cytotoxic drugs (cisplatin or vinorelbine) were examined. PD-L1 expression was analyzed by immunohistochemistry, immunoblotting, and/or fluorescent imaging. Published microarray data were also employed to evaluate our findings. RESULTS AND CONCLUSION: We found correlations between therapy-induced E cadherin downregulation and decreased PD-L1 expression using our cell lines and published microarray data. ShRNA mediated E-cadherin knockdown decreased PD-L1 expression in parental cells, and dual immunofluorescent staining of E-cadherin and PD-L1 suggests co-localization of both molecules. We also observed marked downregulation of PD-L1 in cells with E-cadherin downregulation after chronic treatment with vinorelbine. These results indicate a correlation between therapy induced E-cadherin downregulation and decreased PD-L1 expression, highlighting the importance of re-biopsy after acquisition of resistance to EGFR-TKIs, not only for the evaluation of resistance mechanisms but also for the determination of PD-L1 expression status. PMID- 28577938 TI - Evaluation of the VeriStrat(r) serum protein test in patients with advanced squamous cell carcinoma of the lung treated with second-line afatinib or erlotinib in the phase III LUX-Lung 8 study. AB - OBJECTIVES: Identification of biomarkers associated with clinical benefit may be crucial in establishing optimal treatment choice for patients with squamous cell carcinoma (SCC) of the lung after first-line chemotherapy. In this study, the ability of the VeriStrat serum protein test to predict differential clinical benefit with afatinib versus erlotinib, and the association of VeriStrat status with clinical outcomes irrespective of EGFR-TKI used, was assessed in a retrospective analysis of the phase III LUX-Lung 8 trial. MATERIALS AND METHODS: Pretreatment plasma samples were analyzed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Spectra were evaluated to assign a VeriStrat 'Good' (VS-G) or VeriStrat 'Poor' (VS-P) classification. Overall survival (OS), progression-free survival, and other endpoints were assessed with respect to pretreatment VeriStrat status; OS was the primary efficacy variable. Outcomes with other efficacy endpoints were similar. RESULTS: Of 795 patients randomized in LUX-Lung 8, 675 were classified (VS-G: 412; VS-P: 263). In the VS-G group, OS was significantly longer with afatinib versus erlotinib (HR 0.79 [95% CI: 0.63-0.98]). In the VS-P group, there was no significant difference in OS between afatinib and erlotinib (HR 0.90 [0.70-1.16]). However, there was no interaction between VeriStrat classification and treatment group for OS (pinteraction=0.5303). OS was significantly longer in VS-G versus VS-P patients, both in the overall VeriStrat-classified population (HR 0.41 [0.35-0.49]) and afatinib-treated patients (HR 0.40 [0.31-0.51]). Multivariate analysis showed that VeriStrat was an independent predictor of OS in afatinib-treated patients, regardless of ECOG PS or best response to first-line chemotherapy. CONCLUSION: VS G classification is strongly associated with favorable survival outcomes with either afatinib or erlotinib compared with VS-P classification. In VS-G patients, survival outcomes with afatinib are superior to those with erlotinib. VeriStrat classification may guide treatment decisions in patients with SCC of the lung. ClinicalTrials.gov registration number: NCT01523587. PMID- 28577939 TI - Cigarette smoke extract induces EGFR-TKI resistance via promoting EGFR signaling pathway and ROS generation in NSCLC cell lines. AB - OBJECTIVES: Epithelial growth factor receptor (EGFR) somatic-mutated non-small cell lung cancer (NSCLC) patients with smoking history always show a poor response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The aim of the study is to explore the molecular mechanism of EGFR-TKI resistance induced by cigarette smoke extract and investigate the novel anti-resistance strategies. METHODS: The effect of cigarette smoke extract (CSE) on gefitinib sensitivity, EGFR signaling, apoptosis and reactive oxygen species (ROS) levels were detected in vitro by MTT assays, western blot, flow cytometry and laser scanning confocal microscope, respectively. RESULTS: MTT assays presented that CSE claimed antagonistic effect on gefitinib sensitivity via the up-regulated half maximal inhibitory concentration (IC50) values, western blot showed that CSE instigated EGFR, AKT phosphorylation, while N-Acetyl-l-Cysteine (NAC) could alleviate gefitinib resistance and abort the aberrant phosphorylation in both PC-9 and A549 cells. Confocal microscope and flow cytometry displayed that ROS generation increased after CSE exposure in NSCLC cells and this change could be inhibited by NAC. CONCLUSION: Cigarette smoke extract induces EGFR-TKI resistance via promoting EGFR signaling and ROS generation in NSCLC cell lines which could be suppressed by NAC. Alternatively, combined NAC with EGFR-TKIs to treat EGFR mutated NSCLC patients with smoking history may be a potential choice in clinical setting. PMID- 28577940 TI - Trends, practice patterns and underuse of surgery in the treatment of early stage small cell lung cancer. AB - BACKGROUND: Practice guidelines from the National Comprehensive Cancer Network and the American Society of Clinical Oncology recommend pathologic mediastinal staging and surgical resection for patients with clinically node-negative T1/T2 small cell lung cancer (SCLC), but the extent to which surgery is used is unknown. We sought to assess trends and practice patterns in the use of surgery for SCLC. METHODS: T1 or T2N0M0 SCLC cases were identified in the National Cancer Database (NCDB), 2004-2013. Characteristics of patients undergoing resection were analyzed. Hierarchical logistic regression was used to identify individual and hospital-level predictors of receipt of surgery, adjusting for clinical, demographic and facility characteristics. Trends in resection rates were analyzed over the study period. FINDINGS: 9740 patients were identified with clinical T1 or T2 N0M0 SCLC. Of these, 2210 underwent surgery (22.7%), with 1421 (64.3%) undergoing lobectomy, 739 (33.4%) sublobar resections and 50 (2.3%) pneumonectomies. After adjustment, Medicaid patients were less likely to receive surgery (OR0.65 95% CI 0.48-0.89, p=0.006), as were those with T2 tumors (OR0.25 CI0.22-0.29, p<0.0001). Academic facilities were more likely to resect eligible patients (OR 1.90 CI1.45-2.49, p<0.0001). Between 2004 and 2013, resection rates more than doubled from 9.1% to 21.7%. Overall, 68.7% of patients were not offered surgery despite having no identifiable contraindication. In patients not receiving surgery, only 7% underwent pathologic mediastinal staging. INTERPRETATION: Rates of resection are increasing, but two thirds of potentially eligible patients fail to undergo surgery. Further study is required to address the lack of concordance between guidelines and practice. PMID- 28577941 TI - Quantitative cell-free circulating EGFR mutation concentration is correlated with tumor burden in advanced NSCLC patients. AB - OBJECTIVES: Droplet digital polymerase chain reaction (ddPCR) has shown sufficient concordance in detecting plasma epidermal growth factor receptor (EGFR) status in non-small cell lung cancer (NSCLC), compared to tumor tissues. However, the clinical significance of the quantitative plasma mutated EGFR concentration remains unknown. The purpose of this study was to explore the relationship of plasma mutated EGFR concentration with tumor burden in advanced NSCLC patients. MATERIALS AND METHODS: Using ddPCR, plasma DNA samples prior to administration of therapies from 113 consecutive NSCLC patients were analyzed for EGFR L858R substitution and deletion of exon19 (ex19del). Plasma EGFR status was compared to tumor EGFR status to determine concordance. Then, we assessed the correlation of plasma mutated EGFR concentrations with tumor burden and other tumor characteristics. RESULTS AND CONCLUSION: Compared to tumor EGFR, the concordance rate of plasma and tissue EGFR status was 86.73%. Of the 64 patients who harbored tumor EGFR mutation, plasma mutated EGFR concentrations significantly correlated with number of metastatic sites (Spearman's r=0.4954, p<0.0001), number of lesions (Spearman's r=0.4484, p=0.0002), and sum of measurable lesions' diameters (Spearman's r=0.3539, p=0.0048). Number of metastatic sites was independently associated with mutated EGFR concentration in multiple linear regression. Besides, plasma mutated EGFR concentrations were significantly higher in those with extensive tumor burden (median concentration, 386.9 vs. 13.4copies/mL; p<0.0001) and stage IV disease (median concentration, 244.2 vs. 0copies/mL; p=0.0252). In conclusion, mutated plasma EGFR concentration determined by ddPCR analysis significantly correlated with tumor burden. PMID- 28577942 TI - The components of somatostatin and ghrelin systems are altered in neuroendocrine lung carcinoids and associated to clinical-histological features. AB - BACKGROUND: Lung carcinoids (LCs) are rare tumors that comprise 1-5% of lung malignancies but represent 20-30% of neuroendocrine tumors. Their incidence is progressively increasing and a better characterization of these tumors is required. Alterations in somatostatin (SST)/cortistatin (CORT) and ghrelin systems have been associated to development/progression of various endocrine related cancers, wherein they may become useful diagnostic, prognostic and therapeutic biomarkers. OBJECTIVES: We aimed to evaluate the expression levels of ghrelin and SST/CORT system components in LCs, as well as to explore their putative relationship with histological/clinical characteristics. PATIENTS AND METHODS: An observational retrospective study was performed; 75 LC patients with clinical/histological characteristics were included. Samples from 46 patients were processed to isolate mRNA from tumor and adjacent non-tumor region, and the expression levels of SST/CORT and ghrelin systems components, determined by quantitative-PCR, were compared to those of 7 normal lung tissues. RESULTS: Patient cohort was characterized by mean age 53+/-15 years, 48% males, 34% with tobacco exposure; 71.4/28.6% typical/atypical carcinoids, 21.7% incidental tumors, 4.3% functioning tumors, 17.7% with metastasis. SST/CORT and ghrelin system components were expressed at variable levels in a high proportion of tumors, as well as in adjacent non-tumor tissues, while a lower proportion of normal lung samples also expressed these molecules. A gradation was observed from normal non-neoplastic lung tissues, non-tumor adjacent tissue and LCs, being SST, sst4, sst5, GHS-R1a and GHS-R1b overexpressed in tumor tissue compared to normal tissue. Importantly, several SST/CORT and ghrelin system components displayed significant correlations with relevant clinical parameters, such as necrosis, peritumoral and vascular invasion, or metastasis. CONCLUSION: Altogether, these data reveal a prominent, widespread expression of key SST/CORT/ghrelin system components in LCs, where they display clinical-histological correlations, which could provide novel, valuable markers for NET patient management. PMID- 28577943 TI - Uncommon EGFR mutations in advanced non-small cell lung cancer. AB - Molecular profiling in advanced non-small cell lung cancer (NSCLC) has allowed for the detection of actionable mutations, which has revolutionized the treatment paradigm in this highly fatal disease. Mutations involving the epidermal growth factor receptor (EGFR) gene are most common and the 'classical mutations', exon 19 deletions and the point mutation L858R at exon 21, predict response to EGFR tyrosine kinase inhibitors (TKIs). The 'uncommon' EGFR mutations account for 10 18% of all EGFR mutations and primarily consist of exon 20 insertions, exon 18 point mutations and complex mutations. Improved detection techniques have broadened the spectrum of reported aberrations within the 'uncommon group' but response to TKIs is variable and not fully elucidated. This review provides an overview of the biology and incidence of uncommon EGFR mutations and summarizes reported outcomes when treated with EGFR-TKIs. PMID- 28577944 TI - Growth pattern-based grading of pulmonary adenocarcinoma-Analysis of 534 cases with comparison between observers and survival analysis. AB - OBJECTIVES: The 2015 WHO classification of pulmonary adenocarcinoma recommends recording observed architectural growth patterns in 5% increments for resected tumors, and determining the predominant growth pattern, which seems to be prognostic. There is debate over the best way to implement pattern-based grading, and whether such systems are reproducible. MATERIALS AND METHODS: 534 resected adenocarcinomas were reviewed by 2 pulmonary pathologists to determine predominant pattern and percentages of all observed patterns. Three different grading schemes were applied based on predicted prognosis scores: score 1 (lepidic), score 2 (acinar/papillary), and score 3 (solid/micropapillary/cribriform). Mucinous tumors were separately evaluated as both scores 2 and 3 since their prognosis is more ambiguous. The first grading scheme used the score of the predominant pattern; the second used the worst observed pattern score; and the third scored tumors with >=80% lepidic growth as 1, tumors with >=20% of any score 3 pattern(s) as 3, and all remaining as 2. RESULTS: The predominant pattern assigned by each observer was an exact match in 51.7% of cases, a "close match" in 27.3% (same prognosis score), and a mismatch in 21%. Predominant pattern determined by both observers showed significant stratification of overall and progression-free survival (OS and PFS, respectively). All 3 grading schemes showed a significant difference in OS and PFS determined by both observers; but the worst score scheme provided suboptimal results, likely due to a very small score 1 group, and this scheme did not maintain significance on multivariable analysis. Survival differences for all grading schemes maintained significance whether mucinous was considered score 2 or 3, but mucinous tumors trended towards poor survival. CONCLUSION: Pattern based grading has prognostic significance in pulmonary adenocarcinoma. Interobserver variation is present, but two observers were able to predict significant differences in OS and PFS using various pattern-based grading schemes. PMID- 28577945 TI - Systematic identification of cancer-related long noncoding RNAs and aberrant alternative splicing of quintuple-negative lung adenocarcinoma through RNA-Seq. AB - OBJECTIVES: Lung adenocarcinoma (LUAD) is a common subtype of non-small cell lung cancer prevalent in Asia. There is a dearth of understanding regarding the transcriptome landscape of LUAD without primary known driver mutations. In this study, LUAD samples without well-known driver mutations occurring in EGFR, KRAS, ALK, ROS1 or RET (quintuple-negative) were used for transcriptome study with a focus on long noncoding RNAs (lncRNAs), alternative splicing and gene fusions. MATERIALS AND METHODS: 24 pairs of LUAD and adjacent normal samples and 13 tumor only samples derived from 37 quintuple-negative patients were used. Differentially expressed lncRNA transcripts were detected by paired t-test and were validated by qPCR. Functions of lncRNAs were predicted by co-expressed mRNAs. Aberrant splicing events in LUAD were identified using MISO. In addition, gene fusions were screened by SOAPfuse. RESULTS AND CONCLUSION: In total, 90 and 153 up- or down-regulated lncRNA transcripts were detected in LUAD samples in comparison with the adjacent normal samples. The most significantly differentially expressed lncRNA transcript was ENST00000598996.1 (FENDRR) down regulated in LUAD. By lncRNA-mRNA co-expression analysis, functions of 14 lncRNAs were predicted. The predicted functions included vasculature development, immune response, cell cycle and respiratory gaseous exchange. Furthermore, six co expressed pairs of lncRNAs and their nearby protein coding genes were identified as associated with lung development. This study also identified two highly recurrent (22 in 24) differential exon skipping events occurring in MYH14 and ESYT2 with exon including isoforms of both genes up-regulated in isoform percentage in LUAD samples. On the other hand, two out of 24 LUAD samples possessed the driver mutation exon 14 skipping of MET. The transcriptional alterations of LUAD samples without well-known driver mutations identified in the study can be used as references for future research. The translational values of these transcriptional changes are also worthy of further investigation. PMID- 28577947 TI - Indications for invasive mediastinal staging in patients with early non-small cell lung cancer staged with PET-CT. AB - PURPOSE/OBJECTIVE(S): Appropriate use of invasive mediastinal staging in patients with clinically node-negative NSCLC staged by PET-CT is critical in selecting patients for curative-intent therapy such as surgery or SBRT, but little data exists to guide this decision-making. We examined a large population of patients with clinical stage I NSCLC referred for mediastinoscopy or EBUS to find risk factors for occult N2 lymph nodes and determine which patients benefit from invasive staging. MATERIALS/METHODS: We identified consecutive clinical T1-2N0 NSCLC patients being evaluated for curative-intent therapy between 2011 and 2015. None had evidence of nodal disease by PET-CT; the endpoint was pathologic confirmation of occult N2 disease by EBUS or mediastinoscopy. Tumor size, location, histology, SUVmax, and radiographic appearance were evaluated as determinants of occult N2 disease. Two group comparisons of continuous variables were done with independent t-tests and categorical variables were compared with chi2 or Fisher's exact test. RESULTS: In 284 patients with PET-CT-staged clinical T1-2N0 disease, the prevalence of occult N2 metastases was 7.0%. The negative predictive value of PET-CT was 92.9% and the negative predictive value of mediastinoscopy/EBUS was 96.3%. T2 tumors were more likely to have occult N2 disease than T1 tumors (11.8% v 3.6% p=0.009). Pure solid tumors had greater involvement of N2 nodes than tumors with any ground glass component (12.6% v 3.1%, p<0.001). 17.5% of central tumor cases were found to have occult N2 metastases while 4.4% of patients with peripheral tumors (P<0.001). 33.3% of patients with solid central T2 tumors had occult N2 metastases whereas 2.0% of patients with peripheral T2 tumors with a ground glass component, 1.2% of patients with peripheral T1 tumors with a ground glass component and 3.6% of patients with peripheral T1 solid tumors had N2 metastases. CONCLUSIONS: Invasive mediastinal staging should be strongly encouraged in central tumors and solid T2 tumors because the risk of occult nodal involvement is greater than 10% in these cohorts. However, for patients with peripheral T1 tumors or peripheral T2 tumors with a significant ground glass component, the yield of invasive staging after a negative PET-CT is very low and invasive staging may not be warranted. PMID- 28577948 TI - Vitiligo in a patient with lung adenocarcinoma treated with nivolumab: A case report. AB - Nivolumab, an anti-programmed cell death-1 protein monoclonal antibody, is effective for treating patients with late-stage non-small-cell lung cancer. Immune checkpoint inhibitors such as nivolumab induce various kinds of immune related adverse events, including vitiligo. Vitiligo has been reported in patients with melanoma but not lung cancer. We describe a 75-year-old man with lung adenocarcinoma, stage 4 with pleural and pericardial effusion, that progressed after first-line chemotherapy. Subsequently, he was treated with nivolumab as second-line therapy. After 6days of administering nivolumab, he developed vitiligo suddenly on the trunk of his body. Except for vitiligo, his physical examination was normal, and treatment with nivolumab was well tolerated. Therefore, this treatment was continued without further development or expansion of vitiligo. A computed tomography scan showed a reduction in the size of the lung nodule and stabilization of the pleural and pericardial effusion. This is the first case of vitiligo associated with the use of nivolumab in a patient with lung adenocarcinoma. PMID- 28577946 TI - Reduced Smad4 expression and DNA topoisomerase inhibitor chemosensitivity in non small cell lung cancer. AB - OBJECTIVE: Smad4 is a tumor suppressor that transduces transforming growth factor beta signaling and regulates genomic stability. We previously found that Smad4 knockdown in vitro inhibited DNA repair and increased sensitivity to DNA topoisomerase inhibitors. In this study, we assessed the association between reduced Smad4 expression and DNA topoisomerase inhibitor sensitivity in human non small cell lung cancer (NSCLC) patients and evaluated the relationship between genomic alterations of Smad4 and molecular alterations in DNA repair molecules. MATERIALS AND METHODS: We retrospectively identified NSCLC patients who received etoposide or gemcitabine. Chemotherapeutic response was quantified by RECIST 1.1 criteria and Smad4 expression was assessed by immunohistochemistry. Relationships between Smad4 mutation and DNA repair molecule mutations were evaluated using publically available datasets. RESULTS: We identified 28 individuals who received 30 treatments with gemcitabine or etoposide containing regimens for NSCLC. Reduced Smad4 expression was seen in 13/28 patients and was not associated with significant differences in clinical or pathologic parameters. Patients with reduced Smad4 expression had a larger response to DNA topoisomerase inhibitor containing regimens then patients with high Smad4 expression (-25.7% vs. -6.8% in lesion size, p=0.03); this relationship was more pronounced with gemcitabine containing regimens. The overall treatment response was higher in patients with reduced Smad4 expression (8/14 vs 2/16 p=0.02). Analysis of data from The Cancer Genome Atlas revealed that Smad4 mutation or homozygous loss was mutually exclusive with genomic alterations in DNA repair molecules. CONCLUSIONS: Reduced Smad4 expression may predict responsiveness to regimens that contain DNA topoisomerase inhibitors. That Smad4 signaling alterations are mutually exclusive with alterations in DNA repair machinery is consistent with an important role of Smad4 in regulating DNA repair. PMID- 28577949 TI - Clinical and pathological characteristics of EGFR mutation in operable early stage lung adenocarcinoma. AB - OBJECTIVES: Over the past decade, the biological and clinical characteristics of lung cancer with epidermal growth factor receptor (EGFR) mutation have been well studied. However, most studies have focused on advanced inoperable cancer, and not on resected early-stage lung adenocarcinoma. We aimed to elucidate the differences in the clinicopathological characteristics and postoperative prognosis according to the EGFR mutation status in early-stage lung adenocarcinoma. MATERIALS AND METHODS: We retrospectively collected clinical and pathological data from 369 patients with pathological stage I or II lung adenocarcinoma who underwent complete resection. Clinicopathological characteristics and postoperative prognosis were compared depending on the EGFR mutation status, using the Chi-squared test and the log-rank test, respectively. RESULTS AND CONCLUSION: Of the 369 patients, 160 (43.3%) had EGFR mutation, of which 64 (40.0%) were exon 19 deletion (Del-19) and 90 (56.3%) were exon 21 point mutation L858R. Although there was no difference in overall survival (OS) between patients with and without EGFR mutation (p=0.086), tumors with EGFR mutation were associated with a lower consolidation to tumor ratio (CTR) (p <0.001) and a higher incidence of a lepidic growth pattern by pathological evaluation (p <0.001) compared to those without EGFR mutation. Among tumors with EGFR mutation, there was no difference in OS (p=0.140) between Del-19 and L858R. Tumors with L858R were associated with a lower CTR (p=0.046), and tended to have a higher incidence of a lepidic growth pattern by pathological evaluation (p=0.073) compared to those with Del-19. In conclusion, although EGFR mutation status was not a prognostic indicator after surgery in early-stage lung adenocarcinoma, L858R and Del-19 had different radiological and pathological features. PMID- 28577950 TI - Association of MTH1 expression with the tumor malignant potential and poor prognosis in patients with resected lung cancer. AB - OBJECTIVES: The oxidized purine nucleoside triphosphatase, mutT homolog 1 (MTH1), physiologically sanitizes 8-oxo-dGTP in the nucleotide pool. Previous studies indicated that MTH1 is associated with tumor proliferation and invasion in non small cell lung cancer (NSCLC) cell lines; however, the role of MTH1 in patients with NSCLC remains unclear. MATERIALS AND METHODS: Two patient cohorts that underwent surgery for NSCLC in our institution were investigated retrospectively. In one cohort consisting of 197 patients, the associations between MTH1 expression and clinicopathological factors or prognosis were analyzed. In another cohort consisting of 41 patients, the relationship between MTH1 expression in the tumors and serum oxidative stress levels (evaluated by the diacron-reactive oxygen metabolites [d-ROMs] test) or antioxidant capacity in the patients (evaluated by the biological antioxidant potential (BAP) test) was analyzed. A total of 238 patients were assessed for MTH1 protein levels using immunohistochemistry. RESULTS: Among the 197 patients in the former cohort, 111 (56.3%) exhibited high MTH1 expression, while 86 (43.7%) exhibited low MTH1 expression. Male sex, smoking habit of >=20 pack-years, squamous cell carcinoma, pathological stage >= II, tumor diameter >=30mm, lymph node metastases, pleural invasion, lymphatic permeation and vascular infiltration were significantly associated with high MTH1 expression (p<0.05). The high MTH1 expression group had a significantly worse prognosis than that of the low MTH1 expression group (5 year overall survival: 81.6% vs. 92.3%, p=0.0011; 5-year disease-free survival: 55.0% vs. 83.7%, p=0.0002). d-ROMs and BAP test values were significantly higher in the high than in the low MTH1 expression group (p<0.05). CONCLUSION: This study showed that MTH1 protein expression was closely related to factors associated with a high malignant potential and poor patient survival. MTH1 may be a novel therapeutic target for NSCLC. PMID- 28577952 TI - Stereotactic body radiotherapy for operable early-stage non-small cell lung cancer. AB - PURPOSE: To analyze outcomes of stereotactic body radiotherapy (SBRT) for operable patients with early-stage non-small cell lung cancer (NSCLC) and to evaluate factors associated with outcomes. METHODS: We retrospectively analyzed operable patients with NSCLC, staged as cT1-2N0M0, treated with SBRT between 2006 and 2015. Both biopsy-proven and clinically diagnosed NSCLC were included. Local control and survival rates were calculated and compared between subsets of patients. We investigated factors associated with outcomes. RESULTS: We identified 88 operable patients among 661 patients with cT1-2N0M0 NSCLC. The median age was 79 years (range: 55-88). The median follow-up time after SBRT was 40 months (range: 4-121). Fifty-nine patients had been pathologically diagnosed and the other 29 had been clinically diagnosed as having NSCLC. Local control, cause-specific survival (CSS) and overall survival (OS) at 3 years were 91%, 97% and 90% for T1, and 100%, 82% and 74% for T2, respectively. The CSS and OS at 3 years were 100% and 100% for GGO and 83% and 59% for solid tumors, respectively (p=0.005). On univariate analysis, age and T stage were significantly associated with CSS, and age, the Charlson Comorbidity Index (CCI), and opacity were significantly associated with OS. On multivariate analysis, age and CCI were significantly associated with OS. As for toxicities, Grades 0, 1, 2 and 3 radiation pneumonitis occurred in 37.5%, 47.7%, 13.6% and 1.1% of patients, respectively. No Grade 4 or 5 radiation pneumonitis occurred, and no other toxicities of Grade 2 or above were observed. CONCLUSION: Outcomes of SBRT for operable early stage NSCLC were as good as previous SBRT and surgery studies. Further investigation for selecting good SBRT candidates is warranted in high risk operable patients. PMID- 28577951 TI - Aprepitant for refractory nivolumab-induced pruritus. AB - Although substantial progress has been made in the treatment of non-small-cell lung cancer (NSCLC) patients with immune checkpoint inhibitors (ICIs), severe immune-related adverse events (irAEs) sometimes occur. Here, we report a case of severe refractory pruritus after Stevens-Johnson syndrome (SJS) in a patient with NSCLC treated with nivolumab. The patient was a 76-year-old Japanese woman with advanced NSCLC treated with nivolumab. After the second dose, she experienced severe rash with mucous involvement. We diagnosed SJS and started 50mg of oral prednisolone (1mg/kg). The rash completely resolved after prednisolone was started, but we could not manage the severe pruritus with emollients, antihistamines, and steroids. Finally, we administered aprepitant, an oral neurokinin-1 receptor antagonist, for her refractory pruritus. Her symptoms improved within 5days. Severe refractory pruritus can arise from ICIs, and aprepitant may be a useful treatment. PMID- 28577953 TI - The impact of preoperative elevated serum C-reactive protein on postoperative morbidity and mortality after anatomic resection for lung cancer. AB - INTRODUCTION: The aim of this study was to determine whether preoperative elevated serum C-reactive protein (CRP) is an independent risk factor of postoperative morbidity and mortality after pulmonary resection for lung cancer. MATERIAL AND METHODS: A retrospective analysis of prospectively collected data on 1414 consecutive patients that underwent an anatomic resection for lung cancer was performed. Patients' characteristics, operative procedures and the postoperative outcome were assessed with a standardised data entry form. Univariate and multivariate analyses were conducted to identify factors that affect morbidity and mortality. RESULTS: Postoperative complications occurred in 35.5% of the patients. The mortality rate was 3.2%. Patients with preoperative C reactive protein above 40mg/l showed more overall complications and a higher mortality than patients below this limit. Patients with a CRP level between 3mg/l and 40mg/l had no significant increase in morbidity and mortality compared to patients with values below the detection limit (< 3mg/l). CONCLUSIONS: Preoperative serum C-reactive protein level is an independent and significant indicator for elevated morbidity and mortality after pulmonary resection. We propose the evaluation of CRP levels as a preoperative diagnostic modality of risk assessment in addition to standardised functional testing. PMID- 28577954 TI - Recurrent dysphasia due to nivolumab-induced encephalopathy with presence of Hu autoantibody. AB - A 58-year-old man was being treated for squamous non-small-cell lung cancer with nivolumab. At the 17th of biweekly administrations he presented with global dysphasia, dysarthria and myoclonus in the right upper extremity. MRI showed multiple T2/FLAIR hyperintense lesions in the left hemisphere; lumbar puncture showed lymphocytic pleiocytosis in the CSF without identifiable pathogens. Hu antibodies were present in serum and CSF. Nivolumab was discontinued and corticosteroids were administered. The neurological symptoms gradually improved; MRI showed complete remission of cerebral lesions. After rechallenge with nivolumab his symptoms and cerebral lesions recurred, proving the causal relationship with nivolumab. After tapering of corticosteroids, a second relapse occurred. PMID- 28577955 TI - Surgery Versus Chemotherapy and Radiotherapy For Early and Locally Advanced Small Cell Lung Cancer: A Propensity-Matched Analysis of Survival. AB - BACKGROUND: The role of surgery in small cell lung cancer (SCLC) is controversial. Survival outcomes for resection of stage I-IIIA SCLC compared to chemotherapy-based non-surgical treatment (NST) were examined using propensity matching. METHODS: 29,994 clinical stage I-IIIA SCLC patients, including 2,619 undergoing surgery, were identified in the National Cancer Database. Stage specific propensity scores for receipt of surgery were created. Resected patients were matched 1:1 to those undergoing NST. Overall survival (OS) was assessed using Kaplan-Meier and multivariable Cox models. A separate match was performed comparing Stage I/II patients aged <85 with a Charlson score of 0 who underwent lobectomy with adjuvant chemotherapy (and radiotherapy if node positive) to those treated with multiagent chemotherapy and concurrent chest radiotherapy (CRT) of at least 40 gray. RESULTS: 2,089 patients were matched, and cohorts were well balanced. Surgery was associated with longer survival for Stage I (median OS 38.6 months vs. 22.9 months, HR 0.62 95%CI 0.57-0.69, p<0.0001), but survival differences were attenuated for Stage II (median OS 23.4 months vs. 20.7 months, HR 0.84 95%CI 0.70-1.01, p=0.06) and IIIA (median OS 21.7 vs. 16.0 months, HR 0.71 95%CI 0.60-0.83, p <0.0001). In analyses by T and N stage, longer OS was observed in resected patients with stage T3/T4 N0 (median OS 33.0 vs. 16.8 months, p=0.008) and node positivity(N1+ 24.4 vs. 18.3 months p=0.03; N2+ 20.1 vs. 14.6 months p=0.007). In the subgroup analysis, 507 stage I/II patients receiving lobectomy and adjuvant chemotherapy were matched to patients receiving concurrent CRT. In this cohort, lobectomy with adjuvant chemotherapy was associated with significantly longer survival (median OS 48.6 vs. 28.7 months, p<0.0001). CONCLUSIONS: Surgical resection is associated with significantly longer survival for early SCLC. New randomized trials should assess trimodality therapy in stages I/II, and in node negative disease. PMID- 28577956 TI - Clinical outcomes of platinum-based chemotherapy according to T790M mutation status in EGFR-positive non-small cell lung cancer patients after initial EGFR TKI failure. AB - BACKGROUND: Emergence of the T790M point mutation in exon 20 of epidermal growth factor receptor (EGFR) is the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). It remains unclear whether the efficacy of platinum-doublet chemotherapy is impacted by the presence of the T790M mutation. The aim of this study is to evaluate the efficacy of platinum-doublet chemotherapy after initial EGFR-TKI failure according to the EGFR T790M in patients with advanced EGFR-mutation-positive non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We retrospectively reviewed 50 patients with advanced NSCLC harboring EGFR mutations who underwent rebiopsy to evaluate their T790M mutation status after development of resistance to first-line EGFR-TKIs (gefitinib, erlotinib, or afatinib) and were subsequently treated with second-line platinum based chemotherapy. RESULTS: The median age of patients was 63 years (range, 35 77 years), and 15 (30%) patients were male. Histological examination revealed that all patients had adenocarcinoma, 39 (78%) had stage IV disease, and 11 (22%) patients had postoperative recurrence. Of all, 17 patients (34%) had the T790M mutation by rebiopsy after initial EGFR-TKI failure. The overall response rate (ORR) of platinum-doublet chemotherapy was 24% for both T790M-positive and T790M negative patients. There was no significant difference in the progression-free survival (PFS) in T790M-positive and T790M-negative patients (median PFS, 6.0 months vs. 5.1 months; 95% confidence interval [CI], 0.1-11.9 vs. 4.4-5.8; hazard ratio [HR], 0.90 [95%CI, 0.49-1.66]; P=0.7210). None of the factors were predictive of platinum-doublet chemotherapy efficacy by the multivariate analysis. CONCLUSION: There were no differences in clinical outcomes of platinum based chemotherapy according to the T790M status of NSCLC patients. PMID- 28577957 TI - EGFR T790M mutation testing within the osimertinib AURA Phase I study. AB - OBJECTIVES: Reliable epidermal growth factor receptor (EGFR) mutation testing techniques are required to identify eligible patients with EGFR mutation/T790M positive advanced non-small cell lung cancer (NSCLC), for treatment with osimertinib (AZD9291), an oral, potent, irreversible EGFR tyrosine kinase inhibitor (TKI) selective for EGFR-TKI-sensitizing and T790M resistance mutations over wild-type EGFR. There is no current consensus regarding the best method to detect EGFR T790M mutations. The aim of this study was to describe the concordance between local testing, which used a variety of methods, and central testing, using the cobas(r) EGFR Mutation Test, for EGFR-sensitizing mutations and the T790M resistance mutation. MATERIALS AND METHODS: Tumor samples were obtained from all patients screened for inclusion onto the osimertinib Phase I expansion component of the AURA Phase I/II study (NCT01802632). Samples underwent central laboratory testing for EGFR-sensitizing mutations and T790M resistance mutation using the cobas(r) EGFR Mutation Test. Results were compared with local laboratory test results, based on other testing methodologies including Sanger sequencing, therascreen(r), PNAClampTM, and Sequenom MassARRAY(r). RESULTS: Central laboratory testing was successful in 99% of samples passing histopathology review and testing success rates were comparable across the three central laboratories. Concordance between central and local testing for common sensitizing mutations was high (>98%) and concordance for the T790M mutation was also high (>90%). Tumor heterogeneity, along with other technical factors may have influenced this result. CONCLUSIONS: Within the osimertinib AURA Phase I study, EGFR mutation testing across three centralized laboratories using the cobas(r) EGFR Mutation Test was feasible and successful, with strong concordance between local and central laboratory results, including for T790M. The cobas(r) EGFR Mutation Test has subsequently been approved as the companion diagnostic test for osimertinib in the USA and Japan. PMID- 28577958 TI - Lepidic predominant adenocarcinoma and invasive mucinous adenocarcinoma of the lung exhibit specific mucin expression in relation with oncogenic drivers. AB - OBJECTIVES: To evaluate MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression in invasive lepidic predominant adenocarcinoma (LPA) and invasive mucinous adenocarcinoma (IMA) of the lung, and the impact of oncogenic drivers. MATERIALS AND METHODS: MUC1, MUC2, MUC5B, MUC5AC, MUC6, TTF1 and Hnf4alpha immunohistochemistry was performed on surgical samples from 52 patients with IMA (n=25) or LPA (n=27). We searched for EGFR, KRAS, BRAF, and HER2 mutations and ALK, ROS1, and NRG1 rearrangements. RESULTS: MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression was detected in tumor cells in 77%, 2%, 63%, 36%, and 21% of cases, respectively. MUC1 was significantly more overexpressed in LPA. MUC5B, MUC5AC, and MUC6 were typically detected in goblet cells and overexpressed in IMA. Hnf4alpha-positive IMA (n=11) were TTF1-negative and typically did not expressed MUC1 and expressed MUC5AC and MUC6. Hnf4alpha-negative IMA (n=14) showed a reverse profile of mucins expression, with MUC1 expression and a lack of MUC5AC and MUC6 expression. EGFR-positive status was significantly associated with LPA, MUC1 expression, and no MUC5B, MUC5AC, or MUC6 expression. KRAS-positive status was significantly associated with IMA and MUC5B and MUC5AC expression. CONCLUSIONS: LPA and IMA exhibit specific mucin expression profiles, with MUC1 being associated with LPA, while MUC5B, MUC5AC, and MUC6 were associated with IMA. Hnf4alpha expression and EGFR and KRAS mutations may play a role in mucin expression profiles of these lung adenocarcinoma subtypes. PMID- 28577959 TI - Impact of blood sample collection methods on blood protein profiling studies. AB - Pre-analytical factors have a significant impact on the integrity of blood samples used for qualitative and quantitative protein profiling. Important factors are the type of the blood collection tube and the anticoagulant used. Only a few studies have been performed to assess these variables by comparing only serum and EDTA plasma collection tubes with some target proteins or peptides. In this study, we investigated the protein profile of blood samples collected in serum, EDTA-, heparin-, and citrate plasma tubes. Furthermore, we compared the depletion efficiency of 6 high abundant proteins, the detectable blood protein profile, the variance, and the coverage of the detectable protein sets. The largest differences were found between serum and plasma samples with respect to the peptide number and the occurrence of classical blood proteins. The heparin plasma evidenced a high number of detectable proteins, low global variance and a high similarity to EDTA- and citrate plasma and may therefore be also a useful test tube for blood protein profiling. In addition, a core set of blood proteins were described and the portions and compositions of sampling specific proteins were disclosed. Therefore, pre-analytical issues such as the sample collection method should be considered for protein profiling studies. PMID- 28577960 TI - Diagnostic value of interferon-gamma-induced protein of 10kDa for tuberculous pleurisy: A meta-analysis. AB - BACKGROUND: The accurate diagnosis of tuberculous pleurisy is still a clinical challenge. Many studies reported that interferon-gamma-induced protein of 10kDa (IP-10) plays a role in diagnosing tuberculous pleurisy, but with considerable variance of results. This meta-analysis aimed to evaluate the overall diagnostic accuracy of IP-10 for tuberculous pleurisy. METHODS: PubMed, EMBASE, and other databases were searched for studies examining accuracy of pleural IP-10 for diagnosing tuberculous pleurisy. Related data were extracted and sensitivity/specificity, positive/negative likelihood ratio (PLR/NLR), and diagnostic odds ratio (DOR) were pooled. Summary receiver operating characteristic curve and area under the curve (AUC) were performed and calculated to summarize the overall test performance. RESULTS: Fourteen studies involving 1382 subjects met inclusion criteria, including 715 cases of tuberculous pleurisy and 667 controls. Summary estimates of the diagnostic performance of the IP-10 for tuberculous pleurisy were listed as follows: sensitivity, 0.84 (95%CI 0.81 to 0.87); specificity, 0.90 (95% CI 0.88 to 0.92); PLR, 7.96 (95% CI 5.59 to 11.32); NLR, 0.19 (95% CI 0.15 to 0.24); DOR, 49.82 (95% CI 28.08 to 88.38); and AUC 0.94. No publication bias was detected. CONCLUSION: Pleural IP-10 is a useful diagnostic marker for tuberculous pleurisy. Nevertheless, its result should be interpreted together with the results of conventional test and clinical information of patients. PMID- 28577962 TI - Free Active Chlorine in Sodium Hypochlorite Solutions Admixed with Octenidine, SmearOFF, Chlorhexidine, and EDTA. AB - INTRODUCTION: The therapeutic effects of sodium hypochlorite (NaOCl) solutions are dependent on the levels of free available chlorine (FAC). Mixing these solutions with irrigants can result in significant reductions in FAC. Although the effect of some irrigants on FAC is known, the effect of other commonly used irrigants is not. Thus, the therapeutic ramifications of the concurrent use of these on the efficiency of NaOCl solutions is not known. METHODS: Aliquots of 5.2% (w/v) NaOCl solutions were admixed in proportions of 90:10, 80:20, and 50:50 with the following irrigants: octenidine dihydrochloride (OCT); SmearOFF (Vista Dental Products, Racine, WI), 17% EDTA; and 0.2%, 2%, and 5% chlorhexidine (CHX) solutions. Changes in FAC were measured by iodometric titration. Statistical differences between means were determined using a post hoc Tukey analysis test after an analysis of variance. RESULTS: OCT appeared not to affect FAC and was significantly different than all other irrigants, except for 90:10 and 80:20 mixtures of low concentration (0.2%) CHX. CHX solutions showed a marked concentration- and mixture proportion-dependent detrimental effect on FAC. The reduction of FAC between different concentrations of CHX was statistically significant in 80:20 and 50:50 proportions, with 50:50 mixtures of 5% CHX having the greatest influence. Mixtures containing even small proportions of SmearOFF or EDTA exhibited significant losses in FAC. CONCLUSIONS: OCT has little effect on FAC and can be used concurrently with NaOCl solutions. Higher concentrations of CHX significantly affect FAC. Their combined use with NaOCl solutions should be avoided. EDTA and SmearOFF should not be mixed with NaOCl solutions. PMID- 28577961 TI - Histologic Evaluation of Regenerative Endodontic Procedures with the Use of Chitosan Scaffolds in Immature Dog Teeth with Apical Periodontitis. AB - INTRODUCTION: The aim of this study was to evaluate histologically the newly formed tissues after regenerative endodontic procedures (REPs) in dogs using either a blood clot (BC) or 2 different formulations of a chitosan hydrogel as scaffolds. METHODS: Apical periodontitis was induced by inoculating immature teeth with oral plaque in 4 beagle dogs. Teeth (n = 96) were divided into 2 control (n = 20) and 4 test groups (n = 76) according to the treatment: apexification and REPs with BC, sodium hyaluronate:chitosan (HA:CS) scaffolds, or pectin:chitosan (P:CS) scaffolds. All root canals were disinfected with 2.5% sodium hypochlorite and a triple antibiotic paste intracanal medicament before evoked bleeding, clot formation, or scaffold placement. Thirteen weeks after treatment, the animals were sacrificed and the jaw blocks harvested for histologic processing, histomorphometric analysis, and statistical analysis. RESULTS: The lumens of the root canals were completely filled with mineral trioxide aggregate with evidence of a mineralized apical bridge between the root canal walls in 83% of the samples in the apexification group. Vital vascularized tissue was found in the REP groups; apical closure happened in 66.7% of these treatments, and root growth was detected more often as an increase in thickness (85.6%) than in length (45.6%). The greatest amount of mineralized tissue inside the canal was observed in the BC group, with statistical significance compared with the HA:CS and P:CS groups (P < .05). Further histologic evaluation revealed the presence of apical papilla. CONCLUSIONS: The addition of chitosan scaffolds to blood in regenerative procedures in dogs did not improve the formation of new mineralized tissues along the root canal walls or the histologic evidence of the regeneration of a pulp-dentin complex. PMID- 28577963 TI - Physiological and pathological processes of synaptic plasticity and memory in drug discovery: Do not forget the dose-response curve. AB - The response of a biological system to an endogenous or exogenous molecule depends upon the dose. For this reason, performing dose-response curves is crucial to understand physiological and pathophysiological phenomena, and to predict the effect of a drug. Most of the studies in pharmacological research have been performed according to the classical threshold model, focusing on higher doses able to ensure a biological effect. However, recent evidences pointed out the need to investigate the effect of low doses. Indeed, several molecules behave in a hormetic fashion, i.e. low-doses stimulate whereas high doses inhibit a biological response. This is particularly interesting in CNS, where several physiological molecules involved in neuronal transmission during learning and memory have shown a biphasic effect that might represent the link between physiology and pathology. In this review we will focus on cholinergic, glutamatergic and nitrinergic transmission, because of their central role in learning and memory and their impairment in neurodegenerative disorders such as Alzheimer's disease. Pre-clinical studies performed on healthy adult animals and aged animals, as well as transgenic animal models of AD, have suggested a biphasic DR for acetylcholine, glutamate and nitric oxide. This stresses the relevance to perform DR curves when studying the mechanisms underlying synaptic plasticity and memory, the pharmacological profile of cognitive-enhancing drugs acting on these systems, and the possibility to combine low/ineffective doses of drugs that might have additive/synergistic effects, reducing the unwanted side effects associated to the high doses. PMID- 28577964 TI - RP5063, a novel, multimodal, serotonin receptor modulator, prevents monocrotaline induced pulmonary arterial hypertension in rats. AB - Pulmonary arterial hypertension (PAH), a condition characterized by pulmonary vasculature constriction and remodeling, involves dysregulation of the serotonin (5-HT) receptors 5-HT2A and 5-HT2B. A rat model of monocrotaline (MCT)-induced PAH was used to examine the potential beneficial effects of RP5063, a 5-HT receptor modulator. After a single 60mg/kg dose of MCT, rats were gavaged twice daily (b.i.d.) with vehicle, RP5063 (1, 3, or 10mg/kg), or sildenafil (50mg/kg) for 28 days. RP5063 at a dose as low as 1mg/kg, b.i.d. reduced pulmonary resistance and increased systemic blood oxygen saturation. The highest dose of RP5063 (10mg/kg, b.i.d.) reduced diastolic, systolic, and mean pulmonary pressure, right systolic ventricular pressure, ventilatory pressure, and Fulton's index (ratio of right to left ventricular weight). Doses as low as 3mg/kg RP5063, b.i.d. also increased weight gain and body temperature, suggesting an improvement in overall health of MCT-treated animals. Similar reductions in pulmonary, right ventricular, and ventilatory pressure, pulmonary resistance, and Fulton's index as well as increased systemic blood oxygen saturation were observed in animals treated with the reference agent sildenafil at a higher dose (50mg/kg, b.i.d.). Histological examination revealed that RP5063 produced dose-dependent reductions in pulmonary blood vessel wall thickness and proportion of muscular vessels, similar to sildenafil. RP5063 completely blocked MCT-induced increases in the plasma cytokines TNFalpha, IL-1beta, and IL-6 at all doses. In summary, RP5063 improved pulmonary vascular pathology and hemodynamics, right ventricular pressure and hypertrophy, systemic oxygen saturation, and overall health of rats treated with MCT. PMID- 28577965 TI - Estrogen and Alzheimer's disease: Still an attractive topic despite disappointment from early clinical results. AB - Since publication of the results of the Women Health Initiative Memory Study demonstrating that hormone therapy initiated late after menopause increases the risk of dementia in women, attempts have been made to identify a "critical window of intervention". In the meantime, basic research carried out in the last 10-15 years has reinforced the concept of a strong impact of estrogen in neuroprotection, moving also into novel directions that include characterization of estrogen's effect on non-neuronal cells, mitochondrial function, miRNA production and novel targets for their action in the central nervous system (CNS). All these findings, together with a list of recent animal models of Alzheimer's Disease that appear feasible for the study of estrogen's CNS effect are here summarized and accompanied by the most recent data from clinical trials in which hormone therapy was initiated early after menopause. PMID- 28577966 TI - Efficacy of carbosilane dendrimers with an antiretroviral combination against HIV 1 in the presence of semen-derived enhancer of viral infection. AB - Amyloid fibrils, which are present in semen, were considered to be a cause of topical vaginal gel ineffectiveness in vivo after microbicides failed as HIV-1 prophylaxis. Therefore, it was necessary to determine whether a dendrimer was suitable for further evaluation in an in vitro model of semen-enhanced viral infection (SEVI). We demonstrated that SEVI in TZM.bl cell cultures increased the infectivity of R5-HIV-1NL(AD8), pTHRO.c and pCH058.c isolates, causing higher IC50 values for two polyanionic carbosilane dendrimers, G2-STE16 and G3-S16. However, both dendrimers maintained protection rates of 90% at non-toxic concentrations. When dendrimers were combined with Tenofovir/Maraviroc (TDF/MVC), the anti-HIV-1 effect remained at a minimum IC50 increase between 1- and 7-fold in the presence of amyloid fibrils. In peripheral blood mononuclear cells (PBMC), IC50 values were slightly influenced by the presence of semen. In brief, dendrimers combined with antiretrovirals showed a synergistic effect. This result plays a crucial role in new microbicide formulations, as it overcomes the negative effects of amyloid fibrils. PMID- 28577967 TI - The underexplored question of beta-amyloid monomers. AB - Conceived more than 25 years ago, the amyloid cascade hypothesis of Alzheimer's disease has evolved to accommodate new findings, namely different forms of beta amyloid aggregates and downstream dysfunctions. Yet, the cascade does not mention its very beginning, the beta-amyloid monomer. Here, I will discuss the monomer from a functional evolutionary perspective, highlighting the potential advantages of a native unfolded state that, however, involves an amyloidogenic risk. Finally, I will make a summary of what is known about its functional role in the brain and discuss the implications of its conceivable shortage in the development of Alzheimer's disease. PMID- 28577968 TI - Antibacterial and antifungal properties of dendronized silver and gold nanoparticles with cationic carbosilane dendrons. AB - Water soluble silver nanoparticles (AgNPs) capped with cationic carbosilane dendrons have been synthesized by direct reaction in water of dendrons, silver precursor and a reducing agent. These nanoparticles have been characterized by nuclear magnetic resonance (NMR), transmission electron microscopy (TEM), dynamic light scattering (DLS), thermogravimetric analysis (TGA), ultraviolet spectroscopy (UV), elemental analysis, and zeta potential (ZP). The antibacterial and antifungal properties of the cationic dendrons and dendronized AgNPs and AuNPs with these dendrons have been evaluated against Gram-negative and Gram positive bacterial -including resistant strains- and yeast strains, respectively. The results stand out for the activity of AgNPs covered with first generation dendron compared with this free dendron and corresponding dendronized AuNPs. PMID- 28577969 TI - Lipid/alginate nanoparticle-loaded in situ gelling system tailored for dexamethasone nasal delivery. AB - In this study, we suggest the development of nanoparticle loaded in situ gelling system suitable for corticosteroid nasal delivery. We propose lipid/alginate nanoparticles (size 252.3+/-2.4nm, polydispersity index 0.241, zeta-potential 31.7+/-1.0mV, dexamethasone (Dex) content 255+/-7MUgml-1) dispersed in pectin solution (5mgml-1) that undergoes a sol-gel phase transition triggered by Ca2+ present in nasal mucosa. The viscoelasticity of gel obtained by mixing nanoparticle suspension in pectin continuous phase with simulated nasal fluid (1:1V/V) is characterised by a log-linear shear thinning viscosity behaviour. Observed viscosity corresponds to the range of viscosities of nasal mucus at physiological as well as under disease conditions. Nanoparticle-loaded gel was biocompatible with the selected epithelial cell model and, in comparison to dexamethasone solution, provided reduction in Dex release (t50% 2.1h and 0.6h, respectively) and moderated transepithelial permeation in vitro (Papp 7.88+/-0.15 and 9.73+/-0.57*10-6cms-1, respectively). In conclusion, this study showed the potential of the proposed system to provide local therapeutic effect upon administration of a lower corticosteroid dose and minimize the possibility for adverse effects as it can be easily sprayed as solution and delivered beyond nasal valve, ensure prolonged contact time with nasal mucosa upon gelation, and moderate corticosteroid release and permeation. PMID- 28577970 TI - Development and evaluation of a dimensionless mechanistic pan coating model for the prediction of coated tablet appearance. AB - A mathematical, mechanistic tablet film-coating model has been developed for pharmaceutical pan coating systems based on the mechanisms of atomisation, tablet bed movement and droplet drying with the main purpose of predicting tablet appearance quality. Two dimensionless quantities were used to characterise the product properties and operating parameters: the dimensionless Spray Flux (relating to area coverage of the spray droplets) and the Niblett Number (relating to the time available for drying of coating droplets). The Niblett Number is the ratio between the time a droplet needs to dry under given thermodynamic conditions and the time available for the droplet while on the surface of the tablet bed. The time available for drying on the tablet bed surface is critical for appearance quality. These two dimensionless quantities were used to select process parameters for a set of 22 coating experiments, performed over a wide range of multivariate process parameters. The dimensionless Regime Map created can be used to visualise the effect of interacting process parameters on overall tablet appearance quality and defects such as picking and logo bridging. PMID- 28577971 TI - Prevalence of food allergies and intolerances documented in electronic health records. AB - BACKGROUND: Food allergy prevalence is reported to be increasing, but epidemiological data using patients' electronic health records (EHRs) remain sparse. OBJECTIVE: We sought to determine the prevalence of food allergy and intolerance documented in the EHR allergy module. METHODS: Using allergy data from a large health care organization's EHR between 2000 and 2013, we determined the prevalence of food allergy and intolerance by sex, racial/ethnic group, and allergen group. We examined the prevalence of reactions that were potentially IgE mediated and anaphylactic. Data were validated using radioallergosorbent test and ImmunoCAP results, when available, for patients with reported peanut allergy. RESULTS: Among 2.7 million patients, we identified 97,482 patients (3.6%) with 1 or more food allergies or intolerances (mean, 1.4 +/- 0.1). The prevalence of food allergy and intolerance was higher in females (4.2% vs 2.9%; P < .001) and Asians (4.3% vs 3.6%; P < .001). The most common food allergen groups were shellfish (0.9%), fruit or vegetable (0.7%), dairy (0.5%), and peanut (0.5%). Of the 103,659 identified reactions to foods, 48.1% were potentially IgE-mediated (affecting 50.8% of food allergy or intolerance patients) and 15.9% were anaphylactic. About 20% of patients with reported peanut allergy had a radioallergosorbent test/ImmunoCAP performed, of which 57.3% had an IgE level of grade 3 or higher. CONCLUSIONS: Our findings are consistent with previously validated methods for studying food allergy, suggesting that the EHR's allergy module has the potential to be used for clinical and epidemiological research. The spectrum of severity observed with food allergy highlights the critical need for more allergy evaluations. PMID- 28577973 TI - Membrane-lipid therapy: A historical perspective of membrane-targeted therapies - From lipid bilayer structure to the pathophysiological regulation of cells. AB - Our current understanding of membrane lipid composition, structure and functions has led to the investigation of their role in cell signaling, both in healthy and pathological cells. As a consequence, therapies based on the regulation of membrane lipid composition and structure have been recently developed. This novel field, known as Membrane Lipid Therapy, is growing and evolving rapidly, providing treatments that are now in use or that are being studied for their application to oncological disorders, Alzheimer's disease, spinal cord injury, stroke, diabetes, obesity, and neuropathic pain. This field has arisen from relevant discoveries on the behavior of membranes in recent decades, and it paves the way to adopt new approaches in modern pharmacology and nutrition. This innovative area will promote further investigation into membranes and the development of new therapies with molecules that target the cell membrane. Due to the prominent roles of membranes in the cells' physiology and the paucity of therapeutic approaches based on the regulation of the lipids they contain, it is expected that membrane lipid therapy will provide new treatments for numerous pathologies. The first on-purpose rationally designed molecule in this field, minerval, is currently being tested in clinical trials and it is expected to enter the market around 2020. However, it seems feasible that during the next few decades other membrane regulators will also be marketed for the treatment of human pathologies. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escriba. PMID- 28577974 TI - Sliding mode controller with modified sliding function for DC-DC Buck Converter. AB - This article presents design of Sliding Mode Controller with proportional integral type sliding function for DC-DC Buck Converter for the controlled power supply. The converter with conventional sliding mode controller results in a steady state error in load voltage. The proposed modified sliding function improves the steady state and dynamic performance of the Convertor and facilitates better choices of controller tuning parameters. The conditions for existence of sliding modes for proposed control scheme are derived. The stability of the closed loop system with proposed sliding mode control is proved and improvement in steady state performance is exemplified. The idea of adaptive tuning for the proposed controller to compensate load variations is outlined. The comparative study of conventional and proposed control strategy is presented. The efficacy of the proposed strategy is endowed by the simulation and experimental results. PMID- 28577976 TI - Dual function of MAZ mediated by FOXF2 in basal-like breast cancer: Promotion of proliferation and suppression of progression. AB - Myc-associated zinc finger protein (MAZ) is a transcription factor with C2H2-type zinc-finger motifs that can bind GC-rich cis-elements. MAZ activates the transcription of some cancer-related genes and represses that of others, suggesting that changes in MAZ expression may play different roles in the development and progression of different types or subtypes of cancers depending on its target genes. However, the functions and mechanisms of MAZ in regulating the carcinogenesis and progression of breast cancer have remained unclear. In the current study, we show that MAZ performs dual function in basal-like breast cancer (BLBC): suppression of aggressiveness and promotion of proliferation. Forkhead box F2 (FOXF2) is a novel transcription target of MAZ and mediates the functions of MAZ. The MAZ mRNA level, particularly in combination with the FOXF2 mRNA level, may serve as a prognostic marker for BLBC patients. Our results indicate that the dual function of the MAZ-FOXF2 axis reflect the pleiotropic nature of multifunctional transcription factors in regulating the different stages of cancer development and progression, which could lead to the complexity of cancer diagnosis and treatment. PMID- 28577975 TI - Zic2 promotes tumor growth and metastasis via PAK4 in hepatocellular carcinoma. AB - The dysregulation of transcription factors contributes to the unlimited growth of cancer cells. Zic2 has been shown to be crucial to the progression of human cancers. However, its role in hepatocellular carcinoma (HCC) remains unclear. Our data showed that Zic2 expression gradually increased from normal to cancer to metastatic tissues. Zic2 overexpression promoted, whereas Zic2 knockdown inhibited, cell proliferation and migration in vitro as well as tumor growth and metastasis in vivo. Gene microarray results indicated that PAK4 was a potential target of Zic2. The knockdown of Zic2 decreased, whereas Zic2 re-expression increased, the expression of PAK4. ChIP and luciferase assays indicated that Zic2 directly bound to the PAK4 promoter and modulated its activity. PAK4 interference attenuated Zic2-mediated cell growth via modulating the Raf/MEK/ERK pathway. In a cohort of 615 patients, Zic2 was positively correlated with PAK4 and associated with worse overall and disease-free survival. Multivariate analyses revealed that Zic2 and PAK4 were independent indicators of a poor outcome in HCC. In addition, Zic2 expression was inversely correlated with miR-1271 expression. Re introduction of miR-1271 attenuated Zic2-promoted cell proliferation and migration. Taken together, our findings suggest that the newly identified miR 1271/Zic2/PAK4 axis plays an important role in HCC progression and may serve as a potential therapeutic target for HCC. PMID- 28577978 TI - Social memory engram in the hippocampus. AB - Social memory is one of the crucial components of episodic memories. Gregarious animals living in societies utilize social memory to exhibit the appropriate social behaviors such as aggression, avoidance, cooperative behavior, and even mating behavior. However, the neural mechanisms underlying social memory in the hippocampus remains mysterious. Here, I review some evidence from work done in rodents and primates on the brain region(s) and circuits encoding and/or retrieving social memory, as well as a storage for social memory (i.e. social memory engram neurons). Based on our recent findings that neural ensemble in ventral CA1 sub-region of the hippocampus possesses social memory engram, I would discuss the neural network for social information processing in order to encode social memory; and its evolutionary conservation between rodents and human. PMID- 28577977 TI - Zonisamide ameliorates levodopa-induced dyskinesia and reduces expression of striatal genes in Parkinson model rats. AB - To investigate the difference in results according to the mode of levodopa administration and the effect of zonisamide (ZNS), we analyzed the mRNA expression of dopaminergic and non-dopaminergic receptors in the striatum of Parkinson model rats in relation to the development of levodopa-induced dyskinesia (LID). Unilateral Parkinson model rats were subdivided into 4 groups and treated as follows: no medication (group N), continuous levodopa infusion (group C), intermittent levodopa injection (group I), and intermittent levodopa and ZNS injection (group Z). Two weeks after the treatment, LID was observed in group I and Z, but less severe in group Z. The level of both D1 and D2 receptor mRNAs was elevated in groups I and Z, but only D2 receptor mRNA expression was elevated in group C. Adenosine A2A receptor mRNA showed increased expression only in group I. The level of endocannabinoid CB1 receptor mRNA was elevated in groups N, C, and I, but not in group Z. Intermittent injection of levodopa caused LID, in association with elevated expression of D1 and A2A receptors. ZNS ameliorated the development of LID and inhibited up-regulation of A2A and CB1 receptors. Modulation of these receptors may lead to therapeutic approaches for dyskinesia. PMID- 28577979 TI - Effects of multicomponent training of cognitive control on cognitive function and brain activation in older adults. AB - The aim of this study was to investigate the changes in cognitive functions and brain activation after multicomponent training of cognitive control in non demented older adults, utilizing neuropsychological tests and fMRI. We developed and implemented a computerized Multicomponent Training of Cognitive Control (MTCC), characterized by task variability and adaptive procedures, in order to maximize training effects in cognitive control and transfer to other cognitive domains. Twenty-seven community-dwelling adults, aged 64-77 years, without any history of neurological or psychiatric problems, participated in this study (14 in the training group and 13 in the control group). The MTCC was administered to the participants assigned to the training group for 8 weeks, while those in the control group received no training. Neuropsychological tests and fMRI were administered prior to and after the training. Trained participants showed improvements in cognitive control, recognition memory and general cognitive functioning. Furthermore, the MTCC led to an increased brain activation of the regions adjacent to the baseline cognitive control-related areas in the frontoparietal network. Future studies are necessary to confirm our hypothesis that MTCC improves cognitive functioning of healthy elderly individuals by expanding their frontoparietal network that is involved in cognitive control. PMID- 28577980 TI - Physicochemical properties of pectin from green jelly leaf (Cyclea barbata Miers). AB - The water extract of Green Jelly leaves (GJL) obtained by crushing the leaves in water (1:40) was capable of forming a gel at room temperature. The composition of GJL consisted mainly of carbohydrate (~70w/w), protein (~13% w/w) and minerals (~6% w/w). The mineral portion consisted of mainly calcium (~1.2% w/w), zinc (~0.12% w/w) and magnesium (~0.11% w/w). The isolated polysaccharide fraction (~42.6% w/w) consisted of mainly galacturonic acid (~35.8% w/w) and neutral sugars (~6.8% w/w), with a weight-average molecular weight of ~4.4*105g/mol. The results obtained by Fourier Transform Infra-Red (FTIR) showed that GJL polysaccharide fraction had a fairly similar FTIR fingerprint as the commercial low-methoxyl pectin (LMP). The degree of esterification of the polysaccharide changed drastically (from 97% to 10%) depending on the temperature used during the extraction process. The zeta potential of the extracted polysaccharide showed high negative charged as compared to the commercial LMP but close to sodium alginate. The study showed that the gelation was divalent cation-mediated and probably facilitated by the low degree of esterification which reduced steric hindrance from the methyl ester groups. PMID- 28577972 TI - Electrical synapses in mammalian CNS: Past eras, present focus and future directions. AB - Gap junctions provide the basis for electrical synapses between neurons. Early studies in well-defined circuits in lower vertebrates laid the foundation for understanding various properties conferred by electrical synaptic transmission. Knowledge surrounding electrical synapses in mammalian systems unfolded first with evidence indicating the presence of gap junctions between neurons in various brain regions, but with little appreciation of their functional roles. Beginning at about the turn of this century, new approaches were applied to scrutinize electrical synapses, revealing the prevalence of neuronal gap junctions, the connexin protein composition of many of those junctions, and the myriad diverse neural systems in which they occur in the mammalian CNS. Subsequent progress indicated that electrical synapses constitute key elements in synaptic circuitry, govern the collective activity of ensembles of electrically coupled neurons, and in part orchestrate the synchronized neuronal network activity and rhythmic oscillations that underlie fundamental integrative processes. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve. PMID- 28577981 TI - Thrombin-loaded alginate-calcium microspheres: A novel hemostatic embolic material for transcatheter arterial embolization. AB - Transcatheter arterial embolization (TAE) is the best non-laparotomy choice for solid visceral organs rupture and bleeding nowadays. In our previous study, a new biodegradable macromolecule material thrombin-loaded alginate-calcium microsphere (TACM) was prepared and its characteristics were investigated preliminarily. In this study, we further investigated the biocompatibility of TACMs, as well as physical characteristic, application method and effect of TACMs with thrombus (embolic agent). The in vivo results attested that TACMs were non-irritating and non-genotoxic with desired biocompatibility, although brought about a slight and temporary inflammation. Application research showed that the function of thrombin was inhibited by common contrast agents, and it was impracticable to add contrast agents in TACMs with thrombus for tracing under X-rays in TAE. Then, a novel delivery method was developed. In addition, stress resistance test indicated that the TACMs with thrombus was significantly stronger than single autologous thrombus, the optimized ratio of TACMs to whole blood was 2:3 for forming mixed thrombus. Finally, large animal experiment revealed that the novel embolic agent TACMs mixed thrombus was effective and safe in treating hemorrhage of solid abdominal viscera by TAE. PMID- 28577982 TI - Purification, characterization and biological activities of a polysaccharide from Lepidium meyenii leaves. AB - The characteristics and biological activities of a novel polysaccharide from Lepidium meyenii leaves (LMLP) were investigated. LMLP was purified using DEAE-52 cellulose chromatography followed by SephadexG-100 chromatography. The average molecule weight of LMLP was 58.43kDa and it was composed of galactose, arabinose, rhamnose, glucose and mannose with a relative molar ratio of 5.51:4.05:1.15:0.77:0.01. Antioxidant activity results showed that LMLP presented an EC50 of 3.72mg/mL in scavenging 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical, and it also had reducing power (OD700nm being 0.079 at 1mg/mL). Moreover, LMLP possessed the potential on stimulating immune response of RAW264.7 cells. It could promote proliferation, strengthen phagocytosis function, enhance the expression of CD80, and increase the secretion of nitric oxide (NO) in a dose dependent manner. All of these results suggested that LMLP could be used as a natural ingredient for functional food. PMID- 28577983 TI - Monoamine oxidase inhibitory activity of methoxy-substituted chalcones. AB - The MAO-B inhibitory activity of chalcone (1, 3- diphenyl-2-propen-1-one) based compounds arise from its structural similarity with 1, 4-diphenyl-2-butene, a known MAO-B inhibitor. Based on our previous report, the methoxy-substituted with fluorine containing chalcones are promising reversible MAO-B inhibitors, while in the present study, a series of methoxylated chalcones (C1-C9) bearing substitution on the para position of ring B was synthesized and evaluated for their human monoamine oxidase inhibitory activity. With the exception of (2E)-1 (4-methoxyphenyl)-3-(4-nitrophenyl) prop-2-en-1-one (C7), which is a nonselective inhibitor, the chalcones exhibited competitive, selective, and reversible inhibition of hMAO-B. The most potent compound, (2E)-3-[4-(dimethylamino) phenyl] 1-(4-methoxyphenyl) prop-2-en-1-one (C5), showed the best inhibitory activity towards hMAO-B (IC50=0.29+/-0.011MUM;Ki=0.14+/-0.001MUM). The reversibility of MAO-B inhibition by compound C5 was demonstrated by the recovery of enzyme activity after dialysis of mixtures containing enzyme and inhibitor. The reversiblity of C5 was 25.38+/-1.40 and 92.00+/-3.87% before and after dialysis, respectively. PAMPA was carried out to evaluate the blood-brain barrier effects of the designated compounds. Moreover, the most potent MAO-B inhibitor, C5, was found to be nontoxic towards cultured hepatic cells at 5 and 25MUM, with 97 and 90% viability. Molecular docking study was performed against hMAO-B to observe the binding site interactions of the lead compound. PMID- 28577985 TI - 3D reconstruction of brain section images for creating axonal projection maps in marmosets. AB - BACKGROUND: The brain of the common marmoset (Callithrix jacchus) is becoming a popular non-human primate model in neuroscience research. Because its brain fiber connectivity is still poorly understood, it is necessary to collect and present connection and trajectory data using tracers to establish a marmoset brain connectivity database. NEW METHOD: To visualize projections and trajectories of axons, brain section images were reconstructed in 3D by registering them to the corresponding block-face brain images taken during brain sectioning. During preprocessing, autofluorescence of the tissue was reduced by applying independent component analysis to a set of fluorescent images taken using different filters. RESULTS: The method was applied to a marmoset dataset after a tracer had been injected into an auditory belt area to fluorescently label axonal projections. Cortical and subcortical connections were clearly reconstructed in 3D. The registration error was estimated to be smaller than 200 MUm. Evaluation tests on ICA-based autofluorescence reduction showed a significant improvement in signal and background separation. COMPARISON WITH EXISTING METHODS: Regarding the 3D reconstruction error, the present study shows an accuracy comparable to previous studies using MRI and block-face images. Compared to serial section two-photon tomography, an advantage of the proposed method is that it can be combined with standard histological techniques. The images of differently processed brain sections can be integrated into the original ex vivo brain shape. CONCLUSIONS: The proposed method allows creating 3D axonal projection maps overlaid with brain area annotations based on the histological staining results of the same animal. PMID- 28577987 TI - ALCAR promote adult hippocampal neurogenesis by regulating cell-survival and cell death-related signals in rat model of Parkinson's disease like-phenotypes. AB - Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the nigrostriatal pathway that leading to progressive motor and nonmotor symptoms. The formation of newborn neurons in the adult hippocampus is affected by many factors such as anxiety, depression and impairment in learning and memory that are commonly observed nonmotor symptoms in PD, indicating the role of adult neurogenesis in PD pathophysiology. Acetyl-l-carnitine (ALCAR), regulate mitochondrial metabolism and has been reported to improve cognitive functions in different neurodegenerative disorders through an unknown mechanism. For the first time, we investigated the effect of ALCAR on adult neurogenesis in the 6-hydroxydopamine (6-OHDA) induced rat model of PD-like phenotypes and also explored the possible underlying mechanism of action. A single unilateral administration of 6-OHDA into the medial forebrain bundle reduced neural progenitor cell (NPC) proliferation, long-term survival and neuronal differentiation in the hippocampus. Interestingly, chronic treatment with ALCAR (100 mg/kg/day, i.p) potentially enhanced proliferation, long term survival and neuronal differentiation of NPCs in rat model of PD-like phenotypes. ALCAR treatment stimulates cell survival related signals (AKT and BCL-2) by inhibiting cell death related cues (GSK-3beta and BAX) which might be responsible for a neuroprotective effect of ALCAR in rat model of PD-like phenotypes. We conclude that ALCAR exerts neuroprotective effects against 6-OHDA-induced impairment in hippocampal neurogenesis by regulating cell survival and cell death-related signals. PMID- 28577986 TI - Automated analysis of brain activity for seizure detection in zebrafish models of epilepsy. AB - BACKGROUND: Epilepsy is a chronic neurological condition, with over 30% of cases unresponsive to treatment. Zebrafish larvae show great potential to serve as an animal model of epilepsy in drug discovery. Thanks to their high fecundity and relatively low cost, they are amenable to high-throughput screening. However, the assessment of seizure occurrences in zebrafish larvae remains a bottleneck, as visual analysis is subjective and time-consuming. NEW METHOD: For the first time, we present an automated algorithm to detect epileptic discharges in single channel local field potential (LFP) recordings in zebrafish. First, candidate seizure segments are selected based on their energy and length. Afterwards, discriminative features are extracted from each segment. Using a labeled dataset, a support vector machine (SVM) classifier is trained to learn an optimal feature mapping. Finally, this SVM classifier is used to detect seizure segments in new signals. RESULTS: We tested the proposed algorithm both in a chemically-induced seizure model and a genetic epilepsy model. In both cases, the algorithm delivered similar results to visual analysis and found a significant difference in number of seizures between the epileptic and control group. COMPARISON WITH EXISTING METHODS: Direct comparison with multichannel techniques or methods developed for different animal models is not feasible. Nevertheless, a literature review shows that our algorithm outperforms state-of-the-art techniques in terms of accuracy, precision and specificity, while maintaining a reasonable sensitivity. CONCLUSION: Our seizure detection system is a generic, time-saving and objective method to analyze zebrafish LPF, which can replace visual analysis and facilitate true high-throughput studies. PMID- 28577988 TI - Nexus between mitochondrial function, iron, copper and glutathione in Parkinson's disease. AB - Parkinson's disease is neuropathologically characterised by loss of catecholamine neurons in vulnerable brain regions including substantia nigra pars compacta and locus coeruleus. This review discusses how the susceptibility of these regions is defined by their shared biochemical characteristics that differentiate them from other neurons. Parkinson's disease is biochemically characterised by mitochondrial dysfunction, accumulation of iron, diminished copper content and depleted glutathione levels in these regions. This review also discusses this neuropathology, and provides evidence for how these pathological features are mechanistically linked to each other. This leads to the conclusion that disruption of mitochondrial function, or iron, copper or glutathione metabolism in isolation provokes the pathological impairment of them all. This creates a vicious cycle that drives pathology leading to mitochondrial failure and neuronal cell death in vulnerable brain regions. PMID- 28577989 TI - Hemicholinium-3 sensitive choline transport in human T lymphocytes: Evidence for use as a proxy for brain choline transporter (CHT) capacity. AB - The synaptic uptake of choline via the high-affinity, hemicholinium-3-dependent choline transporter (CHT) strongly influences the capacity of cholinergic neurons to sustain acetylcholine (ACh) synthesis and release. To advance research on the impact of CHT capacity in humans, we established the presence of the neuronal CHT protein in human T lymphocytes. Next, we demonstrated CHT-mediated choline transport in human T cells. To address the validity of T cell-based choline uptake as a proxy for brain CHT capacity, we isolated T cells from the spleen, and synaptosomes from cortex and striatum, of wild type and CHT-overexpressing mice (CHT-OXP). Choline uptake capacity in T cells from CHT-OXP mice was two-fold higher than in wild type mice, mirroring the impact of CHT over-expression on synaptosomal CHT-mediated choline uptake. Monitoring T lymphocyte CHT protein and activity may be useful for estimating human CNS cholinergic capacity and for testing hypotheses concerning the contribution of CHT and, more generally, ACh signaling in cognition, neuroinflammation and disease. PMID- 28577990 TI - The regulation of corticosteroid receptors in response to chronic social defeat. AB - Our previous studies demonstrated that chronic social defeat (CSD) up-regulated expression of the serotonin transporter (SERT) and norepinephrine transporter (NET) in the brain, which was mediated by corticosteroid receptors. In the present study we first analyzed the alterations of corticosteroid receptors in different brain regions after the CSD paradigm. The results showed that CSD significantly reduced glucocorticoid receptor (GR) protein levels in the CA1 and dentate gyrus of the hippocampus, as well as in central and basolateral nuclei of the amygdala, which was accompanied by the translocation of GR from cytoplasm to nuclei. CSD also markedly reduced GR mRNA levels and MR immunoreactivity in the CA1, CA3 and dentate gyrus areas of the hippocampus. Conversely, CSD pronouncedly enhanced GR mRNA and protein levels in the dorsal raphe nucleus and locus coeruleus relative to the control. As an extension of our previous studies, in situ hybridization and immunohistochemical staining demonstrated that CSD regimen caused a notable increase of SERT mRNA levels in the dorsal raphe nucleus and increased SERT immunoreactivities in CA1 and CA3 of the hippocampus, as well as those in the basolateral nuclei of the amygdala. Likewise, CSD regimen resulted in an evident enhancement of NET immunoreactivity in the CA1 of the hippocampus and in the basolateral nuclei of the amygdala. Our current findings suggest that GR expressional alterations in response to CSD are complex and brain region specific, which may correspond to their different functions in these regions. PMID- 28577984 TI - Protein kinase D signaling in cancer: A friend or foe? AB - Protein kinase D is a family of evolutionarily conserved serine/threonine kinases that belongs to the Ca++/Calmodulin-dependent kinase superfamily. Signal transduction pathways mediated by PKD can be triggered by a variety of stimuli including G protein-coupled receptor agonists, growth factors, hormones, and cellular stresses. The regulatory mechanisms and physiological roles of PKD have been well documented including cell proliferation, survival, migration, angiogenesis, regulation of gene expression, and protein/membrane trafficking. However, its precise roles in disease progression, especially in cancer, remain elusive. A plethora of studies documented the cell- and tissue-specific expressions and functions of PKD in various cancer-associated biological processes, while the causes of the differential effects of PKD have not been thoroughly investigated. In this review, we have discussed the structural functional properties, activation mechanisms, signaling pathways and physiological functions of PKD in the context of human cancer. Additionally, we have provided a comprehensive review of the reported tumor promoting or tumor suppressive functions of PKD in several major cancer types and discussed the discrepancies that have been raised on PKD as a major regulator of malignant transformation. PMID- 28577992 TI - Simultaneous detection of 4 prototypic rat parvoviruses using the luminex xTAG assay in laboratory animal health monitoring. AB - There are currently four rat parvoviruses including Kilham rat virus (KRV), Toolans H-1 parvovirus (H-1virus), rat parvovirus type 1a (RPV-1a) and rat minute virus (RMV). Virus detection methods are commonly based on conventional PCR - agarose gel electrophoresis or serological assay methods These methods are both time-consuming and lack specificity. In this study, we developed a bead array xTAG assay for the simultaneous detection and discrimination of four rat parvoviruses. The detection limits ranged from 100 to 1000 copies/MUL of input purified plasmid DNA. We examined 50 clinical specimens and 15 facal samples by xTAG assay and conventional PCR. The results showed a high consistency except for several weak positive infections. It demonstrated that the xTAG-multiplex PCR method is specific, sensitive and suitable for high throughput platforms for rat parvovirus screening of clinical samples and contaminated biological materials. PMID- 28577991 TI - Inhibition of Na+-K+-2Cl- cotransporter attenuates blood-brain-barrier disruption in a mouse model of traumatic brain injury. AB - Traumatic brain injury (TBI) can lead to long-term motor and cognitive dysfunction, which can be at least partly attributed to blood-brain barrier (BBB) disruption. The mechanisms underlying post-TBI BBB disruption, however, are poorly understood thus far. Na+-K+-2Cl- cotransporter isoform 1 (NKCC1) is a universally expressed ion transporter that maintains intracellular ion homeostasis by increasing intracellular K+ and Cl-. Having been characterized in stroke models, NKCC1 is activated in various cell types in the ischemic brain, and is thought to mediate BBB disruption, brain edema, and neuronal cell death. In this study, we tested the hypothesis that inhibition of NKCC1 may improve neurological outcomes via protecting against BBB disruption in a TBI mouse model. Adult male C57BL/6 J mice or NKCC1 deficient mice were subjected to controlled cortical impact (CCI). As an alternative to the genetic-based NKCC1 depletion, bumetanide, a selective NKCC1 inhibitor, was administrated (25 mg/kg, i.p.) 15 min after CCI and then every 6 h up to 48 h. Short-term sensorimotor function recovery was determined by rotarod, cylinder test, grid walking and foot fault test. BBB integrity was examined at 48 h post-CCI by measuring Evans blue extravasation, brain water content, and expression levels of tight junction proteins. Our results revealed that administration of bumetanide or genetic depletion of NKCC1 improved short-term neurological recovery against TBI. Bumetanide treatment markedly decreased brain water content and BBB leakage, correlated with reduction of MMP-9 expression and preventing the degradation of tight junction proteins. These findings suggest an important role of NKCC1 activation in mediating BBB disruption after TBI. Thus, NKCC1 inhibition may offer the potential for improving neurological outcomes in clinical TBI. PMID- 28577993 TI - Fluorescence detection of the transglycosylation activity of amylosucrase. AB - The purpose of this study was to investigate the novel fluorescence-based assay for the transglycosylation activity of amylosucrase (ASase). The transglycosylation activity of ASase from Deinococcus geothermalis (DGAS), ASase from Neisseria polysaccharea (NPAS), and DGAS-B (chimeric ASase wherein the B domain from DGAS was exchanged with the B domain of NPAS in a DGAS background) was applied to modify 4-methlylumberlliferone (MU) to 4-methylumberlliferone glucoside (MUG) using MU as an acceptor and sucrose as a glucoside donor. The result of HPLC (high performance liquid chromatography) show that the bioconversion of MUG with ASases was successfully accomplished using sucrose and MU. Kinetic studies of ASases were performed to determine kinetic parameter for sucrose and MU. The order of overall performance (kcat/Km) of transglycosylation activity for MU among DGAS, DGAS-B and NPAS was as follows: DGAS-B (8.1) > DGAS (5.0) > NPAS (0.4). The fluorescence-based transglycosylation assay using MU has a potential to be used as the detection of transglycosylation activity of ASase and to screen novel ASase variants, which may be improved in their transglycosylation activities. PMID- 28577996 TI - Albumin micro/nanoparticles entrapping liposomes for itraconazole green formulation. AB - Itraconazole-loaded micro/nanoparticles containing albumin and liposomes were prepared by a technological process that avoids the use of organic solvents and crosslinker agents. The particles were characterized, lyophilized and formulated as tablets. Dynamic light scattering was used to determine the hydrodynamic diameter and zeta potential of the particles; optical and scanning-electron microscopy was used to evaluate their morphology. Spherical shaped particles of different sizes and zeta potential were obtained. An exponential relationship between the zeta potential and the albumin/cationic lipid molar ratio was established. Drug entrapment efficiency values were in the range of 51-68%, with no statistical differences among albumin feeding concentrations. Mannitol was used as lyophilization additive and the freeze-dried cake was directly compressed into tablets, suitable for vaginal administration. The results from the in vitro drug delivery assay show the influence of albumin on the itraconazole delivery profile; a rapid release was observed for particles with higher albumin amount compared to those with lower protein content. According to the results of this study, albumin particles entrapping liposomes prove to be a green pharmaceutical vehicle with a high potential for delivery of hydrophobic and highly albumin bound drugs. PMID- 28577995 TI - Equilibrium solubility measurement of compounds with low dissolution rate by Higuchi's Facilitated Dissolution Method. A validation study. AB - Incubation time plays a critical role in the accurate measurement of equilibrium solubility of compounds. Substances which dissolve very slowly generally need long incubation times (days or weeks) to reach equilibrium. However, long times may pose several problems, such as decomposition of solute, molding of buffer, and drifting of pH. Higuchi in 1979 proposed the Facilitated Dissolution Method (FDM) to dramatically reduce incubation time. It employs a small volume of water immiscible organic solvent to partly solubilize the sample and thereby increase the surface area available for dissolution. The method has been used only rarely. In this study we performed a systematic validation of FDM using progesterone as model compound. The reference solubility value, 7.95+/-0.21MUg/mL (p<0.05, n=5), was determined in Britton-Robinson buffer solution (pH7.4) at 25.0 degrees C by the standardized protocol of Saturation Shake-Flask (SSF) method. Also, the solubility was measured by the FDM approach under varied experimental conditions (e.g., type and volume of organic solvent, time of agitation, and amount of solid excess), and compared to the reference value. It was demonstrated that the small amount of organic solvent used in the FDM does not impact the measured solubility, compared to the reference value. Additionally, four compounds of low dissolution rate (dexamethasone, digoxin, haloperidol and cosalane) were used to demonstrate that FDM can reduce the long equilibration time to the standardized 24h (6h stirring and 18h sedimentation). The time dependence of solubility equilibrium was measured by SSF, and the results were compared with those obtained by FDM. Our study, based on >200 solubility experiments, supports the validity of Higuchi's method. In this study we propose a standardized protocol for the FDM, where 1% v/v of organic solvent is used. Octane (or isooctane) was found to be suitable for highly hydrophobic compounds. Alternatively, octanol or 1,2-dichloroethane can be used for less lipophilic compounds. PMID- 28577994 TI - Comparison between two population-based hepatitis B serosurveys with an 8-year interval in Shandong Province, China. AB - BACKGROUND: Tremendous progress has been made in hepatitis B virus (HBV) prevention and control in the last 30 years in China, but it continues to be a major public health problem. The most recently reported population-based seroepidemiological survey on HBV in Shandong Province in China was published in 2006, and an updated baseline for HBV prevalence was badly needed in the province to identify the change in HBV epidemiology in the last decade. METHODS: Two population-based cross-sectional serosurveys were performed among the population aged 1-59 years in the same sample areas in Shandong Province, China in 2006 and 2014, respectively. Data on demographic characteristics were collected. A blood sample was obtained from each person and was tested for hepatitis B surface antigen (HBsAg), antibody against HBsAg (anti-HBs), and antibody against hepatitis B core antigen (anti-HBc). RESULTS: Overall, the prevalence rates of HBsAg, anti-HBs, and anti-HBc were 3.39% (95% confidence interval (CI) 2.51 4.26), 44.96% (95% CI 41.34-48.57), and 24.45% (95% CI 22.19-26.71), respectively, among the population aged 1-59 years in the 2006 serovsurvey; the corresponding prevalence rates were 2.49% (95% CI 1.81-3.17), 48.27% (95% CI 45.63-50.92), and 22.56% (95% CI 20.14-24.97), respectively, in 2014. The prevalence rates of HBsAg and anti-HBc were lower in 2014 than in 2006. Conversely, the prevalence of anti-HBs showed an increase. However, none of these differences were statistically significant (all p>0.05). The prevalence of HBsAg showed an increase among persons aged 20-24 years in 2014 (3.83%) compared with 2006 (2.98%) (t=0.45, p=0.67). Among all occupation groups, the prevalence of HBsAg was lower in 2014 than in 2006, while the prevalence of anti-HBc showed moderate increases in students and farmers (all p>0.05). The prevalence of HBsAg decreased more obviously in urban areas (65.49%) than rural areas (7.07%) from 2006 to 2014. CONCLUSIONS: The epidemiology of HBV infection has changed in Shandong Province, China over the last decade. More attention should be paid to HBV infection among students and farmers. PMID- 28577997 TI - Interfacial interaction track of amorphous solid dispersions established by water soluble polymer and indometacin. AB - The present work studied interfacial interactions of amorphous solid dispersions matrix of indometacin (IMC) that established using PVP K30 (PVP) and PEG 6000 (PEG) by focusing on their interaction forces and wetting process. Infrared spectroscopy (IR), raman spectroscopy, X-ray photoelectron spectra and contact angle instrument were used throughout the study. Hydrogen bond energy formed between PEG and IMC were stronger than that of PVP and IMC evidenced by molecular modeling measurement. The blue shift of raman spectroscopy confirmed that hydrogen bonding forces were formed between IMC and two polymers. The contact angle study can be used as an easy method to determine the dissolution mechanism of amorphous solid dispersions through fitting the profile of contact angle of water on a series of tablets. It is believed that the track of interfacial interactions will certainly become powerful tools to for designing and evaluating amorphous solid dispersions. PMID- 28577998 TI - Involvement of the prelimbic cortex in contextual fear conditioning with temporal and spatial discontinuity. AB - Time plays an important role in conditioning, it is not only possible to associate stimuli with events that overlap, as in delay fear conditioning, but it is also possible to associate stimuli that are discontinuous in time, as shown in trace conditioning for a discrete stimuli. The environment itself can be a powerful conditioned stimulus (CS) and be associated to unconditioned stimulus (US). Thus, the aim of the present study was to determine the parameters in which contextual fear conditioning occurs by the maintenance of a contextual representation over short and long time intervals. The results showed that a contextual representation can be maintained and associated after 5s, even in the absence of a 15s re-exposure to the training context before US delivery. The same effect was not observed with a 24h interval of discontinuity. Furthermore, optimal conditioned response with a 5s interval is produced only when the contexts (of pre-exposure and shock) match. As the pre-limbic cortex (PL) is necessary for the maintenance of a continuous representation of a stimulus, the involvement of the PL in this temporal and contextual processing was investigated. The reversible inactivation of the PL by muscimol infusion impaired the acquisition of contextual fear conditioning with a 5s interval, but not with a 24h interval, and did not impair delay fear conditioning. The data provided evidence that short and long intervals of discontinuity have different mechanisms, thus contributing to a better understanding of PL involvement in contextual fear conditioning and providing a model that considers both temporal and contextual factors in fear conditioning. PMID- 28577999 TI - Ketamine induces brain-derived neurotrophic factor expression via phosphorylation of histone deacetylase 5 in rats. AB - Ketamine shows promise as a therapeutic agent for the treatment of depression. The increased expression of brain-derived neurotrophic factor (BDNF) has been associated with the antidepressant-like effects of ketamine, but the mechanism of BDNF induction is not well understood. In the current study, we demonstrate that the treatment of rats with ketamine results in the dose-dependent rapid upregulation of Bdnf promoter IV activity and expression of Bdnf exon IV mRNAs in rat hippocampal neurons. Transfection of histone deacetylase 5 (HDAC5) into rat hippocampal neurons similarly induces Bdnf mRNA expression in response to ketamine, whereas transfection of a HDAC5 phosphorylation-defective mutant (Ser259 and Ser498 replaced by Ala259 and Ala498), results in the suppression of ketamine-mediated BDNF promoter IV transcriptional activity. Viral-mediated hippocampal knockdown of HDAC5 induces Bdnf mRNA and protein expression, and blocks the enhancing effects of ketamine on BDNF expression in both unstressed and stressed rats, and thereby providing evidence for the role of HDAC5 in the regulation of Bdnf expression. Taken together, our findings implicate HDAC5 in the ketamine-induced transcriptional regulation of Bdnf, and suggest that the phosphorylation of HDAC5 regulates the therapeutic actions of ketamine. PMID- 28578000 TI - Centrosomal MCM7 strengthens the Cep68-VHL interaction and excessive MCM7 leads to centrosome splitting resulting from increase in Cep68 ubiquitination and proteasomal degradation. AB - We have recently reported that Rootletin prevents Cep68 from VHL-mediated proteasomal degradation to maintain centrosome cohesion, unveiling the first underlying mechanism of a linker protein required for maintenance of centrosome cohesion. The minichromosome maintenance (MCM) proteins 2-7 have long been noticed to localize to centrosomes, but their functions at the centrosome are presently unknown. Here, we show that MCM7 directly binds to the centrosomal linker protein Cep68 in vitro and complexes with Cep68 and VHL in vivo. Absence of MCM7 weakened the interaction between Cep68 and VHL, whereas MCM7 overexpression facilitated the Cep68-VHL association. As a result of MCM7 overexpression, Cep68 was targeted for ubiquitination and proteasomal degradation, thereby rendering centrosome splitting. We propose that Cep68 protein level needs to be fine-tuned in order to ensure that its direct interactors, such as the microcephaly protein Cep215 and PCNT, function properly. PMID- 28578001 TI - 1alpha,25-Dihydroxyvitamin D3 enhances TRPV6 transcription through p38 MAPK activation and GADD45 expression. AB - The active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], acts as a ligand for the vitamin D receptor (VDR), and regulates various physiological processes, including calcium and bone metabolism, cellular growth and differentiation, immunity and cardiovascular function. A number of vitamin D derivatives have been synthesized for the treatment of cancer and inflammatory disease, but the adverse effect of hypercalcemic activity due to intestinal calcium absorption has limited wide clinical application. The VDR target gene product TRPV6 is essential for intestinal calcium absorption. Our prior study has demonstrated that 1,25(OH)2D3 induces TRPV6 mRNA expression at lower concentrations than for induction of CYP24A1, a VDR target gene involved in vitamin D inactivation, in intestinal SW480 cells, suggesting an additional mechanism for vitamin D signaling on TRPV6 induction. By searching for a signal transduction pathway involved in 1,25(OH)2D3-induced expression of TRPV6, we found that a p38 mitogen-activated protein kinase (MAPK) inhibitor reduces the expression of TRPV6 but not CYP24A1 in 1,25(OH)2D3-treated SW480 cells. Knockdown experiments showed that p38alpha is involved in 1,25(OH)2D3-induced expression of TRPV6 but not CYP24A1. Treatment with a de novo protein synthesis inhibitor suppressed 1,25(OH)2D3-induced TRPV6 expression. Finally, we found that 1,25(OH)2D3 treatment induced expression of GADD45A, which encodes the GADD45alpha MAPK kinase kinase activator, earlier than TRPV6 expression and that GADD45A knockdown reduced TRPV6 induction by 1,25(OH)2D3. These findings indicate that p38alpha and GADD45alpha are involved in an enhanced vitamin D signaling on TRPV6 expression. PMID- 28578002 TI - MiR-124 contributes to glucocorticoid resistance in acute lymphoblastic leukemia by promoting proliferation, inhibiting apoptosis and targeting the glucocorticoid receptor. AB - Acute lymphoblastic leukemia (ALL) is characterized by the accumulation of abnormal lymphoblasts in the bone marrow and blood. Though great progress has been made for improvement in clinical treatment during the past decades, some children with ALL still relapsed. Glucocorticoid (GC) resistance is an important clinical problem for ALL treatment failure. Therefore, further understanding of the mechanism of GC resistance and exploring novel therapeutic strategies are crucial for improving treatment outcome. The reported involvement of microRNAs (miRNAs) in drug resistance implied that deregulated miRNA expression might contribute to GC treatment response of ALL. However, individual miRNAs and their functional mechanisms potentially involved in the GC response are still largely unknown. In the present study, we found that miR-124 was up-regulated in prednisone insensitive human ALL cell line and prednisone-poor response ALL patients. Furthermore, it was found that miR-124 might contribute to GC resistance by promoting proliferation and inhibiting apoptosis of ALL cells. Importantly, we validated that miR-124, targeted and decreased the expression of glucocorticoid receptor (NR3C1), prevented the inhibitory effect of GC in ALL. These findings strongly suggest that miR-124 is critical in poor GC response and may serve as a potential therapeutic target in ALL with poor GC resistance. PMID- 28578003 TI - Generating level-dependent models of cervical and thoracic spinal cord injury: Exploring the interplay of neuroanatomy, physiology, and function. AB - The majority of spinal cord injuries (SCI) occur at the cervical level, which results in significant impairment. Neurologic level and severity of injury are primary endpoints in clinical trials; however, how level-specific damages relate to behavioural performance in cervical injury is incompletely understood. We hypothesized that ascending level of injury leads to worsening forelimb performance, and correlates with loss of neural tissue and muscle-specific neuron pools. A direct comparison of multiple models was made with injury realized at the C5, C6, C7 and T7 vertebral levels using clip compression with sham-operated controls. Animals were assessed for 10weeks post-injury with numerous (40) outcome measures, including: classic behavioural tests, CatWalk, non-invasive MRI, electrophysiology, histologic lesion morphometry, neuron counts, and motor compartment quantification, and multivariate statistics on the total dataset. Histologic staining and T1-weighted MR imaging revealed similar structural changes and distinct tissue loss with cystic cavitation across all injuries. Forelimb tests, including grip strength, F-WARP motor scale, Inclined Plane, and forelimb ladder walk, exhibited stratification between all groups and marked impairment with C5 and C6 injuries. Classic hindlimb tests including BBB, hindlimb ladder walk, bladder recovery, and mortality were not different between cervical and thoracic injuries. CatWalk multivariate gait analysis showed reciprocal and progressive changes forelimb and hindlimb function with ascending level of injury. Electrophysiology revealed poor forelimb axonal conduction in cervical C5 and C6 groups alone. The cervical enlargement (C5-T2) showed progressive ventral horn atrophy and loss of specific motor neuron populations with ascending injury. Multivariate statistics revealed a robust dataset, rank order contribution of outcomes, and allowed prediction of injury level with single-level discrimination using forelimb performance and neuron counts. Level dependent models were generated using clip-compression SCI, with marked and reliable differences in forelimb performance and specific neuron pool loss. PMID- 28578004 TI - Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease. AB - Striatal neurons forming the indirect pathway (iSPNs) are particularly vulnerable in Huntington's disease (HD). In this study we set out to investigate morphological and physiological alterations of iSPNs in two mouse models of HD with relatively slow disease progression (long CAG repeat R6/2 and zQ175-KI). Both were crossed with a transgenic mouse line expressing eGFP in iSPNs. Using the open-field and rotarod tests, we first defined two time points in relation to the occurrence of motor deficits in each model. Then, we investigated electrophysiological and morphological properties of iSPNs at both ages. Both HD models exhibited increased iSPN excitability already before the onset of motor deficits, associated with a reduced number of primary dendrites and decreased function of Kir- and voltage-gated potassium channels. Alterations that specifically occurred at symptomatic ages included increased calcium release by back-propagating action potentials in proximal dendrites, due to enhanced engagement of intracellular calcium stores. Moreover, motorically impaired mice of both HD models showed a reduction in iSPN spine density and progressive formation of huntingtin (Htt) aggregates in the striatum. Our study therefore reports iSPN-specific alterations relative to the development of a motor phenotype in two different mouse models of HD. While some alterations occur early and are partly non-progressive, others potentially provide a pathophysiological marker of an overt disease state. PMID- 28578005 TI - Isolation, characterization, and differentiation of multipotent neural progenitor cells from human cerebrospinal fluid in fetal cystic myelomeningocele. AB - Despite benefits of prenatal in utero repair of myelomeningocele, a severe type of spina bifida aperta, many of these patients will still suffer mild to severe impairment. One potential source of stem cells for new regenerative medicine based therapeutic approaches for spinal cord injury repair is neural progenitor cells (NPCs) in cerebrospinal fluid (CSF). To this aim, we extracted CSF from the cyst surrounding the exposed neural placode during the surgical repair of myelomeningocele in 6 fetuses (20 to 26weeks of gestation). In primary cultured CSF-derived cells, neurogenic properties were confirmed by in vitro differentiation into various neural lineage cell types, and NPC markers expression (TBR2, CD15, SOX2) were detected by immunofluorescence and RT-PCR analysis. Differentiation into three neural lineages was corroborated by arbitrary differentiation (depletion of growths factors) or explicit differentiation as neuronal, astrocyte, or oligodendrocyte cell types using specific induction mediums. Differentiated cells showed the specific expression of neural differentiation markers (betaIII-tubulin, GFAP, CNPase, oligo-O1). In myelomeningocele patients, CSF-derived cells could become a potential source of NPCs with neurogenic capacity. Our findings support the development of innovative stem-cell-based therapeutics by autologous transplantation of CSF-derived NPCs in damaged spinal cords, such as myelomeningocele, thus promoting neural tissue regeneration in fetuses. PMID- 28578006 TI - Increased Sat2 expression is associated with busulfan-induced testicular Sertoli cell injury. AB - Busulfan is a chemotherapeutic agent used to treat chronic myelogenous leukemia and other myeloproliferative disorders. Increasing evidence has demonstrated that busulfan may induce testicular dysfunction by targeting genes that are expressed in the testis. Here, we showed that spermidine/spermine N1-acetyltransferase 2 (Sat2) was present in testicular Sertoli cells, and its expression was significantly increased by busulfan treatment. To investigate the implications of Sat2 upregulation for cell growth and function, a Sat2-overexpressing TM4 Sertoli cell model was established. Increased Sat2 expression led to inhibited cell proliferation and arrested cell cycle. Based on iTRAQ proteomics analysis, we revealed that Sat2 overexpression is detrimental to cell cycle progression and cell communication, and notably, Sat2 may disturb protein metabolic processes by altering translation regulation and protein complex subunit organization. In summary, the present study provides evidence that Sat2 upregulation induces alterations in the growth and function of Sertoli cells. In testis tissue subjected to busulfan, increased expression of Sat2 can cause cellular injury and subsequent organ damage, which could lead to male infertility. Therefore, Sat2 may be a novel molecular target for treating busulfan-induced testicular toxicity. PMID- 28578008 TI - An adventure with Don. PMID- 28578007 TI - Sensitivity of hiPSC-derived neural stem cells (NSC) to Pyrroloquinoline quinone depends on their developmental stage. AB - Pyrroloquinoline quinone (PQQ) is a factor influencing on the mitochondrial biogenesis. In this study the PQQ effect on viability, total cell number, antioxidant capacity, mitochondrial biogenesis and differentiation potential was investigated in human induced Pluripotent Stem Cells (iPSC) - derived: neural stem cells (NSC), early neural progenitors (eNP) and neural progenitors (NP). Here we demonstrated that sensitivity to PQQ is dependent upon its dose and neural stage of development. Induction of the mitochondrial biogenesis by PQQ at three stages of neural differentiation was evaluated at mtDNA, mRNA and protein level. Changes in NRF1, TFAM and PPARGC1A gene expression were observed at all developmental stages, but only at eNP were correlated with the statistically significant increase in the mtDNA copy numbers and enhancement of SDHA, COX-1 protein level. Thus, the "developmental window" of eNP for PQQ-evoked mitochondrial biogenesis is proposed. This effect was independent of high antioxidant capacity of PQQ, which was confirmed in all tested cell populations, regardless of the stage of hiPSC neural differentiation. Furthermore, a strong induction of GFAP, with down regulation of MAP2 gene expression upon PQQ treatment was observed. This indicates a possibility of shifting the balance of cell differentiation in the favor of astroglia, but more research is needed at this point. PMID- 28578009 TI - Lessons Learned from Early Experiences with Vedolizumab for Steroid-Refractory Acute Graft- versus-Host Disease with Gastrointestinal Involvement. PMID- 28578010 TI - Unrelated Umbilical Cord Blood Transplantation for Sickle Cell Disease Following Reduced-Intensity Conditioning: Results of a Phase I Trial. AB - Hematopoietic stem cell transplantation from HLA-matched sibling donors results in disease-free survival of >90% in patients with sickle cell disease (SCD); however, only approximately 18% of these patients have suitable donors available. Unrelated cord blood transplantation (UCBT) is one way to expand donor options for patients with severe SCD, but historically has been associated with high graft rejection rates (50% to 62%). We hypothesized that the addition of thiotepa to a previously tested reduced-intensity conditioning (RIC) regimen would support engraftment after UCBT in patients with SCD. Nine children (age 3 to 10 years) with cerebrovascular complications of SCD underwent 5-6/6 HLA-matched (A, B, and DRB1 loci) UCBT after conditioning with hydroxyurea, alemtuzumab, fludarabine, thiotepa, and melphalan. A calcineurin inhibitor and mycophenolate mofetil were used for graft-versus-host-disease (GVHD) prophylaxis. With median follow up of 2.1 years (range, 1 to 4.2 years), 7 patients had sustained donor cell engraftment and are free of SCD, and 2 patients had autologous recovery. Acute GVHD (grade II-IV) and mild and moderate chronic GVHD developed in 3 patients, 2 patients, and 1 patient, respectively. At >2 years post-UCBT, 4 of 5 patients discontinued systemic immunosuppression. Seven patients had viral infections (cytomegalovirus, Epstein-Barr virus, respiratory syncytial virus, or adenovirus) and recovered. The 1-year overall survival and disease-free survival rates were 100% and 78%, respectively. Thus, this RIC regimen was able to achieve donor engraftment in the majority of patients. Future efforts will focus on further reducing rates of acute GVHD and viral infection. PMID- 28578011 TI - Homology modeling and in silico prediction of Ulcerative colitis associated polymorphisms of NOD1. AB - Cytosolic pattern recognition receptors play key roles in innate immune response. Nucleotide binding and oligomerisation domain containing protein 1 (NOD1) belonging to the Nod-like receptor C (NLRC) sub-family of Nod-like receptors (NLRs) is important for detection and clearance of intra-cellular Gram negative bacteria. NOD1 is involved in activation of pro-inflammatory pathways. Limited structural data is available for NOD1. Using different templates for each domain of NOD1, we determined the full-length homology model of NOD1. ADP binding amino acids within the nucleotide binding domain (NBD) of NOD1 were also predicted. Key residues in inter-domain interaction were identified by sequence comparison with Oryctolagus cuniculus NOD2, a related protein. Interactions between NBD and winged helix domain (WHD) were found to be conserved in NOD1. Functional and structural effect of single nucleotide polymorphisms within the NOD1 NBD domain associated with susceptibility risk to Ulcerative colitis (UC), an inflammatory disorder of the colon was evaluated by in silico studies. Mutations W219R and L349P were predicted to be damaging and disease associated by prediction programs SIFT, PolyPhen2, PANTHER, SNP&GO, PhD SNP and SNAP2. We further validated the effect of W219R and L349P mutation on NOD1 function in vitro. Elevated mRNA expression of pro-inflammatory cytokines IL8 and IL-1beta was seen as compared to the wild type NOD1 in intestinal epithelial cell line HT29 when stimulated with NOD1 ligand. Thus, these mutations may indeed have a bearing on pathogenesis of inflammation during UC. PMID- 28578012 TI - SMAD1/5 mediates bone morphogenetic protein 2-induced up-regulation of BAMBI expression in human granulosa-lutein cells. AB - Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is a transforming growth factor beta (TGF-beta) type I receptor antagonist that negatively regulates TGF-beta and bone morphogenetic protein (BMP) signaling. BAMBI has been shown to be regulated by TGF-beta signaling; however, whether BAMBI can be regulated by BMP signaling remains to be determined. The aim of this study was to investigate the effect of BMP2 on the regulation of BAMBI expression in human granulosa-lutein cells and the underlying mechanisms. Both primary and immortalized human granulosa-lutein cells were used as research models. Using dual inhibition approaches, our results showed that BMP2 activated SMAD1/5/8 phosphorylation and up-regulated BAMBI mRNA levels, which was reversed by the BMP type I receptor inhibitors, DMH-1 and dorsomorphin, but not by SB431542 (activin/TGF-beta type I receptor inhibitor). Moreover, the combined knockdown of SMAD1 and SMAD5 completely abolished the BMP2-induced up-regulation of BAMBI. Similarly, knockdown of SMAD4 reversed the BMP2-induced up-regulation of BAMBI. Pre-treatment with BMP2 inhibited the TGF-beta1-induced phosphorylation of SMAD2/3 and up-regulation of MMP2, and these inhibitory effects were reversed by knockdown of endogenous BAMBI. Our findings indicate that BAMBI is a BMP responsive gene and that BAMBI participates in the negative feedback regulation of TGF-beta signaling in the human ovary. PMID- 28578015 TI - Therapeutic pro-fibrogenic signaling pathways in fibroblasts. AB - Myofibroblasts (MFs) play a critical role in the progression of chronic inflammatory and fibroproliferative diseases in different tissues/organs, whatever the etiology. Fibrosis is preceded and sustained by persistent injury and inflammatory response in a profibrogenic scenario involving mutual interactions, operated by several mediators and pathways, of MFs and related precursor cells with innate immunity cells and virtually any cell type in a defined tissue. These interactions, mediators and related signaling pathways are critical in initiating and perpetuating the differentiation of precursor cells into MFs that in different tissues share peculiar traits and phenotypic responses, including the ability to proliferate, produce ECM components, migrate and contribute to the modulation of inflammatory response and tissue angiogenesis. Literature studies related to liver, lung and kidney fibrosis have outlined a number of MF-related core regulatory fibrogenic signaling pathways conserved across these different organs and potentially targetable in order to develop effective antifibrotic therapeutic strategies. PMID- 28578014 TI - Carbon monoxide protects against hepatic steatosis in mice by inducing sestrin-2 via the PERK-eIF2alpha-ATF4 pathway. AB - Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has emerged as one of the most common causes of chronic liver disease in developed countries over the last decade. NAFLD comprises a spectrum of pathological hepatic changes, including steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Autophagy, a homeostatic process for protein and organelle turnover, is decreased in the liver during the development of NAFLD. Previously, we have shown that carbon monoxide (CO), a reaction product of heme oxygenase (HO) activity, can confer protection in NAFLD, though the molecular mechanisms remain unclear. We therefore investigated the mechanisms underlying the protective effect of CO on methionine/choline-deficient (MCD) diet-induced hepatic steatosis. We found that CO induced sestrin-2 (SESN2) expression through enhanced mitochondrial ROS production and protected against MCD-induced NAFLD progression through activation of autophagy. SESN2 expression was increased by CO or CO-releasing molecule (CORM2), in a manner dependent on signaling through the protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor-2 alpha (eIF2alpha)/ activating transcription factor-4 (ATF4)-dependent pathway. CO-induced SESN2 upregulation in hepatocytes contributed to autophagy induction through activation of 5'-AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) complex I (mTORC1). Furthermore, we demonstrate that CO significantly induced the expression of SESN2 and enhanced autophagy in the livers of MCD-fed mice or in MCD-media treated hepatocytes. Conversely, knockdown of SESN2 abrogated autophagy activation and mTOR inhibition in response to CO. We conclude that CO ameliorates hepatic steatosis through the autophagy pathway induced by SESN2 upregulation. PMID- 28578016 TI - Engineering in vitro models of hepatofibrogenesis. AB - Chronic liver disease is a major cause of morbidity and mortality worldwide marked by chronic inflammation and fibrosis/scarring, resulting in end-stage liver disease and its complications. Hepatic stellate cells (HSCs) are a dominant contributor to liver fibrosis by producing excessive extracellular matrix (ECM), irrespective of the underlying disease aetiologies, and for many decades research has focused on the development of a number of anti-fibrotic strategies targeting this cell. Despite major improvements in two-dimensional systems (2D) by using a variety of cell culture models of different complexity, an efficient anti fibrogenic therapy has yet to be developed. The development of well-defined three dimensional (3D) in vitro models, which mimic ECM structures as found in vivo, have demonstrated the importance of cell-matrix bio-mechanics, the complex interactions between HSCs and hepatocytes and other non-parenchymal cells, and this to improve and promote liver cell-specific functions. Henceforth, refinement of these 3D in vitro models, which reproduce the liver microenvironment, will lead to new objectives and to a possible new era in the search for antifibrogenic compounds. PMID- 28578017 TI - Functional polymorphism at the miR-502-binding site in the 3' untranslated region of the SETD8 gene increased the risk of prostate cancer in a sample of Iranian population. AB - MicroRNAs (miRNAs), a class of non-coding RNAs, bind to the 3' untranslated regions (3'-UTRs) of target mRNAs and regulate gene expression. Genetic variations in miRNA binding domains influence the susceptibility to several diseases such as cancer. Several studies investigated the impact of single nucleotide polymorphism (SNP) rs16917496 T>C within the 3'-UTR of SETD8 on cancer susceptibility, but the results were controversial. In addition, no study has been conducted to inspect the impact of this SNP in prostate cancer (PCa). Thus, the present study aimed to find out the possible association between rs16917496 polymorphism at the 3'UTR of SETD8 and PCa risk. This case-control study was done on 169 patients with pathologically confirmed PCa and 182 benign prostatic hyperplasia (BPH). Genotyping was done using PCR-RFLP method. The findings revealed that rs16917496 variant significantly increased the risk of PCa in codominant (OR=2.54, 95%CI=1.50-4.30, p<0.001, TC VS TT and OR=3.03, 95%CI=1.63 5.66, p<0.001, CC vs TT), dominant (OR=2.86, 95%CI=1.62-4.43, p<0.001, p<0.001). The C allele significantly increased the risk of PCa (OR=1.72, 95%CI=1.28-2.33, p<0.001) compared to T allele. In conclusion, the findings indicated that rs16917496 polymorphism may be a risk for predisposition to PCa in an Iranian population. Further studies with larger sample sizes and different ethnicities are required to confirm our findings. PMID- 28578018 TI - Rice gene SDL/RNRS1, encoding the small subunit of ribonucleotide reductase, is required for chlorophyll synthesis and plant growth development. AB - A new mutant named sdl (stripe and drooping leaf) was characterized from indica cultivar Zhenong 34 by ethylmethane sulfonate (EMS) mutagenesis. The mutant sdl exhibited development defects including stripe and drooping leaf, dwarfism and deformed floral organs. The gene SDL was found allelic to RNRS1 by map-based cloning, which was homologous to Arabidopsis TSO2 encoding the small subunit of ribonucleotide reductase. The gDNA sequencing results of sdl in mutant showed that there was a repetitive sequence insertion of 138-bp at the 475th bp in the exon. The redundant sequence was conserved in SDL homologous proteins, which contained the active site (tyrosine), as well as two amino acids glutamate and histidine involved in the binding of iron. There were fewer chloroplasts and grana lamellas in sdl leaf compared with those of wild-type. Additionally, the stripe leaves of sdl seedlings were highly sensitive to temperature, since the chlorophyll content was increased with the temperature rising. The drooping leaf of sdl might be resulted from the disappearance of vascular bundles and mesophyll cells in both leaf midrib and lateral veins. Fittingly to the phenotypes of mutant sdl, the expression levels of genes associated with photosynthesis and chlorophyll synthesis were found to be down- or up-regulated at different temperatures in mutant sdl. Also, the transcriptional levels of genes related to plant height and floral organ formation showed obvious differences between wild type and sdl. The "SDL/RNRS1" was, hence, required for the chlorophyll biosynthesis and also played pleiotropic roles in the regulation of plant development. PMID- 28578019 TI - Functional characterization of two bZIP transcription factors in Verticillium dahliae. AB - bZIP transcription factors play various biological roles in stress responses, conidiation, and pathogenicity in pathogenic fungi. Here, we report two bZIP transcription factors (VDAG_08640 and VDAG_08676) of Verticillium dahliae, which were differentially expressed during microsclerotia development and induced by hydrogen peroxide as well. We find that deletion of either gene does not affect microsclerotia formation and the sensitivity to hydrogen peroxide; however, the mutants manifest decreased activity of extracellular peroxidase and laccase. Other phenotypic characterization reveals that VDAG_08676 disruption results in significant reduction of conidial production and virulence, while VDAG_08640 disruption does not lead to observable phenotypic variances compared with the wild-type strain. To elucidate whether they exhibit functional redundancy, double deletion mutants were generated. The double deletion mutants show remarkably increased sensitivity to hydrogen peroxide stress, whereas the two genes are not involved in microsclerotia formation. Taken together, our data demonstrate that a bZIP transcription factor gene VDAG_08676 is involved in the conidial production, oxidative stress response and virulence which may lay a foundation for further analysis of other bZIP transcription factors in V. dahliae. PMID- 28578020 TI - Pathogenicity analysis of novel variations in Chinese Han patients with polycystic kidney disease. AB - OBJECTIVE: Locus and allellic heterogeneity in polycystic kidney disease (PKD) is a great challenge in precision diagnosis. We aim to establish comprehensive methods to distinguish the pathogenic mutations from the variations in PKD1, PKD2 and PKHD1 genes in a limited time and lay the foundation for precisely prenatal diagnosis, preimplantation genetic diagnosis and presymptom diagnosis of PKD. METHODS: Nested PCR combined with direct DNA sequencing were used to screen variations in PKD1, PKD2 and PKHD1 genes. The pathogenicity of de novel variations was assessed by the comprehensive methods including clinic data and literature review, databases query, analysis of co-segregation of the variants with the disease, variant frequency screening in the population, evolution conservation comparison, protein structure analysis and splice sites predictions. RESULTS: 17 novel mutations from 15 Chinese Han families were clarified including 10 mutations in PKD1 gene and 7 mutations in PKHD1 gene. The novel mutations were classified as 4 definite pathogenic, 2 highly likely pathogenic, 4 likely pathogenic, 7 indeterminate by the comprehensive analysis. The results were verified the truth by the follow-up visits. CONCLUSIONS: The comprehensive methods may be useful in distinguishing the pathogenic mutations from the variations in PKD1, PKD2 and PKHD1 genes for prenatal diagnosis and presymptom diagnosis of PKD. Our results also enriched PKD genes mutation spectrum and evolved possible genotype-phenotype correlations of Chinese Han population. PMID- 28578013 TI - Paradoxical roles of dual oxidases in cancer biology. AB - Dysregulated oxidative metabolism is a well-recognized aspect of cancer biology, and many therapeutic strategies are based on targeting cancers by altering cellular redox pathways. The NADPH oxidases (NOXes) present an important enzymatic source of biological oxidants, and the expression and activation of several NOX isoforms are frequently dysregulated in many cancers. Cell-based studies have demonstrated a role for several NOX isozymes in controlling cell proliferation and/or cell migration, further supporting a potential contributing role for NOX in promoting cancer. While various NOX isoforms are often upregulated in cancers, paradoxical recent findings indicate that dual oxidases (DUOXes), normally prominently expressed in epithelial lineages, are frequently suppressed in epithelial-derived cancers by epigenetic mechanisms, although the functional relevance of such DUOX silencing has remained unclear. This review will briefly summarize our current understanding regarding the importance of reactive oxygen species (ROS) and NOXes in cancer biology, and focus on recent observations indicating the unique and seemingly opposing roles of DUOX enzymes in cancer biology. We will discuss current knowledge regarding the functional properties of DUOX, and recent studies highlighting mechanistic consequences of DUOX1 loss in lung cancer, and its consequences for tumor invasiveness and current anticancer therapy. Finally, we will also discuss potentially unique roles for the DUOX maturation factors. Overall, a better understanding of mechanisms that regulate DUOX and the functional consequences of DUOX silencing in cancer may offer valuable new diagnostic insights and novel therapeutic opportunities. PMID- 28578021 TI - Transcriptome profiling of the floral buds and discovery of genes related to sex differentiation in the dioecious cucurbit Coccinia grandis (L.) Voigt. AB - Dioecious species offer an inclusive structure to study the molecular basis of sexual dimorphism in angiosperms. Despite having a small genome and heteromorphic sex chromosomes, Coccinia grandis is a highly neglected dioecious species with little information available on its physical state, genetic orientation and key sex-defining elements. In the present study, we performed RNA-Seq and DGE analysis of male (MB) and female (FB) buds in C. grandis to gain insights into the molecular basis of sex determination in this plant. De novo assembly of 75 million clean reads resulted in 72,479 unigenes for male library and 63,308 unigenes for female library with a mean length of 736bp. 61,458 (85.57%) unigenes displayed significant similarity with protein sequences from publicly available databases. Comparative transcriptome analyses revealed 1410 unigenes as differentially expressed (DEGs) between MB and FB samples. A consistent correlation between the expression levels of DEGs was observed for the RNA-Seq pattern and qRT-PCR validation. Functional annotation showed high enrichment of DEGs involved in phytohormone biosynthesis, hormone signaling and transduction, transcriptional regulation and methyltransferase activity. High induction of hormone responsive genes such as ARF6, ACC synthase1, SNRK2 and BRI1-associated receptor kinase 1 (BAK1) suggest that multiple phytohormones and their signaling crosstalk play crucial role in sex determination in this species. Beside, the transcription factors such as zinc fingers, homeodomain leucine zippers and MYBs were identified as major determinants of male specific expression. Moreover, the detection of multiple DEGs as the miRNA target site implies that a small RNA mediated gene silencing cascade may also be regulating gender differentiation in C. grandis. Overall, the present transcriptome resources provide us a large number of DEGs involved in sex expression and could form the groundwork for unravelling the molecular mechanism of sex determination in C. grandis. PMID- 28578022 TI - Comprehensive molecular characterization of a transgenic pig expressing hCD46 gene. AB - Molecular characterization of transgenic animals is crucial for the phenotype analysis, unintended effects prediction, commercial and economic requirements. In this study, a comprehensive molecular characterization of a transgenic pig, which expressed hCD46 gene, was verified using next-generation sequencing (NGS). One complete and one incomplete sequence of pBSCD46-neo and multiple backbone fragments were inserted into the host genome. The whole insertion sequence was 28,243bp, and 12bp sequence on the genome was deleted during the transgene. The cost of NGS is higher than other molecular methods, in order to reduce the cost and to make the sequencing strategy more economically effective, we carried out a computer simulation to identify the smallest amount of data that could meet the requirements of the molecular characterization analysis. 15* depth of coverage was shown to be sufficient with good accuracy, while 3* might be effective, 20* was recommended. The obtained molecular characterization information would provide a stronger foundation for the safety evaluation of the GM animals. Meanwhile, the gene integrity of the porcine pathogen PERV was analyzed using the same procedure. No complete sequence of the PERV subtype was observed in the porcine genome, which was the same as the previous research. In consequence, NGS combined bioinformatics analysis is a reliable and accurate approach for the molecular characterization of GMOs, even for the safety evaluation. PMID- 28578023 TI - A novel germline gain-of-function variant in PIK3CD. PMID- 28578024 TI - Hexamerization-enhanced CD20 antibody mediates complement-dependent cytotoxicity in serum genetically deficient in C9. AB - We examined complement-dependent cytotoxicity (CDC) by hexamer formation-enhanced CD20 mAb Hx-7D8 of patient-derived chronic lymphocytic leukemia (CLL) cells that are relatively resistant to CDC. CDC was analyzed in normal human serum (NHS) and serum from an individual genetically deficient for C9. Hx-7D8 was able to kill up to 80% of CLL cells in complete absence of C9. We conclude that the narrow C5b-8 pores formed without C9 are sufficient for CDC due to efficient antibody-mediated hexamer formation. In the absence of C9, we observed transient intracellular increases of Ca2+ during CDC (as assessed with FLUO-4) that were extended in time. This suggests that small C5b-8 pores allow Ca2+ to enter the cell, while dissipation of the fluorescent signal accompanying cell disintegration is delayed. The Ca2+ signal is retained concomitantly with TOPRO-3 (viability dye) staining, thereby confirming that Ca2+ influx represents the most proximate mediator of cell death by CDC. PMID- 28578025 TI - Multimarker risk stratification approach at multiple sclerosis onset. AB - Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12 biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels <141pg/ml (OR=6.51, p<0.001). Combination of IL-7 and CXCL10 indicated risk for a specific MS clinical form, where IL-7<141 and CXCL10<570pg/ml were associated with the highest risk for PP MS (OR=22, p=0.01). Unexpectedly, both PP-MS and RR-MS patients shared significantly decreased prototypical biomarkers of inflammation and tissue regeneration in CSF than OND suggesting a defective intrinsic immune response playing a role at the beginning of the disease. PMID- 28578026 TI - alpha-Pyrrolidinononanophenone provokes apoptosis of neuronal cells through alterations in antioxidant properties. AB - In this study, we found that exposure to alpha-pyrrolidinononanophenone (alpha PNP), a highly lipophilic synthetic cathinone, provokes apoptosis of human neuronal SK-N-SH cells. The drug sensitivity of the cells (50% lethal concentration of 12MUM) was similar to those of aortic endothelial and smooth muscle cells, and was higher than those of cells derived from colon, liver, lung and kidney, suggesting that alpha-PNP overdose and abuse cause serious damage in central nervous and vascular systems. SK-N-SH cell treatment with lethal concentrations (20 and 50MUM) of alpha-PNP facilitated the reactive oxygen species (ROS) production. The treatment also prompted elevation of Bax/Bcl-2 ratio, lowering of mitochondrial membrane potential, release of cytochrome-c into cytosol, and resultant activation of caspase-9 and caspase-3. The apoptotic events (caspase-3 activation and DNA fragmentation) were abolished by pretreatment with antioxidants, N-acetyl-l-cysteine and polyethyleneglycol conjugated catalase. These results suggest that ROS production, mitochondrial dysfunction and caspase activation are potential events in the mechanism underlying the alpha-PNP-triggered neuronal cell apoptosis. Intriguingly, the alpha-PNP treatment of SK-N-SH cells was found to promote formation of 4 hydroxynonenal, a reactive aldehyde generated from lipid peroxidation. The alpha PNP treatment also decreased cellular levels of total and reduced glutathiones, expression of gamma-glutamylcysteine synthetase mRNA and glutathione reductase activity. Furthermore, the alpha-PNP treatment resulted in both decrease in proteasomal activities and increase in expression of autophagy-related factors, which were significantly prevented by pretreating with N-acetyl-l-cysteine. Therefore, the ROS formation by alpha-PNP treatment may be ascribable to the decrease in glutathione level through its consumption during 4-hydroxynonenal detoxification and dysfunction of both de novo synthesis and regeneration of glutathione, in addition to impairments in proteasomal and autophagic systems that degrade cellular oxidized components. PMID- 28578027 TI - Agomelatine, a MT1/MT2 melatonergic receptor agonist with serotonin 5-HT2C receptor antagonistic properties, suppresses Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages. AB - OBJECTIVE: This study was performed in an attempt to examine the influence of agomelatine in mitigating the generation of proinflammatory mediators in RAW264.7 murine macrophages exposed to lipopolysaccharide (LPS) obtained from Prevotella intermedia, a gram-negative anaerobic bacterium that is related with various types of periodontal diseases, and the molecular mechanisms behind its effects. DESIGN: LPS from P. intermedia strain ATCC 25611 was prepared employing the conventional phenol-water procedure. Conditioned culture media were analyzed for the levels of nitric oxide (NO), interleukin-1beta (IL-1beta) and IL-6. Real-time PCR analysis was carried out to determine the mRNA levels of inducible NO synthase (iNOS), IL-1beta, IL-6 and SOCS1. Protein expression levels were evaluated by immunoblot test. NF-kappaB-dependent SEAP reporter assay was performed using a reporter cell line. DNA-binding activities of NF-kappaB subunits were analyzed utilizing the ELISA-based kits. RESULTS: Agomelatine was found to down-regulate significantly the generation of iNOS-derived NO, IL-1beta and IL-6 as well as the expression of their mRNAs in cells activated with P. intermedia LPS. Agomelatine decreased NF-kappaB-dependent SEAP release caused by P. intermedia LPS. Agomelatine did not inhibit NF-kappaB transcription induced by LPS at the level of IkappaB-alpha degradation. Instead, LPS-induced nuclear translocation and DNA binding of NF-kappaB p50 subunit was blocked by agomelatine. P. intermedia LPS-elicited activation of STAT1 and STAT3 was reduced notably by co-treatment with agomelatine. Agomelatine showed a tendency to enhance mRNA level of SOCS1 in LPS-activated cells as well. CONCLUSIONS: Agomelatine merits further evaluation to reveal its usefulness on the host modulation of periodontal disease. PMID- 28578029 TI - Investigation of the interaction for three Citrus flavonoids and alpha-amylase by surface plasmon resonance. AB - Flavonoids, a class of natural drugs with broad biological activity, exhibit inhibitory effect on alpha-amylase. Citrus peel is a good source of flavonoids. The real-time interactions between three Citrus flavonoids (naringin, neohesperidin, hesperidin) and alpha-amylase were investigated by surface plasmon resonance biosensor, and were compared with the alpha-amylase inhibitors, acarbose. These results showed the binding affinities of naringin, neohesperidin and hesperidin with alpha-amylase reach the highest at pH6 with KD values of 2.27+/-0.18mM, 3.09+/-0.20mM and 3.51+/-0.09mM, and can be reinforced with 0.2M NaCl and 0.1M CaCl2, respectively. The results of 1, 1-diphenyl-2-picryl hydrazyl radical assay indicate that the antioxidant activities of naringin, neohesperidin and hesperidin are significantly inhibited by interacting with alpha-amylase, and the inhibition percentage are 47.61+/-0.034%, 22.81+/-0.037% and 21.01+/-0.051%, respectively. Additionally, it is found that both the number and the position of hydroxyl group play an important role in the interaction of three Citrus flavonoids and alpha-amylase. These results provide useful information for rapid screening inhibitors of alpha-amylase from plant-based food. PMID- 28578028 TI - Differential expression of transcription factors NF-kappaB and STAT3 in periodontal ligament fibroblasts and gingiva of healthy and diseased individuals. AB - OBJECTIVE: Pathogens and host mediators can activate transcription factors in periodontal cells to bring about gene level alterations, thereby accentuating the periodontal disease process. Nuclear factor-kappa B (NF-kappaB) and signal transducers and activators of transcription 3 (STAT3) are two pivotal transcription factors implicated in chronic inflammatory diseases. But their importance in periodontal pathogenesis has not been investigated in detail. The aim of the present study was to evaluate the expression of activated transcription factors and their target genes in healthy and diseased periodontium. DESIGN: Primary culture of periodontal ligament fibroblasts (PDLF) were established from healthy and diseased periodontium using explant culture methods. NF-kappaB and STAT3 activation in these cells by Porphyromonas gingivalis LPS (lipopolysaccharide) was demonstrated using confocal microscopy and mRNA expression of target genes were evaluated by quantitative real time PCR. NF-kappaB and STAT3 expression in diseased and healthy gingival tissues were analyzed using immunohistochemistry. RESULTS: A basal upregulation of transcription factors and their target genes were noted in diseased PDLF compared to healthy ones. LPS challenge induced differential expression of NF-kappaB and STAT3 and their target genes in diseased PDLF compared to healthy ones. Immunohistochemical analysis revealed significant activation of transcription factors in diseased gingival tissues. CONCLUSION: The findings of the present study reveal the role of transcription factors NF-kappaB and STAT3 in periodontal pathogenesis and disease susceptibility of fibroblast subpopulations in periodontal disease could be mediated through activation of NF-kappaB and STAT3. Since genetic factors are nonmodifyable, transcription factors are promising targets for future host modulation therapy. PMID- 28578030 TI - Behaviour of non-oxidized and oxidized flaxseed oils, as models of omega-3 rich lipids, during in vitro digestion. Occurrence of epoxidation reactions. AB - Fresh and partially oxidized flaxseed oil, as models of omega-3 rich lipids, were submitted to in vitro gastrointestinal digestion. Hydrolysis level, lipid composition and oxidative status of the samples before and after digestion were studied by Proton Nuclear Magnetic Resonance (1H NMR) and Solid Phase Microextraction-Gas Chromatography/Mass Spectrometry (SPME-GC/MS). Although a great degree of lipolysis was reached in both kinds of samples after digestion, it was somewhat lower in the digests of oxidized flaxseed oil. The occurrence of lipid oxidation during digestion was evidenced by decreased unsaturated lipids and increased primary and secondary oxidation products, especially in oxidized samples. In these latter, linolenic-derived monoepoxy-octadecadienoates were the main oxidation products generated. SPME-GC/MS study showed the highest abundances of highly reactive alkadienals (C5-C10), alkatrienals (C9-C10) and linolenic derived 4,5-epoxy-2-heptenals in the headspace of oxidized flaxseed oil digests. Volatile markers of Maillard-type reactions were also detected. PMID- 28578031 TI - Biophysical evaluation of milk-clotting enzymes processed by high pressure. AB - High pressure processing (HPP) is able to promote changes in enzymes structure. This study evaluated the effect of HP on the structural changes in milk-clotting enzymes processed under activation conditions for recombinant camel chymosin (212MPa/5min/10 degrees C), calf rennet (280MPa/20min/25 degrees C), bovine rennet (222MPa/5min/23 degrees C), and porcine pepsin (50MPa/5min/20 degrees C) and under inactivation conditions for all enzymes (600MPa/10min/25 degrees C) including the protease from Rhizomucor miehei. In general, it was found that the HPP at activation conditions was able to increase the intrinsic fluorescence of samples with high pepsin concentration (porcine pepsin and bovine rennet), increase significantly the surface hydrophobicity and induce changes in secondary structure of all enzymes. Under inactivation conditions, increases in surface hydrophobicity and a reduction of intrinsic fluorescence were observed, suggesting a higher exposure of hydrophobic sites followed by water quenching of Trp residues. Moreover, changes in secondary structure were observed (with minor changes seen in Rhizomucor miehei protease). In conclusion, HPP was able to unfold milk-clotting enzymes even under activation conditions, and the porcine pepsin and bovine rennet were more sensitive to HPP. PMID- 28578032 TI - Processing & rheological properties of wheat flour dough and bread containing high levels of soluble dietary fibres blends. AB - Wheat flour doughs were processed with soluble dietary fibres (DF) added up to 40% (w/w flour). DF were made of a ternary mixture of maltodextrins (MT, 3/5), pectins (PE, 1/5) and inulin (IN, 1/5). The addition of DF decreased the specific mechanical energy developed by the mixer, mainly because of water addition. It increased the ratio of storage moduli and the elongational viscosity of the dough, but decreased the strain hardening index. Energy input and rheological changes at mixing largely explained the decreases of porosity characteristic time and stability time during fermentation. It was possible to add up to 30% DF with a moderate increase of bread density, and 20%, with little change of crumb cellular structure. Hence, the changes of bread crumb texture were not mainly due to bread density, but rather likely to the changes of properties of the intrinsic material. Results obtained by addition of single fibre source, especially inulin, deviated from the main trends observed for texture and rheological properties. These results provide a good basis to design breads with increased dietary fibre content. PMID- 28578033 TI - Influence of omega-3 PUFAs on the metabolism of proanthocyanidins in rats. AB - Studies of the bioavailability of proanthocyanidins usually consider them independently of other dietary constituents, while there is a tendency in the field of functional foods towards the combination of different bioactive compounds in a single product. This study examined the long-term effects of omega 3 polyunsaturated fatty acids of marine origin on the metabolic fate of grape proanthocyanidins. For this, female adult Wistar-Kyoto rats were fed (18weeks) with a standard diet supplemented or not with eicosapentaenoic acid/docosahexaenoic acid (1:1, 16.6g/kg feed), proanthocyanidin-rich grape seed extract (0.8g/kg feed) or both. A total of 39 microbial-derived metabolites and 16 conjugated metabolites were detected by HPLC-MS/MS either in urine or in the aqueous fraction of feces. An unexpected significant increase in many proanthocyanidin metabolites in urine and feces was observed in the group supplemented with omega-3 polyunsaturated fatty acids group as compared to the animals fed a standard diet, which contains a small amount of polyphenols. However, proanthocyanidin metabolites in rats given omega-3 polyunsaturated fatty acids and grape seed extract did not significantly differ from those in the group supplemented only with grape seed extract. It was concluded that omega-3 polyunsaturated fatty acids collaborate in the metabolism of polyphenols when present at low doses in the feed matrix, while the capacity of omega-3 polyunsaturated fatty acids to induce microbiota transformations when proanthocyanidins are present at high doses is not relevant compared to that of polyphenols themselves. PMID- 28578034 TI - Determination of the phenolic content, profile, and antioxidant activity of seeds from nine tree peony (Paeonia section Moutan DC.) species native to China. AB - As an important resource of functional food, the seeds of tree peony are rich in phenolic compounds, which are associated with antioxidant activity. However, so far there has not been systematic study on phenolic compositions and antioxidant activity of the seeds from wild tree peony species. The aim of this study was to determine the phenolic content, antioxidant compounds and antioxidant activity of seeds from nine tree peony species native to China. Among the seed samples, Paeonia rockii had the highest total flavonoid content, strongest DPPH and ABTS radical scavenging activities, and strongest cupric reducing capacity; P. decomposita subsp. rotundiloba had the highest total phenolic and flavanol contents, as well as the strongest hydroxyl radical scavenging activity. Sixteen individual phenolic compounds were quantitatively measured, with (+)-catechin being the most abundant component. The content of the phenolic compounds luteolin, paeonol, and the total flavonoid content were significantly correlated with four antioxidant activities. Hierarchical cluster analysis showed that P. rockii and P. decomposita subsp. rotundiloba could be clustered in a group having a high phenolic content and strong antioxidant activity. These results suggest P. rockii and P. decomposita subsp. rotundiloba are the most promising candidates as useful sources of natural antioxidants. PMID- 28578035 TI - Spontaneous variation regarding grape berry skin color: A comprehensive study of berry development by means of biochemical and molecular markers. AB - : Understanding grape berry development and the metabolism of different classes of compounds responsible for traits like berry's color is imperative to control and improve quality aspects of grapes. A colorimetric, biochemical and molecular characterization allowed the comprehensive description of the pigment-related characteristics of nine berry skin color somatic variants, belonging to four different varieties. Although the observed berry skin color variability was not fully explained by MybA locus, the phenolic profiles allowed inferring about specific interferences among the biosynthetic pathways. Data were consistent concerning that grapes showing cyanidin-3-O-glucoside as the major anthocyanin and flavonols with two substituent groups in the lateral B-ring are generally originated by a white ancestor. After retro-mutation, these grapes seem to keep the dysfunction on flavonoid hydroxylases enzymes, which negatively affect the synthesis of both flavonols and anthocyanins with three substituent groups in the lateral B-ring. Overall, the obtained results indicate that the color differences observed between somatic variants are not solely the result of the total amount of compounds synthesized, but rather reflect a different dynamics of the phenolic pathway among the different color variants of the same variety. CHEMICAL COMPOUNDS: Gallic acid (PubChem CID: 370); Caftaric acid (PubChem CID: 6,440,397); Catechin (PubChem CID: 73,160); Epigallocatechin gallate (PubChem CID: 65,064); Quercetin-3-O-galactoside (PubChem CID: 5,281,643); Quercetin-3-O glucoside (PubChem CID: 25,203,368); Malvidin-3-O-glucoside (PubChem CID: 443,652); Peonidin-3-O-p-coumaroylglucoside (PubChem CID: 44,256,849); Malvidin-3 O-p-coumaroylglucoside (PubChem CID: 44,256,988); Resveratrol-3-O-glucoside (PubChem CID: 25,579,167). PMID- 28578036 TI - Phenolic compounds profile and antioxidant properties of six sweet cherry (Prunus avium) cultivars. AB - Sweet cherry (Prunus avium) fruits are a nutritionally important food rich in dietary phenolic compounds. The aim of this study was to investigate the phenolic profile and chemometric discrimination of fruits from six cherry cultivars using a quantitative metabolomics approach, which combine non-targeted mass spectrometry and chemometric analysis. The assessment of the phenolic fingerprint of cherries allowed the tentative identification of 86 compounds. A total of 40 chlorogenic acids were identified in cherry fruit, which pointed out hydroxycinnamic acid derivatives as the main class of phenolics by number of compounds. Among the compounds detected, 40 have been reported for the first time in sweet cherry fruit. Hydroxycinnamic acids are also the quantitatively most represented class of phenolic compounds in the cherry cultivars with the exception of Lapins and Durone della Marca where the most representative class of phenolic compounds were anthocyanins and flavan-3-ols, respectively. This non targeted approach allowed the tentative identification of the cultivar-compound relationships of these six cherry cultivars. Both anthocyanins and colorless phenolic compounds profile appeared to be cultivar-dependent. In detail, anthocyanins and flavonols patterns have the potential to be used for the determination of a varietal assignment of cherries. PMID- 28578037 TI - Bioaccessibility of calcium, iron and magnesium in residues of citrus and characterization of macronutrients. AB - The aim of this study was to estimate bioaccessibility of Ca, Fe and Mg in residues of orange, lime, and their mixture, in order to evaluate the effects of cooking in water on mineral bioaccessibility and also to determine the composition of macronutrients and myo-inositol phosphate content. The citrus samples contained on average 9.53g/100 g moisture, 6.09g/100 g protein, 3.23g/100g ash, 3.15g/100g lipids, 34.26g/100g insoluble fiber, 27.88g/100g soluble fiber and 25.64g/100g carbohydrates. The percentage of soluble and dialyzable minerals ranged from 19.36 to 77.33% and from 5.59 to 69.06% for Fe, from 33.34 to 60.84% and 14.71 to -26.13% for Ca, and from 29.95 to 94.20% and 34.42 to 62.51%, for Mg, respectively. It was verified that cooking influenced the minerals bioaccessibility and increased the dialyzable fraction of Fe and Mg, but decreased the fraction of Ca dialysate, except to orange. No myoinositol phosphate esters were detected. The Principal Component Analysis allowed the separation of different types of citrus residues, but did not discriminate the raw and cooked samples. This study pointed the potential of citrus residue to be used for human consumption and contribute to the necessary dietary minerals and macronutrients, with high content of soluble and insoluble fibers. PMID- 28578038 TI - Particle formation induced by sonication during yogurt fermentation - Impact of exopolysaccharide-producing starter cultures on physical properties. AB - Two major quality defects of yogurt are syneresis and the presence of large particles, and several reasons have been extensively discussed. Vibrations during fermentation, particularly generated by pumps, must be considered as a further cause as latest research showed that both ultrasound and low frequencies induced visible particles. The aim of this study was to investigate the impact of sonication during fermentation with starter cultures differing in exopolysaccharide (EPS) synthesis on the physical properties of set (syneresis, firmness) and stirred yogurt (large particles, laser diffraction, rheology). Skim milk was fermented with starter cultures YC-471 (low EPS) or YF-L 901 (high EPS) (Chr. Hansen) and sonicated for 5min at pH5.2. Sonicated set gels exhibited syneresis and were softer than respective controls. The mechanical treatment was adjusted to quantify visible particles (d>=0.9mm) in stirred yogurts properly. Sonication significantly increased particle numbers, however, the effect was less pronounced when YF-L 901 was used, indicating EPS as a tool to reduce syneresis and particle formation due to vibrations. Rheological parameters and size of microgel particles were rather influenced by starter cultures than by sonication. PMID- 28578039 TI - Kinetics of aflatoxin degradation during peanut roasting. AB - This study investigated aflatoxin degradation during peanut roasting. First, peanuts contaminated with three initial aflatoxin concentrations (35, 332 and 695MUg/kg) were roasted at 180 degrees C for up to 20min. The percentage of aflatoxin degradation after 20min were 55, 64 and 81% for peanuts contaminated with aflatoxin at 35, 332 and 695MUg/kg, respectively. This difference was statistically significant (p<0.05), showing that initial concentration influences aflatoxin reduction. Thereafter, peanut samples contaminated with an initial aflatoxin concentration of 85MUg/kg were roasted at 160, 180 and 200 degrees C for 5, 10, 15, 20 and 25min, then residual concentrations of aflatoxin were determined. Roasting at 160, 180 and 200 degrees C resulted in an aflatoxin reduction of 61.6, 83.6 and 89.7%, respectively. This study has provided quantitative data reinforcing the fact that roasting alone is not enough to control aflatoxins in peanuts. PMID- 28578040 TI - The performance of probiotic fermented sheep milk and ice cream sheep milk in inhibiting enamel mineral loss. AB - The study aimed to evaluate the effects of two different sheep milk-based food matrices - fermented sheep milk and ice cream - with added probiotic bacteria (Lactobacillus casei 431) on dental enamel subjected to an in vitro highly cariogenic challenge. Sixty enamel blocks were selected and randomly allocated into five treatment groups (n=12): conventional fermented sheep milk (CFSM), probiotic fermented sheep milk (PFSM), conventional sheep milk ice cream (CSMIC), probiotic sheep milk ice cream (PSMIC) and control using deionized water. The blocks were subjected to highly cariogenic pH cycling and the products were applied (5min), in a blinded way, once a day to simulate a daily use for 8 consecutive days. A microhardness test was performed before and after the treatment to estimate the percentage of microhardness surface loss (% SML). Scanning electronic microscopy (SEM) was performed to confirm the mineral loss. All groups had lost microhardness after the experiment. However, CFSM and PFSM exhibited the most positive findings when compared to the control in both ice creams. Scanning electron microscopy showed less mineral loss in CFSM and PFSM compared with CSMIC, PSMIC and control after the cariogenic challenge. Overall, fermented milk decreased mineral loss from enamel subjected to a highly cariogenic challenge, regardless of the presence of probiotics in their composition, which had a higher efficacy compared to ice cream. PMID- 28578041 TI - Microbiota source impact in vitro metabolite colonic production and anti proliferative effect of spent coffee grounds on human colon cancer cells (HT-29). AB - Human gut flora-mediated non-digestible fraction of spent coffee grounds (hgf NDSCG) was evaluated for its chemopreventive effect and molecular mechanisms involved on human colon adenocarcinoma HT-29 cell survival using two different microbiota source [lean (L) and overweight (OW)]. The source of human gut flora (hgf) (L or OW) affected the pH of hgf-NDSCG only minimally, but linearly reduced those of hgf-inulin. The variability between lean and overweight microbiota was characterized by the metabolism and/or bioaccessibility of different phenolic metabolites, their intermediate and end products as well as by variable time courses. Apoptosis of colon cancer HT-29 cells depended on the microbiota source with the lean microbiota expressing a low lethal concentration 50 (LC50/L-hgf NDSCG=13.5%). We demonstrate that NDSCG and its colonic metabolite from lean microbiota induced HT-29 cell apoptosis by reducing catalase and 8-iso prostaglandin F2alpha as biomarkers of in vivo oxidative stress as the primary mechanism underlying its overall chemoprotection against colon cancer. PMID- 28578042 TI - Visual attention to food cues is differentially modulated by gustatory-hedonic and post-ingestive attributes. AB - Although attentional biases towards food cues may play a critical role in food choices and eating behaviours, it remains largely unexplored which specific food attribute governs visual attentional deployment. The allocation of visual attention might be modulated by anticipatory postingestive consequences, from taste sensations derived from eating itself, or both. Therefore, in order to obtain a comprehensive understanding of the attentional mechanisms involved in the processing of food-related cues, we recorded the eye movements to five categories of well-standardised pictures: neutral non-food, high-calorie, good taste, distaste and dangerous food. In particular, forty-four healthy adults of both sexes were assessed with an antisaccade paradigm (which requires the generation of a voluntary saccade and the suppression of a reflex one) and a free viewing paradigm (which implies the free visual exploration of two images). The results showed that observers directed their initial fixations more often and faster on items with high survival relevance such as nutrient and possible dangers; although an increase in antisaccade error rates was only detected for high-calorie items. We also found longer prosaccade fixation duration and initial fixation duration bias score related to maintained attention towards high calorie, good taste and danger categories; while shorter reaction times to correct an incorrect prosaccade related to less difficulties in inhibiting distasteful images. Altogether, these findings suggest that visual attention is differentially modulated by both the accepted and rejected food attributes, but also that normal-weight, non-eating disordered individuals exhibit enhanced approach to food's postingestive effects and avoidance of distasteful items (such as bitter vegetables or pungent products). PMID- 28578043 TI - Moisture content during extrusion of oats impacts the initial fermentation metabolites and probiotic bacteria during extended fermentation by human fecal microbiota. AB - Extrusion exposes flour components to high pressure and shear during processing, which may affect the dietary fiber fermentability by human fecal microbiota. The objective of this study was to determine the effect of flour moisture content during extrusion on in vitro fermentation properties of whole grain oats. Extrudates were processed at three moisture levels (15%, 18%, and 21%) at fixed screw speed (300rpm) and temperature (130 degrees C). The extrudates were then subjected to in vitro digestion and fermentation. Extrusion moisture significantly affected water-extractable beta-glucan (WE-BG) in the extrudates, with samples processed at 15% moisture (lowest) and 21% moisture (highest) having the highest concentration of WE-BG. After the first 8h of fermentation, more WE BG remained in fermentation media in samples processed at 15% moisture compared with the other conditions. Also, extrusion moisture significantly affected the production of acetate, butyrate, and total SCFA by the microbiota during the first 8h of fermentation. Microbiota grown on extrudates processed at 18% moisture had the highest production of acetate and total SCFA, whereas bacteria grown on extrudates processed at 15% and 18% moisture had the highest butyrate production. After 24h of fermentation, samples processed at 15% moisture supported lower Bifidobacterium counts than those produced at other conditions, but had among the highest Lactobacillus counts. Thus, moisture content during extrusion significantly affects production of fermentation metabolites by the gut microbiota during the initial stages of fermentation, while also affecting probiotic bacteria counts during extended fermentation. PMID- 28578044 TI - Comparison of static and dynamic sensory product characterizations based on check all-that-apply questions with consumers. AB - The aim of the present work was to compare static and dynamic sensory product characterizations based on check-all-that-apply (CATA) questions with consumers. Three studies involving a total of 310 consumers were carried out. In each study, a between-subjects experimental design was used to compare static sensory characterizations obtained using CATA questions with dynamic characterizations over a relatively short time period using temporal CATA (TCATA). Three different product categories were evaluated (orange juice, strawberry yogurt, and vanilla milk desserts) using 6-11 sensory terms. TCATA data were analysed as CATA considering fixed time periods throughout the evaluation. CATA and TCATA were compared in terms of frequency of use of the terms, sample discrimination, and sample and term configurations. Asking consumers to continuously select the attributes that applied to describe a product and to deselect those that no longer applied during the evaluation period did not substantially modify the average citation proportion of terms or the maximum citation proportion for individual terms for liquid and semi-solid products with a relatively fast oral preparatory phase. Although both methodologies provided similar information, additional insights on how similarities and differences among samples evolved during consumption were obtained with TCATA in the case of products that experience large temporal changes or attributes with strong time-dependency. CATA provided similar information as TCATA for sensory attributes that did not change substantially during the evaluation period. Results from the present work suggest that static and dynamic product sensory characterizations using CATA questions with consumers provide complementary information about consumer experiences with food products. PMID- 28578045 TI - Impact of laccase on the colour stability of structured oil-in-water emulsions. AB - The optical properties of food emulsions play a key role in determining their perceived quality because they are the first sensory cue that many consumers receive. The purpose of the current study was to investigate the impact of a cross-linking enzyme (laccase) on the appearance of structured oil-in-water emulsions containing a lipophilic model colorant (Nile red). A layer-by-layer electrostatic deposition approach was used to prepare oil-in-water emulsions stabilized by interfacial protein-pectin complexes under acidic conditions (pH3.5, 10mM citrate buffer). Laccase (an oxidoreductase) was then added to the system, since this enzyme is often used to covalently cross-link interfacial biopolymer layers. The optical properties of the emulsions were monitored during storage using spectral reflectance to determine the L*a*b values, while the physical properties were monitored by measuring changes in droplet surface charge and particle size distribution. No changes in the size or charge of the droplets were observed during storage, indicating that the emulsions had good physical stability. In the absence of laccase, the emulsions were stable to colour fading, but in the presence of laccase rapid colour changes occurred (red to blue to white). These results have important implications for the formation of structured food emulsions containing certain types of food dyes. PMID- 28578046 TI - The influence of proteases on the browning of dried squid products processed by air-drying. AB - To clarify why mantle meat from Japanese common squid (Todarodes pacificus) dried products discolor dramatically when processed by air-drying, the role of endogenous protease(s) on browning during the processing of dried squid products was studied. The involvement of endogenous protease(s) in the generation of Free Amino Acids (FAAs) participating in the Maillard reaction was characterized. The browning and myosin heavy chain degradation during air-drying were obviously mitigated by the addition of metalloprotease inhibitors, especially EGTA and 1,10 phenanthroline, followed by serine proteinase inhibitor, especially PMSF. The amount of total FAAs in dried products increased by only 0.17% with the addition of 1,10-phenanthroline and 5.0% with added EGTA. In autolysis models, protein autolysis was almost completely inhibited by 1,10-phenanthroline. The addition of, 1,10-phenanthroline inhibited the increase in total FAAs including arginine (Arg), followed by EGTA and PMSF. The results indicated that endogenous metalloproteases and serine proteases might influence the generation of FAAs including Arg, and contribute to product discoloration during air-drying. PMID- 28578047 TI - Betalains and phenolic compounds of leaves and stems of Alternanthera brasiliana and Alternanthera tenella. AB - Betacyanins and phenolic compounds from acetonitrile:acidified water extracts of Alternanthera brasiliana and Alternanthera tenella were characterized and quantified using a high-performance liquid chromatography system coupled with diode array and electrospray mass spectrometry detection. Four betacyanins (amaranthine, isoamaranthine, betanin and isobetanin) were tentatively identified and quantified. Twenty eight phenolic compounds of four different families (hydroxybenzoic and hydroxycinnamic acids, flavones and flavonols) were separated and characterized on the basis of their accurate MS and MS/MS information out of which ten compounds were confirmed by authentic standards. These plant species could be considered as an especially rich source of natural bioactive compounds and potential food colorants. A. brasiliana showed the highest betacyanin and polyphenols content (89MUg/g and 35,243MUg/g, respectively). Among polyphenols, flavonols were the more abundant (kaempferol-glucoside, kaempferol-rutinoside and kaempferol-rhamnosyl-rhamnosyl-glycoside). Meanwhile, A. tenella showed a different polyphenols profile with flavones as major compounds (glucopyranosil vitexin and vitexin). As a novelty, pentosyl-vitexin and pentosyl-isovitexin were detected for the first time in Alternanthera plants. Both A. brasiliana and A. tenella leaves showed high total polyphenol content and in vitro antioxidant activity (FRAP). These results provide an analytical base concerning the phenolic and betalains composition and the antioxidant properties of two members of the promising Alternanthera gender, for subsequent applications, such as functional food ingredients. PMID- 28578048 TI - Microencapsulation of functional strains by high pressure homogenization for a potential use in fermented milk. AB - This study was aimed to evaluate the potential of high pressure homogenization for the microencapsulation of two probiotic lactic acid bacteria, Lactobacillus paracasei A13 and Lactobacillus salivarius subsp. salivarius CET 4063 to produce functional fermented milks. Microcapsules of the considered functional microorganisms were obtained by HPH treatments at 50MPa in the presence of sodium alginate and vegetable oil. The microencapsulated microorganisms were then inoculated as adjuncts to produce fermented milks. As controls were used fermented milks in which the two probiotic lactobacilli were inoculated without encapsulation. The viability of the strains was monitored during almost 2months of refrigerated storage. The survival of lactic acid bacteria after the gastric duodenal simulated test was determined. Fermented milk texture parameters, the presence of exo-polysaccharides and the production of volatile molecules were also evaluated over storage. The microcapsules, for both the considered probiotic strains, were homogeneous and with a size<100MUM and therefore did not adversely affect the sensory properties of the fermented milks. The encapsulation decreased the hyperacidity phenomena generally related to the inclusion of probiotic microorganisms in fermented milks. The lower acidity of the products due to the microencapsulation was fundamental for the improvement of the viability of the starter culture and the sensory characteristics of the products. The microencapsulation conditions increased the resistance to the simulated digestion processes, although the strain Lb. paracasei A13 generally showed a higher resistance to the gastric barrier respect to Lb. salivarius CECT 4063. By contrast, the data obtained showed a reduction of EPS production by the microencapsulation. The volatile profiles showed specific profiles in relation to the probiotic strain used and microencapsulation process. In conclusion, the results of this study underlined the applicative potential of HPH microencapsulation of probiotic microorganisms to produce fermented milk with improved functionality and with enhanced sensory properties. PMID- 28578049 TI - Phytoglycogen to increase lutein solubility and its permeation through Caco-2 monolayer. AB - Increasing the solubility of poorly water-soluble bioactives is essential to enhancing their bioavailability. The objective of this study was to evaluate the impact of phytoglycogen (PG) on water solubility of lutein and its transepithelial permeation across Caco-2 cell monolayers. Solid PG-LT complexes were prepared by combining an acetone solution of LT with an aqueous solution of PG under sonication, followed by centrifugation and vacuum drying of the supernatant as well as a further purification procedure. X-ray powder diffraction and differential scanning calorimetry showed negligible crystalline structure of LT in the PG-LT complex tested. The maximal water solubility of LT (130.65MUg/mL) occurred at the PG/LT combination ratio of 53.3/1, which was significantly higher than that of LT alone (0.56MUg/mL). Remarkably, LT, when complexed with PG, exhibited much-enhanced permeation through Caco-2 monolayer than LT alone, suggesting a potential role of PG to improve LT bioavailability. This study indicated that PG could be applied for the delivery of LT and possibly other hydrophobic ingredients. PMID- 28578050 TI - Cognitive decision strategies adopted by consumers in reminder difference tests: Influence of the authenticity test. AB - Discrimination tests are used in food companies to quantify small differences between products. Within the diversity of methods available, some are quicker to conduct, whereas others are more sensitive or statistically powerful. One class of methods includes the reminder tasks in which the reference product is given before tasting the actual test stimuli. During the task, such a 'reminder' can be compared directly to each test stimulus, or alternatively, only serve to prime the memory of the judge without being taken into account in decision-making. Previous research with trained judges provided evidence for the latter process while research with untrained consumers has provided some evidence for the former process. Two studies were conducted with untrained consumers using the A Not-AR and 2-AFCR reminder tasks. Objectives were to determine the decision strategies used in, and the relative sensitivity of the tasks. In addition, the use of an "authenticity test" was explored to see if this has a positive effect on test performance. In the first study, mayonnaise and ice tea with small stimulus differences (d'<1) were used in A Not-AR and 2-AFCR. Results were compared to those from A Not-A and 2-AFC tasks, with and without an authenticity test. It was difficult to draw clear conclusions on the decision strategy used, though the use of an authenticity test increased the sensitivity for these small differences, as it improved the performance of 6 out of 8 tests. In the second study, ice teas with larger stimulus differences (at two levels) were tested using the A Not-AR and 2-AFCR tasks, in comparison to the same-different task. The results showed that consumers use the less optimal strategies and that the authenticity test decreases performance, which is contradictory to the results of the first study. It seems that for very small stimulus differences the authenticity test can improve performance, but with larger differences the authenticity test decreases performance; it seems to confuse the judges. PMID- 28578051 TI - Will seabass (Dicentrarchus labrax) quality change in a warmer ocean? AB - The impacts of climate change on seafood quality, safety and human health are still unknown. The present study investigated the effect of warming on fatty acids and elements content in two tissues (muscle and liver) of the relevant commercial seabass species (Dicentrarchus labrax). After exposing fish to increased seawater temperature for a period of 60days, higher saturated fatty acid (SFA) levels were observed in fish muscle (2.16% increase); whereas lower SFA levels were observed in fish liver (5.42% decrease). On the other hand, monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) contents decreased in both muscle (1.77% and 0.39%, respectively) and liver (10.54% and 8.11%, respectively) of fish subjected to warmer conditions. Additionally, warming promoted changes in fish elemental profiles, leading to significantly higher levels of Cl in the muscle and lower levels of Rb in the liver. Overall, data showed that fatty acids and elemental contents were affected by temperature, though representing small implications to human health. Moreover, this preliminary study highlights the importance of conducting further seafood risk-benefit assessments under climate change contexts. PMID- 28578052 TI - Arginine prevents thermal aggregation of hen egg white proteins. AB - The control of aggregation and solubilization of hen egg white protein (HEWP) is an important issue for industrial applications of one of the most familiar food protein sources. Here, we investigated the effects of edible amino acids on heat induced aggregation of HEWP. The addition of 0.6M arginine (Arg) completely suppressed the formation of insoluble aggregates of 1mgmL-1 HEWP following heat treatment, even at 90 degrees C for 20min. In contrast, lysine (Lys), glycine (Gly), and sodium chloride (NaCl) did little to suppress the aggregation of HEWP under the same conditions. SDS-PAGE indicated that Arg suppresses the thermal aggregation of almost all types of HEWP at 1mgmL-1. However, Arg did not suppress the thermal aggregation of HEWP at concentrations >=10mgmL-1 and prompted the formation of aggregates. Transmission electron micrographs revealed a high density structure of unfolded proteins in the presence of Arg. These results indicate that Arg exerts a greater suppressive effect on a protein mixture, such as HEWP, than on a single model protein. These observations may propose Arg as a safe and reasonable additive to HEWP for the elimination of microorganisms by allowing an increase in sterilization temperature. PMID- 28578053 TI - Bactericidal effect of 266 to 279nm wavelength UVC-LEDs for inactivation of Gram positive and Gram negative foodborne pathogenic bacteria and yeasts. AB - Recently, UVC-LED technology has been validated as an alternative to irradiation with conventional mercury UV lamps. In this study, we sought to determine primary factors affecting reduction trends shown in several microorganisms. Four major foodborne pathogens (Escherichia coli O157:H7, Salmonella spp. Listeria monocytogenes, Staphylococcus aureus) and spoilage yeasts (Saccharomyces pastorianus, Pichia membranaefaciens), important to the brewing industry, were inoculated onto selective and non-selective media in order to investigate reduction tendencies at 4 different peak wavelengths (266 to 279nm). As irradiation dose increased, inactivation levels for every microorganism were enhanced, but there were different UV-sensitivities in Gram positive bacteria (GP), Gram negative bacteria (GN), and yeasts (Y). Loss of membrane integrity measured by propidium iodide (PI) increased as peak wavelength increased for every microorganism studied. Similar results were observed in membrane potential measured by DiBAC4(3). However, there were contrasting results which showed that greater DNA damage occurred at a lower peak wavelength as measured by Hoechst 33,258. The level of DNA damage was strongly related to trends of microbial inactivation. This study showed that even though membrane damage was present in every microorganism studied, DNA damage was the primary factor for inactivating microorganisms through UVC-LED treatment. PMID- 28578054 TI - Formation of tyramine in yoghurt during fermentation - Interaction between yoghurt starter bacteria and Lactobacillus plantarum. AB - This study aimed to investigate the formation of tyramine during yoghurt fermentation with the focus on interaction between Streptococcus thermophilus RSKK 04082, Lactobacillus delbrueckii subsp. bulgaricus DSM 20081 and Lactobacillus plantarum RSKK 02030. These microorganisms were used in the yoghurt fermentation as single strains or mixed cultures containing double or triple strains. The interactions between microorganisms have been also revealed by determining total free amino acids and the pH of the medium together with the microbial count of the strains. It was observed that L. delbrueckii subsp. bulgaricus DSM 20081 did not produce tyramine while S. thermophilus RSKK 04082 and L. plantarum RSKK 02030 could produce tyramine depending on the fermentation conditions. Synergistic interactions between S. thermophilus RSKK 04082 and L. delbrueckii subsp. bulgaricus DSM 20081 and, between L. delbrueckii subsp. bulgaricus DSM 20081 and L. plantarum RSKK 02030 were found in terms of tyramine production. It was observed in this study that L. delbrueckii subsp. bulgaricus DSM 20081 had indirect effect on accumulation of tyramine in the yoghurts. PMID- 28578055 TI - Effect of cooking and in vitro digestion on the antioxidant activity of dry-cured ham by-products. AB - Dry-cured ham by-products have been traditionally used in Mediterranean household cooking of broths and stews. The aim of this work was to evaluate the effect of cooking treatments and in vitro gastrointestinal digestion on the antioxidant activity of natural peptides found in bones from Spanish dry-cured hams. The antioxidant activity was tested using five different assays and results demonstrated that cooking using conventional household methods increased the antioxidant activity of ham by-products when assessed using different antioxidant assays with the exception of the ABTS radical scavenging measurement assay. Simulated gastrointestinal digestion showed no significant effect on the antioxidant activity of ham by-products and antioxidant activity decreased when assessed using the ORAC and beta-carotene bleaching assays. Analysis by MALDI-TOF MS revealed a considerable breakdown of peptides due to the action of gastrointestinal enzymes, mainly in samples cooked at 100 degrees C for 1h. In addition, 459 peptides derived from 57 proteins were identified and quantified using mass spectrometry in tandem, evidencing that peptides derived from collagen protein were responsible for the differences in antioxidant activities observed between the uncooked and cooked samples after digestion. The results show the potential of dry-cured ham bones as a source of antioxidant peptides that retain their bioactivity after household cooking preparations and gastrointestinal digestion. PMID- 28578056 TI - Advances in edible oleogel technologies - A decade in review. AB - Trans and saturated fat replacers/substitutes have been a tremendously active area of research for the food industry. Unlike polymers used for hydrogels, oleogels utilize small, amphiphilic molecules that self-assemble via highly specific, non-covalent interactions entrapping liquid oil via capillary forces. Edible applications of oleogels have replaced the need for trans unsaturated and saturated fatty acids to structure processed foods. These innovations mitigate the use of hardstock fats that are associated with deleterious health risks and negative consumer perception. Over the past decade, oleogels have made significant strides towards emulating desired sensory traits while maintaining healthy nutritional profile of the oil. Due to the rapid advancements in the past decade, the most promising technologies will be reviewed. PMID- 28578057 TI - Landmarks in the historical development of twenty first century food processing technologies. AB - Over a course of centuries, various food processing technologies have been explored and implemented to provide safe, fresher-tasting and nutritive food products. Among these technologies, application of emerging food processes (e.g., cold plasma, pressurized fluids, pulsed electric fields, ohmic heating, radiofrequency electric fields, ultrasonics and megasonics, high hydrostatic pressure, high pressure homogenization, hyperbaric storage, and negative pressure cavitation extraction) have attracted much attention in the past decades. This is because, compared to their conventional counterparts, novel food processes allow a significant reduction in the overall processing times with savings in energy consumption, while ensuring food safety, and ample benefits for the industry. Noteworthily, industry and university teams have made extensive efforts for the development of novel technologies, with sound scientific knowledge of their effects on different food materials. The main objective of this review is to provide a historical account of the extensive efforts and inventions in the field of emerging food processing technologies since their inception to present day. PMID- 28578058 TI - Toralactone glycoside in Cassia obtusifolia mediates hepatoprotection via an Nrf2 dependent anti-oxidative mechanism. AB - Cassia obtusifolia L. (Leguminosae) seeds are a well-known medicinal food in East Asia and are used to clear liver heat, sharpen vision, lubricate the intestines, and promote bowel movement. The aims of the present study were to identify the hepatoprotective components of C. obtusifolia seeds by bioactivity-guided isolation and to elucidate their mechanisms of action. Ten phenolic glycosides were isolated from the most active ethyl acetate fraction, and their chemical structures were elucidated by spectroscopic analyses. Among the isolated compounds, toralactone 9-O-gentiobioside (5) had the highest hepatoprotective efficacy against tert-butylhydroperoxide-induced cell death in HepG2 cells. Immunoblotting and real-time polymerase chain reaction analyses revealed that the hepatoprotective effects were exerted through nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent antioxidative signaling. Together, these results provide insights into the effects of this medicinal plant as well as a basis for developing hepatoprotective agents as pharmaceuticals and/or nutraceuticals. PMID- 28578059 TI - Phenolic profile and content of sorghum grains under different irrigation managements. AB - Sorghum grain is widely consumed in Sub-Saharan Africa and Asia, as a staple food due to its adaptation to harsh environments. The impact of irrigation regime: full irrigation (100%); deficit irrigation (50%); and severe deficit irrigation (25%) on phenolic profile and content of six sorghum grain genotypes was investigated by high performance liquid chromatography coupled with diode array detection and electrospray ionization mass spectrometry (HPLC-DAD-ESI-MS). A total of 25 individual polyphenols were unequivocally or tentatively identified. Compared to the colored-grain genotypes, the white grained sorghum var. Liberty had a simpler polyphenol profile. The concentrations of the sorghum-specific 3 deoxyanthocyanidins luteolinidin and apigeninidin, were higher under deficit irrigation compared to the other two regimes in all genotypes. These findings will be valuable for the selection of sorghum genotypes for grain production as human food under water deficit conditions, since polyphenol levels can affect the grain's nutritional value and health properties. PMID- 28578060 TI - The impact of fruit and soybean by-products and amaranth on the growth of probiotic and starter microorganisms. AB - The ability of different fruit by-products, okara, and amaranth flour, to support the growth of probiotic and non-probiotic strains was evaluated. The tests were conducted with three commercial starter cultures (Streptococcus thermophilus), ten probiotic strains (seven Lactobacillus spp. and three Bifidobacterium spp. strains), and two harmful bacteria representative of the intestinal microbiota (Escherichia coli and Clostridium perfringens). In vitro fermentability assays were performed using a modified MRS broth supplemented with different fruits (acerola, orange, passion fruit, and mango), and soy (okara) by-products or amaranth flour. Orange and passion-fruit by-products were the substrates that most promoted the growth of bacterial populations, including pathogenic strains. On the other hand, the acerola by-product was the substrate that showed the highest selectivity for beneficial bacteria, since the E. coli and Cl. perfringens populations were lower in the presence of this fruit by-product. Although the passion fruit by-product, okara, and amaranth stimulated the probiotic strains, the growth of the pathogenic strains studied was higher compared to other substrates. Different growth profiles were verified for each substrate when the different strains were compared. Although pure culture models do not reflect bacterial interaction in the host, this study reinforces the fact that the ability to metabolize different substrates is strain-dependent, and acerola, mango, and orange by-products are the substrates with the greatest potential to be used as prebiotic ingredients. PMID- 28578061 TI - Effects of the combination of omega-3 PUFAs and proanthocyanidins on the gut microbiota of healthy rats. AB - omega-3 Polyunsaturated fatty acids (PUFAs) reduce risk factors for cardiovascular diseases (CVD) and other pathologies that involve low-grade inflammation. They have recently been shown to exert complementary functional effects with proanthocyanidins. As the reduction of health-promoting gut bacteria such as lactobacilli and bifidobacteria has been linked to a number of alterations in the host, the aim of this study was to determine whether PUFAs and proanthocyanidins also cooperate in maintaining well-balanced microbiota. To this end, rats were supplemented for 6months with eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) 1:1 (16.6g/kg feed); proanthocyanidin-rich grape seed extract (GSE, 0.8g/kg feed); or both. Plasma adiponectin, cholesterol, and urine nitrites were measured. Gut bacterial subgroups were evaluated in fecal DNA by qRT-PCR. Short-chain fatty acids (SCFAs) were determined in feces by gas chromatography. Body and adipose tissue weights were found to be higher in the animals given omega-3 PUFAs, while their energy intake was lower. Plasma cholesterol was lower in omega-3 PUFA supplemented groups, while adiponectin and urine nitrites were higher. omega-3 PUFAs reduced the population of Lactobacillales and L. acidophilus after 6months of supplementation. GSE significantly reduced L. plantarum and B. longum. The combination of omega-3 PUFAs and GSE maintained the health-promoting bacteria at levels similar to those of the control group. Acetic acid was increased by the omega-3 PUFA individual supplementation, while the combination with GSE kept this value similar to the control value. In conclusion, while individual supplementations with omega-3 PUFAs or GSE modify the populations of Lactobacillus, Bifidobacterium and microbial products (SCFAs), their combination maintains the standard proportions of these bacterial subgroups and their function while also providing the cardiovascular benefits of omega-3 PUFAs. PMID- 28578062 TI - Biotransformed citrus extract as a source of anti-inflammatory polyphenols: Effects in macrophages and adipocytes. AB - Chronic non-communicable diseases such as obesity are preceded by increased macrophage infiltration in adipose tissue and greater secretion of pro inflammatory cytokines. We evaluated the anti-inflammatory potential of Biotransformed extract, and two control extracts: In Natura and Autoclaved. The assays were performed using a cellular model with RAW264.7, 3T3-L1 cells, and RAW264.7 and 3T3-L1 co-culture. The innovation of the study was the use of Biotransformed extract, a unique phenolic extract of a bioprocessed citrus residue. LPS stimulated RAW264.7 cells treated with the Biotransformed extract exhibited lower secretion of TNF-alpha and NO and lower protein expression of NFkappaB. In RAW264.7 and 3T3-L1 co-culture, treatment with 1.0mg/mL of the Biotransformed extract reduced secretion of TNF-alpha (30.7%) and IL-6 (43.4%). Still, the Biotransformed extract caused higher increase in adiponectin in relation to control extracts. When the co-culture received a LPS stimulus, the Autoclaved extract at 1.0mg/mL reduced IL-6 and TNF-alpha concentrations, and raised adiponectin. However, it was noteworthy that the Biotransformed extract was also able to significantly reduce IL-6 concentration while the Natural extract was not. The Biotransformed citrus extract evaluated in this study showed anti-inflammatory activity in macrophages and in co-culture, indicating that bioprocess of citrus residue can contribute to new product development with anti inflammatory potential. PMID- 28578063 TI - Aroma-related cross-modal interactions for sugar reduction in milk desserts: Influence on consumer perception. AB - Reformulation of industrialized products has been regarded as one of the most cost-effective strategies to reduce sugar intake. Although non-nutritive sweeteners have been extensively used to reduce the added sugar content of these products, increasing evidence about the existence of compensatory energy intake mechanisms makes it necessary to develop alternative strategies to achieve rapid sugar reductions. In this context, the aim of the present work was to evaluate aroma-related cross modal interactions for sugar reduction in vanilla milk desserts. In particular, the influence of increasing vanilla concentration and the joint increase of vanilla and starch concentration on consumer sensory and hedonic perception was assessed. Two studies with 100 consumers each were conducted, in which a total of 15 samples were evaluated. For each sample, consumers rated their overall liking and answered a check-all-that-apply (CATA) question comprising 12 flavour and texture terms. Sugar reduction caused significant changes in the flavour and texture characteristics of the desserts. An increase in vanilla concentration had a minor effect on their sensory characteristics. However, increasing both vanilla and starch concentration led to an increase in vanilla flavour and sweetness perception and reduced changes in consumer hedonic perception. These results showed the potential of aroma-related cross modal interactions for minimizing the sensory changes caused by sugar reduction. These strategies could contribute to product reformulation without the need to use non-nutritive sweeteners. PMID- 28578064 TI - Effect of liquid smoking on lipid hydrolysis and oxidation reactions during in vitro gastrointestinal digestion of European sea bass. AB - The effect of smoking using liquid smoke flavourings on the hydrolysis and oxidation of European sea bass lipids during in vitro digestion was investigated. The techniques used were 1H NMR and SPME-GC/MS. The former proved that liquid smoking does not influence the extent of lipolysis, but prevents those lipid oxidation reactions that occur during in vitro digestion of unsmoked samples, giving rise to cis,trans-conjugated dienes associated with hydroperoxy/hydroxy groups. SPME-GC/MS corroborated the results obtained by 1H NMR in relation to the antioxidant effect of smoking under gastrointestinal conditions. Smoked sea bass digests showed lower abundances of volatile oxidation markers derived from omega 3 and omega-6 lipids than unsmoked ones. Moreover, the lowest values were found in the digests of sea bass samples smoked with the flavouring showing the highest phenolic content. For the first time, the bioaccessibility of smoke flavouring components was evidenced, some of them well-known for displaying antioxidant activity. PMID- 28578065 TI - Effect of salt content and type on emulsifying properties of hull soy soluble polysaccharides at acidic pH. AB - Hull soluble polysaccharide (HSPS) is a novel product consisting in a mixture of polysaccharides and proteins extracted from soy hulls by using a methodology based on the extraction of citric pectins. In this work we studied the effect of the addition of two different salts (NaCl and CaCl2) on the emulsifying properties of HSPS at acidic conditions. Low and high homogenization energies were used, obtaining coarse and fine emulsions, respectively. Mean droplet size, the stability against destabilizing processes (creaming, flocculation and coalescence) and the rheological properties of the emulsions were analyzed. Also, the rheology of the O/W interface was studied by using du Nouy ring geometry. Coarse HSPS emulsions were unstable to creaming, being more stable in the presence of salts. In contrast, fine HSPS emulsions showed long-term creaming stability similar to those performed with commercial citric pectin (CCP), although they differ in particle size distribution and flocculation degree. The presence of CaCl2 reduced the mean size of droplets in fine HSPS emulsions and improved their stability to flocculation and coalescence. Significant differences were observed in the rheological behavior of O/W emulsions and interfaces of HSPS and CCP with respect to the salt addition. Our results indicate that HSPS can be used in the formulation and stabilization of acidic O/W emulsions. Besides, HSPS generates emulsions with different characteristics than those obtained with citric pectins. The use of HSPS provides a suitable alternative in food engineering contributing to the exploitation and valorization of soy hulls, which represents an important waste material in soybean processing. PMID- 28578066 TI - Microbial metabolites profile during in vitro human colonic fermentation of breakfast menus consumed by Mexican school children. AB - The nutrition transition promotes the development of childhood obesity. Currently, Mexico is affected by this serious public health problem. The nutritional and functional characterization of a whole menu has a number of advantages over the study of single nutrients. Since breakfast is considered the most important meal of the day, this study aimed to evaluate the metabolite profile produced by in vitro human colonic fermentation of the isolated indigestible fraction (IF) from three different Mexican breakfast (M-B) menus (Modified "MM-B", traditional "TM-B", and alternative "AM-B"), previously identified as commonly consumed by Mexican schoolchildren in Nayarit State, Mexico. The M-B's consist of egg, corn tortilla, beans (higher in TM-B), sugar and chocolate powder (higher in AM-B) and milk, combined in different proportions. The IF in all breakfasts was about 4.7-5.6g/100g FW, with a relatively high content of protein (~21%), which might have negative physiological implications. Fermentation of IF from TM-B resulted in the largest pH decrease after 72h (pH=6.07), with a low short chain fatty acid (SCFA) production (0.75 to 47.23mmol/L), but greater relative concentration of other fatty acids (FA) (C7, C8, C9). Besides, 55 volatile compounds were detected in the fermentation media by SPME-GC-MS and three principal components (PC) were identified. PC1 was influenced by SCFA production, low FA esters production (<8C), and low volatile organic acids production. PC2 was influenced by the decrease in pH and an increase in antioxidant capacity (p<0.0001). These results suggest that the production of different metabolites in the luminal medium may affect the pH and antioxidant status in the colon. Fermentation of IF from TM-M, assessed after 48 and 72h, showed the highest correlation for PC2; the metabolic pattern registered for this IF maybe considered beneficial. PMID- 28578067 TI - In vitro uptake and immune functionality of digested Rosemary extract delivered through food grade vehicles. AB - The digestion, absorption, uptake and bioavailability of a rosemary supercritical fluid extract encapsulated in oil in water emulsion were studied. Two emulsions with opposite surface charge were prepared, containing 7% canola oil, and either 2% lactoferrin or whey protein isolate. When absorption and uptake of carnosic acid and carnosol were followed on Caco-2 cell monolayers, there were no differences with protein type. However, when co-cultures of HT-29 MTX were employed, the presence of mucus caused a higher retention of carnosic acid in the apical layer for lactoferrin emulsions. The immune activity of the bioavailable fractions collected from cell absorption experiments was tested ex vivo on murine splenocytes. Although transport through the intestinal barrier models was low, the bioavailable fractions showed a significant effect on splenocytes proliferation. These results demonstrated the potential of using rosemary supercritical extract through protein stabilized oil in water emulsions, as a food with immunomodulatory functionality. PMID- 28578068 TI - Phenolic profile and fermentation patterns of different commercial gluten-free pasta during in vitro large intestine fermentation. AB - The fate of phenolic compounds, along with short-chain fatty acids (SCFAs) production kinetics, was evaluated on six different commercial gluten-free (GF) pasta samples varying in ingredient compositions, focussing on the in vitro faecal fermentation after the gastrointestinal digestion. A general reduction of both total phenolics and reducing power was observed in all samples, together with a substantial change in phenolic profile over 24h of faecal fermentation, with differences among GF pasta samples. Flavonoids, hydroxycinnamics and lignans degraded over time, with a concurrent increase in low-molecular-weight phenolic acids (hydroxybenzoic acids), alkylphenols, hydroxybenzoketones and tyrosols. Interestingly, discriminant analysis also identified several alkyl derivatives of resorcinol as markers of the changes in phenolic profile during in vitro fermentation. Furthermore, degradation pathways of phenolics by intestinal microbiota have been proposed. Considering the total SCFAs and butyrate production during the in vitro fermentation, different fermentation kinetics were observed among GF pasta post-hydrolysis residues. PMID- 28578069 TI - Model studies on the formation of volatile compounds generated by a thermal treatment of steryl esters with different fatty acid moieties. AB - The consumption of plant sterols is reported to have a beneficial effects on human health, i.e. phytosterols are known for their cholesterol-lowering properties. Whereas, they are prone to oxidation and currently there is ongoing worldwide research aimed at the biological effect of phytosterol oxides. In this study volatile compounds formed during thermal degradation of stigmasteryl esters were identified. The research was conducted using standards of stigmasterol, fatty acids and stigmasteryl esters as well as fat enriched with stigmasteryl esters which were thermally treated at 60 degrees C and 180 degrees C for 12h. Volatile compounds were characterised by SPME-GC-MS. Among the volatiles formed during heating of stigmasteryl esters aldehydes, ketones, alcohols and hydrocarbons were found. The mechanism of the formation of volatile compounds from sterol esters was related to oxidation of steryl and fatty acid moieties. In particular, 2-methyl-3-pentanone and 5-ethyl-6-methyl-3-hepten-2-one were identified as unique degradation products formed from degradation of the steryl moiety specifically, and a mechanism of their formation was suggested. Both volatiles could be a good indicator of thermo-oxidative degradation of functional food products enriched in phytosterols and their esters. PMID- 28578070 TI - Comprehensive characterization of bioactive peptides from Buffalo (Bubalus bubalis) colostrum and milk fat globule membrane proteins. AB - Milk fat is dispersed in milk as small spherical globules stabilized in the form of emulsion by its surrounding membrane, often referred to as fat globule membrane (FGM). Buffalo, a major milking mammal of Asia and second most milking mammal across the globe presents physicochemical features different from that of other ruminant species containing higher content of lipids and proteins. The present study describes characterization of FGM proteins isolated from both buffalo milk and colostrum. A detailed proteomic analysis of peptides generated by in vitro gastrointestinal simulation digestion of buffalo milk and colostrum FGM fractions was performed by nLC-ESI MS/MS. The peptide based clustering of FGM proteins unravelled association of membrane proteins in fat transport, enzymatic activity, general transport, defence, cell signalling, membrane/protein trafficking protein synthesis/binding/folding including unknown functions. Gene annotation, STRING and YLoc analyses provided putative insights into major secretory pathways in milk and colostrum FGM peptides, interactive protein networks including their sub cellular localization. The peptides of milk and colostrum FGM offered cellular protection as powerful antioxidants indicated their promising perspectives in commercial formulations and nutraceuticals. PMID- 28578071 TI - Generalized dispersion analysis of arbitrarily cut monoclinic crystals. AB - Dispersion analysis is applicable to arbitrarily cut monoclinic crystals of unknown orientation in order to find the symmetry axis. By this it is possible to differentiate between the transition moments oriented parallel and normal to the b-axis and to determine the dielectric tensor functions of those two principal directions. Dispersion analysis of arbitrarily cut monoclinic crystals is based on an extension of the evaluation scheme developed for arbitrarily cut orthorhombic crystals. We present dispersion analysis of monoclinic crystals exemplarily on spodumene (LiAl(SiO3)2) and yttrium orthosilicate (Y2SiO5). PMID- 28578072 TI - Meal time behavior difficulties but not nutritional deficiencies correlate with sensory processing in children with autism spectrum disorder. AB - BACKGROUND: Food aversion and nutritional difficulties are common in children with autism spectrum disorder. AIM: To compare meal time behavior of children with autism to their typically developing siblings and to typical controls and to examine if sensory profiles can predict meal time behavior or nutritional deficiencies in the autism group. PMID- 28578074 TI - Ethics and subsequent use of electronic health record data. AB - The digital health landscape in the United States is evolving and electronic health record data hold great promise for improving health and health equity. Like many scientific and technological advances in health and medicine, there exists an exciting narrative about what we can do with the new technology, as well as reflection about what we should do with it based on what we value. Ethical reflections about the use of EHR data for research and quality improvement have considered the important issues of privacy and informed consent for subsequent use of data. Additional ethical aspects are important in the conversation, including data validity, patient obligation to participate in the learning health system, and ethics integration into training for all personnel who interact with personal health data. Attention to these ethical issues is paramount to our realizing the benefits of electronic health data. PMID- 28578073 TI - Identification of endocrine disrupting chemicals acting on human aromatase. AB - Human aromatase is the cytochrome P450 catalysing the conversion of androgens into estrogens playing a key role in the endocrine system. Due to this role, it is likely to be a target of the so-called endocrine disrupting chemicals, a series of compounds able to interfere with the hormone system with toxic effects. If on one side the toxicity of some compounds such as bisphenol A is well known, on the other side the toxic concentrations of such compounds as well as the effect of the many other molecules that are in contact with us in everyday life still need a deep investigation. The availability of biological assays able to detect the interaction of chemicals with key molecular targets of the endocrine system represents a possible solution to identify potential endocrine disrupting chemicals. Here the so-called alkali assay previously developed in our laboratory is applied to test the effect of different compounds on the activity of human aromatase. The assay is based on the detection of the alkali product that forms upon strong alkali treatment of the NADP+ released upon enzyme turnover. Here it is applied on human aromatase and validated using anastrozole and sildenafil as known aromatase inhibitors. Out of the small library of compounds tested, resveratrol and ketoconazole resulted to inhibit aromatase activity, while bisphenol A and nicotine were found to exert an inhibitory effect at relatively high concentrations (100MUM), and other molecules such as lindane and four plasticizers did not show any significant effect. These data are confirmed by quantification of the product estrone in the same reaction mixtures through ELISA. Overall, the results show that the alkali assay is suitable to screen for molecules that interfere with aromatase activity. As a consequence it can also be applied to other molecular targets of EDCs that use NAD(P)H for catalysis in a high throughput format for the fast screening of many different compounds as endocrine disrupting chemicals. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone. PMID- 28578075 TI - From evidence-based to hope-based medicine? Ethical aspects on conditional market authorization of and early access to new cancer drugs. AB - There is a strong patient demand for early access to potentially beneficial cancer drugs. In line with this authorization agencies like the European Medicines Agency are providing drugs with conditional market authorisation based on positive interim analyses. This implies that drugs are used with insecure evidence of efficacy and adverse side-effects. Several authors have pointed to ethical problems with such a system but up to date no indepth ethical analysis of this system is found which is the aim of this article. Drawing of the four generally accepted principles of medical ethics: beneficence, nonmaleficence, respect for autonomy and justice the ethical pros and cons of conditional market authorisation are analysed. From the perspective of beneficence and non maleficence it is found that the main problem is not risk of adverse side-effects to patients, but rather risk of less beneficial outcomes than what can be expected which could change incentives for patients' choice of treatment. This is also related to the extent to which patients might make an autonomous choice, especially taking into account problematic psychological attitudes and biases in medical decision-making. However, the main problem is related to justice and an equitable distribution of scarce health-care resources given the opportunity cost of drugs treatment. When using resources on cancer treatments which later might be found to be less efficacious than was first expected, other patients (in and outside the cancer field) are deprived of potentially more beneficial treatments even though their needs might be equally or more severe. At the same time, demanding more evidence has an ethical cost to patients in terms of depriving them of potential benefits in terms of reduced mortality and morbidity. In order to handle these ethical conflicts further research and analyses are required and it is suggested that pricing strategies and information requirements are alternatives to be further explored. PMID- 28578076 TI - beta1- and beta2-adrenergic receptor stimulation differ in their effects on PGC 1alpha and atrogin-1/MAFbx gene expression in chick skeletal muscle. AB - Adrenaline changes expression of the genes encoding peroxisome proliferator activated receptor-gamma coactivator-1 alpha (PGC-1alpha), which is known as a regulator of muscle size, and atrogin-1/muscle atrophy F-box (MAFbx), which is a muscle-specific ubiquitin ligase. However, the subtype of beta-adrenergic receptor (beta-AR) involved in regulating these genes in skeletal muscle is not yet well defined. In this study, the effects of intraperitoneal injection of adrenaline and three beta1-3-AR selective agonists on chick skeletal muscle metabolism were examined, to evaluate the functions of beta-AR subtypes. Adrenaline decreased atrogin-1/MAFbx mRNA levels accompanied by an increase in PGC-1alpha mRNA and protein levels. However, among the three selective agonists, only the beta1-AR agonist, dobutamine, increased PGC-1alpha mRNA and protein levels, while the beta2-AR agonist, clenbuterol, suppressed atrogin-1/MAFbx mRNA levels. In addition, preinjection of the beta1-AR antagonist, acebutolol, and the beta2-AR antagonist, butoxamine, inhibited the adrenaline-induced increase in PGC 1alpha mRNA levels and the decrease in atrogin-1/MAFbx mRNA levels, respectively. Compared with adrenaline administration, the beta3-AR agonist, BRL37344, decreased PGC-1alpha mRNA levels and increased atrogin-1/MAFbx mRNA levels. These results suggest that, in chick skeletal muscle, PGC-1alpha is induced via the beta1-AR, while atrogin-1/MAFbx is suppressed via the beta2-AR. PMID- 28578077 TI - Oral rehabilitation with implant-supported fixed dental prostheses of a patient with cleidocranial dysplasia. AB - This clinical report describes the oral rehabilitation with implant-supported fixed dental prostheses in the maxilla and mandible of a patient with cleidocranial dysplasia. Cone-beam computed tomography and a tilted implant protocol in the mandible helped to establish a conservative approach for bone preservation, prevent surgical complications, enable proper implant positioning to avoid anatomic structures, and support the fixed dental prostheses. PMID- 28578078 TI - Use it responsibly. PMID- 28578079 TI - Fielding questions of age and experience: Honesty is the best policy. PMID- 28578080 TI - Nitrogen-source preference in blueberry (Vaccinium sp.): Enhanced shoot nitrogen assimilation in response to direct supply of nitrate. AB - Blueberry (Vaccinium sp.) is thought to display a preference for the ammonium (NH4+) form over the nitrate (NO3-) form of inorganic nitrogen (N). This N-source preference has been associated with a generally low capacity to assimilate the NO3- form of N, especially within the shoot tissues. Nitrate assimilation is mediated by nitrate reductase (NR), a rate limiting enzyme that converts NO3- to nitrite (NO2-). We investigated potential limitations of NO3- assimilation in two blueberry species, rabbiteye (Vaccinium ashei) and southern highbush (Vaccinium corymbosum) by supplying NO3- to the roots, leaf surface, or through the cut stem. Both species displayed relatively low but similar root uptake rates for both forms of inorganic N. Nitrate uptake through the roots transiently increased NR activity by up to 3.3-fold and root NR gene expression by up to 4-fold. However, supplying NO3- to the roots did not increase its transport in the xylem, nor did it increase NR activity in the leaves, indicating that the acquired N was largely assimilated or stored within the roots. Foliar application of NO3- increased leaf NR activity by up to 3.5-fold, but did not alter NO3- metabolism related gene expression, suggesting that blueberries are capable of post translational regulation of NR activity in the shoots. Additionally, supplying NO3- to the cut ends of stems resulted in around a 5-fold increase in NR activity, a 10-fold increase in NR transcript accumulation, and up to a 195-fold increase in transcript accumulation of NITRITE REDUCTASE (NiR1) which codes for the enzyme catalyzing the conversion of NO2- to NH4+. These data indicate that blueberry shoots are capable of assimilating NO3- when it is directly supplied to these tissues. Together, these data suggest that limitations in the uptake and translocation of NO3- to the shoots may limit overall NO3- assimilation capacity in blueberry. PMID- 28578081 TI - Expectant management of gallbladder stones after endoscopic removal of common bile duct stones. AB - BACKGROUND: Wait-and-see policy after endoscopic sphincterotomy (ES) for common bile duct (CBD) stones in patients with concomitant gallbladder stones may lead to recurrent biliary complications. The aim of this study was to assess the short and long-term results of wait-and-see policy in patients with intact gallbladder after endoscopic clearance of CBD stones. MATERIALS AND METHODS: From January 1999 to December 2014 a total of 181 consecutive patients with intact gallbladder underwent ES for CBD stones. The main measures of outcome were long-term biliary complications, biliary related mortality, CBD stone recurrence and need for surgical interventions. Secondary outcomes were 30-day mortality and 30-day morbidity. Clinical data were retrospectively collected from hospital records and from the National Registry of Death. RESULTS: During the median follow-up of 3.9 years (IQR 1.6-6.6) late biliary complications were observed in 24 (13.8%) patients. Cumulative biliary related morbidity at 3 and 5 years was 7.6% and 10.8%, respectively. CBD stone recurrence was observed in 9 (5.2%) patients. On demand cholecystectomy was performed in 6 (3.3%) patients. 30-day mortality was 3.9% and 30-day morbidity 9.4%. Overall cumulative mortality rate at 3 and 5 years after ES was 31.4% and 49.7%, respectively. Long-term biliary related mortality was 1.7%. No significant difference in long term complications or biliary mortality was observed between patients< 75 or >=75 years of age. CONCLUSION: Prophylactic cholecystectomy after ES has been shown to reduce mortality even in high-risk patients. In our series late biliary related mortality and morbidity were relatively low, because a considerable number of patients died from non-biliary related causes.However, most biliary-related events seem to occur evenly during the follow-up after ES. A prompt risk assesment and consideration of surgical treatment during index admission may prevent late biliary -related complications. PMID- 28578082 TI - An updated comparison of high- and low-viscosity cement vertebroplasty in the treatment of osteoporotic thoracolumbar vertebral compression fractures: A retrospective cohort study. AB - OBJECTIVE: This study mainly aimed to evaluate complications of cement leakage for osteoporotic thoracolumbar vertebral compression fractures by PVP using HVC, and access the clinical efficacy. METHODS: Between May 2013 and June 2015, 66 patients with osteoporotic thoracolumbar vertebral compression fractures, who underwent PVP (36 HVC and 30 LVC) in our hospital, were enrolled. Cement leakage, Visual Analog Scale (VAS), Oswestry Disability Index (ODI), refracture of the cemented vertebrae, and adjacent vertebral fractures were evaluated. The follow up time was 1 year. RESULTS: The overall cement leakage rate was 30.55% in the HVC group, lower than 77.77% obtained in the LVC group (P = 0.00). The incidence rates of cement leakage into paravertebral area (P = 0.02) and vein (P = 0.04) in the HVC group were significantly lower than those of the LVC group; however, no differences were found for disc space (P = 0.72) and intraspinal space (P = 0.58). There were no differences in VAS, ODI, refracture of cemented vertebrae, and adjacent vertebral fracture between the two groups (P > 0.05). CONCLUSIONS: PVP using HVC not only can reduce cement leakage, especially in the paravertebral area and peripheral vein, but also has satisfactory clinical effect. PMID- 28578083 TI - Lasagna plots to visualize results in surgical studies. AB - BACKGROUND: A lasagna plot is a graphical tool that can display multiple longitudinal outcomes. To our knowledge, lasagna plots have not been used in publications of surgical studies before. The objective of this study was to demonstrate the results of surgical randomized controlled trials (RCTs) with lasagna plots in order to assess whether this can lead to new observations of the data presented in the original studies. MATERIAL AND METHODS: Lasagna plots were created with R for an RCT comparing endovascular and open repair for patients with a ruptured abdominal aortic aneurysm (AJAX trial), an RCT comparing laparoscopy or open surgery combined with either fast track or standard care for patients with colon cancer (LAFA trial) and an RCT comparing preoperative biliary drainage and early surgery for patients with pancreatic cancer (DROP trial). RESULTS: Regarding the AJAX trial, the original article had reported the rate of outcomes at 30 days after repair in two tables. The plots additionally demonstrated the moments of occurrence, increase and decrease of multiple outcomes such as renal replacement therapy and occurrence of death within one plot. These observations were not presented in the original article. The lasagna plots of the LAFA and DROP trial revealed similar new observations on multiple longitudinal outcomes. CONCLUSION: By revealing new observations of the previously published data, lasagna plots generate new hypotheses and theories regarding the outcomes. As such, lasagna plots may be a useful addition to traditional tables and figures and could improve the interpretation of results. PMID- 28578084 TI - A novel surgical strategy for secondary hyperparathyroidism: Purge parathyroidectomy. AB - OBJECTIVE: This study was intended to demonstrate the feasibility and efficacy of purge parathyroidectomy (PPTX) for patients with secondary hyperparathyroidism (SHPT). METHODS: The "seed, environment, and soil" medical hypothesis was first raised, following review of the literatures, to demonstrate the possible causes of persistence or recurrence of SHPT after parathyroidectomy. Subsequently, the novel surgical strategy of PPTX was proposed, which involves comprehensive resection of the fibro-fatty tissues, including visible or invisible parathyroid, within the region surrounded by the thyroid cartilage, bilateral carotid artery sheath, and the brachiocephalic artery. The perioperative information and clinical outcomes of patients who underwent PPTX from June 2016 to December 2016 were analyzed. RESULTS: In total, PPTX was performed safely in nine patients with SHPT from June 2016 to December 2016. The operative time for PPTX ranged from 95 to 135 min, and blood loss ranged from 20 to 40 mL. No patients with perioperative death, bleeding, convulsions, or recurrent laryngeal nerve injury were reported. The preoperative concentration of PTH ranged from 1062 to 2879 pg/mL, and from 12.35 to 72.69 pg/mL on the first day after surgery. In total, 37 parathyroid glands were resected. The postoperative pathologic examination showed that supernumerary or ectopic parathyroid tissues were found within the "non parathyroid" tissues in three patients. No cases encountered persistence or recurrence of SHPT, or severe hypocalcemia during the follow-up period. CONCLUSION: PPTX involves comprehensive resection of supernumerary and ectopic parathyroid tissues, which may provide a more permanent means of reducing PTH levels. PMID- 28578085 TI - Assault in children admitted to trauma centers: Injury patterns and outcomes from a 5-year review of the national trauma data bank. AB - IMPORTANCE: While assault is commonly reported or suspected in children with traumatic wounds, a recent overview of these injuries, especially those requiring trauma surgery consultation is lacking in the literature. OBJECTIVES: Explore the incidence, demographics and injury patterns of children presenting to trauma centers following an assault. DESIGN: Retrospective review of the National Trauma Data Bank 2007 to 2011. SETTING AND PARTICIPANTS: Subjects up to 18 years old with "assault" reported as the intent of injury. Patients were divided into infants (<2 years), young children (2-5 years), children (6-11 years), and adolescents (12-18 years). MAIN OUTCOMES AND MEASURES: Mechanism of injury, injury severity and mortality based on age groups and race. RESULTS: Of 609,207 children, 58,299 (9.6%) were victims of an assault. The median age was 16 years and 81% were male, with a median injury severity score (ISS) of 8. The majority of patients were adolescents (76%), followed by infants (17%) and young children (4%). There was a stepwise increase in the proportion of assaulted Black children with increasing age (23.2% for infants and up to 46.7% for adolescents, trend p < 0.01, effect size: 0.175) while the opposite applied for White children (46.0% for infants and down to 19.5% for adolescents, trend p < 0.01, effect size: 0.230). With increasing age, White subjects had the highest trend of being assaulted during an unarmed fight or brawl (p < 0.01, effect size: 0.393), while for Black victims the highest trend was noted for assault with a firearm (p < 0.01, effect size: 0.323). Almost 2 out of 3 infants sustained severe head trauma (59%). The overall mortality was 8%, highest among young children, where it reached 16% (p < 0.01). CONCLUSIONS: Up to 10% of children admitted following trauma are victims of assault with traumatic brain injuries predominant in infants and firearm injuries predominant in adolescents. Injury patterns largely correlate to age and race. Assault in children is associated with a high mortality risk. These data highlight the magnitude of the problem and calls for further involvement of trauma surgeons to improve outcomes, bring awareness and promote preventative strategies to eliminate assault in children. PMID- 28578086 TI - Is intramedullary fixation of displaced midshaft clavicle fracture superior to plate fixation? Evidence from a systematic review of discordant meta-analyses. AB - OBJECTIVE: An increasing number of meta-analyses comparing intramedullary fixation (IF) with plate fixation (PF) for displaced midshaft clavicle fracture have been reported, but the inconsistent results obtained might confuse decision making. We systematically reviewed discordant meta-analyses for assisting the decision-maker in interpreting and selecting amongst discordant meta-analyses and providing surgical recommendations for displaced midshaft clavicle fracture according to currently best available evidence. METHODS: Meta-analyses on IF and PF for displaced midshaft clavicle fracture were identified by searching PubMed, Emabase and the Cochrane Library. A review of meta-analysis quality and data extraction was individually conducted by two reviewers. The meta-analysis providing the best available evidence was identified using the Jadad decision algorithm. RESULTS: Nine studies were included, five of which were of Level-II evidence and four of which were of Level-III evidence. These meta-analyses scored from 6 to 10 according to the Assessment of Multiple Systematic Reviews instrument. With respect to the Jadad decision algorithm, the best meta-analysis was chosen depending upon publication characteristics and methodology of primary studies, language restrictions, and whether data on individual patients were analysed. A meta-analysis incorporating more randomised controlled trials was eventually selected. The best available evidence indicated that the differences between IF and PF were not significant in terms of shoulder function or the rate of treatment failure. However, IF significantly decreased the operative time and the rate of non-operative complications, especially the rate of infection. CONCLUSIONS: Based on the best available evidence, IF may be superior to PF for treating displaced midshaft clavicle fracture. PMID- 28578087 TI - Role of antioxidant defence, renal toxicity markers and inflammatory cascade in disease progression of acute pyelonephritis in experimental rat model. AB - Urinary tract infections are the most common bacterial infections affecting millions of people each year worldwide. The animal model provides an excellent and suitable system for studying cystitis and pyelonephritis caused by Escherichia coli and other uropathogens. Using this established model, we evaluate the role of antioxidant defence system, renal injury markers, and blood parameters in the diseases progression during Escherichia coli infection on 0th day, 12h and 7th day. The antioxidant enzymes like SOD, CAT, GSH, GPx, GR levels were evaluated. The blood parameters like AST, ALT, ALP, Total protein, BUN, creatinine level were estimated in infection model. The relative organ weights, anti microbial status of kidney, CRP, WBC count were done for the evaluation of inflammatory response associated with the infection. The oxidative stress marker like MDA was also evaluated. Histopathological analysis of renal tissue provides direct vision to tissue damage. The antioxidant status of renal tissue was decreased during the 7th day of infection. Likewise, renal toxicity markers were significantly increased during bacterial infection. The inflammatory markers like CRP, WBC count and oxidative stress marker like MDA were significantly increased by the infection on 7th day. The histopathology of renal tissue also reveals the inflammation and tissue damage associated with acute pyelonephritis. PMID- 28578088 TI - Immune response in bovine neosporosis: Protection or contribution to the pathogenesis of abortion. AB - Neospora caninum is a protozoan parasite with a preference for cattle and dogs as hosts. When N. caninum infection occurs in cattle it induces abortion, bovine neosporosis being a main cause of abortion worldwide. In dairy cattle, the economic burden of neosporosis-associated abortion is so great that it might results in closure of a farm. However, not all infected cows abort and it is not yet understood why this occurs. At present there is no effective treatment or vaccine. This review provides insights on how immune response against the parasite determines protection or contribution to abortion. Aspects on markers of risk of abortion are also discussed. Humoral immune responses are not protective against N. caninum but seropositivity and antibody level can be good markers for a diagnosis of bovine neosporosis and its associated abortion risk. In addition, humoral mechanisms against N. caninum infection and abortion differ in pure-breed and cross-breed pregnant dairy and beef cattle. Concentrations of Pregnancy Associated glycoprotein -2 (PAG-2) can also be used to predict abortion. A partially protective immune response encompasses increased IFN-gamma expression, which has to be counterbalanced by other cytokines such as IL-12 and IL-10, especially towards the end of pregnancy. Although IFN-gamma is required to limit parasite proliferation a critical threshold of the IFN-gamma response is also required to limit adverse effects on pregnancy. In clinical terms, it may be stated that IFN-gamma production and cross-breed pregnancy can protect Neospora infected dairy cows against abortion. PMID- 28578089 TI - Virulence genes, Shiga toxin subtypes, major O-serogroups, and phylogenetic background of Shiga toxin-producing Escherichia coli strains isolated from cattle in Iran. AB - The aim of this study was to investigate the virulence potential of the isolated bovine STEC for humans in Iran. In this study a collection of STEC strains (n = 50) had been provided via four stages, including sampling from feces of cattle, E. coli isolation, molecular screening of Shiga toxin (stx) genes, and saving the STEC strains from various geographical areas in Iran. The STEC isolates were subjected to stx-subtyping, O-serogrouping, and phylo-grouping by conventional polymerase chain reaction (PCR). Occurrence of stx1 (52%) and stx2 (64%) was not significantly different (p = 0.1), and 16% of isolates carried both stx1 and stx2, simultaneously. In addition, 36% and 80% of the isolates were positive for eae and ehxA, respectively. Molecular subtyping showed that stx1a (52%), stx2a (44%), stx2c (44%), and stx2d (30%) were the most prevalent subtypes; two combinations stx2a/stx2c and stx2c/stx2d coexisted in 18% and 10% of STEC strains, respectively. Three important non-O157 serogroups, including O113 (20%), O26 (12%), and O111 (10%), were predominant, and none of the isolates belonged to O157. Importantly, one O26 isolate carried stx1, stx2, eae and ehxA and revealed highly virulent stx subtypes. Moreover, all the 21 serogrouped strains belonged to the B1 phylo-type. Our study highlights the significance of non-O157 STEC strains carrying highly pathogenic virulence genes in cattle population as the source of this pathogen in Iran. Since non-O157 STEC strains are not routinely tried in most diagnostic laboratories, majority of the STEC-associated human infections appear to be overlooked in the clinical settings. PMID- 28578090 TI - Genotyping, antimicrobial resistance and virulence factor gene profiles of vancomycin resistance Enterococcus faecalis isolated from blood culture. AB - BACKGROUND: Enterococcus spp. is the common of intestinal micro flora in humans but nowadays this gram-positive bacterium causes the variety of nosocomial infections. Resistance to antibiotic and also, presence of different virulence genes in the enterococcus spp. can change it to problematic microorganisms in the health care centers. The aim of this study was determined the genotyping, antimicrobial resistance and virulence factor gene profiles of vancomycin resistance Enterococcus faecalis isolated from blood culture. METHODS: In this study, enterococcus isolated from BACTEC was collected and antibiotic susceptibility testing was done according to CLSI recommendation. Important virulence genes and vancomyci resistance genes were detected by PCR and molecular typing was performed by RAPD PCR assay. RESULTS: Nine enterococcus collected from 194 positive BACTEC and seven out of nine were vancomycin-resistant enterococcus (VRE). vanA gene observed in all VRE and none of strains carried vanB and vanC genes. efbaA and gelE virulence factors have been detected in all strains. ace, esp, and cyl virulence factors genes harbored in two, seven and eight isolates respectively. asaI was not detected in any strains. All seven VRE isolates were related to the one specific molecular type and two different molecular types observed in the two vancomycin susceptible enterococci according to molecular epidemiology results. CONCLUSION: More prevalence of the VRE in enterococcus isolated from BACTEC is so important and on the other hand high genetic relationship in the isolated VRE can be very considerable for nosocomial infection committee in the hospital. PMID- 28578091 TI - In vitro assessment of Argemone mexicana, Taraxacum officinale, Ruta chalepensis and Tagetes filifolia against Haemonchus contortus nematode eggs and infective (L3) larvae. AB - Argemone mexicana, Taraxacum officinale, Ruta chalepensis and Tagetes filifolia are plants with deworming potential. The purpose of this study was to evaluate methanolic extracts of aerial parts of these plants against Haemonchus contortus eggs and infective larvae (L3) and identify compounds responsible for the anthelmintic activity. In vitro probes were performed to identify the anthelmintic activity of plant extracts: egg hatching inhibition (EHI) and larvae mortality. Open column Chromatography was used to bio-guided fractionation of the extract, which shows the best anthelmintic effect. The lethal concentration to inhibit 50% of H. contortus egg hatching or larvae mortality (LC50) was calculated using a Probit analysis. Bio-guided procedure led to the recognition of an active fraction (TF11) mainly composed by 1) quercetagitrin, 2) methyl chlorogenate and chlorogenic acid. Quercetagitrin (1) and methyl chlorogenate (2) did not show an important EHI activity (3-14%) (p < 0.05); however, chlorogenic acid (3) showed 100% of EHI (LC50 248 MUg/mL) (p < 0.05). Chlorogenic acid is responsible of the ovicidal activity and it seems that, this compound is reported for the first time with anthelmintic activity against a parasite of importance in sheep industry. PMID- 28578092 TI - Construction of human MASP-2-CCP1/2SP, CCP2SP, SP plasmid DNA nanolipoplexes and the effects on tuberculosis in BCG-infected mice. AB - The lectin pathway, one of the complement cascade systems, provides the primary line of defense against invading pathogens. The serine protease of MASP-2 plays an essential role in complement activation of the lectin pathway. The C-terminal segment of MASP-2 is comprised of the CCP1-CCP2-SP domains, and is the crucial catalytic segment. However, what is the effect of CCP1-CCP2-SP domains in controlling chronic infection is unknown. In order to evaluate the potential impact of CCP1-CCP2-SP domains on tuberculosis, we constructed the human MASP-2 CCP1/2SP, CCP2SP and SP recombinant plasmids, and delivered these plasmids by DNA DOTAP:cholesterol cationic nanolipoplexes to BCG-infected mice. After 21 days post DNA-DOTAP:chol nanolipoplexes application, we analyzed bacteria loads of pulmonary, pathology of granuloma, lymphocyte subpopulations. The C3a, C4a and MASP-2 levels in serum were measured with enzyme-linked immunosorbent assays. Compared to the control group that received GFP DNA-DOTAP:chol nanolipoplexes, MASP-2 CCP1/2SP DNA-DOTAP:chol nanolipoplexes treated group showed significantly enlarged pulmonary granulomas lesion (P < 0.05) and did not reduce bacteria loads in the lung tissue (P < 0.05). Furthermore, the levels of C3a in serum were decreased (P < 0.05), the number and percentage of PD1+ and Tim3+ cells subgroups were increased in BCG-infected mice after treated with MASP-2 CCP1/2SP DNA DOTAP:chol nanolipoplexes (P < 0.05). But, there was no statistical difference in the serum C4a and MASP-2 level among DNA nanolipoplexes treated groups (P > 0.05). These findings provided experimental evidence that MASP-2 CCP1/2SP DNA nanolipoplexes shown the negative efficacy in controlling Mycobacterium tuberculosis infection, and displayed a potential role of down-regulating T-cell mediated immunity in tuberculosis. PMID- 28578094 TI - Salmonella Heidelberg: Genetic profile of its antimicrobial resistance related to extended spectrum beta-lactamases (ESBLs). AB - The objective of this study was to evaluate the phenotypic and genotypic profile of antimicrobial susceptibility and the possible involvement of extended spectrum beta-lactamases (ESBLs) in the resistance profile of Salmonella Heidelberg (SH) isolated from chicken meat. We used 18 SH isolates from chicken meat produced in 2013 in the state of Parana, Southern Brazil. The isolates were submitted to disk diffusion tests and from these results it was possible to determine the number of isolates considered multiresistant and the index of multiple antimicrobial resistance (IRMA) against ten antimicrobials routinely used in human and veterinary medicine. It was considered multidrug resistant the isolate that showed resistance to three or more classes of antibiotics. Another test performed was the disc-approximation in order to investigate interposed zones of inhibition, indicative of ESBLs production. In the isolates that presented multidrug resistance (18/18), a search of resistance genes involved in the production of ESBLs was performed using PCR: blaCMY-2, blaSHV-1, blaTEM-1, blaCTX M2, blaOXA-1, blaPSE-1 and AmpC. The overall antimicrobial resistance was 80.55%. The highest levels of resistance were observed for nalidixic acid and ceftiofur (100%). The most commonly resistance pattern found (42.1%) was A (penicillin cephalosporin-quinolone-tetracycline). The results were negative for ghost zone formation, indicative of ESBLs. However, PCR technique was able to detect resistance genes via ESBLs where the blaTEM-1 gene showed the highest amplification (83.33%), and the second most prevalent genes were blaCMY-2 (38.88%) and AmpC gene (38.88%). The blaOXA-1 and blaPSE-1 genes were not detected. These results are certainly of concern since SH is becoming more prevalent in the South of Brazil and able to cause severe disease in immune compromised individuals, showing high antimicrobial resistance to those drugs routinely used in the treatment and control of human and animal salmonellosis. PMID- 28578093 TI - Direct bacterial loop-mediated isothermal amplification detection on the pathogenic features of the nosocomial pathogen - Methicillin resistant Staphylococcus aureus strains with respiratory origins. AB - Loop-mediated isothermal amplification based detection assays using bacterial culture or colony for direct detection of methicillin resistant Staphylococcus aureus(MRSA) had been developed and evaluated, followed by its extensive application on a large scale of clinical MRSA isolated from respiratory origins, including nasal swabs and sputums. Six primers, including outer primers, inner primers and loop primers, were specifically designed for recognizing eight distinct sequences on four targets: 16SrRNA, femA, mecA and orfX. Twenty-seven reference strains were used to develop, evaluate and optimize this assay. Then, a total of 532 clinical MRSA isolates were employed for each detected targets. And the results were determined through both visual observation of the color change by naked eye and electrophoresis. The specific of each primer had been confirmed, and the optimal amplification was obtained under 65 degrees C for 40 min. The limit of detections (LOD) of bacteria culture LAMP assays were determined to be 104 CFU/ml for 16S rRNA, femA, as well as orfX and 105 CFU/ml for mecA, respectively. The established novel assays on MRSA detection may provide new strategies for rapid detection of foodborne pathogens. PMID- 28578095 TI - Pseudohypophosphatemia associated with high-dose liposomal amphotericin B therapy. AB - BACKGROUND: Hypophosphatemia is commonly observed in critically ill patients. Inorganic phosphorus is quantified by spectrophotometric measurement of a phosphomolybdate complex, a method with multiple documented interferents. Our clinical laboratory was contacted to investigate a case of asymptomatic hypophosphatemia in a patient receiving high-dose liposomal amphotericin B therapy (L-AMB). METHODS: In vitro experiments were performed by spiking L-AMB into residual plasma specimens. Phosphate was measured on the Beckman Coulter AU and Ortho Diagnostics Vitros instruments. RESULTS: When measured on the AU, phosphate in plasma with approximately 250mcg/mL of L-AMB demonstrated a median negative bias of 3.45mg/dL relative to unspiked samples. In contrast, Vitros phosphate measurements demonstrated excellent agreement for specimens with and without L-AMB (median bias -0.2mg/dL). CONCLUSIONS: High L-AMB concentrations induced a significant negative bias on phosphate measured by the AU assay, but did not affect the Vitros assay. Laboratorians and clinicians should be aware of this phenomenon in patients receiving L-AMB who develop unexplained hypophosphatemia. PMID- 28578096 TI - Total hip arthroplasty revision by dual-mobility acetabular cup cemented in a metal reinforcement: A 62 case series at a minimum 5 years' follow-up. AB - INTRODUCTION: Total hip arthroplasty (THA) requires bone reconstruction in case of severe acetabular injury, with risk of dislocation, especially postoperatively. Dual-mobility cups have proved effective in preventing dislocation in THA revision for instability, but their behavior when cemented in a metal reinforcement has been little studied. OBJECTIVES: The present study assessed results for a dual-mobility cup cemented in a metal reinforcement, in terms of aseptic loosening and postoperative instability. MATERIAL AND METHODS: A single-center continuous series of 62 patients receiving such an assembly in THA revision was assessed retrospectively at a minimum 5 years' follow-up. Failure due to aseptic loosening or instability and implant survival at last follow-up were analyzed. RESULTS: Radiological and clinical analysis was performed at a mean 77 months' follow-up. Mean Merle-d'Aubigne-Postel score was 14, Harris score 73 and Oxford-12 score 23.9 at last follow-up. Complications comprised 5 cases of loosening and 2 of dislocation. Loosening risk was significantly greater in case of<2mm cement thickness between cup and reinforcement. Eight-year infection-free survival was 91.9%. DISCUSSION: The present clinical results were comparable to those in series using the same kind of assembly; the dislocation rate was low, but the rate of aseptic loosening was higher than reported elsewhere. Cement thickness between cup and reinforcement was a determining factor for stability. Cup design may also be relevant to loosening. This technique seemed to be a good option in THA revision with severe bone loss. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 28578097 TI - The concept of a waiting period for preoperative patient consent: Prospective study of 51 shoulder arthroscopy cases. AB - INTRODUCTION: The French Code of Public Health (CSP) does not explicitly require that patients should be given a certain amount of time to think about a procedure, except for cosmetic surgery, where 15 days is required (Art. L 6322-2 CSP). We hypothesized that patients require a waiting period during their decision-making process for scheduled shoulder arthroscopy procedure. MATERIALS AND METHODS: This prospective observational study of 51 patients analysed the concept of a waiting period based on a 10-item questionnaire. A comparative statistical approach was used and the P values were calculated using a paired Wilcoxon rank-sum test. RESULTS: Of the 51 patients, 42 (82%) rejected the concept of a waiting period before the procedure and 37 patients (73%) did not want a mandatory waiting period imposed by law. DISCUSSION: This study looked at the decision-making process during scheduled orthopaedic surgery and differentiated between the conscious and unconscious approach corresponding to an active and passive waiting period. A waiting period does not allow patients to make a conceptually deliberative decision that conforms to the criteria defined by the French Health Authority. This study rejects the need for a mandatory waiting period imposed on surgeons and patients as it does not integrate itself into the informative model of ethical decision-making for scheduled shoulder arthroscopy. TYPE OF STUDY: Prospective, observational; level of evidence IV. PMID- 28578098 TI - Hip-spine syndrome: A cadaveric analysis between osteoarthritis of the lumbar spine and hip joints. AB - BACKGROUND: Authors have recently proposed the concept of "hip-spine syndrome", however there exists limited evidence available to differentiate whether these concomitant arthritides are due to anatomic/structural causes, or systemic/metabolic effects. Exploring this relationship has important implications during the evaluation and treatment of both spine and hip disorders a common clinical presentation of many patients. The purpose of this experiment was to investigate the individual contribution of hip arthritis towards the development of spine arthritis, with knee arthritis also being analyzed as a negative (systemic) control. HYPOTHESIS: Hip and spine arthritis are caused by both metabolic and anatomic causes. METHODS: A large, well-organized osteological database was queried, and osteoarthritis of the spine, hip, and knee joints was quantified using a validated scoring criteria. Six hundred and twenty-five specimens were chosen for analysis. Multivariate linear regression models were created to quantify the independent contributions of age, gender, race, height, and arthritis of the spine and hip joints. RESULTS: Age was the strongest predictor of arthritis at each site (standardized betas>0.281, P<0.001 for all). Hip arthritis was a stronger predictor of spine arthritis than was knee arthritis (standardized betas 0.215 and 0.155, respectively, P<0.001 for both). Spine arthritis was also a stronger predictor of hip arthritis than was knee arthritis (standardized betas 0.232 and 0.173, P<0.001 for both). CONCLUSIONS: Anatomic/structural influences about the lumbosacral-pelvic junction contribute towards the development of arthritis that is separate from any systemic/metabolic effects. Surgeons performing total hip arthroplasty should remain aware of these relationships, although future research is necessary regarding optimal surgical treatment of these patients. LEVEL OF EVIDENCE: N/A (cadaveric study). PMID- 28578100 TI - Risk factors associated to bilateral rotator cuff tears. AB - INTRODUCTION: Overuse, micro-traumas, and impingement, isolated or combined, are the more common etiological factors for rotator cuff tears. Metabolic disorders (diabetes, adiposity, hypercholesterolemia), hypertension, cigarette smoking and a genetic predisposition are considered risk factors. However, no study has compared the prevalence of these risk factors in subjects with bilateral and monolateral tears. HYPOTHESIS: Controlateral tears can be observed in patients with symptomatic monolateral rotator cuff lesions, especially in those with comorbidities. MATERIAL AND METHODS: In patients with symptomatic rotator cuff tear, the controlateral shoulders were evaluated by means of ultrasound imaging. Age, BMI, diabetes, hypercholesterolemia, hypertension, cigarette smoking, work habits were registered. Risk factors in subjects with bilateral tears were compared with those with monolateral lesions. RESULTS: Of the 180 subjects recruited, 69 had a tear in the controlateral shoulder. Higher age and BMI values, heavy repetitive work and diabetes were significantly prevalent in these patients. At multivariate analysis, these factors were independently related to a higher probability to detect bilateral tears. DISCUSSION: Metabolic risk factors are more heavily involved in presence of bilateral rotator cuff tears, in comparison to monolateral. TYPE OF STUDY: Original study. LEVEL OF PROOF: IV. PMID- 28578101 TI - Nanoengineered silica: Properties, applications and toxicity. AB - Silica nanoparticles are widely used for biomedical purposes, but also in cosmetic products, food, the car industry, paints, etc. Considering their mega production, one should not ignore their potential hazardous effects on humans, flora and fauna. Human exposure to nanosilica can occur unintentionally in daily life and in industrial settings. Here, we review the common methods of silica nanoparticle production and its applications in biomedical investigations and nanotoxicology. The use of silica nanoparticles in biomedicine is discussed in terms of drug delivery, their responsiveness to different stimuli, theranostic applications and their uses in the food and cosmetic industries. Advantages and limitations of silica nanoparticles are presented and the effects of these nanoparticles are discussed in relation to their route of entry and impact on biochemical and epigenetic processes in human and animal cells. PMID- 28578099 TI - Free vascularised fibular flap harvesting in children: An analysis of donor-site morbidity. AB - BACKGROUND: The free vascularised fibular flap (FVFF) is widely used to treat bone defects, although it must be harvested from a healthy site. The objective of this study was to assess clinical morbidity and radiological changes at the FVFF donor site in children. HYPOTHESIS: Distal fibular stabilisation using a tibial strut decreases the prevalence of valgus ankle deformity. MATERIAL AND METHOD: Thirty-one children managed at two centres between 1994 and 2014 were included. Mean age was 8.9 years (range, 2-14 years) and mean follow-up was 6.6 years (range, 2-21 years). Early and delayed complications were evaluated. RESULTS: Of the 17 early complications, 82.4% resolved fully within 7 months. Valgus ankle deformity developed in 6 (19.4%) patients. Age-residual fibula index under 16 was not significantly associated with valgus ankle deformity, although the P-value was borderline (P<0.058). Residual distal fibula length did not predict valgus ankle deformity. Three techniques were used for fibular reconstruction: syndesmotic screw, tibial strut, and both. None of these techniques prevented the occurrence of valgus ankle deformity. DISCUSSION: Clinical donor-site morbidity after FVFF harvesting, although noticeable, usually resolved promptly. Taken alone, an age-residual fibula index under 16 did not predict valgus ankle deformity. We recommend a distal tibio-fibular quadricortical syndesmotic screw or combined syndesmotic screw-tibial strut fixation to prevent valgus ankle deformity, which is common when a tibial strut is used alone. LEVEL OF EVIDENCE: IV. PMID- 28578105 TI - Aberrant expression of beta-catenin in CD4+ T cells isolated from primary progressive multiple sclerosis patients. AB - Primary progressive multiple sclerosis (PP-MS) is a less common progressive form of MS in approximately 10% of patients that manifest increasingly neurological disability from disease onset. To date, there are no approved treatments for the progressive stage. Therefore, identifying new therapeutic targets could open a new opportunity for PP-MS management. Several lines of evidence suggest the critical role of the Wnt/beta-catenin pathway in immune-mediated diseases, like MS. This study was aimed to investigate whether aberrant expression of beta catenin is involved in PP-MS progression. By western blot analysis the expression of beta-catenin was evaluated in CD4+ cells purified from peripheral blood of PP MS patients. Specifically, nuclear expression of beta-catenin was detected in CD4+ T cells purified from peripheral blood lymphocytes of PP-MS, and not of other neuromuscular diseases. In addition, no relevant expression of Wnt-1 was found in PP-MS patients, suggesting that the increase in nuclear beta-catenin expression in these cells could be independent from canonical Wnt pathway. Taken together, our observations demonstrate that the deregulation of the beta-catenin expression is involved in CD4+ T cells of PP-MS patients. Therefore, inhibitors of beta-catenin pathway could be proposed as a promising candidate strategy for PP-MS cure. PMID- 28578104 TI - Assessing food allergy risks from residual peanut protein in highly refined vegetable oil. AB - Refined vegetable oils including refined peanut oil are widely used in foods. Due to shared production processes, refined non-peanut vegetable oils can contain residual peanut proteins. We estimated the predicted number of allergic reactions to residual peanut proteins using probabilistic risk assessment applied to several scenarios involving food products made with vegetable oils. Variables considered were: a) the estimated production scale of refined peanut oil, b) estimated cross-contact between refined vegetable oils during production, c) the proportion of fat in representative food products and d) the peanut protein concentration in refined peanut oil. For all products examined the predicted risk of objective allergic reactions in peanut-allergic users of the food products was extremely low. The number of predicted reactions ranged depending on the model from a high of 3 per 1000 eating occasions (Weibull) to no reactions (LogNormal). Significantly, all reactions were predicted for allergen intakes well below the amounts reported for the most sensitive individual described in the clinical literature. We conclude that the health risk from cross-contact between vegetable oils and refined peanut oil is negligible. None of the food products would warrant precautionary labelling for peanut according to the VITAL(r) programme of the Allergen Bureau. PMID- 28578103 TI - RIFM fragrance ingredient safety assessment, .alpha.-methylcyclohexylmethyl acetate, CAS Registry Number 13487-27-9. PMID- 28578106 TI - Investigating peri-limb interaction between nociception and vision using spatial depth. AB - In order to adapt behavior to a potentially body damaging threat, it is crucial to coordinate the perception of the location of the threat in external space and that of the location of the potential damage on the body surface. Such ability presupposes interactions between nociceptive stimuli and visual stimuli occurring close to the body. We hypothesized that these interactions would rely on multisensory representations of each limb itself, extending its boundaries slightly into external space, with less influence of the global representation of the body as a whole. In most studies investigating such representations, spatial organization of the somatic and extra-somatic stimuli is made according to an egocentric frame of reference centered on the main axes of the participant's whole body (e.g. the trunk), dissociating the left vs. the right side of space. Here, the contribution of such a body-centered frame was minimized, by placing participants' hands in front of them along their anteroposterior body axis, one at a proximal, the other at a distal location. They performed a temporal order judgment task on pairs of visual stimuli, one delivered close to each hand. Visual stimuli were preceded by nociceptive stimuli applied either on one hand, or on both hands simultaneously (control condition). Results showed that, as compared to the control condition, participants' judgements were biased in favor of the visual stimuli the closest to the stimulated hand, irrespective of their distance from the trunk. This finding supports the idea that the mechanisms underlying nociceptive-visual interactions are based on spatial representations that primarily use the stimulated limb rather than the whole body as a coordinate system. PMID- 28578102 TI - RIFM fragrance ingredient safety assessment, 2-tert-butylcyclohexanol, CAS Registry Number 13491-79-7. PMID- 28578108 TI - An interpenetrating, microstructurable and covalently attached conducting polymer hydrogel for neural interfaces. AB - : This study presents a new conducting polymer hydrogel (CPH) system, consisting of the synthetic hydrogel P(DMAA-co-5%MABP-co-2,5%SSNa) and the conducting polymer (CP) poly(3,4-ethylenedioxythiophene) (PEDOT), intended as coating material for neural interfaces. The composite material can be covalently attached to the surface electrode, can be patterned by a photolithographic process to influence selected electrode sites only and forms an interpenetrating network. The hybrid material was characterized using cyclic voltammetry (CV), impedance spectroscopy (EIS) and X-ray photoelectron spectroscopy (XPS), which confirmed a homogeneous distribution of PEDOT throughout all CPH layers. The CPH exhibited a 2,5 times higher charge storage capacity (CSC) and a reduced impedance when compared to the bare hydrogel. Electrochemical stability was proven over at least 1000 redox cycles. Non-toxicity was confirmed using an elution toxicity test together with a neuroblastoma cell-line. The described material shows great promise for surface modification of neural probes making it possible to combine the beneficial properties of the hydrogel with the excellent electronic properties necessary for high quality neural microelectrodes. STATEMENT OF SIGNIFICANCE: Conductive polymer hydrogels have emerged as a promising new class of materials to functionalize electrode surfaces for enhanced neural interfaces and drug delivery. Common weaknesses of such systems are delamination from the connection surface, and the lack of suitable patterning methods for confining the gel to the selected electrode site. Various studies have reported on conductive polymer hydrogels addressing one of these challenges. In this study we present a new composite material which offers, for the first time, the unique combination of properties: it can be covalently attached to the substrate, forms an interpenetrating network, shows excellent electrical properties and can be patterned via UV-irradiation through a structured mask. PMID- 28578109 TI - Reconstruction of Thoracic Spine Using a Personalized 3D-Printed Vertebral Body in Adolescent with T9 Primary Bone Tumor. AB - BACKGROUND: Neurosurgery and spine surgery have the potential to benefit from the use of 3-dimensional printing (3DP) technology due to complex anatomic considerations and the delicate nature of surrounding structures. We report a procedure that uses a 3D-printed titanium T9 vertebral body implant post T9 vertebrectomy for a primary bone tumor. CASE DESCRIPTION: A 14-year-old female presented with progressive kyphoscoliosis and a pathologic fracture of the T9 vertebra with sagittal and coronal deformity due to a destructive primary bone tumor. Surgical resection and reconstruction was performed in combination with a 3D-printed, patient-specific implant. Custom design features included porous titanium end plates, corrective angulation of the implant to restore sagittal balance, and pedicle screw holes in the 3D implant to assist with insertion of the device. In addition, attachment of the anterior column construct to the posterior pedicle screw construct was possible due to the customized features of the patient-specific implant. CONCLUSIONS: An advantage of 3DP is the ability to manufacture patient-specific implants, as in the current case example. Additionally, the use of 3DP has been able to reduce operative time significantly. Surgical procedures can be preplanned using 3DP patient-specific models. Surgeons can train before performing complex procedures, which enhances their presurgical planning in order to maximize patient outcomes. When considering implants and prostheses, the use of 3DP allows a superior anatomic fit for the patient, with the potential to improve restoration of anatomy. PMID- 28578107 TI - Simultaneous delivery of hydrophobic small molecules and siRNA using Sterosomes to direct mesenchymal stem cell differentiation for bone repair. AB - : The use of small molecular drugs with gene manipulation offers synergistic therapeutic efficacy by targeting multiple signaling pathways for combined treatment. Stimulation of mesenchymal stem cells (MSCs) with osteoinductive small molecule phenamil combined with suppression of noggin is a promising therapeutic strategy that increases bone morphogenetic protein (BMP) signaling and bone repair. Our cationic Sterosome formulated with stearylamine (SA) and cholesterol (Chol) is an attractive co-delivery system that not only forms stable complexes with small interfering RNA (siRNA) molecules but also solubilizes hydrophobic small molecules in a single vehicle, for directing stem cell differentiation. Herein, we demonstrate the ability of SA/Chol Sterosomes to simultaneously deliver hydrophobic small molecule phenamil and noggin-directed siRNA to enhance osteogenic differentiation of MSCs both in in vitro two- and three-dimensional settings as well as in a mouse calvarial defect model. These results suggest a novel liposomal platform to simultaneously deliver therapeutic genes and small molecules for combined therapy. STATEMENT OF SIGNIFICANCE: Application of phenamil, a small molecular bone morphogenetic protein (BMP) stimulator, combined with suppression of natural BMP antagonists such as noggin is a promising therapeutic strategy to enhance bone regeneration. Here, we present a novel strategy to co-deliver hydrophobic small molecule phenamil and noggin-targeted siRNA via cationic Sterosomes formed with stearylamine (SA) and high content of cholesterol (Chol) to enhance osteogenesis and bone repair. SA/Chol Sterosomes demonstrated high phenamil encapsulation efficiency, supported sustained release of encapsulated drugs, and significantly reduced drug dose requirements to induce osteogenic differentiation of mesenchymal stem cells (MSCs). Simultaneous deliver of phenamil and noggin siRNA in a single vehicle synergistically enhanced MSC osteogenesis and calvarial bone repair. This study suggests a new non phospholipid liposomal formulation to simultaneously deliver small molecules and therapeutic genes for combined treatment. PMID- 28578110 TI - Effects of Dexamethasone in the Treatment of Recurrent Chronic Subdural Hematoma. AB - OBJECTIVE: Recurrent chronic subdural hematoma (CSDH) is not rare. Some studies have demonstrated the role of dexamethasone in the medical management of chronic subdural hematoma. However, no systematic study in the treatment of recurrent CSDH has been published. The aim of our study is to evaluate the efficacy and safety of dexamethasone in patients with recurrent CSDH. METHODS: We retrospectively reviewed medical records of consecutive patients from July 2010 to September 2014. A total of 27 patients with symptomatic recurrent CSDH were included in the analysis. Follow-up for each patient consisted of computed tomography or magnetic resonance imaging every 28 days from admission to the resolution of hematoma. Data were collected on hematoma volume, complications, and outcome. RESULTS: Among the 27 patients, 3 patients with recurrent CSDH were only treated by burr hole surgery. Of the other 24 patients who primarily underwent dexamethasone treatment, 17 (70.8%) patients were treated successfully with medical treatment, whereas 7 patients required reoperation. Complications were noted in 3 (12.5%) patients (1 hyperglycemia, 1 urinary tract infection, and 1 pneumonia). There was 1 mortality (4.2%) for massive brain infarction. Twenty one of the 24 patients (87.5%) recovered to their previous functional levels. There was no statistical significance in Fisher text between surgery and dexamethasone regarding success, complication, and functional recovery rate. CONCLUSIONS: Patients with recurrent CSDH can be treated successfully and safely with the nonsurgical medical treatment of dexamethasone. By use of this method, reoperation may be avoided. PMID- 28578111 TI - Surgical Evacuation of Spontaneous Supratentorial Lobar Intracerebral Hemorrhage: Comparison of Safety and Efficacy of Stereotactic Aspiration, Endoscopic Surgery, and Craniotomy. AB - BACKGROUND: The safety and efficacy of craniotomy, endoscopic surgery, and stereotactic aspiration for surgical evacuation of spontaneous supratentorial lobar intracerebral hemorrhage (ICH) is yet uncertain. The present study analyzed the clinical and radiographic data from 99 patients with spontaneous supratentorial lobar ICH, retrospectively, to address this issue. METHODS: Patients who underwent craniotomy, endoscopy surgery, or stereotactic aspiration were assigned to the craniotomy group (n = 31), endoscopy surgery group (n = 32), or stereotactic aspiration group (n = 36), respectively. The characteristics of all the enrolled patients at the time of admission were assimilated. Also, the therapeutic effects of the three surgical procedures were evaluated based on short-term outcomes within 30 days and long-term outcomes at 6 months after the ictus. RESULTS: The results showed that stereotactic aspiration and endoscopic surgery were associated with a superior clinical therapeutic effect in both short term and long-term outcomes than craniotomy for the treatment of spontaneous supratentorial lobar ICH. Notably, severely affected patients with hematoma volume > 60 mL or Glasgow Coma Scale score 4-8 may benefit more from endoscopic surgery than the two other surgical procedures. CONCLUSIONS: The current findings demonstrate that both stereotactic aspiration and endoscopic surgery possess an apparent advantage over craniotomy for the evacuation of spontaneous supratentorial lobar ICH. The endoscopic surgery might be more safe and effective with higher evacuation rate, better functional neurological outcomes, and lower complication and mortality rates. PMID- 28578112 TI - The Neurosurgery Match: A Bibliometric Analysis of 206 First-Year Residents. AB - BACKGROUND AND OBJECTIVE: An important component of the residency application for neurosurgery is research experience and the subsequent number of produced publications. Bibliometrics research has been developed to establish quantitative methods for the standardization of publishing impactful research. This study aims to quantify the research productivity of medical students who successfully matriculated into a Neurosurgery residency program. METHODS: We initially identified first-year neurosurgery residents for the 2016-2017 academic year of all U.S. neurosurgical residency programs through departmental websites. The Scopus database was then queried for all articles published in the years 2006 to 2015 by first-year residents and bibliometric variables, such as publication count, journal impact factors, and author h-index, were extracted. The main outcome measured was residency program, tiered 1-5 by total departmental faculty research output. RESULTS: Two hundred six (206) Scopus records for first-year neurosurgery residents were identified in 99 programs nationwide. Multivariate ordinal regression demonstrated that only h-index was independently associated with tier of matriculation (P = 0.043). H-index was observed to strongly correlate with the number of original research articles (P = 0.005), years since first publication (P < 0.0001), and journal impact factor (P = 0.048) as assessed by multiple linear regression. Notably, h-index was observed to increase by approximately 1 point with every 3 original research articles (B = 0.368) and 4 years since first publication (B = 0.257). CONCLUSIONS: H-index is a powerful research predictor of matching into neurosurgical research institutions and can be improved by starting research early, targeting high impact journals, and participating in original clinical and laboratory investigations. PMID- 28578114 TI - Inside Vietnam's Largest Neurosurgery Department. AB - Cho Ray Hospital is the premier tertiary care center in Ho Chi Minh City, Vietnam's most populous city. The neurosurgical department was founded in 1958 and is currently one of the busiest in the world. Last year the department was responsible for more than 10,000 neurosurgical operations, excluding neuroendovascular cases. Most of the elective cases are craniotomies for complex lesions such as aneurysms, arteriovenous malformations, skull base tumors, gliomas, and meningiomas. Although the neurosurgeons within the department are technically gifted, doing more with less predominates as the mantra at Cho Ray Hospital. The necessity to minimize costs and the scarcity of resources creates many unique circumstances, some of which lag decades behind the rest of the world. Nonetheless, the progress and trajectory of the department has been impressive as the neurosurgical care provided to the Vietnamese public continues to improve. This article describes the current state and future direction of The Department of Neurological Surgery at Cho Ray Hospital. PMID- 28578113 TI - Safety of Percutaneous Dilatational Tracheostomy in Patients with Acute Brain Injury and Reduced PaO2/FiO2 Ratio-Retrospective Analysis of 54 Patients. AB - OBJECTIVE: Percutaneous dilatational tracheostomy (PDT) is a commonly performed method in neurocritical care, and its safety has been proven in numerous studies. Nevertheless, data regarding the application in patients with acute brain injury and poor respiratory function are poor. The purpose of this study was to evaluate the incidence of hypoxemia and hypercapnia during PDT in those patients. METHODS: In a retrospective analysis, we acquired data from 54 patients with an acute brain injury (ABI) and a reduced PaO2/FiO2 ratio (PaO2/FiO2 < 300 mm Hg). In all cases, blood gas analyses before, during, and approximately 12 hours after PDT were available. We reviewed the patients' ventilator settings, results of gas exchange, and radiographic signs of acute respiratory distress syndrome (ARDS). Patients with ARDS were defined using the Berlin criteria. RESULTS: We observed 2 cases (3.6%) of intraoperative hypoxemia (PaO2 < 60 mm Hg) and 4 cases (7.4%) of intraoperative hypercapnia (PaCO2 > 55 mm Hg). Twenty patients fulfilled the Berlin criteria for ARDS. While mean PaO2 did not differ significantly between ARDS and non-ARDS patients, intraoperative hypoxemia only occurred in the ARDS group (2/20). Mean PaCO2 was similar in the ARDS and non-ARDS groups, and cases of hypercapnia were apparent in both groups. The mean PaO2/FiO2 ratio of all patients improved from 229.1 mm Hg before PDT to 255.3 mm Hg. CONCLUSIONS: Regarding the intraoperative gas exchange, indication of PDT in patients with ABI and ARDS should be considered carefully. However, PDT in ABI patients with reduced PaO2/FiO2 ratio alone appears to be a safe procedure. PMID- 28578115 TI - Two-Dimensional High Definition Versus Three-Dimensional Endoscopy in Endonasal Skull Base Surgery: A Comparative Preclinical Study. AB - BACKGROUND AND OBJECTIVE: Three-dimensional (3D) endoscopy has been recently introduced in endonasal skull base surgery. Only a relatively limited number of studies have compared it to 2-dimensional, high definition technology. The objective was to compare, in a preclinical setting for endonasal endoscopic surgery, the surgical maneuverability of 2-dimensional, high definition and 3D endoscopy. METHODS: A group of 68 volunteers, novice and experienced surgeons, were asked to perform 2 tasks, namely simulating grasping and dissection surgical maneuvers, in a model of the nasal cavities. Time to complete the tasks was recorded. A questionnaire to investigate subjective feelings during tasks was filled by each participant. In 25 subjects, the surgeons' movements were continuously tracked by a magnetic-based neuronavigator coupled with dedicated software (ApproachViewer, part of GTx-UHN) and the recorded trajectories were analyzed by comparing jitter, sum of square differences, and funnel index. RESULTS: Total execution time was significantly lower with 3D technology (P < 0.05) in beginners and experts. Questionnaires showed that beginners preferred 3D endoscopy more frequently than experts. A minority (14%) of beginners experienced discomfort with 3D endoscopy. Analysis of jitter showed a trend toward increased effectiveness of surgical maneuvers with 3D endoscopy. Sum of square differences and funnel index analyses documented better values with 3D endoscopy in experts. CONCLUSIONS: In a preclinical setting for endonasal skull base surgery, 3D technology appears to confer an advantage in terms of time of execution and precision of surgical maneuvers. PMID- 28578116 TI - The Timed Up and Go Test as a Diagnostic Criterion in Normal Pressure Hydrocephalus. AB - INTRODUCTION: Normal-pressure hydrocephalus (NPH) is a disease characterized by gait disturbance, urinary incontinence, and dementia. Our objectives were to define an average value of the test for the population, check the specificity and test sensitivity as evaluation criteria and diagnostic testing, and correlate with other already used more frequently. METHODS: A study conducted at the Neurosurgery Division of the Hospital do Servidor Publico Estadual de Sao Paulo in which a group of 30 patients with NPH was submitted to the Mini-Mental State Test Examination, Time Up and Go (TUG), test and Japanese scale for NPH before the Tap Test 3 hours and 72 hours after the Tap Test. After being subjected to ventriculoperitoneal shunt, patients were evaluated 3 months, 6 months, and 12 months after surgery. A control group was used composed of 30 individuals of the same age and who had no diagnosis of NPH who were submitted to the TUG test to determine an average, which was compared with that of patients with NPH. RESULTS: TUG did not show good correlation with other tests used, but there was excellent specificity (0.967) and sensitivity (0.933) for cut-off value of 16.5 seconds for the diagnosis of NPH. CONCLUSIONS: TUG is a good test for the diagnosis of NPH because there is very good specificity and sensitivity, with a mean value of 16.5 seconds as the cut-off. PMID- 28578117 TI - Pipeline Embolization Device in Treatment of 50 Unruptured Large and Giant Aneurysms. AB - INTRODUCTION: Treatment of large (>=20 mm) and giant (>=25 mm) intracranial aneurysms is challenging and can be associated with a high rate of morbidity and mortality. The Pipeline Embolization Device (PED) has been used effectively for the treatment of intracranial aneurysms achieving a high rate of complete occlusion. However, its safety and efficacy in treatment of large and giant aneurysms has not been evaluated fully. METHODS: A retrospective analysis of consecutive aneurysms treated with PED between 2009 and 2016 at 3 academic institutions within the United States was performed. Large (>=20 mm) and giant aneurysms (>=25 mm) were selected for evaluation of occlusion and complication rates following treatment with PED. RESULTS: A total of 50 large and giant aneurysms were individually treated using PED. Aneurysms were fusiform (74%) or saccular (26%) in morphology. PED alone was used for treating 78% of the aneurysms, whereas PED with adjunctive coiling was used for treating 22%. The median length of angiographic follow-up was 13 months (mean follow up 20.4 months). At last follow-up, complete or near-complete occlusion (90-100%) was achieved in 76.9% of aneurysms. Symptomatic thromboembolic complications were encountered in 12% of procedures and symptomatic hemorrhagic complications in 8%. CONCLUSIONS: The use of PED for the treatment of large and giant intracranial aneurysms is associated with good occlusion rates, but also a greater complication rate compared to aneurysms of smaller size. There was no significant difference in occlusion rate based on aneurysm shape or size, number of PEDs placed, or adjunctive coiling. PMID- 28578118 TI - Clinical and Radiologic Outcomes After Fenestration and Partial Wall Excision of Idiopathic Intradural Spinal Arachnoid Cysts Presenting with Myelopathy. AB - BACKGROUND: Intradural spinal arachnoid cysts (ISACs) with associated neurologic deficits are encountered infrequently. Various management strategies have been proposed with minimal data on comparative outcomes. OBJECTIVE: We describe the clinical and radiologic presentation as well as the outcomes of 14 surgically managed patients who presented with an ISAC and associated myelopathy. METHODS: We retrospectively reviewed the clinical course of consecutive patients presenting with neurologic deficits associated with idiopathic ISACs at our institution. The diagnoses were based on preoperative magnetic resonance imaging studies followed by intraoperative and histopathological confirmation. RESULTS: A total of 14 consecutive patients with ISACs (1 cervicothoracic, 12 thoracic, and 1 thoracolumbar) and associated myelopathy were identified. Syringomyelia was noted in 8 patients. All ISACs were treated with cyst fenestration and partial wall resection through a posterior approach. Preoperative neurologic symptoms were noted to be stable or improved in all patients starting at 6-week postoperative follow-up. The median (interquartile range) preoperative mJOA score was 13 (12.0-14.8), whereas the postoperative median score at a mean follow-up of 22 months (range 6-50 months) was 16 (14.0-17.0), which represents a median improvement (DeltamJOA) of 2.0 (1.3-3.0) (P < 0.001). Comparison of DeltamJOA scores between cases without and with associated syrinxes did not reveal a significant difference (P = 0.23). Postoperative magnetic resonance imaging scans revealed spinal cord re-expansion at the level of the ISAC in all cases and either complete or partial syrinx resolution in 7 of 8 cases. CONCLUSIONS: Early treatment with fenestration and partial wall resection allows for cord decompression, syrinx resolution, and gradual resolution of myelopathic symptoms in most cases. PMID- 28578119 TI - Intracranial Aneurysm in Patients with Sickle Cell Disease: A Systematic Review. AB - BACKGROUND: Intracranial aneurysm in patients with sickle cell disease is rare, but with an increased incidence in the recent years. This type of intracranial aneurysm possesses distinctive characteristics, and it has been the subject of case reports and series. MATERIAL AND METHODS: We systematically searched relevant publications through PubMed, EMBASE, Web of Science, and Google Scholar up to December 21, 2016. We extracted data about clinical features and outcomes and then conducted a descriptive analysis. RESULTS: We identified 46 related publications, comprising 111 patients and 218 aneurysms. The mean age was 27 years (range, 5-54 years), and the male:female ratio was 0.96 (52:54). A male predominance existed in children, whereas a female predominance in adults. Age distribution approximated normal distribution, with peak phase between 21 and 30 years. In the child cohort, 13 of 31 (41.9%) aneurysms ruptured, whereas 62 of 79 (78.5%) aneurysms rupturing in the adult cohort. Aneurysms tended to be multiple (45.0%), small (85.6%), and saccular type (90.8%) and they exhibited a preference for posterior circulation (31.7%). Conservation and clipping became the main treatment in children and adults, respectively, but children had more good outcomes (80%) than adults did (67.1%). CONCLUSIONS: Intracranial aneurysms related to sickle cell disease mainly affected patients in their 20s, with a contradictory sex ratio in children and adults. Aneurysms manifested predisposition for multiplicity and posterior circulation. There was no difference between children and adults regarding shape and location of aneurysms. However, children with lower aneurysm rupturing rates had better outcomes than their adult counterparts did. PMID- 28578120 TI - Intraspinal Pressure Monitoring and Extensive Duroplasty in the Acute Phase of Traumatic Spinal Cord Injury: A Systematic Review. AB - OBJECTIVE: The prognosis in cervical spinal cord injury is poor, and surgical and neurointensive care management need further improvement. Monitoring of the intraspinal pressure (ISP) at an early stage after traumatic spinal cord injury (tSCI) is useful clinically. MATERIALS AND METHODS: Obtaining continuous spinal cord perfusion pressure (SCPP) measurements based on the difference between mean arterial pressure and ISP allows offering best medical and surgical treatment during this critical phase of tSCI. A search was carried out with PubMed, Embase, and Google Scholar up to January 10, 2017. Articles resulting from these searches and relevant references cited in those articles were reviewed. RESULTS: The optimal SCPP was found to be between 90 and 100 mm Hg and mean arterial pressure of 110-130. Laminectomy alone was found to be ineffective in the reduction of ISP because it does not lower the pressure exerted by dura on the swollen spinal cord. Therefore, bony decompression with durotomy or duroplasty seems to be the procedure of choice to reduce the ISP less than 20 mm Hg. CONCLUSIONS: A randomized controlled trial is required to determine whether laminectomy with durotomy and monitoring of ISP with SCPP optimization improve neurological recovery after tSCI. PMID- 28578122 TI - Hemimasticatory Spasm with a Single Venous Compression Treated with Microvascular Decompression of the Trigeminal Motor Rootlet. AB - BACKGROUND: Hemimasticatory spasm is a very rare disorder of the trigeminal motor rootlet that is characterized by a paroxysmal involuntary contraction of the jaw closing muscles. The mechanisms for hemimasticatory spasm remain unclear, and an efficient treatment strategy still needs to be developed. CASE DESCRIPTION: We report a case of a successful treatment of hemimasticatory spasm with single venous compression via microvascular decompression of the trigeminal motor rootlet. CONCLUSIONS: Our report shows that a single venous compression may be also responsible for idiopathic hemimasticatory spasm which can be cured by microvascular decompression. This is the first report on hemimasticatory compressed by a single vein in the world. PMID- 28578121 TI - Requirements for a Stable Long-Term Result in Surgical Reduction of Vertebral Fragility Fractures. AB - BACKGROUND: Osteoporotic vertebral fractures are one of the major health problems in the world. Minimally invasive surgical treatment has great advantages compared with conservative treatment in treating these fractures, because it eliminates pain and functional disability. The percutaneous intravertebral expandable titanium device SpineJack (Vexim SA, Balma, France) is beneficial compared with other kyphoplasty devices, showing results that are maintained over time and a reduction in complications. However, controversy exists about the minimum amount of cement that should be used to achieve long-term restoration and which is essential to minimize complications. We reviewed publications studying the maintenance of long-term restoration using this percutaneous expandable titanium device in cadavers. In this study, we show the first long-term work with patients treated with percutaneous expandable titanium device, describing precise indications concerning the minimum amount of cement that should be used. METHODS: Results were evaluated from a clinical study including 178 patient outcomes with long-term follow-up results performed by our team. RESULTS: The mean total quantity of cement injected was 4.4 mL (25% vertebral body filling). The leakage rate was 12.9%, and all of these occurrences were asymptomatic. The mean follow up time was 77 months (60-96 months). All clinical scales improved significantly after the procedure. A recollapse of the treated vertebra was observed in 3 cases (1.6%), and the adjacent fracture rate was 2.2%. CONCLUSIONS: From the results of our study and review of the literature, cement equivalent to 25% of the vertebral body filling volume, when combined with the titanium expandable device, seems to be sufficient to prevent recollapse in osteoporotic and type A.3 fractures. PMID- 28578123 TI - Outcome Evaluation of Patients with Limited Brain Metastasis From Malignant Melanoma, Treated with Surgery, Radiation Therapy, and Targeted Therapy. AB - OBJECTIVE: The incidence of brain metastases from melanoma is increasing. Several effective treatment options are now available but what can be considered the optimal therapeutic strategy is not yet defined. We evaluated the outcome of patients with brain metastatic melanoma in terms of local control rate, brain distant progression, and overall survival. METHODS: The present retrospective study includes only patients with limited brain metastases (<=4) who underwent surgery plus stereotactic radiosurgery (SRS), or SRS alone. Surgical resection was performed in patients with good Karnofsky performance score, single large brain lesions, controlled extracranial disease, and SRS alone in all other cases. Supramargical resection was performed in all patients. The prescribed radiotherapy doses were 24 Gy/1 fraction and 30 Gy in 3-5 fractions for lesions >2.5 cm. Clinical outcome was evaluated by brain magnetic resonance imaging performed 2 months after radiotherapy and then every 3 months. RESULTS: From April 2011 to October 2015, 53 patients were treated. The median age was 54 years (range, 29-82 years). Most of patients had 1-2 brain metastases (86.8%). Twelve patients (22.6%) underwent surgical resection followed by SRS on the tumor bed, and 41 (77.4%) received SRS alone. The median follow-up time was 20.9 months (range, 5.7-61.3 months). The median, 1-, 2-, 3-year overall survival were 11.8 months, 47.2%, 28%, and 21.8%, respectively. Factors recorded as influencing survival were the number of brain metastases, the melanoma-specific graded prognostic assessment score, and BRAF mutated status. CONCLUSIONS: Our data identifier a subset of patients with a more favorable outcome who could take advantage of a more aggressive local approach followed by targeted therapy. PMID- 28578124 TI - Influence of photodynamic therapy on peripheral immune cell populations and cytokine concentrations in head and neck cancer. AB - BACKGROUND: Photodynamic therapy (PDT) represents a palliative treatment option for a selected group of patients with head and neck squamous cell carcinoma (HNSCC). PDT induces a local inflammatory reaction with the potential to initiate antitumor immune responses. However, the systemic impact on peripheral immune cells has not been described so far. METHODS: HNSCC patients (n=9) were treated with PDT in a palliative setting. All patients had previously undergone several oncologic treatment regimens. Blood samples were taken before, during and after PDT. Age-matched healthy donors served as control group (NC, n=15). The frequency and absolute number of T- and B-lymphocytes, CD4+CD39+ regulatory T-cells (Treg) and NK-cells were measured by 10-color flow cytometry. Serum concentrations of T cell related cytokine panel, including HMGB1, IL-6, IL-10 and perforin were measured by bead array and ELISA. RESULTS: In heavily pretreated HNSCC patients, the number and frequency of Treg and NK-cells were increased as compared to NC. PDT induced a further increase of the frequency of Treg and NK-cells in the peripheral blood. Additionally, the serum concentrations of HMGB1, IL-6 and IL-10 showed a significant elevation after treatment with simultaneously decreased perforin levels. CONCLUSION: Although PDT is a local treatment regimen, a systemic inflammatory response with altered peripheral immune cell populations and cytokine concentrations is visible. The increased Treg and NK cell numbers after PDT support the hypothesis that PDT may successfully be combined with NK cell or T cell activating immune checkpoint modulators in HNSCC patients to improve HNSCC specific immunity. PMID- 28578125 TI - Efficient fluorescence detection of protoporphyrin IX in metastatic lymph nodes of murine colorectal cancer stained with indigo carmine. AB - Protoporphyrin IX (PpIX), a biochemical converted from 5-aminolevulinc acid (5 ALA) in living cells, is useful for intraoperative fluorescent detection of cancer metastasis in lymph nodes (LNs). However, unknown is whether the fluorescence of PpIX can be detected in the LNs when they coexist with indigo carmine, a blue dye commonly used for identification of sentinel LNs during surgery. To address this issue, we sought to evaluate the diagnostic usefulness of PpIX fluorescence in the presence of indigo carmine in a mouse LN metastasis model of rectal cancer after administration of 5-ALA. Spectral analysis of pure chemicals revealed that the absorption spectrum of indigo carmine widely overlapped with the fluorescence spectrum of PpIX specifically at the peak of 632nm, a common emission wavelength for detecting PpIX, but not at the other peak of 700nm. Due to such spectral overlap, the PpIX fluorescence intensity was significantly attenuated by mixture with indigo carmine at 632nm, but not at 700nm. Accordingly, fluorescent measurements of the mouse metastatic LN revealed more intense presentation of PpIX at 700nm than at 632nm, indicating that the diagnostic usefulness is greater at 700nm than at 632nm for the indigo carmine dyed LNs after administration of 5-ALA. From these observations, we propose that the fluorescence measurement is more efficient at 700nm than at 632nm for detection of PpIX in metastatic LNs stained with indigo carmine. PMID- 28578126 TI - Ultradeformable liposome loaded with zinc phthalocyanine and [Ru(NH.NHq)(tpy)NO]3+ for photodynamic therapy by topical application. AB - Ultradeformable liposomes (UDLs) as a drug delivery system (DDS), prepared from the unsaturated phospholipid, dioleylphosphocholine (DOPC), and containing the non-ionic surfactant Tween 20 as edge activator, have been explored as topical vehicles for zinc phthalocyanine (ZnPc) and the nitrosyl ruthenium complex [Ru(NH.NHq)(tpy)NO]3+ (RuNO) as a photosensitizers for co-generation of 1O2 and NO as reactive species, respectively. However, in order to ensure that ZnPc was present in the UDLs in its monomeric form - essential for maximal ZnPc photophysical properties - it was necessary to replace 40wt% of the DOPC with the saturated phospholipid, dimyristoylphosphocholine (DMPC). The resultant ZnPc and complex [Ru(NH.NHq)(tpy)NO]3+ containing UDLs were stable for at least a month when stored at 4 degrees C, six times more elastic/deformable than conventional liposome (c-Ls), i.e. liposome prepared using the same weight ratio of lipids but in the absence of Tween 20, and to significantly enhance the in vitro permeation of ZnPc across fresh pig ear skin. The UDLs DDS incorporating ZnPc and [Ru(NH.NHq)(tpy)NO]3+ were toxic (by the MTT assay) towards B16-F10 melanoma cells when irradiated with visible light at 670nm, the maximum absorption of ZnPc, and at a dose of 3.18J/cm2, but not when applied in the absence of light as expected. Based on these results it is proposed that the novel topical UDLs formulation developed is a suitable delivery vehicle for photodynamic therapy. PMID- 28578127 TI - Effects of Cordyceps militaris spent mushroom substrate on mucosal and serum immune parameters, disease resistance and growth performance of Nile tilapia, (Oreochromis niloticus). AB - The aim of present study was determination effects of dietary administration of C. militaris spent mushroom substrate (SMS) on mucosal and serum immune parameters, disease resistance, and growth performance of Nile tilapia (Oreochromis niloticus). Two hundred twenty five fish of similar weight (37.28 +/ 0.10 g) were assigned to the following diets [0 (T1- Control), 5 (T2), 10 (T3), 20 (T4) and 40 g kg-1 (T5) SMS]. After 60 days of feeding trial, growth performance, skin mucus lysozyme and peroxidase activities as well as serum innate immune were measured. In addition, survival rate and innate immune responses were calculated after challenge test (15 days) against Streptococcus agalactiae. The results revealed that regardless of inclusion levels, feeding Nile tilapia with SMS supplemented diets significantly increased skin mucus lysozyme and peroxidase activities as well as serum immune parameters (SL, ACH50, PI, RB, and RB) compared control group (P < 0.05). The highest increment of immune parameters was observed in fish fed 10 g kg-1 SMS which was significantly higher than other treatments (P < 0.05). Also, the relative percent survival (RSP) in T2, T3, T4, and T5 was 61.11%, 88.89%, 66.67, and 55.56%, respectively. Among the supplemented groups, fish fed 10 g kg-1 SMS showed significant higher RPS and resistance to S. agalactiae than other groups (P < 0.05). Regarding the growth performance, SGR, WG, FW, and FCR were remarkably improved (P < 0.05) in SMS groups; the highest improvement observed in 10 g kg-1 SMS treatment. According to these finding, administration of 10 g kg-1 SMS is suggested in tilapia to improve growth performance and health status. PMID- 28578128 TI - An ontologically consistent MRI-based atlas of the mouse diencephalon. AB - In topological terms, the diencephalon lies between the hypothalamus and the midbrain. It is made up of three segments, prosomere 1 (pretectum), prosomere 2 (thalamus), and prosomere 3 (the prethalamus). A number of MRI-based atlases of different parts of the mouse brain have already been published, but none of them displays the segments the diencephalon and their component nuclei. In this study we present a new volumetric atlas identifying 89 structures in the diencephalon of the male C57BL/6J 12 week mouse. This atlas is based on an average of MR scans of 18 mouse brains imaged with a 16.4T scanner. This atlas is available for download at www.imaging.org.au/AMBMC. Additionally, we have created an FSL package to enable nonlinear registration of novel data sets to the AMBMC model and subsequent automatic segmentation. PMID- 28578129 TI - Assessing dynamic functional connectivity in heterogeneous samples. AB - Several methods have been developed to measure dynamic functional connectivity (dFC) in fMRI data. These methods are often based on a sliding-window analysis, which aims to capture how the brain's functional organization varies over the course of a scan. The aim of many studies is to compare dFC across groups, such as younger versus older people. However, spurious group differences in measured dFC may be caused by other sources of heterogeneity between people. For example, the shape of the haemodynamic response function (HRF) and levels of measurement noise have been found to vary with age. We use a generic simulation framework for fMRI data to investigate the effect of such heterogeneity on estimates of dFC. Our findings show that, despite no differences in true dFC, individual differences in measured dFC can result from other (non-dynamic) features of the data, such as differences in neural autocorrelation, HRF shape, connectivity strength and measurement noise. We also find that common dFC methods such as k means and multilayer modularity approaches can detect spurious group differences in dynamic connectivity due to inappropriate setting of their hyperparameters. fMRI studies therefore need to consider alternative sources of heterogeneity across individuals before concluding differences in dFC. PMID- 28578132 TI - Effect of electro-activated aqueous solutions, nisin and moderate heat treatment on the inactivation of Clostridium sporogenes PA 3679 spores in green beans puree and whole green beans. AB - In this work, the synergistic effect of electro-activated solutions (EAS) of potassium acetate and potassium citrate, nisin and moderate heat treatment to inactivate C. sporogenes PA 3679 spores was evaluated in green beans puree and whole green beans. Electro-activated solutions (EAS) of potassium acetate and potassium citrate were generated under 400 mA during 60 min. They were characterized by an oxidation-reduction potential (ORP) and pH values ranged from +300 to +1090 mV and 2.8 to 3.67, respectively. Moreover, the EAS were combined with a bacteriocin nisin at concentrations of 250, 500, 750 and 1000 IU/mL and the targeted sporicidal effect was evaluated under moderate heat treatment. The inoculated mixtures were subjected to temperatures of 95, 105 and 115 degrees C for exposure times of 5, 15 and 30 min. After plate counting, the synergistic effect of the hurdle principle composed of electro-activated solutions, nisin and moderate temperatures was demonstrated. The obtained results showed that the synergistic effect of the used hurdle was able to achieve an inactivation efficacy of 5.9-6.1 log CFU/mL. Furthermore, experiments carried out with whole green beans showed that spore inactivation level was significantly higher and reach 6.5 log CFU/mL. Moreover, spore morphology was examined by transmission electron microscopy and the obtained micrographs showed important damages in all of the treated spores. PMID- 28578131 TI - Predicting behavior change from persuasive messages using neural representational similarity and social network analyses. AB - Neural activity in medial prefrontal cortex (MPFC), identified as engaging in self-related processing, predicts later health behavior change. However, it is unknown to what extent individual differences in neural representation of content and lived experience influence this brain-behavior relationship. We examined whether the strength of content-specific representations during persuasive messaging relates to later behavior change, and whether these relationships change as a function of individuals' social network composition. In our study, smokers viewed anti-smoking messages while undergoing fMRI and we measured changes in their smoking behavior one month later. Using representational similarity analyses, we found that the degree to which message content (i.e. health, social, or valence information) was represented in a self-related processing MPFC region was associated with later smoking behavior, with increased representations of negatively valenced (risk) information corresponding to greater message-consistent behavior change. Furthermore, the relationship between representations and behavior change depended on social network composition: smokers who had proportionally fewer smokers in their network showed increases in smoking behavior when social or health content was strongly represented in MPFC, whereas message-consistent behavior (i.e., less smoking) was more likely for those with proportionally more smokers in their social network who represented social or health consequences more strongly. These results highlight the dynamic relationship between representations in MPFC and key outcomes such as health behavior change; a complete understanding of the role of MPFC in motivation and action should take into account individual differences in neural representation of stimulus attributes and social context variables such as social network composition. PMID- 28578130 TI - Optimal use of EEG recordings to target active brain areas with transcranial electrical stimulation. AB - To demonstrate causal relationships between brain and behavior, investigators would like to guide brain stimulation using measurements of neural activity. Particularly promising in this context are electroencephalography (EEG) and transcranial electrical stimulation (TES), as they are linked by a reciprocity principle which, despite being known for decades, has not led to a formalism for relating EEG recordings to optimal stimulation parameters. Here we derive a closed-form expression for the TES configuration that optimally stimulates (i.e., targets) the sources of recorded EEG, without making assumptions about source location or distribution. We also derive a duality between TES targeting and EEG source localization, and demonstrate that in cases where source localization fails, so does the proposed targeting. Numerical simulations with multiple head models confirm these theoretical predictions and quantify the achieved stimulation in terms of focality and intensity. We show that constraining the stimulation currents automatically selects optimal montages that involve only a few (4-7) electrodes, with only incremental loss in performance when targeting focal activations. The proposed technique allows brain scientists and clinicians to rationally target the sources of observed EEG and thus overcomes a major obstacle to the realization of individualized or closed-loop brain stimulation. PMID- 28578134 TI - Investigation of copy number variation in subjects with major depression based on whole-genome sequencing data. AB - BACKGROUND: Despite recent intensive research using genome-wide association studies, the underlying biological basis of major depressive disorder (MDD) still remains unknown. In contrast to genotyping platforms which identify specific variations, whole-genome sequencing (WGS) allows us to detect all private genetic variations within an individual. So far there have been no studies investigating copy number variations (CNVs) in subjects with MDD using WGS data. METHODS: We obtained complete WGS paired-end reads data of 15 MDD patients and 10 ethnically matched healthy controls. We performed alignments for the sequencing reads and used GASV package to call CNVs including deletion, inversion, translocation and divergence for those subjects. RESULTS: Our results show that, in the Mexican American sample, deletion CNVs were significantly richer in MDD cases than healthy controls on each of 23 chromosomes. However, other types of CNVs failed to reach any significance. In the Australian sample, there was no statistically significant difference of CNVs between MDD cases and controls. Furthermore, we found that the Australian group had significantly more deletion CNVs than the Mexican-American group. LIMITATIONS: High quality WGS costs limited obtaining larger datasets. The GASV package does not currently support duplication or insertion CNVs. CONCLUSIONS: To our knowledge this is the first time that CNVs detected by WGS data are used to study major depression. The conclusion that deletion CNVs are significantly richer in MDD cases than healthy controls is consistent with the previous finding about recurrent depressive disorder by genome-wide association analysis of CNVs on a large genotyping microarray data. PMID- 28578133 TI - Extraintestinal Clostridium difficile infection due to a ribotype different from that isolated from the feces of the patient: A case report. AB - Extraintestinal infections due to Clostridium difficile are uncommon. When such infections occur, extraintestinal C. difficile isolates are usually identical to fecal isolates. We present a rare case of a large postoperative abscess caused by C. difficile infection, in which different C. difficile strains were isolated from the abscess and from feces of the patient. An 82-year-old woman with cutaneous polyarteritis nodosa developed pain, skin ulcers, and extensive necrosis of the right leg. Above-knee amputation was performed without stopping antiplatelet therapy, leading to postoperative hematoma. Six weeks after surgery, a large femoral abscess was detected and C. difficile was isolated. Repeat amputation of the thigh was required to remove the abscess. C. difficile was also cultured from feces despite the lack of intestinal symptoms. However, genetic analysis confirmed that the C. difficile isolates from the abscess and feces were different strains. Thus, C. difficile can cause postoperative infection of a hematoma and the extraintestinal and fecal C. difficile isolates are not necessarily identical in the same patient. PMID- 28578136 TI - Interval setting selection affects ambulatory activity outputs in children with cerebral palsy. AB - INTRODUCTION: Accelerometer based devices have been widely used to assess the ambulatory activity of children with and without functional disabilities. Many researchers who utilize the StepWatch Activity Monitor (SAM) collect at a 60second (60sec) interval setting. The purpose of this study was to assess the effect of SAM interval settings on ambulatory activity outputs in children with cerebral palsy (CP) and typically developing youth. METHODS: Participants wore a SAM which recorded the number of strides every 10seconds (10s) for one week. Raw 10s data was downsampled to combine strides into 60sec intervals. Strides were ensembled into walking bouts with the Intensity/Duration calculated as a percentage of Total Ambulatory Time (TAT). RESULTS: Twenty-eight children with CP (14 boys; avg. 12 yrs. 4 mths.; GMFCS Level I n=4, Level II n=19, Level III n=5) completed testing and 28 age matched typically developing youth (14 boys; avg. 12 yrs. 6 mths.) were included. Using the 10sec interval, ~80% of walking bouts in both groups were less than or equal to 60s. Data recorded at 60sec intervals had higher daily TAT but fewer walking bouts. In children with CP, daily steps were higher using the 60sec interval. At the Easy intensity, the 60sec interval reported an increased volume of Long duration walking, and it rarely identified any Moderate+ intensity activity. CONCLUSIONS: 60sec interval data overestimated low intensity and long duration ambulatory activity. It is imperative that investigators choose a finer interval setting (10sec) to maximize the detection of gait transitions and rest periods which are critical in describing community ambulation of patients with cerebral palsy. PMID- 28578135 TI - Oxylipin mediated stress response of a miraculin-like protease inhibitor in Hexanoic acid primed eggplant plants infested by Colorado potato beetle. AB - Insect-plant interactions are governed by a complex equilibrium between the mechanisms through which plant recognize insect attack and orchestrate downstream signaling events that trigger plant defense responses, and the mechanisms by which insects overcome plant defenses. Due to this tight and dynamic interplay, insight into the nature of the plant defense response can be gained by analyzing changes in the insect herbivores digestive system upon plant feeding. In this work we have identified a Solanum melongena miraculin-like protease inhibitor in the midgut juice of Colorado potato larvae feeding on eggplant plants treated with the natural inducer of plant defenses hexanoic acid. We analyzed the corresponding gene expression by qRT-PCR and our results showed that this eggplant miraculin-like gene enhanced induction contributes to the hexanoic acid priming effect in this Solanaceae species. Moreover, our data evidencing that OPDA might be involved in this gene regulation highlights its potential as biomarker in eggplant plant responses to stress mediated this oxylipin signaling pathway. PMID- 28578137 TI - A pilot study of physical activity and sedentary behavior distribution patterns in older women. AB - The study aims were to investigate free-living physical activity and sedentary behavior distribution patterns in a group of older women, and assess the cross sectional associations with body mass index (BMI). Eleven older women (mean (SD) age: 77 (9) yrs) wore custom-built activity monitors, each containing a tri-axial accelerometer (+/-16g, 100Hz), on the waist and ankle for lab-based walking trials and 4 days in free-living. Daily active time, step counts, cadence, and sedentary break number were estimated from acceleration data. The sedentary bout length distribution and sedentary time accumulation pattern, using the Gini index, were investigated. Associations of the parameters' total daily values and coefficients of variation (CVs) of their hourly values with BMI were assessed using linear regression. The algorithm demonstrated median sensitivity, positive predictive value, and agreement values >98% and <1% mean error in cadence calculations with video identification during lab trials. Participants' sedentary bouts were found to be power law distributed with 56% of their sedentary time occurring in 20min bouts or longer. Meaningful associations were detectable in the relationships of total active time, step count, sedentary break number and their CVs with BMI. Active time and step counts had moderate negative associations with BMI while sedentary break number had a strong negative association. Active time, step count and sedentary break number CVs also had strong positive associations with BMI. The results highlight the importance of measuring sedentary behavior and suggest a more even distribution of physical activity throughout the day is associated with lower BMI. PMID- 28578138 TI - Static and dynamic validation of inertial measurement units. AB - Optical motion capture systems are used to assess human motion. While these systems provide a reliable analysis, they limit collection to a laboratory based setting. Devices such as Inertial Measurement Units (IMUs) have been developed as alternative tools. Commercially available IMUs are utilized for a variety of applications; however limited work has been done to determine the reliability of these devices. The objective of this study was to assess the accuracy and precision of a commercially available IMU, containing tri-axial accelerometers, gyroscopes, and magnetometers, under controlled static and dynamic conditions. The sensor output was validated against the gold standard measures of custom made mechanical testing apparatuses. The IMUs provide an accurate (within 0.6 degrees ) and precise (within 0.1 degrees ) measurement of static sensor orientation and an accurate (within 4.4 degrees per second) and precise (within 0.2 degrees per second) representation of angular velocity. The sensors are more accurate at lower velocities, but the percent error remains relatively constant across all angular velocities. Inclusion of IMUs as an appropriate measurement tool should be based on the application, specific demands and necessary reliability. PMID- 28578139 TI - Altered leverage around the ankle in people with diabetes: A natural strategy to modify the muscular contribution during walking? AB - Diabetes patients display gait alterations compared to controls including a higher metabolic cost of walking. This study aimed to investigate whether differences in external moment arm (ExtMA) and effective mechanical advantage (EMA) at the ankle in diabetes patients could partly explain the increased cost of walking compared to controls. Thirty one non-diabetic controls (Ctrl); 22 diabetes patients without peripheral neuropathy (DM) and 14 patients with moderate/severe diabetic peripheral neuropathy (DPN) underwent gait analysis using a motion analysis system and force plates. The internal Achilles tendon moment arm length was determined using magnetic resonance imaging during weight bearing and ExtMA was calculated using gait analysis. A greater value (P<0.01) for the EMA at the ankle was found in the DPN (0.488) and DM (0.46) groups compared to Ctrl (0.448). The increased EMA was mainly caused by a smaller ExtMA in the DPN (9.63cm; P<0.01) and DM (10.31cm) groups compared to Ctrl (10.42cm) These findings indicate that the ankle plantarflexor muscles would need to generate lower forces to overcome the external resistance during walking compared to controls. Our findings do not explain the previously observedhigher metabolic cost of walking in the DM and DPN groups, but uncover a new mechanism through which patients with diabetes and particularly those with DPN reduce the joint moment at the ankle during walking: by applying the ground reaction force more proximally on the foot, or at an angle directed more towards the ankle, thereby increasing the EMA and reducing the ankle joint moment. PMID- 28578140 TI - Effectiveness of an innovative hip energy storage walking orthosis for improving paraplegic walking: A pilot randomized controlled study. AB - BACKGROUND: The high energy cost of paraplegic walking using a reciprocating gait orthosis (RGO) is attributed to limited hip motion and excessive upper limb loading for support. To address the limitation, we designed the hip energy storage walking orthosis (HESWO) which uses a spring assembly on the pelvic shell to store energy from the movements of the healthy upper limbs and flexion extension of the lumbar spine and hip and returns this energy to lift the pelvis and lower limb to assist with the swing and stance components of a stride. Our aim was to evaluate gait and energy cost indices for the HESWO compared to the RGO in patients with paraplegia. METHODS: The cross-over design was used in the pilot study. Twelve patients with a complete T4-L5 chronic spinal cord injury underwent gait training using the HESWO and RGO. Gait performance (continuous walking distance, as well as the maximum and comfortable walking speeds) and energy expenditure (at a walking speed of 3.3m/min on a treadmill) were measured at the end of the 4-week training session. RESULTS: Compared to the RGO, the HESWO increased continuous walking distance by 24.7% (P<0.05), maximum walking speed by 20.4% (P<0.05) and the comfortable walking speed by 15.3% (P<0.05), as well as decreasing energy expenditure by 13.9% (P<0.05). CONCLUSION: Our preliminary results provide support for the use of the HESWO as an alternative support for paraplegic walking. PMID- 28578141 TI - Physiologic correlates of intraoperative blood transfusion among patients undergoing major gastrointestinal operations. AB - BACKGROUND: Guidelines for transfusion focus on nadir levels of hemoglobin. Hemoglobin triggers may not be helpful, however, in defining appropriate intraoperative use of packed red blood cells. We sought to define the use of intraoperative packed red blood cells relative to quantitative physiologic factors at the time of operation. METHODS: Prospective intraoperative data on patients undergoing a major gastrointestinal operation between 2010 and 2014 were analyzed. Risk of intraoperative transfusion was assessed with multivariable extended Cox models using baseline clinical covariates and time-varying intraoperative covariates. RESULTS: Among 2,316 patients, the mean preoperative hemoglobin was 12.6 g/dL (standard deviation = 2.0 g/dL), while the median estimated blood loss was 200 mL (interquartile range: 100-55 mL). Overall, 357 (15.4%) patients received a transfusion intraoperatively. A greater hazard of transfusion was associated with a greater American Society of Anesthesiologists class (ref: American Society of Anesthesiologists class I-II; American Society of Anesthesiologists class III-IV; hazard ratio = 1.44, 95% confidence interval, 1.18-1.77, P < .001), and a lesser preoperative hemoglobin level (per 1 g/dL increase; hazard ratio = 0.70, 95% confidence interval, 0.65-0.74, P < .001). In addition, an increase in heart rate of 10 beats/min above the cumulative average at any measurement was associated with up to a 30% increased probability of transfusion (hazard ratio = 1.30, 95% confidence interval, 1.15-1.47, P < .001); similarly, an increase in mean arterial pressure of 10 mm Hg was associated with an 8% decreased likelihood of transfusion (hazard ratio = 0.92, 95% confidence interval, 87-0.99, P = .017). In contrast, nadir hemoglobin was not associated with the risk of receiving a transfusion (hazard ratio = 1.10, 95% confidence interval, 0.97-1.23, P = .129). Among patients who received an intraoperative transfusion, 9.2% (n = 33) never had a hemoglobin nadir below 10 g/dL, nor an average mean arterial pressure less than 65 mm Hg or a heart rate greater than 100 beats/min around the time of transfusion. CONCLUSION: Among the intraoperative factors, heart rate, and mean arterial pressure were strongly associated with the likelihood of receiving a transfusion, despite the observation that 9.2% of patients never had a physiologic indicator for transfusion or a nadir hemoglobin below 10 g/dL, suggesting a subset of patients could benefit from a decrease in intraoperative rate of transfusion. PMID- 28578143 TI - Effect of seasonality and Cr(VI) on starch-sucrose partitioning and related enzymes in floating leaves of Salvinia minima. AB - Effects of seasonality and increasing Cr(VI) concentrations on leaf starch sucrose partitioning, sucrose- and starch-related enzyme activities, and carbon allocation toward leaf development were analyzed in fronds (floating leaves) of the floating fern Salvinia minima. Carbohydrates and enzyme activities of Cr exposed fronds showed different patterns in winter and summer. Total soluble sugars, starch, glucose and fructose increased in winter fronds, while sucrose was higher in summer ones. Starch and soluble carbohydrates, except glucose, increased under increasing Cr(VI) concentrations in winter fronds, while in summer ones only sucrose increased under Cr(VI) treatment. In summer fronds starch, total soluble sugars, fructose and glucose practically stayed without changes in all assayed Cr(VI) concentrations. Enzyme activities related to starch and sucrose metabolisms (e.g. ADPGase, SPS, SS and AI) were higher in winter fronds than in summer ones. Total amylase and cFBPase activities were higher in summer fronds. Cr(VI) treatment increased enzyme activities, except ADPGase, in both winter and summer fronds but no clear pattern changes were observed. Data of this study show clearly that carbohydrate metabolism is differently perturbed by both seasonality and Cr(VI) treatment in summer and winter fronds, which affects leaf starch-sucrose partitioning and specific leaf area (SLA) in terms of carbon investment. PMID- 28578142 TI - Impact of lymph node ratio in selecting patients with resected gastric cancer for adjuvant therapy. AB - BACKGROUND: The impact of adjuvant chemotherapy and chemo-radiation therapy in the treatment of resectable gastric cancer remains varied. We sought to define the clinical impact of lymph node ratio on the relative benefit of adjuvant chemotherapy or chemo-radiation therapy among patients having undergone curative intent resection for gastric cancer. METHODS: Using the multi-institutional US Gastric Cancer Collaborative database, 719 patients with gastric adenocarcinoma who underwent curative-intent resection between 2000 and 2013 were identified. Patients with metastasis or an R2 margin were excluded. The impact of lymph node ratio on overall survival among patients who received chemotherapy or chemo radiation therapy was evaluated. RESULTS: Median patient age was 65 years, and the majority of patients were male (56.2%). The majority of patients underwent either subtotal (40.6%) or total gastrectomy (41.0%), with the remainder undergoing distal gastrectomy or wedge resection (18.4%). On pathology, median tumor size was 4 cm; most patients had a T3 (33.0%) or T4 (27.9%) lesion with lymph node metastasis (59.7%). Margin status was R0 in 92.5% of patients. A total of 325 (45.2%) patients underwent resection alone, 253 (35.2%) patients received 5-FU or capecitabine-based chemo-radiation therapy, whereas the remaining 141 (19.6%) received chemotherapy. Median overall survival was 40.9 months, and 5 year overall survival was 40.3%. According to lymph node ratio categories, 5-year overall survival for patients with a lymph node ratio of 0, 0.01-0.10, >0.10 0.25, >0.25 were 54.1%, 53.1 %, 49.1 % and 19.8 %, respectively. Factors associated with worse overall survival included involvement of the gastroesophageal junction (hazard ratio 1.8), T-stage (3-4: hazard ratio 2.1), lymphovascular invasion (hazard ratio 1.4), and lymph node ratio (>0.25: hazard ratio 2.3; all P < .05). In contrast, receipt of adjuvant chemo-radiation therapy was associated with an improved overall survival in the multivariable model (versus resection alone: hazard ratio 0.40; versus chemotherapy: hazard ratio 0.45, both P < .001). The benefit of chemo-radiation therapy for resected gastric cancer was noted only among patients with lymph node ratio >0.25 (versus resection alone: hazard ratio R 0.34; versus chemotherapy: hazard ratio 0.45, both P < .001). In contrast, there was no noted overall survival benefit of chemotherapy or chemo-radiation therapy among patients with lymph node ratio <=0.25 (all P > .05). CONCLUSION: Adjuvant chemotherapy or chemo-radiation therapy was utilized in more than one-half of patients undergoing curative-intent resection for gastric cancer. Lymph node ratio may be a useful tool to select patients for adjuvant chemo-radiation therapy, because the benefit of chemo radiation therapy was isolated to patients with greater degrees of lymphatic spread (ie, lymph node ratio >0.25). PMID- 28578144 TI - Role of PI3K/AKT/mTOR signaling pathway in DBP-induced apoptosis of testicular sertoli cells in vitro. AB - Dibutyl phthalate (DBP) has significant male reproductive toxicity, and the Sertoli cells are the target cells of DBP. This study was to investigate the injury effect induced by DBP on rat testicular Sertoli cells in vitro. MTT results showed that DBP can significantly reduce the survival rate of Sertoli cells; Hoechst staining results showed that the Sertoli cells treated with DBP emerged with typical morphological characteristics of apoptosis, nuclear condensation and chromatin condensation; flow cytometry results showed that DBP significantly increased the apoptotic rate of Sertoli cells, and dose-dependent; Western blotting showed that the expression of PTEN protein in Sertoli cells was significantly higher than that in the control group after treated with different concentrations of DBP for 24h, while the expression of p-PI3K1, p-AKT, p70S6K and 4E-BP1 protein in the PI3K/AKT/mTOR signal pathway were significantly decreased. It is speculated that PTEN/PI3K/AKT/mTOR signaling pathway plays an important role in DBP-induced apoptosis of testicular Sertoli cells in rats. PMID- 28578145 TI - Contraceptive prescriptions for US servicewomen, 2008-2013. AB - OBJECTIVE: To determine the proportion and characteristics of US servicewomen who were prescribed contraception between 2008 and 2013 and to estimate the prevalence of contraceptive utilization among women who deployed during the surveillance period. STUDY DESIGN: This is a descriptive study of all servicewomen of child-bearing potential serving in the active component of the US armed forces at any time between 2008 and 2013. We estimated contraceptive utilization status using pharmacy, procedural and diagnostic codes as recorded in the Defense Medical Surveillance System and Pharmacy Data Transaction Service. Estimates of contraceptive utilization were compared by demographic and military variables, including deployment status. Poisson regression with robust error variance was used to estimate adjusted prevalence ratios and 95% confidence intervals. RESULTS: Among eligible servicewomen (N=375,847), 68.7% received at least one form of contraception during the surveillance period. Contraceptive methods included short acting only (55.6%), long-acting (11.9%), permanent (1.0%) and barrier methods (0.2%). An additional 8.2% received counseling services only without an associated procedure or prescription. After adjusting by several demographic variables, receipt of contraception was highest among women aged 25 29 years and lowest among those aged 17-19 and 45-49 years. Receipt of any contraception was similar across racial/ethnic groups, although Hispanic and black, non-Hispanic women were more likely to receive long-acting reversible contraception. Of those who deployed (N=131,597), 53.6% received contraception before or during their deployment, with 7.9% using long-acting contraception. CONCLUSION: US servicewomen utilize contraception at high levels, with few demographic disparities. Gaps still exist, especially among the youngest women and around the time of deployment. IMPLICATIONS: US servicewomen are prescribed contraception at high levels, but utilization is lower in the youngest servicewomen and around the time of deployment. Such data provide opportunities for development and evaluation of interventions designed to improve access to contraceptive services for all servicewomen and to reduce the rate of unintended pregnancy. PMID- 28578146 TI - Use of clinical performance measures for contraceptive care in Iowa, 2013. AB - OBJECTIVES: To assess feasibility of calculating clinical performance measures for contraceptive care for National Quality Forum submission: the percentage of women aged 15-44 years provided the following: (1) a most or moderately effective contraceptive method (MME) and (2) a long-acting reversible contraceptive (LARC) method. METHODS: We used 2013 Iowa Department of Public Health (IDPH) Title X and Iowa Medicaid data. We stratified Title X data by age and Medicaid data by age and benefit type (family planning waiver (FPW) vs. general Medicaid), and examined variation by residence, public health region and health plan based on program interest. FINDINGS: Among women attending IDPH Title X clinics in 2013 (N=11,584), 86% of women aged 15-20years and 83% of women aged 21-44years were provided MME; and 20% of women aged 15-20years and 20% of women aged 21-44years were provided LARC. Estimates varied across Title X subrecipient agencies, which receive federal funds from IDPH. Among Medicaid FPW clients (N=30,013), 79% of women aged 15-20years and 73% of women aged 21-44years were provided MME; and 12% of women aged 15-20years and 11% of women aged 21-44years were provided LARC. Among general Medicaid clients (N=14,737), 40% of women aged 15-20years and 28% of women aged 21-44years were provided MME; and 5% of women aged 15-20years and 5% of women aged 21-44years were provided LARC. CONCLUSION: A high percentage of IDPH Title X and FPW clients were provided an MME method. No reporting entity had a LARC percentage less than 1%-2%. IMPLICATIONS: Measure calculation using Title X and Medicaid data is feasible and can potentially be used to identify ways to increase access to contraceptive methods. PMID- 28578147 TI - "I wish they could hold on a little longer": physicians' experiences with requests for early IUD removal. AB - OBJECTIVE: This study describes the perceptions and experiences of family physicians when women request early intrauterine device (IUD) removal. STUDY DESIGN: This qualitative study included semistructured individual interviews with 12 physicians who encountered patients seeking early IUD removal. We identified eligible participants via chart review. We analyzed interviews using deductive and inductive techniques to identify content and themes. RESULTS: Physicians consistently referred to IUDs as the "best" or their "favorite" method, and several joked that they tried to "sell" the IUD during contraceptive counseling. Most reported having mixed or negative feelings when patients opted to remove the IUD. Most encouraged their patients to continue the IUD, hoping to delay removal until symptoms resolved so that removal was not needed. Some physicians reported feeling guilty or as if they had "failed" when a patient wanted the IUD removed. Many providers reported a conflict between valuing patient autonomy and feeling that early removal was not in the patient's best interest. CONCLUSIONS: Physicians have complex and contradictory feelings about early IUD removal. While most providers acknowledged the need for patient autonomy, they still reported encouraging IUD continuation based on their own opinion about the IUD. IMPLICATIONS: While IUDs are highly effective and well-liked contraceptives, providers' responses to IUD removal requests have implications for both reproductive autonomy as well as the doctor-patient relationship. More work is needed to ensure that providers remove a patient's IUD when requested. PMID- 28578148 TI - Contraception and reproductive counseling in women with peripartum cardiomyopathy. AB - OBJECTIVES: Pregnancies following a diagnosis of peripartum cardiomyopathy (PPCM) are associated with increased risk for maternal morbidity and mortality. Yet patterns of contraceptive use and reproductive counseling have received little attention. This nationwide registry-based study sought to evaluate patterns and clinical characteristics associated with contraceptive use, and examine the prevalence of contraceptive counseling in women with PPCM. METHODS: From December 2015 to June 2016, 177 PPCM patients (mean age of 34.8+/-5.7years, median time since diagnosis of 3.0+/-4.3years) completed questionnaires about contraceptive use and counseling at registry enrollment. T Tests, chi-square and logistic regression were used to compare demographic and clinical characteristics among women who reported contraceptive use vs. nonuse. RESULTS: Tubal ligation (24.3%), condoms (22.0%) and intrauterine devices (IUDs; 16.4%) were the most common forms of contraception. Among sexually active women, 28.9% reported contraceptive nonuse. Contraceptive users had a lower body mass index higher education, and were less likely to be in a dating relationship, have hypertension, wear an external cardioverter-defibrillator, and use antihypertensive medications compared with nonusers (all p<0.05). Two-thirds of women received counseling about risks of subsequent pregnancies and contraceptive strategies. CONCLUSIONS: This preliminary study indicates that 1 in 4 PPCM patients are sexually active and are not using contraception to prevent PPCM reoccurrence. Although a majority of women did receive reproductive counseling, as many as 25% of patients reported no discussion of contraceptive strategies to prevent unintended pregnancy and heart failure relapse. PMID- 28578149 TI - Abortion and contemporary hip-hop: a thematic analysis of lyrics from 1990-2015. AB - OBJECTIVE: To evaluate the representation of abortion in contemporary hip-hop music, gaining insight into the myriad of attitudes of abortion in the black community. STUDY DESIGN: We used Genius, an online storehouse for lyrical content, to identify songs by querying the database for search terms related to family planning, including slang terms. We then cross-referenced identified songs using an online list of songs about abortion. We analyzed eligible songs using grounded theory in order to identify key themes. RESULTS: Of 6577 songs available, a total of 101 songs performed by 122 individual artists met inclusion criteria. The majority of artists were Black men; five artists were Black women. Key themes were: use of abortion as braggadocio; equating abortion with sin, genocide, or murder; male pressure for women to seek abortion; and the specific association of Planned Parenthood services with abortion. CONCLUSIONS: The moral and ethical themes surrounding abortion in hip-hop lyrics reveal a unique perspective within a marginalized community. The overall negative context of abortion in hip-hop lyrics needs to be reconciled with the gendered, economic, historical, political, racial and ethnic background of hip-hop and rap music in America. IMPLICATIONS: This study is the first to evaluate lyrical content from contemporary popular music in relation to abortion and family planning. Examining the intersection of reproductive rights and popular culture can provide a unique insight into the limited knowledge of the perspectives of abortion in the black community. PMID- 28578150 TI - Standardizing the classification of abortion incidents: the Procedural Abortion Incident Reporting and Surveillance (PAIRS) Framework. AB - OBJECTIVES: To develop and validate standardized criteria for assessing abortion related incidents (adverse events, morbidities, near misses) for first-trimester aspiration abortion procedures and to demonstrate the utility of a standardized framework [the Procedural Abortion Incident Reporting & Surveillance (PAIRS) Framework] for estimating serious abortion-related adverse events. STUDY DESIGN: As part of a California-based study of early aspiration abortion provision conducted between 2007 and 2013, we developed and validated a standardized framework for defining and monitoring first-trimester (<=14weeks) aspiration abortion morbidity and adverse events using multiple methods: a literature review, framework criteria testing with empirical data, repeated expert reviews and data-based revisions to the framework. RESULTS: The final framework distinguishes incidents resulting from procedural abortion care (adverse events) from morbidity related to pregnancy, the abortion process and other nonabortion related conditions. It further classifies incidents by diagnosis (confirmatory data, etiology, risk factors), management (treatment type and location), timing (immediate or delayed), seriousness (minor or major) and outcome. Empirical validation of the framework using data from 19,673 women receiving aspiration abortions revealed almost an equal proportion of total adverse events (n=205, 1.04%) and total abortion- or pregnancy-related morbidity (n=194, 0.99%). The majority of adverse events were due to retained products of conception (0.37%), failed attempted abortion (0.15%) and postabortion infection (0.17%). Serious or major adverse events were rare (n=11, 0.06%). CONCLUSIONS: Distinguishing morbidity diagnoses from adverse events using a standardized, empirically tested framework confirms the very low frequency of serious adverse events related to clinic-based abortion care. IMPLICATIONS: The PAIRS Framework provides a useful set of tools to systematically classify and monitor abortion-related incidents for first-trimester aspiration abortion procedures. Standardization will assist healthcare providers, researchers and policymakers to anticipate morbidity and prevent abortion adverse events, improve care metrics and enhance abortion quality. PMID- 28578151 TI - An updated assessment of postpartum sterilization fulfillment after vaginal delivery. AB - OBJECTIVE: To describe sterilization completion rates after vaginal delivery and indications for unfulfilled procedures. STUDY DESIGN: We used labor and delivery operating room and delivery logs to identify all women over 20years of age with a completed live vaginal birth beyond 24weeks gestation over a 33-month period (March 1, 2012 to November 30, 2014). We reviewed the electronic medical records of all of these patients and identified those who requested a sterilization procedure as indicated in a physician's admission note or antenatal record. RESULTS: We identified 3514 live vaginal births beyond 24weeks gestation during the study period of which 219 requested postpartum sterilization. Sterilization occurred in 114 (52%). The most common reason for unfulfilled procedures was lack of valid federally mandated consent (n=46 [44%]). Fifty-nine percent (27 of 46) of these women had little or no prenatal care. Only one (0.5%) woman had documented completion of consent with the required time elapsed prior to delivery and no consent form available. Of the women with valid consent documentation, the most common indication for an unfulfilled procedure was patient refusal (n=30 [51%]). Body mass index was an independent predictor of an unfulfilled procedure (p<.001) among women with adequate consent. CONCLUSIONS: Inability to complete federally mandated consent is a principal cause of unfulfilled postpartum sterilization and primarily affects women desiring sterilization who lack sufficient prenatal care. Of women who meet consent criteria, the primary reason women eligible for sterilization did not undergo the procedure was due to withdrawing their request. IMPLICATIONS: Because women commonly do not undergo a requested sterilization after vaginal deliveries, antepartum counseling should include alternate contraception choices. Documented consent that fulfills all federally mandated criteria remains the most common barrier to requested sterilization after vaginal delivery; providers and policymakers should work together to help unburden women from this mandate. PMID- 28578153 TI - Racial injustice and family planning: an open letter to our community. PMID- 28578154 TI - Species limits, phylogeography and reproductive mode in the Metarhizium anisopliae complex. AB - An essential first step to elucidating the ecology and life histories of Metarhizium anisopliae-group species as entomopathogens, endophytes and soil adapted fungi is the ability to define species limits and confidently infer a species phylogeny. In a multilocus phylogeny of the core Metarhizium anisopliae species complex, the majority of isolates sampled herein group within the currently defined limits of M. pingshaense, M. anisopliae, M. robertsii and M. brunneum, designated informally as the "PARB" clade. Multilocus phylogenetic analyses reveal pervasive congruent hierarchical structure among the genomic regions analyzed, which suggest that current PARB species delimitations likely encompass additional cryptic complexes. Further, the interpolation of isolates from different continents throughout each species lineage indicates periodic inter-continental dispersals. Although no PARB species has yet been confirmed to produce a sexual state, we demonstrate the mutually exclusive incidence of the MAT1 and MAT2 mating type idiomorphs among individuals in all PARB species. This configuration of mating type is diagnostic of a heterothallic, obligately outcrossing mating system, indicating the conservation of and ongoing potential for sexual reproduction in all PARB species. As one example of the utility of IGS markers, the commercially registered M. anisopliae strain F52, which is widely used for pest control in North America, Canada and Europe, is shown to be a member of the M. brunneum complex. While current PARB species delimitations evidently encompass cryptic partitions, formal recognition of segregate species should be approached cautiously until further evidence of their phylogenetic exclusivity, ecological distinctiveness or other unique attributes is demonstrated. Nevertheless, acknowledgment of these intraspecific partitions will provide a useful conceptual framework to guide future investigations of the community structure, phylogeography, population genetics, ecology and reproductive biology of this recent species radiation. PMID- 28578152 TI - Examining intendedness among pregnancies ending in spontaneous abortion. AB - OBJECTIVES: Spontaneous abortion (SAB) affects over 1 million US women each year, yet little is known about the intendedness of these pregnancies. We examined prevalence and correlates of unintended and unwanted pregnancies ending in SAB. STUDY DESIGN: We used nationally-representative cross-sectional data of US women aged 15-44 from the 2011-2013 National Survey of Family Growth to examine pregnancies ending in SAB. We used modified Poisson regression models to evaluate associations between demographic and pregnancy characteristics with unintended and unwanted pregnancy. RESULTS: Among 1351 pregnancies ending in SAB, 44.5% were unintended (i.e. unwanted or occurring sooner than desired). Younger women with SAB were more likely to report unintended pregnancies than women 30-44 years, and women 15-19 years reported unintended pregnancy most often [adjusted relative risk (aRR)=3.0; 95% confidence interval (CI): 2.2-4.1]. Unintended pregnancy was two times more likely among unmarried than married women [never married: aRR=2.2; 95% CI: 1.7-2.7; previously married: aRR=2.2; 95% CI: 1.7-3.0]. Other factors associated with unintended pregnancy were multiparity compared to nulliparity [aRR=2.6; 95% CI: 1.7-4.1 for >=3 children; aRR=1.8; 95% CI: 1.3-2.5 for 2 children] and inter-pregnancy interval <=12 months compared to >12 months [aRR=1.4; 95% CI: 1.2-1.7]. We found similar associations with unwanted pregnancies ending in SAB (15.3% of pregnancies). Neither race/ethnicity nor socioeconomic indicators were independently associated with unintended or unwanted pregnancy ending in SAB. CONCLUSIONS: Many pregnancies ending in spontaneous abortion are unintended and/or unwanted. Women with pregnancy loss, like all reproductive-aged women, should receive comprehensive counseling about reproductive planning and contraception. IMPLICATIONS: Similar to all pregnancies, nearly half of pregnancies ending in spontaneous abortion are unintended and/or unwanted, suggesting that many women experiencing spontaneous abortion may benefit from a review of family planning desires and the provision of reproductive planning counseling and effective contraception to prevent future undesired pregnancy. PMID- 28578155 TI - Prefrontal-parietal effective connectivity during working memory in older adults. AB - Theoretical models and preceding studies have described age-related alterations in neuronal activation of frontoparietal regions in a working memory (WM) load dependent manner. However, to date, underlying neuronal mechanisms of these WM load-dependent activation changes in aging remain poorly understood. The aim of this study was to investigate these mechanisms in terms of effective connectivity by application of dynamic causal modeling with Bayesian Model Selection. Eighteen healthy younger (age: 20-32 years) and 32 older (60-75 years) participants performed an n-back task with 3 WM load levels during functional magnetic resonance imaging (fMRI). Behavioral and conventional fMRI results replicated age group by WM load interactions. Importantly, the analysis of effective connectivity derived from dynamic causal modeling, indicated an age- and performance-related reduction in WM load-dependent modulation of connectivity from dorsolateral prefrontal cortex to inferior parietal lobule. This finding provides evidence for the proposal that age-related WM decline manifests as deficient WM load-dependent modulation of neuronal top-down control and can integrate implications from theoretical models and previous studies of functional changes in the aging brain. PMID- 28578157 TI - Carbon Dioxide Fluctuations Are Associated with Changes in Cerebral Oxygenation and Electrical Activity in Infants Born Preterm. AB - OBJECTIVES: To evaluate the effects of acute arterial carbon dioxide partial pressure changes on cerebral oxygenation and electrical activity in infants born preterm. STUDY DESIGN: This retrospective observational study included ventilated infants born preterm with acute fluctuations of continuous end-tidal CO2 (etCO2) as a surrogate marker for arterial carbon dioxide partial pressure, during the first 72 hours of life. Regional cerebral oxygen saturation and fractional tissue oxygen extraction were monitored with near-infrared spectroscopy. Brain activity was monitored with 2-channel electroencephalography. Spontaneous activity transients (SATs) rate (SATs/minute) and interval between SATs (in seconds) were calculated. Ten-minute periods were selected for analysis: before, during, and after etCO2 fluctuations of >=5 mm Hg. RESULTS: Thirty-eight patients (mean +/- SD gestational age of 29 +/- 1.8 weeks) were included, with 60 episodes of etCO2 increase and 70 episodes of etCO2 decrease. During etCO2 increases, brain oxygenation increased (regional cerebral oxygen saturation increased, fractional tissue oxygen extraction decreased; P < .01) and electrical activity decreased (SATs/minute decreased, interval between SATs increased; P < .01). All measures recovered when etCO2 returned to baseline. During etCO2 decreases, brain oxygenation decreased (regional cerebral oxygen saturation decreased, fractional tissue oxygen extraction decreased; P < .01) and brain activity increased (SATs/minute increased, P < .05), also with recovery after return of etCO2 to baseline. CONCLUSION: An acute increase in etCO2 is associated with increased cerebral oxygenation and decreased brain activity, whereas an acute decrease is associated with decreased cerebral oxygenation and slightly increased brain activity. Combining continuous CO2 monitoring with near-infrared spectroscopy may enable the detection of otherwise undetected fluctuations in arterial carbon dioxide partial pressure that may be harmful to the neonatal brain. PMID- 28578158 TI - Fetal Hydantoin Syndrome. PMID- 28578156 TI - ApoE influences regional white-matter axonal density loss in Alzheimer's disease. AB - Mechanisms underlying phenotypic heterogeneity in young onset Alzheimer disease (YOAD) are poorly understood. We used diffusion tensor imaging and neurite orientation dispersion and density imaging (NODDI) with tract-based spatial statistics to investigate apolipoprotein (APOE) epsilon4 modulation of white matter damage in 37 patients with YOAD (22, 59% APOE epsilon4 positive) and 23 age-matched controls. Correlation between neurite density index (NDI) and neuropsychological performance was assessed in 4 white-matter regions of interest. White-matter disruption was more widespread in epsilon4+ individuals but more focal (posterior predominant) in the absence of an epsilon4 allele. NODDI metrics indicate fractional anisotropy changes are underpinned by combinations of axonal loss and morphological change. Regional NDI in parieto occipital white matter correlated with visual object and spatial perception battery performance (right and left, both p = 0.02), and performance (nonverbal) intelligence (WASI matrices, right, p = 0.04). NODDI provides tissue-specific microstructural metrics of white-matter tract damage in YOAD, including NDI which correlates with focal cognitive deficits, and APOEepsilon4 status is associated with different patterns of white-matter neurodegeneration. PMID- 28578159 TI - Low Retinol-Binding Protein and Vitamin D Levels Are Associated with Severe Outcomes in Children Hospitalized with Lower Respiratory Tract Infection and Respiratory Syncytial Virus or Human Metapneumovirus Detection. AB - Retinol binding protein and vitamin D were measured in children aged <5 years hospitalized with lower respiratory tract infection and respiratory syncytial virus and/or human metapneumovirus detections. Low vitamin levels were observed in 50% of the children and were associated with significantly elevated risk of the need for intensive care unit admission and invasive mechanical ventilation. PMID- 28578160 TI - Fertility Treatment Is Associated with Stay in the Neonatal Intensive Care Unit and Respiratory Support in Late Preterm Infants. AB - Late preterm infants are at risk for short-term morbidities. We report that late preterm singletons conceived with fertility treatment have increased risk for admission to the neonatal intensive care unit and respiratory support compared with spontaneously conceived infants. Fertility treatment may be a risk factor to consider in managing late preterm infants. PMID- 28578161 TI - Examining the intersection between splicing, nuclear export and small RNA pathways. AB - BACKGROUND: Nuclear Argonaute/small RNA pathways in a variety of eukaryotic species are generally known to regulate gene expression via chromatin modulation and transcription attenuation in a process known as transcriptional gene silencing (TGS). However, recent data, including genetic screens, phylogenetic profiling, and molecular mechanistic studies, also point to a novel and emerging intersection between the splicing and nuclear export machinery with nuclear Argonaute/small RNA pathways in many organisms. SCOPE OF REVIEW: In this review, we summarize the field's current understanding regarding the relationship between splicing, export and small RNA pathways, and consider the biological implications for coordinated regulation of transcripts by these pathways. We also address the importance and available approaches for understanding the RNA regulatory logic generated by the intersection of these particular pathways in the context of synthetic biology. MAJOR CONCLUSIONS: The interactions between various eukaryotic RNA regulatory pathways, particularly splicing, nuclear export and small RNA pathways provide a type of combinatorial code that informs the identity ("self" versus "non-self") and dictates the fate of each transcript in a cell. Although the molecular mechanisms for how splicing and nuclear export impact small RNA pathways are not entirely clear at this early stage, the links between these pathways are widespread across eukaryotic phyla. GENERAL SIGNIFICANCE: The link between splicing, nuclear export, and small RNA pathways is emerging and establishes a new frontier for understanding the combinatorial logic of gene regulation across species that could someday be harnessed for therapeutic, biotechnology and agricultural applications. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue. PMID- 28578162 TI - Rapid convergence of optimal control in NMR using numerically-constructed toggling frames. AB - We present a numerical method for rapidly solving the Bloch equation for an arbitrary time-varying spin-1/2 Hamiltonian. The method relies on fast, vectorized computations such as summation and quaternion multiplication, rather than slow computations such as matrix exponentiation. A toggling frame is constructed in which the Hamiltonian is time-invariant, and therefore has a simple analytical solution. The key insight is that constructing this frame is faster than solving the system dynamics in the original frame. Rapidly solving the Bloch equations for an arbitrary Hamiltonian is particularly useful in the context of NMR optimal control. Optimal control theory can be used to design pulse shapes for a range of tasks in NMR spectroscopy. However, it requires multiple simulations of the Bloch equations at each stage of the algorithm, and for each relevant set of parameters (e.g. chemical shift frequencies). This is typically time consuming. We demonstrate that by working in an appropriate toggling frame, optimal control pulses can be generated much faster. We present a new alternative to the well-known GRAPE algorithm to continuously update the toggling-frame as the optimal pulse is generated, and demonstrate that this approach is extremely fast. The use and benefit of rapid optimal pulse generation is demonstrated for 19F fragment screening experiments. PMID- 28578164 TI - Discriminative ability of commonly used indices to predict adverse outcomes after poster lumbar fusion: a comparison of demographics, ASA, the modified Charlson Comorbidity Index, and the modified Frailty Index. AB - BACKGROUND CONTEXT: As research tools, the American Society of Anesthesiologists (ASA) physical status classification system, the modified Charlson Comorbidity Index (mCCI), and the modified Frailty Index (mFI) have been associated with complications following spine procedures. However, with respect to clinical use for various adverse outcomes, no known study has compared the predictive performance of these indices specifically following posterior lumbar fusion (PLF). PURPOSE: This study aimed to compare the discriminative ability of ASA, mCCI, and mFI, as well as demographic factors including age, body mass index, and gender for perioperative adverse outcomes following PLF. STUDY DESIGN/SETTING: A retrospective review of prospectively collected data was performed. PATIENT SAMPLE: Patients undergoing elective PLF with or without interbody fusion were extracted from the 2011-2014 American College of Surgeons National Surgical Quality Improvement Program (NSQIP). OUTCOME MEASURES: Perioperative adverse outcome variables assessed included the occurrence of minor adverse events, severe adverse events, infectious adverse events, any adverse event, extended length of hospital stay, and discharge to higher-level care. METHODS: Patient comorbidity indices and characteristics were delineated and assessed for discriminative ability in predicting perioperative adverse outcomes using an area under the curve analysis from the receiver operating characteristics curves. RESULTS: In total, 16,495 patients were identified who met the inclusion criteria. The most predictive comorbidity index was ASA and demographic factor was age. Of these two factors, age had the larger discriminative ability for three out of the six adverse outcomes and ASA was the most predictive for one out of six adverse outcomes. A combination of the most predictive demographic factor and comorbidity index resulted in improvements in discriminative ability over the individual components for five of the six outcome variables. CONCLUSION: For PLF, easily obtained patient ASA and age have overall similar or better discriminative abilities for perioperative adverse outcomes than numerically tabulated indices that have multiple inputs and are harder to implement in clinical practice. PMID- 28578165 TI - Antihypertensive and vasorelaxant effects of aqueous extract of Artemisia campestris L. from Eastern Morocco. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia campestris L. (Asteraceae) has many traditional uses, among which treatment of diabetes and hypertension. AIM OF THE STUDY: This study was conducted in order to confirm the antihypertensive and hypotensive effects of A. campestris L. aqueous extract (AcAE) and to explore the underlying mechanism of action of its vasorelaxant effect, besides the acute toxicity. Also, the chemical composition of AcAE was investigated. MATERIAL AND METHODS: the chemical content of AcAE was determined by using HPLC and NMR techniques. The antihypertensive effect was assessed indirectly by tail-cuff method on L-NAME induced hypertensive rats, while the hypotensive action was monitored intravenously by invasive method on normotensive rats. The vasorelaxant effect and vascular mechanism of action were studied in the presence of antagonists and blockers on aorta isolated from normotensive rats. On the other side, the acute toxicity was studied by oral feeding of extract to the mice. RESULTS: The global phytochemical profile of AcAE reveals the presence of several polyphenols as main components. A. campestris L. infusion was characterized by mono- and di-cinnamoyl compounds, with 3,5-dicaffeoylquinic (isochlorogenic A) acid being the main compound, followed by 5-caffeoylquinic (chlorogenic) acid. Vicenin-2 (apigenin 6,8-di-C-glucoside) appeared to be the most abundant compound among flavonoids. The daily treatment with AcAE at 150mg/kg/day prevented the installation of hypertension on L-NAME hypertensive rats, and reduced SBP from 172mmHg up to 144mmHg. At the dose 40mg/kg, AcAE provoked reduction of systolic (SBP), diastolic (DBP) and mean arterial pressure (MAP), without affecting the heart rate. Also, AcAE (10-2-2mg/ml) relaxed the precontracted aorta by 95.8+/ 1.3%. The denudation and preincubation of aorta with atropine, calmidazolium, L NAME, hydroxycobalamin, ODQ, 8-RP-Br-PET-cGMP, thapsigargin and verapamil attenuated the vasorelaxant response, while the pre-treatment with 4-AP, TEA, glibenclamide and BaCl2 did not alter this effect. The oral administration of AcAE (0-6g/kg) reveals no mortality or toxicity. CONCLUSIONS: our study proved that AcAE possess an important antihypertensive, hypotensive and vasorelaxant effect, which is mediated via calmodulin-NO-cGC-PKG pathway, and via inhibition of calcium influx through voltage-operated calcium channels and activation of intracellular calcium mobilization into sarcoplasmic reticulum. Therefore, our findings give first evidence about the traditional use of A. campestris L. as antihypertensive plant. PMID- 28578163 TI - Efficacy and safety of urinary catheters with silver alloy coating in patients with spinal cord injury: a multicentric pragmatic randomized controlled trial. The ESCALE trial. AB - BACKGROUND: Patients with spinal cord injury (SCI) who carry indwelling urinary catheters have an increased risk of urinary tract infection (UTI). Antiseptic silver alloy-coated (SAC) silicone urinary catheters prove to be a promising intervention to reduce UTIs; however, current evidence cannot be extrapolated to patients with SCI. PURPOSE: This study aimed to assess the efficacy of SAC urinary catheters for preventing catheter-associated urinary tract infections. DESIGN/SETTING: This is an open-label, multicenter (developed in Spain, Portugal, Chile, Turkey, and Italy), randomized clinical trial conducted in 14 hospitals from November 2012 to December 2015. PATIENT SAMPLE: Eligible patients were men or women with traumatic or medical SCI, aged >=18 years, requiring an indwelling urinary catheter for at least 7 days. OUTCOME MEASURES: The primary outcome was the incidence of symptomatic UTIs. The secondary outcome included bacteremia in the urinary tract and adverse events. MATERIALS AND METHODS: Patients were randomized to receive a SAC urinary catheter (experimental group) or a standard catheter (control group) for at least 7 days. Data were compared using chi squared test and also calculating the absolute risk difference with a 95% confidence interval. An adjusted analysis including different risk factors of UTI was performed. This study was mainly funded by La Marato de TV3 Foundation (grant number # 112210) and the European Clinical Research Infrastructures Network organization. The funders had no role in the interpretation or reporting of results. RESULTS: A total of 489 patients were included in the study, aged 55 years in the experimental group and aged 57 in the control group (p=.870); 72% were men; 43% were hospitalized patients, and 57% were outpatients (p=1.0). The most frequent cause of SCI was traumatic (73.75%), and the localization was mainly the cervical spine (42.74%). Most of the patients had an A score (complete spinal injury and no motor and sensory is preserved) on the ASIA scale (62.37%). The median time of urethral catheterization was 27 days in the experimental group and 28 days in the control group (p=.202). Eighteen patients (7.41%) in the experimental group and 19 in the control (7.72%) group had a symptomatic UTI (odds ratio [OR] 0.96 [0.49-1.87]). The adjusted analysis revealed no change in the results. Only three patients in the experimental group had bacteremia within the urinary tract. The experimental group presented more adverse events related to the use of a catheter than the control group (OR 0.03 [0.00-0.06]). CONCLUSIONS: The results of this study do not support the routine use of indwelling antiseptic SAC silicone urinary catheters in patients with SCI. However, UTIs associated to long-term urinary catheter use remain a challenge and further investigations are still needed. PMID- 28578167 TI - Novel label-free and high-throughput microchip electrophoresis platform for multiplex antibiotic residues detection based on aptamer probes and target catalyzed hairpin assembly for signal amplification. AB - Novel label-free and multiplex aptasensors have been developed for simultaneous detection of several antibiotics based on a microchip electrophoresis (MCE) platform and target catalyzed hairpin assembly (CHA) for signal amplification. Kanamycin (Kana) and oxytetracycline (OTC) were employed as models for testing the system. These aptasensors contained six DNA strands termed as Kana aptamer catalysis strand (Kana apt-C), Kana inhibit strand (Kana inh), OTC aptamer catalysis strand (OTC apt-C), OTC inhibit strand (OTC inh), hairpin structures H1 and H2 which were partially complementary. Upon the addition of Kana or OTC, the binding event of aptamer and target triggered the self-assembly between H1 and H2, resulting in the formation of many H1-H2 complexes. They could show strong signals which represented the concentration of Kana or OTC respectively in the MCE system. With the help of the well-designed and high-quality CHA amplification, the assay could yield 300-fold amplified signal comparing that from non-amplified system. Under optimal conditions, this assay exhibited a linear correlation in the ranges from 0.001ngmL-1 to 10ngmL-1, with the detection limits of 0.7pgmL-1 and 0.9pgmL-1 (S/N=3) toward Kana and OTC, respectively. The platform has the following advantages: firstly, the aptamer probes can be fabricated easily without labeling signal tags for MCE detection; Secondly, the targets can just react with probes and produce the amplified signal in one-pot. Finally, the targets can be simultaneously detected within 10min in different channels, thus high-throughput measurement can be achieved. Based on this work, it is estimated that this detection platform will be universally served as a simple, sensitive and portable platform for antibiotic contaminants detection in biological and environmental samples. PMID- 28578166 TI - Effect of cervical sympathetic ganglionectomy on facial nerve reconstruction using polyglycolic acid-collagen tubes. AB - A polyglycolic acid-collagen (PGA-c) tube was used as an artificial nerve guide during facial nerve reconstruction performed in a canine model of stellate ganglion block (SGB). The model was generated using a cervical sympathetic ganglionectomy. We evaluated the effects of blood flow on nerve regeneration. First, we resected the left cervical sympathetic ganglion in beagles (n=6). We assessed buccal mucosal blood flow and nasal skin temperatures once per week for 12weeks and Horner's sign 2, 4, and 6months after resection. We compared these values to those measured prior to resection. Blood flow was increased for 6 11weeks, but sympathetic control remained blocked after 6months. Second, we divided beagles into 3 groups: resection models (negative control), from which 7mm of the left facial nerve buccal branch was resected (n=5); reconstruction models, which underwent nerve reconstruction using PGA-c tubes (n=6); and SGB+reconstruction models, which underwent a left cervical sympathetic ganglionectomy immediately after reconstruction (n=6). The right side of the face served as control (n=17). Nerve regeneration was significantly greater in the SGB+reconstruction model dogs than in the reconstruction model dogs, as measured by both electrophysiological and morphological analyses at postoperative week 12. In particular, motor nerve conduction velocity was increased approximately 2-fold (p=0.018). We were able to generate an SGB model with long-term increased blood flow facilitated by the promotion of facial nerve regeneration by PGA-c tubes. PMID- 28578168 TI - Neonatal outcomes in fetuses with cardiac anomalies and the impact of delivery route. AB - BACKGROUND: Congenital fetal cardiac anomalies compromise the most common group of fetal structural anomalies. Several previous reports analyzed all types of fetal cardiac anomalies together without individualized neonatal morbidity outcomes based on cardiac defect. Mode of delivery in cases of fetal cardiac anomalies varies greatly as optimal mode of delivery in these complex cases is unknown. OBJECTIVE: We sought to determine rates of neonatal outcomes for fetal cardiac anomalies and examine the role of attempted route of delivery on neonatal morbidity. STUDY DESIGN: Gravidas with fetal cardiac anomalies and delivery >34 weeks, excluding stillbirths and aneuploidies (n = 2166 neonates, n = 2701 cardiac anomalies), were analyzed from the Consortium on Safe Labor, a retrospective cohort study of electronic medical records. Cardiac anomalies were determined using International Classification of Diseases, Ninth Revision codes and organized based on morphology. Neonates were assigned to each cardiac anomaly classification based on the most severe cardiac defect present. Neonatal outcomes were determined for each fetal cardiac anomaly. Composite neonatal morbidity (serious respiratory morbidity, sepsis, birth trauma, hypoxic ischemic encephalopathy, and neonatal death) was compared between attempted vaginal delivery and planned cesarean delivery for prenatal and postnatal diagnosis. We used multivariate logistic regression to calculate adjusted odds ratio for composite neonatal morbidity controlling for race, parity, body mass index, insurance, gestational age, maternal disease, single or multiple anomalies, and maternal drug use. RESULTS: Most cardiac anomalies were diagnosed postnatally except hypoplastic left heart syndrome, which had a higher prenatal than postnatal detection rate. Neonatal death occurred in 8.4% of 107 neonates with conotruncal defects. Serious respiratory morbidity occurred in 54.2% of 83 neonates with left ventricular outflow tract defects. Overall, 76.3% of pregnancies with fetal cardiac anomalies underwent attempted vaginal delivery. Among patients who underwent attempted vaginal delivery, 66.1% had a successful vaginal delivery. Women with a fetal cardiac anomaly diagnosed prenatally were more likely to have a planned cesarean delivery than women with a postnatal diagnosis (31.7 vs 22.8%; P < .001). Planned cesarean delivery compared to attempted vaginal delivery was not associated with decreased composite neonatal morbidity for all prenatally diagnosed (adjusted odds ratio, 1.67; 95% confidence interval, 0.85-3.30) or postnatally diagnosed (adjusted odds ratio, 0.99; 95% confidence interval, 0.77-1.27) cardiac anomalies. CONCLUSION: Most fetal cardiac anomalies were diagnosed postnatally and associated with increased rates of neonatal morbidity. Planned cesarean delivery for prenatally diagnosed cardiac anomalies was not associated with less neonatal morbidity. PMID- 28578169 TI - Maternal race and intergenerational preterm birth recurrence. AB - BACKGROUND: Preterm birth is a complex disorder with a heritable genetic component. Studies of primarily White women born preterm show that they have an increased risk of subsequently delivering preterm. This risk of intergenerational preterm birth is poorly defined among Black women. OBJECTIVE: Our objective was to evaluate and compare intergenerational preterm birth risk among non-Hispanic Black and non-Hispanic White mothers. STUDY DESIGN: This was a population-based retrospective cohort study, using the Virginia Intergenerational Linked Birth File. All non-Hispanic Black and non-Hispanic White mothers born in Virginia 1960 through 1996 who delivered their first live-born, nonanomalous, singleton infant >=20 weeks from 2005 through 2009 were included. We assessed the overall gestational age distribution between non-Hispanic Black and White mothers born term and preterm (<37 weeks) and their infants born term and preterm (<37 weeks) using Cox regression and Kaplan-Meier survivor functions. Mothers were grouped by maternal gestational age at delivery (term, >=37 completed weeks; late preterm birth, 34-36 weeks; and early preterm birth, <34 weeks). The primary outcomes were: (1) preterm birth among all eligible births; and (2) suspected spontaneous preterm birth among births to women with medical complications (eg, diabetes, hypertension, preeclampsia and thus higher risk for a medically indicated preterm birth). Multivariable logistic regression was used to estimate odds of preterm birth and spontaneous preterm birth by maternal race and maternal gestational age after adjusting for confounders including maternal education, maternal age, smoking, drug/alcohol use, and infant gender. RESULTS: Of 173,822 deliveries captured in the intergenerational birth cohort, 71,676 (41.2%) women met inclusion criteria for this study. Of the entire cohort, 30.0% (n = 21,467) were non-Hispanic Black and 70.0% were non-Hispanic White mothers. Compared to non Hispanic White mothers, non-Hispanic Black mothers were more likely to have been born late preterm (6.8% vs 3.7%) or early preterm (2.8 vs 1.0%), P < .001. Non Hispanic White mothers who were born (early or late) preterm were not at an increased risk of early or late preterm delivery compared to non-Hispanic White mothers born term. The risk of early preterm birth was most pronounced for Black mothers who were born early preterm (adjusted odds ratio, 3.26; 95% confidence interval, 1.77-6.02) compared to non-Hispanic White mothers. CONCLUSION: We found an intergenerational effect of preterm birth among non-Hispanic Black mothers but not non-Hispanic White mothers. Black mothers born <34 weeks carry the highest risk of delivering their first child very preterm. Future studies should elucidate the underlying pathways leading to this racial disparity. PMID- 28578170 TI - Can venous cord gas values predict fetal acidemia? AB - BACKGROUND: Umbilical cord arterial blood gas values are used to diagnose fetal acidemia; however, arterial cord blood specimens are frequently not available. OBJECTIVE: We sought to assess whether umbilical cord venous blood gas values can be used to reliably predict fetal acidemia. STUDY DESIGN: This is an observational study of women with a singleton gestation at a single tertiary care hospital who delivered from September 2010 through August 2015 and had both umbilical cord arterial and venous blood gas samples measured. Fetal acidemia was defined in 2 ways: (1) umbilical cord arterial pH <7.0, and (2) umbilical cord arterial base deficit >=12 mEq/L. Receiver operating characteristic curves for fetal acidemia were generated using umbilical cord venous blood gas values and the areas under the curve were calculated. Umbilical cord venous blood gas cutoffs associated with <1%, <5%, <10%, and <50% probability of acidemia were calculated. RESULTS: Of the 36,325 women who met inclusion criteria, 563 (1.5%) had an umbilical cord arterial pH <7.0 and 1535 (4.2%) had an umbilical cord arterial base deficit >=12 mEq/L. Umbilical cord venous pH was highly predictive of umbilical cord arterial pH <7.0 (area under the curve, 0.955; 95% confidence interval, 0.946-0.965). Similarly, umbilical cord venous base deficit was highly predictive of umbilical cord arterial base deficit >=12 mEq/L (area under the curve, 0.967; 95% confidence interval, 0.963-0.971). While the combination of venous pH and base deficit was statistically significantly more predictive of umbilical cord arterial pH <7.0 (area under the curve, 0.961; 95% confidence interval, 0.952-0.969; P < .001), this difference has negligible clinical meaning. Similarly, the combination of venous pH and base deficit (area under the curve, 0.967; 95% confidence interval, 0.962-0.971) was no more predictive than venous base deficit alone in the prediction of umbilical cord arterial base deficit >=12 mEq (P = .622). The likelihood of an arterial cord venous pH <7.0 was <1%, <5%, <10%, and <50% with cord venous pH of 7.22, 7.16, 7.14, and 7.07, respectively. The likelihood of an arterial cord base deficit >=12 mEq/L was <1%, <5%, <10%, and <50% with cord venous base deficit of 7.0, 8.5, 9.2, and 11.3, respectively. CONCLUSION: Umbilical cord venous pH and base deficit are each highly predictive of fetal acidemia, and can be used to evaluate the likelihood of fetal acidemia in the absence of umbilical cord arterial blood gas values. PMID- 28578171 TI - Nonmedically indicated induction in morbidly obese women is not associated with an increased risk of cesarean delivery. AB - BACKGROUND: The prevalence of morbid obesity (body mass index >=40 kg/m2) in women aged 20-39 years was 7.5% in 2009 through 2010. Morbid obesity is associated with an increased risk of stillbirth compared with normal body mass index, especially >39 weeks' gestation. The data regarding increased risk of cesarean delivery associated with nonmedically indicated induction of labor compared to expectant management in morbidly obese women are limited. OBJECTIVE: We sought to compare the cesarean delivery rate of nonmedically indicated induction of labor with expectant management in morbidly obese women without other comorbidity. STUDY DESIGN: This was a retrospective cohort study from the Consortium on Safe Labor of morbidly obese women with singleton, cephalic gestations without previous cesarean, chronic hypertension, or gestational or pregestational diabetes between 37 0/7 and 41 6/7 weeks' gestation. We examined maternal outcomes including cesarean delivery, operative delivery, third- or fourth-degree laceration, postpartum hemorrhage, and composite maternal outcome (any of: transfusion, intensive care unit admission, venous thromboembolism). We also examined neonatal outcomes including shoulder dystocia, macrosomia (>4000 g), neonatal intensive care unit admission, and composite neonatal outcome (5-min Apgar score <5, stillbirth, neonatal death, or asphyxia or hypoxic-ischemic encephalopathy). Adjusted odds ratios with 95% confidence intervals were calculated, controlling for maternal characteristics, hospital type, and simplified Bishop score. Analyses were conducted at early and full term (37 0/7 to 38 6/7 and 39 0/7 to 40 6/7 weeks' gestation, respectively). Women who delivered between 41 0/7 and 41 6/7 weeks' gestation were included as expectant management group. RESULTS: Of 1894 nulliparous and 2455 multiparous morbidly obese women, 429 (22.7%) and 791 (32.2%) had nonmedically indicated induction, respectively. In nulliparas, nonmedically indicated induction was not associated with increased risks of cesarean delivery and was associated with decreased risks of macrosomia (2.2% vs 11.0%; adjusted odds ratio, 0.24; 95% confidence interval, 0.05-0.70) at early term and decreased neonatal intensive care unit admission (5.1% vs 8.9%; adjusted odds ratio, 0.59; 95% confidence interval, 0.33-0.98) at full term compared with expectant management. In multiparas, nonmedically indicated induction compared with expectant management was associated with a decreased risk of macrosomia at early term (4.2% vs 14.3%; adjusted odds ratio, 0.30; 95% confidence interval, 0.13-0.60), cesarean delivery at full term (5.4% vs 7.9%; adjusted odds ratio, 0.64; 95% confidence interval, 0.41-0.98), and composite neonatal outcome (0% vs 0.6%; adjusted odds ratio, 0.10; 95% confidence interval, <.01-0.89) at full term. CONCLUSION: In morbidly obese women without other comorbidity, nonmedically indicated induction was not associated with an increased risk of cesarean delivery. PMID- 28578172 TI - Major postoperative complications following surgical procedures for pelvic organ prolapse: a secondary database analysis of the American College of Surgeons National Surgical Quality Improvement Program. AB - BACKGROUND: Surgical approaches to the correction of pelvic organ prolapse include abdominal, vaginal, and obliterative approaches. These approaches require vastly different anatomical dissections, surgical techniques, and operative times and are often selected by the patient and surgeon to match preoperative multimorbidity and ability of the patient to tolerate the stress of surgery. OBJECTIVE: We sought to describe the occurrence of postoperative complications occurring after 3 different surgical approaches to treat pelvic organ prolapse: vaginal, abdominal, and obliterative. STUDY DESIGN: We conducted a secondary database analysis of the 2006 through 2014 American College of Surgeons National Surgical Quality Improvement Program participant use data files to analyze patients undergoing procedures for pelvic organ prolapse based on Current Procedural Terminology codes. Women were categorized into 3 surgical approaches to prolapse: vaginal, abdominal, and obliterative. Concomitant hysterectomy and sling were also examined. The primary outcome was a composite of 30-day major postoperative complications. RESULTS: A total of 33,416 women were included in our final analysis: 24,928 vaginal procedures, 6834 abdominal (4461 minimally invasive) procedures, and 1654 obliterative procedures. Concomitant hysterectomies and slings were performed in 17,380 (52.0%) and 10,896 (32.6%) of prolapse procedures. The overall prevalence of composite 30-day major postoperative complications was 3.1% (n/N = 1028/33,416). There were 13 perioperative deaths (0.04%) with no difference in the surgical approaches (P = .55). There were no differences in major postoperative complications between vaginal and abdominal procedures (3.0% vs 3.0%; P = .71). Women undergoing obliterative procedures had an occurrence of major postoperative complications of 5.0% (n/N = 83/1654), P < .001. CONCLUSION: The occurrence of major postoperative complications after prolapse surgery is rare. We did not find a significant difference in major postoperative complications between vaginal and abdominal surgeries for pelvic organ prolapse. In this well-characterized cohort of patients who self-selected surgical approach, women undergoing obliterative surgery had more postoperative complications, likely attributed to increased age and multimorbidity. PMID- 28578173 TI - The first-trimester fetal central nervous system: a novel ultrasonographic perspective. PMID- 28578174 TI - Maternal marijuana use, adverse pregnancy outcomes, and neonatal morbidity. AB - BACKGROUND: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Stillbirth Collaborative Research Network previously demonstrated an association between stillbirth and maternal marijuana use as defined by the presence of 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid in the umbilical cord homogenate. However, the relationship between marijuana use and perinatal complications in live births is uncertain. OBJECTIVE: Our aim was to examine if maternal marijuana use is associated with increased odds of adverse pregnancy outcomes and neonatal morbidity among live-born controls in the Stillbirth Collaborative Research Network cohort. STUDY DESIGN: We conducted a secondary analysis of singleton, live-born controls in the Stillbirth Collaborative Research Network data set. Marijuana use was measured by self report and/or the presence of 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid in umbilical cord homogenate. Tobacco use was measured by self-report and/or presence of any cotinine in maternal serum. Adverse pregnancy outcome was a composite of small for gestational age, spontaneous preterm birth resulting from preterm labor with or without intact membranes, and hypertensive disorders of pregnancy. Neonatal morbidity included neonatal intensive care unit admission and composite neonatal morbidity (pulmonary morbidity, necrotizing enterocolitis, seizures, retinopathy of prematurity, infection morbidity, anemia requiring blood transfusion, neonatal surgery, hyperbilirubinemia, neurological morbidity, or death prior to hospital discharge). Effect of maternal marijuana use on the probability of an adverse outcome was estimated using weighted methodology to account for oversampling in the original study. 11-nor-delta-9 tetrahydrocannabinol-9-carboxylic acid cord homogenate analysis was performed in the subset of women for whom biospecimens were available. Comparisons using logistic modeling, chi2, and t tests were weighted to account for oversampling of preterm births and non-Hispanic blacks. Results are reported as weighted percent and unweighted frequencies. RESULTS: Maternal marijuana use was identified in 2.7% (unweighted frequency 48/1610) of live births. Use was self-reported by 1.6% (34/1610) and detected by 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid in cord homogenate for 1.9% (17/897), n = 3 overlapping. Rate of tobacco use was 12.9% (217/1610), with 10.7% (167/1607) by self-report and 9.5% (141/1313) by serum cotinine. The composite adverse pregnancy outcome was not significantly increased in women with marijuana use compared to nonusers (31.2% vs 21.2%; P = .14). After adjustment for tobacco, clinical, and socioeconomic factors, marijuana use was not associated with the composite adverse pregnancy outcome (adjusted odds ratio, 1.29; 95% confidence interval, 0.56-2.96). Similarly, among women with umbilical cord homogenate and serum cotinine data (n = 765), marijuana use was not associated with adverse pregnancy outcomes (adjusted odds ratio, 1.02; 95% confidence interval, 0.18-5.66). Neonatal intensive care unit admission rates were not statistically different between groups (16.9% users vs 9.5% nonusers, P = .12). Composite neonatal morbidity or death was more frequent among neonates of mothers with marijuana use compared to nonusers (14.1% vs 4.5%; P = .002). In univariate comparisons, the components of the composite outcome that were more frequent in neonates of marijuana users were infection morbidity (9.8% vs 2.4%; P < .001) and neurologic morbidity (1.4% vs 0.3%; P = .002). After adjustment for tobacco, race, and other illicit drug use, marijuana use was still associated with composite neonatal morbidity or death (adjusted odds ratio, 3.11; 95% confidence interval, 1.40-6.91). CONCLUSION: Maternal marijuana use was not associated with a composite of small for gestational age, spontaneous preterm birth, or hypertensive disorders of pregnancy. However, it was associated with an increased risk of neonatal morbidity. PMID- 28578175 TI - Trends in hysterectomy rates among women veterans in the US Department of Veterans Affairs. AB - BACKGROUND: Prior studies demonstrate a higher prevalence of hysterectomy among veterans compared with nonveterans. While studies identify overall decreasing hysterectomy rates in the United States, none report rates of hysterectomy among women veterans. Given the increasing numbers of women veterans using Veterans Affairs health care, there is an ongoing need to ensure high-quality gynecology care. Therefore, it is important to examine current hysterectomy trends, including proportion of minimally invasive surgeries, among veterans using Veterans Affairs health care. OBJECTIVE: Our objective was to describe hysterectomy trends and utilization of minimally invasive hysterectomy in the Veterans Affairs healthcare system. STUDY DESIGN: This longitudinal study used Veterans Affairs clinical and administrative data from fiscal year 2008 to 2014 to identify hysterectomies provided or paid for by Veterans Affairs. Crude and age-adjusted hysterectomy rates were calculated by indication (benign or malignant), mode (abdominal, laparoscopic, vaginal, robotic assisted, unspecified), and source of care (provided vs paid for by Veterans Affairs). Mode and indication for hysterectomy were classified using International Classification of Diseases, ninth revision, codes. The distribution of hysterectomy mode in each year was calculated by indication and source of care. RESULTS: Between fiscal year 2008 and fiscal year 2014, the total hysterectomy rate decreased from 4.0 per 1000 to 2.6 per 1000 unique women veteran Veterans Affairs users. Age-adjusted rates of abdominal hysterectomy for benign indications decreased over the study period from 1.54 per 1000 (95% confidence interval, 1.40-1.69) to 0.77 per 1000 (95% confidence interval, 0.69-0.85) for procedures provided by Veterans Affairs and 0.77 per 1,000 (95% confidence interval, 0.69-0.85) to 0.29 per 1,000 (95% confidence interval, 0.23-0.34) for those paid for by Veterans Affairs. Among hysterectomies for benign indications provided by (n = 5296) or paid for (n = 2610) by Veterans Affairs, the percentage of hysterectomies performed abdominally decreased from 67.2% to 46.8% and from 68.9% to 57.6%, respectively. CONCLUSION: These findings suggest that gynecology care provided within Veterans Affairs has kept pace with national trends in reducing hysterectomy rates and increasing utilization of minimally invasive surgical techniques. PMID- 28578177 TI - The impact of uterine immaturity on obstetrical syndromes during adolescence. AB - Pregnant nulliparous adolescents are at increased risk, inversely proportional to their age, of major obstetric syndromes, including preeclampsia, fetal growth restriction, and preterm birth. Emerging evidence indicates that biological immaturity of the uterus accounts for the increased incidence of obstetrical disorders in very young mothers, possibly compounded by sociodemographic factors associated with teenage pregnancy. The endometrium in most newborns is intrinsically resistant to progesterone signaling, and the rate of transition to a fully responsive tissue likely determines pregnancy outcome during adolescence. In addition to ontogenetic progesterone resistance, other factors appear important for the transition of the immature uterus to a functional organ, including estrogen-dependent growth and tissue-specific conditioning of uterine natural killer cells, which plays a critical role in vascular adaptation during pregnancy. The perivascular space around the spiral arteries is rich in endometrial mesenchymal stem-like cells, and dynamic changes in this niche are essential to accommodate endovascular trophoblast invasion and deep placentation. Here we evaluate the intrinsic (uterine-specific) mechanisms that predispose adolescent mothers to the great obstetrical syndromes and discuss the convergence of extrinsic risk factors that may be amenable to intervention. PMID- 28578176 TI - Research standardization tools: pregnancy measures in the PhenX Toolkit. AB - Only through concerted and well-executed research endeavors can we gain the requisite knowledge to advance pregnancy care and have a positive impact on maternal and newborn health. Yet the heterogeneity inherent in individual studies limits our ability to compare and synthesize study results, thus impeding the capacity to draw meaningful conclusions that can be trusted to inform clinical care. The PhenX Toolkit (http://www.phenxtoolkit.org), supported since 2007 by the National Institutes of Health, is a web-based catalog of standardized protocols for measuring phenotypes and exposures relevant for clinical research. In 2016, a working group of pregnancy experts recommended 15 measures for the PhenX Toolkit that are highly relevant to pregnancy research. The working group followed the established PhenX consensus process to recommend protocols that are broadly validated, well established, nonproprietary, and have a relatively low burden for investigators and participants. The working group considered input from the pregnancy experts and the broader research community and included measures addressing the mode of conception, gestational age, fetal growth assessment, prenatal care, the mode of delivery, gestational diabetes, behavioral and mental health, and environmental exposure biomarkers. These pregnancy measures complement the existing measures for other established domains in the PhenX Toolkit, including reproductive health, anthropometrics, demographic characteristics, and alcohol, tobacco, and other substances. The preceding domains influence a woman's health during pregnancy. For each measure, the PhenX Toolkit includes data dictionaries and data collection worksheets that facilitate incorporation of the protocol into new or existing studies. The measures within the pregnancy domain offer a valuable resource to investigators and clinicians and are well poised to facilitate collaborative pregnancy research with the goal to improve patient care. To achieve this aim, investigators whose work includes the perinatal population are encouraged to utilize the PhenX Toolkit in the design and implementation of their studies, thus potentially reducing heterogeneity in data measures across studies. Such an effort will enhance the overall impact of individual studies, increasing the ability to draw more meaningful conclusions that can then be translated into clinical practice. PMID- 28578178 TI - Frequency and correlates of anticholinergic use among patients with schizophrenia in Denmark: A Nation-wide pharmacoepidemiological study. AB - Anticholinergic medications are used to treat extrapyramidal adverse effects induced by antipsychotics. Anticholinergics are associated with adverse effects: constipation, dry mouth and worsening of cognitive function. Anticholinergics have potential for abuse and are not recommended for long term-treatment. We aimed to investigate the use of anticholinergics in patients with schizophrenia. The national health registers in Denmark were used to examine: The prevalence of anticholinergics in 1996-2012 using a cross-sectional design; geographic variations in the prescription of anticholinergics in 2012; correlates of treatment with anticholinergics. The proportion of patients using anticholinergics decreased significantly from 11.7% in 1996 to 5.7% in 2012. The prescription pattern varied considerably between national regions in 2012, ranging from 4.0% in the Capital Region to 8.1% in the Northern Denmark Region. Long-term use of anticholinergics was predicted by older age, age at debut of schizophrenia, receiving early retirement pension, typical antipsychotic use, antipsychotic polypharmacy, typical + atypical antipsychotics, antidepressant treatment, high doses of antipsychotics measured in defined-daily-dose, physical comorbidity and psychiatrists' greater caseload. Use of anticholinergics declined during the study period, and showed substantial variation across the regions in 2012. Long-term use was linked to typical antipsychotic use and variables that are associated with greater illness severity. PMID- 28578179 TI - Internet use and psychosocial health of school aged children. AB - This study was carried out to determine the internet use and psychosocial health of school aged children. Children in grades 4-7 and their parents were invited to participate. The study group consisted of 737 children. Data were collected using a descriptive form and Pediatric Symptom Checklist-17. Majority of children used internet, one of each five children had psychosocial problem risk. Risk of psychosocial problem was higher in males, children who have 'not working father', use internet 5 years and over, use internet for 3h and over per day. These results suggest that families should be informed about associations between internet use and psychosocial problems that measures should be taken for providing controlled internet use for children. PMID- 28578180 TI - "With a little help from my friends" social predictors of clinical recovery in first-episode psychosis. AB - Social functioning is a conglomerate of factors central to clinical recovery after a first-episode psychosis. There is a lack of studies investigating the relative impact of factors related to social interaction. Disentangling these could facilitate improvement of psychosocial interventions. This study aims to investigate the impact of social interactions on two-year clinical recovery in first-episode psychosis, by examining frequency and satisfaction of relationships with family and friends. A baseline sample of 178 first-episode psychosis individuals were followed up over two years regarding social functioning and clinical status. We longitudinally compared those who were to those who were not recovered using generalized estimating equations analyses. Our results showed that frequency of social interactions with friends was a significant positive predictor of clinical recovery over a two-year period. Perceived satisfaction with relationships, and frequency of family interaction did not show significant effects. We conclude that interaction with friends is a malleable factor that could be targeted for early intervention. This would facilitate protective factors through the preservation of existing social networks and thus reduce the risk of disability associated with long-term psychosis. Findings indicate that even individuals with an inclination towards social withdrawal and isolation could benefit from this type of intervention. PMID- 28578181 TI - Catatonia in an inpatient gerontopsychiatric population. AB - There are limited data on the prevalence of catatonia in the elderly. The aim of this study was to determine the prevalence of catatonia in elderly patients (=/> 65 years) acutely admitted to the psychiatric unit of a general hospital. All patients aged 65 years and above admitted to a general hospital psychiatric unit over a 4-month period were screened for catatonia with the 14-item Bush-Francis Catatonia Screening Instrument (BFCSI). Patients with a minimum of 2 symptoms on the BFCSI were rated with the 23-item Bush-Francis Catatonia Rating Scale (BFCRS). Catatonia was simultaneously evaluated according to DSM-5 criteria. Clinical diagnoses were established using the validated Hungarian versions of the Structured Clinical Interview for DSM-IV Disorders, the Mini Mental State Examination and the Clock Drawing Test. Ninety-eight (28.1%) of the 342 patients admitted to the psychiatric unit during the study period were above 65 years of age; 11 (11.22%) and 6 (6.12%) patients were classified as having catatonia according to the BFCRS and DSM-5 criteria, respectively. The majority of the patients had catatonia due to a medical condition. A significant minority of gerontopsychiatric inpatients present with catatonia. Dementia was not a risk factor for catatonia. PMID- 28578182 TI - A confirmatory factor analysis of the PTSD checklist 5 in veteran and college student samples. AB - An important change in the conceptualization of posttraumatic stress disorder (PTSD) has been the shift from a three-factor model used in the DSM-IV-TR to the current four-factor model used in DSM-5. Early research initially supported the three-factor model, but most recent data suggest a four-factor model provides the best fit. Still other research has examined evidence for a five-factor model that would include depression sequelae. By way of a confirmatory factor analysis, we demonstrate the reliability of DSM-5 PTSD criteria clustering in a sample of 124 OEF/OIF/OND Veterans treated at a VAMC (49% white, 89% men) and a sample of 737 college students (48% white, 78% women). All participants were trauma-exposed, and completed the PTSD Checklist for DSM-5. The current study shows both samples best support a five-factor model over two four factor models considered for the DSM-5, though none provided better than moderate fit. Implications of the current findings regarding the reliability of the new DSM-5 criteria of PTSD will be discussed. PMID- 28578183 TI - Central Precocious Puberty Secondary to Adrenocortical Adenoma in a Female Child: Case Report and Review of the Literature. AB - BACKGROUND: Pediatric adrenocortical tumors are rare but significant causes of virilization and peripheral precocious puberty (PPP). CASE: A 4-year-old girl presented with development of breast, pubic hair, and facial acne. Her bone age was advanced, and her gonadotropin level did not elevate in a gonadotropin releasing hormone (GnRH) test. High levels of dehydroepiandrosterone sulfate, estradiol, and testosterone, and detection of a tumor in the left adrenal gland of the abdomen using computed tomography led to a diagnosis of PPP due to adrenal tumor. Adrenal adenoma was diagnosed with pathology after the tumor was removed. Ultrasonography detected multicystic ovaries before surgery. Although the androgen levels decreased, high estrogen levels persisted after complete tumor resection. Approximately 1 year after the surgery, the patient's breast development persisted, bone age progressed rapidly, and gonadotropin levels increased in a GnRH test. Central precocious puberty was diagnosed, and treatment with GnRH analogues was started. SUMMARY AND CONCLUSION: Adrenal adenoma might present with isosexual PPP as well as virilization in girls. The ovaries should be carefully assessed in these patients. Prolonged exposure to androgen and estrogen might cause ovarian multicysts leading to persistence of high estrogen levels and initiation of central precocious puberty. PMID- 28578184 TI - Rhabdomyosarcoma of the Vagina in an Adolescent Girl. AB - BACKGROUND: Gynecologic neoplasms are rare in children and represent only less than 5% of all childhood tumors. Rhabdomyosarcoma (RMS) of the female genital tract of children accounts for only 3.5% of the cases. CASE: A 16-year-old adolescent presented with a proliferating growth and foul smelling discharge from her vagina, which, on biopsy was diagnosed as RMS. She received chemotherapy and radiation to the primary site. She is alive in remission at 8 years, and with normal menstrual function. SUMMARY AND CONCLUSION: RMS of the vagina is a rare, but highly curable tumor in adolescent girls. Any abnormal vaginal bleeding in girls should be promptly investigated using pelvic examination and appropriate imaging. An organ-preserving approach should be considered in these patients. PMID- 28578186 TI - Revealing allele-specific gene expression by single-cell transcriptomics. AB - Single-cell sequencing has emerged as a revolutionary method that reveals biological processes with unprecedented resolution and scale, and has already greatly impacted biology and medicine. To investigate processes such as alternative splicing, novel exon detection and allele-specific expression (ASE), full-length based single-cell RNA-seq methods are required for broad sequence coverage and single nucleotide polymorphism (SNP) identification. In this review, we revisit recent achievements from studies that used single-cell RNA-seq to advance our understanding of ASE in the context of both autosomal and X chromosome genes. We also recapitulate useful bioinformatic tools developed to identify haplotype phase. PMID- 28578185 TI - Management of Low-Grade Cervical Mullerian Adenosarcoma in a 14-Year-Old Girl. AB - BACKGROUND: Mullerian adenosarcomas of the cervix are composed of benign epithelial and malignant stromal components. The purpose of this report is to describe the clinical and histologic difficulties in diagnosis and to propose fertility-preserving management of low-grade lesions. CASE: A 14-year-old girl presented with a friable lesion found to originate from the anterior cervical lip. Initially, clinical suspicion was for sarcoma botryoides, however, pathologic evaluation revealed a low-grade cervical Mullerian adenosarcoma. Cold knife conization was performed, and the mass was resected with clear margins. SUMMARY AND CONCLUSION: Mullerian adenosarcoma of the cervix is difficult to diagnose in adolescents because of features more commonly associated with alternative diagnoses. For patients with low-grade lesions desiring future fertility, local excision with close follow-up is reasonable. PMID- 28578187 TI - Pupillometric and saccadic measures of affective and executive processing in anxiety. AB - Anxious individuals report hyper-arousal and sensitivity to environmental stimuli, difficulties concentrating, performing tasks efficiently and inhibiting unwanted thoughts and distraction. We used pupillometry and eye-movement measures to compare high vs. low anxious individuals hyper-reactivity to emotional stimuli (facial expressions) and subsequent attentional biases in a memory-guided pro- and antisaccade task during conditions of low and high cognitive load (short vs. long delay). High anxious individuals produced larger and slower pupillary responses to face stimuli, and more erroneous eye-movements, particularly following long delay. Low anxious individuals' pupillary responses were sensitive to task demand (reduced during short delay), whereas high anxious individuals' were not. These findings provide evidence in anxiety of enhanced, sustained and inflexible patterns of pupil responding during affective stimulus processing and cognitive load that precede deficits in task performance. PMID- 28578188 TI - Children's cortisol and externalizing stress symptoms are predictors of adiponectin evolution over two years. AB - BACKGROUND: Adiponectin is an anti-inflammatory, insulin-sensitizing and energy regulating adipocytokine. Consequently, the link between psychosocial stress and inflammatory diseases like the metabolic syndrome might be partially explained by lower adiponectin levels in stress. Nevertheless, the stress-adiponectin association has seldom been tested and no clarity exists about the directionality. METHODS: In the Belgian ChiBS study, serum adiponectin and stress levels were measured in 348 children (5-10y) at baseline and in 168 of them after 2-year follow-up. Psychosocial stress was reported with the Strengths and Difficulties Questionnaire (parental report on emotional, peer, and conduct problems), negative emotions (anger, sadness, anxiety) and negative events. In addition, salivary cortisol diurnal patterns were available from 2days with each 4 samples. Longitudinal linear regression analyses were performed including step wise adjustment for age, sex, socio-economic status, body fat%, physical activity and snack frequency. RESULTS: Despite some positive cross-sectional associations, high daily cortisol output (beta=-0.285), anger (beta=-0.233) and conduct problems (beta=-0.182) were associated with less adiponectin increase over time, in most cases independent of the tested confounders. The other directionality was not significant: no longitudinal prediction of stress by adiponectin. CONCLUSION: In healthy children, daily cortisol output and externalizing stress symptoms were negative predictors of adiponectin evolution. These findings highlight the health compromising effects of psychosocial stress. PMID- 28578190 TI - Correlation between Dynamic Light Scattering and Size Exclusion High Performance Liquid Chromatography for Monitoring the Effect of pH on Stability of Biopharmaceuticals. AB - Aggregate formation is a major problem affecting both safety and efficacy of biopharmaceuticals and is associated with protein immunogenicity. Size exclusion high performance liquid chromatography (SE-HPLC) has always been the gold standard technique for detection and determination of protein aggregates. However, large protein aggregates may be filtered off and build up on top of the column leading to deterioration in column performance. Moreover, low-affinity protein aggregates may dissociate during analysis and thus not detected. On the other hand, dynamic light scattering (DLS) is a simple and non-destructive technique that can detect high molecular weight physical and chemical aggregates in their native environment. Here, three model biopharmaceutical proteins of different physicochemical properties were selected; quadrivalent human papillomavirus virus like particles vaccine (HPV VLP, physically assembled subunit vaccine, 55kDa), pegylated Interferon (PegIFN, pegylated non-glycosylated protein, 31.3kDa) and Pegylated Erythropoietin (PegEPO, pegylated and glycosylated protein, 60kDa). Samples were subjected to forced degradation conditions previously shown to lead to aggregate formation (pH 4.0, 8.0 and 10.0, at 37 degrees C for 24h) and samples were analyzed using DLS and SE-HPLC. Generally, good agreement between the results of DLS and SE-HPLC was noted, regardless of the differences in physicochemical properties of the studied biopharmaceuticals. Results showed that aggregate formation was not detected in some cases by SE-HPLC and the decrease in the concentration of the monomeric forms indicated that such aggregates might have been filtered off the column. Although no single techniques can reveal all aspects of protein stability, DLS can serve as a screening tool to detect aggregate formation and cross-validate SE HPLC results during batch release testing. Owing to its simplicity and low-sample volume requirements, DLS can be used even by hospital pharmacists to confirm absence of protein aggregates immediately before drug administration. PMID- 28578189 TI - Photoactivatable fluorescent probes reveal heterogeneous nanoparticle permeation through biological gels at multiple scales. AB - Diffusion through biological gels is crucial for effective drug delivery using nanoparticles. Here, we demonstrate a new method to measure diffusivity over a large range of length scales - from tens of nanometers to tens of micrometers - using photoactivatable fluorescent nanoparticle probes. We have applied this method to investigate the length-scale dependent mobility of nanoparticles in fibrin gels and in sputum from patients with cystic fibrosis (CF). Nanoparticles composed of poly(lactic-co-glycolic acid), with polyethylene glycol coatings to resist bioadhesion, were internally labeled with caged rhodamine to make the particles photoactivatable. We activated particles within a region of sample using brief, targeted exposure to UV light, uncaging the rhodamine and causing the particles in that region to become fluorescent. We imaged the subsequent spatiotemporal evolution in fluorescence intensity and observed the collective particle diffusion over tens of minutes and tens of micrometers. We also performed complementary multiple particle tracking experiments on the same particles, extending significantly the range over which particle motion and its heterogeneity can be observed. In fibrin gels, both methods showed an immobile fraction of particles and a mobile fraction that diffused over all measured length scales. In the CF sputum, particle diffusion was spatially heterogeneous and locally anisotropic but nevertheless typically led to unbounded transport extending tens of micrometers within tens of minutes. These findings provide insight into the mesoscale architecture of these gels and its role in setting their permeability on physiologically relevant length scales, pointing toward strategies for improving nanoparticle drug delivery. PMID- 28578191 TI - Determination of quetiapine in human plasma by LC-MS/MS and its application in a bioequivalence study. AB - A selective, sensitive and simple high performance liquid chromatography tandem mass spectrometric (HPLC-MS/MS) method for determining quetiapine in human plasma was developed and validated. One-step protein precipitation with acetonitrile was used to pretreat plasma samples. Carbamazepine was used as internal standard. An automated liquid handling workstation with 96-well protein precipitate plate was used to facilitate the process. The chromatographic separation was achieved on a Waters Xbridge C18 column (3.5MUm, 2.1mm*50mm). Gradient elution was set with a mobile phase of acetonitrile/water (containing 10mM ammonium acetate and 0.1% formic acid).The flow rate was 0.4mL/min and total analytical run time was 3min. The analysis was conducted using a triple quadrupole tandem mass spectrometer with an electrospray ionization source operating in positive ion mode. The multiple reaction monitoring of transition were m/z 384.2->253.1 for quetiapine and m/z 237.0->194.0 for carbamazepine, respectively. The linear concentration range for the standard curve of quetiapine was 0.5-400ng/mL for a 5MUL injection of the pretreated sample (original plasma sample, 50MUL). The intra-day and inter day accuracy and precision were all less than 15%. The method was successfully used in a bioequivalence study comparing two quetiapine extended-release tablets in Chinese volunteers. PMID- 28578192 TI - Cross-platform metabolomics investigating the intracellular metabolic alterations of HaCaT cells exposed to phenanthrene. AB - Phenanthrene (Phe) is one of the most abundant Polycyclic aromatic hydrocarbons (PAHs) contamination from various ambient sources, which has a tremendous impact on public health. However, our knowledge regarding its effects on skin remains limited. In this study, we investigated the metabolite profiling of the human keratinocytes HaCaT cells after Phe exposure to understand the toxic effects of Phe exposure on skin. To obtain a broad picture of metabolome with various hydrophilicity, a cross-platform approach with GC-MS and UHPLC-QTOF-MS has been employed. Data were analyzed by multivariate statistical analysis and samples were separated successfully using supervised PLS-DA models. It was shown that the impacts of Phe exposure on HaCaT cells were both dose-related and time-related. A total of 48 Phe-regulated metabolites were identified and among which 19 were confirmed by reference standards. By pathway analysis, amino acid metabolism, glutathione metabolism and glycerophospholipid metabolism were highlighted as the major metabolic pathways disturbed by Phe. Furthermore, it was found that the mechanisms included a reduced amino pool and a reduced antioxidant status. Overall, these results aid in improving understanding of the dermal toxicology related to Phe, and demonstrate this cross-platform approach is suitable for metabolomics researches on HaCaT cells. PMID- 28578193 TI - Measurement of soil lead bioavailability and influence of soil types and properties: A review. AB - Lead (Pb) is a widespread heavy metal which is harmful to human health, especially to young children. To provide a human health risk assessment that is more relevant to real conditions, Pb bioavailability in soils is increasingly employed in the assessment procedure. Both in vivo and in vitro measurements for lead bioavailability are available. In vivo models are time- consuming and expensive, while in vitro models are rapid, economic, reproducible, and reliable while involving more uncertainties. Uncertainties in various measurements create difficulties in accurately predicting Pb bioavailability, resulting in the unnecessary remediation of sites. In this critical review, we utilised available data from in vivo and in vitro studies to identify the key parameters influencing the in vitro measurements, and presented uncertainties existing in Pb bioavailability measurements. Soil type, properties and metal content are reported to influence lead bioavailability; however, the differences in methods for assessing bioavailability and the differences in Pb source limit one's ability to conduct statistical analyses on influences of soil factors on Pb bioavailability. The information provided in the review is fundamentally useful for the measurement of bioavailability and risk assessment practices. PMID- 28578194 TI - Advances in bioelectrochemical systems. PMID- 28578195 TI - Intensive epidermal adsorption and specific venous deposition of carboxyl quantum dots in zebrafish early-life stages. AB - To properly assess the environmental risk of quantum dots (QDs), it is necessary to determine their fate in living organisms, including adsorption, distribution and bioaccumulation under representative environmental or physiological conditions. We comprehensively investigated the fate of QDs with carboxyl terminal functional groups (carboxyl-QDs) in zebrafish (Danio rerio) embryo and larvae subjected to either waterborne exposure or cardiovascular system microinjection. On waterborne exposure, carboxyl-QDs exhibited an intensive adsorption and accumulation in the chorion of embryos, and their predominate target organs were the gill and intestinal tract in larvae. On microinjection, carboxyl-QDs were rapidly delivered into the cardiovascular system and specifically deposited in veins and the capillary network system of zebrafish larvae, but not in the arterial system. Taken together, we found that the exact tissue condition including epidermal structures, mucus secretion and vascular microstructures strongly affected the adsorption, uptake and distribution of carboxyl-QDs in zebrafish. This work highlights the intensive tissue epidermal adsorption and accumulation of carboxyl-QDs and their specific vein and capillary deposition in the cardiovascular system in zebrafish early-life stages. PMID- 28578196 TI - Organic compounds stimulate horizontal transfer of antibiotic resistance genes in mixed wastewater treatment systems. AB - Domestic wastewater treatment plants as a reservoir of antibiotic resistance genes (ARGs) have received much attention, but the effect of dyes on the propagation of ARGs has rarely been investigated. In this study, we investigated the differences in distributions of ARGs and microbial communities using high throughput qPCR and 16S rRNA gene sequencing, respectively, between mixed (dyeing and domestic) wastewater and domestic sewage. The relative abundance of ARGs in inflows of mixed wastewater (IW2 and IW3) was higher than that of domestic wastewater (IW1). The relative abundance of mobile genetic elements in the inflow of textile dyeing wastewater (IDW3) was 3- to 13-fold higher than that in other samples. Moreover, in IDW3, some distinct high abundance ARGs, particularly operons encoding efflux pumps (such as acrR-01, acrB-01 and acrF), were significantly correlated with Streptococcus of the Firmicutes. To explore why the abundance of ARGs was relatively high in mixed wastewater, six representative types of organic compounds in textile dyeing wastewater were used to test the effect on plasmid-based conjugative transfer from E. coli HB101 to E. coli NK5449. These six compounds all facilitated the transfer of resistance-carrying RP4 plasmid, and the highest transfer frequency (approximately 10-5-10-3) was over 4- to 200-fold higher than that in the control group (approximately 10-6-10 5). These results illustrated that the six common residual compounds, particularly low-dose substances in IDW3, could facilitate the dissemination of ARGs in aquatic environments. More importantly, this study revealed for the first time that dyeing contaminants influenced horizontal gene transfer (HGT) of ARGs. PMID- 28578197 TI - Instability of chlorophyll in yellow lupin seedlings grown in soil contaminated with ciprofloxacin and tetracycline. AB - With increasing soil concentrations of ciprofloxacin and tetracycline a decrease of leaf chlorophyll content was observed. Tetracycline was more detrimental than ciprofloxacin. The chlorophyll content in plants growing for ten days on a tetracycline containing soil decreased by 68%. The decrease of chlorophyll concentration was even sharper in new leaves that formed after application of the antibiotic (up to 81% drop). The comparison of absorption spectra of commercial, reagent grade chlorophyll, alone and incubated with antibiotics, has shown that ciprofloxacin and tetracycline can react directly with chlorophyll and decrease its concentration by 47.7% and 48.5%, respectively. The changes in fluorescence spectra confirmed the formation of chlorophyll degradation product. The chlorophyll decay was a second order reaction and depended on antibiotic concentration and duration of exposure. Reaction rate constants differed with antibiotics and their soil concentrations. With increasing contents of antibiotics in soil the constant of chlorophyll degradation rate in lupin plants increased from k = 870 M-1day-1 for 3 mg ciprofloxacin to k = 2490 M-1day-1 for 90 mg ciprofloxacin, and in the case of tetracycline the reaction rate constant increased from k = 1330 M-1day-1 to k = 2910 M-1day-1. The sensitivity of chlorophyll to ciprofloxacin and tetracycline was confirmed by determining EC and TU indices. PMID- 28578198 TI - Synthesis of (+/-)-myo-inositol 4-methylenephosphonate via Rh-Catalyzed hydrogenation of vinylphosphonate. AB - Phosphatidylinositol phosphate (PIP) synthetase is a promising target for the development of new anti-mycobacterium compounds. We previously reported that myo inositol 1-methylenephosphonate showed inhibitory activity against PIP synthetase. Herein, we report the synthesis of unprotected myo-inositol 4 methylenephosphonate, a constitutional isomer of myo-inositol 1 methylenephosphonate and found that the stereoselective hydrogenation of vinylphosphonate proceeded via Rh catalysis. PMID- 28578200 TI - The effects of diatom pore-size on the structures and extensibilities of single mucilage molecules. AB - Diatoms secrete extracellular polymeric substances (EPS), or mucilage, around the cell wall that may serve to aid in motility and form a discrete layer that may help maintain thicker layers of EPS that have a greater role in adhesion. Mucilage molecules adhere to the diatom frustules, which are biosilica skeletons that develop from the diatom cell walls. Here, molecular dynamics methods were used to determine the characteristics of mucilage molecules as a function of pore size; notably 1,4-alpha-D-galacturonic acid, 1,4-beta-glucuronic acid and 1,4 beta-D-mannuronic acid. These uronic acids differ from each other in structure and extensibility as a function of their folding characteristics. Here, we find that when overlain upon a pore, mucilage molecules try to return to their native folded states but are restrained by their interactions with the silica surfaces. Furthermore, the extensibility of mucilage molecules over pore spaces affects the extent of mechanical energy required to straighten them. As such, different EPS molecules will affect sliding, friction and adhesion to subsequent layers of EPS in different ways. We conclude that higher EPS extensibility is homonymous with higher adhesive or frictive resistance since the molecules will be able to strain more before they reach the most extended (and thus rigid) conformation. The research herein is applicable to modern engineering as it yields insight into the biomimetic design of molecules and surfaces for improved adhesion or motility. PMID- 28578199 TI - Structures of the K35 and K15 capsular polysaccharides of Acinetobacter baumannii LUH5535 and LUH5554 containing amino and diamino uronic acids. AB - Capsular polysaccharides were isolated from A. baumannii LUH5535 (K35 CPS) and LUH5554 (K15 CPS) and studied by 1D and 2D 1H and 13C NMR spectroscopy. The CPSs were found to consist of linear tetrasaccharide repeats (K units) containing 2 acetamido-2-deoxy-d-galacturonic acid (K35) or 2,3-diacetamido-2,3-deoxy-d glucuronic acid (K15) and 2,4-diacetamido-2,4,6-trideoxy-d-glucose (both CPSs). The K35 unit includes three O-acetyl groups on different GalNAcA residues. A. baumannii LUH5535 and LUH5554 carry the KL35 and KL15 gene clusters, respectively, and putatively assigned functions of genes in these clusters were consistent with the CPS structures established. PMID- 28578201 TI - Correlated evolutionary rates across genomic compartments in Annonaceae. AB - The molecular clock hypothesis is an important concept in biology. Deviations from a constant rate of nucleotide substitution have been found widely among lineages, genomes, genes and individual sites. Phylogenetic research can accommodate for these differences in applying specific models of evolution. Lineage-specific rate heterogeneity however can generate bi- or multimodal distributions of substitution rates across the branches of a tree and this may mislead phylogenetic inferences with currently available models. The plant family Annonaceae is an excellent case to study lineage-specific rate heterogeneity. The two major sister subfamilies, Annonoideae and Malmeoideae, have shown great discrepancies in branch lengths. We used high-throughput sequencing data of 72 genes, 99 spacers and 16 introns from 24 chloroplast genomes and nuclear ribosomal DNA of 23 species to study the molecular rate of evolution in Annonaceae. In all analyses, longer branch lengths and/or higher substitution rates were found for the Annonoideae compared to the Malmeoideae. The Annonaceae had wide variability in chloroplast length, ranging from minimal 175,684bp to 201,723 for Annonoideae and minimal 152,357 to 170,985bp in Malmeoideae, mostly reflecting variation in inverted-repeat length. The Annonoideae showed a higher GC-content in the conserved parts of the chloroplast genome and higher omega (dN/dS)-ratios than the Malmeoideae, which could indicate less stringent purifying selection, a pattern that has been found in groups with small population sizes. This study generates new insights into the processes causing lineage-specific rate heterogeneity, which could lead to improved phylogenetic methods. PMID- 28578202 TI - Management of atypical polypoid adenomyomas. A case series. AB - OBJECTIVE: Atypical polypoid adenomyomas (APAs) are endometrial, non-malignant, focal, and non-invasive lesions that are intriguing for their histological resemblence to invasive endometrioid adenocarcinoma or malignant mixed Mullerian tumor. The aim of this study was to present our clinical experience, regarding the reproductive outcome, the recurrence rate, and the association with hyperplasia and cancer, in a small series of patients with APA. STUDY DESIGN: Retrospective case series of patients treated for APA in a single private hospital setting from 1998 to 2016. All patients underwent diagnostic hysteroscopy and hysteroscopic removal of the lesion. Follow-up was performed annually with endovaginal ultrasonography and hysteroscopy when necessary. RESULTS: Nine patients (mean age: 37.9 years-old +/-8.3years) were treated because of menorrhagia, infertility, and incidental asymptomatic endometrial lesions with operative hysteroscopy. Mean follow-up was 10.0 years (+/-5.8years). Three patients intended for pregnancy and 2 of them had achieved a full term delivery. There were 2 recurrences (22.2%), two cases of atypical endometrial hyperplasia (22.2%), and 2 patients with endometrioid adenocarcinoma (22.2%), all within the first 5 years. CONCLUSIONS: It appears that APAs exhibit a significant recurrence rate and they may be related both to atypical endometrial hyperplasia and endometrial adenocarcinoma; therefore, clinicians should be aware of these lesions in order to individualize treatment according to the patent's age and fertility history. PMID- 28578203 TI - What next? Preferably development of drugs that are no longer transported by the ABCB1 and ABCG2 efflux transporters. PMID- 28578204 TI - Pericytes and cardiac stem cells: Common features and peculiarities. AB - Clinical data and basic research indicate that the structural and functional alterations that characterize the evolution of cardiac disease towards heart failure may be, at least in part, reversed. This paradigm shift is due to the accumulation of evidence indicating that, in peculiar settings, cardiomyocytes may be replenished. Moving from the consideration that cardiomyocytes are rapidly withdrawn from the cell cycle after birth, independent laboratories have tested the hypothesis that cardiac resident stem/progenitor cells resided in mammalian hearts and were important for myocardial repair. After almost two decades of intensive investigation, several (but partially overlapping) cardiac resident stem/progenitor cell populations have been identified. These primitive cells are characterized by mesenchymal features, unique properties that distinguish them from mesodermal progenitors residing in other tissues, and heterogeneous embryological origins (that include the neural crest and the epicardium). A further layer of complexity is related to the nature, in vivo localization and properties of mesodermal progenitors residing in adult tissues. Intriguingly, these latter, whose possible perivascular pericyte/mural cell origin has been shown, have been identified in human hearts too. However, their exact anatomical localization, pathophysiological role, and their relationship with cardiac stem/progenitor cells are emerging only recently. Therefore, aim of this review is to discuss the different origin, the distinct nature, and the complementary effect of cardiac stem cells and pericytes supporting regenerative strategies based on the combined use of both myogenic and angiogenic factors. PMID- 28578205 TI - Salicylic acid seed priming instigates defense mechanism by inducing PR-Proteins in Solanum melongena L. upon infection with Verticillium dahliae Kleb. AB - Salicylic acid (SA) is a hormone connected with various cellular functions including the fight against invading pathogens. Priming of seeds pre-sowing is a very simple method to the farmers' to produce better growth, yield and manage the pathogens. The present study was aimed to determine the growth and disease resistance ability in brinjal seeds primed with different concentrations (0.25, 0.5, 0.75 and 1.0 mM) of SA under greenhouse conditions. Priming of seeds with SA significantly increased seed germination and seedling vigor with a maximum of 84% and 859.18, respectively at 0.5 mM concentration. Seed priming with SA also reduced Verticillium wilt incidence to 39.25% (at 0.5 mM) under greenhouse conditions and also enhanced the vegetative growth parameters of the plant compared to control. The induced resistance obtained with SA was in line with higher expression of PR-protein (beta-1,3-glucanase and chitinase) related defense enzymes. Further, an increase of 1.7, 2.9, 2.1, 2.5 and 2-fold increase in gene expression of IAA27, MPK1, GPX, chitinase and beta-1,3-glucanase, respectively were observed in SA primed challenge inoculated seedlings than non primed susceptible inoculated controls. The higher expression of IAA27, MPK1, GPX, chitinase and beta-1,3-glucanase correlates with the plant growth promoting and disease protection studies as these genes are vital for increasing plant growth and inducing resistance during host-pathogen interaction. Enhanced activation of defense-related activities in plants upon priming with SA suggests that it alters plant physiology which in turn is useful for production and protection of brinjal. PMID- 28578206 TI - Is Internet addiction transitory or persistent? Incidence and prospective predictors of remission of Internet addiction among Chinese secondary school students. AB - BACKGROUND: Internet addiction (IA) is prevalent among adolescents but it is potentially revertible. Only three Taiwan adolescent studies reported IA remission and a few related factors. We investigated incidence and predictors of remission among Hong Kong Chinese secondary school students with a 12-month longitudinal study. METHODS: IA was defined as Chen Internet Addiction Scale (CIAS) score>63. Validated measures were used to assess students' psychosocial wellbeing at baseline and follow-up. RESULTS: Of 1545 students with IA at baseline, 1296 (83.9%) provided matched baseline/12-month follow-up data; their data were analyzed. Incidence of remission (CIAS<=63 at follow-up) was 59.29/100 person-years. Significant predictors included: 1) baseline CIAS score (ORa=.95), 2) baseline health belief model (HBM) constructs [perception of having severe IA (ORa=.34), perceived susceptibility to IA (ORa=0.82), perceived barrier (ORa=0.95), cue to action from parents (ORa=0.82), and self-efficacy for reducing Internet use (ORa=1.13)], and 3) baseline psychosocial health measures [self esteem (ORa=1.03), severe depression (ORa=0.72) and social anxiety (ORa=0.96)] and their changes over time [depression (ORa=.95), anxiety (ORa=.94), loneliness (ORa=.93), self-esteem (ORa=1.07), positive affect (ORa=1.10) and family support (ORa=1.03)]. Two-thirds (64.3%) of the remission group presented reduced CIAS score>1.5 SD, and recorded larger improvements in psychosocial status over time than the non-remission group. CONCLUSION: Without noticeable interventions, incidence of remission was high and related to improvements in psychosocial health. Most of the HBM constructs, and baseline/changes in psychosocial measures predicted remission. Interventions to increase remission should modify these factors. PMID- 28578207 TI - Schizophrenia: A review of potential biomarkers. AB - OBJECTIVES: Understanding the biological process and progression of schizophrenia is the first step to developing novel approaches and new interventions. Research on new biomarkers is extremely important when the goal is an early diagnosis (prediction) and precise theranostics. The objective of this review is to understand the research on biomarkers and their effects in schizophrenia to synthesize the role of these new advances. METHODS: In this review, we search and review publications in databases in accordance with established limits and specific objectives. We look at particular endpoints such as the category of biomarkers, laboratory techniques and the results/conclusions of the selected publications. RESULTS: The investigation of biomarkers and their potential as a predictor, diagnosis instrument and therapeutic orientation, requires an appropriate methodological strategy. In this review, we found different laboratory techniques to identify biomarkers and their function in schizophrenia. CONCLUSION: The consolidation of this information will provide a large-scale application network of schizophrenia biomarkers. PMID- 28578208 TI - BDNF Val66Met and childhood adversity on response to physical exercise and internet-based cognitive behavioural therapy in depressed Swedish adults. AB - The genetic effect of Brain-derived neurotrophic factor (BDNF) on treatment response in depression is not consistent in the literature. Childhood adversity is a known risk factor for depression which has been reported to increase depression susceptibility by interacting with BDNF genetic variation. We aimed to explore whether the BDNF variation Val66Met and childhood adversity (CA) predicted the treatment response to a 12-week intervention with physical exercise (PE) or internet-based cognitive behavioural therapy (ICBT) when compared with treatment as usual (TAU). A prospective cohort study nested within a randomised control trial was conducted using data from 547 participants with mild to moderate depression. Depression severity at baseline and follow-up was measured using the Montgomery-Asberg Depression Rating Scale. Met allele carriers without exposure to CA and current antidepressant use showed higher treatment response to PE than Val homozygotes. There was no evidence to support that BDNF Val66Met or CA alone predicted treatment response to PE and ICBT. The Met carriers had higher serum mature BDNF level. These data suggest that Met allele carriers benefit more from PE treatment but only if they are not exposed to early adversity. PMID- 28578209 TI - A method for understanding generic procurement of HIV medicines by developing countries with patent protection. AB - Patent protection on medicines may frustrate access by blocking generic competition. Nevertheless, circumstances may still allow for generic procurement to occur anyway, especially for humanitarian cause. But to what extent does this occur? And which legal flexibilities may facilitate such procurement? We attempted to design a replicable methodology that involved linking antiretroviral (ARV) patent data (1260 patents for 12 medicines) from a World Intellectual Property Organization patent study on the 2013 World Health Organization's (WHO) Model List of Essential Medicines to all available matching procurement records in the WHO's Global Price Reporting Mechanism. We then cross-referenced these with lists of legal flexibilities which facilitate generic access where patents have been granted (e.g., supplier companies' patent non-enforcement policies, voluntary and compulsory licenses) to estimate plausible relevance. The patent data corresponded to 1924 generic procurement transactions (1.34 billion units) from 85 countries. While patents were relatively less common in these countries (the median coverage was 20%), over half (53%) of the generic procurements nevertheless aligned with patent protection in the exporting and/or importing country. The disproportionately high relevance of patents despite their lower numbers can be explained by their presence in key medicine-exporting countries and/or those with larger populations. We noted, however, that developing countries still seemed able to buy generic versions of these essential ARVs. A combination of legal flexibilities may have played important roles, but voluntary licensing agreements (VLs) between originator companies and generic ones appeared to align with the largest volumes of generic procurement where we estimated patent protection. If true, VLs may warrant proportionate attention from observers as a heavily relied upon international mechanism for facilitating generic access so that the implications can be better understood; however, we hope others repeat similar studies to investigate whether these results hold with different methodologies and samples of patented medicines, contexts, and timeframes. PMID- 28578210 TI - Public attitudes toward child undervaccination: A randomized experiment on evaluations, stigmatizing orientations, and support for policies. AB - Child undervaccination is a complex public health problem and a contentious social and political issue. Efforts to increase vaccination coverage require understanding how the public evaluates different reasons for child undervaccination, which may influence attitudes, stigmatizing behaviors, and support for vaccination policies. We conducted a vignette experiment with a United States national online sample (n = 1469) to investigate how and why different undervaccination actions shape evaluations (blame, anger, sympathy, differentness, credibility, dangerousness), stigmatizing orientations (social distance, discrimination), and support for particular policies (e.g., research funding, belief exemptions, fines). Each participant was randomly assigned to read one of four vignettes that described a mother who either refused vaccines, delayed vaccines, encountered social barriers to obtaining vaccines, or was up-to date on vaccines for her child. Compared to the up-to-date condition, each undervaccination action predicted significantly more negative evaluations and stigmatizing orientations. Vaccine refusal was the most negatively appraised. Differences in social distance and discrimination were explained by negative evaluations about the parent. These evaluations and orientations predicted support for a range of policies. Negative parental evaluations were associated with increased support for more severe policies. We discuss the implications of these findings for addressing undervaccination and informing health scholarship on stigma. PMID- 28578211 TI - Confined to a tokenistic status: Social scientists in leadership roles in a national health research funding agency. AB - The idea of interdisciplinarity has been taken up by academic and governmental organisations around the world and enacted through science policies, funding programs and higher education institutions. In Canada, interdisciplinarity led to a major transformation in health research funding. In 2000, the federal government closed the Medical Research Council (MRC) and created the Canadian Institutes of Health Research (CIHR). From the outset, CIHR's vision and goals were innovative, as it sought to include the social sciences within its purview alongside more traditional health research sectors. The extent to which it has been successful in this endeavour, however, remains unknown. The aim of our study was to examine how CIHR's intentions to foster inclusiveness and cooperation across disciplines were implemented in the agency's own organisational structure. We focused on social scientists' representation on committees and among decision makers between 2000 and 2015, one of the key mandates of CIHR being to include the social sciences within its remit and support research in this area. We examined the composition of the Governing Council, the Institute Scientific Directors, the Chairs of the College of Reviewers, and two International Review Panels invited by CIHR. We targeted these committees and decision-makers since they hold the power to influence the field of Canadian health research through the decisions they make. Our findings show that, while CIHR was created with the mandate to support the entire spectrum of health-related research-including the social sciences-this call for inclusiveness has not yet been materialized in the agency's organisational structure. Social scientists, as well as researchers from neighbouring disciplines such as social epidemiology, health promotion and the humanities, are still confined to low levels of representation within CIHR's highest echelons. This imbalance limits social scientists' input into health research in Canada and undermines CIHR's interdisciplinary ambition. PMID- 28578212 TI - Contributions of risk preference, time orientation and perceptions to breast cancer screening regularity. AB - Disparities in breast cancer screening are often explained by socioeconomic factors, although a growing body of papers show that risk preference, time orientation and perceptions may explain mammography use. The aim of this paper is to estimate the relative contribution of socioeconomic factors, risk preference, time orientation and perceptions to disparities in breast cancer screening regularity. These determinants are elicited in an experimental laboratory from 178 women aged between 50 and 75 years in France in 2013. The results reveal that risk aversion accounts for 30% of the variance in screening regularity, which is greater than that attributable to socioeconomic determinants (20%), perceptions (11.5%) or time orientation (2%). These results suggest that further investigation on the relationship between risk aversion and screening behaviors is needed to design more comprehensive public health interventions. PMID- 28578213 TI - Influence of broadleaf forest vegetation on atmospheric deposition of airborne radionuclides. AB - The activities of airborne radionuclides 7Be and unsupported 210Pb (210Pbus) were measured in moss samples taken from 17 different locations. The objective was to estimate the influence of the broadleaf forest vegetation on atmospheric deposition of airborne radionuclides attached to aerosols. Two moss samples were collected at each location: within the forest stand (inside the area of the tree canopy projection) and within forest openings (outside the area of the tree canopy projection). Samples were taken in the spring season, before the leaves of trees came forth and in the autumn season, right before fall defoliation. A measurement indicates an absence of variation in 210Pbus concentration, however spring/autumn ratios of 7Be concentrations in mosses showed the expected seasonal difference in 7Be deposition. It was also noted that atmospheric deposition of 7Be at the forest openings was about two times higher than deposition in the forest. Using very simplified models, these measurements can be used to get estimation at how long 7Be and aerosols can reside on the leaves before precipitation eventually wash it to the ground mosses. It was estimated that the mean residence time of aerosols in the leaves was up to 50 days. PMID- 28578214 TI - Biomarker responses to environmental contamination in estuaries: A comparative multi-taxa approach. AB - Estuaries are highly productive ecosystems subjected to numerous anthropogenic pressures with consequent environmental quality degradation. In this study, multiple biomarker responses [superoxide dismutase (SOD), catalase (CAT), ethoxyresorufin O-deethylase (EROD) and glutathione S-transferase (GST) activities, as well as lipid peroxidation (LPO) and DNA damage (DNAd)] were determined in two fish (Dicentrarchus labrax and Pomatoschistus microps) and four macroinvertebrate species (Carcinus maenas, Crangon crangon, Hediste diversicolor and Scrobicularia plana) from the Ria de Aveiro and Tejo estuaries over distinct months. Two sites per estuarine system were selected based on anthropogenic pressures and magnitude of environmental contamination. Antioxidant enzyme activities in fish species suggested a ubiquitous response to oxidative stress, while biotransformation and effect biomarkers exhibited higher spatial and temporal variation. In invertebrate species, biotransformation enzyme activity was clearly less variable than in fish evidencing lower xenobiotic transformation capability. Overall, largest biomarker responses were found in the most contaminated sites (Tejo), yet species-specific patterns were evident. These should be factored in multi-taxa approaches, considering that the differential functional traits of species, such as habitat use, life-stage, feeding or physiology can influence exposure routes and biomarker responses. The Integrated Biomarker Response index highlighted patterns in biomarker responses which were not immediately evident when analyzing biomarkers individually. Overall, results provided insights into the complexity of species responses to contamination in naturally varying estuarine environments. Ultimately, multi-taxa and multi biomarker approaches provide a comprehensive and complementary view of ecosystem health, encompassing diverse forms of biological integration and exposure routes, and allow the validation of results among markers and species. PMID- 28578215 TI - Effects of agomelatine on pentylenetetrazole-induced kindling, kindling associated oxidative stress, and behavioral despair in mice and modulation of its actions by luzindole and 1-(m-chlorophenyl) piperazine. AB - In view of well-evidenced antiepileptic effects of melatonin and few reports of anticonvulsant action of agomelatine, the present study investigated whether agomelatine protects against pentylenetetrazole (PTZ)-induced kindling in mice and kindling-associated oxidative stress, depression, and impairment of spatial memory. In order to explore whether effects are mediated by melatonergic or serotonergic mechanisms, 1-(m-chlorophenyl) piperazine (mCPP), selective 5HT2c receptor agonist and luzindole, melatonergic receptor antagonist, were taken as pharmacological tools. In view of few hepatotoxic reports on agomelatine, the study evaluated effects on hepatic enzyme levels. Swiss strain albino mice were injected with PTZ (25mg/kg, i.p.) once every two days for 5weeks to induce kindling. The effects of agomelatine (10mg/kg, p.o.) alone and in combination with luzindole (2.5mg/kg, i.p.) or mCPP (7mg/kg, i.p.) on seizure severity during induction and % incidence of animals kindled at the end of 5weeks were recorded. Modified forced swim test was used for studying depression-like behavior while spontaneous alternation behavior was used for studying effects on spatial memory. Serum AST and ALT concentrations, cortical and hippocampal malondialdehyde, and reduced glutathione were measured. Agomelatine 10mg/kg, p.o. effectively delayed development of kindling, reduced seizure severity, and decreased % incidence. Luzindole reversed the protective effects of agomelatine while mCPP failed to show such a reversal, indicating melatonergic (and not serotonergic) mechanisms in the observed effects. Agomelatine also showed antioxidant effects that can partially contribute to its anticonvulsant action. In addition, it alleviated PTZ kindling-associated behavioral despair and favorably modulated liver enzymes. Its effects on improvement of kindling-associated spatial memory could possibly be related to its effects on locomotor activity. Agomelatine, thus, could be explored as an adjunct to antiepileptic drugs for seizure control and for alleviating epilepsy-associated depression. PMID- 28578216 TI - Barriers to access to education for young people with epilepsy in Northern Tanzania: A qualitative interview and focus group study involving teachers, parents and young people with epilepsy. AB - OBJECTIVE: Educational outcomes for young people with epilepsy (YPE) in Hai District, Tanzania, are poor, as is commonly observed elsewhere in Sub-Saharan Africa. The reasons for this finding are not well understood, though stigma arising from supernatural concepts of epilepsy is frequently cited as a barrier to YPE accessing education. In this study, we aimed to explore the reasons why many YPE in Tanzania experience poor access to education, and elicit ways in which education could be improved for YPE according to teachers, parents and YPE. METHODS: Ten focus group discussions with teachers were organized in Hai schools between March and May 2016. The themes arising from these discussions were identified, coded, analyzed and tested in semi-structured interviews with 19 YPE and 17 parents identified from a prevalent cohort of YPE identified in 2009. RESULTS: Behavioral problems and learning difficulties were cited as the main barriers to education for YPE. Other barriers included parental stigmatization, teachers' inadequate seizure management, and limited access to specialist schools. Teachers perceived that parents and YPE believe in spiritual etiology and traditional management for epilepsy. However, the majority of teachers, parents, and YPE cited biological etiology and management options, although understanding of epilepsy etiology and management could be improved amongst all groups. SIGNIFICANCE: A multidimensional approach is needed to improve educational access, and hence outcomes, for YPE. Widespread community education is needed to improve knowledge of epilepsy etiology and management. Teachers require seizure management training, and parents need help to recognize YPE's right to education. Educational needs assessments would help to identify YPE requiring specialist schooling, and access to this could be improved. These interventions will likely reduce stigma, ensure appropriate academic and pastoral care at school, and thus enable YPE to attend, and succeed, in education. PMID- 28578218 TI - Has the National Registry of Evidence-based Programs and Practices (NREPP) lost its way? PMID- 28578217 TI - Still "at risk": An examination of how street-involved young people understand, experience, and engage with "harm reduction" in Vancouver's inner city. AB - BACKGROUND: Vancouver is an international leader in implementing interventions to reduce harms related to drug use. However, street-involved young people who use drugs continue to be vulnerable to overdose death, hepatitis C (HCV) infection, and high rates of syringe sharing. To better understand this in the context of the intensive public health response, we examined how young people, who are involved in the 'street drug scene', understood, experienced and engaged with harm reduction. METHODS: Twelve semi-structured interviews were conducted in 2013 with 13 young people (ages 17-28) recruited from the At-Risk Youth Study, a prospective cohort of street-involved and drug-using young people. These interviews were embedded within a larger, eight-year program of ethnographic research and explored participants' understandings of harm reduction, their use of specific services, and their ideas about improving their day-to-day lives. Interviews were transcribed verbatim and a thematic analysis was performed. RESULTS: Young peoples' ideas about harm reduction were diverse and expansive. They articulated the limitations of existing programs, indicating that while they are positioned to reduce the risk of HIV and HCV transmission, they offer little meaningful support to improve young peoples' broader life chances. Young people described strategies to mitigate risk and harm in their own lives, including transitioning to drugs deemed less harmful and attempting to gain access to drug treatment. Finally, young people indicated that spatial considerations (e.g., distance from Vancouver's Downtown Eastside) strongly determined access to services. CONCLUSIONS: In Vancouver, a large, well established harm reduction infrastructure seeks to reduce HIV and HCV transmission among street-involved young people. However, young peoples' multiple understandings, experiences and engagements with harm reduction in this setting illustrate the limitations of the existing infrastructure in improving their broader life chances. PMID- 28578220 TI - Development of disposable membrane hydrophones for a frequency range from 1MHz to 10MHz. AB - A method for fabricating disposable membrane hydrophones is presented. The disposable hydrophones are intended for onetime use in such damaging environments as chemically contaminating fluids and high-amplitude (peak amplitude ~100MPa) shock wave fields, where the use of commercial membrane hydrophones is not recommended. Fabrication of a hydrophone is done using only off-the-shelf components and hand tools, which translates into ease of fabrication and orders of-magnitude reduction in unit cost. In particular, poling and sputtering, the two processes that are chiefly responsible for the cost and difficulty associated with the conventional fabrication method, are replaced with the use of pre-poled polyvinylidene fluoride (PVDF) films and polyethylene terephthalate (PET)-coated aluminum foils, respectively. Despite the seemingly crude construction, these disposable hydrophones can exhibit voltage sensitivity response that compares favorably with that of commercial hydrophones. For example, one prototype having a 2mm*2mm active element shows the end-of-cable voltage sensitivity of -270 (+/ 1.9) dB re 1V/MUPa over the frequency range of 1-10MHz. PMID- 28578219 TI - Identification of new antigen candidates for the early diagnosis of Mycobacterium avium subsp. paratuberculosis infection in goats. AB - Currently Mycobacterium avium subsp. paratuberculosis (MAP) infection is diagnosed through indirect tests based on the immune response induced by the infection. The antigens commonly used in IFN-gamma release assays (IGRA) are purified protein derivative tuberculins (PPD). However, PPDs, lack both specificity (Sp) and sensitivity (Se) in the early phase of infection. This study investigated the potential of 16 MAP recombinant proteins and five lipids to elicit the release of IFN-gamma in goats from herds with or without a history of paratuberculosis. Ten recombinant proteins were selected as potential candidates for the detection of MAP infection in young goats. They were found to detect 25 to 75% of infected shedder (IS) and infected non-shedder (INS) kids younger than 10months of age. In comparison, PPD was shown to detect only 10% of INS and no IS kids. For seven antigens, Se (21-33%) and Sp (>=90%) of IGRA were shown to be comparable with PPD at 20months old. Only three antigens were suitable candidates to detect IS adult goats, although Se was lower than that obtained with PPD. In paratuberculosis-free herds, IGRA results were negative in 97% of indoor goats and 86% of outdoor goats using the 10 antigens. However, 22 to 44% of one-year old outdoor goats were positive suggesting that they may be infected. In conclusion, this study showed that ten MAP recombinant proteins are potential candidates for early detection of MAP infected goats. Combining these antigens could form a possible set of MAP antigens to optimize the Se of caprine IGRA. PMID- 28578221 TI - Dynamic acousto-elastic testing of concrete with a coda-wave probe: comparison with standard linear and nonlinear ultrasonic techniques. AB - The use of nonlinear acoustic techniques in solids consists in measuring wave distortion arising from compliant features such as cracks, soft intergrain bonds and dislocations. As such, they provide very powerful nondestructive tools to monitor the onset of damage within materials. In particular, a recent technique called dynamic acousto-elasticity testing (DAET) gives unprecedented details on the nonlinear elastic response of materials (classical and non-classical nonlinear features including hysteresis, transient elastic softening and slow relaxation). Here, we provide a comprehensive set of linear and nonlinear acoustic responses on two prismatic concrete specimens; one intact and one pre compressed to about 70% of its ultimate strength. The two linear techniques used are Ultrasonic Pulse Velocity (UPV) and Resonance Ultrasound Spectroscopy (RUS), while the nonlinear ones include DAET (fast and slow dynamics) as well as Nonlinear Resonance Ultrasound Spectroscopy (NRUS). In addition, the DAET results correspond to a configuration where the (incoherent) coda portion of the ultrasonic record is used to probe the samples, as opposed to a (coherent) first arrival wave in standard DAET tests. We find that the two visually identical specimens are indistinguishable based on parameters measured by linear techniques (UPV and RUS). On the contrary, the extracted nonlinear parameters from NRUS and DAET are consistent and orders of magnitude greater for the damaged specimen than those for the intact one. This compiled set of linear and nonlinear ultrasonic testing data including the most advanced technique (DAET) provides a benchmark comparison for their use in the field of material characterization. PMID- 28578222 TI - Using prosody to infer discourse prominence in cochlear-implant users and normal hearing listeners. AB - Cochlear implants (CIs) provide speech perception to adults with severe-to profound hearing loss, but the acoustic signal remains severely degraded. Limited access to pitch cues is thought to decrease sensitivity to prosody in CI users, but co-occurring changes in intensity and duration may provide redundant cues. The current study investigates how listeners use these cues to infer discourse prominence. CI users and normal-hearing (NH) listeners were presented with sentences varying in prosody (accented vs. unaccented words) while their eye movements were measured to referents varying in discourse status (given vs. new categories). In Experiment 1, all listeners inferred prominence when prosody on nouns distinguished categories ("SANDWICH"->not sandals). In Experiment 2, CI users and NH listeners presented with natural speech inferred prominence when prosody on adjectives implied contrast across both categories and properties ("PINK horse"->not the orange horse). In contrast, NH listeners presented with simulated CI (vocoded) speech were sensitive to acoustic differences in prosody, but did not use these cues to infer discourse status. Together, this suggests that exploiting redundant cues for comprehension varies with the demands of language processing and prior experience with the degraded signal. PMID- 28578224 TI - Development and validation of a Brief Assessment of Recovery Capital (BARC-10) for alcohol and drug use disorder. AB - BACKGROUND: It has been long established that achieving recovery from an alcohol or other drug use disorder is associated with increased biobehavioral stress. To enhance the chances of recovery, a variety of psychological, physical, social, and environmental resources, known as "recovery capital", are deemed important as they can help mitigate this high stress burden. A 50-item measure of recovery capital was developed (Assessment of Recovery Capital [ARC]), with 10 subscales; however, a briefer version could enhance further deployment in research and busy clinical/recovery support service settings. To help increase utility of the measure, the goal of the current study was to create a shorter version using Item Response Theory models. METHOD: Items were pooled from the original treatment samples from Scotland and Australia (N=450) for scale reduction. A reduced version was tested in an independent sample (N=123), and a Receiver Operating Characteristic Curve was constructed to determine optimal cut-off for sustained remission (>12months abstinence). RESULTS: An abbreviated 10-item measure of recovery capital captured item representation from all 10 original subscales, was invariant across participant's locality and gender, had high internal consistency (alpha=.90), concurrent validity with the original measure (rpb=.90), and predictive validity with sustained remission using a cut-off score of 47. CONCLUSION: The brief assessment of recovery capital 10-item version (BARC-10) concisely measures a single unified dimension of recovery capital that may have utility for researchers, clinicians, and recovery support services. PMID- 28578223 TI - SERPINB2 is regulated by dynamic interactions with pause-release proteins and enhancer RNAs. AB - The SERPINB2 gene is strongly upregulated in inflammatory states. In monocytes, it can constitute up to 1% of total cellular protein. It functions in protection from proteotoxic stress and plays a role in angioedema. The purpose of this study was to define the roles of enhancer RNAs embedded in the SERPIN gene complex. We found that the upstream enhancer RNAs upregulated SERPINB2 and the enhancer RNAs were expressed prior to those of SERPINB2 mRNA. Studies of the SERPINB2 promoter demonstrated the presence of an RNA polymerase II pause-inducing protein, NELF. Stimulation with LPS led to recruitment of the pause-releasing kinase P-TEFb and departure of the pause-inducing protein NELF. RNA immunoprecipitation revealed that NELF and the CDK9 component of P-TEFb bound to the enhancer RNAs after stimulation with distinct kinetics. Knock-down of the enhancer RNAs compromised stimulus induction of promoter and enhancer chromatin changes. Conversely, over expression was associated with enhanced recruitment of c-JUN and increased expression of SERPINB2 mRNA expression. This study is the first to associate enhancer RNAs with SERPINB2 and is the first demonstration of acquisition of NELF binding by enhancer RNAs on chromatin. PMID- 28578225 TI - Progression to established patterns of cigarette smoking among young adults. AB - BACKGROUND: As tobacco control policies have been implemented across the U.S. over the past decade, patterns of smoking cigarettes have significantly changed, particularly among young adults. For many users, the typical daily use pattern of smoking several packs of cigarettes per day has been supplanted by a variety of use patterns, often referred to as light, intermittent, and occasional smoking. METHODS: The aim of this study was to examine progression to established smoking patterns among a nationally representative, longitudinal sample of young adults (n=9791). Using repeated measures latent class techniques (RMLCA), we modeled the distribution of cigarette smoking intensity over time and latent class categories. RESULTS: Findings demonstrate that young adults fall into three discrete classes that reflect probabilities for never to low use, daily use, and variable cigarette use for progression to established use of cigarettes: 79.3% fall into the class of "never or ever users" of cigarettes (no current use of cigarettes), 11.3% fall into the class of "rapid escalators" or daily users of cigarettes, and 9.4% fall into the "dabbler" class. Smoking patterns were found to be stable by the age of 21. CONCLUSIONS: Intervening prior to age 21 has the potential to disrupt progression to established smoking and reduce the long-term health consequences of smoking in this age group. PMID- 28578226 TI - Cocaine use may modify HIV/ART-associated myocardial steatosis and hepatic steatosis. AB - BACKGROUND: It has been recognized that myocardial and hepatic steatosis may be more prevalent in HIV-infected individuals on antiretroviral therapy (ART); however, factors associated with these conditions have not been thoroughly investigated. The goals of this study were (1) to identify the risk factors for myocardial and hepatic steatosis in HIV-infected African Americans (AAs) and explore whether ART use is independently associated with myocardial and hepatic steatosis, and (2) to examine whether and how cocaine use influences any associations of ART use with myocardial and hepatic steatosis. METHODS: Between June 2010 and December 2013, 220 HIV-infected AAs in Baltimore, Maryland, were enrolled in a study investigating HIV/ART-associated myocardial and hepatic damage. Proton magnetic resonance spectroscopy was performed to quantify myocardial and hepatic triglyceride contents. Sociodemographic, medical and laboratory data were also obtained. Robust regression model was employed to perform primary statistical analysis. RESULTS: Robust regression analyses showed that (1) duration of protease inhibitor (PI) use was independently associated with myocardial and hepatic triglyceride contents, (2) duration of PI use was independently associated with myocardial triglyceride in cocaine users (p=0.025), but not in cocaine never-users (p=0.84), and (3) duration of PI use was independently associated with hepatic triglyceride in cocaine users, but not in cocaine never-users (p=0.52). CONCLUSIONS: Cocaine use may trigger/exacerbate the toxicity of PI in ART-associated myocardial and hepatic steatosis, suggesting that cocaine abstinence/reduced use may retard these ART-associated comorbidities. Clinical trials should be conducted to examine whether reduced cocaine use improves HIV/AIDS-associated myocardial and hepatic steatosis. PMID- 28578227 TI - Evaluating the feasibility of fermentation starter inoculated with Bacillus amyloliquefaciens for improving acetoin and tetramethylpyrazine in Baoning bran vinegar. AB - Fermentation starters (Daqu) used in present study included traditional herb Daqu (C Daqu), modified Daqu without herbs (M Daqu) and S Daqu fermented by inoculating acetoin and tetramethylpyrazine high-producing bacterium Bacillus amyloliquefaciens into M Daqu. To evaluate the feasibility of S Daqu combined with M Daqu applied for improving contents of acetoin and tetramethylpyrazine in Baoning bran vinegar without remarkably changing the original microbial community and the other volatiles contents compared with C Daqu, vinegar Pei C, M, M1, M2 and S were correspondingly prepared in lab scale using C Daqu, M Daqu, M1 Daqu (S Daqu: M Daqu=1:9, w/w), M2 Daqu (S Daqu: M Daqu=5:5) and S Daqu. PCR-DGGE suggested that Bacillus, Lactobacillus, Oceanobacillus, Acetobacter, Pichia, Geotrichum and Trichoderma were dominant microbes. Microbial community of M were similar with M1, while that of the others were similar. Differences in physicochemical properties among samples may be ascribed to different enzymes activities of Daqu and bioactivities of microbial metabolism during fermentation. Moreover, total contents of organic acids in M, M1, M2 and S increased by 33.10%, 25.77%, 4.32% and 7.74% relative to C, respectively. Volatiles and PLS-DA analysis suggested that volatile profiles of M were similar with M1, that of M2 were similar with C, while that of S were significantly different with the others. Both M2 Daqu and S Daqu facilitated the formation of acetoin and tetramethylpyrazine. However, M2 Daqu was more efficient for enhancing acetoin and tetramethylpyrazine contents by 191.84% and 123.17% respectively, without significantly changing the other volatiles contents. PMID- 28578228 TI - Keeping it cool: Survival of Giardia cysts and Cryptosporidium oocysts on lettuce leaves. AB - Fresh produce has been recognized as a vehicle for transmission of protozoan parasites for many years, and there are numerous publications regarding their occurrence on such foodstuffs, indicating their potential importance as foodborne parasites. Nevertheless, few studies have been published regarding the effectiveness of this transmission route, and whether contamination is likely to result in transmission. The purpose of this study was to assess the viability of Cryptosporidium oocysts and Giardia cysts, two protozoa associated with both waterborne and foodborne transmission, by spiking fresh produce (lettuce leaves) with viable transmission stages and determining changes in viability. These investigations were performed under different conditions and over time spans that may be used in a regular household; a fridge at 4 degrees C, under ambient temperatures exposed to natural cycles of light during night and day, and inside a cupboard to ensure no light exposure, for a duration of up to two weeks, or as long as the produce remained visually palatable. The major finding from this study is that whereas both Cryptosporidium oocysts and Giardia cysts survive well when kept moist and refrigerated, survival of Giardia cysts was abrogated on lettuce at room temperature. Indeed, almost 50% die-off of Giardia cysts was recorded within the first 24h. Cryptosporidium oocysts had a stable viability throughout the experiment under all the conditions investigated, indicating that fresh produce is a suitable transmission vehicle for Cryptosporidium, even if contamination occurs on-farm and the parasites are exposed to non-favourable storage conditions, as may be common in developing countries. Giardia cysts were not as robust as Cryptosporidium oocysts, and would be probably unlikely to survive under ambient storage conditions on-farm, during sale, or at home. However, if kept refrigerated, then some contaminating Giardia cysts may remain viable and therefore may pose a threat to the consumer. Thus, as the cold chain for transport and storage of fresh produce improves, it is important that similar improvements are implemented to reduce the contamination of fresh produce with parasite transmission stages. PMID- 28578229 TI - Preparation of pompon-like ZnO-PANI heterostructure and its applications for the treatment of typical water pollutants under visible light. AB - Until now, the treatment of multiple water pollutants by using one simple material has still been a challenge. Pompon-like ZnO-Polyaniline heterostructures with different content of Polyaniline as out-layer were synthesized by hydrothermal method and hybridization. Their several applications were subsequently investigated for water pollutants treatment including photo degradation of organic pollutants, photo-induced adsorption of heavy metal ions (Hg(II), Cr(VI)) and inactivation of Pathogenic bacteria (E. coli bacteria and staphylococcus aureus) under visible light. The results indicate that the aforementioned pollutants can be effectively removed by Pompon-like ZnO Polyaniline heterostructure. The enhanced photochemical performance is attributed to: (1) the improved monodispersity and relative large specific surface area of pompon-like ZnO-PANI enhance the production of photo-induced OH and O2-; (2) the high separation efficiency of photo-generated electron-hole pairs, which comes from the synergistic effect of P-N type heterojunction. PMID- 28578230 TI - Corrugated stainless-steel mesh as a simple engineerable electrode module in bio electrochemical system: Hydrodynamics and the effects on decolorization performance. AB - The application of bio-electrochemical system (BESs) is strongly depended on the development of the engineering applicable electrode. Here we described an economical and readily processable electrode module with three-dimensional structure, the corrugated stainless-steel mesh electrode module (c-SMEM). This novel developed electrode module was demonstrated to provide a good hydrodynamic characteristic and significantly enhanced the decolorization performance of the BES when serving for treating azo dye (acid orange 7, AO7) containing wastewater. Compared to the conventional planar electrodes module (p-SMEM), c-SMEM was found to prolong the mean residence time (MRTtheta) of AO7 and change the flow pattern closer to the plug flow. As a result, the maximum enhancement of the volumetric decolorization rate (vDR) can reach to 255%, even when the c-SMEM and p-SMEM have the same electrode surface area. In addition, a techno-economic analysis model was established to elucidated the effects of the decolorization performance and the material cost on the initial capital cost, which revealed the BES with c-SMEM could be economically comparable to or even better than the traditional bio decolorization technologies. These results suggest c-SMEM holds great potential for engineering application, which may help paving the way of applying BES at large-scale. PMID- 28578231 TI - Removal of thallium from aqueous solutions using Fe-Mn binary oxides. AB - In this study, Fe-Mn binary oxides, which harbor the strong oxidative power of manganese dioxide and the high adsorption capacity of iron oxides, were synthesized for Tl(I) removal using a concurrent chemical oxidation and precipitation method. The adsorption of Tl onto the Fe-Mn adsorbent was fast, effective, and selective, with equilibrium sorption reaching over 95% under a broad operating pH (3-12), and high ionic strength (0.1-0.5mol/L). The adsorption can be well fitted with both Langmuir and Freundlich isotherms, and the kinetics can be well described by the pseudo-second-order model. Fourier transform infrared (FT-IR) and X-ray photoelectron spectroscopy (XPS) spectra suggest that surface complexation, oxidation and precipitation were the main mechanisms for the removal of Tl. This study shows that the Fe-Mn binary oxides could be a promising adsorbent for Tl removal. PMID- 28578233 TI - PropS-SH/SiO2 nanocomposite coatings for pyrite oxidation inhibition to control acid mine drainage at the source. AB - To control acid mine drainage (AMD) at the source, a novel nanocomposite coating, based on SiO2 nanoparticles as nanofiller embedded in gamma mercaptopropyltrimethoxysilane (PropS-SH) coating is introduced in this paper. The performance of the PropS-SH/SiO2 (PSS) nanocomposite coatings with a different content of SiO2 nanoparticles on pyrite oxidation inhibition was evaluated by electrochemical measurements and chemical leaching testing. The results of the investigations revealed that the addition of appropriate SiO2 nanoparticles could greatly enhance the passivation efficiency of PropS-SH coating. The best coating was obtained from 3% (v/v) of PropS-SH solution with 2wt% SiO2 nanoparticles as this coating decreased pyrite oxidation by 81.1% (based on Fe release). In addition, the coating mechanism of PSS coatings on pyrite surfaces is presented in this paper. PMID- 28578232 TI - The comparison of Se(IV) and Se(VI) sequestration by nanoscale zero-valent iron in aqueous solutions: The roles of solution chemistry. AB - The sequestration of Se(IV) and Se(VI) by nanoscale zero-valent iron (NZVI) particles were compared under different solution conditions. Firstly, the comparison was conducted at three pH values (4.0, 6.0 and 8.0) in deionized water. Generally, the removal of Se(IV)/Se(VI) by NZVI was more rapid under acidic conditions and the removal efficiency of Se(IV) was much higher than that of Se(VI). Moreover, the pH variation exhibited much larger influence on the sequestration of Se(VI) than that of Se(IV) by NZVI. The spectroscopic analysis showed that both the Se(IV) and Se(VI) were reduced to Se0 and Se2-, while NZVI was transformed into iron (hydr)oxides. When the selenium-NZVI reactions occurred in synthetic groundwater, all the reaction systems were inhibited in varying degrees. The individual effects of humic acid (HA) and typical inorganic ions were also examined. It seems that HA could substantially hinder the sequestration of Se(IV) compared with that in deionized water, while sulfate (SO42-) and bicarbonate (HCO3-) inhibited the Se(VI) removal significantly. Notably, the presence of cations (i.e., Na+ or Ca2+) ions did not cause obvious interference to the Se(IV)/Se(VI) removal by NZVI, while the presence of Ca2+ could alleviate the adverse effect of HA on Se(IV) removal to some degree. PMID- 28578234 TI - The sky is falling III: The effect of deposition from static solid rocket motor tests on juvenile crops. AB - A mixture of combustion products (mainly hydrogen chloride, aluminum oxide, and water) and entrained soil, referred to as Test Fire Soil (TFS), can be deposited on crops during static solid rocket motor tests. The impact of a reported worst case event was previously evaluated by exposing corn and alfalfa to 3200-gTFS/m2 at 54days after emergence. Exposures via soil and leaves were evaluated separately. Reduced growth (soil exposure) and leaf "scorch" (leaf exposure) were attributed mainly to the high chloride concentrations in the TFS (56,000mg/kg). A follow-up study was conducted to evaluate the effect of a typical deposition event (70-gTFS/m2, estimated by radar during several tests) and exposure (soil and leaves simultaneously) on juvenile corn, alfalfa, and winter wheat. Younger crops were used to examine potential age sensitivity differences. Impact was evaluated by comparing the growth, elemental composition, and leaf chlorophyll content of treated and untreated plants. The relationship between deposition exposure and response was also addressed. Growth of corn, alfalfa, and winter wheat exposed to a typical TFS loading was not impacted, although slightly elevated concentrations of aluminum and iron were found in the leaves. At the highest loadings used for the exposure-response experiment, concentrations of chloride and calcium were higher in TFS-exposed corn leaves than in the untreated leaves. Overall results indicate that exposure to a typical deposition event does not adversely impact juvenile crops and that younger plants may be less vulnerable to TFS. However, higher TFS loadings can cause leaf scorch and increase the leaf concentrations of some elements. PMID- 28578235 TI - Simultaneous use of caustic and oxygen for efficient sulfide control in sewers. AB - Periodic caustic shock-loading is a commonly used method for sulfide control in sewers. Caustic shock-loading relies on the elevation of the sewage pH to >=10.5 for several hours, thereby removing sewer pipe biofilms as well as deactivating SRB activity in the remaining biofilm. Although a widely used method, SRB activity is often not completely inhibited, and as such sulfide is still being generated. Here, we propose and experimentally demonstrate an innovative approach which combines caustic with oxygen, another commonly used method, as a dosing strategy for overcoming the drawbacks of caustic shock-loading. Six laboratory scale rising main reactors were subjected to three dosing schemes over a period of three months, namely (i) simultaneous caustic and oxygen addition, (ii) caustic addition and (iii) no chemical addition. Our results showed that the combination of caustic and oxygen achieved efficient sulfide control, leading to a prolonged biofilm recovery period in between caustic shocks. In addition, methane emissions were reduced to a negligible level compared to caustic treatment only. To translate the findings to real-life application, the key parameters obtained during the long-term lab-scale experiments were subjected to extensive simulation studies using the SeweX model under a wide range of conditions commonly found in sewers. Overall, this study highlights the potential of periodic shock-loading and intermittent oxygen injection as combined dosing strategy for efficient sulfide control in sewers. PMID- 28578236 TI - Litter decomposition in hyper-arid deserts: Photodegradation is still important. AB - Photodegradation due to litter exposure to solar UV radiation is presumed to contribute to the surprisingly fast decomposition in some arid and semi-arid regions; however, few studies have directly examined photodegradation effects in hyper-arid regions (annual precipitation <150mm) and its dependence on precipitation. Three litters with different initial qualities (low vs high C:N) were decomposed under full spectrum sunlight (UV radiation) and UV filtering from solar radiation at three sites with contrasting precipitation amounts (144mm, 76mm and 16mm) for 2.5years. UV radiation increased mass loss and litter decomposition rates by 23-70%. UV photodegradation effects (UVE) on litter decomposition rate differed among experimental sites, with significantly stronger effects in less arid sites (144mm and 76mm) than more arid site (16mm). High quality litter (low C:N ratio) showed the fastest decomposition rate, and UVE was also affected by litter quality, but no consistent trend was observed. Litter N loss was greatest in full sunlight and the linear relationships between C and N contents was not changed by UV filtering over time. UV radiation increased C loss of all fractions, and hemicellulose and cell solubles showed significant contributions to litter mass loss. Our findings suggest that UV photodegradation can increase mass loss and nutrient release by the positive priming effects on microbial decomposition in hyper-arid regions, although UVE differed among three sites with contrasting precipitation amounts. PMID- 28578237 TI - Ecotoxicity of the antihistaminic drug cetirizine to Ruditapes philippinarum clams. AB - Cetirizine (CTZ) is an antihistaminic drug present in the aquatic environment, with limited information on its toxicity to organisms inhabiting this system. This study intended to evaluate the effects of CTZ on oxidative stress and energy metabolism biomarkers in the edible clam Ruditapes philippinarum after a 28days exposure to environmentally relevant CTZ concentrations (0.0, 0.3, 3.0, 6.0 and 12.0MUg/L). The results obtained showed that CTZ was accumulated by clams reaching maximum concentrations (up to ~22ng/g FW) at the highest CTZ exposure concentrations (6.0 and 12.0MUg/L). The bioconcentration factor (average maximum values of ~5) decreased at 12.0MUg/L reflecting a reduction in clams uptake or increase of excretion capacity at this condition. The present study revealed that, in general, clams decreased the metabolic potential after exposure to CTZ (decrease in electron transport system activity), a response that led to the maintenance of glycogen content in organisms exposed to CTZ in comparison to control values. Our findings also showed that, CTZ did not exert significant levels of oxidative injury to clams. However, comparing the control with the highest exposure concentrations (6.0 and 12.0MUg/L) a significant increase of the antioxidant enzyme superoxide activity (~53 and ~44%) was observed in clams exposed to CTZ. Moreover, a tendency to increase lipid peroxidation (~14 and ~9%) and carbonyl groups on proteins (~11 and ~3%) was observed in clams exposed to CTZ (6.0 and 12.0MUg/L) compared to control condition. Overall the present study suggests that toxic impacts may be induced in R. philippinarum if exposed for longer periods or higher CTZ concentrations. PMID- 28578238 TI - Combined effects of environmental disturbance and climate warming on insect herbivory in mountain birch in subarctic forests: Results of 26-year monitoring. AB - Both pollution and climate affect insect-plant interactions, but the combined effects of these two abiotic drivers of global change on insect herbivory remain almost unexplored. From 1991 to 2016, we monitored the population densities of 25 species or species groups of insects feeding on mountain birch (Betula pubescens ssp. czerepanovii) in 29 sites and recorded leaf damage by insects in 21 sites in subarctic forests around the nickel-copper smelter at Monchegorsk, north-western Russia. The leaf-eating insects demonstrated variable, and sometimes opposite, responses to pollution-induced forest disturbance and to climate variations. Consequently, we did not discover any general trend in herbivory along the disturbance gradient. Densities of eight species/species groups correlated with environmental disturbance, but these correlations weakened from 1991 to 2016, presumably due to the fivefold decrease in emissions of sulphur dioxide and heavy metals from the smelter. The densities of externally feeding defoliators decreased from 1991 to 2016 and the densities of leafminers increased, while the leaf roller densities remained unchanged. Consequently, no overall temporal trend in the abundance of birch-feeding insects emerged despite a 2-3 degrees C elevation in spring temperatures. Damage to birch leaves by insects decreased during the observation period in heavily disturbed forests, did not change in moderately disturbed forests and tended to increase in pristine forests. The temporal stability of insect-plant interactions, quantified by the inverse of the coefficient of among-year variations of herbivore population densities and of birch foliar damage, showed a negative correlation with forest disturbance. We conclude that climate differently affects insect herbivory in heavily stressed versus pristine forests, and that herbivorous insects demonstrate diverse responses to environmental disturbance and climate variations. This diversity of responses, in combination with the decreased stability of insect-plant interactions, increases the uncertainty in predictions on the impacts of global change on forest damage by insects. PMID- 28578239 TI - Bioaccumulation of pharmaceutically active compounds and endocrine disrupting chemicals in aquatic macrophytes: Results of hydroponic experiments with Echinodorus horemanii and Eichhornia crassipes. AB - Information regarding the bioaccumulation behaviour of pharmaceutically active compounds (PhACs) and endocrine disrupting chemicals (EDCs) in aquatic plants is limited. The present study involved controlled hydroponic experiments to assess uptake and elimination rate constants (ku, ke), bioconcentration factors (BCFs) and translocation factors (TFs) of several PhACs and EDCs in two aquatic macrophyte species, including one submerged species (Echinodorus horemanii) and one free-floating species (Eichhornia crassipes). The results revealed that the studied compounds are readily taken up in these aquatic plants. While bioconcentration factors (BCFs) and translocation factors (TFs) of the test compounds varied substantially, no discernible relationship with physicochemical properties such as octanol-water distribution coefficient (Dow), membrane-water distribution coefficient (Dmw) and organic carbon-water partition coefficient (Koc). Diphenhydramine and triclosan exhibited the highest degree of uptake and bioaccumulation potential. For example, the whole-plant BCF of triclosan in E. horemanii was 4390L/kg, while the whole-plant BCF of diphenhydramine in E. crassipes was 6130L/kg. BCFs of 17beta-estradiol (E2), 17alpha-ethinylestradiol (EE2), estrone (E1) and bisphenol A (BPA) were relatively low (2-150L/kg). BCFs were generally higher in free-floating aquatic macrophyte species compared to the submerged species. For the free-floating species, E. crassipes, the majority of PhACs and EDCs were more allocated in roots compared to leaves, with TFs<1. However, some compounds such as caffeine, atrazine, diphenhydramine, E2 and carbamazepine were more allocated in leaf tissue (TFs>1). The study findings may be useful for design and implementation of phytoremediation systems, as well as aid future modeling and risk assessment initiatives for these emerging organic contaminants. PMID- 28578240 TI - Spatio-temporal topsoil organic carbon mapping of a semi-arid Mediterranean region: The role of land use, soil texture, topographic indices and the influence of remote sensing data to modelling. AB - SOC is the most important indicator of soil fertility and monitoring its space time changes is a prerequisite to establish strategies to reduce soil loss and preserve its quality. Here we modelled the topsoil (0-0.3m) SOC concentration of the cultivated area of Sicily in 1993 and 2008. Sicily is an extremely variable region with a high number of ecosystems, soils, and microclimates. We studied the role of time and land use in the modelling of SOC, and assessed the role of remote sensing (RS) covariates in the boosted regression trees modelling. The models obtained showed a high pseudo-R2 (0.63-0.69) and low uncertainty (s.d.<0.76gCkg-1 with RS, and <1.25gCkg-1 without RS). These outputs allowed depicting a time variation of SOC at 1arcsec. SOC estimation strongly depended on the soil texture, land use, rainfall and topographic indices related to erosion and deposition. RS indices captured one fifth of the total variance explained, slightly changed the ranking of variance explained by the non-RS predictors, and reduced the variability of the model replicates. During the study period, SOC decreased in the areas with relatively high initial SOC, and increased in the area with high temperature and low rainfall, dominated by arables. This was likely due to the compulsory application of some Good Agricultural and Environmental practices. These results confirm that the importance of texture and land use in short-term SOC variation is comparable to climate. The present results call for agronomic and policy intervention at the district level to maintain fertility and yield potential. In addition, the present results suggest that the application of RS covariates enhanced the modelling performance. PMID- 28578241 TI - Distribution of organic and inorganic substances in the sediments of the "Great Backa Canal", a European environmental hotspot. AB - The Great Backa Canal in Serbia is one of the most polluted waterways in Europe. Surface sediments from the canal were subject to systematic annual monitoring between 2007 and 2014 at 33 representative sampling sites. Eight heavy metals (Ni, Zn, Cd, Cr, Cu, Pb, As and Hg), mineral oils, 16 EPA PAHs and selected pesticides and polychlorinated biphenyls (PCB) were monitored. This study aims to evaluate the quality of the sediments and determine the potential ecological risks in order to establish pollutants of interest. The spatial and temporal influence of different and intense sources of pollution are investigated. The analysis includes multivariate statistical methods (factor analysis of principal component analysis (PCA/FA)) in order to assess the extent and origin (anthropogenic or natural, geogenic sources) of the contaminants detected in the sediment samples and the risks the present to the environment. Various sources, predominantly the food industry, were found to be responsible for most of the contamination by Cd, Cu, Cr and Zn, the mineral oils and PAHs (dibenzo[a,h]anthracene and benzo[a]pyrene contributed 86.0% of the total between 2007 and 2014). In contrast, the As was convincingly of geogenic origin, and the Hg, Pb and Ni present exhibit dual origins. Cd and Cu significantly raise the levels of potential ecological risk at all sampling locations, demonstrating the long-term effects of bioaccumulation and biomagnification. Significantly, the results of this work indicate that Cu, As and dibenzo[a,h]anthracene should be added to the EU watch list of emerging contaminants. This is supported by significant national and similar environmental data from countries in the region. PMID- 28578242 TI - Removal of antibiotics (sulfamethazine, tetracycline and chloramphenicol) from aqueous solution by raw and nitrogen plasma modified steel shavings. AB - The removal of sulfamethazine (SMT), tetracycline (TC) and chloramphenicol (CP) from synthetic wastewater by raw (M3) and nitrogen plasma modified steel shavings (M3-plN2) was investigated using batch experiments. The adsorption kinetics could be expressed by both pseudo-first-order kinetic (PFO) and pseudo-second-order kinetic (PSO) models, where correlation coefficient r2 values were high. The values of PFO rate constant k1p and PSO rate constant k2p decreased as SMT-M3>SMT M3-plN2>TC-M3-plN2>TC-M3>CP-M3>CP-M3-plN2 and SMT-M3>SMT-M3-plN2>TC-M3>TC-M3 plN2>CP-M3>CP-M3-plN2, respectively. Solution pH, adsorbent dose and temperature exerted great influences on the adsorption process. The plasma modification with nitrogen gas cleaned and enhanced 1.7-fold the surface area and 1.4-fold the pore volume of steel shavings. Consequently, the removal capacity of SMT, TC, CP on the adsorbent rose from 2519.98 to 2702.55, 1720.20 to 2158.36, and 2772.81 to 2920.11MUg/g, respectively. Typical chemical states of iron (XPS in Fe2p3 region) in the adsorbents which are mainly responsible for removing antibiotics through hydrogen bonding, electrostatic and non- electrostatic interactions and redox reaction were as follows: Fe3O4/Fe2+, Fe3O4/Fe3+, FeO/Fe2+ and Fe2O3/Fe3+. PMID- 28578243 TI - Comparative study on pharmaceuticals adsorption in reclaimed water desalination concentrate using biochar: Impact of salts and organic matter. AB - The synergistic impact of salts and organic matter on adsorption of ibuprofen and sulfamethoxazole by three types of biochar and an activated carbon was investigated using reclaimed water reverse osmosis (RO) concentrate and synthetic solutions spiked with target organic compounds and non-target water constituents (e.g., Na+, Ca2+, Mg2+, K+, Cl-, SO42-, alkalinity, humic acid (HA), and bovine serum albumin (BSA)). Kinetic modeling was used to better understand the adsorption process between the carbon adsorbents and pharmaceuticals and to elucidate the impact of water chemistry on pharmaceuticals adsorption. The adsorption capacity of pharmaceuticals by biochar was affected by their physicochemical properties including ash content, specific surface area, charge, pore volume, as well as hydrophobicity, pi-energy, and speciation of pharmaceuticals. The adsorption of pharmaceuticals in concentrate was pH dependent, the kinetic rate constant increased with deceasing pH due to the electrical interactions between pharmaceutical molecules and adsorbents. High salinity and electrolyte ions in RO concentrate improved adsorption, whereas the presence of carbonate species, HA, and BSA hindered the removal of ibuprofen and sulfamethoxazole. This study revealed the correlation of concentrate water quality on adsorption of pharmaceuticals by biochar and activated carbon. Biochar provides a promising alternative to activated carbon for removal of organic contaminants of emerging concerns in various wastewater and concentrate streams. PMID- 28578244 TI - Performance of Raphidocelis subcapitata exposed to heavy metal mixtures. AB - Microalgae growth inhibition assays are candidates for referent ecotoxicological assays, and are a fundamental part in the strategy to reduce the use of fish and other animal models in aquatic toxicology. In the present work, the performance of Raphidocelis subcapitata exposed to heavy metals following standardized growth inhibition assays has been assessed in three different scenarios: 1) dilutions of single heavy metals, 2) artificial mixture of heavy metals at similar levels than those found in natural rivers and, 3) natural samples containing known mixtures of contaminants (heavy metals). Chemical speciation of heavy metals has been estimated with Eh-pH diagram and Visual MINTEQ software; heavy metal and free heavy metal ion concentrations were used as input data, together with microalgae growth inhibition, for Dr. Fit software. The final goal was to assess the suitability of the ecotoxicological test based on the growth inhibition of microalgae cultures, and the mathematic models based on these results, for regulatory and decision-making purposes. The toxicity of a given heavy metal is not only determined by its chemical speciation; other chemical and biological interaction play an important role in the final toxicity. Raphidocelis subcapitata 48h-h-EC50 for tested heavy metals (especially Cu and Zn) were in agreement with previous studies, when ion metal bioavailability was assumed to be 100%. Nevertheless, the calculated growth inhibition was not in agreement with the obtained inhibition when exposed to the artificial mixture of heavy metals or the natural sample. Interactions between heavy metal ions and the compounds of the culture media and/or the natural sample determine heavy metal bioavailability, and eventually their toxicity. More research is needed for facing the challenge posed by pollutant mixtures as they are present in natural environments, and make microalgae-based assays suitable for pollution management and regulatory purposes. PMID- 28578245 TI - Development of between-trial response strategy adjustments in a continuous action control task: A cross-sectional study. AB - Response strategies are constantly adjusted in ever-changing environments. According to many researchers, this involves executive control. This study examined how children (aged 4-11years) and young adults (aged 18-21years) adjusted response strategies in a continuous action control task. Participants needed to move a stimulus to a target location, but on a minority of the trials (change trials) the target location changed. When this happened, participants needed to change their movement. We examined how performance was influenced by the properties of the previous trial. We found that no-change performance was impaired, but change performance was improved, when a change signal was presented on the previous trial. Extra analyses revealed that the between-trial effects on no-change trials were not influenced by the repetition of the previous stimulus. Combined, these findings provide support for the idea that response strategies were adjusted on a trial-by-trial basis. Importantly, we observed large age related differences in overall change and no-change latencies but observed no differences in response strategy adjustments. This is consistent with findings obtained with other paradigms and suggests that adjustment mechanisms mature at a faster rate than other "executive" action control mechanisms. PMID- 28578246 TI - Appendiceal ganglioneuroma in neurofibromatosis type 2. AB - Here we report the case of a 30-year-old woman with a history of neurofibromatosis type 2 (NF2) who presented with an incidentally discovered pelvic mass on an ultrasound. The identity of the mass remained indeterminate following a CT and MRI, although appendiceal pathology was suspected. An elective laparoscopy and appendectomy were performed without complication and pathology on the specimen demonstrated an appendiceal ganglioneuroma. To our knowledge, there has been no prior documented case of an appendiceal ganglioneuroma in a patient with NF2. Furthermore, the current case is the first to report the MR characteristics of appendiceal ganglioneuromas. PMID- 28578247 TI - Microvascular thrombosis in sepsis: An autopsy study. PMID- 28578248 TI - Gender differences in social anxiety disorder: A review. AB - Gender differences in social anxiety disorder (SAD) have not received much empirical attention despite the large body of research on the disorder, and in contrast to significant literature about gender differences in other disorders such as depression or posttraumatic stress disorder. To address this gap, we comprehensively reviewed the literature regarding gender differences in eight domains of SAD: prevalence, clinical presentation, functioning and impairment, comorbidity, course, treatment seeking, physiological arousal, and the oxytocin system. Findings from the present review indicate that women are more likely to have SAD and report greater clinical severity. Notwithstanding, men with the disorder may seek treatment to a greater extent. According to the present review, the course of SAD seems to be similar for men and women, and findings regarding gender differences in functional impairment and comorbidity are inconclusive. We highlight areas requiring future research and discuss the findings in the context of a number of theoretical perspectives. We believe that further research and integration of scientific findings with existing theories is essential in order to increase our understanding and awareness of gender differences in SAD, thus facilitating gender-sensitive and specifically-tailored interventions for both men and women with the disorder. PMID- 28578251 TI - Cutting-edge platforms in cardiac tissue engineering. AB - As cardiac disease takes a higher toll with each passing year, the need for new therapies to deal with the scarcity in heart donors becomes ever more pressing. Cardiac tissue engineering holds the promise of creating functional replacement tissues to repair heart tissue damage. In an attempt to bridge the gap between the lab and clinical realization, the field has made major strides. In this review, we will discuss state of the art technologies such as layer-by-layer assembly, bioprinting and bionic tissue engineering, all developed to overcome some of the major hurdles faced in the field. PMID- 28578249 TI - Effectiveness of psychoeducational interventions for family carers of people with psychosis: A systematic review and meta-analysis. AB - Psychoeducational interventions for family carers of people with psychosis are effective for improving compliance and preventing relapse. Whether carers benefit from these interventions has been little explored. This systematic review investigated the effectiveness of psychoeducation for improving carers' outcomes, and potential treatment moderators. We searched for randomised controlled trials (RCTs) published in English or Chinese in eight databases. Carers' outcomes included wellbeing, quality of life, global morbidities, burden, and expressed emotion. Thirty-two RCTs were included, examining 2858 carers. Intervention duration ranged from 4 to 52weeks, and contact times ranged from 6 to 42hours. At post intervention, findings were equivocal for carers' wellbeing (SMD 0.103, 95% CI -0.186 to 0.392). Conversely, psychoeducation was superior in reducing carers' global morbidities (SMD -0.230, 95% CI -0.386 to -0.075), perceived burden (SMD 0.434, 95% CI -0.567 to -0.31), negative caregiving experiences (SMD -0.210, 95% CI -0.396 to -0.025) and expressed emotion (SMD -0.161, 95% CI -0.367 to -0.045). The lack of available data precluded meta-analysis of outcomes beyond short-term follow-up. Meta-regression revealed no significant associations between intervention modality, duration, or contact time and outcomes. Further research should focus on improving carers' outcomes in the longer-term and identifying factors to optimise intervention design. PMID- 28578252 TI - Stretching position can affect levator scapular muscle activity, length, and cervical range of motion in people with a shortened levator scapulae. AB - OBJECTIVES: Levator scapulae (LS) muscle stretching exercises are a common method of lengthening a shortened muscle; however, the appropriate stretching position for lengthening the LS in people with a shortened LS remains unclear. The purpose of this study was to compare the effects of different stretching exercise positions on the LS and introduce effective stretching exercise methods to clinicians. PARTICIPANTS: Twenty-four university students (12 men, 12 women) with a shortened LS were recruited. METHODS: LS muscle activity, LS index (LSI), and cervical range of motion (ROM) were measured pre (baseline) and post three different stretching exercise positions (sitting, quadruped, and prone). RESULTS: The LSI and cervical ROM exceeded the minimal detectable change and had significant changes. The LSI was greater in the sitting position than at the baseline (p = 0.01), quadruped position (p < 0.01); the LSI in the prone position presented a higher increase than the quadruped position (p = 0.01). The cervical ROM increased in the sitting position when compared to the baseline (p < 0.01) and quadruped position (p < 0.01). CONCLUSIONS: Stretching the LS in the sitting position was the most effective exercise for improving LS muscle length and cervical ROM. PMID- 28578253 TI - Proton dissociation properties of arylphosphonates: Determination of accurate Hammett equation parameters. AB - Determination of the proton dissociation constants of several arylphosphonic acid derivatives was carried out to investigate the accuracy of the Hammett equations available for this family of compounds. For the measurement of the pKa values modern, accurate methods, such as the differential potentiometric titration and NMR-pH titration were used. We found our results significantly different from the pKa values reported before (pKa1: MAE = 0.16 pKa2: MAE=0.59). Based on our recently measured pKa values, refined Hammett equations were determined that might be used for predicting highly accurate ionization constants of newly synthesized compounds (pKa1=1.70-0.894sigma, pKa2=6.92-0.934sigma). PMID- 28578250 TI - Increases in synthetic cannabinoids-related harms: Results from a longitudinal web-based content analysis. AB - BACKGROUND: Synthetic Cannabinoid Receptor Agonists (SCRA), also known as "K2" or "Spice," have drawn considerable attention due to their potential of abuse and harmful consequences. More research is needed to understand user experiences of SCRA-related effects. We use semi-automated information processing techniques through eDrugTrends platform to examine SCRA-related effects and their variations through a longitudinal content analysis of web-forum data. METHOD: English language posts from three drug-focused web-forums were extracted and analyzed between January 1st 2008 and September 30th 2015. Search terms are based on the Drug Use Ontology (DAO) created for this study (189 SCRA-related and 501 effect related terms). EDrugTrends NLP-based text processing tools were used to extract posts mentioning SCRA and their effects. Generalized linear regression was used to fit restricted cubic spline functions of time to test whether the proportion of drug-related posts that mention SCRA (and no other drug) and the proportion of these "SCRA-only" posts that mention SCRA effects have changed over time, with an adjustment for multiple testing. RESULTS: 19,052 SCRA-related posts (Bluelight (n=2782), Forum A (n=3882), and Forum B (n=12,388)) posted by 2543 international users were extracted. The most frequently mentioned effects were "getting high" (44.0%), "hallucinations" (10.8%), and "anxiety" (10.2%). The frequency of SCRA only posts declined steadily over the study period. The proportions of SCRA-only posts mentioning positive effects (e.g., "High" and "Euphoria") steadily decreased, while the proportions of SCRA-only posts mentioning negative effects (e.g., "Anxiety," 'Nausea," "Overdose") increased over the same period. CONCLUSION: This study's findings indicate that the proportion of negative effects mentioned in web forum posts and linked to SCRA has increased over time, suggesting that recent generations of SCRA generate more harms. This is also one of the first studies to conduct automated content analysis of web forum data related to illicit drug use. PMID- 28578256 TI - Overexpression of long non-coding RNA GHET1 promotes the development of multidrug resistance in gastric cancer cells. AB - BACKGROUND AND AMID: Multidrug resistance (MDR) is the main obstacle to successful chemotherapy for patients with gastric cancer (GC). The GHET1 affects a variety of cancer development, and increased GHET1 promotes gastric carcinoma cell proliferation. This study amid to investigate the effect of GHET1 on the development of MDR in gastric cancer cells. METHODS AND RESULTS: In this study, we observed an increased expression levels of GHET1 in drug-resistant gastric cancer patients and cisplatin-resistant gastric cancer cell lines (BGC823/DPP and SGC7901/DDP cell line). Next, the two cell lines were used to in vitro validation of the effect of GHET1 expression on the MDR development. Silence of GHET1 in the two cisplatin-resistant gastric cancer cell lines inhibited the MDR with rising inhibition rate tested by MTT (methyl thiazolyl tetrazolium) assay. The apoptotic cell rate was analyzed by staining with Annexin V/PI. The results showed that the IC50 (half maximal inhibitory concentration) of the two cisplatin-resistant gastric cancer cell lines transfected with si-GHET1 were significantly reduced. Contrary to inhibition of GHET1 in the two cisplatin-resistant gastric cancer cell lines, we found that overexpression of GHET1 reduced sensitivity of BGC823 and SGC7901 cells to cisplatin with decreased inhibition rate and apoptotic cell rate and increased IC50. Furthermore, the qRT-PCR and western blot results showed that overexpression of GHET1 downregulated Bax expression and upregulated Bcl-2, MDR1 and MRP1 expression in BGC823 and SGC7901 cells. CONCLUSION: Highly expressing GHET1 promoted the development of MDR which was related to the Bax, Bcl-2, MDR1 and MRP1 genes expression in gastric cancer cells. PMID- 28578254 TI - Therapeutic drug monitoring of beta-lactam antibiotics - Influence of sample stability on the analysis of piperacillin, meropenem, ceftazidime and flucloxacillin by HPLC-UV. AB - INTRODUCTION: Therapeutic drug monitoring (TDM) is a useful tool to optimize antibiotic therapy. Increasing interest in alternative dosing strategies of beta lactam antibiotics, e.g. continuous or prolonged infusion, require a feasible analytical method for quantification of these antimicrobial agents. However, pre analytical issues including sample handling and stability are to be considered to provide valuable analytical results. METHODS: For the simultaneous determination of piperacillin, meropenem, ceftazidime and flucloxacillin, a high performance liquid chromatography (HPLC) method including protein precipitation was established utilizing ertapenem as internal standard. Long-term stability of stock solutions and plasma samples were monitored. Furthermore, whole blood stability of the analytes in heparinized blood tubes was investigated comparing storage under ambient conditions and 2-8 degrees C. RESULTS: A calibration range of 5-200MUg/ml (piperacillin, ceftazidime, flucloxacillin) and 2-200MUg/ml (meropenem) was linear with r2>0.999, precision and inaccuracy were <9% and <11%, respectively. The successfully validated HPLC assay was applied to clinical samples and stability investigations. At -80 degrees C, plasma samples were stable for 9 months (piperacillin, meropenem) or 13 months (ceftazidime, flucloxacillin). Concentrations of the four beta-lactam antibiotics in whole blood tubes were found to remain within specifications for 8h when stored at 2-8 degrees C but not at room temperature. CONCLUSIONS: The presented method is a rapid and simple option for routine TDM of piperacillin, meropenem, ceftazidime and flucloxacillin. Whereas long-term storage of beta-lactam samples at -80 degrees C is possible for at least 9 months, whole blood tubes are recommended to be kept refrigerated until analysis. PMID- 28578255 TI - Development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry method for quantification of SR1001, an inverse agonist of retinoid-related orphan receptors, and its application to pharmacokinetic studies in streptozotocin-induced diabetic mice. AB - Retinoic acid receptor-related orphan receptors (RORs) play critical roles in the onset and progression of type I diabetes, an autoimmune disease characterized by the destruction of pancreatic beta-cells. SR1001, an ROR inverse agonist, has been proven to be an effective diabetes treatment in the non-obese diabetic (NOD) mouse model. However, optimization of this treatment is challenging because knowledge of SR1001 pharmacokinetic (PK) behaviors in type I diabetic animals is limited. The aim of our study was to develop and validate a specific and sensitive ultra-performance liquid chromatography-tandem mass spectrometric (UPLC MS/MS) method to measure the concentrations of SR1001 in plasma and biological samples. Using the developed UPLC-MS/MS method, SR1001 linearity ranges in biological matrices were determined to be 5-1000ng/mL, with correlation coefficients of >0.99. The limit of detection (LOD) and limit of quantification (LOQ) values of SR1001 were 1 and 5ng/mL, respectively. And the intra-day and inter-day variances were less than 10%, and accuracy was within 90%-110%. The extraction recoveries of SR1001 were >=80%, and no significant matrix effect was observed. Using the validated UPLC-MS/MS method, levels of SR1001 in plasma and six major organs (heart, liver, spleen, lung, kidney, and brain) were determined in streptozotocin (STZ) -induced diabetic mice. The PK parameters of SR1001 were also calculated. The SR1001 drug concentration-time curves for organs and plasma showed similar trends, and the elimination half-lives of SR1001 in diabetic mice were about 12h. SR1001 was highly bound to plasma protein, resulting in a much higher maximum concentration (Cmax=144394ng/mL) and area under the concentration time curve (AUC0-t=2728258ng/mL*h), but a low tissue/plasma partition coefficient (Kp) value of <0.3. PMID- 28578258 TI - Alternative treatment strategies for neuropathic pain: Role of Indian medicinal plants and compounds of plant origin-A review. AB - Neuropathic pain is a complex, chronic pain state accompanied by tissue injury and nerve damage. This important health issue constitutes a challenge for the modern medicine worldwide. The management of neuropathic pain remains a major clinical challenge, pertaining to an inadequate understanding of pathophysiological mechanisms of neuropathic pain. Various classes of drugs have been reported effective for the management of neuropathic pain viz. opiates, tricyclic antidepressants, and antiepileptic agents. However, association of adverse effects with these drugs hinders their confident prescription in people with neuropathic pain. Recently, various medicinal plants have been reported effective for the management of neuropathic pain. So, it may be prudent to look beyond synthetic drugs pertaining to their unprecedented pharmacotherapeutic effects with lesser adverse effects. The extensive literature review has been carried out from databases such as Science direct, Scifinder, Wiley online library, PubMed, Research gate, Google scholar and Chemical Abstracts. The list of Traditional Indian Medicinal plants (TIMPs) and isolated compounds have been compiled which have been reported effective as an alternative therapy for the management of neuropathic pain. This helps the researchers to discover some novel therapeutic agents against neuropathic pain. PMID- 28578257 TI - Melatonin supplementation plus exercise behavior ameliorate insulin resistance, hypertension and fatigue in a rat model of type 2 diabetes mellitus. AB - INTRODUCTION: The objective was to investigate the effects of melatonin and exercise on insulin resistance (IR), hypertension and fatigue syndrome in a rat model of type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Rats were divided into 5 groups namely normal control (NC), T2DM control group (DC), diabetes plus exercise (DE), diabetes plus oral melatonin supplement (DM) and diabetes plus melatonin and exercise (DME) groups. Melatonin was administered orally 5mg/kg twice daily and 40min swimming/day 5days/week were regimented after diabetes induction. RESULTS: Blood pressure, fasting blood glucose, insulin, IR, serum leptin, lipid profiles, inflammatory cytokines, lipid peroxidation increased significantly (P<0.01) while serum adiponectin, antioxidant activities (superoxide dismutase, glutathione), exercise performance significantly decreased (P<0.001) in the DC group compared with the control group. Combined effects of exercise and melatonin ameliorated markedly hypertension, IR, biochemical alteration induced by diabetes and significantly increased exercise performance (P<0.01). The expression glucose transporter type 4 (GLUT4) mitochondrial biogenesis related proteins such as peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1 alpha), nuclear respiratory factor (NRFs) and mitochondrial transcription factor-A were up-regulated skeletal and cardiac muscle in the DME group. CONCLUSION: Melatonin supplementation in combination with exercise behavior may ameliorate IR, hypertension and exercise performance or fatigue possibly by improving antioxidative activities, hyperlipidemia, inflammatory cytokines via up-regulation of GLUT4, PGC-1 alpha and mitochondrial biogenesis in T2DM rats. PMID- 28578260 TI - Visualizing glycans on single cells and tissues-Visualizing glycans on single cells and tissues. AB - Metabolic oligosaccharide engineering and chemoenzymatic glycan labeling have provided powerful tools to study glycans in living systems and tissue samples. In this review article, we summarize recent advances in this field with a focus on innovative approaches for glycan imaging. The presented applications demonstrate that several of the leading imaging methods, which have revolutionized quantitative cell biology, can be adapted to imaging glycans on single cells and tissues. PMID- 28578261 TI - Quantification of cystatin-C in human serum by stable isotope dilution liquid chromatography electrospray ionization tandem mass spectrometry. AB - Cystatin C (CysC)-based estimated glomerular filtration rate is an excellent marker for early diagnosis of Chronic Kidney Disease (CKD). Particle-enhanced nephelometric immunoassay (PENIA) and particle-enhanced turbidimetric immunoassay (PETIA) are commonly used methods for CysC quantification in clinical testing. However, both of them lack of specificity which mass spectrometry offers. In this paper, an isotope dilution liquid chromatography tandem mass spectrometry (ID-LC MS/MS) method was established for quantification of CysC in human serum. After CysC denaturation, reduction and alkylation of cysteine residues, trypsin was added for proteolytic digestion of CysC. Specific peptide ALDFAVGEYNK was selected as surrogates for intact CysC protein, then quantified CysC by stable isotope-labelled internal standard peptide A[13C615N]LDFAVGEYNK based on calibration curve method. The calibration curves were y=0.1565x-1.6715 (R2=0.988) and y=1.8785x-2.2497 (R2=0.991) for y9 and y6, respectively. The linear range was 0.1-10mg/L and 0.5-15mg/L for y9 and y6, respectively. The limit of quantification (LOQ) was 0.052mg/L. At different concentrations of CysC, the recoveries were in the range of 80.5%-93.7%, the intraday precisions were in the range of 0.3%-2.2%, and the inter-day precisions were in the range of 0.2%-2.8%. The results show that ID-LC-MS/MS and PETIA methods have higher consistency (y=0.8021x+0.6611, p=0.14), and the mean difference of the two methods was 0.29mg/L, and 95% of the individual difference values were in the range of 0.91mg/L-0.33mg/L. PMID- 28578259 TI - The protective effects of compatibility of Aconiti Lateralis Radix Praeparata and Zingiberis Rhizoma on rats with heart failure by enhancing mitochondrial biogenesis via Sirt1/PGC-1alpha pathway. AB - Aconiti Lateralis Radix Praeparata ("Fuzi" in Chinese) in combination with Zingiberis Rhizoma ("Ganjiang" in Chinese) is commonly applied for the treatment of heart failure for thousands of years in China. However, its therapeutic mechanism is still poorly defined. This study aimed to investigate whether the compatibility of Fuzi and Ganjiang can protect rats with acute heart failure by enhancing mitochondrial biogenesis via Sirt1/PGC-1alpha signaling pathway. Hemodynamic parameters, including heart rate and left ventricular maximal rate of pressure rise and decline, were recorded in rats with acute heart failure induced by Propafenone hydrochloride. The serum levels of cardiac enzymes, including creatine kinase, lactate dehydrogenase, brain natriuretic peptide and cardiac troponin T, were also determined. The gene and protein levels of Sirtuin 1 (Sirt1), peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC 1alpha) and their downstream transcription factors were measured as well. The results indicated that Fuzi-Ganjiang herbal couple provided more significant benefits by restoring the left ventricular function and cardiac enzyme activities in comparison with their single use. Moreover, this herbal couple possessed a significant cardio-protection by increasing both gene and protein levels of Sirt1 and PGC-1alpha. In conclusion, the compatibility of Fuzi and Ganjiang had better therapeutic effect than their single use against failing heart, and the underlying mechanisms were partially through increasing mitochondrial biogenesis via Sirt1/PGC-1alpha pathway. PMID- 28578262 TI - Exposure to Deepwater Horizon oil and Corexit 9500 at low concentrations induces transcriptional changes and alters immune transcriptional pathways in sheepshead minnows. AB - The 2010 Deepwater Horizon (DWH) oil spill caused the release of 4.9 million barrels of crude oil into the Gulf of Mexico, followed by the application of 2.9 million L of the dispersant, CorexitTM to mitigate the spread of oil. The spill resulted in substantial shoreline oiling, potentially exposing coastal organisms to polyaromatic hydrocarbon (PAH) and dispersant contaminants. To investigate molecular effects in fish following exposure to environmentally relevant concentrations of DWH oil and dispersants, we exposed adult sheepshead minnows (Cyprinodon variegatus) to two concentrations of high-energy water-accommodated fraction (HEWAF), chemically enhanced water-accommodated fraction (CEWAF) or Corexit 9500TM for 7 and 14days. Resulting changes in hepatic gene expression were measured using 8*15K microarrays. Analytical chemistry confirmed PAH concentrations in HEWAF and CEWAF treatments were low (ranging from 0.26 to 5.98MUg/L), and likely representative of post-spill environmental concentrations. We observed significant changes to gene expression in all treatments (relative to controls), with Corexit and CEWAF having a greater effect on expression patterns in the liver than HEWAF treatments. Sub-network enrichment analysis of biological pathways revealed that the greatest number of altered pathways in high dose HEWAF and CEWAF treatments occurred following a 7-day exposure. Pathways related to immunity comprised the majority of pathways affected in each treatment, followed by pathways related to blood and circulation processes. Our results indicate that oil composition, concentration, and exposure duration all affect molecular responses in exposed fish, and suggest that low-concentration exposures may result in sub-lethal adverse effects. PMID- 28578263 TI - Inorganic phosphorus fertilizer ameliorates maize growth by reducing metal uptake, improving soil enzyme activity and microbial community structure. AB - Recently, several studies have showed that both organic and inorganic fertilizers are effective in immobilizing heavy metals at low cost, in comparison to other remediation strategies for heavy metal-contaminated farmlands. A pot trial was conducted in this study to examine the effects of inorganic P fertilizer and organic fertilizer, in single application or in combination, on growth of maize, heavy metal availabilities, enzyme activities, and microbial community structure in metal-contaminated soils from an electronic waste recycling region. Results showed that biomass of maize shoot and root from the inorganic P fertilizer treatments were respectively 17.8 and 10.0 folds higher than the un-amended treatments (CK), while the biomass in the organic fertilizer treatments was only comparable to the CK. In addition, there were decreases of 85.0% in Cd, 74.3% in Pb, 66.3% in Cu, and 91.9% in Zn concentrations in the roots of maize grown in inorganic P fertilizer amended soil. Consistently, urease and catalase activities in the inorganic P fertilizer amended soil were 3.3 and 2.0 times higher than the CK, whereas no enhancement was observed in the organic fertilizer amended soil. Moreover, microbial community structure was improved by the application of inorganic P fertilizer, but not by organic fertilizer; the beneficial microbial groups such as Kaistobacter and Koribacter were most frequently detected in the inorganic P fertilizer amended soil. The negligible effect from the organic fertilizer might be ascribed to the decreased pH value in soils. The results suggest that the application of inorganic P fertilizer (or in combination with organic fertilizer) might be a promising strategy for the remediation of heavy metals contaminated soils in electronic waste recycling region. PMID- 28578264 TI - Aflatoxin B1 inhibition in Aspergillus flavus by Aspergillus niger through down regulating expression of major biosynthetic genes and AFB1 degradation by atoxigenic A. flavus. AB - Twenty Aspergillus niger strains were isolated from peanuts and 14 strains were able to completely inhibit AFB1 production with co-cultivation. By using a Spin-X centrifuge system, it was confirmed that there are some soluble signal molecules or antibiotics involved in the inhibition by A. niger, although they are absent during the initial 24h of A. flavus growth when it is sensitive to inhibition. In A. flavus, 19 of 20 aflatoxin biosynthetic genes were down-regulated by A. niger. Importantly, the expression of aflS was significantly down-regulated, resulting in a reduction of AflS/AflR ratio. The results suggest that A. niger could directly inhibit AFB1 biosynthesis through reducing the abundance of aflS to aflR mRNAs. Interestingly, atoxigenic A. flavus JZ2 and GZ15 effectively degrade AFB1. Two new metabolites were identified and the key toxic lactone and furofuran rings both were destroyed and hydrogenated, meaning that lactonase and reductase might be involved in the degradation process. PMID- 28578266 TI - Next generation sequencing-based multigene panel for high throughput detection of food-borne pathogens. AB - Contamination of food by chemicals or pathogenic bacteria may cause particular illnesses that are linked to food consumption, commonly referred to as foodborne diseases. Bacteria are present in/on various foods products, such as fruits, vegetables and ready-to-eat products. Bacteria that cause foodborne diseases are known as foodborne pathogens (FBPs). Accurate detection methods that are able to reveal the presence of FBPs in food matrices are in constant demand, in order to ensure safe foods with a minimal risk of causing foodborne diseases. Here, a multiplex PCR-based Illumina sequencing method for FBP detection in food matrices was developed. Starting from 25 bacterial targets and 49 selected PCR primer pairs, a primer collection called foodborne pathogen - panel (FPP) consisting of 12 oligonucleotide pairs was developed. The FPP allows a more rapid and reliable identification of FBPs compared to classical cultivation methods. Furthermore, FPP permits sensitive and specific FBP detection in about two days from food sample acquisition to bioinformatics-based identification. The FPP is able to simultaneously identify eight different bacterial pathogens, i.e. Listeria monocytogenes, Campylobacter jejuni, Campylobacter coli, Salmonella enterica subsp. enterica serovar enteritidis, Escherichia coli, Shigella sonnei, Staphylococcus aureus and Yersinia enterocolitica, in a given food matrix at a threshold contamination level of 101cell/g. Moreover, this novel detection method may represent an alternative and/or a complementary approach to PCR-based techniques, which are routinely used for FBP detection, and could be implemented in (parts of) the food chain as a quality check. PMID- 28578267 TI - Influence of settings management and protection status on recreational uses and pressures in marine protected areas. AB - Coastal populations and tourism are growing worldwide. Consequently outdoor recreational activity is increasing and diversifying. While Marine Protected Areas (MPAs) are valuable for mitigating anthropogenic impacts, recreational uses are rarely monitored and studied, resulting in a lack of knowledge on users' practices, motivation and impacts. Based on boat counts and interview data collected in New Caledonia, we i) explored factors affecting user practices and motivations, ii) constructed fine-scale pressure indices covering activities and associated behaviors, and iii) assessed the relationships between user practices and site selection. User practices were found to depend on protection status, boat type and user characteristics. Pressure indices were higher within no-take MPAs, except for fishing. We found significant relationships between user practices and settings characteristics. In the context of increasing recreational uses, these results highlight options for managing such uses through settings management without jeopardizing the social acceptance of MPAs or the attainment of conservation goals. PMID- 28578265 TI - Lactic acid bacteria involved in cocoa beans fermentation from Ivory Coast: Species diversity and citrate lyase production. AB - Microbial fermentation is an indispensable process for high quality chocolate from cocoa bean raw material. lactic acid bacteria (LAB) are among the major microorganisms responsible for cocoa fermentation but their exact role remains to be elucidated. In this study, we analyzed the diversity of LAB in six cocoa producing regions of Ivory Coast. Ribosomal 16S gene sequence analysis showed that Lactobacillus plantarum and Leuconostoc mesenteroides are the dominant LAB species in these six regions. In addition, other species were identified as the minor microbial population, namely Lactobacillus curieae, Enterococcus faecium, Fructobacillus pseudoficulneus, Lactobacillus casei, Weissella paramesenteroides and Weissella cibaria. However, in each region, the LAB microbial population was composed of a restricted number of species (maximum 5 species), which varied between the different regions. LAB implication in the breakdown of citric acid was investigated as a fundamental property for a successful cocoa fermentation process. High citrate lyase producer strains were characterized by rapid citric acid consumption, as revealed by a 4-fold decrease in citric acid concentration in the growth medium within 12h, concomitant with an increase in acetic acid and lactic acid concentration. The production of citrate lyase was strongly dependent on environmental conditions, with optimum production at acidic pH (pH<5), and moderate temperature (30-40 degrees C), which corresponds to conditions prevailing in the early stage of natural cocoa fermentation. This study reveals that one of the major roles of LAB in the cocoa fermentation process involves the breakdown of citric acid during the early stage of cocoa fermentation through the activity of citrate lyase. PMID- 28578268 TI - Carbon emission allowance allocation with a mixed mechanism in air passenger transport. AB - Air passenger transport carbon emissions have become a great challenge for both governments and airlines because of rapid developments in the aviation industry in recent decades. In this paper, a mixed mechanism composed of a cap-and-trade mechanism and a carbon tax mechanism is developed to assist governments in allocating carbon emission allowances to airlines operating on the routes. Combined this mixed mechanism with an equilibrium strategy, a bi-level multi objective model is proposed for an air passenger transport carbon emission allowance allocation problem, in which a government is considered as a leader and the airlines as the followers. An interactive solution approach integrating a genetic algorithm and an interactive evolutionary mechanism is designed to search for satisfactory solutions of the proposed model. A case study is then presented to show its practicality and efficiency in mitigating carbon emissions. Sensitivity analyses under different tradable and taxable levels are also conducted, which can give the government insights as to the tradeoffs between lowering carbon intensity and improving airlines' operations. The computational results demonstrate that the mixed mechanism can assist greatly in carbon emission mitigation for air passenger transport and therefore, it should be established as part of air passenger transport carbon emission policies. PMID- 28578269 TI - Preparation of chitosan/tripolyphosphate nanoparticles with highly tunable size and low polydispersity. AB - Nanoparticles prepared through the ionotropic gelation of chitosan with tripolyphosphate (TPP) have been extensively studied as vehicles for drug and gene delivery. Though a number of these works have focused on preparing particles with narrow size distributions, the monodisperse particles produced by these methods have been limited to narrow size ranges (where the average particle size was not varied by more than twofold). Here we show how, by tuning the NaCl concentration in the parent chitosan and TPP solutions, low-polydispersity particles with z-average diameters ranging between roughly 100 and 900nm can be prepared. Further, we explore how the size of these particles depends on the method by which the TPP is mixed into the chitosan solution, specifically comparing: (1) single-shot mixing; (2) dropwise addition; and (3) a dilution technique, where chitosan and TPP are codissolved at a high (gelation-inhibiting) ionic strength and then diluted to lower ionic strengths to trigger gelation. Though the particle size increases sigmoidally with the NaCl concentration for all three mixing methods, the dilution method delivers the most uniform/gradual size increase - i.e., it provides the most precise control. Also investigated are the effects of mixture composition and mixing procedure on the particle yield. These reveal the particle yield to increase with the chitosan/TPP concentration, decrease with the NaCl concentration, and vary only weakly with the mixing protocol; thus, at elevated NaCl concentrations, it may be beneficial to increase chitosan and TPP concentrations to ensure high particle yields. Finally, possible pitfalls of the salt-assisted size control strategy (and their solutions) are discussed. Taken together, these findings provide a simple and reliable method for extensively tuning chitosan/TPP particle size while maintaining narrow size distributions. PMID- 28578270 TI - Magnetic nanoparticle incorporated oleogel as iontophoretic drug delivery system. AB - In this article, we validated the use of electric current as an external stimulus to induce an enhancement of drug release from magnetic nanoparticle (MNP) incorporated organogels (magnetogel) under iontophoretic conditions. For this purpose, we adopted a simple, two-step synthesis route to incorporate magnetic (Fe3O4) nanoparticles (MNP) and ciprofloxacin hydrochloride within the network of a soybean oil-based oleogel using stearic acid as gelator. We fabricated a series of MNP incorporated oleogels by varying the wt% of MNPs while keeping a constant weight ratio of soybean oil:stearic acid. The microstructures of the magnetogels were analyzed in MNP concentration-dependent manner by optical microscopy, powder X-ray diffraction, FTIR, mechanical, and electrical studies. Detailed analysis of the electrical properties revealed that the gel sample with a maximum proportion of MNP (S4) allowed the maximum passage of current through it among all the compositions. Under the iontophoretic environment of the active condition, we observed nearly 2.5 fold increase in cumulative drug release in case of sample S4 compared to the corresponding passive condition. These observations suggested that in future, our magnetogel formulation can be further developed as AC field induced 'remote controlled' agent for therapeutic application. PMID- 28578271 TI - A gold nanoparticle coated porcine cholecyst-derived bioscaffold for cardiac tissue engineering. AB - Extracellular matrices of xenogeneic origin have been extensively used for biomedical applications, despite the possibility of heterogeneity in structure. Surface modification of biologically derived biomaterials using nanoparticles is an emerging strategy for improving topographical homogeneity when employing these scaffolds for sophisticated tissue engineering applications. Recently, as a tissue engineering scaffold, cholecyst derived extracellular matrix (C-ECM) has been shown to have several advantages over extracellular matrices derived from other organs such as jejunum and urinary bladder. This study explored the possibility of adding gold nanoparticles, which have a large surface area to volume ratio on C-ECM for achieving homogeneity in surface architecture, a requirement for cardiac tissue engineering. In the current study, gold nanoparticles (AuNPs) were synthesized and functionalised for conjugating with a porcine cholecystic extracellular matrix scaffold. The conjugation of nanoparticles to C-ECM was achieved by 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide/N-hydroxysuccinimide chemistry and further characterized by Fourier transform infrared spectroscopy, environmental scanning electron microscopy, energy dispersive X-ray spectroscopy and thermogravimetric analysis. The physical properties of the modified scaffold were similar to the original C-ECM. Biological properties were evaluated by using H9c2 cells, a cardiomyoblast cell line commonly used for cellular and molecular studies of cardiac cells. The modified scaffold was found to be a suitable substrate for the growth and proliferation of the cardiomyoblasts. Further, the non-cytotoxic nature of the modified scaffold was established by direct contact cytotoxicity testing and live/dead staining. Thus, the modified C-ECM appears to be a potential biomaterial for cardiac tissue engineering. PMID- 28578272 TI - Biomolecules at the amorphous silica/water interface: Binding and fluorescence anisotropy of peptides. AB - We investigate binding of the tripeptides Lys-Trp-Lys (KWK) and Glu-Trp-Glu (EWE) to the amorphous silica surface using atomistic simulations. These peptides were chosen because they were previously utilized in experiments measuring binding affinity and steady-state fluorescence anisotropy from the indole chromophore of the tryptophan residue. Our simulations were performed using silica with surface change density of -0.8 elementary charges per square nanometer, which is expected at neutral pH. Even though positive charged KWK binds more strongly to the negatively charged silica surface, EWE also forms bound complexes with the surface that are stable for at least 15ns of simulation, in agreement with the experiments which revealed evidence for binding of both KWK and EWE to silica. Binding mechanisms include a wide variety of electrostatic interactions, as well as hydrophobic interactions between the indole group and hydrophobic areas of the heterogeneous silica surface. The long-time limit of the fluorescence anisotropy of tryptophan is calculated from the simulations in order to help interpret the recent experiments. We identify several factors which control the magnitude of the fluorescence anisotropy for each binding configuration. PMID- 28578273 TI - Biomimetic mineralized hierarchical hybrid scaffolds based on in situ synthesis of nano-hydroxyapatite/chitosan/chondroitin sulfate/hyaluronic acid for bone tissue engineering. AB - Biomimetic mineralized hybrid scaffolds are widely used as natural bone substitute materials in tissue engineering by mimicking vital characters of extracellular matrix (ECM). However, the fabrication of hybrid scaffolds with suitable mechanical properties and good biocompatibility remains a challenge. To solve the problems mentioned above, biomimetic calcium phosphate mineralized organic-inorganic hybrid scaffold composed of nano hydroxyapatite (nHAP), Chitosan (CS), Chondroitin sulfate (CSA) and hyaluronic acid (HA) with hierarchical micro/nano structures was successfully developed. In this process, an efficient and easy-to-accomplish method combining in situ biomimetic synthesis with freeze-drying technology was applied. The chemical structure of the scaffolds was confirmed by Fourier transform infrared spectroscopy (FTIR) and X ray diffraction (XRD). Surface morphology of scaffolds was characterized by Scanning electron microscopy (SEM). The nHAP/CS/CSA/HA hybrid scaffolds with a well-distributed pore size showed suitable mechanical strength which is not only due to the addition of the nHAP but also the interaction between the positively charged CS and the negatively charged CSA and HA. Simultaneously, the biocompatibility was evaluated by the MTT cytotoxicity assay, alkaline phosphatase (ALP) activity, Hoechst 33258 fluorescence staining. All those results proved that the scaffolds possess good biocompatibility and the components added have enhanced the proliferation and differentiation of osteoblast. Thus, it can be anticipated that the in situ biomimetic mineralized nHAP/CS/CAS/HA hybrid scaffolds will be promising candidates for bone tissue engineering. PMID- 28578274 TI - Synthesis and characterization of a novel organic nitrate NDHP: Role of xanthine oxidoreductase-mediated nitric oxide formation. AB - In this report, we describe the synthesis and characterization of 1,3 bis(hexyloxy)propan-2-yl nitrate (NDHP), a novel organic mono nitrate. Using purified xanthine oxidoreductase (XOR), chemiluminescence and electron paramagnetic resonance (EPR) spectroscopy, we found that XOR catalyzes nitric oxide (NO) generation from NDHP under anaerobic conditions, and that thiols are not involved or required in this process. Further mechanistic studies revealed that NDHP could be reduced to NO at both the FAD and the molybdenum sites of XOR, but that the FAD site required an unoccupied molybdenum site. Conversely, the molybdenum site was able to reduce NDHP independently of an active FAD site. Moreover, using isolated vessels in a myograph, we demonstrate that NDHP dilates pre-constricted mesenteric arteries from rats and mice. These effects were diminished when XOR was blocked using the selective inhibitor febuxostat. Finally, we demonstrate that NDHP, in contrast to glyceryl trinitrate (GTN), is not subject to development of tolerance in isolated mesenteric arteries. PMID- 28578277 TI - Synergistic enzymatic saccharification and fermentation of agar for biohydrogen production. AB - Nowadays, marine biomass is gradually considered as another utilizable material for the sustainable bioenergy development. In the present study, galactose, the main component of agar polysaccharide, was utilized for the biohydrogen production by Enterobacter sp. CN1. The highest hydrogen yield of 303.2mL/g was obtained in the cultivation media containing 5.87g/L of galactose, together with initial pH of 7.3 and incubation temperature of 36 degrees C, after the response surface methodology (RSM) analysis. After the saccharification process by the agarase (AgaXa) and neoagarobiose hydrolase (NH852), the agar hydrolysate obtained was further applied to generate biohydrogen by strain CN1. Under the synergistic enzymatic saccharification and fermentation process, the production of biohydrogen was obtained to be 5047+/-228mL/L from 50g/L of agar, resulting in 3.86-fold higher than the control without enzymatic pretreatment. PMID- 28578279 TI - Microbial stratification structure within cathodic biofilm of the microbial fuel cell using the freezing microtome method. AB - The aim of this study was to investigate the microbial stratification structure within cathodic biofilm of the microbial fuel cell (MFC) using the freezing microtome method. Experiments were conducted in a single-chamber air-cathode MFC with 0.8g/L maltodextrin as substrate for ~30d operation. The maximum power density was 945+/-10mW/m2 in the MFC. Maltodextrin resulted in the relative abundance of Candidatus Saccharibacteria of 37.0% in the anodic biofilm. Different bacterial communities were identified in different layers within the cathodic biofilm. The relative abundance of Enterococcus was 3.7%, 10.5%, and 1.6% in the top (100-150MUm), middle (50-100MUm), and bottom (0-50MUm) layers, respectively. Higher bacterial viability was observed within the top and bottom layers of the cathodic biofilm. Understanding the stratification of bacterial community in cathodic biofilm should be important to control the cathodic biofilm in the MFC. PMID- 28578278 TI - Fungal community and cellulose-degrading genes in the composting process of Chinese medicinal herbal residues. AB - The fungal community and the population of 16S rRNA, 18S rRNA and cellulose degrading genes during the 30-day composting process of Chinese medicinal herbal residues were investigated using Illumina MiSeq and quantitative real-time PCR. An obvious succession of fungal communities occurred during the composting process. Unidentified fungi predominated in the raw materials. As composting progressed, Ascomycota became the most dominant phylum, with Aspergillus being the most dominant genus, and Aspergillus fumigatus making up 99.65% of that genus. Because of the inoculation of cellulolytic fungi in the mature stage, the cellulose degradation rate in inoculation groups was faster and the relative abundances of Aspergillus and the glycoside hydrolase family 7 genes were significantly higher than those in the control groups. These indicated that the fungal inoculants facilitated the degradation of cellulose, increased cellulolytic fungi and optimized the community structure. PMID- 28578276 TI - Decoding NADPH oxidase 4 expression in human tumors. AB - NADPH oxidase 4 (NOX4) is a redox active, membrane-associated protein that contributes to genomic instability, redox signaling, and radiation sensitivity in human cancers based on its capacity to generate H2O2 constitutively. Most studies of NOX4 in malignancy have focused on the evaluation of a small number of tumor cell lines and not on human tumor specimens themselves; furthermore, these studies have often employed immunological tools that have not been well characterized. To determine the prevalence of NOX4 expression across a broad range of solid tumors, we developed a novel monoclonal antibody that recognizes a specific extracellular region of the human NOX4 protein, and that does not cross react with any of the other six members of the NOX gene family. Evaluation of 20 sets of epithelial tumors revealed, for the first time, high levels of NOX4 expression in carcinomas of the head and neck (15/19 patients), esophagus (12/18 patients), bladder (10/19 patients), ovary (6/17 patients), and prostate (7/19 patients), as well as malignant melanoma (7/15 patients) when these tumors were compared to histologically-uninvolved specimens from the same organs. Detection of NOX4 protein upregulation by low levels of TGF-beta1 demonstrated the sensitivity of this new probe; and immunofluorescence experiments found that high levels of endogenous NOX4 expression in ovarian cancer cells were only demonstrable associated with perinuclear membranes. These studies suggest that NOX4 expression is upregulated, compared to normal tissues, in a well-defined, and specific group of human carcinomas, and that its expression is localized on intracellular membranes in a fashion that could modulate oxidative DNA damage. PMID- 28578280 TI - A facile approach to fabricate an immobilized-phosphate zirconium-based metal organic framework composite (UiO-66-P) and its activity in the adsorption and separation of organic dyes. AB - A novel immobilized-phosphate zirconium-based metal-organic framework composite, denoted as UiO-66-P, was synthesized by a solvothermal method using UiO-66 nanoparticles and Na3PO4 ligands. The products were characterized by powder X-ray diffraction, energy dispersive spectrometry, field emission scanning electron microscopy, thermogravimetric analysis, infrared spectroscopy, zeta potential analysis, and gas adsorption measurements. The UiO-66-P nanocrystals, which comprised negatively charged frameworks, exhibited high stability, excellent porosity, and efficient charge-selective capture and separation of the cationic dye Methylene Blue (MB). An uptake capacity of 91.1mgg-1 was achieved at room temperature over 24h when 5mg of UiO-66-P was immersed in 40mL of a 500mgL-1MB solution. This capacity is much higher than that of UiO-66 (24.5mgg-1). The adsorption capability of UiO-66-P for MB was improved by 272% compared to that of pristine UiO-66. The effects of variables such as initial pH, MB concentration, and contact time were investigated. In addition, the as-obtained UiO-66 nanocrystals exhibited excellent adsorption capability for the anionic dyes Congo Red, Acid Chrome Blue K, and Methyl Orange. PMID- 28578281 TI - In situ one-step synthesis of Fe3O4@MIL-100(Fe) core-shells for adsorption of methylene blue from water. AB - A new route for Fe3O4@MIL-100(Fe) core-shells is proposed via in situ one-step hydrothermal strategy, in which Fe3O4 microspheres not only serve as magnetic cores but also provide Fe(III) for MIL-100(Fe) synthesis. The MIL-100(Fe) is uniformly grown as a shell on the surface of Fe3O4, and the shell thickness can be fine-tuned from 73.5 to 148nm by simply controlling the reaction time. Compared with Fe3O4, the surface area and pore volume of the Fe3O4@MIL-100(Fe) are significantly increased while the magnetism is barely affected. The application of Fe3O4@MIL-100(Fe) in adsorption was tested using several dyes as model analytes, and showed high adsorption capacity (221mgg-1) towards methylene blue (MB), which is based on electrostatic interactions and size filter effect. The MB adsorption isotherm follows Langmuir model and pseudo second-order kinetic model. Intra-particle diffusion model reveals that both film and pore diffusions are involved in the rate limiting steps. The adsorption is controlled by enthalpy change rather than entropy effect. DeltaH, DeltaS and DeltaG values indicated that the adsorption process was spontaneous and exothermic. Simple synthesis procedure, immense magnetism, high adsorption capacity and excellent reusability of Fe3O4@MIL-100(Fe) make it an attractive candidate for application of MB removal from polluted environmental samples. PMID- 28578282 TI - Transition from double to single diffusive behavior with increase in polymer concentration for oppositely charged guest - host systems of green fluorescent protein diffusing inside poly-l-lysine solutions. AB - The effect of crowding, background and probe charges and chain flexibility on probe dynamics of Green Fluorescent Protein in polyelectrolyte solutions of poly l-lysine was investigated using Fluorescence Recovery After Photobleaching (FRAP). An interesting double diffusive behavior in FRAP recovery curve was observed at low polymer concentration resulting in two relaxation modes, which disappears with rise in polymer concentration. The fast relaxation mode attributes to diffusion of free protein molecules alone, where as slow mode is credited to polymer adsorbed protein molecules. Absence of double diffusive behavior at higher polymer concentration is argued in terms of varying host chain conformation and the only relaxation mode present is due to movement of free probes alone rather than that of adsorbed proteins. We noticed only a marginal decrease in diffusion coefficient with rise in salt concentration and the trend is reversed when variation in sample viscosity with salt is taken into account. In addition a small but systematic decrease in diffusion coefficient is seen with increase in magnitude of probe charge. Comparison of results with ideal Stoke - Einstein relation brings out the importance of polyelectrolyte effect and indicates ~200 - fold positive deviations from predicted value for both variation in ionic strength and solution pH. PMID- 28578275 TI - Mitochondria-meditated pathways of organ failure upon inflammation. AB - Liver failure induced by systemic inflammatory response (SIRS) is often associated with mitochondrial dysfunction but the mechanism linking SIRS and mitochondria-mediated liver failure is still a matter of discussion. Current hypotheses suggest that causative events could be a drop in ATP synthesis, opening of mitochondrial permeability transition pore, specific changes in mitochondrial morphology, impaired Ca2+ uptake, generation of mitochondrial reactive oxygen species (mtROS), turnover of mitochondria and imbalance in electron supply to the respiratory chain. The aim of this review is to critically analyze existing hypotheses, in order to highlight the most promising research lines helping to prevent liver failure induced by SIRS. Evaluation of the literature shows that there is no consistent support that impaired Ca++ metabolism, electron transport chain function and ultrastructure of mitochondria substantially contribute to liver failure. Moreover, our analysis suggests that the drop in ATP levels has protective rather than a deleterious character. Recent data suggest that the most critical mitochondrial event occurring upon SIRS is the release of mtROS in cytoplasm, which can activate two specific intracellular signaling cascades. The first is the mtROS-mediated activation of NADPH-oxidase in liver macrophages and endothelial cells; the second is the acceleration of the expression of inflammatory genes in hepatocytes. The signaling action of mtROS is strictly controlled in mitochondria at three points, (i) at the site of ROS generation at complex I, (ii) the site of mtROS release in cytoplasm via permeability transition pore, and (iii) interaction with specific kinases in cytoplasm. The systems controlling mtROS-signaling include pro- and anti inflammatory mediators, nitric oxide, Ca2+ and NADPH-oxidase. Analysis of the literature suggests that further research should be focused on the impact of mtROS on organ failure induced by inflammation and simultaneously providing a new theoretical basis for a targeted therapy of overwhelmed inflammatory response. PMID- 28578283 TI - In-situ growth of ZIF-8 on layered double hydroxide: Effect of Zn/Al molar ratios on their structural, morphological and adsorption properties. AB - In-situ growth of Zeolite imidazolate frameworks (ZIFs) on layered double hydroxides (LDHs) to form porous composites is a promising and challenging strategy to develop materials for separation application. Herein, the Zn-Al LDH with different Zn/Al molar ratios was prepared and used as matrix for the growth of ZIF-8 on its surface. The resulting composites were characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), N2 physisorption, thermogravimetric (TG), scanning electron microscope (SEM) and elemental analysis followed by testing for AsV removal from aqueous solution. Results showed that ZIF-8 could form on the surface of LDH with different Zn/Al molar ratios. At low Zn/Al molar ratios, the morphology and surface area of the ZIF/LDH composites and the content of ZIF-8 in the composites were little affected by the Zn/Al molar ratio. With increasing Zn/Al molar ratio, ZIF-8/LDH exhibited a lower surface area, which resulted from reduced content of ZIF-8 caused by impurities generated in the LDH matrix. All ZIF-8/LDH samples showed high AsV adsorption capacity, which was significantly higher than that of pure LDH or ZIF-8. PMID- 28578284 TI - Enhancement of corrosion resistance of polypyrrole using metal oxide nanoparticles: Potentiodynamic and electrochemical impedance spectroscopy study. AB - We introduce a simple and facile strategy for dispersing of nanoparticles within a p-type conducting polymer matrix by in situ electropolymerization using oxalic acid as the supporting electrolyte. Coatings prepared from polypyrrole-nano-metal oxide particles synthesized by in situ polymerization were found to exhibit excellent corrosion resistance much superior to polypyrrole (Ppy) in aggressive environments. The anti-corrosion behavior of polypyrrole films in different states and the presence of TiO2, Mn2O3 and ZnO nanoparticles synthesized by electropolymerization on Al electrodes have been investigated in corrosive solutions using potentiodynamic polarization and electrochemical impedance spectroscopy. The electrochemical response of the coated electrodes in polymer and nanocomposite state was compared with bare electrodes. The use of TiO2 nanoparticles has proved to be a great improvement in the performances of polypyrrole films for corrosion protection of Al samples. The polypyrrole synthesized in the presence of TiO2 nanoparticles coated electrodes offered a noticeable enhancement of protection against corrosion processes. The exceptional improvement of performance of these coatings has been associated with the increase in barrier to diffusion, prevention of charge transport by the nanosize TiO2, redox properties of polypyrrole as well as very large surface area available for the liberation of dopant due to nano-size additive. PMID- 28578286 TI - Enhanced ethanol electro-oxidation reaction on carbon supported Pd-metal oxide electrocatalysts. AB - Various Pd-metal oxide/C electrocatalysts were fabricated using ethylene glycol as a reducing agent in modified microwave-assisted polyol process. The crystal structure and surface morphology were studied using X-ray diffraction and transmission electron microscopy. All prepared Pd-metal oxide/C electrocatalysts exhibited a shift of Pd diffraction planes in the positive direction in relation to that of Pd/C. Highly dispersed palladium nanoparticles were formed on different metal oxide/C supports. The electrocatalytic performance of these electrocatalysts for ethanol oxidation was examined in NaOH solution using cyclic voltammetry, chronoamperometry and electrochemical impedance spectroscopy. An improvement in electrochemical parameters including onset potential, oxidation current density and If/Ib values was recorded at different Pd-metal oxide/C electrocatalysts, especially Pd-NiO/C. Three folds increment in steady state oxidation current density value was also displayed by investigated Pd-metal oxide/C electrocatalysts when contrasted to that of Pd/C to reflect their enhanced stability behavior. PMID- 28578285 TI - Bioinspired catecholic activation of marine chitin for immobilization of Ag nanoparticles as recyclable pollutant nanocatalysts. AB - Being one type of the most abundant marine polysaccharides in nature, chitin has inert chemical properties and thus prolonged been hindered for high-value utilization. A mussel-inspired catecholic chemistry was found to be able to confer nature-derived mesoporous chitin aerogels with high and tunable surface activities. When further combining with their high porosity, high specific surface area, mechanical toughness and unique nanofibrous architecture, these catechol-activated chitin aerogels could be used as a unique supporting matrix to immobilize Ag nanoparticles. Besides the mild synthesis conditions and the merits inherited from pristine chitin, the resultant chitin-Ag hybrid aerogels further exhibited high catalytic activity, excellent recyclability, super solvent endurance and fast regeneration ability. Their high mechanic properties and porous structures also enabled a convenient membrane process to remove organic dyes from water. PMID- 28578287 TI - Sulfur doped-copper oxide nanoclusters synthesized through a facile electroplating process assisted by thiourea for selective photoelectrocatalytic reduction of CO2. AB - Development of effective methods for conversion of CO2 to useful chemicals is considered to be a prospective way in terms of energy economy and chemical industry. Due to the thermodynamic stability of CO2, the application of the low cost eco-friendly catalyst or photocatalyts for CO2 reduction with high efficiency is a challenge. Herein, we report a simple template-free electrochemical approach for the preparation of sulfur doped copper oxide nanoclusters directly on the copper disc electrode using thiourea (TU) as sulfur precursor. The prepared Cu2O/CuO hybrid structures without TU exhibits photoelectrocatalytic fitness for CO2 reduction, while the catalytic activity and stability are significantly improved after sulfur substitution. Surface study by scanning electron microscopy (SEM) and atomic force microscopy (AFM) reveals an improved surface roughness alongside the formation and distribution of uniform nanoclusters of sulfur-substituted copper oxide. Also, optical analyses show a little increasing of band gap from 1.95eV to 2.05eV after sulfur substitution. Based on the experimental results, methanol and acetone are the main CO2 reduction products where, the overpotential of methanol and acetone evolution is in good agreement with the conduction band position of prepared nanoclusters. This work has a high competitive advantage of new sight to develop the novel doped materials via a simple way for high-performance photoelectrocatalysts for energy conversion. PMID- 28578288 TI - Nonlinear thermal radiation and cubic autocatalysis chemical reaction effects on the flow of stretched nanofluid under rotational oscillations. AB - Combined effects of nonlinear thermal radiation and cubic autocatalysis chemical reaction on the three dimensional flow of stretched nanofluid along a rotating sheet have been investigated in this paper. The flow field is assumed to be suspended with magnetic iron oxide nanoparticles (IONPs). Hamilton-Crosser model is applied to measure effective thermal conductivity of nanofluid. Rosseland approximation is employed to obtain the nonlinear radiative heat flux. For novelty and practical point of view, influence of fluctuating surface velocity and periodic surface temperature constraints are incorporated into the governing equations which in turn are made dimension free by employing suitable transformations. For numerical solutions, an explicit finite difference scheme has been proposed under the restrictions of derived stability conditions. PMID- 28578289 TI - Differential interaction behaviors of an alkaloid drug berberine with various bile salts. AB - The present study reports a meticulous characterization of the interaction of a potent anti-cancer drug, berberine chloride (BR) with a series of bile salt aggregates having varying hydrophobicity (sodium deoxycholate (NaDC), sodium cholate (NaC), and sodium taurocholate (NaTC)). The absorption spectrum of BR reveals a complex profile comprised of four distinct peaks. Analysis of the modulations of the absorption spectral properties of BR following interaction with the bile salts raising deeper questions unveils a critical insight into the mode of interaction of the cationic drug (BR) with the bile salts; a greater degree of perturbation of the microenvironment of the isoquinolinic part of BR compared to the benzenoid part. The remarkable modulation of the fluorescence profile of BR with added bile salts provides a sensitive indicator for monitoring the interaction scenario. However, an intriguing observation in this context reveals differential fluorescence behavior of BR in various bile salt aggregates, that is, similar observations in NaDC and NaC (which are legitimately interpreted according to the 'two-step association model') in comparison to NaTC. Such contrasting behavior of BR in NaTC aggregates has been rationalized on the basis of the possibility of formation of dye aggregate facilitated because of the proximity of the cationic drug molecules to the anionic headgroup of NaTC bile salt. Surprisingly, our spectroscopic results evidence for binding location of the drug at the interfacial region in all the bile salt aggregates. To this end, the time-resolved fluorescence decay behavior of the drug within various bile salt aggregates has been meticulously studied. The fluorescence decay results are found to be highly sensitive to the structure and size of the bile salt aggregates eventually leading to characterization of the interaction of the drug with the bile salts in excellent corroboration with the steady-state data. Furthermore, the time-resolved fluorescence anisotropy decay measurements yielded insight into the modulation of rotational dynamical behavior of the drug within the bile salt aggregates. PMID- 28578290 TI - 131I-labeled chitosan hydrogels for radioembolization: A preclinical study in small animals. AB - INTRODUCTION: The purpose of the study was to examine potential of 131I-labeled chitosan hydrogels (Chi) for treatment of liver cancer. METHODS: Orthotopic hepatoma was induced by McA-RH7777-fLuc cells (1*107) that were injected into the left hepatic lobe of rats. Ten days later, tumor-bearing rats evidenced by bioluminescence received 125I-labeled Chi with left hepatic artery access. Pharmacokinetics and excretion (n=8) and biodistribution (n=6/time point) were studied after injection. To examine therapeutic potential, animals (n=8/group) were also treated with Chi labeled with or without 131I. Changes in tumor volume by magnetic resonance (MR) imaging were studied. RESULTS: The rate of tumor induction assessed by bioluminescence imaging was 72% (68/95). Gamma counter and scintigraphy imaging analyses showed accumulation of 125I-labeled Chi dominantly in the liver. A small fraction of 125I-labeled Chi was detected in the stomach (2.02+/-3.07%ID) and muscle (1.37+/-1.48%ID) at 2 d post-treatment. Blood sample analysis showed the maximum blood concentration of 0.09+/-0.03%ID/mL, which peaked at 0.60+/-0.45 d. Over a 4-week period, 31.22+/-8.16%ID were excreted in the urine and 3.5+/-1.3% in the feces. Treatment of Chi (median, 876mm3; IQR, 496mm3-1413mm3) markedly reduced the extent of tumor growth, compared to controls (median, 12,085mm3; IQR, 7786mm3-25,832mm3; P<0.05 vs control). 131I Chi (median, 80mm3; IQR, 35mm3-172mm3; P<0.05 vs control) induced a greater tumor-suppressing effect, compared to Chi alone. CONCLUSIONS: In this study, we have characterized a new radioembolization device, 131I Chi, in vivo and provided evidence for its therapeutic potential. ADVANCES IN KNOWLEDGE: Transarterial embolization is a conceivable treatment option for patients with inoperable liver cancer to mitigate the disease progression. Recently, we have developed chitosan-based hydrogel microparticles. In the present study, the hydrogel microparticles were radiolabeled with 131I for treatment of liver cancer. Our results demonstrated that a hepatic arterial injection of 125I-labeled Chi resulted in substantial liver accumulation, which was accompanied by virtually no extrahepatic deposition. The results of the present study also showed that administration of 131I Chi markedly suppressed tumor growth, compared to controls and to animals receiving unlabeled Chi. 131I-labeled chitosan hydrogel microparticles represent a new therapeutic approach for treatment of liver cancer. PMID- 28578292 TI - WITHDRAWN: Fungal diversity is negatively affected by habitat fragmentation: a meta-analysis. AB - This article that has already been published in , 10.1016/j.mib.2017.03.015 has been withdrawn at the request of the editor and publisher. The publisher regrets that an error occurred which led to the premature publication of this paper. This error bears no reflection on the article or its authors. The publisher apologizes to the authors and the readers for this unfortunate error". The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28578291 TI - Feasibility of bidirectional text messages in evaluating a text-based nutrition education program for low-income parents: Results from the Text2BHealthy program. AB - Text messages are increasingly used in the delivery of health education programs. One appealing aspect of this approach is the possibility of remotely collecting participant data to use in program tailoring or evaluation. The purpose of the present study is to test the feasibility of using text messages to collect participant data. Using data from 33 texted evaluation questions sent through the Text2BHealthy nutrition education program for low-income parents (n=108-1521) response rates under different incentive and prompting strategies were examined. Response rates are generally low across a pilot year and three program years, ranging from 10-55%. While incentives seemed to be ineffective at improving response rates, results indicate that prompting participants to respond may increase response rates. Individuals who respond to an initial question are highly likely to respond to a follow-up question (88-99%) and to report positive behaviors (68-100%). Responses received through text may be unrepresentative and positively biased. Text messages may be a supplemental data collection strategy in nutrition education programs, but low response rates and response bias undermine data quality. PMID- 28578294 TI - Suppressing mosaicism by Au nanowire injector-driven direct delivery of plasmids into mouse embryos. AB - Transgenic animals have become key tools in a variety of biomedical research areas. However, microinjection commonly used for producing transgenic animals has several challenges such as physical and chemical damage to the embryos due to microinjector with buffer, and low transgene integration rates with frequent mosaicism. Here, we report direct delivery of plasmids into mouse embryos using a Au nanowire injector (NWI) that significantly improved transgene integration efficiency and suppressed mosaicism. The Au NWI could deliver plasmid into the pronucleus (PN) of a mouse zygote without buffer and rapidly release it with electric pulse. Because zygote, which is a fertilized 1-cell stage embryo, has two physical barriers (cytoplasmic membrane and zona pellucida), direct delivery of plasmids into PN of zygote is more difficult than into a normal cell type. To penetrate the two physical barriers with minimal disruption of the embryo, we optimized the diameter and length of Au NWI. The mosaicism is more reduced in the Au NWI injected embryos than in micropipette injected embryos, which was determined by the expression of transgene in a blastocyst stage. We suggest that Au NWI can increase the efficiency of gene delivery into zygote with suppressed mosaicism and become a useful alternative. PMID- 28578293 TI - Bio-inspired crosslinking and matrix-drug interactions for advanced wound dressings with long-term antimicrobial activity. AB - There is a growing demand for durable advanced wound dressings for the management of persistent infections after deep burn injuries. Herein, we demonstrated the preparation of durable antimicrobial nanofiber mats, by taking advantage of strong interfacial interactions between polyhydroxy antibiotics (with varying number of OH groups) and gelatin and their in-situ crosslinking with polydopamine (pDA) using ammonium carbonate diffusion method. Polydopamine crosslinking did not interfere with the antimicrobial efficacy of the loaded antibiotics. Interestingly, incorporation of antibiotics containing more number of alcoholic OH groups (NOH >= 5) delayed the release kinetics with complete retention of antimicrobial activity for an extended period of time (20 days). The antimicrobials-loaded mats displayed superior mechanical and thermal properties than gelatin or pDA-crosslinked gelatin mats. Mats containing polyhydroxy antifungals showed enhanced aqueous stability and retained nanofibrous morphology under aqueous environment for more than 4 weeks. This approach can be expanded to produce mats with broad spectrum antimicrobial properties by incorporating the combination of antibacterial and antifungal drugs. Direct electrospinning of vancomycin-loaded electrospun nanofibers onto a bandage gauze and subsequent crosslinking produced non-adherent durable advanced wound dressings that could be easily applied to the injured sites and readily detached after treatment. In a partial thickness burn injury model in piglets, the drug-loaded mats displayed comparable wound closure to commercially available silver-based dressings. This prototype wound dressing designed for easy handling and with long-lasting antimicrobial properties represents an effective option for treating life threatening microbial infections due to thermal injuries. PMID- 28578295 TI - Assessment of neutralizing interleukin-4 effect on CD133 gene expression in colon cancer cell line. AB - Colorectal cancer may be maintained by cancer stem-like cells (CSCs) that express the cell surface marker CD133. CSCs (CD133+cells) exhibits greater resistance to the chemotherapy and this resistance may be mediated in part by an autocrine response to IL4. The aim of the study was to assess the effect of anti-IL4 antibody alone or in combination with chemotherapy on the CD133 expression andthe tumor growth. We used Caco cell line in our experiments and the samples were as the following; untreated colorectal cell line, cells treated by chemotherapy, cells treated by anti-IL4 antibody in 3doses (2.5, 5, 10MUg/ml), cells treatedby combination of chemotherapy and anti-IL4 antibody in 3 doses. Results of our in vitro studies demonstrated that anti-IL4 inhibited growth of Caco cell line in a dose-dependent manner revealing a 32.11% inhibition at the highest concentration (10ug/ml). There was further significant inhibition by combination of anti IL4 and chemotherapy in a dose response manner when compared to group treated by chemotherapy only. These effects were associated with decreased expression of CD133 in tumor cells also. Lastly, anti-IL4 antibody stimulated apoptosis. Our study suggested that neutralizing of IL4 by anti IL4 antibody affect the CD133+ cells may be by increasing their apoptosis. The effects of anti IL4 antibody either, alone or in combination with chemotherapy, inhibited the tumor growth and decreased the viable tumor cells. Furthermore, neutralizing of IL4 increased the efficacy of chemotherapy treatment. PMID- 28578296 TI - Attentional interference is modulated by salience not sentience. AB - Spatial cueing of attention occurs when attention is oriented by the onset of a stimulus or by other information that creates a bias towards a particular location. The presence of a cue that orients attention can also interfere with participants' reporting of what they see. It has been suggested that this type of interference is stronger in the presence of socially-relevant cues, such as human faces or avatars, and is therefore indicative of a specialised role for perspective calculation within the social domain. However, there is also evidence that the effect is a domain-general form of processing that is elicited equally with non-social directional cues. The current paper comprises four experiments that systematically manipulated the social factors believed necessary to elicit the effect. The results show that interference persists when all social components are removed, and that visual processes are sufficient to explain this type of interference, thus supporting a domain-general perceptual interpretation of interference. PMID- 28578299 TI - Preferred diffusion paths for copper electromigration by in situ transmission electron microscopy. AB - Ionic transport in the reverse direction of an electric field is caused by momentum transfer from free electrons to metal ions, i.e., electromigration (EM), which is a critical factor leading to copper (Cu) interconnect failure in integrated circuits under extreme operating conditions. We investigated Cu self diffusion paths under electrical bias using in situ transmission electron microscopy (TEM). An electric current was applied to multigrain Cu lines in the TEM instrument for durations of up to the order of 104s to trace EM-induced Cu movement around voids and hillocks. Combining this approach with scanning nanobeam diffraction, we observed that high-angle grain boundaries exposed to the free surface are the most favored paths for Cu EM, rather than a specific orientation within the grain. On hillocks of accumulated Cu atoms, we directly observed grain growth, accompanied by the formation of Sigma7 high-mobile and Sigma3 twin coincidence site lattice boundaries for effective growth. This study provides insight into the EM mechanism to improve the reliability of metal interconnect design. PMID- 28578297 TI - Targeting and destroying tumor vasculature with a near-infrared laser-activated "nanobomb" for efficient tumor ablation. AB - Attacking the supportive vasculature network of a tumor offers an important new avenue for cancer therapy. Herein, a near-infrared (NIR) laser-activated "nanobomb" was developed as a noninvasive and targeted physical therapeutic strategy to effectively disrupt tumor neovasculature in an accurate and expeditious manner. This "nanobomb" was rationally fabricated via the encapsulation of vinyl azide (VA) into c(RGDfE) peptide-functionalized, hollow copper sulfide (HCuS) nanoparticles. The resulting RGD@HCuS(VA) was selectively internalized into integrin alphavbeta3-expressing tumor vasculature endothelial cells and dramatically increased the photoacoustic signals from the tumor neovasculature, achieving a maximum signal-to-noise ratio at 4 h post-injection. Upon NIR irradiation, the local temperature increase triggered VA to release N2 bubbles rapidly. Subsequently, these N2 bubbles could instantly explode to destroy the neovasculature and further induce necrosis of the surrounding tumor cells. A single-dose injection of RGD@HCuS(VA) led to complete tumor regression after laser irradiation, with no tumor regrowth for 30 days. More importantly, high-resolution photoacoustic angiography, combined with excellent biodegradability, facilitated the precise destruction of tumor neovasculature by RGD@HCuS(VA) without damaging normal tissues. These results demonstrate the great potential of this "nanobomb" for clinical translation to treat cancer patients with NIR laser-accessible orthotopic tumors. PMID- 28578298 TI - Traditional folk beliefs on epilepsy in Norway and Sweden. AB - In Norway and Sweden, epilepsy has for many centuries been considered a strange and mysterious disease. The explanations of its causes have been many and imaginative. One being that epilepsy was caused by the hidden people inhabiting the woods and the mountains. To avoid the disease, these hidden people should not be annoyed. One commonly used treatment principle was to try to place the disease back to the ground, or passing the diseased through a hole or an opening in the nature. Fresh blood from criminals was also considered to have strong antiepileptic properties. In the Scandinavian countries, some of these folk beliefs have been very tenacious. PMID- 28578300 TI - Optimized pre-thinning procedures of ion-beam thinning for TEM sample preparation by magnetorheological polishing. AB - Ion-beam-thinning is a well-established sample preparation technique for transmission electron microscopy (TEM), but tedious procedures and labor consuming pre-thinning could seriously reduce its efficiency. In this work, we present a simple pre-thinning technique by using magnetorheological (MR) polishing to replace manual lapping and dimpling, and demonstrate the successful preparation of electron-transparent single crystal silicon samples after MR polishing and single-sided ion milling. Dimples pre-thinned to less than 30 microns and with little mechanical surface damage were repeatedly produced under optimized MR polishing conditions. Samples pre-thinned by both MR polishing and traditional technique were ion-beam thinned from the rear side until perforation, and then observed by optical microscopy and TEM. The results show that the specimen pre-thinned by MR technique was free from dimpling related defects, which were still residual in sample pre-thinned by conventional technique. Nice high-resolution TEM images could be acquired after MR polishing and one side ion thinning. MR polishing promises to be an adaptable and efficient method for pre thinning in preparation of TEM specimens, especially for brittle ceramics. PMID- 28578303 TI - Mobilising or standing still?A narrative review of Surgical Safety Checklist knowledge as developed in 25 highly cited papers from 2009 to 2016. PMID- 28578304 TI - Digitalisation of medicines: artefact, architecture and time. PMID- 28578302 TI - Fungal dysbiosis in cirrhosis. AB - OBJECTIVE: Cirrhotics have a high rate of infections, which are increasingly fungal or culture-negative in nature. While infected cirrhotics have bacterial dysbiosis, the role of fungi is unclear. We aimed to evaluate gut bacterial and fungal dysbiosis in cross-sectional and longitudinal analyses of outpatient and inpatient cirrhotics and prediction of hospitalisations. METHODS: Cross sectional: Age-matched controls, outpatients (with/without antibiotics) and hospitalised uninfected, culture-negative and culture-positive cirrhotics were included and followed for 90 days. Longitudinal: Three studies were conducted: (1) cirrhotics followed over 6 months, (2) outpatient cirrhotics administered antibiotics per standard of care for 5 days and (3) cirrhotics and controls administered omeprazole over 14 days. In all studies, stool bacterial/fungal profiles were analysed. RESULTS: Cross-sectional: In 143 cirrhotics and 26 controls, bacterial and fungal diversities were significantly linked. Outpatients on antibiotics and patients with culture-positive infections had the lowest diversities. Bacterial and fungal correlations were complex in uninfected, outpatient and control groups but were markedly skewed in infected patients. 21% were admitted on 90-day follow-up. A lower Bacteroidetes/Ascomycota ratio was associated with lower hospitalisations. Longitudinal: Fungal and bacterial profiles were stable on follow-up (5 days and 6 months). After antibiotics, a significantly reduced bacterial and fungal diversity, higher Candida and lower autochthonous bacterial relative abundance were seen. After omeprazole, changes in bacterial diversity and composition were seen but fungal metrics remained stable. CONCLUSION: There is a significant fungal dysbiosis in cirrhosis, which changes differentially with antibiotics and proton pump inhibitor use, but is otherwise stable over time. A combined bacterial-fungal dysbiosis metric, Bacteroidetes/Ascomycota ratio, can independently predict 90-day hospitalisations in patients with cirrhosis. CLINICAL TRIAL NUMBER: NCT01458990. PMID- 28578305 TI - Multiple supratentorial subependymomas causing obstructive hydrocephalus. AB - INTRODUCTION: Subependymomas are benign intraventricular tumours that most often occur asymptomatically and are found incidentally on autopsy. Symptomatic examples requiring surgical intervention are exceedingly rare. CASE PRESENTATION: A 55-year-old man with no history of neurological symptoms presented with multiple episodes of loss of consciousness and increasing headaches. MRI revealed a lobulated intraventricular mass centred at the right Foramen of Monro. Obstructive hydrocephalus with localised midline shift and a second lesion were noted. Right frontal craniotomy with total removal via transcortical resection was performed. DISCUSSION: Symptomatic subependymomas generally present with signs of hydrocephalus due to obstruction of cerebrospinal fluid pathways. There is only one other reported case of multifocal subependymomas in a symptomatic patient. An example of multiple supratentorial subependymomas causing obstructive hydrocephalus has not been previously reported. CONCLUSIONS: Multiple subependymomas are rare. Judicious surgical management with full excision led to symptomatic improvement in our patient. PMID- 28578301 TI - Diurnal cortisol slopes and mental and physical health outcomes: A systematic review and meta-analysis. AB - Changes in levels of the stress-sensitive hormone cortisol from morning to evening are referred to as diurnal cortisol slopes. Flatter diurnal cortisol slopes have been proposed as a mediator between chronic psychosocial stress and poor mental and physical health outcomes in past theory and research. Surprisingly, neither a systematic nor a meta-analytic review of associations between diurnal cortisol slopes and health has been conducted to date, despite extensive literature on the topic. The current systematic review and meta analysis examined associations between diurnal cortisol slopes and physical and mental health outcomes. Analyses were based on 179 associations from 80 studies for the time period up to January 31, 2015. Results indicated a significant association between flatter diurnal cortisol slopes and poorer health across all studies (average effect size, r=0.147). Further, flatter diurnal cortisol slopes were associated with poorer health in 10 out of 12 subtypes of emotional and physical health outcomes examined. Among these subtypes, the effect size was largest for immune/inflammation outcomes (r=0.288). Potential moderators of the associations between diurnal cortisol slopes and health outcomes were examined, including type of slope measure and study quality indices. The possible roles of flatter slopes as either a marker or a mechanism for disease etiology are discussed. We argue that flatter diurnal cortisol slopes may both reflect and contribute to stress-related dysregulation of central and peripheral circadian mechanisms, with corresponding downstream effects on multiple aspects of biology, behavior, and health. PMID- 28578307 TI - A 15-year-old Nepali boy with metastasised colorectal cancer. AB - Nepal suffers from vast inequalities in modern healthcare. The low-income country wrestles with far-reaching insufficiencies in minimal preventative medicine, health awareness, limited infrastructure and difficult topography-all of which contribute to poor access and poor care-seeking behaviour. Our patient came from rural Nepal, where primary healthcare outposts are frequently understaffed and underequipped. He received supportive treatment in his village from the time symptoms presented until he was diagnosed 2 years later, at a tertiary medical centre, with colorectal cancer. An examination of the relevant literature indicates that younger patients often present in later stages of the disease due to initial misdiagnosis or overlooking colorectal cancer as a possibility. Beyond the rarity of the patient's condition, the logistical and financial obstacles he faced in Nepal, particularly outside of the capital of Kathmandu, deterred his access to a higher level of care and delayed his correct diagnosis and treatment. PMID- 28578306 TI - Multiple recurrent ischaemic strokes in a patient with cancer: is there a role for the initiation of anticoagulation therapy for secondary stroke prevention? AB - A 52-year-old woman with a medical history of cervical and thyroid cancer, hypertension, dyslipidaemia, uncontrolled diabetes and heavy smoking was diagnosed with a new metastatic cholangiocarcinoma. While undergoing palliative chemotherapy, she developed dysarthria and left-sided weakness. Imaging studies showed multiple bilateral ischaemic strokes. On hospital days 2 and 5, she developed worsening neurological symptoms and imaging studies revealed new areas of ischaemia on respective days. Subsequent workup did not revealed a clear aetiology for the multiple ischaemic events and hypercoagulability studies were only significant for a mildly elevated serum D-dimer level. Although guidelines are unclear, full-dose anticoagulation with low molecular weight heparin was initiated given her high risk of stroke recurrence. She was discharged to acute rehabilitation but, within a month, she experienced complications of her malignant disease progression and a new pulmonary thromboembolism. The patient died soon after being discharged home with hospice care. PMID- 28578308 TI - An unusual position of retromandibular vein: a surgical challenge in parotid surgeries. AB - A 44-year-old man presented with swelling in the left parotid region. The swelling was firm and Fine Needle Aspiration Cytology report proved pleomorphic adenoma. In the CT scan, the tumour was confined to the superficial lobe of parotid. So, left superficial parotidectomy was planned. Modified Wilson Blair's incision was used. On course of identifying the facial nerve, a large calibre vein was identified running vertically through the parotid substance. Assuming it as retromandibular vein, further dissection was carried out more meticulously. Marginal mandibularbranch of facial nerve was identified near the angle of mandible and retrograde dissection showed the cervicofacial division running medial to retromandibular vein with the main facial nerve trunk lying unusually medial and posterior to it. Adding to it, the temporofacial division was found 'forked' between the branches of retromandibular vein. These variations in head and neck venous channels are not that rare as we believe. All these variations have an embryological basis. Therefore, knowledge and understanding of this complex anatomy will help us preventing devastating complications like bleeding and facial nerve injury in such cases. PMID- 28578309 TI - Two-staged en bloc excision of a retinal haemangioma. AB - A 31-year-old man presented to us with diminution of vision in the right eye which he noticed since 10 days, with a visual acuity of hand motions only. On examination, festooned pupil and a complicated cataract were noted with no view of the retina. Ultrasonography of the right eye showed retinal detachment in all quadrants with suspected areas of traction and membranes in the vitreous. Left eye examination revealed a normal anterior and posterior segment. Intraoperatively, he underwent a pars plana lensectomy following which an inferior large retinal haemangioma was noted with dilated and tortuous feeder artery and draining vein. The haemangioma was managed by a two-staged procedure including ligature of the feeder artery in the first surgery and the en bloc excision of the angioma at the time of the second procedure after significant shrinkage in size of the tumour. PMID- 28578310 TI - Corticosteroid treatment for traumatic acute subdural haematoma, maybe not such a good idea. PMID- 28578311 TI - Orbital myositis presenting with only unilateral orbital pain. PMID- 28578313 TI - High-intensity exercise offers no additional benefit to moderate-intensity exercise in reducing liver fat in patients with non-alcoholic fatty liver disease. PMID- 28578312 TI - A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. AB - Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.Significance: LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963-72. (c)2017 AACR.See related commentary by Parikh and Corcoran, p. 934This article is highlighted in the In This Issue feature, p. 920. PMID- 28578314 TI - Functional and phylogenetic evidence of a bacterial origin for the first enzyme in sphingolipid biosynthesis in a phylum of eukaryotic protozoan parasites. AB - Toxoplasma gondii is an obligate, intracellular eukaryotic apicomplexan protozoan parasite that can cause fetal damage and abortion in both animals and humans. Sphingolipids are essential and ubiquitous components of eukaryotic membranes that are both synthesized and scavenged by the Apicomplexa. Here we report the identification, isolation, and analyses of the Toxoplasma serine palmitoyltransferase, an enzyme catalyzing the first and rate-limiting step in sphingolipid biosynthesis: the condensation of serine and palmitoyl-CoA. In all eukaryotes analyzed to date, serine palmitoyltransferase is a highly conserved heterodimeric enzyme complex. However, biochemical and structural analyses demonstrated the apicomplexan orthologue to be a functional, homodimeric serine palmitoyltransferase localized to the endoplasmic reticulum. Furthermore, phylogenetic studies indicated that it was evolutionarily related to the prokaryotic serine palmitoyltransferase, identified in the Sphingomonadaceae as a soluble homodimeric enzyme. Therefore this enzyme, conserved throughout the Apicomplexa, is likely to have been obtained via lateral gene transfer from a prokaryote. PMID- 28578315 TI - Lysophosphatidic acid acyltransferase 3 tunes the membrane status of germ cells by incorporating docosahexaenoic acid during spermatogenesis. AB - Docosahexaenoic acid (DHA) is one of the essential omega-3 polyunsaturated fatty acids with a wide range of physiological roles important for human health. For example, DHA renders cell membranes more flexible and is therefore important for cellular function, but information on the mechanisms that control DHA levels in membranes is limited. Specifically, it is unclear which factors determine DHA incorporation into cell membranes and how DHA exerts biological effects. We found that lysophosphatidic acid acyltransferase 3 (LPAAT3) is required for producing DHA-containing phospholipids in various tissues, such as the testes and retina. In this study, we report that LPAAT3-KO mice display severe male infertility with abnormal sperm morphology. During germ cell differentiation, the expression of LPAAT3 was induced, and germ cells obtained more DHA-containing phospholipids. Loss of LPAAT3 caused drastic reduction of DHA-containing phospholipids in spermatids that led to excess cytoplasm around its head, which is normally removed by surrounding Sertoli cells via endocytosis at the final stage of spermatogenesis. In vitro liposome filtration assay raised the possibility that DHA in phospholipids promotes membrane deformation that is required for the rapid endocytosis. These data suggest that decreased membrane flexibility in LPAAT3-KO sperm impaired the efficient removal of sperm content through endocytosis. We conclude that LPAAT3-mediated enrichment of cell membranes with DHA-containing phospholipids endows these membranes with physicochemical properties needed for normal cellular processes, as exemplified by spermatogenesis. PMID- 28578317 TI - Collagen type VI-related myopathy. PMID- 28578318 TI - Recurrent brain ischaemia and deep vein thrombosis: the clot thickens. AB - A 65-year-old man presented with two transient ischaemic attacks, and was then found to have a deep vein thrombosis. He later had recurrent ischaemic strokes. After thorough investigation, the only cause we identified was a previously undiagnosed metastatic pancreatic cancer. We describe the assessment of this presentation and discuss the causes and management of cancer-related stroke. PMID- 28578316 TI - Docosahexaenoic acid preserves visual function by maintaining correct disc morphology in retinal photoreceptor cells. AB - Docosahexaenoic acid (DHA) has essential roles in photoreceptor cells in the retina and is therefore crucial to healthy vision. Although the influence of dietary DHA on visual acuity is well known and the retina has an abundance of DHA containing phospholipids (PL-DHA), the mechanisms associated with DHA's effects on visual function are unknown. We previously identified lysophosphatidic acid acyltransferase 3 (LPAAT3) as a PL-DHA biosynthetic enzyme. Here, using comprehensive phospholipid analyses and imaging mass spectroscopy, we found that LPAAT3 is expressed in the inner segment of photoreceptor cells and that PL-DHA disappears from the outer segment in the LPAAT3-knock-out mice. Dynamic light scattering analysis of liposomes and molecular dynamics simulations revealed that the physical characteristics of DHA reduced membrane-bending rigidity. Following loss of PL-DHA, LPAAT3-knock-out mice exhibited abnormalities in the retinal layers, such as incomplete elongation of the outer segment and decreased thickness of the outer nuclear layers and impaired visual function, as well as disordered disc morphology in photoreceptor cells. Our results indicate that PL DHA contributes to visual function by maintaining the disc shape in photoreceptor cells and that this is a function of DHA in the retina. This study thus provides the reason why DHA is required for visual acuity and may help inform approaches for overcoming retinal disorders associated with DHA deficiency or dysfunction. PMID- 28578319 TI - Familial progressive bilateral facial paralysis in Finnish type hereditary amyloidosis. PMID- 28578320 TI - Utility of an app-based system to improve feedback following workplace-based assessment. AB - Objectives: To determine whether an app-based software system to support production and storage of assessment feedback summaries makes workplace-based assessment easier for clinical tutors and enhances the educational impact on medical students. Methods: We monitored our workplace assessor app's usage by Year 3 to 5 medical students in 2014-15 and conducted focus groups with Year 4 medical students and interviews with clinical tutors who had used the apps. Analysis was by constant comparison using a framework based on elements of van der Vleuten's utility index. Results: The app may enhance the content of feedback for students. Using a screen may be distracting if the app is used during feedback discussions. Educational impact was reduced by students' perceptions that an easy-to-produce feedback summary is less valuable than one requiring more tutor time and effort. Tutors' typing, dictation skills and their familiarity with mobile devices varied. This influenced their willingness to use the assessment and feedback mobile app rather than the equivalent web app. Electronic feedback summaries had more real and perceived uses than anticipated both for tutors and students including perceptions that they were for the school rather than the student. Conclusions: Electronic workplace-based assessment systems can be acceptable to tutors and can make giving detailed written feedback more practical but can interrupt the social interaction required for the feedback conversation. Tutor training and flexible systems will be required to minimise unwanted consequences. The educational impact on both tutors and students of providing pre-formulated advice within the app is worth further study. PMID- 28578321 TI - BCMab1-Ra, a novel immunotoxin that BCMab1 antibody coupled to Ricin A chain, can eliminate bladder tumor. AB - Bladder cancer is one of the most common malignancies. However, there is no ideal therapy to cure bladder cancer so far, especially invasive carcinoma. Here, we developed a new antibody-based drug BCMab1-Ra, which was generated by conjugation of BCMab1 (a new monoclonal antibody that specifically recognized the aberrantly glycosylated Integrin a3b1 in bladder cancer) with the ricin A chain (Ra). A patient with multiple bladder cancer received intravescical administration of BCMab1-Ra treatment as a volunteer. After 30 weeks of treatment, no tumor was observed by cystoscope examination. We did not observe any local or systemic side effects. Human anti-mouse antibody (HAMA) was not detectable in the circulation. Results follow-up showed no tumor had been found in every half year review in 3 years. PMID- 28578322 TI - Suppression of STAT3 Signaling by Delta9-Tetrahydrocannabinol (THC) Induces Trophoblast Dysfunction. AB - AIMS: Marijuana is a widely used illicit drug and its consumption during pregnancy has been associated with adverse reproductive outcomes. The purpose of this study was to determine the effects of chronic intake of Delta9 tetrahydrocannabinol (THC), the major component of marijuana, on trophoblast function, placental development, and birth outcomes. METHODS: The pathological characteristics and distribution of cannabinoid receptors in placenta were observed by immunohistochemical (IHC) staining. Cell migration in response to THC was measured by transwell assays. The levels of cannabinoid receptors and Signal Transducer and Activator of Transcription 3 (STAT3) were detected by western blot. RESULTS: We found the placenta expressed two main cannabinoid receptors, suggesting that THC induced biological responses in placental cells. Supporting this hypothesis, we observed dramatic alterations of placental morphology in marijuana users. Using THC and inhibitors of cannabinoid receptors, we demonstrated that THC impaired trophoblast cell migration and invasion partly via cannabinoid receptors. Additionally, pregnant mice injected with THC showed adverse reproductive events including reduced number of fetuses, lower maternal and placental weights. Mechanistically, STAT3 signaling pathway was involved in the THC-induced suppression of trophoblast cell motility and pregnancy outcomes. CONCLUSION: Our study indicates that the STAT3 signaling pathway plays a critical role in THC-induced trophoblast dysfunction. PMID- 28578323 TI - Oxytetracycline Inhibits Mucus Secretion and Inflammation in Human Airway Epithelial Cells. AB - Oxytetracycline is a broad-spectrum antibiotic, but its nonantibacterial effects in the human respiratory tract are unknown. In this study, the effects of oxytetracycline on mucus secretion and inflammation were examined by PCR and ELISA in the human airway epithelial cell line NCI-H292. Oxytetracycline (10 MUg/mL) significantly inhibited TNF-alpha-induced MUC5AC gene expression and MUC5AC protein levels in NCI-H292 cells. It also downregulated IL-8 and IL-1beta gene expression and IL-1beta protein levels. Our findings demonstrated that oxytetracycline suppressed mucus production and inflammation in human respiratory epithelial cells, providing further evidence for the usefulness of oxytetracycline for human airway inflammatory diseases. PMID- 28578324 TI - Eppikajutsuto Protects against Food Allergy Induced by Ovalbumin in a Murine Model. AB - BACKGROUND: Currently, there are no efficient medications available for the prevention and treatment of food allergy (FA). Herbal medicines, including traditional Japanese Kampo medicines (TJKMs), are promising therapeutic drugs. METHODS: We screened 18 TJKMs for treatment of FA symptoms in a mouse FA model induced by ovalbumin (OVA). BALB/c mice were sensitized intraperitoneally by an OVA/aluminum hydroxide gel mixture followed by 4 booster doses of oral OVA and FA symptom induction by 50 mg of OVA. TJKMs were orally administered for 28 days from the day of sensitization to the day before FA symptom induction. Evaluated FA symptoms included a decrease in body temperature and allergic diarrhea. Allergic sensitization was determined by plasma OVA-specific IgE levels. Cytokine mRNA levels in mesenteric lymph nodes, plasma mouse mast cell protease-1, and the number of mast cells in the small and large intestines were analyzed. Additionally, the therapeutic effect of the TJKM eppikajutsuto (EJT) on mast cell degranulation was determined in active anaphylaxis and passive cutaneous anaphylaxis models. RESULTS: EJT effectively prevented FA symptoms. Although OVA specific IgE levels and the intestinal mast cell numbers were not different between the EJT-treated and untreated FA mice, plasma mMcpt1 and IL-4 levels were lower in EJT-treated FA mice than untreated FA mice. EJT could alleviate symptoms in both active and passive anaphylaxis models. CONCLUSION: EJT prevented OVA induced FA symptoms in a mouse model, suggesting that EJT might exert its therapeutic activity via IL-4 suppression and the inhibition of mucosal mast cell degranulation. PMID- 28578325 TI - Survey of Techniques Utilized to Access Ventricular Shunts and Reservoirs. AB - AIMS: This study assessed variations in pediatric neurosurgical technique when accessing shunts and ventricular access devices (VADs). METHODS: A 12-question survey was developed and sent to members of the American Association of Neurological Surgeons (AANS) whose self-identified subspecialty was pediatric neurosurgery. RESULTS: Four hundred and twenty surveys were sent out, and 149 responses were received (35.5% response rate); 95.3% of respondents always use sterile gloves, 55.0% never use a sterile gown, and 69.8% always have a member of the neurosurgery team perform the procedure. The majority of respondents answered "sometimes" for use of a facemask (38.3%), sterile drapes (39.6%), site shaving (45.6%), having an attending present (68.5%), and having an assistant hold the patient's head (78.5%). The majority reported using a 23- or 25-gauge butterfly needle for site entry (96.6%), and betadine or ChloraPrepTM as the preferred antiseptic solution (64.4%). The frequency in which CSF is sent for analysis is not standardized in 31.5% of respondents, and wait time for the antiseptic solution to dry is not standardized in 62.4%. CONCLUSIONS: There is great variation in the technique for accessing shunts and VADs. Future studies are needed to assess whether these discrepancies affect infection rates. PMID- 28578326 TI - Targeting Jurkat T Lymphocyte Leukemia Cells by an Engineered Interferon-Alpha Hybrid Molecule. AB - BACKGROUND/AIMS: Adult T-cell leukemia/lymphoma (ATL) is a very aggressive T cell malignancy that carries a poor prognosis, primarily due to its resistance to chemotherapy and to life-threatening infectious complications. Interferon-alpha (IFNalpha) has been used in combination with the anti-retroviral drug zidovudine to treat patients with ATL. However, the efficacy of long-term therapy is significantly limited due to the systemic toxicity of IFNalpha. METHODS: We utilized phage display library screening to identify short peptides that specifically bind to Jurkat T lymphocyte leukemia cells. By fusing the Jurkat binding peptide to the C-terminus of IFNalpha, we constructed an engineered chimeric IFNalpha molecule (IFNP) for the treatment of ATL. RESULTS: We found that IFNP exhibited significantly higher activity than wild type IFNalpha in inhibiting the growth of leukemia cells and inducing cell blockage at the G0/G1 phase. The synthetic IFNP molecule exerted its antitumor activity by upregulating the downstream genes involved in the STAT1 pathway and in apoptosis. Using a cell receptor binding assay, we showed that this Jurkat-binding peptide facilitated the binding affinity of IFNalpha to the cell surface type I IFN receptor. CONCLUSION: The isolated Jurkat-binding peptide significantly potentiates the therapeutic activity of IFNalpha in T lymphocyte leukemia cells. The engineered IFNP molecule may prove to a novel antitumor approach in the treatment of patients with ATL. PMID- 28578328 TI - Gene and Cell Doping: The New Frontier - Beyond Myth or Reality. AB - The advent of gene transfer technologies in clinical studies aroused concerns that these technologies will be misused for performance-enhancing purposes in sports. However, during the last 2 decades, the field of gene therapy has taken a long and winding road with just a few gene therapeutic drugs demonstrating clinical benefits in humans. The current state of gene therapy is that viral vector-mediated gene transfer shows the now long-awaited initial success for safe, and in some cases efficient, gene transfer in clinical trials. Additionally, the use of small interfering RNA promises an efficient therapy through gene silencing, even though a number of safety concerns remain. More recently, the development of the molecular biological CRISPR/Cas9 system opened new possibilities for efficient and highly targeted genome editing. This chapter aims to define and consequently demystify the term "gene doping" and discuss the current reality concerning gene- and cell-based physical enhancement strategies. The technological progress in the field of gene therapy will be illustrated, and the recent clinical progress as well as technological difficulties will be highlighted. Comparing the attractiveness of these technologies with conventional doping practices reveals that current gene therapy technologies remain unattractive for doping purposes and unlikely to outperform conventional doping. However, future technological advances may raise the attractiveness of gene doping, thus making it easier to develop detection strategies. Currently available detection strategies are introduced in this chapter showing that many forms of genetic manipulation can already be detected in principle. PMID- 28578327 TI - Genetic Predictors of >=5% Weight Loss by Multidisciplinary Advice to Severely Obese Subjects. AB - BACKGROUND: Weight loss success is determined by genetic factors, which may differ according to treatment strategy. METHODS: From a multidisciplinary obesity treatment program involving dietary advice, psychological counseling, and increased physical activity, 587 subjects (68% female; 46.1 +/- 12.4 years; BMI 39.9 +/- 6.3) were recruited. At baseline, a blood sample was drawn for DNA isolation. Genotypes were determined for 30 polymorphisms in 25 candidate genes. The association between genotypes and weight loss was assessed after 3 months (short-term) and after 12 months of treatment (long-term). Weight loss was categorized as >=5% or <5% of initial weight. RESULTS: The G/G genotype of PLIN1 (rs2289487) and PLIN1 (rs2304795), the T/T genotype of PLIN1 (rs1052700), and the C/C genotype of MMP2 predicted >=5% weight loss in the first 3 months. The C/G G/G genotype of PPARgamma (rs1801282) and the T/C genotype of TIMP4 (rs3755724) predicted >=5% weight loss after 12 months. Subjects with the combination of PPARgamma (rs1801282) C/G-G/G and TIMP4 (rs3755724) T/C lost even more weight. CONCLUSION: Polymorphisms in genes related to regulation of fat storage and structural adaptation of the adipocytes are predictors for weight loss success with different genes being relevant for short-term and long-term weight loss success. PMID- 28578329 TI - The Athlete Biological Passport: How to Personalize Anti-Doping Testing across an Athlete's Career? AB - For decades, drug testing has been the main instrument at the disposal of anti doping authorities. The availability in the 1980s of substances identical to those produced by the human body, including the "big 3" (erythropoietin, testosterone, and growth hormone), necessitated a new paradigm in anti-doping. The athlete biological passport (ABP) is a new paradigm, complementary to traditional drug testing, based on the personalized monitoring of doping biomarkers. Athletes who abuse doping substances do so to trigger physiological changes that provide performance enhancement. The ABP aims to detect these changes through its 3 hematological, steroidal, and endocrine modules. Any deviation of a biomarker from what is expected in a healthy physiological condition can be attributable to doping or a medical condition, which, interestingly, is also the criterion used to define a banned substance. Recent advances in proteomics and metabolomics offer immense opportunities to enhance the ABP. The ABP shares multiple aspects with the present customization of health care and personalized medicine. PMID- 28578330 TI - The Efficacy of High-Frequency Repetitive Transcranial Magnetic Stimulation for Improving Apathy in Chronic Stroke Patients. AB - Although repetitive transcranial magnetic stimulation (rTMS) for hemiparesis is beneficial, so far no study has examined the usefulness of rTMS for apathy. Thirteen patients with chronic stroke were assigned randomly to 2 groups: rTMS group (n = 7) and sham stimulation group (n = 6). The patients received 5 sessions of either high-frequency rTMS over the region spanning from the dorsal anterior cingulate cortex (dACC) to medial prefrontal cortex (mPFC) or sham stimulation for 5 days. The severity of apathy was evaluated using the Apathy Scale (AS) and the severity of depression was evaluated using the Quick Inventory of Depressive Symptomatology (QIDS) serially before and after the 5-day protocol. The AS and QIDS scores were significantly improved in the rTMS group, although they were not changed in the sham stimulation group. The degree of change in the AS score was significantly greater in the rTMS group than that in the sham stimulation group. The degree of change in the QIDS score was greater in the rTMS group than that in the sham stimulation group, although the difference was not statistically significant. The application of high frequency rTMS over the dACC and mPFC may be a useful intervention for apathy due to stroke. PMID- 28578332 TI - Editorial Board / Contents / Imprint. PMID- 28578333 TI - PharmaForum. PMID- 28578331 TI - Whole Genome Sequence Identified a Rare Homozygous Pathogenic Mutation of the DSG2 Gene in a Familial Arrhythmogenic Cardiomyopathy Involving Both Ventricles. AB - BACKGROUND: This study was designed to identify the pathogenic mutation in a Chinese family with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) using whole genome sequencing (WGS). METHODS AND RESULTS: Probands II:1 and II:2 underwent routine examinations for diagnosis. Genomic DNA was extracted from the peripheral blood of family members and analyzed using WGS. A total of 60,285 single-nucleotide polymorphisms (SNP) and 13,918 insertions/deletions (InDel) occurring in the exonic regions of genes and predisposing to cardiomyopathies and arrhythmias were identified. When filtered using the 1000 Genomes Project (2014 version), NHLBI ESP6500, and ExAC databases, 12 missense SNP and 2 InDel in exonic regions remained, the allele frequencies of which were <0.01 or unknown. The potentially pathogenic mutations that occurred in the genes DSG2, PKP4, PRKAG2, FOXD4, CTTN, and DMD, which were identified by SIFT or PolyPhen-2 software as "damaging," were validated using Sanger sequencing. Probands II:1 and II:2 shared an extremely rare homozygous mutation in the DSG2 (p.F531C) gene, which was also demonstrated using intersection analysis of WGS data from probands II:1 and II:2. Electron microscopy and histological staining of myocardial biopsies showed widened and destroyed intercalated discs, and interrupted, atrophic, and disarranged myocardial fibers, and hyperplastic interstitial fibers, collagen fibers, and adipocytes were infiltrated and invaded. CONCLUSIONS: A homozygous mutation of DSG2 p.F531C was identified as the pathogenic mutation in patients with ARVC/D involving both ventricles, as a result of widened and impaired intercalated discs, interrupted myocardial fibers, and abnormally hyperplastic interstitial fibers, collagen fibers, and adipocytes. PMID- 28578334 TI - PharmaForum. PMID- 28578335 TI - PharmaForum. PMID- 28578337 TI - PharmaNews. PMID- 28578336 TI - PharmaNews. PMID- 28578338 TI - PharmaNews. PMID- 28578340 TI - MicroRNA-30b Regulates High Phosphorus Level-Induced Autophagy in Vascular Smooth Muscle Cells by Targeting BECN1. AB - BACKGROUND/AIMS: Autophagy is an evolutionarily conserved mechanism that affects the survival and functions of vascular smooth muscle cells (VSMCs). We explored the role of microRNAs (miRNAs) in regulating autophagy in VSMCs exposed to high phosphorus (Pi) levels. METHODS: VSMCs were isolated from the thoracic aorta of rats and were cultured primarily. Real-time PCR was used to measure the mRNA expression of indicated genes. Western blotting was performed to detect the protein expression of autophagy-related markers. RESULTS: We found that treatment with high Pi levels (1 and 3 mM) activated LC3II expression and promoted autophagic flux in VSMCs. Conversely, treatment with an autophagy inhibitor decreased LC3II expression. Pi stimulation dysregulated the expression of several miRNAs such as miR-18a, miR-21, miR-23a, miR-30b, and miR-31a. However, miR-30b overexpression decreased Pi-induced expression of autophagy-related marker genes such as BECN1, ATG5, and LC3b, whereas miR-30b downregulation increased Pi induced expression of these genes. In addition, we found that miR-30b directly targeted BECN1. CONCLUSIONS: These data suggest that miR-30b plays an important role in the regulation of high Pi level-induced autophagy in VSMCs by targeting BECN1. PMID- 28578339 TI - Erythrocyte Sodium Sensitivity and Eryptosis in Chronic Hemodialysis Patients. AB - BACKGROUND/AIMS: In hemodialysis (HD) patients the endothelial and erythrocyte glycocalyx is impaired which in turn correlates with elevated erythrocyte sodium sensitivity (ESS). Additionally, apoptotic erythrocyte death (eryptosis), characterized by phosphatidylserine (PS) exposure on the cell surface, is increased in this population. We aimed to explore the relationship of ESS and eryptosis. METHODS: Blood samples were collected from 11 healthy controls and 20 chronic HD patients before and after midweek HD. ESS was quantified by the salt blood test. PS-exposure, intracellular reactive oxygen species (ROS) of erythrocytes and reticulocytes were assessed by flow cytometry. RESULTS: Compared to controls ESS was significantly higher in HD patients preHD and did not change during treatment. The percentage of eryptotic cells did not differ between controls and patients preHD. However, eryptosis decreased during HD. ESS and eryptosis were uncorrelated, while eryptosis was positively correlated with intracellular ROS and percent reticulocytes. CONCLUSIONS: Higher ESS levels in HD patients indicate a pathologic glycocalyx. ESS and eryptosis were not correlated. The decreased eryptosis postHD may possibly be related to dialytic uremic toxin removal, but is likely multifactorial. The relationship between eryptosis and intracellular ROS warrants further research. PMID- 28578341 TI - Association Between Periodontitis and Low-Grade Albuminuria in Non-Diabetic Adults. AB - BACKGROUND/AIMS: The objective of the present study was to evaluate the clinical association between periodontitis and a high urinary albumin/creatinine ratio (UACR) in individuals without diabetes mellitus. METHODS: Data from the Korean National Health and Nutrition Examination Survey were used for this analysis. A high UACR was defined as UACR>=3.9 mg/g for men and UACR>=7.5 mg/g for women. The WHO community periodontal index (CPI) was used to define periodontitis and assess its severity. RESULTS: The numbers of participants without and with periodontitis were 3,046 and 8,571, respectively. The UACR values were higher in participants with periodontitis than in those without periodontitis. Logistic regression showed that the OR for a high UACR with the presence of periodontitis was 1.14 (P=0.044) on multivariate analysis. CPI score was positively associated with UACR. CONCLUSIONS: Periodontitis was associated with UACR in the non-diabetic participants in this study. Therefore, participants with periodontitis should be closely monitored for UACR, which can function as an early marker for renal injury. PMID- 28578342 TI - Astragaloside-IV Protects Against Heat-induced Apoptosis by Inhibiting Excessive Activation of Mitochondrial Ca2+ Uniporter. AB - BACKGROUND: Heat causes airway damage during inhalation injury because of bronchial epithelial cell damage. Accumulating evidence shows that mitochondrial uniporter (MCU) is involved in cell damage. We investigated the MCU activity after heat treatment and assessed whether Astragaloside-IV (AS-IV) suppresses heat-induced apoptosis in bronchial epithelial cells by inhibiting the activation of the mitochondrial Ca2+ uniporter (MCU), mitochondrial depolarisation and reactive oxygen species (ROS) production. METHODS: The bronchial epithelial cell line 16HBE14o- was heat treated, and cell apoptosis was induced in vitro and in vivo. AS-IV was inorganically administered to Wistar rats twice a day after thermal inhalation injury, and 16HBE140- cells were treated with AS-IV after incubation at 47 degrees C for 5 min. Protein expression was determined using Western blotting and commercial kits, apoptosis with TUNEL staining, mitochondrial channel activity by patch clamp, reactive oxygen species by MitoSOXTM fluorescence, ATP levels and enzyme activities by commercial kits as well as mitochondrial respiration and calcium by fluorescence. RESULTS: AS-IV markedly inhibited heat-induced apoptosis, as indicated by the increased expression of the pro-apoptotic genes Bak, Bik and Bmf and increased expression of the apoptosis markers Bax, cleaved parp, cleaved caspase3 and cytochrome C. We found that MCU activation promoted mitochondrial Ca2+ overload, ATP depletion, mitochondrial ROS production and cytochrome c release and rapidly induced apoptosis. However, AS-IV treatment reduced excessive MCU activation and led to resistance against mitochondrial Ca2+ overload and excessive cytochrome C release; these effects were blocked by the MCU activator spermine. AS-IV treatment elevated ATP production and decreased ROS activity. CONCLUSIONS: MCU plays crucial roles in heat-induced mitochondrial apoptosis in 16HBE140- cells, suggesting a potential target for AS-IV treatment. PMID- 28578343 TI - Filter Size Not the Anticoagulation Method is the Decisive Factor in Continuous Renal Replacement Therapy Circuit Survival. AB - BACKGROUND/AIM: As continuous renal replacement therapy (CRRT) has emerged as a standard therapy in pediatric intensive care units (PICU), many related issues that may have an impact on circuit survival have gained in importance. Objective of the study was an evaluation of factors associated with circuit survival, including anticoagulation (ACG). METHODS: Retrospective study that included 40 patients, who in total received 7636 hours of CRRT during 150 sessions (84 filters, 4260 hours with heparin anticoagulation (Hep-ACG); 66 filters, 3376 hours with regional citrate anticoagulation (RCA)). RESULTS: The Kaplan-Meier analysis of the total circuit survival time depending on the type of ACG did not demonstrate a significant difference between Hep-ACG and RCA. The percentage of clotted filters was significantly higher in case of smaller filters (HF20: 58.8%; ST60: 29.5%; ST100: 15.8%), and their lifetime was significantly lower regardless of ACG (the mean and median lifetime for HF20: 38.7/27.0 h; for ST60: 54.1/72.0 h., for ST100: 62.1/72.0 h, respectively). CONCLUSIONS: Irrespectively of filter size, filter clotting occurs within the first 24 hours after the initiation of CRRT. Most commonly, clotting affects small filters, and their lifetime is significantly shorter as compared to larger filters regardless of the type of the ACG. PMID- 28578344 TI - Comparison of Procalcitonin Guidance-Administered Antibiotics with Standard Guidelines on Antibiotic Therapy in Children with Lower Respiratory Tract Infections: A Retrospective Study in China. AB - OBJECTIVE: To establish the efficacy of an algorithm based on the biomarker procalcitonin (PCT) to reduce antibiotic exposure in pediatric patients with lower respiratory tract infection (LRTI). MATERIALS AND METHODS: The clinical data of 357 patients (<14 years of age) who were discharged home with LRTI from January 1, 2010 to July 31, 2016 were analyzed. Antibiotic exposure, antibiotic prescription rate, length of hospital stay, and antibiotic-associated adverse effects were compared between the PCT group (n = 183) and the standard group (n = 174) using SAS 9.1.3 software. RESULTS: The overall adverse effect rates were similar in both the PCT and standard groups: 42 (22.95%) and 51 (29.31%), respectively. The length of hospital stay was not significantly different between the PCT (9.96 +/- 5.81 days) and standard groups (10.58 +/- 4.24 days) (difference: -0.62%; 95% CI: -1.68 to 0.43). Antibiotic prescribing rates were significantly different in the PCT group compared to the standard group: 54.64% versus 83.91% (difference: -29.26%; 95% CI: -38.31, -20.22; p = 0.23). Mean duration of antibiotic exposure in the PCT group (3.98 +/- 2.17 days) was lower than the standard groups (6.66 +/- 5.59 days) (difference: -2.68%; 95% CI: -3.21 to -2.16). CONCLUSION: This study showed that PCT guidance of antibiotic treatment in children and adolescents with LRTI reduced the duration of antibiotic exposure and antibiotic prescribing rates, but did not affect the adverse effect rate and length of hospital stay. PMID- 28578345 TI - Calcium Channel Opening Rather than the Release of ATP Causes the Apoptosis of Osteoblasts Induced by Overloaded Mechanical Stimulation. AB - BACKGROUND: Stress fracture is one of the most common overuse injuries in athletes. Overloaded mechanical stimulation is an important factor affecting stress fractures, but the mechanism is unclear. METHODS: MC3T3-E1 cells and a polycaprolactone (PCL) scaffold were co-cultured, and finite element analysis (FEA) was used to analyze the load-carrying capability. Cell proliferation was investigated with CCK-8 assays. An alkaline phosphatase (AKP) activity assay was used to evaluate cell differentiation. Cell apoptosis was analyzed using Hoechst/ PI double-labeling, Caspase-3 activity and lactate dehydrogenase (LDH) activity assays. Realtime PCR and Western blotting were used to examine the gene and protein expression, respectively, of Caspase-3 and Caspase-9. Assays of the intracellular calcium with fluorescent probe technique and extracellular ATP with fluorometric assay kit were used to analyze the changes in the intracellular calcium concentration induced by calcium channel opening and the release of ATP, respectively, at different operation times. RESULTS: When the apparent strain reached 10000 uepsilon, the strain scope of fber at levels greater than 4000 uepsilon was 60%. Overloading for 4 days and operation times of 0.5 h and 2 h increased the cell number and AKP secretion. However, apoptosis genes were activated at the same time, and the operation time of 2 h had a significantly greater effect than 0.5 h. At 8 days, the cell numbers were greater for the operation time of 0.5 h than for 2 h, and the 2-h groups had the fastest apoptosis rate. Overloading for 1 day increased intracellular calcium levels and ATP release. The increase in intracellular calcium could be blocked by the addition of N-ethylmaleimide (NEM) or Hank's medium. Overloading for 8 days increased intracellular calcium levels but decreased extracellular ATP, and verapamil blocked the increase in intracellular calcium. CONCLUSION: We found that a simultaneous 'double effect' on osteoblasts was induced by overloading, which promoted cell proliferation, differentiation and apoptosis. Short-term overloading could open the cell membrane calcium channels and release calcium stores to elevate intracellular calcium levels, thereby promoting the proliferation and differentiation of cells to a greater extent than the effect of apoptosis. For long-term overloading, calcium channel opening in the membrane could lead to overloading of intracellular calcium levels, inducing an apoptosis effect that is greater than the effect on proliferation and differentiation. PMID- 28578346 TI - A New Approach to Developing Birth Weight Reference Charts: A Retrospective Observational Study. AB - INTRODUCTION: Birth weight reference charts based on historical infant birth weights have significant bias at preterm gestations because many preterm births are associated with abnormal growth. This study aims to determine whether more accurate birth weight charts can be constructed using data only from births that follow spontaneous onset of labour. MATERIALS AND METHODS: This study was a single-centre retrospective observational study of 115,712 singleton live births. Births were classified as spontaneous or iatrogenic. Quantile regression was used to model the relationship between gestational age, sex, labour onset, and birth weight. Comparison was made of birth weights in the spontaneous and iatrogenic cohorts by gestation, and to existing ultrasound-based charts. RESULTS: Birth weights of spontaneous and iatrogenic births were significantly different for gestational age at the median and 10th centiles. Iatrogenic preterm infants weighed less than their spontaneous preterm counterparts. Median and 10th centile birth weights derived from the spontaneous birth cohort closely approximate previous ultrasound-based curves. DISCUSSION: Iatrogenic births are more likely to be associated with pre-existing growth disturbance. Inclusion of these data has significant impact on centile charts. Birth weight charts derived from only spontaneous births may offer a more accurate reference for clinicians. PMID- 28578347 TI - Consumption of a Mango Fruit Powder Protects Mice from High-Fat Induced Insulin Resistance and Hepatic Fat Accumulation. AB - BACKGROUND/AIMS: The aim of this study was to gain more insight into the beneficial effects of mango fruit powder on the early metabolic adverse effects of a high-fat diet. METHODS: The progressive dose-response effects of mango fruit powder on body composition, circulating parameters, and the expression of genes related to fatty acid oxidation and insulin sensitivity in key tissues were studied in mice fed a moderate (45%) high-fat diet. RESULTS: Findings suggest that mango fruit powder exerts physiological protective effects in the initial steps of insulin resistance and hepatic lipid accumulation induced by a high-fat diet in mice. Moreover, AMPK and SIRT1 appear as key regulators of the observed improvement in fatty acid oxidation capacity, as well as of the improved insulin sensitivity and the increased glucose uptake and metabolism through the glycolytic pathway capacity in liver and skeletal muscle. CONCLUSION: In summary, this study provides evidence that the functional food ingredient (CarelessTM) from mango fruit prevents early metabolic alterations caused by a high-fat diet in the initial stages of the metabolic syndrome. PMID- 28578348 TI - TLR4 Influences Hepatitis B Virus Related Hepatocellular Carcinoma by Regulating the Wnt/beta-Catenin Pathway. AB - BACKGROUND/AIMS: We investigated the correlation between toll-like receptor 4 (TLR4) and beta-catenin for disclosing the potential pathogenesis of hepatocellular carcinoma (HCC). METHODS: Immunohistochemical toolkit was implemented to measure the expression of TLR4 and beta-catenin in 98 cases of HCC tissues and adjacent tissues. After setting up the HepG2.2.15 hepatitis B virus (HBV) related HCC cell line, we divided the cells into the control group, TLR4 siRNA group, beta-catenin siRNA group, and pcDNA.3.1 TLR4 + beta-catenin siRNA group. Western blot, CCK-8 method, Transwell and flow cytometry were used to detect protein expression, cell proliferation, cell migration and invasion as well as cell apoptosis, respectively. Nude mice tumor model was established to observe the effects of TLR4 and beta-catenin on the progression of HBV-related HCC in vivo. RESULTS: The positive rates of TLR4 and beta-catenin were higher in HCC tissues compared with normal tissues. Both the TLR4 siRNA group and beta catenin siRNA group exhibited a decreased expression of beta-catenin. The proliferation, migration and invasion of tumor cells in the above two groups were suppressed, while the cell apoptosis appeared to be stimulated. As suggested by the results from in vivo and in vitro experiments, the up-regulation of TLR4 could antagonize the corresponding effect of beta-catenin siRNA. CONCLUSIONS: TLR4 can affect the expression of beta-catenin and hence influence the progression of HBV-related HCC. PMID- 28578349 TI - PTPRO Promotes Oxidized Low-Density Lipoprotein Induced Oxidative Stress and Cell Apoptosis through Toll-Like Receptor 4/Nuclear Factor kappaB Pathway. AB - BACKGROUND/AIMS: Critical roles of phosphatase receptor type O (PTPRO) and toll like receptor 4 (TLR4) have been implicated in inflammation. However, little is known about their functional effects on atherosclerosis (AS). We aim to study their potential function in AS. METHODS: An oxidized low-density lipoprotein (ox LDL) induced AS model constructed with PTPRO over-expressing RAW264.7 cells and PTPRO knockout macrophages. Cell apoptosis was assayed by flow cytometry and fatty accumulation was evaluated by oil red staining. The production of ROS (reactive oxygen species), SOD (superoxide dismutase), MDA (malondialdehyde), TC (Triglyceride), and TG (total cholesterol) was evaluated. Western blot was performed to detect the expression of CD36, TLR4 and nuclear factor kB (NF kappaB). RESULTS: PTPRO expression was promoted in a dose-dependent and time dependent manner following ox-LDL challenging. In PTPRO-over-expressing cells, CD36 expression and the level of oil-red staining, TC and TG were increased; ROS production, MDA and level of cell apoptosis were improved, but SOD was reduced. However, in PTPRO knockout cells opposite results were found. TLR4 and NF kappaB/p65 phosphorylation was significantly enhanced in PTPRO over-expressing cells, while significantly down-regulated in PTPRO knockout cells. CONCLUSION: PTPRO plays ital roles in AS via promoting ox-LDL induced oxidative stress and cell apoptosis through TLR4/NF-kappaB pathway. PMID- 28578350 TI - Ex utero Intrapartum Treatment to Ventricular Pacing: A Novel Delivery Strategy for Complete Atrioventricular Block with Severe Bradycardia. AB - Fetuses with anti-SSA-mediated complete atrioventricular block (CAVB) are at high risk for perinatal death if they present at <20 weeks of gestation and develop ventricular rates of <55 beats per minute (bpm), cardiac dysfunction, or hydrops [Izmirly et al.: Circulation 2011;124:1927-1935; Jaeggi et al.: J Am Coll Cardiol 2002;39:130-137; Eliasson et al.: Circulation 2011;124:1919-1926]. After our experience with two such fetuses who died with pulseless electrical activity despite being paced within 30 min of birth, we performed an ex utero intrapartum treatment procedure to ventricular pacing on a 36-week CAVB fetus with cardiac dysfunction, mild hydrops, and a ventricular rate of 46 bpm. While still on placental bypass, temporary epicardial ventricular pacing leads were successfully placed; the infant was delivered and made a successful transition to postnatal life. This approach can improve the 11-fold increase in mortality for the preterm fetus with long-standing CAVB, severe bradycardia, and heart failure. PMID- 28578351 TI - Protective Effects of MicroRNA-126 on Human Cardiac Microvascular Endothelial Cells Against Hypoxia/Reoxygenation-Induced Injury and Inflammatory Response by Activating PI3K/Akt/eNOS Signaling Pathway. AB - OBJECTIVE: This study explored the protective effects of the microRNA-126 (miR 126)-mediated PI3K/Akt/eNOS signaling pathway on human cardiac microvascular endothelial cells (HCMECs) against hypoxia/reoxygenation (H/R)-induced injury and the inflammatory response. METHODS: Untreated HCMECs were selected for the control group. After H/R treatment and cell transfection, the HCMECs were assigned to the H/R, miR-126 mimic, mimic-negative control (NC), miR-126 inhibitor, inhibitor-NC, wortmannin (an inhibitor of PI3K) and miR-126 mimic + wortmannin groups. Super oxide dismutase (SOD), nitric oxide (NO), vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) were measured utilizing commercial kits. Quantitative real-time polymerase chain reaction (qRT PCR) and enzyme-linked immunosorbent assay (ELISA) were performed to detect miR 126 expression and the mRNA and protein expression of inflammatory factors. Western blotting was used to determine the expression of key members in the PI3K/Akt/eNOS signaling pathway. ACCK-8 assay and flow cytometry were employed to examine cell proliferation and apoptosis, respectively. The angiogenic ability in each group was detected by the lumen formation test. RESULTS: Compared to the control group, p/t-PI3K, p/t-Akt and p/t-eNOS expression, NO, VEGF and SOD levels, cell proliferation and in vitro lumen formation ability were decreased, while the ROS content, interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF) alpha expression and cell apoptosis were significantly increased in the H/R, mimic-NC, miR-126 inhibitor, inhibitor-NC, wortmannin and miR-126 mimic + wortmannin groups. Additionally, in comparison with the H/R group, the miR-126 mimic group had elevated p/t-PI3K, p/t-Akt and p/t-eNOS expression, increased NO, VEGF and SOD contents, and strengthened cell proliferation and lumen formation abilities but also exhibited decreased ROS content, reduced IL-6, IL-10 and TNF alpha expressions, and weakened cell apoptosis, while the miR-126 inhibitor and wortmannin group exhibited the opposite results. Furthermore, decreased p/t-PI3K, p/t-Akt and p/t-eNOS expressions, decreased NO, VEGF and SOD contents, cell proliferation and lumen formation abilities, as well as increased ROS content, increased IL-6, IL-10 and TNF-alpha expression, and increased cell apoptosis were observed in the miR-126 mimic + wortmannin group compared to themiR-126 mimic group. CONCLUSIONS: These findings indicated that miR-126 protects HCMECs from H/R-induced injury and inflammatory response by activating the PI3K/Akt/ eNOS signaling pathway. PMID- 28578352 TI - Endogenous Parathyroid Hormone Promotes Fracture Healing by Increasing Expression of BMPR2 through cAMP/PKA/CREB Pathway in Mice. AB - BACKGROUND/AIMS: Endogenous parathyroid hormone (PTH) plays an important role in fracture healing. This study investigated whether endogenous PTH regulates fracture healing by bone morphogenetic protein (BMP) and/or the transforming growth factor-beta (TGF-beta) signaling pathway. METHODS: Eight-week-old wild type (WT) and PTH-knockout (PTH KO) male mice were selected, and models of open right-femoral fracture were constructed. Fracture healing and callus characteristics of mice in the two groups were compared by X-ray, micro-computed tomography, histological, and immunohistochemical examinations. Bone marrow mesenchymal stem cells (BMMSCs) of 8-week-old WT and PTHKO male mice were obtained and induced into osteoblasts and chondrocytes. RESULTS: We found that expression levels of Runt-related transcription factor (RUNX2), bone morphogenetic protein-receptor-type II (BMPR2), phosphorylated Smad 1/5/8, and phosphorylated cyclic adenosine monophosphate-responsive element binding protein (CREB) in the callus of PTHKO mice were significantly decreased, whereas no significant difference in expression of SOX9, TGF-betaR2,or pSMAD2/3 was observed between PTHKO and WT mice. Additionally, the activity of osteoblast alkaline phosphatase was low at 7 days post-induction, and was upregulated by addition of PTH or dibutyryl cyclic adenosine monophosphate (dbcAMP) to the cell culture. Furthermore, H89 (protein kinase A inhibitor)eliminated the simulating effects of PTH and dbcAMP, and a low concentration of cyclic adenosine monophosphate (cAMP) was observed in PTHKO mouse BMMSCs. CONCLUSION: These results suggested that endogenous PTH enhanced BMPR2 expression by a cAMP/PKA/CREB pathway in osteoblasts, and increased RUNX2 expression through transduction of the BMP/pSMAD1/5/8 signaling pathway. PMID- 28578353 TI - PI3Kbeta Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors. AB - BACKGROUND/AIMS: High-density lipoproteins (HDL) exert multiple cardioprotective functions on the arterial wall, including the promotion of endothelial cell survival and proliferation. Among mechanism contributing to endothelial protection, it has been reported that apolipoprotein A-I (apoA-I), the major protein in HDL, binds and activates the endothelial ecto-F1-ATPase receptor. This generates extracellular ADP, which in turn promotes endothelial cell survival. In this study we aimed to further investigate the signaling pathway involved downstream of apoA-I-induced ecto-F1-ATPase activation. METHODS: In human umbilical vein endothelial cells (HUVECs), pharmacological and gene silencing approaches were used to study pathways involved downstream ecto-F1-ATPase activation by apoA-I. RESULTS: ApoA-I and HDL both induced Akt phosphorylation. F1-ATPase inhibitors such as inhibitory factor 1 and oligomycin completely blocked apoA-I-induced Akt phosphorylaton and significantly blocked HDL-induced phosphorylation, indicating that this signaling pathway is dependent on ecto-F1 ATPase activation by apoA-I. Further, we were able to specify roles for the P2Y1 ADPreceptor and the PI3Kbeta isoform in this pathway since pharmacological inhibition and silencing of these proteins dramatically inhibited apoA-I-induced Akt phosphorylation and cell proliferation. CONCLUSION: Altogether, these data highlight a key role of the P2Y1/PI3Kbeta axis in endothelial cell proliferation downstream of ecto-F1-ATPase activation by apoA-I. Pharmacological targeting of this pathway could represent a promising approach to enhance vascular endothelial protection. PMID- 28578354 TI - Concurrent CCR7 Overexpression and RelB Knockdown in Immature Dendritic Cells Induces Immune Tolerance and Improves Skin-Graft Survival in a Murine Model. AB - BACKGROUND/AIMS: Skin transplantation aims to cover skin defects but often fails due to immune rejection of the transplantated tissue. Immature dendritic cells (imDCs) induce immune tolerance but have a low migration rate. After stimulation, imDCs transform into mature DCs, which activate immune rejection. Thus, inducing imDC to obtain a high migration counteracts development of immune tolerance. METHODS & RESULTS: We transfected imDCs with a recombinant adenovirus carrying the CCR7 gene (Ad-CCR7) and a small interfering RNA targeting RelB (RelB-siRNA) to concurrently overexpress CCR7 and downregulate RelB expression. Functionally, such cells showed a significantly enhanced migration rate in the chemotactic assay and decreased T-cell proliferation after lipopolysaccharide stimulation in mixed lymphocyte reactions. Cotransfected cells showed an increased ability to induce immune tolerance by upregulating T regulatory (Treg) cells and shifting the Th1/Th2 ratio. Cotransfection of Ad-CCR7 and RelB-siRNA endowed imDCs with resistance to apoptosis and cell death. CCR7 overexpression and RelB knockdown (KD) in imDCs improve skin-graft survival in a murine skin-transplantation model. CONCLUSION: Transfection with Ad-CCR7 and RelB KD in imDCs may be an effective approach inducing immune tolerance, thus being potentially valuable for inhibiting allograft rejection. PMID- 28578356 TI - The relationship between thyroid antibody titer and levothyroxine dose in patients with overt primary hypothyroidism. AB - BACKGROUND: Both excess and insufficient thyroid hormone replacement may produce adverse effects in various target tissues; therefore, understanding factors that affect achievement of target TSH levels is crucial. OBJECTIVE: Investigate the relationship between antibody titers and levothyroxine dose. DESIGN: Retrospective, review of data in medical records. SETTING: Thyroid center of Fatih Sultan Mehmet Education and Research Hospital, Istanbul, Turkey. PATIENTS AND METHODS: The study population consisted of patients that had been diagnosed as having overt primary hypothyroidism and were taking levothyroxine for at least one year. The serum TSH level for an euthyroid state was between 0.5-4 mIU/L. The levels of anti-thyroid peroxidase (TPOAb) considered positive for antibodies were < 5.6 IU/mL and for anti-thyroglobulin (TgAb) autoantibodies < 4.10 IU/ mL. MAIN OUTCOME MEASURE: Daily levothyroxine doses of antibody-positive and negative patients and association of daily drug requirement with antibody titers. RESULTS: The study population consisted of the 303 patients (273 females and 30 males with the mean [SD] age of 46.6 [13.2] years). In the antibody-positive group (n=210) average daily levothyroxine dose was statistically significantly higher than in the antibody-negative group (n=93) (mean of 78.8 [36.7] vs 64.2 [27.1] mg/day, P=.001, respectively). There was a low but statistically significant positive relationship between the TPOAb (r=0.217, P < .01) and TgAb levels (r=0.158, P < .05) and levothyroxine doses in the antibody-positive group. CONCLUSION: Antibody titers are positively associated with larger levothyroxine (LT-4) replacement dosing in patients with autoimmune thyroiditis. LIMITATION: Unknown antibody titers before starting levothyroxine use. PMID- 28578355 TI - Synergistic effect of energy drinks and overweight/obesity on cardiac autonomic testing using the Valsalva maneuver in university students. AB - BACKGROUND: Obesity and caffeine consumption may lead to autonomic disturbances that can result in a wide range of cardiovascular disorders. OBJECTIVES: To determine autonomic disturbances produced by the synergistic effects of overweight or obesity (OW/OB) and energy drinks. DESIGN: Cross-sectional, analytical. SETTING: Physiology department at a university in Saudi Arabia. SUBJECTS AND METHODS: University students, 18-22 years of age, of normal weight (NW) and OW/OB were recruited by convenience sampling. Autonomic testing by the Valsalva ratio (VR) along with systolic and diastolic blood pressure, pulse pressure, and mean arterial blood pressure were measured at baseline (0 minute) and 60 minutes after energy drink consumption. MAIN OUTCOME MEASURE(S): Autonomic disturbance, hemodynamic changes. RESULTS: In 50 (27 males and 23 females) subjects, 21 NW and 29 OW/OB, a significant decrease in VR was observed in OW/OB subjects and in NW and OW/OB females at 60 minutes after energy drink consumption. Values of systolic and diastolic blood pressure, pulse pressure and mean arterial blood pressure were also significantly higher in OW/OB and in females as compared to NW and males. BMI was negatively correlated with VR and diastolic blood pressure at 60 minutes. CONCLUSION: Obesity and energy drinks alter autonomic functions. In some individuals, OW/OB may augment these effects. LIMITATIONS: Due to time and resource restraints, only the acute effects of energy drinks were examined. PMID- 28578357 TI - Is survival after radical cystectomy for bladder cancer in Saudi patients different from that of Western patients? AB - BACKGROUND: Although radical cystectomy (RC) is considered the gold standard treatment of muscle invasive bladder cancer, nearly half of patients develop metastases and ultimately die within 2 years. OBJECTIVE: To assess survival, evaluate different prognostic factors that may affect disease-free survival (DFS) in Saudi patients after RC for carcinoma of the bladder and to compare our results with those of Western countries. DESIGN: Retrospective chart review. SETTING: A tertiary care center in Saudi Arabia. PATIENTS AND METHODS: We collected data on patients who underwent RC for bladder cancer in the period between 1979 and 2014. Demographic, clinical and pathological variables and the application of perioperative chemotherapy were reviewed. Univariate and multivariate analyses were done with DFS as the end point. MAIN OUTCOME MEASURE: Disease-specific survival. RESULTS: On 328 patients for whom data was available, the median follow up was 23 months (range, 2 month-28 years) and median age was 58 years (range, 21-90). Of these patients, 268 were males (81.7%), 235 (71.7%) had urothelial carcinoma (UC), 79 (24.1%) had squamous cell carcinoma (SCC), and 208 (63.4%) had pathological tumor stage 3 or more. The 5-year overall survival (OS) and DFS were 52% and 48%, respectively. There was no statistically significant difference in DFS of patients with UC and pure SCC. On univariate analysis, lymph node status and pathological tumor stage were significant predictors of DFS. Both variables sustained statistical significance in a multivariate analysis. CONCLUSION: Survival following RC is almost the same as others. Moreover, pathological tumor stage and lymph node metastasis were the only independent predictors for survival following RC. Future cooperative prospective studies are required to gain data on our region. LIMITATIONS: Relatively small sample size and retrospective. PMID- 28578358 TI - Incidence and outcome of acute kidney injury by the pRIFLE criteria for children receiving extracorporeal membrane oxygenation after heart surgery. AB - BACKGROUND: Acute kidney injury (AKI) is common in patients treated with extracorporeal membrane oxygenation (ECMO). The RIFLE criteria demonstrate clinical relevance for diagnosing AKI and classifying its severity. OBJECTIVES: To systematically define the incidence, clinical course and outcome of AKI using the pediatric pRIFLE criteria. DESIGN: Retrospective, medical records review. SETTINGS: Pediatric cardiac surgical intensive care units at a tertiary care hospital in Riyadh. PATIENTS AND METHODS: We reviewed the records of all pediatric patients that underwent cardiac surgery and required ECMO postoperatively between 1 January 2011 and 1 January 2016. AKI was classified according to the pRIFLE criteria 48 hours after ECMO initiation. Demographics and concomitant therapies for all patients were collected. MAIN OUTCOME MEASURE(S): Outcome was assessed by recovery from AKI at time of discharge, ICU stay and mortality. RESULTS: Fifty-nine patients needed ECMO after cardiac surgery during the study period. Their mean (SD) age and weight was 11.0 (16.5) month and 5.5 (3.6) kg, respectively. All patients had a central venoarterial ECMO inserted. Fifty-three patients (90%) developed AKI after ECMO initiation. The majority of patients (57%) were categorized as pRIFLE-Failure, having a higher mortality rate (28/34 patients, 82%) in comparison to the pRIFLE-Injury and pRIFLE-Risk groups. Twenty-nine patients (49%) required either peritoneal dialysis (PD), or renal replacement therapy (RRT) or both. For AKI vs non-AKI patients, there was a statistically significant difference between mean (SD) ECMO duration (9.0 [8.00] vs 6.0 [2.0] days; P=.02) and ICU stay (37.0 [41.0] vs 21.0 [5.0] days; P=.03), respectively. The overall mortality rate was 58%, with a significant difference (P=.03) between AKI and non-AKI groups. All the patients who survived had normal creatinine clearance at hospital discharge. CONCLUSION: There is a high incidence of AKI in pediatric patients requiring ECMO after cardiac surgery, and it is associated with higher mortality, increased ECMO duration, and increased ventilator days. LIMITATIONS: Single-center retrospective analysis and the small sample size limited the precision of our estimates in sub-populations. PMID- 28578359 TI - Common nasal deformities among rhinoplasty patients in a university hospital in Saudi Arabia. AB - BACKGROUND: Rhinoplasty has become one of the most common aesthetic procedures in the world. Few studies from the Middle East have described rhinoplasty patients in the region. OBJECTIVE: To investigate common nasal deformities in individuals seeking rhinoplasty at a single institution in Saudi Arabia. DESIGN: Retrospective study and chart review. SETTING: King Abdulaziz University Hospital, Riyadh, Saudi Arabia. PATIENTS AND METHODS: All patients seeking primary rhinoplasty who were 15 years of age and older were included. The types of external nasal deformities were compared by gender and age groups. MAIN OUTCOME MEASURE: Types of external nasal deformities. RESULTS: Of the 248 patients investigated, 113 were male and 135 female. The most common external nasal deformity was a broad dorsum (n=163; 65.7%), followed by a bulbous columella (n=154; 62.1%), and deviation (n=150; 60.5%). Upward columella was most common in older patients, and deviation decreased with age. CONCLUSION: The most common deformity among the study population of Saudis was a wide nasal dorsum, bulbous nasal tip and deviated nose. Studying nasal deformity in some ethnic groups has an influence in selecting and practicing specific rhinoplasty approaches. LIMITATIONS: Study conducted in one hospital and may not be generalizable. PMID- 28578360 TI - Cutaneous T-cell lymphoma in Saudi Arabia: retrospective single-center review. AB - BACKGROUND: Cutaneous T-cell lymphoma (CTCL) is an uncommon disease with various clinical presentations. The hypopigmented type is more common in individuals with a dark skin complexion. Moreover, childhood CTCL is more common in Mediterranean populations in comparison to the West. OBJECTIVE: To describe CTCL in the Saudi population. DESIGN: A retrospective collection of data on all cases of CTCL from 2010-2016. SETTING: Dermatology clinic at a tertiary center in Riyadh, Saudi Arabia. PATIENTS AND METHODS: We collected data on all cases of CTCL diagnosed clinically and confirmed pathologically. MAIN OUTCOME MEASURE(S): The number of cases of CTCL, gender, age at diagnosis and clinical subtypes. RESULTS: The most common presentation among 125 patients was the classic type (patches and plaques) followed by the hypopigmented and poikilodermatous variants. Males were 58% of the population (n=72). The median age at diagnosis was 41 years and the range was 5 to 86 years. Thirteen percent were younger than 20 years of age. CONCLUSION: Hypopigmented and poikilodermatous types of CTCL are more common in our population than in the West. LIMITATION: Retrospective, single-center data may not be generalizable since difficult cases are more likely to be referred to a tertiary center. PMID- 28578361 TI - Current umbilical cord clamping practices and attitudes of obstetricians and midwives toward delayed cord clamping in Saudi Arabia. AB - BACKGROUND: In Saudi Arabia, as in many countries, there is usually no clear definition of the timing of umbilical cord clamping (UCC) in the policies and procedures used by hospitals. The World Health Organization (WHO) recommends delayed cord clamping (DCC) ( > 1 minute after birth) as it can significantly improve hemodynamics and long-term neurodevelopment. OBJECTIVE: To investigate current practices of healthcare professionals on the timing of UCC in Saudi Arabia. DESIGN: Cross-sectional survey. SETTING: Five tertiary hospitals in Riyadh, Saudi Arabia, during May to October 2016. SUBJECTS AND METHODS: Obstetricians and midwives completed a widely-used questionnaire on UCC practices. MAIN OUTCOME MEASURE(S): Current UCC practices and attitudes of obstetricians and midwives toward DCC. RESULTS: Eighty-two obstetricians and 75 midwives completed the questionnaire for a response rate of 80%. The majority of respondents were aged 30 years or older (81%) and 84% were females. Most respondents were non-Saudi (66%) and had an educational level of bachelor's degree or higher (72%). Only 42% of respondents reported the existence of UCC guidelines in their practice; 38% reported the existence of a set time for UCC when the neonate was term and healthy, and only 32% had a set time for UCC in preterm neonates. While lower levels of agreement were reported among obstetricians and midwives on the benefits of DCC for babies requiring positive pressure ventilation, the majority of respondents (69-71%) thought that DCC was generally good for both term and preterm babies and that its benefits extend beyond the neonatal period. CONCLUSIONS: While the majority of obstetricians and midwives that participated in this study had a positive perception toward DCC, this did not translate to their daily practice as most of these professionals reported a lack of existing UCC guidelines in their institutions. Further studies are warranted to confirm these findings. LIMITATIONS: Participant selection by convenience sampling. PMID- 28578362 TI - Student perception of the educational environment in regular and bridging nursing programs in Saudi Arabia using the Dundee Ready Educational Environment Measure. AB - BACKGROUND: Taibah University offers regular nursing (RNP) and nursing bridging (NBP) bachelor programs. We evaluated student perception of the learning environment as one means of quality assurance. OBJECTIVES: To assess nursing student perception of their educational environment, to compare the perceptions of regular and bridging students, and to compare the perceptions of students in the old and new curricula. DESIGN: Cross-sectional survey. SETTING: College of Nursing at Taibah University, Madinah, Saudi Arabia. PATIENTS AND METHODS: The Dundee Ready Educational Environment Measure (DREEM) instrument was distributed to over 714 nursing students to assess perception of the educational environment. Independent samples t test and Pearson's chi square were used to compare the programs and curricula. MAIN OUTCOME MEASURE: The DREEM inventory score. RESULTS: Of 714 students, 271 (38%) were RNP students and 443 (62%) were NBP students. The mean (standard deviation) DREEM score was 111 (25). No significant differences were observed between the programs except for the domain "academic self perceptions" being higher in RNP students (P < .001). Higher mean DREEM scores were observed among students studying the new curriculum in the RNP (P < .001) and NBP (P > .05). CONCLUSION: Nursing students generally perceived their learning environment as more positive than negative. Regular students were more positive than bridging students. Students who experienced the new curriculum were more positive towards learning. LIMITATIONS: The cross-sectional design and unequal gender and study level distributions may limit generalizability of the results. Longitudinal, large-scale studies with more even distributions of participant characteristics are needed. PMID- 28578363 TI - Etiology of optic atrophy: a prospective observational study from Saudi Arabia. AB - BACKGROUND: Optic atrophy (OA) represents permanent retinal ganglion cell loss warranting study to establish etiology. OBJECTIVES: To describe neurogenic causes of OA. DESIGN: Prospective, observational. SETTING: Tertiary care center, Riyadh, Saudi Arabia. PATIENTS AND METHODS: We included consecutive patients of all ages with OA caused by lesions affecting the visual pathways who were referred over a 9-month period (November 2013 to July 2014). Diagnosis was based on visual acuity, ophthalmoscopic features and ancillary tests. Patient demographics, results of a clinical examination, test data and etiology were recorded. For each cause of OA, both gender and age group were analyzed as potential risk factors using simple univariate logistic regression. OA associated with glaucoma and retinal diseases was excluded. MAIN OUTCOME MEASURE: Description of causes of OA. RESULTS: Two hundred and four patients and 353 eyes met inclusion criteria. The median age was 27 years (range 3 months-77 years; interquartile range, 27 years) among 111(54.4%) females and 93(45.6%) males, with no statistically significant difference in age of presentation between the genders. The majority of lesions were bilateral (n=151, 74%). Tumors were the most common cause, accounting for 127 (62.2%) cases. These occurred mostly in adults (72.4%) compared to the pediatric group (OR=3.3, 95% CI: 1.79-6.03; P < .001). Hereditary neoplasia (OR=5.55; 95% CI: 1.67-18.42; P=.005) and metabolic diseases (OR=17.57; 95% CI: 2.15-143.62; P=.007) were more common causes in the pediatric group. There were no significant associations between gender or visual acuity and etiology of OA. In developed nations, OA is frequently the result of ischemia and neuritis. We found many other causes, especially orbital and intracranial tumors. CONCLUSIONS: The frequency of tumors as the cause of OA may represent a higher incidence of aggressive tumors coupled with poor recognition/acknowledgement of symptoms and limited access, resulting in late presentations. LIMITATIONS: These findings may reflect bias from selective referrals to a tertiary center and may not represent all of Saudi Arabia. PMID- 28578364 TI - Xeroderma pigmentosum at a tertiary care center in Saudi Arabia. AB - BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder caused by defective DNA repair that results in extreme sensitivity to ultraviolet (UV) rays. Depending on the type of XP, the disease may affect the skin, eyes and nervous system. OBJECTIVES: Describe the dermatologic manifestations in patients suffering from XP. DESIGN: Retrospective, descriptive review of medical records. SETTING: Dermatology clinic at tertiary care center in Riyadh. PATIENTS AND METHODS: This study included Saudi patients with clinically confirmed XP. MAIN OUTCOME MEASURE(S): Demographic and clinical data including pathology and associated conditions and outcomes. RESULTS: Of 21 patients with XP, the most common manifestation was lentigines, affecting 18 patients (86%). The most common skin cancer was basal cell carcinoma followed by squamous cell carcinoma (SCC) affecting 15 (71.4%) and 9 (42.8%), respectively. Other skin findings included neurofibroma, trichilemmoma and seborrheic keratosis. Ocular involvement included photophobia, which was the most common finding followed by dryness and ocular malignancies. Two patients showed neurological involvement, which correlated with the type of mutation. CONCLUSION: Considering that XP is a rare genetic disease, this description of our patient population will aid in early recognition and diagnosis. LIMITATIONS: Retrospective and small number of patients. Genetic analyses were done for only 5 of the 21 patients. PMID- 28578365 TI - Self-inflicted eye injury. AB - : Individuals with a factitious ocular disorder feign or exaggerate having an eye injury or intentionally produce an eye injury so as to assume the role of a sick person. We report two cases of self-inflicted ocular injury using needle-like foreign bodies and razor that represent possible diagnoses of Munchausen syndrome. Both patients presented with different clinical pictures that misguided the clinical diagnosis and delayed proper management. Although self-inflicted ocular injuries are rare, ophthalmologists should be aware of the possibility of their existence, particularly when caring for patients with psychiatric conditions. SIMILAR CASES PUBLISHED: 13. PMID- 28578366 TI - Soft tissue calcium deposits. PMID- 28578367 TI - Accuracy of cotinine serum test to detect the smoking habit and its association with periodontal disease in a multicenter study. AB - BACKGROUND: The validity of the surveys on self-reported smoking status is often questioned because smokers underestimate cigarette use and deny the habit. It has been suggested that self-report should be accompanied by cotinine test. This report evaluates the usefulness of serum cotinine test to assess the association between smoking and periodontal status in a study with a large sample population to be used in studies with other serum markers in epidemiologic and periodontal medicine researches. MATERIAL AND METHODS: 578 patients who were part of a multicenter study on blood biomarkers were evaluated about smoking and its relation to periodontal disease. Severity of periodontal disease was determinate using clinical attachment loss (CAL). Smoking was assessed by a questionnaire and a blood sample drawn for serum cotinine determination. RESULTS: The optimal cut off point for serum cotinine was 10 ng/ml. Serum cotinine showed greater association with severity of CAL than self-report for mild-moderate CAL [OR 2.03 (CI95% 1.16-3.53) vs. OR 1.08 (CI95% 0.62-1.87) ] advanced periodontitis [OR 2.36 (CI95% 1.30- 4.31) vs. OR 2.06 (CI95% 0.97-4.38) ] and extension of CAL > 3 mm [ OR 1.78 (CI95% 1.16-1.71) vs. 1.37 (CI95% 0.89-2.11)]. When the two tests were evaluated together were not shown to be better than serum cotinine test. CONCLUSIONS: Self-reported smoking and serum cotinine test >= 10ng/ml are accurate ,complementary and more reliable methods to assess the patient's smoking status and could be used in studies evaluating serum samples in large population and multicenter studies. CLINICAL RELEVANCE: The serum cotinine level is more reliable to make associations with the patient's periodontal status than self report questionnaire and could be used in multicenter and periodontal medicine studies. PMID- 28578368 TI - Effect of pre-operatory low-level laser therapy on pain, swelling, and trismus associated with third-molar surgery. AB - BACKGROUND: The extraction of impacted third molars is commonly associated to pain, edema, trismus, limited jaw opening and movements. The aim of this retrospective study is to verify if pre-surgical low-level laser therapy (LLLT) associated with the extraction of impacted lower third molars could add benefits to the postoperative symptoms respect LLLT performed only after surgery. MATERIAL AND METHODS: Data from 45 patients subjected to a surgical extraction of lower third molars were pooled and divided into three groups. Patients that received only routine management were inserted in the control group. Group 1, were patients that received LLLT immediately after surgery and at 24 hours. In group 2 were included patients treated with LLLT immediately before the extraction and immediately after the end of the procedure. Data were analyzed using linear regression and descriptive statistics. RESULTS: Both laser-treated groups were characterized by minor events of post-surgery complications of pain, edema, trismus. The use of NSAIDs in the first 24 hours was significantly inferior in Group 2. CONCLUSIONS: Pre-surgical LLLT treatment seems to increase the analgesic effect of LLLT. However, trismus and edema were reduced in both laser treated groups, independently from the period of irradiation. PMID- 28578369 TI - What is the frequency of anatomical variations and pathological findings in maxillary sinuses among patients subjected to maxillofacial cone beam computed tomography? A systematic review. AB - BACKGROUND: When considering dental implant rehabilitation in atrophic posterior sectors, the maxillary sinuses must be evaluated in detail. Knowledge of the anatomical variations and of the potential lesions found in these structures conditions the outcome of sinus lift procedures and therefore of the dental implants. A systematic review is made to determine the frequency of anatomical variations and pathological findings in maxillary sinuses among patients subjected to cone beam computed tomography (CBCT). MATERIAL AND METHODS: A PubMed (MEDLINE) literature search was made of articles published up until 20 December 2015. The systematic review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). The quality of the studies included in the review was assessed using the Methodological Index for Nonrandomized Studies (MINORS). RESULTS: The combinations of search terms resulted in a list of 3482 titles. Twenty-three studies finally met the inclusion criteria and were entered in the systematic review, comprising a total of 11,971 patients. The most common anatomical variations were pneumatization and sinus septa. The prevalence of maxillary sinus disease ranged from 7.5% to 66%. The most common pathological findings of the maxillary sinus were mucosal thickening, sinusitis and sinus opacification. CONCLUSIONS: Although the main indication of CBCT of the maxillary sinus in dentistry is sinus floor elevation/treatment planning and evaluation prior to dental implant placement, this imaging modality is increasingly also used for endodontic and periodontal purposes. There is no consensus regarding the cutoff point beyond which mucosal thickening of the maxillary sinus should be regarded as pathological, and the definition of maxillary sinusitis moreover varies greatly in the scientific literature. In this regard, international consensus is required in relation to these concepts, with a clear distinction between healthy and diseased maxillary sinuses. PMID- 28578370 TI - Uncommon oral manifestation of lichen sclerosus: critical analysis of cases reported from 1957 to 2016. AB - BACKGROUND: Lichen sclerosus is a mucocutaneous autoimmune disease which might be initiated by infectious pathogens as Borrelia Bugrdorferi and HPV. This disease shows destructive potential and is rarely diagnosed in oral mucosa. The purpose of this paper is to evaluate the characteristics of cases described in literature from 1957 to 2016, looking to provide valuable evidence about clinicopathologic features of this disease. MATERIAL AND METHODS: A MedLine search was performed aiming to find oral lichen sclerosus cases in literature and discuss its demographical and pathological characteristics as well as treatment methods performed for these cases. RESULTS: 34 oral lichen sclerosus cases with histological confirmation and one clinicopathologic study linked with this disease were found in literature. Oral lichen sclerosus affected most commonly female patients, were asymptomatic and not associated to skin or genital lesions. Furthermore, affected patients in a range of 7 - 70-years old (Average age = 31.81). CONCLUSIONS: Oral lichen sclerosus is a rare pathologic process with slight predilection for prepubertal girls, for which topical corticosterois have demonstrated satisfactory therapeutic value. PMID- 28578371 TI - Oral health and systemic inflammatory, cardiac and nitroxid biomarkers in hemodialysis patients. AB - BACKGROUND: Periodontal diseases have systemic inflammatory effects and have been adversely associated with cardiovascular diseases, which are also the most frequent cause of death in the end-stage renal disease. The aim of this cross sectional study was to investigate the oral health and serum biomarkers among the hemodialysis (HD) patients in Slovenia. MATERIAL AND METHODS: 111 HD patients were periodontally examined and their sera were assayed for C reactive protein (CRP), cardiac troponin T (TnT), nitrite/nitrate (NOx) and antibody levels to A. actinomycetemcomitans and P. gingivalis. The association of oral health with systemic response was analyzed with Kruskal-Wallis test, Fisher's exact test and multivariate linear regression. RESULTS: Bleeding on probing without periodontal pockets was present in 5.2%, calculus without periodontal pockets in 42.1%, shallow periodontal pockets in 39.5% and deep periodontal pockets in 13.2% of dentate patients. There were 28.8% edentulous participants. 63.1% of the patients had CRP levels higher than 3 mg/L and 34.2% higher than 10 mg/L. TnT was detectable in all participants, with 25.2% exhibiting levels higher than 100 ng/L. The median level of NOx was 43.1 umol/L. Participants with higher CRP were more likely to be edentulous and have higher TnT levels. A direct association of oral health with TnT or NOx was not detected. CONCLUSIONS: HD patients in Slovenia have compromised oral health and increased serum inflammatory and cardiac biomarkers. Edentulousness was an independent predictor for the increased CRP, indicating a need for improved dental care to retain the teeth as long as possible. PMID- 28578372 TI - Mandibular advancement devices vs nasal-continuous positive airway pressure in the treatment of obstructive sleep apnoea. Systematic review and meta-analysis. AB - BACKGROUND: Obstructive sleep apnoea (OSA) is a common disorder that may affect at least 2 to 4% of the adult population. Nasal-Continuous Positive Airway Pressure (N-CPAP) is today considered the gold standard for the treatment of OSA. The development of oral appliances (OAs) represents a new approach for the management of this pathology. The aim of this systematic review is to compare the efficacy of OAs and N-CPAP in the treatment of patients with mild to severe OSA. MATERIAL AND METHODS: A PubMed-MEDLINE and Cochrane databases search of articles published between 1982 and 2016 comparing the effect of N-CPAP and OAs in OSA patients was conducted during July 2016. The studies were selected and stratified according to PRISMA and SORT criteria. The main outcome measure was post treatment Apnoea-Hypopnoea Index (AHI) while secondary outcomes included post treatment Epworth Score Scale (ESS) score and lowest Oxygen Saturation level. RESULTS: N-CPAP was significantly more effective in suppressing AHI than OA. Moreover, N- CPAP was significantly more effective in increasing post-treatment lowest Oxygen Saturation level than OA. However, no significant different in decreasing ESS values was found between the two treatments. CONCLUSIONS: On the basis of evidence in this review it would appear appropriate to offer OA therapy to those who are unwilling or unable to persist with CPAP therapy. N-CPAP still must be considered the gold standard treatment for OSA and, therefore, OAs may be included in the list of alternative options. PMID- 28578373 TI - Assessment of time intervals in the pathway to oral cancer diagnosis in north westerm Spain. Relative contribution of patient interval. AB - BACKGROUND: Despite continuous advances in diagnosis and therapy, oral cancers are mostly diagnosed at advanced stages with minor survival improvements in the last two decades. Both phenomena have been attributed to delays in the diagnosis. This study aims at quantifying the time elapsed until definitive diagnosis in these patients and the patient interval's contribution. MATERIAL AND METHODS: A hospital-based, ambispective, observational study was undertaken on incident cases with a pathological diagnosis of oral squamous cell carcinoma recruited during 2015 at the Oral and Maxillofacial Surgery services of CHUAC (A Coruna) and POVISA (Vigo) hospitals. RESULTS: 74 consecutive oral cancer patients (59.5% males; median age: 65.0 years (IQ:57-74)) were studied. Most cases (52.7%; n=39) were at advanced stages (TNM III-IV) at diagnosis. The period since first sign/symptom until the patient seeks health care was the longest interval in the pathway to diagnosis and treatment (median: 31.5 days; IQR= 7.0 - 61.0) and represents >60% of the interval since symptom onset until referral to specialised care (pre-referral interval). The average interval assigned to the patient resulted to be relatively larger than the time elapsed since the patient is seen at primary care until a definitive diagnosis is reached (diagnostic interval). Median of the referral interval for primary care professionals: 6.5 days (IQR= 0.0 - 49.2) and accounts for 35% (19% - 51%) of the diagnostic interval. CONCLUSIONS: The patient interval is the main component of the pathway to treatment since the detection of a bodily change until the definitive diagnosis. Therefore, strategies focused on risk groups to shorten this interval should be implemented in order to ease an early diagnosis of symptomatic oral cancer. PMID- 28578374 TI - In vitro comparison of primary stability of two implant designs in D3 bone. AB - BACKGROUND: Primary stability (PS) is a key factor for implant survival rate and depends on implant design or bone quality. The aim of this study was to compare different thread designs implants, evaluating PS with periotest values (PV) and implant stability quotient (ISQ) values through resonance frequency analysis (RFA). MATERIAL AND METHODS: A total of 60 implants (Radhex(r), Inmet-Garnick S.A., Guadalajara, Spain) were placed in freshly bovine ribs in vitro. Two designs were used: 30 tapered body with single thread design (PHI) and 30 tapered body with double thread design implants (PHIA). Both designs were 4mm wide and 12mm long. Implants were placed according to manufacturer's guidelines. OsstellTM and Periotest(r) devices were used to evaluate PS by a blinded independent observer. Computed tomographies (CTs) of the ribs were made (BrightSpeed Series CT systems, GE Healthcare, Milwaukee, WI, USA) and bone quality surrounding each implant was evaluated in Hounsfield Units (HU) using Ez3D Plus software (Vatech Co., Korea). Bone quality was classified according to Misch and Kircos in D1, D2, D3 or D4. RESULTS: All implants were mechanically stable. Only implants placed in D3 bone (350-850 HU) were selected for the study: 28 PHI and 26 PHIA. The one way ANOVA showed significant difference (p < 0.005) among two implants designs in ISQ values (61,55 +/- 6,67 in PHI and 68,94 +/- 5,82 in PHIA). No significant difference (p = 0,171) was shown in PV between two designs (-4,47 +/- 1,39 in PHI and -4,77 +/- 0,87 in PHIA). CONCLUSIONS: Higher PS was found using OsstellTM device in implants with double thread design (PHIA) in comparison to implants with single thread design (PHI) in D3 bone. PMID- 28578376 TI - Letter to Editor: Support to the Spanish language, from Oral Medicine. AB - In the form of a letter to the director, the author provides linguistic comments related to Spanish. He draws attention to some often misused words and suggests some expressions that may improve the use of the Spanish language in scientific texts. PMID- 28578375 TI - Knowledge, aptitudes, and preferences in implant dentistry teaching/training among undergraduate dental students at the University of Barcelona. AB - BACKGROUND: Oral implant rehabilitation should be considered a treatment option for any edentulous patient and Implant Dentistry is currently a discipline taught in the undergraduate formation. The level of knowledge acquired and how the students perceive the quality of training in Implant Dentistry could assess to know if it is necessary to improve the syllabus. MATERIAL AND METHODS: A questionnaire was developed with 11 questions: Basic knowledge (7); Perception of training received (2); Ways in which students would receive training (2). To be responded anonymously and voluntarily for undergraduates students in the Faculty of Dentistry (University of Barcelona, Spain). RESULTS: One hundred and seven students, 76 third year (Group A) and 31 fourth year (Group B) answered the questionnaire. In Group A, 98.68% of students and in Group B 93.54% believed they were poorly informed; 100% of both groups would prefer to receive more training as part of the degree or as postgraduate training through modular courses imparted by experts (A: 71,05%, B: 70,96%) Training through postgraduate programs or training given by private businesses were the least desirable options (A: 42%, B: 64.51%). Questions about basic knowledge acquired received varying responses, which might indicate a certain level of confusion in this area. CONCLUSIONS: The undergraduate syllabus must be revised to include sufficient content and training to allow the student to indicate implant-based treatments based on evidence. Students would prefer training to be included in the undergraduate syllabus. PMID- 28578377 TI - Association of Thyroid-Stimulating Hormone Levels with Microvascular Complications in Type 2 Diabetes Patients. AB - BACKGROUND Subclinical hypothyroidism (SCH) is typically featured by elevated serum concentration of thyroid-stimulating hormone (TSH). This study aimed to determine the relationship between TSH levels and microvascular complications in type 2 diabetes patients. MATERIAL AND METHODS A total of 860 type 2 diabetes patients were enrolled in this cross-sectional study. Subjects were evaluated for anthropometric measurements, thyroid function, diabetic retinopathy, and diabetic kidney disease. TSH was divided into 3 levels: 0.27-2.49 mU/l, 2.5-4.2 mU/l, and >4.2 mU/l. RESULTS Among the participants, 76 subjects (8.8%) were diagnosed with subclinical hypothyroidism (SCH) (male: 6.6% and female: 11.8%). The prevalence of diabetic retinopathy did not differ among the groups (P=0.259). Of the 860 type 2 diabetic subjects, we further excluded invalid or missing data. Therefore, 800 and 860 subjects were included in our study of diabetic retinopathy (DR) and diabetic kidney disease (DKD), respectively. The frequencies of microalbuminuria and macroalbuminuria differed significantly among the different groups. The frequency of DKD was significantly different among the 3 groups (P=0.001) and was higher in subjects with higher TSH levels. After an adjustment for confounding variables, TSH levels were significantly associated with DKD (P<0.001). When compared with subjects with TSH 0.27-2.49 mU/l, the frequency of DKD was higher in subjects with TSH >4.20 mU/l (OR 1.531, 95% CI 1.174-1.997) and with TSH 2.50 4.20 mU/l (OR 1.579, 95% CI 1.098-2.270). However, TSH levels was not significantly correlated with DR (P=0.126). CONCLUSIONS Type 2 diabetic patients with higher TSH values had a higher prevalence of DKD. PMID- 28578378 TI - Genome-Wide Profiling of miRNA and mRNA Expression in Alzheimer's Disease. AB - BACKGROUND Our study aimed to identify key differentially expressed genes (DEGs) and miRNAs (DEmiRNAs) which can serve as potential biomarkers for diagnosis and therapy of Alzheimer's disease (AD). MATERIAL AND METHODS We performed miRNA and mRNA integrated analysis (MMIA) to identify DEGs and DEmiRNAs of AD. The AD specific DEmiRNAs-targets interaction network was contrasted. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed. Q-RT-PCR was used to verify the expression of selected DEGs and DEmiRNAs. RESULTS We conducted MMIA of AD based on 1 miRNA dataset and 3 mRNA datasets derived from the Gene Expression Omnibus (GEO) database; 1759 DEGs and 12 DEmiRNAs were obtained. DEGs of AD were significantly enriched in Huntington's disease and AD. LRP1, CDK5R1, PLCb2, NDUFA4, and DLG4 were 5 DEGs regulated by 4 DEmiRNAs, including miR-26b-5p, miR-26a-5p, miR-107, and miR-103a-3p. These 4 miRNAs were the top 4 miRNAs covering most DEGs. According to the qRT-PCR results, the expression of PLCbeta2, NDUFA4, DLG4, miR-107, and miR-103a-3p was consistent with our integrated analysis. CONCLUSIONS We concluded that LRP1, CDK5R1, PLCbeta2, NDUFA4, and DLG4 may play a role in AD regulated by miR-26b-5p, miR-26a-5p, miR-107, and miR-103a-3p. Our findings will contribute to identification of biomarkers and new strategies for drug design for AD treatment. PMID- 28578380 TI - The zebrafish ventricle: A hub of cardiac endothelial cells for in vitro cell behavior studies. AB - Despite our increasing understanding of zebrafish heart development and regeneration, there is limited information about the distribution of endothelial cells (ECs) in the adult zebrafish heart. Here, we investigate and compare the distribution of cardiac ECs (cECs) in adult mouse and zebrafish ventricles. Surprisingly, we find that (i) active coronary vessel growth is present in adult zebrafish, (ii) ~37 and ~39% of cells in the zebrafish heart are ECs and cardiomyocytes, respectively, a composition similar to that seen in mouse. However, we find that in zebrafish, ~36% of the ventricular tissue is covered with ECs, i.e., a substantially larger proportion than in mouse. Capitalising on the high abundance of cECs in zebrafish, we established a protocol to isolate them with high purity using fluorescent transgenic lines. Our approach eliminates side-effects due to antibody utilisation. Moreover, the isolated cECs maintained a high proliferation index even after three passages and were amenable to pharmacological treatments to study cEC migration in vitro. Such primary cultures will be a useful tool for supplementary in vitro studies on the accumulating zebrafish mutant lines as well as the screening of small molecule libraries on cardiac specific endothelial cells. PMID- 28578379 TI - Social cognition in autism: Face tuning. AB - Faces convey valuable information for social cognition, effective interpersonal interaction, and non-verbal communication. Face perception is believed to be atypical in autism, but the origin of this deficit is controversial. Dominant featural face encoding is suggested to be responsible for face tuning scarcity. Here we used a recently developed Face-n-Food paradigm for studying face tuning in individuals with autistic spectrum disorders (ASD). The key benefit of these images is that single components do not explicitly trigger face processing. In a spontaneous recognition task, adolescents with autism and typically developing matched controls were presented with a set of Face-n-Food images in different degree resembling a face (slightly bordering on the Giuseppe Arcimboldo style). The set of images was shown in a predetermined order from the least to most resembling a face. Thresholds for recognition of the Face-n-Food images as a face in ASD individuals were substantially higher than in typically developing controls: they did not report seeing a face on the images, which controls easily recognized as a face, and gave overall fewer face responses. This outcome not only lends support to atypical face tuning, but provides novel insights into the origin of face encoding deficits in autism. PMID- 28578382 TI - Astragaloside IV alleviates heart failure via activating PPARalpha to switch glycolysis to fatty acid beta-oxidation. AB - In heart failure (HF), energy metabolism pathway in cardiac muscle changes from fatty acid beta-oxidation to glycolysis. However, the exact mechanism is unknown. Sarcoendoplasmic reticulum Ca2+alpha ATPase (SERCA) expression is downregulated and mitochondrial function is reduced in HF, perhaps partly due to a substantially reduced energy supply for excitation-contraction coupling resulting from a lower fatty acid beta-oxidation rate. We investigated whether Astragaloside IV can activate peroxisome proliferator-activated receptor alpha (PPARalpha) to stimulate fatty acid beta-oxidation and increase cardiac energy production, improving mitochondrial function and the efficiency of SERCA in HF. In pressure overload-induced HF mice and isolated hypertrophic myocardial cells, fatty acid beta-oxidation and heart function were substantially strengthened following Astragaloside IV treatment, as demonstrated by the increased expression of PPARalpha and SERCA2a. In vitro, Astragaloside IV regulated energy metabolism by increasing ATP production and enhancing mitochondrial function, attributable to increased oxygen consumption and slightly increased mitochondrial Ca2+ uptake. In HF, Astragaloside IV switched glycolysis to fatty acid beta-oxidation, as confirmed by reduced anaerobic glycolysis and an increased oxygen consumption ratio. These results suggest that Astragaloside IV can stimulate fatty acid beta oxidation and improve mitochondrial function, which may present a novel cardioprotective treatment that inhibits the progress of HF. PMID- 28578383 TI - Cumulative impacts: thermally bleached corals have reduced capacity to clear deposited sediment. AB - The interaction between local, anthropogenic stressors, and larger scale regional/global stressors, is often used to explain the current poor condition of many corals reefs. This form of cumulative pressure is clearly manifested by situations where dredging projects happen to coincide with marine heatwaves that have caused coral bleaching. A key pressure associated with dredging is elevated sedimentation. In this study, 3 coral species (Acropora millepora, Porites spp. and Turbinaria reniformis), representing three common morphologies (branching, massive and foliose respectively), were experimentally induced to bleach by exposure to a temperature of 31 degrees C for 21 d. The corals were then subjected to a range of sedimentation rates (0, 11, 22 and 40 mg cm-2 d-1), and their sediment-rejection ability quantified after 1 and 7 successive sediment deposition events. Bleached corals were less capable of removing sediments from their surfaces, and sediment accumulated 3 to 4-fold more than on normally pigmented corals. Repeated deposition resulted in a ~3-fold increase in the amount of sediment remaining on the corals, regardless of bleaching status. These results suggest that adaptive management practices need to be developed to reduce the impacts of future dredging projects that follow or coincide with elevated sea surface temperatures and coral bleaching events. PMID- 28578385 TI - beta-lapachone suppresses tumour progression by inhibiting epithelial-to mesenchymal transition in NQO1-positive breast cancers. AB - NQO1 is a FAD-binding protein that can form homodimers and reduce quinones to hydroquinones, and a growing body of evidence currently suggests that NQO1 is dramatically elevated in solid cancers. Here, we demonstrated that NQO1 was elevated in breast cancer and that its expression level was positively correlated with invasion and reduced disease free survival (DFS) and overall survival (OS) rates. Next, we found that beta-lapachone exerted significant anti-proliferation and anti-metastasis effects in breast cancer cell lines due to its effects on NQO1 expression. Moreover, we revealed that the anti-cancer effects of beta lapachone were mediated by the inactivation of the Akt/mTOR pathway. In conclusion, these results demonstrated that NQO1 could be a useful prognostic biomarker for patients with breast cancer, and its bioactivatable drug, beta lapachone represented a promising new development and an effective strategy for indicating the progression of NQO1-positive breast cancers. PMID- 28578386 TI - Injectable in situ cross-linking chitosan-hyaluronic acid based hydrogels for abdominal tissue regeneration. AB - Abdominal wall defect caused by open abdomen (OA) or abdominal trauma is a serious issue since it induces several clinical problems. Although a variety of prosthetic materials are commonly employed, complications occur including host soft tissue response, fistula formation and chronic patient discomfort. Recently, abundant natural polymers have been used for injectable hydrogel synthesis in tissue regeneration. In this study, we produced the chitosan - hyaluronic acid (CS/HA) hydrogel and investigated its effects on abdominal tissue regeneration. The physical and biological properties of the hydrogel were demonstrated to be suitable for application in abdominal wounds. In a rat model simulating open abdomen and large abdominal wall defect, rapid cellular response, sufficient ECM deposition and marked neovascularization were found after the application of the hydrogel, compared to the control group and fibrin gel group. Further, the possible mechanism of these findings was studied. Cytokines involved in angiogenesis and cellular response were increased and the skew toward M2 macrophages credited with the functions of anti-inflammation and tissue repair was showed in CS/HA hydrogel group. These findings suggested that CS/HA hydrogel could prevent the complications and was promising for abdominal tissue regeneration. PMID- 28578387 TI - Metabolic responses of a phototrophic sponge to sedimentation supports transitions to sponge-dominated reefs. AB - Declines in coral abundance have been linked to increased sedimentation at many locations across the world and at some of these locations there have been subsequent increases in sponge abundance. These shifts appear counterintuitive as sponges are suspension feeders and many rely on photosymbionts for carbon. At a sedimented reef in Indonesia (Wakatobi) corals have declined and the photoautotrophic sponge Lamellodysidea herbacea is now abundant. We hypothesise that this is partly due to L. herbacea's ability to clear its tissues of high levels of settled-sediment and compensate for associated metabolic demands by altering its respiration rate. Negligible detrimental effects to sponge tissue were observed after treatments up to five times the sedimentation rate of the highly sedimented reef. Rapid sediment clearance occurred that was potentially aided by mucus production. Finally, high sediment exposure caused an immediate reduction in respiration rate, likely due to reduced pumping to prevent clogging, whereas sustained high sedimentation caused an increase in respiration rate, potentially due to the energetic cost of mucus production. Our study provides evidence that some sponges can tolerate environments that appear unsuitable to many corals and with increased sedimentation this acclimation may support further transitions to sponge dominated reefs in the future. PMID- 28578384 TI - Alternative splicing shapes transcriptome but not proteome diversity in Physcomitrella patens. AB - Alternative splicing (AS) can significantly impact the transcriptome and proteome of a eukaryotic cell. Here, using transcriptome and proteome profiling data, we analyzed AS in two life forms of the model moss Physcomitrella patens, namely protonemata and gametophores, as well as in protoplasts. We identified 12 043 genes subject to alternative splicing and analyzed the extent to which AS contributes to proteome diversity. We could distinguish a few examples that unambiguously indicated the presence of two or more splice isoforms from the same locus at the proteomic level. Our results indicate that alternative isoforms have a small effect on proteome diversity. We also revealed that mRNAs and pre-mRNAs have thousands of complementary binding sites for long non-coding RNAs (lncRNAs) that may lead to potential interactions in transcriptome. This finding points to an additional level of gene expression and AS regulation by non-coding transcripts in Physcomitrella patens. Among the differentially expressed and spliced genes we found serine/arginine-rich (SR) genes, which are known to regulate AS in cells. We found that treatment with abscisic (ABA) and methyl jasmonic acids (MeJA) led to an isoform-specific response and suggested that ABA in gametophores and MeJA in protoplasts regulate AS and the transcription of SR genes. PMID- 28578391 TI - Nanoscale spheroidized cementite induced ultrahigh strength-ductility combination in innovatively processed ultrafine-grained low alloy medium-carbon steel. AB - We describe here innovative processing of low alloy medium-carbon steel with a duplex microstructure composed of nanoscale spheroidized cementite (Fe3C) in an ultrafine-grained (UFG) ferritic steel. After multi-pass rolling and intermittent annealing at 550 degrees C for 300 s, the obtained UFG-1 steel showed an average ferrite grain size of ~430 nm, containing nanoscale spheroidized cementite (Fe3C) particles with an average size of ~70 nm. On annealing at 600 degrees C for 300 s, the average size of ferritic grains was increased to ~680 nm and the average size of spheroidized Fe3C particles increased to ~90 nm, referred as UFG-2 steel. Tensile tests indicated that UFG-1 steel had high yield strength (sigma y) of 1260 MPa, and ultimate tensile strength (sigma UTS) of 1400 MPa. These values are higher than that of UFG-2 steel (sigma y = 1080 MPa and sigma UTS = 1200 MPa), suggesting that the strengthening contribution is a cumulative effect of decrease in ferrite grain size and nanoscale cementite. The incoherent interfaces between nanosized particles and the matrix acted as a strong barrier to dislocation motion. The study underscores that nanosized precipitates not only provide strength but also contribute to ductility, which is very encouraging for improving the ductility of medium-carbon steels. PMID- 28578388 TI - Antibody blockade of CLEC12A delays EAE onset and attenuates disease severity by impairing myeloid cell CNS infiltration and restoring positive immunity. AB - The mechanism of dendritic cells (DCs) recruitment across the blood brain barrier (BBB) during neuroinflammation has been the least explored amongst all leukocytes. For cells of myeloid origin, while integrins function at the level of adhesion, the importance of lectins remains unknown. Here, we identified functions of one C-type lectin receptor, CLEC12A, in facilitating DC binding and transmigration across the BBB in response to CCL2 chemotaxis. To test function of CLEC12A in an animal model of multiple sclerosis (MS), we administered blocking antibody to CLEC12A that significantly ameliorated disease scores in MOG35-55 induced progressive, as well as PLP138-151-induced relapsing-remitting experimental autoimmune encephalomyelitis (EAE) mice. The decline in both progression and relapse of EAE occurred as a result of reduced demyelination and myeloid cell infiltration into the CNS tissue. DC numbers were restored in the spleen of C57BL/6 and peripheral blood of SJL/J mice along with a decreased TH17 phenotype within CD4+ T-cells. The effects of CLEC12A blocking were further validated using CLEC12A knockout (KO) animals wherein EAE disease induction was delayed and reduced disease severity was observed. These studies reveal the utility of a DC-specific mechanism in designing new therapeutics for MS. PMID- 28578390 TI - A proof-of-concept study for developing integrated two-photon microscopic and magnetic resonance imaging modality at ultrahigh field of 16.4 tesla. AB - Functional magnetic resonance imaging (fMRI) based on the blood oxygen level dependent (BOLD) contrast has gained a prominent position in neuroscience for imaging neuronal activity and studying effective brain connectivity under working state and functional connectivity at resting state. However, the fundamental questions in regards to fMRI technology: how the BOLD signal inferences the underlying microscopic neuronal activity and physiological changes and what is the ultimate specificity of fMRI for functional mapping of microcircuits, remain unanswered. The capability of simultaneous fMRI measurement and functional microscopic imaging in a live brain thus holds the key to link the microscopic and mesoscopic neural dynamics to the macroscopic brain activity at the central nervous system level. Here we report the first demonstration to integrate high resolution two-photon fluorescence microscopy (TPM) with a 16.4 tesla MRI system, which proves the concept and feasibility for performing simultaneous high resolution fMRI and TPM imaging at ultrahigh magnetic field. PMID- 28578392 TI - An appropriate Wnt/beta-catenin expression level during the remodeling phase is required for improved bone fracture healing in mice. AB - Accumulating evidence demonstrates that the Wnt/beta-catenin signaling pathway plays a dominant role in bone repair. However, the role of Wnt/beta-catenin signaling in the remodeling phase during bone fracture healing is currently unknown. In the present study, beta-catenin was activated at different levels or deleted in mice at the late stage of fracture healing, and the effects on healing quality were investigated. Deletion of beta-catenin disturbed bone remodeling, as confirmed by increased bone resorption and decreased bone formation, and significantly decreased bone strength compared with wildtype mice. In addition, the constitutive activation of beta-catenin significantly increased the bone mass and delayed the bone remodeling process, resulting in slightly impaired bone strength. In contrast, a slight activation of beta-catenin significantly increased bone formation and slightly hindered bone resorption. These effects lead to improved bone fracture healing quality compared with wildtype mice. In summary, the present study provides the first demonstration showing that Wnt/beta catenin signaling should be maintained at a slightly activated level during the late stage of fracture healing to ensure better bone fracture repair. PMID- 28578393 TI - MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma. AB - The emergence of drug resistance continues to be a major hurdle towards improving patient outcomes for the treatment of Multiple Myeloma. MTI-101 is a first-in class peptidomimetic that binds a CD44/ITGA4 containing complex and triggers necrotic cell death in multiple myeloma cell lines. In this report, we show that acquisition of resistance to MTI-101 correlates with changes in expression of genes predicted to attenuate Ca2+ flux. Consistent with the acquired resistant genotype, MTI-101 treatment induces a rapid and robust increase in intracellular Ca2+ levels in the parental cells; a finding that was attenuated in the acquired drug resistant cell line. Mechanistically, we show that pharmacological inhibition of store operated channels or reduction in the expression of a component of the store operated Ca2+ channel, TRPC1 blocks MTI-101 induced cell death. Importantly, MTI-101 is more potent in specimens obtained from relapsed myeloma patients, suggesting that relapse may occur at a cost for increased sensitivity to Ca2+ overload mediated cell death. Finally, we demonstrate that MTI-101 is synergistic when combined with bortezomib, using both myeloma cell lines and primary myeloma patient specimens. Together, these data continue to support the development of this novel class of compounds for the treatment of relapsed myeloma. PMID- 28578394 TI - Integrated proteomic and metabolomic analysis reveals that rhodomyrtone reduces the capsule in Streptococcus pneumoniae. AB - The emergence of antibiotic-resistant pathogenic bacteria is a healthcare problem worldwide. We evaluated the antimicrobial activity of rhodomyrtone, an acylphloroglucinol present in Rhodomyrtus tomentosa leaves, against the human Gram-positive pathogen Streptococcus pneumoniae. The compound exhibited pronounced anti-pneumococcal activity against a broad collection of clinical isolates. We studied the effects at the molecular level by integrated proteomic and metabolomic analysis. The results revealed alterations in enzymes and metabolites involved in several metabolic pathways including amino acid biosynthesis, nucleic acid biosynthesis, glucid, and lipid metabolism. Notably, the levels of two enzymes (glycosyltransferase and UTP-glucose-1-phosphate uridylyltransferase) and three metabolites (UDP-glucose, UDP-glucuronic acid and UDP-N-acetyl-D-galactosamine) participating in the synthesis of the pneumococcal capsule clearly diminished in the bacterial cells exposed to rhodomyrtone. Rhodomyrtone-treated pneumococci significantly possessed less amount of capsule, as measured by a colorimetric assay and visualized by electron microscopy. These findings reveal the utility of combining proteomic and metabolomic analyses to provide insight into phenotypic features of S. pneumoniae treated with this potential novel antibiotic. This can lead to an alternative antibiotic for the treatment of S. pneumoniae infections, because of the growing concern regarding antimicrobial resistance. PMID- 28578395 TI - Polycyclic aromatic hydrocarbons (PAHs) in Chinese forest soils: profile composition, spatial variations and source apportionment. AB - Previous studies reported that forest ecosystems can play a vital role in scavenging anthropogenic polycyclic aromatic hydrocarbons (PAHs) and act as primary reservoirs of these environmental pollutants. The present study aimed to investigate the occurrence, spatial pattern and source apportionment of PAHs across Chinese background forest soils (O- & A-horizons). The 143 soils collected from 30 mountains showed significantly (p < 0.05) higher levels of ?15PAHs (ng g 1 dw) in O-horizon (222 +/- 182) than A-horizon (168 +/- 161). A progressive increase in the levels of lighter PAHs was observed along altitudinal gradient, however heavier PAHs did not show any variations. Carbon contents (TOC & BC) of forest soils were found weakly correlated (p < 0.01) with low molecular weight (LMW)-PAHs but showed no relation with high molecular weight (HMW)-PAHs. Source apportionment results using PMF and PCA revealed that PAHs in forest soils mainly come from local biomass burning and/or coal combustion and attributed that forest soils may become a potential sink for PAHs in the region. PMID- 28578397 TI - Donor and recipient contribution to phenotypic traits and the expression of biomineralisation genes in the pearl oyster model Pinctada margaritifera. AB - Grafting associates two distinct genotypes, each of which maintains its own genetic identity throughout the life of the grafted organism. Grafting technology is well documented in the plant kingdom, but much less so in animals. The pearl oyster, Pinctada margaritifera, produces valuable pearls as a result of the biomineralisation process of a mantle graft from a donor inserted together with a nucleus into the gonad of a recipient oyster. To explore the respective roles of donor and recipient in pearl formation, a uniform experimental graft was designed using donor and recipient oysters monitored for their growth traits. At the same time, phenotypic parameters corresponding to pearl size and quality traits were recorded. Phenotypic interaction analysis demonstrated: 1) a positive correlation between recipient shell biometric parameters and pearl size, 2) an individual donor effect on cultured pearl quality traits. Furthermore, the expressions of biomineralisation biomarkers encoding proteins in the aragonite or prismatic layer showed: 1) higher gene expression levels of aragonite-related genes in the large donor phenotype in the graft tissue, and 2) correlation of gene expression in the pearl sac tissue with pearl quality traits and recipient biometric parameters. These results emphasize that pearl size is mainly driven by the recipient and that pearl quality traits are mainly driven by the donor. PMID- 28578396 TI - Neonicotinoid-induced pathogen susceptibility is mitigated by Lactobacillus plantarum immune stimulation in a Drosophila melanogaster model. AB - Pesticides are used extensively in food production to maximize crop yields. However, neonicotinoid insecticides exert unintentional toxicity to honey bees (Apis mellifera) that may partially be associated with massive population declines referred to as colony collapse disorder. We hypothesized that imidacloprid (common neonicotinoid; IMI) exposure would make Drosophila melanogaster (an insect model for the honey bee) more susceptible to bacterial pathogens, heat stress, and intestinal dysbiosis. Our results suggested that the immune deficiency (Imd) pathway is necessary for D. melanogaster survival in response to IMI toxicity. IMI exposure induced alterations in the host-microbiota as noted by increased indigenous Acetobacter and Lactobacillus spp. Furthermore, sub-lethal exposure to IMI resulted in decreased D. melanogaster survival when simultaneously exposed to bacterial infection and heat stress (37 degrees C). This coincided with exacerbated increases in TotA and Dpt (Imd downstream pro survival and antimicrobial genes, respectively) expression compared to controls. Supplementation of IMI-exposed D. melanogaster with Lactobacillus plantarum ATCC 14917 mitigated survival deficits following Serratia marcescens (bacterial pathogen) septic infection. These findings support the insidious toxicity of neonicotinoid pesticides and potential for probiotic lactobacilli to reduce IMI induced susceptibility to infection. PMID- 28578398 TI - Oscillations in networks of networks stem from adaptive nodes with memory. AB - We present an analytical framework that allows the quantitative study of statistical dynamic properties of networks with adaptive nodes that have memory and is used to examine the emergence of oscillations in networks with response failures. The frequency of the oscillations was quantitatively found to increase with the excitability of the nodes and with the average degree of the network and to decrease with delays between nodes. For networks of networks, diverse cluster oscillation modes were found as a function of the topology. Analytical results are in agreement with large-scale simulations and open the horizon for understanding network dynamics composed of finite memory nodes as well as their different phases of activity. PMID- 28578400 TI - Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fusion and Enhances ATGL Degradation and Triglyceride Accumulation. AB - Lipid droplet (LD)-associated hydrolase (LDAH) is a newly identified LD protein abundantly expressed in tissues that predominantly store triacylglycerol (TAG). However, how LDAH regulates TAG metabolism remains unknown. We found that upon oleic acid loading LDAH translocalizes from the ER to newly formed LDs, and induces LD coalescence in a tubulin-dependent manner. LDAH overexpression and downregulation in HEK293 cells increase and decrease, respectively, TAG levels. Pulse and chase experiments show that LDAH enhances TAG biogenesis, but also decreases TAG turnover and fatty acid release from cells. Mutations in predicted catalytic and acyltransferase motifs do not influence TAG levels, suggesting that the effect is independent of LDAH's enzymatic activity. However, a LDAH alternative-splicing variant missing 90 amino acids at C-terminus does not promote LD fusion or TAG accumulation, while it still localizes to LDs. Interestingly, LDAH enhances polyubiquitination and proteasomal degradation of adipose triglyceride lipase (ATGL), a rate limiting enzyme of TAG hydrolysis. Co expression of ATGL reverses the changes in LD phenotype induced by LDAH, and both proteins counterbalance their effects on TAG stores. Together, these studies support that under conditions of TAG storage in LDs LDAH plays a primarily lipogenic role, inducing LD growth and enhancing degradation of ATGL. PMID- 28578399 TI - Transcription Factor Forkhead Regulates Expression of Antimicrobial Peptides in the Tobacco Hornworm, Manduca sexta. AB - Antimicrobial peptides (AMPs) play an important role in defense against microbial infections in insects. Expression of AMPs is regulated mainly by NF-kappaB factors Dorsal, Dif and Relish. Our previous study showed that both NF-kappaB and GATA-1 factors are required for activation of moricin promoter in the tobacco hornworm, Manduca sexta, and a 140-bp region in the moricin promoter contains binding sites for additional transcription factors. In this study, we identified three forkhead (Fkh)-binding sites in the 140-bp region of the moricin promoter and several Fkh-binding sites in the lysozyme promoter, and demonstrated that Fkh binding sites are required for activation of both moricin and lysozyme promoters by Fkh factors. In addition, we found that Fkh mRNA was undetectable in Drosophila S2 cells, and M. sexta Fkh (MsFkh) interacted with Relish-Rel-homology domain (RHD) but not with Dorsal-RHD. Dual luciferase assays with moricin mutant promoters showed that co-expression of MsFkh with Relish-RHD did not have an additive effect on the activity of moricin promoter, suggesting that MsFkh and Relish regulate moricin activation independently. Our results suggest that insect AMPs can be activated by Fkh factors under non-infectious conditions, which may be important for protection of insects from microbial infection during molting and metamorphosis. PMID- 28578401 TI - RNAseq analysis reveals pathways and candidate genes associated with salinity tolerance in a spaceflight-induced wheat mutant. AB - Salinity stress has become an increasing threat to food security worldwide and elucidation of the mechanism for salinity tolerance is of great significance. Induced mutation, especially spaceflight mutagenesis, is one important method for crop breeding. In this study, we show that a spaceflight-induced wheat mutant, named salinity tolerance 1 (st1), is a salinity-tolerant line. We report the characteristics of transcriptomic sequence variation induced by spaceflight, and show that mutations in genes associated with sodium ion transport may directly contribute to salinity tolerance in st1. Furthermore, GO and KEGG enrichment analysis of differentially expressed genes (DEGs) between salinity-treated st1 and wild type suggested that the homeostasis of oxidation-reduction process is important for salt tolerance in st1. Through KEGG pathway analysis, "Butanoate metabolism" was identified as a new pathway for salinity responses. Additionally, key genes for salinity tolerance, such as genes encoding arginine decarboxylase, polyamine oxidase, hormones-related, were not only salt-induced in st1 but also showed higher expression in salt-treated st1 compared with salt-treated WT, indicating that these genes may play important roles in salinity tolerance in st1. This study presents valuable genetic resources for studies on transcriptome variation caused by induced mutation and the identification of salt tolerance genes in crops. PMID- 28578402 TI - Using bamboo biochar with compost for the stabilization and phytotoxicity reduction of heavy metals in mine-contaminated soils of China. AB - Anthropogenic activities have transformed the global geochemical cycling of heavy metals (HMs). Many physical, chemical and biological methods are used to reduce the toxicity of HMs to humans, plants and environment. This study aimed to investigate the immobilization and phytotoxicity reduction of HMs after application of bamboo biochar (BB) in mine-polluted soil in Feng county (FC) and Tongguan (TG). The results showed that BB application to contaminated soil immobilized HMs (Zn, Pb, Cd and Cu). The soil pH and EC increased and the bioavailability of HMs decreased in FC and TG, whereas Pb and Cu increased in TG soil. The addition of BB reduced HMs uptake in the shoot/root of Brassica juncea. Physiological responses showed that BB application improved the shoot/root growth, dry biomass, and enhanced the chlorophyll (a and b) and carotenoid concentrations in Brassica. The incorporation of BB improved the soil health and accelerated enzymatic activities (beta-glucosidase, alkaline phosphatase and urease) in HMs polluted soils. Antioxidant activities (POD, PPO, CAT and SOD) were also used as biomarkers to determine the negative effects of HMs on the growth of Brassica. Overall, the immobilization potential and phytotoxicity reduction of HMs were confirmed by BCF, TF and MEA for both soils. PMID- 28578403 TI - Fair Topologies: Community Structures and Network Hubs Drive Emergence of Fairness Norms. AB - Fairness has long been argued to govern human behavior in a wide range of social, economic, and organizational activities. The sense of fairness, although universal, varies across different societies. In this study, using a computational model, we test the hypothesis that the topology of social interaction can causally explain some of the cross-societal variations in fairness norms. We show that two network parameters, namely, community structure, as measured by the modularity index, and network hubiness, represented by the skewness of degree distribution, have the most significant impact on emergence of collective fair behavior. These two parameters can explain much of the variations in fairness norms across societies and can also be linked to hypotheses suggested by earlier empirical studies in social and organizational sciences. We devised a multi-layered model that combines local agent interactions with social learning, thus enables both strategic behavior as well as diffusion of successful strategies. By applying multivariate statistics on the results, we obtain the relation between network structural features and the collective fair behavior. PMID- 28578404 TI - A simple and rapid LC-MS/MS method for therapeutic drug monitoring of cetuximab: a GPCO-UNICANCER proof of concept study in head-and-neck cancer patients. AB - Administration of first-in-class anti-EGFR monoclonal antibody cetuximab is contingent upon extensive pharmacogenomic testing. However in addition to tumor genomics, drug exposure levels could play a critical, yet largely underestimated role, because several reports have demonstrated that cetuximab pharmacokinetic parameters, in particular clearance values, were associated with survival in patients. Here, we have developed an original bioanalytical method based upon the use of LC-MS/MS technology and a simplified sample preparation procedure to assay cetuximab in plasma samples from patients, thus meeting the requirements of standard Therapeutic Drug Monitoring in routine clinical practice. When tested prospectively in a pilot study in 25 head-and-neck cancer patients, this method showed that patients with clinical benefit had cetixumab residual concentrations higher than non-responding patients (i.e., 49 +/- 16.3 ug/ml VS. 25.8 +/- 17 ug/ml, p < 0.01 t test). Further ROC analysis showed that 33.8 ug/ml was the Cmin threshold predictive of response with an acceptable sensitivity (87%) and specificity (78%). Mass spectrometry-based therapeutic drug monitoring of cetuximab in head-and-neck cancer patients could therefore help to rapidly predict cetuximab efficacy and to adapt dosing if required. PMID- 28578406 TI - Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins. AB - Mamba venoms contain a multiplicity of three-finger fold aminergic toxins known to interact with various alpha-adrenergic, muscarinic and dopaminergic receptors with different pharmacological profiles. In order to generate novel functions on this structural scaffold and to avoid the daunting task of producing and screening an overwhelming number of variants generated by a classical protein engineering strategy, we accepted the challenge of resurrecting ancestral proteins, likely to have possessed functional properties. This innovative approach that exploits molecular evolution models to efficiently guide protein engineering, has allowed us to generate a small library of six ancestral toxin (AncTx) variants and associate their pharmacological profiles to key functional substitutions. Among these variants, we identified AncTx1 as the most alpha1A adrenoceptor selective peptide known to date and AncTx5 as the most potent inhibitor of the three alpha2 adrenoceptor subtypes. Three positions in the rho Da1a evolutionary pathway, positions 28, 38 and 43 have been identified as key modulators of the affinities for the alpha1 and alpha2C adrenoceptor subtypes. Here, we present a first attempt at rational engineering of the aminergic toxins, revealing an epistasis phenomenon. PMID- 28578407 TI - RNAi Screen and Proteomics Reveal NXF1 as a Novel Regulator of IRF5 Signaling. AB - Interferon regulatory factor 5 (IRF5) is a key transcription factor of innate immunity, which plays an important role in host restriction to viral infection and inflammation. Genome-wide association studies have implied the association of IRF5 with several autoimmune diseases, including systemic lupus erythematosus (SLE), Sjogren's syndrome, inflammatory bowel disease and multiple sclerosis. However, the regulation of IRF5-mediated immunity is not well understood. To uncover new regulators in IRF5 pathway, we used two "omics" approaches: affinity purification coupled with mass spectrometry and a high throughput RNAi screen. Proteomics identified 16 new IRF5 interactors while RNAi-mediated knockdown found 43 regulators of the TLR7-dependent IRF5 signaling pathway. NXF1 was identified in both screens. Stimulation with TLR7 ligand enhances formation of IRF5-NXF1 protein complexes. Gain or loss-of-function experiments revealed NXF1 selectively regulates TLR7-driven IRF5 transcriptional activity, suggesting a new role for NXF1 in the IRF5 signaling pathway. PMID- 28578408 TI - Seed mass of angiosperm woody plants better explained by life history traits than climate across China. AB - Seed mass is a basic trait in studies of functional ecology. Examining how seed mass is affected by biotic and abiotic factors could improve our understanding of ecological strategies in plants. Here we examined the relationships of seed mass with 13 climate variables and seven life history traits, and partitioned the relative effects of life history traits vs. climate, based on seed mass data for 1265 woody angiosperm species in China. Our results showed that seed mass decreased with latitude, and most climate variables were positively correlated with seed mass. Geographic seed mass pattern was affected by both energy and water availability in the growing season, but the effect of energy availability was more important. Seed mass was also significantly related to other traits such as growth form, fruit type, dispersal mode, breeding system, leaf habit, fruit development time, and minimum juvenile period, with growth form and dispersal mode being the most closely related traits. Our results showed that climate explained much less variation in seed mass than life history traits, and that phylogeny played an important role in shaping the large-scale patterns of seed mass. PMID- 28578409 TI - Synchrotron phase-contrast microtomography of coprolites generates novel palaeobiological data. AB - Coprolites (fossil faeces) reveal clues to ancient trophic relations, and contain inclusions representing organisms that are rarely preserved elsewhere. However, much information is lost by classical techniques of investigation, which cannot find and image the inclusions in an adequate manner. We demonstrate that propagation phase-contrast synchrotron microtomography (PPC-SRMUCT) permits high quality virtual 3D-reconstruction of coprolite inclusions, exemplified by two coprolites from the Upper Triassic locality Krasiejow, Poland; one of the coprolites contains delicate beetle remains, and the other one a partly articulated fish and fragments of bivalves. PMID- 28578410 TI - Resveratrol Pretreatment Attenuates Concanavalin A-induced Hepatitis through Reverse of Aberration in the Immune Response and Regenerative Capacity in Aged Mice. AB - Loss of regenerative capacity plays a critical role in age-related autoimmune hepatitis. Evidence implicates SIRT1 and p66shc in cell senescence, apoptosis, oxidative stress, and proliferation. This study investigated the effect of resveratrol on concanavalin A (Con A)-induced hepatitis in aged mice and the roles of SIRT1 and p66shc. Aged mice were administrated resveratrol (30 mg/kg orally) seven times at an interval of 12 h before a single intravenous injection of Con A (20 mg/kg). Results showed that the cytokines, TNF-alpha, IL-6, IFN gamma, and MCP-1, as well as infiltration of macrophages, neutrophils, and T lymphocytes in liver were dramatically enhanced in the mice given only Con A. The aged mouse livers showed markedly raised oxidative stress and cell apoptosis. This oxidative stress further aggravated regenerative dysfunction as indicated by the decreased levels of Ki67, PCNA, Cyclin D1, and Cdk2. Conversely, these phenomena were attenuated by pretreatment with resveratrol. Moreover, resveratrol suppressed the elevation of p66shc in the liver by reversing Con-A-mediated downregulation of SIRT1. The findings suggest that resveratrol protected against Con A-induced hepatitis in aged mice by attenuating an aberration of immune response and liver regeneration, partially via the mechanism of SIRT1-mediated repression of p66shc expression. PMID- 28578411 TI - Red cell distribution width as a significant indicator of medication and prognosis in type 2 diabetic patients. AB - Whether red cell distribution width (RDW) can be a potential indicator for diabetic nephropathy (DN) is unknown. A total of 809 type 2 diabetes mellitus (T2D) patients were divided into 4 groups according to the quartiles (Q) of the RDW (%): Q1 <= 12.4 (n = 229), 12.4 < Q2 <= 12.9 (n = 202), 12.9 < Q3 < 13.5 (n = 168), Q4 >= 13.5 (n = 210). Results showed that the levels in Q4 group was higher in age, disease duration, systolic blood pressure, blood urea nitrogen, creatinine, uric acid and proteinuria but lower in hemoglobin, serum albumin and glycosylated hemoglobin compared to Q1 group. Furthermore, the incidences of DN, diabetic peripheral neuropathy, hypertension and coronary heart disease in the Q3 or Q4 group were higher compared to Q1 group. Medications including calcium channel blockers and antiplatelet therapy also showed higher frequencies in Q3 or Q4 group compared to Q1. Logistic regression indicated that the antiplatelet therapy (OR = 2.065), hypertension (OR = 2.819), creatinine (OR = 4.473) and proteinuria (OR = 2.085) were positively associated with level of Q4 group, but higher hemoglobin (OR = 0.021) and serum Ca2+ (OR = 0.178) were negatively associated with Q4. This data suggest that high level of RDW in T2D patients indicates a higher risk and a poor prognosis for DN. PMID- 28578414 TI - A high-throughput assay for quantitative measurement of PCR errors. AB - The accuracy with which DNA polymerase can replicate a template DNA sequence is an extremely important property that can vary by an order of magnitude from one enzyme to another. The rate of nucleotide misincorporation is shaped by multiple factors, including PCR conditions and proofreading capabilities, and proper assessment of polymerase error rate is essential for a wide range of sensitive PCR-based assays. In this paper, we describe a method for studying polymerase errors with exceptional resolution, which combines unique molecular identifier tagging and high-throughput sequencing. Our protocol is less laborious than commonly-used methods, and is also scalable, robust and accurate. In a series of nine PCR assays, we have measured a range of polymerase accuracies that is in line with previous observations. However, we were also able to comprehensively describe individual errors introduced by each polymerase after either 20 PCR cycles or a linear amplification, revealing specific substitution preferences and the diversity of PCR error frequency profiles. We also demonstrate that the detected high-frequency PCR errors are highly recurrent and that the position in the template sequence and polymerase-specific substitution preferences are among the major factors influencing the observed PCR error rate. PMID- 28578415 TI - Modulation of Peptide Based Nano-Assemblies with Electric and Magnetic Fields. AB - Peptide based nano-assemblies with their self-organizing ability has shown lot of promise due to their high degree of thermal and chemical stability, for biomaterial fabrication. Developing an effective way to control the organization of these structures is important for fabricating application-oriented materials at the molecular level. The present study reports the impact of electric and magnetic field-mediated perturbation of the self-assembly phenomenon, upon the chemical and structural properties of diphenylalanine assembly. Our studies show that, electric field effectively arrests aggregation and self-assembly formation, while the molecule is allowed to anneal in the presence of applied electric fields of varying magnitudes, both AC and DC. The electric field exposure also modulated the morphology of the self-assembled structures without affecting the overall chemical constitution of the material. Our results on the modulatory effect of the electric field are in good agreement with theoretical studies based on molecular dynamics reported earlier on amyloid forming molecular systems. Furthermore, we demonstrate that the self-assemblies formed post electric-field exposure, showed difference in their crystal habit. Modulation of nano-level architecture of peptide based model systems with external stimulus, points to a potentially rewarding strategy to re-work proven nano-materials to expand their application spectrum. PMID- 28578412 TI - Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells. AB - Binary enterotoxins Clostridium (C.) botulinum C2 toxin, C. perfringens iota toxin and C. difficile toxin CDT are composed of a transport (B) and a separate non-linked enzyme (A) component. Their B-components mediate endocytic uptake into mammalian cells and subsequently transport of the A-components from acidic endosomes into the cytosol, where the latter ADP-ribosylate G-actin resulting in cell rounding and cell death causing clinical symptoms. Protein folding enzymes, including Hsp90 and peptidyl-prolyl cis/trans isomerases facilitate transport of the A-components across endosomal membranes. Here, we identified Hsp70 as a novel host cell factor specifically interacting with A-components of C2, iota and CDT toxins to facilitate their transport into the cell cytosol. Pharmacological Hsp70 inhibition specifically prevented pH-dependent trans-membrane transport of A components into the cytosol thereby protecting living cells and stem cell-derived human miniguts from intoxication. Thus, Hsp70-inhibition might lead to development of novel therapeutic strategies to treat diseases associated with bacterial ADP-ribosylating toxins. PMID- 28578417 TI - Wide-angle scanning planar array with quasi-hemispherical-pattern elements. AB - A compact quasi-hemispherical-pattern antenna, two linear wide-angle scanning arrays, and a planar wide-angle scanning array are proposed. To increase the field-of-view scanning range of arrays, a compact low-profile antenna with a quasi-hemispherical pattern is introduced firstly. When the ground is infinite, the proposed antenna has a quasi-hemispherical pattern, i.e., an approximately uniform radiation in the upper half space. Afterward, two linear arrays arranged along the length and width of the proposed antenna's radiation patch are presented. The main beams of the two arrays with 16 active elements can scan from less than -75 degrees to more than +75 degrees . When the linear array element number is 128, the maximum scanning angle can reach 86 degrees . At last, a planar array with 16 * 16 active elements is proposed. In two special planes, xz plane and yz plane, the main beams of the planar array can scan from less than 77 degrees to more than +77 degrees with a gain fluctuation less than 5 dB and a maximum side lobe level (SLL) less than -10 dB. An excellent wide-angle scanning performance both in linear and planar arrays can be obtained using the proposed method. PMID- 28578416 TI - Monocyclic beta-lactams loaded on hydroxyapatite: new biomaterials with enhanced antibacterial activity against resistant strains. AB - The development of biomaterials able to act against a wide range of bacteria, including antibiotic resistant bacteria, is of great importance since bacterial colonization is one of the main causes of implant failure. In this work, we explored the possibility to functionalize hydroxyapatite (HA) nanocrystals with some monocyclic N-thio-substituted beta-lactams. To this aim, a series of non polar azetidinones have been synthesized and characterized. The amount of azetidinones loaded on HA could be properly controlled on changing the polarity of the loading solution and it can reach values up to 17 wt%. Data on cumulative release in aqueous solution show different trends which can be related to the lipophilicity of the molecules and can be modulated by suitable groups on the azetidinone. The examined beta-lactams-HA composites display good antibacterial activity against reference Gram-positive and Gram-negative bacteria. However, the results of citotoxicity and antibacterial tests indicate that HA loaded with 4 acetoxy-1-(methylthio)-azetidin-2-one displays the best performance. In fact, this material strongly inhibited the bacterial growth of both methicillin resistant and methicillin susceptible clinical isolates of S. aureus from surgical bone biopsies, showing to be a very good candidate as a new functional biomaterial with enhanced antibacterial activity. PMID- 28578418 TI - One-Step Fabrication of Pyranine Modified- Reduced Graphene Oxide with Ultrafast and Ultrahigh Humidity Response. AB - A facile one-step supramolecular assembly method is adopted to modify reduced graphene oxide (rGO) with functional organic molecule pyranine for achieving comprehensive humidity sensing performance. The fabricated humidity sensor based on pyranine modified-reduced graphene oxide (Pyr-rGO) exhibits excellent sensing performance with ultrafast (<2 s) and ultrahigh response of IL/IH = 6000 as relative humidity (RH) consecutively changes between 11% and 95%; small hysteresis of 8% RH; reliable repeatability and stability. In addition, a detailed mechanism analysis is performed to investigate the difference in water adsorption and ions transfer under various RH levels. Notably, the one-step supramolecular assembly method to prepare Pyr-rGO provides a new insight into developing novel functional humidity sensing materials with enhanced device performance. PMID- 28578420 TI - A decadal analysis of bioeroding sponge cover on the inshore Great Barrier Reef. AB - Decreasing coral cover on the Great Barrier Reef (GBR) may provide opportunities for rapid growth and expansion of other taxa. The bioeroding sponges Cliona spp. are strong competitors for space and may take advantage of coral bleaching, damage, and mortality. Benthic surveys of the inshore GBR (2005-2014) revealed that the percent cover of the most abundant bioeroding sponge species, Cliona orientalis, has not increased. However, considerable variation in C. orientalis cover, and change in cover over time, was evident between survey locations. We assessed whether biotic or environmental characteristics were associated with variation in C. orientalis distribution and abundance. The proportion of fine particles in the sediments was negatively associated with the presence-absence and the percent cover of C. orientalis, indicating that the sponge requires exposed habitat. The cover of corals and other sponges explained little variation in C. orientalis cover or distribution. The fastest increases in C. orientalis cover coincided with the lowest macroalgal cover and chlorophyll a concentration, highlighting the importance of macroalgal competition and local environmental conditions for this bioeroding sponge. Given the observed distribution and habitat preferences of C. orientalis, bioeroding sponges likely represent site specific - rather than regional - threats to corals and reef accretion. PMID- 28578421 TI - Aetiology and Outcomes of Suspected Infections of the Central Nervous System in Children in Mbarara, Uganda. AB - Infections of the central nervous system (CNS) are severe conditions, leading to neurological sequelae or death. Knowledge of the causative agents is essential to develop guidelines for case management in resource-limited settings. Between August 2009 and October 2012, we conducted a prospective descriptive study of the aetiology of suspected CNS infections in children two months to 12 years old, with fever and at least one sign of CNS involvement in Mbarara Hospital, Uganda. Children were clinically evaluated on admission and discharge, and followed-up for 6 months for neurological sequelae. Pathogens were identified from cerebrospinal fluid (CSF) and blood using microbiological and molecular methods. We enrolled 459 children. Plasmodium falciparum (36.2%) and bacteria in CSF (13.3%) or blood (3.3%) were the most detected pathogens. Viruses were found in 27 (5.9%) children. No pathogen was isolated in 207 (45.1%) children. Patterns varied by age and HIV status. Eighty-three (18.1%) children died during hospitalisation, and 23 (5.0%) during follow-up. Forty-one (13.5%) children had neurological sequelae at the last visit. While malaria remains the main aetiology in children with suspected CNS infections, no pathogen was isolated in many children. The high mortality and high rate of neurological sequelae highlight the need for efficient diagnosis. PMID- 28578422 TI - Three-Dimensional Anisotropic Metamaterials as Triaxial Optical Inclinometers. AB - Split-ring resonators (SRRs) present an attractive avenue for the development of micro/nano scale inclinometers for applications like medical microbots, military hardware, and nanosatellite systems. However, the 180 degrees isotropy of their two-dimensional structure presents a major hurdle. In this paper, we present the design of a three-dimensional (3D) anisotropic SRR functioning as a microscale inclinometer enabling it to remotely sense rotations from 0 degrees to 360 degrees along all three axes (X, Y, and Z), by employing the geometric property of a 3D structure. The completely polymeric composition of the cubic structure renders it transparent to the Terahertz (THz) light, providing a transmission response of the tilted SRRs patterned on its surface that is free of any distortion, coupling, and does not converge to a single point for two different angular positions. Fabrication, simulation, and measurement data have been presented to demonstrate the superior performance of the 3D micro devices. PMID- 28578423 TI - Chicken IFN Kappa: A Novel Cytokine with Antiviral Activities. AB - Interferons (IFNs) are essential components of the host innate immune system and define first-line of defence against pathogens. In mammals, several type I IFNs are identified, however, only limited data is available on the repertoire of IFNs in avian species. Here we report the characterization of chicken IFN-kappa (chIFN kappa) near the type I IFN locus on the sex-determining Z chromosome. Genetic, evolutionary and syntenic analyses indicate that chIFN-kappa is a type I IFN with conserved genetic features and promoter binding sites. chIFN-kappa regulated the IFN-stimulated response element signalling pathways and activated a panel of IFN regulated genes, antiviral mediators and transcriptional regulators. Priming of chicken primary fibroblasts and tracheal organ cultures with chIFN-kappa imparted cellular protections against viral infections both in vitro and ex vivo. To determine whether chIFN-kappa defines the antiviral state in developing chicken embryos, we used replication-competent retroviral RCAS vector system to generate transgenic chicken embryos that constitutively and stably expressed chIFN-kappa. We could demonstrate that chIFN-kappa markedly inhibited the replication of avian RNA viruses in ovo. Collectively, these results shed the light on the repertoire of IFNs in avian species and provide functional data on the interaction of the chIFN-kappa with RNA viruses of poultry and public health importance. PMID- 28578424 TI - Aminophylline restores glucocorticoid sensitivity in a guinea pig model of sudden sensorineural hearing loss induced by lipopolysaccharide. AB - Glucocorticoids have been used to treat hearing loss and vestibular dysfunction for many years. However, some reports have indicated that a subset of patients with these disorders exhibit glucocorticoid insensitivity or resistance. A reduction in histone deacetylase 2 (HDAC2) activity and expression has been reported to play a critical role in glucocorticoid resistance. Here, we investigated the protective effects of aminophylline on HDAC2 expression and glucocorticoid sensitivity in lipopolysaccharide (LPS)-induced sudden sensorineural hearing loss in guinea pigs. We assessed hearing recovery in LPS applied guinea pigs, which were either left untreated or were systemically treated with either dexamethasone, aminophylline, or a combination of the two. We utilized fluorescence microscopy and enzyme-linked immunosorbent assay to analyze the distribution patterns of HDAC2 and detect its levels in the cochlea. We used hematoxylin-eosin staining to examine cochlear histopathological changes. In the absence of treatment, significant hearing loss was detected in LPS-exposed animals. A synergistic effect was observed between aminophylline and dexamethasone in maintaining HDAC2 expression levels, preventing hearing loss in LPS-exposed animals and reducing cochlear damage. This study indicates that aminophylline can restore glucocorticoid sensitivity, which provides a new approach to treating patients with hearing disorders who are refractory to glucocorticoids. PMID- 28578425 TI - Lethal effect of blue light on strawberry leaf beetle, Galerucella grisescens (Coleoptera: Chrysomelidae). AB - In a previous study, we found that blue-light irradiation kills insects such as fruit flies, mosquitos, and flour beetles. However, the lethal effects of blue light on coleopteran field crop pests have not been investigated. Chrysomelidae, a major family in phytophagous beetles, includes many species of crop pests. We investigated the lethal effect of blue light on chrysomelid beetles by examining the mortality of the strawberry leaf beetle Galerucella grisescens irradiated with different wavelengths of blue light during the non-mobile egg or pupal stage by using light-emitting diodes. Fifty to seventy percent of beetles irradiated with 407, 417, 438, or 465-nm lights at 15 * 1018 photons.m-2.s-1 during the egg stage died before hatching; ca. 90% of hatchlings irradiated with 438-nm light during the egg stage died before eclosion; and 35-55% of beetles irradiated with 407, 417, 454, and 465-nm lights at the same intensity during the pupal stage died before eclosion. Field crop pests are considered to have high tolerance to blue light because they are usually exposed to sunlight in their natural habitats. However, this study suggests that blue light can kill some field crop as well as household insect pests. PMID- 28578427 TI - Influences of glutamine administration on response selection and sequence learning: a randomized-controlled trial. AB - Precursors of neurotransmitters are increasingly often investigated as potential, easily-accessible methods of neuromodulation. However, the amino-acid glutamine, precursor to the brain's main excitatory and inhibitory neurotransmitters glutamate and GABA, remains notably little investigated. The current double blind, randomized, placebo-controlled study provides first evidence 2.0 g glutamine administration in healthy adults affects response selection but not motor sequence learning in a serial reaction time task. Specifically, glutamine increased response selection errors when the current target response required a different hand than the directly preceding target response, which might indicate enhanced cortical excitability via a presumed increase in glutamate levels. These results suggest glutamine can alter cortical excitability but, despite the critical roles of glutamate and GABA in motor learning, at its current dose glutamine does not affect sequence learning. PMID- 28578428 TI - Surface modification of polyvinylidene fluoride (PVDF) membrane via radiation grafting: novel mechanisms underlying the interesting enhanced membrane performance. AB - This study provided the first attempt of grafting hydrophobic polyvinylidene fluoride (PVDF) membrane with hydrophilic hydroxyethyl acrylate (HEA) monomer via a radiation grafting method. This grafted membrane showed an enhanced hydrophilicity (10 degrees decrease of water contact angle), water content ratio, settling ability and wettability compared to the control membrane. Interestingly, filtration tests showed an improved dependence of water flux of the grafted membrane on the solution pH in the acidic stage. Atomic force microscopy (AFM) analysis provided in-situ evidence that the reduced surface pore size of the grafted membrane with the solution pH governed such a dependence. It was proposed that, the reduced surface pore size was caused by the swelling of the grafted chain matrix, with the pH increase due to the chemical potential change. It was found that the grafted membrane showed a lower relative flux decreasing rate than the control membrane. Moreover, flux of the bovine serum albumin (BSA) solution was noticeably larger than that of pure water for the grafted membrane. Higher BSA flux than water flux can be explained by the effects of electric double layer compression on the polymeric swelling. This study not only provided a pH-sensitive PVDF membrane potentially useful for various applications, but also proposed novel mechanisms underlying the enhanced performance of the grafted membrane. PMID- 28578426 TI - Prevalence of chronic kidney disease markers: Evidence from a three-million married population with fertility desire in rural China. AB - We aimed to assess the prevalence of chronic kidney diseases (CKD) markers among the married residents with fertility desire in rural China. Demographic and clinical data were collected from the National Free Pre-Conception Health Examination Project. Estimated glomerular filtration rate (eGFR) < 60 mL/min//1.73 m2, proteinuria, and hematuria were defined as markers of CKD. GFR was evaluated by using serum creatinine level and the Asian-modified CKD epidemiology collaboration equation. Automated urine dry chemical and microscopic analyses were employed to identify proteinuria and hematuria. The prevalence of CKD markers was 2.92% in the 3,091,379 participants. eGFR < 60 mL/min//1.73 m2, hematuria and proteinuria was observed in 0.85%, 1.41% and 0.71%, respectively. The prevalence of CKD markers varied greatly across different geographical locations, which was the highest in the Eastern Region (3.86%; 95% confidence interval [CI]: 3.81-3.91%), moderate in the Central Region (2.80%; 95% CI: 2.77 2.82%), and lowest in the Western Region (2.62%; 95% CI: 2.59-2.65%). Hypertension, obesity, positive hepatitis B virus surface antigen (HBsAg), age (increased by every 5 years), female gender, and living area were potential risk factors for CKD. In rural China, the prevalence of CKD markers in the married couples with fertility desire is low. PMID- 28578429 TI - A Potential Role of Esophageal Cancer Related Gene-4 for Atrial Fibrillation. AB - Epidemiological studies have shown a strong correlation between tumor and AF. However, the molecular link between tumor and AF remains unknown. ECRG4, a tumor suppressor gene that is expressed in the A-V node and in sporadic ventricular myocytes, inhibits tumorigenesis and monitors tissue homeostasis by functioning as a 'sentinel' molecule gauging inflammatory and cell proliferative responses. To explore the potential physiological function of Ecrg4 in heart, we evaluated its distribution in heart, analyzed its expression in patients with persistent AF and in a canine AF model, and dissected the molecular events downstream of Ecrg4. The results showed that the level of Ecrg4 expression is homogenously high in atria and the conduction systems and in sporadic ventricular myocytes. Importantly, the expression of Ecrg4 was significantly decreased in atrial appendages of AF patients than patients with SR. Moreover, in rapid pacing canine AF models, the expression of ECRG4 in atria was significantly decreased compared to that of the controls. Mechanistically, knockdown ECRG4 in atrial myocytes significantly shortened the APDs, inhibited the expression of Gja1, and activated pro-inflammatory cascades and genes involved in cardiac remodeling. These results suggest that Ecrg4 may play a critical role in the pathogenesis of AF. PMID- 28578430 TI - Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord. AB - Increased evidence suggests that dysregulation of cholesterol metabolism may be a key event contributing to progression of multiple sclerosis (MS). Using an experimental autoimmune encephalomyelitis (EAE) model of MS we revealed specific changes in the mRNA and protein expression of key molecules involved in the maintaining of cholesterol homeostasis in the rat spinal cord: 3-hydroxy-3 methylglutaryl-coenzyme-A reductase (HMGCR), apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46A1) during the course of disease. The presence of myelin lipid debris was seen only at the peak of EAE in demyelination loci being efficiently removed during the recovery period. Since CYP46A1 is responsible for removal of cholesterol excess, we performed a detailed profiling of CYP46A1 expression and revealed regional and temporal specificities in its distribution. Double immunofluorescence staining demonstrated CYP46A1 localization with neurons, infiltrated macrophages, microglia and astrocytes in the areas of demyelination, suggesting that these cells play a role in cholesterol turnover in EAE. We propose that alterations in the regulation of cholesterol metabolism at the onset and peak of EAE may add to the progression of disease, while during the recovery period may have beneficial effects contributing to the regeneration of myelin sheath and restoration of neuronal function. PMID- 28578431 TI - Antibodies against a beta-glucan-protein complex of Candida albicans and its potential as indicator of protective immunity in candidemic patients. AB - Sera from candidemic and non-candidemic subjects were examined for antibodies against the cell wall beta1,3- and beta1,6-glucans, as well as the beta-glucan associated protein MP65 of Candida species. Although antibodies against each of the above components were detected in all subjects, candidemic patients had lower antibody titers against beta1,3-glucan, but higher antibody titers against beta1,6-glucan and MP65, than non-candidemic subjects. The elevated levels of anti-beta1,6-glucan and -MP65 antibodies found in candidemic patients were independent on the patient risk category, APACHE II score, presence of co morbidities, beta1,3-glucanemia level, Candida isolate, and antifungal treatment. Interestingly, however, the anti-MP65, but not the anti-beta1,6-glucan antibodies, of candidemic patients had higher titers in survivors than in non survivors, particularly in those subject categories with the highest mortality (>65-years old, diabetic, or septic shock patients). Thus, candidemic patients are capable of boosting anti-Candida immune responses upon infection, and some of these responses might be associated to the generation of protective immunity in patients with candidemia. PMID- 28578433 TI - Pelvic Floor Reconstruction After Radical Prostatectomy: A Systematic Review and Meta-analysis of Different Surgical Techniques. AB - Radical prostatectomy (RP) is the gold standard for the treatment of localized PCa. A meta-analysis was conducted to evaluate the effect of different techniques of pelvic floor reconstruction on urinary continence. A comprehensive search was made for trials that evaluated the efficacy of pelvic floor reconstruction. Relevant databases included PubMed, Embase, Cochrane, Ovid, Web of Science databases and relevant trials from the references. Random-effects model was used to estimate risk ratios (RRs) statistics. Pooled results of patients treated with posterior reconstruction (PR) demonstrated complete urinary continence improved at 1-4, 28-42, 90, 180 and 360 days following catheter removal. Anterior suspension (AS) was associated with improvement only at 28-42 days. The anterior reconstruction (AR) + PR was associated with urinary continence at 1-4, 90 and 180 days. AS + PR was not associated with any benefit. And PR improved social urinary continence at 7-14 and 28-42 days. No benefit was associated with AS. AR + PR had better outcomes at 90 and 180 days. AS + PR was significant improved at 28-42 and 90 days. Patients who underwent RP and PR had the least urinary incontinence. No significant benefit was observed after AS. AR + PR and AS + PR had little benefit in the post-operative period. PMID- 28578434 TI - Artificial enamel induced by phase transformation of amorphous nanoparticles. AB - Human tooth enamel has tightly packed c-axis-oriented hydroxyapatite (HAP: Ca10(PO4)6(OH)2) nanorods with high elastic modulus. Fabrication of an enamel architecture in vitro supports the repair of teeth using HAP; however, existing methods require complex and laborious steps to form an enamel-like structure. Here we present a very simple and effective technique for forming artificial enamel in near-physiological solution using a substrate composed of amorphous calcium phosphate (ACP) nanoparticles. Without any functionalized modification of the substrate surface, faint dissolution and successive phase transformation automatically induce formation of an intermediate layer of low-crystalline HAP nanoparticles, on which highly oriented HAP nanorods grow by geometrical selection. We also show that an enamel structure forms on a substrate of amorphous calcium carbonate when the surface nanoparticles react so as to form an intermediate layer similar to that in ACP. Our results demonstrate that there is a wide range of substrate choices for nanorod array formation. Contrary to current understanding, a stable surface designed in nanoscale is not essential for the growth of arranged guest crystals. Reactive amorphous nanoparticles and their transformation efficiently induce a nanorod array structure. PMID- 28578435 TI - High serum uric acid levels may increase mortality and major adverse cardiovascular events in patients with acute myocardial infarction. AB - OBJECTIVES: To determine the validity of uric acid as a potential prognostic marker for long-term outcomes of patients with acute myocardial infarction (AMI) and those with AMI undergoing percutaneous coronary intervention (PCI). Methods: Systematic review and meta-analysis were performed. We retrieved data from retrospective and prospective cohort studies that investigated whether serum uric acid (SUA) level affects the prognosis of patients with AMI. RESULTS: Thirteen studies involving 9371 patients were included. High serum uric acid (HSUA) level increased mid/long-term mortality (risk ratio (RR)=2.32, 95% confidence intervals (CI): 2.00-2.70) and had higher short-term mortality (RR=3.09, 95% CI: 2.58 3.71), higher mid/long-term major adverse cardiovascular events (MACE) risk (RR=1.70, 95% CI: 1.54-1.88), and higher short-term MACE risk (RR=2.47, 95% CI: 2.08-2.92) for patients with AMI. In the PCI subgroup, the HSUA level also increased mid/long-term mortality (RR=2.33, 95% CI: 1.89 to 2.87) and had higher mid/long-term MACE risk (RR=1.64, 95% CI: 1.48-1.82), and higher short-term MACE risk (RR 2.43, 95% CI: 2.02-2.93) for patients who were treated with PCI after AMI. Particularly in the PCI subgroup, a higher short-term mortality (RR=6.70, 95% CI: 3.14-14.31) was presented in the group with lower HSUA cut-off level, and the mortality was higher than the group with higher HSUA cut-off level (RR=2.69, 95% CI: 2.09-3.46). Conclusion: The HSUA level significantly increased the mortality and MACE risk of patients with AMI. Mild elevation of SUA levels (normal range) have started to have a significant impact on the short-term mortality of patients who underwent PCI, and has not received the attention of previous studies. However, this condition should be further investigated. PMID- 28578436 TI - Gonadotropin-releasing hormone agonist triggering with concomitant administration of low doses of human chorionic gonadotropin or a freeze-all strategy in high responders. AB - OBJECTIVES: To compare the live birth rates and moderate/severe ovarian hyperstimulation syndrome (OHSS) rates of 2 different approaches using gonadotropin-releasing hormone (GnRH) agonist triggering in high responder women. Methods: A retrospective cohort study was performed to evaluate intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) outcomes in high responder women who underwent ovulation induction with a GnRH antagonist protocol between April 2011 and March 2015. In group 1 (n=74), GnRH agonist was used for ovulation triggering with the concomitant use of 1500 IU of urinary human chorionic gonadotropin (hCG) immediately after oocyte retrieval followed by fresh ET and standard luteal support. In group 2 (n=48), GnRH agonist was used for triggering after freezing all embryos and subsequent frozen/thawed embryo transfer (FET); this approach is considered the "freeze-all" approach. Results: Baseline characteristics were similar between the groups. The clinical pregnancy rates for group 1 was 45.9% and group 2 was 43.8% (p=0.812, chi-squared test) and live birth rates for group 1 was 40.5% and for group 2 41.7% (p=0.902, chi-squared test) were comparable between groups. In group 1, late-onset OHSS was observed (one severe case and one moderate case) in 2 patients (2.7%). In group 2, none of the patients experienced moderate/severe OHSS. Conclusion: The live birth rate with GnRH agonist triggering and concomitant use of 1500 IU of hCG immediately after oocyte retrieval was similar to that obtained with the freeze-all approach and FET in a subsequent cycle. The administration of a low dose of hCG in GnRH agonist trigger cycles caused moderate/severe OHSS in 2.7% of the patients. PMID- 28578437 TI - Clinical value of combining transvaginal contrast-enhanced ultrasonography with serum human epididymisprotein-4 and the resistance index for early-stage epithelial ovarian cancer. AB - OBJECTIVES: To increase accuracy of the detection and differential diagnosis of the early epithelial ovarian cancer (EOC) with transvaginal contrast-enhanced ultrasonography (TVCEUS) combining serum human epididymisprotein 4 (HE4), and resistance index (RI). Methods: This retrospectively case-control study of 230 patients with ovarian tumors were reviewed at the Department of Gynecology and Obstetrics, Zhongnan Hospital, Wuhan University, Wuhan, China between June 2008 and September 2015. Before the operation of 110 cases with EOC (Group A) and 120 cases of patients with benign ovarian tumor (Group B), we observe and calculate both Groups' tumor vascular contrast-enhanced ultrasonography morphology scores (U), time-intensity curve (TIC) of contrast-enhanced ultrasonography, HE4, and RI. Results were compared with the histopathological analysis results. Results: The ultrasonography morphology scores, peak intensity (PI) enhancement rate (ER) with the parameters of the TIC and HE4 are higher in Group A compared with patients in Group B and the RI was lower than Group B. The detection rates for all indexes in the benign and malignant groups and their comparisons to the histopathological results were determined. The detection rate differences for HE4 (p=0.001), RI (p=0.001), U (p=0.001), PI (p=0.001), and ER (p=0.001) were all statistically significant (p less than 0.05). Conclusion: The high clinical value through combined TVCEUS, HE4, and RI detection can increase the sensitivity of the diagnosis and differential diagnosis of the early EOC. PMID- 28578438 TI - Predictors of blood transfusion following total knee replacement at a tertiary care center in Central Saudi Arabia. AB - OBJECTIVES: To examine the incidence and predictors of blood transfusion following total knee replacement (TKR). Methods: A retrospective study on 462 patients of primary TKR at National Guard Hospital, Riyadh, Kingdom of Saudi Arabia. Descriptive statistics were compared by blood transfusion status and significant variables were further included in the multivariable model. Results: Overall transfusion rate following TKR was 35.3%. Regression analyses identified bilateral surgery, low preoperative hemoglobin (Hb) level, and high amount of blood loss as predictors of blood transfusion. Conclusion: Correction of Hb level prior to surgery, careful hemostasis, and avoiding bilateral surgery may reduce the rate of blood transfusion following TKR. PMID- 28578439 TI - Long-term use of bisphosphonates in osteoporosis. AB - OBJECTIVES: To report and describe the management and response to treatment of patients referred to the osteoporosis clinic after prolonged use of bisphosphonate BPs) (4 years and more) with and without new fracture (any site) or any other new skeletal symptoms. Methods: This is a single center observational retrospective cohort study conducted from January 2009 to May 2016 in a tertiary center. We describe cause of referral, X-rays findings, management, and response to treatment. Results: Thirty-four patients, aged 46-89 years, were collected. Reason for referral included review of therapy (11 patients), recent low trauma fracture (21 patients), or chronic severe thigh pain (2 patients) of unknown etiology. All patients with fracture or thigh pain (23/34 patients) were treated with teriparatide 20 mcg daily. Sixteen of them (16/23) completed teriparatide course (18-24 months), 11 patients had complete healing of fracture at the end of the course, and 5 remained with nonunion of fracture, the remaining 5 patients were lost to follow up. Conclusion: Prolonged use of bisphosphonates can lead to atypical femoral fracture that may involve sites other than femoral shaft or rarely chronic thigh pain without fracture. Teriparatide may facilitates fracture healing and improve thigh pain. PMID- 28578440 TI - Adherence to surviving sepsis guidelines among pediatric intensivists. A national survey. AB - OBJECTIVES: To assess the compliance with the 2006 American College of Critical Care-Pediatric Advanced Life Support (ACCM-PALS) guidelines for sepsis management, and the 2012 surviving sepsis campaign (SSC), for the management of pediatric patients with sepsis and to identify the main barriers to adherence to these guidelines. Methods: In November 2015, a prospective cohort study in which a web based electronic survey using a case scenario to explore the usual management of a child with severe sepsis was designed and sent to all consultant pediatric intensivists practicing in Kingdom of Saudi Arabia (KSA). Adherences to 2012 SSC guidelines and to 4 algorithmic time-specific goals outlined in the ACCM PALS guidelines were measured. Results: Sixty-one (76%) of 80 consultant pediatric intensivists working in KSA responded to the survey. Of the 61 respondents, 94% reported administering antibiotics within one hour of the child presentation, 98% reported starting resuscitation by giving fluid boluses, 93% reported starting vasopressor if the patient remained hypotensive despite fluid resuscitation, and 86% reported they would start hydrocortisone in case of catecholamine refractory shock. In total, 80% of the intensivists reported full adherence to all of the 4 components in the ACCM-PALS bundle; 50% reported that the absence of a locally written protocol was the main barrier to adherence to the SSC guidelines. Conclusion: Pediatric intensivists reported good adherence to the 2006 ACCM-PALS guidelines and 2012 SSC guidelines with some variability in interpretation of the recommendations. The absence of a written protocol was the main reported barrier to adherence to these guidelines. PMID- 28578442 TI - Depression and anxiety among hypertensive and diabetic primary health care patients. Could patients' perception of their diseases control be used as a screening tool? AB - OBJECTIVES: To measure the frequency and identify risk factors of depression and anxiety among diabetic and hypertensive primary health care (PHC) patients. Also to assess whether patients' perception of their chronic diseases control and sleep disturbance could serve as screening tools for depression and anxiety. Methods: This cross-sectional study of 368 PHC patients was conducted in AlKhobar city, Kingdom of Saudi Arabia between April and May 2015. Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 were used as diagnostic tools for depression and anxiety. Results: Frequencies, cross-tabulations and logistic regression tests were performed. Patient's perception of chronic diseases control was significantly associated with the presence of depression and anxiety, while it was not seen in the tested disease control (glycated hemoglobin less than 7% and blood pressure less than 140/90 mm Hg). Sleep disturbance has a high specificity (98.9%) in screening for depression. Overall prevalence of depression or anxiety was 57.3% and detected cases was 23%. Depression comprise 48.7% (39.8% mild, 7.1% moderate, 1.8% severe). Anxiety comprise 38.4% (25.1% mild, 8.8% moderate, 4.4% severe). Co-existence of both disorders was 29.5%. Sleep disturbance, weight change, and low income had an independent significant effect on depression and anxiety. Conclusion: Having no sleep disturbance can rule out 98.9% of depression and anxiety cases. Patient's feelings should be considered in chronic diseases health care plans. Depression or anxiety among diabetic and hypertensive patients have a high morbidity, but with low detection rate. PMID- 28578441 TI - Prevalence of obstructive sleep apnea in children with sickle cell disease at a tertiary hospital in Saudi Arabia. AB - OBJECTIVES: To assess the prevalence of obstructive sleep apnea in Saudi children with sickle cell disease at a tertiary hospital in Kingdom of Saudi Arabia (KSA) using nocturnal polysomnography. Methods: A prospective cross-section study was conducted between 2012 and 2016 in 65 children aged between 2-14 years at Prince Sultan Military Medical City, Riyadh, KSA with sickle cell disease. Patients answered a pediatric sleep questionnaire with the help of an accompanying caregiver and underwent polysomnography in the same night. Results: The final sample included 65 children. Median age was 8.1 years. There were 32 boys (49.2%) and 33 girls (50.8%). Mean hemoglobin was 8.6 (p=0.37) and mean body mass index was 15.6 (p=0.36). The prevalence of obstructive sleep apnea was 80% (52 patients) using an apnea hypopnea index cutoff of >=1 and 7.7% (5 patients) using an apnea hypopnea index cutoff of >=5. Results from the pediatric sleep questionnaire were snoring (73.8%), apnea (32.8%), and bedwetting (46%). Conclusion: Obstructive sleep apnea is common in children with sickle cell disease. PMID- 28578443 TI - Learning environment of the Saudi psychiatry board training program. AB - OBJECTIVES: To assess the learning environment of the Saudi psychiatry board program using the Dutch Residency Educational Climate Test (D-RECT) and to explore residents' perception of different domains of the learning environment. Methods: This was a descriptive cross-sectional study. The D-RECT instrument was distributed to all residents at all training sites of the Saudi psychiatry training program. It is a reliable and valid instrument to measure educational environment at the postgraduate level. Mean scores are presented, t-tests, analysis of variance, and post hoc analysis were used to compare subgroups and pearson's correlation was used to assess relationships. Results: Seventy-eight out of 96 residents responded (81.25%), one third of them were female. Overall D RECT score was 2.76+/-0.55. The supervision subscale scored 2.83+/-0.83, coaching and assessment scored 2.60+/-0.73, feedback scored 2.00+/-0.85, team work scored 2.81+/-0.86, peer collaboration scored 3.54+/-0.84, professional relations between consultants scored 2.71+/-0.95, work is adapted to residents' competence scored 2.71+/-0.86, consultants' attitudes scored 2.71+/-0.86, formal education scored 2.68+/-0.72, and patient handover subscales scored 3.25+/-1.06. Female residents scored significantly higher than their male counterparts and there were no statistical significant difference between years of residency. Cronbach's alpha was 0.936. Conclusion: Most of the learning climate domains scored poorly, which necessitates a rigorous plan for reevaluation and improvement. Furthermore, D-RECT proved to be a reliable instrument and could help in evaluation and improvement of postgraduate training programs. PMID- 28578444 TI - Development of a Saudi Food Frequency Questionnaire and testing its reliability and validity. AB - OBJECTIVES: To create a food frequency questionnaire specifically designed to capture the dietary habits of Saudis and test its validity and reliability. Methods: This investigation is a longitudinal, test-retest study conducted in King Saud University, Riyadh, Kingdom of Saudi Arabia between December 2015 and March 2016. A list of 140 food items was included in the questionnaire where a closed-ended and open-ended approach was used. Regarding past year food frequency consumption and 24 hours dietary recall, body weight and height were collected. Internal consistency, test-retest reliability, completeness of the food list, and criterion validity were assessed. Results: One-hundred and thirty eight participants were interviewed to complete the 24 hours dietary recall and the constructed questionnaire. Approximately 85% of the food items reported in the dietary recall were covered in the food frequency questionnaire. The association of body mass index with meats (regression coefficients: 2.28) and dairy products consumption frequency was statistically significant (regression coefficients: 2.31). A high overall reproducibility rate of the questionnaire was detected (Pearsons' correlation coefficient: 0.78 p less than 0.001). Conclusion: The developed questionnaire has a high reliability and reasonable validity, and suitable for use in nutritional epidemiological investigations in Saudi Arabia. PMID- 28578445 TI - Knowledge of health insurance benefits among male expatriates in Saudi Arabia. AB - OBJECTIVES: To measure expatriates' knowledge of health insurance benefits with respect to outpatient, inpatient, prescription drug, and dental services, and to link this knowledge to sociodemographic and employment characteristic. Methods: Cross-sectional, face-to-face interviews were conducted from March 2015 to February 2016 with a stratified random sample of 3,398 male insured expatriate workers in the private sector of Riyadh, Kingdom of Saudi Arabia. Descriptive analysis, one-way ANOVA, and linear regression were used to interpret data. Data on knowledge of health insurance benefits was compiled by adding the scores of the 4 service category items (outpatient, inpatient, prescription drug, and dental services) to those of the 5 objective knowledge items on copayments. Results: More than 87% of the participants reported knowledge on their health insurance benefits coverage for outpatient, 62% for the inpatient, 86% for the prescription drug and 62% for the dental services. However, 7.5% knew the correct copayments for general practitioner, 64% for the outpatient (inclusive), 13% for the inpatient visits, 15% for the prescription drugs and 9.6% for the dental care. Most personal and job characteristics had associations with knowledge measures. A total of 55% of the overall knowledge variance was explained by the independent variables (R2=0.55), suggesting that other factors also influence knowledge. Conclusion: Expatriates' knowledge of their health insurance benefits is very limited, which indicates the importance of developing a policy for increasing this knowledge among expatriates in Saudi Arabia. PMID- 28578446 TI - Unilateral adrenal infarction in pregnancy secondary to elevated factor VIII. AB - Adrenal infarction in pregnancy is an extremely rare event. We report a case of a 29-year-old pregnant woman at the twenty-fourth week of gestation that presented with an acute episode of severe localized right upper quadrant pain. Her preliminary blood investigations and abdominal ultrasonography were essentially unremarkable. A diagnosis of right adrenal infarction was subsequently established on the basis of a non-enhanced swollen right adrenal gland on CT scanning of the abdomen with contrast, consistent with the clinical presentation. She was treated with subcutaneous low molecular weight heparin (LMWH) until 2 weeks postpartum. A thrombophilia screen post-partum revealed a significantly elevated factor VIII level and a hypercoagulable state that justified prolonged anticoagulation. This case highlights the importance of a high index of suspicion for adrenal infarction in pregnancy on the clinical grounds of otherwise unexplained acute abdominal pain accompanied by suggestive radiological findings, especially in the presence of thrombophilia. PMID- 28578447 TI - Maternal and neonatal outcomes in twin and triplet gestations in Western Saudi Arabia. AB - OBJECTIVES: Tocompare maternal and neonatal complications in twin and triplet gestations at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Methods: Retrospective medical records of 165 women with 144 twin and 21 triplet pregnancies from 2004 to 2011 were analyzed. Comparisons were carried out for maternal complications, gestational age at birth, neonatal birth weight, and neonatal intensive care admission. Results: Most common complications were preterm birth (49%), gestational diabetes mellitus (13.3%), and premature rupture of membrane (4.8%). All triplet pregnancies and 42% twin pregnancies terminated in preterm birth. Gestational length was longer (p less than 0.001) in twin births (36.0 +/- 3.05 weeks) than for triplet births (32 +/- 3.81 weeks). Rates for in vitro fertilization, ovulation induction, and cesareans were higher in women with triplets than in those with twins. Neonatal intensive care unit (NICU) admission was higher (p less than 0.001) for triplets (76.2%) than for twins (23.6%). The mean weight of twins was 2333.83 +/- 558.69 grams and triplets was 1553.41 +/- 569.73 grams. Hyaline membrane disease, neonatal jaundice, and neonatal sepsis were most common neonatal complications. Conclusion: Neonates from triplet pregnancies were preterm, had low birth weight and needed more often NICU admission in comparison to those from twin pregnancies. PMID- 28578449 TI - A profile of out-of-hospital cardiac arrests in Northern Emirates, United Arab Emirates. AB - [No Abstract Available]. PMID- 28578448 TI - Topical corticosteroids knowledge, attitudes, and practices of primary care physicians. AB - OBJECTIVES: To assess knowledge, attitudes, and practices of primary care physicians (PCPs) toward topical corticosteroids (TCs). Methods: A cross sectional, 53-item questionnaire based study on TCs was conducted among PCPs in Riyadh, Kingdom of Saudi Arabia between January and March 2015. A maximum score of 30 was calculated for the knowledge portion. Results: Out of 420 PCPs, 336 responded (80%). Most participants (89.6%) reported prescribing TCs. The mean knowledge score was 17.14 (SD=5.48). Only 39% PCPs correctly identified that there are 7 or 4 TCs potency groups (2 different classification systems). The MBBS/MD and diploma-certified physicians scored lower than board-qualified PCPs (p less than 0.05). Family medicine physicians scored higher than general practitioners (GPs) (p less than 0.05). Hospital-based PCPs scored better than private practice PCPs (p less than 0.05). Moreover, those who felt somewhat comfortable (32.5%) in treating dermatology patients were more knowledgeable (p less than 0.05). Lastly, 76.5% of physicians were interested in attending courses on dermatologic therapies. Conclusion: Knowledge of TCs among PCPs was inadequate. Targeted educational interventions delivered by dermatologists are recommended. PMID- 28578450 TI - Serologic evidence of Toxoplasma gondii infection among cancer patients. A prospective study from Qassim region, Saudi Arabia. AB - [No Abstract Available]. PMID- 28578451 TI - Erratum to: Global skin colour prediction from DNA. PMID- 28578452 TI - Multilevel mutation-selection systems and set-valued duals. AB - A class of measure-valued processes which model multilevel multitype populations undergoing mutation, selection, genetic drift and spatial migration is considered. We investigate the qualitative behaviour of models with multilevel selection and the interaction between the different levels of selection. The basic tools in our analysis include the martingale problem formulation for measure-valued processes and a generalization of the function-valued and set valued dual representations introduced in Dawson-Greven (Spatial Fleming-Viot models with selection and mutation. Lecture notes in mathematics, vol 2092. Springer, Cham, 2014). The dual is a powerful tool for the analysis of the long time behaviour of these processes and the study of evolutionary systems which model phenomena including altruism, the emergence of cooperation and more complex interactions. PMID- 28578453 TI - Prenatal care: associations with prenatal depressive symptoms and social support in low-income urban women. AB - We examined associations of depressive symptoms and social support with late and inadequate prenatal care in a low-income urban population. The sample was prenatal care patients at five community health centers. Measures of depressive symptoms, social support, and covariates were collected at prenatal care entry. Prenatal care entry and adequacy came from birth certificates. We examined outcomes of late prenatal care and less than adequate care in multivariable models. Among 2341 study participants, 16% had elevated depressive symptoms, 70% had moderate/poor social support, 21% had no/low partner support, 37% had late prenatal care, and 29% had less than adequate prenatal care. Women with both no/low partner support and elevated depressive symptoms were at highest risk of late care (AOR 1.85, CI 1.31, 2.60, p < 0.001) compared to women with both good partner support and low depressive symptoms. Those with good partner support and elevated depressive symptoms were less likely to have late care (AOR 0.74, CI 0.54, 1.10, p = 0.051). Women with moderate/high depressive symptoms were less likely to experience less than adequate care compared to women with low symptoms (AOR 0.73, CI 0.56, 0.96, p = 0.022). Social support and partner support were negatively associated with indices of prenatal care use. Partner support was identified as protective for women with depressive symptoms with regard to late care. Study findings support public health initiatives focused on promoting models of care that address preconception and reproductive life planning. Practice-based implications include possible screening for social support and depression in preconception contexts. PMID- 28578454 TI - Determinants of levothyroxine dose required to achieve euthyroidism in pediatric population-a hospital-based prospective follow-up study. AB - : We analyzed the relation of pretreatment anthropometric measures and serum thyrotropin (TSH) with the levothyroxine requirement. Children (3-18 years) brought to endocrine clinic with newly diagnosed acquired primary hypothyroidism were enrolled consecutively and prospectively with follow-up (July 2014 to April 2016). Children were started on levothyroxine, and dose was adjusted at regular intervals until achieved euthyroidism (serum TSH 0.4 to 4.5 mIU/L). The relationship of age, gender, height, weight, and serum TSH with levothyroxine dose was analyzed by univariate and multivariate regression analysis. Data of 51 children (42 girls and 9 boys) was used for the analysis. Age, weight, height, and serum TSH had significant correlation with levothyroxine daily dose based on weight (D/W) and dose based on BSA (D/BSA). Log10 TSH and gender explained ~60% absolute levothyroxine daily requirement. The final model built with height and serum TSH predicted ~85% of D/W and ~80% of D/BSA. CONCLUSION: Pretreatment height and serum TSH can be used to determine levothyroxine dose needed to achieve euthyroidism in a newly diagnosed acquired primary hypothyroidism in children. What is Known: * The starting dose of levothyroxine is currently recommended based on the age of children. What is New: * In pediatric population, the effect of age on levothyroxine daily dose requirements can be explained by pretreatment height. * Pretreatment serum TSH level is an important predictor of levothyroxine daily dose in children with newly diagnosed primary hypothyroidism. PMID- 28578455 TI - Stem cells: from biomedical research towards clinical applications. PMID- 28578457 TI - Non-seminomatous mediastinal germ cell tumor and acute megakaryoblastic leukemia. AB - The association between mediastinal germ cell tumors (MGCT) and acute megakaryoblastic (M7) leukemia has been known for many years. We hereby present this review to better characterize the coexistence of these entities as well as the salient features, the treatment options, and the overall prognosis. A search of PUBMED, Medline, and EMBASE databases via OVID engine for primary articles and case reports under keywords "germ cell tumors" and "acute myeloid leukemia" revealed a total of 26 cases in English that reported MGCT and M7 leukemia. The median age at diagnosis of MGCT was 24 (13-36) years. All cases were stage III. All cases of MGCT were of non-seminomatous origin and one case was unclassified. MGCT occurred prior to the diagnosis of leukemia in 46% of cases and concomitantly in 31% of cases. M7 leukemia was never reported prior to the appearance of MGCT. Complex cytogenetics and hyperdiploidy were the most commonly reported cytogenetic abnormalities. In the 23 cases where the treatment regimen was available, platinum-based chemotherapy directed towards management of the germ cell tumors was used initially in 21 cases and leukemia-directed treatment was used initially in 2 cases only. The median time from diagnosis of MGCT to development of M7 leukemia was 5 (2.25-39) months. Median time to death from the initial diagnosis of MGCT was 6 (0.5-60) months. Patients with a history of MGCT are at higher risk of developing M7 leukemia. They need long-term follow-up with a particular attention to the development of hematological malignancies. The overall prognosis remains poor. PMID- 28578456 TI - Sequential combination of docetaxel with a SHP-1 agonist enhanced suppression of p-STAT3 signaling and apoptosis in triple negative breast cancer cells. AB - : Triple negative breast cancer (TNBC) is an aggressive cancer for which prognosis remains poor. Combination therapy is a promising strategy for enhancing treatment efficacy. Blockade of STAT3 signaling may enhance the response of cancer cells to conventional chemotherapeutic agents. Here we used a SHP-1 agonist SC-43 to dephosphorylate STAT3 thereby suppressing oncogenic STAT3 signaling and tested it in combination with docetaxel in TNBC cells. We first analyzed messenger RNA (mRNA) expression of SHP-1 gene (PTPN6) in a public TNBC dataset (TCGA) and found that higher SHP-1 mRNA expression is associated with better overall survival in TNBC patients. Sequential combination of docetaxel and SC-43 in vitro showed enhanced anti-proliferation and apoptosis associated with decreased p-STAT3 and decreased STAT3-downstream effector cyclin D1 in the TNBC cell lines MDA-MB-231, MDA-MB-468, and HCC-1937. Ectopic expression of STAT3 reduced the increased cytotoxicity induced by the combination therapy. In addition, this sequential combination showed enhanced SHP-1 activity compared to SC-43 alone. Furthermore, the combination treatment-induced apoptosis was attenuated by small interfering RNA (siRNA) against SHP-1 or by ectopic expression of SHP-1 mutants that caused SC-43 to lose its SHP-1 agonist capability. Moreover, combination of docetaxel and SC-43 showed enhanced tumor growth inhibition compared to single-agent therapy in mice bearing MDA-MB-231 tumor xenografts. Our results suggest that the novel SHP-1 agonist SC-43 enhanced docetaxel-induced cytotoxicity by SHP-1 dependent STAT3 inhibition in human triple negative breast cancer cells. TNBC patients with high SHP-1 expressions show better survival. Docetaxel combined with SC-43 enhances cell apoptosis and reduces p-STAT3. SHP-1 inhibition reduces the enhanced effect of docetaxel-SC-43 combination. Docetaxel-SC-43 combination suppresses xenograft tumor growth and reduces p-STAT3. KEY MESSAGES: TNBC patients with high SHP-1 expressions show better survival. Docetaxel combined with SC-43 enhances cell apoptosis and reduces p-STAT3. SHP-1 inhibition reduces the enhanced effect of docetaxel-SC-43 combination. Docetaxel-SC-43 combination suppresses xenograft tumor growth and reduces p-STAT3. PMID- 28578459 TI - Late versus early reduction in traumatic hip dislocations: a meta-analysis. AB - AIMS: Traumatic hip dislocations are considered orthopaedic emergencies that are treated with urgent reduction to decrease the rate of osteonecrosis of the femoral head. The aim of our study was to systematically review the literature that compares late (>6 h from the time of injury) to early (<6 h from the time of injury) reduction in all traumatic hip dislocations. MATERIALS AND METHODS: We searched five databases from 1951 to 2016 for studies that evaluated timing of reduction and osteonecrosis of the femoral head in all traumatic hip dislocations. We performed a meta-analysis using a random-effects model to pool odds ratios (ORs) for a comparison of osteonecrosis of the femoral head between patients undergoing late versus early hip reduction. We also investigated the osteonecrosis rate in low- and high-grade traumatic hip dislocations. Descriptive, quantitative and qualitative data were extracted. RESULTS: Of the 13 articles identified, five studies (retrospective cohort studies) were eligible for the meta-analysis, encompassing a total of 236 traumatic hip dislocations. The pooled odds ratio for osteonecrosis of the femoral head between late and early reduction was in favour of early hip reduction and statistically significant (OR = 5.00, 95% CI: 1.30, 19.29). No significant difference in the rate of osteonecrosis of the femoral head was detected between low- and high grade traumatic hip dislocations according to the time threshold (OR = 1.71, 95% CI: 0.22, 13.22). CONCLUSIONS: The cumulative evidence at present does indicate an association between late hip reduction and higher rate of osteonecrosis of the femoral head in all traumatic hip dislocations. Hence, all traumatic hip dislocations should be reduced as soon as possible to decrease the rate of osteonecrosis of the femoral head. However, the evidence does not indicate an association between the grade of dislocation and rate of osteonecrosis of the femoral head. LEVEL OF EVIDENCE: III. PMID- 28578458 TI - Coronal plane trunk asymmetry is associated with whole-body sagittal alignment in healthy young adolescents before pubertal peak growth. AB - PURPOSE: To investigate coronal plane trunk asymmetry (TA) and its association with sagittal postural alignment in healthy subjects before pubertal peak growth. METHODS: In this cross-sectional baseline study, 1190 healthy pre-peak growth velocity subjects were included. Coronal plane TA was evaluated using back surface topography. Whole-body sagittal alignment (previously validated and objectively classified as neutral, sway-back or leaning-forward) and sagittal spinopelvic profile (trunk lean, lumbar lordosis, thoracic kyphosis, sacral inclination and length of the posteriorly inclined thoracolumbar segment) were determined, as were height, proportion of trunk to body length, body mass index, generalized joint laxity, and handedness. RESULTS: Logistic regression analysis yielded overall sagittal posture class to be independently associated with coronal plane TA: having a leaning-forward posture associated with a nearly three times higher odds of coronal TA (p < 0.001) compared to neutrals. A sway-back was 2.2 times more likely to show TA (p = 0.016) than a neutral, yet only in boys. Significant associations with coronal TA were also found for trunk lean, thoracic kyphosis and body mass index. These correlations, however, were gender and posture class specific. The spinal region where asymmetry is seen, varies according to the whole-body sagittal alignment type: primary thoracic curves were the most frequent in leaning-forwards, whereas primary curves in the lumbar or declive thoracolumbar segment were the most common in sway-backs. CONCLUSIONS: In immature spines without known scoliosis, coronal plane TA is associated with whole-body sagittal alignment. It is more often seen in non-neutral than neutral sagittal posture types. Whether adolescent idiopathic scoliosis is related with postural characteristics before pubertal growth peak, should be addressed in future prospective studies. PMID- 28578460 TI - Genetic variation in potential Giardia vaccine candidates cyst wall protein 2 and alpha1-giardin. AB - Giardia is a prevalent intestinal parasitic infection. The trophozoite structural protein a1-giardin (a1-g) and the cyst protein cyst wall protein 2 (CWP2) have shown promise as Giardia vaccine antigen candidates in murine models. The present study assesses the genetic diversity of a1-g and CWP2 between and within assemblages A and B in human clinical isolates. a1-g and CWP2 sequences were acquired from 15 Norwegian isolates by PCR amplification and 20 sequences from German cultured isolates by whole genome sequencing. Sequences were aligned to reference genomes from assemblage A2 and B to identify genetic variance. Genetic diversity was found between assemblage A and B reference sequences for both a1-g (90.8% nucleotide identity) and CWP2 (82.5% nucleotide identity). However, for a1 g, this translated into only 3 amino acid (aa) substitutions, while for CWP2 there were 41 aa substitutions, and also one aa deletion. Genetic diversity within assemblage B was larger; nucleotide identity 92.0% for a1-g and 94.3% for CWP2, than within assemblage A (nucleotide identity 99.0% for a1-g and 99.7% for CWP2). For CWP2, the diversity on both nucleotide and protein level was higher in the C-terminal end. Predicted antigenic epitopes were not affected for a1-g, but partially for CWP2. Despite genetic diversity in a1-g, we found aa sequence, characteristics, and antigenicity to be well preserved. CWP2 showed more aa variance and potential antigenic differences. Several CWP2 antigens might be necessary in a future Giardia vaccine to provide cross protection against both Giardia assemblages infecting humans. PMID- 28578461 TI - Seroprevalence and risk factors of Toxoplasma gondii infection in invasive raccoons (Procyon lotor) in Central Europe. AB - Toxoplasma gondii is an obligate intracellular protozoan that causes toxoplasmosis in warm-blooded animals. Most mammals, including humans, can become intermediate host, resulting in subclinical infection or even death. Generally, there is limited information on the epidemiology of T. gondii of game species in Germany. As omnivores, raccoons, which are particularly widespread and abundant in Germany, are particularly exposed to infection the parasite. Here, we report the seroprevalence of T. gondii antibodies from 15 study sites located in Luxembourg and Germany. Using the indirect modified agglutination test (MAT), 170 (37.4%; 95% CI: 33.0-41.9) out of 454 raccoons were surveyed to be T. gondii seropositive. While values ranged from 19.0% to 53.3%, there was no significant difference in seroprevalence between study areas. Animal weight had a strong influence on the presence of T. gondii antibodies in raccoon sera, with heavier animals more likely to be seropositive. Our results show that T. gondii infection is widespread in central European raccoons, suggesting a high degree of ecosystem circulation of the parasite. PMID- 28578462 TI - aMMP-8 in correlation to caries and periodontal condition in adolescents-results of the epidemiologic LIFE child study. AB - OBJECTIVES: The suitability of a chairside aMMP-8 test in determination of periodontal inflammation and caries in adolescents was assessed. Secondly, the influence of orthodontic treatment on aMMP-8 test result was analyzed. MATERIALS AND METHODS: Within the LIFE Child study, 434 adolescents (10 to 18 years) were included. Clinical dental examinations comprised caries experience (DMF/T-Index), signs of periodontal inflammation (probing pocket depth, PPD; community periodontal index of treatment needs; CPITN) at six index teeth and oral hygiene (OH). Information about orthodontic appliances (OA) and socioeconomic status (SES) were obtained by validated questionnaires. Test's sensitivity and specificity to detect periodontal inflammation and carious lesions were evaluated. The influence of OA on the test result was analyzed (multivariate model). RESULTS: No associations between age, gender, SES or OH, and test outcome were found (p > 0.05). Positive test results correlated to periodontal findings (CPITN, mean PPD; p < 0.001). However, for the detection of >= 1 site(s) with PPD >= 4 mm, the test's sensitivity and specificity were found to be 61 and 69%, respectively. Multivariate analysis revealed a higher probability for a positive test result in cases of fixed OA (odds ratio 5.02, 95% confidence interval 1.90 13.19). The test had no diagnostic value considering carious lesions. CONCLUSIONS: The chairside aMMP-8 test does not reliably identify adolescents with periodontal inflammation. Positive test results were more frequent in case of OA. CLINICAL RELEVANCE: The chairside aMMP-8 test is no appropriate tool to screen children and adolescents neither for periodontal inflammation nor for carious lesions. PMID- 28578463 TI - Low personal exposure to benzene and 1,3-butadiene in the Swedish petroleum refinery industry. AB - PURPOSE: Petroleum refinery workers are exposed to the carcinogens benzene and 1,3-butadiene. Declining exposures have been reported internationally but information on current exposure in the Swedish refinery industry is limited. The aim was to examine refinery workers' personal exposure to benzene and 1,3 butadiene and increase awareness of exposure conditions by collaboration with involved refineries. METHODS: Altogether 505 repeated personal exposure measurements were performed among workers at two refineries. Full-shift measurements were conducted in different exposure groups using Perkin Elmer diffusive samplers filled with Carbopack X. Mean levels were calculated using mixed-effects models. A large fraction of measurements below the limit of detection (LOD) required imputation of computer-generated data. RESULTS: Mean benzene exposure among process technicians was 15.3 ug/m3 (95% CI 10.4-22.5 ug/m3) and 13.7 ug/m3 (95% CI 8.3-22.7 ug/m3) for Refinery 1 and 2, respectively. Process technicians working outdoors had higher exposure than maintenance workers (20.7 versus 5.9 ug/m3, p < 0.01). Working in the harbour and tank park (Refinery 1), compared with the process area, was associated with higher exposure. The 1,3 butadiene exposure was low, 5.4 and 1.8 ug/m3, respectively. The total variation was generally attributed to within-worker variability. CONCLUSIONS: Low benzene and 1,3-butadiene levels were found among refinery workers. Mean benzene exposure was about 1% of the Swedish occupational limit (1500 ug/m3) and for 1,3 butadiene, exposure was even lower. A large fraction of values below the LOD can be managed by carefully modelled, computer-generated data. PMID- 28578464 TI - Efficient modelling of foliage distribution and crown dynamics in monolayer tree species. AB - In response to the computational limitations of individual leaf-based tree growth models, this article presents a new approach for the efficient characterisation of the spatial distribution of foliage in monolayered trees in terms of 2D foliage surfaces. Much like the recently introduced 3D leaf area density, this concept accommodates local crown plasticity, which is a common weak point in large-scale growth models. Recognizing phototropism as the predominant driver of spatial crown expansion, we define the local light gradient on foliage surfaces. We consider the partial differential equation describing the evolution of a curve expanding along the light gradient and present an explicit solution. The article concludes with an illustration of the incorporation of foliage surfaces in a simple tree growth model for European beech (Fagus sylvatica L.), and discusses perspectives for applications in functional-structural models. PMID- 28578465 TI - Perspectives and Practices of Athletic Trainers and Team Physicians Implementing the 2010 NCAA Sickle Cell Trait Screening Policy. AB - Sickle cell trait (SCT) is usually benign. However, there are some conditions that may lead to SCT-related problems and put athletes with the trait at particular risk. In 2010 the National Collegiate Athletic Association (NCAA) issued a policy that required all Division I (DI) student-athletes to confirm their SCT status or sign a liability waiver to opt out of testing. Athletic trainers and team physicians play key roles in the policy implementation and we examined their perceptions and practices. Between December 2013 and March 2014 we interviewed 13 head athletic trainers and team physicians at NCAA Division I colleges and universities in North Carolina. We used an interview guide with open ended questions covering knowledge of SCT, historical screening and education practices, current implementation, and policy benefits and challenges. Participants were knowledgeable about SCT and thought the policy was beneficial in providing SCT health information to and for student-athletes. Schools varied in provision of genetic counseling, offering the waiver, SCT tests administered, and other aspects. Challenges included: insufficient guidance from the NCAA; financial considerations; and misunderstanding of the relationships of race and ancestry to SCT risk. Athletic staff found the policy valuable, but felt it needs clarity and standardization. PMID- 28578468 TI - Penetrating cardiac injuries: predictive model for outcomes based on 2016 patients from the National Trauma Data Bank. AB - BACKGROUND: Penetrating cardiac injuries are uncommon and lethal. The objectives of this study are to examine the national profile of cardiac injuries, identify independent predictors of outcome, generate, compare and validate previous predictive models for outcomes. We hypothesized that National Trauma Data Bank (NTDB) given its large number of patients, would validate these models. METHODS: The NTDB was queried for data on cardiac injuries, using survival as the main outcome measure. Statistical analysis was performed utilizing univariate and stepwise logistic regression. The stepwise logistic regression model was then compared with other predictive models of outcome. RESULTS: There were 2016 patients with penetrating cardiac injuries identified from 1,310,720 patients. Incidence: 0.16%. Mechanism of injury: GSWs-1264 (63%), SWs-716 (36%), Shotgun/impalement-19/16 (1%). Mean RTS 1.75, mean ISS 27 +/- 23. Overall survival 675 (33%). 830 patients (41%) underwent ED thoracotomy, 47 survived (6%). Survival stratified by mechanism: GSWs 114/1264 (10%), SWs 564/717 (76%). Predictors of outcome for mortality-univariate analysis: vital signs, RTS, ISS, GCS: Field CPR, ED intubation, ED thoracotomy and aortic cross-clamping (p < 0.001). Stepwise logistic regression identified cardiac GSW's (p < 0.001; AOR 26.85; 95% CI 17.21-41.89), field CPR (p = 0.003; AOR 3.65; 95% CI 1.53-8.69), the absence of spontaneous ventilation (p = 0.008; AOR 1.08, 95% CI 1.02-1.14), the presence of an associated abdominal GSW (p = 0.009; AOR 2.58, 95% CI 1.26 5.26) need for ED airway (p = 0.0003 AOR 1386.30; 95% CI 126.0-15251.71) and aortic cross-clamping (p = 0.0003 AOR 0.18; 95% CI 0.11-0.28) as independent predictors for mortality. Overall predictive power of model-93%. CONCLUSION: Predictors of outcome were identified. Overall survival rates are lower than prospective studies report. Predictive model from NTDB generated larger number of strong independent predictors of outcomes, correlated and validated previous predictive models. PMID- 28578467 TI - Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer's disease using functional laser speckle contrast imaging. AB - Increasing evidence from epidemiological, clinical, and experimental studies indicates that cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathogenesis of many types of dementia in the elderly, including both vascular cognitive impairment (VCI) and Alzheimer's disease. Vascular contributions to cognitive impairment and dementia (VCID) include impairment of neurovascular coupling responses/functional hyperemia ("neurovascular uncoupling"). Due to the growing interest in understanding and pharmacologically targeting pathophysiological mechanisms of VCID, there is an increasing need for sensitive, easy-to-establish methods to assess neurovascular coupling responses. Laser speckle contrast imaging (LSCI) is a technique that allows rapid and minimally invasive visualization of changes in regional cerebromicrovascular blood perfusion. This type of imaging technique combines high resolution and speed to provide great spatiotemporal accuracy to measure moment-to-moment changes in cerebral blood flow induced by neuronal activation. Here, we provide detailed protocols for the successful measurement in neurovascular coupling responses in anesthetized mice equipped with a thinned skull cranial window using LSCI. This method can be used to evaluate the effects of anti-aging or anti-AD treatments on cerebromicrovascular health. PMID- 28578469 TI - Brief Report: Is Impaired Classification of Subtle Facial Expressions in Children with Autism Spectrum Disorders Related to Atypical Emotion Category Boundaries? AB - Impairments in recognizing subtle facial expressions, in individuals with autism spectrum disorder (ASD), may relate to difficulties in constructing prototypes of these expressions. Eighteen children with predominantly intellectual low functioning ASD (LFA, IQ <80) and two control groups (mental and chronological age matched), were assessed for their ability to classify emotional faces, of high, medium and low intensities, as happy or angry. For anger, the LFA group made more errors for lower intensity expressions than the control groups, classifications did not differ for happiness. This is the first study to find that the LFA group made more across-valence errors than controls. These data are consistent with atypical facial expression processing in ASD being associated with differences in the structure of emotion categories. PMID- 28578470 TI - Which immobilization is better for distal radius fracture? A prospective randomized trial. AB - INTRODUCTION: The aim of this study was to determine whether an above-elbow cast (AEC) is better than a below-elbow cast (BEC) at maintaining the initial reduction in the orthopaedic management of a distal radius fracture (DRF). METHODS: It is a prospective randomized study carried out in a single emergency trauma department. There were 72 patients older than 55 years of age (55-96) with a distal radius fracture treated orthopaedically. They were randomized into two groups: group B (AEC 32 patients) and group A (BEC 40 patients). Randomization was done by a computer program. Four subgroups were constituted according to the instability criteria: subgroup 4 the most instable fractures. Main outcome was reduction loss from initial reduction to cast removal: it was measured using the volar tilt, radial tilt and radial length on plain radiographs. RESULTS: No differences were observed between group A and B when analysed globally (volar tilt loss p = 0.89 radial tilt loss p = 0.08 ulnar variance p = 0.19). Subgroups analysis revealed less radial tilt reduction loss in group A in patients within subgroup 3 (p = 0.02) and 4 (p = 0.003). DISCUSSION: Results are in contrast to what was expected. Limiting prono-supination AEC is supposed to better maintain initial fracture reduction. Effect of pronation and supination as well as distraction of brachioradialis muscle could have been overestimated until now. CONCLUSION: The above-elbow cast is not better than the below-elbow cast in terms of loss reduction. However, the below-elbow cast more efficiently controls radial tilt reduction. PMID- 28578466 TI - Dopaminergic Regulation of Innate Immunity: a Review. AB - Dopamine (DA) is a neurotransmitter in the central nervous system as well as in peripheral tissues. Emerging evidence however points to DA also as a key transmitter between the nervous system and the immune system as well as a mediator produced and released by immune cells themselves. Dopaminergic pathways have received so far extensive attention in the adaptive branch of the immune system, where they play a role in health and disease such as multiple sclerosis, rheumatoid arthritis, cancer, and Parkinson's disease. Comparatively little is known about DA and the innate immune response, although DA may affect innate immune system cells such as dendritic cells, macrophages, microglia, and neutrophils. The present review aims at providing a complete and exhaustive summary of currently available evidence about DA and innate immunity, and to become a reference for anyone potentially interested in the fields of immunology, neurosciences and pharmacology. A wide array of dopaminergic drugs is used in therapeutics for non-immune indications, such as Parkinson's disease, hyperprolactinemia, shock, hypertension, with a usually favorable therapeutic index, and they might be relatively easily repurposed for immune-mediated disease, thus leading to innovative treatments at low price, with benefit for patients as well as for the healthcare systems. PMID- 28578471 TI - Retrieval evidence of impingement at the third articulation in contemporary dual mobility cups for total hip arthroplasty. AB - PURPOSE: We aimed to assess polyethylene liners of retrieved hips of one design of a dual mobility (DM) cup liner and two designs of femoral stems to better understand the role of femoral stem design on polyethylene impingement. METHODS: This was a case-control study involving 70 retrieved highly cross-linked polyethylene (X3) liners used with ABGII (n = 35) and Rejuvenate (n = 35) stems (Stryker). All polyethylene liners were assessed for evidence of rim deformation and the damage quantified using metrology methods. RESULTS: A total of 80% of polyethylene liners paired with ABGII necks had macroscopic evidence of neck impingement resulting in a raised lip whilst 23% of liners paired with Rejuvenate necks had evidence of a raised lip (p < 0.0001). The height of the raised rims of the DM cups paired with ABGII necks had a median (range) of 139 MUm (72-255). The height of the raised rims of the DM cups paired with Rejuvenate necks had a median (range) of 52 MUm (45-90) (p < 0.0001). CONCLUSION: Our new findings from retrieved dual mobility bearings showed that polyethylene liner rim deformation resulting from impingement with the femoral neck occurs in early in-human function, is circumferential in distribution, and is affected by the stem neck design. We recommend the use of highly polished and non-edged neck designs when used in conjunction with DM cups. PMID- 28578472 TI - Cutaneous Manifestations of ANCA-Associated Small Vessels Vasculitis. AB - Skin lesions are frequent manifestations of underlying systemic conditions, including systemic autoimmune vasculitis. In particular, anti-neutrophil cytoplasmic antibodies (ANCA) are associated with distinct forms of vasculitis characterized by inflammatory cell infiltration of the walls of small and medium sized vessels leading to vascular destruction and tissue necrosis. ANCA associated vasculitis is rare and systemic diseases, which can be classified based on different distribution of vascular inflammation and presence or absence of granulomatosis and asthma. Despite their diversities, ANCA-associated vasculitis, namely microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis, can all display a broad variety of cutaneous manifestations, which can appear during the course of the disease or even as first sign at the time of onset. Different skin manifestations might coexist in the same patient and occur in different occasions during the course of the vasculitis. Thus, a deep knowledge of the spectrum of skin lesions as part of ANCA-associated vasculitis is mandatory for a correct diagnostic process, whenever cutaneous vasculitis is suspected. Due to this broad variety of manifestations, the diagnosis of skin involvement in ANCA-associated vasculitis is very challenging and it must be supported by a detailed medical history, accurate physical examination, specific histopathological analysis of skin biopsy and the presence of ANCA serology. In this review, we focus on the cutaneous manifestations that can develop in the context of ANCA-associated vasculitis, detailing the clinical features, the histopathological aspects as well as the direct immunofluorescence studies for each of the three conditions. Moreover, we acknowledged the differential diagnoses that must be ruled out in the diagnostic process and the main therapeutic approaches available for treatment of ANCA associated vasculitis. PMID- 28578474 TI - Differentiating perforated from non-perforated appendicitis on contrast-enhanced magnetic resonance imaging. AB - BACKGROUND: The role of magnetic resonance imaging (MRI) in pediatric appendicitis is increasing; MRI findings predictive of appendiceal perforation have not been specifically evaluated. OBJECTIVE: To assess the performance of MRI in differentiating perforated from non-perforated appendicitis. MATERIALS AND METHODS: A retrospective review of pediatric patients undergoing contrast enhanced MRI and subsequent appendectomy was performed, with surgicopathological confirmation of perforation. Appendiceal diameter and the following 10 MRI findings were assessed: appendiceal restricted diffusion, wall defect, appendicolith, periappendiceal free fluid, remote free fluid, restricted diffusion within free fluid, abscess, peritoneal enhancement, ileocecal wall thickening and ileus. Two-sample t-test and chi-square tests were used to analyze continuous and discrete data, respectively. Sensitivity and specificity for individual MRI findings were calculated and optimal thresholds for measures of accuracy were selected. RESULTS: Seventy-seven patients (mean age: 12.2 years) with appendicitis were included, of whom 22 had perforation. The perforated group had a larger mean appendiceal diameter and mean number of MRI findings than the non-perforated group (12.3 mm vs. 8.6 mm; 5.0 vs. 2.0, respectively). Abscess, wall defect and restricted diffusion within free fluid had the greatest specificity for perforation (1.00, 1.00 and 0.96, respectively) but low sensitivity (0.36, 0.25 and 0.32, respectively). The receiver operator characteristic curve for total number of MRI findings had an area under the curve of 0.92, with an optimal threshold of 3.5. A threshold of any 4 findings had the best ability to accurately discriminate between perforated and non-perforated cases, with a sensitivity of 82% and specificity of 85%. CONCLUSION: Contrast enhanced MRI can differentiate perforated from non-perforated appendicitis. The presence of multiple findings increases diagnostic accuracy, with a threshold of any four findings optimally discriminating between perforated and non-perforated cases. These results may help guide management decisions as MRI assumes a greater role in the work-up of pediatric appendicitis. PMID- 28578475 TI - Intussusception reduction: Effect of air vs. liquid enema on radiation dose. AB - BACKGROUND: Both air and radiopaque liquid contrast are used to reduce ileocolic intussusception under fluoroscopy. Some suggest air lowers radiation dose due to shorter procedure times. However, air enema likely lowers radiation dose regardless of fluoroscopy time due to less density over the automatic exposure control cells. OBJECTIVES: We test the hypothesis that air enema reduction of ileocolic intussusception results in lower radiation dose than liquid contrast enema independent of fluoroscopy time. We describe a role for automatic exposure control in this dose difference. MATERIALS AND METHODS: We retrospectively evaluated air and liquid intussusception reductions performed on a single digital fluoroscopic unit during a 26-month period. We compared patient age, weight, gender, exam time of day and year, performing radiologist(s), radiographic image acquisitions, grid and magnification use, fluoroscopy time and dose area product. We compared categorical and continuous variables statistically using chi-square and Mann-Whitney U tests, respectively. RESULTS: The mean dose area product was 2.7-fold lower for air enema, 1.3 +/- 0.9 dGy.cm2, than for liquid, 3.5 +/- 2.5 dGy.cm2 (P<0.005). The mean fluoroscopy time was similar between techniques. The mean dose area product/min was 2.3-fold lower for air, 0.6 +/- 0.2 dGy.cm2/min, than for liquid, 1.4 +/- 0.5 dGy.cm2/min (P<0.001). No group differences were identified in other measured dose parameters. CONCLUSION: Fluoroscopic intussusception reduction using air enema uses less than half the radiation dose of liquid contrast enema. Dose savings are independent of fluoroscopy time and are likely due to automatic exposure control interaction. PMID- 28578477 TI - Prevalence of hereditary hemorrhagic telangiectasia in patients operated for cerebral abscess: a retrospective cohort analysis. AB - It is well described that patients with pulmonary arteriovenous malformations (PAVMs) and Hereditary Hemorrhagic Telangiectasia (HHT) have an increased risk of cerebral abscess (CA). However, as both CA and HHT are rare, the proportion of patients with CA who are diagnosed with HHT has not been previously described. A retrospective study was carried out of all patients treated surgically for CA between January 1995 and September 2014 at the Department of Neurosurgery, Odense University Hospital. The cases were then cross-referenced with the Danish HHT database. Eighty patients aged 5-79 years were included. The incidence of CA was 0.33/100,000/year. Two patients (2.5%) were registered as having HHT. Bacterial pathogens were identified in 70% of all cases, most frequently streptococci species (46.3%). The most common predisposing condition was odontogenic infection (20%), followed by post-operative infection (13.8%) and post-trauma (6.3%). Patients undergoing a full diagnostic program to determine predisposing conditions causing CA increased over the 20-year period from 11.8% to 65.2%. The 3-month and 1-year mortality rates were 7.5% and 11.25%, respectively. There is an overrepresentation of HHT patients in a cohort of patients with CA, and HHT should be investigated as the cause of the CA if no other apparent cause can be identified. PMID- 28578476 TI - Lipopolysaccharide Downregulates Kruppel-Like Factor 2 (KLF2) via Inducing DNMT1 Mediated Hypermethylation in Endothelial Cells. AB - KLF2 plays a protective role in antiinflammation and endothelial function, and can be regulated by promoter methylation alteration. Lipopolysaccharide (LPS) is a mediator of inflammatory responses, which causes epigenetic change of certain genes in host cells. We thus aimed to determine whether LPS could control the KLF2 expression by inducing methylation in promoter region. DNA methylation of 16 CpG sites within KLF2 promoter region was detected by bisulfite sequencing PCR. Results showed that methylation at 12 CpG sites were significantly increased in HUVECs after exposure to LPS among the total 16 sites, and the average level was increased by 57%. The KLF2 expressions assessed by reverse transcription quantitative real-time PCR and Western blot were significantly downregulated compared that without LPS simulation. Moreover, both messenger RNA and protein levels of KLF2 in HUVEC co-treated with LPS and DNA methyltransferase (DNMT) 1 small interfering RNA were dramatically higher than that treated with LPS only. Similar result was obtained when the cells were incubated in combination with LPS and 5-aza-2'-deoxycytidine (AZA), suggesting that the reduction of KLF2 expression induced by LPS can be reversed by DNMT1 inhibition. Finally, the presence of AZA changed the expression of genes that depends on KLF2 in LPS stimulated HUVECs, which downregulated the E-selectin and VCAM and increased the eNOS and thrombomodulin expression. Our data demonstrated that LPS exposure resulted in hypermethylation in KLF2 promoter in HUVECs, which subsequently led to downregulation of the KLF2 expression. The study suggested that epigenetic alteration is involved in LPS-induced inflammatory response and provided a new insight into atherogenesis. PMID- 28578473 TI - Geoepidemiology and Immunologic Features of Autoinflammatory Diseases: a Comprehensive Review. AB - The knowledge on systemic autoinflammatory disorders (SAID) is expanding rapidly and new signalling pathways are being decrypted. The concept of autoinflammation has been proposed since 1999, to define a group of diseases with abnormal innate immunity activation. Since then, more than 30 monogenic SAID have been described. In this review, we first describe inflammasomopathies and SAID related to the interleukin-1 pathway. Recent insights into the pathogenesis of familial Mediterranean fever and the function of Pyrin are detailed. In addition, complex or polygenic SAID, such as Still's disease or PFAPA syndrome, are also discussed. Then, major players driving autoinflammation, such as type-1 interferonopathies (including the recently described haploinsuffiency in A20 and otulipenia), TNF associated periodic syndromes, defects in ubiquitination, and SAID with overlapping features of autoimmunity or immunodeficiency. Discoveries of the pathogenic role of mosaicism, intronic defects coupled to the likelihood to identify digenic or polygenic diseases are providing new challenges for physicians and geneticists. This comprehensive review depicts the various SAID, presenting them according to their predominant pathophysiological mechanism, with a particular emphasis on recent findings. Epidemiologic data are also presented. Finally, we propose a practical diagnostic approach to the most common monogenic SAID, based on the most characteristic clinical presentation of these disorders. PMID- 28578478 TI - Smooth pursuits decrease balance control during locomotion in young and older healthy females. AB - Dynamic balance control-characterised as movement of the trunk and lower limbs was assessed during fixation of a fixed target, smooth pursuits and saccadic eye movements in ten young (22.9 +/- 1.5 years) and ten older (72.1 +/- 8.2 years) healthy females walking overground. Participants were presented with visual stimuli to initiate eye movements, and posture and gaze were assessed with motion analysis and eye tracking equipment. The results showed an increase in medial/lateral (ML) trunk movement (C7: p = 0.012; sacrum: p = 0.009) and step width variability (p = 0.052) during smooth pursuits compared to a fixed target, with no changes for saccades compared to a fixed target. The elders demonstrated greater ML trunk movement (sacrum: p = 0.037) and step-width variability (p = 0.037) than the younger adults throughout, although this did not interact with the eye movements. The findings showed that smooth pursuits decreased balance control in young and older adults similarly, which was likely a consequence of more complicated retinal flow. Since healthy elders are typically already at a postural disadvantage, further decreases in balance caused by smooth pursuits are undesirable. PMID- 28578479 TI - Vulnerability associated with "symptoms similar to those of mercury poisoning" in communities from Xingu River, Amazon basin. AB - The Brazilian Amazon is known to be a region with high levels of mercury (Hg) in the environment and studies point to an association between high levels of natural mercury in the mother rock and the vast number of clandestine gold mines. Other studies already report the contamination of fish in this region, as well as high levels of Hg in biological material from environmentally exposed populations. On the other hand, this is one of the least developed regions of the planet and it is necessary to understand the vulnerability factors in these populations that may be intoxicated by this element. The purpose of the present study was to investigate the vulnerability factors in communities from Xingu River-Amazon basin probably exposed to Hg. A cross-selection study in two cities localized in Xingu River was conducted, and the sample contained was 268 individuals. sociodemographic questions, lifestyle, diet habits and health conditions were collated. The majority of the sample was female, between 30 and 59 years old, had less than 3 years of educational level and lived in the local of study more than 240 months. There was regular fish consumption (95.9%), principally carnivorous species (80.5%). The visual problem has a highest prevalence (43.3%) between the health problems and about the symptoms of Hg intoxication, memory loss (42.9%), weakness (35.1%), fatigue (34.3%), mood changes (28.7%) and difficulties in concentration (27.2%) was most reported. The female sex, age over 60, educational level below 3 years of study, did not had flush toilet, smoke and least one chronic non-communicable disease represent higher probability to had symptoms of Hg intoxication. Lack of access to health services, low education level and income evidence the susceptibility of this community to diseases and injuries. The vulnerable groups identified in this study should be a priority in public health and environmental health policies. PMID- 28578481 TI - The association of air temperature with cardiac arrhythmias. AB - The body response to meteorological influences may activate pathophysiological mechanisms facilitating the occurrence of cardiac arrhythmias in susceptible patients. Putative underlying mechanisms include changes in systemic vascular resistance and blood pressure, as well as a network of proinflammatory and procoagulant processes. Such a chain reaction probably occurs within the time window of several hours, so use of daily average values of meteorological elements do not seem appropriate for investigation in this area. In addition, overall synoptic situation, and season-specific combinations of meteorological elements and air pollutant levels probably cause the overall effect rather than a single atmospheric element. Particularly strong interrelations have been described among wind speed, air pressure and temperature, relative air humidity, and suspended particulate matter. This may be the main reason why studies examining the association between temperature and ventricular arrhythmias have found linear positive, negative, J-shaped or no association. Further understanding of the pathophysiological adaptation to atmospheric environment may help in providing recommendations for protective measures during "bad" weather conditions in patients with cardiac arrhythmias. PMID- 28578484 TI - Valbenazine: First Global Approval. AB - Valbenazine (IngrezzaTM) is an orally bioavailable, selective, vesicular monoamine transporter 2 (VMAT2) inhibitor being developed by Neurocrine Biosciences for the treatment of various central nervous system disorders. Valbenazine has been approved in the USA for the treatment of adults with tardive dyskinesia (TD), is at various stages of development in other countries for TD and is in phase 2 development in the USA for Tourette syndrome. This article summarizes the milestones in the development of valbenazine leading to its first global approval in the USA for the treatment of adults with TD. PMID- 28578480 TI - Acute Neuroinflammation Promotes Cell Responses to 1800 MHz GSM Electromagnetic Fields in the Rat Cerebral Cortex. AB - Mobile phone communications are conveyed by radiofrequency (RF) electromagnetic fields, including pulse-modulated global system for mobile communications (GSM) 1800 MHz, whose effects on the CNS affected by pathological states remain to be specified. Here, we investigated whether a 2-h head-only exposure to GSM-1800 MHz could impact on a neuroinflammatory reaction triggered by lipopolysaccharide (LPS) in 2-week-old or adult rats. We focused on the cerebral cortex in which the specific absorption rate (SAR) of RF averaged 2.9 W/kg. In developing rats, 24 h after GSM exposure, the levels of cortical interleukin-1beta (IL1beta) or NOX2 NADPH oxidase transcripts were reduced by 50 to 60%, in comparison with sham exposed animals (SAR = 0), as assessed by RT-qPCR. Adult rats exposed to GSM also showed a 50% reduction in the level of IL1beta mRNA, but they differed from developing rats by the lack of NOX2 gene suppression and by displaying a significant growth response of microglial cell processes imaged in anti-Iba1 stained cortical sections. As neuroinflammation is often associated with changes in excitatory neurotransmission, we evaluated changes in expression and phosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the adult cerebral cortex by Western blot analyses. We found that GSM exposure decreased phosphorylation at two residues on the GluA1 AMPAR subunit (serine 831 and 845). The GSM-induced changes in gene expressions, microglia, and GluA1 phosphorylation did not persist 72 h after RF exposure and were not observed in the absence of LPS pretreatment. Together, our data provide evidence that GSM-1800 MHz can modulate CNS cell responses triggered by an acute neuroinflammatory state. PMID- 28578483 TI - SAND: a Screening for Aphasia in NeuroDegeneration. Development and normative data. AB - Language assessment has a critical role in the clinical diagnosis of neurodegenerative diseases, in particular, in the case of Primary Progressive Aphasia (PPA). The current diagnostic criteria (Gorno-Tempini et al., 2011) identify three main variants on the basis of clinical features and patterns of brain atrophy. Widely accepted tools to diagnose, clinically classify, and follow up the heterogeneous language profiles of PPA are still lacking. In this study, we develop a screening battery, composed of nine tests (picture naming, word and sentence comprehension, word and sentence repetition, reading, semantic association, writing and picture description), following the recommendations of current diagnostic guidelines and taking into account recent research on the topic. All tasks were developed with consideration of the psycholinguistic factors that can affect performance, with the aim of achieving sensitivity to the language deficit to which each task was relevant, and to allow identification of the selective characteristic impairments of each PPA variant. Normative data on 134 Italian subjects pooled across homogeneous subgroups for age, sex, and education are reported. Although further work is still needed, this battery represents a first step towards a concise multilingual standard language examination, a fast and simple tool to help clinicians and researchers in the diagnosis of PPA. PMID- 28578485 TI - Thoughts on the importance of government regulated Chinese medicine terminology standardization. AB - The applications of a standardized Chinese medicine (CM) terminology are ultimately the translation and publication of literature, education, as well as scholarly and legal communication. Over the past 20-30 years the amount of published CM literature, including clinical and experimental research, has increased exponentially. In addition, the numbers of professionally trained Western CM scholars and clinicians have been continuously rising, and they are now forming a considerable academic force that should be taken seriously. Because of the continuous advancements of CM abroad, there is a strong demand for the application of a "common official language" to facilitate this progress and the future developments in the field. A standard to be applied within China is also a necessary work needed for the uniform transmission of the indigenous medical system abroad. PMID- 28578482 TI - High frequencies of circulating Tfh-Th17 cells in myasthenia gravis patients. AB - Recent studies show that the frequencies of circulating follicullar helper T (cTfh) cells are significantly higher in myasthenia gravis (MG) patients compared with healthy controls (HC). And, they are positively correlated with levels of serum anti-acetylcholine receptor antibody (anti-AchR Ab). It is unclear whether cTfh cell subset frequencies are altered and what role they play in MG patients. In order to clarify this, we examined the frequencies of cTfh cell counterparts, their subsets, and circulating plasmablasts in MG patients by flow cytometry. We determined the concentrations of serum anti-AChR Ab by enzyme-linked immunosorbent assay (ELISA). We assayed the function of cTfh cell subsets by flow cytometry and real-time polymerase chain reaction (RT-PCR). We found higher frequencies of cTfh cell counterparts, cTfh-Th17 cells, and plasmablasts in MG patients compared with HC. The frequencies of cTfh cell counterparts and cTfh Th17 cells were positively correlated with the frequencies of plasmablasts and the concentrations of anti-AChR Ab in MG patients. Functional assays showed that activated cTfh-Th17 cells highly expressed key molecular features of Tfh cells including ICOS, PD-1, and IL-21. Results indicate that, just like cTfh cell counterparts, cTfh-Th17 cells may play a role in the immunopathogenesis and the production of anti-AChR Ab of MG. PMID- 28578486 TI - Angelica tenuissima Nakai Ameliorates Cognitive Impairment and Promotes Neurogenesis in Mouse Model of Alzheimer's Disease. AB - OBJECTIVE: To research Angelica tenuissima Nakai (ATN) for use in novel Alzheimer's disease (AD) therapeutics. METHODS: The effect of a 30% ethanol extract of ATN (KH032) on AD-like cognitive impairment and neuropathological and neuroinflammatory changes induced by bilateral intracerebroventricular injections of beta-amyloid (Abeta) peptide (Abeta1-42) was investigated. Male C57Bl/6 mice were randomly divided into 4 groups, 10 in each group. KH032-treated groups were administrated with a low or high dose of KH032 (50 and 200 mg/kg, respectively), intragastrically for 16 days; distilled water was applied in the sham and negative groups. Open fifield test, Y maze and Morris water maze test were used for behavior test and cognitive ability. In addition, the neuroprotective effects of KH032 in Abeta1-42-infused mice on the histopathological markers [neuronspecific nuclear protein (NeuN), Abeta1-42] of neurodegeneration were examined. The levels of glial fibrillary acidic protein (GFAP), NeuN, phosphorylation extracellular signal-regulated kinase (ERK)/ERK, brain-derived neurotrophic factor (BDNF), phosphorylation cAMP response element-binding (CREB)/CREB protein expression were measured by Western blot. RESULTS: KH032 treatment ameliorated cognitive impairments, reduced the overexpression of Abeta1 42, and inhibited neuronal loss and neuroinflammatory response in the Abeta1-42 infused mice. Moreover, KH032 treatment enhanced BDNF expression levels in the hippocampus. Finally, KH032 treatment increased phosphorylation of ERK1/2 and CREB, vital for ERK-CREB signaling. CONCLUSIONS: KH032 attenuated cognitive defificits in the Abeta1-42-infused mice by increasing BDNF expression and ERK1/2 and CREB phosphorylation and inhibiting neuronal loss and neuroinflflammatory response, suggesting that KH032 has therapeutic potential in neurodegenerative disorders such as AD. PMID- 28578487 TI - Gambogic Acid Induces Cell Apoptosis and Inhibits MAPK Pathway in PTEN-/-/p53-/- Prostate Cancer Cells In Vitro and Ex Vivo. AB - OBJECTIVE: To investigate the effect of gambogic acid (GA) on the growth and cell death of castrate resistant prostate cancer (PC) with phosphate and tension homology (PTEN) and p53 genes deleted in vitro and ex vivo, and elucidate the underlying possible molecular mechanisms. METHODS: PTEN-/-/p53-/- PC cells and Los Angeles prostate cancer-4 (LAPC-4) cells were treated with GA for 24 h and 48 h, then cell viability was determined by cell proliferation assay. PTEN-/-/p53-/- PC cells organoids number was calculated under GA treatment for 1 week. In addition, cell titer glo assay was performed to analyze 3 dimensional cell viability of patients derived xenografts (PDX) 170.2 organoids. Flow cytometry was used to detect apoptotic cells treated with GA. And confocal image was performed to detect the apoptotic mitochondrial morphological changes. Apoptotic cell death related protein levels were measured through Western blot (WB) in GA treated cells and organoids. The expression levels of mitogen-activated protein kinases (MAPKs) pathway related ribonucleic acid (RNAs) and proteins were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and WB, respectively. RESULTS: The treatment of GA significantly reduced cell viability of PTEN-/-/p53-/- PC cells and LAPC-4 in a time- and concentration-dependent manner. In organoids, GA showed strong inhibition towards organoids' numbers and diameters and continuously led to a complete organoids inhibition with GA 150 nmol/L. Ex vivo results validated that GA 1 MUmol/L inhibited 44.6% PDX170.2 organoids growth. As for mechanism, flow cytometry detected continuously increased apoptotic portion under GA treatment from 1.98% to 11.78% (6 h) and 29.94% (8 h, P<0.05). In addition, mitochondrial fragmentation emerged in GA treated cells indicated the mitochondrial apoptotic pathway might be involved. Furthermore, WB detected caspases-3, -9 activation and light chain (LC)-3 conversion with GA treatment. WB revealed decreased activity of MAPK pathway and down-regulation of downstream c-fos oncogene RNA level was detected by RT-PCR before undergoing apoptosis (P<0.05). CONCLUSION: GA was a potent anti-tumor compound as for PTEN-/-/p53-/- PC, which contributed to cell apoptosis via inhibition of the MAPK pathway and c-fos. PMID- 28578488 TI - 17beta-Estradiol Increases Non-CpG Methylation in Exon 1 of the Rainbow Trout (Oncorhynchus mykiss) MyoD Gene. AB - MyoD is an important myogenic transcription factor necessary for the differentiation of myogenic precursor cells (MPC) to form mature myotubes, a process essential for muscle growth. Epigenetic markers such as CpH methylation are known gene regulators that are important for the differentiation process. In this study, we investigated whether DNA methylation is a potential mechanism associated with the ability of 17beta-estradiol (E2) to reduce MyoD gene expression and muscle growth in rainbow trout. Rainbow trout received a single intraperitoneal injection of E2 or the injection vehicle (control). Skeletal muscle was collected 24 h post injection and analyzed for DNA methylation within the MyoD gene and the expression of DNA methyltransferases. CpG islands of the MyoD gene were predicted using MethPrimer software, and these regions were PCR amplified and analyzed using bisulfite sequencing. The percent methylation of the targeted CpG did not differ between control and E2-treated fish. However, percent CpH methylation in the MyoD exon 1 region was elevated with E2 treatment. Two of the methylated CpH sites were located in conserved transcription factor binding motifs, estrogen response element (ERE), and Myc binding site. Quantitative real time PCR analysis revealed a significant increase in expression of DNA methyltransferases, Dnmt3a and Dnmt3b, in E2-treated muscle, suggesting an increased genome methylation. Differential CpH methylation in MyoD gene of control and E2-treated fish suggests an epigenetic mechanism through which E2 decreases MyoD gene expression and contributes to reduced muscle growth. PMID- 28578489 TI - Downregulation of lncRNA TUBA4B is Associated with Poor Prognosis for Epithelial Ovarian Cancer. AB - A host of studies have revealed that long non-coding RNAs (lncRNAs) are critically involved in the development and progression of epithelial ovarian cancer. LncRNA TUBA4B is recently identified to be a critical mediator in non small cell lung cancer. However, the clinical roles and biological functions of lncRNA TUBA4B in epithelial ovarian cancer have yet to be fully clarified. The present study was conducted to explore the expression of lncRNA TUBA4B in human epithelial ovarian cancer tissues and potential roles of lncRNA TUBA4B in ovarian cancer cells. The matched epithelial ovarian cancer specimens and adjacent normal tissues were employed to detect the expression of lncRNA TUBA4B. The prognostic value of lncRNA TUBA4B for tumor progression and survival rate was investigated. The effects of lncRNA TUBA4B on ovarian cancer cell proliferation and migration were also explored. The expression of lncRNA TUBA4B was significantly decreased in epithelial ovarian cancer tissue specimens. The low lncRNA TUBA4B level was closely related with pathological grade, FIGO stage and lymph node metastases, and serum CA125 level. Enforced expression of lncRNA TUBA4B obviously reduced the proliferation of SKOV3 cells, and attenuated the activation of ERK and Akt signaling pathways. Our data demonstrate for the first time that lower lncRNA TUBA4B may be a novel independent prognostic biomarker for overall survival of epithelial ovarian cancer. Overexpression of lncRNA TUBA4B inhibits the proliferation of ovarian cancer cells. LncRNA TUBA4B may be an important target for therapeutic intervention in ovarian cancer. PMID- 28578490 TI - The effect of tumor necrosis factor antagonists on functional aortic stiffening. PMID- 28578491 TI - Vitamin D deficiency in systemic sclerosis: a possible role of subclinical liver fibrosis? Retrospective analysis from an Italian cohort. PMID- 28578492 TI - Anti-citrullinated protein antibodies in the diagnosis of rheumatoid arthritis (RA): diagnostic performance of automated anti-CCP-2 and anti-CCP-3 antibodies assays. AB - This study compares the diagnostic performance of a second generation anti-cyclic citrullinated peptide antibody (CCP2) with a third generation anti-CCP antibodies assay (CCP3), as well as the combination of both tests. Serum samples of 127 patients were analyzed. IgG anti-CCP 2 and IgM rheumatoid factor were determined by EliATM technique on a Phadia 250 instrument (Thermo Fisher Scientific), anti CCP3 by the Quanta FlashTM anti-CCP3 IgG kit, BIO-FLASH Rapid Response Chemiluminscence Analyzer (INOVA Diagnostics). Diagnostic performance was compared using ROC-curves, sensitivity, specificity, likelihood ratios, and predictive values. Logistic regressions were used to investigate whether using both tests (anti-CCP2 and anti-CCP3) gives a better prediction of rheumatoid arthritis. At the manufacturer's cut-offs sensitivity and specificity were 79.4 and 61.0% for CCP3 and 80.9 and 69.5% for CCP2. No significant differences could be observed regarding the areas under the curve (AUC) of both ROC-curves. The optimal cut-off point for CCP2 was 10.5 U/ml (sensitivity of 75.0% and specificity of 80.0%) and 5.6 U/ml for CCP3 (sensitivity of 86.9% and specificity of 61.0%). Binary logistic regressions indicated that the likelihood of having rheumatoid arthritis (RA) is significantly higher when testing positive on both CCP2 and CCP3 compared to CCP2 or CCP3 alone. In our cohort, comparable performance was found between the two CCP assays. Positivity for both CCP2 and CCP3 resulted in the most specific identification of RA patients. In patients with joint complaints suspected of having RA and with a weakly positive CCP 2 (>=7 and <=16 U/ml) CCP3 testing could be of additive value for diagnosing RA. PMID- 28578494 TI - Colonization and Gut Flora Modulation of Lactobacillus kefiranofaciens ZW3 in the Intestinal Tract of Mice. AB - This study evaluated the distribution and colonization of Lactobacillus kefiranofaciens ZW3 and determined its capacity to modulate the gut microbiota in an animal model. Based on (1) fluorescence imaging, (2) flow cytometry, and (3) qPCR, we found that ZW3 successfully adhered to mouse mucous tissue and colonized the mouse ileum. Gut microbiota profiling was performed using high-throughput sequencing. After continuous intubation with ZW3 for 1 week, the proportion of Lachnospiraceae, a family of butyric acid-producing bacteria, increased at day 7 (11.9% at day 0 versus 18.4% at day 7). In addition, Lactobacillaceae showed an increasing trend (4% at day 0 versus 13% at day 7) that was accompanied by an observable decline in the Rikenellaceae family (1.58% at day 7, 0.14% at day 14, and 0.75% at day 21) in the tested mouse. The results demonstrate that ZW3 could successfully adhere to and colonize the mouse gut throughout the course of the experiment. The profiling analysis of the gut microbiota also provided evidence supporting the function of ZW3 in improving the intestinal flora of mice. PMID- 28578493 TI - Nailfold videocapillaroscopy results in patients with rheumatoid arthritis. AB - We aimed to analyse the nailfold capillaryscopy findings morphologically and examine their relationship with disease activity and demographic characteristics in patients with rheumatoid arthritis. In accordance with the 2010 ACR/EULAR classification criteria, 201 patients diagnosed with Romatoiad artrit (RA) and 50 healthy controls were included. We analysed capillaroscopic abnormalities such asmegacapillaries, haemorrhages, ramifications and avascular areas in patients affected with rheumatoid arthritis. The findings in our study are as follows: in 45.77% of the RA patients, there were nonspecific capillaryscopy findings. When compared to control group, the incidence of tortuosity, dilated capillary and bushy capillary was higher in RA patients (p values, respectively, 0.110, 0.330, 0.440 and 0.516). In RA patients with Raynaud's phenomenon, the incidence of nonspecific capillaryscopy findings was higher. While there is a weak relationship between tortuosity and the duration of disease, no significant relation was detected between capillaryscopy findings and parameters such as RF, anti-CCP positivity and disease activity score (DAS28). When compared to controls, we have detected that RA patients have more nonspecific capillaryscopic findings. We could not find a relationship between nonspecific capillaryscopic findings and RA'a clinical findings and laboratory parameters. There is a need for a long-term wider-scale follow-up study to investigate whether there is a capillaryscopic pattern that can be correlated with RA's clinical findings. PMID- 28578495 TI - Timeline of Intestinal Adaptation After Malabsortive Surgery: Effect of Luminal Nutrients, Biliopancreatic Secretion, and Glutamine Supplementation. AB - BACKGROUND: The aim of this study was to study the process of intestinal adaptation in the three limbs of the small intestine after malabsorptive bariatric surgery: the biliopancreatic limb, the alimentary limb, and the common channel. These limbs are exposed to different stimuli, namely, gastrointestinal transit and nutrients in the alimentary limb, biliopancreatic secretions in the biliopancreatic limb, and a mix of both in the common channel. We also wished to investigate the effect of glutamine supplementation on the adaptation process. METHODS: Three types of surgery were performed using a porcine model: biliopancreatic bypass (BPBP), massive (75%) short bowel resection as the positive control, and a sham operation (transection) as the negative control. We measured the height and width of intestinal villi, histidine decarboxylase (HDC) activity, and amount of HDC messenger RNA (mRNA) (standard diet or a diet supplemented with glutamine). RESULTS: An increase in HDC activity and mRNA expression was observed in the BPBP group. This increase coincided with an increase in the height and width of the intestinal villi. The increase in villus height was observed immediately after surgery and peaked at 2 weeks. Levels remained higher than those observed in sham-operated pigs for a further 4 weeks. CONCLUSIONS: The intestinal adaptation process in animals that underwent BPBP was less intense than in those that underwent massive short bowel resection and more intense than in those that underwent transection only. Supplementation with glutamine did not improve any of the parameters studied, although it did appear to accelerate the adaptive process. PMID- 28578496 TI - ThDof1.4 and ThZFP1 constitute a transcriptional regulatory cascade involved in salt or osmotic stress in Tamarix hispida. AB - Identification of the upstream regulators of a gene is important to characterize the transcriptional pathway and the function of the gene. Previously, we found that a zinc finger protein (ThZFP1) is involved in abiotic stress tolerance of Tamarix hispida. In the present study, we further investigated the transcriptional pathway of ThZFP1. Dof motifs are abundant in the ThZFP1 promoter; therefore, we used them to screen for transcriptional regulators of ThZFP1. A Dof protein, ThDof1.4, binds to the Dof motif specifically, and was hypothesized as the upstream regulator of ThZFP1. Further study showed that overexpression of ThDof1.4 in T. hispida activated the expression of GUS controlled by the ThZFP1 promoter. In T. hispida, transient overexpression of ThDof1.4 increased the transcripts of ThZFP1; conversely, transient RNAi silencing of ThDof1.4 reduced the expression of ThZFP1. Chromatin immunoprecipitation indicated that ThDof1.4 binds to the ThZFP1 promoter. Additionally, ThDof1.4 and ThZFP1 share similar expression patterns in response to salt or drought stress. Furthermore, like ThZFP1, ThDof1.4 could increase the proline level and enhance ROS scavenging capability to improve salt and osmotic stress tolerance. Together, these results suggested that ThDof1.4 and ThZFP1 form a transcriptional regulatory cascade involved in abiotic stress resistance in T. hispida. PMID- 28578497 TI - Authors' Reply to Luft: "Measuring the Volume-Outcome Relation for Complex Hospital Surgery". PMID- 28578498 TI - CORR Insights(r): Knee Abduction Affects Greater Magnitude of Change in ACL and MCL Strains Than Matched Internal Tibial Rotation In Vitro. PMID- 28578500 TI - Real-World Impact of Cardiovascular Disease and Anemia on Quality of Life and Productivity in Patients with Non-Dialysis-Dependent Chronic Kidney Disease. AB - INTRODUCTION: Patients with chronic kidney disease (CKD) have an increased risk of comorbid conditions, including cardiovascular disease (CVD). Anemia is prevalent in the CKD population and worsens as kidney function declines, resulting in a diminished quality of life and increased morbidity/mortality. The purpose of this secondary analysis was to determine the real-world prevalence of CVD among patients with non-dialysis-dependent CKD (NDD-CKD), with and without comorbid anemia, and to assess the impact of these conditions on quality of life (QoL) and work productivity. METHODS: Data were drawn from the Adelphi CKD Disease-Specific Programme, conducted in France, Germany, Italy, Spain, and the UK (2012). Anonymized data were collected via patient record forms and patient completed questionnaires. Patient data were stratified by anemic status and the presence of CVD comorbidity. RESULTS: Data were collected by physicians for 1993 patients, of whom 867 completed a patient-completed questionnaire. A total of 61.4% of patients had anemia, and the prevalence of anemia increased with CKD stage. Patients with anemia had a higher mean number of cardiovascular comorbidities than non-anemic patients (1.27 vs 0.95, respectively; P < 0.001). The presence of cardiovascular conditions was associated with a significantly reduced QoL (EuroQol EQ-5D-3L visual analog scale: coefficient, -5.68 in anemic patients; P = 0.028) and work productivity and activity impairment (WPAI activity impairment: coefficient, +8.04 in anemic patients; P = 0.032), particularly among anemic patients. CONCLUSIONS: The presence of anemia in this cohort of NDD-CKD patients was high. The presence of concomitant cardiovascular conditions was more common in NDD-CKD patients with comorbid anemia, and was associated with reduced QoL and work productivity outcomes. PMID- 28578499 TI - Thermal treatment of luteolin-7-O-beta-glucoside improves its immunomodulatory and antioxidant potencies. AB - Phytochemicals extracted from flowers, roots and bark, leaves, and other plant sources have been used extensively throughout human history with varying levels of efficacy in prevention and treatment of disease. Recently, advanced methods for characterization and clinical use of these materials have allowed modern understanding of their properties to be used as immunomodulatory agents that act by enhancement of endogenous cytoprotective mechanisms, avoiding interference with normal physiologic signaling and highly effective medical treatment with minimal adverse side effects. Simple methods have been identified for improving their biological effects, such as thermal conditioning by heating or freezing prominent example being heat treatment of lycopene and tetrahydrocannabinol. The present investigation shows improvement of the ability of heat to augment splenocyte proliferation, natural killer (NK) cell activities, and antioxidant capacity of the flavonoid luteolin-7-O-beta-glucoside (L7G) in comparison with the native (non heat-treated) molecule, while further demonstrating that both the native and the heat-treated variants exhibit comparable antioxidant properties, as evidenced by their effects in macrophages by inhibition of nitric oxide production and lysosomal enzyme activity in experiments that strengthen lysosomal membrane integrity. Outcomes of these studies suggest that heat-treated L7G shows promise for use in immunotherapy, including anti-cancer regimens, as shown by its improvement of NK cell cytotoxicity. PMID- 28578501 TI - Monitoring for and Characterizing Crizotinib Progression: A Chart Review of ALK Positive Non-Small Cell Lung Cancer Patients. AB - INTRODUCTION: Crizotinib is recommended as first-line therapy for ALK-positive non-small cell lung cancer (NSCLC), but within a year of treatment initiation many patients develop resistance. With the recent approval of second-generation ALK inhibitors, this study assessed how physicians monitor for and diagnose progression and how they alter treatment following progression on crizotinib. METHODS: A panel of oncologists from the United States were surveyed regarding their monitoring practices and criteria for diagnosing progression on crizotinib. The physicians also retrospectively provided data (March-June 2016) from the medical charts of their adult patients with locally advanced or metastatic ALK positive NSCLC who progressed on crizotinib after the approval (April 2014) of the first second-generation ALK inhibitor, ceritinib. RESULTS: A total of 28 physicians responded to the survey. Data was abstracted on 74 patients. In the physician survey, most physicians (71%) reported monitoring for radiographic progression every 3-4 months. When new lesions were detected, physician response varied. Following a symptomatic isolated lesion, most physicians (75%) would add local therapy and resume crizotinib. Following multiple symptomatic lesions, 96% and 64% of physicians would switch to a new therapy depending on whether the lesions were extracranial or isolated to the brain, respectively. For the patient cohort, physician-defined progression on crizotinib was diagnosed after a median of 10 months, and within 30 days of diagnosis, 86% of patients discontinued crizotinib. Among all patients who discontinued crizotinib, 77% switched to ceritinib, 14% to chemotherapy, and 1% to alectinib. The remaining 7% did not receive additional systemic antineoplastic therapy. CONCLUSION: The findings from this physician survey and retrospective chart review study suggest that physician response to the development of new lesions in crizotinib-treated ALK-positive NSCLC patients varies with location and extent of the lesions. Once patients were considered to have progressed, most of them were immediately switched to ceritinib. FUNDING: Novartis Pharmaceuticals Corporation. PMID- 28578502 TI - Promotor analysis of ESR1 in endometrial cancer cell lines, endometrial and endometriotic tissue. AB - PURPOSE: The nuclear hormone receptor estrogen receptor alpha (ERalpha) is pivotal for numerous processes in the cell. As a transcription factor, it regulates eukaryotic gene expression and affects cellular proliferation and differentiation in target tissues. Moreover, ERalpha is known for its influence on various gynecological diseases and carcinogenesis. Since its expression is often altered in diseased tissues and this alteration was found to be caused by hypermethylation of the ESR1 promotor region in cancer, including breast and colorectal cancer, the aim of this study is to elucidate if the expression of ERalpha is also regulated epigenetically in endometriosis and endometrial cancer. METHODS: Using real-time methylation-specific PCR (rt-MSP), we examined endometrial and endometriotic tissues as well as five endometrial cancer cell lines and compared the methylation status with the actual expression of ERalpha. RESULTS: The results of our study indicate that, though its expression is altered in endometrial and endometriotic tissue, ERalpha is not regulated by methylation of the promotor region in endometriosis. In contrast, three of the five endometrial cancer cell lines are methylated in the promotor region of ESR1. CONCLUSIONS: Thus, further investigation of the connection between ERalpha and endometrial cancer will be the next step. PMID- 28578503 TI - Journal impact factor and methodological quality of surgical randomized controlled trials: an empirical study. AB - PURPOSE: The journal impact factor (IF) is often used as a surrogate marker for methodological quality. The objective of this study is to evaluate the relation between the journal IF and methodological quality of surgical randomized controlled trials (RCTs). METHODS: Surgical RCTs published in PubMed in 1999 and 2009 were identified. According to IF, RCTs were divided into groups of low (<2), median (2-3) and high IF (>3), as well as into top-10 vs all other journals. Methodological quality characteristics and factors concerning funding, ethical approval and statistical significance of outcomes were extracted and compared between the IF groups. Additionally, a multivariate regression was performed. RESULTS: The median IF was 2.2 (IQR 2.37). The percentage of 'low-risk of bias' RCTs was 13% for top-10 journals vs 4% for other journals in 1999 (P < 0.02), and 30 vs 12% in 2009 (P < 0.02). Similar results were observed for high vs low IF groups. The presence of sample-size calculation, adequate generation of allocation and intention-to-treat analysis were independently associated with publication in higher IF journals; as were multicentre trials and multiple authors. CONCLUSION: Publication of RCTs in high IF journals is associated with moderate improvement in methodological quality compared to RCTs published in lower IF journals. RCTs with adequate sample-size calculation, generation of allocation or intention-to-treat analysis were associated with publication in a high IF journal. On the other hand, reporting a statistically significant outcome and being industry funded were not independently associated with publication in a higher IF journal. PMID- 28578504 TI - Focus on O-phosphohydroxylysine, O-phosphohydroxyproline, N 1-phosphotryptophan and S-phosphocysteine. AB - The synthesis and chemistry of the lesser-known phosphoamino acids, O phosphohydroxylysine, O-phosphohydroxyproline, N 1-phosphotryptophan and S phosphocysteine are described in detail. In addition, where anything at all is known, the biological synthesis, occurrence and functions of these phosphoamino acids are described. Of these phosphoamino acids, only N 1-phosphotryptophan has not been reported to occur in proteins; however, apart from the roles of S phosphocysteine in the sugar transporter component (EII) and in catalysis by protein phosphotyrosine phosphatase, little is currently known about the biological roles of the phosphoamino acids when they occur as post-translational modifications. PMID- 28578505 TI - Family history and risk of breast cancer: an analysis accounting for family structure. AB - PURPOSE: Family history is an important risk factor for breast cancer incidence, but the parameters conventionally used to categorize it are based solely on numbers and/or ages of breast cancer cases in the family and take no account of the size and age-structure of the woman's family. METHODS: Using data from the Generations Study, a cohort of over 113,000 women from the general UK population, we analyzed breast cancer risk in relation to first-degree family history using a family history score (FHS) that takes account of the expected number of family cases based on the family's age-structure and national cancer incidence rates. RESULTS: Breast cancer risk increased significantly (P trend < 0.0001) with greater FHS. There was a 3.5-fold (95% CI 2.56-4.79) range of risk between the lowest and highest FHS groups, whereas women who had two or more relatives with breast cancer, the strongest conventional familial risk factor, had a 2.5-fold (95% CI 1.83-3.47) increase in risk. Using likelihood ratio tests, the best model for determining breast cancer risk due to family history was that combining FHS and age of relative at diagnosis. CONCLUSIONS: A family history score based on expected as well as observed breast cancers in a family can give greater risk discrimination on breast cancer incidence than conventional parameters based solely on cases in affected relatives. Our modeling suggests that a yet stronger predictor of risk might be a combination of this score and age at diagnosis in relatives. PMID- 28578506 TI - First international consensus conference on standardization of oncoplastic breast conserving surgery. AB - PURPOSE: To obtain consensus recommendations for the standardization of oncoplastic breast conserving surgery (OPS) from an international panel of experts in breast surgery including delegates from the German, Austrian and Swiss societies of senology. METHODS: A total of 52 questions were addressed by electronic voting. The panel's recommendations were put into context with current evidence and the report was circled in an iterative open email process until consensus was obtained. RESULTS: The panelists considered OPS safe and effective for improving aesthetic outcomes and broadening the indication for breast conserving surgery (BCS) towards larger tumors. A slim majority believed that OPS reduces the rate of positive margins; however, there was consensus that OPS is associated with an increased risk of complications compared to conventional BCS. The panel strongly endorsed patient-reported outcomes measurement, and recommended selected scales of the Breast-QTM-Breast Conserving Therapy Module for that purpose. The Clough bi-level classification was recommended for standard use in clinical practice for indicating, planning and performing OPS, and the Hoffmann classification for surgical reports and billing purposes. Mastopexy and reduction mammoplasty were the only two recognized OPS procedure categories supported by a majority of the panel. Finally, the experts unanimously supported the statement that every OPS procedure should be tailored to each individual patient. CONCLUSIONS: When implemented into clinical practice, the panel recommendations may improve safety and effectiveness of OPS. The attendees agreed that there is a need for prospective multicenter studies to optimize patient selection and for standardized criteria to qualify and accredit OPS training centers. PMID- 28578508 TI - Editorial comment to article: Pediatric Thoracic SCIWORA After Back Bend During Dance Practice: A Retrospective Case Series and Analysis of Trauma Mechanisms. PMID- 28578507 TI - Breast cancer electron intraoperative radiotherapy: assessment of preoperative selection factors from a retrospective analysis of 758 patients and review of literature. AB - PURPOSE: To report our experience with full-dose 21 Gy IORT in early breast cancer patients after breast-conserving surgery to define most important selection factors. METHODS: Seven hundred and fifty eight patients, subjected to conserving surgery and IORT, were retrospectively analyzed evaluating most important clinical outcomes. RESULTS: Median follow up was 5.2 years. Results from Cox analyses defined 2 groups of patients, "suitable" (age > 50 years, non lobular histology, tumour size <= 2 cm, pN0 or pNmic, ki67 <= 20%, non triple negative receptor status and G1-G2) and "unsuitable" for IORT, with a higher rate of breast related events moving from "suitable" to "unsuitable" group. The 5 year rate of IBR is 1.8% in suitable group with significant differences versus unsuitable (1.8 vs. 11.6%, p < 0.005). Same differences between two groups were evidenced in true local relapse (0.6 vs. 6.9%, p < 0.005) and in new ipsilateral BC (1.1 vs. 4.7%, p < 0.015). CONCLUSIONS: In our current practice we consider the following preoperative factors to select patients suitable for IORT: age > 50 years, absence of lobular histology, tumor size <= 2 cm, pN0 or pNmic, according to APBI consensus statement, including also ki67 <= 20%, non triple negative receptor status and G1-G2. PMID- 28578509 TI - A case of awake craniotomy surgery in an 8-year-old girl. PMID- 28578510 TI - Trans-falcine and contralateral sub-frontal electrode placement in pediatric epilepsy surgery: technical note. AB - INTRODUCTION: Phase II monitoring with intracranial electroencephalography (ICEEG) occasionally requires bilateral placement of subdural (SD) strips, grids, and/or depth electrodes. While phase I monitoring often demonstrates a preponderance of unilateral findings, individual studies (video EEG, single photon emission computed tomography [SPECT], and positron emission tomography [PET]) can suggest or fail to exclude a contralateral epileptogenic onset zone. This study describes previously unreported techniques of trans-falcine and sub frontal insertion of contralateral SD grids and depth electrodes for phase II monitoring in pediatric epilepsy surgery patients when concern about bilateral abnormalities has been elicited during phase I monitoring. METHODS: Pediatric patients with medically refractory epilepsy undergoing stage I surgery for phase II monitoring involving sub-frontal and/or trans-falcine insertion of SD grids and/or depth electrodes at the senior author's institution were retrospectively reviewed. Intra-operative technical details of sub-frontal and trans-falcine approaches were studied, while intra-operative complications or events were noted. Operative techniques included gentle subfrontal retraction and elevation of the olfactory tracts (while preserving the relationship between the olfactory bulb and cribriform plate) to insert SD grids across the midline for coverage of the contralateral orbito-frontal regions. Trans-falcine approaches involved accessing the inter-hemispheric space, bipolar cauterization of the anterior falx cerebri below the superior sagittal sinus, and sharp dissection using a blunt elevator and small blade scalpel. The falcine window allowed contralateral SD strip, grid, and depth electrodes to be inserted for coverage of the contralateral frontal regions. RESULTS: The study cohort included seven patients undergoing sub-frontal and/or trans-falcine insertion of contralateral SD strip, grid, and/or depth electrodes from February 2012 through June 2015. Five patients (71%) experienced no intra-operative events related to contralateral ICEEG electrode insertion. Intra-operative events of frontal territory venous engorgement (1/7, 14%) due to sacrifice of anterior bridging veins draining into the SSS and avulsion of a contralateral bridging vein (1/7, 14%), probably due to prior anterior corpus callosotomy, each occurred in one patient. There were no intra-operative or peri-operative complications in any of the patients studied. Two patients required additional surgery for supplemental SD strip and/or depth electrodes via burr hole craniectomy to enhance phase II monitoring. All patients proceeded to stage II surgery for resection of ipsilateral epileptogenic onset zones without adverse events. CONCLUSIONS: Trans-falcine and sub-frontal insertion of contralateral SD strip, grid, and depth electrodes are previously unreported techniques for achieving bilateral frontal coverage in phase II monitoring in pediatric epilepsy surgery. This technique obviates the need for contralateral craniotomy and parenchymal exposure with limited, remediable risks. Larger case series using the method described herein are now necessary. PMID- 28578511 TI - Cranial ultrasound is a reliable first step imaging in children with suspected craniosynostosis. AB - PURPOSE: Skull radiography (SR) and Computed Tomography (CT) are still proposed as the first-line imaging choice for the diagnosis of craniosynostosis (CS) in children with abnormal head shape, but both techniques expose infants to ionizing radiation. Several studies shown that ultrasound may play an important role in the diagnosis of craniosynostosis. The aim of our study is to assess the diagnostic accuracy of cranial ultrasound scan (CUS) and confirm if it is a reliable first step imaging evaluation for the diagnosis of craniosynostosis in newborn. METHOD: A cohort of 196 infants (122/74 males/females), with a mean age of 4 months, clinically suspected to have abnormal closure of cranial sutures, were firstly examined by CUS and then referred to neuroradiologists to perform volumetric CT scan if the suspicion of stenosis was ecographically confirmed; otherwise, a routine follow-up and physical treatment was performed, to observe the evolution of the head shape. RESULTS: Of the 196 children studied by CUS, only two had inconclusive studies due to age limitation (>12 months). Thirty children were diagnosed with cranial synostosis at CUS and verified by CT; all the CUS results were confirmed, except two cases, that were revealed as false positives in the starting phase of the study. Twelve patients with very prominent head deformity and negative CUS underwent CT, which confirmed the CUS results in all of them; one case of closure of both temporal sutures, not studied by CUS, was documented by CT. All the 148 children with poor clinical suspicion and negative CUS underwent just a prolonged clinical follow-up. In all of them, a progressive normalization of head shape was observed, and the craniosynostosis was excluded on a clinical base. CONCLUSIONS: CUS is a highly specific and sensitive imaging technique. In referral centers, expert hands can use it as a reliable first-step screening for infants younger than 1 year, suspected to have a craniosynostosis, thus avoiding unnecessary exposure to ionizing radiation. The "golden age" to obtain the best CUS results is under 6 months of life. Because the method is operator-dependent and there is a learning curve, a case centralization is advisable. PMID- 28578512 TI - Infected colloid cyst. AB - INTRODUCTION: Colloid cysts are the most common pathologic lesions of the third ventricle. Although they are histologically benign, they may grow and can cause the hydrocephalus. A 5-year-old male patient underwent to surgery with the diagnosis of colloid cyst. In operation, after the anterior transcallosal approach, the cyst was punctured by syringe and obviously pus aspirated. CONCLUSION: Colloid cysts mostly remain silent and detected incidentally. Although it is rarely defined, rhinorrhea, hypopituitarism, diabetes insipidus, spasmodic torticollis, drop attack, aseptic meningitis, and coexistence with neurocysticercosis have been reported, but this is the first reported case of an infected colloid cyst. PMID- 28578513 TI - The role of FV 1691G>A, FII 20210G>A mutations and MTHFR 677C>T; 1298A>C and 103G>T FXIII gene polymorphisms in pathogenesis of intraventricular hemorrhage in infants born before 32 weeks of gestation. AB - BACKGROUND: Congenital thrombophilia is associated with an increased intraventricular hemorrhage (IVH) risk among newborns, but it may also play a protective role. The role of genetic polymorphisms involved in the coagulation pathway of IVH pathogenesis is probably a consequence of an increased risk of thrombosis in the fine blood vessels in the germinal matrix region. MATERIAL AND METHODS: The aim of this study was to evaluate the possible relationship between Factor V (FV) 1691G>A, Factor II (FII) 20210G>A mutations and methylenetetrahydrofolate reductase (MTHFR) 677C>T; 1298A>C and Factor XIII (FXIII) 103G>T gene polymorphisms and the occurrence of IVH in 100 infants born from 24 + 0 to 32 + 0 weeks of gestation, born from singleton pregnancy, before 32 + 0 weeks of gestation, exposed to antenatal steroid therapy, and without congenital abnormalities. RESULTS: IVH developed 45 (45%) infants, including 15 (33.33%) diagnosed with IVH stage I, 20 (42.22%) with stage II, 8 (17.77%) with stage III, and 3 (6.66%) with stage IV. Analysis showed a prevalence 4.5 times higher of IVH stages II to IV in infants with the genotype CC (OR 4511 (1147 17.75); p = 0.026) of MTHFR 1298A>C gene polymorphism. Our investigation did not confirm any significant prevalence of IVH development in other studied mutations/polymorphisms. CONCLUSIONS: This study confirmed that the MTHFR 1298A>C polymorphism is associated with the risk of IVH. IVH is a significant problem for preterm infants. In addition to little progress in preventing IVH in preterm babies, substantial research that is focused on understanding the etiology, mechanism, and risk factors for IVH is imperative. In the era of personalized medicine, identification of genetic risk factors creates opportunities to generate preventative strategies. PMID- 28578515 TI - Blood assessment of the expression levels of matrix metalloproteinase 9 (MMP9) and its natural inhibitor, TIMP1 genes in Iranian schizophrenic patients. AB - Schizophrenia (SCZ) is the most severe chronic mental disorder characterized by abnormal social behavior and disrupted emotions and thought. Like other complex neuropsychological disease, SCZ is caused by a combination of genetic and environmental factors but with a high concordance rate. So far, different genetic factors are revealed to be associated with increased risk of developing SCZ. One of the best ways to investigate the genetic basis of the complex disease is to discover the genetic underlying mechanisms of the defective clinical aspects of the patients. In this regard, genes involved in the developmental mechanisms of the brain such as long-term potentiation (LTP) process that is the basis of synaptic plasticity, memory and learning are considered as strong candidates for SCZ. The aim of the present study was to evaluate the expression levels of two genes that are involved in the LTP regulation in the developing and adult brain, Matrix metallopeptidase9 (MMP9) and TIMP metallopeptidase inhibitor 1 (TIMP1) genes in a blood assessment of schizophrenic patients in comparison to healthy controls by means of quantitative real time PCR. The results of the study showed a significant difference in MMP9/TIPM1 ratio between SCZ patients and healthy controls (P = 0.01). However, no significant difference was detected in the expression level of individual MMP9 and TIMP1 genes in SCZ patients versus healthy controls either in total numbers of subject or in sex based subgroups. Considering the relatively small sample size of the current study, there is a need to replicate this study with further investigations about the mechanism of association of these genes and their functions in the pathogenesis of the SCZ. PMID- 28578516 TI - Risk Perception, Sexual Behaviors, and PrEP Adherence Among Substance-Using Men Who Have Sex with Men: a Qualitative Study. AB - The antiretroviral drug combination emtricitabine and tenofovir disoproxil fumarate (TDF/FTC) taken as pre-exposure prophylaxis (PrEP) is effective in preventing HIV infection, yet it also requires adherence and potentially decreases condom use. This study sought to examine these issues among a key population at risk of HIV infection, substance-using men who have sex with men (MSM). We conducted semi-structured interviews with an ethnically diverse sample of 30 young (aged 20-35) MSM prescribed PrEP within a large integrated healthcare system in San Francisco, who had reported recent drug use or hazardous drinking and one or more missed doses of PrEP. We explored participants' risk perception and sexual risk behavior, drug and alcohol use, and PrEP adherence in the context of substance use. Interviews were transcribed and coded using a directed content analysis approach to identify key categories and commonalities, and differences across participants. Salient subcategories included positive psychological effects of being on PrEP (e.g., decreased anxiety, feelings of empowerment), social effects (e.g., reduced HIV stigma), and reduction in overall perceptions of HIV risk. While overall reported use of condoms went down and many reported a brief period of increased condomless sex following PrEP initiation, others continued condom use with most of their sexual partners. Contextual factors influencing their decision to engage in condomless sex included how well they knew the partner and whether the partner was on PrEP or HIV antiretroviral treatment. Factors associated with poor adherence included disruptions in daily routine and use of alcohol and methamphetamine. PrEP-prescribing clinicians should support their patients in making informed decisions about condom use and identifying strategies to maximize adherence in the context of substance use. PMID- 28578517 TI - Phosphate Transporters Expression in Patients with Primary Familial Brain Calcifications. AB - Primary familial brain calcification (PFBC), formerly known as Fahr disease, is a rare neurological disorder characterized by extensive calcification deposits in the brain. So far, four genes have been reported with variations associated with PFBC, SLC20A2, PDGFbeta, PDGFRbeta, and XPR1. Using real-time qPCR, we analyzed the expression of three inorganic phosphate (Pi) transporters (SLC20A1, SLC20A2, and XPR1) in patients with PFBC. Our results showed a significant reduction (~40%) of SLC20A2 expression in the patients carrying mutation whereas no significant change was observed within the patients without known mutations. No difference was detected in SLC20A1 and XPR1 expression between the groups compared to control. The results suggest that mutations in SLC20A2 gene by itself play an import role by reducing its expression in blood of PFBC patients. At the same time, we could not demonstrate a direct co-regulation between the three Pi transporters at mRNA level, once their expression did not change among the groups. PMID- 28578518 TI - Using Simulated Data to Assess Case-Crossover Designs for Studying Less Transient Effects of Drugs. PMID- 28578519 TI - Validation of the Short Gambling Harm Screen (SGHS): A Tool for Assessment of Harms from Gambling. AB - It is common for jurisdictions tasked with minimising gambling-related harm to conduct problem gambling prevalence studies for the purpose of monitoring the impact of gambling on the community. However, given that both public health theory and empirical findings suggest that harms can occur without individuals satisfying clinical criteria of addiction, there is a recognized conceptual disconnect between the prevalence of clinical problem gamblers, and aggregate harm to the community. Starting with an initial item pool of 72 specific harms caused by problematic gambling, our aim was to develop a short gambling harms scale (SGHS) to screen for the presence and degree of harm caused by gambling. An Internet panel of 1524 individuals who had gambled in the last year completed a 72-item checklist, along with the Personal Wellbeing Index, the PGSI, and other measures. We selected 10 items for the SGHS, with the goals of maximising sensitivity and construct coverage. Psychometric analysis suggests very strong reliability, homogeneity and unidimensionality. Non-zero responses on the SGHS were associated with a large decrease in personal wellbeing, with wellbeing decreasing linearly with the number of harms indicated. We conclude that weighted SGHS scores can be aggregated at the population level to yield a sensitive and valid measure of gambling harm. PMID- 28578514 TI - The beneficial effects of HMG-CoA reductase inhibitors in the processes of neurodegeneration. AB - Statins, cholesterol lowering drugs, have been demonstrated to exert beneficial effects in other conditions such as primary and progressing neurodegenerative diseases beyond their original role. Observation that statins ameliorate the neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS) and cerebral ischemic stroke, the neuroprotective effects of these drugs are thought to be linked to their anti-inflammatory, anti oxidative, and anti-excitotoxic properties. Despite the voluminous literature on the clinical advantages of 3-hydroxy-3-methylglutaryl Co-enzyme A reductase (HMGCR) inhibitors (statins) in cardiovascular system, the neuroprotective effects and the underlying mechanisms are little understood. Hence, the present review tries to provide a critical overview on the statin-induced neuroprotection, which are presumed to be associated with the ability to reduce cholesterol, Amyloid-beta and apolipoprotein E (ApoE) levels, decrease reactive oxygen and nitrogen species (ROS and RNS) formation, inhibit excitotoxicity, modulate matrix metalloproteinases (MMPs), stimulate endothelial nitric oxide synthase (eNOS), and increase cerebral blood perfusion. This review is also aimed to illustrate that statins protect neurons against the neuro-inflammatory processes through balancing pro-inflammatory/anti-inflammatory cytokines. Ultimately, the beneficial role of statins in ameliorating the development of PD, AD, MS and cerebral ischemic stroke has been separately reviewed. PMID- 28578520 TI - Episodic and Binge Gambling: An Exploration and Preliminary Quantitative Study. AB - The DSM-5 includes provisions for episodic forms of gambling disorder, with such changes aligned with earlier accounts of potential binge gambling behaviours. However, there is little research that indicates the utility of these classifications of episodic or binge gambling, and this study considered their characteristics in a clinical sample. It involved administration of a new binge gambling screening tool, along with routine measures, to n = 214 patients entering a specialist treatment clinic for gambling problems. Results indicated that episodic gambling was common in this clinical context, with 28 and 32% of patients reporting gambling episodes that were (a) regular and alternating, and (b) irregular and intermittent, respectively. These patterns were distinguished by factors including associations with covariates that indicated differences from continuous gamblers. For example, the irregular episodic gamblers, but not the regular pattern, demonstrated lower levels of problem gambling severity and comorbidity. Rates of potential binge gambling, which was defined in terms of additional criteria, were around 4% and numbers were insufficient for comparable analyses. The findings support inclusion of episodic forms of gambling disorder in the DSM-5, but highlight the need for improved recognition and research on heterogeneous forms of episodic gambling. PMID- 28578521 TI - miR-138 promotes migration and tube formation of human cytomegalovirus-infected endothelial cells through the SIRT1/p-STAT3 pathway. AB - Human cytomegalovirus (HCMV) has been reported to be linked to vascular disease through the induction of neovessel formation. We have previously reported that microRNA (miR)-217 and miR-199a-5p enhance endothelial angiogenesis via inhibition of sirtuin 1 (SIRT1) in HCMV-infected human umbilical vein endothelial cells (HUVECs). Here, we found that miR-138 also suppressed the expression of the SIRT1 protein and stimulated phosphorylation of signal transducer and activator of transcription 3 (p-STAT3). Moreover, the regulation of p-STAT3 expression mediated by SIRT1 was found to promote HCMV-induced angiogenesis. These findings revealed that miR-138 might promote angiogenesis of HCMV-infected HUVECs by activating the SIRT1-mediated p-STAT3 pathway, and this could provide novel insights into HCMV-induced angiogenesis. PMID- 28578522 TI - Evaluation of the oncolytic potential of R2B Mukteshwar vaccine strain of Newcastle disease virus (NDV) in a colon cancer cell line (SW-620). AB - Virotherapy is emerging as an alternative treatment of cancer. Among the candidate oncolytic viruses (OVs), Newcastle disease virus (NDV) has emerged as a promising non-engineered OV. In the present communication, we explored the oncolytic potential of R2B Mukteshwar strain of NDV using SW-620 colon cancer cells. SW-620 cells were xenografted in nude mice and after evaluation of the safety profile, 1 x 107 plaque forming units (PFU) of NDV were inoculated as virotherapeutic agent via the intratumoral (I/T) and intravenous (I/V) route. Tumor growth inhibition was compared with their respective control groups by gross volume and histopathological evaluation. Antibody titer and virus survival were measured by hemagglutination inhibition (HI)/serum neutralization test (SNT) and real-time PCR, respectively. During the safety trial, the test strain did not produce any abnormal symptoms nor weight loss in BALB/c mice. Significant tumor lytic activity was evident when viruses were injected via the I/T route. There was a 43 and 57% tumor growth inhibition on absolute and relative tumor volume basis, respectively, compared with mock control. On the same basis, the I/V route treatment resulted in 40 and 16% of inhibition, respectively. Histopathological examination revealed that the virus caused apoptosis, followed by necrosis, but immune cell infiltration was not remarkable. The virus survived in 2/2 mice until day 10 and in 3/6 mice by day 19, with both routes of administration. Anti-NDV antibodies were generated at moderate level and the titer reached a maximum of 1:32 and 1:64 via the I/T and I/V routes, respectively. In conclusion, the test NDV strain was found to be safe and showed oncolytic activity against the SW-620 cell line in mice. PMID- 28578523 TI - Genetic analysis of porcine circovirus type 2 in China. AB - Porcine circovirus type 2 (PCV2) is the cause of postweaning multisystemic wasting syndrome (PMWS), which encompasses several distinct symptoms in pigs. PCV2 infection and clinical incidence of PMWS have increased in recent years, possibly due to shifts in viral populations and mutations. In this study, we identified PVC2 strains currently afflicting pig populations in mainland China, because this is a prerequisite for developing a specific vaccine to control the spread of PMWS. We collected 235 tissue samples from 16 provinces between 2014 and 2016. Of these, 152 samples were positive for PCV2. We compared the sequences we obtained for the PVC2 capsid gene, ORF2, to those of the Chinese PCV2 sequences deposited in GenBank between 2002 and 2016 (n = 648). Phylogenetic analyses demonstrated that the PCV2d genotype was the most prevalent strain in the sample population included in GenBank and among the positive samples from this study. We also found one PCV2c strain among the GenBank sequences. Furthermore, PCV2a-2F was the predominant genotype in the PCV2a cluster. Amino acid sequence comparisons demonstrated 70.8-100% identity within PCV ORF2 and several consistent mutations in ORF2. More interestingly, six isolates were classified as recombinant strains. Cumulatively, this study represents the first comprehensive description of PCV2 strains distribution, including recent samples, in Chinese porcine populations. We demonstrate the existence of high genetic variability among PVC2 strains and the ability of this virus to rapidly evolve. PMID- 28578524 TI - The role of feedback delay in dual-task performance. AB - Doing two things at once is hard, and it is probably hard for various reasons. Here we aim to demonstrate that one so far barely considered reason is the monitoring of sensory action feedback, which detracts from processing of other concurrent tasks. To demonstrate this, we engaged participants in a psychological refractory period paradigm. The responses in the two tasks produced visual action effects. These effects occurred either immediately or they were delayed for the first of the two responses. We assumed that delaying these effects would engage a process of monitoring visual feedback longer, and delay a concurrent task more, as compared to immediate effects. This prediction was confirmed in two experiments. We discuss the reasons for feedback monitoring and its possible contribution to dual tasking. PMID- 28578525 TI - Emerging features of modality mappings in task switching: modality compatibility requires variability at the level of both stimulus and response modality. AB - The term modality compatibility refers to the similarity between the stimulus modality and the modality of response-related sensory consequences. Previous research showed evidence for modality compatibility benefits in task switching, when participants switch either between two modality compatible tasks (auditory vocal and visual-manual) or between two modality incompatible tasks (auditory manual and visual-vocal). However, it remained unclear whether there is also a modality compatibility benefit when participants switch between a modality compatible and an incompatible task. To this end, in Experiment 1, we kept the same design as in earlier studies, so participants had to switch either between modality compatible or modality incompatible spatial discrimination tasks, but in Experiment 2A, participants switched at the response level (manual/vocal) while we kept the stimulus modality constant across tasks, and in Experiment 2B, they switched at the stimulus level (visual/auditory) while we kept the response modality constant across tasks. We found increased switch costs in modality incompatible tasks in Experiment 1, but no such a difference between modality compatible and incompatible tasks in Experiment 2A and 2B, supporting the idea that modality incompatible tasks increase crosstalk, due to the response-based priming of the competing task, but this crosstalk is reduced if the competing task involves either the same stimulus modality or the same response modality. We conclude that a significant impact of modality compatibility in task switching requires variability at the level of both stimulus and response modality. PMID- 28578526 TI - The rising root sign: the magnetic resonance appearances of post-operative spinal subdural extra-arachnoid collections. AB - We present a case series of symptomatic post-operative spinal subdural extra arachnoid collections that displace the cauda equina roots anteriorly. This is described as the "rising root sign". PMID- 28578527 TI - Tuberous sclerosis and its rare association with macrodactyly and fibrous hamartomas. AB - Tuberous sclerosis complex is a genetic disease that results in abnormal cellular proliferation and hamartoma growths in multiple organ systems. However, macrodactyly and subcutaneous fibrous harmatomas are very uncommon associations with this disease. We see these rare manifestations in our case report of a 16 year-old female with tuberous sclerosis complex and discuss the imaging findings and pathogenetics of these manifestations. Through this, our report aims to expand the known clinical spectrum of features seen in tuberous sclerosis and aid in its diagnosis. PMID- 28578528 TI - Update on operative treatment of scapholunate (SL) instability for radiologists: part 1-SL ligament repair, dorsal capsulodesis and SL ligament reconstruction. AB - Scapholunate instability is the most common form of carpal instability. Imaging (especially radiography) plays an important role in the staging, management and post-operative follow-up of scapholunate (SL) instability. The goals of this article are to review the pre-operative staging of SL instability, the surgical options for repair and reconstruction of the SL ligament, along with the normal postoperative imaging findings as well as complications associated with these surgical options. PMID- 28578529 TI - Particulate matter air pollution: individual choices for improving cardiometabolic well-being. AB - Exposure to small particulate matter (PM2.5) has become the 5th highest ranking risk factor for death, responsible for 4.2 million deaths worldwide. PM pollution is also associated with cardiovascular disease and type 2 diabetes, and may contribute to deteriorate the already poor cardiometabolic outlook of the diabetic patient. Although most sources of outdoor air pollution are well beyond the control of individuals, there is still room for personal action. Health behaviors (smoking cessation, avoiding obesity, and increasing physical activity) may increase the poor life expectancy of individuals in the lowest income quartile of the Western population; moreover, a favorable lifestyle, (no current smoking, no obesity, physical activity at least once weekly, and a healthy diet pattern), may cut by nearly 50% the risk of coronary heart disease among people at high genetic risk. Things seem not immutable, as individual healthy choices do matter. PMID- 28578530 TI - Long lasting prophylaxis of iodine deficiency after a successful information campaign for iodized salt consumption. PMID- 28578531 TI - Discovery and molecular characterization of a novel enamovirus, Grapevine enamovirus-1. AB - In this study, we describe a novel putative Enamovirus member, Grapevine enamovirus-1 (GEV-1), discovered by high-throughput sequencing (HTS). A limited survey using HTS of 17 grapevines (Vitis spp.) from the south, southeast, and northeast regions of Brazil led to the detection of GEV-1 exclusively on southern plants, infecting four grapevine cultivars (Cabernet Sauvignon, Semillon, CG 90450, and Cabernet franc) with a remarkable identity of around 99% at the nucleotide level. This novel virus was only detected in multiple-virus infected plants exhibiting viral-like symptoms. GEV-1 was also detected on a cv. Malvasia Longa by RT-PCR. We performed graft-transmissibility assays on GEV-1. The organization, products, and cis-acting regulatory elements of GEV-1 genome are also discussed here. The near complete genome sequence of GEV-1 was obtained during the course of this study, lacking only part of the 3' untranslated terminal region. This is the first report of a virus in the family Luteoviridae infecting grapevines. Based on its genomic properties and phylogenetic analyses, GEV-1 should be classified as a new member of the genus Enamovirus. PMID- 28578532 TI - New insights on the systematics, palaeoecology and palaeobiology of a plesiosaurian with soft tissue preservation from the Toarcian of Holzmaden, Germany. AB - The Posidonienschiefer Formation (Toarcian) of Holzmaden, Baden-Wurttemberg in southwestern Germany has yielded several excellently preserved plesiosaurian specimens and received considerable research attention. The plesiosaurians found within these deposits are always significantly outnumbered by ichthyosaurs, and close examination of these rare specimens is crucial to a better understanding of the diversity and palaeoecology of Plesiosauria in this very peculiar ecosystem. The plesiosaurian specimen SMNS 51945 found in this area is a juvenile individual consisting of a partial, crushed skull and an exquisitely preserved post-cranial skeleton. Its anatomical characters seem to differ from the long-necked plesiosauroids Microcleidus brachypterygius and Seeleyosaurus guilelmiimperatoris that are the most abundant taxa within the plesiosaurian assemblage. The post cranial skeleton preserves very likely soft tissues composed of buff-coloured and dark-coloured structures around the vertebral column and hindlimb of the animal. A network of buff-coloured fibres located posterior to the hindlimb most likely represents phosphatised collagen fibres as already found in some ichthyosaur specimens, confirming that wing area in plesiosaurians was much larger than that suggested by skeletal remains alone. The specimen also contains gastroliths (sand sized grains mainly composed of quartz) in the stomach cavity suggesting the animal spent at least some of its time in shallow coastal waters, tens or hundreds of kilometres from the final place of burial. PMID- 28578533 TI - Unusually high-pitched neonate distress calls of the open-habitat Mongolian gazelle (Procapra gutturosa) and their anatomical and hormonal predictors. AB - In neonate ruminants, the acoustic structure of vocalizations may depend on sex, vocal anatomy, hormonal profiles and body mass and on environmental factors. In neonate wild-living Mongolian gazelles Procapra gutturosa, hand-captured during biomedical monitoring in the Daurian steppes at the Russian-Mongolian border, we spectrographically analysed distress calls and measured body mass of 22 individuals (6 males, 16 females). For 20 (5 male, 15 female) of these individuals, serum testosterone levels were also analysed. In addition, we measured relevant dimensions of the vocal apparatus (larynx, vocal folds, vocal tract) in one stillborn male Mongolian gazelle specimen. Neonate distress calls of either sex were high in maximum fundamental frequency (800-900 Hz), but the beginning and minimum fundamental frequencies were significantly lower in males than in females. Body mass was larger in males than in females. The levels of serum testosterone were marginally higher in males. No correlations were found between either body mass or serum testosterone values and any acoustic variable for males and females analysed together or separately. We discuss that the high frequency calls of neonate Mongolian gazelles are more typical for closed-habitat neonate ruminants, whereas other open-habitat neonate ruminants (goitred gazelle Gazella subgutturosa, saiga antelope Saiga tatarica and reindeer Rangifer tarandus) produce low-frequency (<200 Hz) distress calls. Proximate cause for the high fundamental frequency of distress calls of neonate Mongolian gazelles is their very short, atypical vocal folds (4 mm) compared to the 7-mm vocal folds of neonate goitred gazelles, producing distress calls as low as 120 Hz. PMID- 28578534 TI - Instruments to measure anxiety in children, adolescents, and young adults with cancer: a systematic review. AB - PURPOSE: The primary objective was to describe anxiety measurement instruments used in children and adolescents with cancer or undergoing hematopoietic stem cell transplantation (HSCT) and summarize their content and psychometric properties. METHODS: We conducted searches of MEDLINE, Embase, PsycINFO, HAPI, and CINAHL. We included studies that used at least one instrument to measure anxiety quantitatively in children or adolescents with cancer or undergoing HSCT. Two authors independently identified studies and abstracted study demographics and instrument characteristics. RESULTS: Twenty-seven instruments, 14 multi-item and 13 single-item, were used between 78 studies. The most commonly used instrument was the State-Trait Anxiety Inventory in 46 studies. Three multi-item instruments (Children's Manifest Anxiety Scale-Mandarin version, PROMIS Pediatric Anxiety Short Form, and the State-Trait Anxiety Inventory) and two single-item instruments (Faces Pain Scale-Revised and 10-cm Visual Analogue Scale, both adapted for anxiety) were found to be reliable and valid in children with cancer. CONCLUSIONS: We identified 14 different multi-item and 13 different single-item anxiety measurement instruments that have been used in pediatric cancer or HSCT. Only three multi-item and two single-item instruments were identified as being reliable and valid among pediatric cancer or HSCT patients and would therefore be appropriate to measure anxiety in this population. PMID- 28578535 TI - Effect of increased water intake on plasma copeptin in healthy adults. AB - PURPOSE: Inter-individual variation in median plasma copeptin is associated with incident type 2 diabetes mellitus, progression of chronic kidney disease, and cardiovascular events. In this study, we examined whether 24-h urine osmolality was associated with plasma copeptin and whether increasing daily water intake could impact circulating plasma copeptin. METHODS: This trial was a prospective study conducted at a single investigating center. Eighty-two healthy adults (age 23.6 +/- 2.9 years, BMI 22.2 +/- 1.5 kg/m2, 50% female) were stratified based upon habitual daily fluid intake volumes: arm A (50-80% of EFSA dietary reference values), arm B (81-120%), and arm C (121-200%). Following a baseline visit, arms A and B increased their water intake to match arm C for a period of 6 consecutive weeks. RESULTS: At baseline, plasma copeptin was positively and significantly associated with 24-h urine osmolality (p = 0.002) and 24-h urine specific gravity (p = 0.003) but not with plasma osmolality (p = 0.18), 24-h urine creatinine (p = 0.09), and total fluid intake (p = 0.52). Over the 6-week follow-up, copeptin decreased significantly from 5.18 (3.3;7.4) to 3.90 (2.7;5.7) pmol/L (p = 0.012), while urine osmolality and urine specific gravity decreased from 591 +/- 206 to 364 +/- 117 mOsm/kg (p < 0.001) and from 1.016 +/- 0.005 to 1.010 +/- 0.004 (p < 0.001), respectively. CONCLUSIONS: At baseline, circulating levels of copeptin were positively associated with 24-h urine concentration in healthy young subjects with various fluid intakes. Moreover, this study shows, for the first time, that increased water intake over 6 weeks results in an attenuation of circulating copeptin. CLINICAL TRIAL REGISTRATION NUMBER: NCT02044679. PMID- 28578536 TI - Population Pharmacokinetic and Exposure-Response Analyses of Prasugrel in Pediatric Patients with Sickle Cell Anemia. AB - BACKGROUND AND OBJECTIVE: Prasugrel, a P2Y12 adenosine diphosphate (ADP) receptor antagonist, inhibits ADP-mediated platelet activation and aggregation in patients with sickle cell anemia (SCA). We developed a population pharmacokinetic (popPK) model in pediatric patients from 2 to <18 years of age with SCA, and performed exposure-response evaluations to characterize the effects of prasugrel in a subset of these patients who weighed 19 kg or more and experienced at least two episodes of vaso-occlusive crises (VOC) in the past year. METHODS: A three compartment popPK model adapted from that used in adults with acute coronary syndrome was used to describe the relationship between plasma concentrations of prasugrel's active metabolite (Pras-AM) and time using data from phase II and III clinical studies in children. A VOC event rate model was developed from the phase III study to explore the exposure-response relationship between Pras-AM exposure and VOC, and included evaluation of covariates. RESULTS: The final popPK model for children with SCA provided a reasonable fit to Pras-AM plasma concentrations over time, with estimates of apparent clearance (CL/F) (172 L/h) and apparent volume of distribution (Vd/F) (51.7 L) that were comparable to previous studies in adults. The final model included weight as a covariate on both CL/F and Vd/F, and age as a covariate on CL/F. Analyses of safety (bleeding events requiring medical intervention) and efficacy (VOC event rate) variables showed no apparent relationship to model-predicted Pras-AM exposure quartiles, and no statistically significant effects of intrinsic or extrinsic factors on the VOC event rate were identified in the VOC event rate model. The effect of post hoc exposures on the VOC event rate did not reach statistical significance. CONCLUSIONS: A popPK model was developed that provided reasonable parameter estimates, goodness-of-fit diagnostics, and visual predictive checks when applied to Pras-AM plasma concentrations in pediatric patients with SCA. Post hoc exposures obtained from this model did not correlate with measures of VOC or bleeding events in this population. PMID- 28578538 TI - Phospholipids of New Zealand Edible Brown Algae. AB - Edible brown algae have attracted interest as a source of beneficial allenic carotenoid fucoxanthin, and glyco- and phospholipids enriched in polyunsaturated fatty acids. Unlike green algae, brown algae contain no or little phosphatidylserine, possessing an unusual aminophospholipid, phosphatidyl-O-[N-(2 hydroxyethyl) glycine], PHEG, instead. When our routinely used technique of 31P NMR analysis of phospholipids was applied to the samples of edible New Zealand brown algae, a number of signals corresponding to unidentified phosphorus containing compounds were observed in total lipids. NI (negative ion) ESI QToF MS spectra confirmed the presence of more familiar phospholipids, and also suggested the presence of PHEG or its isomers. The structure of PHEG was confirmed by comparison with a synthetic standard. An unusual MS fragmentation pattern that was also observed prompted us to synthesise a number of possible candidates, and was found to follow that of phosphatidylhydroxyethyl methylcarbamate, likely an extraction artefact. An unexpected outcome was the finding of ceramidephosphoinositol that has not been reported previously as occurring in brown algae. An uncommon arsenic-containing phospholipid has also been observed and quantified, and its TLC behaviour studied, along with that of the newly synthesised lipids. PMID- 28578537 TI - Identification and Characterization of a Novel Thermophilic, Organic Solvent Stable Lipase of Bacillus from a Hot Spring. AB - A novel lipase gene lip256 was cloned and identified from the genomic library of hot spring strain Bacillus sp. HT19. The deduced amino acid sequence of lip256 has less than 32% identity to a predicted esterase (Cog1752) from Photobacterium leiognathi lrivu.4.1 and contains a novel motif (GTSAG) that differs from other clusters in the lipase superfamily. Following purification, a single band was obtained with a molecular mass of 33 kDa by SDS-PAGE, and the optimal temperature and pH for lipolytic activity of Lip25 were 70 degrees C and 9.0, respectively. Lip256 exhibited high activity at high temperatures, with 40% maximum activity at 80 degrees C and good stability at temperatures ranges between 50 and 80 degrees C. Additionally, the enzyme was highly stable in the presence of butyl alcohol, glycerol, acetonitrile, pyridine, and urea. However, the presence of acetone, methanol, trichloromethane, petroleum ether, hexane, tert-butanol, isopropanol, dithiothreitol, ethylenediaminetetraacetic acid, polyhexamethylene biguanide, dimethyl sulfoxide, benzene, Triton X-100, Tween-20, Tween-80, and sodium dodecyl sulfate suppressed or absolutely inhibited enzyme activity. Furthermore, Ca2+, Mg2+, and Cu2+ suppressed enzyme activity, whereas Na+, Fe3+, K+, Fe2+, and Sr2+ enhanced enzyme activity. The unique characteristics of novel lipase Lip256, including its thermo-alkaliphilic performance, high tolerance toward metal ions, inhibitors, and detergents, and high stability in organic solvents, implied that this enzyme might be an interesting candidate for industrial processes. PMID- 28578539 TI - Fibroblast contributes for osteoblastic phenotype in a MAPK-ERK and sonic hedgehog signaling-independent manner. AB - We hypothesized that a crosstalk between osteoblast and fibroblast (FB) exists, which contributes to bone as a dynamic tissue. Cell-free supernatants were harvested from fibroblast cultures and later subject pre-osteoblasts to investigate there capacity to modulate cell viability and differentiation mechanisms, reporting the possible involvement of Shh signaling as a paracrine mechanism. By exploring immunoblotting technology, we have shown that FB-released factors interfere with osteoblast metabolism by up-regulating the phosphorylation of FAK and Rac-1 proteins at the early stage and later contribute to osteoblast differentiation by up-modulating alkaline phosphatase (ALP) and in vitro mineralization. We also found that Shh signaling was not required during osteoblastic differentiation promoted by the FB-released factors as well as MAPK ERK phosphorylation, while pre-osteoblast cultures subjected to osteogenic medium (O.M.) require downstream transducers of Shh, such as Patched and Gli-1, and MAPK ERK. Altogether, our results indicate for the first time a possible mechanism involved in the crosstalk between fibroblasts and osteoblasts, as it was possible to observe trophic factors released by fibroblasts interfering decisively in osteoblast metabolism in a Shh-independent manner. This study collaborates the body of work that indicates paracrine signaling molecules participate in the crosstalk among bone-resident cells and explains, at least partially, the biological mechanisms responsible for bone tissue dynamism, opening new avenues to understand etiologies of bone diseases. PMID- 28578540 TI - Application of chemometric techniques in studies of toxicity of selected commercially available products for infants and children. AB - The goal of the present study is to assess the impact of the experimental conditions for extraction procedures (time of extraction, thermal treatment and type of extraction media) as applied to several baby and infant products checked for their possible ecotoxicological response when tested by various ecotoxicity tests (Microtox(r), Ostracodtoxkit FTM and Xenoscreen YES/YASTM). The systems under consideration are multidimensional by nature and, therefore, the appropriate assessment approach was intelligent data analysis (chemometrics). Hierarchical cluster analysis (HCA) and principal component analysis (PCA) were selected as reliable data mining methods for the interpretation of the ecotoxicity data. We show that the different experimental conditions have a significant impact on the ecotoxicity levels observed, especially those measured by Microtox(r) and Ostracodtoxkit FTM tests. The time of contact proves to be a very significant factor for all extraction media and ecotoxicity test procedures. The present study is a pioneering effort to offer a specific expert approach for analysing links between the type of test measurement methodology and imposed experimental conditions to mimic real-life circumstances in the use of baby and infant products. PMID- 28578542 TI - Citrate versus heparin anticoagulation in continuous renal replacement therapy in small children. AB - BACKGROUND: Citrate is preferred over heparin as an anticoagulant in adult continuous renal replacement therapy (CRRT). However, its potential adverse effects and data on use in CRRT in infants and toddlers is limited. We conducted a prospective study on using citrate in CRRT in critically ill small children. METHODS: Children who underwent CRRT with the smallest filter in our PICU between November 2011 and November 2016 were included. Both heparin and citrate were applied according to a strict protocol. Our primary outcome was circuit survival time. Secondary outcomes were alkalosis, citrate toxicity, and number of red blood cell transfusions. RESULTS: Heparin was used in six patients (121 circuits, total CRRT time 3723 h). Citrate was used in 14 patients (105 circuits, total CRRT time 4530 h). Median circuit survival time with heparin was 21 h (IQR 14.5 27.5) compared to 45.2 h (IQR 37.5-52.8) with citrate (p < 0.001). Actual administered effluent dose compared to prescribed dose was 85% (IQR 69-98%) with heparin compared to 92% (IQR 88-98%) with citrate (p = 0.31). No patient treated with citrate developed citrate toxicity. No other differences in electrolytes were found between the two CRRT regimes. In the heparin group, a median of 6.5 units of red blood cells (IQR 1.5-23.8) were given during CRRT, compared to three in the citrate group (IQR 2.0-5.0, p = 0.12). CONCLUSIONS: Use of regional citrate significantly prolongs circuit survival time and thereby should increase CRRT efficiency when compared to heparin. In addition, citrate appears safe for CRRT in critically ill small children. PMID- 28578541 TI - Anthropometric and Physical Qualities of Elite Male Youth Rugby League Players. AB - Rugby league is a collision team sport played at junior and senior levels worldwide, whereby players require highly developed anthropometric and physical qualities (i.e. speed, change-of-direction speed, aerobic capacity, muscular strength and power). Within junior levels, professional clubs and national governing bodies implement talent identification and development programmes to support the development of youth (i.e. 13-20 years) rugby league players into professional athletes. This review presents and critically appraises the anthropometric and physical qualities of elite male youth rugby league players aged between 13 and 20 years, by age category, playing standard and playing position. Height, body mass, body composition, linear speed, change-of-direction speed, aerobic capacity, muscular strength and power characteristics are presented and demonstrate that qualities develop with age and differentiate between playing standard and playing position. This highlights the importance of anthropometric and physical qualities for the identification and development of youth rugby league players. However, factors such as maturity status, variability in development, longitudinal monitoring and career attainment should be considered to help understand, identify and develop the physical qualities of youth players. Further extensive research is required into the anthropometric and physical qualities of youth rugby league players, specifically considering national standardised testing batteries, links between physical qualities and match performance, together with intervention studies, to inform the physical development of youth rugby league players for talent identification and development purposes. PMID- 28578543 TI - Lessons Learned From the Implementation of Seek, Test, Treat, Retain Interventions Using Mobile Phones and Text Messaging to Improve Engagement in HIV Care for Vulnerable Populations in the United States. AB - In the United States, little is known about interventions that rely on mobile phones and/or text messaging to improve engagement in HIV care for vulnerable populations. Domestic studies using these technologies as part of the National Institute on Drug Abuse "Seek, Test, Treat, Retain" research initiative were queried regarding intervention components, implementation issues, participant characteristics, and descriptive statistics of mobile phone service delivery. Across five studies with 1,135 predominantly male, minority participants, implementation challenges occurred in three categories: (1) service interruptions; (2) billing/overage issues, and; (3) the participant user experience. Response rules for automated text messages frequently frustrated participants. The inability to reload minutes/texting capacity remotely was a significant barrier to intervention delivery. No study encountered confidentiality breaches. Service interruption was common, even if studies provided mobile phones and plans. Future studies should attend to the type of mobile phone and service, the participant user experience, and human subjects concerns. PMID- 28578545 TI - Modifiable lifestyle factors associated with osteoporosis in Korean men: a case control study. AB - : The prevention, education, and treatment of osteoporosis are all recognized as important components in men as well as women. This study revealed that the lifestyle factors associated with male osteoporosis included being underweight and being a current smoker. Being overweight or obese and having a regular exercise habit were negatively associated with male osteoporosis. PURPOSE: Osteoporosis is a significant health problem in Korea and worldwide. Although osteoporosis is less prevalent in males than in females, the fracture-related mortality rate is higher in males than in females. The aim of this study was to investigate the relationship of modifiable lifestyle factors in males with osteoporosis. METHODS: A case-control study was performed in men who visited a single university hospital for a medical check-up between August 2003 and July 2016. Patients were classified in the case group according to the World Health Organization (WHO) Osteoporosis Criteria. The control group was created by matching patients according to age and check-up date. Lifestyle factors were evaluated by a self-assessment questionnaire. Multivariate conditional logistic regression was used to examine the association between lifestyle factors and male osteoporosis with age stratification at 50 years. RESULTS: A total of 1304 subjects were included in this analysis, 326 of whom were in the case group and 978 of whom were in the control group. Within their age group, subjects with osteoporosis were more often underweight (odds ratio [OR] = 2.35, 95% confidence interval [CI], 1.11-4.98) or more often current smokers (2.22, 1.50-3.28) than control subjects. The subjects who were overweight (0.45, 0.32-0.64), obese (0.19, 0.13-0.27), had an irregular exercise habit (0.64, 0.43-0.94), or had a regular exercise habit (0.40, 0.28-0.57) were more likely to have normal bone status. Alcohol drinking habit had no significant association with male osteoporosis. CONCLUSIONS: Several modifiable lifestyle factors were associated with male osteoporosis. Current smokers at any age and underweight men below age 50 were more likely to have osteoporosis, whereas men who were overweight, obese, or had a regular exercise habit were more likely to have normal bone status, regardless of age. PMID- 28578544 TI - Effects of Minimal Versus Intensive Intervention to Enhance Motivational Interviewing in HIV Care. AB - We conducted a randomized trial comparing the effect of two different levels of motivational interviewing training on clinician communication behaviors and patient experiences. We enrolled 12 HIV clinicians who attended a one-day MI workshop focusing on behavior change counseling skills. We then randomized clinicians to receive (or not) 3-5 rounds of personalized feedback from the MI trainer. We compared outcomes before and after the interventions and between the intervention groups. We tested time-by-study arm interactions to determine if one group improved more than the other. For all analyses, we used generalized estimating equations to account for clustering of patients within clinicians, with Gaussian or negative binomial distributions as appropriate. Patients of clinicians in both intervention groups rated their visits as more MI consistent (6.86 vs. 6.65, p = 0.005) and audio-recording analysis revealed that visits were more patient-centered (1.34 vs. 0.96, p = 0.003) with a more positive patient affect (22.36 vs. 20.84, p < 0.001) after versus before the intervention, without differences between intervention arms. Several specific clinician behaviors such as empathic statements, asking patient opinions and open-ended questions improved more in the workshop+feedback versus the workshop-only intervention arm. A few specific communication behaviors increased (total and complex reflections) after versus before the intervention, without differences between intervention arms. The workshop alone was as effective as the workshop plus feedback in improving patient experiences and overall communication measures. Certain communication behaviors improved more with the more intensive intervention, but these additional benefits may not warrant the extra financial and logistical resources required. PMID- 28578546 TI - Bread and Butter. PMID- 28578547 TI - Controversies and Evolving Concepts in Hospital-Acquired Pneumonia. PMID- 28578548 TI - Using Ventilator-Associated Pneumonia Rates as a Health Care Quality Indicator: A Contentious Concept. AB - Pneumonia is a leading cause of hospital-acquired infections, although reported rates of ventilator-associated pneumonia (VAP) have been declining in recent years. A multifaceted infection prevention approach, using a "ventilator bundle," has been shown to reduce the frequency of VAP, while improving other patient outcomes. Because of difficulties in defining VAP, the Center for Medicare and Medicaid Service introduced a new streamlined ventilator-associated event (VAE) definition in 2013 for the surveillance of complications in mechanically ventilated patients. VAE measures are increasingly being measured by institutions in the United States in place of VAP rates and as a potential measure of the quality of intensive care unit (ICU) care. However, there is increased recognition that the streamlined definitions identify a different subset of patients than those identified by traditional VAP surveillance and that VAP prevention strategies may not impact all the causes of VAE. Also, VAP and VAE rates may not always reflect the quality of care in a given ICU, especially since patient factors, beyond the control of the hospital, may impact the rates of VAP and VAE. In this review, we discuss the issues related to VAP as a quality measure and the areas of uncertainty related to the new VAE definitions. PMID- 28578549 TI - Should We Immediately Start Antibiotics in Every Patient with a Clinical Suspicion of HAP/VAP? AB - Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) remain two of the most commonly diagnosed nosocomial infections. Both are responsible for significant morbidity and mortality in hospitalized patients. The development of HAP and VAP is related to bacterial colonization of the oropharynx (and endotracheal tube in VAP) with subsequent microaspiration and development of clinical infection. Diagnosis is made based on the clinical presentation and can be confirmed by obtaining either noninvasive or invasive microbiology culture specimens. Decisions addressing initiation of antimicrobial therapy can be divided into clinical and bacteriological strategies. These strategies differ in the criteria used to determine the timing of empiric therapy, with the clinical strategy basing the decision on radiographic evidence of infection plus clinical signs and symptoms and the bacteriological strategy requiring growth of pathogens above a certain threshold from invasively obtained culture specimens. Despite the delineated pathways, these decisions remain multifactorial and should also include consideration of patient-related factors, such as immunocompetence, the risk of multidrug-resistant infection, and overall clinical condition. Patients with risk factors or signs of clinical decompensation should have empiric therapy initiated at a lower threshold. However, when possible, therapy should be directed at a confirmed infection following a positive culture result. Decisions regarding specific empiric regimens should be based on the local prevalence of infectious microorganisms along with their associated antimicrobial susceptibilities. Patients deemed at risk of infection with multidrug-resistant pathogens merit broader spectrum therapy, and immunosuppressed patients should have consideration of antifungal coverage. PMID- 28578550 TI - Ventilator-Associated Pneumonia: The Role of Emerging Diagnostic Technologies. AB - Antibiotic resistance has emerged as a key determinant of outcome in patients with serious infections along with the virulence of the underlying pathogen. Within the intensive care unit (ICU) setting, ventilator-associated pneumonia (VAP) is a common nosocomial infection that is frequently caused by multidrug resistant bacteria. Antimicrobial resistance is a growing challenge in the care of critically ill patients. Escalating rates of antibiotic resistance add substantially to the morbidity, mortality, and cost related to infection in the ICU. Both gram-positive organisms, such as methicillin-resistant Staphylococcus aureus and vancomycin-intermediate S. aureus, and gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter species, carbapenem-resistant Enterobacteriaceae, such as the Klebsiella pneumoniae carbapenemase-producing bacteria, and extended spectrum beta-lactamase organisms, have contributed to the escalating rates of resistance seen in VAP and other nosocomial infections. The rising rates of antimicrobial resistance have led to the routine empiric administration of broad-spectrum antibiotics even when bacterial infection is not documented. Moreover, there are several new broader-spectrum antibiotics that have recently become available and others scheduled for approval in the near future. The challenge to ICU clinicians is how to most effectively utilize these agents to maximize patient benefits while minimizing further emergence of resistance. Use of rapid diagnostics may hold the key for achieving this important balance. There is an urgent need for integrating the administration of new and existing antibiotics with the emerging rapid diagnostic technologies in a way that is both cost-effective and sustainable for the long run. PMID- 28578551 TI - Should We Treat Ventilator-Associated Tracheobronchitis with Antibiotics? AB - Patients admitted to intensive care units (ICUs) often require lung organ support. The use of mechanical ventilation, while lifesaving can be associated with subsequent complications. The most common complication in patients under mechanical ventilation is the development of ventilator-associated lower respiratory tract infections (VA-LRTIs). Before the development of VA-LRTI, there is a continuum process that ranges from airway colonization to ventilator associated pneumonia (VAP). There is an intermediate process called ventilator associated tracheobronchitis (VAT). Contemporary treatment of VA-LRTI emphasizes the importance of prompt broad-spectrum antimicrobial therapy. Previous studies reported prolonged duration of mechanical ventilation and ICU stay in patients with VAT. This negative impact on outcome is related to increased inflammation of the lower respiratory tract, sputum production, and higher rates of VAP. Extubation failure and difficult weaning have been reported to be associated with increased sputum volume in mechanically ventilated patients. Antibiotic treatment for VAT patients is still a matter for debate. Observational studies suggested a beneficial effect of antimicrobial treatment in VAT patients, including a reduced duration of mechanical ventilation and lower rates of subsequent VAP. Previous studies demonstrated beneficial effects of systemic and aerosolized antibiotics in preventing VAP in critically ill patients. However, antibiotic treatment is a recognized risk factor for the emergence of multidrug-resistant bacteria. Infections related to these bacteria are associated with increased morbidity, mortality, and cost. Therefore, a large well-designed study is warranted to determine whether patients with VAT should receive antimicrobials. Furthermore, a short course of antimicrobials could be sufficient in these patients. PMID- 28578552 TI - Pharmacokinetic/Pharmacodynamics-Optimized Antimicrobial Therapy in Patients with Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia. AB - Hospital-acquired pneumonia and ventilator-associated pneumonia continue to cause significant morbidity and mortality. With increasing rates of antimicrobial resistance, the importance of optimizing antibiotic treatment is key to maximize treatment outcomes. This is especially important in critically ill patients in intensive care units, in whom the infection is usually caused by less susceptible organisms. In addition, the marked physiological changes that can occur in these patients can cause serious changes in antibiotic pharmacokinetics which in turn alter the attainment of therapeutic drug exposures. This article reviews the various aspects of the pharmacokinetic changes that can occur in the critically ill patients, the barriers to achieving therapeutic drug exposures in pneumonia for systemically delivered antibiotics, the optimization for commonly used antibiotics in hospital- and ventilator-associated pneumonia, the agents that should be avoided in the treatment regimen, as well as the use of adjunctive therapy in the form of nebulized antibiotics. PMID- 28578553 TI - How Should We Treat Hospital-Acquired and Ventilator-Associated Pneumonia Caused by Extended-Spectrum beta-Lactamase-Producing Enterobacteriaceae? AB - Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) due to extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) represent a growing problem. Indeed, ESBL-PE is endemic in many countries, and 5 to 25% of intensive care unit (ICU) patients are ESBL-PE carrier on ICU admission. ESBL-PE HAP/VAP is associated with a higher mortality than HAP/VAP due to susceptible Enterobacteriaceae because the resistance profile decreases the adequacy rate of empiric therapy. ESBL-PE should be considered in the empirical treatment in case of the high burden of ESBL-PE in the unit, in the case of previous ESBL-PE colonization, when the HAP/VAP occurs late, and in patients with shock. A negative active systematic surveillance culture on rectal swab reduced the risk of ESBL-PE VAP to less than 1%. Rapid diagnostic tests are now able to confirm the presence of ESBL-PE in VAP within 24 hours; new molecular methods will provide results within few hours.Adequate treatment usually required carbapenems. The alternative beta-lactams such as beta-lactams/beta-lactamases inhibitor combinations could be proposed as a step-down therapy according to the antibiotic susceptibility result. Optimization of pharmacokinetics requires high dosage and continuous or prolonged infusions for beta-lactams. When the patient is stabilized, a therapy of duration 7 to 8 days is recommended. PMID- 28578554 TI - How Should We Treat HAP/VAP Caused by Carbapenemase-Producing Enterobacteriaceae? AB - Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) represent a common problem in hospital setting worldwide. Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are an emergent problem due to the lack of therapeutic options available, leading to significant increases in morbidity and mortality. CRE have frequently been reported both in HAP/VAP, but limited data regarding the optimal treatment strategy in this setting are available. This review focuses on the current epidemiology of CRE, with a specific focus on HAP/VAP. Moreover, we will suggest a possible strategy for the empiric and targeted treatment of HAP and VAP in which the involvement of CRE is suspected or is confirmed. PMID- 28578555 TI - Infections Due to Acinetobacter baumannii in the ICU: Treatment Options. AB - Bacteria within the genus Acinetobacter (principally A. baumannii-calcoaceticus complex [ABC]) are gram-negative coccobacilli that may cause nosocomial infections in critically ill or debilitated patients (particularly ventilator associated pneumonia and infections of the bloodstream, urinary tract, and wounds). Treatment of Acinetobacter infections is difficult, as Acinetobacter spp. are intrinsically resistant to multiple antimicrobial agents, and have a remarkable ability to acquire new resistance determinants via mechanisms that include plasmids, transposons, integrons, and resistance islands. Since the 1990s, global resistance to antimicrobials has escalated dramatically among ABC. Global spread of multidrug-resistant (MDR)-A. baumannii strains reflects dissemination of a few clones between hospitals, geographic regions, and continents; excessive use of antibiotics amplifies this spread. Many isolates are resistant to all antimicrobials except colistin (polymyxin E) and tigecycline, and some infections are untreatable with existing antimicrobial agents. Antimicrobial resistance poses a serious threat to treat or prevent infections due to ABC. Strategies to curtail environmental colonization with MDR-ABD will require aggressive infection control efforts and cohorting of infected patients. Thoughtful antibiotic strategies are essential to limit the spread of MDR-ABC. Optimal therapy will likely require combination antimicrobial therapy of existing antibiotics as well as development of novel antibiotic classes. PMID- 28578556 TI - Emergence of Antimicrobial Resistance among Pseudomonas aeruginosa: Implications for Therapy. AB - Pseudomonas aeruginosa (PA), a nonlactose fermenting gram-negative bacillus, is a common cause of nosocomial infections in critically ill or debilitated patients, particularly ventilator-associated pneumonia (VAP), and infections of bloodstream, urinary tract, intra-abdominal, wounds/skin/soft tissue. PA rarely affects healthy individuals, but may cause serious infections in patients with chronic structural lung disease, comorbidities, advanced age, impaired immune defenses, or with medical devices (e.g., urinary or intravascular catheters, foreign bodies). Treatment of pseudomonal infections is difficult, as PA is intrinsically resistant to multiple antimicrobials, and may acquire new resistance determinants even while on antimicrobial therapy. Mortality associated with pseudomonal VAP or bacteremias is high (> 35%) and optimal therapy is controversial. Over the past three decades, antimicrobial resistance among PA has escalated globally, via dissemination of several international multidrug resistant "epidemic" clones. We review the emergence of antimicrobial resistance to this pathogen, and discuss approaches to therapy (both empirical and definitive). PMID- 28578557 TI - New Strategies Targeting Virulence Factors of Staphylococcus aureus and Pseudomonas aeruginosa. AB - Morbidity, mortality, and economic burden of nosocomial pneumonia caused by Staphylococcus aureus and Pseudomonas aeruginosa remain high in mechanically ventilated and hospitalized patients despite the use of empirical antibiotic therapy or antibiotics against specific classes of pathogens and procedures to reduce nosocomial infections in hospital settings. Newer agents that neutralize or inhibit specific S. aureus or P. aeruginosa virulence factors may eliminate or reduce the risk for developing pneumonia before or during mechanical ventilation and may improve patient outcomes through mechanisms that differ from those of antibiotics. In this article, we review the types, mechanisms of action, potential advantages, and stage of development of antivirulence agents (AVAs) that hold promise as alternative preventive or interventional therapies against S. aureus- and P. aeruginosa-associated nosocomial pneumonias. We also present and discuss challenges to the effective utilization of AVAs separately from or in addition to antibiotics and the design of clinical trials and meaningful study end points. PMID- 28578558 TI - Is There a Role for Inhaled Antibiotics in the Treatment of Ventilator-Associated Infections? AB - The increasing emergence of multidrug-resistant organisms creates a therapeutic challenge for physicians treating ventilator-associated respiratory infections. As the production of new systemic antibiotics lags far behind the emergence of worsening antibiotic resistance, intensivists are turning to inhaled antibiotics to use as adjunctive therapy. When given properly, these drugs can provide high concentrations of drug in the lung that could not be achieved with intravenous antibiotics without significant systemic toxicity. This review summarizes current evidence describing the use of inhaled antibiotics for the treatment of bacterial ventilator-associated infections. Inhaled adjunctive therapy has been described in numerous small nonrandomized studies and in six recent randomized placebo controlled trials. Inhaled therapy has also been used to treat ventilator associated tracheobronchitis. These preliminary data suggest aerosolized delivery of antimicrobials may effectively treat resistant pathogens with high minimum inhibitory concentrations when used in time-limited protocols and delivered with devices known to deposit antibiotics in the area of infection. Large, multisite, clinical, randomized placebo-controlled studies are needed to confirm these data. PMID- 28578559 TI - Body Position and Ventilator-Associated Pneumonia Prevention. AB - Seminal studies have demonstrated that tracheally intubated, mechanically ventilated patients, positioned in supine horizontal position, are at a high risk of developing ventilator-associated pneumonia, through aspiration of gastric pathogens. In the 1990s, innovative clinical findings promoted a radical change in practice, through the use of the semirecumbent position in all mechanically ventilated patients. Here, we critically review the main indications, pulmonary effects, and controversies on the use of the semirecumbent position. Also, we will depict potential roles of prone and lateral positions in the prevention of ventilator-associated pneumonia. Our review will span from preclinical experimental insights to clinical evidence, and we will discuss potential controversies on the use of the semirecumbent position as the standard of care. We will also detail potential alternatives to ultimately improve outcomes of tracheally intubated and mechanically ventilated patients. PMID- 28578560 TI - Oropharyngeal Decontamination with Antiseptics to Prevent Ventilator-Associated Pneumonia: Rethinking the Benefits of Chlorhexidine. AB - Daily oral care with chlorhexidine for mechanically ventilated patients is ubiquitous in contemporary intensive care practice. The practice is predicated upon meta-analyses suggesting that adding chlorhexidine to daily oral care regimens can reduce ventilator-associated pneumonia (VAP) rates by up to 40%. Close analysis, however, raises three concerns: (1) the meta-analyses are dominated by studies in cardiac surgery patients in whom average duration of mechanical ventilation is < 1 day and thus their risk of VAP is very different from other populations, (2) diagnosing VAP is subjective and nonspecific yet the meta-analyses gave equal weight to blinded and nonblinded studies, potentially biasing them in favor of chlorhexidine, and (3) there is circularity between diagnostic criteria for VAP and chlorhexidine; as an antiseptic, chlorhexidine may decrease the frequency of positive respiratory cultures but fewer cultures does not necessarily mean fewer pneumonias. It is therefore important to look at other outcomes for corollary evidence on whether or not oral chlorhexidine benefits patients. An updated meta-analysis restricted to double-blinded studies in noncardiac surgery patients showed no impact on VAP rates, duration of mechanical ventilation, or intensive care unit length of stay. Instead, there was a possible signal that oral chlorhexidine may increase mortality rates. Observational data have raised similar concerns. This article will review the theoretical basis for adding chlorhexidine to oral care regimens, delineate potential biases in randomized controlled trials comparing oral care regimens with and without chlorhexidine, explore the unexpected mortality signal associated with oral chlorhexidine, and provide practical recommendations. PMID- 28578561 TI - Continental impacts of water development on waterbirds, contrasting two Australian river basins: Global implications for sustainable water use. AB - The world's freshwater biotas are declining in diversity, range and abundance, more than in other realms, with human appropriation of water. Despite considerable data on the distribution of dams and their hydrological effects on river systems, there are few expansive and long analyses of impacts on freshwater biota. We investigated trends in waterbird communities over 32 years, (1983 2014), at three spatial scales in two similarly sized large river basins, with contrasting levels of water resource development, representing almost a third (29%) of Australia: the Murray-Darling Basin and the Lake Eyre Basin. The Murray Darling Basin is Australia's most developed river basin (240 dams storing 29,893 GL) while the Lake Eyre Basin is one of the less developed basins (1 dam storing 14 GL). We compared the long-term responses of waterbird communities in the two river basins at river basin, catchment and major wetland scales. Waterbird abundances were strongly related to river flows and rainfall. For the developed Murray-Darling Basin, we identified significant long-term declines in total abundances, functional response groups (e.g., piscivores) and individual species of waterbird (n = 50), associated with reductions in cumulative annual flow. These trends indicated ecosystem level changes. Contrastingly, we found no evidence of waterbird declines in the undeveloped Lake Eyre Basin. We also modelled the effects of the Australian Government buying up water rights and returning these to the riverine environment, at a substantial cost (>3.1 AUD billion) which were projected to partly (18% improvement) restore waterbird abundances, but projected climate change effects could reduce these benefits considerably to only a 1% or 4% improvement, with respective annual recovery of environmental flows of 2,800 GL or 3,200 GL. Our unique large temporal and spatial scale analyses demonstrated severe long-term ecological impact of water resource development on prominent freshwater animals, with implications for global management of water resources. PMID- 28578563 TI - Greetings from the new Editor-in-Chief of Digestive Endoscopy. PMID- 28578562 TI - Development and Initial Validation of the Alcohol Expectancy Task. AB - BACKGROUND: Although studies have shown that alcohol expectancies are prominent predictors of alcohol initiation and subsequent drinking levels, the questionnaires used to assess these expectancies among young adolescents have been criticized as being time-intensive, biased, and inappropriate. METHODS: In response, we developed the Alcohol Expectancy Task (AET), in which 8 scenarios featuring adults in everyday situations and in different emotional states, accompanied by photographs of a range of beverages (4 alcoholic, 8 nonalcoholic), are displayed on a tablet screen, and participants are then asked to tap on the beverage they think the given person had been drinking. RESULTS: In a first study among 184 adults (75.1% women; mean age = 37.8, SD = 12.2), results from a repeated-measures analysis of variance revealed a strong correspondence between the emotions depicted in the scenarios and how the participants interpreted them. In a second study, this time among 283 third and fourth graders (50.2% girls; mean age = 10.6, SD = 0.69), a confirmatory factor analysis confirmed the 4 factor structure of the AET. The results from a logistic regression analysis showed that the more often young adolescents assigned alcohol to the adults in an arousal-positive mood than to those in a sedation-negative mood, the more likely they were to have already consumed alcohol more than twice. Questionnaire assessed expectancies were unrelated to adolescents' drinking and did not affect the associations of the AET. CONCLUSIONS: The AET has the advantage of being time efficient and convenient and could overcome certain limitations associated with questionnaire-based assessments of alcohol expectancy. PMID- 28578564 TI - Balloon Expulsion Test Does Not Seem to Be Useful for Screening or Exclusion of Dyssynergic Defecation as a Single Test. AB - Background/Aims: Balloon expulsion test (BET) is regarded as a screening tool of dyssynergic defecation (DD). However, some patients with normal BET results may be treated effectively by biofeedback training. This study aims to validate BET as a single screening test. Methods: Two hundred and thirty-two patients who were diagnosed with functional constipation or irritable bowel syndrome with constipation who underwent anorectal manometry (ARM) and BET at Seoul National University Hospital were enrolled. We evaluated the validity of BET based on ARM and electromyography (EMG) during biofeedback training. Results: If BET <= 1 minute was defined as normal, sensitivity and negative predictive value (NPV) of BET in predicting paradoxical contraction based on ARM findings were 71.4% and 13.9%. If BET <= 3 minutes was defined as normal, sensitivity and NPV were 35.2% and 6.6%. Specificity and positive predictive value (PPV) of BET <= 3 minutes criteria were 84.8% and 93.3%. Same analysis was conducted in 107 patients who underwent EMG during biofeedback training. With 1-minute criteria, sensitivity and NPV of BET were 70.3% and 14.3%. With 3 minutes criteria, sensitivity and NPV of BET was 38.6% and 8.8%. Specificity and positive predictive values were both 100.0%. Conclusions: Based on either ARM or EMG during biofeedback training, sensitivity was at most 71.4% and NPV was less than 15.0% irrespective of whether BET was within 1minute or within 3 minutes. BET seems to have a limitation as both a screening test for dyssynergic defecation and a simple assessment to rule out the necessity of biofeedback training. PMID- 28578565 TI - Conditional Network Assembly and Targeted Protein Retention via Environmentally Responsive, Engineered beta-Roll Peptides. AB - Stimulus-responsive biomaterials have applications in many areas of biotechnology, such as tissue engineering, drug delivery, and bioelectrocatalysis. The intrinsically disordered repeat-in-toxin (RTX) domain is a conformationally dynamic peptide that gains beta-roll secondary structure when bound to calcium ions. A smart hydrogel platform was constructed by genetically fusing two rationally designed mutant RTX domains: first, a mutant peptide with hydrophobic interfaces capable of calcium-dependent network assembly, and second, another mutant that conditionally binds the model target protein lysozyme. In this way, the calcium-induced control over the secondary structure of the beta roll peptide was exploited to regulate both the cross-linking and lysozyme binding functionalities. The constructed biomaterial exhibited calcium-dependent gelation and target molecule retention, and erosion experiments showed that beta roll peptides with a higher affinity for lysozyme produced more robust hydrogel networks. This work demonstrates the use of RTX domains for introducing two useful features simultaneously, network cross-linking and target protein binding, and that the calcium-dependent regulation of these systems can be useful for controlling bulk self-assembly and controlled release capabilities. PMID- 28578566 TI - Enhanced Accessibility of Polycyclic Aromatic Hydrocarbons (PAHs) and Heterocyclic PAHs in Industrially Contaminated Soil after Passive Dosing of a Competitive Sorbate. AB - To assess the exposure to polycyclic aromatic hydrocarbons (PAHs) it is important to understand the binding mechanisms between specific soil constituents and the organic pollutant. In this study, sorptive bioaccessibility extraction (SBE) was applied to quantify the accessible PAH fraction in industrially contaminated soil with and without passive dosing of a competitive sorbate. SBE experiments revealed an accessible PAH fraction of 41 +/- 1% (?16 US EPA PAHs + 5 further PAHs). The passive dosing of toluene below its saturation level revealed competitive binding and resulted in an average increase of the accessible fraction to 49 +/- 2%, whereby primarily the accessibility of higher molecular weight PAHs (log Kow > 6) was affected. Competitive binding was verified using the same soil with only desorption-resistant PAHs present. In this experiment, passive dosing of toluene resulted in desorption of 13 +/- 0.4% PAH. We explain increased PAH desorption after addition of toluene by competitive adsorption to high-affinity sorption sites while acknowledging that toluene could additionally have increased PAH mobility within the soil matrix. Findings suggest that the presence of copollutants at contaminated sites deserves specific considerations as these may increase accessibility and thereby exposure and mobility of PAHs. PMID- 28578567 TI - Quantitative Profiling of Endogenous Fat-Soluble Vitamins and Carotenoids in Human Plasma Using an Improved UHPSFC-ESI-MS Interface. AB - Analytical solutions enabling the quantification of circulating levels of liposoluble micronutrients such as vitamins and carotenoids are currently limited to either single or a reduced panel of analytes. The requirement to use multiple approaches hampers the investigation of the biological variability on a large number of samples in a time and cost efficient manner. With the goal to develop high-throughput and robust quantitative methods for the profiling of micronutrients in human plasma, we introduce a novel, validated workflow for the determination of 14 fat-soluble vitamins and carotenoids in a single run. Automated supported liquid extraction was optimized and implemented to simultaneously parallelize 48 samples in 1 h, and the analytes were measured using ultrahigh-performance supercritical fluid chromatography coupled to tandem mass spectrometry in less than 8 min. An improved mass spectrometry interface hardware was built up to minimize the post-decompression volume and to allow better control of the chromatographic effluent density on its route toward and into the ion source. In addition, a specific make-up solvent condition was developed to ensure both analytes and matrix constituents solubility after mobile phase decompression. The optimized interface resulted in improved spray plume stability and conserved matrix compounds solubility leading to enhanced hyphenation robustness while ensuring both suitable analytical repeatability and improved the detection sensitivity. The overall developed methodology gives recoveries within 85-115%, as well as within and between-day coefficient of variation of 2 and 14%, respectively. PMID- 28578568 TI - Calcium l-Lactate Frameworks as Naturally Degradable Carriers for Pesticides. AB - Two porous, chiral metal-organic frameworks (MOFs), Ca14(l lactate)20(acetate)8(C2H5OH)(H2O) (MOF-1201) and Ca6(l-lactate)3(acetate)9(H2O) (MOF-1203), are constructed from Ca2+ ions and l-lactate [CH3CH(OH)COO-], where Ca2+ ions are bridged by the carboxylate and hydroxyl groups of lactate and the carboxylate group of acetate to give a three-dimensional arrangement of Ca(-COO, OH) polyhedra supporting one-dimensional pores with apertures and internal diameters of 7.8 and 9.6 A (MOF-1201) and 4.6 and 5.6 A (MOF-1203), respectively. These MOFs represent the first examples of extended porous structures based on Ca2+ and lactate. They show permanent porosity of 430 and 160 m2 g-1, respectively, and can encapsulate an agriculturally important fumigant, cis-1,3 dichloropropene. MOF-1201 shows a 100 times lower release rate compared with liquid cis-1,3-dichloropropene under the same test conditions (25 degrees C, air flow rate of 1 cm3 min-1). The hydrolysis of MOF-1201 in water makes it the first example of a degradable porous solid carrier for such fumigants. PMID- 28578569 TI - Thermally Stable Metallic Nanoparticles Prepared via Core-Cross-linked Block Copolymer Micellar Nanoreactors. AB - Thermally stable metallic nanoparticles (MNPs) are highly desirable for the melt processing of polymer nanocomposites. However, due to the high surface energy penalty and decreased melting temperature, MNPs are easy to agglomerate and lose their unique properties if there is no protection or confinement layer. In this work, we report a facile and efficient way to synthesize thermally stable MNPs using core-cross-linked polystyrene-b-poly(4-vinylpyridine) (PS-b-P4VP) reverse micelles as nanoreactors. From infrared results, gold, silver, and palladium ions exhibited distinctive coordination to the 4VP groups with varying chelation strengths. Compared to the non-cross-linked micelles, 1,4-dibromobutane (DBB) cross-linking of the P4VP cores provided several advantages. First, it prevented severe swelling of the P4VP cores caused by the reducing agents and subsequent merger of swollen micelles. Second, the quaternized P4VP with hydrophilicity enhanced the uptake speed of precursor metal ions into the cores. Third, the cross-linked cores greatly stabilized the MNPs against the high-temperature environment (e.g., 110 degrees C for 40 h in toluene). In addition, the solubility of the reducing agents also played an important role. Anhydrous hydrazine could swell the P4VP cores and concentric core-shell particle morphology was obtained. On the contrary, triethylsilane could not swell the P4VP cores and thus eccentric core-shell particle morphology was observed. Only the concentric core-shell MNPs exhibited good thermal stability, whereas the eccentric core-shell MNPs did not. This work suggested that these thermally stable MNPs could be good candidates for the melt processing of functional polymer nanocomposites. PMID- 28578570 TI - Superconductivity in Alkaline Earth Metal-Filled Skutterudites BaxIr4X12 (X = As, P). AB - We report superconductive iridium pnictides BaxIr4X12 (X = As and P) with a filled skutterudite structure, demonstrating that Ba filling dramatically alters their electronic properties and induces a nonmetal-to-metal transition with increasing the Ba content x. The highest superconducting transition temperatures are 4.8 and 5.6 K observed for BaxIr4As12 and BaxIr4P12, respectively. The superconductivity in BaxIr4X12 can be classified into the Bardeen-Cooper Schrieffer type with intermediate coupling. PMID- 28578571 TI - Hypervalent-Iodine-Mediated Formation of Epoxides from Carbon(sp2)-Carbon(sp3) Single Bonds. AB - We have developed an efficient method for direct formation of epoxide groups from carbon(sp2)-carbon(sp3) single bonds of beta-keto esters; the reaction is mediated by the water-soluble hypervalent iodine(V) reagent AIBX (5 trimethylammonio-1,3-dioxo-1,3-dihydro-1lambda5-benzo[d][1,2]iodoxol-1-ol anion). On the basis of the results of density functional theory calculations and experimental studies, we propose that the reaction proceeds by a two-stage mechanism involving dehydrogenation of the beta-keto ester substrates and epoxidation of the resulting enone intermediates. The rate-limiting step is abstraction of the beta'-C-H (calculated free energy of activation, 24.5 kcal/mol). PMID- 28578572 TI - The Origins of Dramatic Differences in Five-Membered vs Six-Membered Chelation of Pd(II) on Efficiency of C(sp3)-H Bond Activation. AB - The origin of the unique effectiveness of six-membered chelates on the beta methylene C(sp3)-H activation reactions by Pd(II) catalyst was explained with density functional theory. The Pd(II) catalysts that involve five-membered chelates are inactive in this transformation. Computational studies suggest that the C(sp3)-H bond activation is the rate-limiting step in both cases. The C(sp3) H bond activation with a five-membered chelate is unfavorable by 7.7 kcal/mol compared to the corresponding six-membered chelate with Pd(II). Two factors cause the difference: (1) the dimeric Pd species with five-membered chelation square planar structure is more stable than that with six-membered chelation by 2.0 kcal/mol; (2) steric repulsion between the ArF group of the substrate and the quinoline group of the acetyl-protected aminomethyl quinoline ligand destabilizes the five-membered chelate transition structure by 5.7 kcal/mol. The six-membered chelate of Pd(II) with an acetyl-protected aminoethyl quinoline ligand orients the ligand away from the ArF group of the substrate and alleviates the steric repulsion. PMID- 28578573 TI - Antifungal and Antiviral Cyclic Peptides from the Deep-Sea-Derived Fungus Simplicillium obclavatum EIODSF 020. AB - A new linear peptide simplicilliumtide I (1) and four new cyclic peptides simplicilliumtides J-M (2-5) together with known analogues verlamelins A and B (6 and 7) were isolated from the deep-sea-derived fungal strain Simplicillium obclavatum EIODSF 020. Their structures were elucidated by spectroscopic analysis, and their absolute configurations were further confirmed by chemical structural modification, Marfey's and Mosher's methods. Compounds 2, 6, and 7 showed significant antifungal activity toward Aspergillus versicolor and Curvularia australiensis and also had obvious antiviral activity toward HSV-1 with IC50 values of 14.0, 16.7, and 15.6 MUM, respectively. The structure bioactivity relationship of this type of cyclic peptide was also discussed. This is the first time to discuss the effects of the lactone linkage and the substituent group of the fatty acid chain fragment on the bioactivity of this type of cyclic peptides. This is also the first time to report the antiviral activity of these cyclic peptides. PMID- 28578574 TI - Alternating 5,5-Dimethylcyclopentadiene and Diketopyrrolopyrrole Copolymer Prepared at Room Temperature for High Performance Organic Thin-Film Transistors. AB - We report that the inclusion of nonaromatic 5,5-dimethylcyclopentadiene monomer into a conjugated backbone is an attractive strategy to high performance semiconducting polymers. The use of this monomer enables a room temperature Suzuki copolymerization with a diketopyrrolopyrrole comonomer to afford a highly soluble, high molecular weight material. The resulting low band gap polymer exhibits excellent photo and thermal stability, and despite a large pi-pi stacking distance of 4.26 A, it demonstrates excellent performance in thin-film transistor devices. PMID- 28578575 TI - Mercury Temporal Trends in Top Predator Fish of the Laurentian Great Lakes from 2004 to 2015: Are Concentrations Still Decreasing? AB - Mercury (Hg) concentration trends in top predator fish (lake trout and walleye) of the Great Lakes (GL) from 2004 to 2015 were determined by Kendall-Theil robust regression with a cluster-based age normalization method to control for the effect of changes in lake trophic status. When data from the GLs (except Lake Erie) are combined, a significant decreasing trend in the lake trout Hg concentrations was found between 2004 and 2015 with an annual decrease of 4.1% per year, consistent with the decline in regional atmospheric Hg emissions and water Hg concentrations. However, a breakpoint was detected with a significant decreasing slope (-8.1% per year) before the breakpoint (2010), and no trend after the breakpoint. When the lakes are examined individually, Lakes Superior and Huron, which are dominated by atmospheric Hg inputs and are more likely than the lower lakes to respond to declining emissions from areas surrounding the GL, have significant decreasing trends with rates between 5.2 and 7.8% per year from 2004 to 2015. These declining trends appear to be driven by decreasing regional atmospheric Hg emissions although they may be partly counterbalanced by other factors, including increasing local emissions, food web changes, eutrophication, and responses to global climate change. Lakes Michigan, Erie and Ontario may have been more impacted by these other factors and their trends changed from decreasing to non-decreasing or increasing in recent years. PMID- 28578576 TI - Potential-Induced Aggregation of Anionic Porphyrins at Liquid|Liquid Interfaces. AB - The adsorption and self-aggregation of anionic porphyrins were studied at the polarized water|1,2-dichloroethane (DCE) interface by polarization-modulation total internal reflection fluorescence (PM-TIRF) spectroscopy. 5,10,15,20 Tetrakis(4-sulfonatophenyl)porphyrin diacid (H4TPPS2-) and protoporphyrin IX (H2PP2-) exhibited high surface activities at the interface. The selective excitation of interfacial species in PM-TIRF measurements elucidated the potential-induced aggregation mechanism of the porphyrins. The J-aggregates of H4TPPS2- were reversibly formed only at the water|DCE interface by applying appropriate potentials even when the porphyrins exist as monomers in the aqueous and organic solutions. In the H2PP2- system, the slow aggregation process was found in the negative potential region. The spectral characteristics and the signal phase of PM-TIRF indicated that the H2PP2- monomers were adsorbed with relatively standing orientation and that the long axis of the J-aggregates was nearly in plane of the interface. H2PP2- was also investigated at the biomimetic phospholipid-adsorbed water|DCE interface. The competitive adsorption of neutral glycerophospholipids effectively inhibited the potential-dependent adsorption and interfacial aggregation processes of H2PP2-. The results demonstrated that the aggregation state of the charged species can reversibly be controlled at liquid|liquid interfaces as a function of externally applied potential. PMID- 28578577 TI - Ultrathin Two-Dimensional Covalent Organic Framework Nanosheets: Preparation and Application in Highly Sensitive and Selective DNA Detection. AB - The ability to prepare ultrathin two-dimensional (2D) covalent organic framework (COF) nanosheets (NSs) in high yield is of great importance for the further exploration of their unique properties and potential applications. Herein, by elaborately designing and choosing two flexible molecules with C3v molecular symmetry as building units, a novel imine-linked COF, namely, TPA-COF, with a hexagonal layered structure and sheet-like morphology, is synthesized. Since the flexible building units are integrated into the COF skeletons, the interlayer stacking becomes weak, resulting in the easy exfoliation of TPA-COF into ultrathin 2D NSs. Impressively, for the first time, the detailed structural information, i.e., the pore channels and individual building units in the NSs, is clearly visualized by using the recently developed low-dose imaging technique of transmission electron microscopy (TEM). As a proof-of-concept application, the obtained ultrathin COF NSs are used as a novel fluorescence sensing platform for the highly sensitive and selective detection of DNA. PMID- 28578578 TI - Synthesis of Gold Nanoparticles from Au(I) Ions That Shuttle To Solidify: Application on the Sensor Array Design. AB - Metal-mediated interlocking rings won the 2016 Nobel Prize in Chemistry. The metal-directed interlocking rings in macromolecular systems (e.g., proteins) may be similar to the form of Maxwell's electromagnetic waves; the metal ions may shuttle among the rings in the special environment. To verify this hypothesis, we designed a general approach to synthesize the multicolored gold nanoparticles (GNPs) mediated by Au(I)-directed interlocking rings in proteins. The Au(I) ions shuttled among these interlocking rings in the strong alkaline solution. Through the rapid nucleation method, the multicolored GNPs of different morphology and sizes were synthesized in the multiple honeycombed templates. On the basis of the "three-color" principle of Thomas Young, we extracted the red, green, and blue (RGB) alterations of GNPs to fabricate a visual sensor array for protein discrimination. The fingerprints (DeltaRGB) were obtained from the target proteins and fed into computer programs. The proposed sensing platform was also applied to detect lysozyme in human tears with satisfactory results. Importantly, we forecasted that lysozyme could be the effective drug for curing dacryocystitis and nasolacrimal duct obstruction diseases. PMID- 28578579 TI - Simple and Efficient Generation of Aryl Radicals from Aryl Triflates: Synthesis of Aryl Boronates and Aryl Iodides at Room Temperature. AB - Despite the wide use of aryl radicals in organic synthesis, current methods to prepare them from aryl halides, carboxylic acids, boronic acids, and diazonium salts suffer from limitations. Aryl triflates, easily obtained from phenols, are promising aryl radical progenitors but remain elusive in this regard. Inspired by the single electron transfer process for aryl halides to access aryl radicals, we developed a simple and efficient protocol to convert aryl triflates to aryl radicals. Our success lies in exploiting sodium iodide as the soft electron donor assisted by light. This strategy enables the scalable synthesis of two types of important organic molecules, i.e., aryl boronates and aryl iodides, in good to high yields, with broad functional group compatibility in a transition-metal-free manner at room temperature. This protocol is anticipated to find potential applications in other aryl-radical-involved reactions by using aryl triflates as aryl radical precursors. PMID- 28578580 TI - Meroterpenoids with Antitumor Activities from Guava (Psidium guajava). AB - Psidium guajava L., a species native to South America, has been widely cultivated in the tropical and subtropical areas of China for its popular fruits. The preliminary analysis by liquid chromatography-ultraviolet (LC-UV) indicated the presence of meroterpenoids in the fruits of P. guajava (guava). Subsequent fractionation of the petroleum ether extract resulted in the identification of two new meroterpenoids, psiguajavadials A (1) and B (2), together with 14 previously described meroterpenoids (3-16). Their structures were fully elucidated by comprehensive spectroscopic techniques and theoretical calculations. All of the meroterpenoids showed cytotoxicities against five human cancer cell lines, with guajadial B (12) being the most effective having an IC50 value of 150 nM toward A549 cells. Furthermore, biochemical topoisomerase I (Top1) assay revealed that psiguajavadial A (1), psiguajavadial B (2), guajadial B (12), guajadial C (14), and guajadial F (16) acted as Top1 catalytic inhibitors and delayed Top1 poison-mediated DNA damage. The flow cytometric analysis indicated that the new meroterpenoids psiguajavadials A (1) and B (2) could induce apoptosis of HCT116 cells. These data suggest that meroterpenoids from guava fruit could be used for the development of antitumor agents. PMID- 28578581 TI - Kinetically Controlled Coassembly of Multichromophoric Peptide Hydrogelators and the Impacts on Energy Transport. AB - We report a peptide-based multichromophoric hydrogelator system, wherein pi electron units with different inherent spectral energies are spatially controlled within peptidic 1-D nanostructures to create localized energy gradients in aqueous environments. This is accomplished by mixing different pi-conjugated peptides prior to initiating self-assembly through solution acidification. We can vary the kinetics of the assembly and the degree of self-sorting through the choice of the assembly trigger, which changes the kinetics of acidification. The hydrolysis of glucono-delta-lactone (GdL) provides a slow pH drop that allows for stepwise triggering of peptide components into essentially self-sorted nanostructures based on subtle pKa differences, whereas HCl addition leads to a rapid formation of mixed components within a nanostructure. Using 1H NMR spectroscopy and fiber X-ray diffraction, we determine the conditions and peptide mixtures that favor self-sorting or intimate comixing. Photophysical investigations in the solution phase provide insight into the correlation of energy-transport processes occurring within the assemblies to the structural organization of the pi-systems. PMID- 28578582 TI - High-Yield Functional Molecular Electronic Devices. AB - An ultimate goal of molecular electronics, which seeks to incorporate molecular components into electronic circuit units, is to generate functional molecular electronic devices using individual or ensemble molecules to fulfill the increasing technical demands of the miniaturization of traditional silicon-based electronics. This review article presents a summary of recent efforts to pursue this ultimate aim, covering the development of reliable device platforms for high yield ensemble molecular junctions and their utilization in functional molecular electronic devices, in which distinctive electronic functionalities are observed due to the functional molecules. In addition, other aspects pertaining to the practical application of molecular devices such as manufacturing compatibility with existing complementary metal-oxide-semiconductor technology, their integration, and flexible device applications are also discussed. These advances may contribute to a deeper understanding of charge transport characteristics through functional molecular junctions and provide a desirable roadmap for future practical molecular electronics applications. PMID- 28578583 TI - Alkyne-Bridged Multi[Copper(II) Porphyrin] Structures: Nuances of Orbital Symmetry in Long-Range, Through-Bond Mediated, Isotropic Spin Exchange Interactions. AB - Spin and conformational dynamics in symmetric alkyne-bridged multi[copper(II) porphyrin] structures have been studied in toluene solution at variable temperature using steady-state electron paramagnetic resonance (EPR) spectroscopy. Comparison of the dimer EPR spectra to those of Cu porphyrin monomers shows evidence of an isotropic exchange interaction (Javg) in these biradicaloid structures, manifested by a significant line broadening in the dimer spectra. The extent line broadening depends on molecular structure and temperature, suggesting Javg is modulated by conformational dynamics that impact the torsional angle distribution between the porphyrin-porphyrin least-squares planes. Computational simulation of the experimental EPR spectra, using a developed algorithm for J modulation in flexible organic biradicals, supports this hypothesis. Comparison of ethyne and butadiyne alkyne bridges reveals remarkable sensitivity to orbital interactions between the spacer and the metal, reflected in measurements of Javg as a function of temperature. The results suggest orbital symmetry relationships may be more important than recognized in design of optimized molecular spintronic devices. PMID- 28578585 TI - High-Resolution Air Pollution Mapping with Google Street View Cars: Exploiting Big Data. AB - Air pollution affects billions of people worldwide, yet ambient pollution measurements are limited for much of the world. Urban air pollution concentrations vary sharply over short distances (?1 km) owing to unevenly distributed emission sources, dilution, and physicochemical transformations. Accordingly, even where present, conventional fixed-site pollution monitoring methods lack the spatial resolution needed to characterize heterogeneous human exposures and localized pollution hotspots. Here, we demonstrate a measurement approach to reveal urban air pollution patterns at 4-5 orders of magnitude greater spatial precision than possible with current central-site ambient monitoring. We equipped Google Street View vehicles with a fast-response pollution measurement platform and repeatedly sampled every street in a 30-km2 area of Oakland, CA, developing the largest urban air quality data set of its type. Resulting maps of annual daytime NO, NO2, and black carbon at 30 m-scale reveal stable, persistent pollution patterns with surprisingly sharp small-scale variability attributable to local sources, up to 5-8* within individual city blocks. Since local variation in air quality profoundly impacts public health and environmental equity, our results have important implications for how air pollution is measured and managed. If validated elsewhere, this readily scalable measurement approach could address major air quality data gaps worldwide. PMID- 28578584 TI - Long-Term Dietary Supplementation with Selenium-Enriched Yeast Improves Cognitive Impairment, Reverses Synaptic Deficits, and Mitigates Tau Pathology in a Triple Transgenic Mouse Model of Alzheimer's Disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multiple histopathological changes in the brain and by impairments in memory and cognitive function. Currently, there is no effective treatment that can halt or reverse the progression of this disease. Here, we explored the effects of 3 months of treatment with selenium-enriched yeast (Se yeast), which is commonly used as a source of organic selenium (Se) for nutrition, on cognitive dysfunction and neuropathology in the triple transgenic mouse model of AD (3*Tg-AD mice). As the results revealed that Se-yeast significantly improved the spatial learning and memory retention of 3*Tg-AD mice, promoted neuronal activity, attenuated the activation of astrocytes and microglia, mitigated synaptic deficits, and reduced the levels of total tau and phosphorylated tau though inhibiting the activity of GSK-3beta, dietary supplementation with Se-yeast exerted multiple beneficial effects on the prevention or treatment of AD. These findings provide evidence of a potentially viable compound for AD treatment. PMID- 28578586 TI - Origin of Somatic Mutations in beta-Catenin versus Adenomatous Polyposis Coli in Colon Cancer: Random Mutagenesis in Animal Models versus Nonrandom Mutagenesis in Humans. AB - Wnt signaling is compromised early in the development of human colorectal cancer (CRC) due to truncating nonsense mutations in adenomatous polyposis coli (APC). CRC induced by chemical carcinogens, such as heterocyclic aromatic amines and azoxymethane, in mice also involves dysregulation of Wnt signaling but via activating missense mutations in the beta-catenin oncogene despite the fact that genetically modified mice harboring an inactive APC allele efficiently develop CRC. In contrast, activating mutations in beta-catenin are rarely observed in human CRC. Dysregulation of the Wnt signaling pathway by the two distinct mechanisms reveals insights into the etiology of human CRC. On the basis of calculations related to DNA adduct levels produced in mouse CRC models using mutagens, and the number of stem cells in the mouse colon, we show that two nonsense mutations required for biallelic disruption of APC are statistically unlikely to produce CRC in experiments using small numbers of mice. We calculate that an activating mutation in one allele near the critical GSK3beta phosphorylation site on beta-catenin is >105-times more likely to produce CRC by random mutagenesis due to chemicals than inactivating two alleles in APC, yet it does not occur in humans. Therefore, the mutagenesis mechanism in human CRC cannot be random. We explain that nonsense APC mutations predominate in human CRC because of deamination at 5-methylcytosine at CGA and CAG codons, coupled with the number of human colonic stem cells and lifespan. Our analyses, including a comparison of mutation type and age at CRC diagnosis in U.S. and Chinese patients, also indicate that APC mutations in CRC are not due to environmental mutagens that randomly damage DNA. PMID- 28578587 TI - Next-Generation Magnetic Resonance Imaging Contrast Agents. PMID- 28578588 TI - Commentary on: The Journal's concerns about suicide. PMID- 28578590 TI - The Impact of Prior Activity History on the Influence of Restricted Repetitive Behaviors on Socialization for Children With High-Functioning Autism. AB - Research has demonstrated that incorporating restricted interests of an individual with autism into recess activities is effective at increasing socialization with typically developing peers. However, certain activity contexts may alter the reinforcing influence of the restricted repetitive behaviors (RRBs) depending on an individual's history in that activity. Using an alternating treatment design, this study examined whether an individual's history with an activity affected socialization. RRBs were embedded into activities with a reported positive history (i.e., prior history of positive experiences) and activities with a reported negative history (i.e., prior history of aversive experiences) for participants. Data indicated that socialization increased and remained above baseline levels when RRBs were introduced during activities with a positive history, whereas socialization was minimal when RRBs were introduced in activities with a negative history. Social significance and implications for designing activities that incorporate a child's RRBs are discussed. PMID- 28578591 TI - Post-Doctoral Mentorship Award - have you considered applying? PMID- 28578593 TI - Commentary on Snowdon: 'The Journal's concerns about suicide'. PMID- 28578592 TI - Adjunctive minocycline treatment for major depressive disorder: A proof of concept trial. AB - OBJECTIVE: Conventional antidepressant treatments result in symptom remission in 30% of those treated for major depressive disorder, raising the need for effective adjunctive therapies. Inflammation has an established role in the pathophysiology of major depressive disorder, and minocycline has been shown to modify the immune-inflammatory processes and also reduce oxidative stress and promote neuronal growth. This double-blind, randomised, placebo-controlled trial examined adjunctive minocycline (200 mg/day, in addition to treatment as usual) for major depressive disorder. This double-blind, randomised, placebo-controlled trial investigated 200 mg/day adjunctive minocycline (in addition to treatment as usual) for major depressive disorder. METHODS: A total of 71 adults with major depressive disorder ( Diagnostic and Statistical Manual of Mental Disorders Fourth Edition) were randomised to this 12-week trial. Outcome measures included the Montgomery-Asberg Depression Rating Scale (primary outcome), Clinical Global Impression-Improvement and Clinical Global Impression-Severity, Hamilton Anxiety Rating Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, Social and Occupational Functioning Scale and the Range of Impaired Functioning Tool. The study was registered on the Australian and New Zealand Clinical Trials Register: www.anzctr.org.au , #ACTRN12612000283875. RESULTS: Based on mixed methods repeated measures analysis of variance at week 12, there was no significant difference in Montgomery-Asberg Depression Rating Scale scores between groups. However, there were significant differences, favouring the minocycline group at week 12 for Clinical Global Impression-Improvement score - effect size (95% confidence interval) = -0.62 [-1.8, -0.3], p = 0.02; Quality of Life Enjoyment and Satisfaction Questionnaire score - effect size (confidence interval) = -0.12 [0.0, 0.2], p < 0.001; and Social and Occupational Functioning Scale and the Range of Impaired Functioning Tool score - 0.79 [-4.5, -1.4], p < 0.001. These effects remained at follow-up (week 16), and Patient Global Impression also became significant, effect size (confidence interval) = 0.57 [ 1.7, -0.4], p = 0.017. CONCLUSION: While the primary outcome was not significant, the improvements in other comprehensive clinical measures suggest that minocycline may be a useful adjunct to improve global experience, functioning and quality of life in people with major depressive disorder. Further studies are warranted to confirm the potential of this accessible agent to optimise treatment outcomes. PMID- 28578595 TI - Thymic Hyperplasia Associated with Graves' Disease: Pathophysiology and Proposed Management Algorithm. AB - BACKGROUND: The association between Graves' disease (GD) and thymic hyperplasia (TH) was first described in 1912 and has been reported numerous times thereafter. TH associated with GD presents as an incidental mediastinal mass on chest X-ray or computed tomography (CT). The pathogenesis of TH in the setting of GD is unclear but seems to involve a complex interplay of hormonal and immunological mechanisms. SUMMARY: Here, the effect that thyroid hormones and autoimmunity have on thymic growth and size is reviewed. The authors' experience, along with a review of published case reports, reveals that general physicians may be unfamiliar with this association. This lack of familiarity may result in an aggressive management course, including surgical intervention, along with its associated risks and costs. The differential diagnosis and diagnostic workup of thymic enlargement associated with GD is discussed in light of the available clinical evidence. CONCLUSION: Recent literature confirms the generally benign nature of TH associated with GD, and supports a conservative approach for the diagnostic workup and initial management. Practical management recommendations for thymic enlargement associated with GD have been formulated and are presented here. PMID- 28578594 TI - Novel Somatic RET Mutation Questioning the Causality of the RET I852M Germline Sequence Variant in Multiple Endocrine Neoplasia 2A. PMID- 28578596 TI - High-resolution melting analysis of gyrA codon 84 and grlA codon 80 mutations conferring resistance to fluoroquinolones in Staphylococcus pseudintermedius isolates from canine clinical samples. AB - Staphylococcus pseudintermedius is an opportunistic pathogen of dogs and cats. A high-resolution melting analysis (HRMA) protocol was designed and tested on 42 clinical isolates with known fluoroquinolone (FQ) susceptibility and gyrA codon 84 and grlA codon 80 mutation status. The HRMA approach was able to discriminate between FQ-sensitive and FQ-resistant strains and confirmed previous reports that the main mutation site associated with FQ resistance in S. pseudintermedius is located at position 251 (Ser84Leu) of gyrA. Routine, HRMA-based FQ susceptibility profiles may be a valuable tool to guide therapy. The FQ resistance-predictive power of the assay should be tested in a significantly larger number of isolates. PMID- 28578599 TI - Influence of Chemotherapy Within 30 Days Before ICU Admission on Mortality in Critically Ill Medical Patients With Cancer. AB - BACKGROUND: The main objective was to determine whether the administration of chemotherapy (CT) during the month before intensive care unit (ICU) admission of medical patients with cancer influences the survival rate. The design was a single-institution observational cohort study in an ICU of a tertiary university hospital. METHODS: Our cohort included 248 oncology patients admitted to the ICU from 2005 to 2014 due to nonsurgical problems. Seventy-six (30.6%) patients had received CT in the month before admission (CT group) and 172 did not receive CT (control group). The main outcome measures were ICU, hospital, 30-day, 90-day, and 1-year mortalities. We performed survival analysis using the Kaplan-Meier estimator, comparing both groups using the log-rank test, and multivariate analysis using Cox regression adjusted for gender, age, maximum Sequential Organ Failure Assessment (SOFA), and delta maximum SOFA to calculate the hazard ratios (HRs) and their respective 95% confidence intervals. This association was also evaluated by a graphic representation of survival. RESULTS: The CT group presented an ICU mortality rate of 27.6% versus 25.5% in the control group. The multivariate analysis adjusted for age, sex, and delta maximum SOFA showed significant differences between the groups (HR: 2.12; P = .009). The hospital mortality rate was 55.3% in the CT group compared to 45.4% in the control group (adjusted HR: 1.81; P = .003). At 30 days, the mortality rate was 56.6% in the CT group compared to 46.5% in the control group (adjusted HR: 1.69; P = .008). Mortality at 90 days was 65.8% in the CT group versus 59.9% in the control group (adjusted HR: 1.47; P = .03). One-year mortality was also higher in the CT group (79% vs 72.7%, adjusted HR: 1.44; P = .02). CONCLUSION: The administration of CT in the month before ICU admission in patients with cancer was associated with higher mortality in the ICU, in the hospital, and 30 and 90 days after admission when adjusted for the increase in organ failure measured by delta maximum SOFA. We provide useful new information for decision-making about ICU management of patients with cancer. PMID- 28578597 TI - Optimization of Methods for Articular Cartilage Surface Tissue Engineering: Cell Density and Transforming Growth Factor Beta Are Critical for Self-Assembly and Lubricin Secretion. AB - OBJECTIVE: Lubricin/superficial zone protein (SZP)/proteoglycan4 (PRG4) plays an important role in boundary lubrication in articular cartilage. Lubricin is secreted by superficial zone chondrocytes and synoviocytes of the synovium. The specific objective of this investigation is to optimize the methods for tissue engineering of articular cartilage surface. The aim of this study is to investigate the effect of cell density on the self-assembly of superficial zone chondrocytes and lubricin secretion as a functional assessment. DESIGN: Superficial zone chondrocytes were cultivated as a monolayer at low, medium, and high densities. Chondrocytes at the three different densities were treated with transforming growth factor beta (TGF-beta)1 twice a week or daily, and the accumulated lubricin in the culture medium was analyzed by immunoblots and quantitated by enzyme-linked immunosorbent assay (ELISA). RESULTS: Cell numbers in low and medium densities were increased by TGF-beta1; whereas cell numbers in high-density cell cultures were decreased by twice-a-week treatment of TGF-beta1. On the other hand, the cell numbers were maintained by daily TGF-beta treatment. Immunoblots and quantitation of lubricin by ELISA analysis indicated that TGF beta1 stimulated lubricin secretion by superficial zone chondrocytes at all densities with twice-a-week TGF-beta treatment. It is noteworthy that the daily treatment of TGF-beta1 increased lubricin much higher compared with twice-a-week treatment. CONCLUSIONS: These data demonstrate that daily treatment is optimal for the TGF-beta1 response in a higher density of monolayer cultures. These findings have implications for self-assembly of surface zone chondrocytes of articular cartilage for application in tissue engineering of articular cartilage surface. PMID- 28578598 TI - Hyperthyroidism, Hypothyroidism, and Cause-Specific Mortality in a Large Cohort of Women. AB - BACKGROUND: The prevalence of hyperthyroidism and hypothyroidism is 0.5-4% in iodine-replete communities, but it is 5-10 times higher in women than in men. Those conditions are associated with a broad range of metabolic disorders and cardiovascular diseases. Biological evidence of a role of thyroid hormones in carcinogenesis also exists. However, the association between thyroid dysfunction and cardiovascular disease or cancer mortality risk remains controversial. In a large cohort of women, the associations of hyperthyroidism and hypothyroidism with cause-specific mortality were evaluated after nearly 30 years of follow-up. METHODS: The prospective study included 75,076 women aged 20-89 years who were certified as radiologic technologists in the United States in 1926-1982, completed baseline questionnaires in 1983-1998 from which medical history was ascertained, and reported no malignant disease or benign thyroid disease except thyroid dysfunction. A passive follow-up of this cohort was performed through the Social Security Administration database and the National Death Index-Plus. Cause specific mortality risks were compared according to self-reported thyroid status, with proportional hazards models adjusted for baseline year and age, race/ethnicity, body mass index, family history of breast cancer, and life-style and reproductive factors. RESULTS: During a median follow-up of 28 years, 2609 cancer, 1789 cardiovascular or cerebrovascular, and 2442 other non-cancer deaths were recorded. Women with hyperthyroidism had an elevated risk of breast cancer mortality after 60 years of age (hazard ratio [HR] = 2.04 [confidence interval (CI) 1.16-3.60], 13 cases in hyperthyroid women) compared to women without thyroid disease. Hypothyroid women had increased mortality risks for diabetes mellitus (HR = 1.58 [CI 1.03-2.41], 27 cases in hypothyroid women), cardiovascular disease (HR = 1.20 [CI 1.01-1.42], 179 cases), and cerebrovascular disease (HR = 1.45 [CI 1.01-2.08], 35 cases, when restricting the follow-up to >=10 years after baseline). Other causes of death were not associated with hyperthyroidism or hypothyroidism, though there was a suggestion of an elevated risk of ovarian cancer mortality in hyperthyroid women based on very few cases. CONCLUSION: The excess mortality risks observed in a large, prospective 30-year follow-up of patients with thyroid dysfunction require confirmation, and, if replicated, further investigation will be needed because of the clinical implications. PMID- 28578600 TI - Maternal anxiety associated with in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) outcomes and risk of difficult toddler temperament: A three-year case-control study. PMID- 28578601 TI - Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. AB - BACKGROUND: Olaparib is an oral poly(adenosine diphosphate-ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation. METHODS: We conducted a randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single-agent chemotherapy of the physician's choice (capecitabine, eribulin, or vinorelbine in 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review and was analyzed on an intention-to-treat basis. RESULTS: Of the 302 patients who underwent randomization, 205 were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the olaparib group than in the standard-therapy group (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% confidence interval, 0.43 to 0.80; P<0.001). The response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard-therapy group, and the rate of treatment discontinuation due to toxic effects was 4.9% and 7.7%, respectively. CONCLUSIONS: Among patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, olaparib monotherapy provided a significant benefit over standard therapy; median progression-free survival was 2.8 months longer and the risk of disease progression or death was 42% lower with olaparib monotherapy than with standard therapy. (Funded by AstraZeneca; OlympiAD ClinicalTrials.gov number, NCT02000622 .). PMID- 28578602 TI - Why Do Promising Therapies Stall in Development and How Can We Move Them Forward? AB - There are many reasons that molecules fail to progress to market and various principles of risk-benefit decisions that can help drive the molecule through development. This symposium included discussions on global strategies involved in pushing promising molecules to market, what to do when a molecule stalls in its progress to market, and options for rescuing the molecule and pushing it forward again. Innovative partnerships that bring stalled drugs back into clinical development were also addressed. A regulatory perspective on common reasons for a molecule to fail in its forward progress was presented. In addition, situations arise when a third-party advisory committee can provide input to help overcome issues identified by a regulatory agency. Using examples from the private and public domain, presentations centered on how to repurpose a molecule and when more science is needed. PMID- 28578604 TI - Does palliative chemotherapy provide a palliative effect on symptoms in late palliative stages? An interview study with oncologists. AB - BACKGROUND: The possible chemotherapy effects on symptoms in late stages of palliative chemotherapy are seldom registered in clinical practice or investigated as primary outcomes. The aim was therefore to study physicians' opinions and experiences about chemotherapy effects on symptoms. MATERIAL AND METHODS: Thirty-five physicians (mainly oncologists) with variation as regards age, gender and experience were included in a qualitative study with semi structured interviews. A qualitative content analysis was used for the 30-60 min long interviews. RESULTS: According to all the informants, symptoms were possible to control in successful cases but the chances reduce rapidly with the number of chemotherapy lines. Symptoms possible to control included various types of pain (bone pain, neuropathic cranial as well as meningeal nerve pain, colic pain, "liver" pain, headache and pain from cutaneous metastases); nausea and vomiting caused by obstruction; dyspnoea due to pleural effusions or bronchial obstructions. Also fatigue and B-symptoms were possible targets, as were diagnosis-specific symptom clusters (e.g., liver metastasis causing pain, nausea, tumour fever and night sweats; or head-neck cancers resulting in nerve pain, ulcerations, odour, dysphagia and impaired breathing). Some of the oncologists discussed whether the effects were related to chemotherapy treatment only or partly to premedication with steroids. Despite the claimed effects, the physicians did not keep record on symptoms, they did not evaluate them with validated instruments. CONCLUSIONS: Palliative chemotherapy has a substantial potential to reduce agonizing symptoms especially in first line treatments, but the effect is limited in late stages. The actual awareness of and knowledge about situations where the treatment has a reasonable potential, should be improved and symptoms should be monitored during treatment. PMID- 28578603 TI - AAV Gene Therapy for Alcoholism: Inhibition of Mitochondrial Aldehyde Dehydrogenase Enzyme Expression in Hepatoma Cells. AB - Most ethanol is broken down in the liver in two steps by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH2) enzymes, which metabolize down ethanol into acetaldehyde and then acetate. Some individuals from the Asian population who carry a mutation in the aldehyde dehydrogenase gene (ALDH2*2) cannot metabolize acetaldehyde as efficiently, producing strong effects, including facial flushing, dizziness, hypotension, and palpitations. This results in an aversion to alcohol intake and protection against alcoholism. The large prevalence of this mutation in the human population strongly suggests that modulation of ALDH2 expression by genetic technologies could result in a similar phenotype. scAAV2 vectors encoding ALDH2 small hairpin RNA (shRNA) were utilized to validate this hypothesis by silencing ALDH2 gene expression in human cell lines. Human cell lines HEK-293 and HepG2 were transduced with scAAV2/shRNA, showing a reduction in ALDH2 RNA and protein expression with the two viral concentration assayed (1 * 104 and 1 * 105 vg/cell) at two different time points. In both cell lines, ALDH2 RNA levels were reduced by 90% and protein expression was inhibited by 90% and 52%, respectively, 5 days post infection. Transduced HepG2 VL17A cells (ADH+) exposed to ethanol resulted in a 50% increase in acetaldehyde levels. These results suggest that gene therapy could be a useful tool for the treatment of alcoholism by knocking down ALDH2 expression using shRNA technology delivered by AAV vectors. PMID- 28578605 TI - Mortality Differences Between Traditional Medicare and Medicare Advantage: A Risk Adjusted Assessment Using Claims Data. AB - Medicare Advantage (MA) has grown rapidly since the Affordable Care Act; nearly one-third of Medicare beneficiaries now choose MA. An assessment of the comparative value of the 2 options is confounded by an apparent selection bias favoring MA, as reflected in mortality differences. Previous assessments have been hampered by lack of access to claims diagnosis data for the MA population. An indirect comparison of mortality as an outcome variable was conducted by modeling mortality on a traditional fee-for-service (FFS) Medicare data set, applying the model to an MA data set, and then evaluating the ratio of actual-to predicted mortality in the MA data set. The mortality model adjusted for clinical conditions and demographic factors. Model development considered the effect of potentially greater coding intensity in the MA population. Further analysis calculated ratios for subpopulations. Predicted, risk-adjusted mortality was lower in the MA population than in FFS Medicare. However, the ratio of actual-to predicted mortality (0.80) suggested that the individuals in the MA data set were less likely to die than would be predicted had those individuals been enrolled in FFS Medicare. Differences between actual and predicted mortality were particularly pronounced in low income (dual eligibility), nonwhite race, high morbidity, and Health Maintenance Organization (HMO) subgroups. After controlling for baseline clinical risk as represented by claims diagnosis data, mortality differences favoring MA over FFS Medicare persisted, particularly in vulnerable subgroups and HMO plans. These findings suggest that differences in morbidity do not fully explain differences in mortality between the 2 programs. PMID- 28578606 TI - Community Health Workers and Use of mHealth: Improving Identification of Pregnancy Complications and Access to Care in the Dominican Republic. AB - This article presents the feasibility and acceptability of using mobile health technology by community health workers (CHWs) in San Juan Province, Dominican Republic, to improve identification of pregnancy complications and access to care for pregnant women. Although most women in the Dominican Republic receive four antenatal care visits, poor women and adolescents in remote areas are more likely to have only one initial prenatal visit to verify the pregnancy. This community based research began when community leaders raised concern about the numbers of their mothers who died in childbirth annually; San Juan's maternal mortality rate is 144/100,000 compared to the Caribbean rate of 85/100,000. Eight CHWs in three communities were taught to provide third-trimester antenatal assessment, upload the data on a mobile phone application, send the data to the local physician who monitored data for "red flags," and call directly if a mother had an urgent problem. Fifty-two pregnant women enrolled, 38 were followed to delivery, 95 antenatal care postintake were provided, 2 urgent complications required CHW home management of mothers, and there were 0 deaths. Stakeholders endorsed acceptability of intervention. Preliminary data suggest CHWs using mobile health technology is feasible, linking underserved and formal health care systems with provision of primary care in mothers' homes. PMID- 28578609 TI - An unusual agent for an unusual localization of infective endocarditis. AB - We report on a 32-year-old male patient with acute left-hemispheric stroke caused by embolism due to infective endocarditis affected from the HACEK group. Additionally, atypical findings from the transesophageal echocardiography (TEE) which showed fluttering structures belonging to the papillary muscle could be proven as infectious agents with the help of a glucose positron emission tomography (PET) scan. TEE controls showed increasing vegetation involving the mitral valve so that surgery became necessary. The current work reflects, in detail, the emergent clinical course of this young patient, suffering from both an unusual localization and an infrequent cause of endocarditis and focuses on an actual view to the literature. PMID- 28578610 TI - A Pilot Study of Tobacco Screening and Referral for Smoking Cessation Program among HIV-Infected Patients in France. AB - BACKGROUND: The prevalence of tobacco smoking is high among patients living with HIV, supporting the need for effective targeted interventions. MATERIALS AND METHODS: All current smokers at our outpatient HIV clinic were invited to participate in a smoking cessation program. RESULTS: Of the 716 patients living with HIV, 280 (39%) reported active smoking and were younger, more recently HIV infected and more frequently infected due to intravenous drug use (IDU). One hundred forty-seven (53%) smokers agreed to participate in the smoking cessation program and had a higher Fagerstrom score and were less likely IDU. During follow up, 41 (28%) smokers withdrew from the program. After 6 months, 60 (57%) of the 106 smokers who completed the intervention had stopped tobacco smoking and were more likely to use varenicline, adjusting for a history of depression. CONCLUSION: Our smoking cessation program was feasible. However, strategies to reach and retain in smoking cessation program specific groups such as IDU are needed to improve the smoking cessation cascade. PMID- 28578608 TI - Do Gender-Predominant Primary Health Care Organizations Have an Impact on Patient Experience of Care, Use of Services, and Unmet Needs? AB - Physicians' gender can have an impact on many aspects of patient experience of care. Organization processes through which the influence of gender is exerted have not been fully explored. The aim of this article is to compare primary health care (PHC) organizations in which female or male doctors are predominant regarding organization and patient characteristics, and to assess their influence on experience of care, preventive care delivery, use of services, and unmet needs. In 2010, we conducted surveys of a population stratified sample (N = 9180) and of all PHC organizations (N = 606) in 2 regions of the province of Quebec, Canada. Patient and organization variables were entered sequentially into multilevel regression analyses to measure the impact of gender predominance. Female-predominant organizations had younger doctors and nurses with more expanded role; they collaborated more with other PHC practices, used more tools for prevention, and allotted more time to patient visits. However, doctors spent fewer hours a week at the practice in female-predominant organizations. Patients of these organizations reported lower accessibility. Conversely, they reported better comprehensiveness, responsiveness, counseling, and screening, but these effects were mainly attributable to doctors' younger age. Their reporting unmet needs and emergency department attendance tended to decrease when controlling for patient and organization variables other than doctors' age. Except for accessibility, female-predominant PHC organizations are comparable with their male counterparts. Mean age of doctors was an important confounding variable that mitigated differences, whereas other organization variables enhanced them. These findings deserve consideration to better understand and assess the impacts of the growing number of female-predominant PHC organizations on the health care system. PMID- 28578611 TI - Psychiatric Symptoms and Barriers to Care in HIV-Infected Individuals Who Are Lost to Care. AB - Past studies of barriers to HIV care have not comprehensively assessed psychiatric symptoms, and few have assessed barriers to care among people living with HIV (PLWH) who are lost to care (LTC). We examined psychiatric symptoms, barriers to HIV care, and immune functioning in PLWH who were retained in care (RIC; n = 21) or LTC (n = 21). Participants completed diagnostic interviews for posttraumatic stress disorder (PTSD) and other psychiatric disorders, self-report measures of HIV risk behaviors and psychiatric symptoms, and a blood draw to assess viral load. Compared to RIC participants, LTC participants met criteria for a greater number of psychiatric disorders and reported greater depressive symptoms and more barriers to HIV care. There were no group differences in PTSD severity, risk behaviors, or viral load, suggesting that LTC individuals experience greater psychiatric problems and perceive more barriers to care than RIC participants, but are not less likely to have achieved viral suppression. PMID- 28578612 TI - The effect of progressive resistance training on aerobic fitness and strength in adults with coronary heart disease: A systematic review and meta-analysis of randomised controlled trials. AB - Design We aimed to evaluate the effect of progressive resistance training on cardiorespiratory fitness and muscular strength in coronary heart disease, when compared to control or aerobic training, and when combined with aerobic training. Secondary aims were to evaluate the safety and efficacy of progressive resistance training on other physiological and clinical outcomes. Methods and results Electronic databases were searched from inception until July 2016. Designs included progressive resistance training vs control, progressive resistance training vs aerobic training, and combined training vs aerobic training. From 268,778 titles, 34 studies were included (1940 participants; 71.9% male; age 60 +/- 7 years). Progressive resistance training was more effective than control for lower (standardized mean difference 0.57, 95% confidence interval (0.17-0.96)) and upper (1.43 (0.73-2.13)) body strength. Aerobic fitness improved similarly after progressive resistance training (16.9%) or aerobic training (21.0%); (standardized mean difference -0.13, 95% confidence interval (-0.35-0.08)). Combined training was more effective than aerobic training for aerobic fitness (0.21 (0.09-0.34), lower (0.62 (0.32-0.92)) and upper (0.51 (0.27-0.74)) body strength. Twenty studies reported adverse event information, with five reporting 64 cardiovascular complications, 63 during aerobic training. Conclusion Isolated progressive resistance training resulted in an increase in lower and upper body strength, and improved aerobic fitness to a similar degree as aerobic training in coronary heart disease cohorts. Importantly, when progressive resistance training was added to aerobic training, effects on both fitness and strength were enhanced compared to aerobic training alone. Reporting of adverse events was poor, and clinical gaps were identified for women, older adults, high intensity progressive resistance training and long-term outcomes, warranting future trials to confirm safety and effectiveness. PMID- 28578614 TI - The correlation between direction and amount of retrusive movement and condyle position and joint space. AB - OBJECTIVE: The direction and amount of retrusive movement may be correlated with the amount of joint space and the maximum intercuspal position of the condyle. The aim of this study was to identify any such correlation using an ultrasonic jaw motion analyzer and digital volumetric tomographic (DVT) scans. METHODS: Thirty-five dental students were selected as subjects. DVT scans were obtained using a next-generation i-CAT CBCT unit, and the direction and amount of retrusive movement were measured with a 3-D analyzer. RESULTS: Spearman Rho correlation tests showed no correlation between the amount of retrusive movement and the condyle position and joint space on either the right or left side. DISCUSSION: There is sufficient reason to suggest that retrusive movement of the condyle does not occur in isolation but is influenced by glenoid fossa bone morphology. PMID- 28578613 TI - Suboptimal primary and secondary cardiovascular disease prevention in HIV positive individuals on antiretroviral therapy. AB - Background We aimed to identify the prevalence of cardiovascular risk factors, and investigate preventive cardiovascular medication use and achievement of targets as per Dutch cardiovascular risk management guidelines among human immunodeficiency virus (HIV)-positive and HIV-negative individuals. Design The design was a cross-sectional analysis within an ongoing cohort study. Methods Data on medication use and cardiovascular disease prevalence were available for 528 HIV-positive and 521 HIV-negative participants. We identified cardiovascular risk factors and applied cardiovascular risk management guidelines, mainly focusing on individuals eligible for (a) primary prevention because of high a priori cardiovascular risk, or for (b) secondary prevention. Results One hundred and three (20%) HIV-positive and 77 (15%) HIV-negative participants were classified as having high cardiovascular risk; 53 (10%) HIV-positive and 27 (5%) HIV-negative participants were eligible for secondary prevention. Of HIV-positive individuals 57% at high cardiovascular risk and 42% of HIV-positive individuals eligible for secondary prevention had systolic blood pressures above guideline recommended thresholds. Cholesterol levels were above guideline-recommended thresholds in 81% of HIV-positive individuals at high cardiovascular risk and 57% of HIV-positive individuals eligible for secondary prevention. No statistically significant differences were observed between HIV-positive and HIV-negative participants regarding achievement of targets, except for glycaemic control (glycated haemoglobin <= 53 mmol/mol) among individuals using diabetes medication (90% vs 50%, p = 0.017) and antiplatelet/anticoagulant use for secondary prevention (85% vs 63%, p = 0.045), which were both superior among HIV-positive participants. Conclusions Cardiovascular risk management is suboptimal in both HIV-positive and HIV-negative individuals and should be improved. PMID- 28578607 TI - Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. AB - BACKGROUND: Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. RESULTS: After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group. CONCLUSIONS: The addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly increased overall survival and radiographic progression free survival in men with newly diagnosed, metastatic, castration-sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285 .). PMID- 28578616 TI - Integration of informal recycling sector in Brazil and the case of Sorocaba City. AB - Catadores are people who collect and sell materials that can be recycled. This activity has been done informally in many countries for years. Recently, a recognition process has begun for the informal recycling sector, with public and private initiatives. In Brazil, catadores started out associating with each other in co-operatives in the 1980s. In 2010, the Solid Waste National Policy was approved, promoting the inclusion of theses co-operatives in the formal waste management system. However, only in 25 out of 5670 Brazilian municipalities have hired co-operatives as Private Service Providers. The integration of the informal sector has contributed with social, economic and environmental benefits; income generation, reduction of poverty and resource preservation are highlights. Although there was a legal progress, there are great challenges for various actors involved. This paper aims to diagnose the informal recycling sector, emphasizing the integration process that has happened in Brazil. For this, a substantial literature review and a case study were conducted, applying the tool 'InteRa' to the case of Sorocaba. The case showed that it is possible to improve the integration of catadores in the formal waste management system. The co operatives achieve recycling rates of 2%, higher than the official national rate of 1%. However, we estimate that autonomous pickers increase total recycling in Sorocaba to 9%, still short of the 25% target via source segregation. Therefore, continuing the integration process will benefit both the pickers, and also the municipality through savings on landfill costs. PMID- 28578615 TI - Predictors of public and private healthcare utilization and associated health system responsiveness among older adults in Ghana. AB - BACKGROUND: Previous studies investigating factors associated with healthcare utilization by older Ghanaians lack distinction between public and private health services. The present study examined factors associated with public and private healthcare service use, and the resulting perceived health system responsiveness. OBJECTIVES: To identify factors associated with public and private healthcare utilization among older adults aged 50 and older in Ghana; and to compare perceived differences in health system responsiveness between the private and public sectors. METHODS: Cross-sectional data was analyzed from the World Health Organization Study on global AGEing and adult health (SAGE) Wave 1 in Ghana. Using Andersen's conceptual framework, public and private outpatient care utilization was examined using multinomial logistic regression to estimate and identify predictor variables associated with the type of outpatient healthcare facility accessed. Health system responsiveness was compared using chi-square tests. RESULTS: Of 2517 respondents who used outpatient care in the 12 months preceding interview, 51.7% of respondents used a public facility, 17.8% a private facility, and 30.5% used other facilities. Older age group, higher education and higher wealth were associated with the use of private outpatient healthcare services. Using public outpatient care facilities was associated with having health insurance. Respondents with two or more chronic conditions were more likely to use public and private outpatient care than other facilities. Perceived health system responsiveness was better in private for-profit than in public and private not-for-profit healthcare facilities. CONCLUSIONS: This study suggested that higher wealth and multimorbidity were significant predictors of public and private outpatient healthcare utilization; however, health insurance was a predictor only for the use of public facilities. Future mixed-method studies could further elucidate factors influencing the choice of public and private outpatient healthcare use. PMID- 28578617 TI - A serologic survey of Mycoplasma spp. in farmed bison ( Bison bison) herds in western Canada. AB - Mycoplasma bovis is emerging as an important pathogen of farmed bison in North America and is associated with high morbidity and mortality in affected herds. We developed an in-house ELISA to detect antibodies against Mycoplasma spp. in bison sera. The aims of the study were to estimate the seroprevalence against Mycoplasma spp. in bison herds with or without past history of M. bovis associated disease, and to determine potential risk factors for seropositivity to Mycoplasma spp. in farmed bison in western Canada. A total of 858 serum samples were collected from bison >1 y of age from 19 bison herds. The individual and herd-level seroprevalence of Mycoplasma spp. was 12% and 79%, respectively. The proportion of seropositive animals was 0-41% and 0-9% for herds with or without a history of M. bovis-associated disease, respectively. Mycoplasma spp. appear to be widespread in bison in Manitoba, Saskatchewan, and Alberta. Eight of 11 herds with no history of M. bovis-associated disease were seropositive for Mycoplasma spp., which suggests that bison can be subclinically infected with Mycoplasma spp., or that infection may be underdiagnosed. Although not specific to M. bovis, the in-house ELISA developed to detect antibodies against Mycoplasma spp. may prove to be a valuable herd-level screening tool, providing insight needed for the development of appropriate prevention and control measures for Mycoplasma related disease in bison herds. PMID- 28578618 TI - Retroperitoneal extragastrointestinal giant stromal tumour: A case report. PMID- 28578619 TI - A Meta-Analysis of Outcomes After In Situ Reconstructions for Aortic Graft Infection. AB - OBJECTIVE: To confirm the advantage of in situ reconstruction (ISR) over extra anatomic reconstruction (EAR) for aortic graft infection and determine the most appropriate conduit including autogenous veins, cryopreserved allografts, and synthetic prosthesis (standard, rifampicin of silver polyesters). METHODS: A meta analysis was conducted with rate of mortality, graft occlusion, amputation, and reinfection. A meta-regression was performed with 4 factors: patients' age, presence of prosthetic-duodenal fistula (PDF), virulent organisms, or nonvirulent organisms. RESULTS: In situ reconstruction over EAR seems to favor all events. For the 5 conduits used for ISR, according to operative mortality, age of the patients looks to have a positive correlation only for silver polyester and no conduit present any advantage in the presence of PDF. Reinfection seems to be not significantly different for the 5 conduits, and only autogenous veins appear to have a positive correlation with infecting organisms. CONCLUSION: In situ reconstruction may be considered as first-line treatment. Our results suggest that silver polyesters appear to be most appropriate for older patients, and in order to limit reinfection, autogenous veins are probably the most suitable conduit. PMID- 28578620 TI - Socio-demographic and clinical characteristics of clients seeking assisted conception at Lagos State University Teaching Hospital, Ikeja, Nigeria. AB - The socio-demographic and clinical characteristics of 246 consecutive couples seeking assisted conception in a university teaching hospital in Nigeria from inception in 2011 till 2014 were reviewed restrospectively. Eighty-five (34.5%) were in the 35-40 years age group. The body mass index of the women showed that 111 (45.1%) were overweight. One hundred and ninety five (88%) were referred on account of secondary infertility. The mean duration of infertility was 9.6 +/- 4.8 years. Major factors identified were male factor 128 (52%), ovarian/age related decline in fertility 107 (43.5%), tubal 83 (33.7%) and combined male/female factor 71 (28.9%). One hundred and ninety (77.2%) clients seeking assisted conception were Christians at advanced age (greater than 35 years) with a longstanding duration of infertility of more than 10 years. Government, private and religious organisations need to raise public awareness about the availability of in-vitro fertilisation services as well as encourage early resort to assisted reproductive technologies. Impact statement What we already know: Secondary infertility due mainly to tubal factor is reported to be the commonest cause of infertility in developing countries like Nigeria and clients affected seek assisted reproductive techniques late. What the results of this study add: Male factor infertility is more common amongst infertile couples seeking in vitro fertilisation in LASUTH. The implications of the findings for practice and/or further research: A thorough examination of the male partner followed by investigation is vital at the initial visit so that they can be referred early for assisted conception. PMID- 28578622 TI - Modular minimal invasive extracorporeal circuits: another step toward universal applicability? AB - INTRODUCTION: Safety concerns have been one of the main reasons opposing a wider acceptance of minimal invasive extracorporeal circuits (MiECC). Following an extensive experience and a multitude of modifications, we have set out to employ a modular MiECC as a universal extracorporeal circuit. METHODS: A total of 129 cardiac surgical procedures were performed by a single surgeon in 2013. Excluding procedures done under circulatory arrest or with the potential need of such, the MiECC was utilized in almost 90% of surgeries. Of sixty-two (simple procedures) patients who underwent coronary artery bypass grafting (CABG), aortic valve replacement (AVR) or CABG + AVR, 82% were non-elective, 10% had a left ventricular ejection fraction (EF) <30% and most had an impaired renal function. Thirty-eight patients had more complex surgeries (complex procedures), 37% of which were urgent, 15% had an EF <30% and the majority had renal dysfunction. RESULTS: The 30-day mortality was 5% in simple procedures and 2.5% in complex procedures. The incidence of postoperative atrial fibrillation was 13% and 16%, respectively. Optimum outcome was defined as a freedom from all complications and blood transfusions and was achieved in 52% and 42%, respectively. CONCLUSIONS: This report shows that modular MiECC can be employed with a high safety margin in cardiac surgery. Furthermore, it emphasizes the impact that minimal invasive philosophy could have in improving patient care. PMID- 28578621 TI - Drug-resistant tuberculosis in Zhejiang Province, China: an updated analysis of time trends, 1999-2013. AB - BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) hinder the progress of TB control. OBJECTIVE: To track the trend of drug-resistant tuberculosis (DR-TB) prevalence in Zhejiang Province from 1999 to 2013, and identify risk factors of resistance to second line drugs among MDR-TB patients. DESIGN: Four DR-TB surveys had been done in Zhejiang Province in 1999, 2004, 2008 and 2013 through questionnaires, in which demographic and epidemiological items were included. After questionnaires, drug susceptibility testing (DST) targeted at four first-line drugs was done for all TB patients and DST targeted at six second-line drugs (only in 2008 and 2013) for MDR-TB patients. The drug resistance trend over time was analyzed using the Cochran-Armitage test. The factors associated with resistance to second-line drugs among MDR-TB patients were examined by a multivariate logistic regression model. RESULTS: Of 936 patients enrolled, 27 (3.21%) and 20 (21.28%) MDR-TB cases were registered as new and previously treated cases, respectively. MDR-TB showed a decreasing trend (Z = -3.31, p < 0.01) while resistance to any first-line drugs showed an increasing trend (Z = 5.22, p < 0.001), from 1999 to 2013. The highest resistance rate was shown to ofloxacin among MDR-TB patients both in 2008 (28.8%) and in 2013 (27.7%), while resistance to para-aminosalicylate decreased significantly (Z = -2.06, p = 0.04) between 2008 and 2013. MDR-TB patients aged 45-65 years (OR = 5.00, p = 0.02) were more likely to be resistant to any second line drugs. CONCLUSIONS: DR-TB including MDR-TB remains a major public health problem in Zhejiang Province. Further efforts on MDR-TB control should be conducted to hinder drug resistance, including critical clinical use of anti-TB antibiotics and preventing transmission. PMID- 28578623 TI - Definition of Type II Endoleak Risk Based on Preoperative Anatomical Characteristics. AB - PURPOSE: To define the risk for type II endoleak (EII) after endovascular aneurysm repair (EVAR) based on preoperative anatomical characteristics. METHODS: Between January 2008 and December 2015, 189 patients (mean age 78.4+/-7.6 years; 165 men) underwent standard EVAR. Mean aneurysm diameter was 5.7+/-0.7 cm and mean volume 125.2+/-45.8 cm3. Patients were assigned to the "at-risk" group (n=123, 65%) when at least one of the following criteria was present: patency of a >3-mm inferior mesenteric artery (IMA), patency of at least 3 pairs of lumbar arteries, or patency of 2 pairs of lumbar arteries and a sacral artery or accessory renal artery or any diameter patent IMA; otherwise, patients were entered in the "low-risk" group (n=66, 35%). EII rates and freedom from EII reintervention were compared using Kaplan-Meier curves. Preoperative clinical and anatomical characteristics were evaluated for their association with EII and EII reinterventions using multiple logistic regression analysis; results are presented as the odds ratio (OR) and 95% confidence interval (CI). RESULTS: Freedom from endoleak was lower in the at-risk group compared with the low-risk group at 36 months after EVAR (p=0.04). Freedom from EII-related reinterventions was significantly lower in the at-risk group (80% vs 100%, p=0.001) at 48 months. Based on the multiple regression analysis, the at-risk group had a higher likelihood of both EII (OR 9.91, 95% CI 2.92 to 33.72, p<0.001) and EII-related reinterventions (OR 9.11, 95% CI 1.06 to 78.44, p=0.04). These criteria had 89.4% (95% CI 83.9% to 93.2%) sensitivity and 48.0% (95% CI 40.7% to 55.3%) specificity for EII; sensitivity and specificity for EII reintervention were 100% (95% CI 93.8% to 100%) and 38.8% (95% CI 31.9% to 46.2%). Within the at-risk group, a sac thrombus volume <35% was an additional predictor for both EII (OR 5.21, 95% CI 1.75 to 15.47, p=0.003) and EII-related reinterventions (OR 8.33, 95% CI 2.20 to 31.51, p<0.002). CONCLUSION: The selection criteria effectively discriminated between low-risk patients and patients at risk for EII and associated reinterventions. A thrombus volume <35% was an additional predictor for EII and EII-related reintervention among patients at risk. These criteria may be useful for preemptively selecting patients who may benefit from EII prevention procedures or a more aggressive surveillance protocol. PMID- 28578624 TI - Outcomes After Endovascular Revascularization in Octogenarians and Non Octogenarians With Critical Limb Ischemia. AB - PURPOSE: To determine the outcome and periprocedural risk of endovascular revascularization in octogenarians with critical limb ischemia (CLI) compared with their younger counterparts. METHODS: The multicenter, prospective registry for First-line Treatments in Patients With Critical Limb Ischemia (CRITISCH) enrolled 642 patients treated with endovascular techniques ( ClinicalTrials.gov identifier NCT01877252). The patients were dichotomized according to age <80 years (n=421; mean age 69 years, 292 men; group 1) or >=80 years (n=221; mean age 85 years, 113 men; group 2). The groups had similar distributions in Rutherford categories 4 to 6, but group 1 had more men, smokers, diabetics, and patients on dialysis. The primary composite endpoint of the study was amputation and/or death. Key secondary endpoints were in-hospital mortality and major amputation, as well as major adverse limb events (MALE; any reintervention or major amputation involving the index limb) at 1 year. RESULTS: The in-hospital mortality was 1% in group 1 and 2% in group 2 (p=0.204) and the major amputation rates were 4% and 2% (p=0.169), respectively. Amputation-free survival at 1 year was 75% in group 1 and 77% in group 2 (p=0.340), whereas freedom from MALE was significantly different between the groups [62% group 1 vs 72% group 2; hazard ratio (HR) 1.45, 95% confidence interval (CI) 1.09 to 1.93, p=0.016). Limb salvage was 90% in group 1 and 95% in group 2 (HR 2.16, 95% CI 1.27 to 3.69, p=0.01). CONCLUSION: Octogenarians with CLI treated by endovascular means showed comparable early and 1-year amputation-free survival rates vs their younger counterparts, and limb salvage and freedom from MALE rates were even higher in octogenarians. APPENDIX: The CRITISCH collaborators are Farzin Adili, MD (Darmstadt), Kai Balzer, MD (Bonn), Arend Billing, MD (Offenbach), Dittmar Bockler, MD (Heidelberg), Daniel Brixner, MD (Offenbach), Sebastian E. Debus, MD (Hamburg), Hans-Henning Eckstein, MD (Munchen), Hans-Joachim Florek, MD (Freital), Asimakis Gkremoutis, MD (Frankfurt), Reinhardt Grundmann, MD (Bad Krozingen), Thomas Hupp, MD (Stuttgart), Se-Won Hwang, MD (Muenster), Tobias Keck, MD (Lubeck), Wojciech, Klonek, MD (Cloppenburg), Werner Lang, MD (Erlangen), Bjorn May (Freital), Alexander Meyer, MD (Erlangen), Bernhard Muhling, MD (Biberach), Alexander Oberhuber, MD (Dusseldorf), Holger Reinecke, MD (Munster), Christian Reinhold, MD (Monchengladbach), Ralf Gerhard Ritter, MD (Bielefeld), Hubert Schelzig, MD (Dusseldorf), Christian Schlensack, MD (Tubingen), Thomas Schmitz-Rixen, MD (Frankfurt), Karl-Ludwig Schulte, MD (Berlin), Matthias Spohn, MD (Bamberg), Konstantinos Stavroulakis, MD (Munster), Martin Storck, MD (Karlsruhe), Matthias Trede, MD (Bremen), Barbara Weis-Muller, MD (Monchengladbach), Heiner Wenk (Bremen), Thomas Zeller, MD (Bad Krozingen), Sven Zhorzel, MD (Munich), and Alexander Zimmermann, MD (Munich). PMID- 28578626 TI - The Pathologist 2.0: An Update on Digital Pathology in Veterinary Medicine. AB - Using light microscopy to describe the microarchitecture of normal and diseased tissues has changed very little since the middle of the 19th century. While the premise of histologic analysis remains intact, our relationship with the microscope is changing dramatically. Digital pathology offers new forms of visualization, and delivery of images is facilitated in unprecedented ways. This new technology can untether us entirely from our light microscopes, with many pathologists already performing their jobs using virtual microscopy. Several veterinary colleges have integrated virtual microscopy in their curriculum, and some diagnostic histopathology labs are switching to virtual microscopy as their main tool for the assessment of histologic specimens. Considering recent technical advancements of slide scanner and viewing software, digital pathology should now be considered a serious alternative to traditional light microscopy. This review therefore intends to give an overview of the current digital pathology technologies and their potential in all fields of veterinary pathology (ie, research, diagnostic service, and education). A future integration of digital pathology in the veterinary pathologist's workflow seems to be inevitable, and therefore it is proposed that trainees should be taught in digital pathology to keep up with the unavoidable digitization of the profession. PMID- 28578625 TI - Glomerular Lipidosis in Dogs. AB - Glomerular lipidosis (GL) is characterized by dilated glomerular capillary loops containing lipid-laden cells (foam cells). Previously, GL was considered to be an incidental finding because affected dogs were typically not azotemic. However, the International Renal Interest Society staging system for canine chronic kidney disease has increased the awareness of other clinical parameters (eg, proteinuria and hypertension) that should be included in the assessment of renal function. As such, the aim of this study was to determine clinical abnormalities and concurrent renal lesions in dogs with GL. GL was identified in renal biopsies from 46 dogs evaluated by the International Veterinary Renal Pathology Service. GL was the sole diagnosis in 5 of 46 cases (11%), all of which were proteinuric. All 5 dogs had at least 1 additional clinicopathologic abnormality consistent with renal disease, including hypertension (4), azotemia (3), and/or hypoalbuminemia (2). The remaining 41 dogs had GL in combination with other glomerular lesions, the most common being focal segmental glomerulosclerosis (16, 35%), lesions consistent with juvenile nephropathy (8, 17%), and glomerular amyloidosis (5, 11%). Overall, dogs with severe GL were younger than were those with mild GL ( P < .001). The percentage of glomeruli affected by GL differed by concurrent diagnoses ( P = .034), with the highest percentage of affected glomeruli in dogs with GL alone or those with concurrent juvenile nephropathy. These findings suggest that GL should be a recognized histologic phenotype of glomerular injury associated with clinical renal dysfunction and/or juvenile nephropathies. PMID- 28578627 TI - Coati Bodies: Cytoplasmic Hyaline Globules in the Ganglionic Neurons of Aging Captive Coatis. AB - Intensely eosinophilic and glassy intracytoplasmic inclusions were present in the neurons of the peripheral autonomic ganglia, Meissner's and Auerbach's plexus, and spinal ganglia in 20 aged white-nosed coatis ( Nasua narica, 7-19 years old) and in 4 of 7 brown-nosed coatis ( Nasua nasua, 2-21 years old) from multiple zoological institutions. Inclusions were single to numerous, sometimes distorting the cell. Pheochromocytomas were present in 5 of 16 white-nosed and 2 of 6 brown nosed coatis, although no inclusions were present in the adrenal glands. Histochemically, immunohistochemically, and ultrastructurally, these inclusions were consistent with dense neurosecretory granules. Although similar inclusions have been reported sporadically in the adrenal medulla of humans and several other mammalian species as both incidental and pathologic findings, ganglionic inclusions reported herein appear to be unique and related to age in these species. PMID- 28578628 TI - Relationship Between Immunoglobulin Deposition and Early Lesions of Progressive Glomerulonephropathy in Young Common Marmosets. AB - The authors previously investigated progressive glomerulonephropathy in 2- to 11 year-old common marmosets and characterized age-related changes of the renal glomeruli and development of tubulointerstitial lesions. In this study, immunoglobulin deposition and ultrastructural changes of the glomeruli were investigated in 5 young marmosets from 6 months to 3 years of age with pre-onset or early glomerulonephropathy. In all animals, the foot processes of podocytes were effaced, and IgM was deposited into the glomeruli. In glomeruli without glomerular basement membrane (GBM) alteration, IgM was the only immunoglobulin type deposited in the glomeruli. In cases with more advanced lesions of reticulation and thickening of GBM, IgA and IgG deposits were also observed. Therefore, the authors conclude that IgM may be the primary or earliest immunoglobulin deposited in this nephropathy, whereas IgA and IgG deposition may be connected to the progression of the glomerular lesions. IgM deposition and foot process effacement of podocytes occur early in the life of affected marmosets. PMID- 28578629 TI - Chaetomiaceae Fungi, Novel Pathogens of Equine Neurotropic Phaeohyphomycosis. AB - Many previously unrecognized fungi are emerging as potential pathogens. One such group is dematiaceous fungi of the Chaetomiaceae family (phylum Ascomycota, class Sordariomycetes). These fungi are rare causes of opportunistic, neurotropic phaeohyphomycosis in humans but are not known to cause similar infections in animals. The aims of this study were to investigate equine hyphal mycotic encephalitis, characterize key histopathologic features, and classify causative organisms with molecular diagnostic techniques. Seven cases were evaluated by histopathology. Panfungal PCR targeting the ribosomal RNA large subunit coding region and the noncoding internal transcribed spacer-2 region was performed on DNA extracted from formalin-fixed, paraffin-embedded sections of affected brain, and the resulting sequences were queried against published fungal genomes. Affected animals ranged from 8 to 22 years of age and presented with neurologic signs. Macroscopic lesions within affected brains included multifocal hemorrhage, focal swelling of the thalamus with red and yellow discoloration, and focal cerebral malacia. Major histologic findings included multifocal discrete foci of necrosis, neutrophilic to granulomatous inflammation, vasculitis, and intralesional fungal hyphae variably affecting the cerebrum, thalamus, and brainstem. DNA sequences in 4 cases showed > 98% homology with species within the Chaetomiaceae family, including Acrophialophora fusispora, Acrophialophora levis, and Chaetomium strumarium. Histomorphologically, Chaetomiaceae fungi were 7 to 10 MUm wide, septate, parallel walled, and nonpigmented, with dichotomous branching in affected horses. This case series is the first report of equine mycotic encephalitis caused by members of the Chaetomiaceae family, previously reported as rare emerging pathogens in humans. PMID- 28578630 TI - Neuroaxonal Dystrophy and Cavitating Leukoencephalopathy of Chihuahua Dogs. AB - A novel form of neuroaxonal dystrophy is described in 3 Chihuahua pups, 2 of which were from the same litter. It was characterized not only by accumulation of numerous and widely distributed axonal swellings (spheroids) but also by a severe cavitating leukoencephalopathy. The dogs presented with progressive neurological signs, including gait abnormalities and postural reaction deficits. Magnetic resonance images and gross examination at necropsy revealed dilation of lateral ventricles and cerebral atrophy, accompanied by cavitation of the subcortical white matter. Histopathologically, severe axonal degeneration with formation of large spheroids was found in the cerebral and cerebellar white matter, thalamus, and brainstem nuclei. Small-caliber spheroids were observed in the cerebral and cerebellar gray matter. The telencephalic white matter had severe myelin loss and cavitation with relative sparing of the U-fibers. Different from previously reported cases of canine neuroaxonal dystrophy, in these Chihuahuas the spheroid distribution predominantly involved the white matter with secondary severe leukoencephalopathy. PMID- 28578631 TI - Surfactant Protein A and Napsin A in the Immunohistochemical Characterization of Canine Pulmonary Carcinomas: Comparison With Thyroid Transcription Factor-1. AB - Thyroid transcription factor-1 (TTF-1) is a specific and sensitive marker for canine pulmonary tumors but is also expressed in thyroid carcinomas, which commonly metastasize to lung. Napsin A and surfactant protein A (SP-A) are used in the histologic diagnosis of non-small-cell lung cancer in humans but have not been thoroughly evaluated in neoplasms of dogs. The objective of this study was to compare the efficacy of immunohistochemistry for SP-A, napsin A, and TTF-1 in the diagnosis of canine pulmonary carcinomas. TTF-1, napsin A, and SP-A antibodies were applied to 67 formalin-fixed, paraffin-embedded canine pulmonary tumors. Although each marker had good sensitivity, only 3% (2/67) of lung tumors were negative for SP-A compared with 7% (5/67) and 9% (6/67) for napsin A and TTF 1, respectively. Each antigen was detected in a greater percentage of cells of tumors with acinar or papillary patterns compared with those with squamous differentiation. SP-A immunoreactivity was absent in all 113 nonpulmonary tumors tested. Of 108 normal tissues, SP-A was detected only in lung and in 1 of 6 adrenal, 1 of 3 endometrial, and 1 of 4 hepatic sections. Based on these findings, SP-A and napsin A are useful markers of canine lung epithelial neoplasia. Of these, SP-A is the most sensitive and specific (a possible pitfall is the need to distinguish entrapped normal pulmonary epithelial cells or alveolar macrophages from neoplastic cells) and can be used in combination with TTF-1 or napsin A to improve detection and differentiation of pulmonary carcinomas from metastatic tumors in the canine lung. PMID- 28578632 TI - The Impact of Social Support on Self-care of Patients With Diabetes: What Is the Effect of Diabetes Type? Systematic Review and Meta-analysis. AB - Purpose This meta-analysis examined relationships between social support and self care in type 1 (T1DM) and 2 diabetes mellitus (T2DM). Methods We searched for published and unpublished studies using the following databases: PubMed, Embase, PsycINFO, the Cochrane Library, and Medline. MeSH search terms included "diabetes mellitus," "social support," "caregiver," "self-care," "self-management," "self care skills," and "coping behavior." Studies reporting correlations between social support and self-care were included. Results Initially, 2 095 studies were extracted. After eliminating duplicate and irrelevant studies, 28 studies involving 5 242 patients with diabetes were included. Of these, 22 studies examined T2DM subjects. Social support was significantly associated with self care ( k = 28, r = .28, 95% CI: .21-.34, P < .001). Among the diabetes self-care types, the strongest effect was found for glucose monitoring ( k = 6, r = .21, 95% CI: .08-.33). The relationship between social support and self-care was stronger in T2DM ( k = 22, r = .30, 95% CI: .22-.37), relative to T1DM, samples ( k = 5, r = .22, 95% CI: .02-.38). Conclusion It was concluded that the overall effect size for social support on self-care was moderate, and its strength differed by ethnic majority within the sample, type of social support measures, and publication status. PMID- 28578633 TI - Early pulmonary compliance increase during cardiac surgery predicted post operative lung dysfunction. AB - INTRODUCTION: Lung dysfunction following cardiac surgery is currently viewed as the consequence of atelectasis and lung injury. While the mechanism of atelectasis has been largely detailed, the pathogenesis of lung injury after cardiopulmonary bypass is still unclear. Based upon clinical and experimental studies, we hypothesized that lungs could be injured through a mechanical phenomenon. METHODS: We recorded pulmonary compliance at six key moments of a heart operation in 62 adult patients undergoing elective cardiac surgery. We focused on the period lasting from anesthetic induction to aorta unclamping. We calculated the variation of static and dynamic pulmonary compliance caused by thorax opening; DeltaCstat1 and DeltaCdyn1 and that caused by cardiopulmonary bypass, DeltaCstat2 and DeltaCdyn2. Blood gases were performed under standardized ventilation after anesthetic induction and after surgical closure. The PaO2/FiO2 ratio was calculated. ?PaO2/FiO2 was the criterion for lung dysfunction. We compared DeltaCstat1 and DeltaCdyn1 with both ?PaO2/FiO2 and, respectively, DeltaCstat2 and DeltaCdyn2. RESULTS: Static and dynamic compliance increased with the opening of the thorax and decreased with the start of cardiopulmonary bypass. The PaO2/FiO2 ratio diminished after surgery. DeltaCstat1 and DeltaCdyn1 were negatively correlated with both ?PaO2/FiO2 (r=-0.42; p<0.001 and r=-0.44; p<0.001) and, respectively, with DeltaCstat2 and DeltaCdyn2 (r=-0.59; p<0.001 and r=-0.53; p<0.001). CONCLUSIONS: Increased pulmonary compliance induced by the opening of the thorax is correlated with worsened intrapulmonary shunt after cardiopulmonary bypass. A mechanical phenomenon could be partly responsible for post-operative hypoxemia. PMID- 28578634 TI - Determinants of attending antenatal care at least four times in rural Ghana: analysis of a cross-sectional survey. AB - BACKGROUND: Improving maternal health is a global challenge. In Ghana, maternal morbidity and mortality rates remain high, particularly in rural areas. Antenatal care (ANC) attendance is known to improve maternal health. However, few studies have updated current knowledge regarding determinants of ANC attendance. OBJECTIVE: This study examined factors associated with ANC attendance in predominantly rural Ghana. METHODS: We conducted a cross-sectional study at three sites (i.e. Navrongo, Kintampo, and Dodowa) in Ghana between August and September 2013. We selected 1500 women who had delivered within the two years preceding the survey (500 from each site) using two-stage random sampling. Data concerning 1497 women's sociodemographic characteristics and antenatal care attendance were collected and analyzed, and factors associated with attending ANC at least four times were identified using logistic regression analysis. RESULTS: Of the 1497 participants, 86% reported attending ANC at least four times, which was positively associated with possession of national health insurance (AOR 1.64, 95% CI: 1.14-2.38) and having a partner with a high educational level (AOR 1.64, 95% CI: 1.02-2.64) and negatively associated with being single (AOR 0.39, 95% CI: 0.22-0.69) and cohabiting (AOR 0.57, 95% CI: 0.34-0.97). In site-specific analyses, factors associated with ANC attendance included marital status in Navrongo; marital status, possession of national health insurance, partners' educational level, and wealth in Kintampo; and preferred pregnancy timing in Dodowa. In the youngest, least educated, and poorest women and women whose partners were uneducated, those with health insurance were more likely to report at least four ANC attendances relative to those who did not have insurance. CONCLUSIONS: Ghanaian women with low socioeconomic status were less likely to report at least four ANC attendances during pregnancy if they did not possess health insurance. The national health insurance scheme should include a higher number of deprived women in predominantly rural communities. PMID- 28578636 TI - Knowledge of Deaths in Hotel Rooms Diminishes Perceived Value and Elicits Guest Aversion. AB - Guest deaths are an inevitable aspect of the hospitality industry. In Study 1, participants read a vignette in which the previous guest died of natural causes, suicide, or homicide. Those who learned of a death (a) saw the room as less valuable, (b) opted to stay in a more basic room in which no death occurred, despite both rooms being offered for free, and (c) anticipated feeling uneasy when imagining an overnight stay. In Study 2, we investigated the persistence of this bias. Perceived room value and anticipatory well-being can be expected to return to baseline levels only many years after the death event. Similar to "stigmatized properties" in real estate, these data confirm an irrational and recalcitrant cognitive bias surrounding consumers' views of death-affected hotel rooms. PMID- 28578635 TI - Maternal Hypertension and Mortality in Small for Gestational Age 22- to 29-Week Infants. AB - Infants born before 30 weeks gestational age (GA) to mothers with hypertension (HTN) experience lower rates of mortality and serious morbidities when corrected for maternal and infant characteristics. Growth restriction and maternal HTN are often associated. We sought to determine if small for gestational age (SGA) infants have similarly decreased mortality risk when born to mothers with HTN. We identified 6897 singleton SGA, 22 + 0 to 29 + 6 weeks GA infants born between 2008 and 2011, cared for at 578 North American centers in the Vermont Oxford Network. Chromosomal abnormalities and birth defects were excluded. Mortality rates prior to discharge were compared between 4317 HTN and 2580 comparison infants. Logistic regression was used to adjust for birth weight, infant sex, maternal race, inborn/outborn, antenatal steroid exposure, prenatal care, and GA. Small for gestational age HTN infants were older (mean: 26.9 [1.9] vs 26.6 [2.2] weeks; P < .001) and larger (HTN = 584 [159] g vs 562 [156] g; P < .001) than comparison infants. Death prior to discharge occurred in 29% of HTN and 43% of comparison infants. Univariate analyses revealed lower mortality for HTN infants (odds ratio [OR] = 0.54, 95% confidence interval [CI]: 0.48-0.60). After adjustment, mortality remained lower when compared to non-HTN infants (OR = 0.60, 95% CI: 0.52-0.69). Extremely preterm SGA infants face high rates of mortality. Although maternal HTN is associated with SGA, SGA infants born to mothers with HTN have decreased risk of mortality compared to non-HTN SGA infants, prior to and after adjustment for antenatal and maternal characteristics. This may reflect detrimental physiologic effects associated with alternative mechanisms for fetal growth restriction and is important for parental counseling. PMID- 28578637 TI - Parental Grief After Offspring Suicide and Adaptation to the Loss in Japan. AB - Several reports have indicated that grief and mental health outcomes of people bereaved by suicide vary by their relationship to the deceased. Parents who have lost offspring experience higher levels of distress than those with other relationships to the deceased. However, there are limited studies investigating the experience of parental bereavement by suicide, and further research is needed. The present study aimed to clarify the differences in grief reactions between bereaved parents and those with other relationships to the deceased in Japan and explore a statistical model of adaptation to the loss. In total, 105 bereaved participants completed a questionnaire covering grief reaction, meaning reconstruction, mental health, social context, and demographic variables. Parents scored higher on several grief reaction items and lower in sense-making than those with other relationships. In addition, path analysis showed that sense making acted as a moderator in the experience of loss of offspring and grief reaction. PMID- 28578638 TI - Temporal processing deficit leads to impaired multisensory binding in schizophrenia. AB - INTRODUCTION: Schizophrenia has been characterised by neurodevelopmental dysconnectivity resulting in cognitive and perceptual dysmetria. Hence patients with schizophrenia may be impaired to detect the temporal relationship between stimuli in different sensory modalities. However, only a few studies described deficit in perception of temporally asynchronous multisensory stimuli in schizophrenia. METHODS: We examined the perceptual bias and the processing time of synchronous and delayed sounds in the streaming-bouncing illusion in 16 patients with schizophrenia and a matched control group of 18 participants. RESULTS: Equal for patients and controls, the synchronous sound biased the percept of two moving squares towards bouncing as opposed to the more frequent streaming percept in the condition without sound. In healthy controls, a delay of the sound presentation significantly reduced the bias and led to prolonged processing time whereas patients with schizophrenia did not differentiate between this condition and the condition with synchronous sound. CONCLUSION: Schizophrenia leads to a prolonged window of simultaneity for audiovisual stimuli. Therefore, temporal processing deficit in schizophrenia can lead to hyperintegration of temporally unmatched multisensory stimuli. PMID- 28578640 TI - Inorganic and metal nanoparticles and their antimicrobial activity in food packaging applications. AB - Nanotechnology has revolutionized almost all the fields of science and technology, particularly the food packaging industry. Accordingly, some nanoparticles can be used in food contact materials to preserve food products for longer periods. To date, many inorganic and metal nanoparticles have been implemented to synthesize active food packaging materials and to extend the shelf life of foods. Packaging with nanocomposites containing these nanoparticles offers advantages, such as reduction in the usage of preservatives and higher rate of reactions to inhibit the microbial growth. Nevertheless, the safety issues of employing the metal and inorganic nanoparticles in food packaging are still a major concern and more studies along with clinical trials need to be carried out prior to the mass production of these promising food containers. In this review, we have evaluated recent studies plus the applications of inorganic and metal nanoparticles mostly in food packaging applications along with their antimicrobial properties and reaction mechanisms. Many examples have been provided with the aim of opening new horizons for researchers to implement inorganic and metal nanoparticles in active food packaging field. PMID- 28578642 TI - Studies on Solubility Enhancement of Poorly Soluble NSAID Using Dual Approach of Micro-environmental pH Modulation and Melt Granulation. AB - BACKGROUND: The present work describes the role of melt granulation and microenviron-mental pH modulation technique in solubility enhancement of a poorly water soluble NSAID, Aceclofenac (ACL). ACL is a BCS Class II drug showing dissolution rate limited absorption and pH dependent solubility, with higher solubility at alkaline pH. The limited solubility of ACL affects drug absorption and hence, therapeutic effect as the drug is indicated in conditions of pain where rapid onset of action is desired. METHODS: Solubility enhancement of ACL was carried out by melt granulation technique using Gelucire 50/13 as molten carrier. The solubility of ACL was improved further by incorporating sodium hydrogen carbonate as pH modifier. The granules of ACL thus developed, were compressed into tablets using adsorbing carriers and other tableting excipients. RESULTS: This dual approach not only enhanced ACL solubility but also aided in achieving a pH independent release. The developed tablets exhibited pH independent release as well as enhanced rate of dissolution which is indicated by in vitro dissolution studies and ex-vivo intestinal permeation studies. The pH independent release would ensure absorption of drug throughout the gastrointestinal tract. The solubility enhancement of ACL was further confirmed by characterization studies such as DSC and XRD. CONCLUSION: Thus, the dual approach of melt granulation and micro-environmental pH modulation can be simple and scalable method for solubility enhancement of poorly soluble drugs showing pH dependent dissolution rate limited absorption. PMID- 28578641 TI - Emollient Acceptability in Childhood Atopic Dermatitis: Not All Emollients are Equal. AB - BACKGROUND: Eczema or Atopic Dermatitis (AD) is a common chronic relapsing skin disease associated with impaired quality of life. Regular usage of moisturizer/emollient is the mainstay of management but acceptability of emollient is often suboptimal. We investigated if emollient acceptability is influenced by various clinical factors in AD. METHODS: A survey on frequency of emollient usage, brands, clinical factors including disease severity (Nottingham Eczema Severity Score, NESS), quality of life (Children Dermatology Life Quality Index, CDLQI), Transpidermal Water Loss (TEWL), and Skin Hydration (SH) was performed. Acceptability was classified as very good, good, fair or poor. RESULTS: We evaluated 128 AD patients. NESS correlated with CDLQI and the treatment domain of CDLQI. Emollient usage is elementary for AD treatment. 89.1% of patients reported that doctor's recommendation was the major source of advice when choosing an emollient. Aqueous cream (AQ) and petroleum-derived products were among the commonly used emollients. More aqueous cream users reported fair/poor acceptability (p=0.017) and lower SH (p<0.05). Linear regression showed that patients who thought their emollient as fair or poor were currently using AQ (p=0.003), their emollient not recommended by a doctor (p=0.035), with more severe disease (p=0.04), and had lower emollient usage in winter (p=0.05). CONCLUSION: Physicians play a pivotal role in assisting patients to select an emollient that they will accept and use consistently. The studied emollients are generally acceptable by over 80% patients. However, aqueous cream is least acceptable by patients, making it the least favorable emollient to recommend to patients. PMID- 28578643 TI - Glioblastoma Targeted Gene Therapy Based on pEGFP/p53-Loaded Superparamagnetic Iron Oxide Nanoparticles. AB - BACKGROUND: Blood-brain barrier (BBB) separates the neural tissue from circulating blood because of its high selectivity. This study focused on the in vitro application of magnetic nanoparticles to deliver Tp53 as a gene of interest to glioblastoma (U87) cells across a simulated BBB model that comprised KB cells. MATERIAL AND METHOD: After magnetic and non-magnetic nanoparticles were internalized by KB cells, their location in these cells was examined by transmission electron microscopy. Transfection efficiency of DNA to U87 cells was evaluated by fluorescence microscopy, real time PCR, flowcytometry, and Western immuno-blotting. When a magnetic field was applied, a large number of magnetic nanoparticles accumulated in KB cells, appearing as black dots scattered in the cytoplasm of cells. Fluorescence microscope examination showed that transfection of the DNA to U87 target cells was highest in cells treated with magnetic nanoparticles and exposed to a magnetic field. Also it was reflected in significantly increased mRNA level while the p53 protein level was decreased. CONCLUSION: It could be concluded that a significant increase in total apoptosis was induced in cells by magnetic nanoparticles, coupled with exposure to a magnetic force (p <=0.01) as compared with cells that were not exposed to magnetism. PMID- 28578639 TI - Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. AB - BACKGROUND: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. METHODS: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). RESULTS: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .). PMID- 28578644 TI - MicroRNA Regulation in Osteogenic and Adipogenic Differentiation of Bone Mesenchymal Stem Cells and its Application in Bone Regeneration. AB - BACKGROUND: Bone mesenchymal stem cells (BMSCs) are multipotent stromal cells providing a useful cell source for treating bone diseases and metabolic disorders. BMSCs fate determination and lineage progression are controlled by multiple cytokines, transcriptional factors, signaling pathways, and microRNAs (miRNAs). MiRNAs are small non-coding RNAs that inhibit the posttranscriptional gene expression or degrade their targets. They are closely involved in controlling the key steps of osteogenesis and adipogenesis of BMSCs. OBJECTIVE: We aim to summarize the roles of miRNAs and their pathways in regulating osteogenic and adipogenic differentiation of BMSCs, and sketch its preliminary applications in bone regeneration. METHOD: We reviewed the published literature about the microRNA regulation in osteogenic and adipogenic differentiation of BMSCs. RESULTS: Most of miRNAs are expressed in BMSCs, perform as negative regulators of osteogenesis and have bidirectional effects on adipogenesis. Runx2 and PPARgamma are two key transcriptional factors in osteogenesis and adipogenesis, respectively. CONCLUSION: Anti-miRNAs or miRNA mimics is potential therapeutic strategy to repress pathological miRNAs for cellular therapies to bone diseases. The preliminary applications of miRNAs in BMSCs strongly suggested their bright future in bone regeneration. PMID- 28578645 TI - The Anti-Migraine Effects of M2000 (beta-D-Mannuronic Acid) on a Patient with Rheumatoid Arthritis: Case Report. AB - BACKGROUND: Rheumatoid arthritis (RA) and migraine are both common disorders which are caused by a faulty immune system and autonomic nervous system dysfunction, respectively. Although current treatment outlook has shown a great improvement in these two diseases, however many side effects have been reported. CASE REPORT: We reported a case of 43-years-female that has suffered from rheumatoid arthritis for 3 years with a 6 years history of migraine. She had used different types of medication for both rheumatoid arthritis and migraine but during these 6 years no improvement had been observed and even migraine progression in this patient became worse. She was admitted to the hospital for 12 weeks follow-up to evaluate the effect of beta-D-mannuronic acid (M2000) on her RA disease. MATERIALS AND METHODS: During 12 weeks of M2000 therapy, the signs and symptoms of migraine along with RA indices including Disease Activity Score (DAS28), simple disease activity index (SDAI) and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), anti-cyclic citrullinated peptide antibodies (anti-CCP) and blood determinants were measured. RESULTS AND DISCUSSION: The patient achieved a strong clinical improvement after 12 weeks of M2000 therapy in DAS28, SDAI and laboratory parameters. Moreover, M2000 showed a significant effect on the severity and the duration of migraine pain as well as times of migraine attack. In the present case, both rheumatoid arthritis and migraine as two different inflammatory diseases were diagnosed. Therefore, reducing the inflammation could be a valuable target to decrease the signs and symptoms of migraine and rheumatoid arthritis and help to the treatment process. CONCLUSION: M2000 as a novel designed non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive property is able to treat migraine in addition to its potent efficacy on treatment of rheumatoid arthritis. PMID- 28578646 TI - Clonidine, but not Dexamethasone, Prolongs Ropivacaine-Induced Supraclavicular Brachial Plexus Nerve Block Duration. AB - BACKGROUND: Ultrasound-guided supraclavicular brachial plexus block (USSB) provides excellent postoperative analgesia after upper extremity surgery. Dexamethasone and clonidine have been added to local anesthetics to enhance and prolong the duration of analgesia. OBJECTIVE: The objective of this randomized prospective study is to evaluate the efficacy of dexamethasone, clonidine, or combination of both as adjuvants to ropivacaine on the duration of USSB for postoperative analgesia. METHODS: Patients receiving USSB for postoperative pain control for upper extremity surgery were randomized to one of four groups; ropivacaine 0.5%, ropivacaine 0.5% with 4 mg dexamethasone, ropivacaine 0.5% with 100 mcg clonidine , or ropivacaine 0.5% with 4 mg dexamethasone and 100 mcg clonidine. Pain scores, sensory and motor function were evaluated at post anesthesia care unit (PACU), discharge and at 24 h postoperatively. RESULTS: The duration of sensory and motor blocks was significantly longer in clonidine groups when compared to ropivacaine alone [Sensorial analgesia: ropivacaine alone 13.4+/ 6, Ropivacaine- Clonidine 17.4+/-6; Ropivacaine-Dexamethasone-Clonidine 18.8+/ 6.2; Motor blocks: Ropivacaine 12+/-5, Ropivacaine-Clonidine 16.8+/-5.2, Ropivacaine-Dexamethasone-Clonidine 18.2+/-5.7]. In clonidine groups, there was significant prolongation of motor and sensory block when compared to ropivacaine group alone. CONCLUSION: The results demonstrated that clonidine significantly prolongs the duration of ropivacaine effects for the postoperative analgesia in patient underwent upper arm surgeries. PMID- 28578647 TI - Iodine Prophylaxis in the Case of Nuclear Accident. AB - BACKGROUND: On 26th April, 1986 the greatest accident of nuclear plant in Czernobyl occured and isotopes with high percentage of release were erupted: 33 Xe, 131-I, 132-Te, 134-Cs and 137-Cs. The radioactivity of the isotopes was very high - for instance: 33-Xe 6500 PBq, 131-I 1760 PBq. Rest of the 15 isotopes represented similar radioactivity with shorter percentage of release. The most exposed group of people were 237 liquidators, and 11600 people living around had to be evacuated when the limit dose for a person (5mSv) was crossed. Ionizing radiation on the molecular level produces high energy radicals, water radiolysis and ionization of the atoms leading to damage of the enzymes activity centers and receptors, cell membranes DNA, intracellular lysosomes, and especially important for ATP synthesis - mitochondria. These destructions lead to tissue and organs damage. OBJECTIVE: The aim of this article is the presentation of the protective property of iodine application in the case of nuclear accident. METHODS: In Poland at that time, effective iodine prophylaxis did not exist. In the face of such exposition, a special Governement Commission was appointed. When permissioned maximal dose for children and adolescents 50mSv appeared in some areas of the country, the Commission made a decision about obligatory administration of a single pharmacological dose of potassium iodide for all children and adolescents till age 16. No relevant recent patents were available for this WHO report. RESULTS: In this way, the dose of 131-I to thyroid for inhabitants in high, moderated, and low contaminated regions were reduced by about 45%. However, from 1987 to 1997 increase in prevalence of the differentiated thyroid cancer in adults in Polish population especially in women over 40 years old in the southern part of Poland was observed. CONCLUSION: Actually in European countries work 185 nuclear power plants and to 2045 another 100 is planned. In 1999, WHO issued recommendations on iodine prophylaxis in the case of nuclear accident. PMID- 28578648 TI - Synthetic Peptide Drugs for Targeting Skin Cancer: Malignant Melanoma and Melanotic Lesions. AB - BACKGROUND: Peptides play decisive roles in the skin, ranging from host defense responses to various forms of neuroendocrine regulation of cell and organelle function. Synthetic peptides conjugated to radionuclides or photosensitizers may serve to identify and treat skin tumors and their metastatic forms in other organs of the body. In the introductory part of this review, the role and interplay of the different peptides in the skin are briefly summarized, including their potential application for the management of frequently occurring skin cancers. Special emphasis is given to different targeting options for the treatment of melanoma and melanotic lesions. Radionuclide Targeting: alpha Melanocyte-stimulating hormone (alpha-MSH) is the most prominent peptide for targeting of melanoma tumors via the G protein-coupled melanocortin-1 receptor that is (over-)expressed by melanoma cells and melanocytes. More than 100 different linear and cyclic analogs of alpha-MSH containing chelators for 111In, 67/68Ga, 64Cu, 90Y, 212Pb, 99mTc, 188Re were synthesized and examined with experimental animals and in a few clinical studies. Linear Ac-Nle-Asp-His-D-Phe Arg-Trp-Gly-Lys-NH2 (NAP-amide) and Re-cyclized Cys- Cys-Glu-His-D-Phe-Arg-Trp Cys-Arg-Pro-Val-NH2 (Re[Arg11]CCMSH) containing different chelators at the N- or C-terminus served as lead compounds for peptide drugs with further optimized characteristics. Alternatively, melanoma may be targeted with radiopeptides that bind to melanin granules occurring extracellularly in these tumors. Photosensitizer targeting: A more recent approach is the application of photosensitizers attached to the MSH molecule for targeted photodynamic therapy using LED or coherent laser light that specifically activates the photosensitizer. Experimental studies have demonstrated the feasibility of this approach as a more gentle and convenient alternative compared to radionuclides. PMID- 28578649 TI - Peptides Against Autoimmune Neurodegeneration. AB - The mammalian immune system is a nearly perfect defensive system polished by a hundred million years of evolution. Unique flexibility and adaptivity have created a virtually impenetrable barrier to numerous exogenous pathogens that are assaulting us every moment. Unfortunately, triggers that remain mostly enigmatic will sometimes persuade the immune system to retarget against self-antigens. This civil war remains underway, showing no mercy and taking no captives, eventually leading to irreversible pathological changes in the human body. Research that has emerged during the last two decades has given us hope that we may have a chance to overcome autoimmune diseases using a variety of techniques to "reset" the immune system. In this report, we summarize recent advances in utilizing short polypeptides - mostly fragments of autoantigens - in the treatment of autoimmune neurodegeneration. PMID- 28578650 TI - Snake Venom: From Deadly Toxins to Life-saving Therapeutics. AB - Snakes are fascinating creatures and have been residents of this planet well before ancient humans dwelled the earth. Venomous snakes have been a figure of fear, and cause notable mortality throughout the world. The venom constitutes families of proteins and peptides with various isoforms that make it a cocktail of diverse molecules. These biomolecules are responsible for the disturbance in fundamental physiological systems of the envenomed victim, leading to morbidity which can lead to death if left untreated. Researchers have turned these life threatening toxins into life-saving therapeutics via technological advancements. Since the development of captopril, the first drug that was derived from bradykininpotentiating peptide of Bothrops jararaca, to the disintegrins that have potent activity against certain types of cancers, snake venom components have shown great potential for the development of lead compounds for new drugs. There is a continuous development of new drugs from snake venom for coagulopathy and hemostasis to anti-cancer agents. In this review, we have focused on different snake venom proteins / peptides derived drugs that are in clinical use or in developmental stages till to date. Also, some commonly used snake venom derived diagnostic tools along with the recent updates in this exciting field are discussed. PMID- 28578651 TI - Immunomodulatory Effect of G2013 (alpha-L-Guluronic Acid) on the TLR2 and TLR4 in Human Mononuclear Cells. AB - BACKGROUND: Inhibition of Toll-like receptors (TLRs) signaling has been established as a new method for the development of anti-inflammatory drugs instead of NSAIDs (non-steroid anti-inflammatory drugs). Since the immunomodulatory role of G2013 (alpha-L-Guluronic acid) was reported in some recent experiments, we decided to assess the effects of G2013 on the protein expression of TLR2 and TLR4, their downstream signaling cascade, and the secretion of pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs). METHODS: After blood sampling from 16 healthy donors, PBMCs were isolated and treated with/without lipopolysaccharide (LPS), lipopolyteichoic acid (LTA), and G2013. Flow cytometry was done for detecting the protein expression of TLR2 and TLR4. MyD88, IkappaB, Tollip, and NF-kappaB mRNA expression were assessed by realtime PCR. ELISA was performed for assessing the concentration of IL-1beta and IL-6. RESULTS: G2013 at a concentration of 25 ug/mL (high dose) significantly downregulated NF-kappaB, IkappaB and MyD88 mRNA expression and suppressed the secretion of IL-1beta by PBMCs. The findings indicate that G2013 may exert its regulatory effect under normal condition via Tollip in a dose dependence pathway. Our results demonstrated that G2013 had no profound impact on the protein expression of TLR2 and TLR4. CONCLUSION: In conclusion, our findings point to the immunomodulatory effect of G2013 on the TLR2 and TLR4 signaling cascade and cytokine production by PBMCs. These findings could lead to an establishment of new safe anti-inflammatory drugs in the future. PMID- 28578653 TI - Chemotherapy-induced Takotsubo cardiomyopathy, a case report and review of the literature. AB - BACKGROUND: Several chemotherapy molecules, monoclonal antibodies and tyrosine kinase inhibitors, have been linked to Takotsubo cardiomyopathy (TC). CASE PRESENTATION: In this article, we describe the case of a 45-year-old woman who developed TC after receiving an intra-arterial and intra-venous polychemotherapy for locally advanced epidermoid carcinoma of the anal canal. This is the first described case of TC associated with intra-arterial chemotherapy. CONCLUSIONS: A review of the literature points to 5-fluorouracil as the most common molecule associated with TC and highlights the potential risk associated with rechallenging patient with the same drug. PMID- 28578652 TI - ICORG 10-14: NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric junction International Study (Neo-AEGIS). AB - BACKGROUND: Neoadjuvant therapy is increasingly the standard of care in the management of locally advanced adenocarcinoma of the oesophagus and junction (AEG). In randomised controlled trials (RCTs), the MAGIC regimen of pre- and postoperative chemotherapy, and the CROSS regimen of preoperative chemotherapy combined with radiation, were superior to surgery only in RCTs that included AEG but were not powered on this cohort. No completed RCT has directly compared neoadjuvant or perioperative chemotherapy and neoadjuvant chemoradiation. The Neo AEGIS trial, uniquely powered on AEG, and including comprehensive modern staging, compares both these regimens. METHODS: This open label, multicentre, phase III RCT randomises patients (cT2-3, N0-3, M0) in a 1:1 fashion to receive CROSS protocol (Carboplatin and Paclitaxel with concurrent radiotherapy, 41.4Gy/23Fr, over 5 weeks). The power calculation is a 10% difference in favour of CROSS, powered at 80%, two-sided alpha level of 0.05, requiring 540 patients to be evaluable, 594 to be recruited if a 10% dropout is included (297 in each group). The primary endpoint is overall survival, with a minimum 3-year follow up. Secondary endpoints include: disease free survival, recurrence rates, clinical and pathological response rates, toxicities of induction regimens, post-operative pathology and tumour regression grade, operative in-hospital complications, and health-related quality of life. The trial also affords opportunities for establishing a bio-resource of pre-treatment and resected tumour, and translational research. DISCUSSION: This RCT directly compares two established treatment regimens, and addresses whether radiation therapy positively impacts on overall survival compared with a standard perioperative chemotherapy regimen Sponsor: Irish Clinical Research Group (ICORG). TRIAL REGISTRATION: NCT01726452 . Protocol 10-14. Date of registration 06/11/2012. PMID- 28578654 TI - Progressive resistance training in head and neck cancer patients during concomitant chemoradiotherapy -- design of the DAHANCA 31 randomized trial. AB - BACKGROUND: Head and neck cancer patients undergoing concomitant chemoradiotherapy (CCRT) frequently experience loss of muscle mass and reduced functional performance. Positive effects of exercise training are reported for many cancer types but biological mechanisms need further elucidation. This randomized study investigates whether progressive resistance training (PRT) may attenuate loss of muscle mass and functional performance. Furthermore, biochemical markers and muscle biopsies will be investigated trying to link biological mechanisms to training effects. METHODS: At the Departments of Oncology at Herlev and Aarhus University Hospitals, patients with stage III/IV squamous cell carcinoma of the head and neck, scheduled for CCRT are randomized 1:1 to either a 12-week PRT program or control group, both with 1 year follow-up. Planned enrollment is 72 patients, and stratification variables are study site, sex, p16-status, and body mass index. Primary endpoint is difference in change in lean body mass (LBM) after 12 weeks of PRT, assessed by dual-energy X-ray absorptiometry (DXA). The hypothesis is that 12 weeks of PRT can attenuate the loss of LBM by at least 25%. Secondary endpoints include training adherence, changes in body composition, muscle strength, functional performance, weight, adverse events, dietary intake, self-reported physical activity, quality of life, labor market affiliation, blood biochemistry, plasma cytokine concentrations, NK cell frequency in blood, sarcomeric protein content in muscles, as well as muscle fiber type and fiber size in muscle biopsies. Muscle biopsies are optional. DISCUSSION: This randomized study investigates the impact of a 12-week progressive resistance training program on lean body mass and several other physiological endpoints, as well as impact on adverse events and quality of life. Furthermore, a translational approach is integrated with extensive biological sampling and exploration into cytokines and mechanisms involved. The current paper discusses decisions and methods behind exercise in head and neck cancer patients undergoing concomitant chemoradiotherapy. TRIAL REGISTRATION: Approved by the Regional Ethics Committee for the Capital Region of Denmark (protocol id: H-15003725) and registered retrospectively at ClinicalTrials.gov ( NCT02557529 ) September 11th 2015. PMID- 28578655 TI - Potential mechanisms of resistance to venetoclax and strategies to circumvent it. AB - BACKGROUND: Venetoclax (ABT-199), a first-in-class orally bioavailable BCL-2 selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges. METHODS: In order to gain a more comprehensive insight into the nature of venetoclax resistance mechanisms, we evaluated the changes in the BCL-2 family members at the genetic and expression levels in seven different venetoclax-resistant derived leukemia and lymphoma cell lines. RESULTS: Gene and protein expression analyses identified a number of different alterations in the expression of pro- and anti-apoptotic BCL-2 family members. In the resistant derived cells, an increase in either or both the anti apoptotic proteins BCL-XL or MCL-1, which are not targeted by venetoclax was observed, and either concomitant or exclusive with a decrease in one or more pro apoptotic proteins. In addition, mutational analysis also revealed a mutation in the BH3 binding groove (F104L) that could potentially interfere with venetoclax binding. Not all changes may be causally related to venetoclax resistance and may only be an epiphenomenon. For resistant cell lines showing elevations in BCL-XL or MCL-1, strong synergistic cell killing was observed when venetoclax was combined with either BCL-XL- or MCL-1-selective inhibitors, respectively. This highlights the importance of BCL-XL- and MCL-1 as causally contributing to venetoclax resistance. CONCLUSIONS: Overall our study identified numerous changes in multiple resistant lines; the changes were neither mutually exclusive nor universal across the cell lines tested, thus exemplifying the complexity and heterogeneity of potential resistance mechanisms. Identifying and evaluating their contribution has important implications for both patient selection and the rational development of strategies to overcome resistance. PMID- 28578656 TI - Treatment patterns and real world clinical outcomes in ER+/HER2- post-menopausal metastatic breast cancer patients in the United States. AB - BACKGROUND: With several new therapies becoming available, treatment of metastatic breast cancer (mBC) is evolving. The objective of this study is to describe patient characteristics, treatment patterns and real-world clinical outcomes in post-menopausal women with ER+, HER2- mBC and to obtain insight into patient outcomes and potential unmet needs with current therapies. METHODS: The current study is a physician survey followed by a retrospective chart review of patient medical records by physicians in the US between March and April 2015. One hundred three physicians were asked to complete an online survey aiming to understand their satisfaction and expectations with current available treatments and potential areas of unmet need for mBC patients. Medical records from 178 females were extracted for the chart review. Using these data from medical records, patient characteristics and treatment patterns were analyzed descriptively. Time to progression (TTP) on first line, and progression-free survival (PFS) on second and third line of therapy were analyzed using the Kaplan Meier method. RESULTS: Sixty-seven percent (n = 119) of patients had metastatic disease at initial diagnosis of breast cancer. Mean age at chart data extraction was 65.8 (SD: 9.4) years. Aromatase inhibitors (AIs) were prescribed for 58% and around 13% of patients in first line and second line, respectively. Chemotherapy was prescribed to 14% in first line and 31% in second line. Median TTP on first line therapy was 12 months for patients receiving AIs as compared to 7.9 months for patients receiving chemotherapy. Across all treatment lines, bone pain and fatigue were reported as the main symptoms associated with disease progression which had an impact on patient quality of life. Physicians expressed that prolonging life was deemed the most important treatment goal, followed by preservation or improvement of quality of life. CONCLUSION: In this study the majority of patients received endocrine therapy as first line treatment and current therapies still resulted in a short time to progression in first line. Results from the chart review and the physician survey highlight a quantitative unmet need for more effective treatments which delay disease progression and improve survival outcomes while maintaining quality of life. PMID- 28578658 TI - Identification of the sequence determinants of protein N-terminal acetylation through a decision tree approach. AB - BACKGROUND: N-terminal acetylation is one of the most common protein modifications in eukaryotes and occurs co-translationally when the N-terminus of the nascent polypeptide is still attached to the ribosome. This modification has been shown to be involved in a wide range of biological phenomena such as protein half-life regulation, protein-protein and protein-membrane interactions, and protein subcellular localization. Thus, accurately predicting which proteins receive an acetyl group based on their protein sequence is expected to facilitate the functional study of this modification. As the occurrence of N-terminal acetylation strongly depends on the context of protein sequences, attempts to understand the sequence determinants of N-terminal acetylation were conducted initially by simply examining the N-terminal sequences of many acetylated and unacetylated proteins and more recently by machine learning approaches. However, a complete understanding of the sequence determinants of this modification remains to be elucidated. RESULTS: We obtained curated N-terminally acetylated and unacetylated sequences from the UniProt database and employed a decision tree algorithm to identify the sequence determinants of N-terminal acetylation for proteins whose initiator methionine (iMet) residues have been removed. The results suggested that the main determinants of N-terminal acetylation are contained within the first five residues following iMet and that the first and second positions are the most important discriminator for the occurrence of this phenomenon. The results also indicated the existence of position-specific preferred and inhibitory residues that determine the occurrence of N-terminal acetylation. The developed predictor software, termed NT-AcPredictor, accurately predicted the N-terminal acetylation, with an overall performance comparable or superior to those of preceding predictors incorporating machine learning algorithms. CONCLUSION: Our machine learning approach based on a decision tree algorithm successfully provided several sequence determinants of N-terminal acetylation for proteins lacking iMet, some of which have not previously been described. Although these sequence determinants remain insufficient to comprehensively predict the occurrence of this modification, indicating that further work on this topic is still required, the developed predictor, NT AcPredictor, can be used to predict N-terminal acetylation with an accuracy of more than 80%. PMID- 28578657 TI - In vivo screening reveals interactions between Drosophila Manf and genes involved in the mitochondria and the ubiquinone synthesis pathway. AB - BACKGROUND: Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) and Cerebral Dopamine Neurotrophic Factor (CDNF) form an evolutionarily conserved family of neurotrophic factors. Orthologues for MANF/CDNF are the only neurotrophic factors as yet identified in invertebrates with conserved amino acid sequence. Previous studies indicate that mammalian MANF and CDNF support and protect brain dopaminergic system in non-cell-autonomous manner. However, MANF has also been shown to function intracellularly in the endoplasmic reticulum. To date, the knowledge on the interacting partners of MANF/CDNF and signaling pathways they activate is rudimentary. Here, we have employed the Drosophila genetics to screen for potential interaction partners of Drosophila Manf (DmManf) in vivo. RESULTS: We first show that DmManf plays a role in the development of Drosophila wing. We exploited this function by using Drosophila UAS-RNAi lines and discovered novel genetic interactions of DmManf with genes known to function in the mitochondria. We also found evidence of an interaction between DmManf and the Drosophila homologue encoding Ku70, the closest structural homologue of SAP domain of mammalian MANF. CONCLUSIONS: In addition to the previously known functions of MANF/CDNF protein family, DmManf also interacts with mitochondria related genes. Our data supports the functional importance of these evolutionarily significant proteins and provides new insights for the future studies. PMID- 28578660 TI - Simple adjustment of the sequence weight algorithm remarkably enhances PSI-BLAST performance. AB - BACKGROUND: PSI-BLAST, an extremely popular tool for sequence similarity search, features the utilization of Position-Specific Scoring Matrix (PSSM) constructed from a multiple sequence alignment (MSA). PSSM allows the detection of more distant homologs than a general amino acid substitution matrix does. An accurate estimation of the weights for sequences in an MSA is crucially important for PSSM construction. PSI-BLAST divides a given MSA into multiple blocks, for which sequence weights are calculated. When the block width becomes very narrow, the sequence weight calculation can be odd. RESULTS: We demonstrate that PSI-BLAST indeed generates a significant fraction of blocks having width less than 5, thereby degrading the PSI-BLAST performance. We revised the code of PSI-BLAST to prevent the blocks from being narrower than a given minimum block width (MBW). We designate the modified application of PSI-BLAST as PSI-BLASTexB. When MBW is 25, PSI-BLASTexB notably outperforms PSI-BLAST consistently for three independent benchmark sets. The performance boost is even more drastic when an MSA, instead of a sequence, is used as a query. CONCLUSIONS: Our results demonstrate that the generation of narrow-width blocks during the sequence weight calculation is a critically important factor that restricts the PSI-BLAST search performance. By preventing narrow blocks, PSI-BLASTexB upgrades the PSI-BLAST performance remarkably. Binaries and source codes of PSI-BLASTexB (MBW = 25) are available at https://github.com/kyungtaekLIM/PSI-BLASTexB . PMID- 28578661 TI - Parallel tiled Nussinov RNA folding loop nest generated using both dependence graph transitive closure and loop skewing. AB - BACKGROUND: RNA secondary structure prediction is a compute intensive task that lies at the core of several search algorithms in bioinformatics. Fortunately, the RNA folding approaches, such as the Nussinov base pair maximization, involve mathematical operations over affine control loops whose iteration space can be represented by the polyhedral model. Polyhedral compilation techniques have proven to be a powerful tool for optimization of dense array codes. However, classical affine loop nest transformations used with these techniques do not optimize effectively codes of dynamic programming of RNA structure predictions. RESULTS: The purpose of this paper is to present a novel approach allowing for generation of a parallel tiled Nussinov RNA loop nest exposing significantly higher performance than that of known related code. This effect is achieved due to improving code locality and calculation parallelization. In order to improve code locality, we apply our previously published technique of automatic loop nest tiling to all the three loops of the Nussinov loop nest. This approach first forms original rectangular 3D tiles and then corrects them to establish their validity by means of applying the transitive closure of a dependence graph. To produce parallel code, we apply the loop skewing technique to a tiled Nussinov loop nest. CONCLUSIONS: The technique is implemented as a part of the publicly available polyhedral source-to-source TRACO compiler. Generated code was run on modern Intel multi-core processors and coprocessors. We present the speed-up factor of generated Nussinov RNA parallel code and demonstrate that it is considerably faster than related codes in which only the two outer loops of the Nussinov loop nest are tiled. PMID- 28578659 TI - Rapamycin (mTORC1 inhibitor) reduces the production of lactate and 2 hydroxyglutarate oncometabolites in IDH1 mutant fibrosarcoma cells. AB - BACKGROUND: Multiple studies concluded that oncometabolites (e.g. D-2 hydroxyglutarate (2-HG) related to mutant isocitrate dehydrogenase 1/2 (IDH1/2) and lactate) have tumour promoting potential. Regulatory mechanisms implicated in the maintenance of oncometabolite production have great interest. mTOR (mammalian target of rapamycin) orchestrates different pathways, influences cellular growth and metabolism. Considering hyperactivation of mTOR in several malignancies, the question has been addressed whether mTOR operates through controlling of oncometabolite accumulation in metabolic reprogramming. METHODS: HT-1080 cells - carrying originally endogenous IDH1 mutation - were used in vitro and in vivo. Anti-tumour effects of rapamycin were studied using different assays. The main sources and productions of the oncometabolites (2-HG and lactate) were analysed by 13C-labeled substrates. Alterations at protein and metabolite levels were followed by Western blot, flow cytometry, immunohistochemistry and liquid chromatography mass spectrometry using rapamycin, PP242 and different glutaminase inhibitors, as well. RESULTS: Rapamycin (mTORC1 inhibitor) inhibited proliferation, migration and altered the metabolic activity of IDH1 mutant HT 1080 cells. Rapamycin reduced the level of 2-HG sourced mainly from glutamine and glucose derived lactate which correlated to the decreased incorporation of 13C atoms from 13C-substrates. Additionally, decreased expressions of lactate dehydrogenase A and glutaminase were also observed both in vitro and in vivo. CONCLUSIONS: Considering the role of lactate and 2-HG in regulatory network and in metabolic symbiosis it could be assumed that mTOR inhibitors have additional effects besides their anti-proliferative effects in tumours with glycolytic phenotype, especially in case of IDH1 mutation (e.g. acute myeloid leukemias, gliomas, chondrosarcomas). Based on our new results, we suggest targeting mTOR activity depending on the metabolic and besides molecular genetic phenotype of tumours to increase the success of therapies. PMID- 28578662 TI - Possible contribution of quantum-like correlations to the placebo effect: consequences on blind trials. AB - BACKGROUND: Factors that participate in the biological changes associated with a placebo are not completely understood. Natural evolution, mean regression, concomitant procedures and other non specific effects are well-known factors that contribute to the "placebo effect". In this article, we suggest that quantum-like correlations predicted by a probabilistic modeling could also play a role. RESULTS: An elementary experiment in biology or medicine comparing the biological changes associated with two placebos is modeled. The originality of this modeling is that experimenters, biological system and their interactions are described together from the standpoint of a participant who is uninvolved in the measurement process. Moreover, the small random probability fluctuations of a "real" experiment are also taken into account. If both placebos are inert (with only different labels), common sense suggests that the biological changes associated with the two placebos should be comparable. However, the consequence of this modeling is the possibility for two placebos to be associated with different outcomes due to the emergence of quantum-like correlations. CONCLUSION: The association of two placebos with different outcomes is counterintuitive and this modeling could give a framework for some unexplained observations where mere placebos are compared (in some alternative medicines for example). This hypothesis can be tested in blind trials by comparing local vs. remote assessment of correlations. PMID- 28578663 TI - Cross-border spread, lineage displacement and evolutionary rate estimation of rabies virus in Yunnan Province, China. AB - BACKGROUND: Rabies is an important but underestimated threat to public health, with most cases reported in Asia. Since 2000, a new epidemic wave of rabies has emerged in Yunnan Province, southwestern China, which borders three countries in Southeast Asia. METHOD: We estimated gene-specific evolutionary rates for rabies virus using available data in GenBank, then used this information to calibrate the timescale of rabies virus (RABV) spread in Asia. We used 452 publicly available geo-referenced complete nucleoprotein (N) gene sequences, including 52 RABV sequences that were recently generated from samples collected in Yunnan between 2008 and 2012. RESULTS: The RABV N gene evolutionary rate was estimated to be 1.88 * 10-4 (1.37-2.41 * 10-4, 95% Bayesian credible interval, BCI) substitutions per site per year. Phylogenetic reconstructions show that the currently circulating RABV lineages in Yunnan result from at least seven independent introductions (95% BCI: 6-9 introductions) and represent each of the three main Asian RABV lineages, SEA-1, -2 and -3. We find that Yunnan is a sink location for the domestic spread of RABV and connects RABV epidemics in North China, South China, and Southeast Asia. Cross-border spread from southeast Asia (SEA) into South China, and intermixing of the North and South China epidemics is also well supported. The influx of RABV into Yunnan from SEA was not well supported, likely due to the poor sampling of SEA RABV diversity. We found evidence for a lineage displacement of the Yunnan SEA-2 and -3 lineages by Yunnan SEA-1 strains, and considered whether this could be attributed to fitness differences. CONCLUSION: Overall, our study contributes to a better understanding of the spread of RABV that could facilitate future rabies virus control and prevention efforts. PMID- 28578664 TI - Macrophage migration inhibitory factor promoter polymorphisms (-794 CATT5-8): Relationship with soluble MIF levels in coronary atherosclerotic disease subjects. AB - BACKGROUND: We analyzed the relationship of -794 CATT5-8 MIF polymorphisms with soluble MIF in Coronary Atherosclerotic Disease (CAD) patients. METHODS: A total of 256 patients selected, on which 186 normal-coronary and 70 Coronary artery disease subjects, were recruited in the study (Retrospectively registered). Genotyping of -794 CATT5-8 polymorphisms were performed by PCR and DNA sequencing. Serum MIF levels were measured using an ELISA kit. Patients were classified by coronary angiogram, and CAD based on Gensini's integral degree (angiographic scoring system). RESULTS: The allele frequency and genotype frequency of -794 CATT5-8 did not show any differences in normal-coronary subjects and CAD subjects. In CAD patients, serum MIF levels was lower in CATT (5) subjects than in CATT (7) subjects, while the genotype of -794 CATT5-8 did not show differences in serum MIF levels. In addition, we found a decrease in serum MIF levels in carriers of the (5/5) genotypes the -794 CATT5-8 MIF polymorphisms, although it was not significant. There was no relationship of CAD class and the allele frequency of -794 CATT5-8. CONCLUSIONS: This study found no association between CAD class and -794 CATT5-8 MIF polymorphisms with soluble MIF levels in CAD Subjects. TRIAL REGISTRATION: NCT01750502 (November 2012, Retrospectively registered). PMID- 28578665 TI - Risk factors for dementia in the ninth decade of life and beyond: a study of the Lothian birth cohort 1921. AB - BACKGROUND: With increasing numbers of people surviving beyond eighty years, this section of the population demands attention to reduce the impact of dementia. In order to develop effective preventative strategies, it is essential to understand age-specific risk factor profiles for dementia: do risk factors for dementia in those in their sixties and seventies persist into oldest age? The aims of this study were to determine incident dementia and to investigate the risk profile for dementia from age 79 to 95 years in a well-characterised cohort. METHODS: Participants underwent intelligence testing at age 11 and were followed-up from at 79 years of age. Variables included: age, sex, age 11 IQ, APOE E4, education, diabetes, hypertension, statin use, physical activity at leisure and in occupation, symptoms of depression, height, number of teeth, body mass index, blood pressure, cholesterol and HbA1c. Dementia cases were ascertained from death certificates, electronic patient records and clinical reviews. Logistic regression analysis determined the degree of risk for dementia associated with each variable. Analyses were completed both with and without the physical activity variables due to the significant number of missing data for these variables. RESULTS: Of the eligible cohort, n = 410 participants remained dementia-free and n = 110 had developed probable dementia. When logistic regression analyses contained all variables, complete data was available for n = 234 (n = 48 with dementia). Results demonstrated that positive APOE E4 carrier status (OR: 2.15, 95% CI: 1.04, 4.42) and greater lifetime physical activity (OR: 1.14, 95% CI: 1.02, 1.28) increased the risk for dementia. A reduction in risk for dementia was seen for hypertension (OR: 0.47, 95% CI: 0.23, 0.98). When physical activity variables were excluded, the number with complete data increased to n = 377 (n = 80 with dementia). APOE E4 remained significant (OR: 2.37; 95% CI: 1.37, 4.07), as did hypertension (OR: 0.55; 95% CI: 0.32, 0.93). CONCLUSIONS: Dementia incidence was consistent with expected rates. The risk profile for dementia in this cohort of participants aged 79-95 confirmed previous findings that risk factors differ for those over 79 years. Further evidence is recommended in order that the risk profile for this age group can be accurately determined. PMID- 28578666 TI - Affected family members' experience of, and coping with, aggression and violence within the context of problematic substance use: a qualitative study. AB - BACKGROUND: Families have an important role supporting a family member with problematic substance use (PSU), although this can often be challenging and confronting. Previous research has identified high rates of family aggression and violence within the context of PSU, although few studies have examined this issue from the perspective of affected family members (AFMs) supporting a member with PSU. The aims of the current study were to understand AFMs' experience of aggression and violence while supporting a member with PSU, and to explicate the strategies they used to prevent and cope with this behaviour. METHODS: Semi structured, audio-recorded qualitative interviews were conducted with 31 AFMs from the state of Victoria in Australia. Interpretative Phenomenological Analysis was used to guide data collection and analysis. RESULTS: Almost 70% of participants experienced PSU-related family aggression and/or violence. Two main themes and related sub-themes were abstracted from the data capturing their experiences of this behaviour and the strategies they used to try to prevent and cope in this situation. Aggression and/or violence were variable, changeable and unpredictable; and aggression and/or violence altering social interactions and family dynamics. As a consequence, it was upsetting, stressful and emotionally exhausting to AFMs. In response to this experience, and largely through trial and error, they used several direct strategies to try to prevent and cope with the behaviour; however, most continued to struggle in these circumstances. They also highlighted additional indirect measures, which, if adopted, would enhance their existing direct strategies. CONCLUSIONS: More effective primary, secondary and tertiary preventive measures are needed to address family aggression and violence within the context of PSU. More support is needed for family members affected by PSU to enable them to 'stand up to,' to prevent and cope effectively with this behaviour, and to increase their help-seeking and access to specialist services and support groups. More appropriate policies and social services are needed to meet the needs of AFMs. PMID- 28578668 TI - A retrospective analysis of the risk factors for surgical site infections and long-term follow-up after transpalpebral enucleation in horses. AB - BACKGROUND: Implants are often used to improve the cosmetic appearance of horses after enucleation of the eye. When surgical site infection (SSI) occurs, the implant will almost always be lost. The aim of this study is to collect data on the risk factors for SSIs and report long-term follow-up (cosmetic results and return to work) after transpalpebral enucleations. In this retrospective study, records of horses undergoing transpalpebral enucleation were reviewed (2007-2014) and telephone interviews were used to obtain long term follow-up. The potential risk factors for SSIs (indication for enucleation, use of an implant, standing procedures, duration of surgery, opening of the conjunctival sac and prolonged use of antimicrobials) were analysed for their association with the outcome measure 'SSI' vs 'no SSI' by multivariable binary logistic regression testing. Indications for enucleation were grouped as follows: Group 1 (clean) included equine recurrent uveitis, too small or too large globes, and intraocular tumours, Group 2 (non-clean) included corneal perforation/rupture and infected ulcers and Group 3 (tumour) included extraocular tumours. RESULTS: One hundred and seven cases of enucleation were evaluated. An implant was used in 49 horses. The overall number of SSIs was 8 (7.5%). Multivariable logistic regression testing showed implants (OR 7.5, P = 0.04) and standing procedures (OR 12.1; P = 0.03) were significantly associated with the percentage of SSIs and increased the risk of SSI. The eyes of horses in Groups 2 and 3 trended towards a larger risk for developing SSIs (OR 4.9; P = 0.09 and OR 5.9; P = 0.1, respectively). Prolonged use of antimicrobials, long surgery times and the opening of the conjunctival sac during dissection did not show significant associations with SSI risk. CONCLUSIONS: The risk of SSI after enucleation is low in clean eyes and when no implant is used. Placing an implant or performing a standing enucleation significantly increases the risk of SSIs. Although implants can be used for eyes that fall into Groups 2 and 3, 17% of the horses in these two groups developed an SSI leading to loss of the implant. PMID- 28578667 TI - Molecular characterization of Anopheline (Diptera: Culicidae) mosquitoes from eight geographical locations of Sri Lanka. AB - BACKGROUND: Genus Anopheles is a major mosquito group of interest in Sri Lanka as it includes vectors of malaria and its members exist as species complexes. Taxonomy of the group is mainly based on morphological features, which are not conclusive and can be easily erased while handling the specimens. A combined effort, using morphology and DNA barcoding (using the markers cytochrome c oxidase subunit I (COI) gene and internal transcribed spacer 2 (ITS2) region, was made during the present study to recognize anophelines collected from eight districts of Sri Lanka for the first time. METHODS: Cytochrome c oxidase subunit I and ITS2 regions of morphologically identified anopheline mosquitoes from Sri Lanka were sequenced. These sequences together with GenBank sequences were used in phylogenetic tree construction and molecular characterization of mosquitoes. RESULTS: According to morphological identification, the field-collected adult mosquitoes belonged to 15 species, i.e., Anopheles aconitus, Anopheles annularis, Anopheles barbirostris, Anopheles culicifacies, Anopheles jamesii, Anopheles karwari, Anopheles maculatus, Anopheles nigerrimus, Anopheles pallidus, Anopheles peditaeniatus, Anopheles pseudojamesi, Anopheles subpictus, Anopheles tessellatus, Anopheles vagus, and Anopheles varuna. However, analysis of 123 COI sequences (445 bp) (16 clades supported by strong bootstrap value in the neighbour joining tree and inter-specific distances of >3%) showed that there are 16 distinct species. Identity of the morphologically identified species, except An. subpictus, was comparable with the DNA barcoding results. COI sequence analysis showed that morphologically identified An. subpictus is composed of two genetic entities: An. subpictus species A and species B (inter-specific K2P distance 0.128). All the four haplotypes of An. culicifacies discovered during the present study belonged to a single species. ITS2 sequences (542 bp) were obtained for all the species except for An. barbirostris, An. subpictus species B, An. tessellatus, and An. varuna. Each of these sequences was represented by a single species-specific haplotype. CONCLUSIONS: The present study reflects the importance and feasibility of COI and ITS2 genetic markers in identifying anophelines and their sibling species, and the significance of integrated systematic approach in mosquito taxonomy. Wide distribution of malaria vectors in the country perhaps indicates the potential for re-emergence of malaria in the country. PMID- 28578669 TI - VEGF isoforms have differential effects on permeability of human pulmonary microvascular endothelial cells. AB - BACKGROUND: Alternative splicing of Vascular endothelial growth factor-A mRNA transcripts (commonly referred as VEGF) leads to the generation of functionally differing isoforms, the relative amounts of which have potentially significant physiological outcomes in conditions such as acute respiratory distress syndrome (ARDS). The effect of such isoforms on pulmonary vascular permeability is unknown. We hypothesised that VEGF165a and VEGF165b isoforms would have differing effects on pulmonary vascular permeability caused by differential activation of intercellular signal transduction pathways. METHOD: To test this hypothesis we investigated the physiological effect of VEGF165a and VEGF165b on Human Pulmonary Microvascular Endothelial Cell (HPMEC) permeability using three different methods: trans-endothelial electrical resistance (TEER), Electric cell-substrate impedance sensing (ECIS) and FITC-BSA passage. In addition, potential downstream signalling pathways of the VEGF isoforms were investigated by Western blotting and the use of specific signalling inhibitors. RESULTS: VEGF165a increased HPMEC permeability using all three methods (paracellular and transcellular) and led to associated VE-cadherin and actin stress fibre changes. In contrast, VEGF165b decreased paracellular permeability and did not induce changes in VE-cadherin cell distribution. Furthermore, VEGF165a and VEGF165b had differing effects on both the phosphorylation of VEGF receptors and downstream signalling proteins pMEK, p42/44MAPK, p38 MAPK, pAKT and peNOS. Interestingly specific inhibition of the pMEK, p38 MAPK, PI3 kinase and eNOS pathways blocked the effects of both VEGF165a and VEGF165b on paracellular permeability and the effect of VEGF165a on proliferation/migration, suggesting that this difference in cellular response is mediated by an as yet unidentified signalling pathway(s). CONCLUSION: This study demonstrates that the novel isoform VEGF165a and VEGF165b induce differing effects on permeability in pulmonary microvascular endothelial cells. PMID- 28578670 TI - "Location is surprisingly a lot more important than you think": a critical thematic analysis of push and pull factor messaging used on Caribbean offshore medical school websites. AB - BACKGROUND: Offshore medical schools are for-profit, private enterprises located in the Caribbean that provide undergraduate medical education to students who must leave the region for postgraduate training and also typically to practice. This growing industry attracts many medical students from the US and Canada who wish to return home to practice medicine. After graduation, international medical graduates can encounter challenges obtaining residency placements and can face other barriers related to practice. METHODS: We conducted a qualitative thematic analysis to discern the dominant messages found on offshore medical school websites. Dominant messages included frequent references to push and pull factors intended to encourage potential applicants to consider attending an offshore medical school. We reviewed 38 English-language Caribbean offshore medical school websites in order to extract and record content pertaining to push and pull factors. RESULTS: We found two push and four pull factors present across most offshore medical school websites. Push factors include the: shortages of physicians in the US and Canada that require new medical trainees; and low acceptance rates at medical schools in intended students' home countries. Pull factors include the: financial benefits of attending an offshore medical school; geographic location and environment of training in the Caribbean; training quality and effectiveness; and the potential to practice medicine in one's home country. CONCLUSIONS: This analysis contributes to our understanding of some of the factors behind students' decisions to attend an offshore medical school. Importantly, push and pull factors do not address the barriers faced by offshore medical school graduates in finding postgraduate residency placements and ultimately practicing elsewhere. It is clear from push and pull factors that these medical schools heavily focus messaging and marketing towards students from the US and Canada, which raises questions about who benefits from this offshoring practice. PMID- 28578671 TI - Serious child and adolescent behaviour disorders; a valuation study by professionals, youth and parents. AB - BACKGROUND: In child and youth care, quantitative estimates of the impact of serious behaviour problems have not yet been made. Such input is needed to support decision making on investments in treatment. The aim of this paper was to elicit valuations of social and conduct disorders in children and adolescents from three different perspectives: professionals, youth, and parents. METHODS: We obtained valuations from 25 youth care professionals, 50 children (age 9-10) without serious behaviour problems and 36 adolescents (age 16-17) with and without serious behaviour disorders, and 46 parents with children in the aforementioned age categories. Valuations were estimated from 18 descriptions of behaviour disorders in youth aged 9 and 15 years. Descriptions included Oppositional Defiant Disorder (ODD), Conduct Disorder (CD), and Disruptive Behaviour Disorder (DBD). Comorbid conditions were Attention Deficit Hyperactivity Disorder and substance abuse. Valuations were obtained with the EuroQol questionnaire (EQ-5D-3 L) and a visual analogue scale (VAS). RESULTS: Valuations were generally severe; problems were by and large reported to worsen quality of life by 50% compared to being fully healthy. Professionals regarded DBD with substance abuse as most severe (VAS values 0.41 for children, and 0.43 for adolescents, i.e. less than half of normal). They rated ODD as least severe (VAS values 0.58 for children, 0.59 for adolescents). Children, adolescents and parents gave lower valuations than professionals, and had a wider range of scores, particularly at the lower end of the scale. CONCLUSIONS: Behaviour disorders pose a formidable burden from the perspectives of professionals as well as children, adolescents and parents. These results may support medical decision making to set priorities with regard to prevention and treatment based on perceived severity. PMID- 28578672 TI - Sake lees extract improves hepatic lipid accumulation in high fat diet-fed mice. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is increasing worldwide as one of the leading causes of chronic liver disease. Sake lees (SL) are secondary products of sake manufacturing and are considered to have beneficial effects on human health. To investigate these effects, we used high fat diet (HFD)-fed mice treated with or without the SL extract. METHOD: Mice were the HFD ad libitum for 8 weeks and were administered 500 MUL of distilled water with or without the SL extract (350 mg/mL) by a feeding needle daily for the last 4 weeks. Food intake, body weight, and liver weight were measured. Triacylglycerol content and the mRNA and protein expression levels of various lipid and glucose metabolism-related genes were determined in liver tissues. The levels of triglyceride, free fatty acids, glucose, insulin, and liver cell damage markers were determined in serum. Fatty acid-induced lipid accumulation in HepG2 cells was assessed in the presence or absence of the SL extract. RESULTS: Mice fed a HFD and treated with the SL extract demonstrated a significant reduction in hepatic lipid accumulation and mRNA and protein levels of peroxidome proliferator-activated receptor gamma (PPARgamma), PPARalpha, CD36, and phosphoenolpyruvate carboxykinase 1 in the liver, while the SL extract did not affect body weight and food intake. Moreover, insulin resistance and hepatic inflammation in HFD-fed mice improved after administration of the SL extract. In HepG2 cells, the SL extract suppressed fatty acid-induced intracellular lipid accumulation. CONCLUSIONS: These findings suggest that treatment with the SL extract could potentially reduce the risk of NAFLD development, and that the SL extract may be clinically useful for the treatment of NAFLD. PMID- 28578673 TI - Team social cohesion, professionalism, and patient-centeredness: Gendered care work, with special reference to elderly care - a mixed methods study. AB - BACKGROUND: Healthcare organisations are facing large demands in recruiting employees with adequate competency to care for the increasing numbers of elderly. High degrees of turnover and dissatisfaction with working conditions are common. The gendered notion of care work as 'women's work', in combination with low salaries and status, may contribute to negative work experiences. There is abundant information about the negative aspects of elderly care health services, but little is known about positive aspects of this work. The study aim was to investigate work satisfaction from a gender perspective among Swedish registered nurses, physiotherapists, and occupational therapists, focusing specifically on healthcare services for the elderly. METHODS: A mixed methods approach was adopted in which we combined statistics and open-ended responses from a national survey with qualitative research interviews with healthcare professionals in elderly care organisations. The survey was administered to a random sample of 1578 registered nurses, physiotherapists, and occupational therapists. Qualitative interviews with 17 professionals were conducted in six elderly care facilities. Qualitative and quantitative content analyses, chi2 and constructivist grounded theory were used to analyse the data. RESULTS: There was a statistically significant difference in overall work satisfaction between those who worked in elderly care and those who did not (64 and 74,4% respectively, p <0.001). Nine themes were derived from open-ended responses in the questionnaire. The qualitative interviews revealed four prominent storylines: 'Team social cohesion', 'Career development and autonomy', 'Client-centeredness', and 'Invisible and ignored power structures'. CONCLUSIONS: The results show the complexity of elderly care work and describe several aspects that are important for work satisfaction among health professionals. The results reveal that work satisfaction is dependent on social interrelations and cohesion in the work team, in possibilities to use humour and to have fun together, and in the ability to work as professionals to provide client-centered elderly care. Power relations such as gendered hierarchies were less visible or even ignored aspects of work satisfaction. The storylines are clearly linked to the two central discourses of professionalism and gender equality. PMID- 28578675 TI - A case report of bicornis bicollis uterus with unilateral cervical atresia: an unusual aetiology of chronic debilitating pelvic pain in a Cameroonian teenager. AB - BACKGROUND: Congenital uterine anomalies like bicornis or bicornuate uterus are relatively rare in sub-Saharan Africa. They are associated with an increased rate of spontaneous abortion, preterm delivery, and infertility. The occurrence of bicornis bicollis uterus with unilateral cervical atresia is exceptional and its management is controversial. We hereby report a rare cause of chronic pelvic pain in a Cameroonian teenager due to unilateral obstructive hematometra and hematosalpinx in the non-communicating horn of a bicornis bicollis uterus. CASE PRESENTATION: A 13-year-old premenarchal non-virgin female presented with chronic and severe cyclical crampy pelvic pain. On clinical examination, she had a perforated hymen, a single vagina, and one uterine cervix. A two-dimensional pelvic ultrasonography revealed hematometra but missed out the underlying anomaly. Failure to drain the hematometra by serial cervical dilatations prompted an exploratory laparotomy which revealed: bicornis bicollis uterus with a right rudimentary uterine horn communicating with the vagina and a left non communicating uterine horn distended by hematometra due to a homolateral cervical atresia. She underwent utero-vaginal canalization and a left hemi-hysterotomy with drainage of the hematometra. The postoperative period was uneventful. Regular cyclic menses occurred thereafter beginning at the first postoperative month. She had complete resolution of symptoms without recurrence after six months. CONCLUSION: Due to the risk of compromised fertility from bicornis uterus and the diagnostic challenges akin to resource-limited settings, we highlight the need for a high index of suspicion by healthcare providers when faced with chronic pelvic pain in premenarchal adolescents. PMID- 28578674 TI - Space-time patterns in maternal and mother mortality in a rural South African population with high HIV prevalence (2000-2014): results from a population-based cohort. AB - BACKGROUND: International organs such as, the African Union and the South African Government view maternal health as a dominant health prerogative. Even though most countries are making progress, maternal mortality in South Africa (SA) significantly increased between 1990 and 2015, and prevented the country from achieving Millennium Development Goal 5. Elucidating the space-time patterns and risk factors of maternal mortality in a rural South African population could help target limited resources and policy guidelines to high-risk areas for the greatest impact, as more generalized interventions are costly and often less effective. METHODS: Population-based mortality data from 2000 to 2014 for women aged 15-49 years from the Africa Centre Demographic Information System located in the Umkhanyakude district of KwaZulu-Natal Province, South Africa were analysed. Our outcome was classified into two definitions: Maternal mortality; the death of a woman while pregnant or within 42 days of cessation of pregnancy, regardless of the duration and site of the pregnancy, from any cause related to or exacerbated by the pregnancy or its management but not from unexpected or incidental causes; and 'Mother death'; death of a mother whilst child is less than 5 years of age. Both the Kulldorff and Tango spatial scan statistics for regular and irregular shaped cluster detection respectively were used to identify clusters of maternal mortality events in both space and time. RESULTS: The overall maternal mortality ratio was 650 per 100,000 live births, and 1204 mothers died while their child was less than or equal to 5 years of age, of a mortality rate of 370 per 100,000 children. Maternal mortality declined over the study period from approximately 600 per 100,000 live births in 2000 to 400 per 100,000 live births in 2014. There was no strong evidence of spatial clustering for maternal mortality in this rural population. However, the study identified a significant spatial cluster of mother deaths in childhood (p = 0.022) in a peri-urban community near the national road. Based on our multivariable logistic regression model, HIV positive status (Adjusted odds ratio [aOR] = 2.5, CI 95%: [1.5-4.2]; primary education or less (aOR = 1.97, CI 95%: [1.04-3.74]) and parity (aOR = 1.42, CI 95%: [1.24-1.63]) were significant predictors of maternal mortality. CONCLUSIONS: There has been an overall decrease in maternal and mother death between 2000 and 2014. The identification of a clear cluster of mother deaths shows the possibility of targeting intervention programs in vulnerable communities, as population-wide interventions may be ineffective and too costly to implement. PMID- 28578676 TI - Effects of optical diameter of intraocular lenses with intrascleral fixation on higher-order aberrations. AB - BACKGROUND: Intrascleral fixation of an intraocular lens (IOL) is used in eyes that lack capsular support. The aim of the study is to determine whether a larger optical diameter IOL will decrease the higher-order aberrations (HOAs) when the haptics are extended for intrascleral fixation than a smaller diameter IOL. METHODS: Three-piece acrylic IOLs with 6.0 mm optics (X-60, VA-60BBR) and 7.0 mm optics (X-70, VA-70 AD) were fixed at lengths of 13, 14, 15, 16, or 17 mm. A wavefront analyzer was used to measure the HOAs within the central 3.0 and 5.2 mm optic diameter. RESULTS: The astigmatic aberration within the central 5.2 mm was greater than that within the central 3.0 mm for all IOLs. The HOAs increased significantly with an extension of the IOLs with both optical diameters (P < 0.001). The coma aberration within the central 5.2 mm was greater than that within the central 3.0 mm but it did not increase with an extension of the haptics. The astigmatic aberration of the X-60 IOL was significantly greater than that of the X-70 only at an extension of 17 mm. The astigmatic aberration of the VA-70 AD was not significantly different from that of the VA-60BBR. The cylindrical power changed from 0.047 D in the X-60 to 0.118 D in the VA-70 AD when the IOLs were extended from 13 to 17 mm. CONCLUSION: When three-piece IOLs are highly extended for intrascleral fixation, the astigmatic aberration increases significantly. However, IOLs with 7 mm optics do not have less astigmatic and coma aberrations than IOLs with 6 mm optics. PMID- 28578677 TI - Description of Culicoides (Culicoides) bysta n. sp., a new member of the Pulicaris group (Diptera: Ceratopogonidae) from Slovakia. AB - BACKGROUND: Species of the genus Culicoides Latreille, 1809 (Diptera: Ceratopogonidae) are mainly known as vectors of arboviruses such as bluetongue (BTV) and Schmallenberg (SBV). Among the known vectors, few species within the subgenus Culicoides Latreille, 1809 have been implicated in the transmission of BTV and SBV. Nevertheless, phylogenetic studies had revealed the presence of cryptic and undescribed species in Europe, raising questions about their vectorial role. A previous integrative study, associating morphology and barcode data, raised the hypothesis of the presence of undescribed species in Slovakia. The present study, combining morphological and molecular approaches, is aimed to support the hypothesis and a description of Culicoides bysta n. sp. is provided. METHODS: Series of male and female specimens were dissected and several of them were sequenced for the barcode region of the mitochondrial cytochrome c oxidase subunit 1 gene (cox1). Bayesian inference phylogenetic analyses based on 72 cox1 sequences of the species belonging to the Pulicaris group of the subgenus Culicoides, were carried out and the frequencies of intra/interspecific variations were analyzed. The morphology of abundant material of the new species (31 females and 12 males) was examined and compared with the paratypes of Culicoides boyi Nielsen, Kristensen & Pape, 2015 and with specimens of Culicoides pulicaris Linnaeus, 1758. For females, suture distances on the eyes were newly evaluated as a diagnostic character and for males we assessed a new measurement on the ninth tergite and on the apicolateral processes. RESULTS: Both phylogenetic analysis and barcode distances supported the distinct status of the new species, Culicoides bysta n. sp. described as a member of the Pulicaris group based on the morphology of males and females. The new species is closely related to C. boyi and C. pulicaris but can be distinguished on the basis of the wing pattern and the ratio between the two eye sutures. Both newly evaluated characters, i.e. eyes in females and male genitalia appeared to be diagnostic for distinguishing the new species described herein. CONCLUSIONS: The vector potential of the recently described species C. boyi and C. bysta n. sp. to transmit arboviruses, such as BTV and SBV, is unknown. When considering these two species as being close to C. pulicaris, the previous data, such as the vector implication for C. pulicaris in BTV transmission, should be revaluated in future. PMID- 28578678 TI - Changes in the neuropeptide content of Biomphalaria ganglia nervous system following Schistosoma infection. AB - BACKGROUND: Molluscs, including snails, are prone to parasite infection, which can lead to massive physiological and behavioural changes, yet many of the molecular components involved remain unresolved. Central to this point is the neural system that in snails consists of several ganglia that regulate the animals' physiology and behaviour patterns. The availability of a genomic resource for the freshwater snail Biomphalaria glabrata provides a mean towards the high throughput analysis of changes in the central nervous system (CNS) following infection with Schistosoma miracidia. RESULTS: In this study, we performed a proteomic analysis of the B. glabrata CNS at pre-patent infection, providing a list of proteins that were further used within a protein-protein interaction (PPI) framework against S. mansoni proteins. A hub with most connections for both non-infected and infected Biomphalaria includes leucine aminopeptidase 2 (LAP2), which interacts with numerous miracidia proteins that together belong to the immunoglobulin family of cell adhesion related molecules. We additionally reveal the presence of at least 165 neuropeptides derived from the precursors of buccalin, enterin, FMRF, FVRI, pedal peptide 1, 2, 3 and 4, RYamide, RFamide, pleurin and others. Many of these were present at significantly reduced levels in the snail's CNS post-infection, such as the egg laying hormone, a neuropeptide required to initiate egg laying in gastropod molluscs. CONCLUSIONS: Our analysis demonstrates that LAP2 may be a key component that regulates parasite infection physiology, as well as establishing that parasite induced reproductive castration may be facilitated by significant reductions in reproduction-associated neuropeptides. This work helps in our understanding of molluscan neuropeptides and further stimulates advances in parasite-host interactions. PMID- 28578679 TI - Effectiveness of additional trunk exercises on gait performance: study protocol for a randomized controlled trial. AB - BACKGROUND: Evidence is lacking concerning the effect of additional trunk rehabilitation on gait performance. Investigating gait performance by both clinical and biomechanical outcome measures might lead to new scientific insights into the importance of the trunk during gait rehabilitation in people suffering from stroke. This protocol was written according to the SPIRIT 2013 Statement. METHODS AND DESIGN: An assessor-blinded randomized controlled trial will be conducted in patients with impaired trunk control after stroke. A total of 60 patients will be randomly allocated to the control or the experimental group by means of sealed opaque envelopes. They will receive either 16 h of additional trunk exercises (experimental group) or cognitive exercises (controls) for 1 h a day, 4 days a week for 4 weeks. Patients will also receive 2 h of standard care consisting of physiotherapy and occupational therapy. Gait performance will be assessed clinically by the Tinetti Test and biomechanically by means of a full body gait analysis. In addition, the effect of the exercise protocol on the trunk itself and trunk activities of daily living will be assessed by the Trunk Impairment Scale and the Barthel Index. DISCUSSION: Despite the evidence demonstrating the importance of trunk control after stroke, studies about the effects of trunk rehabilitation on gait performance are inconsistent. In the current study, a more sophisticated treatment protocol will be used to enlarge therapeutic improvements, the relationship between clinical and biomechanical measures of gait performance can be investigated, and the sustainability of the effects of trunk exercises over time will be examined. Since clinical improvements are of greater importance to patients and physiotherapists, clinical assessment scales will be used as primary outcome measures. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02708888 . Registered on 2 March 2016. PMID- 28578680 TI - Survival analysis of under-five mortality using Cox and frailty models in Ethiopia. AB - BACKGROUND: The risk of a child dying before reaching 5 years of age is highest in sub-Saharan African countries. But in Ethiopia, under-five mortality rates have shown a substantial decline. METHODS: For this study, the Cox regression model for fixed and time-dependent explanatory variables was studied for under five mortality in Ethiopia. We adapted survival analysis using the Cox regression model with 2011 Ethiopian Demographic and Health Survey data. RESULTS: From the results, it was found that under-five children who live in Addis Ababa had a lower hazard (risk) of death (p value = 0.048). This could be as a result of higher health facilities and living standards in Addis Ababa, compared to other regions. Under-five children who lived in rural areas had a higher hazard (risk) of death compared to those living in urban areas. In addition, under-five children who lived in rural areas had 18% (p value = 0.01) more hazard (risk) of death than those living in urban areas. Furthermore, with older mothers, the chance of a child dying before reaching the age of 5 is lower. CONCLUSION: The chances of a child dying before reaching the age of 5 are less if the mother does not become pregnant again before the child reaches the age of 5. Therefore, giving birth when older and not becoming pregnant again before the child reaches the age of 5 is one means of reducing under-five mortality. PMID- 28578681 TI - Dysregulation of lysophosphatidic acids in multiple sclerosis and autoimmune encephalomyelitis. AB - Bioactive lipids contribute to the pathophysiology of multiple sclerosis. Here, we show that lysophosphatidic acids (LPAs) are dysregulated in multiple sclerosis (MS) and are functionally relevant in this disease. LPAs and autotaxin, the major enzyme producing extracellular LPAs, were analyzed in serum and cerebrospinal fluid in a cross-sectional population of MS patients and were compared with respective data from mice in the experimental autoimmune encephalomyelitis (EAE) model, spontaneous EAE in TCR1640 mice, and EAE in Lpar2 -/- mice. Serum LPAs were reduced in MS and EAE whereas spinal cord LPAs in TCR1640 mice increased during the 'symptom-free' intervals, i.e. on resolution of inflammation during recovery hence possibly pointing to positive effects of brain LPAs during remyelination as suggested in previous studies. Peripheral LPAs mildly re-raised during relapses but further dropped in refractory relapses. The peripheral loss led to a redistribution of immune cells from the spleen to the spinal cord, suggesting defects of lymphocyte homing. In support, LPAR2 positive T-cells were reduced in EAE and the disease was intensified in Lpar2 deficient mice. Further, treatment with an LPAR2 agonist reduced clinical signs of relapsing-remitting EAE suggesting that the LPAR2 agonist partially compensated the endogenous loss of LPAs and implicating LPA signaling as a novel treatment approach. Graphical summary of lysophosphatidic signaling in multiple sclerosis. PMID- 28578682 TI - Secondary distress in violence researchers: a randomised trial of the effectiveness of group debriefings. AB - BACKGROUND: Secondary distress including emotional distress, vicarious trauma (VT) and secondary traumatic stress (STS) due to exposure to primary trauma victims have been described in helping professionals and in violence researchers. To our knowledge, there are few prevalence studies, and no tailored interventions have been tested to reduce secondary distress in violence researchers. The study aims to (1) describe the epidemiology of secondary distress experienced by violence researchers; to (2) assess the effectiveness of group debriefings in mitigating secondary distress; to (3) assess risk and protective factors. METHODS: We conducted an un-blinded, individually randomised trial with parallel assignment. Eligible participants were 59 Ugandan researchers employed by the Good Schools Study to interview children who experienced violence in a district of Uganda. Fifty-three researchers agreed to participate and were randomly allocated. The intervention group (n = 26) participated in three group debriefings and the control group (n = 27) in three leisure sessions (film viewings). The primary outcome was change in levels of emotional distress (SRQ 20); secondary outcomes were levels of VT and STS at end-line. A paired t-test assessed the difference in mean baseline and end-line emotional distress. Un paired t-tests compared the change in mean emotional distress (baseline vs. end line), and compared levels of VT and STS at end-line. Separate logistic regression models tested the association between end-line emotional distress and a-priori risk or protective factors. RESULTS: Baseline and end-line levels of emotional distress were similar in control (p = 0.47) and intervention (p = 0.59) groups. The superiority of group debriefing over leisure activities in lowering levels of emotional distress in the intervention group (n = 26; difference in SRQ 20 = 0.23 [SD = 2.18]) compared to the control group (n = 26; difference in SRQ 20 = 0.23 [SD = 1.63]) could not be detected (p = 1). In regression analysis (n = 48), baseline distress increased the odds of end-line distress (OR = 16.1, 95%CI 2.82 to 92.7, p = 0.002). Perceived organisational support (OR = 0.09, 95%CI 0.01 to 0.69, p = 0.02) and belief in God (OR = 0.21, 95%CI 0.03 to 1.26, p = 09) was protective against end-line distress. CONCLUSION: We found no evidence that violence researchers experienced elevated emotional distress after doing violence research. There was no difference between group debriefings and leisure activities in reducing distress in our sample. However, the hypotheses presented should not be ruled out in other violence research settings. Our findings suggest that organisational support is a significant protective factor and belief in God may be an important coping mechanism. TRIAL REGISTRATION: Clinical Trials NCT02390778 . Retrospectively registered 19 March 2015. The Good Schools Trial was registered at ( NCT01678846 ), on August 24, 2012. PMID- 28578684 TI - Metal-on-metal hip resurfacing in patients younger than 50 years: a retrospective analysis : 1285 cases, 12-year survivorship. AB - BACKGROUND: The Nordic registry reports patients under 50 years old with total hip replacements realize only 83% 10-year implant survivorship. These results do not meet the 95% 10-year survivorship guideline posed by the UK's National Institute for Health and Care Excellence (NICE) in 2014. METHODS: The purpose of this study is threefold: First, we evaluate if metal-on-metal hip resurfacing arthroplasty meets these high standards in younger patients. Next, we compare outcomes between age groups to determine if younger patients are at higher risk for revision or complication. Lastly, we assess how outcomes between sexes changed over time. From January 2001 to August 2013, a single surgeon performed 1285 metal-on-metal hip resurfacings in patients younger than 50 years old. We compared these to an older cohort matched by sex and BMI. RESULTS: Kaplan-Meier implant survivorship was 96.5% at 10 years and 96.3% at 12 years; this did not differ from implant survivorship for older patients. Implant survivorship at 12 years was 98 and 93% for younger men and women, respectively; survivorship for women improved from 93 to 97% by using exclusively Biomet implants. There were four (0.3%) adverse wear-related failures, with no instances of wear or problematic ion levels since 2009. Activity scores improved from 5.4 +/- 2.3 preoperatively to 7.6 +/- 1.9 postoperatively (p < 0.0001), with 43% of patients reporting a UCLA activity score of 9 or 10. CONCLUSIONS: Hip resurfacing exceeds the stricter 2014 NICE survivorship criteria independently in men and women even when performed on patients under 50 years old. PMID- 28578683 TI - Preoperative Prognostic Nutritional Index is a Significant Predictor of Survival with Bladder Cancer after Radical Cystectomy: a retrospective study. AB - BACKGROUND: To explore the prognostic significance of preoperative prognostic nutritional index (PNI) in bladder cancer after radical cystectomy and compare the prognostic ability of inflammation-based indices. METHODS: We retrospectively analyzed data for 516 patients with bladder cancer who underwent radical cystectomy in our institution between 2006 to 2012. Clinicopathologic characteristics and inflammation-based indices (PNI, neutrophil/lymphocyte ratio [NLR], platelet/lymphocyte ratio [PLR], lymphocyte/monocyte ratio [LMR]) were evaluated by pre-treatment measurements. Overall survival (OS) and progression free survival (PFS) were estimated by the Kaplan-Meier method and compared by log rank test. Multivariate analysis with a Cox proportional hazards model was used to confirm predictors identified on univariate analysis. The association between clinicopathological characteristics and PNI or NLR was tested. RESULTS: Among the 516 patients, the median follow-up was 37 months (interquartile range 20 to 56). On multivariate analysis, PNI and NLR independently predicted OS (PNI: hazard ratio [HR] = 1.668, 95% CI: 1.147-2.425, P = 0.007; NLR: HR = 1.416, 95% CI:1.094 2.016, P = 0.0149) and PFS (PNI: HR = 1.680, 95% CI:1.092-2.005, P = 0.015; NLR: HR = 1.550, 95% CI:1.140-2.388, P = 0.008). Low PNI predicted worse OS for all pathological stages and PFS for T1 and T2 stages. Low PNI was associated with older age (>65 years), muscle-invasive bladder cancer, high American Society of Anesthesiologists grade and anemia. CONCLUSION: PNI and NLR were independent predictors of OS and PFS for patients with bladder cancer after radical cystectomy and PNI might be a novel reliable biomarker for bladder cancer. PMID- 28578685 TI - Being in limbo: Women's lived experiences of pregnancy at 41 weeks of gestation and beyond - A phenomenological study. AB - BACKGROUND: Globally, the prevalence of post term pregnancy (PTP) is about 5-10%, but the rate varies considerably between and within countries. PTP is defined as a pregnancy >=294 days, but the definition is arbitrary. Many studies focusing on the prevalence, risks and management of PTP include pregnancies >=41 gestational weeks (GW). However, qualitative interview studies concerning women's experiences of PTP are lacking. Therefore, the aim of this study was to describe women's lived experiences of a pregnancy >=41 GW. METHOD: The study has a lifeworld research approach. Individual in-depth interviews were conducted from August 2013 to September 2014 with 10 healthy women with an expected normal pregnancy at GW 41 + 1-6 days in Gothenburg, Sweden. Interviews were conducted at the antenatal clinic or in the woman's home, depending on her preference. Data were analysed with a phenomenological reflective lifeworld approach. RESULT: The essence of women's experiences of a pregnancy at GW >= 41 was described as being in limbo, a void characterised by contradictions related to time, giving birth and the condition. Exceeding the estimated date of childbirth implied a period of up to 2 weeks that was not expected. The contradictory aspect was the notion that time passed both slowly and quickly. Negative feelings dominated and increased over time. The women experienced difficulty due to not being in complete control, while at the same time finding it a beneficial experience. Health care professionals focused solely on the due date, while the women felt neither seen nor acknowledged. Lack of information led to searches in social media. Previously, they had trusted the body's ability to give birth, but this trust diminished after GW 41 + 0. In this state of limbo, the women became more easily influenced by people around them, while in turn influencing others. CONCLUSIONS: Being in limbo represents a contradictory state related to time and process of giving birth, when women need to be listened to by healthcare professionals. An understanding of the importance of different information sources, such as family and friends, is necessary. It is vital that women are seen and acknowledged by midwives at the antenatal clinics. In addition, they should be asked how they experience waiting for the birth in order to create a sense of trust and confidence in the process. PMID- 28578687 TI - Target weight achievement and ultrafiltration rate thresholds: potential patient implications. AB - BACKGROUND: Higher ultrafiltration (UF) rates and extracellular hypo- and hypervolemia are associated with adverse outcomes among maintenance hemodialysis patients. The Centers for Medicare and Medicaid Services recently considered UF rate and target weight achievement measures for ESRD Quality Incentive Program inclusion. The dual measures were intended to promote balance between too aggressive and too conservative fluid removal. The National Quality Forum endorsed the UF rate measure but not the target weight measure. We examined the proposed target weight measure and quantified weight gains if UF rate thresholds were applied without treatment time (TT) extension or interdialytic weight gain (IDWG) reduction. METHODS: Data were taken from the 2012 database of a large dialysis organization. Analyses considered 152,196 United States hemodialysis patients. We described monthly patient and dialysis facility target weight achievement patterns and examined differences in patient characteristics across target weight achievement status and differences in facilities across target weight measure scores. We computed the cumulative, theoretical 1-month fluid related weight gain that would occur if UF rates were capped at 13 mL/h/kg without concurrent TT extension or IDWG reduction. RESULTS: Target weight achievement patterns were stable over the year. Patients who did not achieve target weight (post-dialysis weight >= 1 kg above or below target weight) tended to be younger, black and dialyze via catheter, and had shorter dialysis vintage, greater body weight, higher UF rate and more missed treatments compared with patients who achieved target weight. Facilities had, on average, 27.1 +/- 9.7% of patients with average post-dialysis weight >= 1 kg above or below the prescribed target weight. In adjusted analyses, facilities located in the midwest and south and facilities with higher proportions of black and Hispanic patients and higher proportions of patients with shorter TTs were more likely to have unfavorable facility target weight measure scores. Without TT extension or IDWG reduction, UF rate threshold (13 mL/h/kg) implementation led to an average theoretical 1-month, fluid-related weight gain of 1.4 +/- 3.0 kg. CONCLUSIONS: Target weight achievement patterns vary across clinical subgroups. Implementation of a maximum UF rate threshold without adequate attention to extracellular volume status may lead to fluid-related weight gain. PMID- 28578686 TI - Challenges and opportunities of optimal breastfeeding in the context of HIV option B+ guidelines. AB - BACKGROUND: In 2013, the World Health Organization released a new set of guidelines widely known as Option B+. Prior to that there were guidelines released in 2010. Option B+ recommends lifelong antiretroviral treatment for all pregnant and breastfeeding women living with Human Immunodeficiency Virus. The study aimed at investigating challenges and opportunities in implementing Infant and Young Child Feeding in the context of Prevention of Mother To Child Transmission (PMTCT) guidelines among HIV positive mothers of children aged 0-24 months. The study also examined implications presented by implementing the 2013 PMTCT consolidated guidelines in the transition phase from the 2010 approach in Zambia. METHODS: A mixed methods approach was employed in the descriptive cross sectional study utilizing semi structured questionnaires and Focused Group Discussions. Further, data was captured from the Health Information Management System. RESULTS: During the PMTCT transition, associated needs and challenges in institutionalizing the enhanced guidelines from option A and B to option B+ were observed. Nonetheless, there was a decline in Mother to Child Transmission (MTCT) of HIV rates with an average of 4%. Mothers faced challenges in complying with optimal breastfeeding practices owing to lack of community support systems and breast infections due to poor breast feeding occasioned by infants' oral health challenges. Moreover, some mothers were hesitant of lifelong ARVs. Health workers faced programmatic and operational challenges such as compromised counseling services. CONCLUSION: Despite the ambitious timelines for PMTCT transition, the need to inculcate new knowledge and vary known practice among mothers and the shift in counseling content for health workers, the consolidated guidelines for PMTCT proved effective. Some mothers were hesitant of lifelong ARVs, rationalizing the debated paradigm that prolonged chemotherapy/polypharmacy may be a future challenge in the success of ART in PMTCT. Conflicting breast feeding practices was a common observation across mothers thus underpinning the need to strongly invigorate Infant and Young Child Feeding information sharing across the continuum of heath care from facility level to community and up to the family; for cultural norms, practices and attitudes enshrined within communities play a vital role in child care. PMID- 28578688 TI - The ticking time bomb in lifestyle-related diseases among women in the Gulf Cooperation Council countries; review of systematic reviews. AB - BACKGROUND: This study aims to review all published systematic reviews on the prevalence of modifiable cardiovascular disease risk factors among women from the Gulf Cooperation Council countries (GCC). This is the first review of other systematic reviews that concentrates on lifestyle related diseases among women in GCC countries only. METHOD: Literature searches were carried out in three electronic databases for all published systematic reviews on the prevalence of cardiovascular disease risk factors in the GCC countries between January 2000 and February 2016. RESULTS: Eleven systematic reviews were identified and selected for our review. Common reported risk factors for cardiovascular disease were obesity, physical inactivity, diabetes, metabolic syndrome and hypertension. In GCC countries, obesity among the female population ranges from 29 to 45.7%, which is one of the highest rates globally, and it is linked with physical inactivity, ranging from 45 to 98.7%. The prevalence of diabetes is listed as one of the top ten factors globally, and was reported with an average of 21%. Hypertension ranged from 20.9 to 53%. CONCLUSIONS: The high prevalence of lifestyle-related diseases among women population in GCC is a ticking time bomb and is reaching alarming levels, and require a fundamental social and political changes. These findings highlight the need for comprehensive work among the GCC to strengthen the regulatory framework to decrease and control the prevalence of these factors. PMID- 28578689 TI - Race and nativity are major determinants of tuberculosis in the U.S.: evidence of health disparities in tuberculosis incidence in Michigan, 2004-2012. AB - BACKGROUND: The incidence of TB in Michigan was 1.5 per 100,000 people in 2012, roughly half the U.S. incidence. Despite successes in TB control, disparities in TB still exist in Michigan, particularly by race, age, and nativity. A major challenge in understanding disparities in TB burden is distinguishing between TB cases resulting from recent transmission and those resulting from reactivation of latent TB infection, information critical to tailoring control strategies. We examined nine-year trends in tuberculosis (TB) incidence patterns for the entire population of Michigan, and within demographic subgroups. METHODS: Using a cross sectional study of TB surveillance data, we analyzed 1254 TB cases reported in Michigan during 2004-2012. Cases included were those for whom both spoligotyping and 12-locus-MIRU-VNTR results were available. Using a combination of the genotyping information and time of diagnosis, we then classified cases as resulting from either recent transmission or reactivation of latent TB infection. We used multivariable negative binomial regression models to study trends in the TB incidence rate for the entire population and by race, nativity, gender, and age. RESULTS: Overall, the incidence rate of TB declined by an average of 8% per year-11% among recently transmitted cases, and 9% among reactivation cases. For recently transmitted disease, Blacks had an average incidence rate 25 times greater than Whites, after controlling for nativity, gender, and age. For disease resulting from latent TB infection Asians had an average incidence rate 24 times greater than Whites, after controlling for nativity, gender, and age. CONCLUSIONS: Disparities in incidence persist despite ongoing TB control efforts. Greater disparities were observed by race and nativity demonstrating some of the ways that TB incidence is socially patterned. Reducing these disparities will require a multi-faceted approach encompassing the social and environmental contexts of high-risk populations. PMID- 28578690 TI - Evaluation of treatment response and resistance in metastatic renal cell cancer (mRCC) using integrated 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI); The REMAP study. AB - BACKGROUND: Tyrosine kinase inhibitors are the first line standard of care for treatment of metastatic renal cell carcinoma (RCC). Accurate response assessment in the setting of antiangiogenic therapies remains suboptimal as standard size related response criteria do not necessarily accurately reflect clinical benefit, as they may be less pronounced or occur later in therapy than devascularisation. The challenge for imaging is providing timely assessment of disease status allowing therapies to be tailored to ensure ongoing clinical benefit. We propose that combined assessment of morphological, physiological and metabolic imaging parameters using 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) will better reflect disease behaviour, improving assessment of response/non-response/relapse. METHODS/DESIGN: The REMAP study is a single-centre prospective observational study. Eligible patients with metastatic renal cell carcinoma, planned for systemic therapy, with at least 2 lesions will undergo an integrated 18F-FDG PET and MRI whole body imaging with diffusion weighted and contrast-enhanced multiphasic as well as standard anatomical MRI sequences at baseline, 12 weeks and 24 weeks of systemic therapy allowing 18F-FDG standardised uptake value (SUV), apparent diffusion co-efficient (ADC) and normalised signal intensity (SI) parameters to be obtained. Standard of care contrast-enhanced computed tomography CT scans will be performed at equivalent time-points. CT response categorisation will be performed using RECIST 1.1 and alternative (modified)Choi and MASS criteria. The reference standard for disease status will be by consensus panel taking into account clinical, biochemical and conventional imaging parameters. Intra- and inter-tumoural heterogeneity in vascular, diffusion and metabolic response/non-response will be assessed by image texture analysis. Imaging will also inform the development of computational methods for automated disease status categorisation. DISCUSSION: The REMAP study will demonstrate the ability of integrated 18F-FDG PET-MRI to provide a more personalised approach to therapy. We suggest that 18F-FDG PET/MRI will provide superior sensitivity and specificity in early response/non-response categorisation when compared to standard CT (using RECIST 1.1 and alternative (modified)Choi or MASS criteria) thus facilitating more timely and better informed treatment decisions. TRIAL REGISTRATION: The trial is approved by the Southeast London Research Ethics Committee reference 16/LO/1499 and registered on the NIHR clinical research network portfolio ISRCTN12114913 . PMID- 28578691 TI - Acute and chronic effects of aerobic exercise on blood pressure in resistant hypertension: study protocol for a randomized controlled trial. AB - BACKGROUND: Resistant hypertension is a specific condition that affects approximately 10% of subjects with hypertension, and is characterized by persistently high blood pressure levels even using therapy of three or more antihypertensive agents or with blood pressure control using therapy with four or more antihypertensive agents. Changes in lifestyle, such as physical exercise, are indicated for controlling blood pressure. However, investigating studies about this therapy in individuals with resistant hypertension are few. METHODS/DESIGN: This is a randomized controlled clinical trial. Forty-eight patients with resistant hypertension will be submitted to perform four short-term interventions: aerobic exercise sessions (mild-, moderate- and high-intensity) and control session, in random order and on separate days. After the short-term sessions, the patients will be randomly allocated into four groups for 8 weeks of follow-up: mild-, moderate- and high-intensity aerobic exercise, and a control group. The primary outcome is the occurrence of blood pressure reduction (office and ambulatory analysis, and acute and chronic effects). Secondary outcomes are autonomic and hemodynamic mechanisms: cardiac and vasomotor autonomic modulation, spontaneous baroreflex sensitivity, forearm blood flow and vascular resistance. DISCUSSION: The importance of exercise for hypertension has been known for decades, but little is known about the effects on patients with resistant hypertension. This study will help to understand whether different aerobic exercise intensities can induce different responses, as well as by what mechanisms adjustments in blood pressure levels may occur. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02670681 . Registered on 28 January 2016 (first version); Brazilian Registry Platform Clinical Trials: protocol RBR-5q24zh . Registered on 24 June 2015. PMID- 28578693 TI - CDK4/6 inhibitor-SHR6390 exerts potent antitumor activity in esophageal squamous cell carcinoma by inhibiting phosphorylated Rb and inducing G1 cell cycle arrest. AB - BACKGROUND: Cell cycle dysregulation is common in human malignancies, and CDK4/6 inhibitors targeting cell cycle have potential antitumor activity. SHR6390 is a novel small molecule inhibitor specifically targeting the CDK4/6 pathway. However, the role of SHR6390 in esophageal squamous cell carcinoma (ESCC) remains unknown, which will be investigated in our study. METHODS: Eca 109, Eca 9706, and KYSE-510 ESCC cell lines were chosen for further analysis. The effect of SHR6390 on cell viability, cell cycle and cell apoptosis, the status of kinases in Cyclin D1-CDK4/6-Rb pathway were determined by MTS assay, flow cytometry, and western blotting, respectively. Cell-derived and patient-derived xenografts were established to investigate the effects of drugs in vivo. RESULTS: SHR6390 could suppress cell proliferation in vitro cell lines and inhibit tumor growth in vivo PDX models with different drug susceptibility. The effective treatment of SHR6390 induced the inhibition of phosphorylated Rb and cell cycle arrest at G1 phase both in cell lines and in xenografts. SHR6390 combined with paclitaxel or cisplatin offered synergistic inhibitory effects in cell-derived xenografts especially in Eca 9706 xenografts which showed relative lower sensitivity of SHR6390 single. Moreover, low expression of CDK6 and/or high expression of Cyclin D1 might be associated with high sensitivity of SHR6390, which would be validated in the future. CONCLUSIONS: CDK4/6 inhibitor-SHR6390 exerted potential antitumor activity against ESCC cell lines and xenografts, and evaluation of CDK6 and Cyclin D1 expressions might be helpful to select patients beneficial from SHR6390, which provided evidences for future clinical trials. PMID- 28578692 TI - Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma. AB - BACKGROUND: Cutaneous melanoma is the deadliest skin cancer, with an increasing incidence and mortality rate. Currently, staging of patients with primary melanoma is performed using histological biomarkers such as tumor thickness and ulceration. As disruption of the epigenomic landscape is recognized as a widespread feature inherent in tumor development and progression, we aimed to identify novel biomarkers providing additional clinical information over current factors using unbiased genome-wide DNA methylation analyses. METHODS: We performed a comprehensive DNA methylation analysis during all progression stages of melanoma using Infinium HumanMethylation450 BeadChips on a discovery cohort of benign nevi (n = 14) and malignant melanoma from both primary (n = 33) and metastatic (n = 28) sites, integrating the DNA methylome with gene expression data. We validated the discovered biomarkers in three independent validation cohorts by pyrosequencing and immunohistochemistry. RESULTS: We identified and validated biomarkers for, and pathways involved in, melanoma development (e.g., HOXA9 DNA methylation) and tumor progression (e.g., TBC1D16 DNA methylation). In addition, we determined a prognostic signature with potential clinical applicability and validated PON3 DNA methylation and OVOL1 protein expression as biomarkers with prognostic information independent of tumor thickness and ulceration. CONCLUSIONS: Our data underscores the importance of epigenomic regulation in triggering metastatic dissemination through the inactivation of central cancer-related pathways. Inactivation of cell-adhesion and differentiation unleashes dissemination, and subsequent activation of inflammatory and immune system programs impairs anti-tumoral defense pathways. Moreover, we identify several markers of tumor development and progression previously unrelated to melanoma, and determined a prognostic signature with potential clinical utility. PMID- 28578695 TI - SIRT1 ameliorates oxidative stress induced neural cell death and is down regulated in Parkinson's disease. AB - BACKGROUND: Sirtuins (SIRTs) are NAD+ dependent lysine deacetylases which are conserved from bacteria to humans and have been associated with longevity and lifespan extension. SIRT1, the best studied mammalian SIRT is involved in many physiological and pathological processes and changes in SIRT1 have been implicated in neurodegenerative disorders, with SIRT1 having a suggested protective role in Parkinson's disease. In this study, we determined the effect of SIRT1 on cell survival and alpha-synuclein aggregate formation in SH-SY5Y cells following oxidative stress. RESULTS: Over-expression of SIRT1 protected SH SY5Y cells from toxin induced cell death and the protection conferred by SIRT1 was partially independent of its deacetylase activity, which was associated with the repression of NF-kB and cPARP expression. SIRT1 reduced the formation of alpha-synuclein aggregates but showed minimal co-localisation with alpha synuclein. In post-mortem brain tissue obtained from patients with Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies and Alzheimer's disease, the activity of SIRT1 was observed to be down-regulated. CONCLUSIONS: These findings suggests a negative effect of oxidative stress in neurodegenerative disorders and possibly explain the reduced activity of SIRT1 in neurodegenerative disorders. Our study shows that SIRT1 is a pro-survival protein that is downregulated under cellular stress. PMID- 28578694 TI - Worldwide legislative challenges related to psychoactive drugs. AB - The discovery of a "new" psychoactive substance is a relatively exceptional event, while the regulatory response usually involved the assessment of risks to public health and inclusion of the novel substance in the national list of controlled substances. However, in recent years we have witnessed the rapid emergence of new chemical substances, which elude international control and pose a challenge to existing processes and a threat to the credibility of control systems. We currently review and present characteristics of these legal and illegal new substances and issues regarding their global monitoring and regulatory measures already taken, or in the process of being taken, for their control. The concept of prohibition applied in active substance-related legislation is rather hazard ridden as balance is required between the ban on substances of potential therapeutic use and the access on the market of high-risk substances. Current and future laws regarding psychoactive compounds. PMID- 28578696 TI - Nasal delivery of nanoliposome-encapsulated ferric ammonium citrate can increase the iron content of rat brain. AB - BACKGROUND: Iron deficiency in children can have significant neurological consequences, and iron supplementation is an effective treatment of choice. However, traditional routes of iron supplementation do not allow efficient iron delivery to the brain due to the presence of the blood-brain barrier. So an easily delivered iron formulation with high absorption efficiency potentially could find widespread application in iron deficient infants. RESULTS: In this study, we have developed and characterized a nanovesicular formulation of ferric ammonium citrate (ferric ammonium citrate nanoliposomes, FAC-LIP) and have shown that it can increase brain iron levels in rats following nasal administration. FAC was incorporated into liposomes with high efficiency (97%) and the liposomes were small (40 nm) and stable. Following intranasal delivery in rats, FAC-LIP significantly increased the iron content in the olfactory bulb, cerebral cortex, striatum, cerebellum and hippocampus, and was more efficient at doing so than FAC alone. No signs of apoptosis or abnormal cell morphology were observed in the brain following FAC-LIP administration, and there were no significant changes in the levels of SOD and MDA, except in the cerebellum and hippocampus. No obvious morphological changes were observed in lung epithelial cells or tracheal mucosa after nasal delivery, suggesting that the formulation was not overtly toxic. CONCLUSIONS: In this study, nanoscale FAC-LIP proved an effective system delivering iron to the brain, with high encapsulation efficiency and low toxicity in rats. Our studies provide the foundation for more detailed investigations into the applications of niosomal nasal delivery of liposomal formulations of iron as a simple and safe therapy for iron deficiency anemia. Graphical abstract The diagrammatic sketch of "Nasal delivery of nanoliposome-encapsulated ferric ammonium citrate can increase the iron content of rat brain". Nanoliposome encapsulated ferric ammonium citrate (FAC-LIP) was successfully prepared and intranasal administration of FAC-LIP increased both the total iron contents and iron storage protein (FTL) expression in rat olfactory bulb, cerebral cortex, striatum and hippocampus, compared with those of FAC groups. Moreover, there was not overtly toxic affects to brain, lung epithelial cells and tracheal mucosa. PMID- 28578697 TI - Contrasting impacts of ocean acidification and warming on the molecular responses of CO2-resilient oysters. AB - BACKGROUND: This study characterises the molecular processes altered by both elevated CO2 and increasing temperature in oysters. Differences in resilience of marine organisms against the environmental stressors associated with climate change will have significant implications for the sustainability of coastal ecosystems worldwide. Some evidence suggests that climate change resilience can differ between populations within a species. B2 oysters represent a unique genetic resource because of their capacity to better withstand the impacts of elevated CO2 at the physiological level, compared to non-selected oysters from the same species (Saccostrea glomerata). Here, we used proteomic and transcriptomic analysis of gill tissue to evaluate whether the differential response of B2 oysters to elevated CO2 also extends to increased temperature. RESULTS: Substantial and distinctive effects on protein concentrations and gene expression were evident among B2 oysters responding to elevated CO2 or elevated temperature. The combination of both stressors also altered oyster gill proteomes and gene expression. However, the impacts of elevated CO2 and temperature were not additive or synergistic, and may be antagonistic. CONCLUSIONS: The data suggest that the simultaneous exposure of CO2-resilient oysters to near-future projected ocean pH and temperature results in complex changes in molecular processes in order to prevent stress-induced cellular damage. The differential response of B2 oysters to the combined stressors also indicates that the addition of thermal stress may impair the resilience of these oysters to decreased pH. Overall, this study reveals the intracellular mechanisms that might enable marine calcifiers to endure the emergent, adverse seawater conditions resulting from climate change. PMID- 28578698 TI - dictyExpress: a web-based platform for sequence data management and analytics in Dictyostelium and beyond. AB - BACKGROUND: Dictyostelium discoideum, a soil-dwelling social amoeba, is a model for the study of numerous biological processes. Research in the field has benefited mightily from the adoption of next-generation sequencing for genomics and transcriptomics. Dictyostelium biologists now face the widespread challenges of analyzing and exploring high dimensional data sets to generate hypotheses and discovering novel insights. RESULTS: We present dictyExpress (2.0), a web application designed for exploratory analysis of gene expression data, as well as data from related experiments such as Chromatin Immunoprecipitation sequencing (ChIP-Seq). The application features visualization modules that include time course expression profiles, clustering, gene ontology enrichment analysis, differential expression analysis and comparison of experiments. All visualizations are interactive and interconnected, such that the selection of genes in one module propagates instantly to visualizations in other modules. dictyExpress currently stores the data from over 800 Dictyostelium experiments and is embedded within a general-purpose software framework for management of next-generation sequencing data. dictyExpress allows users to explore their data in a broader context by reciprocal linking with dictyBase-a repository of Dictyostelium genomic data. In addition, we introduce a companion application called GenBoard, an intuitive graphic user interface for data management and bioinformatics analysis. CONCLUSIONS: dictyExpress and GenBoard enable broad adoption of next generation sequencing based inquiries by the Dictyostelium research community. Labs without the means to undertake deep sequencing projects can mine the data available to the public. The entire information flow, from raw sequence data to hypothesis testing, can be accomplished in an efficient workspace. The software framework is generalizable and represents a useful approach for any research community. To encourage more wide usage, the backend is open-source, available for extension and further development by bioinformaticians and data scientists. PMID- 28578699 TI - Treating lung cancer with dynamic conformal arc therapy: a dosimetric study. AB - BACKGROUND: Lung cancer patients are often in poor physical condition, and a shorter treatment time would reduce their discomfort. Dynamic conformal arc therapy (DCAT) offers a shorter treatment time than conventional 3D conformal radiotherapy (3D CRT) and is usually available even in departments without inverse planning possibilities. We examined its suitability as a treatment modality for lung cancer patients. METHODS: On a cohort of 35 lung cancer patients, relevant dosimetric parameters were compared in respective DCAT and 3D CRT treatment plans. Radiochromic film dosimetry in an anthropomorphic phantom was used to compare both DCAT and 3D CRT dose distributions against their planned counterparts. RESULTS: In comparison with their 3D CRT counterparts, DCAT plans equal or exceed the agreement between the calculated dose and the dose measured using film dosimetry. In dosimetric comparison, DCAT performed significantly better than 3D CRT in dose conformity to PTV and the number of monitor units used per plan, and significantly worse in dose homogeneity, mean lung dose and lung volume exposed to 5 Gy or more (V5Gy). No significant difference was found in the V20Gy value to lung, dose to 1 cm3 of spinal cord, and the mean dose to oesophagus. Improvements in V20Gy and V5Gy were found to be negatively correlated. DCAT plans differ from 3D CRT by exhibiting a moderate negative correlation between target volume sphericity and dose homogeneity. CONCLUSIONS: With respect to the agreement between the planned and the irradiated dose distribution, DCAT appears at least as reliable as 3D CRT. In specific conditions concerning the patient anatomy and treatment prescription, DCAT may yield more favourable dosimetric parameters. On average, however, conventional 3D CRT usually obtains better dosimetric parameters. We can thus only recommend DCAT as a complementary technique to the conventional 3D CRT. PMID- 28578700 TI - A rare presentation of an acute abdomen: an ileal diverticular perforation. AB - BACKGROUND: This case report highlights the value of prompt intervention of diagnostic laparoscopy in a patient suspects of having an acute abdomen due to an intestinal perforation, where there is a limitation of performing Contrast Enhanced Computed Tomography of abdomen. A previously healthy young adult presenting with an acute abdomen due to a spontaneous ileal perforation, without any associated risk factors is a rare clinical entity in a developing country. Therefore, entertaining an early diagnosis will possibly prevent a fatal consequence. CASE PRESENTATION: A male patient, 29 years old, recently diagnosed as a young hypertensive without any associated factors, currently on antihypertensive treatment, was admitted to our hospital presenting with an acute severe abdominal pain. During initial assessment, the patient was febrile (101 degrees F), ill looking, tachycardic (pulse rate 121 bpm) with rapid shallow breathing. Abdominal examination reviled diffuse guarding and rigidity, more severe on right iliac fossa. Following history and clinical examination probable clinical diagnosis was made as an acute appendicitis with perforation. However, ultrasonography was found to have normal appendix. Contrast Enhanced Computed Tomography was not performed as a subsequent investigation because of the impairment of renal functions of this patient. Though, non-contrast CT would have been ascertained more diagnostic yield, given the critically ill status of this patient we decided to perform urgent diagnostic laparoscopy. It reviled pus in several abdominal cavities and dense adhesions. Therefore, the procedure was converted to a laparotomy and found to have an ileal perforation with diffuse peritoneal contamination. Diseased ileal segment was resected and anastomosed. Followed by peritoneal lavage. CONCLUSION: Ileal perforation due to diverticular disease in a healthy young adult is rare. This case report highlights the importance of considering this clinical entity as a differential diagnosis, the value of early diagnostic laparoscopy, especially in clinical settings with limitations to CT scan, since late diagnosis can give rise to fatal outcome. PMID- 28578701 TI - Distinct pathophysiological cytokine profiles for discrimination between autoimmune pancreatitis, chronic pancreatitis, and pancreatic ductal adenocarcinoma. AB - BACKGROUND: Discriminating between autoimmune pancreatitis (AIP), chronic pancreatitis (CP), and pancreatic ductal adenocarcinoma (PDAC) can be challenging. In this retrospective study, levels of serum and tissue cytokines were analyzed as part of the clinical strategy for the preoperative differentiation between AIP and PDAC. The identification of differential cytokine profiles may help to prevent unnecessary surgical resection and allow optimal treatment of these pathologies. METHODS: To compare the cytokine profiles of AIP, CP, and PDAC patients, serum and pancreatic tissue homogenates were subjected to multiplex analysis of 17 inflammatory mediators. In total, serum from 73 patients, composed of 29 AIP (14 AIP-1 and 15 AIP-2), 17 CP, and 27 PDAC, and pancreatic tissue from 36 patients, including 12 AIP (six AIP-1 and six AIP-2), 12 CP, and 12 PDAC, were analyzed. RESULTS: Comparing AIP and PDAC patients' serum, significantly higher concentrations were found in AIP for interleukins IL 1beta, IL-7, IL-13, and granulocyte colony-stimulating factor (G-CSF). G-CSF also allowed discrimination of AIP from CP. Furthermore, once AIP was divided into subtypes, significantly higher serum levels for IL-7 and G-CSF were measured in both subtypes of AIP and in AIP-2 for IL-1beta when compared to PDAC. G-CSF and TNF-alpha were also significantly differentially expressed in tissue homogenates between AIP-2 and PDAC. CONCLUSIONS: The cytokines IL-1beta, IL-7, and G-CSF can be routinely measured in patients' serum, providing an elegant and non-invasive approach for differential diagnosis. G-CSF is a good candidate to supplement the currently known serum markers in predictive tests for AIP and represents a basis for a combined blood test to differentiate AIP and particularly AIP-2 from PDAC, enhancing the possibility of appropriate treatment. PMID- 28578702 TI - Supplementation of Syzygium cumini seed powder prevented obesity, glucose intolerance, hyperlipidemia and oxidative stress in high carbohydrate high fat diet induced obese rats. AB - BACKGROUND: Obesity and related complications have now became epidemic both in developed and developing countries. Cafeteria type diet mainly composed of high fat high carbohydrate components which plays a significant role in the development of obesity and metabolic syndrome. This study investigated the effect of Syzygium cumini seed powder on fat accumulation and dyslipidemia in high carbohydrate high fat diet (HCHF) induced obese rats. METHOD: Male Wistar rats were fed with HCHF diet ad libitum, and the rats on HCHF diet were supplemented with Syzygium cumini seed powder for 56 days (2.5% w/w of diet). Oral glucose tolerance test, lipid parameters, liver marker enzymes (AST, ALT and ALP) and lipid peroxidation products were analyzed at the end of 56 days. Moreover, antioxidant enzyme activities were also measured in all groups of rats. RESULTS: Supplementation with Syzygium cumini seed powder significantly reduced body weight gain, white adipose tissue (WAT) weights, blood glucose, serum insulin, and plasma lipids such as total cholesterol, triglyceride, LDL and HDL concentration. Syzygium cumini seed powder supplementation in HCHF rats improved serum aspartate amino transferase (AST), alanine amino transferase (ALT), and alkaline phosphatase (ALP) activities. Syzygium cumini seed powder supplementation also reduced the hepatic thiobarbituric acid reactive substances (TBARS) and elevated the antioxidant enzyme superoxide dismutase (SOD) and catalase (CAT) activities as well as increased glutathione (GSH) concentration. In addition, histological assessment showed that Syzygium cumini seed powder supplementation prevented inflammatory cell infiltration; fatty droplet deposition and fibrosis in liver of HCHFD fed rats. CONCLUSION: Our investigation suggests that Syzygium cumini seed powder supplementation prevents oxidative stress and showed anti-inflammatory and antifibrotic activity in liver of HCHF diet fed rats. In addition, Syzygium cumini seed powder may be beneficial in ameliorating insulin resistance and dyslipidemia probably by increasing lipid metabolism in liver of HCHF diet fed rats. PMID- 28578703 TI - Effects of platelet rich plasma (PRP) on human gingival fibroblast, osteoblast and periodontal ligament cell behaviour. AB - BACKGROUND: The use of platelet rich plasma (PRP, GLO) has been used as an adjunct to various regenerative dental procedures. The aim of the present study was to characterize the influence of PRP on human gingival fibroblasts, periodontal ligament (PDL) cells and osteoblast cell behavior in vitro. METHODS: Human gingival fibroblasts, PDL cells and osteoblasts were cultured with conditioned media from PRP and investigated for cell migration, proliferation and collagen1 (COL1) immunostaining. Furthermore, gingival fibroblasts were tested for genes encoding TGF-beta, PDGF and COL1a whereas PDL cells and osteoblasts were additionally tested for alkaline phosphatase (ALP) activity, alizarin red staining and mRNA levels of osteoblast differentiation markers including Runx2, COL1a2, ALP and osteocalcin (OCN). RESULTS: It was first found that PRP significantly increased cell migration of all cells up to 4 fold. Furthermore, PRP increased cell proliferation at 3 and 5 days of gingival fibroblasts, and at 3 days for PDL cells, whereas no effect was observed on osteoblasts. Gingival fibroblasts cultured with PRP increased TGF-beta, PDGF-B and COL1 mRNA levels at 7 days and further increased over 3-fold COL1 staining at 14 days. PDL cells cultured with PRP increased Runx2 mRNA levels but significantly down-regulated OCN mRNA levels at 3 days. No differences in COL1 staining or ALP staining were observed in PDL cells. Furthermore, PRP decreased mineralization of PDL cells at 14 days post seeding as assessed by alizarin red staining. In osteoblasts, PRP increased COL1 staining at 14 days, increased COL1 and ALP at 3 days, as well as increased ALP staining at 14 days. No significant differences were observed for alizarin red staining of osteoblasts following culture with PRP. CONCLUSIONS: The results demonstrate that PRP promoted gingival fibroblast migration, proliferation and mRNA expression of pro-wound healing molecules. While PRP induced PDL cells and osteoblast migration and proliferation, it tended to have little to no effect on osteoblast differentiation. Therefore, while the effects seem to favor soft tissue regeneration, the additional effects of PRP on hard tissue formation of PDL cells and osteoblasts could not be fully confirmed in the present in vitro culture system. PMID- 28578704 TI - Dietary supplementation with n-3-fatty acids in patients with pancreatic cancer and cachexia: marine phospholipids versus fish oil - a randomized controlled double-blind trial. AB - BACKGROUND: Like many other cancer patients, most pancreatic carcinoma patients suffer from severe weight loss. As shown in numerous studies with fish oil (FO) supplementation, a minimum daily intake of 1.5 g n-3-fatty acids (n-3-FA) contributes to weight stabilization and improvement of quality of life (QoL) of cancer patients. Given n-3-FA not as triglycerides (FO), but mainly bound to marine phospholipids (MPL), weight stabilization and improvement of QoL has already been seen at much lower doses of n-3-FA (0,3 g), and MPL were much better tolerated. The objective of this double-blind randomized controlled trial was to compare low dose MPL and FO formulations, which had the same n-3-FA amount and composition, on weight and appetite stabilization, global health enhancement (QoL), and plasma FA-profiles in patients suffering from pancreatic cancer. METHODS: Sixty pancreatic cancer patients were included into the study and randomized to take either FO- or MPL supplementation. Patients were treated with 0.3 g of n-3-fatty acids per day over six weeks. Since the n-3-FA content of FO is usually higher than that of MPL, FO was diluted with 40% of medium chain triglycerides (MCT) to achieve the same capsule size in both intervention groups and therefore assure blinding. Routine blood parameters, lipid profiles, body weight, and appetite were measured before and after intervention. Patient compliance was assessed through a patient diary. Quality of life and nutritional habits were assessed with validated questionnaires (EORTC-QLQ-C30, PAN26). Thirty one patients finalized the study protocol and were analyzed (per-protocol analysis). RESULTS: Intervention with low dose n-3-FAs, either as FO or MPL supplementation, resulted in similar and promising weight and appetite stabilization in pancreatic cancer patients. MPL capsules were slightly better tolerated and showed fewer side effects, when compared to FO supplementation. CONCLUSION: The similar effects between both interventions were unexpected but reliable, since the MPL and FO formulations caused identical increases of n-3-FAs in plasma lipids of included patients after supplementation. The effects of FO with very low n-3-FA content might be explained by the addition of MCT. The results of this study suggest the need for further investigations of marine phospholipids for the improvement of QoL of cancer patients, optionally in combination with MCT. PMID- 28578706 TI - Nutritional status of preschool children attending kindergartens in Kosovo. AB - BACKGROUND: There is very limited data on malnutrition of preschool children in Kosovo. The main objective of the study is to provide a nutritional status profile of preschool children attending kindergartens in Kosovo. METHODS: Cross sectional study of children aged 12-59 months (n = 352 children) and children aged 60-83 months (n = 134) enrolled in public and private kindergartens of Kosovo. Anthropometric measurements used for this study are weight and height of the preschoolers (12-83 months). A measuring board was used for measuring the length/height of children younger than 2 years, while digital weight and height scale Seca 763 was used for measuring of preschool children taller than 110 and Seca 213 was used for measuring the height for children who were shorter than 110 cm. Statistical analyses of underweight and overweight trends across sex and age groups as well as between children from public and private kindergartens were carried out. Qualitative variables were tested with a chi-square test. The differences between groups were assessed with a Student t test for normally distributed variables and a Mann-Whitney test for abnormally distributed numerical variables. RESULTS: The mean z-scores for weight-for-age, height-for age, weight-for-height, and BMI-for-age largely fell within 0.0 and 1.0. The percentage of stunted children is 3%, whereas child wasting is 1.9%. The overall percentage of obese children is 2.3%; furthermore, 8.9% are overweight and 27.3% have a possible risk of being overweight. CONCLUSIONS: The incidence of children underweight is slightly decreasing. The prevalence of overweight and obese children in sample chosen is evident. PMID- 28578705 TI - Prediction of long-term clinical outcomes using simple functional exercise performance tests in patients with COPD: a 5-year prospective cohort study. AB - The 1-min sit-to-stand (1-min STS) test and handgrip strength test have been proposed as simple tests of functional exercise performance in chronic obstructive pulmonary disease (COPD) patients. We assessed the long-term (5-year) predictive performance of the 1-min sit-to-stand and handgrip strength tests for mortality, health-related quality of life (HRQoL) and exacerbations in COPD patients. In 409 primary care patients, we found the 1-min STS test to be strongly associated with long-term morality (hazard ratio per 3 more repetitions: 0.81, 95% CI 0.65 to 0.86) and moderately associated with long-term HRQoL. Neither test was associated with exacerbations. Our results suggest that the 1 min STS test may be useful for assessing the health status and long-term prognosis of COPD patients. This study was registered at http://www.clinicaltrials.gov/ (NCT00706602, 25 June 2008). PMID- 28578707 TI - Meristem culture and subsequent micropropagation of Chilean strawberry (Fragaria chiloensis (L.) Duch.). AB - BACKGROUND: Vegetative propagation of Fragaria sp. is traditionally carried out using stolons. This system of propagation, in addition to being slow, can spread plant diseases, particularly serious being viral. In vitro culture of meristems and the establishment of micropropagation protocols are important tools for solving these problems. In recent years, considerable effort has been made to develop in vitro propagation of the commercial strawberry in order to produce virus-free plants of high quality. These previous results can serve as the basis for developing in vitro-based propagation technologies in the less studied species Fragaria chiloensis. RESULTS: In this context, we studied the cultivation of meristems and establishment of a micropropagation protocol for F. chiloensis. The addition of polyvinylpyrrolidone (PVP) improved the meristem regeneration efficiency of F. chiloensis accessions. Similarly, the use of 6-benzylaminopurine (BAP) in the culture media increased the average rate of multiplication to 3-6 shoots per plant. In addition, the use of 6-benzylaminopurine (BAP), had low levels (near zero) of explant losses due to oxidation. However, plant height as well as number of leaves and roots were higher in media without growth regulators, with average values of 0.5 cm, 9 leaves and 4 roots per plant. CONCLUSIONS: For the first time in Chilean strawberry, meristem culture demonstrated to be an efficient tool for eliminating virus from infected plants, giving the possibility to produce disease free propagation material. Also, the addition of PVP into the basal MS medium improved the efficiency of plant recovery from isolated meristems. Farmers can now access to high quality plant material produced by biotech tools which will improve their technological practices. PMID- 28578708 TI - Effects of neurally adjusted ventilatory assist on air distribution and dead space in patients with acute exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND: Neurally adjusted ventilatory assist (NAVA) could improve patient ventilator interaction; its effects on ventilation distribution and dead space are still unknown. The aim of this study was to evaluate the effects of varying levels of assist during NAVA and pressure support ventilation (PSV) on ventilation distribution and dead space in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: Fifteen mechanically ventilated patients with AECOPD were included in the study. The initial PSV levels were set to 10 cmH2O for 10 min. Thereafter, the ventilator mode was changed to NAVA for another 10 min with the same electrical activity of the diaphragm as during PSV. Furthermore, the ventilation mode was switched between PSV and NAVA every 10 min in the following order: PSV 5 cmH2O; NAVA 50%; PSV 15 cmH2O; and NAVA 150% (relative to the initial NAVA support level). Ventilation distribution in the lung was evaluated in percentages in regions of interest (ROI) of four anteroposterior segments of equal height (ROI1 to ROI4 represents ventral, mid-ventral, mid-dorsal, and dorsal, respectively). Blood gases, ventilation distribution (electrical impedance tomography), diaphragm activity (B mode ultrasonography), and dead space fraction (PeCO2 and PaCO2) were measured. RESULTS: The trigger and cycle delays were lower during NAVA than during PSV. The work of trigger was significantly lower during NAVA compared to PSV. The diaphragm activities based on ultrasonography were higher during NAVA compared to the same support level during PSV. The ventilation distribution in ROI4 increased significantly (P < 0.05) during NAVA compared to PSV (except for a support level of 50%). Similar results were found in ROI3 + 4. NAVA reduced dead space fraction compared to the corresponding support level of PSV. CONCLUSIONS: NAVA was superior to PSV in AECOPD for increasing ventilation distribution in ROI4 and reducing dead space. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02289573 . Registered on 12 November 2014. PMID- 28578709 TI - Genetic diversity of Plasmodium Vivax revealed by the merozoite surface protein-1 icb5-6 fragment. AB - BACKGROUND: Plasmodium vivax remains a potential cause of morbidity and mortality for people living in its endemic areas. Understanding the genetic diversity of P. vivax from different regions is valuable for studying population dynamics and tracing the origins of parasites. The PvMSP-1 gene is highly polymorphic and has been used as a marker in many P. vivax population studies. The aim of this study was to investigate the genetic diversity of the PvMSP-1 gene icb5-6 fragment and to provide more genetic polymorphism data for further studies on P. vivax population structure and tracking of the origin of clinical cases. METHODS: Nested PCR and sequencing of the PvMSP-1 icb5-6 marker were performed to obtain the nucleotide sequences of 95 P. vivax isolates collected from Zhejiang province, China. To investigate the genetic diversity of PvMSP-1, the 95 nucleotide sequences of the PvMSP-1 icb5-6 fragment were genotyped and analyzed using DnaSP v5, MEGA software. RESULTS: The 95 P. vivax isolates collected from Zhejiang province were either indigenous cases or imported cases from different regions around the world. A total of 95 sequences ranging from 390 to 460 bp were obtained. The 95 sequences were genotyped into four allele-types (Sal I, Belem, R III and R-IV) and 17 unique haplotypes. R-III and Sal I were the predominant allele-types. The haplotype diversity (Hd) and nucleotide diversity (Pi) were estimated to be 0.729 and 0.062, indicating that the PvMSP-1 icb5-6 fragment had the highest level of polymorphism due to frequent recombination processes and single nucleotide polymorphism. The values of dN/dS and Tajima's D both suggested neutral selection for the PvMSP-1icb5-6 fragment. In addition, a rare recombinant style of R-IV type was identified. CONCLUSIONS: This study presented high genetic diversity in the PvMSP-1 marker among P. vivax strains from around the world. The genetic data is valuable for expanding the polymorphism information on P. vivax, which could be helpful for further study on population dynamics and tracking the origin of P. vivax. PMID- 28578710 TI - Compliance with Clostridium difficile treatment guidelines: effect on patient outcomes. AB - Guidelines for the severity classification and treatment of Clostridium difficile infection (CDI) were published by Infectious Diseases Society of America (IDSA)/Society for Healthcare Epidemiology of America (SHEA) in 2010; however, compliance and efficacy of these guidelines has not been widely investigated. This present study assessed compliance with guidelines and its effect on CDI patient outcomes as compared with before these recommendations. A retrospective study included all adult inpatients with an initial episode of CDI treated in a single academic center from January 2009 to August 2014. Patients after guideline publication were compared with patients treated in 2009-2010. Demographic, clinical, and laboratory data were collected to stratify for disease severity. Outcome measures included compliance with guidelines, mortality, length of stay (LOS), and surgical intervention for CDI. A total of 1021 patients with CDI were included. Based upon the 2010 guidelines, 42 (28.8%) of 146 patients treated in 2009 would have been considered undertreated, and treatment progressively improved over time, as inadequate treatment decreased to 10.0% (15/148 patients) in 2014 (P = 0.0005). Overall, patient outcomes with guideline-adherent treatment decreased CDI attributable mortality twofold (P = 0.006) and CDI-related LOS by 1.9 days (P = 0.0009) when compared with undertreated patients. Compliance with IDSA/SHEA guidelines was associated with a decreased risk of mortality and LOS in hospitalized patients with CDI. PMID- 28578711 TI - HOSPITAL-BASED HEALTH TECHNOLOGY ASSESSMENT FOR THE ADOPTION OF INNOVATIVE MEDICAL DEVICES WITHIN FRENCH HOSPITALS: OPPORTUNITIES AND CHALLENGES FOR INDUSTRY. AB - OBJECTIVES: Within French university hospitals, some internal committees are in charge of conducting hospital-based health technology assessment (Hb-HTA) to support managerial decisions regarding the adoption of innovations. For manufacturers, hospitals are usually the entry point for new and innovative medical devices, which cannot be accessed without the Hb-HTA committees' approval. Thus, the main objective of this pilot survey was to explore manufacturers' insights into Hb-HTA processes. METHODS: A two-step pilot survey was conducted in 2014. First, semi-structured phone interviews were carried out to capture manufacturers' feedback on the Hb-HTA procedure. Second, a prospective and iterative questionnaire designed to explore manufacturers' market access strategies was administered. RESULTS: Eight manufacturers from the medical device industry completed the retrospective phone interviews, and five of them participated in the prospective survey. According to the overall feedback, the Hb HTA process timeline and transparency are major issues, and the expectations of internal committees, especially in terms of clinical evidence, remain difficult to understand. However, despite this and due to the complexity of reimbursement processes at the national level, manufacturers are increasingly considering hospital adoption through Hb-HTA submission as a viable market access and coverage opportunity. CONCLUSIONS: Our study reaffirms the primary role of hospitals in the diffusion of innovative medical devices. However, to ensure efficient and broad access to innovation, cooperation between local and national HTA bodies is critical and should be promoted. PMID- 28578712 TI - PHARMACOECONOMIC STUDIES IN WORLD HEALTH ORGANIZATION EASTERN MEDITERRANEAN COUNTRIES: REPORTING COMPLETENESS. AB - OBJECTIVES: The aim of this study was to evaluate the extent of reporting necessary information in published health economic research in World Health Organization Eastern Mediterranean Countries (WHO EMC). METHODS: A systematic literature search was conducted using PubMed and Google Scholar to identify pharmacoeconomic studies conducted in WHO EMC. The inclusion criteria for the studies were: (i) original studies, (ii) compared pharmaceutical services or drugs, (iii) conducted in WHO EMC, (iv) manuscript published in English. The articles were reviewed by two independent reviewers using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: A total of seventeen studies were included, each of which were published in seventeen different journals. The mean CHEERS checklist score was 16 +/- 4. Most studies were published in journals outside WHO EMC (n = 12; 71 percent). Cost effectiveness (n = 5; 29 percent) and cost-utility analyses (n = 5; 29 percent) were the most frequently used methods of economic evaluation. CONCLUSIONS: Pharmacoeconomic studies in WHO EMC are limited and sometimes incomplete. Economic evaluation of pharmaceuticals should be encouraged in WHO EMC to ensure the appropriate allocation of healthcare resources. PMID- 28578714 TI - INTIMATE PARTNER VIOLENCE AND CONTRACEPTIVE USE IN INDIA: THE MODERATING INFLUENCE OF CONFLICTING FERTILITY PREFERENCES AND CONTRACEPTIVE INTENTIONS. AB - Several studies report that women exposed to intimate partner violence (IPV) are less likely to use contraception, but the evidence that violence consistently constrains contraceptive use is inconclusive. One plausible explanation for this ambiguity is that the effects of violence on contraceptive use depend on whether couples are likely to have conflicting attitudes to it. In particular, although some men may engage in violence to prevent their partners from using contraception, they are only likely to do so if they have reason to oppose its use. Using a longitudinal follow-up to the Indian National Family Health Survey (NFHS-2), conducted among a sample of rural, married women of childbearing age, this study investigated whether the relationship between IPV and contraceptive use is contingent on whether women's contraceptive intentions contradict men's fertility preferences. Results indicate that women experiencing IPV are less likely to undergo sterilization, but only if they intended to use contraception and their partners wanted more children (Average Marginal Effect (AME)=-0.06; CI= 0.10, -0.01). Violence had no effect on sterilization among women who did not plan to use contraception (AME=-0.02; CI=-0.06, 0.03) or whose spouses did not want more children (AME=-0.01; CI=-0.9, 0.06). These results imply that violence enables some men to resolve disagreements over the use of contraception by imposing their fertility preferences on their partners. They also indicate that unmet need for contraception could be an intended consequence of violence. PMID- 28578713 TI - Delayed-onset haematoma formation after cochlear implantation. AB - OBJECTIVE: This paper presents our experience on delayed-onset haematoma formation after cochlear implantation, a topic which has not been well discussed in the literature. METHOD: Retrospective case review study. RESULTS: Five children who had undergone cochlear implant surgery at 1.5 to 4 years of age (median, 2.5 years) were studied. The haematoma episodes occurred 2-12 years (median, 6 years) after cochlear implantation. Two patients had recurrent episodes. Two of the seven haematoma episodes were managed by needle aspiration alone, four by incision and drainage alone, and one by both needle aspiration and incision and drainage. Other than one patient with coagulopathy, there were no obvious predisposing factors, including trauma. CONCLUSION: The majority of delayed-onset haematomas occurred without obvious predisposing factors. Needle aspiration can differentiate a haematoma from an abscess or cerebrospinal fluid leakage, and it provides an effective immediate therapeutic solution. However, aseptic techniques are emphasised to minimise the chances of an uncomplicated haematoma converting into a septic one. PMID- 28578715 TI - MEDIATION MODELS OF PREGNANCY DESIRES AND UNPLANNED PREGNANCY IN YOUNG, UNMARRIED WOMEN. AB - SummaryThis paper examines the proposition that sexual and contraceptive behaviours mediate the relationship between the pregnancy desires of young, unmarried women and their having an unplanned pregnancy. The sample consisted of 854 18- to 19-year-old women living in Michigan, USA. First, the positive and negative pregnancy desires of these women were measured, as were the women's perceptions of the positive and negative desires of their sexual partners. Then the extent to which these four types of desires, as well as several types of interactions between them, prospectively predicted the occurrence of subsequent pregnancies were tested with logistic regression analyses, initially alone and then after the addition of several types of sexual and contraceptive mediator variables. The results demonstrated that four of the ten significant motivational predictors became non-significant following the introduction of the contraceptive mediator variables and that the predictive strength of the other six significant motivational predictors was substantially reduced by their introduction. A number of factors that may account for only a partial mediational effect in some models are discussed. PMID- 28578717 TI - Biological traits and the complex of parasitoids of the elm pest Orchestes steppensis (Coleoptera: Curculionidae) in Xinjiang, China. AB - The flee-weevil Orchestes steppensis Korotyaev (Coleoptera: Curculionidae) is a steppe eastern Palaearctic species, notable as a serious pest of elms (Ulmus spp., Ulmaceae), by feeding on the leaves (adults) or mining them heavily (larvae), especially of Ulmus pumila L. in Xinjiang, China. We have corrected the previous misidentifications of this weevil in China as O. alni (L.) or O. mutabilis Boheman and demonstrated that it is likely to be an invasive species in Xinjiang. Prior to this study, natural enemies of O. steppensis were unknown in Xinjiang. Resulting from field investigation and rearing in the laboratory during 2013-2016, seven parasitoid species were found to be primary and solitary, attacking larval and pupal stages of the host weevil. Pteromalus sp. 2 is the dominant species and also is the most competitive among the seven parasitoids, which could considered to be a perspective biological control agent of O. steppensis. Yet, the current control of this pest by the local natural enemies in Xinjiang is still currently inefficient, even though in 2016 parasitism was about 36% on U. pumila in Urumqi, so the potential for a classical biological control program against it needs to be further investigated, including an assessment of its parasitoids and other natural enemies in the native range of O. steppensis. The presented information on the natural enemies of this weevil can be also important for a potential classical biological control program against it in North America (Canada and USA), where it is a highly damaging and rapidly spreading invasive species. PMID- 28578716 TI - Univariate and multivariate models for the prediction of life-threatening complications in 586 cases of deep neck space infections: retrospective multi institutional study. AB - OBJECTIVE: To identify deep neck infection factors related to life-threatening complications. METHODS: This retrospective multi-institutional study comprised 586 patients treated for deep neck infections between 2002 and 2012. The statistical significance of variables associated with life-threatening complications of deep neck infections was assessed. RESULTS: During treatment, life-threatening complications occurred in 60 out of 586 cases. On univariate analysis, life-threatening complications were linked to: dyspnoea, neck movement disturbance and dysphonia (all p < 0.001); and parapharyngeal, anterior visceral or pretracheal deep neck involvement (all p < 0.002). Aetiology was significantly linked to tonsils (p < 0.001). Regarding infection type, fasciitis was a significant factor (p < 0.001). Candida albicans was a significant bacterial culture (p < 0.001). A multivariate step-wise model disclosed fewer significant variables: retropharyngeal space (p = 0.005) and major blood vessels area (p = 0.006) involvement, and bacterial culture C albicans (p < 0.001). CONCLUSION: It can be predicted that patients with deep neck infections, with neck movement disturbances, dysphonia, dyspnoea and swelling of the external neck, accompanied by severe pain, and inflammatory changes in the retropharyngeal space and large vessel areas, with culture-confirmed infection of C albicans, are likely to develop life-threatening complications. PMID- 28578719 TI - Stress sensitivity in paranoia: poor-me paranoia protects against the unpleasant effects of social stress. AB - BACKGROUND: The attributional theory of paranoia suggests that paranoid beliefs may protect individuals from low self-esteem and distress (Bentall et al. 2001). The current study tested this theory by investigating a hypothesis that paranoid beliefs in combination with low perceived deservedness of persecution (poor-me beliefs) confer protection against the distress caused by social but not activity related stress. METHODS: Paranoid symptoms, perceived deservedness of persecution, self-esteem, mood, and stress levels of individuals diagnosed with schizophrenia spectrum disorders (N = 91) and healthy controls (N = 52) were assessed in the context of daily life using the experience sampling method. RESULTS: Individuals holding poor-me beliefs (poor-me individuals) showed blunted sensitivity to social but not activity stress. In contrast, individuals holding paranoid beliefs in combination with high perceived deservedness of persecution (bad-me individuals) showed heightened sensitivity to social stress. No consistent differences in reactions to activity stress emerged. Although both poor-me and bad-me individuals reported low self-esteem, this disturbance was particularly characteristic of bad-me individuals. CONCLUSIONS: The results suggest that poor-me paranoid beliefs may protect individuals against the distress associated with unpleasant social situations. The specificity of reactions to social stress is discussed in the context of wider literature. Future directions for research are suggested. PMID- 28578718 TI - Prokaryotic functional expression and activity comparison of three CYP9A genes from the polyphagous pest Helicoverpa armigera. AB - Cytochrome P450s (CYPs or P450s) have been long recognized as very important enzymes in the metabolism of xenobiotic and endogenous compounds, but only a few CYPs have been functionally characterized in insects. The effort in functional characterization of insect P450s is heavily hindered by technical difficulties in preparing active, individual P450 enzymes directly from the target insect. In this paper, we describe the functional expression of two additional pyrethroid resistance-associated CYP9A genes (CYP9A12 and CYP9A17) from the polyphagous pest Helicoverpa armigera in the facile Escherichia coli. The functionality of E. coli produced CYP9A12, CYP9A14, and CYP9A17 was investigated and activities of these CYP9As were compared against three probe substrates after reconstitution with NADPH-dependent cytochrome P450 reductase. The results showed that active forms of CYP9A12 and CYP9A17 were expressed in E. coli with a content of about 1.0-1.5 nmol mg-1 protein in membrane preparations. In vitro assays showed that CYP9A14 was capable of catalyzing O-dealkylation of methoxyresorufin (MROD), ethoxyresorufin (EROD), and benzyloxyresorufin (BROD), while CYP9A12 and CYP9A17 exhibited only MROD and EROD activities. Kinetic studies demonstrated that CYP9A14 had the greatest k cat/K m value for MROD, and CYP9A17 for EROD, while the lowest k cat/K m values for both MROD and EROD were observed for CYP9A12. The distinct biochemical traits suggest that the three paralogous CYP9As may play different roles in xenobiotic metabolism in this important pest. PMID- 28578720 TI - Cochrane Review Summary: Mini-Mental State Examination (MMSE) for the detection of dementia in clinically unevaluated people aged 65 and over in community and primary care populations. PMID- 28578721 TI - Energy and protein requirements of Santa Ines lambs, a breed of hair sheep. AB - An experiment was carried to evaluate the energy and protein requirements for the growth and maintenance of lambs of different sex classes. In all, 38 hair lambs (13.0+/-1.49 kg initial BW and 2 months old) were allocated in a factorial design with diet restriction levels (ad libitum, 30% and 60% feed restriction) and sex classes (castrated and non-castrated males). Four animals from each sex class were slaughtered at the beginning of the trial as a reference group to estimate the initial empty BW and body composition. The remaining lambs were weighed weekly to calculate BW gain (BWG), and when the animals fed ad libitum reached an average BW of 30 kg, all of the experimental animals were slaughtered. Before slaughter, fasted BW (FBW) was determined after 18 h without feed and water. Feed restriction induced reductions in body fat and energy concentration, whereas water restriction showed the opposite effect, and the protein concentration was not affected. The increase in BW promoted increases in body fat and energy content, and these increases were greater in castrated lambs, whereas the protein content was similar between classes tending to stabilize. The net energy required for gain (NEg) and the net protein required for gain (NPg) were not affected by sex class; therefore, an equation was generated for the combined results of both castrated and non-castrated lambs. The NEg varied from 1.13 to 2.01 MJ/day for lambs with BW of 15 and 30 kg and BWG of 200 g. The NPg varied from 24.57 to 16.33 g/day for lambs with BW of 15 and 30 kg and BWG of 200 g. The metabolizable energy efficiency for gain (k g) was 0.37, and the metabolizable protein efficiency for gain (k pg) was 0.28. The net energy required for maintenance (NEm) and the net requirement of protein for maintenance (NPm) did not differ between castrated and non-castrated lambs, with values of 0.241 MJ/kg FBW0.75 per day and 1.30 g/kg FBW0.75 per day, respectively. The metabolizable energy efficiency for maintenance (k m) was 0.60, and the efficiency of metabolizable protein use for maintenance (k pm) was 0.57. Nutritional requirements for growth and maintenance did not differ between castrated and non-castrated lambs. This study emphasizes the importance of updating the tables of international committees and of including data obtained from studies with sheep breeds raised in tropical conditions, with the purpose of improving the productive efficiency of the animals. PMID- 28578722 TI - A Comprehensive Approach Towards Optimizing the Xenon Plasma Focused Ion Beam Instrument for Semiconductor Failure Analysis Applications. AB - The xenon plasma focused ion beam instrument (PFIB), holds significant promise in expanding the applications of focused ion beams in new technology thrust areas. In this paper, we have explored the operational characteristics of a Tescan FERA3 XMH PFIB instrument with the aim of meeting current and future challenges in the semiconductor industry. A two part approach, with the first part aimed at optimizing the ion column and the second optimizing specimen preparation, has been undertaken. Detailed studies characterizing the ion column, optimizing for high-current/high mill rate activities, have been described to support a better understanding of the PFIB. In addition, a novel single-crystal sacrificial mask method has been developed and implemented for use in the PFIB. Using this combined approach, we have achieved high-quality images with minimal artifacts, while retaining the shorter throughput times of the PFIB. Although the work presented in this paper has been performed on a specific instrument, the authors hope that these studies will provide general insight to direct further improvement of PFIB design and applications. PMID- 28578723 TI - Pertussis diagnosis in Belgium: results of the National Reference Centre for Bordetella anno 2015. AB - In 2015, the Belgian National Reference Centre for Bordetella analyzed 4110 respiratory samples by qPCR and 4877 serum samples by serology. Whereas about 50% of respiratory samples were from infants and children below the age of five, serum samples were distributed among all age categories. A total of 394 (9.6%) cases was diagnosed as positive for Bordetella pertussis by qPCR and 844 (17.3%) cases were diagnosed as acute infection by serology (anti-pertussis toxin (PT) IgG > 125 IU/ml). Another 1042 (21.4%) sera had anti-PT IgG between 55 and 125 IU/ml reflecting a vaccination or pertussis infection during the last 1-2 years. Seventy per cent of the pertussis cases diagnosed by qPRC were in infants and children younger than 14 years old, whereas the highest number of sera with anti PT levels >125 IU/ml was in the age group of 10-14 years old. Based on the limited data of the last vaccination (reported for only 15% of the samples), recent booster vaccination in the teenager group may have contributed only minimally to these elevated anti-PT levels. The highest number of sera with anti PT titers between 55 and 125 IU/ml was found in the age category 50-59 years old. It is clear that pertussis continues to be a problem in Belgium and that other vaccination strategies (maternal vaccination, cocoon vaccination) and ultimately better vaccines will be needed to control this highly infectious respiratory disease. PMID- 28578724 TI - Association between gestational diabetes and perinatal depressive symptoms: evidence from a Greek cohort study. AB - : Aim The aim of the present study was to assess the association of gestational diabetes mellitus (GDM) with prenatal and postnatal depressive symptoms in a sample of pregnant women in Greece. BACKGROUND: Earlier research supports a relationship between depression and diabetes, but only a few studies have examined the relationship between GDM and perinatal depressive symptomatology. METHODS: A total of 117 women in their third trimester of pregnancy participated in the study. Demographic and obstetric history data were recorded during women's third trimester of pregnancy. Depressive symptoms were assessed with the validated Greek version of the Edinburg Postnatal Depression Scale (EPDS) at two time points: on the third trimester of pregnancy and on the first week postpartum. Findings Prevalence of GDM was 14.5%. Probable diagnosis of depression occurred for 12% of the sample during the antenatal assessment and 15.1% in the postpartum assessment. In the first week postpartum, women with GDM had significantly higher postpartum (but no antenatal) EPDS scores compared with the non-GDM cohort. In conclusion, GDM appears to be associated with depressive symptoms in the first week postpartum. Clinical implications and recommendations for future research are discussed, emphasizing the importance of closely monitoring women with GDM who seem more vulnerable to developing depressive symptomatology during the postnatal period. PMID- 28578725 TI - Possible Associations between Subitizing, Estimation and Visuospatial Working Memory (VSWM) in Children. AB - Researchers have focused on identifying the mechanisms involved in subitizing and its differences with estimation. Some suggest that subitizing relies on a visual indexing system in charge of the simultaneous individuation of objects that is also used by visuospatial working memory (VSWM). In adults, studies found associations between subitizing and VSWM, in the absence of correlation between VSWM and estimation. The present study analyzed the performance of 120 4 and 6 year-old children in three tasks: dot enumeration to measure subitizing capacity, quantity discrimination for estimation, and Corsi Block-tapping task for VSWM. In the enumeration task RTs (F(9, 1062)=720.59, MSE=734394, p<.001, eta2=.86) and errors (F(9, 1062)=42.15, MSE=.194, p<.001, eta2=.26.) increased with the array, but this growth was statistically significant only from 4 dots onward. Each subject's subitizing range was estimated by fitting RTs with a sigmoid function of number of dots and obtaining the bend point of the curve. Data fit (age 4: R 2 = .88; SD = .08; age 6: R 2 = .91, SD = .08) showed a mean subitizing range of 2.79 (SD = .66) for 4 year-olds and of 3.11 (SD = .64) for 6 year-olds. Subitizing ranges and average RTs showed low association with storage (r = .274; p < .05; r = -.398; p < .001) and average RTs with concurrent processing (r = .412; p < .001) in VSWM. Subitizing range and speed showed no association with estimation speed and a poor association with accuracy (r = .234, p < .01; r = .398, p < .001), which suggests independent systems for small and large quantities. Subitizing and estimation measures correlated with VSWM (p < .01), which suggests that both processes may require VSWM resources. PMID- 28578727 TI - Focused Ion Beam Preparation of Specimens for Micro-Electro-Mechanical System based Transmission Electron Microscopy Heating Experiments. AB - Micro-electro-mechanical systems (MEMS)-based heating holders offer exceptional control of temperature and heating/cooling rates for transmission electron microscopy experiments. The use of such devices is relatively straightforward for nano-particulate samples, but the preparation of specimens from bulk samples by focused ion beam (FIB) milling presents significant challenges. These include: poor mechanical integrity and site selectivity of the specimen, ion beam damage to the specimen and/or MEMS device during thinning, and difficulties in transferring the specimen onto the MEMS device. Here, we describe a novel FIB protocol for the preparation and transfer of specimens from bulk samples, which involves a specimen geometry that provides mechanical support to the electron transparent region, while maximizing the area of that region and the contact area with the heater plate on the MEMS chip. The method utilizes an inclined stage block that minimizes exposure of the chip to the ion beam during milling. This block also allows for accurate and gentle placement of the FIB-cut specimen onto the chip by using simultaneous electron and ion beam imaging during transfer. Preliminary data from Si and Ag on Si samples are presented to demonstrate the quality of the specimens that can be obtained and their stability during in situ heating experiments. PMID- 28578726 TI - Statistically Derived Subtypes and Associations with Cerebrospinal Fluid and Genetic Biomarkers in Mild Cognitive Impairment: A Latent Profile Analysis. AB - OBJECTIVES: Research demonstrates heterogeneous neuropsychological profiles among individuals with mild cognitive impairment (MCI). However, few studies have included visuoconstructional ability or used latent mixture modeling to statistically identify MCI subtypes. Therefore, we examined whether unique neuropsychological MCI profiles could be ascertained using latent profile analysis (LPA), and subsequently investigated cerebrospinal fluid (CSF) biomarkers, genotype, and longitudinal clinical outcomes between the empirically derived classes. METHODS: A total of 806 participants diagnosed by means of the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI criteria received a comprehensive neuropsychological battery assessing visuoconstructional ability, language, attention/executive function, and episodic memory. Test scores were adjusted for demographic characteristics using standardized regression coefficients based on "robust" normal control performance (n=260). Calculated Z scores were subsequently used in the LPA, and CSF-derived biomarkers, genotype, and longitudinal clinical outcome were evaluated between the LPA-derived MCI classes. RESULTS: Statistical fit indices suggested a 3-class model was the optimal LPA solution. The three-class LPA consisted of a mixed impairment MCI class (n=106), an amnestic MCI class (n=455), and an LPA-derived normal class (n=245). Additionally, the amnestic and mixed classes were more likely to be apolipoprotein e4+ and have worse Alzheimer's disease CSF biomarkers than LPA derived normal subjects. CONCLUSIONS: Our study supports significant heterogeneity in MCI neuropsychological profiles using LPA and extends prior work (Edmonds et al., 2015) by demonstrating a lower rate of progression in the approximately one-third of ADNI MCI individuals who may represent "false positive" diagnoses. Our results underscore the importance of using sensitive, actuarial methods for diagnosing MCI, as current diagnostic methods may be over inclusive. (JINS, 2017, 23, 564-576). PMID- 28578728 TI - China's Public Safety Events: A Call to Action. PMID- 28578729 TI - Drivers of dietary behaviours in women living in urban Africa: a systematic mapping review. AB - OBJECTIVE: To (i) systematically review the literature to determine the factors influencing diet and dietary behaviour in women living in urban Africa; (ii) present these in a visual map; and (iii) utilize this to identify potentially important areas for future research. DESIGN: Systematic mapping review. The review protocol was registered at PROSPERO (http://www.crd.york.ac.uk/PROSPERO/; registration number CRD42015017749). Six databases were systematically searched, followed by reference and citation searching. Eligibility criteria included women aged 18-70 years living in urban Africa, any design/methodology, exploring any driver, using any measure of dietary behaviour. Quality appraisal occurred parallel with data extraction. Twelve predominantly cross-sectional quantitative studies were included; reported in seventeen publications. Determinants were synthesized narratively and compiled into a map adapted from an existing ecological model based on research in high-income countries. SETTING: Urban Africa. SUBJECTS: African women aged 18-70 years. RESULTS: Determinants significantly associated with unhealthy dietary behaviour ranged from the individual to macro level, comprising negative body image perception, perceptions of insufficient food quantity and poorer quality, poorer food knowledge, skipping meals, snacking less, higher alcohol consumption, unhealthy overall lifestyle, older age, higher socio-economic status, having an education, lower household food expenditure, frequent eating outside the home and media influence. Marital status and strong cultural and religious beliefs were also identified as possible determinants. CONCLUSIONS: Few studies have investigated drivers of dietary behaviours in urban African settings. Predominantly individual-level factors were reported. Gaps in the literature identified a need for research into the neglected areas: social, physical and macro-level drivers of food choice. PMID- 28578730 TI - Eating frequency and weight and body composition: a systematic review of observational studies. AB - OBJECTIVE: The present review aimed to examine the association of eating frequency with body weight or body composition in adults of both sexes. DESIGN: PubMed, EMBASE and Scopus databases were searched. PRISMA and MOOSE protocols were followed. Observational studies published up to August 2016 were included. The methodological quality of the studies was assessed with the Downs and Black checklist. SETTING: A systematic review of the literature. SUBJECTS: Adults (n 136 052); the majority of studies were developed in the USA and Europe. RESULTS: Thirty-one articles were included in the review: two prospective and twenty-nine cross-sectional studies. Thirteen per cent of the studies received quality scores above 80 %. The assessment of eating frequency and body composition or body weight varied widely across the studies. Potential confounders were included in 73 % of the studies. Fourteen studies reported an inverse association between eating frequency and body weight or body composition, and seven studies found a positive association. The majority of studies applied multiple analyses adjusted for potential confounders, such as sex, age, education, income, smoking, physical activity and alcohol intake. Six studies took into account under-reporting of eating frequency and/or energy intake in the analysis, and one investigated the mediation effect of energy intake. CONCLUSIONS: There is not sufficient evidence confirming the association between eating frequency and body weight or body composition when misreporting bias is taken into account. However, in men, a potential protective effect of high eating frequency was observed on BMI and visceral obesity. PMID- 28578731 TI - Bacterial Infections in Neonates Following Mupirocin-Based MRSA Decolonization: A Multicenter Cohort Study. AB - OBJECTIVE To characterize the risk of infection after MRSA decolonization with intranasal mupirocin. DESIGN Multicenter, retrospective cohort study. SETTING Tertiary care neonatal intensive care units (NICUs) from 3 urban hospitals in the United States ranging in size from 45 to 100 beds. METHODS MRSA-colonized neonates were identified from NICU admissions occurring from January 2007 to December 2014, during which a targeted decolonization strategy was used for MRSA control. In 2 time-to-event analyses, MRSA-colonized neonates were observed from the date of the first MRSA-positive surveillance screen until (1) the first occurrence of novel gram-positive cocci in sterile culture or discharge or (2) the first occurrence of novel gram-negative bacilli in sterile culture or discharge. Mupirocin exposure was treated as time varying. RESULTS A total of 522 MRSA-colonized neonates were identified from 16,144 neonates admitted to site NICUs. Of the MRSA-colonized neonates, 384 (74%) received mupirocin. Average time from positive culture to mupirocin treatment was 3.5 days (standard deviation, 7.2 days). The adjusted hazard of gram-positive cocci infection was 64% lower among mupirocin-exposed versus mupirocin-unexposed neonates (hazard ratio, 0.36; 95% confidence interval [CI], 0.17-0.76), whereas the adjusted hazard ratio of gram-negative bacilli infection comparing mupirocin-exposed and -unexposed neonates was 1.05 (95% CI, 0.42-2.62). CONCLUSIONS In this multicentered cohort of MRSA-colonized neonates, mupirocin-based decolonization treatment appeared to decrease the risk of infection with select gram-positive organisms as intended, and the treatment was not significantly associated with risk of subsequent infections with organisms not covered by mupirocin's spectrum of activity. Infect Control Hosp Epidemiol 2017;38:930-936. PMID- 28578732 TI - Thirty years of human infections caused by Yersinia enterocolitica in northern Spain: 1985-2014. AB - Yersinia enterocolitica infection is a zoonosis with worldwide distribution, gastroenteritis being by far the most common clinical manifestation of human infection. In Gipuzkoa, northern Spain, human Y. enterocolitica infections increased from the mid-1980s to the beginning of the 21st century (from 7.9 to 23.2 annual episodes per 100 000 population) to decrease to 7.2 annual episodes per 100 000 population in the last years of the study. The hospital admission rate due to yersiniosis during the last 15 years of the study was 7.3%. More than 99% of isolates were serotype O:3. Infection affected mainly children under 5 years of age (average rate: 140 episodes per 100 000 population). The incidence in adults was low but hospitalisation increased with age, exceeding 50% in people over 64 years old. PMID- 28578733 TI - Seed treatments with thiamine reduce the performance of generalist and specialist aphids on crop plants. AB - Thiamine is a vitamin that has been shown to act as a trigger to activate plant defence and reduce pathogen and nematode infection as well as aphid settling and reproduction. We have here investigated whether thiamine treatments of seeds (i.e. seed dressing) would increase plant resistance against aphids and whether this would have different effects on a generalist than on specialist aphids. Seeds of wheat, barley, oat and pea were treated with thiamine alone or in combination with the biocontrol bacteria Pseudomonas chlororaphis MA 342 (MA 342). Plants were grown in climate chambers. The effects of seed treatment on fecundity, host acceptance and life span were studied on specialist aphids bird cherry-oat aphid (Rhopalosiphum padi L.) and pea aphid (Acyrthosiphon pisum Harris) and on the generalist green peach aphid (Myzus persicae, Sulzer). Thiamine seed treatments reduced reproduction and host acceptance of all three aphid species. The number of days to reproduction, the length of the reproductive life, the fecundity and the intrinsic rate of increase were found reduced for bird cherry-oat aphid after thiamine treatment of the cereal seeds. MA 342 did not have any effect in any of the plant-aphid combinations, except a weak decrease of pea aphid reproduction on pea. The results show that there are no differential effects of either thiamine or MA 342 seed treatments on specialist and generalist aphids and suggest that seed treatments with thiamine has a potential in aphid pest management. PMID- 28578734 TI - Genetic and environmental aspects in the association between attention-deficit hyperactivity disorder symptoms and binge-eating behavior in adults: a twin study. AB - BACKGROUND: Prior research demonstrated that attention-deficit hyperactivity disorder (ADHD) is associated with binge-eating behavior, binge-eating disorder (BED), and bulimia nervosa (BN). The aim of this study was to investigate these associations in an adult twin population, and to determine the extent to which ADHD symptoms and binge-eating behavior share genetic and environmental factors. METHODS: We used self-reports of current ADHD symptoms and lifetime binge-eating behavior and associated characteristics from a sample of over 18 000 adult twins aged 20-46 years, from the population-based Swedish Twin Registry. Mixed-effects logistic regression was used to examine the association between ADHD and lifetime binge-eating behavior, BED, and BN. Structural equation modeling was used in 13 773 female twins to determine the relative contribution of genetic and environmental factors to the association between ADHD symptoms and binge-eating behavior in female adult twins. RESULTS: ADHD symptoms were significantly associated with lifetime binge-eating behavior, BED, and BN. The heritability estimate for current ADHD symptoms was 0.42 [95% confidence interval (CI) 0.41 0.44], and for lifetime binge-eating behavior 0.65 (95% CI 0.54-0.74). The genetic correlation was estimated as 0.35 (95% CI 0.25-0.46) and the covariance between ADHD and binge-eating behavior was primarily explained by genetic factors (91%). Non-shared environmental factors explained the remaining part of the covariance. CONCLUSIONS: The association between adult ADHD symptoms and binge eating behavior in females is largely explained by shared genetic risk factors. PMID- 28578735 TI - DEVELOPMENTS IN VALUE FRAMEWORKS TO INFORM THE ALLOCATION OF HEALTHCARE RESOURCES. AB - BACKGROUND: In recent years, there has been a surge in the development of frameworks to assess the value of different types of health technologies to inform healthcare resource allocation. The reasons for, and the potential of, these value frameworks were discussed during the 2017 Health Technology Assessment International (HTAi) Policy Forum Meeting. METHODS: This study reflects the discussion, drawing on presentations from invited experts and Policy Forum members, as well as a background paper. RESULTS: The reasons given for a proliferation of value frameworks included: rising healthcare costs; more complex health technology; perceived disconnect between price and value in some cases; changes in societal values; the need for inclusion of additional considerations, such as ethical issues; and greater empowerment of clinicians and patients in defining and using value frameworks. Many Policy Forum participants recommended learning from existing frameworks. Furthermore, there was a desire to agree on the core components of value frameworks, defining the additional value elements as necessary and considering how they might be measured and used in practice. Furthermore, adherence to the principles of transparency, predictability, broad stakeholder involvement, and accountability were widely supported, along with being forward looking, explicit, and consistent across decisions. CONCLUSIONS: Value frameworks continue to evolve with significant implications for global incentives for innovation and access to health technologies. There is a role for the HTA community to address some of the key areas discussed during the meeting, such as defining the core components for assessing the value of a health technology. PMID- 28578736 TI - Perception v. actual intakes of junk food and sugar-sweetened beverages in Australian young adults: assessed using the mobile food record. AB - OBJECTIVE: To determine perception v. actual intakes of energy-dense nutrient poor 'junk food' (JF) and sugar-sweetened beverages (SSB) in young adults, using the mobile food record (mFR). DESIGN: Before-and-after eating images using a 4 d mFR were assessed for standardised 600 kJ (143 kcal) servings of JF and SSB (excluding diet drinks). Participants reported their concern about the health aspects of their diet, perceptions and intentions regarding JF and SSB. SETTING: Perth, Western Australia. SUBJECTS: Adults (n 246) aged 18-30 years. RESULTS: The mean (sd) intake of JF+SSB was 3.7 (2.0) servings/d. Women thinking about drinking less SSB consumed more SSB servings/d (1.5 (1.2)) than men (0.7 (0.5); P<0.05) who were thinking about drinking less. Men not thinking about cutting down JF consumed more servings/d (4.6 (2.4)) than women (2.5 (0.7); P<0.01) who were not thinking about cutting down. Those who paid a lot of attention to the health aspects of their diet consumed less JF+SSB than those who took only a bit of notice (P<0.001), were not really thinking much about it (P<0.001) or who didn't think at all about the health aspects of food (P<0.01). CONCLUSIONS: Perceptions and attitudes regarding JF and SSB were associated with level of consumption. Those not thinking about cutting down their intake of these foods represent an important target group as they consume more than their peers. Further research is needed to identify how amenable young adults are to changing their intake, particularly given the lack of attention paid to the health aspects of their diet. PMID- 28578737 TI - Effects of light-emitting diode light v. fluorescent light on growing performance, activity levels and well-being of non-beak-trimmed W-36 pullets. AB - More energy-efficient, readily dimmable, long-lasting and more affordable light emitting diode (LED) lights are increasingly finding applications in poultry production facilities. Despite anecdotal evidence about the benefits of such lighting on bird performance and behavior, concrete research data were lacking. In this study, a commercial poultry-specific LED light (dim-to-blue, controllable correlated color temperature (CCT) from 4500 to 5300 K) and a typical compact fluorescent light (CFL) (soft white, CCT=2700 K) were compared with regards to their effects on growing performance, activity levels, and feather and comb conditions of non-beak-trimmed W-36 pullets during a 14-week rearing period. A total of 1280-day-old pullets in two successive batches, 640 birds each, were used in the study. For each batch, pullets were randomly assigned to four identical litter-floor rooms equipped with perches, two rooms per light regimen, 160 birds per room. Body weight, BW uniformity (BWU), BW gain (BWG) and cumulative mortality rate (CMR) of the pullets were determined every 2 weeks from day-old to 14 weeks of age (WOA). Activity levels of the pullets at 5 to 14 WOA were delineated by movement index. Results revealed that pullets under the LED and CFL lights had comparable BW (1140+/-5 g v. 1135+/-5 g, P=0.41), BWU (90.8+/ 1.0% v. 91.9+/-1.0%, P=0.48) and CMR (1.3+/-0.6% v. 2.7+/-0.6%, P=0.18) at 14 WOA despite some varying BWG during the rearing. Circadian activity levels of the pullets were higher under the LED light than under the CFL light, possibly resulting from differences in spectrum and/or perceived light intensity between the two lights. No feather damage or comb wound was apparent in either light regimen at the end of the rearing period. The results contribute to understanding the impact of emerging LED lights on pullets rearing which is a critical component of egg production. PMID- 28578738 TI - SHAPING QUALITY THROUGH VISION, STRUCTURE, AND MONITORING OF PERFORMANCE AND QUALITY INDICATORS: IMPACT STORY FROM THE QUEBEC TRAUMA NETWORK. AB - OBJECTIVES: The Quebec Trauma Care Continuum (TCC) was initiated in 1991 with the objective of providing accessible, continuous, efficient, and high quality services for all injury cases in the province. METHODS: The TCC design relied on three key components: (i) the designation of a network of acute care and rehabilitation facilities with specific mandates and responsibilities; (ii) the elaboration of transfer protocols, standing agreements, and governing structures to ensure fluid and optimal patient flow; and (iii) the close monitoring of several indicators to facilitate the continuous evaluation and improvement of the network. RESULTS: Between 1992 and 2002, in-hospital mortality following major trauma decreased from 51.8 percent to 8.6 percent, followed by an additional 24 percent drop between 1999 and 2012. We also observed a 16 percent decrease in average LOS but no change in the incidence of complications or unplanned readmissions. These changes translate into 186 lives saved per year and cost savings, due to shorter LOS, of 6.3 million CD$ per year. The risk-adjusted incidence of in-hospital mortality following major injury between 2006 and 2012 (7 percent) was the lowest of all Canadian provinces. CONCLUSIONS: Strategic transformation of a network's structure and processes, supported by continuous monitoring of validated quality indicators, can lead to significant and sustainable improvements in clinical outcomes. It is hoped that the Quebec trauma story will inspire other jurisdictions and other healthcare sectors. PMID- 28578740 TI - Application of network methods for understanding mental disorders: pitfalls and promise. AB - Galvanized with the availability of sophisticated statistical techniques and large datasets, network medicine has emerged as an active area of investigation. Following this trend, network methods have been utilized to understand the interplay between symptoms of mental disorders. This realistic approach that may provide an improved framework into understanding mental conditions and underlying mechanisms is certainly to be welcomed. However, we have noticed that symptom network studies tend to lose sight of the fundamentals, overlook major limitations embedded in study designs, and make inferences that are difficult to justify with current findings. There is concern that disregarding these flaws may halt the progress of the network approach in psychiatry. Therefore, in this paper, we first attempt to identify the pitfalls: (1) a reductionist understanding of medicine and psychiatry, thereby inadvertently reintroducing the dichotomy of medicine (lung cancer) and psychiatry (depression), (2) a shortsighted view of signs and symptoms, (3) overlooking the limitations of available datasets based on scales with embedded latent class structures, (4) overestimating the importance of the current findings beyond what is supported by the study design. By addressing current issues, the hope is to navigate this rapidly growing field to a more methodologically sound and reproducible path that will contribute to our understanding of mental disorders and its underlying mechanisms. PMID- 28578739 TI - Improving team-based care for children: shared well child care involving family practice nurses. AB - INTRODUCTION: Well child care (WCC) is the provision of routine preventative care and vaccinations to infants and children. In Canada, physicians provide the majority of this type of care, whereas in other developed countries, nurses provide most WCC. New models of shared care between nurses and family physicians should be explored. OBJECTIVE: This pilot project aimed to evaluate the feasibility and acceptability of shared nurse-physician WCC for a cohort of healthy children. METHODS: A total of 20 participants had nurse-physician alternating WCC visits, which were compared with physician-provided WCC visits. The feasibility was evaluated through chart audits and the acceptability was evaluated through interviews with the physicians, nurses, and the patients' parents. RESULTS: The results showed that physicians and nurses discuss a similar percentage of Rourke Baby Record topics, and that families and clinic staff were accepting of this new model of care. CONCLUSION: This intervention could liberate time for Canadian family physicians, thereby improving access to care. PMID- 28578741 TI - Antipsychotic combinations in schizophrenia. AB - In the treatment of resistant schizophrenia, a number of meta-analyses attempted to quantify the efficacy and tolerability of antipsychotic (AP) polypharmacy v. monotherapy with contradictory results. Recently, a systematic review and meta analysis of randomised controlled trials investigated the efficacy and tolerability of AP combination v. monotherapy in schizophrenia. It included 31 studies: 21 double-blind (considered high-quality studies) and 10 open-label (considered low-quality studies). The meta-analysis showed that, overall, the combination of two APs was more effective than monotherapy in terms of symptom reduction (standardised mean difference (SMD) = -0.53, 95% confidence interval (CI) -0.87 to -0.19); however, this result was confirmed only in the subgroup of low-quality studies. Negative symptoms improved when combining a D2 antagonist with a D2 partial agonist (SMD = -0.41, 95% CI -0.79 to -0.03) both in double blind and open-label studies. In the present commentary, the results of this systematic review are critically discussed in terms of their clinical and research implications. PMID- 28578743 TI - TO WHAT EXTENT DO COUPLES' PRE-MARITAL COMMUNICATIONS AFFECT THEIR POST-MARITAL FERTILITY BEHAVIOUR IN INDIA? AB - SummaryReproduction in India is mainly confined to within marriage. The fertility preferences of spouses will not necessarily be the same, but discussion between couples creates scope for understanding between spouses after marriage. Knowing each other's opinions facilitates decision-making on sensitive matters such as contraception use and desired family size. This study used data from the India Human Development Survey-II (2011-12), and was based on a sample of 31,276 currently married women. The aim was to understand the role of pre-marital communication, studied through the choosing of husbands, mutual communication before marriage and duration of time spouses knew each other before marriage on the fertility preferences of couples post-marriage. These preferences included contraception use, who has most say on the number of children and the gap between desired and actual number of offspring. The results showed that wives who knew their husbands or who had any kind of communication with them before marriage had a greater chance of being involved in fertility decisions. However, most fertility decisions were found to be male-driven. Wives who knew their husbands for more than a month before marriage took more decisions on number of children (27%) than those who only knew their husbands from the day of their wedding (20%). Wives were less likely to have more children/sons/daughters than desired if they had some communication with their husbands before marriage. A better understanding of fertility preferences between spouses might help to curb unwanted births through delaying or limiting births by contraception use. Families in India could encourage couples to interact before marriage so they can make collective decisions on contraception use and/or the number of children they have. PMID- 28578742 TI - Applicability of plant-based products in the treatment of Trypanosoma cruzi and Trypanosoma brucei infections: a systematic review of preclinical in vivo evidence. AB - Chagas disease and sleeping sickness are neglected tropical diseases closely related to poverty, for which the development of plant-derived treatments has not been a promising prospect. Thus, we systematicaly review the preclinical in vivo evidence on the applicability of plant-based products in the treatment of Trypanosoma cruzi and Trypanosoma brucei infections. Characteristics such as disease models, treatments, toxicological safety and methodological bias were analysed. We recovered 66 full text articles from 16 countries investigating 91 plant species. The disease models and treatments were highly variable. Most studies used native (n = 36, 54.54%) or exotic (n = 30, 45.46%) plants with ethnodirected indication (n = 45, 68.18%) for trypanosomiasis treatment. Complete phytochemical screening and toxicity assays were reported in only 15 (22.73%) and 32 (48.49%) studies, respectively. The currently available preclinical evidence is at high risk of bias. The absence of or incomplete characterization of animal models, treatment protocols, and phytochemical/toxicity analyses impaired the internal validity of the individual studies. Contradictory results of a same plant species compromise the external validity of the evidence, making it difficult determine the effectiveness, safety and biotechnological potential of plant-derived products in the development of new anti-infective agents to treat T. cruzi and T. brucei infections. PMID- 28578745 TI - Exploratory analysis of meal composition in Australia: meat and accompanying foods. AB - OBJECTIVE: The study of meal patterns and overall diet in relation to health outcomes may be more important than focusing on single nutrients or food groups. The present study aimed to explore the composition of main meals and snacks in the Australian population and examine associations between meat/poultry/fish and other foods. DESIGN: The study utilised 24 h recalls. Meal composition was defined based on average intakes of food groups per meal disaggregated from all food sources. SETTING: 2011-12 National Nutrition and Physical Activity Survey. SUBJECTS: Australian people (n12153) aged 2 years or above. RESULTS: Overall, breakfast was the smallest meal of the day, typically consisting of grains, dairy products and fruit. Lunch was the second largest meal, consisting mostly of grains, non-starchy vegetables and meat/poultry/fish. The largest meal was dinner, comprising meat/poultry/fish, vegetables (starchy and non-starchy), grains and often including discretionary beverages (children) or alcohol (adults). The main food groups consumed at snacking occasions were dairy, fruit, discretionary foods and beverages (including alcohol for adults). The most frequently consumed meat types were beef and chicken at dinner and ham at lunch. Non-starchy vegetables were accompanying foods for red meat, poultry and fish/seafood consumed in varying portion sizes, but did not accompany processed meat. CONCLUSIONS: The present study considered meat, poultry and fish as the meal centre and their accompaniments of other food groups at different eating occasions. These findings expand the background evidence for health professionals developing meal-based framework/guidelines and public health messages. PMID- 28578744 TI - A corner store intervention to improve access to fruits and vegetables in two Latino communities. AB - OBJECTIVE: Investments have been made to alter the food environment of neighbourhoods that have a disproportionate number of unhealthy food venues. Corner store conversions are one strategy to increase access to fruits and vegetables (F&V). Although the literature shows modest success, the effectiveness of these interventions remains equivocal. The present paper reports on the evaluation of Proyecto MercadoFRESCO, a corner store conversion intervention in two Latino communities. DESIGN: A repeated cross-sectional design was employed. Data were stratified by intervention arm and bivariate tests assessed changes over time. Logistic and multiple regression models with intervention arm, time and the interaction of intervention and time were conducted. Supplementary analyses account for clustering of patrons within stores and staggering of store conversions. SETTING: Three stores were converted and five stores served as comparisons in East Los Angeles and Boyle Heights, California, USA. SUBJECTS: Store patrons were interviewed before (n550) and after (n407) the intervention. RESULTS: Relative to patrons of comparison stores, patrons of intervention stores demonstrated more favourable perceptions of corner stores and increased purchasing of F&V during that store visit. Changes were not detected in store patronage, percentage of weekly dollars spent on food for F&V or daily consumption of F&V. CONCLUSIONS: Consistent with some extant food environment literature, findings demonstrate limited effects. Investments should be made in multilevel, comprehensive interventions that target a variety retail food outlets rather than focusing on corner stores exclusively. Complementary policies limiting the availability, affordability and marketing of energy-dense, nutrient poor foods should also be pursued. PMID- 28578746 TI - Heat stress effects on Holstein dairy cows' rumination. AB - The objective of this study was to investigate the relationship between temperature-humidity index (THI) and rumination time (RT) in order to possibly exploit it as a useful tool for animal welfare improvement. During summer 2015 (1 June to 31 August), data from an Italian Holstein dairy farm located in the North of Italy were collected along with environmental data (i.e. ambient temperature and relative humidity) recorded with a weather station installed inside the barn. Rumination data were collected through the Heatime(r) HR system (SCR Engineers Ltd., Hadarim, Netanya, Israel), an automatic system composed of a neck collar with a Tag that records the RT and activity of each cow. A significant negative correlation was observed between RT and THI. Mixed linear models were fitted, including animal and test day as random effects, and parity, milk production level and date of last calving as fixed effects. A statistically significant effect of THI on RT was identified, with RT decreasing as THI increased. PMID- 28578747 TI - The Decomposition of Shared Environmental Influences on Externalizing Syndromes in the Swedish Population: A Multivariate Study. AB - Using information from Swedish population registries, we attempt to decompose the shared environment (C) into four subcomponents: close family, family, household, and community. Among pairs differing in their genetic and geographical/household relationships, we examine three externalizing syndromes: drug abuse (DA), criminal behavior (CB), and alcohol use disorders (AUD). The best-fitting common pathway model suggested that total estimates for C were higher for DA (21% for males and 18% for females) than for AUD (16% and 14%) and CB (17% and 10%). Concerning syndrome-specific influences in males, close family effects were stronger for CB and AUD, while community effects were stronger for DA. The two C components in between community experiences and close family experiences (family and household) were estimated to almost entirely derive from the common latent factor. In females, among the four components of C, the community experiences were just slightly above zero, while the C components referred to as the household effect were almost zero. The total close family experiences were similar and most important across syndromes were also divided into common and specific components. For all syndromes, for both males and females, the effects of additive genetic factors were 2-4 times the size of the total effect of the shared environment. Applying standard methods to novel relationships, we expand our understanding of how the shared environment contributes to individual differences in three externalizing syndromes. PMID- 28578748 TI - Epidemiological Effectiveness and Cost of a Fungal Meningitis Outbreak Response in New River Valley, Virginia: Local Health Department and Clinical Perspectives. AB - OBJECTIVE: We evaluated the effectiveness and cost of a fungal meningitis outbreak response in the New River Valley of Virginia during 2012-2013 from the perspective of the local public health department and clinical facilities. The fungal meningitis outbreak affected 23 states in the United States with 751 cases and 64 deaths in 20 states; there were 56 cases and 5 deaths in Virginia. METHODS: We conducted a partial economic evaluation of the fungal meningitis outbreak response in New River Valley. We collected costs associated with the local health department and clinical facilities in the outbreak response and estimated the epidemiological effectiveness by using disability-adjusted life years (DALYs) averted. RESULTS: We estimated the epidemiological effectiveness of this outbreak response to be 153 DALYs averted among the patients, and the costs incurred by the local health department and clinical facilities to be $30,413 and $39,580, respectively. CONCLUSIONS: We estimated the incremental cost effectiveness ratio of $198 per DALY averted and $258 per DALY averted from the local health department and clinical perspectives, respectively, thereby assisting in impact evaluation of the outbreak response by the local health department and clinical facilities. (Disaster Med Public Health Preparedness. 2018;12:38-46). PMID- 28578750 TI - USING THE HEALTH TECHNOLOGY ASSESSMENT TOOLBOX TO FACILITATE PROCUREMENT: THE CASE OF SMART PUMPS IN A CANADIAN HOSPITAL. AB - OBJECTIVES: The aim of this study was to present the experience of a Canadian hospital-based health technology assessment (HTA) unit that performed the traditional functions of the HTA process along with many other activities to facilitate the choice of smart pumps. METHODS: A rapid literature review was initiated, but little evidence was found. Moreover, the evidence provided was too far from our hospital context. To help our decision makers, we offered them a list of various services based on the skills of our HTA unit staff. RESULTS: To involve our HTA unit in the choice of the new smart pumps led to a strong collaboration between hospital services. After a rapid review on smart pumps, we proceeded to establish the clinical needs, followed by an evaluation of technical features. To ascertain clinical needs, we participated in the establishment of a conformity list for the tender, a failure and mode-effect analysis, an audit on the use of actual smart pumps, and simulation exercises with nurses and doctors to evaluate the ease of use and ergonomics. With regard to technical tests, these were mainly conducted to identify potential dysfunction and to assess the efficiency of the pump. This experience with smart pumps was useful for evidence based procurement and led to the formulation of a nine-step process to guide future work. CONCLUSIONS: HTA units and agencies are faced with rapid development of new technologies that may not be supported by sufficient amount of pertinent published evidence. Under these circumstances, approaches other than evidence based selection might provide useful information. Because these activities may be different from those related to classic HTA, this widens the scope of what can be done in HTA to support decision making. PMID- 28578749 TI - Differential prevalence and correlates of whole blood Epstein-Barr virus DNA between HIV-positive and HIV-negative men who have sex with men in Shanghai, China. AB - This cross-sectional study aimed to examine and compare prevalence and correlates of whole blood Epstein-Barr virus (EBV) DNA between HIV-positive and HIV-negative men who have sex with men (MSM). Five hundred and four HIV-positive MSM and 504 age-matched HIV-negative MSM were recruited from an HIV counseling and testing clinic in Shanghai, China from November 2014 to November 2015 and were administered with a face-to-face questionnaire interview. Whole blood EBV DNA was tested by nested polymerase chain reaction assays on EBNA-1, EBNA-2, and LMP-1 genes. The prevalence of whole blood EBV DNA was 56.0% (95% CI 51.7-60.3%) among HIV-positive MSM and 26.0% (95% CI 22.4-30.0%) among HIV-negative MSM. Whole blood EBV DNA positivity was significantly associated with HIV infection (adjusted odds ratio (aOR) 3.43, 95% CI 2.58-4.57) and frequent intake of pickled, smoked, or salty food (aOR 1.71, 95% CI 1.02-2.86) in the whole sample, and with <200 cells/MUl CD4 cell counts (aOR 1.79, 95% CI 1.05-3.05) and pickled, smoked, or salty food intake (aOR 3.14, 95% CI 1.39-7.08) in HIV-positive group. HIV-infected MSM are at higher risk of active EBV replication than HIV-uninfected MSM, underscoring needs of surveillance and research on EBV-related carcinogenesis in this population. PMID- 28578752 TI - TECHNOLOGY ASSESSMENT IN HOSPITALS: LESSONS LEARNED FROM AN EMPIRICAL EXPERIMENT. AB - OBJECTIVES: Hospital Based Health Technology Assessment (HBHTA) practices, to inform decision making at the hospital level, emerged as urgent priority for policy makers, hospital managers, and professionals. The present study crystallized the results achieved by the testing of an original framework for HBHTA, developed within Lombardy Region: the IMPlementation of A Quick hospital based HTA (IMPAQHTA). The study tested: (i) the HBHTA framework efficiency, (ii) feasibility, (iii) the tool utility and completeness, considering dimensions and sub-dimensions. METHODS: The IMPAQHTA framework deployed the Regional HTA program, activated in 2008 in Lombardy, at the hospital level. The relevance and feasibility of the framework were tested over a 3-year period through a large scale empirical experiment, involving seventy-four healthcare professionals organized in different HBHTA teams for assessing thirty-two different technologies within twenty-two different hospitals. Semi-structured interviews and self-reported questionnaires were used to collect data regarding the relevance and feasibility of the IMPAQHTA framework. RESULTS: The proposed HBHTA framework proved to be suitable for application at the hospital level, in the Italian context, permitting a quick assessment (11 working days) and providing hospital decision makers with relevant and quantitative information. Performances in terms of feasibility, utility, completeness, and easiness proved to be satisfactory. CONCLUSIONS: The IMPAQHTA was considered to be a complete and feasible HBHTA framework, as well as being replicable to different technologies within any hospital settings, thus demonstrating the capability of a hospital to develop a complete HTA, if supported by adequate and well defined tools and quantitative metrics. PMID- 28578751 TI - 25-Hydroxyvitamin D supplementation and health-service utilization for upper respiratory tract infection in young children. AB - OBJECTIVE: Upper respiratory tract infections (URTI) are the most common and costly condition of childhood. Low vitamin D levels have been hypothesized as a risk factor for URTI. The primary objective was to determine if serum vitamin D levels were associated with health-service utilization (HSU) for URTI including hospital admission, emergency department visits and outpatient sick visits. The secondary objectives were to determine whether oral vitamin D supplementation in pregnancy or childhood was associated with HSU for URTI. DESIGN: Cohort study. HSU was determined by linking each child's provincial health insurance number to health administrative databases. Multivariable quasi Poisson regression was used to evaluate the association between 25-hydroxyvitamin D, vitamin D supplementation and HSU for URTI. SETTING: Toronto, Canada. SUBJECTS: Children participating in the TARGet Kids! network between 2008 and 2013. RESULTS: Healthy children aged 0-5 years (n 4962) were included; 52 % were male and mean 25 hydroxyvitamin D was 84 nmol/l (range 11-355 nmol/l). There were 105 (2 %), 721 (15 %) and 3218 (65 %) children with at least one hospital admission, emergency department visit or outpatient sick visit for URTI, respectively. There were no statistically significant associations between 25-hydroxyvitamin D or vitamin D supplementation and HSU for URTI. CONCLUSIONS: A clinically meaningful association between vitamin D (continuously and dichotomized at <50 and <75 nmol/l) and HSU for URTI was not identified. While vitamin D may have other benefits for health, reducing HSU for URTI does not appear to be one of them. PMID- 28578753 TI - Grandmothers' knowledge positively influences maternal knowledge and infant and young child feeding practices. AB - OBJECTIVE: To examine associations between grandmothers' knowledge and infant and young child feeding (IYCF) practices and to test whether the associations are independent of or operate via maternal knowledge. DESIGN: Cross-sectional household survey data from households with a child under 5 years (n 4080). We used multivariate regression analyses, adjusted for child, maternal, grandmother and household characteristics, and district-level clustering, to test associations between grandmothers' knowledge and IYCF practices for children aged 6-24 months living with a grandmother. We used causal mediation to formally test the direct effect of grandmothers' knowledge on IYCF practices v. maternal knowledge mediating these associations. SETTING: Two hundred and forty rural communities, sixteen districts of Nepal. SUBJECTS: Children aged 6-24 months (n1399), including those living with grandmothers (n 748). RESULTS: We found that the odds of optimal breast-feeding practices were higher (early breast-feeding initiation: 2.2 times, P=0.002; colostrum feeding: 4.2 times, P<0.001) in households where grandmothers had correct knowledge v. those with incorrect knowledge. The same pattern was found for correct timing of introduction of water (2.6), milk (2.4), semi-solids (3.2), solids (2.9), eggs (2.6) and meat (2.5 times; all P<0.001). For the two pathways we were able to test, mothers' correct knowledge mediated these associations between grandmothers' knowledge and IYCF practices: colostrum feeding (b=10.91, P<0.001) and the introduction of complementary foods (b=5.18, P<0.001). CONCLUSIONS: Grandmothers' correct knowledge translated into mothers' correct knowledge and, therefore, optimal IYCF practices. Given grandmothers' influence in childcare, engagement of grandmothers in health and nutrition interventions could improve mothers' knowledge and facilitate better child feeding. PMID- 28578754 TI - Internet images of the speech pathology profession. AB - Objective The Internet provides the general public with information about speech pathology services, including client groups and service delivery models, as well as the professionals providing the services. Although this information assists the general public and other professionals to both access and understand speech pathology services, it also potentially provides information about speech pathology as a prospective career, including the types of people who are speech pathologists (i.e. demographics). The aim of the present study was to collect baseline data on how the speech pathology profession was presented via images on the Internet.Methods A pilot prospective observational study using content analysis methodology was conducted to analyse publicly available Internet images related to the speech pathology profession. The terms 'Speech Pathology' and 'speech pathologist' to represent both the profession and the professional were used, resulting in the identification of 200 images. These images were considered across a range of areas, including who was in the image (e.g. professional, client, significant other), the technology used and the types of intervention.Results The majority of images showed both a client and a professional (i.e. speech pathologist). While the professional was predominantly presented as female, the gender of the client was more evenly distributed. The clients were more likely to be preschool or school aged, however male speech pathologists were presented as providing therapy to selected age groups (i.e. school aged and younger adults). Images were predominantly of individual therapy and the few group images that were presented were all paediatric.Conclusion Current images of speech pathology continue to portray narrow professional demographics and client groups (e.g. paediatrics). Promoting images of wider scope to fully represent the depth and breadth of speech pathology professional practice may assist in attracting a more diverse group of people into the profession in the future.What is known about the topic? To date, research has not considered the promotional profile of allied health professionals on the Internet. There has been a lack of consideration of whether the way in which the professions are promoted may affect clients accessing allied health services or people entering careers.What does this paper add? This paper raises awareness of the lack of promotion of a diverse workforce in speech pathology and considers how this may affect changing the professional demographics in the future. It also provides a starting point for documentation in the form of a baseline for tracking future changes. It allows consideration of the fact that when designing health promotional and educational materials, it is crucial that diversity is displayed in the professional role, the client role and the setting in order to provide information and education to the general public about the health services provided.What are the implications for practitioners? The presentation of narrow demographics of both the professional and client may potentially affect people considering speech pathology as a future career. The appearance of narrow client demographics and diagnosis groups may also deter people from accessing services. For example, if the demonstrated images do not show older people accessing speech pathology services, then this may suggest that services are only for children. The results from the present case example are transferrable to other health professions with similar professional demographic profiles (e.g. occupational therapy). Consideration of the need to display a diverse client profile is relevant to all health and medical services, and demonstrates steps towards inclusiveness and increasing engagement of clients who may be currently less likely to access health services (including people who are Aboriginal or from a culturally and linguistically diverse background). PMID- 28578755 TI - Enhancing national data to align with policy objectives: Aboriginal and Torres Strait Islander smoking prevalence at finer geographic levels. AB - Objectives The aim of the study was to assess the utility of national Aboriginal survey data in a regional geospatial analysis of daily smoking prevalence for Aboriginal and Torres Strait Islander Australians and discuss the appropriateness of this analysis for policy and program impact assessment. Methods Data from the last two Australian Bureau of Statistics (ABS) national surveys of Aboriginal and Torres Strait Islander people, the National Aboriginal and Torres Strait Islander Social Survey 2014-15 (n=7022 adults) and the National Aboriginal and Torres Strait Islander Health Survey 2012-13 (n=10896 adults), were used to map the prevalence of smoking by Indigenous regions. Results Daily smoking prevalence in 2014-15 at Indigenous regions ranges from 27.1% (95%CI 18.9-35.3) in the Toowoomba region in Queensland to 68.0% (95%CI 58.1-77.9) in the Katherine region in the Northern Territory. The confidence intervals are wide and there is no significant difference in daily smoking prevalence between the two time periods for any region. Conclusion There are significant limitations with analysing national survey data at finer geographical scales. Given the national program for Indigenous tobacco control is a regional model, evaluation requires finer geographical analysis of smoking prevalence to inform public health progress, policy and program effects. Options to improve the data currently collected include increasing national survey sample sizes, implementing a smoking status question in census surveys, investing in current cohort studies focused on this population or implementing localised surveys. What is known about the topic? The last geospatial analysis of Aboriginal and Torres Strait Islander smoking prevalence was undertaken in 1997. Current national survey data have not been analysed geospatially. What does this paper add? This paper provides new insights into the use of national survey data for understanding regional patterns and prevalence levels of smoking in Aboriginal and Torres Strait Islander populations. What are the implications for practitioners? The findings of the study suggest caution when interpreting prevalence maps and highlight the need for greater sample sizes in national survey data. The analysis is also an opportunity to assess the use of national survey data in evaluating the policy impact of programs targeted at a regional level. PMID- 28578756 TI - Sexual risk behaviours associated with unlicensed driving among young adults in Miami's electronic dance music nightclub scene. AB - Literature indicates that unlicensed driving (UD) offenders report substance use risk behaviours, yet data related to sexual risk behaviours is unknown. This study examined sexual and other risk behaviours among young adults in Miami, Florida, comparing UD and non-UD offenders (n=498). Compared with others, UD offenders were more likely to report group sex history, being high for sex half the time or more, purchasing sex and sexually transmissible infection history. Results suggest that locating sexual risk reduction interventions inside of the justice system would benefit UD offenders. PMID- 28578757 TI - Decision-making under pressure: medical errors in uncertain and dynamic environments. AB - Objective This paper provides a narrative overview of the literature concerning clinical decision-making processes when staff come under pressure, particularly in uncertain, dynamic and emergency situations.Methods Studies between 1980 and 2015 were analysed using a six-phase thematic analysis framework to achieve an in depth understanding of the complex origins of medical errors that occur when people and systems are under pressure and how work pressure affects clinical performance and patient outcomes. Literature searches were conducted using a Summons Search Service platform; search criteria included a variety of methodologies, resulting in the identification of 95 papers relevant to the present review.Results Six themes emerged in the present narrative review using thematic analysis: organisational systems, workload, time pressure, teamwork, individual human factors and case complexity. This analysis highlights that clinical outcomes in emergency situations are the result of a variety of interconnecting factors. These factors may affect the ability of clinical staff in emergency situations to provide quality, safe care in a timely manner.Conclusions The challenge for researchers is to build the body of knowledge concerning the safe management of patients, particularly where clinicians are working under pressure. This understanding is important for developing pathways that optimise clinical decision making in uncertain and dynamic environments.What is known about the topic? Emergency departments (EDs) are characterised by high complexity, high throughput and greater uncertainty compared with routine hospital wards or out-patient situations, and the ED is therefore prone to unpredictable workflows and non-replicable conditions when presented with unique and complex cases.What does this paper add? Clinical decision making can be affected by pressures with complex origins, including organisational systems, workload, time constraints, teamwork, human factors and case complexity. Interactions between these factors at different levels of the decision-making process can increase the complexity of problems and the resulting decisions to be made.What are the implications for practitioners? The findings of the present study provide further evidence that consideration of medical errors should be seen primarily from a 'whole-of-system' perspective rather than as being primarily the responsibility of individuals. Although there are strategies in place in healthcare organisations to eliminate errors, they still occur. In order to achieve a better understanding of medical errors in clinical practice in times of uncertainty, it is necessary to identify how diverse pressures can affect clinical decisions, and how these interact to influence clinical outcomes. PMID- 28578758 TI - The primary health care of transgender adults. AB - Gender dysphoria is associated with significant health disparity. Gender services perform specialised activities such as diagnosis, endocrine management and liaison with surgical services. Although providing these specialised transition services appears to be safe and improves well-being, significant health disparity remains. Engaging primary care providers is an important part of any strategy to improve the health care of transgender people. The relationships between gender dysphoria and a range of primary care issues such as mental health, cardiovascular disease and cancer are explored. PMID- 28578759 TI - Cost savings from a teledentistry model for school dental screening: an Australian health system perspective. AB - Objective The aim of the present study was to compare the costs of teledentistry and traditional dental screening approaches in Australian school children.Methods A cost-minimisation analysis was performed from the perspective of the oral health system, comparing the cost of dental screening in school children using a traditional visual examination approach with the cost of mid-level dental practitioners (MLDPs), such as dental therapists, screening the same cohort of children remotely using teledentistry. A model was developed to simulate the costs (over a 12-month period) of the two models of dental screening for all school children (2.7million children) aged 5-14 years across all Australian states and territories. The fixed costs and the variable costs, including staff salary, travel and accommodation costs, and cost of supply were calculated. All costs are given in Australian dollars.Results The total estimated cost of the teledentistry model was $50million. The fixed cost of teledentistry was $1million and that of staff salaries (tele-assistants, charters and their supervisors, as well as information technology support was estimated to be $49million. The estimated staff salary saved with the teledentistry model was $56million, and the estimated travel allowance and supply expenses avoided were $16million and $14million respectively; an annual reduction of $85million in total.Conclusions The present study shows that the teledentistry model of dental screening can minimise costs. The estimated savings were due primarily to the low salaries of dental therapists and the avoidance of travel and accommodation costs. Such savings could be redistributed to improve infrastructure and oral health services in rural or other underserved areas.What is known about the topic? Caries is a preventable disease, which, if it remains untreated, can cause significant morbidity requiring costly treatment. Regular dental screening and oral health education have the great potential to improve oral health and save significant resources. The use of role substitution, such as using MLDPs to provide oral care has been well acknowledged worldwide because of their ability to provide safe and effective care. The teledentistry approach for dental screening offers a comparable diagnostic performance to the traditional visual approach.What does this paper add? The results of the present study suggest that teledentistry is a practical and economically viable approach for mass dental screening not only for isolated communities, but also for underserved urban communities. The costs of the teledentistry model were substantially lower than the costs associated with a conventional, face-to-face approach to dental screening in both remote and urban areas. The primary driver of net savings is the low salary of MLDPs and avoidance of travel and overnight accommodation by MLDPs.What are the implications for practitioners? The use of lower-cost MLDPs and a teledentistry model for dental screening has the potential to save significant economic and human resources that can be redirected to improve infrastructure and oral care services in underserved regions. In the absence of evidence of the economic usefulness of teledentistry, studies such as the present one can increase the acceptance of this technology among dental care providers and guide future decisions on whether or not to implement teledentistry services. PMID- 28578760 TI - [Bacillus thuringiensis: New applications for an old acquaintance?] PMID- 28578761 TI - Research Pearls: The Significance of Statistics and Perils of Pooling. AB - A series of articles on statistics are intended for an audience of clinicians, as well as statisticians and authors. Statistical significance is different than clinical significance. Understanding of clinical outcomes, value, quality, or generalizability requires critical analysis of medical research literature to ensure that statistical analyses have been properly applied and interpreted. PMID- 28578762 TI - Editorial Commentary: All-Suture Anchors, Foam Blocks, and Biomechanical Testing. AB - Barber's biomechanical work is well known to Arthroscopy's readers as thorough, comprehensive, and inclusive of new designs as they become available. In "All Suture Anchors: Biomechanical Analysis of Pullout Strength, Displacement, and Failure Mode," the latest iteration, Barber and Herbert test all-suture anchors in both porcine femurs and biphasic foam. While we await in vivo clinical trials that compare all-suture anchors to currently used anchors, Barber and Herbert have provided data to inform anchor choice, and using their biomechanical data at time zero from all-suture anchor trials in an animal model, we can determine the anchors' feasibility for human clinical investigations. PMID- 28578763 TI - Editorial Commentary: To Move or Not to Move the Shoulder, That Is the Question. AB - Whether to use an immediate range of motion exercise protocol or, rather, to delay the initiation of rehabilitation exercises for patients after arthroscopic rotator cuff repair presents a significant dilemma for the treating surgeon. The study "The Effect of Early Range of Motion on Quality of Life, Clinical Outcome, and Repair Integrity After Arthroscopic Rotator Cuff Repair" by Mazzocca, Arciero, Shea, Apostolakos, Solovyova, Gomlinski, Wojcik, Tafuto, Stock, and Cote reveals that no differences in quality of life scores or rotator cuff healing were identified after comparing 2 groups of patients undergoing either immediate (within 3 days) or delayed (after 28 days) postoperative rehabilitation protocols. These results underscore the fact that little data has been published to date that demonstrates an optimum time period for initiating postoperative rehabilitation after rotator cuff repair. PMID- 28578764 TI - Editorial Commentary: With New Technology Comes New Responsibility: Do the Complications of Hip Arthroscopy See Us More Often Than We See Them? AB - A database study of the codes for hip arthroscopy reports a rate of major and minor complications that is higher than previously reported in the literature. The relative risk of conversion to hip replacement or a subsequent fracture or dislocation is greater than in the general population. PMID- 28578765 TI - Editorial Commentary: Not All Cortical Suspensory Fixation Devices Are Created Equal. AB - Fixed-loop and adjustable-loop cortical suspensory fixation devices are both available as graft fixation options for surgeons. Fixed devices require facilities to manage various available sizes in the inventory, whereas adjustable devices are a true one-size-fits-all device requiring one inventory item for all cases. Adjustable-loop devices are also the only device that allows for postfixation tightening that may be advantageous for the surgeon who desires to tighten and retighten the graft construct once again before the case is completed. PMID- 28578766 TI - Editorial Commentary: Elbow Lateral Epicondylitis (Tennis Elbow) Surgery Works, but Is Not Often Indicated. AB - In the small percentage of patients who do not respond to nonoperative approaches to tennis elbow, surgery-whether it is open, arthroscopic, or percutaneous provides near 90% satisfaction rates. PMID- 28578767 TI - Electronic Communication of Protected Health Information: Privacy, Security, and HIPAA Compliance. AB - PURPOSE: Technology has enhanced modern health care delivery, particularly through accessibility to health information and ease of communication with tools like mobile device messaging (texting). However, text messaging has created new risks for breach of protected health information (PHI). In the current study, we sought to evaluate hand surgeons' knowledge and compliance with privacy and security standards for electronic communication by text message. METHODS: A cross sectional survey of the American Society for Surgery of the Hand membership was conducted in March and April 2016. Descriptive and inferential statistical analyses were performed of composite results as well as relevant subgroup analyses. RESULTS: A total of 409 responses were obtained (11% response rate). Although 63% of surgeons reported that they believe that text messaging does not meet Health Insurance Portability and Accountability Act of 1996 security standards, only 37% reported they do not use text messages to communicate PHI. Younger surgeons and respondents who believed that their texting was compliant were statistically significantly more like to report messaging of PHI (odds ratio, 1.59 and 1.22, respectively). DISCUSSION: A majority of hand surgeons in this study reported the use of text messaging to communicate PHI. Of note, neither the Health Insurance Portability and Accountability Act of 1996 statute nor US Department of Health and Human Services specifically prohibits this form of electronic communication. To be compliant, surgeons, practices, and institutions need to take reasonable security precautions to prevent breach of privacy with electronic communication. CLINICAL RELEVANCE: Communication of clinical information by text message is not prohibited under Health Insurance Portability and Accountability Act of 1996, but surgeons should use appropriate safeguards to prevent breach when using this form of communication. PMID- 28578768 TI - Commentary on "Electronic Communication of Protected Health Information: Privacy, Security, and HIPAA Compliance". PMID- 28578769 TI - Compressive Neuropathy of the Ulnar Nerve: A Perspective on History and Current Controversies. AB - The untoward effects resulting from compression of the ulnar nerve have been recognized for almost 2 centuries. Initial treatment of cubital tunnel syndrome focused on complete transection of the nerve at the level of the elbow, resulting in initial alleviation of pain but significant functional morbidity. A number of subsequent techniques have been described including in situ decompression, subcutaneous transposition, submuscular transposition, and most recently, endoscopic release. This manuscript focuses on the historical aspects of each of these treatments and our current understanding of their efficacy. PMID- 28578770 TI - Commentary on "Compressive Neuropathy of the Ulnar Nerve: A Perspective on History and Current Controversies". PMID- 28578771 TI - Letter Regarding "Cost of Immediate Surgery Versus Nonoperative Treatment for Trigger Finger in Diabetic Patients". PMID- 28578772 TI - ? PMID- 28578773 TI - [The economic burden of cancer and the access to innovation should boost the use of real world data]. PMID- 28578774 TI - Editorial foreword-SI: Blue growth. PMID- 28578775 TI - Corrigendum to "Functional and immunohistochemical characterization of CCEae3a, a carboxylesterase associated with temephos resistance in the major arbovirus vectors Aedes aegypti and Ae. albopictus" [Insect Biochem. Mol. Biol. 74 (July 2016) 61-67]. PMID- 28578777 TI - In Reply I-Prescribing More Stringent Design of Randomized Clinical Trials of Omega-3 Polyunsaturated Fatty Acids. PMID- 28578778 TI - In Reply II-Prescribing More Stringent Design of Randomized Clinical Trials of Omega-3 Polyunsaturated Fatty Acids. PMID- 28578776 TI - Prescribing More Stringent Design of Randomized Clinical Trials of Omega-3 Polyunsaturated Fatty Acids. PMID- 28578779 TI - An Accident Waiting to Happen: Thoracic Aortic Aneurysm. PMID- 28578780 TI - An Editor's Walk With Mayo Clinic Proceedings, 1999-2017: Promises, Aspirations, and Reflections. PMID- 28578781 TI - Differences Between Alcoholic and Nonalcoholic Patients With Wernicke Encephalopathy: A Multicenter Observational Study. AB - OBJECTIVE: To analyze the differences in characteristics and prognosis between alcoholic and nonalcoholic patients with Wernicke encephalopathy (WE). PATIENTS AND METHODS: A retrospective observational cohort of 468 patients diagnosed with WE with at least 2 Caine criteria was selected from all patients discharged with a diagnosis of WE from 21 medical centers in Spain from January 1, 2000, through December 31, 2012. Demographic, clinical, and outcome variables were described. RESULTS: Among the 468 patients, the most common risk factor was alcoholism (n=434 [92.7%]). More than one-third of patients (n=181 [38.7%]) had the classic WE triad of symptoms (ocular signs, cerebellar dysfunction, and confusion). Among 252 patients for whom magnetic resonance imaging data were available, 135 (53.6%) had WE-related lesions and 42 (16.7%) had cerebellar lesions. Of the 468 patients, 25 (5.3%) died during hospitalization. Alcoholic patients presented more frequently than nonalcoholic patients with cerebellar signs (P=.01) but less frequently with ocular signs (P=.02). Alcoholic patients had a significantly higher frequency of hyponatremia (P=.04) and decreased platelet count (P=.005) compared with nonalcoholics. Alcoholic patients were diagnosed earlier than nonalcoholics (median time to diagnosis, 1 vs 4 days; P=.001) and had shorter hospitalizations (13 vs 23 days; P=.002). CONCLUSION: Compared with nonalcoholic patients, alcoholic patients with WE are more likely to present with cerebellar signs and less likely to have ocular signs. Diagnosis may be delayed in nonalcoholic patients. Mortality in the present series was lower than described previously. PMID- 28578782 TI - Associations Between Anthropometric Measurements and Cardiometabolic Risk Factors in White European and South Asian Adults in the United Kingdom. AB - OBJECTIVE: To investigate the association of 4 anthropometric measurements with cardiometabolic risk factors in a UK biethnic sample of South Asians (SAs) and white Europeans (WEs). PATIENTS AND METHODS: Baseline data were collected from adults of WE and SA origin participating in the Leicester arm of the Anglo-Danish Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care (ADDITION-Leicester) study between August 2004 and December 2007. Overall, 6268 WE and SA adults had measures of body mass index, waist circumference, waist-to-hip ratio, and waist-to-height ratio assessed between June 18, 2004, and December 4, 2007. Hypertension, dyslipidemia, and dysglycemia were established from venous blood samples using standard definitions. Crude and adjusted (covariates used were age, sex, ethnicity, smoking, and alcohol consumption) odds ratios were calculated using multivariate logistic regression. Receiver operating characteristic curves and the area under the curve were used to calculate optimal cut points for the whole cohort and for both ethnic groups. RESULTS: Increases in all anthropometric measurements resulted in a higher odds ratio for each of the risk factors in both the crude and adjusted models (P<.001). The adjusted odds ratios for dyslipidemia, hypertension, and dysglygemia ranged from 1.30 to 1.35, from 1.36 to 1.52, and from 1.62 to 1.75 (P<.001 for all), respectively, in WEs. The adjusted odds ratio for dyslipidemia, hypertension, and dysglygemia ranged from 1.50 to 1.65 (P<.01), from 1.40 to 1.60 (P<.01), and from 1.96 to 2.11 (P<.001 for all), respectively, in SAs. The areas under the receiver operating characteristic curves for all the anthropometric measurements had low accuracy (P<.70) for the whole cohort and when stratified by ethnicity and sex. CONCLUSION: There is insufficient evidence to recommend replacing body mass index with another anthropometric measurement for the ethnically diverse population in the United Kingdom. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00318032. PMID- 28578783 TI - Biology and Treatment of Aggressive Fibromatosis or Desmoid Tumor. AB - Aggressive fibromatosis, also known as desmoid-type fibromatosis (DTF) or desmoid tumor, is an uncommon locally invasive tumor. Because of its low incidence and variable behavior, DTF is often first seen by physicians who are not familiar with it, and recent advances in understanding this disease have led to changes in treatment approaches. The Wnt (beta-catenin) pathway appears to play a key role in DTF pathogenesis, and recent studies of DTF biology suggest a possible model of DTF pathogenesis. Histologically, DTF shows a poorly circumscribed proliferation of myofibroblast-like cells with variable collagen deposition, similar to the proliferative phase of wound healing, and DTF has been associated with trauma and pregnancy. Desmoid-type fibromatosis may be a useful model of the tumor stroma in carcinomas as well as other fibrosing diseases such as progressive pulmonary fibrosis. The clinical course of DTF can vary greatly among patients, complicating the determination of the optimal treatment approach. Treatment options include surgery, nonsteroidal anti-inflammatory drugs with or without hormonal manipulation, chemotherapy, radiation therapy, and other forms of local therapy. Many treatments have been used, but these are not without toxicities. Because of the variable nature of the disease and the potential morbidity of treatment, some cases of DTF may do better without treatment; simple observation is often the best initial treatment. This review used a PubMed search from January 1, 1980, through October 31, 2016, using the terms fibromatosis and desmoid and discusses DTF disease characteristics, pathophysiology, and treatment options as well as examines several cases illustrating key points in the biology and treatment of this heterogeneous disease. PMID- 28578784 TI - Making Dysphagia Easier to Swallow: A Review for the Practicing Clinician. AB - Evaluating a patient with dysphagia can be a complex and daunting task. In this article, we present a practical approach to the evaluation, physical examination, and subsequent work-up of dysphagia that is applicable to practicing physicians. PMID- 28578787 TI - Gastric Signet Ring Cell Carcinoma. PMID- 28578786 TI - Treatment of Glioma in the 21st Century: An Exciting Decade of Postsurgical Treatment Advances in the Molecular Era. AB - The past decade has brought about major changes in the way we classify and have begun to approach patients with high-grade glioma. As we trend toward personalized medicine, we are now able to utilize the molecular characteristics of each individual's tumor in order to tailor their treatment, particularly if the patient is elderly or has a poor performance status at baseline. We address the state of the practice as of 2016 in regard to chemotherapy, immunotherapy, and tumor-treating fields. The goal of this review is to enhance readers' understanding of the nuances that are allowing clinicians to tailor the treatment of high-grade glioma more specifically. PMID- 28578788 TI - African Mask by Danillo Zanella. AB - Recognizing the contribution art has had in the Mayo Clinic environment since the original Mayo Clinic Building was finished in 1914, Mayo Clinic Proceedings features some of the numerous works of art displayed throughout the buildings and grounds on Mayo Clinic campuses as interpreted by the author. PMID- 28578785 TI - Alzheimer Disease: Scientific Breakthroughs and Translational Challenges. AB - Alzheimer disease (AD) was originally conceived as a rare disease that caused presenile dementia but has come to be understood as the most prevalent cause of dementia at any age worldwide. It has an extended preclinical phase characterized by sequential changes in imaging and cerebrospinal fluid biomarkers with subtle memory decline beginning more than a decade before the emergence of symptomatic memory loss heralding the beginning of the mild cognitive impairment stage. The apolipoprotein E epsilon4 allele is a prevalent and potent risk factor for AD that has facilitated research into its preclinical phase. Cerebral Abeta levels build from preclinical through early dementia stages followed by hyperphosphorylated tau-related pathology, the latter driving cognitive deficits and dementia severity. Structural and molecular imaging can now recapitulate the neuropathology of AD antemortem. Autosomal dominant forms of early-onset familial AD gave rise to the amyloid hypothesis of AD, which, in turn, has led to therapeutic trials of immunotherapy designed to clear cerebral amyloid, but to date results have been disappointing. Genome-wide association studies have identified multiple additional risk factors, but to date none have yielded an effective alternate therapeutic target. Current and future trials aimed at presymptomatic individuals either harboring cerebral amyloid or at genetically high risk offer the hope that earlier intervention might yet succeed where trials in patients with established dementia have failed. A major looming challenge will be that of expensive, incompletely effective disease-modifying therapy: who and when to treat, and how to pay for it. PMID- 28578792 TI - Functional and clinical outcomes of total ankle arthroplasty in elderly compared to younger patients. AB - BACKGROUND: Total ankle arthroplasty (TAA) is becoming an increasingly utilized procedure for the management of end-stage ankle arthritis. Elderly patients are the fastest growing segment of the population in the western world, creating a unique challenge to the health economics of our era. Determining if elderly patients with end-stage ankle arthritis demonstrate the same improvements in clinical outcomes and functional measures of gait following TAA would be valuable. This can aid to evaluate the utilization of TAA in this enlarging cohort of our population. METHODS: Consecutive series of twenty-one patients over the age of 70, who underwent TAA for end-stage ankle arthritis, was prospectively compared to a series of twenty-one patients aged 50-60, who underwent the same procedure by single surgeon during same time period. Clinical outcomes were measured with outcome scores including VAS pain score, AOFAS Ankle and Hindfoot Score, and the SF-36. Three-dimensional gait analysis was performed preoperatively and at a minimum of one year postoperatively, to measure temporal spatial, kinematic, and kinetic parameters of gait. Mixed model multivariate statistical analysis was used to evaluate and compare the independent contributions to outcomes of the surgical intervention over time; of patient age; and of time-plus-age interaction, as these influenced both the clinical outcomes and the functional gait outcomes. RESULTS: Statistically significant improvements in VAS pain scores, AOFAS ankle/hindfoot scores, and SF-36 scores were demonstrated in both age groups. Following surgery, there were improvements in all parameters of gait, including temporal-spatial parameters as step length and walking velocity; kinematic parameters, including, increase in total range of motion to a total of 17-19 degrees ; and kinetic parameters, including increase in ankle power and moment. The improvements both in clinical and gait outcomes were equivalent in the two age groups. CONCLUSIONS: In this comparative study, it is shown that both elderly patients over the age of 70 and younger patients aged 50-60 demonstrated equivalent improvements clinical and gait outcomes following ankle arthroplasty. This may be important data both for clinical decision-making and the health economics for our ageing population. PMID- 28578791 TI - Letrozole, an aromatase inhibitor, reduces post-peak age-related regression of rooster reproductive performance. AB - This study was designed to evaluate orally administrated Letrozole (Lz) on reproductive performance, plasma testosterone and estradiol concentrations and relative abundance of mRNA of GnRH, FSH and LH in roosters. Ross 308 roosters (n=32) that were 40-weeks of age were individually housed and received a basal standard diet supplemented different amounts of capsulated Lz [0 (Lz-0), 0.5 (Lz 0.5), 1 (Lz-1) or 1.5 (Lz-1.5), mg Lz/bird/day] for 12 weeks. Sperm quality variables and plasma testosterone and estradiol concentrations were assessed from the first to the tenth week of the treatment period. Semen samples from the 11th to 12th week were used for artificial insemination and eggs were collected and allotted to assess fertility and hatchability rates. Relative abundance of hypothalamic and pituitary GnRH, LH and FSH mRNA was evaluated at the end of 12th week. The results indicated that total and forward sperm motility as well as egg hatchability rate were greater in the Lz-0.5 group. Greater sperm concentrations, ejaculate volume, sperm plasma membrane integrity, testis index and fertility rates were recorded for both Lz-0.5 and Lz-1 groups compared with the Lz-0 group (P<0.05). Body weight, percentage of sperm abnormalities, and sperm plasma membrane functionality were not affected by treatment. Testosterone and estradiol concentrations were negatively related with greater testosterone concentrations in the Lz-1.5 group which had lesser estradiol concentrations. Relative mRNA transcript abundance for GnRH, LH and FSH was Lz dose responsive being greater in the treated groups; however, this trend plateaued for GnRH and for the relative abundance of both LH and FSH mRNA was less in the Lz-1.5 group than the other treatment groups. It is concluded that Lz may be an effective treatment to improve age related post-peak reproductive performance of roosters. PMID- 28578790 TI - The Role of Interneurons in Autism and Tourette Syndrome. AB - The brain includes multiple types of interconnected excitatory and inhibitory neurons that together allow us to move, think, feel, and interact with the environment. Inhibitory interneurons (INs) comprise a small, heterogeneous fraction, but they exert a powerful and tight control over neuronal activity and consequently modulate the magnitude of neuronal output and, ultimately, information processing. IN abnormalities are linked to two pediatric psychiatric disorders with high comorbidity: autism spectrum disorder (ASD) and Tourette syndrome (TS). Studies probing the basis of this link have been contradictory regarding whether the causative mechanism is a reduction in number, dysfunction, or gene aberrant expression (or a combination thereof). Here, we integrate different theories into a more comprehensive view of INs as responsible for the symptomatology observed in these disorders. PMID- 28578789 TI - Unravelling and Exploiting Astrocyte Dysfunction in Huntington's Disease. AB - Astrocytes are abundant within mature neural circuits and are involved in brain disorders. Here, we summarize our current understanding of astrocytes and Huntington's disease (HD), with a focus on correlative and causative dysfunctions of ion homeostasis, calcium signaling, and neurotransmitter clearance, as well as on the use of transplanted astrocytes to produce therapeutic benefit in mouse models of HD. Overall, the data suggest that astrocyte dysfunction is an important contributor to the onset and progression of some HD symptoms in mice. Additional exploration of astrocytes in HD mouse models and humans is needed and may provide new therapeutic opportunities to explore in conjunction with neuronal rescue and repair strategies. PMID- 28578793 TI - Medium to long-term results of 130 Ankle Evolutive System total ankle replacements-Inferior survival due to peri-implant osteolysis. AB - BACKGROUND: The study reports the medium to long-term results of 130 Ankle Evolutive System total ankle replacements operated at a single-centre. Previously high amount of peri-implant osteolysis was reported from the same material. METHODS: Between 2002 and 2008 one hundred and thirty consecutive ankles replaced with AES ankle prosthesis were followed both radiologically and clinically. RESULTS: The five-year survival was 87.3% (95% confidence interval (CI) 80.0 92.0%), and ten-year survival 74.9% (95% confidence interval (CI) 65.4-82.2%) at a median follow-up time of 96 months (range 2-161; 8 years). Peri-implant osteolysis was found in 91 (70%) ankles, marked in 78 (60%). 44 ankles (34%) have been revised by filling of the cavities, 24 (18%) by fusion, and 6 by further replacement, resulting in the revision rate of 58%. Osteolysis was the main reason for all revisions. The improvement of the Kofoed Score and pain points was significant (all p<0.0001), and the subjective patient satisfaction was good. CONCLUSIONS: Outcome of the current study was seriously affected by osteolysis and is inferior compared to previous reports. PMID- 28578794 TI - Results at a minimum follow-up of 5 years of a ligaments-compatible total ankle replacement design. AB - BACKGROUND: A new design of 3-part ankle replacement was developed to achieve compatibility with the natural ligaments by allowing certain fibers to remain isometric during passive motion. METHODS: We evaluate 75 ankle prostheses implanted from July 2003 to December 2008, at a mean follow-up 6.5+/-1.1years (range 5-9 years). The mean age at surgery was 62+/-13years (range 29-82). RESULTS: The mean AOFAS scores achieved at pre-op and at last follow-up were respectively 37+/-5 (23-45) and 78+/-8 (64-98). (p<0.001). Clinical range of motion of the ankle measured by goniometer pre op was 1 degrees +/-2 of dorsiflexion and 12 degrees +/-4 degrees of plantarflexion; at last follow-up range of motion increased to 6 degrees +/-5 degrees in dorsiflexion (p<0.01) and 18 degrees +/-7 degrees in plantarflexion (p<0.05). Radiographs showed no loosening and little signs of radiolucency. Two revisions necessitated component removal, neither for implant loosening. The overall survival rate was 97.3%. CONCLUSIONS: Function and Range-of-motion showed significant improvements. These results demonstrate that ligaments-compatible shaped talar and tibial components, with a fully conforming interposed meniscal bearing, can provide satisfactory survival rates and clinical outcomes in the middle term. PMID- 28578795 TI - Heterotopic ossification after total ankle replacement: The role of prosthesis alignment. AB - BACKGROUND: The aetiology of heterotopic ossifications (HO) after total ankle arthroplasty (TAR) remains controversial. The aim of the study was to evaluate the prevalence and localisation of HO and the effect of alignment. METHODS: 88 TARs with a series of radiological controls and follow-up of 36 months were evaluated. Frontal and sagittal alignment parameters (alfa and beta angle defined by Hintermann) and tibial coverage were evaluated. RESULTS: The prevalence and grading of HO increased over time, mostly in the posterior gutter. Varus alignment correlated with HO increase in the ventral and lateral gutters the first year. A dorsally located rotational centre correlated with total HO growth and HO in the posterior gutter. These correlations were not detected after 3 years, as HO were seen in all prostheses, regardless of alignment. CONCLUSIONS: HO grow over time with a prevalence up to 100% after 3 years. TAR alignment correlates with gutter-specific HO formation within the first year. PMID- 28578797 TI - Editorial for the special issue "total ankle replacement". PMID- 28578796 TI - Are periprosthetic osteolytic lesions in ankle worth bone grafting? AB - BACKGROUND: We retrospectively evaluated the medium-term follow-up of bone grafting due to periprosthetic osteolytic lesions in ankles. METHODS: 34 ankles (32 patients) with total ankle arthroplasty (TAA) underwent re operation. Indications were large periprosthetic osteolytic lesions or continuous growing of the lesions. The osteolytic lesions were imaged by CT before reoperation and once a year after that. The mean CT follow-up after re operation was 3.8 years (range, 2-6.2 years). Patient's clinical outcome was also monitored. RESULTS: Osteolysis continued to progress in 44 bone grafted lesions (68%) in CT follow-up. Pain (p=0.04) and location of the lesion (p=0.03) were associated with progression of osteolysis. In 18 bone grafted osteolytic lesions (28%) the radiological survival remained excellent. 25 out of 34 ankles showed improvement of the function after bone grafting. CONCLUSIONS: There is no established treatment protocol for osteolysis around TAA. Bone grafting is one alternative in the treatment of osteolytic lesions. PMID- 28578798 TI - Identifying the learning curve for total ankle replacement using a mobile bearing prosthesis. AB - BACKGROUND: Total ankle arthroplasty remains a technically demanding surgery highly influenced by the operator experience. However, no consensus exists regarding the ideal number of cases that need to be performed before a surgeon is considered proficient. The aim of this study was to identify the learning curve of a specific replacement system with regards to intraoperative and postoperative outcomes. METHODS: The first 31 patients undergoing total ankle arthroplasty were examined. No additional procedures were performed at the time of the TAA. Intraoperative characteristics, postoperative complications, as well as clinical and radiologic outcomes were assessed with 24-month follow-up. Learning curves, examining the relationship between surgeon experience and patient outcomes, were determined using the Moving Average Method. RESULTS: The operatory time, and the risk of intraoperative fractures decreased with increasing surgeon experience with the learning curve stabilizing after the 14th and 24th patient, respectively. Furthermore, there appeared to be a learning curve associated with most of the important clinical and radiological outcomes. The number of patients required to stabilize the learning curve for the VAS, ROM, and AOFAS was 11, 14 and 28, respectively. Radiographically, there appeared to be a learning curve of 22 patients required to stabilize the tibio-talar ratio. There was no learning curve associated with the SF-12 PCS and MCS as well as the alpha-, beta-, and gamma-angle. CONCLUSION: This study demonstrates that a surgical learning curve does indeed exist when performing TAA. Most of the operative variables as well as clinical and radiological outcomes stabilize after a surgeon has performed 28 cases. PMID- 28578799 TI - Tibial slope in total ankle arthroplasty: Anterior or lateral approach. AB - BACKGROUND: A new total ankle arthroplasty (TAA) system performed through a lateral approach provides direct visualization of the centre of rotation, allowing for accurate reconstruction of the joint alignment and less bone resection. Radiographic references are needed to describe deformities and plan the surgical procedures. The tibial slope is an important factor when treating malalignment. The aim of this study is to show if there is any difference regarding the post-operative tibial slope (beta angle) measurement comparing a fixed-bearing TAA through a lateral approach and a mobile-bearing TAA through an anterior approach. METHODS: The study included 217 ankles. Between May 2011 and April 2015, 77 patients underwent a TAA with a mobile-bearing implant through an anterior approach and 45 with a fixed-bearing implant through a lateral approach: in these patients the beta angle was measured 2 and 12 months postoperatively. 95 subjects with unilateral post-traumatic ankle arthritis composed the control group: in these patients we measured the anterior distal tibial angle (ADTA) of the controlateral, non arthritic tibiotalar joint. RESULTS: In the mobile-bearing group, the mean beta angle at 2 and 12 months postoperatively was 86.4+/-3.1 and 86.8+/-3.1 (p-value=0.12). In the fixed-bearing group, the mean beta angle at 2 and 12 months postoperatively was 83.1+/-5.4 and 83.9+/-6.5 (p-value=0.26). A statistically significant difference was found between the beta angle of the two groups. In the control group the mean ADTA was 84.9+/-2.5. A non-statistically significant difference was observed only between beta angle of the fixed-bearing group and the ADTA of the control group. CONCLUSIONS: Regarding the tibial slope, fixed-bearing TAA through a lateral approach showed a more anatomic placement. In contrast, beta angle in mobile-bearing group appeared more reproducible than fixed-bearing group. PMID- 28578800 TI - Geometric analysis of the talus and development of a generic talar prosthetic. AB - BACKGROUND: Trauma to the talus can result in fracture, avascular necrosis and structural collapse. Treatment has been limited to surgical fusion and total ankle arthroplasty. Total ankle arthroplasty may not be an appropriate treatment for avascular necrosis while surgical fusion of the joint limits mobility. Custom made implants have recently been used to address these limitations but have lengthy delays between injury and surgery and higher associated costs. A generic talar prosthesis available in various sizes may serve as a suitable alternative. METHODS: The geometric variation between shapes of individual tali was determined using 3D geometric models of 91 tali created from CT-scan data. Comparisons were done to determine if tali are one shape. The best shape was determined for each sex, and was compared to determine if a unisex implant would be possible. A geometric template for the implant in multiple sizes was created and compared to the models. RESULTS: The average of the average deviation between tali after volume scaling was found to be less than 1mm on the main articulating surfaces. One shape group was found for the talus. The female and male tali were found to be similar and a unisex implant template was created. CONCLUSIONS: Ten generic talar implant sizes were determined to be sufficient to match the size and shape of the 91 tali examined in this study. PMID- 28578801 TI - Sagittal tibiotalar translation and clinical outcomes in mobile and fixed-bearing total ankle replacement. AB - BACKGROUND: Sagittal implant malalignment after total ankle replacement (TAR) has been considered to be a possible cause for premature implant failure. In a prior study, the change over time of the tibiotalar ratio (T-T ratio), which is the ratio between the posterior longitudinal talar length and the full longitudinal talar length, was assessed in 66 TARs where an unconstrained, mobile-bearing implant was implanted. The analysis documented an increase in the T-T ratio between 2 and 6 months post-surgery (on average from 34.6% to 37.2%). We hypothesized that this change might have been related to the presence of a mobile bearing insert. In order to test our hypothesis, we designed a study to compare the translation of the talus in TARs performed with an unconstrained, mobile bearing implant (designated the "Mobile ankle") and those performed with a semi constrained, fixed-bearing implant (designated the "Fixed ankle"). METHODS: The study included 71 consecutive patients (71 ankles) who underwent TAR with the Mobile ankle and 24 consecutive patients (24 ankles) who received the Fixed ankle from May 2011 to December 2014. Patients were assessed clinically and radiologically preoperatively (T0), at 6 months (T2) and 12 months (T3) post surgery. There was also a radiological assessment at 2 months post-surgery (T1). RESULTS: The comparison of the T-T ratio between the two implant groups and over time indicated an interaction between time and group, therefore the changes of the T-T ratio over time were affected by the implant type factor (P<0.001). The changes of the postoperative T-T ratio over time were not significant in the Fixed ankle group (35.7+/-6.7% at T1, T2, and T3; P=1.0 for each pairwise comparison). In the Mobile ankle group, the T-T ratio at 2 months (34.4+/-5.5%) was significantly different to the T-T ratio at 6 months (37.0+/-5.8%; P<0.001; i.e. there was a significant posterior translation of the talus). The AOFAS score increased from preop to 12 months post-surgery in both the Mobile ankle (72.7+/ 12.8 at 12 months; P<0.001) and the Fixed ankle (85.0+/-9.7 at 12 months; P<0.001). CONCLUSION: The significant posterior translation of the talus from 2 to 6 months documented only in the Mobile ankle group may have been associated with the presence of the mobile bearing interface. PMID- 28578802 TI - Spontaneous resolution of posterior ankle joint loose bodies after total ankle replacement: A case report. AB - Late stage ankle osteoarthritis often presents with debilitating pain. It is common to find osteophytes and loose body formation around the joint. Total ankle arthroplasty can preserve joint mobility and pain relieve for such patient. However, when trying to remove the osteophytes and loose bodies at the posterior ankle joint, there is risk of damaging posterior structures such as the neurovascular bundle during the procedure. We are presenting a case where the posterior loose bodies remained untouched during the operation, and patient showed spontaneous resolution of the lesions with time. Patient enjoyed good function outcome after the surgery. PMID- 28578803 TI - Head and neck cancer cell radiosensitization upon dual targeting of c-Abl and beta1-integrin. AB - Integrin-mediated cell adhesion to extracellular matrix (ECM) critically contributes to cancer cell therapy resistance and DNA double strand break (DSB) repair. c-Abl tyrosine kinase has been linked to both of these processes. Based on our previous findings indicating c-Abl hyperphosphorylation on tyrosine (Y) 412 and threonine (T) 735 upon beta1-integrin inhibition, we hypothesized c-Abl tyrosine kinase as an important mediator of beta1-integrin signaling for radioresistance. In a panel of 8 cell lines from different solid cancer types grown in 3D laminin-rich ECM cultures, we targeted beta1 integrin with AIIB2 (mAb) and c-Abl with Imatinib with and without X-ray irradiation and subsequently examined clonogenic survival, residual DSBs, protein expression and phosphorylation. Single or combined treatment with AIIB2 and Imatinib resulted in cell line-dependent cytotoxicity. Intriguingly, we identified a subgroup of this cell line panel that responded with a higher degree of radiosensitization to AIIB2/Imatinib relative to both single treatments. In this subgroup, we observed a non-statistically significant trend between the radioresponse and phospho-c-Abl Y412. Mechanistically, impairment of DNA repair seems to be associated with radiosensitization upon AIIB2/Imatinib and AIIB2/Imatinib-related radiosensitization could be reduced by exogenous overexpression of either wildtype or constitutively active c-Abl forms relative to controls. Our data generated in more physiological 3D cancer cell culture models suggest c-Abl as further determinant of radioresistance and DNA repair downstream of beta1 integrin. For solid cancers, c-Abl phosphorylation status might be an indicator for reasonable Imatinib application as adjuvant for conventional radio(chemo)therapy. PMID- 28578804 TI - Human anterolateral entorhinal cortex volumes are associated with cognitive decline in aging prior to clinical diagnosis. AB - We investigated whether older adults without subjective memory complaints, but who present with cognitive decline in the laboratory, demonstrate atrophy in medial temporal lobe (MTL) subregions associated with Alzheimer's disease. Forty community-dwelling older adults were categorized based on Montreal Cognitive Assessment (MoCA) performance. Total gray/white matter, cerebrospinal fluid, and white matter hyperintensity load were quantified from whole-brain T1-weighted and fluid-attenuated inversion recovery magnetic resonance imaging scans, whereas hippocampal subfields and MTL cortical subregion volumes (CA1, dentate gyrus/CA2/3, subiculum, anterolateral and posteromedial entorhinal, perirhinal, and parahippocampal cortices) were quantified using high-resolution T2-weighted scans. Cognitive status was evaluated using standard neuropsychological assessments. No significant differences were found in the whole-brain measures. However, MTL volumetry revealed that anterolateral entorhinal cortex (alERC) volume-the same region in which Alzheimer's pathology originates-was strongly associated with MoCA performance. This is the first study to demonstrate that alERC volume is related to cognitive decline in undiagnosed community-dwelling older adults. PMID- 28578805 TI - Expression system for heterologous protein expression in the filamentous fungus Aspergillus unguis. AB - Heterologous protein expression in filamentous fungi is advantageous, especially in the context of large scale production of high volume low value recombinant proteins. However, such systems are rare and not available in public domain. A novel filamentous fungus - Aspergillus unguis NII 08123 was used as host for developing a protein expression system. An expression cassette was assembled using A. nidulans glyceraldehyde 3 phosphate dehydrogenase promoter (Pgapd), tryptophan synthase transcription terminator (TtrpC) and hygromycin resistance gene (hph) as selection marker. The enhanced green fluorescent protein (GFP) gene from Aequorea victoria was used as the model test protein for the evaluation of the expression system. The genetic transformation of this novel fungus was optimized through electroporation. Use of heterologous signal peptides resulted in high levels of secreted expression. The fungal host-expression system combination was tested successfully for the expression of the recombinant therapeutic protein-human interferon beta (HuIFNbeta). PMID- 28578806 TI - Bio-mining the forest ecosystem of North East India for identification of antimicrobial metabolites from fungi through submerged fermentation. AB - In this study, fungi isolated from less explored forest soil ecosystem of Northeast India were studied for the production of potential antimicrobial metabolites (AMM). Out of the 68 fungi isolated from forest soil of Manipur, 7 of them showed AMA against the test pathogens. Among them, Aspergillus terreus (IBSD F4) showed the most significant activity against Staphylococcus aureus (ATCC 25923), Bacillus anthracis (IBSD-C370), Pseudomonas fluorescens (ATCC-13525), Salmonella typhimurium (ATCC-14028), Escherichia coli (ATCC-25922) and Candida albicans (ATCC-10231). The active metabolite was harvested from the fermentation broth of Aspergillus terreus and purified by column chromatography and semi preparative-HPLC. The compound was identified as 'Sclerotionigrin A' on the basis of UV-vis spectra, MS and NMR analyses. This compound was reported for the first time from A. terreus. The study highlights, the importance of exploring microbes from forest soil for identification of bioactive metabolites for future drug development. PMID- 28578807 TI - Bio-oil from fast pyrolysis of lignin: Effects of process and upgrading parameters. AB - Effects of process parameters on the yield and chemical profile of bio-oil from fast pyrolysis of lignin and the processes for lignin-derived bio-oil upgrading were reviewed. Various process parameters including pyrolysis temperature, reactor types, lignin characteristics, residence time, and feeding rate were discussed and the optimal parameter conditions for improved bio-oil yield and quality were concluded. In terms of lignin-derived bio-oil upgrading, three routes including pretreatment of lignin, catalytic upgrading, and co-pyrolysis of hydrogen-rich materials have been investigated. Zeolite cracking and hydrodeoxygenation (HDO) treatment are two main methods for catalytic upgrading of lignin-derived bio-oil. Factors affecting zeolite activity and the main zeolite catalytic mechanisms for lignin conversion were analyzed. Noble metal based catalysts and metal sulfide catalysts are normally used as the HDO catalysts and the conversion mechanisms associated with a series of reactions have been proposed. PMID- 28578808 TI - Real-time monitoring of intracellular redox changes in Methylococcus capsulatus (Bath) for efficient bioconversion of methane to methanol. AB - This study aimed to develop a novel method for real-time monitoring of the intracellular redox states in a methanotroph Methylococcus capsulatus, using Peredox as a genetically encoded fluorescent sensor of the NADH:NAD+ ratio. As expected, the fluorescence derived from the Peredox-expressing M. capsulatus transformant increased by supplementation of electron donor compounds (methane and formate), while it decreased by specifically inhibiting the methanol oxidation reaction. Electrochemical measurements confirmed that the Peredox fluorescence reliably represents the intracellular redox changes. This study is the first to construct a reliable redox-monitoring method for methanotrophs, which will facilitate to develop more efficient methane-to-methanol bioconversion processes. PMID- 28578809 TI - Formulation and utilisation of spent anaerobic digestate fluids for the growth and product formation of single cell algal cultures in heterotrophic and autotrophic conditions. AB - Spent anaerobically digested effluents of agricultural origin were collected and treated using membrane filtration to achieve three-large particle free-nutrient streams of N:P ratios of 16.53, 3.78 and 14.22. Three algal species were grown on these streams, achieving good levels of bioremediation of digester fluids simultaneously with biomass and associated end product formation. Nannochloropsis oceanica and Scenedesmus quadricuada, where proven highly effective in remediating the streams achieving ammonia and phosphate reduction over 60% while for Schizochytrium limacinum SR21 these serve as an ideal production medium for lipids and biomass reaching 16.70w/w% and 1.42gL-1 correspondingly. These processes thus provide treatment of sludge, avoiding the disposal problems by land spreading. The solid components are nutrient depleted but rich in organic matter as a soil enhancer, while the fluids rich in nutrients can be efficiently utilised for growth to generate high value materials of microalgae facilitating water reclamation. PMID- 28578810 TI - Imaging Intra-abdominal Burkitt's Lymphoma: From Discrete Bowel Wall Thickening to Diffuse Soft Tissue Infiltration. AB - Burkitt's lymphoma is a highly aggressive non-Hodgkin's B-cell lymphoma, which often presents with intra-abdominal involvement. The purpose of this pictorial review is to illustrate the various intra-abdominal imaging findings of Burkitt's lymphoma. Extranodal disease at presentation is common, including involvement of the bowel, stomach, pancreas, spleen, and mesentery. PMID- 28578811 TI - Clinical Decision Support in Computerized Providers' Order Entry for Imaging Tests in Canada. PMID- 28578812 TI - Determinants of duration of untreated psychosis among first-episode psychosis patients in Denmark: A nationwide register-based study. AB - BACKGROUND: Information on determinants of duration of untreated psychosis (DUP) is still needed to inform campaigns targeting people with first episode psychosis (FEP). This nation-wide study analysed the association between demographic factors (age, sex, ethnicity, marital status, and geographic area), premorbid and illness-related factors (global functional level, substance misuse, and contact to police), healthcare factors (referral source and first FEP contact) and DUP. METHOD: The study population of 1266 patients aged 15-25years diagnosed with FEP (ICD10 F20.0-F20.99) was drawn from the Danish National Indicator Project during 2009-2011. The study population was combined with data from national administrative registers. A multinomial regression model was estimated to analyse the impact of demographic, premorbid and illness-related, and healthcare factors on DUP. RESULTS: One third of the population had a DUP below 6months. DUP longer than 12months was associated with older age at onset, being female, having cannabis misuse, and living in peripheral municipalities. Being charged by the criminal authorities during one year before FEP was associated with a DUP over 6months. CONCLUSION: DUP is related to a number of demographic, premorbid and healthcare factors. These findings suggest that future information campaigns should focus on increasing the awareness of early signs of psychosis not only among mental health professionals but also other professionals in contact with adolescents such as the police. It may also be useful to consider how to target information campaigns towards persons living in peripheral areas. PMID- 28578813 TI - Multiclass method for the determination of pharmaceuticals and personal care products in compost from sewage sludge using ultrasound and salt-assisted liquid liquid extraction followed by ultrahigh performance liquid chromatography-tandem mass spectrometry analysis. AB - An analytical method for the analysis of 16 pharmaceuticals and personal care products in compost from sewage sludge is successfully validated. Ultrasound assisted extraction with a mixture of acetonitrile:ethyl acetate (1:1, v/v) containing 10% (v/v) of acetic acid was carried out. Two cycles of extraction of 10min were applied. A clean-up of the extracts using salt-assisted liquid-liquid extraction (SALLE) was also included. Experimental design was used for the optimization of the main parameters involved in the extraction and cleaned-up steps. The chromatographic separation was carried out by ultrahigh performance liquid chromatography using a mobile phase gradient mixture of a 13mM buffer ammonium formate solution (pH 9.25) (solvent A) and methanol (solvent B). An ACQUITY UPLC(r) BEH C18 column (1.7MUm; 2.1*50mm) column was used. Analytes were separated in less than 11min. The compounds were detected and quantified using single reaction monitoring electrospray tandem mass spectrometry. The limits of detection calculated ranged from 0.5 to 4ngg-1d.w., and the limits of quantification from 2 to 13ngg-1d.w. Recoveries from 93% to 111%, with relative standar deviations lower than 11% in all cases, were obtained. The method was applied to natural compost samples. High concentrations of some analytes were found. Ketoprofen (510ngg-1d.w.), methylparaben (240ngg-1d.w.), diclofenac (175ngg-1d.w.) and flufenamic acid (128ngg-1d.w.) were the most abundant. PMID- 28578814 TI - Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. AB - BACKGROUND: One of the main complications in patients with muscular dystrophies is cardiac dysfunction. The literature on cardiac involvement in patients with Fukuyama congenital muscular dystrophy (FCMD) is limited. AIM: To compare cardiac involvement between patients with FCMD and Duchenne muscular dystrophy (DMD). METHODS: We compared cardiac involvement between 30 patients with FCMD and 181 patients with DMD using echocardiography and serum biomarkers. All patients were receiving regular checkups at Kobe University Hospital. We used single regression analysis to compare echocardiographic parameters, age, and serum biomarkers. RESULTS: Almost all clinical and echocardiographic parameters were lower in patients with FCMD than DMD. The brain natriuretic peptide concentration in patients with FCMD showed no correlation with age or left ventricular ejection fraction (r=0.231, p=0.22 and r=0.058, p=0.76, respectively). A log-rank test revealed that the risk of left ventricular systolic dysfunction was lower in patients with FCMD than DMD (p=0.046, hazard ratio=0.348). CONCLUSION: The clinical progression of cardiac dysfunction is significantly milder in patients with FCMD than DMD, while skeletal muscle involvement is significantly worse in patients with FCMD. These data suggest that the pathophysiological findings of FCMD can be explained by less severe cardiac dysfunction in FCMD than DMD. PMID- 28578815 TI - Three years' experience with the first pediatric hospice in Asia. AB - OBJECTIVE: Pediatric hospice has been the adoption of several service provision models in highly developed countries such as UK, Germany, Australia or Canada for a few decades, yet it has seldom been the case in the Asian Continent. This study aimed to evaluate the newest challenge for the children with Life-threatening illness (LTI) and described the characteristic of pediatric palliative care at the first pediatric hospice in Japan. METHODS: A retrospective review of all patients at our pediatric hospice in these three years was conducted. Of the 294 cases reviewed, 269 cases were eligible for analysis. RESULTS: We reviewed 269 patients admitted during the first three years. Most patients required intensive medical intervention. Patients were hospitalized in our pediatric hospice not only for end-of-life care (EOL), but also for respite care. Only 7% of the patients were with cancer. To support children and family to make the most of their time together, we provided a range of medical and recreational care. It is expected that the pediatric hospice will extend and establish cooperation with other hospitals or community services. CONCLUSION: Three years' experience of pediatric palliative care at the first pediatric hospice in the Asian Continent is encouraging. Further experience and improved communication with other pediatric service providers as well as their education in palliative care will enhance the recognition of the capacity of our hospice and support the needs of more children. Furthermore, we would like to introduce the idea of pediatric hospice and spread it throughout the Asian Continent in the future. PMID- 28578816 TI - Characteristics of headaches in Japanese elementary and junior high school students: A school-based questionnaire survey. AB - PURPOSE: Few studies have investigated pediatric headaches in Japan. Thus, we examined the lifetime prevalence and characteristics of headaches among elementary and junior high school students in Japan. METHODS: In this school based study, children aged 6-15years completed a questionnaire based on the diagnostic criteria of the International Classification of Headache Disorders 3beta to assess headache characteristics and related disability. RESULTS: Of the 3285 respondents, 1623 (49.4%) experienced headaches. Migraine and tension-type headaches (TTH) were reported by 3.5% and 5.4% of elementary school students, respectively, and by 5.0% and 11.2% of junior high school students. Primary headaches increased with age. Compared with TTH sufferers, the dominant triggers in migraine sufferers were hunger (odds ratio=4.7), sunny weather (3.3), and katakori (neck and shoulder pain) (2.5). Compared with TTH, migraine caused higher headache-related frustration (P=0.010) as well as difficulty concentrating (P=0.017). Migraine-related disability was greater among junior high school students (feeling fed up or irritated, P=0.028; difficulty concentrating, P=0.016). TTH-related disability was also greater among junior high school students (feeling fed up or irritated, P=0.035). Approximately half of the students who complained of headache-related disability were not receiving medical treatment. CONCLUSION: This is the first detailed study of headaches in Japanese children to include elementary school students. Nearly 50% of the school children reported headaches and the disruption of daily activities caused by migraine was higher among junior high students than elementary school students. PMID- 28578817 TI - Childhood idiopathic spinal cord infarction: Description of 7 cases and review of the literature. AB - OBJECTIVES: To describe the clinical course, neuroimaging findings and functional outcome of idiopathic spinal cord infarction (SCI) in adolescents. METHODS: Retrospective and descriptive analyses of seven patients with idiopathic SCI and 50 additional cases from the literature were included. Data collected concerned clinical presentation, MRI findings, initial diagnosis, treatments and functional outcome at the last medical visit. RESULTS: Mean age at presentation was 13.2years (range 13-15). All patients presented a sudden and painful acute myelopathy with <24h time to maximal symptoms manifestation. A suspected trigger related to a minor effort was reported in 3/7 cases. Six patients presented with paraplegia, one with paraparesis. All had bladder dysfunction needing catheterization. Three patients had an initial misdiagnosis. Initial MRI was considered as normal in 2 cases. In the 5 other cases, T2-weighted-MR images showed hyperintensity within the thoracolumbar spinal cord, affecting mostly the anterior spinal artery territory. Evidence for associated spinal growth dystrophy were present in 6/7 cases. Mean follow-up time was 27.4months (range 3-46): 2 patients recovered autonomous ambulation, 4 patients regained walking ability with aids and one child (the shortest follow-up) remained wheelchair-dependent. A neurogenic bladder was still reported in 6/7 children at the last visit. Complementary analyses with literature cases were consistent with the findings obtained in our cohort. CONCLUSION: Idiopathic SCI typically occurs in adolescence with a rapid onset and painful acute myelopathy. The MRI shows a T2 hyperintense signal within the spinal cord and provides evidence for an ischemic mechanism. Etiology remains unclear in most cases even though some specific risk factors for this age must play an important role in the pathogenesis, such as mechanical constraints on the immature spine. PMID- 28578818 TI - Clinical milestones in Parkinson's disease: A 7-year population-based incident cohort study. AB - INTRODUCTION: Clinical staging of Parkinson's disease (PD) is important for patient management and prognosis. The non-motor and functional features visual hallucinations, recurrent falls, dementia and nursing home placement are currently not included in clinical staging schemes, but have been suggested as clinical milestones with important prognostic implications in advanced PD. In this study, we sought to evaluate the potential of these four milestone events for clinical staging and prognosis during the early years of the disease. METHODS: We recruited 185 patients with incident PD and monitored prospectively every six months through seven years for emergence and consequences of four clinical milestones. RESULTS: One or more milestones were reached in 53.0%. Of the patients who reached the milestones, visual hallucinations appeared after a median of 3.3 (interquartile range 1.3-4.9) years from diagnosis, recurrent falls after 3.8 (2.8-5.2) years, dementia after 4.0 (2.1-4.8) years and nursing home placement after 5.4 (3.9-6.7) years. Presence of any milestone was associated with occurrence of other milestones (relative risks 1.9-6.3; all p <= 0.001). Experiencing two or more milestones increased the risk of death during the study (relative risk 2.7, p = 0.03). CONCLUSIONS: In early PD, visual hallucinations, recurrent falls, dementia and nursing home placement appear closely interrelated, possibly reflecting a shared neuropathological disease stage. All events convey important and sinister information on PD status and prognosis and are relatively easily accessible during routine clinical consultations. Therefore, they appear highly useful as clinical PD milestones and could possibly be incorporated into a novel disease rating scale. PMID- 28578819 TI - Home based training for dexterity in Parkinson's disease: A randomized controlled trial. AB - BACKGROUND: Patients with Parkinson's disease exhibit disturbed manual dexterity. This impairment leads to difficulties in activities of daily living, such as buttoning a shirt or hand-writing. The aim of the present study was to investigate the effectiveness of a home-based dexterity program on fine motor skills in a single-blinded, randomized controlled trial, in patients with Parkinson's disease. METHODS: One hundred and three patients with Parkinson's disease (aged between 48 and 80 years, Hoehn & Yahr stage I-IV) were randomized to either a home-based dexterity program (HOMEDEXT) or Thera-band program. All patients trained over a period of 4 weeks, 5 times/week, 30 min for each session. A baseline, post-intervention, and follow-up assessment (12 weeks later, time period without intervention) were done. The primary outcome measure was dexterity as measured with the Nine Hole peg test (9-HPT). Secondary outcome measures included strength, motor parkinsonian symptoms, dexterity-related activities of daily living (ADL) and Health-related Quality of Life (HrQoL). RESULTS: There was a significant difference in favor of the HOMEDEXT group as compared to the Thera band group on the primary outcome 9-HPT (p = 0.006) and dexterity-related ADL (p = 0.02) at post intervention. No significant differences were found for the other outcomes, nor at follow-up. CONCLUSION: This is the first randomized controlled trial showing that an intensive, task specific home-based dexterity program significantly improved fine motor skills in Parkinson's disease. The effect generalized to dexterity-related ADL functions. As these improvements did not sustain, the finding suggest that continuous training is required to maintain the benefit. PMID- 28578820 TI - Formulas for Calculated Osmolarity and Osmolal Gap: A Study of Diagnostic Accuracy. AB - BACKGROUND: The osmolal gap has been used for decades to screen for exposure to toxic alcohols. However, several issues may affect its reliability. We aimed to develop equations to calculate osmolarity with improved performance when used to screen for intoxication to toxic alcohols. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 7,525 patients undergoing simultaneous measurements of osmolality, sodium, potassium, urea, glucose, and ethanol or undergoing similar measurements performed within 30 minutes of a measurement of toxic alcohol levels at a single tertiary-care center from April 2001 to June 2016. Patients with detectable toxic alcohols were excluded. INDEX TEST: Equations to calculate osmolarity using multiple linear regression. OUTCOMES: The performance of new equations compared with published equations developed to calculate osmolarity, and to diagnose toxic alcohol intoxications more accurately. RESULTS: We obtained 7,525 measurements, including 100 with undetectable toxic alcohols. Among them, 3,875 had undetectable and 3,650 had detectable ethanol levels. In the entire cohort, the best equation to calculate osmolarity was 2.006*Na + 1.228*Urea + 1.387*Glucose + 1.207*Ethanol (values in mmol/L, R2=0.96). A simplified equation, 2.0*Na + 1.2*Urea + 1.4*Glucose + 1.2*Ethanol, had a similar R2 with 95% of osmolal gap values between -10.9 and 13.8. In patients with undetectable ethanol concentrations, the range of 95% of osmolal gap values was narrower than previous published formulas, and in patients with detectable ethanol concentrations, the range was narrower or similar. We performed a subanalysis of 138 cases for which both the toxic alcohol concentration could be measured and the osmolal gap could be calculated. Our simplified equation had superior diagnostic accuracy for toxic alcohol exposure. LIMITATIONS: Single center, no external validation, limited number of cases with detectable toxic alcohols. CONCLUSIONS: In a large cohort, coefficients from regression analyses estimating the contribution of glucose, urea, and ethanol were higher than 1.0. Our simplified formula to precisely calculate osmolarity yielded improved diagnostic accuracy for suspected toxic alcohol exposures than previously published formulas. PMID- 28578821 TI - Zika Virus: Mechanisms of Infection During Pregnancy. AB - Immune status changes during pregnancy, with pro-inflammatory and anti inflammatory contexts at different stages, making pregnant women potentially more susceptible to various infections. Infection by Zika virus during pregnancy can cause developmental damage to the fetus, and the altered immune response during pregnancy could contribute to disease during Zika infection. PMID- 28578822 TI - Survival time with pacemaker implantation for dogs diagnosed with persistent atrial standstill. AB - OBJECTIVES: To evaluate survival time in dogs with persistent atrial standstill after pacemaker implantation and to compare the survival times for cardiac related vs. non-cardiac deaths. Secondary objectives were to evaluate the effects of breed and the presence of congestive heart failure (CHF) at the time of diagnosis on survival time. ANIMALS: Twenty dogs with persistent atrial standstill and pacemaker implantation. METHODS: Medical records were searched to identify dogs diagnosed with persistent atrial standstill based on electrocardiogram that underwent pacemaker implantation. Survival after pacemaker implantation was analyzed using the Kaplan-Meier method. RESULTS: The median survival time after pacemaker implantation for all-cause mortality was 866 days. There was no significant difference (p=0.573) in median survival time for cardiac (506 days) vs. non-cardiac deaths (400 days). The presence of CHF at the time of diagnosis did not affect the survival time (P=0.854). No difference in median survival time was noted between breeds (P=0.126). CONCLUSIONS: Dogs with persistent atrial standstill have a median survival time of 866 days with pacemaker implantation, though a wide range of survival times was observed. There was no difference in the median survival time for dogs with cardiac-related deaths and those without. Patient breed and the presence of CHF before pacemaker implantation did not affect median survival time. PMID- 28578823 TI - [Chemotherapy for colorectal cancer: Pragmatic assessment of prescription changes and relative dose intensity]. AB - INTRODUCTION: Chemotherapy induced toxicities can generate changes in prescribing and relative dose intensity which have an impact on therapeutic efficacy. METHOD: This is a prospective observational study performed in hepato-gastroenterology department for 6 months. All patients treated for colorectal cancer and beginning a protocol with at least one parenteral drug have been included. RESULTS: Among the 48 patients enrolled, 85.4% of them had at least one prescription change, which concerned 30.3% of 238 cycles. Of the 766 analyzed prescription lines, 16.6% of them were postponed and/or 6.7% had modified dosage and/or 5.6% were stopped prematurely. Grades 2 to 4 adverse reactions were responsible for at least one change prescribing to 64.6% of patients and 17.6% of cycles. Toxicity induced prescription changes were mainly due to clinical toxicities (79.3%). The rate of patients with a relative dose intensity greater than 70% was 92.9% in adjuvant state, 66.7% and 62.5% in metastatic state first line and second and subsequent line. CONCLUSION: High-grade clinical toxicities are the main chemotherapy prescription change pattern in colorectal cancer. Knowledge of toxicities before the patient's arrival is expected to target patients for which the drug preparation can be anticipated and for which a cycle postponement, dose adjustment or discontinuation is necessary. PMID- 28578824 TI - Improving the malaria transmission-blocking activity of a Plasmodium falciparum 48/45 based vaccine antigen by SpyTag/SpyCatcher mediated virus-like display. AB - Malaria is a devastating disease caused by Plasmodium parasites, resulting in almost 0.5 million deaths per year. The Pfs48/45 protein exposed on the P. falciparum sexual stages is one of the most advanced antigen candidates for a transmission-blocking (TB) vaccine in the clinical pipeline. However, it remains essential to identify an optimal vaccine formulation that can facilitate induction of a long-lasting TB anti-Pfs48/45 response. Here we report on the development and evaluation of two Pfs48/45-based virus-like particle (VLP) vaccines generated using the AP205 SpyTag/Catcher VLP system. Two different recombinant proteins (SpyCatcher-R0.6C and SpyCatcher-6C), comprising the Pfs48/45-6C region, were covalently attached to the surface of Spy-tagged Acinetobacter phage AP205 VLPs. Resulting Pfs48/45-VLP complexes appeared as non aggregated particles of ~30nm, each displaying an average of 216 (R0.6C) or 291 (6C) copies of the antigens. Both R0.6C and 6C VLP conjugates were strongly reactive with a monoclonal antibody (mAb45.1) targeting a conformational TB Pfs48/45 epitope, suggesting that the TB epitope is accessible for immune recognition on the particles. To select the most suitable vaccine formulation for downstream clinical studies the two VLP vaccines were tested in CD1 mice using different adjuvant formulations. The study demonstrates that VLP-display of R0.6C and 6C significantly increases antigen immunogenicity when using Montanide ISA 720 VG as extrinsic adjuvant. PMID- 28578826 TI - Estimating the number of children in formal alternative care: Challenges and results. AB - Given the relatively large body of literature documenting the adverse impacts of institutionalization on children's developmental outcomes and well-being, it is essential that countries work towards reducing the number of children in alternative care (particularly institutional care), and, when possible, reunite children with their families. In order to do so, reliable estimates of the numbers of children living in such settings are essential. However, many countries still lack functional administrative systems for enumerating children living outside of family care. The purpose of this paper is to provide a snapshot of the availability and coverage of data on children living in residential and foster care from some 142 countries covering more than 80 per cent of the world's children. Utilizing these country-level figures, it is estimated that approximately 2.7 million children between the ages of 0 and 17 years could be living in institutional care worldwide. Where possible, the article also presents regional estimates of the number of children living in residential and foster care. This work represents an important step to systematically identify and compile sources of data on children in alternative care and provides updated global and regional estimates on the magnitude of the issue. Its findings contribute to raising awareness of the urgent need to strengthen the capacity of countries to improve national systems for counting, monitoring and reporting on these vulnerable children. PMID- 28578825 TI - The impact of a clinical pathway on patient postoperative recovery following pancreaticoduodenectomy. AB - BACKGROUND: Pancreaticoduodenectomies (PD) are complex surgical procedures. Clinical pathways (CPW) are surgical process improvement tools that guide postoperative recovery and are associated with high quality care. Our objective was to report the quality of surgical care following implementation of a CPW. METHODS: We developed and implemented a CPW for patients undergoing PD at a single high volume hepato-pancreato-biliary (HPB) centre. Patient outcomes were collected prospectively during the implementation period. A comparator cohort was selected by identifying patients that underwent a PD prior to CPW development. RESULTS: 122 patients underwent a PD during the CPW implementation period; 83 patients were initiated on the CPW. 74 patients underwent PD during the 12-month period prior to the CPW. The median hospital stay decreased after the implementation of the CPW (11 vs 8 days, p < 0.01) with no significant changes to mortality, morbidity, reoperation, or readmission rates. In-hospital complications were significantly higher in patients that were not initiated on the CPW (54% vs 74%, p = 0.03). CONCLUSION: Results suggest the CPW reduced variability and allowed a greater proportion of patients to receive all elements of care, resulting in improved quality and efficiency of care based on current best evidence recommendations. PMID- 28578827 TI - A phylogenetic framework for the kingdom Fungi based on 18S rRNA gene sequences. AB - The usage of molecular phylogenetic approaches is critical to advance the understanding of systematics and community processes in the kingdom Fungi. Among the possible phylogenetic markers (or combinations of them), the 18S rRNA gene appears currently as the most prominent candidate due to its large availability in public databases and informative content. The purpose of this work was the creation of a reference phylogenetic framework that can serve as ready-to-use package for its application on fungal classification and community analysis. The current database contains 9329 representative 18S rRNA gene sequences covering the whole fungal kingdom, a manually curated alignment, an annotated and revised phylogenetic tree with all the sequence entries, updated information on current taxonomy, and recommendations of use. Out of 201 total fungal taxa with more than two sequences in the dataset, 179 were monophyletic. From another perspective, 66% of the entries had a tree-derived classification identical to that obtained from the NCBI taxonomy, whereas 34% differed in one or the other rank. Most of the differences were associated to missing taxonomic assignments in NCBI taxonomy, or the unexpected position of sequences that positioned out of their theoretically corresponding clades. The strong correlation observed with current fungal taxonomy evidences that 18S rRNA gene sequence-based phylogenies are adequate to reflect genealogy of Fungi at the levels of order and above, and justify their further usage and exploration. PMID- 28578828 TI - Complete resection of locally advanced ovarian carcinoma fixed to the pelvic sidewall and involving external and internal iliac vessels. AB - OBJECTIVE: Locally advanced ovarian carcinomas may be fixed to the pelvic sidewall, and although these often involve the internal iliac vessels, they rarely involve the external iliac vessels. Such tumors are mostly considered inoperable. We present a surgical technique for complete resection of locally advanced ovarian carcinoma fixed to the pelvic sidewall and involving external and internal iliac vessels. METHODS: A 69-year-old woman presented with ovarian carcinoma fixed to the right pelvic sidewall, which involved the right external and internal iliac arteries and veins and the right lower ureter, rectum, and vagina. We cut the external iliac artery and vein at the bifurcation and at the inguinal ligament to resect the external artery and vein. Then, we reconstructed the arterial and venous supplies of the right external artery and vein with grafts. After creating a wide space immediately inside of the sacral plexus to allow the tumor fixed to pelvic sidewall with the internal iliac vessels to move medially, we performed total internal iliac vessel resection. RESULTS: We achieved complete en bloc tumor resection with the right external and internal artery and vein, right ureter, vagina, and rectum adhering to the tumor. There were no intra- or postoperative complications, such as bleeding, graft occlusion, infection, or limb edema. CONCLUSION: Exfoliation from the sacral plexus and total resection with external and internal iliac vessels enables complete resection of the tumor fixed to the pelvic sidewall. PMID- 28578829 TI - Understanding and Improving Recruitment to Randomised Controlled Trials: Qualitative Research Approaches. AB - CONTEXT: The importance of evidence from randomised trials is now widely recognised, although recruitment is often difficult. Qualitative research has shown promise in identifying the key barriers to recruitment, and interventions have been developed to reduce organisational difficulties and support clinicians undertaking recruitment. OBJECTIVE: This article provides an introduction to qualitative research techniques and explains how this approach can be used to understand-and subsequently improve-recruitment and informed consent within a range of clinical trials. EVIDENCE ACQUISITION: A literature search was performed using Medline, Embase, and CINAHL. All studies with qualitative research methods that focused on the recruitment activity of clinicians were included in the review. EVIDENCE SYNTHESIS: The majority of studies reported that organisational difficulties and lack of time for clinical staff were key barriers to recruitment. However, a synthesis of qualitative studies highlighted the intellectual and emotional challenges that arise when combining research with clinical roles, particularly in relation to equipoise and patient eligibility. To support recruiters to become more comfortable with the design and principles of randomised controlled trials, interventions have been developed, including the QuinteT Recruitment Intervention, which comprises in-depth investigation of recruitment obstacles in real time, followed by implementation of tailored strategies to address these challenges as the trial proceeds. CONCLUSIONS: Qualitative research can provide important insights into the complexities of recruitment to trials and inform the development of interventions, and provide support and training initiatives as required. Investigators should consider implementing such methods in trials expected to be challenging or recruiting below target. PATIENT SUMMARY: Qualitative research is a term used to describe a range of methods that can be implemented to understand participants' perspectives and behaviours. Data are gathered from interviews, focus groups, or observations. In this review, we demonstrate how this approach can be used to understand-and improve-recruitment to clinical trials. Taken together, our review suggests that healthcare professionals can find recruiting to trials challenging and require support with this process. PMID- 28578830 TI - Understanding perspectives on major system change: A comparative case study of public engagement and the implementation of urgent and emergency care system reconfiguration. AB - OBJECTIVES: Major changes have been made to how emergency care services are configured in several regions in the Republic of Ireland. This study investigated the hypothesis that engagement activities undertaken prior to these changes influenced stakeholder perspectives on the proposed changes and impacted on the success of implementation. METHODS: A comparative case-study approach was used to explore the changes in three regions. These regions were chosen for the case study as the nature of the proposals to reconfigure care provision were broadly similar but implementation outcomes varied considerably. Documentary analysis of reconfiguration planning reports was used to identify planned public engagement activities. Semi-structured interviews with 74 purposively-sampled stakeholders explored their perspectives on reconfiguration, engagement activities and public responses to reconfiguration. Framework analysis was used, integrating inductive and deductive approaches. RESULTS: Approaches to public engagement and success of implementation differed considerably across the three cases. Regions that presented the public with the reconfiguration plan alone reported greater public opposition and difficulty in implementing changes. Engagement activities that included a range of stakeholders and continued throughout the reconfiguration process appeared to largely address public concerns, contributing to smoother implementation. CONCLUSIONS: The presentation of reconfiguration reports alone is not enough to convince communities of the case for change. Genuine, ongoing and inclusive engagement offers the best opportunity to address community concerns about reconfiguration. PMID- 28578831 TI - Dependence on acyl chain length of energy and volume parameters of the gel to liquid-crystalline transition of 1,2-diacylphosphatidylcholines. Theoretical consideration. AB - The effect of acyl chain length on energy and volume parameters of gel to liquid crystal transitions in phospholipids is analyzed. It is demonstrated that simple structural and thermodynamic considerations allow predicting some thermodynamic and volume characteristics of transitions and their dependencies on the acyl chains length. PMID- 28578832 TI - A biophysical approach to quantify skeletal stem cells trans-differentiation as a model for the study of osteoporosis. AB - The stroma of human bone marrow contains a population of skeletal stem cells (hBM MSC) which are common ancestors, among the others, of osteoblasts and adipocytes. It has been proposed that the imbalance between hBM-MSC osteogenesis and adipogenesis, which naturally accompanies bone marrow senescence, may contribute to the development of bone-associated diseases, like osteoporosis. The possibility to reproduce this mechanism in vitro has been demonstrated, providing a good model to disclose the details of the complex bone-fat generation homeostasis. Nevertheless, the lack of a simple approach to quantitatively assess the actual stage of a cellular population hindered the adoption of this in vitro model. In this work, the direct differentiation of hBM-MSCs towards a single (osteo or adipo) lineage was characterized using quantitative biophysical and biological approaches, together with the parallel process of trans differentiation from one lineage to the other. The results confirm that the original plasticity of hBM-MSCs is maintained along the initial stages of the differentiation, showing that in vitro conversion of pre-osteoblasts into adipocytes and, vice versa, of pre-adipocytes into osteoblasts is extremely efficient, comparable with the direct differentiation. Moreover, a method based on digital holography is proposed, providing a quantitative indication of the phenotype stage along differentiation. PMID- 28578833 TI - Life values of elderly people suffering from incurable cancer: A literature review. AB - OBJECTIVE: Due to aging Western societies, older patients suffering from incurable cancer will present themselves more often to health care professionals. To be of service to these severely ill elderly patients, more knowledge is needed on which life values are guiding them through their last phases of life. This review aims to describe which life values play an important part in the lives of elderly people suffering from incurable cancer. METHODS: We conducted a literature review with a structured search to identify empirical studies (January 1950-February 2016) using six databases. RESULTS: The analysis of thirty articles resulted in the extensive description of eight life values: comfort, continuity, humility, dignity, honesty, optimism, hope and preparedness. CONCLUSION: Elderly patients suffering from incurable cancer use the abovementioned life values to give meaning to a life interrupted by disease. Furthermore, these values will play a role in communication and decision-making. PRACTICE IMPLICATIONS: Knowledge about life values can help professionals discuss and clarify personal preferences with elderly patients suffering from incurable cancer, contributing to more personalized care and treatment. Communication should focus on to what extent patient empowerment, life-prolonging treatment and the involvement of the patient's supporting systems suit the wishes of these patients. PMID- 28578834 TI - The Joy of Victory and the Agony of Defeat. PMID- 28578835 TI - The Link Between Radiation Optimization and Quality. PMID- 28578836 TI - [Contribution of histopathology in the diagnosis of mycetoma in a Cameroonian trader and possibility of an urban contamination]. AB - BACKGROUND: Mycetoma are rare cutaneous affections caused by pathogens such as fungi or bacteria. They settle preferentially on limb extremities. We are going to talk about an original case of mycetoma in a young Cameroonian trader. OBSERVATION: A cutaneous mass with multiple draining sinuses was received at the anatomy and cytopathology laboratory. That mass was from a 30-year-old male trader, with no particular medical history and living in Yaounde, who was received for a lesion at the sole of the foot, which appeared some months before. This lesion started like a tough and painless nodule, which later showed draining sinuses to the skin. The surgical resection of the tissue mass was performed. The histopathological analysis with special staining procedures, which was later on performed, revealed mycetoma caused by fungi. DISCUSSION: This observation describes an original case of fungal mycetoma, which occured in a Cameroonian trader living in an urban milieu away from any mycetoma endemic zone. This case confirms the undeniable or undisputable contribution of histopathology in diagnosis of certainty. To our knowledge and according to available data, it is a premiere to find a case of mycetoma described in an urban milieu in Cameroon. PMID- 28578838 TI - Coffee and tea breaks for liver health. PMID- 28578837 TI - Coffee and herbal tea consumption is associated with lower liver stiffness in the general population: The Rotterdam study. AB - BACKGROUND & AIMS: Coffee and tea have been proposed to limit the progression of liver fibrosis in established liver disease, but it is unknown if this is also true for subclinical fibrosis. We therefore aimed to evaluate whether coffee and tea consumption are associated with liver stiffness in the general population. METHODS: The Rotterdam Study is an ongoing prospective population-based cohort. We included participants who underwent transient elastography, ultrasound and completed a food frequency questionnaire. Coffee and tea consumption were categorized into no, moderate (>0-3), or frequent (?3) intake (cups/day), and tea further into green, black and herbal tea (no/any). Significant fibrosis was defined as liver stiffness measurements (LSM) ?8.0kPa. We performed regression analyses relating coffee and tea intake with fibrosis, steatosis and log transformed LSM and adjusted for energy, sugar and creamer intake, age, gender, BMI, steatosis/LSM, HOMA-IR, ALT, alcohol, smoking, soda, healthy diet index and physical activity. RESULTS: We included 2,424 participants (age 66.5+/-7.4; 43% male) of whom 5.2% had LSM ?8.0kPa and 34.6% steatosis. Proportion of LSM ?8.0kPa decreased with higher coffee consumption (7.8%, 6.9% and 4.1% for no, moderate and frequent respectively; Ptrend=0.006). This inverse association was confirmed in multivariable regression (ORmod 0.75, 95% CI 0.33-1.67; ORfreq 0.39, 95% CI 0.18-0.86; p=0.005). Amongst tea consumers, only herbal tea consumers (36.3%) had lower log-transformed LSM after adjustment (Beta-0.05, 95% CI-0.08;-0.02, p=0.001). Subtypes of tea were associated with steatosis in univariate but not multivariable analysis. CONCLUSIONS: In the general population, frequent coffee and herbal tea consumption were inversely related with liver stiffness but not steatosis. Longitudinal analyses, as well as studies validating and unravelling underlying mechanisms are needed. LAY SUMMARY: The Rotterdam Study is a large ongoing population study of suburban inhabitants of Rotterdam in whom data on liver stiffness, as proxy for liver fibrosis, presence of fatty liver on ultrasound and detailed information on coffee and tea consumption were obtained in 2,424 participants. The consumption of herbal tea and daily consumption of three or more cups of coffee was related to the presence of lower liver stiffness, independent of a great number of other lifestyle and environmental factors. Previous studies have found a protective effect of coffee on established liver disease and we now show for the first time that this effect is already measurable in the general population. PMID- 28578839 TI - The Combination of Preoperative Bone Marrow Lesions and Partial-Thickness Cartilage Loss Did Not Result in Inferior Outcomes After Medial Unicompartmental Knee Arthroplasty. AB - BACKGROUND: The purpose of this study is to compare patient-reported outcomes and revision rates between medial unicompartmental knee arthroplasty (UKA) patients based on the presence of medial bone marrow lesions (BMLs) and/or partial- vs full-thickness cartilage loss. METHODS: BMLs were graded on preoperative magnetic resonance imaging (MRI) findings from 174 UKAs performed between 2009 and 2013 using the MRI Osteoarthritis Knee Score criteria by a single evaluator blinded to the patient's outcome. A second evaluator blinded to the MRI findings and postoperative outcomes assessed medial joint space present on both weight-bearing and valgus stress radiographs. Preoperative and postoperative Knee Society Knee Scores, Pain Scores, and Function Scores were then compared between 4 groups of patients: patients with BML with either partial- or full-thickness cartilage loss, and patients without BML with either partial- or full-thickness cartilage loss. RESULTS: In total, 152 of 174 (87%) patients had minimum 2-year follow-up. One patient in the no BML/full-thickness loss group was converted to total knee arthroplasty secondary to arthrofibrosis; however, there were no statistical differences in revision rate between the 4 groups as no other revisions were performed (P = .61). Similarly, preoperative and postoperative Knee Society Knee Scores, Pain Scores, and Function Scores did not differ between groups, nor did postoperative University of California, Los Angeles activity scores. CONCLUSION: Medial tibial BMLs were not associated with inferior outcomes, either in patients with partial- or full-thickness cartilage loss. Although the current results do not allow for the presence of preoperative BML to be considered an indication for UKA, these results definitively support that BMLs are not a contraindication for medial UKA. PMID- 28578840 TI - Acute Kidney Injury After First-Stage Joint Revision for Infection: Risk Factors and the Impact of Antibiotic Dosing. AB - BACKGROUND: Scarce literature exists regarding risk factors associated with postoperative acute kidney injury (AKI) after first-stage revision procedures. The purpose of this study was to determine risk factors for AKI and the efficacy of intra-articular antibiotics in infection eradication. METHODS: We retrospectively identified 247 patients who underwent a 2-stage revision procedure for the treatment of hip or knee periprosthetic joint infection. We applied previously published diagnostic criteria for AKI to determine its incidence and risk factors for its development. RESULTS: A 26% incidence of AKI was found after first-stage joint revision for infection. Higher body mass index (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.01-1.13; P = .02), lower baseline hemoglobin level (OR, 0.70; 95% CI, 0.51-0.96; P = .03), and existence of a comorbid condition (OR, 2.67; 95% CI, 1.26-5.64; P = .01) were significant risk factors for AKI. Neither a higher dose of vancomycin (OR, 0.99; 95% CI, 0.88 1.11; P = .83) nor tobramycin (OR, 0.89; 95% CI, 0.77-1.04; P = .15) used in the cement spacer increased the risk of AKI. Each unit increase in vancomycin dose in the cement spacer decreased the odds of failing to clear the infection at 1 and 2 years by a factor of 0.82 (95% CI, 0.70-0.95; P = .01). CONCLUSION: AKI after first-stage revision procedures for periprosthetic joint infection occurs more commonly than previously reported. Patients with identified risk factors should be managed carefully with attention paid to hemoglobin levels, to avoid AKI after this procedure. Further research is needed to determine the optimal local antibiotic type and dosing to maximize infection clearance and minimize potential side effects. PMID- 28578841 TI - Povidone-Iodine-Based Solutions for Decolonization of Nasal Staphylococcus aureus: A Randomized, Prospective, Placebo-Controlled Study. AB - BACKGROUND: Nasal Staphylococcus aureus decolonization reduces the risk of surgical site infections after orthopedic procedures. Povidone-iodine (PI)-based solutions have shown promising results in bacteria decolonization. The unique physiology of the nose may pose challenges for the bioactivity profiles of PI solutions. This study compared the antibacterial efficacy of an off-the-shelf PI product with a specifically manufactured PI-based skin and nasal antiseptic (SNA). METHODS: This randomized, placebo-controlled study was conducted at a single institution between April 2014 and July 2015. Four hundred and twenty-nine patients undergoing primary or revision total joint arthroplasty, femoroacetabular osteoplasty, pelvic osteotomy, or total shoulder arthroplasty were included. 10% off-the-shelf PI, 5% PI-based SNA, or saline (placebo) were used for nasal decolonization. Baseline cultures were taken immediately preoperatively, followed by treatment of both nares twice for 2 minutes with 4 applicators. Reculturing of the right nostril occurred at 4 hours and the left at 24 hours. RESULTS: Ninety-five of the 429 patients (22.1%) had a positive culture result for S. aureus; 13 (3.03%) were methicillin-resistant S. aureus. Of these 95, 29 were treated with off-the-shelf PI, 34 with SNA, and 32 with saline swabs. At 4 hours post-treatment, S. aureus culture was positive in 52% off-the-shelf PI patients, 21% SNA patients, and 59% saline patients. After 24 hours posttreatment, S. aureus culture was positive in 72% off-the-shelf PI patients, 59% SNA patients, and 69% saline group. SNA was significantly more effective at decolonizing S. aureus over the 4-hour time interval (P = .003); no significant difference was observed over the 24-hour time interval between the 3 groups. CONCLUSION: A single application of PI-based SNA before surgery may be effective in eliminating nasal S. aureus in over two-thirds of patients. Off-the-shelf PI swabs were not as effective at 4 hours as the specifically manufactured product for S. aureus decolonization. PMID- 28578842 TI - What is the Impact of a Spinal Fusion on Acetabular Implant Orientation in Functional Standing and Sitting Positions? AB - BACKGROUND: This study used EOS imaging of primary total hip arthroplasty (THA) patients, with and without predating spinal fusion, to investigate (1) the impact of spinal fusion on acetabular implant anteversion and inclination, and (2) whether more extensive spinal fusion (fusion starting above the thoracolumbar junction or extension of fusion to the sacrum) affects acetabular implant orientation differently than lumbar only spinal fusion. METHODS: Ninety-three patients had spinal fusion (case group), and 150 patients were without spinal fusion (controls). None of the patients experienced dislocation. The change in sacral slope (SS) and cup orientation from standing to sitting was measured. RESULTS: Mean SS change from the standing to sitting positions was -7.9 degrees in the fusion group vs -18.4 degrees in controls (P = .0001). Mean change in cup inclination from the standing to sitting positions was 4.9 degrees in the fusion group vs 10.2 degrees in controls (P = .0001). Mean change in cup anteversion from standing to sitting positions was 7.1 degrees in the fusion group vs 12.1 degrees in controls (P = .0001). For each additional level of spinal fusion, the change in SS from standing to sitting positions decreased by 1.6(95% confidence interval [CI], 2.2073-1.0741), the change in cup inclination decreased by 0.8(95% CI, 0.380-1.203), and the change in cup anteversion decreased by 0.9(95% CI, 0.518-1.352; P < .001 in all cases). CONCLUSION: Patients with spinal fusion demonstrated less adaptability of the lumbosacral junction. Longer spinal fusion or inclusion of the pelvis in the fusion critically impacts hip-spine biomechanics and significantly affects the ability to compensate in the standing to-sitting transition. PMID- 28578843 TI - Total Hip Arthroplasty in Patients With Multifactorial Perceived Limb Length Discrepancy. AB - BACKGROUND: Patients with advanced hip arthritis can present with multifactorial limb length discrepancies (LLDs) owing to bony shortening from growth arrest, proximal hip migration, soft-tissue contractures, and pelvic obliquity. The patient perceives an LLD that is a combination of true LLD and apparent LLD. METHODS: We retrospectively reviewed 7 cases with multifactorial mean perceived LLD of 7.7 cm (range, 3.6-11 cm) that underwent primary total hip arthroplasty and auxiliary soft-tissue procedures. Perceived LLD, true LLD, and apparent LLD were defined and were compared before and after surgery in this cohort of patients with a mean follow-up of 57.4 months. RESULTS: The mean perceived LLD at final follow-up was 1.0 +/- 0.9 cm compared with that of 7.7 +/- 2.6 cm preoperatively (P < .05). Postoperative true LLD was 0.7 +/- 0.8 cm compared with that of 3.2 +/- 0.8 cm preoperatively (P < .05). At final follow-up, all 7 patients were ambulating without any assistive devices and were satisfied with their surgical outcome. CONCLUSION: With careful preoperative clinical and radiographic assessments as well as planning for multifactorial perceived LLD, this can be adequately corrected with primary total hip arthroplasty and auxiliary soft-tissue procedures resulting in good radiologic and functional outcomes. PMID- 28578844 TI - Does the Dual-Mobility Hip Prosthesis Produce Better Joint Kinematics During Extreme Hip Flexion Task? AB - BACKGROUND: Total hip arthroplasty (THA) using dual-mobility (DM) design permits larger hip range of motion. However, it is unclear how it benefits the patients during activities of daily living. The purpose was to compare kinematic variables of the operated limb between THA patients using either DM or single-bearing (SB) implants during a squat task. METHODS: Twenty-four THA patients were randomly assigned to either a DM or SB implant and matched to 12 healthy controls (CTRLs). They underwent 3-dimensional squat motion analysis before and 9 months after surgery. Sagittal and frontal plane angles of the pelvis and the hip were analyzed using statistical parametric mapping. Paired analyses compared presurgery and postsurgery squat depth. RESULTS: Peak sagittal pelvis angle of DM was closer to normal compared with that of SB. Both implant groups had similar hip angle patterns and magnitude but significantly lower than the CTRLs. SB reached a much large hip abduction compared with the other groups. Both surgical groups had significantly worst squat depth than the CTRLs. CONCLUSION: Neither THA implant groups were able to return pelvis and hip kinematics to the level of CTRLs. The deficit of DM implants at the pelvis combined with the poorer functional scores should caution clinicians to use this implant design in active patients. SB design causes a larger hip abduction to reach their maximum squat depth. Post-THA rehabilitation should focus on improving joint range of motion and strength. PMID- 28578845 TI - How Do Preoperative Medications Influence Outcomes After Total Joint Arthroplasty? AB - BACKGROUND: Recent health care policy changes require hospitals and physicians to demonstrate improved quality. In 2012, a prospective database was formed with the Blue Cross and Blue Shield of Michigan to improve quality of care. The purpose of this study was to analyze patient preoperative medication as predictors of outcomes after total joint arthroplasty. METHODS: Data were collected on patient's preoperative medications from 2012 to 2015 using a total joint arthroplasty database. Medications were categorized as antiplatelet, antimicrobial, anticoagulant, narcotic, steroid, insulin, or oral diabetes medication. Outcomes included hospital length of stay (LOS), discharge disposition/destination, and 90-day readmission. Univariate and multivariate regression analyses were performed. RESULTS: A total of 3959 patients were studied. Eighty percent (3163 patients) were discharged home. The remainder (795) went to an extended-care facility (ECF). Patients discharged to an ECF were taking more medications (1.13 vs 0.80 in total knee arthroplasty; 1.18 vs 0.83 in total hip arthroplasty; P <.001). Patients who were readmitted took more medications (1.0 vs 0.85; P <.01). There were more discharges to an ECF in narcotic, steroid, and diabetes medication users. Patients taking anticoagulants, narcotics, insulin, and antiplatelets had greater readmission rates. There was a significant correlation between the number of medications and an increased LOS. CONCLUSION: Patients taking more medications were more frequently discharged to an ECF and had increased LOS and readmission rates. Narcotics and diabetic medications had the greatest influence. Category and quantity of preoperative medications can be used as predictors of outcomes after arthroplasty surgery. PMID- 28578846 TI - WITHDRAWN: The Congruence and Joint Space Width of the Lateral Compartment Can Be Restored After Medial Unicompartmental Knee Arthroplasty. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28578847 TI - A prospective study to validate the Polish language version of the European Organisation for Research and Treatment of Cancer (EORTC) Colorectal Liver Metastases (QLQ-LMC21) module. AB - PURPOSE: This validation study was designed to assess the psychometric validity and quality of the Polish translation of the EORTC QLQ-LMC21 questionnaire in Polish colorectal patients suffering with liver metastases. METHODS: Patients with either histopathological or imaging confirmation of colorectal cancer with liver metastases, with a minimum of three months survival, were eligible for this study. These patients completed the Polish version of the EORTC core QLQ-C30, the QLQ-LMC21 module, and a demographic data questionnaire. The questionnaires were completed twice, once before undergoing either hepatectomy (n = 63) or palliative treatment (n = 97) and three months after the primary treatment. Standardized analyses of validity and reliability were performed. RESULTS: One hundred and sixty patients were enrolled in this study with the mean age of the hepatectomy group 64.3 +/- 14.1 and 66.1 +/- 12.7 for the palliative treatment group. The QLQ LMC21 exhibited positive internal consistency with Cronbach's alpha coefficients ranging from 0.72 to 0.90. The multi-trait scaling analysis demonstrated adequate convergent and discriminant validity. Test-retest reliability was undertaken with 40 patients (25%) with the ICCs for each item ranging from 0.64 to 0.88. The hepatectomy group had a significantly greater Karnofsky Performance Score than the palliative treatment group (p.<0.001). Overall there were weak correlations between the two questionnaires which confirm that the QLQ-LMC21 addresses health issues not assessed in the QLQ-C30. CONCLUSION: The Polish version of the QLQ LMC21 proved to be a valid and reliable questionnaire to use in conjunction with the QLQ-C30 core questionnaire. PMID- 28578848 TI - Study on pharmacokinetics and bioequivalence of Vonoprazan pyroglutamate in rats by liquid chromatography with tandem mass spectrometry. AB - Vonoprazan Fumarate (TAK-438F) is a new and effective drug approved in Japan in 2014 for treatment and prevention of acid-related diseases (ARDs), which exhibits many advantages compared with traditional proton-pump inhibitors (PPIs). However, the clinical applications of TAK0-438F suffers limitation due to the lack of injection dosage form. Efforts to overcome this limitation lead to the systhesis of Vonoprazan pyroglutamate (TAK-438P) for its high water solubility and more potent antisecretory effect. This was the first report to establish and validate a reliable and sensitive LC-MS/MS method for the quantification of TAK-438P in rat plasma and tissues (heart, liver, spleen, liver, kidney, rain, stomach and small intestine). All the features of the developed method suggested it was within bioanalytical criteria recommended by regulatory authorities. Furthermore, the developed method was applied to the exploration of the bioequivalence between TAK-438P and TAK-438F, as well as the pharmacokinetics and tissue distribution of TAK-438P. The results showed that there was no significant differences between TAK-438P and TAK-438F after oral administration of the same dose. Besides, TAK 438P was rapidly absorbed and eliminated in rat plasma. And it was widely distributed and there was no long-term accumulation in most tissues. Notably, more than 2000ng/mL was observed in stomach 12h after oral administration. The high accumulation revealed that stomach was likely to be the target organs of TAK 438P. PMID- 28578849 TI - Effectiveness of training final-year undergraduate nutritionists in motivational interviewing. AB - OBJECTIVES: To assess the efficacy of a motivational interviewing (MI) training programme on trainee nutritionists. METHODS: A repeated measures design was applied to assess clinician behaviours in a 'helping' conversation. Participants were 32 nutrition students, assessed at baseline and one-month follow-up. RESULTS: The training significantly reduced the use of closed questions and MI non-adherent behaviours (MINA) (P for both=<0.001). Trainees significantly increased reflections, affirmations, summaries (P for all=<0.001) and the use of open questions (P=<0.013) which are all key indicators of MI beginner-competence. The talk-time ratio of the nutritionists also changed significantly, in favour of the client which serves as an indication of MI being used effectively. There were also significant increases in 'global' scores for empathy, direction, autonomy/support, collaboration and evocation. CONCLUSIONS: Newly trained nutritionists 1 month post-training have a consultation style which suggested positive outcomes for clients. The trainees' scores at the one month post training assessment were verifiable as 'beginning proficiency'. PRACTICE IMPLICATIONS: Behaviour change counselling skills for nutritionists were enhanced, at one month post-training. MI training workshops with video feedback enhances communication skills which are likely to lead to positive consultation behaviour changes in the trainee nutritionists. PMID- 28578850 TI - Time-Resolved Proteomics Extends Ribosome Profiling-Based Measurements of Protein Synthesis Dynamics. AB - Ribosome profiling is a widespread tool for studying translational dynamics in human cells. Its central assumption is that ribosome footprint density on a transcript quantitatively reflects protein synthesis. Here, we test this assumption using pulsed-SILAC (pSILAC) high-accuracy targeted proteomics. We focus on multiple myeloma cells exposed to bortezomib, a first-line chemotherapy and proteasome inhibitor. In the absence of drug effects, we found that direct measurement of protein synthesis by pSILAC correlated well with indirect measurement of synthesis from ribosome footprint density. This correlation, however, broke down under bortezomib-induced stress. By developing a statistical model integrating longitudinal proteomic and mRNA-sequencing measurements, we found that proteomics could directly detect global alterations in translational rate caused by bortezomib; these changes are not detectable by ribosomal profiling alone. Further, by incorporating pSILAC data into a gene expression model, we predict cell-stress specific proteome remodeling events. These results demonstrate that pSILAC provides an important complement to ribosome profiling in measuring proteome dynamics. PMID- 28578851 TI - Cold tolerance and biochemical response of unfed Dermacentor silvarum ticks to low temperature. AB - The important pathogen vector Dermacentor silvarum is widely distributed in China. However, the tick's adaptation to low winter temperatures remains poorly understood. We therefore investigated the cold hardiness and physiological and biochemical responses of D. silvarum ticks exposed to low temperatures. The results indicated that the lower lethal temperatures (LT50s) for larvae, nymphs, females and males were -16.9 degrees C, -15.8 degrees C, -20.0 degrees C and 20.1 degrees C, respectively. The discriminating temperatures (resulting in 20% survival) for larvae, nymphs, females and males were -18.5 degrees C, -20.0 degrees C, -21.7 degrees C and -22.6 degrees C, respectively. The supercooling temperature points (at which body fluids spontaneously freeze) of larvae, nymphs, females and males averaged -20.0 degrees C, -23.5 degrees C, -24.2 degrees C and 23.9 degrees C, respectively. These results indicate that adult ticks are more tolerant to cold than the immatures. Low-temperature stress can enhance adult cold hardiness and trigger decreases in glycogen and protein in both females and males, whereas nymphs displayed different biochemical responses, including an increase in water and total fat content. An increase of glycerol observed in nymphs and females suggests that glycerol is important for cold hardiness. The findings of this study will help to define the dispersal limits for D. silvarum and thus inform the need for tick control efforts. PMID- 28578853 TI - Environmental consequences of the flooding of the Bay Park Sewage Treatment Plant during Superstorm Sandy. AB - Failure of the Bay Park Sewage Treatment Plant (STP) during Superstorm Sandy led to adverse effects in the waters of Hempstead Bay, Long Island, NY. These appear to be related to large discharges of partially treated sewage through its primary and auxiliary outfalls. Modeled dilution discharges indicate that sewage infiltrated the bay, remaining up to 10days. Water column impacts included salinity and dissolved oxygen declines, and biological oxygen demand and nitrogen concentration increases. While the STP does not appear to have released fecal coliform, there were elevated levels of enterococci within the bay for a considerable period following the storm, probably from multiple sources. The STP's reduced functioning and associated environmental impacts, even with resilience upgrades, are not conducive to removing the bay from the list of Impaired Water Bodies. The results reinforce the need to transfer the discharge from the existing outfall to the ocean. PMID- 28578854 TI - Evaluating Dancing With Parkinson's: Reflections from the perspective of a community organization. AB - In 2015, Dancing With Parkinson's (DWP), a Toronto-based community organization, participated in the Ontario Brain Institute's (OBI) newly launched Evaluation Support Program. This paper reflects on that experience. In particular, we identify the key lessons derived from the OBI initiative, discuss how these lessons have informed DWP practice going forward, and highlight what we consider to be the most valuable aspects of the Evaluation Support Program. While we now recognize the need to establish an evaluation culture within DWP, we find that there are significant challenges associated with both building and sustaining evaluation capacity in the context of a small community-based organization. Whereas DWP has built considerable strengths in terms of informal evaluation capacity, on its own, such capacity is insufficient to, for example, demonstrate DWP's impact to outside audiences or successfully scale up the program. PMID- 28578852 TI - Radioactive iodine therapy, molecular imaging and serum biomarkers for differentiated thyroid cancer: 2017 guidelines of the French Societies of Nuclear Medicine, Endocrinology, Pathology, Biology, Endocrine Surgery and Head and Neck Surgery. PMID- 28578855 TI - Experiments in evaluation capacity building: Enhancing brain disorders research impact in Ontario. AB - This paper is the introductory paper on a forum on evaluation capacity building for enhancing impacts of research on brain disorders. It describes challenges and opportunities of building evaluation capacity among community-based organizations in Ontario involved in enhancing brain health and supporting people living with a brain disorder. Using an example of a capacity building program called the "Evaluation Support Program", which is run by the Ontario Brain Institute, this forum discusses multiple themes including evaluation capacity building, evaluation culture and evaluation methodologies appropriate for evaluating complex community interventions. The goal of the Evaluation Support Program is to help community-based organizations build the capacity to demonstrate the value that they offer in order to improve, sustain, and spread their programs and activities. One of the features of this forum is that perspectives on the Evaluation Support Program are provided by multiple stakeholders, including the community-based organizations, evaluation team members involved in capacity building, thought leaders in the fields of evaluation capacity building and evaluation culture, and the funders. PMID- 28578856 TI - Environmental performances of different configurations of a material recovery facility in a life cycle perspective. AB - The study evaluated the environmental performances of an integrated material recovery facility (MRF) able to treat 32kt/y of unsorted mixed waste, made of residuals from household source separation and separate collection. The facility includes a mechanical sorting platform for the production of a solid recovered fuel (SRF) utilized in an external waste-to-energy plant, bio-cells for tunnel composting of organic fraction, and a sanitary landfill for the safe disposal of ultimate waste. All the MRF sub-units have been analysed in depth in order to acquire reliable data for a life cycle assessment study, focused on the environmental performances of different configurations of the facility. The study investigated a "past" configuration, including just mechanical sorting, landfilling and biogas combustion in a gas engine, and the "present" one, which includes also a composting unit. Two possible "future" configurations, having a gasifier inside the MRF battery limits, have been also analysed, assessing the performances of two fluidized bed reactors of different size, able to gasify only the residues generated by the sorting platform or the whole amount of produced SRF, respectively. The analysis evaluated the contributions of each unit in the different configurations and allowed a reliable assessment of the technological evolution of the facility. The results quantified the positive effect of the inclusion of an aerobic treatment of the waste organic fraction. The SRF gasification in situ appears to improve the MRF environmental performances in all the impact categories, with the exclusion of that of global warming. PMID- 28578857 TI - Surface treatment with Fenton for separation of acrylonitrile-butadiene-styrene and polyvinylchloride waste plastics by flotation. AB - Surface treatment with Fenton was applied to flotation separation of acrylonitrile-butadienestyrene (ABS) and polyvinylchloride (PVC). After treatment, the floatability of ABS has a dramatic decrease, while the floatability of PVC is not affected. Fourier transform infrared spectroscopy (FT IR) spectra and X-ray photoelectron spectroscopy (XPS) spectra were recorded to ascertain the mechanism of Fenton treatment. FT-IR and XPS analysis confirms that the introduction of oxygen-containing group occurs on the surface of ABS. The optimum conditions are molar ration (H2O2:Fe2+) 10000, H2O2 concentration 0.4M/L, pH 5.8, treatment time 2min and temperature 25 degrees C, frother concentration 15mg/L and flotation time 3min. Particle sizes and mixing ratios were also investigated. Plastic mixtures of ABS and PVC with different particle sizes and mixing ratios can be effectively separated. The purity of ABS and PVC are up to 100% and 99.78%, respectively; the recovery of ABS and PVC are up to 99.89% and 100%, respectively. A practical, environmentally friendly and effective reagent, namely Fenton, was originally applied to surface treatment of ABS and PVC waste plastics for flotation separation of their mixtures. PMID- 28578858 TI - Long chain fatty acids (LCFA) evolution for inhibition forecasting during anaerobic treatment of lipid-rich wastes: Case of milk-fed veal slaughterhouse waste. AB - A detailed study of a solid slaughterhouse waste (SHW) anaerobic treatment is presented. The waste used in this study is rich in lipids and proteins residue. Long chain fatty acids (LCFA), coming from the hydrolysis of lipids were inhibitory to anaerobic processes at different degrees. Acetogenesis and methanogenesis processes were mainly affected by inhibition whereas disintegration and hydrolysis processes did not seem to be affected by high LCFA concentrations. Nevertheless, because of the high energy content, this kind of waste is very suitable for anaerobic digestion but strict control of operating conditions is required to prevent inhibition. For that, two inhibition indicators were identified in this study. Those two indicators, LCFA dynamics and LCFA/VSbiomass ratio proved to be useful to predict and to estimate the process inhibition degree. PMID- 28578859 TI - A two-stage treatment for Municipal Solid Waste Incineration (MSWI) bottom ash to remove agglomerated fine particles and leachable contaminants. AB - In this lab study, a two-stage treatment was investigated to achieve the valorization of a municipal solid waste incineration (MSWI) bottom ash fraction below 4mm. This fraction of MSWI bottom ash (BA) is the most contaminated one, containing potentially toxic elements (Cu, Cr, Mo and Sb), chlorides and sulfates. The BA was treated for recycling by separating agglomerated fine particles (<=125um) and soluble contaminants by using a sequence of sieving and washing. Initially, dry sieving was performed to obtain BA-S (<=125um), BA-M (0.125-1mm) and BA-L (1-4mm) fractions from the original sample. The complete separation of fine particles cannot be achieved by conventional sieving, because they are bound in a cementitious matrix around larger BA grains. Subsequently, a washing treatment was performed to enhance the liberation of the agglomerated fine particles from the BA-M and BA-L fractions. These fine particles were found to be similar to the particles of BA-S fraction in term of chemical composition. Furthermore, the leaching behavior of Cr, Mo Sb, chlorides and sulfates was investigated using various washing parameters. The proposed treatment for the separation of agglomerated fine particles with dry sieving and washing (L/S 3, 60min) was successful in bringing the leaching of contaminants under the legal limit established by the Dutch environmental norms. PMID- 28578860 TI - Assessment on the leakage hazard of landfill leachate using three-dimensional excitation-emission fluorescence and parallel factor analysis method. AB - A large number of simple and informal landfills exist in developing countries, which pose as tremendous soil and groundwater pollution threats. Early warning and monitoring of landfill leachate pollution status is of great importance. However, there is a shortage of affordable and effective tools and methods. In this study, a soil column experiment was performed to simulate the pollution status of leachate using three-dimensional excitation-emission fluorescence (3D EEMF) and parallel factor analysis (PARAFAC) models. Sum of squared residuals (SSR) and principal component analysis (PCA) were used to determine the optimal components for PARAFAC. A one-way analysis of variance showed that the component scores of the soil column leachate were significant influenced by landfill leachate (p<0.05). Therefore, the ratio of the component scores of the soil under the landfill to that of natural soil could be used to evaluate the leakage status of landfill leachate. Furthermore, a hazard index (HI) and a hazard evaluation standard were established. A case study of Kaifeng landfill indicated a low hazard (level 5) by the use of HI. In summation, HI is presented as a tool to evaluate landfill pollution status and for the guidance of municipal solid waste management. PMID- 28578861 TI - Recovery of zinc and cadmium from spent batteries using Cyphos IL 102 via solvent extraction route and synthesis of Zn and Cd oxide nanoparticles. AB - The overall aim of this study is to separate and recover zinc and cadmium from spent batteries. For this purpose Cyphos IL 102 diluted in toluene was employed for the extraction and recovery of Zn and Cd from Zn-C and Ni-Cd batteries leach liquor. The influence of extractant concentration for the leach liquors of Zn-C (0.01-0.05mol/L) and Ni-Cd (0.04-0.20mol/L) batteries has been investigated. Composition of the leach liquor obtained from Zn-C/Ni-Cd spent batteries is Zn - 2.18g/L, Mn - 4.59g/L, Fe - 4.0*10-3g/L, Ni - 0.2*10-3g/L/Cd - 4.28g/L, Ni - 0.896*10-1g/L, Fe - 0.148g/L, Co - 3.77*10-3g/L, respectively. Two stage counter current extraction at A/O 1:1 and 3:2 with 0.04mol/L and 0.2mol/L Cyphos IL 102 for Zn and Cd, respectively provide more than 99.0% extraction of both the metal ions with almost negligible extraction of associated metal ions. A stripping efficiency of around 99.0% for Zn and Cd was obtained at O/A 1:1 using 1.0mol/L HNO3 in two and three counter current stages, respectively. ZnO and CdO were also synthesized using the loaded organic phase and characterized using XRD, FE-SEM and EDX techniques. XRD peaks of ZnO and CdO correspond to zincite and monteponite, respectively. The average particle size was ~27.0nm and ~37.0nm for ZnO and CdO, respectively. The EDX analysis of ZnO and CdO shows almost 1:1 atomic percentage. PMID- 28578862 TI - Stenotrophomonas maltophilia: A rare cause of peritonitis in capd patients. PMID- 28578863 TI - Estimating the cascade of hepatitis C testing, care and treatment among people who inject drugs in Australia. AB - BACKGROUND: Hepatitis C virus (HCV) infection is endemic among people who inject drugs (PWID) globally. Despite high prevalence, treatment uptake is low, with cumulative uptake <10% in most settings. This study aimed to populate the cascade of HCV testing, care and treatment among PWID using data collected in Australia prior to the introduction of broadly accessible interferon-free direct-acting antiviral (DAA) therapies in March 2016. METHODS: The Australian Needle and Syringe Program Survey is a cross-sectional surveillance system that recruits ~2300 PWID annually and collects behavioural data and dried blood samples (DBS). HCV antibody and ribonucleic acid (RNA) test results from DBS collected in 2015 were combined with data on HCV diagnostic testing, care and treatment to populate the HCV cascade among Australian PWID. RESULTS: Among an estimated 93,000 PWID in Australia in 2015, the majority (89%) had a lifetime history of HCV antibody testing. More than half (57%) of PWID tested HCV antibody positive and of these, 79% had detectable HCV RNA consistent with active infection. Less than half (46%) of HCV antibody positive PWID had received confirmatory HCV RNA testing. Among the estimated 43,201 PWID with active infection or chronic infection that had been successfully treated, 31% had received specialist HCV assessment, 8% had received antiviral treatment and 3% were cured. CONCLUSION: This study provides baseline estimates of the cascade of HCV testing, care and treatment among PWID through enhancement of a well-established surveillance mechanism. Characterisation of the HCV cascade among PWID will be crucial to evaluating and monitoring the roll out of direct-acting antiviral therapies in Australia, including assessing potential HCV treatment as prevention benefits. PMID- 28578864 TI - Exposure to fentanyl-contaminated heroin and overdose risk among illicit opioid users in Rhode Island: A mixed methods study. AB - BACKGROUND: Illicit fentanyl use has become wide spread in the US, causing high rates of overdose deaths among people who use drugs. This study describes patterns and perceptions of fentanyl exposure among opioid users in Rhode Island. METHODS: A mixed methods study was conducted via questionnaire with a convenience sample of 149 individuals using illicit opioids or misusing prescription opioids in Rhode Island between January and November 2016. Of these, 121 knew of fentanyl and reported known or suspected exposure to fentanyl in the past year. Semi structured interviews were conducted with the first 47 participants. RESULTS: Study participants were predominantly male (64%) and white (61%). Demographic variables were similar across sample strata. Heroin was the most frequently reported drug of choice (72%). Self-reported exposure to illicit fentanyl in the past year was common (50.4%, n=61). In multivariate models, regular (at least weekly) heroin use was independently associated with known or suspected fentanyl exposure in the past year (adjusted prevalence ratio (APR)=4.07, 95% CI: 1.24 13.3, p=0.020). In interviews, users described fentanyl as unpleasant, potentially deadly, and to be avoided. Participants reporting fentanyl exposure routinely experienced or encountered non-fatal overdose. Heroin users reported limited ability to identify fentanyl in their drugs. Harm reduction strategies used to protect themselves from fentanyl exposure and overdose, included test hits, seeking prescription opioids in lieu of heroin, and seeking treatment with combination buprenorphine/naloxone. Participants were often unsuccessful in accessing structured treatment programs. CONCLUSION: Among illicit opioid users in Rhode Island, known or suspected fentanyl exposure is common, yet demand for fentanyl is low. Fentanyl-contaminated drugs are generating user interest in effective risk mitigation strategies, including treatment. Responses to the fentanyl epidemic should be informed by the perceptions and experiences of local users. The rapid scale-up of buprenorphine/naloxone provision may slow the rate of fentanyl-involved overdose deaths. PMID- 28578867 TI - Impact of a self-control promotion program on nursing students. AB - OBJECTIVE: To describe the characteristics of positive mental health in nursing students, and to determine the impact of a self-control promotion program. METHOD: A quasi-experimental controlled trial including 72 second-year of Vitoria Gasteiz University Nursing School. RESULTS: The lowest scores in every measurement were for the self-control factor (F3). There were no statistically significant differences in self-control (F3) between the groups. CONCLUSION: This program shows higher scores in inter-personal relationship skills. PMID- 28578865 TI - Initiating HCV treatment with direct acting agents in opioid agonist treatment: When to start for people co-infected with HIV? AB - BACKGROUND: Direct acting antivirals (DAA) raise the possibility of eliminating Hepatitis C virus (HCV) among people who inject drugs (PWID). However, concerns regarding treatment retention and reinfection challenge implementation efforts. Opioid agonist treatment (OAT) provides an opportunity to engage HCV-positive PWID into DAA-based treatment. Our objective was to identify when OAT adherence sufficiently improved to inform DAA initiation in OAT settings, assuming continuous OAT retention for at least twelve weeks is necessary to complete the DAA treatment course. METHODS: This was a retrospective cohort study of HCV/HIV co-infected PWID from a population-level linked administrative database of people diagnosed and living with HIV in British Columbia, Canada between 01/1996 and 12/2013. We used monthly follow-up data after initial OAT entry and considered the effects of demographics, disease severity, and HIV and OAT treatment characteristics over time on the probability of subsequent OAT retention of >=12 weeks, and >=8 weeks for sensitivity analysis. We fit a generalized linear mixed model to the overall study population, and on stratified samples of those continuously engaged on combination antiretroviral therapy (>=95% ART adherence). A set of monthly indicator variables (months 1, ..., 7, >7) were included to fulfil the study objective. RESULTS: Our study included 1427 HCV/HIV co-infected PWID (39.0% female, 68.8% OAT-naive). The odds of subsequent twelve-week retention in OAT were statistically significantly greater in month 3 versus month 1 (adjusted odds ratio: 1.18; 95% confidence interval: 1.02, 1.37); and the odds of subsequent 8-week retention in OAT were statistically significantly greater in month 2 versus month 1 (1.15, 95% CI: 1.02, 1.31). Among continuously ART adherent individuals, the odds of subsequent twelve-week retention were not statistically significantly greater than in month 1 (month 2: 1.12 (0.82, 1.51); month 3: 1.08 (0.79, 1.47); month 4: 1.24 (0.91, 1.71)). CONCLUSION: We provide evidence that among HCV/HIV co-infected PWID, those retained in OAT for three or more months had higher odds of completing an additional twelve weeks of OAT, compared to no difference in those already receiving ART. These data may have implications for adherence to DAA therapy and further studies are needed to understand the optimal timing of DAA therapy in PWID receiving and not receiving OAT. PMID- 28578866 TI - Nitrogen losses to the environment following food-based digestate and compost applications to agricultural land. AB - The anaerobic digestion of food waste for energy recovery produces a nutrient rich digestate which is a valuable source of crop available nitrogen (N). As with any 'new' material being recycled to agricultural land it is important to develop best management practices that maximise crop available N supply, whilst minimising emissions to the environment. In this study, ammonia (NH3) and nitrous oxide (N2O) emissions to air and nitrate (NO3-) leaching losses to water following digestate, compost and livestock manure applications to agricultural land were measured at 3 sites in England and Wales. Ammonia emissions were greater from applications of food-based digestate (c.40% of total N applied) than from livestock slurry (c.30% of total N applied) due to its higher ammonium-N content (mean 5.6 kg/t compared with 1-2 kg/t for slurry) and elevated pH (mean 8.3 compared with 7.7 for slurry). Whilst bandspreading was effective at reducing NH3 emissions from slurry compared with surface broadcasting it was not found to be an effective mitigation option for food-based digestate in this study. The majority of the NH3 losses occurred within 6 h of spreading highlighting the importance of rapid soil incorporation as a method for reducing NH3 emissions. Nitrous oxide losses from food-based digestates were low, with emission factors all less than the IPCC default value of 1% (mean 0.45 +/- 0.15%). Overwinter NO3- leaching losses from food-based digestate were similar to those from pig slurry, but much greater than from pig farmyard manure or compost. Both gaseous N losses and NO3- leaching from green and green/food composts were low, indicating that, in these terms, compost can be considered as an 'environmentally benign' material. These findings have been used in the development of best practice guidelines which provide a framework for the responsible use of digestates and composts in agriculture. PMID- 28578868 TI - Not unusual, just different! Chemistry, biology and applications of G-quadruplex nucleic acids. PMID- 28578869 TI - Social interaction facilitates word learning in preverbal infants: Word-object mapping and word segmentation. AB - In natural settings, infants learn spoken language with the aid of a caregiver who explicitly provides social signals. Although previous studies have demonstrated that young infants are sensitive to these signals that facilitate language development, the impact of real-life interactions on early word segmentation and word-object mapping remains elusive. We tested whether infants aged 5-6 months and 9-10 months could segment a word from continuous speech and acquire a word-object relation in an ecologically valid setting. In Experiment 1, infants were exposed to a live tutor, while in Experiment 2, another group of infants were exposed to a televised tutor. Results indicate that both younger and older infants were capable of segmenting a word and learning a word-object association only when the stimuli were derived from a live tutor in a natural manner, suggesting that real-life interaction enhances the learning of spoken words in preverbal infants. PMID- 28578870 TI - The essential oil of Allium sativum as an alternative agent against Candida isolated from dental prostheses. AB - BACKGROUND: The colonization of the surfaces of dental prostheses by Candida albicans is associated with the development of denture stomatitis. In this context, the use of fluconazole has been proposed, but its disadvantage is microbial resistance. Meanwhile, the oil of Allium sativum has shown an effect in controlling biofilm formation by C. albicans. AIMS: The objective of this study was to determine the antifungal activities of the essential oil of A. sativum and fluconazole against clinical isolates of Candida species obtained from rigid, acrylic-based partial or total dentures and to compare these agents' effects on both biofilm and planktonic cells. METHODS: A total of 48 clinical isolates obtained from the acrylic surface of partial or complete dentures were examined, and the following species were identified: C. albicans, Candida glabrata, Candida tropicalis, and Candida krusei. For each isolate, the antifungal activities of the essential oil of A. sativum and fluconazole against both biofilm and planktonic cells were evaluated using the Clinical & Laboratory Standards Institute (CLSI) M27-A3 method. The isolates were also evaluated by semiquantitative XTT reduction. RESULTS: All planktonic Candida isolates were susceptible to the essential oil of A. sativum, whereas 4.2% were resistant to fluconazole. Regarding susceptibilities in biofilms, 43.8% of biofilms were resistant to A. sativum oil, and 91.7% were resistant to fluconazole. CONCLUSIONS: All planktonic cells of the different Candida species tested are susceptible to <1mg/ml A. sativum oil, and the majority are susceptible to fluconazole. Susceptibility decreases in biofilm cells, with increased resistance to fluconazole compared with A. sativum oil. The essential oil of A. sativum is thus active against clinical isolates of Candida species obtained from dentures, with effects on both biofilm and planktonic cells in vitro. PMID- 28578871 TI - Subclassification of pN3 staging systems for penile cancer: Proposal for modification of the current TNM classification. AB - OBJECTIVE: To validate the clinical and prognostic significance of our proposed pN3 subclassification in penile cancer. MATERIALS AND METHODS: A retrospective analysis of 509 patients with penile cancer undergoing partial, total penectomy or inguinal lymphadenectomy or pelvic lymphadenectomy at Sun Yat-sen University Cancer Center was reevaluated by pathologists. pN3 stage was subclassified into pN3a (extranodal extension of any inguinal lymph node [LN] metastasis only) and pN3b (pelvic LN metastasis). The t test and chi-square test were applied to assess the comparability of pN3a and pN3b with clinicopathologic features. Univariable and multivariable statistical analyses were used to evaluate prognostic effect with cancer-specific survival. RESULTS: Among 509 patients, 71 patients with pN3 stage cancer were divided into 39 with pN3a and 32 with pN3b. The median number of LNs removed and the number of positive LNs were 27 and 3, respectively. The 3-year cancer-specific survival in pN3a and pN3b groups was significantly different at 47.9% and 28.6% (P = 0.003). In multivariable analysis, pN3 subclassification was an independent predictor for cancer-specific mortality (hazard ratio = 2.77; 95% CI: 1.170-6.558; P = 0.02). Adding pN3 subclassification to a multivariable model including pT stage, tumor grade, side involvement, lymphovascular invasion, number of positive LNs, and adjuvant therapy increased predictive accuracy for cancer-specific mortality from 0.665 to 0.695 (P<0.001). CONCLUSIONS: Subclassification helps better distinguish patients with pN3 penile cancer with increased risk of disease progression and cancer related mortality. PMID- 28578872 TI - An Atlas of beta-Glucuronidases in the Human Intestinal Microbiome. AB - Microbiome-encoded beta-glucuronidase (GUS) enzymes play important roles in human health by metabolizing drugs in the gastrointestinal (GI) tract. The numbers, types, and diversity of these proteins in the human GI microbiome, however, remain undefined. We present an atlas of GUS enzymes comprehensive for the Human Microbiome Project GI database. We identify 3,013 total and 279 unique microbiome encoded GUS proteins clustered into six unique structural categories. We assign their taxonomy, assess cellular localization, reveal the inter-individual variability within the 139 individuals sampled, and discover 112 novel microbial GUS enzymes. A representative in vitro panel of the most common GUS proteins by read abundances highlights structural and functional variabilities within the family, including their differential processing of smaller glucuronides and larger carbohydrates. These data provide a sequencing-to-molecular roadmap for examining microbiome-encoded enzymes essential to human health. PMID- 28578873 TI - Mechanism-Informed Refinement Reveals Altered Substrate-Binding Mode for Catalytically Competent Nitroreductase. AB - Nitroreductase (NR) from Enterobacter cloacae reduces diverse nitroaromatics including herbicides, explosives, and prodrugs, and holds promise for bioremediation, prodrug activation, and enzyme-assisted synthesis. We solved crystal structures of NR complexes with bound substrate or analog for each of its two half-reactions. We complemented these with kinetic isotope effect (KIE) measurements elucidating H-transfer steps essential to each half-reaction. KIEs indicate hydride transfer from NADH to the flavin consistent with our structure of NR with the NADH analog nicotinic acid adenine dinucleotide (NAAD). The KIE on reduction of p-nitrobenzoic acid (p-NBA) also indicates hydride transfer, and requires revision of prior computational mechanisms. Our mechanistic information provided a structural restraint for the orientation of bound substrate, placing the nitro group closer to the flavin N5 in the pocket that binds the amide of NADH. KIEs show that solvent provides a proton, enabling accommodation of different nitro group placements, consistent with the broad repertoire of NR. PMID- 28578874 TI - Dissecting the Specificity of Adenosyl Sulfamate Inhibitors Targeting the Ubiquitin-Activating Enzyme. AB - Targeting the activating enzymes (E1) of ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) has emerged as a promising anti-cancer strategy, possibly overcoming the ineffectiveness of proteasome inhibitors against solid tumors. Here, we report crystal structures of the yeast ubiquitin E1 (Uba1) with three adenosyl sulfamate inhibitors exhibiting different E1 specificities, which are all covalently linked to ubiquitin. The structures illustrate how the chemically diverse inhibitors are accommodated within the adenylation active site. When compared with the previously reported structures of various E1 enzymes, our structures provide the basis of the preferences of these inhibitors for different Ub/Ubl-activating enzymes. In vitro inhibition assays and molecular dynamics simulations validated the specificities of the inhibitors as deduced from the structures. Taken together, the structures establish a framework for the development of additional compounds targeting E1 enzymes, which will display higher potency and selectivity. PMID- 28578875 TI - Structural and Dynamics Characterization of the MerR Family Metalloregulator CueR in its Repression and Activation States. AB - CueR (Cu export regulator) is a metalloregulator protein that "senses" Cu(I) ions with very high affinity, thereby stimulating DNA binding and the transcription activation of two other metalloregulator proteins. The crystal structures of CueR when unbound or bound to DNA and a metal ion are very similar to each other, and the role of CueR and Cu(I) in initiating the transcription has not been fully understood yet. Using double electron-electron resonance (DEER) measurements and structure modeling, we investigate the conformational changes that CueR undergoes upon binding Cu(I) and DNA in solution. We observe three distinct conformations, corresponding to apo-CueR, DNA-bound CueR in the absence of Cu(I) (the "repression" state), and CueR-Cu(I)-DNA (the "activation" state). We propose a detailed structural mechanism underlying CueR's regulation of the transcription process. The mechanism explicitly shows the dependence of CueR activity on copper, thereby revealing the important negative feedback mechanism essential for regulating the intracellular copper concentration. PMID- 28578876 TI - Noise and pitch interact during the cortical segregation of concurrent speech. AB - Behavioral studies reveal listeners exploit intrinsic differences in voice fundamental frequency (F0) to segregate concurrent speech sounds-the so-called "F0-benefit." More favorable signal-to-noise ratio (SNR) in the environment, an extrinsic acoustic factor, similarly benefits the parsing of simultaneous speech. Here, we examined the neurobiological substrates of these two cues in the perceptual segregation of concurrent speech mixtures. We recorded event-related brain potentials (ERPs) while listeners performed a speeded double-vowel identification task. Listeners heard two concurrent vowels whose F0 differed by zero or four semitones presented in either clean (no noise) or noise-degraded (+5 dB SNR) conditions. Behaviorally, listeners were more accurate in correctly identifying both vowels for larger F0 separations but F0-benefit was more pronounced at more favorable SNRs (i.e., pitch * SNR interaction). Analysis of the ERPs revealed that only the P2 wave (~200 ms) showed a similar F0 x SNR interaction as behavior and was correlated with listeners' perceptual F0-benefit. Neural classifiers applied to the ERPs further suggested that speech sounds are segregated neurally within 200 ms based on SNR whereas segregation based on pitch occurs later in time (400-700 ms). The earlier timing of extrinsic SNR compared to intrinsic F0-based segregation implies that the cortical extraction of speech from noise is more efficient than differentiating speech based on pitch cues alone, which may recruit additional cortical processes. Findings indicate that noise and pitch differences interact relatively early in cerebral cortex and that the brain arrives at the identities of concurrent speech mixtures as early as ~200 ms. PMID- 28578878 TI - Abdominal aneurysm: An uncommon cause of low back pain. PMID- 28578877 TI - Progression of changes in the sensorial elements of the cochlear and peripheral vestibular systems: The otitis media continuum. AB - Our study aimed to evaluate pathologic changes in the cochlear (inner and outer hair cells and stria vascularis) and vestibular (vestibular hair cells, dark, and transitional cells) sensorial elements in temporal bones from donors who had otitis media. We studied 40 temporal bones from such donors, which were categorized in serous otitis media (SOM), serous-purulent otitis media (SPOM), mucoid/mucoid-purulent otitis media (MOM/MPOM), and chronic otitis media (COM); control group comprised 10 nondiseased temporal bones. We found significant loss of inner and outer cochlear hair cells in the basal turn of the SPOM, MOM/MPOM and COM groups; significant loss of vestibular hair cells was observed in the MOM/MPOM and COM groups. All otitis media groups had smaller mean area of the stria vascularis in the basal turn of the cochlea when compared to controls. In conclusion, our study demonstrated more severe pathologic changes in the later stages of the continuum of otitis media (MOM/MPOM and COM). Those changes seem to progress from the basal turn of the cochlea (stria vascularis, then inner and outer hair cells) to the middle turn of the cochlea and to the saccule and utricle in the MOM/MPOM and COM stages. PMID- 28578879 TI - Diaphragmatic paralysis in eosinophilic granulomatosis with polyangiitis. PMID- 28578881 TI - Increased Myogenic and Protein Turnover Signaling in Skeletal Muscle of Chronic Obstructive Pulmonary Disease Patients With Sarcopenia. AB - BACKGROUND: Sarcopenia was recently recognized as an independent condition by an International Classification of Diseases, Tenth Revision, Clinical Modification code, and is a frequently observed comorbidity in chronic obstructive pulmonary disease (COPD). Muscle mass is primarily dictated by the balance between protein degradation and synthesis, but their relative contribution to sarcopenia is unclear. OBJECTIVE: We aimed to assess potential differential molecular regulation of protein degradation and synthesis, as well as myogenesis, in the skeletal muscle of COPD patients with and without sarcopenia. METHODS: Muscle biopsies were obtained from the vastus lateralis muscle. Patients with COPD were clustered based on sarcopenia defined by low appendicular skeletal muscle mass index (nonsarcopenic COPD, n = 53; sarcopenic COPD, n = 39), and compared with healthy nonsarcopenic controls (n = 13). The mRNA and protein expression of regulators and mediators of ubiquitin-proteasome system (UPS), autophagy-lysosome system (autophagy), and protein synthesis were analyzed. Furthermore, mRNA expression of myogenesis markers was assessed. RESULTS: UPS signaling was unaltered, whereas indices of UPS regulation (eg, FOXO1 protein; p-FOXO3/FOXO3), autophagy signaling (eg, LC3BII/I; p-ULK1[Ser757]/ULK1), and protein synthesis signaling (eg, AKT1; p-GSK3B/GSK3B; p-4E-BP1/4E-BP1) were increased in COPD. These alterations were even more pronounced in COPD patients with sarcopenia (eg, FOXO1 protein; p-FOXO1/FOXO1; LC3BII/I; p-ULK(Ser555); p-AKT1/AKT1; AKT1; p-4E BP1). Furthermore, myogenic signaling (eg, MYOG) was increased in COPD despite a concomitant increase of myostatin (MSTN) mRNA expression, with no difference between sarcopenic and nonsarcopenic COPD patients. CONCLUSION: Together with elevated myogenic signaling, the increase in muscle protein turnover signaling in COPD, which is even more prominent in COPD patients with sarcopenia, reflects molecular alterations associated with muscle repair and remodeling. PMID- 28578880 TI - Quality of Care In Nursing Homes In Brazil. AB - BACKGROUND: There is an increased demand for nursing homes (NHs) in middle-income countries such as Brazil. To monitor the quality of NHs, there is a need for reliable instruments to assess the extent to which the care provided meets the expectations and rights of residents and their families. PURPOSE: To evaluate the reliability, applicability, and measurement results of an instrument for assessing the quality of NH care assessment. METHODS: We conducted a cross sectional study in 31 NHs, applying the Observable Indicators of Nursing Home Care Quality Instrument (OINHQ) adapted to the Brazilian context. The instrument includes 30 infrastructure and process indicators measured by direct observation grouped into seven domains: Communication; Care Delivery; Grooming; Odors; Environment-Basic; Environment-Access; and Environment-Homelike. To assess feasibility and reliability, 3 pairs of raters with different profiles (health professionals, health inspectors, and potential residents) were independently involved in data collection. We calculated Cronbach alpha for internal consistency of the instrument, Overall Agreement Index (OAI), and Prevalence Adjusted Bias-Adjusted Kappa (PABAkappa) for interrater reliability and analyzed the baseline NH quality through individual indicators, dimensions, and facilities. RESULTS: The OINHQ was in general reliable, with good internal consistency (Cronbach alpha = 0.93) and interrater agreement (mean OAI = 75%; PABAkappa = 0.49). NH quality is not homogeneous (overall mean = 2.9, ranging by facility between 1.9 and 3.7, on a scale of 1-5). Process-related indicators (mean = 2.7) are generally worse than structure-related indicators (mean = 3.5). The best domains were associated with Odors (mean = 4.1) and Grooming (mean = 3.9), whereas the priority domains for receiving improvement interventions were Care Delivery (mean = 2.0) and Environment-Homelike (mean = 2.5). CONCLUSIONS: Baseline evaluation of NH quality shows remarkable variability among facilities and ample room for improvement. PMID- 28578882 TI - Exercise for Disease Prevention and Management: A Precision Medicine Approach. PMID- 28578883 TI - Hospital-at-home Integrated Care Program for Older Patients With Orthopedic Processes: An Efficient Alternative to Usual Hospital-Based Care. AB - OBJECTIVE: To compare outcomes and costs for patients with orthogeriatric conditions in a home-based integrated care program versus conventional hospital based care. DESIGN: Quasi-experimental longitudinal study. SETTING: An acute care hospital, an intermediate care hospital, and the community of an urban area in the North of Barcelona, in Southern Europe. PARTICIPANTS: In a 2-year period, we recruited 367 older patients attended at an orthopedic/traumatology unit in an acute hospital for fractures and/or arthroplasty. INTERVENTION: Patients were referred to a hospital-at-home integrated care unit or to standard hospital-based postacute orthogeriatric unit, based on their social support and availability of the resource. MEASUREMENTS: We compared home-based care versus hospital-based care for Relative Functional Gain (gain/loss of function measured by the Barthel Index), mean direct costs, and potential savings in terms of reduction of stay in the acute care hospital. RESULTS: No differences were found in Relative Functional Gain, median (Q25-Q75) = 0.92 (0.64-1.09) in the home-based group versus 0.93 (0.59-1) in the hospital-based group, P =.333. Total health service direct cost [mean (standard deviation)] was significantly lower for patients receiving home-based care: ?7120 (3381) versus ?12,149 (6322), P < .001. Length of acute hospital stay was significantly shorter in patients discharged to home based care [10.1 (7)] than in patients discharged to the postacute orthogeriatric hospital-based unit [15.3 (12) days, P < .001]. CONCLUSION: The hospital-at-home integrated care program was suitable for managing older patients with orthopedic conditions who have good social support for home care. It provided clinical care comparable to the hospital-based model, and it seems to enable earlier acute hospital discharge and lower direct costs. PMID- 28578885 TI - Endodontic Board Certification: A Review of Factors Affecting the Certification Rate. AB - INTRODUCTION: Board certification identifies clinicians who possess advanced proficiency and expertise within their field. Only 23% of endodontists are board certified (the lowest among all dental specialties). The aim of this study was to determine the factors that influence endodontists' decisions regarding the completion of board certification. METHODS: A 16-question survey was e-mailed to 5073 US endodontists and residents who are American Association of Endodontists members. RESULTS: A total of 1603 endodontists and residents responded, corresponding to an overall response rate of 31.6%. Of those respondents, 73.8% felt board certification was important. Among endodontists, 32% were board certified, 24.4% had plans of becoming board certified, and 43.6% had no plans to become board certified. The most common reasons for not pursuing board certification were "graduated too long ago," "don't have time," "process is too long," and "not required to become an endodontist." Board-certified endodontists were more likely to believe board certification was important compared with their non-board-certified counterparts (97.5% vs 60.3%, P < .0001), and were more likely to have received training at programs that encouraged and provided assistance in completion of the certification process. Residents were more likely to plan on becoming certified compared with non-board-certified endodontists (89.6% vs 35.9%). CONCLUSIONS: Despite widespread agreement regarding the importance of board certification, a strikingly low percentage of endodontists are board certified. Views provided by endodontists and endodontic residents provide insight that may be used to guide changes that will effectively increase the percentage of board-certified endodontists. PMID- 28578884 TI - MicroRNA-335-5p Plays Dual Roles in Periapical Lesions by Complex Regulation Pathways. AB - INTRODUCTION: MicroRNA-335-5p has been reported to regulate osteogenic and chondrogenic differentiations of mesenchymal stem cells. The aim of this study was to explore the function and regulation mechanism of miR-335-5p in apical periodontitis (AP). METHODS: Total RNAs were extracted from human periodontal ligament fibroblasts (HPDLFs), 10 AP tissues, and 6 healthy periodontal ligament tissues using lysis buffer. Gene expression was detected using real-time polymerase chain reaction. The Dual Luciferase Assay (Promega, Madison, WI) was used to test miR-335-5p directly targeted urokinase-type plasminogen activator receptor (uPAR) and the receptor activator of nuclear factor kappa-B ligand (RANKL). Western Blot was used to detect protein expressions of RANKL, uPAR, and the fragile X-related 1 gene (FXR1). The enzyme-linked immunosorbent assay was used to detect the secretions of interleukin 6, tumor necrosis factor alpha, and RANKL. Data were analyzed using the Student t test. RESULTS: miR-335-5p acted as a positive mediator in HPDLF inflammation (P < .05). Two targets of miR-335-5p, uPAR and RANKL, were identified. Interestingly, uPAR was repressed by miR-335-5p at the basal level, but it can be relieved from miR-335-5p-mediated repression, which is called derepression, when HPDLFs were subjected to lipopolysaccharide stimulation. miR-335-5p promoted RANKL in HPDLFs regardless of whether or not it was under inflammatory conditions (P < .05). We proved FXR1 was responsible for the derepression of uPAR from miR-335-5p (P < .01). Both FXR1 and uPAR were positive mediators in HPDLF inflammation (P < .05). miR-335-5p, uPAR, RANKL, and FXR1 had the same expression profiles in HPDLF inflammation and AP tissues (P < .05). CONCLUSIONS: Our data showed that miR-335-5p may play dual roles in AP, and it might be considered as a target for therapeutic potency in clinical applications. PMID- 28578886 TI - Antibacterial Properties of Chitosan Nanoparticles and Propolis Associated with Calcium Hydroxide against Single- and Multispecies Biofilms: An In Vitro and In Situ Study. AB - INTRODUCTION: The aim of this study was to evaluate the efficacy of chitosan nanoparticles (CNPs) and ethanolic propolis extract (EPE) incorporated into a calcium hydroxide paste (Ca[OH]2) to kill bacterial biofilms. METHODS: Human root canal dentin was infected with Enterococcus faecalis for 21 days and also intraorally for 48 hours followed by incubation in brain-heart infusion for 48 hours to standardize biofilm growth. Ca(OH)2 pastes associated or not with CNPs or EPE were tested on biofilms for 7 and 14 days. Distilled water was used for control purposes. After the treatment procedures, microbiological analysis was performed to determine the reduction in E. faecalis colonies. Confocal microscopy was used to determine the percentage of cell viability in polymicrobial biofilms before and after the exposure to the experimental intracanal medications. RESULTS: All experimental pastes were able to significantly reduce the E. faecalis colony-forming units (CFU) after 7 or 14 days (P < .05). However, the CFU reduction was significantly improved when CNPs were incorporated into the Ca(OH)2 paste (P < .05). The multispecies biofilms treated with Ca(OH)2 showed similar percentages of bacterial viability to the control regardless of the exposure time (P > .05). The viable cell count significantly dropped in the Ca(OH)2/CNPs groups for both 7 and 14 days (P < .05), whereas the Ca(OH)2/EPE groups were only effective in eliminating bacteria during the first 7 days of treatment (P < .05). CONCLUSIONS: Incorporating CNPs into pastes of Ca(OH)2 could potentially be beneficial when using interappointment intracanal medications because of their ability to kill bacteria in short- and long-term exposure. PMID- 28578887 TI - A Retrospective, Radiographic Outcomes Assessment of 1960 Initial Posterior Root Canal Treatments Performed by Endodontists and Dentists. AB - INTRODUCTION: The Air Force Dental Service has established evidence-based treatment standards for endodontics, including 3-dimensional filling of the canal system, cuspal coverage restoration of endodontically treated posterior teeth, and use of rubber dam. The purpose of this retrospective study was to determine the effect of these standards on outcomes of initial posterior root canal treatments (RCTs) completed by Air Force (AF) and civilian dentists with and without accredited postgraduate training. METHODS: Treatment and follow-up radiographs of AF members who had an initial posterior RCT completed in 2011 were evaluated. A survey of all radiographs was performed to determine the (1) RCT obturation quality, (2) healing of periapical pathosis, and (3) presence and quality of cuspal coverage restorations. RESULTS: A total of 2262 RCTs were examined, with 1960 RCTs meeting inclusion criteria for at least 1 evaluation category. For RCT obturation quality, 1810 RCTs were evaluated, and 96.0% were considered adequate. For cuspal coverage restorations, 1856 RCTs were evaluated, and of these 2.7% were inadequately restored. Healing of periapical pathosis was 91.5% and 85.7% for AF and referred civilian providers, respectively. Survivability was 94.4% for endodontists, 95.3% for AF general dentists with additional training, 87.9% for AF general dentists without additional training, and 78.4% for civilian general dentists. Overall, survivability was 94.1% for a follow-up period ranging up to 47 months, with a mean of 27 months. CONCLUSIONS: In this retrospective, radiographic analysis, evidence-based practices as followed in the Air Force Dental Service and accredited postgraduate training resulted in improved treatment outcomes. PMID- 28578888 TI - Comparative Evaluation of Chemotactic Factor Effect on Migration and Differentiation of Stem Cells of the Apical Papilla. AB - INTRODUCTION: Cell homing strategies could potentially be used in regenerative endodontic procedures (REPs) to promote the progressive coronal migration of stem cells, including stem cells of the apical papilla (SCAPs), along with formation of a new vascular network without the need for intentional apical trauma and intracanal bleeding. Although many chemotactic factors have been investigated for different mesenchymal stem cells, their effect on SCAP migration and differentiation is not fully understood. This study aimed to comparatively evaluate the effect of stromal cell-derived factor 1 (SDF-1), transforming growth factor beta 1 (TGF-beta1), platelet-derived growth factor, granulocyte colony stimulating factor (G-CSF), or fibroblast growth factor 2 (FGF-2) on the migration and differentiation of SCAPs. METHODS: A characterized SCAP cell line was fluorescently labeled with Vybrant DiO dye (Life Technologies, Grand Island, NY) and used in transwell migration assays. Cells were subjected to 1, 10, or 100 ng/mL of each factor or a combination of factors followed by detection in a fluorescent plate reader. Lastly, SCAP differentiation into a mineralizing phenotype was evaluated in the presence or absence of the tested factors by quantitative alizarin red staining and alkaline phosphatase activity. Data were analyzed with 1-way analysis of variance with the Tukey post hoc test. RESULTS: Maximum migration was observed with G-CSF or FGF-2, which was significantly greater than the effects observed by the other tested factors. A combination of G CSF with TGF-beta1 significantly augmented both migration and differentiation into a mineralizing phenotype. CONCLUSIONS: G-CSF appears to be well suited to be further investigated as a key chemotactic factor in cell homing-based regenerative endodontic procedures. PMID- 28578889 TI - Telescopic Dental Needles versus Conventional Dental Needles: Comparison of Pain and Anxiety in Adult Dental Patients of Kerman University of Medical Sciences-A Randomized Clinical Trial. AB - INTRODUCTION: Pain felt during dental injections is dependent on dental anxiety. Patients feel increased pain if anxiety in the treatment environment is high, and therefore it is important to reduce anxiety during treatment to reduce pain. The purpose of this study was to compare pain and anxiety levels experienced during injections using a newly invented telescopic-coated dental needle that covers the conventional needle and also has the capability of applying topical anesthesia through its unique design with the conventional dental injection needle. METHODS: Dental injection anxiety questionnaires were completed by 60 adult patients who were randomly assigned to either the telescopic (a newly invented telescopic coated dental needle that covers the needles) or the conventional group. Patients also completed visual analog scales to rate their pain perception during injection, their overall experience, and their future anticipated anxiety. Wilcoxon, Mann-Whitney, and Student t tests were used for statistical analysis. Statistical significance was defined as P < .05. RESULTS: A total of 25 men and 35 women with an age range of 19-55 years (mean age of 38.7 +/- 2.31 years) participated in this study. Pain levels reported during the injection using the telescopic-coated needle (4.13 +/- 1.37) were significantly lower than those using the conventional needle (5.63 +/- 1.57), with statistically significant differences between the 2 groups (P < .05). Patients experienced significantly lower overall postinjection anxiety (P < .05) and had more positive overall experience ratings with the telescopic-coated needles. CONCLUSIONS: A new telescopic-coated dental needle was superior to a conventional injection system in pain perception and in reducing postinjection dental anxiety. PMID- 28578890 TI - Dynamic Torsional and Cyclic Fracture Behavior of ProFile Rotary Instruments at Continuous or Reciprocating Rotation as Visualized with High-speed Digital Video Imaging. AB - INTRODUCTION: This study examined the dynamic fracture behavior of nickel titanium rotary instruments in torsional or cyclic loading at continuous or reciprocating rotation by means of high-speed digital video imaging. METHODS: The ProFile instruments (size 30, 0.06 taper; Dentsply Maillefer, Ballaigues, Switzerland) were categorized into 4 groups (n = 7 in each group) as follows: torsional/continuous (TC), torsional/reciprocating (TR), cyclic/continuous (CC), and cyclic/reciprocating (CR). Torsional loading was performed by rotating the instruments by holding the tip with a vise. For cyclic loading, a custom-made device with a 38 degrees curvature was used. Dynamic fracture behavior was observed with a high-speed camera. The time to fracture was recorded, and the fractured surface was examined with scanning electron microscopy. RESULTS: The TC group initially exhibited necking of the file followed by the development of an initial crack line. The TR group demonstrated opening and closing of a crack according to its rotation in the cutting and noncutting directions, respectively. The CC group separated without any detectable signs of deformation. In the CR group, initial crack formation was recognized in 5 of 7 samples. The reciprocating rotation exhibited a longer time to fracture in both torsional and cyclic fatigue testing (P < .05). The scanning electron microscopic images showed a severely deformed surface in the TR group. CONCLUSIONS: The dynamic fracture behavior of NiTi rotary instruments, as visualized with high-speed digital video imaging, varied between the different modes of rotation and different fatigue testing. Reciprocating rotation induced a slower crack propagation and conferred higher fatigue resistance than continuous rotation in both torsional and cyclic loads. PMID- 28578891 TI - Autotransplantation of Mandibular Third Molar with Buccal Cortical Plate to Replace Vertically Fractured Mandibular Second Molar: A Novel Technique. AB - Tooth replacement often leads to inadequate vertical volume in the recipient site bone when a tooth has been extracted because of a vertical root fracture (VRF). This case report presents the autotransplantation of a mandibular third molar (tooth #32) with the attached buccal cortical plate to replace a mandibular second molar (tooth #31) diagnosed with a VRF. After extraction of tooth #31, the recipient socket was prepared based on the size measured in advance with cone beam computed tomographic imaging. The precise and calculated osteotomy of the cortical bone of tooth #32 allowed for the exact placement of the donor tooth in the position of tooth #31. The total extraoral time was only 25 minutes. The block was fixed to the recipient socket with an osteosynthesis screw and splinted with a double resin wire for 8 weeks. At the 6-month follow-up, the screw was removed, and the stability of the tooth and the regeneration obtained throughout the vestibular area were confirmed. At the 2-year follow-up, the transplanted tooth was asymptomatic and maintained a normal bone level. Advantages of autotransplantation over dental implants include maintenance of proprioception, possible orthodontic movements, and a relatively low cost. This case report demonstrates that an autotransplantation of a third molar attached to its buccal cortical plate is a viable option to replace teeth with a VRF. PMID- 28578892 TI - Proteome Expression in Human Periodontal Ligament after Delayed Hypothermic Preservation. AB - INTRODUCTION: Previous occasional successes after delayed replantation suggest that the presence of viable cells may not be the only factor for successful periodontal regeneration in delayed replantation. Various other factors such as proteins or the extracellular matrix (ECM) may play a role in this process. The purpose of this study was to characterize changes in the proteome components of periodontal ligament (PDL) tissue after hypothermic preservation of the tooth. METHODS: Extracted teeth were divided into 4 groups: immediate sampling, sampling after 1 week of preservation at 4 degrees C, sampling after 2 weeks of preservation at 4 degrees C, and sampling after 1 week of dry storage at room temperature as a negative control. PDL tissues were collected from the root and stored immediately in liquid nitrogen. The tissues were subjected to 2 dimensional gel electrophoresis, and spot selection was executed. Selected spots that maintained the protein volume were then processed with matrix-assisted laser desorption and ionization time-of-flight mass spectrometry to identify the nature of the proteins. RESULTS: Thirty-five selected spots were analyzed. Sixteen spots were identified as vimentin, and 3 spots were type VI collagen. The size of the 16 vimentin spots decreased gradually with increasing storage time, from 0 to 2 weeks, and decreased rapidly after dry storage. However, only the dry storage group differed significantly from the immediately sampled group. CONCLUSIONS: Vimentin was the most prominent protein followed by type VI collagen in volumetrically maintained protein spots. Although these proteins are known to be closely related with ECM integrity, the role of these proteins in delayed replantation is beyond the scope of this study. Further studies are needed to elucidate the possible role of these proteins for periodontal healing of delayed replantation. PMID- 28578893 TI - Long-term Success of Nonvital, Immature Permanent Incisors Treated With a Mineral Trioxide Aggregate Plug and Adhesive Restorations: A Case Series from a Private Endodontic Practice. AB - This case series evaluated the long-term clinical outcome of nonvital immature teeth treated with mineral trioxide aggregate (MTA) as an apical barrier and an adhesive restoration with or without a fiber post. Eighty-three teeth in 72 patients were treated by the first author with an apical MTA plug and an adhesive restoration of composite resin and in 45 of the 83 teeth 1 or more fiber posts. All of the patients had been referred to the first author's private endodontic practice with at least 1 immature tooth with signs of pulpal necrosis and subsequent apical periodontitis that had been caused by a variety of traumatic dental injuries. Three teeth presented had dens invaginatus. Of 83 teeth, 69 teeth in 60 patients were available for follow-up after 5 to 15 years (recall rate = 83%). The mean follow-up time was 8.29 years. No teeth were lost because of a root fracture. Ninety-six percent (66/69) of the recalled teeth were characterized as healed. Based on periapical radiographs and clinical examination, 96% of teeth treated with the MTA barrier technique and adhesive restorations were characterized as "healed" and were in function after 5 to 15 years (mean = 8.29 years). These results indicate that this is a viable and predictable treatment approach for the long-term success of nonvital immature teeth. PMID- 28578894 TI - Assessment of a Cavity to Optimize Ultrasonic Efficiency to Remove Intraradicular Posts. AB - INTRODUCTION: The study assessed an in vitro protocol for the removal of cast metal posts using ultrasonic vibration in multirooted teeth by drilling a cavity in the coronal portion of the post followed by ultrasound application in the cavity. METHOD: Forty endodontically treated molars received intraradicular cast posts and were divided into 4 groups according to the removal protocol: the control group, no cavity and no ultrasonic vibration; the ultrasonic group, no cavity and ultrasonic vibration in the coronal portion of the core; the cavity group, a cavity in the core and no ultrasonic vibration; and the cavity ultrasonic group, a cavity in the core and ultrasonic vibration inside the cavity. The traction test was performed on all samples using a universal testing machine (EMIC DL-2000; EMIC Equipamentos e Sistemas de Ensaio LTDA, Sao Jose dos Pinhais, PR, Brazil) at a speed of 1 mm/min, obtaining values in Newtons. The data were statistically analyzed using analysis of variance and the Tukey-Kramer test (P < .05). RESULTS: The results showed statistically significant differences between the tested groups (control group = 322.74 N, ultrasonic group = 283.09 N, cavity group = 244.00 N, and cavity ultrasonic group = 237.69 N). The lowest mean strength was found in the group that received ultrasonic vibration inside the cavity. CONCLUSIONS: Preparing a cavity in the coronal core followed by ultrasonic vibration reduces the traction force required for removal. The removal protocol was effective for removing posts in multirooted teeth cemented with zinc phosphate. PMID- 28578895 TI - CDC-reported assisted reproductive technology live-birth rates may mislead the public. AB - The Centre for Disease Control and Prevention (CDC) publicly reports assisted reproductive technology live-birth rates (LBR) for each US fertility clinic under legal mandate. The 2014 CDC report excluded 35,406 of 184,527 (19.2%) autologous assisted reproductive technology cycles that involved embryo or oocyte banking from LBR calculations. This study calculated 2014 total clinic LBR for all patients utilizing autologous oocytes two ways: including all initiated assisted reproductive technology cycles or excluding banking cycles, as done by the CDC. The main limitation of this analysis is the CDC report did not differentiate between cycles involving long-term banking of embryos or oocytes for fertility preservation from cycles involving short-term embryo banking. Twenty-seven of 458 (6%) clinics reported over 40% of autologous cycles involved banking, collectively performing 12% of all US assisted reproductive technology cycles. LBR in these outlier clinics calculated by the CDC method, was higher than the other 94% of clinics (33.1% versus 31.1%). However, recalculated LBR including banking cycles in the outlier clinics was lower than the other 94% of clinics (15.5% versus 26.6%). LBR calculated by the two methods increasingly diverged based on proportion of banking cycles performed by each clinic reaching 4.5-fold, thereby, potentially misleading the public. PMID- 28578896 TI - Severe aortic stenosis in dextrocardia with situs invertus and anomalous single coronary ostium treated with transcatheter aortic valve replacement. AB - Dextrocardia with situs inversus presents a unique anatomy with right-sided vascular system that may be associated with a number of additional cardiac and vascular malformations. A rare association is the presence of a single coronary artery ostium. To our knowledge, this is the first reported case of transcatheter aortic valve replacement using Edwards SAPIEN S3 valve in Dextrocardia patient with single coronary artery take off. PMID- 28578897 TI - Inadvertent anastomosis of the left internal mammary artery to the great cardiac vein. AB - We present an uncommon and underreported complication of coronary artery bypass graft surgery: erroneous anastomosis of the left internal mammary artery to the great cardiac vein. The iatrogenic aorto-coronary arteriovenous fistula with left to-right shunting resulted in dilation of the coronary sinus, a supporting secondary finding. Factors predisposing to this inadvertent anastomosis include an intramyocardial segment of the left anterior descending coronary artery, demonstrated in this case, as well as epicardial fat and potentially fibrosis of the underlying myocardium. PMID- 28578898 TI - Reimagining the Special Supplemental Nutrition Program for Women, Infants, and Children Career Ladder as Requirements Change for Registered Dietitian Nutritionists. PMID- 28578899 TI - 2015 Evidence Analysis Library Evidence-Based Nutrition Practice Guideline for the Management of Hypertension in Adults. AB - Hypertension (HTN) or high blood pressure (BP) is among the most prevalent forms of cardiovascular disease and occurs in approximately one of every three adults in the United States. The purpose of this Evidence Analysis Library (EAL) guideline is to provide an evidence-based summary of nutrition therapy for the management of HTN in adults aged 18 years or older. Implementation of this guideline aims to promote evidence-based practice decisions by registered dietitian nutritionists (RDNs), and other collaborating health professionals to decrease or manage HTN in adults while enhancing patient quality of life and taking into account individual preferences. The systematic review and guideline development methodology of the Academy of Nutrition and Dietetics were applied. A total of 70 research studies were included, analyzed, and rated for quality by trained evidence analysts (literature review dates ranged between 2004 and 2015). Evaluation and synthesis of related evidence resulted in the development of nine recommendations. To reduce BP in adults with HTN, there is strong evidence to recommend provision of medical nutrition therapy by an RDN, adoption of the Dietary Approaches to Stop Hypertension dietary pattern, calcium supplementation, physical activity as a component of a healthy lifestyle, reduction in dietary sodium intake, and reduction of alcohol consumption in heavy drinkers. Increased intake of dietary potassium and calcium as well as supplementation with potassium and magnesium for lowering BP are also recommended (fair evidence). Finally, recommendations related to lowering BP were formulated on vitamin D, magnesium, and the putative role of alcohol consumption in moderate drinkers (weak evidence). In conclusion, the present evidence-based nutrition practice guideline describes the most current recommendations on the dietary management of HTN in adults intended to support the practice of RDNs and other health professionals. PMID- 28578901 TI - Pharmacological treatments and risk of readmission to hospital for unipolar depression in Finland: a nationwide cohort study. AB - BACKGROUND: Little is known about the comparative effectiveness of long-term pharmacological treatments for severe unipolar depression. We aimed to study the effectiveness of pharmacological treatments in relapse prevention in a nationwide cohort of patients who had been admitted to hospital at least once as a result of unipolar depression. METHODS: Our nationwide cohort study investigated the risk of readmission to hospital in 1996-2012 in all patients in Finland who had been admitted to hospital at least once for unipolar depression (without a diagnosis of schizophrenia or bipolar disorder) in Finland between Jan 1, 1987, and Dec 31, 2012. We used nationwide databases to obtain data for hospital admission, mortality, and dispensed medications. Exposure and non-exposure periods for medications were established using the PRE2DUP method. The primary analysis was within-individual analysis of readmission to hospital in the total cohort, in which each individual was used as his or her own control to eliminate selection bias. Putative survival and protopathic biases were controlled in sensitivity analyses. Since 33 independent statistical comparisons were done for specific medications, the level of statistical significance was set at p<0.0015. FINDINGS: Data from 123 712 patients were included in the total cohort, with a mean follow up time of 7.9 years (SD 5.3). Lithium use was associated with a lower risk of re admission to hospital for mental illness than was no lithium use (hazard ratio [HR] 0.47 [95% CI 0.40-0.55]; p<0.0001), whereas the groups of antidepressants (HR 1.10 [1.06-1.13]; p<0.0001) and antipsychotics (HR 1.16 [1.12-1.20]; p<0.0001) were not associated with a reduced risk of readmission to hospital. Risk of hospital readmission was lower during lithium therapy alone (HR 0.31 [0.21-0.47]; p<0.0001) than during use of lithium with antidepressants (HR 0.50 [0.43-0.59]; p<0.0001). After lithium, clozapine (HR 0.65 [0.46-0.90]; p=0.010) and amitriptyline (HR 0.75 [0.70-0.81]; p<0.0001) were the specific agents associated with the next lowest risk of readmission. In the sensitivity analyses controlling for survival and protopathic biases, all drugs were associated with lower rates of readmission to hospital than they were in the primary analysis, showing the same rank order in comparative effectiveness. The lowest mortality was observed during antidepressant use (HR 0.56 [0.54-0.58]; p<0.0001). INTERPRETATION: Our results indicate that lithium, especially without concomitant antidepressant use, is the pharmacological treatment associated with the lowest risk of hospital readmission for mental illness in patients with severe unipolar depression, and the outcomes for this measure related to antidepressants and antipsychotics are poorer than lithium. Lithium treatment should be considered for a wider population of severely depressed patients than those currently considered, taking into account its potential risks and side-effects. FUNDING: The Finnish Ministry of Health. PMID- 28578902 TI - Lithium for long-term treatment of unipolar depression. PMID- 28578900 TI - Family Home Food Environment and Nutrition-Related Parent and Child Personal and Behavioral Outcomes of the Healthy Home Offerings via the Mealtime Environment (HOME) Plus Program: A Randomized Controlled Trial. AB - BACKGROUND: Research has demonstrated a significant positive association between frequent family meals and children's dietary intake; however, the promotion of healthful family meals has not been rigorously tested for key food environment and nutrition-related behavioral outcomes in a randomized trial. OBJECTIVE: To describe family home food environment and nutrition-related parent and child personal and behavioral outcomes of the Healthy Home Offerings via the Mealtime Environment Plus program, the first rigorously tested family meals intervention targeting childhood obesity prevention. DESIGN: Randomized controlled trial. Baseline, postintervention (12 months, 93% retention), and follow-up (21 months, 89% retention) data (surveys and dietary recalls) were collected. PARTICIPANTS/SETTING: Children aged 8 to 12 years (N=160) and their parents were randomized to intervention (n=81) or control (n=79) groups. INTERVENTION: The intervention included five parent goal-setting calls and 10 monthly sessions delivered to families in community settings that focused on experiential nutrition activities and education, meal planning, cooking skill development, and reducing screen time. MAIN OUTCOME MEASURES: Family home food environment outcomes and nutrition-related child and parent personal and behavioral outcomes. STATISTICAL ANALYSES PERFORMED: Analyses used generalized linear mixed models. Primary comparisons were contrasts between intervention and control groups at postintervention and follow-up, with adjustments for child age and parent education. RESULTS: Compared with control parents, intervention parents showed greater improvement over time in scores of self-efficacy for identifying appropriate portion sizes, with significant differences in adjusted means at both post-intervention (P=0.002) and follow-up (P=0.01). Intervention children were less likely to consume at least one sugar-sweetened beverage daily at post intervention than control children (P=0.04). CONCLUSIONS: The Healthy Home Offerings via the Mealtime Environment Plus program involved the entire family and targeted personal, behavioral, and environment factors important for healthful changes in the home food environment and children's dietary intake. The intervention improved two nutrition-related behaviors and this may inform the design of future family meal interventions. PMID- 28578903 TI - Intrinsic capabilities of Leptospermum javanicum in inducing apoptosis and suppressing the metastatic potential of human lung carcinoma cells. AB - The active isolate of LF1 in Leptospermum javanicum was further looked into its capabilities in provoking an apoptotic reaction and suppressing the metastasis process in treated non-small lung cancer cells. LF1 underwent isolation and purification to yield a white powder which was identified as Betulinic acid (BA) via NMR, LCMS and IR spectroscopy. The isolate, BA, which produced an encouraging cytotoxic effect against non-small lung cancer cells (A549 and NCI-H1299) through the MTT assay, was further assessed with TUNEL, Sub-G1 population quantification, acridine orange/ethidium bromide staining as well as activated caspase-3 detection. The results pointed towards the induction of apoptosis as a result of increasing doses of BA, regardless of the p53 status in both cell lines. Treatment with BA also prevented an effective attachment of the invasive A549 cells onto a new culture surface in addition to diminishing the migratory potential of treated cells across a porous membrane. Further investigation through the ELISA detection and gelatin zymography showed an adverse effect to production of matrix metalloproteinase-2 (MMP-2) while the levels of matrix metalloproteinase-9 (MMP-9) were not negatively affected. The findings from this study validate the potential of L. javanicum as a potential anti-cancer treatment as stated in our previous study. The isolate, BA not only showed a capacity in inducing apoptotic cell death in non-small lung cancer cells, but managed to distort the ability of the cancer cells in effectively undergoing the metastasis process. PMID- 28578904 TI - Role of RAS/Wnt/beta-catenin axis activation in the pathogenesis of podocyte injury and tubulo-interstitial nephropathy. AB - Renin-angiotensin system (RAS) plays a key role in the development and progression of chronic kidney disease (CKD). Recent studies have demonstrated activation of Wnt/beta-catenin pathway by RAS in CKD. However, the underlying mechanisms of RAS and Wnt/beta-catenin signaling interaction and their contribution to the pathogenesis of CKD have not been fully elucidated. Present study is designed to investigate the role of RAS/Wnt/beta-catenin axis activation in tubulo-interstitial fibrosis and glomerulosclerosis by the cultured HK-2 and podocytes. HK-2 cells and podocytes are treated by angiotensin II (Ang II). Ang II up-regulates expression of various Wnt mRNA and active beta-catenin protein in HK-2 cells and podocytes in the time- and dose-dependent manners. In addition, Ang II induces injury, oxidative stress and inflammation and impaired Nrf2 activation in HK-2 cells and podocytes. This was accompanied by up-regulations of RAS components as well as Wnt1, activated beta-catenin and its target proteins. RAS/Wnt/beta-catenin axis activation results in epithelial-to-mesenchymal transition in HK-2 cells and injuries podocytes. The effect of Ang II is inhibited by losartan and ICG-001, a Wnt/beta-catenin inhibitor. We further found that treatment with natural products, ergone, alisol B 23-acetate and pachymic acid B inhibit extracellular matrix accumulation in HK-2 cells and attenuated podocyte injury, in part, by inhibiting Ang II induced RAS/Wnt/beta-catenin axis activation. In summary, activation of RAS/Wnt/beta-catenin axis results in podocytes and tubular epithelial cell, injury and up-regulations of oxidative, inflammatory and fibrotic pathways. These adverse effects are ameliorated by ergone, alisol B 23-acetate and pachymic acid B. Therefore, these natural products could be considered as novel Wnt/beta-catenin signaling inhibitors and anti-fibrotic agents. PMID- 28578906 TI - Corrigendum to "Quantitative proteomics and integrative network analysis identified novel genes and pathways related to osteoporosis" [J. Proteomics 142 (16 June 2016) 45-52]. PMID- 28578905 TI - Attentional resources modulate error processing-related brain electrical activity: Evidence from a dual-task design. AB - Attention plays an important role in the processing of error, but only a few studies have explored the relationship between them. The current study used a dual-task paradigm, combining the classic flanker task with a working memory load task, to explore how changes in the amount of attentional resources modulate error negativity (Ne) and error positivity (Pe). The results showed that the reduction of attentional resources overall caused a decrease in Pe amplitude, especially in the late stage of Pe, which had a significant diminution in amplitude. However, changes in the amount of attentional resources did not cause significant changes in the Ne amplitude. These results suggest that the early stage of error processing in the Ne time window is less affected by attention, but the Pe stage is regulated by attentional resources, especially in the late Pe stage. PMID- 28578907 TI - Eosinophilic esophagitis induced by aeroallergen sublingual immunotherapy in an enteral feeding tube-dependent pediatric patient. PMID- 28578908 TI - Prospective evaluation of electronic medical record penicillin allergy documentation at a tertiary community teaching hospital. PMID- 28578909 TI - Editorial overview: A feast of structural glycobiology. PMID- 28578910 TI - E6AP inhibits G-CSFR turnover and functions by promoting its ubiquitin-dependent proteasome degradation. AB - Granulocyte colony-stimulating factor receptor (G-CSFR) plays a crucial role in regulating myeloid cell survival, proliferation, and neutrophilic granulocyte precursor cells maturation. Previously, we demonstrated that Fbw7alpha negatively regulates G-CSFR and its downstream signaling through ubiquitin-proteasome mediated degradation. However, whether additional ubiquitin ligases for G-CSFR exist is not known. Identifying multiple E3 ubiquitin ligases for G-CSFR shall improve our understanding of activation and subsequent attenuation of G-CSFR signaling required for differentiation and proliferation. Here, for the first time we demonstrate that E6 associated protein (E6AP), an E3 ubiquitin ligase physically associates with G-CSFR and targets it for ubiquitin-mediated proteasome degradation and thereby attenuates its functions. We further show that E6AP promoted G-CSFR degradation leads to reduced phosphorylation of signal transducer and activator of transcription 3 (STAT3) which is required for G-CSF dependent granulocytic differentiation. More importantly, our finding shows that E6AP also targets mutant form of G-SCFR (G-CSFR-T718), frequently observed in severe congenital neutropenia (SCN) patients that very often culminate to AML, however, at a quite slower rate than wild type G-CSFR. In addition, our data showed that knockdown of E6AP restores G-CSFR and its signaling thereby promoting granulocytic differentiation. Collectively, our data demonstrates that E6AP facilitates ubiquitination and subsequent degradation of G-CSFR leading to attenuation of its downstream signaling and inhibition of granulocytic differentiation. PMID- 28578912 TI - Advance Care Planning in Cardiology. PMID- 28578911 TI - Metalloproteinases in extracellular vesicles. AB - Extracellular vesicles (EVs) have emerged as pivotal mediators of intercellular communications in local and distant microenvironments under patho/physiological conditions. EVs contain bioactive materials such as proteins, RNA transcripts, microRNAs and even DNAs, and recent work on their protein profiles has revealed the existence of metalloproteinases including the cell surface-anchored sheddases ADAMs (a disintegrin and metalloproteinases) and soluble ADAMTSs (ADAMs with thrombospondin motifs) as well as cell surface-bound and soluble MMPs (matrix metalloproteinases) from various cell types and body fluids. EV-associated metalloproteinases can alter the make-up of EVs by ectodomain shedding, exert a shedding activity after being taken up by target cells, or directly contribute to degradation of extracellular matrix surrounding cells. In addition, metalloproteinase-loaded EV cargoes sometimes stimulate critical signaling pathways, actively participating in tumor progression. This review focuses on recent findings and knowledge about metalloproteinases in EV biology, and we discuss their potential involvement in human diseases, highlighting the context of tumor cells and their microenvironment. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman. PMID- 28578913 TI - Cardiac Troponin and Exercise; Still Much to Learn. PMID- 28578914 TI - The future of 'addiction': Critique and composition. PMID- 28578916 TI - Telling different stories, making new realities: The ontological politics of 'addiction' biographies. AB - Personal narratives of alcohol and other drug addiction circulate widely in popular culture and they also have currency in professional therapeutic settings. Despite this, relatively little research has explored the conventions operating in these narratives and how they shape people's experiences and identities. While research in this area often proceeds on the premise that addiction biographies are straightforwardly 'true' accounts, in this paper we draw on the insights of critical alcohol and other drug scholarship, and the concept of 'ontological politics' to argue that biographies produce normative ideas about addiction and those said to be experiencing it. Our analysis compares traditional addiction narratives with the biographies we reconstructed from qualitative interviews with 60 people in Australia who describe themselves as having an 'addiction', 'dependence' or drug 'habit'. We track how addiction is variously enacted in these accounts and comment on the effects of particular enactments. By attending to the ways in which people cope, even thrive, with the kind of consumption that would attract a diagnosis of addiction or dependence, the biographies we produced disrupt the classic narrative of increasing drug use, decline and eventual collapse. Doing so allows for consideration of the benefits of consumption, as well as the ways that people carefully regulate it to minimise harms. It also constitutes individuals as active in managing consumption-an important move that challenges dominant understandings of addiction as a disorder of compulsivity. We conclude by considering the implications of our attempt to provide an alternative range of narratives, which resonate with people's diverse experiences. PMID- 28578915 TI - Iterating 'addiction': Residential relocation and the spatio-temporal production of alcohol and other drug consumption patterns. AB - Addiction is generally understood to be characterised by a persistent pattern of regular, heavy alcohol and other drug consumption. Current models of addiction tend to locate the causes of these patterns within the body or brain of the individual, sidelining relational and contextual factors. Where space and place are acknowledged as key factors contributing to consumption, they tend to be conceived of as static or fixed, which limits their ability to account for the fluid production and modulation of consumption patterns over time. In this article we query individualised and decontextualised understandings of the causes of consumption patterns through an analysis of accounts of residential relocation from interviews undertaken for a large research project on experiences of addiction in Australia. In conducting our analysis we conceptualise alcohol and other drug consumption patterns using Karen Barad's notions of intra-action and spatio-temporality, which allow for greater attention to be paid to the spatial and temporal dimensions of the material and social processes involved in generating consumption patterns. Drawing on 60 in-depth interviews conducted with people who self-identified as experiencing an alcohol and other drug addiction, dependence or habit, our analysis focuses on the ways in which participant accounts of moving enacted space and time as significant factors in how patterns of consumption were generated, disrupted and maintained. Our analysis explores how consumption patterns arose within highly localised relations, demonstrating the need for understandings of consumption patterns that acknowledge the indivisibility of space and time in their production. In concluding, we argue for a move away from static conceptions of place towards a more dynamic conception of spatio-temporality, and suggest the need to consider avenues for more effectively integrating place and time into strategies for generating preferred consumption patterns and initiating and sustaining change where desired. PMID- 28578918 TI - Ca2+ signaling, apoptosis and autophagy in the developing cochlea: Milestones to hearing acquisition. AB - In mammals, the sense of hearing arises through a complex sequence of morphogenetic events that drive the sculpting of the auditory sensory epithelium into its terminally functional three-dimensional shape. While the majority of the underlying mechanisms remain unknown, it has become increasingly clear that Ca2+ signaling is at center stage and plays numerous fundamental roles both in the sensory hair cells and in the matrix of non-sensory, epithelial and supporting cells, which embed them and are tightly interconnected by a dense network of gap junctions formed by connexin 26 (Cx26) and connexin 30 (Cx30) protein subunits. In this review, we discuss the intricate interplay between Ca2+ signaling, connexin expression and function, apoptosis and autophagy in the crucial steps that lead to hearing acquisition. PMID- 28578917 TI - STAT3 inhibition by STA21 increases cell surface expression of MICB and the release of soluble MICB by gastric adenocarcinoma cells. AB - NKG2D is an activating receptor expressed on NK cells that binds to a variety of ligands, including MICA and MICB. These cell surface glycoproteins are overexpressed under cellular transformation, thus playing an important role in cell-mediated immune response to tumors. STAT3 is a transcription factor that is constitutively active in cancer. It negatively regulates MICA expression on target cells, while its inhibition enhances NK cell cytotoxicity against tumors. In this work, we aimed to describe the effect of STAT3 signaling inhibition by STA21 on the regulation of MICB expression in gastric adenocarcinoma cells and its effect on the cytotoxic function of NK cells. Treatment of gastric adenocarcinoma cells with STA21 induced an increase in MICB expression and soluble MICB secretion, as well as a variable pattern on effector cell degranulation. Soluble MICB secretion by gastric adenocarcinoma cells was not affected by metalloprotease inhibition. We also observed that primary gastric adenocarcinoma tissue released soluble MICB into the extracellular milieu. Recombinant MICB induced a significant decrease in the levels of NKG2D receptor on effector NK and CD8+ T cells, which correlated with an impaired cytotoxic function. Altogether, our data provide evidence that STAT3 signaling pathway regulates MICB expression on gastric adenocarcinoma cells and that recombinant soluble MICB compromises the cytolytic activity of NK cells. PMID- 28578919 TI - Opioid consumption and pain in gynecological cancer patients treated with interstitial brachytherapy. AB - PURPOSE: Interstitial brachytherapy (ISBT) has advantages over the intracavitary techniques in the treatment of gynecological malignancies. The insertion of catheters into tumor enables higher dose conformality and normal tissue sparing. However ISBT can be associated with pain due its invasiveness. The goal of this study is to assess pain and opioid consumption of patients implanted with a perineal ISBT applicator. METHODS AND MATERIALS: Forty-eight patients were treated with ISBT from September 2014 to April 2016. Mean age was 63. Malignancies included 18 cervical cancers, 12 vaginal, 14 recurrent endometrial, and four others. Patient characteristics and technical ISBT data were collected. Opioid consumption was quantified as oral morphine equivalent per day (OMEq/day) from postimplant until removal. Pain score levels were collected by using an 11 point scoring system. RESULTS: Twenty-three patients had a single ISBT implantation, whereas 25 had a second. Twenty-eight patients required IV-patient controlled analgesia. Mean OMEq/day for the first insertion was 55 mg. In the second insertion, an increase of 22 mg was seen (p = 0.0004). Patients with IV patient-controlled analgesia had higher opioid consumption (OMEq/day 69.8 mg vs 32.1 mg, p = 0.001) and maximum pain scores (5.5 vs 3.4, p = 0.007) as compared with patients on oral opioids. Higher levels of pain were detected in the first hours postimplant. Previous opioids and age were associated with increased opioid consumption. CONCLUSIONS: Pain from perineal-ISBT can be managed with oral opioids in a select group of patients. For repeat insertions, there may be an increase in opioid consumption. While age and previous opioids affected opioid requirements, other factors such as number of needles and insertion depth were not associated factors. PMID- 28578920 TI - Clinical factors and dosimetry associated with the development of prostate brachytherapy-related urethral strictures: A matched case-control study. AB - PURPOSE: Urethral strictures are a rare complication of prostate brachytherapy (BXT), with prior studies showing radiation dose to the bulbomembranous urethra as being associated with stricture formation. This retrospective case-control study explored clinical and dosimetric parameters associated with the development of BXT-related urethral strictures. METHODS AND MATERIALS: A cohort of 34 patients developed urethral strictures after BXT at our institution for the period of 2008-2014. Each case was matched with two controls (68 controls) that had not developed a urethral stricture according to similar baseline clinical and dosimetric parameters. Stricture development was compared with clinical (i.e., age, smoking status, diabetes, hypertension, vascular disease, International Prostate Symptom Score, hormones) and dosimetric (i.e., prostate, urethra, urethral segments [base, midgland, apex, extraprostatic, and 5 mm margin]) variables. Statistical modeling approaches such as univariate, multivariate, and subset selection methods for risk prediction were applied to identify parameter(s) with best predictive ability of toxicity. The performances of models were ranked according to Akaike information criterion score. RESULTS: The results show that the R2 statistic increases from 6%, when only one parameter is included in the model, to almost 33%, when all the parameters are included. The best-fit subset of parameters included pretreatment International Prostate Symptom Score sum, urethra D30 Gy, urethra D5 Gy, and intraprostatic urethra with 5-mm margin V200 at the apex having the highest ability to predict the development of urinary strictures. CONCLUSIONS: This study used statistical modeling, a novel approach in prostate BXT dosimetric studies, to identify a subset of parameters with predictive ability in identifying patients who develop urethral strictures. PMID- 28578921 TI - Impaired social cognition in schizophrenia during the Ultimatum Game: An EEG study. AB - BACKGROUND: Schizophrenia has a core feature of cognitive dysfunctions. Since these deficits are predictive for patients' functional outcome, understanding their origin is of great importance to improve their daily lives. A specific component of the deficit involves social decision-making, which can be studied using the Ultimatum Game (UG). In this task, a "proposer" proposes a share of money to a "responder", who can either accept or reject this offer. If the responder accepts the proposal, both win money. If the responder refuses, both players end up with nothing. Therefore, the UG evaluates decision-making strategies and social interaction. METHODS: We compared the neuronal bases of schizophrenic patients with healthy controls, while performing the UG. Electroencephalography (EEG) was used to find differences in the event-related potential (ERP) components typical for the UG, namely the P2 and feedback-related negativity (FRN). Source reconstruction was further used to define the origin of these differences. RESULTS: In the proposer condition, no differences were found in amplitude of the P2 and FRN components. In contrast, in the responder condition, significant differences were found for the amplitude of the FRN (p=0.009). Using source reconstruction, a different activation in a border zone of the dorsolateral and the medial prefrontal cortex was revealed in schizophrenic patients to underlie this component. CONCLUSIONS: We suggest that the difference found in the FRN amplitude is associated with difficulties of patients in interpreting another's behavior. Although schizophrenic patients correctly activate neuronal bases in the proposer condition, they were not able to activate the same networks in the responder condition, thereby exposing their difficulties in social interaction. PMID- 28578923 TI - Acoustic startle response and its modulation in schizophrenia and autism spectrum disorder in Asian subjects. AB - The acoustic startle response (ASR) and its modulation, including prepulse inhibition (PPI), are considered to be promising neurophysiological indices for translational research in psychiatry. Impairment of the PPI has been reported in several psychiatric disorders, but particularly in schizophrenia, where PPI is considered to be a candidate endophenotype of the disorder. Although the profiles of the ASR differ between races, recent studies of single ethnicity samples in Asia were in accord with a number of studies from Western countries, in reporting that patients with schizophrenia exhibit impaired PPI. The PPI of the ASR is known to develop before 8years of age, and PPI impairment has only been reported in adults (not children) with autism spectrum disorder (ASD), which involves atypical features that are present from early development. Recent Asian studies of children with ASD suggest that comprehensive investigation of the ASR and its modulation, including the startle response to weak startle stimuli, peak startle latency, and PPI, may contribute to an understanding of the impairment of the neural circuitry in children with ASD and its comorbid behavioral problems. In this review, we review recent findings on the ASR and its modulation from Asian countries, and discuss its potential use for studying sensorimotor gating and its relationship to schizophrenia and ASD. In conclusion, the ASR and its modulation can provide a well-established global neurophysiological index for translational research in psychiatric disorders. Future studies investigating the development of sensorimotor gating in early development may contribute to prevention of psychiatric disorders. PMID- 28578922 TI - Depression and clinical high-risk states: Baseline presentation of depressed vs. non-depressed participants in the NAPLS-2 cohort. AB - Depressed mood appears to be highly prevalent in clinical high risk (CHR) samples. However, many prior CHR studies utilize modest size samples and do not report on the specific impact of depression on CHR symptoms. The aim of the current paper is to investigate the prevalence of depressive disorders and the impact of lifetime depression on baseline clinical presentation and longitudinal outcomes in a large cohort of individuals meeting CHR criteria in the second phase of the North American Prodrome Longitudinal Study (NAPLS-2). Depression was assessed both categorically (via DSM-IV-TR diagnoses) and symptomatically (using a clinician-rated scale of depressive symptoms) within a sample of 764 individuals at CHR and 279 controls. Current and lifetime depressive disorders were highly prevalent (60%) in this sample. Depression diagnoses were associated with more pronounced negative and general symptoms; individuals with remitted depression had significantly less severe negative, disorganized, and general symptoms and better social and role functioning relative to those with current depression. Current mood disturbance, as measured by scores on a clinician-rated symptom scale, contributed beyond the impact of positive and negative symptoms to impairments in social functioning. Both symptomatic and diagnostic baseline depression was significantly associated with decreased likelihood of remission from CHR status; however depression did not differentially distinguish persistent CHR status from transition to psychosis at follow-up. These findings suggest that depressed mood may function as a marker of poor prognosis in CHR, yet effective treatment of depression within this population can yield improvements in symptoms and functioning. PMID- 28578924 TI - Letter to the Editor: Influence of rTMS on smoking in patients with schizophrenia. PMID- 28578925 TI - Identification of Candida species in vaginal flora using conventional and molecular methods. AB - Vaginal swab samples were collected both from women with signs of acute vulvovaginal candidiasis (VVC; n=270) and from healthy controls (n=100). The microscopic examination revealed a significant difference in the proportion of positive cultures of Candida between the VVC (33%) and control (21%) groups. To determine the frequency of different species, positive cultures were analyzed using the germ tube test, CHROMagar medium, API 20 AUX System and DNA analysis. CHROMagar and API 20 AUX System tests identified 67% of samples as C. albicans. Out of these, 42% appeared to be C. dubliniensis when the specific primers in the polymerase chain reaction (PCR) were used. We observed the prevalence of Candida species isolated from the vagina in descending order as follows: C. albicans (38 39%), C. glabrata (32-33%), C. dubliniensis (28-29%) and C. tropicalis (0-1%) for both the VVC and the control group. PMID- 28578926 TI - The use of porcine corrosion casts for teaching human anatomy. AB - In teaching and learning human anatomy, anatomical autopsy and prosected specimens have always been indispensable. However, alternative methods must often be used to demonstrate particularly delicate structures. Corrosion casting of porcine organs with Biodur E20(r) Plus is valuable for teaching and learning both gross anatomy and, uniquely, the micromorphology of cardiovascular, respiratory, digestive, and urogenital systems. Assessments of casts with a stereomicroscope and/or scanning electron microscope as well as highlighting cast structures using color coding help students to better understand how the structures that they have observed as two-dimensional images actually exist in three dimensions, and students found using the casts to be highly effective in their learning. Reconstructions of cast hollow structures from (micro-)computed tomography scans and videos facilitate detailed analyses of branching patterns and spatial arrangements in cast structures, aid in the understanding of clinically relevant structures and provide innovative visual aids. The casting protocol and teaching manual we offer can be adjusted to different technical capabilities and might also be found useful for veterinary or other biological science classes. PMID- 28578927 TI - Synergistic Signaling by Light and Acetylcholine in Mouse Iris Sphincter Muscle. AB - The mammalian pupillary light reflex (PLR) involves a bilateral brain circuit whereby afferent light signals in the optic nerve ultimately drive iris-sphincter muscle contraction via excitatory cholinergic parasympathetic innervation [1, 2]. Additionally, the PLR in nocturnal and crepuscular sub-primate mammals has a "local" component in the isolated sphincter muscle [3-5], as in amphibians, fish, and bird [6-10]. In mouse, this local PLR requires the pigment melanopsin [5], originally found in intrinsically photosensitive retinal ganglion cells (ipRGCs) [11-19]. However, melanopsin's presence and effector pathway locally in the iris remain uncertain. The sphincter muscle itself may express melanopsin [5], or its cholinergic parasympathetic innervation may be modulated by suggested intraocular axonal collaterals of ipRGCs traveling to the eye's ciliary body or even to the iris [20-22]. Here, we show that the muscarinic receptor antagonist, atropine, eliminated the effect of acetylcholine (ACh), but not of light, on isolated mouse sphincter muscle. Conversely, selective genetic deletion of melanopsin in smooth muscle mostly removed the light-induced, but not the ACh-triggered, increase in isolated sphincter muscle's tension and largely suppressed the local PLR in vivo. Thus, sphincter muscle cells are bona fide, albeit unconventional, photoreceptors. We found melanopsin expression in a small subset of mouse iris sphincter muscle cells, with the light-induced contractile signal apparently spreading through gap junctions into neighboring muscle cells. Light and ACh share a common signaling pathway in sphincter muscle. In summary, our experiments have provided details of a photosignaling process in the eye occurring entirely outside the retina. PMID- 28578929 TI - Morphological Diversity of C. elegans Sensory Cilia Instructed by the Differential Expression of an Immunoglobulin Domain Protein. AB - Cilia on dendritic endings of sensory neurons organize distinct types of sensory machinery [1]. Ciliated endings display neuron-type-specific patterns of membrane elaborations [1-3], but it is not well understood how such neuron-type-specific morphologies are generated and whether they are coupled to the specification of other identity aspects of a terminally differentiated sensory neuron. In the course of a genome-wide analysis of members of a small family of immunoglobulin domain proteins, we found that OIG-8, a previously uncharacterized transmembrane protein with a single immunoglobulin (Ig) domain, instructs the distinct, neuron type-specific elaboration of ciliated endings of different olfactory neuron types in the nematode C. elegans. OIG-8 protein localizes to ciliated endings of these sensory neurons, and is transcribed at different levels in distinct olfactory neuron types. oig-8 expression levels correlate with the extent of sensory cilia growth and branching patterns. Loss of oig-8 leads to a reduction in the branching patterns of cilia, whereas raising the levels of oig-8 results in an increase in elaborations. Levels of OIG-8 expression are controlled by the specific combination of a terminal selector type of transcription factors that also specify other identity features of distinct olfactory neuron types. PMID- 28578928 TI - Functional Interactions between Newborn and Mature Neurons Leading to Integration into Established Neuronal Circuits. AB - From development up to adulthood, the vertebrate brain is continuously supplied with newborn neurons that integrate into established mature circuits. However, how this process is coordinated during development remains unclear. Using two photon imaging, GCaMP5 transgenic zebrafish larvae, and sparse electroporation in the larva's optic tectum, we monitored spontaneous and induced activity of large neuronal populations containing newborn and functionally mature neurons. We observed that the maturation of newborn neurons is a 4-day process. Initially, newborn neurons showed undeveloped dendritic arbors, no neurotransmitter identity, and were unresponsive to visual stimulation, although they displayed spontaneous calcium transients. Later on, newborn-labeled neurons began to respond to visual stimuli but in a very variable manner. At the end of the maturation period, newborn-labeled neurons exhibited visual tuning curves (spatial receptive fields and direction selectivity) and spontaneous correlated activity with neighboring functionally mature neurons. At this developmental stage, newborn-labeled neurons presented complex dendritic arbors and neurotransmitter identity (excitatory or inhibitory). Removal of retinal inputs significantly perturbed the integration of newborn neurons into the functionally mature tectal network. Our results provide a comprehensive description of the maturation of newborn neurons during development and shed light on potential mechanisms underlying their integration into a functionally mature neuronal circuit. PMID- 28578931 TI - Artificial Synaptic Rewiring Demonstrates that Distinct Neural Circuit Configurations Underlie Homologous Behaviors. AB - Behavioral homology is often assumed to involve similarity in underlying neuronal mechanisms. Here, we provide a counterexample where homologous behaviors are produced by neurons with different synaptic connectivity. The nudibranch molluscs Melibe leonina and Dendronotus iris exhibit homologous swimming behaviors, consisting of alternating left and right body flexions. The swim central pattern generators (CPGs) in both species are composed of bilaterally symmetric interneurons, which are individually identified and reciprocally inhibit their contralateral counterparts, contributing to left-right burst alternation in the swim motor patterns. In Melibe, the swim CPG contains two parts that interact to produce stable rhythmic bursting; one part is the primary half-center kernel, and the other part, which consists of a bilateral pair of neurons called Si3, regulates period length. The Dendronotus swim CPG is simpler, with Si3 being part of the primary half-center oscillator. Application of curare (d-tubocurarine) selectively blocked the Si3 synapses in both species. In Melibe, curare application caused the burst duration of the swim motor pattern to lengthen, whereas in Dendronotus, curare halted bursting altogether. In both species, replacing the curare-blocked Si3 synapses with artificial synapses using dynamic clamp restored the original rhythmic bursting, thereby affirming the roles of those synapses. The curare-impaired bursting in Dendronotus was also restored by rewiring the homologous neurons into a Melibe-like primary half-center oscillator configuration, indicating that the connectivity itself could account for species differences in circuit responses to curare. The results suggest that synaptic connectivity diverged during evolution while behavior was conserved. PMID- 28578930 TI - Meal Timing Regulates the Human Circadian System. AB - Circadian rhythms, metabolism, and nutrition are intimately linked [1, 2], although effects of meal timing on the human circadian system are poorly understood. We investigated the effect of a 5-hr delay in meals on markers of the human master clock and multiple peripheral circadian rhythms. Ten healthy young men undertook a 13-day laboratory protocol. Three meals (breakfast, lunch, dinner) were given at 5-hr intervals, beginning either 0.5 (early) or 5.5 (late) hr after wake. Participants were acclimated to early meals and then switched to late meals for 6 days. After each meal schedule, participants' circadian rhythms were measured in a 37-hr constant routine that removes sleep and environmental rhythms while replacing meals with hourly isocaloric snacks. Meal timing did not alter actigraphic sleep parameters before circadian rhythm measurement. In constant routines, meal timing did not affect rhythms of subjective hunger and sleepiness, master clock markers (plasma melatonin and cortisol), plasma triglycerides, or clock gene expression in whole blood. Following late meals, however, plasma glucose rhythms were delayed by 5.69 +/- 1.29 hr (p < 0.001), and average glucose concentration decreased by 0.27 +/- 0.05 mM (p < 0.001). In adipose tissue, PER2 mRNA rhythms were delayed by 0.97 +/- 0.29 hr (p < 0.01), indicating that human molecular clocks may be regulated by feeding time and could underpin plasma glucose changes. Timed meals therefore play a role in synchronizing peripheral circadian rhythms in humans and may have particular relevance for patients with circadian rhythm disorders, shift workers, and transmeridian travelers. PMID- 28578933 TI - Extracorporeal Membrane Oxygenation, Pulmonary Embolectomy, and Right Ventricular Assist Device for Massive Pulmonary Embolism. AB - Consensus regarding the management of massive pulmonary embolism (PE) and persistent shock after thrombolysis is lacking. A 30-year-old man collapsed with massive PE 3 days after an exploratory laparotomy for penetrating trauma, and he remained hypoxic and hypotensive despite thrombolytic therapy. Extracorporeal membrane oxygenation (ECMO) was instituted as a bridge to surgical embolectomy, and placement of a right ventricular assist device (RVAD) was used to facilitate separation from cardiopulmonary bypass. After 48 hours, the RVAD was removed, and the patient survived to discharge. ECMO and temporary RVAD to support surgical embolectomy are lifesaving therapeutic considerations. PMID- 28578932 TI - Ovarian Hormones Organize the Maturation of Inhibitory Neurotransmission in the Frontal Cortex at Puberty Onset in Female Mice. AB - The frontal cortex matures late in development, showing dramatic changes after puberty onset, yet few experiments have directly tested the role of pubertal hormones in cortical maturation. One mechanism thought to play a primary role in regulating the maturation of the neocortex is an increase in inhibitory neurotransmission, which alters the balance of excitation and inhibition. We hypothesized that pubertal hormones could regulate maturation of the frontal cortex by this mechanism. Here, we report that manipulations of gonadal hormones do significantly alter the maturation of inhibitory neurotransmission in the cingulate region of the mouse medial frontal cortex, an associative region that matures during the pubertal transition and is implicated in decision making, learning, and psychopathology. We find that inhibitory neurotransmission, but not excitatory neurotransmission, increases onto cingulate pyramidal neurons during peri-pubertal development and that this increase can be blocked by pre-pubertal, but not post-pubertal, gonadectomy. We next used pre-pubertal hormone treatment to model early puberty onset, a phenomenon increasingly observed in girls living in developed nations. We find that pre-pubertal hormone treatment drives an early increase in inhibitory neurotransmission in the frontal cortex, but not the somatosensory cortex, suggesting that earlier puberty can advance cortical maturation in a regionally specific manner. Pre-pubertal hormone treatment also accelerates maturation of tonic inhibition and performance in a frontal-cortex dependent reversal-learning task. These data provide rare evidence of enduring, organizational effects of ovarian hormones at puberty and provide a potential mechanism by which gonadal hormones could regulate the maturation of the associative neocortex. PMID- 28578936 TI - A case of esophageal tuberculosis with unusual endoscopic feature. AB - A 59-year-old man experienced epigastric pain and an upper gastrointestinal endoscopy revealed a bulging lesio n 0.5*0.6cm in size in the middle esophagus. EUS showed a homogenous hypoechoic lesion, which interrupted the five layers structure of esophageal wall. Biopsies revealed epithelioid granuloma with central caseous necrosis and several acid-fast bacilli. PMID- 28578934 TI - Reprint of: MicroRNA profiling of human intermediate monocytes. AB - Among the three human monocyte subsets, intermediate CD14++CD16+ monocytes have been characterized as particularly proinflammatory cells in experimental studies and as potential biomarkers of cardiovascular risk in clinical cohorts. To further substantiate the distinct role of intermediate monocytes within human monocyte heterogeneity, we assessed subset-specific expression of miRNAs as central epigenetic regulators of gene expression. We hypothesized that intermediate monocytes have a distinct miRNA profile compared to classical and non-classical monocytes. By using small RNA-seq we analyzed 662 miRNAs in the three monocyte subsets. We identified 38 miRNAs that are differentially expressed in intermediate monocytes compared to both classical and non-classical monocytes with a p value of <10-10, of which two miRNAs - miR-6087 (upregulated) and miR 150-5p (downregulated) - differed in their expression more than ten-fold. Pathway analysis of the 38 differentially expressed miRNAs linked intermediate monocytes to distinct biological processes such as gene regulation, cell differentiation, toll-like receptor signaling as well as antigen processing and presentation. Moreover, differentially expressed miRNAs were connected to those genes that we previously identified as markers of intermediate monocytes. In aggregation, we provide first genome-wide miRNA data in the context of monocyte heterogeneity, which substantiate the concept of monocyte trichotomy in human immunity. The identification of miRNAs that are specific for intermediate monocytes may allow to develop strategies, which particularly target this cell population while sparing the other two subsets. PMID- 28578935 TI - Extracorporeal photochemotherapy in mycosis fungoides. AB - OBJECTIVES: Extracorporeal photo-chemotherapy (ECP, photopheresis) is an approved treatment modality for mycosis fungoides (MF). Our aim is to present our ECP data for MF. METHODS: We retrospectively evaluated 50 MF patients who received ECP for clinical activity, toxicity, and response and outcome rates, and we compared these with combination therapies. RESULTS: The overall response rate (ORR) was 42% (21/50), while the median time to response was 11months (range, 3-48months). Ten of the responders (48%) had 3 or more treatment lines prior to ECP. Eight patients (16%) had adverse events related to ECP. The overall survival (OS) of 50 patients was 72months (range, 3-211). There was no statistically significant difference in the OS in early-stage vs late-stage patients (77 vs 69months, P=0.077). The stage 3 and 4 patients received an average of 31 cycles compared to 55 cycles in stage 1 and 2 patients (P=0.006). The increased extent of ECP was not correlated with the response. Combined treatment with ECP significantly improved the OS (84months vs 62months, P=0.005). DISCUSSION: A low frequency of side effects and improved OS observed in combination therapy makes ECP a favorable option for treating MF. PMID- 28578937 TI - Active HCV infection is associated with increased circulating levels of interferon-gamma (IFN-gamma)-inducible protein-10 (IP-10), soluble CD163 and inflammatory monocytes regardless of liver fibrosis and HIV coinfection. AB - BACKGROUND AND OBJECTIVE: Interferon-gamma (IFN-gamma)-inducible protein-10 (IP 10), soluble (s) CD163 and sCD14 play an important role in the pathogenesis of HCV and HIV infection and are involved in inflammation and liver fibrosis. The aim of the present study was to evaluate at a single time point, plasma soluble biomarkers and inflammatory monocytes subsets in different groups of subjects: (i) HIV monoinfected patients on suppressive ART; (ii) HIV/HCV coinfected patients on ART, with undetectable HIV viremia (including either subjects who had active HCV replication or those who cleared HCV); (iii) HCV monoinfected individual with active viral replication. METHODS: Hundred and twenty-nine plasma samples were analyzed including HCV and HIV monoinfected patients, HIV/HCV coinfected patients, with active HCV infection (AHI) or with HCV viral clearance (VHC) and healthy donors (HD). Levels of IP-10, sCD163 and sCD14 were measured by ELISA. Absolute cell counts of monocyte subpopulations were enumerated in whole blood by using flow cytometric analyses. RESULTS: IP-10 and sCD163 plasma levels were higher in HCV monoinfected and in AHI coinfected pts compared to HIV monoinfected and HD, whereas sCD14 levels were higher only in HIV monoinfected patients. Considering the degree of fibrosis, sCD163 and sCD14 levels positively correlated with kPa values (as assessed by fibroscan) and FIB-4 in HCV monoinfected group. On the other hand, IP-10 did not correlate with the fibrosis stage and it was found increased also in patients with low fibrosis. Moreover, we found an increase of the inflammatory NCM subset, in non-cirrhotic HCV subjects, while no alterations were observed in HIV, AHI and VHC. CONCLUSIONS: Our study suggests a scenario in which active HCV infection is associated with a strong pro inflammatory state, even in the initial stage of liver fibrosis, regardless the presence of HIV coinfection, thus underlying the need of an early anti-HCV treatment. PMID- 28578939 TI - Clinical significance of C/D box small nucleolar RNA U76 as an oncogene and a prognostic biomarker in hepatocellular carcinoma. AB - BACKGROUND: Recent evidence has suggested novel roles of small nucleolar RNAs (snoRNAs) in tumorigenicity. However, the roles of C/D box snoRNA U76 (SNORD76) in the development of hepatocellular carcinoma (HCC) remain unknown. Herein, we systematically evaluated dysregulation of snoRNAs in HCC and clarified the biomarker potential and biological significance of SNORD76 in HCC. METHODS: We performed quantitative analyses of the expression of SNORD76 in 66 HCC specimens to compare its expression pattern between tumor tissue and matched non-tumor tissue. The effects of SNORD76 on HCC tumorigenicity were investigated in SK-Hep1 and Huh7 cells as well as in a xenograft nude mouse model. RESULTS: SNORD76 expression was significantly upregulated in HCC tissues compared to corresponding non-tumor tissues. This upregulation of SNORD76 in HCC tumors was significantly associated with poorer patient survival. Furthermore, inhibiting SNORD76 expression suppressed cell proliferation by inducing G0/G1 cell cycle arrest and apoptosis. Low SNORD76 expression also resulted in decreased HCC growth in an animal model. Conversely, overexpressing SNORD76 promoted cell proliferation. SNORD76 increased HCC cell invasion by inducing epithelial-mesenchymal transition (EMT). Finally, we found that SNORD76 promoted HCC tumorigenicity through activation of the Wnt/beta-catenin pathway. CONCLUSIONS: Therefore, we demonstrated for the first time that SNORD76 may function as a novel tumor promoter in HCC and may serve as a promising prognostic biomarker in patients with HCC. PMID- 28578938 TI - Overexpression of NEDD9 promotes cell invasion and metastasis in hepatocellular carcinoma. AB - Neural precursor cell expressed, developmentally downregulated 9 (NEDD9), is a focal adhesion scaffold protein which has been associated with metastasis in several cancers. Recent study found that NEDD9 expression was upregulated in HCC. However, the precise function of NEDD9 in HCC is still unclear. In the present study, we demonstrated that high NEDD9 expression was associated with the invasiveness of HCC in clinical samples. Moreover, by gain-and-loss function studies, we revealed that silencing of NEDD9 expression inhibited cancer cells proliferation, migration and invasion, while upregulated expression of NEDD9 promoted invasion and metastasis of HCC cells in vitro and in vivo. Further studies revealed that NEDD9 inversely regulated E-cadherin in HCC cells and HCC tissues, which indicated that NEDD9 might promotes the invasion and metastasis of HCC cells through the downregulation of E-cadherin, possibly by inducing EMT. On the whole, our findings thus indicate that NEDD9 may serve as a metastasis promoting gene and potential therapeutic target for the treatment of hepatocellular carcinoma. PMID- 28578940 TI - Complete genome sequence of multidrug-resistant Staphylococcus cohnii ssp. urealyticus strain SNUDS-2 isolated from farmed duck, Republic of Korea. AB - OBJECTIVES: Staphylococcus cohnii has become increasingly recognized as a potential pathogen of clinically significant nosocomial and farm animal infections. This study was designed to determine the genome of a multidrug resistant S. cohnii subsp. urealyticus strain SNUDS-2 isolated from a farmed duck in Korea. METHODS: Genomic DNA was sequenced using the PacBio RS II system. The complete genome was annotated and the presence of antimicrobial resistance and virulence genes were identified. RESULTS: The annotated 2,625,703 bp genome contained various antimicrobial resistance genes conferring resistance to beta lactam, aminoglycosides, fluoroquinolones, phenicols and trimethoprim. The virulence-associated three synergistic hemolysins have been identified in the strain. CONCLUSIONS: To the best of our knowledge, this is the first complete genome of S. cohnii, and will provide important insights into the biodiversity of CoNS and valuable information for the control of this emerging pathogen. PMID- 28578942 TI - Twin-singleton early-life survival in sub-Saharan Africa. PMID- 28578943 TI - Efficient synthesis of secondary amines by reductive amination of curdlan Staudinger ylides. AB - Staudinger-related reactions between azides and phosphines are important in organic chemistry due to their chemoselectivity, high efficiency, and mild reaction conditions. Staudinger reduction of azides affords highly reactive iminophosphorane ylides; the reactivity of the negatively charged ylide nitrogen atom has not previously been fully explored in polysaccharide chemistry. Curdlan, a natural, biocompatible, and bioactive beta-1,3-glucan with low toxicity, has remarkable potential in biomedical and pharmaceutical applications. Herein we describe a new method for preparation of regioselectively iminated/aminated curdlan derivatives via a Staudinger ylide. 6-Azido-6-deoxy-2,4-di-O-acyl-curdlan was treated with triphenylphosphine to generate the highly nucleophilic iminophosphorane intermediate which afforded: i) 6-imino curdlans by reaction with several aromatic aldehydes, and ii) 6-monoalkylamino curdlans by reductive amination using these aldehydes and NaBH3CN. This new chemistry combined with our previous results makes available valuable primary, secondary, and tertiary amines, quaternary ammonio derivatives, and amides, all with complete C-6 regioselectivity for the N-substitution. PMID- 28578941 TI - Mortality among twins and singletons in sub-Saharan Africa between 1995 and 2014: a pooled analysis of data from 90 Demographic and Health Surveys in 30 countries. AB - BACKGROUND: Sub-Saharan Africa has the world's highest under-5 and neonatal mortality rates as well as the highest naturally occurring twin rates. Twin pregnancies carry high risk for children and mothers. Under-5 mortality has declined in sub-Saharan Africa over the last decades. It is unknown whether twins have shared in this reduction. METHODS: We pooled data from 90 Demographic and Health Surveys for 30 sub-Saharan Africa countries on births reported between 1995 and 2014. We used information on 1 685 110 singleton and 56 597 twin livebirths to compute trends in mortality rates for singletons and twins. We examined whether the twin-singleton rate ratio can be attributed to biological, socioeconomic, care-related factors, or birth size, and estimated the mortality burden among sub-Saharan African twins. FINDINGS: Under-5 mortality among twins has declined from 327.7 (95% CI 312.0-343.5) per 1000 livebirths in 1995-2001 to 213.0 (196.7-229.2) in 2009-14. This decline of 35.0% was much less steep than the 50.6% reduction among singletons (from 128.6 [95% CI 126.4-130.8] per 1000 livebirths in 1995-2001 to 63.5 [61.6-65.3] in 2009-14). Twins account for an increasing share of under-5 deaths in sub-Saharan Africa: currently 10.7% of under-5 mortality and 15.1% of neonatal mortality. We estimated that about 315 000 twins (uncertainty interval 289 000-343 000) die in sub-Saharan African each year. Excess twin mortality cannot be explained by common risk factors for under 5 mortality, including birthweight. The difference with singletons was especially stark for neonatal mortality (rate ratio 5.0, 95% CI 4.5-5.6). 51.7% of women pregnant with twins reported receiving medical assistance at birth. INTERPRETATION: The fate of twins in sub-Saharan Africa is lagging behind that of singletons. An alarming one-fifth of twins in the region dies before age 5 years, three times the mortality rate among singletons. Twins account for a substantial and growing share of under-5 and neonatal mortality, but they are largely neglected in the literature. Coordinated action is required to improve the situation of this extremely vulnerable group. FUNDING: None. PMID- 28578944 TI - Pullulan: A novel molecule for biomedical applications. AB - Pullulan is an imperative natural polymer produced commercially by yeast like fungus Aureobasidium pullulans. It is non-toxic, non-immunogenic, non carcinogenic and non-mutagenic in nature. The structure of pullulan consist unique linkage pattern with two alpha-(1->4) and one alpha-(1->6) glycosidic bonds in maltotriose repeating units (G3). Pullulan endows distinctive physical traits due to the presence of nine hydroxyl groups on glucopyranose rings of G3 units. It can be derivatized in various forms by substituting these hydroxyl groups to enhance its utility in biomedical applications. Pullulan and its derivatives are completely explored for their applications in food and pharmaceutical industries. Owing to these special properties, native pullulan and its derivatives possess potential application in multiple diagnostics. This review presents elaborated discussion on role of pullulan and its derivatives in various biomedical applications e.g. drug delivery, gene targeting, tissue engineering, vaccination, plasma substitution, chaperone-like activity, medical imaging, insulinotropic activity, pharmaceutical dosages formation, coating, etc. PMID- 28578945 TI - beta-CD assisted aqueous dissolution of cetylpicolinium dichromates (CPDC) Evolution of a class of green water compatible lipopathic Cr(VI) oxidants. AB - Water-insoluble lipopathic dichromates have been successfully solubilized in aqueous phase by the entrapment of their hydrophobic tails in beta-cyclodextrin (beta-CD) non-polar cavity. Aqueous solubility of alpha-, beta-, and gamma- cetylpicolinium dichromate (CPDC) molecules, synthesized in our lab, has been studied to find their suitability for Cr(VI) oxidation purposes in water medium. The analysis of phase solubility shows the existence of a Bs type curve and its significance has been fully deciphered through dynamic light scattering (DLS) analysis. The limiting concentration of beta-CD up to which it can induce 1:1 host-guest complexation with the CPDC entities, has been determined and the stoichiometry has been confirmed from Job's plot. The binding constant and complexation efficiency of the beta-CD-CPDC complexes have been determined and temperature effect on these parameters has been discussed through thermodynamic calculations. Analyses of viscosity variation of the aqueous solutions of the complexes have been done and correlated with the solubilization phenomenon. PMID- 28578946 TI - Nanostructure and physical properties of cellulose nanofiber-carbon nanotube composite films. AB - We studied the nanostructure and physical properties of cellulose nanofiber-multi walled carbon nanotube (CNF-MWNT) composite films prepared via MWNT aqueous dispersion using 4-O-methyl-alpha-d-glucuronoxylan as a MWNT dispersion aid. The composite film had high electrical conductivity (1.05S/cm), good mechanical properties (Young's modulus: 10.1GPa, tensile strength: 173.4MPa) and a low coefficient of thermal expansion (7ppm/K). FE-SEM imaging showed that the carbon nanotubes dispersed homogeneously and made reinforcing networks in the matrix of cellulose nanofibers. Improvement in the physical properties of cellulose nanofiber film by adding MWNTs is due to this composite structure. PMID- 28578947 TI - Structural characterization and immunomodulatory activity of a water soluble polysaccharide isolated from Botrychium ternatum. AB - As a folk medicine, Botrychium ternatum has been used for thousands of years in China. In the present work, a water soluble polysaccharide BTp1 was extracted and purified from B. ternatum. Based on the MALDI matrix 3-aminoquinoline-alpha-cyano 4-hydroxycinnamic acid, the molecular weight of BTp1 was determined to be 11638Da directly. Monosaccharide analysis showed that BTp1 was composed of arabinose (Ara). Combining enzymatic hydrolysis and subsequent MALDI-TOF analysis, a linear backbone of BTp1, consisted of (1->5)-linked alpha-l-Araf, was inferred quickly. Then according to NMR experiments, the whole structure of BTp1 was established. The repeating unit of BTp1 was deduced as a linear backbone with branches at O-2, O-3 and its neighboring O-2 positions terminated with (1->)-linked alpha-l-Araf, respectively. The immunomodulatory assay exhibited that BTp1 could significantly enhance the viability and promote the release of NO in RAW 264.7 cells, suggesting that BTp1 could be a potential immunomodulatory agent in pharmacological fields. PMID- 28578948 TI - Gelation of rhamnogalacturonan I is based on galactan side chain interaction and does not involve chemical modifications. AB - The article presents the structural principles of microwave-induced formation of new gel type from pectic rhamnogalacturonan I (RG-I). The backbone of gel-forming RG-I does not contain consecutive galacturonic residues and modifying groups that can be the cause of junction zone formation as it occurs in course of classical ways of pectin gelation. Microwave irradiation does not cause destruction and chemical modifications of RG-I. Removal of half of galactan chains from RG-I leads to loss of gelling capability pointing out on their leading role in this process. Rising of intensity of the bands attributed to galactose and glycosidic linkages in RG-I gel comparing to solution where this polymer exists as molecule associate indicates that the spatial organization of galactans in gel is changed. A model of the RG-I gelation is proposed: being destabilized at volumetric microwave heating RG-I associates are repacked forming network where RG-I molecules are entangled by galactan chains. PMID- 28578949 TI - Surface properties and surface free energy of cellulosic etc mucoadhesive polymers. AB - The paper presents the sorption and wettability properties for several mucoadhesive polymers (Carbopol 974P NF (carbomer polymer; carboxy polymethylene), Noveon AA-1, (polycarbophil; acrylic acid polymer crosslinked with divinyl glycol) HPMC (hypromellose; cellulose 2-hydroxyethyl methyl ester) and HEC (cellulose 2-hydroxyethyl ether) and a film-forming polymer Kollidon VA 64 (polyvinylpyrrolidone-vinyl acetate copolymer)) commonly used in controlled drug delivery systems. Moreover, the surface energy of powders was determined using the data obtained according to the three types of experimental investigation. The contact angle measurements for powders were performed according to the Washburn method and using the capillary rise technique. Whereas the sessile drop method was performed on the compressed discs of mucoadhesive polymers. For the surface characterization the IGC technique was also applied. The results obtained by different methods, for both: wettability and surface energies, were compared and correlated. The presented study showed significant differences in the morphology and surface properties of mucoadhesion polymers considered. It was confirmed that for the accurate quantification of the free surface energy (and its components), for mucoadhesive polymers considered, not only the IGC in finite concentration, but also the Washburn method should be used. PMID- 28578950 TI - Characterization of a novel natural cellulosic fiber from Juncus effusus L. AB - This study aims to assess the morphology and properties of fibers extracted from a wild natural plant largely available in Algeria known as Juncus effusus L. (JE). The morphology and diameter of the fiber bundles extracted from the stem of the JE plant were characterized by optical and scanning electron microscopy. The functional groups of the extracted lignocellulosic JE fibers were studied by FTIR, their thermal degradation behavior was investigated by TGA and their crystallinity was determined using X-ray diffraction technique. In addition, mechanical characterization was carried out using tensile tests on the lignocellulosic fiber in order to evaluate their strength, strain at break and Young's modulus. In view of the dispersion in the obtained experimental results, the latter were analyzed using the Weibull statistical laws with two and three parameters. PMID- 28578951 TI - Bio-stimuli-responsive multi-scale hyaluronic acid nanoparticles for deepened tumor penetration and enhanced therapy. AB - In this study, we developed bio-stimuli-responsive multi-scale hyaluronic acid (HA) nanoparticles encapsulated with polyamidoamine (PAMAM) dendrimers as the subunits. These HA/PAMAM nanoparticles of large scale (197.10+/-3.00nm) were stable during systematic circulation then enriched at the tumor sites; however, they were prone to be degraded by the high expressed hyaluronidase (HAase) to release inner PAMAM dendrimers and regained a small scale (5.77+/-0.25nm) with positive charge. After employing tumor spheroids penetration assay on A549 3D tumor spheroids for 8h, the fluorescein isothiocyanate (FITC) labeled multi-scale HA/PAMAM-FITC nanoparticles could penetrate deeply into these tumor spheroids with the degradation of HAase. Moreover, small animal imaging technology in male nude mice bearing H22 tumor showed HA/PAMAM-FITC nanoparticles possess higher prolonged systematic circulation compared with both PAMAM-FITC nanoparticles and free FITC. In addition, after intravenous administration in mice bearing H22 tumors, methotrexate (MTX) loaded multi-scale HA/PAMAM-MTX nanoparticles exhibited a 2.68-fold greater antitumor activity. PMID- 28578952 TI - Chitosan nanoparticles from marine squid protect liver cells against N diethylnitrosoamine-induced hepatocellular carcinoma. AB - Rationale of this study was framed to investigate the protective effect and anti cancer property of nanoparticles based on chitosan isolated from squid, Sepioteuthis lessoniana, on hepatic cells in N-Nitrosodiethylamine-induced hepatocellular carcinoma in rats. The results conferred that the chitosan nanoparticle supplementation had a protective effect on liver cells by reducing the levels of marker enzymes and bilirubin and thus increasing the albumin levels. The level of reduced glutathione, ascorbic acid and alpha-tocopherol significantly increased in both post- and pre-treatment with chitosan nanoparticles. The levels of antioxidant enzymes were enhanced and lipid peroxidation products were diminished while treating nitrosodiethylamine-induced hepatocellular carcinoma with chitosan nanoparticles. Supplementation of chitosan nanoparticles had potent anti-hyperlipidemic property that was evidenced by monitoring the serum lipid levels and its components. Animals pre-treated with chitosan nanoparticles along with nitrosodiethylamine showed a significant reduction in the total cholesterol and triglycerides levels with increase in the levels of phospholipids and free fatty acids. Chitosan nanoparticles treated rats showed significant increment in high-density lipoprotein cholesterol and reduction in low-density lipoprotein and very low-density lipoprotein cholesterol when compared with levels in nitrosodiethylamine-induced hepatocellular carcinoma. Nitrosodiethylamine-induced carcinoma changes on circulation and hepatic antioxidant defense mechanism were regulated by chitosan nanoparticles, concluding that the chitosan nanoparticles have a potent protective effect on liver cells which might be due to its robust antioxidant and anti-lipidemic property. PMID- 28578953 TI - Calcinated tea and cellulose composite films and its dielectric and lead adsorption properties. AB - In this paper, calcinated tea and cellulose composite (CTCC) films were fabricated via solution casting method. Chemical structure, morphology, crystallinity and thermal stability of the fabricated films were characterized by using Fourier transform infrared spectroscopy, scanning electron microscopy, X ray diffraction and thermogravimetric analysis. The effect of calcinated tea loading on the properties of the prepared CTCC films was studied. The results suggest that the prepared CTCC films show higher mechanical properties, thermal stability and dielectric constant than the neat cellulose film. In addition, the CTCC films adsorb Pb2+ ions and its adsorption performance depends on the calcinated tea content and pH level. The CTCC films are useful for sensors, flexible capacitor as well as lead adsorption applications. PMID- 28578954 TI - Thermal stability increase in metallic nanoparticles-loaded cellulose nanocrystal nanocomposites. AB - Due to the potential of CNC-based flexible materials for novel industrial applications, the aim of this work is to improve the thermal stability of cellulose nanocrystals (CNC) films through a straightforward and scalable method. Based of nanocomposite approach, five different metallic nanoparticles (ZnO, SiO2, TiO2, Al2O3 and Fe2O3) have been co-assembled in water with CNCs to obtain free-standing nanocomposite films. Thermogravimetric analysis (TGA) reveals an increased thermal stability upon nanoparticle. This increase in the thermal stability reaches a maximum of 75 degrees C for the nanocomposites having 10wt% of Fe2O3 and ZnO. The activation energies of thermodegradation process (Ea) determined according to Kissinger and Ozawa-Flynn-Wall methods further confirm the delayed degradation of CNC nanocomposites upon heating. Finally, the changes induced in the crystalline structure during thermodegradation were followed by wide angle X-ray diffraction (WAXD). It is also observed that thermal degradation proceeds at higher temperatures for nanocomposites having metallic nanoparticles. Overall, experimental findings here showed make nanocomposite approach a simple low-cost environmentally-friendly strategy to overcome the relatively poor thermal stability of CNCs when extracted via sulfuric acid assisted hydrolysis of cellulose. PMID- 28578955 TI - Photochemical synthesis of silver nanoparticles on chitosans/montmorillonite nanocomposite films and antibacterial activity. AB - Silver nanoparticles (AgNPs) were synthetized on chitosans/montmorillonite nanocomposite films by photochemical method. Nanocomposites were prepared using chitosans with different molar masses and deacetylation degrees, as well as modified with diethylaminoethyl (DEAE) and dodecyl groups. AgNPs formation on the films was followed by the appearance of the plasmon band around 440nm as a function of irradiation time. TEM images revealed AgNPs with spherical morphology for all nanocomposites. For nanocomposites using modified chitosans, the AgNPs synthesis occurred quickly (1.5h) while for the others films it was above 11h. The film of modified chitosan with dodecyl and DEAE groups presented smaller and more uniform nanoparticles size along mixture of exfoliated and intercalated structures. This modified chitosan is an amphiphilic compound that can act controlling the size/shape of the AgNPs. The results of antibacterial activity suggested that all nanocomposite-AgNPs films inhibited the growth of Escherichia coli and Bacillus subtilis. PMID- 28578957 TI - Synthesis of graft copolymers based on hyaluronan and poly(3-hydroxyalkanoates). AB - This work reports the synthesis and characterisation of new amphiphilic hyaluronan (HA) grafted with poly(3-hydroxyalkanoates) (PHAs) conjugates. Hydrolytic depolymerisation of PHAs was used for the synthesis of defined oligo(3 hydroxyalkanoates)-containing carboxylic terminal moieties. A kinetic study of the depolymerisation was followed to prepare oligomers of required molecular weight. PHAs were coupled with hydroxyl groups of HA mediated by N, N' carbonyldiimidazole (CDI) or HSTU Tetramethyl-O-(N-succinimidyl) uronium hexafluorophosphate. For the first time, the covalent bonding of oligo derivatives of P(3-hydroxybutyrate), P(3-hydroxyoctanoate), P(3-hydroxyoctanoate co-3-hydroxydecanoate) and P(3-hydroxyoctanoate-co-3-hydroxydecanoate-co-3 hydroxydodecanoate) and HA was achieved by "grafting to" strategy. Achieved grafting degree was a function of hydrophobicity of PHA, Mw and polarity of the solvent. The most suitable reaction conditions were observed for oligo (3 hydroxybutyrate) grafted to HA (grafting degree of 14%). Graft copolymers were characterized by FT-IR, NMR, DSC and SEC-MALLS. Graft copolymers can be physically loaded with hydrophobic drugs and may serve as drug delivery system. PMID- 28578956 TI - Synthesis of xanthan gum graft copolymer and its application for controlled release of highly water soluble Levofloxacin drug in aqueous medium. AB - Graft copolymers (XG-g-PNVP-1 to XG-g-PNVP-5) of xanthan gum (XG) and poly(N vinyl-2-pyrrolidone) (PNVP) was synthesized by free radical polymerization using peroxymonosulphate/thiourea redox pair. The synthesized graft copolymers were well characterized by 1H NMR, FTIR, XRD, SEM, TGA/DTA and AFM analyses. The optimum conditions for maximum grafting were determined by varying the concentrations of N-vinyl-2-pyrrolidone (NVP) from 10*10-2 to 18*10-2moldm-3; the grafting ratios increases up to 14*10-2moldm-3, while thereafter decreased. Graft copolymer (XG-g-PNVP-D) hybrid was prepared to load levofloxacin drug, about 15mg drug was loaded; and its release was studied in phosphate buffer solution (PBS) at pH 7.4 on 37+/-0.1 degrees C; About 80% drug was released in 36h. PMID- 28578958 TI - Synthesis and characterization of alginic acid ester derivatives. AB - Esters derivatives of alginic acid (Alg) were prepared in carboxylic acid/carboxylic acid anhydrides system by using aqueous perchloric acid as the catalyst. Degree of substitution of hydroxyl group of Alg was estimated to be 2, showing that the hydroxyl group of Alg was fully esterified. Alg acid esters showed the solubility to common organic solvents such as acetone and chloroform. In particular, alginic acid hexanoate formed self-standing solvent-cast film, although the film showed brittle mechanical behavior. Furthermore, Alg esters showed glass transition temperature (Tg) in a temperature range between 100 and 200 degrees C, that is in the same range as the conventional synthetic amorphous polymers. It was also shown that the Tg gradually lowered with the increasing acyl side chain length. These results show that Alg esters are plastic materials with tunable organosolubility and thermal properties. PMID- 28578959 TI - Enzymatic production of N-acetyl-d-glucosamine from crayfish shell wastes pretreated via high pressure homogenization. AB - This study presents an efficient pretreatment of crayfish shell using high pressure homogenization that enables N-acetyl-d-glucosamine (GlcNAc) production by chitinase. Firstly, the chitinase from Serratia proteamaculans NJ303 was screened for its ability to degrade crayfish shell and produce GlcNAc as the sole product. Secondly, high pressure homogenization, which caused the crayfish shell to adopt a fluffy netted structure that was characterized by Scanning electron microscope (SEM), Fourier transform infrared spectrometer (FT-IR), X-ray diffraction (XRD), was evaluated as the best pretreatment method. In addition, the optimal conditions of high pressure homogenization of crayfish shell were determined to be five cycles at a pressure of 400bar, which achieved a yield of 3.9g/L of GlcNAc from 25g/L of crayfish shell in a batch enzymatic reaction over 1.5h. The results showed high pressure homogenization might be an efficient method for direct utilization of crayfish shell for enzymatic production of GlcNAc. PMID- 28578960 TI - Starch-based nanocapsules fabricated through layer-by-layer assembly for oral delivery of protein to lower gastrointestinal tract. AB - Anionic carboxymethyl starch (CMS) and cationic quaternary ammonium starch (QAS), were used to fabricate nanocapsules through electrostatic layer by layer (LbL) alternate deposition onto colloidal BSA particles. An ideal starch-based colloidal nanocapsule was achieved by adjusting the degree of substitution (DS) and weight average molecular molar mass (Mw) of CMS. The nanocapsules fabricated by CMS with lower DS or Mw possessed more compact and stable core-shell structure, which favoured the BSA delivery from the upper gastrointestinal tract (GIT) to the colon. In particular, CMS/QAS nanocapsules constructed by CMS with lower DS and Mw showed better colon-specific delivery and release performance in simulated GIT fluid after 7days' storage in different kinds of beverage (33.04% 46.35% in upper GIT, 52.70%-64.97% in colon, respectively). These findings demonstrated that CMS/QAS nanocapsules constructed by CMS with lower DS and Mw can be further exploited as a potential oral delivery system for protein to colon. PMID- 28578961 TI - Novel nano-particulated exopolysaccharide produced by Klebsiella sp. PHRC1.001. AB - In recent decades, microbial synthesis of polysaccharides with special functional properties has attracted increasing attention. This work reported a novel exopolysaccharide (EPS)-producing strain, Klebsiella sp. PHRC1.001 isolated from activated sludge. Physicochemical, rheological, emulsifying and toxicological properties of the obtained EPS were characterized. The EPS was mainly composed of d-glucose and l-arabinose, and was found to exist in aqueous solution in a nano particulated form (~50nm in diameter) with a strong tendency of aggregation. Rheological analysis showed that the EPS aqueous solution was a typical pseudoplastic fluid at higher concentration and could form weak gel upon alkaline treatment followed by neutralization. The EPS exhibited excellent emulsifying properties in stabilizing oil-in-water emulsions presumably by a Pickering mechanism owing to its nanoparticle structure. Acute toxicity test showed that 1.8g EPS per kg of body weight caused no toxic effect on mice. PHRC1.001 EPS has the potential to be a novel industrial polysaccharide. PMID- 28578962 TI - Curcumin-loaded dual pH- and thermo-responsive magnetic microcarriers based on pectin maleate for drug delivery. AB - Magnetic microgels with pH- and thermo-responsive properties were developed from the pectin maleate, N-isopropyl acrylamide, and Fe3O4 nanoparticles. The hybrid materials were characterized by infrared spectroscopy, scanning electron microscope coupled with X-ray energy dispersive spectroscopy, wide angle X-ray scattering, Zeta potential, and magnetization hysteresis measurements. Curcumin (CUR) was loaded into the microgels, and release assays were carried out in simulated environments (SGF and SIF) at different conditions of temperature (25 or 37 degrees C). A slow and sustainability CUR release was achieved under external magnetic field influence. Loaded CUR displayed stability, bioavailability and greater solubility regarding free CUR. Besides, the cytotoxicity assays showed that magnetic microgels without CUR could suppress the Caco-2 cells growth. So, the pectin maleate, N-isopropyl acrylamide, and Fe3O4 could be tailored to elicit hybrid-based materials with satisfactory application in the medical arena. PMID- 28578963 TI - Response of live Newcastle disease virus encapsulated in N-2-hydroxypropyl dimethylethyl ammonium chloride chitosan nanoparticles. AB - We have synthesized N-2-hydroxypropyl dimethylethyl ammonium chloride chitosan (N 2-HFCC) with higher water solubility than chitosan. To evaluate its potential as delivery carrier, NDV encapsulated in N-2-HFCC/CMC nanoparticles (NDV/La Sota-N-2 HFCC/CMC-NPs) with a diameter of 252.2+/-32.68nm, Zeta potential of 41.1+/ 0.89mV, encapsulation efficiency of 96.6+/-0.72% and loading capacity of 53.2+/ 1.11% were prepared. NDV/La Sota-N-2-HFCC/CMC-NPs are a novel type of attenuated live vaccine encapsulated in nanoparticles. These nanoparticles displayed lower cytotoxicity and higher stability. Their bioactivity was maintained when they were stored for three months at the room temperature. Release assay in vitro showed that NDV could be sustainably released after an initial burst release. In vivo immunization showed that immunization of specific pathogen free chickens with NDV/La Sota-N-2-HFCC/CMC-NPs intranasally induced high titers of serum antibody, significantly promoted lymphocyte proliferation and caused higher levels of interleukine-2 and interference-gamma. These results indicated that N-2 HFCC/CMC nanoparticles could serve as an efficient and safe delivery vehicle for mucosal immunity, and have a great potential in medical applications. PMID- 28578964 TI - Biocompatible nanogel derived from functionalized dextrin for targeted delivery of doxorubicin hydrochloride to MG 63 cancer cells. AB - The present article demonstrates the targeted delivery of doxorubicin hydrochloride to human osteosarcoma cancer cell lines (MG 63) using functionalized dextrin based crosslinked, pH responsive and biocompatible nanogel. The nanogel has been prepared through Michael-type addition reaction using dextrin (Dxt), N, N'-methylene bisacrylamide (MBA, as crosslinker), acrylic acid (AA, as monomer) and potassium persulfate (KPS, as initiator). The structure, composition, morphology of the nanogel have been explored using FTIR and 1H NMR spectroscopy, XRD, TGA, DSC, CHN and AFM analyses. The TEM analysis confirmed that the size of nanogel appeared within 100nm, while DLS study indicates that the diameter of the nanogel remained between 113 and 126nm. The AFM study implied the porous morphology of the synthesized nanogel. The rheological study suggests the gel behaviour of the synthesized nanogel at 37+/ 0.1 degrees C. Difference in% swelling at pH 5.5 and 7.4 indicates pH responsiveness of the nanogel. The in vitro cytocompatibility results ascertained that the nanogel is non-toxic to human mesenchymal stem cells (hMSCs). In vitro cellular uptake study confirmed that FITC-loaded nanogel can cross the cellular membrane and be well uptake by the cell cytoplasm. The nanogel could efficiently encapsulate doxorubicin hydrochloride (Dox) with the loading efficiency of 27+/ 0.2% after 72h. The Dox-loaded nanogel demonstrates anti-cancer activity towards MG 63 cancer cells and release the encapsulated drug in a controlled way. PMID- 28578965 TI - Preparation and evaluation of polyurethane/cellulose nanowhisker bimodal foam nanocomposites for osteogenic differentiation of hMSCs. AB - Biocompatible and biodegradable polyurethanes (PUs) based on polycaprolactone diol (PCL) were prepared and filled with cellulose nanowhiskers (CNWs) obtained from wastepaper. The incorporated polyurethane nanocomposites were used to prepare foamed scaffolds with bimodal cell sizes through solvent casting/particulate leaching method. Sodium chloride and sugar porogens were also prepared to fabricate the scaffolds. The mechanical and thermal properties of PU/CNW nanocomposites were investigated. Incorporation of different CNWs resulted in various structures with tunable mechanical properties and biodegradability. All bimodal foam nanocomposites were biodegradable and also non-cytotoxic as revealed by MTT assay using SNL fibroblast cell line. PU/CNW foam scaffolds were used for osteogenic differentiation of human mesenchymal stem cells (hMSCs). Based on the results, such PU/CNW nanocomposites could support proliferation and osteogenic differentiation of hMSCs in three-dimensional synthetic extracellular matrix (ECM). PMID- 28578966 TI - New findings on green sweet pepper (Capsicum annum) pectins: Rhamnogalacturonan and type I and II arabinogalactans. AB - Polysaccharides were extracted from sweet pepper (Capsicum annum) with hot water and named ANW (9% yield). Starch was precipitated by freeze-thaw treatment, while pectic polysaccharides (8% yield) remained soluble and consisted of GalA (67.0%), Rha (1.6%), Ara (6.4%), Xyl (0.3%), Gal (6.7%) and Glc (4.4%). A highly methoxylated homogalacturonan (HG, degree of methylesterification of 85% and degree of acetylation of 5%), and type I and type II arabinogalactans (AG-I and AG-II) were observed in NMR analyses. These were fractionated with Fehling's solution to give HG (5.5% yield) and AG fractions (0.6% yield). AG-I and AG-II were further separated by ultrafiltration. AG-II (0.2% yield) consisted of Ara (17.1%), Gal (36.0%), Rha (5.6%) and GalA (12.0%), had a molecular weight of 5.3*104g/mol and methylation and 1H/13C HSQC-DEPT-NMR analyses showed that it was anchored in type I rhamnogalacturonan. This is the first study that reports the presence of AG-I and AG-II in sweet pepper fruits. PMID- 28578968 TI - Physicochemical characterization and antitumour activity of exopolysaccharides produced by Lactobacillus casei SB27 from yak milk. AB - Two high molecular weight fractions (LW1 and LW2) of exopolysaccharides (EPSs) produced by Lactobacillus casei SB27 were isolated from yak milk obtained from the Gansu Tibetan area of China. GC-MS, FTIR spectroscopy, methylation analysis and FE-SEM analysis were performed to elucidate the physicochemical characterization of these two fractions, and their in vitro antitumour activities were also evaluated. The molecular weights (Mws) of LW1 and LW2 as determined by HPGPC were 25.10 and 12.34kDa, respectively. Monosaccharide composition analysis revealed that LW1 and LW2 were mainly composed of galactose (52.4% and 57.4%, mol%) and glucose (29.1% and 22.2%, mol%), respectively. Methylation results showed that the main chain of LW1 likely involves (1->4)-linked Galp and (1->4) linked Glcp with its side chains being (1->4,6)-linked Galp through the O-6 position connected to the backbone, whereas the main chain of LW2 likely involves (1->4)-linked Galp and (1->4)-linked Glcp with its side chains being (1->3)-Galp through the O-6 position of (1->3,6)-Galp linked to the main chain. Evaluation of the microcosmic morphology, as revealed by FE-SEM analysis of the two EPS fractions, showed a sheet-like appearance with a folded surface and a compact structure. The results from in vitro antitumour tests indicated that both LW1 and LW2 could significantly inhibit the proliferation of HT-29 colorectal cancer cells and up-regulated the expressions of Bad, Bax, Caspase-3 and -8 genes. Finally, TEM images revealed the apoptotic morphological changes of HT-29 cells induced by LW1 and LW2. Our results suggested that LW1 and LW2 possess potential not only for use in functional food products but also as a source of natural antitumour drugs. PMID- 28578967 TI - Preparation and characterization of antioxidant edible chitosan films incorporated with epigallocatechin gallate nanocapsules. AB - Antioxidant edible films based on chitosan hydrochloride (CHC) and epigallocatechin gallate (EGCG)-loaded nanocapsules (NCs) were developed. The CHC films incorporated with NCs were prepared by a casting method in three different proportions. The obtained films were characterized using the techniques including scanning electron microscopy, Fourier transform infrared spectroscopy and X-ray diffraction. Meanwhile, the mechanical and color properties, optical transmittance, EGCG release profile and antioxidant activity were also determined. The addition of NCs to CHC films increased their tensile strength (TS) and the percent elongation at break (%E). Lightness was significantly decreased in the NCs embedded films compared to controls, which in turn led to high antioxidant activity and excellent barrier properties against visible light. EGCG was rapidly released into food simulant although the concentration fluctuates over time. Therefore, these films can prevent the oxidation of fatty food stuffs. PMID- 28578969 TI - Nerve growth factor loaded heparin/chitosan scaffolds for accelerating peripheral nerve regeneration. AB - Artificial chitosan scaffolds have been widely investigated for peripheral nerve regeneration. However, the effect was not as good as that of autologous grafts and therefore could not meet the clinical requirement. In the present study, the nerve growth factor (NGF) loaded heparin/chitosan scaffolds were fabricated via electrostatic interaction for further improving nerve regeneration. The physicochemical properties including morphology, wettability and composition were measured. The heparin immobilization, NGF loading and release were quantitatively and qualitatively characterized, respectively. The effect of NGF loaded heparin/chitosan scaffolds on nerve regeneration was evaluated by Schwann cells culture for different periods. The results showed that the heparin immobilization and NGF loading did not cause the change of bulk properties of chitosan scaffolds except for morphology and wettability. The pre-immobilization of heparin in chitosan scaffolds could enhance the stability of subsequently loaded NGF. The NGF loaded heparin/chitosan scaffolds could obviously improve the attachment and proliferation of Schwann cells in vitro. More importantly, the NGF loaded heparin/chitosan scaffolds could effectively promote the morphology development of Schwann cells. The study may provide a useful experimental basis to design and develop artificial implants for peripheral nerve regeneration and other tissue regeneration. PMID- 28578970 TI - Rheological properties of N-[(2-hydroxyl)-propyl-3-trimethyl ammonium] chitosan chloride. AB - N-[(2-hydroxyl)-propyl-3-trimethyl ammonium] chitosan chloride (HTCC) was synthesized using 1-allyl-3-methylimidazole chloride (AmimCl) as a homogeneous green reaction media. The effects of polymer concentration, temperature, cation valence, anion type and concentration of inorganic salt, and degree of substitution (DS) on the rheological properties of HTCC were investigated. The apparent viscosity indicated that HTCC solution was a typical pseudoplastic fluid, which could be described by Ostwald de Waele and Cross-empirical models. The viscoelastic properties showed the formation of gel-like structures. Temperature showed slight effect on the apparent viscosity of HTCC solution, while the DS of HTCC showed remarkable effect on the apparent viscosity. At a low shear rate, the apparent viscosities of HTCC solution increased firstly with an increase of cNaCl from 0 to 40mmol/L, and then decreased with further increasing cNaCl to 60mmol/L. At a high shear rate, the opposite trends were observed. The variation of HTCC molecular construction under different inorganic salt conditions was confirmed by scanning electron microscopy, meanwhile, the variation mechanism was proposed. PMID- 28578971 TI - Printing and impact properties of cationised hollow cellulosic fiber based polyester/cotton composite. AB - Hollow fibers materials have been potentially used and gaining increasing attention in recent years. In this study, Egyptian hollow fibers have been blended with cotton and polyester wastes at different weft counts using open-end spinning. The blended fabrics were subjected for cationisation followed by printing with reactive and acid dyes. The performance of impact properties of cationised hollow fiber reinforced polyester/cotton hybrid composites was studied. The results demonstrated that the physical and color properties of blended fabrics are greatly influenced by alkali pretreatment and cationisation of hybrid composites as well as the weft counts. The pretreatment decreases the resistance of the waxy layer on the surface of hollow fiber and increased markedly the efficiency of printing. Besides, the pretreatment supplied for hybrid composites accomplished the required color balance that can bring about reasonable fastness properties. These studies provided referential knowledge for printing of hollow cellulosic-based composite materials. PMID- 28578973 TI - Rapid shape memory TEMPO-oxidized cellulose nanofibers/polyacrylamide/gelatin hydrogels with enhanced mechanical strength. AB - TEMPO-oxidized cellulose nanofibers/polyacrylamide/gelatin shape memory hydrogels were successfully fabricated through a facile in-situ free-radical polymerization method, and double network was formed by chemically cross-linked polyacrylamide (PAM) network and physically cross-linked gelatin network. TEMPO-oxidized cellulose nanofibers (TOCNs) were introduced to improve the mechanical properties of the hydrogel. The structure, shape memory behaviors and mechanical properties of the resulting composite gels with varied gel compositions were investigated. The results obtained from those different studies revealed that TOCNs, gelatin, and PAM could mix with each other homogeneously. Due to the thermoreversible nature of the gelatin network, the composite hydrogels exhibited attractive thermo-induced shape memory properties. In addition, good mechanical properties (strength >200kPa, strain >650%) were achieved. Such composite hydrogels with good shape memory behavior and enhanced mechanical strength would be an attractive candidate for a wide variety of applications. PMID- 28578972 TI - Hydrazine treatment improves conductivity of bacterial cellulose/graphene nanocomposites obtained by a novel processing method. AB - A novel method to prepare BC nanocomposites reinforced with reduced graphene oxide (RGO) is reported. A simple hydrazine treatment is shown to in-situ reduce the graphene oxide (GO) incorporated to BC films while increasing their conductivity. Raman spectroscopy was used to confirm the presence of graphene and assess the effect of the hydrazine treatment on its structure. XRD tests revealed no changes on BC structure. We hypothesize that this treatment removes the hydroxyl and epoxy groups present on the reduced graphene and increases the content of nonoxygenated carbon. These changes account for the increase in conductivity of the BC-based films, which behaved as an insulating material before the hydrazine treatment and reach an average conductivity value of 12S/m after such a treatment. PMID- 28578974 TI - AOT reverse micelles as versatile reaction media for chitosan nanoparticles synthesis. AB - It is known that Chitosan (Ch) can be used in several applications, such as antimicrobial agent or as drug delivery agent. However, being its water dispersibility very low at physiological pH it is necessary to find a way to improve it. One attractive strategy is to synthesize Chitosan Nanoparticles (Ch NPs). In this work, a versatile method to obtain Ch-NPs with different and controlled sizes, that were successfully prepared by cross-linking reaction of glutaraldehyde and native chitosan inside of n-heptane/sodium 1,4-bis-2 ethylhexylsulfosuccinate (AOT)/water reverse micelles (RMs) is presented. Highly monodisperse NPs were synthesized as confirmed by Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM) techniques. The particle size was dependent on the reactants concentration, cross-linking degree and mainly the amount of water inside of the AOT RMs used as nanoreactors. While the cross linking is quite difficult to control in bulk water, the reaction inside the RMs is more manageable and efficient. PMID- 28578976 TI - Rice stubble as a new biopolymer source to produce carboxymethyl cellulose blended films. AB - Rice stubble is agricultural waste consisting of cellulose which can be converted to carboxymethyl cellulose from rice stubble (CMCr) as a potential biomaterial. Plasticizer types (glycerol and olive oil) and their contents were investigated to provide flexibility for use as food packaging material. Glycerol content enhanced extensibility, while olive oil content improved the moisture barrier of films. Additionally, CMCr showed potential as a replacement for up to 50% of commercial CMC without any changes in mechanical and permeability properties. A mixture of plasticizers (10% glycerol and 10% olive oil) provided blended film with good water barrier and mechanical properties comparable with 20% individual plasticizer. Principle component (PC) analysis with 2 PCs explained approximately 81% of the total variance, was a useful tool to select a suitable plasticizer ratio for blended film production. Therefore, CMCr can be used to form edible film and coating as a renewable environmentally friendly packaging material. PMID- 28578975 TI - pH-Sensitive drug delivery system based on hydrophobic modified konjac glucomannan. AB - Amphiphilic aliphatic amines grafted konjac glucomannan (KGM-g-AH8, KGM-g-AH12 and KGM-g-AH18) micelles were prepared via a simple two-step synthesis with Schiff's base as the "switch" to achieve intracellular acid-triggered curcumin release. The KGM-g-AH8 self-assembled into spherical nano-micelles (107.6+/ 11.6nm) in an aqueous medium, and presented high curcumin loading capacity as well as good physical stability in 28 days. The in vitro curcumin release behaviors proved the controlled release property and the endosomal/lysosomal pH response of KGM-g-AH8 micelles. The cytotoxicity and cellular uptake studies were also investigated to exhibit the intracellular pH-sensitivity, safety and biocompatibility of KGM-g-AH8 micelles. This research focuses on the feasibility of KGM-based micelles to be extrapolated as promising strategies for cancer therapy and offers new potential options for intracellular drug delivery. PMID- 28578977 TI - The Dorsal Frontoparietal Network: A Core System for Emulated Action. AB - The dorsal frontoparietal network (dFPN) of the human brain assumes a puzzling variety of functions, including motor planning and imagery, mental rotation, spatial attention, and working memory. How can a single network engage in such a diversity of roles? We propose that cognitive computations relying on the dFPN can be pinned down to a core function underlying offline motor planning: action emulation. Emulation creates a dynamic representation of abstract movement kinematics, sustains the internal manipulation of this representation, and ensures its maintenance over short time periods. Based on these fundamental characteristics, the dFPN has evolved from a pure motor control network into a domain-general system supporting various cognitive and motor functions. PMID- 28578978 TI - Modality of treatment and potential outcome of Wilson disease in Taiwan: A population-based longitudinal study. AB - BACKGROUND/PURPOSE: This study aimed to investigate the epidemiology, the preference of medication, and the potential outcome of Wilson disease in Taiwan. We aimed to provide better therapeutic options for patients with Wilson disease based on the data generated from this study. METHODS: We utilized the National Health Insurance Research Database (NHIRD), which stores clinical records of nearly 99% of Taiwan's residents. The database used is a random sample of two million out of 23-million beneficiaries in Taiwan's NHIRD in 2005. The integrated medical records of these two-million cases were collected from 2000 to 2011. Subjects of Wilson disease were identified as those with International Classification of Diseases, Ninth Revision (ICD-9) code 275.1 and the specific prescription drugs (including d-penicillamine, zinc, and trientine) in either outpatient clinic or inpatient records. RESULTS: During the study period, 66 cases of Wilson disease were identified. The male to female ratio was 1.75. The average prevalence rate was 1.81 per 100,000 and the average annual diagnosis rate was 0.22 per 100,000. The diagnosis was mostly established at 20-24 and 10 14 years of age, followed by 25-29 years. Fifty four of all subjects (81.8%) started the treatment with d-penicillamine, compared with zinc (12.1%) and trientine (6.1%). Among these 66 cases, 27 (40.9%) had liver cirrhosis and three (4.5%) underwent liver transplantation due to liver failure. CONCLUSION: d penicillamine is still the most popular prescription of Wilson disease, followed by zinc monotherapy. Although chronic liver injury cannot be avoided, a favorable potential outcome is well demonstrated in this population-based study. PMID- 28578979 TI - HIV associated kidney diseases: Clarifying concordance between renal failure in HIV infection and histopathologic manifestations at kidney biopsy. AB - Patients with HIV infection have a wide spectrum of renal diseases. Some are known to be the direct effect of the viral infection while others are renal diseases that also occur in uninfected populations. HIV associated nephropathy (HIVAN) is considered to be a subtype of primary focal and segmental glomerulosclerosis that is distinct in HIV infected patients. It is more frequent in the African-American population and associated with mutations of the apolipoprotein L1 (APOL1) gene. HIV associated immune complex kidney disease (HIVICD) encompasses a spectrum of HIV associated renal diseases characterized by the presence of immune complex deposition within glomeruli. Thrombotic microangiopathy (TMA) is a complication of HIV infection that presents with hemolytic anemia, thrombocytopenia, and renal failure. TMA in HIV patients is associated with very high mortality. Lastly, the multitude of antiretroviral drugs used for treatment of HIV infections can result in nephrotoxicity. Although a kidney biopsy may not be the first line study for renal disease, knowledge of the different histopathologic features of HIV-associated and unassociated diseases is of paramount importance in the treatment and subsequent outcome of renal function in HIV infected patients. In this review we will describe the histopathologic features and discuss the pathophysiology of the entities previously named. PMID- 28578980 TI - Clinical Skills Passport: A Method to Increase Participation in Clinical Skills by Medical Students During a Surgery Clerkship. AB - OBJECTIVE: To prospectively evaluate the effect of introducing a clinical skills "passport" on medical students' reporting of their experience with basic clinical skills. DESIGN: A prospective longitudinal intervention study was conducted. Medical students were administered a questionnaire at the conclusion of their 12 week surgery clerkship regarding their experience with 15 clinical skills, inquiring whether they had "learned on surgery clerkship", "learned before surgery clerkship", or "not learned". Preintervention baseline data were obtained for 2 consecutive academic years (n = 213 students). In the third year, students (n = 124) were given a clinical skills passport to document performance of 8 of the 15 skills under the supervision of a surgical resident or faculty member. After excluding from analysis those students who learned a skill before their surgery clerkship, the fraction of students who reported learning clinical skills during their surgery clerkship before and after the introduction of the clinical skills passport was compared using Fisher exact test and chi-squared test, where appropriate (p <= 0.003 was considered significant; Bonferroni correction for multiple comparisons). SETTING: Washington University School of Medicine. PARTICIPANTS: A total of 337 medical students completing the junior surgery clerkship over a 3-year period were included in the study. RESULTS: All 337 students completed a survey. Considering each skill individually, survey response rate was 5045/5055 (99.8%). Combining all responses for all skills, the fraction of students reporting that skills were learned on the surgery clerkship increased after the introduction of the clinical skills passport (1498/1938 [77%] preintervention vs. 974/1109 [88%] postintervention, p < 0.0001, chi square). After the introduction of the clinical skills passport, the fraction of students reporting that a skill was "learned on surgery clerkship" significantly increased for the 8 skills listed on the passport (1026/1699 [83%] preintervention vs. 685/714 [96%] postintervention, p < 0.0001, chi square), but did not increase for the 7 skills not listed on the passport (472/695 [68%] preintervention vs. 289/395 [73%] postintervention, p = 0.08, chi square). Considering each skill individually, after the introduction of the clinical skills passport, the fraction of students reporting that a skill was "learned on surgery clerkship" significantly increased for 4/15 skills (all listed on the clinical passport) and decreased for 0/15 skills (p < 0.003, Fisher exact test, 2 tailed). CONCLUSIONS: Institution of a clinical skills passport system during a surgery clerkship increased medical student reporting of their performance of basic clinical skills. PMID- 28578982 TI - Are we doing right suggesting a non-operative management for suspected appendicitis in children? PMID- 28578981 TI - Robotic Pancreatoduodenectomy Biotissue Curriculum has Validity and Improves Technical Performance for Surgical Oncology Fellows. AB - OBJECTIVE: Obtaining the proficiency on the robotic platform necessary to safely perform a robotic pancreatoduodenectomy is particularly challenging. We hypothesize that by instituting a proficiency-based robotic training curriculum we can enhance novice surgeons' skills outside of the operating room, leading to a shorter learning curve. DESIGN: A biotissue curriculum was designed consisting of sewing artificial organs to simulate a hepaticojejunostomy (HJ), gastrojejunostomy (GJ), and pancreaticojejunostomy (PJ). Three master robotic surgeons performed each biotissue anastomosis to assess validity. Using video review, trainee performance on biotissue drills was evaluated for time, errors and objective structured assessment of technical skills (OSATS) by 2 blinded graders. SETTING: This study is conducted at the University of Pittsburgh Medical Center (Pittsburgh, PA), a tertiary care academic teaching hospital. PARTICIPANTS: In total, 14 surgical oncology fellows completed the biotissue curriculum. RESULTS: Fourteen fellows performed 196 anastomotic drills during the first year: 66 (HJ), 64 (GJ), and 66 (PJ). The fellows' performances were analyzed as a group by attempt. The attendings' first attempt outperformed the fellows' first attempt in all metrics for every drill (all p < 0.05). More than 5 analyzed attempts of the HJ, there was improvement in time, errors, and OSATS (all p < 0.01); however, no metric reached attending performance. For the GJ, time, errors, and OSATS all improved more than 5 attempts (all p < 0.01), whereas only errors and OSATS reached proficiency. For the PJ, errors and OSATS both improved over attempts (p < 0.01) and reached proficiency; however, time did not statistically improve nor reach proficiency. The graders scoring correlated for errors and OSATS (p < 0.0001). CONCLUSION: A pancreatoduodenectomy biotissue curriculum has face and construct validity. The curriculum is feasible and improves errors and technical performance. Time is the most difficult technical parameter to improve. This curriculum is a valid tool for teaching robotic pancreatoduodenectomies with established milestones for reaching optimum performance. PMID- 28578983 TI - Staff and Redman response to placenta letter by Brosens. PMID- 28578984 TI - Comparison of dimensional accuracy of conventionally and digitally manufactured intracoronal restorations. AB - STATEMENT OF PROBLEM: Advances have been made in digital dentistry for the fabrication of dental prostheses, but evidence regarding the efficacy of digital techniques for the fabrication of intracoronal restorations is lacking. PURPOSE: The purpose of this in vitro study was to compare the dimensional accuracy of intracoronal restorations fabricated with digital and conventional techniques. MATERIAL AND METHODS: A sound mandibular molar tooth received a standard onlay preparation, and onlays were fabricated with 1 of 3 fabrication techniques. In group CC, the onlays were made after conventional impression and conventional fabrication of a resin pattern. In group CP, the onlays were made after conventional impression and 3-dimensional (3D) printing of the pattern. In group IP, the onlays were made after intraoral scanning, and 3D printing produced the resin pattern. Ten specimens in each group (N=30) were evaluated. Glass-ceramic restorations were fabricated using the press technique. The replica technique was used to assess the marginal fit. Each replica was assessed at 8 points. One-way ANOVA was used to compare the marginal discrepancy among the 3 groups. The Tukey honest significant differences test was applied for pairwise comparisons of the groups (alpha=.05). RESULTS: No significant differences were noted in the marginal discrepancy at the gingival margin among the 3 groups (P=.342), but significant differences were noted among the 3 groups in the pulpal (P=.025) and lingual (P=.031) areas. Comparison of the absolute discrepancy among the 3 groups revealed that only groups CC and CP were significantly different (P=.020) from each other. CONCLUSIONS: Within the limitations of this in vitro study, the conventional method yielded more accuracy than the 3D printing method, and no differences were found between the methods which used the 3D printer (groups CP and IP). PMID- 28578985 TI - Attention focus and self-touch in toddlers: The moderating effect of attachment security. AB - The superior self-regulation and attention-regulation abilities of securely attached children have been repeatedly demonstrated. However, the mechanisms that allow securely attached children to exhibit higher levels of attention focus than insecurely attached (anxious-ambivalent and anxious-avoidant) children need to be explored. One possible mechanism that has been hypothesized to play a role in focusing attention is self-touch. Previous research has shown that 10-year-old children exhibit more bilateral self-touch (i.e., both hands are simultaneously moving onto each other or on the body, and both hands are in contact with each other or with the body), but not lateral self-touch (i.e., one hand is moving on the other hand or on the body, and the hand is in contact with the other hand or with the body), when they focus attention on a task. Because bilateral coordination is still developing during childhood, we expected that lateral self touch, instead of bilateral self-touch, may be associated with attention focus for toddlers. The objectives of the present study were to examine whether securely attached toddlers exhibit more self-touch, particularly lateral self touch, while they focus on a task than while they do not focus on a task. We expected to find that the association between lateral self-touch and attention focus is not as strong for insecurely attached toddlers. Data from forty-nine mother-child dyads were employed for analyses. The attachment classification of the children was determined using the Strange Situation. The duration of attention focus and self-touch behavior during a reading task were coded. An association between lateral self-touch and attention focus was found for children of all attachment classifications. This association was particularly strong for securely attached children. We discuss the possibility that securely attached toddlers may use lateral self-touch to regulate attention. PMID- 28578986 TI - Chronic corticosterone-induced impaired cognitive flexibility is not due to suppressed adult hippocampal neurogenesis. AB - Hippocampal neurogenesis has been implicated in the etiology of depression. Recent studies suggest new neurons add flexibility to hippocampal-dependent learning and memory. We hypothesized that suppressed hippocampal neurogenesis may contribute to impaired cognitive flexibility associated with depression. The chronic corticosterone (CORT)-induced animal model of depression was used. In Experiment 1, rats received either CORT (40mg/kg) or vehicle injections for 21days and were subjected to Water maze during the last six days of drug treatment. No group differences were found during the spatial learning phase; however, cognitive flexibility, measured by reversal training, was significantly impaired in the CORT-treated rats. The probe test revealed enhanced memory of the new platform location for the CORT-treated rats. Given the time newborn neurons require to mature, we presumed if impaired cognitive flexibility seen in Experiment 1 were due to suppressed neurogenesis, terminating CORT treatment 3days prior to behavioural testing should still induce the impairment. Therefore, Experiment 2 was similar to Experiment 1, except that CORT injections were terminated 3days prior to behavioural assessment. However, not only was spatial learning significantly enhanced in the CORT-treated rats, but there were also no group differences during reversal or probe tests. Bromodeoxyruidine, administered a day after the first drug treatments in both experiments, was quantified and revealed the number of new neurons were the same in both groups in both experiments. Results suggest cognitive flexibility is impaired in the CORT induced animal model of depression; an effect that is reversible and independent of suppressed hippocampal neurogenesis. PMID- 28578987 TI - Chronic cerebral hypoperfusion independently exacerbates cognitive impairment within the pathopoiesis of Parkinson's disease via microvascular pathologys. AB - To date, the role of microvascular pathology and chronic cerebral hypoperfusion (CHH) in the development of mild cognitive impairment in Parkinson's disease (PD MCI) is unclear. Here, we investigated how the combined injury through interaction of CHH and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity act as an exacerbating element to damagae cognitive fuction in a mouse model. In the present study, C57BL/6 mice underwent MPTP injection. Subjects were classified into a PD with normal cognitive performance (PDCN) group or a PD-MCI group using the Morris Water Maze test. Further, CHH was induced by stenosis of the bilateral common carotid arteries (BCCAs). Consequently, the animals were divided into 7 groups: they are control, sham, BCCAs, PDCN, PD-MCI, PDCN+BCCAs and PD-MCI+BCCAs. The Morris Water Maze test, open field test, histological investigation and western blotting were performed to analyze cerebral microvascular impairment in each group. The results showed that CHH and MPTP injection caused spatial memory and behavioral impairment, accompanied by microvascular impairment and down-regulation of ZO-1 and Occludin at the protein level compared to the control group. The above injuries were synergistically exacerbated in the PDCN+BCCAs group and the PD-MCI+BCCAs group, which paralleled the elevated expression of p-MAPK and p-Akt. In short, our data demonstrate that CHH and MPTP caused cognitive and microvascular impairment separately. Moreover, CHH may exacerbate cognitive impairment in a mouse model of PD. The study provides a new opportunity for understanding the pathogenesis of PD-MCI. PMID- 28578988 TI - The effect of hippocampal NMDA receptor blockade by MK-801 on cued fear extinction. AB - Extinction of conditioned fear has been suggested to be a new form of learning instead of erasure of what was originally learned, and the process is NMDA (N methyl d-aspartate) receptor (NMDAR) dependent. Most of studies have so far revealed the important roles of NMDARs in the amygdala and medial prefrontal cortex (mPFC) in cued fear extinction. Although the ventral hippocampus has intimately reciprocal connections with the amygdala and mPFC, the role of its NMDARs in cued fear extinction remains unclear. The present experiment explored the issue by bilateral pre-extinction microinjection of the noncompetitive NMDAR antagonist MK-801 into the ventral hippocampus. Four groups of rats were given habituation, tone cued fear conditioning, fear extinction training and extinction test. Prior to extinction training, rats received bilateral infusions of either MK-801 (1.5, 3, or 6MUg/0.5MUl) or saline. Our results showed that MK-801 reduced freezing on the first trial of extinction training with no impact on within session acquisition of extinction, and that the lower doses of MK-801 resulted in increased freezing on the extinction retrieval test. These findings suggest that ventral hippocampal NMDARs are necessary for the consolidation of tone cued fear extinction. PMID- 28578989 TI - [Changing patterns of medication prescription for COPD patients in France. Impact of long-acting muscarinic antagonists' availability]. AB - INTRODUCTION: We studied the pattern changes over time of medication prescriptions for COPD and their conformity with French and international recommendations using data from patients in the prospective French cohort "Initiatives BPCO". METHOD: Eight hundred and forty-six patients have been included during a first period from August, 2001 till May 2006 (n=425) and a second period from June, 2006 till June, 2012 (n=421). The pivotal date was based on the tiotropium availability in France. RESULTS: During period 1, we recruited older patients (average 65 vs 64 years), less often women (19 vs 26 %) and having less severe airflow obstruction (mean FEV1 48 vs 54 %). The ICS prescriptions decreased in mild COPD, but there was no change for inhaled long-acting beta-2 agonist (LABA) (68 %). The use of LABA+LAMA association without ICS increased from 0.9 to 7 %, but remained lower than the fixed LABA+ICS association (26 %), less often prescribed than the triple association LABA+ICS+LAMA (32.5 % in period 2). The use of long-acting bronchodilators increased from 68 to 80 % between both periods. Vaccinations and rehabilitation remained insufficiently prescribed. LAMA had been added but did not appear to replace other drugs. PMID- 28578990 TI - Outcomes of Ultrasound-Guided Thrombin Injection of Nongroin Arterial Pseudoaneurysms. AB - PURPOSE: To evaluate success and complication rates of percutaneous ultrasound guided thrombin injection of nongroin pseudoaneurysms (PSAs). MATERIALS AND METHODS: Retrospective review of a prospectively maintained institutional database yielded 39 cases of arterial PSAs occurring at nongroin sites that were treated with percutaneous ultrasound-guided thrombin injection between 2000 and 2016 (average patient age 69.2 y +/- 14.0). Of PSAs, 74.4% (29/39) arose in the upper extremities, and 92.3% (36/39) were iatrogenic. The brachial artery was the most commonly affected vessel (51.3% [20/39]), and arterial access was the most common cause (56.4% [22/39]). Average overall PSA size was 2.4 cm (range, 0.5-7.2 cm); average amount of thrombin injected was 320 IU (range, 50-2,000 IU). Technical success was defined as absence of flow within the PSA immediately after thrombin injection. Treatment success was defined as sustained thrombosis on follow-up imaging obtained at 1-3 days after treatment. RESULTS: Technical and treatment success rates of thrombin injections were 100% (39/39) and 84.8% (28/33), respectively. Longer term follow-up imaging (average 71 d; range, 12-201 d) was available for 7 of the treatment successes with 100% (7/7) showing sustained thrombosis. Comparing treatment successes and failures, there was no significant difference in average PSA size (2.3 cm vs 2.0 cm, P = .51) or average amount of thrombin injected (360 IU vs 180 IU, P = .14). There were no complications. CONCLUSIONS: Ultrasound-guided thrombin injection is a safe, efficacious treatment option for PSAs arising in nongroin locations. PMID- 28578991 TI - Oncolytic VSV Primes Differential Responses to Immuno-oncology Therapy. AB - Vesicular stomatitis virus encoding the IFNbeta transgene (VSV-IFNbeta) is a mediator of potent oncolytic activity and is undergoing clinical evaluation for the treatment of solid tumors. Emerging preclinical and clinical data suggest treatment of tumors with oncolytic viruses may sensitize tumors to checkpoint inhibitors and increase the anti-tumor immune response. New generations of immuno oncology molecules including T cell agonists are entering clinical development and could be hypothesized to enhance the activity of oncolytic viruses, including VSV-IFNbeta. Here, we show that VSV-IFNbeta exhibits multiple mechanisms of action, including direct cell killing, stimulation of an innate immune response, recruitment of CD8 T cells, and depletion of T regulatory cells. Moreover, VSV IFNbeta promotes the establishment of a CD8 T cell response to endogenous tumor antigens. Our data demonstrate a significant enhancement of anti-tumor function for VSV-IFNbeta when combined with checkpoint inhibitors, but not OX40 agonists. While the addition of checkpoint inhibitors to VSV-IFNbeta generated robust tumor growth inhibition, it resulted in no increase in viral replication, transgene expression, or immunophenotypic changes beyond treatment with VSV-IFNbeta alone. We hypothesize that tumor-specific T cells generated by VSV-IFNbeta retain activity due to a lack of immune exhaustion when checkpoint inhibitors were used. PMID- 28578992 TI - Reprint of: The impact of fragility fracture and approaches to osteoporosis risk assessment worldwide. AB - Osteoporosis constitutes a major public health problem, through its association with age-related fractures, particularly of the hip, vertebrae, distal forearm and humerus. Substantial geographic variation has been noted in the incidence of osteoporotic fractures worldwide, with Western populations (North America, Europe and Oceania), reporting increases in hip fracture throughout the second half of the 20th century, with a stabilisation or decline in the last two decades. In developing populations however, particularly in Asia, the rates of osteoporotic fracture appears to be increasing. The massive global burden consequent to osteoporosis means that fracture risk assessment should be a high priority amongst health measures considered by policy makers. The WHO operational definition of osteoporosis, based on a measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), has been used globally since the mid 1990s. However, although this definition identifies those at greatest individual risk of fracture, in the population overall a greater total number of fractures occur in individuals with BMD values above threshold for osteoporosis diagnosis. A number of web-based tools to enable the inclusion of clinical risk factors, with or without BMD, in fracture prediction algorithms have been developed to improve the identification of individuals at high fracture risk, the most commonly used globally being FRAX(r). Access to DXA, osteoporosis risk assessment, case finding and treatment varies worldwide, but despite such advances studies indicate that a minority of men and women at high fracture risk receive treatment. Importantly, research is ongoing to demonstrate the clinical efficacy and cost-effectiveness of osteoporosis case finding and risk assessment strategies worldwide. The huge burden caused by osteoporosis related fractures to individuals, healthcare systems and societies should provide a clear impetus for the progression of such approaches. PMID- 28578994 TI - Synthesis, molecular docking, and biological activity of polyfluoroalkyl dihydroazolo[5,1-c][1,2,4]triazines as selective carboxylesterase inhibitors. AB - To search for effective and selective inhibitors of carboxylesterase (CaE), a series of 7-hydroxy-7-polyfluoroalkyl-4,7-dihydroazolo[5,1-c][1,2,4]triazines has been synthesized. Their inhibitory activity against acetylcholinesterase, butyrylcholinesterase, and CaE were investigated using the methods of enzyme kinetics and molecular docking. It was shown that the tested compounds are reversible selective CaE inhibitors of mixed type. Elongation of the polyfluoroalkyl substituent and the presence of an ester, preferably the ethoxycarbonyl group, enhance inhibitory activity toward CaE. Furthermore, the compounds with a tetrazole ring are more active against CaE than their triazole analogues. The obtained kinetic data are well explained by the results of molecular docking, according to which there is a similar orientation of triazolo- and tetrazolotriazines in the active site of CaE and the opposite one for pyrazolotriazines. In the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assay, all of the studied tetrazolotriazines and some pyrazolotriazines demonstrated good antiradical activity comparable with a standard antioxidant, Trolox. The leading compounds were nonafluorobutyl substituted tetrazolo- and 7 phenylpyrazolotriazines, which possess effective and selective CaE inhibitory activity as well as additional useful radical-scavenging properties. PMID- 28578993 TI - A statistical view of protein chemical synthesis using NCL and extended methodologies. AB - Native chemical ligation and extended methodologies are the most popular chemoselective reactions for protein chemical synthesis. Their combination with desulfurization techniques can give access to small or challenging proteins that are exploited in a large variety of research areas. In this report, we have conducted a statistical review of their use for protein chemical synthesis in order to provide a flavor of the recent trends and identify the most popular chemical tools used by protein chemists. To this end, a protein chemical synthesis (PCS) database (http://pcs-db.fr) was created by collecting a set of relevant data from more than 450 publications covering the period 1994-2017. A preliminary account of what this database tells us is presented in this report. PMID- 28578995 TI - About cardiovascular effects associated with non-insulin antidiabetics: importance of patient therapeutic education and spontaneous reporting of adverse effects. PMID- 28578996 TI - Chain length effect on the structure and stability of antimicrobial peptides of the (RW)n series. AB - Three peptides containing (RW)n-NH2 units (where n=4, 6, and 8) have been chosen to study the effect of the chain length on the structure and stability of the peptide using Fourier transform infrared (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) techniques. Their interactions with Escherichia coli (E. coli) membrane mimetic vesicles are discussed. Infrared results indicate that addition of (RW)n NH2 units increases intermolecular H bonds with antiparallel orientation. TGA and DSC results reveal that (RW)6-NH2 shows the optimal chain length in terms of stability and all three peptides show a preferential interaction with one of the anionic lipids in E. coli membranes. SEM images of (RW)4-NH2 present large aggregates while those of (RW)6-NH2 and (RW)8-NH2 present layers of sheet-like structure. In the presence of model membranes, (RW)n-NH2 show fibrillar peptide superstructures. This study suggests that repeating structures of (RW)n-NH2 promotes lateral assembly. PMID- 28578997 TI - "The human use of human beings": Interdisciplinarity, transdisciplinarity and all that in biophysics and beyond. AB - : Biophysics, just by looking at its name, indicates an interdisciplinary scientific activity, although the notion of interdisciplinarity, as such, seems to be not widely or specifically discussed by biophysicists. The same seems to have happened as well in the early stages of the development of cybernetics, notably in Norbert Wiener's writings. This situation seems to contrast with what has happened in subsequent developments of cybernetics ideas, notably in general system theory and cognitive sciences. After a few general reflections on the notion of interdisciplinarity, its sophisticated variants and the path leading to the birth of cognitive science, we shall refer to Wiener's thought to extracts aspects and indications that could be useful today, also for what concerns the social responsibility of scientists, which could be seen as stemming from a very general form of interdisciplinarity. HIGHLIGHTS: After a few general reflections on the notion of interdisciplinarity, its sophisticated variants and the path leading to the birth of cognitive science, we shall refer to Wiener's thought to extracts aspects and indications that could be useful today, also for what concerns the social responsibility of scientists. PMID- 28578998 TI - Comparative analysis on inactivation kinetics of between piezotolerant and piezosensitive mutant strains of Saccharomyces cerevisiae under combinations of high hydrostatic pressure and temperature. AB - We previously obtained a pressure-tolerant (piezotolerant) and a pressure sensitive (piezosensitive) mutant strain, under ambient temperature, from Saccharomyces cerevisiae strain KA31a. The inactivation kinetics of these mutants were analyzed at 150 to 250MPa with 4 to 40 degrees C. By a multiple regression analysis, the pressure and temperature dependency of the inactivation rate constants k values of both mutants, as well as the parent strain KA31a, were well approximated with high correlation coefficients (0.92 to 0.95). For both mutants, as well as strain KA31a, the lowest k value was shown at a low pressure levels with around ambient temperature. The k value approximately increased with increase in pressure level, and with increase and decrease in temperature. The piezosensitive mutant strain a924E1 showed piezosensitivity at all pressure and temperature levels, compared with the parent strain KA31a. In contrast, the piezotolerant mutant strain a2568D8 showed piezotolerance at 4 to 20 degrees C, but did not show significant piezotolerance at 40 degrees C. These results of the variable influence of temperature on pressure inactivation of these strains would be important for better understanding of piezosensitive and piezotolerant mechanisms, as well as the pressure inactivation mechanism of S. cerevisiae. PMID- 28578999 TI - Utility and tolerability of the long-pulsed 1064-nm neodymium:yttrium-aluminum garnet (LP Nd:YAG) laser for treatment of symptomatic or disfiguring vascular malformations in children and adolescents. AB - BACKGROUND: Vascular malformations manifest with pain, bleeding, disability, and disfigurement in a subset of children. There are scant data available on the utility and tolerability of laser surgery for symptomatic or disfiguring non-port wine stain vascular malformations in children. OBJECTIVE: The objective of this study was to determine the utility and tolerability of the 1064-nm long-pulsed neodymium:yttrium-aluminum-garnet (LP Nd:YAG) laser for treatment of symptomatic or disfiguring vascular malformations in children. METHODS: We conducted a retrospective review of 29 pediatric patients with non-port-wine stain vascular malformations who were treated with the LP Nd:YAG laser at our institution. We report patient characteristics, treatment parameters, outcomes, and complications. RESULTS: Blinded assessment of clinical efficacy revealed good to excellent results in 66.7% of patients treated and poor to fair results in 25%. The overall rate of complications was 27%, with minor skin breakdown and blistering being the most common. LIMITATIONS: Our conclusions are limited by small sample size, pretreatment and posttreatment photographs in only a subset of patients, and lack of long-term follow-up. CONCLUSION: The LP Nd:YAG laser is a well-tolerated and effective treatment modality for a variety of non-port-wine stain vascular malformations in children. PMID- 28579000 TI - Re: Timing of Adverse Prostate Cancer Reclassification on First Surveillance Biopsy: Results from the Canary Prostate Cancer Active Surveillance Study: L. C. Macleod, W. J. Ellis, L. F. Newcomb, Y. Zheng, J. D. Brooks, P. R. Carroll, M. E. Gleave, R. S. Lance, P. S. Nelson, I. M. Thompson, Jr., A. A. Wagner, J. T. Wei and D. W. Lin J Urol 2017;197:1026-1033. PMID- 28579001 TI - Reply by Authors. PMID- 28579002 TI - New flexible endoscopes: Surprising bacterial colonization post-disinfection. PMID- 28579003 TI - An unusual cause of massive hematemesis after treatment with terlipressin. PMID- 28579004 TI - siRNA delivery system based on magnetic nanovectors: Characterization and stability evaluation. AB - Gene therapy and particularly small interfering RNA (siRNA) is a promising therapeutic method for treatment of various human diseases, especially cancer. However the lack of an ideal delivery system limits its clinical applications. Effective anticancer drug development represents the key for translation of research advances into medicines. Previously we reported, the optimization of magnetic siRNA nanovectors (MSN) formulation based on superparamagnetic iron oxide nanoparticles (SPION) and chitosan for systemic administration. This work aimed at using rational design to further optimize and develop MSN. Therefore, formulated MSN were first purified, then their physical and chemical properties were studied mainly through capillary electrophoresis. 95% of siRNA was found enclosed within the purified MSN (pMSN). pMSN showed colloidal stability at pH 7.4, effective protection of siRNA against ribonuclease degradation up to 24 hours and few siRNA release (less than 10%) at pH 7.4. These findings push toward further evaluation studies in vitro and/or in vivo, indicating the appropriateness of pMSN for cancer theranostics. PMID- 28579005 TI - Tadalafil solid dispersion formulations based on PVP/VA S-630: Improving oral bioavailability in rats. AB - Here, solid dispersion (SD) techniques were utilized to improve the oral bioavailability of tadalafil (TDF). Poly(vinyl pyrrolidone-covinyl acetate) (PVP/VA S-630; 60% VP and 40% VA; MW 50,000) SD formulations were previously found to improve the solubility and dissolution (%) of TDF. The effect of various weak acids and bases on SD formulations was also investigated herein. PVP/VA S 630 SD formulations in combination with weak acids and bases increased the apparent solubility of TDF. After 1h, the apparent solubility of PVP/VA S-630 SD formulations with MgO, meglumine, and tartaric acid were significantly higher by 387.0+/-4.17, 376.8+/-9.88, and 308.8+/-4.17MUg/mL, respectively, than those of SD formulations without weak acids and bases (166.8+/-0.50MUg/mL). The dissolution (%) of SD formulations with weak acids was under 60%; however, the dissolution (%) of those containing MgO, meglumine, and NaHCO3 was over 80% in distilled water (specifically 85.6%, 89.9%, and 91.6%, respectively). The optimal SD formulation contained meglumine (B-2); both its apparent solubility after 24h and dissolution (%) were the highest among all SD formulations. The B-2 SD formulation showed no toxicity in Caco-2 cells after 24h. The area under the concentration-time curve (AUClast) and peak plasma concentration (Cmax) of the orally administered B-2 SD formulation was greater than that with Cialis(r) powder in rats. We conclude that the B-2 SD formulation significantly improves the apparent solubility and dissolution (%) of TDF over that of commercially available products (i.e., Cialis(r)). Moreover, the B-2 SD formulation improves the relative bioavailability (BA) of TDF (21.9%) over that of Cialis(r). PMID- 28579006 TI - Incremental shuttle walk test distance and autonomic dysfunction predict survival in pulmonary arterial hypertension. AB - BACKGROUND: To ensure effective monitoring of pulmonary arterial hypertension (PAH), a simple, reliable assessment of exercise capacity applicable over a range of disease severity is needed. The aim of this study was to assess the ability of the incremental shuttle walk test (ISWT) to correlate with disease severity, measure sensitivity to change, and predict survival in PAH. METHODS: We enrolled 418 treatment-naive patients with PAH with baseline ISWT within 3 months of cardiac catheterization. Clinical validity and prognostic value of ISWT distance were assessed at baseline and 1 year. RESULTS: ISWT distance was found to correlate at baseline with World Health Organization functional class, Borg score, and hemodynamics without a ceiling effect (all p < 0.001). Walking distance at baseline and after treatment predicted survival; the area under the receiver operating characteristic curve for ability of ISWT distance to predict mortality was 0.655 (95% confidence interval 0.553-0.757; p = 0.004) at baseline and 0.737 (95% confidence interval 0.643-0.827; p < 0.001) at 1 year after initiation of treatment. Change in ISWT distance also predicted survival (p = 0.04). Heart rate (HR) and systolic blood pressure (SBP) parameters reflecting autonomic response to exercise (highest HR, change in HR, HR recovery at 1 minute >18 beats/min, highest SBP, change in SBP, and 3-minute SBP ratio) were significant predictors of survival (all p < 0.05). CONCLUSIONS: In patients with PAH, the ISWT is simple to perform, allows assessment of maximal exercise capacity, is sensitive to treatment effect, predicts outcome, and has no ceiling effect. Also, measures of autonomic function made post-exercise predict survival in PAH. PMID- 28579008 TI - Histology and grading are important prognostic factors in synovial sarcoma. AB - INTRODUCTION: The diagnosis of synovial sarcoma (SS) is currently based on clinical, morphological, immunohistochemical and cytogenetic data. Some of these factors such as grade and histology, specific translocations (SS18-SSX1 vs. SS18 SSX2) and the reduced expression of INI1, were proposed as prognostic variables. The aim of this study was to verify whether histological (grading and histology) and molecular (type of SSX translocation and INI1 expression) characteristics of SS influence the prognosis of the disease. MATERIAL AND METHODS: We retrospectively evaluated 196 patients affected by SS of the extremities treated at our Institution (Istituto Ortopedico Rizzoli, Bologna, Italy). All cases were histologically revised and tumor grade was assessed according to the FNLCC system. Tissue specimens were retrospectively evaluated to check for SS18-SSX fusion type and INI1 expression. RESULTS: Most SS were monophasic, 28% were biphasic. Eighty tumors (41%) were grade 3. Sixty percent harbored SSX1 translocation, 40% SSX2; 51% maintained the expression of INI1. Sarcoma specific survival (OS) was 56.6% at 5 years and 46.9% at 10 years. Prognosis was worse in those patients monophasic SS (p = 0.011) as in those with a grade 3 tumors (p = 0.083). No correlation was found neither between SSX fusion type nor INI1 expression and survival. LR-free survival was 78.9% at 5 years and 75.9% at 10 years. A higher LR rate was observed in tumors with SSX2 translocation and (p = 0.049) in grade 3 SS (0 = 0.028). DISCUSSION: Our data confirm that not all cases of SS present the same severe outcome. High-risk patients identified on the basis of these parameters may qualify for an aggressive treatment approach. PMID- 28579007 TI - Association between preoperative characteristics and risk of anaesthesia-related death in dogs in small-animal referral hospitals in Japan. AB - OBJECTIVE: To explore the major risk factors linking preoperative characteristics and anaesthesia-related death in dogs in referral hospitals in Japan. STUDY DESIGN: Observational cohort study. ANIMALS: From April 1, 2010 to March 31, 2011, 4323 dogs anaesthetized in 18 referral hospitals in Japan. METHODS: Questionnaire forms were collated anonymously. Death occurring within 48 hours after extubation was considered as an anaesthesia-related death. Patient outcome (alive or dead) was set as the outcome variable. Preoperative general physical characteristics, complete blood cell counts, serum biochemical examinations and intraoperative complications were set as explanatory variables. The risk factors for anaesthesia-related death were evaluated using chi-square test or Fisher's exact test, followed by multivariable logistic regression analysis of the data. Significance was set at p < 0.05. RESULTS: Thirteen dogs that died from surgical error or euthanasia were excluded from statistical analysis. The total mortality rate in this study was 0.65% [28/4310 dogs; 95% confidence interval (CI), 0.41 0.89]. Furthermore, 75% (95% CI, 55.1-89.3) of anaesthesia-related deaths occurred in dogs with pre-existing diseases. Most of the deaths occurred postoperatively (23/28; 82.1%; 95% CI, 63.1-93.9). Preoperative serum glucose concentration <77 mg dL-1 (6/46; 13.0%; 95% CI, 4.9-26.3), disturbance of consciousness (6/50; 12.0%; 95% CI, 4.5-24.3), white cell count >15,200 MUL-1 (16/499; 3.4%; 95% CI, 1.9-5.5) and American Society of Anesthesiologists grade III-V (19/1092; 1.7%; 95% CI, 1.1-2.7) were identified as risk factors for anaesthesia-related death. Intraoperative hypoxaemia (8/34; 23.5%; 95% CI, 10.7 41.2) and tachycardia (4/148; 2.7%; 95% CI, 0.7-6.8) were also risk factors for anaesthesia-related death. CONCLUSIONS AND CLINICAL RELEVANCE: The results revealed that certain preoperative characteristics were associated with increased odds of anaesthesia-related death, specifically low serum glucose concentration and disturbances of consciousness. Greater attention to correcting preanaesthetic patient abnormalities may reduce the risk of anaesthesia-related death. PMID- 28579010 TI - [Maxillary, buccal and dental expressions of hyperparathyroidisms]. AB - States of chronic parathyroid hypersecretion, related to a primitive parathyroid abnormality (adenoma, hyperplasia), or to a cause of chronic calcipenia (renal failure, vitamin D deficiency...) have a major impact on bone remodeling, alveolodental structures. Thinning of the lamina dura, maxillary or mandibular brown tumors, giant cell epulis are the most emblematic signs of the primary hyperparathyroidism. Other expressions are related to genetic factors such as fibrous tumors of the jaw in conjunction with mutations in the gene coding for parafibromin. PMID- 28579009 TI - Seasonal variation of transcriptomic and biochemical parameters of cockles (Cerastoderma edule) related to their infection by trematode parasites. AB - Bivalve populations are controlled by several biotic and abiotic factors. Parasitism is among the biotic factors but is often neglected. In the present study, we focused on the transcriptomic and biochemical responses of Cerastoderma edule when parasitized as first intermediate host by the trematode Bucephalus minimus (sporocyst, the most damaging stage), and taking into account seasonal patterns. In order to test the hypothesis that the presence of B. minimus compromises cockle regular gene expression and biochemical performance and increases their vulnerability to other parasite species infection, cockles were sampled every other month during one year in Arcachon Bay (French Atlantic coast). Overall, results showed that B. minimus induced its first intermediate host defence mechanism against oxidative stress (mainly at gene level), increased host metabolism and energy demand especially in summer (revealed at both gene and biochemical level, although without significant differences) and was accompanied by a higher metacercariae abundance. Results allowed to accept the posted hypothesis and to conclude that transcriptomic and biochemical markers can provide additional and ecologically relevant information about parasite effects on their hosts, reflecting the invasion effects of pathogens but also the environmental conditions that animals experience. PMID- 28579011 TI - [Severe neuropsychiatric symptoms due to vitamin b3 deficiency]. PMID- 28579012 TI - Description of interventions is under-reported in physical therapy clinical trials. AB - BACKGROUND: Amongst several barriers to the application of quality clinical evidence and clinical guidelines into routine daily practice, poor description of interventions reported in clinical trials has received less attention. Although some studies have investigated the completeness of descriptions of non pharmacological interventions in randomized trials, studies that exclusively analyzed physical therapy interventions reported in published trials are scarce. OBJECTIVES: To evaluate the quality of descriptions of interventions in both experimental and control groups in randomized controlled trials published in four core physical therapy journals. METHODS: We included all randomized controlled trials published from the Physical Therapy Journal, Journal of Physiotherapy, Clinical Rehabilitation, and Archives of Physical Medicine and Rehabilitation between June 2012 and December 2013. Each randomized controlled trial (RCT) was analyzed and coded for description of interventions using the checklist developed by Schroter et al. RESULTS: Out of 100 RCTs selected, only 35 RCTs (35%) fully described the interventions in both the intervention and control groups. Control group interventions were poorly described in the remaining RCTs (65%). CONCLUSIONS: Interventions, especially in the control group, are poorly described in the clinical trials published in leading physical therapy journals. A complete description of the intervention in a published report is crucial for physical therapists to be able to use the intervention in clinical practice. PMID- 28579014 TI - Executive summary of the consensus document on osteoporosis in HIV-infected individuals. AB - Osteoporosis has become an emerging comorbid condition in people living with HIV (PLWH). The increase in survival and the progressive aging of PLWH will make this complication more frequent in the near future. In addition to the traditional risk factors affecting the general population, factors directly or indirectly associated with HIV infection, including antiretroviral therapy, can increase the risk of osteoporosis. The present article is an executive summary of the document that updates the previous recommendations on the prevention and treatment of osteoporosis in PLWH. This document is intended for all professionals who work in clinical practice in the field of HIV infection. PMID- 28579015 TI - Erratum to: "An outbreak of acute norovirus gastroenteritis in a boarding school in Zamora, Spain" [Enferm Infecc Microbiol Clin 2017;35(4):264-5]. PMID- 28579016 TI - Executive summary of the GESIDA/National AIDS Plan Consensus Document on Antiretroviral Therapy in Adults Infected by the Human Immunodeficiency Virus (Updated January 2017). AB - Antiretroviral therapy (ART) is recommended for all patients infected by HIV-1. The objective of ART is to achieve an undetectable plasma viral load (PVL). Initial ART should be based on a combination of 3 drugs, including 2 nucleoside reverse transcriptase inhibitors (tenofovir in either of its two formulations plus emtricitabine or abacavir plus lamivudine) and another drug from a different family. Four of the recommended regimens, all of which have an integrase inhibitor as the third drug (dolutegravir, elvitegravir boosted with cobicistat or raltegravir), are considered preferential, whereas a further 3 regimens (based on elvitegravir/cobicistat, rilpivirine, or darunavir boosted with cobicistat or ritonavir) are considered alternatives. We present the reasons and criteria for switching ART in patients with an undetectable PVL and in those who present virological failure, in which case salvage ART should include 3 (or at least 2) drugs that are fully active against HIV. We also update the criteria for ART in specific situations (acute infection, HIV-2 infection, pregnancy) and comorbidities (tuberculosis or other opportunistic infections, kidney disease, liver disease and cancer). PMID- 28579013 TI - Modern pain neuroscience in clinical practice: applied to post-cancer, paediatric and sports-related pain. AB - BACKGROUND: In the last decade, evidence regarding chronic pain has developed exponentially. Numerous studies show that many chronic pain populations show specific neuroplastic changes in the peripheral and central nervous system. These changes are reflected in clinical manifestations, like a generalized hypersensitivity of the somatosensory system. Besides a hypersensitivity of bottom-up nociceptive transmission, there is also evidence for top-down facilitation of pain due to malfunctioning of the endogenous descending nociceptive modulatory systems. These and other aspects of modern pain neuroscience are starting to be applied within daily clinical practice. However, currently the application of this knowledge is mostly limited to the general adult population with musculoskeletal problems, while evidence is getting stronger that also in other chronic pain populations these neuroplastic processes may contribute to the occurrence and persistence of the pain problem. Therefore, this masterclass article aims at giving an overview of the current modern pain neuroscience knowledge and its potential application in post-cancer, paediatric and sports-related pain problems. PMID- 28579017 TI - Whole breast nodal irradiation using supine VMAT and prone 3D planning: A case study. AB - The purpose of this study was to compare the variations in doses to the ipsilateral lung and heart between the supine whole breast and nodal volumetric modulated arc therapy (VMAT) technique and the prone 3-dimensional conformal radiation therapy (3DCRT) technique. In this study, 3 patients who were simulated in the prone and supine positions were planned using supine VMAT and prone 3DCRT techniques to compare planning target volume (PTV) coverage as well as dose to organs at risk (ORs), including the heart and ipsilateral lung. Although all constraints were met, the ideal treatment technique depended on the patient's anatomy and lumpectomy location. Supine VMAT provided excellent coverage to the target structures but encountered difficulty in limiting dose to the ipsilateral lung and heart. When compared with the supine VMAT technique, the prone 3DCRT limited dose to the ipsilateral lung and heart but provided less dose coverage to the target volumes. PMID- 28579019 TI - Laparoscopic extraperitoneal colostomy (with video). PMID- 28579018 TI - Does using a polyethylene RM press-fit cup modify the preparation of the acetabulum and acetabular offset in primary hip arthroplasty? AB - INTRODUCTION: When performing total hip arthroplasty (THA), it is important to maintain the femoral and acetabular offsets to ensure good joint stability and to restore the function of the hip abductor muscles. In our practice, we mainly use a lateralized stem and hollow out the acetabulum to the quadrilateral plate to accommodate a press-fit polyethylene cup. However, the repercussions of this preparation method, which is driven by the cup's design, are not known. We carried out a retrospective study to assess: (1) the changes in the femoral and acetabular offset; (2) the height of the center of rotation; and (3) the repercussions on wear. HYPOTHESIS: We hypothesized there would be no significant differences between the preoperative and postoperative femoral and acetabular offsets. PATIENTS AND METHODS: We reviewed 88 primary THA cases performed with the RM PressfitTM cup that had a minimum of 5 years' follow-up. A lateralized self-locking Muller-type cemented femoral stem was used in 92.0% of cases and a standard stem in 8.0%. Measurements were done on plain radiographs with MHPTM and Mesurim ProTM software. The average follow-up was 6.5 years (5-8). RESULTS: On average, the acetabular offset was reduced by 2.75mm+/-5.9 mm (range: -17.5 to +10.6 mm) (P<0.001) and the femoral offset was increased by 0.01mm+/-5.5 mm (range: -17.8 to +11.0 mm) (P=0.99). In terms of total offset, medialization of 2.74mm+/-7 mm (range: -17.7 to +18.2mm) was found (P=0.001). The acetabular center of rotation was on average 4.77mm+/-5.1 mm higher (P<0.001). The mean annual wear at the more recent follow-up (min.: 5 years) was 0.068mm (range: 0.01 to 0.25mm) per year. The wear was not impacted by having more than 5mm change in offset. DISCUSSION: Measurements of acetabular offset revealed statistically significant medialization due to the type of implant used and the surgical technique. The anatomical technique consists of positioning the cup in subchondral bone without contacting the quadrilateral plate. This preserves bone stock, which may be useful later on if the cup is revised, particularly in younger patients. Conversely, the femoral offset did not change significantly, despite the use of lateralized stems in 92.0% of cases. We measured an annual wear rate of 0.068mm per year, which is lower than in other published studies, possibly because our patient population was older. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 28579022 TI - Erratum to "Clinical characteristics of cardioembolic transient ischemic attack: Comparison with non-cardioembolic transient ischemic attack": Journal of Stroke & Cerebrovascular Diseases 2014:23:82169-82173. PMID- 28579021 TI - Utility of the Revised Version of the Ability for Basic Movement Scale in Predicting Ambulation during Rehabilitation in Poststroke Patients. AB - OBJECTIVE: This study aims to test the hypothesis that the Revised Version of the Ability for Basic Movement Scale (ABMSII) can predict ambulation during rehabilitation in poststroke patients. SUBJECTS AND METHODS: The study included first-ever stroke patients who were admitted to the rehabilitation ward and were dependent in walking. ABMSII scores were assessed by physical therapists on admission to the hospital. Functional ambulation category (FAC) was assessed every 2 weeks during hospitalization. The primary outcome was independent ambulation, defined as 4 points or higher on the FAC. RESULTS: After setting the inclusion criteria, data of 374 stroke patients (mean age: 70 years, 153 women) were eligible for the analysis. Of these, 193 patients achieved independent ambulation during hospitalization. The ABMSII score was significantly higher in the patients who regained independent walking ability than in those who required assistance in walking. Based on receiver operating characteristic curve analysis, an ABMSII score of 16 points or higher had a sensitivity of 93% and a specificity of 71%. Kaplan-Meier curve analysis after log-rank test demonstrated a significantly higher event rate in patients with an ABMSII score of 16 or higher compared to those with an ABMSII score lower than 16. Univariate and multivariate Cox regression analyses identified the ABMSII score as a significant and independent predictor of ambulation during rehabilitation. CONCLUSION: Our results suggest that the ABMSII score is a potentially useful tool to predict ambulation during rehabilitation in poststroke patients. PMID- 28579020 TI - Psychosine, a marker of Krabbe phenotype and treatment effect. AB - Newborn screening (NBS) for Krabbe disease, a rare neurodegenerative disorder caused by deficient galactocerebrosidase (GALC) enzyme activity, has recently been implemented in a number of US states. However, the spectrum of phenotypic manifestations associated with deficient GALC activity complicates the management of screen-positive newborns and underscores the need to identify clinically relevant biomarkers. Earlier studies with a small number of patients identified psychosine, a substrate of the GALC enzyme, as a potential biomarker for Krabbe disease. In this study, we provide, for the first time, longitudinal data on dried blood spot (DBS) psychosine concentrations in different Krabbe disease phenotypes for both untreated patients and those treated with hematopoietic stem cell transplantation (HSCT). Our cohort included patients previously identified by NBS to be at high risk to develop Krabbe disease. Substantially elevated DBS psychosine concentration during the newborn period was found to be a highly specific marker for infantile Krabbe disease. This finding supports the use of DBS psychosine concentration as a second-tier NBS test to aid in the identification of patients who require urgent evaluation for HSCT. In addition, longitudinal assessments showed that both natural disease progression and treatment with HSCT were associated with decreases in DBS psychosine concentrations. Based on these findings we provide recommendations for the interpretation of psychosine concentrations in DBS specimens collected during the first year of life. Future studies should aim to better delineate the relationship between DBS psychosine concentration and disease onset in patients with later-onset forms of Krabbe disease. PMID- 28579024 TI - Longitudinal monitoring of Cryptosporidium species in pre-weaned dairy calves on five farms in Shanghai, China. AB - In pre-weaned dairy calves, the zoonotic and pathogenic species Cryptosporidium parvum is the dominant Cryptosporidium species in most industrialized nations. In several studies in China, however, C. bovis has been the dominant one. To further examine the distribution of Cryptosporidium species in pre-weaned dairy calves in China, 818 fecal specimens were collected from five farms in Shanghai, with repeated samplings (up to five times) on each farm. PCR-restriction fragment length polymorphism (RFLP) analysis of the small subunit rRNA gene was used to detect and genotype Cryptosporidium spp. Cryptosporidium parvum was subtyped by sequence analysis of the 60kDa glycoprotein gene. Cryptosporidium occurrence on farms varied between 25.0% (Farm 2) and 55.0% (Farm 4), with a mean infection rate of 37.0%. Three Cryptosporidium species were detected, including C. bovis (193/303 or 63.7%), C. parvum (72/303 or 23.8%) and C. ryanae (32/303 or 10.6%). Concurrent infection of C. bovis and C. ryanae was detected in six (1.9%) animals. During the first two samplings, C. bovis was the dominant species on four farms and C. parvum was detected on only one farm (Farm 1). One of the study farms (Farm 3) started to have C. parvum at the third sampling. C. parvum was associated with the occurrence of moderate or watery diarrhea, while C. bovis was not. All C. parvum were subtype IIdA19G1, which is dominant in China but rare elsewhere. Genotyping and subtyping results indicated that the introduction of C. parvum to Farm 3 was caused by brief housing of several bull calves from another farm. Data from the study suggest that C. parvum is still uncommon in pre-weaned dairy calves in China and measures should be developed to prevent its spread in the country. PMID- 28579023 TI - Fatal pulmonary cysticercosis caused by Cysticercus longicollis in a captive ring tailed lemur (Lemur catta). AB - Here we describe fatal pulmonary cysticercosis caused by Cysticercus longicollis, the larval stage of Taenia crassiceps in a 15-year-old female ring-tailed lemur (Lemur catta) from Sarajevo Zoo. After sudden death, the lemur was subjected to necropsy and large multicystic structure, subdivided with fibrous septa and filled with numerous translucent, oval to ellipsoid bladder-like cysts (cysticerci), almost completely replacing right lung lobe was observed. In addition, numerous free and encysted cysticerci were found in the thoracic cavity. Histopathology revealed connective tissue outlined cavities that compress lung parenchyma. Each cavity contained several thin walled cysticerci with single inverted protoscolex, one or more suckers and rostelum with two rows of hooks. In many of the cysticerci one or several exogenous buds of daughter cysticerci were observed. Based on morphology and microscopic appearance the parasite was identified as C. longicollis. Subsequent molecular analysis and sequencing confirmed presumptive diagnosis. To our knowledge, this case represents the first report of T. crassiceps and cysticercosis caused by C. longicollis in Bosnia and Herzegovina. PMID- 28579026 TI - A flow cytometric assessment of the lymphocyte immunophenotypes in dogs naturally infected with Babesia rossi. AB - Immunity to Babesia infection requires both innate and acquired responses, including cell mediated- and humoral responses. The aims of this study were to investigate the variation in selected peripheral blood lymphocyte phenotypes in dogs with virulent babesiosis at presentation and over time after treatment, and to determine whether these were correlated with the severity of clinical signs. Forty-four dogs naturally infected with B. rossi were studied and 5 healthy dogs were included as controls. Blood samples were collected from the jugular vein at admission, prior to any treatment, and at 24h and 48-72h. Leukocytes were incubated with canine specific, fluorochrome conjugated anti-CD3, anti-CD4, anti CD8, and anti-B cell markers. Babesia-infected dogs were divided into complicated or uncomplicated groups on clinical grounds and in-house laboratory assays. The percentage CD3+ lymphocytes in the complicated group was lower compared to the controls (P=0.014) and uncomplicated group (P=0.007). The percentage CD4+ T lymphocytes in the complicated group was lower compared to the controls (P=0.027) and uncomplicated group (P=0.014). Both the complicated as well as the uncomplicated groups expressed a lower percentage CD8+ T lymphocytes compared to the control group (P<0.001 and P=0.005, respectively). The percentage B lymphocytes was higher in the complicated group at 48-72h. These findings could indicate the presence of a functional immune suppression secondary to increased apoptosis or redistribution of effector lymphocytes and/or a combination of other immune modulatory mechanisms induced by B. rossi infection. PMID- 28579025 TI - Vector competence of Aedes albopictus (Skuse) and Aedes aegypti (Linnaeus) for Plasmodium gallinaceum infection and transmission. AB - Avian malaria caused by Plasmodium gallinaceum is an important mosquito-borne disease. Eradication of this disease remains problematic since its competent vectors are diverse and widely distributed across the globe. Several mosquito species were implicated as competent vectors for this parasite. However, studies on vector competence for P. gallinaceum remain limited. In this study, vector competence in the two most predominant mosquito vectors in tropical countries, Aedes albopictus and Ae. aegypti, was compared. In order to determine their infection rates, Ae. albopictus (>F10), Ae. aegypti (>F10), and Ae. aegypti ( F10) and Ae. aegypti (> F10) and 40-60% by infected Ae. aegypti (F10) and Ae. aegypti (>F10) were highly competent vectors for P. gallinaceum infections. These mosquitoes play a crucial role in the transmission cycle of this parasite in nature. PMID- 28579027 TI - Molecular detection of Toxoplasma gondii in the slaughter sheep and goats from North India. AB - Toxoplasma gondii is an obligate intracellular parasite that infects almost all the warm blooded animals, including human beings. The disease usually remains asymptomatic but is a serious concern for pregnant women, developing foetus and immuno-compromised individuals. We collected 400 cardiac/skeletal muscle tissue samples from slaughter sheep (177) and goat (223) intended for human consumption from Punjab, Uttar Pradesh and Chandigarh states/union territory in North India. The samples were pepsin-HCl digested and DNA was extracted from all the digested samples. Nested-PCR was carried out to amplify 580bp and 531bp bands with external and internal sets of primers specific for B1 gene of T. gondii. Molecularly, six (1.5%) isolates of T. gondii were detected. In PCR, T. gondii DNA were detected from 1.69% and 1.34% of the sheep and goat samples, respectively. Three PCR amplified products were sequenced in both the directions and readable sequences were obtained. Due to a low level of polymorphism in the targeted B1 gene, the clonal lineages of different isolates could not be determined. The results indicate that T. gondii in slaughter sheep and goat presents a low food safety risk for public health in North India. PMID- 28579028 TI - Cattle fever tick, Rhipicephalus (Boophilus) microplus (Acari: Ixodidae): Potential control on pastures by the application of urea fertilizer. AB - The southern cattle fever tick, Rhipicephalus (Boophilus) microplus, spends as much as 80-90% of its life cycle as a larva questing for a host. Standard control methods are limited to on-host applications, leaving a need for methods directed at the pasture infesting stages. Reports from Brazil indicate that pasture fertilization can reduce tick numbers. Granular urea was tested using standard pesticide efficacy methods in both the laboratory and field trials to determine if there was a significant impact on adult reproduction and larval survival. Under the conditions of this present study, there was no detectable effect on either female adults or larval stages. Ammonification in the soil may be a key factor limiting the impact of fertilizer treatments. PMID- 28579029 TI - Pharmacokinetics and anthelmintic efficacy of injectable eprinomectin in goats. AB - The objective of this study was to assess the pharmacokinetics and the anthelmintic efficacy of eprinomectin (Eprecis(r) 20mg/mL) following subcutaneous administration to goats. Forty non-lactating female Alpine goats aged between one and three years and weighing between 32.7 and 59.5kg, were randomly allocated to one of the following groups (8 animals per group): two groups were not infected and were treated at a dose of either 0.2 or 0.4mg/kg BW of eprinomectin, two groups were experimentally infected with nematodes and treated at 0.2 or 0.4mg/kg BW of eprinomectin similarly and one group was infected and left untreated (control). Infection consisted in a single and simultaneous administration of 5000 Haemonchus contortus and 12,500 Trichostrongylus colubriformis infective larvae. No local or general adverse reaction was visually observed whatever the dose rate. The maximal plasma concentrations (Cmax) were 20.68+/-12.85 vs 39.79+/ 17.25MUg/L and the plasma bioavailabilities (AUC) 83.45+/-34.75 vs 169.37+/ 43.44MUg*d/L for 0.2 vs 0.4mg/kg respectively. The efficacy against H. contortus and T. colubriformis was 97.8 and 98.7% at 0.2mg/kg and 98.4% and >99.9% at 0.4mg/kg respectively. The differences in worm burdens between the two dose rates were only significant for T. colubriformis. These results indicate that injectable eprinomectin is a potent anthelmintic against the two major gastrointestinal nematodes in goats. Additional information is needed regarding pharmacokinetics in lactating goats and milk residues. PMID- 28579030 TI - Broad spectrum anthelmintic resistance of Haemonchus contortus in Northern NSW of Australia. AB - On a sheep farm in Northern New South Wales (NSW) of Australia a degree of anthelmintic resistance was suspected. With noticeable clinical signs of infection and sheep not responding to treatment, a faecal egg count reduction test was conducted to ascertain the broad spectrum of anthelmintic resistance at this farm. A number of classes of anthelmintics were assessed including organophosphate, macrocyclic lactone (ML) and in combination an ML, benzimidazole, levamisole and salicylanilide. In addition, the more recently registered classes of anthelmintics, monepantel (amino-acetonitrile derivative) and derquantel/abamectin combination (spiroindole+ML) were included. Ninety merino sheep naturally infected with a field strain of Haemonchus contortus were randomly allocated to 6 treatment groups (15 animals/group). Sheep were subsequently treated based on label recommendations and individual bodyweight. Faecal samples were collected post-treatment on Days 7, 14 and 21 to conduct faecal egg counts and group bulk larval cultures. Broad spectrum anthelmintic resistance was confirmed at this site with treatment efficacies ranging from 21.3% (monepantel) to 93.8% (derquantel/abamectin combination) against the H. contortus strain. Furthermore, resistance to the multi-combination anthelmintic containing 4 active ingredients was evident (52.5%). This broad spectrum of resistance highlights the need for integration of alternative sustainable methods in parasite control in order to slow development of resistance and increase the life time effectiveness of anthelmintics. PMID- 28579031 TI - The antiparasitic activity of avenacosides against intestinal nematodes. AB - Avena sativa L., 1753 (Poaceae) is used as feed for livestock and as a crop rotation agent. The purpose of the study was to examine the molecular mechanisms behind the antihelminth activity of the oat saponins avenacoside B (AveB) and 26 desglucoavenacoside B (26DGAveB) by evaluating their effect on Heligmosomoides bakeri, a parasitic nematode of mice. The avenacosides AveB and 26DGAveB were separated and purified from A. sativa green leaves, and their mycotoxic activity was confirmed against the fungus Trichoderma harzianum. The anti-nematode activity of the avenacosides was measured by egg hatching assay. In the surviving L3 larvae exposed to avenacosides, the expression of CED-9, a protein of the apoptosis pathway, was identified by Western blotting. The protein profile of L3 larvae was monitored by High Performance Liquid Chromatography (HPLC). The action of saponins on glycoprotein pump (Pgp) activity in L3 larvae was compared to that of the pump blocker Verapamil (VPL). A mouse model was used to measure the infectivity of L3 larvae exposed to AveB and 26DGAveB, and the outcome of the immune response. Both compounds induced morphological changes in larvae and blocked Pgp activity; however, only 26DGAveB provoked expression of CED-9. The infected mice displayed changes in the molecular pattern of larval proteins and enhanced IL-4 production, indicating that avenacosides reduced the infectivity of H. bakeri larvae. In avenacosides, the residue without glucose at the C26 position demonstrated greater anti-nematode activity. Our findings indicate that A. sativa compounds are natural products with anti-parasitic activity. PMID- 28579032 TI - Genetic analyses of Chinese isolates of Toxoplasma gondii reveal a new genotype with high virulence to murine hosts. AB - A great deal of evidence demonstrates that a strongly clonal population structure of Toxoplasma gondii strains exists in humans and animals in North America and Europe, while the strains from South America are genetically separate and more diverse. Potential differences in virulence between different strains mean that an understanding of strain diversity is important to human and animal health. However, to date, only one predominant genotype, ToxoDB#9 (Chinese I), and a few other genotypes, including ToxoDB#205, have been identified in China. By using DNA sequence-based phylogenetic analyses, we have re-evaluated the population structure of T. gondii strains collected from China and compared them with other global strains. Based on phylogenetic analysis of restriction fragment length polymorphisms, multilocus sequence typing and intron sequences from T. gondii, we propose that the Chinese isolates described as Chinese I are divided into two groups called Chinese I and Chinese III. Our results demonstrate that significant differences were found in mouse mortality caused by some Chinese strains, and also the archetypal I, II, III strains in mice. Furthermore, a comparison of cyst loading in the brains of infected rats showed some Chinese strains to be capable of a high degree of cyst formation. Furthermore we show that genotyping using neutral genetic markers may not be a useful predictor of pathogenic phenotypes. PMID- 28579034 TI - NO signaling in retinal bipolar cells. AB - Nitric oxide (NO) is a neuromodulator involved in physiological and pathological processes in the retina. In the inner retina, a subgroup of amacrine cells have been shown to synthesize NO, but bipolar cells remain controversial as NO sources. This study correlates NO synthesis in dark-adapted retinas, through labeling with the NO marker DAF-FM, with neuronal nitric oxide synthase (nNOS) and inducible NOS expression, and presence of the NO receptor soluble guanylate cyclase in bipolar cells. NO containing bipolar cells were morphologically identified by dialysis of DAF fluorescent cells with intracellular dyes, or by DAF labeling followed by immunohistochemistry for nNOS and other cellular markers. DAF fluorescence was observed in all types of bipolar cells that could be identified, but the most intense DAF fluorescence was observed in bipolar cells with severed processes, supporting pathological NO signaling. Among nNOS expressing bipolar cells, type 9 was confirmed unequivocally, while types 2, 3a, 3b, 4, 5, 7, 8 and the rod bipolar cell were devoid of this enzyme. These results establish specific bipolar cell types as NO sources in the inner retina, and support the involvement of NO signaling in physiological and pathological processes in the inner retina. PMID- 28579033 TI - Does oxidative stress play any role in diabetic cataract formation? ----Re evaluation using a thioltransferase gene knockout mouse model. AB - Oxidative stress is a known risk factor in senile cataract formation. In recent years, it has been suggested that oxidation may also be associated with cataract induced by hyperglycemia, but this concept has not been well examined or validated. Since thioltransferase (TTase) is one of the key enzymes that regulates redox homeostasis and protects against oxidative stress in the lens, we have used TTase gene knockout (KO) mice as a model to examine this new concept. Lenses from 4 months old TTase KO and wild-type (WT) mice were incubated in TC199 culture medium containing 30 mM glucose for 48 h. Each lens was assessed for opacity, graded by LOCSII system, and the wet weight was recorded after which it was homogenized in lysis buffer and analyzed for water-soluble protein and free glutathione (GSH). In vivo studies were carried out using 4 months old TTase KO and WT mouse groups. Each mouse received two consecutive days of intraperitoneal streptozotozin (STZ) injections to induce diabetes. The lenses were examined weekly for 4 weeks using a slit-lamp biomicroscope, and then extracted and analyzed for levels of GSH, water-soluble protein, ATP and protein-GSH mixed disulfide (PSSG). TTase KO lenses cultured in high glucose developed a mild cortical opacity but slightly more than that of the WT lenses. Both groups had similar contents of soluble proteins and GSH. Exposure to high glucose did not change the soluble protein level but did suppress GSH by 20% in lenses with or without TTase. STZ-induced diabetic KO mice also developed a higher degree of mild cortical lens opacity compared to that of the diabetic WT controls. Similar 15-20% losses in lens GSH and ATP were found after one-month induced diabetes in WT and KO mice. There was a 20% greater amount of PSSG in the lenses of TTase KO than the WT control. Under diabetic condition, both groups displayed more glutathionylated proteins in the beta-actin (42 kDa) and lens crystallin proteins (18-22 kDa) regions, and some additional modified proteins at 15-17 kDa and 60-70 kDa, with a total 20-30% PSSG increment in both groups. In conclusion, we have found that hyperglycemia induced some oxidative stress-associated biochemical changes with mild lens opacity in both WT and KO mice. However, these changes were only marginally higher in the TTase KO mouse than that of the WT control, suggesting that TTase deletion may only play a minor role in the early stage of hyperglycemia-induced cataract formation in the mice. PMID- 28579035 TI - Measuring satisfaction with appearance: Validation of the FACE-Q scales for double-eyelid blepharoplasty with minor incision in young Asians- retrospective study of 200 cases. AB - BACKGROUND: Double eye-lid surgery is one of the most popular performed aesthetic procedures in young Asians. Reliable measurement of patient reported outcomes is crucial for facial aesthetics. The FACE-Q is a new patient-reported outcome tool (PRO) composed of numerous independently functioning scales and checklists designed to measure outcomes. Here we described FACE-Q scales for double eye-lid surgery with minor incision in young Asians. METHODS: 200 patients (400 eyes) aged from 21 to 30 years-old were recruited from 2012 to 2014. They underwent minor incision procedure for double-eyelid blepharoplasty, epicanthic fold correction, excessive orbit fat removal and blepharoptosis correction simultaneously. An incision of 1 cm long in the middle of upper eyelid and modified Park's Z-plasty for epicanthus correction were designed. Three stitches were carried out in levator aponeurosis-inferior dermis procedure. By the middle incision in the upper eyelid, blepharoptosis correction and excessive orbit fat removal can be executed. Those patients were asked to complete anonymously the FACE-Q by e-mail. FACE-Q scores were assessed for each domain (range, 0 to 100), with higher scores indicating greater satisfaction with appearance or superior quality of life. RESULTS: After a mean of 2 years' follow-up, postoperative complications included partial or complete loss of the double-eyelid fold in 8 and 0 cases, respectively, no hypertrophic scar formation, and asymmetric fold in four cases. One patient received re-operation on blepharoptosis correction. Except hematoma occurring in one female case, no obvious edema was observed. Patients demonstrated high levels of satisfaction with eye appearance overall (mean +/- SD, 81.7 +/- 18.3). Quality of Life Patients exhibited high levels of quality of life, including in social confidence (95.4 +/- 12.6), psychological well-being (97.8 +/- 10.3), and early life impact of the procedure (90.2 +/- 13.4). Patients reported high satisfaction with the decision to undergo and the outcome of the procedure. CONCLUSIONS: Minimally invasive procedure is a reliable tool for correcting disfigurement in double-eyelid blepharoplasty. However, this method is not suitable for those cases whose upper eyelids are featured by relaxation. Excessive amount of skin must be removed. Patients who responded in this study were extremely satisfied with their decision to undergo double-eyelid surgery and the outcomes and quality of life following the procedure. PMID- 28579036 TI - Analysis of surgical results and of residual postoperative deformities in preaxial polydactyly of the hand. AB - PURPOSE: Polydactyly is the most common congenital anomaly of the hand. It may occur as a separate event or as part of a syndrome, with preaxial polydactyly of the hand (or thumb duplication) being the most common among Caucasians. The present study analyzed the surgical results and the residual postoperative deformities of patients with thumb duplication. METHODS: Thirty-one patients with duplicated thumbs were surgically treated from January 2002 to April 2008 and 19 of them, who had returned during the late postoperative period, were evaluated. Each case was typed according to Wassel's classification into seven types and the most common category was type IV. Removal of radial component was done in 18 patients aged on average 51 months. RESULTS: Patients and parents were satisfied with both the functional results and the appearance of the reconstructed thumb. In the subjective evaluation of residual deformities, axis deviation and residual prominence were commonly found. There were coherencies in data between both subjective and objective outcomes. The children that had difficulty in holding very small objects in the subjective functional result were the same children with residual deformities in the objective result. Patient's age at surgery and Wassel's type influenced the analysis of residual postoperative deformities. There was statistically significant difference in cases of type VII and in patients operated at more than three years of age. Correlation between type VII and patient's age at time of surgery was found. The children with type VII duplication were operated later. CONCLUSIONS: For a better result, surgical correction should be performed before three years of age, thus correcting all the changes detected, mainly in type VII, in order to reduce the incidence of residual deformity. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28579037 TI - Risk factors for recurrence of facial basal cell carcinoma after surgical excision: A follow-up analysis. AB - BACKGROUND: Several tumour features and surgical factors have been implicated in an increased risk of BCC recurrence after excision; however, there are limited data on facial lesions specifically. This study sought to evaluate risk factors of facial BCC, which may influence future treatment and follow-up regimes. METHODS: Facial BCCs excised from a single surgeon practice over a 2-year period were included in the study. Data pertaining to patient demographics, lesion depth of invasion, surface area, excision margins, perineural infiltration, location, previous history of recurrence, histological subtype and ulceration were extracted. A search of recurrence was conducted over the following 70-80 months. RESULTS: In total, 331 cases of facial BCC were included, and 10 lesions recurrences (3%) were identified within the observation period. Infiltrative (p = 0.02) and micronodular (p = 0.04) subtypes as well as incomplete or close (within 1 mm) peripheral (p = 0.01) and deep excision margins (p = 0.04) were significantly associated with tumour recurrence. Five of the 10 recurrent lesions had been re-excised for a recurrence previously, placing them at much greater risk of future recurrence (p = 0.00). CONCLUSIONS: Incomplete and close excision margins, infiltrative and micronodular subtypes and previous excision are strong risk factors for facial BCC recurrence. Although depth of invasion, perineural infiltration, ulceration and surface area may indicate the aggressive nature of a lesion, the results suggest that with adequate excision margins, these factors may not influence the recurrence rate. The strongest risk factor was a lesion having already recurred after previous excision, and it suggested that these lesions be treated with particular caution and a closer follow-up regime be employed. PMID- 28579038 TI - Successful resolution of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis during the treatment course of acute lymphoblastic leukemia. PMID- 28579039 TI - Total mismatch of diffusion-weighted imaging and susceptibility-weighted imaging in patients with acute cerebral ischemia. AB - BACKGROUND AND PURPOSE: Multiple hypointense vessels (MHV) on susceptibility weighted imaging (SWI) is associated with an increased oxygen demand in acute cerebral ischemia. Occasionally, some patients exhibit extensive MHV on SWI despite of negative diffusion-weighted imaging (DWI), which is a phenomenon called total mismatch DWI-SWI. We analyzed the clinical characteristics and imaging findings in patients with the total DWI-SWI mismatch. MATERIALS AND METHODS: We selected patients with total DWI-SWI mismatch who underwent MRI within 12hours from onset. To evaluate the degree of collateral flow, we graded vessels on post-contrast time-of-flight MR angiography as 3 groups. Perfusion lesion volume was measured using threshold of>6seconds of mean transit time on perfusion-weighted imaging. RESULTS: Total DWI-SWI mismatch was found in 10 (2.7%) out of 370 patients. Four out of 10 patients were excluded due to lack of data on perfusion studies. Hence 6 patients were finally selected in the study. Two patients with internal carotid artery dissection were treated with emergent stenting, one patient with intravenous thrombolysis and mechanical thrombectomy, and two patients with drug-induced hypertension. All of the enrolled patients exhibited extensive MHV on SWI and good collateral flows. The mean perfusion lesion volume was 72.6+/-15.3ml (range 0-325.0ml). Clinical outcome was favorable in all of the patients (mRS at 3 months, 0). CONCLUSIONS: Our results demonstrate that total mismatch of DWI-SWI is associated with good collateral flow and may be a predictor of good response to treatment in patients with acute cerebral ischemia. PMID- 28579040 TI - Autonomy and self-esteem of women who donate to an oocyte cryopreservation bank in the Netherlands. AB - Worldwide, oocyte donors donate voluntarily or receive varying amounts of money for donation. This raises ethical questions regarding the appropriateness of financial compensation, and the possibility of undue inducement and exploitation of oocyte donors. Are these donors capable of making an independent, well considered decision? Regarding this matter, it is important to examine aspects such as autonomy-connectedness and self-esteem. In this cross-sectional study, demographic characteristics and donation motivations were assessed in 92 women who attended the University Medical Center (UMC) Utrecht as potential oocyte donors between June 2012 and July 2016. Demographic characteristics were assessed. Motivations were recorded in semi-structured interviews (response rate 59%). The Rosenberg Self-Esteem Scale was used to assess level of self-esteem. The Autonomy-Connectedness Scale was used to measure the level of autonomy connectedness. The typical oocyte donor at the UMC Utrecht is a well-educated, employed, 31-year-old woman living with her partner in a completed family with two children, and donating on altruistic grounds. The donors showed higher autonomy-connectedness scores than the average female Dutch population and do not lack self-esteem (questionnaire response rate 66%). Concerns regarding exploitation and attraction of women with lower socioeconomic status, with shortcomings in autonomy-connectedness and self-esteem, could not be confirmed in this group. PMID- 28579041 TI - Clinical Perspectives of Digital Dermatitis in Dairy and Beef Cattle. AB - Digital dermatitis is a polybacterial disease process of dairy and beef cattle. Lesions are most commonly identified on the plantar aspect of the interdigital cleft of the hind limbs. Treponema spp are routinely present in large numbers of active lesions. Lesions are painful to the touch and can result in clinical lameness. The infectious nature generally results in endemic infection of cattle herds and management requires a comprehensive and integrated multipronged approach. This article provides current perspectives regarding management and treatment of digital dermatitis on dairy and beef cattle operations and provides a review for clinicians dealing with a clinical outbreak. PMID- 28579042 TI - Pathogenesis and Treatment of Bovine Foot Rot. AB - Bovine foot rot (BFR) is an infectious disease of the interdigital skin and subcutaneous tissues of beef and dairy cattle that occurs under a variety of management and environmental settings. The anaerobic, gram-negative bacteria Fusobacterium necrophorum, Porphyromonas levii, and Prevotella intermedia are commonly isolated from lesions. A multitude of host, agent, and environmental factors contribute to the development of BFR. Initiation of systemic antimicrobial therapy early in the course of disease commonly leads to resolution. Delays in treatment may result in extension of infection into deeper bone, synovial structures, or ligamentous structures, and the prognosis for recovery is reduced. PMID- 28579043 TI - Mobility Scoring of Finished Cattle. AB - Lameness is among the most important welfare and production issues affecting dairy cattle. Recently, it has received significant research emphasis. Certain events in 2013 within the cattle industry heightened the focus on mobility issues in finished cattle. Scoring systems are needed in the finished cattle industry to capture and measure mobility issues at packing facilities. The North American Meat Institute Animal Welfare Committee helped facilitate the creation of a scoring system to evaluate mobility of cattle at packing plants, providing the cattle industry with a tool to benchmark and improve the welfare of finished cattle. PMID- 28579044 TI - Diagnosis and Prognosis of Common Disorders Involving the Proximal Limb. AB - Claw diseases are the principal cause of lameness in cattle. They can be easily diagnosed by examining the feet while the animal is in the trimming chute. Lameness originating from the proximal limb is more challenging because it is less visible. The author describes a systematic approach to diagnose upper limb lameness. The most common causes of lameness are reviewed with special emphasis on physical examinations and appropriate diagnostic tools. PMID- 28579045 TI - Traumatic Lesions of the Sole. AB - Traumatic lesions of the sole are a common cause of lameness in beef and dairy cattle. This article provides a brief description of traumatically induced conditions with specific attention to underlying causes, treatment, and prevention. Lameness, traumatic lesions of the sole, sole punctures, thin soles, thin sole toe ulcers, toe tip necrosis syndrome, and toe abscesses are discussed. PMID- 28579046 TI - Pathogenesis and Treatment of Toe Lesions in Cattle Including "Nonhealing" Toe Lesions. AB - Toe lesions in cattle include apical white line disease, thin soles, toe ulcers, toe necrosis, digital dermatitis-associated toe ulcers/toe necrosis, and fracture of the claw capsule and the apex of the distal phalanx. For anatomic reasons, the early stages of toe abnormalities (thin sole, apical white line disease, toe ulcer) are at risk of developing into a bone infection. The prevalence of toe lesions differs in dairy herds and feedlots: it is low at the animal level in feedlots and dairies; however, the herd prevalence of toe lesions can reach 50% in dairy herds with endemic digital dermatitis infection. PMID- 28579047 TI - Surgical Procedures of the Distal Limb for Treatment of Sepsis in Cattle. AB - With a thorough knowledge of the anatomy of the foot, and basic surgical instruments, digit surgery can be performed in field situations. Sepsis of the distal interphalangeal and proximal interphalangeal joints should be treated surgically because conservative treatment is often ineffective. Most of the diseases described in this article are chronic and often the animals have been suffering for some time. Perioperative analgesia is important to alleviate the pain of those animals. All those procedures should be performed under local or regional anesthesia. PMID- 28579048 TI - A Review of the Relationship Between Hoof Trimming and Dairy Cattle Welfare. AB - A narrative integrative review on the evidence for hoof trimming found 16 articles on efficacy, frequency, and associations with behavior and physiologic parameters. Review of these studies revealed (1) hoof trimming is associated with behavior and physiologic changes; (2) increasing the frequency of hoof trimming seems to decrease the incidence of hoof lesions; (3) there is limited research to support any particular technique; and (4) descriptions of the hoof trimming techniques used is inadequate in most articles. To increase scientific support for hoof trimming practices, current knowledge gaps in technique, timing, and frequency of hoof trimming need to be addressed. PMID- 28579049 TI - Treatment Options for Lameness Disorders in Organic Dairies. AB - Animal welfare is an essential aspect of organic dairying. Consequently, adequate lameness control should be a central component of on-farm health monitoring programs. The combination of organic management practices, including grazing requirements that are combined with different types of housing, results in unique features determining the cows' feet and legs health condition. Because the use of therapeutic resources is limited, preventive management and early detection of lameness is critical in organic dairies. This article discusses the relevant aspects of prevention and treatment options of lameness disorders in organic dairy farms. PMID- 28579050 TI - An Update on the Assessment and Management of Pain Associated with Lameness in Cattle. AB - Lameness affects the cattle industry via both economic losses and welfare considerations. In addition to production deficits, the pain and distress associated with lameness have been documented. Evaluation and prevalence of lame cattle are among the primary factors in third-party welfare audit programs. Mean lameness prevalence in herds has been reported to be as high as 36.8%, although a less than 10% prevalence of lame cattle was reported by some producers. Note that lameness is usually underreported by producers compared with independent observers, potentially because of a decreased sensitivity in detecting lame cattle. PMID- 28579051 TI - Bovine Lameness. PMID- 28579052 TI - An overview of experimental designs in HPLC method development and validation. AB - Chemometric approaches have been increasingly viewed as precious complements to high performance liquid chromatographic practices, since a large number of variables can be simultaneously controlled to achieve the desired separations. Moreover, their applications may efficiently identify and optimize the significant factors to accomplish competent results through limited experimental trials. The present manuscript discusses usefulness of various chemometric approaches in high and ultra performance liquid chromatography for (i) methods development from dissolution studies and sample preparation to detection, considering the progressive substitution of traditional detectors with tandem mass spectrometry instruments and the importance of stability indicating assays (ii) method validation through screening and optimization designs. Choice of appropriate types of experimental designs so as to either screen the most influential factors or optimize the selected factors' combination and the mathematical models in chemometry have been briefly recalled and the advantages of chemometric approaches have been emphasized. The evolution of the design of experiments to the Quality by Design paradigm for method development has been reviewed and the Six Sigma practice as a quality indicator in chromatography has been explained. Chemometric applications and various strategies in chromatographic separations have been described. PMID- 28579054 TI - Hospital mortality in cirrhotic patients at a tertiary care center in Latin America. PMID- 28579053 TI - Iron-deficiency anemia as a subclinical celiac disease presentation in an Argentinian population. AB - BACKGROUND: There is a wide heterogeneity in the reports of celiac disease prevalence in iron-deficiency anemia patients. AIM: To determine the prevalence of celiac disease in patients with iron-deficiency anemia. MATERIALS AND METHODS: Adult patients with a diagnosis of iron-deficiency anemia were enrolled for upper endoscopy with duodenal biopsies. Healthy volunteers that underwent upper endoscopy were enrolled as controls. RESULTS: A total of 135 patients with iron deficiency anemia and 133 controls were enrolled. Celiac disease prevalence was higher in the iron-deficiency anemia group [11.11 vs. 1.51%, OR: 8.18 (1.83 36.55), P=.001). Of the celiac disease patients in the iron-deficiency anemia group, 73.3% had at least one endoscopic sign suggesting villous atrophy, whereas 100% of the celiac disease patients in the control group presented with at least one endoscopic sign. CONCLUSIONS: Patients with iron-deficiency anemia have an increased risk for celiac disease. Up to 25% of these patients may not present any endoscopic sign suggesting villous atrophy. PMID- 28579055 TI - Jean Lhermitte on Consciousness. PMID- 28579056 TI - [Computerized oculomotor training in dyslexia: A randomized, crossover clinical trial in pediatric population]. AB - OBJECTIVE: Several studies have reported abnormal oculomotor capacities leading to reading/writing difficulties among dyslexic children. However, no randomized clinical trial has been conducted to determine whether oculomotor training improves reading/writing skills of these children. The present study aims to evaluate the efficacy of computer-based oculomotor training among dyslexic children. METHOD: Crossover randomized trial with enrollment from January 12, 2015 to July 24, 2015, and follow-up to February 4, 2016. Eleven children (aged 7 to 12 years old) with dyslexia were included in a French psychiatric unit. The computer-based oculomotor training consisted of exercises focused on control of saccadic movements (reflexes and voluntary saccades), vergences and visual attention and memory. At baseline, 3 and 6 months, participants were assessed on reading and writing skills as well as phonological skills, visuo-attentional skills and verbal memory using the French batterie analytique du langage ecrit (BALE). Saccadic and antisaccadic ocular movements (latencies and gains) were recorded using a specific device. Several Anova models were performed to test whether oculomotor training improves reading, writing and phonological, verbal memory and visuo-attentional skills. Our analyses were considered exploratory (alpha at 5%). RESULTS: No effect of oculomotor training was found on reading skills. However, oculomotor training was associated with a short-term effect (after 3 months of training) on several tests measuring phonological skills (syllabic suppression; P-value=0.022), visuo-attentional skills (search of anarchic verbal cues; P-value=0.035) and verbal memory (digit span backward; P value=0.022) and with a long-term effect (3 months after the end of the 3 months of training) on a measure of writing skills (regular words; P-value=0.019). Finally, training was associated with an increase of saccadic latencies indicating an increase of visuo-attentional skills (P-value=0.026). CONCLUSIONS: Our results suggested that computer-based oculomotor training might be effective on writing skills and several cognitive skills among dyslexic children, but future clinical trials are needed to confirm our results. PMID- 28579057 TI - Insulin initiation status of primary care physicians in Turkey, barriers to insulin initiation and knowledge levels about insulin therapy: A multicenter cross-sectional study. AB - AIMS: Our aim was to evaluate the insulin initiation status, barriers to insulin initiation and knowledge levels about treatment administered by primary care physicians (PCP). METHODS: We conducted our study in accordance with a multicenter, cross-sectional design in Turkey, between July 2015 and July 2016. A questionnaire inquiring demographic features, status of insulin initiation, obstacles to insulin initiation and knowledge about therapy of the PCPs was administered during face-to-face interviews. RESULTS: 84 PCPs (19%) (n=446, mean age=41.5+/-8.4years, 62.9% male and 90.0% ministry certified family physicians) initiated insulin therapy in the past. Most of the stated primary barriers (51.9%, n=230) were due to the physicians. The most relevant barrier was "lack of clinical experience" with a rate of 19% (n=84 of the total). The average total knowledge score was 5.7+/-2.0 for the family medicine specialist, and 3.8+/-2.1 for the ministry certified family physicians (p=0.000, maximum knowledge score could be 10). CONCLUSIONS: The status of insulin initiation in Turkey by the primary care physicians is inadequate. Medical education programs and health care systems may require restructuring to facilitate insulin initiation in primary care. PMID- 28579060 TI - Human dihydrolipoamide dehydrogenase (E3) deficiency: Novel insights into the structural basis and molecular pathomechanism. AB - This review summarizes our present view on the molecular pathogenesis of human (h) E3-deficiency caused by a variety of genetic alterations with a special emphasis on the moonlighting biochemical phenomena related to the affected (dihydro)lipoamide dehydrogenase (LADH, E3, gene: dld), in particular the generation of reactive oxygen species (ROS). E3-deficiency is a rare autosomal recessive genetic disorder frequently presenting with a neonatal onset and premature death; the highest carrier rate of a single pathogenic dld mutation (1:94-1:110) was found among Ashkenazi Jews. Patients usually die during acute episodes that generally involve severe metabolic decompensation and lactic acidosis leading to neurological, cardiological, and/or hepatological manifestations. The disease owes its severity to the fact that LADH is the common E3 subunit of the alpha-ketoglutarate (KGDHc), pyruvate (PDHc), and branched chain alpha-keto acid dehydrogenase complexes and is also part of the glycine cleavage system, hence the malfunctioning of LADH simultaneously incapacitates several central metabolic pathways. Nevertheless, the clinical pictures are usually not unequivocally portrayed through the loss of LADH activities and imply auxiliary mechanisms that exacerbate the symptoms and outcomes of this disorder. Enhanced ROS generation by disease-causing hE3 variants as well as by the E1-E2 subcomplex of the hKGDHc likely contributes to selected pathogeneses of E3 deficiency, which could be targeted by specific drugs or antioxidants; lipoic acid was demonstrated to be a potent inhibitor of ROS generation by hE3 in vitro. Flavin supplementation might prove to be beneficial for those mutations triggering FAD loss in the hE3 component. Selected pathogenic hE3 variants lose their affinity for the E2 component of the hPDHc, a mechanism which warrants scrutiny also for other E3-haboring complexes. PMID- 28579058 TI - The challenge of living with diabetes in women and younger adults: A structural equation model. AB - BACKGROUND: Attitudes toward diabetes care are different between genders and age groups. Furthermore, diabetes related challenges may cause psychosocial problems. Therefore, we were to compare the psychosocial status and glycemic control in women and men with type 2 diabetes (T2D) in different age-groups. METHODS: 441 adults with T2D were recruited. Demographic, self-care behavior, resources and affective variables as well as the health related quality of life (HRQoL) were measured. The median age of 55 was used as the cut-off for the age comparison. Structured equation modeling (SEM) investigated the relationship between age, gender, psychosocial factors and glycemic control. RESULTS: Finally, 203 women and 177 men completed the study (86.1%). There was no significant difference in mean duration of T2D, or glycemic control between genders or age-groups. Women, especially those below the median age of 55, had significantly higher level of diabetes-related distress (2.16+/-0.94 vs. 1.92+/-0.81), depression (9.67+/-5.37 vs. 7.54+/-5.06), and anxiety (19.81+/-12.04 vs. 12.81+/-9.04, P<0.05 for all comparisons), while people above the age of 55 reported better self-management and patient-physician relationship. HRQoL was lower in women compared to men (0.77+/-0.23 vs. 0.81+/-0.18, P=0.02). The final SEM suggested that the effect (standardized beta coefficient) of gender and age on affective variables was 0.25 and -0.19 (P<0.05), respectively, though psychosocial factors did not directly influence HbA1c. CONCLUSIONS: This study shows that psychosocial factors are associated with age and gender in patients with T2D; with younger women demonstrating higher level of depressive symptoms, anxiety, and diabetes-related distress independent of status of glycemic control. PMID- 28579061 TI - Classification of Fluorescein Breakup Patterns: A Novel Method of Differential Diagnosis for Dry Eye. AB - PURPOSE: To investigate the relationship between fluorescein breakup patterns (FBUPs) and clinical manifestations in dry eye cases. DESIGN: Cross-sectional study. METHODS: In 106 eyes of 106 subjects (19 male, 87 female; mean age: 64.2 years), FBUPs were categorized into 1 of the following 5 break (B) types: area (AB, n = 19); spot (SB, n = 22); line (LB, n = 24); dimple (DB, n = 19); random (RB, n = 22 eyes); and dry eye-related symptoms using the visual analog scale (VAS, 100 mm = maximum), tear meniscus radius (TMR, mm), tear film lipid layer interference grade (IG) (grades 1-5; 1 = best) and spread grade (SG) (grades 1-4; 1 = best), tear film noninvasive breakup time (NIBUT, seconds), fluorescein breakup time (FBUT, seconds), corneal-epithelial damage (CED) score (15 points = maximum), ocular surface epithelial damage (OSED) score (9 points = maximum), and the Schirmer 1 test (ST1, mm) were examined and compared between each FBUP. RESULTS: In each FBUP, eye dryness and fatigue were the severest symptoms. Characteristic symptoms were sensitivity to light, heavy eyelids, pain, foreign body sensation, difficulty opening the eye, and discharge for AB, heavy eyelids for SB, and foreign-body sensation for LB. Statistically significant differences were found in TMR (AB-SB, -DB, and -RB; LB-RB), IG (AB-all other FBUP; LB-SB and DB), and SG (AB-all other FBUPs), FBUT (AB-LB, -DB, and -RB; SB-DB and -RB; LB RB; DB-RB), and NIBUT (AB-all other FBUPs; SB-DB and-RB, and LB-RB), CED (AB-all other FBUPs; LB-SB, -DB, and -RB) and OSED (AB-SB, -LB, and -DB; LB-SB, -DB, and RB), and ST1 (AB-SB, -DB, and -LB) (P < .05 in each comparison). CONCLUSIONS: The 5 different FBUPs constituted different groups, reflecting different pathophysi ologies. PMID- 28579059 TI - Neuroketotherapeutics: A modern review of a century-old therapy. AB - Neuroketotherapeutics represent a class of bioenergetic medicine therapies that feature the induction of ketosis. These therapies include medium-chain triglyceride supplements, ketone esters, fasting, strenuous exercise, the modified Atkins diet, and the classic ketogenic diet. Extended experience reveals persons with epilepsy, especially pediatric epilepsy, benefit from ketogenic diets although the mechanisms that underlie its effects remain unclear. Data indicate ketotherapeutics enhance mitochondrial respiration, promote neuronal long-term potentiation, increase BDNF expression, increase GPR signaling, attenuate oxidative stress, reduce inflammation, and alter protein post translational modifications via lysine acetylation and beta-hydroxybutyrylation. These properties have further downstream implications involving Akt, PLCgamma, CREB, Sirtuin, and mTORC pathways. Further studies of neuroketotherapeutics will enhance our understanding of ketone body molecular biology, and reveal novel central nervous system therapeutic applications. PMID- 28579062 TI - Distribution of Nonperfusion Area on Ultra-widefield Fluorescein Angiography in Eyes With Diabetic Macular Edema: DAVE Study. AB - PURPOSE: To explore the distribution of nonperfusion area (NPA) in eyes with diabetic macular edema (DME) and its relationship with the severity of DME. DESIGN: Prospective, observational case series. METHODS: Forty eyes of 29 patients with treatment-naive DME who participated in the DAVE study (NCT01552408) were included. Ultra-widefield fluorescein angiography images were sent to the Doheny Image Reading Center, where they were montaged and corrected using stereographic projection to adjust for peripheral distortion. Two experienced, independent/masked certified graders manually segmented the NPA and the total visible retinal area (TRA), and computed the NPA and TRA in square millimeters (mm2). The ischemic index (ISI) was calculated. The distributions of NPA and ISI within different retinal zones were correlated with the severity of DME. RESULTS: In 40 eyes with treatment-naive DME (mean age, 55.8 years) visual acuity (VA) (mean 59.6 EDTRS letters) was correlated with central macular thickness (CMT) (mean 536.9 MUm, R = -0.418, P = .008) and macular volume (MV) (mean 11.9 mm3, R = -0.449, P = .004). The NPA and ISI among the different retinal zones were significantly different (NPA: P < .001; ISI: P = .005). The NPA and ISI in the midperiphery were negatively associated with CMT (NPA: P = .04; ISI: P = .02). However, the global NPA and ISI for the entire retina were not associated with CMT or MV (P > .05). CONCLUSION: In eyes with DME, the ISI increases with increasing distance from the fovea. The severity of DME does not appear to correlate with global NPA and ISI. PMID- 28579063 TI - Choroidal Changes Associated With Subretinal Drusenoid Deposits in Age-related Macular Degeneration Using Swept-source Optical Coherence Tomography. AB - PURPOSE: To compare choroidal vascular features of eyes with and without subretinal drusenoid deposits (SDD), using swept-source optical coherence tomography (SS OCT). DESIGN: Multicenter, cross-sectional study. METHODS: We prospectively recruited patients with intermediate age-related macular degeneration (AMD), without other vitreoretinal pathology. All participants underwent complete ophthalmic examination, color fundus photography (used for AMD staging), and spectral-domain OCT (to evaluate the presence of SDD). SS OCT was used to obtain automatic macular choroidal thickness (CT) maps, according to the Early Treatment Diabetic Retinopathy Study (ETDRS) sectors. For data analysis, we considered mean choroidal thickness as the arithmetic mean value of the 9 ETDRS sectors. SS OCT en face images of choroidal vasculature were also captured and converted to binary images. Choroidal vascular density (CVD) was calculated as a percent area occupied by choroidal vessels in a 6-mm-diameter submacular circular. Choroidal vessel volume was calculated by multiplying the average CVD by macular area and CT. Multilevel mixed linear models (to account for the inclusion of 2 eyes of same subject) were performed for analysis. RESULTS: We included 186 eyes (n = 118 subjects), 94 (50.5%) presenting SDD. Multiple regression analysis revealed that, controlling for age, eyes with SDD presented a statistically thinner mean CT (beta = -21.9, P = .006) and CT in all the individual ETDRS fields (beta <= -18.79, P <= .026). Mean choroidal vessel volume was also significantly reduced in eyes with SDD (beta = -0.003, P = .007). No significant associations were observed with mean CVD. CONCLUSION: In subjects with intermediate AMD, choroidal thickness and vessel volume are reduced in the presence of subretinal drusenoid deposits. PMID- 28579064 TI - Practice Patterns Among Eye Care Providers at US Teaching Hospitals With Regard to Assessing and Educating Patients About Smoking. AB - PURPOSE: To investigate practice patterns of eye care providers at academic medical centers in the United States (US) with regard to assessing patients' smoking status and exposure, educating patients regarding ocular risks of smoking, and counseling patients about smoking cessation. DESIGN: Cross-sectional survey. METHODS: An anonymous survey including multiple choice and Likert-style questions was constructed on http://www.surveymonkey.com and emailed to the coordinators of all 113 US ophthalmology residency programs, with a request to forward to all faculty, fellows, residents, and optometrists at their institution. Main outcome measures include proportion of eye care providers who assess patients' smoking status, educate patients regarding ocular risks of smoking, and discuss with patients smoking cessation options. RESULTS: Of the 292 respondents, 229 (78%) "always" or "periodically" ask patients about their smoking status, 251 (86%) "seldom" or "never" ask patients about secondhand smoke exposure, 245 (84%) "always" or "periodically" educate patients about ocular diseases associated with smoking, 142 (49%) "seldom" or "never" ask patients who smoke about their willingness to quit smoking, and 249 (85%) "seldom" or "never" discuss potential methods and resources to assist with smoking cessation. CONCLUSIONS: Most eye care providers assess patients' smoking status and educate patients regarding ocular risks of smoking. However, approximately half do not ask, or seldom ask, about patients' willingness to quit smoking, and most do not discuss smoking cessation options. PMID- 28579065 TI - Engineering a sprayable and elastic hydrogel adhesive with antimicrobial properties for wound healing. AB - Hydrogel-based bioadhesives have emerged as alternatives for sutureless wound closure, since they can mimic the composition and physicochemical properties of the extracellular matrix. However, they are often associated with poor mechanical properties, low adhesion to native tissues, and lack of antimicrobial properties. Herein, a new sprayable, elastic, and biocompatible composite hydrogel, with broad-spectrum antimicrobial activity, for the treatment of chronic wounds is reported. The composite hydrogels were engineered using two ECM-derived biopolymers, gelatin methacryloyl (GelMA) and methacryloyl-substituted recombinant human tropoelastin (MeTro). MeTro/GelMA composite hydrogel adhesives were formed via visible light-induced crosslinking. Additionally, the antimicrobial peptide Tet213 was conjugated to the hydrogels, instilling antimicrobial activity against Gram (+) and (-) bacteria. The physical properties (e.g. porosity, degradability, swellability, mechanical, and adhesive properties) of the engineered hydrogel could be fine-tuned by varying the ratio of MeTro/GelMA and the final polymer concentration. The hydrogels supported in vitro mammalian cellular growth in both two-dimensional and three dimensional cultures. The subcutaneous implantation of the hydrogels in rats confirmed their biocompatibility and biodegradation in vivo. The engineered MeTro/GelMA-Tet213 hydrogels can be used for sutureless wound closure strategies to prevent infection and promote healing of chronic wounds. PMID- 28579066 TI - Renal Transplantation Using Stone-bearing Deceased Donor Kidneys-Experience of a Transplant Center in China. AB - OBJECTIVE: To evaluate the outcomes of transplantation of deceased donor stone bearing kidneys. METHODS: A total of 32 patients who received renal transplantation at our center from July 2011 to June 2016 were included. Eight recipients received kidneys with incidental renal stone(s) (stone group). Twenty four recipients received kidneys without renal stones (non-stone group). The transplantation outcomes of the 2 groups were compared. RESULTS: There was 1 case of postoperative urinary tract infection in the stone group, and 2 cases in the non-stone group. No ureteral obstruction or hydronephrosis occurred in either group. No significant difference was found in the incidence of complications, serum creatinine level, and estimated glomerular filtration rate between the groups (all, P >.05). No deaths occurred in either group during the follow-up period. One recipient had postoperative calculi recurrence, and 4 recipients had residual calculi before transplantation. However, these patients had no symptomatic nephrolithiasis or obstruction, and their renal functions were normal. CONCLUSION: Transplantation of deceased donor stone-bearing kidneys can achieve comparable outcomes of deceased donor non-stone-bearing kidneys. PMID- 28579069 TI - Serous Carcinoma of the Testicle and the Paratesticular Tissue: Case Report and Literature Review. AB - Ovarian-type epithelial lesions of the testicle and the paratesticular tissue are uncommon, especially invasive serous adenocarcinoma with only 18 cases reported in the literature. Although the majority of these tumors occur in adults with an age range from 16 to 87 years, only 1 patient was less than 10 years old. Herein, we report only the second case of invasive serous adenocarcinoma occurring in the first decade of life, that of a 7-year-old boy. Additionally, clinical presentation, imaging, histopathology, immunohistochemistry, and clinical follow up of invasive serous adenocarcinoma of the testicle are discussed, along with a review of the literature. PMID- 28579068 TI - The Impact of Age on Urethroplasty Success. AB - OBJECTIVE: To determine if age is an independent predictor of surgical success in patients undergoing urethroplasty. Urethroplasty performed by excision and primary anastomosis depends on vascular collateralization. Successful augmented urethroplasty depends on graft neovascularization. Older patients have more comorbid conditions including peripheral vascular disease associated with reduced penile blood flow. METHODS: This is a retrospective review of urethroplasties from 11 institutions. Primary outcome was functional success at 1 year from surgery, defined as freedom from post-urethroplasty procedures. Secondary outcome was freedom from cystoscopic evidence of stricture recurrence at 3 months. Study outcomes were compared between 2 age cohorts (<60 years old and >=60 years old). Multivariable logistic regression analysis evaluated the influence of patient factors on our primary and secondary outcomes, using age as a continuous variable. RESULTS: Of 322 urethroplasties, 258 were performed in patients <60 years and 64 in patients >=60 years. Median follow-up was 1.8 years. The following were not significantly different between groups: stricture length or location, smoking status, number of previous urethrotomies or dilations, and urethroplasty type. The following were more common in patients >=60 years: diabetes, hypertension, hyperlipidemia, coronary artery and peripheral vascular disease, chronic obstructive pulmonary disease, and cancer. There was no difference in need for repeat procedures or anatomic recurrence between age groups or with increasing age. Stricture length was the only statistically significant clinical factor. CONCLUSION: Urethroplasty success may be affected by comorbidities but not age. Age alone should not be used as an absolute exclusion criterion for men needing urethral reconstruction. PMID- 28579067 TI - The Beneficial Effect of Fesoterodine, a Competitive Muscarinic Receptor Antagonist on Erectile Dysfunction in Streptozotocin-induced Diabetic Rats. AB - OBJECTIVE: To investigate the possible role of fesoterodine (a competitive muscarinic receptor antagonist) on erectile dysfunction in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: A total of 16 adult male Sprague-Dawley rats were equally divided into control and diabetic groups. Diabetes was induced by a single intravenous injection of streptozotocin (25-35 mg/kg). In vivo erectile responses were evaluated by the stimulation of cavernosal nerves, and measurements were repeated after the intracavernosal injection of fesoterodine (1 uM) in rats. The relaxation responses to fesoterodine were examined via incubation with various inhibitors. The relaxant responses of corpus cavernosum (CC) strips were observed in the presence or the absence of fesoterodine (10 uM). RESULTS: Intracavernous administration of fesoterodine restored in vivo erectile response at 5.0- and 7.5-V levels, except for 2.5 V in diabetic rats. Basal intracavernosal pressure (5.4 +/- 0.9 mm Hg) in diabetic rats was markedly increased after injection of fesoterodine (33.9 +/- 7.9 mm Hg, P <.001). In bath studies, fesoterodine resulted in a relaxation of CC in a concentration-dependent manner, which was reduced in diabetic rats. Nifedipine (l-type Ca2+ channel blocker) inhibited maximum fesoterodine-induced relaxation by 58%. The nonselective K+ channel blocker tetraethylammonium and glibenclamide incubation did not change the relaxant response to fesoterodine. The relaxant responses to acetylcholine (10 uM), electrical field stimulation (10 Hz), and sodium nitroprusside (0.01 uM) in diabetic rats were increased after incubation with fesoterodine (10 uM). CONCLUSION: Fesoterodine improved erectile function and relaxation of isolated strips of rat CC. The underlying mechanism of fesoterodine is likely due to the blocking of l-type calcium channels independent of the nitric oxide-cyclic guanosine monophosphate pathway. Further investigations are warranted to fully elucidate the restorative effects of fesoterodine on overactive bladder-induced diabetic erectile dysfunction. PMID- 28579070 TI - Improving Teamwork: Evaluating Workload of Surgical Team During Robot-assisted Surgery. AB - OBJECTIVE: To investigate the cognitive and physical workload experienced by each operating room team member for different types of urologic procedures. METHODS: Surgeons, anesthesiologists, surgical fellows, bedside assistants, circulating nurses, and scrub nurses completed the National Aeronautics and Space Administration Task Load Index questionnaire for various urologic robot-assisted surgery procedures. A total of 338 questionnaires from 55 unique individuals were collected. Workload differences by role, type of procedure, and surgery duration were analyzed using analysis of variance for each of the 6 domains of the National Aeronautics and Space Administration Task Load Index. The effects of trainees' participation on their perceived workload and the workloads of the lead surgeon and bedside assistant were analyzed with correlation. RESULTS: The role of the surgical team was significant for all the scales of workload, and there was a main effect type of surgery on temporal demand and frustration. Frustration was higher for prostatectomy in comparison to cystectomy for the trainee surgeon. On the other hand, it was lower for the anesthesiologist, bedside assistant, and the circulating nurse. There was no effect of procedural complexity on workload. Regardless of surgical complexity, the trainees performed approximately 40% of the procedure without significantly impacting their perceived workload. CONCLUSION: This study provides an analysis of variations and contributors to workload parameters and serves as a platform to optimize team members' workload during robot-assisted surgery. PMID- 28579071 TI - Tranylcypromine in mind (Part II): Review of clinical pharmacology and meta analysis of controlled studies in depression. AB - It has been over 50 years since a review has focused exclusively on the monoamine oxidase (MAO) inhibitor tranylcypromine (TCP). A new review has therefore been conducted for TCP in two parts which are written to be read preferably in close conjunction: part I - pharmacodynamics, pharmacokinetics, drug interactions, toxicology; and part II - clinical studies with meta-analysis of controlled studies in depression, practice of TCP treatment, place in therapy. The irreversible and nonselective MAO-A/B inhibitor TCP has been confirmed as an efficacious and safe antidepressant drug. For the first time, a meta-analysis of controlled clinical trials in depression demonstrated that TCP is superior to placebo (pooled logOR=0.509, 95%CI=0.026 to 0.993, 4 studies) and equal to other antidepressants (pooled logOR=0.208, 95%CI=-0.128 to 0.544, 10 studies). In treatment resistant depression (TRD) after tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), TCP was superior to placebo (logOR=2.826, 95%CI=1.494 to 4.158, one study) and non-established antidepressants (pooled logOR=1.976, 95%CI=0.907 to 3.045, 4 studies), and was equal to other MAO inhibitors and an antidepressant combination (pooled logOR= 0.366, 95%CI=-0.869 to 0.137, 4 studies). Controlled studies revealed that TCP might provide a special advantage in the treatment of atypical depression, which was supported by a recent PET study of MAO-A activity in brain. However, TCP treatment remains beset with the need for a mandatory tyramine-restricted diet and is therefore limited to use as a third-line antidepressant according to recent treatment algorithms and guidelines for depression treatment. On the other hand, the effort needed to maintain a tyramine-restricted diet may have been overestimated in the perception of both doctors and patients, which may have led to relative underuse of TCP. Interaction with serotonergic drugs bears the risk of severe serotonin toxicity (SST) and combination with indirect sympathomimetic drugs may result in hypertensive crisis which both adds to the risks of TCP. At the same time, TCP has low to no risks of central anticholinergic, sedative, cardiac conduction, body weight, hemostatic effects, or pharmacokinetic drug interactions. Neuroprotection by MAO inhibitors due to reduced oxidative stress is becoming increasingly studied. Taken together, TCP is being increasingly recognized as an important option in systematic treatment approaches for patients suffering from severe courses of depression, such as TRD and atypical depression, by offering a MAO-related pathophysiological rationale. PMID- 28579072 TI - The impact of comorbid post-traumatic stress disorder in patients with major depressive disorder on clinical features, pharmacological treatment strategies, and treatment outcomes - Results from a cross-sectional European multicenter study. AB - This international, multicenter, cross-sectional study comprising 1346 adult in- and outpatients with major depressive disorder (MDD) investigated the association between MDD as primary diagnosis and comorbid post-traumatic stress disorder (PTSD). In a cross-sectional data collection process, the presence of comorbid PTSD was determined by the Mini International Neuropsychiatric Interview (MINI) and the patients' socio-demographic, clinical, psychopharmacological, and response information were obtained. Clinical features between MDD with and without concurrent PTSD were compared using descriptive statistics, analyses of covariance (ANCOVA), and binary logistic regression analyses. 1.49% of the MDD patients suffered from comorbid PTSD. Significantly more MDD + comorbid PTSD patients exhibited atypical features, comorbid anxiety disorders (any comorbid anxiety disorder, panic disorder, agoraphobia, and social phobia), comorbid bulimia nervosa, current suicide risk, and augmentation treatment with low-dose antipsychotic drugs. In the binary logistic regression analyses, the presence of atypical features (odds ratio (OR) = 4.49, 95%CI:1.01-20.12; p<=.05), any comorbid anxiety disorder (OR = 3.89, 95%CI:1.60-9.44; p = .003), comorbid panic disorder (OR = 6.45, 95%CI:2.52-16.51; p = .001), comorbid agoraphobia (OR = 6.51, 95%CI:2.54-16.68; p<=.001), comorbid social phobia (OR = 6.16, 95%CI:1.71 22.17; p<=.001), comorbid bulimia nervosa (OR = 10.39, 95%CI:1.21-88.64; p = .03), current suicide risk (OR = 3.58, 95%CI:1.30-9.91; p = .01), and augmentation with low-potency antipsychotics (OR = 6.66, 95%CI:2.50-17.77; p<.001) were associated with concurrent PTSD in predominant MDD. Major findings of this study were (1.) the much lower prevalence rate of comorbid PTSD in predominant MDD compared to the reverse prevalence rates of concurrent MDD in primary PTSD, (2.) the high association to comorbid anxiety disorders, and (3.) the increased suicide risk due to concurrent PTSD. PMID- 28579074 TI - Cytosolic Proteostasis Networks of the Mitochondrial Stress Response. AB - Mitochondrial stress requires timely intervention to prevent mitochondrial and cellular dysfunction. Re-establishing the correct protein homeostasis is crucial for coping with mitochondrial stress and maintaining cellular homeostasis. The best-characterized adaptive pathways for mitochondrial stress involve a signal originating from stressed mitochondria that triggers a nuclear response. However, recent findings have shown that mitochondrial stress also affects a complex network of protein homeostasis pathways in the cytosol. We review how mitochondrial dysregulation affects cytosolic proteostasis by regulating the quantity and quality of protein synthesis, protein stability, and protein degradation, leading to an integrated regulation of cellular metabolism and proliferation. This mitochondria to cytosol network extends the current model of the mitochondrial stress response, with potential applications in the treatment of mitochondrial disease. PMID- 28579075 TI - Thoughts on public policy to increase family-based care and decrease institutional care. AB - Many countries are in the earliest stage of reforming the care sector. Reformers face challenges as they develop public policy to expand family based care and shrink institutional care. To mention a few: installing the keystone component of care reform - a system to monitor and support children post-institutionalization; enabling children to grow up where they belong, in families; meeting children's basic needs where they should live, in their own communities; meeting children's basic needs where many actually live, in institutions; strengthening the social service workforce; and elevating the political priority of poor and vulnerable children through evidence-based advocacy. Care reform must be sold in the political marketplace. Evidence-based, tactical advocacy is key to reforming care policy and winning the public resources needed to gear-up programs for the care, protection and development of vulnerable children. PMID- 28579077 TI - Phylogenomic analysis of Lake Malawi cichlid fishes: Further evidence that the three-stage model of diversification does not fit. AB - Adaptive radiations could often occur in discrete stages. For instance, the species flock of ~1000 species of Lake Malawi cichlid fishes might have only diverged once between rocky and sandy environments during the initial stage of their diversification. All further diversification within the rock-dwelling (mbuna) or sand-dwelling (utaka) cichlids would have occurred during a subsequent second stage of extensive trophic evolution that was followed by a third stage of sexual trait divergence. We provide an improved phylogenetic framework for Malawi cichlids to test this three-stage hypothesis based on newly reconstructed phylogenetic relationships among 32 taxonomically disparate Malawi cichlids species. Using several reconstruction methods and 1037 ultra-conserved element (UCE) markers, we recovered a molecular phylogeny that confidently resolved relationships among most of the Malawi lineages sampled when a bifurcating framework was enforced. These bifurcating reconstructions also indicated that the sand-dwelling species Cyathochromis obliquidens was well-nested within the primarily rock-dwelling radiation known as the mbuna. In contrast to predictions from the three-stage model of vertebrate diversification, the recovered phylogeny reveals an initial colonization of rocky reefs, followed by substantial diversification of rock-dwelling lineages, and then at least one instance of subsequent evolution back into sandy habitats. This repeated evolution into major habitat types provides further evidence that the three-stage model of Malawi cichlid diversification has numerous exceptions. PMID- 28579073 TI - Advances on the Transfer of Lipids by Lipid Transfer Proteins. AB - Transfer of lipid across the cytoplasm is an essential process for intracellular lipid traffic. Lipid transfer proteins (LTPs) are defined by highly controlled in vitro experiments. The functional relevance of these is supported by evidence for the same reactions inside cells. Major advances in the LTP field have come from structural bioinformatics identifying new LTPs, and from the development of countercurrent models for LTPs. However, the ultimate aim is to unite in vitro and in vivo data, and this is where much progress remains to be made. Even where in vitro and in vivo experiments align, rates of transfer tend not to match. Here we set out some of the advances that might test how LTPs work. PMID- 28579076 TI - Resilience in young children involved with child protective services. AB - Child maltreatment increases the risk of poor developmental outcomes. However, some children display resilience, meaning they are high-functioning despite their adverse experiences. To date, few research studies have examined protective factors among very young maltreated children. Yet, domains of resilience, and the protective factors that promote resilience among maltreated children, are likely to differ by developmental stage. Drawing on ecological systems theory and life course theory, we examined how protective factors at multiple ecological levels across early childhood were related to social and cognitive resilience among very young children involved with child protective services. The results demonstrated that the buffering effects of protective factors varied by social or cognitive resilience and the cumulative effects of protective factors were more consistently related to later resilience than protective factors at specific time points. In addition, the influence of specific protective factors on resilience slightly varied by initial in-home or out-of-home placement. These findings have important policy and research implications for promoting optimal development among children involved in child protective services. PMID- 28579079 TI - Ontogenetic changes in the expression of immune related genes in response to immunostimulants and resistance against white spot syndrome virus in Litopenaeus vannamei. AB - In recent years, researchers have focused on viral and plant immunostimulants which could have beneficial effects in disease prevention and control in shrimp culture. At present, the application of the recombinant VP28 protein (r-VP28) and herbal immunostimulant has been considered as a more effective approach to prevent white spot syndrome (WSS) by enhancing the immune response in shrimp. In the present study, expression of selected immune related genes in response to r VP28 and herbal immunostimulant mix (HIM) were separately studied qualitatively and quantitatively by RT-PCR and real time PCR, respectively during ontogenetic development from nauplius to juvenile stage in Litopenaeus vannamei. The mRNA expression level of immune related genes such as anti-lipopolysaccharides (ALF), Lysozyme, cMnSOD, Crustin, Prophenoloxidase, Tumor necrosis factor receptor associated factor 6 (TRAF6) and Haemocyanin were found to be up-regulated significantly in different ontogenetic development stages of shrimp fed with r VP28 and HIM formulated diets. Relative percent survival (RPS) was determined in shrimp fed with immunostimulants formulated diets after oral challenge with WSSV. The survival of WSSV challenged shrimp was found to be higher in immunostimulants treated groups when compared to untreated group. The results of PCR, ELISA and real time PCR revealed the absence of WSSV in WSSV-challenged shrimp after 20 days of treatment with immunostimulants. Among these immunostimulants, HIM was found to be more effective when compared to r-VP28. After a survey of literature, we are of the opinion that this might be the first report on the expression of immune genes during ontogenetic development of L. vannamei in response to immunostimulants. PMID- 28579078 TI - Developmentally Supportive Care in Congenital Heart Disease: A Concept Analysis. AB - THEORETICAL PRINCIPLES: Improved survival of infants and children with congenital heart disease experience has led to recognition that up to half of congenital heart disease survivors also experience developmental delay. Developmentally supportive care is a care model shown in Neonatal Intensive Care Units to be associated with improved outcomes, but developmentally supportive practices with premature infants may not be equally effective in the cardiac population that includes all ages. PHENOMENA ADDRESSED: The purpose of this paper is to present a concept analysis using the Walker and Avant method in order to identify and define characteristics of developmentally supportive care as it may be applied to the population of neonates, infants, and children with congenital heart disease. A theoretical definition of developmentally supportive care is presented. RESEARCH LINKAGES: This concept analysis will provide nurses and allied health professionals with a theoretical basis to implement high quality, family-centered care that meets individual developmental needs in a population at high risk for developmental sequelae. Nursing implications for developmentally supportive care as it applies to infants and children with heart disease are discussed. PMID- 28579080 TI - Using spontaneous commentary of nursing home residents to develop resident centered measurement tools: A case study. AB - Nursing home (NH) residents routinely complete surveys that assess their health, well-being, preferences, and care needs. Such surveys reveal important information, however, are largely based on the concerns of providers as opposed to the concerns of residents. Thus, researchers must enhance efforts to ensure that these surveys are guided by the priorities, needs, and concerns of residents. We present a case study to demonstrate how spontaneous commentary of NH residents holds particular efficacy for ensuring that measurement tools are guided by the needs, concerns, and priorities of residents. Spontaneous comments from NH residents (N = 370) collected as part of a study developing the Preferences for Everyday Living Inventory for NH residents (PELI-NH) were used to refine the PELI-NH across key phases of measurement development. This work demonstrates how the spontaneous commentary of NH residents may contribute to the refinement of NH measurement tools, and allow researchers to base these tools on the needs and priorities of NH residents. PMID- 28579081 TI - Adverse drug events reported by rural older adults. AB - Adverse drug events (ADEs) impact the health and safety of older adults. ADEs may lead to unplanned medical visits that influence health and related costs. The purpose of this study was to explore ADEs reported by rural, community-dwelling older adults. Data were collected on 138 participants' demographics, physical and mental health, sleep, medications, and ADEs. One or more ADEs were reported by 48% of participants, including central nervous symptom disturbances (16%), dry mouth (12%), hoarseness, gastrointestinal irritation, and decreased libido (all 8%). Poor sleep and poor physical health were associated with higher reported ADEs (p < 0.05). Older adults (ages 79-99) and those with higher physical health were 60% less likely to report ADEs. Those with poorer sleep quality were 50% more likely to report ADEs. Viable strategies are needed to monitor and reduce ADEs in community-dwelling older adults who use multiple medications to manage poor health and poor sleep. PMID- 28579082 TI - Validity and reliability of the Polish version of myasthenia gravis - Quality of life questionnaire - 15 item. AB - AIM: The myasthenia gravis-quality of life questionnaire 15 item (MG-QOL15) is a short, and easy to use disease-specific quality of life (QOL) tool in myasthenia gravis. The aim of this study was to validate and adapt the Polish version of the MG-QOL15. MATERIALS AND METHODS: The total number of 50 patients with MG were qualified for the examination. Each patient underwent neurological examination and completed the quality of life evaluation questionnaire MQ-QOL 15 after translation and back-translation. Additionally, each patient was asked to evaluate the quality of his/her life by means of questionnaire SF-36 in Polish language version. RESULTS: The MG-QOL15 was found to have high internal consistency, test-retest reliability, and concurrent validity. CONCLUSION: The MG QOL15 is accepted to be a valid, reliable, valuable tool for measuring disease specific QOL in Polish patients with MG. PMID- 28579084 TI - Javea consensus guidelines for the treatment of Candida peritonitis and other intra-abdominal fungal infections in non-neutropenic critically ill adult patients. AB - BACKGROUND: Although the management of the invasive candidiasis has improved in the last decade, controversial issues yet remain, especially in the diagnostic and therapeutic approaches to Candida peritonitis and other forms of intra abdominal fungal infections. AIMS: We sought to identify core clinical knowledge about intra-abdominal fungal infections and to achieve high-agreement recommendations required to care for critically ill adult patients with Candida peritonitis and other forms of intra-abdominal fungal infection. METHODS: A biregional Spanish survey, to elucidate the consensus about the already mentioned fungal infections by means of the Delphi technique, was conducted anonymously by e-mail with 29 multidisciplinary experts in invasive fungal infections from 14 hospitals in the Valencia and Murcia communities during 2014. Respondents included intensivists, anesthesiologists, microbiologists, pharmacologists, and infectious disease specialists, who answered 31 questions prepared by a coordination group after a strict review of the literature from the 5 previous years. The educational objectives spanned 6 categories: epidemiology, microbiological diagnosis, clinical diagnosis, antifungal treatment, de escalation therapy, and special situations. The agreement required among the panelists for each item to be selected had to be higher than 70%. After extracting the recommendations from the selected items, a meeting at which the experts were asked to validate the previously selected recommendations in a second round of scoring took place. RESULTS: After the second round, 36 recommendations were validated according to the following distribution: epidemiology (5), microbiological diagnosis (4), clinical diagnosis (4), antifungal treatment (3), de-escalation therapy (4), and special situations (16). CONCLUSIONS: Treatment of Candida peritonitis and other forms of intra-abdominal fungal infections in ICU patients requires a broad range of knowledge application and skills that our recommendations address. Based on the DELPHI methodology, these recommendations might help to optimize the therapeutic management of these patients in special situations and in various scenarios to improve their outcome. PMID- 28579085 TI - Update on the management of intra-abdominal Candida infections. PMID- 28579083 TI - [Candida glabrata vaginitis: The great ignored?] PMID- 28579086 TI - Effects of exogenous isoprenoid diphosphates on in vivo attachment to bacteriochlorophyllide c in the green sulfur photosynthetic bacterium Chlorobaculum tepidum. AB - Metabolic substitution of the esterifying chain in bacteriochlorophyll (BChl) c in green photosynthetic bacteria grown by supplementation of exogenous alcohols has attracted attentions to study supramolecular structures and biogenesis of major antenna complexes chlorosomes in these bacteria as well as BChl pigment biosynthesis. Actual substrates in the enzymatic attachment of the esterifying moieties to the precursor of BChl c, namely bacteriochlorophyllide (BChlide) c, in these bacteria are believed to be diphosphate esters of alcoholic substrates, although only intact alcohols have so far been supplemented in the bacterial cultures. We report herein BChl c compositions in the green sulfur photosynthetic bacterium Chlorobaculum tepidum by supplementation with geranyl and geranylgeranyl diphosphates. The supplementation of these diphosphates hardly produced BChl c derivatives esterified with geraniol and geranylgeraniol in Cba. tepidum, whereas these BChl c derivatives were accumulated by supplementation of intact geraniol and geranylgeraniol. The sharp contrast of the incorporation efficiency of the supplemental isoprenoid moieties in BChl c using the isoprenoid diphosphates to that by the isoprenoid alcohols was mainly ascribable to less penetration abilities of the diphosphate substrates into Cba. tepidum cells because of their anionic and polar diphosphate moiety. PMID- 28579088 TI - On-farm conditions that compromise animal welfare that can be monitored at the slaughter plant. AB - Handling and stunning at slaughter plants has greatly improved through the use of numerical scoring. The purpose of this paper is to encourage the use of numerical scoring systems at the slaughter plants to assess conditions that compromise welfare that occurred either during transport or on the farm. Some of the transport problems that can be assessed are bruises, death losses, and injured animals. Welfare issues that occurred on the farm that can be assessed at the abattoir are body condition, lameness, lesions, injuries, animal cleanliness and internal pathology. There are important welfare issues that cannot be assessed at slaughter. They are on-farm euthanasia methods, use of analgesics during surgeries, and the type of animal housing systems. Welfare evaluations at slaughter have the potential to greatly improve welfare. PMID- 28579087 TI - The protective role of Helicobacter pylori neutrophil-activating protein in childhood asthma. AB - BACKGROUND: Helicobacter pylori quantity and HP-NAP gene expression were evaluated in the faeces of healthy and asthmatic children. METHODS: H. pylori DNAs and RNAs were isolated from the stool samples of 92 asthmatic children (AC; 3-8 years) and 88 healthy controls (HC). Quantitative PCR was used to determine the quantity of H. pylori and HP-NAP expression relative to the 16S rRNA (reference gene). Gene expression was analysed using the delta delta-Ct method. RESULTS: H. pylori DNA was detected in the stool samples of 18 (20.4%) of the 88 HC (p<0.0001, OR=0.79) and none of AC. No meaningful statistical differences were found between individuals with positive and negative family histories for asthma in AC and HC (p>0.05). H. pylori quantity was higher in seven of 18 H. pylori positive samples, but HP-NAP expression levels were low in four of these seven samples. Based on a multivariate logistic regression analysis of these three variables together, only males displayed a significant difference based on gender differences (p<0.02) and it was determined that, based on the OR value of 0.46 and the 95% CI range of 0.241-0.888, male gender was an independent protective factor in asthma. CONCLUSIONS: HP-NAP levels vary to the relative concentrations of bacteria in the stationary or late logarithmic phases. Different napA expression levels may be caused by different endogenous napA gene expression or different environmental conditions. PMID- 28579089 TI - Muscle strength and force development in high- and low-functioning elderly men: Influence of muscular and neural factors. AB - BACKGROUND: Aging leads to a loss of muscle strength and functional capacity likely resulting from a combination of neural and muscle alterations. The aim of this study was to identify possible disparities in muscle strength and force development profiles in high- and low-functioning elderly men and to investigate muscular and neurophysiological factors that could explain the differences. METHODS: Sixty community-dwelling men in good general health were divided in two groups based on a functional capacity (FC) z-score derived from 6 tests of the Short Physical Performance Battery and Senior Fitness Test (Normal and fast 4m walk tests, normal and fast Timed-up and go, chair and stair tests). Extensor strength of the lower limbs (LL) was obtained for concentric (CLES) contraction and combined with lean masses of LL (LLLM) to yield concentric (CLES/LLLM) index. Similarly, extensor strength of the right Quadriceps Femoris (IKES) was obtained during maximal voluntary isometric contraction (MVC) and combined with right thigh lean mass (rTLM) to produce an isometric strength (IKES/rTLM) index. A muscular profile was obtained from: ascending and descending force slopes during the MVC; Vastus Lateralis (VL) muscle twitches parameters (amplitude, contraction and 1/2 relaxation times); the knee joint velocity (KV) as well as integrated EMG (iEMG) were determined for a sit-to-stand functional evaluation; muscle phenotype. A neurophysiological profile was established from: the spinal excitability (Hmax/Mmax ratio); motoneuron conduction velocity (CV); the completeness of muscle activation (% of force reserve), median power frequency (MPF) and mean amplitude (MA) of the VL EMG signal during MVC. RESULTS: Coincidently, age did not differ between groups. Strength and force indices, descending force slopes for MVC, KV and iEMG during the sit-to-stand evaluation and FC parameters were all significantly (p<0.05) lower in the LoFC group than in the HiFC group. In contrast, no difference was observed between groups in: LLLM and rTLM, Hmax/Mmax ratio, CV, twitch parameters and muscle phenotype. CONCLUSION: The lower concentric and isometric strengths found in the LoFC group could not be accounted for by muscular factors. Similarly, peripheral nervous systems alterations could not explain group differences. It can be suggested that modifications within the central nervous system may be responsible for the differences in the functional status of healthy elderly individuals. Finally, more complex and demanding tasks, such as those requiring greater intensity or coordination, may further clarify how healthy elderly individuals with low and high functional capacities differ. PMID- 28579090 TI - Right ventricular perforation as a complication of fluoroscopy-guided pericardiocentesis. PMID- 28579092 TI - Coronary artery aneurysm formation following implantation of a bioresorbable vascular scaffold for in-stent restenosis. AB - Coronary artery aneurysm (CAA) formation is a rare complication of coronary intervention that may develop after implantation of bare-metal or drug-eluting stents. The etiology of this entity appears to be multifactorial and its prognosis is poorly understood, but it has been associated with an increased risk of stent thrombosis. To date few cases of CAAs related to bioresorbable vascular scaffold (BVS) implantation have been reported, and the development of CAA after BVS implantation for the treatment of in-stent restenosis (ISR) has not been previously described. Here we present two cases of CAA formation after BVS, which represent the first demonstration of CAA formation after the use of BVS for ISR. PMID- 28579094 TI - A special JMR issue: Methodological advances in EPR spectroscopy and imaging. PMID- 28579091 TI - Characteristics and outcomes of heart failure hospitalization before implementation of a heart failure clinic: The PRECIC study. AB - OBJECTIVE: This study aims to characterize patients hospitalized for acute heart failure (HF) in an internal medicine department and their one-year mortality and rate of rehospitalization for decompensated HF. METHODS: This retrospective observational study enrolled all patients discharged in 2012 after hospitalization for acute HF. Discharge summaries, clinical records and telephone interviews were analysed. The data reports to the year before implementation of a heart failure clinic. RESULTS: Four hundred and twenty-nine patients were enrolled, with a mean age of 79 years, 62.5% female. The most prevalent comorbidity and etiology was hypertension (86.7%) and the most frequent decompensation trigger was infection. HF with preserved ejection fraction (HFpEF) was present in 70.5%. In-hospital mortality was 7.9%. At discharge more than half of the patients were prescribed beta-blockers (52.8%) and angiotensin-converting enzyme inhibitors (52%). Women presented a significantly higher proportion of HFpEF than men (75.3% vs. 62.7%, p=0.01). Patients with diabetes and those with ischemic etiology had significantly higher proportions of HF with reduced ejection fraction (HFrEF) (34.8% vs. 24.3% in non-diabetic patients, p=0.027, and 56.2% vs. 15.6% for other etiologies, p<0.001). The HFrEF group were more frequently discharged under beta-blockers and spironolactone (75.2% vs. 46.4% in the HFpEF group, p<0.001 and 31.2% vs. 12.6% in the HFpEF group, p<0.001, respectively). Mortality was 34.3% and rehospitalization for HF was 30.5% in one year follow-up. CONCLUSIONS: The population characterized is an elderly one, mainly female and with HFpEF. Nearly a third of patients died and/or were rehospitalized in the year following discharge. PMID- 28579093 TI - The enduring impact of historical and structural racism on urban violence in Philadelphia. AB - Public health approaches to crime and injury prevention are increasingly focused on the physical places and environments where violence is concentrated. In this study, our aim is to explore the association between historic place-based racial discrimination captured in the 1937 Home Owners Loan Corporation (HOLC) map of Philadelphia and present-day violent crime and firearm injuries. The creators of the 1937 HOLC map zoned Philadelphia based in a hierarchical system wherein first grade and green color zones were used to indicate areas desirable for government backed mortgage lending and economic development, a second-grade or blue zone for areas that were already developed and stable, a third-grade or yellow zone for areas with evidence of decline and influx of a "low grade population," and fourth grade or red zone for areas with dilapidated or informal housing and an "undesirable population" of predominately Black residents. We conducted an empirical spatial analysis of the concentration of firearm assaults and violent crimes in 2013 through 2014 relative to zoning in the 1937 HOLC map. After adjusting for socio-demographic factors at the time the map was created from the 1940 Census, firearm injury rates are highest in historically red-zoned areas of Philadelphia. The relationship between HOLC map zones and general violent crime is not supported after adjusting for historical Census data. This analysis extends historic perspective to the relationship between emplaced structural racism and violence, and situates the socio-ecological context in which people live at the forefront of this association. PMID- 28579095 TI - Recent progress in synchrotron-based frequency-domain Fourier-transform THz-EPR. AB - We describe frequency-domain Fourier-transform THz-EPR as a method to assign spin coupling parameters of high-spin (S>1/2) systems with very large zero-field splittings. The instrumental foundations of synchrotron-based FD-FT THz-EPR are presented, alongside with a discussion of frequency-domain EPR simulation routines. The capabilities of this approach is demonstrated for selected mono- and multinuclear HS systems. Finally, we discuss remaining challenges and give an outlook on the future prospects of the technique. PMID- 28579097 TI - EPR-based distance measurements at ambient temperature. AB - Pulsed dipolar (PD) EPR spectroscopy is a powerful technique allowing for distance measurements between spin labels in the range of 2.5-10.0nm. It was proposed more than 30years ago, and nowadays is widely used in biophysics and materials science. Until recently, PD EPR experiments were limited to cryogenic temperatures (T<80K). Recently, application of spin labels with long electron spin dephasing time at room temperature such as triarylmethyl radicals and nitroxides with bulky substituents at a position close to radical centers enabled measurements at room temperature and even at physiologically relevant temperatures by PD EPR as well as other approaches based on EPR (e.g., relaxation enhancement; RE). In this paper, we review the features of PD EPR and RE at ambient temperatures, in particular, requirements on electron spin phase memory time, ways of immobilization of biomolecules, the influence of a linker between the spin probe and biomolecule, and future opportunities. PMID- 28579096 TI - Delocalisation of photoexcited triplet states probed by transient EPR and hyperfine spectroscopy. AB - Photoexcited triplet states play a crucial role in photochemical mechanisms: long known to be of paramount importance in the study of photosynthetic reaction centres, they have more recently also been shown to play a major role in a number of applications in the field of molecular electronics. Their characterisation is crucial for an improved understanding of these processes with a particular focus on the determination of the spatial distribution of the triplet state wavefunction providing information on charge and energy transfer efficiencies. Currently, active research in this field is mostly focussed on the investigation of materials for organic photovoltaics (OPVs) and organic light emitting diodes (OLEDs). As the properties of triplet states and their spatial extent are known to have a major impact on device performance, a detailed understanding of the factors governing triplet state delocalisation is at the basis of the further development and improvement of these devices. Electron Paramagnetic Resonance (EPR) has proven a valuable tool in the study of triplet state properties and both experimental methods as well as data analysis and interpretation techniques have continuously improved over the last few decades. In this review, we discuss the theoretical and practical aspects of the investigation of triplet states and triplet state delocalisation by transient continuous wave and pulse EPR and highlight the advantages and limitations of the presently available techniques and the current trends in the field. Application of EPR in the study of triplet state delocalisation is illustrated on the example of linear multi-porphyrin chains designed as molecular wires. PMID- 28579100 TI - High-field/high-pressure ESR. AB - We present a historical review of high-pressure ESR systems with emphasis on our recent development of a high-pressure, high-field, multi-frequency ESR system. Until 2000, the X-band system was almost established using a resonator filled with dielectric materials or a combination of the anvil cell and dielectric resonators. Recent developments have shifted from that in the low-frequency region, such as X-band, to that in multi-frequency region. High-pressure, high field, multi-frequency ESR systems are classified into two types. First are the systems that use a vector network analyzer or a quasi-optical bridge, which have high sensitivity but a limited frequency region; the second are like our system, which has a very broad frequency region covering the THz region, but lower sensitivity. We will demonstrate the usefulness of our high-pressure ESR system, in addition to its experimental limitations. We also discuss the recent progress of our system and future plans. PMID- 28579099 TI - Rapid-scan EPR imaging. AB - In rapid-scan EPR the magnetic field or frequency is repeatedly scanned through the spectrum at rates that are much faster than in conventional continuous wave EPR. The signal is directly-detected with a mixer at the source frequency. Rapid scan EPR is particularly advantageous when the scan rate through resonance is fast relative to electron spin relaxation rates. In such scans, there may be oscillations on the trailing edge of the spectrum. These oscillations can be removed by mathematical deconvolution to recover the slow-scan absorption spectrum. In cases of inhomogeneous broadening, the oscillations may interfere destructively to the extent that they are not visible. The deconvolution can be used even when it is not required, so spectra can be obtained in which some portions of the spectrum are in the rapid-scan regime and some are not. The technology developed for rapid-scan EPR can be applied generally so long as spectra are obtained in the linear response region. The detection of the full spectrum in each scan, the ability to use higher microwave power without saturation, and the noise filtering inherent in coherent averaging results in substantial improvement in signal-to-noise relative to conventional continuous wave spectroscopy, which is particularly advantageous for low-frequency EPR imaging. This overview describes the principles of rapid-scan EPR and the hardware used to generate the spectra. Examples are provided of its application to imaging of nitroxide radicals, diradicals, and spin-trapped radicals at a Larmor frequency of ca. 250MHz. PMID- 28579101 TI - Perspectives of shaped pulses for EPR spectroscopy. AB - This article describes current uses of shaped pulses, generated by an arbitrary waveform generator, in the field of EPR spectroscopy. We show applications of sech/tanh and WURST pulses to dipolar spectroscopy, including new pulse schemes and procedures, and discuss the more general concept of optimum-control-based pulses for applications in EPR spectroscopy. The article also describes a procedure to correct for experimental imperfections, mostly introduced by the microwave resonator, and discusses further potential applications and limitations of such pulses. PMID- 28579098 TI - Membrane remodeling by amyloidogenic and non-amyloidogenic proteins studied by EPR. AB - The advancement in site-directed spin labeling of proteins has enabled EPR studies to expand into newer research areas within the umbrella of protein membrane interactions. Recently, membrane remodeling by amyloidogenic and non amyloidogenic proteins has gained a substantial interest in relation to driving and controlling vital cellular processes such as endocytosis, exocytosis, shaping of organelles like endoplasmic reticulum, Golgi and mitochondria, intracellular vesicular trafficking, formation of filopedia and multivesicular bodies, mitochondrial fusion and fission, and synaptic vesicle fusion and recycling in neurotransmission. Misregulation in any of these processes due to an aberrant protein (mutation or misfolding) or alteration of lipid metabolism can be detrimental to the cell and cause disease. Dissection of the structural basis of membrane remodeling by proteins is thus quite necessary for an understanding of the underlying mechanisms, but it remains a formidable task due to the difficulties of various common biophysical tools in monitoring the dynamic process of membrane binding and bending by proteins. This is largely since membranes generally complicate protein structure analysis and this problem is amplified for structural analysis in the presence of different types of membrane curvatures. Recent EPR studies on membrane remodeling by proteins show that a significant structural information can be generated to delineate the role of different protein modules, domains and individual amino acids in the generation of membrane curvature. These studies also show how EPR can complement the data obtained by high resolution techniques such as X-ray and NMR. This perspective covers the application of EPR in recent studies for understanding membrane remodeling by amyloidogenic and non-amyloidogenic proteins that is useful for researchers interested in using or complimenting EPR to gain better understanding of membrane remodeling. We also discuss how a single protein can generate different type of membrane curvatures using specific conformations for specific membrane structures and how EPR is a versatile tool well-suited to analyze subtle alterations in structures under such modifying conditions which otherwise would have been difficult using other biophysical tools. PMID- 28579102 TI - Wideband frequency-swept excitation in pulsed EPR spectroscopy. AB - Excitation of electron spins with monochromatic rectangular pulses is limited to bandwidths that are smaller than the spectral widths of most organic radicals and much smaller than the spectral widths of transition and rare earth metal ions. With frequency-swept pulses, bandwidths of up to 800MHz have previously been attained for excitation and detection of spin packets at frequencies of about 9.6GHz and bandwidths of up to 2.5GHz in a polarization transfer experiment at frequencies of about 34GHz. The remaining limitations, mainly due to resonator bandwidth and due to pulse length restrictions are discussed. Flip angles for state-space rotations on passage of a transition can generally be computed from the critical adiabaticity by the Landau-Zener-Stuckelberg-Majorana expression. For hyperbolic secant pulses, the Demkov-Kunike model describes excitation for spin packets within and outside the sweep range. Well within the sweep range, the Bloch-Siegert phase shift is proportional to critical adiabaticity to a very good approximation. Because of the dependence of both flip angle and coherence phase on critical adiabaticity, it is advantageous to use pairs of amplitude and frequency modulation functions that provide such offset-independent adiabaticity. Compensation for the resonator response function should restore offset independent adiabaticity. Whereas resonance offsets and Bloch-Siegert phase can be refocused at certain pulse length ratios, phase dispersion in coupled spin systems cannot generally be refocused. Based on the bandwidth limitations that arise from spin dynamics, requirements are derived for a spectrometer that achieves precise spin control over wide bands. The design of such a spectrometer and hardware characterization by EPR experiments are discussed. PMID- 28579103 TI - ELDOR-detected NMR: A general and robust method for electron-nuclear hyperfine spectroscopy? AB - ELDOR-detected NMR (EDNMR) performed at higher magnetic fields is becoming an increasingly popular alternative to conventional ENDOR for the characterization of electron-nuclear hyperfine interactions owing to its enhanced sensitivity. However there are two key problems that limit its widespread adoption, with factors controlling: (i) lineshape distortions and; (ii) overall spectral resolution, still largely understood only at a qualitative level. Indeed highly anisotropic (dipolar) coupled species are particularly problematic in the EDNMR experiment. Nor is it clear as to whether line intensities measured in EDNMR can provide quantitative information. Here we describe how all these problems can be overcome for a nitroxide radical as model system. We introduce a simulation procedure/protocol for the simulation of EDNMR line-shapes collected over a range of high turning angle (HTA) pulse lengths. It is shown that spectral line-shapes can be robustly reproduced and that the intensities of spectral lines and the spin nutation behavior can be quantitatively assessed. This broadens the scope of the EDNMR experiment as a generally applicable, quantitative double resonance method. PMID- 28579104 TI - Understanding heme proteins with hyperfine spectroscopy. AB - Heme proteins are versatile proteins that are involved in a large number of biological processes. Many spectroscopic methods are used to gain insight into the different mechanistic processes governing heme-protein functions. Since many (intermediate) states of heme proteins are paramagnetic, electron paramagnetic resonance (EPR) methods, such as hyperfine spectroscopy, offer unique tools for these investigations. This perspective gives an overview of the use of state-of the-art hyperfine spectroscopy in heme research, focusing on the advantages, limits and challenges of the different techniques. PMID- 28579105 TI - EPR approaches to heterogeneous catalysis. The chemistry of titanium in heterogeneous catalysts and photocatalysts. AB - Paramagnetic species are often involved in catalytic or photocatalytic reactions occurring at the solid-gas interface of heterogeneous catalysts. In this contribution we will provide an overview of the wealth and breadth of information that can be obtained from EPR in the characterization of paramagnetic species in such systems, illustrating the advantages that modern pulsed EPR methodologies can offer in monitoring the elementary processes occurring within the coordination sphere of surface transition-metal ions. To do so we selected three representative systems, where titanium ions in low oxidation states act as active catalytic sites, trying to outline the methodological approaches which characterize the application of EPR techniques and the questions that can be answered and addressed relative to the characterization of heterogeneous catalytic materials. PMID- 28579107 TI - [Recent dyspnea in an 86-year-old woman]. PMID- 28579108 TI - [Abnormal nails and chronic cough]. PMID- 28579106 TI - Pre-pregnancy BMI-specific optimal gestational weight gain for women in Japan. AB - BACKGROUND: The Institute of Medicine (IOM) guidelines are the most widely used guidelines on gestational weight gain; however, accumulation of evidence that body composition in Asians differs from other races has brought concern regarding whether their direct application is appropriate. We aimed to study to what extent optimal gestational weight gain among women in Japan differs by pre-pregnancy body mass index (BMI) and to compare estimated optimal gestational weight gain to current Japanese and Institute of Medicine (IOM) recommendations. METHODS: We retrospectively studied 104,070 singleton pregnancies among nulliparous women in 2005-2011 using the Japanese national perinatal network database. In five pre pregnancy BMI sub-groups (17.0-18.4, 18.5-19.9, 20-22.9, 23-24.9, and 25-27.4 kg/m2), we estimated the association of the rate of gestational weight gain with pregnancy outcomes (fetal growth, preterm delivery, and delivery complications) using multivariate regression. RESULTS: Weight gain rate associated with the lowest risk of adverse outcomes decreased with increasing BMI (12.2 kg, 10.9 kg, 9.9 kg, 7.7 kg, and 4.3 kg/40 weeks) for the five BMI categories as described above, respectively. Current Japanese guidelines were lower than optimal gains, with the lowest risk of adverse outcomes for women with BMI below 18.5 kg/m2, and current IOM recommendations were higher than optimal gains for women with BMI over 23 kg/m2. CONCLUSION: Optimal weight gain during pregnancy varies largely by pre-pregnancy BMI, and defining those with BMI over 23 kg/m2 as overweight, as proposed by the World Health Organization, may be useful when applying current IOM recommendations to Japanese guidelines. PMID- 28579109 TI - [Fracture of unusual cause]. PMID- 28579110 TI - Chest ultrasound versus chest X-rays for detecting pneumonia in children: Why compare them each other if together can improve the diagnosis? PMID- 28579111 TI - Clinical features and prognosis of infective endocarditis in children: Insights from a Tunisian multicentre registry. AB - BACKGROUND: Infective endocarditis (IE) is a rare condition in the paediatric setting. No data on the epidemiology and prognosis of IE in children are available from North African countries. AIM: To investigate the epidemiological profile and prognosis of IE in children in Tunisia. METHODS: All patients aged<=18 years presenting with IE in three Tunisian tertiary care centres between January 1997 and September 2013 were included. Clinical features and 30-day and 6 month mortality rates were studied. Factors predictive of death at 6-month follow up were determined. RESULTS: A total of 73 patients were included in the present study. The mean age was 12+/-4.8 years; 35 (50.7%) patients were male. Rheumatic heart disease (RHD) was the underlying heart disease in 17 (23.3%) cases and IE occurred in a structurally normal heart in 36 (49.3%) cases. Staphylococcus species were isolated in 17 (23.3%) cases. Regarding IE localization, the mitral valve was involved in 28 (38.4%) cases and the aortic valve in 14 (19.2%) cases. Recourse to surgery was reported in 37 (50.7%) cases. Thirty-day and 6-month mortality rates were 13.6% and 19.2%, respectively. Heart failure on admission or during the hospital course, acute renal failure and neurological complications were significantly associated with death at 6-month follow-up in the univariate analysis and after adjustment for age and sex. CONCLUSIONS: In the Tunisian context, IE in children is still characterized by the high prevalence of RHD as an underlying heart disease. Short- and long-term mortality rates remain high. Heart failure, acute renal failure and neurological complications are significantly associated with death at 6-month follow-up. PMID- 28579112 TI - Early mortality after heart transplantation related to IgA anti-beta2 glycoprotein I antibodies. AB - BACKGROUND: The presence of pre-formed IgA anti-beta2-glycoprotein I antibodies (IgA-aB2GP1ab) has been related to early graft loss after kidney transplant. Because beta2-glycoprotein I is produced in both the kidney and heart, we aimed to assess whether the presence of these antibodies may also be associated with poor outcomes after heart transplantation (HT). METHODS: A 2-year follow-up retrospective analysis of 151 consecutive patients who underwent HT between 2004 and 2012 was performed to assess the role of this pre-formed antibody type in HT. The population was divided into 2 groups according to the presence of IgA: Group 1 was positive for IgA-aB2GP1ab (47 patients, 31.1%), and Group 2 was negative for IgA-Ab2GP1ab (104 patients, 68.9%). RESULTS: Early mortality rates within the first 3 months were higher in Group 1 (27.7%) than in Group 2 (9.6%). No differences in donor and recipient characteristics or in causes of death were observed between groups. Multivariate analysis identified the presence of IgA aB2GP1ab, female gender and blood type A as independent risks factors for early mortality after HT. A greater incidence of thrombotic events during the first 3 months post-HT in Group 1 (23.4% vs 5.8%) and a greater presence of risk factors for thrombotic events, which may have exacerbated them, were observed. After this period, no increase in mortality or in thrombotic events was found when the 2 groups were compared. CONCLUSION: Pre-transplant presence of IgA-aB2GP1ab is associated with both increased early mortality rates and higher thrombotic events after HT. PMID- 28579114 TI - Potential impact of a shock requirement on adult heart allocation. PMID- 28579113 TI - Waiting list outcomes in pediatric lung transplantation: Poor results for children listed in adult transplant programs. AB - BACKGROUND: Low case volume has been associated with lower survival after pediatric lung transplantation. Our aim was to analyze waitlist outcomes among pediatric lung transplant centers in the USA. METHODS: We studied a cohort of 1,139 pediatric candidates listed in the Organ Procurement and Transplantation Network for lung transplantation between 2002 and 2014. Of these candidates, 720 (63.2%) received a transplant. Candidates were divided into groups according to the clinical activity of the center of listing: high-volume pediatric (>=4 transplants per year); low-volume pediatric (<4 transplants per year); and adult (transplant volume predominantly in adults). We used multivariate Cox regression analysis to identify independent risk factors for waitlist mortality. We also determined the transplant rate-or likelihood of transplant after listing-over the study period. RESULTS: Fifty-eight percent of the children and adolescents were listed in adult centers where the resultant transplant rate was low-only 42% received a transplant compared with 93% in pediatric programs. Listing in an adult program was also the most significant risk factor for death on the waiting list (hazard ratio 15.6, 95% confidence interval 5.8 to 42.1). CONCLUSIONS: Most children (58%) are listed for lung transplantation in adult centers and have a reduced rate of transplantation and a greater chance of waitlist mortality. PMID- 28579115 TI - Bleeding and thrombosis associated with ventricular assist device therapy. AB - Over the past decade, continuous-flow rotary pumps have dramatically improved survival for patients with advanced systolic heart failure. Bleeding and thrombosis, however, continue to be the Achilles heel of left ventricular assist device (LVAD) therapy. There is a dynamic and complex interaction between the patient and pump. The net effect of a variety of hematologic derangements, such as hemolysis, high-molecular-weight von Willebrand degradation, platelet activation and diminished pulsatility, is poorly understood. A combination of these factors mediates the common adverse events of gastrointestinal bleeding, device thrombosis and stroke. In this review we incorporate information from translational investigations in LVAD patients to understand how continuous-flow pumps activate the coagulation system and platelets predisposing to thrombosis, while, in parallel, degrade high-molecular-weight von Willebrand factor and trigger abnormal angiogenesis predisposing to bleeding. Finally, we propose novel strategies to develop a personalized approach to anti-thrombotic monitoring and titration of anti-coagulants to minimize the bleeding and thrombotic event rates of future LVAD recipients. PMID- 28579116 TI - SIRT3 prevents angiotensin II-induced renal tubular epithelial-mesenchymal transition by ameliorating oxidative stress and mitochondrial dysfunction. AB - Silent mating type information regulation 2 homolog 3 (SIRT3) is a major protective mediator that ameliorates oxidative stress and mitochondrial dysfunction, which are associated with the pathogenesis of epithelial-mesenchymal transition (EMT). The present study was aimed to investigate the potential role of SIRT3 in renal tubular EMT both in vitro and in vivo. Firstly, we showed that the expression of SIRT3 was repressed in angiotensin II-induced EMT. SIRT3 deficiency triggered EMT response, while over-expression of SIRT3 attenuated EMT response. In addition, over-expression of SIRT3 repressed AngII-induced excessive production of mitochondrial superoxide, as well as mitochondrial dysfunction evidenced by the maintenance of mitochondrial number and morphology, and the stabilization of mitochondrial membrane potential. In conclusion, these findings identify a protective role of SIRT3 against angiotensin II-induced EMT in the kidney, and suggest SIRT3 upregulation is a potential therapeutic strategy for the treatment of renal tubulointerstitial fibrosis. PMID- 28579117 TI - Key amino acid residue in Melanocortin-1 receptor (melanocyte alpha-MSH receptor) for ligand selectivity. AB - The melanocortin-1 receptor (MC1R) is a subtype of the melanocortin receptor family and NDP-alpha-MSH is a non-selective agonist for MC1R. The core sequence of NDP-alpha-MSH, His-Phe-Arg-Trp, is important for ligand binding and biological activities at the melanocortin receptor subtypes (MCRs). A recent study indicates that Trp9 in NDP-alpha-MSH plays an important role in ligand selectivity. Deletion of Trp9 in NDP-alpha-MSH (des-Trp9-NDP-alpha-MSH) resulted in loss of agonist activity at MC4R, although remains agonist activity at MC1R. The molecular basis for this receptor ligand selectivity is unknown. In this study we examined what region of the MC1R is responsible for des-NDP-alpha-MSH selectivity. Our results indicate that (1) substitution of TM3 of MC4R with the corresponding region of MC1R switches des-Trp9-NDP-alpha-MSH from no activity to agonist; (2) des-Trp9-NDP-alpha-MSH exhibits agonistic activity at the L133M mutation of the MC4R; and (3) substitution of non-conserved amino acid residue M128 in TM3 of MC1R significantly reduced des-Trp9-NDP-alpha-MSH agonist activity. Our results demonstrate that amino acid residue 128 in TM3 of MC1R, or amino acid residue L133 in TM3 of the MC4R, play crucial roles in ligand des-Trp9 NDP-alpha-MSH selectivity at MC1R or MC4R. PMID- 28579118 TI - Targeting post-translational histone modifications for the treatment of non medullary thyroid cancer. AB - Genomic and epigenetic alterations are now being exploited as molecular targets in cancer treatment. Abnormalities involving the post-translational modification of histones have been demonstrated in thyroid cancer, and they are regarded as promising molecular targets for novel drug treatment of tumors that are resistant to conventional therapies. After a brief overview of the histone modifications most commonly associated with human malignancies, we will review recently published preclinical and clinical findings regarding the use of histone-activity modulators in thyroid cancers. Particular attention will be focused on their use as re-differentiating or anti-proliferating agents, the differential effects observed when they are used alone and in combination with other targeted drugs, and current prospects for their use in the treatment of thyroid cancer. PMID- 28579120 TI - Vitamin D and the brain: Genomic and non-genomic actions. AB - 1,25(OH)2D3 (vitamin D) is well-recognized as a neurosteroid that modulates multiple brain functions. A growing body of evidence indicates that vitamin D plays a pivotal role in brain development, neurotransmission, neuroprotection and immunomodulation. However, the precise molecular mechanisms by which vitamin D exerts these functions in the brain are still unclear. Vitamin D signalling occurs via the vitamin D receptor (VDR), a zinc-finger protein in the nuclear receptor superfamily. Like other nuclear steroids, vitamin D has both genomic and non-genomic actions. The transcriptional activity of vitamin D occurs via the nuclear VDR. Its faster, non-genomic actions can occur when the VDR is distributed outside the nucleus. The VDR is present in the developing and adult brain where it mediates the effects of vitamin D on brain development and function. The purpose of this review is to summarise the in vitro and in vivo work that has been conducted to characterise the genomic and non-genomic actions of vitamin D in the brain. Additionally we link these processes to functional neurochemical and behavioural outcomes. Elucidation of the precise molecular mechanisms underpinning vitamin D signalling in the brain may prove useful in understanding the role this steroid plays in brain ontogeny and function. PMID- 28579121 TI - Design of potent dipeptidyl peptidase IV (DPP-4) inhibitors by employing a strategy to form a salt bridge with Lys554. AB - We report a design strategy to obtain potent DPP-4 inhibitors by incorporating salt bridge formation with Lys554 in the S1' pocket. By applying the strategy to the previously identified templates, quinoline 4 and pyridines 16a, 16b, and 17 have been identified as subnanomolar or nanomolar inhibitors of human DPP-4. Docking studies suggested that a hydrophobic interaction with Tyr547 as well as the salt bridge interaction is important for the extremely high potency. The design strategy would be useful to explore a novel design for DPP-4 inhibitors having a distinct structure with a unique binding mode. PMID- 28579119 TI - Function of the vitamin D endocrine system in mammary gland and breast cancer. AB - The nuclear receptor for 1alpha,25-dihydroxycholecalciferol (1,25D), the active form of vitamin D, has anti-tumor actions in many tissues. The vitamin D receptor (VDR) is expressed in normal mammary gland and in many human breast cancers suggesting it may represent an important tumor suppressor gene in this tissue. When activated by 1,25D, VDR modulates multiple cellular pathways including those related to energy metabolism, terminal differentiation and inflammation. There is compelling pre-clinical evidence that alterations in vitamin D status affect breast cancer development and progression, while clinical and epidemiological data are suggestive but not entirely consistent. The demonstration that breast cells express CYP27B1 (which converts the precursor vitamin D metabolite 25D to the active metabolite 1,25D) and CYP24A1 (which degrades both 25D and 1,25D) provides insight into the difficulties inherent in using dietary vitamin D, sun exposure and/or serum biomarkers of vitamin D status to predict disease outcomes. Emerging evidence suggests that the normally tight balance between CYP27B1 and CYP24A1 becomes deregulated during cancer development, leading to abrogation of the tumor suppressive effects triggered by VDR. Research aimed at understanding the mechanisms that govern uptake, storage, metabolism and actions of vitamin D steroids in normal and neoplastic breast tissue remain an urgent priority. PMID- 28579122 TI - Design, synthesis, in silico and in vitro evaluation of thiophene derivatives: A potent tyrosine phosphatase 1B inhibitor and anticancer activity. AB - A series of novel methyl 4-(4-amidoaryl)-3-methoxythiophene-2-carboxylate derivatives were designed against the active site of protein tyrosine phosphatise 1B (PTP1B) enzyme using MOE.2008.10. These molecules are also subjected for in silico toxicity prediction studies and considering their corresponding drug scores, it implied that, the molecules are promising as anticancer agents. The designed compounds were synthesized by using suitable methods and characterized. They were subjected to inhibitory activity against PTP1B and in vitro anticancer activity by MTT assay. Most of the tested compounds showed potent inhibitory activity against PTP1B, among the compounds tested, compound 5b exhibited the highest activity (IC50=5.25uM) and remarkable cytotoxic activity at 0.09uM of IC50 against the MCF-7 cell line. In addition to this, compound 5c also showed potential anticancer activity at 2.22uM of IC50 against MCF-7 and 0.72uM against HepG2 cell lines as well as PTP1B inhibitory activity at IC50 of 6.37uM. PMID- 28579123 TI - Synthesis and structure-activity relationship study of novel quinazolinone-based inhibitors of MurA. AB - MurA is an intracellular bacterial enzyme that is essential for peptidoglycan biosynthesis, and is therefore an important target for antibacterial drug discovery. We report the synthesis, in silico studies and extensive structure activity relationships of a series of quinazolinone-based inhibitors of MurA from Escherichia coli. 3-Benzyloxyphenylquinazolinones showed promising inhibitory potencies against MurA, in the low micromolar range, with an IC50 of 8uM for the most potent derivative (58). Furthermore, furan-substituted quinazolinones (38, 46) showed promising antibacterial activities, with MICs from 1ug/mL to 8ug/mL, concomitant with their MurA inhibitory potencies. These data represent an important step towards the development of novel antimicrobial agents to combat increasing bacterial resistance. PMID- 28579124 TI - Sinus Tachycardia With Variable QRS Morphology. AB - Wolff-Parkinson-White-type ventricular preexcitation was recognized for the first time in a 67-year-old man four days after aortic valve replacement. The preexcitation was intermittent. PMID- 28579125 TI - Prognostic Implications of Left Ventricular Global Longitudinal Strain in Predialysis and Dialysis Patients. AB - Chronic kidney disease (CKD) is a worldwide growing epidemic associated with an increased risk of cardiovascular morbidity and mortality. Left ventricular (LV) global longitudinal strain (GLS) is a measure of LV systolic function associated with prognosis in the general population. However, little is known about the association between LV GLS and survival in patients with CKD. The aim of the present study was to investigate the prognostic implications of LV GLS in predialysis and dialysis patients specifically. LV GLS was measured in a retrospective cohort of predialysis and dialysis patients (CKD stage 3b to 5) who underwent clinically indicated echocardiography between 2004 and 2015. Patients were divided into 4 groups according to quartiles of LV GLS: first quartile (LV GLS <=10.6%, worst function), second quartile (LV GLS 10.7% to 15.1%), third quartile (LV GLS 15.2% to 17.8%), and fourth quartile (LV GLS >=17.9%, best function). The primary end point was all-cause mortality. Of 304 patients (62 +/- 14 years, 66% male), 65% were in predialysis and 35% in dialysis. During a median follow-up of 29 months (interquartile range 16 to 58 months), 34% of patients underwent renal transplantation and 36% died. Patients with LV GLS <=10.6% showed significantly worse prognosis compared with the other groups (log-rank test, p <0.001). LV GLS <=10.6% was significantly associated with increased risk of all cause mortality (hazard ratio 2.18, 95% CI 1.17 to 4.06, p = 0.014) after correcting for age, gender, albumin levels, atrial fibrillation, and renal transplantation. In conclusion, in predialysis and dialysis patients, severely impaired LV GLS is independently associated with an increased risk of mortality. PMID- 28579127 TI - Peritenolysis and Debridement for Main Body (Mid-Portion) Achilles Tendinopathy in Athletic Patients: Results of 107 Procedures. AB - Achilles tendinopathy in the main body (mid-portion) of the tendon is a common pathologic finding among active and athletic populations and can be debilitating without proper and adequate treatment. Numerous surgical approaches for this common pathologic finding have been reported, with variable outcomes. We evaluated the surgical outcomes of peritenolysis and debridement of main body Achilles tendinopathy among athletic populations using the return to activity (RTA) and decreased desired activity (DDA) as our primary outcome measures. A total of 100 patients underwent 107 procedures by the senior author (A.S.) from January 2001 through December 2015 met the inclusion criteria, 65 (65%) of whom were runners. The mean follow-up duration was 106.6 +/- 55.5 months from the index procedure, and the mean interval necessary to RTA for the entire group was 10.9 +/- 5.3 weeks. The average RTA after debridement was 14.1 +/- 5.2 weeks and after peritenolysis was 7.3 +/- 2.0 weeks (p = .00001). Of the 100 patients, 3 (3%) had experienced a DDA at the last follow-up visit. With >97% of the patients able to return to their desired activities, we have concluded that peritenolysis and debridement are favorable surgical techniques for main body Achilles tendinopathy. PMID- 28579126 TI - Forefoot Adduction Is a Risk Factor for Jones Fracture. AB - Jones fractures are among the most common fractures of the foot; however, much remains unknown about their etiology. The purpose of the present study was to further examine the risk factors of forefoot and hindfoot alignment on Jones fractures using an epidemiologic study design. We used a retrospective, matched, case-control study design. Cases consisted of patients with acute, isolated Jones fractures confirmed on plain film radiographs seen at our institute from January 2009 to December 2013. Patients presenting with pain unrelated to metatarsal fractures served as controls. Controls were matched to cases by age (+/-2 years), gender, and year of presentation. Weightbearing foot radiographs were assessed for 13 angular relationships by a single rater. Conditional multivariable logistic regression was used to identify important risk factors. Fifty patients with acute Jones fractures and 200 controls were included. The only significant variables in the final multivariable model were the metatarsus adductus angle (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.08 to 1.25) and fourth/fifth intermetatarsal angle (OR 0.69, 95% CI 0.57 to 0.83)-both measures of static forefoot adduction. The presence of metatarsus adductus (defined as >15 degrees ) on foot radiographs was associated with a 2.4 times greater risk of a Jones fracture (adjusted OR 2.4, 95% CI 1.2 to 4.8). We have concluded that the risk of Jones fracture increases with an adducted forefoot posture. In our population, which consisted primarily of patients presenting after a fall (10 of 50; 20%) or misstep/inversion injury (19 of 50; 38%), the hindfoot alignment appeared to be a less important factor. PMID- 28579128 TI - The role of hunger state and dieting history in neural response to food cues: An event-related potential study. AB - A history of dieting to lose weight has been shown to be a robust predictor of future weight gain. A potential factor in propensity towards weight gain is the nature of people's reactions to the abundance of highly palatable food cues in the environment. Event Related Potentials (ERPs) have revealed differences in how the brain processes food cues between obese and normal weight individuals, as well as between restrained and unrestrained eaters. However, comparisons by weight status are not informative regarding whether differences predate or follow weight gain in obese individuals and restrained eating has not consistently been found to predict future weight gain. The present study compared ERP responses to food cues in non-obese historic dieters (HDs) to non-obese never dieters (NDs). HDs showed a blunted N1 component relative to NDs overall, and delayed N1 and P2 components compared to NDs in the hungry state, suggesting that early, perceptual processing of food cues differs between these groups, especially when food deprived. HDs also showed a more hunger-dependent sustained ERP (LPP) compared to NDs. Future research should test ERP-based food cue responsivity as a mediator between dieting history and future weight gain to better identify those most at risk for weight gain as well as the nature of their vulnerability. PMID- 28579129 TI - Theta-gamma coupling in hippocampus during working memory deficits induced by low frequency electromagnetic field exposure. AB - The dramatically increased use of electricity is raising major concerns as to the consequences of the interaction between electromagnetic field (EMF) and neurobiology. The aim of this study is to investigate the effects of magnetic field on working memory in the hippocampal region by analyzing local field potentials (LFPs) and spikes pattern in vivo. In present study, mice were exposed to EMF (50Hz, 1mT), static magnetic field (SMF, 1mT), or placed in the exposure tube but without EMF exposure (SHAM), respectively. During the exposure for 7 consecutive days, mice were subjected to perform working memory (WM) tasks in Y maze, and multichannel electrophysiology signals from hippocampus of mice were recorded during the test, from which LFPs, spike firing rates, band power at different frequencies, and theta-gamma modulation index (MI) were analyzed in details. From our results, correct choice rate during WM task was found significantly decreased in EMF group after 3-day exposure, which was consistent with noticeable decline in firing rate. Starting from Day 3 after EMF exposure, the power of theta (4-12Hz) and gamma (LG, 30-60Hz) before reference point (RP) in Y-maze were also found to be descending, together with decrease of oscillatory activities of theta and gamma frequencies. The results indicated that MI between theta and gamma could play a significant role in modulating the spikes discharge and encoding WM. Therefore, the analysis of theta-gamma coupling and its oscillation strength may provide a new perspective for mechanistic investigation of EMF-induced WM deficits. PMID- 28579130 TI - Vascular aging: Molecular mechanisms and potential treatments for vascular rejuvenation. AB - Aging is the main risk factor contributing to vascular dysfunction and the progression of vascular diseases. In this review, we discuss the causes and mechanisms of vascular aging at the tissue and cellular level. We focus on Endothelial Cell (EC) and Smooth Muscle Cell (SMC) aging due to their critical role in mediating the defective vascular phenotype. We elaborate on two categories that contribute to cellular dysfunction: cell extrinsic and intrinsic factors. Extrinsic factors reflect systemic or environmental changes which alter EC and SMC homeostasis compromising vascular function. Intrinsic factors induce EC and SMC transformation resulting in cellular senescence. Replenishing or rejuvenating the aged/dysfunctional vascular cells is critical to the effective repair of the vasculature. As such, this review also elaborates on recent findings which indicate that stem cell and gene therapies may restore the impaired vascular cell function, reverse vascular aging, and prolong lifespan. PMID- 28579131 TI - The Art and Science of Lifelong Singing. PMID- 28579132 TI - Optimization of sagittal and coronal planes with robotic-assisted unicompartmental knee arthroplasty. AB - BACKGROUND: One of the anatomic goals of total knee arthroplasty (TKA) is optimizing in the coronal and sagittal plane. Accurate alignments of both planes have been correlated to functional outcome and range of motion. There is a paucity of evidence on the accuracy of unicompartmental knee arthroplasty (UKA) in balancing biplanar knee alignment - specifically sagittal plane alignment. Because robotic assisted UKA has an advantage of more accurately manipulating sagittal plane for optimal alignment and kinematics based on pre-operative and intraoperative CT planning we assessed the accuracy. METHODS: We reviewed the clinical and radiographic information of 94 robotic assisted UKA surgeries for balancing of sagittal and coronal knee anatomy using radiographic parameters, such as posterior condylar offset ratio (PCOR), posterior tibial slope (PTS), femoral-tibial angle, and joint line. RESULTS: In the sagittal plane, we found no significant difference between pre and postoperative PCOR values. As planned, PTS was significantly lower after UKA compared to the native knee (4.91 degrees vs 2.28 degrees ; p<0.0001). In the coronal plane, there was no significant difference in the joint line however pre and post-operative mechanical axis were significantly different (5.43 degrees +/-2.58 of varus vs. 2.76 degrees +/-2.14 of varus; p<0.0001). CONCLUSION: This study attempts to quantify sagittal and coronal plane alignment after robotic assisted UKA. More attention should be paid to the role of sagittal plane alignment after UKA. We believe modifying posterior tibial slope, while maintaining PCOR is fundamental in achieving native kinematics and optimizing range of motion in the sagittal plane. This may be best accomplished using robotic techniques for UKA. PMID- 28579133 TI - Two-stage flap repair of severe hypospadias: Usefulness of the tubularized incised plate urethroplasty. AB - PURPOSE: The use of flaps in the two-stage repair of posterior hypospadias associated with severe chordee has been well established. Despite the almost certain guarantee of flap take, complications such as diverticuli are still relatively high. While different applications of the tubularized incised plate have been described, experience with the application of the technique to the two stage flap repair is very limited. A previous local review of 15 cases performed at the present institution during the period 1998-2003, using the technique as described by Rekit, revealed fistulae and diverticulum rates of 20% and 27%, respectively. With the primary objective of improving surgical outcome, the midline incision was incorporated into the two-stage flap repair. MATERIALS AND METHODS: Between 2004 and 2015, 35 boys (aged 2-15 years) with severe hypospadias that required excision of the urethral plate were operated using the two-stage flap technique. The first stage involved mobilization of preputeal or dorsal penile skin (if circumcised) to the ventral surface, as described by Retik. After a minimum interval of 6 months, the second-stage operation was performed in a way similar to the technique of tubularized incised plate urethroplasty, as popularized by Snodgrass, and involved a preliminary midline incision on the neo urethral plate followed by tubularization and multilayered closure. RESULTS: All but one flap took successfully. The outcome was satisfactory in 80% of patients, and there was a fistula rate of 14% ( Summary Table). One patient had a complete breakdown of the flap and was successfully treated about 12 months later by repeating the second stage of the operation. No case of diverticulum or stricture was recorded. DISCUSSION: Even though there was a marginal improvement in the fistula rate, the most striking observation was the complete absence of diverticulum or stricture. With a reported incidence rate of 20-63%, different authors have reported diverticulum formation (despite the absence of distal obstruction) to be a major problem of the two-stage flap technique. Attempts by these authors at reducing the risk of diverticulum by reducing flap size have tended to increase the risk of strictures. This has been the main reason given by some authors for abandoning the technique. The main limitations of the present study included the wide age range of the patients and the small sample size. CONCLUSION: The inclusion of a midline incision in a two-stage flap urethroplasty for proximal hypospadias appears to prevent the development of diverticulum. PMID- 28579134 TI - The impact of obesity on pediatric inpatients with urinary tract infections in the United States. AB - INTRODUCTION: Urinary tract infections (UTI) are common infectious disorders, and obesity is an increasing public health problem worldwide. Several studies have suggested that childhood obesity may be associated with the development of UTI. However, the potential effects of obesity on the clinical outcomes of UTI in children remain unknown. MATERIALS AND METHODS: Hospital discharge records for patients aged 18 years or younger with a diagnosis of UTI were extracted from the 2012 Kids' Inpatient Database. We used the International Classification of Diseases, Ninth Revision, Clinical Modification codes, and classified each patient as obese or not. We compared the total hospitalization costs, total length of hospital stay in days, and risks of hypertension, acute kidney injury, and septicemia between obese and non-obese patients, using propensity score matching and stabilized inverse probability weighting methods. RESULTS: Of 51,918 patients with UTI, 1488 were obese and 50,430 were non-obese. A multivariable logistic regression model calculated propensity scores using baseline characteristics as dependent variables. One-to-one propensity matching created 1488 pairs. In the propensity-matched analyses, a significant difference was observed between the obese and the non-obese for risks of hypertension (8.1% vs. 1.8%; risk ratio 4.44; 95% CI 2.95-6.71). The total mean hospitalization cost in the obese group was 1.29 times higher than that in the non-obese group (95% CI 1.13-1.47). The total mean length of hospital stay in the obese group was 1.29 times longer than that in the non-obese group (95% CI 1.16-1.44). Stabilized inverse probability weighting analyses showed similar results to the propensity matched analyses (Table), except for a significant result for the risk ratio for acute kidney injury (risk ratio 1.64; 95% CI 1.18-2.26. CONCLUSIONS: These findings indicate that obesity may be an important risk factor for hypertension and acute kidney injury among hospitalized children with UTI. Obesity may also be an economically complicating factor for their hospitalizations, which indicates the importance of the prevention for obesity. PMID- 28579136 TI - ACCIDENTAL DUPLICATION: Role of Intralesional Bleomycin in Orbital Lymphangioma: A Prospective Study. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.jaapos.2017.03.007. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 28579135 TI - Urinary tract infection after voiding cystourethrogram. AB - BACKGROUND: Reported rates of post-procedural urinary tract infection (ppUTI) after voiding cystourethrogram (VCUG) are highly variable (0-42%). OBJECTIVE: This study aimed to determine the risk of ppUTI after cystogram, and evaluate predictors of ppUTI. STUDY DESIGN: A retrospective cohort study of children undergoing VCUG or radionuclide cystogram (henceforth 'cystogram') was conducted. Children with neurogenic bladder who underwent cystogram in the operating room and without follow-up at the study institution were excluded. Incidence of symptomatic ppUTI within 7 days after cystogram was recorded. Predictors of ppUTI were evaluated using univariate statistics. RESULTS: A total of 1108 children (54% female, median age 1.1 years) underwent 1203 cystograms: 51% were on periprocedural antibiotics, 75% had a pre-existing urologic diagnosis (i.e., vesicoureteral reflux (VUR) or hydronephrosis; not UTI alone), and 18% had a clinical UTI within 30 days before cystogram. Of the cystograms, 41% had an abnormal cystogram and findings included VUR (82%), ureterocele (6%), and diverticula (6%). Twelve children had a ppUTI (1.0%; four girls, five uncircumcised boys, three circumcised boys; median age 0.9 years). Factors significantly associated with diagnosis of a ppUTI (Summary fig.) included: pre existing urologic diagnosis prior to cystogram (12/12, 100% of patients with ppUTI), abnormal cystogram results (11/12, 92%), and use of periprocedural antibiotics (11/12, 92%). All 11 children with an abnormal cystogram had VUR >= Grade III. However, among all children with VUR >= Grade III, 4% (11/254) had a ppUTI. DISCUSSION: This is the largest study to date that has examined incidence and risk factors for ppUTI after cystogram. The retrospective nature of the study limited capture of some clinical details. This study demonstrated that the risk of ppUTI after a cystogram is very low (1.0% in this cohort). Having a pre existing urologic diagnosis such as VUR or hydronephrosis was associated with ppUTI; therefore, children with moderate or high-grade VUR on cystogram may be at highest risk. Development of ppUTI after cystogram also highlighted the potential for a delay in diagnosis or oversight of a healthcare-associated infection due to several factors: 1) cystograms may be ordered, performed/interpreted, and followed up by multiple different providers; and 2) such infections are not captured by traditional healthcare-associated infection surveillance strategies. CONCLUSIONS: The risk of ppUTI after a cystogram is very low. Only children with pre-existing urologic diagnoses developed ppUTI in this study. This study's findings suggest that children undergoing a cystogram should not be given peri procedural antibiotic prophylaxis for the sole purpose of ppUTI prevention. PMID- 28579137 TI - Golf-related injuries treated in United States emergency departments. AB - OBJECTIVE: This study investigates unintentional non-fatal golf-related injuries in the US using a nationally representative database. METHODS: This study analyzed golf-related injuries treated in US hospital emergency departments from 1990 through 2011 using the National Electronic Injury Surveillance System database. Injury rates were calculated using golf participation data. RESULTS: During 1990 through 2011, an estimated 663,471 (95% CI: 496,370-830,573) individuals >=7years old were treated in US emergency departments for golf related injuries, averaging 30,158 annually or 12.3 individuals per 10,000 golf participants. Patients 18-54years old accounted for 42.2% of injuries, but injury rates per 10,000 golf participants were highest among individuals 7-17years old (22.1) and >=55years old (21.8) compared with 18-54years old (7.6). Patients >=55years old had a hospital admission rate that was 5.01 (95% CI: 4.12-6.09) times higher than that of younger patients. Injured by a golf club (23.4%) or struck by a golf ball (16.0%) were the most common specified mechanisms of injury. The head/neck was the most frequently injured body region (36.2%), and sprain/strain (30.6%) was the most common type of injury. Most patients were treated and released (93.7%) and 5.9% required hospitalization. CONCLUSIONS: Although golf is a source of injury among all age groups, the frequency and rate of injury were higher at the two ends of the age spectrum. Given the higher injury and hospital admission rates of patients >=55years, this age group merits the special attention of additional research and injury prevention efforts. PMID- 28579138 TI - Referrals for CT scans in mild TBI patients can be aided by the use of a brain electrical activity biomarker. PMID- 28579139 TI - A Phase I Study of Neoadjuvant Chemotherapy With Nab-Paclitaxel, Doxorubicin, and Cyclophosphamide in Patients With Stage II to III Breast Cancer. AB - BACKGROUND: The aims of this study were to assess the safety and tolerability of nanoparticle albumin bound paclitaxel (nab-paclitaxel), doxorubicin, and cyclophosphamide as combination therapy for breast cancer patients in the neoadjuvant setting and to assess the overall clinical response and pathologic complete response (pCR). PATIENTS AND METHODS: Twenty-six women with newly diagnosed stage II to III histologically or cytologically proven adenocarcinoma of the breast with negative HER2 status were enrolled. Patients were treated with nab-paclitaxel 100 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 on day 1 and nab-paclitaxel 100 mg/m2 on day 8 in a 21-day cycle for 6 cycles total. RESULTS: Most adverse events attributed to treatment were decreased white blood cell count, neutropenia, anemia, thrombocytopenia, and lymphopenia with a median duration of 8 days. Fifteen of 23 (65.2%; 95% confidence interval [CI], 45.7% 84.6%) had a complete clinical response and 8 of 23 (34.7%; 95% CI, 15.2%-54.1%) had a partial clinical response for an overall clinical response rate of 100%. Thirteen of 23 patients (56.5%; 95% CI, 36.2%-76.7%) had a pCR. All 10 triple negative breast cancer (TNBC) patients (100%) achieved a pCR. CONCLUSION: The regimen of nab-paclitaxel, doxorubicin, and cyclophosphamide chemotherapy was well tolerated and resulted in high clinical as well as pathologic responses, particularly in TNBC. PMID- 28579140 TI - Alteration of paraoxonase, arylesterase and lactonase activities in people around fluoride endemic area of Tamil Nadu, India. AB - BACKGROUND: Toxicity due to excess fluoride concentration in drinking water is of great concern in people who rely only on the ground water as their water source in many region of the world. METHODS: We collected samples and examined the toxicity of fluoride in a population residing at Salem, Dharmapuri and Krishnagiri districts of Tamil Nadu, India and measured HDL bound enzyme (PON1), erythrocyte membrane bound enzymes (acetylcholinesterase, AChE) and adenosine 5' triphosphatase (ATPases), plasma enzyme (butyrylcholinesterase, BChE) and rate limiting enzyme in heme biosynthesis (delta aminolevulinic acid dehydratase, delta-ALAD) activities. RESULTS: In fluorosis patients, formation of lipid peroxidation product was more in erythrocytes than in plasma. The observation further revealed that there was 50% reduction in the activity of HDL bound anti atherogenic enzyme-paraoxonase (PON1). The activities of membrane bound and signaling enzymes (acetylcholinesterase - AChE and adenosine 5' triphosphatase - ATPase) of erythrocyte were also diminished. These results suggested that there was defectiveness in the signaling and energy metabolism in fluorosis patients. Altered isoenzyme pattern of lactate dehydrogenase (LDH) in fluorosis samples was observed. Furthermore, the result suggested that both the heart (LDH 1) and liver (LDH 5) were most affected by fluoride toxicity. The study also provided reference values for tests which are used to predict the severity of fluoride toxicity. CONCLUSION: The toxic effect of fluoride was due to the collective effects on vital protective system rather than single factor. PMID- 28579141 TI - Diagnostic potential of inflammatory biomarkers in early childhood caries - A case control study. AB - BACKGROUND: Early Childhood Caries (ECC) is most common chronic infectious disease of childhood. Diagnosis of dental caries has been limited to clinical, visual and radiographic methods but its inflammatory component remained unexplored. Hence, this study aims to evaluate salivary levels of inflammatory cytokines in children with ECC to assess their potential as non-invasive biomarkers. METHODS: 50 subjects were recruited (25 ECC patients and 25 healthy children). Saliva samples were taken from all subjects and collected again from patients after rehabilitative intervention. Levels of IL-6, IL-8 and TNF-alpha were determined using ELISA. Cytokines level were statistically correlated with each other and with DMF score along with ROC curve analysis. RESULTS: Salivary levels of IL-6, IL-8 & TNF-alpha were significantly higher in patients which got significantly reduced after rehabilitative intervention. Levels of these cytokines were significantly associated with severity of dental caries. These cytokines were correlating with each other along with DMF score upon Spearman correlation. ROC curve reveals optimum sensitivity and specificity of these cytokines for diagnosis in ECC with absolute levels observed for IL-6. CONCLUSIONS: Significant elevation of IL-6, IL-8 and TNF-alpha with optimum sensitivity and specificity might imply their involvement as potential non invasive diagnostic/prognostic markers in ECC. PMID- 28579142 TI - Stability of lyophilized pooled sera as quality control materials for tumor marker assays in external quality assessment. AB - BACKGROUND: External quality assessment (EQA) requires stable quality control (QC) materials. We evaluated the stability of QC materials made of lyophilized and liquid pooled sera for the tumor markers alpha-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 125, and carbohydrate antigen 19-9. METHODS: Specimens of the 4 tumor markers were collected from the sera of patients and stored at -20 degrees C. After sera collection and pooling, liquid or lyophilized samples were stored at -20 degrees C, 5 degrees C, or room temperature. Tumor markers were quantified on days 0, 1, 4, 7, 14, 30, and 90 of storage. Internal QC results were analyzed, and the effects of heat inactivation and sucrose addition were assessed. RESULTS: Heat inactivation lowered tumor marker levels in lyophilized pooled sera, whereas sucrose addition had no effect. The coefficients of variation of the internal QC results were stable, whereas those of lyophilized samples were higher than those of liquid samples. Tumor marker levels were significantly lower in lyophilized samples (p<0.05) and did not significantly differ according to storage temperature. A declining trend over time was observed for all tumor markers. CONCLUSIONS: Lyophilized QC materials are insufficiently stable for use in EQA among clinical laboratories. PMID- 28579143 TI - Energy from poultry waste: An Aspen Plus-based approach to the thermo-chemical processes. AB - A particular approach to the task of energy conversion of a residual waste material was properly experienced during the implementation of the national funded Enerpoll project. This project is a case study developed in the estate of a poultry farm that is located in a rural area of central Italy (Umbria Region); such a farm was chosen for the research project since it is almost representative of many similar small-sized breeding realties of the Italian regional context. The purpose of the case study was the disposal of a waste material (i.e. poultry manure) and its energy recovery; this task is in agreement with the main objectives of the new Energy Union policy. Considering this background, an innovative gasification plant (300KW thermal power) was chosen and installed for the experimentation. The novelty of the investigated technology is the possibility to achieve the production of thermal energy burning just the produced syngas and not directly the solid residues. This aspect allows to reduce the quantity of nitrogen released in the atmosphere by the exhaust flue gases and conveying it into the solid residues (ashes). A critical aspect of the research program was the optimization of the pretreatment (reduction of the water content) and the dimensional homogenization of the poultry waste before its energy recovery. This physical pretreatment allowed the reduction of the complexity of the matrix to be energy enhanced. Further to the real scale plant monitoring, a complete Aspen Plus v.8.0 model was also elaborated for the prediction of the quality of the produced synthesis gas as a function of both the gasification temperature and the equivalence ratio (ER). The model is an ideal flowchart using as input material just the homogenized and dried material. On the basis of the real monitored thermal power (equal to about 200kW average value in an hour) the model was used for the estimation of the syngas energy content (i.e. LHV) that resulted in the range of 3-5MJ/m3 for an equivalence ratio (ER) equal to 0.2. PMID- 28579144 TI - E-waste collection in Italy: Results from an exploratory analysis. AB - This study looks at the performance of household electrical and electronic waste (WEEE) collection in 20 Italian regions from 2008 to 2015. The impact of several explicative variables on the results of e-waste collection is evaluated. The independent variables are socio-economic and demographic ones (age, gender, household size, education level, migration and income) along with technical organisational variables (population density, presence of metropoles, macro regions, characteristics of the territory, percentage of household waste collected separately and number of e-waste collection points). The results show that the presence of collection points, the percentage of household waste collected separately and the percentage of females are positively correlated with the kg collected per inhabitant per year. For example, a variation of 1% of input (presence of collection points) corresponds to a 0.25% variation in the output (collection results) while 1% difference in the percentage of females in the population corresponds to a 7.549% difference in the collection rate. Population density, instead, is negatively correlated. It is interesting to note that there is a discrepancy between the Southern regions and the Centre regions (the former have an outcome 0.66 times lower than the latter) while the Northern regions perform similarly to the Centre ones. Moreover, the first year (2008) had a very low performance compared to the following years when the scheme constantly improved, mainly due to the additional collection points available. The Stochastic Frontier Model allows for the identification of the optimal production function among the 20 Italian regions. The best performing region is Tuscany (in the Centre), followed by Sardinia and Sicily (in the South). PMID- 28579145 TI - How to prepare the patient for robotic surgery: before and during the operation. AB - Robotic surgery in the treatment of gynecologic diseases continues to evolve and has become accepted over the last decade. The advantages of robotic-assisted laparoscopic surgery over conventional laparoscopy are three-dimensional camera vision, superior precision and dexterity with EndoWristed instruments, elimination of operator tremor, and decreased surgeon fatigue. The drawbacks of the technology are bulkiness and lack of tactile feedback. As with other surgical platforms, the limitations of robotic surgery must be understood. Patient selection and the types of surgical procedures that can be performed through the robotic surgical platform are critical to the success of robotic surgery. First, patient selection and the indication for gynecologic disease should be considered. Discussion with the patient regarding the benefits and potential risks of robotic surgery and of complications and alternative treatments is mandatory, followed by patient's signature indicating informed consent. Appropriate preoperative evaluation-including laboratory and imaging tests-and bowel cleansing should be considered depending upon the type of robotic-assisted procedure. Unlike other surgical procedures, robotic surgery is equipment intensive and requires an appropriate surgical suite to accommodate the patient side cart, the vision system, and the surgeon's console. Surgical personnel must be properly trained with the robotics technology. Several factors must be considered to perform a successful robotic-assisted surgery: the indication and type of surgical procedure, the surgical platform, patient position and the degree of Trendelenburg, proper port placement configuration, and appropriate instrumentation. These factors that must be considered so that patients can be appropriately prepared before and during the operation are described. PMID- 28579146 TI - Myelin breakdown in human Huntington's disease: Multi-modal evidence from diffusion MRI and quantitative magnetization transfer. AB - Huntington's disease (HD) leads to white matter (WM) degeneration that may be due to an early breakdown in axon myelination but in vivo imaging correlates of demyelination remain relatively unexplored in HD compared to other neurodegenerative diseases. This study investigated HD-related effects on a putative marker of myelin, the macromolecular proton fraction (MMPF) from quantitative magnetization transfer and on fractional anisotropy, axial and radial diffusivity from diffusion tensor MR-imaging. Microstructural differences were studied in WM pathways of the basal ganglia and motor systems known to be impaired in HD: the corpus callosum, the cortico-spinal tract, the anterior thalamic radiation, fibers between prefrontal cortex and caudate and between supplementary motor area and putamen. Principal component analysis was employed for dimensionality reduction. Patients showed reductions in a component with high loadings on MMPF in all WM pathways and a trend for increases in a component loading on axial and radial diffusivities but no differences in a component loading on fractional anisotropy. While patients' performance in executive functioning was impaired, their working memory span was preserved. Inter individual differences in the diffusivity component correlated with patients' performance in clinical measures of the United Huntington Disease Rating Scale. In summary, HD-related reductions in MMPF suggest that myelin breakdown contributes to WM impairment in human HD and emphasize the potential of quantitative MRI metrics to inform about disease pathogenesis. Disease severity in manifest HD, however, was best captured by non-specific diffusivity metrics sensitive to multiple disease and age-related changes. PMID- 28579147 TI - Retirements and succession of nursing faculty in 2016-2025. AB - BACKGROUND: Faculty retirement has been a growing concern for the nursing education community given the impact it may have on preparing the future nursing workforce. PURPOSE: To estimate faculty retirements in 2016-2015 and to assess the impact of retirements on the faculty workforce. METHOD: The Least-Squares Regression and the Cohort Component Methods were used to project retirements. DISCUSSION: The study projected that total retirements in 2016-2025 would equal one third of faculty in 2015. Retirees are likely to come from current faculty aged 60 or older, and faculty aged 50-59 are likely to be their replacements. The impact of the retiring faculty on the faculty workforce will be huge given their overrepresentation in doctoral attainment, senior rank, and ability for graduate level teaching. CONCLUSION: The findings suggest a sense of urgency for the nursing education community to address the impending exodus of senior faculty and to develop younger faculty for their successful succession. PMID- 28579148 TI - Effect of Time of Administration of Teriparatide on Bone Mineral Density in Glucocorticoid-Induced Osteoporosis. AB - Teriparatide (TPTD) (recombinant DNA origin human parathormone [1-34]) is approved for the treatment of glucocorticoid-induced osteoporosis (GIO). There are reports of factors that affect the response to TPTD in GIO treatment. This work describes the case of a 71-yr-old woman diagnosed with lupus nephropathy treated with 40 mg/d of meprednisone, and who suffered multiple vertebral fractures. Despite treatment with a single 5 mg dose of zoledronic acid, the patient continued to have vertebral fractures. Treatment with 20 ug/d of subcutaneous TPTD (PTH1-34, Forteo; Eli Lilly Co., Indianapolis, IN) was initiated. Nine months after the onset of treatment, bone mineral density (BMD) assessment showed a 5% decrease in lumbar spine BMD. Factors potentially affecting the results were analyzed. The patient reported injecting TPTD at night and was instructed to inject TPTD in the morning before breakfast. After changing the time of TPTD administration and 22 mo after initiating treatment, BMD assessment was repeated and showed an 18% increase at the lumbar spine and no new vertebral fractures. The time of TPTD administration might affect the response to TPTD in GIO treatment. PMID- 28579149 TI - Assessment of dyspnea and dynamic hyperinflation in male patients with chronic obstructive pulmonary disease during a six minute walk test and an incremental treadmill cardiorespiratory exercise test. AB - : The six minute walk test (6MWT) is a standardized test that provides information on exercise capacity in patients with COPD. It is considered a submaximal test in opposition to incremental cardiopulmonary exercise tests (CPET) that provide valuable information on all the systems involved in exercise. OBJECTIVES: 1. To compare the perceptive, physiological responses and degree of dynamic hyperinflation during two exercise tests: the 6MWT and the incremental CPET on a treadmill. 2. To evaluate how dyspnea is related to dynamic hyperinflation (DH) and other functional parameters in both tests. METHODS: 29 stable COPD male patients, age 68+/-5.8 years, mean post-bronchodilator FEV1 57+/ 11%, were recruited. To evaluate dynamic hyperinflation, inspiratory capacity (IC) was measured at rest and upon completing each one of the tests. At the same time, perceived dyspnea and leg discomfort were rated on specific modified Borg scales. RESULTS: The mean walk distance in 6MWT was 494+/-88m. The Borg scale rating for shortness of breath upon completing the test was 4.7+/-2, whilst 2.9+/ 2 for leg discomfort. IC changed from 2.53+/-0.63l before to 2.34+/-0.60l after completion of the test. In the treadmill CPET, maximal oxygen consumption (VO2max) was 21.8+/-5mL/kg/min with 6.6+/-2 dyspnea and 4.3+/-2 leg discomfort on Borg scales. IC changed from 2.17+/-0.53l to 1.20+/-0.43l. CONCLUSIONS: Dynamic hyperinflation occurs in male COPD patients during submaximal exercise such as the 6MWT. This phenomenon is more pronounced after incremental CPET on a treadmill. Despite being dyspnea the dominant limiting symptom for both tests, we observed different physiological responses. PMID- 28579150 TI - Renewed push to strengthen vector control globally. PMID- 28579152 TI - Development of a Spanish Food Exchange List: Application of Statistical Criteria to a Rationale Procedure. PMID- 28579153 TI - Outcomes of external septorhinoplasty in a Turkish male population. AB - INTRODUCTION: The first and one of the most important steps in facial plastic surgery is accurate preoperative facial analysis and recording of data that may help the surgeon to check the outcomes of his/her techniques, promoting a surgeon's professional development. OBJECTIVE: To evaluate the esthetic outcomes of external septorhinoplasty relevant to ethnic facial harmony and to investigate the relationship of the columellar incision scar with the type of skin and columellar incision type in a Turkish population. METHODS: In total, 28 consecutive adult male patients with a mean age of 32.14+/-10.66 years (range: 18 61 years) were included the study. Primary outcomes were preoperative and postoperative photogrammetric facial analyses of the patients including measurement of nasofrontal angle, nasolabial angle and nasal projection ratios (Gode) assessed according to the data derived from the Rhinobase program. Results were compared to facial proportions of the Turkish population. Columellar incision scar scores related to the Fitzpatrick skin type classification of the patients and columellar incision types used for the external approach were secondary outcomes of the study. RESULTS: Mean preoperative and postoperative nasofrontal angles were 148.04 degrees +/-8.18 degrees and 144.50 degrees +/ 7.15 degrees , respectively, while mean preoperative and postoperative nasolabial angles were 87.59 degrees +/-14.01 degrees and 98.50 degrees +/-9.71 degrees , respectively. Mean preoperative and postoperative nasal tip projection ratios were 0.56+/-0.05 and 0.60+/-0.06, respectively. The differences between pre- and postoperative measurements were all significantly different and were in accordance with Turkish nasal harmony. Columellar inverted "V" incisions were performed in 15 (53.6%) patients while "V" incisions were used in 13 (46.4%) patients. Fitzpatrick skin Type 4 was seen in 46.42% of the patients, Fitzpatrick Type 3 in 46.42% and Fitzpatrick Type 2 in 7.14% of the patients. No significant difference was seen between columellar scar scores according to skin type and columellar incision type used for external septorhinoplasty. CONCLUSIONS: This study demonstrated that outcomes for nasofrontal angle, nasolabial angle and nasal tip projection ratios analyzed using the Rhinobase program in patients who underwent external septorhinoplasty were similar to reference values for the Turkish population. PMID- 28579154 TI - The effect of arousal on regulation of negative emotions using cognitive reappraisal: An ERP study. AB - Because the effectiveness of the emotion regulation strategy cognitive reappraisal may vary with emotion intensity, we investigated how stimulus arousal affects reappraisal success. Participants up- and down-regulated emotional responses using cognitive reappraisal to low and high arousing unpleasant pictures while the electroencephalogram (EEG) was recorded. Up-regulation resulted in more negative self-reported valence, while down-regulation resulted in less negative self-reported valence regardless of stimulus arousal, suggesting that subjective reappraisal success does not vary with emotional intensity. Participants felt that down-regulation of emotional responses to low arousing unpleasant pictures was easiest, which is in line with previous findings that participants showed a greater preference for reappraisal in low than high arousing situations. The late positive potential (LPP) amplitude was enhanced by down-regulation of high arousing unpleasant pictures. Even though this effect was unexpected and is opposite to the typical effect of down-regulation on the LPP, it is in line with several previous studies. Potential explanations for LPP regulation effects in the unexpected direction, such as strategy selection and task design, are evaluated. Suggestions and recommendations for future research are discussed, including using trial-by-trial manipulation of regulation instructions and studying the effect of stimulus arousal on up- and down regulation of positive emotions. PMID- 28579155 TI - Corrigendum to "Midwifery continuity of carer in an area of high socio-economic disadvantage in London: A retrospective analysis of Albany Midwifery Practice outcomes using routine data (1997-2009)" [Midwifery 48 (2017) 1-10]. PMID- 28579151 TI - Validation of the Association of RECIST Changes With Survival in Men With Metastatic Castration-Resistant Prostate Cancer Treated on SWOG Study S0421. AB - BACKGROUND: Phase 2 trials evaluating new agents for metastatic castration resistant prostate cancer (mCRPC) have relied on bone scan and prostate-specific antigen changes to assess activity. Given the increasing detection of measurable disease, Response Evaluation Criteria in Solid Tumors (RECIST) changes warrant consideration to evaluate activity. We validated the association of RECIST 1.0 changes with survival in men with mCRPC receiving docetaxel. PATIENTS AND METHODS: Data for men with measurable disease from the Southwest Oncology Group (SWOG) S0421, a phase 3 trial in men with mCRPC receiving docetaxel and prednisone plus placebo or atrasentan, were used. Cox proportional hazards regression was used to evaluate the association of RECIST 1.0 outcomes within 120 days, ie, unconfirmed partial response (uPR), stable disease, and progressive disease (PD), with overall survival (OS) from day 120, adjusted for prognostic factors. RESULTS: Overall, 326 men were evaluable for landmark analysis, of whom 23 had PD, 230 stable disease, and 73 uPR. OS beyond day 120 was significantly different (P = .004) among these subgroups, with median (95% confidence interval) OS of 7.1 (3.5-8.8), 13.4 (11.4-15.6), and 16.3 (10.0-19.6) months for those with PD, stable disease, and uPR, respectively. In a multivariable model, the hazard ratio (95% confidence interval) for patients with PD was 2.47 (1.42-4.29) compared to patients with an uPR (P = .002). CONCLUSION: The association of RECIST 1.0 changes with OS in men with mCRPC receiving docetaxel was validated. Given limitations of bone scan and prostate-specific antigen alterations, improvements in objective RECIST 1.0 changes should be reported in phase 2 trials before launching phase 3 trials. PMID- 28579156 TI - The type 2 diabetes susceptibility TCF7L2 gene variants affect postprandial glucose and fat utilization in non-diabetic subjects. PMID- 28579158 TI - Protective Strategies Against Dysphonia in Teachers: Preliminary Results Comparing Voice Amplification and 0.9% NaCl Nebulization. AB - OBJECTIVE: This study aimed to compare the effects of two protective strategies, voice amplification (VA) and 0.9% NaCl nebulization (NEB), on teachers' voice in the work setting. METHODS: An interventional evaluator-blind study was conducted, assigning 53 teachers from two public high schools to one of the two protective strategy groups (VA or NEB). Vocal function was assessed in a sound-treated booth before and after a 4-week period. Assessment included the severity of voice impairment (Consensus Auditory-Perceptual Evaluation of Voice [CAPE-V]), acoustic analysis of fundamental frequency (f0), sound pressure level (SPL), jitter, shimmer, glottal-to-noise excitation ratio (GNE), noise (VoxMetria), and the self rated Screening Index for Voice Disorder (SIVD). Data were statistically analyzed using SPSS Statistics (version 22) with a significance level of P <= 0.05. Effect size was calculated using Cohen's d coefficient. RESULTS: There were no statistical differences between groups at baseline in terms of age, sex, time of teaching, teaching workload, and voice outcomes, except for SPL. During postintervention between groups, NEB displayed lower SIVD scores (VA = 3; NEB = 0; P = 0.018) and VA had lower acoustic irregularity (VA = 3.19; NEB = 3.69; P = 0.027), with moderate to large effect size. Postintervention within-groups decreased CAPE-V for VA (pretest = 31.97; posttest = 28.24; P = 0.021) and SIVD for NEB (pretest = 3; posttest = 0; P = 0.001). SPL decreased in both groups, NEB decreased in men only, and VA decreased in both men and women. NEB increased f0 for female participants (P <= 0.001). CONCLUSION: Both VA and NEB may help mitigate dysphonia in different pathways, being potential interventions for protecting teachers' voices in the work setting. An ongoing study with a control group will further support these preliminary results. PMID- 28579157 TI - Compound mechanism of fatal neck injury: A case report of a tiger attack in a zoo. AB - Fatal injuries caused by attacks by large wild cats are extremely rare in forensic medical practice in Europe. There are very few cases described in the forensic medical literature concerning incidents in zoos similar to the tiger attack on a 58-year-old male zoo employee that we present here. While preparing a runway for tigers, the man was attacked by a male Sumatran tiger. Another zoo employee was an eyewitness to the accident; in his testimony he described the sequence of events in detail. The autopsy showed the injuries typical of a tiger attack: traces of claws and canine teeth indicating that the victim of the attack was knocked down from behind, along with deep and extensive fatal wounds to the neck. The injuries were inflicted by means of a compound mechanism: tissues were penetrated by the animal's canines, crushed with great force (transfixing injury), and violently distended. The skin revealed four characteristic deep wounds caused by canines as well as bite marks resulting from the action of six incisors. The neck area revealed extensive damage, including torn muscles, the esophagus and trachea, large blood vessels of the neck, and fractures of vertebrae C2 and C5 with internal channels resulting directly from penetration by the animal's canines. The mechanism of distension, as a result of the animal jerking its head after biting the victim in the neck, produced a complete tear of the spine and the vertebral arteries, as well as an intramural rupture of the carotid arteries which has never been described before. In the interests of a detailed assessment of bone damage, the cervical spine was macerated. The applied autopsy techniques and detailed analysis of injuries enabled us to demonstrate the compound mechanism that inflicted them, combining penetration of tissues by the canines, crushing, and distension. PMID- 28579159 TI - Comparison of Effects Produced by Physiological Versus Traditional Vocal Warm-up in Contemporary Commercial Music Singers. AB - PURPOSE: The present study aimed to observe whether physiological warm-up and traditional singing warm-up differently affect aerodynamic, electroglottographic, acoustic, and self-perceived parameters of voice in Contemporary Commercial Music singers. METHODS: Thirty subjects were asked to perform a 15-minute session of vocal warm-up. They were randomly assigned to one of two types of vocal warm-up: physiological (based on semi-occluded exercises) or traditional (singing warm-up based on open vowel [a:]). Aerodynamic, electroglottographic, acoustic, and self perceived voice quality assessments were carried out before (pre) and after (post) warm-up. RESULTS: No significant differences were found when comparing both types of vocal warm-up methods, either in subjective or in objective measures. Furthermore, the main positive effect observed in both groups when comparing pre and post conditions was a better self-reported quality of voice. Additionally, significant differences were observed for sound pressure level (decrease), glottal airflow (increase), and aerodynamic efficiency (decrease) in the traditional warm-up group. CONCLUSION: Both traditional and physiological warm-ups produce favorable voice sensations. Moreover, there are no evident differences in aerodynamic and electroglottographic variables when comparing both types of vocal warm-ups. Some changes after traditional warm-up (decreased intensity, increased airflow, and decreased aerodynamic efficiency) could imply an early stage of vocal fatigue. PMID- 28579160 TI - Complex Energy Metabolic Changes in Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction. AB - Alterations in cardiac energy metabolism contribute to the severity of heart failure. However, the energy metabolic changes that occur in heart failure are complex, and are dependent not only on the severity and type of heart failure present, but also on the coexistence of common comorbidities such as obesity and type 2 diabetes. In this article we review the cardiac energy metabolic changes that occur in heart failure. An emphasis is made on distinguishing the differences in cardiac energy metabolism between heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) and in clarifying the common misconceptions surrounding the fate of fatty acids and glucose in the failing heart. The major key points from this article are: (1) mitochondrial oxidative capacity is reduced in HFpEF and HFrEF; (2) fatty acid oxidation is increased in HFpEF and reduced in HFrEF (however, oxidative metabolism of fatty acids in HFrEF still exceeds that of glucose); (3) glucose oxidation is decreased in HFpEF and HFrEF; (4) there is an uncoupling between glucose uptake and oxidation in HFpEF and HFrEF, resulting in an increased rate of glycolysis; (5) ketone body oxidation is increased in HFrEF, which might further reduce fatty acid and glucose oxidation; and finally, (6) branched chain amino acid oxidation is impaired in HFrEF. The understanding of these changes in cardiac energy metabolism in heart failure are essential to allow the development of metabolic modulators in the treatment of heart failure. PMID- 28579162 TI - Extended Bridge to Heart and Lung Transplantation Using Pumpless Extracorporeal Lung Assist. AB - In end-stage idiopathic pulmonary artery hypertension (iPAH), centrally cannulated Novalung (Novalung GmbH, Hechingen, Germany) pumpless extracorporeal lung assist (pECLA) decompresses the pulmonary artery for bridge to transplantation. We report placing a 45-year-old man with end-stage iPAH and right heart failure on centrally cannulated pECLA for 82 days as a bridge to heart and double-lung transplantation (HLTx). To our knowledge, this is the longest reported bridge to transplantation in Canada and the first successful bridge to HLTx. We demonstrate how pECLA permits mobility, facilitating physiotherapy to ensure fitness for transplantation. Considering the irreversible right heart failure, HLTx remains suitable in iPAH. PMID- 28579161 TI - Late Self-Apposition With One-Year Persisting Uncoverage of Malapposed Bioresorbable Polymeric Struts. PMID- 28579163 TI - Use of Two-Dimensional Ultrasonographically Guided Access to Reduce Access Related Complications for Transcatheter Aortic Valve Replacement. AB - BACKGROUND: Major vascular complications have been associated with increased mortality and morbidity in patients undergoing transcatheter aortic valve replacement (TAVR). Our objective was to compare vascular and bleeding outcomes with the routine use of 2-dimensional ultrasonography (2D-US) guided femoral artery access in percutaneous transfemoral TAVR compared with traditional anatomic landmark palpation with angiographically-guided access. METHODS: This single-centre retrospective cohort study was conducted in Ontario, Canada. We enrolled patients from January 1, 2012-June 30, 2016. Routine 2D-US was used in all transfemoral TAVR after January 1, 2014; before this, all cases were performed with angiographic guidance alone. RESULTS: The primary outcome of interest was the composite of any access-related red blood cell transfusion or vascular/bleeding complications. Definitions were based on the Valve Academic Research Consortium (VARC-2) criteria. Fully adjusted multivariable regression models were developed to determine the impact of 2D-US. The study cohort included 387 patients, 109 (28%) of whom underwent femoral artery puncture guided by anatomic and angiographic landmarks, whereas 278 (72%) patients had 2D-US guidance. After adjusting for baseline differences in our multivariable models, we found that 2D-US-guided access was associated with an odds ratio of 0.42 (95% confidence interval, 0.25-0.70; P < 0.01) for the composite end point of access related vascular or bleeding complications and red blood cell transfusion. CONCLUSIONS: The routine use of 2D-US in transfemoral TAVR was associated with substantial reductions in access-related vascular and bleeding complications. PMID- 28579164 TI - Impact of strut thickness on acute mechanical performance: A comparison study using optical coherence tomography between DESolve 150 and DESolve 100. AB - OBJECTIVE: To evaluate the acute performance of a novolimus-eluting bioresorbable scaffold (BRS) with different strut thickness (DESolve system 150 and 100) using optical coherence tomography (OCT) in terms of appropriate scaffold deployment. BACKGROUND: Outcome after BRS implantation seen in registries and meta-analyses continue to show a higher rate of scaffold thrombosis than those reported with DES. Thus, second scaffold generations with lower strut thickness might have potential advantages in terms of flow disturbance. However, whether mechanical properties are comparable has to be evaluated. METHODS AND RESULTS: Fifty-seven patients undergoing OCT-guided scaffold implantation were enrolled consecutively in this retrospective study. The final pullback after DESolve 150 (n=42) and DESolve 100 (n=15) were compared. The following indices were calculated: mean and minimum area, residual area stenosis, incomplete strut apposition, tissue prolapse, eccentricity and symmetry indexes, strut fracture, and edge dissection. Most patients suffered a multi vessel disease. Maximum pre-dilatation balloon inflation pressure was 13.5+/-3.2 vs 14.5+/-2.5atm. OCT analysis showed a minimal lumen area of 6.1+/-1.9 vs 5.2+/-1.6mm2, p=0.06. Mean residual area stenosis was 15.3% vs 21.3, p=0.22. Mean eccentricity index did not differ significantly (0.8+/-0.1 vs 0.6+/-0.1, p=0.61). Prolapse area was 4.5+/-8.8 vs 5.6+/-9.8mm2. CONCLUSION: OCT showed similar post-procedural scaffold geometry and outcome indicating that both BRS may be implanted with good acute performance. However, the trend towards a smaller MLA and a higher percentage of RAS suggest a decreased radial strength for the 100MUm BRS. The attempt to reduce strut thickness should not result in loss of radial strength. CONDENSED ABSTRACT: Rates of scaffold thrombosis after bioresorbable scaffold (BRS) implantation are reported to be higher than after metallic stent (DES) implantation. Thus, second scaffold generations with lower strut thickness might have potential advantages in terms of flow disturbance. We aimed to evaluate the acute performance of a novolimus-eluting BRS with different strut thickness (DESolve system 150 and 100) using optical coherence tomography (OCT) in terms of appropriate scaffold deployment. OCT showed similar post-procedural scaffold geometry and outcome indicating that both BRS may be implanted with good acute performance. However, the data suggest a decreased radial strength for the 100MUm BRS. PMID- 28579165 TI - Independent influences of excessive body weight and elevated blood pressure from childhood on left ventricular geometric remodeling in adulthood. AB - BACKGROUND: Obesity and hypertension are two risk factors of left ventricular hypertrophy (LVH) in adults. We aimed to examine the impacts of body weight and blood pressure (BP) from childhood on adult LV geometric remodeling. METHODS: The study cohort consisted of 1256 adults aged 27-42years who had 2-10 measurements of body mass index (BMI) and BP from childhood in 1987 to adulthood in 2010. We calculated the cumulative and incremental values of BMI and BP from childhood to adulthood. In adulthood, four LV geometric patterns were defined based on the values of left ventricular mass index (g/m2.7) and relative wall thickness: normal geometry, concentric remodeling (CR), eccentric hypertrophy (EH) and concentric hypertrophy (CH). RESULTS: The prevalence of abnormal LV geometric patterns in adults was 26.4% for CR, 2.0% for EH and 2.5% for CH. For childhood values, systolic BP (Odds Ratio [OR]=1.26, 95% confidence interval [CI]=1.08 1.47) but not BMI (OR=1.06, 95%CI=0.93-1.18) was associated with adult CR, whereas BMI (OR=3.53, 95%CI=2.09-5.98) but not systolic BP (OR=1.04, 95%CI=0.65 1.66) was associated with adult EH. Both childhood BMI (OR=2.69, 95%CI=1.77-4.09) and systolic BP (OR=1.64, 95%CI=1.07-2.51) were independently associated with adult CH. For adulthood, cumulative and incremental values, BMI and systolic BP were independently associated with adult CR, EH and CH. CONCLUSION: Excessive body weight and elevated BP from childhood have independent influences on the development of adult LV geometric remodeling. PMID- 28579166 TI - Transfemoral aortic valve implantation using a self-expanding transcatheter heart valve without pre-dilation. AB - BACKGROUND: The aim of the present study was to investigate whether transfemoral implantation of the Acurate neo transcatheter heart valve without pre-dilation is feasible. METHODS: Between December 2014 and December 2016, 294 patients were treated with the Acurate neo prosthesis at our center. Of these, 72 cases were performed without pre-dilation. The decision to omit pre-dilation was at the discretion of the operator, preferably in the case of mild to moderate aortic valve calcification (AVC). Propensity matching (1:1) resulted in 48 cases in each group. Main outcomes of interest were device success according to VARC-2 criteria, residual aortic regurgitation (AR) >= 2 degrees , and rate of post dilation. RESULTS: Median [IQR] age in patients without pre-dilation was 82.7 years [78.6-85.6], STS score was 4.6% [3.4-6.1], and AVC-score was 1436 AU [1043 1682] with mild and moderate AVC in 63.9% and 36.1% of cases, respectively. Device success was achieved in 94.4% of cases, post-dilation was necessary in 26.4%, and one (1.4%) patient had moderate AR. In the matched population, there were no differences regarding device success, rate of AR >= 2 degrees , need for post-dilation, and post-procedural mean gradient, but the group without pre dilation had shorter procedure (34.0 min [27.0-38.8] vs. 43.0 min [34.3-52.0]; p < 0.001) and fluoroscopy times (7.4 min [5.7-9.0] vs. 9.9 min [7.9-13.5]; p < 0.001). CONCLUSION: In select patients with mild to moderate AVC, transfemoral implantation of the Acurate neo without pre-dilation is feasible and safe. This allows for a straightforward procedure that may be performed without rapid pacing in the majority of cases. PMID- 28579167 TI - Risk and predictors of readmission for heart failure following a myocardial infarction between 2004 and 2013: A Swedish nationwide observational study. AB - BACKGROUND: Data are scarce regarding the risk, temporal trends and predictors of late-onset heart failure (LOHF) after acute myocardial infarction (AMI). We aimed at studying the risk and predictors of LOHF and the composite event of LOHF or death after AMI. METHODS: AMI patients first entered in the nationwide SWEDEHEART registry between 2004 and 2013 were included. Patients with a prior history of heart failure (HF) and those who died in-hospital were excluded. Dates and ICD codes for LOHF in the national patient and death registries were used to determine time to first readmission due to LOHF and/or death. RESULTS: A total of 150,566 AMI patients were included in the analysis. The 1-year, 2-year and 5-year cumulative risk of developing LOHF were 11.4%, 14.6% and 21.8% respectively. The risk of LOHF within 2years decreased from 15.5% to 14.4% (2004-2005 vs 2010 2011), p<0.001. Calendar year was protective of LOHF/death after adjustment (HR 0.96, 95% CI 0.94-0.98, p<0.001). In-hospital HF, age, diabetes mellitus, chronic kidney disease, peripheral arterial disease, chronic obstructive pulmonary disease and atrial fibrillation, were strong predictors of LOHF. Risk profile improved and use of evidence based therapies increased during the time period. CONCLUSIONS: Survivors of AMI remain at a continued risk of LOHF. However, the overall risk of LOHF shows a decreasing trend after an index AMI over time. Lower risk of LOHF may relate to decreasing burden of comorbidities and increasing use of evidence based treatments. PMID- 28579169 TI - Corrigendum to "Transcription factor Reb1 is required for proper transcriptional start site usage at the divergently transcribed TFC6-ESC2 locus in Saccharomyces cerevisiae" [Gene 594 (2016) 108-116]. PMID- 28579168 TI - Drug-coated versus bare-metal stents for elderly patients: A predefined sub-study of the LEADERS FREE trial. AB - BACKGROUND: The randomized, LEADERS FREE trial showed superior safety and efficacy of a polymer-free DCS vs. a bare metal stent in high-bleeding risk patients with only one month dual antiplatelet treatment. We report characteristics and outcomes of the pre-specified group of elderly patients (aged >=75). METHODS: Age >75 was one of the trial's inclusion criteria. The main additional criteria were: need for oral anticoagulants, recent bleeding, anemia, chronic renal failure and cancer. All patients received 1month DAPT only. Both primary endpoints (efficacy: clinically driven TLR and safety: composite of cardiac death, MI and stent thrombosis) as well as bleeding were recorded up to 390days. RESULTS: 1564 elderly patients (63.4% of the population) were enrolled with a mean of 2 inclusion criteria/patient. The primary safety endpoint was reached less frequently in DCS than BMS patients (10.7 vs. 14.3%, p=0.03), as was the primary efficacy endpoint (5.8 vs. 10.8% p=0.0003). Major bleeding rates were high and similar in both groups (7.3 vs. 8.2%, p=0.55). For the 562 (23.4%) patients with age as sole entry criterion, trends were similar for DCS and BMS patients respectively: safety endpoint (7.3%vs.11.4% p=0.10) and Cd TLR (4.7 vs. 13.2% p=0.0003), but for both groups, major bleeding occurred less frequently than for elderly patients with more comorbid conditions (3.6%vs. 2.8%). CONCLUSION: Compared to a BMS, use of a DCS together with a short one-month DAPT course was associated with significant safety and efficacy benefits for the elderly patients enrolled in LEADERS FREE. PMID- 28579170 TI - Vaccination coverage in a cohort of HIV-infected patients receiving care at an AIDS outpatient clinic in Espirito Santo, Brazil. AB - This cross-sectional study assessed the immunization status of human immune deficiency virus (HIV)-infected patients receiving care at an outpatient clinic in Brazil. The sociodemographic characteristics, CD4 count and HIV viral load of 281 out of 612 adult outpatients were analyzed. A total of 331 patients were excluded because of no availability of vaccination cards. Chi-square or Fisher's exact test were used. Immunization coverage was higher for diphtheria/tetanus (59.79%) and hepatitis B (56.7%), and lowest for hepatitis A (6.8%) and for meningococcal group C (6%). Only 11.74% of the patients had received the influenza virus vaccine yearly since their HIV-infection diagnosis. No vaccination against influenza (p<0.034) or hepatitis B (p<0.029) were associated with CD4 counts <500cells/mL; no vaccination against flu or pneumococcus were associated with detectable HIV viral load (p<0.049 and p<0.002, respectively). Immunization coverage is still very low among HIV-infected adults in this setting despite recommendations and high infection-related mortality. PMID- 28579171 TI - The NDR/LATS protein kinases in immunology and cancer biology. AB - The NDR (nuclear Dbf2-related)/LATS (large tumour suppressor) family of kinases represents a subclass of the AGC (protein kinase A (PKA)/PKG/PKC-like) group of serine/threonine protein kinases. Members of the NDR/LATS family are vital components of conserved pathways controlling essential cellular processes, such as proliferation (cell cycle progression) and cell death. In particular, the central involvement of NDR/LATS as YAP/TAZ kinases in the Hippo tissue growth control pathway has gained much interest. In this review, we summarise the roles of mammalian NDR1/2 (aka STK38/STK38L) and LATS1/2 in immunity and cancer biology. We also discuss the activation mechanisms of NDR/LATS involving Ste20 like kinases and the MOB1 signal transducer, followed by an overview of NDR/LATS knockout mouse models. We further review the mutation and expression status of NDR/LATS in human cancers and their possible predictive and/or prognostic value in cancer treatment. PMID- 28579172 TI - Techno-economic analysis of glucosamine and lipid production from marine diatom Cyclotella sp. AB - A techno-economic analysis (TEA) was performed on glucosamine and lipid production from a marine diatom Cyclotella sp. in raceway open pond (RWP) and tubular photobioreactor (PBR) cultivation systems. Two PBR operating schemes were assessed: one to produce high lipid (HL) content, and another to produce high chitin (HC) content. In order to generate 1kg of glucosamine, 9700kg (RWP)/1050kg (PBR HL) freshwater, 40kg CO2, 0.70kg nitrogen, 0.18kg phosphorus, and 1.2kg silicon nutrients are required for algae cultivation with water and nutrient recovery. With a price of $1.5 for lipid as coproduct, the projected selling price of glucosamine were $35/kg, $106/kg and $82/kg for RWP, PBR HL, and PBR HC systems, respectively. Currently, these prices are not competitive with industrial shellfish-derived glucosamine, but can be reduced by technology improvements such as producing food grade lipid, increasing algal productivity or chitin content. PMID- 28579173 TI - Current status on metabolic engineering for the production of l-aspartate family amino acids and derivatives. AB - The l-aspartate amino acids (AFAAs) are constituted of l-aspartate, l-lysine, l methionine, l-threonine and l-isoleucine. Except for l-aspartate, AFAAs are essential amino acids that cannot be synthesized by humans and most farm animals, and thus possess wide applications in food, animal feed, pharmaceutical and cosmetics industries. To date, a number of amino acids, including AFAAs have been industrially produced by microbial fermentation. However, the overall metabolic and regulatory mechanisms of the synthesis of AFAAs and the recent progress on strain construction have rarely been reviewed. Aiming to promote the establishment of strains of Corynebacterium glutamicum and Escherichia coli, the two industrial amino acids producing bacteria, that are capable of producing high titers of AFAAs and derivatives, this paper systematically summarizes the current progress on metabolic engineering manipulations in both central metabolic pathways and AFAA synthesis pathways based on the category of the five-word strain breeding strategies: enter, flow, moderate, block and exit. PMID- 28579174 TI - Production of 5-aminovaleric acid in recombinant Corynebacterium glutamicum strains from a Miscanthus hydrolysate solution prepared by a newly developed Miscanthus hydrolysis process. AB - This study examined nine expired industrial Corynebacterium glutamicum strains with high lysine producing capability for enhanced production of 5-AVA. C. glutamicum KCTC 1857 exhibiting the highest lysine production was transformed with either original Pseudomonas putida davBA genes, encoding the 5-AVA biosynthesis pathway, or C. glutamicum codon-optimized davBA genes. C. glutamicum KCTC 1857 expressing the original genes had superior cell viability and 5-AVA production capability compared to the other strain. This strain produced 39.93g/L of 5-AVA, which is the highest titer reported to date in fed-batch fermentation from glucose. Indeed, Miscanthus hydrolysate solution prepared from a novel process, comprising pretreatment, hydrolysis, purification, and concentration, was used as feedstock for 5-AVA production. A total of 12.51g/L 5-AVA was produced from the Miscanthus hydrolysate; this value is 34.7% higher than that obtained from glucose in batch fermentation. PMID- 28579175 TI - An exopolysaccharide (EPS) from a Lactobacillus plantarum BR2 with potential benefits for making functional foods. AB - A high molecular weight EPS of glucomannan nature was recovered and purified to get an yield of 2.8+/-0.5g/L from Lb. plantarum BR2 and it displayed potent antioxidant activity with 29.8% radical scavenging activity and 19% total antioxidant capacity. At 100ug/ml concentration, it is capable of inhibiting the alpha amylase activity by 10% and at 300ug/ml, it drastically inhibited the alpha glucosidase activity by 67% which indicates its antidiabetic potential. More interestingly, at a concentration level of 0.1%, it reduced the cholesterol level by a margin of 45% in an in vitro assay. The sample didn't reveal any cytotoxicity against H9C2 normal cells indicating its potential for safe use as a food additive. PMID- 28579176 TI - Comparative cradle-to-grave life cycle assessment of biogas production from marine algae and cattle manure biorefineries. AB - The environmental impacts resulting from the cradle-to-grave life cycles of Enteromorpha prolifera macroalgae and cattle manure biorefineries are assessed and compared. Sensitivity analysis is carried out to evaluate the response of the impacts to changes in biogas application by using Simapro 7.3.3. Three scenarios are considered in the biorefineries. In the first and second scenarios, the biogas produced is considered to be used for electricity production and transportation, respectively. In the third scenario, the biogas is considered to be recycled back to the systems. Process energy requirements and transportation of inputs contribute the largest share of the overall impacts. The cattle manure biorefinery is slightly more eco-friendly than the macroalgae biorefinery in Scenarios 1 and 2 because it requires more eco-friendly inputs. However, the macroalgae biorefinery becomes more eco-friendly than the cattle manure biorefinery in Scenario 3 because macroalgae require less energy and water for biogas production. PMID- 28579177 TI - Greenhouse gas emissions and the links to plant performance in a fixed-film activated sludge membrane bioreactor - Pilot plant experimental evidence. AB - The present study explores the interlinkages among the operational variables of a University of Cape Town (UCT) Integrated Fixed Film Activated Sludge (IFAS) membrane bioreactor (MBR) pilot plant. Specifically, dedicated experimental tests were carried out with the final aim to find-out a constitutive relationship among operational costs (OCs), effluent quality index (EQI), effluent fines (EF). Greenhouse gas (GHG) emissions were also included in the study. Results showed that the EQI increases at low flow rate likely due to the dissolved oxygen (DO) limitation in the biological processes. Direct GHGs increase with the increasing of the air flow due to the anoxic N2O contribution. Irreversible membrane fouling reduce from 98% to 85% at the air flow rate of 0.57m3h-1 and 2.56m3h-1, respectively. However, the increase of the air flow rate leads to the increase of the N2O-N flux emitted from the MBR (from 40% to 80%). PMID- 28579178 TI - Waste biorefineries: Enabling circular economies in developing countries. AB - This paper aims to examine the potential of waste biorefineries in developing countries as a solution to current waste disposal problems and as facilities to produce fuels, power, heat, and value-added products. The waste in developing countries represents a significant source of biomass, recycled materials, chemicals, energy, and revenue if wisely managed and used as a potential feedstock in various biorefinery technologies such as fermentation, anaerobic digestion (AD), pyrolysis, incineration, and gasification. However, the selection or integration of biorefinery technologies in any developing country should be based on its waste characterization. Waste biorefineries if developed in developing countries could provide energy generation, land savings, new businesses and consequent job creation, savings of landfills costs, GHG emissions reduction, and savings of natural resources of land, soil, and groundwater. The challenges in route to successful implementation of biorefinery concept in the developing countries are also presented using life cycle assessment (LCA) studies. PMID- 28579179 TI - Commentary: Cubital tunnel syndrome caused by intraneural or extraneural ganglion cysts-case report and review of the literature: Ulnar nerve ganglion cysts: Drawing closer to shore. PMID- 28579180 TI - Endoscopic DIEP flap dissection (eDIEP): An experimental cadaveric study. PMID- 28579182 TI - Acute Pancreatitis Has a Long-term Deleterious Effect on Physical Health Related Quality of Life. AB - BACKGROUND & AIMS: It is not clear how acute pancreatitis (AP) affects health related quality of life (HRQOL). We aimed to determine the long-term independent effect of AP on physical and mental HRQOL. METHODS: We analyzed data from 91 patients (mean 52 years of age, 54% women) admitted with AP to the University of Pittsburgh Medical Center from 2011 to 2015 who responded to telephone surveys at a median of 14 months after hospital discharge (interquartile range, 12-16 months). Individuals who did not answer the telephone survey were sent a questionnaire by regular mail. Patients answered questions from the 12-Item Short Form Survey, and answers were used to calculate mental component summary (MCS) and physical component summary (PCS) scores with norm-based scoring (normal >=50). HRQOL for these subjects was compared with that of age- and sex-matched individuals without pancreatitis (1:2) identified from the North American Pancreatitis Study. We controlled for other covariates using multivariable regression analysis. RESULTS: At follow-up, individuals with AP had a significantly lower PCS score (46.2 +/- 11.8) than did control subjects (51.1 +/- 9.5; P < .01), but a similar MCS score. A 4-point reduction of the PCS was attributed to AP after controlling for sociodemographic factors and medical comorbidities. The only pancreatitis-related factor associated with low PCS score was multisystem organ failure. Presence of abdominal pain, analgesic use, disability, and current smoking at the time of follow-up were also associated with lower PCS scores. Etiology of AP, disease severity (by Revised Atlanta classification), use of nutritional support, and performance of pancreatic interventions did not affect HRQOL at follow-up. CONCLUSIONS: In a 14-month follow-up of patients hospitalized with AP, we found a meaningful, independent, and deleterious effect of AP in the physical HRQOL of these patients, compared to individuals without AP. Further research is needed to determine the duration of this impairment and to evaluate the effects of modifying risk factors. PMID- 28579181 TI - Estrogen Replacement Reduces Risk and Increases Survival Times of Women With Hepatocellular Carcinoma. AB - BACKGROUND & AIMS: Environmental factors have been identified that affect risk of hepatocellular carcinoma (HCC), but little is known about the effects of sex hormones on liver cancer development or outcome. The authors investigated whether menopause hormone therapy (MHT) affects risk, age at onset, or outcome of HCC. METHODS: We performed a case-control study of 234 female patients treated for HCC at a tertiary medical center and with 282 healthy women (controls) from January 1, 2004 through May 31, 2015. We collected detailed information on environmental exposures, ages of menarche and menopause, hysterectomies, and uses of birth control and MHT. We performed multivariable logistic and Cox regression analyses to determine the independent effects of factors associated with women on risk and clinical outcome in HCC. The primary outcomes were effect of MHT on HCC risk, the relationship between MHT with hepatitis virus infection on HCC development, and effect of MHT on age at HCC onset or survival after diagnosis of HCC. RESULTS: The estimated adjusted odds ratio (AOR) for HCC in women who ever used estrogen was 0.53 (95% confidence interval [CI], 0.32-0.88). This association was supported by the older age of HCC onset among estrogen users (mean, 64.5 +/- 0.9 years) vs nonusers (mean 59.2 +/- 1.1 years; P = .001) and the reduced risk of HCC among long-term users (more than 5 years) (AOR, 0.36; 95% CI, 0.20-0.63). Users of estrogen also had a reduced risk for hepatitis-associated HCC: AOR for users, 4.37 (95% CI, 1.67-11.44) vs AOR for nonusers, 17.60 (95% CI, 3.88-79.83). Estrogen use reduced risk of death from HCC (hazard ratio, 0.55; 95% CI, 0.40 0.77; P = .01). Median overall survival times were 33.5 months for estrogen users (95% CI, 25.7-41.3 months) and 24.1 months for nonusers (95% CI, 19.02-29.30 months; P = .008). CONCLUSION: In a case-control study of women with HCC vs female control subjects at a single center, we associated use of estrogen MHT with reduced risk of HCC and increased overall survival times of patients with HCC. Further studies are needed to determine the benefits of estrogen therapy for women and patients with HCC, and effects of tumor expression of estrogen receptor. PMID- 28579183 TI - Confluence of Epidemics of Hepatitis C, Diabetes, Obesity, and Chronic Kidney Disease in the United States Population. AB - BACKGROUND & AIMS: Obesity, kidney disease, and diabetes are common conditions that can affect outcomes of patients with chronic hepatitis C. The authors aimed to quantify the burden of these comorbid conditions among adults with chronic hepatitis C in the United States and to estimate the risk of death among people with chronic hepatitis C and comorbidities. METHODS: The authors conducted cross sectional and prospective analyses of 13,726 participants in the third National Health and Nutrition Examination Survey (NHANES III) and 23,691 participants of NHANES 1999-2012. Serum samples were analyzed for the presence of antibodies to hepatitis C virus (anti-HCV); in samples found to be positive for anti-HCV, the authors quantified HCV RNA (viral load). Individuals with anti-HCV and detectable HCV RNA were considered to have chronic hepatitis C. Comorbidities were defined using self-reported, physical examination, and laboratory data, as available. The authors used logistic models and predictive margins to estimate the adjusted prevalence of comorbidities in patients with chronic hepatitis C. The authors used Poisson regression models to estimate adjusted mortality rates based on chronic hepatitis C status, with or without comorbidities. Cox proportional hazards regression models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause, cardiovascular, and cancer mortality according to chronic hepatitis C status, with and without comorbidities. RESULTS: Among persons with chronic hepatitis C, the demographic-adjusted prevalence estimate of diabetes was 17.9% (95% CI, 11.2%-27.5%) and of obesity was 20.9% (95% CI, 12.4%-29.5%). Overall, 69.6% of persons with chronic hepatitis C had at least 1 major cardiometabolic comorbidity (95% CI, 62.1%-76.2%). Only 38% of adults with chronic hepatitis C reported a diagnosis of liver disease. Chronic hepatitis C was associated with a substantially increased risk of death (HR, 2.45), especially in the presence of diabetes (HR, 3.24) or chronic kidney disease (HR, 4.39). CONCLUSION: In an analysis of NHANES data, the authors found that individuals with chronic hepatitis C have a high burden of major cardiometabolic comorbidities. Diabetes and chronic kidney disease, in particular, are associated with substantial excess mortality in persons with chronic hepatitis C. PMID- 28579184 TI - Response from the author on "An Intervention to Improve the Catheter Associated Urinary Tract Infection Rate in a Medical Intensive Care Unit: Direct Observation of Catheter Insertion Procedure". PMID- 28579185 TI - Are dietary reports in a case-control study on thyroid cancer biased by risk perception of Chernobyl fallout? AB - BACKGROUND: In retrospective case-control studies performed following nuclear tests or nuclear accidents, individual thyroid radiation dose reconstructions are based on fallout and meteorological data from the residential area, demographic characteristics, and lifestyle as well as dietary information. Collecting the latter is a controversial step, as dietary declarations may be affected by the subjects' beliefs about their risk behavior. This report analyses the potential for such bias in a case-control study performed in eastern France. METHODS: The study included 765 cases of differentiated thyroid carcinoma matched with 831 controls. Risk perceptions and beliefs of cases and controls were compared using Chi2 tests and differences in dietary reports were analyzed using a two-way ANOVA. RESULTS: In general, atmospheric pollution and living near a nuclear power plant were the two major risks that may influence thyroid cancer occurrence cited by cases and controls. When focusing in particular on the consequences of the Chernobyl accident, cases were more likely to think that the consequences were responsible for thyroid cancer occurrence than controls. Vegetable consumption during the two months after the Chernobyl accident was correlated with the status of subjects, but not to their beliefs. Conversely, consumption of fresh dairy products was not correlated with the status or beliefs of subjects. CONCLUSION: We found no evidence of systematic bias in dietary reports according to the status or beliefs held by subjects about the link between thyroid cancer occurrence and Chernobyl fallout. As such, these dietary reports may be used in further studies involving individual dosimetric reconstructions. PMID- 28579186 TI - Endocannabinoid modulation of homeostatic and non-homeostatic feeding circuits. AB - The endocannabinoid system has emerged as a key player in the control of eating. Endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide (AEA), modulate neuronal activity via cannabinoid 1 receptors (CB1Rs) in multiple nuclei of the hypothalamus to induce or inhibit food intake depending on nutritional and hormonal status, suggesting that endocannabinoids may act in the hypothalamus to integrate different types of signals informing about the animal's energy needs. In the mesocorticolimbic system, (endo)cannabinoids modulate synaptic transmission to promote dopamine release in response to palatable food. In addition, (endo)cannabinoids act within the nucleus accumbens to increase food's hedonic impact; although this effect depends on activation of CB1Rs at excitatory, but not inhibitory inputs in the nucleus accumbens. While hyperactivation of the endocannabinoid system is typically associated with overeating and obesity, much evidence has emerged in recent years suggesting a more complicated system than first thought - endocannabinoids promote or suppress feeding depending on cell and input type, or modulation by various neuronal or hormonal signals. This review presents our latest knowledge of the endocannabinoid system in non-homeostatic and homeostatic feeding circuits. In particular, we discuss the functional role and cellular mechanism of action by endocannabinoids within the hypothalamus and mesocorticolimbic system, and how these are modulated by neuropeptide signals related to feeding. In light of recent advances and complexity in the field, we review cannabinoid-based therapeutic strategies for the treatment of obesity and how peripheral restriction of CB1R antagonists may provide a different mechanism of weight loss without the central adverse effects. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". PMID- 28579188 TI - Effects of Histamine 2-receptor Antagonists and Proton Pump Inhibitors on the Pharmacokinetics of Gefitinib in Patients With Non-small-cell Lung Cancer. AB - INTRODUCTION: In this study, we investigated the degree of drug interactions between gefitinib and gastric acid suppressants (ie, histamine 2-receptor antagonists [H2RAs] or proton pump inhibitors [PPIs]) with a clinical standard dose in Japanese patients with non-small-cell lung cancer. METHODS: Retrospectively, 47 patients were divided into 3 groups: gefitinib therapy with a PPI (15 patients) or an H2RA (8 patients) or gefitinib therapy alone (24 patients). On day 15 after beginning gefitinib therapy (administration at 08:00) with or without H2RA (administration twice daily at 08:00 and 18:30) or PPI (administration once daily at 08:00 or 18:30), whole blood samples were collected just prior to and at 1, 2, 4, 6, 8, 12, and 24 hours after administration. RESULTS: The total area under the observed plasma concentration-time curve (AUC0 24) and the maximum and trough plasma concentrations of gefitinib with the PPI were significantly lower than those without the PPI. The AUC0-24 of gefitinib with PPI administration in either the morning or evening were significantly lower than those without PPI administration (P = .015 and .049, respectively); however, there were no significant differences in gefitinib AUC0-24 between patients taking PPI in the morning and evening. No significant differences were observed in gefitinib exposure among the 3 CYP2C19 genotypes. The AUC0-24 of gefitinib with H2RA tended to be lower than that without H2RA. CONCLUSION: If the plasma concentrations of gefitinib cannot be monitored, the combination of gefitinib and PPI should be avoided, and an H2RA should also be used carefully. PMID- 28579187 TI - Functional MRI BOLD response in sickle mice with hyperalgesia. AB - Patients with sickle cell anemia (SCA) have abnormal hemoglobin (sickle hemoglobin S) leading to the crystallization of hemoglobin chains in red blood cells (RBCs), which assume sickle shape and display reduced flexibility. Sickle RBCs (sRBCs) adhere to vessel walls and block blood flow, thus preventing oxygen delivery to the tissues leading to vaso-occlusive crises (VOC), acute pain and organ damage. SCA patients often have chronic pain that can be attributed to inflammation, vasculopathy, neuropathy, ischemia-reperfusion injury and organ damage. Blood oxygenation level-dependent (BOLD) based functional magnetic resonance imaging (fMRI) technique that is commonly used for noninvasively mapping spontaneous or evoked brain activation in human or animal models has been applied in this study to assess abnormal oxygenation change in the brains of mice with SCA in response to hypoxia. We found that hyperalgesic HbSS-BERK sickle mice with chronic pain display reduced BOLD response to a hypoxia challenge compared to their control HbAA-BERK mice. Hypoxia/reoxygenation (H/R) treated sickle mice under acute pain episode exhibit even smaller BOLD signal changes than sickle mice without H/R, suggestive of correlations between cerebral BOLD signal changes and nociception. PMID- 28579189 TI - Identification of intervention categories for aquatic physical therapy in pediatrics using the International Classification of Functioning, Disability and Health-Children and Youth: a global expert survey. AB - OBJECTIVE: To identify intervention categories encountered by physical therapists working in aquatic therapy with disabled children, using the International Classification of Functioning, Disability and Health-Children and Youth (ICF-CY). METHODS: Aquatic physical therapists were asked to describe concepts related to the functioning of disabled children and their contextual factors. Data were collected in three rounds using the Delphi technique. All answers were translated ('linked') to the ICF-CY and analyzed to determine the degree of consensus. RESULTS: Answers were linked and organized into four diagnostic groups. Overall, in the four groups, 41 Body Functions, 8 Body Structures, 36 Activities and Participation, and 6 Environmental Factors categories were identified as intervention targets. In addition, 8 Environmental Factors that influence aquatic physical therapy were identified. CONCLUSIONS: This study highlights the variety of intervention categories available to aquatic physical therapists when treating children in the water. PMID- 28579191 TI - Mentorship of Junior Faculty Members in Academic Radiology. PMID- 28579192 TI - "I'm Not Going to Let You Do Anything to Me". PMID- 28579193 TI - Relativity Screens for Misvalued Medical Services: Impact on Noninvasive Diagnostic Radiology. AB - PURPOSE: In 2006, the AMA/Specialty Society Relative Value Scale Update Committee (RUC) introduced ongoing relativity screens to identify potentially misvalued medical services for payment adjustments. We assess the impact of these screens upon the valuation of noninvasive diagnostic radiology services. METHODS: Data regarding relativity screens and relative value unit (RVU) changes were obtained from the 2016 AMA Relativity Assessment Status Report. All global codes in the 2016 Medicare Physician Fee Schedule with associated work RVUs were classified as noninvasive diagnostic radiology services versus remaining services. The frequency of having ever undergone a screen was compared between the two groups. Screened radiology codes were further evaluated regarding the RVU impact of subsequent revaluation. RESULTS: Of noninvasive diagnostic radiology codes, 46.0% (201 of 437) were screened versus 22.2% (1,460 of 6,575) of remaining codes (P < .001). Most common screens for which radiology codes were identified as potentially misvalued were (1) high expenditures (27.5%) and (2) high utilization (25.6%). The modality and body region most likely to be identified in a screen were CT (82.1%) and breast (90.9%), respectively. Among screened radiology codes, work RVUs, practice expense RVUs, and nonfacility total RVUs decreased in 20.3%, 65.9%, and 75.3%, respectively. All screened CT, MRI, brain, and spine codes exhibited decreased total RVUs. CONCLUSION: Policymakers' ongoing search for potentially misvalued medical services has disproportionately impacted noninvasive diagnostic radiology services, risking the introduction of unintended or artificial shifts in physician practice. PMID- 28579194 TI - Mentoring a New Generation of Leaders for Breast Imaging: The Breast Cancer Screening Leadership Group. PMID- 28579190 TI - Effect of low-level laser therapy (LLLT) and light-emitting diodes (LEDT) applied during combined training on performance and post-exercise recovery: protocol for a randomized placebo-controlled trial. AB - BACKGROUND: Previous studies have shown positive results of phototherapy for improving performance and accelerating recovery; however, the effects of phototherapy during training and after a primary adaptation remain unclear. The aim of this randomized controlled trial is to analyze the effects of phototherapy and combined training on clinical, functional, and psychological outcomes and on vascular endothelial growth factor. METHODS: This randomized placebo-controlled trial by stratified sample will involve 45 healthy male participants. In phase 1, the participants will undergo six weeks of combined training (sprints and squats). In phase 2, participants will be allocated through stratified randomization (based on adaptation capacity) into three groups: active phototherapy group (AG), placebo group (PG), and non-treatment control group (CG). A new six-week training program will then start and the participants will receive the recovery strategy between sprints and squats. The primary outcome will be maximal isometric contraction. The secondary outcomes include strength and power testing, maximal incremental test, squat jump, sprint test, muscle soreness, pain threshold, perceptions of exertion and recovery, psychological questionnaire, and vascular endothelial growth factor. CONCLUSIONS: This will be the first trial to include phototherapy during training. We believe that this strategy will combine the ergogenic and prophylactic effects in the same session. Furthermore, an application protocol performed after primary adaptation may reflect the real effect of the technique. PMID- 28579195 TI - Provider Perspectives of the Complexities of Follow-Up of Abnormal Mammographic Findings. PMID- 28579196 TI - A Puzzle of Life: Crafting Ribosomal Subunits. AB - The biogenesis of eukaryotic ribosomes is a complicated process during which the transcription, modification, folding, and processing of the rRNA is coupled with the ordered assembly of ~80 ribosomal proteins (r-proteins). Ribosome synthesis is catalyzed and coordinated by more than 200 biogenesis factors as the preribosomal subunits acquire maturity on their path from the nucleolus to the cytoplasm. Several biogenesis factors also interconnect the progression of ribosome assembly with quality control of important domains, ensuring that only functional subunits engage in translation. With the recent visualization of several assembly intermediates by cryoelectron microscopy (cryo-EM), a structural view of ribosome assembly begins to emerge. In this review we integrate these first structural insights into an updated overview of the consecutive ribosome assembly steps. PMID- 28579197 TI - miR-491 inhibits skeletal muscle differentiation through targeting myomaker. AB - The myogenesis of skeletal muscle has several stages, including satellite cell proliferation, differentiation, fusion and specific muscle formation. Recent studies have shown that myomaker, a muscle-specific transmembrane protein, was critical for myoblasts fusion. However, the regulatory mechanism of myomaker and its effects on myogenesis remain elusive. In this study, miR-491 was identified as a post-transcriptional regulator of myomaker, which binds specifically to its 3' untranslated region leading to its down-regulation. At the end of myotube differentiation, the expression levels of miR-491 increased drastically, while myomaker was significantly down-regulated, which indicated that miR-491 shut down the expression of myomaker. Functional studies showed that miR-491 overexpression suppressed muscle cell differentiation and adult muscle regeneration, while the inhibition of miR-491 promoted myotube differentiation. Taken together, our findings identified miR-491 as a novel negative regulator of myogenic differentiation through targeting myomaker. PMID- 28579198 TI - Considerations for Initiating a Sodium-Glucose Co-Transporter 2 Inhibitor in Adults With Type 2 Diabetes Using Insulin. AB - In order to meet and maintain glycemic control, pharmacological management of individuals with type 2 diabetes typically begins with metformin followed by the introduction of other oral antihyperglycemic agents as needed. In some patients, the aggressive and progressive degeneration of pancreatic beta cell activity means insulin therapy will become a given. The need to routinely monitor blood glucose levels coupled with the undesirable effects associated with insulin primarily hypoglycemia and weight gain-commonly contribute to physician and patient inertia. The new beta-cell-independent sodium-glucose co-transporter 2 (SGLT2) inhibitors are approved for combination use with all of the currently approved oral and injectable antihyperglycemic classes. The addition of SGLT2 inhibitors to background insulin therapy has the potential to afford many benefits and, in some cases, may reduce the incidence of insulin-associated side effects. This article reviews the available literature on SGLT2 inhibitor-insulin combination therapy and underscores the issues that should be considered prior to introducing SGLT2 inhibitors to individuals with type 2 diabetes who are already on insulin (with or without other antihyperglycemic agents) to ensure individualization of therapy. PMID- 28579199 TI - Comorbid Conditions in Canadians Hospitalized Because of Diabetes. AB - OBJECTIVES: The number of hospital discharges involving type 1 or type 2 diabetes as the first-listed diagnosis has increased over the past few decades. Such cases are commonly associated with various comorbidities. We analyzed data collected from hospital separations in Canada to determine the number and proportion of comorbid conditions in Canadians hospitalized because of diabetes. METHODS: The most responsible diagnosis (MRDx) of diabetes (ICD-10-CA: E10 [type 1 diabetes] or E11 [type 2 diabetes]) was identified from acute care hospital separations (Discharge Abstract Database) from 2013 to 2014 in all Canadian jurisdictions except Quebec. Hospital separations were calculated by 5-year age groups and sex. The most common comorbid (secondary) diagnoses were identified for hospital separations with diabetes as the MRDx, and the average lengths of stay associated with diabetes were determined. RESULTS: The total number of hospital separations in 2013-2014 in Canada (excluding Quebec) with diabetes as the MRDx in all ages was 30,422, and males represented more than half (58.7%) of the separations. The median age group when diabetes is the MRDx is 60 to 64. For all patients hospitalized with an MRDx of diabetes, there were 2.2% deaths. Hypertension was the most common comorbid diagnosis in patients with diabetes as the MRDx, followed by glomerular disorders, peripheral angiopathy and acute renal failure. CONCLUSIONS: Hospitalizations resulting from diabetes are associated with vascular comorbidities, and hypertension is the most common. Prevention of shared predisposing factors should reduce the burden of hospitalizations associated with diabetes. PMID- 28579200 TI - In sickness and in health: The many roles of the minichromosome maintenance proteins. AB - Cell division is a tightly-regulated process that involves the contribution of a large number of proteins. Before they are able to undergo mitosis, cells must first synthesize new DNA, effectively and accurately duplicating their genome. This occurs during what is called the S-phase and requires a fine control in order to avoid replication errors. The synthesis of new DNA takes place in the origin, specific locations in the genome where the double strands of DNA are unwound and separated, allowing for the binding of proteins and complexes that will build new strands of the genomic material, using the existing ones as molds, in what is referred to as semi-conservative process. While the overall flow of the DNA synthesis process has been elucidated, its regulation and the exact role of its contributors are not yet entirely understood. It is believed that the Minichromosome Maintenance (MCM) proteins occupy a central role in DNA synthesis. Given their contribution to a central aspect in the conservation of life, further studies have been launched to understand how the MCM proteins may affect or be affected by pathologies involving cell division, such as neoplasia. In this review, we aim to give an overview on the members of the MCM family, what their functions are in a healthy environment and how they are altered in cancer. PMID- 28579201 TI - Comment on Perioperative analgesic profile of dexmedetomidine infusions in morbidly obese undergoing bariatric surgery: A meta-analysis and trial sequential analysis. PMID- 28579203 TI - Comment on Long-term effects of bariatric surgery on patients with obesity and chromosome 19.11-2 microdeletion. PMID- 28579204 TI - Is the buckle bursting? - disparity and access to bariatric surgery. PMID- 28579202 TI - Use of prescribed opioids before and after bariatric surgery: prospective evidence from a U.S. multicenter cohort study. AB - BACKGROUND: Limited evidence suggests bariatric surgery may not reduce opioid analgesic use, despite improvements in pain. OBJECTIVE: To determine if use of prescribed opioid analgesics changes in the short and long term after bariatric surgery and to identify factors associated with continued and postsurgery initiated use. SETTING: Ten U.S. hospitals. METHODS: The Longitudinal Assessment of Bariatric Surgery-2 is an observational cohort study. Assessments were conducted presurgery, 6 months postsurgery, and annually postsurgery for up to 7 years until January 2015. Opioid use was defined as self-reported daily, weekly, or "as needed" use of a prescribed medication classified as an opioid analgesic. RESULTS: Of 2258 participants with baseline data, 2218 completed follow-up assessment(s) (78.7% were female, median body mass index: 46; 70.6% underwent Roux-en-Y gastric bypass). Prevalence of opioid use decreased after surgery from 14.7% (95% CI: 13.3-16.2) at baseline to 12.9% (95% CI: 11.5-14.4) at month 6 but then increased to 20.3%, above baseline levels, as time progressed (95% CI: 18.2 22.5) at year 7. Among participants without baseline opioid use (n = 1892), opioid use prevalence increased from 5.8% (95% CI: 4.7-6.9) at month 6 to 14.2% (95% CI: 12.2-16.3) at year 7. Public versus private health insurance, more pain presurgery, undergoing subsequent surgeries, worsening or less improvement in pain, and starting or continuing nonopioid analgesics postsurgery were significantly associated with higher risk of postsurgery initiated opioid use. CONCLUSION: After bariatric surgery, prevalence of prescribed opioid analgesic use initially decreased but then increased to surpass baseline prevalence, suggesting the need for alternative methods of pain management in this population. PMID- 28579205 TI - Surgery-related gastrointestinal symptoms in a prospective study of bariatric surgery patients: 3-year follow-up. AB - BACKGROUND: Having accurate information on bariatric surgery-related gastrointestinal (GI) symptoms is critical for patient care. OBJECTIVE: To report on surgery-related GI symptoms over the first 3 years following Roux-en-Y gastric bypass and laparoscopic adjustable gastric band. SETTING: Three academic medical centers in the United States. METHODS: As a substudy of the Longitudinal Assessment of Bariatric Surgery Consortium, 183 participants (pre-surgery median body mass index = 45.1 kg/m2; median age = 46 yr; 83.1% female). completed the Eating Disorder Examination-Bariatric Surgery Version interview at>=1 annual assessment. Patients self-reported frequency of dysphagia, dumping syndrome, and spontaneous vomiting. RESULTS: Prevalence of dysphagia at least once weekly decreased post-laparoscopic adjustable gastric band surgery from 43.9% (95% confidence interval [CI], 32.2-55.6) in year 1 to 27.5% (95% CI, 15.2-39.9) in year 3 (P = .02). Dysphagia and dumping at least once weekly also appeared to decrease in years 1-3 post-Roux-en-Y gastric bypass (i.e., from 16.7% [95% CI, 9.4-24.1] to 10.9% [95% CI, 4.0-17.8] and from 9.9% [95% CI, 4.3-15.5] to 6.3% [95% CI, 1.7-10.9], respectively), but power was limited to evaluate trends. Vomiting at least once weekly was rare (<6%) in years 1-3 following both procedures. Controlling for potential confounders and surgical procedure, loss of control eating at least once weekly was associated with higher risk of at least once weekly dysphagia (relative risk = 2.01, 95% CI, 1.36-2.99, P = .001). CONCLUSIONS: The prevalence of bariatric surgery-related GI symptoms appears to decrease across follow-up. Symptoms were associated with loss of control eating, suggesting a target for clinical intervention. PMID- 28579206 TI - Motor neuron disease of very long disease duration or Charcot-Marie-Tooth disease? A novel phenotype related to the SOD1 p.E22G variant. PMID- 28579207 TI - Peripheral nerve involvement in Fabry's disease: Which investigations? A case series and review of the literature. AB - BACKGROUND: Peripheral nerve system (PNS) involvement is common in Fabry's disease (FD), predominantly affecting the small nerve fibers that are difficult to investigate with conventional electrophysiological methods. PATIENTS AND METHODS: Eighteen patients followed for Fabry's disease underwent a prospective series of electroneurophysiological explorations, including a study of the cardiac parasympathetic autonomic nervous system (ANS) and electrochemical skin conductance (ESC) tests. Data were compared with those obtained in 18 matched healthy controls. RESULTS: All patients had at least one clinical sign suggestive of neuropathy: 16 reported an acrosyndrome and 12 had dyshidrosis. Cold hypoesthesia was found in 15 patients and heat hypoesthesia in 13. Electroneurophysiological investigations and study of the cardiac parasympathetic ANS were normal in all patients. The ESC was significantly lower in FD patients compared with controls. CONCLUSION: PNS involvement is common in FD and should be suspected in patients exhibiting an acrosyndrome, dyshidrosis and/or cold hypoesthesia. Conventional electrophysiological investigations are normal. New techniques, such as ESC, provide early diagnosis of small fiber involvement that currently requires more sophisticated tests difficult to apply in routine practice. PMID- 28579208 TI - Louis Delasiauve (1804-1893), an alienist at the dawn of epileptology and pediatric psychiatry. AB - This paper aims to honor the memory of the alienist Louis Delasiauve (1804-1893). His classification of the different types of epilepsy based on clinical symptoms is still relevant today and made him a precursor of contemporary epileptology. In 1851, Delasiauve clinically and etiologically isolated 'acute mental confusion' (acute confusional state) from all other forms of dementia. Never deviating from his republican and progressive ideals, he devoted himself throughout the 19th century to treating those insane asylum patients who received the poorest care: epileptics and children with intellectual disabilities. Studying functional cognitive disability as well as mental disability secondary to congenital malformations, Delasiauve developed a novel specific form of pedagogy to deal with delays in cognitive development. This made him one of the initiators of institutional pediatric psychiatry. His ideas would be carried forward by his favorite student, Desire-Magloire Bourneville (1840-1909). Committed to social welfare, Delasiauve worked relentlessly to improve access to healthcare for the least fortunate throughout France. As a passionate supporter of universal, free and secular education, he participated in a major movement away from religious establishments that involved opening a public school in every French canton. PMID- 28579209 TI - Extended-interval Dosing of Gentamicin in Premature Neonates Born at <32 Weeks' Gestation and >7 Days of age. AB - PURPOSE: Extended-interval dosing (EID) regimens of gentamicin have been validated for treating confirmed or suspected early- and late-onset sepsis in preterm infants in the first week of life. Despite the marked changes in volume of distribution and renal clearance in preterm infants after the first few days of life, few studies have validated EID regimens of gentamicin in this population. The objective of the study was to evaluate an EID regimen of gentamicin in infants born at <32 weeks' gestational age and aged >7 days. METHODS: This observational study of an EID regimen was conducted in 39 infants. Dosing interval was based on the serum drug concentration at 22 hours after the administration of the first dose of 5 mg/kg. Gentamicin peak (5-12 ug/mL) and trough (<2 ug/mL) levels were compared to those in a historical control group of 39 infants who received traditional-interval dosing (TID) of 2.5 mg/kg of gentamicin with dosing intervals of 8, 12, or 24 hours. FINDINGS: There were no differences in birthweight, gestational age at birth, postmenstrual age, weight at the start of gentamicin administration, postnatal age, small for gestational age status, antenatal corticosteroid use, or postnatal indomethacin exposure between the 2 groups. In the EID group, dosing intervals were 24 hours in 30 infants, 36 hours in 6 infants, and 48 hours in 3 infants. Compared with the TID group (n = 39), the EID group had a significantly higher peak level (median, 9.0 vs 4.7 ug/mL) and a significantly lower trough level (median, 0.7 vs 1.1 ug/mL) (both, P < 0.001). On regression analysis, the postmenstrual age was correlated significantly with trough levels in the EID group. There was no adverse effect on renal function in either group. On follow-up, 1 infant in the EID group and 2 infants in the TID group had evidence of sensorineural hearing loss. IMPLICATIONS: In infants born at <32 weeks' gestation and >7 days of age, an EID gentamicin regimen, with a dosing interval based on a single concentration measurement at 22 hours after the administration of the first dose, achieved therapeutic peak and trough levels and performed significantly better than did a TID regimen in reaching target peak and trough levels. Larger-scale trials are needed for assessing the clinical efficacy (treatment failure/success) of these regimens. PMID- 28579210 TI - Microcosting Study of Rituximab Subcutaneous Injection Versus Intravenous Infusion. AB - PURPOSE: The goal of this study is to identify and compare all direct costs of intravenous and subcutaneous rituximab given to patients with diffuse large B cell lymphoma in the Netherlands. METHODS: Using a prospective, observational, bottom-up microcosting study, we collected primary data on the direct medical costs of the preparation, administration, and acquisition of rituximab. Drug costs and costs of drug wastage, labor costs, material costs, and outpatient costs were identified using standardized forms, structured using prices from official pricelists, and compared for the intravenous and subcutaneous forms of rituximab. FINDINGS: Measurements were taken on 53 rituximab administrations (33 intravenous and 20 subcutaneous) and on 13 rituximab preparation (7 intravenous and 6 subcutaneous). The mean total costs were ?2176.77 for the intravenous infusion and ?1911.09 for the subcutaneous injection. The estimated difference of ?265.17 (95% CI, ?231.99-'?298.35) per administration was mainly attributable to differences in time spent in the chemotherapy unit, related outpatient costs, drug wastage, and drug costs. IMPLICATIONS: Rituximab administered in the form of subcutaneous injection is less costly than its intravenous form. With their equal effectiveness taken into account, subcutaneous rituximab administration can result in significant savings when transferred to the total diffuse large B-cell lymphoma population in the Netherlands. PMID- 28579211 TI - Author Reply. PMID- 28579212 TI - Editorial Comment. PMID- 28579213 TI - Author Reply. PMID- 28579214 TI - Editorial Comment. PMID- 28579215 TI - [Vogt-Koyanagi-Harada disease]. AB - Vogt-Koyanagi-Harada (VKH) disease is defined as a severe bilateral, chronic granulomatous panuveitis associated with serous retinal detachments, disk edema, and vitritis, with central nervous system, auditory, and integumentary manifestations. It is an autoimmune inflammatory condition mediated by T cells that target melanocytes in individuals genetically susceptible to the disease. Vogt-Koyanagi-Harada disease presents clinically in 4 different phases: prodromal, acute inflammatory, chronic, and recurrent, with extraocular manifestations including headache, meningitis, hearing loss, poliosis, and vitiligo. Optical coherence tomography (OCT) allows earlier diagnosis of VKH disease by revealing heterogeneous exudative detachments of the retina in the acute stage and choroidal thickening, and by demonstrating choroidal thinning in the chronic stage. Treatment of this disease is initially with intravenous corticosteroids, with, if needed, a transition to immunosuppressant drugs for long-term control. Patients with VKH disease can have good final visual outcomes if treated promptly and aggressively. PMID- 28579216 TI - Foveal hypoplasia documented with OCT-Angiography in an albino patient. PMID- 28579217 TI - Encephalitis secondary to diethylcarbamazine treatment in a patient with ocular loiasis. PMID- 28579218 TI - Choroidal nevus or melanoma? Choroidal neovascularisation as a confounder in choroidal nevus. PMID- 28579219 TI - [Visual outcomes after Descemet's membrane endothelial keratoplasty]. AB - OBJECTIVES: Evaluation and monitoring at 6 months after Descemet's membrane endothelial keratoplasty (DMEK) in patients with Fuchs endothelial dystrophy and study of factors influencing visual rehabilitation and postoperative quality of life. METHODS: Prospective, consecutive, interventional study of 35 eyes of 32 patients with Fuchs endothelial dystrophy who underwent surgery from February 2015 to February 2016 by DMEK. Measurement at D10, M1, M3, M6 of visual acuity, graft endothelial cell density, pachymetry, and intraocular pressure, and performance at M6 of aberrometry, macular OCT and a quality of life survey (NEI VFQ-25). Post-DMEK aberrations are compared to those from control patients selected for refractive surgery. RESULTS: Visual acuity improvement at 6 months was statistically significant (P<0.0001), as well as pachymetry decrease (P<0.0001), endothelial cell loss (P<0.0001) and intraocular pressure increase (P=0.003). We observed a statistically significant difference between post-DMEK aberrations and those of control subjects for all aberrations from 2nd to 5th order. There were no postoperative correlations between visual acuity, pachymetry, intraocular pressure, or endothelial cell loss. The global quality of life score at six months was 87, corresponding to a good quality of life. We did not find a link between the global NEI-VFQ-25 score and visual acuity or visual aberrations. Ninety percent of patients surveyed reported a postoperative general improvement in quality of life at M6. CONCLUSION: DMEK provides good visual rehabilitation and an improvement in quality of life for patients with Fuchs endothelial dystrophy. Higher order optical aberrations in these patients, although higher than in a healthy population, are negligible and have no impact on quality of vision or postoperative quality of life. PMID- 28579221 TI - STAT3 in cancer: A double edged sword. AB - The transcription factor signal transducer and activator of transcription (STAT) 3 is activated downstream of cytokines, growth factors and oncogenes to mediate their functions under both physiological and pathological conditions. In particular, aberrant/unrestrained STAT3 activity is detected in a wide variety of tumors, driving multiple pro-oncogenic functions. For that, STAT3 is widely considered as an oncogene and is the object of intense translational studies. One of the distinctive features of this factor is however, its ability to elicit different and sometimes contrasting effects under different conditions. In particular, STAT3 activities have been shown to be either pro-oncogenic or tumor suppressive according to the tumor aetiology/mutational landscape, suggesting that the molecular bases underlining its functions are still incompletely understood. Here we discuss some of the properties that may provide the bases to explain STAT3 heterogeneous functions, and in particular how post-translational modifications contribute shaping its sub-cellular localization and activities, the cross talk between these activities and cell metabolic conditions, and finally how its functions can control the behaviour of both tumor and tumor microenvironment cell populations. PMID- 28579220 TI - The polymorphism rs17782313 near MC4R gene is related with anthropometric changes in women submitted to bariatric surgery over 60 months. AB - OBJECTIVE: Evaluate whether the polymorphism rs17782313 near MC4R gene influences long-term outcomes after bariatric surgery. METHODS: The rs16782313 polymorphism was genotyped in 217 individuals undergoing bariatric surgery and analyzed in detail in 141 women. Data for comorbidities, BMI, excess weight loss (EWL), and body composition were obtained before and during 60 months after surgery. RESULTS: The risk allele was found in 65 (47%) of the 141 women. Pre-surgical body weight and BMI were higher in carriers of the rs17782313 polymorphism (CC + CT group) than in non-carriers (TT group) (p = 0.039 and 0.047, respectively). The number of women who acquired surgical success (EWL > 50%), was lower in CC + CT group compared to TT group (p = 0.015). The minimum BMI seen during the 60 months of follow-up was higher in CC + CT group compared to TT group (p = 0.028). The number of women who presented BMI < 30 kg/m2 (no longer classified as obesity) after 24 months of surgery was inferior in CC + CT group (6 out 35 patients - 17%) than in TT group (19 out 49 patients - 37%, p = 0.043). Moreover, the number of patients maintaining BMI > 35 kg/m2 were higher carriers (18 out 35 patients - 51%) compare to non-carriers (16 out 49 patients - 32%, p = 0.045). CONCLUSION: Women with extreme obesity carrying rs17782313 MC4R polymorphism present a higher pre-surgical BMI, are more unlikely to reach non-obesity BMI (<30 kg/m2) and tend to maintain a BMI > 35 kg/m2 that characterize treatment failure. PMID- 28579222 TI - Use of the Intermittent Abdominal Pressure Ventilation to guarantee speech in a tracheostomized Amyotrophic Lateral Sclerosis patient. PMID- 28579223 TI - Tuberculosis, alcohol and tobacco: Dangerous liaisons. PMID- 28579224 TI - The frequency of lung cancer in patients with pulmonary hamartomas: An evaluation of clinical, radiological, and pathological features and follow-up data of 96 patients with pulmonary hamartomas. AB - PURPOSE: To investigate the frequency of lung cancer in patients with pulmonary hamartomas and to evaluate clinical, radiological, and pathological characteristics of pulmonary hamartomas. BASIC PROCEDURES: We reviewed pathology records of pulmonary hamartomas diagnosed between 2003 and 2014. Medical records and the hospital electronic database were also reviewed for each patient to obtain clinical, radiological, and pathological characteristics of pulmonary hamartomas and accompanying malignancies. MAIN FINDINGS: Ninety-six patients with pulmonary hamartomas were identified. There were 26 females (27%) and 70 males (73%), with a mean age of 56.2 years (range 22-87 years). Malignancies were detected in 23 patients (24%), which developed previously in five patients (1 synchronous, 4 metachronous lesions), and concomitantly in 18 patients (with origin from the lung in 17 patients and from the pleura in 1 patient). PRINCIPAL CONCLUSIONS: Our results show that patients with pulmonary hamartomas may have coexisting lung malignancies. PMID- 28579226 TI - Reprising the role of CD4 cell count in HIV programmes. PMID- 28579225 TI - Effect of point-of-care CD4 cell count results on linkage to care and antiretroviral initiation during a home-based HIV testing campaign: a non blinded, cluster-randomised trial. AB - BACKGROUND: HIV disease staging with referral laboratory-based CD4 cell count testing is a key barrier to the initiation of antiretroviral treatment (ART). Point-of-care CD4 cell counts can improve linkage to HIV care among people living with HIV, but its effect has not been assessed with a randomised controlled trial in the context of home-based HIV counselling and testing (HBCT). METHODS: We did a two-arm, cluster-randomised, controlled efficacy trial in two districts of western Kenya with ongoing HBCT. Housing compounds were randomly assigned (1:1) to point-of-care CD4 cell counts (366 compounds with 417 participants) or standard-of-care (318 compounds with 353 participants) CD4 cell counts done at one of three referral laboratories serving the study catchment area. In each compound, we enrolled people with HIV not engaged in care in the previous 6 months. All participants received post-test counselling and referral for HIV care. Point-of-care test participants received additional counselling on the result, including ART eligibility if CD4 was less than 350 cells per MUL, the cutoff in Kenyan guidelines. Participants were interviewed 6 months after enrolment to ascertain whether they sought HIV care, verified through chart reviews at 23 local clinics. The prevalence of loss to follow-up at 6 months (LTFU) was listed as the main outcome in the study protocol. We analysed linkage to care at 6 months (defined as 1-LTFU) as the primary outcome. All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT02515149. FINDINGS: We enrolled 770 participants between July 1, 2013, and Feb 28, 2014. 692 (90%) had verified linkage to care status and 78 (10%) were lost to follow-up. Of 371 participants in the point-of-care group, 215 (58%) had linked to care within 6 months versus 108 (34%) of 321 in the standard-of-care group (Cox proportional multivariable hazard ratio [HR] 2.14, 95% CI 1.67-2.74; log rank p<0.0001). INTERPRETATION: Point-of-care CD4 cell counts in a resource limited HBCT setting doubled linkage to care and thereby improved ART initiation. Given the substantial economic and logistic hindrances to providing ART for all people with HIV in resource-limited settings in the near term, point of care CD4 cell counts might have a role in prioritising care and improving linkage to care. FUNDING: US Centers for Disease Control and Prevention. PMID- 28579227 TI - D-TGA Combined With Left Arch Atresia of a Double Aortic Arch. AB - A three-month-old female underwent an arterial switch operation for transposition of the great arteries (TGA) with concomitant ventricular septal defect (VSD). After the operation, the patient suffered from stubborn pulmonary infection with increased airway resistance, and could not be weaned from a ventilator. Multispiral computed tomography (CT) scanning suggested a double aortic arch with left arch atresia. The patient underwent a second procedure to resection the left aortic arch. The patient gradually recovered and was successfully weaned from the ventilator. PMID- 28579229 TI - Residential exposure to traffic noise and leisure-time sports - A population based study. AB - BACKGROUND: Traffic levels have been found a significant environmental predictor for physical inactivity. A recent study suggested that traffic noise annoyance was associated with lower physical activity. OBJECTIVES: We investigated associations between modelled residential traffic noise and leisure-time sports. METHODS: In the Diet, Cancer and Health cohort, we performed cross-sectional analyses using data from the baseline questionnaire (1993-97), and longitudinal analyses of change between baseline and follow-up (2000-02). People reported participation (yes/no) and hours of leisure-time sport, from which we calculated MET hrs/week. Present and historical addresses from 1987 to 2002 were found in national registries, and traffic noise was modelled 1 and 5 years before enrolment, and from baseline to follow-up. Analyses were performed using logistic and linear regression. RESULTS: Traffic noise exposure 5 years before baseline was associated with higher prevalence odds ratio of non-participation in leisure time sports; significantly for road traffic noise (odds ratio (OR): 1.10; 95% confidence interval (CI): 1.07-1.13) and borderline for railway noise (OR: 1.03; 95% CI: 0.99-1.07), per 10dB. In longitudinal analyses, a 10dB higher road traffic noise was associated with a higher prevalence odds ratio of ceasing (OR: 1.12; 95% CI: 1.07-1.18) and a lower prevalence odds ratio of initiating (OR: 0.92; 95% CI: 0.87-0.96) leisure-time sports. Exposure to railway noise was negatively associated with baseline MET hrs/week, whereas no association was found in longitudinal analyses, or for road traffic noise. CONCLUSION: The study suggests that long-term exposure to residential road traffic noise is negatively associated with leisure-time sports. Results for railway noise were less consistent. PMID- 28579228 TI - Association of Systemic Inflammation Score With Atrial Fibrillation: A Case Control Study With Propensity Score Matching. AB - BACKGROUND: Inflammation plays a key role in the initiation and progression of atrial fibrillation (AF). We developed a novel systemic inflammation score (SIS) based on integration of biomarkers used routinely in clinical settings. We aim to explore the association between SIS and AF. METHODS: A matched case-control study with 376 pairs of AF cases and controls was performed using a propensity score matching system. The SIS was developed by integrating albumin (ALB), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocytes to monocytes ratio (LMR). Univariate and multivariate analyses were performed to examine the association of each marker and SIS with AF. RESULTS: The conditional multivariate logistic regression analysis showed that elevated levels of ALB and LMR were significantly associated with decreased risk of AF with an OR of 0.74 (95% CI: 0.65, 0.85) and 0.73 (95% CI: 0.64, 0.83), respectively. Patients with elevated SIS had a significantly higher risk of AF. Compared to the patients with SIS equal to 1, the patients with SIS equal to 3 and 4 had an OR of 2.16 (95% CI: 1.40 3.32), and 2.55 (95% CI: 1.66, 3.92), respectively. The SIS was positively correlated with left atrial diameter and right atrial diameter in patients with AF. CONCLUSIONS: In conclusion, this study provides further clinical epidemiological evidence that systemic inflammatory status was correlated with AF. The SIS, as an index to evaluate the intensity of systemic inflammatory status, could be useful for early prediction of AF development and understanding of AF mechanism. PMID- 28579230 TI - Comparative incidence dynamics and serotypes of meningitis, bacteremic pneumonia and other-IPD in young children in the PCV era: Insights from Israeli surveillance studies. AB - INTRODUCTION: Widespread introduction of pneumococcal conjugated vaccines (PCVs) impacted on invasive pneumococcal disease (IPD). However, IPD reduction may not be similar in all outcomes within IPD. We assessed PCV7/PCV13 impact on pneumococcal meningitis, bacteremic pneumonia (BP) and other (non-meningitis, non pneumonia) IPD episodes in children <5years in Israel. METHODS: A prospective, population-based, active nationwide surveillance. All pneumococcal invasive episodes with positive blood/CSF cultures, July 2000 through June 2016, were included. Three sub-periods were defined: pre-PCV (2000-2008), PCV7 (2009-2011) and PCV13 (2014-2016). Incidence rate ratios (IRRs) were calculated. RESULTS: Overall, 4321 episodes were recorded; 456 (10.6%) meningitis, 1478 (34.2%) pneumonia and 2387 (55.2%) other-IPD. In the pre-PCV period, proportion of serotypes in PCV13, but not in PCV7 (mainly serotypes 1, 5 and 19A) was higher in BP (43.3%) compared with other-IPD episodes (32.8%, p<0.001) and similar to that of meningitis (37.6%, p=0.1). The proportion of episodes in children <12months was higher in meningitis (52.1%) compared with pneumonia (23.2%) and other-IPD episodes (39.5%; p<0.001 for both). The declines of the 3 entities were not similar; Meningitis rate non-significantly declined by 24% (IRR=0.76; 95% CI 0.57 1.01), while BP and other-IPD rates significantly declined by 57% and 70%, respectively. In contrast to other entities, BP did not decline significantly after PCV7 introduction but started to decline only after PCV13 introduction. Rates of meningitis, pneumonia and other-IPD caused by PCV13-serotypes (VT13) substantially declined by 88%, 95% and 97%, respectively, comparing PCV13 and the pre-PCV periods. However, diseases caused by non-VT13 increased by 256%, 302% in meningitis and pneumonia, respectively, but only 116% in other-IPD. CONCLUSIONS: Following PCV7/PCV13 introduction, rates of episodes caused by VT13 were substantially reduced in all 3 groups. However, differences in age distribution, serotype replacement and specific serotype decrease suggest different pathogenesis and host susceptibility between the 3 entities. PMID- 28579231 TI - Optimized production and purification of Coxsackievirus B1 vaccine and its preclinical evaluation in a mouse model. AB - Coxsackie B viruses are among the most common enteroviruses, causing a wide range of diseases. Recent studies have also suggested that they may contribute to the development of type 1 diabetes. Vaccination would provide an effective way to prevent CVB infections, and the objective of this study was to develop an efficient vaccine production protocol for the generation of novel CVB vaccines. Various steps in the production of a formalin-inactivated Coxsackievirus B1 (CVB1) vaccine were optimized including the Multiplicity Of Infection (MOI) used for virus amplification, virus cultivation time, type of cell growth medium, virus purification method and formulation of the purified virus. Safety and immunogenicity of the formalin inactivated CVB1 vaccine was characterized in a mouse model. Two of the developed methods were found to be optimal for virus purification: the first employed PEG-precipitation followed by gelatin chromatography and sucrose cushion pelleting (three-step protocol), yielding 19 fold increase in virus concentration (0.06ug/cm2) as compared to gold standard method. The second method utilized tandem sucrose pelleting without a PEG precipitation step, yielding 83-fold increase in virus concentration (0.24ug/cm2), but it was more labor-intensive and cannot be efficiently scaled up. Both protocols provide radically higher virus yields compared with traditional virus purification protocols involving PEG-precipitation and sucrose gradient ultracentrifugation. Formalin inactivation of CVB1 produced a vaccine that induced a strong, virus-neutralizing antibody response in vaccinated mice, which protected against challenge with CVB1 virus. Altogether, these results provide valuable information for the development of new enterovirus vaccines. PMID- 28579232 TI - ChAdOx1 and MVA based vaccine candidates against MERS-CoV elicit neutralising antibodies and cellular immune responses in mice. AB - The Middle East respiratory syndrome coronavirus (MERS-CoV) has infected more than 1900 humans, since 2012. The syndrome ranges from asymptomatic and mild cases to severe pneumonia and death. The virus is believed to be circulating in dromedary camels without notable symptoms since the 1980s. Therefore, dromedary camels are considered the only animal source of infection. Neither antiviral drugs nor vaccines are approved for veterinary or medical use despite active research on this area. Here, we developed four vaccine candidates against MERS CoV based on ChAdOx1 and MVA viral vectors, two candidates per vector. All vaccines contained the full-length spike gene of MERS-CoV; ChAdOx1 MERS vaccines were produced with or without the leader sequence of the human tissue plasminogen activator gene (tPA) where MVA MERS vaccines were produced with tPA, but either the mH5 or F11 promoter driving expression of the spike gene. All vaccine candidates were evaluated in a mouse model in prime only or prime-boost regimens. ChAdOx1 MERS with tPA induced higher neutralising antibodies than ChAdOx1 MERS without tPA. A single dose of ChAdOx1 MERS with tPA elicited cellular immune responses as well as neutralising antibodies that were boosted to a significantly higher level by MVA MERS. The humoral immunogenicity of a single dose of ChAdOx1 MERS with tPA was equivalent to two doses of MVA MERS (also with tPA). MVA MERS with mH5 or F11 promoter induced similar antibody levels; however, F11 promoter enhanced the cellular immunogenicity of MVA MERS to significantly higher magnitudes. In conclusion, our study showed that MERS-CoV vaccine candidates could be optimized by utilising different viral vectors, various genetic designs of the vectors, or different regimens to increase immunogenicity. ChAdOx1 and MVA vectored vaccines have been safely evaluated in camels and humans and these MERS vaccine candidates should now be tested in camels and in clinical trials. PMID- 28579234 TI - Protective immunity against Megalocytivirus infection in rock bream (Oplegnathus fasciatus) following CpG ODN administration. AB - Rock bream iridovirus (RBIV) disease in rock bream (Oplegnathus fasciatus) remains an unsolved problem in Korea aquaculture farms. CpG ODNs are known as immunostimulant, can improve the innate immune system of fish providing resistance to diseases. In this study, we evaluated the potential of CpG ODNs to induce anti-viral status protecting rock bream from different RBIV infection conditions. We found that, when administered into rock bream, CpG ODN 1668 induces better antiviral immune responses compared to other 5 CpG ODNs (2216, 1826, 2133, 2395 and 1720). All CpG ODN 1668 administered fish (1/5ug) at 2days before infection (1.1*107) held at 26 degrees C died even though mortality was delayed from 8days (1ug) and 4days (5ug). Similarly, CpG ODN 1668 administered (5ug) at 2days before infection (1.2*106) held at 23/20 degrees C had 100% mortality; the mortality was delayed from 9days (23 degrees C) and 11days (20 degrees C). Moreover, when CpG ODN 1668 administered (1/5/10ug) at 2/4/7days before infection or virus concentration was decreased to 1.1*104 and held at 20 degrees C had mortality rates of 20/60/30% (2days), 30/40/60% (4days) and 60/60/20% (7days), respectively, for the respective administration dose, through 100 dpi. To investigate the development of a protective immune response, survivors were re-infected with RBIV (1.1*107) at 100 and 400 dpi, respectively. While 100% of the previously unexposed fish died, 100% of the previously infected fish survived. The high survival rate of fish following re-challenge with RBIV indicates that protective immunity was established in the surviving rock bream. Our results showed the possibility of developing preventive measures against RBIV using CpG ODN 1668 by reducing RBIV replication speed (i.e. water temperature of 20 degrees C and infection dose of 1.1*104). PMID- 28579233 TI - A Phase 2 randomized, observer-blind, placebo-controlled, dose-ranging trial of aluminum-adjuvanted respiratory syncytial virus F particle vaccine formulations in healthy women of childbearing age. AB - OBJECTIVE: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants. We are developing an RSV fusion (F) protein nanoparticle vaccine for immunization of third trimester pregnant women to passively protect infants through transfer of RSV-specific maternal antibodies. The present trial was performed to assess the immunogenicity and safety of several formulations of RSV F vaccine in 1-dose or 2-dose schedules. METHODS: Placebo, or vaccine with 60MUg or 120MUg RSV F protein and 0.2, 0.4, or 0.8mg aluminum, were administered intramuscularly on Days 0 and 28 to healthy women 18-35years old. Immunogenicity was assessed from Days 0 through 91 based on anti-F IgG and palivizumab competitive antibody (PCA) by ELISA, and RSV A and B neutralizing antibodies by microneutralization (MN) assay. Solicited adverse events were collected through Day 7 and unsolicited adverse events through Day 91. RESULTS: All formulations were well-tolerated, with no treatment-related serious adverse events. Anti-F IgG and PCA responses were correlated and increased after both doses, while MN increased significantly only after the first dose, then plateaued. The timeliest and most robust antibody responses followed one dose of 120MUg RSV F protein and 0.4mg aluminum, but persistence through 91days was modestly (~25%) superior following two doses of 60MUg RSV F protein and 0.8mg aluminum. Western blot analysis showed RSV infections in active vaccinees were reduced by 52% overall (p=0.009 overall) over the Day 0 through 90 period. CONCLUSIONS: RSV F nanoparticle vaccine formulations were well tolerated and immunogenic. The optimal combination of convenience and rapid response for immunization in the third trimester occurred with 120MUg RSV F and 0.4mg aluminum, which achieved peak immune responses in 14days and sufficient persistence through 91days to allow for passive transfer of IgG antibodies to the fetus. NCT01960686. PMID- 28579235 TI - Haematopoietic TLR4 deletion attenuates perivascular brown adipose tissue inflammation in atherosclerotic mice. AB - AIMS: To investigate whether haematopoietic TLR4 deletion attenuates perivascular brown adipose tissue inflammation in atherosclerotic mice. METHODS AND RESULTS: Experiments were performed using irradiated LDL receptor-deficient (LDLR-/-) mice with marrow from either TLR4-deficient (TLR4-/-) or age-matched wild-type (WT) mice. After 12 weeks of being fed a high-cholesterol diet, TLR4-/-->LDLR-/- mice developed fewer atherosclerotic lesions in the aorta compared to WT->LDLR-/- mice. This effect was associated with an increase in multilocular lipid droplets and mitochondria in perivascular adipose tissue (PVAT). Immunofluorescence analysis confirmed that there was an increase in capillary density and M2 macrophage infiltration, accompanied by a decrease in tumour necrosis factor (TNF)-alpha expression in the localized PVAT of TLR4-/-->LDLR-/- mice. In vitro studies indicated that bone marrow-derived macrophages (BMDMs) from WT mice demonstrated an M1-like phenotype and expression of inflammatory cytokines induced by palmitate. These effects were attenuated in BMDMs isolated from TLR4-/ mice. Furthermore, brown adipocytes incubated with conditioned medium (CM) derived from palmitate-treated BMDMs, exhibited larger and more unilocular lipid droplets, and reduced expression of brown adipocyte-specific markers and perilipin-1 compared to those observed in brown adipocytes exposed to CM from palmitate-treated BMDMs of TLR4-/- mice. This decreased potency was primarily due to TNF-alpha, as demonstrated by the capacity of the TNF-alpha neutralizing antibody to reverse these effects. CONCLUSIONS: These results suggest that haematopoietic-specific deletion of TLR4 promotes PVAT homeostasis, which is involved in reducing macrophage-induced TNF-alpha secretion and increasing mitochondrial biogenesis in brown adipocytes. PMID- 28579237 TI - Case of Percutaneous Extracorporeal Femoro-Femoral Bypass for Acute Limb Ischemia From Large Bore Access. PMID- 28579236 TI - Biodegradable Polymer Biolimus-Eluting Stents Versus Durable Polymer Everolimus Eluting Stents in Patients With Coronary Artery Disease: Final 5-Year Report From the COMPARE II Trial (Abluminal Biodegradable Polymer Biolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent). AB - OBJECTIVES: This analysis investigates the 5-year outcomes of the biodegradable polymer biolimus-eluting stent (BP-BES) and durable polymer everolimus-eluting stent (DP-EES) in an all-comers population undergoing percutaneous coronary intervention. BACKGROUND: Recent 1- and 3-year results from randomized trials have indicated similar safety and efficacy outcomes of BP-BES and DP-EES. Whether benefits of the biodegradable polymer device arise over longer follow-up is unknown. Moreover, in-depth, prospective, long-term follow-up data on metallic drug-eluting stents with durable or biodegradable polymers are scarce. METHODS: The COMPARE II trial (Abluminal Biodegradable Polymer Biolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent) was a prospective, randomized, multicenter, all-comers trial in which 2,707 patients were randomly allocated (2:1) to BP-BES or DP-EES. The pre-specified endpoint at 5 years was major adverse cardiac events, a composite of cardiac death, nonfatal myocardial infarction, or target vessel revascularization. RESULTS: Five-year follow-up was available in 2,657 patients (98%). At 5 years, major adverse cardiac events occurred in 310 patients (17.3%) in the BP-BES group and 142 patients (15.6%) in the DP-EES group (p = 0.26). The rate of the combined safety endpoint all-cause death or myocardial infarction was 15.0% in the BP-BES group versus 14.8% in the DP-EES group (p = 0.90), whereas the efficacy measure target vessel revascularization was 10.6% versus 9.0% (p = 0.18), respectively. Interestingly, definite stent thrombosis rates did not differ between groups (1.5% for BP-BES vs. 0.9% for DP-EES; p = 0.17). CONCLUSIONS: The 5-year analysis comparing biodegradable polymer-coated BES and the durable polymer-coated EES confirms the initial early- and mid-term results regarding similar safety and efficacy outcomes in this all-comers percutaneous coronary intervention population. PMID- 28579238 TI - A New Method for Hemostasis of a Pseudoaneurysm Using Autologous Blood. PMID- 28579239 TI - Not All Immobile Bioprosthetic Valve Cusps Are Thrombosed. PMID- 28579240 TI - First Observation of a "Golden Tube" After Complete Resorption of a Bioresorbable Vascular Scaffold in a Transplanted Patient With Cardiac Allograft Vasculopathy. PMID- 28579241 TI - A Dual-Snare Percutaneous Retrieval of Venous Stent Embolization to the Right Heart. PMID- 28579244 TI - Setting up a successful special interest study group: five-year reflection. PMID- 28579243 TI - Anchors for sutures to fix pedicled flaps to the floor of the mouth in reconstructions for cancer. PMID- 28579245 TI - Dentigerous cysts associated with impacted third molars in adults after decompression: a prospective survey of reduction in volume using computerised analysis of cone-beam computed tomographic images. AB - We prospectively investigated in adults the decompression of dentigerous cysts associated with impacted third molars at high risk of iatrogenic damage during extraction. The computerised calculated volumetric postoperative reductions measured by cone-beam computed tomography at four and eight months were correlated with the duration of treatment, initial volume, and patient's age. We prospectively monitored 14 adult patients with 14 dentigerous cysts that were associated with impacted third molars, for eight months after decompression. The mean (SD) reduction in volume during the first eight months was 71 (14) % (51% after the first four months and 20% after the second four months), with a monthly reduction rate of 9%. Both the total decrease in volume (a) and the monthly rate of reduction (b) were significantly associated (p<0.01) and linearly correlated with the duration of decompression [r (a)=-0.89, r (b)=-0.61] and initial volume [r (a)=r (b)=0.92], but not with the patient's age (p=0.49) [r (a)=r (b)=0.04]. The trend towards reduction in volume within a period of eight months of treatment allowed us to better understand the duration of decompression required. PMID- 28579246 TI - Neocondylar formation after resection of the mandible and reconstruction with a vascularised iliac crest free flap: rare case. AB - Tumours in the mandible often necessitate the removal of both mandibular and condylar bone. A free vascularised bone flap is a common choice for reconstruction, but it is rare for adults to form a new condyle after it. We describe a patient in whom a new condyle did form after reconstruction with a vascularised iliac crest free flap. PMID- 28579247 TI - Nonalcoholic fatty liver disease in patients with acute ischemic stroke is associated with more severe stroke and worse outcome. AB - BACKGROUND: There is a paucity of data regarding the association between nonalcoholic fatty liver disease (NAFLD) and acute ischemic stroke. Stroke is largely preventable, so that knowledge of risk factors is essential to achieve reductions in the stroke rate and resulting disease burden. OBJECTIVE: The aim of the present study was to evaluate the prognostic value of NAFLD on stroke severity and outcome. METHODS: We prospectively studied 200 patients who were admitted with acute ischemic stroke between September 2013 and August 2015. Demographic and vascular risk factors were detailed for all subjects. The severity of stroke was assessed with National Institutes of Health Stroke Scale score at admission. NAFLD was defined as serum alanine aminotransferase and/or aspartate aminotransferase levels above the upper limit of normal in the absence of other causes of elevated aminotransferase levels. The outcome was assessed with the modified Rankin scale score at discharge. RESULTS: NAFLD was found in 42.5% of the study population. The prevalence of diabetes was significantly higher among patients with NAFLD than those without NAFLD (P = .001). Waist circumference was significantly higher among patients with NAFLD than those without NAFLD (P < .05). Patients with NAFLD had significantly higher glucose, Triglycerides, Low density lipoprotein, serum alanine aminotransferase and aspartate aminotransferase than those without NAFLD (P < .05 for each comparison). National Institutes of Health Stroke Scale score at admission and modified Rankin scale score at discharge were significantly higher in patients with NAFLD than those without NAFLD (P < .05 for each comparison). CONCLUSION: NAFLD was found in 42.5% of acute ischemic stroke patients. NAFLD might be associated with more severe stroke and worse outcome. PMID- 28579242 TI - Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases. AB - Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model "Mitomouse" (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA 5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial. PMID- 28579248 TI - Echocardiography-Derived Left Ventricular Outflow Tract Gradient and Left Ventricular Posterior Wall Thickening Are Associated with Outcomes for Anatomic Repair in Congenitally Corrected Transposition of the Great Arteries. AB - BACKGROUND: Congenitally corrected transposition of the great arteries is a rare form of congenital heart disease. Management is controversial; options include observation, physiologic repair, and anatomic repair. Assessment of morphologic left ventricle preparedness is key in timing anatomic repair. This study's purpose was to review the modalities used to assess the morphologic left ventricle preoperatively and to determine if any echocardiographic variables are associated with outcomes. METHODS: A retrospective review of patients with congenitally corrected transposition of the great arteries eligible for anatomic repair at Lucile Packard Children's Hospital from 2000 to 2016 was conducted. Inclusion criteria were (1) presurgical echocardiography, magnetic resonance imaging, and cardiac catheterization and (2) clinical follow-up information. Echocardiographic measurements included left ventricular (LV) single-plane Simpson's ejection fraction, LV eccentricity index, LV posterior wall thickening, pulmonary artery band (PAB)/LV outflow tract (LVOT) pressure gradient, and LV and right ventricular strain. Magnetic resonance imaging measurements included LV mass, ejection fraction, eccentricity index, and LV thickening. LV pressure, PAB/LVOT gradient, right ventricular pressure, pulmonary vascular resistance, and Qp/Qs constituted catheterization data. Outcomes included achieving anatomic repair within 1 year of assessment in patients with LVOT obstruction or within 1 year of pulmonary artery banding and freedom from death, transplantation, or heart failure at last follow-up. RESULTS: Forty-one patients met the inclusion criteria. PAB/LVOT gradients of 85.2 +/- 23.4 versus 64.0 +/- 32.1 mm Hg (P = .0282) by echocardiography and 60.1 +/- 19.4 versus 35.9 +/- 18.9 mm Hg (P = .0030) by catheterization were associated with achieving anatomic repair and freedom from death, transplantation, and heart failure. Echocardiographic LV posterior wall thickening of 35.4 +/- 19.8% versus 20.6 +/- 15.0% (P = .0017) and MRI LV septal wall thickening of 37.1 +/- 18.8% versus 19.3 +/- 18.8% (P = .0306) were associated with achieving anatomic repair. Inter- and intraobserver variability for echocardiographic measurements was very good. CONCLUSIONS: PAB/LVOT gradient and LV posterior wall thickening are highly reproducible echocardiographic measurements that reflect morphologic LV performance and can be used in assessing patients with congenitally corrected transposition of the great arteries undergoing anatomic repair. PMID- 28579249 TI - Response to the letter to the editor regarding an article, "Takotsubo cardiomyopathy in amyotrophic lateral sclerosis". PMID- 28579250 TI - DNA methylation of extracellular matrix remodeling genes in children exposed to arsenic. AB - Several novel mechanistic findings regarding to arsenic's pathogenesis has been reported and some of them suggest that the etiology of some arsenic induced diseases are due in part to heritable changes to the genome via epigenetic processes such as DNA methylation, histone maintenance, and mRNA expression. Recently, we reported that arsenic exposure during in utero and early life was associated with impairment in the lung function and abnormal receptor for advanced glycation endproducts (RAGE), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) sputum levels. Based on our results and the reported arsenic impacts on DNA methylation, we designed this study in our cohort of children exposed in utero and early childhood to arsenic with the aim to associate DNA methylation of MMP9, TIMP1 and RAGE genes with its protein sputum levels and with urinary and toenail arsenic levels. The results disclosed hypermethylation in MMP9 promotor region in the most exposed children; and an increase in the RAGE sputum levels among children with the mid methylation level; there were also positive associations between MMP9 DNA methylation with arsenic toenail concentrations; RAGE DNA methylation with iAs, and %DMA; and finally between TIMP1 DNA methylation with the first arsenic methylation. A negative correlation between MMP9 sputum levels with its DNA methylation was registered. In conclusion, arsenic levels were positive associated with the DNA methylation of extracellular matrix remodeling genes;, which in turn could modifies the biological process in which they are involved causing or predisposing to lung diseases. PMID- 28579252 TI - Biological implications of selenium in adolescent rats exposed to binge drinking: Oxidative, immunologic and apoptotic balance. AB - Alcohol intermittent binge drinking (BD) during adolescence decreases the levels of selenium (Se), a trace element that plays a key biological role against oxidative damage in hepatocytes through different selenoproteins such as the antioxidant enzymes glutathione peroxidases (GPx1 and Gpx4) and selenoprotein P (SelP). In this context, it has been found that GPx4 has an essential antioxidant role in mitochondria modulating the apoptosis and NF-kB activation (a factor intimately related to apoptosis and immune function). To further investigate the effectiveness of selenium supplementation in oxidative balance, inflammation and apoptosis, the present study examined the protective effects of 0.4ppm of dietary selenite administrated to adolescent rats exposed to BD. BD consumption depleted Se deposits in all the tissues studied. In liver, GPx1 activity and expression were decreased leading to protein and lipid hepatic oxidation. Moreover GPx4 and NF-kB expression were also decreased in liver, coinciding with an increase in caspase-3 expression. This hepatic profile caused general liver damage as shown the increased serum transaminases ratio AST/ALT. Proinflammatory serum citokines and chemocines were decreased. Se supplementation therapy used restored all these values, even AST levels. These findings suggest for first time that Se supplementation is a good strategy against BD liver damage during adolescence, since it increases GPx1 and GPx4 expression and avoids NF-kB downregulation and caspase-3 upregulation, leading to a better oxidative, inflammatory and apoptotic liver profile. The therapy proposed could be considered to have a great biological efficacy and to be suitable for BD exposed teenagers in order to avoid future hepatic complications. PMID- 28579253 TI - Molecular evidence of Borrelia burgdorferi sensu lato in patients in Brazilian central-western region. AB - We aimed to detect DNA of Borrelia burgdorferi in whole blood and serum samples of patients with clinical symptoms and epidemiology compatible with Brazilian Lyme-like disease. Four patients with positive epidemiological histories were recruited for the study. Blood samples were collected, screened by serologic testing by ELISA and Western blotting and molecular identification of B. burgdorferi by amplifying a fragment of the conserved gene that synthesizes the hook flagellar flgE. The results showed positive serology and for the first time, the presence of B. burgdorferi sensu lato in humans in the Midwest region of Brazil. The resulting sequences were similar to GenBank corresponding sequences of B. burgdorferi flgE gene. By neighbor-joining the phylogenetic analysis, the flgE sequence of the Brazilian strain clustered in a monophyletic group with the sequence of B. burgdorferi sensu lato under 100% bootstrap support. This study opens up promising perspectives and reinforces the need for additional studies to determine the epidemiological characteristics of the disease, as well as the impact of the prevalence of Brazilian borreliosis in Mato Grosso do Sul State, Brazil. PMID- 28579251 TI - Perinatal exposure to organohalogen pollutants decreases vasopressin content and its mRNA expression in magnocellular neuroendocrine cells activated by osmotic stress in adult rats. AB - Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are environmental pollutants that produce neurotoxicity and neuroendocrine disruption. They affect the vasopressinergic system but their disruptive mechanisms are not well understood. Our group reported that rats perinatally exposed to Aroclor-1254 (A1254) and DE-71 (commercial mixtures of PCBs and PBDEs) decrease somatodendritic vasopressin (AVP) release while increasing plasma AVP responses to osmotic activation, potentially emptying AVP reserves required for body-water balance. The aim of this research was to evaluate the effects of perinatal exposure to A1254 or DE-71 (30mgkg/day) on AVP transcription and protein content in the paraventricular and supraoptic hypothalamic nuclei, of male and female rats, by in situ hybridization and immunohistochemistry. cFOS mRNA expression was evaluated in order to determine neuroendocrine cells activation due to osmotic stimulation. Animal groups were: vehicle (control); exposed to either A1254 or DE-71; both, control and exposed, subjected to osmotic challenge. The results confirmed a physiological increase in AVP-immunoreactivity (AVP-IR) and gene expression in response to osmotic challenge as reported elsewhere. In contrast, the exposed groups did not show this response to osmotic activation, they showed significant reduction in AVP-IR neurons, and AVP mRNA expression as compared to the hyperosmotic controls. cFOS mRNA expression increased in A1254 dehydrated groups, suggesting that the AVP-IR decrease was not due to a lack of the response to the osmotic activation. Therefore, A1254 may interfere with the activation of AVP mRNA transcript levels and protein, causing a central dysfunction of vasopressinergic system. PMID- 28579254 TI - Comprehensive Mapping of HIV-1 Escape from a Broadly Neutralizing Antibody. AB - Precisely defining how viral mutations affect HIV's sensitivity to antibodies is vital to develop and evaluate vaccines and antibody immunotherapeutics. Despite great effort, a full map of escape mutants has not been delineated for an anti HIV antibody. We describe a massively parallel experimental approach to quantify how all single amino acid mutations to HIV Envelope (Env) affect neutralizing antibody sensitivity in the context of replication-competent virus. We apply this approach to PGT151, a broadly neutralizing antibody recognizing a combination of Env residues and glycans. We confirm sites previously defined by structural and functional studies and reveal additional sites of escape, such as positively charged mutations in the antibody-Env interface. Evaluating the effect of each amino acid at each site lends insight into biochemical mechanisms of escape throughout the epitope, highlighting roles for charge-charge repulsions. Thus, comprehensively mapping HIV antibody escape gives a quantitative, mutation-level view of Env evasion of neutralization. PMID- 28579257 TI - Pregnancy After Fontan-Kreutzer Surgery. PMID- 28579256 TI - Marfan Syndrome and Loeys-Dietz Syndrome in Children: A Multidisciplinary Team Experience. PMID- 28579258 TI - Factors associated with mild cognitive impairment in a population-based cohort. PMID- 28579255 TI - Lysosomal Degradation Is Required for Sustained Phagocytosis of Bacteria by Macrophages. AB - Clearance of bacteria by macrophages involves internalization of the microorganisms into phagosomes, which are then delivered to endolysosomes for enzymatic degradation. These spatiotemporally segregated processes are not known to be functionally coupled. Here, we show that lysosomal degradation of bacteria sustains phagocytic uptake. In Drosophila and mammalian macrophages, lysosomal dysfunction due to loss of the endolysosomal Cl- transporter ClC-b/CLCN7 delayed degradation of internalized bacteria. Unexpectedly, defective lysosomal degradation of bacteria also attenuated further phagocytosis, resulting in elevated bacterial load. Exogenous application of bacterial peptidoglycans restored phagocytic uptake in the lysosomal degradation-defective mutants via a pathway requiring cytosolic pattern recognition receptors and NF-kappaB. Mammalian macrophages that are unable to degrade internalized bacteria also exhibit compromised NF-kappaB activation. Our findings reveal a role for phagolysosomal degradation in activating an evolutionarily conserved signaling cascade, which ensures that continuous uptake of bacteria is preceded by lysosomal degradation of microbes. PMID- 28579259 TI - Clinical location of the fourth and fifth intercostal spaces as a percent of the length of the sternum. AB - OBJECTIVES: To verify accurate placement of the precordial ECG leads by identifying the 4th and 5th intercostal spaces as a function of the length of the sternum. This should decrease the percentage of lead misplacement leading to misdiagnoses. METHODS: The population consisted of patients and healthy volunteers. The proposed method compared palpation of the 4th and 5th intercostal spaces to a percentile of the sternal length. Location of the 4th and 5th intercostal space using a simple device was evaluated to assist in proper placement of the precordial leads to obtain accurate diagnosis. RESULTS: The location of the 4th and 5th intercostal space is related to the length of the sternum. It is 77% of the sternal length that measures 15cm for the 4th intercostal space. The position of the V1 and V2 electrodes decreases to 57% when the sternal length is 26cm. Similar data was obtained to locate the 5th intercostal space with proper position of V4-V6 electrodes. Tables are provided to facilitate this process. An instrument was designed to measure the 4th and 5th intercostal space as a function of the sternal length. CONCLUSIONS: The location of the 4th and 5th intercostal space is identified based on the length of the sternum. PMID- 28579260 TI - Serum cystatin C levels are associated with coronary artery calcification in women without chronic kidney disease. AB - BACKGROUND: Chronic renal disease (CKD) is a determinant of coronary artery calcification (CAC), which is a predictor of cardiovascular events. However, in a population without CKD, the association between CAC and renal function is unclear. CAC is affected by sex. This study aimed to determine whether serum cystatin C, a sensitive marker of kidney function, or sex differences are associated with CAC in patients without CKD. METHODS: We evaluated 456 consecutive patients (61+/-13 years, 42% women) without CKD and evidence of coronary artery disease. The CAC (Agatston) score was examined by multidetector computed tomography. RESULTS: When patients were categorized into three CAC groups based on the Agatston score, mild (<10), moderate (11-399), and severe (>=400) in each sex, serum cystatin C levels gradually increased by severity of CAC in women, but not men. Receiver operating characteristic curve analysis showed that, in women, a cut-off value of 0.97mg/l for cystatin C discriminated patients with severe CAC with a sensitivity of 71% and specificity of 77% (area under the curve, 0.74; 95% CI: 0.62-0.86; p<0.01). Multivariate logistic analysis showed that serum cystatin C was not associated with severe CAC in all patients and men, but this association was observed in women (OR: 7.80 for cystatin C>=0.97mg/l, 95% CI: 1.76-34.6, p<0.01). CONCLUSION: Higher serum cystatin C levels are associated with greater CAC in women without CKD. Measurement of cystatin C may be useful for identifying women who are at high risk for cardiovascular disease. PMID- 28579261 TI - Are axial intervertebral disc biomechanics determined by osmosis? AB - The intervertebral disc faces high compressive forces during daily activities. Axial compression induces creeping fluid loss and reduction in disc height. With degeneration, disc fluids and height are progressively lost, altering biomechanics. It is assumed that this reduction of fluids is caused by a decline of osmolality within the disc due to proteoglycan depletion. Here we investigate the isolated effect of a reduction in osmosis on the biomechanical properties of the intervertebral disc. Continuous diurnal loading was applied to healthy caprine intervertebral discs in a loaded disc culture system for a total of 6days. We increased testing bath osmolality with two doses of polyethylene-glycol (PEG), thereby reducing the osmotic gradient between the disc and the surrounding fluid. This way we could study the isolated effect of reduced osmosis on axial creep, without damaging the disc. We evaluated: daily creep and recovery, recovery time-constants and compressive stiffness. Additionally, we investigated water content. There was a strong dose-dependent effect of PEG concentration on water content and axial creep behaviour: disc height, amplitude and rate of creep and recovery were all significantly reduced. Axial compressive stiffness of the disc was not affected. Reduction of water content and amplitude of creep and recovery showed similarity to degenerative disc biomechanics. However, the time constants increased, indicating that the hydraulic permeability was reduced, in contrast to what happens with degeneration. This suggests that besides the osmotic gradient, the permeability of the tissues determines healthy intervertebral disc biomechanics. PMID- 28579264 TI - Discussion. PMID- 28579262 TI - Contact forces in the tibiofemoral joint from soft tissue tensions: Implications to soft tissue balancing in total knee arthroplasty. AB - Proper tension of the knee's soft tissue envelope is important during total knee arthroplasty; incorrect tensioning potentially leads to joint stiffness or instability. The latter remains an important trigger for revision surgery. The use of sensors quantifying the intra-articular loads, allows surgeons to assess the ligament tension at the time of surgery. However, realistic target values are missing. In the framework of this paper, eight non-arthritic cadaveric specimens were tested and the intra-articular loads transferred by the medial and lateral compartment were measured using custom sensor modules. These modules were inserted below the articulating surfaces of the proximal tibia, with the specimens mounted on a test setup that mimics surgical conditions. For both compartments, the highest loads are observed in full extension. While creating knee flexion by lifting the femur and flexing the hip, mean values (standard deviation) of 114N (71N) and 63N (28N) are observed at 0 degrees flexion for the medial and lateral compartment respectively. Upon flexion, both medial and lateral loads decrease with mean values at 90 degrees flexion of 30N (22N) and 6N (5N) respectively. The majority of the load is transmitted through the medial compartment. These observations are linked to the deformation of the medial and lateral collaterals, in addition to the anatomy of the passive soft tissues surrounding the knee. In conclusion, these findings provide tangible clinical guidance in assessing the soft tissue loads when dealing with anatomically designed total knee implants. PMID- 28579263 TI - Early and late outcomes with prolonged open chest management after cardiac surgery. AB - OBJECTIVES: Open chest management (OCM) is an important intervention for patients who are unable to undergo sternal closure after cardiac surgery. This study reviews the factors associated with a prolonged need for this intervention and investigates its association with early and late mortality. METHODS: Patients undergoing OCM from January 2009 to December 2014 were reviewed. Differences in the median duration of OCM when a perioperative variable was present versus its absence were determined and variables significant at P <= .1 were analyzed using Poisson regression for factors associated with prolonged OCM. Multivariable logistic regression and Cox proportional hazards models were developed to investigate perioperative factors that were associated with early and late mortality. RESULTS: A total of 201 patients (5%) required OCM and the overall median duration of this intervention was 3 days. The use a temporary assist device (median, 7 vs 2 days; P < .001), pneumonias (median, 11 vs 3 days; P < .001), sternal re-explorations (median, 6 vs 2 days; P < .001), and renal failure (median, 6 vs 3 days; P = .02) were among the factors that were highly associated with prolonged OCM using Poisson regression. Thirty-day mortalities occurred in 32 patients (16%) and were significantly associated with emergency surgery (P = .03), sternal re-explorations (P = .001), and OCM duration (median, 6 vs 3 days; P = .02). On multivariable logistic regression and Cox analysis, delaying sternal closure by 1-day increments increased the risk of early and late mortality by 11% (P = .01), and 9% (P < .001), respectively. CONCLUSIONS: Prolonged OCM was associated with increasing perioperative morbidity and a higher risk of early and late mortality. PMID- 28579265 TI - Importance of chewing, saliva, and swallowing function in patients with advanced oral cancer undergoing preoperative chemoradiotherapy: a prospective study of quality of life. AB - The primary objective of this study was to investigate the quality of life (QOL) of patients with oral squamous cell carcinoma (OSCC) undergoing curative neoadjuvant chemoradiotherapy followed by radical tumour resection and simultaneous oral cavity reconstruction, using two validated questionnaires. A secondary objective was to assess clinical variables predicting post-treatment dysfunction in chewing, saliva, and swallowing. Thirty-five patients with locally advanced OSCC who underwent preoperative chemoradiotherapy were recruited prospectively. All patients completed both the University of Washington Quality of Life version 4 questionnaire (UW-QOL) and the Functional Assessment of Cancer Therapy-Head & Neck version 4 questionnaire (FACT-H&N). UW-QOL and FACT-H&N items were associated with clinical variables. Nearly three-quarters of OSCC patients perceived good to excellent levels of overall QOL after preoperative chemoradiotherapy. Chewing difficulties, decreased salivary function, and swallowing dysfunction were the most frequent complaints of OSCC patients. Items related to food intake were significantly worse in OSCC patients older than 60 years and those with T4 tumours, as well as those without alcohol intake. Chewing, saliva, and swallowing are the most significant issues in patients with OSCC undergoing preoperative chemoradiotherapy. The results of this study may help guide treatment decisions for OSCC patients based on more accurate expectations of adverse effects of cancer treatment. PMID- 28579266 TI - A longitudinal study of changes in psychosocial well-being during orthognathic treatment. AB - The aim was to evaluate changes in the psychosocial well-being of orthognathic surgery patients (n=22) during treatment and to compare results with those of adults not requiring orthognathic treatment (n=22). Patient data were collected before treatment (T0), after the first orthodontic examination (T1), three times during treatment (T2-T4), and 1 year after surgery (T5). In this article, only data corresponding to patient stage T5 are reported for the control subjects. Participants filled in a structured diary and the modified version of the Secord and Jourard body image questionnaire, the Orthognathic Quality of Life Questionnaire, the Rosenberg Self-Esteem Scale, and the Acceptance and Action Questionnaire II. Moreover, patients filled in the Symptom Checklist-90. After the placement of orthodontic appliances (T2), orthognathic quality of life, self esteem, and psychological flexibility were lower and psychiatric symptoms increased. Improvements were observed from T2 to T5 in orthognathic quality of life, body image, self-esteem, psychological flexibility, and psychiatric symptoms. Treatment resulted in improvements from T0 to T5 in orthognathic quality of life, body image, and psychiatric symptoms. At T5, patient psychosocial well-being was comparable to or even better than that of control subjects. Orthognathic treatment seems to support psychological well-being, but the range of individual variation is wide. PMID- 28579267 TI - Preliminary Results of a Simplified Breast MRI Protocol to Characterize Breast Lesions: Comparison with a Full Diagnostic Protocol and a Review of the Current Literature. AB - RATIONALE AND OBJECTIVES: This study aimed to investigate whether a simplified breast magnetic resonance imaging (MRI) protocol consisting of a localizer, one precontrast sequence, and three time-point postcontrast sequences (at 28 seconds, 84 seconds and 252 seconds after the contrast agent administration) is suitable for the characterization of breast lesions as compared to a full diagnostic protocol (FDP). This study also aimed to review the current literature concerning abbreviated breast MRI protocols and offer an alternative protocol. MATERIALS AND METHODS: Breast magnetic resonance (MR) examinations with detected breast lesions of 98 patients were retrospectively evaluated. Two expert radiologists in consensus reviewed the simplified breast protocol (SBP) first and only thereafter the regular FDP, recording a diagnosis for each detected lesion for both protocols. Receiver operating characteristic curve analysis was performed to determine the diagnostic performance of the SBP compared to the standard FDP. A revision of the previously reported abbreviated breast magnetic resonance protocols was also carried out. RESULTS: A total of 180 lesions were identified; of these, 110 (61%) were malignant and 70 (39%) were benign. Of the 110 malignant lesions, 86 (78%) were invasive ductal carcinoma, 18 (16%) were invasive lobular carcinoma, and 6 (6%) were ductal carcinoma in situ. Areas under the curve for the receiver operating characteristic curves for the SBP vs the FDP were equivalent (0.98 vs 0.99, respectively; P = 0.76). The SBP could be performed in approximately 6 minutes and 58 seconds, compared to 14 minutes and 48 seconds for the FDP. CONCLUSIONS: An SBP protocol including a late postcontrast time point is accurate for the characterization of breast lesions and was comparable to the standard FDP protocol, allowing a potential reduction of the total acquisition and interpretation times. PMID- 28579268 TI - Knowledge and attitudes toward HIV/AIDS among the general population of Jeddah, Saudi Arabia. AB - BACKGROUND: In contrast to most regions of the world where a decline of the HIV epidemic can be seen, data from the Middle East and North Africa (MENA) region suggests increasing incidence among key populations in the region. Accurate data collection has long been limited by social, cultural, and religious taboos. Understanding knowledge levels and attitudes toward HIV/AIDS is an important component to design adequate and culturally appropriate awareness and prevention programs. METHODS: A survey was conducted including 3841 participants during a series of public HIV/AIDS awareness campaigns from 2013 to 2015 in Jeddah, Saudi Arabia. Participants completed a questionnaire including socio-demographic data, and questions around knowledge and attitudes toward HIV/AIDS. A knowledge score was created. Frequencies were calculated for all variables, mean knowledge scores were compared using non-parametric tests. Categorical variables were compared using Chi-squared test. The mean knowledge score was 5.2 out of 9 possible points. Respondents in the age class 19-25, respondents with university degrees, and those who know people living with HIV/AIDS had higher scores. Overall the attitude toward people living with HIV/AIDS was negative, more than 40% suggested that HIV positive people should be isolated and less than 20% would support a marriage with an HIV positive person. Negative attitudes were more common among people in older age groups, with a lower educational background, and respondents that did not know anyone living with HIV/AIDS. CONCLUSION: Knowledge gaps and negative attitudes of the general public toward people living with HIV/AIDS have been identified and can be used to tailor educational campaigns in Saudi Arabia. PMID- 28579269 TI - IRF2-INPP4B axis participates in the development of acute myeloid leukemia by regulating cell growth and survival. AB - Acute myeloid leukemia (AML) is a highly heterogeneous disease, which results in the fact that patient management has remained disappointingly uniform. Therefore, the molecular mechanism underlying AML needs to be further investigated. Here in this study, we identify the interferon-regulatory factor 2 (IRF2) as a novel regulator in human AML. We show that IRF2 knockdown inhibits growth, colony formation of OCI/AML-2, OCI/AML-3, and THP-1 cells. In addition, IRF2 knockdown induces apoptosis of AML cells by regulating the apoptotic effectors Bcl-2, Bax and Caspase 3. Further mechanism analysis shows that inositol polyphosphate-4 phosphatase, type-II (INPP4B) contributes to the effects of IRF2 on apoptosis and growth of AML cells. IRF2 binds INPP4B promoter and promotes INPP4B expression in AML cells. Restoration of the expression of INPP4B blocks the effects of IRF2 knockdown on apoptosis and colony formation in OCI/AML-2 and OCI/AML-3 cells. In conclusion, IRF2 serves as an important regulator in AML by targeting INPP4B. Therefore, IRF2 may be a potential target for AML treatment. PMID- 28579270 TI - Reply. PMID- 28579271 TI - Endoscopy in Pregnant Women With Liver Cirrhosis. PMID- 28579272 TI - Endoscopy for Inflammatory Bowel Disease During Pregnancy: Only When There Is a Strong Indication. PMID- 28579273 TI - Crohn's and a Cough: Connecting the Dots. PMID- 28579274 TI - The Need for Appropriate Comparisons: A Response to Ravi et al. PMID- 28579275 TI - Reply. PMID- 28579276 TI - Are public-private partnerships the solution to tackle neglected tropical diseases? A systematic review of the literature. AB - Pharmaceutical companies are reluctant to invest in research and development (R&D) of products for neglected tropical diseases (NTDs) mainly due to the low ability-to-pay of health insurance systems and of potential consumers. The available preventive and curative interventions for NTDs mostly rely on old technologies and products that are often not adequate. Moreover, NTDs mostly affect populations living in remote rural areas and conflict zones, thereby hampering access to healthcare. The challenges posed by NTDs have led to the proliferation of a variety of public-private partnerships (PPPs) in the last decades. We conducted a systematic review to assess the functioning and impact of these partnerships on the development of and access to better technologies for NTDs. Our systematic review revealed a clear lack of empirical assessment of PPPs: we could not find any impact evaluation analyses, while these are crucial to realize the full potential of PPPs and to progress further towards NTDs elimination. PMID- 28579277 TI - Autoimmune severe acute fulminant hepatic failure (FHF) during pregnancy. PMID- 28579278 TI - Higher 30 Day Mortality in Patients with Familial Abdominal Aortic Aneurysm after EVAR. AB - OBJECTIVES: To determine the influence of a positive family history for aneurysms on clinical success and mortality after endovascular aneurysm repair (EVAR). METHODS: From 2009 to 2011, 1262 patients with abdominal aortic aneurysms (AAA) treated by EVAR were enrolled in a prospective, industry sponsored clinical registry ENGAGE. Patients were classified into familial and sporadic AAA patients according to baseline clinical reports. Clinical characteristics, aneurysm morphology, and follow-up were registered. The primary endpoint was clinical success after EVAR, a composite of technical success and freedom from the following complications: AAA increase >5 mm, type I and III endoleak, rupture, conversion, secondary procedures, migration, and occlusion. Secondary endpoints were the individual components of clinical success, 30 day mortality, and aneurysm related and all cause mortality. RESULTS: Of the 1262 AAA patients (89.5% male and mean age 73.1 years), 86 patients (6.8%) reported a positive family history and were classified as familial AAA. Duration of follow-up was 4.4 +/- 1.7 years. Patients with familial AAA were more often female (18.6% vs. 9.9%, p = .012). No difference was observed in aneurysm morphology. There was no significant difference in clinical success between patients with familial and sporadic AAA (72.1% vs. 79.3%, p=.116). Familial AAA patients had a higher 30 day mortality after EVAR (4.7% vs. 1.0%, adjusted HR 5.7, 1.8-17.9, p = .003) as well as aneurysm related mortality (5.8% vs. 1.3%, adjusted HR 5.4, 1.9-14.9, p = .001), while no difference was observed in all cause mortality (19.8% vs. 24.3%, adjusted HR 0.8, 0.5-1.4, p = .501). CONCLUSIONS: The current study shows a higher 30 day mortality after EVAR in familial AAA patients. Future studies should determine the role of family history in AAA treatment, suitability for endovascular or open repair, and on adaptation of post-operative surveillance. For the time being, patients with familial forms of AAA should be considered at higher risk for EVAR and warrant extra vigilance. PMID- 28579279 TI - A Fishy Subclavian Artery Pseudoaneurysm. PMID- 28579280 TI - Thrombosis of Cross-pubic Collateral Veins After a Long Haul Flight in a Patient With Chronic Left Ilio-femoral Venous Obstruction. PMID- 28579281 TI - Interfractional variability of respiration-induced esophageal tumor motion quantified using fiducial markers and four-dimensional cone-beam computed tomography. AB - PURPOSE: To investigate the interfractional variability of respiration-induced esophageal tumor motion using fiducial markers and four-dimensional cone-beam computed tomography (4D-CBCT) and assess if a 4D-CT is sufficient for predicting the motion during the treatment. MATERIALS AND METHODS: Twenty-four patients with 63 markers visible in the retrospectively reconstructed 4D-CBCTs were included. For each marker, we calculated the amplitude and trajectory of the respiration induced motion. Possible time trends of the amplitude over the treatment course and the interfractional variability of amplitudes and trajectory shapes were assessed. Further, the amplitudes measured in the 4D-CT were compared to those in the 4D-CBCTs. RESULTS: The amplitude was largest in the cranial-caudal direction of the distal esophagus (mean: 7.1mm) and proximal stomach (mean: 7.8mm). No time trend was observed in the amplitude over the treatment course. The interfractional variability of amplitudes and trajectory shapes was limited (mean: <=1.4mm). Moreover, small and insignificant deviation was found between the amplitudes quantified in the 4D-CT and in the 4D-CBCT (mean absolute difference: <=1.0mm). CONCLUSIONS: The limited interfractional variability of amplitudes and trajectory shapes and small amplitude difference between 4D-CT based and 4D-CBCT-based measurements imply that a single 4D-CT would be sufficient for predicting the respiration-induced esophageal tumor motion during the treatment course. PMID- 28579282 TI - A radiosensitivity gene signature and PD-L1 status predict clinical outcome of patients with invasive breast carcinoma in The Cancer Genome Atlas (TCGA) dataset. AB - BACKGROUND AND PURPOSE: We investigated the link between the radiosensitivity gene signature and programmed cell death ligand 1 (PD-L1) status and clinical outcome in order to identify a group of patients that would possibly receive clinical benefit of radiotherapy (RT) combined with anti-PD1/PD-L1 therapy. MATERIAL AND METHODS: We validated the identified gene signature related to radiosensitivity and analyzed the PD-L1 status of invasive breast cancer in The Cancer Genome Atlas (TCGA) dataset. To validate the gene signature, 1045 patients were selected and divided into two clusters using a consensus clustering algorithm based on their radiosensitive (RS) or radioresistant (RR) designation according to their prognosis. Patients were also stratified as PD-L1-high or PD L1-low based on the median value of CD274 mRNA expression level as surrogates of PD-L1. RESULTS: Patents assigned to the RS group had decreased risk of recurrence free survival (RFS) rate than patients in the RR group by univariate analysis (HR 0.45, 95% CI 0.25-0.81, p=0.008) only when treated with RT. The RS group was independently associated with the PD-L1-high group, and CD274 mRNA expression was significantly higher in the RS group (p<0.001) than the RR group. In the PD-L1 high group, the RS group was associated with better RFS compared to the RR group (HR 0.37, 95% CI 0.16-0.87, p=0.022) in multivariate analysis. The level of PD-L1 expression may represent the immunogenicity of tumors, and thus, we speculated that the PD-L1-high group had more immunogenic tumors, which could be more sensitive to radiation-induced immunologic cell death. CONCLUSION: We first evaluated the predictive value of the radiosensitivity gene signature and described a relationship with this radiosensitivity gene signature and PD-L1. The radiosensitivity gene signature and PD-L1 status were important factors for prediction of the clinical outcome of RT in patients with invasive breast cancer and may be used for selecting patients who will benefit from RT combined with anti-PD1/PDL1 therapy. PMID- 28579283 TI - Optimizing management of upper tract urothelial carcinoma. AB - Upper tract urothelial cancer (UTUC) is a rare cancer of the urothelium, comprising only a fraction of cases as compared to urothelial tumors of the bladder. As a result, systemic treatment approaches in bladder cancer are often applied to patients with UTUC. Given the anatomical location of these tumors, the age, the comorbid conditions of these patients with UTUC, and the need for radical nephroureterectomy for treatment, most patients have substantial impairment of renal reserve. There is growing evidence for the benefit of perioperative chemotherapy in this disease. Patients with UTUC have high rates of microsatellite instability and fibroblast growth factor receptor 3 mutations as compared to their bladder counterparts presenting unique, important subsets in UTUC. Immune checkpoint inhibitors targeting the programmed death receptor 1 and ligand have provided a new second-line treatment option for patients with UTUC and appear particularly well suited for patients with microsatellite instability. More work in understanding the molecular gene signatures and its relationship to response to chemotherapy, immunotherapy, and targeted therapy is needed to continually optimize care for patients with all stages of disease. Advances in UTUC are possible, when one accounts for the unique clinical and biological features of this disease. PMID- 28579284 TI - Mechanism of physical stress-induced inhibition of ovarian estradiol secretion in anesthetized rats. AB - This study examined the site of main integration center in the physical stress induced inhibition of ovarian estradiol secretion because of ovarian sympathetic nerve (superior ovarian nerve: SON) activation in anesthetized rats. In central nervous system-intact rats, electrical stimulation of the tibial afferent nerve at 10V increased the efferent activity of the SON by 39+/-13% and reduced the ovarian secretion of estradiol by 34+/-7%. These responses were observed in decerebrate rats but were abolished in spinal rats. Thus, the main integration center for this ovarian hormonal response is located in the brain stem. PMID- 28579285 TI - The Experience of Advanced Practice Nurses in US Emergency Care Settings. AB - INTRODUCTION: Little information has been published regarding the actual practice, training, and validation of basic skills and competencies needed by the advanced practice registered nurse (APRN) in the emergency care setting. The purpose of this study was to (1) identify skills being performed by APRNs practicing in emergency care settings (2); explore types of training; and (3) describe competency validation. Additionally, we explored frequency of skill use and facilitators and barriers to performing a skill to the full extent of training and education. METHODS: An exploratory mixed-methods study was performed incorporating a self-report survey and focus group interviews. RESULTS: The educational path to advanced practice nursing in emergency care settings is not standardized. Few programs incorporate or address the need for APRNs to receive acute care training across the life span, which is the hallmark of emergency nursing practice. Similarly, training is reported as fragmented, and validation of skills for both nurse practitioners and clinical nurse specialists can vary. APRN practice autonomy is affected by the presence of other providers (specifically physicians), institutional culture, and state boards of nursing that regulate practice. DISCUSSION: Integrated educational and orientation programs are needed that address high-acuity patients across the life span. Additionally, a more nuanced approach to assessing APRN capabilities as a combination of hard (clinical emergency) and soft (communication and organizational) skills may be an appropriate framework within which to examine the advanced practice role. Future research should continue to evaluate training, competency assessment, and outcomes for APRNs in the emergency care setting. PMID- 28579286 TI - HIV/AIDS infection: The beginning of the end for today's greatest pandemic? AB - Recently, there have been significant advances in the fight against human immunodeficiency virus, which have increased the hopes of definitively halting its dissemination and of starting the decline of the epidemic it has caused. Transmission of the infection was drastically reduced when infected patients were given antiretroviral treatments, which boosted the diffusion of treatments to middle- and low-income countries. Global therapy coverage has doubled in recent years; meanwhile the incidence of new infections has decreased. Various curative strategies are also actively being investigated, including those aiming to induce cell resistance to the infection through gene therapy and the elimination of latent virus reservoirs. This article reviews the current situation and future developments in terms of controlling the pandemic and, eventually, curing the infection. PMID- 28579287 TI - Effect of one- or two-level posterior lumbar interbody fusion on global sagittal balance. AB - BACKGROUND CONTEXT: Sagittal imbalance is associated with poor clinical outcomes in patients with degenerative lumbar disease. However, there is no consensus on the impact of posterior lumbar interbody fusion (PLIF) on local and global sagittal balance. PURPOSE: To reveal the effect of one- or two-level PLIF on global sagittal balance. DESIGN/SETTING: A retrospective case-control study. PATIENTS SAMPLE: This study included 88 patients who underwent a one- or two level PLIF for spinal stenosis with spondylolisthesis. OUTCOME MEASURES: Clinical and radiological parameters were measured pre- and postoperatively. METHODS: All patients were followed up for >2 years. Clinical outcomes included a visual analog scale, Oswestry Disability Index, and EuroQol 5-dimension questionnaire (EQ-5D). Radiological parameters were measured using whole-spine standing lateral radiographs. Fusion, loosening, subsidence rates, and adverse events were also evaluated. Patients were divided into two groups according to their preoperative C7-S1 sagittal vertical axis (SVA): Group N: SVA<=5 cm vs Group I: SVA>5 cm; they were also divided according to postoperative changes in C7-S1 SVA. Clinical and radiological outcomes were compared between the groups. RESULTS: All clinical outcomes and radiological parameters improved postoperatively. C7-S1 SVA improved (-1.6 cm) after L3-L5 fusion, but it was compromised (+3.6 cm) after L4-S1 fusion (p=.001). Preoperative demographic and clinical data showed no difference except in the anxiety or depression domain of EQ-5D. No differences were found in postoperative clinical outcomes. Lumbar lordosis, pelvic tilt, and thoracic kyphosis slightly improved in Group N, whereas C7-S1 SVA decreased from 9.5 cm to 3.8 cm (p<.001) in Group I. Furthermore, all sagittal parameters improved in Group I. On comparing the postoperative changes in C7-S1 SVA, we found that the decreasing trend in the postoperative C7-S1 SVA was related to a larger preoperative C7-S1 SVA (p=.030) and a more proximal level fusion (L3-L5 vs L4-S1, p=.033). CONCLUSIONS: Global sagittal balance improved after short-level lumbar fusion surgery in patients having spinal stenosis with spondylolisthesis who showed preoperative sagittal imbalance. Restoration of sagittal balance predominantly occurred after L3-L4, L4-L5, or L3-L5 PLIF. However, no such restoration was observed after L5-S1 or L4-S1 PLIF. Thus, we could anticipate sagittal balance restoration after performing PLIF at L3-L4 or L4-L5 level. However, caution is required when planning for L5-S1 fusion if preoperative sagittal imbalance is present. PMID- 28579289 TI - Effects of anti-somatostatin agents on glucose metabolism. AB - The anti-somatostatin agents used to treat acromegaly, Cushing's disease and neuroendocrine tumours also have hyperglycaemic effects. This is particularly true for pasireotide. Hyperglycaemic events are seen in 57-73% of patients with Cushing's treated with pasireotide, with a need to initiate antidiabetic treatment in about 50% of these patients. In acromegaly, treatment with pasireotide induces hyperglycaemia in 29-61% of patients. Pasireotide-induced hyperglycemia occurs early, within the first 3 months of treatment, due to a decrease in insulin secretion secondary to a fall in secretion of GLP-1 and GIP, and potentially also due to a direct inhibitory effect of pasireotide on beta cells. Close monitoring of blood glucose is mandatory in all patients during the first 3 months of treatment with pasireotide. Where necessary, antidiabetic treatment should be initiated, preferably with a DPP-4 inhibitor or a GLP-1 receptor agonist, both of which have proven efficacy in the control of hyperglycaemia induced by pasireotide. PMID- 28579288 TI - Movat Pentachrom stain reveals unexpected high osteogenesis rate in aortic valves. AB - BACKGROUND AND AIM OF THE STUDY: Aortic valve (AV) stenosis is the most common valvular heart disease with an incidence of 3% for people >= 65years in the industrialized world with indication for a surgical or transcatheter valve replacement. Researchers suppose osteogenic processes as key mechanisms in calcific aortic valve stenosis. Recently, Torre et al. published impressive histological analyses and detected osseous and/or chondromatous metaplasia in 15.6% of 6685 native calcified aortic valves. Therefore one HE section per valve originated from the area with the greatest extent of calcification was analyzed. Aim of our experimental setup was to identify regions of neo-osteogenesis and to determine the rate of specimens with active mineralization in human aortic valve tissue by Movat Pentachrom staining of sections of lager tissue segments. METHODS: Operational replaced aortic valves of 35 patients, 15 female and 20 male with an average age of 66.2 years were formalin fixed and decalcified using Osteosoft(r)-solution. Tissue samples were cut and 2MUm specimens were stained with Movat Pentachrom to visualize osteogenic regions. Instead of screening a large number of sections, tissue samples were cut up to five times with at least 100MUm space each if no region of osseous and/or chondromatous metaplasia was visible. RESULTS/CONCLUSIONS: Using this setup, a region of osseous metaplasia was detected in 25 (71.4%) of 35 samples analyzed. In some cases, these regions were small sized and only visible due to the bright color of Movat Pentachrom stain. This leads to the suggestion that a higher rate of calcified aortic valve samples would be classified as cusps with areas of neo-osteogenesis after staining with Movat Pentachrom stain and by the systematic analysis of larger parts of the tissue blocks. PMID- 28579290 TI - Improved outcomes and value in staged hybrid extent II thoracoabdominal aortic aneurysm repair. AB - OBJECTIVE: Complex Crawford extent II thoracoabdominal aortic aneurysms (TAAAs) can be treated in a hybrid manner with proximal thoracic endovascular aneurysm repair, followed by staged distal open thoracoabdominal repair. This study evaluated the outcomes and health care-associated value of this new method compared with traditional open repair over 10 years. METHODS: A prospectively collected database was used to identify all patients with an extent II TAAA undergoing repair at a single institution between 2005 and 2015. Patient characteristics, postoperative outcomes, and incidence of major adverse events (MAEs; renal failure, spinal cord ischemia, death) were compared. After adjusting for time since surgery, value was analyzed looking at quality (1/MAE) divided by cost (total health system cost). This was multiplied by a constant to set the value of open TAAA repair to 100. RESULTS: A total of 113 consecutive patients underwent extent II TAAA repairs, of whom 25 (22.1%) had a staged hybrid approach with a median of 129 days between procedures. No baseline differences in demographic or comorbidity variables existed between groups (P > .05). The hybrid group had shorter operative time (255 vs 306 minutes; P = .01), shorter postoperative length of stay (10.1 vs 13.3 days; P = .02), and reduced blood loss (1300 vs 2600 mL; P = .01) at the time of open operation. Despite higher rates of acute kidney injury in the hybrid group (76.0% vs 51.1%; P = .03), there was no difference in renal failure (8.0% vs 4.5%; P = .84). The incidence of MAEs was lower in the staged hybrid group (20.0% vs 48.9%; P = .01), without a difference in hospital mortality (4.0% vs 3.4%; P = .89). Median total cost was higher in the hybrid group ($112,920 vs $72,037; P = .003). Value was improved in the hybrid group by 56% using mean cost and 178% by median cost. CONCLUSIONS: The 20% MAE rate associated with staged hybrid repair of extent II TAAA was significantly decreased compared with open repair, with a relative reduction of >50%. Despite higher total hospital costs, staged hybrid repair had 56% to 178% higher health care-related value compared with standard open repair. In an era of increasing focus on costs and quality, staged hybrid repair of extensive TAAAs is associated with fewer complications than open TAAA repair, resulting in a good value investment from a resource utilization perspective. PMID- 28579291 TI - Successful use of partial aneurysmectomy and repair approach for managing complications of arteriovenous fistulas and grafts. AB - OBJECTIVE: Arteriovenous fistulas and grafts may often be associated with localized complications related to aneurysms/pseudoaneurysms, buttonholes, or structural defects that require proper management to ensure continued access functionality for hemodialysis. Partial aneurysmectomy and repair (PAR) is a targeted surgical approach specifically designed for managing these complications. The basic concepts of PAR include resecting unhealthy or excessive tissue over an access, reconstructing the vascular access lumen using in situ vascular wall or tissue when possible, and closing overlying skin with healthy margins to promote reliable healing. This report analyzes the clinical outcomes of PAR in a large clinical series. METHODS: The demographic and outcome data of patients who underwent PARs at an ambulatory surgery center from 2009 to 2016 were collected and analyzed. RESULTS: A total of 220 PAR operations were performed in 209 patients, of which 185 had fistulas and 24 had grafts. In the fistula group, 11 patients underwent subsequent staged aneurysm repairs. Comparing the fistula group (n = 185) vs the graft group (n = 24): men were 63% vs 29%, the mean age was 60.1 +/- 14.8 vs 63.9 +/- 16.0 years, diabetic patients were 54% vs 75%, the mean age of the accesses at the time of repair was 5.3 +/- 3.2 vs 5.0 +/- 4.0 years, the upper arm accesses were 69% vs 88%, the forearm accesses were 31% vs 12%, and the mean follow-up was 27.9 +/- 21.9 vs 14.0 +/- 11.6 months. A pneumatic tourniquet was used during 81% of the fistula and 42% of the graft operations. Dialysis catheters were required in 2% of the patients in the fistula group and 4% in the graft group to continue hemodialysis. After repair operations, the primary patency, assisted primary patency, and secondary patency rates of the whole access conduit for the fistula group were 45%, 96%, and 98% at 1 year; 28%, 91%, and 96% at 2 years; and 19%, 87%, and 95% at 3 years, respectively. The same patency rates of the graft group were 31%, 70%, and 96% at 6 months and 10%, 57%, and 96% at 1 year, respectively. Two fistulas and one graft were lost <=30 days postoperatively. CONCLUSIONS: PAR is a reliable approach for managing localized arteriovenous access complications related to aneurysms/pseudoaneurysms, buttonholes, or structural defects. Given its simplicity and reliability, we recommend PAR as a first-line choice for managing these complications of arteriovenous fistulas and a choice in selected arteriovenous graft patients. PMID- 28579292 TI - Current practice of thoracic outlet decompression surgery in the United States. AB - BACKGROUND: Thoracic outlet syndrome (TOS) and its management are relatively controversial topics. Most of the literature reporting the outcomes of surgical decompression for TOS derives from single-center experiences. The objective of our study was to describe the current state of TOS surgery among hospitals that participate in the American College of Surgeons National Surgical Quality Improvement Program database. METHODS: Our study sample consisted of patients from the 2005 to 2014 American College of Surgeons National Surgical Quality Improvement Program database who underwent first or cervical rib resection as their index procedure and whose constellation of diagnosis and procedure codes identified them as having neurogenic, arterial, or venous TOS. Patient and procedure characteristics were determined, as were the 30-day incidence of specific complications including nerve injury. Multimodel inference was used for multivariable analysis of the composite outcome of readmission or reoperation <=30 days. RESULTS: We identified 1431 patients undergoing operation for TOS: 83% for neurogenic TOS, 3% for arterial TOS, and 12% for venous TOS. Vascular surgeons performed 90% of procedures. Only four patients (0.3%) demonstrated evidence of nerve injury. The rate of bleeding complication requiring transfusion was also quite low, at 1.4%. The 30-day incidence of readmission or reoperation, or both, in our study cohort was 8.6%. The risk of this outcome was increased in patients with a higher American Society of Anesthesiologists Physical Status Classification, those whose procedure was for non-neurogenic symptoms, and those whose procedure took longer to complete. CONCLUSIONS: The findings of our study will provide surgeons who advocate for the surgical management of TOS with reassurance that such intervention is associated with an extremely low risk of disability resulting from iatrogenic nerve injury and major bleeding events. PMID- 28579293 TI - WITHDRAWN: The optimal procedure of modified Rex shunt for the treatment of extrahepatic portal hypertension in children. PMID- 28579294 TI - Prognosis of septic shock. PMID- 28579295 TI - Spontaneous rupture of inferior vena cava. AB - Spontaneous ruptures of the inferior vena cava (IVC) are rare. The mortality rate is high associated with all IVC injuries despite prompt resuscitation or operation. We present a case of 68-year-old women with spontaneous IVC dissection, presented as acute chest pain. Chest CT demonstrated a large amount of hemopericardium, and dilated inferior vena cava (IVC), suggesting cardiac tampon. Subsequently, hypovolemic shock and cardiac arrest occurred. After resuscitation, abdomen CT angiography was taken to find bleeding focus. Second CT demonstrated massive contrast extravasation to pericardial space due to rupture of IVC. Patient expired due to multi-organ failure. PMID- 28579296 TI - The challenge of coprescription of antiplatelet therapy and oral anticoagulants. PMID- 28579297 TI - Re: Nicola Fossati, Peter-Paul M. Willemse, Thomas Van den Broeck, et al. The Benefits and Harms of Different Extents of Lymph Node Dissection During Radical Prostatectomy for Prostate Cancer: A Systematic Review. Eur Urol. In Press. http://dx.doi.org/10.1016/j.eururo.2016.12.003: Lymphadenectomy and Radical Prostatectomy: Science or Pseudoscience? PMID- 28579298 TI - Regulation of GSK-3 activity by curcumin, berberine and resveratrol: Potential effects on multiple diseases. AB - Natural products or nutraceuticals promote anti-aging, anti-cancer and other health-enhancing effects. A key target of the effects of natural products may be the regulation of the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway. This review will focus on the effects of curcumin (CUR), berberine (BBR) and resveratrol (RES), on the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway, with a special focus on GSK-3. These natural products may regulate the pathway by multiple mechanisms including: reactive oxygen species (ROS), cytokine receptors, mirco-RNAs (miRs) and many others. CUR is present the root of turmeric (Curcuma longa). CUR is used in the treatment of many disorders, especially in those involving inflammatory processes which may contribute to abnormal proliferation and promote cancer growth. BBR is also isolated from various plants (Berberis coptis and others) and is used in traditional medicine to treat multiple diseases/conditions including: diabetes, hyperlipidemia, cancer and bacterial infections. RES is present in red grapes, other fruits and berries such as blueberries and raspberries. RES may have some anti-diabetic and anti-cancer effects. Understanding the effects of these natural products on the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway may enhance their usage as anti-proliferative agent which may be beneficial for many health problems. PMID- 28579299 TI - SGLT2 Inhibition by Empagliflozin Promotes Fat Utilization and Browning and Attenuates Inflammation and Insulin Resistance by Polarizing M2 Macrophages in Diet-induced Obese Mice. AB - Sodium-glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion (UGE), leading to blood glucose reductions and weight loss. However, the impacts of SGLT2 inhibition on energy homeostasis and obesity-induced insulin resistance are less well known. Here, we show that empagliflozin, a SGLT2 inhibitor, enhanced energy expenditure and attenuated inflammation and insulin resistance in high-fat-diet-induced obese (DIO) mice. C57BL/6J mice were pair-fed a high-fat diet (HFD) or a HFD with empagliflozin for 16weeks. Empagliflozin administration increased UGE in the DIO mice, whereas it suppressed HFD-induced weight gain, insulin resistance, and hepatic steatosis. Moreover, empagliflozin shifted energy metabolism towards fat utilization, elevated AMP-activated protein kinase and acetyl-CoA carbolxylase phosphorylation in skeletal muscle, and increased hepatic and plasma fibroblast growth factor 21 levels. Importantly, empagliflozin increased energy expenditure, heat production, and the expression of uncoupling protein 1 in brown fat and in inguinal and epididymal white adipose tissue (WAT). Furthermore, empagliflozin reduced M1-polarized macrophage accumulation while inducing the anti-inflammatory M2 phenotype of macrophages within WAT and liver, lowering plasma TNFalpha levels and attenuating obesity related chronic inflammation. Thus, empagliflozin suppressed weight gain by enhancing fat utilization and browning and attenuated obesity-induced inflammation and insulin resistance by polarizing M2 macrophages in WAT and liver. PMID- 28579300 TI - Correcting a Fundamental Flaw in the Paradigm for Antimicrobial Susceptibility Testing. AB - The emergence and prevalence of antibiotic-resistant bacteria are an increasing cause of death worldwide, resulting in a global 'call to action' to avoid receding into an era lacking effective antibiotics. Despite the urgency, the healthcare industry still relies on a single in vitro bioassay to determine antibiotic efficacy. This assay fails to incorporate environmental factors normally present during host-pathogen interactions in vivo that significantly impact antibiotic efficacy. Here we report that standard antimicrobial susceptibility testing (AST) failed to detect antibiotics that are in fact effective in vivo; and frequently identified antibiotics that were instead ineffective as further confirmed in mouse models of infection and sepsis. Notably, AST performed in media mimicking host environments succeeded in identifying specific antibiotics that were effective in bacterial clearance and host survival, even though these same antibiotics failed in results using standard test media. Similarly, our revised media further identified antibiotics that were ineffective in vivo despite passing the AST standard for clinical use. Supplementation of AST medium with sodium bicarbonate, an abundant in vivo molecule that stimulates global changes in bacterial structure and gene expression, was found to be an important factor improving the predictive value of AST in the assignment of appropriate therapy. These findings have the potential to improve the means by which antibiotics are developed, tested, and prescribed. PMID- 28579301 TI - Incidence, presentation and outcome of toxoplasmosis in HIV infected in the combination antiretroviral therapy era. AB - BACKGROUND: HIV-associated incidence and prognosis of cerebral toxoplasmosis (CTX) is not well established during later years. METHODS: From the Danish HIV Cohort Study, we identified 6325 HIV-infected individuals. We assessed incidence, mortality, predictive and prognostic factors of CTX during the pre-combination antiretroviral therapy (pre-cART; 1995-1996) and cART-era (1997-2014). Adjusted incidence rate ratios (aIRR), mortality rate ratios (aMRR) and 95% confidence intervals (CI) were assessed using Poisson regression analysis. RESULTS: CTX IR was 1.17/1000 PYR (95% CI 0.93-1.47). We observed no change in CTX-risk in the first year after HIV-diagnosis, but a substantial reduction in mortality in the first 3 months after CTX diagnosis when comparing the cART-era to the pre-cART era; {(aIRR: 0.79; 95% CI: 0.37-1.72) (aMRR: 0.15; 95% CI: 0.06-0.38)}. For individuals surviving the first year after HIV-diagnosis or the first 3 months after CTX-diagnosis, IRR and MRR had declined to minimal levels {(aIRR: 0.06; 95% CI: 0.03-0.10); (aMRR: 0.02; 95% CI: 0.01-0.05)}. Three years after CTX-diagnosis 30% of the patients still had neurological deficits. CONCLUSION: Although, CTX remains an important cause of morbidity and mortality in the cART-era, with high prevalence of neurological sequelae, incidence and mortality has largely declined, especially among those surviving the first year after diagnosis. PMID- 28579303 TI - First report of Candida auris in Oman: Clinical and microbiological description of five candidemia cases. PMID- 28579304 TI - Modelled seasonal influenza mortality shows marked differences in risk by age, sex, ethnicity and socioeconomic position in New Zealand. AB - OBJECTIVES: Influenza is responsible for a large number of deaths which can only be estimated using modelling methods. Such methods have rarely been applied to describe the major socio-demographic characteristics of this disease burden. METHODS: We used quasi Poisson regression models with weekly counts of deaths and isolates of influenza A, B and respiratory syncytial virus for the period 1994 to 2008. RESULTS: The estimated average mortality rate was 13.5 per 100,000 people which was 1.8% of all deaths in New Zealand. Influenza mortality differed markedly by age, sex, ethnicity and socioeconomic position. Relatively vulnerable groups were males aged 65-79 years (Rate ratio (RR) = 1.9, 95% CI: 1.9, 1.9 compared with females), Maori (RR = 3.6, 95% CI: 3.6, 3.7 compared with European/Others aged 65-79 years), Pacific (RR = 2.4, 95% CI: 2.4, 2.4 compared with European/Others aged 65-79 years) and those living in the most deprived areas (RR = 1.8, 95% CI: 1.3, 2.4) for New Zealand Deprivation (NZDep) 9&10 (the most deprived) compared with NZDep 1&2 (the least deprived). CONCLUSIONS: These results support targeting influenza vaccination and other interventions to the most vulnerable groups, in particular Maori and Pacific people and men aged 65-79 years and those living in the most deprived areas. PMID- 28579306 TI - Corrigendum to "A bead-based immunofluorescence-assay on a microfluidic dielectrophoresis platform for rapid dengue virus detection" [Biosens. Bioelectron. 95 (2017) 174-180]. PMID- 28579305 TI - Frequent capsule switching in 'ultra-virulent' meningococci - Are we ready for a serogroup B ST-11 complex outbreak? AB - The meningococcal ST-11 complex (cc11) causes large invasive disease outbreaks with high case fatality rates, such as serogroup C (MenC) epidemics in industrialised nations in the 1990s and the serogroup W epidemic currently expanding globally. Glycoconjugate vaccines are available for serogroups A, C, W and Y. Broad coverage protein-based vaccines have recently been licensed against serogroup B meningococci (MenB), however, these do not afford universal MenB protection. Capsular switching from MenC to MenB among cc11 organisms is concerning because a large MenB cc11 (B:cc11) outbreak has the potential to cause significant morbidity and mortality. This study aimed to assess the potential for licensed and developmental non-capsular meningococcal vaccines to protect against B:cc11. The population structure and vaccine antigen distribution was determined for a panel of >800 geo-temporally diverse, predominantly MenC cc11 and B:cc11 genomes. The two licensed vaccines potentially protect against many but not all B:cc11 meningococci. Furthermore, strain coverage by these vaccines is often due to a single vaccine antigen and both vaccines are highly susceptible to vaccine escape owing to the apparent dispensability of key proteins used as vaccine antigens. cc11 strains with MenB and MenC capsules warrant special consideration when formulating future non-capsular meningococcal vaccines. PMID- 28579307 TI - Tricuspid annular plane systolic excursion in dogs with myxomatous mitral valve disease with and without pulmonary hypertension. AB - OBJECTIVES: To evaluate tricuspid annular plane systolic excursion (TAPSE) in dogs with myxomatous mitral valve disease (MMVD) with or without pulmonary hypertension (PH) and to study the correlations with clinical and echocardiographic parameters. ANIMALS: The study population included 99 dogs with MMVD and tricuspid regurgitation. METHODS: This is a prospective clinical study. All dogs received a transthoracic echocardiographic evaluation, including 2D, M mode, echo-Doppler, and tissue Doppler measurements. The TAPSE was measured from the left apical four-chamber view and normalized for the effect of body weight (nTAPSE). The dogs were grouped according to the severity of MMVD (American College of Veterinary Internal Medicine guidelines) and presence/absence and severity of PH. Significant differences between TAPSE or nTAPSE and echocardiographic parameters were analyzed among the MMVD and PH severity groups. Correlations between TAPSE or nTAPSE and echocardiographic parameters were calculated. RESULTS: Tricuspid annular plane systolic excursion or nTAPSE were not significantly different among dogs of the MMVD or PH severity groups. Significant correlations were obtained between TAPSE and body weight, left ventricular and atrial dimensions, early diastolic septal and early diastolic and systolic tricuspid annulus velocity (p<0.001); nTAPSE was significantly correlated with normalized end-diastolic left ventricular dimension and fractional shortening (p<0.001). CONCLUSIONS: The results show that neither TAPSE nor nTAPSE are reduced in dogs with MMVD with or without PH. It remains unclear if the right ventricle function is not reduced or if a reduced right ventricle function is masked by the contraction of the left ventricle through ventricular interdependence. PMID- 28579308 TI - A dual functional peptide-auxiliary conjugate for C-to-N and N-to-C sequential native chemical ligation of glycopeptides. AB - Long, homogeneously glycosylated peptides and proteins can be assembled from multiple segments via sequential chemoselective reactions. The efficiency of the synthesis depends on the effectiveness and number of steps and on their compatibility with glycosylation methods. Here, we present how the combination of auxiliary-mediated native chemical ligation and thioester generation via hydrazinolysis from Wang-type resin enables multiple, sequential N-to-C and C-to N ligations. The method can be applied to glycosylated peptides and peptide alpha thioesters and has the potential to be further extended to sequential glycosylation, thus paving the way to the synthesis of complex homogeneous glycoproteins. We applied this methodology to the synthesis of long MUC1 variants comprising 2, 4 and 6 tandem repeats and three O-glycosylations. PMID- 28579302 TI - Direct-acting antiviral treatment against hepatitis C virus infection in HIV Infected patients - "En route for eradication"? AB - OBJECTIVES: Direct-Acting Antivirals (DAAs) opened a new era in HCV treatment. We report the impact of HCV treatment in French HIV-HCV coinfected patients. METHODS: All HIV-HCV patients from the Dat'AIDS cohort followed between 2012 and 2015 were included. HCV status was defined yearly as naive, spontaneous cure, sustained virological response (SVR12), failure or reinfection. RESULTS: Among 32,945 HIV-infected patients, 15.2% were positive for anti-HCV antibodies. From 2012 to 2015, HCV incidence rate increased from 0.35%PY to 0.69%PY in MSM, while median incidence was 0.08%PY in other patients. Median reinfection rate was 2.56%PY in MSM and 0.22%PY in other patients. HCV treatment initiation rate rose from 8.2% in 2012 to 29.6% (48.0% in pre-treated patients vs 22.6% in naive patients). SVR12 rate increased from 68.7% to 95.2%. By the end of 2015, 62.7% of the patients were cured either spontaneously or following SVR. CONCLUSIONS: HCV treatment dramatically increased in HIV-HCV patients in France from 2012 to 2015 resulting in HCV cure in nearly two-thirds of the patients in this cohort. Combined with a declining HCV prevalence, the prevalence of active HCV infection among HIV patients will drastically decrease in the forthcoming years. PMID- 28579309 TI - Genetic variation in the first-pass metabolism of ethinylestradiol, sex hormone binding globulin levels and venous thrombosis risk. AB - BACKGROUND: Use of ethinylestradiol, one of the active ingredients in combined oral contraceptives, affects the incidence of venous thrombosis. To explain why some women develop thrombosis when using oral contraceptives and others do not, we hypothesized a role for the first-pass metabolism of ethinylestradiol in the liver. We set out to determine the association between genetic variation in the first-pass metabolism of ethinylestradiol, venous thrombosis risk and the effect on Sex-hormone-binding-globulin (SHBG) levels. METHODS: Premenopausal women were included from two case-control studies: LETS (103 cases; 159 controls) and MEGA (397 cases; 796 controls). Haplotype-tagging SNPs were selected in 11 candidate genes; COMT, CYP1A2, CYP2C9, CYP3A4, CYP3A5, SULT1A1, SULT1E1, UGT1A1, UGT1A3, UGT1A9, UGT2B7. Venous thrombosis risk was expressed as odds ratios (OR) with 95% confidence intervals (CI). For SHBG levels, mean differences with 95%CI were estimated in combined oral contraceptive-using control subjects from the MEGA study. RESULTS: Two copies of haplotype D in the UGT2B7 gene increased venous thrombosis risk (ORLETS: 3.78; ORMEGA: 2.61) as well as SHBG levels (mean difference 27.6nmol/L, 95%CI: -61.7 to 116.9 compared with no copies) in oral contraceptive users and not in non-users. In oral contraceptive users, haplotype A and B in the CYP3A4 gene were associated with venous thrombosis risk, but not in non-users; however, the effect on SHBG levels was not directional with the risk. None of the other haplotypes were associated with venous thrombosis. CONCLUSION: Genetic variation in the UGT2B7 gene may, in part, explain venous thrombosis risk in combined oral contraceptive users. PMID- 28579310 TI - A comparative analysis of novel cardiovascular biomarkers in patients with chronic heart failure. AB - BACKGROUND: Heart failure (HF) with reduced ejection fraction remains a major therapeutic challenge. The aim of this study was to investigate the role of novel cardiovascular biomarkers, i.e. soluble suppression of tumorigenicity (sST2), growth-differentiation factor-15 (GDF-15), soluble urokinase plasminogen activator receptor (suPAR) and heart-type fatty acid binding protein (H-FABP) in patients with ischaemic (ICM) or dilative cardiomyopathy (DCM). MATERIALS AND METHODS: A total of 200 patients were enrolled in this study: 65 were diagnosed with DCM and 59 patients suffering from ICM were included. 76 patients without coronary artery disease or signs of heart failure were included as controls. Plasma samples of all patients were analyzed by use of ELISA. RESULTS: Levels of sST2, suPAR and H-FABP were significantly higher in ICM and DCM patients compared to the control group (p<0.0001). However, there were no significant differences between ICM and DCM in biomarker levels. Ejection fraction correlated inversely with cardiac biomarkers (sST2 p<0.0001, GDF-15 p=0.0394, suPAR p=0.0029, H-FABP p<0.0001). Similarly, CRP levels also showed a positive correlation with cardiac biomarkers. Renal insufficiency (p<0.0001) and diabetes (sST2 p=0.0021, GDF-15 p=0.0055, suPAR p=0.0339, H-FABP p=0.0010) were significantly associated with a rise in cardiac biomarkers. CONCLUSION: Novel cardiovascular biomarkers such as ST2, GDF-15, uPAR and H-FABP could offer a great potential for more precise diagnostic in ICM and DCM patients. H-FABP was the most promising marker in our study, followed by sST2, uPAR and GDF-15. Additional prospective studies will be necessary to further evaluate the potential clinical benefits in routine treatment of HF. PMID- 28579311 TI - Lower cognitive performance among long-term type 1 diabetes survivors: A case control study. AB - OBJECTIVE: Patients with type 1 diabetes (T1D) have an increased risk of cognitive dysfunction. The cognitive decrement is believed to depend on macro- and microvascular complications and long disease duration. Some patients do not develop these complications, but still report cognitive symptoms. We examined if long-standing T1D without complications is associated with lower cognitive performance. METHODS: A group of patients (n=43) with long-standing T1D (>30years) without micro- or macro vascular complications was compared with a non diabetic control group (n=86) on six cognitive tests which probed episodic memory, semantic memory, episodic short-term memory, visual attention and psychomotor speed. Each patient was matched with two controls regarding age, gender and education. A linear mixed effect model was used to analyze the data. RESULTS: The mean age was 57years and mean duration was 41years. Patients with diabetes had lower diastolic blood pressure but BMI, waist circumference, systolic blood pressure and smoking did not differ between groups. Patients had lower results than non-diabetic controls in episodic short-term memory (p<0.001) and also lower values on a test that mirrors visual attention and psychomotor speed (p=0.019). CONCLUSIONS: Long-standing T1D was associated with lower cognitive performance, regardless of other diabetes-related complications. PMID- 28579312 TI - Validation of a quick screening instrument for measuring fear of hypoglycaemia in persons with diabetes. PMID- 28579313 TI - The Impact of Probiotic Soy Milk Consumption on Oxidative Stress Among Type 2 Diabetic Kidney Disease Patients: A Randomized Controlled Clinical Trial. AB - OBJECTIVE: Diabetic kidney disease (DKD) is one the most important complications of diabetes leading to end-stage renal disease. This study aimed to determine the effects of probiotic soy milk consumption on oxidative stress biomarkers in type 2 DKD patients. METHODS: Forty-eight patients were randomly assigned to consume a diet containing 200 mL/day probiotic soy milk in the intervention group or soy milk in the control condition. As determinants of oxidative stress, malondialdehyde, 8-iso-prostaglandin F2alpha, oxidized glutathione, total antioxidant capacity, reduced glutathione (GSH), glutathione peroxidase, and glutathione reductase were measured after 8 weeks of intervention according to the standard protocol. RESULTS: Between groups analysis showed that DKD patients in the probiotic soy milk group had a higher mean value of GSH compared with those in the soy milk group. In the final adjusted model, this difference remained significant. Consistently, oxidized glutathione concentration was significantly reduced among patients in the probiotic soy milk group. Also, for activity levels of antioxidant enzymes including glutathione peroxidase and glutathione reductase, significant increased levels were observed between 2 intervention groups in the final adjusted model. However, no significant reduction of the serum 8-iso-prostaglandin F2alpha or malondialdehyde and no induction of TAC concentrations within and between the 2 groups in the crude and adjusted models were detected. CONCLUSION: Overall, the results demonstrate that probiotic soy milk consumption could improve some oxidative stress factors among DKD patients. Further longitudinal studies with consideration of individual variation should be conducted. PMID- 28579314 TI - Spot Urine-guided Salt Reduction in Chronic Kidney Disease Patients. AB - OBJECTIVE: Dietary salt restriction is important in patients with chronic kidney disease (CKD) to reduce hypertension, cardiovascular events, progression of CKD, and mortality. However, recommending salt reduction for patients is difficult without knowing their actual sodium intake. This study evaluated the effectiveness of spot urine-guided salt reduction in CKD outpatients. DESIGN: A prospective cohort study was used. SUBJECTS: This study included a total of 127 adult outpatients (aged 60 +/- 18 years, 80 males) with CKD. Their baseline estimated glomerular filtration rate was 51.4 +/- 25.1 (mL/minute/1.73 m2), and 64 (50%) of them were with CKD stage 3a or 3b (both 32 [25%]). INTERVENTION: We informed the patients of their individual spot urine-estimated salt intake every time they visited the outpatient clinic. Based on the data, the nephrologist encouraged the patients to achieve their salt restriction goal. MAIN OUTCOME MEASURE: The primary outcome was the estimated salt excretion, and the secondary outcome was the urinary protein-to-Cr ratio (UPCR). Multiple regression analyses were performed to clarify the contributing factors of changes in both outcomes. RESULTS: Over a follow-up of 12 months, the median number of patients' visits was 7 (5-8). The estimated salt intake was significantly reduced from 7.98 +/- 2.49 g/day to 6.77 +/- 1.77 g/day (P < .0001). The median UPCR was also reduced from 0.20 (0.10-0.80) to 0.10 (0.10-0.48) (P < .0001). On multiple regression analysis, a reduction in UPCR was positively associated with the baseline UPCR and a reduction in systolic blood pressure significantly (P < .0001 and P < .01, respectively) as well as positively correlated with a reduction in the estimated salt intake, with borderline significance (P = .08). CONCLUSIONS: Providing spot urine-estimated salt intake feedback effectively motivated CKD patients to reduce their salt intake. Spot urine-guided salt reduction may slow CKD progression through decreased urinary protein excretion. PMID- 28579315 TI - Dementia prevalence, care arrangement, and access to care in Lebanon: A pilot study. AB - INTRODUCTION: In North Africa and the Middle East, studies about dementia prevalence are scarce. A pilot study was conducted in Lebanon to assess dementia prevalence, using the Arabic-validated 10/66 Dementia Research Group (DRG) diagnostic assessment for case ascertainment. The study also examined care arrangement and access to care. METHODS: A random sample of 502 persons older than 65 years and their informant were recruited from Beirut and Mount Lebanon governorates through multistage cluster sampling. RESULTS: The crude and age standardized dementia prevalences were 7.4% and 9.0%, respectively. People with dementia were mainly cared for by relatives at home. Access to formal care was very limited. DISCUSSION: Dementia prevalence in Lebanon ranks high within the global range of estimates. These first evidence-based data about disease burden and barriers to care serve to raise awareness and call for social and health care reform to tackle the dementia epidemic in Lebanon and in North Africa and the Middle East. PMID- 28579316 TI - Effect of light intensity on ovarian gene expression, reproductive performance and body weight of rabbit does. AB - The objective of the experiment was to find the minimum light intensity which could improve reproduction by examining its effect on ovarian gene expression, reproductive performance and body weight of rabbit does with three different light intensities: 60 (L), 80 (M), and 100 (H)lx. A total of 144 Rex-rabbits submitted to a 49-day reproductive regimen were used in this study. Ovaries were collected and relative abundance of mRNA for ovarian proteins of interest was examined with real-time PCR. Amount of protein for proteins of interest was examined by immunohistochemistry. Reproductive performance and doe bodyweight of the first three consecutive reproductive periods after initiation of the light intensity treatments were evaluated. The results provided evidence that light intensity had no effect on relative abundance of estradiol receptor-alpha (ER alpha), follicle stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR), gonadotropin releasing hormone receptor 1 (GnRHR1) and progesterone receptor (PGR) mRNA. The relative abundance of growth hormone receptor (GHR) mRNA was, however, greater in Group L than M and H (P<0.05). No difference was observed for all reproductive indices as a result of submission to the three light intensities (P>0.05). The bodyweight of the does in Group L was greater than the other two groups at first insemination, second insemination and the second postpartum period (P<0.05). There was no difference in bodyweight after the second postpartum period (P>0.05). These observations suggest that light intensity between 60 and 100lx has no effect on the reproductive performance of rabbit does, however, the amounts of GHR mRNA and growth hormone (GH) protein were affected and the greater light intensity had a negative effect on bodyweight between the time of the first insemination and the second partum period. PMID- 28579317 TI - Six3 in a small population of progenitors at E8.5 is required for neuroretinal specification via regulating cell signaling and survival in mice. AB - Neuroretina and retinal pigment epithelium (RPE) are differentiated from the progenitors in optic vesicles, but it is unclear when and how the two lineages are segregated. Manipulation of chick embryos reveals that the early anteroventral optic vesicle is crucial for neuroretinal development, but the molecular mechanism is unclear. Homeodomain transcription factor Six3 is required for neuroretinal specification and is dispensable for RPE formation, but the cell fates of Six3-deficient progenitors and the origins of remnant RPE are unknown. Here, we performed lineage tracing of Six3-Cre positive cells in wild-type and Six3-deficient mouse embryos. Six3-Cre positive progenies were found in a population of progenitors in the anteroventral optic pits/vesicles starting at E8.5, and were found in neuroretina, optic stalk, ventral forebrain, but not RPE, at E10.5. Six3-deletion in the small population of progenitors at E8.5 was sufficient to cause rostral expansion of Wnt8b and drastic reduction of Fgf8/MAPK signaling, ablating neuroretinal specification without affecting RPE. Lineage tracing revealed Six3-deficient progenitors at E8.5 were eventually lost and the remnant RPE was derived from Six3-Cre negative cells. Thus, Six3 in a small population of progenitors expressing Six3-Cre at E8.5 is required for neuroretinal specification via regulating cell signaling and survival in mice. PMID- 28579321 TI - [An X-ray with a suprise: Osteopoikilosis]. PMID- 28579320 TI - T Cell Immunity and Zika Virus Vaccine Development. AB - The recent Zika virus (ZIKV) epidemic has created an urgent need for a safe and effective vaccine. There is still a dearth of knowledge about ZIKV immunity, but years of investigation into the immunobiology of other flaviviruses has helped to accelerate the development of a ZIKV vaccine. Although the humoral immune response generates the primary correlate of protection from disease, robust T cell responses could enhance ZIKV vaccine efficacy. Additionally, pre-existing immunity to related flaviviruses could generate cross-reactive T cells that may affect immune responses upon vaccination. In this review, we summarize the key discoveries in the area of flavivirus T cell immunity and postulate on how these findings can inform ZIKV vaccine strategies for inducing protective immunity. PMID- 28579319 TI - Immunological Functions of the Omentum. AB - The omentum is a visceral adipose tissue with unique immune functions. Although it is primarily an adipose tissue, the omentum also contains lymphoid aggregates, called milky spots (MSs), that contribute to peritoneal immunity by collecting antigens, particulates, and pathogens from the peritoneal cavity and, depending on the stimuli, promoting a variety of immune responses, including inflammation, tolerance, or even fibrosis. Reciprocal interactions between cells in the MS and adipocytes regulate their immune and metabolic functions. Importantly, the omentum collects metastasizing tumor cells and supports tumor growth by immunological and metabolic mechanisms. Here we summarize our current knowledge about the development, organization, and function of the omentum in peritoneal immunity. PMID- 28579318 TI - The zebrafish kidney mutant zeppelin reveals that brca2/fancd1 is essential for pronephros development. AB - The zebrafish kidney is conserved with other vertebrates, making it an excellent genetic model to study renal development. The kidney collects metabolic waste using a blood filter with specialized epithelial cells known as podocytes. Podocyte formation is poorly understood but relevant to many kidney diseases, as podocyte injury leads to progressive scarring and organ failure. zeppelin (zep) was isolated in a forward screen for kidney mutants and identified as a homozygous recessive lethal allele that causes reduced podocyte numbers, deficient filtration, and fluid imbalance. Interestingly, zep mutants had a larger interrenal gland, the teleostean counterpart of the mammalian adrenal gland, which suggested a fate switch with the related podocyte lineage since cell proliferation and cell death were unchanged within the shared progenitor field from which these two identities arise. Cloning of zep by whole genome sequencing (WGS) identified a splicing mutation in breast cancer 2, early onset (brca2)/fancd1, which was confirmed by sequencing of individual fish. Several independent brca2 morpholinos (MOs) phenocopied zep, causing edema, reduced podocyte number, and increased interrenal cell number. Complementation analysis between zep and brca2ZM_00057434 -/- zebrafish, which have an insertional mutation, revealed that the interrenal lineage was expanded. Importantly, overexpression of brca2 rescued podocyte formation in zep mutants, providing critical evidence that the brca2 lesion encoded by zep specifically disrupts the balance of nephrogenesis. Taken together, these data suggest for the first time that brca2/fancd1 is essential for vertebrate kidney ontogeny. Thus, our findings impart novel insights into the genetic components that impact renal development, and because BRCA2/FANCD1 mutations in humans cause Fanconi anemia and several common cancers, this work has identified a new zebrafish model to further study brca2/fancd1 in disease. PMID- 28579322 TI - ER Membrane Phospholipids and Surface Tension Control Cellular Lipid Droplet Formation. AB - Cells convert excess energy into neutral lipids that are made in the endoplasmic reticulum (ER) bilayer. The lipids are then packaged into spherical or budded lipid droplets (LDs) covered by a phospholipid monolayer containing proteins. LDs play a key role in cellular energy metabolism and homeostasis. A key unanswered question in the life of LDs is how they bud off from the ER. Here, we tackle this question by studying the budding of artificial LDs from model membranes. We find that the bilayer phospholipid composition and surface tension are key parameters of LD budding. Phospholipids have differential LD budding aptitudes, and those inducing budding decrease the bilayer tension. We observe that decreasing tension favors the egress of neutral lipids from the bilayer and LD budding. In cells, budding conditions favor the formation of small LDs. Our discovery reveals the importance of altering ER physical chemistry for controlled cellular LD formation. PMID- 28579323 TI - Type I Interferon in Chronic Virus Infection and Cancer. AB - Type I interferons (IFN-Is) are emerging as key drivers of inflammation and immunosuppression in chronic infection. Control of these infections requires IFN I signaling; however, prolonged IFN-I signaling can lead to immune dysfunction. IFN-Is are also emerging as double-edged swords in cancer, providing necessary inflammatory signals, while initiating feedback suppression in both immune and cancer cells. Here, we review the proinflammatory and suppressive mechanisms potentiated by IFN-Is during chronic virus infections and discuss the similar, newly emerging dichotomy in cancer. We then discuss how this understanding is leading to new therapeutic concepts and immunotherapy combinations. We propose that, by modulating the immune response at its foundation, it may be possible to widely reshape immunity to control these chronic diseases. PMID- 28579324 TI - Evolutionary Convergence and Divergence in NLR Function and Structure. AB - The recognition of cellular damage caused by either pathogens or abiotic stress is essential for host defense in all forms of life in the plant and animal kingdoms. The NOD-like receptors (NLRs) represent a large family of multidomain proteins that were initially discovered for their role in host defense in plants and vertebrates. Over recent years the wide distribution of NLRs among metazoans has become apparent and their origins have begun to emerge. Moreover, intense study of NLR function has shown that they play essential roles beyond pathogen recognition - in the regulation of antigen presentation, cell death, inflammation, and even in embryonic development. We summarize here the latest insights into NLR biology and discuss examples of converging and diverging evolution of NLR function and structure. PMID- 28579325 TI - A peptide disrupting the D2R-DAT interaction protects against dopamine neurotoxicity. AB - Dopamine reuptake from extracellular space to cytosol leads to accumulation of dopamine, which triggers neurotoxicity in dopaminergic neurons. Previous studies have shown that both dopamine D2 receptor (D2R) and dopamine transporter (DAT) are involved in dopamine neurotoxicity. However, blockade of either D2R or DAT causes side effects due to antagonism of other physiological functions of these two proteins. We previously found that DAT can form a protein complex with D2R and its cell surface expression is facilitated via D2R-DAT interaction, which regulates dopamine reuptake and intracellular dopamine levels. Here we found that an interfering peptide (DAT-S1) disrupting the D2R-DAT interaction protects neurons against dopamine neurotoxicity, and this effect is mediated by inhibiting DAT cell surface expression and inhibiting both caspase-3 and PARP-1 cleavage. This study demonstrates the role of the D2R-DAT complex in dopamine neurotoxicity and investigated the potential mechanisms, which might help better understand the mechanisms of dopamine neurotoxicity. The peptide may provide some insights to improve treatments for dopamine neurotoxicity and related diseases, such as Parkinson's disease, as well as methamphetamine- and 3,4-methsylenedioxy methamphetamine-induced neurotoxicity. PMID- 28579326 TI - RIP1-RIP3-DRP1 pathway regulates NLRP3 inflammasome activation following subarachnoid hemorrhage. AB - The NLRP3 inflammasome functions as a crucial component of the inflammatory response in early brain injury (EBI) after subarachnoid hemorrhage (SAH). However, the mechanisms underlying the activation of NLRP3 inflammasome has not been well elucidated. In this study, we hypothesized the RIP1-RIP3-DRP1 pathway was involved in the activation of the NLRP3 inflammasome following SAH. SAH was induced by endovascular perforation in rats. Necrostatin-1 (Nec-1) or mitochondrial division inhibitor (Mdivi-1) was administered 1h after SAH by intraperitoneal injection. SAH grade, neurological function, brain water content, Western blot, ROS assay, immunofluorescence and transmission electron microscopy were performed. SAH led to the upregulation of RIP1, RIP3, phosphorylated DRP1 and NLRP3 inflammasome. Nec-1 treatment reduced RIP1, RIP3, phosphorylated DRP1 and NLRP3 inflammasome, subsequently alleviated brain edema and neurological deficits at 24h following SAH. The treatment with Mdivi-1 inhibited the expression of DRP1 protein, attenuated mitochondria damage and the generation of ROS, inhibited NLRP3 inflammasome and ameliorated brain edema and neurological deficits at 24h after SAH. The activation of the NLRP3 inflammasome in EBI after SAH was mediated by RIP1-RIP3-DRP1 pathway. Nec-1 and Mdivi-1 can inhibit inflammation and improve neurological function after SAH. PMID- 28579327 TI - Manipulating cognitive reserve: Pre-injury environmental conditions influence the severity of concussion symptomology, gene expression, and response to melatonin treatment in rats. AB - In an effort to understand the factors that contribute to heterogeneity in outcomes often associated with mTBI in youth, this study examined the role of premorbid differences in cognitive reserve on post-concussive symptoms (PCS), molecular markers, and treatment response. Male and female rats matured in one of three environmental conditions (Stress, Enrichment, Control), received a mTBI in adolescence, and were randomized to melatonin or placebo treatment. All animals underwent a behavioural test battery designed to examine PCS. Using prefrontal cortex and hippocampus tissue, expression of 9 genes was assessed in an effort to determine how the brain's epigenome was influenced by cognitive reserve, mTBI, and melatonin. Enrichment increased cognitive reserve (CR) and prevented lingering symptoms. Conversely, stress was associated with progressive worsening and manifestation of PCS in the longer-term. Melatonin was able to restore baseline function for control and enriched animals, but was ineffective for the stress condition. Epigenetic change in the prefrontal cortex was largely driven by the injury, while gene expression changes in the hippocampus were dependent upon cognitive reserve. The occurrence and severity of PCS is dependent upon a complex and multifaceted array of factors that modify behavioural and epigenetic responses to mTBI and its treatment. PMID- 28579328 TI - The evaluations of 99mTc cyclopentadienyl tricarbonyl triphenyl phosphonium cation for multidrug resistance. AB - A triphenylphosphonium cation, [99mTc]Technetium cyclopentadienyltricarbonyl-6 hexanoyl-triphenylphosphonium cation ([99mTc]3) was prepared to target multidrug resistance (MDR). The radiotracer was evaluated in the MDR-negative MCF-7 and MDR positive MCF-7/ADR cell lines in vitro, as well as animal models in vivo. [99mTc]3 was proofed to be a substrate of P-glycoprotein and multidrug resistant protein 1, and showed a higher accumulation in the MDR-negative MCF-7 cells compared to 99mTc-sestamibi in vitro. The MCF-7 tumor-to-MCF-7/ADR tumor ratio of [99mTc]3 was ~3 at 1hp.i. in the biodistribution study. These results demonstrated the capability of the radiotracer to detect multidrug resistance in tumor cells. PMID- 28579329 TI - The synthesis, structure-toxicity relationship of cisplatin derivatives for the mechanism research of cisplatin-induced nephrotoxicity. AB - Cisplatin is a widely used antineoplastic drug, while its nephrotoxicity limits the clinical application. Although several mechanisms contributing to nephrotoxicity have been reported, the direct protein targets are unclear. Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay in human renal proximal tubule cells (HK-2) and pig kidney epithelial cells (LLC-PK1). To the best of our knowledge, this study represented the first report regarding the structure toxicity relationship (STR) of cisplatin derivatives. The potency of biotin pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity. PMID- 28579330 TI - New insights into pradimicin biosynthesis revealed by two O-methyltransferases. AB - Pradimicins are a group of antiviral and antifungal natural products from Actinomadura hibisca. Two putative O-methyltransferase genes, pdmF and pdmT, are present in the pradimicin biosynthetic gene cluster. However, there is only one methoxy group (11-OCH3) in pradimicins. Through heterologous expression and in vitro reactions with various substrates, PdmF was characterized as the C-11 O methyltransferase with a relatively broad substrate specificity. To probe the role of PdmT in pradimicin biosynthesis, the corresponding gene was disrupted through homologous recombination, leading to the production of pradimicinone II. This enzyme was then expressed in Escherichia coli with an N-terminal His6 tag and purified by Ni-NTA chromatography. Reaction of pradimicinone II with PdmT generated 7-O-methylpradimicinone II, confirming that this enzyme is a C-7 O methyltransferase. Characterization of PdmT suggests a novel pathway that leads to the "flip" of 7-OH to C-14 in pradimicin biosynthesis. PMID- 28579331 TI - Intersectionality: An Understudied Framework for Addressing Weight Stigma. AB - INTRODUCTION: Obesity is an ongoing public health concern in the U.S. Weight stigma is linked to a number of obesogenic health outcomes, which complicate obesity treatment and prevention. Despite higher rates of obesity in female and minority populations, little research has examined weight stigma in non-white women and men. This study investigated intersectionality in weight stigma and health-related coping responses to stigmatizing experiences across racial groups. METHODS: In 2015, a total of 2,378 adults completed questionnaires about weight stigma, weight bias internalization, and coping strategies. Analyses were conducted in 2016. RESULTS: No differences in weight stigma emerged as a function of race or gender, but women reported higher weight bias internalization (B=0.19, p=0.004). Further, black men and women reported less weight bias internalization than white men and women (B=-0.43, p=0.009). Compared with white women, black women were less likely to cope with stigma using disordered eating (B=-0.57, p=0.001), whereas Hispanic women were more likely to cope with stigma using disordered eating (B=0.39, p=0.020). Black men were more likely than white men to cope with stigma via eating (B=-0.49, p=0.017). CONCLUSIONS: Findings highlight that weight stigma is equally present across racial groups, but that groups internalize and cope with stigma in different ways, which exacerbate health risks. Increased research and policy attention should address stigma as an obstacle in prevention and treatment for obesity to reduce weight-based inequities in underserved populations. PMID- 28579333 TI - "What can I do when he/she doesn't want to eat?": Maternal strategies for ensure children's food consumption in early childhood. AB - This cross-sectional analysis aimed to analyze the strategies used by mothers of children aged 2-3 to ensure their food consumption as well as to investigate the maternal and family characteristics associated with using these strategies. Data of 463 mothers who use the public health care system in Porto Alegre, Brazil, were analyzed. Among these mothers, 58.5% (n = 271) used some type of strategy. However, 42.4% (n = 115) of mothers did not identify their behavior as a strategy to ensure their children's food consumption. In regard to the type of strategy used, 69% (n = 187) were classified as information strategies and 43.2% (n = 117) as trading strategies. Maternal age and educational level were inversely associated with the use of trading strategies (p < 0.05), indicating that the adolescent mothers and mothers with less schooling more often used strategies that have been shown by the literature not to be conducive to positive long-term results. In 46.9% (n = 123) of the cases, some types of food were involved in the mothers' strategies, generally ultra-processed foods (46.3% n = 57). We conclude that the use of strategies to promote children's food consumption considered appropriate by the mothers is a fairly common practice. Health care professionals should consider mothers' perceptions and attitudes about the subject in order to conseil them as to the best feeding practices for their children, as the use of these strategies can be detrimental to the formation of eating behaviors. PMID- 28579332 TI - Structures of RNA Polymerase Closed and Intermediate Complexes Reveal Mechanisms of DNA Opening and Transcription Initiation. AB - Gene transcription is carried out by RNA polymerases (RNAPs). For transcription to occur, the closed promoter complex (RPc), where DNA is double stranded, must isomerize into an open promoter complex (RPo), where the DNA is melted out into a transcription bubble and the single-stranded template DNA is delivered to the RNAP active site. Using a bacterial RNAP containing the alternative sigma54 factor and cryoelectron microscopy, we determined structures of RPc and the activator-bound intermediate complex en route to RPo at 3.8 and 5.8 A. Our structures show how RNAP-sigma54 interacts with promoter DNA to initiate the DNA distortions required for transcription bubble formation, and how the activator interacts with RPc, leading to significant conformational changes in RNAP and sigma54 that promote RPo formation. We propose that DNA melting is an active process initiated in RPc and that the RNAP conformations of intermediates are significantly different from that of RPc and RPo. PMID- 28579334 TI - Corrigendum to "Protein-based nanotoxicology assessment strategy" [Nanomed Nanotechnol Biol Med. 2017;13(3):1229-1233]. PMID- 28579335 TI - Identification and functional characterization of the pheromone biosynthesis activating neuropeptide receptor isoforms from Mamestra brassicae. AB - In most moth species, including Mamestra brassicae, pheromone biosynthesis activating neuropeptide (PBAN) regulates pheromone production. Generally, PBAN acts directly on the pheromone gland (PG) cells via its specific G protein coupled receptor (i.e. PBANR) with Ca2+ as a second messenger. In this study, we identified cDNAs encoding three variants (A, B and C) of the M. brassicae PBANR (Mambr-PBANR). The full-length coding sequences were transiently expressed in cultured Trichoplusia ni cells and Sf9 cells for functional characterization. All three isoforms dose-dependently mobilized extracellular Ca2+ in response to PBAN analogs with Mambr-PBANR-C exhibiting the greatest sensitivity. Fluorescent confocal microscopy imaging studies demonstrated binding of a rhodamine red labeled ligand (RR10CPBAN) to all three Mambr-PBANR isoforms. RR10CPBAN binding did not trigger ligand-induced internalization in cells expressing PBANR-A, but did in cells expressing the PBANR-B and -C isoforms. Furthermore, activation of the PBANR-B and -C isoforms with the 18 amino acid Mambr-pheromonotropin resulted in co-localization with a Drosophila melanogaster arrestin homolog (Kurtz), whereas stimulation with an unrelated peptide had no effect. PCR-based profiling of the three transcripts revealed a basal level of expression throughout development with a dramatic increase in PG transcripts from the day of adult emergence with PBANR-C being the most abundant. PMID- 28579337 TI - Cryopreservation of canine sperm using egg yolk and soy bean based extenders. AB - Animal protein-based extenders are widely used despite being a potential source of bacterial or mycoplasma contamination. Its replacement with vegetal protein based extenders could represent an interesting alternative for dog sperm cryopreservation. This technique could be further improved by the addition of Tris-Glucose-Citric acid (TGC) that could physically protect the spermatozoa and improve its homeostasis. The aim of this study was to evaluate a cryopreservation protocol for dog spermatozoa using a soybean-based extender (LP1(p)) as well as the effects of the addition of (TGC) immediately after the semen collection. Eleven ejaculates from purebred adult dogs were collected, centrifuged in the absence or presence of TGC and processed as fresh or cryopreserved spermatozoa with: egg yolk-based extender (CaniPRO) or LP1(p). Freezing the spermatozoa in LP1(p) reduced the amplitude of the lateral head displacement, the percentage of spermatozoa that showed the intact acrosome and the mitochondrial function (P<0.05). These samples also showed a trend towards increased percentage of apoptotic spermatozoa (P<0.05). The addition of TGC before centrifugation did not improve the seminal parameters and adversely affected motility (P<0.05) in the spermatozoa cryopreserved in CaniPRO. However, TGC did not affect motility and increased (P<0.05) the percentage of intact acrosomes in the spermatozoa cryopreserved in LP1(p), reaching similar values than those cryopreserved in CaniPRO. In conclusion, LP1(r) plus TGC provide the same level of protection to dog spermatozoa cryopreservation than the egg yolk based extender CaniPRO when comparing standard post-thaw sperm quality parameters. PMID- 28579336 TI - Relationship Between Use of Videogames and Sexual Health in Adult Males. AB - BACKGROUND: Videogame use is increasingly prevalent in people of all ages, and despite the wide amount of scientific evidence proving a role for electronic entertainment in human health, there is no evidence about the relation between use of videogames and sexual health. AIM: To investigate the association between use of videogames and male sexual health. METHODS: We administered the two validated questionnaires, the Premature Ejaculation Diagnostic Tool (PEDT) and the International Index of Erectile Function (IIEF-15), to men 18 to 50 years old recruited through social networks and specific websites. In addition to the questionnaires, volunteers were asked to provide information on their gaming habit and lifestyle. OUTCOMES: An extended version of the IIEF-15 and PEDT, including data about gaming habits and relevant lifestyles. RESULTS: From June 18, 2014 through July 31, 2014, 599 men 18 to 50 years old completed the questionnaires. One hundred ninety-nine men reported no sexual activity during the previous 4 weeks; four records were rejected because of inherent errors. The remaining 396 questionnaires were analyzed, with 287 "gamers" (playing >1 hour/day on average) and 109 "non-gamers" providing all the required information. We found a lower prevalence of premature ejaculation in gamers compared with non gamers (mean PEDT score = 3.57 +/- 3.38 vs 4.52 +/- 3.7, P < .05, respectively). Analysis of the IIEF-15 showed no significant differences between gamers and non gamers in the domains of erectile function, orgasmic function, and overall satisfaction. Median scores for the sexual desire domain were higher for non gamers (median score [interquartile range] 9 [8-9] vs 9 [8-10], respectively; P = .0227). CLINICAL IMPLICATIONS: These results support the correlation between videogame use and male sexual health. Compared with non-gamers, men playing videogames for more than 1 hour/day were less likely to have premature ejaculation but more likely to have decreased sexual desire. STRENGTHS AND LIMITATIONS: This is the first study aimed to assess male sexual health in gamers. We identified an association between PEDT and IIEF scores and videogame use; however, these findings require validation through interventional studies. Furthermore, volunteers were recruited through social networks, thus increasing the risk of recruitment bias. CONCLUSION: To our knowledge, this is the first observational study investigating the link between electronic entertainment and male sexuality, specifically for ejaculatory response and sexual desire. Sansone A, Sansone M, Proietti M, et al. Relationship Between Use of Videogames and Sexual Health in Adult Males. J Sex Med 2017;14:898-903. PMID- 28579338 TI - Serine-like proteolytic enzymes from common carp Cyprinus carpio L. seminal plasma are able to degrade sperm proteins. AB - The application of zymography, with sperm proteins as a substrate, allowed for the first time the visualisation of two serine proteinases with a molecular weight of 76 and 163kDa from common carp Cyprinus carpio L. seminal plasma. Twenty four hours of incubation in a development solution with a pH of 7.5 and incubation at 37 degrees C were the best conditions for the visualisation of serine proteinase; however, proteolysis was also observed at 4 degrees C. Our results indicate that serine proteinase from common carp seminal plasma with a molecular weight of 76 and 163kDa may be involved in the degradative mechanism of sperm proteins. This mechanism may be responsible for the removal of damaged sperms by the digestion of native sperm proteins. PMID- 28579339 TI - Prognostic value of alkaline phosphatase in patients with acute coronary syndromes. AB - OBJECTIVES: The objective of the study was to investigate the association between alkaline phosphatase (AP) activity and prognosis of patients with acute coronary syndrome (ACS). DESIGN AND METHODS: The study included 2134 patients with ACS undergoing percutaneous coronary intervention. All included patients had baseline AP measurements available. The receiver operating characteristic curve analysis showed that the best cut-off of AP for mortality prediction was 98.0U/L. Using this cut-off, patients were divided into two groups: a group with AP>98.0U/L (n=493) and a group with AP<=98.0U/L (n=1641). The primary endpoint was 3-year mortality. RESULTS: Overall, there were 229 deaths over the follow-up: 90 deaths among patients with an AP >98.0U/L and 139 deaths among patients with an AP<=98.0U/L (Kaplan-Meier estimates of 3-year total mortality, 19.5% and 9.3%, respectively; adjusted hazard ratio [HR]=1.37, 95% confidence interval [CI] 1.10 1.70, P=0.004 for each unit higher log AP). Cardiac deaths occurred in 157 patients: 66 deaths among patients with an AP>98.0U/L and 91 deaths among patients with an AP<=98.0U/L (Kaplan-Meier estimates of 3-year cardiac mortality, 14.3% and 6.0%, respectively; adjusted HR=1.32 [1.02-1.70], P=0.033, for each unit higher log AP). The C-statistic of the multivariable model with baseline variables was 0.836 [0.807-0.866] and it increased to 0.842 [0.814-0.874] after inclusion of AP (P=0.045). CONCLUSIONS: In patients presenting with an ACS and treated with percutaneous coronary intervention, elevated AP activity is associated with increased risk of subsequent mortality. PMID- 28579340 TI - APRI test and hyaluronic acid as non-invasive diagnostic tools for post HCV liver fibrosis: Systematic review and meta-analysis. AB - BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) accounts for a sizable proportion of chronic liver disease cases and represents the most common indication for liver transplantation. Precise diagnosis of hepatic fibrosis stage is considered a funnel-neck in proper management and follow-up of HCV-infected patients. Given the possible complications of liver biopsy, a non-invasive method for assessing hepatic fibrosis is needed. This study aimed to evaluate the diagnostic accuracy of APRI and hyaluronic acid as non-invasive diagnostic assessment tools for post HCV liver fibrosis. PATIENTS AND METHODS: Systematic literature searching identified studies performed on Egyptian territory to evaluate APRI and hyaluronic acid as non-invasive tests of fibrosis and using liver biopsy as the reference standard. Meta-analysis was performed for areas with an adequate number of publications. Validation of meta- analysis on APRI was done on a subset of 150 treatment-naive post-hepatitis C patients. RESULTS: Both APRI and hyaluronic acid have superior predictive power for hepatic cirrhosis (F4) than for significant fibrosis (F2-F3). The pooled estimate for sensitivities and specificities of APRI and hyaluronic acid to diagnose F4 were (84% and 82%) and (83% and 89%) respectively. In the subgroup of treatment naive post-hepatitis C patients, APRI had higher diagnostic performance to diagnose liver cirrhosis with 93.8% sensitivity and 72.4% specificity (AUC; 0.908, 95%CI; 0.851-0.965, p value; <0.001) compared to its accuracy to diagnose significant hepatic fibrosis with 65.1% sensitivity and 77.8% (AUC; 0.685, 95% CI; 0.59-0.78, p-value; 0.001). CONCLUSION: APRI score and hyaluronic acid levels are simple and reliable non invasive markers to detect advanced fibrosis among post-hepatitis C patients. PMID- 28579341 TI - Percutaneous ultrasound-guided fiducial marker placement for liver cancer robotic stereotactic radio-surgery treatment: A comparative analysis of three types of markers and needles. AB - BACKGROUND AND STUDY AIMS: Percutaneous placement of fiducial markers is required to perform stereotactic body radiation therapy (SBRT) for liver neoplastic lesions. This prospective trial was designed to evaluate the feasibility and safety of percutaneous ultrasound-guided placement of three different types of markers in patients with liver cancer referred for SBRT. PATIENTS AND METHODS: Fifty patients underwent percutaneous ultrasound-guided implantation of a fiducial marker in the liver. Three sizes of needles were used: 25 gauge (G), 22G, and 17G. The 25G and 22G needles contained gold anchor markers of 0.28*10mm and 0.4 *10mm size, respectively. In contrast, the 17G needle contained a gold grain marker of 1*4mm. Each patient received 1-6 markers, depending on lesion size and numbers. Technical feasibility and the occurrence of adverse events were registered. Computed tomography scans were acquired prior to SBRT to evaluate the location, visibility, or complications related to the markers. RESULTS: A total of 163 needles were used to deliver 163 markers in 50 patients. No major complications occurred. Minor complication occurrence rate was 12%. The total complication occurrence for all type of markers was 8.5%. No complications were observed with the use of the gold anchor marker of 0.4 *10mm size. Variance analysis of the three markers showed a significant difference in the frequency of complications amongst the three markers (p<0.01). CONCLUSION: Percutaneous ultrasound-guided placement of fiducial markers for SBRT of liver neoplastic lesions is safe and feasible. In our series, the 22G needle showed some advantage in terms of handling and safety when compared with the 25G and 17G needles. In addition, the gold anchor marker of 0.4 *10mm size displayed a lower percentage of displacement. PMID- 28579342 TI - Prevalence of hepatitis C virus genotypes and subtypes in Lebanese population and major high risk groups. AB - BACKGROUND AND STUDY AIMS: The prevalence of hepatitis C in Lebanon is low. It is estimated at 0.2% of the total population. The aim of our study is to evaluate the exact prevalence of each genotype on a large scale population and in each potential source of infection. PATIENTS AND METHODS: We reviewed all the data in the Ministry of Public Health related to patients who have submitted their file for treatment during a period of 9years ranging from January 2005 till December 2013. RESULTS: The genotype distribution in 1031 Lebanese patients was as following: Genotype 1 was the most predominant representing 47% followed by genotype 4 representing 34% then genotype 3 representing14%. Concerning sex distribution and routes of infection, there was a male predominance in intravenous drug users (IVDU), whereas approximately equal distribution was noted in haemodialysis and transfusion groups. A female predominance was noted in the "unknown" mode of infection. Concerning age distribution and routes of infection, a mean age of 27 was noted in the IVDU group, whereas mean age of 60 in the transfusion group and 50 in the haemodialysis group. In patients who acquired the infection post transfusion or during haemodialysis, genotype 1 was the most predominant, whereas in IVDU, genotype 3 was the most predominant. Concerning sub genotyping: subtype 1b was the most predominant (84%) in genotype 1. in genotype 2 subtype b with 75%, all genotype 3 were subtype a, in genotype 4 subtype a represents 50% of genotype followed by subtype e in 30%. CONCLUSION: Our data concerning Lebanese population demonstrate that genotype 1 is the most prevalent genotype followed by genotype 4. In IVU, we noted genotype-3 and -1 being the most prevalent in relation to clustering in this high risk group. This distribution differs from most surrounding countries and all other Arab countries. PMID- 28579343 TI - Relationship between liver injury and serum cytokeratin 18 levels in asymptomatic hepatitis B virus carriers and in patients with chronic hepatitis B infection. AB - BACKGROUND AND STUDY AIMS: Apoptosis represents a well-known mechanism of cell death involved in most chronic liver injuries. Our aim was to investigate the serum fragment level of cytokeratin 18 (CK18), M30, in asymptomatic hepatitis B virus (HBV) carriers and patients with chronic hepatitis B (CHB) and to evaluate the relationship between serum M30 levels and the severity of hepatic injury. PATIENTS AND METHODS: Asymptomatic HBV carriers (n=169), patients with CHB (n=100), and healthy control subjects (n=43) were enrolled in the study. Serum CK18 (M30) levels were analysed in all subjects. Liver biopsy for histopathological assessment was performed in asymptomatic HBV carriers and in patients with CHB infection. RESULTS: Serum CK18 (M30) levels were significantly higher in asymptomatic HBV carriers (198.77+/-77.62U/L) than in healthy control subjects (146.92+/-40.18U/L). Patients with CHB (283.02+/-147.45U/L) had significantly higher CK18 (M30) levels than asymptomatic HBV carriers (p=0.001). The diagnostic efficacy of CK18 (M30) levels in distinguishing patients with HBeAg-negative CHB from asymptomatic HBV carriers was found to be moderate (c statistics: 0.695), and the diagnostic cut-off value of CK18 (M30) was 262U/L (specificity: 85%, sensitivity: 48%, positive likelihood ratio: 3.35, and negative likelihood ratio: 0.60). There was a positive correlation between serum CK18 (M30) levels and histological activity index scores in asymptomatic HBV carriers and patients with CHB. CONCLUSIONS: Serum CK18 (M30) levels may be a valuable indicator in distinguishing asymptomatic HBV carriers from patients with HBeAg-negative CHB when considered together with ALT and HBV-DNA levels. PMID- 28579344 TI - Evaluation of gastro-oesophageal reflux disease in wheezy infants using 24-h oesophageal combined impedance and pH monitoring. AB - BACKGROUND AND STUDY AIMS: Gastro-oesophageal reflux disease (GERD) is incriminated as a cause of non-asthmatic infantile wheeze. To date, no diagnostic test is considered standard for GERD-related airway reflux diagnosis. Oesophageal combined multiple channel intraluminal impedance and pH (MII-pH) monitoring is proposed to be a sensitive tool for evaluation of all GERD including infantile wheeze. We aimed to determine the GERD prevalence amongst wheezy infants in the first year of life using combined MII-pH versus pH monitoring alone and evaluate the sensitivity and specificity of objective MII-pH monitoring parameters in GERD associated infantile wheeze diagnosis compared to those of lipid-laden macrophage index (LLMI). PATIENTS AND METHODS: Thirty-eight wheezy infants below 1year of age were evaluated for GERD using oesophageal combined MII-pH monitoring and LLMI. RESULTS: Totally, 60.5% of cases had abnormal MII-pH; only 7.9% of them had abnormal pH monitoring. LLMI was significantly higher in wheezy infants with abnormal MII-pH than infants with normal MII-pH monitoring (112+/-88 versus 70+/ 48; P=0.036). The current definitions of abnormal MII-pH study, reflux index>=10% and distal reflux episodes>=100, had low sensitivity (23%) but high specificity (100% and 96%, respectively) in GERD-related aspiration diagnosis defined by LLMI>=100. Using ROC curves, bolus contact time>=2.4% and proximal reflux episodes>=46 had 61% and 54% sensitivity and 64% and 76% specificity, respectively, in GERD-related aspiration diagnosis. CONCLUSION: Combined MII-pH is superior to pH monitoring in reflux-associated infantile wheeze diagnosis. Objective data including proximal reflux episodes and bolus contact time should be combined with the current parameters used in reflux-associated infantile wheeze diagnosis. PMID- 28579345 TI - Efficacy and safety of midazolam and ketamine in paediatric upper endoscopy. AB - BACKGROUND AND STUDY AIM: Upper endoscopy can be successfully carried out in children under deep sedation and anaesthesia. However, the best method of upper endoscopy for children who require gastrointestinal intervention has yet to be defined. The aim of this study is to investigate the efficacy and safety of the sedation induced by intravenous midazolam and ketamine during upper endoscopy in children. PATIENTS AND METHODS: This study included patients ages 3-18years who had undergone upper endoscopy. All subjects received IV midazolam and ketamine. During the intervention, hypoxia, tachycardia, bradycardia, hypertension, and hypotension were recorded. After the intervention, euphoria, dysphoria, vertigo, visual problems (such as diplopia and nystagmus), and emergencies (such as arrhythmia, convulsion, and hallucination), among other findings, were recorded. Older children who were capable of expressing themselves were questioned to help determine these conditions. RESULTS: The mean age of the study group was was 11.9+/-3.42years; 54% of the patients were females, and 46% were males. During the upper endoscopy, hypoxia occurred in 9% of patients, mild hypertension in 14%, hypotension in 5%, tachycardia in 23%, bradycardia in 8%, and flushing urticaria in 2%. After the upper endoscopy, one of the most common complications was sore throat, which occurred in 24% of patients. Vomiting was observed in 14% of patients, dizziness in 24%, diplopia in 27%, euphoria in 3% (5 patients), dysphoria in 4%, and hallucination in 4%. Of the total patients, 4% required oxygen supply with a face mask. CONCLUSION: The results of our study showed that the use of IV midazolam and ketamine during upper endoscopy in children was safe and effective. PMID- 28579347 TI - Concomitant or Staged Transcatheter Treatment for Severe Combined Aortic and Mitral Valve Disease. PMID- 28579346 TI - Combined spontaneous bacterial empyema and peritonitis in cirrhotic patients with ascites and hepatic hydrothorax. AB - BACKGROUND AND STUDY AIMS: Spontaneous bacterial empyema (SBEM) is an underestimated condition in patients with ascites and hepatic hydrothorax with a high mortality. This study aimed to find whether spontaneous bacterial peritonitis (SBP) is a prerequisite for SBEM. PATIENTS AND METHODS: 3000 HCV related cirrhotic patients with ascites and hydrothorax were screened for the presence of SBP (ascitic fluid neutrophils >250/mm3) and SBEM (positive pleural fluid culture and neutrophils >250/mm3 or negative pleural fluid culture and neutrophils >500/mm3 with no evidence of pneumonia/parapneumonic effusion on chest radiograph or CT). RESULTS: The prevalence of SBEM in cirrhotic patients was 1.2% (36/3000) unlike SBP (1.6%; 48/3000). SBEM was detected in 51.4% of the patients with hepatic hydrothorax (36/70). A total of 70 patients had concomitant ascites and hydrothorax, namely SBP (n=17), SBEM (n=5), and dual SBP and SBEM (n=31), whereas 17 patients had sterile concomitant ascites and hydrothorax. Age, sex, liver function, kidney function tests, complete blood count, INR, MELD, MELD Na, blood chemistry, and culture/sensitivity for ascitic and pleural fluid were statistically not different (p>0.05) between SBP and dual SBP and SBEM patients. Escherichia coli and Klebsiella pneumoniae were detected in the culture. From univariate analysis, no predictors of dual SBP and SBEM were detected. CONCLUSION: SBEM is a part of SBP in cirrhotic patients with ascites and hydrothorax. PMID- 28579348 TI - Ten-year survival after endoscopic stent placement as a bridge to surgery in obstructing colon cancer. AB - BACKGROUND AND AIMS: Self-expandable metal stents are used increasingly in the treatment of obstructing colorectal cancer (CRC). Although endoscopic colon stenting is widely accepted in palliation, disagreement exists about its role in a curative setting. This study aims to describe long-term survival data in a large patient group treated with colon stenting as a bridge to surgery for CRC. METHODS: This prospective study included 97 patients who presented in a Belgian hospital between 1998 and 2013 with obstructing, although potentially curable, CRC. All patients underwent endoscopic stenting as a bridge to surgery. Procedure related adverse events and long-term follow-up data were retrospectively collected and compared with the CRC mortality in Belgium in the same time span. RESULTS: Overall survival in this observational cohort did not differ significantly from survival in all Belgian patients with CRC in the same period (P = .14). One-year, 5-year, and 10-year survival rates were similar in both groups (95.9% vs 79.0%; 54.7% vs 51.2%; 41.0% vs 35.6%, respectively). The technical success rate was 94.8%. Seventy-three patients did not experience any adverse event. Stent migration occurred in 9 patients, whereas micro-perforations and macro-perforations were observed in 14 patients, without influence on survival. Incidence rates of peritoneal metastases did not differ between patients with and without any type of perforation (22.2% vs 15.2%, respectively; P = .47). The type of stent influenced the overall adverse event risk, mainly driven by a significant increase in stent migration in case of Wallstent enteral (Boston Scientific Corporation, Natick, Mass). CONCLUSIONS: Colon stenting before surgery is effective and did not worsen the survival outcome in patients with obstructing CRC who were treated with curative intent, which affirms the role for stenting as a bridge to surgery. PMID- 28579349 TI - Electromagnetic-guided placement of nasoduodenal feeding tubes versus endoscopic placement: a randomized, multicenter trial. AB - BACKGROUND AND AIMS: Electromagnetic-guided placement (EMP) of a nasoduodenal feeding tube by trained nurses is an attractive alternative to EGD-guided placement (EGDP). We aimed to compare EMP and EGDP in outpatients, ward patients, and critically ill patients with normal upper GI anatomy. METHODS: In 3 centers with no prior experience in EMP, patients were randomized to placement of a single-lumen nasoduodenal feeding tube either with EGDP or EMP. The primary endpoint was post-pyloric position of the tube on abdominal radiography. Patients were followed for 10 days to assess patency and adverse events. The analyses were performed according to the intention-to-treat principle. RESULTS: In total, 160 patients were randomized to EGDP (N = 76) or EMP (N = 84). Three patients withdrew informed consent, and no abdominal radiography was performed in 2 patients. Thus, 155 patients (59 intensive care unit, 38%) were included in the analyses. Rates of post-pyloric tube position between EGDP and EMP were comparable (79% vs 82%, odds ratio 1.16; 90% confidence interval, 0.58-2.38; P = .72). Adverse events were observed in 4 patients after EMP (hypoxia, GI blood loss, atrial fibrillation, abdominal pain) and in 4 after EGDP (epistaxis N = 2, GI blood loss, hypoxia). Costs of tube placements were lower for EMP compared with EGDP: $519.09 versus $622.49, respectively (P = .04). CONCLUSIONS: Success rates and safety of EMP and EGDP in patients with normal upper GI anatomy were comparable. Lower costs and potential logistic advantages may drive centers to adopt EMP as their new standard of care. (Clinical trial registration number: NTR4286.). PMID- 28579350 TI - Azithromycin Modulates 3',5'-cyclic Diguanylic Acid Signaling in Pseudomonas aeruginosa. AB - Macrolides have been reported to exert a variety of effects on both host immunomodulation and repression of bacterial pathogenicity. In this study, we report that the 3',5'-cyclic diguanylic acid (c-di-GMP) signaling system, which regulates virulence in Pseudomonas aeruginosa, is affected by the macrolide azithromycin. Using DNA microarray analysis, we selected a gene encoding PA2567 related to c-di-GMP metabolism that was significantly affected by azithromycin treatment. Expression of the PA2567 gene was significantly repressed by azithromycin in a time- and dose-dependent manner, whereas no difference in PA2567 gene expression was observed in the absence of azithromycin. In-frame deletion of the PA2567 gene affected both virulence factors and the quorum sensing system, and significantly decreased total bacteria in a mouse pneumonia model compared to the wild-type strain (P < 0.05). These results suggest that macrolides possess the ability to modulate c-di-GMP intracellular signaling in P. aeruginosa. PMID- 28579351 TI - Preclinical abuse liability assessment of ABT-126, an agonist at the alpha7 nicotinic acetylcholine receptor (nAChR). AB - ABT-126 is a nicotinic acetylcholine receptor (nAChR) agonist that is selective for the alpha7 subtype of the receptor. nAChRs are thought to play a role in a variety of neurocognitive processes and have been a pharmacologic target for disorders with cognitive impairment, including schizophrenia and Alzheimer's disease. As part of the preclinical safety package for ABT-126, its potential for abuse was assessed. While the involvement of the alpha4beta2 subtype of the nicotinic receptor in the addictive properties of nicotine has been demonstrated, the role of the alpha7 receptor has been studied much less extensively. A number of preclinical assays of abuse potential including open-field, drug discrimination and self-administration were employed in male rats. ABT-126 had modest effects on locomotor activity in the open-field assay. In nicotine and d amphetamine drug discrimination assays, ABT-126 administration failed to produce appreciable d-amphetamine-like or nicotine-like responding, suggesting that its interoceptive effects are distinct from those of these drugs of abuse. In rats trained to self-administer cocaine, substitution with ABT-126 was similar to substitution with saline, indicating that it lacks reinforcing effects. No evidence of physical dependence was noted following subchronic administration. Overall, these data suggest that ABT-126 has a low potential for abuse. Together with other literature on this drug class, it appears that drugs that selectively activate alpha7 nAChRs are not likely to result in abuse or dependence. PMID- 28579353 TI - In vitro differentiation of menstrual blood stem cells into keratinocytes: A potential approach for management of wound healing. AB - The skin wounds caused by insults should be treated immediately to restore the functions and integrity. Recent studies suggest that stem cells-based therapies may be applicable in wound healing. Newly defined menstrual blood-derived stem cells (MenSCs) show high rate of cell proliferation and trans-differentiation potency to various cell types. However, MenSCs potential to generate keratinocyte for future therapeutic use of skin lesions has been remained to investigate. We cultivated MenSCs in the presence of isolated foreskin derived-keratinocytes using an indirect co-culture system and evaluated efficiency of this protocol to generate keratinocytes using immunofluorescent staining and Real Time PCR technique. Our results showed that differentiated keratinocytes express epidermal/keratinocytes lineage specific markers such as K14, p63, and involucrin at both mRNA and protein levels. Immunofluorescent staining showed the expression of involucrin and K14 in differentiated cells in contrast to undifferentiated cells. Moreover, mRNA expression levels of K14 (11.1 folds, p = 0.001), p63 (10.23 folds, p = 0.001), and involucrin (2.94 folds, p = 0.001) were higher in differentiated MenSCs compared to non-cocultured cells. Therefore, we firstly presented evidence about differentiation capability of MenSCs into epidermal/keratinocytes lineage. Considering the advantages of MenSCs such as great accessibility, these stem cells are promising for stem cells-based therapies of skin defects. PMID- 28579354 TI - Factors related to the association of social anxiety disorder and alcohol use among adolescents: a systematic review. AB - OBJECTIVE: To identify the risk factors related to the association between social anxiety disorder and alcohol use in adolescents. SOURCE OF DATA: The PICO research strategy was used to perform a systematic review in Medline, LILACS, Pubmed, IBECS and Cochrane Library databases. DeCS/MeSH: Phobic Disorders, Adolescent, Behavior, Ethanol, Risk Factors, and the Boolean operator "AND" were used. Inclusion criteria were: cross-sectional, prospective/retrospective cohort, and case-control studies, carried out in adolescents (10-19 years), original articles on social anxiety disorder and alcohol use published between 2010 and 2015. Studies that did not report the terms "anxiety disorder" and "alcohol use" in the title and abstract were excluded. SYNTHESIS OF DATA: 409 articles were retrieved; after the exclusion of 277 repeated articles, the following were eligible: 94 in MEDLINE, 68 in Pubmed, 12 in IBCS, and three in LILACS. Titles and abstracts were independently read by two examiners, which resulted in the selection of eight articles for the analysis. Risk factors associated to the two disorders were female gender, age, peer approval and affective problems for alcohol use, confrontation situations and/or compliance reasons, frequency of alcohol use, and secondary comorbidities, such as depression and generalized anxiety. CONCLUSIONS: It is necessary to assess the period of social anxiety disorders first symptom onset, as well as the risks for alcohol use in order to establish corrective intervention guidelines, especially for socially anxious students. PMID- 28579355 TI - Expression, purification and characterization of a novel recombinant SVTLE, r agkihpin-2, from Gloydius halys Pallas venom gland in Escherichia coli. AB - In our previous work, a thrombin-like enzyme (TLE), agkihpin, was successfully isolated, purified, cloned and named from the venom of Gloydius halys Pallas, having fibrinolytic, fibrinogenolytic and thrombosis-reduced activities, attenuating migration of liver cancer cell, and without bleeding risk. To explore the possibility of agkihpin as a thrombolytic and/or anti-metastasis agent in the future, in this study recombinant agkihpin was expressed and purified in Escherichia coli, and its biological activities investigated. Thus, r-agkihpin-2 was successfully expressed and purified and confirmed by Western blot and peptide mass fingerprinting. After purification and renaturation, 46 mg (399 U) of active r-agkihpin-2 was obtained from 1 L bacterial culture. The results of the arginine esterase activity assay, fibrin plate test fibrinogenolytic activity assay, thrombin-induced venous thrombosis assay, Scratch-Wound assay and bleeding assay showed that active r-agkihpin-2 had slightly lower TAME hydrolytic, fibrinolytic, fibrinogenolytic, thrombus-reduced and migration-attenuated activities than those of native agkihpin, and had no bleeding risk. These findings confirmed that, active r-agkihpin-2 could be further investigated for thrombolytic and/or anti metastasis drug discovery in the future. PMID- 28579352 TI - Clinical Features Associated with Delirium Motor Subtypes in Older Inpatients: Results of a Multicenter Study. AB - OBJECTIVE: To date motor subtypes of delirium have been evaluated in single center studies with a limited examination of the relationship between predisposing factors and motor profile of delirium. We sought to report the prevalence and clinical profile of subtypes of delirium in a multicenter study. METHODS: This is a point prevalence study nested in the "Delirium Day 2015", which included 108 acute and 12 rehabilitation wards in Italy. Delirium was detected using the 4-AT and motor subtypes were measured with the Delirium Motor Subtype Scale (DMSS). A multinomial logistic regression was used to determine the factors associated with delirium subtypes. RESULTS: Of 429 patients with delirium, the DMSS was completed in 275 (64%), classifying 21.5% of the patients with hyperactive delirium, 38.5% with hypoactive, 27.3% with mixed and 12.7% with the non-motor subtype. The 4-AT score was higher in the hyperactive subtype, similar in the hypoactive, mixed subtypes, while it was lowest in the non-motor subtype. Dementia was associated with all three delirium motor subtypes (hyperactive, OR 3.3, 95% CI: 1.2-8.7; hypoactive, OR 2.8, 95% CI: 1.2-6.5; mixed OR 2.6, 95% CI: 1.1-6.2). Atypical antipsychotics were associated with hypoactive delirium (OR 0.23, 95% CI: 0.1-0.7), while intravenous lines were associated with mixed delirium (OR 2.9, 95% CI: 1.2-6.9). CONCLUSIONS: The study shows that hypoactive delirium is the most common subtype among hospitalized older patients. Specific clinical features were associated with different delirium subtypes. The use of standardized instruments can help to characterize the phenomenology of different motor subtypes of delirium. PMID- 28579356 TI - Mutations in matrix protein 1 and nucleoprotein caused human-specific defects in nuclear exportation and viral assembly of an avian influenza H7N1 virus. AB - Nuclear exportation of influenza ribonucleoprotein is a vital step in viral replication cycle. In this study a particular H7N1 (A/ostrich/Zimbabwe/222 E3/1996) virus showed exclusively nuclear localization of the viral nucleoprotein (NP) only in human cell lines but not in cell lines of other species suggesting a human-specific nuclear exportation defect. After 10 passages in human lung cells, an adapted strain (H7N1:P10) could efficiently replicate and export viral NP in human cells. Mutations in the NP and matrix M1 gene at position 297 and 227, respectively, were found to rescue the defect. While the NP mutant showed a comparable ratio of total to NP-associated negative-sense RNA in the cytoplasm as compared to the wild type, the M1 mutant showed an increase in free negative sense RNA in the cytoplasm. These indicated that the NP mutation might cause a nuclear export defect, whereas the M1 mutation might cause a defect in ribonucleoprotein assembly step. PMID- 28579357 TI - Indocyanine green fluorescence-guided surgery after IV injection in metastatic colorectal cancer: A systematic review. AB - OBJECTIVE: Indocyanine green fluorescence-guided surgery (ICG-FGS) has emerged as a potential new imaging modality for improving the detection of hepatic, lymph node (LN), and peritoneal metastases in colorectal cancer (CRC) patients. The aim of this paper is to review the available literature in the clinical setting of ICG-FGS for tumoral detection in various fields of metastatic colorectal disease. METHODS: PubMed and Medline literature databases were searched for original articles on the use of ICG in the setting of clinical studies on colorectal cancer. The search terms used were "near-infrared fluorescence", "intraoperative imaging", "indocyanine green", "human" and "colorectal cancer". RESULTS: ICG fluorescence imaging (ICG-FI) is clearly supported as an intraoperative technique that allows the detection of additional superficial hepatic metastases of CRC. Data on the role of ICG-FI in the intraoperative detection of peritoneal metastases and LN metastases are scarce but encouraging and ICG-FI could potentially improve the staging and treatment of these patients. CONCLUSION: ICG FI is a promising imaging technique in the detection of small infraclinic LN, hepatic, and peritoneal metastatic deposits that may allow better staging and more complete surgical resection with a potential prognostic benefit for patients. PMID- 28579358 TI - The impact of T1 renal tumor characteristics on baseline renal function in patients undergoing partial nephrectomy: A renal scan based objective assessment. AB - INTRODUCTION AND OBJECTIVES: To objectively assess the impact of renal tumors characteristics and other measurable factors on baseline renal function in patient undergoing partial nephrectomy (PN). METHODS: Patients who underwent laparoscopic PN for a T1 renal mass between 2012 and 2016 and who also had a mercapto-acetyltriglycine renal scan prior to surgery were retrieved from a single institution prospectively-collected database. Split renal function (SRF) and Effective Renal Plasma Flow (ERPF) for both the operated kidney and the unaffected contralateral were calculated. Patient demographics and tumor characteristics (e.g. size, location and; nephrometry score) were assessed. Renal function of both the operated and the unaffected; contralateral kidney were compared. Statistical analysis was performed by using Statistica 8.0 (StatSoft). RESULTS: 227 patients were deemed eligible and included in the analysis. Univariable analysis showed a significant impact of age-adjusted CCI (p = 0.027), hypertension (p = 0.031) and age (p < 0.001) on operated kidney ERPF. Gender (p = 0.011), hypertension (p = 0.042), CCI (both standard and age-adjusted, p = 0.021 and = 0.003, respectively) and age (p < 0.001) were significantly; associated with contralateral unaffected kidney ERPF. Multivariable analysis confirmed age (p < 0.001) and hypertension (p < 0.021) as independent factors in both the operated and the unaffected kidney. CONCLUSIONS: Characteristics of the renal mass (including nephrometry score and size) seem to have no clinically relevant impact on baseline renal function in patients undergoing partial nephrectomy for cT1 renal tumors. Age, hypertension and co-morbidities confirm to represent un modifiable significant factors influencing baseline renal function. PMID- 28579359 TI - Evolution in treatment strategy for metastatic spine disease: Presently evolving modalities. AB - The advent of minimally invasive surgery (MIS) in the surgical management armamentarium and stereotactic radiosurgery in the domain of radiotherapy, has led to a major evolution in treatment of metastatic spine disease (MSD). We reviewed the recent literature to discuss evolution from open to MIS approaches in MSD and the concurrent evolution in radiotherapy. This will provide a sound base for further development and understanding of treatment paradigms in MSD. Literature review showed that evolution of surgery can be traced from inappropriate open surgery (i.e. laminectomy) to appropriate open (i.e. posterior instrumentation and decompression) and further to minimally invasive surgery. This transition was concurrent with the introduction of radiotherapy and its evolution in management of MSD. Evidence shows that presently, the best clinical outcomes are achieved by surgery with timely postoperative radiotherapy. To make surgery an appealing choice in MSD, surgical morbidity needs to be minimized when planning postoperative oncological treatment. MIS approaches have advantages such as early wound healing enabling early introduction of radiotherapy, reduced intraoperative blood loss and shortened hospital stay. Pain reduction and neurological improvement are comparable to open surgery. A multidisciplinary team approach including spinal surgeons, medical & radiation oncologists is mandatory, as the treatment options are constantly evolving. Advancement in radiotherapy with introduction of MIS can be a game-changer in MSD due to reduced peri operative morbidity, allowing earlier postoperative radiotherapy/chemotherapy. We also provide our treatment algorithm which relies on clinical presentation and radiological appearance of spinal cord compression, providing an overview of treatment strategy. PMID- 28579360 TI - Complications of long and intermediate term venous catheters in cystic fibrosis patients: A multicenter study. AB - BACKGROUND: Totally implantable venous access devices (TIVADs) or peripherally inserted central venous catheters (PICCs) are commonly used in the care of patients with cystic fibrosis (CF), but they are associated with various complications, including thrombosis, infection, and insertion site symptoms. METHODS: We conducted a retrospective review of PICC and TIVAD use in adults and children with CF over an 8-year period at 3 accredited care centers. Patient attributes included CFTR genotype, comorbidities, lung function, body mass index, use of anticoagulation, and respiratory tract microbiology. Catheter data included line type, caliber, and lumen number. We assessed practice variation by surveying physicians. RESULTS: In a population of 592 CF patients, 851 PICC and 61 TIVADs were placed between January 1, 2003 and July 1, 2011. Larger catheter caliber and increased lumen number were risk factors for PICC complications in adults. Patient-related risk factors for PICC complications included poor nutritional status, infection with Burkholderia cepacia spp., and having >=5 lines inserted during the study period. The probability of a PICC complication varied across centers (2.6% to 14.1%, p=0.001) and remained significant after adjustment for patient-and line-related risk factors. The median complication free survival of TIVADs, however, did not vary significantly by center (p=0.85). CONCLUSIONS: This is the first longitudinal, multicenter assessment of complication rates for PICCs and TIVADs in a large cohort of adults and children with CF. Specific patient- and catheter-related characteristics were associated with increased risk of complications. Center effects on complication rates were observed for PICCs. PMID- 28579361 TI - Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin. AB - Microtubule-targeting agents (MTAs) are some of the clinically most successful anti-cancer drugs. Unfortunately, instances of multidrug resistances to MTA have been reported, which highlights the need for developing MTAs with different mechanistic properties. One less explored class of MTAs are [1,2,4]triazolo[1,5 a]pyrimidines (TPs). These cytotoxic compounds are microtubule-stabilizing agents that inexplicably bind to vinblastine binding site on tubulin, which is typically targeted by microtubule-destabilizing agents. Here we used cellular, biochemical, and structural biology approaches to address this apparent discrepancy. Our results establish TPs as vinca-site microtubule-stabilizing agents that promote longitudinal tubulin contacts in microtubules, in contrast to classical microtubule-stabilizing agents that primarily promote lateral contacts. Additionally we observe that TPs studied here are not affected by p-glycoprotein overexpression, and suggest that TPs are promising ligands against multidrug resistant cancer cells. PMID- 28579362 TI - Changes in transcranial magnetic stimulation outcome measures in response to upper-limb physical training in stroke: A systematic review of randomized controlled trials. AB - BACKGROUND: Physical training is known to be an effective intervention to improve sensorimotor impairments after stroke. However, the link between brain plastic changes, assessed by transcranial magnetic stimulation (TMS), and sensorimotor recovery in response to physical training is still misunderstood. We systematically reviewed reports of randomized controlled trials (RCTs) involving the use of TMS over the primary motor cortex (M1) to probe brain plasticity after upper-limb physical training interventions in people with stroke. METHODS: We searched 5 databases for articles published up to October 2016, with additional studies identified by hand-searching. RCTs had to investigate pre/post intervention changes in at least one TMS outcome measure. Two independent raters assessed the eligibility of potential studies and reviewed the selected articles' quality by using 2 critical appraisal scales. RESULTS: In total, 14 reports of RCTs (pooled participants=358; mean 26+/-12 per study) met the selection criteria. Overall, 11 studies detected plastic changes with TMS in the presence of clinical improvements after training, and these changes were more often detected in the affected hemisphere by using map area and motor evoked potential (MEP) latency outcome measures. Plastic changes mostly pointed to increased M1/corticospinal excitability and potential interhemispheric rebalancing of M1 excitability, despite sometimes controversial results among studies. Also, the strength of the review observations was affected by heterogeneous TMS methods and upper-limb interventions across studies as well as several sources of bias within the selected studies. CONCLUSIONS: The current evidence encourages the use of TMS outcome measures, especially MEP latency and map area to investigate plastic changes in the brain after upper-limb physical training post-stroke. However, more studies involving rigorous and standardized TMS procedures are needed to validate these observations. PMID- 28579363 TI - Current advances on fermentative biobutanol production using third generation feedstock. AB - Biobutanol is gaining more attention as a potential alternative to ethanol, and the demand for fermentative biobutanol production has renewed interest. The main challenge faced in biobutanol production is the availability of feedstock. Using conventional agricultural biomass as feedstock is controversial and less efficient, while microalgae, the third generation feedstock, are considered promising feedstock for biobutanol production due to their high growth rate and high carbohydrates content. This review is primarily focused on biobutanol production by using carbohydrate-rich microalgal feedstock. Key technologies and challenges involved in producing butanol from microalgae are discussed in detail and future directions are also presented. PMID- 28579364 TI - False-positive results in pharmacoepidemiology and pharmacovigilance. AB - False-positive constitute an important issue in scientific research. In the domain of drug evaluation, it affects all phases of drug development and assessment, from the very early preclinical studies to the late post-marketing evaluations. The core concern associated with this false-positive is the lack of replicability of the results. Aside from fraud or misconducts, false-positive is often envisioned from the statistical angle, which considers them as a price to pay for type I error in statistical testing, and its inflation in the context of multiple testing. If envisioning this problematic in the context of pharmacoepidemiology and pharmacovigilance however, that both evaluate drugs in an observational settings, information brought by statistical testing and the significance of such should only be considered as additional to the estimates provided and their confidence interval, in a context where differences have to be a clinically meaningful upon everything, and the results appear robust to the biases likely to have affected the studies. In the following article, we consequently illustrate these biases and their consequences in generating false positive results, through studies and associations between drug use and health outcomes that have been widely disputed. PMID- 28579365 TI - A novel Python program for implementation of quality control in the ELISA. AB - The use of semi-quantitative assays such as the enzyme-linked immunosorbent assay (ELISA) requires stringent quality control of the data. However, such quality control is often lacking in academic settings due to unavailability of software and knowledge. Therefore, our aim was to develop methods to easily implement Levey-Jennings quality control methods. For this purpose, we created a program written in Python (a programming language with an open-source license) and tested it using a training set of ELISA standard curves quantifying the Fab fragment of an anti-cocaine monoclonal antibody in mouse blood. A colorimetric ELISA was developed using a goat anti-human anti-Fab capture method. Mouse blood samples spiked with the Fab fragment were tested against a standard curve of known concentrations of Fab fragment in buffer over a period of 133days stored at 4 degrees C to assess stability of the Fab fragment and to generate a test dataset to assess the program. All standard curves were analyzed using our program to batch process the data and to generate Levey-Jennings control charts and statistics regarding the datasets. The program was able to identify values outside of two standard deviations, and this identification of outliers was consistent with the results of a two-way ANOVA. This program is freely available, which will help laboratories implement quality control methods, thus improving reproducibility within and between labs. We report here successful testing of the program with our training set and development of a method for quantification of the Fab fragment in mouse blood. PMID- 28579366 TI - "Two-in-One" approach for bioassay selection for dual specificity antibodies. AB - Dual specific antibodies and bispecific antibodies that recognize two different antigen targets are currently being regarded as very effective therapeutics for complex human diseases. While effective, designing and developing a bioassay strategy for dual specific antibodies that is reflective of the mechanism of action (MoA) and also measures the dual activities of antibodies pose unique and exciting challenges. An important question asked while developing a bioassay for dual specific antibodies is, "How many bioassays will be needed, one bioassay or two separate bioassays?" Here we present an approach of using one bioassay for a dual specific antibody that targets two receptors in signaling pathways. The presented assay is able to measure the antibody effects on both target bindings, which would not be achievable using two separate assays. Furthermore, this assay can detect changes in the binding of either target, which impact overall efficacy of the antibody. Its improved sensitivity enables substituting two binding assays with this one bioassay for lot release and stability testing to measure any changes on either target binding, ensuring consistency between lots. This is a single-bioassay approach for a dual specific antibody that is MoA reflective of the intended therapeutic indication. The demonstrated assay development and bridging study strategy for this bioassay for a dual specific mAb1 could be applicable to the other dual specific, bispecific antibodies, and antibodies used for combination therapy. PMID- 28579367 TI - Early postnatal handling reduces hippocampal amyloid plaque formation and enhances cognitive performance in APPswe/PS1dE9 mice at middle age. AB - In rodents, fragmented and low levels of maternal care have been implicated in age-related cognitive decline and the incidence and progression of Alzheimer's pathology. In contrast, enhancing early postnatal maternal care has been associated with improved cognitive function later in life. Here we examined whether early postnatal handling of mouse pups from postnatal days 2-9 enhanced maternal care and whether this affected cognition and Alzheimer pathology at 5 and 11months of age in the APPswe/PS1dE9 mouse model for Alzheimer's disease. Brief, 15min daily episodes of separating offspring from their dams from postnatal days 2-9 (early handling, EH) increased maternal care of the dam towards her pups upon reunion. At 11 (but not 5) months of age, EH APPswe/PS1dE1 mice displayed significantly reduced amyloid plaque pathology in the hippocampus. At this age, EH also prevented short-term working memory deficits while restoring impairments in contextual fear memory formation in APPswe/PS1dE9 mice. EH did not modulate amyloid pathology in the amygdala, nor did it affect auditory fear conditioning deficits in APPswe/PS1dE9 mice. We conclude that increased levels of maternal care during the early life period delays amyloid accumulation and cognitive decline in an Alzheimer's mouse model, involving the hippocampus, but not to the amygdala. These studies highlight the importance of the early postnatal period in modulating resilience to develop Alzheimer's pathology later in life. PMID- 28579368 TI - Letter to the editor - Adverse events associated with the use of cervical spine manipulation or mobilization and patient characteristics. PMID- 28579369 TI - Getting a Manual Wheelchair Over a Threshold Using the Momentum Method: A Descriptive Study of Common Errors. AB - OBJECTIVES: To (1) document the success of learners' attempts to overcome a threshold in a manual wheelchair while using the momentum method; (2) describe the frequency and nature of any errors observed; and (3) compare the characteristics of participants who were or were not successful on their first attempts. DESIGN: Cross-sectional, observational study following Strengthening the Reporting of Observational Studies in Epidemiology guidelines. SETTING: Indoor obstacle course in a rehabilitation center. PARTICIPANTS: Able-bodied students (N=214) learning the threshold skill. INTERVENTION: Participants attempted to get over the Wheelchair Skills Test (WST) threshold (2cm high, 1.5m wide, and 10cm in the line of progression) in a manual wheelchair. MAIN OUTCOME MEASURES: From each participant's video recording of the first attempt, we assigned a WST score for the skill and described any errors noted. RESULTS: The WST scores for the first attempts were "pass" for 16 (7.5%), "pass with difficulty" for 100 (46.7%), and "fail" for 98 (45.8%). Eventually, requiring up to 6 attempts, 203 participants (94.9%) were successful (pass or pass with difficulty). Twenty-six different error types were identified. With the use of logistic regression analysis, the odds ratio of failing on the first attempt for women versus men was 2.71 (95% confidence interval, 1.23-6.00) (P=.0138). CONCLUSIONS: Only about half of able-bodied people learning the threshold skill using the momentum method are successful on their first attempts, although almost all are successful with further practice and feedback. During the first attempts, there are a wide variety of errors, primarily in the popping phase of the skill. Those who are successful on their first attempts are more likely to be men. These findings have implications for the assessment and training of the threshold skill. PMID- 28579370 TI - The blood donor with hemochromatosis: To be or not to be! PMID- 28579371 TI - Influence of argon on temperature modulation and neurological outcome in hypothermia treated rats following cardiac arrest. AB - AIM OF THE STUDY: Combining xenon and mild therapeutic hypothermia (MTH) after cardiac arrest (CA) confers a degree of protection that is greater than either of the two interventions alone. However, xenon is very costly which might preclude a widespread use. We investigated whether the inexpensive gas argon would enhance hypothermia induced neurologic recovery in a similar manner. METHODS: Following nine minutes of CA and three minutes of cardiopulmonary resuscitation 21 male Sprague-Dawley rats were randomized to receive MTH (33 degrees C for 6h), MTH plus argon (70% for 1h), or no treatment. A first day condition score assessed behaviour, motor activity and overall condition. A neurological deficit score (NDS) was calculated daily for seven days following the experiment before the animals were killed and the brains harvested for histopathological analysis. RESULTS: All animals survived. Animals that received MTH alone showed best overall neurologic function. Strikingly, this effect was abolished in the argon augmented MTH group, where animals showed worse neurologic outcome being significant in the first day condition score and on day one to three and five in the NDS in comparison to MTH treated rats. Results were reflected by the neurohistopathological analysis. CONCLUSION: Our study demonstrates that argon augmented MTH does not improve functional recovery after CA in rats, but may even worsen neurologic function in this model. PMID- 28579372 TI - Can resuscitation bring positive changes for paramedics? Polish experiences. PMID- 28579374 TI - Activated plasmacytoid dendritic cells regulate type 2 innate lymphoid cell mediated airway hyperreactivity. AB - BACKGROUND: Allergic asthma is a prevalent inflammatory disease of the airways caused by dysregulated immune balance in the lungs with incompletely understood pathogenesis. The recently identified type 2 innate lymphoid cells (ILC2s) play significant roles in the pathogenesis of asthma. Although ILC2-activating factors have been identified, the mechanisms that suppress ILC2s remain largely unknown. Plasmacytoid dendritic cells (pDCs) are important in antiviral immunity and in maintaining tolerance to inert antigens. OBJECTIVE: We sought to address the role of pDCs in regulating ILC2 function and ILC2-mediated airway hyperreactivity (AHR) and lung inflammation. METHODS: We used several murine models, including BDCA-2-diphtheria toxin receptor (DTR) transgenic and IFN-alpha receptor 1 deficient mice, as well as purified primary ILC2s, to reach our objective. We extended and validated our findings to human ILC2s. RESULTS: We show that activation of pDCs through Toll-like receptor 7/8 suppresses ILC2-mediated AHR and airway inflammation and that depletion of pDCs reverses this suppression. We further show that pDCs suppress cytokine production and the proliferation rate while increasing the apoptosis rate of ILC2s through IFN-alpha production. Transcriptomic analysis of both human and murine ILC2s confirms the activation of regulatory pathways in ILC2s by IFN-alpha. CONCLUSION: Activation of pDCs alleviates AHR and airway inflammation by suppressing ILC2 function and survival. Our findings reveal a novel regulatory pathway in ILC2-mediated pulmonary inflammation with important clinical implications. PMID- 28579373 TI - Post ROSC pulse-oximetry derived perfusion index and thirty days survival after out-of-hospital cardiac arrest. New insights from the Pavia CARe (Pavia Cardiac Arrest Registry). PMID- 28579375 TI - Assessment of thunderstorm-induced asthma using Google Trends. PMID- 28579376 TI - A new measure to assess asthma's effect on quality of life from the patient's perspective. AB - BACKGROUND: The Asthma Impact on Quality of Life Scale (A-IQOLS) assesses the negative effect of asthma on quality of life (QoL) from the patient's perspective by using dimensions of Flanagan's Quality of Life Scale (QOLS), a measure of current QoL. OBJECTIVES: We sought to determine and compare the psychometric properties of the A-IQOLS and QOLS, including their sensitivities to differences and change in asthma status. METHODS: In a test-retest design (3- to 5-week interval) adults with persistent asthma underwent spirometry and were administered the A-IQOLS, other asthma outcome measures (Asthma Control Test, Asthma Symptom Utility Index, and the Marks and Juniper Asthma Quality of Life Questionnaires), and the QOLS. RESULTS: Participants' (n = 147) mean age was 49 years, 76% were white, 12% were Hispanic, and 65% were female. A-IQOLS and QOLS scores were significantly correlated with other asthma outcomes scores, except FEV1, but shared relatively low common variance with these measures. A-IQOLS but not QOLS score changes were significantly correlated with changes in asthma outcomes. An A-IQOLS standard error of measurement of 0.27 implies that a within person score change of +/-0.73 or greater constitutes a true change. The QOLS standard error of measurement was 0.43. CONCLUSIONS: A-IQOLS provides a reliable, valid, and unique assessment of the patient-perceived negative effect of asthma on QoL that is suitable for use in asthma clinical research and potentially in clinical care. Further studies are needed in diverse patient populations. QOLS, a measure of current QoL, is less sensitive to disease status changes but might be useful in characterizing study populations, in treatment adherence research, and as a clinical and research tool in patients with multiple, severe, and/or life limiting chronic conditions. PMID- 28579377 TI - Dendritic cells conditioned by activin A-induced regulatory T cells exhibit enhanced tolerogenic properties and protect against experimental asthma. AB - BACKGROUND: Previously, we demonstrated that regulatory T (Treg) cells induced by the cytokine activin-A suppress TH2-mediated allergic responses and linked airway disease. Still, the effects of activin-A-induced regulatory T (Act-A-iTreg) cells on the regulation of dendritic cell (DC)-driven allergic inflammation remain elusive. OBJECTIVE: Here we investigated whether Act-A-iTreg cells can modulate DC responses and endow them with enhanced tolerogenic functions. METHODS: Using adoptive cell transfer studies in mouse models of allergic airway disease, we examined the effects of Act-A-iTreg cells on DC phenotype, maturation status, and TH2 cell priming potential. Genome-wide gene expression profiling characterized the transcriptional networks induced in tolerogenic DCs by Act-A-iTreg cells. The ability of DCs conditioned by Act-A-iTreg cells (Act-A-iTreg cell-modified DCs) to protect against experimental asthma, and the mechanisms involved were also explored. RESULTS: Act-A-iTreg cell-modified DCs exhibited a significantly impaired capacity to uptake allergen and stimulate naive and TH2 effector responses on allergen stimulation in vivo accompanied by markedly attenuated inflammatory cytokine release in response to LPS. Gene-profiling studies revealed that Act-A-iTreg cells dampened crucial TH2-skewing transcriptional networks in DCs. Administration of Act-A-iTreg cell-modified DCs ameliorated cardinal asthma manifestations in preventive and therapeutic protocols through generation of strongly suppressive forkhead box P3+ Treg cells. Finally, programed death protein 1/programmed death ligand 1 signaling pathways were essential in potentiating the generation of DCs with tolerogenic properties by Act-A-iTreg cells. CONCLUSION: Our studies reveal that Act-A-iTreg cells instruct the generation of a highly effective immunoregulatory circuit encompassing tolerogenic DCs and forkhead box P3+ Treg cells that could be targeted for the design of novel immunotherapies for allergic disorders. PMID- 28579378 TI - A systematic survey of the methods literature on the reporting quality and optimal methods of handling participants with missing outcome data for continuous outcomes in randomized controlled trials. AB - OBJECTIVE: To conduct (1) a systematic survey of the reporting quality of simulation studies dealing with how to handle missing participant data (MPD) in randomized control trials and (2) summarize the findings of these studies. STUDY DESIGN AND SETTING: We included simulation studies comparing statistical methods dealing with continuous MPD in randomized controlled trials addressing bias, precision, coverage, accuracy, power, type-I error, and overall ranking. For the reporting of simulation studies, we adapted previously developed criteria for reporting quality and applied them to eligible studies. RESULTS: Of 16,446 identified citations, the 60 eligible generally had important limitations in reporting, particularly in reporting simulation procedures. Of the 60 studies, 47 addressed ignorable and 32 addressed nonignorable data. For ignorable missing data, mixed model was most frequently the best on overall ranking (9 times best, 34.6% of times tested) and bias (10, 55.6%). Multiple imputation was also performed well. For nonignorable data, mixed model was most frequently the best on overall ranking (7, 46.7%) and bias (8, 57.1%). Mixed model performance varied on other criteria. Last observation carried forward (LOCF) was very seldom the best performing, and for nonignorable MPD frequently the worst. CONCLUSION: Simulation studies addressing methods to deal with MPD suffered from serious limitations. The mixed model approach was superior to other methods in terms of overall performance and bias. LOCF performed worst. PMID- 28579381 TI - Ophthalmic manifestations in hepatitis-associated aplastic anemia (HAAA): Case report. PMID- 28579380 TI - [Acute spontaneous corneal hydrops in a patient with pellucid marginal corneal degeneration]. PMID- 28579379 TI - Incorporating patients' views in guideline development: a systematic review of guidance documents. AB - OBJECTIVES: To assess how guidance documents for developing clinical guidelines (CGs) address the incorporation of patients' views in CGs. STUDY DESIGN AND SETTING: Systematic review to identify the methodology provided in guidance documents for incorporating (1) patients or representatives and (2) patients' views in the CG development process. The search was performed in 2017 in five databases. Two authors selected the studies, and data extraction was double checked. RESULTS: We included guidance documents from 56 institutions. Of those, 40 (71.4%) recommended the inclusion of patients or their representatives, mainly for developing recommendations (14/40, 35.0%); reviewing the final version (13/40, 32.5%); formulating clinical questions (13/40, 32.5%); defining the scope and objectives (10/40, 25.0%); and dissemination and implementation (10/40, 25.0%). Concrete methods on how to incorporate patients were provided by 47.5% (19/40) of institutions. Forty (71.4%) institutions provided additional strategies to incorporate patients' views. The majority (30/40, 75.0%) suggested sources for obtaining these views (consultation with patients [24/40, 60.0%], using panels' judgment [10/40, 25.0%], conducting de novo research [10/40, 25.0%], or a systematic review [9/40, 22.5%]). CONCLUSION: Although most institutions suggest incorporating patients and their views when developing CGs, little detail is provided on how to do this. Institutions should provide more guidance as this could have a positive impact in guideline applicability. PMID- 28579382 TI - [An unusual form of capsular cataract in a diabetic patient]. PMID- 28579383 TI - Clinical and biological phenotypes of frontotemporal dementia: Perspectives for disease modifying therapies. AB - Frontotemporal Dementia (FTD) is a progressive neurodegenerative condition which encompasses a group of clinically, neuropathologically and genetically heterogeneous disorders characterized by selective involvement of the frontal and temporal lobes. FTD is characterized by changes in behaviour and personality, frontal executive deficits and language dysfunction. Different phenotypes have been defined on the basis of presenting clinical symptoms, behavioural variants of FTD (bvFTD) and primary progressive aphasia (PPA), which includes nonfluent/agrammatic variant PPA (avPPA) and semantic variant PPA (svPPA). These presentations can overlap with atypical parkinsonian disorders (i.e., corticobasal syndrome, progressive supranuclear palsy) and amyotrophic lateral sclerosis. Each syndrome can be associated with one or more neuropathological hallmark, and in some cases it may be due to autosomal inherited disorder caused by mutations in a number of genes. Currently, there is no specific treatment available to prevent disease progression. FTD treatment is based on symptomatic management, and most therapies lack quality evidence from randomized, placebo controlled clinical trials. Recent advances in the understanding of FTD pathophysiology and genetics have led to the development of potentially disease modifying therapies. In this review, we discussed current knowledge and recommendations with regards to symptomatic and disease-modifying therapies. PMID- 28579384 TI - Managing molars with severe molar-incisor hypomineralization: A cost effectiveness analysis within German healthcare. AB - OBJECTIVES: Dentists have a range of options for managing molars with severe molar-incisor hypomineralization (MIH), each with different long-term implications. The cost-effectiveness of managing molars with severe MIH was assessed. METHODS: A mixed public-private-payer perspective within German healthcare was adopted. Individuals with one to four severely MIH-affected molars were followed over their lifetime. We compared: (1) removal of the tooth/teeth and orthodontic alignment of the second and third molars (Ex/Ortho); (2) restoration of the tooth using resin composite (Comp); (3) restoration using an indirect metal crown after temporizing it using a preformed metal crown (PMC/IR). The health outcome was tooth retention years. Transition probabilities were estimated based on the best available evidence. Cost calculations were based on German dental fee catalogues. Monte-Carlo microsimulations were performed for cost-effectiveness-analysis. RESULTS: If extraction was performed at the optimal age (9.5/11 years for maxillary/mandibular molars), Ex/Ortho was most cost effective (67 years, 446-938 Euro). Comp (51 years, 1911 Euro) and PMC/IR were dominated (50 years, 2033 Euro). This cost-effectiveness ratio was also determined when >1 molar was treated. If extraction was performed later, assuming no spontaneous alignment, Ex/Ortho was more costly than Comp, at least when only 1 molar was treated. CONCLUSIONS: For molars with severe MIH, extraction at the optimal age and, if needed, orthodontic alignment can be cost-effective, especially when >1 molar is affected. For single molars where the chance of spontaneous alignment is low, Comp might also be considered. These findings apply to German healthcare and within the limitations of this study only. CLINICAL SIGNIFICANCE: When deciding how to manage molars with severe MIH, both tooth retention, with lower costs but higher needs for re-treatments, and tooth removal, with possible need for orthodontic alignment, can be considered. Considering cost-effectiveness, the latter may be preferable, especially if the age of extraction is chosen correctly, or several molars are affected. PMID- 28579386 TI - MicroRNA and chronic pain: From mechanisms to therapeutic potential. AB - Chronic pain is a major public health issue with an incidence of 20-25% worldwide that can take different forms like neuropathic, cancer-related or inflammatory pain. Chronic pain often limits patients in their daily activities leading to despair. Thus, the goal of treatments is to relieve pain sufficiently to enable patients to go back to a normal life. Unfortunately, few patients with chronic pain obtain complete relief from the analgesics that are currently available. It is thus of prime importance to get a better understanding of chronic pain mechanisms to design new therapeutic strategies and pain-killers. In this sense, the study of microRNA (miRNAs) in chronic pain conditions could lead to a breakthrough in pain management. miRNAs have emerged as master regulators of gene expression in the nervous system where they contribute to neuronal network plasticity. The involvement of miRNAs in the maladaptive plasticity mechanisms of chronic pain is now well documented. Here, we review studies conducted in different animal models and in patients that screened chronic pain-related miRNAs and their targets. Clinical studies suggest that miRNAs expression could reflect the high variability among pain patients that could help to categorize patients and finally lead to personalized therapies. We also point out the different strategies investigated to design miRNA-based analgesics. Finally, we highlight the current miRNA-based clinical trials to hypothesize their potential as therapeutic tool for chronic pain. PMID- 28579385 TI - Response of carious enamel to TiF4 varnish treatment under diverse cariogenic activities in situ. AB - OBJECTIVE: To compare the effect of TiF4 and NaF varnishes on demineralized bovine enamel under different cariogenic activities in situ. METHODS: Twenty subjects participated of this in situ study with 3 crossover phases (14days each), in which they wore palatal appliances containing demineralized bovine enamel samples (8 samples/appliance for phase) treated with TiF4, NaF (all with 2.45% F) or placebo varnish. The samples were subjected to different cariogenic conditions (1. absence of biofilm accumulation and sucrose exposure; 2. presence of biofilm and absence of sucrose exposure; 3. presence of biofilm and 20% sucrose exposure 4*/day; 4. presence of biofilm and 20% sucrose exposure 8*/day). All were exposed to fluoride dentifrice (2*/day). The mineral content and lesion depth were evaluated using transverse microradiography (TMR) and the data were subjected to RM two-way ANOVA/Bonferroni tests (p<0.05). RESULTS: TiF4 varnish significantly increased the remineralization of artificial carious lesions compared to placebo, regardless of the cariogenic activity. On the other hand, the remineralizing effect of NaF varnish was dependent on the cariogenic activity. For NaF, remineralization happened only in conditions 1 and 3 compared to placebo varnish (p<0.0001). NaF was unable to prevent further demineralization under biofilm accumulation and sucrose exposure 8*/day (condition 4). In the absence of fluoride treatment, demineralization happened in all conditions, except in the condition 1. CONCLUSION: Therefore, 4% TiF4 varnish was the only treatment able to improve enamel remineralization regardless of the cariogenic activity, while NaF varnish failed in preventing further demineralization under high cariogenic activity in situ. CLINICAL SIGNIFICANCE: 4% TiF4 varnish showed better remineralizing effect compared to NaF varnish, which was seen regardless of the cariogenic activity. This is a promising finding to support the indication of TiF4 in the clinic. PMID- 28579387 TI - Treatment advances in small cell lung cancer (SCLC). AB - Small cell lung cancer (SCLC) is an aggressive tumor characterized by rapid doubling time and high propensity for early development of disseminated disease. Although most patients respond to initial therapy with a platinum doublet, the majority of those with limited stage and virtually all patients with metastatic disease eventually develop tumor progression for which there are limited treatment options. There have been no recent changes in the treatment of SCLC, with platinum plus etoposide and topotecan as the standard first-line and second line respectively, neither showing survival benefit over the combination of cyclophosphamide, doxorubicin and vincristine, which was developed in the 1970s. More recently, a new understanding of the biology of SCLC has led to the development of novel drugs, of which the most promising are the immune checkpoint inhibitors and the antibody drug conjugate rovalpituzumab tesirine. PMID- 28579388 TI - Targeting cysteine proteases in trypanosomatid disease drug discovery. AB - Chagas disease and human African trypanosomiasis are endemic conditions in Latin America and Africa, respectively, for which no effective and safe therapy is available. Efforts in drug discovery have focused on several enzymes from these protozoans, among which cysteine proteases have been validated as molecular targets for pharmacological intervention. These enzymes are expressed during the entire life cycle of trypanosomatid parasites and are essential to many biological processes, including infectivity to the human host. As a result of advances in the knowledge of the structural aspects of cysteine proteases and their role in disease physiopathology, inhibition of these enzymes by small molecules has been demonstrated to be a worthwhile approach to trypanosomatid drug research. This review provides an update on drug discovery strategies targeting the cysteine peptidases cruzain from Trypanosoma cruzi and rhodesain and cathepsin B from Trypanosoma brucei. Given that current chemotherapy for Chagas disease and human African trypanosomiasis has several drawbacks, cysteine proteases will continue to be actively pursued as valuable molecular targets in trypanosomatid disease drug discovery efforts. PMID- 28579389 TI - SCCT President's Page: 2017 - A very productive year setting the stage for future success. PMID- 28579390 TI - Fluorescent markers of various organelles in the wheat pathogen Zymoseptoria tritici. AB - Development of novel strategies to control fungal plant pathogens requires understanding of their cellular organisation and biology. Live cell imaging of fluorescent organelle markers has provided valuable insight into various aspects of their cell biology, including invasion strategies in plant pathogenic fungi. Here, we introduce a set of 17 vectors that encode fluorescent markers to visualize the plasma membrane, endoplasmic reticulum (ER), chromosomes, the actin cytoskeleton, peroxisomes and autophagosomes in the wheat pathogen Zymoseptoria tritici. We fused either enhanced green-fluorescent protein (eGFP) or a codon optimised version of GFP (ZtGFP) to homologues of a plasma membrane-located Sso1 like syntaxin, an ER signalling and retention peptide, a histone H1 homologue, the LifeAct actin-binding peptide, a mitochondrial acetyl-CoA dehydrogenase, a peroxisomal import signal and a homologue of the ubiquitin-like autophagosomal protein Atg8. We expressed these markers in wildtype strain IPO323 and confirmed the specificity of these markers by counterstaining or physiological experiments. This new set of molecular tools will help understanding the cell biology of the wheat pathogen Z. tritici. PMID- 28579391 TI - A RHO Small GTPase Regulator ABR Secures Mitotic Fidelity in Human Embryonic Stem Cells. AB - Pluripotent stem cells can undergo repeated self-renewal while retaining genetic integrity, but they occasionally acquire aneuploidy during long-term culture, which is a practical obstacle for medical applications of human pluripotent stem cells. In this study, we explored the biological roles of ABR, a regulator of RHO family small GTPases, and found that it has pivotal roles during mitotic processes in human embryonic stem cells (hESCs). Although ABR has been shown to be involved in dissociation-induced hESC apoptosis, it does not appear to have direct effects on cell survival unless cell-cell contact is impaired. Instead, we found that it is important for faithful hESC division. Mechanistically, ABR depletion compromised centrosome dynamics and predisposed the cell to chromosome misalignment and missegregation, which raised the frequency of aneuploidy. These results provide insights into the mechanisms that support the genetic integrity of self-renewing hESCs. PMID- 28579392 TI - BPTF Maintains Chromatin Accessibility and the Self-Renewal Capacity of Mammary Gland Stem Cells. AB - Chromatin remodeling is a key requirement for transcriptional control of cellular differentiation. However, the factors that alter chromatin architecture in mammary stem cells (MaSCs) are poorly understood. Here, we show that BPTF, the largest subunit of the NURF chromatin remodeling complex, is essential for MaSC self-renewal and differentiation of mammary epithelial cells (MECs). BPTF depletion arrests cells at a previously undefined stage of epithelial differentiation that is associated with an incapacity to achieve the luminal cell fate. Moreover, genome-wide analysis of DNA accessibility following genetic or chemical inhibition, suggests a role for BPTF in maintaining the open chromatin landscape at enhancers regions in MECs. Collectively, our study implicates BPTF in maintaining the unique epigenetic state of MaSCs. PMID- 28579393 TI - Long Noncoding RNA Moderates MicroRNA Activity to Maintain Self-Renewal in Embryonic Stem Cells. AB - Of the thousands of long noncoding RNAs expressed in embryonic stem cells (ESCs), few have known roles and fewer have been functionally implicated in the regulation of self-renewal and pluripotency, or the reprogramming of somatic cells to the pluripotent state. In ESCs, Cyrano is a stably expressed long intergenic noncoding RNA with no previously assigned role. We demonstrate that Cyrano contributes to ESC maintenance, as its depletion results in the loss of hallmarks of self-renewal. Delineation of Cyrano's network through transcriptomics revealed widespread effects on signaling pathways and gene expression networks that contribute to ESC maintenance. Cyrano shares unique sequence complementarity with the differentiation-associated microRNA, mir-7, and mir-7 overexpression reduces expression of a key self-renewal factor to a similar extent as Cyrano knockdown. This suggests that Cyrano functions to restrain the action of mir-7. Altogether, we provide a view into the multifaceted function of Cyrano in ESC maintenance. PMID- 28579395 TI - Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo. AB - A major challenge for clinical application of pluripotent stem cell therapy for Parkinson's disease (PD) is large-scale manufacturing and cryopreservation of neurons that can be efficiently prepared with minimal manipulation. To address this obstacle, midbrain dopamine neurons were derived from human induced pluripotent stem cells (iPSC-mDA) and cryopreserved in large production lots for biochemical and transplantation studies. Cryopreserved, post-mitotic iPSC-mDA neurons retained high viability with gene, protein, and electrophysiological signatures consistent with midbrain floor-plate lineage. To test therapeutic efficacy, cryopreserved iPSC-mDA neurons were transplanted without subculturing into the 6-OHDA-lesioned rat and MPTP-lesioned non-human-primate models of PD. Grafted neurons retained midbrain lineage with extensive fiber innervation in both rodents and monkeys. Behavioral assessment in 6-OHDA-lesioned rats demonstrated significant reversal in functional deficits up to 6 months post transplantation with reinnervation of the host striatum and no aberrant growth, supporting the translational development of pluripotent cell-based therapies in PD. PMID- 28579394 TI - Primate Primordial Germ Cells Acquire Transplantation Potential by Carnegie Stage 23. AB - Primordial germ cells (PGCs) are the earliest embryonic progenitors in the germline. Correct formation of PGCs is critical to reproductive health as an adult. Recent work has shown that primate PGCs can be differentiated from pluripotent stem cells; however, a bioassay that supports their identity as transplantable germ cells has not been reported. Here, we adopted a xenotransplantation assay by transplanting single-cell suspensions of human and nonhuman primate embryonic Macaca mulatta (rhesus macaque) testes containing PGCs into the seminiferous tubules of adult busulfan-treated nude mice. We discovered that both human and nonhuman primate embryonic testis are xenotransplantable, generating colonies while not generating tumors. Taken together, this work provides two critical references (molecular and functional) for defining transplantable primate PGCs. These results provide a blueprint for differentiating pluripotent stem cells to transplantable PGC-like cells in a species that is amenable to transplantation and fertility studies. PMID- 28579397 TI - Meta-analysis of heparin therapy for preventing venous thromboembolism in acute spinal cord injury. AB - OBJECTIVE: Venous thromboembolism (VTE) is a frequent complication in patients with acute spinal cord injury (SCI) and may have serious consequences. This study aimed to assess the efficacy and safety of heparin and low-molecular-weight heparin (LMWH) venous thromboprophylaxis in patients with acute SCI. METHODS: PubMed, Web of Science, EMBASE and the Cochrane library were searched from January 1980 to August 2016. The primary outcome was the incidence of VTE. Secondary outcomes included the incidences of Deep-vein thrombosis (DVT), pulmonary embolism (PE) and major bleeding. RESULTS: A total of 11 studies including 1605 patients qualified for inclusion. Four studies evaluated the efficacy of heparin treatment compared with placebo or no treatment. There were significant differences between the two treatments, and the summary RR was 0.35 (95% confidence interval (CI) 0.15-0.87; P = 0.02). Seven studies compared low dose unfractionated heparin (LDUH) with LMWH. The incidence of VTE was not significantly different between the two treatments (RR 1.09, 95% CI 0.63-1.89; P = 0.76). There were no differences in the incidence of major bleeding with unfractionated heparin versus LMWH (summary RR 1.32, 95% CI 0.62-2.84; P = 0.47). CONCLUSIONS: In this meta-analysis, heparin exhibited protective effects compared with placebo or no treatment with respect to the occurrence of VTE; there were no differences between LMWH and unfractionated heparin with ret to thromboembolism prophylaxis efficacy. LMWH did not reduce the risk of bleeding compared with LDUH. PMID- 28579396 TI - THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation. AB - THAP1 (THAP [Thanatos-associated protein] domain-containing, apoptosis-associated protein 1) is a ubiquitously expressed member of a family of transcription factors with highly conserved DNA-binding and protein-interacting regions. Mutations in THAP1 cause dystonia, DYT6, a neurologic movement disorder. THAP1 downstream targets and the mechanism via which it causes dystonia are largely unknown. Here, we show that wild-type THAP1 regulates embryonic stem cell (ESC) potential, survival, and proliferation. Our findings identify THAP1 as an essential factor underlying mouse ESC survival and to some extent, differentiation, particularly neuroectodermal. Loss of THAP1 or replacement with a disease-causing mutation results in an enhanced rate of cell death, prolongs Nanog, Prdm14, and/or Rex1 expression upon differentiation, and results in failure to upregulate ectodermal genes. ChIP-Seq reveals that these activities are likely due in part to indirect regulation of gene expression. PMID- 28579398 TI - Evaluation of the expression level of 12/15 lipoxygenase and the related inflammatory factors (CCL5, CCL3) in respiratory syncytial virus infection in mice model. AB - Human respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection during early childhood and imposes a great burden on patients, parents, and society. Disease is thought to be caused, at least partially, by an excessive immune response. Pulmonary leukocyte infiltration is the result of a coordinated expression of diverse chemokines with distinct cellular specificities. Lipoxygenases (LOXs), as a key enzyme catalyzing deoxygenation of poly unsaturated fatty acids, regulate inflammation and have been suggested to play an important role in the immune response in viral infection. To expand our understanding on the possible role of LOX in respiratory viral infection, we studied the 12/15- lipoxygenase expression in RSV-related airway inflammation, and the related inflammatory chemokines, Chemokine (C-C motif) ligand 5 (CCL5) and Chemokine (C-C motif) ligand 3(CC L3) in both lung tissue and Bronchoalveolar lavage (BAL) fluid during experimental RSV infection. RSV infection induced mRNA expression of CCL5 and CCL3 in both BAL and lung tissue cells. In addition RSV infection enhanced expression of 12/15-LOX in both BAL and lung cells. In conclusion, we confirm that RSV infection leads to the increased expression of 12/15 LOX and the related chemokines CCL5 and CCL3 in BAL fluid and lung tissue cells suggesting that the 12/15 LOX pathway could serve as a candidate target for prevention and treatment of RSV infection. PMID- 28579399 TI - Prevention of IcaA regulated poly N-acetyl glucosamine formation in Staphylococcus aureus biofilm through new-drug like inhibitors: In silico approach and MD simulation study. AB - OBJECTIVES: The effectiveness of various ligands against the protein structure of IcaA of the IcaABCD gene locus of Staphylococcus aureus were examined using the approach of structure based drug designing in reference with the protein's efficiency to form biofilms. RESULTS: Four compounds CID42738592, CID90468752, CID24277882, and CID6435208 were secluded from a database of 31,242 inhibitory ligands on the justification of the evaluated values falling under the four - tier structure based virtual screening. Under this principle value of least binding energy, human oral absorption and ADME properties were taken into consideration. Using the Glide module of Schrodinger, the above mentioned ligands showed an effective action against the protein IcaA which showed reduced activity as a glucosaminyl transferase. The complex of protein and ligand with best docking score was chosen for simulation studies. CONCLUSIONS: Structure based drug designing for the protein IcaA has given us potential leads as anti - biofilm agents. These screened out ligands might enable the development of new therapeutic strategies aimed at disrupting Staphylococcus aureus biofilms. The complex was showing stability towards the end of time for which it has been put for simulation. Thus molecule could be considered for making of biofilms. PMID- 28579400 TI - Emotion regulation in mood and anxiety disorders: A meta-analysis of fMRI cognitive reappraisal studies. AB - Emotion regulation by means of cognitive reappraisal has been widely studied with functional magnetic resonance imaging (fMRI). To date, several meta-analyses of studies using cognitive reappraisal tasks in healthy volunteers have been carried out, but no meta-analyses have yet been performed on the fMRI data of clinical populations with identified alterations in emotion regulation capacity. We provide a comprehensive meta-analysis of cognitive reappraisal fMRI studies in populations of patients with mood or anxiety disorders, yielding a pooled sample of 247 patients and 262 controls from thirteen independent studies. As a distinguishing feature of this meta-analysis, original statistical brain maps were obtained from six of these studies. Our primary results demonstrated that patients with mood and anxiety disorders recruited the regulatory fronto-parietal network involved in cognitive reappraisal to a lesser extent in comparison to healthy controls. Conversely, they presented increased activation in regions that may be associated with the emotional experience (i.e., insula, cerebellum, precentral and inferior occipital gyri) and in regions whose activation may be the consequence of compensatory mechanisms (i.e., supramarginal gyri and superior parietal lobule). Moreover, activations in the left ventrolateral prefrontal cortex and the left superior temporal gyrus were associated with reinterpretation emotion regulation strategies, whereas medial frontal and parietal activations were associated with the deployment of distancing strategies. The regions revealed by this meta-analysis conform to a pattern of dysfunctional brain activation during cognitive reappraisal common to mood and anxiety disorders. As such, this neural pattern may reflect a transdiagnostic feature of these disorders. PMID- 28579401 TI - Node-based learning of differential networks from multi-platform gene expression data. AB - Recovering gene regulatory networks and exploring the network rewiring between two different disease states are important for revealing the mechanisms behind disease progression. The advent of high-throughput experimental techniques has enabled the possibility of inferring gene regulatory networks and differential networks using computational methods. However, most of existing differential network analysis methods are designed for single-platform data analysis and assume that differences between networks are driven by individual edges. Therefore, they cannot take into account the common information shared across different data platforms and may fail in identifying driver genes that lead to the change of network. In this study, we develop a node-based multi-view differential network analysis model to simultaneously estimate multiple gene regulatory networks and their differences from multi-platform gene expression data. Our model can leverage the strength across multiple data platforms to improve the accuracy of network inference and differential network estimation. Simulation studies demonstrate that our model can obtain more accurate estimations of gene regulatory networks and differential networks than other existing state-of-the-art models. We apply our model on TCGA ovarian cancer samples to identify network rewiring associated with drug resistance. We observe from our experiments that the hub nodes of our identified differential networks include known drug resistance-related genes and potential targets that are useful to improve the treatment of drug resistant tumors. PMID- 28579402 TI - MIDAS: Mining differentially activated subpaths of KEGG pathways from multi-class RNA-seq data. AB - : Pathway based analysis of high throughput transcriptome data is a widely used approach to investigate biological mechanisms. Since a pathway consists of multiple functions, the recent approach is to determine condition specific sub pathways or subpaths. However, there are several challenges. First, few existing methods utilize explicit gene expression information from RNA-seq. More importantly, subpath activity is usually an average of statistical scores, e.g., correlations, of edges in a candidate subpath, which fails to reflect gene expression quantity information. In addition, none of existing methods can handle multiple phenotypes. To address these technical problems, we designed and implemented an algorithm, MIDAS, that determines condition specific subpaths, each of which has different activities across multiple phenotypes. MIDAS utilizes gene expression quantity information fully and the network centrality information to determine condition specific subpaths. To test performance of our tool, we used TCGA breast cancer RNA-seq gene expression profiles with five molecular subtypes. 36 differentially activate subpaths were determined. The utility of our method, MIDAS, was demonstrated in four ways. All 36 subpaths are well supported by the literature information. Subsequently, we showed that these subpaths had a good discriminant power for five cancer subtype classification and also had a prognostic power in terms of survival analysis. Finally, in a performance comparison of MIDAS to a recent subpath prediction method, PATHOME, our method identified more subpaths and much more genes that are well supported by the literature information. AVAILABILITY: http://biohealth.snu.ac.kr/software/MIDAS/. PMID- 28579403 TI - CeFra-seq: Systematic mapping of RNA subcellular distribution properties through cell fractionation coupled to deep-sequencing. AB - The subcellular trafficking of RNA molecules is a conserved feature of eukaryotic cells and plays key functions in diverse processes implicating polarised cellular activities. Large-scale imaging and subcellular transcriptomic studies suggest that regulated RNA localization is a highly prevalent process that appears to be disrupted in several neuromuscular disorders. These features underline the importance and usefulness of implementing procedures to assess global transcriptome subcellular distribution properties. Here, we present a method combining biochemical fractionation of cells and high-throughput RNA sequencing (CeFra-seq) that enables rapid and efficient systematic mapping of RNA cytotopic distributions in cells. The described procedure involves biochemical fractionation to derive extracts of nuclear, cytosolic, endomembrane, cytoplasmic insoluble and extracellular material from cell culture lines. The RNA content of each fraction can then be profiled by deep-sequencing, revealing global subcellular signatures. We provide a detailed protocol for the CeFra-seq procedure along with relevant validation steps and data analysis guidelines to graphically represent RNA spatial distribution features. As a complement to imaging approaches, CeFra-seq represents a powerful and scalable tool to investigate global alterations in RNA trafficking. PMID- 28579405 TI - Human embryo research in Belgium: an overview. AB - OBJECTIVE: To present an overview of the numbers and types of human embryos used in research projects in Belgium from 2007 to 2015. DESIGN: Analysis of all research proposals approved by the Federal Commission for Medical and Scientific Research on Embryos In Vitro. SETTING: Not applicable. PATIENT(S): Not applicable. MAIN OUTCOME MEASURE(S): Number of embryos used for research, number of embryos created for research, and areas of embryo research. RESULT(S): Since 2007, 15,811 embryos were used for 36 research projects. In total, 10,492 (66%) fresh supernumerary embryos (unfit for transfer or freezing) were used, 4,083 (26%) frozen supernumerary embryos (donated by parents whose child wish was completed or abandoned), and 1,236 (8%) embryos created for research. Most projects focused on research into embryo development. Fresh supernumerary embryos were mainly used for human embryonic stem cell (hESC) research. Frozen supernumerary embryos were almost exclusively used for research into embryo development and for hESC research. Embryos created for research were used for research into embryo development, oocyte research, research into cryopreservation of oocytes, and hESC research. CONCLUSION(S): Having concrete data on embryo research is crucial for an informed debate. Moreover, these data are necessary to find out trends in research such as the numbers of embryos needed and the areas of research. Data collection requires a sufficiently clear definition of "research" and "embryo." These conceptual questions frequently reveal lack of clarity in legislation. PMID- 28579404 TI - Transcriptome-wide measurement of translation by ribosome profiling. AB - Translation is one of the fundamental processes of life. It comprises the assembly of polypeptides whose amino acid sequence corresponds to the codon sequence of an mRNA's ORF. Translation is performed by the ribosome; therefore, in order to understand translation and its regulation we must be able to determine the numbers and locations of ribosomes on mRNAs in vivo. Furthermore, we must be able to examine their redistribution in different physiological contexts and in response to experimental manipulations. The ribosome profiling method provides us with an opportunity to learn these locations, by sequencing a cDNA library derived from the short fragments of mRNA covered by the ribosome. Since its original description, the ribosome profiling method has undergone continuing development; in this article we describe the method's current state. Important improvements include: the incorporation of sample barcodes to enable library multiplexing, the incorporation of unique molecular identifiers to enable to removal of duplicated sequences, and the replacement of a gel-purification step with the enzymatic degradation of unligated linker. PMID- 28579406 TI - Revisiting the management of recurrent implantation failure through freeze-all policy. AB - OBJECTIVE: To determine whether a freeze-all policy for in vitro human blastocysts improves the ongoing pregnancy rate in patients with recurrent implantation failure (RIF). DESIGN: Prospective cohort study. SETTING: Single private center. PATIENT(S): A total of 171 women with RIF divided into two groups: freeze-all policy group (n = 81) and fresh embryo transfer (ET) group (n = 90). INTERVENTION(S): Freeze-all policy. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate. RESULT(S): The clinical pregnancy rate (52% vs. 28%; odds ratio [OR] 1.86; 95% confidence interval [CI], 1.29-2.68) and ongoing pregnancy rate (44% vs. 20%; OR 2.2; 95% CI, 1.04-3.45) were statistically significantly higher in the freeze-all group than the fresh ET group, respectively. The implantation rate was also statistically significant (freeze-all group 44.2% vs. fresh ET group 15.8%; OR 2.80; 95% CI, 2.00-3.92). CONCLUSION(S): The freeze-all policy statistically significantly improved the ongoing pregnancy and implantation rates. Thus, a freeze-all policy is likely to be the new key to helping open the black box of RIF. These findings also are useful for further investigating the adverse effect of controlled ovarian stimulation on in vitro fertilization outcomes. PMID- 28579408 TI - Pregnancy outcome of in vitro fertilization after Essure and laparoscopic management of hydrosalpinx: a systematic review and meta-analysis. AB - OBJECTIVE: To assess and compare pregnancy outcomes in hydrosalpinx (HX) patients treated by Essure, laparoscopic salpingectomy, and proximal tubal occlusion (LPTO) before IVF. DESIGN: Systematic review and meta-analysis. SETTING: University-affiliated teaching hospital. PATIENT(S): Women undergoing Essure, laparoscopic salpingectomy, and LPTO for HX before IVF. INTERVENTION(S): The overall combined risk estimates were calculated by means of fixed- or random effects models. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (CPR) and live birth rate (LBR). RESULT(S): In total, 3,065 patients were included in 33 studies. Thirteen of them were comparative studies among 3 surgical methods and no intervention. In the analysis of comparative studies, there were no significant differences in implantation rate (IR), CPR, and ongoing pregnancy rate/LBR between salpingectomy and LPTO groups. The CPR, IR, and LBR of Essure were significantly lower than those of the laparoscopic surgery (salpingectomy and LPTO) group, with a CPR of 34.1% vs. 44.0% (relative risk [RR] 0.71; 95% confidence interval [CI] [0.51, 0.98]), an IR of 17.3% vs. 38.0% (RR 0.45; 95% CI [0.27, 0.74]), and an LBR of 22.2% vs. 37.4% (RR 0.57; 95% CI [0.35, 0.91]). CONCLUSION(S): Management of HX by laparoscopic salpingectomy and LPTO yielded the same effect on the improvement of the pregnancy outcome after IVF. The hysteroscopic placement of Essure devices to treat HX before IVF produces inferior pregnancy outcomes compared with those following the laparoscopic approach. More multicenter randomized, controlled trials are warranted in future research to further examine the conclusion from this meta-analysis. PMID- 28579407 TI - Detailed investigation into the cytogenetic constitution and pregnancy outcome of replacing mosaic blastocysts detected with the use of high-resolution next generation sequencing. AB - OBJECTIVE: To determine the pregnancy outcome potential of mosaic embryos, detected by means of preimplantation genetic screening (PGS) with the use of next generation sequencing (NGS). DESIGN: Retrospective study. SETTING: Genetics laboratories. PATIENT(S): PGS cycles during which either mosaic or euploid embryos were replaced. INTERVENTION(S): Blastocysts were biopsied and processed with the use of NGS, followed by frozen embryo transfer. Trophectoderm (TE) biopsies were classified as mosaic if they had 20%-80% abnormal cells. MAIN OUTCOME MEASURE(S): Implantation, miscarriage rates, and ongoing implantation rates (OIRs) were compared between euploid and types of mosaic blastocysts. RESULT(S): Complex mosaic embryos had a significantly lower OIR (10%) than aneuploidy mosaic (50%), double aneuploidy mosaic (45%), and segmental mosaic (41%). There was a tendency for mosaics with 40%-80% abnormal cells to have a lower OIR than those with <40% (22% vs. 56%). However, few embryos (n = 34) with a mosaic error in 40%-80% of the TE sample were replaced. There was no difference between monosomic and trisomic mosaics or between entire chromosome mosaicism or segmental mosaicism. Implantation rates were significantly higher (70% vs. 53%), miscarriage rates lower (10% vs. 25%), and OIRs higher (63% vs. 40%) after euploid embryo transfer than after mosaic embryo transfer. CONCLUSION(S): Forty one percent of mosaic embryos produced an ongoing implantation. Complex mosaic blastocysts had a lower OIR than other mosaics. Mosaic monosomies performed as well as mosaic trisomies and mosaic segmental aneuploidies. The results suggest that embryos with >40% abnormal cells and those with multiple mosaic abnormalities (chaotic mosaics) are likely to have lower OIRs and should be given low transfer priority. PMID- 28579409 TI - Sclerotherapy in the management of ovarian endometrioma: systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the efficacy of sclerotherapy for ovarian endometrioma on the risk of recurrence, clinical symptoms, and reproductive function. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Patients who underwent sclerotherapy of ovarian endometrioma. INTERVENTION(S): An electronic-based search with the use of Pubmed, Embase, Ovid Medline, Google Scholar, Clinicaltrials.gov, and the Cochrane Central Register of Controlled Trials. MAIN OUTCOME MEASURE(S): Recurrence rate, symptoms relief, fertility outcome, and adverse events. RESULT(S): Eighteen studies were included in our review. The overall recurrence rates of endometrioma after sclerotherapy ranged from 0 to 62.5%. The risk of recurrence was significantly higher in women who were treated by means of ethanol washing than by means of ethanol retention. The number of oocytes retrieved was higher after endometrioma sclerotherapy compared with laparoscopic cystectomy, but clinical pregnancy rates were similar. There was no difference in the number of oocytes retrieved and the clinical pregnancy rates between the sclerotherapy-treated group with and the untreated group. CONCLUSION(S): Sclerotherapy for ovarian endometrioma may be considered in symptomatic women who plan to conceive. PMID- 28579410 TI - Characterization of hormonal profiles during the luteal phase in regularly menstruating women. AB - OBJECTIVE: To characterize the variability of hormonal profiles during the luteal phase in normal cycles. DESIGN: Observational study. SETTING: Not applicable. PATIENT(S): Ninety-nine women contributing 266 menstrual cycles. INTERVENTION(S): The women collected first morning urine samples that were analyzed for estrone-3 glucuronide, pregnanediol-3-alpha-glucuronide (PDG), FSH, and LH. The women had serum P tests (twice per cycle) and underwent ultrasonography to identify the day of ovulation. MAIN OUTCOME MEASURE(S): The luteal phase was divided into three parts: the early luteal phase with increasing PDG (luteinization), the midluteal phase with PDG >=10 MUg/mg Cr (progestation), and the late luteal phase (luteolysis) when PDG fell below 10 MUg/mg Cr. RESULT(S): Long luteal phases begin with long luteinization processes. The early luteal phase is marked by low PDG and high LH levels. Long luteinization phases were correlated with low E1G and low PDG levels at day 3. The length of the early luteal phase is highly variable between cycles of the same woman. The duration and hormonal levels during the rest of the luteal phase were less correlated with other characteristics of the cycle. CONCLUSION(S): The study showed the presence of a prolonged pituitary activity during the luteinization process, which seems to be modulated by an interaction between P and LH. This supports a luteal phase model with three distinct processes: the first is a modulated luteinization process, whereas the second and the third are relatively less modulated processes of progestation and luteolysis. PMID- 28579411 TI - Freeze-only versus fresh embryo transfer in a multicenter matched cohort study: contribution of progesterone and maternal age to success rates. AB - OBJECTIVE: To compare implantation and ongoing pregnancy rates in freeze-only versus fresh transfer cycles. DESIGN: Retrospective matched cohort study. SETTING: Not applicable. PATIENT(S): Women selected using a matching algorithm for similar distributions of clinical characteristics for a total of 2,910 cycles (1,455 fresh cohort and 1,455 freeze-only cohort). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation and ongoing pregnancy rates. RESULT(S): Implantation and ongoing pregnancy rates were statistically significantly higher in the freeze-only transfer cohort than in the matched fresh transfer cohort: ongoing pregnancy rate for freeze-only was 52.0% (95% confidence interval [CI], 49.4-54.6) and for fresh was 45.3% (95% CI, 42.7-47.9), odds ratio (OR) 1.31 (95% CI, 1.13-1.51). In a stratified analysis, the odds of ongoing pregnancy after freeze-only transfer were statistically significantly higher for women both above and below age 35 with progesterone concentration >1.0 ng/mL (age <=35: OR 1.38 [1.11-1.71]; age >35: OR 1.73 [1.34-2.24]). For women with progesterone concentration <=1.0 ng/mL, no statistically significant difference in freeze-only odds of ongoing pregnancy was observed in either age group. The sensitivity analysis revealed that increasing maternal age alone (regardless of progesterone) trended toward a more beneficial effect of freeze-only cycles. A lower progesterone concentration was associated with statistically significantly higher ongoing pregnancy odds for fresh but not freeze-only cycles. CONCLUSION(S): Freeze-only transfer protocols are associated with statistically significantly higher ongoing implantation and pregnancy rates compared with fresh transfer cycles. This effect is most pronounced for cycles with progesterone >1.0 ng/mL at trigger and may also be stronger for older patients. PMID- 28579413 TI - Fertility in adult women with classic galactosemia and primary ovarian insufficiency. AB - OBJECTIVE: To study pregnancy chance in adult women with classic galactosemia and primary ovarian insufficiency. Despite dietary treatment, >90% of women with classic galactosemia develop primary ovarian insufficiency, resulting in impaired fertility. For many years, chance of spontaneous conception has not been considered, leading to counseling for infertility. But an increasing number of reports on pregnancies in this group questions whether current counseling approaches are correct. DESIGN: Multicenter retrospective observational study. SETTING: Metabolic centers. PATIENT(S): Adult women (aged >18 y) with confirmed classic galactosemia and primary ovarian insufficiency were included. INTERVENTION(S): Participants and medical records were consulted to obtain study data in a standardized manner with the use of a questionnaire. MAIN OUTCOME MEASURE(S): Conception opportunities, time to pregnancy, pregnancy outcome, hormone replacement therapy use, fertility counseling, and the participants' vision of fertility were evaluated. Potential predictive factors for increased pregnancy chance were explored. RESULT(S): Eighty-five women with classic galactosemia and primary ovarian insufficiency participated. Twenty-one women actively attempted to conceive or did not take adequate contraceptive precautions. Of these 21 women, nine became pregnant spontaneously (42.9%). This was higher than reported in primary ovarian insufficiency due to other causes (5% 10%). After a period of 12 months, a cumulative proportion of 27.8% of couples had conceived, which increased to 48.4% after 24 months and 61.3% after 27 months. Predictive factors could not be identified. A considerable miscarriage rate of 30% was observed (6 of 20 pregnancies). Although a substantial proportion of women expressed a child-wish (n = 28/53; 52.8%), the vast majority of participants (n = 43/57; 75.4%) considered conceiving to be highly unlikely, owing to negative counseling in the past. CONCLUSION(S): The pregnancy rate in women with classic galactosemia and primary ovarian insufficiency was higher than for women with primary ovarian insufficiency of any cause. This shifting paradigm carries significant implications for fertility counseling and potential application of fertility preservation techniques. PMID- 28579414 TI - Recurrent implantation failure is another indication for the freeze-all strategy. PMID- 28579415 TI - Elagolix for the management of heavy menstrual bleeding associated with uterine fibroids: results from a phase 2a proof-of-concept study. AB - OBJECTIVE: To evaluate the safety and efficacy of elagolix vs. placebo and elagolix with low-dose E2/progestogen add-back therapy. DESIGN: Proof-of-concept, dose-ranging, multiple-cohort study. SETTING: Clinics. PATIENT(S): Premenopausal women with fibroids and heavy menstrual bleeding (menstrual blood loss [MBL] >80 mL per cycle). INTERVENTION(S): Three months' treatment with elagolix alone: 100 mg twice daily (BID), 200 mg BID, 300 mg BID, 400 mg once daily (QD), or 600 mg QD (all but the 600 mg QD arm were placebo controlled); or elagolix plus add-back therapy: 200 mg BID plus continuous low-dose E2 0.5 mg/norethindrone acetate 0.1 mg or elagolix 300 mg BID plus E2 1 mg continuously and cyclical P 200 mg. MAIN OUTCOME MEASURE(S): Least-squares mean percentage change in MBL; adverse events (AEs). RESULT(S): Mean age was 41.8 years; 73.8% were black; mean baseline MBL was 267 mL. Of randomized women (elagolix alone, n = 160; placebo, n = 50; elagolix with add-back therapy, n = 61), 228 of 271 completed the 3-month treatment period. The MBL percentage change from baseline to last 28 days was significantly greater with elagolix alone (range, -72% to -98%; dose-dependent reduction was highest with 300 mg BID) vs. placebo (range, -8% to -41%); mean percentage changes with add-back regimens were -80% to -85%. Overall AEs were dose independent (elagolix alone, 70.0%-81.3%) but lower with placebo (56.0%) and add-back regimens (55.6%-70.6%). Hot flush was the most common AE (elagolix alone, 45.5%-62.5%; placebo, 12.0%; add-back regimens, 18.5%-26.5%). CONCLUSION(S): Elagolix significantly reduced heavy menstrual bleeding in women with fibroids. Low-dose add-back regimens substantially reduced flushing. CLINICAL TRIAL REGISTRATION NUMBER: NCT01441635. PMID- 28579417 TI - Lesbian, gay, bisexual, transgender content on reproductive endocrinology and infertility clinic websites. AB - OBJECTIVE: To assess geographical distribution and practice characteristics of fertility clinics inclusive of lesbian, gay, bisexual, and transgender (LGBT) patients. DESIGN: Cross-sectional analysis. SETTING: Not applicable. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Prevalence and geographical distribution of fertility clinic websites with LGBT-specific content, indicated by keywords and home page cues specific to the LGBT patient population. Assessment of relationship between LGBT-specific content and clinic characteristics, including U.S. region, clinic size, private versus academic setting, and state-mandated fertility insurance coverage. RESULT(S): Of 379 websites analyzed, 201 (53%) contained LGBT content. Clinics with the highest proportion of LGBT website content were in the Northeast (59/82, 72%) and West (63/96, 66%), while the lowest proportion was in the Midwest (29/74, 39%) and South (50/127, 39%). Most frequently used terms included lesbian (72%), LGBT/LGBTQ (69%), and gay (68%), while less used terms included trans/transgender (32%) and bisexual (15%). Larger clinic size was associated with LGBT-specific website content (odds ratio, 4.42; 95% confidence interval, 2.07-9.67). Practice type and state-mandated fertility insurance coverage were not associated with a clinic website having LGBT content. CONCLUSION(S): Over half of Society for Assisted Reproductive Technology member fertility clinics included LGBT content on their websites, yet those in the Midwest and South were significantly less likely to do so. Predictive factors for having LGBT website content included location in northeastern and western regions and increasing clinic size. Further studies are needed to evaluate whether inclusion of LGBT content on clinic websites impacts use of reproductive services by the LGBT patient population. PMID- 28579416 TI - Psychological and emotional concomitants of infertility diagnosis in women with diminished ovarian reserve or anatomical cause of infertility. AB - OBJECTIVE: To examine the magnitude and predictors of emotional reactions to an infertility diagnosis in two groups of women: those with diminished ovarian reserve (DOR), and those clinically diagnosed with an anatomical cause of infertility (ACI). DESIGN: Cross-sectional study. SETTING: Academic and private fertility clinics. PATIENT(S): Women diagnosed with DOR (n = 51) and women diagnosed with ACI (n = 51). INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Fertility Problem Inventory (infertility distress), Rosenberg Self Esteem Scale, Health Orientation Scale (emotional reactions to receiving a diagnosis). RESULT(S): Women with DOR had statistically significantly higher infertility distress scores than women with ACI and higher scores on subscales assessing distress from social concerns, sexual concerns, and a need for parenthood. In both groups, higher self-esteem was associated with lower infertility distress. Hierarchical multiple regression analyses revealed that for women with DOR and those with ACI lower infertility distress but not self-esteem predicted a more positive emotional reaction toward receiving a fertility diagnosis. CONCLUSION(S): Women diagnosed with DOR have greater infertility distress but similar self-esteem and emotional reactions to their diagnosis compared with women who have an anatomical cause of infertility. These results suggest that for both groups distress surrounding infertility itself may influence the way women respond to learning the cause of their infertility. PMID- 28579418 TI - Early genetic restoration of lubricin expression in transgenic mice mitigates chondrocyte peroxynitrite release and caspase-3 activation. AB - OBJECTIVE: This study investigated the ability of endogenous lubricin secretion to restore joint health following a brief <21 day, postnatal lubricin-null state, in a C57BL/6J Prg4 gene trap (GT) mouse under the control of cre-recombinase. Previously we showed that re-expression of lubricin at 21 days was partly restorative of joint lubrication. DESIGN: The tibio-femoral joints of adult C57BL/6J mice containing lubricin, lacking lubricin, and postnatally lacking lubricin until restoration of lubricin expression at 7 days or 14 days of age were evaluated ex vivo. At 8-weeks of age, whole joint coefficient of friction (COF), and caspase-3 activation were measured and the tibial-femoral joints histologically analyzed for degenerative changes, following progressive cyclic loading. The peroxynitrite content of femoral head cartilage from these mice prior to cyclic loading was measured. RESULTS: Mice that underwent gene recombination at 7 and 14 days of age did not reestablish low COF as joint cycling time increased and were histopathologically indistinguishable from the joints of lubricin-null littermates. However, cartilage from tibio-femoral joints that underwent recombination at 7 and 14 days of age had significantly fewer caspase-3 positive cells and significantly reduced peroxynitrite content compared to lubricin-null littermates. CONCLUSIONS: The biological effects of lubricin, which include limiting inflammation via peroxynitrite production and caspase-3 activation, may be achieved without completely restituting low COF. However, fully recapitulating low COF may require undamaged cartilage surfaces or absence of biofouling, which may interfere with the activity of lubricin. PMID- 28579419 TI - The effect of catheter displacement and anatomical variations on the dose distribution in MRI-guided focal HDR brachytherapy for prostate cancer. AB - PURPOSE: The aim of this study was to analyze the effect of catheter displacement and anatomical variations of prostate and organs at risk on dose distribution in MRI-guided 19 Gy single fraction focal high-dose-rate brachytherapy (HDR-BT) of the prostate. METHODS AND MATERIALS: Seventeen patients with localized prostate cancer were enrolled in a prospective trial investigating focal HDR-BT in a 1.5 T MRI-HDR-BT facility. The diagnostic MRI delineations were registered with intraoperative MR scan, and a single fraction of 19 Gy was applied to the visible tumor. Self-anchoring umbrella catheters were used for HDR-BT delivery. A 1.5 T MRI was performed directly after ultrasound (US)-guided catheter placement for treatment planning. After treatment and before removal of catheters, a posttreatment 1.5 T MRI was performed. Regions of interest were also delineated on the posttreatment MR images and the catheters of 17 patients were reconstructed. The dose plan was constructed for the posttreatment MRI scan to assess the influence of catheter migration and anatomical variation on the dose delivered to the target and the organs at risk. Also on the posttreatment MRI, the complete catheter reconstruction was reassessed, to correct for, for example, bending of the catheters. The displacement of catheters between the MRI scans was determined by comparing the catheter tip positions on the treatment planning and posttreatment 1.5 T MRI scans. RESULTS: The displacements of 241 catheters were investigated. Average (range) displacements of the umbrella catheters are 0.6 (0 2.9) mm in the x-direction, 0.5 (0-2.1) mm in the y-direction, and 0.9 (0-5.5) mm in the z-direction. In 3 patients, the displacement was >4 mm and up to 5.5 mm. This occurred in respectively 1/13, 1/16, and 1/18 catheters in these patients. The dosimetric differences between the intraoperative treatment and the posttreatment plans were in most patients less than 1.5 Gy. In 4 patients, a dose difference in clinical target volume D95 of >2 Gy up to 5.8 Gy was reported. No discrimination can be made between dose differences due to catheter displacement and/or organ movement/anatomy changes. CONCLUSIONS: In general, catheter displacements were in the order of a mm and differences in dose to the clinical target volume and the organs at risk between the treatment and posttreatment plans smaller than 1.5 Gy. In some patients, dose differences up to 5.8 Gy were determined, due to either individual larger catheter displacement and/or anatomy changes. A longer followup is necessary to assess the clinical implications of individual large dose differences. PMID- 28579420 TI - Dynamic processes in biological membrane mimics revealed by quasielastic neutron scattering. AB - Neutron scattering is a powerful tool to study relaxation processes in biological membrane mimics in space and time. Combining different inelastic and quasielastic neutron scattering techniques, a large dynamic range can be covered: from atomic to mesoscopic lengths and from femto- to some hundreds of nanoseconds in time. This allows studies on e.g. the diffusion of lipids, the membrane undulation motions, the dispersion of sound waves in membranes as well as the mutual interactions of membrane constituents such as lipids, proteins, and additives. In particular, neutron scattering provides a quite direct experimental approach to the inter-atomic and inter-molecular potentials on length and time scales which are perfectly accessible by molecular dynamics (MD) simulations. Neutron scattering experiments may thus substantially support the further refinement of biomolecular force fields for MD simulations by supplying structural and dynamical information with high spatial and temporal resolution. In turn, MD simulations support the interpretation of neutron scattering data. The combination of both, neutron scattering experiments and MD simulations, yields an unprecedented insight into the molecular interactions governing the structure and dynamics of biological membranes. This review provides an overview of the molecular dynamics in biological membrane mimics as revealed by neutron scattering. It focuses on the latest findings such as the fundamental molecular mechanism of lateral lipid diffusion as well as the influence of additives and proteins on the short-time dynamics of lipids. Special emphasis is placed on the comparison of recent neutron scattering and MD simulation data with respect to molecular membrane dynamics on the pico- to nanosecond time scale. PMID- 28579421 TI - An Interactive Ambulatory Nephrology Curriculum for Internal Medicine Interns: Design, Implementation, and Participant Feedback. AB - While diminishing nephrology fellow recruitment is a known issue, more work is needed to evaluate possible interventions to reverse this trend. We designed and implemented a curriculum to increase exposure to ambulatory nephrology among internal medicine interns. The curriculum focused on key aspects of outpatient nephrology practice, including supervised clinic visits, formal themed didactic content, and an online interactive forum with assigned evidence-based readings and small-group responses to relevant cases. We obtained postcourse surveys from all participating interns. Of the 43 interns who took part in the first year of the ambulatory nephrology curriculum, 100% reported a positive didactic experience and 91% reported a positive interactive online experience. 77% reported an improvement in their familiarity with clinical nephrology practice (median 2-point increase in familiarity score on a 7-point scale, P<0.001 by signed rank testing). Qualitative feedback included praise for the high-yield topics covered by the lectures and energizing teachers. In conclusion, we successfully implemented an ambulatory nephrology curriculum using a framework that integrated formal didactics, interactive online learning, and key clinical components of outpatient nephrology care. Future investigation will evaluate whether early implementation of this curriculum is associated with increased pursuit of nephrology as a career. PMID- 28579422 TI - Atazanavir-Associated Crystalline Nephropathy. AB - Crystalline nephropathy can occur following treatment with multiple therapeutic agents. We describe a human immunodeficiency virus (HIV)-infected patient treated for 2 years with combination antiretroviral therapy including atazanavir (ATV). Kidney biopsy revealed a crystalline nephropathy associated with diffuse chronic and granulomatous interstitial inflammation. Following the biopsy, treatment with ATV was discontinued and kidney function returned to pretreatment baseline levels. ATV, which has a well-established association with nephrolithiasis, is a rare but important cause of crystalline nephropathy. Recognition of this association and prompt withdrawal of the offending agent are critical to optimize outcomes. PMID- 28579424 TI - Reflections on a Question: "Would You Offer Dialysis?" PMID- 28579423 TI - Serum Phosphorus and Risk of Cardiovascular Disease, All-Cause Mortality, or Graft Failure in Kidney Transplant Recipients: An Ancillary Study of the FAVORIT Trial Cohort. AB - BACKGROUND: Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B-based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs. PREDICTOR: Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization. RESULTS: During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92-1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15-1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04-1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00-1.31), transplant failure (HR, 1.72; 95% CI, 1.46-2.01), and mortality (HR, 1.34; 95% CI, 1.15-1.54). LIMITATIONS: We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites. CONCLUSIONS: Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted. PMID- 28579425 TI - Diarrhoeal disease trends in the GBD 2015 study: optimism tempered by scepticism. PMID- 28579427 TI - Infections of Wolbachia may destabilize mosquito population dynamics. AB - Recent efforts in controlling mosquito-borne diseases focus on biocontrol strategies that incapacitate pathogens inside mosquitoes by altering the mosquito's microbiome. A case in point is the introduction of Wolbachia into natural mosquito populations in order to eliminate Dengue virus. However, whether this strategy can successfully control vector-borne diseases is debated; particularly, how artificial infection affects population dynamics of hosts remains unclear. Here, we show that natural Wolbachia infections are associated with unstable mosquito population dynamics by contrasting Wolbachia-infected versus uninfected cage populations of the Asian tiger mosquito (Aedes albopictus). By analyzing weekly data of adult mosquito abundances, we found that the variability of the infected populations is significantly higher than that of the uninfected. The elevated population variability is explained by increased instability in dynamics, as quantified by system nonlinearity (i.e., state dependence). In addition, predictability of infected populations is substantially lower. A mathematical model analysis suggests that Wolbachia may alter mosquito population dynamics by modifying larval competition of hosts. These results encourage examination for effects of artificial Wolbachia establishment on mosquito populations, because an enhancement of population variability with reduced predictability could pose challenges in management. Our findings have implications for application of microbiome alterations in biocontrol programs. PMID- 28579428 TI - Biochanin A enhances RORgamma activity through STAT3-mediated recruitment of NCOA1. AB - Interleukin (IL)-17-producing T cells play important roles in autoimmunity, chronic inflammation and host protection against extracellular bacteria and fungi. The retinoic acid receptor-related orphan receptors (ROR) alpha and gamma are key regulators of the IL-17-producing phenotype. We previously showed that the isoflavone biochanin A enhanced ROR-mediated transcriptional activity. Here, we investigated the possible mechanisms underlying this ROR activation. Biochanin A-treated murine thymoma EL4 and primary splenocytes demonstrated enhanced induction of IL-17. Biochanin A also induced tyrosine-phosphorylation of signal transducer and activator of transcription 3 (STAT3) in these cells. Stable knockdown of either RORgamma or STAT3 in EL4 cells canceled biochanin A-induced upregulation of IL-17 expression. Importantly, biochanin A enhanced complex formation between RORgamma and STAT3 or nuclear-receptor coactivator 1 (NCOA1). Furthermore, the biochanin A-induced RORgamma-NCOA1 complex was disrupted by a dominant negative mutant of STAT3 or by the STAT3 specific inhibitor Stattic. These results suggest that biochanin A activates RORgamma-dependent IL-17 transcription through the enhancement of STAT3 phosphorylation and STAT3-mediated recruitment of NCOA1 to RORgamma. PMID- 28579429 TI - The EGF receptor inhibits the signaling of dopamine D3 receptor through the phosphorylation of GRK2 on tyrosine residues. AB - Receptor transactivation or crosstalk are terms referring to instances in which the signaling of a given receptor is regulated by a different class of receptor. The epidermal growth factor (EGF) and the dopaminergic systems in the brain are closely related to schizophrenia with respect to both etiology and treatment. Thus, we investigated the functional interactions between the EGF receptor (EGFR), which belongs to the receptor tyrosine kinase family, and the dopamine D2 like receptors (D2R, D3R, and D4R), which are members of the G protein-coupled receptor (GPCR) family. Among D2-like receptors, the signaling of D3R was selectively inhibited by EGFR stimulation. Moreover loss-of-function assays showed that tyrosine-phosphorylated GRK2 mediates this inhibition by acting on the second intracellular loop of D3R. Considering that both EGFR and D3R are closely related to schizophrenia, this study could provide new molecular insight into the etiology of the disorder. PMID- 28579426 TI - Estimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015. AB - BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) provides an up-to-date analysis of the burden of diarrhoeal diseases. This study assesses cases, deaths, and aetiologies spanning the past 25 years and informs the changing picture of diarrhoeal disease worldwide. METHODS: We estimated diarrhoeal mortality by age, sex, geography, and year using the Cause of Death Ensemble Model (CODEm), a modelling platform shared across most causes of death in the GBD 2015 study. We modelled diarrhoeal morbidity, including incidence and prevalence, using a meta-regression platform called DisMod-MR. We estimated aetiologies for diarrhoeal diseases using a counterfactual approach that incorporates the aetiology-specific risk of diarrhoeal disease and the prevalence of the aetiology in diarrhoea episodes. We used the Socio-demographic Index, a summary indicator derived from measures of income per capita, educational attainment, and fertility, to assess trends in diarrhoeal mortality. The two leading risk factors for diarrhoea-childhood malnutrition and unsafe water, sanitation, and hygiene-were used in a decomposition analysis to establish the relative contribution of changes in diarrhoea disability-adjusted life-years (DALYs). FINDINGS: Globally, in 2015, we estimate that diarrhoea was a leading cause of death among all ages (1.31 million deaths, 95% uncertainty interval [95% UI] 1.23 million to 1.39 million), as well as a leading cause of DALYs because of its disproportionate impact on young children (71.59 million DALYs, 66.44 million to 77.21 million). Diarrhoea was a common cause of death among children under 5 years old (499 000 deaths, 95% UI 447 000-558 000). The number of deaths due to diarrhoea decreased by an estimated 20.8% (95% UI 15.4-26.1) from 2005 to 2015. Rotavirus was the leading cause of diarrhoea deaths (199 000, 95% UI 165 000-241 000), followed by Shigella spp (164 300, 85 000-278 700) and Salmonella spp (90 300, 95% UI 34 100-183 100). Among children under 5 years old, the three aetiologies responsible for the most deaths were rotavirus, Cryptosporidium spp, and Shigella spp. Improvements in safe water and sanitation have decreased diarrhoeal DALYs by 13.4%, and reductions in childhood undernutrition have decreased diarrhoeal DALYs by 10.0% between 2005 and 2015. INTERPRETATION: At the global level, deaths due to diarrhoeal diseases have decreased substantially in the past 25 years, although progress has been faster in some countries than others. Diarrhoea remains a largely preventable disease and cause of death, and continued efforts to improve access to safe water, sanitation, and childhood nutrition will be important in reducing the global burden of diarrhoea. FUNDING: Bill & Melinda Gates Foundation. PMID- 28579430 TI - CRY2 is suppressed by FOXM1 mediated promoter hypermethylation in breast cancer. AB - Loss of CRY2 confers aggressive phenotypes to breast cancer. However, the mechanism of its downregulation and its prognostic value in breast cancer are still not clear. Our data mining in TCGA breast cancer cohort (TCGA-BRCA) showed that the luminal A subtype of breast cancer had the highest CRY2 expression, while the basal-like subtype had the lowest CRY2 expression. The ER+ group had significantly higher CRY2 expression than the ER- group. Demethylation treatment using 5-AZA-dC significantly restored CRY2 expression in MDA-MB-231 and BT549 cells. Co-expression analysis in TCGA-BRCA showed a strong negative correlation between CRY2 and FOXM1 (Pearson's r = -0.62). FOXM1 overexpression in MCF-7 cells reduced CRY2 expression, while FOXM1 knockdown in MDA-MB-231 cells increased CRY2 expression. Demethylation significantly abrogated FOXM1 induced CRY2 suppression in MCF-7 cells. Bioinformatic scanning predicted a common FOXM1 binding site in CRY2 transcript 1 and transcript 2 promoter. The following studies confirmed that through binding with DNMT3b, FOXM1 can bind to CRY2 promoter and enhance methylation in this region. Univariate analysis based on Cox proportional hazards model and the following NPI and AOL adjusted studies in bc-GenExMiner 4.0 showed that high CRY2 expression was an independent indicator of reduced risk of metastatic relapse (MR) in ER+ breast cancer patients, but not in ER- breast cancer. With these findings, we infer that FOXM1 is a negative regulator of CRY2 in breast cancer via enhancing methylation in CRY2 promoter and its high expression is an independent predictor of favorable MR-free survival in ER+ breast cancer patients. PMID- 28579431 TI - Direct interaction between selenoprotein R and Abeta42. AB - Amyloid-beta (Abeta) peptides have taken a central role in AD research, the aggregation of Abeta peptide is involved in the progression of Alzheimer's disease (AD). The 35th amino acid was methionine (Met) in Abeta peptides and it's redox state is critical in determining the biological activity of Abeta. It has been suggested that oxidation of Met35 (Met35O) plays a key role in the formation of paranuclei and in the control of oligomerization pathway choice. As an antioxidative selenoenzyme, Selenoprotein R (SelR) plays important roles in reducing the R-form of MetO to Met to maintain intracellular redox balance. However, the relationship between SelR and Abeta was little investigated. Here, we found that SelR can directly interact with Abeta42, and the interaction between SelR and Abeta42 was verified by fluorescence resonance energy transfer (FRET), co-immunoprecipitation (co-IP), and pull-down assays. SelR is closely related to AD, its biological functions in human brain become a research focus. This work implies that SelR makes it capable of modulating Abeta42 aggregation and provides a novel avenue for further study on the mechanism of SelR in AD prevention. PMID- 28579433 TI - Taxifolin enhances osteogenic differentiation of human bone marrow mesenchymal stem cells partially via NF-kappaB pathway. AB - Taxifolin, a flavonoid compound, has been reported to stimulate osteogenic differentiation in osteoblasts. The present study investigated whether taxifolin affects the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) and the molecular mechanisms involved. The proliferation and osteogenic differentiation of hBMSCs in the presence of taxifolin were examined by CCK-8 assay, alkaline phosphatase (ALP) activity, ALP staining and Alizarin red staining. The expression of osteogenic differentiation markers were detected by real-time quantitative PCR (RT-PCR) analysis and western blot assay. The activation of potential related pathways was examined by luciferase reporter assay, immunofluorescence and western blot analysis. Taxifolin treatment increased osteogenic differentiation of hBMSCs without cytotoxicity. Luciferase reporter assay showed that taxifolin could not activate estrogen receptor pathway, but inhibit TNF-alpha-induced NF-kappaB signaling pathway activation in osteogenic induction condition. Moreover, the nucleus translocation of NF-kappaB under TNF-alpha treatment was inhibited by taxifolin treatment. The taxifolin induced osteogenic differentiation effects of hBMSCs were abolished by TNF-alpha treatment. In conclusion, our results suggested that taxifolin could promote osteogenesis of hBMSCs, partially through antagonism of NF-kappaB signaling pathway. PMID- 28579432 TI - Synergistic anti-tumor activity of Nimotuzumab in combination with Trastuzumab in HER2-positive breast cancer. AB - Breast cancer is characterized with poor prognosis and high recurrence. HER2 is highly expressed in breast cancer and is a target for cancer therapy and prevention. Here, we investigated the anti-tumor activity of the combination of an HER2 inhibitor, trastuzumab with an EGFR-inhibitor, nimotuzumab in HER2 overexpressing breast cancer. Our data showed that a greater anti-tumor activity from the combination of trastuzumab and nimotuzumab than any alone usage of above antibody both in vitro and in vivo. Based on the combination index value, our data demonstrated that nimotuzumab synergistically enhanced trastuzumab-induced cell growth inhibition. Furthermore, we investigated the possible mechanism of this synergistic efficacy induced by trastuzumab plus nimotuzumab. Data showed that the combination was more potent in reducing the phosphorylation of HER2 and ERK1/2. We also found that the synergistic inhibition was partly attributed to the ROS generation and repression of NRF2 pathway that is known to promote cell growth. These results support the clinical development of this two-drug regimen for the treatment of HER2-amplified breast cancer. PMID- 28579434 TI - Polyethylene glycol modified PAMAM dendrimer delivery of kartogenin to induce chondrogenic differentiation of mesenchymal stem cells. AB - Partly PEGylated polyamidoamine (PAMAM) dendrimer was used as the nanocarrier for the cytoplasmic delivery of kartogenin (KGN) to induce chondrogenic differentiation of mesenchymal stem cells (MSCs). Here, KGN was conjugated to the surface of PAMAM and the end group of polyethylene glycol (PEG) to obtain PEG PAMAM-KGN (PPK) and KGN-PEG-PAMAM (KPP) conjugate, respectively. The effects of PPK and KPP on the in vitro chondrogenic differentiation of MSCs were evaluated. KPP induced higher expression of chondrogenic markers than PPK and free KGN. In particular, after treatment of KPP, CBF beta nuclear localization intensity was significantly increased, indicating enhanced efficacy of chondrogenesis. The fluorescein labeled PEG-PAMAM was capable to persist in the joint cavity for a prolonged time of both healthy and osteoarthritis (OA) rats. Thus, PEG-PAMAM could be a useful nanocarrier for intra-articular (IA) delivery of drug to treat OA. PMID- 28579435 TI - Graphene nanoparticles as osteoinductive and osteoconductive platform for stem cell and bone regeneration. AB - The potential of graphene-based nanoparticles (GNPs) has recently gained significant attention in biomedicine, especially in tissue engineering. In this study, we investigated the osteoinductive and osteoconductive effects of low oxygen content graphene (LOG) nanoparticles on adult mesenchymal stem cells (MSCs) in vitro and in vivo. We showed that adult goat MSCs were viable in the presence of 0.1 mg/mL LOG and retained their stem cell properties. A 3D scaffold made from agarose was used to encapsulate MSCs and LOG nanoparticles. Scanning electron microscopy demonstrated the cell morphology and adherence of MSCs to LOG in the 3D form. The LOG and MSCs in the 3D scaffold were xenogenically implanted into a rat unicortical tibial bone defect. The combination of MSCs and LOG nanoparticles resulted in improved active bone formation and increased mineralization. These results strengthen the applicability of LOG nanoparticles as an adjunct treatment for bone tissue engineering. PMID- 28579436 TI - Intranasal vaccination with an adjuvanted polyphosphazenes nanoparticle-based vaccine formulation stimulates protective immune responses in mice. AB - The most promising strategy to sustainably prevent infectious diseases is vaccination. However, emerging as well as re-emerging diseases still constitute a considerable threat. Furthermore, lack of compliance and logistic constrains often result in the failure of vaccination campaigns. To overcome these hurdles, novel vaccination strategies need to be developed, which fulfill maximal safety requirements, show maximal efficiency and are easy to administer. Mucosal vaccines constitute promising non-invasive approaches able to match these demands. Here we demonstrate that nanoparticle (polyphosphazenes)-based vaccine formulations including c-di-AMP as adjuvant, cationic innate defense regulator peptides (IDR) and ovalbumin (OVA) as model antigen were able to stimulate strong humoral and cellular immune responses, which conferred protection against the OVA expressing influenza strain A/WSN/OVAI (H1N1). The presented results confirm the potency of nanoparticle-based vaccine formulations to deliver antigens across the mucosal barrier, but also demonstrate the necessity to include adjuvants to stimulate efficient antigen-specific immune responses. PMID- 28579437 TI - Quality-by-design of nanopharmaceuticals - a state of the art. AB - Pharmaceutical Quality-by-Design is a risk-based approach of drug development relying on the understanding of both the product and the process. This state of the art analyzes 24 studies published during the last ten years. A risk modeling of the nanomaterial formulation and manufacturing is firstly presented. After a brief history of the QbD approach, its basic components are recalled in a second part. The most critical material attributes, process parameters, quality variables and measurement technologies are reviewed. Specific deficiencies are also emphasized such as the absence of prior risk assessment, production scale up, process analytical technology and control strategy. Finally, perspectives and development priorities are drawn to improve the implementation of this integrative approach of quality and safety in nanomedicine. PMID- 28579438 TI - Imiquimod induced ApoE-deficient mice might be a composite animal model for the study of psoriasis and dyslipideamia comorbidity. AB - BACKGROUND: Psoriasis patients are at increased risk of developing lipid metabolism disturbances. Both psoriasis and dyslipideamia not only closely interact in disease development, but occur as mutual side effects in some medicine treatment. The interactive mechanism of the two diseases is complicated and still unclear. OBJECTIVE: Here, we proposed applying imiquimod on the dorsal skin of ApoE-/- mice to establish a composite animal model which formed psoriasiform skin lesions under hyperlipidemic condition. METHOD: By comparison with corresponding wild-type(C57BL/6) mice, the composite mice model was evaluated by skin pathological features, lipid levels, immune inflammatory factors in order to clarify the diseases interplay mechanism. In addition, IL-17 mAb treatment was applied to observe the effect of IL-17 antibody on the composite animal model. RESULTS: The results verified that imiquimod-induced ApoE /- mice model presented keratinocyte hyperplasia, parakeratosis, inflammatory cells infiltration and elevated serum lipid levels, and also reflected the complex interaction between inflammation and lipid metabolism. IL-17 mAb could inhibit psoriasis skin lesions with lipid accumulation via STAT3 pathway, but no influence on elevated serum cholesterol. CONCLUSIONS: Imiquimod-induced ApoE-/- mice model presented the pathological features of psoriasis and dyslipideamia, which could be an ideal composite animal model for the study of pathogenesis and pharmacotherapeutics of psoriasis and dyslipideamia comorbidity. PMID- 28579439 TI - Serum Biomarkers of Erectile Dysfunction in Diabetes Mellitus: A Systematic Review of Current Literature. AB - INTRODUCTION: Erectile dysfunction (ED) is a common complication in patients with diabetes mellitus (DM). However, the utility of serum biomarkers as clinical surrogates for the development and/or progression of ED is unknown. AIM: To summarize the current literature for serum biomarkers for ED in DM and emphasize areas for future research. MAIN OUTCOME MEASURES: Human subject data demonstrating the utility of serum markers for the development and progression of ED in patients with DM. METHODS: We performed a systematic PubMed-Medline search in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement using Medical Subject Headings (MeSH) for articles published from January 1, 2000 through December 31, 2016 of serum biomarkers for development or progression of ED in patients with DM using erectile dysfunction [MeSH] AND (biomarkers [MeSH] or inflammation mediators [MeSH] or intercellular signaling peptides and proteins [MeSH] or cell adhesion molecules [MeSH]). A thorough review of these studies was completed. RESULTS: Of the 327 abstracts screened, 12 full-text studies were assessed and 1 study was excluded. Eleven studies assessing serum biomarkers for ED in patients with DM were included in this review. The most studied serum biomarkers for ED in men with DM included endothelial dysfunction markers such as serum E-selectin, endothelial progenitor cells, and endothelial microparticles and specific markers of inflammation such as interleukin-10, ratio of tumor necrosis factor-alpha to interleukin-10, and reactive oxygen species such as nitric oxide and malondialdehyde. Reliable serum biomarkers will enable earlier diagnosis and objective monitoring of disease progression and responses to treatment in patients with ED. CONCLUSION: Serum biomarkers for ED in men with DM are very limited. Future longitudinal studies with uniform patient characteristics are needed to evaluate the potential clinical use of serum biomarkers in men with DM for the development and progression of ED. Patel DP, Craig JR, Myers JB, et al. Serum Biomarkers of Erectile Dysfunction in Diabetes Mellitus: A Systematic Review of Current Literature. Sex Med Rev 2017:5:339-348. PMID- 28579440 TI - A single tube system for the detection of Mycobacterium tuberculosis DNA using gold nanoparticles based FRET assay. AB - The global combat against MTB is limited by challenges in accurate affordable detection. In this study, a rapid, affordable, single tube system for detection of unamplified MTB16s rDNA was developed. Utilizing a AuNP based FRET system, this assay achieved a sensitivity and specificity of 98.6% and 90% respectively. PMID- 28579442 TI - Phosphaturic mesenchymal tumor of the nasal cavity and paranasal sinuses: A clinical curiosity presenting a diagnostic challenge. AB - Phosphaturic mesenchymal tumor (PMT) is a rare mesenchymal neoplasm associated with tumor-induced osteomalacia (TIO) and elevated serum FGF-23. Common in extremities, PMT rarely occurs in sinonasal region. We report a series of sinonasal PMT diagnosed at our institute over a 6-year period. Six cases of sinonasal PMT were identified during this period, of which five presented with features of TIO. Median age of patients was 45.5 years. All six tumors were composed of stellate to spindled cells, with prominent staghorn vasculature in four cases. Typical smudgy matrix was seen in all cases, but only focally; grungy calcification was absent. Accurate diagnosis of PMTs is imperative, as complete excision leads to dramatic resolution of TIO symptoms. Lack of knowledge of this entity prevents clinicians from ordering relevant investigations. Absence of specific morphological features, like grungy calcification, and presentation at atypical locations makes the diagnosis challenging. Awareness of this entity is essential in order to suspect PMT in patients presenting with a soft tissue mass and features of TIO, however unusual the location may be. PMID- 28579443 TI - Value-Based pricing and the end of pharmaceutical pricing as we know it? A case study on sorafenib and axitinib. PMID- 28579444 TI - Three-Dimensional Computed Tomography Analysis of the Posterior Tibial Slope in 100 Knees. AB - BACKGROUND: The posterior tibial slope (PTS) is an important consideration in knee arthroplasty. However, there is still no consensus for the optimal slope. The objectives of this study were (1) to reliably determine the native PTS in this population using 3-dimensional computed tomography scans and (2) to determine the normal reference range for PTS in this population. METHODS: One hundred computed tomography scans of disease-free knees were analyzed. A 3 dimensional reconstructed image of the tibia was generated and aligned to its anatomic axis in the coronal and sagittal planes. The tibia was then rotationally aligned to the tibial plateau (tibial centroid axis) and PTS was measured from best-fit planes on the surface of the proximal tibia and individually for the medial and lateral plateaus. This was then repeated with the tibia rotationally aligned to the ankle (transmalleolar axis). RESULTS: When rotationally aligned to the tibial plateau, the mean PTS, medial PTS, and lateral PTS were 11.2 degrees +/- 3.0 (range, 4.7 degrees -17.7 degrees ), 11.3 degrees +/- 3.2 (range, 2.7 degrees -19.7 degrees ), and 10.9 degrees +/- 3.7 (range, 3.5 degrees -19.4 degrees ), respectively. When rotationally aligned to the ankle, the mean PTS, medial PTS, and lateral PTS were 11.4 degrees +/- 3.0 (range, 5.3 degrees -19.3 degrees ), 13.9 degrees +/- 3.7 (range, 3.1 degrees -24.4 degrees ), and 9.7 degrees +/- 3.6 (range, 0.8 degrees -17.7 degrees ), respectively. CONCLUSION: The PTS in the normal Asian knee is on average 11 degrees (mean) with a reference range of 5 degrees -17 degrees (mean +/- 2 standard deviation). This has implications to surgery and implant design. PMID- 28579445 TI - Clinical and Radiographic Outcomes of Total Hip Arthroplasty With a Specific Liner in Small Asian Patients: Influence of Patient-Related, Implant-Related, and Surgical Factors on Femoral Head Penetration. AB - BACKGROUND: We evaluated the clinical and radiographic outcomes, including femoral head penetration, of total hip arthroplasty performed using a specific polyethylene (PE) liner in small Asian patients at 10 years after the index surgery. In addition, we investigated whether femoral head penetration was affected by patient-related, implant-related, and surgical factors. METHODS: Between August 2002 and June 2005, for cementless primary total hip arthroplasty, we used acetabular PE liners that were manufactured from GUR 1050 resin, machined from isostatic compression-molded bar stock, and sterilized with a gamma ray irradiation in argon gas. We assessed 82 hips in 78 patients who received these liners. RESULTS: The mean Harris hip score improved from 41.0 preoperatively to 84.5 at 10 years postoperatively. Periprosthetic osteolysis was observed in 7 hips (9.8%). No acetabular component migration was detected, and no revision surgery was performed 10 years postoperatively. The mean steady-state wear rate was 0.031 mm/y, which was lower than the wear rate for other conventional PE liners of the previous studies. Among the patient-related, implant-related, and surgical factors, sex was significantly associated with the mean steady-state wear rate, with a higher rate in male patients than in female patients. CONCLUSION: PE acetabular liners used in small Asian patients show similar clinical outcomes and reduced wear compared with those of other liners. In addition, sex is significantly associated with the mean steady-state wear rate, and the steady-state wear rate is higher in male patients than in female patients. PMID- 28579446 TI - Incidence and Risk Factors for Blood Transfusion in Total Joint Arthroplasty: Analysis of a Statewide Database. AB - BACKGROUND: Significant attempts have been made to adopt practices to minimize blood transfusion after total joint arthroplasty (TJA) because of transfusion cost and potential negative clinical consequences including allergic reactions, transfusion-related lung injuries, and immunomodulatory effects. We aimed to evaluate risk factors for blood transfusion in a large cohort of TJA patients. METHODS: We used the all-payer California Healthcare Cost and Utilization Project data from 2006 to 2011 to examine the trends in utilization of blood transfusion among arthroplasty patients (n = 320,746). We performed descriptive analyses and multivariate logistic regression clustered by hospital, controlling for Deyo Charlson comorbidity index, age, insurance type (Medicaid vs others), gender, procedure year, and race/ethnicity. RESULTS: Eighteen percent (n = 59,038) of TJA patients underwent blood transfusion during their surgery, from 15% with single knee to 45% for bilateral hip arthroplasty. Multivariate analysis indicated that compared with the referent category of single knee arthroplasty, single hip had a significantly higher odds of blood transfusion (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.68-1.83), as did bilateral knee (OR, 3.57; 95% CI, 3.20-3.98) and bilateral hip arthroplasty (OR, 6.17; 95% CI, 4.85-7.85). Increasing age (eg, age >=80 years; OR, 2.99; 95% CI, 2.82-3.17), Medicaid insurance (OR, 1.36; 95% CI, 1.27-1.45), higher comorbidity index (eg, score of >=3; OR, 2.33; 95% CI, 2.22-2.45), and females (OR, 1.75; 95% CI, 1.70-1.80) all had significantly higher odds of blood transfusion after TJA. CONCLUSION: Primary hip arthroplasties have significantly greater risk of transfusion than knee arthroplasties, and bilateral procedures have even greater risk, especially for hips. These factors should be considered when evaluating the risk for blood transfusions. PMID- 28579441 TI - The role of ticks in the maintenance and transmission of Crimean-Congo hemorrhagic fever virus: A review of published field and laboratory studies. AB - This manuscript is part of a series of reviews that aim to cover published research on Crimean-Congo hemorrhagic fever (CCHF) and its etiological agent, CCHF virus (CCHFV). The virus is maintained and transmitted in a vertical and horizontal transmission cycle involving a variety of wild and domestic vertebrate species that act as amplification hosts, without showing signs of illness. These vertebrates have traditionally been considered reservoirs of CCHFV, but in fact they develop only a transient viremia, while the virus can persist in ticks for their entire lifespan, and can also be transmitted vertically to the next generation. As a result, ticks are now considered to be both the vector and the reservoir for the virus. CCHFV has been detected in a wide range of tick species, but only a few have been proven to be vectors and reservoirs, mainly because most published studies have been performed under a broad variety of conditions, precluding definitive characterization. This article reviews the published literature, summarizes current knowledge of the role of ticks in CCHFV maintenance and transmission and provides guidance for how to fill the knowledge gaps. Special focus is given to existing data on tick species in which vertical passage has been demonstrated under natural or experimental conditions. At the same time, we identify earlier reports that used unreliable methods and perceptions to ascribe a vector role to some species of ticks, and have contributed to confusion regarding viral transmission. We also examine epidemiological pathways of CCHFV circulation and discuss priority areas for future research. PMID- 28579447 TI - Are the Outcomes of Revision Knee Arthroplasty for Flexion Instability the Same as for Other Major Failure Mechanisms? AB - BACKGROUND: Aseptic loosening, infection, and flexion instability have emerged as the leading etiologies for revision after total knee arthroplasty (TKA). Although studies have reported improved outcomes after revision TKA, the relative functional and clinical outcomes of patients revised for flexion instability and other failure etiologies have not been extensively reported. The aim of the study was to compare the functional and patient-reported outcomes of revision TKA for the common failure etiologies. METHODS: We retrospectively reviewed records of 228 consecutive cases of revision TKA from 2008 to 2014. Revisions performed for aseptic loosening (n = 53), septic revisions (n = 48), and isolated flexion instability (n = 45) with a minimum of 18 months follow-up were included for analysis. Revision for all other etiologies (n = 82) were excluded. The Modified Knee Society Score (KSS), KSS Function, and Western Ontario and McMaster Universities Osteoarthritis Index were recorded for all cases. A 7-point Likert scale was used to record patient's perception of outcomes after revision surgery and analyzed based on etiology. RESULTS: Although all groups showed improvement in outcome after revision TKA, the changes in Modified KSS and KSS-Function varied according to the etiology of failure of the primary procedure with the smallest improvement being reported by the flexion instability group. CONCLUSION: Patients undergoing revision for isolated flexion instability have less improvement in functional outcome as compared with other etiologies. We hypothesize this is due to a higher baseline preoperative knee function in the flexion instability group. PMID- 28579448 TI - Conversion of Hip Hemiarthroplasty to Total Hip Arthroplasty Utilizing a Dual Mobility Construct Compared With Large Femoral Heads. AB - BACKGROUND: Conversion of hemiarthroplasty to total hip arthroplasty (THA) has a historically high, up to 20%, postoperative dislocation rate. As such, dual mobility (DM) constructs are an attractive option to mitigate this complication. We analyzed survivorship free of revision, complications, and clinical outcomes of hemiarthroplasties conversion to THAs utilizing DM constructs compared with large femoral heads (>=36 mm). METHODS: Conversion of 16 hemiarthroplasties to THAs with a specific DM construct compared with 13 conversions utilizing large femoral heads (>=36 mm) from 2011 to 2014 were reviewed. Mean age at conversion in the DM group was 75 years (range, 57-93 years); 75% were female. Significantly more patients with a dislocated hemiarthroplasty were converted to DM constructs compared to large femoral heads (44% vs 0%; P = .01). Mean follow-up was 3 years. RESULTS: Survivorship free of revision was 100% in the DM group compared with 92% in the large femoral head cohort at 2 years (P = .7). One (8%) patient converted to a large femoral head underwent revision to a constrained liner for recurrent dislocations while no patients experienced a postoperative dislocation in the DM group (P = .4). Harris Hip Scores improved from 54 to 82 (P < .01) in the DM group, and from 52 to 86 in the large femoral head group (P < .01). CONCLUSION: Larger effective femoral heads used during conversion of hemiarthroplasties to THAs resulted in high survivorship free of revision, minimal complications, and excellent clinical outcomes at short-term follow-up. In patients at highest risk for postoperative dislocation, including those with dislocating hemiarthroplasties, DM constructs resulted in no postoperative dislocations. PMID- 28579449 TI - Structural dynamics of the nuclear pore complex. AB - Nuclear pore complexes (NPCs) are the sole conduits that facilitate macromolecular exchange between the nucleus and cytosol. Recent advancements have led to a more highly resolved NPC structure. However, our understanding of the NPC modus operandi that facilitates transport selectivity, and speed, of diverse cargoes remains incomplete. For the most part, assorted cargo-complexes of different sizes traverse the NPC central channel in milliseconds, yet little is known about the nanoscopic movements of its barrier-forming Phe-Gly nucleoporins (FG Nups) and related sub-structures at transport-relevant time and length scales. Here, we discuss how dynamic FG Nup behavior may confer NPCs with an effective permeability barrier according to the functional needs of the cell. Moreover, we postulate that structural flexibility might resonate throughout the NPC framework from the cytoplasmic filaments to the nuclear basket. PMID- 28579450 TI - Drosophila Short stop as a paradigm for the role and regulation of spectraplakins. AB - Spectraplakins are evolutionarily well conserved cytoskeletal linker molecules that are true members of three protein families: plakins, spectrins and Gas2-like proteins. Spectraplakin genes encode at least 7 characteristic functional domains which are combined in a modular fashion into multiple isoforms, and which are responsible for an enormous breadth of cellular functions. These functions are related to the regulation of actin, microtubules, intermediate filaments, intracellular organelles, cell adhesions and signalling processes during the development and maintenance of a wide variety of tissues. To gain a deeper understanding of this enormous functional diversity, invertebrate genetic model organisms, such as the fruit fly Drosophila, can be used to develop concepts and mechanistic paradigms that can inform the investigation in higher animals or humans. Here we provide a comprehensive overview of our current knowledge of the Drosophila spectraplakin Short stop (Shot). We describe its functional domains and isoforms and compare them with those of the mammalian spectraplakins dystonin and MACF1. We then summarise its roles during the development and maintenance of the nervous system, epithelia, oocytes and muscles, taking care to compare and contrast mechanistic insights across these functions in the fly, but especially also with related functions of dystonin and MACF1 in mostly mammalian contexts. We hope that this review will improve the wider appreciation of how work on Drosophila Shot can be used as an efficient strategy to promote the fundamental concepts and mechanisms that underpin spectraplakin functions, with important implications for biomedical research into human disease. PMID- 28579451 TI - The fifth sense: Mechanosensory regulation of alpha-actinin-4 and its relevance for cancer metastasis. AB - Metastatic cancer cells invading through dense tumor stroma experience internal and external forces that are sensed through a variety of mechanosensory proteins that drive adaptations for specific environments. Alpha-actinin-4 (ACTN4) is a member of the alpha-actinin family of actin crosslinking proteins that is upregulated in several types of cancers. It shares 86% protein similarity with alpha-actinin-1, another non-muscle ACTN isoform, which appears to have a more modest role, if any, in cancer progression. While they share regulatory mechanisms, such as phosphorylation, calcium binding, phosphatidyl inositol binding, and calpain cleavage, alpha-actinin-4 exhibits a unique mechanosensory regulation that alpha-actinin-1 does not. This behavior is mediated, at least in part, by each protein's actin-binding affinity as well as the catch-slip-bond behavior of the actin binding domains. We will discuss currently known modes of ACTN4 regulation, their interactions, and how mechanosensation may provide major therapeutic targeting potential for cancer metastasis. PMID- 28579454 TI - Efficacy of intramuscular moxifloxacin in the treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus. AB - Fluoroquinolones have been well studied in the treatment of chronic osteomyelitis due to their beneficial pharmacokinetic (PK) and pharmacodynamic profiles. The purpose of this study was to determine the efficacy of intramuscular (IM) moxifloxacin administration in the treatment of experimental osteomyelitis by methicillin-resistant Staphylococcus aureus. Following an experimental osteomyelitis animal model described previously, three groups of rabbits (A = control; B = IM moxifloxacin administration; C = PK study of moxifloxacin penetration into bone) were evaluated. Three weeks after bacterial inoculation, surgical debridement was performed in all animals and IM treatment commenced for Groups B and C. Sacrifice was performed in an A:B group animal ratio of 1:2 at weekly intervals from 7th to 42nd day post debridement and from 21st to 56th day post debridement for Groups A and B, respectively (including 2-week interval without antibiotics for Group B). Cancellous bone was harvested for microbiological and histopathological analyses at re-operation and sacrifice for Groups A and B. Cortical bone moxifloxacin levels were measured in Group C following 7, 14, 35 and 42 days of treatment. In Group A, bacterial growth after surgical debridement was significant, whereas high eradication rates were observed in Group B. Radiological abnormalities and histopathological findings were evaluated. Moxifloxacin bone levels, observed in Group C, were approximately 43 times higher than the minimum inhibitory concentration, with no difference found between infected and healthy tibial bone. The therapeutic protocol was very effective in this model of experimental osteomyelitis. However, further evaluation of these results in clinical studies is crucial. PMID- 28579453 TI - Building dialogues between clinical and biomedical research through cross-species collaborations. AB - Today, biomedical science is equipped with an impressive array of technologies and genetic resources that bolster our basic understanding of fundamental biology and enhance the practice of modern medicine by providing clinicians with a diverse toolkit to diagnose, prognosticate, and treat a plethora of conditions. Many significant advances in our understanding of disease mechanisms and therapeutic interventions have arisen from fruitful dialogues between clinicians and biomedical research scientists. However, the increasingly specialized scientific and medical disciplines, globalization of science and technology, and complex datasets often hinder the development of effective interdisciplinary collaborations between clinical medicine and biomedical research. The goal of this review is to provide examples of diverse strategies to enhance communication and collaboration across diverse disciplines. First, we discuss examples of efforts to foster interdisciplinary collaborations at institutional and multi institutional levels. Second, we explore resources and tools for clinicians and research scientists to facilitate effective bi-directional dialogues. Third, we use our experiences in neurobiology and human genetics to highlight how communication between clinical medicine and biomedical research lead to effective implementation of cross-species model organism approaches to uncover the biological underpinnings of health and disease. PMID- 28579452 TI - The role of MACF1 in nervous system development and maintenance. AB - Microtubule-actin crosslinking factor 1 (MACF1), also known as actin crosslinking factor 7 (ACF7), is essential for proper modulation of actin and microtubule cytoskeletal networks. Most MACF1 isoforms are expressed broadly in the body, but some are exclusively found in the nervous system. Consequentially, MACF1 is integrally involved in multiple neural processes during development and in adulthood, including neurite outgrowth and neuronal migration. Furthermore, MACF1 participates in several signaling pathways, including the Wnt/beta-catenin and GSK-3 signaling pathways, which regulate key cellular processes, such as proliferation and cell migration. Genetic mutation or dysregulation of the MACF1 gene has been associated with neurodevelopmental and neurodegenerative diseases, specifically schizophrenia and Parkinson's disease. MACF1 may also play a part in neuromuscular disorders and have a neuroprotective role in the optic nerve. In this review, the authors seek to synthesize recent findings relating to the roles of MACF1 within the nervous system and explore potential novel functions of MACF1 not yet examined. PMID- 28579455 TI - Killing kinetics of minocycline, doxycycline and tosufloxacin against macrolide resistant Mycoplasma pneumoniae. AB - Macrolide-resistant Mycoplasma pneumoniae (MRMP) has emerged and is increasing worldwide. In a 2011 outbreak of MRMP infections in Japan, symptoms failed to improve in many patients who initially received macrolides; the therapeutic agent was then changed to minocycline (MIN), doxycycline (DOX) or tosufloxacin (TFX). In this study, the bactericidal effects of these three agents against MRMP were evaluated. Time-kill kinetics against MRMP and macrolide-susceptible M. pneumoniae (MSMP) were determined for 5 days at concentrations corresponding to the respective minimum inhibitory concentration (MIC) and 2 * MIC, i.e. 1 ug/mL and 2 ug/mL for MIN, 0.5 ug/mL and 1 ug/mL for DOX, and 0.5 ug/mL and 1 ug/mL for TFX. The post-antibiotic effects (PAE) of these agents in culture against MRMP were also examined based on their pharmacokinetic parameters in children. Following exposure of MRMP and MSMP to up to twice the respective MICs of MIN, DOX and TFX, viable cells initially numbering 106 CFU/mL had decreased similarly to 103 CFU/mL after 4 days. Clarithromycin and azithromycin showed good bactericidal action against MSMP but not against MRMP. PAEs against MRMP appeared superior with MIN and DOX compared with TFX. In infection with M. pneumoniae having a generation time exceeding 6 h, a therapeutic agent must be selected in consideration of pharmacokinetic parameters, not MICs alone. PMID- 28579456 TI - Detection of the plasmid-mediated mcr-1 gene in clinical KPC-2-producing Escherichia coli isolates in Brazil. PMID- 28579458 TI - Cerium oxide nanoparticles promote HSA fibrillation in vitro. AB - Physicochemical characterization of CeO2NPs using UV-vis, FTIR and XRD have confirmed the characteristic identity and fluorite phase of their crystalline nature. The interaction studies between cerium oxide nanoparticles (CeO2NPs) and HSA were investigated using fluorescence emission and synchronous spectra, UV-vis absorbance, FTIR, FT-Raman and Circular Dichroism spectroscopy. Thermodynamic parameters and Stern-Volmer plot has conveyed the existence of the ground state complex raised due to static quenching. Synchronous and Three-Dimensional fluorescence spectra have conveyed the affinity of CeO2NPs towards Trp and Tyr residues. Results obtained from the FTIR and FT-Raman studies have evidenced minor changes in the amide and amino acid residues band position. Circular Dichroism studies have quantified the conformational changes due to the loss in their alpha helical contents of the secondary structures. Fibrillation studies using Congo red (CR), Thioflavin T (ThT) and Tryptophan emission (Trp) assay have suggested the promoting role of CeO2NPs against HSA fibrillation. CD studies have shown the enhanced percentage of beta sheet structures in the fibrillar samples that reconfirm the increased effect of CeO2NPs during the fibrillation process. PMID- 28579459 TI - Utilization of chemically modified pearl millet starches in preparation of custards with improved cold storage stability. AB - Custards were prepared using five ingredients: milk powder, modified pearl millet starch, sugar, vanilla essence and water. The effect of adding hydroxypropylated starch (HPS), succinylated starch (SUS), oxidised starch (OXS) and acetylated starch (ACS) on cold storage stability, pasting, textural and sensory properties was studied and compared to custards containing native pearl millet starch (NS). Interestingly, all chemically modified starches reduced syneresis and no water weeping was observed in custard sample incorporating hydroxypropylated starch (HPC) even after 7days of cold storage. Viscoamylographic analysis revealed that custard containing succinylated starch (SUC) had the highest peak viscosity (108.8 BU), whereas HPC showed the least set back viscosity (19.0 BU). Sensory results suggested that assessors preferred HPC over other custards. Custards are preferred for their chewy semi-solid texture. Incorporation of hydroxypropylated starch (HPS) increased hardness, gumminess and chewiness which subsequently led to higher sensory scores during subjective analysis. Also, no retrogradation peak was observed for HPS and acetylated starch (ACS) when rescanned after 14 days. Thus, it could be concluded that HPS could be used in custards to confer low temperature stability by reducing syneresis. PMID- 28579457 TI - Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock. AB - Severity of multiple organ failure is significantly impacted by age and gender in patients with hemorrhagic shock. However, the molecular mechanisms underlying the enhanced organ injury are not fully understood. AMP-activated protein kinase (AMPK) is a pivotal orchestrator of metabolic responses during stress. We investigated whether hemorrhage-induced myocardial injury is age and gender dependent and whether treatment with metformin, an AMPK activator, affords cardioprotective effects. C57/BL6 young (3-5months) and mature (9-12months) male and female mice were subjected to hemorrhagic shock by blood withdrawing followed by resuscitation with blood and Lactated Ringer's solution. Vehicle-treated young and mature mice of both genders had a similar elevation of plasma inflammatory cytokines at 3h after resuscitation. However, vehicle-treated male mature mice experienced hemodynamic instability and higher myocardial damage than young male mice, as evaluated by echocardiography, histology and cardiovascular injury biomarkers. There was also a gender-dependent difference in cardiovascular injury in the mature group as vehicle-treated male mice exhibited more severe organ injury than female mice. At molecular analysis, vehicle-treated mature mice of both genders exhibited a marked downregulation of AMPKalpha activation and nuclear translocation of peroxisome proliferator-activated receptor gamma co activator alpha when compared with young mice. Treatment with metformin improved cardiovascular function and survival in mature animals of both genders. However, specific cardioprotective effects of metformin were gender-dependent. Metformin did not affect hemodynamic or inflammatory responses in young animals. Thus, our data suggest that targeting metabolic recovery with metformin may be a potential treatment approach in severe hemorrhage in adult population. PMID- 28579460 TI - Structural characterization of an immunostimulating polysaccharide from the stems of a new medicinal Dendrobium species: Dendrobium Taiseed Tosnobile. AB - Dendrobium Taiseed Tosnobile, a new Dendrobium species developed by crossbreeding Dendrobium tosaense and Dendrobium nobile, exhibits the characteristics of high mass production and high polysaccharide content. This study investigated the structural characterization and immunostimulating effects of a polysaccharide isolated from D. Taiseed Tosnobile (DTTPS). DTTPS was fractioned using a DEAE 650M column to obtain the major neutral polysaccharide (DTTPS-N). The structural characteristics of DTTPS-N were investigated through high-performance anion exchange chromatography, high-performance size exclusion chromatography, gas chromatography-mass spectrometry, and nuclear magnetic resonance spectroscopy. In the immunostimulating experiment, BALB/c mice were administered DTTPS (100 and 300mg/kg) daily for 3 weeks. The results revealed that DTTPS-N comprised arabinose, galactose, glucose, mannose, and xylose at a ratio of 1:1.5:3.0:29.9:1.3. DTTPS-N comprised (1->3; 1->4)-Man as the backbone, and its average molecular weight was 281kDa. Pharmacological experiments demonstrated that DTTPS substantially increased the population of splenic natural killer (NK) cells, NK cytotoxicity, macrophage phagocytosis, and cytokine induction. This is the first study to demonstrate the structural characteristics and immunopharmacological effects of an active polysaccharide derived from D. Taiseed Tosnobile. PMID- 28579461 TI - Covalently bonded pancreatic lipase onto the dithiocarbamate/chitosan-based magnetite: Stepwise fabrication of Fe3O4@CS/NHCS-Lip as a novel and promising nanobiocatalyst. AB - In the present paper, porcine pancreas lipase (PPL) was immobilized to a new version of magnetite via a novel stepwise dithiocarbamate/chitosan-based method in alternation to glutaraldehyde. Magnetic chitosan nanocomposite was post modified to produce dithiocarbamate moieties on the surface through amine functions. Then, immobilization of lipase was successfully achieved on the surface of magnetically separable Fe3O4@CS/NHCS2H via a post-modification. Each step of immobilization was carefully monitored by characterization and all were successfully proved. Comparison of immobilized enzyme with free enzyme showed that the method of immobilization is efficient. PMID- 28579462 TI - Enhancing the performance of starch-based wood adhesive by silane coupling agent(KH570). AB - To investigate the improved performance of silane coupling agents on starch-based wood adhesive, we prepared adhesive samples using gamma-Methacryloxypropyl trimethoxy silane(KH570) as a cross-linking agent.The results found that the addition of KH570 resulted in enhanced shear strength and storage stability. The addition of KH570 also promoted the thermal stability due to increase the number of covalent bonds.Furthermore, the KH570 enhanced the shear-thinning property and weakened the pseudoplastic behavior of the adhesive. The characterization of copolymers was carried out via Fourier transform infrared spectroscopy (FTIR), X ray diffraction analysis (XRD) and thermal analysis. The performing XPS analysis and morphological structures of adhesive were evaluated by X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). In conclusion, 6% KH570 (KH570:starch, w;w) could be used to prepare starch-based wood adhesives with superior performance and stability. PMID- 28579463 TI - Modified apple polysaccharide prevents colitis through modulating IL-22 and IL 22BP expression. AB - Chronic intestinal inflammation enhances cell proliferation, angiogenesis, and migration, then promotes the development of colorectal cancer (CRC). Many ingredients of apples have been proven to have anti-inflammatory properties, and show benefits for colitis treatment. In our previous studies, we found modified apple polysaccharide (MAP) could prevent colitis associated colorectal carcinogenesis effectively. Herein, we further our study to observe the effect of MAP on dextran sodium sulfate (DSS)-induced colitis and to investigate the possible mechanisms. IL-22 has both pathogenic and protective effects during intestinal tissue damage. It could be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP). A DSS-induced colitis mouse model, a mouse CRC cell line MCA-38 and a mouse dendritic cell line DC2.4 were treated with MAP. Western blot, ELISA, BrdU staining and a co-culture system were used to detect the expression of IL-22 and IL-22BP. MAP significantly protected ICR mice against DSS-induced colitis, and inhibited the growth of MCA-38 cells. The mechanisms may be that MAP down-regulated IL-22 level and up-regulated expression of IL-22BP. These data may provide another molecular basis for understanding how apples act to prevent colitis and suggest that MAP has a potential to treat colitis and prevent CRC. PMID- 28579464 TI - Extraction optimization, preliminary characterization and antioxidant activities of polysaccharides from Glycine soja. AB - Single-factor experiment and Central Composite Design (CCD) was applied to optimize the ultrasound-assisted extraction (UAE) conditions of polysaccharides from Glycine soja (CGPS), and a preliminary characterization of three polysaccharide fractions (CGPS, GPS-1, and GPS-2) and their antioxidant activities were investigated. Under the optimal conditions: ratio of liquid to solid 42.7mL/g, extraction power 293.7W, extraction temperature 68.9 degrees C, and extraction time 34.7min, the experimental CGPS yield was 6.04mg/g. CGPS was further purified by DEAE-cellulose and Sephadex-100 chromatography to obtain two fractions (GPS-1 and GPS-2), and their monosaccharides compositions were characterized by HPLC. Fourier-transform infrared spectra (FT-IR) indicated the chemical structures of them. Moreover, they exhibited high antioxidant activities in a concentration-dependent manner in vitro. In summary, the present study suggested that UAE was a very effective method to extract polysaccharides from Glycine soja and the polysaccharides could be explored as potential antioxidant agents for medicine and function food. PMID- 28579465 TI - Preparation and characterization of potato starch-thymol dispersion and film as potential antioxidant and antibacterial materials. AB - The antioxidant/antimicrobial capacity and physical properties of potato starch dispersions enriched with polysorbate-thymol micelle were investigated. Results showed that potato starch have radical scavenging and antibacterial activities only in the presence of polysorbate-thymol but with lower level than polysorbate thymol alone. The decrease in the antioxidant and antibacterial activities may be attributed to the encapsulation of thymol in the starch chain. Polysorbate-thymol caused a decrease in the particle size and viscosity and an increase in the zeta potential of the starch dispersions. Futhermore, polysorbate-thymol leads to a decrease in the tensile strength, rigidity and swelling, and an increase in the flexibility, solubility and water vapour permeability of the starch films. Atomic force microscopy revealed polysorbate-thymol micelles in the film matrix enclosed by polysaccharide crystal. Scanning electron microscope analysis indicated that polysorbate-thymol caused a coarse film microstructure with the distributed crack in the film matrix. Based on the results, the antioxidant and antibacterial activities of the starch-polysorbate-thymol make starch film suitable for food packaging and preservation. PMID- 28579466 TI - Zein/caseinate/pectin complex nanoparticles: Formation and characterization. AB - In this study, pectin was used as coating material to form zein/caseinate/pectin complex nanoparticles through pH adjustment and heating treatment for potential oral delivery applications. The preparation conditions were studied by applying heating treatment at different pHs, either the isoelectric point of zein (pH 6.2) or caseinate (pH 4.6), or consecutively at both pHs. The particulate characteristics, including particle size, polydispersity index, and zeta potential were monitored for complex nanoparticles formed under different preparation conditions. The complex nanoparticles generally exhibited particle size smaller than 200nm with narrow distribution, spherical shape, and strong negative charge. Fourier transform infrared and fluorescence spectroscopy revealed that hydrophobic interactions and hydrogen bonds were involved in the formation of complex nanoparticles, in addition to electrostatic interactions. Fresh colloidal dispersion and freeze-dried powders varied in their morphology, depending on their preparation conditions. Our results suggested that heating pH and sequence significantly affected the morphology of complex nanoparticles, and pectin coating exerted stabilization effect under simulated gastrointestinal conditions. The present study provides insight into the formation of protein/polysaccharide complex nanoparticles under different preparation conditions. PMID- 28579468 TI - Gallic acid induced dose dependent inhibition of lysozyme fibrillation. AB - Amyloidosis is primarily characterized by the deposition of misfolded protein aggregates. Although the natural polyphenols have long been known as effective amyloid inhibitors, the mechanistic details of their inhibitory actions still remain unclear. Our present study explores the inhibition mechanism of polyphenols by studying the anti-amyloidogenic property of gallic acid (GA), the smallest structural unit of tea polyphenols, on hen egg white lysozyme (HEWL) at physiological pH. Using various spectroscopic techniques such as UV-vis, fluorescence, circular dichroism and dynamic light scattering, and microscopic techniques such as TEM and FESEM, it has been shown that GA potentially inhibits the self-aggregation process in a concentration dependent manner. Gel electrophoresis studies suggest that the o-dihydroxy moiety of GA is oxidized into the quinone moiety and H2O2 in the system under the experimental conditions. The quinone binds near the hydrophobic region of HEWL and restricts hydrophobic exposure. Cyclic voltammetry studies reveal that the Met residues of HEWL are oxidized by H2O2 to highly polar sulfoxide-modified side chains. The partially unfolded intermediates formed under the denaturing conditions employed remain in contact with the solvent thus preventing further aggregation. PMID- 28579467 TI - Fluorescence switch biosensor based on quantum dots and gold nanoparticles for discriminative detection of lysozyme. AB - It is important to detect lysozyme (LYZ) in a simple and rapid manner because of its potential application in the treatment of diseases and in the food industry. In this study, it was observed that the strong fluorescence of LYZ-modified Quantum Dots (QDs-LYZ) could be effectively quenched by gold nanoparticle(AuNPs) modified with antibodies against LYZ (anti-LYZ) due to fluorescence resonance energy transfer (FRET) between QDs-LYZ and anti-LYZ-AuNPs. The fluorescence can be reversibly recovered by LYZ (on state) owing to specific competitive interactions between LYZ, QDs-LYZ and anti-LYZ-AuNPs. The interaction of QDs-LYZ with anti-LYZ-AuNPs was studied by absorption, fluorescence spectroscopy and transmission electron microscopy (TEM). Under optimal conditions, LYZ can be detected with a linear range of 50-1000ng/mL and a detection limit (LOD) of 33.43ng/mL. This rapid and selective QD-based sensor was successfully applied for quantitation of LYZ in actual egg products. Furthermore, the strategy described in this report could be followed conveniently to establish similar immunosensors for the rapid detection of other proteins using corresponding antibodies. PMID- 28579469 TI - Helicobacter pylori, Its Urease and Carbonic Anhydrases, and Macrophage Nitric Oxide Synthase. PMID- 28579470 TI - Towards objective hand hygiene technique assessment: validation of the ultraviolet-dye-based hand-rubbing quality assessment procedure. AB - Ultraviolet spectrum markers are widely used for hand hygiene quality assessment, although their microbiological validation has not been established. A microbiology-based assessment of the procedure was conducted. Twenty-five artificial hand models underwent initial full contamination, then disinfection with UV-dyed hand-rub solution, digital imaging under UV-light, microbiological sampling and cultivation, and digital imaging of the cultivated flora were performed. Paired images of each hand model were registered by a software tool, then the UV-marked regions were compared with the pathogen-free sites pixel by pixel. Statistical evaluation revealed that the method indicates correctly disinfected areas with 95.05% sensitivity and 98.01% specificity. PMID- 28579472 TI - Identifying environmental reservoirs of Clostridium difficile with a scent detection dog: preliminary evaluation. AB - BACKGROUND AND AIM: Prompted by an article describing a dog trained to detect Clostridium difficile in patients, our institution evaluated a dog's ability to detect C. difficile scent from equipment and surfaces to assist in strategic deployment of adjunctive cleaning measures. METHODS: An expert in drug and explosives scent dog handling trained a canine to identify odours from pure cultures and/or faecal specimens positive for C. difficile. Methods used to assess explosive and drug detection dogs were adapted and included evaluation of (i) odour recognition, using containers positive and negative for the scent of C. difficile, and of (ii) search capability, on a simulation ward with hidden scents. After demonstration that the canine could accurately and reliably detect the scent of C. difficile, formal assessments of all clinical areas began. FINDINGS: Odour recognition (N = 75 containers) had a sensitivity of 100% and specificity of 97%. Search capability was 80% sensitive and 92.9% specific after removal of results from one room where dog and trainer fatigue influenced performance. Both odour recognition and search capability had an overall sensitivity of 92.3% and specificity of 95.4%. The clinical unit sweeps over a period of five months revealed a sensitivity of 100% in alerting on positive quality control hides. These clinical unit sweeps also resulted in 83 alerts during 49 sweep days. CONCLUSION: A dog can be trained to accurately and reliably detect C. difficile odour from environmental sources to guide the best deployment of adjunctive cleaning measures and can be successfully integrated into a quality infection control programme. PMID- 28579471 TI - First case of vaccine-strain varicella infection as manifestation of HIV in healthcare worker: a case report and review of the literature. AB - Live-attenuated varicella vaccination is safe in non-immunocompromised populations and is associated with rare non-serious adverse events. A healthcare worker (HCW) developed varicella infection, and exposure investigation led to immunization against varicella in an exposed non-immune HCW. Subsequently, vaccine-strain-induced disseminated varicella and progressive outer retinal necrosis in the exposed HCW resulted in identification of undiagnosed human immunodeficiency virus infection. This article reviews serious adverse events from varicella vaccination, and extreme caution is advised prior to live vaccination of HCWs. PMID- 28579473 TI - Duodenal gangliocytic paraganglioma: Endoscopy, sonography and F-18 FDG PET/CT imaging. PMID- 28579474 TI - Cytology brushing of a pancreas cyst wall for the diagnosis of cystic neuroendocrine tumor: When FNA fails. PMID- 28579475 TI - "Turning the outside in": Bariatric gastroplication. PMID- 28579476 TI - Modeling neurodegenerative diseases with patient-derived induced pluripotent cells: Possibilities and challenges. AB - The rising prevalence of progressive neurodegenerative diseases coupled with increasing longevity poses an economic burden at individual and societal levels. There is currently no effective cure for the majority of neurodegenerative diseases and disease-affected tissues from patients have been difficult to obtain for research and drug discovery in pre-clinical settings. While the use of animal models has contributed invaluable mechanistic insights and potential therapeutic targets, the translational value of animal models could be further enhanced when combined with in vitro models derived from patient-specific induced pluripotent stem cells (iPSCs) and isogenic controls generated using CRISPR-Cas9 mediated genome editing. The iPSCs are self-renewable and capable of being differentiated into the cell types affected by the diseases. These in vitro models based on patient-derived iPSCs provide the opportunity to model disease development, uncover novel mechanisms and test potential therapeutics. Here we review findings from iPSC-based modeling of selected neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia and spinocerebellar ataxia. Furthermore, we discuss the possibilities of generating three-dimensional (3D) models using the iPSCs-derived cells and compare their advantages and disadvantages to conventional two-dimensional (2D) models. PMID- 28579478 TI - Absolute venomics: Absolute quantification of intact venom proteins through elemental mass spectrometry. AB - : We report the application of a hybrid element and molecular MS configuration for the parallel absolute quantification of MUHPLC-separated intact sulfur containing venom proteins, via ICP triple quadrupole MS and 32S/34S isotope dilution analysis, and identification by ESI-QToF-MS of the toxins of the medically important African black-necked spitting cobra, Naja nigricollis (Tanzania); New Guinea small-eyed snake, Micropechis ikaheka; and Papuan black snake, Pseudechis papuanus. The main advantage of this approach is that only one generic sulfur-containing standard is required to quantify each and all intact Cys- and/or Met-containing toxins of the venom proteome. The results of absolute quantification are in reasonably good agreement with previously reported relative quantification of the most abundant protein families. However, both datasets depart in the quantification of the minor ones, showing a tendency for this set of proteins to be underestimated in standard peptide-centric venomics approaches. The molecular identity, specific toxic activity, and concentration in the venom, are the pillars on which the toxicovenomics-aimed discovery of the most medically relevant venom toxins, e.g. those that need to be neutralized by an effective therapeutic antivenom, should be based. The pioneering venom proteome-wide absolute quantification shown in this paper represents thus a significant advance towards this goal. The potential of ICP triple quadrupole MS in proteomics in general, and venomics in particular, is critically discussed. BIOLOGICAL SIGNIFICANCE: Animal venoms provide excellent model systems for investigating interactions between predators and prey, and the molecular mechanisms that contribute to adaptive protein evolution. On the other hand, numerous cases of snake bites occur yearly by encounters of humans and snakes in their shared natural environment. Snakebite envenoming is a serious global public health issue that affects the most impoverished and geopolitically disadvantaged rural communities in many tropical and subtropical countries. Unveiling the temporal and spatial patterns of venom variability is of fundamental importance to understand the molecular basis of envenoming, a prerequisite for developing therapeutic strategies against snakebite envenoming. Research on venoms has been continuously enhanced by advances in technology. The combined application of next generation transcriptomic and venomic workflows has demonstrated unparalleled capabilities for venom characterization in unprecedented detail. However, mass spectrometry is not inherently quantitative, and this analytical limitation has sparked the development of methods to determine absolute abundance of proteins in biological samples. Here we show the potential of a hybrid element and molecular MS configuration for the parallel ESI-QToF-MS and ICP-QQQ detection and absolute quantification of intact sulfur-containing venom proteins via 32S/34S isotope dilution analysis. This configuration has been applied to quantify the toxins of the medically important African snake Naja nigricollis (Tanzania), and the Papuan species Micropechis ikaheka and Pseudechis papuanus. PMID- 28579477 TI - Two highly divergent lineages of exfoliative toxin B-encoding plasmids revealed in impetigo strains of Staphylococcus aureus. AB - Exfoliative toxin B (ETB) encoded by some large plasmids plays a crucial role in epidermolytic diseases caused by Staphylococcus aureus. We have found as yet unknown types of etb gene-positive plasmids isolated from a set of impetigo strains implicated in outbreaks of pemphigus neonatorum in Czech maternity hospitals. Plasmids from the strains of clonal complex CC121 were related to archetypal plasmid pETBTY4. Sharing a 33-kb core sequence including virulence genes for ETB, EDIN C, and lantibiotics, they were assigned to a stand-alone lineage, named pETBTY4-based plasmids. Differing from each other in the content of variable DNA regions, they formed four sequence types. In addition to them, a novel unique plasmid pETB608 isolated from a strain of ST130 was described. Carrying conjugative cluster genes, as well as new variants of etb and edinA genes, pETB608 could be regarded as a source of a new lineage of ETB plasmids. We have designed a helpful detection assay, which facilitates the precise identification of the all described types of ETB plasmids. PMID- 28579479 TI - Anti-obesogenic and hypolipidemic effects of a glucagon-like peptide-1 receptor agonist derived from the saliva of the Gila monster. AB - INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor (R) agonists are a class of incretin mimetic drugs that have been used for the treatment of type 2 diabetes mellitus and also considered strong candidates for the treatment of obesity. The original prototypical drug in this class is the exenatide, a synthetic peptide with the same structure as the native molecule, exendin-4, found in the saliva of the Gila monster (Heloderma suspectum suspectum lizard). OBJECTIVES: To identify and compare the anti-obesogenic, antidyslipidemic and antidiabetogenic effects of agonism in GLP-1R by exenatide on two distinct models of obesity: induced by hypothalamic injury (MSG) or high-calorie diet (DIO). METHODS: To obtain MSG, neonatal rats were daily subcutaneously injected with 4 g monosodium glutamate/kg, for 10 consecutive days. To obtain DIO, 72-75 days old rats received hyperlipid food and 30% sucrose for drinking up to 142-145 days old. Untreated healthy rats with the same age were used as control. General biometric and metabolic parameters were measured. RESULTS: MSG was characterized by decreased naso-anal length, food and fluid intake, plasma protein and glucose decay rate per minute after insulin administration (KITT), as well as increased Lee index (body mass0.33/naso-anal length), mass of retroperitoneal and periepididymal fat pads, glycemia, triglycerides (TG), LDL and VLDL. Exenatide ameliorated KITT and food and fluid intake, and it also restored glycemia in MSG. DIO was characterized by glucose intolerance, increased body mass, Lee index, fluid intake, mass of retroperitoneal and periepididymal fat pads, glycemia, glycated hemoglobin (HbA1c), TG, VLDL and total cholesterol, as well as decreased food intake and KITT. Exenatide restored glycemia, HbA1c, TG, VLDL, total cholesterol and body mass, and it also ameliorated food and fluid intake, KITT and mass of retroperitoneal fat pad in DIO. CONCLUSIONS: The hypothalamic injury and the high-calorie diet induce dyslipidemia and glycemic dysregulation in addition to obesity in rats. The usual therapeutic dose of exenatide in humans is antidiabetogenic in both these obesity models, but is anti-obesogenic and hypolipidemic only in diet-induced obesity. Agonists of GLP-1R are promising anti obesogenic and antidyslipidemic drugs in the early stages of the obesity, in which the integrity of the nervous system was unaffected. PMID- 28579480 TI - Sensory reactivity, empathizing and systemizing in autism spectrum conditions and sensory processing disorder. AB - Although the DSM-5 added sensory symptoms as a criterion for ASC, there is a group of children who display sensory symptoms but do not have ASC; children with sensory processing disorder (SPD). To be able to differentiate these two disorders, our aim was to evaluate whether children with ASC show more sensory symptomatology and/or different cognitive styles in empathy and systemizing compared to children with SPD and typically developing (TD) children. The study included 210 participants: 68 children with ASC, 79 with SPD and 63 TD children. The Sensory Processing Scale Inventory was used to measure sensory symptoms, the Autism Spectrum Quotient (AQ) to measure autistic traits, and the Empathy Quotient (EQ) and Systemizing Quotient (SQ) to measure cognitive styles. Across groups, a greater sensory symptomatology was associated with lower empathy. Further, both the ASC and SPD groups showed more sensory symptoms than TD children. Children with ASC and SPD only differed on sensory under-reactivity. The ASD group did, however, show lower empathy and higher systemizing scores than the SPD group. Together, this suggest that sensory symptoms alone may not be adequate to differentiate children with ASC and SPD but that cognitive style measures could be used for differential diagnosis. PMID- 28579482 TI - Precuneus degeneration and isolated apathy in patients with Parkinson's disease. AB - INTRODUCTION: To investigate isolated apathy in a set of consecutively enrolled Parkinson's disease (PD) patients without dementia, depression, and significant motor response fluctuations, by conducting neuropsychological and neuroimaging analyses. METHODS: One hundred twenty-four patients were eligible for inclusion in this study. Clinical information and data were collected from a predefined neuropsychological test battery, including the mini-mental status examination, apathy scale, geriatric depression scale, digit span test, Boston naming test, Seoul verbal learning test, controlled oral word association test, go-no-go test, and the Rey figure copy test. From matched groups of 10 non-apathetic and 12 apathetic patients in the initial cohort and 9 healthy controls, [18F]fluorodeoxyglucose positron emission tomography and volumetric magnetic resonance images were acquired. RESULTS: Apathy was detected in 59.7% of the initial cohort. Apathetic patients had lower scores in the digit span forward, digit span backward, and immediate recall of verbal learning tests than did those without apathy (p <0.05). The results were unaffected by parkinsonian motor severity and medication dose. Neuroimaging analyses revealed precuneus atrophy and hypometabolism in patients with isolated apathy. These precuneus changes were well-correlated with apathy severity (p <0.001). Apathy severity was also positively correlated with gray matter volume in the superior frontal gyrus and cerebellar vermis, and with metabolism in the medial frontal and anterior cingulate regions (p < 0.001). CONCLUSIONS: PD patients with isolated apathy showed attention and working memory dysfunction, and precuneus degeneration might be related to this distinctive nonmotor symptom in PD. PMID- 28579483 TI - S-nitrosylation of GAD65 is implicated in decreased GAD activity and oxygen induced seizures. AB - Breathing oxygen at partial pressures >=2.5 atmospheres absolute, which can occur in diving and hyperbaric oxygen (HBO2) therapy, can rapidly become toxic to the central nervous system (CNS). This neurotoxicity culminates in generalized EEG epileptiform discharges, tonic-clonic convulsions and ultimately death. Increased production of neuronal nitric oxide (NO) has been implicated in eliciting hyperoxic seizures by altering the equilibrium between glutamatergic and GABAergic synaptic transmission. Inhibition of glutamic acid decarboxylase (GAD) activity in HBO2 promotes this imbalance; however, the mechanisms by which this occurs is unknown. Therefore, we conducted a series of experiments using mice, a species that is highly susceptible to CNS oxygen toxicity, to explore the possibility that NO modulates GABA metabolism. Mice were exposed to 100% oxygen at 4 ATA for various durations, and brain GAD and GABA transaminase (GABA-T) activity, as well as S-nitrosylation of GAD65 and GAD67 were determined. HBO2 inhibited GAD activity by 50% and this was negatively correlated with S nitrosylation of GAD65, whereas GABA-T activity and S-nitrosylation of GAD67 were unaltered. These results suggest a new mechanism by which NO alters GABA metabolism, leading to neuroexcitation and seizures in HBO2. PMID- 28579481 TI - Scientific Advances in Thoracic Oncology 2016. AB - Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas, including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for NSCLC, SCLC, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review. PMID- 28579484 TI - Acylethanolamides and endocannabinoid signaling system in dorsal striatum of rats exposed to perinatal asphyxia. AB - Endocannabinoids (eCBs) and acylethanolamides (AEs) have lately received more attention due to their neuroprotective functions in neurological disorders. Here we analyze the alterations induced by perinatal asphyxia (PA) in the main metabolic enzymes and receptors of the eCBs/AEs in the dorsal striatum of rats. To induce PA, we used a model developed by Bjelke et al. (1991). Immunohistochemical techniques were carried out to determine the expression of neuronal and glial markers (NeuN and GFAP), eCBs/AEs synthesis and degradation enzymes (DAGLalpha, NAPE-PLD and FAAH) and their receptors (CB1 and PPARalpha). We found a decrease in NAPE-PLD and PPARalpha expression. Since NAPE-PLD and PPARalpha take part in the production and reception of biochemical actions of AEs, such as oleoylethanolamide, these results may suggest that PA plays a key role in the regulation of this system. These data agree with previous results obtained in the hippocampus and encourage us to develop further studies using AEs as potential neuroprotective compounds. PMID- 28579485 TI - Cerebral metabolic change in Parkinson's disease patients with anxiety: A FDG-PET study. AB - OBJECT: To detect the cerebral metabolic bases of Parkinson's disease (PD) patients with anxiety. METHODS: Totally 28 idiopathic PD patients without depression (17-item Hamilton Depression Rating Scale, HAMD score <14) were enrolled in our study. All subjects were classified into PD with anxiety (PD-A) (n=13) and PD without anxiety (PD-NA) (n=15) by cutoff score of 11 according to Hamilton Anxiety Rating Scale (HAMA). Besides, age- and gender- matched healthy controls (HCs) (n=15) were selected. A resting-state F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan was applied to estimate cerebral metabolic activity. All statistical analyses were performed using IBM SPSS Statistics V20.0.0 software, while statistical parametric mapping software (SPM) was used to analyze the FDG-PET images. RESULTS: PD-A showed decreased glucose metabolism in the bilateral orbitofrontal cortex (OFC, BA10 and BA11) when compared with PD-NA. Significant decrease of cerebral glucose metabolism in the bilateral OFC, bilateral supplementary motor area (SMA, BA6), bilateral dorsal anterior cingulate cortex (dACC, BA32), right dorsolateral prefrontal cortex (dlPFC, BA9), right ventrolateral prefrontal cortex (vlPFC, BA44), right putamen and left caudatum was detected in PD-A compared with HCs. There was significant reduced glucose metabolism of the bilateral SMA in PD-NA when compared with HCs (uncorrected p<0.005). CONCLUSION: The anxiety of PD was associated with the metabolic reductions of PFC and striatal areas. OFC, part of PFC, could be taken as a characteristic feature for anxiety in PD. This metabolic pattern suggested that deficits of prefrontostriatal pathways might affect anxiety mood in PD. PMID- 28579486 TI - No effect of C1473G polymorphism in the tryptophan hydroxylase 2 gene on the response of the brain serotonin system to chronic fluoxetine treatment in mice. AB - Selective serotonin reuptake inhibitors (SSRIs) are antidepressants that block serotonin transporter (SERT) and increase serotonin (5-HT) level in the synaptic cleft. The interaction between SERT and the key enzyme of 5-HT synthesis in the brain, tryptophan hydroxylase 2 (TPH2), is essential to maintain the brain 5-HT level. The G allele of C1473G polymorphism in Tph2 gene decreases enzyme activity by half in mouse brain. Here we studied effect of C1473G polymorphism on the reaction of brain 5-HT system to chronic fluoxetine treatment (120mg/l in drinking water, for 3 weeks) in adult males of the congenic B6-1473C and B6-1473G mouse lines with high and low enzyme activity, respectively. The polymorphism did not affect the levels of 5-HT, its metabolite, 5-hydroxyindoleacetic acid (5 HIAA) and Tph2 gene mRNA in the brain. Fluoxetine significantly attenuated 5-HT levels in the cortex and striatum, 5-HIAA concentrations in the cortex, hippocampus, striatum and midbrain, and Tph2 gene expression in the midbrain. However, we did not observed any effect of the genotype x treatment interaction on these neurochemical characteristics. Therefore, C1473G polymorphism does not seem to play an essential role in the reaction of the brain 5-HT system to chronic fluoxetine treatment. PMID- 28579488 TI - Effective cell-free drug screening protocol for protein-protein interaction. AB - Specific protein-protein interaction (PPI) is an essential feature of many cellular processes however, targeting these interactions by small molecules is highly challenging due to the nature of the interaction interface. Thus, screening for PPI inhibitors requires enormous number of compounds. Here we describe a simple and improved protocol designed for a search of direct PPI inhibitors. We engineered a bacterial expression system for the split-Renilla luciferase (RL) complementation assay that monitors PPI. This enables production of large quantities of the RL fusion proteins in a simple and cost effective manner that is suitable for very large screens. Subsequently, inhibitory compounds are analyzed in a similar complementation assay in living cultured mammalian cells to select for those that can penetrate cells. We applied this method to NF-kappaB, a family of dimeric transcription factors that plays central roles in immune responses, cell survival and aging, and its dysregulation is linked to many pathological states. This strategy led to the identification of several direct NF-kappaB inhibitors. As the described protocol is very straightforward and robust it may be suitable for many pairs of interacting proteins. PMID- 28579489 TI - A Novel Protocol for Planning and Navigation in Craniofacial Surgery: A Preclinical Surgical Study. AB - PURPOSE: In modern craniofacial surgery, the accuracy of osteotomies plays a central role in surgical technique. To reach a higher level of accuracy, many centers use virtual presurgical planning. In the past decade, some surgeons also have applied navigational approaches to craniofacial procedures. In this work, a novel protocol for surgical planning and intraoperative navigation is described and validated in a preclinical setting to determine its accuracy in guiding osteotomies. MATERIALS AND METHODS: This study was based on planning a set of osteotomies using 3-dimensional models of computed tomographic images of human skulls. The planned osteotomies were reproduced on real skulls using an optical infrared navigation system. Positions of the performed osteotomies and planned osteotomies were compared. Results were described as the mean positional error and as a Lin concordance coefficient. The Bland-Altman interval of agreement also was defined to assess a range that could include 95% of possible errors. RESULTS: The mean error was 0.044 mm (95% confidence interval [CI], -0.128 to +0.216), the Lin concordance interval was 0.999 (95% CI, 0.999-1.000), and the Bland-Altman limit of agreement ranged from -1.500 to +1.589 mm. CONCLUSIONS: These results show a submillimetric mean error and a very narrow interval of agreement, providing preclinical validation of this new protocol and suggesting that it could be applied in a clinical setting. PMID- 28579487 TI - Intoxication by gamma hydroxybutyrate and related analogues: Clinical characteristics and comparison between pure intoxication and that combined with other substances of abuse. AB - OBJECTIVE: To study the profile of European gamma-hydroxybutyrate (GHB) and gammabutyrolactone (GBL) intoxication and analyse the differences in the clinical manifestations produced by intoxication by GHB/GBL alone and in combination with other substances of abuse. METHOD: We prospectively collected data on all the patients attended in the Emergency Departments (ED) of the centres participating in the Euro-DEN network over 12 months (October 2013 to September 2014) with a primary presenting complaint of drug intoxication (excluding ethanol alone) and registered the epidemiological and clinical data and outcomes. RESULTS: We included 710 cases (83% males, mean age 31 years), representing 12.6% of the total cases attended for drug intoxication. Of these, 73.5% arrived at the ED by ambulance, predominantly during weekend, and 71.7% consumed GHB/GBL in combination with other substances of abuse, the most frequent additional agents being ethanol (50%), amphetamine derivatives (36%), cocaine (12%) and cannabis (8%). Among 15 clinical features pre-defined in the project database, the 3 most frequently identified were altered behaviour (39%), reduced consciousness (34%) and anxiety (14%). The severity ranged from mild cases requiring no treatment (308 cases, 43.4%) to severe cases requiring admission to intensive care (103 cases, 14.6%) and mechanical ventilation (49 cases, 6.9%). No deaths were reported. In comparison with only GHB/GBL consumption, patients consuming GHB/GBL with co-intoxicants presented more vomiting (15% vs. 3%, p<0.001) and cardiovascular symptoms (5.3% vs. 1.5%, p<0.05), a greater need for treatment (59.8% vs. 48.3%, p<0.01) and a longer ED stay (11.3% vs. 3.6% patients with ED stay >12h, p<0.01). CONCLUSIONS: The profile of the typical GHB/GBL-intoxicated European is a young male, requiring care for altered behaviour and reduced level of consciousness, mainly during the weekend. The clinical features are more severe when GHB is consumed in combination with other substances of abuse. PMID- 28579490 TI - Habituation is altered in neuropsychiatric disorders-A comprehensive review with recommendations for experimental design and analysis. AB - Abnormalities in the simplest form of learning, habituation, have been reported in a variety of neuropsychiatric disorders as etiologically diverse as Autism Spectrum Disorder, Fragile X syndrome, Schizophrenia, Parkinson's Disease, Huntington's Disease, Attention Deficit Hyperactivity Disorder, Tourette's Syndrome, and Migraine. Here we provide the first comprehensive review of what is known about alterations in this form of non-associative learning in each disorder. Across several disorders, abnormal habituation is predictive of symptom severity, highlighting the clinical significance of habituation and its importance to normal cognitive function. Abnormal habituation is discussed within the greater framework of learning theory and how it may relate to disease phenotype either as a cause, symptom, or therapy. Important considerations for the design and interpretation of habituation experiments are outlined with the hope that these will aid both clinicians and basic researchers investigating how this simple form of learning is altered in disease. PMID- 28579491 TI - Recommendation to reconsider examining cannabis subtypes together due to opposing effects on brain, cognition and behavior. AB - Cannabis use represents a major public health issue throughout the globe. Yet, we still lack the most fundamental knowledge on long-term effects of cannabis on neural, cognitive, and behavioral function. Part of this stems from how cannabis has been measured historically. To this end, most empirical examinations of cannabis have consolidated all types of cannabis collectively. However, this approach obscures differences in how cannabinoids operate. In this commentary, we address the contrasting properties of tetrahydrocannabinol (THC) and cannabidiol (CBD) and their opposing effects on cognitive function. In addition, we address the increase in cannabis potency throughout the past two decades and how that impacts generalizability of early data to evaluations of contemporary public health. We underscore the urgent need for future research to disaggregate examination of THC from CBD, along with the importance of measuring cannabis potency to more effectively unravel its influence on cognitive function and other health issues. PMID- 28579493 TI - Sex-specific effects of leisure-time physical activity on cause-specific mortality in NHANES III. AB - Associations between leisure time physical activity (LTPA) and all-cause mortality seem quite strong, however, less is known about the association of LTPA and cause-specific mortality. To examine this association data from the Third National Health and Nutrition Examination Survey (NHANES III), including 15,307 individuals of the non-institutionalized civilian United States population, were used. Data were collected from 1988 to 1994 with a mortality follow-up until 2006. LTPA was assessed during home interviews in which participants specified their LTPA and the performed frequency during the past month. Cox proportional hazards regression models were applied to analyze the risk of cause-specific mortality regarding LTPA. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed. An inverse association of LTPA with CVD mortality was observed for men and women combined for irregular (HR 0.66; 95% CI 0.51-0.85), and for regular activity (HR 0.58; 95% CI 0.47-0.72). An inverse association of LTPA with CVD mortality was observed only in women for irregular (HR 0.64; 95% CI 0.49-0.84) and for regular activity (HR 0.55; 95% CI 0.43-0.72). In men, no significant associations were seen. For mortality caused by respiratory diseases, a decreased mortality was also observed in the combined group (men and women) but after separating according to sex a decreased mortality was only observed in women. No statistically significant association of LTPA with cancer mortality was observed. Our data support an inverse association between LTPA and CVD and respiratory disease mortality in women, but not in men, and no associations with cancer. PMID- 28579492 TI - Characterizing the course of non-suicidal self-injury: A cognitive neuroscience perspective. AB - Non-suicidal self-injury (NSSI) has received increasing recognition as a clinically significant phenomenon. Although in most individuals who engage in NSSI, this behavior is short-lived, for a significant proportion of these individuals, NSSI follows a chronic course. There is a need for research advancing our understanding of the mechanisms of risk for NSSI, and how these mechanisms may change over time to account for the persistence of this behavior. In the current paper, a conceptual framework is proposed for characterizing the processes underlying the transition from initial engagement in NSSI to a chronic trajectory of this behavior. In particular, a case is made for conceptualizing NSSI as a habitual behavior as defined within a cognitive neuroscience perspective, with support from the existing theoretical and empirical literature. Finally, potential mechanisms are articulated for the development of chronic NSSI within this conceptual framework and recommendations presented for empirically evaluating this conceptualization of NSSI in future research in this area. PMID- 28579494 TI - Body height and mortality - mortality follow-up of four Swiss surveys. AB - BACKGROUND: Adult body height is largely determined by genetics, but also by dietary factors, which in turn depend on socioeconomic status and lifestyle. We examined the association between adult body height and mortality in Switzerland, a country with three main language regions with different cultural background. METHODS: We included 16,831 men and 18,654 women, who participated in Swiss population-based health surveys conducted 1977-1993 and who were followed up until end of 2008. Multivariable Cox proportional hazards models were computed to examine the association of body height with overall, cardiovascular, and cancer mortality. RESULTS: We observed a positive association between adult body height and all-cause mortality in women (HR=1.34, 95% CI 1.10-1.62, tallest vs. average women). In men, mortality risk decreased with increasing height, with shortest men tending to have higher (1.06, 0.94-1.19) and tallest men a lower (0.94, 0.77 1.14) risk compared with men of average height (p-trend 0.0001). Body height was associated with cancer mortality in women, such that tallest women had a higher risk of dying from cancer than women of average height (1.37, 1.02-1.84), but there was no such association in men (0.95, 0.69-1.30). In both sexes, height was not associated with cardiovascular mortality in a statistically significant manner. CONCLUSION: Our study does not support an inverse association of body height with all-cause mortality. On the contrary, our data suggests a higher overall risk in taller women, mainly driven by a positive association between body height and cancer mortality. PMID- 28579495 TI - Healthy lifestyle and glucagon-like peptide-1 in young and healthy adults: A population-based study. AB - A healthy lifestyle is associated with a lower risk of cardiovascular events and mortality, but underlying mechanisms are not fully understood. The aim of our study was to investigate the relationships between a healthy lifestyle and glucagon-like peptide-1 (GLP-1), an incretin hormone with both glycemic and cardiovascular properties. Healthy participants aged 25-41years without cardiovascular disease, diabetes or a body mass index (BMI) >35kg/m2 were enrolled in a population-based study. The following metrics were used to build a lifestyle score ranging from 0 to 7 (a higher score indicating a healthier lifestyle): blood pressure (BP) (<120/80mmHg), plasma levels of glycated hemoglobin (<5.7%), total cholesterol levels (<200mg/dl), BMI (<25kg/m2), not smoking cigarettes, moderate (>=150min/week) or vigorous (>=75min/week) physical activity and a healthy diet. Among 2133 participants median age was 36.7years and 53.3% were female. GLP-1 levels decreased significantly from 39.5 to 30.9ng/l (p<0.0001) across increasing lifestyle score categories. This linear relationship persisted in multivariable adjusted linear regression models (B for GLP-1 per 1 unit increase of the lifestyle score -0.06; 95% confidence intervals -0.07, 0.04; p<0.0001). Individual health metrics that were significantly associated with GLP-1 were a normal BMI (-0.07; -0.12, -0.03; p=0.001), low total cholesterol levels (-0.07; -0.12, -0.03; p=0.001), normal BP (-0.05; -0.10, 0.00; p=0.047) and not smoking (-0.06; -0.10, -0.01; p=0.01). A healthy lifestyle is strongly associated with lower GLP-1 levels in young and healthy adults. PMID- 28579496 TI - Prevalence of use and perceptions of risk of novel and other alternative tobacco products among sexual minority adults: Results from an online national survey, 2014-2015. AB - Sexual minority (lesbian, gay, and bisexual [LGB]) populations experience disparities in cigarette use, but sparse evidence exists about novel and other alternative tobacco product use. In this study, we compared rates of novel and other alternative tobacco product use, risk perceptions, and worldview between LGB and heterosexual (HET) adults. An online survey administered in 2014-2015, using a weighted probability sample of 11,525 U.S. adults, assessed awareness of tobacco products; ever and current use of e-cigarettes, cigars, little cigars and cigarillos, and hookahs; perceptions of e-cigarettes; and worldview (individualism vs. communitarianism). Bivariate and adjusted multivariable analyses were performed to determine differences between LGB and HET groups. In the adjusted analyses, LGB adults were 1.5 times more likely to have ever used e cigarettes (95% CI 1.2-1.9) and 1.9 times more likely to have ever used hookahs (95% CI 1.5-2.4) as compared to HET adults. A lower percentage of LGB adults, as compared to HET adults (16.7% vs. 19.2%), believed that exposure to vapors from e cigarettes was "harmful" and reported that they "did not know" of any harm (35.1% vs. 39.8%). LGB were 20% less likely than were HET adults to endorse an individualistic worldview. These results suggest that a disparity exists, whereby LGB adults are more likely to have used e-cigarettes and hookahs. In addition, although vapor from e-cigarettes contains nicotine and other chemicals, LGB adults are less likely to perceive exposure to secondhand vapor as harmful. Tailored awareness campaigns and interventions are needed to convey the risks and curb use of these products. PMID- 28579497 TI - High-risk human papillomavirus detection in self-sampling compared to physician taken smear in a responder population of the Dutch cervical screening: Results of the VERA study. AB - In 2017 the cervical cancer screening program in The Netherlands will be revised. Cervical smears will primarily be tested for the presence of high-risk human papillomavirus (hrHPV) instead of cytology, and vaginal self-sampling will be offered to non-responders. This includes a potential risk that part of the women who would otherwise opt for a cervical smear will wait for self-sampling. However, self-sampling for hrHPV in a responder population has never been studied yet. The aim of this study was to investigate the applicability and accuracy of self-sampling in detecting hrHPV in a screening responder population. A total of 2049 women, aged 30-60years, participating in the screening program in The Netherlands were included from April 2013 to May 2015. After they had their cervical smear taken, women self-collected a cervicovaginal sample with a brush based device, the Evalyn Brush. Both the cervical smear and self-sample specimen were tested with the COBAS 4800 HPV platform. The hrHPV prevalence was 8.0% (95% CI 6.9-9.2) among the physician-taken samples, and 10.0% (95% CI 8.7-11.3) among the self-samples. There was 96.8% (95% CI 96.0-97.5) concordance of hrHPV prevalence between self-samples and physician-taken samples. Women in our study evaluated self-sampling as convenient (97.1%), user-friendly (98.5%), and 62.8% preferred self-sampling over a physician-taken sampling for the next screening round. In conclusion, self-sampling showed high concordance with physician-taken sampling for hrHPV detection in a responder screening population and highly acceptable to women. Implementation of HPV-self-sampling for the responder population as a primary screening tool may be considered. PMID- 28579498 TI - Re-evaluating the effect of age on physical activity over the lifespan. AB - Advancements in accelerometer analytic and visualization techniques allow researchers to more precisely identify and compare critical periods of physical activity (PA) decline by age across the lifespan, and describe how daily PA patterns may vary across age groups. We used accelerometer data from the 2003 2006 cohorts of the National Health and Nutrition Examination Survey (NHANES) (n=12,529) to quantify total PA as well as PA by intensity across the lifespan using sex-stratified, age specific percentile curves constructed using generalized additive models. We additionally estimated minute-to-minute diurnal PA using smoothed bivariate surfaces. We found that from childhood to adolescence (ages 6-19) across sex, PA is sharply lower by age partially due to a later initiation of morning PA. Total PA levels, at age 19 are comparable to levels at age 60. Contrary to prior evidence, during young adulthood (ages 20-30) total and light intensity PA increases by age and then stabilizes during midlife (ages 31 59) partially due to an earlier initiation of morning PA. We additionally found that males compared to females have an earlier lowering in PA by age at midlife and lower total PA, higher sedentary behavior, and lower light intensity PA in older adulthood; these trends seem to be driven by lower PA in the afternoon compared to females. Our results suggest a re-evaluation of how emerging adulthood may affect PA levels and the importance of considering time of day and sex differences when developing PA interventions. PMID- 28579499 TI - Changes in cigarette prices, affordability, and brand-tier consumption after a tobacco tax increase in Thailand: Evidence from the Global Adult Tobacco Surveys, 2009 and 2011. AB - Despite the 2009 implementation of a tobacco tax increase in Thailand, smoking rates remained unchanged between 2009 and 2011. Prior evidence has linked cigarette tax increases to compensatory behaviours aimed at lowering the cost of smoking, such as switching to lower-priced cigarette brands. Using data from 2009 and 2011 Global Adult Tobacco Surveys in Thailand, we estimated unadjusted changes in cigarette prices paid, cigarette affordability, and consumption of cigarettes in three price categories classified as upper-, middle-, and lower priced brand tiers (or price tertiles). We used ordered logit regression to analyse the correlates of price-tier choice and to estimate the change in price tier consumption adjusted for demographic and region characteristics. Between 2009 and 2011, real cigarette prices increased, but the affordability of cigarettes remained unchanged overall. There was a significant reduction in the consumption of cigarette brands in the top price-tier overall, accompanied by increases in the consumption of brands in the bottom and middle price-tiers, depending on the region. Adjusted estimates from the logit models indicate that, on average, the proportion of smokers selecting brands from upper- and middle price-tiers decreased while consumption of lower price-tier brands increased during the study period. The estimated shifts in consumption from more expensive to less expensive cigarette brands and the overall lack of change in cigarette affordability in Thailand between 2009 and 2011 are both factors that may have contributed to the observed lack of change in smoking rates after the 2009 tax increase. PMID- 28579500 TI - Balance is key: Exploring the impact of daily self-reported physical activity and sedentary behaviours on the subjective health status of older adults. AB - Research has identified physical activity and sedentary behaviours as independent predictors of successful aging; however, few studies have explored interactions between these constructs in relation to older adult health. The present study utilized data from the General Social Survey (Cycle 24) to calculate proportion of time engaging in sedentary and physically active behaviours during waking hours, and examined its impact on self-rated health and physical health limitations (e.g., difficulty walking) in older adults (N=3557; >=65years). Results suggest this proportion has a significant impact on three health measures; as proportion of daily minutes becomes more physically active or less sedentary, the better one's health status tends to be. Specifically, the proportion was positively associated with self-rated general health (ORPoor Excellent=17.57; p<0.05) and self-rated mental health (ORPoor-Excellent=4.68; p<0.05). Reporting health limitations was less likely to occur with increases in the proportion (OR=0.30; p<0.05). These findings suggest the need for further examining daily time-balances between physical activity and sedentary behaviours in order to create a comprehensive health profile for older adults. PMID- 28579501 TI - The contribution of rising adiposity to the increasing prevalence of diabetes in the United States. AB - OBJECTIVE: We assessed the contribution of increasing adiposity to the rising prevalence of diabetes in the United States over the period 1988-2014. RESEARCH DESIGN AND METHODS: Data from NHANES III (1988-1994) and continuous waves (1999 2014) were pooled for the current study. Diabetes status was assessed using data on Hemoglobin A1c. We estimated a multivariable logistic regression model that predicted the odds of having diabetes as a function of age, sex, racial/ethnic group, educational attainment, and period of observation. At a second stage, we introduced measures of general and abdominal adiposity into the model. Changes in coefficients pertaining to period of observation between the first and second models were interpreted as indicating the extent to which adiposity can account for trends in the prevalence of diabetes. Sensitivity analyses were conducted to investigate how alternative definitions of adiposity and diabetes status would affect results. RESULTS: The predicted prevalence of diabetes rose by 2.59%/yr between 1988 and 2014 after adjusting for changes in population composition. Increasing adiposity explained 72% of the rise in diabetes. Results were consistent for men and women. CONCLUSIONS: Rising levels of adiposity explained the large majority of the rise in diabetes prevalence between 1988 and 2014. PMID- 28579502 TI - Sugary beverage taxation in South Africa: Household expenditure, demand system elasticities, and policy implications. AB - South Africa faces a severe and growing obesity epidemic. Obesity and its co morbidities raise public and private expenditures on healthcare. Sugary beverages are heavily consumed in South Africa and are linked to the onset of overweight and obesity. Excise taxation of sugary beverages has been proposed and adopted in other settings as a means to reduce harms from their consumption. A tax on the sugar content of non-alcoholic beverages has been proposed for implementation in South Africa, however, the public health effects and revenue raising potential of this measure hinges on estimates of the targeted beverages own- and cross-price elasticities. This study applies demand system methods by combining expenditure survey data and sub-national price data to provide the first estimates of price and expenditure elasticities for categories of soft drinks that would be subject to South Africa's proposed sugary beverage tax. The results suggest that demand for these products is sufficiently price-elastic such that a significant reduction in consumption may result from a tax. PMID- 28579503 TI - Effect of the good school toolkit on school staff mental health, sense of job satisfaction and perceptions of school climate: Secondary analysis of a cluster randomised trial. AB - The Good School Toolkit, a complex behavioural intervention delivered in Ugandan primary schools, has been shown to reduce school staff-perpetrated physical violence against students. We aimed to assess the effect of this intervention on staff members' mental health, sense of job satisfaction and perception of school climate. We analysed data from a cluster-randomised trial administered in 42 primary schools in Luwero district, Uganda. The trial was comprised of cross sectional baseline (June/July 2012) and endline (June/July 2014) surveys among staff and students. Twenty-one schools were randomly selected to receive the Toolkit, whilst 21 schools constituted a wait-listed control group. We generated composite measures to assess staff members' perceptions of the school climate and job satisfaction. The trial is registered at clinicaltrials.gov (NCT01678846). No schools dropped out of the study and all 591 staff members who completed the endline survey were included in the analysis. Staff in schools receiving the Toolkit had more positive perspectives of their school climate compared to staff in control schools (difference in mean scores 2.19, 95% Confidence Interval 0.92, 3.39). We did not find any significant differences for job satisfaction and mental health. In conclusion, interventions like the Good School Toolkit that reduce physical violence by school staff against students can improve staff perceptions of the school climate, and could help to build more positive working and learning environments in Ugandan schools. PMID- 28579504 TI - The Impact and Effectivity of an Inventory Survey for a Stroke Registry in Iwate Prefecture. AB - BACKGROUND: The accuracy of a stroke registration program in Iwate prefecture was greatly affected by cooperation from medical facilities and doctors in the field. The number of registered cases from noncore hospitals was less, but the accuracy of registration was unknown. This report presents the impact and effectivity of an inventory survey of the stroke registry. SUBJECTS AND METHODS: Details of subjects living in coastal and northern regions of Iwate Prefecture who developed a cerebrovascular attack between 2012 and 2014 were obtained from the Iwate Stroke Registry through an inventory survey. Annual incidence rate from core hospitals and noncore hospitals were compared. To evaluate factors registered from noncore hospitals, multivariate analyses were performed for sex, age, living area, type of stroke, and past history of cerebrovascular diseases. RESULTS: Annual crude incidence rate for 100,000 residual populations were 428.8 in men and 351.2 in women from core hospitals and 38.5 in men and 43.7 in women from noncore hospitals. Ratios of noncore hospitals against all the hospitals were 8.3% for men and 11.1% for women. Multivariate analyses for age, ischemic type of stroke, past history of cerebrovascular diseases, and living in areas without a core hospital were significant; however, sex was not a significant factor. CONCLUSION: The inventory survey of the stroke registry program in the Iwate prefecture was useful to prevent missing data of stroke cases from noncore hospitals, including patients who are elderly, with ischemic stroke onset, with a past history of stroke, or living in areas without core hospitals. PMID- 28579505 TI - Relationship between Post-Thrombolysis Blood Pressure and Outcome in Acute Ischemic Stroke Patients Undergoing Thrombolysis Therapy. AB - BACKGROUND: The management of blood pressure (BP) for acute ischemic stroke (AIS) patients undergoing thrombolysis is still under debate. The purpose of this study was (1) to explore the association between post-thrombolysis BP and functional outcome and (2) to examine whether post-thrombolysis BP can predict functional outcome in Chinese AIS patients undergoing thrombolysis therapy. METHODS: From December 2012 to November 2016, AIS patients undergoing thrombolysis were reviewed retrospectively in the Department of Neurology at Xuanwu Hospital. The BP levels were measured before and immediately after thrombolysis. Clinical outcomes, which comprised favorable outcome (modified Rankin Scale score 0-2) and unfavorable outcome (modified Rankin Scale score 3-6) at 3 months, were analyzed by logistic regression model. A receiver operating characteristic curve was used to evaluate the predictive value of post-thrombolysis BP. RESULTS: Patients with unfavorable outcome at 3 months had a higher post-thrombolysis systolic BP than those with favorable outcome (P = .015). Multivariate analysis showed that post thrombolysis systolic BP below 159.5 mm Hg was associated with favorable outcome. According to the receiver operating characteristic curve, post-thrombolysis systolic BP was a predictor of functional outcome with an area under the curve of .573 (95% confidence interval = .504-.642). CONCLUSIONS: Our study indicated that post-thrombolysis systolic BP is a predictor of functional outcome for Chinese AIS patients undergoing thrombolysis therapy. It is reasonable for AIS patients to keep post-thrombolysis systolic BP below 159.5 mm Hg to obtain a favorable outcome. PMID- 28579506 TI - Does Perturbation Training Prevent Falls after Discharge from Stroke Rehabilitation? A Prospective Cohort Study with Historical Control. AB - BACKGROUND: Individuals with stroke fall frequently, and no exercise intervention has been shown to prevent falls post stroke. Perturbation-based balance training (PBT), which involves practicing reactions to instability, shows promise for preventing falls in older adults and individuals with Parkinson's disease. This study aimed to determine if PBT during inpatient stroke rehabilitation can prevent falls after discharge into the community. METHODS: Individuals with subacute stroke completed PBT as part of routine inpatient rehabilitation (n = 31). Participants reported falls experienced in daily life for up to 6 months post discharge. Fall rates were compared to a matched historical control group (HIS) who did not complete PBT during inpatient rehabilitation. RESULTS: Five of 31 PBT participants, compared to 15 of 31 HIS participants, reported at least 1 fall. PBT participants reported 10 falls (.84 falls per person per year) whereas HIS participants reported 31 falls (2.0 falls per person per year). When controlled for follow-up duration and motor impairment, fall rates were lower in the PBT group than the HIS group (rate ratio: .36 [.15, .79]; P = .016). CONCLUSIONS: These findings suggest that PBT is promising for reducing falls post stroke. While this was not a randomized controlled trial, this study may provide sufficient evidence for implementing PBT in stroke rehabilitation practice. PMID- 28579507 TI - A Case of Ruptured Vertebrobasilar Junction Aneurysm Associated with Subclavian Steal Phenomenon. AB - A 77-year-old woman with arteriovenous shunt for hemodialysis in the left forearm suffered from subarachnoid hemorrhage due to the rupture of a saccular aneurysm located on the left lateral wall of vertebrobasilar junction. Her left subclavian artery was severely stenosed and subclavian steal phenomenon was demonstrated on the digital subtraction angiography. Embolization of the parent artery including the aneurysm using detachable coils resulted in the successful obliteration of the aneurysm through the revascularized left subclavian artery. This is the first case in which the vertebrobasilar junction aneurysm would be caused by the hemodynamic stress due to the subclavian steal phenomenon combined with the shunt for hemodialysis in the left forearm. PMID- 28579508 TI - Decompressive Hemicraniectomy for Malignant Middle Cerebral Artery Stroke: South Asian Experience. AB - BACKGROUND: The randomized trials showed improved outcome and reduced mortality in malignant middle cerebral artery (MMCA) undergoing Decompressive hemicraniectomy (DHC) within 48 hours of stroke onset. Despite high prevalence of stroke, especially in younger individuals, high and short-term mortality from stroke in South Asian and Middle East, there is little published data on DHC in patients with MMCA stroke. METHODS: This is a retrospective, multicenter cross sectional study to measure outcome following DHC using the modified Rankin Scale (mRS) and dichotomized as favorable (mRS <= 4) or unfavorable (mRS > 4), at 3 months. RESULTS: In total, 137 patients underwent DHC. At 90 days, mortality was 16.8%; 61.3% of patients survived with an mRS of 4 or less and 38.7% had an mRS greater than 4. Age (55 years), diabetes (P = .004), hypertension (P = .021), pupillary abnormality (P = .048), uncal herniation (P = .007), temporal lobe involvement (P = .016), additional infarction (MCA + anterior cerebral artery, posterior cerebral artery) (P = .001), and infarction growth rates (P = .025) were significantly higher in patients with unfavorable prognosis in univariate analysis. Multivariate analysis showed age, additional infarction, septum pellucidum deviation greater than 1 cm, and uncal herniation to be associated with a significantly poor prognosis. Time to surgery had no impact on outcome (P = .109). CONCLUSIONS: Similar to the results of the studies from the West, DHC Improves functional outcome in predominantly South Asian patients with MMCA Stroke. PMID- 28579509 TI - Real-Time Distal, Multifocal, Repeated Lenticulostriate Bleeding Points during Thrombectomy in a Patient with Acute Variable M1 Occlusion: A Case Report and a Literature Review. AB - BACKGROUND: Intracerebral hemorrhage can be classified as either primary or secondary to various conditions such as vascular anomalies or stroke. We present a case of real-time incident detected on digital subtraction angiography (DSA) during thrombectomy in a patient with acute variable M1 occlusion. MATERIALS AND METHODS: A comprehensive literature search of the PubMed and Scopus databases was conducted: this is the first real-time visualization using DSA of a basal ganglia hematoma formation secondary to distal multifocal bleeding points just before a thrombectomy in a patient with acute variable M1 occlusion. CONCLUSION: We suggest that the positions of the clot before and during the procedure be compared always. PMID- 28579510 TI - An Examination of Stroke Risk and Burden in South Asians. AB - BACKGROUND: South Asians (India, Pakistan, Sri Lanka, Bangladesh, Nepal, and Bhutan) are at a disproportionately higher risk of stroke and heart disease due to their cardiometabolic profile. Despite evidence for a strong association between diabetes and stroke, and growing stroke risk in this ethnic minority notwithstanding reports of higher stroke mortality irrespective of country of residence-the explanation for the excess risk of stroke remains unknown. METHODS: We have used extensive literature review, epidemiologic studies, morbidity and mortality records, and expert opinions to examine the burden of stroke among South Asians, and the risk factors identified thus far. RESULTS: We summarize existing evidence and indicate gaps in current knowledge of stroke epidemiology among South Asian natives and immigrants. CONCLUSIONS: This research focuses attention on a looming epidemic of stroke mainly due to modifiable risk factors, but also new determinants that might aggravate the effect of vascular risk factors in South Asians causing more disabling strokes and death. PMID- 28579511 TI - Streamlining Workflow for Endovascular Mechanical Thrombectomy: Lessons Learned from a Comprehensive Stroke Center. AB - BACKGROUND: Recently, 5 randomized controlled trials confirmed the superiority of endovascular mechanical thrombectomy (EMT) to intravenous thrombolysis in acute ischemic stroke with large-vessel occlusion. The implication is that our health systems would witness an increasing number of patients treated with EMT. However, in-hospital delays, leading to increased time to reperfusion, are associated with poor clinical outcomes. This review outlines the in-hospital workflow of the treatment of acute ischemic stroke at a comprehensive stroke center and the lessons learned in reduction of in-hospital delays. METHODS: The in-hospital workflow for acute ischemic stroke was described from prehospital notification to femoral arterial puncture in preparation for EMT. Systematic review of literature was also performed with PubMed. RESULTS: The implementation of workflow streamlining could result in reduction of in-hospital time delays for patients who were eligible for EMT. In particular, time-critical measures, including prehospital notification, the transfer of patients from door to computed tomography (CT) room, initiation of intravenous thrombolysis in the CT room, and the mobilization of neurointervention team in parallel with thrombolysis, all contributed to reduction in time delays. CONCLUSIONS: We have identified issues resulting in in-hospital time delays and have reported possible solutions to improve workflow efficiencies. We believe that these measures may help stroke centers initiate an EMT service for eligible patients. PMID- 28579512 TI - Homocysteine up-regulates endothelin type A receptor in vascular smooth muscle cells through Sirt1/ERK1/2 signaling pathway. AB - Sirtuin 1 (Sirt1) is a longevity gene that has protective effects in cardiovascular diseases (CVDs). The endothelin type A (ETA) receptor is involved in pathogenesis of CVDs. The extracellular signal related kinases 1 and 2 (ERK1/2) signaling pathway is involved in regulation of the ETA receptor induced by some CVD risk factors in vascular smooth muscle cells (VSMCs). Hyperhomocysteinemia (HHcy) is an independent risk factor for CVDs. The present study was designed to investigate the hypothesis that homocysteine up-regulates ETA receptor through the Sirt1/ERK1/2 signaling pathway. In vitro experiments were performed in the rat superior mesenteric artery. The rat superior mesenteric artery was cultured with or without homocysteine (Hcy) in the presence and absence of Resveratrol (Res, a Sirt1 agonist), SRT1720 (a specific Sirt1 agonist) or U0126 (an ERK1/2 signaling pathway inhibitor) in serum-free medium for 24h. In vivo, the rats received subcutaneous injections of Hcy in the presence of or absence of Res or U0126 for 3weeks. The contractile response to ET-1 was studied using a sensitive myograph. In addition, the level of protein expression was determined using western blotting. Hcy significantly increased the expression of ETA receptor and also increased the ETA receptor-mediated contractile response induced by ET-1 in vitro. These effects were inhibited by Res, SRT1720 and U0126 treatment. In addition, Hcy down-regulated the level of Sirt1, and up-regulated the level of phosphorylated ERK1/2, which was reversed upon Res or SRT1720 treatment. In vivo results showed that HHcy results in the up-regulation of ETA receptor expression, and elevated blood pressure in rats. However, Res and U0126 could block these effects, respectively. In conclusion, these results suggest that Hcy regulates ETA receptor expression via the Sirt1/ERK1/2 signaling pathway in VSMCs. PMID- 28579513 TI - MicroRNAs and altered metabolism of clear cell renal cell carcinoma: Potential role as aerobic glycolysis biomarkers. AB - BACKGROUND: Warburg Effect is a metabolic switch that occurs in most of cancer cells but its advantages are not fully understood. This switch is known to happen in renal cell carcinoma (RCC), which is the most common solid cancer of the adult kidney. RCC carcinogenesis is related to pVHL loss and Hypoxia Inducible Factor (HIF) activation, ultimately leading to the activation of several genes related to glycolysis. MicroRNAs (miRNAs) regulate gene expression at a post transcriptional level and are also deregulated in several cancers, including RCC. SCOPE OF REVIEW: This review focuses in the miRNAs that direct target enzymes involved in glycolysis and that are deregulated in several cancers. It also reviews the possible application of miRNAs in the improvement of clinical patients' management. MAJOR CONCLUSIONS: Several miRNAs that direct target enzymes involved in glycolysis are downregulated in cancer, strongly influencing the Warburg Effect. Due to this strong influence, FDG-PET can possibly benefit from measurement of these miRNAs. Restoring their levels can also bring an improvement to the current therapies. GENERAL SIGNIFICANCE: Despite being known for almost a hundred years, the Warburg Effect is not fully understood. MiRNAs are now known to be intrinsically connected with this effect and present an opportunity to understand it. They also open a new door to improve current diagnosis and prognosis tests as well as to complement current therapies. This is urgent for cancers like RCC, mostly due to the lack of an efficient screening test for early relapse detection and follow-up and the development of resistance to current therapies. PMID- 28579514 TI - Recognition of long-range enhancer-promoter interactions by adding genomic signatures of segmented regulatory regions. AB - Enhancer-promoter interaction (EPI) is an important cis-regulatory mechanism in the regulation of tissue-specific gene expression. However, it still has limitation to precisely identity these interactions so far. In this paper, using diverse genomic features for various regulatory regions, we presented a computational approach to predict EPIs with improved accuracies. Meanwhile, we comprehensively studied more potential regulatory factors that are important to EPIs prediction, such as nucleosome occupancy, enhancer RNA; and found the cell line-specificity and region-specificity of the contributions of diverse regulatory signatures. By adding genomic signatures of segmented regulatory regions, our best accuracies of cross-validation test were about 11%-16% higher than the previous results, indicating the location-specificity of genomic signatures in a regulatory region for predicting EPIs. Additionally, more training samples and related features can provide reliable performances in new cell lines. Consequently, our study provided additional insights into the roles of diverse signature features for predicting long-range EPIs. PMID- 28579515 TI - ChromBiSim: Interactive chromatin biclustering using a simple approach. AB - : Combinatorial patterns of histone modifications sketch the epigenomic locale. Specific positions of these modifications in the genome are marked by the presence of such signals. Various methods highlight such patterns on global scale hence missing the local patterns which are the actual hidden combinatorics. We present ChromBiSim, an interactive tool for mining subsets of modifications from epigenomic profiles. ChromBiSim efficiently extracts biclusters with their genomic locations. It is the very first user interface based and multiple cell type handling tool for decoding the interplay of subsets of histone modifications combinations along their genomic locations. It displays the results in the forms of charts and heat maps in accordance with saving them in files which could be used for post analysis. ChromBiSim tested on multiple cell types produced in total 803 combinatorial patterns. It could be used to highlight variations among diseased versus normal cell types of any species. AVAILABILITY: ChromBiSim is available at (http://sourceforge.net/projects/chrombisim) in C-sharp and python languages. PMID- 28579516 TI - A model of differentiation in quantum bioinformatics. AB - Differentiation is a universal process found in various phenomena of nature. As seen in the example of cell differentiation, the creation diversity on individual's character is caused by environmental interactions. In this paper, we try to explain its mechanism, which has been discussed mainly in Biology, by using the formalism of quantum physics. Our approach known as quantum bioinformatics shows that the temporal change of statistical state called decoherence fits to describe non-local phenomena like differentiation. PMID- 28579517 TI - Early regional wall distension is strongly associated with vulnerability to ventricular fibrillation but not arrhythmia triggers following coronary occlusion in vivo. AB - Wall stress may favor ischemic ventricular arrhythmias, yet its association with ventricular fibrillation (VF) or ventricular ectopy has been inconsistent among studies and its potential arrhythmogenicity across the cardiac cycle is unclear. In 91 open-chest pigs undergoing 40-50 min left anterior descending artery occlusion, we assessed the association between diastolic or systolic distension of the ischemic area and the incidence of ventricular premature beats (VPBs) and VF. End-diastolic segment length (EDL) and systolic bulging ([maximum systolic length-EDL] * 100/EDL) were measured by ultrasonic crystals. Fifteen minutes after occlusion, EDL increased to 112.7 +/- 5.6% of baseline (P < 0.001) and systolic bulging averaged 3.4 +/- 2.2%. Median VPB number was 52 (IQR, 16-110), 2 (0-7) in phase Ia and 49 (13-94) in phase Ib. VF occurred in 26 animals (28.6%), the first episode appearing 24 +/- 6 min after occlusion. EDL increase was associated with subsequent VF (115.9 +/- 5.7 and 111.4 +/- 5.1% in animals with and without VF, P < 0.001) and with the number of VF episodes (P = 0.001) but not with VPB number, overall (r = 0.028, P = 0.801) or in phases Ia or Ib. Systolic bulging was related neither to VF occurrence (3.2 +/- 2.2 and 3.5 +/- 2.2%, respectively, P = 0.561) nor to VBP number (r = 0.095, P = 0.397). EDL increase predicted VF after adjusting for ischemic area size and K+ levels (odds ratio for 1% increase: 1.17, 95%CI 1.06-1.29, P = 0.001). Thus, diastolic regional ventricular distension predicts VF occurrence after coronary occlusion whereas neither diastolic nor systolic distension is associated with ventricular ectopy, which suggests that distension favors VF by acting on the arrhythmic substrate but not on arrhythmia triggers. PMID- 28579518 TI - Cognitive impairment in agricultural workers and nearby residents exposed to pesticides in the Coquimbo Region of Chile. AB - Chronic exposure to organophosphate pesticides is a worldwide public health concern associated with several psychiatric disorders and dementia. Most existing studies on the effects of pesticides only evaluate agricultural workers. Therefore, this study sought to establish if individuals indirectly exposed to pesticides, such as residents in agricultural areas, also suffer cognitive impairments. Neuropsychological evaluations were carried out on three groups (n=102): agricultural workers directly exposed to pesticides (n=32), individuals living in agricultural areas indirectly (i.e. environmentally) exposed to pesticides (n=32), and an unexposed control group (n=38). The assessed cognitive processes included memory, executive functions, attention, language praxis, and visuoconstruction. The direct exposure group performed significantly lower in executive function, verbal fluency, and visual and auditory memory tests than the indirect exposure group, which, in turn, performed worse than the unexposed group. Even after adjusting for age, gender, and educational level, both exposure groups showed higher rates of cognitive deficit than control individuals. In conclusion, both direct and indirect chronic exposure to pesticides affects cognitive functioning in adults and, consequently, actions should be taken to protect the health of not only agricultural workers, but also of residents in agricultural areas. PMID- 28579519 TI - Contributions of polygenic risk for obesity to PTSD-related metabolic syndrome and cortical thickness. AB - BACKGROUND: Research suggests that posttraumatic stress disorder (PTSD) is associated with metabolic syndrome (MetS) and that PTSD-associated MetS is related to decreased cortical thickness. However, the role of genetic factors in these associations is unclear. This study evaluated contributions of polygenic obesity risk and PTSD to MetS and of MetS and polygenic obesity risk to cortical thickness. METHODS: 196 white, non-Hispanic veterans of the wars in Iraq and Afghanistan underwent clinical diagnostic interviews, physiological assessments, and genome-wide genotyping; 168 also completed magnetic resonance imaging scans. Polygenic risk scores (PRSs) for obesity were calculated from results of a prior genome-wide association study (Speliotes et al., 2010) and PTSD and MetS severity factor scores were obtained. RESULTS: Obesity PRS (beta=0.15, p=0.009) and PTSD (beta=0.17, p=0.005) predicted MetS and interacted such that the association between PTSD and MetS was stronger in individuals with greater polygenic obesity risk (beta=0.13, p=0.02). Whole-brain vertex-wise analyses suggested that obesity PRS interacted with MetS to predict decreased cortical thickness in left rostral middle frontal gyrus (beta=-0.40, p<0.001). CONCLUSIONS: Results suggest that PTSD, genetic variability, and MetS are related in a transactional fashion wherein obesity genetic risk increases stress-related metabolic pathology, and compounds the ill health effects of MetS on the brain. Genetic proclivity towards MetS should be considered in PTSD patients when prescribing psychotropic medications with adverse metabolic profiles. Results are consistent with a growing literature suggestive of PTSD-related accelerated aging. PMID- 28579521 TI - Evaluation of S100B blood level as a biomarker to avoid computed tomography in patients with mild head trauma under antithrombotic medication. AB - PURPOSE: The goal of this prospective study was to analyze the potential of S100B protein as a negative predictive marker for intracranial hemorrhage (ICH) after mild head trauma (MHT) in patient under antithrombotic medication. METHODS: Patients under antithrombotic medication who had MHT were consecutively included in this study. S100B blood levels were determined from samples drawn within 6hours after injury and were analyzed with the results of head CT performed within the 24hours after injury. Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of S100B levels for the detection of ICH, with a cut-off set at 0.105MUg/L, were calculated. RESULTS: A total of 308 patients (151 men and 157 women) with a mean age of 79.1+/-10.5years (SD) were included in the analysis. CT was positive for the presence of ICH in 33 patients (10.7%; 95% CI: 7.5-14.7%). In the study population, S100B showed a sensitivity of 84.8% (95%CI: 68.1-94.9%), a specificity of 30.2% (95% CI: 24.8 36.0%), a NPV of 94.3% (95% CI: 87.2-98.1%), and a PPV of 12.7% (95% CI: 8.6 17.9%) for the diagnosis of ICH. CONCLUSION: The results of this study suggest that a S100B serum level<0.105MUg/L has a high NPV for ICH after mild head trauma in patients under antithrombotic medication. PMID- 28579522 TI - Thermal ablation and immunomodulation: From preclinical experiments to clinical trials. AB - Accumulating evidence has shown that thermal ablation can induce spontaneous distant tumor regression, which is also known as abscopal effect. Abscopal effect might depend upon the activation of antitumor immune response. However, such responses induced by thermal ablation had been thought to be usually weak and that they rarely induce distant tumor regression. Recently, results of several preclinical and clinical studies have suggested that thermal ablation can induce therapeutically effective systemic antitumor immune response if appropriate immunomodulators are combined. To elucidate the mechanisms of these promising strategies, effects of thermal ablation on the immune system are overviewed. Furthermore, recent promising preclinical and clinical studies examining enhancement of systemic antitumor immune response by combining thermal ablation and immunomodulation are summarized. PMID- 28579523 TI - Efficacy of Spirulina platensis diet supplements on disease resistance and immune related gene expression in Cyprinus carpio L. exposed to herbicide atrazine. AB - The present study evaluated the immunotoxicological effects of the herbicide atrazine (ATZ) at sub-lethal concentrations and the potential ameliorative influence of Spirulina platensis (SP) over a sub-chronic exposure period on Cyprinus carpio L., also known as common carp. Common carp was sampled after a 40 days exposure to ATZ (428 MUg/L) and SP (1%), individually or in combination to assess the non-specific immune response, changes in mRNA expression of immune related genes [lysozyme (LYZ), immunoglobulin M (IgM), and complement component 3 (C3)] in the spleen, and inflammatory cytokines (interleukins IL-1beta and IL-10) in the head kidney using real-time PCR. Additionally, disease resistance to Aeromonas sobria was evaluated. The results revealed that ATZ exposure caused a significant decline in most of the hematological variables, lymphocyte viability, and lysozyme and bactericidal activity. Moreover, ATZ increased the susceptibility to disease, reflected by a significantly lower post-challenge survival rate of the carp. ATZ may induce dysregulated expression of immune related genes leading to downregulation of mRNA levels of IgM and LYZ in the spleen. However, expression of C3 remained unaffected. Of the cytokine-related genes examined, IL-1B was up-regulated in the head kidney. In contrast, the expression of IL-10 gene was down-regulated in the ATZ-exposed group. The SP supplementation resulted in a significant improvement in most indices; however, these values did not match with that of the controls. These results may conclude that ATZ affects both innate and adaptive immune responses through the negative transcriptional effect on genes involved in immunity and also due to the inflammation of the immune organs. In addition, dietary supplements with SP could be useful for modulation of the immunity in response to ATZ exposure, thereby presenting a promising feed additive for carps in aquaculture. PMID- 28579520 TI - Live imaging of the innate immune response in neonates reveals differential TLR2 dependent activation patterns in sterile inflammation and infection. AB - Activation of microglial cells in response to brain injury and/or immune stimuli is associated with a marked induction of Toll-like receptors (TLRs). While in adult brain, the contribution of individual TLRs, including TLR2, in pathophysiological cascades has been well established, their role and spatial and temporal induction patterns in immature brain are far less understood. To examine whether infectious stimuli and sterile inflammatory stimuli trigger distinct TLR2 mediated innate immune responses, we used three models in postnatal day 9 (P9) mice, a model of infection induced by systemic endotoxin injection and two models of sterile inflammation, intra-cortical IL-1beta injection and transient middle cerebral artery occlusion (tMCAO). We took advantage of a transgenic mouse model bearing the dual reporter system luciferase/GFP under transcriptional control of a murine TLR2 promoter (TLR2-luc-GFP) to visualize the TLR2 response in the living neonatal brain and then determined neuroinflammation, microglial activation and leukocyte infiltration. We show that in physiological postnatal brain development the in vivo TLR2-luc signal undergoes a marked ~30-fold decline and temporal-spatial changes during the second and third postnatal weeks. We then show that while endotoxin robustly induces the in vivo TLR2-luc signal in the living brain and increases levels of several inflammatory cytokines and chemokines, the in vivo TLR2-luc signal is reduced after both IL-1beta and tMCAO and the inflammatory response is muted. Immunofluorescence revealed that microglial cells are the predominant source of TLR2 production during postnatal brain development and in all three neonatal models studied. Flow cytometry revealed developmental changes in CD11b+/CD45+ and CD11b+/Ly6C+ cell populations, involvement of cells of the monocyte lineage, but lack of Ly6G+ neutrophils or CD3+ cells in acutely injured neonatal brains. Cumulatively, our results suggest distinct TLR2 induction patterns following PAMP and DAMP - mediated inflammation in immature brain. PMID- 28579524 TI - Characterization and expression analysis of grouper (Epinephelus coioides) co stimulatory molecules CD83 and CD80/86 post Cryptocaryon irritans infection. AB - Co-stimulatory molecules (CD83, CD80 and CD86), belong to immunoglobulin superfamily, are type I membrane glycoprotein, which express on antigen presenting cells and provide the second signal for the activation of T lymphocytes. In the present study, we cloned the grouper's CD83 (675 bp) and CD80/86 (876 bp). Homology analysis showed that both EcCD83 and EcCD80/86 shares the highest amino acid similarity (51% and 47%) for the overall sequence with puffer fish (Takifugu rubripes). Some conserved features and important functional residues in mammalian CD83, CD80 and CD86 were also identified from these molecules of teleosts including grouper, suggesting the function of both molecules may be conserved among vertebrates. In transfected HEK293T cells, both molecules localized on the membrane surface. Tissue distribution analysis showed both EcCD83 and EcCD80/86 mRNAs were mainly expressed in immune organs, and EcCD80/86 was extremely higher expressed in mucosal immune tissues including skin and gill than systematic immune organs, which indicates these co-stimulatory molecules may prime T cell activation in local mucosal tissues. In Cryptocaryon irritans infected groupers, the expression level of EcCD83 and EcCD80/86 were both seen significant up-regulation in the skin at most tested time points. PMID- 28579525 TI - Evolutionary conserved mechanisms pervade structure and transcriptional modulation of allograft inflammatory factor-1 from sea anemone Anemonia viridis. AB - Gene family encoding allograft inflammatory factor-1 (AIF-1) is well conserved among organisms; however, there is limited knowledge in lower organisms. In this study, the first AIF-1 homologue from cnidarians was identified and characterised in the sea anemone Anemonia viridis. The full-length cDNA of AvAIF-1 was of 913 bp with a 5' -untranslated region (UTR) of 148 bp, a 3'-UTR of 315 and an open reading frame (ORF) of 450 bp encoding a polypeptide with149 amino acid residues and predicted molecular weight of about 17 kDa. The predicted protein possesses evolutionary conserved EF hand Ca2+ binding motifs, post-transcriptional modification sites and a 3D structure which can be superimposed with human members of AIF-1 family. The AvAIF-1 transcript was constitutively expressed in all tested tissues of unchallenged sea anemone, suggesting that AvAIF-1 could serve as a general protective factor under normal physiological conditions. Moreover, we profiled the transcriptional activation of AvAIF-1 after challenges with different abiotic/biotic stresses showing induction by warming conditions, heavy metals exposure and immune stimulation. Thus, mechanisms associated to inflammation and immune challenges up-regulated AvAIF-1 mRNA levels. Our results suggest its involvement in the inflammatory processes and immune response of A. viridis. PMID- 28579526 TI - Overview of human genetic susceptibility to malaria: From parasitemia control to severe disease. AB - Malaria is a life-threatening blood disease caused by the protozoan Plasmodium. Infection may lead to several different patterns of symptoms in the host: asymptomatic state, uncomplicated disease or severe disease. Severe malaria occurs mostly in young children and is a major cause of death. Disease is thought to result from the sequestration of parasites in the small blood vessels of the brain and the deregulation of key immune system elements. The cellular and molecular regulatory mechanisms underlying the pathogenesis of disease are however not fully understood. What is known it is that the genetic determinants of the host play an important role in the severity of the disease and the outcome of infection. Here we review the most convincing results obtained through genetic epidemiology studies concerning the genetic control of malaria in human caused by Plasmodium falciparum infection. The identification of genes conferring susceptibility or resistance to malaria might improve diagnosis and treatment. PMID- 28579527 TI - Role of IL28B genotype in the liver stiffness increase in untreated patients with chronic hepatitis C. AB - The role of interleukin (IL)28B has been deepened in the treatment response to pegylated-interferon in patients affected by chronic hepatitis C (CHC). However, recently the IL28B genotypes were also related to hepatic fibrosis progression in untreated patients, using the liver biopsy. The aim of this prospective and longitudinal study was to assess the role of different IL28B genotypes in the liver stiffness progression in a cohort of untreated subjects affected by CHC. We included in this analysis all untreated patients affected by CHC and followed for at least 5years with the annual evaluation of liver stiffness using Fibroscan(r). All enrolled subjects were genotyped for rs8099917 and rs12979860 IL28B polymorphisms. In the study period, 266 patients were considered. After 5years we observed the following median stiffness increases: 6.7kPa [5.1-7.8] in TT/CC, 4.9kPa [4.1-5.0] in TT/TC, 3.4kPa [3.2-3.8] in TG/TC and 1.7kPa [1.2-1.9] in GG/TT. These values were statistically significant in all groups (p<0.001). In the multivariate analysis resulted as predictive factors of liver stiffness progression the following: IL28B TT/CC genotype (OR=4.571; 95%IC=2.381-12.994; p<0.001) and IL28B GG/TT genotype (OR=0.510; 95%IC=0.289-0.712; p=0.007). In this study we evidenced that IL28B genotypes were associated with a different level of liver stiffness increase after 5years and could be used to select the patients who should be treated with priority. PMID- 28579528 TI - Substance P enhances endogenous neurogenesis to improve functional recovery after spinal cord injury. AB - Endogenous neural stem cells (NSCs) are the most promising sources for replacing cells lost after spinal cord injury (SCI). We have previously shown that substance P (SP), a neuropeptide, improves functional recovery after SCI and increases the numbers of cells in lesion sites, but how this occurs is unclear. Here, we investigate whether SP regulates the neurogenesis of resident NSCs as well as exerting a beneficial effect on functional improvement. We found that SP (5nmol/kg) treatment markedly improved functional recovery and elicited robust activation of endogenous NSCs and boosted the number of EdU+ proliferating cells differentiating into neurons, but it reduced astroglial differentiation in the lesion sites. Consistently, treatment with SP (10nM) in vitro significantly increased the proliferation of NSCs via activating the Erk1/2 signaling pathway and promoted neuronal differentiation but not astroglial differentiation. These results suggest that SP may represent a potential therapeutic agent for SCI via enhancing endogenous neurogenesis. PMID- 28579529 TI - Genes directly regulated by NF-kappaB in human hepatocellular carcinoma HepG2. AB - It has been well-known that over activation of NF-kappaB has close relationship with hepatitis and hepatocellular carcinoma (HCC). However, the complete and exact underlying molecular pathways and mechanisms still remain not fully understood. By manipulating NF-kappaB activity with its recognized activator TNFalpha and using ChIP-seq and RNA-seq techniques, this study identified 699 NF kappaB direct target genes (DTGs) in a widely used HCC cell line, HepG2, including 399 activated and 300 repressed genes. In these NF-kappaB DTGs, 216 genes (126 activated and 90 repressed genes) are among the current HCC gene signature. In comparison with NF-kappaB target genes identified in LPS-induced THP-1 and TNFalpha-induced HeLa cells, only limited numbers (24-46) of genes were shared by the two cell lines, indicating the HCC specificity of identified genes. Functional annotation revealed that NF-kappaB DTGs in HepG2 cell are mainly related with many typical NF-kappaB-related biological processes including immune system process, response to stress, response to stimulus, defense response, and cell death, and signaling pathways of MAPK, TNF, TGF-beta, Chemokine, NF-kappa B, and Toll-like receptor. Some NF-kappaB DTGs are also involved in Hepatitis C and B pathways. It was found that 82 NF-kappaB DTGs code secretory proteins, which include CCL2 and DKK1 that have already been used as HCC markers. Finally, the NF kappaB DTGs were further confirmed by detecting the NF-kappaB binding and expression of 14 genes with ChIP-PCR and RT-PCR. This study thus provides a useful NF-kappaB DTG list for future studies of NF-kappaB-related molecular mechanisms and theranostic biomarkers of HCC. PMID- 28579531 TI - Automated extraction of potential migraine biomarkers using a semantic graph. AB - PROBLEM: Biomedical literature and databases contain important clues for the identification of potential disease biomarkers. However, searching these enormous knowledge reservoirs and integrating findings across heterogeneous sources is costly and difficult. Here we demonstrate how semantically integrated knowledge, extracted from biomedical literature and structured databases, can be used to automatically identify potential migraine biomarkers. METHOD: We used a knowledge graph containing more than 3.5 million biomedical concepts and 68.4 million relationships. Biochemical compound concepts were filtered and ranked by their potential as biomarkers based on their connections to a subgraph of migraine related concepts. The ranked results were evaluated against the results of a systematic literature review that was performed manually by migraine researchers. Weight points were assigned to these reference compounds to indicate their relative importance. RESULTS: Ranked results automatically generated by the knowledge graph were highly consistent with results from the manual literature review. Out of 222 reference compounds, 163 (73%) ranked in the top 2000, with 547 out of the 644 (85%) weight points assigned to the reference compounds. For reference compounds that were not in the top of the list, an extensive error analysis has been performed. When evaluating the overall performance, we obtained a ROC-AUC of 0.974. DISCUSSION: Semantic knowledge graphs composed of information integrated from multiple and varying sources can assist researchers in identifying potential disease biomarkers. PMID- 28579530 TI - Late onset nonsyndromic hearing loss in a Dongxiang Chinese family is associated with the 593T>C variant in the mitochondrial tRNAPhe gene. AB - We report here the clinical, genetic, molecular and biochemical characterization of a four-generation Dongxiang Chinese pedigree with suggestively maternally transmitted non-syndromic hearing loss. Five of 10 matrilineal relatives exhibited variable severity and age at onset of sensorineural hearing loss. The average ages at onset of hearing loss in matrilineal relatives of this family were 29years. Molecular analysis of their mitochondrial genomes identified the tRNAPhe 593T>C variant belonging to Asian haplogroup G2a2a. The m.593T>C variant resided at the position 17 of DHU-loop, where the position is important for the structure and function of tRNA. It was anticipated that the m.593T>C variant altered the structure and function of tRNAPhe. By using lymphoblastoid cell lines derived from the Chinese family, we showed a 46% decreases in the steady-state level of tRNAPhe in mutant cell lines. Western blotting analysis showed ~35% reduction in the levels of mitochondrial translation in mutant cell lines carrying the m.593T>C variant. Impaired mitochondrial translation is apparently a primary contributor to the marked reduction in the rate of respiratory capacity. The respiratory deficiency lowed mitochondrial ATP production in the mutant cell lines. These data provide the evidence that mitochondrial dysfunctions caused by the m.593T>C variant lead to late-onset nonsyndromic hearing loss. Thus, our findings may provide the new insights into the understanding of pathophysiology and valuable information for management and treatment of maternally inherited hearing loss. PMID- 28579532 TI - Dashboard visualizations: Supporting real-time throughput decision-making. AB - Providing timely and effective care in the emergency department (ED) requires the management of individual patients as well as the flow and demands of the entire department. Strategic changes to work processes, such as adding a flow coordination nurse or a physician in triage, have demonstrated improvements in throughput times. However, such global strategic changes do not address the real time, often opportunistic workflow decisions of individual clinicians in the ED. We believe that real-time representation of the status of the entire emergency department and each patient within it through information visualizations will better support clinical decision-making in-the-moment and provide for rapid intervention to improve ED flow. This notion is based on previous work where we found that clinicians' workflow decisions were often based on an in-the-moment local perspective, rather than a global perspective. Here, we discuss the challenges of designing and implementing visualizations for ED through a discussion of the development of our prototype Throughput Dashboard and the potential it holds for supporting real-time decision-making. PMID- 28579533 TI - De-identification of clinical notes via recurrent neural network and conditional random field. AB - De-identification, identifying information from data, such as protected health information (PHI) present in clinical data, is a critical step to enable data to be shared or published. The 2016 Centers of Excellence in Genomic Science (CEGS) Neuropsychiatric Genome-scale and RDOC Individualized Domains (N-GRID) clinical natural language processing (NLP) challenge contains a de-identification track in de-identifying electronic medical records (EMRs) (i.e., track 1). The challenge organizers provide 1000 annotated mental health records for this track, 600 out of which are used as a training set and 400 as a test set. We develop a hybrid system for the de-identification task on the training set. Firstly, four individual subsystems, that is, a subsystem based on bidirectional LSTM (long short term memory, a variant of recurrent neural network), a subsystem-based on bidirectional LSTM with features, a subsystem based on conditional random field (CRF) and a rule-based subsystem, are used to identify PHI instances. Then, an ensemble learning-based classifiers is deployed to combine all PHI instances predicted by above three machine learning-based subsystems. Finally, the results of the ensemble learning-based classifier and the rule-based subsystem are merged together. Experiments conducted on the official test set show that our system achieves the highest micro F1-scores of 93.07%, 91.43% and 95.23% under the "token", "strict" and "binary token" criteria respectively, ranking first in the 2016 CEGS N-GRID NLP challenge. In addition, on the dataset of 2014 i2b2 NLP challenge, our system achieves the highest micro F1-scores of 96.98%, 95.11% and 98.28% under the "token", "strict" and "binary token" criteria respectively, outperforming other state-of-the-art systems. All these experiments prove the effectiveness of our proposed method. PMID- 28579534 TI - Molecular markers of oocyte differentiation in European eel during hormonally induced oogenesis. AB - Reproduction in captivity is a key study issue in Anguilla anguilla as a possible solution for its dwindling population. Understanding the mechanisms controlling the production of ribosomal building blocks during artificially induced oocyte maturation could be particularly interesting. Transcription levels of ribosomal biogenesis associated genes could be used as markers to monitor oogenesis. Eels from the Albufera Lagoon were injected with carp pituitary extract for 15weeks and ovaries in previtellogenic (PV) stage (non-injected), in early-, mid-, late vitellogenesis (EV, MV, LV), as well as in migratory nucleus stage (MN) were analysed. 5S rRNA and related genes were highly transcribed in ovaries with PV oocytes. As oocytes developed, transcriptional levels of genes related to 5S rRNA production (gtf3a), accumulation (gtf3a, 42sp43) and nucleocytoplasmic transport (rpl5, rpl11) and the 5S/18S rRNA index decreased (PV>EV>MV>LV>MN). On the contrary, 18S rRNA was at its highest at MN stage while ubtf1 in charge of activating RNA-polymerase I and synthesising 18S rRNA behaved as 5S related genes. Individuals that did not respond (NR) to the treatment showed 5S/18S index values similar to PV females, while studied genes showed EV/LV-like transcription levels. Therefore, NR females fail to express the largest rRNAs, which could thus be taken as markers of successful vitellogenesis progression. In conclusion, we have proved that the transcriptional dynamics of ribosomal genes provides useful tools to characterize induced ovarian development in European eels. In the future, such markers should be studied as putative indicators of response to hormonal treatments and of the quality of obtained eel oocytes. PMID- 28579535 TI - Distributional shift of urea production site from the extraembryonic yolk sac membrane to the embryonic liver during the development of cloudy catshark (Scyliorhinus torazame). AB - Urea is an essential osmolyte for marine cartilaginous fishes. Adult elasmobranchs and holocephalans are known to actively produce urea in the liver, muscle and other extrahepatic organs; however, osmoregulatory mechanisms in the developing cartilaginous fish embryo with an undeveloped urea-producing organ are poorly understood. We recently described the contribution of extraembryonic yolk sac membranes (YSM) to embryonic urea synthesis during the early developmental period of the oviparous holocephalan elephant fish (Callorhinchus milii). In the present study, to test whether urea production in the YSM is a general phenomenon among oviparous Chondrichthyes, we investigated gene expression and activities of ornithine urea cycle (OUC) enzymes together with urea concentrations in embryos of the elasmobranch cloudy catshark (Scyliorhinus torazame). The intracapsular fluid, in which the catshark embryo develops, had a similar osmolality to seawater, and embryos maintained a high concentration of urea at levels similar to that of adult plasma throughout development. Relative mRNA expressions and activities of catshark OUC enzymes were significantly higher in YSM than in embryos until stage 32. Concomitant with the development of the embryonic liver, the expression levels and activities of OUC enzymes were markedly increased in the embryo from stage 33, while those of the YSM decreased from stage 32. The present study provides further evidence that the YSM contributes to embryonic urea homeostasis until the liver and other extrahepatic organs become fully functional, and that urea-producing tissue shifts from the YSM to the embryonic liver in the late developmental period of oviparous marine cartilaginous fishes. PMID- 28579537 TI - Cullen's Sign: Not Always Acute Pancreatitis. PMID- 28579539 TI - Preparation of acellular scaffold for corneal tissue engineering by supercritical carbon dioxide extraction technology. AB - : In this study, we developed a novel method using supercritical carbon dioxide (SCCO2) to prepare acellular porcine cornea (APC). Under gentle extraction conditions using SCCO2 technology, hematoxylin and eosin staining showed that cells were completely lysed, and cell debris, including nuclei, was efficiently removed from the porcine cornea. The SCCO2-treated corneas exhibited intact stromal structures and appropriate mechanical properties. Moreover, no immunological reactions and neovascularization were observed after lamellar keratoplasty in rabbits. All transplanted grafts and animals survived without complications. The transplanted APCs were opaque after the operation but became transparent within 2weeks. Complete re-epithelialization of the transplanted APCs was observed within 4weeks. In conclusion, APCs produced by SCCO2 extraction technology could be an ideal and useful scaffold for corneal tissue engineering. STATEMENT OF SIGNIFICANCE: We decellularized the porcine cornea using SCCO2 extraction technology and investigated the characteristics, mechanical properties, and biocompatibility of the decellularized porcine cornea by lamellar keratoplasty in rabbits. To the best of our knowledge, this is the first report describing the use of SCCO2 extraction technology for preparation of acellular corneal scaffold. We proved that the cellular components of porcine corneas had been efficiently removed, and the biomechanical properties of the scaffold were well preserved by SCCO2 extraction technology. SCCO2-treated corneas maintained optical transparency and exhibited appropriate strength to withstand surgical procedures. In vivo, the transplanted corneas showed no evidence of immunological reactions and exhibited good biocompatibility and long-term stability. Our results suggested that the APCs developed by SCCO2 extraction technology could be an ideal and useful scaffold for corneal replacement and corneal tissue engineering. PMID- 28579536 TI - Effects of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children With Obesity. AB - BACKGROUND & AIMS: Consumption of sugar is associated with obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and cardiovascular disease. The conversion of fructose to fat in liver (de novo lipogenesis [DNL]) may be a modifiable pathogenetic pathway. We determined the effect of 9 days of isocaloric fructose restriction on DNL, liver fat, visceral fat (VAT), subcutaneous fat, and insulin kinetics in obese Latino and African American children with habitual high sugar consumption (fructose intake >50 g/d). METHODS: Children (9-18 years old; n = 41) had all meals provided for 9 days with the same energy and macronutrient composition as their standard diet, but with starch substituted for sugar, yielding a final fructose content of 4% of total kilocalories. Metabolic assessments were performed before and after fructose restriction. Liver fat, VAT, and subcutaneous fat were determined by magnetic resonance spectroscopy and imaging. The fractional DNL area under the curve value was measured using stable isotope tracers and gas chromatography/mass spectrometry. Insulin kinetics were calculated from oral glucose tolerance tests. Paired analyses compared change from day 0 to day 10 within each child. RESULTS: Compared with baseline, on day 10, liver fat decreased from a median of 7.2% (interquartile range [IQR], 2.5% 14.8%) to 3.8% (IQR, 1.7%-15.5%) (P < .001) and VAT decreased from 123 cm3 (IQR, 85-145 cm3) to 110 cm3 (IQR, 84-134 cm3) (P < .001). The DNL area under the curve decreased from 68% (IQR, 46%-83%) to 26% (IQR, 16%-37%) (P < .001). Insulin kinetics improved (P < .001). These changes occurred irrespective of baseline liver fat. CONCLUSIONS: Short-term (9 days) isocaloric fructose restriction decreased liver fat, VAT, and DNL, and improved insulin kinetics in children with obesity. These findings support efforts to reduce sugar consumption. ClinicalTrials.gov Number: NCT01200043. PMID- 28579538 TI - Late Recurrence of Barrett's Esophagus After Complete Eradication of Intestinal Metaplasia is Rare: Final Report From Ablation in Intestinal Metaplasia Containing Dysplasia Trial. AB - BACKGROUND & AIMS: The goal of treatment for Barrett's esophagus (BE) with dysplasia is complete eradication of intestinal metaplasia (CEIM). The long-term durability of CEIM has not been well characterized, so the frequency and duration of surveillance are unclear. We report results from a 5-year follow-up analysis of patients with BE and dysplasia treated by radiofrequency ablation (RFA) in the randomized controlled Ablation of Intestinal Metaplasia Containing Dysplasia (AIM) trial. METHODS: Participants for the AIM Dysplasia trial (18-80 years old) were recruited from 19 sites in the United States and had endoscopic evidence of non-nodular dysplastic BE <=8 cm in length. Subjects (n = 127) were randomly assigned (2:1 ratio) to receive either RFA (entire BE segment ablated circumferentially) or a sham endoscopic procedure; patients in the sham group were offered RFA treatment 1 year later, and all patients were followed for 5 years. We collected data on BE recurrence (defined as intestinal metaplasia in the tubular esophagus) and dysplastic BE recurrence among patients who achieved CEIM. We constructed Kaplan-Meier estimates and applied parametric survival analysis to examine proportions of patients without any recurrence and without dysplastic recurrence. RESULTS: Of 127 patients in the AIM Dysplasia trial, 119 received RFA and met inclusion criteria. Of those 119, 110 (92%) achieved CEIM. Over 401 person-years of follow-up (mean, 3.6 years per patient; range, 0.2-5.8 years), 35 of 110 (32%) patients had recurrence of BE or dysplasia, and 19 (17%) had dysplasia recurrence. The incidence rate of BE recurrence was 10.8 per 100 person-years overall (95% CI, 7.8-15.0); 8.3 per 100 person-years among patients with baseline low-grade dysplasia (95% CI, 4.9-14.0), and 13.5 per 100 person years among patients with baseline high-grade dysplasia (95% CI 8.8-20.7). The incidence rate of dysplasia recurrence was 5.2 per 100 person-years overall (95% CI 3.3-8.2); 3.3 per 100 person-years among patients with baseline low-grade dysplasia (95% CI 1.5-7.2), and 7.3 per 100 person-years among patients with baseline high-grade dysplasia (95% CI 4.2-12.5). Neither BE nor dysplasia recurred at a constant rate. There was a greater probability of recurrence in the first year following CEIM than in the following 4 years combined. CONCLUSIONS: In this analysis of prospective cohort data from the AIM Dysplasia trial, we found BE to recur after CEIM by RFA in almost one third of patients with baseline dysplastic disease; most recurrences occurred during the first year after CEIM. However, patients who achieved CEIM and remained BE free at 1 year after RFA had a low risk of BE recurrence. Studies are needed to determine when surveillance can be decreased or discontinued; our study did not identify any BE or dysplasia recurrence after 4 years of surveillance. PMID- 28579541 TI - Nanostructured raspberry-like gelatin microspheres for local delivery of multiple biomolecules. AB - : Multicompartment particles, which are particles composed of smaller building units, have gained considerable interest during the past decade to facilitate simultaneous and differential delivery of several biomolecules in various applications. Supercritical carbon dioxide (CO2) processing is an industrial technology widely used for large-scale synthesis and processing of materials. However, the application of this technology for production of multicompartment particles from colloidal particles has not yet been explored. Here, we report the formation of raspberry-like gelatin (RLG) microparticles composed of gelatin nanoparticles as colloidal building blocks through supercritical CO2 processing. We show that these RLG microparticles exhibit a high stability upon dispersion in aqueous media without requiring chemical cross-linking. We further demonstrate that these microparticles are cytocompatible and facilitate differential release of two different model compounds. The strategy presented here can be utilized as a cost-effective route for production of various types of multicompartment particles using colloidal particles with suitable interparticle interactions. STATEMENT OF SIGNIFICANCE: Multicompartment particles have gained considerable interest during the past decade to facilitate simultaneous and differential delivery of multiple biomolecules in various biomedical applications. Nevertheless, common methods employed for the production of such particles are often complex and only offer small-scale production. Here, we report the formation of raspberry-like gelatin (RLG) microparticles composed of gelatin nanoparticles as colloidal building blocks through supercritical CO2 processing. We show that these microparticles are cytocompatible and facilitate differential release of two model compounds with different molecular sizes, promising successful applications in various biomedical areas. Summarizing, this paper presents a novel strategy that can be utilized as a cost-effective route for production of various types of multicompartment particles using a wide range of colloidal building blocks. PMID- 28579540 TI - A multi-defense strategy: Enhancing bactericidal activity of a medical grade polymer with a nitric oxide donor and surface-immobilized quaternary ammonium compound. AB - : Although the use of biomedical devices in hospital-based care is inevitable, unfortunately, it is also one of the leading causes of the nosocomial infections, and thus demands development of novel antimicrobial materials for medical device fabrication. In the current study, a multi-defense mechanism against Gram positive and Gram-negative bacteria is demonstrated by combining a nitric oxide (NO) releasing agent with a quaternary ammonium antimicrobial that can be covalently grafted to medical devices. Antibacterial polymeric composites were fabricated by incorporating an NO donor, S-nitroso-N-acetyl-penicillamine (SNAP) in CarboSil(r) polymer and top coated with surface immobilized benzophenone based quaternary ammonium antimicrobial (BPAM) small molecule. The results suggest that SNAP and BPAM individually have a different degree of toxicity towards Gram positive and Gram-negative bacteria, while the SNAP-BPAM combination is effective in reducing both types of adhered viable bacteria equally well. SNAP-BPAM combinations reduced the adhered viable Pseudomonas aeruginosa by 99.0% and Staphylococcus aureus by 99.98% as compared to the control CarboSil films. Agar diffusion tests demonstrate that the diffusive nature of NO kills bacteria beyond the direct point of contact which the non-leaching BPAM cannot achieve alone. This is important for potential application in biofilm eradication. The live-dead bacteria staining shows that the SNAP-BPAM combination has more attached dead bacteria (than live) as compared to the controls. The SNAP-BPAM films have increased hydrophilicity and higher NO flux as compared to the SNAP films useful for preventing blood protein and bacterial adhesion. Overall the combination of SNAP and BPAM imparts different attributes to the polymeric composite that can be used in the fabrication of antimicrobial surfaces for various medical device applications. STATEMENT OF SIGNIFICANCE: A significant increase in the biomedical device related infections (BDRIs), inability of the currently existing antimicrobial strategies to combat them and a proportional rise in the associated morbidity demands development of novel antimicrobial surfaces. Some of the major challenges associated with the currently used therapeutics are: antibiotic resistance and cytotoxicity. In the current study, engineered polymeric composites with multi-defense mechanism were fabricated to kill bacteria via both active and passive mode. This was done by incorporating a nitric oxide (NO) donor S-nitroso-N-acetypenicillamine (SNAP) in a medical grade polymer (CarboSil(r)) and a benzophenone based quaternary ammonium antimicrobial small molecule (BPAM) was surface immobilized as the top layer. The developed biomaterial was tested with Gram-positive and Gram-negative strains and was found to be effective against both the strains resulting in up to 99.98% reduction in viable bacterial count. This preventative strategy can be used to fabricate implantable biomedical devices (such as catheters, stents, extracorporeal circuits) to not only significantly limit biofilm formation but also to reduce the antibiotic dose which are usually given post infections. PMID- 28579543 TI - Exenatide-loaded microsphere/thermosensitive hydrogel long-acting delivery system with high drug bioactivity. AB - A series of mixed hydrogels of PLGA-PEG-PLGA and PCLA-PEG-PCLA were synthesized, and investigated in terms of their critical micelle concentration, stability and thermosensitive properties. Also, some mixed hydrogel was selected to prepare Depot-gel-in-Ms-in-Matrix-gel system for the treatment of type 2 diabetes mellitus. Briefly, Exenatide (EXT) loaded hydrogels was encapsulated in PLGA microspheres (Ms) and further encapsulated into blank hydrogel. The mechanism of Exenatide release involved drug diffusion, hydrogel diffusion, PLGA erosion and mixed hydrogel erosion. The results showed that EXT release in vitro was at a sustained rate for 46days, because it is controlled by the inner-deport-gel, the Ms matrix and the outer-Matrix-gel successively. No burst release or platform was observed due to the interception function and control function of the outer Matrix-gel. The biological activity of EXT was protected, because the hydrophilic EXT molecules tend to distribute in the hydrophilic domain of the mixed hydrogel. In vivo, a single injection of Depot-gel-in-Ms-in-Matrix-gel allowed mice to maintain a stable blood glucose concentration and well-controlled body weight for 20days. In addition, results of oral glucose tolerance test and Hematoxylin-Eosin staining demonstrated that triple-barrier Depot-gel-in-Ms-in-Matrix-gel was a promising hydrophilic protein/polypeptide-loaded long-acting system with high drug bioactivity. PMID- 28579542 TI - Modeling in the quality by design environment: Regulatory requirements and recommendations for design space and control strategy appointment. AB - Mathematical models can be used as an integral part of the quality by design (QbD) concept throughout the product lifecycle for variety of purposes, including appointment of the design space and control strategy, continual improvement and risk assessment. Examples of different mathematical modeling techniques (mechanistic, empirical and hybrid) in the pharmaceutical development and process monitoring or control are provided in the presented review. In the QbD context, mathematical models are predominantly used to support design space and/or control strategies. Considering their impact to the final product quality, models can be divided into the following categories: high, medium and low impact models. Although there are regulatory guidelines on the topic of modeling applications, review of QbD-based submission containing modeling elements revealed concerns regarding the scale-dependency of design spaces and verification of models predictions at commercial scale of manufacturing, especially regarding real-time release (RTR) models. Authors provide critical overview on the good modeling practices and introduce concepts of multiple-unit, adaptive and dynamic design space, multivariate specifications and methods for process uncertainty analysis. RTR specification with mathematical model and different approaches to multivariate statistical process control supporting process analytical technologies are also presented. PMID- 28579544 TI - Could clinical photochemical internalisation be optimised to avoid neuronal toxicity? AB - Photochemical Internalisation (PCI) is a novel drug delivery technology in which low dose photodynamic therapy (PDT) can selectively rupture endo/lysosomes by light activation of membrane-incorporated photosensitisers, facilitating intracellular drug release in the treatment of cancer. For PCI to be developed further, it is important to understand whether nerve damage is an impending side effect when treating cancers within or adjacent to nervous system tissue. Dorsal root ganglion (DRG) neurons and their associated satellite glia were subjected to PCI treatment in a 3D co-culture system following incubation with photosensitisers: meso-tetraphenylporphine (TPPS2a) or tetraphenylchlorin disulfonate (TPCS2a) and Bleomycin. Results from the use of 3D co-culture models demonstrate that a cancer cell line PCI30 and satellite glia were more sensitive to PCI than neurons and mixed glial cells, athough neurite length was affected. Neurons in culture survived PCI treatment under conditions sufficient to kill tumour cells, suggesting cancers within or adjacent to nervous system tissue could be treated with this novel technology. PMID- 28579545 TI - Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. AB - Reactive oxygen species (ROS) are reactive intermediates of molecular oxygen that act as important second messengers within the cells; however, an imbalance between generation of reactive ROS and antioxidant defense systems represents the primary cause of endothelial dysfunction, leading to vascular damage in both metabolic and atherosclerotic diseases. Endothelial activation is the first alteration observed, and is characterized by an abnormal pro-inflammatory and pro thrombotic phenotype of the endothelial cells lining the lumen of blood vessels. This ultimately leads to reduced nitric oxide (NO) bioavailability, impairment of the vascular tone and other endothelial phenotypic changes collectively termed endothelial dysfunction(s). This review will focus on the main mechanisms involved in the onset of endothelial dysfunction, with particular focus on inflammation and aberrant ROS production and on their relationship with classical and non-classical cardiovascular risk factors, such as hypertension, metabolic disorders, and aging. Furthermore, new mediators of vascular damage, such as microRNAs, will be discussed. Understanding mechanisms underlying the development of endothelial dysfunction is an important base of knowledge to prevent vascular damage in metabolic and cardiovascular diseases. PMID- 28579546 TI - Mono(2-ethylhexyl) phthalate induces autophagy-dependent apoptosis through lysosomal-mitochondrial axis in human endothelial cells. AB - Mono(2-ethylhexyl) phthalate (MEHP), the active metabolite of di(2-ethylhexyl) phthalate (DEHP), has been known to have adverse effects on the reproductive system, urologic systems, hepatic, developmental toxicities and carcinogenicity. However, the effect of MEHP on cardiovascular toxicity remains unclear. Therefore, we aimed to evaluate the cytotoxic effects of MEHP and the possible molecular mechanism. We found that treatment of EA.hy 926 cells with MEHP induced autophagy at earlier time (6 h) in this study. Lysosomal membrane permeabilization (LMP) occurred, after treatment with MEHP for 12 h, followed by the release of cathepsin B. Autophagy inhibitor 3-methyladenine (3MA) attenuated MEHP-induced LMP and the release of cathepsin B in EA.hy 926 cells. Additionally, MEHP induced collapse of mitochondrial transmembrane potential, which was evidenced by JC-1 staining. Addition of 3MA relieved MEHP-induced apoptosis as assessed by the expression of caspase 3 and TUNEL assay, indicating that MEHP induced apoptosis was autophagy-dependent. Cathepsin B inhibitor, CA-074 Me, suppressed MEHP-induced the mitochondria release of cytochrome c and apoptosis as well. In summary, our results suggest that MEHP induced autophagy-dependent apoptosis in EA.hy 926 cells through the lysosomal-mitochondrial axis. This study provides new mechanistic insights into MEHP-induced cardiovascular toxicity. PMID- 28579547 TI - Probabilistic assessment method of the non-monotonic dose-responses-Part I: Methodological approach. AB - More and more studies aim to characterize non-monotonic dose response curves (NMDRCs). The greatest difficulty is to assess the statistical plausibility of NMDRCs from previously conducted dose response studies. This difficulty is linked to the fact that these studies present (i) few doses tested, (ii) a low sample size per dose, and (iii) the absence of any raw data. In this study, we propose a new methodological approach to probabilistically characterize NMDRCs. The methodology is composed of three main steps: (i) sampling from summary data to cover all the possibilities that may be presented by the responses measured by dose and to obtain a new raw database, (ii) statistical analysis of each sampled dose-response curve to characterize the slopes and their signs, and (iii) characterization of these dose-response curves according to the variation of the sign in the slope. This method allows characterizing all types of dose-response curves and can be applied both to continuous data and to discrete data. The aim of this study is to present the general principle of this probabilistic method which allows to assess the non-monotonic dose responses curves, and to present some results. PMID- 28579548 TI - Syndecan-1: A Quantitative Marker for the Endotheliopathy of Trauma. AB - BACKGROUND: Endothelial glycocalyx breakdown elicits syndecan-1 shedding and endotheliopathy of trauma (EoT). We hypothesized that a cutoff syndecan-1 level can identify patients with endothelial dysfunction who would have poorer outcomes. STUDY DESIGN: We conducted a prospective observational study. Trauma patients with the highest level of activation admitted from July 2011 through September 2013 were eligible. We recorded demographics, injury type/severity (Injury Severity Score), physiology and outcomes data, and quantified syndecan-1 and soluble thrombomodulin from plasma with ELISAs. With receiver operating characteristic curve analysis, we defined EoT+ as the syndecan-1 cutoff level that maximized the sum of sensitivity and specificity (Youden index) in predicting 24-hour in-hospital mortality. We stratified by this cutoff and compared both groups. Factors associated with 30-day in-hospital mortality were assessed with multivariable logistic regression (adjusted odds ratios and 95% CIs reported). RESULTS: From receiver operating characteristic curve analysis (area under the curve = 0.71; 95% CI 0.58 to 0.84), we defined EoT+ as syndecan-1 level >=40 ng/mL (sensitivity = 0.62, specificity = 0.73). Of the 410 patients evaluated, 34% (n = 138) were EoT+ patients, who presented with higher Injury Severity Scores (p < 0.001) and blunt trauma frequency (p = 0.016) than EoT- patients. Although EoT+ patients had lower systolic blood pressure (median 119 vs 128 mmHg; p < 0.001), base excess and hemoglobin were similar between groups. The proportion of transfused (EoT+ 71.7% vs EoT- 36.4%; p < 0.001) and deceased EoT+ patients (EoT+ 24.6% vs EoT- 12.1%; p < 0.001) was higher. EoT+ was significantly associated with 30-day in-hospital mortality (adjusted odds ratio = 2.23; 95% CI 1.22 to 4.04). CONCLUSIONS: A syndecan-1 level >=40 ng/mL identified patients with significantly worse outcomes, despite admission physiology similar to those without the condition. PMID- 28579549 TI - The use of microperimetry in assessing visual function in age-related macular degeneration. AB - Microperimetry is a novel technique for assessing visual function that appears particularly suitable for age-related macular degeneration (AMD). Compared with standard automated perimetry, microperimetry offers several unique features. It simultaneously images the fundus, incorporates an eye-tracking system to correct the stimulus location for fixation loss, and identifies any preferred retinal loci. We identified 52 articles that met the inclusion criteria for a systematic review of microperimetry in the assessment of visual function in AMD. We discuss microperimetry and AMD in relation to disease severity, structural imaging outcomes, other measures of visual function, and evaluation of the efficacy of surgical and/or medical therapies in clinical trials. The evidence for the use of microperimetry in the functional assessment of AMD is encouraging. Disruptions of the ellipsoid zone band and retinal pigment epithelium are clearly associated with reduced differential light sensitivity despite the maintenance of good visual acuity. Reduced differential light sensitivity is also associated with outer segment thinning and retinal pigment epithelium thickening in early AMD and with both a thickening and a thinning of the whole retina in choroidal neovascularization. Microperimetry, however, lacks the robust diffuse and focal loss age-corrected probability analyses associated with standard automated perimetry, and the technique is currently limited by this omission. PMID- 28579550 TI - The application of optical coherence tomography angiography in retinal diseases. AB - Optical coherence tomography angiography (OCTA) is a new, noninvasive imaging technique that generates real-time volumetric data on chorioretinal vasculature and its flow pattern. With the advent of high-speed optical coherence tomography, established enface chorioretinal segmentation, and efficient algorithms, OCTA generates images that resemble an angiogram. The principle of OCTA involves determining the change in backscattering between consecutive B-scans and then attributing the differences to the flow of erythrocytes through retinal blood vessels. OCTA has shown promise in the evaluation of common ophthalmologic diseases such as diabetic retinopathy, age-related macular degeneration, and retinal vascular occlusions. It quantifies vascular compromise reflecting the severity of diabetic retinopathy. OCTA detects the presence of choroidal neovascularization in exudative age-related macular degeneration and maps loss of choriocapillaris in nonexudative age-related macular degeneration. We describe principles of OCTA and findings in common and some uncommon retinal pathologies. Finally, we summarize its potential future applications. Its current limitations include a relatively small field of view, inability to show leakage, and a tendency for image artifacts. Further larger studies will define OCTAs utility in clinical settings and establish if the technology may offer its utility in decreasing morbidity through early detection and guide therapeutic interventions in retinal diseases. PMID- 28579551 TI - Antiproliferative activity against leukemia cells of sesquiterpene lactones from the Turkish endemic plant Centaurea drabifolia subsp. detonsa. AB - The apolar organic extract obtained from aerial parts of Centaurea drabifolia Sibth. & Sm. subsp. detonsa (Bornm.) Wagenitz, growing wild in Turkey, was investigated for the first time for its secondary metabolite composition. Seven sesquiterpene lactones belonging to the guaiane class (1-7), including the new compound 4, along with a fatty acid lactone derivative (8), were isolated. The structures of these compounds were established by spectroscopic analysis, including 2D NMR spectroscopic techniques, with the stereostructure of the new guaiane 4 determined with the help of MTPA derivatization. Cytotoxic activities of compounds 1-7 were evaluated against two cancer cell lines, namely acute lymphoblastic leukemia (CCRF-CEM) and its multidrug-resistant subline CEM/ADR5000. Results showed that aguerin B (1) and cynaropicrin (2) showed a potent activity on both cell lines revealing interesting details about the structure-activity relationships in the class of acylated guaiane sesquiterpenes. PMID- 28579552 TI - Sesquiterpene lactones with unusual structure. Their biogenesis and biological activity. AB - The given review provides data on the new sesquiterpene lactones with unusual structure isolated from various natural sources, e.g. fungi, plants, marine growth; about their spread, biological activity, and the presumed biogenetic pathway of their formation. An attempt was made to biologically justify a wide structural formation variety of new sesquiterpene lactones with the unique structure. PMID- 28579553 TI - New sesquiterpene acid and inositol derivatives from Inula montana L. AB - A phytochemical investigation of the ethanol extract of leaves and flowers of Inula montana L. led to the isolation of one new sesquiterpene acid called Eldarin (1) and four new inositol derivatives, Myoinositol,1,5-diangelate-4,6 diacetate (2), Myoinositol,1,6-diangelate-4,5-diacetate (3), Myoinositol-1 angelate-4,5-diacetate-6-(2-methylbutirate) (4), Myoinositol-1-angelate-4,5 diacetate-6-isovalerate (5) isolated for the first time, along with eleven known compounds described for the first time in Inula montana, 1beta-Hydroxyarbusculin A (6), Artemorin (7), Santamarin (8), Chrysosplenol C (9), 6-Hydroxykaempferol 3,7-dimethyl ether (10), Reynosin (11), Calenduladiol-3-palmitate (12), Costunolide (13), 4-Hydroxy-3,5-dimethoxybenzenemethanol (14), 9beta Hydroxycostunolide (15) and Hispidulin (16). Structural elucidation has been carried out by spectral methods, such as 1D and 2D NMR, IR, UV and HR-ESI-MS. These compounds have been tested in vitro for anti-inflammatory and cytotoxic activity on macrophages RAW 264.7. As a result, compounds 2, 3, 7, 13, 14, 15 and 16 showed a release of NO with IC50 value <30MUM on macrophages. PMID- 28579555 TI - Continuing medical education and sponsorship by the healthcare industry - new opportunities and challenges. PMID- 28579554 TI - STAT3 gain-of-function mutations associated with autoimmune lymphoproliferative syndrome like disease deregulate lymphocyte apoptosis and can be targeted by BH3 mimetic compounds. AB - Autoimmune lymphoproliferative syndrome (ALPS) is typically caused by mutations in genes of the extrinsic FAS mediated apoptotic pathway, but for about 30% of ALPS-like patients the genetic diagnosis is lacking. We analyzed 30 children with ALPS-like disease of unknown cause and identified two dominant gain-of-function mutations of the Signal Transducer And Activator Of Transcription 3 (STAT3, p.R278H, p.M394T) leading to increased transcriptional activity. Hyperactivity of STAT3, a known repressor of FAS, was associated with decreased FAS-mediated apoptosis, mimicking ALPS caused by FAS mutations. Expression of BCL2 family proteins, further targets of STAT3 and regulators of the intrinsic apoptotic pathway, was disturbed. Cells with hyperactive STAT3 were consequently more resistant to intrinsic apoptotic stimuli and STAT3 inhibition alleviated this effect. Importantly, STAT3-mutant cells were more sensitive to death induced by the BCL2-inhibitor ABT-737 indicating a dependence on anti-apoptotic BCL2 proteins and potential novel therapeutic options. PMID- 28579556 TI - Coronary physiological parameters at a crossroads. PMID- 28579558 TI - Inflammatory coronary ectasia identified by three-dimensional volume rendering of 18F-Fluorodeoxyglucose PET/CT. PMID- 28579557 TI - Intravenous beta-blockers in patients with ST-elevation myocardial infarction treated with primary PCI. PMID- 28579559 TI - How should I treat an unexpected deadlock at the time of transcatheter aortic valve prosthesis implantation? PMID- 28579561 TI - Normal values of offline exhaled and nasal nitric oxide in healthy children and teens using chemiluminescence. AB - : Nitric oxide (NO) can be used to detect respiratory or ciliary diseases. Fractional exhaled nitric oxide (FeNO) measurement can reflect ongoing eosinophilic airway inflammation and has a diagnostic utility as a test for asthma screening and follow-up while nasal nitric oxide (nNO) is a valuable screening tool for the diagnosis of primary ciliary dyskinesia. The possibility of collecting airway gas samples in an offline manner offers the advantage to extend these measures and improve the screening and management of these diseases, but normal values from healthy children and teens remain sparse. METHODS: Samples were consecutively collected using the offline method for eNO and nNO chemiluminescence measurement in 88 and 31 healthy children and teens, respectively. Offline eNO measurement was also performed in 30 consecutive children with naive asthma and/or respiratory allergy. RESULTS: The normal offline eNO value was determined by the following regression equation -8.206 + 0.176 * height. The upper limit of the norm for the offline eNO value was 27.4 parts per billion (ppb). A separate analysis was performed in children, pre-teens and teens, for which offline eNO was 13.6 +/- 4.7 ppb, 16.3 +/- 13.7 ppb and 20.0 +/- 7.2 ppb, respectively. The optimal cut-off value of the offline eNO to predict asthma or respiratory allergies was 23.3 ppb, with a sensitivity and specificity of 77% and 91%, respectively. Mean offline nNO was determined at 660 ppb with the lower limit of the norm at 197 ppb. CONCLUSION: The use of offline eNO and nNO normal values should favour the widespread screening of respiratory diseases in children of school age in their usual environment. PMID- 28579560 TI - Role of intratubular pressure during the ischemic phase in acute kidney injury. AB - Acute kidney injury (AKI) induced by clamping of renal vein or pedicle is more severe than clamping of artery, but the mechanism has not been clarified. In the present study, we tested our hypothesis that increased proximal tubular pressure (Pt) during the ischemic phase exacerbates kidney injury and promotes the development of AKI. We induced AKI by bilateral clamping of renal arteries, pedicles, or veins for 18 min at 37 degrees C, respectively. Pt during the ischemic phase was measured with micropuncture. We found that higher Pt was associated with more severe AKI. To determine the role of Pt during the ischemic phase on the development of AKI, we adjusted the Pt by altering renal artery pressure. We induced AKI by bilateral clamping of renal veins, and the Pt was changed by adjusting the renal artery pressure during the ischemic phase by constriction of aorta and mesenteric artery. When we decreased renal artery pressure from 85 +/- 5 to 65 +/- 8 mmHg, Pt decreased from 53.3 +/- 2.7 to 44.7 +/- 2.0 mmHg. Plasma creatinine decreased from 2.48 +/- 0.23 to 1.91 +/- 0.21 mg/dl at 24 h after renal ischemia. When we raised renal artery pressure to 103 +/- 7 mmHg, Pt increased to 67.2 +/- 5.1 mmHg. Plasma creatinine elevated to 3.17 +/- 0.14 mg.dl.24 h after renal ischemia. Changes in KIM-1, NGAL, and histology were in the similar pattern as plasma creatinine. In summary, we found that higher Pt during the ischemic phase promoted the development of AKI, while lower Pt protected from kidney injury. Pt may be a potential target for treatment of AKI. PMID- 28579562 TI - Crystal structure and electrostatic properties of prednisolone acetate studied using a transferred multipolar atom model. AB - Prednisolone acetate {systematic name: 2-[(8S,9S,10R,13S,14S,17R)-11,17-dihydroxy 10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate}, is an ophthalmic drug that belongs to the class of corticosteroids. Its crystal structure was refined using the classical independent atom model (IAM) and a transferred multipolar atom model using the ELMAM2 database. The results of both refinements have been compared. The ELMAM2 refinement was found to be superior in terms of the refinement statistics. It has been shown that certain electron-density-derived properties can be calculated on the basis of the transferred parameters for crystals which diffract to ordinary resolution. The procedure proves helpful in understanding the mode of action of the drug molecule. PMID- 28579563 TI - Synthesis and characterization of a photochromic magnesium(II) coordination polymer based on a naphthalene diimide ligand. AB - Naphthalene diimides, which are planar, chemically robust and redox-active, are an attractive class of electron-deficient dyes, which can undergo a single reversible one-electron reduction to form stable radical anions in the presence of electron donors upon irradiation. This makes them excellent candidates for organic linkers in the construction of photochromic coordination polymers. Such a photochromic one-dimensional linear coordination polymer has been prepared using N,N'-bis(3-carboxyphenyl)naphthalene-1,8:4,5-tetracarboximide (H2BBNDI). Crystallization of H2BBNDI with magnesium nitrate in an N,N'-dimethylformamide (DMF)/ethanol/H2O mixed-solvent system under solvothermal conditions afforded the one-dimensional coordination polymer catena-poly[[bis(dimethylformamide kappaO)magnesium(II)]-bis[MU-N-(3-carboxylatophenyl)-N'-(3 carboxylphenyl)naphthalene-1,8:4,5-tetracarboximide-kappa2O:O']], [Mg(C28H13N2O8)2(C3H7NO)2]n. The asymmetric unit contains half of a magnesium cation, one HBBNDI- ligand and one DMF molecule. Two partially deprotonated HBBNDI- ligands bridge two magnesium cations to form a one-dimensional chain. Strong inter-chain pi-pi interactions between the naphthalene rings of the HBBNDI ligand and the imide rings of adjacent chains provide a two-dimensional structure. The supramolecular three-dimensional framework is stabilized by pi-pi interactions between naphthalene rings of neighbouring two-dimensional supramolecular networks. The complex exhibits a reversible photochromic behaviour, which may originate from the photoinduced electron-transfer generation of radicals in the HBBNDI- ligand. PMID- 28579564 TI - The first-row transition-metal series of tris(ethylenediamine) diacetate complexes [M(en)3](OAc)2 (M is Mn, Fe, Co, Ni, Cu, and Zn). AB - The crystal structures of the first-row transition-metal series of tris(ethylenediamine-kappa2N,N')metal(II) diacetate, [M(C2H8N2)3](CH3CO2)2, with M = Mn, Fe, Co, Ni, Cu, and Zn, are reported. The complexes are all isostructural, crystallizing in a centrosymmetric triclinic cell and possessing an asymmetric unit composed of one [M(en)3]2+ cation and two symmetrically independent acetate anions. In the unit cell, the two complex cations are inversion-generated enantiomers, possessing the energetically favoured Delta(lambdalambdalambda) and Lambda(deltadeltadelta) configurations. The complex cations and acetate anions combine through a series of N-H...O hydrogen bonds to generate a three-dimensional network in the crystals. The other notable feature of the series is a significant Jahn-Teller distortion for the d9 Cu2+ complex. PMID- 28579565 TI - Diphenylalanine in tetrahydrofuran: a highly potent candidate for the development of novel nanomaterials. AB - The peptide di-L-phenylalanine (FF) has emerged as a highly potent candidate for the development of novel nanomaterials. The unprotected peptide was dissolved in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) mixed with tetrahydrofuran (THF) and single crystals of the THF monosolvate, C18H20N2O3.C4H8O, were grown by slow evaporation in a 'vial-in-closed-bottle' system. THF is a molecule that can only act as a hydrogen-bond acceptor. Thus, the hydrogen-bond patterns observed in the crystal structures at 100 and 299 K are different compared to that of crystals grown from water and methanol [Mason et al. (2014). ACS Nano. 8, 1243-1253]. PMID- 28579566 TI - A dihydro-beta-agarofuran sesquiterpene from Maytenus boaria. AB - The natural compound (1S,4S,5S,6R,7R,8R,9R,10S)-6-acetoxy-4,9,10-trihydroxy 2,2,5a,9-tetramethyloctahydro-2H-3,9a-methanobenzo[b]oxepin-5-yl furan-3 carboxylate, C22H30O9, (I), is a beta-agarofuran sesquiterpene isolated from the seeds of Maytenus boaria as part of a study of the secondary metabolites from Chilean flora. The compound presents a central structure formed by a decalin system esterified with acetate at site 1 and furan-3-carboxylate at site 9. The chirality of the skeleton can be described as 1S,4S,5S,6R,7R,8R,9R,10S, which is consistent with that suggested by NMR studies. Unlike previously reported structures of sesquiterpenes containing a pure dihydro-beta-agarofuran skeleton, (I) exhibits a three-dimensional hydrogen-bonded network. PMID- 28579567 TI - Optical properties of (Z)-2-(2-phenylhydrazinylidene)acenaphthen-1(2H)-one: a potential electron donor in organic solar cells. AB - Electron-donating molecules play an important role in the development of organic solar cells. (Z)-2-(2-Phenylhydrazinylidene)acenaphthen-1(2H)-one (PDAK), C18H12N2O, was synthesized by a Schiff base reaction. The crystal structure shows that the molecules are planar and are linked together forming 'face-to-face' assemblies held together by intermolecular C-H...O, pi-pi and C-H...pi interactions. PDAK exhibits a broadband UV-Vis absorption (200-648 nm) and a low HOMO-LUMO energy gap (1.91 eV; HOMO is the highest occupied molecular orbital and LUMO is the lowest unoccupied molecular orbital), while fluorescence quenching experiments provide evidence for electron transfer from the excited state of PDAK to C60. This suggests that the title molecule may be a suitable donor for use in organic solar cells. PMID- 28579568 TI - Synthesis and crystal structures of a 3-acetylated (20S,24S)-ocotillol-type saponin and its C-24 epimer. AB - In order to study the in vivo protective effect on myocardial ischemia, (20S,24R) epoxydammarane-12beta,25-diol, (V), and (20S,24S)-epoxydammarane-12beta,25-diol, (VI), were synthesized through a novel synthetic route. Two key intermediates, namely (20S,24R)-3-acetyl-20,24-epoxydammarane-3beta,12beta,25-triol, (III) [obtained as the hemihydrate, C32H54O5.0.5H2O, (IIIa), and the ethanol hemisolvate, C32H54O5.0.5C2H5OH, (IIIb), with identical conformations but different crystal packings], and (20S,24S)-3-acetyl-20,24-epoxydammarane 3beta,12beta,25-triol, C32H54O5, (IV), were obtained during the synthesis. The structures were confirmed by 1H NMR, 13C NMR and HRMS analyses, and single crystal X-ray diffraction. Molecules of (IIIa) are extended into a two dimensional network constructed with water molecules linked alternately through intermolecular O-H...O hydrogen bonds, which are further stacked into a three dimensional network. Compound (IIIb) contains two completely asymmetric molecules, which are linked in a disordered manner through intermolecular C-H...O hydrogen bonds. While the crystal stacks in compound (IV) are linked via weak C H...O hydrogen bonds, the hydrogen-bonded chains extend helically along the crystallographic b axis. PMID- 28579569 TI - A twofold interpenetrating three-dimensional heterometallic metal-organic framework with pcu topology based on 2-methylbiphenyl-4,4'-dicarboxylic acid. AB - The 2-methylbiphenyl-4,4'-dicarboxylate (mbpdc2-) ligand has versatile coordination modes and can be used to construct multinuclear structures. Despite this, reports of the synthesis of coordination complexes involving this ligand are scarce. The title compound, poly[[triaquadi-MU3-hydroxido-hexakis(MU4-2 methylbiphenyl-4,4'-dicarboxylato)calcium(II)hexazinc(II)] monohydrate], {[CaZn6(C15H10O4)6(OH)2(H2O)3].H2O}n, has been prepared by the hydrothermal assembly of Zn(NO3)2.6H2O, CaCl2 and 2-methylbiphenyl-4,4'-dicarboxylic acid. Two ZnII atoms adopt a four-coordinated distorted tetrahedral geometry by bonding to three O atoms from three different 2-methylbiphenyl-4,4'-dicarboxylate (mbpdc2-) dianionic ligands and one bridging hydroxide O atom. For the remaining ZnII atom, a five-coordinate environment is completed half the time by one carboxylate O atom, and then the same carboxylate O atom and an aqua O atom are present the other half of the time, giving a six-coordinate environment. The CaII atom is coordinated by six O atoms to give an octahedral coordination geometry. The supramolecular secondary building unit (SBU) is a hamburger-like heptanuclear unit (Zn6CaO30) and these units are interconnected through mbpdc2- carboxylate groups to generate a three-dimensional framework with the pcu topology. The single net leaves voids that are filled by mutual interpenetration of an independent equivalent framework in a twofold interpenetrating architecture. The title compound shows thermal stability up to 673 K. The excitation and luminescence data showed the emission of a bright-blue fluorescence. PMID- 28579570 TI - A charge-transfer salt composed of methyl viologen and hexacyanidoferrate(II). AB - The methyl viologen dication, used under the name Paraquat as an agricultural reagent, is a well-known electron-acceptor species that can participate in charge transfer (CT) interactions. The determination of the crystal structure of this species is important for accessing the CT interaction and CT-based properties. The title hydrated salt, bis(1,1'-dimethyl-4,4'-bipyridine-1,1'-diium) hexacyanidoferrate(II) octahydrate, (C12H14N2)2[Fe(CN)6].8H2O or (MV)2[Fe(CN)6].8H2O [MV2+ is the 1,1'-dimethyl-4,4'-bipyridine-1,1'-diium (methyl viologen) dication], crystallizes in the space group P21/c with one MV2+ cation, half of an [Fe(CN)6]4- anion and four water molecules in the asymmetric unit. The FeII atom of the [Fe(CN)6]4- anion lies on an inversion centre and has an octahedral coordination sphere defined by six cyanide ligands. The MV2+ cation is located on a general position and adopts a noncoplanar structure, with a dihedral angle of 40.32 (7) degrees between the planes of the pyridine rings. In the crystal, layers of electron-donor [Fe(CN)6]4- anions and layers of electron acceptor MV2+ cations are formed and are stacked in an alternating manner parallel to the direction of the -2a + c axis, resulting in an alternate layered structure. PMID- 28579571 TI - Supramolecular architectures in two 1:1 cocrystals of 5-fluorouracil with 5 bromothiophene-2-carboxylic acid and thiophene-2-carboxylic acid. AB - In solid-state engineering, cocrystallization is a strategy actively pursued for pharmaceuticals. Two 1:1 cocrystals of 5-fluorouracil (5FU; systematic name: 5 fluoro-1,3-dihydropyrimidine-2,4-dione), namely 5-fluorouracil-5-bromothiophene-2 carboxylic acid (1/1), C5H3BrO2S.C4H3FN2O2, (I), and 5-fluorouracil-thiophene-2 carboxylic acid (1/1), C4H3FN2O2.C5H4O2S, (II), have been synthesized and characterized by single-crystal X-ray diffraction studies. In both cocrystals, carboxylic acid molecules are linked through an acid-acid R22(8) homosynthon (O H...O) to form a carboxylic acid dimer and 5FU molecules are connected through two types of base pairs [homosynthon, R22(8) motif] via a pair of N-H...O hydrogen bonds. The crystal structures are further stabilized by C-H...O interactions in (II) and C-Br...O interactions in (I). In both crystal structures, pi-pi stacking and C-F...pi interactions are also observed. PMID- 28579572 TI - A new phosphorescent heteroleptic cuprous complex with a neutral 2-methylquinolin 8-ol ligand: synthesis, structure characterization, properties and TD-DFT calculations. AB - Luminescent CuI complexes have emerged as promising substitutes for phosphorescent emitters based on Ir, Pt and Os due to their abundance and low cost. The title heteroleptic cuprous complex, [9,9-dimethyl-4,5 bis(diphenylphosphanyl)-9H-xanthene-kappa2P,P](2-methylquinolin-8-ol kappa2N,O)copper(I) hexafluorophosphate, [Cu(C10H9NO)(C39H32OP2)]PF6, conventionally abbreviated as [Cu(Xantphos)(8-HOXQ)]PF6, where Xantphos is the chelating diphosphine ligand 9,9-dimethyl-4,5-bis(diphenylphosphanyl)-9H-xanthene and 8-HOXQ is the N,O-chelating ligand 2-methylquinolin-8-ol that remains protonated at the hydroxy O atom, is described. In this complex, the asymmetric unit consists of a hexafluorophosphate anion and a whole mononuclear cation, where the CuI atom is coordinated by two P atoms from the Xantphos ligand and by the N and O atoms from the 8-HOXQ ligand, giving rise to a tetrahedral CuP2NO coordination geometry. The electronic absorption and photoluminescence properties of this complex have been studied on as-synthesized samples, whose purity had been determined by powder X-ray diffraction. In the detailed TD-DFT (time dependent density functional theory) studies, the yellow emission appears to be derived from the inter-ligand charge transfer and metal-to-ligand charge transfer (M+L')->LCT excited state (LCT is ligand charge transfer). PMID- 28579573 TI - Dinuclear cobalt(II) complexes with double phosphate ester bridges and tetradentate ligands having anisole or quinoline appendages. AB - Phosphate esters provide a rigid and stable polymeric backbone in nucleic acids. Metal complexes with phosphate ester groups have been synthesized as structural and spectroscopic models of phosphate-containing enzymes. Dinucleating ligands are used extensively to synthesize model complexes since they provide the support required to stabilize such complexes. The crystal structures of two dinuclear CoII complexes, namely bis(MU-diphenyl phosphato-kappa2O:O')bis({2-methoxy-N,N bis[(pyridin-2-yl)methyl]aniline-kappa4N,N',N'',O}cobalt(II)) bis(perchlorate), [Co(C12H10O4P)2(C19H19N3O)2](ClO4)2, and bis(MU-diphenyl phosphato kappa2O:O')bis({N,N-bis[(pyridin-2-yl)methyl]quinolin-8-amine kappa4N,N',N'',O}cobalt(II)) bis(perchlorate), [Co(C12H10O4P)2(C21H18N4)2](ClO4)2, with tetradentate 2-methoxy-N,N-bis[(pyridin 2-yl)methyl]aniline (L1) and N,N-bis[(pyridin-2-yl)methyl]quinolin-8-amine (L2) ligands are reported. The complexes have similar structures, with distorted octahedral geometries around the metal centres. Both are centrosymmetric (Z' = 0.5), with the CoII centres doubly bridged by diphenyl phosphate ester groups. A number of aromatic-aromatic interactions are present and differ between the two complexes as the anisole group in L1 is replaced by a quinoline group in L2. A detailed study of these interactions is presented. PMID- 28579574 TI - A one-dimensional silver(I) coordination polymer based on 5-methyl-1,3,4 thiadiazol-2-amine and pyridine-2,3-dicarboxylate. AB - The bifunctional pyridine-2,3-dicarboxylic acid (H2pdc) ligand has one N atom and four O atoms, which could bind more than one AgI centre with diverse binding modes. A novel infinite one-dimensional AgI coordination polymer, namely catena poly[[silver(I)-(MU2-pyridine-2,3-dicarboxylato-kappa2N:O3)-silver(I)-tris(MU2-5 methyl-1,3,4-thiodiazol-2-amine-kappa2N:N')] monohydrate ethanol monosolvate], {[Ag2(C7H3NO4)(C3H5N3S)3].H2O.C2H5OH}n, has been synthesized using H2pdc and 5 methyl-1,3,4-thiadiazol-2-amine (tda), and characterized by single-crystal X-ray diffraction. One AgI atom is located in a four-coordinated AgN4 tetrahedral geometry and the other AgI atom is in a tetrahedral AgN3O geometry. A dinuclear AgI cluster formed by three tda ligands with a paddelwheel configuration is bridged by the dianionic pdc2- ligand into a one-dimensional coordination polymer. Interchain N-H...O hydrogen bonds extend the one-dimensional chains into an undulating two-dimensional sheet. The sheets are further packed into a three dimensional supramolecular framework by interchain N-H...O hydrogen bonds. PMID- 28579575 TI - Prenatal and early postnatal NOAEL-dose clothianidin exposure leads to a reduction of germ cells in juvenile male mice. AB - Neonicotinoids are pesticides used worldwide. They bind to insect nicotinic acetylcholine receptors (nAChRs) with high affinity. We previously reported that clothianidin (CTD), one of the latest neonicotinoids, reduced antioxidant expression and induced germ cell death in the adult testis of vertebrates. Here, we investigated the male reproductive toxicity of prenatal and early postnatal exposure to CTD, because it is likely that developmental exposure more severely affects the testis compared to adults due to the absence of the blood-testis barrier. Pregnant C57BL/6 mice were given water gel blended with CTD (0, 10 or 50 mg/kg/day; no-observed-adverse-effect-level [NOAEL for mice]: 47.2 mg/kg/day) between gestational day 1 and 14 days post-partum. We then examined the testes of male offspring at postnatal day 14. The testis weights and the numbers of germ cells per seminiferous tubule were decreased in the CTD-50 group, and abnormal tubules containing no germ cells appeared. Nevertheless, the apoptotic cell number and proliferative activity were not significantly different between the control and CTD-exposed groups. There were no significant differences in the androgen-related parameters, such as the Leydig cell volume per testis, the Sertoli cell number and the tubule diameter. The present study is the first demonstration that in utero and lactational exposures to CTD at around the NOAEL for mice reduce the germ cell number, but our findings suggest that these exposures do not affect steroidogenesis in Leydig cells during prenatal or early postnatal life. PMID- 28579576 TI - Automated Ablation Annotation Algorithm Reduces Re-conduction of Isolated Pulmonary Vein and Improves Outcome After Catheter Ablation for Atrial Fibrillation. AB - BACKGROUND: Durable pulmonary vein isolation (PVI) is critical in reducing recurrence after radiofrequency catheter ablation for atrial fibrillation (AF). The VISITAG Module, an automatic annotation system that takes account of catheter stability and contact force (CF), might be useful in accomplishing this.Methods and Results:In 49 patients undergoing VISITAG-guided AF ablation (group A), we set the following automatic annotation criteria: catheter stability range of motion <=1.5 mm, duration >=5 s, CF >=5 g, time >=25% and tag diameter at 6 mm. We used ablation >20 s and force-time integral >150 gs at each site, then moved to the next site where a new tag appeared that overlapped with the former tag. Results and outcome were retrospectively compared for 42 consecutive patients undergoing CF-guided AF ablation without this algorithm (group B). Successful PVI at completion of the initial anatomical line was more frequent in group A than B (66.3% vs. 36.9%, P=0.0006) while spontaneous PV reconnection was less frequent (14.2% vs. 30.9%, P=0.0014) and procedure time was shorter (138+/-35 min vs. 180+/-44 min, P<0.001). One-year success rate off anti-arrhythmic drugs was higher in group A (91.8% vs. 69.1%, log rank P=0.0058). CONCLUSIONS: An automated annotation algorithm with an optimal setting reduced acute resumption of left atrium-PV conduction, shortened procedure time, and improved AF ablation outcome. PMID- 28579578 TI - The T-Box transcription factor 3 in development and cancer. AB - T-box factors comprise an archaic family of evolutionary conserved transcription factors that regulate patterns of gene expression essential for embryonic development. The T-box transcription factor 3 (TBX3), a member of this family, is expressed in several tissues and plays critical roles in, among other structures, the heart, mammary gland and limbs and haploinsufficiency of the human TBX3 gene is the genetic basis for the autosomal dominant disorder, ulnar-mammary syndrome. Overexpression of TBX3 on the other hand has been linked to several cancers including melanoma, breast, pancreatic, liver, lung, head and neck, ovarian, bladder carcinomas and a number of sarcoma subtypes. Furthermore, there is strong evidence that TBX3 promotes oncogenesis by impacting proliferation, tumour formation, metastasis as well as cell survival and drug resistance. More recently, TBX3 was however shown to also have tumour suppressor activity in fibrosarcomas and thus its functions in oncogenesis appear to be context dependent. Identification of the upstream regulators of TBX3 and the molecular mechanism(s) underpinning its oncogenic roles will make valuable contributions to cancer biology. PMID- 28579577 TI - Evaluation of Venous Drainage Patterns for Skull Base Meningioma Surgery. AB - The evaluation of venous drainage patterns prior to surgery for skull base meningioma is important owing to their deep location and the vulnerability of surrounding vascular structures. In recent years, the microsurgical skull base approach has matured as a surgical technique, making it an important option for reducing complications related to skull base meningioma surgery. In addition, knowledge of the venous anatomy can prevent venous drainage route disturbance and potentially life-threatening complications. Hence, this topic review aimed to provide an overview of normal venous anatomy as it relates to the microsurgical skull base approach, discuss known changes in venous drainage routes that are associated with the progression of skull base meningioma and the selection of an appropriate operative approach with the highest likelihood of preserving venous drainage structures. PMID- 28579579 TI - Regulation of zygotic gene activation by chromatin structure and epigenetic factors. AB - After fertilization, the genomes derived from an oocyte and spermatozoon are in a transcriptionally silent state before becoming activated at a species-specific time. In mice, the initiation of transcription occurs at the mid-one-cell stage, which represents the start of the gene expression program. A recent RNA sequencing analysis revealed that the gene expression pattern of one-cell embryos is unique and changes dramatically at the two-cell stage. However, the mechanism regulating this alteration has not yet been elucidated. It has been shown that chromatin structure and epigenetic factors change dynamically between the one- and two-cell stages. In this article, we review the characteristics of transcription, chromatin structure, and epigenetic factors in one- and two-cell mouse embryos and discuss the involvement of chromatin structure and epigenetic factors in the alteration of transcription that occurs between these stages. PMID- 28579580 TI - Molecular prevalence and genotyping of Chlamydia spp. in wild birds from South Korea. AB - Wild birds are reservoirs for Chlamydia spp. Of the total 225 samples from wild birds during January to September 2016 in Korea, 4 (1.8%) and 2 (0.9%) showed positive for Chlamydia psittaci and Chlamydia gallinacea, respectively. Phylogenetic analyses and comparisons of sequence identities for outer-membrane protein A (ompA) revealed that Korean C. psittaci fall into three previously known genotypes; genotype E, 1V and 6N, whereas the Korean C. gallinacea were classified as new variants of C. gallinacea. Our study demonstrates that wild birds in South Korea carry at least two Chlamydia species: C. psittaci and C. gallinacea, and provides new information on the epidemiology of avian chlamydiosis in wild birds. PMID- 28579581 TI - A nasal osteoma with an acute course in a Japanese Black heifer. AB - A 14-month-old Japanese Black heifer presented with unilateral epistaxis and mild swelling of the right face. Radiography revealed a mass with increased radiopacity on the right side of the nasal bridge, extending to the left side. Intranasal endoscopy confirmed a large tumor-like structure protruding into the nasal cavity. Following euthanasia, cranial computed tomography (CT) was performed, revealing a tumor 24.3 * 17.5 * 14.8 cm in size. The tumor occupied the entire right nasal cavity and the frontal and sphenoid sinuses. Histopathological examination revealed that the tumor consisted of well differentiated trabecular bones and loose connective tissue. Based on these findings, a diagnosis of osteoma was established. This report describes a case of osteoma with an acute course in a Japanese Black heifer. PMID- 28579583 TI - A case of intussusceptions at two parts of the ileum caused by an ileus tube. AB - An 87-year-old woman was admitted to our hospital for paralytic ileus, and she was treated using an ileus tube. Although her symptoms improved, abdominal fullness developed again on day 3 after ileus tube insertion. Abdominal computed tomography indicated intussusceptions at the ileum and the terminal part of the ileum;therefore, an emergency surgery was performed. During the surgery, antegrade intussusceptions were found in the ileum 60cm from the ileocecal valve and the terminal part of the ileum into the ascending colon. The intussusception of the anal side was resolved by manual reduction, but the oral side needed a partial resection of small bowel because of the presence of necrosis. There were no lesions, such as tumors, at the intussusceptions sites. Therefore, the two intussusceptions were thought to be caused by the ileus tube. We diagnosed a rare case of intussusceptions in the two parts of the ileum as a complication of the placement of an ileus tube. PMID- 28579582 TI - Steroidogenic enzyme expression in estrogen production in the goat gastrointestinal (GI) tract and the effect of castration. AB - Extragonadal tissues are known to produce estrogens. At these sites, the C19 precursor is important for aromatase expression for the production of estrogen. Aromatase expression is tissue-specific and is controlled by hormones. Recent studies have shown that rat gastric parietal cells expressed aromatase. Our first objective was to investigate steroidogenic enzyme expression in estrogen biosynthesis; the second objective was to investigate which site(s) of the GI tract expressed steroidogenic enzymes; and the third objective was to assess the effects of castration on steroidogenic enzyme expression. CYP19A1, 17beta-HSD3, CYP17A1, 3beta-HSD and P450scc were quantified in the GI tract by real-time PCR. CYP19A1 was detected mainly in the body and pyloric regions of the abomasum, while we detected weak expression of CYP19A1 in other parts of GI tract. In addition, the expression of 17beta-HSD3 and CYP17A1 was detected in abomasum. 3beta-HSD expression was observed in duodenum and jejunum, while P450scc was not detectable in any part of GI tract. Immunohistochemical results showed immunolocalization of aromatase in parietal cells. Aromatase expression was observed to increase after castration. Furthermore, immunohistochemical results demonstrated that parietal cells also produced luteinizing hormone receptor (LHR). These results indicate steroidogenic enzymes required for the biosynthesis of estrogen were expressed, and the abomasum appeared to be the responsible organ for estrogen biosynthesis in the goat GI tract. In addition, parietal cells were responsible for estrogen production and the expression of LHR. Castration increased aromatase expression in abomasum through LH mediation. PMID- 28579584 TI - A rapidly growing, large, mature retroperitoneal teratoma in an adult male patient. AB - A 40-year-old man complaining of abdominal distention was referred to our hospital. Computed tomography of the abdomen demonstrated a very large abdominal mass with fat and calcification. The size of the mass rapidly increased from 30cm to 40cm over two weeks. The tumor was removed and diagnosed by pathological examination to be a retroperitoneal mature cystic teratoma that contained a 40-cm long, mature intestinal tract-like cyst, together with bone marrow and fat. The rapid growth of the tumor may have been caused by an increased secretion in the cyst. PMID- 28579585 TI - A case of liver abscess caused by appendicitis which was considered to be drained from hepatobronchial fistula. AB - A 52-year-old man was referred to our hospital complaining of right lower abdominal pain. He was diagnosed with appendicitis complicated with a liver abscess and underwent an appendectomy. After antibiotic treatment following surgery, the liver abscess penetrated the right lung, which was considered to be drained from a hepatobronchial fistula. Due to the effect of drainage, the liver abscess immediately improved and the patient was subsequently discharged. PMID- 28579586 TI - A case of pancreatic intraepithelial neoplasia-3 with autoimmune pancreatitis. AB - We report a case of pancreatic intraepithelial neoplasia-3 (PanIN-3) with autoimmune pancreatitis (AIP). The patient, a 75-year-old man, had been diagnosed to have AIP with stenosis of the main pancreatic duct. After six years, computed tomography demonstrated dilatation of the main pancreatic duct in the mid pancreas. Although we could not confirm the presence of any pancreatic tumor on the basis of imaging modalities alone, cytological examination of the pancreatic juice obtained by endoscopic retrograde pancreatography revealed atypical cells. Therefore, we performed pancreatoduodenectomy and obtained a pathologic diagnosis of PanIN-3 with AIP. The present case is informative in the context of pancreatic carcinogenesis in AIP. PMID- 28579587 TI - Direct-acting antiviral agents improved nephrotic syndrome associated with refractory pleural effusion and ascites caused by hepatitis C virus-related nephropathy: a case report. AB - A 74-year-old man with hepatitis C virus (HCV)-related cirrhosis was admitted because of dyspnea. Laboratory investigations revealed severe proteinuria (4.0g/day), low serum albumin level, and cryoglobulinemia. Computed tomography showed massive pleural effusion and ascites. Because these effusions were leaky and the hepatic reserve was relatively intact, we thought these were mainly caused by nephrotic syndrome. Renal biopsy revealed membranoproliferative glomerulonephritis with mesangial proliferation and excessive matrix deposition. Based on these histopathological findings and the presence of cryoglobulinemia, a diagnosis of HCV-related nephropathy was performed. Therefore, antiviral therapy was initiated with direct-acting antiviral (DAA) agents (daclatasvir+asunaprevir). Serum HCV-RNA level was observed to be negative at week 8, which was followed by an alleviation of proteinuria and a gradual decrease in the pleural effusion and ascites. HCV-related nephropathy should be considered in the differential diagnosis of patients with chronic hepatitis C and refractory ascites. DAA agents are effective in the treatment of these patients. PMID- 28579588 TI - A case of primary amyloidosis with spontaneous hepatic rupture. AB - A 79-year-old man was diagnosed to have primary amyloid light-chain (AL) amyloidosis with associated liver damage and prominent hepatomegaly. He was followed up without any treatment. One year after the diagnosis, he was taken to the hospital with a sudden onset of features of shock. Computed tomography revealed hepatic rupture, and he was treated by emergent transcutaneous arterial embolization. However, the procedure was unable to save his life. AL amyloidosis with prominent hepatomegaly is considered to be a risk factor for spontaneous liver rupture and intra-abdominal hemorrhage. PMID- 28579589 TI - The 58th Congress of the Japanese Society of Gastroenterology. PMID- 28579590 TI - The history, present status and future perspective of ESD for GI tract cancer. PMID- 28579591 TI - Cutting edge of esophageal ESD. PMID- 28579592 TI - Recent evidences on endoscopic submucosal dissection for early gastric cancer. PMID- 28579593 TI - Current status of colorectal ESD and challenge to the limit. PMID- 28579594 TI - Exploration of Underlying Mechanism of Anti-adipogenic Activity of Sulfuretin. AB - Sulfuretin is a natural flavonoid found in the plant Rhus verniciflua STOKES. The plant has been traditionally used as medicinal agent for antiviral, cathartic, diaphoretic, anti-rheumatic and sedative activities in East Asia. In this study we isolated and identified sulfuretin from R. verniciflua and investigated its anti-adipogenic activity against 3T3-L1 preadipocytes cells. We evaluated the effects of sulfuretin on the adipogenic transcription factors like peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha (C/EBPalpha), fatty acid synthase (FAS), Fabp4, adiponectin and zinc fingerprint protein (Zfp) 521 by gene expression (real-time QPCR) and Western blot analysis. Sulfuretin treatment at Day 0 and 2 showed significant reduction of lipid production in 3T3-L1 cells in concentration dependent manner. Gene expression analysis (real-time PCR) revealed that sulfuretin inhibited the both major adipogenic factors (C/EBPalpha, C/EBPbeta and PPARgamma) and minor adipogenic factors (sterol regulatory element-binding protein (SREBP1c), adiponectin, FAS, Fabp4, Zfp423, and Ebf1). Western blot analysis showed the increased expression of beta-catenin and suppression of PPARgamma after sulfuretin treatment. Overall, sulfuretin is a natural flavonoid having potent anti-adipogenic activity through the suppression of major adipogenic factors C/EBPalpha, C/EBPbeta and PPARgamma, which initiate adipogenesis. PMID- 28579595 TI - Study on the Increased Probability of Detecting Adverse Drug Reactions Based on Bayes' Theorem: Evaluation of the Usefulness of Information on the Onset Timing of Adverse Drug Reactions. AB - In order to avoid adverse drug reactions (ADRs), pharmacists are reconstructing ADR-related information based on various types of data gathered from patients, and then providing this information to patients. Among the data provided to patients is the time-to-onset of ADRs after starting the medication (i.e., ADR onset timing information). However, a quantitative evaluation of the effect of onset timing information offered by pharmacists on the probability of ADRs occurring in patients receiving this information has not been reported to date. In this study, we extracted 40 ADR-drug combinations from the data in the Japanese Adverse Drug Event Report database. By applying Bayes' theorem to these combinations, we quantitatively evaluated the usefulness of onset timing information as an ADR detection predictor. As a result, when information on days after taking medication was added, 54 ADR-drug combinations showed a likelihood ratio (LR) in excess of 2. In particular, when considering the ADR-drug combination of anaphylactic shock with levofloxacin or loxoprofen, the number of days elapsed between start of medication and the onset of the ADR was 0, which corresponded to increased likelihood ratios (LRs) of 138.7301 or 58.4516, respectively. When information from 1-7 d after starting medication was added to the combination of liver disorder and acetaminophen, the LR was 11.1775. The results of this study indicate the clinical usefulness of offering information on ADR onset timing. PMID- 28579596 TI - Aldehyde dehydrogenase activity identifies a subpopulation of canine adipose derived stem cells with higher differentiation potential. AB - Adipose-derived stem cells (ADSCs) are abundant and readily obtained, and have been studied for their clinical applicability in regenerative medicine. Some surface antigens have been identified as markers of different ADSC subpopulations in mice and humans. However, it is unclear whether functionally distinct subpopulations exist in dogs. To address this issue, we evaluated aldehyde dehydrogenase (ALDH) activity-a widely used stem cell marker in mice and humans by flow cytometry. Approximately 20% of bulk ADSCs showed high ALDH activity. Compared to cells with low activity (ALDHLo), the high-activity (ALDHHi) subpopulation exhibited a higher capacity for adipogenic and osteogenic differentiation. This is the first report of distinct ADSC subpopulations in dogs that differ in terms of adipogenic and osteogenic differentiation potential. PMID- 28579597 TI - Pharmacokinetics of ceftiofur in healthy and lipopolysaccharide-induced endotoxemic newborn calves treated with single and combined therapy. AB - The aim of this research was to compare plasma pharmacokinetics of ceftiofur sodium (CS) in healthy calves, and in calves with experimentally induced endotoxemia. Six calves received CS (2.2 mg/kg, IM) 2 hr after intravenous administration of 0.9% NaCl (Ceft group). After a washout period, the same 6 calves received CS 2 hr after intravenous injection of lipopolysaccharide (LPS+Ceft group). Another group of 6 calves received a combination of drug therapies that included CS 2 hr after administration of 0.9% NaCl (Comb group). A third group of 6 calves received the same combination therapy regimen 2 hr after intravenous injection of lipopolysaccharide (LPS+Comb group). Plasma concentrations of CS and all desfuroylceftiofur-related metabolites were determined using HPLC, and its pharmacokinetic properties were determined based on a two-compartment model. The peak concentration of CS in the LPS+Comb group occurred the earliest, and the clearance rate of CS was the highest in the Comb and LPS+Comb groups (P<0.05). The elimination half-life of CS in the LPS+Ceft group was longer than that in the Ceft and Comb groups (P<0.05). The results of this study indicate that combined therapies and endotoxemic status may alter the plasma pharmacokinetics of CS in calves. PMID- 28579599 TI - Bilateral Arm Gangrene Associated With Heparin-Induced Thrombocytopenia After Extracorporeal Cardiopulmonary Resuscitation. PMID- 28579598 TI - Rabbit models for biomedical research revisited via genome editing approaches. AB - Although the laboratory rabbit has long contributed to many paradigmatic studies in biology and medicine, it is often considered to be a "classical animal model" because in the last 30 years, the laboratory mouse has been more often used, thanks to the availability of embryonic stem cells that have allowed the generation of gene knockout (KO) animals. However, recent genome-editing strategies have changed this unrivaled condition; so far, more than 10 mammalian species have been added to the list of KO animals. Among them, the rabbit has distinct advantages for application of genome-editing systems, such as easy application of superovulation, consistency with fertile natural mating, well optimized embryo manipulation techniques, and the short gestation period. The rabbit has now returned to the stage of advanced biomedical research. PMID- 28579600 TI - Incidence, Management and Short-Term Outcome of Stroke in a General Population of 1.4 Million Japanese - Shiga Stroke Registry. AB - BACKGROUND: This study determined the current status of the incidence, management, and prognosis of stroke in Japan using a population-based stroke registry.Methods and Results:Shiga Stroke Registry is an ongoing population-based registry that covers approximately 1.4 million residents of Shiga Prefecture. Cases of acute stroke were identified using standard definitions through surveillance of both all acute-care hospitals with neurology/neurosurgery facilities and death certificates in 2011. A total of 2,956 stroke cases and 2,176 first-ever stroke cases were identified. The age- and sex-adjusted incidence rate for first-ever stroke using the 2013 European Standard Population as standard was per 100,000 person-years: 91.3 for ischemic stroke, 36.4 for intracerebral hemorrhage, and 13.7 for subarachnoid hemorrhage. It was estimated that approximately 220,000 new strokes occurred in 2011 in Japan. Among the 2,956 cases, most stroke patients underwent neuroimaging, 268 received surgical or endovascular treatment, and 2,158 had rehabilitation therapy; 78 patients received intravenous thrombolysis. A total of 1,846 stroke patients had died or were dependent at hospital discharge, and 390 died within 28 days of onset. CONCLUSIONS: Incidence rates of stroke by subtypes were clarified and the total number of new strokes in Japan was estimated. More than half of stroke patients die or become dependent after a stroke. This study re-emphasized the importance of public health measures in reducing the burden of stroke in Japan. PMID- 28579601 TI - Efficacy of Intensive Radiofrequency Energy Delivery to the Localized Dense Scar Area in Post-Infarction Ventricular Tachycardia Ablation - A Comparative Study With Standard Strategy Targeting the Infarcted Border Zone. AB - BACKGROUND: Several reports have demonstrated the importance of severely low voltage areas as arrhythmogenic substrates of ventricular tachycardia (VT). However, a comparative study of dense scar-targeted and infarcted border zone targeted strategies has not been reported.Methods and Results:We divided 109 consecutive patients with VT post-infarction from 6 centers into 2 groups according to the ablation strategy used: dense scar-targeted ablation (DS ablation, 48%) or border zone-targeted ablation (BZ ablation, 52%). During DS ablation, we attempted to identify VT isthmuses in the dense scar areas (<=0.6 mV) using detailed pace mapping, and linear ablation lesions were applied mainly to those areas. During BZ ablation, linear ablation of standard low voltage areas (0.5-1.5 mV) was performed along with good pace map sites of the clinical VT. Acute success was defined as complete success (no VTs inducible) or partial success (clinical VT was noninducible). The acute complete success rate was significantly higher for DS ablation than for BZ ablation (62% vs. 42%, P=0.043). During a median follow-up of 37 months, the VT-free survival rate was significantly higher for DS ablation than for BZ ablation (80% vs. 58% at 48 months; log-rank P=0.038). CONCLUSIONS: DS ablation may be a more effective therapy for post-infarction VT than BZ ablation in terms of the acute complete success rate and long-term follow-up. PMID- 28579602 TI - Lipid-Lowering Therapy With Monoclonal Antibodies to Proprotein Convertase Subtilisin-Kexin Type 9 - Lessons From Recent Clinical Trials. PMID- 28579603 TI - Rapamycin Treatment for Benign Multicystic Peritoneal Mesothelioma: A Rare Disease with a Difficult Management. AB - BACKGROUND Benign multicystic peritoneal mesothelioma (BMPM) is a rare intra abdominal tumor. Although considered by many to be benign, this tumor has a high local recurrence rate. Because of its rarity, preoperative diagnosis is difficult and its origin and pathogenesis are uncertain. There are no evidence-based treatment strategies for BMPM. It is agreed that the best treatment strategy for BMPM is the combination of surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). An increasing body of evidence supports a pivotal role of the cytoplasmic serine/threonine kinase mTOR in the development and progression of several neoplastic diseases and specific mTOR inhibitors, including rapamycin, have been suggested as potential therapeutic options for different cancers. CASE REPORT A 65-year-old male with end-stage renal disease on hemodialysis for seven years presented with BMPM. He underwent surgery to remove multiple peritoneal cysts, but four months later he experienced a recurrence of the disease. Immunohistochemistry of the cysts demonstrated a high level of phosphorylation of p70S6 kinase, a downstream mTOR target, and since a target therapy that blocks PI3K/Akt/mTOR pathway has been shown to have a scientific and logical rationale to treat this rare intra-abdominal neoplasia, we started the patient on low dose rapamycin therapy, an mTOR inhibitor. Long-term mTOR inhibition resulted in a complete and stable remission of BMPM. CONCLUSIONS The current case is the first report of BMPM successfully treated with rapamycin, which resulted in a long-lasting response to mTOR inhibition. PMID- 28579604 TI - Association of Dopamine D1 and D3 Receptor Gene Polymorphisms with Essential Hypertension in 3 Ethnic Groups in China. AB - Background Material and Methods Results Conclusions. PMID- 28579605 TI - Aging Reversal and Healthy Longevity is in Reach: Dependence on Mitochondrial DNA Heteroplasmy as a Key Molecular Target. AB - Recent trends in biomedical research have highlighted the potential for effecting significant extensions in longevity with enhanced quality of life in aging human populations. Within this context, any proposed method to achieve enhanced life extension must include therapeutic approaches that draw upon essential biochemical and molecular regulatory processes found in relatively simple single cell organisms that are evolutionarily conserved within complex organ systems of higher animals. Current critical thinking has established the primacy of mitochondrial function in maintaining good health throughout plant and animal phyla. The mitochondrion represents an existentially defined endosymbiotic model of complex organelle development driven by evolutionary modification of a permanently enslaved primordial bacterium. Cellular mitochondria are biochemically and morphologically tailored to provide exponentially enhanced ATP dependent energy production accordingly to tissue- and organ-specific physiological demands. Thus, individual variations in longevity may then be effectively sorted according to age-dependent losses of single-cell metabolic integrity functionally linked to impaired mitochondrial bioenergetics within an aggregate presentation of compromised complex organ systems. Recent empirical studies have focused on the functional role of mitochondrial heteroplasmy in the regulation of normative cellular processes and the initiation and persistence of pathophysiological states. Accordingly, elucidation of the multifaceted functional roles of mitochondrial heteroplasmy in normal aging and enhanced longevity will provide both a compelling genetic basis and potential targets for therapeutic intervention to effect meaningful life extension in human populations. PMID- 28579606 TI - Isoniazid Prophylaxis for Latent Tuberculosis Infections in Liver Transplant Recipients in a Tuberculosis-Endemic Area. AB - BACKGROUND Isoniazid (INH) prophylaxis (Px) has good efficacy for preventing tuberculosis (TB) in the general population. However, its use for the treatment of latent TB infections (LTBI) in liver transplant (LT) recipients is challenging because little is known about INH-induced hepatotoxicity in graft recipients. We evaluated the efficacy and safety of INH Px in LT recipients. MATERIAL AND METHODS From March 2008 to December 2012, we retrospectively reviewed data on 277 patients who received LT at a single center. We examined the results of tuberculin skin tests and interferon-gamma release assays, use of INH, INH induced hepatotoxicity, and post-LT TB occurrence. RESULTS Among 277 recipients, 7 cases of post-transplant TB were detected (2.52%). Seventeen patients received post-transplant INH Px. Among INH Px recipients, post-LT TB infection did not occur. Hepatotoxicity after INH Px was significantly lower in the patients who received INH Px at an aspartate aminotransferase (AST) level that was less than 50 U/L than in those who received INH Px at an AST level that was more than 50 U/L (P=0.046, 0.002). CONCLUSIONS INH is likely to be effective for preventing post-LT TB recurrence in LTBI. However, because of INH-induced hepatotoxicity, it is better to avoid using it in the early post-LT period and to wait to initiate INH Px until liver function is stable in LT recipients. PMID- 28579607 TI - Plant genetics: Branching out for crop improvement. PMID- 28579608 TI - Genome watch: Klebsiella pneumoniae: when a colonizer turns bad. PMID- 28579609 TI - Bacterial evolution: The origins of pathogenic enterococci. PMID- 28579610 TI - Bacterial physiology: An inside job on metabolism. PMID- 28579611 TI - Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need. PMID- 28579612 TI - Immunology: ACE in neutrophil antibacterial defence. PMID- 28579613 TI - Bioengineering: Kidney glomerulus-on-a-chip. PMID- 28579614 TI - Cystic kidney disease: A new osmoregulatory role for HNF-1beta. PMID- 28579616 TI - Enhancement of endocytic uptake of HIV-1 virions into CD4-negative epithelial cells by HIV-1 gp41 via its interaction with POB1. PMID- 28579615 TI - Type 3 innate lymphoid cell-derived lymphotoxin prevents microbiota-dependent inflammation. AB - Splenomegaly is a well-known phenomenon typically associated with inflammation. However, the underlying cause of this phenotype has not been well characterized. Furthermore, the splenomegaly phenotype seen in lymphotoxin (LT) signaling deficient mice is characterized by increased numbers of splenocytes and splenic neutrophils. Splenomegaly, as well as the related phenotype of increased lymphocyte counts in non-lymphoid tissues, is thought to result from the absence of secondary lymphoid tissues in LT-deficient mice. We now present evidence that mice deficient in LTalpha1beta2 or LTbetaR develop splenomegaly and increased numbers of lymphocytes in non-lymphoid tissues in a microbiota-dependent manner. Antibiotic administration to LTalpha1beta2- or LTbetaR-deficient mice reduces splenomegaly. Furthermore, re-derived germ-free Ltbr-/- mice do not exhibit splenomegaly or increased inflammation in non-lymphoid tissues compared to specific pathogen-free Ltbr-/- mice. By using various LTbeta- and LTbetaR conditional knockout mice, we demonstrate that retinoic acid-related orphan receptor gammaT-positive type 3 innate lymphoid cells provide the required active LT signaling to prevent the development of splenomegaly. Thus, this study demonstrates the importance of LT-mediated immune responses for the prevention of splenomegaly and systemic inflammation induced by microbiota. PMID- 28579618 TI - A preference to bond? Male prairie voles form pair bonds even in the presence of multiple receptive females. AB - Pair bonds are the cornerstone of a monogamous relationship. When individuals of the same species engage in monogamy and promiscuity (i.e. alternative reproductive tactics) it can be difficult to determine which tactic confers greater fitness, as measures of fitness can be difficult to ascertain. However, in these circumstances, whether animals preferentially establish pair bonds can reveal decisions that presumably reflect the animals' assessment of how to best maximize reproductive success. In nature, the majority of prairie voles, Microtus ochrogaster, establishes pair bonds and engages in social monogamy while a minority of individuals remains single and presumably mates promiscuously. The existence of these two tactics raises the interesting question: do bonded male prairie voles choose to 'settle' (for just one partner) or are they preferentially 'settling down'? To determine which of these two tactics is preferred, we provided single male prairie voles simultaneous access to two sexually receptive females for 24 h and then subsequently tested males in 'partner preference tests' with each female independently contrasted with a novel female. We aimed to determine whether males would form a pair bond with one, both or none of the original females. We found that males formed pair bonds with one of the two females. We also investigated male- and female-initiated aggression and found that during the bonding process males were more aggressive with females that they did not ultimately form a bond with. In the partner preference tests, males showed more aggression towards unfamiliar females than towards familiar females. Mismatches in male- and female-initiated aggression suggest that aggressive interactions may be perpetuated more by males than by females. Taken together, our results demonstrate that under conditions that are ideal for forgoing bonding and engaging in multiple matings, males choose to establish a pair bond, suggesting that selective pressures may have facilitated bonding by males. PMID- 28579617 TI - HDAC1,2 inhibition and doxorubicin impair Mre11-dependent DNA repair and DISC to override BCR-ABL1-driven DSB repair in Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia. AB - Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL) expressing BCR-ABL1 oncoprotein is a major subclass of ALL with poor prognosis. BCR-ABL1-expressing leukemic cells are highly dependent on double strand break (DSB) repair signals for their survival. Here we report that a first in-class HDAC1,2 selective inhibitor and doxorubicin (a hyper-CVAD chemotherapy regimen component) impair DSB repair networks in Ph+ B-cell precursor ALL cells using common as well as distinct mechanisms. The HDAC1,2 inhibitor but not doxorubicin alters nucleosomal occupancy to impact chromatin structure, as revealed by MNase-Seq. Quantitative mass spectrometry of the chromatin proteome along with functional assays showed that the HDAC1,2 inhibitor and doxorubicin either alone or in combination impair the central hub of DNA repair, the Mre11 Rad51-DNA ligase 1 axis, involved in BCR-ABL1-specific DSB repair signaling in Ph+ B-cell precursor ALL cells. HDAC1,2 inhibitor and doxorubicin interfere with DISC (DNA damage-induced transcriptional silencing in cis)) or transcriptional silencing program in cis around DSB sites via chromatin remodeler-dependent and independent mechanisms, respectively, to further impair DSB repair. HDAC1,2 inhibitor either alone or when combined with doxorubicin decreases leukemia burden in vivo in refractory Ph+ B-cell precursor ALL patient-derived xenograft mouse models. Overall, our novel mechanistic and preclinical studies together demonstrate that HDAC1,2 selective inhibition can overcome DSB repair 'addiction' and provide an effective therapeutic option for Ph+ B-cell precursor ALL. PMID- 28579619 TI - Rates and Routes of Hysterectomy for Benign Indications in Austria 2002 - 2014. AB - INTRODUCTION: Rates and routes of hysterectomy have implications for quality, costs and training. This study analyzed rates of benign hysterectomy and surgical approaches for benign hysterectomy in Austria from 2002 to 2014. MATERIAL AND METHODS: This was a population-based retrospective observational study of coding data from all acute care hospitals (public and private) in Austria. Main outcome measures were numbers of women undergoing hysterectomy for benign indications in Austria per year and the route of hysterectomy for benign indications. RESULTS: The number of benign hysterectomies performed per year declined from 10 675 in 2002 to 7747 in 2014, a decline of 27%. The use of vaginal hysterectomy was stable (53% and 47%, respectively). Use of laparoscopic techniques increased (5% in 2002, 32% in 2014) whereas use of abdominal hysterectomy decreased (41% and 20%, respectively). CONCLUSIONS: Numbers of benign hysterectomies performed per year in Austria declined substantially between 2002 and 2014. Use of vaginal hysterectomy was stable at about 50%, whereas increased use of laparoscopic techniques was associated with lower rates of open hysterectomy. PMID- 28579620 TI - C-Section Prevalence Among Obese Mothers and Neonatal Hypoglycemia: a Cohort Analysis of the Department of Gynecology and Obstetrics of the University of Lubeck. AB - INTRODUCTION: Data from the World Health Organization (WHO) demonstrates an increasing prevalence of obesity in Western countries. This study investigates the influence of obesity on the mode of delivery and the occurrence of hypoglycemia in newborns. MATERIALS AND METHODS: A retrospective analysis of all deliveries at the Department of Gynecology and Obstetrics of the University of Lubeck, Germany was conducted over a period of eleven years with the primary outcome as non-elective C-sections and hypoglycemia of newborns from obese mothers. Patients were divided into six subgroups according to WHO weight classifications as follows: control group body mass index (BMI) 18.5 - 24.9 kg/m 2 , n = 7712; general obesity BMI >= 25 kg/m 2 , n = 4227; overweight BMI 25 - 29.9 kg/m 2 , n = 2628; obesity I degrees BMI 30 - 34.9 kg/m 2 , n = 1017; obesity II degrees BMI 35 - 39.9 kg/m 2 , n = 370; obesity III degrees BMI >= 40 kg/m 2 , n = 212. RESULTS: Analysis of the primary outcome shows an increased incidence of non-elective C-sections with an elevated BMI (general obesity vs. control group: 20.5 vs. 15.9%, p < 0.001; OR 1.3; 95% CI 1.2 - 1.4) and elevated rates of neonatal hypoglycemia in newborns of obese mothers (general obesity vs. control group: 0.6 vs. 0.3%, p < 0.05; OR 1.8; 95% CI 1.0 - 3.0). CONCLUSIONS: Obesity is an essential obstetric risk factor. Obese women face an increased risk of non-elective C-sections, and newborns of obese mothers suffer from elevated rates of hypoglycemia. PMID- 28579621 TI - Fetal Pathology of Neural Tube Defects - An Overview of 68 Cases. AB - INTRODUCTION: The prevalence of neural tube defects worldwide is 1 - 2 per 1000 neonates. Neural tube defects result from a disturbance of neurulation in the 3rd or 4th week of development and thus represent the earliest manifestation of organ malformation. Neural tube defects (NTD) are classified into cranial dysraphism leading to anencephaly or meningoencephalocele and spinal dysraphism with or without meningomyelocele. In isolated form they have multifactorial causes, and the empirical risk of recurrence in Central Europe is 2%. As associated malformations they tend to occur sporadically, and in monogenic syndromes they follow Mendelian inheritance patterns with a high risk of recurrence. PATIENTS: Autopsies were performed on 68 fetuses following a prenatal diagnosis of NTD and induced abortion. RESULTS: The incidence of NTDs in our autopsied fetuses was 8% and 11% in fetuses with malformations. The percentage of fetuses with anencephaly, encephalocele or spina bifida was 24, 18, and 60%*, respectively. Analysis of the sex distribution showed a female preponderance in cranial dysraphisms but the sex distribution of spina bifida cases was equal. The extent and localization of NTDs varied, with lumbosacral cases clearly predominating. The proportion of isolated, associated and syndromic neural tube defects was 56, 23.5 and 20.6% respectively. In the majority of syndromes, the neural tube defect represented a not previously observed syndromic feature. CONCLUSION: The high proportion of NTDs with monogenic background underlines the importance of a syndrome oriented fetal pathology. At the very least it requires a thourough photographic and radiographic documentation of the fetal phenotype to enable the genetic counsellor to identify a syndromic disorder. This is necessary to determine the risk of recurrence, arrange confirming mutation analyses and offer targeted prenatal diagnosis in subsequent pregnancies. PMID- 28579622 TI - Physical Exercise During Pregnancy - How Active Are Pregnant Women in Germany and How Well Informed? AB - INTRODUCTION: There is sufficient evidence showing the positive effects of physical exercise on various aspects of pregnancy. This study evaluates knowledge and status of physical exercise among pregnant women. METHODS: The standardised paper-pencil questionnaire "Pregnancy Physical Activity Questionnaire" (PPAQ) as well as general demographic questions were used to assess the exercise behaviour of study participants. 83 questionnaires completed by women presenting to the Kiel University Hospital for antenatal assessment were included in the analysis. RESULTS: At the time of questionnaire completion 10 women were in the first trimester of pregnancy, 64 in the second, and 9 in the third. Just less than 90% of participants felt they had been informed "sufficiently" on the topic physical exercise during pregnancy, over 50% felt they were "well" or "very well" informed. Just less than half of participants received their information from a doctor (either their gynaecologist or general practitioner) and none of these felt "insufficiently" informed. Almost 80% of participants reported still doing no sport or less exercise than before falling pregnant. The maximum proportional energy expenditure for recreational activity - just under 20% - was in the third trimester. Women who felt they had been well counselled tended to have higher activity levels. CONCLUSION: Study participants demonstrated a clear decline in physical exercise during pregnancy despite clear evidence of the benefits of regular exercise for pregnant women, and despite participants feeling they were well informed. Detailed information on the recommendations for physical exertion in pregnancy should form an integral part of antenatal counselling. PMID- 28579624 TI - Challenges to global control and/or elimination of NTDs: threats of animal reservoirs of human infections. PMID- 28579623 TI - Reference Curve for the Mean Uterine Artery Pulsatility Index in Singleton Pregnancies. AB - INTRODUCTION: Doppler sonography of the uterine artery (UA) is done to monitor pregnancies, because the detected flow patterns are useful to draw inferences about possible disorders of trophoblast invasion. Increased resistance in the UA is associated with an increased risk of preeclampsia and/or intrauterine growth restriction (IUGR) and perinatal mortality. In the absence of standardized figures, the normal ranges of the various available reference curves sometimes differ quite substantially from one another. The causes for this are differences in the flow patterns of the UA depending on the position of the pulsed Doppler gates as well as branching of the UA. Because of the discrepancies between the different reference curves and the practical problems this poses for guideline recommendations, we thought it would be useful to create our own reference curves for Doppler measurements of the UA obtained from a singleton cohort under standardized conditions. MATERIAL AND METHODS: This retrospective cohort study was carried out in the Department of Obstetrics of the Charite - Universitatsmedizin Berlin, the Department for Obstetrics and Prenatal Medicine of the University Hospital Halle (Saale) and the Center for Prenatal Diagnostics and Human Genetics Kurfurstendamm 199. Available datasets from the three study locations were identified and reference curves were generated using the LMS method. Measured values were correlated with age of gestation, and a cubic model and Box-Cox power transformation (L), the median (M) and the coefficient of variation (S) were used to smooth the curves. RESULTS: 103 720 Doppler examinations of the UA carried out in singleton pregnancies from the 11th week of gestation (10 + 1 GW) were analyzed. The mean pulsatility index (Mean PI) showed a continuous decline over the course of pregnancy, dropping to a plateau of around 0.84 between the 23rd and 27th GW, after which it decreased again. CONCLUSION: Age of gestation, placental position, position of pulsed Doppler gates and branching of the UA can all change the flow pattern. The mean pulsatility index (Mean PI) showed a continuous decrease over time. There were significant differences between our data and alternative reference curves. A system of classifying Doppler studies and a reference curve adapted to the current technology are urgently required to differentiate better between physiological and pathological findings. PMID- 28579625 TI - Prevalence of potentially zoonotic gastrointestinal parasites in canine faeces in Ibadan, Nigeria. AB - BACKGROUND: Humans can get infected through direct or indirect contact with infective stages of zoonotic parasites shed to the environment through dog faeces. OBJECTIVES: This study was designed to investigate the presence of gastrointestinal parasites present in dog faeces shed on the street of Ibadan metropolis, one of the largest cities in Africa. METHODS: Twenty-three locations were randomly selected using grid-sampling method. A total of 203 faecal samples collected from the streets of selected areas were processed for detection of helminth eggs and protozoan oocysts using flotation technique. Eggs/oocysts per gram of faeces was counted using modified McMaster technique. RESULTS: The prevalence of gastrointestinal parasites was 43.3% (88/203). Single and multiple infections were 69 (78.4%) and 19 (21.6%) respectively. The parasites detected were Ancylostoma sp. 24.6% (50/88) Isospora sp. 14.2% (29/88), Toxocara sp. 9.8% (20/88), Uncinaria sp. 2.5% (5/88) and Strongyloides sp, 3.9% (8/88). Ancylostoma sp. (320 * 102 epg) and Uncinaria sp. (5 * 102 epg) had the highest and least intensity respectively. Streets within residential areas having markets had the highest number of positive samples. All the genera of parasites detected in this study have zoonotic potential. CONCLUSION: The high prevalence of zoonotic parasites detected in dog faeces from Ibadan metropolis showed that infected stray dogs roam the streets and constitute potential risk to human health. This study suggests the need for enforcement of laws restraining roaming or straying dogs and proper veterinary care of dogs. FUNDING: None declared. PMID- 28579626 TI - A narrative synthesis of illustrative evidence on effects of capitation payment for primary care: lessons for Ghana and other low/middle-income countries. AB - OBJECTIVE: To analyse and synthesize available international experiences and information on the motivation for, and effects of using capitation as provider payment method in country health systems and lessons and implications for low/middle-income countries. METHODS: We did narrative review and synthesis of the literature on the effects of capitation payment on primary care. RESULTS: Eleven articles were reviewed. Capitation payment encourages efficiency: drives down cost, serves as critical source of income for providers, promotes adherence to guidelines and policies, encourages providers to work better and give health education to patients. It, however, induces reduction in the quantity and quality of care provided and encourages skimming on inputs, underserving of patients in bad state of health, "dumping" of high risk patients and negatively affect patient-provider relationship. CONCLUSION: The illustrative evidence adduced from the review demonstrates that capitation payment in primary care can create positive incentives but could also elicit un-intended effects. However, due to differences in country context, policy makers in Ghana and other low/middle income countries may only be guided by the illustrative evidence in their design of a context-specific capitation payment for primary care. FUNDING: Netherlands Fellowship Programme (NFP), Fellowship number: NFP-PhD.12/352. PMID- 28579628 TI - A review of Intra-uterine foetal deaths at the Cape Coast Teaching Hospital. AB - AIM: To estimate the rate of IUFD/Stillbirths (SB). STUDY DESIGN: This is a retrospective review of delivery suite records from Jan 1 2013 to Dec 31 2014. METHODS: Study was undertaken at the Cape Coast Teaching Hospital (CCTH) in the Central region of Ghana. All pregnant women who had their babies at the delivery suite of CCTH have their records hand written in Ghana health service approved and distributed delivery records book. We identified all patients with IUFD/SB from this delivery suite record book which is kept on the delivery suite. The data collected included the age, parity, mode of delivery, total blood loss, sex of the foetus and condition of foetus i.e. Macerated stillbirth (MSB) or fresh still birth (FSB). Of the 315 IUFDs found in the records book, 26 were incompletely filled, and 13 were abortions (<28 weeks) and therefore excluded. The analysis is therefore based on 276 completed documentations. The data collected from the delivery suite records were analysed using STATA version 11.0. RESULTS: Of the 315 IUFD/SBs documented in the delivery suite record book, 13 were abortions (<28 weeks), leaving 302 IUFD/SBs. Of this number, 26 had incomplete data and were excluded from the analysis. The analysis was thus based on 276 IUFD/SBs with complete data. Over the study period there were 5176 deliveries, giving a stillbirth rate of 58.5/1000 deliveries. Majority of the IUFD occurred in women 20-35 years of age (74.7%), and who have had two or less births (66.7%). The mean maternal age at which IUFD occurred was 29 years. CONCLUSION: Our review shows that the SBR of 58.5/1000, over the two years, at CCTH is high. We suggest further studies to focus on the reasons for IUFDs and what interventions can be applied to reduce it. FUNDING: No internal or external funds sourced. PMID- 28579627 TI - Carriage of sub-microscopic sexual and asexual Plasmodium falciparum stages in the dry season at Navrongo, Ghana. AB - BACKGROUND: We investigated the prevalence of sub-microscopic Plasmodium falciparum infections and gametocyte carriage in asymptomatic individuals in Navrongo in northern Ghana, an area of seasonal malaria transmission. DESIGN: A cross sectional study of 209 randomly selected participants of all age-groups was conducted in February and March, 2015. METHODS: Capillary blood samples collected from these individuals were used for the detection of both asexual and gametocyte stage parasites by microscopy, reverse transcriptase polymerase chain reaction (RT-PCR) and conventional nested PCR methods. The prevalence data as determined by microscopy and molecular methods were compared using chi-square tests. RESULTS: Parasitaemia from these asymptomatic infections ranged from 40 to 3,520 parasites/ul of blood (geometric mean parasitaemia = 732 parasites/ul). The prevalence of asymptomatic P. falciparum carriage was 4.8% (10/209) and 13.9% (29/209) using microscopy and RT-PCR respectively. The overall prevalence of sub microscopic infections in the total number of samples analysed was 9.1% (19/209) and 66% (19/29) of the asymptomatic infections. P. falciparum gametocytemia detected by microscopy was 1% (2/209) and 3.8% (8/209) by PCR. CONCLUSION: This is the first report of sub-microscopic asexual and gametocytes infections in the dry season in a seasonal malaria transmission area in Ghana. It has established that persistent latent malaria infections occur and that these could supply the source of parasites for the next transmission season. The findings highlight the presence of sub-microscopic infections and therefore the need for active case detection surveillance to eliminate "asymptomatic reservoir" parasites and consequently break the transmission of the disease in Ghana. FUNDING: Bill and Melinda Gates Foundation grant awarded to Noguchi Memorial Institute for Medical Research Postdoctoral and Postgraduate Training in Infectious Diseases Research (Global Health Grant # OPP52155); National Institutes of Health grant (NIH-NIAID RO1 # 1RO1AI099623) to MDW; European Developing Countries Clinical Trials Partnership (EDCTP)-West African Network of Excellence for Clinical Trials in TB, AIDS and Malaria (WANETAM) (Project code CB.07.41700.007). PMID- 28579629 TI - Prevalence and pattern of prescription errors in a Nigerian kidney hospital. AB - OBJECTIVES: To determine (i) the prevalence and pattern of prescription errors in our Centre and, (ii) appraise pharmacists' intervention and correction of identified prescription errors. DESIGN: A descriptive, single blinded cross sectional study. SETTING: Kidney Care Centre is a public Specialist hospital. The monthly patient load averages 60 General Out-patient cases and 17.4 in-patients. PARTICIPANTS: A total of 31 medical doctors (comprising of 2 Consultant Nephrologists, 15 Medical Officers, 14 House Officers), 40 nurses and 24 ward assistants participated in the study. One pharmacist runs the daily call schedule. Prescribers were blinded to the study. Prescriptions containing only galenicals were excluded. INTERVENTIONS: An error detection mechanism was set up to identify and correct prescription errors. Life-threatening prescriptions were discussed with the Quality Assurance Team of the Centre who conveyed such errors to the prescriber without revealing the on-going study. MAIN OUTCOME MEASURES: Prevalence of prescription errors, pattern of prescription errors, pharmacist's intervention. RESULTS: A total of 2,660 (75.0%) combined prescription errors were found to have one form of error or the other; illegitimacy 1,388 (52.18%), omission 1,221(45.90%), wrong dose 51(1.92%) and no error of style was detected. Life-threatening errors were low (1.1-2.2%). Errors were found more commonly among junior doctors and non-medical doctors. Only 56 (1.6%) of the errors were detected and corrected during the process of dispensing. CONCLUSION: Prescription errors related to illegitimacy and omissions were highly prevalent. There is a need to improve on patient-to-healthcare giver ratio. A medication quality assurance unit is needed in our hospitals. FUNDING: No financial support was received by any of the authors for this study. PMID- 28579630 TI - Quality of Health Care in Ghana: Mapping of Interventions and the Way Forward. AB - BACKGROUND: Ghana has made major strides in improving access to health services. Despite these improvements, Ghana did not meet the Millennium Development Goals 4 and 5. Quality of care is a major factor that could explain this shortfall. OBJECTIVE: To understand current practice and to identify needs in the area of quality of care in Ghana for improving health outcomes and to guide the National Institute for Health and Care Excellence (NICE) in supporting the care quality improvement efforts in Ghana. METHODS: The directory of existing standards, guidelines and protocols of the Ghana Health Service was reviewed and sixteen in depth interviews were conducted to identify interventions that addressed quality of care. Additional information was obtained during a NICE scoping visit to Accra followed by a study tour of Ghanaian stakeholders to NICE and to the National Health Service. RESULTS: Since 1988, 489 policy interventions have been identified that address quality of care. Among them, the development of health protocols and guidelines were the most frequent interventions (n=150), followed by health policies and strategies (n=106); interventions related to health information (n=77); development of training manuals and staff training (n=69); development of regulations (n=38) and interventions related to organisation of services (n=15). CONCLUSIONS: Ghana has made significant efforts in developing guidelines, policies and conducting in-service training. Supervision, monitoring and evaluation have also received attention. However, less effort has been made in developing processes and systems and involving communities and service users. Some recommendations were made to guide the future work on quality of care. FUNDING: Rockefeller Foundation. PMID- 28579631 TI - Fibrodysplasia ossificans progressiva: a case report. AB - Fibrodysplasia Ossificans Progressiva is a rare debilitating disorder of the musculoskeletal system affecting one in two million individuals. It is characterized by progressive extraskeletal ossification of soft tissues resulting in the original skeleton being encased in unyielding new bone leading to disability and ultimately death from cardiorespiratory failure. The present case brings to light the delays and potential pitfalls in diagnosis as a result of the rarity of the condition. PMID- 28579632 TI - A Multi-Functional Microelectrode Array Featuring 59760 Electrodes, 2048 Electrophysiology Channels, Stimulation, Impedance Measurement and Neurotransmitter Detection Channels. AB - Biological cells are characterized by highly complex phenomena and processes that are, to a great extent, interdependent. To gain detailed insights, devices designed to study cellular phenomena need to enable tracking and manipulation of multiple cell parameters in parallel; they have to provide high signal quality and high spatiotemporal resolution. To this end, we have developed a CMOS-based microelectrode array system that integrates six measurement and stimulation functions, the largest number to date. Moreover, the system features the largest active electrode array area to date (4.48*2.43 mm2) to accommodate 59,760 electrodes, while its power consumption, noise characteristics, and spatial resolution (13.5 MUm electrode pitch) are comparable to the best state-of-the-art devices. The system includes: 2,048 action-potential (AP, bandwidth: 300 Hz to 10 kHz) recording units, 32 local-field-potential (LFP, bandwidth: 1 Hz to 300 Hz) recording units, 32 current recording units, 32 impedance measurement units, and 28 neurotransmitter detection units, in addition to the 16 dual-mode voltage-only or current/voltage-controlled stimulation units. The electrode array architecture is based on a switch matrix, which allows for connecting any measurement/stimulation unit to any electrode in the array and for performing different measurement/stimulation functions in parallel. PMID- 28579633 TI - Rapid and Accurate C-V Measurements. AB - We report a new technique for the rapid measurement of full capacitance-voltage (C-V) characteristic curves. The displacement current from a 100 MHz applied sine wave, which swings from accumulation to strong inversion, is digitized directly using an oscilloscope from the metal-oxide-semiconductor (MOS) capacitor under test. A C-V curve can be constructed directly from this data but is severely distorted due to non-ideal behavior of real measurement systems. The key advance of this work is to extract the system response function using the same measurement set-up and a known MOS capacitor. The system response correction to the measured C-V curve of the unknown MOS capacitor can then be done by simple deconvolution. No de-skewing and/or leakage current correction is necessary, making it a very simple and quick measurement. Excellent agreement between the new fast C-V method and C-V measured conventionally by an LCR meter is achieved. The total time required for measurement and analysis is approximately 2 seconds, which is limited by our equipment. PMID- 28579634 TI - Dynamic susceptibility of concentric permalloy rings with opposite chirality vortices. AB - The high frequency dynamic behaviour of concentric permalloy nanorings with vortex domain structures with a thickness of 20 nm, a width in the range of 100 nm-250 nm, and a separation in the range of 10 nm-600 nm is investigated by micromagnetic simulations. The aim is to explore the ferromagnetic resonance of the concentric ring structure as a function of geometric parameters of the system. The dynamic susceptibility spectrum and spatial localization of the ferromagnetic resonance mode are investigated for varying ring widths and separations. The frequency of oscillation is significantly impacted by the presence of the magnetostatic interaction between each ring and can be modulated by a variation in the ring width and separation. The spatial localization of the uniform mode is found to vary as a function of ring separation, which corresponds to a large variation in amplitude of the real and imaginary components of the dynamic susceptibility. PMID- 28579635 TI - Investigation of nanoyarn preparation by modified electrospinning setup. AB - Higher ordered structures of nanofibers, including nanofiber-based yarns and cables, have a variety of potential applications, including wearable health monitoring systems, artificial tendons, and medical sutures. In this study, twisted assemblies of polyacrylonitrile (PAN), polyvinylidene fluoride trifluoroethylene (PVDF-TrFE), and polycaprolactone (PCL) nanofibers were fabricated via a modified electrospinning setup, consisting of a rotating cone shaped copper collector, two syringe pumps, and two high voltage power supplies. The fiber diameters and twist angles varied as a function of the rotary speed of the collector. Mechanical testing of the yarns revealed that PVDF-TrFe and PCL yarns have a higher strain-to-failure than PAN yarns, reaching 307% for PCL nanoyarns. For the first time, the porosity of nanofiber yarns was studied as a function of twist angle, showing that PAN nanoyarns are more porous than PCL yarns. PMID- 28579636 TI - The Changing Nonlinear Relationship between Income and Terrorism. AB - This article reinvestigates the relationship between real per capita gross domestic product (GDP) and terrorism. We devise a terrorism Lorenz curve to show that domestic and transnational terrorist attacks are each more concentrated in middle-income countries, thereby suggesting a nonlinear income-terrorism relationship. Moreover, this point of concentration shifted to lower income countries after the rising influence of the religious fundamentalist and nationalist/separatist terrorists in the early 1990s. For transnational terrorist attacks, this shift characterized not only the attack venue but also the perpetrators' nationality. The article then uses nonlinear smooth transition regressions to establish the relationship between real per capita GDP and terrorism for eight alternative terrorism samples, accounting for venue, perpetrators' nationality, terrorism type, and the period. Our nonlinear estimates are shown to be favored over estimates using linear or quadratic income determinants of terrorism. These nonlinear estimates are robust to additional controls. PMID- 28579637 TI - The Economic Importance of Financial Literacy: Theory and Evidence. AB - This paper undertakes an assessment of a rapidly growing body of economic research on financial literacy. We start with an overview of theoretical research which casts financial knowledge as a form of investment in human capital. Endogenizing financial knowledge has important implications for welfare as well as policies intended to enhance levels of financial knowledge in the larger population. Next, we draw on recent surveys to establish how much (or how little) people know and identify the least financially savvy population subgroups. This is followed by an examination of the impact of financial literacy on economic decision-making in the United States and elsewhere. While the literature is still young, conclusions may be drawn about the effects and consequences of financial illiteracy and what works to remedy these gaps. A final section offers thoughts on what remains to be learned if researchers are to better inform theoretical and empirical models as well as public policy. PMID- 28579638 TI - Marriage-Market Constraints and Mate-Selection Behavior: Racial, Ethnic, and Gender Differences in Intermarriage. AB - Despite theoretical consensus that marriage markets constrain mate selection behavior, few studies directly evaluate how local marriage market conditions influence intermarriage patterns. Using data from the American Community Survey, we examine what aspects of marriage markets influence mate selection; assess whether the associations between marriage market conditions and intermarriage are uniform by gender and across pan-ethnic groups; and investigate the extent to which marriage market conditions account for group differences in intermarriage patterns. Relative group size is the most salient and consistent determinant of intermarriage patterns across pan-ethnic groups and by gender. Marriage market constraints typically explain a larger share of pan-ethnic differences in intermarriage rates than individual traits, suggesting that scarcity of co-ethnic partners is a key reason behind decisions to intermarry. When faced with market constraints, men are more willing or more successful than women in crossing racial and ethnic boundaries in marriage. PMID- 28579639 TI - The Intergenerational Transmission of Union Instability in Early Adulthood. AB - Research on the intergenerational transmission of divorce should be expanded to incorporate disrupted nonmarital cohabitations. The current study (1) examined the transmission of union instability from parents to offspring using Waves I and IV of Add Health, (2) replaced the binary variables (divorced versus non divorced) typically used in this literature with count variables (number of disrupted unions), (3) relied on independent sources for data on parents' and offspring's union disruptions to minimize same-source bias, (4) assessed the mediating role of 11 theoretically derived variables (many not previously considered in this literature), and (5) incorporated information on discord in intact parental unions. Parent and offspring union disruptions were positively linked, with each parental disruption associated with a 16% increase in the number of offspring disruptions, net of controls. The mediators collectively accounted for 44% of the estimated intergenerational effect. Parent discord in intact unions also was associated with more offspring disruptions. PMID- 28579641 TI - Framing and Claiming: How Information-Framing Affects Expected Social Security Claiming Behavior. AB - This paper provides evidence that Social Security benefit claiming decisions are strongly affected by framing and are thus inconsistent with expected utility theory. Using a randomized experiment that controls for both observable and unobservable differences across individuals, we find that the use of a "breakeven analysis" encourages early claiming. Respondents are more likely to delay when later claiming is framed as a gain, and the claiming age is anchored at older ages. Additionally, the financially less literate, individuals with credit card debt, and those with lower earnings are more influenced by framing than others. PMID- 28579642 TI - An overview of recent research in marine biological invasions. AB - The Topical Collection on Invasive Species includes 50 articles addressing many tenets of marine invasion ecology. The collection covers important topics relating to propagule pressure associated with transport vectors, species characteristics, attributes of recipient ecosystems, invasion genetics, biotic interactions, testing of invasion hypotheses, invasion dynamics and spread, and impacts of nonindigenous species. This article summarizes some of the collection's highlights. PMID- 28579643 TI - Necessary but Insufficient: Why Measurement Invariance Tests Need Online Probing as a Complementary Tool. AB - Cross-national data production in social science research has increased dramatically in recent decades. Assessing the comparability of data is necessary before drawing substantive conclusions that are based on cross-national data. Researchers assessing data comparability typically use either quantitative methods such as multigroup confirmatory factor analysis or qualitative methods such as online probing. Because both methods have complementary strengths and weaknesses, this study applies both multigroup confirmatory factor analysis and online probing in a mixed-methods approach to assess the comparability of constructive patriotism and nationalism, two important concepts in the study of national identity. Previous measurement invariance tests failed to achieve scalar measurement invariance, which prohibits a cross-national comparison of latent means (Davidov 2009). The arrival of the 2013 ISSP Module on National Identity has encouraged a reassessment of both constructs and a push to understand why scalar invariance cannot be achieved. Using the example of constructive patriotism and nationalism, this study demonstrates how the combination of multigroup confirmatory factor analysis and online probing can uncover and explain issues related to cross-national comparability. PMID- 28579645 TI - Is Science for Us? Black Students' and Parents' Views of Science and Science Careers. AB - There are widespread policy concerns to improve (widen and increase) science, technology, engineering, and mathematics participation, which remains stratified by ethnicity, gender, and social class. Despite being interested in and highly valuing science, Black students tend to express limited aspirations to careers in science and remain underrepresented in post-16 science courses and careers, a pattern which is not solely explained by attainment. This paper draws on survey data from nationally representative student cohorts and longitudinal interview data collected over 4 years from 10 Black African/Caribbean students and their parents, who were tracked from age 10-14 (Y6-Y9), as part of a larger study on children's science and career aspirations. The paper uses an intersectional analysis of the qualitative data to examine why science careers are less "thinkable" for Black students. A case study is also presented of two young Black women who "bucked the trend" and aspired to science careers. The paper concludes with implications for science education policy and practice. PMID- 28579640 TI - Comparing fixed and collapsing boundary versions of the diffusion model. AB - Optimality studies and studies of decision-making in monkeys have been used to support a model in which the decision boundaries used to evaluate evidence collapse over time. This article investigates whether a diffusion model with collapsing boundaries provides a better account of human data than a model with fixed boundaries. We compared the models using data from four new numerosity discrimination experiments and two previously published motion discrimination experiments. When model selection was based on BIC values, the fixed boundary model was preferred over the collapsing boundary model for all of the experiments. When model selection was carried out using a parametric bootstrap cross-fitting method (PBCM), which takes into account the flexibility of the alternative models and the ability of one model to account for data from another model, data from 5 of 6 experiments favored either fixed boundaries or boundaries with only negligible collapse. We found that the collapsing boundary model produces response times distributions with the same shape as those produced by the fixed boundary model and that its parameters were not well-identified and were difficult to recover from data. Furthermore, the estimated boundaries of the best-fitting collapsing boundary model were relatively flat and very similar to those of the fixed-boundary model. Overall, a diffusion model with decision boundaries that converge over time does not provide an improvement over the standard diffusion model for our tasks with human data. PMID- 28579644 TI - Complex Organic Molecules tracing shocks along the outflow cavity in the high mass protostar IRAS 20126+4104. AB - We report on subarcsecond observations of complex organic molecules (COMs) in the high-mass protostar IRAS 20126+4104 with the Plateau de Bure Interferometer in its most extended configurations. In addition to the simple molecules SO, HNCO and H213CO, we detect emission from CH3CN, CH3OH, HCOOH, HCOOCH3, CH3OCH3, CH3CH2CN, CH3COCH3, NH2CN, and (CH2OH)2. SO and HNCO present a X-shaped morphology consistent with tracing the outflow cavity walls. Most of the COMs have their peak emission at the putative position of the protostar, but also show an extension towards the south(east), coinciding with an H2 knot from the jet at about 800-1000 au from the protostar. This is especially clear in the case of H213CO and CH3OCH3. We fitted the spectra at representative positions for the disc and the outflow, and found that the abundances of most COMs are comparable at both positions, suggesting that COMs are enhanced in shocks as a result of the passage of the outflow. By coupling a parametric shock model to a large gas-grain chemical network including COMs, we find that the observed COMs should survive in the gas phase for ~ 2000 yr, comparable to the shock lifetime estimated from the water masers at the outflow position. Overall, our data indicate that COMs in IRAS 20126+4104 may arise not only from the disc, but also from dense and hot regions associated with the outflow. PMID- 28579646 TI - Beyond Boys' Bad Behavior: Paternal Incarceration and Cognitive Development in Middle Childhood. AB - A growing number of American school-aged children have incarcerated or formally incarcerated parents necessitating a more comprehensive understanding of the intergenerational effects of mass imprisonment. Using the Fragile Families Study, I assess whether having an incarcerated father impacts children's cognitive skill development into middle childhood. While previous studies have primarily found effects for boys' behavior problems, matching models and sensitivity analyses demonstrate that experiencing paternal incarceration by age 9 is associated with lower cognitive skills for both boys and girls and these negative effects hold net of a pre-paternal incarceration measure of child cognitive ability. Moreover, I estimate that paternal incarceration explains between 2 and 15 percent of the Black-White achievement gap at age 9. These findings represent new outcomes of importance and suggest that paternal incarceration may play an even larger role in the production of intergenerational inequalities for American children than previously documented. PMID- 28579647 TI - Carbon nanotube/paraffin/montmorillonite composite phase change material for thermal energy storage. AB - A composite phase change material (PCM) comprised of organic montmorillonite (OMMT)/paraffin/grafted multi-walled nanotube (MWNT) is synthesized via ultrasonic dispersion and liquid intercalation. The microstructure of the composite PCM has been characterized to determine the phase distribution, and thermal properties (latent heat and thermal conductivity) have been measured by differential scanning calorimetry (DSC) and a thermal constant analyzer. The results show that paraffin molecules are intercalated in the montmorillonite layers and the grafted MWNTs are dispersed in the montmorillonite layers. The latent heat is 47.1 J/g, and the thermal conductivity of the OMMT/paraffin/grafted MWNT composites is 34% higher than that of the OMMT/paraffin composites and 65% higher than that of paraffin. PMID- 28579648 TI - Adenocarcinoma of the Cecum with Rare Splenic Metastasis. AB - Isolated splenic metasisis is a rare finding in colorectal carcinoma. We report a case of metastatic cecal adenocarcinoma to the spleen. In spring 2011, a 53 yearold woman underwent en bloc right hemicolectomy with partial omentectomy. The tumor was Stage III pT3 pN2a M0. She received four months of modified FOLFOX6 chemotherapy and one month of capecitabine. In spring 2012, a PET/CT revealed a low attenuation focus in the spleen consistent with metastatic adenocarcinoma, so she underwent splenectomy. Additional imaging has revealed no disease recurrence. There are only a small number of case reports for isolated splenic metastasis; thus, no standardized treatment course has been developed. PMID- 28579649 TI - A viscoactive constitutive modeling framework with variational updates for the myocardium. AB - We present a constitutive modeling framework for contractile cardiac mechanics by formulating a single variational principle from which incremental stress-strain relations and kinetic rate equations for active contraction and relaxation can all be derived. The variational framework seamlessly incorporates the hyperelastic behavior of the relaxed and contracted tissue along with the rate - and length - dependent generation of contractile force. We describe a three element, Hill-type model that unifies the active tension and active deformation approaches. As in the latter approach, we multiplicatively decompose the total deformation gradient into active and elastic parts, with the active deformation parametrizing the contractile Hill element. We adopt as internal variables the fiber, cross-fiber, and sheet normal stretch ratios. The kinetics of these internal variables are modeled via definition of a kinetic potential function derived from experimental force-velocity relations. Additionally, we account for dissipation during tissue deformation by adding a Newtonian viscous potential. To model the force activation, the kinetic equations are coupled with the calcium transient obtained from a cardiomyocyte electrophysiology model. We first analyze our model at the material point level using stress and strain versus time curves for different viscosity values. Subsequently, we couple our constitutive framework with the finite element method (FEM) and study the deformation of three dimensional tissue slabs with varying cardiac myocyte orientation. Finally, we simulate the contraction and relaxation of an ellipsoidal left ventricular model and record common kinematic measures, such as ejection fraction, and myocardial tissue volume changes. PMID- 28579650 TI - IMPROVED Cr II log(gf ) VALUES AND ABUNDANCE DETERMINATIONS IN THE PHOTOSPHERES OF THE SUN AND METAL-POOR STAR HD 84937. AB - New emission branching fraction (BF) measurements for 183 lines of the second spectrum of chromium (Cr II) and new radiative lifetime measurements from laser induced fluorescence for 8 levels of Cr+ are reported. The goals of this study are to improve transition probability measurements in Cr II and reconcile solar and stellar Cr abundance values based on Cr I and Cr II lines. Eighteen spectra from three Fourier Transform Spectrometers supplemented with ultraviolet spectra from a high-resolution echelle spectrometer are used in the BF measurements. Radiative lifetimes from this study and earlier publications are used to convert the BFs into absolute transition probabilities. These new laboratory data are applied to determine the Cr abundance log epsilon in the Sun and metal-poor star HD 84937. The mean result in the Sun is = 5.624+/-0.009 compared to = 5.644 +/- 0.006 on a scale with the hydrogen abundance log epsilon(H) = 12 and with the uncertainty representing only line-to line scatter. A Saha (ionization balance) test on the photosphere of HD 84937 is also performed, yielding = 3.417 +/- 0.006 and 30 eV)> = 3.3743+/-30.011 for this dwarf star. We find a correlation of Cr with the iron-peak element Ti, suggesting an associated nucleosynthetic production. Four iron-peak elements (Cr along with Ti, V, and Sc) appear to have a similar (or correlated) production history-other iron-peak elements appear not to be associated with Cr. PMID- 28579651 TI - Copper-Catalyzed Electrophilic Amination of Heteroaromatic and Aromatic C-H Bonds via TMPZnCl*LiCl Mediated Metalation. PMID- 28579652 TI - Enantioselective Synthesis of alpha-Bromonitroalkanes for Umpolung Amide Synthesis: Preparation of tert-Butyl ((1R)-1-(4-(benzyloxy)phenyl)-2-bromo-2 nitroethyl)carbamate. PMID- 28579653 TI - Housing First, but What Comes Second? A Qualitative Study of Resident, Staff and Management Perspectives on Single-Site Housing First Program Enhancement. AB - Single-site Housing First (HF) is associated with reduced publicly funded service utilization and costs and alcohol-related harm for chronically homeless individuals with severe alcohol problems. Many residents, however, continue to experience alcohol-related problems after their move into single-site HF. Thus, it is necessary to explore areas for program enhancement after individuals move into single-site HF. To this end, we collected qualitative data via 30 hours of naturalistic observation, staff focus groups (n = 3), and one-on-one interviews with single-site HF residents (n = 44), program staff (n = 7), and agency management (n = 4). Qualitative analyses were used to construct a conceptual or thematic description of residents', staff's, and management's suggestions for program enhancement, which comprised 3 areas: (a) enhancing training and support for staff, (b) increasing residents' access to meaningful activities, and (c) exploring alternate pathways to recovery. Development of programming addressing these areas may help residents continue to reduce alcohol-related harm and improve health and quality of life after their move into single-site HF. PMID- 28579654 TI - Trajectories of Organized Activity Participation Among Urban Adolescents: Associations with Young Adult Outcomes. AB - Organized activity participation provides opportunities for adolescents to develop assets that may support favorable outcomes in young adulthood. Activity participation may be especially beneficial for marginalized youth as they are likely to face stressors that increase risk of negative outcomes. We used growth mixture modeling (GMM) to identify activity participation trajectories among African American adolescents in an urban, disadvantaged community (Wave 1: mean age=14.86 years, SD=0.64; 49% male, N=681). We also investigated if young adult outcomes differed by trajectory subgroups. Our results suggested a three-class model best fit the data: low, decreasing (74%), moderate, consistent (21%) and moderate, increasing participation subgroups (5%). Adolescents in the increasing subgroup reported higher life satisfaction and lower substance use in young adulthood compared to the decreasing subgroup. Youth who increase participation in activities over time may experience greater opportunities for building assets related to positive development that support health and well-being into young adulthood. PMID- 28579655 TI - Development of tunable miniature piezoelectric-based scanners validated by the combination of two scanners in a direct image relay technique. AB - Miniature piezoelectric actuators are commonly used as a compact means to relay images for numerous endoscopic applications. These scanners normally consist of an electrically driven lead zirconate titanate (PZT) tube that oscillates an optical fiber at its resonant frequency. The diameter and length of the PZT and fiber, the attachment of the fiber to the PZT, as well as the driving signal determine the main characteristics of the scan-frequency and amplitude of vibration. We present a new, robust, and repeatable method for producing miniature PZT actuators. The described technology allows for continuous tuning of the scanner mechanical properties during the assembly stage, enabling adjustment of resonant frequency and subsequent amplitude of vibration without a priori knowledge of the fiber's mechanical properties. The method consists of manufacturing high-precision fiber-holding plastic inserts with diamond turning lathes that allow for the fiber length to be quickly varied and locked during operation in order to meet the preferred performance. This concept of tuned PZTs was demonstrated with an imaging technique that combined two scanners oscillating in unison at the ends of a single optical fiber to relay images without the need to correlate the driving signal with a detector. PMID- 28579657 TI - From Elementary School to Midlife: Childhood Personality Predicts Behavior During Cognitive Testing over Four Decades Later. AB - The current study uses a prospective, longitudinal design and lifespan perspective to understand how child personality relates to directly observed adult behavior during cognitive testing. Teacher assessments of child Big Five personality in elementary school were correlated with directly observed behaviors during a videotaped cognitive test four decades later. Past work suggested Openness and Conscientiousness may relate to task-relevant academic behaviors. Childhood Openness was associated with several behaviors, even after controlling for participant's cognitive performance. Childhood Conscientiousness was also related to behavior, but not as expected. Other Big Five ratings were not reliably related to behavior. The study examined personality stability in a unique way and suggests a further examination of how Openness in children manifests in later behavior. PMID- 28579656 TI - Design and fabrication of a miniature objective consisting of high refractive index zinc sulfide lenses for laser surgery. AB - A miniature laser ablation probe relying on an optical fiber to deliver light requires a high coupling efficiency objective with sufficient magnification in order to provide adequate power and field for surgery. A diffraction-limited optical design is presented that utilizes high refractive index zinc sulfide to meet specifications while reducing the miniature objective down to two lenses. The design has a hypercentric conjugate plane on the fiber side and is telecentric on the tissue end. Two versions of the objective were built on a diamond lathe-a traditional cylindrical design and a custom-tapered mount. Both received an antireflective coating. The objectives performed as designed in terms of observable resolution and field of view as measured by imaging a 1951 USAF resolution target. The slanted edge technique was used to find Strehl ratios of 0.75 and 0.78, respectively, indicating nearly diffraction-limited performance. Finally, preliminary ablation experiments indicated threshold fluence of gold film was comparable to similar reported probes. PMID- 28579658 TI - Human-Robot Collaboration Dynamic Impact Testing and Calibration Instrument for Disposable Robot Safety Artifacts. AB - The Dynamic Impact Testing and Calibration Instrument (DITCI) is a simple instrument with a significant data collection and analysis capability that is used for the testing and calibration of biosimulant human tissue artifacts. These artifacts may be used to measure the severity of injuries caused in the case of a robot impact with a human. In this paper we describe the DITCI adjustable impact and flexible foundation mechanism, which allows the selection of a variety of impact force levels and foundation stiffness. The instrument can accommodate arrays of a variety of sensors and impact tools, simulating both real manufacturing tools and the testing requirements of standards setting organizations. A computer data acquisition system may collect a variety of impact motion, force, and torque data, which are used to develop a variety of mathematical model representations of the artifacts. Finally, we describe the fabrication and testing of human abdomen soft tissue artifacts, used to display the magnitude of impact tissue deformation. Impact tests were performed at various maximum impact force and average pressure levels. PMID- 28579661 TI - Identifying technology innovations for marginalized smallholders-A conceptual approach. AB - This paper adds a contribution in the existing literature in terms of theoretical and conceptual background for the identification of idle potentials of marginal rural areas and people by means of technological and institutional innovations. The approach follows ex-ante assessment for identifying suitable technology and institutional innovations for marginalized smallholders in marginal areas-divided into three main parts (mapping, surveying and evaluating) and several steps. Finally, it contributes to the inclusion of marginalized smallholders by an improved way of understanding the interactions between technology needs, farming systems, ecological resources and poverty characteristics in the different segments of the poor, and to link these insights with productivity enhancing technologies. PMID- 28579662 TI - Gentrification and Residential Mobility in Philadelphia. AB - Gentrification has provoked considerable controversy surrounding its effects on residential displacement. Using a unique individual-level, longitudinal data set, this study examines mobility rates and residential destinations of residents in gentrifying neighborhoods during the recent housing boom and bust in Philadelphia for various strata of residents and different types of gentrification. We find that vulnerable residents, those with low credit scores and without mortgages, are generally no more likely to move from gentrifying neighborhoods compared with their counterparts in nongentrifying neighborhoods. When they do move, however, they are more likely to move to lower-income neighborhoods. Residents in gentrifying neighborhoods at the aggregate level have slightly higher mobility rates, but these rates are largely driven by more advantaged residents. These findings shed new light on the heterogeneity in mobility patterns across residents in gentrifying neighborhoods and suggest that researchers should focus more attention on the quality of residential moves and nonmoves for less advantaged residents, rather than mobility rates alone. PMID- 28579659 TI - Emotion Regulation and the Transdiagnostic Role of Repetitive Negative Thinking in Adolescents with Social Anxiety and Depression. AB - Social anxiety and depression are common mental health problems among adolescents and are frequently comorbid. Primary aims of this study were to (1) elucidate the nature of individual differences in specific emotion regulation deficits among adolescents with symptoms of social anxiety and depression, and (2) determine whether repetitive negative thinking (RNT) functions as a transdiagnostic factor. A diverse sample of adolescents (N = 1065) completed measures assessing emotion regulation and symptoms of social anxiety and depression. Results indicated that adolescents with high levels of social anxiety and depression symptoms reported decreased emotional awareness, dysregulated emotion expression, and reduced use of emotion management strategies. The hypothesized structural model in which RNT functions as a transdiagnostic factor exhibited a better fit than an alternative model in which worry and rumination function as separate predictors of symptomatology. Findings implicate emotion regulation deficits and RNT in the developmental psychopathology of youth anxiety and mood disorders. PMID- 28579660 TI - The Effects of Psychotherapy for Major Depressive Disorder on Daily Mood and Functioning: A Longitudinal Experience Sampling Study. AB - Experience sampling methodology (ESM) was used in a randomized controlled trial of short-term therapy to examine changes in daily affect and reactivity to daily event appraisals among depressed patients. Fifty-five depressed adults (mean age 37 years, 80% female) were randomly assigned to one of two therapy conditions. Using an interactive voice response system, participants rated activities and emotional functioning eight times per day for seven days. Thirty-one participants completed treatment and repeated ESM post-treatment. Broad improvements in mood, cognition, and physical functioning were similar across treatment conditions, with the largest improvements for markers of positive affect. Participants demonstrated increased resilience, i.e., diminished reactivity to stressors at post-treatment. Changes in reactivity to positive daily situations were minimal. Findings underscore the utility of ESM in psychotherapy research and the importance of including measures of both positive and negative affect and experiences. PMID- 28579663 TI - News for assimilation or integration? Examining the functions of news in shaping acculturation experiences of immigrants in the Netherlands and Spain. AB - This study investigates the functions of news media in shaping acculturation experiences of new economic and refugee immigrants in the Netherlands and Spain. Focus group data revealed that consumption of host country news media was mainly connected to immigrants' deliberate strategies to assimilate the culture, politics and language of the host society, while exposure to transnational news was viewed in terms of strategies of integration in both countries. We also observed that participants' educational background and language skills combined with their perceptions of the host country's news have an impact on the use they make of news for assimilating and/or integrating into the host society. Finally, important sociopolitical conditions of the context influenced the ways participants use the news media in their process of acculturation. PMID- 28579664 TI - Walking in Two French Neighborhoods: A Study of How Park Numbers and Locations Relate to Everyday Walking. AB - Research indicates that people are drawn to green spaces with attractive amenities. This study extends that finding by comparing walking patterns in two neighborhoods with different numbers of parks; parks did not differ in rated attractiveness nor did neighborhoods differ substantially in rated walkability. Adults, aged 32-86 years (n = 90), drew their 3 most recent walking routes on maps of their neighborhood. Analyses showed that participants' round trips were longer by 265.5 meters (.16 mile) in the neighborhood with a single, large, centrally located park (p < .02). However, participants in the neighborhood with multiple, small, more distributed parks, visited more streets, p < .001, more streets with green spaces, p < .038, and used more varied routes, p < .012. Results suggest there are potential benefits to both layouts. Large centralized parks may invite longer walks; smaller, well-distributed parks may invite more varied routes suggestive of appropriation and motivation processes. Both layouts might be combined in a single neighborhood to attract more walkers. PMID- 28579666 TI - Optical design and Initial Results from The National Institute of Standards and Technology's AMMT/TEMPS Facility. AB - The National Institute of Standards and Technology's (NIST) Physical Measurement and Engineering Laboratories are jointly developing the Additive Manufacturing Measurement Testbed (AMMT)/ Temperature and Emittance of Melts, Powders and Solids (TEMPS) facilities. These facilities will be co-located on an open architecture laser-based powder bed fusion system allowing users full access to the system's operation parameters. This will provide users with access to machine independent monitoring and control of the powder bed fusion process. In this paper there will be emphasis on the AMMT, which incorporates in-line visible light collection optics for monitoring and feedback control of the powder bed fusion process. We shall present an overview of the AMMT/TEMPS program and its goals. The optical and mechanical design of the open architecture powder-bed fusion system and the AMMT will also be described. In addition, preliminary measurement results from the system along with the current status of the system will be described. PMID- 28579665 TI - FOXP3-stained image analysis for follicular lymphoma: Optimal adaptive thresholding with maximal nucleus coverage. AB - Immunohistochemical detection of FOXP3 antigen is a usable marker for detection of regulatory T lymphocytes (TR) in formalin fixed and paraffin embedded sections of different types of tumor tissue. TR plays a major role in homeostasis of normal immune systems where they prevent auto reactivity of the immune system towards the host. This beneficial effect of TR is frequently "hijacked" by malignant cells where tumor-infiltrating regulatory T cells are recruited by the malignant nuclei to inhibit the beneficial immune response of the host against the tumor cells. In the majority of human solid tumors, an increased number of tumor-infiltrating FOXP3 positive TR is associated with worse outcome. However, in follicular lymphoma (FL) the impact of the number and distribution of TR on the outcome still remains controversial. In this study, we present a novel method to detect and enumerate nuclei from FOXP3 stained images of FL biopsies. The proposed method defines a new adaptive thresholding procedure, namely the optimal adaptive thresholding (OAT) method, which aims to minimize under-segmented and over-segmented nuclei for coarse segmentation. Next, we integrate a parameter free elliptical arc and line segment detector (ELSD) as additional information to refine segmentation results and to split most of the merged nuclei. Finally, we utilize a state-of-the-art super-pixel method, Simple Linear Iterative Clustering (SLIC) to split the rest of the merged nuclei. Our dataset consists of 13 region of-interest images containing 769 negative and 88 positive nuclei. Three expert pathologists evaluated the method and reported sensitivity values in detecting negative and positive nuclei ranging from 83-100% and 90-95%, and precision values of 98-100% and 99-100%, respectively. The proposed solution can be used to investigate the impact of FOXP3 positive nuclei on the outcome and prognosis in FL. PMID- 28579667 TI - Interior Tomography from Differential Phase Contrast Data via Hilbert Transform Based on Spline Functions. AB - X-ray phase contrast imaging is an important mode due to its sensitivity to subtle features of soft biological tissues. Grating-based differential phase contrast (DPC) imaging is one of the most promising phase imaging techniques because it works with a normal x-ray tube of a large focal spot at a high flux rate. However, a main obstacle before this paradigm shift is the fabrication of large-area gratings of a small period and a high aspect ratio. Imaging large objects with a size-limited grating results in data truncation which is a new type of the interior problem. While the interior problem was solved for conventional x-ray CT through analytic extension, compressed sensing and iterative reconstruction, the difficulty for interior reconstruction from DPC data lies in that the implementation of the system matrix requires the differential operation on the detector array, which is often inaccurate and unstable in the case of noisy data. Here, we propose an iterative method based on spline functions. The differential data are first back-projected to the image space. Then, a system matrix is calculated whose components are the Hilbert transforms of the spline bases. The system matrix takes the whole image as an input and outputs the back-projected interior data. Prior information normally assumed for compressed sensing is enforced to iteratively solve this inverse problem. Our results demonstrate that the proposed algorithm can successfully reconstruct an interior region of interest (ROI) from the differential phase data through the ROI. PMID- 28579669 TI - How Important is Parental Education for Child Nutrition? AB - Existing evidence on the impacts of parental education on child nutrition is plagued by both internal and external validity concerns. In this paper we try to address these concerns through a novel econometric analysis of 376,992 preschool children from 56 developing countries. We compare a naive least square model to specifications that include cluster fixed effects and cohort-based educational rankings to reduce biases from omitted variables before gauging sensitivity to sub-samples and exploring potential explanations of education-nutrition linkages. We find that the estimated nutritional returns to parental education are: (a) substantially reduced in models that include fixed effects and cohort rankings; (b) larger for mothers than for fathers; (c) generally increasing, and minimal for primary education; (d) increasing with household wealth; (e) larger in countries/regions with higher burdens of undernutrition; (f) larger in countries/regions with higher schooling quality; and (g) highly variable across country sub-samples. These results imply substantial uncertainty and variability in the returns to education, but results from the more stringent models imply that even the achievement of very ambitious education targets would only lead to modest reductions in stunting rates in high-burden countries. We speculate that education might have more impact on the nutritional status of the next generation if school curricula focused on directly improving health and nutritional knowledge of future parents. PMID- 28579668 TI - Cognitive Attributes of Adequate and Inadequate Responders to Reading Intervention in Middle School. AB - No studies have investigated the cognitive attributes of middle school students who are adequate and inadequate responders to Tier 2 reading intervention. We compared students in Grades 6 and 7 representing groups of adequate responders (n = 77) and inadequate responders who fell below criteria in (a) comprehension (n = 54); (b) fluency (n = 45); and (c) decoding, fluency, and comprehension (DFC; n = 45). These students received measures of phonological awareness, listening comprehension, rapid naming, processing speed, verbal knowledge, and nonverbal reasoning. Multivariate comparisons showed a significant Group-by-Task interaction: the comprehension-impaired group demonstrated primary difficulties with verbal knowledge and listening comprehension, the DFC group with phonological awareness, and the fluency-impaired group with phonological awareness and rapid naming. A series of regression models investigating whether responder status explained unique variation in cognitive skills yielded largely null results consistent with a continuum of severity associated with level of reading impairment, with no evidence for qualitative differences in the cognitive attributes of adequate and inadequate responders. PMID- 28579670 TI - Modeling Preference and Willingness to Pay for Drought Tolerance (DT) in Maize in Rural Zimbabwe. AB - Maize plays a leading role in the food security of millions in southern Africa, yet it is highly vulnerable to the moisture stress brought about by the erratic rainfall patterns that characterize weather systems in the area. Developing and making drought-tolerant maize varieties available to farmers in the region has thus long been a key goal on the regional development agenda. Farm-level adoption of these varieties, however, depends on local perceptions of the value they add, along with willingness to pay (WTP) for it. Focusing on Zimbabwe, this research aimed at estimating the implicit prices farmers are willing to pay for drought tolerance in maize compared to other preferred traits. Using a choice experiment framework, we generated 12,600 observations from a random sample of 1,400 households in communal areas within 14 districts of Zimbabwe. Taste parameters and heterogeneities were estimated using the generalized multinomial logit model (G-MNL). The results reveal drought tolerance, grain yield, covered cob tip, cob size, and semi-flint texture to be the most preferred traits by farm households in Zimbabwe. The WTP estimates show that farmers are willing to pay a premium for drought tolerance equal to 2.56, 7, 3.2, and 5 times higher than for an additional ton of yield per acre, bigger cob size, larger grain size, and covered cob tip, respectively. We suggest designing and implementing innovative ways of promoting DT maize along with awareness-raising activities to enhance contextual understandings of drought and drought risk to speed adoption of new DT maize varieties by risk-prone farming communities. Given the high level of rural literacy and the high rate of adoption of improved maize, trait-based promotion and marketing of varieties constitutes the right strategy. PMID- 28579672 TI - A new method for robust mixture regression. AB - Finite mixture regression models have been widely used for modelling mixed regression relationships arising from a clustered and thus heterogenous population. The classical normal mixture model, despite its simplicity and wide applicability, may fail in the presence of severe outliers. Using a sparse, case specific, and scale-dependent mean-shift mixture model parameterization, we propose a robust mixture regression approach for simultaneously conducting outlier detection and robust parameter estimation. A penalized likelihood approach is adopted to induce sparsity among the mean-shift parameters so that the outliers are distinguished from the remainder of the data, and a generalized Expectation-Maximization (EM) algorithm is developed to perform stable and efficient computation. The proposed approach is shown to have strong connections with other robust methods including the trimmed likelihood method and M estimation approaches. In contrast to several existing methods, the proposed methods show outstanding performance in our simulation studies. PMID- 28579671 TI - Losses, inefficiencies and waste in the global food system. AB - Losses at every stage in the food system influence the extent to which nutritional requirements of a growing global population can be sustainably met. Inefficiencies and losses in agricultural production and consumer behaviour all play a role. This paper aims to understand better the magnitude of different losses and to provide insights into how these influence overall food system efficiency. We take a systems view from primary production of agricultural biomass through to human food requirements and consumption. Quantities and losses over ten stages are calculated and compared in terms of dry mass, wet mass, protein and energy. The comparison reveals significant differences between these measurements, and the potential for wet mass figures used in previous studies to be misleading. The results suggest that due to cumulative losses, the proportion of global agricultural dry biomass consumed as food is just 6% (9.0% for energy and 7.6% for protein), and 24.8% of harvest biomass (31.9% for energy and 27.8% for protein). The highest rates of loss are associated with livestock production, although the largest absolute losses of biomass occur prior to harvest. Losses of harvested crops were also found to be substantial, with 44.0% of crop dry matter (36.9% of energy and 50.1% of protein) lost prior to human consumption. If human over-consumption, defined as food consumption in excess of nutritional requirements, is included as an additional inefficiency, 48.4% of harvested crops were found to be lost (53.2% of energy and 42.3% of protein). Over-eating was found to be at least as large a contributor to food system losses as consumer food waste. The findings suggest that influencing consumer behaviour, e.g. to eat less animal products, or to reduce per capita consumption closer to nutrient requirements, offer substantial potential to improve food security for the rising global population in a sustainable manner. PMID- 28579674 TI - IR Residency: Did Anyone See This Coming? PMID- 28579673 TI - Spatial and temporal variations in airborne Ambrosia pollen in Europe. AB - The European Commission Cooperation in Science and Technology (COST) Action FA1203 "SMARTER" aims to make recommendations for the sustainable management of Ambrosia across Europe and for monitoring its efficiency and cost-effectiveness. The goal of the present study is to provide a baseline for spatial and temporal variations in airborne Ambrosia pollen in Europe that can be used for the management and evaluation of this noxious plant. The study covers the full range of Ambrosia artemisiifolia L. distribution over Europe (39 degrees N-60 degrees N; 2 degrees W-45 degrees E). Airborne Ambrosia pollen data for the principal flowering period of Ambrosia (August-September) recorded during a 10-year period (2004-2013) were obtained from 242 monitoring sites. The mean sum of daily average airborne Ambrosia pollen and the number of days that Ambrosia pollen was recorded in the air were analysed. The mean and standard deviation (SD) were calculated regardless of the number of years included in the study period, while trends are based on those time series with 8 or more years of data. Trends were considered significant at p < 0.05. There were few significant trends in the magnitude and frequency of atmospheric Ambrosia pollen (only 8% for the mean sum of daily average Ambrosia pollen concentrations and 14% for the mean number of days Ambrosia pollen were recorded in the air). The direction of any trends varied locally and reflected changes in sources of the pollen, either in size or in distance from the monitoring station. Pollen monitoring is important for providing an early warning of the expansion of this invasive and noxious plant. PMID- 28579675 TI - Decision Making in Interventional Oncology: Intra-arterial Therapies for Metastatic Colorectal Cancer-Y90 and Chemoembolization. AB - Colorectal cancer is the third most common cancer in the United States and the liver is the most common site of metastatic disease. The presence and extent of hepatic metastases are a major prognostic indicator. Although surgical resection is the accepted first-line therapy for colorectal liver metastasis, only 20 to 25% of patients are eligible for resection due to the extent and location of disease. This article discusses the current role of transarterial therapies in the treatment of colorectal liver metastases. PMID- 28579676 TI - Decision Making: Intra-arterial Therapies for Cholangiocarcinoma-TACE and TARE. AB - The incidence of intrahepatic cholangiocarcinoma (ICC) has been increasing in recent years and now represents the second most common primary hepatic cancer in the United States. The prognosis is dismal without surgical resection. In patients ineligible to receive curative treatments, locoregional therapies represent a diverse array of techniques that can stabilize or reverse tumor progression to improve overall survival and reduce tumor-related symptoms. Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) have been demonstrated to be efficacious methods for this patient population. Deciding between these two options is challenging. This article reviews the differences in patient selection, preprocedural evaluation, financial considerations and availability, quality of life, and rates of complications and overall survival. PMID- 28579677 TI - Decision Making for Selection of Transarterial Locoregional Therapy of Metastatic Neuroendocrine Tumors. AB - Transarterial locoregional therapies (LRTs) are indispensable components of the modern interventional oncologic therapy of liver-dominant metastatic neuroendocrine tumors (NETs). The scope of available LRTs and their nuanced differences mandates a thorough understanding of their relative applicability and effectiveness in certain clinical circumstances to prescribe appropriate, patient specific, image-guided therapy. This article aims to provide an overview of transarterial LRT options for liver-dominant metastatic NETs and therapy selection by reviewing procedure types, their advantages and disadvantages, and comparative efficacy in common case scenarios. PMID- 28579678 TI - Transarterial Chemoembolization and Radioembolization across Barcelona Clinic Liver Cancer Stages. AB - Transarterial chemoembolization (TACE) is a well-established treatment for hepatocellular carcinoma (HCC). TACE has a clearly delineated role within the Barcelona Clinic Liver Cancer (BCLC) staging framework, and TACE has been shown to bridge patients to transplantation and to downsize patients' tumor burden to meet transplantation criteria. Radioembolization (RE) also has an evolving role in the treatment of HCC. RE has evidence-based applications across the range of BCLC stages ranging from segmentectomy for patients with solitary lesions not amenable to ablation to lobar therapy for patients with multifocal HCC, and to treatment of advanced disease with portal vein thrombosis. This article aims to elucidate the evidence behind these therapies and to provide a rationale for their utilization across the spectrum of BCLC stages in the treatment of HCC. PMID- 28579679 TI - Yttrium-90 Radioembolization for Metastatic Colorectal Cancer: Outcomes by Number of Lines of Therapy. AB - Metastatic colorectal cancer represents the most common liver malignancy, and imparts a very poor prognosis for those who develop this disease. Unlike primary liver tumors such as hepatocellular carcinoma, which largely develops in patients with underlying cirrhosis, most metastatic liver tumor patients have normal underlying liver function. Owing to this, most will succumb to tumoral replacement of the liver rather than from underlying liver dysfunction. Radioembolization represents a treatment modality that can be used in multiple fashions to treat one or both lobes of the liver. Techniques depend on whether the procedure is used as first-line, second/third-line, or as salvage therapy. Outcomes and complications of radioembolization are presented in this article, as well as background information on colorectal cancer and systemic therapies. PMID- 28579680 TI - Decision Making: Osteoplasty, Ablation, or Combined Therapy for Spinal Metastases. AB - Metastatic disease involving the spine and pelvis is common, often resulting in significant pain and disability. Several percutaneous interventions have been described, including osteoplasty, ablation, and screw fixation, that when used alone or in combination can significantly reduce pain and disability from metastatic bone disease. Although it is possible to make a significant impact in patient care with basic principles and techniques, certain advanced techniques can extend the application of percutaneous interventions while minimizing morbidity. PMID- 28579681 TI - Making the Case: Intra-arterial Therapy for Less Common Metastases. AB - Intra-arterial therapies have high antitumor activity for both primary and secondary hepatic malignancies. Selective infusions allow increased delivery of cytoreductive therapy to the tumor bed while sparing the normal hepatic parenchyma. These therapies are now often applied in the outpatient setting or with short overnight hospital stays and have a growing role in the treatment of liver-dominant disease from metastatic colorectal cancer and from neuroendocrine tumors. Less commonly, intra-arterial therapies are applied to treat secondary hepatic malignancies from breast cancer, melanoma, pancreatic adenocarcinoma, and soft-tissue sarcomas. The available data are limited and generally retrospective observational cohort series of single institutions. The purpose of this article is to summarize the recent literature on outcomes for intra-arterial therapy in nonsurgical patients. Multi-institutional registries and prospective data are greatly needed, as intra-arterial therapies are increasingly applied in these patients to stop progression of chemorefractory tumors. PMID- 28579682 TI - The Intersection of Palliative Care and Interventional Radiology: Enhancing Understanding and Collaboration. AB - In the treatment of cancer patients, many interventional radiologic procedures are palliative in nature. The goal for these therapies is often something other than cure, such as prolonged survival or improved quality of life. The goals of therapy should be matched with the patient's wishes, and must include open communication between the health care provider and the patient. Hospice and palliative medicine is its own specialty, and a multidisciplinary approach to the care of cancer patients should include discussions with these health care specialists. This article will briefly define palliative care in general, describe the specialty of hospice and palliative medicine, and discuss how hospice differs from palliative care. Finally, it will highlight opportunities for interventional radiology specialists to incorporate more deliberately palliative care skills and competencies into their own practice and to collaborate with palliative care specialists. PMID- 28579684 TI - Decision Making: Thermal Ablation Options for Small Renal Masses. AB - Renal cell carcinoma is a relatively common tumor, with an estimated 63,000 new cases being diagnosed in the United States in 2016. Surgery, be it with partial or total nephrectomy, is considered the mainstay of treatment for many patients. However, those patients with small renal masses, typically less than 3 to 4 cm in size who are deemed unsuitable for surgery, may be suitable for percutaneous thermal ablation. We review the various treatment modalities, including radiofrequency ablation, microwave ablation, and cryoablation; discuss the advantages and disadvantages of each method; and review the latest data concerning the performance of the various ablative modalities compared with each other, and compared with surgery. PMID- 28579685 TI - Decision Making in Interventional Oncology: Ablative Options in the Lung. AB - Image-guided ablation is safe and effective for the treatment of both primary and metastatic tumors in the lung. This article reviews the three most commonly used ablative options: radiofrequency ablation, microwave ablation, and cryoablation. We describe the advantages of each ablation modality in the lung and how to choose the most appropriate ablation device based on patient and tumor characteristics. The optimal technique for lung ablation is discussed and technical tips for improving clinical outcome are described. PMID- 28579683 TI - Metastatic Liver Disease: Indications for Locoregional Therapy and Supporting Data. AB - Metastatic liver disease is a major cause of cancer-related morbidity and mortality. Surgical resection is considered the only curative treatment, yet only a minority is eligible. Patients who present with unresectable disease are treated with systemic agents and/or locoregional therapies. The latter include thermal ablation and catheter-based transarterial interventions. Thermal ablation is reserved for those with limited tumor burden. It is used to downstage the disease to enable curative surgical resection, as an adjunct to surgery, or in select patients it is potentially curative. Transarterial therapies are indicated in those with more diffuse disease. The goals of care are to palliate symptoms and prolong survival. The indications and supporting data for thermal ablation and transarterial interventions are reviewed, technical and tumor factors that need to be considered prior to intervention are outlined, and finally several cases are presented. PMID- 28579686 TI - Interventional Oncology Service Development. AB - Interventional oncology is rapidly expanding its suite of oncologic therapies, providing unique proven therapeutic benefits. To grow a practice alongside other oncology specialties, knowledge of cancer fundamentals is required. Areas of interest include methods to assess disease stage, treatment toxicity, and response. Additionally, techniques to leverage opportunities and resources available at one's institution toward practice development and efficiency will be reviewed. PMID- 28579688 TI - Intravascular Ultrasound-Guided Intervention for May-Thurner Syndrome. PMID- 28579690 TI - Percutaneous Aortic Fenestration for Symptomatic Type B Aortic Dissection. PMID- 28579687 TI - Therapeutic Ultrasound and Prostate Cancer. AB - Therapeutic ultrasound approaches including high-intensity focused ultrasound (HIFU) are emerging as popular minimally invasive alternative treatments for localized, low-to-intermediate risk prostate cancer. FDA approval was recently granted for two ultrasound-guided HIFU devices. Clinical trials for devices using MRI guidance are ongoing. The current level of evidence for whole-gland ultrasound ablation suggests that its clinical efficacy and adverse event rates including erectile dysfunction and urinary incontinence are similar to current definitive therapies such as radical prostatectomy and external-beam radiotherapy. Short-term data suggest that more focal therapy could reduce the rates of adverse events. PMID- 28579689 TI - Overview of Staging Systems for Hepatocellular Carcinoma and Implications for Interventional Radiology. PMID- 28579691 TI - Does prediction error drive one-shot declarative learning? AB - The role of prediction error (PE) in driving learning is well-established in fields such as classical and instrumental conditioning, reward learning and procedural memory; however, its role in human one-shot declarative encoding is less clear. According to one recent hypothesis, PE reflects the divergence between two probability distributions: one reflecting the prior probability (from previous experiences) and the other reflecting the sensory evidence (from the current experience). Assuming unimodal probability distributions, PE can be manipulated in three ways: (1) the distance between the mode of the prior and evidence, (2) the precision of the prior, and (3) the precision of the evidence. We tested these three manipulations across five experiments, in terms of peoples' ability to encode a single presentation of a scene-item pairing as a function of previous exposures to that scene and/or item. Memory was probed by presenting the scene together with three choices for the previously paired item, in which the two foil items were from other pairings within the same condition as the target item. In Experiment 1, we manipulated the evidence to be either consistent or inconsistent with prior expectations, predicting PE to be larger, and hence memory better, when the new pairing was inconsistent. In Experiments 2a-c, we manipulated the precision of the priors, predicting better memory for a new pairing when the (inconsistent) priors were more precise. In Experiment 3, we manipulated both visual noise and prior exposure for unfamiliar faces, before pairing them with scenes, predicting better memory when the sensory evidence was more precise. In all experiments, the PE hypotheses were supported. We discuss alternative explanations of individual experiments, and conclude the Predictive Interactive Multiple Memory Signals (PIMMS) framework provides the most parsimonious account of the full pattern of results. PMID- 28579692 TI - Targeted Muscle Reinnervation for the Upper and Lower Extremity. AB - Myoelectric devices are controlled by electromyographic signals generated by contraction of residual muscles, which thus serve as biological amplifiers of neural control signals. Although nerves severed by amputation continue to carry motor control information intended for the missing limb, loss of muscle effectors due to amputation prevents access to this important control information. Targeted Muscle Reinnervation (TMR) was developed as a novel strategy to improve control of myoelectric upper limb prostheses. Severed motor nerves are surgically transferred to the motor points of denervated target muscles, which, after reinnervation, contract in response to neural control signals for the missing limb. TMR creates additional control sites, eliminating the need to switch the prosthesis between different control modes. In addition, contraction of target muscles, and operation of the prosthesis, occurs in reponse to attempts to move the missing limb, making control easier and more intuitive. TMR has been performed extensively in individuals with high-level upper limb amputations and has been shown to improve functional prosthesis control. The benefits of TMR are being studied in individuals with transradial amputations and lower limb amputations. TMR is also being investigated in an ongoing clinical trial as a method to prevent or treat painful amputation neuromas. PMID- 28579693 TI - A new sawshark, Pristiophorus laevis, from the Eocene of Antarctica with comments on Pristiophorus lanceolatus. AB - The highly fossiliferous Eocene deposits of the Antarctic Peninsula are among the most productive sites for fossil remains in the Southern Hemisphere and offer rare insights into high-latitude faunas during the Palaeogene. Chondrichthyans, which are represented by abundant isolated remains, seemingly dominate the marine assemblages. Eocene Antarctic sawsharks have only been known from few isolated rostral spines up to now, that were assigned to Pristiophorus lanceolatus. Here, we present the first oral teeth of a sawshark from the Eocene of Seymour Island and a re-evaluation of previously described Pristiophorus remains from Gondwana consisting exclusively of rostral spines. The holotype of Pristiophorus lanceolatus represents a single, abraded and insufficiently illustrated spine from the Oligocene of New Zealand. All other Cenozoic rostral spines assigned to this species are morphologically very indistinct and closely resemble those of living taxa. Consequently, we regard this species as dubious and introduce a new species, Pristiophorus laevis, based on oral teeth. The combination of dental characteristics of the new species makes it unique compared to all other described species based on oral teeth. Rostral spines from the Eocene of Seymour Island are assigned to this new species whereas those from other Cenozoic Gondwana localities remain ambiguous. PMID- 28579695 TI - Self-powered, autonomous Biological Oxygen Demand biosensor for online water quality monitoring. AB - Standard Biological Oxygen Demand (BOD) analysis requires 5 days to complete. To date, microbial fuel cell biosensors used as an alternative method for BOD assessment requires external apparatus, which limits their use for on-line monitoring in remote, off-grid locations. In this study, a self-powered, floating biosensor was developed for online water quality monitoring. This approach eliminated the need for external apparatus and maintenance that would otherwise be required by other techniques. The biosensor was able to detect urine in freshwater and turn ON a visual and sound cues (85 dB). The energy needed to operate the biosensor was produced by the system itself with the use of electroactive microorganisms, inside microbial fuel cells. The Chemical Oxygen Demand (COD) was used as a fast method of biosensor validation. When urine concentration exceeded the lower threshold, corresponding to a COD concentration of 57.7 +/- 4.8 mgO2 L-1, the biosensor turned the alarm ON. The shortest observed actuation time, required to switch ON the alarm was 61 min, when the urine concentration was 149.7 +/- 1.7 mgO2 L-1. Once the sensor was switched ON, the signal was emitted until the urine organic load decreased to 15.3 +/- 1.9 mgO2 L-1. When ON, the microbial fuel cell sensor produced a maximum power of 4.3 mW. When switched OFF, the biosensor produced 25.4 MUW. The frequency of the signal was proportional to the concentration of urine. The observed frequencies varied between 0.01 and 0.59 Hz. This approach allowed to correlate and quantitatively detect the presence of water contamination, based on signal frequency. The sensor was operating autonomously for 5 months. This is the first report of a self-powered, autonomous device, developed for online water quality monitoring. PMID- 28579694 TI - Bilingualism Influences Structural Indices of Interhemispheric Organization. AB - Bilingualism represents an interesting model of possible experience-dependent alterations in brain structure. The current study examines whether interhemispheric adaptations in brain structure are associated with bilingualism. Corpus callosum volume and cortical thickness asymmetry across 13 regions of interest (selected to include critical language and bilingual cognitive control areas) were measured in a sample of Spanish-English bilinguals and age- and gender-matched monolingual individuals (N = 39 per group). Cortical thickness asymmetry of the anterior cingulate region differed across groups, with thicker right than left cortex for bilinguals and the reverse for monolinguals. In addition, two adjacent regions of the corpus callosum (mid-anterior and central) had greater volume in bilinguals. The findings suggest that structural indices of interhemispheric organization in a critical cognitive control region are sensitive to variations in language experience. PMID- 28579696 TI - Unsupported Micellar Palladium Nanoparticles for Biphasic Hydrogenation and Isomerization of Hydrophobic Allylic Alcohols in Water. AB - This article presents the evaluation of water-soluble palladium nanoparticles with hydrophobic active sites that are ideal for the biphasic colloidal catalysis of water-insoluble organic substrates in aqueous solution. Palladium nanoparticles stabilized with omega-carboxylate-functionalized alkanethiolate are first synthesized using omega-carboxylate-S-alkylthiosulfate as their ligand precursor. The biphasic catalysis is carried out for the reaction of hydrophobic allylic alcohols without using any additional mixing solvent or surfactant, which results in the complete consumption of substrates under the atmospheric pressure of H2 gas and at room temperature in less than 24 h. Systematic investigations on the influence of pH and substrate size are also performed to examine the utility of these thiolate-capped palladium nanoparticles as structurally stable and water soluble micellar catalysts for the biphasic reaction. PMID- 28579697 TI - Hydrodynamically-driven drug release during interstitial flow through hollow fibers implanted near lymphatics. AB - Current drug delivery devices (DDD) are mainly based on the use of diffusion as the main transport process. Diffusion-driven processes can only achieve low release rate because diffusion is a slow process. This represents a serious obstacle in the realization of recent successes in the suppression of lymphatic metastasis and in the prevention of limb and organ transplant rejection. Surprisingly, it was overlooked that there is a more favorable drug release mode which can be achieved when a special DDD is implanted near lymphatics. This opportunity can be realized when the interstitial fluid flow penetrates a drug delivery device of proper design and allows such fluid to flow out of it. This design is based on hollow fibers loaded with drug and whose hydrodynamic permeability is much higher than that of the surrounding tissue. The latter is referred to as hollow fiber of high hydrodynamic permeability (HFHP). The interstitial flow easily penetrates the hollow fiber membrane as well as its lumen with a higher velocity than that in the adjacent tissue. The interstitial liquid stream entering the lumen becomes almost saturated with drug as it flows out of the HFHP. This is due to the drug powder dissolution in the lumens of HFHP which forms a strip of drug solution that crosses the interstitium and finally enters the lymphatics. This hydrodynamically-driven release (HDR) may exceed the concomitant diffusion-driven release (DDR) by one or even two orders of magnitude. The hydrodynamics of the two-compartment media is sufficient for developing the HDR theory which is detailed in this paper. Convective diffusion theory for two compartments (membrane of hollow fiber and adjacent tissue) is required for exact quantification when a small contribution of DDR to predominating HDR is present. Hence, modeling is important for HDR which would lead to establishing a new branch in physico-chemical hydrodynamics. The release rate achieved with the use of HFHP increases proportional to the number of hollow fibers in the fabric employed in drug delivery. Based on this contribution, it is now possible to simultaneously provide high release rates and long release durations, thus overcoming a fundamental limitation in drug delivery. Perhaps this breakthrough in long-term drug delivery has potential applications in targeting lymphatics and in treating cancer and cancer metastasis without causing the serious side effects of systemic drugs. PMID- 28579699 TI - Enantioselective synthesis of new oxazolidinylthiazolidines as enzyme inhibitors. AB - The synthesis of new oxazolidinylthiazolidines bicycles, oxygen analogues of bisthiazolidines, also known as metallo-beta-lactamase inhibitors is described. The reaction of beta-aminoalcohols and 2,5-dihydroxy-1,4-dithiane led to oxazolidinylthiazolidines and/or dithia-azabicycles as the main products. The distribution pattern depends mainly on the aminoalcohol substituents. In a one pot reaction, four new bonds are formed in good yields and with high atom efficiency. When the oxazolidinylthiazolidines are formed, two stereogenic centres are generated with high enantiospecificity. The reaction mechanism is discussed based on crystallographic data and interconversion studies. Two oxazolidinylthiazolidines were evaluated as inhibitors of the potent lactamase NDM-1 and compound 4f displayed competitive inhibition with Ki = 1.6 +/- 0.6 uM. PMID- 28579698 TI - Size of nest-cavity entrance influences male attractiveness and paternal provisioning in house wrens. AB - In altricial birds, parental provisioning is plastic and can respond to a variety of environmental stimuli. In this study, we manipulated the size of entrances into artificial nest cavities (i.e., nestboxes) in a population of house wrens (Troglodytes aedon) as a means of manipulating a male's sexual attractiveness, and examined changes in parental provisioning. Nest cavities with large entrances are less desirable as nesting sites, and the males at these sites are less attractive to females. Therefore, we predicted that males at boxes that had large entrances would invest more in parental care (i.e., those that succeeded in finding a mate would provision their offspring at a higher rate) than males at nestboxes with small entrances. As predicted, males provisioned their offspring with food at the highest rates at nestboxes with enlarged entrances, and male provisioning effort positively predicted the number of fledglings they produced per egg. Males at these boxes provisioned more than their mates and more than females and males at nestboxes with small entrances. At nestboxes with small entrances, males provisioned at the same rate as females, and female provisioning did not differ significantly between treatments, on average. Male and female provisioning rates were negatively correlated, such that the increase in provisioning by males at nestboxes with enlarged entrances did not enhance nestling condition, likely because food delivery by females declined with increased provisioning by males. However, the amount of time females spent providing warmth for their ectothermic young increased with increases in male provisioning, suggesting that levels of male parental care altered the mode, not necessarily the extent, of care provided by females. These findings suggest that male provisioning is related to sexual attractiveness, and that sexual conflict over biparental care may not be as simple as the assessment of food provisioning might otherwise suggest. PMID- 28579700 TI - Acute intrapelvic cup migration: advantages of adyuvant Stoppa approach for implant removal/reconstruction. A case report. PMID- 28579701 TI - A novel approach based on preference-based index for interval bilevel linear programming problem. AB - This paper proposes a new methodology for solving the interval bilevel linear programming problem in which all coefficients of both objective functions and constraints are considered as interval numbers. In order to keep as much uncertainty of the original constraint region as possible, the original problem is first converted into an interval bilevel programming problem with interval coefficients in both objective functions only through normal variation of interval number and chance-constrained programming. With the consideration of different preferences of different decision makers, the concept of the preference level that the interval objective function is preferred to a target interval is defined based on the preference-based index. Then a preference-based deterministic bilevel programming problem is constructed in terms of the preference level and the order relation [Formula: see text]. Furthermore, the concept of a preference delta-optimal solution is given. Subsequently, the constructed deterministic nonlinear bilevel problem is solved with the help of estimation of distribution algorithm. Finally, several numerical examples are provided to demonstrate the effectiveness of the proposed approach. PMID- 28579703 TI - Poisson type inequalities with respect to a cone and their applications. AB - In this paper, we establish new Poisson type inequalities with respect to a cone. As applications, the integral representations of harmonic functions are also obtained. PMID- 28579702 TI - A new localization set for generalized eigenvalues. AB - A new localization set for generalized eigenvalues is obtained. It is shown that the new set is tighter than that in (Numer. Linear Algebra Appl. 16:883-898, 2009). Numerical examples are given to verify the corresponding results. PMID- 28579704 TI - Maternal health Indicators Signal Optimism. PMID- 28579705 TI - Attitude and Practice of Birth Attendants Regarding the Presence of Male Partner at Delivery in Nigeria. AB - BACKGROUND: Despite increasing request for the male partners' presence at delivery in developing countries, the view and practice of birth attendants remained poorly understood.This study aimed to evaluate the perception, attitude and practice of birth attendants concerning the requests in Nigeria. METHODS: A prospective, cross-sectional survey involving consenting birth attendants was conducted in six public and six private health facilities in North Central Nigeria. Statistical analysis was done with SPSS-version 20.0; p-value <0.05 was considered statistically significant. RESULTS: Among 564 participants (24.8% male, 75.2% female), 465(82.4%) support the presence of male partners at delivery, 409(72.5%) desire to be with their partner at delivery, 434(77.0%) had previous request for male partner's presence at delivery while 225(51.8%) declined it due to perception that men will disturb. Among the male partners allowed at delivery, 92(44.0%) did not disturb the birth attendant while 5(2.4%) ended in litigation. Among birth attendants who allowed men at delivery in the past, 160(76.6%) will allow men in the future. There was no statistical significance regarding the age, gender, cadre or year of service of birth attendants and attitude to a protocol change to allow men at delivery. Birth attendants who support the presence of men at delivery showed positive attitude (OR33.178, 95%CI6.996-157.358; p<0.001) while those who opined that men would disturb at delivery had a negative attitude (OR0.306, 95%CI0.124-0.755); p0.010) to possible protocol change. CONCLUSION: Despite perceived negative effects of allowing male partners at delivery, many birth attendants are willing to allow them if necessary structural modifications are instituted. PMID- 28579706 TI - Hepatotoxicity Due to Antituberculosis Therapy among Paediatric Patients Seen at the University of Ilorin Teaching Hospital, North Central Nigeria. AB - BACKGROUND: The liver is vulnerable to injury from the first line anti tuberculosis drugs. This may result in mortality, long term morbidity and reduced compliance to therapy. Nigeria recently introduced fixed drug combinations in the treatment of children amid concerns of hepatotoxicity. A 6-year-old boy was treated in our unit had fulminant hepatic failure two weeks after completing his anti-tuberculosis therapy. This prompted the unit to investigate hepatotoxicity due to anti-tuberculosis therapy among children. There is no data on the incidence of hepatotoxicity due to antituberculosis therapy among Nigerian children, and no uniform guide to monitoring of patients exists. The objective of this study was to investigate the incidence of hepatotoxicity among children receiving anti-tuberculosis therapy. METHODS: A cross-sectional study was conducted among all 62 cases that completed treatment over a two year period. Liver Function Tests was done at baseline and 2 and 5 months of therapy. Elevation of Alanine aminotransferase and/or Aspartate aminotransferase above 3 times the reference values was considered an indication of hepatotoxicity. RESULTS: A total of 62 patients aged 3 months -17 years were treated at our unit during the study period. Twenty-two (35.5%) had elevated liver enzymes at baseline. Four (6.5%) had elevation of alanine aminotransferase of 3 times the upper limit at 2 months, but at 5 months, tests were within normal limits in all patients. Hepatotoxicity defined as liver enzymes above 3 times upper limit was not documented among the 62 cases treated over the period. CONCLUSION: Hepatotoxicity due to antituberculosis therapy is uncommon in children, hence repeated routine evaluation of liver function may not be necessary in all patients receiving anti-TB therapy. PMID- 28579707 TI - Barriers to Contraceptive Uptake among Women of Reproductive Age in a Semi-Urban Community of Ekiti State, Southwest Nigeria. AB - BACKGROUND: Globally, unplanned pregnancy and sexually transmitted infections (STIs) persist as a significant threat to women's reproductive health. In Nigeria, despite huge resources committed to family planning programs by stakeholders, contraceptive use has been very low. This study aimed at unraveling the barriers to the use of modern contraceptives among women of reproductive age (15-49 years) in Ise-Ekiti community, Ekiti State, Southwest Nigeria. METHODS: This study was a cross sectional study among women aged 15-49 years. A multi stage sampling technique was used in the recruitment of respondents from the community. An interviewer-administered questionnaire was used to collect data. Data were analyzed using SPSS version 15. RESULTS: Although contraceptive awareness among respondents was high 496(98.6%), only 254 of the 503 respondents were using modern contraceptive methods giving a Contraceptive Prevalence Rate (CPR) of 50.5%. Among those not using any form of contraceptives, some identifiable barriers to contraceptive use includes desire for more children, 62(39.5%), partner disapproval, 40(25.5%), and fear of side-effects, 23(14.6%). Factors associated with contraceptive uptake include marital status (p=0.028), educational level (p=0.041) and religion (p=0.043) with traditional worshippers having the least uptake. CONCLUSION: This study showed that awareness to modern forms of contraceptives does translate into use. The identified barriers to contraceptive uptake suggest the need to improve uptake of contraceptives through a community-based and culturally acceptable intervention as doing this will go a long way in addressing some of these barriers. PMID- 28579708 TI - Field-Based Evidence of Single and Few Doses of Annual Ivermectin Treatment Efficacy in Eliminating Skin Microfilaria Load after a Decade of Intervention. AB - BACKGROUND: Impact assessment of community-based ivermectin treatment control of onchocerciasis is required to determine its effectiveness. This study was conducted to evaluate geographic coverage and demographic ivermectin treatment compliance. METHODS: The number of village dosage were obtained from the community based distributors. Bioclinical data of participants comprising gender, age, number of treatment received from inception and dosage were obtained. Each participant was subjected to physical examination for palpable nodule and other skin clinical signs and symptoms of onchocerciasis. Visual acuity test was done using the Snellen illiterate E-chart. Eye examination was performed using touch loop and handheld ophthalmoscope. Skin snips from both iliac crests were incubated overnight at 28-32 degrees C and emerged micrifilaria enumerated under an inverted microscope. The changes in epidemiological indices at post-decade of mass drug administration were compared with baseline data. RESULTS: Village annual ivermectin treatment doses averaged 62%, ranging between 10-100%. Individual treatment compliance rate was generally low with an average of 4 treatments and a range between 0-10. Despite variations in treatment compliance, there were significant improvements in some onchocercal morbidities. These include reduced number and severity of itching, visual impairment, papular onchodermatitis, onchocercomata (palpable nodules) and leopard skin. Ivermectin treatment halted development of new blind cases, except the case of a man who had optic nerve disease and became blind 2 years after ivermectin treatment had commenced. There was a significant overall reduction in parasite burden with very low mean skin microfilaria load of 1.7mf per skin snip and 3.7% skin mf prevalence, compared to baseline data of 17.7mf and 37.9% respectively. The palpable nodule was also drastically reduced from 14.5% to 6.4%. Outcome of this study has practically demonstrated that even a single dose ivermectin treatment is capable of clearing skin mf load on a long-term basis. This assertion is exemplified by the result obtained from Bomjock village that had taken treatment only at inception, and the prevalence rate was reduced from 70% to about 9.0% at post-decade of intervention. CONCLUSION: It can be inferred that high demographic coverage with annual treatment doses, it is feasible to attain a shorter time (within a decade) contrary to the anticipated longer-term projection. PMID- 28579709 TI - Timing of First Antenatal Care Visit and its Associated Factors among Pregnant Women Attending Public Health Facilities in Addis Ababa, Ethiopia. AB - BACKGROUND: Early initiation of antenatal care visits is an essential component of services to improving maternal and new born health. The Ethiopian Demographic and Health Survey conducted in 2011 indicated that only 11% of pregnant women start antenatal care in the first trimester. However, detailed study to identify factors associated with late initiation of care has not been conducted in Addis Ababa where access to health services is almost universal. The aim of this study was to assess the level of late first antenatal care visit and the associated factors. METHODS: Facility based cross sectional study was conducted in public health centers in Addis Ababa. The health centers with experience of at least more than two years were selected randomly, one form each sub-city. The study subjects were pregnant women visiting the facilities for the first time during the index pregnancy. The study health centers were selected randomly from each sub-city, and the study women were recruited consecutively until the required sample size was achieved. Data were collected using pre-tested questionnaire. Logistic regression analysis was done to identify factors associated with late ANC initiation. RESULT: A total of 979 women participated in the study; 411(42.0%; 95% CI of 38.9%, 45.1%) of them came for their first ANC visit late, after 16 weeks of gestation. Wrongly perceived ANC initiation schedule was the strongest predictor of late initiation. After controlling for basic demographic and obstetric factors, the odds of starting the first antenatal care visit late was higher for women who did not know the antennal care initiation schedule correctly compared to women who knew the schedule correctly (AOR6.6; 95% CI 3.03, 14.03). CONCLUSION: Over 40% of pregnant women do not initiate ANC visit in the first trimester largely due to lack of correct knowledge of the recommended ANC schedule. PMID- 28579710 TI - Assessment of Knowledge of Acute Kidney Injury among Non-Nephrology Doctors in Two Government Hospitals in Ondo City, Southwest, Nigeria. AB - BACKGROUND: Adequate knowledge of acute kidney injury (AKI) among doctors is essential for its prevention, early diagnosis and management. Assessing knowledge of AKI among doctors is necessary to identify areas of deficiencies and key areas to be emphasized when organizing educational programs aimed at improving AKI care. This study determined the knowledge of AKI among non-nephrology doctors in Ondo City, Southwest Nigeria. MATERIALS AND METHODS: This was a cross-sectional descriptive study carried out in two government hospitals in Ondo City using a self-administered pretested questionnaire that assessed knowledge of AKI among non-nephrology doctors. P-value of < 0.05 was taken as significant. RESULTS: Eighty-one doctors participated in the study with a median post-graduation experience of 5.5 years. Sixty-one (78.2%) were in surgical specialty while the remaining worked in medical specialty. Only 1(1.2%) of the respondents had good knowledge of AKI, 56(69.2%) had fair knowledge while the remaining 24 (29.6%) had poor knowledge of AKI. Identified areas of deficiencies in knowledge of AKI were in mode of presentation, risk factors, potentially nephrotoxic medications, criteria for AKI definition and staging, newer AKI biomarkers and indications for renal replacement therapy. There was no significant association between knowledge of AKI and specialty (p=0.593) or year of practice (p=0.312). CONCLUSION: There were significant deficiencies in the knowledge of AKI amongst most non-nephrology doctors in Ondo city. We therefore recommend regular in-service training on AKI for practicing doctors. PMID- 28579711 TI - Nutritional Status and Effect of Maternal Employment among Children Aged 6-59 Months in Wolayta Sodo Town, Southern Ethiopia: A Cross-sectional Study. AB - BACKGROUND: Childhood malnutrition remains common in many parts of the world; the magnitude of worldwide stunting, underweight and wasting in children under five years of age were 24.7 %, 15.1 % and 7.8 %, respectively. More than 150 million children under the age of five years in the developing world are malnourished. Ethiopia is one of the countries in sub-Saharan Africa with the highest rates of malnutrition. In Ethiopia, 44.4% and 9.7% of children under-five years old were stunted and wasted, respectively. This study was aimed to assess nutritional status and effect of maternal employment among children aged 6-59 months. METHODS: A cross-sectional study was conducted in Wolayta Sodo Town, Southern Ethiopia. Socio-demographic characteristics, child feeding and healthcare seeking practice of mothers, and child's anthropometric status were assessed. Probability proportional to size sampling approach was used to select a sample of 316 mothers having children aged 6-59 months. The study was ethically approved by Institutional Review Board of Health Science College, Hawasa University. RESULT: The overall result revealed that the prevalence of stunting was 22.2%, of which 21.8% and 22.6% were in children of employed and unemployed mothers, respectively. Low-weight-for age was 10.8% for children of employed mothers and 13.4% for children of unemployed mothers. Wasting was 8.8% and 10.8% for children of employed and unemployed mothers, respectively. There was no statistically significant association between maternal employment and nutritional status of their children. However, chronic malnutrition (stunting) was influenced by being educated mother (OR: 0.37) child age group of 24-59 months (OR: 0.36) and households' fifth wealth quintile (OR: 0.28). CONCLUSION: Low prevalence of stunting was observed. Stunting is a public health concern in the study area. Furthermore, stunting is significantly influenced by mothers' education, household wealth and child age. However, maternal employment was not statistically associated with child nutritional status. Thus, nutritional intervention initiatives should focus on improving household food security, maternal education and agricultural diversification. PMID- 28579712 TI - Level of Awareness and Knowledge of Breast Cancer in Nigeria. A Systematic Review. AB - BACKGROUND: Despite reports of improved awareness of breast cancer entity and seemingly upbeat levels of other awareness subthemes in Nigeria, patients continue to present late when treatment is least rewarding. This paradoxical trend of both rising awareness and late presentation coupled with reports suggesting other competing drivers of late presentation question the "theory of poor awareness" as the foremost driver of late presentations. By aggregating available data, we aimed to assess what still constitutes poor breast cancer awareness in Nigeria in order to suggest how to allocate resources to reverse the paradox. METHOD: Studies conducted on Nigerian populace from 2000 to date were reviewed systematically. Search was made in PROSPERO, PubMed/MEDLINE, AJOL, Cochrane library, GOOGLE, ResearchGate and ACADEMIA. Primary outcome was level of awareness about breast cancer entity. RESULT: Fifty-one eligible (48 descriptive surveys, 3 interventional ones) studies were reviewed. They included 19,598 respondents (98.5% females; 43% rural dwellers). 17,086(87.2%) were laypersons in various walks of life; 2,512(12.8%) were healthcare professionals. There were high levels of awareness of breast cancer entity, BSE, knowledge of fatality and benefit of early detection (weighted percentages 80.6%, 60.1%, 73.2% and 73.9% respectively). Weighted percentages of knowledge of symptoms/signs was 45.1%. Weighted percentages of sense of susceptibility and performance of BSE were low 26.8% and 22.9% respectively. Generally, rate of performance of screening did not vary with changes in the level of awareness/knowledge of concepts. CONCLUSION: In general, low awareness of breast cancer may not be the direct and foremost driver of persistent late presentation in Nigeria. PMID- 28579713 TI - Nutritional Status of Under Five Children in Ethiopia: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Undernutrition is the outcome of insufficient food intake and recurrent infectious diseases. The baseline levels of undernutrition remain so high that Ethiopia still needs to continue substantial investment in nutrition.Therefore, the aim of this study was to obtain estimates of over-time trends in the prevalence of undernutrition in Ethiopia and to determine risk factors for undernutrition among children of under five years of age. METHODS: Cross-sectional studies published in English from 1997 to 2015 focusing the prevalence of stunting, wasting and underweight in children aged 0-5 years (n = 39,585) in Ethiopia were included in this systematic review and meta-analysis. We searched in PubMed and Scopus databases and other articles manually. Two review authors independently selected studies for inclusion, extracted data and assessed the risk of bias in the included studies. The protocol number of the study is PROSPERO 2015: CRD42015027940. RESULTS: Eighteen studies were included and the overall pooled prevalence estimate of stunting, underweight and wasting was 42.0% (95% CI: 37.0, 46.0), 33.0 % (95% CI: 27.0, 39.0) and 15.0% (95% CI: 12.0, 19.0), respectively. The sensitivity analyses resulted in the prevalence of stunting, 40% (95% CI: 32.0, 48.0; I2=99.19%), prevalence of underweight, 33%(95% CI: 24.0, 42.0; I2=99.34%) and wasting rate equal to 19%(95% CI: 14.0, 24.0; I2=99.19%). Cumulative analysis revealed a stabilization trend of stunting and underweight (1996-2010) followed by an upward trend (2010-2014). Child age, child sex, complementary food, poor dietary diversity, diarrheal diseases, maternal education, maternal height, residential area and socio- economic status were significant risk factors for undernutrition. CONCLUSION: The result of the meta analysis of thes observational studies revealed that the trend of undernutrition in Ethiopia indicates that there is an increment of chronic malnutrition cases in recent years, and the prevalence of undernutrition remains extremely high. Thus, the implementation of policies to reverse child undernutrition should get maximum emphasis. PMID- 28579714 TI - Neumann's Tumor: A Case Report. AB - BACKGROUND: The congenital granular cell tumour of the newborn, also known as congenital epulis or Neumann's tumor, is rare. It occurs on the gingiva of the anterior alveolar ridge of the jaws. This lesion behaves in a benign manner and no recurrent or metastatic lesions have been reported. CASE REPORT: We are reporting a 2-day-old female neonate, who came to our unit with a well defined, solitary, firm mass arising from the maxillary anterior region measuring about 3.5 cms in diameter and causing difficulty in breast feeding but no hindrance to the airway. The mass was surgically excised under general anesthesia. Postoperative wound healing was uneventful. CONCLUSION: We have shared our experience in handling this rare type of tumor. We have presented the clinical features and the different modalities of its treatment to spread awareness among clinicians for better management of similar tumors. PMID- 28579715 TI - Combination of Encephalo-Myo-Pial-Synangiosis and Encephalo-Arterio-Pial Synangiosis Procedure in Pediatric Moya-Moya Disease. AB - BACKGROUND: Moya-moya disease in children is a cerebrovascular disorder that may cause cerebral ischemic or hemorrhage. CASE DETAILS: We report an 8-year-old boy that was admitted with the chief complaint of repeated sudden half left body paralyze. MRA showed acute thrombotic infarction in the right hemisphere and internal carotid artery stenosis in the form of puffs of smokes. Indirect revascularization surgical procedure with combination of Encephalo-myo-pial synangiosis (EMS) and Encephalo-arterio-pial-synangiosis (EAS) was performed. It resulted in a good response. CONCLUSION: Moya-moya disease can lead to permanent neurological disability if untreated. Satisfactory outcome was noted following combination surgery management with EMS and EAS. PMID- 28579716 TI - Clinically Confirmed Congenital Rubella Syndrome: The Role of Echocardiography. AB - BACKGROUND: Congenital rubella syndrome (CRS) affects thousands of children in the developing world because rubella vaccination is not routinely available in most of these countries. Among its many manifestations, congenital heart disease is life threatening. CASE DETAILS: A 9-month-old infant presented with whitish lesions over her left eye. She was evaluated with echocardiography that revealed peripheral pulmonary stenosis and patent ductus arteriosus. She had severe acute malnutrition and clinically confirmed congenital rubella syndrome (CRS). There was no available serologic test to confirm the diagnosis. CONCLUSION: This case was presented to demonstrate typical dual features of CRS by echocardiography and to emphasize the benefit of vaccination to prevent deleterious complications from congenital rubella syndrome. PMID- 28579717 TI - Thoracic Ectopia Cordis in an Ethiopian Neonate. AB - BACKGROUND: Ectopia Cordis is defined as complete or partial displacement of the heart outside the thoracic cavity. It is a rare congenital defect with failure of fusion of the sternum with extra thoracic location of the heart. The estimated prevalence of this case is 5.5 to 7.9 per million live births. CASE PRESENTATION: We had a case of a 16-hour-old male neonate weighing 2.9kg with externally visible, beating heart over the chest wall. Initial treatment included covering the heart with sterile-saline soaked dressing, starting systemic antibiotics and supportive care. A staged surgical approach to this defect with the initial aim of replacement of the heart to the thoracic cavity was opted. The neonate died twenty minutes after the surgical intervention due to cardiogenic shock despite adequate resuscitative measures. CONCLUSION: This case report underscores the missed opportunity of antenatal ultra-sonographic diagnosis and the challenge of Ectopia Cordis treatment in Ethiopia. PMID- 28579718 TI - Constructing Abstraction Hierarchies Using a Skill-Symbol Loop. AB - We describe a framework for building abstraction hierarchies whereby an agent alternates skill- and representation-construction phases to construct a sequence of increasingly abstract Markov decision processes. Our formulation builds on recent results showing that the appropriate abstract representation of a problem is specified by the agent's skills. We describe how such a hierarchy can be used for fast planning, and illustrate the construction of an appropriate hierarchy for the Taxi domain. PMID- 28579719 TI - Unverified Patient-Reported Errors: A False Alarm Can Have Real Consequences. AB - Unverified patient-reported errors can have real consequences. PMID- 28579720 TI - Drug Companies Breathe Easier As PDUFA VI Heads for Approval. AB - Drug companies breathe easier as PDUFA VI heads for approval. PMID- 28579721 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 28579722 TI - Pharmaceutical Approval Update. AB - Ribociclib (Kisqali) for HR+/HER2- advanced or metastatic breast cancer in postmenopausal women; safinamide (Xadago) as adjunctive treatment for patients with Parkinson's disease; and avelumab (Bavencio) for metastatic Merkel cell carcinoma. PMID- 28579724 TI - Cancer Immunotherapy, Part 1: Current Strategies and Agents. AB - This article, the first in a series of three, introduces cancer immunology, cancer immunotherapy strategies, and the classes of anticancer therapeutic agents. PMID- 28579723 TI - Pimavanserin (Nuplazid): A Treatment for Hallucinations and Delusions Associated With Parkinson's Disease. AB - Pimavanserin (Nuplazid) for the treatment of hallucinations and delusions associated with Parkinson's disease. PMID- 28579725 TI - Cost-Savings From an Antipsychotic Tablet-Splitting Program. AB - BACKGROUND: Newer atypical antipsychotics such as aripiprazole (Abilify, Otsuka) and lurasidone (Latuda, Sunovion) have favorable safety and efficacy profiles, but their use is limited by high cost. University Hospitals Richmond Medical Center initiated an antipsychotic tablet-splitting program in August 2015 to counter the costs based on the identical pricing structure of aripiprazole and lurasidone doses. METHODS: A retrospective chart review was completed for all patients dispensed aripiprazole or lurasidone oral tablets from May 1, 2015, through December 31, 2015, to evaluate the potential cost-savings for our facility. Findings were extrapolated to 12 months to estimate an annual cost savings from tablet splitting. RESULTS: Two-hundred thirty-five charts were reviewed during this eight-month period. Estimated annual savings ranged from $3,617 for lurasidone 20-mg tablets to $6,637 for aripiprazole 5-mg tablets. The antipsychotic tablet-splitting program for lurasidone and aripiprazole resulted in 30% to 50% annual savings for each individual medication strength. Previous literature suggests variable percentage of weight deviation in tablet-splitting studies; however, small deviations in weight may not be clinically relevant for antipsychotic agents based on their mechanism of action. CONCLUSIONS: Aripiprazole and lurasidone are optimal agents for tablet splitting. Initiation of a tablet-splitting program has the potential to save up to 50% of drug costs for an inpatient hospital. Splitting of aripiprazole and lurasidone tablets may decrease drug cost and waste while ensuring patient accessibility to treatment. PMID- 28579726 TI - Inpatient Antineoplastic Medication Administration And Associated Drug Costs: Institution of a Hospital Policy Limiting Inpatient Administration. AB - BACKGROUND: Cancer treatment costs are increasing; the global cost of antineoplastic medications rose to $83.7 billion in 2015. As a result, it is imperative for institutions to implement cost-saving strategies and to maximize reimbursement for costly medications such as antineoplastic drugs. OBJECTIVES: Evaluate the necessity and drug costs of administering antineoplastic medications in the inpatient setting and explore savings associated with the 2013 implementation of an institutional policy that defined criteria necessitating inpatient administration of antineoplastic medication. METHODS: We conducted a retrospective chart review of patients receiving inpatient antineoplastic medications during January, April, July, and October of 2010, 2012, 2014, and 2015 at a community teaching hospital. Necessity of chemotherapy administration during the hospital admission was determined based on adherence to institutional policy. RESULTS: Records of 648 patients admitted for chemotherapy were reviewed. The annualized numbers of chemotherapy regimens received during inpatient admission in 2010, 2012, 2014, and 2015 were 537, 618, 369, and 420, respectively. Of all regimens administered in the inpatient setting, 80% in 2010, 78% in 2012, 83% in 2014, and 91% in 2015 met institutional policy criteria for inpatient administration (P = 0.005). The annualized average wholesale price of antineoplastic medications administered to patients that did not meet criteria for inpatient drug administration decreased from $269,049 in 2010 to $105,447 in 2015. A trend in the chemotherapy regimens administered was apparent; only one regimen (carboplatin/paclitaxel), which is relatively inexpensive, was administered to more than 5% of patients in 2015, and all patients receiving monoclonal antibodies in 2015 met criteria for inpatient administration. CONCLUSIONS: Implementation of a policy defining the appropriate criteria necessitating inpatient administration of antineoplastic medications has the potential to decrease the number of inpatient administrations and associated drug costs. PMID- 28579727 TI - Immunotherapies in Late-Stage Development for Patients With Severe SLE and/or Lupus Nephritis. AB - We review the immunomodulatory agents in development for systemic lupus erythematosus, a relatively uncommon disorder affecting women of childbearing age. PMID- 28579728 TI - EASL International Liver Congress 2017. AB - The latest in hepatology research was presented at this year's European Association for the Study of the Liver (EASL) International Liver Congress. PMID- 28579730 TI - Research Briefs. PMID- 28579729 TI - Academy of Managed Care Pharmacy. AB - Highlights of the AMCP Annual Meeting included marketplace trends, the affordability crisis, and the issues facing value-based contracting. PMID- 28579732 TI - Impact of E * B shear flow on low-n MHD instabilities. AB - Recently, the stationary high confinement operations with improved pedestal conditions have been achieved in DIII-D [K. H. Burrell et al., Phys. Plasmas 23, 056103 (2016)], accompanying the spontaneous transition from the coherent edge harmonic oscillation (EHO) to the broadband MHD turbulence state by reducing the neutral beam injection torque to zero. It is highly significant for the burning plasma devices such as ITER. Simulations about the effects of E * B shear flow on the quiescent H-mode (QH-mode) are carried out using the three-field two-fluid model in the field-aligned coordinate under the BOUT++ framework. Using the shifted circular cross-section equilibriums including bootstrap current, the results demonstrate that the E * B shear flow strongly destabilizes low-n peeling modes, which are mainly driven by the gradient of parallel current in peeling dominant cases and are sensitive to the Er shear. Adopting the much more general shape of E * B shear ([Formula: see text]) profiles, the linear and nonlinear BOUT++ simulations show qualitative consistence with the experiments. The stronger shear flow shifts the most unstable mode to lower-n and narrows the mode spectrum. At the meantime, the nonlinear simulations of the QH-mode indicate that the shear flow in both co- and counter directions of diamagnetic flow has some similar effects. The nonlinear mode interaction is enhanced during the mode amplitude saturation phase. These results reveal that the fundamental physics mechanism of the QH-mode may be shear flow and are significant for understanding the mechanism of EHO and QH-mode. PMID- 28579731 TI - Do lesbians overestimate alcohol use norms? Exploring the potential utility of personalized normative feedback interventions to reduce high-risk drinking in Southern California lesbian communities. AB - This study examines the potential utility of social norms-based approaches to reduce heavy alcohol use in lesbian community settings. In a sample of 278 Southern Californian lesbians recruited from social media networks to complete an online survey, the majority of participants overestimated the quantity of alcohol consumed by their lesbian peers and more frequent lesbian bar attendance was associated with elevated perceptions of how much other lesbians drink. Greater than 90% of participants expressed interest in receiving personalized normative feedback, suggesting that culturally tailored personalized normative feedback interventions focused on correcting perceptions of heavy drinking may be successful in mitigating the alcohol-related risks of lesbians in Southern California, and potentially beyond. PMID- 28579733 TI - Foreword to Special Issue: Papers from the 58th Annual Meeting of the APS Division of Plasma Physics, October 31-November 4, 2016, San Jose, California, USA. PMID- 28579734 TI - The basis for cosmic ray feedback: Written on the wind. AB - Star formation and supermassive black hole growth in galaxies appear to be self limiting. The mechanisms for self-regulation are known as feedback. Cosmic rays, the relativistic particle component of interstellar and intergalactic plasma, are among the agents of feedback. Because cosmic rays are virtually collisionless in the plasma environments of interest, their interaction with the ambient medium is primarily mediated by large scale magnetic fields and kinetic scale plasma waves. Because kinetic scales are much smaller than global scales, this interaction is most conveniently described by fluid models. In this paper, I discuss the kinetic theory and the classical theory of cosmic ray hydrodynamics (CCRH) which follows from assuming cosmic rays interact only with self-excited waves. I generalize CCRH to generalized cosmic ray hydrodynamics, which accommodates interactions with extrinsic turbulence, present examples of cosmic ray feedback, and assess where progress is needed. PMID- 28579735 TI - Barriers and Facilitators to Provision of Influenza and Pneumococcal Vaccines in Home Health Care Agencies. AB - The recommendations for influenza and pneumococcal vaccines are widely known yet the rates of both immunizations for home health care patients are 70 percent or less. The purpose of this study was to identify the facilitators and barriers to immunizations ultimately to improve vaccination rates among home health care patients. Using a multi-case study approach with five agencies and one group of administrators, facilitators included providing patients with a vaccine "card" and using the agency electronic medical record (EMR) for decision support/reminders. We determined that there were patient barriers (misperceptions about vaccines in general, difficulty in recalling vaccine status) and provider barriers (misperceptions about vaccines among health care workers, home health care agencies not receiving accurate information from other providers or difficulty in determining vaccine status). PMID- 28579736 TI - HUMAN CAPITAL GROWTH AND POVERTY: EVIDENCE FROM ETHIOPIA AND PERU. AB - In this paper we use high quality data from two developing countries, Ethiopia and Peru, to estimate the production functions of human capital from age 1 to age 15. We characterize the nature of persistence and dynamic complementarities between two components of human capital: health and cognition. We also explore the implications of different functional form assumptions for the production functions. We find that more able and higher income parents invest more, particularly at younger ages when investments have the greatest impacts. These differences in investments by parental income lead to large gaps in inequality by age 8 that persist through age 15. PMID- 28579737 TI - Electronic properties of alpha-UH3 stabilized by Zr. AB - Pure hydride of the alpha-UH3 type without any beta-UH3 admixture was prepared by high-pressure hydrogenation of bcc U stabilized by Zr. Such material, characterized by a general formula (UH3)1-x Zr x , is stable in air at ambient and elevated temperatures. H release is observed between 400-450 degrees C similar to beta-UH3. Its stability allowed to measure magnetic properties, specific heat, and electrical resistivity in a wide temperature range. Despite rather different crystal structure and inter-U spacing, the electronic properties are almost identical to beta-UH3. Its ferromagnetic ground state with Curie temperature TC ~ 180 K (weakly and non-monotonously dependent on Zr concentration) and U moments of 1.0 MUB indicate why mixtures of alpha- and beta UH3 exhibited only one transition. Magnetic ordering leads to a large spontaneous magnetostriction omegas = 3.2*10-3, which can be explained by the increase of the spin moment between the paramagnetic (Disordered Local Moment) and the ferromagnetic state. The role of orbital moments in magnetism is indicated by fully relativistic electronic structure calculations. PMID- 28579739 TI - Quantitative Study of Thermal Disturbances Due to Nonuniformly Perfused Tumors in Peripheral Regions of Women's Breast. AB - BACKGROUND: Mathematical modeling of biothermal processes is widely used to enhance the quantitative understanding of thermoregulation system of human body organs. This quantitative knowledge of thermal information of various human body organs can be used for developing clinical applications. In the past, investigators have studied thermal distribution in hemisphere-shaped human breast in the presence of sphere-shaped tumor. The shape and size of the breast as well as tumor may also affect thermal distribution which can have serious implications in thermography. In this article, a model of thermal disturbances in peripheral regions of ellipsoid-shaped human breast involving ellipse-shaped nonuniformly perfused tumor has been developed for a 2-dimensional steady-state case. The modeling study will provide biomedical scientists vital insights of thermal changes occurring due to the shape and size of breast and tumor which can influence the development of protocols of thermography for diagnosis of tumors in women's breast. METHOD: We have incorporated the significant parameters such as blood flow, metabolic activity, and thermal conductivity in the thermal model for normal and malignant tissues. The controlled metabolic activity has been incorporated for normal tissues, and uncontrolled metabolic activity has been incorporated for tumor regions. The peripheral regions of breast are divided into 3 major layers, namely, epidermis, dermis, and subdermal tissues. An ellipse shaped nonuniformly perfused tumor is assumed to be present in dermal layers. The nonuniformly perfused tumor is divided into 2 natural components, namely, the necrotic core and tumor periphery. The outer surface of the breast is assumed to be exposed to the environment, and the heat loss takes place by conduction, convection, radiation, and evaporation. The finite element approach is used to obtain the solution. The numerical results have been used to study the effect of shape and size of tumor on temperature distribution in matured breast of different shapes. RESULTS: By selecting appropriate model parameters, we have shown the spatial thermal variation in matured breast of different shapes which could be replicated by the proposed model. We have also shown the thermal disturbances caused by different shapes and sizes of tumors by selecting appropriate values of parameters. In addition, the thermal information from our model provides us the basis for prediction of shape and size of tumors in terms of change of the slope of temperature profiles at the junction of tumor and normal tissues and tumor periphery and tumor core. CONCLUSIONS: The proposed model was successfully used to study the impact of different sizes and shapes of nonuniformly perfused tumor on thermograms in peripheral regions of ellipse shaped woman's breast. The proposed model is more realistic in terms of shape and size of tumors and woman's breast in comparison with earlier models reported in the literature. The finite element discretization of breast into large number of triangular ring elements effectively models the heterogeneity of region. The changes in slope of the thermal curves at the junctions of various peripheral and tumor layers are due to the nonhomogeneous nature of the region. The location of major thermal disturbances in the tissues indicates the presence of tumor. The change in the slope of the thermal curves gives us idea about the position, type, and size of the tumors in the peripheral tissues. This thermal information can be exploited for detection of tumors by thermographic techniques. PMID- 28579738 TI - A Novel Optical Bioimaging Method for Direct Assessment of Ovarian Cancer Chemotherapy Response at Laparoscopy. AB - In patients with advanced ovarian cancer (AOC), additional imaging of disseminated disease at laparoscopy could complement conventional imaging for estimation of chemotherapy response. We developed an image segmentation method and evaluated its use in making accurate and objective measurements of peritoneal metastases in comparison to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. A software tool using a custom ImageJ macro-based approach was employed to estimate lesion size by converting image pixels into unit length. The software tool was tested as a proof-of-principle in an AOC patient with two isolated peritoneal deposits. Image analysis of representative laparoscopic snapshots before and after three cycles of neoadjuvant chemotherapy (NACT) revealed an average tumor nodule response ratio (TNRR) of 40% (partial response), which was in concordance with RECIST evaluation by computed tomography (CT). We demonstrated the feasibility of using this novel anatomical analysis for direct assessment of chemotherapy response in an AOC patient as an adjunct to RECIST criteria. PMID- 28579741 TI - Time-Based Switching Control of Genetic Regulatory Networks: Toward Sequential Drug Intake for Cancer Therapy. AB - As cancer growth and development typically involves multiple genes and pathways, combination therapy has been touted as the standard of care in the treatment of cancer. However, drug toxicity becomes a major concern whenever a patient takes 2 or more drugs simultaneously at the maximum tolerable dosage. A potential solution would be administering the drugs in a sequential or alternating manner rather than concurrently. This study therefore examines the feasibility of such an approach from a switched system control perspective. Particularly, we study how genetic regulatory systems respond to sequential (switched) drug inputs using the time-based switching mechanism. The design of the time-driven drug switching function guarantees the stability of the genetic regulatory system and the repression of the diseased genes. Simulation results using proof-of-concept models and the proliferation and survival pathways with sequential drug inputs show the effectiveness of the proposed approach. PMID- 28579740 TI - Applying Multivariate Adaptive Splines to Identify Genes With Expressions Varying After Diagnosis in Microarray Experiments. AB - PURPOSE: To analyze a microarray experiment to identify the genes with expressions varying after the diagnosis of breast cancer. METHODS: A total of 44 928 probe sets in an Affymetrix microarray data publicly available on Gene Expression Omnibus from 249 patients with breast cancer were analyzed by the nonparametric multivariate adaptive splines. Then, the identified genes with turning points were grouped by K-means clustering, and their network relationship was subsequently analyzed by the Ingenuity Pathway Analysis. RESULTS: In total, 1640 probe sets (genes) were reliably identified to have turning points along with the age at diagnosis in their expression profiling, of which 927 expressed lower after turning points and 713 expressed higher after the turning points. K means clustered them into 3 groups with turning points centering at 54, 62.5, and 72, respectively. The pathway analysis showed that the identified genes were actively involved in various cancer-related functions or networks. CONCLUSIONS: In this article, we applied the nonparametric multivariate adaptive splines method to a publicly available gene expression data and successfully identified genes with expressions varying before and after breast cancer diagnosis. PMID- 28579742 TI - Intravitreal use of bone marrow mononuclear fraction containing CD34+ stem cells in patients with atrophic age-related macular degeneration. AB - PURPOSE: To evaluate the therapeutic potential and safety of intravitreal injections of bone marrow mononuclear fraction (BMMF) containing CD34+ cells in patients with atrophic age-related macular degeneration (AMD). METHODS: Ten patients with atrophic AMD and best-corrected visual acuity (BCVA) in the worse seeing eye of <=20/100 were enrolled in this study. The bone marrow from all patients was aspirated and processed for mononuclear cell separation. A 0.1 mL suspension of BMMF CD34+ cells was injected into the vitreous cavity of the worse seeing eye. Patients were evaluated at Baseline and 1,3,6,9 and 12 months after injection. Ophthalmic evaluation included BCVA measurement, microperimetry, infrared imaging, fundus autofluorescence and SD-optical coherence tomography at all study visits. Fluorescein angiography was performed at Baseline and at 6 and 12 months after intravitreal therapy. RESULTS: All patients completed the 6-month follow-up, and six completed the 12-month follow-up. Prior to the injection, mean BCVA was 1.18 logMAR (20/320-1), ranging from 20/125 to 20/640-2, and improved significantly at every follow-up visit, including the 12-month one, when BCVA was 1.0 logMAR (20/200) (P<0.05). Mean sensitivity threshold also improved significantly at 6, 9 and 12 months after treatment (P<0.05). Considering the area of atrophy identified by fundus autofluorescence, significant mean BCVA and mean sensitivity threshold improvement were observed in patients with the smallest areas of atrophy. Fluorescein angiography did not identify choroidal new vessels or tumor growth. CONCLUSION: The use of intravitreal BMMF injections in patients with AMD is safe and is associated with significant improvement in BCVA and macular sensitivity threshold. Patients with small areas of atrophy have a better response. The paracrine effect of CD34+ cells may explain the functional improvement observed; however, larger series of patients are necessary to confirm these preliminary findings. PMID- 28579743 TI - Novel positioning sensor with real-time feedback for improved postoperative positioning: pilot study in control subjects. AB - INTRODUCTION: Repair of retinal detachment frequently requires use of intraocular gas. Patients are instructed to position themselves postoperatively to appose the intraocular bubble to the retinal break(s). We developed a novel wearable wireless positioning sensor, which provides real-time audiovisual feedback on the accuracy of positioning. METHODS: Eight healthy volunteers wore the wireless sensor for 3 hours while instructed to maintain their head tilted toward the 2 o'clock meridian with no audiovisual feedback. Positioning accuracy was recorded. The subjects repeated the experiment for 3 hours with the audiovisual feedback enabled. RESULTS: With no audiovisual feedback, the percentage of time greater than 10 degrees out of position varied from 8.9% to 93.9%. With audiovisual feedback enabled, these percentages ranged from 9.4% to 65%. Three subjects showed significant improvement in their time out of position (P<0.01, Fisher's exact test). Four subjects demonstrated a nonsignificant improvement, and one subject had a significant increase in time out of position with feedback (P<0.01). When pooled, all subjects demonstrated a statistically significant decrease in degrees out of position (P<0.001, Wilcoxon test) and a statistically significant improvement in total time out of position (P<0.001). CONCLUSION: The novel positioning sensor showed improved positioning compliance in half of the healthy volunteers during our short pilot study. Other subjects derived little benefit from the feedback. The causes for this observation are unclear. However, given the significant improvement as a group, this new technology could be beneficial to patients who struggle with postoperative positioning. PMID- 28579744 TI - Randomized comparison of in vivo performance of two point-of-care tear film osmometers. AB - PURPOSE: To compare the in vivo precision of two commercially available point-of care osmometers among normal subjects with no dry eye disease. METHODS: Twenty healthy adults with healthy ocular surfaces were evaluated by licensed eye care practitioners. All subjects had low Ocular Surface Disease Index score (<5), normal tear breakup time (>10 seconds), and no evidence of corneal fluorescein staining. Five consecutive measurements of tear osmolarity were measured on each eye using each of the two osmometers: the TearLab Osmolarity System (TearLab) and the I-Med i-Pen (i-Pen), for a total of 200 measurements per device. Performance of the osmometers was determined by specificity, estimated by the percentage of osmolarity data at or below the clinical cutoff (308 mOsm/L) and precision, and represented by the standard deviation per subject. In addition, to assess analytical performance, on each day of patient testing, standardized osmolarity quality control solutions (338 mOsm/L) were tested on the TearLab per manufacturer instructions. i-Pen manufacturer instructions do not neither provide for, nor recommend quality control procedures. RESULTS: The mean age of the 20 subjects was 27+/-8 years (range: 19-48 years, 16 females, four males). Over 2 months of testing, the TearLab reported analytical performance on quality control solutions of 335.8+/-4.2 mOsm/L with a coefficient of variation of 1.3%. In the subject cohort, 90.9% of TearLab measurements were in the normal range <=308 mOsm/L. The i-Pen reported 37.5% of all measurements in the normal range. The average intra-subject osmolarity of the TearLab was 295.4+/-8.6 mOsm/L, which was significantly lower and less variable than the i-Pen, which reported an average of 319.4+/-20.3 mOsm/L (P<0.001). When the measurements were grouped by subject, the TearLab accurately identified 100% of subjects as normal while the i-Pen accurately identified only 15% of subjects as normal. CONCLUSION: In this randomized comparative study of two point-of-care osmometers among normal, healthy non-dry eye subjects, the TearLab Osmolarity System demonstrated accuracy, precision, and agreement with clinical interpretation in line with the manufacturer claims. The i-Pen lacked sufficient performance to delineate subjects with and without dry eye disease. PMID- 28579745 TI - Lifitegrast ophthalmic solution in the treatment of signs and symptoms of dry eye disease: design, development, and place in therapy. AB - A new topical ophthalmic medication, lifitegrast 5%, was recently approved by the US Food and Drug Administration for use in dry eye patients. Lifitegrast is an integrin antagonist that decreases inflammation on the ocular surface, thereby improving dry eye disease (DED). Through a series of prospective, multicenter, randomized, masked, placebo-controlled studies in >2,000 patients total, lifitegrast was shown to be effective for improvement in both the signs and symptoms of DED. A subsequent study focused on the safety profile of lifitegrast and demonstrated that the majority of adverse events were mild and resolved over time. Lifitegrast is now available for use in clinical practice. PMID- 28579746 TI - Psychological morbidity in Leber's hereditary optic neuropathy depends on phenotypic, social, economic, and genetic factors. PMID- 28579747 TI - Prevalence of and risk factors for age-related macular degeneration in Nepal: the Bhaktapur Retina Study. AB - AIM: This study aimed to explore the prevalence of and risk factors for age related macular degeneration (AMD) in an elderly population in Nepal. SUBJECTS AND METHODS: This is a population-based, cross-sectional study. A sample size of 2,100 was calculated. A total of 1,860 (88.6%) subjects aged >60 years were enrolled for the study from 30 clusters in the district. Detailed history, visual acuity, and anterior segment and posterior segment examinations were performed. AMD was graded according to the International ARM Epidemiological Study Group. RESULTS: Among the total study population, 659 subjects had any AMD (35.43%; 95% confidence interval [CI]: 33.25-37.65), 484 had mild dry AMD (26.02%; 95% CI: 24.04-28.08), 143 had intermediate dry AMD (7.69%; 95% CI: 6.52-8.99), 19 had geographic atrophy (1.02%; 95% CI: 0.61-1.59), and 13 had wet AMD (0.70%; 95% CI: 0.37-1.19). The overall prevalence of early and late AMD was 33.71% and 1.72%, respectively. Among subjects with dry and wet AMD, 36.53% and 46.1% had visual impairment, while 2.78% and 23.08% were blind, respectively. In multivariate analysis, AMD was significantly higher in subjects with an increased number of cigarettes smoked per day (odds ratio [OR] 1.02, 95% CI: 1.01-1.04; P=0.007) and in subjects with pseudophakia (OR 1.45, 95% CI: 1.12-1.87; P=0.005). CONCLUSION: One-third of the population aged >=60 years have some form of AMD. There was a significant association with the number of cigarettes consumed and with previous cataract surgery. PMID- 28579748 TI - Functional characterization of rs2229094 (T>C) polymorphism in the tumor necrosis factor locus and lymphotoxin alpha expression in human retina: the Retina 4 project. AB - PURPOSE: The objective of this study is to determine the expression and localization of lymphotoxin alpha (LTA) in human retinas and the functionality of one of its polymorphisms rs2229094 (C13R) (T>C), previously associated with proliferative vitreoretinopathy (PVR) development. MATERIALS AND METHODS: Total RNA from three healthy human retinas were extracted and subjected to reverse transcription-polymerase chain reaction (RT-PCR) analysis, using flanking primers of LTA cDNA. In addition, three human eyes with retinal detachment (RD) and three healthy control eyes were subjected to immunohistochemistry (IHC) with a specific antibody against LTA. The functionality of T and C alleles was assessed by using pCEFL-Flag expression vector and transient transfection assays in COS-1 cell line. In addition, expression analysis by RT-PCR, Western blot and subcellular localization of both alleles and by immunofluorescence assay was performed. RESULTS: RT-PCR analysis revealed no significant levels of messenger RNA (mRNA) LTA in healthy human retinas. Sequential IHC staining showed differences between healthy human and RD retinas. No differences in mRNA and protein expression levels and in subcellular localization between both alleles were found. Both alleles were located in the cytoplasm of COS-1 cells. CONCLUSION: Although results suggest lack of functionality, the differences found in IHC study and its strong association with PVR and its relationship with tumor necrosis factor locus, warrant further studies and could justify the use of this polymorphism as a valid biomarker to identify high-risk patients to develop PVR after RD. PMID- 28579749 TI - Comprehensive review of visual defects reported with topiramate. AB - OBJECTIVE: The objective of this study was to analyze clinical patterns of visual field defects (VFDs) reported with topiramate treatment and assess possible mechanism of action (MOA) for antiepileptic drug (AED) associated VFDs. METHODS: A comprehensive topiramate database review included preclinical data, sponsor's clinical trials database, postmarketing spontaneous reports, and medical literature. All treatment-emergent adverse events (TEAEs) suggestive of retinal dysfunction/damage were summarized. Relative risk (RR) was computed from topiramate double-blind, placebo-controlled trials (DBPCTs) data. RESULTS: Preclinical studies and medical literature review suggested that despite sharing gamma-aminobutyric acid (GABA)-ergic MOA with other AEDs, topiramate treatment was not associated with VFDs. TEAEs suggestive of retinal dysfunction/damage were observed in 0.3%-0.7% of adults and pediatric patients with topiramate (N=4,679) versus <=0.1% with placebo (N=1,834) in DBPCTs for approved indications (epilepsy and migraine prophylaxis); open-label trials (OLTs) and DBPCTs for investigational indications had similar incidence. Overall, 88% TEAEs were mild or moderate in severity. Serious TEAEs were very rare (DBPCTs: 0%; OLTs: <=0.1%), and most were not treatment limiting, and resolved. The most common visual TEAEs (approved indications) were VFD, scotoma, and optic atrophy. The incidence of TEAEs in DBPCTs (approved and investigational indications) was higher in topiramate-treated (N=9,169) versus placebo-treated patients (N=5,023; 0.36% vs 0.24%), but the RR versus placebo-treated patients was not significant (RR: 1.51 [95% confidence interval: 0.78, 2.91]). CONCLUSION: VFDs do not appear to be a class effect for AEDs with GABA-ergic MOA. The RR for VFDs is not significantly different between topiramate and placebo treatment. PMID- 28579750 TI - Refractive predictability in eyes with intraocular gas tamponade - results of a prospective controlled clinical trial. AB - PURPOSE: To determine the postoperative refractive error in eyes with intraocular gas tamponade in combined phacovitrectomy using a Z-haptic intraocular lens (IOL). METHODS: This prospective non-randomized case-control study compared patients with combined phacovitrectomy with or without intraocular gas tamponade to cataract surgery-only. The main outcome measure was the IOL power prediction error (PE). Secondary outcome measures were spherical equivalent, anterior chamber depth (ACD), and axial length. RESULTS: Thirty-four patients with epiretinal membranes and 18 patients with cataract only were enrolled. There were no statistically significant (P>0.05) differences of IOL power PE or postoperative ACDs (P=0.952-1.00). Nevertheless, IOL power PE indicated a myopic shift in cases with phacovitrectomy independent of gas tamponade (P=1.00). No statistically significant between-group differences between secondary outcome measures were observed. CONCLUSION: A myopic shift after phacovitrectomy seems to be independent of the use of intraocular gas tamponade. When using a Z-haptic IOL, aiming for slight residual hyperopia (+0.50 D) is suggested in patients having phacovitrectomy. PMID- 28579751 TI - Treatment of moderate-to-high hyperopia with the WaveLight Allegretto 400 and EX500 excimer laser systems. AB - PURPOSE: To evaluate the efficacy of treating patients with +3.00 diopters (D) to +6.00 D of hyperopia via laser-assisted in situ keratomileusis (LASIK) with the WaveLight Allegretto 400 and EX500 excimer laser systems. SETTING: Private clinical ophthalmology practice. PATIENTS AND METHODS: This was a retrospective study of patients undergoing LASIK treatments of +3.00 to +6.00 D on two different WaveLight laser systems: 163 eyes on the 400 (Hertz) Hz system and 54 eyes on the 500 Hz system. The duration of follow-up was 6 months postoperation. Data were evaluated for uncorrected distance visual acuity, corrected distance visual acuity (CDVA), spherical equivalents (SEQs), and changes in these parameters (eg, loss of vision, regression over time). RESULTS: Treatment with both lasers was safe and effective, with loss of one line of CDVA in four of 162 eyes using the 400 Hz laser system, and none of the 54 eyes with the 500 Hz laser system. Overall, regression >=0.75 D from goal at 6 months was observed in 11.7% (19/163) of eyes in the 400 Hz laser group and 9.26% (5/54) of eyes in the 500 Hz laser group (regression >=0.50 D =77.9% [127/163] and 77.8% [42/54], respectively). The mean SEQ regressions for all eyes with moderate hyperopia were 0.10 and 0.18 D for those with high hyperopia. CONCLUSIONS: Both the 400 and 500 Hz excimer laser systems were safe and effective for the LASIK treatment of moderate-to-high hyperopia. The overall rate of regression was low and the amount of regression was relatively small with both systems. PMID- 28579752 TI - Comparison of visual acuity, refractive outcomes, and satisfaction between LASIK performed with a microkeratome and a femto laser. AB - PURPOSE: To compare refractive outcomes, visual acuities, and satisfaction of patients between those treated with laser-assisted in situ keratomileusis (LASIK) using a Hansatome microkeratome (HM) and femto-assisted laser (FAL). METHODS: This was a retrospective analysis of 1,366 eyes in 687 patients who underwent LASIK with an HM (n=1,137) and an FAL (n=229) at the two centers of Hashmanis Hospital, Karachi, Pakistan. Refractive outcomes, including sphere, cylinder, and spherical equivalent in diopters (D), and visual acuities were assessed both preoperatively and at 1 month follow-up. Patient satisfaction was gauged by contacting the patient at the time of chart review. RESULTS: The postoperative median sphere, cylinder, and spherical equivalent values for those treated with FAL were 0.3+/-0.7 (-5.5-1.8), -0.5+/-0.6 (-5.0-1.0), and 0.0+/-0.7 (-6.0-1.6), respectively. For the HM arm, they were 0.0+/-1.28 (-10.8-6.8), -0.5+/-0.5 (-4.5 1.5), and -0.3+/-1.3 (-11.6-6.8), respectively. All preoperative values were statistically insignificant between the groups, while postoperative values were significant with P-values <0.001. Predictability and efficacy index was higher for the FAL (92.1%, 1.00) than the HM group (82.2%, 0.84). Similarly, patient satisfaction was slightly higher for those treated with FAL (93.3%) than HM (91.4%). CONCLUSION: Our large retrospective analysis of eyes that have undergone LASIK using HM and FAL shows superior refractive outcomes in the latter, with special regard to procedural efficacy and predictability. PMID- 28579753 TI - Automated retinal imaging and trend analysis - a tool for health monitoring. AB - Most current diagnostic devices are expensive, require trained specialists to operate and gather static images with sparse data points. This leads to preventable diseases going undetected until late stage, resulting in greatly narrowed treatment options. This is especially true for retinal imaging. Future solutions are low cost, portable, self-administered by the patient, and capable of providing multiple data points, population analysis, and trending. This enables preventative interventions through mass accessibility, constant monitoring, and predictive modeling. PMID- 28579754 TI - Paradoxical SAPHO syndrome observed during anti-TNFalpha therapy for Crohn's disease. AB - Currently, anti-TNFalpha antibodies are used to treat Crohn's disease. We report on a 45-year-old Japanese female with Crohn's disease developing SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome following exposure to the anti-TNFalpha antibody adalimumab. Initially, adalimumab induced remission, but the patient showed SAPHO syndrome 11 weeks following the start of adalimumab therapy for the first time. Cutaneous and articular involvement were exacerbating the condition, so adalimumab was discontinued and the patient was put on low-dose methotrexate to control her symptoms. To our knowledge, this is the first report of SAPHO syndrome occurring during anti-TNF therapy, which is thought to be a paradoxical response to adalimumab. PMID- 28579755 TI - Past and current perspective on new therapeutic targets for Type-II diabetes. AB - Loss of pancreatic beta-cell function is a hallmark of Type-II diabetes mellitus (DM). It is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. Recently, United Kingdom Prospective Diabetes Study reported that Type-II DM is a progressive disorder. Although, DM can be treated initially by monotherapy with oral agent; eventually, it may require multiple drugs. Additionally, insulin therapy is needed in many patients to achieve glycemic control. Pharmacological approaches are unsatisfactory in improving the consequences of insulin resistance. Single therapeutic approach in the treatment of Type-II DM is unsuccessful and usually a combination therapy is adopted. Increased understanding of biochemical, cellular and pathological alterations in Type-II DM has provided new insight in the management of Type-II DM. Knowledge of underlying mechanisms of Type-II DM development is essential for the exploration of novel therapeutic targets. Present review provides an insight into therapeutic targets of Type-II DM and their role in the development of insulin resistance. An overview of important signaling pathways and mechanisms in Type-II DM is provided for the better understanding of disease pathology. This review includes case studies of drugs that are withdrawn from the market. The experience gathered from previous studies and knowledge of Type-II DM pathways can guide the anti-diabetic drug development toward the discovery of clinically viable drugs that are useful in Type-II DM. PMID- 28579756 TI - Effect of a food supplement containing berberine, monacolin K, hydroxytyrosol and coenzyme Q10 on lipid levels: a randomized, double-blind, placebo controlled study. AB - PURPOSE: To evaluate the ability of the new food supplement, Body Lipid (BL), containing red yeast rice, berberine, coenzyme Q10 and hydroxytyrosol, to lower the LDL-C in patients with mild-to-moderate hypercholesterolemia and to assess the overall safety profile of the product. METHODS: In this multicenter, randomized, double-blind, placebo and active comparator (the marketed Armolipid Plus(r) [AM]) controlled study, 158 hypercholesterolemic patients were randomized following a 4-week dietary run-in period. After 4 weeks of treatment with a daily oral dose of the new food supplement BL, AM or placebo, plus diet, the main outcome was the decrease of LDL-C, total cholesterol (TC), and triglyceride levels. FINDINGS: The absolute changes of LDL-C and TC levels from baseline, at week 4 were: -39.1 mg/dL +/-17.76 and -45.9 mg/dL +/-21.54, respectively in the BL group; 5.7 mg/dL +/-14.98 and 2.4 mg/dL +/-18.43, respectively in the placebo group. Results were statistically significant. In terms of mean percentage, BL was shown to be more effective in lowering LDL-C levels as compared to placebo and the active comparator (AM), with a reduction of -26.3%, +4.2%, -18.3%, respectively. Five adverse events (AEs) were reported by five patients after the initiation of the study treatment: two in the BL group (influence and insomnia), two in the AM group (ear pain and rash), and one in the placebo group (back pain). All AEs were mild in intensity, except for back pain (severe). The case of insomnia in the BL group and the case of rash in the AM group were judged as treatment related. The safety review of the laboratory (blood and urine) analyses, vital signs and physical findings did not show any clinical effect of the study products on any of the parameters. IMPLICATIONS: BL showed a good efficacy and safety profile and, for this reason, it can be considered an alternative to pharmacological treatment, for patients with mild-to-moderate hypercholesterolemia. PMID- 28579757 TI - Profile of sarilumab and its potential in the treatment of rheumatoid arthritis. AB - In recent years the use of biotechnological agents has drastically revolutionized the therapeutic approach and the progression of rheumatoid arthritis (RA). In particular, interleukin-6 (IL-6) has been demonstrated as a pivotal cytokine in the pathogenesis of the disease by contributing to both the innate and the adaptive immune system perturbation, and to the production of acute-phase proteins involved in the systemic expression of the disorder. The first marketed IL-6 blocker was tocilizumab, a humanized anti-IL-6 receptor (anti-IL-6R) monoclonal antibody. The successful use of tocilizumab in RA has encouraged the development of other biologic agents specifically targeting the IL-6 pathway, either directed against IL-6 cytokine (sirukumab, olokizumab, and clazakizumab) or IL-6 receptor (sarilumab). One Phase II and six Phase III randomized controlled trials demonstrated a broad efficacy of sarilumab across all RA patient subtypes, ranging from methotrexate (MTX) to tumor necrosis factor inhibitor insufficient responders. In particular, sarilumab as monotherapy demonstrated a clear head-to-head superiority over adalimumab in MTX-intolerant subjects. In addition, compared with tocilizumab, sarilumab showed a similar safety profile with significantly higher affinity and longer half-life, responsible for a reduction of the frequency of administration (every other week instead weekly). All these aspects may be important in defining the strategy for positioning sarilumab in the treatment algorithm of RA. Indeed, observational data coming from post-marketing real-life studies may provide crucial additional information for better understanding the role of sarilumab in the management of the disease. This review summarizes both the biological role of IL-6 in RA and the clinical data available on sarilumab as an alternative therapeutic option in RA patients. PMID- 28579759 TI - A randomized trial of individual versus group-format exercise and self-management in individuals with Parkinson's disease and comorbid depression. AB - BACKGROUND: Depression is common in people with Parkinson's disease (PD), and exercise is known to improve depression and PD. However, lack of motivation and low self-efficacy can make exercise difficult for people with PD and comorbid depression (PD-Dep). A combined group exercise and chronic disease self management (CDSM) program may improve the likeli-hood that individuals will engage in exercise and will show a reduction in depression symptoms. The purpose of this study was to compare changes in depression in PD-Dep between individual versus group exercise plus CDSM and to examine participant adherence and perception of the interventions. METHODS: Participants (N=30) were randomized to either Enhanced EXerCisE thErapy for PD (EXCEED; group CDSM and exercise) or self guided CDSM plus exercise. Outcomes were change in depression assessed with the Montgomery-Asberg Depression Rating Scale (MADRS), cognition, apathy, anxiety, sleep, quality of life, motor function, self-efficacy, and patient satisfaction. RESULTS: Both groups showed significant improvement in MADRS (P<0.001) with no significant group difference. Individuals in EXCEED group enjoyed the group dynamics but noted difficulty with the fixed-time sessions. CONCLUSION: Both group CDSM plus exercise and self-guided CDSM plus exercise can improve depression in PD-Dep. These findings suggest that development of a remotely delivered group-based CDSM format plus manualized exercise program could be useful for this population. PMID- 28579760 TI - Understanding deprescribing of preventive cardiovascular medication: a Q methodology study in patients. AB - BACKGROUND: Patients with low cardiovascular disease (CVD) risk potentially use preventive cardiovascular medication unnecessarily. Our aim was to identify various viewpoints and beliefs concerning the preventive CVD management of patients with low CVD risk using preventive cardiovascular medication. Furthermore, we investigated whether certain viewpoints were related to a preference for deprescription or the continuation of preventive cardiovascular medication. METHODS: In 2015, we purposively sampled patients from the intervention arm of the Evaluating Cessation of STatins and Antihypertensive Treatment In primary Care (ECSTATIC) trial in the Netherlands for this study. Participants made Q-sorts by ranking 43 statements concerning preventive CVD management from "totally disagree" to "totally agree". These Q-sorts were analyzed using PQMethod 2.35 software. A varimax procedure presented the distinguishing viewpoints that were favored by our participants. We used group discussion quotations to underline our findings. For validation purposes, we asked participants how well each viewpoint fitted them. RESULTS: Of 291 invited patients, 33 participated. Thirty-one Q-sorts were analyzed. The following three viewpoints were found: 1) a controlling viewpoint, in which patients held the belief that monitoring blood pressure and cholesterol levels is important (n=13, of which seven had their medication deprescribed and six continued their medication); 2) an autonomous viewpoint, in which patients showed a dislike of medication (n=8, of which seven had their medication deprescribed and one had it continued); and 3) an afraid viewpoint, in which patients were fearful of developing CVD (n=8, of which two had their medication deprescribed and six had it continued). Seventy-four percent of the participants believed that the viewpoint to which they were assigned was a good fit. CONCLUSION: Three well discriminating viewpoints about preventive CVD management were determined. Knowing and recognizing these viewpoints is effective for general practitioners when discussing the deprescribing of preventive cardiovascular medications with patients and may be used to promote implementation of deprescription. PMID- 28579758 TI - Development of antiproliferative long-circulating liposomes co-encapsulating doxorubicin and curcumin, through the use of a quality-by-design approach. AB - The aim of this work was to use the quality-by-design (QbD) approach in the development of long-circulating liposomes co-loaded with curcumin (CUR) and doxorubicin (DOX) and to evaluate the cytotoxic potential of these liposomes in vitro using C26 murine colon carcinoma cell line. Based on a risk assessment, six parameters, namely the phospholipid, CUR and DOX concentrations, the phospholipid:cholesterol molar ratio, the temperature during the evaporation and hydration steps and the pH of the phosphate buffer, were identified as potential risk factors for the quality of the final product. The influence of these variables on the critical quality attributes of the co-loaded liposomal CUR and DOX was investigated: particle size, zeta potential, drug loading and entrapment efficiency. For this, a 26-2 factorial design was employed to establish a proper regression model and to generate the contour plots for the responses. The obtained data served to establish the design space for which different combinations of variables yielded liposomes with characteristics within predefined specifications. The validation of the model was carried out by preparing two liposomal formulations corresponding to the robust set point from within the design space and one outside the design space and calculating the percentage bias between the predicted and actual experimental results. The in vitro antiproliferative test showed that at higher CUR concentrations, the liposomes co-encapsulating CUR and DOX had a greater cytotoxic effect than DOX loaded liposomes. Overall, this study showed that QbD is a useful instrument for controlling and optimizing the manufacturing process of liposomes co-loaded with CUR and DOX and that this nanoparticulate system possesses a great potential for use in colon cancer therapy. PMID- 28579761 TI - Barriers and facilitators associated with colonoscopy completion in individuals with multiple chronic conditions: a qualitative study. AB - BACKGROUND: A recommendation to undergo a colonoscopy, an invasive procedure that requires commitment and motivation, planning (scheduling and finding a driver) and preparation (diet restriction and laxative consumption), may be uniquely challenging for individuals with multiple chronic conditions (MCCs). This qualitative study aimed to describe the barriers and facilitators to colonoscopy experienced by such patients. MATERIALS AND METHODS: Semistructured focus groups were conducted with male Veterans who were scheduled for outpatient colonoscopy and either failed to complete the procedure or completed the examination. Focus group recordings were transcribed and analyzed by an inductive grounded approach using constant comparative analysis. RESULTS: Forty-four individuals aged 51-83 years participated in this study (23 adherent and 21 nonadherent). Participants had an average of 7.4 chronic conditions (range 2-14). The five most common chronic conditions were hypertension (75%), hyperlipidemia (75%), osteoarthritis/degenerative joint disease (59%), atherosclerotic heart disease (48%), and diabetes mellitus (36%). We identified four unique themes that influenced motivation to undergo a colonoscopy: competing medical priorities, low perceived benefit, a prior negative colonoscopy experience, and pre-existing medical conditions. Additionally, we identified four themes that influenced individuals' ability to complete the examination: difficulty with bowel cleansing, difficulty with travel, worry about exacerbation of pre-existing conditions, and heightened concerns about potential complications. CONCLUSION: MCCs are common in individuals referred for colonoscopy and generate unique barriers to colonoscopy completion related to medication, dietary changes, transportation, preparation processes, symptoms exacerbation, and complication concerns. Future research should examine whether tailored interventions that include education and support in addressing the unique barriers can enhance colonoscopy completion. PMID- 28579763 TI - Trends of Dengue Disease Epidemiology. AB - Dengue disease is an emerging mosquito-borne viral infection transmitted between humans by Aedes spp. that are distributed mainly in the tropical and subtropical region along with chikungunya and zika diseases. The distribution of dengue disease is influenced by local variation, such as geography, rainfall, temperature, and rapid urbanization or migration. The epidemy of mosquito-borne infection significantly led to increased number of cases and hyperendemicity which induce a more severe form of dengue accompanied by cocirculation of chikungunya and zika. The rapid global spreading of dengue disease created public health burdens that are presently unfulfilled by the absence of specific therapy, simple diagnosis tool for the early phase, and effective and efficient vector control system. This review highlights the current situation of dengue distribution, epidemiology, and new strategies for early dengue diagnosis and risk prediction of severity that can be used to improve oversight and alleviate the heavy burden of the disease. PMID- 28579764 TI - Is Zika Virus an Emerging TORCH Agent? An Invited Commentary. AB - Zika virus (ZIKV) is a mosquito-borne arbovirus from the family Flaviviridae, which had caused some epidemics since its discovery in 1947 without any significant impacts on public health. In 2015, however, a 20-fold increase in congenital microcephaly cases in northeastern Brazil was attributed to prenatally acquired ZIKV infection. Traditionally, TORCH agents have 4 common characteristics including causing a mild illness in infected mother, vertical transmission to fetus, developing several anomalies in the affected fetus, and in some instances, maternal therapy may not ameliorate fetal prognosis. Prenatal ZIKV infection has shown the aforementioned characteristics during the recent epidemics in South America and the Caribbean region; therefore, it should be considered as an emerging TORCH agent that may seriously threaten public health. Fetal ultrasound can be used as a safe, inexpensive, and easy-to-access imaging modality for detecting suspicious cases of congenital Zika syndrome in utero and suggesting confirmatory diagnostic examinations to these patients. PMID- 28579762 TI - Prepartal Energy Intake Alters Blood Polymorphonuclear Leukocyte Transcriptome During the Peripartal Period in Holstein Cows. AB - In the dairy industry, cow health and farmer profits depend on the balance between diet (ie, nutrient composition, daily intake) and metabolism. This is especially true during the transition period, where dramatic physiological changes foster vulnerability to immunosuppression, negative energy balance, and clinical and subclinical disorders. Using an Agilent microarray platform, this study examined changes in the transcriptome of bovine polymorphonuclear leukocytes (PMNLs) due to prepartal dietary intake. Holstein cows were fed a high straw, control-energy diet (CON; NEL = 1.34 Mcal/kg) or overfed a moderate-energy diet (OVE; NEL = 1.62 Mcal/kg) during the dry period. Blood for PMNL isolation and metabolite analysis was collected at -14 and +7 days relative to parturition. At an analysis of variance false discovery rate <0.05, energy intake (OVE vs CON) influenced 1806 genes. Dynamic Impact Approach bioinformatics analysis classified treatment effects on Kyoto Encyclopedia of Genes and Genomes pathways, including activated oxidative phosphorylation and biosynthesis of unsaturated fatty acids and inhibited RNA polymerase, proteasome, and toll-like receptor signaling pathway. This analysis indicates that processes critical for energy metabolism and cellular and immune function were affected with mixed results. However, overall interpretation of the transcriptome data agreed in part with literature documenting a potentially detrimental, chronic activation of PMNL in response to overfeeding. The widespread, transcriptome-level changes captured here confirm the importance of dietary energy adjustments around calving on the immune system. PMID- 28579767 TI - Cognitive decline in normal aging and its prevention: a review on non pharmacological lifestyle strategies. AB - The purpose of this study is to examine the effects of the selected non pharmacological lifestyle activities on the delay of cognitive decline in normal aging. This was done by conducting a literature review in the four acknowledged databases Web of Science, Scopus, MEDLINE, and Springer, and consequently by evaluating the findings of the relevant studies. The findings show that physical activities, such as walking and aerobic exercises, music therapy, adherence to Mediterranean diet, or solving crosswords, seem to be very promising lifestyle intervention tools. The results indicate that non-pharmacological lifestyle intervention activities should be intense and possibly done simultaneously in order to be effective in the prevention of cognitive decline. In addition, more longitudinal randomized controlled trials are needed in order to discover the most effective types and the duration of these intervention activities in the prevention of cognitive decline, typical of aging population groups. PMID- 28579765 TI - Effects of a giant exercising board game intervention on ambulatory physical activity among nursing home residents: a preliminary study. AB - PURPOSE: This study examined the effects of a giant (4*3 m) exercising board game intervention on ambulatory physical activity (PA) and a broader array of physical and psychological outcomes among nursing home residents. MATERIALS AND METHODS: A quasi-experimental longitudinal study was carried out in two comparable nursing homes. Ten participants (aged 82.5+/-6.3 and comprising 6 women) meeting the inclusion criteria took part in the 1-month intervention in one nursing home, whereas 11 participants (aged 89.9+/-3.1 with 8 women) were assigned to the control group in the other nursing home. The giant exercising board game required participants to per-form strength, flexibility, balance and endurance activities. The assistance provided by an exercising specialist decreased gradually during the intervention in an autonomy-oriented approach based on the self-determination theory. The following were assessed at baseline, after the intervention and after a follow-up period of 3 months: PA (steps/day and energy expenditure/day with ActiGraph), cognitive status (mini mental state examination), quality of life (EuroQol 5-dimensions), motivation for PA (Behavioral Regulation in Exercise Questionnaire-2), gait and balance (Tinetti and Short Physical Performance Battery), functional mobility (timed up and go), and the muscular isometric strength of the lower limb muscles. RESULTS AND CONCLUSION: In the intervention group, PA increased from 2,921 steps/day at baseline to 3,358 steps/day after the intervention (+14.9%, P=0.04) and 4,083 steps/day (+39.8%, P=0.03) after 3 months. Energy expenditure/day also increased after the intervention (+110 kcal/day, +6.3%, P=0.01) and after 3 months (+219 kcal/day, +12.3%, P=0.02). Quality of life (P<0.05), balance and gait (P<0.05), and strength of the ankle (P<0.05) were also improved after 3 months. Such improvements were not observed in the control group. The preliminary results are promising but further investigation is required to confirm and evaluate the long-term effectiveness of PA interventions in nursing homes. PMID- 28579766 TI - Effects of multi-domain interventions in (pre)frail elderly on frailty, functional, and cognitive status: a systematic review. AB - BACKGROUND: Frailty is an aging syndrome caused by exceeding a threshold of decline across multiple organ systems leading to a decreased resistance to stressors. Treatment for frailty focuses on multi-domain interventions to target multiple affected functions in order to decrease the adverse outcomes of frailty. No systematic reviews on the effectiveness of multi-domain interventions exist in a well-defined frail population. OBJECTIVES: This systematic review aimed to determine the effect of multi-domain compared to mono-domain interventions on frailty status and score, cognition, muscle mass, strength and power, functional and social outcomes in (pre)frail elderly (>=65 years). It included interventions targeting two or more domains (physical exercise, nutritional, pharmacological, psychological, or social interventions) in participants defined as (pre)frail by an operationalized frailty definition. METHODS: The databases PubMed, EMBASE, CINAHL, PEDro, CENTRAL, and the Cochrane Central register of Controlled Trials were searched from inception until September 14, 2016. Additional articles were searched by citation search, author search, and reference lists of relevant articles. The protocol for this review was registered on PROSPERO (CRD42016032905). RESULTS: Twelve studies were included, reporting a large diversity of interventions in terms of content, duration, and follow-up period. Overall, multi-domain interventions tended to be more effective than mono-domain interventions on frailty status or score, muscle mass and strength, and physical functioning. Results were inconclusive for cognitive, functional, and social outcomes. Physical exercise seems to play an essential role in the multi-domain intervention, whereby additional interventions can lead to further improvement (eg, nutritional intervention). CONCLUSION: Evidence of beneficial effects of multi-domain compared to mono-domain interventions is limited but increasing. Additional studies are needed, focusing on a well-defined frail population and with specific attention to the design and the individual contribution of mono domain interventions. This will contribute to the development of more effective interventions for frail elderly. PMID- 28579768 TI - Clinical characteristics of COPD patients with tidal expiratory flow limitation. AB - We have used impulse oscillometry to identify COPD patients with tidal expiratory flow limitation (EFL), which is a measurement related to small airway disease. We report that 37.4% of COPD patients had EFL; these patients had multiple clinical characteristics of more severe disease including lower forced expiratory volume in 1 second values, greater hyperinflation, reduced exercise performance, and increased small airway impairment. We highlight that EFL can be used to identify a subgroup of COPD patients with distinct characteristics associated with small airway disease. PMID- 28579769 TI - Ampicillin resistance in Haemophilus influenzae from COPD patients in the UK. AB - BACKGROUND: Haemophilus influenzae is commonly isolated from the airways of COPD patients. Antibiotic treatment may cause the emergence of resistant H. influenzae strains, particularly ampicillin-resistant strains, including beta-lactamase negative ampicillin resistance (BLNAR) strains. Genetic identification using ftsI sequencing is the optimum method for identifying mutations within BLNAR strains. The prevalence of BLNAR in COPD patients during the stable state has not been reported. We investigated the antibiotic resistance patterns of H. influenzae present in the sputum of stable COPD patients, focusing on ampicillin resistance; the prevalence of enzyme and non-enzyme-mediated ampicillin resistance was determined. A subset of patients was followed up longitudinally to study H. influenzae strain switching and antibiotic sensitivity changes. PATIENTS AND METHODS: Sputum sampling was performed in 61 COPD patients, with 42 samples obtained at baseline; H. influenzae was detected by polymerase chain reaction in 28 samples. In all, 45 patients completed the follow-up for 2 years; 24 H. influenzae isolates were obtained. RESULTS: Disk diffusion showed the highest antibiotic resistance in the penicillin antibiotic group (eg, 67% for ampicillin) and macrolides (eg, 46% for erythromycin), whereas all isolates were susceptible to quinolones. Of the 16 isolates resistant to ampicillin, 9 (56%) were beta lactamase positive. The beta-lactamase-negative isolates were further investigated; none of these fulfilled the phenotypic BLNAR classification criteria of ampicillin minimum inhibitory concentration >1 ug/mL, and only one demonstrated an ftsI mutation. Frequent H. influenzae strain switching was confirmed using multilocus sequence typing and was associated with changes in the antibiotic sensitivity pattern. CONCLUSION: We observed an overidentification of ampicillin resistance by disk diffusion. The majority of ampicillin resistance was due to enzyme production. H. influenzae strain changes during the stable state may be associated with a change in antibiotic sensitivity; this has implications for empirical antibiotic prescribing. PMID- 28579770 TI - Proteasome activity related with the daily physical activity of COPD patients. AB - BACKGROUND: COPD is a debilitating disease that affects patients' daily lives. One's daily physical activity (DPA) decreases due to multifactorial causes, and this decrease is correlated with a poor prognosis in COPD patients. Muscle wasting may at least be partly due to increased activity of the ubiquitin proteasome pathway and apoptosis. METHODS: This study investigated the relationships among DPA, circulating proteasome activity, and protein carbonyl in COPD patients and healthy subjects (HSs). This study included 57 participants (42 patients and 15 healthy subjects). Ambulatory DPA was measured using actigraphy, and oxygen saturation was measured with a pulse oximeter. RESULTS: COPD patients had lower DPA, lower 6 min walking distance (6MWD), lower delta saturation pulse oxygenation (SpO2) during the 6MWT, and lower delta SpO2 during DPA than HSs. COPD patients had higher proteasome activity and protein carbonyl than HSs. Circulating proteasome activity was significantly negatively correlated with DPA (r=-0.568, P<0.05) in COPD patients, whereas delta SpO2 during the 6MWT was significantly positively correlated with proteasome activity (r=0.685, P<0.05) in HSs. Protein carbonyl was significantly negatively correlated with the body mass index (r=-0.318, P<0.05), mid-arm circumference (r=0.350, P<0.05), calf circumference (r=0.322, P<0.05), forced expiratory volume in the first second (r= 0.441, P<0.01), and 6MWD (r=-0.313, P<0.05) in COPD patients. Our results showed no significant difference in inflammatory markers (interleukin-6 and tumor necrosis factor-alpha) or ubiquitin between the two groups. CONCLUSION: COPD patients had lower DPA levels and higher circulating proteasome activity than HSs, and a negative correlation of DPA with circulating proteasome activity. PMID- 28579771 TI - A cross-sectional survey of current treatment and symptom burden of patients with COPD consulting for routine care according to GOLD 2014 classifications. AB - BACKGROUND: As part of the Respiratory Disease Specific Program (DSP) conducted to provide observations of clinical practice from a physician and matched patient viewpoint, this study aimed to establish how patients with COPD are treated according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification system and to quantify the symptom burden. METHODS: Data were obtained from the Respiratory DSP, a cross-sectional survey of patients with a diagnosis of COPD consulting for routine care in France, Germany, Italy, Spain, the UK, and the USA during the third quarter of 2013. Patients' exacerbation risk and symptom data were used for classification into GOLD groups A-D based on GOLD 2014 criteria. Prescribing practices were stratified by physician type and time since patient diagnosis. RESULTS: A total of 903 physicians participated in the Respiratory DSP, with data from 1,641 patients included in this analysis. Most patients were classified into GOLD groups B (n=742; 45.2%) and D (n=704; 42.9%). Patients in groups A and D were most likely to be treated in line with GOLD recommendations (61.5% and 77.5%, respectively), compared with 40.1% for group B. Patients with a diagnosis within the past 12 months were more likely to be treated according to recommendations. Inhaled corticosteroids (ICSs) in combination with one or more long-acting bronchodilator were prescribed across all GOLD groups. Patterns of treatment were, in general, similar for patients treated by a primary care physician or a pulmonologist. COPD assessment test scores >=10 indicating a high symptom burden were reported for >80% of patients. CONCLUSION: This analysis confirmed a high symptom burden among patients with COPD and indicates some misalignment of prescribing with GOLD recommendations, particularly regarding the role of ICS/long-acting beta2-agonist (LABA) and ICS/LABA + long-acting muscarinic antagonist combinations across the different GOLD groups. PMID- 28579772 TI - Delayed but successful response to noninvasive ventilation in COPD patients with acute hypercapnic respiratory failure. AB - BACKGROUND: We evaluated a new noninvasive ventilation (NIV) protocol that allows the pursuit of NIV in the case of persistent severe respiratory acidosis despite a first NIV challenge in COPD patients with acute hypercapnic respiratory failure (AHRF). PATIENTS AND METHODS: A prospective observational multicentric pilot study was conducted in three tertiary hospitals over a 12-month study period. A total of 155 consecutive COPD patients who were admitted for AHRF and treated by NIV were enrolled. Delayed response to NIV was defined as a significant clinical improvement in the first 48 h following NIV initiation despite a persistent severe respiratory acidosis (pH <7.30) after the first 2 h of NIV trial. RESULTS: NIV failed in only 10 patients (6.5%). Delayed responders to NIV (n=83, 53%) exhibited similar nutritional status, comorbidities, functional status, frailty score, dyspnea score, and severity score at admission, compared with early responders (n=62, 40%). Only age (66 vs 70 years in early responders; P=0.03) and encephalopathy score (3 [2-4] vs 3 [2-4] in early responders; P=0.015) were different among the responders. Inhospital mortality did not differ between responders to NIV (n=10, 12% for delayed responders vs n=10, 16% for early responders, P=0.49). A second episode of AHRF occurred in 20 responders (14%), equally distributed among early and delayed responders to NIV (n=9, 14.5% in early responders vs n=11, 13% in delayed responders; P=0.83), with a poor survival rate (n=1, 5%). CONCLUSION: Most of the COPD patients with AHRF have a successful outcome when NIV is pursued despite a persistent severe respiratory acidosis after the first NIV trial. The outcome of delayed responders is similar to the one of the early responders. On the contrary, the second episode of AHRF during the hospital stay carries a poor prognosis. PMID- 28579773 TI - Identification of thyroxine-binding globulin as a candidate plasma marker of chronic obstructive pulmonary disease. AB - Biomarkers for the management of chronic obstructive pulmonary disease (COPD) are limited. The aim of this study was to explore new plasma biomarkers in patients with COPD. Thyroxine-binding globulin (THBG) was initially identified by proteomics in a discovery panel and subsequently verified by enzyme-linked immunosorbent assay in another verification panel with a 1-year follow-up. THBG levels were elevated in patients with COPD (9.2+/-2.3 MUg/mL) compared to those of the controls (6.6+/-2.0 MUg/mL). Receiver operating characteristic curves suggested that THBG was able to slightly differentiate between patients with COPD and controls (area under the curve [AUC]: 0.814) and performed better if combined with fibrinogen (AUC: 0.858). THBG was more capable of distinguishing Global Initiative for Obstructive Lung Disease stages I-III and IV (AUC: 0.851) compared with fibrinogen (AUC 0.582). THBG levels were negatively associated with predicted percentage forced expiratory volume in 1 s and positively related to predicted percentage residual volume, RV/percentage total lung capacity, and percentage low-attenuation area. COPD patients with higher baseline THBG levels had a greater risk of acute exacerbation (AE) than those with lower THBG levels (P=0.014, by Kaplan-Meier curve; hazard ratio: 4.229, by Cox proportional hazards model). In summary, THBG is a potential plasma biomarker of COPD and can assist in the management of stable stage and AEs in COPD patients. PMID- 28579774 TI - ATP synthesis in the energy metabolism pathway: a new perspective for manipulating CdSe quantum dots biosynthesized in Saccharomyces cerevisiae. AB - Due to a growing trend in their biomedical application, biosynthesized nanomaterials are of great interest to researchers nowadays with their biocompatible, low-energy consumption, economic, and tunable characteristics. It is important to understand the mechanism of biosynthesis in order to achieve more efficient applications. Since there are only rare studies on the influences of cellular energy levels on biosynthesis, the influence of energy is often overlooked. Through determination of the intracellular ATP concentrations during the biosynthesis process, significant changes were observed. In addition, ATP synthesis deficiency caused great decreases in quantum dots (QDs) biosynthesis in the Deltaatp1, Deltaatp2, Deltaatp14, and Deltaatp17 strains. With inductively coupled plasma-atomic emission spectrometry and atomic absorption spectroscopy analyses, it was found that ATP affected the accumulation of the seleno-precursor and helped with the uptake of Cd and the formation of QDs. We successfully enhanced the fluorescence intensity 1.5 or 2 times through genetic modification to increase ATP or SeAM (the seleno analog of S-adenosylmethionine, the product that would accumulate when ATP is accrued). This work explains the mechanism for the correlation of the cellular energy level and QDs biosynthesis in living cells, demonstrates control of the biosynthesis using this mechanism, and thus provides a new manipulation strategy for the biosynthesis of other nanomaterials to widen their applications. PMID- 28579775 TI - Capsaicin-loaded nanolipoidal carriers for topical application: design, characterization, and in vitro/in vivo evaluation. AB - Capsaicin has been used in clinical applications for the treatment of pain disorders and inflammatory diseases. Given the strong pungency and high oil/water partition coefficient of capsaicin, capsaicin-loaded nanolipoidal carriers (NLCs) were designed to increase permeation and achieve the analgesic, anti-inflammatory effect with lower skin irritation. Capsaicin-loaded NLCs were prepared and later optimized by the Box-Behnken design. The physicochemical characterizations, morphology, and encapsulation of the capsaicin-loaded NLCs were subsequently confirmed. Capsaicin-loaded NLCs and capsaicin-loaded NLCs gel exhibited sustained release and no cytotoxicity properties. Also, they could significantly enhance the penetration amount, permeation flux, and skin retention amounts of capsaicin due to the application of NLCs. To study the topical permeation mechanism of capsaicin, 3,3'-dioctadecyloxacarbocyanine perchlorate (Dio) was used as a fluorescent dye. Dio-loaded NLCs and Dio-loaded NLCs gel could effectively deliver Dio up to a skin depth of 260 and 210 MUm, respectively, primarily through the appendage route on the basis of version skin sections compared with Dio solution, which only delivered Dio up to 150 MUm. In vivo therapeutic experiments demonstrated that capsaicin-loaded NLCs and capsaicin loaded NLCs gel could improve the pain threshold in a dose-dependent manner and inhibit inflammation, primarily by reducing the prostaglandin E2 levels in the tissue compared with capsaicin cream and capsaicin solution. Meanwhile, skin irritation was reduced, indicating that application of NLCs could decrease the irritation caused by capsaicin. Overall, NLCs may be a potential carrier for topical delivery of capsaicin for useful pain and inflammation therapy. PMID- 28579776 TI - Aptamer-conjugated PEGylated quantum dots targeting epidermal growth factor receptor variant III for fluorescence imaging of glioma. AB - The extent of resection is a significant prognostic factor in glioma patients. However, the maximum safe resection level is difficult to determine due to the inherent infiltrative character of tumors. Recently, fluorescence-guided surgery has emerged as a new technique that allows safe resection of glioma. In this study, we constructed a new kind of quantum dot (QD)-labeled aptamer (QD-Apt) nanoprobe by conjugating aptamer 32 (A32) to the QDs surface, which can specially bind to the tumors. A32 is a single-stranded DNA capable of binding to the epidermal growth factor receptor variant III (EGFRvIII) specially distributed on the surface of glioma cells. To detect the expression of EGFRvIII in human brain tissues, 120 specimens, including 110 glioma tissues and 10 normal brain tissues, were examined by immunohistochemistry, and the results showed that the rate of positive expression of EGFRvIII in the glioma tissues was 41.82%, and 0.00% in normal brain tissues. Besides, the physiochemical properties of QD-Apt nanoparticles (NPs) were thoroughly characterized. Biocompatibility of the NPs was evaluated, and the results suggested that the QD-Apt was nontoxic in vivo and vitro. Furthermore, the use of the QD-Apt in labeling glioma cell lines and human brain glioma tissues, and target gliomas in situ was also investigated. We found that not only could QD-Apt specially bind to the U87-EGFRvIII glioma cells but also bind to human glioma tissues in vitro. Fluorescence imaging in vivo with orthotopic glioma model mice bearing U87-EGFRvIII showed that QD-Apt could penetrate the blood-brain barrier and then selectively accumulate in the tumors through binding to EGFRvIII, and consequently, generate a strong fluorescence, which contributed to the margins of gliomas that were visualized clearly, and thus, help the surgeons realize the maximum safe resection of glioma. In addition, QD-Apt can also be applied in preoperative diagnosis and postoperative examination of glioma. Therefore, these achievements facilitate the use of tumor targeted fluorescence imaging in the diagnosis, surgical resection, and postoperative examination of glioma. PMID- 28579777 TI - Electrohydrodynamic fabrication of core-shell PLGA nanoparticles with controlled release of cisplatin for enhanced cancer treatment. AB - Increasing the clinical efficacy of toxic chemotherapy drugs such as cisplatin (CDDP), via targeted drug delivery, is a key area of research in cancer treatment. In this study, CDDP-loaded poly(lactic-co-glycolic acid) (PLGA) polymeric nanoparticles (NPs) were successfully prepared using electrohydrodynamic atomization (EHDA). The configuration was varied to control the distribution of CDDP within the particles, and high encapsulation efficiency (>70%) of the drug was achieved. NPs were produced with either a core-shell (CS) or a matrix (uniform) structure. It was shown that CS NPs had the most sustained release of the 2 formulations, demonstrating a slower linear release post initial "burst" and longer duration. The role of particle architecture on the rate of drug release in vitro was confirmed by fitting the experimental data with various kinetic models. This indicated that the release process was a simple diffusion mechanism. The CS NPs were effectively internalized into the endolysosomal compartments of cancer cells and demonstrated an increased cytotoxic efficacy (concentration of a drug that gives half maximal response [EC50] reaching 6.2 uM) compared to free drug (EC50 =9 uM) and uniform CDDP-distributed NPs (EC50 =7.6 uM) in vitro. Thus, these experiments indicate that engineering the structure of PLGA NPs can be exploited to control both the dosage and the release characteristics for improved clinical chemotherapy treatment. PMID- 28579778 TI - Iron oxide nanoparticles induce cytokine secretion in a complement-dependent manner in a human whole blood model. AB - Iron oxide nanoparticles (IONPs) are promising nanomaterials for biomedical applications. However, their inflammatory potential has not been fully established. Here, we used a lepirudin anti-coagulated human whole blood model to evaluate the potential of 10 nm IONPs to activate the complement system and induce cytokine production. Reactive oxygen species and cell death were also assessed. The IONPs activated complement, as measured by C3a, C5a and sC5b-9, and induced the production of pro-inflammatory cytokines in a particle-dose dependent manner, with the strongest response at 10 ug/mL IONPs. Complement inhibitors at C3 (compstatin analog Cp40) and C5 (eculizumab) levels completely inhibited complement activation and secretion of inflammatory mediators induced by the IONPs. Additionally, blockade of complement receptors C3aR and C5aR1 significantly reduced the levels of various cytokines, indicating that the particle-induced secretion of inflammatory mediators is mainly C5a and C3a mediated. The IONPs did not induce cell death or reactive oxygen species, which further suggests that complement activation alone was responsible for most of the particle-induced cytokines. These data suggest that the lepirudin anti-coagulated human whole blood model is a valuable ex vivo system to study the inflammatory potential of IONPs. We conclude that IONPs induce complement-mediated cytokine secretion in human whole blood. PMID- 28579780 TI - Aggregation is a critical cause of poor transfer into the brain tissue of intravenously administered cationic PAMAM dendrimer nanoparticles. AB - Dendrimers have been expected as excellent nanodevices for brain medication. An amine-terminated polyamidoamine dendrimer (PD), an unmodified plain type of PD, has the obvious disadvantage of cytotoxicity, but still serves as an attractive molecule because it easily adheres to the cell surface, facilitating easy cellular uptake. Single-photon emission computed tomographic imaging of a mouse following intravenous injection of a radiolabeled PD failed to reveal any signal in the intracranial region. Furthermore, examination of the permeability of PD particles across the blood-brain barrier (BBB) in vitro using a commercially available kit revealed poor permeability of the nanoparticles, which was suppressed by an inhibitor of caveolae-mediated endocytosis, but not by an inhibitor of macropinocytosis. Physicochemical analysis of the PD revealed that cationic PDs are likely to aggregate promptly upon mixing with body fluids and that this prompt aggregation is probably driven by non-Derjaguin-Landau- Verwey Overbeek attractive forces originating from the surrounding divalent ions. Atomic force microscopy observation of a freshly cleaved mica plate soaked in dendrimer suspension (culture media) confirmed prompt aggregation. Our study revealed poor transfer of intravenously administered cationic PDs into the intracranial nervous tissue, and the results of our analysis suggested that this was largely attributable to the reduced BBB permeability arising from the propensity of the particles to promptly aggregate upon mixing with body fluids. PMID- 28579781 TI - Investigating the use of curcumin-loaded electrospun filaments for soft tissue repair applications. AB - Electrospun filaments represent a new generation of medical textiles with promising applications in soft tissue repair. A potential strategy to improve their design is to combine them with bioactive molecules. Curcumin, a natural compound found in turmeric, is particularly attractive for its antioxidant, anti inflammatory, and antimicrobial properties. However, investigating the range of relevant doses of curcumin in materials designed for tissue regeneration has remained limited. In this paper, a wide range of curcumin concentrations was explored and the potential of the resulting materials for soft tissue repair applications was assessed. Polydioxanone (PDO) filaments were prepared with various amounts of curcumin: 0%, 0.001%, 0.01%, 0.1%, 1%, and 10% (weight to weight ratio). The results from the present study showed that, at low doses (<=0.1%), the addition of curcumin has no influence on the spinning process or on the physicochemical properties of the filaments, whereas higher doses lead to smaller fiber diameters and improved mechanical properties. Moreover, filaments with 0.001% and 0.01% curcumin stimulate the metabolic activity and proliferation of normal human dermal fibroblasts (NHDFs) compared with the no-filament control. However, this stimulation is not significant when compared to the control filaments (0%). Highly dosed filaments induce either the inhibition of proliferation (with 1%) or cell apoptosis (with 10%) as a result of the concentrations of curcumin found in the medium (9 and 32 MUM, respectively), which are near or above the known toxicity threshold of curcumin (~10 MUM). Moreover, filaments with 10% curcumin increase the catalase activity and glutathione content in NHDFs, indicating an increased production of reactive oxygen species resulting from the large concentration of curcumin. Overall, this study suggested that PDO electrospun filaments loaded with low amounts of curcumin are more promising compared with higher concentrations for stimulating tissue repair. This study also highlighted the need to explore lower concentrations when using polymers as PDO, such as those with polycaprolactone and other degradable polyesters. PMID- 28579782 TI - Effect of aripiprazole on non-24-hour sleep-wake rhythm disorder comorbid with major depressive disorder: a case report. AB - BACKGROUND: Patients with non-24-hour sleep-wake rhythm disorder (N24SWD) exhibit a sleep pattern that is asynchronous with the external light-dark cycle, typically involving a cycling, relapsing-remitting pattern of sleep disturbances, including nighttime insomnia and daytime sleepiness. Here, we report the case of a patient with N24SWD comorbid with major depressive disorder, who was successfully treated with a low dose of aripiprazole. CASE PRESENTATION: A 47 year-old female presented with an 8-year complaint of difficulty falling asleep and waking up in the morning. The patient was diagnosed with major depressive disorder at the age of 35 years and was treated with various antidepressants since that time. At the age of 40 years, the patient's sleep-wake cycle began to extend without exacerbation of depressive symptoms. The patient was diagnosed with N24SWD at the age of 43 years. Ramelteon 8 mg/d and then melatonin 1 mg/d were administered, but these did not provide effective treatment. In January 2016, after treatment with aripiprazole 3 mg/d in the morning for 4 weeks, the patient's sleep-wake cycle became markedly synchronized to the environmental light-dark cycle. Her sleep-wake cycle remained synchronized when the same dose of aripiprazole was administered for at least 6 months. CONCLUSION: Treatment refractory asynchrony of the sleep-wake cycle in an N24SWD patient with depression was successfully treated with aripiprazole. Although the detailed mechanism of action is unclear, aripiprazole may be an appropriate treatment for patients with circadian rhythm sleep-wake disorders. PMID- 28579779 TI - Antibacterial properties and toxicity from metallic nanomaterials. AB - The era of antibiotic resistance is a cause of increasing concern as bacteria continue to develop adaptive countermeasures against current antibiotics at an alarming rate. In recent years, studies have reported nanoparticles as a promising alternative to antibacterial reagents because of their exhibited antibacterial activity in several biomedical applications, including drug and gene delivery, tissue engineering, and imaging. Moreover, nanomaterial research has led to reports of a possible relationship between the morphological characteristics of a nanomaterial and the magnitude of its delivered toxicity. However, conventional synthesis of nanoparticles requires harsh chemicals and costly energy consumption. Additionally, the exact relationship between toxicity and morphology of nanomaterials has not been well established. Here, we review the recent advancements in synthesis techniques for silver, gold, copper, titanium, zinc oxide, and magnesium oxide nanomaterials and composites, with a focus on the toxicity exhibited by nanomaterials of multidimensions. This article highlights the benefits of selecting each material or metal-based composite for certain applications while also addressing possible setbacks and the toxic effects of the nanomaterials on the environment. PMID- 28579784 TI - Hirayama disease (monomelic amyotrophy) clinically confused for carpal tunnel syndrome. AB - Hirayama disease (HD) is a rare motor neuron disorder that involves a single upper extremity. It is clinically characterized by weakness and atrophy of the muscles of the hand and forearm. This article presents a 19-year-old woman who visited the orthopedics outpatient clinic with weakness and atrophy in her right hand and was clinically diagnosed with advanced stage carpal tunnel syndrome and scheduled for surgical intervention; she was later diagnosed with HD by an electrophysiological study. As a result, it has been found that a careful electrophysiological study and neurological examination can be used to diagnose HD. In this way, advanced stage carpal tunnel syndrome will be ruled out and patients will be spared from an unnecessary surgical operation. PMID- 28579783 TI - Developmental and behavioral outcomes of uncomplicated monochorionic diamniotic twins born in the third trimester. AB - BACKGROUND: Relatively little is known about the neurodevelopmental and behavioral outcomes of monochorionic diamniotic (MCDA) twin pregnancies where there are no antenatal complications peculiar to monochorionicity or prematurity. METHODS: Twenty-two MCDA twins (44 children) with an average age of 4.3 years, and with no antenatal complications detected by 28 weeks of gestation, were recruited from a feto-maternal unit database. Parents completed a battery of neurodevelopmental and behavioral assessment questionnaires. RESULTS: Eighteen children (41%) were identified as having developmental or behavioral concerns, predominantly of mild severity, which in turn were associated with a lower birth weight of medium effect size (Cohen's d=0.59). CONCLUSION: MCDA twins delivered in the third trimester with no antenatal monochorionic complications in the first two trimesters appear to be at risk for subtle neurodevelopmental difficulties, associated with a lower birth weight. Ongoing developmental surveillance of these children during preschool-age is indicated for early identification and intervention. PMID- 28579785 TI - Dexmedetomidine for the management of postictal agitation after electroconvulsive therapy with S-ketamine anesthesia. AB - OBJECTIVES: Postictal agitation (PIA) represents one of the most common complications during a modified electroconvulsive therapy (ECT) course. Its clinical management can be challenging especially in cases with poor response to benzodiazepines. Dexmedetomidine, a highly selective alpha-2 adrenoceptor agonist acting predominantly in the locus coeruleus, exerts sedative effects without causing relevant respiratory depression. To the best of our knowledge, this is the first study that aimed to assess the impact of dexmedetomidine use with S ketamine anesthesia on PIA reduction in ECT. PATIENTS AND METHODS: We retrospectively analyzed 7 patients who underwent 178 ECT sessions with S ketamine anesthesia between June 2011 and July 2015 at the Central Institute of Mental Health Mannheim. In 101 sessions, the patients received dexmedetomidine in combination with S-ketamine anesthesia. The decision for dexmedetomidine use was based on individual clinical presentation (patients with positive PIA history). A multivariate repeated measurement logistic regression analysis was conducted to investigate the effect of dexmedetomidine use on the occurrence of PIA. We hypothesized that the use of dexmedetomidine reduced the incidence of PIA also in combination with S-ketamine anesthesia. RESULTS: The prevalence of PIA in ECT sessions with dexmedetomidine administration was lower (mean per patient, 34% vs 62%). In the multivariate logistic regression analysis, the use of dexmedetomidine predicted the non-occurrence of PIA in a highly significant manner (P=0.001, z=-3.83, odds ratio =0.011-0.303). CONCLUSION: Adjunctive use of dexmedetomidine to S-ketamine anesthesia in ECT seems to be a promising tool for the management of intractable PIA syndrome. PMID- 28579786 TI - Topiramate add-on treatment associated with normalization of prolactin levels in a patient with schizophrenia. AB - Topiramate has been used increasingly in the management of psychiatric conditions. Clinical trials demonstrated that topiramate augmentation was effective in controlling negative symptoms in schizophrenia. This case report presents a case of a 38-year-old man with schizophrenia who achieved full negative symptom remission upon the adjunctive use of topiramate. However, the remarkable finding of this case is the concomitant decrease in the level of prolactin when topiramate (50 mg/day) was started and the rebound after discontinuation of topiramate. Previous studies stated that topiramate could prevent antipsychotic-induced weight gain and adverse metabolic effects. To the authors' knowledge, no study has reported that topiramate augmentation could be a treatment strategy for antipsychotic-induced hyperprolactinemia. This finding could be verified by well-designed clinical trials. PMID- 28579787 TI - The impact of comorbid psychiatric disorders on methadone maintenance treatment in opioid use disorder: a prospective cohort study. AB - OBJECTIVE: There is a significant interindividual variability in treatment outcomes in methadone maintenance treatment (MMT) for opioid use disorder (OUD). This prospective cohort study examines the impact of comorbid psychiatric disorders on continued illicit opioid use in patients receiving MMT for OUD. METHODS: Data were collected from 935 patients receiving MMT in outpatient clinics between June 2011 and June 2015. Using linear regression analysis, we evaluated the impact of having a comorbid psychiatric disorder on continued illicit opioid use during MMT, adjusting for important confounders. The main outcome measure was percentage of opioid-positive urine screens for 6 months. We conducted a subgroup analysis to determine the influence of specific comorbid psychiatric disorders, including substance use disorders, on continued illicit opioid use. RESULTS: Approximately 80% of participants had at least one comorbid psychiatric disorder in addition to OUD, and 42% of participants had a comorbid substance use disorder. There was no significant association between having a psychiatric comorbidity and continuing opioid use (P=0.248). Results from subgroup analysis, however, suggest that comorbid tranquilizer (beta=20.781, P<0.001) and cocaine (beta=6.344, P=0.031) use disorders are associated with increased rates of continuing opioid use. CONCLUSION: Results from our study may serve to guide future MMT guidelines. Specifically, we find that cocaine or tranquilizer use disorder, comorbid with OUD, places patients at high risk for poor MMT outcomes. Treatment centers may choose to gear more intensive therapy toward such populations. PMID- 28579788 TI - Primary angle-closure glaucomas disturb regional spontaneous brain activity in the visual pathway: an fMRI study. AB - OBJECTIVE: To explore the underlying regional brain activity deficits in the visual cortex in patients with primary angle-closure glaucoma (PACG) relative to normal controls (NCs) using regional homogeneity (ReHo) method, and its relationship with behavioral performances. PATIENTS: Twenty PACG patients (10 females, 10 males; mean age +/- standard deviation [SD]: 54.42+/-9.46 years) and 20 age-, and sex status-matched NCs (10 females, 10 males; mean age +/- SD: 53.75+/-9.16 years) were included in this study. MEASUREMENTS AND RESULTS: Compared with NCs, patients with PACG showed significant atrophic peripapillary retinal nerve fiber layer (pRNFL) and neuroretinal rim area, increased optic disk cup-to-disc ratio (CDR) and optic disk volume (P<0.05), higher ReHo value in the left fusiform gyrus, left cerebellum anterior lobe, right frontal-temporal space, and right insula, and lower ReHo value in the bilateral middle occipital gyrus, left claustrum, and right paracentral lobule lobe. The receiver operating characteristic analysis revealed these different areas with high value of area under curve, and high degree of sensitivity and specificity. The mean beta values of these different areas were extracted. In PACG, the duration of disease showed a negative correlation with the mean beta value of left cerebellum anterior lobe (r=-0.453, P=0.045) and a positive correlation with right middle occipital gyrus (r=0.586, P=0.007); left middle occipital gyrus showed positive correlations with duration of disease (r=0.562, P=0.01) and left pRNFL (r=0.49, P=0.028); left claustrum had a positive correlation with left CDR (r=0.515, P=0.02); and right paracentral lobule lobe demonstrated a positive correlation with left pRNFL (r=0.623, P=0.003). CONCLUSION: PACG is involved in abnormal spontaneous brain activity in multiple brain areas, and such changes are associated with clinical performances, which may reflect the underlying pathologic mechanism and play important roles in the initiation and progression of PACG. PMID- 28579789 TI - A retrograde y-stenting of the trachea for treatment of mediastinal fistula in an unusual situation. AB - INTRODUCTION: Stents have been used for quite some time for the treatment of benign and malignant airway stenosis. Silicon stents are preferred for benign situations, whereas metallic self-expanding stents are preferred for malignant comorbidities. PATIENT AND METHODS: In general, stents can be placed in different approach directions, although in pulmonary medicine it is logical to apply only antegrade techniques - until now. A 63-year-old patient, 168 cm height and 53 kg weight on referral, suffered chronical diseases. The patient was diagnosed with a papillary thyroid carcinoma in 1989, which was treated by resection and radiotherapy. In the following years, she developed a stenosis of the esophagus. The decision to try endobronchial stenting was made upon the plan to close that fistula with a pedicled omentum majus replacement through the diaphragmal opening of the esophagus. This surgical plastic needed an abutment and a secured continuous airway replacement above the tracheostoma level. A Freitag stent (FS), 11 cm in length (110-25-40) and an inner diameter of 13 mm, was placed successfully retrograde into the trachea and completely bridged the big fistula. Unfortunately the patient passed away due to pulmonary infections after several weeks. DISCUSSION: In this case report, a successful but unusual case of retrograde stent placement of a modified FS is presented. PMID- 28579790 TI - Comparison of the clinical features and outcomes of infective endocarditis between hemodialysis and non-hemodialysis patients. AB - Hemodialysis (HD) patients are more susceptible to infective endocarditis (IE) due to the increased risk of bacterial invasion through intravascular access. However, it remains unclear whether the causative organisms and outcomes of IE in HD patients differ from those in non-HD patients. This study clarified the differences in clinical presentation and outcomes between HD and non-HD patients. At our hospital, we performed a retrospective study of 39 HD and 51 non-HD patients with echocardiography-confirmed IE between June 2000 and February 2007. No differences in sex, intravenous drug use, previous diagnosis of congestive heart failure, and previous valvular surgery were observed between these two groups. The number of patients with diabetic mellitus in these two groups was significantly different (28.2% HD vs 5.9% non-HD patients). The C-reactive protein levels in the two groups were not significantly different. By contrast, the erythrocyte sedimentation rate was significantly higher in the HD patients (HD vs non-HD: 87.2+/-33.32 vs 52.96+/-28.19). The incidence of IE involving the mitral valve (MV; 45.1%) or the aortic valve (AV; 43.1%) was similar among the non-HD patients, whereas a preference of IE involving the MV (79.5%) over the AV (15.4%) was noted among the HD patients. The HD patients had a significantly higher Staphylococcus aureus infection rate (HD: 46.2%; non-HD: 27.5%). The proportion of methicillin-resistant S. aureus (MRSA; 83.8%) infection accounting for S. aureus IE in the HD group was higher than that (28.6%) in the non-HD group. The in-hospital mortality rate did not differ between the two groups. In conclusion, compared with non-HD patients, a propensity of IE involving the MV and a higher MRSA infection rate were observed in HD patients. The in-hospital mortality rate of echocardiography-confirmed IE did not differ between the two groups. PMID- 28579791 TI - Color M-mode echocardiography-derived propagation velocity of descending aorta decreases with aging. AB - BACKGROUND: Arterial stiffness (AS) can be determined by some noninvasive tests such as pulse wave velocity (PWV). Atherosclerosis is also detectable by some ultrasonographic techniques such as color M-mode-derived propagation velocity measured along the origin of the descending aorta (AVP). AIM: The aim of the study was to find out a possible relationship between atherosclerosis and AVP and whether AVP can be used as a parameter of AS. MATERIALS AND METHODS: The study group was composed of 134 people from routine screening examination who were >=40 years old, completely healthy, and without any known disease and use of any drug. PWV has been determined to show aortic stiffness, and carotid artery intima- media thickness (CIMT) was measured for subclinical atherosclerosis. AVP values were obtained from all participants, and correlations were calculated between these parameters and age. RESULTS: AVP decreased (r=-0.902, P<0.001) and PWV increased (r=0.854, P<0.001) significantly with increasing age. CIMT also increased with aging (r=0.518, P<0.001). There were significant correlations between AVP and PWV (r=-0.832, P<0.001) and AVP and CIMT (r=-0.345, P<0.001). CONCLUSION: Transthoracic echocardiographic determination of AVP can be used as a simple measurement of AS and correlates well with PWV, age, and CIMT in healthy people. PMID- 28579793 TI - Future challenges for occupational health services can be prevented by proactive collaboration with the companies using the services: a participatory and reflection project. AB - BACKGROUND: There is clearly a need for research in the field of occupational health service (OHS) for applying new perspectives. Proactive collaboration is needed between the OHSs and the companies. The customers of the companies using the services should be able to safeguard themselves from the health problems caused by the work environment through proactive collaboration with the OHSs. OBJECTIVE: The main purpose of this interdisciplinary study was to explore how the stakeholders reflected to create and agree on core values for future challenges in OHS, as seen from the perspectives of OHS professionals and customer companies. METHODOLOGY: An action research process was conducted. This study was divided into three phases. In phase I, the data were collected from interviews and diaries of interdisciplinary occupational health professionals (n=12). A focus group that sampled the eight managers of the customer companies was also included. In phase II, a questionnaire was developed with 24 questions focusing on examining the future challenges for OHS. The questionnaire was sent to customer companies (n=116). In phase III, a scoping review was undertaken. RESULTS: Three categories emerged from the analysis: "Balancing complex situations" clarified the complexity regarding senior employees; "Working with a proactive approach" indicated the need for working with a new proactive approach supporting sustainable health; and "Collaborate internally and externally" showed good relationships between the customer and the OHS, which is a mutual responsibility to both the partners. CONCLUSION: The results outlined that it is necessary to take action to apply new proactive health promotions, with a focus on workplace health promotion. The results also indicated that interventions for senior employees are of importance. This study was done in collaboration with the stakeholders from the occupational health care service center and the managers from the customer companies. The use of a participatory research design, including close collaboration with the participants, allows the researchers to see the challenges. PMID- 28579792 TI - Amyotrophic lateral sclerosis: improving care with a multidisciplinary approach. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, leading to death within an average of 2-3 years. A cure is yet to be found, and a single disease-modifying treatment has had a modest effect in slowing disease progression. Specialized multidisciplinary ALS care has been shown to extend survival and improve patients' quality of life, by providing coordinated interprofessional care that seeks to address the complex needs of this patient group. This review examines the nature of specialized multidisciplinary care in ALS and draws on a broad range of evidence that has shaped current practice. The authors explain how multidisciplinary ALS care is delivered. The existing models of care, the role of palliative care within multidisciplinary ALS care, and the costs of formal and informal care are examined. Critical issues of ALS care are then discussed in the context of the support rendered by multidisciplinary-based care. The authors situate the patient and family as key stakeholders and decision makers in the multidisciplinary care network. Finally, the current challenges to the delivery of coordinated interprofessional care in ALS are explored, and the future of coordinated interprofessional care for people with ALS and their family caregivers is considered. PMID- 28579795 TI - Bone Marrow Lesion: Image, Clinical Presentation, and Treatment. AB - In this article, the cause, histology, imaging characteristics, clinical presentation, and treatment of these lesions are thoroughly discussed. Bone marrow edema is the generic term classically used to describe the high-signal intensity alterations detected on magnetic resonance fluid-sensitive sequences. The significance of bone marrow edema for the patient's clinical condition and the prognosis of the affected joint is being increasingly investigated and discussed, and situations characterized by subchondral insufficiency are receiving increasing attention. More recent studies found some important correlations between bone marrow lesions and patient's pain and osteoarthritis progression. Conservative treatment is based on anti-inflammatory and analgesic uses according to the patient's pain, combined with reduced load on the affected limb. Regarding surgical treatment, subchondroplasty is an option still in development, albeit with promising initial results. PMID- 28579794 TI - Diagnostic Applications of Nuclear Magnetic Resonance-Based Urinary Metabolomics. AB - Metabolomics is a rapidly growing field with potential applications in various disciplines. In particular, metabolomics has received special attention in the discovery of biomarkers and diagnostics. This is largely due to the fact that metabolomics provides critical information related to the downstream products of many cellular and metabolic processes which could provide a snapshot of the health/disease status of a particular tissue or organ. Many of these cellular products eventually find their way to urine; hence, analysis of urine via metabolomics has the potential to yield useful diagnostic and prognostic information. Although there are a number of analytical platforms that can be used for this purpose, this review article will focus on nuclear magnetic resonance based metabolomics. Furthermore, although there have been many studies addressing different diseases and metabolic disorders, the focus of this review article will be in the following specific applications: urinary tract infection, kidney transplant rejection, diabetes, some types of cancer, and inborn errors of metabolism. A number of methodological considerations that need to be taken into account for the development of a clinically useful optimal test are discussed briefly. PMID- 28579796 TI - The Impact of Injector-Based Contrast Agent Administration on Bolus Shape and Magnetic Resonance Angiography Image Quality. AB - OBJECTIVE: To compare injector-based contrast agent (CA) administration with hand injection in magnetic resonance angiography (MRA). METHODS: Gadobutrol was administered in 6 minipigs with 3 protocols: (a) hand injection (one senior technician), (b) hand injection (6 less-experienced technicians), and (c) power injector administration. The arterial bolus shape was quantified by test bolus measurements. A head and neck MRA was performed for quantitative and qualitative comparison of signal enhancement. RESULTS: A significantly shorter time to peak was observed for protocol C, whereas no significant differences between protocols were found for peak height and bolus width. However, for protocol C, these parameters showed a much lower variation. The MRA revealed a significantly higher signal-to-noise ratio for injector-based administration. A superimposed strong contrast of the jugular vein was found in 50% of the hand injections. CONCLUSIONS: Injector-based CA administration results in a more standardized bolus shape, a higher vascular contrast, and a more robust visualization of target vessels. PMID- 28579797 TI - Manganese-Enhanced Magnetic Resonance Imaging and Studies of Rat Behavior: Transient Motor Deficit in Skilled Reaching, Rears, and Activity in Rats After a Single Dose of MnCl2. AB - Manganese-enhanced magnetic resonance imaging (MEMRI) has been suggested to be a useful tool to visualize and map behavior-relevant neural populations at large scale in freely behaving rodents. A primary concern in MEMRI applications is Mn2+ toxicity. Although a few studies have specifically examined toxicity on gross motor behavior, Mn2+ toxicity on skilled motor behavior was not explored. Thus, the objective of this study was to combine manganese as a functional contrast agent with comprehensive behavior evaluation. We evaluated Mn2+ effect on skilled reach-to-eat action, locomotion, and balance using a single pellet reaching task, activity cage, and cylinder test, respectively. The tests used are sensitive to the pathophysiology of many neurological and neurodegenerative disorders of the motor system. The behavioral testing was done in combination with a moderate dose of manganese. Behavior was studied before and after a single, intravenous infusion of MnCl2 (48 mg/kg). The rats were imaged at 1, 3, 5, 7, and 14 days following infusion. The results show that MnCl2 infusion resulted in detectable abnormalities in skilled reaching, locomotion, and balance that recovered within 3 days compared with the infusion of saline. Because some tests and behavioral measures could not detect motor abnormalities of skilled movements, comprehensive evaluation of motor behavior is critical in assessing the effects of MnCl2. The relaxation mapping results suggest that the transport of Mn2+ into the brain is through the choroid plexus-cerebrospinal fluid system with the primary entry point and highest relaxation rates found in the pituitary gland. Relaxation rates in the pituitary gland correlated with measures of motor skill, suggesting that altered motor ability is related to the level of Mn circulating in the brain. Thus, combined MEMRI and behavioral studies that both achieve adequate image enhancement and are also free of motor skills deficits are difficult to achieve using a single systemic dose of MnCl2. PMID- 28579799 TI - Effect of Supplementation With Chitosan on Weight, Cardiometabolic, and Other Risk Indices in Wistar Rats Fed Normal and High-Fat/High-Cholesterol Diets Ad Libitum. AB - The aim was to investigate effect of chitosan on markers of obesity and cardiometabolic risk in rats fed normal chow (NC) or high-fat/high-cholesterol diet (HF/HCD). Forty male rats were fed NC or HF/HCD for 3 months, then divided into 4 groups: group A fed NC, group B: NC + chitosan, group C: HF/HCD, and group D: HF/HCD + chitosan. Food intake and weight were recorded, and serum glucose, lipid profile, insulin, leptin, gamma glutamyl transferase (GGT), and tumor necrosis factor alpha were measured at beginning and after 12 weeks. Atherogenic index (AI), low-density lipoprotein cholesterol:high-density lipoprotein cholesterol (LDL-C:HDL-C), and homeostatic model assessment of insulin resistance (HOMA-IR) were calculated. At the end of study, food intake was significantly increased in group B; mean values of triglycerides, total cholesterol, LDL-C, LDL C:HDL-C, and AI were decreased in group B and group D; mean leptin was increased in group A and decreased in group B; and mean values of insulin, HOMA-IR, and GGT were increased in group C. The results from this study suggest that chitosan improved lipid profile, insulin sensitivity, and oxidative stress caused by HF/HCD. PMID- 28579798 TI - An Update on Clinical Burden, Diagnostic Tools, and Therapeutic Options of Staphylococcus aureus. AB - Staphylococcus aureus is an important pathogen responsible for a variety of diseases ranging from mild skin and soft tissue infections, food poisoning to highly serious diseases such as osteomyelitis, endocarditis, and toxic shock syndrome. Proper diagnosis of pathogen and virulence factors is important for providing timely intervention in the therapy. Owing to the invasive nature of infections and the limited treatment options due to rampant spread of antibiotic resistant strains, the trend for development of vaccines and antibody therapy is increasing at rapid rate than development of new antibiotics. In this article, we have discussed elaborately about the host-pathogen interactions, clinical burden due to S aureus infections, status of diagnostic tools, and treatment options in terms of prophylaxis and therapy. PMID- 28579802 TI - Association between clinicopathological features and survival in patients with primary and paired metastatic colorectal cancer and KRAS mutation. AB - The KRAS gene mutation is involved in several types of tumors. However, the potential role of the KRAS mutation in human primary and paired metastatic colorectal cancer (CRC) among different nationalities is poorly understood. In the present study, we assessed the relationship between KRAS mutation status and overall survival (OS) and disease-free survival (DFS) in 230 patients with primary and paired metastatic CRC. The KRAS mutation rate in primary CRC tissue was 43.0% (99/230), which was higher than in paired metastatic CRC, which was 31.9% (23/72; P<0.001). Clinicopathologically, the KRAS gene mutation rate was higher in tumors that had infiltrated more deeply (T3, T4) and in lymph node (LN) metastases (N1/N2) (P=0.029 and P=0.010, respectively). The KRAS gene status did not differ between the Han and Uyghur nationalities in both primary and metastatic CRC. In 72 paired cases, the KRAS mutation rate in primary CRC was significantly higher than in metastatic CRC (P<0.001) and in metastatic CRC that had infiltrated more deeply (T3, T4) (P=0.034). In the metastatic cases, the KRAS gene mutation rate was higher in patients aged over 65 years (P=0.035). Specifically, KRAS mutation was correlated with a poorer OS and DFS (P=0.004 and P=0.029, respectively). In our study, 35 patients with wild-type KRAS who received cetuximab targeted therapy had a better DFS than patients with mutant KRAS (P=0.029). The results of the current study demonstrate that the KRAS status is significantly associated with infiltrating LN metastases and the TNM stage in primary CRC. In addition, the results show that the KRAS mutation is significantly more common in primary tumors than in paired metastatic CRC, and the KRAS mutation is correlated with a shorter OS and DFS, as patients with wild type KRAS who received cetuximab experienced a longer DFS. PMID- 28579804 TI - Expression of urinary miRNAs targeting NLRs inflammasomes in bladder cancer. AB - AIM OF THE STUDY: Inflammasome, a large complex of NOD-like receptors (NLRs), drives tumor growth and progression. The present study aimed at exploring the alteration in expression of urinary inflammasome-related microRNAs (miRNAs) in bladder cancer (BC). Our previous report demonstrated the up-regulation of NLRs genes (NLRP3, NLRP4, NLRP9 and NAIP) in urine sediments of patients harboring BC. The expression levels of miRNAs targeting these NLRs (miR-146a-5p, miR-106a-5p, miR-17-5p, miR-223-3p, miR-141-3p, miR-19a-3p, miR-145-5p, miR-185-5p) were assayed in the same patient cohort. MATERIALS AND METHODS: Forty-six subjects affected by BC, 28 healthy controls (CTR0) and 31 subjects with histologically confirmed bladder inflammation (CTR1) were recruited. Total RNA was extracted from urine sediment and resulting cDNA was used for amplification by real-time polymerase chain reaction. MiRNA expression levels were evaluated and compared among selected groups. Patients were further stratified according to tumor stage, grade and risk of recurrence and progression. Moreover, non-muscle invasive low grade and high-grade (HG) BC patients were compared. RESULTS: MiR 141-3p and miR 19a-3p expression decreased in CTR1 with respect to both BC and CTR0. In contrast, miR-146a-5p was up-regulated in BC compared with CTR0. MiR106a-5p, miR17-5p and miR19a-5p were significantly up-regulated in HG, high-risk (HR) and non-muscle invasive HG BC patients, while miR-185-5p was significantly higher in muscle invasive tumors, according to T stage stratification. CONCLUSION: The increased expression of miRNAs targeting NLRs in HG and HR BC patients is in accordance with the decrease in NLR mRNAs observed in our previous report. These data corroborate the direct role of NLR genes and respective regulatory miRNAs in BC making these inflammasome-related molecules a reliable non-invasive tool for BC diagnosis. PMID- 28579803 TI - The prognostic value of neutrophil-lymphocyte ratio is superior to derived neutrophil-lymphocyte ratio in advanced gastric cancer treated with preoperative chemotherapy and sequential R0 resection: a 5-year follow-up. AB - AIM: The role of neutrophil-lymphocyte ratio (NLR) and derived neutrophil lymphocyte ratio (d-NLR) in outcome prediction is assessed in patients with advanced gastric cancer receiving preoperative chemotherapy in a 5-year follow-up cohort. PATIENTS AND METHODS: Patients undergoing preoperative chemotherapy and sequential R0 resection for advanced gastric cancer were enrolled from July 2004 to November 2011. Wilcoxon matched-pairs signed-rank test was used to evaluate the change of peripheral blood parameters. Receiver operating curve was used to identify the optimal cutoff values of NLR and d-NLR. Survival function was analyzed using Kaplan-Meier curves and Cox proportional hazard model. RESULTS: Significant difference was found between baseline and post-chemotherapy blood parameters, including leukocytes, neutrophils, lymphocytes, NLR and d-NLR (all P<0.05). High baseline NLR group (NLR >=2.230) had a significant shorter recurrence-free survival (RFS) (hazard ratio [HR] =1.814, 95% confidence interval [95% CI]: 1.112-2.960, P=0.015) and shorter overall survival (OS) (HR =1.867, 95% CI: 1.129-3.089, P=0.013) than those of the low baseline NLR group (NLR <2.230). High baseline d-NLR group (d-NLR >=1.885) also had a shorter RFS (HR =1.805, 95% CI: 1.116-2.919, P=0.014) and shorter OS (HR =1.783, 95% CI: 1.091-2.916, P=0.019) than those of the low baseline d-NLR group (d-NLR <1.885). However, post chemotherapy NLR and d-NLR showed no prognostic significance on RFS and OS (all P>0.05). Multivariate analysis showed that higher baseline NLR but not d-NLR was identified as an independent factor associated with worse RFS (HR =1.707, 95% CI: 1.042-2.797, P=0.034) and worse OS (HR =1.758, 95% CI: 1.058-2.919, P=0.029). CONCLUSION: Baseline NLR and d-NLR may serve as convenient, easily measured prognostic indicators in advanced gastric cancer treated with preoperative chemotherapy and sequential R0 resection, especially to baseline NLR, which showed independent prognostic significance on RFS and OS, while post-chemotherapy NLR and d-NLR lost their usefulness due to the inhibition of bone marrow hematopoietic function. Patients with high baseline NLR and d-NLR values need multimodal therapy. PMID- 28579805 TI - Bisdemethoxycurcumin in combination with alpha-PD-L1 antibody boosts immune response against bladder cancer. AB - Curcumin was recently discovered to strengthen immune response through multiple mechanisms. Cytotoxic CD8+ T-cells play a critical role in modulating anticancer immune response, but is severely restricted by T-cell exhaustion. Bladder carcinomas express PD-L1 and can abrogate CD8+ T-cell response. Thus, we hypothesized that bisdemethoxycurcumin, a natural dimethoxy derivative of curcumin, may provide a favorable environment for T-cell response against bladder cancer when used in combination with alpha-PD-L1 antibody. Immunocompetent C56BL/6 mouse models bearing subcutaneous or lung metastasized MB79 bladder cancer were established to validate this conjecture. We found that bisdemethoxycurcumin significantly increased intratumoral CD8+ T-cell infiltration, elevated the level of IFN-gamma in the blood, and decreased the number of intratumoral myeloid-derived suppressor cells. Furthermore, alpha-PD-L1 antibody protected these amplified CD8+ T-cells from exhaustion, and therefore facilitated the secretion of IFN-gamma, granzyme B, and perforin through these CD8+ T-cells. As a result, this combination treatment strategy significantly prolonged survival of intraperitoneal metastasized bladder cancer bearing mice, suggesting that bisdemethoxycurcumin in combination with alpha-PD-L1 antibody may be promising for bladder cancer patients. PMID- 28579800 TI - Meat and Nicotinamide: A Causal Role in Human Evolution, History, and Demographics. AB - Hunting for meat was a critical step in all animal and human evolution. A key brain-trophic element in meat is vitamin B3 / nicotinamide. The supply of meat and nicotinamide steadily increased from the Cambrian origin of animal predators ratcheting ever larger brains. This culminated in the 3-million-year evolution of Homo sapiens and our overall demographic success. We view human evolution, recent history, and agricultural and demographic transitions in the light of meat and nicotinamide intake. A biochemical and immunological switch is highlighted that affects fertility in the 'de novo' tryptophan-to-kynurenine-nicotinamide 'immune tolerance' pathway. Longevity relates to nicotinamide adenine dinucleotide consumer pathways. High meat intake correlates with moderate fertility, high intelligence, good health, and longevity with consequent population stability, whereas low meat/high cereal intake (short of starvation) correlates with high fertility, disease, and population booms and busts. Too high a meat intake and fertility falls below replacement levels. Reducing variances in meat consumption might help stabilise population growth and improve human capital. PMID- 28579806 TI - Ezh2, a novel target in detection and therapy of breast cancer. PMID- 28579808 TI - MicroRNA-216a promotes the metastasis and epithelial-mesenchymal transition of ovarian cancer by suppressing the PTEN/AKT pathway. AB - MicroRNAs, a group of posttranscriptional regulators of numerous genes, are active participators during the development and progression of ovarian cancer (OC). This study confirmed for the first time that miR-216a was gradually increased in normal, benign, borderline, and OC tissues and that its expression was significantly upregulated in all OC cell lines. Analysis of its clinical association demonstrated that elevated expression of miR-216a was associated with lymph node metastasis and advanced FIGO stage and was correlated with the poor survival of OC patients. Functional experiments showed that miR-216a overexpression potentiated the migration and invasion of CAOV3 cells while miR 216a inhibition reduced the migration and invasion of SKOV-3 cells. Both gain and lose of function assay showed that miR-216a promoted epithelial-mesenchymal transition (EMT) of OC cells. Mechanistically, phosphatase and tensin homolog (PTEN) was confirmed as a direct downstream target of miR-216a in OC cells. Alerting miR-216a expression in OC cells modulated the activity of PTEN/AKT pathway in OC cells. Furthermore, this study confirmed that miR-216a exerted its promoting effects on the metastatic behaviors and EMT of OC cells by inhibiting PTEN/AKT pathway. Taken together, this study demonstrates that miR-216a exerts a promoting role in the metastasis of OC and can serve as a promising biomarker and an attractive therapeutic target of OC. PMID- 28579807 TI - Effects of chemopreventive agents on the incidence of recurrent colorectal adenomas: a systematic review with network meta-analysis of randomized controlled trials. AB - BACKGROUND: Protective effects of several chemopreventive agents (CPAs) against colorectal adenomas have been well documented in randomized controlled trials (RCTs); however, there is uncertainty regarding which agents are the most effective. METHODS: We searched for RCTs published up until September 2016. Retrieved trials were evaluated using risk of bias. We performed both pairwise analysis and network meta-analysis (NMA) of RCTs to compare the effects of CPAs on the recurrence of colorectal adenomas (primary outcome). Using NMA, we ranked CPAs based on efficacy. RESULTS: We identified 20 eligible RCTs enrolling 12,625 participants with a history of colorectal cancer or adenomas who were randomly assigned to receive either a placebo or one of 12 interventions. NMA using all trials demonstrated that celecoxib 800 mg/day (relative risk [RR] 0.61, 95% confidence interval [CI] 0.45-0.83), celecoxib 400 mg/day (RR 0.70, 95% CI 0.55 0.87), low-dose aspirin (RR 0.75, 95% CI 0.59-0.96) and calcium (RR 0.81, 95% CI 0.69-0.96) were significantly associated with a reduction in the recurrence of any adenomas. NMA results were consistent with those from pairwise meta-analysis. The evidence indicated a high (celecoxib), moderate (low-dose aspirin) and low (calcium) Grading of Recommendations, Assessment, Development and Evaluation (GRADE) quality. NMA ranking showed that celecoxib 800 mg/day and celecoxib 400 mg/day were the best CPAs, followed by low-dose aspirin and calcium. Considering advanced adenoma recurrence, only celecoxib 800 mg/day and celecoxib 400 mg/day were demonstrated to have a protective effect (RR 0.37, 95% CI 0.27-0.52 vs RR 0.48, 95% CI 0.38-0.60, respectively). CONCLUSION: The available evidence from NMA suggests that celecoxib is more effective in reducing the risk of recurrence of colorectal adenomas, followed by low-dose aspirin and calcium. Since cyclooxygenase-2 (COX-2) inhibitors (eg, celecoxib) are associated with important cardiovascular events and gastrointestinal harms, more attention is warranted toward CPAs with a favorable benefit-to-risk ratio, such as low-dose aspirin and calcium. PMID- 28579801 TI - Meat Intake and the Dose of Vitamin B3 - Nicotinamide: Cause of the Causes of Disease Transitions, Health Divides, and Health Futures? AB - Meat and vitamin B3 - nicotinamide - intake was high during hunter-gatherer times. Intake then fell and variances increased during and after the Neolithic agricultural revolution. Health, height, and IQ deteriorated. Low dietary doses are buffered by 'welcoming' gut symbionts and tuberculosis that can supply nicotinamide, but this co-evolved homeostatic metagenomic strategy risks dysbioses and impaired resistance to pathogens. Vitamin B3 deficiency may now be common among the poor billions on a low-meat diet. Disease transitions to non communicable inflammatory disorders (but longer lives) may be driven by positive 'meat transitions'. High doses of nicotinamide lead to reduced regulatory T cells and immune intolerance. Loss of no longer needed symbiotic 'old friends' compounds immunological over-reactivity to cause allergic and auto-immune diseases. Inhibition of nicotinamide adenine dinucleotide consumers and loss of methyl groups or production of toxins may cause cancers, metabolic toxicity, or neurodegeneration. An optimal dosage of vitamin B3 could lead to better health, but such a preventive approach needs more equitable meat distribution. Some people may require personalised doses depending on genetic make-up or, temporarily, when under stress. PMID- 28579809 TI - miR-124 suppresses proliferation and invasion of nasopharyngeal carcinoma cells through the Wnt/beta-catenin signaling pathway by targeting Capn4. AB - BACKGROUND: Recent studies have demonstrated that microRNA 124 (miR-124) acts as a tumor suppressor in nasopharyngeal carcinoma (NPC); however, the exact molecular mechanism by which miR-124 exerts tumor suppression has not been well elucidated. MATERIALS AND METHODS: We performed quantitative real-time PCR (qRT PCR) to measure the expression of metastasis associated lung adenocarcinoma transcript 1, miR-124, and calpain small subunit 1 (Capn4) mRNAs in NPC cell lines. We also performed western blot analysis to detect the levels of Capn4. Furthermore, we performed MTT assay and transwell invasion assay to determine the proliferation and invasion ability of two NPC cell lines, namely, HONE1 and CNE2 cells, respectively. The verification of targets of miR-124 was performed using prediction softwares and luciferase reporter analysis. RESULTS: According to our results, the expression of Capn4 was found to be elevated, whereas the expression of miR-124 was lowered in NPC cell lines compared with normal nasopharyngeal cells. When we preformed overexpression of miR-124, it suppressed the proliferation and invasion of NPC cells. Moreover, miR-124 suppressed the expression of Capn4 by targeting Capn4 in HONE1 and CNE2 cells. When we preformed overexpression of Capn4, it reversed the inhibitory effect of miR-124 on the proliferation and invasion of NPC cells. Furthermore, miR-124-Capn4 axis decreased the levels of beta-catenin, cyclin D1, and c-Myc, the components of the Wnt/beta-catenin signaling pathway. CONCLUSION: The suppression of proliferation and invasion of NPC cells by miR-124 were achieved by the regulation of Wnt/beta catenin signaling pathway by targeting Capn4. The results of this study revealed a novel miR-124-Capn4 regulatory axis in NPC cell lines, providing a better understanding of the pathogenesis of NPC and a promising therapeutic target for patients with NPC. PMID- 28579810 TI - Leucine-rich glioma inactivated 3: integrative analyses support its prognostic role in glioma. AB - BACKGROUND: Leucine-rich glioma inactivated 3 (LGI3) is a secreted protein member of LGI family. We previously reported that LGI3 was expressed in brain, adipose tissues and skin, where it played roles as a multifunctional cytokine. We postulated that LGI3 may be involved in cytokine network in cancers. AIM: This study aimed to analyze differentially expressed genes in glioma tissues and glioma cohort data to investigate the prognostic role of LGI3 and its receptors. MATERIALS AND METHODS: Expression microarray data from Gene Expression Omnibus and glioma cohort data were analyzed using bioinformatic tools for statistical analysis, protein-protein interactions, functional enrichment and pathway analyses and prognostic association analysis. RESULTS: We found that LGI3 and its receptors, ADAM22 and ADAM23, were significantly downregulated in glioma tissues. Eleven upregulated genes and two downregulated genes in glioma tissues were found to be the previously reported LGI3-regulated genes. Protein-protein interaction network analysis showed that 85% of the LGI3-regulated and glioma-altered genes formed a cluster of interaction network. Functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed the association of these genes with hypoxia responses, p53 and Akt signaling and various cancer-related pathways including glioma. Analysis of expression microarray data of glioma cohorts demonstrated that low expression levels of LGI3, ADAM22 and ADAM23 were significantly associated with poor prognosis of glioma. CONCLUSION: These results propose that LGI3 and its receptors may play a prognostic role in glioma. PMID- 28579811 TI - The prognostic value of nodal skip metastasis in resectable thoracic esophageal squamous cell carcinoma. AB - PURPOSE: This study aimed to investigate the incidence of nodal skip metastasis (NSM) to identify the risk factors that influence NSM and to assess the prognostic value of NSM in patients with thoracic esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Between January 2009 and December 2013, 285 patients with ESCC with positive lymph nodes who underwent complete resection were enrolled. RESULTS: For the entire group, NSM occurred in 32.3% (92/285) of patients. The median survival time and 5-year survival rate in the NSM group were 28 months and 12.0%, respectively, compared with 36.3 months and 25.0%, respectively, in the non-NSM group (P=0.008). Both N stage (P=0.001) and T stage (P=0.014) were associated with the incidence of NSM. NSM (P=0.008), T stage (P=0.000), and N stage (P=0.000) were independent prognostic factors for survival. In the NSM group, T stage (P=0.014) and N stage (P=0.000) were independent prognostic factors for survival. CONCLUSION: It was concluded that NSM is common in ESCC and is associated with poor survival. PMID- 28579812 TI - Cost per care of the first year of direct antiviral agents in the Liguria Region: a multicenter analysis. AB - AIMS: Despite the remarkable efficacy shown in clinical practice, concerns have been raised about the costs associated with direct antiviral agent (DAA) therapy. This article presents the real-life costs for DAA treatment sustained by the Italian National Health Service in the Liguria Region (Northern Italy). METHODS: A retrospective analysis of the cost per care sustained for DAA treatment, relating to the period from January 1 to December 31, 2015 in five centers in Liguria was performed. All patients undergoing DAA-based treatments for hepatitis C virus (HCV) infection were enrolled. On-treatment costs included: HCV treatment, laboratory test, outpatient services, attended visits, drugs used for the management of adverse events (erythropoietin, albumin or red blood cell packs) and inpatient service admissions. RESULTS: In total, 327 patients were enrolled. No difference in terms of sustained virologic response (SVR) rate among different treatments was reported. The majority (85.0%) of patients did not report any side effects and only 15 (4.6%) required hospital admission. Forty-two patients (12.8%) required high-cost drugs for the management of adverse events. The overall cost sustained was ?14,744,433. DAA+/-ribavirin (RBV) accounted for the wide majority of this cost (98.9%; ?14,585,123). Genotype (GT) 1, the most commonly treated GT, was associated with an average cost of ?43,445 per patient. Detailed analysis of the costs for GT 1 showed the treatment based on ritonavir boosted paritaprevir/ombitasvir + dasabuvir+/-RBV with an average cost of ?24,978 (RBV+) and ?25,448 (RBV-) per patient was the most cost-effective. The average cost per SVR was ?48,184. Once again, the ritonavir boosted paritaprevir/ombitasvir + dasabuvir regimen was associated with the lowest cost/SVR (?25,448/SVR [GT 1b] and similar results for other GTs). CONCLUSION: Antiviral regimen is the major contributor to costs in the treatment of HCV infection. Appropriate regimen selection could result in a major cost saving, which can be reinvested to allow more patients to be treated. PMID- 28579813 TI - Evaluation of the treatment patterns and economic burden of dysmenorrhea in Japanese women, using a claims database. AB - PURPOSE: This study aimed to describe treatment patterns and estimate health care resource utilization and associated costs among Japanese women with dysmenorrhea, using a claims database. METHODS: This was a retrospective analysis using health insurance data from the Japan Medical Data Center, assessing female patients aged 18-49 years with newly diagnosed primary or secondary dysmenorrhea. Treatment pattern analyses focused on hormonal medications, analgesics, hemostatic agents, traditional Chinese medicine (TCM), and gynecological surgeries. Data were collected on health care resource utilization and costs associated with medications, imaging procedures, and inpatient and outpatient care in both patients and matched controls. RESULTS: The analysis included 6,315 women with dysmenorrhea (3,441 primary; 2,874 secondary). The most commonly prescribed initial therapies were low-dose estrogen progestins (LEPs, 37.7%) and TCM (30.0%), with substantial differences between primary (LEPs: 27.4%, TCM: 38.8%) and secondary (LEPs: 50.2%, TCM: 19.5%) dysmenorrhea cohorts. Surgery was conducted in <5% of all patients. Both primary and secondary cohorts of dysmenorrhea had significantly higher mean total health care costs compared to controls within the 1-year period following diagnosis (Case-primary: 191,680 JPY [1,916 USD]; secondary: 246,488 JPY [2,465 USD], Control-primary: 83,615 JPY [836 USD]; secondary: 90,711 JPY [907 USD]) (p<0.0001). After adjusting for baseline characteristics, these costs were 2.2 and 2.9 times higher for primary and secondary dysmenorrhea cohorts, respectively, compared with matched controls, (both p<0.0001). The main driver of these excess costs was outpatient care, with eight additional physician visits per year among dysmenorrhea patients compared to controls (p<0.0001). CONCLUSION: Considerable heterogeneity in treatment patterns was observed, with relatively low utilization of LEPs in patients with primary dysmenorrhea and those treated by internal medicine physicians. Total annual health care costs were approximately 2-3 times higher in patients with dysmenorrhea compared to women without the condition. PMID- 28579814 TI - In-center hemodialysis absenteeism: prevalence and association with outcomes. AB - OBJECTIVE: The aim of this study was to determine the rate of missed treatments among hemodialysis (HD) patients, and the association between treatment nonadherence and clinical outcomes. DATA SOURCE: The data used in this study were based on electronic medical records and Medicare claims. STUDY DESIGN: This is a retrospective, observational study. PRINCIPAL FINDINGS: HD patients miss 9.9% of all treatments. Approximately half of the missed treatments are due to observable medical events, predominantly hospitalizations, while half result from nonadherence ("absence"). A single absence is associated with a 1.4-fold greater risk of hospitalization, and a 2.2-fold greater risk of death in the subsequent 30 days. CONCLUSION: Treatment nonadherence is common among HD patients and is associated with adverse outcomes. Interventions that improve adherence may improve patient health and reduce costs. PMID- 28579815 TI - Pollution and acne: is there a link? AB - In recent years, the critical role that inflammation may play in the development and progression of acne has become increasingly recognized. The prevalence of acne is similar between Asian and Caucasian women, but Asian women have a higher prevalence of inflammatory acne. They also report their symptoms exacerbate during periods of high air pollution. The objective of this study was to review the current evidence that links air pollution to worsening of acne symptoms. Firstly, a group of five Asian and three European scientists with expertise in Dermatology reviewed the current literature and described current acne treatment practices in their countries. During this activity, they identified the need for further epidemiological and clinical research. Secondly, additional studies ensued which provided evidence that acne symptoms might exacerbate in regions of high ambient air pollution. Based on these findings, the authors suggest that people with acne should protect the natural barrier function of their skin with emollients and ultraviolet (UV)A/UVB protection. PMID- 28579816 TI - Tattoo removal with ingenol mebutate. AB - An increasing number of people are getting tattoos; however, many regret the decision and seek their removal. Lasers are currently the most commonly used method for tattoo removal; however, treatment can be lengthy, costly, and sometimes ineffective, especially for certain colors. Ingenol mebutate is a licensed topical treatment for actinic keratoses. Here, we demonstrate that two applications of 0.1% ingenol mebutate can efficiently and consistently remove 2 week-old tattoos from SKH/hr hairless mice. Treatment was associated with relocation of tattoo microspheres from the dermis into the posttreatment eschar. The skin lesion resolved about 20 days after treatment initiation, with some cicatrix formation evident. The implications for using ingenol mebutate for tattoo removal in humans are discussed. PMID- 28579818 TI - Healing of Achilles tendon partial tear following focused shockwave: a case report and literature review. AB - Achilles tendinopathy is a common cause of posterior heel pain and can progress to partial tendon tear without adequate treatment. Effects of traditional treatments vary, and many recent reports focus on the use of extracorporeal shockwave therapy (ESWT) for Achilles tendinopathy but not for Achilles tendon partial tear. Here, we report the case of a 64-year-old female suffering from severe left heel pain for half a year. All treatment and rehabilitation were less effective until ESWT was applied. Each course of focused shockwave therapy included 2500 shots with energy flux density from 0.142 mJ/mm2 to 0.341 mJ/mm2. The visual analog scale decreased from nine to one degree. High-resolution musculoskeletal ultrasonography was performed before and 1 month after the treatment, which revealed healing of the torn region and decrease in inflammation. ESWT had shown to be an alternative treatment for Achilles tendon partial tear under safety procedure and ultrasound observation. PMID- 28579817 TI - The impact of internet-based cognitive behavior therapy on work ability in patients with depression - a randomized controlled study. AB - OBJECTIVES: The aim of this randomized controlled trial (RCT) was to investigate the effects of internet-based cognitive behavior therapy (ICBT) treatment for depression compared to treatment-as-usual (TAU) on improving work ability and quality of life in patients with mild-to-moderate depression. We also examined whether patients treated with ICBT returned to work more rapidly, that is, had fewer days of sick leave, than patients treated with TAU. DESIGN: This study is based on material from the PRIM-NET RCT that took place between 2010 and 2013. SETTING: Primary care centers in Region Vastra Gotaland, Sweden, population about 1.6 million. PATIENTS: A total of 77 patients with depression randomized to either ICBT (46 patients) or TAU (31 patients). Mean age of participants was 35.8 years, and 67.5% were women. MAIN OUTCOME MEASURES: Work ability was measured with the Work Ability Index, depressive symptoms with Montgomery Asberg Depression Rating Scale - self-rating version (MADRS-S), quality of life with EuroQoL-5D (EQ-5D), and number of sick leave days. RESULTS: Both groups showed an association between improved work ability and reduction of depressive symptoms and between improved work ability and better quality of life. ICBT could not be shown to improve work ability more than TAU among patients with mild-to-moderate depression. There were no differences between the groups concerning number of patients with sick leave or number of sick leave days. CONCLUSION: Our study indicates that a high level of work ability has an association with high health related quality of life in patients with mild-to-moderate depression, whether they are treated with ICBT or TAU. ICBT has previously been found to be cost effective and can be seen as a good alternative to TAU. In addition to the ICBT, an intervention oriented toward the work place might improve work ability and reduce the number of sick leave days among patients with depression. PMID- 28579819 TI - Outcomes and prognostic variables of radiofrequency zygapophyseal joint neurotomy in Utah workers' compensation patients. AB - PURPOSE: The prevalence of radiofrequency zygapophyseal joint neurotomy (RFN) has increased substantially across the past decade. Limited research exists that has examined pre-procedure predictors of RFN outcomes, particularly within workers' compensation populations. The purpose of this study was to determine if pre procedure biopsychosocial variables are predictive of outcomes in a cohort of compensated Utah patients who have undergone RFN. PATIENTS AND METHODS: This was a retrospective cohort study consisting of a review of pre-procedure medical records and a telephone outcome survey. The sample consisted of 101 compensated workers from Utah who had undergone RFN. Fifty-six patients (55%) responded to the outcome survey. Patients were an average of 46 months post-neurotomy at the time of follow-up. Outcome measures included patient satisfaction, disability status, Roland-Morris Disability Questionnaire, Stauffer-Coventry Index, and Short-Form Health Survey-36 (v.2). Statistical techniques utilized included frequencies, mean comparisons, and logistic and multiple regressions. RESULTS: Forty percent of patients were totally disabled at the time of follow-up. Lawyer involvement, older age, and a positive history of depression were predictors of poor outcomes in logistic and multiple regression equations. CONCLUSION: Presurgical biopsychosocial variables were predictive of multidimensional patient outcomes, and a high rate of total disability was observed. Additional research on the effectiveness of RFN for workers' compensation patients is recommended. PMID- 28579820 TI - Cannabis and intractable chronic pain: an explorative retrospective analysis of Italian cohort of 614 patients. AB - BACKGROUND: Despite growing interest in the therapeutic use of cannabis to manage chronic pain, only limited data that address these issues are available. In recent years, a number of nations have introduced specific laws to allow patients to use cannabis preparations to treat a variety of medical conditions. In 2015, the Italian government authorized the use of cannabis to treat several diseases, including chronic pain generally, spasticity in multiple sclerosis, cachexia and anorexia among AIDS and cancer patients, glaucoma, Tourette syndrome, and certain types of epilepsy. We present the first snapshot of the Italian experience with cannabis use for chronic pain over the initial year of its use. METHODS: This is a retrospective case series analysis of all chronic pain patients treated with oral or vaporized cannabis in six hubs during the initial year following the approval of the new Italian law (December 2015 to November 2016). We evaluated routes of administration, types of cannabis products utilized, dosing, and effectiveness and safety of the treatment. RESULTS: As only one of the six centers has extensively used cannabinoids for intractable chronic pain (614 patients of 659), only the population from Azienda Ospedaliero Universitaria Pisana (Pisa) was considered. Cannabis tea was the primary mode of delivery, and in almost all cases, it was used in association with all the other pain treatments. Initial and follow-up cannabinoid concentrations were found to vary considerably. At initial follow-up, 76.2% of patients continued the treatment, and <15% stopped the treatment due to side effects (none of which were severe). CONCLUSION: We present the first analysis of Italian clinical practice of the use of cannabinoids for a large variety of chronic pain syndromes. From this initial snapshot, we determined that the treatment seems to be effective and safe, although more data and subsequent trials are needed to better investigate its ideal clinical indication. PMID- 28579821 TI - Opioid analgesics-related pharmacokinetic drug interactions: from the perspectives of evidence based on randomized controlled trials and clinical risk management. AB - BACKGROUND: Multimorbidity results in complex polypharmacy which may bear a risk of drug interactions. A better understanding of opioid analgesics combination therapy used for pain management could help warrant medication safety, efficacy, and economic relevance. Until now there has been no review summarizing the opioid analgesics-related pharmacokinetic drug interactions from the perspective of evidence based on randomized controlled trials (RCTs). METHOD: A literature search was performed using PubMed, MEDLINE, and the Cochrane Library, using a PRISMA flowchart. RESULTS: Fifty-two RCTs were included for data interpretation. Forty-two RCTs (80.8%) were conducted in healthy volunteers, whereas 10 RCTs (19.2%) enrolled true patients. None of the opioid-drug/herb pairs was listed as contraindications of opioids involved in this review. Circumstances in which opioid is comedicated as a precipitant drug include morphine-P2Y12 inhibitors, morphine-gabapentin, and methadone-zidovudine. Circumstances in which opioid is comedicated as an object drug include rifampin-opioids (morphine, tramadol, oxycodone, methadone), quinidine-opioids (morphine, fentanyl, oxycodone, codeine, dihydrocodeine, methadone), antimycotics-opioids (buprenorphine, fentanyl, morphine, oxycodone, methadone, tilidine, tramadol), protease inhibitors-opioids (ritonavir, ritonavir/lopinavir-oxycodone, ritonavir-fentanyl, ritonavir tilidine), grapefruit juice-opioids (oxycodone, fentanyl, methadone), antidepressants-opioids (paroxetine-tramadol, paroxetine-hydrocodone, paroxetine oxycodone, escitalopram-tramadol), metoclopramide-morphine, amantadine-morphine, sumatriptan-butorphanol nasal sprays, ticlopidine-tramadol, St John's wort oxycodone, macrolides/ketolides-oxycodone, and levomepromazine-codeine. RCTs investigating the same combination, almost unanimously, drew consistent conclusions, except two RCTs on amantadine-intravenous morphine combination where a different amantadine dose was used and two RCTs on morphine-ticagrelor combination where healthy volunteers and true patients were enrolled, respectively. RCTs investigating in true patients may reflect a realistic clinical scenario and overcome the limitation of RCTs performed in healthy volunteers under standardized conditions. Further research opportunities are also presented in this review. CONCLUSION: Effective and safe combination therapy of opioids can be achieved by promoting the awareness of potential changes in therapeutic efficacy and toxicities, prescribing alternatives or changing administration strategy, tailoring dose, reviewing the appropriateness of orders, and paying attention to medication monitoring. PMID- 28579822 TI - Quantitative sensory testing measures individual pain responses in emergency department patients. AB - BACKGROUND: Refining and individualizing treatment of acute pain in the emergency department (ED) is a high priority, given that painful complaints are the most common reasons for ED visits. Few tools exist to objectively measure pain perception in the ED setting. We speculated that variation in perception of fixed painful stimuli would explain individual variation in reported pain and response to treatment among ED patients. MATERIALS AND METHODS: In three studies, we 1) describe performance characteristics of brief quantitative sensory testing (QST) in 50 healthy volunteers, 2) test effects of 10 mg oxycodone versus placebo on QST measures in 18 healthy volunteers, and 3) measure interindividual differences in nociception and treatment responses in 198 ED patients with a painful complaint during ED treatment. QST measures adapted for use in the ED included pressure sensation threshold, pressure pain threshold (PPT), pressure pain response (PPR), and cold pain tolerance (CPT) tests. RESULTS: First, all QST measures had high inter-rater reliability and test-retest reproducibility. Second, 10 mg oxycodone reduced PPR, increased PPT, and prolonged CPT. Third, baseline PPT and PPR revealed hyperalgesia in 31 (16%) ED subjects relative to healthy volunteers. In 173 (88%) ED subjects who completed repeat testing 30 minutes after pain treatment, PPT increased and PPR decreased (Cohen's dz 0.10 0.19). Verbal pain scores (0-10) for the ED complaint decreased by 2.2 (95% confidence intervals [CI]: 1.9, 2.6) (Cohen's dz 0.97) but did not covary with the changes in PPT and PPR (r=0.05-0.13). Treatment effects were greatest in ED subjects with a history of treatment for anxiety or depression (Cohen's dz 0.26 0.43) or with baseline hyperalgesia (Cohen's dz 0.40-0.88). CONCLUSION: QST reveals individual differences in perception of fixed painful stimuli in ED patients, including hyperalgesia. Subgroups of ED patients with hyperalgesia and psychiatric history report larger treatment effects on ED pain and QST measures. PMID- 28579823 TI - Use of immediate-release opioids as supplemental analgesia during management of moderate-to-severe chronic pain with buprenorphine transdermal system. AB - BACKGROUND: The buprenorphine transdermal system (BTDS) is approved in the US for the management of chronic pain. Due to its high affinity for MU-opioid receptors with a slow dissociation profile, buprenorphine may potentially displace or prevent the binding of competing MU-opioid-receptor agonists, including immediate release (IR) opioids, in a dose-dependent manner. Health care professionals may assume that the use of IR opioids for supplemental analgesia during BTDS therapy is not acceptable. MATERIALS AND METHODS: This post hoc analysis evaluated the use of IR opioids as supplemental analgesia during the management of moderate severe chronic pain with BTDS at 52 US sites (BUP3015S, NCT01125917). Patients were categorized into IR-opioid and no-IR-opioid groups. At each visit of the extension phase, adverse events, concomitant medications, and information from the Brief Pain Inventory (BPI) were recorded. RESULTS: The most common supplemental IR opioids prescribed during BTDS treatment (n=354) were hydrocodone acetaminophen and oxycodone-acetaminophen. The mean daily dose of IR opioids (morphine equivalents) for supplemental analgesia was 22 mg. At baseline, BPI - pain intensity and BPI - interference scores were higher for patients in the IR opioid group. In both treatment groups, scores improved by week 4, and then were maintained throughout 6 months of the open-label extension trial. The incidence of treatment-emergent adverse events was similar in both groups. CONCLUSION: Patients who were prescribed IR opioids reported lower scores for BPI pain intensity and pain interference to levels similar to patients receiving BTDS without IR opioids, without increasing the rate or severity of treatment-emergent adverse events. Patients prescribed concomitant use of IR opioids with BTDS had greater treatment persistence. The results of this post hoc analysis provide support for the concomitant use of IR opioids for supplemental analgesia during the management of moderate-severe chronic pain with BTDS. PMID- 28579824 TI - Tumor necrosis factor alpha modulates sodium-activated potassium channel SLICK in rat dorsal horn neurons via p38 MAPK activation pathway. AB - The dorsal horn (DH) of the spinal cord is the integrative center that processes and transmits pain sensation. Abnormal changes in ion channel expression can enhance the excitability of pain-related DH neurons. Sodium-activated potassium (KNa) channels are highly expressed particularly in the central nervous system; however, information about whether rat DH neurons express the SLICK channel protein is lacking, and the direct effects on SLICK in response to inflammation and the potential signaling pathway mediating such effects are yet to be elucidated. Here, using cultured DH neurons, we have shown that tumor necrosis factor-alpha inhibits the total outward potassium current IK and the KNa current predominantly as well as induces a progressive loss of firing accommodation. However, we found that this change in channel activity is offset by the p38 inhibitor SB202190, thereby suggesting the modulation of SLICK channel activity via the p38 MAPK pathway. Furthermore, we have demonstrated that the tumor necrosis factor-alpha modulation of KNa channels does not occur at the level of SLICK channel gating but arises from possible posttranslational modification. PMID- 28579825 TI - Durapain in symptomatic treatment of severe acute pain: a post-marketing, prospective, multicenter, observational study - PRIME study. AB - OBJECTIVE: To assess the effectiveness, overall tolerability, and gastrointestinal (GI) tolerability of Durapain (fixed dose combination of tramadol hydrochloride immediate release [50 mg] and diclofenac sodium sustained release [75 mg]) in symptomatic treatment of severe acute pain in physician's routine clinical practice. MATERIALS AND METHODS: In this prospective, multicenter, observational, post-marketing study, adult patients (aged 18-60 years) with severe acute pain were treated with tramadol hydrochloride/diclofenac sodium as per approved prescribing information. Evaluation was done at base-line, day 2, and day 5. Primary end point was pain intensity difference from baseline to day 5. RESULTS: A total of 351 patients (mean age 44.2 years; male 43%; female 57%) were included. The mean pain score was reduced from 9.2+/-1.09 at baseline to 2.8+/-1.73 at day 5 (p<0.0001). The number of patients with severe intensity of pain reduced from 100% at baseline to 18.3% at day 2 and 6.96% at day 5. According to the patient assessment, 68.36% of patients reported tolerability as "very good to good", whereas according to physician's assessment, "very good to good" tolerability was reported in 68.27% of patients. Five (1.43 %) patients discontinued the study because of adverse drug reaction. Five patients developed nine GI-related events of moderate intensity. Two patients developed three adverse reactions (burning sensation in urine, giddiness, and urine retention) other than GI events. No serious adverse drug reactions were reported during the study period. CONCLUSION: Tramadol hydrochloride/diclofenac sodium is an effective and well-tolerated treatment in Indian patients with severe acute pain. Treatment with tramadol hydrochloride/diclofenac sodium provides significant pain relief on day 2 and maintained until day 5 without any serious adverse reactions. PMID- 28579828 TI - The Effect of Quercetin on Pro- and Anti-Inflammatory Cytokines in a Prenatally Stressed Rat Model of Febrile Seizures. AB - Febrile seizures are childhood convulsions resulting from an infection that leads to an inflammatory response and subsequent convulsions. Prenatal stress has been shown to heighten the progression and intensity of febrile seizures. Current medications are costly and have adverse effects associated with prolonged use. Quercetin flavonoid exhibits anti-inflammatory, anti-convulsant, and anti-stress effects. This study was aimed to investigate the therapeutic effect of quercetin in a prenatally stressed rat model of febrile seizures. We hypothesized that quercetin will alleviate the effects of prenatal stress in a febrile seizure rat model. On gestational day 13, Sprague-Dawley rat dams were subjected to restraint stress for 1 hour/d for 7 days. Febrile seizures were induced on postnatal day 14 on rat pups by intraperitoneally injecting lipopolysaccharide followed by kainic acid and quercetin on seizure onset. Hippocampal tissue was harvested to profile cytokine concentrations. Our results show that quercetin suppresses prenatal stress-induced pro-inflammatory marker (interleukin 1 beta) levels, subsequently attenuating febrile seizures. This shows that quercetin can be therapeutic for febrile seizures in prenatally stressed individuals. PMID- 28579829 TI - Natural and synthetic progestins enrich cancer stem cell-like cells in hormone responsive human breast cancer cell populations in vitro. AB - Clinical trials and studies have shown that combination estrogen/progestin hormone replacement therapy, but not estrogen therapy alone or placebo, increases breast cancer risk in postmenopausal women. Using animal models, we have previously shown that both natural and synthetic progestins (including medroxyprogesterone acetate [MPA], a synthetic progestin used widely in the clinical setting) accelerate the development of breast tumors in vivo and increase their metastasis to lymph nodes. Based on these observations, we have hypothesized that progestin-induced breast cancer tumor growth and metastasis may be mediated by an enrichment of the cancer stem cell (CSC) pool. In this study, we used T47-D and BT-474 hormone-responsive human breast cancer cells to examine the effects of progestin on phenotypic and functional markers of CSCs in vitro. Both natural and synthetic progestins (10 nM) significantly increased protein expression of CD44, an important CSC marker in tumor cells. MPA increased the levels of both CD44 variants v3 and v6 associated with stem cell functions. This induction of CD44 was blocked by the antiprogestin RU-486, suggesting that this process is progesterone receptor (PR) dependent. CD44 induction was chiefly progestin dependent. Because RU-486 can bind other steroid receptors, we treated PR-negative T47-DCO-Y cells with MPA and found that MPA failed to induce CD44 protein expression, confirming that PR is essential for progestin-mediated CD44 induction in T47-D cells. Further, MPA treatment of T47-D cells significantly increased the activity of aldehyde dehydrogenase (ALDH), another CSC marker. Finally, two synthetic progestins, MPA and norethindrone, significantly increased the ability of T47-D cells to form mammospheres, suggesting that enrichment of the CD44high, ALDHbright subpopulation of cancer cells induced by MPA exposure is of functional significance. Based on our observations, we contend that exposure of breast cancer cells to synthetic progestins leads to an enrichment of the CSC pool, supporting the development of progestin-accelerated tumors in vivo. PMID- 28579830 TI - Effect of reduced dietary fat on estradiol, adiponectin, and IGF-1 levels in postmenopausal women with breast cancer. AB - INTRODUCTION: In recent years, epidemiological studies have strongly related obesity with an increased risk of developing postmenopausal breast cancer. The aromatization of fatty tissue increases the levels of estradiol and adiponectin, which is correlated with the body mass index (BMI). It is of interest to investigate the effect of reducing BMI on estradiol, adiponectin, and IGF-1, as reducing BMI could be a new strategy to limit the risk of recurrence during the adjuvant treatment of breast cancer. OBJECTIVE: The aim of this study is to investigate the effect of reduced dietary fat on the levels of serum estradiol, adiponectin, and IGF-1 among postmenopausal Mexican women with breast cancer. METHODS: In this controlled clinical trial, 100 female patients were randomly divided into two groups and followed for six months. Group 1 (n = 50) was subjected to reduced dietary fat, whereas Group 2 (n = 50) was subjected to a control diet. The levels of serum estradiol and testosterone were determined using an enzyme-linked immunosorbent assay, whereas the concentrations of adiponectin and IGF-1 were determined using a radioimmunoassay. RESULTS: The patients subjected to reduced dietary fat showed a significant difference in BMI (27.93 +/- 4.45 vs 26.05 +/- 2.65; p = 0.01) and waist circumference (99.92 vs 91.59 cm; p = 0.0001) after the treatment. Moreover, a significant decrease in serum estradiol was observed (21.23 +/- 14.32 vs 16.05 +/- 10.25 ng/mL; p < 0.001). The adiponectin concentration also decreased significantly (47.53 +/- 12.19 vs 42.52 +/- 12.34 ug/mL; p = 0.004), while IGF-1 and testosterone did not show significant changes (p > 0.05). In addition, BMI had a relationship with serum adiponectin (r = -0.27; p = 0.02) and estradiol (r = 0.37; p = 0.001). CONCLUSION: The current study shows that reducing BMI decreases serum estradiol and adiponectin. Large clinical trials are needed to investigate the role of adiponectin in breast cancer development in obese women. PMID- 28579827 TI - Optogenetic Modulation of Intracellular Signalling and Transcription: Focus on Neuronal Plasticity. AB - Several fields in neuroscience have been revolutionized by the advent of optogenetics, a technique that offers the possibility to modulate neuronal physiology in response to light stimulation. This innovative and far-reaching tool provided unprecedented spatial and temporal resolution to explore the activity of neural circuits underlying cognition and behaviour. With an exponential growth in the discovery and synthesis of new photosensitive actuators capable of modulating neuronal networks function, other fields in biology are experiencing a similar re-evolution. Here, we review the various optogenetic toolboxes developed to influence cellular physiology as well as the diverse ways in which these can be engineered to precisely modulate intracellular signalling and transcription. We also explore the processes required to successfully express and stimulate these photo-actuators in vivo before discussing how such tools can enlighten our understanding of neuronal plasticity at the systems level. PMID- 28579831 TI - The regulation of steroid receptors by epigallocatechin-3-gallate in breast cancer cells. AB - It has been reported that phytoestrogen epigallocatechin gallate (EGCG) suppresses cancer cell proliferation and may have antitumor properties. In this study, we analyzed the effects of EGCG on estrogen receptor alpha (ERalpha) and progesterone receptor in hormone-dependent T-47D breast cancer cells. Western blot analysis revealed EGCG induced a concentration-dependent decrease in ERalpha protein levels, with a 56% reduction occurring with 60 uM EGCG when compared to controls. Downregulation of ERalpha protein levels was observed after 24-hour co treatment of T-47D cells with 60 uM EGCG and 10 nM 17beta-estradiol (E2). The proliferative effect of E2 on cell viability was reversed when treated in combination with EGCG. In contrast, the combination of EGCG with the pure ER antagonist, ICI 182, 780, showed no further reduction in cell number as only 5% of the cells were viable after 6 days of treatment. These studies may provide further understanding of the interactions among flavonoids and steroid receptors in breast cancer cells. PMID- 28579832 TI - APF530 versus ondansetron, each in a guideline-recommended three-drug regimen, for the prevention of chemotherapy-induced nausea and vomiting due to anthracycline plus cyclophosphamide-based highly emetogenic chemotherapy regimens: a post hoc subgroup analysis of the Phase III randomized MAGIC trial. AB - BACKGROUND: APF530, a novel extended-release granisetron injection, was superior to ondansetron in a guideline-recommended three-drug regimen in preventing delayed-phase chemotherapy-induced nausea and vomiting (CINV) among patients receiving highly emetogenic chemotherapy (HEC) in the double-blind Phase III Modified Absorption of Granisetron In the prevention of CINV (MAGIC) trial. PATIENTS AND METHODS: This MAGIC post hoc analysis evaluated CINV prevention efficacy and safety of APF530 versus ondansetron, each with fosaprepitant and dexamethasone, in patient subgroup receiving an anthracycline plus cyclophosphamide (AC) regimen. Patients were randomized 1:1 to APF530 500 mg subcutaneously (granisetron 10 mg) or ondansetron 0.15 mg/kg intravenously (IV) (<=16 mg); stratification was by planned cisplatin >=50 mg/m2 (yes/no). Patients were to receive fosaprepitant 150 mg IV and dexamethasone 12 mg IV on day 1, then dexamethasone 8 mg orally once daily on day 2 and twice daily on days 3 and 4. Patients were mostly younger females (APF530 arm, mean age 54.1 years, female, 99.3%; ondansetron arm, 53.8 years, female 98.3%). The primary end point was delayed-phase (>24-120 hours) complete response (CR). RESULTS: APF530 versus ondansetron regimens achieved numerically better CINV control in delayed and overall (0-120 hours) phases for CR, complete control, total response, rescue medication use, and proportion with no nausea. APF530 trends are consistent with the overall population, although not statistically superior given the underpowered AC subgroup analysis. The APF530 regimen in this population was generally well tolerated, with safety comparable to that of the overall population. CONCLUSION: APF530 plus fosaprepitant and dexamethasone effectively prevented CINV among patients receiving AC-based HEC, a large subgroup in whom CINV control has traditionally been challenging. PMID- 28579826 TI - Inflammation and Epithelial-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma: Fighting Against Multiple Opponents. AB - Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and one of the most lethal human cancers. Inflammation is a critical component in PDAC initiation and progression. Inflammation also contributes to the aggressiveness of PDAC indirectly via induction of epithelial-mesenchymal transition (EMT), altogether leading to enhanced resistance to chemotherapy and poor survival rates. This review gives an overview of the key pro-inflammatory signaling pathways involved in PDAC pathogenesis and discusses the role of inflammation in induction of EMT and development of chemoresistance in patients with PDAC. PMID- 28579833 TI - Multiple myeloma in Niger Delta, Nigeria: complications and the outcome of palliative interventions. AB - BACKGROUND: Multiple myeloma (MM) is one of the hematological malignancies that require palliative care. This is because of the life-threatening nature and the suffering associated with the illness. The aim of this study is to bring to the fore the complications experienced by people living with MM in the Niger-Delta region of Nigeria and the outcome of various palliative interventions. METHODS: This was a 10-year multi-center retrospective study of 26 patients diagnosed and managed in three major centers in the Niger-Delta region of Nigeria from January 2003 to December 2012. Information on the clinical, laboratory, radiological data, and palliative treatment was obtained at presentation and subsequently at intervals of 3 months until the patient was lost to follow-up. RESULT: The mean duration from onset of symptoms to diagnosis was 13.12 months (95% CI, 6.65 19.58). A total of 16 (61.5%), eight (30.8%), and two subjects (7.7%) presented in Durie-Salmon (DS) stages III, II, and I, respectively. The complications presented by patients at diagnoses included bone pain (84.6%), anemia (61.5%), nephropathy (23.1%), and hemiplegia (35%). All the patients received analgesics, while 50.0% received blood transfusion, 56.7% had surgery performed, 19% had hemodialysis, and 3.8% received radiotherapy. A total of 10 (38%) patients benefited from bisphosphonates (BPs). A total of 57.6% of patients were on melphalan-prednisone (MP) double regimen, while 19% and 8% patients were on MP thalidomide and MP-bortezomib triple regimens, respectively. A total of 3.8% of patients at DS stage IIIB disease had autologous stem-cell transplantation (ASCT). Only 7.6% of the myeloma patients survived up to 5 years post diagnosis. The overall mean survival interval was 39.7 months (95% CI, 32.1-47.2). CONCLUSION: Late diagnosis and inadequate palliative care account for major complications encountered by MM patients in the Niger-Delta region of Nigeria. This could be responsible for the poor prognostic outcome and low survival interval of MM individuals in this region. There is, therefore, a need to improve the quality of palliative care received by myeloma patients in this region. This is achievable via provision of relevant and affordable health care facilities for diagnosis and treatment of the disease. PMID- 28579834 TI - Hypoglycemia: a review of definitions used in clinical trials evaluating antihyperglycemic drugs for diabetes. AB - OBJECTIVE: To understand the severity and potential impact of heterogeneity in definitions of hypoglycemia used in diabetes research, we aimed to review the hypoglycemia definitions adopted in randomized controlled trials (RCTs). METHODS: We reviewed 109 RCTs included in the Canadian Agency for Drugs and Technologies in Health reports for the second- and third-line therapy for the patients with type 2 diabetes (T2D). RESULTS: Nearly 60% (n=66) of the studies reviewed presented the definitions for overall hypoglycemia, and another 20% (n=22) of the studies reported the results for hypoglycemia but did not report a definition. Among these 66 studies, only 9 (14%) followed the American Diabetes Association/European Medicines Agency specified guidelines to define hypoglycemia, with an exact threshold of plasma glucose <=3.9 mmol/L. Fifty-two of the 66 studies (79%) used a threshold considerably lower than the recommended <=3.9 mmol/L, and 16 studies used a threshold between 3.8 and 4.0 mmol/L. The proportion of the trials that used a cutoff value of <3.1 mmol/L appeared to be slightly similar among the more commonly used non-insulin treatments, GLP-1s (7 of 18 [39%]), thiazolidinediones (TZDs; 6 of 11 [55%]), DPP-4s (12 of 19 [64%]), and sulfonylureas (11 of 20 [55%]). Among trials with intermediate-long-acting insulins (neutral protamine Hagedorn insulin, detemir, glargine), 7 of 26 trials (27%) used a cutoff of <3.1 mmol/L. The definition of severe hypoglycemia was also subject to substantial heterogeneity, in both the utilized threshold and accompanying soft definitions. CONCLUSION: This review demonstrates that substantial heterogeneity exists in the definition of overall, severe/major, and nocturnal hypoglycemia across RCTs investigating T2D interventions. PMID- 28579835 TI - Transmission of health care-associated infections from roommates and prior room occupants: a systematic review. AB - Pathogens that cause health care-associated infections (HAIs) are known to survive on surfaces and equipment in health care environments despite routine cleaning. As a result, the infection status of prior room occupants and roommates may play a role in HAI transmission. We performed a systematic review of the literature evaluating the association between patients' exposure to infected/colonized hospital roommates or prior room occupants and their risk of infection/colonization with the same organism. A PubMed search for English articles published in 1990-2014 yielded 330 studies, which were screened by three reviewers. Eighteen articles met our inclusion criteria. Multiple studies reported positive associations between infection and exposure to roommates with influenza and group A streptococcus, but no associations were found for Clostridium difficile, methicillin-resistant Staphylococcus aureus, Cryptosporidium parvum, or Pseudomonas cepacia; findings were mixed for vancomycin-resistant enterococci (VRE). Positive associations were found between infection/colonization and exposure to rooms previously occupied by patients with Pseudomonas aeruginosa and Acinetobacter baumannii, but no associations were found for resistant Gram-negative organisms; findings were mixed for C. difficile, methicillin-resistant S. aureus, and VRE. Although the majority of studies suggest a link between exposure to infected/colonized roommates and prior room occupants, methodological improvements such as increasing the statistical power and conducting universal screening for colonization would provide more definitive evidence needed to establish causality. PMID- 28579838 TI - Extraordinary and prolonged erlotinib-induced clinical response in a patient with EGFR wild-type squamous lung cancer in third-line therapy: a case report. AB - Several small molecules, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib and afatinib, have been demonstrated to significantly improve clinical outcomes in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC), but erlotinib activity in EGFR wild-type squamous carcinoma is still highly debated. Here, we describe a prolonged and unexpected clinical response to erlotinib in a male former heavy cigarette smoker with wild-type EGFR squamous-cell cancer. PMID- 28579837 TI - Knowledge about cervical cancer screening and its practice among female health care workers in southern Ethiopia: a cross-sectional study. AB - BACKGROUND: Cervical cancer remains a major cause of morbidity and mortality among the women in the world. Early screening for cervical cancer is a key intervention in reduction of maternal deaths. Health care workers have a significant contribution to improve cervical cancer screening practice among women. Hence, this study aimed to assess the knowledge and practice of cervical cancer screening among female health care workers in southern Ethiopia. METHODS: Institution-based cross-sectional study was conducted during March and April, 2015. All hospitals in Hawassa city administration and Sidama zone were purposively selected. A simple random sampling technique was used to draw the health centers. After proportional allocations to their respective health facilities, a total of 367 female health workers were selected by simple random sampling technique. A structured and pretested questionnaire was used to collect the data. Data were entered to SPSS version 20.0 for further analysis. Logistic regression analyses were used to see the association of different variables. RESULTS: Out of the total respondents, 319 (86.9%) had a good level of knowledge on cervical cancer. Similarly, a majority of them, 329 (89.6%), 321 (87.5%), and 295 (80.4%), knew about the risk factors, symptoms, and outcomes of cervical cancer, respectively. More than two thirds of the respondents, 283 (77.1%), knew that there is a procedure used to detect premalignant cervical lesions and 138 (37.6%) of them mentioned visual inspection with acetic acid as a screening method. In this study, only 42 (11.4%) of the respondents were screened for cervical cancer (confidence interval [CI]: 8.7, 13.9). Being a physician (adjusted odds ratio [AOR] =0.12, 95% CI: 0.02, 0.79) and working in a cervical cancer screening center (AOR =0.14, 95% CI: 0.03, 0.68) had a lower odds of cervical cancer screening practices. CONCLUSIONS: Significant numbers of health care workers were knowledgeable on cervical cancer. Cervical cancer screening among health care workers in southern Ethiopia was found to be low. Being a physician and working in a screening center had lower odds of cervical cancer screening practice. In spite of having adequate knowledge on cervical cancer the reasons for low practice of cervical cancer screening among health care workers needs to be investigated. PMID- 28579839 TI - Solitary neurofibroma of eyelid masquerading as chalazion. AB - Neurofibroma, a benign peripheral nerve sheath tumor, usually appears together with cafe-au-lait spots, iris nodules, and other tumors within the scope of neurofibromatosis von Recklinghausen type 1 tumors. A solitary neurofibroma of the eyelid is relatively rare. In this case report, we present a 39-year-old woman who had a lesion on the eyelid crease, previously treated as a chalazion. Due to persistent wound crusting, the lesion was excised above the tarsus. Pathological examination revealed a solitary neurofibroma. The patient did not have other clinical symptoms of neurofibromatosis, and there was no recurrence of the nodule during the 1-year follow-up. PMID- 28579836 TI - Update on the renal toxicity of iodinated contrast drugs used in clinical medicine. AB - An important side effect of diagnostic contrast drugs is contrast-induced acute kidney injury (CI-AKI; a sudden decrease in renal function) occurring 48-72 hours after injection of a contrast drug that cannot be attributed to other causes. Its existence has recently been challenged, because of some retrospective studies in which the incidence of AKI was not different between subjects who received a contrast drug and those who did not, even using propensity score matching to prevent selection bias. For some authors, only patients with estimated glomerular filtration rate <30 mL/min/1.73 m2 are at significant risk of CI-AKI. Most agree that when renal function is normal, there is no CI-AKI risk. Many experimental studies, however, are in favor of the existence of CI-AKI. Contrast drugs have been shown to cause the following changes: renal vasoconstriction, resulting in a rise in intrarenal resistance (decrease in renal blood flow and glomerular filtration rate and medullary hypoxia); epithelial vacuolization and dilatation and necrosis of proximal tubules; potentiation of angiotensin II effects, reducing nitric oxide (NO) and causing direct constriction of descending vasa recta, leading to formation of reactive oxygen species in isolated descending vasa recta of rats microperfused with a solution of iodixanol; increasing active sodium reabsorption in the thick ascending limbs of Henle's loop (increasing O2 demand and consequently medullary hypoxia); direct cytotoxic effects on endothelial and tubular epithelial cells (decrease in release of NO in vasa recta); and reducing cell survival, due to decreased activation of Akt and ERK1/2, kinases involved in cell survival/proliferation. Prevention is mainly based on extracellular volume expansion, statins, and N-acetylcysteine; conflicting results have been obtained with nebivolol, furosemide, calcium channel blockers, theophylline, and hemodialysis. PMID- 28579840 TI - Antecedents of positive self-disclosure online: an empirical study of US college students' Facebook usage. AB - This study investigates the factors predicting positive self-disclosure on social networking sites (SNSs). There is a formidable body of empirical research relating to online self-disclosure, but very few studies have assessed the antecedents of positive self-disclosure. To address this literature gap, the current study tests the effects of self-esteem, life satisfaction, social anxiety, privacy concerns, public self-consciousness (SC), and perceived collectivism on positive self-disclosure on SNSs. Data were collected online via Qualtrics in April 2013. Respondents were undergraduate students from the University of Connecticut. Using ordinary least squares regression, the current study found that self-esteem and perceived collectivism increased positive self disclosure, life satisfaction, and privacy concerns decreased positive self disclosure, and the effects of social anxiety and public SC were not significant. PMID- 28579841 TI - Handover checklist: testing a standardization process in an Italian hospital. AB - OBJECTIVES: This study aimed to standardize and rationalize the handover, a critical and essential moment in common health care practices, through the realization of an efficient and standardized checklist, which could be used daily to ensure complete, thorough and effective handover. The principal purpose of the implementation of the handover is to reduce errors due to superficial and insufficient communication. METHODS: The "operative group" defined the phases to the realization of the delineated aims: at first, the direct observation and the consequent realization of a handover checklist model and then, the experimental phases (trials). The handover checklist model was used for a month and it was daily and duly completed by the doctors who took part in the trial. To prove the success of the study, three questionnaires were distributed on different occasions. RESULTS: Analyzing the answers to the questionnaires, the importance of the handover has come to light and that for the most part, the doctors consider it an essential and irreplaceable moment in daily health care work. Moreover, it became obvious that the use of the handover checklist guaranteed a considerable improvement in the traditional handover in terms of security, completeness, care continuity and clarity. The handover checklist was completely appreciated by the majority of the participant doctors who agree with the definitive introduction of it in their unit. CONCLUSIONS: Our study indicated the consistency of the handover checklist as an instrument to implement the handover and, indirectly, to improve the quality of the care. PMID- 28579843 TI - Optical Coherence Tomographic Angiography Imaging in Age-Related Macular Degeneration. AB - Optical coherence tomographic angiography (OCTA) is emerging as a rapid, noninvasive imaging modality that can provide detailed structural and flow information on retinal and choroidal vasculature. This review contains an introduction of OCTA and summarizes the studies to date on OCTA imaging in age related macular degeneration. PMID- 28579845 TI - Factors Affecting the Perceived Effectiveness of Pictorial Health Warnings on Cigarette Packages in Gulf Countries: A Cross-sectional Study. AB - OBJECTIVES: To explore the perceived effectiveness of pictorial health warning (PHW) labels required by the Gulf Cooperation Council, to compare them with the Food and Drug Administration-approved PHW labels, and to determine factors affecting their perceived effectiveness. METHODS: A cross-sectional study using a convenience sample of adult smokers and nonsmokers was conducted. The data were collected through a self-administered online questionnaire. The perceived effectiveness scores of PHW labels were calculated and compared among different subgroups using the Kruskal-Wallis test and the Dunn multiple comparison test at a .05 significance level. RESULTS: Of the 90 people invited to participate in the survey, 77 (86%) completed it, with 39 (50%) nonsmokers, 22 (29%) smokers, and 16 (21%) former smokers. Overall, labels having graphic images of illness or pathology are perceived to be most effective. Smokers generally perceived labels significantly less effective compared with former smokers and nonsmokers. Also, 55 respondents (71%) suggested that the presence of a telephone quit-line would be effective. CONCLUSIONS: Smoking status and image type had the most effect on the perceived effectiveness of the PHW labels on cigarette packs. Pictorial health warning labels with graphic images of pathology and a telephone quit-line are perceived to be most effective. PMID- 28579844 TI - Health Effects of Waterpipe Tobacco Use: Getting the Public Health Message Just Right. AB - Many public health messages benchmark the harms of waterpipe tobacco against those of cigarettes, usually using numerical magnitudes of risk. This approach, although well intentioned, could be perceived as alarmist, damaging scientific credibility, and giving an unintended impression that one tobacco product is less harmful than the other. This commentary makes clear the harm waterpipe tobacco smoking poses to public health by describing its mechanism of use, consumption uptake, toxicologic profile, and documented health outcomes, as well as challenge existing thinking that toxicologic assessments are the most appropriate way to frame waterpipe tobacco health promotion messages. How can we describe the health effects of waterpipe tobacco without undermining its toxicity nor falling into the temptation of alarmist messaging? Several recommendations are provided. PMID- 28579842 TI - Short- and long-term health consequences of sleep disruption. AB - Sleep plays a vital role in brain function and systemic physiology across many body systems. Problems with sleep are widely prevalent and include deficits in quantity and quality of sleep; sleep problems that impact the continuity of sleep are collectively referred to as sleep disruptions. Numerous factors contribute to sleep disruption, ranging from lifestyle and environmental factors to sleep disorders and other medical conditions. Sleep disruptions have substantial adverse short- and long-term health consequences. A literature search was conducted to provide a nonsystematic review of these health consequences (this review was designed to be nonsystematic to better focus on the topics of interest due to the myriad parameters affected by sleep). Sleep disruption is associated with increased activity of the sympathetic nervous system and hypothalamic pituitary-adrenal axis, metabolic effects, changes in circadian rhythms, and proinflammatory responses. In otherwise healthy adults, short-term consequences of sleep disruption include increased stress responsivity, somatic pain, reduced quality of life, emotional distress and mood disorders, and cognitive, memory, and performance deficits. For adolescents, psychosocial health, school performance, and risk-taking behaviors are impacted by sleep disruption. Behavioral problems and cognitive functioning are associated with sleep disruption in children. Long-term consequences of sleep disruption in otherwise healthy individuals include hypertension, dyslipidemia, cardiovascular disease, weight-related issues, metabolic syndrome, type 2 diabetes mellitus, and colorectal cancer. All-cause mortality is also increased in men with sleep disturbances. For those with underlying medical conditions, sleep disruption may diminish the health-related quality of life of children and adolescents and may worsen the severity of common gastrointestinal disorders. As a result of the potential consequences of sleep disruption, health care professionals should be cognizant of how managing underlying medical conditions may help to optimize sleep continuity and consider prescribing interventions that minimize sleep disruption. PMID- 28579846 TI - Analysis of blood donor pre-donation deferral in Dubai: characteristics and reasons. AB - BACKGROUND: To ensure an adequate and safe blood supply, it is crucial to select suitable donors according to stringent eligibility criteria. Understanding the reasons for donor deferral can help in planning more efficient recruitment strategies and evaluating donor selection criteria. This study aims to define donor pre-donation deferral rates, causes of deferral, and characteristics of deferred donors in Dubai. MATERIALS AND METHODS: This retrospective study was conducted on all donors who presented for allogeneic blood donation between January 1, 2010, until June 30, 2013, in Dubai Blood Donation Centre, accredited by the American Association of Blood Banks. The donation and deferral data were analyzed to determine the demographic characteristics of accepted and deferred donors, and frequency analyses were also conducted. RESULTS: Among 142,431 individuals presenting during the study period, 114,827 (80.6%) were accepted for donation, and 27,604 (19.4%) were deferred. The overall proportion of deferrals was higher among individuals less than 21 years old (35%, P<0.000), females (44% were deferred compared to 15% of males, P<0.0001), and first-time donors (22% were deferred vs 14% of repeat donors, P<0.0001). The main causes for a temporary deferral were low hemoglobin and high blood pressure. DISCUSSION: The deferral rate among blood donors in Dubai is relatively high compared to the internationally reported rates. This rate was higher among first-time donors and females, with low hemoglobin as the major factor leading to a temporary deferral of donors. Strategies to mitigate deferral and improve blood donor retention are urged in Dubai to avoid additional stress on the blood supply. PMID- 28579847 TI - Correlation Between Preoperative Serum Carcinoembryonic Antigen Levels and Expression on Pancreatic and Rectal Cancer Tissue. AB - Carcinoembryonic antigen (CEA)-targeted imaging and therapeutic agents are being tested in clinical trials. If CEA overexpression in malignant tissue corresponds with elevated serum CEA, serum CEA could assist in selecting patients who may benefit from CEA-targeted agents. This study aims to assess the relationship between serum CEA and CEA expression in pancreatic (n = 20) and rectal cancer tissues (n = 35) using histopathology. According to local laboratory standards, a serum CEA >3 ng/mL was considered elevated. In pancreatic cancer patients a significant correlation between serum CEA and percentage of CEA-expressing tumor cells was observed (P = .04, rho = .47). All 6 patients with homogeneous CEA expression in the tumor had a serum CEA >3 ng/mL. Most rectal cancer tissues (32/35) showed homogeneous CEA expression, independent of serum CEA levels. This study suggests that selection of pancreatic cancer patients for CEA-targeted agents via serum CEA appears adequate. For selection of rectal cancer patients, serum CEA levels are not informative. PMID- 28579848 TI - Gender nonconforming youth: current perspectives. AB - Beginning with a case vignette, a discussion follows of the reformulation of theories of gender development taking into consideration the recent upsurge of gender nonconforming and transgender youth presenting for gender services and also in the culture at large. The three predominant models of pediatric gender care are reviewed and critiqued, along with a presentation of the recently developed interdisciplinary model of gender care optimal in the treatment of gender nonconforming youth seeking either puberty blockers or cross-sex hormones. PMID- 28579849 TI - Vulnerable Habitats Alter African Meliponine Bee's (Hymenoptera: Apidae) Assemblages in an Eastern Afromontane Biodiversity Hotspot. AB - Habitat degradation has over time formed synergy with other factors to contribute to dwindling populations of both fauna and flora by altering their habitats. The disturbance of natural habitats affects the diversity of both vertebrates and invertebrates by altering both feeding and nesting sites for which organisms are known to depend on for survival. Little is known of the extent to which vulnerable habitats could shape the diversity of most indigent pollinators such as African meliponine bee species in tropical ecosystems. This study was conducted to determine how disturbance could shape the natural occurrence of African meliponine bee species in different ecological habitats of Taita Hills, leading to changes in their diversity. A total of four species depicted by the Renyi diversity profile was recorded in five of the six main habitat types surveyed, and a further extrapolation with Shannon index (EH) also predicted the highest species richness of 4.24 in a deciduous habitat type. These meliponine bee species (Hypotrigona gribodoi, Hypotrigona ruspolii, Meliponula ferruginea (black), and Plebeina hildebrandti) were observed to be unevenly distributed across all habitats, further indicating that mixed deciduous habitat was more diverse than acacia-dominated bush lands, grasslands, and exotic forest patches. Geometric morphometrics categorized all four meliponine bee species into two major clusters-cluster 1 (H gribodoi, H ruspolii, M ferruginea (black)) and cluster 2 (P hildebrandti)-and further discriminated populations against the 4 potential habitats they are likely to persist or survive in. Each habitat appeared to consist of a cluster of subpopulations and may possibly reveal ecotypes within the four meliponine populations. This has revealed that unprecedented conversions of natural habitats to agroecosystems are a key driving factor causing increased habitat isolation and vulnerability in this Afromontane region which may potentially distort local assemblages of native pollinators, such as meliponine bee species. PMID- 28579850 TI - Coexisting Sickle Cell Anemia and Sarcoidosis: A Management Conundrum! AB - Sickle cell disease and Sarcoidosis are conditions that are more common in the African American population. In this report we share an unfortunate patient who had hepatic sarcoidosis but could not receive steroids since that precipitated acute liver failure. We have discussed potential therapy options but we need more options that improve mortality. PMID- 28579851 TI - Transformation of Follicular Lymphoma to a High-Grade B-Cell Lymphoma With MYC and BCL2 Translocations and Overlapping Features of Burkitt Lymphoma and Acute Lymphoblastic Leukemia: A Case Report and Literature Review. AB - Most commonly, histologic transformation (HT) from follicular lymphoma (FL) manifests as a diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). Less frequently, HT may result in a high-grade B-cell lymphoma (HGBL) with MYC and B-cell lymphoma protein 2 (BCL2) and/or BCL6 gene rearrangements, also known as "double-hit" or "triple-hit" lymphomas. In the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms, the category B-cell lymphoma, unclassifiable was eliminated due to its vague criteria and limiting diagnostic benefit. Instead, the WHO introduced the HGBL category, characterized by MYC and BCL2 and/or BCL6 rearrangements. Cases that present as an intermediate phenotype of DLBCL and Burkitt lymphoma (BL) will fall within this HGBL category. Very rarely, HT results in both the intermediate DLBCL and BL phenotypes and exhibits lymphoblastic features, in which case the WHO recommends that this morphologic appearance should be noted. In comparison with de novo patients with DLBCL, NOS, those with MYC and BCL2 and/or BCL6 gene rearrangements have a worse prognosis. A 63-year-old woman presented with left neck adenopathy. Laboratory assessments, including complete blood count, complete metabolic panel, serum lactate dehydrogenase, and beta2-microglobulin, were all normal. A whole body computerized tomographic (CT) scan revealed diffuse adenopathy above and below the diaphragm. An excisional node biopsy showed grade 3A nodular FL. The Ki67 labeling index was 40% to 50%. A bone marrow biopsy showed a small focus of paratrabecular CD20+ lymphoid aggregates. She received 6 cycles of bendamustine (90 mg/m2 on days +1 and +2) and rituximab (375 mg/m2 on day +2), with each cycle delivered every 4 weeks. A follow-up CT scan at completion of therapy showed a partial response with resolution of axillary adenopathy and a dramatic shrinkage of the large retroperitoneal nodes. After 18 months, she had crampy abdominal pain in the absence of B symptoms. Positron emission tomography with 2-deoxy-2 [fluorine-18] fluoro-d-glucose integrated with CT (18F-FDG PET/CT) scan showed widespread adenopathy, diffuse splenic involvement, and substantial marrow involvement. Biopsy of a 2.4-cm right axillary node (SUVmax of 16.1) showed involvement by grade 3A FL with a predominant nodular pattern of growth. A bone marrow biopsy once again showed only a small focus of FL. She received idelalisib (150 mg twice daily) and rituximab (375 mg/m2, monthly) beginning May 2015. After 4 cycles, a repeat CT scan showed a complete radiographic response. Idelalisib was subsequently held while she received corticosteroids for immune-mediated colitis. A month later, she restarted idelalisib with a 50% dose reduction. After 2 weeks, she returned to clinic complaining of bilateral hip and low lumbar discomfort but no B symptoms. A restaging 18F-FDG PET/CT in January 2016 showed dramatic marrow uptake. A bone marrow aspirate showed sheets of tumor cells representing a spectrum from intermediate-sized cells with lymphoblastic features to very large atypical cells with multiple nucleoli. Two distinct histologies were present; one remained consistent with the patient's known FL with a predominant nodular pattern and the other consistent with HT (the large atypical cells expressed PAX5, CD10, BCL2, and c-MYC and were negative for CD20, MPO, CD34, CD30, and BCL6). Focal areas showed faint, heterogeneous expression of terminal deoxynucleotidyl transferase best seen on the clot section. Ki67 proliferation index was high (4+/4). Fluorescence in situ hybridization analysis showed 2 populations with MYC amplification and/or rearrangement and no evidence of BCL6 rearrangement; a karyotype analysis showed a complex abnormal female karyotype with t(14;18) and multiple structural and numerical abnormalities. She started dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with concomitant prophylactic intrathecal methotrexate and cytarabine. She had but a short-lived response before dying in hospice from progressive lymphoma. Whether idelalisib could provide a microenvironment for selection of more aggressive clones needs to be addressed. Our patient's clinical course is confounded by the incorporation of idelalisib while being further complicated by the complexity of HT and the mechanisms in which first-line chemotherapy regimens affect double-hit lymphoma. PMID- 28579853 TI - Kasabach-Merritt Phenomenon: Classic Presentation and Management Options. AB - Kasabach-Merritt phenomenon (KMP) is a rare consumptive coagulopathy associated with specific vascular tumors, kaposiform hemangioendothelioma, and tufted angioma. Kasabach-Merritt phenomenon, characterized by profound thrombocytopenia, hypofibrinogenemia, elevated fibrin split products, and rapid tumor growth, can be life-threatening. Severe symptomatic anemia may also be present. With prompt diagnosis and management, KMP can resolve and vascular tumors have been shown to regress. This review highlights the clinical presentation, histopathology, management, and treatment of KMP associated with kaposiform hemangioendothelioma, and less frequently tufted angioma. A classic clinical case is described to illustrate the presentation and our management of a patient with KMP. PMID- 28579852 TI - Treatment of Myelofibrosis: Old and New Strategies. AB - Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm that is mainly characterised by reactive bone marrow fibrosis, extramedullary haematopoiesis, anaemia, hepatosplenomegaly, constitutional symptoms, leukaemic progression, and shortened survival. As such, this malignancy is still orphan of curative treatments; indeed, the only treatment that has a clearly demonstrated impact on disease progression is allogeneic haematopoietic stem cell transplantation, but only a minority of patients are eligible for such intensive therapy. However, more recently, the discovery of JAK2 mutations has also led to the development of small-molecule JAK1/2 inhibitors, the first of which, ruxolitinib, has been approved for the treatment of MF in the United States and Europe. In this article, we report on old and new therapeutic strategies that proved effective in early preclinical and clinical trials, and subsequently in the daily clinical practice, for patients with MF, particularly concerning the topics of anaemia, splenomegaly, iron overload, and allogeneic stem cell transplantation. PMID- 28579854 TI - Acute Myeloid Leukemia With Inv(16)(p13q22) Associated With Hidden Systemic Mastocytosis: Case Report and Review of Literature. AB - Systemic mastocytosis (SM) is a condition associated with clonal neoplastic proliferation of mast cells. In up to 40% of systemic mastocytosis cases, an associated clonal hematological disease of non-mast cell lineage, such as acute myeloid leukemia (AML), is diagnosed before, simultaneously with, or after the diagnosis of SM. Herein, we report a case of a 30-year-old man diagnosed with AML with inv(16) (p13;q22) CBFB:MYH11. Associated mastocytosis was not noted at diagnosis and was only detected in the bone marrow at time of remission after successful chemotherapy. The diagnosis of mastocytosis was based on the demonstration of a multifocal dense mast cell infiltrate in the marrow biopsy with aberrant immunophenotype, with coexpression of tryptase, CD117, and CD25. The mast cells showed atypical morphology mostly with irregular nuclear contour, bilobed or multilobed nuclei with cytoplasmic hypogranulation or irregular metachromatic granule distribution, and some cells with eccentric nucleus or spindle shape. Reexamination of the pretherapeutic bone marrow with immunostain for tryptase and CD25 revealed that mastocytosis was present from the start but masked by extensive blast proliferation. This case indicates that mast cell infiltrates are sometimes underappreciated at the original diagnosis of AML with inv(16) and that the concurrent diagnosis of SM with AML requires a high index of suspicion supported with comprehensive morphologic and immunohistochemical evaluation for a neoplastic mast cell proliferation. PMID- 28579856 TI - Estimation of Platelet Counts and Other Hematological Parameters in Pseudothrombocytopenia Using Alternative Anticoagulant: Magnesium Sulfate. AB - The platelet count, mean platelet volume, and other hematological parameters were compared in blood samples anticoagulated with MgSO4 and EDTA. A total of 15 samples were taken, and the platelet counts were observed to be significantly high in MgSO4-anticoagulated blood samples ranging from 53 * 103 to 499 * 103/MUL, whereas in EDTA-anticoagulated blood samples, the counts ranged from 10 * 103 to 353 * 103/MUL. This increased platelet count was also statistically significant with the P value being .005. The morphology of red blood cells and white blood cells in Leishman-stained smears from MgSO4-anticoagulated blood was below average. In conclusion, MgSO4 can be used as an alternative anticoagulant only to estimate the platelet counts in EDTA-induced pseudothrombocytopenia. PMID- 28579855 TI - Thromboprophylaxis With Apixaban in Patients Undergoing Major Orthopedic Surgery: Meta-Analysis and Trial-Sequential Analysis. AB - BACKGROUND: Venous thromboembolism (VTE) is a potentially fatal complication of orthopedic surgery, and until recently, few antithrombotic compounds were available for postoperative thromboprophylaxis. The introduction of the non vitamin K antagonists oral anticoagulants (NOAC), including apixaban, has extended the therapeutic armamentarium in this field. Therefore, estimation of NOAC net clinical benefit in comparison with the established treatment is needed to inform clinical decision making. OBJECTIVES: Systematic review to assess the efficacy and safety of apixaban 2.5 mg twice a day versus low-molecular-weight heparins (LMWH) for thromboprophylaxis in patients undergoing knee or hip replacement. DATA SOURCES: MEDLINE, Embase, and CENTRAL were searched from inception to September 2016, other systematic reviews, reference lists, and experts were consulted. STUDY ELIGIBILITY CRITERIA PARTICIPANTS AND INTERVENTION: All major orthopedic surgery randomized controlled trials comparing apixaban 2.5 mg twice daily with LMWH, reporting thrombotic and bleeding events. DATA EXTRACTION: Two independent reviewers, using a predetermined form. STUDY APPRAISAL AND SYNTHESIS METHODS: The Cochrane tool to assess risk bias was used by two independent authors. RevMan software was used to estimate pooled risk ratio (RR) and 95% confidence intervals (95% CI) using random-effects meta analysis. Trial sequential analysis (TSA) was performed in statistical significant results to evaluate whether cumulative sample size was powered for the obtained effect. Overall confidence in cumulative evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group methodology. RESULTS: Four studies comparing apixaban 2.5 mg twice daily with LMWH were included, with a total of 11.828 patients (55% undergoing knee and 45% hip replacement). The overall risk of bias across studies was low. In comparison with LMWH (all regimens), apixaban showed a significantly lower risk of VTE events and overall mortality combined (RR: 0.63, 95% CI: 0.42-0.95, I2 = 84%, n = 8346), but not of major VTE events (RR: 0.62, 95% CI: 0.32-1.19, I2 = 63%, n = 9493), or of symptomatic VTE events and VTE-related mortality combined (RR: 1.14, 95% CI: 0.68-1.90, I2 = 0%, n = 11 879). Trial sequential analysis showed that the risk reduction obtained for VTE and mortality was based on underpowered cumulative sample size and effect dimension. Subgroup analysis according to LMWH regimens showed that apixaban reduced the risk of VTE events and overall mortality, and major VTE events, when compared with LMWH once daily, without differences between apixaban and LMWH twice daily. CONCLUSIONS: There is low to moderate evidence that in patients undergoing knee or hip replacement, apixaban seems equally effective and safe to LMWH twice a day. When compared with LMWH once a day, apixaban seems a superior thromboprophylaxis option. However, the results are underpowered which precludes definite answers regarding the true net clinical benefit of apixaban versus LMWH in this clinical context. PMID- 28579858 TI - Cardiovascular Magnetic Resonance Imaging-Incremental Value in a Series of 361 Patients Demonstrating Cost Savings and Clinical Benefits: An Outcome-Based Study. AB - BACKGROUND: This study was designed to assess the clinical impact and cost benefit of cardiovascular magnetic resonance imaging (CMR). In the face of current health care cost concerns, cardiac imaging modalities have come under focused review. Data related to CMR clinical impact and cost-benefit are lacking. METHODS AND RESULTS: Retrospective review of 361 consecutive patients (pts) who underwent CMR exams was conducted. Indications for CMR were tabulated for appropriateness criteria. Components of the CMR exam were identified along with evidence of clinical impact. The cost of each CMR exam was ascertained along with cost savings attributable to the CMR exam for calculation of an incremental cost effectiveness ratio. A total of 354 of 361 pts (98%) had diagnostic quality studies. Of the 361 pts, 350 (97%) had at least 1 published Appropriateness Criterion for CMR. A significant clinical impact attributable to CMR exam results was observed in 256 of 361 pts (71%). The CMR exam resulted in a new diagnosis in 69 of 361 (27%) pts. Cardiovascular magnetic resonance imaging results avoided invasive procedures in 38 (11%) pts and prevented additional diagnostic testing in 26 (7%) pts. Comparison of health care savings using CMR as opposed to current standards of care showed a net cost savings of $833 037, ie, per patient cost savings of $2308. CONCLUSIONS: Cardiovascular magnetic resonance imaging provides diagnostic image quality in >98% of cases. Cardiovascular magnetic resonance imaging findings have documentable clinical impact on patient management in 71% of pts undergoing the exam, in a cost beneficial manner. PMID- 28579859 TI - Clot in Lung, Clot in Heart: A Case Report of Tumor-Like Thrombus in Right Atrium. AB - Tumor-like formation of thrombus in the right atrial cavity is rare. It may be mistaken for a myxoma. The exact pathophysiology of an isolated thrombus in the heart is still unclear. Management to prevent complications such as pulmonary thromboembolism depends on the clinical judgment of a cardiologist. This report describes a 76-year-old woman with right atrial thrombus causing subsequent pulmonary thromboembolism in right lung. She initially presented to us with pulmonary embolism, and later, an incidental finding of a mass in her right atrium revealed an association of thrombus in heart with thrombus in lung. The challenging management was to resect this thrombus which was fixed to atrial septum, and a trial of anticoagulation did not resolve it. Exact management of such incidental findings in right heart cavities is not well established. Some cases may benefit from resection of such formed fixed thrombus. PMID- 28579857 TI - Toward a Biology-Driven Treatment Strategy for Peripheral T-cell Lymphoma. AB - T-cell and natural killer-cell lymphomas are a relatively rare and heterogeneous group of diseases that are difficult to treat and usually have poor outcomes. To date, therapeutic interventions are of limited efficacy and there is a pressing need to find better treatments. In recent years, advances in molecular biology have helped to elucidate the underlying genetic complexity of this group of diseases and to identify mutations and signaling pathways involved in lymphomagenesis. In this review, we highlight the unique biological characteristics of some of the different subtypes and discuss how these may be targeted to provide more individualized and effective treatment approaches. PMID- 28579860 TI - Distinguishing Motor Weakness From Impaired Spatial Awareness: A Helping Hand! AB - Our patient, aged 73 years, had background peripheral neuropathy of unknown cause, stable for several years, which caused some difficulty in walking on uneven ground. He attended for a teaching session but now staggered in, a new development. He had apparent weakness of his right arm, but there was difficulty in distinguishing motor weakness from impaired spatial awareness suggestive of parietal lobe dysfunction. With the patient seated, eyes closed, and left arm outstretched, S.A.R. lifted the patient's right arm and asked him to indicate when both were level. This confirmed motor weakness. Urgent computed tomographic scan confirmed left subdural haematoma and its urgent evacuation rapidly resolved the patient's symptoms. Intrigued by our patient's case, we explored further and learnt that in rehabilitation medicine, the awareness of limb position is commonly viewed in terms of joint position sense. We present recent literature evidence indicating that the underlying mechanisms are more subtle. PMID- 28579861 TI - Cryptogenic Organizing Pneumonia With Lung Nodules Secondary to Pulmonary Manifestation of Crohn Disease. AB - Crohn disease is an immune-mediated inflammatory condition with gastrointestinal and extraintestinal manifestations in patients. Pulmonary involvement of Crohn disease is one manifestation. There have been case reports which have shown Crohn disease and lung nodules which were noted to be histopathological as cryptogenic organizing pneumonia (COP). In our case, a 22-year-old woman with Crohn disease was seen with complaints of chest pain and cough. Computed tomographic scan of chest showed multiple bilateral lung nodules, for which biopsy was done, which showed COP. The case study is followed by a deeper discussion of COP and the extraintestinal manifestation seen in inflammatory bowel disease. PMID- 28579862 TI - Assessment of Hypogonadism in Men With Type 2 Diabetes: A Cross-Sectional Study From Saudi Arabia. AB - BACKGROUND/OBJECTIVES: A high incidence of hypogonadism in men with type 2 diabetes (T2D) has been globally reported. This study aimed to determining the frequency of hypogonadism and related risk factors among men with T2D in a single site hospital in Saudi Arabia. DESIGN AND METHODS: A cross-sectional study was performed on 157 men with T2D (between 30 and 70 years of age). Using a prestructured questionnaire, the demographic features of these patients were gathered and their medical records were referred to gather information regarding the duration of the diabetes, smoking habits, and the presence of retinopathy, neuropathy, and nephropathy. Besides these, the biochemical parameters, total testosterone (TT), free testosterone, sex hormone-binding globulin, follicle stimulating hormone, luteinizing hormone, prolactin, serum lipids, and glycosylated hemoglobin were also recorded. All the patients submitted the fully completed Androgen Deficiency in Aging Male (ADAM) questionnaire. The combination of symptoms (positive ADAM score) plus a TT level ?8 nmol/L constituted the condition of hypogonadism. RESULTS: The total frequency of hypogonadism was 22.9% (36/157). Of the 157 total patients, 123 (78.3%) were shown to be ADAM positive, and of these, 90 (73.2%) exhibited decreased libido, 116 (94.3%) had weak erections, and 99 (80.5%) reported more than 3 symptoms of ADAM. Of these hypogonadic patients, 22.2% (n = 8) revealed primary hypogonadism, whereas 77.8% (n = 28) showed secondary hypogonadism. From the univariate analysis conducted, significant relationship was observed between treatment type, body mass index (BMI), and hypogonadism. The regression analysis showed BMI acting an independent risk factor of hypogonadism. CONCLUSIONS: Saudi men with T2D revealed a high incidence of hypogonadism. Body mass index was identified as an independent risk factor for hypogonadism. PMID- 28579863 TI - Is Tolerance Broken in Autoimmunity? AB - Autoimmune diseases are classified into about 80 different types based on their specificity related to system, organ and/or tissue. About 5% of the western population is affected by this anomaly, but its worldwide incidence is unknown. Autoimmune diseases are heterogeneous in nature and clinical manifestations range from benign disorders to life-threatening conditions. Autoimmunity strikes at any stage of life, but age and/or gender also play role in onset of some of these anomalies. The autoimmune pathogenesis is initiated by the origination of autoantigens, which leads to the development of autoantibodies followed by auto immunogenicity and the ultimate onset of autoimmunity. There is a lack of suitable therapies to treat autoimmune diseases, because mechanisms involved in the onset of these anomalies were poorly understood. Present therapies are limited to symptomatic treatment and come with severe side effects. Here, I described the molecular mechanisms and cellular events involved in the initiation of autoimmunity and proposed better strategies to modulate such molecular and cellular anomalies, which will help in preventing and/or controlling autoimmune pathogenesis and ultimately aid in enhancing the quality of life. PMID- 28579864 TI - Evaluation of Neonatal Transport in Western Switzerland: A Model of Perinatal Regionalization. AB - Neonatal transport is an essential part of regionalization for highly specialized neonatal intensive care. This retrospective analysis of prospectively collected data on neonatal transport activity in a large Swiss perinatal network more than 1 year, aimed to quantify this activity, to identify the needs for staff, and the demands regarding know-how and equipment. Of the 565 admissions to the tertiary neonatology clinic, 176 (31.2%) were outborn patients, transported as emergencies to the level III unit. In 71.6% of cases, respiratory insufficiency was one of the reasons for transfer. Circadian and weekly distribution showed increased transport activity on workdays between 8 am and 10 pm, but regular demands for emergency transports regardless of the time frame require a neonatal transport team available 24/7. This study highlights the importance of neonatal transport and unveils several functional and infrastructural insufficiencies, which led to suggestions for improvement. PMID- 28579865 TI - Adaptation of Maternal-Fetal Physiology to Exercise in Pregnancy: The Basis of Guidelines for Physical Activity in Pregnancy. AB - Only 50 years ago obstetric care providers and women had many concerns regarding whether exercise during pregnancy created a harmful competition for substrate resources between the fetus and the mother. Animal and human research in the past 50 years, which includes acute and chronic aerobic exercise during pregnancy, has a reassuring margin of safety throughout gestation in women. Maternal physiology adapts to pregnancy changes involving the cardiorespiratory and glucometabolic alterations. Due to these changes, pregnant women have slight differences in response to acute exercise sessions. Chronic exposure to aerobic exercise before and during pregnancy is associated with numerous maternal and neonatal adaptations which may have short- and long-term benefits to maternal and child health. On the basis of the consistent evidence of safety of exercise during pregnancy, multiple nations and health care organizations, including the American College of Obstetrics and Gynecology, recommend moderate exercise for 20 to 30 minutes most days of the week. Despite the 15 to 20 years since the first recommendations were made, only 10% to 15% of pregnant women meet this recommendation. It seems there may be 2 foci for failure to achieve these exercise recommendations: patient specific and culturally driven and/or obstetric provider not recommending regular exercise due to lack of knowledge or motivation. This article addresses the provider knowledge by a review of the normal (at rest) physiologic adaptation to pregnancy. Then, we provide a detailed description of the type and intensity of controlled experiments that document the safety of exercise during pregnancy. The short- and long-term benefits are reviewed, including the safety in moderate-risk women. PMID- 28579867 TI - Health Disparities in Women. AB - Clinical Medicine Insights: Women's Health is an international, open-access, peer reviewed journal which considers manuscripts on all aspects of the diagnosis, management, and prevention of disorders specific to women, in addition to related genetic, pathophysiological, and epidemiological topics. Clinical Medicine Insights: Women's Health aims to provide researchers working in this complex, quickly developing field with online, open access to highly relevant scholarly articles by leading international researchers. In a field where the literature is ever-expanding, researchers increasingly need access to up-to-date, high-quality scholarly articles on areas of specific contemporary interest. This supplement is on Health Disparities in Women. This supplement aims to address this by presenting high-quality articles that allow readers to distinguish the signal from the noise. The editor in chief hopes that through this effort, practitioners and researchers will be aided in finding answers to some of the most complex and pressing issues of our time. PMID- 28579866 TI - Prevalence and Predictors of Hypovitaminosis D Among Female University Students in Tabuk, Saudi Arabia. AB - BACKGROUND: A high hypovitaminosis D prevalence has repeatedly been reported in Middle Eastern countries. Previous data regarding the vitamin D status of young women in Saudi Arabia and the related hypovitaminosis D risk factors are scarce, so this research assessed hypovitaminosis D prevalence and its risk factors among apparently healthy female university students in Tabuk, Saudi Arabia. METHODS: This cross-sectional research used a convenience sample of healthy female students (n = 180) aged between 19 and 25 years in May 2016. Information was gathered on the participants' sociodemographics, health, lifestyle, dietary intakes, anthropometry, and serum 25-hydroxyvitamin D (25(OH)D), and a logistic regression analysis was performed to assess hypovitaminosis D risk factors. RESULTS: The sample's hypovitaminosis D prevalence (25(OH)D <30 ng/mL) was 80.6%. The main determinants of hypovitaminosis D were as follows: urban residence (odds ratio [OR] = 6.54; 95% confidence interval [CI], 2.74-5.63), rare sun exposure (OR = 6.14; 95% CI, 2.15-17.55), and insufficient vitamin D intake (OR = 2.50; 95% CI, 1.07-5.81). CONCLUSIONS: The findings emphasize that despite plentiful sunshine, Saudi Arabia and the Middle East face a vitamin D deficiency epidemic. Vitamin D status must therefore be assessed at the national level so that strategies aimed at boosting vitamin D levels can be instigated. PMID- 28579868 TI - Evidence-Based Brief Obsessive-Compulsive Scale. PMID- 28579870 TI - Tumor necrosis factor alpha Inhibition for Alzheimer's Disease. AB - Tumor necrosis factor alpha (TNF-alpha) plays a central role in the pathophysiology of Alzheimer's disease (AD). Food and Drug Administration approved biologic TNF-alpha inhibitors are thus a potential treatment for AD, but they do not cross the blood-brain barrier. In this short review, we discuss the involvement of TNF-alpha in AD, challenges associated with the development of existing biologic TNF-alpha inhibitors for AD, and potential therapeutic strategies for targeting TNF-alpha for AD therapy. PMID- 28579869 TI - Management of Viral Central Nervous System Infections: A Primer for Clinicians. AB - Viruses are a common cause of central nervous system (CNS) infections with many host, agent, and environmental factors influencing the expression of viral diseases. Viruses can be responsible for CNS disease through a variety of mechanisms including direct infection and replication within the CNS resulting in encephalitis, infection limited to the meninges, or immune-related processes such as acute disseminated encephalomyelitis. Common pathogens including herpes simplex virus, varicella zoster, and enterovirus are responsible for the greatest number of cases in immunocompetent hosts. Other herpes viruses (eg, cytomegalovirus, John Cunningham virus) are more common in immunocompromised hosts. Arboviruses such as Japanese encephalitis virus and Zika virus are important pathogens globally, but the prevalence varies significantly by geographic region and often season. Early diagnosis from radiographic evidence and molecular (eg, rapid) diagnostics is important for targeted therapy. Antivirals may be used effectively against some pathogens, although several viruses have no effective treatment. This article provides a review of epidemiology, diagnostics, and management of common viral pathogens in CNS disease. PMID- 28579872 TI - Medicons: toward clinical examination diagrams standardization in medical documentation. AB - BACKGROUND: Electronic patient records (EPRs) allow efficient and accurate medical documentation. Diagrams have traditionally been used to document clinical signs in patient notes. The interpretation of these diagrams may vary among doctors across a range of specialties, but this has never been tested previously. This study investigated how common diagrams were interpreted and explored the use of digitalized diagrams - Medicons in creating a common language to be used in digital clinical examination proformas. MATERIALS AND METHODS: A cross-sectional survey utilizing a multiple-choice questionnaire was carried out across London hospitals. Seventeen digitalized examination diagrams were included in a multiple choice questionnaire to test doctors' perception and explore their opinions of diagram usage. The questionnaire was sent to junior doctors in training. RESULTS: A total of 206 responses were received from 31 foundation year 1 trainees, 45 foundation year 2 trainees, 94 core surgical trainees and 36 core medical trainees. Diagrams were interpreted correctly, on average, 75% of the time. The majority of doctors (94%) felt that diagrams facilitated the understanding of clinical examination, documentation of pathologic site (98%) and improved the efficiency of documentation (89.8%). All doctors felt that diagrams may benefit overall medical care provision. CONCLUSION: Digitalizing signs and symptoms in EPR will enhance clinical documentation and may contribute to better patient care. New initiatives need to be employed to increase the use of diagrams - Medicons, as young doctors perceived these to improve clinical documentation. Standardized electronic proformas should be included into EPR to improve the efficiency and accuracy of clinical examination documentation. PMID- 28579871 TI - Innovative curriculum for second-year Harvard-MIT medical students: practicing communication skills with volunteer patients giving immediate feedback. AB - PURPOSE: Medical students are expected to develop excellent communication skills. The purpose of our study was to create an innovative communication skills exercise using real volunteer patients and physician co-teachers for students to practice communication skills while receiving immediate feedback. METHOD: This is a mixed methods study where second-year medical students participated in the communication skills exercise with real patients and physician co-teachers giving immediate feedback. Clinical scenarios reflected the patients' actual experiences. Students acted out roles as physicians. Physicians co-taught with the patients and gave immediate feedback to students. Students completed an anonymous written survey at the end of the exercise. Qualitative and quantitative responses were recorded. Student feedback from the 2014 surveys was used to modify the teaching designs to increase active role play opportunities by having only two students in each group and doubling the number of stations with real patients. RESULTS: Students rated the overall exercise and the utility of patient volunteers in learning how to communicate on a Likert scale of 1-5, where in this medical school traditionally 1 is excellent and 5 is poor. In 2014, the exercises were rated with a mean score of 1.47 (SD 0.621). In 2015, the exercises were rated with a mean score of 1.03 (SD 0.62). In 2016, the exercises were rated with a mean score of 1.27 (SD 0.52). ANOVA analysis (p=0.002) and Bonferroni corrections indicate a statistically significant difference between combined mean scores of the exercise in 2014 and 2015 (p=0.001). No difference was shown between 2014 and 2016 or 2015 and 2016. CONCLUSIONS: Medical students rated practicing communication skills with real patient volunteers and physician co teachers giving immediate feedback in their preclinical years very highly. Student feedback indicated that they preferred active roles and increased opportunities to practice their communication skills. PMID- 28579873 TI - Effect of aqueous extract of black pepper and ajwa seed on liver enzymes in alloxan-induced diabetic Wister albino rats. AB - The aim of the present study was to investigate the effects of aqueous extract of black pepper and ajwa seed on liver enzymes in alloxan-induced diabetic Wister albino rats to show the preventive and ameliorating effects in hyperglycemic rats. Rats were divided into 6 groups; normal control rats, diabetic control rats, glibenclamide treated rats, black pepper treated rats, ajwa seed treated rats and black pepper plus ajwa seed treated rats. Hyperglycemia was induced in the treatments groups by a single intraperitoneal injection of alloxan at 150 mg/kg body weight. The extracts were administered via oral incubation, doses were glibenclamide 10 mg/kg, black pepper 50 mg/kg, ajwa seed 500 mg/kg and their mixture 500 mg/kg body weight for a period of 8 weeks. Serum glucose, AST, ALT and ALP were assayed using spectrophotometric method. Results showed that ajwa seed and mixture significantly reduced glucose level. AST level was significantly reduced by mixture treated group. No significant difference was observed between different aqueous extract treated group in ALT and ALP level. The study indicates that black pepper and ajwa seed extract to some extend normalized the glucose and liver enzyme activities in alloxanized diabetic rats. PMID- 28579874 TI - History of Gumboro (infectious bursal disease) in Pakistan. AB - Infectious Bursal Disease is the second important viral disease of poultry which affects the young growing pullets. The end fate appears in huge economic losses to poultry industry. Throughout the world, cheapest source of animal protein is chicken meat. It was initially reported in Europe; soon it spreads worldwide and causes drastic losses. In Pakistan, first of all this disease was reported in 1971. It is the first review to track the IBDV history in Pakistan. It provides comprehensive details of forty-six years researchers work in controlling this important disease. Different scientists worked to fill the gap areas to achieve the goal. Present review covers all the research aspects being explored in Pakistan since first report. PMID- 28579875 TI - Investigation on the immunomodulatory activities of Sarcodon imbricatus extracts in a cyclophosphamide (CTX)-induced immunosuppressanted mouse model. AB - Aims: Sarcodon imbricatus, an edible fungus, is widely used in Asian medicine because of its significant pharmacological activities. In the present study, we investigated the immunomodulatory effects of polysaccharide-enriched S. imbricatus extracts (SP) in cyclophosphamide (CTX)-induced immunosuppressed mice. Results: Astragalus polysaccharide (AP) was used as a positive control. Compared with CTX-induced immunosuppressed mice, thirty-day SP treatment strongly enhanced the organ indexes of spleen and thymus and suppressed hind paw swelling. Both AP and SP increased the serum levels of immunoglobulin (IgA, IgG, and IgM), and suppressed the overproduction of interleukin-2 (IL-2). Moreover, SP reduced methane dicarboxylic aldehyde levels, and increased the total antioxidant capacity, superoxide dismutase, and glutathione peroxidase in both serum and liver tissues of CTX-induced immunosuppressed mice. Conclusion: S. imbricatus extracts significantly improved immune function in CTX-induced immunosuppressed mice via modulation of oxidative systems. PMID- 28579876 TI - Anti-tumor activity of sulfated polysaccharides from Sargassum fusiforme. AB - In this study, our purpose is to discover the correlation between polysaccharides sulfated structure and anti-tumor activity. Sulfated polysaccharide from Sargassum fusiforme were synthesized with the chlorosulfonic acid pyridine method. The inhibitory effect of Sargassum fusiforme polysaccharides and the application of MTT assay before and after chemical modification on the proliferation of hepatocellular carcinoma HepG-2 cells in vitro were studied. Sulfated polysaccharide from sargassum fusiforme DS is 0.803. The modified polysaccharide has certain inhibitory effect on HepG-2 cells, and its inhibition on the cells growth has improved compared with the original SFPs. The sulfated polysaccharide from Sargassum fusiforme has the ability to enhance anti-tumor activities. PMID- 28579877 TI - The application of graphene oxidized combining with decellularized scaffold to repair of sciatic nerve injury in rats. AB - This paper combined the decellularized scaffold of sciatic nerve of rats with graphene oxidized (GO), studied and facilitated the regeneration of sciatic nerve of rats, and provided the basis for the clinical application of nanomaterials. GO was prepared through improving Hammer's Method. Fourier Infrared Spectrum was used to scan and detect the functional groups in GO of sample by using the pellet method, the microcosmic morphological appearance of GO was observed by using the scanning electron microscope. The GO/decellularized scaffold were prepared and operation bridging of injured sciatic nerve was conducted by using the oscillation mixing method. BL-420F Biofunctional Experiment System was used to detect nerve action potential and the maximum tension value of muscles, and the fiber structure of nerve was observed under H-7650 Transmission Electron Microscope (TEM). Scanning electron microscope observed that GO presented a folded and curly single-layer sheet structure. It was soluble in water through ultrasound, brownish, the Fourier Transform Infrared Spectrometer detected the absorption peaks of carbonyl, hydroxy and carboxy, proving that the surface of GO material had many functional groups containing oxygen. Decellularized scaffold combining with GO was applied to repair injury of sciatic nerve, the nerve action potential, maximum tension value of muscle, wet weight value of gastrocnemius, thickness of gastrocnemius, thickness of myelin sheath and diameter of axon of the decellularized scaffold combining with GO group were obviously higher than the decellularized scaffold group and the self-rotating group, approaching to the normal value. All the data were represented by means +/- standard deviation ([Formula: see text]) and processed by adopting SPSS 11.0 software. Comparisons among groups were analyzed by variance, and the comparison of two means was detected by student t. The detection level adopted alpha = 0.05, when P < 0.05, it could be considered that there were significant differences. GO could combine with the biomaterial-decellularized scaffold to repair the injury of sciatic nerve and facilitate the regeneration of injured nerve. This provided new thoughts and theoretical & experimental bases for nanomaterials to be applied to clinic treatment of repair of nerve injury. PMID- 28579878 TI - The effect of different proportions of astragaloside and curcumin on DM model of mice. AB - This paper aims to study the effects of different proportion of astragaloside and curcumin on STZ induced Diabetes Mellitus (DM) model of mice, and to select a better proportion of active components. Its ultimate purpose is to lay a basis for the follow-up research on astragaloside-curcumin capsule. Increase-decrease baseline geometric proportion design method and comprehensive performance evaluation utilised to study the effect of different proportion of astragaloside and curcumin on DM mice models, which have an intravenous tail injection of STZ. The proportions of the two components are 10:0, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, 0:10 respectively. And we will screen out the optimal composition. Blood glycated serum protein (GSP), hepatic glycogen and insulin tested to observe pathological changes in the pancreas. The mice DM model was copied successfully. Compared with the model group, groups treated with the metformin and with different proportions of astragaloside and curcumin help lower the blood glucose levels and GSP levels, increase glycogen stores of model mice by different degrees, and avoid pathological changes of pancreas in the model mice. The ratio of 3:7 was selected as the optimal one, based on the comprehensive performance evaluation method, followed by the ratio of 4:6. The optimal proportion of DM models is 3:7, followed by 4:6. The ratio of total astragaloside and curcumin can lower blood glucose levels, GSP levels, promote the formation of glycogen, and improve the pathological changes of pancreas in the model mice. PMID- 28579879 TI - Sonographic diagnosis and clinical significance of umbilical arterial atresia. AB - To evaluate the feasibility of antenatal sonographic diagnosis of umbilical arterial atresia and its clinical significance. Data of 5 cases with umbilical arterial atresia diagnosed in our hospital were studied retrospectively. The antenatal ultrasonogram of umbilical arterial atresia was obtain, and the pathological examination of umbilical cords and the prognosis of neonates were analyzed. Among 5 cases with umbilical arterial atresia in this group, 1 case with double umbilical arterial atresia was found with dead fetus in uterus, and the rest 4 cases with single umbilical arterial atresia were found with survival fetuses. In the latter 4 cases with live fetus, once umbilical arterial atresia was diagnosed, cesarean section was performed to terminate pregnancy, and the 4 fetus were all healthy. The chromosome karyotypes and S/D value of umbilical arteries were showed normal in all 5 cases. Accurate antenatal diagnosis can be made according to the specific ultrasonogram of umbilical arterial atresia. Instant intervention should be performed upon observing umbilical arterial atresia with live fetus, so as to avoid dead fetus as much as possible. PMID- 28579880 TI - Expression of CD44 standard form and variant isoforms in human bone marrow stromal cells. AB - Human Bone Marrow Stromal Cells (hBMSCs) can migrate from bone marrow to injured tissues, where they may differentiate into different types of new cells for replacement of dysfunctional cells. CD44 plays an important role in stem cell movement. The expression distribution of CD44 standard form (CD44S) and CD44 variants (CD44V) is closely related to cell movement and tissue migration. The aim of this study was to evaluate the expressions of CD44S and CD44V in hBMSCs. The hBMSCs from four human subjects were cultured in vitro. Phenotypic properties were analyzed by flow cytometry, and adipocyte and osteoblast differentiations were evaluated at passage 4. The expressions of CD44S and CD44V were examined using quantitative real-time polymerase chain reaction (q-PCR). Results showed that hBMSCs were successfully cultured, with positive expressions of markers of mesenchymal cells (CD90, CD73, CD105), and negative expressions of markers of hematopoietic cells (CD34, CD45). The cultured hBMSCs can be induced to differentiate into adipocytes and osteoblasts. Q-PCR results showed that the expression of CD44S was significantly higher than the expressions of different CD44V isoforms in different samples. These results revealed significant differences in the distributions of CD44S and CD44V gene expressions, demonstrating a dominant CD44S expression in hBMCSs. PMID- 28579881 TI - Impacts of triamcinolone acetonide on femoral head chondrocytic structures in lumbosacral plexus block. AB - Objective: To investigate impacts of triamcinolone acetonide (TRI) on femoral head chondrocytic (FHC) structures when used for lumbosacral plexus block (LPB). Methods: A total of 32 6-month-old New Zealand white rabbits were selected (averagely weighing 2.75-3.25 kg) and added TRI into nerve block solution for LPB. The rabbit were randomly divided into four groups: group A1: 2.5 ml * 2 times, group A2 2.5 ml * 4 times, group B1 5 ml * 2 times, and group B2 5 ml * 4 times; the time interval among the injection was 5 days, and the structural changes of FHC were the observed using 50/100/200 light microscope; the modified Mankin pathological scoring was also performed for the evaluation. Results: There exhibited significant microscopic changes of FHC structures between the rabbits performed LPB and the normal rabbits, among which group B2 exhibited the most serious FHC damages, and the Mankin pathological score in group B2 was much higher than those in the other three groups, and the scores of the experimental group were higher than the control group. Conclusions: The addition of TRI in LPB can damage the FHC structures, and large-dose (5 ml/once) and long-course (four times) will result in more serious injuries. PMID- 28579883 TI - The intervention effect of different distribution ratio of Astragalus total saponins and curcumin on the DM rats model. AB - Through the study of the effect of different ratio of Astragalus Total Saponins (ATS) and curcumin on Diabetes Mellitu (DM) model rats, we want to improve the screening model of the distribution ratio in Chinese Medicine, screening out the optimal proportion of the prevention and control of DM. By injecting streptozotocin (STZ) in the tail vein of rats to induct the DM rats model, we measured the dynamic change, insulin and insulin antibody (IAA) levels, glycosylated serum protein (GSP) content, lipid metabolism and the changes of renal pathology in DM model rats. The different distribution ratio of ATS and Curcumin can significantly reduce GSP, total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL); significantly increased serum insulin levels and high density lipoprotein (HDL) content, significantly decreased IAA level on the DM rats model induced by STZ. Different proportions of ATS and Curcumin have a good therapeutic effect on DM model rats, and 6:4 is the optimal proportion for the prevention and treatment of DM. PMID- 28579882 TI - The influence of connective tissue growth factor on rabbit ligament injury repair. AB - OBJECTIVES: The injured anterior cruciate ligament (ACL) is deemed to exhibit an impaired healing response and attempts at surgical repair have not been successful. Connective tissue growth factor (CTGF) is reported to be associated with wound healing, probably through transforming growth factor beta1 (TGF beta1). METHODS: A rabbit ACL injury model was used to study the effect of CTGF on ligament recovery. Quantitative real-time PCR was performed for detection of changes in RNA levels of TGF-beta1, type 1 collagen (COL-I), type 2 collagen (COL II), SRY-related high mobility group-box gene9 (Sox9), metalloproteinase-1 (TIMP 1) as well as matrix metallopeptidase 13 (MMP-13). And expression of related proteins was detected by western blotting. RESULTS: The current study showed that CTGF could promote the recovery of inured anterior cruciate ligament. It can up regulate the mRNA and expression of TGF-beta1, COL-I, COL-II, Sox9, as well as the tissue inhibitor of TIMP-1, and down-regulated the mRNA and expression of MMP 13, suggesting the curative effect of CTGF on injured rabbit ligament is through regulating these cellular factors. CONCLUSION: This finding revealed the mechanism of CTFG's healing role in injured tissues and provided new possibilities of treating injured tissues and wound healing by using CTFG. PMID- 28579884 TI - Effect of medicated serum of Curcumae Radix extract on mRNA expression of TIMP-1, MMPs-13 and aI-collagen of HSC-T6 cell. AB - To study the effect of medicated serum of Curcumae Radix (Yujin) on the mRNA expression of Tissue inhibitor of metalloproteinase-1 (TIMP-1), Matrix metalloproteinases-13 (MMPs-13) and aI-collagen of Hepatic stellate cell-T6 (HSC T6) cell. Twenty SD rats were randomly divided into 4 groups: high dose of Yujin group (16.2 g kg-1), medium dose of Yujin group (8.1 g kg-1), low dose of Yujin group (4.05 g kg-1) and blank control group (with the same volume of 0.9% saline). Yujin extract or 0.9% saline were administered daily by gavage to rats for 4d, after once administration of full-day dose for 1 h on the fourth day, ether anaesthesia was given, and blood was taken from abdominal aortic in asepsis condition for preparation of medicated serum. HSC-T6 cells were divided into 5 groups: high dose medicated serum of Yujin group, medium dose medicated serum of Yujin group, low dose medicated serum of Yujin group, medicated serum of blank control group and negative control group (added with the same volume of PBS instead of rat serum), after 48 h of simultaneous acting on HSC-T6 cells in all groups by the medicated serum with a concentration of 10%, the mRNA expression level of TIMP-1, MMPs-13 and aI-collagen was analyzed with RT-PCR. Compared with the negative control group, the mRNA expression level of TIMP-1, MMPs-13 and aI collagen in all experimental groups increased significantly. Compared with the control group, the mRNA expression of aI-collagen and TIMP-1 was obviously inhibited in all medicated serum of Yujin groups (P < 0.01), meanwhile, the mRNA expression level of MMPs-13 was effectively improved (P < 0.05). The medicated serum of Yujin had an effect on the production and degradation of Extracellular matrix (ECM) of HSC-T6 cell. PMID- 28579885 TI - Effect of Gu Tong Xian capsule on expression level of type I, II collagen and BMP 2 mRNA in rabbits with fracture during long-distance running. AB - The study aims to analyze and investigate the effects of Gu Tong Xian Capsule on the expression level of type I, II collagen and BMP-2 mRNA in rabbits with fracture during long-distance running. 60 adult healthy rabbits were selected as research objects, and then randomly divided into three groups including model group, positive control group and treatment group, each containing 20 rabbits. The three groups were treated with saline gastric lavage, powder for fracture and trauma, and Gu Tong Xian capsule, respectively. The rabbits of the three groups were respectively sacrificed at 1st week, 2nd weeks and 4th week after operation for sample collection. After that, the expression levels of bone collagen type I, II and BMP-2 of three groups were measured and compared with each other. At all stages, the transcriptional level of type I collagen mRNA in the treatment group were significantly higher than that in the positive control group and model group (p < 0.05); Transcriptional level of type II collagen mRNA in the treatment group increased significantly in the first week, then gradually declined in the 2nd and 4th week, with significantly difference to the model group and the positive control group (p < 0.05). In addition, the transcriptional level of bone morphogenetic protein BMP-2 mRNA at fracture site of the treatment group was higher than that of model group and positive control group (p < 0.05). Gu Tong Xian Capsule can significantly promote fracture healing of experiment rabbits and reduce fracture healing time. Moreover, it can well regulate the expression levels of type I, II collagen and transcriptional level ofBMP-2 mRNA in experiment rabbits with fracture. PMID- 28579886 TI - D-4F decreases the expression of Abeta protein through up-regulating long non coding RNA sirt1-as in SAMP8 mice. AB - : Cholesterol plays key roles on (Abeta) metabolism and production. D-4F is the apolipoprotein A-I mimetic peptide which has been revealed a critical role in regulation cholesterol. We aimed at identifying the effects of D-4F on Abeta production in SAMP8 and the underlying mechanisms. METHODS: SAMP8 mice (n = 15) were randomized into three groups for treatment with D-4F given in drinking water: high-dose group (0.5 mg/ml), low-dose group (0.3 mg/ml) and control group (just drinking water). The heart, kidney, liver and brain were obtained from SAMP8 (9 of them included in the analysis). The long non-coding RNA sirt1-as was measured in all tissues. The immunohistochemistry, western blot qRT-PCR were performed to determine the sirt1-as and the relevant proteins or RNAs levels. RESULTS: After treated with D-4F, the sirt1-as has been significantly upregulated in brain, rather than heart, kidney or liver. Specially, sirt1-as was significantly up-regulated by high dose of D-4F in the hippocampus area (p = 0.007) compared with control group. Further analysis revealed that D-4F up regulates the expression of SIRT1. We also found that D-4F treatment significantly increased the reverse cholesterol transport related proteins liver X receptor alpha (LXRalpha) and ATP-binding cassette transporter A1 (ABCA1, p < 0.05). Finally, the amyloid beta-protein (Abeta protein) was statistically lower than that in the control group (p < 0.05). CONCLUSION: Our observation indicated that D-4F decreases the expression of Abeta protein through up-regulating long non coding RNA sirt1-as and its downstream proteins which may involve in reverse cholesterol transport. PMID- 28579887 TI - Optimization extraction and bioactivities of polysaccharide from wild Russula griseocarnosa. AB - The extraction conditions and biological activities of polysaccharides from wild Russula griseocarnosa (PRG) were investigated. Response Surface Methodology (RSM) with a Box-Behnken Design (BBD) was used to optimize extraction conditions. The optimal extraction parameters of PRG were as follows: extracting time 4 h, extraction temperature 77.3 degrees C and liquid-solid ratio 42.5 g/L. Furthermore, the data demonstrated that PRG exhibited antioxidant activities evidenced by reducing power to scavenge the DPPH, ABTS, hydroxyl radical and superoxide radical. PRG showed the activity of anti-cervical carcinoma cells Hela and Siha. In conclusion this study offered an efficient extraction method of wild Russula griseocarnosa polysaccharide, and the results suggested PRG had good antioxidant and inhibitory activities against cervical carcinoma cells, and PRG could be developed as a novel natural functional food. PMID- 28579888 TI - Pharmacokinetics of a liposomal formulation of doxorubicin in rats. AB - Background: Measuring free drug concentration following systemic administration of a liposomal drug is a crucial aspect of the assessment of its in vivo behavior. Therefore we require an efficient method to separate free drug in the plasma from encapsulated drug. Objectives: To study the pharmacokinetics of free doxorubicin (DOX) released from liposomal doxorubicin (L-DOX) in rats. Methods: L DOX was prepared with encapsulation efficiency of 90% and was injected intravenously into rats. A solid-phase extraction (SPE) method coupled with UPLC MS/MS was used to measure the concentration of F-DOX in rat plasma without disrupting the integrity of L-DOX. Results: This method exhibited a linear range of F-DOX from 0.2 to 200 ng/mL. Recovery, precision, linearity and accuracy of this technique appear satisfactory for pharmacokinetic study. The constituents of F-DOX ranged from 5.35% to 14.09% of total DOX in plasma at each time point measured after L-DOX administration. Conclusion: SPE method was suitable for studying the pharmacokinetics of F-DOX in rats receiving L-DOX. PMID- 28579889 TI - Phenylethanoid Glycosides of Cistanche on menopausal syndrome model in mice. AB - Cistanche is the traditional and precious Chinese herbal, with two thousand years of use history in China. It has the effect on tonifying kidney, strong supplement to the liver and kidney, and replenishing essence and blood, known as the "desert ginseng". Here, we explored the mechanism of Phenylethanoid Glycosides of Cistanche (PGC) to the model mice of menopausal syndrome, as well as the therapeutic effect and characteristics of PGC to the menopausal syndrome. In this study, KM mice were reproduced by the complete resection of the ovaries on both sides of the back to establish the model mice of menopausal syndrome (MPS), and received distilled water or drugs, respectively. Model mice received distilled water. Mice received 200 mg/(kg day) high doses of Phenylethanoid Glycosides of Cistanche (HPGC), and 100 mg/(kg day) medium doses of Phenylethanoid Glycosides of Cistanche (MPGC), and 50 mg/(kg day) low doses of Phenylethanoid Glycosides of Cistanche (LPGC). After 21 days, it could determine the number of independent activities and the number of standing, the latent period of first entering the dark room, and the electric number. It also calculated the viscera index of uterus, thymus, spleen, measured the levels of estradiol (E2), testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in the serum. Furthermore, it observed the pathological changes of uterus, thymus, spleen and pituitary of mice. The results showed that behavioral indicators: Compared with the model group (MG), HPGC, MPGC, LPGC could increase the independent activities (P < 0.01); HPGC, MPGC could increase the number of standing, the latent period of first entering the dark room, and reduce the electric number (P < 0.01); LPGC could increase the number of standing (P < 0.05); Viscera index: Compared with MG, HPGC, MPGC could increase the viscera index of uterus, thymus, spleen (P < 0.01); LPGC could increase the viscera index of uterus (P < 0.05); Serum index: Compared with MG, all groups could decrease the levels of LH in the serum (P < 0.01); HPGC, MPGC could improve the levels of E2, T and decrease the levels of LH, FSH in the serum (P < 0.01); LPGC could improve the levels of E2 and decrease the levels of FSH in the serum (P < 0.05). Meanwhile, it had the trend to improve the levels of T in the serum. Pathological changes: Compared with MG, HPGC could significant improve the pathological changes of uterus, thymus, spleen and pituitary of mice; other groups also has a certain effect. The results indicated that PGC could improve the sex hormone disorder of MPS, and restore the function of uterus, thymus and spleen, with better therapeutic effect on MPS. PMID- 28579890 TI - The first multiplication atom-bond connectivity index of molecular structures in drugs. AB - In the field of medicine, there are a large number of new drugs synthesis every year. Before entering the clinical stage, it needs a lot of work on drug testing of the various properties. Due to the lack of a large number of laboratory technician, laboratory equipment and reagents, the drug testing of many biochemical properties are not completed. Theoretical medicine provides a theoretical way for medical researchers to obtain the pharmaceutical properties of compounds by calculation tricks. In this paper, the first multiplication atom bond connectivity index of several common drugs structure are studied, and the accurate expressions are determined. These theoretical conclusions provide practical guiding significance for pharmaceutical engineering. PMID- 28579891 TI - Protective effect of chlorogenic acid on the focal cerebral ischemia reperfusion rat models. AB - OBJECTIVE: The aim of the study was to investigate the protective characteristic of chlorogenic acid, a natural glucosyl xanthone found in Lonicera Japonica on the cerebral ischemia reperfusion injury and the underlying mechanism. METHODS: Focal cerebral ischemia reperfusion model was built by blocking the left middle cerebral artery in rats by using the suture-occluded method. Before operation, the corresponding drugs were given for each group once a day for 7 days. After 1 h of final administration, the model was built, after operation, reperfusion was conducted for 22 h, Before the reperfusion 10 min tail vein injection of large, medium and small dose of chlorogenic acid and then mortality was calculated, and Neurological deficit score (NDS) was conducted, and serum was collected to measure the NSE level; a 2 mm thick brain slice located at the intersection of optic nerves was collected for TTC staining, and the percentage of cerebral infarction area was calculated; brain homogenate was collected to measure the ICAM-1, VCAM-1, EPO and HIF-1alpha levels in brain tissue of cerebral ischemia reperfusion rat models; NGF was detected using immunohistochemical method; the morphological changes in brain tissue was observed with HE staining. RESULTS: All focal cerebral ischemia reperfusion rat models were duplicated successfully. Every chlorogenic acid group with different dosage can significantly reduce the mortality, NDS and cerebral infarction area of rats, and significantly increase the EPO, HIF-1alpha and NGF levels in brain tissue; significantly improve the pathological lesions of hippocampus and cortex in brain tissue. CONCLUSION: The results showed that chlorogenic acid could protect the focal cerebral ischemia reperfusion injury rat models by adjusting the inflammatory factor, hypoxia factor and nerve growth factor. PMID- 28579892 TI - The effects of low-molecular-weight heparin on lung and pulmonary artery injuries in acute pulmonary embolism rat model via platelet-derived growth factor-beta. AB - OBJECTIVE: To evaluate the effects of anticoagulant agent (low-molecular-weight heparin, LMWH) on the pulmonary artery intima hyperplasia of rats with acute pulmonary embolism (APE) by assaying platelet-derived growth factor-beta (PDGF beta). METHODS: A total of 90 Sprague-Dawley rats were randomly assigned into the sham, APE, and LMWH groups with 30 rats in each group. The APE rat models were established by injecting autologous blood clots via external jugular veins. In each group, six mice were sacrificed at the 1st day (D1), 4th day (D4), 7th day (D7), 14th day (D14), and 28th (D28) subsequent to the induction of APE to collect the lungs. Right ventricle pressure (RVP) and mean pulmonary arterial pressure (mPAP) were measured. Western blot and RT-PCR analyses were used to assess PDGF-beta expression at various time points. In addition, changes in lung pathology were evaluated using hematoxylin and eosin (H&E) staining and electron microscope. RESULTS: The overall success rate of establishing APE rat models was 85.7% (60/70). There was no difference in mPAP between the sham group and the APE group at the D1, D4, D7, and D14. However, at the D28, mPAP in the APE group was significantly higher than that in the sham group. There was no difference among the three groups regarding RVP. PDGF-beta expression were decreased in the LMWH group at all time points compared with the sham and APE groups (P < 0.01). Furthermore, pulmonary embolism, alveolar wall necrosis and hemorrhage, and inflammation were significantly attenuated in the LMWH group compared with the sham and APE groups subsequent to the induction of APE. CONCLUSION: LMWH attenuates lung and pulmonary artery injuries and improves prognosis. Decreased PDGF-beta in the lungs may be the important factor in the effects observed. PMID- 28579893 TI - Melatonin alleviates acute spinal cord injury in rats through promoting on progenitor cells proliferation. AB - The previous studies have shown that melatonin is beneficial for nervous system after spinal cord injury (SCI). After SCI, the endogenous neural stem/progenitor cells (eNSPCs) proliferate and differentiate into neurons and glial cells. In the present study, we examined the effect of melatonin on eNSPCs proliferation and differentiation in SCI rat model. SCI rat model was established by dropping a 10 g rod from the height of 25 mm. Then, the rats were randomly divided into the control group, the melatonin treated group, and the G3335 treated group. The Basso-Beattie-Bresnahan locomotor rating scale (BBB scale) was used to evaluate the recovery of locomotor function after SCI. Flow cytometry was used to evaluate eNSPCs proliferation and differentiation. The rats in the melatonin treated group demonstrated significantly faster locomotor function recovery and more eNSPCs proliferation and differentiation. However, these effects were abolished in the G3335 treated group. Melatonin can effectively promote locomotor function recovery via improving eNSPCs proliferation and differentiation after SCI. PMID- 28579894 TI - Osteogenic differentiation of bone marrow mesenchymal stem cells by magnetic nanoparticle composite scaffolds under a pulsed electromagnetic field. AB - This study was conducted to investigate the effect of magnetic nanoparticle composite scaffold under a pulsed electromagnetic field on bone marrow mesenchymal stem cells (BMSCs), which was achieved by examining the biological behaviors of cell adhesion, proliferation and differentiation on the surface of the scaffolds. This may provide some experimental evidence for the use of magnetic nanoparticles in medical application. The magnetic nanoparticle composite scaffolds were evaluated and characterized by the following indexes: the cell proliferation was detected by the CCK-8 method, the alkaline phosphatase (ALP) activity was examined by a detection kit, and the expression of type I collagen and osteocalcin gene were evaluated by RT-PCR. The CCK-8 test showed that there was no significant difference in Group A (BMSCs-seeded magnetic scaffolds under the electromagnetic field), B (BMSCs-seeded magnetic scaffolds) and C (BMSCs cultured alone) (P > 0.05). The value for the ALP activity in Group A was higher than the other two groups. In addition, the RT-PCR results showed that the expression of type I collagen gene in Group A was enhanced (P < 0.05), suggesting that the magnetic nanoparticles combined with the pulsed electromagnetic field had a positive effect on the osteogenic differentiation of BMSCs. However, the expression of osteocalcin was not significantly different in three groups (P > 0.05). To conclude, magnetic nanoparticles may induce the osteogenic differentiation with the action of the pulsed electromagnetic field. PMID- 28579895 TI - Characteristics studies of molecular structures in drugs. AB - In theoretical medicine, topological indices are defined to test the medicine and pharmacy characteristics, such as melting point, boiling point, toxicity and other biological activities. As basic molecular structures, hexagonal jagged rectangle and distance-regular structure are widely appeared in medicine, pharmacy and biology engineering. In this paper, we study the chemical properties of hexagonal jagged-rectangle from the mathematical point of view. Several vertex distance-based indices are determined. Furthermore, the Wiener related indices of distance-regular structure are also considered. PMID- 28579896 TI - The cytoprotective effects of Delta-17 fatty acid desaturase on injured HUVECs and its underlying mechanism. AB - Endothelium toxicity has been involved in early endothelial dysfunction to show the pathogenesis of multiple cardiovascular disease that shows atherosclerosis and its complications. Saturated free fatty acids are the main inducing factors of endothelial cell apoptosis and inflammatory cytokines. In humans, stearoyl-CoA desaturase 1 (SCD-1) is a restriction step to saturation to unsaturated fatty acid desaturation, which plays a beneficial role protecting endothelial cells against lipotoxicity. Delta-17 fatty acid desaturase (FAD) is a newly identified FAD which shares 55% identity at the amino acid level with SCD-1. Whether Delta 17 FAD has similar beneficial effect remains poorly understood. Oxidized low density lipoprotein (ox-LDL) was used to induce lipotoxicity in human umbilical vein endothelial cells (HUVECs) to establish a model of oxidative injury. Then HUVECs were transfected with FAD lentivirus to introduce cytoprotective effects. The alterations in cell proliferation and apoptosis, nitric oxide content, malonyldialdehyde (MDA) content, SOD enzyme content, LDH content, GSH-PX level, vascular growth factor (VEGF) expression were evaluated. Studies showed that ox LDL-induced excess HUVEC apoptosis can be abrogated by upregulation of Delta-17 FAD. The nitric oxide content, GSH-PX content, and SOD enzyme content were increased and the activity of MDA was suppressed by upregulation of Delta-17 FAD. In addition, upregulation of Delta-17 FAD significantly increased VEGF expression. In vitro tube formation assay showed that Delta-17 FAD promoted angiogenesis to a significant degree. These results suggest that Delta-17 fatty acid desaturase may have beneficial action in the prevention of ox-LDL-induced cellular damage. PMID- 28579897 TI - TSA protects H9c2 cells against thapsigargin-induced apoptosis related to endoplasmic reticulum stress-mediated mitochondrial injury. AB - : Endoplasmic reticulum stress (ERS) activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. Recently, TSA has shown protective effects on ERS and its mechanisms related to ER pathway has been previously characterized. However, whether TSA exerts its protective role via metabolic events remain largely undefined. Objectives: To explore the possible involvement of the metabolic changes during ERS and to better understand how TSA influence mitochondrial function to facilitate cellular adaptation. Results: TSA is an inhibitor of histone deacetylase which could significantly inhibit H9c2 cell apoptosis induced by Thapsigargin (TG). It also intervene the decrease of mitochondrial membrane potential. By immunofluorescence staining, we have shown that GRP78 was concentrated in the perinuclear region and co-localized with ER. However, treatments with TG and TSA could let it overlap with the mitochondrial marker MitoTracker. Cellular fractionation also confirmed the location of GRP78 in mitochondrion. CONCLUSIONS: TSA decreases ERS-induced cell apoptosis and mitochondrial injury may related to enhance the location of GRP78 in mitochondrion. PMID- 28579898 TI - Effect of Motherwort total alkaloids on the prostate hyperplasia mice model of pathological changes of related tissue morphology induced by the fetal urogenital sinus implants. AB - AIM: The research was to study the effect of Motherwort total alkaloids on the prostate hyperplasia mice model of pathological changes of related tissue morphology. RESULTS: Compared with the model group(MG), Motherwort total alkaloid high, medium dose group(HD, MD) could significantly reduced the pathological changes of the prostate (P < 0.01); Finasteride(FG) and Motherwort total alkaloid low dose group(LD) could significantly reduce the pathological changes of the prostate (P < 0.05); Longbishu capsules(LG), Finasteride, Motherwort total alkaloid medium dose group could significantly reduce the pathological changes of the kidney (P < 0.01); Motherwort total alkaloid low dose group could significantly reduce the pathological changes of the kidney (P < 0.05); Motherwort total alkaloids could improve the pathological changes of the thymus and spleen. CONCLUSION: Motherwort total alkaloid can improve the pathological changes of prostatic hyperplasia in mice. PMID- 28579899 TI - Effects of the Rabdosia rubescens total flavonoids on focal cerebral ischemia reperfusion model in rats. AB - The effect of the Rabdosia rubescens total flavonoids on focal cerebral ischemia reperfusion model in rats was observed. The model group, nimodipine group, cerebral collateral group, and large, medium and small dose group of the Rabdosia rubescens total flavonoids were administered with corresponding drugs but sham operation group and model group were administered the same volume of 0.5%CMC, 1 times a day, continuous administration of 7 d. After 1 h at 7 d to medicine, left incision in the middle of the neck of rats after anesthesia, we can firstly expose and isolate the left common carotid artery (CCA), and then expose external carotid artery (ECA) and internal carotid artery (ICA). The common carotid artery and the external carotid artery are ligated. Then internal carotid artery with arterial clamp is temporarily clipped. Besides, cut the incision of 0.2 mm from 5 cm of the bifurcation of the common carotid artery. A thread Line bolt is inserted with more than 18-20 mm from bifurcation of CCA into the internal carotid artery until there is resistance. Then the entrance of the middle cerebral artery is blocked and internal carotid artery is ligated (the blank group only exposed the left blood vessel without Plugging wire). Finally it is gently pulled out the plug line after 2 h. Results: Compared with the model mice, Rabdosia rubescens total flavonoids can significantly relieve the injury of brain in hippocampus and cortex nerve cells; experimental rat focal cerebral ischemia was to improve again perfusion model of nerve function defect score mortality; significantly reduce brain homogenate NOS activity and no content, MDA, IL-1, TNF a, ICAM-1 content; increase in brain homogenate SOD and ATPase activity (P < 0.05, P < 0.01); and reduce the serum S-100beta protein content. Each dose group of the Rabdosia rubescens total flavonoids has a better Improvement effect on focal cerebral ischemia reperfusion model in rats. PMID- 28579901 TI - Acitretin modulates HaCaT cells proliferation through STAT1- and STAT3-dependent signaling. AB - Acitretin has been a valuable option for the treatment of psoriasis, however, the molecular events of acitretin leading to the normalization of keratinocytes differentiation on psoriasis patients have not been fully explored. To investigate whether there were certain relationship between keratinocytes proliferation and JAK/STAT signaling pathways in psoriasis, and how acitretin modulated the signaling pathways. HaCaT cells, an in vitro immortal human keratinocyte cell line, was chosen as a in vitro model of psoriasis. The small interfering RNA targeting STAT1 (siRNA-STAT1) and STAT3 (siRNA-STAT3) were subsequently transfected into the HaCaT cells which were treated with or without acitretin. We found that HaCaT cells proliferation and the expression of STAT1 or STAT3 were inhibited by acitretin, siRNA-STAT1 and siRNA-STAT3. Our experimental data shows that acitretin might inhibit HaCaT cells proliferation in psoriasis by decreasing the expression of STAT- and STAT3-dependent mechanism. PMID- 28579900 TI - Imperatorin protects H9c2 cardiomyoblasts cells from hypoxia/reoxygenation induced injury through activation of ERK signaling pathway. AB - BACKGROUND: Imperatorin is a compound found in plants and has been widely used in Chinese medicine for many years. It has many pharmacological effects, including the recently reported anti-apoptotic function, however, the mechanism largely remains unclear. This study is aimed to elucidate the mechanism of Imperatorin's anti-apoptotic function. METHODS: A model of hypoxia and reoxygenation (H/R) treated h9c2 cardiomyoblasts was successfully constructed. The cells were treated with H/R condition, and followed by adding Imperatorin alone, Imperatorin with ERK inhibitor and/or ERK inhibitor alone, to examine the cell viability by Cell Counting Kit-8 assay, cell apoptosis rate by flow cytometry, and ERK expression by Western-blot under different conditions. RESULTS: The results showed that imperatorin exerted protective effect on h9c2 cells from H/R injure. It was also found that it not only increased cell viability but also reduced the apoptotic rate for H/R treated h9c2 cells. The experiments also demonstrated that imperatorin could upregulate the expression levels of both ERK1 and ERK2, which is a key step in ERK signaling pathway activation. CONCLUSIONS: These findings provided evidence that imperatorin could increase the cell viability and lower apoptotic rate in H/R treated h9c2 cells, and could also enhance the expression of ERK1/ERK2, demonstrating imperatorin's protective effect on H/R injured h9c2 cells through ERK signaling pathway. PMID- 28579902 TI - Polysaccharide extracted from Chinese white wax scale ameliorates 2,4 dinitrochlorobenzene-induced atopic dermatitis-like symptoms in BALB/c mice. AB - Atopic dermatitis (AD) is a common inflammatory skin disease with high rates of morbidity and is associated with erythema, pruritus, scaling of affected areas of skin. It is extremely important to introduce a therapeutic agent which has significant anti-inflammatory effect with less side-effect for treatment of AD. This study evaluated the effect of a natural compound from herbal extracts, the crude polysaccharide extracted from the white wax scale (CWPS), on AD-like mice. Repeated applications of 2,4-dinitrochlorobenzene (DNCB) were performed on ear and dorsal skin of BALB/c mice to induce AD-like symptoms and skin lesions. Oral administration of CWPS decreased serum IgE level and limited the infiltration of mast cells and eosinophils to the dermal tissues in the DNCB-induced AD mice. In addition, CWPS reduced Th1 and Th17 responses, leading to an attenuated cutaneous inflammatory response. Furthermore, in vitro study also demonstrated that CWPS limited T cell activation and cytokines (i.e. IFN-gamma and IL-17) production induced by DNCB. We conclude that CWPS attenuates DNCB-induced AD-like skin lesion through modulating T cell-elicited immune responses and CD4+ T cell polarization, and could be exploited as a new therapeutic approach for AD. PMID- 28579903 TI - Study on apoptosis effect of human breast cancer cell MCF-7 induced by lycorine hydrochloride via death receptor pathway. AB - As research was conducted on the early apoptosis of human breast cancer cell MCF 7 caused by lycorine hydrochloride and the expression of the related apoptosis proteins. The early-period apoptosis rate of human breast cancer cell MCF-7 was tested with the AnnexinV/PI double staining and flow cytometry. The Western Blotting method was also used to detect the protein expression conditions of Fas, FasL, Caspase-8 and Bid. The results showed that the higher the dose, the higher the rate of apoptosis and that the rate of apoptosis was dependent on the dose; the relative protein activity of Fas, FasL, Caspase-8 and bid gradually rose with the increase of lycorine dosage and the activities revealed certain dose independence. Results showed that lycorine hydrochloride could induce the apoptosis of human breast cancer cell MCF-7 through the death receptor pathway. PMID- 28579904 TI - Oridonin inhibits breast cancer growth and metastasis through blocking the Notch signaling. AB - BACKGROUND: Oridonin is a diterpenoid isolated from Rabdosia rubescens with potent anticancer activity. The aim of our study is to investigate the role of oridonin to inhibit growth and metastasis of human breast cancer cells. METHODS: The effect of oridonin on proliferation was evaluated by MTT assay, cell migration and invasion were evaluated by transwell migration and invasion assays in human breast cancer cells. The inhibitive effect of oridonin in vivo was determined by using xenografted nude mice. In addition, the expression of Notch receptors (Notch 1-4) was detected by western blot. RESULTS: Oridonin inhibited human breast cancer cells in vitro and in vivo. In addition, oridonin significantly induced human breast cancer cells apoptosis. Furthermore, the oridonin treatment not only inhibited cancer cell migration and invasion, but more significantly, decreased the expression of Notch 1-4 protein. CONCLUSION: Our results suggest that the inhibitive effect of oridonin is likely to be driven by the inhibition of Notch signaling pathway and the resulting increased apoptosis. PMID- 28579905 TI - Effects of Fuzheng Paidu tablet immunization on AIDS BALB/c mice. AB - AIM: To establish a Friend murine leukemia virus (FLV)-induced immunodeficient BALB/C mouse model and investigate the effects of Fuzheng Paidu tablets on the body weight, thymus, spleen, and CD4+ and CD8+ T lymphocytes of FLV-infected mice. FLV was passaged twice in BALB/c mice. The infected mice were divided into six groups of ten mice based on their weights. The groups included the normal control group; virus control group; AZT group; high- (2.8 g/kg), medium- (1.4 g/kg), and low-dose (0.7 g/kg) Fuzheng Paidu tablet groups; and Fuzheng Paidu decoction (10 g/kg) group. The mice were administered Fuzheng Paidu tablets via gavage for 21 days. The body weight and changes in the thymus, spleen, and CD4+ and CD8+ T lymphocytes of each mouse were measured. RESULTS: The splenic weight of the virus control group is significantly higher than that of the normal control group, with significant splenomegaly. In addition, the splenic inhibition indices of the AZT group and the high- and medium-dose Fuzheng Paidu tablet groups were approximately 93.80%, 37.80%, and 28.07%, respectively. Furthermore, the high and medium dose Fuzheng Paidu tablets could increase the thymus weights of the infected mice. CONCLUSION: Fuzheng Paidu tablets could inhibit splenomegaly, lower the splenic indices, and increase the thymic weights and thymic indices of FLV-induced immunodeficient mice. PMID- 28579906 TI - Dexmedetomidine attenuates neuropathic pain in chronic constriction injury by suppressing NR2B, NF-kappaB, and iNOS activation. AB - The effective treatment of patients suffering from neuropathic pain remains challenging. Dexmedetomidine (DEX) possesses anti-inflammatory activity. However, the role of DEX in neuropathic pain is still unclear. The aim of the present study was to examine DEX an alpha2-adrenoceptor agonist could improve pain hypersensitivity and reduce inflammatory in a chronic constriction injury (CCI) model of the sciatic nerve in Sprague-Dawley rats. Dex was intrathecally administrated 1-h after operation. The paw mechanical withdrawal threshold (MWT) and paw withdrawal thermal latency (PWTL) were measured on day 1 before operation and on days 1, 7, 14 and 21 after operation, respectively. On day 21, all the rats were decapitated to collect the L4-6 segments of the spinal cord to examine IL-1, TNF-alpha, IL-6, NR2B, NF-kappaB, and iNOS mRNA levels using RT-PCR. The postoperative MWT and PWTL were significantly decreased in CCI, and DEX groups as compared to those before surgery and Sham group (P < 0.05). And DEX reversed this trend (P < 0.05). Interleukin 1 (IL-1), tumor necrosis factor alpha (TNF-alpha), IL-6 mRNA expression significantly increased postsurgery in CCI group as compared to that of Sham group (P < 0.05); DEX blocked increased IL-1, TNF-alpha, IL-6, N methyl-D-aspartate (NMDA) receptor 2B (NR2B), nuclear factor kappaB (NF-kappaB), and inducible isoform of nitric oxide synthase (iNOS) mRNA levels (P < 0.05). DEX may alleviate neuropathic hypersensitivity and inflammation partially by inhibiting NR2B, NF-kappaB, and iNOS expression in the spinal cord of rats with neuropathic pain resulting from CCI of the sciatic nerve. PMID- 28579907 TI - The comparative study of clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury. AB - In the present study we compared the clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury. A total of 150 patients were enrolled in the present study and were divided into two groups with 75 patients in each group, receiving baclofen or tolperisone, respectively. We used Modified Ashworth Scale, Medical research council scale, Barthel Index, and Coefficient of efficacy to measure clinical efficacy. After 6-week treatment, both groups demonstrated significant improvement in muscle tone, muscle strength and functional outcome (Group I, 1.55 +/- 0.053, 2.79 +/- 0.032, 59.31 +/- 1.32; Group II, 1.57 +/- 0.053, 3.04 +/- 0.032, 73 +/- 1.32 respectively). There was no significant difference regarding improvement in muscle tone and muscle strength between the two groups (Group I, 1.055 +/- 0.053 vs Group II, 1.57 +/- 0.053; Group I, 2.79 +/- 0.032 vs Group II, 3.04 +/- 0.032, p > 0.05). However, the improvement in functional outcomes was greater in group II as compared to that in group I (Group I, 59.31 +/- 1.32 vs Group II, 73 +/- 1.32, p < 0.05). In addition, overall efficacy coefficient was greater for group II as compared to group I (Group I, 3.6 vs Group II, 2.3, p < 0.05). Group I had more side effects compared to Group II. Compared to baclofen, tolperisone offers greater improvement in activities of daily living compared to baclofen. PMID- 28579908 TI - Effect of different component ratio of Astragalus total saponins and Verbena total glycosides on the cerebral infarction area and serum biochemical indicators in the focal cerebral ischemia-reperfusion rat model. AB - Our purpose is to study the effect of different component ratio of Astragalus Total Saponins (ATS) and Verbena Total Glycosides (VTG) on the cerebral infarction area and the serum biochemical indicators in the focal cerebral ischemia-reperfusion rat model. Compared with the model group, different component ratio of ATS and VTG could significantly improve the neurological deficit scores to the focal cerebral ischemia-reperfusion rat model, and the group of 7:3, 6:4, 5:5 got the best results; it could reduce the mortality of rat model to a certain extent, and the group of 5:5 group got the best results; it can significantly reduce the cerebral infarction area, and the group of 7:3, 5:5, 4:6 got the best results; it could significantly reduce the content of TNF-alpha, and the group of 8:2, 6:4 got the best results; it could significantly reduce the content of NO, and the group of 7:3, 5:5 got the best results; it could significantly increase the content of SOD, and the group of 6:4, 5:5 got the best results. This indicates that different component ratio of ATS and VTG may protect the damage of focal cerebral ischemia-reperfusion rat model to a certain extent, which are compared using the comprehensive weight method and the ratio of 5:5 was proved to be the optimal active ratio. PMID- 28579909 TI - The alleviative effects of metformin for lipopolysaccharide-induced acute lung injury rat model and its underlying mechanism. AB - For patients who have sepsis, acute lung injury (ALI) causes most of death. Metformin (Met) is an anti-hyperglycemic agent and it has extensive pharmacological properties. This study aimed to analyze the influence of Met on lipopolysaccharide (LPS) -induced ALI. Met (1, 2, and 4 mg/kg) were injected and LPS was injected 30 min later. The data suggested Met can reduce release of inflammatory cytokines and bronchoalveolar lavage fluid (BALF) protein expression, reduce lung wet/dry ratio, and significantly improve LPS-induced lung destruction during ALI. In addition, Met inhibits LPS-induced neutrophil and macrophage infiltration, reduces MPO activity, and promotes AMPK-alpha1 expression in lung tissues. Our data suggested that metformin alleviates capillary injury during ALI via AMPK-alpha1. PMID- 28579910 TI - Influence of biological, experiential and psychological factors in wine preference segmentation. AB - BACKGROUND AND AIMS: We sought to determine the influence of selected biological, experiential and psychological variables on self-reported liking and consumption of wine in a sample of 329 Ontario wine consumers. METHODS AND RESULTS: Cluster analysis revealed three distinct groups, representing plausible market segments: wine lovers; dry table wine likers/sweet dislikers; and sweet wine likers/fortified dislikers. These groups differ in level of wine expertise, wine adventurousness, alcohol intake, bitterness from 6-n-propylthiouracil (PROP), and several demographic variables. PROP hypo-tasters (n=113) and PROP hyper-tasters (n=112) differed in liking scores for nine of the 11 wine styles [ANCOVA, P(F)<0.05]. When wines were grouped according to their dominant sensory properties (dry, sweet, carbonation and heat), liking scores for PROP hyper tasters were higher than those of PROP hypo-tasters for all classes. Scores also varied with age, expertise and gender for some products. Effect sizes (eta squared) were generally greatest for age, and those for PROP responsiveness were of similar magnitude as those for gender. As expected, wine consumption frequency was higher for men and experts, and increased with age. CONCLUSIONS: Age is the most robust and consistent driver of wine liking and intake of the variables examined. Taste phenotype also contributes significantly to variation in wine liking. SIGNIFICANCE OF THE STUDY: Ontario wine consumers fall into one of three wine liking clusters, which differ in experiential, biological, psychological and demographic features that can be targeted through branding and marketing strategies. PMID- 28579911 TI - Impact of the Lymphatic Filariasis Control Program towards elimination of filariasis in Vanuatu, 1997-2006. AB - BACKGROUND: Lymphatic filariasis (LF) occurs when filarial parasites are transmitted to humans through mosquitoes. The filarial worms affect the lymphatic system which leads to abnormal enlargement of body parts, chronic pain, disability, and social discrimination. In 1999, a commitment was made to eliminate LF from the Pacific Region by 2010. The Pacific Program to Eliminate LF began, with Vanuatu being one of the 16 endemic countries included in this program. METHODS: In 1997/1998 a LF prevalence baseline survey was conducted to determine the need for mass drug administration (MDA) in Vanuatu. In 1999, the Vanuatu Lymphatic Filariasis Control Program was established, and nationwide MDA was implemented from 2000 to 2004. LF prevalence was collected during the MDA through sentinel site and spot check surveys, and after 5 years of MDA. MDA implementation methods included health worker training, social mobilization, and culturally appropriate health promotion strategies. RESULTS: LF prevalence at baseline was 4.79%; after MDA this declined to 0.16% in 2005/2006. Average MDA coverage ranged from 75.5-81.5% across 5 years. All three evaluation units surveyed in 2005/2006 were below the 1% threshold required to stop MDA. CONCLUSIONS: The LF Control Program between 1997 and 2006 was successful in reducing LF prevalence to <1%. High MDA coverage was a critical component of this success. This period of the Vanuatu LF Control Program played an important role in helping to eliminate LF in Vanuatu. PMID- 28579912 TI - Interaction of bilingualism and Attention-Deficit/Hyperactivity Disorder in young adults. AB - One hundred and sixty-eight young adult participants were classified as monolingual or bilingual and as having a previously reported clinical diagnosis of ADHD or not to create four groups. All participants completed tests of language proficiency, ADHD ratings, and executive control. Both bilingualism and ADHD are generally associated with poorer vocabulary knowledge, but bilingualism and ADHD are associated with opposite effects on executive control. Consistent with this literature, bilinguals performed more poorly than monolinguals on the vocabulary test but contrary to predictions, the ADHD group performed somewhat better on language ability than the non-ADHD group, attesting to their high functioning status. For the flanker task, both bilinguals and non-ADHD participants showed less cost in performing in the conflict condition than in the baseline condition. For the stop-signal task, ADHD status interfered more with performance by bilinguals than monolinguals, suggesting a greater burden of ADHD on executive function for this group. PMID- 28579913 TI - RAS pathway biomarkers for breast cancer prognosis. AB - Metastatic breast cancer is a highly heterogeneous, rapidly evolving and devastating disease that challenges our ability to find curative therapies. RAS pathway activation is an understudied research area in breast cancer. EGFR/RAS pathway activation is prevalent in breast cancer with poor prognosis. The prognostic RAS pathway biomarkers can be used to identify resistant tumour clones, stratify patients and guide therapies. PMID- 28579915 TI - Microbiome variation in corals with distinct depth distribution ranges across a shallow-mesophotic gradient (15-85 m). AB - Mesophotic coral ecosystems (MCEs) are generally poorly studied, and our knowledge of lower MCEs (below 60 m depth) is largely limited to visual surveys. Here, we provide a first detailed assessment of the prokaryotic community associated with scleractinian corals over a depth gradient to the lower mesophotic realm (15-85 m). Specimens of three Caribbean coral species exhibiting differences in their depth distribution ranges (Agaricia grahamae, Madracis pharensis and Stephanocoenia intersepta) were collected with a manned submersible on the island of Curacao, and their prokaryotic communities assessed using 16S rRNA gene sequencing analysis. Corals with narrower depth distribution ranges (depth-specialists) were associated with a stable prokaryotic community, whereas corals with a broader niche range (depth-generalists) revealed a higher variability in their prokaryotic community. The observed depth effects match previously described patterns in Symbiodinium depth zonation. This highlights the contribution of structured microbial communities over depth to the coral's ability to colonize a broader depth range. PMID- 28579914 TI - Hydrogen generation by reaction of Si nanopowder with neutral water. AB - Si and its oxide are nonpoisonous materials, and thus, it can be taken for medical effects. We have developed a method of generation of hydrogen by use of reactions of Si nanopowder with water in the neutral pH region. Si nanopowder is fabricated by the simple bead milling method. Si nanopowder reacts with water to generate hydrogen even in cases where pH is set at the neutral region between 7.0 and 8.6. The hydrogen generation rate strongly depends on pH and in the case of pH 8.0, ~55 ml/g hydrogen which corresponds to that contained in approximately 3 L saturated hydrogen-rich water is generated in 1 h. The reaction rate for hydrogen generation greatly increases with pH, indicating that the reacting species is hydroxide ions. The change of pH after the hydrogen generation reaction is negligibly low compared with that estimated assuming that hydroxide ions are consumed by the reaction. From these results, we conclude the following reaction mechanism: Si nanopowder reacts with hydroxide ions in the rate determining reaction to form hydrogen molecules, SiO2, and electrons in the conduction band. Then, generated electrons are accepted by water molecules, resulting in production of hydrogen molecules and hydroxide ions. The hydrogen generation rate strongly depends on the crystallite size of Si nanopowder, but not on the size of aggregates of Si nanopowder. The present study shows a possibility to use Si nanopowder for hydrogen generation in the body in order to eliminate hydroxyl radicals which cause various diseases. PMID- 28579916 TI - Kilonovae. AB - The mergers of double neutron star (NS-NS) and black hole (BH)-NS binaries are promising gravitational wave (GW) sources for Advanced LIGO and future GW detectors. The neutron-rich ejecta from such merger events undergoes rapid neutron capture (r-process) nucleosynthesis, enriching our Galaxy with rare heavy elements like gold and platinum. The radioactive decay of these unstable nuclei also powers a rapidly evolving, supernova-like transient known as a "kilonova" (also known as "macronova"). Kilonovae are an approximately isotropic electromagnetic counterpart to the GW signal, which also provides a unique and direct probe of an important, if not dominant, r-process site. I review the history and physics of kilonovae, leading to the current paradigm of week-long emission with a spectral peak at near-infrared wavelengths. Using a simple light curve model to illustrate the basic physics, I introduce potentially important variations on this canonical picture, including: [Formula: see text]day-long optical ("blue") emission from lanthanide-free components of the ejecta; [Formula: see text]hour-long precursor UV/blue emission, powered by the decay of free neutrons in the outermost ejecta layers; and enhanced emission due to energy input from a long-lived central engine, such as an accreting BH or millisecond magnetar. I assess the prospects of kilonova detection following future GW detections of NS-NS/BH-NS mergers in light of the recent follow-up campaign of the LIGO binary BH-BH mergers. PMID- 28579917 TI - Higgs EFT for 2HDM and beyond. AB - We discuss the validity of the Standard Model Effective Field Theory (SM EFT) as the low-energy effective theory for the two-Higgs-doublet Model (2HDM). Using the up-to-date Higgs signal strength measurements at the LHC, one can obtain a likelihood function for the Wilson coefficients of dimension-6 operators in the EFT Lagrangian. Given the matching between the 2HDM and the EFT, the constraints on the Wilson coefficients can be translated into constraints on the parameters of the 2HDM Lagrangian. We discuss under which conditions such a procedure correctly reproduces the true limits on the 2HDM. Finally, we employ the SM EFT to identify the pattern of the Higgs boson couplings that are needed to improve the fit to the current Higgs data. To this end, one needs, simultaneously, to increase the top Yukawa coupling, decrease the bottom Yukawa coupling, and induce a new contact interaction of the Higgs boson with gluons. We comment on how these modifications can be realized in the 2HDM extended by new colored particles. PMID- 28579918 TI - Two-body decays of gluino at full one-loop level in the quark-flavour violating MSSM. AB - We study the two-body decays of the gluino at full one-loop level in the Minimal Supersymmetric Standard Model with quark-flavour violation (QFV) in the squark sector. The renormalisation is done in the [Formula: see text] scheme. The gluon and photon radiations are included by adding the corresponding three-body decay widths. We discuss the dependence of the gluino decay widths on the QFV parameters. The main dependence stems from the [Formula: see text]-[Formula: see text] mixing in the decays to up-type squarks, and from the [Formula: see text] [Formula: see text] mixing in the decays to down-type squarks due to the strong constraints from B-physics on the other quark-flavour-mixing parameters. The full one-loop corrections to the gluino decay widths are mostly negative and of the order of about -10%. The QFV part stays small in the total width but can vary up to -8% for the decay width into the lightest [Formula: see text] squark. For the corresponding branching ratio the effect is somehow washed out by at least a factor of two. The electroweak corrections can be as large as 35% of the SUSY QCD corrections. PMID- 28579925 TI - Cyber-Physical Human Systems: Putting People in the Loop. AB - This article outlines the challenge to understand how to integrate people into a new generation of cyber-physical-human systems (CPHSs) and proposes a human service capability description model to help. PMID- 28579926 TI - Defeating Buffer Overflow: A Trivial but Dangerous Bug. AB - The C programming language was invented more than 40 years ago. It is infamous for buffer overflows. We have learned a lot about computer science, language design, and software engineering since then. Because it is unlikely that we will stop using C any time soon, we present some ways to deal with BOF. Many of these techniques are also useful for other programing languages and other classes of vulnerabilities. PMID- 28579923 TI - One rule for the goose, one for the gander? Wrongfulness and harmfulness in determining reactions to offenders and victims of crime. AB - People's reactions to offenders and victims of crime follow different rationales. Whereas the punishment of the offender is primarily determined by the severity of the crime (which includes its foreseeable harmful consequences), the actual harm that is experienced by the victim drives the need for his or her support and assistance. With the introduction of the Victim Impact Statement (VIS), in which victims are allowed to express the (harmful) consequences of the crime on their lives, the question is raised whether allowing such victim input during criminal proceedings would influence the offender's sentence. The main goal of the current research is to disentangle how a crime's wrongfulness and harmfulness influence people's reactions to offenders and victims. We show that, whereas people's perceptions of the offender (and the outcome of the trial) are influenced by the severity of the crime, people's judgements related to the victim are more likely to be influenced by an interaction between the severity of the crime and the experienced harm of the crime. That is, in this study no support was found for the argument that the delivery of a VIS would lead to a violation of the proportionality principle. PMID- 28579924 TI - Income inequality and fear of crime across the European region. AB - This paper aims to take a holistic approach to studying fear of crime by testing predictors at multiple levels of analyses. Data from the European Social Survey (N = 56,752 from 29 countries) were used to test and extend the Income Inequality and Sense of Vulnerability Hypotheses. The findings confirm that (1) individuals in societies with greater income inequalities are more fearful of crime, and (2) older or disabled people as well as women report greater fear of crime. Contrary to the hypotheses, ethnic majority and not ethnic minority members report greater fear of crime, if they reside in high income inequality countries. It is further demonstrated that fear of crime explains the inverse association between income inequality and subjective well-being in this particular subsample. PMID- 28579927 TI - Identification of Osteoporosis-Associated Protein Biomarkers from Ovariectomized Rat Urine. AB - OBJECTIVE: Osteoporotic fracture is one of the most common health risks and aggravates the quality of life among postmenopausal women worldwide. In this study, osteoporosis-associated protein biomarkers were identified from urine of osteoporotic female Sprague-Dawley rats developed by ovariectomy. METHOD: Four months after the operation, the bone mineral density of the femur of ovariectomized rats was significantly lowered in comparison with that of the sham operated rats. The protein profiles of the urine samples collected from the sham, ovariectomized (OVX) and 2 month-old non-operated (Young) rats were compared by 2 D gel and MS spectrometry. RESULTS: Proteins consistently expressed between Young and sham but differentially expressed in OVX rats were selected and identified. One down-regulated 21 kDa protein, superoxide dismutase (SOD), and 1 up-regulated 53-54 kDa protein, alph-1-antitrypsin (A1AT), were selected from urine of the ovariectomized rats by 2-D gel analysis. Further, a total of 30 with 19 up regulated and 11-down-regulated proteins were selected by LC-MS analysis with more than 2-fold differences in spectral counts. The fact that SOD and A1AT are also listed in the 30 differential proteins suggests that our biomarker isolation procedure suitably represents osteoporosis-associated proteins in urine. CONCLUSION: Supporting the facts, the differential expressions of SOD and A1AT in urine could be validated by Western blotting. These urinary osteoporosis associated proteins have high potentials to become candidates for non-invasive diagnosis of osteoporosis from urine. PMID- 28579922 TI - Solution of an elusive pigment crystal structure from a thin film: a combined X ray diffraction and computational study. AB - Epindolidione, a hydrogen-bonded derivative of the organic semiconductor tetracene, is an organic pigment which has previously been used to produce stable OFETs with relatively high hole mobilities. Despite its use as an inkjet pigment and organic semiconductor, the crystal structure of epindolidione has proved elusive and is currently unknown. In this work, we report a crystal structure solution of epindolidione determined from vapor deposited thin films using a combined experimental and theoretical approach. The structure is found to be similar to one of the previously reported epindolidione derivatives and is most likely a surface-mediated polymorph, with a slightly different crystal packing compared to the bulk powder. The effect of substrate temperature on film morphology and structure is also investigated, where it is found that the crystallite orientation can be tuned by deposition at different substrate temperatures. The results also illustrate the possibilities for crystal structures to be solved from thin films. PMID- 28579928 TI - Single cell amperometry reveals curcuminoids modulate the release of neurotransmitters during exocytosis from PC12 cells. AB - We used single cell amperometry to examine whether curcumin and bisdemethoxycurcumin (BDMC), substances that are suggested to affect learning and memory, can modulate monoamine release from PC12 cells. Our results indicate both curcumin and BDMC need long-term treatment (72 h in this study) to influence exocytosis effectively. By analyzing the parameters calculated from single exocytosis events, it can be concluded that curcumin and BDMC affect exocytosis through different mechanisms. Curcumin accelerates the event dynamics with no significant change of the monoamine amount released from single exocytotic events, whereas BDMC attenuates the amount from single exocytotic event with no significant change of the event dynamics. This comparison of the effect of curcumin and BDMC on exocytosis at the single cell level brings insight into their different mechanisms, which might lead to different biological actions. The effect of curcumin and BDMC on the opening and closing of the exocytotic fusion pore were also investigated. These results might be helpful for understanding the improvement of learning and memory and the anti-depression properties of curcuminoids. PMID- 28579929 TI - Microfabricated, Massive Electrochemical Arrays of Uniform Ultramicroelectrodes. AB - We report the preparation and electrochemical characterization of massive electrochemical arrays containing as many as 110,000 highly uniform ultramicroelectrodes (UMEs). These arrays were microfabricated using conventional photolithography techniques on a gold-coated silicon chip in a simple three-step method. Photoresist polymer was used as an effective insulating matrix to define 2 MUm, 3 MUm, and 4 MUm diameter circular UMEs across a 1 * 1 mm2 area. The UME arrays are high uniform and contain tens of thousands of active disk-shape UMEs slightly recessed in thin films of photoresist. These arrays were tested with cyclic voltammetry and copper electrodeposition to assess the adhesion of photoresist to the gold surface as well as to examine their electrochemical activity. Numerical simulations were performed to further validate their electrochemical response. These UME arrays can be a useful platform for fundamental understanding molecular transport in uniform electrochemical arrays and designing highly-sensitive electroanalytical sensors. PMID- 28579930 TI - Protodioscin, Isolated from the Rhizome of Dioscorea tokoro Collected in Northern Japan is the Major Antiproliferative Compound to HL-60 ?Leukemic Cells. AB - BACKGROUND: The rhizome of Oni-dokoro (a wild yam, Dioscorea tokoro) has extremely bitter taste and is not generally regarded edible;, however, in northern part of Japan, such as Iwate and a part of Aomori, it is used as health promoting food. To clarify the reason, we examined the biologically active compounds in the rhizome collected at Iwate and compared them from the other area in literature. METHODS: The acetonitrile extract from northern part of Japan was purified by bioassay-guided separation using antiproliferative activity to human leukemia HL-60 cell, and protodioscin (PD) was isolated and identified by instrumental analyses as the major active compound. RESULTS: PD known as a saponin with four sugar moieties, an inhibitor for platelet aggregation, and a low density lipoprotein (LPL) lowering agent, displayed strong growth inhibitory effect to HL-60. The literature search suggested that the rhizome from other area contained dioscin and other saponins with three sugar moieties as their major component. We assume that the edible and health promoting effect of the rhizome in the particular area is partially derived from these different components. CONCLUSION: We were interested in the differences of utilization in the rhizome of wild yam Dioscorea tokoro, and examined the chemical composition in the rhizome to find protodioscin as antiproliferative compound to HL-60. In the report from other area, the rhizome exhibited dioscin as the major compound. Our study indicated that the protodioscin/dioscin composition varied regionally, although the reason is still needs to be investigated. PMID- 28579932 TI - Oral health-related quality of life and loneliness among older adults. AB - Loneliness is a serious concern in aging populations. The key risk factors include poor health, depression, poor material circumstances, and low social participation and social support. Oral disease and tooth loss have a significant negative impact on the quality of life and well-being of older adults. However, there is a lack of studies relating oral health to loneliness. This study investigated the association between oral health-related quality of life (through the use of the oral impact on daily performances-OIDP-measure) and loneliness amongst older adults living in England. Data from respondents aged 50 and older from the third (2006-2007) and fifth (2010-2011) waves of the English Longitudinal Study of Ageing were analyzed. In the cross-sectional logistic regression model that adjusted for socio-demographic, socio-economic, health, and psychosocial factors, the odds of loneliness were 1.48 (1.16-1.88; p < 0.01) higher amongst those who reported at least one oral impact compared to those with no oral impact. Similarly, in the fully adjusted longitudinal model, respondents who reported an incident oral impact were 1.56 times (1.09-2.25; p < 0.05) more likely to become lonely. The association between oral health-related quality of life and loneliness was attenuated after adjusting for depressive symptoms, low social participation, and social support. Oral health-related quality of life was identified as an independent risk factor for loneliness amongst older adults. Maintaining good oral health in older age may be a protective factor against loneliness. PMID- 28579931 TI - The Occurrence of Veterinary Pharmaceuticals in the Environment: A Review. AB - It is well known that there is a widespread use of veterinary pharmaceuticals and consequent release into different ecosystems such as freshwater bodies and groundwater systems. Furthermore, the use of organic fertilizers produced from animal waste manure has been also responsible for the occurrence of veterinary pharmaceuticals in agricultural soils. This article is a review of different studies focused on the detection and quantification of such compounds in environmental compartments using different analytical techniques. Furthermore, this paper reports the main challenges regarding veterinary pharmaceuticals in terms of analytical methods, detection/quantification of parent compounds and metabolites, and risks/toxicity to human health and aquatic ecosystems. Based on the existing literature, it is clear that only limited data is available regarding veterinary compounds and there are still considerable gaps to be bridged in order to remediate existing problems and prevent future ones. In terms of analytical methods, there are still considerable challenges to overcome considering the large number of existing compounds and respective metabolites. A number of studies highlight the lack of attention given to the detection and quantification of transformation products and metabolites. Furthermore more attention needs to be given in relation to the toxic effects and potential risks that veterinary compounds pose to environmental and human health. To conclude, the more research investigations focused on these subjects take place in the near future, more rapidly we will get a better understanding about the behavior of these compounds and the real risks they pose to aquatic and terrestrial environments and how to properly tackle them. PMID- 28579934 TI - Caring too much? Lack of public services to older people reduces attendance at work among their children. AB - The need to provide care for older people can put a strain on their adult children, potentially interfering with their work attendance. We tested the hypothesis that public care for older people (nursing homes or home care services) would moderate the association between having an older parent in need of care and reduced work attendance among the adult children. The analysis used data from a survey of Norwegian employees aged 45-65 (N = 529). Institutional care for older people in need of care (i.e. nursing homes) was associated with improved work attendance among their children-their daughters in particular. Data also indicated a moderating effect: the link between the parents' reduced health and reduced work attendance among the children was weaker if the parent lived in a nursing home. However, the results were very different for home-based care: data indicated no positive effects on adult children's work attendance when parents received non-institutionalised care of this kind. Overall, the results suggest that extending public care service to older people can improve their children's ability to combine work with care for parents. However, this effect seems to require the high level of care commonly provided by nursing homes. Thus, the current trend towards de-institutionalising care in Europe (and Norway in particular) might hamper work attendance among care-giving adult children, women in particular. Home care services to older people probably need to be extended if they are intended as a real alternative to institutional care. PMID- 28579933 TI - Changes in admission to long-term care institutions in the Netherlands: comparing two cohorts over the period 1996-1999 and 2006-2009. AB - Using data from two cohorts, we examine to what extent a decline in institutional care in the Netherlands is associated with changes in the need for care and/or societal factors. We compared older adults, aged 65-89, who were admitted to a long-term care (LTC) institution in the period 1996-1999 and 2006-2009. Using the Andersen model, we tested per block of predisposing, enabling and need factors, which factors were significant predictors of admission to institutional care. With a Blinder-Oaxaca decomposition regression, we decomposed the difference in admission to an LTC institution between the period 1996-1999 and 2006-2009 into a part that is due to differences in health needs and other factors such as effect of policy, social values, and technology. Between 1996 and 2006, the percentage of co-residing partners and income increased and the average level of loneliness decreased significantly. The prevalence of disability, chronic diseases, however, increased. Whereas the care by partners declined, the formal care by professionals increased. Although the observed decline in the admission rate to institutional care was relatively small across the 10 years (from 5.3 % in 1996 1999 to 4.5 % in 2006-2009, a 15 % decrease), the probability of admission in 2006-2009 was relatively much lower when accounting for changes in the health and social conditions of the participants: the probability was 1.7-2.1 % point lower for adults in the period 2006-2009 compared to 1996-1999, a 32-40 % decrease. Our results show that the decline in the admission rate to LTC institutions is not the result of changes in need. The decline is suggested to be the combined effect of changes in policy, technological advances and changes in social norms. PMID- 28579935 TI - Smoking cessation among European older adults: the contributions of marital and employment transitions by gender. AB - Knowledge about the potential effects of stressful events on smoking cessation is helpful for the design of health interventions. Previous studies on this topic tended to group together adults of all ages and of both genders. We investigate the contribution of marital and employment losses on smoking cessation by gender, specifically among older adults in Europe. We used panel data from waves 4 (2011) and 5 (2013) of the Survey of Health, Ageing and Retirement in Europe for 3345 male and 3115 female smokers at baseline aged 50 and over from 13 countries. The associations between marital and employment losses and smoking cessation were derived from logistic regression models for each gender, controlling for age, educational attainment, diseases incidence and country of residence. Interactions between gender and marital and employment losses were tested. Over the analysed period, 119 smokers became widowed or divorced (1.8 %), 318 became retired (4.9 %) and 100 became unemployed (1.5 %). Becoming widowed or divorced was associated with lower probability of smoking cessation among both men (OR 0.36, 95 % CI 0.14 0.94) and women (OR 0.46, 95 % CI 0.21-0.99). Transitions to unemployment and to retirement were not significantly associated with smoking cessation (OR 0.62, 95 % CI 0.25-1.49; and OR 0.68, 95 % CI 0.43-1.07, respectively). Gender differences in the association between marital and employment losses and smoking cessation were not statistically significant (p value > 0.05 for all interactions). Health interventions should take into account that male and female older adults affected by marital loss are at risk of continuing smoking. PMID- 28579936 TI - Validation of abridged mini-mental state examination scales using population based data from Sweden and USA. AB - The objective of this study is to validate two abridged versions of the mini mental state examination (MMSE): one intended for use in face-to-face interviews, and the other developed for telephonic interviews, using data from Sweden and the US to validate the abridged scales against dementia diagnoses as well as to compare their performance to that of the full MMSE scale. The abridged versions were based on eight domains from the original MMSE scale. The domains included in the MMSE-SF were registration, orientation, delayed recall, attention, and visual spatial ability. In the MMSE-SF-C, the visual spatial ability item was excluded, and instead, one additional orientation item was added. There were 794 participants from the Swedish HARMONY study [mean age 81.8 (4.8); the proportion of cognitively impaired was 51 %] and 576 participants from the US ADAMS study [mean age 83.2 (5.7); the proportion of cognitively impaired was 65 %] where it was possible to compare abridged MMSE scales to dementia diagnoses and to the full MMSE scale. We estimated the sensitivity and specificity levels of the abridged tests, using clinical diagnoses as reference. Analyses with both the HARMONY and the ADAMS data indicated comparable levels of sensitivity and specificity in detecting cognitive impairment for the two abridged scales relative to the full MMSE. Receiver operating characteristic curves indicated that the two abridged scales corresponded well to those of the full MMSE. The two abridged tests have adequate validity and correspond well with the full MMSE. The abridged versions could therefore be alternatives to consider in larger population studies where interview length is restricted, and the respondent burden is high. PMID- 28579937 TI - Development of a method for reliable power input measurements in conventional and single-use stirred bioreactors at laboratory scale. AB - Power input is an important engineering and scale-up/down criterion in stirred bioreactors. However, reliably measuring power input in laboratory-scale systems is still challenging. Even though torque measurements have proven to be suitable in pilot scale systems, sensor accuracy, resolution, and errors from relatively high levels of friction inside bearings can become limiting factors at smaller scales. An experimental setup for power input measurements was developed in this study by focusing on stainless steel and single-use bioreactors in the single digit volume range. The friction losses inside the air bearings were effectively reduced to less than 0.5% of the measurement range of the torque meter. A comparison of dimensionless power numbers determined for a reference Rushton turbine stirrer (NP = 4.17 +/- 0.14 for fully turbulent conditions) revealed good agreement with literature data. Hence, the power numbers of several reusable and single-use bioreactors could be determined over a wide range of Reynolds numbers between 100 and >104. Power numbers of between 0.3 and 4.5 (for Re = 104) were determined for the different systems. The rigid plastic vessels showed similar power characteristics to their reusable counterparts. Thus, it was demonstrated that the torque-based technique can be used to reliably measure power input in stirred reusable and single-use bioreactors at the laboratory scale. PMID- 28579938 TI - The Connected Steady State Model and the Interdependence of the CSF Proteome and CSF Flow Characteristics. AB - Here we show that the hydrodynamic radii-dependent entry of blood proteins into cerebrospinal fluid (CSF) can best be modeled with a diffusional system of consecutive interdependent steady states between barrier-restricted molecular flux and bulk flow of CSF. The connected steady state model fits precisely to experimental results and provides the theoretical backbone to calculate the in vivo hydrodynamic radii of blood-derived proteins as well as individual barrier characteristics. As the experimental reference set we used a previously published large-scale patient cohort of CSF to serum quotient ratios of immunoglobulins in relation to the respective albumin quotients. We related the inter-individual variances of these quotient relationships to the individual CSF flow time and barrier characteristics. We claim that this new concept allows the diagnosis of inflammatory processes with Reibergrams derived from population-based thresholds to be shifted to individualized judgment, thereby improving diagnostic sensitivity. We further use the source-dependent gradient patterns of proteins in CSF as intrinsic tracers for CSF flow characteristics. We assume that the rostrocaudal gradient of blood-derived proteins is a consequence of CSF bulk flow, whereas the slope of the gradient is a consequence of the unidirectional bulk flow and bidirectional pulsatile flow of CSF. Unlike blood-derived proteins, the influence of CSF flow characteristics on brain-derived proteins in CSF has been insufficiently discussed to date. By critically reviewing existing experimental data and by reassessing their conformity to CSF flow assumptions we conclude that the biomarker potential of brain-derived proteins in CSF can be improved by considering individual subproteomic dynamics of the CSF system. PMID- 28579940 TI - Comparison of IVA and GIG-ICA in Brain Functional Network Estimation Using fMRI Data. AB - Spatial group independent component analysis (GICA) methods decompose multiple subject functional magnetic resonance imaging (fMRI) data into a linear mixture of spatially independent components (ICs), some of which are subsequently characterized as brain functional networks. Group information guided independent component analysis (GIG-ICA) as a variant of GICA has been proposed to improve the accuracy of the subject-specific ICs estimation by optimizing their independence. Independent vector analysis (IVA) is another method which optimizes the independence among each subject's components and the dependence among corresponding components of different subjects. Both methods are promising in neuroimaging study and showed a better performance than the traditional GICA. However, the difference between IVA and GIG-ICA has not been well studied. A detailed comparison between them is demanded to provide guidance for functional network analyses. In this work, we employed multiple simulations to evaluate the performances of the two approaches in estimating subject-specific components and time courses under conditions of different data quality and quantity, varied number of sources generated and inaccurate number of components used in computation, as well as the presence of spatially subject-unique sources. We also compared the two methods using healthy subjects' test-retest resting-state fMRI data in terms of spatial functional networks and functional network connectivity (FNC). Results from simulations support that GIG-ICA showed better recovery accuracy of both components and time courses than IVA for those subject-common sources, and IVA outperformed GIG-ICA in component and time course estimation for the subject-unique sources. Results from real fMRI data suggest that GIG-ICA resulted in more reliable spatial functional networks and yielded higher and more robust modularity property of FNC, compared to IVA. Taken together, GIG-ICA is appropriate for estimating networks which are consistent across subjects, while IVA is able to estimate networks with great inter-subject variability or subject unique property. PMID- 28579939 TI - The Role of Co-chaperones in Synaptic Proteostasis and Neurodegenerative Disease. AB - Synapses must be preserved throughout an organism's lifespan to allow for normal brain function and behavior. Synapse maintenance is challenging given the long distances between the termini and the cell body, reliance on axonal transport for delivery of newly synthesized presynaptic proteins, and high rates of synaptic vesicle exo- and endocytosis. Hence, synapses rely on efficient proteostasis mechanisms to preserve their structure and function. To this end, the synaptic compartment has specific chaperones to support its functions. Without proper synaptic chaperone activity, local proteostasis imbalances lead to neurotransmission deficits, dismantling of synapses, and neurodegeneration. In this review, we address the roles of four synaptic chaperones in the maintenance of the nerve terminal, as well as their genetic links to neurodegenerative disease. Three of these are Hsp40 co-chaperones (DNAJs): Cysteine String Protein alpha (CSPalpha; DNAJC5), auxilin (DNAJC6), and Receptor-Mediated Endocytosis 8 (RME-8; DNAJC13). These co-chaperones contain a conserved J domain through which they form a complex with heat shock cognate 70 (Hsc70), enhancing the chaperone's ATPase activity. CSPalpha is a synaptic vesicle protein known to chaperone the t SNARE SNAP-25 and the endocytic GTPase dynamin-1, thereby regulating synaptic vesicle exocytosis and endocytosis. Auxilin binds assembled clathrin cages, and through its interactions with Hsc70 leads to the uncoating of clathrin-coated vesicles, a process necessary for the regeneration of synaptic vesicles. RME-8 is a co-chaperone on endosomes and may have a role in clathrin-coated vesicle endocytosis on this organelle. These three co-chaperones maintain client function by preserving folding and assembly to prevent client aggregation, but they do not break down aggregates that have already formed. The fourth synaptic chaperone we will discuss is Heat shock protein 110 (Hsp110), which interacts with Hsc70, DNAJAs, and DNAJBs to constitute a disaggregase. Hsp110-related disaggregase activity is present at the synapse and is known to protect against aggregation of proteins such as alpha-synuclein. Congruent with their importance in the nervous system, mutations of these co-chaperones lead to familial neurodegenerative disease. CSPalpha mutations cause adult neuronal ceroid lipofuscinosis, while auxilin mutations result in early-onset Parkinson's disease, demonstrating their significance in preservation of the nervous system. PMID- 28579941 TI - Chronic Ketamine Exposure Causes White Matter Microstructural Abnormalities in Adolescent Cynomolgus Monkeys. AB - Acute and repeated exposures to ketamine mimic aspects of positive, negative, and cognitive symptoms of schizophrenia in humans. Recent studies by our group and others have shown that chronicity of ketamine use may be a key element for establishing a more valid model of cognitive symptoms of schizophrenia. However, current understanding on the long-term consequences of ketamine exposure on brain circuits has remained incomplete, particularly with regard to microstructural changes of white matter tracts that underpin the neuropathology of schizophrenia. Thus, the present study aimed to expand on previous investigations by examining causal effects of repeated ketamine exposure on white matter integrity in a non human primate model. Ketamine or saline (control) was administered intravenously for 3 months to male adolescent cynomolgus monkeys (n = 5/group). Diffusion tensor imaging (DTI) experiments were performed and tract-based spatial statistics (TBSS) was used for data analysis. Fractional anisotropy (FA) was quantified across the whole brain. Profoundly reduced FA on the right side of sagittal striatum, posterior thalamic radiation (PTR), retrolenticular limb of the internal capsule (RLIC) and superior longitudinal fasciculus (SLF), and on the left side of PTR, middle temporal gyrus and inferior frontal gyrus were observed in the ketamine group compared to controls. Diminished white matter integrity found in either fronto-thalamo-temporal or striato-thalamic connections with tracts including the SLF, PTR, and RLIC lends support to similar findings from DTI studies on schizophrenia in humans. This study suggests that chronic ketamine exposure is a useful pharmacological paradigm that might provide translational insights into the pathophysiology and treatment of schizophrenia. PMID- 28579942 TI - Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice. AB - Age is characterized by chronic inflammation, leading to synaptic dysfunction and dementia because the clearance of protein waste is reduced. The clearance of proteins depends partly on the permeation of the blood-brain barrier (BBB) or on the exchange of water and soluble contents between the cerebrospinal fluid (CSF) and the interstitial fluid (ISF). A wealth of evidence indicates that physical exercise improves memory and cognition in neurodegenerative diseases during aging, such as Alzheimer's disease (AD), but the influence of physical training on glymphatic clearance, BBB permeability and neuroinflammation remains unclear. In this study, glymphatic clearance and BBB permeability were evaluated in aged mice using in vivo two-photon imaging. The mice performed voluntary wheel running exercise and their water-maze cognition was assessed; the expression of the astrocytic water channel aquaporin 4 (AQP4), astrocyte and microglial activation, and the accumulation of amyloid beta (Abeta) were evaluated with immunofluorescence or an enzyme-linked immunosorbent assay (ELISA); synaptic function was investigated with Thy1-green fluorescent protein (GFP) transgenic mice and immunofluorescent staining. Voluntary wheel running significantly improved water-maze cognition in the aged mice, accelerated the efficiency of glymphatic clearance, but which did not affect BBB permeability. The numbers of activated astrocytes and microglia decreased, AQP4 expression increased, and the distribution of astrocytic AQP4 was rearranged. Abeta accumulation decreased, whereas dendrites, dendritic spines and postsynaptic density protein (PSD95) increased. Our study suggests that voluntary wheel running accelerated glymphatic clearance but not BBB permeation, improved astrocytic AQP4 expression and polarization, attenuated the accumulation of amyloid plaques and neuroinflammation, and ultimately protected mice against synaptic dysfunction and a decline in spatial cognition. These data suggest possible mechanisms for exercise-induced neuroprotection in the aging brain. PMID- 28579946 TI - Corrigendum: Reconsidering Tonotopic Maps in the Auditory Cortex and Lemniscal Auditory Thalamus in Mice. AB - [This corrects the article on p. 14 in vol. 11, PMID: 28293178.]. PMID- 28579944 TI - Impaired Spinal Glucocorticoid Receptor Signaling Contributes to the Attenuating Effect of Depression on Mechanical Allodynia and Thermal Hyperalgesia in Rats with Neuropathic Pain. AB - Although depression-induced altered pain perception has been described in several laboratory and clinical studies, its neurobiological mechanism in the central nervous system (CNS), particularly in the spinal dorsal horn, remains unclear. Therefore, in this study, we aimed to clarify whether nociceptive sensitivity of neuropathic pain is altered in the olfactory bulbectomy (OB) model of depression and whether glucocorticoid receptor (GR), which is involved in the etio pathologic mechanisms of both major depression and neuropathic pain, contributes to these processes in the spinal dorsal horn of male Sprague-Dawley rats. The results showed that mechanical allodynia and thermal hyperalgesia induced by spinal nerve ligation (SNL) were attenuated in OB-SNL rats with decreased spinal GR expression and nuclear translocation, whereas non-olfactory bulbectomy (NOB) SNL rats showed increased spinal GR nuclear translocation. In addition, decreased GR nuclear translocation with normal mechanical nociception and hypoalgesia of thermal nociception were observed in OB-Sham rats. Intrathecal injection (i.t.) of GR agonist dexamethasone (Dex; 4 MUg/rat/day for 1 week) eliminated the attenuating effect of depression on nociceptive hypersensitivity in OB-SNL rats and aggravated neuropathic pain in NOB-SNL rats, which was associated with the up regulation of brain-derived neurotrophic factor (BDNF), TrkB and NR2B expression in the spinal dorsal horn. The present study shows that depression attenuates the mechanical allodynia and thermal hyperalgesia of neuropathic pain and suggests that altered spinal GR-BDNF-TrkB signaling may be one of the reasons for depression-induced hypoalgesia. PMID- 28579947 TI - Commentary: Gene Therapy: A Promising Approach for Neuroprotection in Parkinson's Disease? PMID- 28579945 TI - LFP Oscillations in the Mesencephalic Locomotor Region during Voluntary Locomotion. AB - Oscillatory rhythms in local field potentials (LFPs) are thought to coherently bind cooperating neuronal ensembles to produce behaviors, including locomotion. LFPs recorded from sites that trigger locomotion have been used as a basis for identification of appropriate targets for deep brain stimulation (DBS) to enhance locomotor recovery in patients with gait disorders. Theta band activity (6-12 Hz) is associated with locomotor activity in locomotion-inducing sites in the hypothalamus and in the hippocampus, but the LFPs that occur in the functionally defined mesencephalic locomotor region (MLR) during locomotion have not been determined. Here we record the oscillatory activity during treadmill locomotion in MLR sites effective for inducing locomotion with electrical stimulation in rats. The results show the presence of oscillatory theta rhythms in the LFPs recorded from the most effective MLR stimulus sites (at threshold <=60 MUA). Theta activity increased at the onset of locomotion, and its power was correlated with the speed of locomotion. In animals with higher thresholds (>60 MUA), the correlation between locomotor speed and theta LFP oscillations was less robust. Changes in the gamma band (previously recorded in vitro in the pedunculopontine nucleus (PPN), thought to be a part of the MLR) were relatively small. Controlled locomotion was best achieved at 10-20 Hz frequencies of MLR stimulation. Our results indicate that theta and not delta or gamma band oscillation is a suitable biomarker for identifying the functional MLR sites. PMID- 28579949 TI - Commentary: Adenosine A2A Receptor Blockade Prevents Rotenone-Induced Motor Impairment in a Rat Model of Parkinsonism. PMID- 28579950 TI - Editorial: Impact of Diet on Learning, Memory and Cognition. PMID- 28579948 TI - Modulation of Low-Voltage-Activated Inward Current Permeable to Sodium and Calcium by DARPP-32 Drives Spontaneous Firing of Insect Octopaminergic Neurosecretory Cells. AB - Identification of the different intracellular pathways that control phosphorylation/dephosphorylation process of ionic channels represents an exciting alternative approach for studying the ionic mechanisms underlying neuronal pacemaker activity. In the central nervous system of the cockroach Periplaneta americana, octopaminergic neurons, called dorsal unpaired median (DUM; DUM neurons), generate spontaneous repetitive action potentials. Short-term cultured adult DUM neurons isolated from the terminal abdominal ganglion (TAG) of the nerve cord were used to study the regulation of a tetrodotoxin-sensitive low voltage-activated (LVA) channel permeable to sodium and calcium (Na/Ca), under whole cell voltage- and current-clamp conditions. A bell-shaped curve illustrating the regulation of the amplitude of the maintained current vs. [ATP]i was observed. This suggested the existence of phosphorylation mechanisms. The protein kinase A (PKA) inhibitor, H89 and elevating [cyclic adenosine 3', 5' monophosphate, cAMP]i, increased and decreased the current amplitude, respectively. This indicated a regulation of the current via a cAMP/PKA cascade. Furthermore, intracellular application of PP2B inhibitors, cyclosporine A, FK506 and PP1/2A inhibitor, okadaic acid decreased the current amplitude. From these results and because octopamine (OA) regulates DUM neuron electrical activity via an elevation of [cAMP]i, we wanted to know if, like in vertebrate dopaminergic neurons, OA receptor (OAR) stimulation could indirectly affect the current via PKA-mediated phosphorylation of Dopamine- and cAMP-regulated Phosphoprotein-32 (DARPP-32) known to inhibit PP1/2A. Experiments were performed using intracellular application of phospho-DARPP-32 and non-phospho-DARPP-32. Phospho DARPP-32 strongly reduced the current amplitude whereas non-phospho-DARPP-32 did not affect the current. All together, these results confirm that DARPP-32 mediated inhibition of PP1/2A regulates the maintained sodium/calcium current, which contributes to the development of the pre-depolarizing phase of the DUM neuron pacemaker activity. PMID- 28579951 TI - Communicative-Pragmatic Assessment Is Sensitive and Time-Effective in Measuring the Outcome of Aphasia Therapy. AB - A range of methods in clinical research aim to assess treatment-induced progress in aphasia therapy. Here, we used a crossover randomized controlled design to compare the suitability of utterance-centered and dialogue-sensitive outcome measures in speech-language testing. Fourteen individuals with post-stroke chronic non-fluent aphasia each received two types of intensive training in counterbalanced order: conventional confrontation naming, and communicative pragmatic speech-language therapy (Intensive Language-Action Therapy, an expanded version of Constraint-Induced Aphasia Therapy). Motivated by linguistic-pragmatic theory and neuroscience data, our dependent variables included a newly created diagnostic instrument, the Action Communication Test (ACT). This diagnostic instrument requires patients to produce target words in two conditions: (i) utterance-centered object naming, and (ii) communicative-pragmatic social interaction based on verbal requests. In addition, we administered a standardized aphasia test battery, the Aachen Aphasia Test (AAT). Composite scores on the ACT and the AAT revealed similar patterns of changes in language performance over time, irrespective of the treatment applied. Changes in language performance were relatively consistent with the AAT results also when considering both ACT subscales separately from each other. However, only the ACT subscale evaluating verbal requests proved to be successful in distinguishing between different types of training in our patient sample. Critically, testing duration was substantially shorter for the entire ACT (10-20 min) than for the AAT (60-90 min). Taken together, the current findings suggest that communicative-pragmatic methods in speech-language testing provide a sensitive and time-effective measure to determine the outcome of aphasia therapy. PMID- 28579953 TI - Corrigendum: Multi-modal, Multi-measure, and Multi-class Discrimination of ADHD with Hierarchical Feature Extraction and Extreme Learning Machine Using Structural and Functional Brain MRI. AB - [This corrects the article on p. 157 in vol. 11, PMID: 28420972.]. PMID- 28579943 TI - E3 Ubiquitin Ligases Neurobiological Mechanisms: Development to Degeneration. AB - Cells regularly synthesize new proteins to replace old or damaged proteins. Deposition of various aberrant proteins in specific brain regions leads to neurodegeneration and aging. The cellular protein quality control system develop various defense mechanisms against the accumulation of misfolded and aggregated proteins. The mechanisms underlying the selective recognition of specific crucial protein or misfolded proteins are majorly governed by quality control E3 ubiquitin ligases mediated through ubiquitin-proteasome system. Few known E3 ubiquitin ligases have shown prominent neurodevelopmental functions, but their interactions with different developmental proteins play critical roles in neurodevelopmental disorders. Several questions are yet to be understood properly. How E3 ubiquitin ligases determine the specificity and regulate degradation of a particular substrate involved in neuronal proliferation and differentiation is certainly the one, which needs detailed investigations. Another important question is how neurodevelopmental E3 ubiquitin ligases specifically differentiate between their versatile range of substrates and timing of their functional modulations during different phases of development. The premise of this article is to understand how few E3 ubiquitin ligases sense major molecular events, which are crucial for human brain development from its early embryonic stages to throughout adolescence period. A better understanding of these few E3 ubiquitin ligases and their interactions with other potential proteins will provide invaluable insight into disease mechanisms to approach toward therapeutic interventions. PMID- 28579952 TI - Brain Network for the Core Deficits of Semantic Dementia: A Neural Network Connectivity-Behavior Mapping Study. AB - Individuals with semantic dementia (SD) typically suffer from selective semantic deficits due to degenerative brain atrophy. Although some brain regions have been found to be correlated with the semantic impairments of SD patients, it is unclear if the damage is actually responsible for SD patients' semantic disorders because these findings were primarily obtained by examining the roles of local individual regions themselves without considering the influence of other regions that are functionally or structurally connected to the local individual regions. To resolve this problem, we investigated, from the brain network perspective, the relationship between the brain-network measures of regions and connections with semantic performance in 17 SD patients. We found that the severity of semantic deficits of SD patients was significantly correlated with the degree centrality values of the left anterior hippocampus (aHIP). Moreover, the semantic performance of the patients was also significantly correlated with the strength of gray matter functional connectivity of this region and two other regions: the left temporal pole/insula (TP/INS) and the left middle temporal gyrus. We further observed that the strength of the white matter structural connectivity of the left aHIP-left TP/INS tract could effectively predict the semantic performance of SD patients. When we controlled for a wide range of potential confounding factors (e.g., total gray matter volume), the above effects still held well. These findings revealed the critical brain network with the left aHIP as the center that could be contributing to the semantic impairments of SD. PMID- 28579954 TI - Linear Parameter Varying Identification of Dynamic Joint Stiffness during Time Varying Voluntary Contractions. AB - Dynamic joint stiffness is a dynamic, nonlinear relationship between the position of a joint and the torque acting about it, which can be used to describe the biomechanics of the joint and associated limb(s). This paper models and quantifies changes in ankle dynamic stiffness and its individual elements, intrinsic and reflex stiffness, in healthy human subjects during isometric, time varying (TV) contractions of the ankle plantarflexor muscles. A subspace, linear parameter varying, parallel-cascade (LPV-PC) algorithm was used to identify the model from measured input position perturbations and output torque data using voluntary torque as the LPV scheduling variable (SV). Monte-Carlo simulations demonstrated that the algorithm is accurate, precise, and robust to colored measurement noise. The algorithm was then used to examine stiffness changes associated with TV isometric contractions. The SV was estimated from the Soleus EMG using a Hammerstein model of EMG-torque dynamics identified from unperturbed trials. The LPV-PC algorithm identified (i) a non-parametric LPV impulse response function (LPV IRF) for intrinsic stiffness and (ii) a LPV-Hammerstein model for reflex stiffness consisting of a LPV static nonlinearity followed by a time invariant state-space model of reflex dynamics. The results demonstrated that: (a) intrinsic stiffness, in particular ankle elasticity, increased significantly and monotonically with activation level; (b) the gain of the reflex pathway increased from rest to around 10-20% of subject's MVC and then declined; and (c) the reflex dynamics were second order. These findings suggest that in healthy human ankle, reflex stiffness contributes most at low muscle contraction levels, whereas, intrinsic contributions monotonically increase with activation level. PMID- 28579955 TI - 10 Hz Amplitude Modulated Sounds Induce Short-Term Tinnitus Suppression. AB - Objectives: Acoustic stimulation or sound therapy is proposed as a main treatment option for chronic subjective tinnitus. To further probe the field of acoustic stimulations for tinnitus therapy, this exploratory study compared 10 Hz amplitude modulated (AM) sounds (two pure tones, noise, music, and frequency modulated (FM) sounds) and unmodulated sounds (pure tone, noise) regarding their temporary suppression of tinnitus loudness. First, it was hypothesized that modulated sounds elicit larger temporary loudness suppression (residual inhibition) than unmodulated sounds. Second, with manipulation of stimulus loudness and duration of the modulated sounds weaker or stronger effects of loudness suppression were expected, respectively. Methods: We recruited 29 participants with chronic tonal tinnitus from the multidisciplinary Tinnitus Clinic of the University of Regensburg. Participants underwent audiometric, psychometric and tinnitus pitch matching assessments followed by an acoustic stimulation experiment with a tinnitus loudness growth paradigm. In a first block participants were stimulated with all of the sounds for 3 min each and rated their subjective tinnitus loudness to the pre-stimulus loudness every 30 s after stimulus offset. The same procedure was deployed in the second block with the pure tone AM stimuli matched to the tinnitus frequency, manipulated in length (6 min), and loudness (reduced by 30 dB and linear fade out). Repeated measures mixed model analyses of variance (ANOVA) were calculated to assess differences in loudness growth between the stimuli for each block separately. Results: First, we found that all sounds elicit a short-term suppression of tinnitus loudness (seconds to minutes) with strongest suppression right after stimulus offset [F(6, 1331) = 3.74, p < 0.01]. Second, similar to previous findings we found that AM sounds near the tinnitus frequency produce significantly stronger tinnitus loudness suppression than noise [vs. Pink noise: t(27) = -4.22, p < 0.0001]. Finally, variants of the AM sound matched to the tinnitus frequency reduced in sound level resulted in less suppression while there was no significant difference observed for a longer stimulation duration. Moreover, feasibility of the overall procedure could be confirmed as scores of both tinnitus loudness and questionnaires were lower after the experiment [tinnitus loudness: t(27) = 2.77, p < 0.01; Tinnitus Questionnaire: t(27) = 2.06, p < 0.05; Tinnitus Handicap Inventory: t(27) = 1.92, p = 0.065]. Conclusion: Taken together, these results imply that AM sounds, especially in or around the tinnitus frequency, may induce larger suppression than unmodulated sounds. Future studies should thus evaluate this approach in longitudinal studies and real life settings. Furthermore, the putative neural relation of these sound stimuli with a modulation rate in the EEG alpha band to the observed tinnitus suppression should be probed with respective neurophysiological methods. PMID- 28579956 TI - Music Training and Education Slow the Deterioration of Music Perception Produced by Presbycusis in the Elderly. AB - The perception of music depends on the normal function of the peripheral and central auditory system. Aged subjects without hearing loss have altered music perception, including pitch and temporal features. Presbycusis or age-related hearing loss is a frequent condition in elderly people, produced by neurodegenerative processes that affect the cochlear receptor cells and brain circuits involved in auditory perception. Clinically, presbycusis patients have bilateral high-frequency hearing loss and deteriorated speech intelligibility. Music impairments in presbycusis subjects can be attributed to the normal aging processes and to presbycusis neuropathological changes. However, whether presbycusis further impairs music perception remains controversial. Here, we developed a computerized version of the Montreal battery of evaluation of amusia (MBEA) and assessed music perception in 175 Chilean adults aged between 18 and 90 years without hearing complaints and in symptomatic presbycusis patients. We give normative data for MBEA performance in a Latin-American population, showing age and educational effects. In addition, we found that symptomatic presbycusis was the most relevant factor determining global MBEA accuracy in aged subjects. Moreover, we show that melodic impairments in presbycusis individuals were diminished by music training, while the performance in temporal tasks were affected by the educational level and music training. We conclude that music training and education are important factors as they can slow the deterioration of music perception produced by age-related hearing loss. PMID- 28579959 TI - Corrigendum: Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy. AB - [This corrects the article on p. 49 in vol. 8, PMID: 28228726.]. PMID- 28579958 TI - Exploring Pharmacological Mechanisms of Lavender (Lavandula angustifolia) Essential Oil on Central Nervous System Targets. AB - Lavender essential oil is traditionally used and approved by the European Medicines Agency (EMA) as herbal medicine to relieve stress and anxiety. Some animal and clinical studies reveal positive results in models of anxiety and depression although very little research has been done on molecular mechanisms. Our work consisted of evaluating the effects of lavender (Lavandula angustifolia) essential oil on central nervous system well-established targets, such as MAO-A, SERT, GABAAand NMDA receptors as well as in vitro models of neurotoxicity. The results showed that lavender essential oil and its main components exert affinity for the glutamate NMDA-receptor in a dose-dependent manner with an IC50 value of 0.04 MUl/mL for lavender oil. In addition, lavender and linalool were also able to bind the serotonin transporter (SERT) whereas they did not show affinity for GABAA-benzodiazepine receptor. In three different models of neurotoxicity, lavender did not enhance the neurotoxic insult and improved viability of SH-SY5Y cells treated with hydrogen peroxide. According to our data, the anxiolytic and antidepressant-like effects attributed to lavender may be due to an antagonism on the NMDA-receptor and inhibition of SERT. This study suggests that lavender essential oil may exert pharmacological properties via modulating the NMDA receptor, the SERT as well as neurotoxicity induced by hydrogen peroxide. PMID- 28579957 TI - The Epigenomics of Embryonic Pathway Signaling in Colorectal Cancer. AB - Colorectal cancer (CRC) is the second-leading cause of cancer death in developed countries. While early detection (e.g., colonoscopy) generally yields excellent outcomes, metastatic and drug-resistant disease is uniformly fatal, and non compliance for screening remains over 25%. Familial CRCs (10% of total cases) primarily include mutations in the gene APC. Somatic disease is linked to several environmental several risk factors, including mutations in WNT, KRAS, and TGFbeta. To reflect the genesis/progression of CRC, a series of five discrete stages, from normal colon mucosa to fully invasive carcinoma, each regulated by specific "gatekeeper" genes, remains well-accepted after 20 years. However, many CRC tumors do not possess those particular mutations, suggesting alternative mechanisms. More recently, embryo-like "cancer stem cells" have been proposed to undergo self-renewal and drive tumorigenesis (and possibly, metastasis), as governed by specific "epigenomic" alterations. Here, we review recent literature describing possible mechanisms that underlie these phenotypes, including cancer "stemness," believed by many to associate with the epithelial-to-mesenchymal transition (EMT). We further propose that the maintenance of undifferentiated phenotypes, by the activity of distinct transcription factors, facilitates chromatin remodeling and phenotypic plasticity. With that regard, we support recent assertions that EMT is not an "either/or" event, but rather a continuous spectrum of mesenchymal vs. epithelial phenotypes (in various degrees of aberrant differentiation/undifferentiation). Finally, we discuss possible methods of pharmacologically targeting such aberrant epigenomes, with regard to their possible relevance toward halting, or even reversing, colorectal cancer progression. PMID- 28579960 TI - Modeling the Mechanics of Cell Division: Influence of Spontaneous Membrane Curvature, Surface Tension, and Osmotic Pressure. AB - Many cell division processes have been conserved throughout evolution and are being revealed by studies on model organisms such as bacteria, yeasts, and protozoa. Cellular membrane constriction is one of these processes, observed almost universally during cell division. It happens similarly in all organisms through a mechanical pathway synchronized with the sequence of cytokinetic events in the cell interior. Arguably, such a mechanical process is mastered by the coordinated action of a constriction machinery fueled by biochemical energy in conjunction with the passive mechanics of the cellular membrane. Independently of the details of the constriction engine, the membrane component responds against deformation by minimizing the elastic energy at every constriction state following a pathway still unknown. In this paper, we address a theoretical study of the mechanics of membrane constriction in a simplified model that describes a homogeneous membrane vesicle in the regime where mechanical work due to osmotic pressure, surface tension, and bending energy are comparable. We develop a general method to find approximate analytical expressions for the main descriptors of a symmetrically constricted vesicle. Analytical solutions are obtained by combining a perturbative expansion for small deformations with a variational approach that was previously demonstrated valid at the reference state of an initially spherical vesicle at isotonic conditions. The analytic approximate results are compared with the exact solution obtained from numerical computations, getting a good agreement for all the computed quantities (energy, area, volume, constriction force). We analyze the effects of the spontaneous curvature, the surface tension and the osmotic pressure in these quantities, focusing especially on the constriction force. The more favorable conditions for vesicle constriction are determined, obtaining that smaller constriction forces are required for positive spontaneous curvatures, low or negative membrane tension and hypertonic media. Conditions for spontaneous constriction at a given constriction force are also determined. The implications of these results for biological cell division are discussed. This work contributes to a better quantitative understanding of the mechanical pathway of cellular division, and could assist the design of artificial divisomes in vesicle-based self-actuated microsystems obtained from synthetic biology approaches. PMID- 28579961 TI - Characterization of Annexin V Fusion with the Superfolder GFP in Liposomes Binding and Apoptosis Detection. AB - Programed cell death is a critical and unavoidable part of life. One of the most widely used markers for dying cells, by apoptosis or pyroptosis, is the redistribution of phosphatidylserine (PS) from the inner to the outer plasma membrane leaflet. Annexin V protein is a sensitive and specific probe to mark this event because of its high affinity to the exposed PS. Beyond that, annexin V can bind to any PS-containing phospholipid bilayer of almost all tiny forms of membranous vesicles like blood platelets, exosomes, or even nanostructured liposomes. In this work, recombinant human annexin V was produced as a fusion with a highly fluorescent superfolder derivative of the green fluorescent protein (sfGFP) in Escherichia coli. The fusion protein(sfGFP-ANXV, 64 kDa), annexin V (ANXV, 40 kDa), and sfGFP (27 kDa) were separately produced after cloning their encoding genes in pRSET plasmid, and all proteins were expressed in a soluble form, then purified in high yields because of their N-terminal 6* His tag (~150 mg of pure protein per 1 L culture). Superiority of this fluorescent fusion protein over fluorescein-conjugated annexin V was demonstrated in binding to phospholipids (and their liposomes), prepared from natural sources (soya bean and egg yolk) that have different content of PS, by using different methods including ELISA, dot-blotting, surface plasmon resonance, and flow cytometry. We also applied fluorescent annexin V in the detection of apoptotic cells by flow cytometry and fluorescent microscopy. Interestingly, sfGFP-ANXV fusion was more sensitive to early apoptotic stressed HeLa cells than fluorescein-conjugated ANXV. This highly expressed and functional sfGFP-ANXV fusion protein provides a promising ready-to-use molecular tool for quantifying liposomes (or similarly exosomes) and detecting apoptosis in cells. PMID- 28579963 TI - Olesoxime Inhibits Cardioplegia-Induced Ischemia/Reperfusion Injury. A Study in Langendorff-Perfused Rabbit Hearts. AB - Objective: During cardioplegia, which is often used in cardiac surgery, the heart is subjected to global ischemia/reperfusion injury, which can result in a post operative impairment of cardiac function. Mitochondria permeability transition pores (MPTP) play a key role in cardiomyocyte survival after ischemia/reperfusion injury. It was shown in clinical settings that blockers of MPTP like cyclosporine might have a positive influence on cardiac function after cardioplegic arrest. Olesoxime, which is a new drug with MPTP blocking activity, has been introduced as a neuroprotective therapeutic agent. This drug has not been investigated on a possible positive effect in ischemia/reperfusion injury in hearts. Therefore, the aim of our study was to investigate possible effects of olesoxime on cardiac recovery after cardioplegic arrest. Methods: We evaluated 14 mature Chinchilla bastard rabbits of 1,500-2,000 g. Rabbit hearts were isolated and perfused with constant pressure according to Langendorff. After induction of cardioplegic arrest (30 ml 4 degrees C cold Custodiol cardioplegia without and with 5 MUmol/L olesoxime, n = 7 each) the hearts maintained arrested for 90-min. Thereafter, the hearts were re-perfused for 60 min. At the end of each experiment left ventricular samples were frozen in liquid nitrogen for ATP measurements. Furthermore, heart slices were embedded in paraffin for histological analysis. During the entire experiment hemodynamic and functional data such as left ventricular pressure (LVP), dp/dt(max) and (min), pressure rate product (PRP), coronary flow, pO2, and pCO2 were also assessed. Results: Histological analysis revealed that despite the same ischemic burden for both groups markers of nitrosative and oxidative stress were significantly lower in the olesoxime group. Moreover, hearts of the olesoxime-group showed a significantly faster and better hemodynamic recovery during reperfusion. In addition, tissue ATP-levels were significantly higher in the olesoxime treated hearts. Conclusions: Olesoxime significantly protected the cardiac muscle from ischemia/reperfusion injury. PMID- 28579966 TI - Problematic Alcohol Use among University Students. AB - BACKGROUND: Alcohol is attributable to many diseases and injury-related health conditions, and it is the fifth leading risk factor of premature death globally. Hence, the objective of this study was to assess the proportion and associated factors of problematic alcohol use among University students. MATERIAL AND METHODS: Cross-sectional study was conducted among 725 randomly selected University students from November to December 2015. Data were collected by self administered questionnaire, and problematic alcohol use was assessed by Alcohol Use Disorder Identification Test. Chi-square test was used to show association of problematic use and each variable and major predicators was identified using logistic regression with 95% confidence interval (CI); and variables with p-value less than 0.05 were considered statistically significant. RESULTS: About 83 (11.4%) of the samples were problematic alcohol users of which 6.8% had medium level problems and 4.6% had high level problems. Significantly associated variables with problematic alcohol use among students were presence of social phobia (AOR = 1.7, 95% CI: 1.0, 2.8), lifetime use of any substance (AOR = 6.9, 95% CI: 3.8, 12.7), higher score in students cumulative grade point average (AOR = 0.6, 95% CI: 0.4, 0.9), and having intimate friend who use alcohol (AOR = 2.2, 95% CI: 1.3, 3.8). CONCLUSION: Problematic alcohol use among university students was common and associated with social phobia, poor academic achievement, lifetime use of any substance, and peer pressure. Strong legislative control of alcohol in universities is important to reduce the burden of alcohol. PMID- 28579967 TI - Leader Narcissism and Outcomes in Organizations: A Review at Multiple Levels of Analysis and Implications for Future Research. AB - Narcissists often pursue leadership and are selected for leadership positions by others. At the same time, they act in their own best interest, putting the needs and interests of others at risk. While theoretical arguments clearly link narcissism and leadership, the question whether leader narcissism is good or bad for organizations and their members remains unanswered. Narcissism seems to have two sides, a bright and a dark one. This systematic literature review seeks to contribute to the ongoing academic discussion about the positive or negative impact of leader narcissism in organizations. Forty-five original research articles were categorized according to outcomes at three levels of analysis: the dyadic level (focusing on leader-follower relationships), the team level (focusing on work teams and small groups), and the organizational level. On this basis, we first summarized the current state of knowledge about the impact that leader narcissism has on outcomes at different levels of analysis. Next, we revealed similarities and contradictions between research findings within and across levels of analysis, highlighting persistent inconsistencies concerning the question whether leader narcissism has positive or negative consequences. Finally, we outlined theoretical and methodological implications for future studies of leader narcissism. This multi-level perspective ascertains a new, systematic view of leader narcissism and its consequences for organizations and their stakeholders. The article demonstrates the need for future research in the field of leader narcissism and opens up new avenues for inquiry. PMID- 28579964 TI - Association between Polymorphisms in MicroRNAs and Risk of Urological Cancer: A Meta-Analysis Based on 17,019 Subjects. AB - Accumulating evidence has demonstrated that some single nucleotide polymorphisms (SNPs) existing in miRNAs correlate with the susceptibility to urological cancers. However, a clear consensus still not reached due to the limited statistical power in individual study. Thus, we concluded a meta-analysis to systematically evaluate the association between microRNA SNPs and urological cancer risk. Eligible studies were collected from PubMed, Embase, Web of Science, and CNKI databases. Pooled odds ratio (OR) and corresponding 95% confidence interval (95% CI) were calculated to assess the strength of the relationships between three SNPs (miR-196a2, C>T rs11614913; miR-146a, G>C rs2910164; and miR 499, A>G rs3746444) and the risk of urological cancers. In addition, the stability of our analysis was evaluated by publication bias, sensitivity and heterogeneity analysis. Overall, a total of 17,019 subjects from 14 studies were included in this meta-analysis. We found that CT (miR-196a2, C>T rs11614913) was a risk factor for renal cell carcinoma (CT vs. CC: OR = 1.72, 95%CI = 1.05-2.80, P = 0.03, I2 = 66%), especially in Asian population (CT vs. CC: OR = 1.17, 95%CI = 1.04-1.32, P < 0.01, I2 = 0%). miR-146a G>C rs2910164 was a protective factor of urological cancers (C vs. G: OR = 0.87, 95%CI = 0.81-0.93, P < 0.01, I2 = 0%), especially for bladder cancer. miR-499 A>G rs3746444 was correlated with an increased risk of urological cancers, specifically in Asian population. In conclusion, our meta-analysis suggests that polymorphisms in microRNAs, miR 196a2, C>T rs11614913, miR-146a G>C rs2910164 and miR-499 A>G rs3746444, may be associated with the development of urological cancers and the risks mainly exist in Asian populations. PMID- 28579962 TI - The Crosstalk between the Gut Microbiota and Mitochondria during Exercise. AB - Many physiological changes occur in response to endurance exercise in order to adapt to the increasing energy needs, mitochondria biogenesis, increased reactive oxygen species (ROS) production and acute inflammatory responses. Mitochondria are organelles within each cell that are crucial for ATP production and are also a major producer of ROS and reactive nitrogen species during intense exercise. Recent evidence shows there is a bidirectional interaction between mitochondria and microbiota. The gut microbiota have been shown to regulate key transcriptional co-activators, transcription factors and enzymes involved in mitochondrial biogenesis such as PGC-1alpha, SIRT1, and AMPK genes. Furthermore, the gut microbiota and its metabolites, such as short chain fatty acids and secondary bile acids, also contribute to host energy production, ROS modulation and inflammation in the gut by attenuating TNFalpha- mediated immune responses and inflammasomes such as NLRP3. On the other hand, mitochondria, particularly mitochondrial ROS production, have a crucial role in regulating the gut microbiota via modulating intestinal barrier function and mucosal immune responses. Recently, it has also been shown that genetic variants within the mitochondrial genome, could affect mitochondrial function and therefore the intestinal microbiota composition and activity. Diet is also known to dramatically modulate the composition of the gut microbiota. Therefore, studies targeting the gut microbiota can be useful for managing mitochondrial related ROS production, pro-inflammatory signals and metabolic limits in endurance athletes. PMID- 28579965 TI - Neural Correlates of Psychotherapeutic Treatment of Post-traumatic Stress Disorder: A Systematic Literature Review. AB - OBJECTIVES: Post-traumatic stress disorder (PTSD) is a common psychiatric disease with changes in neural circuitries. Neurobiological models conceptualize the symptoms of PTSD as correlates of a dysfunctional stress reaction to traumatic events. Functional imaging studies showed an increased amygdala and a decreased prefrontal cortex response in PTSD patients. As psychotherapeutic approaches represent the gold standard for PTSD treatment, it is important to examine its underlying neurobiological correlates. METHODS: Studies published until August 2016 were selected through systematic literature research in the databases PubMed, PsychInfo, and Cochrane Library's Central Register of Controlled Trials or were identified manually by searching reference lists of selected articles. Search terms were "neural correlates" OR "fMRI" OR "SPECT," AND "therapy" AND "PTSD." A total of 19 articles were included in the present review whereof 15 studies compared pre-to-post-therapy signal changes, six studies related pre treatment activity to pre-to-post-symptom improvement, and four studies compared neural correlates of responders versus non-responders. The disposed therapy forms were cognitive behavioral therapy (CBT), eye movement desensitization and reprocessing, cognitive therapy, exposure therapy, mindfulness-based intervention, brief eclectic psychotherapy, and unspecified therapy. RESULTS: Successful psychotherapy of PTSD was repeatedly shown to be accompanied by decreased activity in the amygdala and the insula as well as increased activity in the dorsal anterior cingulate cortex (dACC) and hippocampus. Elevated dACC activity prior to treatment was related to subsequent treatment success and a positive predictor for treatment response. Elevated amygdala and insula pre treatment activities were related to treatment failure. DISCUSSION: Decreased activity in limbic brain regions and increased activity in frontal brain areas in PTSD patients after successful psychotherapeutic treatment might reflect regained top-down control over previously impaired bottom-up processes. PMID- 28579969 TI - Ten Years toward Equity: Preliminary Results from a Follow-Up Case Study of Academic Computing Culture. AB - Just over 10 years ago, we conducted a culture study of the Computer Science Department at the flagship University of Illinois at Urbana-Champaign, one of the top five computing departments in the country. The study found that while the department placed an emphasis on research, it did so in a way that, in conjunction with a lack of communication and transparency, devalued teaching and mentoring, and negatively impacted the professional development, education, and sense of belonging of the students. As one part of a multi-phase case study spanning over a decade, this manuscript presents preliminary findings from our latest work at the university. We detail early comparisons between data gathered at the Department of Computer Science at the University of Illinois at Urbana Champaign in 2005 and our most recent pilot case study, a follow-up research project completed in 2016. Though we have not yet completed the full data collection, we find it worthwhile to reflect on the pilot case study data we have collected thus far. Our data reveals improvements in the perceptions of undergraduate teaching quality and undergraduate peer mentoring networks. However, we also found evidence of continuing feelings of isolation, incidents of bias, policy opacity, and uneven policy implementation that are areas of concern, particularly with respect to historically underrepresented groups. We discuss these preliminary follow-up findings, offer research and methodological reflections, and share next steps for applied research that aims to create positive cultural change in computing. PMID- 28579970 TI - Predicting Disability after Ischemic Stroke Based on Comorbidity Index and Stroke Severity-From the Virtual International Stroke Trials Archive-Acute Collaboration. AB - BACKGROUND AND AIM: The availability and access of hospital administrative data [coding for Charlson comorbidity index (CCI)] in large data form has resulted in a surge of interest in using this information to predict mortality from stroke. The aims of this study were to determine the minimum clinical data set to be included in models for predicting disability after ischemic stroke adjusting for CCI and clinical variables and to evaluate the impact of CCI on prediction of outcome. METHOD: We leverage anonymized clinical trial data in the Virtual International Stroke Trials Archive. This repository contains prospective data on stroke severity and outcome. The inclusion criteria were patients with available stroke severity score such as National Institutes of Health Stroke Scale (NIHSS), imaging data, and outcome disability score such as 90-day Rankin Scale. We calculate CCI based on comorbidity data in this data set. For logistic regression, we used these calibration statistics: Nagelkerke generalised R2 and Brier score; and for discrimination we used: area under the receiver operating characteristics curve (AUC) and integrated discrimination improvement (IDI). The IDI was used to evaluate improvement in disability prediction above baseline model containing age, sex, and CCI. RESULTS: The clinical data among 5,206 patients (55% males) were as follows: mean age 69 +/- 13 years, CCI 4.2 +/- 0.8, and median NIHSS of 12 (IQR 8, 17) on admission and 9 (IQR 5, 15) at 24 h. In Model 2, adding admission NIHSS to the baseline model improved AUC from 0.67 (95% CI 0.65-0.68) to 0.79 (95% CI 0.78-0.81). In Model 3, adding 24-h NIHSS to the baseline model resulted in substantial improvement in AUC to 0.90 (95% CI 0.89 0.91) and increased IDI by 0.23 (95% CI 0.22-0.24). Adding the variable recombinant tissue plasminogen activator did not result in a further change in AUC or IDI to this regression model. In Model 3, the variable NIHSS at 24 h explains 87.3% of the variance of Model 3, follow by age (8.5%), comorbidity (3.7%), and male sex (0.5%). CONCLUSION: Our results suggest that prediction of disability after ischemic stroke should at least include 24-h NIHSS and age. The variable CCI is less important for prediction of disability in this data set. PMID- 28579968 TI - Problem Gambling among Adolescent Girls in Croatia-The Role of Different Psychosocial Predictors. AB - Although, compared to boys, adolescent girls gamble less often and less problematically, prevalence studies still show significant numbers of at risk/problem gamblers among girls. However, girl gambling has been on the sidelines of adolescent gambling research. The available studies usually focus only on a narrow set of correlates often ignoring that adolescent gambling is a complex phenomenon determined by various factors. Also, they often measure gambling related consequences with instruments that are not specifically developed for use on adolescents. In order to contribute to a better understanding of adolescent gambling this study focuses on problem gambling among girls. We consider different social, cognitive, motivational and behavioral factors as predictors of girl problem gambling. A total of 1,372 high-school girls from 7 Croatian cities participated in the study. They provided data on their gambling activities, peer gambling, cognitive distortions related to gambling, motivation for gambling, and levels of general risky behavior. As the only instrument developed specifically for use on adolescents, the Canadian Adolescent Gambling Inventory was used to examine adverse gambling consequences. Results show 7.4% of girls can be considered regular gamblers, and out of those who gambled at least once in their lifetime (n = 862), 11.2% already experience mild adverse consequences because of their gambling (at risk gamblers), with 3.2% experiencing serious consequences (problem gamblers). In general, girls seem to prefer lotto and scratch cards, but sports betting seems to be the preferred game of choice among regular girl gamblers. A hierarchical regression model confirmed the importance of much the same factors identified as risky for the development of problem gambling among adolescent boys-cognitive distortions, motives to earn money, to be better at gambling and to relax, the experiences of winning large and the drive to continue gambling, together with social factors such as having friends who also gamble, being involved in other risky and delinquent behavior and higher gambling frequency. Results call into question the importance of the motive to feel better for adolescent girls problem gambling. We discuss implications of our findings for both universal and indicated youth gambling prevention programs. PMID- 28579972 TI - Editorial: Vestibular Migraine. PMID- 28579971 TI - Altered Default Mode Network on Resting-State fMRI in Children with Infantile Spasms. AB - Infantile spasms (IS) syndrome is an age-dependent epileptic encephalopathy, which occurs in children characterized by spasms, impaired consciousness, and hypsarrhythmia. Abnormalities in default mode network (DMN) might contribute to the loss of consciousness during seizures and cognitive deficits in children with IS. The purpose of the present study was to investigate the changes in DMN with functional connectivity (FC) and amplitude of low-frequency fluctuation (ALFF), the two methods to discover the potential neuronal underpinnings of IS. The consistency of the two calculate methods of DMN abnormalities in IS patients was also our main focus. To avoid the disturbance of interictal epileptic discharge, our testing was performed within the interictal durations without epileptic discharges. Resting-state fMRI data were collected from 13 patients with IS and 35 sex- and age-matched healthy controls. FC analysis with seed in posterior cingulate cortex (PCC) was used to compare the differences between two groups. We chose PCC as the seed region because PCC is the only node in the DMN that directly interacts with virtually all other nodes according to previous studies. Furthermore, the ALFF values within the DMN were also calculated and compared between the two groups. The FC results showed that IS patients exhibited markedly reduced connectivity between posterior seed region and other areas within DMN. In addition, part of the brain areas within the DMN showing significant difference of FC had significantly lower ALFF signal in the patient group than that in the healthy controls. The observed disruption in DMN through the two methods showed that the coherence of brain signal fluctuation in DMN during rest was broken in IS children. Neuronal functional impairment or altered integration in DMN would be one neuroimaging characteristic, which might help us to understand the underlying neural mechanism of IS. Further studies are needed to determine whether the disturbed FC and ALFF observed in the DMN are related to cognitive performance in IS patients. PMID- 28579973 TI - Conflicting Role of Mycobacterium Species in Multiple Sclerosis. AB - Mycobacterium is a genus of aerobic and acid-fast bacteria, which include several pathogenic organisms that cause serious diseases in mammals. Previous studies have associated the immune response against mycobacteria with multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system with unknown etiology. The role of mycobacteria in the pathological process has been controversial and often conflicting. We provide a detailed review of the mycobacteria that have been linked to MS over the last three decades, with a focus on Mycobacterium bovis bacille Calmette-Guerin vaccine for human and oral exposure to Mycobacterium avium subsp. paratuberculosis. We will also discuss the exposure and genetic susceptibility to mycobacterial infection, the protective role of vaccination, as well as the possible mechanisms involved in initiating or worsening MS symptoms, with particular emphasis on the molecular mimicry between mycobacterial and human proteins. Finally, we will introduce topics such as heat shock proteins and recognition by innate immunity, and toll-like receptor signaling-mediated responses to Mycobacterium exposure. PMID- 28579974 TI - Tracheoesophageal Fistula Caused by Tracheostomy in a Patient with Myasthenia Gravis after a Myasthenic Crisis. AB - A 57-year-old woman with myasthenia gravis (MG), who had experienced a myasthenic crisis, complained of coughing while drinking. At first, this appeared to be a sequela of the myasthenic crisis. However, after further investigation, the problem was identified as a tracheoesophageal fistula, a complication of tracheostomy. Here, we describe this special case in the hope that we can improve diagnostic accuracy by providing a reminder for other physicians to consider the differences between MG and tracheoesophageal fistula. It is very important to pay more attention to such situations in clinical scenarios and administer the most appropriate treatment without delay. PMID- 28579975 TI - The Eight and a Half Year Journey of Undiagnosed AD: Gene Sequencing and Funding of Advanced Genetic Testing Has Led to Hope and New Beginnings. AB - BACKGROUND: Activity-dependent neuroprotective protein (ADNP) is one of the most prevalent de novo mutated genes in syndromic autism spectrum disorders, driving a general interest in the gene and the syndrome. AIM: The aim of this study was to provide a detailed developmental case study of ADNP p.Tyr719* mutation toward improvements in (1) diagnostic procedures, (2) phenotypic scope, and (3) interventions. METHODS: Longitudinal clinical and parental reports. RESULTS: AD (currently 11-year-old) had several rare congenital anomalies including imperforate anus that was surgically repaired at 2 days of age. Her findings were craniofacial asymmetries, global developmental delay, autistic behaviors (loss of smile and inability to make eye contact at the age of 15 months), and slow thriving as she gradually matures. Comprehensive diagnostic procedures at 3 years resulted in no definitive diagnosis. With parental persistence, AD began walking at 3.5 years (skipping crawling). At the age of 8.5 years, AD was subjected to whole exome sequencing, compared to the parents and diagnosed as carrying an ADNP p.Tyr719* mutation, a causal recurring mutation in ADNP (currently ~17/80 worldwide). Brain magnetic resonance imaging demonstrated mild generalized cerebral volume loss with reduced posterior white matter. AD is non-verbal, communicating with signs and word approximations. She continues to make slow but forward developmental progress, and her case teaches newly diagnosed children within the ADNP Kids Research Foundation. CONCLUSION: This case study emphasizes the importance of diagnosis and describes, for the first time, early motor intervention therapies. Detailed developmental profile of selected cases leads to better treatments. PMID- 28579976 TI - Microbial Community Dynamics in Soil Depth Profiles Over 120,000 Years of Ecosystem Development. AB - Along a long-term ecosystem development gradient, soil nutrient contents and mineralogical properties change, therefore probably altering soil microbial communities. However, knowledge about the dynamics of soil microbial communities during long-term ecosystem development including progressive and retrogressive stages is limited, especially in mineral soils. Therefore, microbial abundances (quantitative PCR) and community composition (pyrosequencing) as well as their controlling soil properties were investigated in soil depth profiles along the 120,000 years old Franz Josef chronosequence (New Zealand). Additionally, in a microcosm incubation experiment the effects of particular soil properties, i.e., soil age, soil organic matter fraction (mineral-associated vs. particulate), O2 status, and carbon and phosphorus additions, on microbial abundances (quantitative PCR) and community patterns (T-RFLP) were analyzed. The archaeal to bacterial abundance ratio not only increased with soil depth but also with soil age along the chronosequence, coinciding with mineralogical changes and increasing phosphorus limitation. Results of the incubation experiment indicated that archaeal abundances were less impacted by the tested soil parameters compared to Bacteria suggesting that Archaea may better cope with mineral-induced substrate restrictions in subsoils and older soils. Instead, archaeal communities showed a soil age-related compositional shift with the Bathyarchaeota, that were frequently detected in nutrient-poor, low-energy environments, being dominant at the oldest site. However, bacterial communities remained stable with ongoing soil development. In contrast to the abundances, the archaeal compositional shift was associated with the mineralogical gradient. Our study revealed, that archaeal and bacterial communities in whole soil profiles are differently affected by long term soil development with archaeal communities probably being better adapted to subsoil conditions, especially in nutrient-depleted old soils. PMID- 28579977 TI - In silico Prediction, in vitro Antibacterial Spectrum, and Physicochemical Properties of a Putative Bacteriocin Produced by Lactobacillus rhamnosus Strain L156.4. AB - A bacteriocinogenic Lactobacillus rhamnosus L156.4 strain isolated from the feces of NIH mice was identified by 16S rRNA gene sequencing and MALDI-TOF mass spectrometry. The entire genome was sequenced using Illumina, annotated in the PGAAP, and RAST servers, and deposited. Conserved genes associated with bacteriocin synthesis were predicted using BAGEL3, leading to the identification of an open reading frame (ORF) that shows homology with the L. rhamnosus GG (ATCC 53103) prebacteriocin gene. The encoded protein contains a conserved protein motif associated a structural gene of the Enterocin A superfamily. We found ORFs related to the prebacteriocin, immunity protein, ABC transporter proteins, and regulatory genes with 100% identity to those of L. rhamnosus HN001. In this study, we provide evidence of a putative bacteriocin produced by L. rhamnosus L156.4 that was further confirmed by in vitro assays. The antibacterial activity of the substances produced by this strain was evaluated using the deferred agar spot and spot-on-the lawn assays, and a wide antimicrobial activity spectrum against human and foodborne pathogens was observed. The physicochemical characterization of the putative bacteriocin indicated that it was sensitive to proteolytic enzymes, heat stable and maintained its antibacterial activity in a pH ranging from 3 to 9. The activity against Lactobacillus fermentum, which was used as an indicator strain, was detected during bacterial logarithmic growth phase, and a positive correlation was confirmed between bacterial growth and production of the putative bacteriocin. After a partial purification from cell free supernatant by salt precipitation, the putative bacteriocin migrated as a diffuse band of approximately 1.0-3.0 kDa by SDS-PAGE. Additional studies are being conducted to explore its use in the food industry for controlling bacterial growth and for probiotic applications. PMID- 28579978 TI - The Highly Conserved Asp23 Family Protein YqhY Plays a Role in Lipid Biosynthesis in Bacillus subtilis. AB - In most bacteria, fatty acid biosynthesis is an essential process that must be controlled by the availability of precursors and by the needs of cell division. So far, no mechanisms controlling synthesis of malonyl-coenzyme A (CoA), the committed step in fatty acid synthesis, have been identified in the Gram-positive model bacterium Bacillus subtilis. We have studied the localization and function of two highly expressed proteins of unknown function, YqhY and YloU. Both proteins are members of the conserved and widespread Asp23 family. While the deletion of yloU had no effect, loss of the yqhY gene induced the rapid acquisition of suppressor mutations. The vast majority of these mutations affect subunits of the acetyl-CoA carboxylase (ACCase) complex, the enzyme that catalyzes the formation of malonyl-CoA. Moreover, lack of yqhY is accompanied by the formation of lipophilic clusters in the polar regions of the cells indicating an increased activity of ACCase. Our results suggest that YqhY controls the activity of ACCase and that this control results in inhibition of ACCase activity. Hyperactivity of the enzyme complex in the absence of YqhY does then provoke mutations that cause reduced ACCase activity. PMID- 28579980 TI - Vaginal Lactobacillus Inhibits HIV-1 Replication in Human Tissues Ex Vivo. AB - Lactobacillus species, which dominate vaginal microbiota of healthy reproductive age women, lower the risks of sexually transmitted infections, including the risk of human immunodeficiency virus (HIV) acquisition. The exact mechanisms of this protection remain to be understood. Here, we investigated these mechanisms in the context of human cervico-vaginal and lymphoid tissues ex vivo. We found that all six Lactobacillus strains tested in these systems significantly suppressed HIV type-1 (HIV-1) infection. We identified at least three factors that mediated this suppression: (i) Acidification of the medium. The pH of the undiluted medium conditioned by lactobacilli was between 3.8 and 4.6. Acidification of the culture medium with hydrochloric acid (HCl) to this pH in control experiments was sufficient to abrogate HIV-1 replication. However, the pH of the Lactobacillus conditioned medium (CM) diluted fivefold, which reached ~6.9, was also suppressive for HIV-1 infection, while in control experiments HIV-1 infection was not abrogated when the pH of the medium was brought to 6.9 through the use of HCl. This suggested the existence of other factors responsible for HIV-1 inhibition by lactobacilli. (ii) Lactic acid. There was a correlation between the concentration of lactic acid in the Lactobacillus-CM and its ability to suppress HIV-1 infection in human tissues ex vivo. Addition of lactic acid isomers D and L to tissue culture medium at the concentration that corresponded to their amount released by lactobacilli resulted in HIV-1 inhibition. Isomer L was produced in higher quantities than isomer D and was mostly responsible for HIV-1 inhibition. These results indicate that lactic acid, in particular its L-isomer, inhibits HIV 1 independently of lowering of the pH. (iii) Virucidal effect. Incubation of HIV 1 in Lactobacillus-CM significantly suppressed viral infectivity for human tissues ex vivo. Finally, lactobacilli adsorb HIV-1, serving as a sink decreasing the number of free virions. In summary, we found that lactobacilli inhibit HIV-1 replication in human tissue ex vivo by multiple mechanisms. Further studies are needed to evaluate the potential of altering the spectra of vaginal microbiota as an effective strategy to enhance vaginal health. Human tissues ex vivo may serve as a test system for these strategies. PMID- 28579979 TI - Why Quorum Sensing Controls Private Goods. AB - Cell-cell communication, also termed quorum sensing (QS), is a widespread process that coordinates gene expression in bacterial populations. The generally accepted view is that QS optimizes the cell density-dependent benefit attained from cooperative behaviors, often in the form of secreted products referred to as "public goods." This view is challenged by an increasing number of cell associated products or "private goods" reported to be under QS-control for which a collective benefit is not apparent. A prominent example is nucleoside hydrolase from Pseudomonas aeruginosa, a periplasmic enzyme that catabolizes adenosine. Several recent studies have shown that private goods can function to stabilize cooperation by co-regulated public goods, seemingly explaining their control by QS. Here we argue that this property is a by-product of selection for other benefits rather than an adaptation. Emphasizing ecophysiological context, we propose alternative explanations for the QS control of private goods. We suggest that the benefit attained from private goods is associated with high cell density, either because a relevant ecological condition correlates with density, or because the private good is, directly or indirectly, involved in cooperative behavior. Our analysis helps guide a systems approach to QS, with implications for antivirulence drug design and synthetic biology. PMID- 28579981 TI - Assessing the Risk of Probiotic Dietary Supplements in the Context of Antibiotic Resistance. AB - Probiotic bacteria are known to harbor intrinsic and mobile genetic elements that confer resistance to a wide variety of antibiotics. Their high amounts in dietary supplements can establish a reservoir of antibiotic resistant genes in the human gut. These resistant genes can be transferred to pathogens that share the same intestinal habitat thus resulting in serious clinical ramifications. While antibiotic resistance of probiotic bacteria from food, human and animal sources have been well-documented, the resistant profiles of probiotics from dietary supplements have only been recently studied. These products are consumed with increasing regularity due to their health claims that include the improvement of intestinal health and immune response as well as prevention of acute and antibiotic-associated diarrhea and cancer; but, a comprehensive risk assessment on the spread of resistant genes to human health is lacking. Here, we highlight recent reports of antibiotic resistance of probiotic bacteria isolated from dietary supplements, and propose complementary strategies that can shed light on the risks of consuming such products in the context of a global widespread of antibiotic resistance. In concomitant with a broader screening of antibiotic resistance in probiotic supplements is the use of computational simulations, live imaging and functional genomics to harvest knowledge on the evolutionary behavior, adaptations and dynamics of probiotics studied in conditions that best represent the human gut including in the presence of antibiotics. The underlying goal is to enable the health benefits of probiotics to be exploited in a responsible manner and with minimal risk to human health. PMID- 28579982 TI - The Role of Ribonucleases and sRNAs in the Virulence of Foodborne Pathogens. AB - Contaminated food is the source of many severe infections in humans. Recent advances in food science have discovered new foodborne pathogens and progressed in characterizing their biology, life cycle, and infection processes. All this knowledge has been contributing to prevent food contamination, and to develop new therapeutics to treat the infections caused by these pathogens. RNA metabolism is a crucial biological process and has an enormous potential to offer new strategies to fight foodborne pathogens. In this review, we will summarize what is known about the role of bacterial ribonucleases and sRNAs in the virulence of several foodborne pathogens and how can we use that knowledge to prevent infection. PMID- 28579983 TI - Effect of Dietary Minerals on Virulence Attributes of Vibrio cholerae. AB - Vibrio cholerae is a water-borne pathogen responsible for causing a toxin mediated profuse diarrhea in humans, leading to severe dehydration and death in unattended patients. With increasing reports of antibiotic resistance in V. cholerae, there is a need for alternate interventional strategies for controlling cholera. A potential new strategy for treating infectious diseases involves targeting bacterial virulence rather than growth, where a pathogen's specific mechanisms critical for causing infection in hosts are inhibited. Since bacterial motility, intestinal colonization and cholera toxin are critical components in V. cholerae pathogenesis, attenuating these virulence factors could potentially control cholera in humans. In this study, the efficacy of sub-inhibitory concentration (SIC, highest concentration not inhibiting bacterial growth) of essential minerals, zinc (Zn), selenium (Se), and manganese (Mn) in reducing V. cholerae motility and adhesion to intestinal epithelial cells (Caco-2), cholera toxin production, and toxin binding to the ganglioside receptor (GM1) was investigated. Additionally, V. cholerae attachment and toxin production in an ex vivo mouse intestine model was determined. Further, the effect of Zn, Se and Mn on V. cholerae virulence genes, ctxAB (toxin production), fliA (motility), tcpA (intestinal colonization), and toxR (master regulon) was determined using real time quantitative PCR. All three minerals significantly reduced V. cholerae motility, adhesion to Caco-2 cells, and cholera toxin production in vitro, and decreased adhesion and toxin production in mouse intestine ex vivo (P < 0.05). In addition, Zn, Se, and Mn down-regulated the transcription of virulence genes, ctxAB, fliA, and toxR. Results suggest that Zn, Se, and Mn could be potentially used to reduce V. cholerae virulence. However, in vivo studies in an animal model are necessary to validate these results. PMID- 28579984 TI - Mutations of the Transporter Proteins GlpT and UhpT Confer Fosfomycin Resistance in Staphylococcus aureus. AB - With the increasing spread of methicillin-resistant Staphylococcus aureus worldwide, fosfomycin has begun to be used more often, either alone or in combination with other antibiotics, for treating methicillin-resistant S. aureus infections, resulting in the emergence of fosfomycin-resistant strains. Fosfomycin resistance is reported to be mediated by fosfomycin-modifying enzymes (FosA, FosB, FosC, and FosX) and mutations of the target enzyme MurA or the membrane transporter proteins UhpT and GlpT. Our previous studies indicated that the fos genes might not the major fosfomycin resistance mechanism in S. aureus, whereas mutations of glpT and uhpT seemed to be more related to fosfomycin resistance. However, the precise role of these two genes in S. aureus fosfomycin resistance remains unclear. The aim of the present study was to investigate the role of glpT and uhpT in S. aureus fosfomycin resistance. Homologous recombination was used to knockout the uhpT and glpT genes in S. aureus Newman. Gene complementation was generated by the plasmid pRB473 carrying these two genes. The fosfomycin minimal inhibitory concentration (MIC) of the strains was measured by the E-test to observe the influence of gene deletion on antibiotic susceptibility. In addition, growth curves were constructed to determine whether the mutations have a significant influence on bacterial growth. Deletion of uhpT, glpT, and both of them led to increased fosfomycin MIC 0.5 MUg/ml to 32 MUg/ml, 4 MUg/ml, and >1024 MUg/ml, respectively. By complementing uhpT and glpT into the deletion mutants, the fosfomycin MIC decreased from 32 to 0.5 MUg/ml and from 4 to 0.25 MUg/ml, respectively. Moreover, the transporter gene-deleted strains showed no obvious difference in growth curves compared to the parental strain. In summary, our study strongly suggests that mutations of uhpT and glpT lead to fosfomycin resistance in S. aureus, and that uhpT mutation may play a more important role. The high resistance and low biological fitness cost resulting from uhpT and glpT deletion suggest that these strains might have an evolutionary advantage in a fosfomycin-rich clinical situation, which should be closely monitored. PMID- 28579985 TI - Pathogenic Characteristics of Staphylococcus aureus Endovascular Infection Isolates from Different Clonal Complexes. AB - Staphylococcus aureus is a major cause of bacteremia and, even with appropriate clinical management, causes high morbidity, and mortality due to its involvement in endovascular complications and metastatic infections. Through different pathogenic in vivo and in vitro models we investigated the behavior of S. aureus most relevant clonal complexes (CCs) causing endovascular complications. We analyzed 14 S. aureus strains representing CC5, CC8, CC15, CC30, and CC45 that caused endovascular complications, including methicillin susceptible and resistant isolates and strains with different functionality of the agr global regulator. Their adherence to collagen, interaction with the endothelium, resistance to immune attack, capacity to form biofilm and virulence in the Galleria mellonella model were analyzed. CC30 and CC45 showed greater adhesion to collagen and CC8 showed a trend towards higher rate of intracellular persistence in endothelial cells. All CCs exhibited similar tolerance to neutrophil antimicrobial peptide hNP-1 and were capable of forming biofilms under static conditions. The virulence assay in the G. mellonella model demonstrated that CC15 and CC30 were the most and least virulent, respectively. The analysis of the genomic sequences of the most relevant virulence genes identified some CC15 specific gene patterns (absence of enterotoxins and sak gene) and variants (mainly in leucocidins and proteases), but did not reveal any gene or variant that could be responsible for the increased virulence detected for CC15 strains. Even though all the CCs were capable of causing endovascular complications, our results showed that different CCs are likely to produce these complications through different mechanisms which, if confirmed in more sophisticated models, would indicate the need to more specific management and therapeutic approaches. PMID- 28579986 TI - HIV Aspartic Peptidase Inhibitors Modulate Surface Molecules and Enzyme Activities Involved with Physiopathological Events in Fonsecaea pedrosoi. AB - Fonsecaea pedrosoi is the main etiological agent of chromoblastomycosis, a recalcitrant disease that is extremely difficult to treat. Therefore, new chemotherapeutics to combat this fungal infection are urgently needed. Although aspartic peptidase inhibitors (PIs) currently used in the treatment of human immunodeficiency virus (HIV) have shown anti-F. pedrosoi activity their exact mechanisms of action have not been elucidated. In the present study, we have investigated the effects of four HIV-PIs on crucial virulence attributes expressed by F. pedrosoi conidial cells, including surface molecules and secreted enzymes, both of which are directly involved in the disease development. In all the experiments, conidia were treated with indinavir, nelfinavir, ritonavir and saquinavir (100 MUM) for 24 h, and then fungal cells were used to evaluate the effects of HIV-PIs on different virulence attributes expressed by F. pedrosoi. In comparison to untreated controls, exposure of F. pedrosoi cells to HIV-PIs caused (i) reduction on the conidial granularity; (ii) irreversible surface ultrastructural alterations, such as shedding of electron dense and amorphous material from the cell wall, undulations/invaginations of the plasma membrane with and withdrawal of this membrane from the cell wall; (iii) a decrease in both mannose-rich glycoconjugates and melanin molecules and an increase in glucosylceramides on the conidial surface; (iv) inhibition of ergosterol and lanosterol production; (v) reduction in the secretion of aspartic peptidase, esterase and phospholipase; (vi) significant reduction in the viability of non pigmented conidia compared to pigmented ones. In summary, HIV-PIs are efficient drugs with an ability to block crucial biological processes of F. pedrosoi and can be seriously considered as potential compounds for the development of new chromoblastomycosis chemotherapeutics. PMID- 28579988 TI - An Expanded Role for HLA Genes: HLA-B Encodes a microRNA that Regulates IgA and Other Immune Response Transcripts. AB - We describe a novel functional role for the HLA-B locus mediated by its intron encoded microRNA (miRNA), miR-6891-5p. We show that in vitro inhibition of miR 6891-5p impacts the expression of nearly 200 transcripts within the B lymphoblastoid cell line (B-LCL) COX, affecting a large number of metabolic pathways, including various immune response networks. The top affected transcripts following miR-6891-5p inhibition are those encoding the heavy chain of IgA. We identified a conserved miR-6891-5p target site on the 3'UTR of both immunoglobulin heavy chain alpha 1 and 2 (IGHA1 and IGHA2) transcripts and demonstrated that this miRNA modulates the expression of IGHA1 and IGHA2. B-LCLs from IgA-deficient patients expressed significantly elevated levels of miR-6891 5p when compared with unaffected family members. Upon inhibition of miR-6891-5p, IgA mRNA expression levels were increased, and IgA secretion was restored in the B-LCL of an IgA-deficient patient. These findings indicate that miR-6891-5p regulates IGHA1 and IGHA2 gene expression at the posttranscriptional level and suggest that increase in miR-6891-5p levels may contribute to the etiology of selective IgA deficiency. PMID- 28579987 TI - Killer Immunoglobulin-Like Receptor Allele Determination Using Next-Generation Sequencing Technology. AB - The impact of natural killer (NK) cell alloreactivity on hematopoietic stem cell transplantation (HSCT) outcome is still debated due to the complexity of graft parameters, HLA class I environment, the nature of killer cell immunoglobulin like receptor (KIR)/KIR ligand genetic combinations studied, and KIR+ NK cell repertoire size. KIR genes are known to be polymorphic in terms of gene content, copy number variation, and number of alleles. These allelic polymorphisms may impact both the phenotype and function of KIR+ NK cells. We, therefore, speculate that polymorphisms may alter donor KIR+ NK cell phenotype/function thus modulating post-HSCT KIR+ NK cell alloreactivity. To investigate KIR allele polymorphisms of all KIR genes, we developed a next-generation sequencing (NGS) technology on a MiSeq platform. To ensure the reliability and specificity of our method, genomic DNA from well-characterized cell lines were used; high-resolution KIR typing results obtained were then compared to those previously reported. Two different bioinformatic pipelines were used allowing the attribution of sequencing reads to specific KIR genes and the assignment of KIR alleles for each KIR gene. Our results demonstrated successful long-range KIR gene amplifications of all reference samples using intergenic KIR primers. The alignment of reads to the human genome reference (hg19) using BiRD pipeline or visualization of data using Profiler software demonstrated that all KIR genes were completely sequenced with a sufficient read depth (mean 317* for all loci) and a high percentage of mapping (mean 93% for all loci). Comparison of high-resolution KIR typing obtained to those published data using exome capture resulted in a reported concordance rate of 95% for centromeric and telomeric KIR genes. Overall, our results suggest that NGS can be used to investigate the broad KIR allelic polymorphism. Hence, these data improve our knowledge, not only on KIR+ NK cell alloreactivity in HSCT but also on the role of KIR+ NK cell populations in control of viral infections and diseases. PMID- 28579989 TI - Acute Simian Immunodeficiency Virus Infection Triggers Early and Transient Interleukin-7 Production in the Gut, Leading to Enhanced Local Chemokine Expression and Intestinal Immune Cell Homing. AB - The intestinal barrier, one of the first targets of HIV/simian immunodeficiency virus (SIV) is subjected to major physiological changes during acute infection. Having previously shown that pharmaceutical injection of interleukin-7 (IL-7) triggers chemokine expression in many organs leading to massive T-cell homing, in particular to the intestine, we here explored mucosal IL-7 expression as part of the cytokine storm occurring during the acute phase of SIV infection in rhesus macaques. Quantifying both mRNA and protein in tissues, we demonstrated a transient increase of IL-7 expression in the small intestine of SIV-infected rhesus macaques, starting with local detection of the virus by day 3 of infection. We also observed increased transcription levels of several chemokines in the small intestine. In infected macaques, ileal IL-7 expression correlated with the transcription of four of these chemokines. Among these chemokines, the macrophage and/or T-cell attractant chemokines CCL4, CCL25, and CCL28 also demonstrated increased transcription in uninfected IL-7-treated monkeys. Through immunohistofluorescence staining and image analysis, we observed increased CD8+ T cell numbers and stable CD4+ T-cell counts in the infected lamina propria (LP) during hyperacute infection. Concomitantly, circulating CCR9+beta7+ CD4+ and CD8+ T-cells dropped during acute infection, suggesting augmented intestinal homing of gut-imprinted T-cells. Finally, CD4+ macrophages transiently decreased in the submucosa and concentrated in the LP during the first days of infection. Overall, our study identifies IL-7 as a danger signal in the small intestine of Chinese rhesus macaques in response to acute SIV infection. Through stimulation of local chemokine expressions, this overexpression of IL-7 triggers immune cell recruitment to the gut. These findings suggest a role for IL-7 in the initiation of early mucosal immune responses to SIV and HIV infections. However, IL-7 triggered CD4+ T-cells and macrophages localization at viral replication sites could also participate to viral spread and establishment of viral reservoirs. PMID- 28579990 TI - The Major Qualitative Characteristics of Olive (Olea europaea L.) Cultivated in Southwest China. AB - Olive trees, originated from Mediterranean, have been cultivated in China for decades and show great adaption to local environment. However, research on this topic is limited. In this study, the major qualitative characteristics and changes of olive grown in southwest China were investigated. The results showed that oil accumulated during fruit development and reached its maximum value when fruit had fully ripened. Phenolic and flavonoid contents increase rapidly in the early growth stage (0-90 DAFB) and then begin to decrease as fruit ripens. Compared with olive from the Mediterranean, olive from China has special characteristics: higher moisture content in the fruit combined with lower percentages of unsaturated fatty acids and oil content. This is due to southwest China's climate which is wetter and cooler compared to the Mediterranean. Our study suggests that southwest China's higher annual rainfall might contribute to higher fruit moisture content while its low temperatures would be conducive to higher unsaturated fatty acid levels in the fruit. PMID- 28579991 TI - Population Genetic Structure and Phylogeography of Camellia flavida (Theaceae) Based on Chloroplast and Nuclear DNA Sequences. AB - Camellia flavida is an endangered species of yellow camellia growing in limestone mountains in southwest China. The current classification of C. flavida into two varieties, var. flavida and var. patens, is controversial. We conducted a genetic analysis of C. flavida to determine its taxonomic structure. A total of 188 individual plants from 20 populations across the entire distribution range in southwest China were analyzed using two DNA fragments: a chloroplast DNA fragment from the small single copy region and a single-copy nuclear gene called phenylalanine ammonia-lyase (PAL). Sequences from both chloroplast and nuclear DNA were highly diverse; with high levels of genetic differentiation and restricted gene flow. This result can be attributed to the high habitat heterogeneity in limestone karst, which isolates C. flavida populations from each other. Our nuclear DNA results demonstrate that there are three differentiated groups within C. flavida: var. flavida 1, var. flavida 2, and var. patens. These genetic groupings are consistent with the morphological characteristics of the plants. We suggest that the samples included in this study constitute three taxa and the var. flavida 2 group is the genuine C. flavida. The three groups should be recognized as three management units for conservation concerns. PMID- 28579992 TI - Determination of Leaf Water Content by Visible and Near-Infrared Spectrometry and Multivariate Calibration in Miscanthus. AB - Leaf water content is one of the most common physiological parameters limiting efficiency of photosynthesis and biomass productivity in plants including Miscanthus. Therefore, it is of great significance to determine or predict the water content quickly and non-destructively. In this study, we explored the relationship between leaf water content and diffuse reflectance spectra in Miscanthus. Three multivariate calibrations including partial least squares (PLS), least squares support vector machine regression (LSSVR), and radial basis function (RBF) neural network (NN) were developed for the models of leaf water content determination. The non-linear models including RBF_LSSVR and RBF_NN showed higher accuracy than the PLS and Lin_LSSVR models. Moreover, 75 sensitive wavelengths were identified to be closely associated with the leaf water content in Miscanthus. The RBF_LSSVR and RBF_NN models for predicting leaf water content, based on 75 characteristic wavelengths, obtained the high determination coefficients of 0.9838 and 0.9899, respectively. The results indicated the non linear models were more accurate than the linear models using both wavelength intervals. These results demonstrated that visible and near-infrared (VIS/NIR) spectroscopy combined with RBF_LSSVR or RBF_NN is a useful, non-destructive tool for determinations of the leaf water content in Miscanthus, and thus very helpful for development of drought-resistant varieties in Miscanthus. PMID- 28579993 TI - Selection and Validation of Appropriate Reference Genes for Quantitative Real Time PCR Normalization in Staminate and Perfect Flowers of Andromonoecious Taihangia rupestris. AB - Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) is the most commonly used and powerful method for gene expression analysis due to its high sensitivity, specificity, and high throughput, and the accuracy of this approach depends on the stability of reference genes used for normalization. Taihangia rupestris Yu and Li (Rosaceae), an andromonoecious plant, produces both bisexual flowers and unisexual male flowers within the same individual. Using qRT PCR technique, investigation of the gene expression profiling in staminate and perfect flowers would improve our understanding of the molecular mechanism in regulation of flower formation and sex differentiation in andromonoecious T. rupestris. To accurate normalize the gene expression level in Taihangia flower, 16 candidate reference genes, including 10 traditional housekeeping genes, and 6 newly stable genes, were selected based on transcriptome sequence data and previous studies. The expressions of these genes were assessed by qRT-PCR analysis in 51 samples, including 30 staminate and perfect flower samples across developmental stages and 21 different floral tissue samples from mature flowers. By using geNorm, NormFinder, BestKeeper, and comprehensive RefFinder algorithms, ADF3 combined with UFD1 were identified as the optimal reference genes for staminate flowers, while the combination of HIS3/ADF3 was the most accurate reference genes for perfect floral samples. For floral tissues, HIS3, UFD1, and TMP50 were the most suitable reference genes. Furthermore, two target genes, TruPI, and TruFBP24, involved in floral organ identity were selected to validate the most and least stable reference genes in staminate flowers, perfect flowers, and different floral tissues, indicating that the use of inappropriate reference genes for normalization will lead to the adverse results. The reference genes identified in this study will improve the accuracy of qRT-PCR quantification of target gene expression in andromonoecious T. rupestris flowers, and will facilitate the functional genomics studies on flower development and sex differentiation in the future. PMID- 28579995 TI - Live Imaging of Shoot Meristems on an Inverted Confocal Microscope Using an Objective Lens Inverter Attachment. AB - Live imaging of above ground meristems can lead to new insights in plant development not possible from static imaging of fixed tissue. The use of an upright confocal microscope offers several technical and biological advantages for live imaging floral or shoot meristems. However, many departments and core facilities possess only inverted confocal microscopes and lack the funding for an additional upright confocal microscope. Here we show that imaging of living apical meristems can be performed on existing inverted confocal microscopes with the use of an affordable and detachable InverterScope accessory. PMID- 28579994 TI - Identification of High-Temperature Tolerant Lentil (Lens culinaris Medik.) Genotypes through Leaf and Pollen Traits. AB - Rising temperatures are proving detrimental for various agricultural crops. Cool season legumes such as lentil (Lens culunaris Medik.) are sensitive to even small increases in temperature during the reproductive stage, hence the need to explore the available germplasm for heat tolerance as well as its underlying mechanisms. In the present study, a set of 38 core lentil accessions were screened for heat stress tolerance by sowing 2 months later (first week of January; max/min temperature >32/20 degrees C during the reproductive stage) than the recommended date of sowing (first week of November; max/min temperature <32/20 degrees C during the reproductive stage). Screening revealed some promising heat-tolerant genotypes (IG2507, IG3263, IG3297, IG3312, IG3327, IG3546, IG3330, IG3745, IG4258, and FLIP2009) which can be used in a breeding program. Five heat-tolerant (HT) genotypes (IG2507, IG3263, IG3745, IG4258, and FLIP2009) and five heat sensitive (HS) genotypes (IG2821, IG2849, IG4242, IG3973, IG3964) were selected from the screened germplasm and subjected to further analysis by growing them the following year under similar conditions to probe the mechanisms associated with heat tolerance. Comparative studies on reproductive function revealed significantly higher pollen germination, pollen viability, stigmatic function, ovular viability, pollen tube growth through the style, and pod set in HT genotypes under heat stress. Nodulation was remarkably higher (1.8-22-fold) in HT genotypes. Moreover, HT genotypes produced more sucrose in their leaves (65-73%) and anthers (35-78%) that HS genotypes, which was associated with superior reproductive function and nodulation. Exogenous supplementation of sucrose to in vitro-grown pollen grains, collected from heat-stressed plants, enhanced their germination ability. Assessment of the leaves of HT genotypes suggested significantly less damage to membranes (1.3-1.4-fold), photosynthetic function (1.14-1.17-fold) and cellular oxidizing ability (1.1-1.5-fold) than HS genotypes, which was linked to higher relative leaf water content (RLWC) and stomatal conductance (gS). Consequently, HT genotypes had less oxidative damage (measured as malondialdehyde and hydrogen peroxide concentration), coupled with a higher expression of antioxidants, especially those of the ascorbate-glutathione pathway. Controlled environment studies on contrasting genotypes further supported the impact of heat stress and differentiated the response of HT and HS genotypes to varying temperatures. Our studies indicated that temperatures >35/25 degrees C were highly detrimental for growth and yield in lentil. While HT genotypes tolerated temperatures up to 40/30 degrees C by producing fewer pods, the HS genotypes failed to do so even at 38/28 degrees C. The findings attributed heat tolerance to superior pollen function and higher expression of leaf antioxidants. PMID- 28579996 TI - Cyanogenic Glucosides and Derivatives in Almond and Sweet Cherry Flower Buds from Dormancy to Flowering. AB - Almond and sweet cherry are two economically important species of the Prunus genus. They both produce the cyanogenic glucosides prunasin and amygdalin. As part of a two-component defense system, prunasin and amygdalin release toxic hydrogen cyanide upon cell disruption. In this study, we investigated the potential role within prunasin and amygdalin and some of its derivatives in endodormancy release of these two Prunus species. The content of prunasin and of endogenous prunasin turnover products in the course of flower development was examined in five almond cultivars - differing from very early to extra-late in flowering time - and in one sweet early cherry cultivar. In all cultivars, prunasin began to accumulate in the flower buds shortly after dormancy release and the levels dropped again just before flowering time. In almond and sweet cherry, the turnover of prunasin coincided with increased levels of prunasin amide whereas prunasin anitrile pentoside and beta-D-glucose-1-benzoate were abundant in almond and cherry flower buds at certain developmental stages. These findings indicate a role for the turnover of cyanogenic glucosides in controlling flower development in Prunus species. PMID- 28579997 TI - Physiological Effect of Cutting Height and High Temperature on Regrowth Vigor in Orchardgrass. AB - Producers of orchardgrass (Dactylis glomerata L.) hay in the Mid-Atlantic US have experienced a reduction in regrowth vigor and a decline in the persistence of their swards. The common management practice for the region is to harvest the first growth of hay by cutting at 2.5-7.5 cm height in May or June. We hypothesize that high temperature and low cutting height interact to limit the regrowth rate. To test this, orchardgrass plants were cut to either 2.5 or 7.5 cm and then placed into environmentally controlled chambers with a constant temperature of 20 or 35 degrees C. Stubble was harvested on days 0, 1, 3, and 11 following cutting and subjected to metabolite analysis. Photosynthetic parameters were measured in the regrown leaves on days 3 and 11, and regrowth biomass was recorded on day 11. Under optimal growth temperature (20 degrees C), vegetative regrowth upon defoliation was significantly enhanced when more stubble tissue remained. However, this advantage was not observed under heat stress. Defoliation generally decreases the abundance of carbohydrate reserves in stubble. Interestingly, high temperature stimulated the accumulation of starch and ethanol soluble carbohydrates in plants cut to 7.5 cm. The similar trends were also observed in protein, amino acids, nitrate, and ammonium. These responses were not pronounced in plants cut to 2.5 cm, presumably due to inhibited photosynthesis and photosystem II photochemistry. Overall, we anticipated that heat-activated metabolite accumulation is part of adaptive response to the stress. However, modified allocation of carbohydrate and nitrogen reserves leads to reduced vegetative regrowth upon defoliation. These data suggest that cutting height management for orchardgrass may be more effective for its regrowth vigor and productivity in cool seasons or when cool weather follows hay harvest. PMID- 28579998 TI - ABA Represses the Expression of Cell Cycle Genes and May Modulate the Development of Endodormancy in Grapevine Buds. AB - Recently, the plant hormone abscisic acid (ABA) has been implicated as a key player in the regulation of endodormancy (ED) in grapevine buds (Vitis vinifera L). In this study, we show that in the vine, the expression of genes related to the biosynthesis of ABA (VvNCED1; VvNCED2) and the content of ABA are significantly higher in the latent bud than at the shoot apex, while the expression of an ABA catabolic gene (VvA8H3) showed no significant difference between either organ. A negative correlation between the content of ABA and transcript levels of cell cycle genes (CCG) was found in both tissues. This result suggested that ABA may negatively regulate the expression of CCG in meristematic tissues of grapevines. To test this proposition, the effect of ABA on the expression of CCG was analyzed in two meristematic tissues of the vine: somatic embryos and shoot apexes. The results indicated that cell cycle progression is repressed by ABA in both organs, since it down-regulated the expression of genes encoding cyclin-dependent kinases (VvCDKB1, VvCDKB2) and genes encoding cyclins of type A (VvCYCA1, VvCYCA2, VvCYCA3), B (VvCYCB), and D (VvCYCD3.2a) and up-regulated the expression of VvICK5, a gene encoding an inhibitor of CDKs. During ED, the content of ABA increased, and the expression of CCG decreased. Moreover, the dormancy-breaking compound hydrogen cyanamide (HC) reduced the content of ABA and up-regulated the expression of CCG, this last effect was abolished when HC and ABA were co-applied. Taken together, these results suggest that ABA-mediated repression of CCG transcription may be part of the mechanism through which ABA modulates the development of ED in grapevine buds. PMID- 28580000 TI - Phosphorus Over-Fertilization and Nutrient Misbalance of Irrigated Tomato Crops in Brazil. AB - Over the past 20 years, the use of center-pivot irrigation has increased tomato (Solanum lycopersicum L.) yields in Brazil from 42 Mg ha-1 to more than 80 Mg ha 1. In the absence of field trials to support fertilizer recommendations, substantial amounts of phosphorus (P) have been applied to crops. Additional P dosing has been based on an equilibrated nutrient P budget adjusted for low-P fertilizer-use efficiency in high-P fixing tropical soils. To document nutrient requirements and prevent over-fertilization, tissue samples and crop yield data can be acquired through crop surveys and fertilizer trials. Nevertheless, most tissue diagnostic methods pose numerical difficulties that can be avoided by using the nutrient balance concept. The objectives of this study were to model the response of irrigated tomato crops to P fertilization in low- and high-P soils and to provide tissue diagnostic models for high crop yield. Three P trials, arranged in a randomized block design with six P treatments (0-437 kg P ha-1) and three or four replications, were established on a low-P soil in 2013 and high-P soils in 2013 and 2014, totaling 66 plots in all. Together with crop yield data, 65 tissue samples were collected from tomato farms. We found no significant yield response to P fertilization, despite large differences in soil test P (coefficient of variation, 24%). High- and low-yield classes (cutoff: 91 Mg fruits ha-1) were classified by balance models with 78-81% accuracy using logit and Cate-Nelson partitioning models. The critical Mahalanobis distance for the partition was 5.31. Tomato yields were apparently not limited by P but were limited by calcium. There was no evidence that P fertilization should differ between center-pivot-irrigated and rain-fed crops. Use of the P budget method to arrive at the P requirement for tomato crops proved to be fallacious, as several nutrients should be rebalanced in Brazilian tomato cropping systems. PMID- 28579999 TI - Development of Chloroplast and Nuclear DNA Markers for Chinese Oaks (Quercus Subgenus Quercus) and Assessment of Their Utility as DNA Barcodes. AB - Chloroplast DNA (cpDNA) is frequently used for species demography, evolution, and species discrimination of plants. However, the lack of efficient and universal markers often brings particular challenges for genetic studies across different plant groups. In this study, chloroplast genomes from two closely related species (Quercus rubra and Castanea mollissima) in Fagaceae were compared to explore universal cpDNA markers for the Chinese oak species in Quercus subgenus Quercus, a diverse species group without sufficient molecular differentiation. With the comparison, nine and 14 plastid markers were selected as barcoding and phylogeographic candidates for the Chinese oaks. Five (psbA-trnH, matK-trnK, ycf3 trnS, matK, and ycf1) of the nine plastid candidate barcodes, with the addition of newly designed ITS and a single-copy nuclear gene (SAP), were then tested on 35 Chinese oak species employing four different barcoding approaches (genetic distance-, BLAST-, character-, and tree-based methods). The four methods showed different species identification powers with character-based method performing the best. Of the seven barcodes tested, a barcoding gap was absent in all of them across the Chinese oaks, while ITS and psbA-trnH provided the highest species resolution (30.30%) with the character- and BLAST-based methods, respectively. The six-marker combination (psbA-trnH + matK-trnK + matK + ycf1 + ITS + SAP) showed the best species resolution (84.85%) using the character-based method for barcoding the Chinese oaks. The barcoding results provided additional implications for taxonomy of the Chinese oaks in subg. Quercus, basically identifying three major infrageneric clades of the Chinese oaks (corresponding to Groups Quercus, Cerris, and Ilex) referenced to previous phylogenetic classification of Quercus. While the morphology-based allocations proposed for the Chinese oaks in subg. Quercus were challenged. A low variation rate of the chloroplast genome, and complex speciation patterns involving incomplete lineage sorting, interspecific hybridization and introgression, possibly have negative impacts on the species assignment and phylogeny of oak species. PMID- 28580001 TI - Eggplant Resistance to the Ralstonia solanacearum Species Complex Involves Both Broad-Spectrum and Strain-Specific Quantitative Trait Loci. AB - Bacterial wilt (BW) is a major disease of solanaceous crops caused by the Ralstonia solanacearum species complex (RSSC). Strains are grouped into five phylotypes (I, IIA, IIB, III, and IV). Varietal resistance is the most sustainable strategy for managing BW. Nevertheless, breeding to improve cultivar resistance has been limited by the pathogen's extensive genetic diversity. Identifying the genetic bases of specific and non-specific resistance is a prerequisite to breed improvement. A major gene (ERs1) was previously mapped in eggplant (Solanum melongena L.) using an intraspecific population of recombinant inbred lines derived from the cross of susceptible MM738 (S) * resistant AG91-25 (R). ERs1 was originally found to control three strains from phylotype I, while being totally ineffective against a virulent strain from the same phylotype. We tested this population against four additional RSSC strains, representing phylotypes I, IIA, IIB, and III in order to clarify the action spectrum of ERs1. We recorded wilting symptoms and bacterial stem colonization under controlled artificial inoculation. We constructed a high-density genetic map of the population using single nucleotide polymorphisms (SNPs) developed from genotyping by-sequencing and added 168 molecular markers [amplified fragment length polymorphisms (AFLPs), simple sequence repeats (SSRs), and sequence-related amplified polymorphisms (SRAPs)] developed previously. The new linkage map based on a total of 1,035 markers was anchored on eggplant, tomato, and potato genomes. Quantitative trait locus (QTL) mapping for resistance against a total of eight RSSC strains resulted in the detection of one major phylotype-specific QTL and two broad-spectrum QTLs. The major QTL, which specifically controls three phylotype I strains, was located at the bottom of chromosome 9 and corresponded to the previously identified major gene ERs1. Five candidate R-genes were underlying this QTL, with different alleles between the parents. The two other QTLs detected on chromosomes 2 and 5 were found to be associated with partial resistance to strains of phylotypes I, IIA, III and strains of phylotypes IIA and III, respectively. Markers closely linked to these three QTLs will be crucial for breeding eggplant with broad-spectrum resistance to BW. Furthermore, our study provides an important contribution to the molecular characterization of ERs1, which was initially considered to be a major resistance gene. PMID- 28580002 TI - Nanoparticles Alter Secondary Metabolism in Plants via ROS Burst. AB - The particles within the size range of 1 and 100 nm are known as nanoparticles (NPs). NP-containing wastes released from household, industrial and medical products are emerging as a new threat to the environment. Plants, being fixed to the two major environmental sinks where NPs accumulate - namely water and soil, cannot escape the impact of nanopollution. Recent studies have shown that plant growth, development and physiology are significantly affected by NPs. But, the effect of NPs on plant secondary metabolism is still obscure. The induction of reactive oxygen species (ROS) following interactions with NPs has been observed consistently across plant species. Taking into account the existing link between ROS and secondary signaling messengers that lead to transcriptional regulation of secondary metabolism, in this perspective we put forward the argument that ROS induced in plants upon their interaction with NPs will likely interfere with plant secondary metabolism. As plant secondary metabolites play vital roles in plant performance, communication, and adaptation, a comprehensive understanding of plant secondary metabolism in response to NPs is an utmost priority. PMID- 28580003 TI - RNA Interference: A Novel Source of Resistance to Combat Plant Parasitic Nematodes. AB - Plant parasitic nematodes cause severe damage and yield loss in major crops all over the world. Available control strategies include use of insecticides/nematicides but these have proved detrimental to the environment, while other strategies like crop rotation and resistant cultivars have serious limitations. This scenario provides an opportunity for the utilization of technological advances like RNA interference (RNAi) to engineer resistance against these devastating parasites. First demonstrated in the model free living nematode, Caenorhabtidis elegans; the phenomenon of RNAi has been successfully used to suppress essential genes of plant parasitic nematodes involved in parasitism, nematode development and mRNA metabolism. Synthetic neurotransmitants mixed with dsRNA solutions are used for in vitro RNAi in plant parasitic nematodes with significant success. However, host delivered in planta RNAi has proved to be a pioneering phenomenon to deliver dsRNAs to feeding nematodes and silence the target genes to achieve resistance. Highly enriched genomic databases are exploited to limit off target effects and ensure sequence specific silencing. Technological advances like gene stacking and use of nematode inducible and tissue specific promoters can further enhance the utility of RNAi based transgenics against plant parasitic nematodes. PMID- 28580004 TI - Genetic Analysis of NBS-LRR Gene Family in Chickpea and Their Expression Profiles in Response to Ascochyta Blight Infection. AB - Ascochyta blight is one of the major diseases of chickpea worldwide. The genetic resistance to ascochyta blight in chickpea is complex and governed by multiple QTLs. However, the molecular mechanism of quantitative disease resistance to ascochyta blight and the genes underlying these QTLs are still unknown. Most often disease resistance is determined by resistance (R) genes. The most predominant R-genes contain nucleotide binding site and leucine rich repeat (NBS LRR) domains. A total of 121 NBS-LRR genes were identified in the chickpea genome. Ninety-eight of these genes contained all essential conserved domains while 23 genes were truncated. The NBS-LRR genes were grouped into eight distinct classes based on their domain architecture. Phylogenetic analysis grouped these genes into two major clusters based on their structural variation, the first cluster with toll or interleukin-1 like receptor (TIR) domain and the second cluster either with or without a coiled-coil domain. The NBS-LRR genes are distributed unevenly across the eight chickpea chromosomes and nearly 50% of the genes are present in clusters. Thirty of the NBS-LRR genes were co-localized with nine of the previously reported ascochyta blight QTLs and were tested as potential candidate genes for ascochyta blight resistance. Expression pattern of these genes was studied in two resistant (CDC Corinne and CDC Luna) and one susceptible (ICCV 96029) genotypes at different time points after ascochyta blight infection using real-time quantitative PCR. Twenty-seven NBS-LRR genes showed differential expression in response to ascochyta blight infection in at least one genotype at one time point. Among these 27 genes, the majority of the NBS-LRR genes showed differential expression after inoculation in both resistant and susceptible genotypes which indicates the involvement of these genes in response to ascochyta blight infection. Five NBS-LRR genes showed genotype specific expression. Our study provides a new insight of NBS-LRR gene family in chickpea and the potential involvement of NBS-LRR genes in response to ascochyta blight infection. PMID- 28580005 TI - Investigating the Genetic Diversity, Population Differentiation and Population Dynamics of Cycas segmentifida (Cycadaceae) Endemic to Southwest China by Multiple Molecular Markers. AB - Climate change, species dispersal ability and habitat fragmentation are major factors influencing species distribution and genetic diversity, especially for the range-restricted and threatened taxa. Here, using four sequences of chloroplast DNAs (cpDNAs), three nuclear genes (nDNAs) and 12 nuclear microsatellites (SSRs), we investigated the genetic diversity, genetic structure, divergence time and population dynamics of Cycas segmentifida D. Y. Wang and C. Y. Deng, a threatened cycad species endemic to Southwest China. High levels of genetic diversity and genetic differentiation were revealed in C. segmentifida. Haplotypes of networks showed two evolutionary units in C. segmentifida, with the exception of the nuclear gene GTP network. Meanwhile, the UPGMA tree, structure and PCoA analyses suggested that 14 populations of C. segmentifida were divided into two clades. There was significant effect of isolation by distance (IBD) in this species. However, this species did not display a significant phylogeographic structure. The divergence time estimation suggested that its haplotypes diverged during the Middle Pleistocene. Additionally, the population dynamics inferred from different DNA sequences analyses were discordant. Bottleneck analysis showed that populations of C. segmentifida did not experience any recent bottleneck effect, but rather pointed to a contraction of its effective population size over time. Furthermore, our results suggested that the population BM which held an intact population structure and occupied undisturbed habitat was at the Hardy Weinberg equilibrium, implying that this population is a free-mating system. These genetic features provide important information for the sustainable management of C. segmentifida. PMID- 28580006 TI - Identification of QTL and Qualitative Trait Loci for Agronomic Traits Using SNP Markers in the Adzuki Bean. AB - The adzuki bean (Vigna angularis) is an important grain legume. Fine mapping of quantitative trait loci (QTL) and qualitative trait genes plays an important role in gene cloning, molecular-marker-assisted selection (MAS), and trait improvement. However, the genetic control of agronomic traits in the adzuki bean remains poorly understood. Single-nucleotide polymorphisms (SNPs) are invaluable in the construction of high-density genetic maps. We mapped 26 agronomic QTLs and five qualitative trait genes related to pigmentation using 1,571 polymorphic SNP markers from the adzuki bean genome via restriction-site-associated DNA sequencing of 150 members of an F2 population derived from a cross between cultivated and wild adzuki beans. We mapped 11 QTLs for flowering time and pod maturity on chromosomes 4, 7, and 10. Six 100-seed weight (SD100WT) QTLs were detected. Two major flowering time QTLs were located on chromosome 4, firstly VaFld4.1 (PEVs 71.3%), co-segregating with SNP marker s690-144110, and VaFld4.2 (PEVs 67.6%) at a 0.974 cM genetic distance from the SNP marker s165-116310. Three QTLs for seed number per pod (Snp3.1, Snp3.2, and Snp4.1) were mapped on chromosomes 3 and 4. One QTL VaSdt4.1 of seed thickness (SDT) and three QTLs for branch number on the main stem were detected on chromosome 4. QTLs for maximum leaf width (LFMW) and stem internode length were mapped to chromosomes 2 and 9, respectively. Trait genes controlling the color of the seed coat, pod, stem and flower were mapped to chromosomes 3 and 1. Three candidate genes, VaAGL, VaPhyE, and VaAP2, were identified for flowering time and pod maturity. VaAGL encodes an agamous-like MADS-box protein of 379 amino acids. VaPhyE encodes a phytochrome E protein of 1,121 amino acids. Four phytochrome genes (VaPhyA1, VaPhyA2, VaPhyB, and VaPhyE) were identified in the adzuki bean genome. We found candidate genes VaAP2/ERF.81 and VaAP2/ERF.82 of SD100WT, VaAP2-s4 of SDT, and VaAP2/ERF.86 of LFMW. A candidate gene VaUGT related to black seed coat color was identified. These mapped QTL and qualitative trait genes provide information helpful for future adzuki bean candidate gene cloning and MAS breeding to improve cultivars with desirable growth periods, yields, and seed coat color types. PMID- 28580007 TI - Corrigendum: Earlywood and Latewood Stable Carbon and Oxygen Isotope Variations in Two Pine Species in Southwestern China during the Recent Decades. AB - [This corrects the article on p. 2050 in vol. 7, PMID: 28119725.]. PMID- 28580008 TI - Corrigendum: Salicylic acid and reactive oxygen species interplay in the transcriptional control of defense genes expression. AB - [This corrects the article on p. 171 in vol. 6, PMID: 25852720.]. PMID- 28580010 TI - Molecular and genetic insights into an infantile epileptic encephalopathy - CDKL5 disorder. AB - BACKGROUND: The discovery that mutations in cyclin-dependent kinase-like 5 (CDKL5) gene are associated with infantile epileptic encephalopathy has stimulated world-wide research effort to understand the molecular and genetic basis of CDKL5 disorder. Given the large number of literature published thus far, this review aims to summarize current genetic studies, draw a consensus on proposed molecular functions, and point to gaps of knowledge in CDKL5 research. METHODS: A systematic review process was conducted using the PubMed search engine focusing on CDKL5 studies in the recent ten years. We analyzed these publications and summarized the findings into four sections: genetic studies, CDKL5 expression patterns, molecular functions, and animal models. We also discussed challenges and future directions in each section. RESULTS: On the clinical side, CDKL5 disorder is characterized by early onset epileptic seizures, intellectual disability, and stereotypical behaviors. On the research side, a series of molecular and genetic studies in human patients, cell cultures and animal models have established the causality of CDKL5 to the infantile epileptic encephalopathy, and pointed to a key role for CDKL5 in regulating neuronal function in the brain. Mouse models of CDKL5 disorder have also been developed, and notably, manifest behavioral phenotypes, mimicking numerous clinical symptoms of CDKL5 disorder and advancing CDKL5 research to the preclinical stage. CONCLUSIONS: Given what we have learned thus far, future identification of robust, quantitative, and sensitive outcome measures would be the key in animal model studies, particularly in heterozygous females. In the meantime, molecular and cellular studies of CDKL5 should focus on mechanism-based investigation and aim to uncover druggable targets that offer the potential to rescue or ameliorate CDKL5 disorder-related phenotypes. PMID- 28580011 TI - Bacterial pathogens and health problems of Acipenser gueldenstaedtii and Acipenser baerii sturgeons reared in the eastern Black Sea region of Turkey. AB - Farming sturgeons is an economically important practice in a number of Asian and European countries. However, since it is not widely implementedin Turkey, fertilized eggs necessary for research and industrial activities are imported from Germany. Due to the interest of several fish farms in culturing sturgeon in Turkey and the lack of relevant data, this study investigated bacteria related health problems of two different sturgeon species, the diamond sturgeon (Acipenser gueldenstaedtii) and the Siberian sturgeon (Acipenser baerii). The fungal, parasitic and bacterial pathogens found in these fish were investigated until the fish reached about 3 kg of weight (3+ years). A number of bacterial disease pathogens (Acinetobacter radioresistens, some Aeromonas and Pseudomonas species and Bacillus mycoides) and parasite Trichodina sp. and fungus Saprolegnia sp. were identified in the fish. Both phenotypic and molecular characterizations of the isolated bacteria were performed. Furthermore, swim bladder and spinal problems, cannibalism, tumor growth and mechanical injuries on the external surface of the fish were observed during the study period. PMID- 28580009 TI - The Emerging Role of the Cytoskeleton in Chromosome Dynamics. AB - Chromosomes underlie a dynamic organization that fulfills functional roles in processes like transcription, DNA repair, nuclear envelope stability, and cell division. Chromosome dynamics depend on chromosome structure and cannot freely diffuse. Furthermore, chromosomes interact closely with their surrounding nuclear environment, which further constrains chromosome dynamics. Recently, several studies enlighten that cytoskeletal proteins regulate dynamic chromosome organization. Cytoskeletal polymers that include actin filaments, microtubules and intermediate filaments can connect to the nuclear envelope via Linker of the Nucleoskeleton and Cytoskeleton (LINC) complexes and transfer forces onto chromosomes inside the nucleus. Monomers of these cytoplasmic polymers and related proteins can also enter the nucleus and play different roles in the interior of the nucleus than they do in the cytoplasm. Nuclear cytoskeletal proteins can act as chromatin remodelers alone or in complexes with other nuclear proteins. They can also act as transcription factors. Many of these mechanisms have been conserved during evolution, indicating that the cytoskeletal regulation of chromosome dynamics is an essential process. In this review, we discuss the different influences of cytoskeletal proteins on chromosome dynamics by focusing on the well-studied model organism budding yeast. PMID- 28580012 TI - One-year trajectory analysis for ADHD symptoms and its associated factors in community-based children and adolescents in Taiwan. AB - BACKGROUND: Several longitudinal studies have shown the partial symptomatic persistence of attention-deficit hyperactivity disorder (ADHD) in clinic-based samples. However, little is known about the patterns and trajectories of ADHD symptoms in community-based populations. METHODS: To differentiate developmental trajectories of ADHD symptoms over 1 year, with a four-wave quarterly follow-up in children and adolescents in the community of Taiwan, we conducted this prospective study in 1281 students in grade 3, 5, and 8. All the students in the regular classes rather than special educational classes were eligible and recruited to the study. Inattention, hyperactivity-impulsivity, and opposition defiance were rated by parent reports on the Chinese version of the Swanson, Nolan, and Pelham Version IV Scale (SNAP-IV). Group-based trajectory modeling and multivariable regression analyses were used to explore the individual, family and social factors associated with differential trajectories. RESULTS: Trajectories were classified as Low (29.9-40.6%), Intermediate (52.5-58.5%) and High (6.9 12.5%) based on the symptom severity of ADHD symptoms assessed by the SNAP-IV. The proportion of children in the high ADHD trajectory might approximately reflect the prevalence of ADHD in Taiwan. The following factors differentiated High from Low trajectories: male gender, more externalizing problems, fewer prosocial behaviors, school dysfunction, more home behavioral problems, and less perceived family support. CONCLUSIONS: Our findings that the concurrent conditions of emotional or externalizing problems, as well as impaired school and home function at baseline, might differentiate the high ADHD symptoms trajectory from others could help developing the specific measures for managing high ADHD symptoms over time in a school setting. PMID- 28580014 TI - Methane potentials of wastewater generated from hydrothermal liquefaction of rice straw: focusing on the wastewater characteristics and microbial community compositions. AB - BACKGROUND: Hydrothermal liquefaction (HTL) has been well studied for the bio-oil production from biomass. However, a large amount of wastewater with high organic content is also produced during the HTL process. Therefore, the present study investigated the methane potentials of hydrothermal liquefaction wastewater (HTLWW) obtained from HTL of rice straw at different temperatures (170-320 degrees C) and residence times (0.5-4 h). The characteristics (e.g., total organic content, organic species, molecular size distribution, etc.) of the HTLWW were studied, and at the same time, microbial community compositions involved in AD of HTLWW were analyzed. RESULTS: The highest methane yield of 314 mL CH4/g COD was obtained from the sample 200 degrees C-0.5 h (HTL temperature at 200 degrees C for 0.5 h), while the lowest methane yield 217 mL CH4/g COD was obtained from the sample 320 degrees C-0.5 h. These results were consistent with the higher amounts of hard biodegradable organics (furans, phenols, etc.) and lower amounts of easily biodegradable organics (sugars and volatile fatty acids) present in sample 320 degrees C-0.5 h compared to sample 200 degrees C-0.5 h. Size distribution analysis showed that sample 320 degrees C-0.5 h contained more organics with molecular size less than 1 kDa (79.5%) compared to sample 200 degrees C-0.5 h (66.2%). Further studies showed that hard biodegradable organics were present in the organics with molecular size higher than 1 kDa for sample 200 degrees C-0.5 h. In contrast, those organics were present in both the organics with molecular size higher and less than 1 kDa for sample 320 degrees C-0.5 h. Microbial community analysis showed that different microbial community compositions were established during the AD with different HTLWW samples due to the different organic compositions. For instance, Petrimonas, which could degrade sugars, had higher abundance in the AD of sample 200 degrees C-0.5 h (20%) compared to sample 320 degrees C-0.5 h (7%). The higher abundance of Petrimonas was consistent with the higher content of sugars in sample 200 degrees C-0.5 h. The higher Petrimonas abundance was consistent with the higher content of sugars in sample 200 degrees C-0.5 h. The genus Syntrophorhabdus could degrade phenols and its enrichment in the AD of sample 320 degrees C-0.5 h might be related with the highest content of phenols in the HTLWW. CONCLUSIONS: HTL parameters like temperature and residence time affected the biodegradability of HTLWW obtained from HTL of rice straw. More hard biodegradable organics were produced with the increase of HTL temperature. The microbial community compositions during the AD were also affected by the different organic compositions in HTLWW samples. PMID- 28580013 TI - A comparative study of anaerobic fixed film baffled reactor and up-flow anaerobic fixed film fixed bed reactor for biological removal of diethyl phthalate from wastewater: a performance, kinetic, biogas, and metabolic pathway study. AB - BACKGROUND: Phthalic acid esters, including diethyl phthalate (DEP), which are considered as top-priority and hazardous pollutants, have received significant attention over the last decades. It is vital for industries to select the best treatment technology, especially when the DEP concentration in wastewater is high. Meanwhile, anaerobic biofilm-based reactors are considered as a promising option. Therefore, in the present study, for the biological removal of DEP from synthetic wastewater, two different anaerobic biofilm-based reactors, including anaerobic fixed film baffled reactor (AnFFBR) and up-flow anaerobic fixed film fixed bed reactor (UAnFFFBR), were compared from kinetic and performance standpoints. As in the previous studies, only the kinetic coefficients have been calculated and the relationship between kinetic coefficients and their interpretation has not been evaluated, the other aim of the present study was to fill this research gap. RESULTS: In optimum conditions, 90.31 and 86.91% of COD as well as 91.11 and 88.72% of DEP removal were achieved for the AnFFBR and UAnFFFBR, respectively. According to kinetic coefficients (except biomass yield), the AnFFBR had better performance as it provided a more favorable condition for microbial growth. The Grau model was selected as the best mathematical model for designing and predicting the bioreactors' performance due to its high coefficients of determination (0.97 < R2). With regard to the insignificant variations of the calculated Grau kinetic coefficients (KG) when the organic loading rate (with constant HRT) increased, it can be concluded that both of the bioreactors can tolerate high organic loading rate and their performance is not affected by the applied DEP concentrations. CONCLUSIONS: Both the bioreactors were capable of treating low-to-high strength DEP wastewater; however, according to the experimental results and obtained kinetic coefficients, the AnFFBR indicated higher performance. Although the AnFFBR can be considered as a safer treatment option than the UAnFFFBR due to its lower DEP concentrations in sludge, the UAnFFFBR had lower VSS/TSS ratio and sludge yield, which could make it more practical for digestion. Finally, both the bioreactors showed considerable methane yield; however, compared to the UAnFFFBR, the AnFFBR had more potential for bioenergy production. Although both the selected bioreactors achieved nearly 90% of DEP removal, they can only be considered as pre-treatment methods according to the standard regulations and should be coupled with further technology. PMID- 28580015 TI - Removal of the product from the culture medium strongly enhances free fatty acid production by genetically engineered Synechococcus elongatus. AB - BACKGROUND: Cyanobacterial mutants engineered for production of free fatty acids (FFAs) secrete the products to the medium and hence are thought to be useful for biofuel production. The dAS1T mutant constructed from Synechococcus elongatus PCC 7942 has indeed a large capacity of FFA production, which is comparable to that of triacylglycerol production in green algae, but the yield of secreted FFAs is low because the cells accumulate most of the FFAs intracellularly and eventually die of their toxicity. To increase the FFA productivity, enhancement of FFA secretion is required. RESULTS: Growth of dAS1T cells but not WT cells was inhibited in a liquid medium supplemented with 0.13 g L-1 of palmitic acid. This suggested that when FFA accumulates in the medium, it would inhibit the release of FFA from the cell, leading to FFA accumulation in the cell to a toxic level. To remove FFAs from the medium during cultivation, an aqueous-organic two-phase culture system was developed. When the dAS1T culture was overlaid with isopropyl myristate (IM), the final cell density, cellular chlorophyll content, and the photosynthetic yield of PSII were greatly improved. The total amount of extracellular FFA was more than three times larger than that in the control culture grown without IM, with most of the secreted FFAs being recovered in the IM layer. The cellular FFA content was decreased by more than 85% by the presence of the IM layer. Thus, the two-phase culture system effectively facilitated FFA secretion out of the cell. An average FFA excretion rate of 1.5 mg L-1 h-1 was attained in the 432 h of cultivation, with a total amount of excreted FFA being 0.64 g L-1 of culture. These figures were more than three times higher than those reported previously for the cyanobacteria-based FFA production systems. CONCLUSIONS: Removal of FFA from the culture medium is important for improving the productivity of the FFA production system using cyanobacteria. Further increase in productivity would require an increase in both the rates of FFA production in the cell and active FFA export across the plasma membrane. PMID- 28580016 TI - Induction of immune gene expression and inflammatory mediator release by commonly used surgical suture materials: an experimental in vitro study. AB - BACKGROUND: Surgeons have a range of materials to choose from to complete wound closure, yet surprisingly very little is still known about the body's immune response to the suture materials in current use. The growing literature of adverse suture material reactions provided the objective of this study, to use in vitro assays to quantify levels of inflammation produced by seven commonly used suture materials in surgical procedures. METHODS: Human monocyte/macrophage THP-1 cells were exposed to suture materials for 1, 3 and 5 days. Gene expression and protein secretion of six inflammatory cytokines and two cell surface markers were assessed using qPCR and ELISA respectively, with LPS exposure providing a positive control. Furthermore, a IL-1beta/IL-1RA marker ratio was assessed to determine the balance between pro-/anti-inflammatory expression. RESULTS: The findings from our in vitro study suggest that four commonly used suture materials cause upregulation of pro-inflammatory markers indicative of an early foreign body reaction, with no balance from anti-inflammatory markers. CONCLUSIONS: As prolonged early pro-inflammation is known to produce delayed wound healing responses, the knowledge produced from this study has potential to improve informed surgical decision making and patient safety. This work has the capability to reduce suture-related adverse immune reactions, and therefore positively affect patient outcomes. PMID- 28580020 TI - From the Sylvia Plath Effect to Social Justice: Moving Forward With Creativity. AB - The author contrasts an early research passion, creativity and mental illness, with his current interest in creativity and social justice. Kaufman's initial research revolved around the Sylvia Plath Effect, yet was insensitive to broader implications or concerns. As his thinking about creativity has evolved, he is currently more focused on a more positive use for creativity - namely, how creativity can help issues of fairness and equity. PMID- 28580017 TI - Complete genome sequence of Vibrio campbellii strain 20130629003S01 isolated from shrimp with acute hepatopancreatic necrosis disease. AB - BACKGROUND: Vibrio campbellii is widely distributed in the marine environment and is an important pathogen of aquatic organisms such as shrimp, fish, and mollusks. An isolate of V. campbellii carrying the pirABvp gene, causing acute hepatopancreatic necrosis disease (AHPND), has been reported. There are no previous reports about the complete genome of V. campbellii causing AHPND (VCAHPND). To extend our understanding of the pathogenesis of VCAHPND at the genomic level, the genome of V. campbellii 20130629003S01 isolated from a shrimp with AHPND was sequenced and analysed. RESULTS: The complete genome sequence of V. campbellii 20130629003S01 was generated using the PacBio RSII platform with single molecule, real-time sequencing. The 20130629003S01 strain consists of two circular chromosomes (3,621,712 bp in chromosome 1 and 2,245,751 bp in chromosome 2) and four plasmids of 70,066, 204,531, 143,140, and 86,121 bp. The genome contains a total of 5855 protein coding genes, 134 tRNA genes and 37 rRNA genes. The average nucleotide identity value of 20130629003S01 and other reference V. campbellii strains was 97.46%, suggesting that they are closely related. CONCLUSIONS: The genome sequence of V. campbellii 20130629003S01 and its comparative analysis with other V. campbellii strains that we present here are important for a better understanding of the genomic characteristics of VCAHPND. PMID- 28580019 TI - Attitudes and interest in technology-based treatment and the remote monitoring of smoking among adolescents and emerging adults. AB - INTRODUCTION: Despite the public health relevance of smoking in adolescents and emerging adults, this group remains understudied and underserved. High technology utilization among this group may be harnessed as a tool for better understanding of smoking, yet little is known regarding the acceptability of mobile health (mHealth) integration. METHODS: Participants (ages 14-21) enrolled in a smoking cessation clinical trial provided feedback on their technology utilization, perceptions, and attitudes; and interest in remote monitoring for smoking. Characteristics that predicted greater technology acceptability for smoking treatment were also explored. RESULTS: Participants (N=87) averaged 19 years old and were mostly male (67%). Technology utilization was high for smart phone ownership (93%), Internet use (98%), and social media use (94%). Despite this, only one-third of participants had ever searched the Internet for cessation tips or counseling (33%). Participants showed interest in mHealth-enabled treatment (48%) and felt that it could be somewhat helpful (83%). Heavier smokers had more favorable attitudes toward technology-based treatment, as did those with smartphones and unlimited data. CONCLUSIONS: Our results demonstrate high technology utilization, favorable attitudes towards technology, and minimal concerns. Technology integration among this population should be pursued, though in a tailored fashion, to accomplish the goal of providing maximally effective, just-in-time interventions. PMID- 28580018 TI - The burden of obesity in the current world and the new treatments available: focus on liraglutide 3.0 mg. AB - The prevalence of obesity increases worldwide. Treating obesity and its associated health problems has a significant economic impact on health care systems. The unsatisfactory long-term outcomes observed in the obesity treatment are due to its complex pathophysiology and the inherent difficulties associated with maintenance of lifestyle modifications. Determined by genetic and environmental factors, obesity has been officially recognized as a chronic disease, an action that allowed the recognition of anti-obesity drugs as legitimate therapeutic options to address the growing obesity endemic. Like other chronic diseases, obesity requires long-term treatment. Pharmacological interventions, when used as an adjunct to lifestyle changes, are useful to facilitate clinically meaningful weight loss, which may impact on obesity associated comorbid conditions. In the past, medications for weight reduction were limited. However, the landscape has changed and new drugs provide additional options for weight management. Among the new drugs, liraglutide is the most studied, especially regarding its effects on the limbic system. As an adjunct to a reduced-calorie diet and increased physical activity, treatment with liraglutide 3.0 mg provides a statistically significant and clinically meaningful weight loss. Liraglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist that shares 97% homology to native GLP-1. Receptor agonists of GLP-1, including liraglutide, have emerged as effective therapies for type 2 diabetes and obesity. This review will address the major findings concerning the central regulation of appetite and the main studies that evaluated new drugs for obesity treatment, with a greater focus on liraglutide 3.0 mg. PMID- 28580022 TI - Value-Personality Link Measured With Novel Instruments Developed With an Emic Perspective. AB - The first aim of this study is to investigate whether instruments developed with an emic approach in Turkey produce the same trait-value links obtained with studies using near universal instruments, and if emic traits and value concepts are composed under agency and communal conceptions. So, the first aim of this study is to inspect the conceptual similarities in the links between traits and values. The second aim is to examine the moderating effect of disposable income on the strength of the trait-value relationship. Undergraduate and graduate students (N = 595) from six universities in Istanbul responded to the Personality Profile Scale (PPS) and the Life Goal Values (LGV) questionnaire. Second order factor analysis indicated that indigenous value and trait items were representative of communal and agency conceptions. Furthermore, most of the value trait links revealed with regression analysis, and the sinusoid relationships revealed with Pearson correlation coefficients were consistent with the findings measured with near universal instruments. Additionally found relationships between traits and especially conservation values can be interpreted as the instrumentality of agentic traits for personal as well for social focused values. Disposable income had a moderating effect on five trait-value relationships and three out of five were weaker in the low-income group. PMID- 28580021 TI - A Cognitive Distortions and Deficits Model of Suicide Ideation. AB - Although cognitive distortions and deficits are known risk factors for the development and escalation of suicide ideation and behaviour, no empirical work has examined how these variables interact to predict suicide ideation. The current study proposes an integrative model of cognitive distortions (hopelessness and negative evaluations of self and future) and deficits (problem solving deficits, problem solving avoidance, and cognitive rigidity). To test the integrity of this model, a sample of 397 undergraduate students completed measures of deficits, distortions, and current suicide ideation. A structural equation model demonstrated excellent fit, and findings indicated that only distortions have a direct effect on suicidal thinking, whereas cognitive deficits may exert their effects on suicide ideation via their reciprocal relation with distortions. Findings underscore the importance of both cognitive distortions and deficits for understanding suicidality, which may have implications for preventative efforts and treatment. PMID- 28580023 TI - Do Work Beliefs Moderate the Relationship Between Work Interruptions, Wellbeing and Psychosomatic Symptoms? AB - The purpose of this study was to explore the moderating effects of work beliefs in the relationship between work interruptions and general health, wellbeing and reports of psychosomatic symptoms. Self-report data were gathered from 310 employees from different occupational sectors. Results revealed that beliefs in hard work and morality ethic moderated the positive appraisal of work interruptions and acted as protective factors on impaired general health and wellbeing. The relationship was stronger among employees who endorsed strong beliefs in hard work and did not have regard for morality/ethics as a value. Likewise, beliefs in delay of gratification and morality/ethics moderated positive appraisal of work interruptions and reduced psychosomatic complaints. More specifically, the relationship was stronger among employees who had strong belief in the values of delayed gratification and weaker morality/ethics. These findings indicate that organisations should adopt work ideology or practices focused on work values particularly of hard work, delay of gratification and conformity to morality as protective factors that reduce the impact of work interruptions on employees' general health and wellbeing. PMID- 28580024 TI - Relationships Between Career Indecision, Search for Work Self-Efficacy, and Psychological Well-Being in Italian Never-Employed Young Adults. AB - Although different studies have investigated career choices as cognitive acts of decision-making, non-cognitive components also play an important role. The study tries to develop an empirically based model of career decision-making process linking cognitive (search for work self-efficacy - SWSE) and non-cognitive (psychological well-being - PWB) components. In particular, the study investigates, among 148 never-employed Italian young adults, to what extent the relationship between SWSE and career indecision in terms of lack of readiness (LoR) can be explained by their common relationship with PWB. Results highlighted that SWSE is negatively associated with LoR when considered in absence of PWB. However, when PWB was included in one comprehensive model, it was positively associated with SWSE and negatively related to LoR. Moreover, the presence of PWB nullified the negative association between SWSE and LoR, meaning that PWB shares a large extent of variance with these variables. Implications are discussed in the light of theoretical expectations and limitations. PMID- 28580025 TI - Using a Computer Simulation to Improve Psychological Readiness for Job Interviewing in Unemployed Individuals of Pre-Retirement Age. AB - Unemployed individuals of pre-retirement age face significant challenges in finding a new job. This may be partly due to their lack of psychological readiness to go through a job interview. We view psychological readiness as one of the psychological attitude components. It is an active conscious readiness to interact with a certain aspect of reality, based on previously acquired experience. It includes a persons' special competence to manage their activities and cope with anxiety. We created Job Interview Simulation Training (JIST) - a computer-based simulator, which allowed unemployed job seekers to practice interviewing repeatedly in a stress-free environment. We hypothesized that completion of JIST would be related to increase in pre-retirement job seekers' psychological readiness for job interviewing in real life. Participants were randomized into control (n = 18) and experimental (n = 21) conditions. Both groups completed pre- and post-intervention job interview role-plays and self reporting forms of psychological readiness for job interviewing. JIST consisted of 5 sessions of a simulated job interview, and the experimental group found it easy to use and navigate as well as helpful to prepare for interviewing. After finishing JIST-sessions the experimental group had significant decrease in heart rate during the post-intervention role-play and demonstrated significant increase in their self-rated psychological readiness, whereas the control group did not have changes in these variables. Future research may help clarify whether JIST is related to an increase in re-employment of pre-retirement job seekers. PMID- 28580026 TI - Can the Factor Structure of Defense Style Questionnaire (DSQ-40) Contribute to Our Understanding of Parental Acceptance/Rejection, Bullying, Victimization and Perceived Well-Being in Greek Early Adolescents? AB - Defense Style Questionnaire (DSQ) is a self-report instrument designed to measure defense mechanisms. Although commonly used, the DSQ-40 has not been validated in early adolescent populations. The present study sought to determine the factor validity of the DSQ-40 in a sample of Greek primary school students (N = 265). Further, it aimed to investigate the relationship between defense mechanisms and perceived parental acceptance/rejection, the participation in bullying (either as bully or victim) as well as self-reported well being. Participants completed the Greek version of DSQ-40, adapted for use by this particular age group as well as measures in order to examine its convergent and discriminant validity. The findings support a four-factor solution as the most adequate for our data. Further, it was found that defense mechanisms are related to perceived parental acceptance and rejection. Finally, the results showed that the DSQ-40 can effectively discriminate participants with high/low bullying/victimization and perceived well-being. Our results indicate that the DSQ-40 is appropriate for use in late childhood. Implications for clinical practice and future studies that would confirm the appropriateness of the scale's use in younger populations are also discussed. PMID- 28580027 TI - The Effect of Mortality Salience and Type of Life on Personality Evaluation. AB - Mortality salience, or awareness of the inevitability of one's own death, generates a state of anxiety that triggers a defense mechanism for the control of thinking that affects different human activities and psychological processes. This study aims to analyze the effect of mortality salience on the formation of impressions. The sample comprised 135 women who made inferences about a woman's personality from information about her life (type of life, LT: positive, negative), provided through five words, all positive or negative, that appeared surrounding a photograph, together with a sixth word that indicated whether she was "dead" or "alive" at the time (mortality manipulation, MM: dead, alive). The results pointed to a more negative assessment of life (Dead M - Alive M = -1.16, SE = .236, p < .001), emotional stability (Dead M - Alive M = -1.13, SE = .431, p = .010), and responsibility (Dead M - Alive M = -1.14, SE = .423, p = .008) only when the participants had access to negative information about the person assessed, and she was known to be dead. We discuss the results within the framework of Terror Management Theory, and analyze the different effects that the manipulation of mortality has on the formation of impressions depending on the type of information available. PMID- 28580028 TI - Vignette Research on Messy and Confusing Problems in Primary Mental Healthcare. AB - The average primary care psychologist feels an ever-widening gap between objective, measurable reality as described and the complex and dynamic reality they experience. To obtain a better understanding of this complex dynamic reality, we conducted an exploratory mixed-method study of primary care psychologists. We asked our participants to write vignettes about messy and confusing problems in the complex context of mental healthcare. We then examined the data in portions, exposed the patterns in the data, and subsequently analysed all in conjunction. The 113 vignettes showed experiences of psychologists dealing not only with the patient, but also with the family of the patient and/or employers, working together with other healthcare professionals, struggling with dilemmas and having mixed feelings. However, using the Cynafin Framework, 36% of the vignettes were still rated as simple. Was it because those vignettes contained fewer words (p = .006)? Or because it is difficult to grasp complexity when cause and effect are intertwined with emotions, norms and values? In the discussion, we suggest examining a complex dynamic system in terms of both the consistency of its various elements and the dynamics of the system. We also discuss how to optimize the system's adaptive self-organizing ability and how to challenge ourselves to invent negative feedback loops that can keep the complex system in equilibrium. PMID- 28580029 TI - How Does Mentoring Contribute to Gen Y Employees' Intention to Stay? An Indian Perspective. AB - The present study is aimed at investigating the impact of mentoring on intention to stay of Gen Y employees working in Indian IT industry. Also, the mediating roles of perceived organization support and affective commitment are examined. Primary data were collected from a sample of 314 Gen Y employees (born between 1980-2000) from IT industry in Delhi, NCR India. Data analysis was carried out using AMOS and SPSS to test sequential mediation. Findings reveal that mentoring has a direct influence on intention to stay of Gen Y employees and perceived organization support and affective commitment sequentially mediate the relationship between the two. This study contributes to the literature on mentoring, perceived organization support, affective commitment, and intention to stay. PMID- 28580030 TI - Conservation Motivation, Social Equality and Left-Right Ideological Preferences in Western and Eastern Europe. AB - We investigated how attitudes towards social equality can influence the relationship between conservation motivation (or openness) and personal ideological preferences on the left-right dimension, and how this relationship pattern differs between Western and Central & Eastern European (CEE) respondents. Using data from the European Social Survey (2012) we found that individual-level of conservation motivation reduces cultural egalitarianism in both the Western European and the CEE regions, but its connection with economic egalitarianism is only relevant in the CEE region where it fosters economic egalitarianism. Since both forms of egalitarianism were related to leftist ideological preferences in Western Europe, but in the CEE region only economic egalitarianism was ideologically relevant, we concluded that the classic "rigidity of the right" phenomenon is strongly related to cultural (anti)egalitarianism in Western Europe. At the same time, conservation motivation serves as a basis for the "rigidity of the left" in the post-socialist CEE region, in a great part due to the conventional egalitarian economic views. PMID- 28580032 TI - Psychology's Fragmentation and Neglect of Foundational Assumptions: An Interview With Fiona J. Hibberd. PMID- 28580031 TI - The Meaning of Voices in Understanding and Treating Psychosis: Moving Towards Intervention Informed by Collaborative Formulation. AB - From a medical perspective, hearing voices is perceived as a symptom of mental illness and their content as largely irrelevant. The effectiveness of antipsychotic medication has made it central to the treatment of psychosis. However pharmacological treatment alone is rarely sufficient for this disabling condition. This review examined the feasibility of formulating an understanding of the meaning of voices in psychosis to inform intervention. Examination of the literature demonstrated the need for a paradigm shift to a recovery model, drawing on biopsychosocial factors in formulating an understanding of the meaning of voices in the context of a person's life. Providing the opportunity to talk about their experiences may aid the development of an interpersonally coherent narrative representing opportunities for psychological growth. Findings have implications for treatment planning and assessment of outcome. Collaborative formulation regarding the subjective meaning of voices may aid in understanding their development and maintenance and guide intervention. Hearing voices with reduced negative effects on wellbeing and functioning may reduce distress and improve quality of life even in the presence of voices. CFT, CBT, Relating Therapy and Open Dialogue may be effective in applying these principles. Findings are limited by the lack of controlled studies. Further controlled studies and qualitative explorations of individual experiences are recommended. PMID- 28580033 TI - Dynamics of blood flow and thrombus formation in a multi-bypass microfluidic ladder network. AB - The reaction dynamics of a complex mixture of cells and proteins, such as blood, in branched circulatory networks within the human microvasculature or extravascular therapeutic devices such as extracorporeal oxygenation machine (ECMO) remains ill-defined. In this report we utilize a multi-bypass microfluidics ladder network design with dimensions mimicking venules to study patterns of blood platelet aggregation and fibrin formation under complex shear. Complex blood fluid dynamics within multi-bypass networks under flow were modeled using COMSOL. Red blood cells and platelets were assumed to be non-interacting spherical particles transported by the bulk fluid flow, and convection of the activated coagulation factor II, thrombin, was assumed to be governed by mass transfer. This model served as the basis for predicting formation of local shear rate gradients, stagnation points and recirculation zones as dictated by the bypass geometry. Based on the insights from these models, we were able to predict the patterns of blood clot formation at specific locations in the device. Our experimental data was then used to adjust the model to account for the dynamical presence of thrombus formation in the biorheology of blood flow. The model predictions were then compared to results from experiments using recalcified whole human blood. Microfluidic devices were coated with the extracellular matrix protein, fibrillar collagen, and the initiator of the extrinsic pathway of coagulation, tissue factor. Blood was perfused through the devices at a flow rate of 2 uL/min, translating to physiologically relevant initial shear rates of 300 and 700 s-1 for main channels and bypasses, respectively. Using fluorescent and light microscopy, we observed distinct flow and thrombus formation patterns near channel intersections at bypass points, within recirculation zones and at stagnation points. Findings from this proof-of-principle ladder network model suggest a specific correlation between microvascular geometry and thrombus formation dynamics under shear. This model holds potential for use as an integrative approach to identify regions susceptible to intravascular thrombus formation within the microvasculature as well as extravascular devices such as ECMO. PMID- 28580034 TI - The Effect of Co0.2Mn0.8Fe2O4 Ferrite Nanoparticles on the C2 Canine Mastocytoma Cell Line and Adipose-Derived Mesenchymal Stromal Stem Cells (ASCs) Cultured Under a Static Magnetic Field: Possible Implications in the Treatment of Dog Mastocytoma. AB - Cobalt manganese ferrite nanoparticles have application potential in the biomedical field, however there is limited information concerning the biological response. The aim of this work was to investigate the cytotoxic potential of cobalt-manganese ferrite nanoparticles in canine mastocytoma tumor cells (C2) and adipose-derived mesenchymal stromal stem cells (ASCs) cultured under a static magnetic field (MF). In this study, we investigated the viability and proliferation rate of ASC and C2 cells cultured with Co0.2Mn0.8Fe2O4 nanoparticles under 0.5T MF. We observed cells morphology and measured intracellular ROS generation. Thermal observations were used to characterize the thermotrophic cell behavior in different condition and RNA level of heat shock proteins and apoptotic genes was measured. Nanoparticles reduced cell viability, caused cell damage, i.e., through the formation of reactive oxygen species (ROS) and increased transcriptional level of apoptotic genes (Bcl-2, Bax, p53, p21). In addition, we have found that C2 mastocytoma cells cultured with metal oxide nanoparticles under MF exhibited unexpected biological responses, including thermotolerance and apoptotic response induced by the expression of heat shock proteins and ROS produced under a MF. Our results suggest that stimulation using MF and Co0.2Mn0.8Fe2O4 nanoparticles is involved in mechanisms associated with controlling cell proliferative potential signaling events. We can state that significant differences between normal and cancer cells in response to nanoparticles and MF are apparent. Our results show that nanoparticles and MF elevate the temperature in vitro in tumor cells, thereby increasing the expression of ROS as well as heat shock proteins. PMID- 28580035 TI - Acetic Acid Ketonization over Fe3O4/SiO2 for Pyrolysis Bio-Oil Upgrading. AB - A family of silica-supported, magnetite nanoparticle catalysts was synthesised and investigated for continuous-flow acetic acid ketonisation as a model pyrolysis bio-oil upgrading reaction. The physico-chemical properties of Fe3O4/SiO2 catalysts were characterised by using high-resolution transmission electron microscopy, X-ray absorption spectroscopy, X-ray photo-electron spectroscopy, diffuse reflectance infrared Fourier transform spectroscopy, thermogravimetric analysis and porosimetry. The acid site densities were inversely proportional to the Fe3O4 particle size, although the acid strength and Lewis character were size-invariant, and correlated with the specific activity for the vapour-phase acetic ketonisation to acetone. A constant activation energy (~110 kJ mol-1), turnover frequency (~13 h-1) and selectivity to acetone of 60 % were observed for ketonisation across the catalyst series, which implies that Fe3O4 is the principal active component of Red Mud waste. PMID- 28580036 TI - Well-Being During Recession in the UK. AB - This article explores the impact of the recent recession on the well-being of the UK working age population by comparing two measures of well-being. One is a measure of evaluative subjective well-being, a measure which previous research has shown to be stable in the UK throughout the economic crisis. The second is a different but complementary measure of positive psychological health. By comparing the trajectories of these two measures using the same sample and modelling techniques the analysis examines how different measures may lead to different interpretations. Six waves of longitudinal data from Understanding Society and the British Household Panel Survey (BHPS) are used. Latent curve models are used to analyse change over time. The results corroborate previous research showing that people's evaluative subjective well-being remained relatively stable, on average, throughout the economic crisis. In contrast, the positive psychological health measure was found to decline significantly during the recession period. The paper highlights that what we measure matters. Using single measures as summaries of well-being masks the complexity of the term, and given their appeal in the social policy arena, single measures of well-being can be seen as problematic in some scenarios. PMID- 28580038 TI - Design of HIFU transducers to generate specific nonlinear ultrasound fields. AB - Various clinical applications of high intensity focused ultrasound (HIFU) have different requirements on the pressure level and degree of nonlinear waveform distortion at the focus. Applications that utilize nonlinear waves with developed shocks are of growing interest, for example, for mechanical disintegration as well as for accelerated thermal ablation of tissue. In this work, an inverse problem of determining transducer parameters to enable formation of shocks with desired amplitude at the focus is solved. The solution was obtained by performing multiple direct simulations of the parabolic Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation for various parameters of the source. It is shown that results obtained within the parabolic approximation can be used to describe the focal region of single element spherical sources as well as complex transducer arrays. It is also demonstrated that the focal pressure level at which fully developed shocks are formed mainly depends on the focusing angle of the source and only slightly depends on its aperture and operating frequency. Using the simulation results, a 256-element HIFU array operating at 1.5 MHz frequency was designed for a specific application of boiling-histotripsy that relies on the presence of 90 100 MPa shocks at the focus. The size of the array elements and focusing angle of the array were chosen to satisfy technical limitations on the intensity at the array elements and desired shock amplitudes in the focal waveform. Focus steering capabilities of the array were analysed using an open-source T-Array software developed at Moscow State University. PMID- 28580040 TI - Pseudo Prune Belly Syndrome: Diagnosis Revealed by Imaging - A Case Report and Brief Review. AB - BACKGROUND: Prune Belly Syndrome (PBS) is a rare entity, usually found in male neonates. It comprises complex urinary tract anomalies, bilateral undescended testis and absence of anterior abdominal wall muscles. Patients with unilateral abdominal wall deficiency, unilateral undescended testis and female neonates with abdominal wall laxity are classified as Pseudo Prune Belly syndrome (PPBS). Reports on PPBS do not highlight the radiological and imaging characteristics of this syndrome and the current literature on the role of newer imaging modalities, such as Magnetic Resonance Imaging (MRI), remains relatively sparse. We describe a new case of PPBS and emphasize the role of imaging, especially ultrasound and MRI in the process of diagnosis and briefly review the subject. CASE REPORT: A male infant of four months of age was referred for evaluation of left-sided cryptorchidism. Clinical examination revealed laxity of the left abdominal wall. Ultrasound examination of the abdomen, pelvis and scrotum was performed together with routine laboratory tests. Ultrasound examination was followed by intravenous urography, voiding cysto-urethrography and MRI of the abdomen. On ultrasound, the left testis was located in the inguinal canal, the right kidney was slightly enlarged and the left kidney could not be localized. Ultrasound appearances suggested chronic obstruction in the urinary bladder. Intravenous urography, voiding cysto-urethrography and MRI confirmed the ultrasound diagnosis and also revealed a left dysplastic kidney with a dilated, tortuous ureter. Clinical and imaging features were consistent with pseudo prune belly syndrome (PPBS). CONCLUSIONS: We report a new occurrence of PPBS, a rare entity. The imaging approach for a comprehensive evaluation of the renal system in PPBS, especially with MRI, is emphasized. PMID- 28580037 TI - Anti-Phospholipase A2 Receptor Autoantibody: A New Biomarker for Primary Membranous Nephropathy. AB - Primary membranous nephropathy (also known as idiopathic membranous nephropathy, IMN) is an organ specific autoimmune kidney disease characterized by the development of immune complex deposits in the sub-epithelial spaces, podocyte effacement and glomerular capillary wall thickening in the later stages. Clinical studies have demonstrated that over 70% of patients with IMN possess circulating autoimmune antibodies specifically targeting the phospholipase A2 receptor (PLA2R) on the surface of podocytes. The autoantibodies only bind to the extracellular portion of PLA2R under the non-reducing condition, indicating that the epitope in PLA2R is conformational requiring specific disulfide bonds to maintain its structure. We recently have successfully located the dominant epitope in PLA2R to the extreme N-terminus of the receptor. This finding has opened a new direction for understanding the pathogenesis of anti-PLA2R autoantibody induced IMN and offered a strong basis for developing sensitive clinical assays for IMN diagnosis and prognosis, and potentially, new therapeutic approaches for IMN treatment. PMID- 28580039 TI - Giemsa-stained pseudo-micronuclei in rat skin treated with vitamin D3 analog, pefcalcitol. AB - BACKGROUND: Pefcalcitol, an analog of vitamin D3 (VD3), is an anti-psoriatic drug candidate that is designed to achieve much higher pharmacological effects, such as keratinocyte differentiation, than those of VD3, with fewer side effects. Genotoxicity of the compound was evaluated in a rat skin micronucleus (MN) test. RESULTS: In the rat skin MN test, pefcalcitol showed positive when specimens were stained with Giemsa, whereas neither an in vitro chromosome aberration test in CHL cells nor an in vivo bone marrow MN test in rats indicated clastogenicity. To elucidate the causes of the discrepancy, the MN specimens were re-stained with acridine orange (AO), a fluorescent dye specific to nucleic acid, and the in vivo clastogenicity of the compound in rat skin was re-evaluated. The MN-like granules that had been stained by Giemsa were not stained by AO, and AO-stained specimens indicated that pefcalcitol did not increase the frequency of micronucleated (MNed) cells. Histopathological evaluation suggested that the MN-like granules in the epidermis were keratohyalin granules contained in keratinocytes, which had highly proliferated after treatment with pefcalcitol. CONCLUSIONS: Pefcalcitol was concluded to be negative in the rat skin MN test. The present study demonstrated that Giemsa staining gave a misleading positive result in the skin MN test, because Giemsa stained keratohyalin granules. PMID- 28580041 TI - Imaging Diagnosis of a Rare Presacral Tumour. AB - BACKGROUND: Primary tumors in the presacral (retrorectal) space are extremely rare in adults, with an estimated incidence of 0.0025 to 0.014 in large referral centers. Congenital varieties are most common and comprise two thirds of these tumors. Primary retroperitoneal sarcomas in the pelvic region are extremely rare. We report the ultrasound and the corresponding Computed Tomography (CT) features of a rare presacral fibrosarcoma in an adult woman, in whom the diagnosis was confirmed by a CT-guided biopsy. CASE REPORT: A 54-year-old woman presented with a history of lumbar and perineal pain and painful defecation. Rectal examination revealed a hard mass in the retrorectal space. The patient was referred for imaging and a laboratory evaluation with a clinical diagnosis of a presacral mass. An abdominal ultrasound was followed by laboratory evaluation of routine hematological and hepato-renal parameters, abdomino-pelvic CT and a CT-guided biopsy. The imaging studies showed a presacral solid mass with nodular calcifications. There was conspicuous absence of cystic or adipose contents and of sacral erosion/destruction. However, hepatic metastasis was present. All imaging features suggested a retroperitoneal sarcoma in the pelvic region with metastases to the liver. The diagnosis was confirmed by CT-guided biopsy. CONCLUSIONS: We are reporting a new case of a very rare entity, a presacral fibrosarcoma. The imaging approach and the analysis leading to an appropriate differential diagnosis and final diagnosis is highlighted in our case report. PMID- 28580042 TI - Role of Computed Tomography (CT) in Localisation and Characterisation of Suprahyoid Neck Masses. AB - BACKGROUND: Suprahyoid neck lesions are difficult to assess only by means of clinical inspection and therefore imaging techniques are required to precisely evaluate suprahyoid neck spaces. The aim of this study was to evaluate the distinctive role of computed tomography in the assessment of anatomical source and pathological type of masses involving the suprahyoid neck spaces. MATERIAL/METHODS: Sixty patients presenting with suprahyoid neck masses underwent computed tomography of the neck. The CT findings were correlated with histopathological findings and a final diagnosis was made. RESULTS: Overall, male preponderance was seen except in the case of parotid space lesions where female predominance was seen. The most common aetiology was squamous cell carcinoma and the majority of cases (30%) were seen in patients aged 41-50 years. The majority of lesions were found in the pharyngeal mucosal space (n=16) with squamous cell carcinoma being the most common pathology. In the parotid space, pleomorphic adenoma and in the prestyloid parapharyngeal space, squamous cell carcinoma were the most common lesions, respectively. In the retropharyngeal space, an equal incidence of malignant and inflammatory aetiologies was seen. Abscesses were the most common lesions in the prevertebral space. The pleomorphic adenoma was the most common benign tumour and was also the second most common tumour in the suprahyoid neck spaces. CT had an excellent correlation with histopathological findings with sensitivity of 96.4%, specificity of 100%, positive predictive value of 100% and a negative predictive value of 91.67%. CONCLUSIONS: Computed tomography definitely has a major role to play in the evaluation of suprahyoid neck masses as it has an excellent correlation with post-operative histopathological diagnosis. PMID- 28580043 TI - Delayed Small Bowel Perforation with Findings of Severe Ischemia Following Blunt Abdominal Trauma. AB - BACKGROUND: Isolated small bowel perforation following blunt abdominal trauma (BAT) is an uncommon situation with high morbidity and mortality rates, and delayed small bowel perforation is even rarer. The pathophysiology of this condition is not clear in all cases. To the best of our knowledge, this is the first case report of delayed small bowel perforation following BAT with extensive portomesenteric vein gas. CASE REPORT: A 33-year-old male patient was admitted to the emergency department after a car accident. His initial abdominal CT showed no signs of posstraumatic injury. However, follow-up CT, performed after deterioration in his general condition, showed jejunal dilatation, intestinal intramural gas, portomesenteric vein gas, extensive intraperitoneal gas and intraabdominal free fluid. CT findings and emergent laparotomy findings were both compatible with small bowel ischemia-necrosis and perforation. CONCLUSIONS: Delayed small bowel perforation following BAT is thought to occur secondary to mesenteric hematoma formation or mesenteric tear complications. Our patient did not have any mesenteric injury or hematoma on initial abdominal CT. We are not aware of any other case report of delayed small bowel perforation following BAT without signs of intraabdominal injury on initial imaging and extensive portomesenteric vein gas on follow-up imaging. Ischemic bowel necrosis was the main cause of portomesenteric vein gas in our case. Posttraumatic patients should be kept under medical observation and abdominal CT should be preferred for imaging in case of a deterioration in the general condition and laboratory findings or appearance of new abdominal complaints. PMID- 28580044 TI - An intra-droplet particle switch for droplet microfluidics using bulk acoustic waves. AB - To transfer cell- and bead-assays into droplet-based platforms typically requires the use of complex microfluidic circuits, which calls for methods to switch the direction of the encapsulated particles. We present a microfluidic chip where the combination of acoustic manipulation at two different harmonics and a trident shaped droplet-splitter enables direction-switching of microbeads and yeast cells in droplet microfluidic circuits. At the first harmonic, the encapsulated particles exit the splitter in the center daughter droplets, while at the second harmonic, the particles exit in the side daughter droplets. This method holds promises for droplet-based assays where particle-positioning needs to be selectively controlled. PMID- 28580045 TI - Evaluation and comparison of two microfluidic size separation strategies for vesicle suspensions. AB - Two size-based separation strategies are evaluated for suspensions consisting of giant unilamellar vesicles with a broad, continuous distribution of diameters. Microfluidic devices were designed to separate an initial suspension into larger and smaller particles via either filtration or inertial focusing. These separation mechanisms were tested with suspensions of vesicles and suspensions of rigid spheres separately to illustrate the effect of deformability on separation ability. We define several separation metrics to assess the separation ability and to enable comparison between separation strategies. The filtration device significantly reduced the polydispersity of the separated vesicle fractions relative to the starting suspension and displayed an ability to separate vesicle suspensions at high throughputs. The device that utilized inertial focusing exhibited adequate polydispersity reduction and performed best with diluted vesicle suspensions. The inertial device had fewer issues with debris and trapped air, leading to short device preparation times and indicating a potential for continuous separation operation. PMID- 28580046 TI - Characterization of microfluidic clamps for immobilizing and imaging of Drosophila melanogaster larva's central nervous system. AB - Drosophila melanogaster is a well-established model organism to understand biological processes and study human diseases at the molecular-genetic level. The central nervous system (CNS) of Drosophila larvae is widely used as a model to study neuron development and network formation. This has been achieved by using various genetic manipulation tools such as microinjection to knock down certain genes or over-express proteins for visualizing the cellular activities. However, visualization of an intact-live neuronal response in larva's Central Nervous System (CNS) is challenging due to robust digging/burrowing behaviour that impedes neuroimaging. To address this problem, dissection is used to isolate and immobilize the CNS from the rest of the body. In order to obtain a true physiological response from the Drosophila CNS, it is important to avoid dissection, while the larva should be kept immobilized. In this paper, a series of microfluidic clamps were investigated for intact immobilization of the larva. As a result, an optimized structure for rapid mechanical immobilization of Drosophila larvae for CNS imaging was determined. The clamping and immobilization processes were characterized by imaging and movement measurement of the CNS through the expression of genetically encoded Calcium sensor GCaMP5 in all sensory and cholinergic interneurons. The optimal structure that included two 3D constrictions inside a narrowed channel considerably reduced the internal CNS capsule movements. It restricts the CNS movement to 10% of the motion from a glued larva and allows motion of only 10 +/- 30 MUm over 350 s immobilization which was sufficient for CNS imaging. These larva-on-a-chip platforms can be useful for studying CNS responses to sensory cues such as sound, light, chemosensory, tactile, and electric/magnetic fields. PMID- 28580047 TI - Quantifying the Spatial Inequality and Temporal Trends in Maternal Smoking Rates in Glasgow. AB - Maternal smoking is well known to adversely affect birth outcomes, and there is considerable spatial variation in the rates of maternal smoking in the city of Glasgow, Scotland. This spatial variation is a partial driver of health inequalities between rich and poor communities, and it is of interest to determine the extent to which these inequalities have changed over time. Therefore in this paper we develop a Bayesian hierarchical model for estimating the spatio-temporal pattern in smoking incidence across Glasgow between 2000 and 2013, which can identify the changing geographical extent of clusters of areas exhibiting elevated maternal smoking incidences that partially drive health inequalities. Additionally, we provide freely available software via the R package CARBayesST to allow others to implement the model we have developed. The study period includes the introduction of a ban on smoking in public places in 2006, and the results show an average decline of around 11% in maternal smoking rates over the study period. PMID- 28580048 TI - Probing Transient Valence Orbital Changes with Picosecond Valence-to-Core X-ray Emission Spectroscopy. AB - We probe the dynamics of valence electrons in photoexcited [Fe(terpy)2]2+ in solution to gain deeper insight into the Fe-ligand bond changes. We use hard X ray emission spectroscopy (XES), which combines element specificity and high penetration with sensitivity to orbital structure, making it a powerful technique for molecular studies in a wide variety of environments. A picosecond-time resolved measurement of the complete 1s X-ray emission spectrum captures the transient photoinduced changes and includes the weak valence-to-core (vtc) emission lines that correspond to transitions from occupied valence orbitals to the nascent core-hole. Vtc-XES offers particular insight into the molecular orbitals directly involved in the light-driven dynamics; a change in the metal ligand orbital overlap results in an intensity reduction and a blue energy shift in agreement with our theoretical calculations and more subtle features at the highest energies reflect changes in the frontier orbital populations. PMID- 28580049 TI - Review Strategies to Recruit and Retain Rural Patient Participating Self management Behavioral Trials. AB - Self-management plays a vital role in improving health outcomes and reducing costs in patients with cardiovascular disease (CVD) and associated risk factors. Based on existing studies, rural residents with CVD and/or risk factors show low engagement in self-management behaviors. Due to low participation in behavioral intervention trials, the most promising mechanism to promote self-management among rural populations is unknown. In turn, the purpose of this article is to review the evidence that supports strategies to recruit and retain rural patients to participate in behavioral intervention trials aimed to promote self-management of CVD and its risk factors. This review is expected to assist researchers in identifying effective solutions to overcome barriers in the recruitment and retention processes when conducting intervention research studies on the self management of CVD in rural communities. PMID- 28580050 TI - A new method for determining the optimal lagged ensemble. AB - We propose a general methodology for determining the lagged ensemble that minimizes the mean square forecast error. The MSE of a lagged ensemble is shown to depend only on a quantity called the cross-lead error covariance matrix, which can be estimated from a short hindcast data set and parameterized in terms of analytic functions of time. The resulting parameterization allows the skill of forecasts to be evaluated for an arbitrary ensemble size and initialization frequency. Remarkably, the parameterization also can estimate the MSE of a burst ensemble simply by taking the limit of an infinitely small interval between initialization times. This methodology is applied to forecasts of the Madden Julian Oscillation (MJO) from version 2 of the Climate Forecast System version 2 (CFSv2). For leads greater than a week, little improvement is found in the MJO forecast skill when ensembles larger than 5 days are used or initializations greater than 4 times per day. We find that if the initialization frequency is too infrequent, important structures of the lagged error covariance matrix are lost. Lastly, we demonstrate that the forecast error at leads >=10 days can be reduced by optimally weighting the lagged ensemble members. The weights are shown to depend only on the cross-lead error covariance matrix. While the methodology developed here is applied to CFSv2, the technique can be easily adapted to other forecast systems. PMID- 28580051 TI - Cerebral Misery Perfusion on Susceptibility Weighted Imaging in Acute Carotid Dissection. AB - The cerebral vasculature incorporates several fail-safes that must be breached before an irreversible ischemic event takes place. In particular, when autoregulatory vasodilatation fails secondary to falling cerebral perfusion pressure (CPP; stage I hemodynamic failure), increases in the oxygen extraction fraction work to maintain the cerebral metabolic rate of oxygen. Previously, failure of this mechanism, stage II hemodynamic failure, or misery perfusion, has been imaged via positron emission tomography/computed tomography (PET/CT). Current susceptibility-weighted sequences (SWI) allow for more efficient imaging of this physiology. In this case, we identify an incident of reversible ischemia caused by spontaneous carotid artery dissection using a combination of diffusion weighted imaging (DWI) and SWI. The level of hemodynamic failure identified by the imaging sequences elevated the urgency of neurointervention, expediting the patient's arrival to the neurointerventional table and thus avoiding impending irreversible ischemia. PMID- 28580052 TI - MRI diagnosis of infantile Alexander disease in a 14 month old African boy. AB - Alexander disease, also known as fibrinoid leukodystrophy, is a rare leukoencephalopathy which occurs due to a mutation in the glial fibrillary acid protein (GFAP) gene. Magnetic resonance imaging (MRI) has proven to be highly sensitive in making the diagnosis. Typical MRI findings, in combination with positive genetic blood analysis, confirm the diagnosis. PMID- 28580053 TI - Persistent proatlas with additional segmentation of the craniovertebral junction The Tsuang-Goehmann-Malformation. AB - Case study description and analysis of a complex craniovertebral dysplasia in an 8-year-old male patient, in which conventional cervical spine radiographs demonstrated a regularly differentiated occipital base, as well as the presence of two lateral masses of the proatlas vertebra and two lateral masses of the atlas vertebra. Further assessment included computed tomography of the occipital base and the upper cervical spine as well as three-dimensional reconstruction. Malsegmentation of the fourth occipital vertebra can result in various anomalies that are known as 'manifestation of the proatlas'. The occurrence of a persistent proatlas with additional segmentation of the craniovertebral junction represents an extremely rare dysplasia. To our knowledge, it is the second report concerning the persistence of a complete human proatlas vertebra. We consider the biomechanical and embryological particularities of this complex dysplasia to represent sufficient basis for future differentiation from other malformations of the fourth occipital vertebra. Comprehensive literature review and discussion about the entity will be provided. PMID- 28580054 TI - Percutaneous Cholecystostomy and Hydrodissection in Radiofrequency Ablation of Liver Subcapsular Leiomyosarcoma Metastasis Adjacent to the Gallbladder: Protective Effect. AB - Uterine leiomyosarcoma is an uncommon pathology, predominantly found in aged population. Patients with metastatic disease have poor survival and therapy mainly consists of palliative systemic chemotherapy. However, more aggressive strategies such as radiofrequency ablation (RFA) may benefit patients with limited secondary disease. RFA is considered a simple and safe modality for treatment of hepatic lesions. The benefits related to RFA include low morbidity, short hospital stay and the possibility to repeat the procedure when necessary due to recurrences. However, minor and major complications related to mechanical and thermal damage may occur, especially in cases of tumors adjacent to extrahepatic organs and those at subcapsular position. This case report shows a successful RFA of two hepatic subcapsular leiomyosarcoma metastases neighbouring the gallbladder, without a safe cleavage plane from it. Combined hydrodissection, percutaneous cholecystostomy and continuous irrigation were performed as effective techniques to prevent thermal injury. Clinical and radiological follow up demonstrates no local complication. PMID- 28580056 TI - A pictorial review of reconstructive foot and ankle surgery: elective lesser forefoot procedures. AB - This pictorial review focuses on basic procedures performed within the field of podiatric surgery, specifically for elective procedures of the lesser forefoot including the correction of hammertoes and lesser metatarsal deformities. Our goal is to demonstrate objective radiographic parameters that surgeons utilize to initially define the deformity, lead to procedure selection and judge post operative outcomes. We hope that radiologists will employ this information to improve their assessment of post-operative radiographs following reconstructive foot surgeries. First, relevant radiographic measurements are defined and their role in procedure selection explained. Second, the specific surgical procedures of the digital arthroplasty, digital arthrodesis, lesser metatarsal osteotomy, and correction of metatarsus adductus are described in detail. Finally, specific plain film radiographic findings that judge post-operative outcomes for each procedure are detailed. PMID- 28580055 TI - Lipofibromatous Hamartoma of the Median Nerve: A Case Report. AB - Lipofibromatous hamartoma is a rare and slow growing benign fibro-fatty tumor. It is characterized by the proliferation of mature adipocytes within the epineurium and the perineurium of the peripheral nerves. In the upper extremity, it most commonly affects the median nerve. Median nerve involvement commonly leads to pain, numbness, paresthesia and carpal tunnel syndrome. This article presents a case of lipofibromatous hamartoma in an 8-year-old child followed by a discussion of the epidemiology, diagnosis, imaging details and treatment options for this condition. PMID- 28580057 TI - Case of Spigelian hernia with incarcerated appendix. AB - Spigelian hernias are uncommon lateral ventral wall hernias with a significant rate of incarceration; these hernias often produce nonspecific clinical signs and symptoms as well as elusive imaging findings. Although there are reported cases of incarcerated appendices within Spigelian hernias, this case specifically illustrates the diagnostic difficulty these hernias present to both surgeons and radiologists. Additionally, we discuss important anatomy, demographics and risk factors, clinical symptoms, imaging pitfalls and recommendations for repair based on a review of literature. PMID- 28580058 TI - Hydrocele in the Canal of Nuck - CT appearance of a developmental groin anomaly. AB - Hydrocele in the Canal of Nuck is a condition of female fetal development. The Canal of Nuck is a patent tubular peritoneal fold that travels with the round ligament to its attachment on the labia major. Failure of complete obliteration of the Canal of Nuck during fetal development predisposes females to development of a hydrocele or an inguinal hernia during post-pubertal or adult stages. We present a case of a 21 year old female with a tender reducible labial mass diagnosed as a Hydrocele in the Canal of Nuck. PMID- 28580059 TI - Single coronary artery arising from the right sinus of Valsalva presenting with chest pain. AB - Single coronary artery is a rare anomaly, with a reported incidence of 0.024%. It can be diagnosed on coronary computed tomography angiography, where the presence of ostial narrowing and compression between the great vessels must be carefully excluded, since these malignant forms can lead to sudden cardiac death and other ischemic complications. We describe a case of single coronary artery arising from the right sinus of Valsalva presenting with symptoms of ischemic chest pain. PMID- 28580060 TI - Amyand's Hernia: A Case Report. AB - Amyand's hernia is a rare and atypical hernia characterized by the herniation of the appendix into the inguinal sac. This hernia may be present without symptoms until inflammation of the appendix may lead to incarceration, strangulation, necrosis, perforation or rupture. Early symptoms include tenderness and inguinal swelling which may be misdiagnosed as a strangulated hernia. This condition can be difficult to diagnose clinically. Ultrasound and Computed Tomography may aid in diagnosis. This article presents a rare case of Amyand's hernia followed by a discussion of the epidemiology, diagnosis, imaging details and treatment options for this condition. PMID- 28580061 TI - Disseminated Peritoneal Leiomyomatosis Status Post Laparoscopic Hysterectomy with Morcellation. AB - Uterine leiomyomas (fibroids) are common benign neoplasms, which develop from the muscular tissue of the uterus with an estimated incidence of 20-40% in women of reproductive age. In the early nineties, power morcellators were introduced and became commonly used during hysterectomy for symptomatic fibroids. However, if all fragments are not removed, they may parasitize to other blood supply and present as abdominal or pelvic masses. Unfortunate cases have also been reported in which uterine sarcomas seeded throughout the abdomen and pelvis secondary to morcellation. The Food and Drug Administration (FDA) estimates that 1 in 350 women undergoing hysterectomy or myomectomy for fibroids is found to have an unsuspected uterine sarcoma. As a result, the FDA issued a press release in 2014 discouraging the use of power morcellators. Recently, the FDA approved a new containment device, the PneumoLiner, for use with certain power morcellation devices. However, it is unknown if this device will help to reduce the risk of seeding fibroids and unsuspected uterine malignancies. We present a case in which a patient who underwent morcellation therapy for symptomatic fibroids presented with recurrent abdominal and pelvic leiomyomas mimicking malignancy. PMID- 28580062 TI - Dermoid of the oral cavity: case report with histopathology correlation and review of literature. AB - Dermoid cysts are rare masses of the oral cavity derived from ectodermal elements. These are benign, slow-growing tumors that are typically asymptomatic but cause complications of inflammation or dysphagia, dystonia, and airway encroachment due to mass effects. We report the case of a 17 year old female with a painless mass in the left side of the oral cavity. Ultrasound findings demonstrated non-specific findings of a cystic lesion, and definite diagnosis was made with contrast-enhanced CT and intraoperatively with pathologic confirmation. This retrospective report highlights the challenges in evaluating masses of the oral cavity with imaging and provides a comprehensive discussion on imaging of oral masses on various imaging modalities to guide diagnosis and management. PMID- 28580063 TI - Imaging Findings of Ulceroglandular Tularemia. AB - Francisella tularensis, the causative organism in Tularemia, is a relatively rare disease. There are a few radiological clues to elucidate its presence when suspicion arises. There should be strong consideration for Tularemia in the differential of any patient with its classic symptoms, diffuse cervical lymphadenopathy with evidence of necrosis, and enlarged adenoids. Ultrasound may demonstrate suppurative lymphadenopathy suggestive of infection, as in the case presented. CT often will demonstrate the extent of lymphadenopathy. On chest radiography, tularemia pneumonia is often the presenting finding, which may demonstrate bilateral or lobar infiltrates. Additionally, hilar lymphadenopathy and pleural effusions are often associated findings. Cavitary lesions may be present, which are better delineated on CT scan. We present a case of a 7-year old male who presented with a painful right-sided palpable neck mass for 9 days, who was diagnosed with Tularemia after numerous admissions. PMID- 28580064 TI - Spontaneous Rupture of the Uterine Artery in an Otherwise Normal Pregnancy. AB - Spontaneous rupture of a uterine artery in pregnancy is associated with a high rate of mortality. Although uterine artery rupture has been associated with postpartum hemorrhage, it is rarely found during pregnancy. Unfortunately, clinical signs and symptoms are usually vague and nonspecific. We report a case of a 36-year-old woman at 20 weeks gestation presenting with abdominal pain who was found to have a spontaneous uterine artery rupture. To our knowledge, this is the first case report demonstrating imaging findings in a patient with this condition. Our patient underwent successful ligation of the uterine vessel with preservation of both mother and fetus. We will discuss possible etiologies of uterine artery rupture during pregnancy, associated imaging findings, and management options. PMID- 28580066 TI - Honoring our helpers. AB - This special issue of the Journal of Radiology Case Reports honors the reviewers who donated their time and expertise throughout the year 2016 to the high quality and success of this journal. PMID- 28580065 TI - Lateral Thoracic Artery Pseudoaneurysm as a Result of Penetrating Chest Trauma. AB - Pseudoaneurysms are potentially fatal complications of vascular trauma; however, they are rarely seen as the sole complication of penetrating injury. We present a case of a pseudoaneurysm with an associated arteriovenous fistula of the left lateral thoracic artery as a result of direct trauma from a knife stab. The patient presented only with a painful, swollen left pectoralis muscle. Upon diagnosis, he was taken to the interventional radiology suite and treated successfully with fluoroscopic guided coil embolization. Cases such as these are infrequent and should encourage more aggressive use of contrast enhanced computed tomography imaging for soft tissue injury, as a missed traumatic pseudoaneurysm may result in life-threatening hemorrhage. PMID- 28580067 TI - Image-guided Percutaneous Transhepatic Removal of Fish Bone from Liver Abscess. AB - We present a case of a woman who was diagnosed with a hepatic abscess secondary to a migrated fish bone. As the patient did not improve after percutaneous drainage of the abscess, image-guided percutaneous transhepatic removal of the fish bone was performed. Fish bones in hepatic abscesses are typically removed surgically, with the fish bone left in situ in a number of cases. There has been only another reported case of percutaneous transhepatic fish bone removal. We conclude that in the rare case of a hepatic abscess complicating fish bone migration, image-guided percutaneous transhepatic removal of the offending foreign body is a feasible alternative to surgery, especially in high surgical risk patients. PMID- 28580068 TI - Mucoepidermoid carcinoma of the airways in a young adult male. AB - Mucoepidermoid carcinoma (MEC) of the airways is a rare entity most often found in young patients. We present a case of a 23 year old patient with symptoms of pneumonia, which progresses to a pulmonary abscess within a week. Diagnostic work up reveals an endobronchial obstruction by a pedunculated low grade MEC. A literature review is provided and radiological appearances are described. PMID- 28580069 TI - Granulomatous Mastitis in a Transgender Patient. AB - Granulomatous mastitis is a rare and benign inflammatory condition of the breast most commonly affecting women of child-bearing age as well as patients on oral contraceptives. This condition is important to identify due to its diagnostic mimicry of malicious entities such as breast carcinoma. Clinical and radiological findings are nonspecific and may overlap with breast carcinomas, thus pathologic confirmation is often necessary for definitive diagnosis. Although cases of granulomatous mastitis have been described in cisgender females, there have been no reported cases in the transgender patient, a growing patient population with few imaging guidelines. Transgender patients are at risk of developing this breast entity due to the use of long-term hormone treatments or presence of residual breast tissue. A trial of antibiotics or steroids may be administered. However, surgical treatment is often necessary in recurrent or refractory cases. PMID- 28580070 TI - Isolated Spongy Urethral Rupture from Abrupt Coital Distractive Force. AB - The classic presentation of penile fracture is a cracking or snap sound, with sharp pain, immediate detumescence, swelling, deformation and ecchymosis. A penile fracture involves rupture of the tunica albuginea of one or both corpora cavernosa. Concomitant urethral rupture is reported to occur in 10% to 20% of penile fracture cases. Isolated urethral injury without penile fracture is extremely rare. We report the first case of isolated pendulous urethral rupture from an abrupt coital distractive force. We include a literature review and discussion of isolated urethral trauma secondary to sexual intercourse. Retrograde urethrography rendered a stunning clinical image which was integral to the diagnosis and management of this patient's injury. PMID- 28580072 TI - Non-intubated thoracic surgery under thoracic epidural anesthesia. PMID- 28580071 TI - Factors to bear in mind regarding the use of dexmedetomidine. PMID- 28580073 TI - Anesthetic induced neurotoxicity in children. PMID- 28580074 TI - Perioperative lung protection. AB - Perioperative pulmonary complications are known to be a major cause of morbidity and mortality, and as such, contribute a large burden to the health care system globally. Anesthesiologists have an important role during the perioperative period to identify patients at risk of these complications and intervene in order to reduce them. After describing perioperative pulmonary complications and risk factors for such, this article will address preoperative, intraoperative, and postoperative lung protective strategies to try and reduce the risk of these complications. PMID- 28580077 TI - Statistical data presentation. AB - Data are usually collected in a raw format and thus the inherent information is difficult to understand. Therefore, raw data need to be summarized, processed, and analyzed. However, no matter how well manipulated, the information derived from the raw data should be presented in an effective format, otherwise, it would be a great loss for both authors and readers. In this article, the techniques of data and information presentation in textual, tabular, and graphical forms are introduced. Text is the principal method for explaining findings, outlining trends, and providing contextual information. A table is best suited for representing individual information and represents both quantitative and qualitative information. A graph is a very effective visual tool as it displays data at a glance, facilitates comparison, and can reveal trends and relationships within the data such as changes over time, frequency distribution, and correlation or relative share of a whole. Text, tables, and graphs for data and information presentation are very powerful communication tools. They can make an article easy to understand, attract and sustain the interest of readers, and efficiently present large amounts of complex information. Moreover, as journal editors and reviewers glance at these presentations before reading the whole article, their importance cannot be ignored. PMID- 28580075 TI - Role of vasopressin in current anesthetic practice. AB - Arginine vasopressin (AVP), also known as antidiuretic hormone, is a peptide endogenously secreted by the posterior pituitary in response to hyperosmolar plasma or systemic hypoperfusion states. When administered intravenously, it causes an intense peripheral vasoconstriction through stimulation of V1 receptors on the vascular smooth muscle. Patients in refractory shock associated with severe sepsis, cardiogenic or vasodilatory shock, or cardiopulmonary bypass have inappropriately low plasma levels of AVP ('relative vasopressin deficiency') and supersensitivity to exogenously-administered AVP. Low doses of AVP and its synthetic analog terlipressin can restore vasomotor tone in conditions that are resistant to catecholamines, with preservation of renal blood flow and urine output. They are also useful in the treatment of refractory arterial hypotension in patients chronically treated with renin-angiotensin system inhibitors, cardiac arrest, or bleeding esophageal varices. In the perioperative setting, they represent attractive adjunct vasopressors in advanced shock states that are unresponsive to conventional therapeutic strategies. PMID- 28580078 TI - Does preoperative anxiety felt by patients requested to participate in clinical trials related to general anesthesia before elective surgery depend on temperament? AB - BACKGROUND: Preoperative anxiety may differ according to patient temperament. It will be increased when patients are requested to participate in a study involving anesthesia. The purpose of this study was to show that the anxiety felt when patients are requested to participate may differ according to temperament in both patients who agree and disagree to participate. METHODS: Three hundred and twenty one patients over age 18 with American Society of Anesthesiologists 1 and 2 completed a survey questionnaire. The degree of anxiety was measured according to patient temperament. It was compared on the basis of the State-Trait Anxiety Inventory (STAI) and visual analogue scale (VAS). RESULTS: In the agreed group, the degree of anxiety measured by "usual, present STAI" and VAS in the monitors (those who want to know as much as possible about anesthesia and surgery) was significantly higher than that in the blunters (those who want to know as little as possible) (P = 0.041 for the "usual STAI", 0.017 for "present STAI", and 0.001 for VAS, respectively). Among patients with a lower educational level, the numbers of blunters and monitors were 57 (79%) and 32 (59%), respectively, indicating that the ratio of blunters was significantly higher (P = 0.026). CONCLUSIONS: Both traits of patients in each group were influenced by psychological burdens. The anxiety of the monitors who agreed to participate was significantly higher than that of blunters. In addition to temperament, education level affects participation. Obtaining consent for participation by understanding temperament and considering factors that may reduce the participation rate will be required. PMID- 28580076 TI - Postoperative acute kidney injury. AB - Acute kidney injury (AKI) after cardiac surgery is a common and serious complication. Several definitions of AKI have been proposed recently, and include both increases in serum creatinine levels and decreases in urine output as diagnostic criteria. The pathophysiology of postoperative AKI is complex and involves both ischemic injury and systemic inflammation. Identifying risk factors, such as old age, underlying diabetes, heart failure, and obesity, may aid in the application of preventative methods for postoperative AKI. Additionally, recognizing different risks after different types of surgical procedures would be valuable. Novel biomarkers that could detect AKI more precisely at an earlier time point are being investigated. Several new biomarkers have been assessed in large multi-center studies and are believed to accommodate conventional clinical findings in diagnosing postoperative AKI. In high-risk patients, preventative measures, such as the maintenance of adequate hemodynamics and sufficient fluid resuscitation, could lower the incidence of postoperative AKI. Avoiding nephrotoxic agents and optimizing preoperative hemoglobin levels to avoid excessive transfusions would also be beneficial. In situations in which medical management fails to maintain sufficient urine output and acid-base and electrolyte homeostasis, early initiation of renal replacement therapy should be considered. PMID- 28580079 TI - The effect of triazolam premedication on anxiety, sedation, and amnesia in general anesthesia. AB - BACKGROUND: Benzodiazepines have been used preoperatively as part of an anesthesia regimen to attenuate the anxiety of patients. In this study, we aimed to examine the effect of oral triazolam, a short-acting benzodiazepine, on anxiety, sedation, and amnesia. METHODS: Ninety patients, aged 20-55 years, were randomly assigned to receive no premedication, or to receive triazolam 0.25 mg or 0.375 mg 1 h before anesthesia. Anxiety score, sedation score, blood pressure, heart rate and psychomotor performance were measured on the evening before surgery and on the day of surgery. Additional tests of psychomotor performance were performed in the postanesthesia care unit and on the next day of surgery. The occurrence of amnesia, bispectral index (BIS), recovery profiles and patient satisfaction with overall anesthesia care were also evaluated. RESULTS: Changes in the anxiety and sedation scores on the day of surgery were not significantly different among groups, whereas the increases in systolic blood pressure and heart rate were significantly less in both triazolam groups. The triazolam groups both showed a higher incidence of high satisfaction scores (>= 2). The two triazolam groups also showed similar outcomes, except for a dose-dependent increase in the number of patients with amnesia and BIS values < 90. Delayed recovery from general anesthesia and psychomotor impairment were not observed in the triazolam groups. CONCLUSIONS: Triazolam 0.25 mg or 0.375 mg reduced the hemodynamic changes associated with anxiety, produced potent amnesia, and improved patient satisfaction. We suggest that triazolam can be used effectively as anesthetic premedication in adults. PMID- 28580080 TI - Postoperative nausea and vomiting after thyroidectomy: a comparison between dexmedetomidine and remifentanil as part of balanced anesthesia. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is the major complication related to general anesthesia, occurring in 60-80% of patients after thyroidectomy. The objective of this study was to compare the effects of an intraoperative dexmedetomidine infusion with remifentanil, as anesthetic adjuvants of balanced anesthesia, on PONV in patients undergoing thyroidectomy. METHODS: Eighty patients scheduled for thyroidectomy were randomized into the following two groups: 1) The dexmedetomidine group (Group D), who received an initial loading dose of dexmedetomidine (1 ug/kg over 10 min) during the induction of anesthesia, followed by a continuous infusion at a rate of 0.3-0.5 ug/kg/h; 2) the remifentanil group (group R), who received remifentanil at an initial target effect site concentration of 4 ng/ml during the induction of anesthesia, followed by a target effect site concentration of 2-3 ng/ml. PONV was assessed during the first 24 hours in 2 time periods (0-2 h and 2-24 h). The pain intensity, sedation score, extubation time, and hemodynamics were also assessed. RESULTS: During the 2 time periods, the incidence and severity of PONV in group D were significantly lower than in group R. In addition, the need for rescue antiemetics was significantly lower in group D than in group R. The effect of dexmedetomidine on postoperative pain relief (2-24 h) was superior to that of remifentanil. The hemodynamics were similar in both groups, whereas eye opening and extubation time were delayed in group D. CONCLUSIONS: Adjuvant use of intraoperative dexmedetomidine infusion may be effective for the prevention of PONV. PMID- 28580081 TI - The prognostic value of procalcitonin, C-reactive protein and cholesterol in patients with an infection and multiple organ dysfunction. AB - BACKGROUND: To establish the prognostic value of procalcitonin, C-reactive protein and cholesterol levels for mortality in patients with an infection and multiple organ dysfunction. METHODS: A prospective case-control study was performed, including 67 patients admitted to the intensive care unit with an infection and multiple organ dysfunction in whom cholesterol, procalcitonin, and C-reactive protein levels were measured on admission and during the course of treatment. RESULTS: The associations between in-hospital mortality and procalcitonin, C-reactive protein, and cholesterol levels were analyzed. Logistic regression analysis showed that cholesterol (odds ratio [OR], 1.858; 95% CI, 1.170-2.949; P = 0.009) and C-reactive protein (OR, 4.408; 95% CI, 2.019-9.624; P < 0.001) levels were predictors of mortality. A receiver operating characteristic curve analysis yielded an area under the curve (AUC) of 0.774 and 95% CI of 0.693 0.855 (P < 0.001) for C-reactive protein, an AUC of 0.66 and 95% CI of 0.535 0.784 (P = 0.019) for procalcitonin, and an AUC of 0.654 and 95% CI of 0.593 0.715 (P < 0.001) for cholesterol as predictors of mortality. When combined with the bioscore system for mortality, these markers yielded an AUC of 0.845 and 95% CI of 0.770-0.921 (P < 0.001), with sensitivity of 89.1% and specificity of 83.1%. CONCLUSIONS: The combination of procalcitonin, C-reactive protein, and cholesterol levels in a single scoring system yielded high predictive value for mortality. PMID- 28580082 TI - Integration of pain scores, morphine consumption and demand/delivery ratio to evaluate patient-controlled analgesia: the C-SIA score. AB - BACKGROUND: Patient-controlled analgesia (PCA) is used to manage postoperative pain. Postoperatively, some patients need to be re-instructed on its correct use. This study explores the efficacy of re-instruction and illustrates a comprehensive version of the Silverman integrated approach (C-SIA), based on the integration of static and dynamic pain scores, morphine consumption, and the ratio between demanded and delivered PCA boluses (the DD ratio). METHODS: In total, 50 patients operated on for colorectal surgery were studied retrospectively. The change in DD ratio after re-instruction was analyzed as the primary endpoint. Re-instructed and not re-instructed subjects were compared according to DD ratio, pain scores, and morphine consumption. A secondary comparison was performed using the SIA and C-SIA scores, to illustrate the reliability of the latter tool. Agreement between C-SIA and SIA score was assessed using a Bland-Altman analysis. RESULTS: In re-instructed patients, the DD ratio decreased after re-education (P = 0.011). Re-instructed patients had higher DD ratios (P = 0.018) and pain scores at rest (P = 0.024) and movement (P = 0.012) at 24 h after surgery than not re-instructed subjects. These differences disappeared at the 48 h visit. Both the SIA and C-SIA scores reflected these findings. C-SIA scores showed a higher coefficient of correlation with the DD ratio (r = 0.815; P < 0.001) than SIA scores (r = 0.663; P < 0.001). The C-SIA scores, in absolute values, being based on more variables, were, on average, 2.5 times the SIA score. CONCLUSIONS: Re-instruction is effective for optimizing PCA therapy. The C-SIA is an alternative to the SIA score that gives an overall measure of PCA therapy efficacy. PMID- 28580083 TI - Implementation of clinical practice changes by experienced anesthesiologists after simulation-based ultrasound-guided regional anesthesia training. AB - BACKGROUND: Anesthesiologists who have finished formal training and want to learn ultrasound-guided regional anesthesia (UGRA) commonly attend 1 day workshops. However, it is unclear whether participation actually changes clinical practice. We assessed change implementation after completion of a 1 day simulation-based UGRA workshop. METHODS: Practicing anesthesiologists who participated in a 1 day UGRA course from January 2012 through May 2014 were surveyed. The course consisted of clinical observation of UGRA procedures, didactic lectures, ultrasound scanning, hands-on perineural catheter placement, and mannequin simulation. The primary outcome was the average number of UGRA blocks per month reported at follow-up versus baseline. Secondary outcomes included preference for ultrasound as the nerve localization technique, ratings of UGRA teaching methods, and obstacles to performing UGRA. RESULTS: Survey data from 46 course participants (60% response rate) were included for analysis. Participants were (median [10th-90th percentile]) 50 (37-63) years old, had been in practice for 17 (5-30) years, and were surveyed 27 (10-34) months after their UGRA training. Participants reported performing 24 (4-90) blocks per month at follow-up compared to 10 (2-24) blocks at baseline (P < 0.001). Compared to baseline, more participants at follow-up preferred ultrasound for nerve localization. The major obstacle to implementing UGRA in clinical practice was time pressure. CONCLUSIONS: Participation in a 1 day simulation-based UGRA course may increase UGRA procedural volume by practicing anesthesiologists. PMID- 28580084 TI - Characteristics of the similarity index in a Korean medical journal. AB - BACKGROUND: Journal editors have exercised their control over submitted papers having a high similarity index. Despite widespread suspicion of possible plagiarism on a high similarity index, our study focused on the real effect of the similarity index on the value of a scientific paper. METHODS: This research examined the percent values of the similarity index from 978 submitted (420 published) papers in the Korean Journal of Anesthesiology since 2012. Thus, this study aimed to identify the correlation between the similarity index and the value of a paper. The value of a paper was evaluated in two distinct phases (during a peer-review process vs. after publication), and the value of a published paper was evaluated in two aspects (academic citation vs. social media appearance). RESULTS: Yearly mean values of the similarity index ranged from 16% to 19%. There were 254 papers cited at least once and 179 papers appearing at least once in social media. The similarity index affected the acceptance/rejection of a paper in various ways; although the influence was not linear and the cutoff measures were distinctive among the types of papers, both extremes were related to a high rate of rejection. After publication, the similarity index had no effect on academic citation or social media appearance according to the paper. CONCLUSIONS: The finding suggested that the similarity index no longer had an influence on academic citation or social media appearance according to the paper after publication, while the similarity index affected the acceptance/rejection of a submitted paper. Proofreading and intervention for finalizing the draft by the editors might play a role in achieving uniform quality of the publication. PMID- 28580086 TI - Non-intubated thoracoscopic surgery for decortication of empyema under thoracic epidural anesthesia: a case report. AB - General anesthesia is the main strategy for almost all thoracic surgeries. However, a growing body of literature has reported successful cases of non intubated thoracic surgery with regional anesthesia. This alternative strategy not only prevents complications related to general anesthesia, such as lung injury, incomplete re-expansion and intubation related problems, but also accords with trends of shorter hospital stay and lower overall costs. We experienced a successful case of non-intubated thoracoscopic decortication for a 68-year-old man who was diagnosed as empyema while the patient kept spontaneously breathing with moderate sedation under thoracic epidural anesthesia. The patient showed a fast recovery without concerns of general anesthesia related complications and effective postoperative analgesia through thoracic epidural patient-controlled analgesia device. This is the first report of non-intubated thoracoscopic surgery under thoracic epidural anesthesia in Korea, and we expect that various well designed prospective studies will warrant the improvement of outcomes in non intubated thoracoscopic surgery. PMID- 28580085 TI - Apocynin preserves glutamatergic neurons in the basolateral amygdala in mice with neonatal sevoflurane exposure. AB - BACKGROUND: Neonatal exposure to anesthetics induces neuronal apoptosis and long term cognitive dysfunction in rodents. We showed that the nicotinamide adenine dinucleotide phosphate-oxidase inhibitor apocynin not only reduces neurotoxicity by decreasing superoxide levels and preventing mitochondrial dysfunction but also improves long-term memory impairment in neonatal mice exposed to sevoflurane. We also found that after the contextual fear conditioning test, glutamatergic neurons expressed c-Fos (neural activation) regardless of previous exposure to sevoflurane. Moreover, there were fewer c-Fos-expressing glutamatergic neurons in the basolateral amygdala (BLA) after exposure to sevoflurane than after exposure to carrier gas. In this study, we investigated whether the administration of apocynin prior to sevoflurane exposure would preserve glutamatergic neurons in the BLA. METHODS: Apocynin (50 mg/kg) was injected intraperitoneally into six-day old male mice 30 min before 6 h of exposure to 3% sevoflurane or carrier gas only. The mice were allowed to mature and then were subjected to the contextual fear conditioning test. The neural activation and neuron population in the BLA were investigated 2 h later. RESULTS: Administration of apocynin prior to neonatal sevoflurane exposure not only prevented learning deficits but also preserved c-Fos-expressing glutamatergic neurons in the BLA. CONCLUSIONS: Apocynin mitigates the cognitive impairment induced by neonatal sevoflurane exposure and preserves c-Fos-expressing glutamatergic neurons in the basolateral amygdala. PMID- 28580088 TI - Liver transplantation in Jehovah's Witnesses: two cases report. AB - Liver transplantation is especially challenging in patients who are Jehovah's Witnesses because their religious beliefs prohibit the receipt of blood products. We present two cases of living donor liver transplantation performed in adult Jehovah's Witnesses in South Korea without the use of blood products. In the first case, preoperative erythropoiesisstimulation therapy increased hemoglobin levels from 8.1 to 13.1 g/dl after 9 weeks. In the second case, hemoglobin levels increased from 7.4 to 10.8 g/dl after 6 months of erythropoiesis-stimulation therapy. With the combination of acute normovolemic hemodilution, intraoperative cell salvage, and use of transfusion alternatives, liver transplantation was successfully performed without transfusion of blood products. PMID- 28580087 TI - Successful early application of extracorporeal membrane oxygenation to support cardiopulmonary resuscitation for a patient suffering from severe malignant hyperthermia and cardiac arrest: a case report. AB - Malignant hyperthermia (MH) may lead to metabolic crisis of skeletal muscle in susceptible individuals following exposure to triggering agents such as volatile anesthetics or depolarizing muscle relaxants. MH is a rare and a potentially lethal disease, which can lead to cardiac arrest. We report a case of severe MH, in which the rapidly evolving signs of hypermetabolism eventually resulted in cardiac arrest. Despite conventional treatments following cardiopulmonary resuscitation, the patient's vital signs did not improve. Therefore, we applied extracorporeal membrane oxygenation for providing hemodynamic support. PMID- 28580089 TI - Anesthetic experience of frontotemporal dementia patient with severe autonomic dysfunction: a case report. AB - Anesthetic experience in frontotemporal dementia (FTD) with severe hypotension associated autonomic dysfunction has not yet been reported. Here in case, we report on the case of treatment with vasopressin to refractory hypotension in FTD patient. A 54-year-old male presented with a ten-year history of FTD with frequent syncope. The patient was scheduled to undergo subtotal gastrectomy for resection of stomach cancer. During the operation, sudden hypotension occurred and it was refractory to fluid and 1 unit of blood resuscitation and did not respond to catecholamine. Transesophageal echocardiography showed normal heart with adequate volume state. After intravenous administration of arginine vasopressin, the patient's vital signs returned to baseline values. Arginine vasopressin might be considered as a valuable alternative for treatment of severe refractory hypotension in autonomic dysfunction patients with FTD. PMID- 28580090 TI - Less explored off-label indications of dexmedetomidine. PMID- 28580091 TI - Effects of sugammadex on the coronary circulation: direct effects on coronary vessels or hypersensitivity (Kounis syndrome)? PMID- 28580092 TI - Corrigendum: A first step toward understanding patient safety. AB - [This corrects the article on p. 429 in vol. 69, PMID: 27703622.]. PMID- 28580094 TI - An aqueous molecular tube with polyaromatic frameworks capable of binding fluorescent dyes. AB - An aqueous molecular tube composed of polyaromatic frameworks with peripheral hydrophilic groups was prepared. The new tube has a well-defined hydrophobic cavity with a diameter of ~1 nm and quantitatively binds two molecules of fluorescent coumarin dyes in aqueous solutions. The bound coumarin dimers in a stacked fashion exhibit unusual excimer-like emissions in the confined space through efficient host-guest energy transfer. PMID- 28580096 TI - Hydrogen dangling bonds induce ferromagnetism in two-dimensional metal-free graphitic-C3N4 nanosheets. AB - Ferromagnetic two-dimensional (2D) ultrathin nanosheets hold great promise for next generation electronics. Ferromagnetic metal-free materials that usually possess only an s/p electronic configuration with weak spin-orbit coupling and a large spin relaxation time, would play an important role in constructing future spintronic devices. However, the absence of an intrinsic spin ordering structure in most metal-free materials greatly hampers the widening scope of ferromagnetic 2D nanostructures as well as in-depth understanding of their ferromagnetic nature. Herein, the induction of intrinsic ferromagnetism in 2D metal-free g-C3N4 ultrathin nanosheets has been achieved through a new effective strategy whereby hydrogen dangling bonds are introduced. In our case, g-C3N4 ultrathin nanosheets with hydrogen dangling bonds showed obvious room temperature ferromagnetic behavior that could even be tuned by the concentration of hydrogen. This work will pave a new pathway to engineer the properties of 2D nanomaterial systems. PMID- 28580093 TI - Photobiomodulation and the brain: a new paradigm. AB - Transcranial photobiomodulation (PBM) also known as low level laser therapy (tLLLT) relies on the use of red/NIR light to stimulate, preserve and regenerate cells and tissues. The mechanism of action involves photon absorption in the mitochondria (cytochrome c oxidase), and ion channels in cells leading to activation of signaling pathways, up-regulation of transcription factors, and increased expression of protective genes. We have studied PBM for treating traumatic brain injury (TBI) in mice using a NIR laser spot delivered to the head. Mice had improved memory and learning, increased neuroprogenitor cells in the dentate gyrus and subventricular zone, increased BDNF and more synaptogenesis in the cortex. These highly beneficial effects on the brain suggest that the applications of tLLLT are much broader than at first conceived. Other groups have studied stroke (animal models and clinical trials), Alzheimer's disease, Parkinson's disease, depression, and cognitive enhancement in healthy subjects. PMID- 28580095 TI - Macromolecular prodrugs of ribavirin: towards a treatment for co-infection with HIV and HCV. AB - Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) represent tremendous healthcare burdens with a large proportion of patients hosting the two viruses at the same time. An altered hepatic function and immunity as well as cross-interference of drugs make treatment of co-infection increasingly challenging. Herein we report the first design of macromolecular prodrugs (MP) with concurrent success in fighting HIV and alleviating hepatitis (liver inflammation). To achieve this, polymer compositions were systematically screened in a broad range of molar mass and content of ribavirin - a broad spectrum antiviral agent. For the first time, we report that ribavirin is efficacious in fighting HIV and in the form of MP, the treatment is safe, both in terms of lack of association of ribavirin with red blood cells and lack of toxicity upon cellular internalization. The lead polymer compositions were also potent in anti inflammatory assays with relevance to viral hepatitis - thus making up formulations with potential for treatment of co-infection with HIV and HCV. PMID- 28580097 TI - Visualising the membrane viscosity of porcine eye lens cells using molecular rotors. AB - The plasma membranes of cells within the eye lens play an important role in metabolite transport within the avascular tissue of the lens, maintaining its transparency over the entire lifespan of an individual. Here we use viscosity sensitive 'molecular rotors' to map the microscopic viscosity within these unusual cell membranes, establishing that they are characterised by an unprecedentedly high degree of lipid organisation. PMID- 28580099 TI - Intra- versus intermolecular electron transfer in radical nucleophilic aromatic substitution of dihalo(hetero)arenes - a tool for estimating pi-conjugation in aromatic systems. AB - In this paper, the application of the double radical nucleophilic aromatic substitution (SRN1) in various dihalogenated, mostly diiodinated, pi-conjugated systems as a tool for qualitatively estimating their pi-conjugation is described. This approach uses electron delocalisation as a measure of pi-conjugation. Electron injection into the pi-system is achieved via reaction of an intermediate aryl radical, itself generated from a dihalogenated pi-system via SET-reduction of the C-I bond and subsequent reaction with a thiolate anion. The generated arene radical anion can then further react with the second aryl-halogen moiety within the pi-system via an intramolecular electron transfer process. The efficiency of this intramolecular electron transfer is related to the pi conjugation of the radical anion. If the pi-conjugation within the aromatic unit is weak, the arene radical anion reacts via an intermolecular ET with the starting dihalide. The intramolecular ET process delivers a product of a double SRN1 substitution whereas the intermolecular ET pathway provides a product of a mono- SRN1 substitution. By simple product analysis of mono- versus double substitution, pi-conjugation can be qualitatively evaluated. This mechanistic tool is applied to various dihalogenated pi-conjugated systems and the results are discussed within the context of pi-conjugation. The conjugation mode within the pi-system and the length of the aromatic system are varied, and the effect of relative positioning of the two halides within small pi-systems is also addressed. PMID- 28580098 TI - Hollow carbon nanobubbles: monocrystalline MOF nanobubbles and their pyrolysis. AB - While bulk-sized metal-organic frameworks (MOFs) face limits to their utilization in various research fields such as energy storage applications, nanoarchitectonics is believed to be a possible solution. It is highly challenging to realize MOF nanobubbles with monocrystalline frameworks. By a spatially controlled etching approach, here, we can achieve the synthesis of zeolitic imidazolate framework (ZIF-8) nanobubbles with a uniform size of less than 100 nm. Interestingly, the ZIF-8 nanobubbles possess a monocrystalline nanoshell with a thickness of around 10 nm. Under optimal pyrolytic conditions, the ZIF-8 nanobubbles can be converted into hollow carbon nanobubbles while keeping their original shapes. The structure of the nanobubble enhances the fast Na+/K+ ion intercalation performance. Such remarkable improvement cannot be realized by conventional MOFs or their derived carbons. PMID- 28580100 TI - Mild, visible light-mediated decarboxylation of aryl carboxylic acids to access aryl radicals. AB - Herein we present the first example of aryl radical formation via the visible light-mediated decarboxylation of aryl carboxylic acids using photoredox catalysis. This method constitutes a mild protocol for the decarboxylation of cheap and abundant aryl carboxylic acids and tolerates both electron-rich substrates and those lacking ortho-substitution. The in situ formation of an acyl hypobromite is proposed to prevent unproductive hydrogen atom abstraction and trapping of the intermediate aroyloxy radical, enabling mild decarboxylation. PMID- 28580102 TI - Highly sensitive and multiplexed quantification of mRNA splice variants by the direct ligation of DNA probes at the exon junction and universal PCR amplification. AB - Alternative messenger RNA (mRNA) splicing is a basic mechanism of gene regulation. In general, reverse transcription and polymerase based primer extension limit the sensitivity and selectivity of the current detection of mRNA splice variants, respectively. Here, we show that, using the ligation of two properly designed probes at the exon junction combined with universal PCR amplification, as little as a single copy of a mRNA splice variant per cell can be accurately determined, and the dynamic range covers six orders of magnitude. Three mRNA splice variants were measured from total RNA samples derived from different cell lines. Moreover, by encoding the ligation probes with different lengths, multiplexed mRNA splice variants can be simultaneously detected in one tube PCR amplification using electrophoretic separation. PMID- 28580101 TI - Highly specific and rapid glycan based amperometric detection of influenza viruses. AB - Rapid and precise detection of influenza viruses in a point of care setting is critical for applying appropriate countermeasures. Current methods such as nucleic acid or antibody based techniques are expensive or suffer from low sensitivity, respectively. We have developed an assay that uses glucose test strips and a handheld potentiostat to detect the influenza virus with high specificity. Influenza surface glycoprotein neuraminidase (NA), but not bacterial NA, cleaved galactose bearing substrates, 4,7di-OMe N-acetylneuraminic acid attached to the 3 or 6 position of galactose, to release galactose. In contrast, viral and bacterial NA cleaved the natural substrate, N-acetylneuraminic acid attached to the 3 or 6 position of galactose. The released galactose was detected amperometrically using a handheld potentiostat and dehydrogenase bearing glucose test strips. The specificity for influenza was confirmed using influenza strains and different respiratory pathogens that include Streptococcus pneumoniae and Haemophilus influenzae; bacteria do not cleave these molecules. The assay was also used to detect co-infections caused by influenza and bacterial NA. Viral drug susceptibility and testing with human clinical samples was successful in 15 minutes, indicating that this assay could be used to rapidly detect influenza viruses at primary care or resource poor settings using ubiquitous glucose meters. PMID- 28580103 TI - Controlling superstructural ordering in the clathrate-I Ba8M16P30 (M = Cu, Zn) through the formation of metal-metal bonds. AB - Order-disorder-order phase transitions in the clathrate-I Ba8Cu16P30 were induced and controlled by aliovalent substitutions of Zn into the framework. Unaltered Ba8Cu16P30 crystallizes in an ordered orthorhombic (Pbcn) clathrate-I superstructure that maintains complete segregation of metal and phosphorus atoms over 23 different crystallographic positions in the clathrate framework. The driving force for the formation of this Pbcn superstructure is the avoidance of Cu-Cu bonds. This superstructure is preserved upon aliovalent substitution of Zn for Cu in Ba8Cu16-x Zn x P30 with 0 < x < 1.6 (10% Zn/Mtotal), but vanishes at greater substitution concentrations. Higher Zn concentrations (up to 35% Zn/Mtotal) resulted in the additional substitution of Zn for P in Ba8M16+y P30-y (M = Cu, Zn) with 0 <= y <= 1. This causes the formation of Cu-Zn bonds in the framework, leading to a collapse of the orthorhombic superstructure into the more common cubic subcell of clathrate-I (Pm3n). In the resulting cubic phases, each clathrate framework position is jointly occupied by three different elements: Cu, Zn, and P. Detailed structural characterization of the Ba-Cu-Zn-P clathrates-I via single crystal X-ray diffraction, joint synchrotron X-ray and neutron powder diffractions, pair distribution function analysis, electron diffraction and high resolution electron microscopy, along with elemental analysis, indicates that local ordering is present in the cubic clathrate framework, suggesting the evolution of Cu-Zn bonds. For the compounds with the highest Zn content, a disorder-order transformation is detected due to the formation of another superstructure with trigonal symmetry and Cu-Zn bonds in the clathrate-I framework. It is shown that small changes in the composition, synthesis, and crystal structure have significant impacts on the structural and transport properties of Zn-substituted Ba8Cu16P30. PMID- 28580104 TI - Highly specific imaging of mRNA in single cells by target RNA-initiated rolling circle amplification. AB - Detection of single-cell gene expression with high spatial and sequence resolution is a key challenge in single cell biology. Herein, we propose a robust method for the direct detection of mRNA, termed target RNA-initiated rolling circle amplification, which enables imaging of mRNA with single-nucleotide and near-single-molecule resolution in single cells. By utilizing a Splint R ligase capable of efficiently catalyzing the ligation of a padlock probe by the target RNA, the method can enable the efficient detection of mRNA without reverse transcription (detection efficiency over 20%). Meanwhile, attributed to the ligation-based recognition process, the method confers specificity sufficient to genotype mRNAs with one-nucleotide variations. The method has enabled the spatial mapping and correlation analysis of gene expression in single cells which could help us to elucidate the gene functions and regulatory mechanisms. This method offers an mRNA profiling ability with high spatial resolution and sequence specificity, thus is expected to be a single-cell analysis platform for not only investigating gene expression, but also potentially for analyzing single nucleotide variants or mRNA alternative splicing at single-cell level. PMID- 28580106 TI - Photocurrent of BiVO4 is limited by surface recombination, not surface catalysis. AB - Bismuth vanadate is one of the most promising photoanode materials for photoelectrochemical water splitting. In order to achieve high photocurrents the surface of BiVO4 always has to be modified with water oxidation catalysts, such as cobalt phosphate (CoPi), FeOOH, or NiFeO x . While this has generally been attributed to the poor intrinsic catalytic activity of BiVO4, detailed insight into the fate of the photogenerated charge carriers at the surface is still lacking. We used intensity modulated photocurrent spectroscopy (IMPS) to investigate the surface carrier dynamics of bare and CoPi-modified spray deposited BiVO4 films. Using a model developed by Peter et al., it was possible to distinguish the reaction rate constants for surface recombination and charge transfer to the electrolyte. We found that modification with CoPi reduced the surface recombination of BiVO4 with a factor of 10-20, without significantly influencing the charge transfer kinetics. Control experiments with RuO x , one of the best known OER electrocatalysts, did not affect surface recombination and led to an actual decrease of the photocurrent. These results show that the main role of the CoPi is to passivate the surface of BiVO4 and that, contrary to earlier assumptions, the photocurrent of BiVO4 is limited by surface recombination instead of charge transfer. The importance of surface recombination is well recognized for conventional semiconductors in the field of photovoltaics; these findings show that it may also play a crucial role in oxide-based semiconductors for photoelectrochemical energy conversion. PMID- 28580105 TI - Reversible solvatomagnetic switching in a single-ion magnet from an entatic state. AB - A vast impact on molecular nanoscience can be achieved using simple transition metal complexes as dynamic chemical systems to perform specific and selective tasks under the control of an external stimulus that switches "ON" and "OFF" their electronic properties. While the interest in single-ion magnets (SIMs) lies in their potential applications in information storage and quantum computing, the switching of their slow magnetic relaxation associated with host-guest processes is insufficiently explored. Herein, we report a unique example of a mononuclear cobalt(ii) complex in which geometrical constraints are the cause of easy and reversible water coordination and its release. As a result, a reversible and selective colour and SIM behaviour switch occurs between a "slow-relaxing" deep red anhydrous material (compound 1) and its "fast-relaxing" orange hydrated form (compound 2). The combination of this optical and magnetic switching in this new class of vapochromic and thermochromic SIMs offers fascinating possibilities for designing multifunctional molecular materials. PMID- 28580108 TI - Anion-pi catalysis: bicyclic products with four contiguous stereogenic centers from otherwise elusive diastereospecific domino reactions on pi-acidic surfaces. AB - Anion-pi interactions have been introduced recently to catalysis. The idea of stabilizing anionic intermediates and transition states on pi-acidic surfaces is a new fundamental concept. By now, examples exist for asymmetric enolate, enamine, iminium and transamination chemistry, and the first anion-pi enzyme has been created. Delocalized over large aromatic planes, anion-pi interactions appear particularly attractive to stabilize extensive long-distance charge displacements during domino processes. Moving on from the formation of cyclohexane rings with five stereogenic centers in one step on a pi-acidic surface, we here focus on asymmetric anion-pi catalysis of domino reactions that afford bicyclic products with quaternary stereogenic centers. Catalyst screening includes a newly synthesized, better performing anion-pi version of classical organocatalysts from cinchona alkaloids, and anion-pi enzymes. We find stereoselectivities that are clearly better than the best ones reported with conventional catalysts, culminating in unprecedented diastereospecificity. Moreover, we describe achiral salts as supramolecular chirality enhancers and report the first artificial enzyme that operates in neutral water with anion-pi interactions, i.e., interactions that are essentially new to enzymes. Evidence in support of contributions of anion-pi interactions to asymmetric catalysis include increasing diastereo- and enantioselectivity with increasing rates, i.e., asymmetric transition-state stabilization in the presence of pi-acidic surfaces and inhibition with the anion selectivity sequence NO3- > Br- > BF4- > PF6-. PMID- 28580107 TI - (Phosphanyl)phosphaketenes as building blocks for novel phosphorus heterocycles. AB - Although BH3 simply coordinates the endocyclic P of (phospholidino)phosphaketene 1Dipp , the bulkier B(C6F5)3 gives rise to a zwitterionic diphosphirenium, which is a novel type of 2pi-electron aromatic system as shown by the calculated NICS values. While the reaction of 1Dipp with Na[PCO(dioxane) x ] is unselective, the same reaction with the sterically bulky (phospholidino)phosphaketene 1Ar** [Ar** = 2,6-bis[di(4-tert-butylphenyl)methyl]-4-methylphenyl selectively affords a sodium bridged dimer containing a hitherto unknown lambda3,lambda5,lambda3 triphosphete core. The latter formally results from "P-" addition to a 1,3-P/C dipole. Similarly, adamantyl isonitrile adds to 1Dipp giving a 4-membered phosphacycle. In contrast to 1, the phosphaketene derived from the electrophilic diazaphospholidine-4,5-dione is unstable and reacts with a second molecule of Na[PCO(dioxane) x ] to afford a 1,3,4-oxadiphospholonide derivative. PMID- 28580109 TI - Photoswitchable interlocked thiodiglycolamide as a cocatalyst of a chalcogeno Baylis-Hillman reaction. AB - En route to a photoswitchable interlocked catalyst we have proved the ability of thiodiglycolamide to act as a template in the formation of hydrogen-bonded [2]rotaxanes. X-ray diffraction studies reveal the shielding of the sulfide atom by the macrocycle. A series of molecular shuttles are described as having an isomerizable fumaramide and thiodiglycolamide binding sites for controlling the relative ring position at will. By employing these systems as photoregulated catalysts, the TiCl4-mediated chalcogeno-Morita-Baylis-Hillman reaction is tested. In the presence of the maleamide shuttle, in which the sulfide function is encapsulated by the macrocycle, a complete loss in control of the geometry of the produced aldol is observed. The E-aldol adduct is predominantly obtained when the photoisomerized fumaramide shuttle, in which the sulfide function is exposed, is used. PMID- 28580110 TI - Superconductivity and magnetism in iron sulfides intercalated by metal hydroxides. AB - Inspired by naturally occurring sulfide minerals, we present a new family of iron based superconductors. A metastable form of FeS known as the mineral mackinawite forms two-dimensional sheets that can be readily intercalated by various cationic guest species. Under hydrothermal conditions using alkali metal hydroxides, we prepare three different cation and metal hydroxide-intercalated FeS phases including (Li1-x Fe x OH)FeS, [(Na1-x Fe x )(OH)2]FeS, and K x Fe2-y S2. Upon successful intercalation of the FeS layer, the superconducting critical temperature Tc of mackinawite is enhanced from 5 K to 8 K for the (Li1-x Fe x OH) delta+ intercalate. Layered heterostructures of [(Na1-x Fe x )(OH)2]FeS resemble the natural mineral tochilinite, which contains an iron square lattice interleaved with a hexagonal hydroxide lattice. Whilst heterostructured [(Na1-x Fe x )(OH)2]FeS displays long-range magnetic ordering near 15 K, K x Fe2-y S2 displays short range antiferromagnetism. PMID- 28580111 TI - Electronic properties of the boroxine-gold interface: evidence of ultra-fast charge delocalization. AB - We performed a combined experimental and theoretical study of the assembly of phenylboronic acid on the Au(111) surface, which is found to lead to the formation of triphenylboroxines by spontaneous condensation of trimers of molecules. The interface between the boroxine group and the gold surface has been characterized in terms of its electronic properties, revealing the existence of an ultra-fast charge delocalization channel in the proximity of the oxygen atoms of the heterocyclic group. More specifically, the DFT calculations show the presence of an unoccupied electronic state localized on both the oxygen atoms of the adsorbed triphenylboroxine and the gold atoms of the topmost layer. By means of resonant Auger electron spectroscopy, we demonstrate that this interface state represents an ultra-fast charge delocalization channel. Boroxine groups are among the most widely adopted building blocks in the synthesis of covalent organic frameworks on surfaces. Our findings indicate that such systems, typically employed as templates for the growth of organic films, can also act as active interlayers that provide an efficient electronic transport channel bridging the inorganic substrate and organic overlayer. PMID- 28580112 TI - Rh-catalyzed regiodivergent hydrosilylation of acyl aminocyclopropanes controlled by monophosphine ligands. AB - A Rh-catalyzed regiodivergent hydrosilylation of acyl aminocyclopropanes has been developed. Acyl aminocyclopropanes were reacted with hydrosilanes in the presence of Rh catalysts to afford ring-opened hydrosilylated adducts through carbon carbon (C-C) bond cleavage of the cyclopropane ring. The regioselectivity of the addition of silanes (linear or branched) can be switched by changing the monophosphine ligand. This C-C bond cleavage/hydrosilylation methodology is applicable to the synthesis of silanediol precursors. PMID- 28580113 TI - Methyltransferase-directed covalent coupling of fluorophores to DNA. AB - We report an assay for determining the number of fluorophores conjugated to single plasmid DNA molecules and apply this to compare the efficiency of fluorophore coupling strategies for covalent DNA labelling. We compare a copper catalyzed azide-alkyne cycloaddition reaction, amine to N-hydroxysuccinimidyl ester coupling reaction and strain-promoted azide-alkyne cycloaddition reaction for fluorescent DNA labelling. We found increased labelling efficiency going from the amine to N-hydroxysuccinimidyl ester coupling reaction to the copper catalyzed azide-alkyne cycloaddition and found the highest degree of DNA labelling with the strain-promoted azide-alkyne cycloaddition reaction. We also examined the effect of labelling on the DNA structure using atomic force microscopy. We observe no distortions or damage to the DNA that was labeled using the amine to N-hydroxysuccinimidyl ester and strain-promoted azide-alkyne cycloaddition coupling reactions. This was in contrast to the copper-catalyzed azide-alkyne cycloaddition reaction, which, despite the use of copper coordinating ligands in the labelling mixture, leads to some structural DNA damage (single-stranded DNA breaks). PMID- 28580114 TI - Catalyst displacement assay: a supramolecular approach for the design of smart latent catalysts for pollutant monitoring and removal. AB - Latent catalysts can be tuned to function smartly by assigning a sensing threshold using the displacement approach for targeted analytes. Three cyano bridged bimetallic complexes were synthesized as "smart" latent catalysts through the supramolecular assembly of different metallic donors [FeII(CN)6]4-, [FeII(tBubpy)(CN)4]2-, and FeII(tBubpy)2(CN)2 with a metallic acceptor [CuII(dien)]2+. The investigation of both their thermodynamic and kinetic properties on binding with toxic pollutants provided insight into their smart off on catalytic capabilities, enabling us to establish a threshold-controlled catalytic system for the degradation of pollutants such as cyanide and oxalate. With these smart latent catalysts, a new catalyst displacement assay (CDA) was demonstrated and applied in a real wastewater treatment process to degrade cyanide pollutants in both domestic (level I, untreated) and industrial wastewater samples collected in Hong Kong, China. The smart system was adjusted to be able to initiate the catalytic oxidation of cyanide at a threshold concentration of 20 MUM (the World Health Organization's suggested maximum allowable level for cyanide in wastewater) to the less harmful cyanate under ambient conditions. PMID- 28580115 TI - Photoinduced electron transfer from rylenediimide radical anions and dianions to Re(bpy)(CO)3 using red and near-infrared light. AB - A major goal of artificial photosynthesis research is photosensitizing highly reducing metal centers using as much as possible of the solar spectrum reaching Earth's surface. The radical anions and dianions of rylenediimide (RDI) dyes, which absorb at wavelengths as long as 950 nm, are powerful photoreductants with excited state oxidation potentials that rival or exceed those of organometallic chromophores. These dyes have been previously incorporated into all-organic donor acceptor systems, but have not yet been shown to reduce organometallic centers. This study describes a set of dyads in which perylenediimide (PDI) or naphthalenediimide (NDI) chromophores are attached to Re(bpy)(CO)3 through either the bipyridine ligand or more directly to the Re center via a pyridine ligand. The chromophores are reduced with a mild reducing agent, after which excitation with long-wavelength red or near-infrared light leads to reduction of the Re complex. The kinetics of electron transfer from the photoexcited anions to the Re complex are monitored using transient visible/near-IR and mid-IR spectroscopy, complemented by theoretical spectroscopic assignments. The photo-driven charge shift from the reduced PDI or NDI to the complex occurs in picoseconds regardless of whether PDI or NDI is attached to the bipyridine or to the Re center, but back electron transfer is found to be three orders of magnitude slower with the chromophore attached to the Re center. These results will inform the design of future catalytic systems that incorporate RDI anions as chromophores. PMID- 28580116 TI - Shape-transformable liquid metal nanoparticles in aqueous solution. AB - Stable suspensions of eutectic gallium indium (EGaIn) liquid metal nanoparticles form by probe-sonicating the metal in an aqueous solution. Positively-charged molecular or macromolecular surfactants in the solution, such as cetrimonium bromide or lysozyme, respectively, stabilize the suspension by interacting with the negative charges of the surface oxide that forms on the metal. The liquid metal breaks up into nanospheres via sonication, yet can transform into rods of gallium oxide monohydroxide (GaOOH) via moderate heating in solution either during or after sonication. Whereas heating typically drives phase transitions from solid to liquid (via melting), here heating drives the transformation of particles from liquid to solid via oxidation. Interestingly, indium nanoparticles form during the process of shape transformation due to the selective removal of gallium. This dealloying provides a mechanism to create indium nanoparticles at temperatures well below the melting point of indium. To demonstrate the versatility, we show that it is possible to shape transform and dealloy other alloys of gallium including ternary liquid metal alloys. Scanning transmission electron microscopy (STEM), energy-dispersive X-ray spectroscopy (EDS) mapping, and X-ray diffraction (XRD) confirm the dealloying and transformation mechanism. PMID- 28580118 TI - Total chemical synthesis of SUMO-2-Lys63-linked diubiquitin hybrid chains assisted by removable solubilizing tags. AB - Small ubiquitin like modifier (SUMO) proteins are known to regulate many important cellular processes such as transcription and apoptosis. Recently, hybrid SUMO-ubiquitin chains containing SUMO-2 linked to Lys63-di-ubiquitin were found to play a major role in DNA repair. Despite some progress in understanding the role of these hybrid chains in DNA repair, there are various fundamental questions remaining to be answered. To further investigate the importance of hybrid SUMO-ubiquitin chains in DNA repair, the homogenous material of these chains, and their unique analogues, are needed in workable quantities. By applying advanced chemical strategies for protein synthesis, we report the first total chemical synthesis of four different SUMO-2-Lys63-linked di-ubiquitin hybrid chains, in which the di-ubiquitin is linked to different lysines in SUMO. In these syntheses, the usefulness of removable solubilizing tags is demonstrated, and two different approaches were examined in terms of reliability and efficiency. In the first approach, a poly-Arg tag was attached to the C terminus of SUMO via a 3,4-diaminobenzoic acid cleavable linker, whereas in the second we attached the tag via a phenylacetamidomethyl linker, which can be cleaved by PdCl2. The comparison between these different strategies offers guidelines for future scale-up preparation of these analogues and other proteins, which currently use synthetic peptide intermediates that are difficult to handle and purify. The availability of the SUMO-ubiquitin hybrid chains opens up new opportunities for studying the role of these chains in DNA repair and other cellular processes. PMID- 28580117 TI - Two-photon fluorescent probe for revealing drug-induced hepatotoxicity via mapping fluctuation of peroxynitrite. AB - Drug-induced injury has attracted increasing attention in public health issues. Among them, hepatotoxicity has been regarded as the leading clinical problem caused by drug toxicity. However, owing to the complexity of the involved pathophysiological mechanisms and the lack of noninvasive, straightforward, and real-time tools, drug-induced hepatotoxicity has rarely been predicted satisfactorily. In this paper, by utilizing the reactive species peroxynitrite (ONOO-) as a biomarker, we present a two-photon fluorescent probe, TP-KA, holding rapid response, high specificity and sensitivity towards ONOO-, to investigate drug (acetaminophen and tolcapone)-related liver injury and the remediate effect of N-acetyl cysteine (NAC). With the support of TP-KA, we obtained direct and visual evidence of the upregulation of ONOO- during drug challenge both in live cells and mice, which was accompanied by liver tissue injury and tyrosine nitration. These findings demonstrate that ONOO- is a good and appropriate biomarker of hepatotoxicity, and nitrosative stress may be necessary for acetaminophen and tolcapone to exert their toxicity. Moreover, TP-KA can be employed as a powerful tool to pre-detect drug-induced organism injury and study the effect of antidotes. PMID- 28580119 TI - Pentavalent lanthanide nitride-oxides: NPrO and NPrO- complexes with N=Pr triple bonds. AB - The neutral molecule NPrO and its anion NPrO- are produced via co-condensation of laser-ablated praseodymium atoms with nitric oxide in a solid neon matrix. Combined infrared spectroscopy and state-of-the-art quantum chemical calculations confirm that both species are pentavalent praseodymium nitride-oxides with linear structures that contain Pr=N triple bonds and Pr=O double bonds. Electronic structure studies show that the neutral NPrO molecule features a 4f0 electron configuration and a Pr(v) oxidation state similar to that of the isoelectronic PrO2+ ion, while its NPrO- anion possesses a 4f1 electron configuration and a Pr(iv) oxidation state. The neutral NPrO molecule is thus a rare lanthanide nitride-oxide species with a Pr(v) oxidation state, which follows the recent identification of the first Pr(v) oxidation state in the PrO2+ and PrO4 complexes (Angew. Chem. Int. Ed., 2016, 55, 6896). This finding indicates that lanthanide compounds with oxidation states of higher than +IV are richer in chemistry than previously recognized. PMID- 28580120 TI - Chemical synthesis of a homoserine-mutant of the antibacterial, head-to-tail cyclized protein AS-48 by alpha-ketoacid-hydroxylamine (KAHA) ligation. AB - An antibacterial cyclic AS-48 protein was chemically synthesized by alpha ketoacid-hydroxylamine (KAHA) ligation. Initial challenges associated with the exceptionally hydrophobic segments arising from the amphiphilic nature of the protein were resolved by the development of bespoke reaction conditions for hydrophobic segments, using hexafluoroisopropanol (HFIP) as a co-solvent. The synthetic protein displays similar biological activity and properties to those of the native protein. To support the current understanding of its antibacterial mode of action, we demonstrate the ability of AS-48 to be incorporated into synthetic multilamellar vesicles (MLVs). PMID- 28580121 TI - A 2-aza-Cope reactivity-based platform for ratiometric fluorescence imaging of formaldehyde in living cells. AB - Formaldehyde (FA) is a major reactive carbonyl species (RCS) that is naturally produced in living systems through a diverse array of cellular pathways that span from epigenetic regulation to the metabolic processing of endogenous metabolites. At the same time, however, aberrant elevations in FA levels contribute to pathologies ranging from cancer and diabetes to heart, liver, and neurodegenerative diseases. Disentangling the complex interplay between FA physiology and pathology motivates the development of chemical tools that can enable the selective detection of this RCS in biological environments with spatial and temporal fidelity. We report the design, synthesis, and biological evaluation of ratiometric formaldehyde probe (RFAP) indicators for the excitation ratiometric fluorescence imaging of formaldehyde production in living systems. RFAP-1 and RFAP-2 utilize FA-dependent aza-Cope reactivity to convert an alkylamine-functionalized coumarin platform into its aldehyde congener with a ca. 50 nm shift in the excitation wavelength. The probes exhibit visible excitation and emission profiles, and high selectivity for FA over a variety of RCS and related reactive biological analytes, including acetaldehyde, with up to a 6-fold change in the fluorescence ratio. The RFAP indicators can be used to monitor changes in FA levels in biological samples by live-cell imaging and/or flow cytometry. Moreover, RFAP-2 is capable of visualizing differences in the resting FA levels between wild-type cells and models with a gene knockout of ADH5, a major FA-metabolizing enzyme, establishing the utility of this ratiometric detection platform for identifying and probing sources of FA fluxes in biology. PMID- 28580122 TI - Insights into the excitonic processes in polymeric photocatalysts. AB - Understanding the photoexcitation processes in semiconductors is critical for the design of advanced photocatalytic materials. Nevertheless, traditional viewpoints focus on photogenerated free charge carriers, which are somehow invalid once the many-body effects are taken into account, especially for polymeric photocatalysts. Here we systematically investigate the photoexcitation processes involved in the polymer matrix of graphitic carbon nitride (g-C3N4) by combining photoluminescence spectroscopy and ultrafast transient absorption spectroscopy, validating the strong excitonic effects in the well-known photocatalyst for the first time. The identification of the robust triplet-triplet annihilation process, in which two triplet excitons collide to produce a singlet exciton, highlights an important nonradiative depopulation pathway of excited species and thereby offers potential strategies to regulate the photocatalytic activities of polymeric g-C3N4. The work establishes a new understanding of the photocatalytic mechanism in the polymeric g-C3N4 matrix, and thus paves the way for designing effective polymeric photocatalysts through excitonic engineering. PMID- 28580123 TI - Temporal control of i-motif switch lifetimes for autonomous operation of transient DNA nanostructures. AB - Functional DNA nanotechnology creates increasingly complex behaviors useful for sensing, actuation or computation, as enabled via the integration of dynamic and responsive structural DNA motifs. However, temporally controlled and dynamic DNA structures with programmable lifetimes, that are able to operate autonomously and self-revert to the starting state are challenging to achieve due to tedious and very system-specific sequence design. Here, we present a straightforward concept to program transient lifetimes into DNA duplexes based on the pH-sensitive DNA i motif switch. We integrate the i-motif switch with an internal, non-linear pH resetting function using a rationally designed chemical reaction framework, by which the switch autonomously undergoes a complete "off-on-off"-cycle without the use of additional external triggers. The lifetime of the activated "on"-state (i.e. the hybridized state) can be systematically programmed over several hours. The system can be readily implemented into hybrid DNA structures on larger length scales. Focusing on autonomous materials, we demonstrate temporal control of transient fluorescence signals and temporary aggregation of gold nanoparticles. PMID- 28580128 TI - Imagining tomorrow's university: open science and its impact. AB - As part of a recent workshop entitled "Imagining Tomorrow's University", we were asked to visualize the future of universities as research becomes increasingly data- and computation-driven, and identify a set of principles characterizing pertinent opportunities and obstacles presented by this shift. In order to establish a holistic view, we take a multilevel approach and examine the impact of open science on individual scholars as well as on the university as a whole. At the university level, open science presents a double-edged sword: when well executed, open science can accelerate the rate of scientific inquiry across the institution and beyond; however, haphazard or half-hearted efforts are likely to squander valuable resources, diminish university productivity and prestige, and potentially do more harm than good. We present our perspective on the role of open science at the university. PMID- 28580127 TI - Improving agricultural knowledge management: The AgTrials experience. AB - Background: Opportunities to use data and information to address challenges in international agricultural research and development are expanding rapidly. The use of agricultural trial and evaluation data has enormous potential to improve crops and management practices. However, for a number of reasons, this potential has yet to be realized. This paper reports on the experience of the AgTrials initiative, an effort to build an online database of agricultural trials applying principles of interoperability and open access. Methods: Our analysis evaluates what worked and what did not work in the development of the AgTrials information resource. We analyzed data on our users and their interaction with the platform. We also surveyed our users to gauge their perceptions of the utility of the online database. Results: The study revealed barriers to participation and impediments to interaction, opportunities for improving agricultural knowledge management and a large potential for the use of trial and evaluation data. Conclusions: Technical and logistical mechanisms for developing interoperable online databases are well advanced. More effort will be needed to advance organizational and institutional work for these types of databases to realize their potential. PMID- 28408973 TI - A multi-scale computational model of the effects of TMS on motor cortex. AB - The detailed biophysical mechanisms through which transcranial magnetic stimulation (TMS) activates cortical circuits are still not fully understood. Here we present a multi-scale computational model to describe and explain the activation of different pyramidal cell types in motor cortex due to TMS. Our model determines precise electric fields based on an individual head model derived from magnetic resonance imaging and calculates how these electric fields activate morphologically detailed models of different neuron types. We predict neural activation patterns for different coil orientations consistent with experimental findings. Beyond this, our model allows us to calculate activation thresholds for individual neurons and precise initiation sites of individual action potentials on the neurons' complex morphologies. Specifically, our model predicts that cortical layer 3 pyramidal neurons are generally easier to stimulate than layer 5 pyramidal neurons, thereby explaining the lower stimulation thresholds observed for I-waves compared to D-waves. It also shows differences in the regions of activated cortical layer 5 and layer 3 pyramidal cells depending on coil orientation. Finally, it predicts that under standard stimulation conditions, action potentials are mostly generated at the axon initial segment of cortical pyramidal cells, with a much less important activation site being the part of a layer 5 pyramidal cell axon where it crosses the boundary between grey matter and white matter. In conclusion, our computational model offers a detailed account of the mechanisms through which TMS activates different cortical pyramidal cell types, paving the way for more targeted application of TMS based on individual brain morphology in clinical and basic research settings. PMID- 28580126 TI - Early embryo mortality in natural human reproduction: What the data say. AB - It is generally accepted that natural human embryo mortality during pregnancy is high - losses of 70% and higher from fertilisation to birth are frequently claimed. The first external sign of pregnancy occurs two weeks after fertilisation with a missed menstrual period. Establishing the fate of embryos before this is challenging, and hampered by a lack of data on the efficiency of fertilisation under natural conditions. Four distinct sources are cited to justify quantitative claims regarding embryo loss: (i) a hypothesis published by Roberts & Lowe in TheLancet is widely cited but has no quantitative value; (ii) life table analyses give consistent assessments of clinical pregnancy loss, but cannot illuminate losses at earlier stages of development; (iii) studies that measure human chorionic gonadotrophin (hCG) reveal losses in the second week of development and beyond, but not before; and (iv) the classic studies of Hertig and Rock offer the only direct insight into the fate of human embryos from fertilisation under natural conditions. Re-examination of Hertig's data demonstrates that his estimates for fertilisation rate and early embryo loss are highly imprecise and casts doubt on the validity of his numerical analysis. A recent re-analysis of hCG study data suggests that approximately 40-60% of embryos may be lost between fertilisation and birth, although this will vary substantially between individual women. In conclusion, it is clear that some published estimates of natural embryo mortality are exaggerated. Although available data do not provide a precise estimate, natural human embryo mortality is lower than is often claimed. PMID- 28580129 TI - Case Report: Orbital metastasis as the presenting feature of lung cancer. AB - Orbital metastasis from lung cancer as an initial presenting symptom is a rare entity, which may paradoxically delay the diagnosis and initiation of correct management, due to the confusion of it being primary orbital pathology. Herein we report a case of a 58 year old woman, who presented with painful orbital swelling along with diminution in her vision. The patient was initially thought to have a primary eye lesion; however chest X-ray was suggestive of a lung mass, which was confirmed by chest computed topography followed by ultrasound guided fine needle aspiration cytology. The patient was then referred to a cancer centre for further management. This case report aims to increase the knowledge about this metastasis as a probable cause of orbital symptoms in certain subsets of patients, so that correct therapeutic decisions may be made in the future. PMID- 28580124 TI - Sex-dependent effects of maternal corticosterone and SSRI treatment on hippocampal neurogenesis across development. AB - BACKGROUND: Postpartum depression affects approximately 15% of mothers and represents a form of early life adversity for developing offspring. Postpartum depression can be treated with prescription antidepressants like fluoxetine (FLX). However, FLX can remain active in breast milk, raising concerns about the consequences of neonatal FLX exposure. The hippocampus is highly sensitive to developmental stress, and males and females respond differently to stress at many endpoints, including hippocampal plasticity. However, it is unclear how developmental exposure to FLX alters the trajectory of hippocampal development. The goal of this study was to examine the long-term effects of maternal postpartum corticosterone (CORT, a model of postpartum depression) and concurrent FLX on hippocampal neurogenesis in male and female offspring. METHODS: Female Sprague-Dawley rat dams were treated daily with either CORT or oil and FLX or saline from postpartum days 2-23. Offspring were perfused on postnatal day 31 (pre-adolescent), postnatal day 42 (adolescent), and postnatal day 69 (adult). Tissue was processed for doublecortin (DCX), an endogenous marker of immature neurons, in the dorsal and ventral hippocampus. RESULTS: Maternal postpartum CORT reduced density of DCX-expressing cells in the dorsal hippocampus of pre adolescent males and increased it in adolescent males, suggesting that postpartum CORT exposure disrupted the typical progression of the density of DCX-expressing cells. Further, among offspring of oil-treated dams, pre-adolescent males had greater density of DCX-expressing cells than pre-adolescent females, and maternal postpartum CORT prevented this sex difference. In pre-adolescent females, maternal postpartum FLX decreased the density of DCX-expressing cells in the dorsal hippocampus compared to saline. As expected, maternal CORT reduced the density of DCX-expressing cells in adult female, but not male, offspring. The combination of maternal postpartum CORT/FLX diminished density of DCX-expressing cells in dorsal hippocampus regardless of sex or age. CONCLUSIONS: These findings reveal how modeling treatment of postpartum depression with FLX alters hippocampal neurogenesis in developing offspring differently depending on sex, predominantly in the dorsal dentate gyrus and earlier in life. PMID- 28580130 TI - Cell signaling promoting protein carbonylation does not cause sulfhydryl oxidation: Implications to the mechanism of redox signaling. AB - Reactive oxygen species (ROS) have been recognized as second messengers, however, targeting mechanisms for ROS in cell signaling have not been defined. While ROS oxidizing protein cysteine thiols has been the most popular proposed mechanism, our laboratory proposed that ligand/receptor-mediated cell signaling involves protein carbonylation. Peroxiredoxin-6 (Prx6) is one protein that is carbonylated at 10 min after the platelet-derived growth factor (PDGF) stimulation of human pulmonary artery smooth muscle cells. In the present study, the SulfoBiotics Protein Redox State Monitoring Kit Plus (Dojindo Molecular Technologies) was used to test if cysteine residues of Prx6 are oxidized in response to the PDGF stimulation. Human Prx6 has a molecular weight of 25 kDa and contains two cysteine residues. The Dojindo system adds the 15 kDa Protein-SHifter if these cysteine residues are reduced in the cells. Results showed that, in untreated cells, the Prx6 molecule predominantly exhibited the 55 kDa band, indicating that both cysteine residues are reduced in the cells. Treatment of cells with 1 mM H 2O 2 caused the disappearance of the 55 kDa band and the appearance of a 40 kDa band, suggesting that the high concentration of H 2O 2 oxidized one of the two cysteine residues in the Prx6 molecule. By contrast, PDGF stimulation had no effects on the thiol status of the Prx6 molecule. We concluded that protein carbonylation is a more sensitive target of ROS during ligand/receptor-mediated cell signaling than sulfhydryl oxidation. PMID- 28580132 TI - Case Report: Making a diagnosis of familial renal disease - clinical and patient perspectives. AB - BACKGROUND: A precise molecular genetic diagnosis has become the gold standard for the correct identification and management of many inherited renal diseases. METHODS: Here we describe a family with familial focal segmental glomerulosclerosis, and include a clinical and patient perspective on the diagnostic workup and relaying of genetic results following whole exome sequencing. RESULTS: Through next generation sequencing approaches, we identified a pathogenic mutation in TRPC6, the underlying cause of the phenotype. The identification of this mutation had important clinical consequences for the family, including allowing a living-unrelated kidney transplant to proceed in the index case. There are also wider ranging social and ethical dilemmas presented when reaching a genetic diagnosis like this one, which are explored here by both physicians and the index case. CONCLUSIONS: Through physician and patient perspectives in a family with inherited renal failure we explore the implications and the magnitude of a molecular genetic diagnosis. PMID- 28580131 TI - Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions. AB - There are more and more data concerning the role of cellular metabolism in innate immune cells, such as macrophages or conventional dendritic cells. However, few data are available currently concerning plasmacytoid dendritic cells (PDC), another type of innate immune cells. These cells are the main type I interferon (IFN) producing cells, but they also secrete other pro-inflammatory cytokines (e.g., tumor necrosis factor or interleukin [IL]-6) or immunomodulatory factors (e.g., IL-10 or transforming growth factor-beta). Through these functions, PDC participate in antimicrobial responses or maintenance of immune tolerance, and have been implicated in the pathophysiology of several autoimmune diseases. Recent data support the idea that the glycolytic pathway (or glycolysis), as well as lipid metabolism (including both cholesterol and fatty acid metabolism) may impact some innate immune functions of PDC or may be involved in these functions after Toll-like receptor (TLR) 7/9 triggering. Some differences may be related to the origin of PDC (human versus mouse PDC or blood-sorted versus FLT3 ligand stimulated-bone marrow-sorted PDC). The kinetics of glycolysis may differ between human and murine PDC. In mouse PDC, metabolism changes promoted by TLR7/9 activation may depend on an autocrine/paracrine loop, implicating type I IFN and its receptor IFNAR, explaining a delayed glycolysis. Moreover, PDC functions can be modulated by the metabolism of cholesterol and fatty acids. This may occur via the production of lipid ligands that activate nuclear receptors (e.g., liver X receptor [LXR]) in PDC or through limiting intracellular cholesterol pool size (by statins or LXR agonists) in these cells. Finally, lipid-activated nuclear receptors ( i.e., LXR or peroxisome proliferator activated receptor) may also directly interact with pro-inflammatory transcription factors, such as NF-kappaB. Here, we discuss how glycolysis and lipid metabolism may modulate PDC functions and how this may be harnessed in pathological situations where PDC play a detrimental role. PMID- 28580134 TI - What is open peer review? A systematic review. AB - BACKGROUND: "Open peer review" (OPR), despite being a major pillar of Open Science, has neither a standardized definition nor an agreed schema of its features and implementations. The literature reflects this, with a myriad of overlapping and often contradictory definitions. While the term is used by some to refer to peer review where the identities of both author and reviewer are disclosed to each other, for others it signifies systems where reviewer reports are published alongside articles. For others it signifies both of these conditions, and for yet others it describes systems where not only "invited experts" are able to comment. For still others, it includes a variety of combinations of these and other novel methods. METHODS: Recognising the absence of a consensus view on what open peer review is, this article undertakes a systematic review of definitions of "open peer review" or "open review", to create a corpus of 122 definitions. These definitions are then systematically analysed to build a coherent typology of the many different innovations in peer review signified by the term, and hence provide the precise technical definition currently lacking. RESULTS: This quantifiable data yields rich information on the range and extent of differing definitions over time and by broad subject area. Quantifying definitions in this way allows us to accurately portray exactly how ambiguously the phrase "open peer review" has been used thus far, for the literature offers a total of 22 distinct configurations of seven traits, effectively meaning that there are 22 different definitions of OPR in the literature. CONCLUSIONS: Based on this work, I propose a pragmatic definition of open peer review as an umbrella term for a number of overlapping ways that peer review models can be adapted in line with the ethos of Open Science, including making reviewer and author identities open, publishing review reports and enabling greater participation in the peer review process. PMID- 28580133 TI - The elephant shark methylome reveals conservation of epigenetic regulation across jawed vertebrates. AB - BACKGROUND: Methylation of CG dinucleotides constitutes a critical system of epigenetic memory in bony vertebrates, where it modulates gene expression and suppresses transposon activity. The genomes of studied vertebrates are pervasively hypermethylated, with the exception of regulatory elements such as transcription start sites (TSSs), where the presence of methylation is associated with gene silencing. This system is not found in the sparsely methylated genomes of invertebrates, and establishing how it arose during early vertebrate evolution is impeded by a paucity of epigenetic data from basal vertebrates. METHODS: We perform whole-genome bisulfite sequencing to generate the first genome-wide methylation profiles of a cartilaginous fish, the elephant shark Callorhinchus milii. Employing these to determine the elephant shark methylome structure and its relationship with expression, we compare this with higher vertebrates and an invertebrate chordate using published methylation and transcriptome data. Results: Like higher vertebrates, the majority of elephant shark CG sites are highly methylated, and methylation is abundant across the genome rather than patterned in the mosaic configuration of invertebrates. This global hypermethylation includes transposable elements and the bodies of genes at all expression levels. Significantly, we document an inverse relationship between TSS methylation and expression in the elephant shark, supporting the presence of the repressive regulatory architecture shared by higher vertebrates. CONCLUSIONS: Our demonstration that methylation patterns in a cartilaginous fish are characteristic of higher vertebrates imply the conservation of this epigenetic modification system across jawed vertebrates separated by 465 million years of evolution. In addition, these findings position the elephant shark as a valuable model to explore the evolutionary history and function of vertebrate methylation. PMID- 28579921 TI - A search for new phenomena in pp collisions at [Formula: see text] in final states with missing transverse momentum and at least one jet using the [Formula: see text] variable. AB - A search for new phenomena is performed in final states containing one or more jets and an imbalance in transverse momentum in pp collisions at a centre-of-mass energy of 13[Formula: see text]. The analysed data sample, recorded with the CMS detector at the CERN LHC, corresponds to an integrated luminosity of 2.3[Formula: see text]. Several kinematic variables are employed to suppress the dominant background, multijet production, as well as to discriminate between other standard model and new physics processes. The search provides sensitivity to a broad range of new-physics models that yield a stable weakly interacting massive particle. The number of observed candidate events is found to agree with the expected contributions from standard model processes, and the result is interpreted in the mass parameter space of fourteen simplified supersymmetric models that assume the pair production of gluinos or squarks and a range of decay modes. For models that assume gluino pair production, masses up to 1575 and 975[Formula: see text] are excluded for gluinos and neutralinos, respectively. For models involving the pair production of top squarks and compressed mass spectra, top squark masses up to 400[Formula: see text] are excluded. PMID- 28580136 TI - Acute mechanical circulatory support for cardiogenic shock: the "door to support" time. AB - Cardiogenic shock (CS) remains a major cause of in-hospital mortality in the setting of acute myocardial infarction. CS begins as a hemodynamic problem with impaired cardiac output leading to reduced systemic perfusion, increased residual volume within the left and right ventricles, and increased cardiac filling pressures. A critical step towards the development of future algorithms is a clear understanding of the treatment objectives for CS. In this review, we introduce the "door to support" time as an emerging target of therapy to improve outcomes associated with CS, define four key treatment objectives in the management of CS, discuss the importance of early hemodynamic assessment and appropriate selection of acute mechanical circulatory support (AMCS) devices for CS, and introduce a classification scheme that identifies subtypes of CS based on cardiac filling pressures. PMID- 28580135 TI - SNP-SNP interactions as risk factors for aggressive prostate cancer. AB - Prostate cancer (PCa) is one of the most significant male health concerns worldwide. Single nucleotide polymorphisms (SNPs) are becoming increasingly strong candidate biomarkers for identifying susceptibility to PCa. We identified a number of SNPs reported in genome-wide association analyses (GWAS) as risk factors for aggressive PCa in various European populations, and then defined SNP SNP interactions, using PLINK software, with nucleic acid samples from a New Zealand cohort. We used this approach to find a gene x environment marker for aggressive PCa, as although statistically gene x environment interactions can be adjusted for, it is highly impossible in practicality, and thus must be incorporated in the search for a reliable biomarker for PCa. We found two intronic SNPs statistically significantly interacting with each other as a risk for aggressive prostate cancer on being compared to healthy controls in a New Zealand population. PMID- 28580137 TI - Unusual Blue-Shifted Acid-Responsive Photoluminescence Behavior in 6-Amino-8 cyanobenzo[1,2-b]indolizines. AB - 6-Amino-8-cyanobenzo[1, 2-b]indolizines, a new class of photoluminescent materials, exhibit reversible pH-dependent optical properties characterized by an uncommon and dramatic blue shift in fluorescence emission when protonated. Acid titration and NMR spectroscopy experiments reveal that, rather than the anticipated N-protonation, C-protonation and loss of aromaticity is responsible for the observed photophysical changes. Efficient synthesis from indole-2 carboxaldehydes makes variously substituted versions of this nucleus readily available to tune optical and pH effects. PMID- 28580138 TI - Plasma membrane association facilitates conformational changes in the Marburg virus protein VP40 dimer. AB - Filovirus infections cause hemorrhagic fever in humans and non-human primates that often results in high fatality rates. The Marburg virus is a lipid-enveloped virus from the Filoviridae family and is closely related to the Ebola virus. The viral matrix layer underneath the lipid envelope is formed by the matrix protein VP40 (VP40), which is also involved in other functions during the viral life cycle. As in the Ebola virus VP40 (eVP40), the recently determined X-ray crystal structure of the Marburg virus VP40 (mVP40) features loops containing cationic residues that form a lipid binding basic patch. However, the mVP40 basic patch is significantly flatter with a more extended surface than in eVP40, suggesting the possibility of differences in the plasma membrane interactions and phospholipid specificity between the VP40 dimers. In this paper, we report on molecular dynamics simulations that investigate the roles of various residues and lipid types in PM association as well as the conformational changes of the mVP40 dimer facilitated by membrane association. We compared the structural changes of the mVP40 dimer with the mVP40 dimer in both lipid free and membrane associated conditions. Despite the significant structural differences in the crystal structure, the Marburg VP40 dimer is found to adopt a configuration very similar to the Ebola VP40 dimer after associating with the membrane. This conformational rearrangement upon lipid binding allows Marburg VP40 to localize and stabilize at the membrane surface in a manner similar to the Ebola VP40 dimer. Consideration of the structural information in its lipid-interacting condition may be important in targeting mVP40 for novel drugs to inhibit viral budding from the plasma membrane. PMID- 28580140 TI - Analysis of the lifetime and culling reasons for AI boars. AB - BACKGROUND: The aim of the study was to analyze the lifetime and culling reasons for boars used in insemination centers (AI centers). METHODS: The data collected from 355 culled boars from 1998 to 2013 included: age at start of semen collection, boar herd life, culling reason, daily gain and lean meat content, and number of ejaculates not meeting sales requirements after dilution. Culling reasons were divided into 7 groups: low semen value (LSV), low or lack of libido (LL), leg problems (LP), infectious diseases (ID), old age (OA), reduced demand for semen from the given boar (RD), and others (OT). RESULTS: The most common culling reasons for boars were LSV (23.7%) and RD (22.5%). It was observed that the lowest daily gains were noted in boars culled due to OA. Boars culled due to OA and RD were maintained in production for the longest time (over 1000 d), for LSV and ID retention was about 700 d, and due to LL below 400 d. The survival probability was over 0.9 until 1.5 yr, and just over 0.2 until 4 yr. The highest relative frequency was observed in the 36th and 42nd mo of life (over 16%). Hazard risk analysis revealed a more than 10 times higher risk of culling in the case of LL, ID or OT, in comparison to OA. CONCLUSIONS: The results can be used as a direct point of reference for the identification of emerging problems in AI boar exploitation and the development of an appropriate culling policy in AI centers. PMID- 28580141 TI - Factor analysis of the adolescent version of the Eating Disorders Examination Questionnaire (EDE-Q): results from Swedish general population and clinical samples. AB - BACKGROUND: Although the Eating Disorder Examination Questionnaire (EDE-Q) is perhaps the single most widely used self-report measure of eating disorder (ED) symptoms, important questions remain about its validity and applicability in relation to particular groups of individuals, especially adolescents of both genders. METHODS: The present study investigated the factor structure of the adolescent version of the Eating Disorder Examination Questionnaire (EDE-Q) in samples of Swedish girls and boys from the general population and girls with a diagnosed eating disorder. Girls (N = 239) and boys (N = 248) aged between 13 and 15 years who were attending school, and girls (N = 570) aged between 12 and 14 years who were in treatment for an eating disorder at a specialist eating disorder clinic were assessed on the adolescent version of the EDE-Q. RESULTS: The adolescent version of the EDE-Q demonstrated satisfactory levels of internal consistency. However, confirmatory factor analysis (CFA) failed to support the four-factor model of the EDE-Q. Parallel analysis (PA) and subsequent exploratory factor analysis (EFA) suggested that the adolescent version of the EDE-Q comprises one underlying factor in young adolescent girls (both clinical and general population), centred on Dissatisfaction with Shape and Weight. In boys three factors were found: Weight-related Concerns, Body Discomfort and Restraint. CONCLUSIONS: The EDE-Q appears to measure different underlying aspects of eating disorder psychopathology in young teenagers compared to adults. The dimensions underlying disordered eating in young girls may become increasingly differentiated with time. There appear to be important gender-based differences in the dimensions underlying the EDE-Q in young teenagers. Therapists should be alert to beliefs that girls have about the importance of shape and weight, while in boys it may be more important to be attentive to how they feel about their bodies in relation to weight. PMID- 28580144 TI - Oxygen-induced doping on reduced PEDOT. AB - The conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) has shown promise as air electrode in renewable energy technologies like metal-air batteries and fuel cells. PEDOT is based on atomic elements of high abundance and is synthesized at low temperature from solution. The mechanism of oxygen reduction reaction (ORR) over chemically polymerized PEDOT:Cl still remains controversial with eventual role of transition metal impurities. However, regardless of the mechanistic route, we here demonstrate yet another key active role of PEDOT in the ORR mechanism. Our study demonstrates the decoupling of conductivity (intrinsic property) from electrocatalysis (as an extrinsic phenomenon) yielding the evidence of doping of the polymer by oxygen during ORR. Hence, the PEDOT electrode is electrochemically reduced (undoped) in the voltage range of ORR regime, but O2 keeps it conducting; ensuring PEDOT to act as an electrode for the ORR. The interaction of oxygen with the polymer electrode is investigated with a battery of spectroscopic techniques. PMID- 28580142 TI - Enhanced pyroelectric and piezoelectric properties of PZT with aligned porosity for energy harvesting applications. AB - This paper demonstrates the significant benefits of exploiting highly aligned porosity in piezoelectric and pyroelectric materials for improved energy harvesting performance. Porous lead zirconate (PZT) ceramics with aligned pore channels and varying fractions of porosity were manufactured in a water-based suspension using freeze-casting. The aligned porous PZT ceramics were characterized in detail for both piezoelectric and pyroelectric properties and their energy harvesting performance figures of merit were assessed parallel and perpendicular to the freezing direction. As a result of the introduction of porosity into the ceramic microstructure, high piezoelectric and pyroelectric harvesting figures of merits were achieved for porous freeze-cast PZT compared to dense PZT due to the reduced permittivity and volume specific heat capacity. Experimental results were compared to parallel and series analytical models with good agreement and the PZT with porosity aligned parallel to the freezing direction exhibited the highest piezoelectric and pyroelectric harvesting response; this was a result of the enhanced interconnectivity of the ferroelectric material along the poling direction and reduced fraction of unpoled material that leads to a higher polarization. A complete thermal energy harvesting system, composed of a parallel-aligned PZT harvester element and an AC/DC converter, was successfully demonstrated by charging a storage capacitor. The maximum energy density generated by the 60 vol% porous parallel-connected PZT when subjected to thermal oscillations was 1653 MUJ cm-3, which was 374% higher than that of the dense PZT with an energy density of 446 MUJ cm-3. The results are beneficial for the design and manufacture of high performance porous pyroelectric and piezoelectric materials in devices for energy harvesting and sensor applications. PMID- 28580139 TI - Factors predicting the instant effect of motor function after subthalamic nucleus deep brain stimulation in Parkinson's disease. AB - BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for Parkinson's disease (PD), the predictive effect of levodopa responsiveness on surgical outcomes was confirmed by some studies, however there were different conclusions about that through long- and short-term follow-ups. We aimed to investigate the factors which influence the predictive value of levodopa responsiveness, and discover more predictive factors of surgical outcomes. METHODS: Twenty-three PD patients underwent bilateral STN-DBS and completed our follow-up. Clinical evaluations were performed 1 week before and 3 months after surgery. RESULTS: STN-DBS significantly improved motor function of PD patients after 3 months; preoperative levodopa responsiveness and disease subtype predicted the effect of DBS on motor function; gender, disease duration and duration of motor fluctuations modified the predictive effect of levodopa responsiveness on motor improvement; the duration of motor fluctuations and severity of preoperative motor symptoms modified the predictive effect of disease subtype on motor improvement. CONCLUSIONS: The intensity of levodopa responsiveness served as a predictor of motor improvement more accurately in female patients, patients with shorter disease duration or shorter motor fluctuations; PD patients with dominant axial symptoms benefit less from STN-DBS compared to those with limb-predominant symptoms, especially in their later disease stage. PMID- 28580143 TI - Tunable thermodynamic activity of La x Sr1-x Mn y Al1-y O3-delta (0 <= x <= 1, 0 <= y <= 1) perovskites for solar thermochemical fuel synthesis. AB - Nonstoichiometric metal oxides with variable valence are attractive redox materials for thermochemical and electrochemical fuel processing. To guide the design of advanced redox materials for solar-driven splitting of CO2 and/or H2O to produce CO and/or H2 (syngas), we investigate the equilibrium thermodynamics of the La x Sr1-x Mn y Al1-y O3-delta perovskite family (0 <= x <= 1, 0 <= y <= 1) and La0.6Ca0.4Mn0.8Al0.2O3-delta , and compare them to those of CeO2 as the baseline. Oxygen nonstoichiometry measurements from 1573 to 1773 K and from 0.206 to 180 mbar O2 show a tunable reduction extent, increasing with increasing Sr content. Maximal nonstoichiometry of 0.32 is established with La0.2Sr0.8Mn0.8Al0.2O3-delta at 1773 K and 2.37 mbar O2. As a trend, we find that oxygen capacities are most sensitive to the A-cation composition. Partial molar enthalpy, entropy and Gibbs free energy changes for oxide reduction are extracted from the experimental data using defect models for Mn4+/Mn3+ and Mn3+/Mn2+ redox couples. We find that perovskites exhibit typically decreasing enthalpy changes with increasing nonstoichiometries. This desirable characteristic is most pronounced by La0.6Sr0.4Mn0.4Al0.6O3-delta , rendering it attractive for CO2 and H2O splitting. Generally, perovskites show lower enthalpy and entropy changes than ceria, resulting in more favorable reduction but less favorable oxidation equilibria. The energy penalties due to larger temperature swings and excess oxidants are discussed in particular. Using electronic structure theory, we conclude with a practical methodology estimating thermodynamic activity to rationally design perovskites with variable stoichiometry and valence. PMID- 28580146 TI - Use of physiological knowledge to control the invasive sea lamprey (Petromyzon marinus) in the Laurentian Great Lakes. AB - Sea lamprey (Petromyzon marinus) control in the Laurentian Great Lakes of North America is an example of using physiological knowledge to successfully control an invasive species and rehabilitate an ecosystem and valuable fishery. The parasitic sea lamprey contributed to the devastating collapse of native fish communities after invading the Great Lakes during the 1800s and early 1900s. Economic tragedy ensued with the loss of the fishery and severe impacts to property values and tourism resulting from sea lamprey-induced ecological changes. To control the sea lamprey and rehabilitate the once vibrant Great Lakes ecosystem and economy, the Great Lakes Fishery Commission (Commission) was formed by treaty between Canada and the United States in 1955. The Commission has developed a sea lamprey control programme based on their physiological vulnerabilities, which includes (i) the application of selective pesticides (lampricides), which successfully kill sedentary sea lamprey larvae in their natal streams; (ii) barriers to spawning migrations and associated traps to prevent infestations of upstream habitats and remove adult sea lamprey before they reproduce; and (iii) the release of sterilized males to reduce the reproductive potential of spawning populations in select streams. Since 1958, the application of the sea lamprey control programme has suppressed sea lamprey populations by ~90% from peak abundance. Great Lakes fish populations have rebounded and the economy is now thriving. In hopes of further enhancing the efficacy and selectivity of the sea lamprey control programme, the Commission is exploring the use of (i) sea lamprey chemosensory cues (pheromones and alarm cues) to manipulate behaviours and physiologies, and (ii) genetics to identify and manipulate genes associated with key physiological functions, for control purposes. Overall, the Commission capitalizes on the unique physiology of the sea lamprey and strives to develop a diverse integrated programme to successfully control a once devastating invasive species. PMID- 28580147 TI - The quantification of reproductive hormones in the hair of captive adult brown bears and their application as indicators of sex and reproductive state. AB - Recognizing the potential value of steroid hormone measurements to augment non invasive genetic sampling, we developed procedures based on enzyme-linked immunoassays to quantify reproductive steroid hormone concentrations in brown bear (Ursus arctos) hair. Then, using 94 hair samples collected from eight captive adult bears over a 2-year period, we evaluated (i) associations between hair concentrations of testosterone, progesterone, estradiol and cortisol; (ii) the effect of collecting by shaving vs. plucking; and (iii) the utility of reproductive hormone profiles to differentiate sex and reproductive state. Sample requirements (125 mg of guard hair) to assay all hormones exceeded amounts typically obtained by non-invasive sampling. Thus, broad application of this approach will require modification of non-invasive techniques to collect larger samples, use of mixed (guard and undercoat) hair samples and/or application of more sensitive laboratory procedures. Concentrations of hormones were highly correlated suggesting their sequestration in hair reflects underlying physiological processes. Marked changes in hair hormone levels during the quiescent phase of the hair cycle, coupled with the finding that progesterone concentrations, and their association with testosterone levels, differed markedly between plucked and shaved hair samples, suggests steroids sequestered in hair were likely derived from various sources, including skin. Changes in hair hormone concentrations over time, and in conjunction with key reproductive events, were similar to what has been reported concerning hormonal changes in the blood serum of brown bears. Thus, potential for the measurement of hair reproductive hormone levels to augment non-invasive genetic sampling appears compelling. Nonetheless, we are conducting additional validation studies on hair collected from free ranging bears, representative of all sex, age and reproductive classes, to fully evaluate the utility of this approach for brown bear conservation and research. PMID- 28580148 TI - Post-tuberculosis mycetoma: bronchoscopic removal. AB - A 76-year-old male non-smoker presented to our institution with cough and haemoptysis. He had been treated for cavitatory pulmonary Mycobacterium tuberculosis of the right upper lobe 10 years previously. Chest radiograph and subsequent computed tomography (CT) of the chest demonstrated a right upper cavity containing a mass suspicious for mycetoma. Flexible bronchoscopy under conscious sedation demonstrated a mass obstructing the anterior segment of the right upper lobe. The abnormality was subsequently removed using a flexible endobronchial cryoprobe. Histopathological analysis demonstrated abundant fungal organisms morphologically consistent with Aspergillus species. Microbiological culture of the bronchoalveolar lavage (BAL) from the cavity isolated both Aspergillus fumigatus and Staphylococcus aureus. The patient was commenced on the anti-fungal drug posaconazole and received a course of flucloxacillin. Three months later, there was no endobronchial obstruction and lavage of the affected cavity again isolated Staphylococcus aureus without Aspergillus species. Repeat thoracic CT and flexible bronchoscopy demonstrated no further re-occurrence of the mycetoma at 3 months. PMID- 28580154 TI - Parry Romberg syndrome presenting with a giant intracranial aneurysm: a case report. AB - A giant intracranial aneurysm was diagnosed in a 10-year-old girl when she developed a right abducens nerve palsy. The aneurysm was treated successfully. Six years later, however, she presented with a progressive en coup de sabre deformity, leading to the diagnosis Parry Romberg Syndrome (PRS), a rare diagnosis characterized by hemifacial atrophy of skin, subcutaneous tissue, skeletal muscle and bones and often associated with various non-specific intracerebral abnormalities. In this patient retrospective analysis of computed tomography and magnetic resonance imaging imaging indeed revealed intracerebral calcifications and aspecific white matter lesions. Remarkably, in this patient the giant intracranial aneurysm turned out to be the presenting symptom of PRS years before the characteristic facial deformities became apparent. PMID- 28580152 TI - Brugada phenocopy in a patient with acute pulmonary embolism presenting with recurrent syncope. AB - Brugada phenocopy (BrP) refers to a group of clinical conditions that have etiologies distinct from Brugada syndrome (BrS). Although both demonstrate features of ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), one must be distinguished from the other as their treatment options are different. We report a male patient who presented with recurrent syncope with a Brugada and a S1Q3T3 pattern on the ECG. Acute pulmonary embolism (APE) complicated by BrS was suspected. Twenty-four hours Holter monitoring did not demonstrate any evidence of ventricular arrhythmias. Computed tomography pulmonary angiogram confirmed the presence of an APE. He was treated with low molecular weight heparin and a repeat ECG taken the next day showed resolution of the Brugada and S1Q3T3 patterns. This case report illustrates that APE and BrS can present with similar clinical and electrocardiographic features of recurrent syncope and Brugada pattern, respectively. PMID- 28580149 TI - Suite of simple metrics reveals common movement syndromes across vertebrate taxa. AB - BACKGROUND: Because empirical studies of animal movement are most-often site- and species-specific, we lack understanding of the level of consistency in movement patterns across diverse taxa, as well as a framework for quantitatively classifying movement patterns. We aim to address this gap by determining the extent to which statistical signatures of animal movement patterns recur across ecological systems. We assessed a suite of movement metrics derived from GPS trajectories of thirteen marine and terrestrial vertebrate species spanning three taxonomic classes, orders of magnitude in body size, and modes of movement (swimming, flying, walking). Using these metrics, we performed a principal components analysis and cluster analysis to determine if individuals organized into statistically distinct clusters. Finally, to identify and interpret commonalities within clusters, we compared them to computer-simulated idealized movement syndromes representing suites of correlated movement traits observed across taxa (migration, nomadism, territoriality, and central place foraging). RESULTS: Two principal components explained 70% of the variance among the movement metrics we evaluated across the thirteen species, and were used for the cluster analysis. The resulting analysis revealed four statistically distinct clusters. All simulated individuals of each idealized movement syndrome organized into separate clusters, suggesting that the four clusters are explained by common movement syndrome. CONCLUSIONS: Our results offer early indication of widespread recurrent patterns in movement ecology that have consistent statistical signatures, regardless of taxon, body size, mode of movement, or environment. We further show that a simple set of metrics can be used to classify broad-scale movement patterns in disparate vertebrate taxa. Our comparative approach provides a general framework for quantifying and classifying animal movements, and facilitates new inquiries into relationships between movement syndromes and other ecological processes. PMID- 28580145 TI - Lysosome-oriented, dual-stage pH-responsive polymeric micelles for beta-Lapachone delivery. AB - beta-Lapachone (beta-lap), a novel anticancer agent, is bioactivated by NADP(H):quinone oxidoreductase 1 (NQO1), an enzyme over-expressed in numerous tumors, including lung, pancreas, breast, and prostate cancers. Fast renal clearance and methemaglobinemia / hemolytic side-effects from the clinical formulation (beta-lap-hydroxyl propyl-beta-cyclodextrin complex) hindered its clinical translation. Here, we investigated a dual model pH responsive polymers for beta-lap delivery. Three pH-sensitive linkages, including acylhydrazone, ketal and imine bonds for beta-lap prodrug syntheses result in an aryl imine linkage the most optimal linkage. The conversion to beta-lap was 2.8%, 4.5% and 100% at pH 7.4, 6.5 and 5.0 in 8 h, respectively. beta-lap aryl imine prodrug conjugated ultra pH-sensitive (UPS) polymer reached high beta-lap loading density (8.3%) and exhibited dual-stages responsiveness to pH variation. In pHs under pHt, at stage I, micelle immediately dissociation and subsequently entering stage II, micelles start quickly release beta-lap. In vitro release study showed that the micelles constantly release beta-lap (14.9 +/- 0.1%) at pHs above pHt in 72 h, whereas boosted release of beta-lap (79.4 +/- 1.2%) at pH 5.0. Micelle intracellular distribution predominantly in the lysosome organelle guaranteed their pH responsive dissociation and subsequently beta-lap controlled release. The M-P micelles retained NQO1-dependent cytotoxicity in A549 lung cancer cells, similar to free drug in both efficacy and mechanism of cell death. The lysosome oriented dual-stage ultra pH responsive beta-lap prodrug micelles potentially offer an alternative nanotherapeutic strategy for lung, as well as other NQO1+ cancer therapies. PMID- 28580155 TI - Intense, flu-like symptoms in women using menstrual devices: always think of staphylococcal Toxic Shock Syndrome. PMID- 28580156 TI - Castleman's disease with TAFRO syndrome: a case report from Syria. AB - Castleman's disease is a rare disorder, yet a rarer newly described syndrome called TAFRO syndrome was discovered to accompany it. TAFRO represents the constellation of symptoms (Thrombocytopenia, Anasarca, MyeloFibrosis, Renal failure, Organomegaly). Most cases were described in Japan. We present the first case of TAFRO syndrome in Syria. A 58-year-old Caucasian male with no relevant history presented with fatigue, oliguria, decreased platelets, increased creatinine level, hepatosplenomegaly, ascites, pitting edema and lymph node enlargement. Possible differential diagnoses were excluded by laboratory, radiologic and cytologic tests including TB, malignancy and autoimmune diseases. A biopsy of a supraclavicular lymph node confirmed Castleman disease. Our patient had Catleman's disease, and presented with only four diagnostic criteria for TAFRO syndrome (Myelofibrosis was absent) in addition to other minor characteristics (microcytic anemia, negative HIV and HHV-8 infections.) which make the presentation consistent with TAFRO syndrome described in the Japanese cases. The criteria for diagnosing TAFRO syndrome are still changing, and the pathophysiology behind it is unclear. We recommend further research to understand this syndrome taking into account that its prevalence might be worldwide. PMID- 28580153 TI - Complete pathological response of multiple huge liver metastases of colon cancer: a case report. AB - We report a case of a pathological complete response (pCR) with chemotherapy for multiple huge liver metastases from colon cancer. A 59-year-old woman presented with anorexia and weight loss. Laboratory tests revealed elevated liver enzyme levels and tumor markers. A computed tomography/positron emission tomography computed tomography scan revealed a transverse colon tumor and unresectable liver masses measuring 9.0 cm in maximum diameter in segments 7 and 8, with another mass in segment 6. She underwent laparoscopic colectomy and was administered FOLFOX + BV. After 11-cycles of chemotherapy, the liver masses became resectable with a partial response, so hepatectomy was performed. On the final histopathological analysis, all lesions were fibrotic without any viable cancer cells. The patient is alive without recurrence 2 years after resection. We believe this is the largest tumor of unresectable colorectal liver metastasis (CRLM) that has ever resulted in pCR with chemotherapy. FOLFOX + Bev was thus found to be an effective treatment for unresectable CRLM. PMID- 28580151 TI - Transcriptomic and metabolomic analyses of cucumber fruit peels reveal a developmental increase in terpenoid glycosides associated with age-related resistance to Phytophthora capsici. AB - The oomycete, Phytophthora capsici, infects cucumber (Cucumis sativus L.) fruit. An age-related resistance (ARR) to this pathogen was previously observed in fruit of cultivar 'Vlaspik' and shown to be associated with the peel. Young fruits are highly susceptible, but develop resistance at ~10-12 days post pollination (dpp). Peels from resistant (16 dpp) versus susceptible (8 dpp) age fruit are enriched with genes associated with defense, and methanolic extracts from resistant age peels inhibit pathogen growth. Here we compared developing fruits from 'Vlaspik' with those of 'Gy14', a line that does not exhibit ARR. Transcriptomic analysis of peels of the two lines at 8 and 16 dpp identified 80 genes that were developmentally upregulated in resistant 'Vlaspik' 16 dpp versus 8 dpp, but not in susceptible 'Gy14' at 16 dpp. A large number of these genes are annotated to be associated with defense and/or specialized metabolism, including four putative resistance (R) genes, and numerous genes involved in flavonoid and terpenoid synthesis and decoration. Untargeted metabolomic analysis was performed on extracts from 8 and 16 dpp 'Vlaspik' and 'Gy14' fruit peels using Ultra Performance Liquid Chromatography and Quadrupole Time-of-Flight Mass Spectrometry. Multivariate analysis of the metabolomes identified 113 ions uniquely abundant in resistant 'Vlaspik' 16 dpp peel extracts. The most abundant compounds in this group had relative mass defects consistent with terpenoid glycosides. Two of the three most abundant ions were annotated as glycosylated nor-terpenoid esters. Together, these analyses reveal potential mechanisms by which ARR to P. capsici may be conferred. PMID- 28580150 TI - Additive QTLs on three chromosomes control flowering time in woodland strawberry (Fragaria vesca L.). AB - Flowering time is an important trait that affects survival, reproduction and yield in both wild and cultivated plants. Therefore, many studies have focused on the identification of flowering time quantitative trait locus (QTLs) in different crops, and molecular control of this trait has been extensively investigated in model species. Here we report the mapping of QTLs for flowering time and vegetative traits in a large woodland strawberry mapping population that was phenotyped both under field conditions and in a greenhouse after flower induction in the field. The greenhouse experiment revealed additive QTLs in three linkage groups (LG), two on both LG4 and LG7, and one on LG6 that explain about half of the flowering time variance in the population. Three of the QTLs were newly identified in this study, and one co-localized with the previously characterized FvTFL1 gene. An additional strong QTL corresponding to previously mapped PFRU was detected in both field and greenhouse experiments indicating that gene(s) in this locus can control the timing of flowering in different environments in addition to the duration of flowering and axillary bud differentiation to runners and branch crowns. Several putative flowering time genes were identified in these QTL regions that await functional validation. Our results indicate that a few major QTLs may control flowering time and axillary bud differentiation in strawberries. We suggest that the identification of causal genes in the diploid strawberry may enable fine tuning of flowering time and vegetative growth in the closely related octoploid cultivated strawberry. PMID- 28580158 TI - Opana-induced thrombotic microangiopathy masquerading as thrombotic thrombocytopenic purpura. AB - Opana (oxymorphone) is a powerful semi-synthetic opioid agonist used for chronic pain management that is ingested orally. However, improper injection of Opana can lead to a rare and fatal blood disorder known as thrombotic microangiopathy. Opana-induced thrombotic microangiopathy can be easily mistaken for thrombotic thrombocytopenic purpura (TTP), leading to the initiation of therapeutic plasma exchange. Current literature has conflicting views on the necessity of therapeutic plasma exchange for the treatment of Opana-induced thrombotic microangiopathy. In our case report, a 47-year-old Caucasian male was admitted with a presentation suspicious for TTP then underwent therapeutic plasma exchange without clinical improvement. With supportive treatment only, the patient eventually improved and later admitted to intravenously abusing oral Opana 1-2 days prior to becoming ill. PMID- 28580159 TI - Azithromycin-induced cholestatic hepatitis. AB - Since its introduction >20 years ago, Azithromycin has been widely used owing to its broad spectrum and good tolerability, especially when used for <7 days. In literature, there are only very few, sporadic reports available of patients developing cholestatic hepatitis following treatment with it. The current case study describes a 69-year old patient, with a medical history that included significant alcohol consumption, who presented with jaundice following a 3-day course of Azithromycin. Following a transjugular liver biopsy, he was managed with a short course of corticosteroids and his liver function gradually improved and finally normalized ~2 months after discontinuation of Azithromycin. PMID- 28580157 TI - Incidental finding of a primary thyroid tuberculosis. AB - Thyroid tuberculosis (TT) is a very rare condition, even in countries where tuberculosis is endemic. However, the prevalence of tuberculosis has increased worldwide and thyroid involvement can be a primary manifestation of the disease. We present the case of a 43-year-old patient with this diagnosis and perform a review of the related literature. After searching for similar case reports in Western Europe since 2010 we identified six cases in four countries. TT should be considered in the differential diagnosis of a thyroid nodule. Fine-needle aspiration cytology and polymerase chain reaction are useful tools as preoperative diagnosis. Typical caseous necrotic granulomas are the hallmark in biopsy. PMID- 28580160 TI - Oxcarbazepine-induced Stevens-Johnson syndrome: a pediatric case report. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis are two rare but life-threatening diseases characterized by detachment of epidermis, bullous skin lesions and mucous membrane erosions. Anti-epileptic drugs are highly suspected to be the causative agents. Although carbamazepine (CBZ) is the most associated anti-epileptic drug, oxcarbazepine (OXC), which is a monohydrated derivative of CBZ, is proposed to be safer because of the different metabolism of the two drugs. Herein, we report a case of SJS induced by oxcarbazepine. A 6-year-old boy with benign rolandic epilepsy, admitted to our hospital with generalized maculopapular rash after starting oxcarbazepine. The diagnosis of SJS was made with cytotoxic skin lesions and mucous membrane involvement. After discontinuing of the drug and topical corticosteroid initiation, the lesions were improved. We report this case to attract attention to the serious side effect of this anti epileptic drug. PMID- 28580163 TI - What do parents want for their children who are overweight when visiting the paediatrician? AB - OBJECTIVE: The objective of this study was to determine whether parental preferences regarding primary care weight-management strategies differ by child age, gender, overweight severity, race/ethnicity or parental agreement that their child is overweight. METHODS: A survey was administered to parents of 2- to 18 year-old children who are overweight at an academic primary-care clinic regarding perception of child overweight, helpful/harmfulness of having the child present during weight discussions, and dietary-advice preferences. Multivariable analyses examined factors associated with preferred weight-management strategies, after adjustment for parent/child characteristics. RESULTS: Eighty-three per cent of parents agreed that a child's presence during weight discussions is helpful/very helpful, 74% that paediatricians should prescribe specific diets, and 55% preferred specific vs. general dietary advice only (N = 219). In multivariable analyses, characteristics associated with helpfulness of child presence included older child age (vs. 2-5 year olds, 6-11 year olds: odds ratio [OR], 4.6; 95% CI, 1.3-16; 12- to 18-year-olds: OR, 23; 95% CI, 4-136), male gender (OR, 5.0; 95% CI, 1.7-10) and obesity (vs. overweight: OR, 2.8; 95% CI, 1.7-12). Characteristics associated with preferring specific diets included Latino race/ethnicity (OR, 5.3; 95% CI, 3-12), older age (vs. 2-5 year olds, 6-11 year olds: OR, 2.8; 95% CI, 1.1-7; 12-18 year olds: OR, 3.7; 95% CI, 1.5-10) and agreement that the child is overweight (OR, 2.3; 95% CI, 1.1-5) and, for specific dietary advice, older age (vs. 2-5 year olds: OR, 2.3; 95% CI, 1.1-5) and agreement that the child is overweight (OR, 2.1; 95% CI, 1.2-4). CONCLUSIONS: Findings suggest that weight-management strategies tailored to child age, gender, over-weight severity, race/ethnicity and parental agreement that their child is overweight may prove useful in improving child weight status. PMID- 28580161 TI - Early onset of Fazio-Londe syndrome: the first case report from the Arabian Peninsula. AB - Fazio-Londe syndrome is a rare neurological disorder presenting with sensorineural deafness, bulbar palsy and respiratory compromise that is caused by mutation in the SLC52A3 gene, which encodes the intestinal (hRFT2) riboflavin transporter. We report a patient with early onset of Fazio-Londe syndrome as the first case report in Saudi Arabia with rapid regression to death at 24 months of age. PMID- 28580164 TI - Mindfulness-Based Cognitive Therapy (MBCT) programme for depression in people with early stages of dementia: study protocol for a randomised controlled feasibility study. AB - BACKGROUND: Depression and dementia are major public health problems in the UK. Depression in early-stage dementia is very common and significantly reduces quality of life, speeds cognitive decline and increases functional impairment. Mindfulness-Based Cognitive Therapy (MBCT) is an effective depression prevention programme, and the National Institute for Clinical Excellence (NICE) has suggested that MBCT is a priority for implementation. Alongside this, there is emerging evidence demonstrating promising results in relation to the benefits of adapted mindfulness interventions for people with dementia, suggesting that it could be beneficial in reducing depressive symptoms and in slowing deterioration in cognitive functions such as sustained attention, distraction inhibition and task switching. METHODS: The design is a single-blind randomised controlled feasibility trial. Participants with mild to moderate depression and early stages of dementia will be recruited from the participating memory services. Participants will receive either immediate or delayed access to an 8-week MBCT programme. Participants will be assessed by a blind assessor and complete cognitive and mood-related outcome measures before and after the intervention. This feasibility study will test the trial design and assess recruitment, retention, acceptability and adherence, as well as providing preliminary efficacy data. DISCUSSION: This study will inform the design and sample size for a future full randomised controlled trial (RCT), which will be carried out to determine the effectiveness of the intervention in reducing depressive symptoms in people with early stages of dementia. TRIAL REGISTRATION: ClinicalTrials.gov ISRCTN16382776. PMID- 28580162 TI - Role of medical resource level in iodine deficiency disorder. AB - BACKGROUND: Iodine deficiency disorders (IDDs) refer to a series of diseases caused by the human body's insufficient iodine intake. Edible salt became iodized in China in 1996, which yielded remarkable results. We have known that IDDs is associated with iodine in the human body, but it is not clear whether IDDs is related to medical resource level. METHODS: We collected the number of IDDs cases and an index for the level of medical resource from 31 provinces, autonomous regions and municipalities directly under the central government in China. All data came from the China Statistical Yearbook of Health and Family Planning issued in 2013 by the Peking Union Medical College Publishing House. Data standardization and linear regression analysis were used. RESULTS: The results showed that IDDs correlated with the number of beds in medical and health institutions, number of medical health personnel, number of medical and health institutions, total health expenditure, average health expenditure per capita, medical insurance for urban resident and new rural cooperative medical rural residents (P < 0.01). In a multiple linear regression, IDDs was most significantly associated with the number of beds in hospitals, the number of rural health personnel, the number of basic medical and health institutions and government health expenditure for these institutions. CONCLUSION: Based on the experimental data, we concluded that IDDs had a positive connection with the medical resource level, and basic and rural areas had a more significant association with IDDs. This analysis provides new and explicit ideas for iodine prevention and control work in China. PMID- 28580165 TI - Managing challenging behaviour in preschool children post-traumatic brain injury with online clinician support: protocol for a pilot study. AB - BACKGROUND: Traumatic brain injury (TBI) in children is associated with a range of poor long-term outcomes, including behavioural disturbances. Parents can experience high levels of stress and injury-related burden, and evidence suggests that distressed parents are less likely to adopt positive parenting styles to manage their child's behaviour. The 'Signposts for Building Better Behaviour' program is a parenting programme that was originally developed to assist parents of children with an intellectual disability in managing their child's behaviour. More recently, it has been adapted to include a TBI module, to assist parents in managing post-TBI behaviour. However, geographical and financial barriers remain, preventing many parents from accessing the programme in the standard face-to-face modality. This project aims to investigate the feasibility and acceptability of the programme when delivered with clinician support via videoconferencing. METHODS/DESIGN: The sample for this feasibility study will be recruited from the Royal Children's Hospital, Melbourne, and the Victorian Paediatric Rehabilitation Service. Participants will be the parents of a child who sustained a TBI between the ages of 2.0 and 6.11, within the previous 2 years. The parents of 15 children will complete the programme, with clinician support via videoconferencing, while the parents of a further 15 children will form a treatment as usual wait-list control group. Parents complete questionnaires assessing their child's behaviour, as well as assessing their own mental health, sense of parenting competency, disciplinary style, and family functioning. These will be completed upon enrolment in the study regarding their child's pre-injury behaviour and then again pre-intervention, immediately post-intervention, and 4 months post intervention. Parents who complete the intervention will also complete questionnaires assessing their satisfaction with the programme and its delivery. Information will be collected on the feasibility, clinical practicality, and acceptability of the programme when delivered through this medium. DISCUSSION: This study is the first to investigate the feasibility of delivering post-child TBI behavioural intervention via videoconferencing in Australia. Preliminary findings from this study may support the development of a larger randomised controlled trial. It is hoped that programme delivery through this medium would facilitate better access to the programme, enabling improved long-term outcomes for families. TRIAL REGISTRATION: ANZCTR, ACTRN12616001574437. PMID- 28580166 TI - MOF as an evolutionarily conserved histone crotonyltransferase and transcriptional activation by histone acetyltransferase-deficient and crotonyltransferase-competent CBP/p300. AB - Recent studies indicate that histones are subjected to various types of acylation including acetylation, propionylation and crotonylation. CBP and p300 have been shown to catalyze multiple types of acylation but are not conserved in evolution, raising the question as to the existence of other enzymes for histone acylation and the functional relationship between well-characterized acetylation and other types of acylation. In this study, we focus on enzymes catalyzing histone crotonylation and demonstrate that among the known histone acetyltransferases, MOF, in addition to CBP and p300, also possesses histone crotonyltransferase (HCT) activity and this activity is conserved in evolution. We provide evidence that CBP and p300 are the major HCTs in mammalian cells. Furthermore, we have generated novel CBP/p300 mutants with deficient histone acetyltransferase but competent HCT activity. These CBP/p300 mutants can substitute the endogenous CBP/p300 to enhance transcriptional activation in the cell, which correlates with enhanced promoter crotonylation and recruitment of DPF2, a selective reader for crotonylated histones. Taken together, we have identified MOF as an evolutionarily conserved HCT and provide first cellular evidence that CBP/p300 can facilitate transcriptional activation through histone acylation other than acetylation, thus supporting an emerging role for the non-acetylation type of histone acylation in transcription and possibly other chromatin-based processes. PMID- 28580168 TI - CAML mediates survival of Myc-induced lymphoma cells independent of tail-anchored protein insertion. AB - Calcium-modulating cyclophilin ligand (CAML) is an endoplasmic reticulum (ER) protein that functions, along with WRB and TRC40, to mediate tail-anchored (TA) protein insertion into the ER membrane. Physiologic roles for CAML include endocytic trafficking, intracellular calcium signaling, and the survival and proliferation of specialized immune cells, recently attributed to its requirement for TA protein insertion. To identify a possible role for CAML in cancer cells, we generated EMU-Myc transgenic mice that carry a tamoxifen-inducible deletion allele of Caml. In multiple B-cell lymphoma cell lines derived from these mice, homozygous loss of Caml activated apoptosis. Cell death was blocked by Bcl-2/Bcl xL overexpression; however, rescue from apoptosis was insufficient to restore proliferation. Tumors established from an EMU-Myc lymphoma cell line completely regressed after tamoxifen administration, suggesting that CAML is also required for these cancer cells to survive and grow in vivo. Cell cycle analyses of Caml deleted lymphoma cells revealed an arrest in G2/M, accompanied by low expression of the mitotic marker, phospho-histone H3 (Ser10). Surprisingly, lymphoma cell viability did not depend on the domain of CAML required for its interaction with TRC40. Furthermore, a small protein fragment consisting of the C-terminal 111 amino acid residues of CAML, encompassing the WRB-binding domain, was sufficient to rescue growth and survival of Caml-deleted lymphoma cells. Critically, this minimal region of CAML did not restore TA protein insertion in knockout cells. Taken together, these data reveal an essential role for CAML in supporting survival and mitotic progression in Myc-driven lymphomas that is independent of its TA protein insertion function. PMID- 28580167 TI - Sequential EMT-MET induces neuronal conversion through Sox2. AB - Direct neuronal conversion can be achieved with combinations of small-molecule compounds and growth factors. Here, by studying the first or induction phase of the neuronal conversion induced by defined 5C medium, we show that the Sox2 mediated switch from early epithelial-mesenchymal transition (EMT) to late mesenchymal-epithelial transition (MET) within a high proliferation context is essential and sufficient for the conversion from mouse embryonic fibroblasts (MEFs) to TuJ+ cells. At the early stage, insulin and basic fibroblast growth factor (bFGF)-induced cell proliferation, early EMT, the up-regulation of Stat3 and Sox2, and the subsequent activation of neuron projection. Up-regulated Sox2 then induced MET and directed cells towards a neuronal fate at the late stage. Inhibiting either stage of this sequential EMT-MET impaired the conversion. In addition, Sox2 could replace sequential EMT-MET to induce a similar conversion within a high proliferation context, and its functions were confirmed with other neuronal conversion protocols and MEFs reprogramming. Therefore, the critical roles of the sequential EMT-MET were implicated in direct cell fate conversion in addition to reprogramming, embryonic development and cancer progression. PMID- 28580169 TI - Endogenous miRNA Sponge LincRNA-ROR promotes proliferation, invasion and stem cell-like phenotype of pancreatic cancer cells. AB - The long intergenic non-coding RNA, regulator of reprogramming (linc-ROR) is an oncogene and plays a key role in the embryonic stem cell maintenance and is involved in cancer progression. The objective of this study was to analyze linc ROR expression in pancreatic ductal adenocarcinoma (PDAC) and determine the regulation effects of linc-ROR on proliferation and invasion of cancer cells, as well as properties of cancer stem-like cells (CSLCs). In this study, we found that linc-ROR was up-regulated in PDAC tissues and related to poor prognosis. Linc-ROR knockdown in pancreatic cancer cells inhibited cell growth and arrested in G1 phrase. Suppressed linc-ROR expression also attenuated cancer cell migration, invasion, and epithelial-mesenchymal transition. We observed that linc ROR expression was increased in CSLCs. Importantly, linc-ROR knockdown impaired the properties and tumorigenesis of pancreatic CSLCs in vivo. Mechanistically, we found that linc-ROR functioned as a competing endogenous RNA (ceRNA) to several tumor suppressor microRNAs, particularly some members of let-7 family. We conclude that, as a crucial oncogene, linc-ROR promotes cell proliferation, invasiveness and contributes to stem cell properties of CSLCs in PDAC via acting as a ceRNA to regulate function of microRNAs. The linc-ROR is a potential therapeutic target for PDAC. PMID- 28580170 TI - Cell-free chromatin from dying cancer cells integrate into genomes of bystander healthy cells to induce DNA damage and inflammation. AB - Bystander cells of the tumor microenvironment show evidence of DNA damage and inflammation that can lead to their oncogenic transformation. Mediator(s) of cell cell communication that brings about these pro-oncogenic pathologies has not been identified. We show here that cell-free chromatin (cfCh) released from dying cancer cells are the key mediators that trigger both DNA damage and inflammation in the surrounding healthy cells. When dying human cancer cells were cultured along with NIH3T3 mouse fibroblast cells, numerous cfCh emerged from them and rapidly entered into nuclei of bystander NIH3T3 cells to integrate into their genomes. This led to activation of H2AX and inflammatory cytokines NFkappaB, IL 6, TNFalpha and IFNgamma. Genomic integration of cfCh triggered global deregulation of transcription and upregulation of pathways related to phagocytosis, DNA damage and inflammation. None of these activities were observed when living cancer cells were co-cultivated with NIH3T3 cells. However, upon intravenous injection into mice, both dead and live cells were found to be active. Living cancer cells are known to undergo extensive cell death when injected intravenously, and we observed that cfCh emerging from both types of cells integrated into genomes of cells of distant organs and induced DNA damage and inflammation. gammaH2AX and NFkappaB were frequently co-expressed in the same cells suggesting that DNA damage and inflammation are closely linked pathologies. As concurrent DNA damage and inflammation is a potent stimulus for oncogenic transformation, our results suggest that cfCh from dying cancer cells can transform cells of the microenvironment both locally and in distant organs providing a novel mechanism of tumor invasion and metastasis. The afore-described pro-oncogenic pathologies could be abrogated by concurrent treatment with chromatin neutralizing/degrading agents suggesting therapeutic possibilities. PMID- 28580171 TI - In silico analysis of pathways activation landscape in oral squamous cell carcinoma and oral leukoplakia. AB - A subset of patients with oral squamous cell carcinoma (OSCC), the most common subtype of head and neck squamous cell carcinoma (HNSCC), harbor dysplastic lesions (often visually identified as leukoplakia) prior to cancer diagnosis. Although evidence suggest that leukoplakia represents an initial step in the progression to cancer, signaling networks driving this progression are poorly understood. Here, we applied in silico Pathway Activation Network Decomposition Analysis (iPANDA), a new bioinformatics software suite for qualitative analysis of intracellular signaling pathway activation using transcriptomic data, to assess a network of molecular signaling in OSCC and pre-neoplastic oral lesions. In tumor samples, our analysis detected major conserved mitogenic and survival signaling pathways strongly associated with HNSCC, suggesting that some of the pathways identified by our algorithm, but not yet validated as HNSCC related, may be attractive targets for future research. While pathways activation landscape in the majority of leukoplakias was different from that seen in OSCC, a subset of pre-neoplastic lesions has demonstrated some degree of similarity to the signaling profile seen in tumors, including dysregulation of the cancer-driving pathways related to survival and apoptosis. These results suggest that dysregulation of these signaling networks may be the driving force behind the early stages of OSCC tumorigenesis. While future studies with larger leukoplakia data sets are warranted to further estimate the values of this approach for capturing signaling features that characterize relevant lesions that actually progress to cancers, our platform proposes a promising new approach for detecting cancer-promoting pathways and tailoring the right therapy to prevent tumorigenesis. PMID- 28580172 TI - RalBP1 and p19-VHL play an oncogenic role, and p30-VHL plays a tumor suppressor role during the blebbishield emergency program. AB - Cancer stem cells evade apoptotic death by blebbishield emergency program, which constructs blebbishields from apoptotic bodies and drives cellular transformation. Von Hippel-Lindau (VHL) plays both tumor suppressor and oncogenic roles, and the reason behind is poorly understood. Here we demonstrate that dimers and trimers of p19-VHL interact with RalBP1 to construct blebbishields. Expression of RalBP1, p19-VHL, and high-molecular weight VHL is required to evade apoptosis by blebbishield-mediated transformation. In contrast, p30-VHL plays a tumor suppressor role by inhibiting blebbishield-mediated transformation. Furthermore, target genes of VHL that suppress oxidative stress were elevated during blebbishield-mediated cellular transformation. Thus, RalBP1 and p19-VHL play an oncogenic role, whereas p30-VHL plays a tumor suppressor role during the blebbishield emergency program by regulating oxidative stress management genes. PMID- 28580173 TI - Sesn2 gene ablation enhances susceptibility to gentamicin-induced hair cell death via modulation of AMPK/mTOR signaling. AB - The process of gentamicin-induced hair cell damage includes the activation of oxidative stress processes. Sestrins, as stress-responsive proteins, protect cells against oxidative stress. Sestrins, particularly Sestrin-2, suppress excessive reactive oxygen species (ROS) accumulation and inhibit mammalian target of rapamycin complex 1 (mTORC1). Thus, we addressed the role of Sestrin-2 in the regulation of sensory hair cell survival after gentamicin exposure. Here, we show that Sestrins were expressed in the inner ear tissues, and Sestrin-2 immunolocalized in sensory hair cells and spiral ganglion (SG). The expression of Sestrin-2 was unchanged, and later downregulated, in gentamicin-treated explants from wild-type mice in vitro. Compared with wild-type mice, Sestrin-2 knockout mice exhibited significantly greater hair cell loss in gentamicin-treated cochlear explants. Significant downregulation of phosphorylation of AMP-activated protein kinase alpha (AMPKalpha) and upregulation of the 70-kDa ribosomal protein S6 kinase (p70S6K) were measured in wild-type cochlear explants exposed to gentamicin compared with their untreated controls. Such regulatory effect was not observed between explants from untreated and gentamicin-treated knockout mice. The gentamicin effect on mTOR signaling was rapamycin-sensitive. Thus, our data provide evidence that Sestrin-2 plays an important role in the protection of hair cells against gentamicin, and the mTOR signaling pathway appears to be modulated by gentamicin during hair cell death. PMID- 28580174 TI - Effects of concomitant inactivation of p53 and pRb on response to doxorubicin treatment in breast cancer cell lines. AB - Loss of TP53 and RB1 function have both been linked to poor response to DNA damaging drugs in breast cancer patients. We inactivated TP53 and/or RB1 by siRNA mediated knockdown in breast cancer cell lines varying with respect to ER/PgR and Her-2 status as well as TP53 and RB1 mutation status (MCF-7, T47D, HTB-122 and CRL2324) and determined effects on cell cycle arrest, apoptosis and senescence with or without concomitant treatment with doxorubicin. In T47D cells, we found the cell cycle phase distribution to be altered when inactivating TP53 (P=0.0003) or TP53 and RB1 concomitantly (P<=0.001). No similar changes were observed in MCF 7, HTB-122 or CRL2324 cells. While no significant change was observed for the CRL2324 cells upon doxorubicin treatment, MCF-7, T47D as well as HTB-122 cells responded to knockdown of TP53 and RB1 in concert, with a decrease in the fraction of cells in G1/G0-phase (P=0.042, 0.021 and 0.027, respectively). Inactivation of TP53 and/or RB1 caused no change in induction of apoptosis. Upon doxorubicin treatment, inactivation of TP53 or RB1 separately caused no induction of apoptosis in MCF-7 and HTB-122 cells; however, concomitant inactivation leads to a slightly reduced activation of apoptosis. Interestingly, upon doxorubicin treatment, concomitant inactivation of TP53 and RB1 caused a decrease in senescence in MCF-7 cells (P=0.027). Comparing the effects of concomitant knockdown on apoptosis and senescence, we observed a strong interaction (P=0.001). We found concomitant inactivation of TP53 and RB1 to affect various routes of response to doxorubicin treatment in breast cancer cells. PMID- 28580175 TI - Differential cytokine withdrawal-induced death sensitivity of effector T cells derived from distinct human CD8+ memory subsets. AB - CD8+ central memory (CM) and effector memory (EM) T-cell subsets exhibit well established differences in proliferative and protective capacity after infectious challenge. However, their relative sensitivity to apoptosis has been largely overlooked, despite the importance of programmed cell death in regulating effector T-cell homeostasis. Here we demonstrate that primary human effector T cells derived from the CD8+ EM subset exhibit significantly higher sensitivity to cytokine withdrawal-induced cell death (CWID), a critical intrinsic apoptosis program responsible for culling cells once an infection is cleared and interleukin-2 (IL-2) levels diminish. Interestingly, we found no differences in the expression of IL-2 or IL-2 receptor components in cells originating from either subset. Relative to CM-derived effectors, however, EM-derived T cells displayed more mitochondrial instability and greater caspase activity. Indeed, we found that heightened CWID sensitivity in EM-derived effectors coincided with higher expression of the pro-apoptotic Bcl-2 family protein BIM, both at steady state and with de novo induction following withdrawal of exogenous IL-2. These data point to 'imprinted' differences in BIM protein regulation, preserved by CD8+ CM and EM progeny, which govern their relative sensitivity to CWID. In addition, we detected a burst of autophagy after IL-2 withdrawal, which was better maintained in CM-derived T cells. Both subsets showed increased, equivalent CWID sensitivity upon treatment with autophagy inhibitors, suggesting sustained autophagy could preferentially protect CM-derived T cells from apoptosis. These findings offer new insight into how CM CD8+ T cells display superior effector cell expansion and more persistent memory responses in vivo relative to EM-derived T cells, based in part on decreased CWID sensitivity. PMID- 28580176 TI - Engineering affinity agents for the detection of hemi-methylated CpG sites in DNA. AB - Wild-type methyl-CpG-binding domain (MBD) proteins specifically bind symmetrically methylated DNA sequences, and assays have been developed that use these proteins for profiling DNA methylation. Here, we use directed evolution in the yeast surface display format to identify a new protein variant that binds hemi-methylated CpG dinucleotides. PMID- 28580177 TI - Rapid multistep kinetic model generation from transient flow data. AB - Today, the generation of kinetic models is still seen as a resource intensive and specialised activity. We report an efficient method of generating reaction profiles from transient flows using a state-of-the-art continuous-flow platform. Experimental data for multistep aromatic nucleophilic substitution reactions are collected from an automated linear gradient flow ramp with online HPLC at the reactor outlet. Using this approach, we generated 16 profiles, at 3 different inlet concentrations and 4 temperatures, in less than 3 hours run time. The kinetic parameters, 4 rate constants and 4 activation energies were fitted with less than 4% uncertainty. We derived an expression for the error in the observed rate constants due to dispersion and showed that such error is 5% or lower. The large range of operational conditions prevented the need to isolate individual reaction steps. Our approach enables early identification of the sensitivity of product quality to parameter changes and early use of unit operation models to identify optimal process-equipment combinations in silico, greatly reducing scale up risks. PMID- 28580178 TI - Antibody Reactivity of B Cells in Lupus Patients with Increased Disease Activity and ARID3a Expression. AB - Earlier studies showed that the DNA-binding protein, Bright/ARID3a bound to a subset of human and mouse immunoglobulin heavy chain promoters where it enhanced expression. Indeed, mice with transgenic expression of ARID3a in all B lymphocytes have expanded MZ B cells and produce anti-nuclear antibodies (ANAs). Consistent with our findings in mice, we observed that human systemic lupus erythematosus (SLE) patients had expanded numbers of peripheral blood ARID3a+ B cells that were associated with increased disease activity (p = 0.0038). We hypothesized that ARID3a+ naive B cells would eventually produce autoantibodies, explaining associations between ARID3a expression and disease activity in lupus. Unlike healthy controls, ARID3a was expressed in the naive B cell population in SLE patients, and we hypothesized that these might represent expansions of autoreactive cells. Therefore, monoclonal antibodies were generated from single sorted naive B cells derived from patients with normal (ARID3aN) and high (ARID3aH) numbers of ARID3a+ B cells. We found that ARID3a expression did not correlate with autoantibody expression. Furthermore, measures of antigen specificities of autoreactive antibodies did not reveal skewing toward particular proteins. These data suggest that the association of increased disease activity in SLE with numbers of ARID3a+ B lymphocytes may be mediated by an antibody independent mechanism. PMID- 28580179 TI - Metal Bioaccumulation by Estuarine Food Webs in New England, USA. AB - Evaluating the degree of metal exposure and bioaccumulation in estuarine organisms is important for understanding the fate of metals in estuarine food webs. We investigated the bioaccumulation of Hg, methylmercury (MeHg), Cd, Se, Pb, and As in common intertidal organisms across a watershed urbanization gradient of coastal marsh sites in New England to relate metal exposure and bioaccumulation in fauna to both chemical and ecological factors. In sediments, we measured metal and metalloid concentrations, total organic carbon (TOC) and SEM-AVS (Simultaneously extracted metal-acid volatile sulfides). In five different functional feeding groups of biota, we measured metal concentrations and delta 15N and delta 13C signatures. Concentrations of Hg and Se in biota for all sites were always greater than sediment concentrations whereas Pb in biota was always lower. There were positive relationships between biota Hg concentrations and sediment concentrations, and between biota MeHg concentrations and both pelagic feeding mode and trophic level. Bioavailability of all metals measured as SEM-AVS or Benthic-Sediment Accumulation Factor was lower in more contaminated sites, likely due to biogeochemical factors related to higher levels of sulfides and organic carbon in the sediments. Our study demonstrates that for most metals and metalloids, bioaccumulation is metal specific and not directly related to sediment concentrations or measures of bioavailability such as AVS SEM. PMID- 28580180 TI - The role of reactive oxygen species in the antimicrobial activity of pyochelin. AB - The increase in prevalence of antimicrobial-resistant bacteria (ARB) is currently a serious threat, thus there is a need for new antimicrobial compounds to combat infections caused by these ARB. An antimicrobial-producing bacterium, Burkholderia paludis was recently isolated and was able to produce a type of siderophore with antimicrobial properties, later identified as pyochelin. The chelating ability of pyochelin has been well-characterized but not for its antimicrobial characteristics. It was found that pyochelin had MIC values (MBC values) of 3.13 ug/mL (6.26 ug/mL) and 6.26 ug/mL (25.00 ug/mL) against three Enterococcus strains and four Staphylococcus strains. Pyochelin was able to inhibit E. faecalis ATCC 700802 (a vancomycin-resistant strain) in a time and dose dependent manner via killing kinetics assay. It was demonstrated that pyochelin enhanced the production of intracellular reactive oxygen species (ROS) over time, which subsequently caused a significant increase in malondialdehyde (MDA) production (a marker for lipid peroxidation) and ultimately led to cell death by disrupting the integrity of the bacterial membrane (validated via BacLight assay). This study has revealed the mechanism of action of pyochelin as an antimicrobial agent for the first time and has shown that pyochelin might be able to combat infections caused by E. faecalis in the future. PMID- 28580181 TI - Intercellular Adhesion Molecular-5 as Marker in HIV Associated Neurocognitive Disorder. AB - Despite the use of antiretroviral drugs HIV associated neurocognitive disorders (HAND) are still common in HIV-seropositive patients. Identification of HIV patients with cognitive impairment in early-stage might benefit a great deal from disease progression monitoring and treatment adjustment. Intercellular adhesion molecule-5 (ICAM5), characteristically expressed on neuron, may suppress immune functions by inhibition of T cell activation in central nervous system. Previous studies have shown that ICAM5 could be detected in patients with brain injury. To investigate the relationship between cognitive impairment and ICAM5 in HIV patients, we compared soluble ICAM5 levels in paired CSF and plasma specimens from HIV-infected individuals with or without neurocognitive impairment. sICAM5 concentrations were measured by ICAM5 ELISA kit. A total of 41 Patients were classified into HIV infected with normal cognition (HIV-NC) and impaired cognition groups (HIV-CI) based on Memorial Sloan-Kettering Scale. CSF and plasma levels of sICAM5 in HIV-CI patients were significantly higher than HIV-NC group (p<0.0001, p=0.0054 respectively). sICAM5 concentrations in plasma strongly correlated with sICAM5 in CSF (r=0.7250, p<0.0001) and S100B in CSF (r=0.3812, p<0.0139). Among 6 follow-up patients we found that sICAM5 levels in CSF and plasma might change consistently with HAND progression. In summary, we have shown that the expressions of sICAM5 in CSF and plasma may correlate with neurocognitive impairment in HIV infected patients. The elevation of sICAM5 in plasma were correspond with that in CSF as a consequence of blood-brain barrier permeability changes. ICAM5 can serve as a potential and readily accessible biomarker to predict HIV associated neurocognitive disorder. PMID- 28580182 TI - Cerebral Microvascular Accumulation of Tau Oligomers in Alzheimer's Disease and Related Tauopathies. AB - The importance of vascular contributions to cognitive impairment and dementia (VCID) associated with Alzheimer's disease (AD) and related neurodegenerative diseases is increasingly recognized, however, the underlying mechanisms remain obscure. There is growing evidence that in addition to Abeta deposition, accumulation of hyperphosphorylated oligomeric tau contributes significantly to AD etiology. Tau oligomers are toxic and it has been suggested that they propagate in a "prion-like" fashion, inducing endogenous tau misfolding in cells. Their role in VCID, however, is not yet understood. The present study was designed to determine the severity of vascular deposition of oligomeric tau in the brain in patients with AD and related tauopathies, including dementia with Lewy bodies (DLB) and progressive supranuclear palsy (PSP). Further, we examined a potential link between vascular deposition of fibrillar Abeta and that of tau oligomers in the Tg2576 mouse model. We found that tau oligomers accumulate in cerebral microvasculature of human patients with AD and PSP, in association with vascular endothelial and smooth muscle cells. Cerebrovascular deposition of tau oligomers was also found in DLB patients. We also show that tau oligomers accumulate in cerebral microvasculature of Tg2576 mice, partially in association with cerebrovascular Abeta deposits. Thus, our findings add to the growing evidence for multifaceted microvascular involvement in the pathogenesis of AD and other neurodegenerative diseases. Accumulation of tau oligomers may represent a potential novel mechanism by which functional and structural integrity of the cerebral microvessels is compromised. PMID- 28580184 TI - A Fine-Tune Role of Mir-125a-5p on Foxn1 During Age-Associated Changes in the Thymus. AB - Decline of transcription factor FoxN1, which predominantly regulates thymic epithelial cell (TEC) differentiation and homeostasis lifelong, is demonstrated to be casually related to age-related thymic involution. Whereas, a global role of microRNAs (miRNAs) has also been demonstrated to control and maintain TEC constituting thymic microenvironment and to be changed in expression profile in the aged thymus. Therefore, it is urgently necessary to build knowledge regarding whether and which miRNAs regulate FoxN1 gene in the aged thymus. We primarily compared changes in miRNA expression profile between young and aged murine TECs with Mus musculus miRBase-V20 arrays (containing 1892 unique probes), and clearly identified and validated that at least one miRNA, miR-125a-5p, was increased in aged thymus. Applying miR-125a-5p mimics was able to inhibit FoxN1 3'UTR luciferase activity in a 293T cell line and to suppress FoxN1 expression in murine TEC Z210 cells. Since a single miRNA can play a fine-tuning role to regulate expression of multiple genes and a single gene can be regulated by multiple miRNAs, our result adds a single miRNA, miR-125a-5p, into the panel of FoxN1-regulating miRNAs associated with thymic aging. PMID- 28580183 TI - Role of Pro-Inflammatory Cytokines and Vitamin D in Probable Alzheimer's Disease with Depression. AB - Symptoms of depression are present in a significant proportion of Alzheimer's disease (AD) patients. While epidemiological studies have shown a strong association between depression and AD, it has not been established whether depression is a risk factor or merely a co-morbidity of AD. It is also uncertain if depression affects the pathogenesis of AD. In this paper, we address these questions by measuring the serum levels of two common metabolic risk factors of AD and depression, inflammatory cytokines (IL 6 and TNF alpha) and serum 25 hydroxyvitamin D, in a case-control study. We measured the serum levels of IL 6, TNF alpha and 25-hydroxyvitamin D in age-matched healthy controls (n= 60) and in AD patients without depression (n=26) or AD patients with depression (n=34), and statistically analyzed the changes in these parameters among different groups under this study. Our results show that in AD there is a significant increase in IL 6 and TNF alpha and a marked decrease in 25-hydroxyvitamin D in the peripheral circulation compared to age-matched healthy controls. Furthermore, AD patients with depression have even significantly higher levels of IL 6 or TNF alpha and a lower level of 25-hydroxyvitamin D in circulation than in AD patients without depression. We also found a strong statistical correlation between the disease severity and the serum levels of IL 6, TNF alpha and 25-hydroxyvitamin D in AD patients with depression. These results suggest that altered circulating levels of common metabolic risk factors lead to the co-existence of depression with AD in many patients, and when they co-exist, the depression presumably affects the severity of AD presentations through more aggravated changes in these risk factors. PMID- 28580185 TI - The Soluble VEGF Receptor sFlt-1 Contributes to Impaired Neovascularization in Aged Mice. AB - The mechanism by which angiogenesis declines with aging is not fully understood. Soluble vascular endothelial growth factor receptor 1 (VEGFR1) form (sFlt1) contributes to endothelial dysfunction in pathological conditions. However, the roles of sFlt1 in ischemia-induced neovascularizationof aged animals have not been investigated. To study aging-related sFlt1 change and its impact on ischemia induced neovascularization, a hindlimb ischemia model was applied to young and aged mice. Blood flow imaging assay revealed that the blood flow recovery remained impaired throughout the follow-up period. At day 14, immunostaining showed lesser capillary formation in the aged mice. An ELISA showed that the aged mice had increased plasma sFlt-1 levels at indicated time points after surgery. On operative day 4, the aged ischemic muscles had decreased levels of p-VEGFR2 and p-Akt and increased levels of sFlt-1, Wnt5a, and SC35 genes or/and protein as well as increased numbers of inflammatory cells (macrophages and leucocytes) and matrix metalloproteinase-9 activity. Immnunofluorescence showed that Flt-1 was co localized with CD11b+ macrophages of aged ischemic muscles. Hypoxia stimulated sFlt1 expression in CD11b+ cells of aged bone-marrow (BM), and this effect was diminished by siWnt5a. The cultured medium of aged mice BM-derived CD11b+ cells suppressed human endothelial cell (EC) and endothelial progenitor cell (EPC) angiogenic actions induced by VEGF, and these decreases were improved by treatment with siWnt5a-conditioned medium. Thus, aging appears to decline neovascularization in response to ischemic stress via the VEGFR2/Akt signaling inactivation in ECs and ECPs that is mediated by Wnt5a/SC35 axis activated macrophages-derived sFlt1 production in advanced age. PMID- 28580186 TI - Mash1-dependent Notch Signaling Pathway Regulates GABAergic Neuron-Like Differentiation from Bone Marrow-Derived Mesenchymal Stem Cells. AB - GABAergic neuronal cell grafting has promise for treating a multitude of neurological disorders including epilepsy, age-related memory dysfunction, Alzheimer's disease and schizophrenia. However, identification of an unlimited source of GABAergic cells is critical for advancing such therapies. Our previous study implied that reprogramming of bone marrow-derived mesenchymal stem cells (BMSCs) through overexpression of the Achaete-scute homolog 1 (Ascl1, also called Mash1) could generate GABAergic neuron-like cells. Here, we investigated mechanisms underlying the conversion of BMSCs into GABAergic cells. We inhibited gamma-secretase (an enzyme that activates Notch signaling) with N-[N-(3,5 difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) or manipulated the expression of Notch signaling components such as the recombination signal binding protein for immunoglobulin kappa J region (RBPJ), hairy and enhancer of split-1 (Hes1) or Mash1. We demonstrate that inhibition of gamma-secretase through DAPT down-regulates RBPJ and Hes1, up-regulates Mash1 and results in an enhanced differentiation of BMSCs into GABAergic cells. On the other hand, RBPJ knockdown in BMSCs has no effect on Mash1 gene expression whereas Hes1 knockdown increases the expression of Mash1. Transduction of Mash1 in BMSCs also increases the expression of Hes1 but not RBPJ. Moreover, increased GABAergic differentiation in BMSCs occurs with concurrent Mash1 overexpression and Hes1 silencing. Thus, the Mash1-dependent Notch signaling pathway regulates GABAergic neuron-like differentiation of BMSCs. These results also suggest that genetic engineering of BMSCs is a useful avenue for obtaining GABAergic neuron-like donor cells for the treatment of neurological disorders. PMID- 28579919 TI - Electron efficiency measurements with the ATLAS detector using 2012 LHC proton proton collision data. AB - This paper describes the algorithms for the reconstruction and identification of electrons in the central region of the ATLAS detector at the Large Hadron Collider (LHC). These algorithms were used for all ATLAS results with electrons in the final state that are based on the 2012 pp collision data produced by the LHC at [Formula: see text] = 8 [Formula: see text]. The efficiency of these algorithms, together with the charge misidentification rate, is measured in data and evaluated in simulated samples using electrons from [Formula: see text], [Formula: see text] and [Formula: see text] decays. For these efficiency measurements, the full recorded data set, corresponding to an integrated luminosity of 20.3 fb[Formula: see text], is used. Based on a new reconstruction algorithm used in 2012, the electron reconstruction efficiency is 97% for electrons with [Formula: see text] [Formula: see text] and 99% at [Formula: see text] [Formula: see text]. Combining this with the efficiency of additional selection criteria to reject electrons from background processes or misidentified hadrons, the efficiency to reconstruct and identify electrons at the ATLAS experiment varies from 65 to 95%, depending on the transverse momentum of the electron and background rejection. PMID- 28580188 TI - On the Relationship between Energy Metabolism, Proteostasis, Aging and Parkinson's Disease: Possible Causative Role of Methylglyoxal and Alleviative Potential of Carnosine. AB - Recent research shows that energy metabolism can strongly influence proteostasis and thereby affect onset of aging and related disease such as Parkinson's disease (PD). Changes in glycolytic and proteolytic activities (influenced by diet and development) are suggested to synergistically create a self-reinforcing deleterious cycle via enhanced formation of triose phosphates (dihydroxyacetone phosphate and glyceraldehyde-3-phosphate) and their decomposition product methylglyoxal (MG). It is proposed that triose phosphates and/or MG contribute to the development of PD and its attendant pathophysiological symptoms. MG can induce many of the macromolecular modifications (e.g. protein glycation) which characterise the aged-phenotype. MG can also react with dopamine to generate a salsolinol-like product, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinaline (ADTIQ), which accumulates in the Parkinson's disease (PD) brain and whose effects on mitochondria, analogous to MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine), closely resemble changes associated with PD. MG can directly damage the intracellular proteolytic apparatus and modify proteins into non degradable (cross-linked) forms. It is suggested that increased endogenous MG formation may result from either, or both, enhanced glycolytic activity and decreased proteolytic activity and contribute to the macromolecular changes associated with PD. Carnosine, a naturally-occurring dipeptide, may ameliorate MG induced effects due, in part, to its carbonyl-scavenging activity. The possibility that ingestion of highly glycated proteins could also contribute to age-related brain dysfunction is briefly discussed. PMID- 28580187 TI - Associations among Metabolism, Circadian Rhythm and Age-Associated Diseases. AB - Accumulating epidemiological studies have implicated a strong link between age associated metabolic diseases and cancer, though direct and irrefutable evidence is missing. In this review, we discuss the connection between Warburg effects and tumorigenesis, as well as adaptive responses to environment such as circadian rhythms on molecular pathways involved in metabolism. We also review the central role of the sirtuin family of proteins in physiological modulation of cellular processes and age-associated metabolic diseases. We also provide a macroscopic view of how the circadian rhythm affects metabolism and may be involved in cell metabolism reprogramming and cancer pathogenesis. The aberrations in metabolism and the circadian system may lead to age-associated diseases directly or through intermediates. These intermediates may be either mutated or reprogrammed, thus becoming responsible for chromatin modification and oncogene transcription. Integration of circadian rhythm and metabolic reprogramming in the holistic understanding of metabolic diseases and cancer may provide additional insights into human diseases. PMID- 28580192 TI - Fast Component Pursuit for Large-Scale Inverse Covariance Estimation. AB - The maximum likelihood estimation (MLE) for the Gaussian graphical model, which is also known as the inverse covariance estimation problem, has gained increasing interest recently. Most existing works assume that inverse covariance estimators contain sparse structure and then construct models with the l1 regularization. In this paper, different from existing works, we study the inverse covariance estimation problem from another perspective by efficiently modeling the low-rank structure in the inverse covariance, which is assumed to be a combination of a low-rank part and a diagonal matrix. One motivation for this assumption is that the low-rank structure is common in many applications including the climate and financial analysis, and another one is that such assumption can reduce the computational complexity when computing its inverse. Specifically, we propose an efficient COmponent Pursuit (COP) method to obtain the low-rank part, where each component can be sparse. For optimization, the COP method greedily learns a rank one component in each iteration by maximizing the log-likelihood. Moreover, the COP algorithm enjoys several appealing properties including the existence of an efficient solution in each iteration and the theoretical guarantee on the convergence of this greedy approach. Experiments on large-scale synthetic and real-world datasets including thousands of millions variables show that the COP method is faster than the state-of-the-art techniques for the inverse covariance estimation problem when achieving comparable log-likelihood on test data. PMID- 28580194 TI - Can transposons be the obstacle to identical genetic cloning from somatic cells? PMID- 28580191 TI - Motor Imagery-Based Rehabilitation: Potential Neural Correlates and Clinical Application for Functional Recovery of Motor Deficits after Stroke. AB - Motor imagery (MI), defined as the mental implementation of an action in the absence of movement or muscle activation, is a rehabilitation technique that offers a means to replace or restore lost motor function in stroke patients when used in conjunction with conventional physiotherapy procedures. This article briefly reviews the concepts and neural correlates of MI in order to promote improved understanding, as well as to enhance the clinical utility of MI-based rehabilitation regimens. We specifically highlight the role of the cerebellum and basal ganglia, premotor, supplementary motor, and prefrontal areas, primary motor cortex, and parietal cortex. Additionally, we examine the recent literature related to MI and its potential as a therapeutic technique in both upper and lower limb stroke rehabilitation. PMID- 28580199 TI - The Role of Systemic Risk Factors in Diabetic Retinopathy. AB - Diabetic retinopathy is an increasingly common medical issue in the United States. The risk of developing the disease or having the disease progress is caused by many systemic health factors. This article examines the existing literature on the links between glycemic control, arterial hypertension, high cholesterol and hyperlipidemia, obesity, inflammatory markers, sleep-disordered breathing, and exercise with risk of diabetic retinopathy development and prevention. The literature shows benefit for good glycemic and blood pressure control. The effects of cholesterol, and lipid control, inflammatory markers, sleep-disordered breathing, obesity, and exercise are less well established. PMID- 28580196 TI - Somatizing the transposons action. AB - The somatic mobilization of transposable elements is more common than previously thought. In this review we discuss how the intensity and the biologic consequences of somatic mobilization are dependent on the transposable elements landscapes of each genome, and on the "momentum" of each particular TE with respect to the mechanisms that control its transposition and the possibility to escape this control. Additionally, the biologic consequences of somatic mobilization vary among organisms that show an early separation between the germline and somatic cells and those organisms that do not exhibit this separation or that reproduce asexually. In the former, somatic transposition can be involved in phenotypic plasticity, detrimental conditions such as disease, or processes such as aging. For the organisms without separation between the germ and soma, somatic mobilization can be a source of genetic variability. PMID- 28580195 TI - Physical enrichment of transposon mutants from saturation mutant libraries using the TraDISort approach. AB - Transposon-insertion sequencing methods are finding their way into the molecular toolbox of many fields of microbiology. These methods can identify the genomic locations and density of transposon insertions in saturated transposon mutant libraries and can be used to make inferences on gene function. For example, where no insertions or very few insertions are identified within a gene in a mutant library grown under permissive conditions, the gene may be essential. Furthermore, where mutations are enriched or lost in a gene after passaging the library through a selective process, the gene is likely to be involved in phenotypes linked to the process. Typically, a fitness based selection such as a stress condition is used in these experiments and the processed sequencing data are used to identify genes required for fitness under the selection. Our research team recently expanded the utility of the transposon directed insertion sequencing (TraDIS) method by applying a physical separation of a transposon mutant library mediated by fluorescence activated cell sorting, rather than a fitness-based selection. This approach, which we have named "TraDISort" is significant because it allows the study of phenotypes that are not linked to cell survival. The TraDISort approach has a broad range of future applications, in drug development, metabolic engineering and in studies of basic bacterial cell physiology. PMID- 28580198 TI - Depictions of nursing home residents in US newspapers: successful ageing versus frailty. AB - The media shape both what people consider significant and how people think about key issues. This paper explored the cultural beliefs and stereotypes that underlie media portrayals of nursing homes. The analysis of texts of 157 articles about nursing homes published from 1999 to 2008 on the front pages of four major market American newspapers (The New York Times, Chicago Tribune, Los Angeles Times and The Washington Post) was conducted using a qualitative approach inspired by comparative narrative and critical discourse analysis. Results suggest two major themes, each with several narrative components: (a) managing disposable lives (bodies outliving bank accounts; making frailty affordable; and the economics of triage); and (b) retaining purchasing power as successful ageing (consumption as a sign of market participation, spending money as an indicator of autonomy; and financial planning as preparation for future decline). Thus, the results indicate that nursing home residency in-and-of-itself is not a marker of unsuccessful ageing. This, instead, depends, in part, on the extent of choice available as a result of the level of financial solvency. This study shines light on the betwixt and between zone that distinguishes the Third and Fourth Ages; that is, independence versus dependence in old age. If individuals in a nursing home retain control over the management of their lives through the maintenance of financial independence, even if physically frail, association of nursing home residence with the Fourth Age may be ameliorated. PMID- 28580202 TI - The "Empty Chairs" Approach to Learning: Simulation-Based Train the Trainer Program in Mzuzu, Malawi. AB - Together, a group of Canadian colleagues from St. John's, Newfoundland, Calgary, Alberta (some via Doha) and London, Ontario introduced the first Train the Trainer in Simulation-Based Learning (TTT-SBL) program in Mzuzu Central Hospital and Mzuzu University in Malawi. The team led by Elaine Sigalet (Doha) and consisting of Ian Wishart (Calgary), Faizal Haji (London) and Adam Dubrowski (St. John's) was invited to Malawi by Norman Lufesi to conduct a two-day TTT-SBL course for facilitators who teach an Emergency Triage, Assessment and Treatment (ETAT) plus Trauma course. The following technical report describes this course. All trainees-facilitators who took part in the first iteration of the TTT-SBL course were asked to participate in teaching an ETAT course and modify it to include elements of simulation. The new format of ETAT resulted in a reduction of time necessary to conduct the course from four days (based on historical data) to 2.5 days. PMID- 28580200 TI - Treatment Outcomes of Rare Retromolar Trigone Squamous Cell Carcinoma Using Combined Modalities. AB - BACKGROUND: Retromolar trigone squamous cell carcinoma is relatively uncommon and due to its complex anatomy has always remained a challenge in terms of loco regional control and survival. Surgery, radiotherapy, and chemotherapy as combined modalities have been used but high recurrence rates result in poor outcome. METHODS: We have retrospectively evaluated records of 62 patients treated in Head and Neck Oncology unit of Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH and RC), Lahore, Pakistan from 2004 to 2014 who were included based on the criteria of histopathological proven squamous cell carcinoma of retromolar trigone (RMT) treated with radical intent. Diagnostic workup for all patients involved clinical examination, imaging modalities usually magnetic resonance imaging (MRI), computerized tomography (CT), Orthopantomogram (OPG), and chest x-ray (CXR) to evaluate regional and distant metastasis, respectively. Kaplan-Meier survival curves were used to depict survival. RESULTS: The study was comprised of 36 male and 26 female patients. Treatment modalities used are surgery only (n = 1), radiotherapy alone (n = 13), radiotherapy followed by surgery (n = 10), chemoradiotherapy (n = 16), induction chemotherapy followed by concurrent chemoradiotherapy (n = 19), induction chemotherapy followed by surgery, and radiotherapy (n = 2). Surgical interventions include wide local excisions (n = 6), marginal mandibulectomy (n = 4), and segmental mandibulectomy (n = 4). Surgical margins were clear in 54%, close in 38%, and involved in 8% of patients. AJCC 7th edition showed cT1 8%, cT2 22%, cT3 14%, and cT4 56% while pT1 2%, pT2 3%, and pT4 8%. During follow-up, 18% patients have come up with local recurrence, 22% showed persistent disease while 9% have presented with distant metastasis. The five-year and overall survivals are 38% and 22%, respectively. CONCLUSION: Retromolar trigone involvement poses many vital structures at risk of involvement. Late presentation results in involvement of masticator space compromising both mouth opening and surgical outcomes. Surgery and radiotherapy have shown comparable results in disease control. Bone invasion has shown poor outcome in terms of loco-regional control and overall survival. PMID- 28580201 TI - Bibliometric Assessment of the Global Scientific Production of Nitazoxanide. AB - INTRODUCTION: Nitazoxanide is a member of a new class of drug, thiazolides, and it was discovered in 1984 with antimicrobial activity effect against anaerobic bacteria, Hepatitis virus, protozoa, and helminths. METHODS: A bibliometric study on four databases (1984-2016) - Medline, Scopus, LILACS, and SciELO - characterizing the global scientific production of nitazoxanide. We determined the quantity, quality (number of citations), and types of studies developed by each country, characterizing them by years, international cooperation, development, place of publication, authors (with its H-index), and groups with higher impact. RESULTS: There were 512 articles in Medline - the higher scientific production is from the USA (19.71%), Switzerland (7.51%), and Mexico (7.27%). There were 1,440 articles in Scopus - from the USA (8.98%), Mexico (2.13%), and India (1.65%). There were 405 articles in LILACS - from Mexico (4.69%), the USA (4.2%), and Peru (2.47%). There were 47 articles in SciELO - from Brazil (34.04%), Venezuela (21.28%), and Colombia (14.89%). The H-index of nitazoxanide is 75 - the USA (26), Egypt (12), and Canada (10) were the countries contributing more with that. CONCLUSIONS: Nitazoxanide research has been highly important. Nevertheless, it is relatively limited when compared with other drugs. Its research has been led by the USA, as revealed in this bibliometric assessment. Although some developing countries, where it is used especially for protozoa and helminths, probably have its influence, and this explains the fact that Mexico and India, among others, are the top countries in the scientific production of this anti-infective agent. This bibliometric study evidenced a relatively low number of publications, however, it has been increased in recent years. PMID- 28580204 TI - Post-Transfusion Purpura: A Case Report of an Underdiagnosed Phenomenon. AB - Post-transfusion purpura is a rare transfusion-related complication that often goes undiagnosed. It is due to alloimmunization against platelet antigens which leads to acute profound thrombocytopenia following the transfusion of any platelet-containing product (red blood cells or platelets). It is commonly seen in multiparous women. Here, we report a case of post-transfusion purpura in a 56 year-old multiparous woman who developed acute thrombocytopenia seven days following a packed red blood cell transfusion. We will discuss the clinical presentation, diagnosis, workup and treatment of this rare disease. It is important to recognize this entity separately and to include it in the differential diagnosis of acute thrombocytopenia after a recent blood transfusion. Treatment for this condition consists of intravenous immunoglobulins, corticosteroids or plasmapheresis. PMID- 28580190 TI - Geroprotectors: A Unified Concept and Screening Approaches. AB - Although the geroprotectors discovery is a new biomedicine trend and more than 200 compounds can slow aging and increase the lifespan of the model organism, there are still no geroprotectors on the market. The reasons may be partly related to the lack of a unified concept of geroprotector, accepted by the scientific community. Such concept as a system of criteria for geroprotector identification and classification can form a basis for an analytical model of anti-aging drugs, help to consolidate the efforts of various research initiatives in this area and compare their results. Here, we review the existing classification and characteristics of geroprotectors based on their effect on the survival of a group of individuals or pharmaceutics classes, according to the proposed mechanism of their geroprotective action or theories of aging. After discussing advantages and disadvantages of these approaches, we offer a new concept based on the maintenance of homeostatic capacity because aging can be considered as exponential shrinkage of homeostatic capacity leading to the onset of age-related diseases and death. Besides, we review the most promising current screening approaches to finding new geroprotectors. Establishing the classification of existing geroprotectors based on physiology and current understanding of the nature of aging is essential for putting the existing knowledge into a single system. This system could be useful to formulate standards for finding and creating new geroprotectors. Standardization, in turn, would allow easier comparison and combination of experimental data obtained by different research groups. PMID- 28580203 TI - Single Fraction Stereotactic Radiosurgery for Retreatment of Skull Base Recurrent Head and Neck Malignancies. AB - INTRODUCTION: Recurrent head and neck carcinomas are notoriously difficult to treat. Salvage surgery, brachytherapy, and repeat external beam radiotherapy have all been utilized, achieving modest local control at the expense of elevated toxicity. We performed a retrospective review to evaluate the efficacy of single fraction stereotactic radiosurgery (SRS) for the treatment of recurrent head and neck carcinomas. METHODS: Eighteen previously irradiated patients diagnosed with a locoregionally recurrent head and neck malignancy and treated with single fraction SRS from 2000 to 2016 were analyzed. Actuarial rates for local control (LC) and overall survival (OS) were calculated with Kaplan-Meier estimates. RESULTS: Median follow-up was 16.1 months and SRS dose was 13.3 Gy. One-year rate of LC was 52.7% (95% confidence interval [CI] 29%-72%). Median OS was 25.4 months. Parotid gland primary had an increased risk of progressive disease (PD) following SRS (hazard ratio [HR] 4.24, p=0.02). Squamous cell histology was negatively associated with OS (HR 3.85, p=0.03). One patient experienced grade 2 radionecrosis. CONCLUSIONS: Single fraction SRS is an acceptable treatment for previously irradiated patients with recurrent head and neck primary malignancies. Dose escalation to optimize LC should be examined. PMID- 28580205 TI - Solid Variant of an Aneurysmal Bone Cyst of the Thoracic Spine. AB - The solid variant of an aneurysmal bone cyst (ABC) has been observed very rarely, especially those involving the spine. In this case report, we present a very unusual tumour of the thoracic spine which was managed by 360 decompression via posterior-only approach and stabilization. A 16-year-old boy presented to us with a sudden onset of weakness in both lower limbs leading to paraplegia. He also had a history of back and chest pain over the past one year. A collapse of the T5 vertebrae on plain radiograph was observed. The patient was immediately shifted to the operation theatre with an initial plan of a total en bloc spondylectomy of the T5. However, intraoperatively, histology favored a solid-ABC variant rather than a spindle cell tumour or giant cell tumour. Thus, the initial plan was revised to a 360 decompression without resecting the body en bloc via a posterolateral approach. After surgery, complete resolution of his sensory and motor dysfunction was achieved. His chest and back pain also resolved. The diseased vertebral body gradually healed and new bone formation was seen at 18 months postoperatively. This case report concludes that a solid variant of an ABC should be considered as a differential diagnosis for tumours involving the spine. An intraoperative frozen section procedure should be undertaken, especially during emergency situations. Early diagnosis and appropriate surgical management play an important role in the successful management of a solid variant of ABC. PMID- 28580189 TI - Vitamin D and Chronic Diseases. AB - Vitamin D is one of the essential nutrients to sustain the human health. As a member of the steroid hormone family, it has a classic role in regulating metabolism of calcium and a non-classic role in affecting cell proliferation and differentiation. Epidemiological studies have shown that 25OHD deficiency is closely associated with common chronic diseases such as bone metabolic disorders, tumors, cardiovascular diseases, and diabetes. 25OHD deficiency is also a risk factor for neuropsychiatric disorders and autoimmune diseases. 25OHD deficiency is highly prevalent in the world. It is therefore necessary to know the adverse health effects of 25OHD deficiency, and to design interventions and early treatments for those who are likely to have low levels of 25OHD. PMID- 28580193 TI - How the Same Core Catalytic Machinery Catalyzes 17 Different Reactions: the Serine-Histidine-Aspartate Catalytic Triad of alpha/beta-Hydrolase Fold Enzymes. AB - Enzymes within a family often catalyze different reactions. In some cases, this variety stems from different catalytic machinery, but in other cases the machinery is identical; nevertheless, the enzymes catalyze different reactions. In this review, we examine the subset of alpha/beta-hydrolase fold enzymes that contain the serine-histidine-aspartate catalytic triad. In spite of having the same protein fold and the same core catalytic machinery, these enzymes catalyze seventeen different reaction mechanisms. The most common reactions are hydrolysis of C-O, C-N and C-C bonds (Enzyme Classification (EC) group 3), but other enzymes are oxidoreductases (EC group 1), acyl transferases (EC group 2), lyases (EC group 4) or isomerases (EC group 5). Hydrolysis reactions often follow the canonical esterase mechanism, but eight variations occur where either the formation or cleavage of the acyl enzyme intermediate differs. The remaining eight mechanisms are lyase-type elimination reactions, which do not have an acyl enzyme intermediate and, in four cases, do not even require the catalytic serine. This diversity of mechanisms from the same catalytic triad stems from the ability of the enzymes to bind different substrates, from the requirements for different chemical steps imposed by these new substrates and, only in about half of the cases, from additional hydrogen bond partners or additional general acids/bases in the active site. This detailed analysis shows that binding differences and non catalytic residues create new mechanisms and are essential for understanding and designing efficient enzymes. PMID- 28580206 TI - Idiopathic pulmonary fibrosis in East Asian. AB - Idiopathic pulmonary fibrosis (IPF) is a rare lung disease with a prognosis that can be worse than that of many cancers. Recent studies have improved our understanding of IPF and new treatment options have become available. However, most studies are conducted predominantly in Western countries while few are conducted in East Asian countries. The distribution, effectiveness of treatment, and prognosis for IPF differ among Westerners and East Asians, but whether the heterogeneity of IPF in East Asians is the result of ethnic differences and geographic variability is unclear. This study highlights the current prevalence of IPF and its characteristics in the East Asian population and it provides valuable information to understand the current clinical status of patients with IPF in light of recent advances in its diagnosis and treatment. PMID- 28580197 TI - Transposable elements in Drosophila. AB - Transposable elements (TEs) are mobile genetic elements that can mobilize within host genomes. As TEs comprise more than 40% of the human genome and are linked to numerous diseases, understanding their mechanisms of mobilization and regulation is important. Drosophila melanogaster is an ideal model organism for the study of eukaryotic TEs as its genome contains a diverse array of active TEs. TEs universally impact host genome size via transposition and deletion events, but may also adopt unique functional roles in host organisms. There are 2 main classes of TEs: DNA transposons and retrotransposons. These classes are further divided into subgroups of TEs with unique structural and functional characteristics, demonstrating the significant variability among these elements. Despite this variability, D. melanogaster and other eukaryotic organisms utilize conserved mechanisms to regulate TEs. This review focuses on the transposition mechanisms and regulatory pathways of TEs, and their functional roles in D. melanogaster. PMID- 28580209 TI - Surgical management of hepatolithiasis: A minireview. AB - Hepatolithiasis is highly prevalent in Asia but rare in Western countries. However, the incidence of hepatolithiasis may be increasing in Western countries due to the increased rate of immigration from areas where hepatolithiasis is prevalent. There are many non-surgical treatments for hepatolithiasis, but surgical management remains the best curative treatment for some cases of hepatolithiasis. Surgical treatments can remove biliary stones and relieve stricture of the bile ducts. This review describes the indications for and the outcomes of surgical treatment of hepatolithiasis, including liver resection and liver transplantation. PMID- 28580208 TI - Heart transplantation in patients with dystrophinopathic cardiomyopathy: Review of the literature and personal series. AB - Cardiomyopathy associated with dystrophinopathies [Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy (XL-dCM) and cardiomyopathy of Duchenne/Becker (DMD/BMD) carriers] is an increasing recognized manifestation of these neuromuscular disorders and notably contributes to their morbidity and mortality. Dystrophinopathic cardiomyopathy (DCM) is the result of the dystrophin protein deficiency at the myocardium level, parallel to the deficiency occurring at the skeletal muscle level. It begins as a "presymptomatic" stage in the first decade of life and evolves in a stepwise manner toward pictures of overt cardiomyopathy (hypertrophic stage, arrhythmogenic stage and dilated cardiomyopathy). The final stage caused by the extensive loss of cardiomyocytes results in an irreversible cardiac failure, characterized by frequent episodes of acute congestive heart failure (CHF), despite a correct pharmacological treatment. The picture of a severe dilated cardiomyopathy with intractable heart failure is typical of BMD, XL-dCM and cardiomyopathy of DMD/BMD carriers, while it is less frequently observed in patients with DMD. Heart transplantation (HT) is the only curative therapy for patients with dystrophinopathic end-stage heart failure who remain symptomatic despite an optimal medical therapy. However, no definitive figures exist in literature concerning the number of patients with DCM transplanted, and their outcome. This overview is to summarize the clinical outcomes so far published on the topic, to report the personal series of dystrophinopathic patients receiving heart transplantation and finally to provide evidence that heart transplantation is a safe and effective treatment for selected patients with end-stage DCM. PMID- 28580207 TI - Aortic intramural hemorrhage: A distinct disease entity with mystery. AB - Aortic intramural hemorrhage (IMH) is one of the disease processes that comprise the spectrum of acute aortic syndrome (AAS) with clinical manifestations and a mortality rate similar to those of classic aortic dissection (AD). However, IMH should be considered as a distinct disease entity rather than a precursor to classic dissection because of differences in their pathology, etiology, natural history, and imaging findings. Multidetector computed tomography (CT) is recommended as the first-line diagnostic imaging modality for IMH, but transesophageal echocardiography (TEE) and magnetic resonance imaging (MRI) are also helpful. There is still debate over the appropriate treatment of IMH. Medical treatment of type B IMH appears effective and safe, while surgical treatment is recommended for type A IMH. Thoracic endovascular aortic repair (TEVAR) is a promising treatment for selected patients, and more clinical evidence needs to be assembled. PMID- 28580211 TI - Dent disease: Same CLCN5 mutation but different phenotypes in two brothers in China. AB - Dent disease is an X-linked recessive proximal tubular disorder that affects mostly male patients in childhood or early adult life, caused by mutations in CLCN5 (Dent disease 1) or OCRL (Dent disease 2) genes, respectively. It presents mainly with hypercalciuria, low-molecular-weight proteinuria, nephrocalcinosis and progressive renal failure. We report here the same CLCN5 mutation but different phenotypes in two Chinese brothers, and speculate on the possible reasons for the variability of the genotype-phenotype correlations. PMID- 28580210 TI - Immunosuppressive medication is not associated with surgical site infection after surgery for intractable ulcerative colitis in children. AB - Pediatric ulcerative colitis (UC) sometimes progresses to an intractable condition for medical therapy. The surgical management of UC is challenging because of difficult procedures and frequent infectious complications. The aim of this study was to survey surgical procedures and infectious complications in pediatric patients with UC in Japan and to assess the relationship between preoperatively administered immunosuppressive drugs and postoperative surgical site infection (SSI). A survey of pediatric patients treated from 2000 to 2012 was sent to 683 facilities nationwide. Secondary questionnaires were sent to physicians who followed up patients with UC who had undergone surgery with the aim of assessing the relationships between postoperative SSI and selected preoperative patient characteristics, disease severity, medications, and operative procedures. Data for 136 patients (77 boys and 59 girls) were assessed. Median age at surgery was 14.1 years (range: 2.4-18.9 years). Surgery was performed in one stage in 35 cases, two stages in 57 cases, and three stages in 44 cases. SSI occurred in 36/136 patients (26%). According to multiple logistic regression analysis, there were statistically significant associations between SSI and staged surgery (three/one, OR: 6.7, 95% CI: 2.1-25.5, p = 0.0007; three/two, OR: 3.4, 95% CI: 1.4-8.6, p = 0.0069) and female sex (OR: 2.3, 95% CI: 1.0-5.4, p = 0.0434). Preoperative medications and incidence of SSI were not significantly associated. Preoperative immunosuppressive medication does not affect the incidence of SSI. Three-stage surgery and female sex are independent predictors of development of postoperative SSIs in pediatric patients with UC. PMID- 28580212 TI - Diagnosis of Morquio-A patients in Mexico: How far are we from prompt diagnosis? AB - Mucopolysaccharidosis IV A, better known as Morquio-A syndrome, is a rare condition with severe skeletal and multiorgan involvement. Sometimes is not easy to differentiate from other skeletal dysplasias. Prior to definitive diagnosis, patients have been delayed or misdiagnosis due to lack of knowledge of local physicians about this disease. The aim of this study is to compare the age of onset of clinical manifestations, age of diagnosis, as seen by the parent or primary caregiver and compare this age with other population reports worldwide. Self-administered questionnaires were conducted to the primary caregiver of confirmed patients, collecting information about the onset of symptoms, age, previous diagnoses and biological variables (age, gender, sex). Data from 50 patients, 23 men and 27 women was obtained. Mean age at definitive diagnosis was 5.6 years, age at onset of signs or symptoms was 4.14 years starting with pigeon chest deformity, valgus knees at 4.5 years, stiff hands and increasing mobility of wrists to the 5.8 years, followed by limitation to lift shoulders to 7.1 years. In 78% of patients the diagnosis was by a geneticist. First and subsequent observed clinical changes were orthopedic, starting as early as 4.4 years as noted by parents. Rise of suspicious may delay 16 months' average to definitive diagnosis based on other multi-systemic findings. The most frequent specialist aid in diagnosis is a clinical geneticist followed by orthopedic surgeon. The diagnosis of Morquio-A disease in Mexico is as early as reports from other centers. PMID- 28580213 TI - A fatal case of herpes simplex virus hepatitis in a pregnant patient. AB - We present a middle aged pregnant woman who developed signs and symptoms of acute liver failure and was found to have herpes simplex virus hepatitis. Patient had an emergent delivery and was started on antiviral therapy, but unfortunately due to the severity of her liver failure, she passed away. The importance of reporting this case is to emphasize on the importance of considering herpes simplex infection in pregnant women who present with acute liver failure, and the importance of early administration of antiviral therapy. PMID- 28580214 TI - Anaplastic myxopapillary ependymoma in an infant: Case report and literature review. AB - A 7-month-old boy presented with gastrointestinal disturbance, mild neurologic deficit of the left lower extremity and levo-scoliosis of the thoracic spine. Magnetic resonance imaging demonstrated a large intramedullary lesion involving the thoracic spine, from level T1 to T11. Histologic analysis showed a glial tumor with fibrillary processes arranged in radial pattern around mucoid fibrovascular cores with a high proliferative index (focally up to 80%) and prominent vascular endothelial hyperplasia. These findings were consistent with an anaplastic myxopapillary ependymoma. Subtotal resection was performed via a T3 T10 laminoplasty. A ventricular shunt was placed, and the patient subsequently received chemoradiation therapy. To date, this is the second case of a myxopapillary ependymoma with high-grade anaplastic features and the first case in an infant reported in the literature. PMID- 28580215 TI - A novel PGK1 mutation associated with neurological dysfunction and the absence of episodes of hemolytic anemia or myoglobinuria. AB - Phosphoglycerate kinase (PGK) deficiency affects three different organs: red blood cells (RBC), the central nervous system, and muscles. Next-generation sequencing identified a hemizygous PGK1 mutation (p.V217I) in a 16-year-old Japanese male patient presenting with intellectual disability and episodes of muscle weakness of unknown etiology. Enzymatic analysis demonstrated slightly lower RBC-PGK activity and compensatory increases of other glycolysis enzymes. This is the first PGK1 mutation found through next-generation sequencing. PMID- 28580217 TI - Silence pancreatitis in systemic lupus erythematosus. AB - We present here a systemic lupus erythematosus (SLE) related biochemically silent pancreatitis which was assessed via computed tomography in a 35-year-old woman. A patient with a twelve-year history of SLE presented with exacerbation of symptoms of the basic disease, with SLE Disease Activity Index > 15. She was referred to inpatient care. Dosage of corticosteroid and azathioprine for SLE was increased; subclinically and biochemically silent pancreatitis had developed, and was not diagnosed within an appropriate time. On the 15th hospital day, the patient died due to multisystem organ failure, which was defined as a consequence of clinically and biochemically silent pancreatitis in systemic lupus erythematosus. PMID- 28580216 TI - Septic thrombophlebitis of the internal jugular vein, a case of Lemierre's syndrome. AB - An 18-year-old gentleman with a history of recurrent tonsillitis presented to the emergency room complaining of worsening sore throat. He was found to have a peritonisillar abscess, and imaging revealed a non-occlusive left internal jugular vein thrombosis. Lemierre's syndrome is a rare, potentially fatal condition characterized by internal jugular vein thrombosis with septicemia following an acute oropharyngeal infection. While anticoagulation is the mainstay of treatment of deep venous thromboembolism (DVT) and pulmonary embolism (PE), the use of therapy is controversial in septic thrombophlebitis. This is counterintuitive since a common reported complication is pulmonary emboli. Early in the course of thrombophlebitis, while the thrombus is firmly attached, antibiotics may be all that is necessary to treat the condition. PMID- 28580218 TI - Cryotherapy as a conservative treatment modality for gingival enlargement in a patient with Sturge-Weber Syndrome. AB - This case report describes a case of Sturge-Weber syndrome reported for unilateral gingival enlargement and bleeding from gingiva in maxillary left region. Initial treatment in the form of scaling and root planing was done but recurrence was observed after one year of follow up. Instead of performing conventional surgery, an alternative conservative treatment was planned in the form of cryotherapy with the help of closed nitrous oxide probe. Seeing the satisfactory results obtained, cryotherapy can be suggested as an atraumatic, bloodless and effective chair side procedure for treating vascular gingival enlargement. PMID- 28580219 TI - Defining rare diseases in China. AB - China has the world's largest population of people with rare diseases. However, defining rare diseases remains a challenge in China. Over the past few decades, several definitions have been proposed but they have yet to be agreed to by all stakeholders. To overcome this impasse, a list of several rare diseases has recently been created. This rare disease list might be used in place of a prevalence-based definition, especially in healthcare policy-making. PMID- 28580220 TI - Pancreatic lipomatosis in cystic fibrosis: Rare manifestation of an uncommon disease. AB - Cystic fibrosis is deemed to be uncommon in India. The presentation is usually in the childhood although more cases are now being recognized in adolescence and adulthood. We report a case of an adolescent male who had been treated for recurrent pulmonary infections and received anti-tubercular therapy for a possible diagnosis of sputum negative pulmonary tuberculosis and was evaluated for steatorrhea. The presence of pancreatic exocrine insufficiency along with pancreatic lipomatosis suggested the diagnosis of cystic fibrosis. PMID- 28580221 TI - Improving the Resolution of Kendrick Mass Defect Analysis for Polymer Ions with Fractional Base Units. AB - The concept of a fractional base unit for the Kendrick mass defect (KMD) analysis of polymer ions is introduced for the first time. A fraction of the ethylene oxide (EO) repeat unit (namely EO/8) has been used for the KMD analysis of a poly(ethylene oxide) and found to amplify the variations of KMD between monoisotopic and 13C isotopes, producing an isotopically resolved KMD plot at full scale when the KMD plot computed with EO is fuzzy. The expansion of the KMD dimension using a fractional base unit has then been successfully used to unequivocally discriminate all the distributions from a blend of poly(ethylene oxide)s in a high resolution KMD plot calculated with EO/3 as base unit. Extending the concept of fractional base units to other repeat units, the visualization of the co-oligomers from a poly(ethylene oxide-b-propylene oxide-b ethylene oxide) triblock copolymer has been dramatically improved using a fraction of the propylene oxide repeat unit (namely PO/3) in an oligomer and isotope resolved plot. High resolution KMD plots were eventually calculated from tandem mass spectra of poly(dimethylsiloxane) ions using a fraction of the dimethylsiloxane (DMS) unit (namely DMS/6) with clearer point alignments and a discrimination of all the product ion series, out of reach of the KMD analysis using DMS. Versatile and producing high resolution KMD plots, the introduction of fractional base units is believed to be a major step towards the implementation of the KMD analysis as a routine data mining tool for mass spectrometry in polymer chemistry. PMID- 28580222 TI - Prediction of Hopeless Peptides Unlikely to be Selected for Targeted Proteome Analysis. AB - In targeted proteomics using liquid chromatography-tandem triple quadrupole mass spectrometry (LC/MS/MS) in the selected reaction monitoring (SRM) mode, selecting the best observable or visible peptides is a key step in the development of SRM assay methods of target proteins. A direct comparison of signal intensities among all candidate peptides by brute-force LC/MS/MS analysis is a concrete approach for peptide selection. However, the analysis requires an SRM method with hundreds of transitions. This study reports on the development of a method for predicting and identifying hopeless peptides to reduce the number of candidate peptides needed for brute-force experiments. Hopeless peptides are proteotypic peptides that are unlikely to be selected for targets in SRM analysis owing to their poor ionization characteristics. Targeted proteomics data from Escherichia coli demonstrated that the relative ionization efficiency between two peptides could be predicted from sequences of two peptides, when a multivariate regression model is used. Validation of the method showed that >20% of the candidate peptides could be successfully eliminated as hopeless peptides with a false positive rate of less than 2%. PMID- 28580223 TI - Carotid cavernous fistula with central retinal artery occlusion and Terson syndrome after mid-facial trauma. AB - Objectives: To report a rare occurrence combination of central retinal artery occlusion (CRAO) and Terson syndrome in a Barrow's type A carotid cavernous fistula (CCF) patient. Methods: Observational case report. Results: A twenty-year old male patient with a history of road traffic accident presented with periorbital swelling and redness in the left eye. Examination revealed a CRAO with intraretinal and preretinal hemorrhages. On imaging, type A CCF and subarachnoid hemorrhage were detected. He underwent embolization of the fistula for cosmetic blemish. The possible mechanisms and clinical implications are discussed. Conclusion: Patients with a head injury can have serious ocular damage. Posterior segment manifestations of CCFs are varied and at times can occur in various rare combinations, making it challenging. Early recognition of these rare manifestations and a multi-disciplinary approach are needed in patients with head trauma. PMID- 28580224 TI - Upper eyelid angiolipoma associated friction in the glide zone. AB - A 74-year-old man was examined for a mass in the left upper eyelid. It was inconspicuous in inspection. There was no visual restriction, however a feeling of friction on the superior orbit during lid movement. Through eyelid crease lid incision, a solitary lesion appeared in the preaponeurotic space that orginated from the upper tarsal plate. Excisional biopsy revealed adipose proliferation with patch form vessels. This case represents the second reported angiolipoma of the eyelid in English literature. PMID- 28580225 TI - Fracture heuristics: surgical decision for approaches to distal radius fractures. A surgeon's perspective. AB - Introduction: The aim of the present study is to develop a heuristic that could replace the surgeon's analysis for the decision on the operative approach of distal radius fractures based on simple fracture characteristics. Patients and methods: Five hundred distal radius fractures operated between 2011 and 2014 were analyzed for the surgeon's decision on the approach used. The 500 distal radius fractures were treated with open reduction and internal fixation through palmar, dorsal, and dorsopalmar approaches with 2.4 mm locking plates or underwent percutaneous fixation. The parameters that should replace the surgeon's analysis were the fractured palmar cortex, and the frontal and the sagittal split of the articular surface of the distal radius. Results: The palmar approach was used for 422 (84.4%) fractures, the dorsal approach for 39 (7.8%), and the combined dorsopalmar approach for 30 (6.0%). Nine (1.8%) fractures were treated percutaneously. The correlation between the fractured palmar cortex and the used palmar approach was moderate (r=0.464; p<0.0001). The correlation between the frontal split and the dorsal approach, including the dorsopalmar approach, was strong (r=0.715; p<0.0001). The sagittal split had only a weak correlation for the dorsal and dorsopalmar approach (r=0.300; p<0.0001). Discussion: The study shows that the surgical decision on the preferred approach is dictated through two simple factors, even in the case of complex fractures. Conclusion: When the palmar cortex is displaced in distal radius fractures, a palmar approach should be used. When there is a displaced frontal split of the articular surface, a dorsal approach should be used. When both are present, a dorsopalmar approach should be used. These two simple parameters could replace the surgeon's analysis for the surgical approach. PMID- 28580226 TI - Social Network Factors and Addictive Behaviors among College Students. AB - PURPOSE OF THE REVIEW: To provide an overview of studies within the past five years examining the impact of social network factors on addictive behaviors among college students, to discuss gaps, limitations, and controversies in the field, and to summarize with a discussion of future directions and implications for interventions. RECENT FINDINGS: A review of 13 studies indicated that greater network exposure, centrality, reciprocated ties, and more tightly interconnected networks were associated with greater alcohol use and other addictive behaviors among college students. SUMMARY: Greater research is needed that expands beyond alcohol use to other addictive behaviors among college students. Additionally, more studies are needed that longitudinally study the impact of changes in social networks on addictive behaviors and vice versa, as well as studies examining sociocentric (whole) networks. Social network approaches offer innovative perspectives in understanding social influences on addictive behaviors and novel intervention strategies for potentially reducing addictive behaviors among college students. PMID- 28580228 TI - Food Addiction Beliefs Amongst the Lay Public: What Are the Consequences for Eating Behaviour? AB - PURPOSE OF REVIEW: The current paper reviews recent research on perceptions of food addiction in the lay public. It also examines the potential consequences of such beliefs for eating behaviour. RECENT FINDINGS: Surveys suggest that, within community samples, the majority of individuals believe that certain foods are addictive, and that food addiction causes obesity. Further, many people believe themselves to be 'food addicts', and these individuals demonstrate increased patterns of aberrant eating. However, there is also initial experimental evidence to suggest that believing oneself to be a food addict leads to short-term food restriction. SUMMARY: To reconcile these findings, a self-perpetuating relationship between food addiction beliefs and aberrant eating is proposed. Specifically, in the short term, food addiction beliefs may encourage individuals to avoid certain foods. However, attempts at restriction may eventually lead to increased cravings and disinhibition, thus reinforcing perceptions of oneself as a food addict. These possibilities merit scrutiny in future research. PMID- 28580227 TI - Does Cannabis Composition Matter? Differential Effects of Delta-9 tetrahydrocannabinol and Cannabidiol on Human Cognition. AB - PURPOSE OF REVIEW: The lack of clarity about the effect of cannabis use on cognition may be attributable to the considerable heterogeneity among studies in terms of cannabis composition. This article selectively reviews studies examining the distinctive effects of cannabinoids on human cognition, particularly those of delta-9-tetrahydrocannabinol (Delta9-THC) and cannabidiol (CBD). RECENT FINDINGS: Research indicates that ?9-THC administration acutely impairs cognition, particularly memory and emotional processing. Limited evidence suggests that CBD administration might improve cognition in cannabis users but not in individuals with neuropsychiatric disorders. Moreover, studies indicate that some acute Delta9-THC-induced cognitive impairments may be prevented if Delta9-THC is administered in combination or following CBD treatment. Delta9-THC and CBD have also shown opposite effects on cognition-related brain activation, possibly reflecting their antagonistic behavioral effects. SUMMARY: Research suggests greater cognitive impairments in individuals when exposed to high ?9-THC or low CBD cannabis. It is unclear whether at specific concentrations CBD might outweigh any harmful effects of Delta9-THC on cognition. PMID- 28580229 TI - Mindfulness Reduces Reactivity to Food Cues: Underlying Mechanisms and Applications in Daily Life. AB - PURPOSE OF REVIEW: Mindfulness-based interventions are becoming increasingly popular as a means to facilitate healthy eating. We suggest that the decentering component of mindfulness, which is the metacognitive insight that all experiences are impermanent, plays an especially important role in such interventions. To facilitate the application of decentering, we address its psychological mechanism to reduce reactivity to food cues, proposing that it makes thoughts and simulations in response to food cues less compelling. We discuss supporting evidence, applications, and challenges for future research. RECENT FINDINGS: Experimental and correlational studies consistently find that the adoption of a decentering perspective reduces subjective cravings, physiological reactivity such as salivation, and unhealthy eating. SUMMARY: We suggest that the decentering perspective can be adopted in any situation to reduce reactivity to food cues. Considering people's high exposure to food temptations in daily life, this makes it a powerful tool to empower people to eat healthily. PMID- 28580230 TI - The Use of Long-Acting Injectable Antipsychotics in Schizophrenia. AB - Schizophrenia is a mostly chronic mental disorder, and symptomatic relapse is frequently observed. It is often associated with social and/or occupational decline that can be difficult to reverse. Most patients with the illness need long-term pharmacological treatment, and antipsychotic drugs represent the mainstay of clinical care. Long-acting injectable antipsychotics (LAIs) are an important alternative to oral medication, particularly advantageous in the context of compliance management. Several new-generation antipsychotics (NGAs), including risperidone, olanzapine, paliperidone, and aripiprazole, have become available as long-acting formulations, and new evidence has been accumulating. To date, all of the NGA LAIs have demonstrated a statistically and clinically significant decrease of relapse rates over placebo. The results of clinical trials comparing NGA LAIs with oral antipsychotics (OAPs) are not consistent, as being influenced considerably by study design. Superiority of LAIs to OAPs in efficacy is most evident in mirror image and cohort studies. New-generation LAIs are comparable to their oral mother compounds regarding safety and tolerability if one disregards potential injection site complications. There is little evidence of efficacy differences between the available LAIs, but they have different characteristics in terms of pharmacodynamic and pharmacokinetic profiles, injection interval, cost, requirements for oral supplementation, as well as adverse events. Considering these differences is useful for selecting LAIs for the treatment of individual patients. There is increasing evidence suggesting the use of LAIs in special patient groups, such as first-episode or forensic schizophrenia patients. This article reviews data on the use of NGA LAIs in schizophrenia and discusses current issues from clinical and methodological perspectives. PMID- 28580232 TI - Mineralization of a sulfonated textile dye Reactive Red 31 from simulated wastewater using pellets of Aspergillus bombycis. AB - BACKGROUND: Reactive Red 31, applied extensively in the commercial textile industry, is a hazardous and persistent azo dye compound often present in dye manufacturing and textile industrial effluents. Aspergillus bombycis strain was isolated from dye contaminated zones of Gujarat Industrial Development Corporation, Vatva, Ahmedabad, India. The decolorization potential was monitored by the decrease in maximum absorption of the dye using UV-visible spectroscopy. Optimization of physicochemical conditions was carried out to achieve maximum decolorization of Reactive Red 31 by fungal pellets. RESULTS: Pellets of A. bombycis strain were found to decolorize this dye (20 mg/L) under aerobic conditions within 12 h. The activity of azoreductase, laccase, phenol oxidase and Manganese peroxidase in fungal culture after decolorization was about 8, 7.5, 19 and 23.7 fold more than before decolorization suggesting that these enzymes might be induced by the addition of Reactive Red 31 dye, and thus results in a higher decolorization. The lab-scale reactor was developed and mineralization of Reactive Red 31 dye by fungal pellets was studied at 6, 12 and 24 h of HRT (hydraulic retention time). At 12 h of HRT, decolorization potential, chemical oxygen demand (COD) and total organic carbon reduction (TOC) was 99.02, 94.19, and 83.97%, respectively, for 20 mg/L of dye concentration. CONCLUSIONS: Dye decolorization potential of A. bombycis culture was influenced by several factors such as initial dye concentration, biomass concentration, pH, temperature, and required aerated conditions. Induction of azoreductase, laccase, phenol oxidase, and Mn-peroxidase enzymes was observed during dye decolorization phase. A. bombycis pellets showed potential in mineralization of dye in the aerobic reactor system. Isolated fungal strain A. bombycis showed better dye decolorization performance in short duration of time (12 h) as compared to other reported fungal cultures.Graphical abstractDegradation of RR31 dye in developed aerobic fungal pelleted reactor. PMID- 28580231 TI - Hormones and Neuropeptide Receptor Heteromers in the Ventral Tegmental Area. Targets for the Treatment of Loss of Control of Food Intake and Substance Use Disorders. AB - Hormones and neuropeptides represent biological correlates of internal homeostatic signals detected and integrated in the hypothalamus, which establishes a robust functional connection with the ventral tegmental area (VTA). The hypothalamus-VTA connection determines the ability of these signals to influence central dopaminergic neurotransmission and, therefore, their ability to increase responsiveness to their reward-associated stimuli and to establish appropriate associative learning. The hypothalamus also provides the main source of the multiple neuropeptides that are released in the VTA. With volume transmission of neuropeptides and hormones, extrasynaptic receptors within the VTA provide a fine-tune mechanism, which depends on the ability of molecularly different G protein-coupled receptors (GPCRs) to form heteromers. GPCR heteromer is defined as a macromolecular complex composed of at least two different receptor units (protomers) with biochemical properties that are demonstrably different from those of its individual components. GPCR heteromers can provide unique allosteric properties to specific ligands, which provides new avenues for drug development. We have identified specific GPCR heteromers in the VTA that integrate orexin and CRF neurotransmission and opioid and galanin neurotransmission, which play a very significant role in the modulation of dopaminergic neuronal activity and which can constitute targets for the treatment of loss of control of food intake and substance use disorders. PMID- 28580233 TI - Connecting Bone and Fat: The Potential Role for Sclerostin. AB - : Sclerostin (SOST), a protein secreted from mature osteocytes in response to mechanical unloading and other stimuli, inhibits the osteogenic Wnt/beta-catenin pathway in mesenchymal stem cells (MSCs) impeding their ability to differentiate into mineralizing osteoblasts. PURPOSE: This review summarizes the crosstalk between adipose tissue and bone. It also reviews the origin, regulation, and role of SOST in osteogenesis and brings attention to an emerging role of this protein in the regulation of adipogenesis. RECENT FINDINGS: Bone-derived molecules that drive MSC adipogenesis have not previously been identified, but recent findings suggest that SOST signaling may induce adipogenesis. In vivo SOST acts locally to induce changes in bone and, in vitro, increases adipogenesis in 3T3-L1 preadipocytes. SUMMARY: SOST is able to induce adipogenesis in certain preadipocytes, however bone-specific studies are needed to determine the effect of local SOST concentrations in healthy and disease models on bone marrow adipose tissue. PMID- 28580234 TI - GROWING UP IS HARD TO DO: AN EMPIRICAL EVALUATION OF MATURATION AND DESISTANCE. AB - PURPOSE: With an increase in longitudinal datasets and analyses, scholars have made theoretical advances toward understanding desistance, using biological, social, and psychological factors. In an effort to integrate the theoretical views on desistance, some scholars have argued that each of these views represents a piece of adult maturation. Yet to date, research has not empirically examined an integrated perspective. The purpose of this study is to conduct an exploratory examination of various "domains" of maturation to determine whether they explain desistance from crime separately and as a whole. METHODS: Using the Rutgers Health and Human Development Project, a longitudinal study spanning ages 12-31, we develop exploratory measures of maturation in five domains: 1) adult social roles, 2) identity/cognitive, 3) psychosocial, 4) civic, and 5) neurocognitive. We then utilize growth curve models to examine the relationship between these domains and crime over time. RESULTS: Although each of the domains is associated with crime at the bivariate level, only three (i.e., psychosocial, identity/cognitive transformation, and adult social role) remain significant in the growth curve models (2 in within-individual analyses). In addition, a combined measure of maturation is related to crime, indicating that greater maturation through emerging adulthood has a negative effect on criminal behavior and is, therefore, a factor influencing desistance. CONCLUSIONS: Maturation emerges as a promising approach to integrating the multiple theoretical views that characterize the literature on desistance from crime. Further research should develop additional domains and determine the best approach for measurement. PMID- 28580235 TI - Integrative Health Services in School Health Clinics. AB - Objective: Mental health treatment today incorporates neurobiology, genetics, neuro-imaging, and pharmacologic mechanisms, offering more options to patients. For some, these modern approaches are not viable choices due to reasons such as limited access to care, cost, intolerable side effects, and, in the pediatric population, fears of potential long-term effects. With the growing prevalence of chronic health conditions, concerns for age of onset, (McGorry, Purcell, Goldstone, & Amminger, 2011) and a growing population of mental health patients, cost-effective and evidence-based treatment options should be evaluated. Integrative treatments, also known as complementary and alternative medicine (CAM), may offer interventions that meet today's clinical needs. Method: To evaluate evidence-based treatment options, we initiated the school-based integrative health program (IHP) in January 2011 at three high schools located in Massachusetts. Our goal was two-fold: first, to design a holistic treatment program and evaluate several integrative modalities, and; second, to determine the feasibility of providing a CAM health program through school clinics. Our protocol utilized three integrative treatments that addressed stress and anxiety conditions. Anxiety disorders are the most common mental illness affecting over 40 million adults in the US (Anxiety and Depression Association of America). Results: The program has been successfully implemented. Preliminary results indicate that this intervention decreased anxiety in these youth. Conclusion: Providing integrative techniques to students in the school setting has the potential to decrease barriers to accessing care, lowering treatment costs and decreasing school absenteeism by instituting care on-site. Offering a holistic approach to treatment in schools is feasible. Because utilizing these approaches involves their active participation, adolescents can acquire life-long skills that improve their ability to cope and confront inevitable life stressors. PMID- 28580236 TI - Penicillium citrinum: Opportunistic pathogen or idle bystander? A case analysis with demonstration of galactomannan cross-reactivity. AB - We present a case of an immunocompromised woman with fever, pulmonary infiltrates and multiple bronchoalveolar lavage (BAL) cultures positive for Penicillium citrinum with a concomitant high BAL galactomannan level. We report the results of Aspergillus galactomannan testing performed on culture supernatants from her P. citrinum strain that confirmed the suspected cross-reactivity. Finally, we discuss the clinical significance and antifungal susceptibility of P. citrinum in our case and review the literature. PMID- 28579920 TI - Measurements of top-quark pair differential cross-sections in the [Formula: see text] channel in pp collisions at [Formula: see text] TeV using the ATLAS detector. AB - This article presents measurements of [Formula: see text] differential cross sections in a fiducial phase-space region, using an integrated luminosity of 3.2 fb[Formula: see text] of proton-proton data at a centre-of-mass energy of [Formula: see text] TeV recorded by the ATLAS experiment at the LHC in 2015. Differential cross-sections are measured as a function of the transverse momentum and absolute rapidity of the top quark, and of the transverse momentum, absolute rapidity and invariant mass of the [Formula: see text] system. The [Formula: see text] events are selected by requiring one electron and one muon of opposite electric charge, and at least two jets, one of which must be tagged as containing a b-hadron. The measured differential cross-sections are compared to predictions of next-to-leading order generators matched to parton showers and the measurements are found to be consistent with all models within the experimental uncertainties with the exception of the Powheg-Box [Formula: see text] Herwig++ predictions, which differ significantly from the data in both the transverse momentum of the top quark and the mass of the [Formula: see text] system. PMID- 28580238 TI - Rapid breeding and varietal replacement are critical to adaptation of cropping systems in the developing world to climate change. AB - Plant breeding is a key mechanism for adaptation of cropping systems to climate change. Much discussion of breeding for climate change focuses on genes with large effects on heat and drought tolerance, but phenology and stress tolerance are highly polygenic. Adaptation will therefore mainly result from continually adjusting allele frequencies at many loci through rapid-cycle breeding that delivers a steady stream of incrementally improved cultivars. This will require access to elite germplasm from other regions, shortened breeding cycles, and multi-location testing systems that adequately sample the target population of environments. The objective of breeding and seed systems serving smallholder farmers should be to ensure that they use varieties developed in the last 10 years. Rapid varietal turnover must be supported by active dissemination of new varieties, and active withdrawal of obsolete ones. Commercial seed systems in temperate regions achieve this through competitive seed markets, but in the developing world, most crops are not served by competitive commercial seed systems, and many varieties date from the end of the Green Revolution (the late 1970s, when the second generation of modern rice and wheat varieties had been widely adopted). These obsolete varieties were developed in a climate different than today's, placing farmers at risk. To reduce this risk, a strengthened breeding system is needed, with freer international exchange of elite varieties, short breeding cycles, high selection intensity, wide-scale phenotyping, and accurate selection supported by genomic technology. Governments need to incentivize varietal release and dissemination systems to continuously replace obsolete varieties. PMID- 28580237 TI - Combination liposomal amphotericin B, posaconazole and oral amphotericin B for treatment of gastrointestinal Mucorales in an immunocompromised patient. AB - Mucormycosis is a life threatening infection caused by fungi in the order Mucorales. Mucormycosis can affect any organ system with rhino-orbital-cerebral and pulmonary infections being the most predominant infection types. Gastrointestinal mucormycosis is rare and accounts for only 4-7% of all cases. Here, we present a case of invasive gastrointestinal mucormycosis in an immunocompromised host treated with systemic and topical anti-mold therapy. PMID- 28580239 TI - Improving nutrition through biofortification: A review of evidence from HarvestPlus, 2003 through 2016. AB - Biofortification is a feasible and cost-effective means of delivering micronutrients to populations that may have limited access to diverse diets and other micronutrient interventions. Since 2003, HarvestPlus and its partners have demonstrated that this agriculture-based method of addressing micronutrient deficiency through plant breeding works. More than 20 million people in farm households in developing countries are now growing and consuming biofortified crops. This review summarizes key evidence and discusses delivery experiences, as well as farmer and consumer adoption. Given the strength of the evidence, attention should now shift to an action-oriented agenda for scaling biofortification to improve nutrition globally. To reach one billion people by 2030, there are three key challenges: 1) mainstreaming biofortified traits into public plant breeding programs; 2) building consumer demand; and 3) integrating biofortification into public and private policies, programs, and investments. While many building blocks are in place, institutional leadership is needed to continue to drive towards this ambitious goal. PMID- 28580240 TI - Endoscopic Fusion of the Accessory Navicular Synchondrosis That Has No Diastasis. AB - Accessory navicular bone is a common accessory ossicle of the foot and is present in 10% to 14% of normal feet. Less than 1% of the accessory navicular bones are symptomatic. Degenerative or traumatic disruption of the accessory navicular synchondrosis is one of the main causes of symptomatic accessory navicular. The disrupted synchondrosis may or may not be associated with diastasis of the synchondrosis. Fusion of the synchondrosis is indicated if the pain fails to respond to conservative measures. The purpose of this Technical Note is to describe a minimally invasive approach for fusion of the synchondrosis that has no diastasis. PMID- 28580241 TI - Lateral Capsular Fixation: An Implant-Free Technique to Prevent Meniscal Allograft Extrusion. AB - Although several surgical techniques have been described to perform meniscal allograft transplantation with good clinical results and although different methods of capsular stabilization can be found in the literature, there is no standard surgical technique to prevent a common complication in the most of series: the tendency to a radial displacement or extrusion of the transplanted menisci. We present a simple, reproducible, and implant-free technique to perform a lateral capsular fixation (capsulodesis) at the time of only the soft-tissue fixation technique of meniscal allograft transplantation in an effort to reduce or prevent the risk of graft extrusion. Using a minimum of two 2.4-mm tunnels drilled from the contralateral side of the tibia with the help of a regular tibial anterior cruciate ligament guide, a capsular attachment to the lateral tibial plateau is obtained. PMID- 28580245 TI - Arthroscopic Rotator Cuff Augmentation: Surgical Technique Using Bovine Collagen Bioinductive Implant. AB - Symptomatic partial-thickness rotator cuff tears and full-thickness tears with poor tissue quality often pose a dilemma for orthopaedic surgeons. Despite advances in repair techniques and fixation devices, retear rates remain high. Progression of partial-thickness tears has been noted to be over 50%, with remaining fibers seeing increased strain. Patch augmentation that induces a healing response while decreasing peak strain of adjacent tissue is becoming more popular among orthopaedic surgeons. Therefore, we present an all-arthroscopic technique guide for application of a Food and Drug Administration-approved bovine bioinductive patch (Rotation Medical, Plymouth, MN). PMID- 28580244 TI - Arthroscopic Technique for Isolated Posterolateral Rotational Instability of the Knee. AB - Isolated posterolateral corner injury is an uncommon injury that could be a source of unexplained knee pain and dysfunction. Most of these patients present instability caused by concomitant ligament injuries. Numerous studies have shown open approach posterolateral repair or reconstruction surgeries to restore posterolateral rotational stability. Still, there is a certain population of patients who present posterolateral rotation instability without significant injury to the fibular collateral ligament, popliteal fibular ligament, and popliteus tendon. The posterolateral capsular ligament is critical to provide posterolateral rotation stability. In this Technical Note, with video, we show a completely arthroscopic approach to stabilize the posterolateral corner, by stabilizing the posterior lateral joint capsule with the lateral meniscus attached to the rim of the lateral tibial plateau. PMID- 28580249 TI - Endoscopic Adhesiolysis of Flexor Hallucis Longus Muscle. AB - Adhesion of the flexor hallucis longus (FHL) muscle to the distal tibia can occur after distal tibial fracture, distal fibular fracture, low tibial osteotomy, soft tissue injury at the posterior ankle, subclinical compartment syndrome of the distal deep posterior compartment of the leg, or Volkmann contracture after deep posterior compartment syndrome of the leg. The purpose of this Technical Note is to report the endoscopic approach of FHL muscle adhesiolysis. It is indicated in patients with symptomatic adhesion of the FHL muscle and contraindicated if there is entrapment of the FHL muscle or tendon in the fracture callus or if there is extensive fibrosis and contracture of the FHL muscle as a result of Volkmann contracture after deep posterior compartment syndrome of the leg. PMID- 28580243 TI - Reconstruction of the Popliteomeniscal Fascicles for Treatment of Recurrent Subluxation of the Lateral Meniscus. AB - Recurrent subluxation of the lateral meniscus is characterized by episodes of mechanical locking of the knee joint. To completely preclude the posterior segment of the lateral meniscus from undergoing anterior dislocation during deep knee flexion, the structures to which it is attached need to be relatively taut. The posterosuperior popliteomeniscal fascicle retains its tension during deep knee flexion; therefore, reconstruction of the posterosuperior and anteroinferior popliteomeniscal fascicles was performed with an autograft harvested from the iliotibial band. This technique provides stabilization of the posterior segment of the lateral meniscus during deep knee flexion without interfering with the normal movement of the lateral meniscus throughout the range of motion of the knee joint. PMID- 28580246 TI - Endoscopic Resection of Giant Cell Tumor of the Extensor Tendon of the Foot. AB - The localized form of giant cell tumor of the tendon sheath is one of the most common soft tissue tumors of the foot and ankle region. It is characteristically a benign, sharply localized peritendinous fibrous mass in the synovial or tendinous spaces. The purpose of this Technical Note is to present the technical details of endoscopic resection of giant cell tumor of the extensor tendon of the foot with preservation of the tendon. It is indicated in the localized form of giant cell tumor of the extensor tendon at the foot dorsum. It is contraindicated in cases with a diffuse giant cell tumor, a giant cell tumor of the extensor tendon at the phalangeal level, or involvement of the flexor tendon. PMID- 28580247 TI - Repair of Proximal Hamstring Tears: A Surgical Technique. AB - Proximal hamstring tears are among the most common sports-related injuries. These injuries often occur as strains or partial tears at the proximal muscle belly or the musculotendinous junction, with avulsion injuries of the proximal attachment occurring less frequently. Regardless of the mechanism, they produce functional impairment and negatively affect an athlete's performance. Various classifications for these injuries are reported in the literature. Early surgical treatment is recommended for patients with either a 2-tendon tear/avulsion with more than 2 cm retraction or those with complete 3-tendon tears. Surgery can be performed in the chronic phase but it is technically demanding because of scar formation and tendon retraction. This Technical Note describes a biomechanically validated surgical technique for repair of the proximal hamstring tears. PMID- 28580252 TI - Arthroscopic Hip Labral Augmentation Technique With Iliotibial Band Graft. AB - The importance of the acetabular labrum has been well documented for the function and overall health of the hip joint. Several biomechanical studies have shown the sealing effect of the acetabular labrum. In the past decade, labral repair procedures have gained increased attention, with the literature suggesting that the outcomes after hip arthroscopy are directly related to labral preservation. However, a primary labral repair can be challenging in cases of hypoplastic, ossified, or complex and irreparable labral tears in which there is insufficient tissue to perform a primary repair. For these cases, labral reconstruction becomes a viable option with good outcomes at short-term and midterm follow-up. A subset of these patients may show viable remnants of the labral circumferential fibers but, because of the low tissue volume, these remnant fibers are unable to maintain the suction seal. In this situation, a labral augmentation may be a viable alternative to labral reconstruction while preserving as much native labral tissue as possible. The purpose of this Technical Note is to describe an arthroscopic hip labral augmentation technique using iliotibial band autograft or allograft. PMID- 28580248 TI - Management of the Stiff Shoulder With Arthroscopic Circumferential Capsulotomy and Axillary Nerve Release. AB - Management of the stiff shoulder is a common and frequently daunting clinical scenario. Arthroscopic capsular release is usually an option for management of severe, chronic glenohumeral joint contractures when conservative treatment fails. Technical hurdles including a thickened capsule, reduction in joint volume, and difficulty with positioning the shoulder intraoperatively can make this procedure challenging. In addition, incomplete release and recalcitrant stiffness are frequent issues. We believe a complete release of the capsule entails special attention to the axillary pouch and requires identification and protection of the axillary nerve. We present a technique for a complete arthroscopic circumferential capsulotomy and detail our approach to safely dissect and protect the axillary nerve under arthroscopic visualization. PMID- 28580257 TI - Posterior Surgical Approach to the Knee. AB - Posterior knee approaches are reliable techniques to address the treatment of various pathologies of the posterior region of the knee, including Baker cyst excision, tibial plateau fracture fixation, posterior cruciate ligament avulsions and inlay reconstructions, femoral condyle cartilage procedures, posterior meniscal repair and loose body removal among others. Surgery in the posterior knee region can be challenging because of the presence of neurovascular structures including the tibial nerve, popliteal artery and vein, and common peroneal nerve; thus, it is less commonly performed. The purpose of this Technical Note is to describe the posteromedial approach to the knee, its anatomic considerations, and how to avoid complications related to the surgical approach. PMID- 28580242 TI - Anatomic Femoral and Tibial Tunnel Placement During Anterior Cruciate Ligament Reconstruction: Anteromedial Portal All-Inside and Outside-In Techniques. AB - Tunnel malposition is one of the most common technical reasons for anterior cruciate ligament reconstruction failure. Small changes in tunnel placement can result in significant differences in outcome. More anatomic placement of the tunnels can lead to greater knee stability and a more accurate reproduction of native knee kinematics. This Technical Note describes 2 tibial tunnel-independent methods to obtain anatomic femoral tunnel placement. The all-inside anteromedial portal technique requires only minimal surgical incisions but allows precise femoral tunnel placement. However, hyperflexion of the knee is required, adequate surgical assistance is necessary, and this technique may be susceptible to graft tunnel mismatch. The outside-in technique may be more beneficial in obese patients, skeletally immature patients, or revision cases. On the downside, it does require an additional 2-cm surgical incision. This article also provides surgical pearls to fine-tune tibial tunnel placement. PMID- 28580254 TI - Use of a Cutting Instrument for Fresh Osteochondral Distal Tibia Allograft Preparation: Treatment of Glenoid Bone Loss. AB - Glenoid bone loss presents a major risk for glenohumeral instability that has been well recognized as a cause of instability recurrence after attempted Bankart repair, and although most surgeons consider the Latarjet procedure as the gold standard, failures can occur with this technique as well and the search for alternative grafts to address glenoid bone loss is a major topic of ongoing research in the field. Of these techniques, the distal tibia allograft (DTA) has been shown to provide an excellent option to restore glenoid biomechanics, due to its congruency with the humeral head, dense bony quality, and the facility of harvest. The correct preparation of the DTA is essential to provide the most anatomic reconstruction possible and to avoid damage to the graft. The purpose of this Technical Note is to present our technique for cutting the DTA in detail, using a special workstation to optimize this procedure. PMID- 28580253 TI - Arthroscopic Patellar Lateral Facetectomy. AB - Isolated patellofemoral osteoarthritis is relatively prevalent, with the lateral facet of the patella being the most commonly affected portion. This pathology can be a result of a patellar maltracking syndrome, patella instability, or idiopathic degenerative changes. A thorough diagnostic work-up with a physical examination and imaging studies are mandatory for a proper diagnosis and to rule out other causes of patellofemoral knee pain. These patients are often treated nonoperatively with exercises for patella mobility, intra-articular injections, braces, patellar tracking, quadriceps balance and strength, and activity modification. Patients with lateral patellar pain that is refractory to nonoperative management, and who have a clear bony deformity on the patella overriding the lateral aspect of the trochlea, can benefit from surgical intervention. We recommend an arthroscopic lateral patellar facetectomy because the joint can be dynamically assessed, treated, and re-evaluated intraoperatively to ensure that normal bony contact has been restored. PMID- 28580251 TI - Multiligament Reconstruction of the Knee in the Setting of Knee Dislocation With a Medial-Sided Injury. AB - Multiple ligament knee injuries are complex pathologies that often result from traumatic knee dislocations. Both a high level of suspicion and a thorough clinical and radiographic examination are mandatory to diagnose and identify all injured structures. Reconstruction of all injured ligaments is recommended to aid in early mobilization and to avoid joint stiffness or graft failure. For knee dislocations involving injury to the anterior cruciate ligament, posterior cruciate ligament, and medial-sided structures, a repair and augmentation of the medial collateral ligament, together with an anatomic reconstruction of the anterior cruciate ligament and double-bundle posterior cruciate ligament, is recommended. In the setting of these complex reconstructions, there are several technical aspects that require consideration to ensure concise and efficient treatment of these injuries. Graft choice, sequence of reconstruction, tunnel position and orientation, and graft tensioning all pose surgical challenges, and require dedicated preoperative preparation and planning. The purpose of this Technical Note is to report a safe, effective, and reproducible surgical technique for treatment of multiligament injuries in the setting of a knee dislocation with a medial-sided component (classified as KD-III-M in the Schenck classification system). PMID- 28580250 TI - Combined All-Inside Anterior Cruciate Ligament Reconstruction and Minimally Invasive Posterolateral Corner Reconstruction Using Ipsilateral Semitendinosus and Gracilis Autograft. AB - The anterior cruciate ligament (ACL) is the most commonly injured knee ligament, particularly among adolescents and young adults. Unrecognized posterolateral laxity is understood as a major cause of ACL reconstruction failure, and concomitant injury to the posterolateral corner (PLC) is prevalent and underdetected. We advocate screening all ACL-deficient knees for PLC injury and present a technique combining minimally invasive PLC reconstruction with anatomic all-inside ACL reconstruction. The combined procedure uses only the ipsilateral hamstring tendons representing a major surgical advantage over traditional management approaches. The semitendinosus is quadrupled and attached to 2 adjustable suspensory cortical fixation devices to form the ACL graft. The gracilis tendon is looped through the fibula head and secured in a single femoral tunnel for the PLC reconstruction via 2 minimally invasive incisions. The use of a single femoral PLC tunnel combined with a single femoral ACL socket minimizes the risk of tunnel convergence. PMID- 28580262 TI - Minimally Invasive Combined Anterior and Anterolateral Stabilization of the Knee Using Hamstring Tendons and Adjustable-Loop Suspensory Fixation Device: Surgical Technique. AB - Despite the numerous techniques described regarding isolated anterior cruciate ligament (ACL) reconstruction, many authors have reported that residual knee rotational instability is not always eliminated. The combination of lateral extra articular knee tenodesis and ACL reconstruction is an alternative surgical approach with very promising clinical results. The purpose of this article is to describe a reliable and reproducible technique of combined ACL reconstruction and lateral extra-articular knee tenodesis using a continuous looped hamstring tendon autograft. A 4-strand graft inside the joint and a 2-strand graft for the tenodesis are attached to 2 adjustable-loop button suspensory fixation devices. PMID- 28580256 TI - Biologic Inlay Osteochondral Reconstruction: Arthroscopic One-Step Osteochondral Lesion Repair in the Knee Using Morselized Bone Grafting and Hyaluronic Acid Based Scaffold Embedded With Bone Marrow Aspirate Concentrate. AB - Cartilage injury of the knee that is associated with significant subchondral bone loss can result in great morbidity, and treatment options that provide durable repair are limited. Osteochondral autograft and allograft reconstruction of these lesions has been used extensively; however, these techniques often require a more invasive surgical exposure, and restoring the natural articular surface radius of curvature can be challenging, particularly in larger lesions. Cell-based repair of these lesions, using autologous chondrocytes in conjunction with bone grafting, has been used with success, although this procedure requires the patient to undergo 2 operations, and access is often restricted due to the high associated costs. Comparable medium-term clinical outcomes have been shown with scaffold-associated mesenchymal stem cell grafting, and this cell-based procedure may also be performed arthroscopically to minimize patient morbidity. In cases of cartilage injury associated with bone loss, this procedure has great potential to repair osteochondral injury when used in conjunction with bone grafting. We present the one-step arthroscopic technique of biologic inlay osteochondral reconstruction in the knee, using an autologous bone graft and a hyaluronic acid based scaffold embedded with bone marrow aspirate concentrate, to treat full thickness cartilage lesions associated with significant subchondral bone loss. PMID- 28580259 TI - Posterolateral Rotatory Instability of the Elbow: Part I. Mechanism of Injury and the Posterolateral Rotatory Drawer Test. AB - Posterolateral rotatory instability (PLRI) is the most commonly encountered pattern of elbow instability. It is the result of disruption of the lateral collateral ligament complex leading to a posterolateral rotatory subluxation of the ulna and radial head. A number of examination maneuvers have been described to assist in clinical identification of PLRI. Despite this, some inconsistency in the description of these techniques remains in the orthopaedic literature. This Technical Note details the mechanism of injury and patient presentation, and emphasizes the primacy of the posterolateral rotatory drawer test in the assessment of PLRI while providing video instruction on how it should be performed. PMID- 28580258 TI - A Method for Capsular Management and Avoidance of Iatrogenic Instability: Minimally Invasive Capsulotomy in Hip Arthroscopy. AB - Most surgeons create a T-shaped or interportal capsulotomy to ensure good visibility when performing hip arthroscopy. This entails transecting the iliofemoral ligament, which may or may not be repaired at the end of the procedure. Cases of iatrogenic hip instability and pain after hip arthroscopy suggest that the iliofemoral ligament plays a crucial role in the stability of the hip joint, and thus preservation should be a goal in hip arthroscopy. We describe a minimally invasive iliofemoral ligament-sparing capsulotomy, guided by the reflected head of the rectus tendon, that can be easily repaired after arthroscopic rim trimming, labral refixation, and offset correction. PMID- 28580255 TI - Arthroscopy-Assisted Fabella Excision: Surgical Technique. AB - The fabella is an anatomic variant not seen in all individuals and can potentially be a source of chronic knee pain due to chondromalacia, osteoarthritis, fractures, or biomechanical pressure against the lateral femoral condyle. It is situated intra-articular, close to the lateral femoral condyle, the lateral gastrocnemius head tendon, and the fabellofibular ligament. Given its rarity, the diagnosis of a symptomatic fabella is often overlooked when evaluating patients with persistent posterolateral knee pain. However, this diagnosis should always be considered, especially in high-performance runners, bikers, and triathletes. Although nonoperative management can potentially resolve symptoms associated with this condition, fabella excision via arthroscopically assisted surgery is a reliable and safe alternative to treat patients who do not benefit from nonsurgical treatment. We present our technique detailing fabella excision for treatment of posterolateral knee pain, which includes an arthroscopic evaluation of the fabella to assess damage to the femoral condyle and minimize over-resection and potential damage to surrounding structures. PMID- 28580261 TI - All-Arthroscopic Coracoclavicular Ligament Reconstruction Surgical Technique Using a Semitendinosus Allograft and Tenodesis Screws. AB - Acromioclavicular joint injuries account for 9% of shoulder girdle injuries and are most often associated with direct blows to the shoulder or axially directed forces onto the ipsilateral extremity. Type IV, V, and VI injuries are generally managed surgically, whereas type I and II injuries are treated with sling immobilization, early shoulder range of motion, and physical therapy. Type III injuries are more controversial but are generally managed surgically in the active and high-demand patient. When surgical treatment is indicated, the primary goal of a coracoclavicular (CC) ligament reconstruction is to restore anatomic reduction of the acromioclavicular joint and reconstruct the biomechanical forces of the CC ligaments. Many open surgical techniques are currently used to achieve these goals but can increase patient morbidity. We describe a technique for an all-arthroscopic CC ligament reconstruction using a semitendinosus allograft and BioComposite tenodesis screws (Arthrex) without disruption of the deltoid attachment onto the distal clavicle. PMID- 28580260 TI - Posterolateral Rotatory Instability of the Elbow: Part II. Supplementary Examination and Dynamic Imaging Techniques. AB - Currently, a number of examination and imaging techniques exist for diagnosing posterolateral rotatory instability of the elbow. Although the posterolateral rotatory drawer is the primary examination maneuver, other special tests include the lateral pivot-shift test, prone push-up test, chair push-up test, and tabletop push-up test. In addition, posterolateral rotatory instability can be evaluated using radiography, magnetic resonance imaging, dynamic fluoroscopy, or dynamic ultrasound. In this Technical Note, each of these tests is described in detail. Video instruction is also provided to further explain the techniques and provide examples of positive tests. PMID- 28580263 TI - Flexor Hallucis Longus Tenosynovitis and First Metatarsophalangeal Synovitis After Penetrating Nail Prick Injury: Treated by Zone 3 Flexor Hallucis Longus Tendoscopy and Metatarsosesamoid Arthroscopy. AB - Pedal penetrating nail prick injury around the first metatarsal head can result in persistent synovitis of the first metatarsophalangeal joint and tenosynovitis of the flexor hallucis longus tendon. Exploration and debridement is indicated if the condition does not improve with antibiotics. Open surgery requires extensive dorsal and plantar incisions. The purpose of this Technical Note is to report the combined arthroscopic and tendoscopic approaches to address the first metatarsophalangeal joint and flexor hallucis longus tendon pathologies. Because it is a result of a pedal injury, the layer-by-layer exploration and debridement is from plantar dorsally. It starts with zone 3 flexor hallucis longus tendoscopy, followed by arthroscopy of the metatarsosesamoid compartment, and finally arthroscopy of the metatarsophalangeal compartment. PMID- 28580267 TI - Fatigue Behavior of Nitinol Anterior Cruciate Ligament Graft and Inappropriate Femoral Tunnel Placement: Single-Stage Revision Anterior Cruciate Ligament Reconstruction Surgery. AB - Anterior cruciate ligament (ACL) injury is the most common ligament injury in the knee, and progressive instability and disability may develop in a significant number of patients. The incidence of ACL reconstruction is rapidly increasing, as is the number of failures. Although ACL reconstruction is a common procedure, less than satisfactory outcomes have been reported to occur in up to 25% of patients. The reasons for clinical failure after ACL reconstruction are numerous but can be broadly separated into 3 categories: technical, biological, and mechanical failures. It is generally thought that poor tunnel positioning (especially the femoral tunnel) is the most common technical error. Revision ACL reconstruction can be performed in 1 or 2 stages. The decision to perform a multistage approach is based on the position and size of the original tunnels. The varied success rates and associated advantages and disadvantages of each method have resulted in controversy as to the best treatment for revision ACL surgery. We describe our preferred operative technique to remove a fractured nitinol synthetic ACL graft and manage single-stage revision ACL reconstruction without bone grafting. PMID- 28580265 TI - Bone Marrow Aspirate Concentrate Harvesting and Processing Technique. AB - Bone marrow obtained by iliac crest aspiration is a common source for harvesting mesenchymal stem cells, other progenitor cells, and associated cytokine/growth factors. Recent studies have reported good to excellent outcomes with the use of bone marrow aspirate concentrate (BMAC) for pain relief in the treatment of focal chondral lesions and osteoarthritis of the knee. However, the harvesting and processing technique are crucial to achieve satisfactory results. Several studies have examined outcomes after BMAC injection, with encouraging results, but there is a lack of consensus in terms of the frequency of injection, the amount of BMAC that is injected, and the timing of BMAC injections. The purpose of this Technical Note was to describe a standardized bone marrow aspiration harvesting technique and processing method. PMID- 28580264 TI - Correction of Recurred Hallux Valgus Deformity by Endoscopic Distal Soft Tissue Procedure. AB - The underlying reason for recurrence of hallux valgus deformity after bunion surgery is multifactorial and includes surgeon-based and patient-based factors as well as original components of deformity initially unaddressed at the index procedure. Surgical treatment of a recurred hallux valgus deformity should be undertaken using the same guidelines for correction of a primary hallux valgus deformity. It requires correction of bony alignment, restoration of joint congruity, and achievement of soft tissue balance. The purpose of this Technical Note is to describe the details of endoscopic soft tissue procedure to correct a recurred hallux valgus deformity. To successfully complete this procedure, adequate lateral release to achieve soft tissue balance around the first metatarsophalangeal joint with reduction of the sesamoid bones is mandatory. PMID- 28580268 TI - Endoscopic Resection of Medial Extra-articular Cysts of the Knee. AB - Although most of the parameniscal cysts are very small and asymptomatic, some of them can present with a painful mass or snapping knee. Because parameniscal cysts are almost always associated with horizontal meniscal tears, arthroscopic partial meniscectomy of the involved part of meniscus and intra-articular cyst drainage has become the most accepted procedure. However, arthroscopic cyst decompression through partial meniscectomy to the meniscocapsular junction to expose the communication between the cyst and the knee joint may sacrifice some of the healthy parts of the meniscus especially when meniscal tear is peripheral. Moreover, internal drainage may not be an adequate treatment for a cyst larger than 5 cm in size or a multiloculated cyst. The excision of the cyst is a more appropriate treatment option in these situations. The purpose of this Technical Note is to describe the details of endoscopic resection of medial extra-articular cysts of the knee. This technique is indicated in symptomatic medial extra articular cysts of the knee with peripheral or no tear of the medial meniscus, especially if the cysts are large and multiloculated. PMID- 28580266 TI - Open Patellar Tendon Tenotomy, Debridement, and Repair Technique Augmented With Platelet-Rich Plasma for Recalcitrant Patellar Tendinopathy. AB - Patellar tendinopathy is a disabling condition that frequently affects the athletic population, especially athletes undergoing repetitive impact forces as a result of jumping and landing activities. Most cases are initially treated conservatively, but if symptoms persist, surgical treatment is warranted. Options for surgical treatment include both arthroscopic and open techniques. The purpose of this Technical Note is to detail our open patellar tendon tenotomy, debridement, and repair technique augmented with platelet-rich plasma. PMID- 28580270 TI - Anatomical Glenoid Reconstruction Using Fresh Osteochondral Distal Tibia Allograft After Failed Latarjet Procedure. AB - In the treatment of recurrent anterior glenohumeral instability, the Latarjet procedure has been shown to fail. This results in a need for viable revisional procedures for patients who present with this challenging pathology. We report our preferred technique for anatomical glenoid reconstruction using a fresh osteochondral distal tibia allograft after a failed Latarjet procedure. This bony augmentation technique employs a readily available dense, weight-bearing osseous tissue source that has excellent conformity, as well as the added benefit of a cartilaginous surface to correct chondral deficiencies. Given its effectiveness in the Latarjet revision setting and low complication rate, the distal tibia allograft is a reasonable treatment option. PMID- 28580269 TI - Complete Arthroscopic Synovectomy in Management of Recalcitrant Septic Arthritis of the Knee Joint. AB - Septic arthritis of the knee is a potentially life-threatening condition and can be associated with many late complications. The key of success of management of septic arthritis of the knee joint is early aggressive treatment of surgical debridement and decompression and antibiotic therapy. In adults, arthroscopic drainage with synovectomy is the treatment of choice in septic arthritis of the knee, with lower rates of infectious recurrence than needle aspiration and better functional results than open surgery. Repeated arthroscopic debridement and drainage is needed in case of delayed treatment with an advanced arthroscopic stage of the infection, early unfavorable course, or multiresistant germ. In these situations, synovectomy should be as complete as possible to maximize the reduction of the bacterial burden and avoid the need of further debridement. The purpose of this Technical Note is to describe the details of complete arthroscopic synovectomy of the knee joint. This includes 2 circles of circumferential synovectomy. One circle is in the axial plane and includes the intercondylar notch, anterior, posterior, medial, and lateral compartments. The other circle is in the coronal plane and includes the supra-patellar pouch, medial and lateral recesses, and the anterior compartment. PMID- 28580271 TI - Meniscal Allograft Transplantation With Soft Tissue in Bone Socket Fixation: Arthroscopic Technique With Technical Pearls. AB - Meniscal allograft transplantation may slow the progression of degenerative changes in the meniscus-deficient knee. The current literature suggests patients can experience good early to mid-term satisfaction and patient-reported outcomes with reasonable expectations of return to work. More ambitious applications in athletes have also shown good results although long-term data are lacking. Traditionally, meniscal allograft transplantation has been considered an open procedure with incorporation of bone blocks from the allograft source. However, as arthroscopic techniques have advanced, it has become possible to perform this procedure through a predominantly arthroscopic approach while securing the soft tissue graft in bone tunnels. The current demonstration provides this background and technical pearls for success in arthroscopic meniscal allograft transplantation. PMID- 28580272 TI - Proximal Patellar Tendon Repair: Internal Brace Technique With Unicortical Buttons and Suture Tape. AB - Patellar tendon ruptures may be considerably limiting, especially in younger and highly active patients. These injuries ultimately result in a complete inability to maintain extension of the knee, thereby placing strict impediment on physical activity. As a result, a durable repair construct via surgery is necessary to allow patients to return to their preinjury activity level. Because of the inherent difficulty in maintaining patellar tendon position after repair, and to avoid failure of the tendon healing to the patella, we recommend using an internal brace construct. The construct uses bone tunnels in the patella and also cortical buttons on the tibia with suture tape whipstitched through the tendon. We feel that this provides an enhanced fixation construct. The purpose of this Technical Note is to describe our preferred method for proximal patellar tendon repair via an internal brace construct with unicortical buttons and suture tape. PMID- 28580273 TI - All-Suture Repair for Compressive Rotator Cuff Tears: Reducing the Traction of the Tissue. AB - Tears of the rotator cuff are a frequent pathology, but the best surgical procedure remains unclear. The arthroscopic approach has become the gold standard, but there are many different suture configurations that can be used. We describe an all-suture repair system with which the anatomical reduction of the rotator cuff is achieved performing traction from the anchor of the lateral row to subsequently performing a suture bridge suture from the medial row. The major advantage of this technique is that it creates compression forces and minimizing tensioning of the tissue. PMID- 28580274 TI - Hip Arthroscopy Capsular Closure: The Figure of Eight Technique. AB - Hip arthroscopy techniques have continued to evolve for femoroacetabular impingement and other intra-articular pathologies. However, there is still debate about the importance and technique of routine capsular closure. We present an efficient and reliable technique for creating a watertight capsular closure to prevent iatrogenic macro and microinstability. This Technical Note details our stepwise technique using figure of eight sutures to obtain a complete and secure capsular closure. PMID- 28580275 TI - Forecasting Trends in Disability in a Super-Aging Society: Adapting the Future Elderly Model to Japan. AB - Japan has experienced pronounced population aging, and now has the highest proportion of elderly adults in the world. Yet few projections of Japan's future demography go beyond estimating population by age and sex to forecast the complex evolution of the health and functioning of the future elderly. This study estimates a new state-transition microsimulation model - the Japanese Future Elderly Model (FEM) - for Japan. We use the model to forecast disability and health for Japan's future elderly. Our simulation suggests that by 2040, over 27 percent of Japan's elderly will exhibit 3 or more limitations in IADLs and social functioning; almost one in 4 will experience difficulties with 3 or more ADLs; and approximately one in 5 will suffer limitations in cognitive or intellectual functioning. Since the majority of the increase in disability arises from the aging of the Japanese population, prevention efforts that reduce age-specific morbidity can help reduce the burden of disability but may have only a limited impact on reducing the overall prevalence of disability among Japanese elderly. While both age and morbidity contribute to a predicted increase in disability burden among elderly Japanese in the future, our simulation results suggest that the impact of population aging exceeds the effect of age-specific morbidity on increasing disability in Japan's future. PMID- 28580276 TI - The dynamics of physical and mental health in the older population. AB - Mental and physical aspects are both integral to health but little is known about the dynamic relationship between them. We consider the dynamic relationship between mental and physical health using a sample of 11,203 individuals in six waves (2002-2013) of the English Longitudinal Study of Ageing (ELSA). We estimate conditional linear and non-linear random-effects regression models to identify the effects of past physical health, measured by Activities of Daily Living (ADL), and past mental health, measured by the Centre for Epidemiological Studies Depression (CES-D) scale, on both present physical and mental health. We find that both mental and physical health are moderately state-dependent. Better past mental health increases present physical health significantly. Better past physical health has a larger effect on present mental health. Past mental health has stronger effects on present physical health than physical activity or education. It explains 2.0% of the unobserved heterogeneity in physical health. Past physical health has stronger effects on present mental health than health investments, income or education. It explains 0.4% of the unobserved heterogeneity in mental health. These cross-effects suggest that health policies aimed at specific aspects of health should consider potential spill-over effects. PMID- 28580277 TI - Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion. AB - OBJECTIVES: Genome-wide association studies (GWAS) have identified >100 loci independently contributing to type 2 diabetes (T2D) risk. However, translational implications for precision medicine and for the development of novel treatments have been disappointing, due to poor knowledge of how these loci impact T2D pathophysiology. Here, we aimed to measure the expression of genes located nearby T2D associated signals and to assess their effect on insulin secretion from pancreatic beta cells. METHODS: The expression of 104 candidate T2D susceptibility genes was measured in a human multi-tissue panel, through PCR-free expression assay. The effects of the knockdown of beta-cell enriched genes were next investigated on insulin secretion from the human EndoC-betaH1 beta-cell line. Finally, we performed RNA-sequencing (RNA-seq) so as to assess the pathways affected by the knockdown of the new genes impacting insulin secretion from EndoC betaH1, and we analyzed the expression of the new genes in mouse models with altered pancreatic beta-cell function. RESULTS: We found that the candidate T2D susceptibility genes' expression is significantly enriched in pancreatic beta cells obtained by laser capture microdissection or sorted by flow cytometry and in EndoC-betaH1 cells, but not in insulin sensitive tissues. Furthermore, the knockdown of seven T2D-susceptibility genes (CDKN2A, GCK, HNF4A, KCNK16, SLC30A8, TBC1D4, and TCF19) with already known expression and/or function in beta cells changed insulin secretion, supporting our functional approach. We showed first evidence for a role in insulin secretion of four candidate T2D-susceptibility genes (PRC1, SRR, ZFAND3, and ZFAND6) with no previous knowledge of presence and function in beta cells. RNA-seq in EndoC-betaH1 cells with decreased expression of PRC1, SRR, ZFAND6, or ZFAND3 identified specific gene networks related to T2D pathophysiology. Finally, a positive correlation between the expression of Ins2 and the expression of Prc1, Srr, Zfand6, and Zfand3 was found in mouse pancreatic islets with altered beta-cell function. CONCLUSIONS: This study showed the ability of post-GWAS functional studies to identify new genes and pathways involved in human pancreatic beta-cell function and in T2D pathophysiology. PMID- 28580278 TI - FGF21 does not require adipocyte AMP-activated protein kinase (AMPK) or the phosphorylation of acetyl-CoA carboxylase (ACC) to mediate improvements in whole body glucose homeostasis. AB - OBJECTIVE: Fibroblast growth factor 21 (FGF21) shows great potential for the treatment of obesity and type 2 diabetes, as its long-acting analogue reduces body weight and improves lipid profiles of participants in clinical studies; however, the intracellular mechanisms mediating these effects are poorly understood. AMP-activated protein kinase (AMPK) is an important energy sensor of the cell and a molecular target for anti-diabetic medications. This work examined the role of AMPK in mediating the glucose and lipid-lowering effects of FGF21. METHODS: Inducible adipocyte AMPK beta1beta2 knockout mice (ibeta1beta2AKO) and littermate controls were fed a high fat diet (HFD) and treated with native FGF21 or saline for two weeks. Additionally, HFD-fed mice with knock-in mutations on the AMPK phosphorylation sites of acetyl-CoA carboxylase (ACC)1 and ACC2 (DKI mice) along with wild-type (WT) controls received long-acting FGF21 for two weeks. RESULTS: Consistent with previous studies, FGF21 treatment significantly reduced body weight, adiposity, and liver lipids in HFD fed mice. To add, FGF21 improved circulating lipids, glycemic control, and insulin sensitivity. These effects were independent of adipocyte AMPK and were not associated with changes in browning of white (WAT) and brown adipose tissue (BAT). Lastly, we assessed whether FGF21 exerted its effects through the AMPK/ACC axis, which is critical in the therapeutic benefits of the anti-diabetic medication metformin. ACC DKI mice had improved glucose and insulin tolerance and a reduction in body weight, body fat and hepatic steatosis similar to WT mice in response to FGF21 administration. CONCLUSIONS: These data illustrate that the metabolic improvements upon FGF21 administration are independent of adipocyte AMPK, and do not require the inhibitory action of AMPK on ACC. This is in contrast to the anti-diabetic medication metformin and suggests that the treatment of obesity and diabetes with the combination of FGF21 and AMPK activators merits consideration. PMID- 28580280 TI - Rasal2 deficiency reduces adipogenesis and occurrence of obesity-related disorders. AB - OBJECTIVE: Identification of additional regulatory factors involved in the onset of obesity is important to understand the mechanisms underlying this prevailing disease and its associated metabolic disorders and to develop therapeutic strategies. Through isolation and analysis of a mutant, we aimed to uncover the function of a Ras-GAP gene, Rasal2 (Ras protein activator like 2), in the development of obesity and related metabolic disorders and to obtain valuable insights regarding the mechanism underlying the function. METHODS: An obesity based genetic screen was performed to identify an insertional mutation that disrupts the expression of Rasal2 (Rasal2PB/PB mice). Important metabolic parameters, such as fat mass and glucose tolerance, were measured in Rasal2PB/PB mice. The impact of Rasal2 on adipogenesis was evaluated in the mutant mice and in 3T3-L1 preadipocytes treated with Rasal2 siRNA. Ras and ERK activities were then evaluated in Rasal2-deficient preadipocytes or mice, and their functional relationships with Rasal2 on adipogenesis were investigated by employing Ras and MEK inhibitors. RESULTS: Rasal2PB/PB mice showed drastic decrease in Rasal2 expression and a lean phenotype. The mutant mice displayed decreased adiposity and resistance to high-fat diet induced metabolic disorders. Further analysis indicated that Rasal2 deficiency leads to impaired adipogenesis in vivo and in vitro. Moreover, while Rasal2 deficiency resulted in increased activity of both Ras and ERK in preadipocytes, reducing Ras, but not ERK, suppressed the impaired adipogenesis. CONCLUSIONS: Rasal2 promotes adipogenesis, which may critically contribute to its role in the development of obesity and related metabolic disorders and may do so by repressing Ras activity in an ERK-independent manner. PMID- 28580279 TI - Brown adipose tissue (BAT) specific vaspin expression is increased after obesogenic diets and cold exposure and linked to acute changes in DNA methylation. AB - OBJECTIVE: Several studies have demonstrated anti-diabetic and anti-obesogenic properties of visceral adipose tissue-derived serine protease inhibitor (vaspin) and so evoked its potential use for treatment of obesity-related diseases. The aim of the study was to unravel physiological regulators of vaspin expression and secretion with a particular focus on its role in brown adipose tissue (BAT) biology. METHODS: We analyzed the effects of obesogenic diets and cold exposure on vaspin expression in liver and white and brown adipose tissue (AT) and plasma levels. Vaspin expression was analyzed in isolated white and brown adipocytes during adipogenesis and in response to adrenergic stimuli. DNA-methylation within the vaspin promoter was analyzed to investigate acute epigenetic changes after cold-exposure in BAT. RESULTS: Our results demonstrate a strong induction of vaspin mRNA and protein expression specifically in BAT of both cold-exposed and high-fat (HF) or high-sugar (HS) fed mice. While obesogenic diets also upregulated hepatic vaspin mRNA levels, cold exposure tended to increase vaspin gene expression of inguinal white adipose tissue (iWAT) depots. Concomitantly, vaspin plasma levels were decreased upon obesogenic or thermogenic triggers. Vaspin expression was increased during adipogenesis but unaffected by sympathetic activation in brown adipocytes. Analysis of vaspin promoter methylation in AT revealed lowest methylation levels in BAT, which were acutely reduced after cold exposure. CONCLUSIONS: Our data demonstrate a novel BAT-specific regulation of vaspin gene expression upon physiological stimuli in vivo with acute epigenetic changes that may contribute to cold-induced expression in BAT. We conclude that these findings indicate functional relevance and potentially beneficial effects of vaspin in BAT function. PMID- 28580281 TI - Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway. AB - OBJECTIVE: Glucagon-like peptides (GLPs) are secreted from enteroendocrine cells in response to nutrients and bile acids and control metabolism via actions on structurally-related yet distinct G protein coupled receptors. GLP-1 regulates gut motility, appetite, islet function, and glucose homeostasis, whereas GLP-2 enhances intestinal nutrient absorption. GLP-1R agonists are used to treat diabetes and obesity, and a GLP-2R agonist is approved to treat short bowel syndrome. Unexpectedly, reports of gallbladder disease have been associated with the use of both GLP-1R and GLP-2R agonists and after bariatric surgery, although the mechanisms remain unknown. METHODS: We investigated whether GLP-1 or GLP-2 acutely controls gallbladder (GB) volume and whether GLP-2 regulates GB muscle activity in mice. The expression of Tgr5, Glp2r, and Glp1r was assessed in mouse GB, and the effects of GLP-2 on hepatic bile acid (BA) flow, intestinal and liver BA uptake, and GB gene expression were determined. GLP-2 regulation of GB volume was assessed in wildtype, Glp2r-/- and Tgr5-/- mice. The effect of GLP-2 on GB smooth muscle (GBSM) calcium transients was characterized ex vivo. RESULTS: Acute administration of the GLP-1R agonist exendin-4 lowered glucose but had no effect on GB volume in mice. In contrast, GLP-2 rapidly enhanced GB filling in a dose dependent manner, actions maintained in the presence of cholecystokinin, and mediated through the canonical GLP-2R. GLP-2 also rapidly induced immediate early gene expression in GB, consistent with detection of the endogenous Glp2r in GB RNA. The ability of GLP-2 to increase GB volume was not abrogated by systemic administration of hexamethonium, propranolol, a vasoactive peptide receptor antagonist or N-Nitroarginine methyl ester, and was maintained in Tgr5-/- mice. In contrast, lithocholic acid, a Tgr5 agonist, increased GB filling in Glp2r-/- but not in Tgr5-/- mice. GLP-2 had no effect on ileal uptake or hepatic clearance of taurocholic acid or on hepatic bile flow, yet reduced the frequency of spontaneous calcium transients in murine GBSM ex vivo, in a tetrodotoxin sensitive manner. CONCLUSIONS: Our data extend endocrine concepts of regulation of GB filling beyond FXR-FGF15/19 and the direct effects of BA via Tgr5, to encompass a novel BA-Tgr5-L cell GLP-2 axis providing nutrient-mediated feedback from BA to terminate meal-related GB contraction. These findings have implications for conditions characterized by elevated circulating levels of GLP-2 such as after bariatric surgery and the development and use of agents that promote Tgr5 activation, L cell secretion, or GLP-2R agonism for the treatment of metabolic disease. PMID- 28580283 TI - Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic beta cells. AB - OBJECTIVE: The transcription factors (TF) Foxa2 and Pdx1 are key regulators of beta-cell (beta-cell) development and function. Mutations of these TFs or their respective cis-regulatory consensus binding sites have been linked to maturity diabetes of the young (MODY), pancreas agenesis, or diabetes susceptibility in human. Although Foxa2 has been shown to directly regulate Pdx1 expression during mouse embryonic development, the impact of this gene regulatory interaction on postnatal beta-cell maturation remains obscure. METHODS: In order to easily monitor the expression domains of Foxa2 and Pdx1 and analyze their functional interconnection, we generated a novel double knock-in homozygous (FVFPBFDHom) fluorescent reporter mouse model by crossing the previously described Foxa2-Venus fusion (FVF) with the newly generated Pdx1-BFP (blue fluorescent protein) fusion (PBF) mice. RESULTS: Although adult PBF homozygous animals exhibited a reduction in expression levels of Pdx1, they are normoglycemic. On the contrary, despite normal pancreas and endocrine development, the FVFPBFDHom reporter male animals developed hyperglycemia at weaning age and displayed a reduction in Pdx1 levels in islets, which coincided with alterations in beta-cell number and islet architecture. The failure to establish mature beta-cells resulted in loss of beta cell identity and trans-differentiation towards other endocrine cell fates. Further analysis suggested that Foxa2 and Pdx1 genetically and functionally cooperate to regulate maturation of adult beta-cells. CONCLUSIONS: Our data show that the maturation of pancreatic beta-cells requires the cooperative function of Foxa2 and Pdx1. Understanding the postnatal gene regulatory network of beta-cell maturation will help to decipher pathomechanisms of diabetes and identify triggers to regenerate dedifferentiated beta-cell mass. PMID- 28580282 TI - Hepatic gene therapy rescues high-fat diet responses in circadian Clock mutant mice. AB - OBJECTIVE: Circadian Clock gene mutant mice show dampened 24-h feeding rhythms and an increased sensitivity to high-fat diet (HFD) feeding. Restricting HFD access to the dark phase counteracts its obesogenic effect in wild-type mice. The extent to which altered feeding rhythms are causative for the obesogenic phenotype of Clock mutant mice, however, remains unknown. METHODS: Metabolic parameters of wild-type (WT) and ClockDelta19 mutant mice (MT) were investigated under ad libitum and nighttime restricted HFD feeding. Liver circadian clock function was partially rescued by hydrodynamic tail vein delivery of WT-Clock DNA vectors in mutant mice and transcriptional, metabolic, endocrine and behavioral rhythms studied. RESULTS: Nighttime-restricted feeding restored food intake, but not body weight regulation in MT mice under HFD, suggesting Clock-dependent metabolic dysregulation downstream of circadian appetite control. Liver-directed Clock gene therapy partially restored liver circadian oscillator function and transcriptome regulation without affecting centrally controlled circadian behaviors. Under HFD, MT mice with partially restored liver clock function (MT LR) showed normalized body weight gain, rescued 24-h food intake rhythms, and WT like energy expenditure. This was associated with decreased nighttime leptin and daytime ghrelin levels, reduced hepatic lipid accumulation, and improved glucose tolerance. Transcriptome analysis revealed that hepatic Clock rescue in MT mice affected a range of metabolic pathways. CONCLUSION: Liver Clock gene therapy improves resistance against HFD-induced metabolic impairments in mice with circadian clock disruption. Restoring or stabilizing liver clock function might be a promising target for therapeutic interventions in obesity and metabolic disorders. PMID- 28580285 TI - Opposing effects of prostaglandin E2 receptors EP3 and EP4 on mouse and human beta-cell survival and proliferation. AB - OBJECTIVE: Hyperglycemia and systemic inflammation, hallmarks of Type 2 Diabetes (T2D), can induce the production of the inflammatory signaling molecule Prostaglandin E2 (PGE2) in islets. The effects of PGE2 are mediated by its four receptors, E-Prostanoid Receptors 1-4 (EP1-4). EP3 and EP4 play opposing roles in many cell types due to signaling through different G proteins, Gi and GS, respectively. We previously found that EP3 and EP4 expression are reciprocally regulated by activation of the FoxM1 transcription factor, which promotes beta cell proliferation and survival. Our goal was to determine if EP3 and EP4 regulate beta-cell proliferation and survival and, if so, to elucidate the downstream signaling mechanisms. METHODS: beta-cell proliferation was assessed in mouse and human islets ex vivo treated with selective agonists and antagonists for EP3 (sulprostone and DG-041, respectively) and EP4 (CAY10598 and L-161,982, respectively). beta-cell survival was measured in mouse and human islets treated with the EP3- and EP4-selective ligands in conjunction with a cytokine cocktail to induce cell death. Changes in gene expression and protein phosphorylation were analyzed in response to modulation of EP3 and EP4 activity in mouse islets. RESULTS: Blockade of EP3 enhanced beta-cell proliferation in young, but not old, mouse islets in part through phospholipase C (PLC)-gamma1 activity. Blocking EP3 also increased human beta-cell proliferation. EP4 modulation had no effect on ex vivo proliferation alone. However, blockade of EP3 in combination with activation of EP4 enhanced human, but not mouse, beta-cell proliferation. In both mouse and human islets, EP3 blockade or EP4 activation enhanced beta-cell survival in the presence of cytokines. EP4 acts in a protein kinase A (PKA)-dependent manner to increase mouse beta-cell survival. In addition, the positive effects of FoxM1 activation on beta-cell survival are inhibited by EP3 and dependent on EP4 signaling. CONCLUSIONS: Our results identify EP3 and EP4 as novel regulators of beta-cell proliferation and survival in mouse and human islets ex vivo. PMID- 28580284 TI - NNT reverse mode of operation mediates glucose control of mitochondrial NADPH and glutathione redox state in mouse pancreatic beta-cells. AB - OBJECTIVE: The glucose stimulation of insulin secretion (GSIS) by pancreatic beta cells critically depends on increased production of metabolic coupling factors, including NADPH. Nicotinamide nucleotide transhydrogenase (NNT) typically produces NADPH at the expense of NADH and DeltapH in energized mitochondria. Its spontaneous inactivation in C57BL/6J mice was previously shown to alter ATP production, Ca2+ influx, and GSIS, thereby leading to glucose intolerance. Here, we tested the role of NNT in the glucose regulation of mitochondrial NADPH and glutathione redox state and reinvestigated its role in GSIS coupling events in mouse pancreatic islets. METHODS: Islets were isolated from female C57BL/6J mice (J-islets), which lack functional NNT, and genetically close C57BL/6N mice (N islets). Wild-type mouse NNT was expressed in J-islets by adenoviral infection. Mitochondrial and cytosolic glutathione oxidation was measured with glutaredoxin 1-fused roGFP2 probes targeted or not to the mitochondrial matrix. NADPH and NADH redox state was measured biochemically. Insulin secretion and upstream coupling events were measured under dynamic or static conditions by standard procedures. RESULTS: NNT is largely responsible for the acute glucose-induced rise in islet NADPH/NADP+ ratio and decrease in mitochondrial glutathione oxidation, with a small impact on cytosolic glutathione. However, contrary to current views on NNT in beta-cells, these effects resulted from a glucose-dependent reduction in NADPH consumption by NNT reverse mode of operation, rather than from a stimulation of its forward mode of operation. Accordingly, the lack of NNT in J-islets decreased their sensitivity to exogenous H2O2 at non-stimulating glucose. Surprisingly, the lack of NNT did not alter the glucose-stimulation of Ca2+ influx and upstream mitochondrial events, but it markedly reduced both phases of GSIS by altering Ca2+-induced exocytosis and its metabolic amplification. CONCLUSION: These results drastically modify current views on NNT operation and mitochondrial function in pancreatic beta-cells. PMID- 28580287 TI - Insulin controls food intake and energy balance via NPY neurons. AB - OBJECTIVES: Insulin signaling in the brain has been implicated in the control of satiety, glucose homeostasis and energy balance. However, insulin signaling is dispensable in energy homeostasis controlling AgRP or POMC neurons and it is unclear which other neurons regulate these effects. Here we describe an ancient insulin/NPY neuronal network that governs energy homeostasis across phyla. METHODS: To address the role of insulin action specifically in NPY neurons, we generated a variety of models by selectively removing insulin signaling in NPY neurons in flies and mice and testing the consequences on energy homeostasis. RESULTS: By specifically targeting the insulin receptor in both fly and mouse NPY expressing neurons, we found NPY-specific insulin signaling controls food intake and energy expenditure, and lack of insulin signaling in NPY neurons leads to increased energy stores and an obese phenotype. Additionally, the lack of insulin signaling in NPY neurons leads to a dysregulation of GH/IGF-1 axis and to altered insulin sensitivity. CONCLUSIONS: Taken together, these results suggest that insulin actions in NPY neurons is critical for maintaining energy balance and an impairment of this pathway may be causally linked to the development of metabolic diseases. PMID- 28580286 TI - Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development. AB - OBJECTIVE: Poor fetal nutrition increases the risk of type 2 diabetes in the offspring at least in part by reduced embryonic beta-cell growth and impaired function. However, it is not entirely clear how fetal nutrients and growth factors impact beta-cells during development to alter glucose homeostasis and metabolism later in life. The current experiments aimed to test the impact of fetal nutrients and growth factors on endocrine development and how these signals acting on mTOR signaling regulate beta-cell mass and glucose homeostasis. METHOD: Pancreatic rudiments in culture were used to study the role of glucose, growth factors, and amino acids on beta-cell development. The number and proliferation of pancreatic and endocrine progenitor were assessed in the presence or absence of rapamycin. The impact of mTOR signaling in vivo on pancreas development and glucose homeostasis was assessed in models deficient for mTOR or Raptor in Pdx1 expressing pancreatic progenitors. RESULTS: We found that amino acid concentrations, and leucine in particular, enhance the number of pancreatic and endocrine progenitors and are essential for growth factor induced proliferation. Rapamycin, an mTORC1 complex inhibitor, reduced the number and proliferation of pancreatic and endocrine progenitors. Mice lacking mTOR in pancreatic progenitors exhibited hyperglycemia in neonates, hypoinsulinemia and pancreatic agenesis/hypoplasia with pancreas rudiments containing ductal structures lacking differentiated acinar and endocrine cells. In addition, loss of mTORC1 by deletion of raptor in pancreatic progenitors reduced pancreas size with reduced number of beta-cells. CONCLUSION: Together, these results suggest that amino acids concentrations and in particular leucine modulates growth responses of pancreatic and endocrine progenitors and that mTOR signaling is critical for these responses. Inactivation of mTOR and raptor in pancreatic progenitors suggested that alterations in some of the components of this pathway during development could be a cause of pancreatic agenesis/hypoplasia and hyperglycemia. PMID- 28580288 TI - Restoration of Lepr in beta cells of Lepr null mice does not prevent hyperinsulinemia and hyperglycemia. AB - OBJECTIVE: The adipose-derived hormone leptin plays an important role in regulating body weight and glucose homeostasis. Leptin receptors are expressed in the central nervous system as well as peripheral tissues involved in regulating glucose homeostasis, including insulin-producing beta cells of the pancreas. Previous studies assessing the role of leptin receptors in beta cells used Cre loxP to disrupt the leptin receptor gene (Lepr) in beta cells, but variable results were obtained. Furthermore, recombination of Lepr was observed in the hypothalamus or exocrine pancreas, in addition to the beta cells, and Lepr in non beta cells may have compensated for the loss of Lepr in beta cells, thus making it difficult to assess the direct effects of Lepr in beta cells. To determine the significance of Lepr exclusively in beta cells, we chose to selectively restore Lepr in beta cells of Lepr null mice (LeprloxTB/loxTB). MATERIALS AND METHODS: We used a mouse model in which endogenous expression of Lepr was disrupted by a loxP flanked transcription blocker (LeprloxTB/loxTB), but was restored by Cre recombinase knocked into the Ins1 gene, which is specifically expressed in beta cells (Ins1Cre). We bred LeprloxTB/loxTB and Ins1Cre mice to generate LeprloxTB/loxTB and LeprloxTB/loxTBIns1Cre mice, as well as Leprwt/wt and Leprwt/wtIns1Cre littermate mice. Male and female mice were weighed weekly between 6 and 11 weeks of age and fasting blood glucose was measured during this time. Oral glucose was administered to mice aged 7-12 weeks to assess glucose tolerance and insulin secretion. Relative beta and alpha cell area and islet size were also assessed by immunostaining and analysis of pancreas sections of 12-14 week old mice. RESULTS: Male and female LeprloxTB/loxTB mice, lacking whole-body expression of Lepr, had a phenotype similar to db/db mice characterized by obesity, hyperinsulinemia, glucose intolerance, and impaired glucose stimulated insulin secretion. Despite restoring Lepr in beta cells of LeprloxTB/loxTB mice, fasting insulin levels, blood glucose levels and body weight were comparable between LeprloxTB/loxTBIns1Cre mice and LeprloxTB/loxTB littermates. Furthermore, glucose tolerance and insulin secretion in male and female LeprloxTB/loxTBIns1Cre mice were similar to that observed in LeprloxTB/loxTB mice. Analysis of pancreatic insulin positive area revealed that restoration of Lepr in beta cells of LeprloxTB/loxTB mice did not prevent hyperplasia of insulin positive cells nor did it rescue Glut-2 expression. CONCLUSION: Collectively, these data suggest that direct action of leptin on beta cells is insufficient to restore normal insulin secretion and glucose tolerance in mice without leptin receptor signaling elsewhere. PMID- 28580289 TI - Endocannabinoid-dependent disinhibition of orexinergic neurons: Electrophysiological evidence in leptin-knockout obese mice. AB - OBJECTIVES: In the ob/ob mouse model of obesity, chronic absence of leptin causes a significant increase of orexin (OX) production by hypothalamic neurons and excessive food intake. The altered OX level is linked to a dramatic increase of the inhibitory innervation of OX producing neurons (OX neurons) and the over expression of the endocannabinoid 2-arachidonoylglycerol (2-AG) by OX neurons of ob/ob mice. Little is known about the function of the excitatory synapses of OX neurons in ob/ob mice, and their modulation by 2-AG. In the present study, we fill this gap and provide the first evidence of the overall level of activation of OX neurons in the ob/ob mice. METHODS: We performed in vitro whole-cell patch clamp recordings on OX neurons located in the perifornical area of the lateral hypothalamus in acute brain slices of wt and ob/ob mice. We identified OX neurons on the basis of their electrophysiological membrane properties, with 96% of concordance with immunohistochemisty. RESULTS: We found that OX neurons of ob/ob mice are innervated by less efficient and fewer excitatory synapses than wt mice. Consequently, ob/ob OX neurons show more negative resting membrane potential and lower action potential firing frequency than wt. The bath application of the cannabinoid type-1 receptor agonist WIN55,212-2, depresses both the excitatory and the inhibitory synapses in ob/ob animals, but only the excitatory synapses in wt animals. Finally, the physiologic release of 2-AG induces a prevalent depression of inhibition (disinhibition) of OX neurons in ob/ob animals but not in wt. CONCLUSIONS: In ob/ob mice, chronic absence of leptin induces a 2-AG mediated functional disinhibition of OX neurons. This helps explain the increase of OX production and, consequently, the excessive food intake of ob/ob mice. PMID- 28580290 TI - FGF21 resistance is not mediated by downregulation of beta-klotho expression in white adipose tissue. AB - OBJECTIVE: Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates metabolic homeostasis. Previous work has suggested that impairment of FGF21 signaling in adipose tissue may occur through downregulation of the obligate FGF21 co-receptor, beta-klotho, which leads to "FGF21 resistance" during the onset of diet-induced obesity. Here, we sought to determine whether maintenance of beta-klotho expression in adipose tissue prevents FGF21 resistance and whether other mechanisms also contribute to FGF21 resistance in vivo. METHODS: We generated adipose-specific beta-klotho transgenic mice to determine whether maintenance of beta-klotho expression in adipose tissue prevents FGF21 resistance in vivo. RESULTS: beta-klotho protein levels are markedly decreased in white adipose tissue, but not liver or brown adipose tissue, during diet-induced obesity. Maintenance of beta-klotho protein expression in adipose tissue does not alleviate impaired FGF21 signaling in white adipose or increase FGF21 sensitivity in vivo. CONCLUSIONS: In white adipose tissue, downregulation of beta-klotho expression is not the major mechanism contributing to impaired FGF21 signaling in white adipose tissue. PMID- 28580291 TI - beta3-Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: Mediation through the mTOR pathway. AB - OBJECTIVE: Today, the presence and activity of brown adipose tissue (BAT) in adult humans is generally equated with the induced accumulation of [2-18F]2 fluoro-2-deoxy-d-glucose ([18F]FDG) in adipose tissues, as investigated by positron emission tomography (PET) scanning. In reality, PET-FDG is currently the only method available for in vivo quantification of BAT activity in adult humans. The underlying assumption is that the glucose uptake reflects the thermogenic activity of the tissue. METHODS: To examine this basic assumption, we here followed [18F]FDG uptake by PET and by tissue [3H]-2-deoxy-d-glucose uptake in wildtype and UCP1(-/-) mice, i.e. in mice that do or do not possess the unique thermogenic and calorie-consuming ability of BAT. RESULTS: Unexpectedly, we found that beta3-adrenergically induced (by CL-316,243) glucose uptake was UCP1 independent. Thus, whereas PET-FDG scans adequately reflect glucose uptake, this acute glucose uptake is not secondary to thermogenesis but is governed by an independent cellular signalling, here demonstrated to be mediated via the previously described KU-0063794-sensitive mTOR pathway. CONCLUSIONS: Thus, PET FDG scans do not exclusively reveal active BAT deposits but rather any tissue possessing an adrenergically-mediated glucose uptake pathway. In contrast, we found that the marked glucose uptake-ameliorating effect of prolonged beta3 adrenergic treatment was UCP1 dependent. Thus, therapeutically, UCP1 activity is required for any anti-diabetic effect of BAT activation. PMID- 28580292 TI - Non-invasive, multimodal analysis of cortical activity, blood volume and neurovascular coupling in infantile spasms using EEG-fNIRS monitoring. AB - Although infantile spasms can be caused by a variety of etiologies, the clinical features are stereotypical. The neuronal and vascular mechanisms that contribute to the emergence of infantile spasms are not well understood. We performed a multimodal study by simultaneously recording electroencephalogram and functional Near-infrared spectroscopy in an intentionally heterogeneous population of six children with spasms in clusters. Regardless of the etiology, spasms were accompanied by two phases of hemodynamic changes; an initial change in the cerebral blood volume (simultaneously with each spasm) followed by a neurovascular coupling in all children except for the one with a large porencephalic cyst. Changes in cerebral blood volume, like the neurovascular coupling, occurred over frontal areas in all patients regardless of any brain damage suggesting a diffuse hemodynamic cortical response. The simultaneous motor activation and changes in cerebral blood volume might result from the involvement of the brainstem. The inconstant neurovascular coupling phase suggests a diffuse activation of the brain likely resulting too from the brainstem involvement that might trigger diffuse changes in cortical excitability. PMID- 28580297 TI - Comparison of natural and artificial odor lures for nilgai (Boselaphus tragocamelus) and white-tailed deer (Odocoileus virginianus) in South Texas: Developing treatment for cattle fever tick eradication. AB - Cattle fever ticks (CFT), vectors of bovine babesiosis and anaplasmosis, were eradicated from the United States by 1943, but are frequently reintroduced from neighboring border states of Mexico via stray cattle and wildlife hosts including white-tailed deer (Odocoileus virginianus) (WTD) and nilgai antelope (Boselaphus tragocamelus). Nilgai antelope are exotic bovids from India that are hosts of CFT, have large home ranges as compared to WTD, thus have the potential to spread CFT through the landscape. Currently, there are no methods to control CFT on nilgai. Odor lures were evaluated to determine if nilgai could be attracted to a central point for development of control methods. Four treatments, nilgai offal a natural odor lure was used as the positive control; and compared to three artificial odors; screw worm lure, volatile fatty acids, citronella oil. Studies were conducted on a free-ranging population of nilgai at the East Foundation's Santa Rosa Ranch (Kenedy Co., near Riviera, Texas, USA). Game cameras were used to document visitation to the lures. In the ten randomly placed transects, 110 nilgai and 104 WTD were photographed. Offal had significantly more visits by nilgai (71% of total visits) than screwworm (15%), VFA (11%), and citronella (4%). For WTD, there was no significant difference in visitation at the lure treatments. PMID- 28580293 TI - Acupuncture modulates the abnormal brainstem activity in migraine without aura patients. AB - Migraine is a common neurological disease with a high prevalence and unsatisfactory treatment options. The specific pathophysiological mechanisms of migraine remain unclear, which restricts the development of effective treatments for this prevalent disorder. The aims of this study were to 1) compare the spontaneous brain activity differences between Migraine without Aura (MwoA) patients and healthy controls (HCs), using amplitude of low-frequency fluctuations (ALFF) calculation method, and 2) explore how an effective treatment (verum acupuncture) could modulate the ALFF of MwoA patients. One hundred MwoA patients and forty-six matched HCs were recruited. Patients were randomized to four weeks' verum acupuncture, sham acupuncture, and waiting list groups. Patients had resting state BOLD-fMRI scan before and after treatment, while HCs only had resting state BOLD-fMRI scan at baseline. Headache intensity, headache frequency, self-rating anxiety and self-rating depression were used for clinical efficacy evaluation. Compared with HCs, MwoA patients showed increased ALFF in posterior insula and putamen/caudate, and reduced ALFF in rostral ventromedial medulla (RVM)/trigeminocervical complex (TCC). After longitudinal verum acupuncture treatment, the decreased ALFF of the RVM/TCC was normalized in migraine patients. Verum acupuncture and sham acupuncture have different modulation effects on ALFF of RVM/TCC in migraine patients. Our results suggest that impairment of the homeostasis of the trigeminovascular nociceptive pathway is involved in the neural pathophysiology of migraines. Effective treatments, such as verum acupuncture, could help to restore this imbalance. PMID- 28580294 TI - Gender differences in the structural connectome of the teenage brain revealed by generalized q-sampling MRI. AB - The question of whether there are biological differences between male and female brains is a fraught one, and political positions and prior expectations seem to have a strong influence on the interpretation of scientific data in this field. This question is relevant to issues of gender differences in the prevalence of psychiatric conditions, including autism, attention deficit hyperactivity disorder (ADHD), Tourette's syndrome, schizophrenia, dyslexia, depression, and eating disorders. Understanding how gender influences vulnerability to these conditions is significant. Diffusion magnetic resonance imaging (dMRI) provides a non-invasive method to investigate brain microstructure and the integrity of anatomical connectivity. Generalized q-sampling imaging (GQI) has been proposed to characterize complicated fiber patterns and distinguish fiber orientations, providing an opportunity for more accurate, higher-order descriptions through the water diffusion process. Therefore, we aimed to investigate differences in the brain's structural network between teenage males and females using GQI. This study included 59 (i.e., 33 males and 26 females) age- and education-matched subjects (age range: 13 to 14 years). The structural connectome was obtained by graph theoretical and network-based statistical (NBS) analyses. Our findings show that teenage male brains exhibit better intrahemispheric communication, and teenage female brains exhibit better interhemispheric communication. Our results also suggest that the network organization of teenage male brains is more local, more segregated, and more similar to small-world networks than teenage female brains. We conclude that the use of an MRI study with a GQI-based structural connectomic approach like ours presents novel insights into network-based systems of the brain and provides a new piece of the puzzle regarding gender differences. PMID- 28580298 TI - Camallanus emydidius n. sp. (Nematoda: Camallanidae) in Trachemys dorbigni (Dumeril & Bibron, 1835) (Testudines: Emydidae) from Southern Brazil. AB - This paper describes a new species of Camallanus found in the freshwater turtle Trachemys dorbigni. Sixty hosts collected in Southern Brazil were examined. All hosts (100%) were parasitized by a new species of Camallanus, which was described as Camallanus emydidius n. sp. The new species differs from other Camallanus species of freshwater turtles mainly because of the morphology of the right spicule, the number of male precloacal and postcloacal papillae, and the presence of "mucrons" in the female posterior extremity. PMID- 28580296 TI - Cortical gyrification is abnormal in children with prenatal alcohol exposure. AB - OBJECTIVES: Prenatal alcohol exposure (PAE) adversely affects early brain development. Previous studies have shown a wide range of structural and functional abnormalities in children and adolescents with PAE. The current study adds to the existing literature specifically on cortical development by examining cortical gyrification in a large sample of children with PAE compared to controls. Relationships between cortical development and intellectual functioning are also examined. EXPERIMENTAL DESIGN: Included were 92 children with PAE and 83 controls ages 9-16 from four sites in the Collaborative Initiative on FASD (CIFASD). All PAE participants had documented heavy PAE. All underwent a formal evaluation of physical anomalies and dysmorphic facial features. MRI data were collected using modified matched protocols on three platforms (Siemens, GE, and Philips). Cortical gyrification was examined using a semi-automated procedure. PRINCIPAL OBSERVATIONS: Whole brain group comparisons using Monte Carlo z simulation for multiple comparisons showed significantly lower cortical gyrification across a large proportion of the cerebral cortex amongst PAE compared to controls. Whole brain comparisons and ROI based analyses showed strong positive correlations between cortical gyrification and IQ (i.e. less developed cortex was associated with lower IQ). CONCLUSIONS: Abnormalities in cortical development were seen across the brain in children with PAE compared to controls. Cortical gyrification and IQ were strongly correlated, suggesting that examining mechanisms by which alcohol disrupts cortical formation may yield clinically relevant insights and potential directions for early intervention. PMID- 28580295 TI - Regional brain network organization distinguishes the combined and inattentive subtypes of Attention Deficit Hyperactivity Disorder. AB - Attention Deficit Hyperactivity Disorder (ADHD) is characterized clinically by hyperactive/impulsive and/or inattentive symptoms which determine diagnostic subtypes as Predominantly Hyperactive-Impulsive (ADHD-HI), Predominantly Inattentive (ADHD-I), and Combined (ADHD-C). Neuroanatomically though we do not yet know if these clinical subtypes reflect distinct aberrations in underlying brain organization. We imaged 34 ADHD participants defined using DSM-IV criteria as ADHD-I (n = 16) or as ADHD-C (n = 18) and 28 matched typically developing controls, aged 8-17 years, using high-resolution T1 MRI. To quantify neuroanatomical organization we used graph theoretical analysis to assess properties of structural covariance between ADHD subtypes and controls (global network measures: path length, clustering coefficient, and regional network measures: nodal degree). As a context for interpreting network organization differences, we also quantified gray matter volume using voxel-based morphometry. Each ADHD subtype was distinguished by a different organizational profile of the degree to which specific regions were anatomically connected with other regions (i.e., in "nodal degree"). For ADHD-I (compared to both ADHD-C and controls) the nodal degree was higher in the hippocampus. ADHD-I also had a higher nodal degree in the supramarginal gyrus, calcarine sulcus, and superior occipital cortex compared to ADHD-C and in the amygdala compared to controls. By contrast, the nodal degree was higher in the cerebellum for ADHD-C compared to ADHD-I and in the anterior cingulate, middle frontal gyrus and putamen compared to controls. ADHD-C also had reduced nodal degree in the rolandic operculum and middle temporal pole compared to controls. These regional profiles were observed in the context of no differences in gray matter volume or global network organization. Our results suggest that the clinical distinction between the Inattentive and Combined subtypes of ADHD may also be reflected in distinct aberrations in underlying brain organization. PMID- 28580299 TI - Whole-genome shotgun sequence of phenazine-producing endophytic Streptomyces kebangsaanensis SUK12. AB - Streptomyces sp. produces bioactive compounds with a broad spectrum of activities. Streptomyces kebangsaanesis SUK12 has been identified as a novel endophytic bacteria isolated from ethnomedicinal plant Portulaca olerace, and was found to produce the phenazine class of biologically active antimicrobial metabolites. The potential use of the phenazines has led to our research interest in determining the genome sequence of Streptomyces kebangsaanensis SUK12. This Whole Genome Shotgun project has been deposited at DDBJ/ENA/GenBank under the accession number PRJNA269542. The raw sequence data are available [https://www.ncbi.nlm.nih.gov/Traces/study/?acc=SRP105770]. PMID- 28580300 TI - Resveratrol attenuates triglyceride accumulation associated with upregulation of Sirt1 and lipoprotein lipase in 3T3-L1 adipocytes. AB - AIM: We aimed to investigate the effect of resveratrol (Rsv) on expression of genes regulating triglyceride (TG) accumulation and consumption in differentiated 3T3-L1 preadipocytes. METHODS: 3T3-L1 preadipocytes were cultured in DMEM supplemented with 10% fetal calf serum. Upon reaching confluence, cells were induced to differentiate for 4 days, cultured for 10 days for TG accumulation, and then incubated with Rsv (0, 25 or 50 MUM) for 3 days. TG accumulation was analyzed by Oil Red-O staining. To understand how Rsv regulates TG accumulation and consumption, changes in gene and protein expressions of several factors associated with free fatty acid (FFA) uptake and beta-oxidation were investigated by real-time RT-PCR and Western blot. For further elucidation of underlying mechanisms, we also investigated gene expressions using Sirtuin1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha) siRNA. RESULTS: Rsv dose dependently enhanced Sirt1 expression and reduced TG accumulation. Rsv-induced reduction of TG accumulation was abolished by inhibition of Sirt1 and PGC1alpha. Rsv also enhanced expressions of genes involved in FFA uptake [peroxisome proliferator-activated receptor-gamma (PPARgamma) and lipoprotein lipase] and in beta-oxidation regulation [PGC1-alpha and carnitine palmitoyl-transferase 1a (CPT1a)]. All these effects were abolished by Sirt1 inhibition. CONCLUSION: The present results suggest that Rsv may augment synthesis and oxidation of fatty acid, and possibly increases energy utilization efficiency in adipocytes through activation of Sirt1. The present study may provide meaningful evidence supporting the efficacy of Rsv in the treatment of obesity. PMID- 28580302 TI - Comparative study on the degradation of dibutyl phthalate by two newly isolated Pseudomonas sp. V21b and Comamonas sp. 51F. AB - Dibutyl phthalate is (DBP) the top priority toxicant responsible for carcinogenicity, teratogenicity and endocrine disruption. This study demonstrates the DBP degradation capability of the two newly isolated bacteria from municipal solid waste leachate samples. The isolated bacteria were designated as Pseudomonas sp. V21b and Comamonas sp. 51F after scanning electron microscopy, transmission electron microscopy, Gram-staining, antibiotic sensitivity tests, biochemical characterization, 16S-rRNA gene identification and phylogenetic studies. They were able to grow on DBP, benzyl butyl phthalate, monobutyl phthalate, diisodecyl phthalate, dioctyl phthalate, and protocatechuate. It was observed that Pseudomonas sp. V21b was more efficient in DBP degradation when compared with Comamonas sp. 51F. It degraded 57% and 76% of the initial DBP in minimal salt medium and in DBP contaminated samples respectively. Kinetics for the effects of DBP concentration on Pseudomonas sp. V21b and Comamonas sp. 51F growth was also evaluated. Stoichiometry for DBP degradation and biomass formation were compared for both the isolates. Two major metabolites diethyl phthalate and monobutyl phthalates were identified using GC-MS in the extracts. Key genes were amplified from the genomes of Pseudomonas sp. V21b and Comamonas sp. 51F. DBP degradation pathway was also proposed. PMID- 28580301 TI - Adipose stem cells from obese patients show specific differences in the metabolic regulators vitamin D and Gas5. AB - Adipose tissue is a significant source of mesenchymal stem cells for regenerative therapies; however, caution should be taken as their environmental niche can affect their functional properties. We have previously demonstrated the negative impact of obesity on the function of adipose-derived stem cells (ASCs). Here we have evaluated other possible properties and targets that are altered by obesity such as the recently described long non-coding molecule Gas5, which is involved in glucocorticoid resistance. Using ASCs isolated from obese (oASCs) and control subjects (cASCs), we have analyzed additional metabolic and inflammatory conditions that could be related with their impaired therapeutic potential and consequently their possible usefulness in the clinic. PMID- 28580303 TI - The Role of Bromodomain Testis-Specific Factor, BRDT, in Cancer: A Biomarker and A Possible Therapeutic Target. AB - Cancer cells have recently been shown to activate hundreds of normally silent tissue-restricted genes, including a specific subset associated with cancer progression and poor prognosis. Within these genes, a class of testis-specific genes designed as cancer/testis, attracted special attention because of their oncogenic roles as well as their potential use in immunotherapy. Here we focus on one of these genes encoding the testis-specific member of the bromodomain and extra-terminal (BET) family, known as BRDT. Aberrant activation of BRDT was first detected in lung cancers. In this study, we report that the frequency of BRDT's aberrant activation in lung cancer varies according to the histological subtypes and in contrast with other cancer/testis genes, it is rarely expressed in other solid tumours. The functional characterization of BRDT in its physiological setting in male germ cells is now painting a clear portrait of its normal activity and also suggests possible underlying oncogenic activities, when the gene is ectopically activated in cancers. Also, these functional studies of BRDT point to specific anti-cancer therapeutic strategies that could be used to "high jack" BRDT's action and turn it against cancer cells, which express this gene. Finally, BRDT's expression could be used as a biomarker for cell sensitivity to BET bromodomain inhibitors, which have become newly available as anti-cancer drugs. PMID- 28580305 TI - Expression of hsa-MIR-204, RUNX2, PPARgamma, and BCL2 in Bone Marrow Derived Mesenchymal Stem Cells from Multiple Myeloma Patients and Normal Individuals. AB - OBJECTIVE: Multiple Myeloma (MM) is a heterogeneous cytogenetic disorder in which clonal plasma cells proliferate in the bone marrow (BM) and cause bone destruction. The BM microenvironment plays a crucial role in pathogenesis of this disease, and mesenchymal stem cells (MSCs) are one of the key players. Herein, we propose to investigate the expressions of hsa-MIR-204, runt-related transcription factor 2 (RUNX2), peroxisome proliferator-activated receptor gamma (PPARgamma), and B-cell lymphoma 2 (BCL2) as factors involved in osteogenesis, adipogenesis, and MSC survival in BM-MSCs from MM patients and normal individuals. MATERIALS AND METHODS: In this experimental study, we isolated MSCs from BM aspirates of MM patients and healthy donors. Total RNA were extracted before and after co-culture with L363 myeloma cells. Gene expressions of RUNX2, PPARgamma, BCL2, and hsa-MIR 204 were assessed by quantitive real time polymerase chain reaction (qRT-PCR). RESULTS: Higher levels of RUNX2, PPARgamma, and hsa-MIR-204 expressions existed in MM- MSCs compared to normally derived (ND)-MSCs. BCL2 expression decreased in MM- MSCs. We observed different results in the co-culture model. CONCLUSION: In general, the MM-MSCs gene expression profile differed compared to ND- MSCs. Upregulation of RUNX2, PPARgamma, and hsa-MIR-204 in MM-MSCs compared to ND- MSCs would result in formation of bone defects. Downregulation of BCL2 would lead to MM-MSC cell death. PMID- 28580304 TI - Significance of Inactivated Genes in Leukemia: Pathogenesis and Prognosis. AB - Epigenetic and genetic alterations are two mechanisms participating in leukemia, which can inactivate genes involved in leukemia pathogenesis or progression. The purpose of this review was to introduce various inactivated genes and evaluate their possible role in leukemia pathogenesis and prognosis. By searching the mesh words "Gene, Silencing AND Leukemia" in PubMed website, relevant English articles dealt with human subjects as of 2000 were included in this study. Gene inactivation in leukemia is largely mediated by promoter's hypermethylation of gene involving in cellular functions such as cell cycle, apoptosis, and gene transcription. Inactivated genes, such as ASPP1, TP53, IKZF1 and P15, may correlate with poor prognosis in acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML), respectively. Gene inactivation may play a considerable role in leukemia pathogenesis and prognosis, which can be considered as complementary diagnostic tests to differentiate different leukemia types, determine leukemia prognosis, and also detect response to therapy. In general, this review showed some genes inactivated only in leukemia (with differences between B-ALL, T-ALL, CLL, AML and CML). These differences could be of interest as an additional tool to better categorize leukemia types. Furthermore; based on inactivated genes, a diverse classification of Leukemias could represent a powerful method to address a targeted therapy of the patients, in order to minimize side effects of conventional therapies and to enhance new drug strategies. PMID- 28580307 TI - Liquid Chromatography Mass Spectrometry-Based Metabolite Pathway Analyses of Myeloma and Non-Hodgkin's Lymphoma Patients. AB - OBJECTIVE: This study attempted to identify altered metabolism and pathways related to non-Hodgkin's lymphoma (NHL) and myeloma patients. MATERIALS AND METHODS: In this retrospective study, we collected plasma samples from 11 patients-6 healthy controls with no evidence of any blood cancers and 5 patients with either multiple myeloma (n=3) or NHL (n=2) during the preliminary study period. Samples were analyzed using quadrupole time-of-flight liquid chromatography mass spectrometry (LC-MS). Significant features generated after statistical analyses were used for metabolomics and pathway analysis. RESULTS: Data after false discovery rate (FDR) adjustment at q=0.05 of features showed 136 for positive and 350 significant features for negative ionization mode in NHL patients as well as 262 for positive and 98 features for negative ionization mode in myeloma patients. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis determined that pathways such as steroid hormone biosynthesis, ABC transporters, and arginine and proline metabolism were affected in NHL patients. In myeloma patients, pyrimidine metabolism, carbon metabolism, and bile secretion pathways were potentially affected by the disease. CONCLUSION: The results have shown tremendous differences in the metabolites of healthy individuals compared to myeloma and lymphoma patients. Validation through quantitative metabolomics is encouraged, especially for the metabolites with significantly expression in blood cancer patients. PMID- 28580306 TI - Enterolactone Reduces Telomerase Activity and The Level of Its Catalytic Subunit in Breast Cancer Cells. AB - OBJECTIVE: There is a positive correlation between higher serum phytoestrogen concentrations and lower risk of breast cancer. The activation of telomerase is crucial for the growth of cancer cells; therefore, the aim of this study was to examine the effects of enterolactone (ENL) and enterodiol (END) on this enzyme. MATERIALS AND METHODS: In this experimental study, we performed the viability assay to determine the effects of different concentrations of ENL and END on cell viability, and the effective concentrations of these two compounds on cell growth. We used western blot analysis to evaluate human telomerase reverse transcriptase catalytic subunit (hTERT) expression and polymerase chain reaction (PCR)-ELISA based on the telomeric repeat amplification protocol (TRAP) assay for telomerase activity. RESULTS: Both ENL and END, at 100 MUM concentrations, significantly (P<0.05) reduced cell viability. However, only the 100 MUM concentration of ENL significantly (P<0.05) decreased hTERT protein levels and telomerase activity. Lower concentrations of ENL did not have any significant effects on telomerase activity and hTERT protein levels. CONCLUSION: High concentration of ENL decreased the viability of MCF-7 breast cancer cells and inhibited the expression and activity of telomerase in these cells. Although END could reduce breast cancer cell viability, it did not have any effect on telomerase expression and activity. PMID- 28580308 TI - A Novel Approach on Drug Delivery: Investigation of A New Nano-Formulation of Liposomal Doxorubicin and Biological Evaluation of Entrapped Doxorubicin on Various Osteosarcoma Cell Lines. AB - OBJECTIVE: In this study we prepared a novel formulation of liposomal doxorubicin (L- DOX). The drug dose was optimized by analyses of cellular uptake and cell viability of osteosarcoma (OS) cell lines upon exposure to nanoliposomes that contained varying DOX concentrations. We intended to reduce the cytotoxicity of DOX and improve characteristics of the nanosystems. MATERIALS AND METHODS: In this experimental study, we prepared liposomes by the pH gradient hydration method. Various characterization tests that included dynamic light scattering (DLS), cryogenic transmission electron microscopy (Cryo-TEM) imaging, and UV- Vis spectrophotometry were employed to evaluate the quality of the nanocarriers. In addition, the CyQUANT(r) assay and fluorescence microscope imaging were used on various OS cell lines (MG-63, U2-OS, SaOS-2, SaOS-LM7) and Human primary osteoblasts cells, as novel methods to determine cell viability and in vitro transfection efficacy. RESULTS: We observed an entrapment efficiency of 84% for DOX within the optimized liposomal formulation (L-DOX) that had a liposomal diameter of 96 nm. Less than 37% of DOX released after 48 hours and L-DOX could be stored stably for 14 days. L-DOX increased DOX toxicity by 1.8-4.6 times for the OS cell lines and only 1.3 times for Human primary osteoblasts cells compared to free DOX, which confirmed a higher sensitivity of the OS cell lines versus Human primary osteoblasts cells for L-DOX. We deduced that L- DOX passed more freely through the cell membrane compared to free DOX. CONCLUSION: We successfully synthesized a stealth L-DOX that contained natural phospholipid by the pH gradient method, which could encapsulate DOX with 84% efficiency. The resulting nanoparticles were round, with a suitable particle size, and stable for 14 days. These nanoparticles allowed for adequately controlled DOX release, increased cell permeability compared to free DOX, and increased tumor cell death. L-DOX provided a novel, more effective therapy for OS treatment. PMID- 28580309 TI - Up-Regulation of FOXC2 and FOXQ1 Is Associated with The Progression of Gastric Type Adenocarcinoma. AB - OBJECTIVE: Forkhead box (FOX) proteins are important regulators of the epithelial to-mesenchymal transition (EMT), which is the main mechanism of cancer metastasis. Different studies have shown their potential involvement in progression of cancer in different tissues such as breast, ovary and colorectum. In this study, we aimed to analyze the expression of genes encoding two FOX proteins in gastric adenocarcinoma. MATERIALS AND METHODS: In this experimental case-control study, the expression of FOXC2 and FOXQ1 was examined in 31 gastric adenocarcinoma tumors and 31 normal adjacent gastric tissues by reverse transcription polymerase chain reaction (PCR). RESULTS: The expression of both genes was significantly up-regulated in gastric adenocarcinoma tumors compared with the normal tissues (P<0.05). The differential expression of these two genes was also correlated with the grade of tumors (P<0.01). CONCLUSION: We show that up-regulation of FOXC2 and FOXQ1 are likely to be involved in the progression of gastric adenocarcinoma. PMID- 28580310 TI - ANRIL Genetic Variants in Iranian Breast Cancer Patients. AB - OBJECTIVE: The genetic variants of the long non-coding RNA ANRIL (an antisense noncoding RNA in the INK4 locus) as well as its expression have been shown to be associated with several human diseases including cancers. The aim of this study was to examine the association of ANRIL variants with breast cancer susceptibility in Iranian patients. MATERIALS AND METHODS: In this case-control study, we genotyped rs1333045, rs4977574, rs1333048 and rs10757278 single nucleotide polymorphisms (SNPs) in 122 breast can- cer patients as well as in 200 normal age-matched subjects by tetra-primer amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR). RESULTS: The TT genotype at rs1333045 was significantly over-represented among pa- tients (P=0.038) but did not remain significant after multiple-testing correction. In addi- tion, among all observed haplotypes (with SNP order of rs1333045, rs1333048 rs4977574 and rs10757278), four haplotypes were shown to be associated with breast cancer risk. However, after multiple testing corrections, TCGA was the only haplotype which remained significant. CONCLUSION: These results suggest that breast cancer risk is significantly associated with ANRIL variants. Future work analyzing the expression of different associated ANRIL haplotypes would further shed light on the role of ANRIL in this disease. PMID- 28580311 TI - Enhanced DNA Damages of Human Prostate Cancer Cells Induced by Radiofrequency Capacitive Hyperthermia Pre- and Post X-rays: 6 MV versus 15 MV. AB - OBJECTIVE: This study aimed to determine the effect of 13.56 MHz radiofrequency (RF) capacitive hyperthermia (HT) on radiosensivity of human prostate cancer cells pre and post X-ray radiation treatment (RT). MATERIALS AND METHODS: In this experimental study, the human prostate cancer cell line DU145 was cultured as 300 um diameter spheroids. We divided the spheroids into group I: control, group II: HT at 43C for 30 minutes (HT), group III: 4 Gy irradiation with 6 MV X-ray [RT (6 MV)], group IV: 4 Gy irradiation with 15 MV X-ray [RT (15 MV)], group V: HT+RT (6 MV), group VI: HT+RT (15 MV), group VII: RT (6 MV)+HT, and group VIII: RT (15 MV)+HT. The alkaline comet assay was used to assess DNA damages in terms of tail moment (TM). Thermal enhancement factor (TEF) was obtained for the different treatment combinations. RESULTS: Mean TM increased with increasing photon energy. Group II had significantly greater TM compared to group I. Groups III and IV also had significantly higher TM compared to group I. Significant differences in TM existed between groups V, VII, and III (P<0.05). We observed significant differences in TM between groups VI, VIII, and IV. TEF values demonstrated that enhanced response to radiation was more pronounced in group V compared to the other combined treatments. CONCLUSION: Our results suggest that HT applied before RT leads to higher radiosensivity compared to after RT. HT at 43C for 30 minutes added to 6 MV X-ray causes higher enhancement of radiation compared to 15 MV X ray. PMID- 28580312 TI - The Role of Radiofrequency Hyperthermia in The Radiosensitization of A Human Prostate Cancer Cell Line. AB - OBJECTIVE: This study evaluated enhanced induced DNA damages and apoptosis of a spheroid culture of DU145 prostate cancer cells treated by a combination of radiofrequency hyperthermia (RF HT) with radiation treatment (RT) from an external radiotherapy machine compared to RT alone. MATERIALS AND METHODS: In this experimental study, DU145 cells were cultured as spheroids until they reached 300 um in diameter. We exposed these cultures to either: RF HT for 90 minutes at 43C originated from a Celsius TCS system, RF HT followed by RT at doses of 2 Gy or 4 Gy (15 MV energy) with 15-minute interval, or RT alone at the above mentioned doses. The trypan blue exclusion assay, alkaline comet assay, and annexin V/PI flow cytometry were performed to measure cell viability, the amount of DNA damage in an individual cell as the tail moment, and percentage of induced cell apoptosis in response to treatments explained. RESULTS: We calculated the thermal enhancement factor (TEF) for the combined treatment regime. RF HT followed by the 4 Gy dose of RT resulted in minimum viability (85.33 +/- 1.30%), the highest tail moment (1.98 +/- 0.18), and highest percentage of apoptotic cells (64.48 +/- 3.40%) compared to the other treatments. The results of the TEF assay were 2.54 from the comet assay and 2.33 according to flow cytometry. CONCLUSION: The present data suggest that combined treatment of mega voltage X rays and RF HT can result in significant radiosensitization of prostate cancer cells. PMID- 28580314 TI - Continuous or Transient High Level of Glucose Exposure Differentially Increases Coronary Artery Endothelial Cell Proliferation and Human Colon Cancer Cell Proliferation. AB - We studied effect of high glucose levels on coronary artery endothelial cell proliferation and human colon cancer cell proliferation. To examine the long-term effect of glucose exposure on cell growth, cells were cultured for 14 days in the absence or presence of 183 mg/dL D-glucose addition in the culture medium. Short effect of elevated glucose levels was examined by addition of 183 mg/dL D-glucose addition in the culture medium for just one hour per day followed by changing the culture to standard medium (5.5 mM D-glucose) during the next 23-hours period. Cell proliferation was estimated by 2,3-Bis (2-methoxy-4-nitro-5-sulfophenyl)-2H tetrazolium-5-carbox-anilide (XTT) assay and phosphor-Erk western blot analysis. We found that coronary artery endothelial cell proliferation was significantly increased in the culture medium with the acute one-hour addition of 183 mg/dL D glucose compared to the absence or chronic presence of 183 mg/dL D-glucose addition in the culture medium. In contrast, colon cancer cell proliferation was significantly increased in the continuous presence of 183 mg/dL D-glucose addition in the culture medium compared to the acute one-hour addition of glucose. The extent of Erk2 phosphorylation paralleled with the relative changes in cellular proliferation in both cell types. Taken together, these results suggested that continuous or transient high level of glucose exposure differentially effects coronary artery endothelial and human colon cancer cell proliferation. PMID- 28580313 TI - The Effect of Inflammatory Status on Butyrate and Folate Uptake by Tumoral (Caco 2) and Non-Tumoral (IEC-6) Intestinal Epithelial Cells. AB - OBJECTIVE: Colorectal cancer (CRC) is the second leading cause of cancer death in occidental countries. Chronic inflammatory bowel disease (crohn's disease and ulcerative colitis) is associated with an increased risk for CRC development. The aim of this work was to investigate the relationship between inflammatory status and absorption of nutrients with a role in CRC pathogenesis. MATERIALS AND METHODS: In this experimental study, we evaluated the in vitro effect of tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IF-gamma), and acetylsalicylic acid on 14C-butyrate (14C- BT), 3H-folic acid (3H-FA) uptake, and on proliferation, viability and differentiation of Caco-2 and IEC-6 cells in culture. RESULTS: The proinflammatory cytokines TNF-alpha and INF-gamma were found to decrease uptake of a low concentration of 14C-BT (10 uM) by Caco-2 (tumoral) and IEC-6 (normal) intestinal epithelial cell lines. However, the effect of TNF-alpha and INF-gamma in IEC-6 cells is most probably related to a cytotoxic and antiproliferative impact. In contrast, INF-gamma increases uptake of a high concentration (10 mM) of 14C-BT in Caco-2 cells. The anticarcinogenic effect of BT (10 mM) in these cells is not affected by the presence of this cytokine. On the other hand, acetylsalicylic acid stimulates 14C-BT uptake by Caco-2 cells and potentiates its antiproliferative effect. Finally, both TNF alpha and INF-gamma cause a significant decrease in 3H-FA uptake by Caco-2 cells. CONCLUSION: The inflammatory status has an impact upon cellular uptake of BT and FA, two nutrients with a role in CRC pathogenesis. Moreover, the anti inflammatory acetylsalicylic acid potentiates the anticarcinogenic effect of BT in Caco-2 cells by increasing its cellular uptake. PMID- 28580315 TI - Coexistence of KRAS and BRAF Mutations in Colorectal Cancer: A Case Report Supporting The Concept of Tumoral Heterogeneity. AB - The detection of KRAS and BRAF mutations is a crucial step for the correct therapeutic approach and predicting the epidermal growth factor receptor (EGFR) targeted therapy resistance of colorectal carcinomas. The concomitant KRAS and BRAF mutations occur rarely in the colorectal cancers (CRCs) with the prevalence of less than 0.001% of the cases. In patients with KRAS-mutant tumors, BRAF mutations should not regularly be tested unless the patient is participating in a clinical trial enriching for the presence of KRAS or BRAF-mutated tumor. The current report demonstrates a case with advanced adenocarcinoma of the colon showing the coexistence of KRAS and BRAF mutations and may have profound clinical implications for disease progression and therapeutic responses. PMID- 28580316 TI - Interactome Mapping Guided by Tissue-Specific Phosphorylation in Age-Related Macular Degeneration. AB - The current study aims to determine the molecular mechanisms of age-related macular degeneration (AMD) using the phosphorylation network. Specifically, we examined novel biomarkers for oxidative stress by protein interaction mapping using in vitro and in vivo models that mimic the complex and progressive characteristics of AMD. We hypothesized that the early apoptotic reactions could be initiated by protein phosphorylation in region-dependent (peripheral retina vs. macular) and tissue-dependent (retinal pigment epithelium vs. retina) manner under chronic oxidative stress. The analysis of protein interactome and oxidative biomarkers showed the presence of tissue- and region-specific post-translational mechanisms that contribute to AMD progression and suggested new therapeutic targets that include ubiquitin, erythropoietin, vitronectin, MMP2, crystalline, nitric oxide, and prohibitin. Phosphorylation of specific target proteins in RPE cells is a central regulatory mechanism as a survival tool under chronic oxidative imbalance. The current interactome map demonstrates a positive correlation between oxidative stress-mediated phosphorylation and AMD progression and provides a basis for understanding oxidative stress-induced cytoskeletal changes and the mechanism of aggregate formation induced by protein phosphorylation. This information could provide an effective therapeutic approach to treat age-related neurodegeneration. PMID- 28580317 TI - Altruistic behavior: mapping responses in the brain. AB - Altruism is an important social construct related to human relationships and the way many interpersonal and economic decisions are made. Recent progress in social neuroscience research shows that altruism is associated with a specific pattern of brain activity. The tendency to engage in altruistic behaviors is associated with greater activity within limbic regions such as the nucleus accumbens and anterior cingulate cortex in addition to cortical regions such as the medial prefrontal cortex and temporoparietal junction. Here, we review existing theoretical models of altruism as well as recent empirical neuroimaging research demonstrating how altruism is processed within the brain. This review not only highlights the progress in neuroscience research on altruism but also shows that there exist several open questions that remain unexplored. PMID- 28580318 TI - Targeting Ongoing DNA Damage in Multiple Myeloma: Effects of DNA Damage Response Inhibitors on Plasma Cell Survival. AB - Human myeloma cell lines (HMCLs) and a subset of myeloma patients with poor prognosis exhibit high levels of replication stress (RS), leading to DNA damage. In this study, we confirmed the presence of DNA double-strand breaks (DSBs) in several HMCLs by measuring gammaH2AX and RAD51 foci and analyzed the effect of various inhibitors of the DNA damage response on MM cell survival. Inhibition of ataxia telangiectasia and Rad3-related protein (ATR), the main kinase mediating the response to RS, using the specific inhibitor VE-821 induced more cell death in HMCLs than in control lymphoblastoid cells and U266, an HMCL with a low level of DNA damage. The absence of ATR was partially compensated by ataxia telangiectasia-mutated protein (ATM), since chemical inhibition of both kinases using VE-821 and KU-55933 significantly increased the death of MM cells with DNA damage. We found that ATM and ATR are involved in DSB repair by homologous recombination (HR) in MM. Inhibition of both kinases resulted in a stronger inhibition that may underlie cell death induction, since abolition of HR using two different inhibitors severely reduced survival of HMCLs that exhibit DNA damage. On the other hand, inhibition of the other route involved in DSB repair, non-homologous end joining (NHEJ), using the DNA-PK inhibitor NU7441, did not affect MM cell viability. Interestingly, we found that NHEJ inhibition did not increase cell death when HR was simultaneously inhibited with the RAD51 inhibitor B02, but it clearly increased the level of cell death when HR was inhibited with the MRE11 inhibitor mirin, which interferes with recombination before DNA resection takes place. Taken together, our results demonstrate for the first time that MM cells with ongoing DNA damage rely on an intact HR pathway, which thereby suggests therapeutic opportunities. We also show that inhibition of HR after the initial step of end resection might be more appropriate for inducing MM cell death, since it prevents the occurrence of a compensatory NHEJ repair mechanism. These preclinical observations provide the rationale for its clinical evaluation. PMID- 28580320 TI - Who will perform my autopsy? PMID- 28580319 TI - The Association of OASL and Type I Interferons in the Pathogenesis and Survival of Intracellular Replicating Bacterial Species. AB - The type I IFN response quickly became associated with its role in the innate immune response to viral infection. The past few years have seen the significance of IFNs expand in breadth to include non-viral pathogens. Previous work has identified that following viral infection, type I IFN signaling induces the production of the 2'-5'-oligoadenylate synthetase (OAS) family, which include OAS1, OAS2, OAS3, and OAS-like (OASL) protein. OASL was identified to be strongly induced following viral infection through engaging the RNA sensor RIG-I and increasing signaling through this pathway to enhance the anti-viral type I IFN response. Surprisingly, infection with viral dsDNA revealed an IFN inhibitory role and therefore pro-viral function of OASL through the inhibition of the cGAS cytosolic DNA sensing mechanism. Intracellular bacteria are able to activate the cytosolic DNA sensing pathway, however the role of OASL during bacterial infection is largely unknown. Vacuolar pathogenic microbes such as mycobacteria induce OASL early post infection, where it functions in a prosurvival fashion by inhibiting autophagic mechanisms and antimicrobial peptide expression. This suggests an underestimated role of OASL in the innate immune response to infection with a variety of pathogens and points to OASL-associated modulation of the type I IFN response. OASL may therefore play a critical role in defining the outcome of infection. We provide a brief update on the recent developments of the OAS family of proteins in response to DNA and RNA virus infections, as well as discuss evidence of Oasl expression in response to a number of cytosolic and vacuolar replicating bacterial pathogens. PMID- 28580321 TI - Clostridium difficile infection. PMID- 28580322 TI - Bone marrow necrosis and fat embolism: an autopsy report of a severe complication of hemoglobin SC disease. AB - Sickle Cell Disease encompasses a group of disorders related with the hemoglobin S and other hemoglobin genotypes. The clinical manifestation and the severity of symptoms are dependent on the specific genotype. In this setting, homozygous genotype (HbSS) presents an early onset of symptoms and a low expectancy of lifetime. However, the SC genotype (HbSC), which apparently shows a less severe clinical course, may exhibit the same complications of HbSS. These complications are usually manifested late in the course of life, when compared with the HbSS patients. It is noteworthy that HbSC may present a normal hematocrit, and therefore stays unknown until the first complication, that may be disastrous. The authors report a case of an African-Descendant woman, aging 65 years, with no previous diagnosis of anemia who sought medical attention because of a thoracic back pain followed by fever and altered mental status. The clinical picture deteriorated very fast with multiple organ failure and death. The autopsy findings concluded by generalized vaso-occlusive crisis, bone marrow necrosis and bone marrow and fat embolism, mainly to the lungs and kidney. The authors call attention for the knowledge of this severe life threatening complication, mainly in a country with a high Afro-Descendant population. PMID- 28580323 TI - Dicephalus dipus dibrachius twins: report of an autopsy case. AB - Dicephalus dipus dibrachius twins are a rare form of conjoined twins. An autopsy of conjoined dicephalus twins is reported. The diagnosis was performed during the pregnancy and the family received a judicial authorization for termination of pregnancy. The preterm newborn progressed to cardiac arrest and died following a court order to terminate the pregnancy. The conceptus presented two arms, two legs, a trunk, two heads, and a single umbilical cord. The two spinal columns presented vertebral fusion in the sacral region. The heart exhibited complex malformations. The external genitalia were female; and cytogenetic analysis confirmed female sex (46, XX). This analysis also corroborated the etiopathogenic hypotheses described for this abnormality, which proposes failures in embryonic formation rather than specific chromosomal alterations. Current identification of cases by ultrasound permits medical management and multidisciplinary action with the family, enabling the legal termination of pregnancy. PMID- 28580324 TI - Metastatic congenital neuroblastoma associated with in situ neuroblastoma: case report and review of literature. AB - Although neonatal tumors are rare, neuroblastoma is the most common neoplasia among them. These tumors, which usually involve children in early infancy, are derived from neural crest cells of adrenal gland medulla or sympathetic ganglia. Even though congenital metastatic neuroblastoma presents a favorable prognosis, it may lead to death if not recognized and treated early on. The authors report the case of a 2-month-old child who was born from in vitro fertilization, and whose diagnosis was made after birth. The form of presentation of this case as a metastatic disease concerning this age group is noteworthy. PMID- 28580325 TI - Thanatophoric dysplasia: case report of an autopsy complemented by postmortem computed tomographic study. AB - Thanatophoric dysplasia (TD) is one of the most common lethal skeletal dysplasias, which was first designated as thanatophoric dwarfism and described in 1967. The authors report a case of a Caucasian girl with TD, born to a 31-year old woman without comorbidities. The newborn presented respiratory distress immediately after delivery, progressing to death in less than 2 hours. An autopsy was carried out after postmortem tomographic examination. The autopsy findings depicted extensive malformations of the skeletal system and the brain. The aim of this report is to discuss the pathogenesis and correlate the morphologic features of TD that were disclosed at the tomography and the autopsy. PMID- 28580326 TI - Cat-scratch disease presenting as multiple hepatic lesions: case report and literature review. AB - Although infectious diseases are the most prevalent cause of fevers of unknown origin (FUO), this diagnosis remains challenging in some pediatric patients. Imaging exams, such as computed tomography (CT) are frequently required during the diagnostic processes. The presence of multiple hypoattenuating scattered images throughout the liver associated with the history of cohabitation with cats should raise the suspicion of the diagnosis of cat-scratch disease (CSD), although the main etiologic agent of liver abscesses in childhood is Staphylococcus aureus. Differential diagnosis by clinical and epidemiological data with Bartonella henselae is often advisable. The authors report the case of a boy aged 2 years and 9 months with 16-day history of daily fever accompanied by intermittent abdominal pain. Physical examination was unremarkable. Abdominal ultrasound performed in the initial work up was unrevealing, but an abdominal CT that was performed afterwards disclosed multiple hypoattenuating hepatic images compatible with the diagnosis of micro abscesses. Initial antibiotic regimen included cefotaxime, metronidazole, and oxacillin. Due to the epidemiology of close contact with kittens, diagnosis of CSD was considered and confirmed by serologic tests. Therefore, the initial antibiotics were replaced by clarithromycin orally for 14 days followed by fever defervescence and clinical improvement. The authors call attention to this uncommon diagnosis in a child presenting with FUO and multiple hepatic images suggestive of micro abscesses. PMID- 28580328 TI - Ovarian adenosarcoma simulating a simple cyst in a young patient. AB - Mullerian adenosarcoma is a rare, mixed tumor that can occur throughout the female genital tract, but is most commonly found in the uterus. Ovarian adenosarcoma is rarer and has a poorer prognosis than uterine adenosarcoma. Data on the clinicopathological features of ovarian adenosarcoma are limited, and, due to its rarity, the management is controversial. The authors report a case of a 25 year-old patient who presented with recurrent abdominal pain. Sonography and laparotomy showed an ovarian cyst, and pathologic examination confirmed the diagnosis of cystic low-grade adenosarcoma. The patient remains free of recurrence 6 months after diagnosis. The authors call attention to the differential diagnosis of ovarian masses, especially in young patients, and to the lack of evidence on the management of this neoplasm in the literature. PMID- 28580327 TI - Early stage primary gastric diffuse large B-cell lymphoma in a young HIV-positive patient. AB - HIV infection is known to be associated with the development of a wide range of neoplasia. About 25 to 40% of HIV-positive patients will present some kind of malignancy in the course of the disease; among them 10% are non-Hodgkin lymphomas (NHL) and 20% of these are represented by the diffuse large B-cell lymphoma. HIV positive patients have a relative risk of 110 times higher to develop neoplasia, than the non-infected population. The gastrointestinal (GI) tract is the most frequent extranodal site of involvement. However, the primary GI lymphoma is rare. The authors present a case of a 31-year-old male patient with a 16-year history of HIV infection, who deliberately withdrew the Highly Active Antiretroviral Therapy (HAART) regimen and was hospitalized because of a respiratory infection. Because of a long-term complaint of dyspepsia, an upper gastrointestinal endoscopy was performed disclosing a large elevated and ulcerated gastric lesion, which biopsy revealed a diffuse large B-cell lymphoma. Clinical, imaging and laboratory tests showed an early stage diagnosis: Lugano stage I. Although not frequent, the authors alert to considering this neoplasia in all HIV-positive patients with dyspeptic symptoms. PMID- 28580330 TI - Analysis of Relative Biological Effectiveness of Proton Beams and Iso-effective Dose Profiles Using Geant4. AB - BACKGROUND: The assessment of RBE quantity in the treatment of cancer tumors with proton beams in treatment planning systems (TPS) is of high significance. Given the significance of the issue and the studies conducted in the literature, this quantity is fixed and is taken as equal to 1.1. OBJECTIVE: The main objective of this study was to assess RBE quantity of proton beams and their variations in different depths of the tumor. This dependency makes RBE values used in TPS no longer be fixed as they depend on the depth of the tumor and therefore this dependency causes some changes in the physical dose profile. MATERIALS AND METHODS: The energy spectrum of protons was measured at various depths of the tumor using proton beam simulations and well as the complete simulation of a cell to a pair of DNA bases through Monte Carlo GEANT4. The resulting energy spectrum was used to estimate the number of double-strand breaks generated in cells. Finally, RBE values were calculated in terms of the penetration depth in the tumor. RESULTS AND CONCLUSION: The simulation results show that the RBE value not fixed terms of the depth of the tumor and it differs from the clinical value of 1.1 at the end of the dose profile and this will lead to a non-uniform absorbed dose profile. Therefore, to create a uniform impact dose area, deep-finishing systems need to be designed by taking into account deep RBE values. PMID- 28580329 TI - Takotsubo cardiomyopathy: an overlooked cause of chest pain. AB - Takotsubo cardiomyopathy (TTC), also known as apical ballooning syndrome, broken heart syndrome, or stress-induced cardiomyopathy, is defined as a transient disturbance of the left ventricle, which is quite often associated with electrocardiographic abnormalities that may mimic acute myocardial infarction. The syndrome is also characterized by a mild alteration of cardiac biomarkers in absence of coronary blood flow obstruction on the coronariography. Clinical presentation is often manifested by angina, dyspnea, syncope, and arrhythmias. Peculiarly, the left ventricle takes the form of "tako-tsubo" (a Japanese word for "octopus trap") on the imaging workup. The authors report the case of a post menopausal, hypertensive, dyslipidemic and type-II diabetic woman admitted at the emergency service with acute chest pain post physical exertion. Electrocardiogram showed signs of ischemia and myocardial necrosis markers were mildly increased. Echocardiography and ventriculography showed apical and mid-ventricular akinesia, with mild atherosclerotic coronary lesions. Thus diagnostic workup and the outcome followed the diagnostic criteria for TTC. The authors called attention to the potential of overlooking this diagnosis, since this syndrome is still not widely recognized. PMID- 28580331 TI - Beam Collimation during Lumbar Spine Radiography: A Retrospective Study. AB - INTRODUCTION: Collimating the primary beam to the area of diagnostic interest (ADI) has been strongly recommended as an effective method to reduce patient's radiation dose and to improve image quality during radiology practice. Lack or inadequate collimation results in excessive radiation dose to patients and deterioration image quality. OBJECTIVE: To assess the quality of beam collimation during lumbar spine radiography at two general hospitals in Ahvaz, Iran. MATERIALS AND METHODS: We retrospectively reviewed 830 digital antero-posterior (AP) lumbar spine radiographs in term of beam collimation. For each radiograph, the distance between current and optimal collimation was calculated (in cm). The area of ADI and total field size for each radiograph were also calculated (in cm2). RESULTS: The total mean ADI and irradiated region outside ADI for each radiograph were estimated 360 and 454 cm2, respectively. The total irradiated region outside ADI was 1.26 times more than ADI. In contrast to cranial regions outside ADI, caudal regions were more commonly included inside the primary beam (12% vs. 24.4%; P-value <0.005). At least in 62% of radiographs evaluated, ovaries were included in the primary beam. CONCLUSION: Radiographers should make considerable effort to limit the primary beam to the ADI to reduce patient's exposure and to increase image quality. PMID- 28580332 TI - Enhancement of Toxic Substances Clearance from Blood Equvalent Solution and Human Whole Blood through High Flux Dialyzer by 1 MHz Ultrasound. AB - BACKGROUND: Hemodialysis is a process of removing waste and excess fluid from blood when kidneys cannot function efficiently. It often involves diverting blood to the filter of the dialysis machin to be cleared of toxic substances. Fouling of pores in dialysis membrane caused by adhesion of plasma protein and other toxins will reduce the efficacy of the filtre. OBJECTIVE: In This study, the influence of pulsed ultrasound waves on diffusion and the prevention of fouling in the filter membrane were investigated. MATERIAL AND METHODS: Pulsed ultrasound waves with frequency of 1 MHz at an intensity of 1 W/cm2 was applied to the high flux (PES 130) filter. Blood and blood equivalent solutions were passed through the filter in separate experimental setups. The amount of Creatinine, Urea and Inulin cleared from both blood equvalent solution and human whole blood passed through High Flux (PES 130) filter were measured in the presence and absence of ultrasound irradiation. Samples were taken from the outlet of the dialyzer every five minutes and the clearance of each constituent was calculated. RESULTS: Statistical analysis of the blood equvalent solution and whole blood indicated the clearance of Urea and Inulin in the presence of ultrasound increased (p<0.05), while no significant effects were observed for Creatinine. CONCLUSION: It may be concluded that ultrasound, as a mechanical force, can increase the rate of clearance of some toxins (such as middle and large molecules) in the hemodialysis process. PMID- 28580333 TI - Oral Administration of Vitamin C, Cimetidine and Famotidine on Micronuclei Induced by Low Dose Radiation in Mouse Bone Marrow Cells. AB - BACKGROUND: In many studies, chemicals and natural materials were tested to reduce the harmful effects of radiation. It is known that Famotidine and vitamin C reduce DNA damage. OBJECTIVE: The aim of this study was to evaluate the radioprotective effect of vitamin C, Cimetidine and Famotidine on gamma-radiation induced damage on mouse bone marrow. METHODS: Six-to-seven week male NMRI mice (28 g +/-3) were randomly divided into fourteen groups: control, 2Gy irradiation, six group drugs without irradition (Famotidine, Cimetidine, vitaminC, Fam-Cim, Fam-Vit, Cim-Vit), six groups received drugs and 2Gy radiation with a 60Co |gamma|-ray source at room temperature 22 +/- 2 degrees C. The mice were killed 48 hours after irradiation by cervical dislocation. Slides were prepared from bone marrow cells and stained in May-Granwald and Giemsa. Finally, the cells were counted with microscope, frequencies of polychromatic erythrocyte (PCE), normochoromatic erythrocyte (NCE) and their micronuclated cell were recorded. PCE / PCE + NCE were calculated. RESULTS: There were significant differences of MNPCE/1000PCE, MNNCE/1000NCE and PCE/PCE+NCE among different groups with similar radiation doses (p<=0.01). Moreover, there were significant differences of MNPCE/1000PCE and PCE/PCE+NCE among different doses of radiation (p<=0.01). While considering MNNCE/1000NCE, there were no significant differences among silimar groups with radiation dose (p?0.05). CONCLUSION: Oral administration of Famotidine, vitamin C and Cimetidine demonstrate reliable and similar radioprotective effects. Additionally, the protective effect of single use of these drugs was similar to the combination form. Thus, the oral use of combination, 48 hours after irradiation cannot induce more radioprotective effect. PMID- 28580334 TI - Melatonin Role in Ameliorating Radiation-induced Skin Damage: From Theory to Practice (A Review of Literature). AB - Normal skin is composed of epidermis and dermis. Skin is susceptible to radiation damage because it is a continuously renewing organ containing rapidly proliferating mature cells. Radiation burn is a damage to the skin or other biological tissues caused by exposure to radiofrequency energy or ionizing radiation. Acute skin reaction is the most frequently occurring side effect of radiation therapy. Generally, any chemical/biological agent given before or at the time of irradiation to prevent or ameliorate damage to normal tissues is called a radioprotector. Melatonin is a highly lipophilic substance that easily penetrates organic membranes and therefore is able to protect important intracellular structures including mitochondria and DNA against oxidative damage directly at the sites where such a kind of damage would occur. Melatonin leads to an increase in the molecular level of some important antioxidative enzymes such as superoxide, dismotase and glutation-peroxidase, and also a reduction in synthetic activity of nitric oxide. There is a large body of evidence which proves the efficacy of Melatonin in ameliorating UV and X ray-induced skin damage. We propose that, in the future, Melatonin would improve the therapeutic ratio in radiation oncology and ameliorate skin damage more effectively when administered in optimal and non-toxic doses. PMID- 28580335 TI - Adaptive Response Induced by Pre-Exposure to 915 MHz Radiofrequency: A Possible Role for Antioxidant Enzyme Activity. AB - BACKGROUND: Over the past few years, the rapid use of high frequency electromagnetic fields like mobile phones has raised global concerns about the negative health effects of its use. Adaptive response is the ability of a cell or tissue to better resist stress damage by prior exposure to a lesser amount of stress. This study aimed to assess whether radiofrequency radiation can induce adaptive response by changing the antioxidant balance. MATERIALS AND METHODS: In order to assess RF-induced adaptive response in tissues, we evaluated the level of GSH and the activity of GR in liver. 50 rats were divided into 5 groups. Three groups were pre-exposed to 915 MHz RF radiation, 4 hours per day for one week at different powers, as low, medium and high. 24 hours after the last exposure to radiation, they were exposed to 4 Gy sublethal dose of gamma radiation and then sacrificed after 5 hours. Their livers were removed, washed and were kept at -80o C until used. RESULTS: Our finding showed that pre-exposure to 915 MHz radiofrequency radiation with specific power could induce adaptive response in liver by inducing changes in the activity and level of antioxidant enzymes. CONCLUSION: It can be concluded that pre-exposure to microwave radiation could increase the level of GSH and the activity of GR enzyme, although these increases were seen just in low power group, and the GR activity was indicated in medium power group. This increase protects tissue from oxidative damage induced by sublethal dose of gamma radiation. PMID- 28580336 TI - Simulation study of Hemodynamic in Bifurcations for Cerebral Arteriovenous Malformation using Electrical Analogy. AB - BACKGROUND AND OBJECTIVE: Cerebral Arteriovenous Malformation (CAVM) hemodynamic is disease condition, results changes in the flow and pressure level in cerebral blood vessels. Measuring flow and pressure without catheter intervention along the vessel is big challenge due to vessel bifurcations/complex bifurcations in Arteriovenous Malformation patients. The vessel geometry in CAVM patients are complex, composed of varying diameters, lengths, and bifurcations of various angles. The variations in the vessel diameter and bifurcation angle complicate the measurement and analysis of blood flow features invasively or non-invasively. METHODS: In this paper, we proposed a lumped model for the bifurcation for symmetrical and asymmetrical networks in CAVM patients. The models are created using MATLAB Simulation software for various bifurcation angles. Each bifurcation angle created using electrical network- RLC. The segmentation and pre-processing of bifurcation vessels are implemented using adaptive segmentation. The proposed network address clinicians problem by measuring hemodynamic non-invasively. The method is applicable for any types of bifurcation networks with different bifurcation angles in CAVM patients. RESULTS: In this work, we constructed a mathematical model, measured hemodynamic for 23 patients (actual and simulated cases) with 60 vessel bifurcation angles variations. The results indicate that comparisons evidenced highly significant correlations between values computed by the lumped model and simulated mechanical model for both networks with p < 0.0001. A P value of less than 0.05 considered statistically significant. CONCLUSION: In this paper, we have modelled different bifurcation types and automatically display pressure and flow non-invasively at different node and at different angles of bifurcation in the complex vessel with help of bifurcation parameters, using lumped parameter model. We have simulated for different bifurcation angles and diameters of vessel for various imaging modality and model extend for different organs. This will help clinicians to measure haemodynamic parameters noninvasively at various bifurcations, where even catheter cannot be reached. PMID- 28580337 TI - Neural Network-Based Learning Kernel for Automatic Segmentation of Multiple Sclerosis Lesions on Magnetic Resonance Images. AB - BACKGROUND: Multiple Sclerosis (MS) is a degenerative disease of central nervous system. MS patients have some dead tissues in their brains called MS lesions. MRI is an imaging technique sensitive to soft tissues such as brain that shows MS lesions as hyper-intense or hypo-intense signals. Since manual segmentation of these lesions is a laborious and time consuming task, automatic segmentation is a need. MATERIALS AND METHODS: In order to segment MS lesions, a method based on learning kernels has been proposed. The proposed method has three main steps namely; pre-processing, sub-region extraction and segmentation. The segmentation is performed by a kernel. This kernel is trained using a modified version of a special type of Artificial Neural Networks (ANN) called Massive Training ANN (MTANN). The kernel incorporates surrounding pixel information as features for classification of middle pixel of kernel. The materials of this study include a part of MICCAI 2008 MS lesion segmentation grand challenge data-set. RESULTS: Both qualitative and quantitative results show promising results. Similarity index of 70 percent in some cases is considered convincing. These results are obtained from information of only one MRI channel rather than multi-channel MRIs. CONCLUSION: This study shows the potential of surrounding pixel information to be incorporated in segmentation by learning kernels. The performance of proposed method will be improved using a special pre-processing pipeline and also a post processing step for reducing false positives/negatives. An important advantage of proposed model is that it uses just FLAIR MRI that reduces computational time and brings comfort to patients. PMID- 28580338 TI - Exposure to Visible Light Emitted from Smartphones and Tablets Increases the Proliferation of Staphylococcus aureus: Can this be Linked to Acne? AB - BACKGROUND: Due to rapid advances in modern technologies such as telecommunication technology, the world has witnessed an exponential growth in the use of digital handheld devices (e.g. smartphones and tablets). This drastic growth has resulted in increased global concerns about the safety of these devices. Smartphones, tablets, laptops, and other digital screens emit high levels of short-wavelength visible light (i.e. blue color region in the visible light spectrum). MATERIAL AND METHODS: At a dark environment, Staphylococcus aureus bacteria were exposed to the light emitted from common tablets/smartphones. The control samples were exposed to the same intensity of light generated by a conventional incandescent light bulb. The growth rate of bacteria was examined by measuring the optical density (OD) at 625 nm by using a spectrophotometer before the light exposure and after 30 to 330 minutes of light exposure. RESULTS: The growth rates of bacteria in both smartphone and tablet groups were higher than that of the control group and the maximum smartphone/control and tablet/control growth ratios were observed in samples exposed to digital screens' light for 300 min (ratios of 3.71 and 3.95, respectively). CONCLUSION: To the best of our knowledge, this is the first study that investigates the effect of exposure to light emitted from digital screens on the proliferation of Staphylococcus aureus and its association with acne pathogenesis. Our findings show that exposure to short-wavelength visible light emitted from smartphones and tablets can increase the proliferation of Staphylococcus aureus. PMID- 28580339 TI - Can Evolutionary-based Brain Map Be Used as a Complementary Diagnostic Tool with fMRI, CT and PET for Schizophrenic Patients? AB - OBJECTIVE: In this research, a new approach termed as "evolutionary-based brain map" is presented as a diagnostic tool to classify schizophrenic and control subjects by distinguishing their electroencephalogram (EEG) features. METHODS: Particle swarm optimization (PSO) is employed to find discriminative frequency bands from different EEG channels. By deploying the energy of those selected frequency bands from different channels within each time frame (window) on the scalp geometry, a sort of two dimensional points along with their values are created; by applying Lagrange interpolation, an image can be constructed. Finally, by averaging the images belonging to successive time frames, an evolutionary-based brain map is created. RESULTS: In this study, twenty subjects from each group voluntarily participated and their EEG signals were caught from 20 channels. The energy of selected bands for different channels are arranged in a feature vector for each time frame and applied to Fisher linear discriminant analysis (FLDA) resulting in 83.74% diagnostic accuracy between the two groups. The achieved result by the proposed method was much higher than applying the energy of standard EEG bands (delta, theta, alpha, beta and gamma) to the same classifier which just provided 77.04% accuracy. Applying T-test to the achieved results supports the supremacy of the proposed method as an automatic powerful diagnostic tool. CONCLUSION: The proposed brain map is capable of highlighting the same physiological and anatomical changes which are observed in fMRI, PET and CT as differentiable indicators between controls and schizophrenic patients. PMID- 28580340 TI - A System for Continuous Estimating and Monitoring Cardiac Output via Arterial Waveform Analysis. AB - BACKGROUND: Cardiac output (CO) is the total volume of blood pumped by the heart per minute and is a function of heart rate and stroke volume. CO is one of the most important parameters for monitoring cardiac function, estimating global oxygen delivery and understanding the causes of high blood pressure. Hence, measuring CO has always been a matter of interest to researchers and clinicians. Several methods have been developed for this purpose, but a majority of them are either invasive, too expensive or need special expertise and experience. Besides, they are not usually risk free and have consequences. OBJECTIVE: Here, a semi invasive system was designed and developed for continuous CO measurement via analyzing and processing arterial pulse waves. RESULTS: Quantitative evaluation of developed CO estimation system was performed using 7 signals. It showed that it has an acceptable average error of (6.5%) in estimating CO. In addition, this system has the ability to consistently estimate this parameter and to provide a CO versus time curve that assists in tracking changes of CO. Moreover, the system provides such curve for systolic blood pressure, diastolic blood pressure, average blood pressure, heart rate and stroke volume. CONCLUSION: Evaluation of the results showed that the developed system is capable of accurately estimating CO. The curves which the system provides for important parameters may be valuable in monitoring hemodynamic status of high-risk surgical patients and critically ill patients in Intensive Care Units (ICU). Therefore, it could be a suitable system for monitoring hemodynamic status of critically ill patients. PMID- 28580341 TI - Targeting innate immunity to downmodulate adaptive immunity and reverse type 1 diabetes. AB - Type 1 diabetes (T1D) is characterized by specific destruction of pancreatic insulin-producing beta cells accompanied by evidence of beta-cell-directed autoimmunity such as autoreactive T cells and islet autoantibodies (IAAs). Currently, T1D cannot be prevented or reversed in humans. T1D is easy to prevent in the nonobese diabetic (NOD) spontaneous mouse model but reversing new-onset T1D in mice is more difficult. Since the discovery of the T-cell receptor in the 1980s and the subsequent identification of autoreactive T cells directed toward beta-cell antigens (eg, insulin, glutamic acid decarboxylase), the dream of antigen-specific immunotherapy has dominated the field with its promise of specificity and limited side effects. While such approaches have worked in the NOD mouse, however, dozens of human trials have failed. Broader immunosuppressive approaches (originally cyclosporine, subsequently anti-CD3 antibody) have shown partial successes (e.g., prolonged C peptide preservation) but no major therapeutic efficacy or disease reversal. Human prevention trials have failed, despite the ease of such approaches in the NOD mouse. In the past 50 years, the incidence of T1D has increased dramatically, and one explanation is the "hygiene hypothesis", which suggests that decreased exposure of the innate immune system to environmental immune stimulants (e.g., bacterial products such as Toll-like receptor (TLR) 4-stimulating lipopolysaccharide [LPS]) dramatically affects the adaptive immune system and increases subsequent autoimmunity. We have tested the role of innate immunity in autoimmune T1D by treating acute-onset T1D in NOD mice with anti-TLR4/MD-2 agonistic antibodies and have shown a high rate of disease reversal. The TLR4 antibodies do not directly stimulate T cells but induce tolerogenic antigen-presenting cells (APCs) that mediate decreased adaptive T cell responses. Here, we review our current knowledge and suggest future prospects for targeting innate immunity in T1D immunotherapy. PMID- 28580342 TI - A simple rat model of in situ reversible obstructive jaundice in situ reversible obstructive jaundice model. AB - PURPOSE: To develop a simple and reliable rat model of in situ reversible obstructive jaundice with low morbidity and mortality rates. METHODS: Rats were divided into 4 groups with 8 rats each: the sham-operated (SH) group only underwent laparotomy, the control internal drainage (ID-C) group underwent choledochoduodenostomy, the new internal drainage (ID-N) group and the long-term internal drainage (ID-L) group underwent choledochocholedochostomy. Common bile duct ligation was performed in all the drainage groups 7 days before reversal procedures. All rats were sacrificed for samples 7 days after the last operation except rats of the ID-L group that survived 28 days before sacrifice. Body weight, liver function, histopathological changes, morbidity and mortality were assessed. RESULTS: One rat died and 2 rats had complications with tube blockage in the ID-C group. No death or complications occurred in the ID-N and ID-L groups. The drainage tube remained patent in the long-term observation ID-L group. Body weight showed no significant difference between the ID-C and ID-N groups after 7 days drainage. Liver function was not fully recovered in the ID-C and ID-N groups after 7 days drainage, but statistical differences were only observed in the ID-C group compared with the SH and ID-L groups. Periportal inflammation and bile duct proliferation showed severer in the ID-C group than in the ID-N group. CONCLUSION: The present study provided an efficient, simple, and reliable rat model that is especially suitable for long-term or consecutive studies of reversible obstructive jaundice. PMID- 28580343 TI - Effectiveness of thymoquinone, zeolite, and platelet-rich plasma in model of corrosive oesophagitis induced in rats. AB - PURPOSE: The effectiveness of platelet-rich plasma (PRP), thymoquinone, and zeolite in corrosive esophageal burns was investigated in a rat model. METHODS: Four groups were comprised as containing 10 rats in each group. For group I, oesophagitis was induced and no other procedure was performed (control group). For group II, oesophagitis was induced and thymoquinone was administered for 1 week via oral gavage once a day (thymoquinone group). For group III, oesophagitis was induced for 1 week via oral gavage once a day (PRP group). For group IV, oesophagitis was induced and zeolite was administered for 1 week via oral gavage once a day (zeolite group). On the 10th day, the rats were sacrificed under anaesthesia and venous blood sampling was performed from the vena portae. The oesophaguses were totally excised. Biochemically, interleukin (IL)-1B, IL-6, TNF alpha, and MCP-1 were examined from venous blood. Inflammation score was evaluated histopathologically in oesophageal tissue that was collected. RESULTS: There was a statistically significant difference among groups in terms of IL-1, IL-6, MCP levels, compared to the control group; median IL-1, IL-6, MCP levels of thymoquinone, PRP, and zeolite groups were statistically significantly lower. There was a statistically significant difference among groups in terms of inflammation scores, compared to group I; median inflammation scores of groups II, III and IV were statistically significantly lower thymoquinone. CONCLUSION: PRP, and zeolite exhibited positive effect on recovery in oesophagitis by reducing inflammation in the involved segment. PMID- 28580344 TI - Comparison of effects of the tacrolimus and cyclosporine A on the colon anastomosis recovery of rats. AB - PURPOSE: This study aims to examine and compare the effects of immunosuppressant cyclosporine A (CsA) and tacrolimus (TAC) on colon anastomosis recovery. METHODS: Forty rats were randomly divided into 4 groups. The 4 groups were determined as follows: control group; sham group, given %0.09 NaCl; TAC group, given 0.5 mg/kg/day tacrolimus; and CsA group, given 5 mg/kg/day CsA. A 6-cm midabdomen incision was performed on the rats. An incision of all layers on the right colon was performed. Then anastomosis was undertaken. Laparotomy was performed on the seventh day postoperation. The colon bursting pressures were evaluated, histopathological examinations were undertaken, and E-cadherin expression and tissue hydroxyproline levels were evaluated. RESULTS: Statistically significant differences were observed among bursting pressures of the groups (P < 0.001). The value was significantly low in TAC and CsA groups when compared to control and sham groups (P < 0.05). The tissue hydroxyproline levels were significantly low in TAC group compared to control group (P = 0.03). Fibroblast density and neovascularization were significantly greater in the control group compared to the TAC group (P < 0.05). Levels of collagen had decreased significantly in TAC group compared to other groups (P < 0.05). CONCLUSION: Our study showed that TAC may have a negative effect of colon anastomosis recovery. The lowest anastomosis bursting pressure was detected in TAC group. Also, collagen, hydroxyproline, fibroblast, neovascularization and E-Cadherin levels were comparatively lower in TAC group. CsA did not cause any significant changes to tissue hydroxyproline, collagen, fibroblast, and E-Cadherin levels. PMID- 28580346 TI - Prospective, double center, 1-year results of adjustable gastric banding with MIDBAND (gastro-gastric suture vs. non-gastro-gastric suture). AB - PURPOSE: Although laparoscopic adjustable gastric banding (LAGB) is a popular bariatric procedure, few comprehensive studies have been investigated on the use of non-gastro-gastric sutures (NGGSs) for decreasing postoperative complications. This study aimed to assess and compare the safety and effectiveness of MIDBAND with or without gastro-gastric sutures (GGSs). METHODS: Between February 2013 and March 2014, 41 severely obese patients underwent primary LAGB using pars flaccid technique at double center in South Korea. Excess weight loss, operative time and postoperative complications were assessed and compared between a GGS group (group 1) and a NGGS group (group 2), and patients were followed monthly for 1 year. RESULTS: Mean body mass indices in groups 1 and 2 were 38.4 +/- 4.7 and 38.9 +/- 5.0 kg/m2, respectively, and mean percentage excess weight losses (%EWLs) were 59.9% +/- 28.4% and 50.9% +/- 20.0%, respectively, at 6 months, and 75.8% +/- 26.6% and 72.5% +/- 27.5%, respectively, at 12 months, and these intergroup differences of %EWL were not significant (P = 0.256 and P = 0.704, respectively). Mean operative time (57.2 minutes) was shorter in group 2 than in group 1 (79.2 minutes) (P < 0.001). In terms of complications, pouch dilatation rates were similar in the 2 groups, and no case of gastric band erosion was encountered. CONCLUSION: Operative time was shorter in the NGGS group, and pouch dilatation rates and %EWL were similar in the 2 groups. We conclude NGGS using MIDBAND is both straightforward and effective. A long-term prospective comparative study is needed to demonstrate the safety and efficacy of NGGS. PMID- 28580345 TI - Extended versus peripancreatic lymph node dissection for the treatment of left sided pancreatic cancer. AB - PURPOSE: The pathways of lymphatic metastases differ according to the tumor location in pancreatic cancer patients. However, it is unclear whether extended lymph node dissection (LND) is essential for all left-sided pancreatic cancer. The aim of this study is to evaluate the survival outcomes according to the extent of LND and tumor location in patients with left-sided pancreatic cancer. METHODS: January 2005 to December 2013, we retrospectively identified 107 patients who underwent curative intent surgery for left-sided pancreatic cancer. The left-sided pancreatic cancer was defined as a tumor located in pancreatic body or tail. The extent of LND was divided into 2 groups: extended LND and peripancreatic LND. The extended LND group included celiac and superior mesenteric LNs. RESULTS: We included 107 patients with left-sided pancreatic cancer; 59 patients with pancreatic body cancer and 48 patients with pancreatic tail cancer. The median follow-up period was 17 months (range, 3-110 months). Fifty patients with pancreatic body cancer and 30 patients with pancreatic tail cancer underwent extended LND. In patients with pancreatic body cancer, extended LND was associated with improved disease-free survival (DFS) (P = 0.010) and overall survival (P = 0.014). However, extended LND was not associated with DFS in patients with pancreatic tail cancer. CONCLUSION: Extended LND could improve survival in patients with pancreatic body cancer. However, extended LND had no survival benefit for the treatment of pancreatic tail cancer. PMID- 28580347 TI - Laparoscopic surgery for colorectal cancer in patients over 80 years of age: the morbidity outcomes. AB - PURPOSE: The aim of this study was to compare the outcomes between patients under 60 years of age and older patients over 80 years of age who underwent laparoscopic colorectal surgery with colorectal cancer. METHODS: A retrospective analysis of 519 colorectal patients who underwent laparoscopic colorectal surgery for colorectal adenocarcinoma between January 2007 and December 2012 was collected and categorized into 2 groups of patients, those under 60 years of age (n = 404) and those over 80 years of age (n = 115). RESULTS: The group of patients over 80 years of age had a significantly higher ASA physical status classification (P < 0.001), more preoperative comorbidities (P < 0.001), had a tendency towards more tumors in a colonic location (P = 0.034), and more advanced American Joint Committee on Cancer TNM stage (P = 0.001). A higher proportion of right hemicolectomy and abdominoperineal resection was performed and more transfusions were required in the group of patients over 80 years of age (P = 0.002 and P = 0.001, respectively). There were no significant differences in operative time, conversion rate, resection margins, and numbers of harvested lymph nodes, hospital stay, and morbidity between the 2 groups. No postoperative mortality was found in the present study. The 3-year DFS for over 80 years age group and under 60 years age group were 73.5% and 73.9%, respectively (P = 0.770). CONCLUSION: Laparoscopic colorectal surgery was effective and safe for elderly patients over 80 years of age and resulted in postoperative outcomes similar to those in younger patients. The postoperative morbidity after laparoscopic colorectal cancer surgery was not increased in over 80 years of age. PMID- 28580348 TI - Impact of high-grade obstruction on outcomes in patients with appendiceal inflammatory masses managed by nonoperative treatment. AB - PURPOSE: To retrospectively assess the impact of high-grade obstructions identified on initial CT on outcomes of patients with appendiceal inflammatory masses managed by nonoperative treatment. METHODS: Institutional Review Boards approved this retrospective study and informed consent was waived. Included were 52 consecutive patients diagnosed with appendiceal inflammatory masses by CT scan and managed by nonoperative treatment. The main outcome measure was treatment failure and secondary outcomes were complications and initial and total hospital stay. Patient demographics, inflammatory markers, and CT findings for presence of an appendiceal inflammatory mass and high-grade obstruction were assessed. Patients with and without high-grade obstruction were compared for patient characteristics and outcomes using Fisher exact test and Student t-test. RESULTS: Among 52 patients, 14 (27%) had high-grade obstruction on CT examination at presentation. No significant differences were observed in patient characteristics (P > 0.05), treatment failure (P = 0.33), complications (P = 0.29), or initial (P = 0.73) or total (P = 0.72) hospitalization between patients with and without high-grade obstruction. CONCLUSION: For patients who were managed by nonoperative treatment for appendiceal inflammatory masses, the presence of high-grade obstruction identified on initial CT scan did not significantly affect outcomes of treatment failure, complications, and initial and total hospitalization. PMID- 28580349 TI - Ultrasound fusion imaging with real-time navigation for the surveillance after endovascular aortic aneurysm repair. AB - Ultrasound can be an effective alternative to computed tomography for surveillance following endovascular aneurysm repair (EVAR). Recently, ultrasound fusion imaging with the real-time navigation system was introduced. Here we described 3 patients who underwent post-EVAR surveillance using this novel technique. Complete coregistration was achieved in all patients. The origin of left renal artery was selected for the target of coregistration. Ultrasound fusion imaging was useful to differentiate the confusing lesion and to evaluate the complete resolution of endoleak and newly developed delayed endoleak. Ultrasound fusion image with real-time navigation system can be a feasible imaging tool for post-EVAR surveillance. PMID- 28580350 TI - Colon perforation due to embolization coil for internal iliac aneurysm. AB - Coil migration is an extremely rare but hazardous complication of aneurysmal coil embolization. Only 1 case report has described coil migration following endovascular exclusion to gastrointestinal (GI) tract. We report the experience of a case of colon penetration caused by embolization coil placed for internal iliac aneurysm. A 66-year-old man visited the Emergency Department for hematochezia that had persisted for 3 months. Stent insertion and coil embolization of left internal iliac artery aneurysm had been performed on the patient 18 months ago. Colonoscopy was performed. It suggested penetration of sigmoid colon by embolization coil and diverticulum. Angiography revealed extravasation of contrast media at left internal iliac artery. Covered stent deployment was done in the left internal iliac artery. One week after the stent insertion, the patient underwent anterior resection, aneurysm resection, and coil removal. The patient recovered without complications. He was discharged at 2 weeks after the operation. PMID- 28580351 TI - Transition in Patients with Congenital Heart Disease in Germany: Results of a Nationwide Patient Survey. AB - BACKGROUND: A growing number of adults with congenital heart disease (ACHD) pose a particular challenge for health care systems across the world. Upon turning into 18 years, under the German national health care system, ACHD patients are required to switch from a pediatric to an adult cardiologist or an ACHD-certified provider. To date, reliable data investigating the treatment situation of ACHD patients in Germany are not available. MATERIALS AND METHODS: An online survey was conducted in collaboration with patient organizations to address the life situation and the conditions of health care provision for ACHD patients in Germany. ACHD patients were recruited from the database of the National Register for Congenital Heart Defects (NRCHD) and informed about the survey via email, websites, and social networks. A total of 1,828 ACHD patients (1,051 females) participated in this study. The mean age was 31.7 +/- 11.7 years. Participants were surveyed about treating physicians and the institution mainly involved in the treatment of their CHD. In addition, participants were asked questions to assess the level of trust toward their treating physician and their familiarity with the term "ACHD-certified provider." RESULTS: Among the surveyed patients, 25.4% stated that they attended a specific ACHD clinic at a heart center regularly, 32.7% were treated in a private practice setting by a pediatric cardiologist, 32.4% in a private practice (adult) cardiology setting, and 9.5% were treated by an "other physician." Only 24.4% of the male and 29.7% of the female ACHD patients were familiar with the term "ACHD-certified provider." CONCLUSION: The transfer from pediatric cardiology to ACHD care requires further attention as many adult patients have not transferred to certified ACHD providers. The question of whether ACHD patients in Germany are offered consistent and adequate care should also be investigated in more detail. The answers regarding the ACHD certification are particularly disappointing and indicative of a large information gap and inadequate education in clinical practice. PMID- 28580352 TI - Recent Spatiotemporal Patterns of US Lung Cancer by Histologic Type. AB - BACKGROUND: After a period of increasing rates, lung cancer incidence is declining in the US for men and women. We investigated lung cancer rate patterns by gender, geographic location, and histologic subtype, and for total lung cancer (TLC), for the entire study period, and for 2000-2011 from 17 surveillance, epidemiology, and end results areas. METHODS: For each gender-histologic type combination, time trend plots and maps of age-adjusted rates are presented. Time trend significance was tested by joinpoint regression analysis. Spatial random effects models were applied to examine effects of sociodemographic factors, health insurance coverage, smoking, and physician density at the county level. Linked micromap plots illustrate patterns for important model predictors. RESULTS: Declining incidence trends occurred for TLC (p < 0.05, entire period). Squamous cell carcinoma trends increased for females only (p < 0.05). Small cell carcinoma trends declined overall, p < 0.05, but recently increased faster for females than males. Adenocarcinoma rates initially declined, but were significantly increasing by 2004, p < 0.05. Counties with higher current smoking and family poverty were strongly associated with higher risk for all gender histologic types (p < 0.0001, for both variables). County socioeconomic status was associated with higher risk for all lung cancer subtypes for females, p < 0.02. Counties with more diagnostic radiologists were associated with higher TLC rates (p < 0.03); counties with greater primary care physician access were associated with lower TLC rates (p < 0.03). TLC incidence rates were higher in eastern and southern states than western areas. Male rates were higher than female rates along the West Coast. Males and females had similar small cell rate patterns, with higher rates in the Midwest and southeast. Squamous cell carcinoma and adenocarcinoma rate patterns were similar to TLC patterns, except for relatively higher female adenocarcinoma rates in the northeast and northwest. CONCLUSION: Geographic patterns and declining time trends for incident lung cancer are consistent with previous mortality patterns. Male-female time trend and geographic pattern differences occur by histologic type. Time trends remain significant, even after adjustment for significant covariates. Knowledge of the variation of lung cancer incidence by region and histologic type is useful for surveillance and for implementing lung cancer control efforts. PMID- 28580353 TI - Development and Validation of a Novel Real-time Assay for the Detection and Quantification of Vibrio cholerae. AB - Vibrio cholerae O1 and O139 has been known for its ability to cause epidemics. These strains produce cholera toxin which is the main cause of secretory diarrhea. V. cholerae non-O1 and non-O139 strains are also capable of causing gastroenteritis as well as septicemia and peritonitis. It has been proven that virulence factors such as T6SS, hapA, rtxA, and hlyA are present in almost all V. cholerae strains. It is imperative that viable but non-culturable cells of V. cholerae are also detected since they are also known to cause diarrhea. Thus, the aim of this study was to develop an assay that detects all V. cholerae regardless of their serotype, culturable state, and virulence genes present, by targeting the species specific conserved ompW sequence. The developed assay meets these goals with 100% specificity and is capable of detecting as low as 5.46 copy number of V. cholerae. Detection is rapid since neither lengthy incubation period nor electrophoresis is required. The assay had excellent repeatability (CV%: 0.24 1.32) and remarkable reproducibility (CV%: 1.08-3.7). Amplification efficiencies in the 89-100% range were observed. The assay is more economical than Taqman based multiplex real-time PCR assays. Compared to other real-time assays, the ompW assay is specific and sensitive, has better repeatability and reproducibility, and is more economical. PMID- 28580354 TI - How a Training Program Is Transforming the Role of Traditional Birth Attendants from Cultural Practitioners to Unique Health-care Providers: A Community Case Study in Rural Guatemala. AB - In low- and middle-income countries (LMICs), where the rates of maternal mortality continue to be inappropriately high, there has been recognition of the importance of training traditional birth attendants (TBAs) to help improve outcomes during pregnancy and childbirth. In Guatemala, there is no national comprehensive training program in place despite the fact that the majority of women rely on TBAs during pregnancy and childbirth. This community case study presents a unique education program led by TBAs for TBAs in rural Guatemala. Discussion of this training program focuses on programming implementation, curriculum development, sustainable methodology, and how an educational partnership with the current national health-care system can increase access to health care for women in LMICs. Recent modifications to this training model are also discussed including how a change in the clinical curriculum is further integrating TBAs into the national health infrastructure. The training program has demonstrated that Guatemalan TBAs are able to improve their basic obstetrical knowledge, are capable of identifying and referring early complications of pregnancy and labor, and can deliver basic prenatal care that would otherwise not be provided. This training model is helping transform the role of the TBA from a sole cultural practitioner to a validated health-care provider within the health care infrastructure of Guatemala and has the potential to do the same in other LMICs. PMID- 28580355 TI - Adults Experiencing Homelessness in the US-Mexico Border Region: A Photovoice Project. AB - Homelessness is a social, economic, and political crisis in the United States. In particular, the US-Mexico Border region has seen a surge of homelessness, specifically among veterans, women victims of intimate partner violence, and immigrants. In 2014, 12 persons in El Paso, TX, with experience of being homeless used the photovoice methodology to participate in a project titled, "The Voices and Images of the Residents of the Opportunity Center for the Homeless: A Visual Project on the Identity and Challenges Homeless Adults Face on the Border Region." The project was led by faculty from the Department of Social Work and facilitated by graduate students from the Departments of Social Work, Sociology, and Anthropology at the University of Texas at El Paso. In partnership with the Opportunity Center for the Homeless, a community-based organization, a gallery of photographs with respective narratives was produced along with a video documentary. The participants identified four themes: broken systems, invisibility, opportunities and what works, and growth and determination. These themes represent participants' life experiences with homelessness and their aspirations. In addition to the photo gallery, participants supported the development of a Call to Action asking the community, policy, and decision makers to commit to changing the current social, economic, and political conditions affecting individuals experiencing homelessness. The gallery, Call to Action, and overall participant experiences with photovoice were shared during local, regional, and national conferences and events, including three State of the Homeless Conferences led by the Opportunity Center for the Homeless in partnership with the university. PMID- 28580356 TI - Fungal Histidine Phosphotransferase Plays a Crucial Role in Photomorphogenesis and Pathogenesis in Magnaporthe oryzae. AB - Two-component signal transduction (TCST) pathways play crucial roles in many cellular functions such as stress responses, biofilm formation, and sporulation. The histidine phosphotransferase (HPt), which is an intermediate phosphotransfer protein in a two-component system, transfers a phosphate group to a phosphorylatable aspartate residue in the target protein(s), and up-regulates stress-activated MAP kinase cascades. Most fungal genomes carry a single copy of the gene coding for HPt, which are potential antifungal targets. However, unlike the histidine kinases (HK) or the downstream response regulators (RR) in two component system, the HPts have not been well-studied in phytopathogenic fungi. In this study, we investigated the role of HPt in the model rice-blast fungal pathogen Magnaporthe oryzae. We found that in M. oryzae an additional isoform of the HPT gene YPD1 was expressed specifically in response to light. Further, the expression of light-regulated genes such as those encoding envoy and blue-light harvesting protein, and PAS domain containing HKs was significantly reduced upon down-regulation of YPD1 in M. oryzae. Importantly, down-regulation of YPD1 led to a significant decrease in the ability to penetrate the host cuticle and in light dependent conidiation in M. oryzae. Thus, our results indicate that Ypd1 plays an important role in asexual development and host invasion, and suggest that YPD1 isoforms likely have distinct roles to play in the rice-blast pathogen M. oryzae. PMID- 28580357 TI - Impact of Compression Stockings vs. Continuous Positive Airway Pressure on Overnight Fluid Shift and Obstructive Sleep Apnea among Patients on Hemodialysis. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is common in edematous states, notably in hemodialysis patients. In this population, overnight fluid shift can play an important role on the pathogenesis of OSA. The effect of compression stockings (CS) and continuous positive airway pressure (CPAP) on fluid shift is barely known. We compared the effects of CS and CPAP on fluid dynamics in a sample of patients with OSA in hemodialysis, through a randomized crossover study. METHODS: Each participant performed polysomnography (PSG) at baseline, during CPAP titration, and after 1 week of wearing CS. Neck circumference (NC) and segmental bioelectrical impedance were done before and after PSG. RESULTS: Fourteen patients were studied (53 +/- 9 years; 57% men; body mass index 29.7 +/- 6.8 kg/m2). Apnea-hypopnea index (AHI) decreased from 20.8 (14.2; 39.6) at baseline to 7.9 (2.8; 25.4) during CPAP titration and to 16.7 (3.5; 28.9) events/h after wearing CS (CPAP vs. baseline, p = 0.004; CS vs. baseline, p = 0.017; and CPAP vs. CS, p = 0.017). Nocturnal intracellular trunk water was higher after wearing CS in comparison to baseline and CPAP (p = 0.03). CS reduced the fluid accumulated in lower limbs during the day, although not significantly. Overnight fluid shift at baseline, CPAP, and CS was -183 +/- 72, -343 +/- 220, and -290 +/- 213 ml, respectively (p = 0.006). Overnight NC increased at baseline (0.7 +/- 0.4 cm), decreased after CPAP (-1.0 +/- 0.4 cm), and while wearing CS ( 0.4 +/- 0.8 cm) (CPAP vs. baseline, p < 0.0001; CS vs. baseline, p = 0.001; CPAP vs. CS, p = 0.01). CONCLUSION: CS reduced AHI by avoiding fluid retention in the legs, favoring accumulation of water in the intracellular component of the trunk, thus avoiding fluid shift to reach the neck. CPAP improved OSA by exerting local pressure on upper airway, with no impact on fluid redistribution. CPAP performed significantly better than CS for both reduction of AHI and overnight reduction of NC. Complementary studies are needed to elucidate the mechanisms by which CPAP and CS reduce NC. PMID- 28580358 TI - Belatacept As an Alternative to Calcineurin Inhibitors in Patients with Solid Organ Transplants. AB - The goal of immunosuppression in transplantation has shifted to improving long term outcomes, reducing drug-induced toxicities while preserving the already excellent short-term outcomes. Long-term gains in solid organ transplantation have been limited at least partly due to the nephrotoxicity and metabolic side effects of calcineurin inhibitors (CNIs). The alloimmune response requires activation of the costimulatory pathway for T cell proliferation and amplification. Belatacept is a molecule that selectively blocks T cell costimulation. In June 2011, the U.S. Food and Drug Administration approved it for maintenance immunosuppression in kidney transplantation based on two open label, randomized, phase III trials. Since its introduction, belatacept has shown promise in both short- and long-term renal transplant outcomes in several other trials. It exhibits a superior side effect profile compared to CNIs with a comparable efficacy. Across all solid organ transplants, the burden of chronic kidney disease, its associated cardiovascular morbidity, mortality, and inferior patient/allograft survival is a well-documented problem. In this review, we aim to discuss the evidence behind the use of belatacept in solid organ transplants as an effective alternative to CNIs for renal rescue in patients with acute and/or chronic kidney injury. PMID- 28580360 TI - Complete Cranial Iliac Osteotomy to Approach the Lumbosacral Foramen. AB - An approach using a complete cranial iliac osteotomy (CCIO) to access the lumbosacral (LS) foramen in dogs from lateral was developed using cadavers and applied in a clinical patient with degenerative lumbosacral stenosis (DLSS). The foraminal enlargement in the cadavers and the patient was documented on postoperative CT scans. The preoperative CT scan of the patient showed moderate cranial telescoping of the sacral roof and a moderate central disk protrusion, leading to moderate to severe compression of the cauda equina. In addition, there was lateral spondylosis with consequential stenosis of the right LS foramen. The right L7 nerve had lost its fat attenuation and appeared thickened. After a routine L7S1 dorsal laminectomy with a partial discectomy, a CCIO was performed, providing good access to the LS foramen and the adhesions around the proximal L7 nerve caudoventral to the foramen. The osteotomy was stabilized with a locking plate and a cerclage wire. The dog recovered well from the procedures and after 36 h, the dog walked normally and was discharged from the hospital. Eight and 16 weeks later, the signs of the DLSS had markedly improved. From these data, it can be concluded that the CCIO is a useful approach to the LS foramen and intervertebral disk in selected patients with DLSS, giving good access to the structures around the LS foramen. PMID- 28580361 TI - Neuroprotection via RNA-binding protein RBM3 expression is regulated by hypothermia but not by hypoxia in human SK-N-SH neurons. AB - OBJECTIVE: Therapeutic hypothermia is an established treatment for perinatal asphyxia. Yet, many term infants continue to die or suffer from neurodevelopmental disability. Several experimental studies have demonstrated a beneficial effect of mild-to-moderate hypothermia after hypoxic injury, but the understanding of hypothermia-induced neuroprotection remains incomplete. In general, global protein synthesis is attenuated by hypothermia, but a small group of RNA-binding proteins including the RNA-binding motif 3 (RBM3) is upregulated in response to cooling. The aim of this study was to establish an in vitro model to investigate the effects of hypoxia and hypothermia on neuronal cell survival, as well as to examine the kinetics of concurrent cold-shock protein RBM3 gene expression. METHODS: Experiments were performed by using human SK-N-SH neurons exposed to different oxygen concentrations (21%, 8%, or 0.2% O2) for 24 hours followed by moderate hypothermia (33.5 degrees C) or normothermia for 24, 48, or 72 hours. Cell death was determined by quantification of lactate dehydrogenase and neuron-specific enolase releases into the cell cultured medium, and cell morphology was assessed by using immunofluorescence staining. The regulation of RBM3 gene expression was assessed by reverse transcriptase-quantitative polymerase chain reaction and Western blot analysis. RESULTS: Exposure to hypoxia (0.2% O2) for 24 hours resulted in significantly increased cell death in SK-N-SH neurons, whereas exposure to 8% O2 had no significant impact on cell viability. Post-hypoxia treatment with moderate hypothermia for 48 or 72 hours rescued the neurons from hypoxia-induced cell death. Moreover, exposure to severe hypoxia led to observable cell swelling, which was also attenuated by moderate hypothermia. Finally, moderate hypothermia but not hypoxia led to the induction of RBM3 expression on both transcriptional and translational levels. CONCLUSION: Moderate hypothermia protects neurons from hypoxia-induced cell death. The expression of the cold-shock protein RBM3 is induced by moderate hypothermia and could be one possible mediator of hypothermia-induced neuroprotection. PMID- 28580363 TI - Targeted metabolomics in colorectal cancer: a strategic approach using standardized laboratory tests of the blood and urine. AB - BACKGROUND: Glycolytic markers have been detected in colorectal cancer (CRC) using advanced analytical methods. METHODS: Using commercially available assays, by-products of anaerobic metabolism were prospectively measured in the blood and urine of 20 patients with metastatic colorectal cancer (mCRC) and 20 patients with local disease. Twenty-four-hour urine citrate, plasma lactate, ketones, venous blood gas, anion gap, and osmolar gap were investigated. Results of patients with metastatic and local CRC were compared using two-sample t-tests or equivalent nonparametric tests. In addition, plasma total CO2 concentrations in our local hospital (5,931 inpatients and 1,783 outpatients) were compared retrospectively with those in our dedicated cancer center (1,825 outpatients) over 1 year. RESULTS: The average venous pCO2 was higher in patients with mCRC (50.2 mmHg; standard deviation [SD]=9.36) compared with those with local disease (42.8 mmHg; SD=8.98), p=0.045. Calculated serum osmolarity was higher in mCRC and attributed to concomitant sodium and urea elevations. In our retrospective analysis, plasma total CO2 concentrations (median=27 mmol/L) were higher in cancer patients compared to both hospital inpatients (median=23 mmol/L) and outpatients (median=24 mmol/L), p<0.0001. CONCLUSION: Patients with mCRC had higher venous pCO2 levels than those with local disease. Although causation cannot be established, we hypothesize that pCO2 elevation may stem from a perturbed metabolism in mCRC. PMID- 28580364 TI - Modelling lexical access in speech production as a ballistic process. PMID- 28580362 TI - KEMTUB012-NI2, a novel potent tubulysin analog that selectively targets hypoxic cancer cells and is potentiated by cytochrome p450 reductase downregulation. AB - PURPOSE: There is an urgent need to develop effective therapies and treatment strategies to treat hypoxic tumors, which have a very poor prognosis and do not respond well to existing therapies. METHODS: A novel hypoxia-targeting agent, KEMTUB012-NI2, was synthesized by conjugating a 2-nitroimidazole hypoxia targeting moiety to a synthetic tubulysin, a very potent antimitotic. Its hypoxic selectivity and mode of action were studied in breast cancer cell lines. RESULTS: KEMTUB012-NI2 exhibited a similar selectivity for hypoxic cells to that of tirapazamine, a well-established hypoxia-targeting agent, but was >1,000 times more potent in cell cytotoxicity assays. The hypoxia-targeting mechanism for both KEMTUB012-NI2 and tirapazamine was selective and mediated by one-electron reductases. However, while cytochrome p450 reductase (POR) downregulation could inhibit tirapazamine cytotoxicity, it actually sensitized hypoxic cells to KEMTUB012-NI2. CONCLUSION: KEMTUB012-NI2 is a potent new agent that can selectively target hypoxic cancer cells. The hypoxia selectivity of KEMTUB012-NI2 and tirapazamine appears to be differentially activated by reductases. Since reductases are heterogeneously expressed in tumors, the different activation mechanisms will allow these agents to complement each other. Combining POR downregulation with KEMTUB012-NI2 treatment could be a new treatment strategy that maximizes efficacy toward hypoxic tumor cells while limiting systemic toxicity. PMID- 28580359 TI - The Diverse AAA+ Machines that Repair Inhibited Rubisco Active Sites. AB - Gaseous carbon dioxide enters the biosphere almost exclusively via the active site of the enzyme ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco). This highly conserved catalyst has an almost universal propensity to non productively interact with its substrate ribulose 1,5-bisphosphate, leading to the formation of dead-end inhibited complexes. In diverse autotrophic organisms this tendency has been counteracted by the recruitment of dedicated AAA+ (ATPases associated with various cellular activities) proteins that all use the energy of ATP hydrolysis to remodel inhibited Rubisco active sites leading to release of the inhibitor. Three evolutionarily distinct classes of these Rubisco activases (Rcas) have been discovered so far. Green and red-type Rca are mostly found in photosynthetic eukaryotes of the green and red plastid lineage respectively, whereas CbbQO is associated with chemoautotrophic bacteria. Ongoing mechanistic studies are elucidating how the various motors are utilizing both similar and contrasting strategies to ultimately perform their common function of cracking the inhibited Rubisco active site. The best studied mechanism utilized by red type Rca appears to involve transient threading of the Rubisco large subunit C terminal peptide, reminiscent of the action performed by Clp proteases. As well as providing a fascinating example of convergent molecular evolution, Rca proteins can be considered promising crop-improvement targets. Approaches aiming to replace Rubisco in plants with improved enzymes will need to ensure the presence of a compatible Rca protein. The thermolability of the Rca protein found in crop plants provides an opportunity to fortify photosynthesis against high temperature stress. Photosynthesis also appears to be limited by Rca when light conditions are fluctuating. Synthetic biology strategies aiming to enhance the autotrophic CO2 fixation machinery will need to take into consideration the requirement for Rubisco activases as well as their properties. PMID- 28580365 TI - Low-Quality Housing Is Associated With Increased Risk of Malaria Infection: A National Population-Based Study From the Low Transmission Setting of Swaziland. AB - BACKGROUND: Low-quality housing may confer risk of malaria infection, but evidence in low transmission settings is limited. METHODS: To examine the relationship between individual level housing quality and locally acquired infection in children and adults, a population-based cross-sectional analysis was performed using existing surveillance data from the low transmission setting of Swaziland. From 2012 to 2015, cases were identified through standard diagnostics in health facilities and by loop-mediated isothermal amplification in active surveillance, with uninfected subjects being household members and neighbors. Housing was visually assessed in a home visit and then classified as low, high, or medium quality, based on housing components being traditional, modern, or both, respectively. RESULTS: Overall, 11426 individuals were included in the study: 10960 uninfected and 466 infected (301 symptomatic and 165 asymptomatic). Six percent resided in low-quality houses, 26% in medium-quality houses, and 68% in high-quality houses. In adjusted models, low- and medium-quality construction was associated with increased risk of malaria compared with high-quality construction (adjusted odds ratio [AOR], 2.11 and 95% confidence interval [CI], 1.26-3.53 for low vs high; AOR, 1.56 and 95% CI, 1.15-2.11 for medium vs high). The relationship was independent of vector control, which also conferred a protective effect (AOR, 0.67; 95% CI, .50-.90) for sleeping under an insecticide treated bed net or a sprayed structure compared with neither. CONCLUSIONS: Our study adds to the limited literature on housing quality and malaria risk from low transmission settings. Housing improvements may offer an attractive and sustainable additional strategy to support countries in malaria elimination. PMID- 28580367 TI - Improving temporal resolution of ultrafast electron diffraction by eliminating arrival time jitter induced by radiofrequency bunch compression cavities. AB - The temporal resolution of sub-relativistic ultrafast electron diffraction (UED) is generally limited by the radio frequency (RF) phase and amplitude jitter of the RF lenses that are used to compress the electron pulses. We theoretically show how to circumvent this limitation by using a combination of several RF compression cavities. We show that if powered by the same RF source and with a proper choice of RF field strengths, RF phases, and distances between the cavities, the combined arrival time jitter due to RF phase jitter of the cavities is cancelled at the compression point. We also show that the effect of RF amplitude jitter on the temporal resolution is negligible when passing through the cavity at a RF phase optimal for (de)compression. This will allow improvement of the temporal resolution in UED experiments to well below 100 fs. PMID- 28580366 TI - Nanotip-based photoelectron microgun for ultrafast LEED. AB - We present the design and fabrication of a micrometer-scale electron gun for the implementation of ultrafast low-energy electron diffraction from surfaces. A multi-step process involving photolithography and focused-ion-beam nanostructuring is used to assemble and electrically contact the photoelectron gun, which consists of a nanotip photocathode in a Schottky geometry and an einzel lens for beam collimation. We characterize the low-energy electron pulses by a transient electric field effect and achieve pulse durations of 1.3 ps at an electron energy of 80 eV. First diffraction images in a backscattering geometry (at 50 eV electron energy) are shown. PMID- 28580368 TI - Monitoring nonadiabatic avoided crossing dynamics in molecules by ultrafast X-ray diffraction. AB - We examine time-resolved X-ray diffraction from molecules in the gas phase which undergo nonadiabatic avoided-crossing dynamics involving strongly coupled electrons and nuclei. Several contributions to the signal are identified, representing (in decreasing strength) elastic scattering, contributions of the electronic coherences created by nonadiabatic couplings in the avoided crossing regime, and inelastic scattering. The former probes the charge density and delivers direct information on the evolving molecular geometry. The latter two contributions are weaker and carry spatial information through the transition charge densities (off-diagonal elements of the charge-density operator). Simulations are presented for the nonadiabatic harpooning process in the excited state of sodium fluoride. PMID- 28580369 TI - Transient process spectroscopy for the direct observation of inter-molecular photo-dissociation. AB - Transient process spectroscopy has previously been thought to be applicable only to the analysis of intra-molecular processes. Two metal ion bridges used in the present work have allowed us to visualize real-time variations of the molecular vibration frequencies during photo-disproportionation inside bimolecule aggregates, which directly shows transient inter-molecular reactions. PMID- 28580370 TI - Robotic Assist-As-Needed as an Alternative to Therapist-Assisted Gait Rehabilitation. AB - OBJECTIVE: Body Weight Supported Treadmill Training (BWSTT) with therapists' assistance is often used for gait rehabilitation post-stroke. However, this training method is labor-intensive, requiring at least one or as many as three therapists at once for manual assistance. Previously, we demonstrated that providing movement guidance using a performance-based robot-aided gait training (RAGT) that applies a compliant, assist-as-needed force-field improves gait pattern and functional walking ability in people post-stroke. In the current study, we compared the effects of assist-as-needed RAGT combined with functional electrical stimulation and visual feedback with BWSTT to determine if RAGT could serve as an alternative for locomotor training. METHODS: Twelve stroke survivors were randomly assigned to one of the two groups, either receiving BWSTT with manual assistance or RAGT with functional electrical stimulation and visual feedback. All subjects received fifteen 40-minutes training sessions. RESULTS: Clinical measures, kinematic data, and EMG data were collected before and immediately after the training for fifteen sessions. Subjects receiving RAGT demonstrated significant improvements in their self-selected over-ground walking speed, Functional Gait Assessment, Timed Up and Go scores, swing-phase peak knee flexion angle, and muscle coordination pattern. Subjects receiving BWSTT demonstrated significant improvements in the Six-minute walk test. However, there was an overall trend toward improvement in most measures with both interventions, thus there were no significant between-group differences in the improvements following training. CONCLUSION: The current findings suggest that RAGT worked at least as well as BWSTT and thus may be used as an alternative rehabilitation method to improve gait pattern post-stroke as it requires less physical effort from the therapists compared to BWSTT. PMID- 28580372 TI - INFLUENCE OF THE CIVIC COMMUNITY RELIGIOUS ENVIRONMENT ON FAMILY POVERTY: A MULTILEVEL ANALYSIS. AB - This study integrates research in the civic community tradition and structuralist and individualist perspectives on poverty to assess the relationship between religious-based civic community structures and family poverty in the United States. Using multilevel analyses of 2006-2008 American Community Survey, 2000 Census of Population and Housing, and 2000 Religious Congregations and Membership Survey data, results demonstrate that the presence of Mainline Protestant and Catholics adherents within communities - measured as the percentage of a community's population comprised of Mainline Protestant and Catholic adherents - is significantly and negatively associated with family poverty risks, net of other family and community factors. That is, in communities with a greater presence of Mainline Protestants and Catholics, there were also lower risks of families being in poverty. These findings suggest the importance of the ecology of religion within communities in understanding poverty outcomes for families. PMID- 28580371 TI - Kinase modulation of androgen receptor signaling: implications for prostate cancer. AB - Androgens and androgen receptors play essential roles in the development and progression of prostate cancer, a disease that claims roughly 28,000 lives annually. In addition to androgen biding, androgen receptor activity can be regulated via several post-translational modifications such as ubiquitination, acetylation, phosphorylation, methylation & SUMO-ylation. Off these modifications, phosphorylation has been the most extensively studied. Modification by phosphorylation can alter androgen receptor localization, protein stability and transcriptional activity, ultimately leading to changes in the biology of cancer cells and cancer progression. Understanding, role of phosphorylated androgen receptor species holds the key to identifying a potential therapeutic drug target for patients with prostate cancer and castrate resistant prostate cancer. Here, we present a brief review of recently discovered protein kinases phosphorylating AR, focusing on the functional role of phosphorylated androgen receptor species in prostate cancer and castrate resistant prostate cancer. PMID- 28580373 TI - Acousto-optic modulation and opto-acoustic gating in piezo-optomechanical circuits. AB - Acoustic wave devices provide a promising chip-scale platform for efficiently coupling radio frequency (RF) and optical fields. Here, we use an integrated piezo-optomechanical circuit platform that exploits both the piezoelectric and photoelastic coupling mechanisms to link 2.4 GHz RF waves to 194 THz (1550 nm) optical waves, through coupling to propagating and localized 2.4 GHz acoustic waves. We demonstrate acousto-optic modulation, resonant in both the optical and mechanical domains, in which waveforms encoded on the RF carrier are mapped to the optical field. We also show opto-acoustic gating, in which the application of modulated optical pulses interferometrically gates the transmission of propagating acoustic pulses. The time-domain characteristics of this system under both pulsed RF and pulsed optical excitation are considered in the context of the different physical pathways involved in driving the acoustic waves, and modelled through the coupled mode equations of cavity optomechanics. PMID- 28580374 TI - Non-Hermitian engineering of synthetic saturable absorbers for applications in photonics. AB - We introduce a new type of synthetic saturable absorber based on quantum-inspired Jx photonic arrays. We demonstrate that the interplay between optical Kerr nonlinearity, interference effects and non-Hermiticity through radiation loss leads to a nonlinear optical filtering response with two distinct regimes of small and large optical transmissions. More interestingly, we show that the boundary between these two regimes can be very sharp. The threshold optical intensity that marks this abrupt "phase transition" and its steepness can be engineered by varying the number of the guiding elements. The practical feasibility of these structures as well as their potential applications in laser systems and optical signal processing are also discussed. PMID- 28580375 TI - RNA-protein UV-crosslinking Assay. AB - RNA-protein interactions play a crucial role in every aspect of RNA metabolism, and also plays a major role in post-transcriptional gene regulation. RNA-binding proteins have been implicated in viral gene expression (Ray and Das, 2002) and microRNA-mediated gene regulation (Poria et al., 2016). Here we have described the protocol which (1) covalently links transiently interacting RNA-protein complexes by UV crosslinking, (2) removes the unprotected RNA by RNase digestion and (3) detects the RNA-protein complexes by SDS-PAGE analysis. This protocol provides a rapid and reliable means to directly assay RNA-protein interactions and their kinetics using purified proteins and also help in identifying novel RNA protein interactions. PMID- 28580376 TI - Reversible Cryo-arrests of Living Cells to Pause Molecular Movements for High resolution Imaging. AB - Fluorescence live-cell imaging by single molecule localization microscopy (SMLM) or fluorescence lifetime imaging microscopy (FLIM) in principle allows for the spatio-temporal observation of molecular patterns in individual, living cells. However, the dynamics of molecules within cells hamper their precise observation. We present here a detailed protocol for consecutive cycles of reversible cryo arrest of living cells on a microscope that allows for a precise determination of the evolution of molecular patterns within individual living cells. The usefulness of this approach has been demonstrated by observing ligand-induced clustering of receptor tyrosine kinases as well as their activity patterns by SMLM and FLIM (Masip et al., 2016). PMID- 28580377 TI - Optimization of Curvilinear Needle Trajectories for Transforamenal Hippocampotomy. AB - BACKGROUND: The recent development of MRI-guided laser-induced thermal therapy (LITT) offers a minimally invasive alternative to craniotomies performed for tumor resection or for amygdalohippocampectomy to control seizure disorders. Current LITT therapies rely on linear stereotactic trajectories that mandate twist-drill entry into the skull and potentially long approaches traversing healthy brain. The use of robotically-driven, telescoping, curved needles has the potential to reduce procedure invasiveness by tailoring trajectories to the curved shape of the ablated structure and by enabling access through natural orifices. OBJECTIVE: To investigate the feasibility of using a concentric tube robot to access the hippocampus through the foramen ovale to deliver thermal therapy and thereby provide a percutaneous treatment for epilepsy without drilling the skull. METHODS: The skull and both hippocampi were segmented from dual CT/MR image volumes for 10 patients. For each of the 20 hippocampi, a concentric tube robot was designed and optimized to traverse a trajectory from the foramen ovale to and through the hippocampus from head to tail. RESULTS: Across all 20 cases, the mean distances (error) between hippocampus medial axis and backbone of the needle were 0.55 mm, 1.11 mm, and 1.66 mm for best, mean, and worst case, respectively. CONCLUSION: These curvilinear trajectories would provide accurate transforamenal delivery of an ablation probe to typical hippocampus volumes. This strategy has the potential to both decrease the invasiveness of the procedure and increase the completeness of hippocampal ablation. PMID- 28580379 TI - Synthesis of 2-Oxo-1, 2-Dihydroquinoline Chemotype with Multiple Attachment Points as Novel Screening Compounds for Drug Discovery. AB - The 2-oxo-1, 2-dihydroquinoline Chemotype is well represented among screening compound collection. However, the chemical space of 2-oxo-1, 2-dihydroquinoline has not been thoroughly investigated. In this work we report the synthesis of a small but novel 2-oxo-1, 2-dihydroquinoline compound array for screening purposes, especially in drug discovery, possessing three convenient point of diversity. PMID- 28580378 TI - Behavioral Economic Laboratory Research in Tobacco Regulatory Science. AB - OBJECTIVES: Research that can provide a scientific foundation for the United States Food and Drug Administration (FDA) tobacco policy decisions is needed to inform tobacco regulatory policy. One factor that affects the impact of a tobacco product on public health is its intensity of use, which is determined, in part, by its abuse liability or reinforcing efficacy. Behavioral economic tasks have considerable utility for assessing the reinforcing efficacy of current and emerging tobacco products. METHODS: This paper provides a narrative review of several behavioral economic laboratory tasks and identifies important applications to tobacco regulatory science. RESULTS: Behavioral economic laboratory assessments, including operant self-administration, choice tasks and purchase tasks, can be used generate behavioral economic data on the effect of price and other constraints on tobacco product consumption. These tasks could provide an expedited simulation of the effects of various tobacco control policies across populations of interest to the FDA. CONCLUSIONS: Tobacco regulatory research questions that can be addressed with behavioral economic tasks include assessments of the impact of product characteristics on product demand, assessments of the abuse liability of novel and potential modified risk tobacco products (MRTPs), and assessments of the impact of conventional and novel products in vulnerable populations. PMID- 28580380 TI - Recurrent Dislocation of the Proximal Interphalangeal Joint of the Finger: A Rare Issue in Hand Surgery. AB - Recurrent dislocation is not common in small joints. This report presents a recurrent dislocation of the proximal interphalangeal joint of the ring finger in a 23-years-old man. Recurrent dislocation was addressed successfully by repairing the avulsed volar plate to the base of the middle phalanx, followed by 6 weeks of splint immobilization. PMID- 28580381 TI - A Conceptual Framework for Barriers to the Recruitment and Retention of Rural CVD Participants in Behavior Intervention Trials. AB - BACKGROUND: Rural residents diagnosed with cardiovascular disease (CVD) or with CVD-related risks are underrepresented in behavioral intervention trials based on an extensive review of published studies. The low participation rate of rural residents weakens both the internal and external validity of published studies. Moreover, compared to urban residents, limited research exists to describe the unique barriers that limit the participation of rural residents in behavioral intervention trials. OBJECTIVE: The purpose of this review is to identify a conceptual framework (CF) underpinning common barriers faced by rural CVD patients to enroll in behavioral intervention trials. METHODS: We conducted a literature review using several electronic databases to obtain a representative sample of research articles, synthesized the evidence, and developed a CF to explain the barriers that may affect the research participation rate of rural residents with CVD or related risks. RESULTS: We found our evidence-based CF well explained the barriers for rural CVD patients to take part in behavioral intervention trials. Besides contextual factors (i.e. patient, community and research levels), other common factors impacting rural patients' intent to enroll are lack of awareness and understanding about behavioral trials, limited support from their healthcare providers and social circles, unfavorable attitudes, and the lack of opportunity to participating research. CONCLUSION AND IMPLICATION OF RESULT: The findings demonstrate the evidence-based model consisting of interlinked multi-level factors may help our understanding of the barriers encountered by rural CVD patients participating interventions to promote behavioral change. The implication for researchers is that identifying and developing strategies to overcome the barriers precedes conducting studies in rural communities. PMID- 28580382 TI - Differences in the Treatment of Benign Prostatic Hyperplasia: Comparing the Primary Care Physician and the Urologist. AB - INTRODUCTION: Benign prostatic hyperplasia is a prevalent chronic condition with expenditures exceeding $1 billion each year. Little is known about management of patients by primary care physicians compared to urologists. We assessed changes in management after medication initiation in these two settings. METHODS: From the Chronic Condition Warehouse 5% sample of Medicare beneficiaries linked to Medicare Part D data, we defined a cohort of men, 66 to 90 years old, with initial prescriptions for alpha-blocker, 5-alpha reductase inhibitor (5-ARI), or both. We assessed the initial change in therapy for up to four years after medication initiation: add a medication, switch medication, stop medication, or have surgery/retention. We estimated the cumulative incidence functions from competing risks data, and tested equality across groups (primary care physician vs. urologist). RESULTS: 5714 men started medication with a primary care physician, 1970 with a urologist. The most common change in treatment after medication initiation across all groups was medication discontinuation (55% alpha blocker; 46% 5-ARI; 30% combination therapy cumulative incidence at 3 years). Patients who started with primary care physicians were more likely to discontinue BPH-related medications, than patients with urologists (HR 1.19; 95% CI 1.09 - 1.29). The majority of patients who stopped alpha blocker therapy did not have further BPH therapy. CONCLUSIONS: Men given combination therapy are most likely to have continued medication use. Surgical therapy and retention are relatively rare events. Patients who initiate care with urologists are more likely to continue medical therapy than patients with care initiated by primary care providers. PMID- 28580383 TI - Resection of granulomatous tissue resolves silicone induced hypercalcemia. AB - Because of the increasing trend of body contour enhancements with injections, implants, and fillers, clinicians should be on high alert for the possibility of silicone-induced hypercalcemia as one of the differential diagnoses in a patient with history of silicone use. Hypercalcemia as a result of silicone injections has been reported, and there is concern that there will be more cases given the popularity of cosmetic silicone. Cases involved a mother and daughter (70 & 55 years) who presented in 2013 with hypercalcemia after cosmetic silicone injections in 2007. Evaluation showed 1, 25-dihydroxyvitamin D-mediated hypercalcemia and progressive renal dysfunction; lymph node biopsy showed granulomatous silicone lymphadenitis. MRI of the pelvis revealed abnormal signal enhancement within the subcutaneous gluteal adipose tissue and enlarged inguinal lymph nodes. For persistent hypercalcemia and hypercalciuria, surgical resection of silicone material and granulomas is a successful approach to normalize the serum calcium level. PMID- 28580384 TI - Genetic risk score based on the prevalence of vertebral fracture in Japanese women with osteoporosis. AB - A genetic risk score (GRS) was developed for predicting fracture risk based on the prevalence of vertebral fractures in 441 Japanese females with osteoporosis. A total of 979 (858 nonsynonymous and 121 silent) single-nucleotide polymorphisms (SNPs) located in 74 osteoporosis-susceptibility genes were genotyped and evaluated for their association with fracture prevalence. Four SNPs (protein kinase domain containing, cytoplasmic [PKDCC; rs4952590], CDK5-regulatory subunit associated protein 1-like 1 [CDKAL1; rs4712556], wingless-type MMTV-integration site family member 16 [WNT16; rs2707466], and G-patch domain-containing gene 1 [GPATCH1; rs10416265]) showed a significant association (p < 0.05) with the fracture, in which the minor allele of the former two SNPs was the protective allele and that of the latter two SNPs was the risk allele. Applying a dominant genetic model, we allotted - 1 point each to the protective-allele carriers and 1 point each to the risk-allele carriers, and GRS values were calculated as the sum of the points. The receiver-operating characteristic curves showed that GRS adequately predicted vertebral fracture. For the model predicted by the GRS with and without the effect of age, areas under the curves were 0.788 (95% confidence interval [CI]: 0.736-0.840) and 0.667 (95% CI: 0.599-0.735), respectively. Multiple logistic regression analysis revealed that the odds ratio for the association between fracture prevalence and GRS was 3.27 (95% CI: 1.36-7.87, p = 0.008) for scores of - 1 to 0 (n = 303) and 12.12 (95% CI: 4.19-35.07, p < 0.001) for scores of 1 to 2 (n = 35) relative to a score of - 2 (n = 103). The GRS based on the four SNPs could help identify at-risk individuals and enable implementation of preventive measures for vertebral fracture. PMID- 28580385 TI - Modeling and remodeling effects of intermittent administration of teriparatide (parathyroid hormone 1-34) on bone morphogenetic protein-induced bone in a rat spinal fusion model. AB - BACKGROUND: Bone morphogenetic protein (BMP)-based tissue engineering has focused on inducing new bone efficiently. However, modeling and remodeling of BMP-induced bone have rarely been discussed. Teriparatide (parathyroid hormone [PTH] 1-34) administration initially increases markers of bone formation, followed by an increase in bone resorption markers. This unique activity would be expected to accelerate the modeling and remodeling of new BMP-induced bone. METHODS: Male Sprague-Dawley rats underwent posterolateral spinal fusion surgery and implantation of collagen sponge containing either 50 MUg recombinant human (rh)BMP-2 or saline. PTH 1-34 (60 MUg/kg, 3 times/week) or saline injections were continued from preoperative week 2 week to postoperative week 12. The volume and quality of newly formed bone were monitored by in vivo micro-computed tomography and analyses of bone histomorphometry and serum bone metabolism markers were conducted at postoperative week 12. RESULTS: Microstructural indices of the newly formed bone were significantly improved by PTH 1-34 administration, which significantly decreased the tissue volumes of the fusion mass at postoperative week 12 compared to that at postoperative week 2. Bone histomorphometry and serum analyses showed that PTH administration significantly increased both bone formation and resorption markers. Analysis of the histomorphometry of cortical bone identified predominant periosteal bone resorption and endosteal bone formation. CONCLUSIONS: Long-term intermittent administration of PTH 1-34 significantly accelerated the modeling and remodeling of new BMP-induced bone. CLINICAL RELEVANCE: Our results suggest that the combined administration of rhBMP 2 and PTH 1-34 facilitates qualitative and quantitative improvements in bone regeneration, by accelerating bone modeling and remodeling. PMID- 28580386 TI - Hospitalizations for osteoporosis-related fractures: Economic costs and clinical outcomes. AB - BACKGROUND: Osteoporotic fractures frequently require inpatient care, and are associated with elevated risks of morbidity, mortality, and re-hospitalization. A comprehensive evaluation of healthcare costs, resource utilization, and outcomes associated with osteoporosis (OP)-related fractures treated in US hospitals was undertaken. METHODS: A retrospective analysis using the Premier Perspective Database (2010 - 2013) was conducted. Study population comprised patients aged >= 50 years hospitalized with a principal diagnosis of a closed or pathologic fracture commonly associated with OP; the first qualifying hospitalization was designated the "index admission". Patients with evidence of major trauma, malignancy, or other non-OP conditions that may lead to pathologic fracture during the index admission were excluded. Study measures included healthcare costs (in 2013 USD), length of stay (LOS), intensive care unit (ICU) use, and mortality during the index admission, as well as 60-day fracture-related readmission. RESULTS: A total of 268,477 patients were admitted to hospital (n = 548 hospitals) with a principal diagnosis of an OP-related fracture; mean (SD) age was 78 (11) years, 75% were female, 69% had >= 2 comorbidities, and 82% of patients had a diagnostic code for accidental fall. Among all OP-related fracture admissions, mean (95% CI) hospital cost was $12,839 (12,784-12,893) and LOS was 5.1 (5.1-5.1) days; during the admission, ICU use was 7.4% (7.3-7.5) and mortality was 1.5% (1.5-1.6), and during the 60-day post-discharge period, fracture-related readmission was 2.3% (2.2-2.4). CONCLUSIONS: Hospital costs associated with the acute treatment of OP-related fractures are substantial, especially among patients with fractures of the hip, femur, and spine. Among patients with vertebral fractures-the second most common reason for admission mortality and ICU use were notably high, and costs and LOS were higher than among those with non-vertebral fractures (excluding hip). Interventions that are effective in reducing fracture risk have the potential to yield substantial cost savings. PMID- 28580388 TI - Association of gastrointestinal events with osteoporosis treatment initiation and treatment compliance in Germany: An observational study. AB - BACKGROUND: Gastrointestinal (GI) events are common in postmenopausal women treated for osteoporosis. The influence of GI events on treatment initiation and treatment compliance is the subject of ongoing research. OBJECTIVE: The objectives of this study were (i) to determine the association of GI events with receipt of treatment in patients newly diagnosed with osteoporosis, and (ii) among treated patients, to determine the association of GI events with treatment compliance. METHODS: This was a retrospective analysis of claims data carried out in Germany using the Mediplus database. Data were collected from January 1992 through December 2010. The dual-objective study design required two distinct cohorts. Cohort 1 comprised women aged >= 55 with a diagnosis of osteoporosis. GI events were recorded for the 12 month periods before and after the date of diagnosis. Time-varying Cox regression and discrete choice models were used, respectively, to assess the association of post-diagnosis GI events with the initiation of pharmacologic treatment (yes versus no) and the type of treatment initiated (bisphosphonates versus non-bisphosphonates). Cohort 2 comprised women aged >= 55 who initiated an oral bisphosphonate (alendronate, ibandronate, or risedronate). GI events were recorded for the 12 month periods before and after the date of bisphosphonate initiation, and a logistic regression model was employed to determine if pre-treatment or post-treatment GI events were associated with patient compliance, defined as a medication possession ratio (MPR) of >= 60%, with sensitivity analyses at MPR >= 80%. RESULTS: In cohort 1 (N = 18,813), 13.8% of patients had GI events in the pre-diagnosis period, and 14.8% had GI events in the post-diagnosis period. Among the patients with post diagnosis GI events, 93.2% remained untreated during the post-index year, 6.2% were treated with bisphosphonates, and 0.6% received non-bisphosphonates. The respective percentages in patients without post-diagnosis GI events were 81.3%, 16.7%, and 1.9%. A post-diagnosis GI event decreased the likelihood of receiving any osteoporosis treatment (versus no treatment) by 83% (HR 0.17, 95% CI 0.14 0.20) and also decreased the likelihood of receiving a bisphosphonate (versus a non-bisphosphonate) by 39% (OR 0.61, 95% CI 0.54-0.68). In cohort 2 (N = 6040), 17.1% of patients had GI events in the year before treatment initiation, and 19.1% had GI events in the year after treatment initiation. At 12 months post treatment initiation, GI events were more frequent in patients with pre-treatment GI events (53.2%) than in those without pre-treatment GI events (12.0%). Post treatment GI events decreased the likelihood of attaining compliance defined as an MPR >= 60% (OR 0.84, 95% CI 0.73-0.97) but not an MPR >= 80% (OR 0.91, 95% CI 0.79-1.06). CONCLUSIONS: In German women newly diagnosed with osteoporosis, GI events decreased the likelihood of receiving treatment and were associated with the choice of treatment. In women initiating oral bisphosphonates, post-treatment GI events were associated with reduced patient compliance. PMID- 28580387 TI - Impaired glucose tolerance attenuates bone accrual by promoting the maturation of osteoblasts: Role of Beclin1-mediated autophagy. AB - Patients with type 2 diabetes mellitus (T2DM) experience a 1.5-3.5 fold increase in fracture risk, but the mechanisms responsible for these alterations in bone biomechanical properties remain elusive. Macroautophagy, often referred to as autophagy, is regulated by signaling downstream of the insulin receptor. Metabolic changes associated with the progression of glucose intolerance have been shown to alter autophagy in various tissues, but limited information is available in relation to bone cells. The aim of this study was to (a) investigate whether autophagy is altered in bone tissue during impaired glucose tolerance, and (b) determine how autophagy impacts osteoblast differentiation, activity, and maturation. Four-week-old, male C57BL/6 mice were fed a control (Con) or high fat (HF) diet for 2, 8, or 16 wks. Mice on the HF diet demonstrated elevated fasting blood glucose and impaired glucose tolerance. Reduced trabecular bone in the femoral neck was evident in the mice on the HF diet by 8 wks compared to Con mice. Histological evaluation of the tibia suggested that the high fat diet promoted terminal differentiation of the osteoblast to an osteocyte. This shift of the osteoblasts towards a non-mineralizing, osteocyte phenotype appears to be coordinated by Beclin1-mediated autophagy. Consistent with these changes in the osteoblast in vivo, the induction of autophagy was able to direct MC3T3-E1 cells towards a more mature osteoblast phenotype. Although these data are somewhat observational, further investigation is warranted to determine if Beclin1 mediated autophagy is essential for the terminal differentiation of the osteoblasts and whether autophagy is having a protective or deleterious effect on bone in T2DM. PMID- 28580389 TI - The F-actin modulator SWAP-70 controls podosome patterning in osteoclasts. AB - Osteoclasts are bone resorbing cells acting as key mediators of bone disorders. Upon adhesion to bone, osteoclasts polarize and reorganize their cytoskeleton to generate a ring-like F-actin-rich structure, the sealing zone, wherein the osteoclast's resorptive organelle, the ruffled border, is formed. The dynamic self-organization of actin-rich adhesive structures, the podosomes, from clusters to belts is crucial for osteoclast-mediated bone degradation. Mice lacking the protein SWAP-70 display an osteopetrotic phenotype due to defective bone resorption caused by impaired actin ring formation in Swap-70-/- osteoclasts. To further elucidate the mechanisms underlying this defect, we investigated the specific function of SWAP-70 in the organization and dynamics of podosomes. These detailed studies show that the transition from podosome clusters to rings is impaired in Swap-70-/- osteoclasts. Live cell imaging of dynamic F-actin turnover and SWAP-70 localization during podosome patterning indicate that SWAP-70 is dispensable for cluster formation but plays a key role in F-actin ring generation. Our data provide insights in the role of SWAP-70's F-actin binding domain and pleckstrin homology (PH) domain in the proper localization of SWAP-70 and formation of a peripheral podosome belt, respectively. Ex vivo bone analyses revealed that SWAP-70-deficient osteoclasts exhibit defective ruffled border formation and V-ATPase expression. Our findings suggest an important role of membrane binding of SWAP-70 for the regulation of actin dynamics, which is essential for podosome patterning, and thus for the resorptive activity of osteoclasts. PMID- 28580390 TI - Glucocorticoid receptor-mediated cis-repression of osteogenic genes requires BRM SWI/SNF. AB - Glucocorticoids are an effective therapy for a variety of severe inflammatory and autoimmune disorders; however, the therapeutic use of glucocorticoids is severely limited by their negative side effects, particularly on osteogenesis. Glucocorticoids regulate transcription by binding to the glucocorticoid receptor (GR), which then binds the promoters of target genes to induce either activation or repression. The gene activation effects of nuclear hormone receptors broadly require the cooperation of the chromatin remodeling complex known as SWI/SNF, which is powered by an ATPase core. The well-studied SWI/SNF ATPase, BRG1, is required for gene activation by a spectrum of nuclear hormone receptors including GR. However, glucocorticoid-induced side effects specifically related to impaired osteogenesis are mostly linked with GR-mediated repression. We have considered whether cis-repression of osteogenic genes by GR may be mediated by a distinct subclass of SWI/SNF powered by the alternative ATPase, BRM. BRM does not have an essential role in mammalian development, but plays a repressor role in osteoblast differentiation and favors adipogenic lineage selection over osteoblast commitment, effects that mirror the repressor effects of GR. The studies reported here examine three key GR cis-repression gene targets, and show that GR association with these promoters is sharply reduced in BRM deficient cells. Each of these GR-targeted genes act in a different way. Bglap encodes osteocalcin, which contributes to normal maturation of osteoblasts from committed pre osteoblasts. The Per3 gene product acts in uncommitted mesenchymal stem cells to influence the osteoblast/adipocyte lineage selection point. Fas ligand, encoded by FasL, is a means by which osteoblasts can modulate bone degradation by osteoclasts. Repression of each of these genes by glucocorticoid favors bone loss. The essential role of BRM in cooperation with GR at each of these control points offers a novel mechanistic understanding of the role of GR in bone loss. PMID- 28580391 TI - Case series: Odontohypophosphatasia or missed diagnosis of childhood/adult-onset hypophosphatasia? - Call for a long-term follow-up of premature loss of primary teeth. AB - INTRODUCTION: Hypophosphatasia, a metabolic bone disease caused by a tissue nonspecific alkaline phosphatase deficiency, leads to undermineralization of bone and/or teeth, impaired vitamin B6 metabolism, and a spectrum of disease presentation. At the mild end of the spectrum, it presents as pathologic fractures in later adulthood. Patients with isolated dental manifestations, typically presenting as premature loss of primary teeth, are classified as having odontohypophosphatasia (odontoHPP). A subset of patients diagnosed with odontoHPP in childhood can later develop extra-dental manifestations that constitute childhood- or adult-onset hypophosphatasia. CASE REPORTS METHODS/RESULTS: Retrospective data related to onset, detailed clinical course, and method of diagnosis were collected as part of a natural history of adult patients with hypophosphatasia. Of 9 initial patients, all had low serum alkaline phosphatase levels for their age and gender at adult presentation (Table 2). The majority (8/9) demonstrated childhood dental signs of hypophosphatasia as the initial clinical manifestation: premature loss of primary teeth (7/9), absent primary teeth (1/9), and delayed loss of primary teeth (1/9). Despite childhood dental presentation and/or other signs/symptoms, diagnosis of hypophosphatasia was delayed 20-54 years (median = 46) since the primary tooth problems and 8-45 years (median = 27) since the first fracture or onset of a major adult tooth problem. CONCLUSION: Patients with primary tooth loss in childhood were often diagnosed with hypophosphatasia later in life. Pediatric patients classified as having odontoHPP under present practice can manifest significant disease burden later in life. PMID- 28580393 TI - Estrogen depletion and drug treatment alter the microstructure of type I collagen in bone. AB - The impact of estrogen depletion and drug treatment on type I collagen fibril nanomorphology and collagen fibril packing (microstructure) was evaluated by atomic force microscopy (AFM) using an ovariectomized (OVX) rabbit model of estrogen deficiency induced bone loss. Nine month-old New Zealand white female rabbits were treated as follows: sham-operated (Sham; n = 11), OVX + vehicle (OVX + Veh; n = 12), OVX + alendronate (ALN, 600 MUg/kg/wk., s.c.; n = 12), and OVX + cathepsin-K inhibitor L-235 (CatKI, 10 mg/kg, daily, p.o.; n = 13) in prevention mode for 27 weeks. Samples from the cortical femur and trabecular lumbar vertebrae were polished, demineralized, and imaged using AFM. Auto-correlation of image patches was used to generate a vector field for each image that mathematically approximated the collagen fibril alignment. This vector field was used to compute an information-theoretic entropy that was employed as a quantitative fibril alignment parameter (FAP) to allow image-to-image and sample to-sample comparison. For all samples, no change was observed in the average FAP values; however significant differences in the distribution of FAP values were observed. In particular, OVX + Veh lumbar vertebrae samples contained a tail of lower FAP values representing regions of greater fibril alignment. OVX + ALN treatment resulted in a FAP distribution with a tail indicating greater alignment for cortical femur and less alignment for trabecular lumbar vertebrae. OVX + CatKI treatment gave a distribution of FAP values with a tail indicating less alignment for cortical femur and no change for trabecular lumbar vertebrae. Fibril alignment was also evaluated by considering when a fibril was part of discrete bundles or sheets (classified as parallel) or not (classified as oblique). For this analysis, the percentage of parallel fibrils in cortical femur for the OVX group was 17% lower than the Sham group. OVX + ALN treatment partially prevented the proportion of parallel fibrils from decreasing and OVX + CatKI treatment completely prevented a change. In trabecular lumbar vertebrae, there was no difference in the percentage of parallel fibrils between Sham and any of the other treatment groups. PMID- 28580392 TI - A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women. AB - BACKGROUND: Osteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50-70% of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA) women in a GWAS meta-analysis. METHODS: Data on clinical fractures (all fractures except fingers, toes, face, skull or sternum) were analyzed among AA female participants in the Women's Health Initiative (WHI) (N = 8155), Cardiovascular Health Study (CHS) (N = 504), BioVU (N = 704), Health ABC (N = 651), and the Johnston County Osteoarthritis Project (JoCoOA) (N = 291). Affymetrix (WHI) and Illumina (Health ABC, JoCoOA, BioVU, CHS) GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~ 2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta analysis. Genome-wide significance was set at P < 5 * 10- 8. RESULTS: One SNP, rs12775980 in an intron of SVIL on chromosome 10p11.2, reached genome-wide significance (P = 4.0 * 10- 8). Although this SNP has a low minor allele frequency (0.03), there was no evidence for heterogeneity of effects across the studies (I2 = 0). This locus was not reported in any previous osteoporosis related GWA studies. We also interrogated previously reported GWA-significant loci associated with fracture or bone mineral density in our data. One locus (SMOC1) generalized, but overall there was not substantial evidence of generalization. Possible reasons for the lack of generalization are discussed. CONCLUSION: This GWAS meta-analysis of fractures in African American women identified a potentially novel locus in the supervillin gene, which encodes a platelet-associated factor and was previously associated with platelet thrombus formation in African Americans. If validated in other populations of African descent, these findings suggest potential new mechanisms involved in fracture that may be particularly important among African Americans. PMID- 28580394 TI - Intraskeletal variation in human cortical osteocyte lacunar density: Implications for bone quality assessment. AB - Osteocytes and their lacunocanalicular network have been identified as the regulator of bone quality and function by exerting extensive influence over metabolic processes, mechanical adaptation, and mineral homeostasis. Recent research has shown that osteocyte apoptosis leads to a decrease in bone quality and increase in bone fragility mediated through its effects on remodeling. The purpose of this study is to investigate variation in cortical bone osteocyte lacunar density with respect to major factors including sex, age, and intracortical porosity to establish both regional and systemic trends. Samples from the midshaft femur, midshaft rib and distal one-third diaphysis of the radius were recovered from 30 modern cadaveric individuals (15 males and 15 females) ranging from 49 to 100 years old. Thick ground undecalcified histological (80 MUm) cross-sections were made and imaged under bright field microscopy. Osteocyte lacunar density (Ot.Lc.N/B.Ar) and intracortical porosity (%Po.Ar) were quantified. No significant sex differences in Ot.Lc.N/B.Ar or %Po.Ar were found in any element. Linear regressions demonstrated a significant decrease in osteocyte lacunar density (Ot.Lc.N/B.Ar) and increase in intracortical porosity (%Po.Ar) with age for the sex-pooled sample in the femur (R2 = 0.208, 0.297 respectively) and radius (R2 = 0.108, 0.545 respectively). Age was unable to significantly predict osteocyte lacunar density or intracortical porosity in the rib (R2 = 0.058, 0.114 respectively). Comparisons of regression coefficients demonstrated a systemic trend in the decrease in osteocyte lacunar density (Ot.Lc.N/B.Ar) and increase in intracortical porosity (%Po.Ar) with age. In each element, intracortical porosity was significantly negatively correlated with lacunar density for which the radius demonstrated the strongest relationship (r = - 0.746). Using pore number (Po.N) as a proxy for available vascularity to support the osteocyte population, Po.N was able to predict 61.8% of variation in osteocyte lacunar number (Ot.Lc.N) in the rib. The femur and radius also demonstrated significant relationships between these variables (R2 = 0.560 and 0.397 respectively). The results from this study indicate that although the femur, radius and rib may be experiencing systemically influenced declines in osteocyte lacunar density, there may be differential effects at each anatomical site potentially due to age related changes in mechanical loading. With decreasing osteocyte lacunar density in each element, intracortical porosity increased with likely direct impacts on gross bone strength. This study provides a foundation upon which to build interpretations of osteocyte lacunar density values and their effect on differential fracture risk for aging individuals. PMID- 28580396 TI - Combined aerobic and resistance training improves bone health of female cancer survivors. AB - INTRODUCTION: Cancer pathogenesis and resulting treatment may lead to bone loss and poor skeletal health in survivorship. The purpose of this investigation was to evaluate the influence of 26 weeks of combined aerobic and resistance-training (CART) exercise on bone mineral density (BMD) in a multi-racial sample of female cancer survivors. METHODS: Twenty-six female cancer survivors volunteered to undergo CART for 1 h/day, 3 days/week, for 26 weeks. The Improving Physical Activity After Cancer Treatment (IMPAACT) Program involves supervised group exercise sessions including 20 min of cardiorespiratory training, 25 min of circuit-style resistance-training, and 15 min of abdominal exercises and stretching. BMD at the spine, hip, and whole body was assessed using dual-energy X-ray absorptiometry (DXA) before and after the intervention. Serum markers of bone metabolism (procollagen-type I N-terminal propeptide, P1NP, and C-terminal telopeptides, CTX) were measured at baseline, 13 weeks, and at study completion. RESULTS: Eighteen participants, with the average age of 63.0 +/- 10.3 years, completed the program. Mean duration since completion of cancer treatment was 6.2 +/- 10.6 years. Paired t-tests revealed significant improvements in BMD of the spine (0.971 +/- 0.218 g/cm2 vs. 0.995 +/- 0.218 g/cm2, p = 0.012), hip (0.860 +/ 0.184 g/cm2 vs. 0.875 +/- 0.191 g/cm2, p = 0.048), and whole body (1.002 +/- 0.153 g/cm2 vs. 1.022 +/- 0.159 g/cm2, p = 0.002). P1NP declined 22% at 13 weeks and 28% at 26 weeks in comparison to baseline (p < 0.01) while CTX showed a non significant decrease of 8% and 18% respectively. CONCLUSIONS: We report significant improvements in BMD at the spine, hip, and whole body for female cancer survivors who completed 26 weeks of CART. This investigation demonstrates the possible effectiveness of CART at improving bone health and reducing risk of osteoporosis for women who have completed cancer treatment. The IMPAACT Program appears to be a safe and feasible way for women to improve health after cancer treatment. PMID- 28580395 TI - Effects of total flavonoids from Drynariae Rhizoma prevent bone loss in vivo and in vitro. AB - Estrogen deficiency is one of the major causes of osteoporosis in postmenopausal women. Drynariae Rhizoma is a widely used traditional Chinese medicine for the treatment of bone diseases. In this study, we investigated the therapeutic effects of the total Drynariae Rhizoma flavonoids (DRTF) on estrogen deficiency induced bone loss using an ovariectomized rat model and osteoblast-like MC3T3-E1 cells. Our results indicated that DRTF produced osteo-protective effects on the ovariectomized rats in terms of bone loss reduction, including decreased levels of bone turnover markers, enhanced biomechanical femur strength and trabecular bone microarchitecture deterioration prevention. In vitro experiments revealed that the actions of DRTF on regulating osteoblastic activities were mediated by the estrogen receptor (ER) dependent pathway. Our data also demonstrated that DRTF inhibited osteoclastogenesis via up-regulating osteoprotegrin (OPG), as well as down-regulating receptor activator of NF-kappaB ligand (RANKL) expression. In conclusion, this study indicated that DRTF treatment effectively suppressed bone mass loss in an ovariectomized rat model, and in vitro evidence suggested that the effects were exerted through actions on both osteoblasts and osteoclasts. PMID- 28580397 TI - Imaging and mapping of mouse bone using MALDI-imaging mass spectrometry. AB - Matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) is an advanced method used globally to analyze the distribution of biomolecules on tissue cryosections without any probes. In bones, however, hydroxyapatite crystals make it difficult to determine the distribution of biomolecules using MALDI-IMS. Additionally, there is limited information regarding the use of this method to analyze bone tissues. To determine whether MALDI-IMS analysis of bone tissues can facilitate comprehensive mapping of biomolecules in mouse bone, we first dissected femurs and tibiae from 8-week-old male mice and characterized the quality of multiple fixation and decalcification methods for preparation of the samples. Cryosections were mounted on indium tin oxide-coated glass slides, dried, and then a matrix solution was sprayed on the tissue surface. Images were acquired using an iMScope at a mass-to-charge range of 100-1000. Hematoxylin eosin, Alcian blue, Azan, and periodic acid-Schiff staining of adjacent sections was used to evaluate histological and histochemical features. Among the various fixation and decalcification conditions, sections from trichloroacetic acid treated samples were most suitable to examine both histology and comprehensive MS images. However, histotypic MS signals were detected in all sections. In addition to the MS images, phosphocholine was identified as a candidate metabolite. These results indicate successful detection of biomolecules in bone using MALDI-IMS. Although analytical procedures and compositional adjustment regarding the performance of the device still require further development, IMS appears to be a powerful tool to determine the distribution of biomolecules in bone tissues. PMID- 28580398 TI - Histomorphometric analysis of minimodeling in the vertebrae in postmenopausal patients treated with anti-osteoporotic agents. AB - Minimodeling is a type of focal bone formation that is characterized by the lack of precedent bone erosion by osteoclasts. Although this form of bone formation has been described for more than a decade, how anti-osteoporotic agents that are currently used in clinical practice affect the kinetics of minimodeling is not fully understood. We performed a bone morphometric analysis using human vertebral specimens collected from postmenopausal patients who underwent spinal surgery. Patients were divided into three groups according to osteoporosis medication; non treated, Eldecalcitol (ELD, a vitamin D derivative that has recently been approved to treat patients with osteoporosis in Japan)-treated, and bisphosphonate-treated groups. Five to six patients were enrolled in each group. There was a trend toward enhanced minimodeling in ELD-treated patients and suppressed of it in bisphosphonate-treated patients compared with untreated patients. The differences of minimodeling activity between ELD-treated and bisphosphonate-treated patients were statistically significant. The present study suggests that ELD and bisphosphonates have opposite effects on minimodeling from one another, and show that minimodeling also takes place in vertebrae as has been described for the ilium and femoral head in humans. PMID- 28580399 TI - Does pamidronate enhance the osteogenesis in mesenchymal stem cells derived from fibrous hamartoma in congenital pseudarthrosis of the tibia? AB - Neurofibromatosis type 1 (NF1) is a commonly occurring genetic disorder in children. Mutation in the NF1 gene has its implication in poor osteoblastic capabilities. We hypothesised that pamidronate will enhance the osteoblastic potential of the mesenchymal stem cells (MSCs) derived from lipofibromatosis tissue of children with congenital pseudarthrosis tibia (CPT) associated with NF1. In this study, bone marrow MSCs (BM MSCs) and CPT MSCs were obtained from three patients undergoing salvage surgeries/bone grafting (healthy controls) and those undergoing excision of the hamartoma and corrective surgeries respectively. The effects of pamidronate (0, 10 nM, 100 nM and 1 MUM) on cell proliferation, toxicity and differentiation potential were assessed and the outcome was measured by staining and gene expression. Our outcome showed that CPT MSCs had more proliferation rate as compared to BM MSCs. All 3 doses of pamidronate did not cause any toxicity to the cells in both the groups. The CPT MSCs showed less differentiation with pamidronate compared to the healthy control MSCs. This was quantitated by staining and gene expression analysis. Therefore, supplementation with pamidronate alone will not aid in bone formation in patients diagnosed with CPT. An additional stimulus is required to enhance bone formation. PMID- 28580401 TI - Transient osteoporosis: Not just the hip to worry about. AB - Transient osteoporosis (TO) is a clinical syndrome characterized by joint pain and the presence of bone marrow edema on magnetic resonance imaging (MRI), both of which spontaneously resolve over time. Transient osteoporosis most commonly affects the hip, but also may involve other lower extremity sites. TO likely represents a disorder that may be monoarticular or "migratory" with involvement of two or more lower extremity sites sequentially affected over a number of months. We report on two cases of transient osteoporosis, one involving the knee and one involving the hip, demonstrating the utility of serial bone mineral density measurements at both sites. Additionally, we are able to report on the microarchitectural changes seen at the distal femur on ultra-high resolution (7 T) MRI. Case #1 describes a recurrence of transient osteoporosis of the hip three years after a similar presentation at the contralateral hip and highlights the findings of rapidly changing bone mineral density in this clinical syndrome. In contrast to the spine, hip and forearm, peripheral bone density measurements at the knee are rarely reported and to our knowledge Case #2 represents the first report of transient osteoporosis of the knee demonstrating bone density findings similar to that seen in the hip. We postulate that transient osteoporosis of the knee is part of a clinical spectrum most commonly seen in the hip and one that is marked by lower extremity joint pain, bone marrow edema on MRI and transient decreases in bone mineral density all of which spontaneously resolve without sequelae. PMID- 28580400 TI - Replacement of daily load attenuates but does not prevent changes to the musculoskeletal system during bed rest. AB - The dose-response effects of exercise in reduced gravity on musculoskeletal health have not been well documented. It is not known whether or not individualized exercise prescriptions can be effective in preventing the substantial loss in bone mineral density and muscle function that have been observed in space flight and in bed rest. In this study, typical daily loads to the lower extremities were quantified in free-living subjects who were then randomly assigned to control or exercise groups. Subjects were confined to 6 degree head-down bed rest for 84 days. The exercise group performed individually prescribed 1 g loaded locomotor exercise to replace their free-living daily load. Eleven subjects (5 exercise, 6 control) completed the protocol. Volumetric bone mineral density results from quantitative computed tomography demonstrated that control subjects lost significant amounts of bone in the intertrochanteric and total hip regions (p < 0.0125), whereas the exercise group showed no significant change from baseline in any region (p > 0.0125). Pre-and post-bed rest muscle volumes were calculated from analysis of magnetic resonance imaging data. The exercise group retained a larger percentage of their total quadriceps and gastrocnemius muscle volume (- 7.2% +/- 5.9, - 13.8% +/- 6.1, respectively) than their control counterparts (- 23.3% +/- 5.9, - 33.0 +/- 8.2, respectively; p < 0.01). Both groups significantly lost strength in several measured activities (p < 0.05). The declines in peak torque during repeated exertions of knee flexion and knee extension were significantly less in the exercise group than in the control group (p < 0.05) but work done was not significantly different between groups (p > 0.05). The decline in VO2max was 17% +/- 18 in exercising subjects (p < 0.05) and 31% +/- 13 in control subjects (p = 0.003; difference between groups was not significant p = 0.26). Changes in blood and urine measures showed trends but no significant differences between groups (p > 0.05). In summary, the decline in a number of important measures of musculoskeletal and cardiovascular health was attenuated but not eliminated by a subject-specific program of locomotor exercise designed to replace daily load accumulated during free living. We conclude that single daily bouts of exposure to locomotor exercise can play a role in a countermeasures program during bed rest, and perhaps space flight, but are not sufficient in their own right to ensure musculoskeletal or cardiovascular health. PMID- 28580403 TI - Damage accumulation of bovine bone under variable amplitude loads. AB - Stress fractures, a painful injury, are caused by excessive fatigue in bone. This study on damage accumulation in bone sought to determine if the Palmgren-Miner rule (PMR), a well-known linear damage accumulation hypothesis, is predictive of fatigue failure in bone. An electromagnetic shaker apparatus was constructed to conduct cyclic and variable amplitude tests on bovine bone specimens. Three distinct damage regimes were observed following fracture. Fractures due to a low cyclic amplitude loading appeared ductile ( 4000 MUepsilon), brittle due to high cyclic amplitude loading (> 9000 MUepsilon), and a combination of ductile and brittle from mid-range cyclic amplitude loading (6500 -6750 MUepsilon). Brittle and ductile fracture mechanisms were isolated and mixed, in a controlled way, into variable amplitude loading tests. PMR predictions of cycles to failure consistently over-predicted fatigue life when mixing isolated fracture mechanisms. However, PMR was not proven ineffective when used with a single damage mechanism. PMID- 28580402 TI - Bone microstructure in men assessed by HR-pQCT: Associations with risk factors and differences between men with normal, low, and osteoporosis-range areal BMD. AB - PURPOSE: The primary objective of this study was to analyze the relationships between bone microstructure and strength, and male osteoporosis risk factors including age, body mass index, serum 25-hydroxyvitamin D level, and testosterone level. A secondary objective was to compare microstructural and strength parameters between men with normal, low, and osteoporosis-range areal bone mineral density (aBMD). METHODS: Seventy-eight healthy male volunteers (mean age 62.4 +/- 7.8 years, range 50-84 years) were recruited. The participants underwent dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) of the ultra-distal radius and tibia. From the HR-pQCT images, volumetric bone mineral density (BMD) and cortical and trabecular bone microstructure were evaluated, and bone strength and cortical load fraction (Ct.LF) were estimated using micro-finite element analysis (MUFEA). RESULTS: Age was more strongly correlated with bone microstructure than other risk factors. Age had significant positive correlations with cortical porosity at both ultra-distal radius and tibia (r = 0.36, p = 0.001, and r = 0.47, p < 0.001, respectively). At the tibia, age was negatively correlated with cortical BMD, whereas it was positively correlated with trabecular BMD. In MUFEA, age was negatively correlated with Ct.LF, although not with bone strength. Compared with men with normal aBMD, men with low or osteoporosis-range aBMD had significantly poor trabecular bone microstructure and lower bone strength at the both sites, while there was no significant difference in cortical bone. CONCLUSIONS: Cortical bone microstructure was negatively affected by aging, and there was a suggestion that the influence of aging may be particularly important at the weight-bearing sites. PMID- 28580404 TI - The associations of exposure to combined hormonal contraceptive use on bone mineral content and areal bone mineral density accrual from adolescence to young adulthood: A longitudinal study. AB - BACKGROUND: The association of long term combined hormone based contraceptives (CHC) use on bone mineral content (BMC) and areal bone mineral density (aBMD) development remains controversial, as it appears that the relationship may be age dependent. The purpose of this study was to investigate the long-term associations of CHC exposure on the accrual of bone parameters from adolescence into young-adulthood. METHODS: 110 women (67 exposed to CHC) were drawn from the Pediatric Bone Mineral Accrual Study (PBMAS). Serial measures of total body (TB), lumbar spine (LS) and femoral neck (FN) BMC and aBMD were assessed by DXA (a total of 950 scans) and aligned by biological age (BA, years from peak height velocity [PHV]). Multilevel random effects models were constructed to assess the time dependent associations between annual CHC exposure and the development of bone parameters. RESULTS: After BA, height, lean tissue mass, fat mass, calcium and vitamin D intake, and physical activity were controlled, it was observed that those individuals exposed to CHC 6-years post PHV developed significantly less ( 0.00986 +/- 0.00422 g/cm2) TB aBMD than their non CHC exposed peers. Additionally, there were significant BA by CHC exposure interactions, where CHC exposure 6-years or more post PHV resulted in developing less TB BMC (-4.94 +/- 2.41 g), LS BMC (-0.29 +/- 0.11 g) and LS aBMD (-0.00307 +/- 0.00109 g/cm2). One year after the attainment of PHV, CHC users were predicted to have 1.2% more TB BMC, 3.8% more LS BMC and 1.7% more LS aBMD than non-users. At 9-years post PHV the predicted differences showed that CHC users had 0.9% less TB BMC and 2.7% less LS BMC and 1.6% less LS BMD than those not exposed to CHC. CONCLUSIONS: CHC may not hinder the development of BMC or aBMD during adolescence; however, exposure 6-years or more after PHV may be detrimental. PMID- 28580405 TI - Exploration of solar radiation data from three geo-political zones in Nigeria. AB - In this paper, readings of solar radiation received at three meteorological sites in Nigeria were analysed. Analysis of Variance (ANOVA) statistical test was carried out on the data set to observe the significant differences on radiations for each quarter of the specified years. The data were obtained in raw form from Nigerian Meteorological Agency (NIMET), Oshodi, Lagos. In order to get a clear description and visualization of the fluctuations of the radiation data, each year were considered independently, where it was discovered that for the 3rd quarter of each year, there is a great fall in the intensity of the solar radiation to as low as 73.27 (W/m2), 101.66 (W/m2), 158.51 (W/m2) for Ibadan, Port-Harcourt and Sokoto respectively. A detailed data description is available for the averages across months for each quarter. The data can provide insights on the health implications of exposure to solar radiation and the effect of solar radiation on climate change, food production, rainfall and flood patterns. PMID- 28580406 TI - The Consumer Motivation Scale: A detailed review of item generation, exploration, confirmation, and validation procedures. AB - This data article offers a detailed description of analyses pertaining to the development of the Consumer Motivation Scale (CMS), from item generation and the extraction of factors, to confirmation of the factor structure and validation of the emergent dimensions. The established goal structure - consisting of the sub goals Value for Money, Quality, Safety, Stimulation, Comfort, Ethics, and Social Acceptance - is shown to be related to a variety of consumption behaviors in different contexts and for different products, and should thereby prove useful in standard marketing research, as well as in the development of tailored marketing strategies, and the segmentation of consumer groups, settings, brands, and products. PMID- 28580407 TI - MC3T3 osteoblast-like cells cultured at alkaline pH: Microarray data (Affymetrix GeneChip Mouse 2.0 ST). AB - It is well known that pH plays a pivotal role in the control of bone remodeling. However, no comprehensive gene expression data are available for the effects of alkaline pH on osteoblasts. We cultured differentiating MC3T3-E1 osteoblast-like cells at pH 7.4, 7.8, and 8.4 for 14 days. To identify differential gene expression, microarray data were collected with Affymetrix GeneChips. The data were validated by real-time PCRs for five genes that were found to be greatly regulated in the GeneChip-experiments (DMP1, FABP4, SFRP2 and TNFRSF19) or considered relevant for the terminal function of osteoblasts (DMP1 and ATF4). All the data are available from the Gene Expression Omnibus database (GEO accession: GSE84907). Here, we provide pathway analyses of known protein coding genes that were down-regulated or up-regulated by greater than 2.0-fold. The regulation datasets obtained from comparisons of pH 7.8 and 7.4, as well as pH 8.4 and 7.4 share a high number of differentially expressed genes. When comparing pH 8.4 and 7.8, other genes mainly emerge, suggesting not only a simple amplification of the effects at pH 8.4 that were already induced at pH 7.8 but also the induction of different pathways. For a more detailed analysis, different mammalian functional gene networks were assigned to each dataset. After merging and manual optimization of the network graphs, three combined functional gene networks were obtained that reflected distinct pH-dependent cellular responses. A common feature of the networks was the central role of p38 MAP kinase. The microarray data presented here are related to the research article doi:10.1016/j.bbrep.2017.02.001 (Galow et al., 2017) [1]. PMID- 28580409 TI - Data from proteome analysis of Lasiodiplodia theobromae (Botryosphaeriaceae). AB - Trunk disease fungi are a global problem affecting many economically important fruiting trees. The Botryosphaeriaceae are a family of trunk disease fungi that require detailed biochemical characterization in order to gain insight into their pathogenicity. The application of a modified Folch extraction to protein extraction from the Botryosphaeriaceae Lasiodiplodia theobromae generated an unprecedented data set of protein identifications from fragmentation analysis and de novo peptide sequencing of its proteome. This article contains data from protein identifications obtained from a database-dependent fragmentation analysis using three different proteomics algorithms (MSGF, Comet and X! Tandem via the SearchGUI proteomics pipeline program) and de novo peptide sequencing. Included are data sets of gene ontology annotations using an all-Uniprot ontology database, as well as a Saccharomyces cerevisiae-only and a Candida albicans-only ontology database, in order to discern between those proteins involved in common functions with S. cerevisiae and those in common with the pathogenic yeast C. albicans. Our results reveal the proteome of L. theobromae contains more ontological categories in common to C. albicans, yet possesses a much wider metabolic repertoire than any of the yeasts studied in this work. Many novel proteins of interest were identified for further biochemical characterization and annotation efforts, as further discussed in the article referencing this article (1). Interactive Cytoscape networks of molecular functions of identified peptides using an all-Uniprot ontological database are included. Data, including raw data, are available via ProteomeXchange with identifier PXD005283. PMID- 28580410 TI - Systemic tacrolimus in the treatment of recalcitrant mucosal lichen planus. PMID- 28580408 TI - Data on the association of the nuclear envelope protein Sun1 with nucleoli. AB - SUN proteins participate in diverse cellular activities, many of which are connected to the nuclear envelope. Recently, the family member SUN1 has been linked to novel biological activities. These include the regulation of nucleoli, intranuclear compartments that assemble ribosomal subunits. We show that SUN1 associates with nucleoli in several mammalian epithelial cell lines. This nucleolar localization is not shared by all cell types, as SUN1 concentrates at the nuclear envelope in ganglionic neurons and non-neuronal satellite cells. Database analyses and Western blotting emphasize the complexity of SUN1 protein profiles in different mammalian cells. We constructed a STRING network which identifies SUN1-related proteins as part of a larger network that includes several nucleolar proteins. Taken together, the current data highlight the diversity of SUN1 proteins and emphasize the possible links between SUN1 and nucleoli. PMID- 28580411 TI - Recurrent halo nevus: Dermoscopy and confocal microscopy features. PMID- 28580412 TI - Metastatic cutaneous apocrine carcinoma: Multidisciplinary approach achieving complete response with adjuvant chemoradiation. PMID- 28580413 TI - Eosinophilic folliculitis in association with chronic lymphocytic leukemia: A clinicopathologic series. PMID- 28580414 TI - Anomaly in the education-health gradient: Biomarker profiles among adults with subbaccalaureate attainment levels. AB - This Short Communication builds on recent findings that documented an anomaly in the education-health gradient: adults who attended college but did not earn a BA (the subbaccalaureate group) reported an equal or higher level of health problems than adults with high school (HS) diploma. Our aim is to test whether this anomaly holds when we eliminate potential reporting differences, by examining biomarker levels in the subbaccalaureate vs HS groups. Using the restricted 1999 2012 NHANES, we estimate models of biomarkers for cardiovascular and metabolic diseases as a function of educational attainment, including three subbaccalaureate levels: "some college", vocational associate degree (AA), and academic AA. The data show that adults with "some college" or vocational AA have no systematic advantage over HS graduates in most biomarker indices while academic AA is associated with a significantly better risk profile compared to HS. The findings indicate that the adults with some college and vocational AA degrees do not benefit from their college experience in terms of improved physiological risk profile. This pattern underscores the need to understand and explain the anomalous health pattern that concerns 28% of American adults in the subbaccalaureate group among whom many reap little health payoffs to postsecondary schooling. PMID- 28580415 TI - KID Project: an internet-based digital video atlas of capsule endoscopy for research purposes. AB - BACKGROUND AND AIMS: Capsule endoscopy (CE) has revolutionized small-bowel (SB) investigation. Computational methods can enhance diagnostic yield (DY); however, incorporating machine learning algorithms (MLAs) into CE reading is difficult as large amounts of image annotations are required for training. Current databases lack graphic annotations of pathologies and cannot be used. A novel database, KID, aims to provide a reference for research and development of medical decision support systems (MDSS) for CE. METHODS: Open-source software was used for the KID database. Clinicians contribute anonymized, annotated CE images and videos. Graphic annotations are supported by an open-access annotation tool (Ratsnake). We detail an experiment based on the KID database, examining differences in SB lesion measurement between human readers and a MLA. The Jaccard Index (JI) was used to evaluate similarity between annotations by the MLA and human readers. RESULTS: The MLA performed best in measuring lymphangiectasias with a JI of 81 +/- 6 %. The other lesion types were: angioectasias (JI 64 +/- 11 %), aphthae (JI 64 +/- 8 %), chylous cysts (JI 70 +/- 14 %), polypoid lesions (JI 75 +/- 21 %), and ulcers (JI 56 +/- 9 %). CONCLUSION: MLA can perform as well as human readers in the measurement of SB angioectasias in white light (WL). Automated lesion measurement is therefore feasible. KID is currently the only open-source CE database developed specifically to aid development of MDSS. Our experiment demonstrates this potential. PMID- 28580416 TI - GluA2-Lacking AMPA Receptors and Nitric Oxide Signaling Gate Spike-Timing Dependent Potentiation of Glutamate Synapses in the Dorsal Raphe Nucleus. AB - The dorsal raphe nucleus (DRn) receives glutamatergic inputs from numerous brain areas that control the function of DRn serotonin (5-HT) neurons. By integrating these synaptic inputs, 5-HT neurons modulate a plethora of behaviors and physiological functions. However, it remains unknown whether the excitatory inputs onto DRn 5-HT neurons can undergo activity-dependent change of strength, as well as the mechanisms that control their plasticity. Here, we describe a novel form of spike-timing-dependent long-term potentiation (tLTP) of glutamate synapses onto rat DRn 5-HT neurons. This form of synaptic plasticity is initiated by an increase in postsynaptic intracellular calcium but is maintained by a persistent increase in the probability of glutamate release. The tLTP of glutamate synapses onto DRn 5-HT is independent of NMDA receptors but requires the activation of calcium-permeable AMPA receptors and voltage-dependent calcium channels. The presynaptic expression of the tLTP is mediated by the retrograde messenger nitric oxide (NO) and activation of cGMP/PKG pathways. Collectively, these results indicate that glutamate synapses in the DRn undergo activity dependent synaptic plasticity gated by NO signaling and unravel a previously unsuspected role of NO in controlling synaptic function and plasticity in the DRn. PMID- 28580418 TI - Human-induced changes in the distribution of rainfall. AB - A likely consequence of global warming will be the redistribution of Earth's rain belts, affecting water availability for many of Earth's inhabitants. We consider three ways in which planetary warming might influence the global distribution of precipitation. The first possibility is that rainfall in the tropics will increase and that the subtropics and mid-latitudes will become more arid. A second possibility is that Earth's thermal equator, around which the planet's rain belts and dry zones are organized, will migrate northward. This northward shift will be a consequence of the Northern Hemisphere, with its large continental area, warming faster than the Southern Hemisphere, with its large oceanic area. A third possibility is that both of these scenarios will play out simultaneously. We review paleoclimate evidence suggesting that (i) the middle latitudes were wetter during the last glacial maximum, (ii) a northward shift of the thermal equator attended the abrupt Bolling-Allerod climatic transition ~14.6 thousand years ago, and (iii) a southward shift occurred during the more recent Little Ice Age. We also inspect trends in seasonal surface heating between the hemispheres over the past several decades. From these clues, we predict that there will be a seasonally dependent response in rainfall patterns to global warming. During boreal summer, in which the rate of recent warming has been relatively uniform between the hemispheres, wet areas will get wetter and dry regions will become drier. During boreal winter, rain belts and drylands will expand northward in response to differential heating between the hemispheres. PMID- 28580419 TI - Light penetration structures the deep acoustic scattering layers in the global ocean. AB - The deep scattering layer (DSL) is a ubiquitous acoustic signature found across all oceans and arguably the dominant feature structuring the pelagic open ocean ecosystem. It is formed by mesopelagic fishes and pelagic invertebrates. The DSL animals are an important food source for marine megafauna and contribute to the biological carbon pump through the active flux of organic carbon transported in their daily vertical migrations. They occupy depths from 200 to 1000 m at daytime and migrate to a varying degree into surface waters at nighttime. Their daytime depth, which determines the migration amplitude, varies across the global ocean in concert with water mass properties, in particular the oxygen regime, but the causal underpinning of these correlations has been unclear. We present evidence that the broad variability in the oceanic DSL daytime depth observed during the Malaspina 2010 Circumnavigation Expedition is governed by variation in light penetration. We find that the DSL depth distribution conforms to a common optical depth layer across the global ocean and that a correlation between dissolved oxygen and light penetration provides a parsimonious explanation for the association of shallow DSL distributions with hypoxic waters. In enhancing understanding of this phenomenon, our results should improve the ability to predict and model the dynamics of one of the largest animal biomass components on earth, with key roles in the oceanic biological carbon pump and food web. PMID- 28580417 TI - Impact of Early Consumption of High-Fat Diet on the Mesolimbic Dopaminergic System. AB - Increasing evidence suggest that consumption of high-fat diet (HFD) can impact the maturation of brain circuits, such as during adolescence, which could account for behavioral alterations associated with obesity. In the present study, we used behavioral sensitization to amphetamine to investigate the effect of periadolescent HFD exposure (pHFD) in rats on the functionality of the dopamine (DA) system, a central actor in food reward processing. pHFD does not affect responding to an acute injection, however, a single exposure to amphetamine is sufficient to induce locomotor sensitization in pHFD rats. This is paralleled by rapid neurobiological adaptations within the DA system. In pHFD-exposed animals, a single amphetamine exposure induces an increase in bursting activity of DA cells in the ventral tegmental area (VTA) as well as higher DA release and greater expression of (tyrosine hydroxylase, TH) in the nucleus accumbens (NAc). Post-synaptically, pHFD animals display an increase in NAc D2 receptors and c-Fos expression after amphetamine injection. These findings highlight the vulnerability of DA system to the consumption of HFD during adolescence that may support deficits in reward-related processes observed in obesity. PMID- 28580420 TI - A pressure-induced topological phase with large Berry curvature in Pb1-x Sn x Te. AB - The picture of how a gap closes in a semiconductor has been radically transformed by topological concepts. Instead of the gap closing and immediately reopening, topological arguments predict that, in the absence of inversion symmetry, a metallic phase protected by Weyl nodes persists over a finite interval of the tuning parameter (for example, pressure P). The gap reappears when the Weyl nodes mutually annihilate. We report evidence that Pb1-x Sn x Te exhibits this topological metallic phase. Using pressure to tune the gap, we have tracked the nucleation of a Fermi surface droplet that rapidly grows in volume with P. In the metallic state, we observe a large Berry curvature, which dominates the Hall effect. Moreover, a giant negative magnetoresistance is observed in the insulating side of phase boundaries, in accord with ab initio calculations. The results confirm the existence of a topological metallic phase over a finite pressure interval. PMID- 28580422 TI - HSP105 prevents depression-like behavior by increasing hippocampal brain-derived neurotrophic factor levels in mice. AB - Heat shock proteins (HSPs) are stress-induced chaperones that are involved in neurological disease. Although increasingly implicated in behavioral disorders, the mechanisms of HSP action, and the relevant functional pathways, are still unclear. We examined whether oral administration of geranylgeranylacetone (GGA), a known HSP inducer, produced an antidepressant effect in a social defeat stress model of depression in mice. We also investigated the possible molecular mechanisms involved, particularly focusing on hippocampal neurogenesis and neurotrophic factor expression. In stressed mice, hippocampal HSP105 expression decreased. However, administration of GGA increased HSP105 expression and improved depression-like behavior, induced hippocampal cell proliferation, and elevated brain-derived neurotrophic factor (BDNF) levels in mouse hippocampus. Co treatment with GGA and the BDNF receptor inhibitor K252a suppressed the antidepressant effects of GGA. HSP105 knockdown decreased BDNF mRNA levels in HT22 hippocampal cell lines and hippocampal tissue and inhibited the GGA-mediated antidepressant effect. These observations suggest that GGA administration is a therapeutic candidate for depressive diseases by increasing hippocampal BDNF levels via HSP105 expression. PMID- 28580421 TI - Compliant substratum guides endothelial commitment from human pluripotent stem cells. AB - The role of mechanical regulation in driving human induced pluripotent stem cell (hiPSC) differentiation has been minimally explored. Although endothelial cell (EC) fate from hiPSCs has been demonstrated using small molecules to drive mesoderm induction, the effects of substrate stiffness with regard to EC differentiation efficiency have yet to be elucidated. We hypothesized that substrate compliance can modulate mesoderm differentiation kinetics from hiPSCs and affect downstream EC commitment. To this end, we used polydimethylsiloxane (PDMS)-a transparent, biocompatible elastomeric material-as a substrate to study EC commitment of hiPSCs using a stepwise differentiation scheme. Using physiologically stiff (1.7 MPa) and soft (3 kPa) PDMS substrates, compared to polystyrene plates (3 GPa), we demonstrate that mechanical priming during mesoderm induction activates the Yes-associated protein and drives Wnt/beta catenin signaling. When mesoderm differentiation was induced on compliant PDMS substrates in both serum and serum-free E6 medium, mesodermal genetic signatures (T, KDR, MESP-1, GATA-2, and SNAIL-1) were enhanced. Furthermore, examination of EC fate following stiffness priming revealed that compliant substrates robustly improve EC commitment through VECad, CD31, vWF, and eNOS marker expression. Overall, we show that substrate compliance guides EC fate by enhancing mesoderm induction through Wnt activation without the addition of small molecules. These findings are the first to show that the mechanical context of the differentiation niche can be as potent as chemical cues in driving EC identity from hiPSCs. PMID- 28580423 TI - Van der Waals engineering of ferromagnetic semiconductor heterostructures for spin and valleytronics. AB - The integration of magnetic material with semiconductors has been fertile ground for fundamental science as well as of great practical interest toward the seamless integration of information processing and storage. We create van der Waals heterostructures formed by an ultrathin ferromagnetic semiconductor CrI3 and a monolayer of WSe2. We observe unprecedented control of the spin and valley pseudospin in WSe2, where we detect a large magnetic exchange field of nearly 13 T and rapid switching of the WSe2 valley splitting and polarization via flipping of the CrI3 magnetization. The WSe2 photoluminescence intensity strongly depends on the relative alignment between photoexcited spins in WSe2 and the CrI3 magnetization, because of ultrafast spin-dependent charge hopping across the heterostructure interface. The photoluminescence detection of valley pseudospin provides a simple and sensitive method to probe the intriguing domain dynamics in the ultrathin magnet, as well as the rich spin interactions within the heterostructure. PMID- 28580424 TI - How and when does an anticancer drug leave its binding site? AB - Obtaining atomistic resolution of drug unbinding from a protein is a much sought after experimental and computational challenge. We report the unbinding dynamics of the anticancer drug dasatinib from c-Src kinase in full atomistic resolution using enhanced sampling molecular dynamics simulations. We obtain multiple unbinding trajectories and determine a residence time in agreement with experiments. We observe coupled protein-water movement through multiple metastable intermediates. The water molecules form a hydrogen bond bridge, elongating a specific, evolutionarily preserved salt bridge and enabling conformation changes essential to ligand unbinding. This water insertion in the salt bridge acts as a molecular switch that controls unbinding. Our findings provide a mechanistic rationale for why it might be difficult to engineer drugs targeting certain specific c-Src kinase conformations to have longer residence times. PMID- 28580425 TI - Ultrastretchable, transparent triboelectric nanogenerator as electronic skin for biomechanical energy harvesting and tactile sensing. AB - Rapid advancements in stretchable and multifunctional electronics impose the challenge on corresponding power devices that they should have comparable stretchability and functionality. We report a soft skin-like triboelectric nanogenerator (STENG) that enables both biomechanical energy harvesting and tactile sensing by hybridizing elastomer and ionic hydrogel as the electrification layer and electrode, respectively. For the first time, ultrahigh stretchability (uniaxial strain, 1160%) and transparency (average transmittance, 96.2% for visible light) are achieved simultaneously for an energy-harvesting device. The soft TENG is capable of outputting alternative electricity with an instantaneous peak power density of 35 mW m-2 and driving wearable electronics (for example, an electronic watch) with energy converted from human motions, whereas the STENG is pressure-sensitive, enabling its application as artificial electronic skin for touch/pressure perception. Our work provides new opportunities for multifunctional power sources and potential applications in soft/wearable electronics. PMID- 28580427 TI - Incidental finding of low brown adipose tissue activity in endurance-trained individuals: Methodological considerations for positron emission tomography. AB - Brown adipose tissue (BAT) in adults has been shown to have a meaningful impact on energy expenditure and cold-induced thermogenesis. Data from rodent research have suggested that exercise may be a promising method of increasing BAT activity, with potential applications to the treatment and prevention of obesity and diabetes. However, emerging human research using positron emission tomography (PET) with [18F] Fluorodeoxyglucose (FDG) has identified lower BAT activity in endurance-trained athletes compared to sedentary controls, despite similar metabolic rate responses to cold exposure. Here we report a similar incidental finding in a pilot study that included a sample of 2 endurance athletes and 10 untrained individuals. This incidental finding motivated a retrospective analysis of the data aimed at assessing the potential confounding influence of muscle FDG uptake on BAT estimation. Results indicated that athletes skewed the relationship between body mass index (BMI) and supraclavicular fat (sFAT) FDG uptake, while a non-significant inverse relationship between muscle FDG uptake and sFAT FDG uptake was also observed. The current retrospective analysis provides preliminary evidence suggesting that BAT estimation may be biased in endurance-trained individuals, which may relate to skeletal muscle FDG uptake. These results point to important methodological considerations for estimating BAT activity via FDG uptake, for which we propose potential solutions that facilitate unbiased estimation of BAT activity in groups that differ in terms of lean body mass and physical activity level. PMID- 28580426 TI - Methylmercury uptake and degradation by methanotrophs. AB - Methylmercury (CH3Hg+) is a potent neurotoxin produced by certain anaerobic microorganisms in natural environments. Although numerous studies have characterized the basis of mercury (Hg) methylation, no studies have examined CH3Hg+ degradation by methanotrophs, despite their ubiquitous presence in the environment. We report that some methanotrophs, such as Methylosinus trichosporium OB3b, can take up and degrade CH3Hg+ rapidly, whereas others, such as Methylococcus capsulatus Bath, can take up but not degrade CH3Hg+. Demethylation by M. trichosporium OB3b increases with increasing CH3Hg+ concentrations but was abolished in mutants deficient in the synthesis of methanobactin, a metal-binding compound used by some methanotrophs, such as M. trichosporium OB3b. Furthermore, addition of methanol (>5 mM) as a competing one carbon (C1) substrate inhibits demethylation, suggesting that CH3Hg+ degradation by methanotrophs may involve an initial bonding of CH3Hg+ by methanobactin followed by cleavage of the C-Hg bond in CH3Hg+ by the methanol dehydrogenase. This new demethylation pathway by methanotrophs indicates possible broader involvement of C1-metabolizing aerobes in the degradation and cycling of toxic CH3Hg+ in the environment. PMID- 28580429 TI - Specific targeting of the deubiquitinase and E3 ligase families with engineered ubiquitin variants. AB - The ubiquitin proteasome system (UPS) has garnered much attention due to its potential for the development of therapeutics. Following a successful clinical application of general proteasome inhibitors much effort has been devoted to targeting individual UPS components including E3 enzymes and deubiquitinases that control specificity of ubiquitination. Our group has developed a novel approach for targeting the UPS proteins using engineered ubiquitin variants (Ubvs). These drug-like proteins can serve as valuable tools to study biological function of UPS components and assist in the development of small molecules for clinical use. In this review, we summarize studies of Ubvs targeting members of three major families, including deubiquitinases, HECT E3 ligases, and CRL E3 ligases. In particular, we focus on Ubv binding mechanisms, structural studies, and effects on enzyme function. Furthermore, new insights gained from the Ubvs are discussed in the context of small molecule studies. PMID- 28580428 TI - Peptide-Mediated Nanopore Detection of Uranyl Ions in Aqueous Media. AB - Uranium is one of the most common radioactive contaminants in the environment. As a major nuclear material in production, environmental samples (like soil and groundwater) can provide signatures on uranium production activity inside the facility. Thus, developing a new and portable analytical technology for uranium in aqueous media is significant not only for environmental monitoring, but also for nonproliferation. In this work, a label-free method for the detection of uranyl (UO22+) ions is developed by monitoring the translocation of a peptide probe in a nanopore. Based on the difference in the number of peptide events in the absence and presence of uranyl ions, nanomolar concentration of UO22+ ions could be detected in minutes. The method is highly selective; micromolar concentrations of Cd2+, Cu2+, Zn2+, Ni2+, Pb2+, Hg2+, Th4+, Mg2+, and Ca2+ would not interfere with the detection of UO22+ ions. In addition, simulated water samples were successfully analyzed. PMID- 28580431 TI - Sperm and sex peptide stimulate aggression in female Drosophila. AB - Female aggression towards other females is associated with reproduction in many taxa, and traditionally thought to be related to the protection or provisioning of offspring, such as through increased resource acquisition. However, the underlying reproductive factors causing aggressive behaviour in females remain unknown. Here we show that female aggression in the fruit fly Drosophila melanogaster is strongly stimulated by the receipt of sperm at mating, and in part by an associated seminal fluid protein, the sex peptide. We further show that the post-mating increase in female aggression is decoupled from the costs of egg production and from post-mating decreases in sexual receptivity. Our results suggest that male ejaculates can have a surprisingly direct influence on aggression in recipient females. Male ejaculate traits thus influence the female social competitive environment with potentially far-reaching ecological and evolutionary consequences. PMID- 28580432 TI - Random sequences are an abundant source of bioactive RNAs or peptides. AB - It is generally assumed that new genes arise through duplication and/or recombination of existing genes. The probability that a new functional gene could arise out of random non-coding DNA is so far considered to be negligible, since it seems unlikely that such a RNA or protein sequence could have an initial function that influences the fitness of an organism. We have here tested this question systematically, by expressing clones with random sequences in E . coli and subjecting them to competitive growth. Contrary to expectations, we find that random sequences with bioactivity are not rare. In our experiments we find that up to 25% of the evaluated clones enhance the growth rate of their cells and up to 52% inhibit growth. Testing of individual clones in competition assays confirms their activity and provides an indication that their activity could be exerted either by the transcribed RNA or the translated peptide. This suggests that transcribed and translated random parts of the genome could indeed have a high potential to become functional. The results also suggest that random sequences may become an effective new source of molecules for studying cellular functions, as well as for pharmacological activity screening. PMID- 28580430 TI - The evolution and population diversity of human-specific segmental duplications. AB - Segmental duplications contribute to human evolution, adaptation and genomic instability but are often poorly characterized. We investigate the evolution, genetic variation and coding potential of human-specific segmental duplications (HSDs). We identify 218 HSDs based on analysis of 322 deeply sequenced archaic and contemporary hominid genomes. We sequence 550 human and nonhuman primate genomic clones to reconstruct the evolution of the largest, most complex regions with protein-coding potential (n=80 genes/33 gene families). We show that HSDs are non-randomly organized, associate preferentially with ancestral ape duplications termed "core duplicons", and evolved primarily in an interspersed inverted orientation. In addition to Homo sapiens-specific gene expansions (e.g., TCAF1/2), we highlight ten gene families (e.g., ARHGAP11B and SRGAP2C) where copy number never returns to the ancestral state, there is evidence of mRNA splicing, and no common gene-disruptive mutations are observed in the general population. Such duplicates are candidates for the evolution of human-specific adaptive traits. PMID- 28580433 TI - Limited impact of neonatal or early infant schedules of 7-valent pneumococcal conjugate vaccination on nasopharyngeal carriage of Streptococcus pneumoniae in Papua New Guinean children: A randomized controlled trial. AB - Streptococcus pneumoniae is a leading cause of pneumonia, the most common cause of childhood death. Papua New Guinean children experience high rates of nasopharyngeal pneumococcal colonization within weeks of birth, predisposing them to pneumococcal disease. In a trial to determine the safety and immunogenicity of early infant vaccination with 7-valent pneumococcal conjugate vaccine (7vPCV), we investigated the impact of early schedules on pneumococcal carriage. Infants were randomized at birth to receive 7vPCV in a 0-1-2-month (n = 101) or a 1-2-3-month (n = 105) schedule or no 7vPCV (n = 106). All children received 23-valent pneumococcal polysaccharide vaccine at age 9 months. We cultured nasopharyngeal swabs (NPS) collected at ages 1, 2, 3, 4 weeks and 3, 9, 18 months, and middle ear discharge if present. Pneumococcal serotypes were identified by the Quellung reaction. A total of 1761 NPS were cultured. The prevalence of pneumococcal carriage was 22% at 1 week of age, rising to 80% by age 3 months and remained >70% thereafter, with high-density carriage in 42% of pneumococcus-positive samples. We identified 63 different serotypes; 43% of isolates from controls were 13vPCV serotypes. There were no significant differences in 7vPCV serotype carriage between 7vPCV recipients and controls at any age (22% vs. 31% at 9 months, p = 0.2). At age 9 months the prevalence of non-7vPCV carriage was 17% higher in 7vPCV recipients (48%) than in controls (25%, p = 0.02). More non-7vPCV serotypes were isolated from ear discharge in 16 7vPCV recipients than from 4 controls (48% vs. 25%, p = 0.13). The limited impact of neonatal or accelerated infant 7vPCV schedules on vaccine serotype carriage is probably due to the early onset of dense carriage of a broad range of pneumococcal serotypes. While serotype-independent pneumococcal vaccines are needed in high-risk populations, the underlying environmental factors and sources of infection must be investigated. http://clinicaltrials.gov/ct2/show/NCT00219401. PMID- 28580435 TI - The National Heart, Lung, and Blood Institute Small Business Program: A Comprehensive Ecosystem for Biomedical Product Development. AB - Small companies working to develop products in the cardiovascular space face numerous challenges, from regulatory, intellectual property, and reimbursement barriers to securing funds to keep the lights on and reach the next development milestone. Most small companies that spin out from universities have the scientific knowledge, but product development expertise and business acumen are also needed to be successful. Other challenges include reduced interest in early stage technologies (Pharma & Biotech 2015 in Review, EP Vantage) and limited deal flow for cardiovascular products (Gormley B., Wall Street Journal, September 15, 2014). The NHLBI small business program is a comprehensive ecosystem designed to address these critical challenges and to provide resources and expertise to assist early stage companies developing cardiovascular and other products within the institute's mission. This article describes steps that NHLBI has taken to enhance our small business program to more effectively translate basic discoveries into commercial products to benefit patients and public health, including enhancing internal expertise and developing non-financial resources to assist small businesses as they develop their products and seek private sector investment and partnership. PMID- 28580436 TI - TELEHEALTH ALLOWS FOR CLINICAL TRIAL PARTICIPATION AND MULTIMODALITY THERAPY IN A RURAL PATIENT WITH STAGE 4 NON-SMALL CELL LUNG CANCER. AB - Oligometastatic non-small cell lung cancer (NSCLC) has a poor prognosis for rural patients with traditional therapies. Implementation of multi-modality systemic therapy in conjunction with surgical resection can dramatically improve overall survival, leading to clinical complete remission. The currently accepted indications for resection in oligometastatic NSCLC include brain and adrenal metastases. Rural populations are known to have disparities in care of complex malignancies and the use of telehealth has been shown to improve outcomes. We present a case of a rural patient with stage IV NSCLC, who was able to participate in two clinical trials, undergo trimodality therapy, and remain disease-free for 18 months, whose care was facilitated via telehealth video conferencing with a tertiary care center. PMID- 28580434 TI - The Promise and Challenge of Induced Pluripotent Stem Cells for Cardiovascular Applications. AB - The recent discovery of human-induced pluripotent stem cells (iPSCs) has revolutionized the field of stem cells. iPSCs have demonstrated that biological development is not an irreversible process and that mature adult somatic cells can be induced to become pluripotent. This breakthrough is projected to advance our current understanding of many disease processes and revolutionize the approach to effective therapeutics. Despite the great promise of iPSCs, many translational challenges still remain. In this article, we review the basic concept of induction of pluripotency as a novel approach to understand cardiac regeneration, cardiovascular disease modeling and drug discovery. We critically reflect on the current results of preclinical and clinical studies using iPSCs for these applications with appropriate emphasis on the challenges facing clinical translation. PMID- 28580437 TI - Lower Baseline Germinal Center Activity and Preserved Th1 Immunity Are Associated With Hepatitis B Vaccine Response in Treated HIV Infection. AB - BACKGROUND: Why HIV-infected individuals have poor responses to standard dose and schedule hepatitis B virus immunization is not well understood. METHODS: We compared the serologic and cellular immune profiles of treated HIV-infected individuals with similar durations of infection and preserved CD4 counts (> 350 cells/microliter) by hepatitis B vaccine (HBV) response before and after vaccination. RESULTS: Similar levels of immune activation and plasma cytokine profile were found between non-responders and responders. The baseline plasma levels of CXCL-13, a surrogate of germinal center reactivity, were significantly lower in HBV responders compared to HBV non-responders and were a predictor of both vaccine response and titer. Furthermore, response to HBV vaccination was associated with a significantly higher frequency of circulating IgGhigh memory B cells post vaccination and preserved Th1 antigen-specific T-cell responses. CONCLUSIONS: Taken together, our data suggest that preserved Th1 responses are associated with hepatitis B vaccine response in treated HIV infection. PMID- 28580438 TI - Discovery of a Diaminopyrimidine FLT3 Inhibitor Active against Acute Myeloid Leukemia. AB - Profiling of the kinase-binding capabilities of an aminopyrimidine analogue detected in a cellular screen of the St. Jude small-molecule collection led to the identification of a novel series of FMS-like tyrosine kinase 3 (FLT3) inhibitors. Structure-activity relationship studies led to the development of compounds exhibiting good potency against MV4-11 and MOLM13 acute myelogenous leukemia cells driven by FLT3, regardless of their FLT3 mutation status. In vitro pharmacological profiling demonstrated that compound 5e shows characteristics suitable for further preclinical development. PMID- 28580439 TI - Deviation from van't Hoff Behavior of Solids at Low Temperature. AB - As a sequel to results obtained on the low-temperature behavior of liquids, a similar study is presented for solids. A molecule in a solid interacts with the other molecules of the crystal so that it is subjected to a specific multimolecular potential, kT0. At temperature T < T0, the molecules are localized, and at T > T0, they can participate in processes like self-diffusion and evaporation. As a consequence, the van't Hoff equation is disobeyed at a low temperature and properties like vapor pressure, diffusion rate, or reactivity are zero below the specific temperature, T0, which here can be interpreted as a temperature of thermal stability of the solid. To account for this view, the van't Hoff equation, represented by the green curve in the figure, is extended with a suitable pre-exponential factor, leading to the red curve. Three examples, taken from the literature, are analyzed to demonstrate its applicability. These examples are: the thermal dissociation of calcium carbonate, the sublimation equilibrium pressure of naphthalene, and that of ice. For some other solids, equilibria and dynamic properties, X(T), are examined by means of extrapolations in the X(T) versus T domain, showing the presence of an arrest temperature, which coincides, within experimental accuracy, with the T0 value obtained from the corresponding vapor pressure. As with liquids, kT0 is found to be proportional to the molecular pair potential. PMID- 28580440 TI - Exploiting a host-commensal interaction to promote intestinal barrier function and enteric pathogen tolerance. AB - Commensal intestinal bacteria can prevent pathogenic infection; however, limited knowledge of the mechanisms by which individual bacterial species contribute to pathogen resistance has restricted their potential for therapeutic application. Here, we examined how colonization of mice with a human commensal Enterococcus faecium protects against enteric infections. We show that E. faecium improves host intestinal epithelial defense programs to limit Salmonella enterica serotype Typhimurium pathogenesis in vivo in multiple models of susceptibility. E. faecium protection is mediated by a unique peptidoglycan hydrolase, SagA, and requires epithelial expression of pattern recognition receptor components and antimicrobial peptides. Ectopic expression of SagA in non-protective and probiotic bacteria is sufficient to enhance intestinal barrier function and confer resistance against S. Typhimurium and Clostridium difficile pathogenesis. These studies demonstrate that specific factors from commensal bacteria can be used to improve host barrier function and limit the pathogenesis of distinct enteric infections. PMID- 28580442 TI - Cation Exchange in the Presence of Oil in Porous Media. AB - Cation exchange is an interfacial process during which cations on a clay surface are replaced by other cations. This study investigates the effect of oil type and composition on cation exchange on rock surfaces, relevant for a variety of oil recovery processes. We perform experiments in which brine with a different composition than that of the in situ brine is injected into cores with and without remaining oil saturation. The cation-exchange capacity (CEC) of the rocks was calculated using PHREEQC software (coupled to a multipurpose transport simulator) with the ionic composition of the effluent histories as input parameters. We observe that in the presence of crude oil, ion exchange is a kinetically controlled process and its rate depends on residence time of the oil in the pore, the temperature, and kinetic rate of adsorption of the polar groups on the rock surface. The cation-exchange process occurs in two stages during two phase flow in porous media. Initially, the charged sites of the internal surface of the clays establish a new equilibrium by exchanging cations with the aqueous phase. At later stages, the components of the aqueous and oleic phases compete for the charged sites on the external surface or edges of the clays. When there is sufficient time for crude oil to interact with the rock (i.e., when the core is aged with crude oil), a fraction of the charged sites are neutralized by the charged components stemming from crude oil. Moreover, the positively charged calcite and dolomite surfaces (at the prevailing pH environment of our experiments) are covered with the negatively charged components of the crude oil and therefore less mineral dissolution takes place when oil is present in porous media. PMID- 28580441 TI - Impact of Subclinical Hypothyroidism on Cardiometabolic Biomarkers in Women. AB - CONTEXT: Whether subclinical hypothyroidism (SCH) is associated with cardiometabolic abnormalities is uncertain. OBJECTIVE: To examine diverse cardiometabolic biomarkers across euthyroid, SCH, and overt hypothyroidism (HT) in women free of cardiovascular disease (CVD). DESIGN: Cross-sectional adjusted associations for lipids, lipoprotein subclasses, lipoprotein insulin resistance score, inflammatory, coagulation, and glycemic biomarkers by ANCOVA for thyroid categories or TSH quintiles on a Women's Health Study subcohort. SETTING: Outpatient. PATIENTS OR OTHER PARTICIPANTS: Randomly sampled 3,914 middle-aged and older women for thyroid function analysis (thyroid-stimulating hormone [TSH], free T4), of whom 3,321 were not on lipid lowering therapy. INTERVENTION: None. MAIN OUTCOME MEASURE: Associations of SCH and HT with cardiometabolic markers. RESULTS: Going from euthyroid to HT, the lipoprotein subclasse profiles were indicative of insulin resistance [respective values and p for trend]: larger VLDL size (nm)[51.5 (95%CI51.2, 51.8) to 52.9 (51.8, 54.1) p=0.001]; higher LDL particles concentration (nmol/L)[1283 (95%CI1267, 1299) to 1358 (1298, 1418) p=0.004] and smaller LDL size. There was worsening lipoprotein insulin resistance score from euthyroid 49.2 (95%CI 48.3, 50.2) to SCH 52.1 (95%CI 50.1, 54.0), and HT 52.1 (95%CI 48.6, 55.6), p for trend 0.008. Of the other biomarkers, SCH and HT were associated with higher hs-CRP and HbA1c. For increasing TSH quintiles results were overall similar. CONCLUSIONS: In apparently healthy women, SCH cardiometabolic profiles indicated worsening insulin resistance and higher CVD risk markers compared with euthyroid individuals, despite similar LDL and total cholesterol. These findings suggest that cardiometabolic risk may increase early in the progression towards SCH and OH. PMID- 28580443 TI - Reduced Prothrombinase Inhibition by Tissue Factor Pathway Inhibitor Contributes to the Factor V Leiden Hypercoagulable State. AB - Activated factor V (FVa) and factor X (FXa) form prothrombinase, which converts prothrombin to thrombin. The alpha isoform of tissue factor (TF) pathway inhibitor (TFPI) dampens early procoagulant events, partly by interacting with FV. FV Leiden (FVL) is the most common genetic thrombophilia in Caucasians. Thrombosis risk is particularly elevated in women with FVL taking oral contraceptives, which produce acquired TFPIalpha deficiency. In mice, FVL combined with 50% reduction in TFPI causes severe thrombosis and perinatal lethality. However, a possible interaction between FVL and TFPIalpha has not been defined in humans. Here, we examined this interaction using samples from patients with FVL in thrombin generation and fibrin formation assays. In dilute TF- or FXa initiated reactions, these studies exposed a TFPI-dependent activation threshold for coagulation initiation that was greatly reduced by FVL. The reduced threshold was progressively overcome with higher concentrations of TF or FXa. Plasma assays using anti-TFPI antibodies or a TFPI peptide that binds and inhibits FVa demonstrated that the decreased activation threshold resulted from reduced TFPIalpha inhibition of prothrombinase. In assays using purified proteins, TFPIalpha was a 1.7-fold weaker inhibitor of prothrombinase assembled with FVL than with FV. Thus, FVL reduces the threshold for initiating coagulation, and this threshold is further reduced in situations of low TFPIalpha concentration. Individuals with FVL are likely prone to thrombosis in response to weak procoagulant stimuli that would not initiate blood clot formation in individuals with FV. PMID- 28580445 TI - Association of maternal and umbilical cord blood leptin concentrations and abnormal color Doppler indices of umbilical artery with fetal growth restriction. AB - BACKGROUND: Fetal growth restriction (FGR) is a condition with heterogeneous pathophysiology which characterized by fetal weight less than the tenth percentile for gestational age. Several factors have impact on maternal, placental and fetal due to growth restriction. OBJECTIVE: The aim of this study was to investigate the relationship between levels of leptin in the cord, and serum leptin of mothers also abnormal color Doppler indices of umbilical artery with fetal growth restriction. MATERIALS AND METHODS: This is a cross sectional study conducted in Isfahan, Iran, 2015-2016. We recruited 40 women with singleton pregnancies complicated by fetal growth restriction (Group I) and 40 pregnant women with normal fetal growth (Group II) with matched age. Maternal serum and umbilical artery leptin levels were determined with Enzyme-Linked immunosorben method. Also, color Doppler ultrasound of umbilical artery was performed. RESULTS: Mean maternal and fetal leptin levels were lower in the FGR group compared to the normal group (36.58+/-(20.99) and 7.42 +/-(4.08)vs. 47.32+/ (22.50) and 30.49+/-(14.50) respectively). Also, mean fetal leptin level was lower in the group with abnormal color Doppler sonographic indices compared to the normal group (7. 40 +/-(4.10)vs 27.06+/-(15.80), respectively). CONCLUSION: This study indicated that maternal and fetal leptin levels are correlated with FGR originating from damaged placental function; also fetal leptin level can indicate changes in color Doppler sonographic indices. PMID- 28580444 TI - Maternal Anemia during pregnancy and infant low birth weight: A systematic review and Meta-analysis. AB - BACKGROUND: Infant low birth weight is one of the major problems in different societies. Different reports have provided different results regarding the relationship between maternal anemia and infant low birth weight in different months of pregnancy. OBJECTIVE: The aim of this study was to determine the relationship between maternal anemia during pregnancy and infant low birth weight. MATERIALS AND METHODS: This systematic review was conducted using related keywords in national (Sid, Iran.doc, Iran medex and Magiran) and international (PubMed, Science Direct, Cochrane, Medline, Web of Science, Scopus, Springer, Embase, Google scholar) databases. Relative risks and confidence intervals were extracted from each study. The results were combined using random-effects model for meta-analysis. The I2 index was also used to measure heterogeneity between the studies. RESULTS: Overall, 17 studies with a total sample size of 245407 entered the final meta-analysis and demonstrated that the relative risk for maternal anemia in the first, second and third trimester of pregnancy were 1.26 (95% CI: 1.03-1.55), 0.97 (95% CI: 0.57-1.65), and 1.21 (95% CI: 0.84-1.76), respectively. The relationship between maternal anemia and infant low birth weight in the first trimester of pregnancy was significant. CONCLUSION: Maternal anemia, especially during the first trimester of pregnancy, can be considered as a risk factor for pregnancy outcomes. Therefore, one needs to take the necessary steps to cure this disease in order to reduce the incidence of infant low birth weight. PMID- 28580446 TI - Protective effects of melatonin on testis histology following acute torsion detorsion in rats. AB - BACKGROUND: Testicular damage due to spermatic cord torsion may lead to infertility. It is probably because of changes in oxidative stress factors such as malondialdehyde. OBJECTIVE: To investigate the protective effect of melatonin (MLT), as an antioxidant, on testicular damage induced by acute unilateral spermatic cord torsion and detorsion (T/D) in rats. MATERIALS AND METHODS: In this experimental study, 48 adult male Wistar rats were randomly divided into three groups (8 rats/group): sham group underwent right scrotal surgery only., the T/D group underwent right testicular torsion (for 1 hr) and detorsion, and the melatonin group underwent right testicular torsion, received 25 ug/kg melatonin intraperitoneally immediately after surgery of T/D. Then the histological parameters and malondialdehyde (MDA) changes were evaluated. RESULTS: Torsion and detorsion decreased the diameter of the tubules significantly compared to controls (p=0.003). Melatonin could increase the diameter, but it was not significant (p=0.26). The heights of the epithelium were constant in sham, T/D, and melatonin groups without any significant difference between groups (p=0.98). Based on Johnsen's score, spermatogenesis was normal in the sham group. The torsion significantly injured all lineage cells (p<0.001). There was no any spermatid or sperm in the seminiferous tubules. Melatonin improved the spermatogenesis significantly (p=0.02), but could not improve MDA level significantly (p=0.99). CONCLUSION: Severe degenerative changes of testis were induced by acute unilateral spermatic cord torsion and detorsion in rats, but it had no effect on MDA level. PMID- 28580447 TI - Association of regional disparity of obstetrics and gynecologic services with children and infants mortality rates: A cross-sectional study. AB - BACKGROUND: Equity in distribution of resources is considered as an important priority in health care systems. Equitable distribution of obstetrics and gynecology (Ob/Gyn) services in the country level is critical in maternal and neonatal health for qualitative promotion of maternal care in pregnancy, delivery, and post-delivery periods. OBJECTIVE: The present study aimed at determining regional disparity of obstetrics and gynecology services and its association with children and infants mortality rates. MATERIALS AND METHODS: This was a descriptive-analytical study conducted in 2015 to investigate distribution of Ob/Gyn services using three indicators of number of nursing and midwifery personnel, total Ob/Gyn specialists, and total delivery beds among 30 provinces of the country. Equity criteria in the present study included population, normal vaginal deliveries, cesarean sections, and total deliveries. Data were gathered using a researcher-made form and Stata 12 was used to calculate Gini coefficient. The association of Ob/Gyn services with children and infant mortality rates was investigated using SPSS package and linear regression test. RESULTS: The lowest Gini coefficient was observed in distribution of nursing and midwifery personnel in delivery wards in terms of vaginal delivery (0.38 from 1) and the highest value was related to distribution of Ob/Gyn specialists in terms of vaginal delivery (0.73 from 1). Infant mortality was significantly associated with number of nursing and midwifery personnel in delivery wards, and total number of Ob/Gyn specialists. CONCLUSION: Considering new population policies in Iran and increased fertility rate, it is recommended to facilitate accessibility of the required services for the women, particularly those of reproductive age. PMID- 28580448 TI - Serum ferritin concentration in early pregnancy and risk of subsequent development of gestational diabetes: A prospective study. AB - BACKGROUND: Elevated serum ferritin concentration is associated with insulin resistance and diabetes. Recently it has also been described in gestational diabetes mellitus (GDM). OBJECTIVE: A prospective study was done to determine whether there was a relationship between serum ferritin concentration in early pregnancy and the risk of GDM. MATERIALS AND METHODS: A study was performed on 1,384 pregnant women with gestational age of 12-16 weeks. A blood sample was obtained for measurement of ferritin in the first trimester. Diagnosis of GDM was done by 75 gr oral glucose tolerance test between 24-28 wk. RESULTS: Women who developed GDM had a higher concentration of serum ferritin than women who did not develop GDM (p=0.01). A ferritin concentration of 45 ng/ml was calculated to be the 75th percentile for healthy pregnant women. Considering this level 32% in the GDM group and 25.2%of normal subjects exhibited high ferritin levels (p=0.01). The risk of GDM with these high levels of ferritin was 1.4-fold higher than that for subjects with lower concentrations. The Odds Ratio was 1.4 (95% CI= 1-1.87) (p=0.01). After adjusted for age Odds Ratio was 1.38 (95% CI=1.02-1.86) (p=0.03) and after adjustment for pre-pregnancy Body Mass index, the adjusted odds ratio was 1.31 (CI= 0.96-1.79) (p=0.08). After multivariable adjustment (age and body mass index), the adjusted odds ratio was 1.3 (0.95-1.8) (p=0.09). CONCLUSION: High serum ferritin can be regarded as a significant risk factor for the development of gestational diabetes. PMID- 28580449 TI - Administration of high dose of methamphetamine has detrimental effects on sperm parameters and DNA integrity in mice. AB - BACKGROUND: Methamphetamine (MA) was shown to have harmful effects on male reproductive system. OBJECTIVE: To investigate probable effects of daily administration of MA on sperm parameters and chromatin/DNA integrity in mouse. MATERIAL AND METHODS: Thirty-five NMRI male mice were divided into five groups including low, medium, and high dosage groups which were injected intraperitoneally with 4, 8 and 15 mg/kg/day for 35 days, respectively. Normal saline was injected in sham group and no medications were used in control group. Then, the mice were killed and caudal epididymis of each animal was cut and placed in Ham's F10 medium for sperm retrieval. To evaluate sperm chromatin abnormalities, the aniline blue, toluidine blue and chromomycine A3 were used. For sperm DNA integrity and apoptosis, the acridine orange, sperm chromatin dispersion, and TUNEL assay were applied. For sperm morphology, Papanicolaou staining was done. RESULTS: Normal morphology and progressive motility of spermatozoa decreased in medium and high dosage groups in comparison with the control group (p=0.035). There was a significant increase in rate of aniline blue, toluidine blue, and chromomycine A3 positive spermatozoa in high dosage group. In a similar manner, there was an increase in rates of acridine orange, TUNEL and sperm chromatin dispersion positive sperm cells in high dosage group with respect to others. CONCLUSION: MA abuse in a dose-dependent manner could have detrimental effects on male reproductive indices including sperm parameters and sperm chromatin/DNA integrity in mice. PMID- 28580450 TI - Expression of placental growth factor mRNA in preeclampsia. AB - BACKGROUND: Preeclampsia (PE) is a serious complication of pregnancy with hallmarks of incomplete placentation, placental ischemia and endothelial dysfunction. Imbalance between vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and their receptors play important role in pathophysiology of PE. OBJECTIVE: This study was aimed to asses PlGF mRNA expression in placenta of women affected with PE. MATERIAL AND METHODS: In this cross-sectional study, expression of PlGF mRNA was evaluated in 26 mild PE cases, 15 severe preeclamptic women and 20 normotensive controls. Patients were sub classified as early onset PE (9) and late onset (32). After RNA extraction, PlGF expression was quantified with qRT-PCR. RESULTS: The results of PlGF mRNA expression between mild-severe, and early-late onset PE patients showed no statistically significant difference compared with the control group (p=0.661, p=0.205 respectively). CONCLUSION: Despite we found no distinct differential expression of PlGF mRNA in placental tissue of PE patients compared with control women, but according to decreased level of this angiogenic factor in PE even before clinical onset of the disease, determining molecular mechanisms related to reduced secretion of PlGF into the maternal circulation may be useful for future therapeutics. PMID- 28580451 TI - A Case with late onset of ambiguous genitalia. AB - BACKGROUND: Ambiguous genitalia is an uncommon situation that happens between 1 and 2 per every 1000 live births and falls under the umbrella diagnosis of disorders of sexual development. CASE: In this article, we report a case of male pseudohermaphroditism with ambiguous genitalia. The proband was a 12 yr old girl without any uterus or ovarian tissues. Karyotype of the case is 46, XY. Genes involved in sexual differentiation such as AR, SRD5A2, LH, LHR, FSH, 17 B HSD and SRY genes were sequenced in both directions. No mutations were found in these genes either. CONCLUSION: It seems advisable to be cautious in similar cases, and revise protocol for tracing the genes involved in the patients. PMID- 28580452 TI - Effects of simultaneous prenatal exposures to organophosphate and synthetic pyrethroid insecticides on infant neurodevelopment at three months of age. AB - Both prenatal organophosphate (OP) and pyrethroid (PYRE) insecticide exposures have been inconsistently linked with poorer neurodevelopmental outcomes. However, given that neither exposure occurs in isolation, and both classes are neurotoxic, it is important to consider both classes when evaluating these outcomes. Employing biomarkers of pesticide exposure, this research describes the effects of prenatal urinary metabolite levels of PYRE and OP insecticides, measured in both the second and third trimesters of pregnancy and postnatal urinary metabolite levels measured at 2 months of age, on child neurodevelopment at three months of age. Neurodevelopmental data were obtained by administration of the Bayley Scales of Infant Development-II (BSID-II). Generalized linear models using maximum likelihood estimation were used to evaluate the relationship between the indicators of motor and mental neurobehavioral development obtained for 118 infants and prenatal insecticide exposure, accounting for the concurrent infant insecticide exposure. Urinary measures of the PYRE metabolites 3-phenoxybenzoic acid (3PBA) and trans-3-(2,2-dichlorovinyl)-2,2 dimethylcyclopropane-1-carboxylic acid (trans-DCCA) in the third trimester of pregnancy had significant, albeit opposite, effects on mental functioning at three months of age. We observed no significant (p < 0.05) effects on motor development. These results were robust to second month infant urine measures of 3,5,6-trichloro-2-pyridinol (metabolite of OP chlorpyrifos), which independently had a significant and negative influence on mental functioning. Prenatal PYRE exposures exert heterogeneous effects by class on mental, but not motor, functioning at three months of age. PMID- 28580453 TI - Reactive Oxygen Species in HIV Infection. AB - Reactive oxygen species (ROS) are a family of oxygen molecules with an unpaired electron and play an important role in homeostasis and pathogenesis. The reactive molecules modify lipids, proteins and nucleic acids, and modulate a wide range of cellular functions. The importance of ROS in infection has been established through clinical and in vitro studies. Here we review the role of oxidative stress in HIV pathogenesis, the impact of ROS on immune responses in HIV patients, and ROS-mediated regulation of HIV infection. Future studies on the interplay between ROS and HIV infection may offer a new strategy for prevention and treatment. PMID- 28580454 TI - A Discontinuous Potential Model for Protein-Protein Interactions. AB - Protein-protein interactions play an important role in many biologic and industrial processes. In this work, we develop a two-bead-per-residue model that enables us to account for protein-protein interactions in a multi-protein system using discontinuous molecular dynamics simulations. This model deploys discontinuous potentials to describe the non-bonded interactions and virtual bonds to keep proteins in their native state. The geometric and energetic parameters are derived from the potentials of mean force between sidechain sidechain, sidechain-backbone, and backbone-backbone pairs. The energetic parameters are scaled with the aim of matching the second virial coefficient of lysozyme reported in experiment. We also investigate the performance of several bond-building strategies. PMID- 28580455 TI - Detection of Nuclei in H&E Stained Sections Using Convolutional Neural Networks. AB - Detection of nuclei is an important step in phenotypic profiling of histology sections that are usually imaged in bright field. However, nuclei can have multiple phenotypes, which are difficult to model. It is shown that convolutional neural networks (CNN)s can learn different phenotypic signatures for nuclear detection, and that the performance is improved with the feature-based representation of the original image. The feature-based representation utilizes Laplacian of Gaussian (LoG) filter, which accentuates blob-shape objects. Several combinations of input data representations are evaluated to show that by LoG representation, detection of nuclei is advanced. In addition, the efficacy of CNN for vesicular and hyperchromatic nuclei is evaluated. In particular, the frequency of detection of nuclei with the vesicular and apoptotic phenotypes is increased. The overall system has been evaluated against manually annotated nuclei and the F-Scores for alternative representations have been reported. PMID- 28580456 TI - Predictors of Adherence to Nicotine Replacement Therapy (Nicotine Patch) Among Homeless Persons Enrolled in a Randomized Controlled Trial Targeting Smoking Cessation. AB - INTRODUCTION: Adherence to smoking cessation treatment is generally low, especially among socio-economically disadvantaged groups including individuals experiencing homelessness and those with mental illnesses. Despite the high smoking rates in homeless populations (~70%) no study to date has systematically examined predictors of adherence to nicotine replacement therapy (NRT) in this population. OBJECTIVE: The aim of this secondary analysis was to identify predictors of adherence to NRT in a smoking cessation trial conducted among homeless smokers. METHODS: Secondary analysis of data from a randomized controlled trial enrolling 430 persons who were homeless and current cigarette smokers. Participants were assigned to one of the two study conditions to enhance smoking cessation: Motivational Interviewing (MI; 6 sessions of MI + 8 weeks of NRT) or Standard Care (Brief advice to quit+ 8 weeks of NRT). The primary outcome for the current analysis was adherence to NRT at end of treatment (8 weeks following randomization). Adherence was defined as a total score of zero on a modified Morisky adherence scale). Demographic and baseline psychosocial, tobacco related, and substance abuse measures were compared between those who did and did not adhere to NRT. RESULTS: After adjusting for confounders, smokers who were depressed at baseline (OR=0.58, 95% CI, 0.38-0.87, p=0.01), had lower confidence to quit (OR=1.10, 95% CI, 1.01-1.19, p=0.04), were less motivated to adhere (OR=1.04, 95% CI, 1.00-1.07, p=0.04), and were less likely to be adherent to NRT. Further, age of initial smoking was positively associated with adherence status (OR= 0.83, 95% CI, 0.69-0.99, p=0.04). CONCLUSION: These results suggest that smoking cessation programs conducted in this population may target increased adherence to NRT by addressing both depression and motivation to quit. TRIAL REGISTRATION: clinicaltrials.gov: NCT00786149. PMID- 28580458 TI - Structured Sparse Kernel Learning for Imaging Genetics Based Alzheimer's Disease Diagnosis. AB - A kernel-learning based method is proposed to integrate multimodal imaging and genetic data for Alzheimer's disease (AD) diagnosis. To facilitate structured feature learning in kernel space, we represent each feature with a kernel and then group kernels according to modalities. In view of the highly redundant features within each modality and also the complementary information across modalities, we introduce a novel structured sparsity regularizer for feature selection and fusion, which is different from conventional lasso and group lasso based methods. Specifically, we enforce a penalty on kernel weights to simultaneously select features sparsely within each modality and densely combine different modalities. We have evaluated the proposed method using magnetic resonance imaging (MRI) and positron emission tomography (PET), and single nucleotide polymorphism (SNP) data of subjects from Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The effectiveness of our method is demonstrated by both the clearly improved prediction accuracy and the discovered brain regions and SNPs relevant to AD. PMID- 28580459 TI - Cultural Shift or Linguistic Drift? Comparing Two Computational Measures of Semantic Change. AB - Words shift in meaning for many reasons, including cultural factors like new technologies and regular linguistic processes like subjectification. Understanding the evolution of language and culture requires disentangling these underlying causes. Here we show how two different distributional measures can be used to detect two different types of semantic change. The first measure, which has been used in many previous works, analyzes global shifts in a word's distributional semantics; it is sensitive to changes due to regular processes of linguistic drift, such as the semantic generalization of promise ("I promise." "It promised to be exciting."). The second measure, which we develop here, focuses on local changes to a word's nearest semantic neighbors; it is more sensitive to cultural shifts, such as the change in the meaning of cell ("prison cell" "cell phone"). Comparing measurements made by these two methods allows researchers to determine whether changes are more cultural or linguistic in nature, a distinction that is essential for work in the digital humanities and historical linguistics. PMID- 28580457 TI - A Liver Index and its Relationship to Indices of HCC Aggressiveness. AB - A Hepatocellular (HCC) Aggressiveness Index was recently constructed, consisting of the sum of the scores for the 4 clinical parameters of maximum tumor size, multifocality, presence of portal vein thrombus and blood alphafetoprotein levels. It was observed that there was an association with several liver function tests. We have now formed a Liver Index from the 4 liver parameters with the highest hazard ratios with respect to HCC aggressiveness, namely: blood total bilirubin, gamma glutamyl transpeptidase (GGTP), albumin and platelet levels (cirrhosis surrogate). We found that the scores for the Liver Index related significantly to survival, but also to the Aggressiveness Index and to its individual HCC components as well as showing significant trends with the components. These results support the hypothesis that liver function is not only an important prognostic factor in HCC patients, but may also be involved in HCC biology and aggressiveness. Blood albumin, GGTP, albumin and platelet levels were used to create a Liver Index that related significantly to parameters of HCC aggressiveness. PMID- 28580460 TI - State Estimation with Sensor Recalibrations and Asynchronous Measurements for MPC of an Artificial Pancreas to Treat T1DM. AB - A novel state estimation scheme is proposed for use in Model Predictive Control (MPC) of an artificial pancreas based on Continuous Glucose Monitor (CGM) feedback, for treating type 1 diabetes mellitus. The performance of MPC strategies heavily depends on the initial condition of the predictions, typically characterized by a state estimator. Commonly employed Luenberger-observers and Kalman-filters are effective much of the time, but suffer limitations. Three particular limitations are tackled by the proposed approach. First, CGM recalibrations, step changes that cause highly dynamic responses in recursive state estimators, are accommodated in a graceful manner. Second, the proposed strategy is not affected by CGM measurements that are asynchronous, i.e., neither of fixed sample-period, nor of a sample-period that is equal to the controller's. Third, the proposal suffers no offsets due to plant-model mismatches. The proposed approach is based on moving-horizon optimization. PMID- 28580461 TI - Bonding Durability of a Self-etch Adhesive to Normal Versus Smear-layer Deproteinized Dentin: Effect of a Reducing Agent and Plant-extract Antioxidant. AB - PURPOSE: To evaluate the effect of a reducing agent and plant-extract antioxidant on the bonding durability of a self-etch adhesive to normal and NaOCl-treated, smear-layer-deproteinized dentin. MATERIALS AND METHODS: Flat smear-layer-covered dentin surfaces from 60 extracted human molars were prepared by removing the occlusal enamel. The teeth were divided into two groups with or without NaOCl deproteinizing treatment for 30 s, and further divided into three subgroups as follows: no application of antioxidant, application of Accel (p-toluenesulfinic acid sodium salt solution) for 5 s, or application of rosmarinic acid solution for 5 s. All treated dentin surfaces were bonded with a two-step self-etch adhesive (Clearfil SE Bond) and restored with composite (Clearfil AP-X). The bonded teeth were sectioned into a hourglass-shaped sticks with a composite dentin bonded interface area of 1.0 mm2. After storage in artificial saliva for 24 h or 1 year, the specimens were subjected to the microtensile bond strength test (n = 15). Data were statistically analyzed with three-way ANOVA, Tukey's post-hoc test, and the t-test (p < 0.05). RESULTS: Without an antioxidant, 1-year storage significantly reduced the bond strengths of the self-etch adhesive to normal and smear-layer-deproteinized dentin compared with those after 24-h storage (p < 0.05). Application of Accel and rosmarinic acid restored the compromised initial bond strengths to smear-layer-deproteinized dentin (p < 0.05), and prevented long-term deterioration of bond strengths to both normal and smear-layer-deproteinized dentin (p > 0.05). CONCLUSION: Application of Accel and rosmarinic acid improved bonding durability of the self-etch adhesive to both normal and smear-layer-deproteinized dentin. PMID- 28580462 TI - Does Tack Curing Luting Cements Affect the Final Cure? AB - PURPOSE: Short initial light curing or "tack curing" is used to create a semi-gel state in luting cements for easier excess material cleanup. The effect of tack curing on the final cure of luting cements was measured in terms of hardness. MATERIALS AND METHODS: Three cement types were tested: two dual-curing composite cements (RelyX Unicem 2; Maxcem Elite); three light-curing veneer cements (Choice 2; Variolink Esthetic LC; RelyX Veneer); and two self-curing resin-modified glass ionomer (RMGI) luting cements (RelyX Luting Plus; Nexus RMGI). Cements were placed in 1.5 * 2 * 8 mm plaster slots covered with orange glass during curing and were cured from one end. Tack curing was performed for 2 to 5 s using an LED curing light, followed 2 min later by 10-40 s final light curing or self-curing, as per manufacturer instructions (n = 10). Control groups received only final light curing or self-curing. After 24 h storage (37 degrees C, 100% humidity), Vickers hardness was measured in 0.5-mm depth increments. Results were analyzed using two-way ANOVA and pairwise comparisons (alpha = 0.05). RESULTS: The hardness of dual-curing and light-curing cements significantly decreased with increasing depth (p = 0.0001). Tack curing of dual-curing and light-curing cements tended to increase hardness at all depths, except near the surface for light-curing veneer cements. Self-curing cements showed no hardness reduction with depth and no effect from tack curing. CONCLUSION: Although a slight surface hardness reduction may occur in light-curing veneer cements, the overall effect on three luting cement types was insignificant or resulted in only a slight increase in depth-of-cure. PMID- 28580463 TI - Effect of Cavity Contamination by Blood and Hemostatic Agents on Marginal Adaptation of Composite Restorations. AB - PURPOSE: To determine the effects of contamination of tooth cavities by hemostatic agents applied after blood contamination on marginal adaptation of composite restorations bonded with etch-and-rinse and self-etch adhesives. MATERIALS AND METHODS: Cervical cavities (n = 10 per group) were contaminated with blood and subsequently treated with aluminum chloride (Racestyptine) or ferric sulfate (Astringedent, ViscoStat) hemostatic agents. After water rinsing, composite restorations were placed using either an etch-and-rinse (OptiBond FL) or self-etch (OptiBond All-in-One) adhesive. EDS-based elemental surface analysis was performed, and marginal integrity was evaluated using SEM both before and after thermomechanical loading. The percentage of continuous margins in enamel (%CEM) and dentin (%CDM) was statistically analyzed (p < 0.05). RESULTS: No statistically significant differences in %CEM and %CDM were observed between hemostatic-contaminated groups and uncontaminated controls after thermomechanical loading, irrespective of the adhesive used. Specimens contaminated with aluminum chloride-based Racestyptine showed a significantly higher final %CEM when the etch-and-rinse adhesive was applied (OptiBond FL) than with the self-etch adhesive (OptiBond All-in-One). CONCLUSION: Cavity contamination with hemostatic agents, applied after blood contamination and removed with water spray, does not compromise marginal adaptation in enamel and dentin. In the case of contamination by an aluminum-chloride hemostatic agent, the tested etch-and-rinse approach resulted in a higher percentage of continuous enamel margins of composite restorations than did the self-etch approach. PMID- 28580464 TI - Addition of Na2CO3 Improves the Shelf Life of Experimental 4-META Self-etch Primer. AB - PURPOSE: The objective of this study was to assess the influence of the addition of Na2CO3 on the shelf life and bond strength of 4-META self-etch primer. MATERIALS AND METHODS: Two 4-META self-etch primers were experimentally formulated with and without the addition of Na2CO3 (primer A and primer B, respectively). The primers were stored at 37 degrees C for several periods of time after formulation. Clearfil SE Bond Primer (Kuraray Noritake Dental) was used as a control. A composite was bonded to bovine dentin using a combination of the primer and a bonding agent (Clearfil SE Bond), and the shear bond strengths were measured. Changes in the pH of the experimental primers were monitored and macroscopic observations were made as a function of the storage periods. RESULTS: With 0-day storage, the bond strength of primer A was equivalent to that of primer B and significantly lower than that of Clearfil SE Primer. The bond strengths of primer A were stable during 90-day storage; by contrast, the bond strengths of primer B significantly decreased during 7-day storage. primer A exhibited stable pH values during 180-day storage; primer B exhibited significantly lower pH than primer A with 0-day storage and discolored gelation during 7-day storage. CONCLUSION: By adding Na2CO3, the shelf life of the 4-META self-etch primer was obviously improved without significant deterioration in dentin bond strength. Adjusting the pH to around 4.5 was effective for obtaining sufficient bond strength and hydrolytic stability of the primer. PMID- 28580465 TI - Effect of MDP-containing Silane and Adhesive Used Alone or in Combination on the Long-term Bond Strength and Chemical Interaction with Lithium Disilicate Ceramics. AB - PURPOSE: To evaluate the effect of a silane and an adhesive containing MDP, used alone or combined in the same solution, on the microshear bond strength (MUSBS) to lithium disilicate ceramics immediately and after 1-year water storage, and compare the bond strength results with the Raman spectra of the treated lithium disilicate surfaces. MATERIALS AND METHODS: A total of 30 CAD/CAM blocks of lithium disilicate (LD; IPS e.max CAD) were cut into four square sections (6 x 6 x 6 mm; n = 60 per group) and processed as recommended by the manufacturer. The LD specimens were divided into 12 groups according to the following independent variables: silane coupling agent (no silane; silane without 10-MDP [MBS, Monobond S]; silane with 10-MDP [MB+, Monobond Plus]) and adhesive + luting composite (no adhesive + Enforce; no adhesive + RelyX Ultimate; Prime & Bond Elect [PBE], a silane- and MDP-free universal adhesive + Enforce; Scotchbond Universal Adhesive [SBU], a silane- and MDP-containing universal adhesive + RelyX Ultimate). After each treatment, cylindrical, transparent matrices were filled with a luting composite and light cured. Specimens were stored in water (37 degrees C for 24 h or 1 year) and submitted to the microshear bond strength (MUSBS) test. The failure pattern and MUSBS were statistically evaluated (alpha = 0.05). In addition, specimens were examined for chemical interaction using Raman spectroscopy. RESULTS: The use of the adhesive PBE alone showed higher mean MUSBS compared with both groups with silane (MSB or MB+) without PBE (p < 0.001) at 24 h. The use of the SBU adhesive or MBS silane alone, as well as MB+ associated with SBU, showed higher mean MUSBS (p < 0.001) at 24 h. After 1-year water storage, all groups showed a significant decrease in mean MUSBS. However, the application of PBE or SBU associated with MB+ silane showed higher 1-year mean MUSBS (p < 0.001). In terms of chemical interaction, when silane (MSB or MB+) was applied, only a slight decrease of Si-O peaks occurred. Otherwise, when PBE or SBU adhesives were applied, methacrylate peaks were only observed in the SBU groups. CONCLUSION: The best results in terms of bond strength after water storage were obtained when an MDP-containing silane was associated with a universal adhesive. The use of a simplified bonding protocol that includes either a silane or a universal adhesive is not recommended. PMID- 28580466 TI - Optical sensing of mechanical pressure based on diffusion measurement in polyacrylamide cell-like barometers. AB - Diffusion and transport of small molecules within hydrogel networks are of high interest for biomedical and pharmaceutical research. Herein, using fluorescence correlation spectroscopy (FCS), we experimentally showed that the diffusion time in the hydrogel was directly related to the mechanical state (compression or swelling) and thus to the volume fraction of the gel. Following this observation, we developed cell-like barometers in the form of PAA microbeads, which when incorporated between cells and combined with a diffusion-based optical readout could serve as the first biosensors to measure the local pressure inside the growing biological tissues. To illustrate the potential of the present method, we used multicellular spheroids (MCS) as a tissue model, and it was observed that the growth-associated tissue stress was lower than 1 kPa, but significantly increased when an external compressive stress was applied. PMID- 28580467 TI - A novel singlet oxygen involved peroxymonosulfate activation mechanism for degradation of ofloxacin and phenol in water. AB - This study proposed a new and previously unconsidered reaction mechanism in the activation of peroxymonosulfate. We report that singlet oxygen (1O2) rather than OH or SO4- was the dominant reactive oxygen species towards the efficient degradation of ofloxacin and phenol, demonstrating a promising application in real wastewater treatment. PMID- 28580468 TI - GaS0.5Te0.5 monolayer as an efficient water splitting photocatalyst. AB - Herein, two-dimensional materials for photocatalytic water splitting are drawing more attention due to the larger surface areas for photocatalytic reactions and shorter migration distances for photogenerated carriers. In this present study, we systematically investigated the fundamental electronic properties of GaS1-xTex monolayers (x = 0, 0.125, 0.25, 0.5, 0.75, 0.875, and 1) for water splitting based on density functional theory (DFT) using the HSE06 functional. The simulation of the defect formation energy under each experimental synthetic condition shows that the Te substitutional impurity in GaS can be relatively easily realized under Ga-rich conditions. Our results show that the GaS0.5Te0.5 monolayer is a direct band gap (2.09 eV) semiconductor, which is attributed to the elevation of Te px/py states at the Gamma point by the strain effect. Moreover, the GaS0.5Te0.5 monolayer has appropriate band edge alignment with respect to the water redox potentials in both acidic and neutral environments. Additionally, the carrier effective mass of the GaS0.5Te0.5 monolayer along the direction of Gamma -> K is smaller than those of pristine GaS and GaTe monolayers, which can cause the carriers to quickly transfer from the photogenerated center to the surface of the photocatalyst. These results imply that the GaS0.5Te0.5 monolayer is a promising candidate as a visible-light water splitting photocatalyst, which should be properly synthesized and tested in further experimental investigations. PMID- 28580469 TI - Photoprotection: extending lessons learned from studying natural sunscreens to the design of artificial sunscreen constituents. AB - Evolution has ensured that plants and animals have developed effective protection mechanisms against the potentially harmful effects of incident ultraviolet radiation (UVR). Tanning is one such mechanism in humans, but tanning only occurs post-exposure to UVR. Hence, there is ever growing use of commercial sunscreens to pre-empt overexposure to UVR. Key requirements for any chemical filter molecule used in such a photoprotective capacity include a large absorption cross section in the UV-A and UV-B spectral regions and the availability of one or more mechanisms whereby the absorbed photon energy can be dissipated without loss of the molecular integrity of the chemical filter. Here we summarise recent experimental (mostly ultrafast pump-probe spectroscopy studies) and computational progress towards unravelling various excited state decay mechanisms that afford the necessary photostability in chemical filters found in nature and those used in commercial sunscreens. We also outline ways in which a better understanding of the photophysics and photochemistry of sunscreen molecules selected by nature could aid the design of new and improved commercial sunscreen formulations. PMID- 28580470 TI - New insights into the chemistry of ionic alkylorganic carbonates: a computational study. AB - A library of hydrogenated, perfluorinated aliphatic and aromatic (p-substituted) alcohols are selected together with a combination of superbases (SBs) and metal hydrides (MHs) to understand the thermodynamic parameters of the binary mixtures once serving as sorbents for the capture of CO2via ionic organic alkyl-carbonate (RCO3-) formation. Data are obtained using density functional theory (DFT) calculations with the B3LYP/6-31+G* level of theory and compared with the experimental results acquired from the literature using different spectroscopic techniques. It is found that the capturing process has a favourable enthalpic contribution and an unfavourable entropic penalty regardless the identity of the base, where the enthalpy values of alcohol/MH binary mixtures are almost two-fold higher compared to their SB-based mixtures. The utilisation of perfluorinated aliphatic alcohols instead of hydrogenated alcohols shows a negative impact on the formation of carbonate adducts, due to the less reactive alkoxide anion along the carbon skeleton, which is attributed to the low charge density of the nucleophilic oxygen atom. While perfluorinated phenol shows a higher reactivity than the parent phenol. The calculations indicate that the reactivity of phenolic compounds is highly affected by the electronic nature of the substituting groups, in which p-substituted phenols are more reactive towards CO2 capturing when electron releasing groups are utilised. A pronounced solvent effect is observed, in which the alkylcarbonate salts (RCO3- SBH+) are stabilized in solvents with high dielectric constant (e.g., DMSO and MeCN). Simulated NMR and IR spectra of RCO3- are consistent with those reported for the affiliated systems, which fortifies the results obtained for the unexplored substrate/MH mixtures, filling a gap in the literature of CO2 sequestration using CO2 binding organic liquids (CO2BOLs) and enabling a fair/quick prediction of potential substrates to be used as CO2 sorbents. PMID- 28580471 TI - A metal-organic framework as a flask: photophysics of confined chromophores with a benzylidene imidazolinone core. AB - Photophysics and dynamics of chromophores with a benzylidene imidazolinone core, responsible for emission of green fluorescent protein variants, were studied as a function of host topology by three approaches. Coordinative, non-coordinative, and "fastened" immobilization were utilized to study chromophore emission. Variable-temperature quadrupolar spin-echo 2H NMR spectra are reported. PMID- 28580472 TI - Staged phase separation in the I-I-N tri-phase region of platelet-sphere mixtures. AB - Mixtures of colloids with different sizes or shapes are ubiquitous in nature and extensively applied in industries. Phase transition pathways and kinetics in this model system should be investigated because of the difficulty in observing tri phase coexistence in colloidal platelet-sphere mixtures. Similar to the polymer sphere mixtures, the phase transition pathway has three main categories. Analytical results show a staged phase transition process in which the mixture first separates into one or two metastable phases, then further separates, and subsequently reaches tri-phase equilibrium. Unique to our system, and different from the gas-liquid-crystal coexistence in colloid-polymer mixtures, the platelet sphere mixture reached a gas-liquid-liquid crystal (nematic) coexistence. Thus, the different phases are easy to distinguish using the birefringence of the liquid crystals. In addition, the volume fraction of the liquid crystal formation in the ZrP platelet suspensions is much lower than for the crystal formation in hard spheres. PMID- 28580473 TI - Concise synthesis of oxacyclic compounds using highly discriminative two-way transformations of alpha,beta-unsaturated esters in the presence of enones. AB - Highly discriminative transformation of alpha,beta-unsaturated esters in the presence of enones using two types of phosphonium salts, and their application to the synthesis of oxacyclic compounds in six steps in one pot have been achieved. PMID- 28580474 TI - Total synthesis of (+/-)-20S-hydroxy-1,2-dehydro-pseudoaspidospermidine via a C-H activation/transannular cyclization strategy. AB - A total synthesis to the pseudoaspidospermidine family via a C-H activation/transannular cyclization strategy has been accomplished. The applicability of this approach is showcased in the concise synthesis (ten steps) of (+/-)-20S-hydroxy-1,2-dehydro-pseudoaspidospermidine (4) starting from literature known compound 11. Via a joint synthetic sequence we were also able to address the related iboga alkaloid (+/-)-isovelbanamine (7) in nine steps. Key features of this synthesis are a transannular cyclization to generate the pseudoaspidospermidine skeleton (C-H activation) and a Witkop photocyclization reaction providing a 9-membered lactam. It is also worth mentioning that the joint synthetic sequence can be carried out on a multigram scale. PMID- 28580475 TI - Controlling the spin and valley degeneracy splitting in monolayer MnPSe3 by atom doping. AB - Monolayer manganese chalcogenophosphates MnPSe3 possess a pair of non-degenerate energy valleys in the vicinities of the vertices of the hexagonal Brillouin zone, which exhibit fascinating optical valley polarization. However, the spin is still degenerate due to antiferromagnetic coupling between Mn ions. In this paper we propose a strategy to realize simultaneously the spin and valley degeneracy splitting by the doping-induced Zeeman effect in monolayer MnPSe3. Using first principles calculations we demonstrate that in Zn-doped monolayer MnPSe3 a valley splitting of larger than 20 meV and a spin splitting of larger than 100 meV can be achieved simultaneously. The doping-induced spin and valley splitting is attractive for spintronics and valleytronics as it creates differences in various energy scales between valleys and between spins, which will facilitate the access and manipulation of the valley and spin degrees of freedom by electrical gating in addition to optical pumping. PMID- 28580476 TI - A square-planar nickel dithiolate complex as an efficient molecular catalyst for the electro- and photoreduction of protons. AB - A square-planar nickel(ii) dithiolate complex is an active molecular catalyst for both photoreduction of protons from water with a turnover number (>1500) and electroreduction of protons from weakly acidic solutions with remarkable turnover frequencies (5575 s-1 at -1.92 V and 1441 s-1 at -1.61 V vs. SCE). DFT calculations provide in-depth insight into the catalytic cycle of the electrochemical reaction, suggesting that the sulfur atoms play crucial roles in proton exchange and hydrogen formation. PMID- 28580477 TI - [11C]Cyanation of arylboronic acids in aqueous solutions. AB - A copper-mediated 11C-cyanation method employing arylboronic acids and [11C]HCN has been developed. This method was applied to the radiochemical synthesis of a wide range of aromatic 11C-nitriles in aqueous solutions. The use of readily accessible arylboronic acids as precursors makes this method complementary to the well-established 11C-cyanation methods that utilize aryl halide precursors. PMID- 28580478 TI - Organotin-based receptors for anions and ion pairs. AB - The field of anion recognition has developed into an area of tremendous significance over the recent decades due to the role of anions in biological and environmental systems, contributing significantly to the more general domain of supramolecular chemistry. So far, a number of receptors have been designed for anion recognition, synthesized and evaluated, most involving hydrogen bonding donors (urea, amide, pyrrole, imidazolium and hydroxyl groups), pi-acidic aryl rings, Lewis acidic metals (boron, tin, aluminium, mercury and uranium) and positively charged polyammonium moieties. With the rapid progress in this field, the role of counterions in modulating the binding strength and selectivity of a specific ion has been recognized, leading to the design and discovery of more robust ion pair receptors. Among various recognition strategies that are presently available for anions and ion pairs, the development of Lewis acidic element-based receptors offers an attractive alternative to the hydrogen bond donor-based receptors, by which both anion and Lewis base recognition can be achieved. Consequently, researchers have focused a great deal of attention on such receptors and this sub-branch of recognition chemistry is expanding rapidly. In recent years, the desired selectivity and binding strength have been achieved for various anions by tuning the Lewis acidity through variation of substituents about the metal center. The easy access, rich molecular diversity and strong Lewis acidity of organotin compounds led to the development of organotin-based molecular receptors for anions and ion pairs. This feature article highlights the advances in the design, synthesis and applications of organotin-based receptors, mainly focusing on our group's contributions. PMID- 28580479 TI - Highly sensitive novel cathodic electrochemiluminescence of tris(2,2' bipyridine)ruthenium(ii) using glutathione as a co-reactant. AB - Herein, glutathione was used as a co-reactant for the first time to generate a novel, highly stable, and enhanced cathodic electrochemiluminescence (ECL) on a simple bare glassy carbon electrode (GCE) surface using the Ru(bpy)32+ molecule in an alkaline pH phosphate buffer solution (PBS). PMID- 28580480 TI - Modeling of diameter-dependent Fe and Co ultrathin nanowires from first principles calculations. AB - We present the electronic, magnetic, thermoelectric and optical properties of ferromagnetic metal nanowires (NWs) made of iron (Fe) and cobalt (Co) atoms using a first principles approach. Each property has been investigated as a function of atomic arrangement and nanowire diameter. Magnetic anisotropy is predicted originating from the spin-orbit coupling. Significant delocalization of electronic charge density is found in Fe nanowires with the increase in nanowire diameter, while the charge distribution anisotropy manifests in all the studied nanowire configurations. The thermoelectric properties exhibit strong coupling to the nanowire configuration and diameter. Thermal conductivity shows large divergence from the bulk iron and cobalt. The optical properties show the strongest increase for nanowires with large diameters. The theoretical modeling of configuration- and diameter-dependent nanowire properties serves as a cornerstone for future utilization of nanowire films in a variety of applications. PMID- 28580482 TI - Particles with selective wetting affect spinodal decomposition microstructures. AB - We have used mesoscale simulations to study the effect of immobile particles on microstructure formation during spinodal decomposition in ternary mixtures such as polymer blends. Specifically, we have explored a regime of interparticle spacings (which are a few times the characteristic spinodal length scale) in which we might expect interesting new effects arising from interactions among wetting, spinodal decomposition and coarsening. In this paper, we report three new effects for systems in which the particle phase has a strong preference for being wetted by one of the components (say, A). In the presence of particles, microstructures are not bicontinuous in a symmetric mixture. An asymmetric mixture, on the other hand, first forms a non-bicontinuous microstructure which then evolves into a bicontinuous one at intermediate times. Moreover, while wetting of the particle phase by the preferred component (A) creates alternating A-rich and B-rich layers around the particles, curvature-driven coarsening leads to shrinking and disappearance of the first A-rich layer, leaving a layer of the non-preferred component in contact with the particle. At late simulation times, domains of the matrix components coarsen following the Lifshitz-Slyozov-Wagner law, R1(t) ~ t1/3. PMID- 28580481 TI - Mode coupling theory for nonequilibrium glassy dynamics of thermal self-propelled particles. AB - We present a mode coupling theory study for the relaxation and glassy dynamics of a system of strongly interacting self-propelled particles, wherein the self propulsion force is described by Ornstein-Uhlenbeck colored noise and thermal noises are included. Our starting point is an effective Smoluchowski equation governing the distribution function of particle positions, from which we derive a memory function equation for the time dependence of density fluctuations in nonequilibrium steady states. With the basic assumption of the absence of macroscopic currents and standard mode coupling approximation, we can obtain expressions for the irreducible memory function and other relevant dynamic terms, wherein the nonequilibrium character of the active system is manifested through an averaged diffusion coefficient D[combining macron] and a nontrivial structural function S2(q) with q being the magnitude of wave vector q. D[combining macron] and S2(q) enter the frequency term and the vertex term for the memory function, and thus influence both the short time and the long time dynamics of the system. With these equations obtained, we study the glassy dynamics of this thermal self propelled particle system by investigating the Debye-Waller factor fq and relaxation time taualpha as functions of the persistence time taup of self propulsion, the single particle effective temperature Teff as well as the number density rho. Consequently, we find the critical density rhoc for given taup shifts to larger values with increasing magnitude of propulsion force or effective temperature, in good accordance with previously reported simulation work. In addition, the theory facilitates us to study the critical effective temperature T for fixed rho as well as its dependence on taup. We find that T increases with taup and in the limit taup -> 0, it approaches the value for a simple passive Brownian system as expected. Our theory also well recovers the results for passive systems and can be easily extended to more complex systems such as active-passive mixtures. PMID- 28580483 TI - Copper-catalyzed construction of eight-membered rings via oxidative ring expansion and intermolecular cyclization sequencing of indoles with amidines: efficient synthesis of benzo[1,3,5]triazocin-6(5H)-ones. AB - Novel and efficient synthesis of eight-membered nitrogen heterocycles in one pot by copper-catalyzed oxidative ring expansion and intermolecular cyclization sequencing of indoles with amidines has been described. This protocol features easily available substrates and high step-economy. More importantly, dioxygen as the most ideal oxidant was employed under mild reaction conditions. A variety of valuable benzo[1,3,5]triazocin-6(5H)-one derivatives bearing functional groups were assembled in middle to good yields. PMID- 28580484 TI - Catalytic asymmetric [2+2] cycloaddition between quinones and fulvenes and a subsequent stereoselective isomerization to 2,3-dihydrobenzofurans. AB - The catalytic enantioselective [2+2] cycloaddition between quinones and fulvenes was achieved, for the first time, by the use of a chiral copper(ii) complex catalyst. The transformation afforded a series of enantiomerically enriched [6,4,5]-tricyclic cyclobutane derivatives in good yields with excellent regio- and stereoselectivities. Furthermore, the [2+2] adducts could be easily converted into formal [3+2] adducts efficiently and stereoselectively. PMID- 28580485 TI - Modeling soft, permeable matter with the proper generalized decomposition (PGD) approach, and verification by means of nanoindentation. AB - Understanding sliding and load-bearing mechanisms of biphasic soft matter is crucial for designing synthetic replacements of cartilage, contact-lens materials or coatings for medical instruments. Interstitial fluid pressurization is believed to be the intrinsic load-carrying phenomenon governing the frictional properties. In this study, we have characterized permeability and identified the fluid contribution to the support of load during Atomic Force Microscopy (AFM) nanoindentation of soft polymer brushes in aqueous environments, by means of the Proper Generalized Decomposition (PGD) approach. First, rate-dependent AFM nanoindentation was performed on a poly(acrylamide) (PAAm) brush in an aqueous environment, to probe the purely elastic as well as poro-viscoelastic properties. Second, a biphasic model decoupling the fluid and solid load contributions was proposed, using Darcy's equation for liquid flow in porous media. Using realistic time-dependent simulations requires many direct solutions of the 3D partial differential equation, making modeling very time-consuming. To efficiently alleviate the time-consumption of multi-dimensional modeling, we used PGD to solve a Darcy model defined in a 7D domain, considering all the unknowns and material properties as extra coordinates of the problem. The obtained 7D simulation results were compared to the experimental results by using a direct Newton algorithm, since all sensitivities with respect to the model parameters are readily available. Thus, a simulation-based solution for depth- and rate dependent permeability can be obtained. From the PGD-based model permeability is calculated, and the velocity- and pressure-fields in the material can be obtained in real-time in 3D by adjusting the parameters to the experimental values. The result is a step forward in understanding the fluid flow, permeability and fluid contributions to the load support of biphasic soft matter. PMID- 28580486 TI - The Role of Endogenous Opioid System in the Regulation of Heart Tolerance to Stress-Induced Damage. AB - In Wistar rats, stress was modeled by 24-h immobilization in a supine posture and stress-induced damage to the heart was assessed by accumulation of 99mTc pyrophosphate in the myocardium. The intensity of stress reaction was measured by serum levels of cortisol and insulin. Both stressinduced damage to the heart and intensity of stress reaction were examined under control conditions and in rats treated with opioid receptor antagonists naltrexone, methylnaltrexone bromide, MR2266, and ICI174.864. Activation of central MU-opioid receptors with endogenous opioids aggravated stress-induced cardiomyopathy, while stimulation of peripheral MU-opioid receptors produced a cardioprotective effect. The stress-induced damage to the heart was not directly related to up-regulation of cortisol secretion in response to 24-h immobilization. Blockade of the central opioid receptors promoted a decrease in cortisol level in stressed rats. PMID- 28580487 TI - Role of Cyclic Nucleotides in the Effect of Hydrogen Sulfide on Contractions of Rat Jejunum. AB - We studied the role of cyclic nucleotides in the influence of hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS, 200 MUM), on motor activity of rat jejunum. NaHS reduced spontaneous and carbachol-induced contractions of rat jejunum segment, which suggests that H2S can act through mechanisms involving muscarinic receptor activation. Against the background of a membrane-penetrating non-hydrolyzable cAMP analogue or under conditions of adenylate cyclase blockade, the inhibitory effect of NaHS on the carbachol-induced contractions was maintained. Against the background of elevated cGMP concentration or guanylate cyclase inhibition, the reduction of carbachol-induced contractions upon exposure to NaHS was less pronounced than in control. It was hypothesized that H2S induces relaxation of carbachol-induced jejunum contractions, affecting protein kinase G targets or activating cGMP synthesis. PMID- 28580488 TI - Internalization of Vectorized Liposomes Loaded with Plasmid DNA in C6 Glioma Cells. AB - We studied internalization of vector nanocarriers loaded with plasmid DNA into C6 glioma cells. For improving selectivity of plasmid delivery, the liposomes were conjugated with monoclonal antibodies to VEGF and its receptor VEGFR2. Flow cytofluorometry and laser scanning confocal microscopy showed more intensive (more than 2-fold) internalization and accumulation of antibody-vectorized liposomes in C6 glioma cells in comparison with the control (liposomes conjugated with non-specific antibodies and non-vectorized liposomes). Using quantitative analysis of fluorescent signal, we showed that cationic immunoliposomes significantly more effective delivered pCop-Green-N plasmid DNA and ensured effective transfection of C6 glioma cells. PMID- 28580489 TI - Features of Blood Supply to Axillary Lymph Nodes in Breast Cancer Patients. AB - Numerical density of vessels in axillary lymph node structures in breast cancer patients was studied by light microscopy with antibodies to CD34. The correlation between the stage of breast cancer and vascularization of lymph nodes was analyzed. The development of breast cancer was followed by rapid and significant increase in the number of blood vessel in axillary lymph nodes in general and in all their specific areas, especially in the paracortex and medullary substance. Strong or very strong positive correlation between the stage of tumor process and parameters of vascularization was observed in various areas of the axillary lymph nodes. No significant differences in node vascularization were observed between women without breast cancer and women with stage I breast cancer; the differences were found only starting from stage II. Considerable vascularization of lymph nodes can be a symptom of malignant tumor growth in the area of lymph collection. The duration of the tumor process and the size of the tumor can be indirectly evaluated by the increase in vessel number in lymph nodes. PMID- 28580490 TI - Estimation of Expression of Oral Fluid Biomarkers in the Diagnosis of Pretumor Diseases of Oral Mucosa. AB - Complex clinical, dental, and morphological investigation, and ELISA of levels of MMP-2, 8, 9, and TIMP-1 and 2 in the saliva was performed during primary examination of patients with premalignant lesions of maxillofacial area and practically healthy volunteers. Levels of all study MMP in the saliva significantly differed (p<=0.05) in patients with premalignant lesions and the control. These patients were also characterized by a significant (0.1<=p<=0.05) changes in TIMP concentrations (toward pathological pattern) comparing to the control. Pattern of correlations between parameters of MMP-2 expression might be a marker for early diagnostics of a premalignant lesion independently on the dental health. Observed features of biomarker expression in patients with premalignant lesions might reflect the appearance of a cascade of biochemical reactions followed by the activation of production of proteinases and their inhibitors as a response to the exposure to etiological factors. Clinical and morphological diagnosis of a premalignant lesion in the maxillofacial area was confirmed by the immunological analysis of biomarker expression in the saliva, which can be used for monitoring and screening of population. PMID- 28580491 TI - Effect of Transplantation of Mesenchymal Stem Cells on the Density of Pial Microvascular Network in Spontaneously Hypertensive Rats of Different Age. AB - Using a TV device for studying microcirculation (*40), we analyzed the density of the whole microvascular network and the density of arterioles in the pia mater of the sensorimotor cortex in SHR rats of different ages (3-4 and 12 months) after intracerebral transplantation of human mesenchymal stem cells. We found that the density of pial microvascular network in SHR rats receiving transplantation of human mesenchymal stem cells increased to a level observed in young Wistar-Kyoto rats. PMID- 28580492 TI - Effect of Concentration of Collagen Gel on Functional Activity of Bone Marrow Mesenchymal Stromal Cells. AB - Collagen I gels with protein concentrations of 1, 2, and 3.5 mg/ml were prepared and embedded in a porous polylactide scaffold to reduce their contraction. Concentration of the gel did not affect its degradation. Collagen gels promoted the formation of cell networks. The cells in the collagen gel with a concentration of 1 mg/ml embedded in polylactide scaffold had elongated spindle like shape, in contrast to flattened cells in collagen gel of the same concentration not embedded in the scaffold. Stabilization of the collagen gel in the polylactide scaffold promoted active synthesis of laminin and fibronectin by cells as soon as on day 5 of culturing in comparison with that in free collagen substrate. PMID- 28580493 TI - Cytokine Production in Mixed Cultures of Mesenchymal Stromal Cells from Wharton's Jelly and Peripheral Blood Lymphocytes. AB - We compared the production of 19 humoral factors in mixed cultures of mesenchymal stromal cells from Wharton's jelly and allogenic peripheral blood lymphocytes. For evaluation of the specificity of immunosuppressive activity of mesenchymal stromal cells, comparative analysis of the production of these humoral factors in mixed cultures of lymphocytes and epithelial BxPC-3 cells was conducted. The production of soluble factors in both mono- and mixed cultures significantly correlated (p<0.05). The maximum production was found for proinflammatory chemokine IP-10 and IFN-gamma and anti-inflammatory cytokine IL-10. The major difference of mesenchymal stromal cells from epithelial BxPC-3 cells was 7-fold higher production of IL-10, which can explain the immunosuppressive effect of mesenchymal stromal cells. PMID- 28580494 TI - Efficacy of low-level laser therapy in carpal tunnel syndrome management: a systematic review and meta-analysis. AB - We performed this meta-analysis to investigate the efficacy of low-level laser therapy (LLLT), a physiotherapy modality with anti-inflammatory and analgesic effects, in the management of mild-to-moderate carpal tunnel syndrome (CTS). We searched PubMed, Web of Knowledge, Scopus, Cochrane Central, and Virtual Health Library for randomized controlled trials (RCTs) that compared the effects of LLLT with or without splinting versus placebo on functional and electromyographic outcomes in CTS. All outcomes were pooled as mean differences (MD) under the inverse variance or random effects model, using the statistical add-in (MetaXL, version 5.0). Eight RCTs (473 patients/631 wrists) were eligible for the final analysis. The overall effect estimates did not favor LLLT therapy group over placebo in all primary outcomes: visual analogue scale (MD -1.11, 95% CI [-2.58, 0.35]), symptom severity scale score (MD -1.41, 95% CI [-5.12, 2.29]), and functional status scale score (MD -1.33, 95% CI [-3.27, 0.61]). However, LLLT was superior to placebo in terms of grip strength (MD 2.19, 95% CI [1.63, 2.76]) and inferior to placebo in terms of sensory nerve action potential (MD -2.74, 95% CI [-3.66, -1.82]). Laser therapy is superior to placebo in terms of improving the grip strength; however, no significant difference was found between both groups in terms of functional status improvement, pain reduction, or motor electrodiagnostic evaluations. Further high-quality trials with longer follow-up periods are required to establish the efficacy of LLLT for CTS treatment. PMID- 28580495 TI - Factors associated with sexual quality of life among midlife women in Serbia. AB - PURPOSE: To assess factors associated with better sexual quality of life (QOL) in midlife period among women who are and are not sexually active. METHODS: Participants were 500 women aged 40-65 years from Belgrade, Serbia. Data were collected through general questionnaire (regarding socio-demographic characteristics, lifestyle habits, general medical, and gynecological history) in which one item investigated having partnered sexual activity (heterosexual intercourses). The sexual domain of the Utian Quality of Life Scale was used to assess the sexual QOL. The sexual QOL consisted of reflections on the satisfaction with frequency of sexual interactions, as well as sexual and romantic life in general. Higher scores indicated better sexual QOL. RESULTS: Most women were sexually active in midlife (81.6%). The mean sexual QOL score for the overall sample was 9.99 (range 3-15). The level of sexual QOL did not differ between sexually active and non-active women. Factors associated with better sexual QOL in sexually active menopausal women were being married or coupled, being physically active, having more children, having hot flushes, and not having tachycardia. Factors associated with better sexual QOL in sexually inactive menopausal women were drinking alcohol, being physically active, not having insomnia or skin rash. CONCLUSIONS: Sexual QOL among Serbian urban midlife women was good and did not differ between women who were sexually active and those who were not. Further studies are needed to determine in what manner women who are not sexually active in midlife achieve high level of satisfaction with their sexual QOL. PMID- 28580497 TI - Fatal and non-fatal drowning in rivers. PMID- 28580496 TI - Concurrent midurethral sling excision or lysis at the time of repeat sling for treatment of recurrent or persistent stress urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: Limited evidence guides operative technique in primary midurethral sling (MUS) lysis or excision at the time of repeat sling placement for persistent or recurrent stress urinary incontinence (SUI). Our objective is to compare subjective improvement in patients undergoing repeat MUS placement with and without concurrent primary sling lysis or removal. METHODS: This was a retrospective cohort study with a prospective survey of patients who underwent two MUS placements for SUI at a single institution from January 1996 to December 2015. After patient identification, the electronic record was queried for demographic and perioperative data. Subjects then completed the Urogenital Distress Index, (UDI-6), Incontinence Severity Index (ISI), and the Incontinence Impact Questionnaire (IIQ-7). Subjects were also asked if they would choose to undergo repeat MUS surgery again. RESULTS: Sixty-one patients were included. 17 out of 61 (28%) underwent concomitant primary sling lysis or excision, and 44 out of 61 (72%) did not. Fifty-seven percent (n = 35) completed the survey. Of the respondents, the median ISI score was 4 (1-8), with no difference between groups; 14 out of 35 (40%) reported the presence of bothersome urge incontinence, 11 out of 35 (31%) reported bothersome stress urinary incontinence, and 8 out of 35 (23%) reported symptoms of voiding dysfunction, with no difference between groups. 57% of patients (20 out of 35) would undergo repeat MUS placement again. CONCLUSIONS: In a small cohort, concurrent excision of the primary sling at the time of repeat MUS did not improve subjective outcomes. Many patients reported urinary urgency and voiding symptoms, and only about half of patients would choose to undergo the surgery again if given the choice. PMID- 28580498 TI - Falls-Related Drug Use and Risk of Falls Among Older Adults: A Study in a US Medicare Population. AB - BACKGROUND: Approximately one-third of community-dwelling older adults fall each year, and approximately 10% have falls requiring medical services. Among other factors, research studies have linked certain medications with an increased risk of falls. OBJECTIVE: The aim of this study was to examine the risk of falls relative to use patterns among new and continuing falls-related drug (FRD) users. METHODS: A 10% random sample, insured in AARP(r) Medicare Supplement and AARP Medicare Part D Rx plans, was utilized to define new and continuing FRD users. New users had a 12-month pre-period without FRD use, whereas continuing users had at least one FRD in the pre-period. Both groups had 12-month follow-up after initiating or continuing FRD use. Characteristics associated with the risk of falls for new and continuing users were determined using multivariate logistic regression models. RESULTS: Among insureds, 44% used at least one of the FRD classes. Of these, 29% were new users (N = 35,340) and 71% were continuing users (N = 121,488). Fall rates for the two subgroups were similar at 7 and 8%, respectively. Characteristics associated with the risk of falls were previous injurious fall, use of two or more classes of FRDs, older age, poorer health, and being female. New users were at higher risk than continuing users. CONCLUSION: New users of FRDs were at highest risk of falls, and continuing users were at increased risk, especially with higher numbers of FRD classes. Both groups could benefit from falls awareness and prevention programs. PMID- 28580500 TI - Vascular calcifications on the preoperative radiograph: harbinger of tourniquet failure in patients undergoing total knee arthroplasty? AB - OBJECTIVE: Vascular calcifications on the preoperative radiograph of patients scheduled for total knee arthroplasty (TKA) often give rise to concern, as their clinical relevance remains uncertain. The aim of this study was to investigate whether these vascular calcifications-especially medial artery calcifications (MACs), which increase arterial stiffness-were associated with tourniquet failure and thus with increased intraoperative blood loss. MATERIALS AND METHODS: A total of 765 patients who underwent primary TKA with a tourniquet (cuff pressure 350 mmHg) between 2009 and 2011 were screened for vascular calcifications on the preoperative radiograph. Vascular calcifications were classified into intimal and medial artery calcifications. Intraoperative blood loss of patients with and without MAC was compared, and a mixed linear regression model was used to adjust for the presence of several confounding factors (e.g., obesity, operating time). RESULTS: None of the 50 (6.5%) patients with MAC showed signs of tourniquet failure. Intraoperative blood loss of patients with MAC was not significantly elevated compared to the overall study group (p = 0.592) even when corrected for the presence of several confounding factors. CONCLUSION: We found no evidence that vascular calcifications seen on the preoperative radiograph might be associated with tourniquet failure. However, surgeons should be aware of this possibility as tourniquet failure might become more common considering the ongoing trend toward minimizing cuff pressures. PMID- 28580502 TI - In Vitro Bioavailability of Calcium, Magnesium, Iron, Zinc, and Copper from Gluten-Free Breads Supplemented with Natural Additives. AB - The aim of this study was to measure the content of calcium, magnesium, iron, zinc, and copper and determine the bioavailability of these ingredients in gluten free breads fortified with milk and selected seeds. Due to the increasing prevalence of celiac disease and mineral deficiencies, it has become necessary to produce food with higher nutritional values which maintains the appropriate product characteristics. This study was designed for gluten-free breads fortified with milk and seeds such as flax, poppy, sunflower seeds, pumpkin seeds or nuts, and flour with amaranth. Subsequently, digestion was performed in vitro and the potential bioavailability of the minerals was measured. In the case of calcium, magnesium, iron, and copper, higher bioavailability was observed in rice bread, and, in the case of copper and zinc, in buckwheat bread. This demonstrated a clear increase in bioavailability of all the minerals when the bread were enriched. However, satisfactory results are obtained only for the individual micronutrients. PMID- 28580503 TI - Indian Pediatric Postgraduate's Perspective on Future Career Intentions: Correspondence. PMID- 28580504 TI - Emotion-Focused Cognitive-Behavioral Therapy for Youth with Anxiety Disorders: A Randomized Trial. AB - Difficulties with emotion regulation are a core feature of anxiety disorders (ADs) in children and adults. Interventions with a specific focus on emotion regulation are gaining empirical support. Yet, no studies to date have compared the relative efficacy of such interventions to existing evidence-based treatments. Such comparisons are necessary to determine whether emotion-focused treatments might be more effective for youth exhibiting broad emotion-regulation difficulties at pretreatment. This study examined an emotion-focused cognitive behavioral therapy (ECBT) protocol in comparison to traditional cognitive behavioral therapy (CBT) in a sample of children with a primary anxiety disorder diagnosis. Moderation analyses examined whether children with higher levels of emotion dysregulation at pretreatment would show greater levels of improvement in ECBT than CBT. Ninety-two youth ages 7 to 12 years (58% male) with a primary diagnosis of separation anxiety disorder, generalized anxiety disorder, or social phobia were included. Participants were randomly assigned to ECBT or CBT. Results showed that youth in both conditions demonstrated similar improvements in emotion regulation and that pretreatment levels of emotion dysregulation did not moderate treatment outcomes. Additional analyses showed that ECBT and CBT were similarly effective on diagnostic, severity, and improvement measures. Future work is needed to further explore the ways that emotion regulation is related to treatment outcome for anxious youth. PMID- 28580501 TI - Predispositions to Leukemia in Down Syndrome and Other Hereditary Disorders. AB - OPINION STATEMENT: Leukemia is the most common pediatric cancer and accounts for approximately one third of childhood malignancies. There are germline genetic alterations that significantly increase the risk of developing hematopoietic malignancies in childhood. In this review, we describe a number of these hereditary disorders and their clinical features. These predispositions to cancer syndromes can be attributed to DNA repair/genetic instability, RAS pathway dysfunction, bone marrow failure, telomeropathies, immunodeficiencies, transcription factor abnormalities, pure familial leukemia, and aneuploidy. We focus especially on acute myeloid leukemia associated with Down syndrome, but also include other hereditary syndromes in this review. Recent advances in high throughput genotyping technology have identified new genetic variations prone to human leukemia. Understanding of the mechanism of leukemia development in these hereditary syndromes allows us to gain insight into leukemogenesis in general and suggests therapeutic strategies based on these findings. PMID- 28580505 TI - Photophysical Properties of a Novel and Biologically Active 3(2H)-Pyridazinone Derivative Using Solvatochromic Approach. AB - Herein, we report photophysical properties of a novel and biologically active 3(2H)-pyridazinone derivative 5-(4-chloro-2-hydoxy-phenyl)-2-phenyl-2H-pyridazin 3-one [CHP] molecule using solvatochromic approaches. Absorption and fluorescence spectra of CHP molecule have been measured at room temperature in various solvents of different polarities. From this, it is observed that the positions, intensities and shapes of the absorption and emission bands are usually modified. Experimentally, the ground and excited state dipole moments are estimated using solvatochromic shift method which involves Lippert's, Bakshiev's and Kawski Chamma-Viallet's equations. Theoretically, the ground state dipole moment was estimated using the Gaussian-09 program. The value of ground state dipole moment estimated using experimental and theoretical methods are well correlated. This inference that the molecular geometry is taken for CHP molecule under theoretical and experimental methods are similar. Further, we observed that the excited state dipole moment (MU e ) is greater than the ground state dipole moment (MU g ) which indicates that the excited state is more polar than the ground state. Furthermore, we have estimated an angle between the ground and excited state dipole moments. In addition, we have estimated the fluorescence quantum yield of CHP molecule using Rhodamine B as a standard reference in different solvents. PMID- 28580506 TI - Prolonged Overall Treatment Time and Lack of Skin Rash Negatively Impact Overall Survival in Locally Advanced Head and Neck Cancer Patients Treated with Radiotherapy and Concomitant Cetuximab. AB - BACKGROUND: Cetuximab, a chimeric monoclonal antibody against EGFR sensitizes tumors to radiotherapy (RT), but is associated with skin and mucosal toxicity. OBJECTIVE: We report outcomes and tolerance of definitive RT in association with cetuximab in patients with locally advanced squamous cell carcinoma (LASCC) of the head and neck. PATIENTS AND METHODS: Between 2006 and 2011, 92 consecutive patients with LASCC of the head and neck were treated with RT and concomitant weekly cetuximab. Median age was 61.7 years. Most patients presented with oropharyngeal tumors (52.2%) and stage IV disease (77.2%). RESULTS: Sixty-nine patients received at least 7 cycles of cetuximab. Cetuximab was stopped at the first infusion following allergic reactions in four patients. During RT, 37% of patients developed grade >= 3 dermatitis; grade >= 2 cetuximab-induced rash occurred in 43 patients (46.7%). Severe mucositis (grade >= 3) affected 57.6% of patients. Ten percent of patients did not receive the full course of RT, and temporary discontinuation due to acute toxicity was frequent and affected 37 patients (53%). The median RT overall treatment time (OTT) in patients with interrupted RT was 56 days (47-75) compared to 51 days (47-65) in patients who did not require toxicity-related radiation interruptions (p < 0.05). After a median follow-up of 17.5 months (1.3-107.6) for all patients, median overall survival was 17.9 months (95% CI: 12.7-23.2), and loco-regional control (LRC) was 9.2 months (95% CI: 3.9-14.4). On multivariate analysis, hemoglobin concentration and occurrence of rash grade >= 2 were independent prognostic factors for LRC (p = 0.023 and p = 0.006, respectively). Lack of rash and extended OTT negatively impacted overall survival (p = 0.048 and 0.052, respectively). CONCLUSIONS: Skin and mucosal toxicity remains an issue in patients with LASCC of the head and neck treated with concomitant cetuximab and RT. Severe toxicity leads to treatment interruptions and prolonged overall treatment time, with consequent decreased overall survival in these patients. PMID- 28580507 TI - Retrospective Evaluation of Thromboembolism Risk in Ovarian Cancer Patients Treated with Bevacizumab. AB - BACKGROUND: Bevacizumab is used in addition to standard, platinum-based chemotherapy to treat advanced-stage ovarian cancer patients. Thrombosis is a well-documented adverse effect of bevacizumab. OBJECTIVE: The aim of this study was to identify predictive parameters for thromboembolic events in ovarian cancer patients and to explain how bevacizumab increases the risk of these events. PATIENTS AND METHODS: Fifty-seven FIGO stage III ovarian cancer patients who underwent cytoreductive surgery and chemotherapy were identified and included in this retrospective study. Twenty-six patients were treated with carboplatin and paclitaxel (CP) only (control group), and 31 patients received CP with bevacizumab (study group). The two groups were compared with regard to thrombosis risk factors and laboratory parameters (total leukocytes, platelet count, hemoglobin, APTT, prothrombin time, INR, fibrinogen levels, D-dimer concentration) before treatment, after each course of chemotherapy, and during thromboembolic events. RESULTS: Only patients in the group receiving bevacizumab experienced venous thromboembolism (VTE) (p=0.03, chi2 test). VTE occurred on average at the 13th cycle of chemotherapy. Patients who experienced VTE had increased BMI before chemotherapy as compared to patients with no thromboembolic event (27.2 vs. 23.3, p=0.005, Mann-Whitney test). D-dimer concentration before treatment was also elevated more in patients affected by VTE (3132.5) than in the non-VTE group (956.43) (p=0.0007, Mann-Whitney test). During the first four administrations of chemotherapy in patients with future VTE, there was a reduction in D-dimer concentration and an extension of APTT. A D-Dimer level higher than 485 ng/mL prior to first chemotherapy indicates for a risk of VTE with 94% sensitivity and 36% specificity. CONCLUSIONS: An elevated D-dimer level and high BMI before chemotherapy are risk factors for VTE in ovarian cancer patients receiving bevacizumab. Bevacizumab possibly increases the risk for VTE. PMID- 28580509 TI - Erratum to: Perfusion index and left ventricular output correlation in healthy term infants. PMID- 28580508 TI - Economics of Early Warning Scores for identifying clinical deterioration-a systematic review. AB - AIM: In 2013, a National Early Warning System (EWS) was implemented in Ireland. Whilst evidence exists to support the clinical effectiveness of EWS in the acute health care setting, there is a paucity of information on their cost and cost effectiveness. The objective of this systematic literature review was to critically evaluate the economic literature on the use of EWS in adult patients in acute health care settings for the timely detection of physiological deterioration. METHODS: A systematic literature review was conducted to accumulate the economic evidence on the use of EWS in adult patients in acute health care settings. RESULTS: The search yielded one health technology assessment, two budget impact analyses and two cost descriptions. Three of the studies were Irish, and considered the national EWS system. A Dutch study reported financial consequences of a single parameter EWS, as part of a rapid response system, in a surgical ward. The fifth study examined an advanced triage system in a medical emergency admission unit in Wales. CONCLUSIONS: The economic evidence on the use of EWS amongst adult patients in acute health care settings for the timely detection of physiological deterioration is limited. Further research is required to investigate the cost effectiveness of EWS, and the appropriateness of using standard methods to do so. The recent implementation of a national EWS in Ireland offers a unique opportunity to bridge this gap in the literature to examine the costs and cost effectiveness of a nationally implemented EWS system. PMID- 28580510 TI - Bone mineral density at femoral neck and lumbar spine in adults with type 1 diabetes: a meta-analysis and review of the literature. AB - : We performed a meta-analysis to evaluate the femoral neck and lumbar spine bone mineral density (BMD) in adults with type 1 diabetes (T1D) compared with controls. Adults with T1D have modestly lower BMD at femoral neck and lumbar spine than adults without diabetes. INTRODUCTION: Fracture risk is four to sixfold higher in adults with T1D. Since BMD is one of the major contributors for fracture risk, we performed a meta-analysis to evaluate differences in femoral neck and lumbar spine BMD between adults with T1D and controls. METHODS: MEDLINE, Ovid, and the Cochrane library and abstracts from various scientific meetings were searched. Studies reporting the femoral neck and/or lumbar spine BMD in adults (age > 20 years) with T1D in comparison with people without diabetes were selected. General linear mixed models were used to assess differences in BMD at femoral neck and lumbar spine between subjects with T1D and controls adjusting for age, sex, and dual x-ray absorptiometry (DXA) instruments. RESULTS: Sixteen studies met the inclusion criteria. The femoral neck BMD was modestly lower in adults with T1D compared to controls (-0.055 g/cm2; 95% CI: -0.065, -0.045). There were no differences in lumbar spine BMD between adults with T1D and controls (0.0062 g/cm2; 95% CI -0.04, 0.016). However, in a sensitivity analysis, lumbar spine BMD was modestly lower in adults with T1D compared to controls ( 0.035 g/cm2; -0.049, -0.02). Studies using Lunar DXA instruments have reported higher lumbar spine and femoral neck BMD compared to studies using Hologic DXA instruments. CONCLUSION: Femoral neck and lumbar spine BMD were modestly lower in adults with T1D compared to controls. However, this modest reduction in femoral neck and lumbar spine BMD cannot explain much higher observed fracture risk in adults with T1D. PMID- 28580511 TI - Effect of recent spinal cord injury on the OPG/RANKL system and its relationship with bone loss and the response to denosumab therapy. AB - : There is marked bone loss after spinal cord injury (SCI); however, its pathogenesis and clinical management remain unclear. The increased circulating levels of receptor activator of nuclear factor kB ligand (RANKL) associated with bone loss shortly after SCI and the prevention of bone loss with denosumab treatment suggest a contributory role of RANKL in SCI-induced osteoporosis. INTRODUCTION: Bone turnover and bone loss are markedly increased shortly after SCI. However, the pathogenesis and clinical management of this process remain unclear, especially the role of the osteoprotegerin (OPG)/RANKL system in this disorder. The aim of this study was to analyze serum levels of OPG and RANKL in bone loss associated with recent SCI and the effect of denosumab treatment on these mediators. METHODS: Twenty-three males with recent complete SCI were prospectively included. Serum OPG and RANKL levels, bone turnover markers (PINP, bone ALP, CTX), and bone mineral density (BMD) were assessed at baseline, at 6 months of follow-up, prior to initiating denosumab, and 6 months after treatment. The results were compared with a healthy control group. RESULTS: At baseline, SCI patients showed higher RANKL levels vs. controls which were correlated with days since-SCI and total hip BMD loss at 6 months. OPG levels were similar to controls at baseline. After denosumab treatment, OPG showed no changes, whereas RANKL levels became undetectable in 67% of patients. Patients with undetectable RANKL during treatment showed better response in femoral BMD and bone markers vs. patients with detectable RANKL at 6 months of denosumab. Increased parathormone (PTH) levels during treatment were negatively correlated with RANKL changes. CONCLUSIONS: RANKL levels are increased after SCI and related to BMD loss at the proximal femur, becoming undetectable after denosumab treatment. The effect of denosumab on preventing sublesional bone loss, especially in patients with undetectable levels during treatment, suggests a contributory role of RANKL in this process. PMID- 28580512 TI - Comparative Effect of Calcium Channel Blockers on Glomerular Function in Hypertensive Patients with Diabetes Mellitus. AB - BACKGROUND: We conducted a retrospective cohort study to evaluate and compare the longitudinal effect of monotherapy with L-, L/T-, L/N-, and L/N/T-type calcium channel blockers (CCBs) on estimated glomerular filtration rate (eGFR), and to investigate the association of treatment duration with eGFR in diabetic patients with hypertension. METHODS: Using a clinical database, we identified new users of five CCBs, i.e. amlodipine (L-type, n = 693), nifedipine (L-type, n = 189), azelnidipine (L/T-type, n = 91), benidipine (L/N/T-type, n = 183), and cilnidipine (L/N-type, n = 61). We used a multivariable regression model to evaluate and compare the effects of these drugs on eGFR and serum creatinine, up to 12 months after initiation of study drug administration. RESULTS: There was no significant association between treatment duration and both eGFR and serum creatinine level with all CCB types. In addition, there was no significant difference in mean change in eGFR among the five CCBs, with any treatment duration. CONCLUSIONS: Our findings suggest that monotherapy with an L-, L/T-, L/N/T-, or L/N-type CCB may have little influence on renal function parameters and may be safely used in hypertensive patients with diabetes. PMID- 28580513 TI - Cumulative live birth and surplus embryo incidence after frozen-thaw cycles in PCOS: how many oocytes do we need? AB - PURPOSE: This study aimed to evaluate the cumulative live birth rate (CLBR) and surplus embryo rate of polycystic ovarian syndrome (PCOS) patients during in vitro fertilization and embryo transfer (IVF-ET) treatment. METHODS: In this retrospective cohort study, we analyzed 1142 PCOS patients who underwent first IVF in our institution between January 2011 and December 2014. All patients were categorized into five groups according to the number of oocytes retrieved. Main outcomes include CLBR and surplus embryo rate. RESULTS: A strong correlation was observed between number of oocytes retrieved and CLBR as well as surplus embryo rate in PCOS patients. CLBR was elevated with the increasing number of oocytes and plateaued when oocyte number was up to ten, whereas the surplus embryo rate steadily increased in line with the increase of oocyte number. Patients transferred with frozen embryos showed higher CLBR and LBR during first ET than patients transferred with fresh embryos. CONCLUSIONS: For PCOS patients, retrieving more than ten oocytes leads to no significant benefit to CLBR but generates surplus embryos. Thus, moderate ovarian stimulation should be reconsidered during IVF treatment. PMID- 28580514 TI - Complete protection against cryodamage of cryopreserved whole bovine and human ovaries using DMSO as a cryoprotectant. AB - PURPOSE: This study aims to determine the optimal cryopreservation protocol for whole ovaries intended for preservation of fertility in women. METHODS: We investigated the optimal cryopreservation procedure for whole ovaries in a bovine model. The following parameters were investigated to determine their effect on ovarian tissue viability: type of cryoprotectant, administration route of the cryoprotectant (perfusion and/or submersion), and the maximum tolerable interval between death of the animal and start of the cryopreservation process. The resulting optimal cryopreservation procedure for bovine ovaries was subsequently tested on human ovaries. In vitro glucose uptake, histology, and immunohistochemistry were used to assess the integrity of the ovarian tissue. RESULTS: Starting the cryopreservation procedure (including perfusion with and submersion in DMSO) within 10-15 min after death of the animal proved critical, resulting in a 90-100% protection level against cryodamage. When cryopreserving human ovaries using the same protocol, over 95% protection against cryodamage was observed on all tissue levels. In addition, no apparent morphological damage to either the follicles or the vascular endothelium was observed. CONCLUSION: Our findings suggest that using the optimized protocol presented in this paper allows good cryopreservation of whole human ovaries and represents an important step in considering whole ovary autotransplantation for clinically applied fertility preservation. PMID- 28580515 TI - Dabigatran reduces thrombin-induced platelet aggregation and activation in a dose dependent manner. AB - Dabigatran is an oral anticoagulant and a reversible inhibitor of thrombin. Further, dabigatran might affect platelet function through a direct effect on platelet thrombin receptors. The aim was to investigate the effect of dabigatran on platelet activation and platelet aggregation. Healthy donor blood was incubated with dabigatran 0, 50, 500 ng/mL, corresponding to the therapeutic range of dabigatran peak plasma concentrations, and 10,000 ng/mL comprising a supra-therapeutic dabigatran plasma level. Platelet aggregation was tested with 96-well aggregometry. Flow cytometry was used to test platelet activation and platelet thrombin receptor expression (SPAN-12 and WEDE-15 expression). Agonists were thrombin, thrombin receptor-activating peptide, protease-activated receptor 4 agonist, collagen, collagen-related peptide, arachidonic acid, and adenosine diphosphate. All concentrations of dabigatran fully inhibited platelet aggregation for thrombin up to 2 IU/mL, while dabigatran did not affect platelet aggregation by other agonists. Platelet activation (percentage of platelets positive for activated GPIIb/IIIa, CD63, P-selectin) was reduced after thrombin stimulation in samples with dabigatran levels >=500 ng/mL. After stimulation with thrombin, the percentage of activated GPIIb/IIIa-positive platelets was 99.8 +/- 0.2% without dabigatran, 14.7 +/- 4.7% with 500 ng/mL dabigatran, and 4.2 +/- 0.2% with 10,000 ng/mL dabigatran, both p < 0.001 when compared to samples without dabigatran. Also, the receptor expression of GPIIb/IIIa, CD63, and P selectin were reduced after dabigatran treatment. The expression of thrombin receptors was reduced at dabigatran on >= 500 ng/mL. In conclusion, dabigatran exclusively inhibits thrombin-induced platelet activation and aggregation with a dose-dependent response. Platelet stimulation with other agonists was not affected by dabigatran. PMID- 28580516 TI - Indian girls have higher bone mineral content per unit of lean body than boys through puberty. AB - Our aim is to describe changes in the muscle-bone unit assessed as a ratio of bone mineral content (BMC) to lean body mass (LBM) through puberty at total body and various skeletal sites in Indian boys and girls. A cross-sectional study was conducted (888 children, 480 boys, aged 5-17 years) in Pune, India. Pubertal staging was assessed. BMC, LBM and fat percentage at the arms, legs, android, gynoid and total body (less the head) were assessed by dual energy X-ray absorptiometry. The amount of BMC per unit LBM (BMC/LBM) was computed. Changes in mean BMC/LBM at 5 Tanner (pubertal) stages after adjustment for age and fat percentage were calculated. In boys, adjusted BMC/LBM was significantly higher with successive Tanner stages [legs (TS-II vs TS-I), android (TS-III vs TS-II, TS IV vs TS-III) and gynoid region (TS-III vs TS-II and TS-II vs TS-I) (p < 0.05)]. In girls, adjusted BMC/LBM was significantly higher with successive Tanner stages at total body, legs and gynoid (TS-III vs TS-II; TS-II vs TS-I; TS-V vs TS-IV), arms (TS-I to TS-V) and android regions (TS-V vs TS-IV) (p < 0.05). Boys had significantly higher adjusted BMC/LBM than girls at earlier Tanner stages (TS-I to TS-III), whereas girls had significantly higher adjusted BMC/LBM than boys at later Tanner stages (TS-IV, TS-V) (p < 0.05). Indian boys and girls showed higher total and regional body, and age- and fat percentage-adjusted BMC/LBM with successive pubertal stages. Girls had higher BMC/LBM than boys which may possibly act as a reservoir for later demands of pregnancy and lactation. PMID- 28580517 TI - Regulation of Primary Polymerization of Fibrin by Blood Anticoagulant System Components. AB - Experimental data on the involvement of the blood anticoagulant system components (heparin complex compounds, short regulatory peptides) in fibrin formation processes are presented. Inhibition of thrombin activity and interactions of short glyproline peptides and their heparin complexes with fibrin monomer molecules are demonstrated. Peptides and their heparin complexes prevent the formation of primary polymeric fibrin and exhibit fibrin-depolymerizing activity on the formed polymeric fibrin. The mechanisms underlying the effects of heparin complexes on degradation of fibrin not stabilized with factor XIIIa is discussed on the basis of the results of spectral analysis and coagulation tests. PMID- 28580518 TI - The Role of Free Radical Oxidation in the Development of Experimental Urate Nephropathy. AB - We studied the dynamics of activity of antioxidant enzymes under conditions of experimental urate kidney damage in rats. Combined administration of uric (0.145 g) and oxonium (0.3 g) acids to laboratory animals modulated free radical oxidation in the kidneys, and especially, in the blood. During the week 1, activity of free radical processes decreased, which was probably determined by the antioxidant effect of increasing blood concentration of uric acid. After 2-3 weeks of experimental pathology, the development of oxidative stress was observed, probably due to predominance of prooxidant activity of uric acid. PMID- 28580519 TI - Psychopharmacological Effects of JNK Inhibitor in Posthypoxic Encephalopathy and Mechanisms of Their Development. AB - Psychopharmacological effects of JNK inhibitor were studied using a mouse model of posthypoxic encephalopathy. The preparation exhibited a pronounced cerebroprotective effect manifested in normalization of orientation and exploratory behavior and conditioned responses in posthypoxic mice. These effects were accompanied by marked elevation of neural stem cell content in the paraventricular region of the brain. PMID- 28580520 TI - Enzyme Immunoassay of Antibodies to Endogenous Bioregulators for Evaluating the Risk of Heart Disease. AB - The levels of natural antibodies to beta-endorphin, bradykinin, histamine, dopamine, and serotonin were measured in 271 cardiological patients in order to evaluate the severity of their clinical status. The patients were distributed into groups differing by the course of the pathological process. The levels of natural antibodies to all antigens were maximum in patients with cardiosclerosis: the content of antibodies to beta-endorphin surpassed the control by 46%, to histamine by 62%, to bradykinin by 36%, to dopamine by 49%, and to serotonin by 65%. PMID- 28580522 TI - Antiangiogenic Effects of Nerve Growth Factor Loop 4 Monomeric Dipeptide Mimetic. AB - The effects of GK-1, a monomeric dipeptide mimetic of nerve growth factor (NGF) loop 4, on angiogenesis were studied in vitro and in vivo. Experiments on human umbilical vein endothelial cells HUVEC showed that the test compound did not affect tubulogenesis (initial stage of angiogenesis) and prevented realization of the angiogenic effect of NGF and its dimeric dipeptide mimetic GK-2. Experiments on rat hind limb ischemia model demonstrated that GK-1 (1 mg/kg/day intraperitoneally over 14 days) significantly reduced the density of the capillary network in ischemic tissue and increased the number and area of Zenker necrosis in comparison with the control. These data suggest that GK-1 exhibits a pronounced antiangiogenic activity. PMID- 28580523 TI - Effects of Combined Transplantation of Multipotent Mesenchymal Stromal and Hemopoietic Stem Cells on Regeneration of the Hemopoietic Tissue. AB - The effect of allogenic combined transplantation of placental multipotent mesenchymal stromal and hemopoietic stem cells on regeneration of the myeloid tissue and spleen after acute blood loss was studied in laboratory mice. Combined transplantation of these cells did not change the content of cytogenetically modified cells in the bone marrow under normal conditions, but reduced their levels after acute blood loss. Combined transplantation of multipotent mesenchymal stromal and hemopoietic stem cells promoted activation of erythropoiesis and granulocytopoiesis. The major morphometric and cytological parameters of the white pulp of the spleen decreased, presumably due to immunosuppressive effect of multipotent mesenchymal stromal cells. PMID- 28580521 TI - Effects of Nitrosyl Iron Complexes with Thiocarbamide and Its Aliphatic Derivatives on Activities of Ca2+-ATPase of Sarcoplasmic Reticulum and cGMP Phosphodiesterase. AB - We studied the effects of water-soluble cationic dinitrosyl iron complexes with thiocarbamide and its aliphatic derivatives, new synthetic analogs of natural NO donors, active centers of nitrosyl [1Fe-2S]proteins, on activities of Ca2+-ATPase of sarcoplasmic reticulum and cGMP phosphodiesterase. Nitrosyl iron complexes [Fe(C3N2H8S)Cl(NO)2]0[Fe(NO)2(C3N2H8S)2]+Cl- (I), [Fe(SC(N(CH3)2)2(NO)2]Cl (II), [Fe(SC(NH2)2)2(NO)2Cl*H2O (III), and [Fe(SC(NH2)2)2(NO)2]2SO4*H2O (IV) in a concentration of 10-4 M completely inhibited the transporting and hydrolytic functions of Ca2+-ATPase. In a concentration of 10-5 M, they inhibited active Ca2+ transport by 57+/-6, 75+/-8, 80+/-8, and 85+/-9% and ATP hydrolysis by 0, 40+/-4, 48+/-5, and 38+/-4%, respectively. Complex II reversibly and noncompetitively inhibited the hydrolytic function of Ca2+-ATPase (Ki=1.7*10-6 M). All the studied iron-sulphur complexes in a concentration of 10-4 M inhibited cGMP phosphodiesterase function. These data suggest that the studied complexes can exhibit antimetastatic, antiaggregation, vasodilatatory, and antihypertensive activities. PMID- 28580524 TI - Experimental Verification of the Bernstein Effect "Repetition without Repetition". AB - The necessity of studying the Bernstein effect "repetition without repetition" is dictated by the absence of quantitative description of this effect and models that could describe such unique phenomena as repeated limb movements in a person in various mental states. In 30 nominally healthy volunteers (15 men, 15 women aged 24-25 years), tappingrams and tremorograms were recorded using an eddy current sensor with an oscillatory circuit (1 MHz) and an amplifier with recording frequency 0-1000 Hz and minimum amplitude of 0.01 mm. The results were recorded as files, processed as matrices of paired comparisons of samples, the number of matching sample pairs was determined (significance level p>0.05), and phase trajectories of finger movement were plotted. The effect was observed for both tapping and tremor and it is advisable to calculate the parameters of quasi attractors that changed upon shifts in homeostasis. PMID- 28580525 TI - Effects of Polyelectrolyte Microcapsules with Different Surface Charge on Erythrocyte Sedimentation Rate. AB - Relationship between changes in the erythrocyte sedimentation rate in rats and concentration and charge of polyelectrolyte microcapsules was studied by the Panchenkov method. Positively charged microcapsules reduced erythrocyte sedimentation rate in a concentrationdependent manner. This effect was related to a decrease in the content of high-molecularweight proteins in the plasma due to their adsorption in positively charged microcapsules with polyacrylamide surface layer. PMID- 28580526 TI - Deformable appearance pyramids for anatomy representation, landmark detection and pathology classification. AB - PURPOSE: Representation of anatomy appearance is one of the key problems in medical image analysis. An appearance model represents the anatomies with parametric forms, which are then vectorised for prior learning, segmentation and classification tasks. METHODS: We propose a part-based parametric appearance model we refer to as a deformable appearance pyramid (DAP). The parts are delineated by multi-scale local feature pyramids extracted from an image pyramid. Each anatomy is represented by an appearance pyramid, with the variability within a population approximated by local translations of the multi-scale parts and linear appearance variations in the assembly of the parts. We introduce DAPs built on two types of image pyramids, namely Gaussian and wavelet pyramids, and present two approaches to model the prior and fit the model, one explicitly using a subspace Lucas-Kanade algorithm and the other implicitly using the supervised descent method (SDM). RESULTS: We validate the performance of the DAP instances with difference configurations on the problem of lumbar spinal stenosis for localising the landmarks and classifying the pathologies. We also compare them with classic methods such as active shape models, active appearance models and constrained local models. Experimental results show that the DAP built on wavelet pyramids and fitted with SDM gives the best results in both landmark localisation and classification. CONCLUSION: A new appearance model is introduced with several configurations presented and evaluated. The DAPs can be readily applied for other clinical problems for the tasks of prior learning, landmark detection and pathology classification. PMID- 28580527 TI - Non-occlusive mesenteric ischemia in a patient with left ventricular assist device implantation. AB - Non-occlusive mesenteric ischemia (NOMI) is a devastating complication after cardiac surgery. Once patients develop NOMI, intra-mesenteric infusion of vasodilators and/or emergent laparotomy is usually required, but the mortality is extraordinarily high even with intensive treatment. We present a case of salvage of a patient with NOMI complicated with severe right ventricular dysfunction after left ventricular assist device (LVAD) implantation using maximum treatment with emergent laparotomy and temporary right ventricular assist device implantation. To the best of our knowledge, this is the first successful salvage case of NOMI in a LVAD patient. We believe that hemodynamic optimization using maximum treatment is critically important to achieve salvage. PMID- 28580528 TI - Retraction Note to: Genome Shuffling Enhances Lipase Production of Thermophilic Geobacillus Sp. PMID- 28580529 TI - Abnormal baseline brain activity in Alzheimer's disease patients with depression: a resting-state functional magnetic resonance imaging study. AB - PURPOSE: As one of the most common mental disorders and the most important precursor of suicide in Alzheimer's disease (AD), depression is associated with a decline in both well-being and daily functioning. At present, the diagnosis of AD patients with depression (D-AD) is largely dependent on clinical signs and symptoms, and the precise neural correlate underlying D-AD is still not fully understood. METHODS: The current study sought to investigate low-frequency oscillations at the voxel level in D-AD patients based on the amplitude of low frequency fluctuations (ALFF) measured using resting-state functional magnetic resonance imaging. We examined 22 D-AD patients and 21 non-depressed AD (nD-AD) patients. RESULTS: The results revealed that D-AD patients exhibited increased ALFF values in the left caudate and thalamus and decreased ALFF values in the left middle temporal pole compared with nD-AD patients. CONCLUSION: These findings may provide further insight into the underlying neuropathophysiology of AD with depression. PMID- 28580530 TI - Endovascular treatment in patients with carotid artery dissection and intracranial occlusion: a systematic review. AB - PURPOSE: Recently, multiple randomised controlled trials showed efficacy of endovascular treatment over traditional care in patients with acute ischemic stroke due to an intracranial anterior circulation occlusion. Internal carotid artery (ICA) dissection with a concomitant intracranial occlusion is a rare but important cause of severe acute ischemic stroke. Although this subtype of acute ischemic stroke is mostly treated with endovascular treatment, treatment outcomes are still sparsely studied. This study assesses the clinical outcome and reperfusion rates by means of a systematic review. METHODS: Electronic databases of PubMed, EMBASE and Web of Science were searched up to October 1, 2016 for articles describing endovascular treatment in patients with intracranial artery occlusion and ICA dissection. RESULTS: Sixteen studies were included in the analysis. Most studies showed favourable outcome and successful reperfusion. However, most included studies had a high risk of bias. CONCLUSION: In the reviewed studies, endovascular treatment in patients with ICA dissection and concomitant proximal intracranial occlusion was associated with favourable outcome. This could point in the direction of endovascular treatment being a beneficial treatment method for these patients. However, this review has only taken data of a limited group of patients into account. A pooled analysis of patients from recently published endovascular treatment trials and running registries is therefore recommended. PMID- 28580531 TI - Age-related changes of white matter association tracts in normal children throughout adulthood: a diffusion tensor tractography study. AB - PURPOSE: The aim of this study is to study the age, gender and lateral asymmetry related white matter changes of long association tracts throughout late childhood and adolescence into adulthood using diffusion tensor tractography (DTT). METHODS: DTT was performed in 44 healthy subjects aged 7-45 years. Fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), Trace, density and volume were calculated for long association tracts, namely the inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), uncinate fasciculus, superior longitudinal fasciculus (SLF) and its arcuate fibres. FA and diffusivity indices were correlated as function of age using Pearson correlation test. Comparison between males and females, and comparison between both hemispheres among all participants were also performed. A p value less than .01 was considered significant. RESULTS: The majority of the examined tracts (SLF and IFOF of both hemispheres, and the arcuate fasciculus, uncinate fasciculus, and ILF of the left hemisphere) followed a common pattern of metric changes with age. This pattern was characterized by significant FA increase accompanied by reduction in RD, Trace without significant AD changes. The right arcuate fasciculus showed similar pattern but without significant FA changes. The right uncinate and right ILF fasciculus demonstrated significant reduction in RD, Trace and AD, with and without significant FA increase, respectively. Left hemispheric dominance regarding the FA and diffusivity indices was demonstrated in uncinate fasciculus with no significant gender-related differences. CONCLUSION: Significant microstructural tract-specific maturation processes continue throughout late childhood into adulthood. These processes may represent stages in a cascade of age-related maturation in white matter microstructure. PMID- 28580532 TI - Follow-up CT and CT angiography after intracranial aneurysm clipping and coiling improved image quality by iterative metal artifact reduction. AB - PURPOSE: This paper aims to evaluate a new iterative metal artifact reduction algorithm for post-interventional evaluation of brain tissue and intracranial arteries. METHODS: The data of 20 patients that underwent follow-up cranial CT and cranial CT angiography after clipping or coiling of an intracranial aneurysm was retrospectively analyzed. After the images were processed using a novel iterative metal artifact reduction algorithm, images with and without metal artifact reduction were qualitatively evaluated by two readers, using a five point Likert scale. Moreover, artifact strength was quantitatively assessed in terms of CT attenuation and standard deviation alterations. RESULTS: The qualitative analysis yielded a significant increase in image quality (p = 0.0057) in iteratively processed images with substantial inter-observer agreement (K = 0.72), while the CTA image quality did not differ (p = 0.864) and even showed vessel contrast reduction in six cases (30%). The mean relative attenuation difference was 27% without metal artifact reduction vs. 11% for iterative metal artifact reduction images (p = 0.0003). CONCLUSIONS: The new iterative metal artifact reduction algorithm enhances non-enhanced CT image quality after clipping or coiling, but in CT-angiography images, the contrast of adjacent vessels can be compromised. PMID- 28580533 TI - Quantitative assessment on blood-brain barrier permeability of acute spontaneous intracerebral hemorrhage in basal ganglia: a CT perfusion study. AB - PURPOSE: Blood-brain barrier (BBB) damage aggravates perihematomal edema, and edema volume predicts prognosis independently. But the BBB permeability at the late stage of acute intracerebral hemorrhage (ICH) patients is uncertain. We aimed to assess the BBB permeability of spontaneous basal ganglia ICH using computed tomographic perfusion (CTP) and investigates its relationship with hematoma and perihematomal edema volume. METHODS: We performed CTP on 54 consecutive ICH patients within 24 to 72 h after symptom onset. Permeability surface area product (PS) derived from CTP imaging was measured in hematoma, "high-PS spot," perihematoma, normal-appearing, hemispheric, and contralateral regions. Hematoma and edema volumes were calculated from non-contrast CT. RESULTS: "High-PS spot" and perihematoma regions had higher PS than the contralateral regions (p < 0.001). Hematoma PS was lower than that in the contralateral regions (p < 0.001). Perihematoma PS of the large-hematoma group was higher than that of the small-hematoma group (p = 0.011). Perihematomal edema volume correlated positively with hematoma volume (beta = 0.864, p < 0.001) and perihematoma PS (beta = 0.478, p < 0.001). Perihematoma PS correlated positively with hematoma volume (beta = 0.373, p = 0.005). CONCLUSIONS: Locally elevated perihematoma PS was found in most spontaneous basal ganglia ICH patients within 24 to 72 h after symptom onset. Perihematoma PS was higher in larger hematomas and was associated with larger edema volume. At this period, BBB leakage is likely to be an important factor in edema formation. PMID- 28580534 TI - Fatal Pulmonary Mucormycosis due to Rhizopus homothallicus. AB - We report here a case of cavitary pneumonia due to Rhizopus homothallicus in a diabetic patient. This is the first proven case of R. homothallicus infection in Western countries and the third case described worldwide. The organism was isolated from lung biopsy and identified after amplification and sequencing of the internal transcribed spacer region. PMID- 28580535 TI - Metabolically inactive insulin: friend or foe in the prevention of autoimmune diabetes? AB - About 20 years ago an American study suggested that daily subcutaneous injections of a metabolically inactive insulin analogue with a single amino acid substitution (aspartic acid instead of phenylalanine) at position 25 of the B chain was as effective as intact insulin in preventing autoimmune diabetes in NOD mice. In this issue of Diabetologia Gronholm et al (DOI: 10.1007/s00125-017-4276 5 ) report that parenteral administration of the same insulin analogue has no preventive effect whatsoever on the development of diabetes in NOD mice; in fact, high doses of the metabolically inactive insulin accelerated disease development. The authors were also unable to show any tolerogenic effect of an insulin peptide mimetope given via a subcutaneous osmotic pump. These data do not support the use of metabolically inactive insulin for the prevention of autoimmune diabetes and question whether insulin alone, intact or inactivated has any role in preventing progression to symptomatic diabetes. Future and ongoing intervention trials in humans with preclinical type 1 diabetes should indicate whether the administration of oral insulin has any protective, neutral or even predisposing effects on the development of symptomatic diabetes. PMID- 28580537 TI - CT imaging spectrum of infiltrative renal diseases. AB - Most renal lesions replace the renal parenchyma as a focal space-occupying mass with borders distinguishing the mass from normal parenchyma. However, some renal lesions exhibit interstitial infiltration-a process that permeates the renal parenchyma by using the normal renal architecture for growth. These infiltrative lesions frequently show nonspecific patterns that lead to little or no contour deformity and have ill-defined borders on CT, making detection and diagnosis challenging. The purpose of this pictorial essay is to describe the CT imaging findings of various conditions that may manifest as infiltrative renal lesions. PMID- 28580538 TI - LI-RADS M (LR-M): definite or probable malignancy, not specific for hepatocellular carcinoma. AB - LI-RADS v2017 introduces major changes to the diagnostic criteria for LR-M observations to better guide radiologists in the use of this malignant category designation. LR-M is intended to preserve the specificity of the LI-RADS algorithm for diagnosis of HCC while not losing sensitivity for diagnosis of malignancy. The purpose of this paper is to provide a brief background on LR-M, discuss the diagnostic criteria new to v2017, special considerations for its application, and management implications. PMID- 28580539 TI - The light bulb sign in pheochromocytoma. PMID- 28580536 TI - Annexin A2 Plus Low-Dose Tissue Plasminogen Activator Combination Attenuates Cerebrovascular Dysfunction After Focal Embolic Stroke of Rats. AB - Previous studies showed recombinant annexin A2 (rA2) in combination with low-dose tissue-type plasminogen activator (tPA) improved thrombolytic efficacy and long term neurological outcomes after embolic focal ischemia in rats. The objective of this study was to investigate the effects and mechanisms of the combination in early BBB integrity and cerebrovascular patency in the rat focal embolic stroke model. Ischemic brain infarct volume and hemorrhagic transformation were quantified at 24 h after stroke. At an earlier time point, 16 h after stroke, BBB integrity was evaluated by IgG extravasation, and the involved mechanisms were assessed for tight junction ZO-1 and adhesion junction ve-cadherin protein expression, matrix metalloproteinase activation, extracellular matrix collagen IV and endothelial barrier antigen expression, and activation of microglia/macrophages and astrocytes. While at the same time point, cerebrovascular patency was assessed by intravascular fibrin and platelet depositions. At 24 h after stroke, the combination showed significant reduction in brain infarction and intracerebral hemorrhage. At 16 h after stroke onset, the combination therapy significantly reduced BBB disruption, and improved preservation of the junction proteins ZO-1 and ve-cadherin, decreased activation of matrix metalloproteinase, inhibited degradation of extracellular matrix collagen IV and endothelial barrier antigen, and reduced microglia/macrophage and astrocytes activations. Meanwhile, the combination also significantly improved cerebrovascular patency by reducing intravascular fibrin and platelet depositions in the peri-infarct brain tissues. These results suggest the beneficial effects of the rA2 plus low-dose tPA combination may be mediated in part by the amelioration of BBB disruption and improvement of cerebrovascular patency. PMID- 28580540 TI - Updates for the radiologist in non-muscle-invasive, muscle-invasive, and metastatic bladder cancer. AB - Urothelial bladder cancer is a common malignancy requiring a multidisciplinary approach to treatment. Significant recent advances have been made in terms of the genetic and molecular characterization of bladder cancer subtypes, and novel treatment approaches are being investigated and approved. Given the important role of imaging in the diagnosis, staging, and follow-up of this disease, it is necessary for radiologists to remain up-to-date in terms of nomenclature and standards of care. In this review, recent developments in bladder cancer characterization and treatment will be discussed, with reference to the contributions of imaging in non-muscle-invasive, muscle-invasive, and metastatic settings. PMID- 28580542 TI - Comparison of surgical and non-surgical orthodontic treatment approaches on occlusal and cephalometric outcomes in patients with Class II Division I malocclusions. AB - BACKGROUND: This study aimed to examine end-of-treatment outcomes of severe Class II Division I malocclusion patients treated with surgical or non-surgical approaches. This study tests the hypotheses that occlusal outcomes (ABO-OGS) and cephalometric outcomes differ between these groups. METHODS: A total of 60 patients were included: 20 of which underwent surgical correction and 40 of which did not. Cast grading of initial and final study models was performed and information was gathered from pre- to post-treatment cephalometric radiographs. The end-of-treatment ABO-OGS and cephalometric outcomes were compared to Mann Whitney U tests and multivariable linear regression models. RESULTS: Following adjustment for multiple confounders (age, gender, complexity of case, and skeletal patterns), the final deband score (ABO-OGS) was similar for both groups (23.8 for surgical group versus 22.5 for non-surgical group). Those treated surgically had a significantly larger reduction in ANB angle, 3.4 degrees reduction versus 1.5 degrees reduction in the non-surgical group (p = 0.002). The surgical group also showed increased maxillary incisor proclination (p = 0.001) compared to the non-surgical group. This might be attributed to retroclination of maxillary incisors during treatment selection in the non surgical group-namely, extraction of premolars to mask the discrepancy. CONCLUSIONS: Those treated surgically had a significantly larger reduction in ANB angle and increased maxillary incisor proclination compared to those treated non surgically with no significant changes in occlusal outcomes. PMID- 28580541 TI - Decalcification prevention around orthodontic brackets bonded to bleached enamel using different topical agents. AB - BACKGROUND: The present study was conducted to evaluate the effect of different topical agents utilized for prevention of enamel decalcification around orthodontic brackets bonded to bleached and non-bleached enamel. METHODS: Human maxillary premolars (n = 120) were divided into two equal groups. Teeth in group I were left without bleaching while those in group II were bleached with Vivastyle gel. Metal brackets were bonded to all the teeth using light-cured adhesive. Each group was divided into six equal subgroups (A, B, C, D, E, and F). In subgroup A, no material was applied (control). In subgroups B, C, D, E, and F, the following materials were applied respectively: Profluorid varnish, Enamel Pro Varnish, Ortho-Choice Ortho-Coat, GC Tooth Mousse, and GC MI Paste Plus. All teeth were cycled in a demineralization solution/artificial saliva for 15 days. Laser fluorescence was used to measure the level of enamel mineralization. The data were statistically analyzed. RESULTS: Regarding the non-bleaching subgroups, all studied material revealed significant demineralization reduction in comparison to the control subgroup (P < 0.05). Ortho-Choice Ortho-Coat revealed the highest significant effect while GC Tooth Mousse showed the least effect. In bleached subgroups, Profluorid varnish, Enamel Pro Varnish, and Ortho-Choice Ortho-Coat significantly reduced demineralization (P < 0.05) while either GC MI Paste Plus or GC Tooth Mousse had no significant effects (P > 0.05). CONCLUSIONS: Ortho-Choice Ortho-Coat, and Profluorid and Enamel Pro varnishes could be utilized successfully to reduce enamel demineralization around brackets bonded to either bleached or non-bleached enamel. GC MI Paste Plus and GC Tooth Mousse were effective only in non-bleached enamel. PMID- 28580543 TI - Assessment of alternatives to environmental toxic formalin for DNA conservation in biological specimens. AB - One essential step of museum and clinical specimen preservation is immersion in a fixative fluid to prevent degradation. Formalin is the most largely used fixative, but its benefit is balanced with its toxic and carcinogenic status. Moreover, because formalin-fixation impairs nucleic acids recovery and quality, current museum wet collections and formalin-fixed, paraffin-embedded clinical samples do not represent optimal tanks of molecular information. Our study has been developed to compare formalin to two alternative fixatives (RCL2(r) and ethanol) in a context of molecular exploitation. Based on a unique protocol, we created mammalian fixed collections, simulated the impact of time on preservation using an artificial ageing treatment and followed the evolution of specimens' DNA quality. DNA extraction yield, purity, visual integrity and qualitative and quantitative ability to amplify the Cox1 gene were assessed. Our results show that both RCL2 and ethanol exhibit better performances than formalin. They do not impair DNA extraction yield, and more importantly, DNA alteration is delayed over the preservation step. The use of RCL2 or ethanol as fixative in biological collections may insure a better exploitation of the genetic resources they propose. PMID- 28580544 TI - Impact of regulation on English and Welsh water-only companies: an input-distance function approach. AB - The assessment of productivity change over time and its drivers is of great significance for water companies and regulators when setting urban water tariffs. This issue is even more relevant in privatized water industries, such as those in England and Wales, where the price-cap regulation is adopted. In this paper, an input-distance function is used to estimate productivity change and its determinants for the English and Welsh water-only companies (WoCs) over the period of 1993-2009. The impacts of several exogenous variables on companies' efficiencies are also explored. From a policy perspective, this study describes how regulators can use this type of modeling and results to calculate illustrative X factors for the WoCs. The results indicate that the 1994 and 1999 price reviews stimulated technical change, and there were small efficiency gains. However, the 2004 price review did not accelerate efficiency change or improve technical change. The results also indicated that during the whole period of study, the excessive scale of the WoCs contributed negatively to productivity growth. On average, WoCs reported relatively high efficiency levels, which suggests that they had already been investing in technologies that reduce long term input requirements with respect to exogenous and service-quality variables. Finally, an average WoC needs to improve its productivity toward that of the best company by 1.58%. The methodology and results of this study are of great interest to both regulators and water-company managers for evaluating the effectiveness of regulation and making informed decisions. PMID- 28580546 TI - Dye removal of AR27 with enhanced degradation and power generation in a microbial fuel cell using bioanode of treated clinoptilolite-modified graphite felt. AB - This work studied the performance of a laboratory-scale microbial fuel cell (MFC) using a bioanode that consisted of treated clinoptilolite fine powder coated onto graphite felt (TC-MGF). The results were compared with another similar MFC that used a bare graphite felt (BGF) bioanode. The anode surfaces provided active sites for the adhesion of the bacterial consortium (NAR-2) and the biodegradation of mono azo dye C.I. Acid Red 27. As a result, bioelectricity was generated in both MFCs. A 98% decolourisation rate was achieved using the TC-MGF bioanode under a fed-batch operation mode. Maximum power densities for BGF and TC-MGF bioanodes were 458.8 +/- 5.0 and 940.3 +/- 4.2 mW m-2, respectively. GC-MS analyses showed that the dye was readily degraded in the presence of the TC-MGF bioanode. The MFC using the TC-MGF bioanode showed a stable biofilm with no biomass leached out for more than 300 h operation. In general, MFC performance was substantially improved by the fabricated TC-MGF bioanode. It was also found that the TC-MGF bioanode with the stable biofilm presented the nature of exopolysaccharide (EPS) structure, which is suitable for the biodegradation of the azo dye. In fact, the EPS facilitated the shuttling of electrons to the bioanode for the generation of bioelectricity. PMID- 28580547 TI - A dynamic modelling of nutrient metabolism in a cyclic activated sludge technology (CAST) for treating low carbon source wastewater. AB - A new mathematical model incorporating biopolymer kinetics and the process of the simultaneous storage and growth are established for the treatment of low carbon source wastewater with a high effluent quality and energy efficiency. A set of initial parameter values was assigned as a combination of estimated values, literature-based values, and fitted values to simulate a cyclic activated sludge technology (CAST) system effectively. Compared with experimental data from the CAST system, the calibrated model demonstrated a good performance. Model simulations indicated that the recommended condition for a CAST fed with low carbon source wastewater was a volume ratio of the anoxic zone to the aerobic zone of 7/28. Moreover, using high-throughput 16S rRNA gene sequencing not only characterised the microbial communities in the CAST reactors operated under two feeding ratios but also indirectly validated the model predictions. PMID- 28580545 TI - Polymer nanoparticles containing essential oils: new options for mosquito control. AB - Mosquitoes (Diptera: Culicidae) are vectors of important parasites and pathogens causing death, poverty and social disability worldwide. The overuse of synthetic insecticides to control mosquito vectors lead to resistance, adverse environmental effects and high operational costs. Therefore, the development of eco-friendly control tools is an important public health challenge. In this study, two different essential oils (EO) (geranium, Geranium maculatum, and bergamot, Citrus bergamia) loaded polymeric nanoparticle (PN) were elaborated using polyethylene glycol (PEG) and chitosan (Qx) as the polymeric matrix/coating. In addition, the mosquito larvicidal acute and residual activity of the PN was evaluated on Culex pipiens pipiens. The physicochemical characterization of PN revealed that PEG-PN had sizes <255 nm and encapsulation efficiency between 68 and 77%; Qx-PN showed sizes <535 nm and encapsulation efficiency between 22 and 38%. From the toxicological test, it was observed that Qx-PN produced higher acute and residual activity than PEG-PN. Overall, this study highlights that polymer nanoparticles containing essential oil are a promising source of eco-friendly mosquito larvicidal products. PMID- 28580548 TI - Development of an eco-friendly mosquitocidal agent from Alangium salvifolium against the dengue vector Aedes aegypti and its biosafety on the aquatic predator. AB - Plant extracts with their enriched chemical constituents have established potential alternative mosquito control agents. In this research, we developed an eco-friendly mosquitocidal agent from Alangium salvifolium leaves against the dengue and Zika virus vector Aedes aegypti and we investigated its biosafety on the mosquito aquatic predator Toxorhynchites splendens. Results showed that the methanolic extract of A. salvifolium leaves was composed by eight main compounds, with major peak area for hexadecenoic acid (21.74%). LC50 and LC90 values calculated on Ae. aegypti fourth instar larvae were 104.80 and 269.15 ppm respectively. The methanolic extract tested at 100 ppm decreased the alpha-beta carboxylesterase and SOD ratio significantly and upregulated the GST and CYP450 level. The A. salvifolium methanolic extract displayed significant repellent and adulticidal activity at 100 and 400 ppm respectively. The treatment with 100 ppm of the methanolic extract led to 210 min of protection from Ae. aegypti bites. Four hundred parts per million of the extract showed 98% adult mortality within 30 min from the treatment. Lastly, biosafety assays on the mosquito aquatic predator Tx. splendens showed that the toxicity of the A. salvifolium extract was significantly lower if compared to the cypermethrin-based treatments. The methanolic extract of A. salvifolium showed a maximum of 47.3% mortality rate at the concentration of 1000 ppm, while 0.7 ppm of cypermethrin achieved 91.3% mortality rate on Tx. splendens. Overall, our study enhances basic knowledge on how to improve natural larvicidal agents against dengue and Zika virus mosquito vector with harmless responses on non-target aquatic predators. PMID- 28580549 TI - Experimental study on the stability of the ClHgSO3- in desulfurization wastewater. AB - Wet flue gas desulfurization technologies have received much concern for their superior performance on co-controlling the acid gases and mercury. However, high concentrations of mercury-containing desulfurization wastewater, which discharge from wet flue gas desulfurization system regularly, have received researchers' attention since it might generate the risk of secondary pollution. In this paper, the species of mercuric complexes in the desulfurization wastewater was investigated. It speculated that ClHgSO3- might determine the residual rate of Hg2+ in the desulfurization wastewater. Besides, the stability of ClHgSO3- on the condition of various wastewater features was also evaluated. The experiment revealed that the high temperature and high pH level promoted the decomposition of ClHgSO3-. SO32- could restrain the decomposition of ClHgSO3- gently; the Hg2+ residual rate was determined by the new mercury complexes which compounded by Hg2+ and SO32-. The decrease of SO42- and increase of Ca2+ concentrations could also stimulate the stability of ClHgSO3- in wastewater. Cu2+ and Fe2+ disturbed the stability of complexes for their catalysis and reduction activities. The study proposed that the ClHgSO3- probably decomposes and releases Hg0 in two pathways. Furthermore, changes of the water's features could disturb the balance of Hg2+-Cl--SO32- systems, which might stimulate the decomposition of ClHgSO3. PMID- 28580550 TI - Magnetic signature, geochemistry, and oral bioaccessibility of "technogenic" metals in contaminated industrial soils from Sindos Industrial Area, Northern Greece. AB - The objective of this study was to assess the contamination level of potentially harmful elements (PHEs) in industrial soils and how this relates to environmental magnetism. Moreover, emphasis was given to the determination of the potential mobile fractions of typically "technogenic" metals. Therefore, magnetic and geochemical parameters were determined in topsoils (0-20 cm) collected around a chemical industry in Sindos Industrial Area, Thessaloniki, Greece. Soil samples were presented significantly enriched in "technogenic" metals such Cd, Pb, and Zn, while cases of severe soil contamination were observed in sampling sites north-west of the industrial unit. Contents of Cd, Cr, Cu, Ni, Pb, Mo, Sb, Sn, and Zn in soils and pollution load index (PLI) were highly correlated with mass specific magnetic susceptibility (chi lf). Similarly, enrichment factor (EF) and geoaccumulation index (I geo) for "technogenic" Pb and Zn exhibited high positive correlation factors with chi lf. Principal component analysis (PCA) classified PHEs along with the magnetic variable (chi lf) into a common group indicating anthropogenic influence. The water extractable concentrations were substantially low, while the descending order of UBM (Unified BARGE Method) extractable concentrations in the gastric phase was Zn > Pb > As > Cd, yet Cd showed the highest bioaccessibility (almost 95%). PMID- 28580551 TI - Investigating the relationship between lead speciation and bioaccessibility of mining impacted soils and dusts. AB - Lead (Pb) bioaccessibility measurements have been the subject of much research in recent years, given the desire to develop a cost-effective and reliable alternative method to estimate its bioavailability from soils and dusts. This study investigates the relationship between Pb bioaccessibility estimated using the Relative Bioavailability Leaching Procedure (RBALP) and solid phase speciation of Pb using mining impacted soils and associated dusts. Solid phase speciation was conducted prior to and after RBALP extractions. The average Pb concentrations were 59, 67, and 385 mg/kg for top soil, sub-soil, and house dust samples, respectively. Lead bioaccessibility in selected top soils and dusts ranged from 16.7 to 57.3% and 8.9 to 98.1%, respectively. Solid phase speciation of Pb in <250 MUm residues prior to and after RBALP extraction revealed 83% decrease in Pb bound to carbonate fraction after RBALP extraction. This accounts for 69% of RBALP-extractable Pb. Besides contribution from carbonate bound Pb, 76.6 and 53.2% of Pb bound to Mn oxyhydroxides and amorphous Fe and Al oxyhydroxides contributed to bioaccessible Pb, respectively. However, Pb bound to Mn oxyhydroxides and amorphous Fe and Al oxyhydroxides account for only 13.8 and 20.0% of total RBALP-extractable Pb, respectively. Both non-specifically bound and easily exchangeable fractions and strongly bound inner-sphere complexes were also part of bioaccessible Pb. The present study demonstrates that bioaccessible Pb is released from both soil solution phase Pb as well as that from all soil solid phase with the most contribution being from Pb bound to carbonate mineral phase. PMID- 28580553 TI - [The Development of Psychiatric and Mental Health Nursing in Taiwan: Reflection From the Perspective of Recovery]. AB - Evidence-based nursing science has identified psychological recovery, partnership, and medication adherence as factors that have influenced the development of mental health care. This article discusses the process by which mental health care has developed from a medical / rehabilitation-focused model to a model that focuses on patient empowerment. The current model aims to assist patients to achieve self-awareness and to develop coping skills that enhance their motivation to transform. Medical advances have improved the control of psychiatric symptoms. Following the introduction of 2nd generation antipsychotics, patients were invited to establish decisions related to these prescription medications. Under the principles of patient-centered service, Taiwanese mental health professionals have changed their relationship with patients from a therapeutic model to a mutual-partnership model. Furthermore, investigations of the therapeutic care of patients with mental illness have used the needs of patients as their starting point and emphasized various aspects of patient and caregiver needs. Taiwanese mental health professionals are searching for a model of mental health care that is superior to the traditional operative framework of medical authority. PMID- 28580552 TI - Ability of T1 Lipase to Degrade Amorphous P(3HB): Structural and Functional Study. AB - An enzyme with broad substrate specificity would be an asset for industrial application. T1 lipase apparently has the same active site residues as polyhydroxyalkanoates (PHA) depolymerase. Sequences of both enzymes were studied and compared, and a conserved lipase box pentapeptide region around the nucleophilic serine was detected. The alignment of 3-D structures for both enzymes showed their active site residues were well aligned with an RMSD value of 1.981 A despite their sequence similarity of only 53.8%. Docking of T1 lipase with P(3HB) gave forth high binding energy of 5.4 kcal/mol, with the distance of 4.05 A between serine hydroxyl (OH) group of TI lipase to the carbonyl carbon of the substrate, similar to the native PhaZ7 Pl . This suggests the possible ability of T1 lipase to bind P(3HB) in its active site. The ability of T1 lipase in degrading amorphous P(3HB) was investigated on 0.2% (w/v) P(3HB) plate. Halo zone was observed around the colony containing the enzyme which confirms that T1 lipase is indeed able to degrade amorphous P(3HB). Results obtained in this study highlight the fact that T1 lipase is a versatile hydrolase enzyme which does not only record triglyceride degradation activity but amorphous P(3HB) degradation activity as well. PMID- 28580554 TI - [Self-Awareness of Disease Stigma: Reflections of Healthcare Professionals]. AB - People who suffer from disease frequently experience disease-related stigmas. Stigma presents in daily life during normal human interactions. The stereotypes promoted by the media often impact public opinion significantly. Moreover, healthcare professionals may exacerbate stigmatization due to their misunderstanding of patients and their disease issues. Therefore, the reflection on stigma of healthcare professionals cannot be ignored. The present article illustrates the issue of stigmas held by healthcare professionals, their related stigmas, and their self-awareness. It is hoped that all healthcare professionals may cooperate to develop an anti-stigma strategy and to become true spokespersons for their patients. PMID- 28580555 TI - [Care of Individuals With Bipolar Disorders]. AB - Bipolar disorder (BD) is a severe mental illness that is characterized by chronicity, pervasive instability, and relatively high rates of recurrence and suicide. Current evidence supports that adverse circles among hereditary and genetic factors, neuroinflamation, and social rhythm constitute a crucial etiology. Pharmacological treatment is the first priority for BD patients during the acute stage. Pharmacological and psychosocial treatments should be combined during the maintenance stage in order to help patients self-manage medication, effectively control mood swings, enhance disease self-management and social functions, decrease the risks of relapse and re-hospitalization, and stabilize overall health. The present article firstly introduces the characteristics and etiological assumptions related to BD, the related evidence-based care models and their effects, and the early development of an evidence-based care model, the BalancingMySwing group, for BD patients in Taiwan. This article provides updated information to clinicians who are involved in caring for this population. Moreover, the existing data related to biological and psychosocial factors for BD in Taiwan is insufficient and developing individual-tailored psychosocial intervention is urgently needed. The authors hope that this article will elicit greater concern for this issue from policy decision-makers and healthcare providers. PMID- 28580556 TI - [The Application of Body-Mind-Spirit Integrated Psychotherapy in Nursing Practice]. AB - Body-mind-spirit integrated psychotherapy reflects the core value of nursing by emphasizing the inseparable concept of body, mind, and spirit and caring for the holistic needs of the patient. Body-mind-spirit integrated psychotherapy was developed based on Western psychotherapy (positive psychology and forgiveness therapy), traditional Chinese medicine, and the Eastern philosophies of Buddhism, Taoism, and Confucianism. The present paper describes the holistic concepts that underpin this therapeutic approach. Physical health is sustained through proper nutrition, physical relaxation, and harmonized breathing; psychological well being helps maintain inner peace and harmony in interpersonal relationships; and spiritual well-being helps develop an optimistic and meaningful life. We report on several cases in which body-mind-spirit integrated psychotherapy was applied to the care of clients with depressive disorders and of breast cancer survivors and their partners as well as the related efficacy of this intervention in these cases. Finally, we discuss the potential for culturally-enriched psychotherapy to help clients transform illness suffering into life-growth experiences. PMID- 28580557 TI - [Localization Establishment of an Interdisciplinary Intervention Model to Prevent Post-Operative Delirium in Older Patients Based on 'Hospital Elder Life Program']. AB - BACKGROUND: Postoperative delirium is a significant complication in elderly patients. The occurrence of delirium may increase the related physical and psychological risks, delay the length of hospital stays, and even lead to death. According to the current evidence-based model, the application of interdisciplinary intervention may effectively prevent delirium, shorten the length of hospital stays, and save costs. PURPOSE: To establish a culturally appropriate interdisciplinary intervention model for preventing postoperative delirium in older Chinese patients. METHODS: The authors adapted the original version of the Hospital Elder Life Program (HELP(c)) from the Hebrew Senior Life Institute for Aging Research of Harvard University by localizing the content using additional medical resources and translating the modified instrument into Chinese. Furthermore, the final version of this interdisciplinary intervention model for postoperative delirium was developed in accordance with the "guideline of delirium: diagnosis, prevention and management produced by the National Institute for Health and Clinical Excellence in 2010" and the "clinical practice guideline for postoperative delirium in older adults" produced by American geriatrics society in 2014. Finally, the translated instrument was revised and improved using discussions, consultations, and pilot study. RESULTS: The abovementioned procedure generated an interdisciplinary intervention model for preventing postoperative delirium that is applicable to the Chinese medical environment. The content addresses personnel structure and assignment of responsibility; details of interdisciplinary intervention protocols and implementation procedures; and required personnel training. CONCLUSIONS: The revised model is expected to decrease the occurrence of post-operative delirium and other complications in elderly patients, to help them maintain and improve their function, to shorten the length of their hospital stays, and to facilitate recovery. PMID- 28580558 TI - [The Determinants of Dysphagia in Patients With Stroke During Hospitalized Rehabilitation]. AB - BACKGROUND: Stroke was the third leading cause of death in Taiwan in 2014. A study found that 53.61% of stroke patients suffered from dysphagia disorder during the rehabilitation phase, which may result in lung aspiration and death. The determinants of dysphagia among nationally hospitalized-rehabilitation stroke patients have not been explored comprehensively. PURPOSE: To explore the incidence of dysphagia among hospitalized-rehabilitation stroke patients and the related determinants of dysphagia. METHODS: This descriptive and correlational research design employed a convenience sample of 130 hospitalized stroke patients from rehabilitation wards at a northern regional hospital in Taiwan. A questionnaire and functional assessment were used to collect data. Instruments used included personal and clinical characteristics data questionnaire, the National Institute of Health Stroke Scale (NIHSS), Barthel Index, Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Standardization Swallowing Assessment (SSA), and Acute Stroke Dysphagia Screening (ASDS). Data analyses contained descriptive statistics and logistic regression. RESULTS: The incidence of stroke dysphagia was 63.8% (SSA) and 64.6% (ASDS), respectively. Age, marital status, stroke site, stroke severity (NIHSS), and cognitive status (MMSE) were identified as significant determinants of dysphagia in bivariate logistic regression, whereas stroke severity and cognitive status were identified as significant independent determinants of dysphagia in multivariate logistic regression. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Two-thirds of the participant sample were affected by dysphagia, for which NIHSS and cognitive status were identified as significant determinants. Thus, nurses may conduct early screening for high risk populations based on patients' clinical characteristics in order to reduce aspiration pneumonia problems and to improve the quality of clinical care for dysphagia patients. PMID- 28580559 TI - [Translation and Development of the Chinese-Version Patient Privacy Scale]. AB - BACKGROUND: The unauthorized releasing of confidential patient information is a serious problem worldwide. Nurses, the healthcare professionals who are in most frequent contact with patients, have access to a significant amount of confidential patient information and play a key role in protecting patient privacy. However, currently, there is no proper tool to measure the level to which clinical nurses protect the privacy of their patients in China. PURPOSE: To translate the patient privacy scale (PPS) into Chinese and to test the reliability and validity of this Chinese version. METHODS: The original scale was developed by Ozturk, Bahcecik, and Ozcelik (2014) to identify whether nurses protect or violate patient privacy in the workplace. This study used the "back translation" method to translate the scale. A total of 616 nurses in two tertiary hospitals in the Western region of China were enrolled to test the internal consistency, test-retest reliability, and construct validity of the translated scale. RESULTS: The Cronbach's coefficients of the total scale and its 5 factors ranged from .84 to .94; the split half reliability was .91; the test-retest reliability was .82; and the content validity index was .95. Explanatory factor analysis revealed that the 5 factors explained 64.98% of the total variance. CONCLUSIONS: The Chinese version of the PPS is reliable and valid, and may be used to reliably assess the behaviors of nurses with regard to protecting the privacy of their patients. The scale may also be used to evaluate the effects of training on patient privacy protection. PMID- 28580560 TI - [A Symbol of Connectedness Between the Self and the Tribal Home: Betel Quid in the Lives of Indigenous Taiwanese]. AB - BACKGROUND: Betel quid chewing plays a significant role in the development of oral cancer, yet the high prevalence of betel quid use remains a serious health problem in Taiwan, especially among indigenous Taiwanese. PURPOSE: The present study aimed to understand the reasons behind betel-quid chewing among indigenous Taiwanese people by examining the larger context of their culture and traditions. METHODS: This descriptive, qualitative study recruited ten regular betel quid indigenous chewers using purposive and snowball sampling. Four of the participants were interviewed individually and the remaining six comprised a focus group. Data were collected using in-depth interviews with semi-structured guidelines and analyzed using qualitative content analysis following the process of open coding, identifying codes, giving meaningful names to codes, putting similar codes in categories, and grouping categories into themes. RESULTS: Most of the participants associated betel quid with significant aspects of life, with betel quid symbolizing social belonging. In indigenous cultures, betel nut embodies the enduring companionship of lifelong friends. For the study participants, chewing betel quid was associated with symbolic meanings associated with the following five themes: betel quid chewing helps reinforce self-identity and sense of belonging; betel quid is considered a traditional symbol of love and marriage; betel quid reflects the celebration of simple abundance in indigenous life; betel quid represents an attitude toward life that accentuates the importance of learning to live in everlasting harmony with the environment and nature; and betel quid chewing is used to cure physical ailments and mitigate dental problems. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Beliefs related to chewing betel quid deeply impact the attitudes of indigenous people toward this behavior. Because chewing betel quid is an essential part of Taiwanese indigenous community life, the cultural and symbolic meanings of this practice must be taken into consideration when drafting related policies and developing cessation programs in order to help indigenous betel-quid chewers effectively reduce the risk of developing oral cancers. PMID- 28580561 TI - [Using Interdisciplinary Cooperation to Improve the Rate of Proper Performance of a Hand Exercise Among Hemodialysis Patients With Arteriovenous Fistula Construction]. AB - BACKGROUND & PROBLEMS: Patients who undergo new arteriovenous fistula (AVF) construction as part of their hemodialysis treatment program are required to perform hand exercises properly in order to maintain AVF function. However, poor performance of these hand exercises currently results in the failure of many patients to preserve AVF function. PURPOSE: To increase the rate of performing this hand exercise properly from 55% to 80%. RESOLUTION: A comprehensive investigation identified the following five main problems: (a) Insufficient muscular endurance; (b) Resistance was not labeled on the ball; (c) Difficulties with maintaining a grip on the ball during the exercise; (d) Lack of standardized education procedures; and (e) Nurses lack latest knowledge on the hand exercise. The strategies used to improve the situation included: (a) Interdisciplinary team cooperation with physiotherapists to design individualized resistance training regimens; (b) Exercise tool improvement; (c) Standardized AVF care; (d) Continuous education for nursing staffs; and (e) Seed teacher program for hand exercise. RESULTS: The rate of proper hand exercise performance increased from 55% to 93%. CONCLUSIONS: This nursing project involved an interdisciplinary team that included physiotherapists in order to successfully improve the rate at which the hand exercise was performed properly. This positive experience may be applied to other hemodialysis departments in the treatment of patients with AVF. PMID- 28580562 TI - [Applying Team Resource Management to Accelerate Rewarming Among Patients Undergoing General Anesthesia]. AB - BACKGROUND & PROBLEMS : Hypothermia is the cause of multiple problems such as delayed awaking from anesthesia, feelings of discomfort, increased oxygen consumption, and increased risks of surgical wound infection and complications. A review of the record of post-operative patients receiving general anesthesia (GA) revealed that only 74% of the patients in our post-anesthesia room (PAR) had restored their body temperature to 36C after 60 minutes. Through situation analysis, several causes were identified, including insufficient warming facilities, lack of standard procedures and an audit system, lack of knowledge regarding hyperthermia among nurses, and the incompleteness of perioperative warming interventions performed by the healthcare team. PURPOSE: The aim of the present project was to apply team resource management (TRM) to raise the rate of body temperature restoration to 36 degrees C after 60 minutes in our post anesthesia room (PAR) from 74% to 100%. RESOLUTION: Several strategies were implemented to accelerate the post-operative rewarming for patients receiving GA, including: establishment of standard operating procedures for warming, conducting routine audits, purchasing warming facilities, conducting in-service education, applying TRM, and cooperating with nurses in operating rooms on executing the warming plan. RESULT: After implementing these strategies, our PAR achieved a 100% success rate in raising the body temperature of postoperative patients to 36 degrees C after 60 minutes. CONCLUSIONS: The result demonstrates that hypothermia may be effectively avoided and that the quality of post-operative care may be effectively improved through transdisciplinary teamwork. PMID- 28580563 TI - [New Treatment for Vascular Thrombosis Prevention in Patients With Atrial Fibrillation: Left Atrial Appendage Occlusion]. AB - Atrial fibrillation (AF) is a common type of arrhythmia that increases significantly the risk of blood clots in the heart and of stroke. Therefore, stroke prevention is a key goal of AF treatment. In the past, patients were required to take anticoagulants for the remainder of their life, to regularly the monitor international normalized ratio (INR) of prothrombin time (PT), and to avoid possible negative interactions with various drugs and foods. Left atrial appendage occlusion (LAAO), a novel device and technique, was thus developed for AF patients with contraindications to anticoagulants and a high risk of bleeding. When using this technique, the occluder is placed on the left atrial appendage in order to effectively prevent blood stasis and thrombi accumulation. Transesophageal echocardiogram and computed tomography are conducted prior to the LAAO procedure, which is similar to the procedure used for cardiac catheterization. After the LAAO procedure, the patient remains in the intensive care unit (ICU), where vital signs, bleeding at the puncture site, and pericardial tamponade complications are monitored. Health education on daily activities, anticoagulant use, and regular follow-up should be given prior to hospital discharge. While LAAO may not reduce the incidence of stroke, the benefits of this procedure include a significant reduction in bleeding complications as compared to procedures that use oral anticoagulants. Further studies including long-term follow up and in-depth examinations of this procedure are necessary. The present article offers a reference for clinical staffs who are responsible for the care of patients treated using the LAAO procedure. PMID- 28580564 TI - [Using the FOCUS Family Intervention in Caring for a Patient-Spouse Dyad With Advanced Colorectal Cancer]. AB - The care-related burdens of the spouses of advanced cancer patients often impact negatively on their physical health, emotional well-being, social functioning, and quality of life. Thus, dyad interventions have been created to meet the demands of advanced cancer patients and their spouses. However, the application of dyadic care in clinical settings is currently rather limited in Taiwan. The present case study involved a patient with advanced colorectal cancer and malignant bowel obstruction whose disease-related demands had eroded the patient's physical, psychological, and spiritual health. The patient's condition placed overwhelming stress on the spouse, jeopardizing the relationship of the dyad. This article elaborates the implementation of the FOCUS program with the goal of helping the dyad achieve better disease adjustment through family involvement, optimistic attitude, effective coping, better symptom management, and uncertainty reduction. Through this delineated experience, the authors hope to help healthcare providers achieve a higher quality of care while caring for patient-family dyads with colorectal cancer. PMID- 28580565 TI - [Reducing the Care-Related Burdens of a Family Caregiver of a Person With Mild Cognitive Impairment: A Home-Based Case Management Program]. AB - The long-term care of cognitively impaired patients with concomitant behavioral problems brings great stress and burdens to family caregivers. The present article describes a family caregiver with multiple chronic diseases who concurrently shouldered primary care responsibilities for her husband, a patient with mild cognitive impairment, problematic behaviors, and medication non adherence issues. The period of care was between September 23rd and December 29th, 2015. Data on physiological, psychological, and social burdens were collected based on a stress process model for family caregiving. We then applied a home-based, individually tailored intervention, which included nursing education, skills training, listening/counseling, and resource connecting, that effectively helped the family caregiver reduce her burdens. Our assessment identified nursing-care-related problems as the primary source of caregiver burden in this case, with identified stressors including a lack of knowledge regarding patient care, medication management problems, sleep disorders, and inadequate social resources. Using continuous care interactions, we established a trust relationship with the family caregiver, prioritized her needs, and provided dementia care knowledge and skills, which gradually improved her caregiving competence. Our instruction included increasing caregiver understanding of the disease course of dementia, related problematic behaviors, and medication management. Our intervention enhanced the disease awareness of the caregiver and helped her become more positive about her caregiving tasks. Therefore, the negative impacts on her family were reduced. Social support and long-term care resources further reduced her burden and improved her quality of life. PMID- 28580567 TI - Cytohistological discrepancies of cervico-vaginal smears and HPV status. AB - OBJECTIVES: Discrepancies between abnormal cervical cytology or high-risk human papillomavirus (HR-HPV) status (cytolo-gy negative/HPV positive) and subsequent histological findings are a common occurrence. After using co-testing, the dis crepancies between the HR-HPV status and cervical cytology have become an issue. In this study, we aimed to determine the characteristics of women with a discrepancy between histology and cytology/HR-HPV status, in terms of diagnosis, review and identification. MATERIAL AND METHODS: A total of 52 women, patients of the University Hospital between 2013-2015, with cytohistologi-cal or HR-HPV status discrepancy were recruited for the study and retrospectively analyzed. The cytological samples were liquid-based Pap smears, classified according to the 2001 Bethesda system. The HR-HPV status was identified using the Hybrid Capture 2 HR-HPV DNA assay. The histological samples were obtained by cervical biopsy as well as large loop exci-sion of the transformation zone (LLETZ). RESULTS: A cytohistological discrepancy was demonstrated in patients with (-)cytology/HR HPV(+), ASCUS, LSIL, ASC-H, HSIL, AGC-NOS: 17.3%, 23.07%, 26.9%, 9.5%, 17.3% and 5.7%, respectively. When the degree of atypia in cytology increases, the concurrency of cervical cytology with biopsy also increases. A positive HR-HPV co test result (19/24, 79.1%) was observed in nearly all CIN2 >= (+) cases. Our study emphasizes the significance of HR-HPV testing to determine CIN2 >= (+) cases, even in the presence of a normal cytological result. CONCLUSIONS: In case of cytohistological or HR-HPV discrepancies, a careful review of the HR-HPV status and the degree of cytological atypia should be performed before further intervention. PMID- 28580568 TI - Causes and frequency of tocophobia - own experiences. AB - OBJECTIVES: The phenomenon of tocophobia (pathological fear of labor) has not been fully explored. Currently, there are no diagnostic criteria that would enable its detection or make it recognizable as a disease entity. The aim of study was to determine the degree of anxiety/tocophobia as well as to learn about and analyze the causes of this phenomenon in Polish pregnant women. MATERIAL AND METHODS: The prospective study included 120 pregnant women in the third trimester of gestation from February to May 2016. The study was performed with the use of a standardized and revised version of the Labor Anxi-ety Questionnaire (KLP II) designed by Putynski and Paciorek (1997) as well as a proprietary interview questionnaire and structured data documentation form. RESULTS: In 6.7% of the subjects, the level of labor anxiety was very high (> 18 in KLP II). It was the highest in women over 30 years of age (Pearson's chi squared test = 0.00422; p < 0.05). It has been shown that successive childbirths have an im-pact on the degree of anxiety (p = 0.04217).The highest level of anxiety was noted in primiparous women. In 85% of the subjects, anxiety was caused by fear of labor pain. 56.7% of the tested women did not use any professional help in the preparation for childbirth and motherhood. CONCLUSIONS: Primiparas and women over 30 years of age experience very high levels of fear significantly more frequently. The lack of proper preparation for childbirth determines the occurrence of tocophobia. Ante-natal classes and prenatal education based on standards of obstetric care should be promoted in order to reduce or eliminate fear of natural labor. PMID- 28580566 TI - Animal models for disc degeneration-an update. AB - Intervertebral disc degeneration is considered a major cause of back pain that places a heavy burden on society, both because of its effect on the physiology of individuals and its consequences on the world economy. During the past few decades, research findings in the pre-clinical setting have led to a significant increase in the understanding of intervertebral disc degeneration, although many aspects of the disease remain unclear. The goal of this review is to summarize existing animal models for disc degeneration studies and the difficulties that are associated with the use of such models. A firm understanding of the cellular and molecular events that ensue as a result of injuries, as well as environmental factors, could be instrumental in the development of targeted therapies for the treatment of intervertebral disc degeneration. PMID- 28580569 TI - Gestational diabetes mellitus/hyperglycaemia during pregnancy in Poland in the years 2010-2012 based on the data from the National Health Fund. AB - OBJECTIVES: The incidence of gestational diabetes varies depending on a country and it is extremely difficult to analyse. The aim of the study was to assess the incidence of gestational diabetes in Polish population. MATERIAL AND METHODS: Based on the data from the National Health Fund (NHF) the authors analysed reports regarding deliveries performed and then, determined the rates of gestational diabetes/hyperglycaemia during pregnancy and pregestational diabetes in Poland in the years 2010-2012. RESULTS AND CONCLUSIONS: In Poland, the incidence of gestational diabetes was estimated to be 4.665% in 2010, 6.918% in 2011 and 7.489% in 2012. The incidence of pregestational diabetes was 1.067% in 2010, 1.116% in 2011 and 0.932% in 2012. PMID- 28580570 TI - IL16 and IL18 gene polymorphisms in women with gestational diabetes. AB - OBJECTIVES: Gestational diabetes mellitus is a carbohydrate intolerance that occurs during pregnancy. Various inflammatory mediators are considered to be risk factors leading to GDM development. Among them are pro-inflammatory cytokines, such as IL16 and IL18. The aim of this study was to examine the association between IL16 and IL18 polymorphisms and GDM. MATERIAL AND METHODS: This study included 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance (NGT). All samples were genotyped in duplicate using allelic discrimination assays with TaqMan(r) probes. RESULTS: We observed that there was a decreased frequency of IL16 rs4778889 CC genotype carriers among women with GDM (CC vs. CT + TT: OR = 0.14; 95% CI = 0.02-1.15; p = 0.034). However, there was no significant difference in the distri-bution of alleles (C vs. T: OR = 0.81; 95% CI = 0.54-1.21; p = 0.30). There was a decreased frequency of the IL18 rs187238 G allele among GDM women (G vs. C: OR = 0.71; 95% CI = 0.53-0.96; p = 0.027). We also observed a decreased frequency of the IL18 rs1946518 T allele among women with GDM; however, this difference had only borderline statistical significance. We observed an association between IL18 rs187238, rs1946518 and BMI in pregnant women. CONCLUSIONS: The results of this study suggest that IL18 rs187238 and rs1946518 polymorphisms may be associated with an increased risk of GDM as well as with BMI in pregnant women. PMID- 28580571 TI - Ultrasound guided balloon catheterisation: a new method of fetal lower urinary tract obstruction management. AB - OBJECTIVES: Fetal lower urinary tract obstruction (LUTO), most often associated with presence of posterior urethral valves, poses high risk of perinatal mortality or postnatal renal failure. Looking for a method of causative treatment we have devel-oped a technique of fetal urethroplasty with a coronary angioplasty balloon catheter inserted under an ultrasonographic guidance via an 18-gauge needle introduced transabdominally to fetal bladder. MATERIAL AND METHODS: We have used this procedure in three women with singleton pregnancies (two primiparas and one multipara, 32-35 years of age), diagnosed with fetal megacystis at 12-16 weeks of gestation. Urethral catheterization was carried out at 16-18 weeks and an unobstructed urine flow was achieved in all three cases immediately after the procedure, followed by a resolution of megacystis and normalization of amniotic fluid volume. RESULTS: In all three cases, the post procedure period was uneventful. In the first two fetuses, amniotic fluid volume re-mained normal until 30 weeks of gestation when a gradual development of oligohydramnios and some signs of renal cystic dysplasia were observed. Nevertheless, both pregnancies were continued till term (37 and 39 weeks, respectively) and two boys without signs of pulmonary hypoplasia were delivered. The third patient is currently 25 weeks pregnant; volume of amniotic fluid in her fetus is normal and no signs of urinary flow obstruction or renal dysplasia have been recorded thus far. CONCLUSIONS: Although some technical aspects of the procedure still need to be established, it seems worth consideration as a form of potentially least traumatic intrauterine intervention in fetuses with lower urinary tract obstruction. PMID- 28580572 TI - The impact of low molecular weight heparin on obstetric outcomes among unexplained recurrent miscarriages complicated with methylenetetrahydrofolate reductase gene polymorphism. AB - OBJECTIVES: The association between methylenetetrahydrofolate reductase gene polymorphisms and unexplained recurrent miscarriage is elusive. The recommendations for improving pregnancy outcomes in these patients keep changing based on the available evidence. The aim of this study is to analyze the impact of low molecular weight heparin on obstetric outcomes of recurrent miscarriage patients complicated with methylenetetrahydrofolate reductase gene polymorphism. MATERIAL AND METHODS: We reviewed medical records of 121 patients with a history of recurrent miscarriage complicated by methylenetetrahydrofolate reductase gene polymorphisms, retrospectively. From among them, 68 patients were treated only with folic acid and iron. The remaining 53 patients were treated with folic acid, iron and prophylactic doses of low molecular weight heparin. The subsequent pregnancy outcomes of these patients were noted. RESULTS: The live birth rate was higher in patients with anticoagulant therapy than in patients without anticoagulant therapy (48.5% vs. 69.8%, respectively, p: 0.015) and the congenital anomaly rate was lower in anticoagulant therapy group (17.6% vs. 3.8%, respectively, p: 0.022). The other obstetric outcomes were found to be similar between the two groups. CONCLUSIONS: The current study demonstrated that low molecular weight heparin improved the live birth rates among unex-plained recurrent miscarriage patients complicated with methylenetetrahydrofolate reductase gene polymorphisms. How-ever, the routine use of low molecular weight heparin did not improve the late pregnancy complications in these selected patients in the eastern region of our country. Further studies are needed to discriminate the effect of anticoagulation on the live birth rate of each of methylenetetrahydrofolate reductase gene polymorphism type. PMID- 28580573 TI - Fetal neck tumors - antenatal and intrapartum management. AB - In this review article we describe the ante- and perinatal management of fetal neck tumors. Although there are rare congenital anomalies, the clinical consequences for the fetus may be fatal and include airways obstruction, heart insufficiency, pulmonary hypoplasia and cosmetic effect. The right management allows to decrease the fetal and neonatal mortality and morbidity associated with the disease. It includes intrauterine therapy in some cases, mostly in a goitrus hypothyroidism of the fetus, but firstly, an assessment of the fetal airways patency with a subsequent, eventual Ex-Utero Intrapartum Treatment (EXIT). PMID- 28580574 TI - Primary hyperparathyroidism in pregnancy - a review of literature. AB - Hyperparathyroidism during pregnancy is diagnosed in 0.5-1.4% women and poses a serious challenge. Symptoms of primary hyperparathyroidism (PHP), namely fatigue, lethargy and proximal muscle weakness, are unspecific and could be mistaken as complaints naturally present during pregnancy. Thus, diagnosis is usually delayed. Moreover, the complications of PHP are very common. They occur in 67% of mothers and even in up to 80% of progeny. Appropriate management is a matter of debate. According to clinical symptoms, biochemical evaluation and trimester of pregnancy an operation or conservative management should be introduced. The recognition and understanding of the illness is therefore vital. Due to the lack of unequivocal guidelines concerning pregnancy and PHP, in this review we will analyze recent findings to facilitate proper proceedings. PMID- 28580575 TI - Favourable pregnancy outcome in a woman with secondary pulmonary hypertension complicating mitral stenosis. AB - Pulmonary hypertension (PH) is a rare condition with a high incidence of maternal and perinatal mortality (30-56% and 10-13%, respectively). Pulmonary hypertension is a contraindication to pregnancy because of high risk of maternal death, therefore the World Health Organisation (WHO) advises to discuss a termination in the event of pregnancy with women suffering from PH. PMID- 28580576 TI - Managing epilepsy in women of childbearing age - Polish Society of Epileptology and Polish Gynecological Society Guidelines. PMID- 28580577 TI - Comparison of induction of labour regimes for termination of pregnancy, with and without mifepristone, from 20 to 41 weeks gestation. AB - AIM: To investigate the efficacy of mifepristone for induction of labour in pregnancies at 20-41 weeks' gestation, by comparing the outcomes of length of labour and duration of admission in women with and without mifepristone pretreatment. METHOD: In this retrospective cohort study, all women who underwent a medical termination of a singleton pregnancy between 20 and 41 weeks gestation for either a fetal abnormality or fetal death in utero between 1 January, 2009 and 1 January, 2014 were identified. Women who went into spontaneous labour, required a primary surgical delivery or had a multiple pregnancy were not included. RESULTS: The total number of women included in the study was 147: 63 in the mifepristone treatment and 84 in the no mifepristone treatment. In the group of women induced after mifepristone pre-treatment there was a 38% reduction in the median duration of labour, with 2.5 h in the group treated with mifepristone versus 4.0 h in women induced without (P = 0.001). We also found a 50% reduction in the number of days admitted to hospital with the length of admission being 1 day versus 2 days (P = 0.005). CONCLUSION: This study supports the hypothesis that in pregnancies greater than 20 weeks, the duration of labour and length of admission are reduced when induction of labour for termination of pregnancy is preceded by treatment with mifepristone. PMID- 28580578 TI - Cervical cancer in women under 25 years of age in Queensland, Australia: To what extent is the diagnosis made by screening cytology? AB - INTRODUCTION: The current Australian National Cervical Screening Program (NCSP) involves biennial, cytology-based screening of women from the age of 18 years. From December, 2017 this will change to a five-yearly human papilloma virus-based screening commencing at age 25. There is some concern that the new program may delay the opportunistic detection of cervical cancers in women under 25 years. AIM: (1) To review all cases of invasive cervical cancer in Queensland women under the age of 25 over the last 28 years. (2) To determine symptoms and screening history prior to diagnosis. METHODS: A retrospective cohort study was undertaken at the Queensland Centre for Gynaecological Cancer (QCGC) and the Queensland Cancer Registry (QCR) of all women aged between 13 and 25 years diagnosed with cervical cancer in Queensland between 1984 and 2012. Demographic data and symptoms prior to diagnosis were extracted from the QCGC and QCR databases. RESULTS: A total of 56 women aged 13-25, were diagnosed with cervical cancer and treated at the QCGC between 1984 and 2012. The commonest reason for the diagnosis of cancer was investigation of abnormal symptoms (n = 22, 39%) rather than routine Pap smear abnormalities (n = 15, 26%). CONCLUSIONS: Consistent with the world literature, there is a very low incidence of cervical cancer in women under 25 years of age, irrespective of the age of commencement of screening, or the screening interval. Our study lends some support to the proposed commencement age of 25 years in the new NCSP. PMID- 28580579 TI - Secukinumab sustains good efficacy and favourable safety in moderate-to-severe psoriasis after up to 3 years of treatment: results from a double-blind extension study. AB - BACKGROUND: Secukinumab has demonstrated significant efficacy with a good safety profile through 1 year in plaque psoriasis. Given the chronic nature of this disease, long-term follow-up is needed to evaluate psoriasis therapies fully. OBJECTIVES: To determine the long-term (3-year) efficacy and safety of secukinumab in moderate-to-severe psoriasis. METHODS: Patients completing 52 weeks of secukinumab treatment in the SCULPTURE core study entered an extension in which they continued the same double-blind regimens. Dosing regimens included a fixed-interval schedule (FI; every 4 weeks) and retreatment as needed (RAN), in which patients were withdrawn from secukinumab and received placebo until the start of relapse, at which time secukinumab every 4 weeks was reinitiated. The study was registered with number NCT01640951. RESULTS: In total 168 patients receiving secukinumab 300 mg FI and 172 receiving secukinumab 300 mg RAN entered the extension. Secukinumab 300 mg FI sustained high efficacy: at the end of year 3, the proportion of responders achieving >= 90% improvement in Psoriasis Area and Severity Index (PASI 90) was 63.8%, and of PASI 100 responders it was 42.6%. The mean absolute PASI remained low (2-4) from week 52 to week 152 with 300 mg FI, with approximately two-thirds of patients reporting no impact of skin disease on their lives (Dermatology Life Quality Index of 0 or 1). Improvements in overall and subscale scores on all quality-of-life instruments were well sustained. As in the core study, FI dosing was consistently more efficacious than RAN. No new safety signals were identified to year 3. CONCLUSIONS: Secukinumab 300 mg FI sustained high responses and improved quality of life with no new safety concerns through 3 years. PMID- 28580580 TI - Illicit Drug Delivery Via Administration of Human Blood. AB - The physiological, psychological, and social consequences associated with illicit drug use are well documented. In addition to the effects directly related to the drug(s), the delivery mechanism can precipitate other serious health conditions. A case is reported where an individual stopped by law enforcement was discovered to be in possession of a vial containing a red-colored fluid, which the person stated was blood and contained fentanyl. Analysis by headspace GC, ELISA, and LC TOF/MS screening in with mass spectral confirmation revealed the presence of several substances, including ethanol, methamphetamine, amphetamine, MDA, 6 monoacetylmorphine, codeine, morphine, alprazolam, delta-9 THC, ephedrine, pseudoephedrine, and norpseudoephedrine; serology testing verified the fluid was consistent with human blood. Methamphetamine was present at a dosage form amount (11 mg). The purpose of this study was to detail the analytical findings, interpret their meaning, and discuss the public health concerns associated with the drug delivery by the administration of human blood. PMID- 28580581 TI - Comparison of partial least squares and random forests for evaluating relationship between phenolics and bioactivities of Neptunia oleracea. AB - BACKGROUND: Neptunia oleracea is a plant consumed as a vegetable and which has been used as a folk remedy for several diseases. Herein, two regression models (partial least squares, PLS; and random forest, RF) in a metabolomics approach were compared and applied to the evaluation of the relationship between phenolics and bioactivities of N. oleracea. In addition, the effects of different extraction conditions on the phenolic constituents were assessed by pattern recognition analysis. RESULTS: Comparison of the PLS and RF showed that RF exhibited poorer generalization and hence poorer predictive performance. Both the regression coefficient of PLS and the variable importance of RF revealed that quercetin and kaempferol derivatives, caffeic acid and vitexin-2-O-rhamnoside were significant towards the tested bioactivities. Furthermore, principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) results showed that sonication and absolute ethanol are the preferable extraction method and ethanol ratio, respectively, to produce N. oleracea extracts with high phenolic levels and therefore high DPPH scavenging and alpha-glucosidase inhibitory activities. CONCLUSION: Both PLS and RF are useful regression models in metabolomics studies. This work provides insight into the performance of different multivariate data analysis tools and the effects of different extraction conditions on the extraction of desired phenolics from plants. (c) 2017 Society of Chemical Industry. PMID- 28580582 TI - Modulating inflammation and neuroprotection in multiple sclerosis. AB - Multiple sclerosis (MS) is a neurological disorder of the central nervous system with a presentation and disease course that is largely unpredictable. MS can cause loss of balance, impaired vision or speech, weakness and paralysis, fatigue, depression, and cognitive impairment. Immunomodulation is a major target given the appearance of focal demyelinating lesions in myelin-rich white matter, yet progression and an increasing appreciation for gray matter involvement, even during the earliest phases of the disease, highlights the need to afford neuroprotection and limit neurodegenerative processes that correlate with disability. This review summarizes key aspects of MS pathophysiology and histopathology with a focus on neuroimmune interactions in MS, which may facilitate neurodegeneration through both direct and indirect mechanisms. There is a focus on processes thought to influence disease progression and the role of oxidative stress and mitochondrial dysfunction in MS. The goals and efficacy of current disease-modifying therapies and those in the pipeline are discussed, highlighting recent advances in our understanding of pathways mediating disease progression to identify and translate both immunomodulatory and neuroprotective therapeutics from the bench to the clinic. PMID- 28580584 TI - Nitrato-Functionalized Task-Specific Ionic Liquids as Attractive Hypergolic Rocket Fuels. AB - Hypergolic ionic liquids (HILs) as potential replacements for hydrazine derivatives have attracted increasing interest over the last decade. Previous studies on HILs have mostly concentrated on the anionic innovations of ionic liquids to shorten the ignition delay (ID) time, but little attention has been paid to cationic modifications and their structure-property relationships. In this work, we present a new strategy of cationic functionalization by introducing the energetic nitrato group into the cationic units of HILs. Interestingly, the introduction of oxygen-rich nitrato groups into the cationic structure significantly improved the combustion performance of HILs with larger flame diameters and duration times. The density-specific impulse (rhoIsp ) of these novel HILs are all above 279.0 s g cm-3 , much higher than that of UDMH (215.7 s g cm-3 ). In addition, the densities of these HILs are in the range of 1.22-1.39 g cm-3 , which is much higher than that of UDMH (0.79 g cm-3 ), showing their higher loading capacity than hydrazine-derived fuels in a propellant tank. This promising strategy of introducing nitrato groups into the cationic structures has provided a new platform for developing high-performing HILs with improved combustion properties. PMID- 28580585 TI - Effect of sequential comparison on active processing of sound duration. AB - Previous studies on active duration processing on sounds showed opposing results regarding the predominant involvement of the left or right hemisphere. Duration of an acoustic event is normally judged relative to other sounds. This requires sequential comparison as auditory events unfold over time. We hypothesized that increasing the demand on sequential comparison in a task increases the involvement of the left auditory cortex. With the current fMRI study, we investigated the effect of sequential comparison in active duration discrimination by comparing a categorical with a comparative task. During the categorical task, the participant had to categorize the tones according to their duration (short vs long). During the comparative task, they had to decide for each tone whether its length matched the tone presented before. We used the contralateral noise procedure to reveal the degree of participation of the left and right auditory cortex during these tasks. We found that both tasks more strongly involve the left than the right auditory cortex. Furthermore, the left auditory cortex was more strongly involved during comparison than during categorization. Together with previous studies, this suggests that additional demand for sequential comparison during processing of different basic acoustic parameters leads to an increased recruitment of the left auditory cortex. In addition, the comparison task more strongly involved several brain areas outside the auditory cortex, which may also be related to the demand for additional cognitive resources as compared to the more efficient categorization of sounds. Hum Brain Mapp 38:4459-4469, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28580586 TI - The Plight of Veterans. PMID- 28580583 TI - Simultaneous multislice imaging for native myocardial T1 mapping: Improved spatial coverage in a single breath-hold. AB - PURPOSE: To develop a saturation recovery myocardial T1 mapping method for the simultaneous multislice acquisition of three slices. METHODS: Saturation pulse prepared heart rate independent inversion recovery (SAPPHIRE) T1 mapping was implemented with simultaneous multislice imaging using FLASH readouts for faster coverage of the myocardium. Controlled aliasing in parallel imaging (CAIPI) was used to achieve minimal noise amplification in three slices. Multiband reconstruction was performed using three linear reconstruction methods: Slice- and in-plane GRAPPA, CG-SENSE, and Tikhonov-regularized CG-SENSE. Accuracy, spatial variability, and interslice leakage were compared with single-band T1 mapping in a phantom and in six healthy subjects. RESULTS: Multiband phantom T1 times showed good agreement with single-band T1 mapping for all three reconstruction methods (normalized root mean square error <1.0%). The increase in spatial variability compared with single-band imaging was lowest for GRAPPA (1.29 fold), with higher penalties for Tikhonov-regularized CG-SENSE (1.47-fold) and CG SENSE (1.52-fold). In vivo multiband T1 times showed no significant difference compared with single-band (T1 time +/- intersegmental variability: single-band, 1580 +/- 119 ms; GRAPPA, 1572 +/- 145 ms; CG-SENSE, 1579 +/- 159 ms; Tikhonov, 1586 +/- 150 ms [analysis of variance; P = 0.86]). Interslice leakage was smallest for GRAPPA (5.4%) and higher for CG-SENSE (6.2%) and Tikhonov regularized CG-SENSE (7.9%). CONCLUSION: Multiband accelerated myocardial T1 mapping demonstrated the potential for single-breath-hold T1 quantification in 16 American Heart Association segments over three slices. A 1.2- to 1.4-fold higher in vivo spatial variability was observed, where GRAPPA-based reconstruction showed the highest homogeneity and the least interslice leakage. Magn Reson Med 78:462-471, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28580588 TI - Response to "Relationships between Acute and Postacute Care Providers: Measurement and Estimation". PMID- 28580587 TI - Heme oxygenase-1 directly binds STAT3 to control the generation of pathogenic Th17 cells during neutrophilic airway inflammation. AB - BACKGROUND: Specific JAK/STAT pathways play a critical role in the functional differentiation of distinct Th subsets. Previously, we showed that HO-1, a stress inducible protein, inhibits Th17 cell differentiation and alleviates neutrophilic airway inflammation, but the responsible molecular basis remains unclear. METHODS: We employed Th17-skewing differentiation and NEA mouse models to study the role of HO-1 in regulating IL-6-STAT3-RORgammat/SOCS3 signaling pathway to control Th17 cell-mediated neutrophilic airway inflammation. The levels of cytokines and expressions of relative signaling molecules were measured by ELISA, western blot, and qPCR, respectively. Frequency of CD4+ IL-17A+ , CD4+ IL-6R+ , and CD4+ IL-23R+ cells was analyzed by FCM. The interaction between HO-1 and signaling pathway-related proteins was determined by co-immunoprecipitation and western blot. RESULTS: Here, we show that hemin-induced HO-1 overexpression is required to mediate this process. Specifically, HO-1 decreased STAT3 phosphorylation but not IL-6R/IL-23R expression or JAK1/JAK2 activation in CD4+ T cells. The effect was accompanied by co-inhibition of SOCS3, a negative feedback factor of STAT3 activation. HO-1 bound to three domains on STAT3 (DNA-binding, linker, and transactivation domains) to directly regulate STAT3 activation. Conversely, either forced expression of a constitutively active STAT3 mutant or application of small-interfering RNA (siRNA) for HO-1 reversed these effects. CONCLUSIONS: Our data suggest that HO-1 exerts its inhibitory effect on Th17 cell differentiation by directly associating and blocking STAT3 phosphorylation. We speculate that hemin may be a potential therapeutic candidate for the treatment of other types of immune and pulmonary inflammatory-related diseases. PMID- 28580589 TI - Pancake Bond Orders of a Series of pi-Stacked Triangulene Radicals. AB - Conjugated radicals are capable of forming pi-stacking "pancake-bonded" dimers. Members of the family of triangulene hydrocarbons, non-Kekule neutral multiradicals, can utilize more than one singly occupied molecular orbital (SOMO) to form multiple pancake-bonded dimers with formal bond orders of up to five. The resulting dimer binding energies can be quite high and the intermolecular contacts rather small compared to the respective van der Waals values. The preferred configurations are driven by the large stabilization energy of overlapping SOMOs. PMID- 28580590 TI - Severe postwar malnutrition did not have a negative impact on the earnings and subsequent pensions of German men born in 1945-1948. AB - AIM: Poverty has often been associated with malnutrition, stunted growth, impaired cognitive development and poor earnings. We studied whether these associations were found in German men born and raised shortly after World War II during severe and long-standing nationwide malnutrition. METHODS: We analysed German old-age pension payments, as a rough measure of lifetime earnings, in German men born from 1932 to 1960 and compared the at-risk-of-poverty rates of German men born in 1945-1948 versus 1935-1938 and 1955-1958. RESULTS: Substantially fewer women worked during this period and their longer life expectancy makes their pension payments difficult to interpret. We therefore limited our analysis to men. Men born in the 1930s received the highest monthly old-age pensions and these declined slightly in men born from 1945 to 1948, indicating a minute impairment in work-related income in cohorts born shortly after the war. We also found that there was no evidence for increased at-risk-of poverty rates in men born in 1945-1948 versus those born in 1935-1938 and in 1955 1958. CONCLUSION: Being born and raised following World War II was associated with a minute work and pension impairment that was not visible in the at-risk-of poverty rates. These findings question statements associating early childhood nutrition and future lifetime earnings. PMID- 28580591 TI - The human guanylate-binding proteins hGBP-1 and hGBP-5 cycle between monomers and dimers only. AB - Belonging to the dynamin superfamily of large GTPases, human guanylate-binding proteins (hGBPs) comprise a family of seven isoforms (hGBP-1 to hGBP-7) that are strongly upregulated in response to interferon-gamma and other cytokines. Accordingly, several hGBPs are found to exhibit various cellular functions encompassing inhibitory effects on cell proliferation, tumor suppression as well as antiviral and antibacterial activity; however, their mechanism of action is only poorly understood. Often, cellular functions of dynamin-related proteins are closely linked to their ability to form nucleotide-dependent oligomers, a feature that also applies to hGBP-1 and hGBP-5. hGBPs are described as monomers, dimers, tetramers, and higher oligomeric species, the function of which is not clearly established. Therefore, this work focused on the oligomerization capability of hGBP-1 and hGBP-5, which are reported to assemble to homodimers and homotetramers. Employing independent methods such as size-exclusion chromatography, which relies on the hydrodynamic radius, and multiangle light scattering, which relies on the mass of the protein, revealed that previous interpretations regarding the size of the proteins and their complexes have to be revised. Additional studies using inter- and intramolecular Forster resonance energy transfer demonstrated that nucleotide-triggered intramolecular structural changes lead to a more extended shape of hGBP-1 being responsible for the appearance of larger oligomeric species. Thus, previously reported tetrameric and dimeric species of hGBP-1 and hGBP-5 were unmasked as dimers and monomers, respectively, with their shapes depending on both the bound nucleotide and the ionic strength of the solution. PMID- 28580593 TI - Refining the Pediatric Evaluation of Disability Inventory-Patient-Reported Outcome (PEDI-PRO) item candidates: interpretation of a self-reported outcome measure of functional performance by young people with neurodevelopmental disabilities. AB - AIM: This study examined the item interpretability and rating scale use of the Pediatric Evaluation of Disability Inventory-Patient-Reported Outcome (PEDI-PRO) by young people with developmental disabilities. The PEDI-PRO assesses the functional performance of discrete functional tasks in the context of everyday life situations. METHOD: A two-phase cognitive interview design was implemented with a convenience sample of 37 young people (mean age 19y, SD 2y 5mo; 13 males and 24 females; 68% with intellectual disability) with developmental disabilities. In phase I, 182 item candidates were each reviewed by an average of four young people. In phase II, 103 items were carried forward or revised and each reviewed by an average of seven additional young people. Two raters coded responses for intended item interpretation and performance quality; codes were analysed using descriptive statistics. Qualitative analysis explored young people's self-evaluation process. RESULTS: Items were interpreted as intended by most young people (mean 86%). Young people can use PEDI-PRO response categories appropriately to describe their performance: 94% of positive performance descriptions coincided with a positive response category choice; 73% of negative descriptions coincided with a negative response category choice. Young people interpreted items in a literal manner, and their self-evaluation incorporated the use of supports that facilitate functional performance. INTERPRETATION: The PEDI PRO's measurement framework appears to support the self-evaluation of functional performance of young people with developmental disabilities. PMID- 28580592 TI - Shape-Controlled Hollow Mesoporous Silica Nanoparticles with Multifunctional Capping for In Vitro Cancer Treatment. AB - A series of multifunctional shape-controlled nonspherical hollow mesoporous silica nanoparticles (HMSNs) drug carriers have been prepared by employing Fe2 O3 with four morphologies (capsule, cube, rice, and rhombus) as a sacrificial template and a multifunctional cap as the encapsulating shell. The resulting shape-controlled nonspherical HMSNs perfectly replicate the original morphology of the Fe2 O3 templates, which possess a high specific surface area, good monodispersity, perpendicular mesoporous channels, and excellent biocompatibility. After modification of polyethylene glycol (PEG) and folic acid (FA), the shape-controlled HMSN core and functional shell can then be integrated into a single device (HMSNs-PEG-FA) to provide an efficient and tumor-cell selective drug-delivery system. The shape-controlled HMSNs and HMSNs-PEG-FA all show controlled pH-responsive release behavior for the anticancer drug doxorubicin hydrochloride (DOX). The in vitro results indicate that HMSNs-PEG-FA is biocompatible and selectively targets HeLa cells (overexpressed folate receptors). Fluorescence images show that desirable surface modification and the nonspherical shape effectively facilitate cellular internalization of HMSNs. It is expected that the construction of these unique nanomaterials with controlled morphology through the hard-templating technique may also provide useful information for the design of nanoscale multifunctional systems. PMID- 28580594 TI - Multiple single nucleotide polymorphism analysis and association of specific genotypes in FHIT, SAMD4A, and ANKRD17 in Indian patients with oral cancer. AB - BACKGROUND: Oral cancer has a high incidence primarily because of tobacco chewing habits. However, a small proportion of habitues develop oral cancer, implying a role for genomic variants in its susceptibility. METHODS: Thirteen single nucleotide polymorphisms (SNPs) in an Indian cohort comprising patients with oral cancer (n = 500) and healthy controls (n = 500) were genotyped using allelic discrimination real-time polymerase chain reaction (PCR). RESULTS: Prevalence of SNPs rs11130760, rs1957358, rs2306058, rs4883543, rs12637722, rs1457115, rs2353292, rs709821, rs2194861, rs4789378, rs3827538, rs2667552, and rs2886093 was determined in the Indian cohort. A significant association of rs11130760 GG (odds ratio [OR] 1.41; 95% confidence interval [CI] 1.08-1.84) and rs1957358 TT (OR 1.44; 95% CI 1.10-1.90) indicated increased risk; whereas rs1957358 TC (OR 0.67; 95% CI 0.53-0.87) and rs2306058 CT (OR 0.72; 95% CI 0.56-0.93) reflected decreased risk. The SNP rs11130760 wild-type (WT) allele G indicated an increased risk for oral cancer (OR 1.38; 95% CI 1.09-1.73), whereas SNP allele T indicated a decreased risk (OR 0.73; 95% CI 0.58-0.92) for oral cancer. CONCLUSION: Our study identified SNPs with susceptibility to oral cancer in high-risk populations. PMID- 28580595 TI - Mutation screening of 10 cancer susceptibility genes in unselected breast cancer patients. AB - Variants of cancer susceptibility genes other than BRCA1/2 have been proved to be associated with increased risks of breast cancer. This study was performed to investigate the spectrum and prevalence of mutations in 10 cancer susceptibility genes in paired tumor/normal tissues of 292 unselected Chinese breast cancer patients. We performed an analysis of germline and somatic variants in ATM, CDH1, CHEK2, ESR1, GATA3, MAP3K1, MSH2, PALB2, RB1 and STK11 genes by integrating microfluidic PCR-based target enrichment and next-generation sequencing technologies. In total, 3 germline and 25 somatic deleterious mutations were found among 27 patients (9.25%), and 17 of them were novel mutations. Most deleterious mutations were prevalent in luminal A invasive breast cancer (P = .014). We also observed 83 variants of uncertain significance (VUS) in 100 patients (34.25%), 23 of which were predicted to be deleterious by in silico prediction programs (MetaSVM and MetaLR). VUS carriers had higher positive rate of lymph node metastasis than non-carriers (P = .008) and were predominantly present in ER+ tumors (P = .018). Our findings would enhance the understanding of the molecular mechanisms of breast cancer in Chinese population. PMID- 28580596 TI - Cervical cancer screening in a low-resource setting: a pilot study on an HPV based screen-and-treat approach. AB - Cervical cancer (CC) is the leading cause of cancer-related death among women in sub-Saharan Africa, primarily because of limited access to effective screening and preventive treatment. Our aim was to assess the feasibility of a human papillomavirus (HPV)-based CC screen-and-treat approach in a low-resource context. We recruited 1012 women aged 30-49 years through a CC screening campaign conducted in the District Hospital of Dschang, Cameroon. Participants performed HPV self-sampling, which was tested for high-risk HPV (HR-HPV) DNA using the point-of-care Xpert HPV assay. All HPV-positive women were invited for visual inspection with acetic acid and Lugol's iodine (VIA/VILI) to exclude CC or enable triage. A cervical sample for histological analysis was also collected. Women positive for HPV 16/18/45 and for other HR-HPV with pathological VIA/VILI were selected to undergo treatment with thermocoagulation. The HPV prevalence in the study population was 18.5% (n = 187); of these cases, 20 (10.6%), 42 (22.3%) and 140 (74.9%) were positive for HPV16, HPV18/45 and other HR-HPV types, respectively. Overall, 107/185 (57.8%) VIA/VILI examinations were classified as pathological and 78 (42.2%) as normal. Women positive for HPV16/18/45 were 4.2 times more likely to harbor cervical intraepithelial neoplasia grade 2 or worse (CIN2+) than those with other HPV types. The specificity of HPV 16/18/45 genotypes for detection of high-grade lesions among HR-HPV positive women was higher than that of VIA/VILI in all age groups. The sensitivity and specificity of VIA/VILI in detecting CIN2+ among HPV positive women were 80% and 44%, respectively. Overall, 110/121 screen-positive women (90.9%) were eligible for, and were treated with, thermocoagulation. An HPV-based screen-and-treat approach is feasible in a low-resource context and may contribute to improving the effectiveness of CC prevention programs. Immediate thermocoagulation treatment for women who are HPV16- and/or HPV18/45-positive is a practical approach for the treatment of CIN2+. The combination of HPV-testing and VIA/VILI for CC screening might reduce overtreatment. PMID- 28580598 TI - Transforming Social Regularities in a Multicomponent Community-Based Intervention: A Case Study of Professionals' Adaptability to Better Support Parents to Meet Their Children's Needs. AB - This paper presents an in-depth case study of the dynamic processes of mutual adjustment that occurred between two professional teams participating in a multicomponent community-based intervention (CBI). Drawing on the concept of social regularities, we focus on patterns of social interaction within and across the two microsystems involved in delivering the intervention. Two research strategies, narrative analysis and structural network analysis, were used to reveal the social regularities linking the two microsystems. Results document strategies and actions undertaken by the professionals responsible for the intervention to modify intersetting social regularities to deal with a problem situation that arose during the course of one intervention cycle. The results illustrate how key social regularities were modified in order to resolve the problem situation and allow the intervention to continue to function smoothly. We propose that these changes represent a transition to a new state of the ecological intervention system. This transformation appeared to be the result of certain key intervening mechanisms: changing key role relationships, boundary spanning, and synergy. The transformation also appeared to be linked to positive setting-level and individual-level outcomes: confidence of key team members, joint planning, decision-making and intervention activities, and the achievement of desired intervention objectives. PMID- 28580597 TI - False fMRI activation after motion correction. AB - Motion correction of echo-planar imaging (EPI) data used in functional MRI (fMRI) is an essential preprocessing step performed prior to statistical analysis. At ultra-high resolution fMRI, current requirements regarding translational and rotational motion may no longer be acceptable. This prompts the need for a systematic investigation of the effects of motion correction procedures with in vivo fMRI data. Here we systematically evaluated the effect of retrospective motion correction with freely available fMRI analysis software packages (FSL, AFNI, and SPM) on activation maps using fMRI data acquired with prospective motion detection, to identify and quantify confounding effects of retrospective motion correction, and to evaluate its dependence on spatial resolution and motion correction algorithms. Brain activation maps were obtained for two different resolutions, an ultrahigh, that is, 0.653 mm3 , and a more widely used 2.03 mm3 isotropic resolutions at 7 T. The EPI data were acquired using simultaneous non-image-based optical moire phase tracking (MPT) of physical motion. The results showed that image-based motion detection, performed by SPM8 software package, may be erroneous in high-field fMRI data with partial brain coverage and can introduce spurious motion leading to false-positive and false negative activation. Further analyses demonstrated that limited acquisition field of view has the dominant influence on the effect. Hum Brain Mapp 38:4497-4510, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28580599 TI - The two faces of avoidance: Time-frequency correlates of motivational disposition in blood phobia. AB - Contrary to other phobias, individuals with blood phobia do not show a clear-cut withdrawal disposition from the feared stimulus. The study of response inhibition provides insights into reduced action disposition in blood phobia. Twenty individuals with and 20 without blood phobia completed an emotional go/no-go task including phobia-related pictures, as well as phobia-unrelated unpleasant, neutral, and pleasant stimuli. Behavioral results did not indicate a phobia specific reduced action disposition in the phobic group. Time-frequency decomposition of event-related EEG data showed a reduction of right prefrontal activity, as indexed by an increase in alpha power (200 ms), for no-go mutilation trials in the phobic group but not in controls. Moreover, theta power (300 ms) increased specifically for phobia-related pictures in individuals with, but not without, blood phobia, irrespective of go or no-go trial types. Passive avoidance of phobia-related stimuli subtended by the increased alpha in the right prefrontal cortex, associated with increased emotional salience indexed by theta synchronization, represents a possible neurophysiological correlate of the conflicting motivational response in blood phobia. Through the novel use of time frequency decomposition in an emotional go/no-go task, the present study contributed to clarifying the neurophysiological correlates of the overlapping motivational tendencies in blood phobia. PMID- 28580600 TI - Secretory diarrhea and hypokalemia associated with colonic pseudo-obstruction: A case study and systematic analysis of the literature. AB - BACKGROUND: Colonic pseudo-obstruction (CPO) is characterized by colonic distention in the absence of mechanical obstruction or toxic megacolon. Concomitant secretory diarrhea (SD) with hypokalemia (SD-CPO) due to gastrointestinal (GI) loss requires further characterization. AIM: To perform a systematic review of SD-CPO, report a case study, and compare SD-CPO with classical CPO (C-CPO). METHODS: We performed a search of MEDLINE, EMBASE, Cochrane, and Scopus for reports based on a priori criteria for CPO, SD and GI loss of potassium. An additional case at Mayo Clinic was included. RESULTS: Nine publications met inclusion criteria, with a total of 14 cases. Six studies had high, three moderate, and our case high methodological quality. Median age was 74 years (66-97), with 2:1 male/female ratio. Kidney disease was present in 6/14 patients. Diarrhea was described as profuse, watery, or viscous in 10 patients. Median serum, stool, and urine potassium concentrations (mmol/L) were 2.4 (range: 1.9-3.1), 137 (100-180), and 17 (8-40), respectively. Maximal diameter of colon and cecum (median) were 10.2 cm and 10.5 cm, respectively. Conservative therapy alone was effective in five out of 14 patients. Median potassium supplementation was 124 mEq/d (40-300). Colonic decompression was effective in three out of six patients; one had a total colectomy; three out of 14 had died. The main differences between SD-CPO and C-CPO were lower responses to treatments: conservative measures (35.7% vs 73.6%, P=.01), neostigmine (17% vs 89.2%, P<.001), and colonic decompression (50% vs 82.4%, P=.02). CONCLUSION: SD-CPO is a rare phenotype associated with increased fecal potassium and is more difficult to treat than C-CPO. PMID- 28580601 TI - Morphological and chemical variation of Stemona tuberosa from southern China - Evidence for heterogeneity of this medicinal plant species. AB - The occurrence of bioactive alkaloids and tocopherols was studied in 15 different provenances of Stemona tuberosa Lour. collected in southern China, to examine chemical variation of individuals that show notable differences in flower characteristics. Morphological variations stimulated examination of chemical characteristics of these individuals. Methanolic root extracts of 15 individuals of S. tuberosa were comparatively assessed with HPLC-UV-DAD/ELSD. Five of seven compounds were co-chromatographically identified. Two compounds were isolated and their structure elucidated using NMR and MS. Amounts of alkaloids and tocopherols were determined using HPLC-UV-DAD/ELSD with the external standard method. Five alkaloids, tuberostemonine (1), tuberostemonine A (2), neotuberostemonine (3), tuberostemonine N (4), stemoninine (5) and two 3,4-dehydrotocopherol derivatives were identified. Within S. tuberosa alkaloid accumulation tends either towards tuberostemonine (1) or stemoninine (5). All individuals show a notable co occurrence of compounds 1 or 5 and 3,4-dehydro-delta-tocopherol (6). These results coincide with differences in flower morphology of S. tuberosa. Stemona tuberosa, as defined in the Flora of China, shows a remarkable variation in flower morphology and additionally in the accumulation of alkaloids. The obtained data show the need for future species delimitation to either species or subspecies level. PMID- 28580602 TI - Randomised study showed that recorded maternal voices reduced pain in preterm infants undergoing heel lance procedures in a neonatal intensive care unit. AB - AIM: Alleviating pain in neonates should be the goal of all caregivers. We evaluated whether recorded maternal voices were safe and effective in limiting pain in preterm infants undergoing heel lance procedures in the neonatal intensive care unit of an Italian children's hospital. METHODS: This prospective, controlled study took place from December 2013 to December 2015. We enrolled 40 preterm infants, born at a 26-34 weeks of gestation, at a corrected gestational age 29-36 weeks and randomised them to listen or not listen to a recording of their mother's voice during a painful, routine heel lance for blood collection. Changes in the infants' Premature Infant Pain Profile, heart rate, oxygen saturation and blood pressure during the procedure were compared by analysis of variance. Possible side effects, of apnoea, bradycardia, seizures and vomiting, were also recorded. RESULTS: Both groups showed a marked increase in PIPP scores and decrease in oxygen saturation during the procedure, but infants in the treatment group had significantly lower PIPP scores (p = 0.00002) and lower decreases in oxygen saturation (p = 0.0283). No significant side effects were observed. CONCLUSION: Using recorded maternal voices to limit pain in preterm infants undergoing heel lance procedures appeared safe and effective. PMID- 28580603 TI - Enhancement of high glucose-induced PINK1 expression by melatonin stimulates neuronal cell survival: Involvement of MT2 /Akt/NF-kappaB pathway. AB - Hyperglycemia is a representative hallmark and risk factor for diabetes mellitus (DM) and is closely linked to DM-associated neuronal cell death. Previous investigators reported on a genome-wide association study and showed relationships between DM and melatonin receptor (MT), highlighting the role of MT signaling by assessing melatonin in DM. However, the role of MT signaling in DM pathogenesis is unclear. Therefore, we investigated the role of mitophagy regulators in high glucose-induced neuronal cell death and the effect of melatonin against high glucose-induced mitophagy regulators in neuronal cells. In our results, high glucose significantly increased PTEN-induced putative kinase 1 (PINK1) and LC-3B expressions; as well it decreased cytochrome c oxidase subunit 4 expression and MitotrackerTM fluorescence intensity. Silencing of PINK1 induced mitochondrial reactive oxygen species (ROS) accumulation and mitochondrial membrane potential impairment, increased expressions of cleaved caspases, and increased the number of annexin V-positive cells. In addition, high glucose stimulated melatonin receptor 1B (MTNR1B) mRNA and PINK1 expressions were reversed by ROS scavenger N-acetyl cysteine pretreatment. Upregulation of PINK1 expression in neuronal cells is suppressed by pretreatment with MT2 receptor specific inhibitor 4-P-PDOT. We further showed melatonin stimulated Akt phosphorylation, which was followed by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) phosphorylation and nuclear translocation. Silencing of PINK1 expression abolished melatonin-regulated mitochondrial ROS production, cleaved caspase-3 and caspase-9 expressions, and the number of annexin V-positive cells. In conclusion, we have demonstrated the melatonin stimulates PINK1 expression via an MT2 /Akt/NF-kappaB pathway, and such stimulation is important for the prevention of neuronal cell apoptosis under high glucose conditions. PMID- 28580604 TI - Challenges in educating patients and parents about differences in sex development. AB - This article reviews practical approaches to talking with parents and youth about Differences in Sex Development (DSD) which are conditions that affect chromosomal, gonadal, or anatomic sexual development, one of the most personal, and in our society, private areas of life. Talking with parents and patients about these conditions can be challenging given the complexity of sexual development and the sensitive nature of the information being shared. Changing approaches to disclosing or communicating information about conditions, such as DSD are reviewed as well as factors leading to revision in the diagnostic nomenclature. Building on these developments, strategies used by an established DSD team to enhance shared decision making and partnership with families and patients are presented followed by examples of how some particularly challenging, but not uncommon clinical situations were approached. The paper concludes by endorsing the importance of understanding the social and cultural needs and beliefs of the parents and patients with DSD to set the stage for effective disclosure of medical facts. To be most useful to parents and youth, medical disclosure needs to include discussion of practical implications and strategies to help families and patients digest, understand, and work with the information provided. PMID- 28580605 TI - Morphologic and topographic radiologic features of human papillomavirus-related and -unrelated oropharyngeal carcinoma. AB - BACKGROUND: The purpose of this study was to compare the clinicoradiologic characteristics of human papillomavirus (HPV)-related (HPV-positive) and HPV unrelated (HPV-negative) oropharyngeal carcinoma (OPC). METHODS: Primary tumor and lymph node features of HPV-positive and HPV-negative OPCs from 2008 to 2013 were compared on pretreatment CT/MRI. Intrarater/interrater concordance was assessed. Multivariable analyses identified factors associated with HPV positivity to be used in nomogram construction. RESULTS: Compared to HPV-negative (n = 194), HPV-positive (n = 488) tumors were more exophytic (73% vs 63%; p = .02) with well-defined border (58% vs 47%; p = .033) and smaller axial dimensions; lymph node involvement predominated (89% vs 69%; p < .001) with cystic appearance (45% vs 32%; p = .009) but similar topography. Intrarater/interrater concordance varied (fair to excellent). Nomograms combining clinical (age, sex, smoking pack-years, subsite, T/N classification) and/or radiologic (nonnecrotic tumor and cystic lymph node) features were used to weigh the likelihood of HPV-driven tumors (area under the curve [AUC] = 0.84). CONCLUSION: HPV-positive OPC has different radiologic tumor (exophytic/well defined border/smaller axial dimension) and lymph node (cystic) features but similar lymph node topography. PMID- 28580607 TI - Chromatin accessibility and guide sequence secondary structure affect CRISPR-Cas9 gene editing efficiency. AB - Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (CRISPR-Cas9) systems have emerged as the method of choice for genome editing, but large variations in on-target efficiencies continue to limit their applicability. Here, we investigate the effect of chromatin accessibility on Cas9 mediated gene editing efficiency for 20 gRNAs targeting 10 genomic loci in HEK293T cells using both SpCas9 and the eSpCas9(1.1) variant. Our study indicates that gene editing is more efficient in euchromatin than in heterochromatin, and we validate this finding in HeLa cells and in human fibroblasts. Furthermore, we investigate the gRNA sequence determinants of CRISPR-Cas9 activity using a surrogate reporter system and find that the efficiency of Cas9-mediated gene editing is dependent on guide sequence secondary structure formation. This knowledge can aid in the further improvement of tools for gRNA design. PMID- 28580608 TI - Improving the quality of transition and transfer of care in young adults with congenital heart disease. AB - The transition and transfer from pediatric to adult care is becoming increasingly important as improvements in the diagnosis and management of congenital heart disease allow patients to live longer. Transition is a complex and continuous process that requires careful planning. Inadequate transition has adverse effects on patients, their families and healthcare delivery systems. Currently, significant gaps exist in patient care as adolescents transfer to adult care and there are little data to drive the informed management of transition and transfer of care in adolescent congenital heart disease patients. Appropriate congenital heart disease care has been shown to decrease mortality in the adult population. This paper reviews the transition and transfer of care processes and outlines current congenital heart disease specific guidelines in the United States and compares these recommendations to Canadian and European guidelines. It then reviews perceived and real barriers to successful transition and identifies predictors of success during transfer to adult congenital heart disease care. Lastly, it explores how disease-specific markers of outcomes and quality indicators are being utilized to guide transition and transfer of care in other chronic childhood illnesses, and identifies existing knowledge gaps and structural impediments to improving the management of transition and transfer among congenital heart disease patients. PMID- 28580609 TI - Speaking to children and their families about congenital heart disease: Ushering in a new era of healthcare literacy. PMID- 28580606 TI - Combating multidrug-resistant Plasmodium falciparum malaria. AB - Over the past 50 years, Plasmodium falciparum has developed resistance against all antimalarial drugs used against it: chloroquine, sulphadoxine-pyrimethamine, quinine, piperaquine and mefloquine. More recently, resistance to the artemisinin derivatives and the resulting failure of artemisinin-based combination therapy (ACT) are threatening all major gains made in malaria control. Each time resistance has developed progressively, with delayed clearance of parasites first emerging only in a few regions, increasing in prevalence and geographic range, and then ultimately resulting in the complete failure of that antimalarial. Drawing from this repeated historical chain of events, this article presents context-specific approaches for combating drug-resistant P. falciparum malaria. The approaches begin with a context of drug-sensitive parasites and focus on the prevention of the emergence of drug resistance. Next, the approaches address a scenario in which resistance has emerged and is increasing in prevalence and geographic extent, with interventions focused on disrupting transmission through vector control, early diagnosis and treatment, and the use of new combination therapies. Elimination is also presented as an approach for addressing the imminent failure of all available antimalarials. The final drug resistance context presented is one in which all available antimalarials have failed; leaving only personal protection and the use of new antimalarials (or new combinations of antimalarials) as a viable strategy for dealing with complete resistance. All effective strategies and contexts require a multipronged, holistic approach. PMID- 28580610 TI - Acute and long-term effects of endovascular debanding of pulmonary arteries in a swine model. AB - OBJECTIVES: The primary objective of this study was to demonstrate that pulmonary artery (PA) debanding via cardiac catheterization using balloon angioplasty is feasible and safe in swine. The secondary objectives were to determine the acute and long-term effects of this therapy. DESIGN: This is a chronic survival experimental study in newborn swine. BACKGROUND: PA bands are used in infants for transient palliation of congenital heart defects with excessive pulmonary blood flow. Although rare, if these defects should close spontaneously or become hemodynamically insignificant, a sternotomy and occasionally cardiopulmonary bypass may still be required for band removal. Alternatively, debanding could be accomplished through less invasive methods. INTERVENTIONS: The main pulmonary artery was banded in three piglets, and the left pulmonary artery in five piglets via mini-thoracotomy at a mean weight of 2.5 kg. Following a threefold increase in weight, the piglets underwent PA debanding via balloon angioplasty. Four piglets were sacrificed to evaluate the acute effects. The remainder were followed to evaluate long-term effects. Histopathology was performed on all piglets. OUTCOME MEASURES: Reintervention rates. Histopathologic consequences of high pressure balloon angioplasty used for PA debanding acutely and after reinterventions. RESULTS: Debanding was performed at a mean weight of 8.1 +/- 2.23 kg. The median preintervention gradient across the band was 18 mm Hg. Debanding was successful in all piglets. The median postintervention gradient was 3.5 mm Hg. All piglets in the long-term model required re-interventions for recurrent stenosis at mean weights of 26 +/- 1.6 and 61 +/- 3.2 kg. Histopathology demonstrated vessel wall injury in only one piglet. CONCLUSIONS: Endovascular PA debanding can be safely achieved in a swine model. Angioplasty following debanding may be necessary for recurrent stenosis. This catheter-based therapy may provide a less-invasive alternative to surgery. PMID- 28580611 TI - Isolated pulmonary regurgitation causes decreased right ventricular longitudinal function and compensatory increased septal pumping in a porcine model. AB - AIM: Longitudinal ventricular contraction is a parameter of cardiac performance with predictive power. Right ventricular (RV) longitudinal function is impaired in patients with free pulmonary regurgitation (PR) following corrective surgery for Tetralogy of Fallot (TOF). It remains unclear whether this is a consequence of the surgical repair, or whether it is inherent to PR. The aim of this study was to assess the relationship between longitudinal, lateral and septal pumping in a porcine model of isolated PR. METHODS: Piglets were divided into a control (n = 8) group and a treatment (n = 12) group, which received a stent in the pulmonary valve orifice, inducing PR. After 2-3 months, animals were subjected to cardiac magnetic resonance imaging. A subset of animals (n = 6) then underwent percutaneous pulmonary valve replacement (PPVR) with follow-up 1 month later. Longitudinal, lateral and septal contributions to stroke volume (SV) were quantified by measuring volumetric displacements from end-diastole to end-systole in the cardiac short axis and long axis. RESULTS: PR resulted in a lower longitudinal contribution to RV stroke volume, compared to controls (60.0 +/- 2.6% vs. 73.6 +/- 3.8%; P = 0.012). Furthermore, a compensatory increase in septal contribution to RVSV was observed (11.0 +/- 1.6% vs. -3.1 +/- 1.5%; P < 0.0001). The left ventricle (LV) showed counter-regulation with an increased longitudinal LVSV. Changes in RV longitudinal function were reversed by PPVR. CONCLUSION: These findings suggest that PR contributes to decreased RV longitudinal function in the absence of scarring from cardiac surgery. Measurement of longitudinal RVSV may aid risk stratification and timing for interventional correction of PR in TOF patients. PMID- 28580612 TI - Utility of basophil activation testing to assess perioperative anaphylactic reactions in real-world practice. AB - INTRODUCTION: Perioperative anaphylactic reactions due to drugs and substances associated with general anesthesia can potentially be life-threatening. The objective of this study was to investigate the significance of the basophil activation test (BAT) for allergy diagnosis work up. METHODS: A total of 14 patients (5 men, 9 women; mean age: 57.8 years) with clinical records of anaphylactic reactions under general anesthesia were studied by means of anesthesia records, skin and serological tests. Eleven healthy subjects without any history of allergic sensitization to anaesthetic drugs served as controls. BATs based on stimulation of whole blood cells measuring CD63 activation of basophils and using CCR3 as basophil marker by flow cytometry (Flow CAST(r), BUHLMANN Laboratories AG, Schonenbuch, Switzerland) were performed with the following substances (in dependence on the history and the skin tests of the patient): analgesics (acetylsalicylic acid, celecoxib, diclofenac, ibuprofen, indometacin, metamizole, paracetamol, propyphenazone, tramadol), antibiotics (PPL (benzylpenicilloyl polylysine), MDM (minor determinant mixture), amoxicillin, cefuroxime, ciprofloxacin, doxycycline, erythromycin, roxithromycin, sulfamethoxazole, trimethoprim), local anesthetics (articaine, bupivacaine, lidocaine, prilocaine, procaine, methyl-4-hydroxybenzoate), narcotics and NMBA (atracurium, cisatracurium, etomidate, neostigmine, midazolam, mivacurium, pancuronium, propofol, pyridostigmine, succinylcholine, sufentanil, thiopental, vecuronium), and other individual substances. RESULTS: Three patients showed positive results in the BAT: One to metamizole, one to PPL, and one to pancuronium. BATs with these substances were negative in controls. CONCLUSIONS: The BAT should be used complementary to skin tests, especially if IgE-mediated mechanisms are presumed and skin tests are inconclusive. A positive reaction in BAT identifies the culprit agent with high probability. PMID- 28580613 TI - Update of the ATTRACT force field for the prediction of protein-protein binding affinity. AB - Determining the protein-protein interactions is still a major challenge for molecular biology. Docking protocols has come of age in predicting the structure of macromolecular complexes. However, they still lack accuracy to estimate the binding affinities, the thermodynamic quantity that drives the formation of a complex. Here, an updated version of the protein-protein ATTRACT force field aiming at predicting experimental binding affinities is reported. It has been designed on a dataset of 218 protein-protein complexes. The correlation between the experimental and predicted affinities reaches 0.6, outperforming most of the available protocols. Focusing on a subset of rigid and flexible complexes, the performance raises to 0.76 and 0.69, respectively. (c) 2017 Wiley Periodicals, Inc. PMID- 28580614 TI - Instrumentalisation of the health system: An examination of the impact on nursing practice and patient autonomy. AB - Most current management systems of healthcare institutions correspond to a model of market ethics with its demands of competitiveness. This approach has been called managerialism and is couched in terms of much-needed efficiencies and effective management of budgetary constraints. The aim of this study was to analyse the decision-making of nurses through the impact of health institution management models on clinical practice. Based on Foucault's ethical theory, a qualitative study was conducted through a discourse analysis of the nursing records in a hospital unit. The results revealed that the health institution standardises health care practice, which has an impact on professional and patient autonomy as it pertains to decision-making. The results of this research indicate that resistance strategies in the internal structures of health organisations can replace the normalisation and instrumentalisation of professional practice aimed at promoting patient self-determination. PMID- 28580615 TI - Angiopoietin-2 acts as a survival factor for chronic lymphocytic leukemia B cells throughout Tie-2 receptor engagement. PMID- 28580616 TI - Deceased organ donors with central nervous system neoplasm. PMID- 28580617 TI - PCPF-M model for simulating the fate and transport of pesticides and their metabolites in rice paddy field. AB - BACKGROUND: The PCPF-1 model was improved for forecasting the fate and transport of metabolites in addition to parent compounds in rice paddies. In the new PCPF-M model, metabolites are generated from the dissipation of pesticide applied in rice paddies through hydrolysis, photolysis and biological degradations. The methodology to parameterize the model was illustrated using two scenarios for which uncertainty and sensitivity analyses were also conducted. RESULTS: In a batch degradation experiment, the hourly forecasted concentrations of fipronil and its metabolites in paddy water were very accurate. In a field-scale experiment, the hourly forecasted concentrations of fipronil in paddy water and paddy soil were accurate while the corresponding daily forecasted concentrations of metabolites were adequate. The major contributors to the variation of the forecasted metabolite concentrations in paddy water and paddy soil were the formation fractions of the metabolites. The influence of uncertainty included in input parameters on the forecasted metabolite concentration was high during the peak concentration of metabolite in paddy water. In contrast, in paddy soil, the metabolite concentrations forecasted several days after the initial pesticide application were sensitive to the uncertainty incorporated in the input parameters. CONCLUSION: The PCPF-M model simultaneously forecasts the concentrations of a parent pesticide and up to three metabolites. The model was validated using fipronil and two of its metabolites in paddy water and paddy soil. The model can be used in the early stage of the pesticide registration process and in risk assessment analysis for the evaluation of pesticide exposure. (c) 2017 Society of Chemical Industry. PMID- 28580618 TI - Bovine thyroglobulin gene polymorphisms and their association with sexual precocity in Guzerat bulls. AB - Puberty is a stage of sexual development determined by the interaction of environmental factors and genetic mechanisms. Among them, thyroid function plays a key role in sexual development and spermatogenic function and is under the control of several genes, including the well-described thyroglobulin gene (TG). Previous reports have shown genetic association between thyroid function and selected single nucleotide polymorphisms (SNPs) in taurine cattle. Therefore, the identification of genetic mechanisms involved in the regulation of this trait can assist with the selection for early pubertal bulls, thus improving genetic progress in livestock breeding. The aim of this study was to validate the association between TG SNPs and age at puberty in zebuine bulls. Three SNPs (rs110406764, rs109662686, rs109057985) were genotyped in 159 Guzerat animals using SEQUENOM technology. Results showed a significant association (p < .05) between the studied SNPs and puberty age, in agreement with our previous reports in a taurine breed. Interestingly, allele frequencies were different from those already reported, being GAT the most favourable allele for age at puberty in Guzerat (94.4 days lower). Overall, our findings corroborate previous reports and reinforce the importance of genetic influence in the regulation of sexual development and puberty through a thyroid pathway in zebuine cattle. PMID- 28580619 TI - Impact of microvascular obstruction on left ventricular local remodeling after reperfused myocardial infarction. AB - PURPOSE: To evaluate by cardiac magnetic resonance imaging (MRI) the impact of microvascular obstruction (MVO) on regional left ventricular (LV) wall characteristics and local remodeling after acute myocardial infarction (AMI). MATERIALS AND METHODS: In all, 114 AMI patients underwent cardiac MRI at 3T within 2-4 days (baseline) and at 6 months (follow-up) after reperfusion. Late gadolinium enhancement and cine sequences were performed. The impact of MVO (ie, presence and extent) on regional wall thickening (WT, %), end-diastolic wall thickness (EDWT, mm), and local cavity change (mm) of LV were quantitatively analyzed. Local cavity change, calculated as surface-to-surface distance from registered endocardial surface meshes of cine imaging datasets acquired initially and at follow-up, was used to assess local remodeling. RESULTS: MVO was detected in 69 patients (60.5%). WT was significantly lower when MVO was present (P < 0.05); and it was inversely related to MVO transmural extent (P < 0.0001). WT improvement was significantly worsened when MVO was present in segments with infarct transmural extent exceeding 50%. Significant wall thinning occurred at follow-up in segments with infarct transmural extent >75% with further thinning by MVO presence; and EDWT decreased with increasing MVO transmural extent (P < 0.0001). LV cavity shrank in patients without MVO, whereas it dilated in those with MVO. Local cavity changes were not significantly different by a region-to region analysis throughout the LV within each group (P = 0.57 and 0.74, respectively). CONCLUSION: MVO has a significant adverse effect on LV wall characteristics and LV remodeling. Postinfarct remodeling seems to be globally mediated rather than locally mediated during the first 6 months. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:499-510. PMID- 28580620 TI - Adjuvant chemotherapy in resectable synovial sarcoma. AB - INTRODUCTION: The role of adjuvant chemotherapy (AC) for synovial sarcoma (SS) is controversial. Using a large national dataset we evaluate the impact of AC on overall survival (OS) following curative-intent resection of SS. METHODS: Patients with stage I-III SS 2004-2012 undergoing resection were identified in the National Cancer Data Base. Clinicopathologic factors associated with OS were identified using Cox proportional-hazard modeling, adjusting for factors associated with receipt of AC. RESULTS: Among 544 patients, 131 received AC. Median age of the cohort was 42 years; 269 were female. AC was not associated with OS in univariate analysis in the overall cohort. After stratification by stage, AC was associated with prolonged OS in univariate analysis in stage III patients only (P = 0.028), which remained significant in multivariable analysis (P = 0.033). Other factors associated with OS in stage III patients were age >55 years, (P = 0.001), positive margins (P = 0.037), biphasic histology (P = 0.013), and adjuvant radiation (P < 0.001). The association between AC and OS remained significant after adjustment for factors predictive of receipt of AC. CONCLUSIONS: In this national cohort, AC was associated with prolonged OS for SS for stage III patients but not in lower stages. Less restricted use of this therapy may be warranted in this population. PMID- 28580621 TI - Functional outcomes of fasciocutaneous free flap and pectoralis major flap for salvage total laryngectomy. AB - BACKGROUND: Pectoralis major muscle flaps (PMMFs) and fasciocutaneous free flaps (FFFs) are commonly used for reconstruction of the surgical defect after salvage total laryngectomy. This study compared swallowing function in patients who underwent reconstruction with either PMMF or FFF. METHODS: This study was based on a retrospective cohort of patients treated at the CHU de Quebec between January 2000 and March 2015. Demographics, chemoradiation data, surgical protocol, pathologic results, complications, evolution, esophageal dilation, diet intake, and feeding tube dependence were documented. RESULTS: A total of 126 patients were analyzed (93 PMMFs and 33 FFFs). Of the patients who received PMMFs, 38.7% had a limited oral intake compared to 15.2% of patients who received FFFs (odds ratio [OR] 3.54; 95% confidence interval [CI] 1.25-9.99; P = .02). The need for esophageal dilation tended to be greater for PMMF patients (25% vs 9%; OR 3.38; 95% CI 0.94-12.13; P = .06). Complication rates were similar. CONCLUSION: The FFF reconstruction led to better results in terms of swallowing function than PMMF reconstruction. PMID- 28580623 TI - The relationship of circulating relaxin-2 concentrations with short-term prognosis in patients with acute heart failure: the RELAHF study. PMID- 28580624 TI - Coupled effects of wind-storms and drought on tree mortality across 115 forest stands from the Western Alps and the Jura mountains. AB - Damage due to wind-storms and droughts is increasing in many temperate forests, yet little is known about the long-term roles of these key climatic factors in forest dynamics and in the carbon budget. The objective of this study was to estimate individual and coupled effects of droughts and wind-storms on adult tree mortality across a 31-year period in 115 managed, mixed coniferous forest stands from the Western Alps and the Jura mountains. For each stand, yearly mortality was inferred from management records, yearly drought from interpolated fields of monthly temperature, precipitation and soil water holding capacity, and wind storms from interpolated fields of daily maximum wind speed. We performed a thorough model selection based on a leave-one-out cross-validation of the time series. We compared different critical wind speeds (CWSs) for damage, wind-storm, and stand variables and statistical models. We found that a model including stand characteristics, drought, and storm strength using a CWS of 25 ms-1 performed the best across most stands. Using this best model, we found that drought increased damage risk only in the most southerly forests, and its effect is generally maintained for up to 2 years. Storm strength increased damage risk in all forests in a relatively uniform way. In some stands, we found positive interaction between drought and storm strength most likely because drought weakens trees, and they became more prone to stem breakage under wind-loading. In other stands, we found negative interaction between drought and storm strength, where excessive rain likely leads to soil water saturation making trees more susceptible to overturning in a wind-storm. Our results stress that temporal data are essential to make valid inferences about ecological impacts of disturbance events, and that making inferences about disturbance agents separately can be of limited validity. Under projected future climatic conditions, the direction and strength of these ecological interactions could also change. PMID- 28580622 TI - Heightened amygdala responsiveness in s-carriers of 5-HTTLPR genetic polymorphism reflects enhanced cortical rather than subcortical inputs: An MEG study. AB - Short allele carriers (S-carriers) of the serotonin transporter gene (5-HTTLPR) show an elevated amygdala response to emotional stimuli relative to long allele carriers (LL-homozygous). However, whether this reflects increased responsiveness of the amygdala generally or interactions between the amygdala and the specific input systems remains unknown. It is argued that the amygdala receives input via a quick subcortical and a slower cortical pathway. If the elevated amygdala response in S-carriers reflects generally increased amygdala responding, then group differences in amygdala should be seen across the amygdala response time course. However, if the difference is a secondary consequence of enhanced amygdala-cortical interactions, then group differences might only be present later in the amygdala response. Using magnetoencephalography (MEG), we found an enhanced amygdala response to fearful expressions starting 40-50 ms poststimulus. However, group differences in the amygdala were only seen 190-200 ms poststimulus, preceded by increased superior temporal sulcus (STS) responses in S carriers from 130 to 140 ms poststimulus. An enhanced amygdala response to angry expressions started 260-270 ms poststimulus with group differences in the amygdala starting at 160-170 ms poststimulus onset, preceded by increased STS responses in S-carriers from 150 to 160 ms poststimulus. These suggest that enhanced amygdala responses in S-carriers might reflect enhanced STS-amygdala connectivity in S-carriers. Hum Brain Mapp 38:4313-4321, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28580625 TI - Mineralocorticoid receptor antagonist pattern of use in heart failure with reduced ejection fraction: findings from BIOSTAT-CHF. AB - AIMS: Mineralocorticoid receptor antagonists (MRAs) are recommended (unless contraindicated) to all patients with heart failure with reduced ejection fraction (HFrEF). However, MRAs are still largely underused in routine clinical practice. This study aims to describe the determinants and pattern of use of MRAs in HFrEF. METHODS AND RESULTS: BIOSTAT-CHF is a European multicentre, prospective study which enrolled patients suboptimally treated with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) and/or beta-blockers, with the aim of optimizing guideline-based use of these agents. From the original 2516 subjects, this retrospective post hoc analysis included the 1325 patients with an indication for MRA therapy (i.e. left ventricular ejection fraction <=35%, estimated glomerular filtration rate >=30 mL/min/1.73 m2 , K+ <=5.0 mmol/L). The mean age was 66.1 +/- 12.2 years. At baseline an MRA was prescribed to 741 (56%) patients. Patients who were prescribed MRAs at baseline were younger, more often male, had higher body mass index, lower sodium, higher proportion of hypertension history and ACEi/ARB prescription (all P < 0.05). Of the 1049 patients who completed the baseline plus the 9 month visit, 585 (56%) had an MRA prescribed at baseline and 662 (63%) had an MRA prescribed at 9 months. Among the 585 patients with MRA at baseline, 91 (16%) had discontinued therapy and among the 461 (44%) patients without MRA at baseline 168 (36%) had initiated therapy subsequently. MRA discontinuation was more likely in subjects with higher left ventricular ejection fraction and NYHA class III/IV (P < 0.05 for both). MRA prescription both at baseline and 9 months was not associated with the outcome of death or heart failure hospitalization (adjusted hazard ratio 1.02, 95% confidence interval 0.66-1.58; P = 0.93). CONCLUSIONS: In this prospective observational study across Europe, MRAs were largely under-prescribed and frequently discontinued. Owing to these dynamic changes, outcome inferences are inconclusive. PMID- 28580626 TI - Gender-specific differences in the molecular signatures of adult Eosinophilic Oesophagitis. PMID- 28580629 TI - Three-dimensional patterning in biomedicine: Importance and applications in neuropharmacology. AB - Nature manufactures biological systems in three dimensions with precisely controlled spatiotemporal profiles on hierarchical length and time scales. In this article, we review 3D patterning of biological systems on synthetic platforms for neuropharmacological applications. We briefly describe 3D versus 2D chemical and topographical patterning methods and their limitations. Subsequently, an overview of introducing a third dimension in neuropharmacological research with delineation of chemical and topographical roles is presented. Finally, toward the end of this article, an explanation of how 3D patterning has played a pivotal role in relevant fields of neuropharmacology to understand neurophysiology during development, normal health, and disease conditions is described. The future prospects of organs-on-a- like devices to mimic patterned blood-brain barrier in the context of neurotherapeutic discovery and development for the prioritization of lead candidates, membrane potential, and toxicity testing are also described. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1369 1382, 2018. PMID- 28580628 TI - Mortality in the Waikato Hospital Systemic Sclerosis Cohort. AB - OBJECTIVE: To characterize the causes of mortality and standardised mortality ratio in a cohort of patients with systemic sclerosis (SSc). METHODS: A cohort of 132 patients enrolled at the Waikato Systemic Sclerosis Clinic was prospectively followed from 2005 to 2016. Patient demographics, diagnoses and laboratory reports were used to assess risk of mortality and generate standardised mortality ratios (SMR). Survival was analyzed using Kaplan-Meier methods. RESULTS: Of the cohort of 132 patients, 20 (15%) were deceased by the end of the study period. The median age of diagnosis and death was 52 years (range 13-86) and 71 years (range 42-87) respectively. Seventy percent of deaths were SSc related and the leading causes of death were due to pulmonary arterial hypertension (PAH), interstitial lung disease (ILD) and scleroderma renal crisis (SRC). Patients diagnosed after the age of 60 had renal or cardiac manifestations and were associated with a significantly increased risk of mortality. The overall SMR was 2.59 (95% CI 1.67-4.01) and was higher in those with diffuse versus limited SSc (6.46, 95% CI 3.08-13.54 vs. 1.93, 95% CI 1.10-3.41) and males (4.17, 95% CI 1.74 10.02 vs. 2.30, 95% CI 1.39-3.81). CONCLUSION: This study demonstrated an increased risk of mortality in patients with SSc relative to that of the general population. An excess in risk was observed particularly in those with diffuse SSc and in males. Renal and cardiac involvement were found to be significant indicators of mortality and reinforces the necessity of screening for these complications. PMID- 28580627 TI - Age-related modulation of angiogenesis-regulating factors in the swine meniscus. AB - An in-depth knowledge of the native meniscus morphology and biomechanics in its different areas is essential to develop an engineered tissue. Meniscus is characterized by a great regional variation in extracellular matrix components and in vascularization. Then, the aim of this work was to characterize the expression of factors involved in angiogenesis in different areas during meniscus maturation in pigs. The menisci were removed from the knee joints of neonatal, young and adult pigs, and they were divided into the inner, intermediate and outer areas. Vascular characterization and meniscal maturation were evaluated by immunohistochemistry and Western blot analysis. In particular, expression of the angiogenic factor Vascular Endothelial Growth Factor (VEGF) and the anti angiogenic marker Endostatin (ENDO) was analysed, as well as the vascular endothelial cadherin (Ve-CAD). In addition, expression of Collagen II (COLL II) and SOX9 was examined, as markers of the fibro-cartilaginous differentiation. Expression of VEGF and Ve-CAD had a similar pattern in all animals, with a significant increase from the inner to the outer part of the meniscus. Pooling the zones, expression of both proteins was significantly higher in the neonatal meniscus than in young and adult menisci. Conversely, the young meniscus revealed a significantly higher expression of ENDO compared to the neonatal and adult ones. Analysis of tissue maturation markers showed an increase in COLL II and a decrease in SOX9 expression with age. These preliminary data highlight some of the changes that occur in the swine meniscus during growth, in particular the ensemble of regulatory factors involved in angiogenesis. PMID- 28580630 TI - The midgut microbiota plays an essential role in sand fly vector competence for Leishmania major. AB - For many arthropod vectors, the diverse bacteria and fungi that inhabit the gut can negatively impact pathogen colonization. Our attempts to exploit antibiotic treatment of colonized Phlebotomus duboscqi sand flies in order to improve their vector competency for Leishmania major resulted instead in flies that were refractory to the development of transmissible infections due to the inability of the parasite to survive and to colonize the anterior midgut with infective, metacyclic stage promastigotes. The parasite survival and development defect could be overcome by feeding the flies on different symbiont bacteria but not by feeding them on bacterial supernatants or replete medium. The inhibitory effect of the dysbiosis was moderated by lowering the concentration of sucrose (<30% w/v) used in the sugar feeds to maintain the colony. Exposure of promastigotes to 30% sucrose was lethal to the parasite in vitro. Confocal imaging revealed that the killing in vivo was confined to promastigotes that had migrated to the anterior plug region, corresponding to the highest concentrations of sucrose. The data suggest that sucrose utilization by the microbiota is essential to promote the appropriate osmotic conditions required for the survival of infective stage promastigotes in vivo. PMID- 28580632 TI - Mortality review as a teaching tool in the tropics. PMID- 28580631 TI - Kawasaki disease: Medical therapies. AB - Medical therapies in patients with Kawasaki disease (KD) are administered to reduce the prevalence of coronary aneurysms, reduce systemic inflammation, and prevent coronary thrombosis. All patients with acute KD should be treated with intravenous immunoglobulin (IVIG) 2 g/kg, generally administered over 10-12 hours. Aspirin has never been shown to prevent aneurysms, but is given for its anti-inflammatory and antipyretic effects until the patient has been afebrile for ~2 days, then lowered to an antiplatelet dose. Adjunctive therapy with a longer course of corticosteroids, together with IVIG and aspirin, may be considered for primary treatment in patients at high risk for development of aneurysms. For patients who have persistent or recrudescent fever after IVIG treatment without other explanation, adjunctive therapies include retreatment with IVIG, a tapering course of corticosteroids, infliximab, cyclosporine, cyclophosphamide, and other immunomodulatory therapies. Antithrombotic therapies are tailored to the risk of thrombosis, and range from aspirin alone for 4-6 weeks in children without aneurysms to a combination of anticoagulation and antiplatelet therapy for those with giant aneurysms. PMID- 28580633 TI - Smad7 positively regulates keratinocyte proliferation in psoriasis. AB - BACKGROUND: Transforming growth factor (TGF)-beta1 exerts inhibitory effects on keratinocyte proliferation. OBJECTIVES: To examine whether Smad7, a known inhibitor of TGF-beta1 signalling, is involved in psoriasis-associated keratinocyte hyperproliferation. METHODS: Smad7 was evaluated in skin sections of patients with psoriasis and healthy controls and in mice with Aldara-induced skin pathology by real-time polymerase chain reaction and immunohistochemistry. To assess whether Smad7 positively regulates in vivo keratinocyte growth, mice treated with Aldara received daily cutaneous administration of Smad7 antisense oligonucleotide (AS). Keratin (K)6 and K16, cell-cycle-associated factors, cell cycle and cell proliferation were evaluated in HaCaT cells either treated with Smad7 AS or transfected with Smad7 plasmid and in mice given Smad7 AS. RESULTS: Smad7 was highly expressed in keratinocytes of patients with psoriasis and of mice treated with Aldara. In HaCaT cells, Smad7 knockdown inhibited cell growth, reduced K6 and K16 expression and promoted accumulation of cells in the S-phase of the cell cycle. Smad7-deficient keratinocytes exhibited reduced levels of CDC25A protein, a phosphatase that facilitates progression of cells through the S phase, and hyperphosphorylation of eukaryotic initiation factor 2 (eIF2)alpha, a negative regulator of CDC25 protein translation. Consistently, Smad7 overexpression in HaCaT cells was followed by induction of K6 and K16 and increased cell proliferation. Topical application of Smad7 AS to Aldara-treated mice reduced epidermal thickness. CONCLUSIONS: Our data show that Smad7 is overexpressed in human and murine psoriasis and suggest a key role of this molecule in the control of keratinocyte proliferation. PMID- 28580634 TI - New by-products rich in bioactive substances from the olive oil mill processing. AB - BACKGROUND: Olive oil extraction generates a large amount of residue consisting mainly of the pomace and leaves when using a two-phase centrifugation system. The aim of this study was to assess the content of phenolic and triterpene compounds in the by-products produced in Spanish olive oil mills. RESULTS: Olive pomace had concentrations of phenolic and triterpene substances lower than 2 and 3 g kg-1 , respectively. The leaves contained a high concentration of these substances, although those collected from ground-picked olives had lost most of their phenolic compounds. Moreover, the sediment from the bottom of the olive oil storage tanks did not have a significant amount of these substances. By contrast, a new by-product called olive pomace skin has been revealed as a very rich source of triterpenic acids, the content of which can reach up to 120 g kg-1 in this waste product, maslinic acid comprising around 70% of total triterpenics. CONCLUSION: Among the by-products generated during extraction of olive oil, olive pomace skin has been discovered to be a very rich source of triterpenic acids, which can reach up to 120 g kg-1 of the waste. These results will contribute to the valorization of olive oil by-products. (c) 2017 Society of Chemical Industry. PMID- 28580635 TI - A cross-sectional study of the catheter management of neurogenic bladder after traumatic spinal cord injury. AB - AIMS: This cross-sectional study describes the catheter management of neurogenic bladder (NGB) in patients with traumatic spinal cord injury (tSCI) with emphasis on the motivations behind transitions between intermittent (IC) and indwelling catheters. METHODS: Patients at the Minneapolis VA with history of tSCI who utilized either intermittent catheterization (IC), urethral (UC) or suprapubic (SP) catheters, participated in a voluntary, anonymous survey regarding their bladder management strategies. RESULTS: A total of 100 patients participated, 94% were male and 90% Caucasian with median age of 61 years. Patients with current UC or SP were older than those utilizing IC (P = 0.002). The median age at injury and years since SCI were 32 years and 20.5 years, respectively. The median time with current modality was 11 years. A total of 27% of all patients reported at least one transition between catheter type. A total of 14 of 54 patients using IC had prior use of UC or SP, while 12/25 patients using SP and 10/21 patients using UC had prior use of IC. The most common reasons to stop IC included inconvenience, physician recommendation, and dislike of IC. A total of 53% of patients currently using UC or SP reported never using IC. Patients currently using SP were more content with their current catheterization method than those using UC or IC (P = 0.046). CONCLUSIONS: Among patients using catheters for NGB, intermittent catheterization was the most common modality utilized and the transition between intermittent and indwelling catheter was most often influenced by patient preferences and clinician recommendations. PMID- 28580636 TI - Relationship between co-morbidities at diagnosis, survival and ultimate cause of death in patients with chronic lymphocytic leukaemia (CLL): a prospective cohort study. AB - The ultimate cause of death for most patients with newly diagnosed chronic lymphocytic leukaemia (CLL) and its relationship to co-morbid health conditions is poorly defined. We conducted a prospective cohort study that systematically followed 1143 patients diagnosed with CLL between June 2002 and November 2014. Comorbid health conditions at the time of CLL diagnosis and their relationship to survival and cause of death were evaluated. Collectively, 1061 (93%) patients had at least one co-morbid health condition at the time of CLL diagnosis (median number 3). Despite this, 89% of patients had a low-intermediate Charlson Comorbidity Index score (CCI) at diagnosis. After a median follow-up of 6 years, 225 patients have died. Death was due to CLL progression in 85 (46%) patients, infection in 14 (8%) patients, other cancer in 35 (19%) patients and comorbid health conditions in 50 (27%) patients. Higher CCI score and a greater number of major comorbid health conditions at the time of CLL diagnosis was associated with shorter non-CLL specific survival, but not with shorter CLL-specific survival on multivariate analysis. In conclusion, CLL and CLL-related complications (infections and second cancers) are the overwhelming cause of death in patients with CLL, regardless of CCI score and number of comorbid health conditions at diagnosis. PMID- 28580637 TI - Influence of plerixafor on the mobilization of CD34+ cell subpopulations and lymphocyte subtypes. AB - BACKGROUND: Peripheral blood stem cells mobilized with granulocyte-colony stimulating factor (G-CSF) with or without chemotherapy are routinely used for autologous hematopoietic cell transplantation. Plerixafor, a chemokine-receptor inhibitor, increases the amount of circulating CD34+ cells and improves harvest results. However, limited information is available regarding the composition of apheresis products with respect to CD34+ and lymphocyte subtypes collected after various mobilization regimens. STUDY DESIGN AND METHODS: We used a recently established single-platform multicolor flow-cytometric analysis including CD45RA and CD133 to define CD34+ subpopulations and lymphocyte subsets in products obtained either after G-CSF with or without chemotherapy alone (G, n = 40) or with addition of plerixafor (GP, n = 40). RESULTS: Absolute numbers of white blood cells and lymphocyte subtypes were significantly higher after plerixafor, which was not observed for absolute CD34+ counts. However, distinct differences in terms of CD34+ subtypes were observed. The most primitive multipotent progenitors (CD45RA-CD133+CD34+CD38low ) predominated significantly after G (median, 49.2%; range, 15.2%-63%) compared to GP (median, 34.4%; range, 12%-62%; p < 0.001), whereas more differentiated subsets clearly prevailed after GP. CONCLUSION: In contrast to the findings of other authors, our study shows a clear shift toward more committed CD34+ subsets after plerixafor in poor mobilizers and elucidates the importance of informative surface markers like CD45RA and CD133 in addition to CD38 to discriminate earlier from more committed CD34+ cells. Further studies are needed to analyze whether these findings have an impact on clinical outcome. PMID- 28580638 TI - Emotional reactivity and regulation in individuals with psychopathic traits: Evidence for a disconnect between neurophysiology and self-report. AB - Individuals with psychopathic traits often demonstrate blunted reactivity to negative emotional stimuli. However, it is not yet clear whether these individuals also have difficulty regulating their emotional responses to negative stimuli. To address this question, participants with varying levels of psychopathic traits (indexed by the Triarchic Measure of Psychopathy; Patrick, 2010) completed a task in which they passively viewed, increased, or decreased their emotions to negative picture stimuli while electrocortical activity was recorded. During passive viewing of negative images, higher boldness, but not higher disinhibition or meanness, was associated with reduced amplitude of the late positive potential (LPP), an ERP that indexes reactivity to emotionally relevant stimuli. However, all participants demonstrated expected enhancement of the LPP when asked to increase their emotional response. Participants did not show expected suppression of the LPP when asked to decrease their emotional response. Contrary to the electrophysiological data, individuals with higher boldness did not self-report experiencing blunted emotional response during passive viewing trials, and they reported experiencing greater emotional reactivity relative to other participants when regulating (e.g., both increasing and decreasing) their emotions. Results suggest inconsistency between physiological and self-report indices of emotion among high-bold individuals during both affective processing and regulation. PMID- 28580639 TI - Mesenchymal Stem Cells Stabilize Axonal Transports for Autophagic Clearance of alpha-Synuclein in Parkinsonian Models. AB - Genome-wide association studies have identified two loci, SNCA and the microtubule (MT)-associated protein tau, as common risk factors for Parkinson's disease (PD). Specifically, alpha-synuclein directly destabilizes MT via tau phosphorylation and induces axonal transport deficits that are the primary events leading to an abnormal accumulation of alpha-synuclein that causes nigral dopaminergic cell loss. In this study, we demonstrated that mesenchymal stem cells (MSCs) could modulate cytoskeletal networks and trafficking to exert neuroprotective properties in wild-type or A53T alpha-synuclein overexpressing cells and mice. Moreover, we found that eukaryotic elongation factor 1A-2, a soluble factor derived from MSCs, stabilized MT assembly by decreasing calcium/calmodulin-dependent tau phosphorylation and induced autophagolysosome fusion, which was accompanied by an increase in the axonal motor proteins and increased neuronal survival. Our data suggest that MSCs have beneficial effects on axonal transports via MT stability by controlling alpha-synuclein-induced tau phosphorylation, indicating that MSCs may exert a protective role in the early stages of axonal transport defects in alpha-synucleinopathies. Stem Cells 2017;35:1934-1947. PMID- 28580640 TI - Region-based association tests for sequencing data on survival traits. AB - Family-based designs enriched with affected subjects and disease associated variants can increase statistical power for identifying functional rare variants. However, few rare variant analysis approaches are available for time-to-event traits in family designs and none of them applicable to the X chromosome. We developed novel pedigree-based burden and kernel association tests for time-to event outcomes with right censoring for pedigree data, referred to FamRATS (family-based rare variant association tests for survival traits). Cox proportional hazard models were employed to relate a time-to-event trait with rare variants with flexibility to encompass all ranges and collapsing of multiple variants. In addition, the robustness of violating proportional hazard assumptions was investigated for the proposed and four current existing tests, including the conventional population-based Cox proportional model and the burden, kernel, and sum of squares statistic (SSQ) tests for family data. The proposed tests can be applied to large-scale whole-genome sequencing data. They are appropriate for the practical use under a wide range of misspecified Cox models, as well as for population-based, pedigree-based, or hybrid designs. In our extensive simulation study and data example, we showed that the proposed kernel test is the most powerful and robust choice among the proposed burden test and the existing four rare variant survival association tests. When applied to the Diabetes Heart Study, the proposed tests found exome variants of the JAK1 gene on chromosome 1 showed the most significant association with age at onset of type 2 diabetes from the exome-wide analysis. PMID- 28580642 TI - Underreported use of palliative care and patient-reported outcome measures to address reduced quality of life in patients with calciphylaxis: a systematic review. AB - Calciphylaxis is associated with significant morbidity and mortality. Palliative care (PC) is a subspecialty that treats the pain and stress of serious illness. To assess whether the role of quality of life (QoL) indices, patient-reported outcome measures and PC have been studied in patients with calciphylaxis, we performed a systematic literature review. Several databases were searched from inception to October 2016 according to modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. We searched for papers on calciphylaxis that mentioned the symptoms and supportive needs of patients, QoL or outcome measures to report symptom severity, and the involvement of PC. Twelve papers met the inclusion criteria. Reported patient symptoms included pain, skin lesion resolution and pruritus, with the first being the most frequently reported. Four papers measured pain using a previously verified patient-reported outcome measure, including the Visual Analogue Scale. One paper used a verified QoL measure, the Dermatology Quality of Life Index. No tool was used consistently. Eight papers reported the use of hospice care or PC in the treatment of calciphylaxis. No outcome measure was used to prompt PC involvement. Overall, QoL indices, patient-reported outcome measures and PC are underreported in the treatment of calciphylaxis. PC may be a resource to assist in symptom management and adaptive coping strategies for patients from the onset of disease. PMID- 28580641 TI - Melatonin reduces endoplasmic reticulum stress and corneal dystrophy-associated TGFBIp through activation of endoplasmic reticulum-associated protein degradation. AB - Endoplasmic reticulum (ER) stress is emerging as a factor for the pathogenesis of granular corneal dystrophy type 2 (GCD2). This study was designed to investigate the molecular mechanisms underlying the protective effects of melatonin on ER stress in GCD2. Our results showed that GCD2 corneal fibroblasts were more susceptible to ER stress-induced death than were wild-type cells. Melatonin significantly inhibited GCD2 corneal cell death, caspase-3 activation, and poly (ADP-ribose) polymerase 1 cleavage caused by the ER stress inducer, tunicamycin. Under ER stress, melatonin significantly suppressed the induction of immunoglobulin heavy-chain-binding protein (BiP) and activation of inositol requiring enzyme 1alpha (IRE1alpha), and their downstream target, alternative splicing of X-box binding protein 1(XBP1). Notably, the reduction in BiP and IRE1alpha by melatonin was suppressed by the ubiquitin-proteasome inhibitor, MG132, but not by the autophagy inhibitor, bafilomycin A1, indicating involvement of the ER-associated protein degradation (ERAD) system. Melatonin treatment reduced the levels of transforming growth factor-beta-induced protein (TGFBIp) significantly, and this reduction was suppressed by MG132. We also found reduced mRNA expression of the ERAD system components HRD1 and SEL1L, and a reduced level of SEL1L protein in GCD2 cells. Interestingly, melatonin treatments enhanced SEL1L levels and suppressed the inhibition of SEL1L N-glycosylation caused by tunicamycin. In conclusion, this study provides new insights into the mechanisms by which melatonin confers its protective actions during ER stress. The results also indicate that melatonin might have potential as a therapeutic agent for ER stress-related diseases including GCD2. PMID- 28580644 TI - Relationships between Acute and Postacute Care Providers: Measurement and Estimation. PMID- 28580643 TI - Insights into PG-binding, conformational change, and dimerization of the OmpA C terminal domains from Salmonella enterica serovar Typhimurium and Borrelia burgdorferi. AB - Salmonella enterica serovar Typhimurium can induce both humoral and cell-mediated responses when establishing itself in the host. These responses are primarily stimulated against the lipopolysaccharide and major outer membrane (OM) proteins. OmpA is one of these major OM proteins. It comprises a N-terminal eight-stranded beta-barrel transmembrane domain and a C-terminal domain (OmpACTD ). The OmpACTD and its homologs are believed to bind to peptidoglycan (PG) within the periplasm, maintaining bacterial osmotic homeostasis and modulating the permeability and integrity of the OM. Here we present the first crystal structures of the OmpACTD from two pathogens: S. typhimurium (STOmpACTD ) in open and closed forms and causative agent of Lyme Disease Borrelia burgdorferi (BbOmpACTD ), in closed form. In the open form of STOmpACTD , an aspartate residue from a long beta2 alpha3 loop points into the binding pocket, suggesting that an anion group such as a carboxylate group from PG is favored at the binding site. In the closed form of STOmpACTD and in the structure of BbOmpACTD , a sulfate group from the crystallization buffer is tightly bound at the binding site. The differences between the closed and open forms of STOmpACTD , suggest a large conformational change that includes an extension of alpha3 helix by ordering a part of beta2 alpha3 loop. We propose that the sulfate anion observed in these structures mimics the carboxylate group of PG when bound to STOmpACTD suggesting PG anchoring mechanism. In addition, the binding of PG or a ligand mimic may enhance dimerization of STOmpACTD , or possibly that of full length STOmpA. PMID- 28580645 TI - A systematic review of factors influencing knowledge management and the nurse leaders' role. AB - AIM: To describe factors facilitating or inhibiting the development of registered nurses' competency and nurse leader's role in knowledge management. BACKGROUND: Nurses' competency directly influences patient safety and the quality and effectiveness of patient care. Challenges of nurse leaders in knowledge management include acquiring, assessing and utilising current knowledge and assessing and enhancing competency. EVALUATION: A systematic search was conducted in PubMed, CINAHL, SCOPUS and ERIC databases in April 2015. The search identified 18 relevant research articles published between 2009 and 2015. The quality of the studies was appraised in accordance with study designs. KEY ISSUE: Knowledge management is facilitated by an organisation culture that supports learning, sharing of information and learning together. Leader commitment and competency were factors related to leadership facilitating knowledge management. CONCLUSION: Nurse leaders need evidence-based interventions to support shared learning and to create infrastructures that facilitate competence development. Future research is especially needed to evaluate connections between knowledge management and patient outcomes. IMPLICATIONS FOR NURSING MANAGEMENT AND LEADERSHIP: The results of this review can be utilised in enhancing factors to facilitate knowledge management in clinical practice and identifying nurse leaders' role in strengthening nurses' competency. PMID- 28580646 TI - Secukinumab is superior to fumaric acid esters in treating patients with moderate to-severe plaque psoriasis who are naive to systemic treatments: results from the randomized controlled PRIME trial. AB - BACKGROUND: Secukinumab is a fully human antibody that neutralizes interleukin 17A. It has significant efficacy and a favourable safety profile in moderate-to severe plaque psoriasis and psoriatic arthritis. OBJECTIVES: To compare secukinumab with fumaric acid esters (FAEs) in a randomized controlled trial. METHODS: In this 24-week, randomized, open-label, multicentre study with blinded assessment, patients with moderate-to-severe plaque psoriasis, naive to systemic treatments, were randomized to receive secukinumab 300 mg subcutaneously or oral FAEs. The primary end point was >= 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75 response) at week 24, and missing patients were considered responders if they were responders at the time of dropout. RESULTS: In total 202 patients were randomized and 200 were treated with at least one dose. Outcomes at week 24 were available for 147 and imputed for 53 patients. Discontinuations were mostly due to adverse events, and occurred more frequently in the FAE group (1.9% vs. 40.0%). At week 24, significantly more patients receiving secukinumab compared with FAEs achieved PASI 75 response (89.5% vs. 33.7%, P < 0.001), PASI 90 response (75.2% vs. 18.9%, P < 0.001) and Dermatology Life Quality Index 0 or 1 response (71.4% vs. 25.3%, P < 0.001). CONCLUSIONS: Secukinumab demonstrated superior efficacy to FAEs in patients with psoriasis over a 24-week period. PMID- 28580647 TI - Diagnosis-specific self-image predicts longitudinal suicidal ideation in adult eating disorders. AB - OBJECTIVE: Eating disorders (ED) are prevalent, serious illnesses with elevated mortality, mainly attributable to suicide. Predictors of suicidality include binge/purge symptomatology, impulsivity, and psychiatric comorbidity, as well as personality factors. Recent research has also shown self-image (the Structural Analysis of Social Behavior, SASB, model) to predict manifest suicide attempts in ED, and the study explored suicide risk prediction to increase knowledge of warning signs and intervention targets. METHOD: Participants were adult ED patients registered in the Stepwise clinical database (N = 1537) with anorexia nervosa (AN), bulimia nervosa (BN), binge-eating disorder (BED), or other specified feeding and eating disorder (OSFED). The SASB self-image questionnaire was used in stepwise regressions to predict 12-month suicidal ideation, both self and clinician-rated, in models both excluding and including baseline clinical variables. RESULTS: Validation analyses showed fair correspondence between outcome variables as well as with suicide attempts. Different variables predicted suicidality in different diagnoses, over and above baseline clinical variables in all but one regression model. Low Self-protection was important in AN and BN, high Self-control in AN, and high Letting go of the self in BN. For BED, self blame explained variance, and in OSFED, lack of self-love. DISCUSSION: Findings are in line with research showing differential self-image-based prediction of important outcomes in ED, with noteworthy consistencies across diagnoses and suicidality variables. Strengths included the large sample, and limitations pertained to measures, attrition and Type II error risk. Replication is needed, but findings are consistent with some previous work and offers clinical and research implications. PMID- 28580648 TI - Paired Associative Stimulation Delivered by Pairing Movement-Related Cortical Potentials With Peripheral Electrical Stimulation: An Investigation of the Duration of Neuromodulatory Effects. AB - BACKGROUND: Novel paired associative stimulation (novel-PAS), delivered by pairing movement-related cortical potentials (MRCPs) with electrical stimulation of somatosensory afferents, is an innovative neuromodulatory intervention. Novel PAS results in increased corticomotor excitability and has potential as a rehabilitative adjunct to improve outcomes following stroke. The duration of its excitatory effect has important implications for how this novel PAS intervention might be applied within a traditional therapy session, but previous research has not explored its effects beyond 30 min post-intervention. OBJECTIVE: The objective was to explore changes in corticomotor excitability in healthy participants, over a 60-min period following a single session of novel-PAS. MATERIALS AND METHOD: Ten healthy adults completed a single session of novel-PAS, delivered by pairing 50 MRCPs with peripheral electrical stimulation. TMS was used to elicit motor evoked potentials (MEPs) of the tibialis anterior (TA) muscle, immediately prior to the intervention, and at 0, 30, 45, and 60 min post intervention. RESULTS: When compared with pre-intervention, there was a statistically significant increase in the mean TA MEP amplitudes at 0 (p = 0.006), 30 (p = 0.006), 45 (p = 0.027), and 60 min post-intervention (p = 0.020). CONCLUSION: Corticomotor excitability is increased for 60 min following this novel-PAS intervention. Future research could investigate the optimal method of combining this neuromodulatory technique with traditional therapy. PMID- 28580649 TI - Myeloperoxidase-antineutrophil cytoplasmic antibody causes different renal diseases by immune-complex formation and pauci-immune mechanism: A case report. AB - Antineutrophil cytoplasmic antibody (ANCA) has been known to cause pauci-immune crescentic glomerulonephritis. In addition, several reports described membranous glomerulonephritis (MN) concurrent with ANCA-associated glomerulonephritis. Because the two glomerular diseases simultaneously appear in an ANCA-positive patient, the mechanisms whereby ANCA causes the two different glomerular diseases remain ambiguous. Herein, we report a case of 19-year-old man who presented with hematuria, pre-nephrotic proteinuria, and high titer of myeloperoxidase (MPO) ANCA. The first renal biopsy revealed MN with chronic glomerular scar lesions of unknown etiology. Predominant immunoglobulin (Ig) G1 subclass and negative phospholipase-A2 receptor staining, together with granular-positive glomerular capillary co-localization of MPO and IgG staining, suggested secondary MN due to MPO-MPO-ANCA immune-complex. Five years later, the patient presented with fever, severe renal dysfunction, and alveolar hemorrhage with high titer of MPO-ANCA that indicated pulmonary renal syndrome due to ANCA-associated vasculitis. The second renal biopsy revealed pauci-immune crescentic glomerulonephritis without either apparent MN-lesion or glomerular IgG staining. This is the first reported case showing that MPO-ANCA caused two different glomerular diseases, MN and pauci immune crescentic glomerulonephritis, in the same patient at the different time points. Our case indicated that common MPO-ANCA might cause different glomerular diseases by different immune mechanisms. PMID- 28580650 TI - Maternal near-misses at a provincial hospital in Papua New Guinea: A prospective observational study. AB - BACKGROUND: Maternal near-miss indices are World Health Organisation (WHO) recognised indicators that may improve our understanding of factors associated with maternal morbidity and mortality. In Papua New Guinea (PNG) where maternal mortality is among the highest in the world, only one study has documented near miss indices in a tertiary-level hospital, but none from provincial hospitals where the majority of under-privileged women access healthcare services. AIMS: To determine the near-miss ratio, maternal mortality index (MMI), and associated maternal indices for Modilon Hospital in Madang Province of PNG. METHODS: All women attending Modilon Hospital who met the WHO maternal near-miss definition and/or a WHO-modified (PNG-specific) near-miss definition, were prospectively enrolled. RESULTS: There were 6019 live births during the audit period; 163 women presented with life-threatening conditions (153 near-misses and 10 maternal deaths). The maternal near-miss ratio was 25.4/1000 live births and the maternal mortality ratio (MMR) was 166/100 000 live births, with a maternal death to near miss ratio of 1:15.3. The severe maternal outcome ratio was 27.1/1000 live births and the total mortality index was 6.8%. Higher proportions of near-miss women were aged >=30 years, nulliparous, illiterate, from rural communities, lacked formal employment, referred from peripheral health facilities, unbooked, had history of still births and were anaemic. CONCLUSION: Sociodemographic factors such as women's rights, education level and status in society, in addition to appropriate health reforms with greater financial and political support are urgently needed to ensure underprivileged women in rural PNG have access to family planning, supervised deliveries and skilled emergency obstetric care. PMID- 28580651 TI - Data fabrication and other reasons for non-random sampling in 5087 randomised, controlled trials in anaesthetic and general medical journals. AB - Randomised, controlled trials have been retracted after publication because of data fabrication and inadequate ethical approval. Fabricated data have included baseline variables, for instance, age, height or weight. Statistical tests can determine the probability of the distribution of means, given their standard deviation and the number of participants in each group. Randomised, controlled trials have been retracted after the data distributions have been calculated as improbable. Most retracted trials have been written by anaesthetists and published by specialist anaesthetic journals. I wanted to explore whether the distribution of baseline data in trials was consistent with the expected distribution. I wanted to determine whether trials retracted after publication had distributions different to trials that have not been retracted. I wanted to determine whether data distributions in trials published in specialist anaesthetic journals have been different to distributions in non-specialist medical journals. I analysed the distribution of 72,261 means of 29,789 variables in 5087 randomised, controlled trials published in eight journals between January 2000 and December 2015: Anaesthesia (399); Anesthesia and Analgesia (1288); Anesthesiology (541); British Journal of Anaesthesia (618); Canadian Journal of Anesthesia (384); European Journal of Anaesthesiology (404); Journal of the American Medical Association (518) and New England Journal of Medicine (935). I chose these journals as I had electronic access to the full text. Trial p values were distorted by an excess of baseline means that were similar and an excess that were dissimilar: 763/5015 (15.2%) trials that had not been retracted from publication had p values that were within 0.05 of 0 or 1 (expected 10%), that is, a 5.2% excess, p = 1.2 * 10-7 . The p values of 31/72 (43%) trials that had been retracted after publication were within 0.05 of 0 or 1, a rate different to that for unretracted trials, p = 1.03 * 10-10 . The difference between the distributions of these two subgroups was confirmed by comparison of their overall distributions, p = 5.3 * 10-15 . Each journal exhibited the same abnormal distribution of baseline means. There was no difference in distributions of baseline means for 1453 trials in non-anaesthetic journals and 3634 trials in anaesthetic journals, p = 0.30. The rate of retractions from JAMA and NEJM, 6/1453 or 1 in 242, was one-quarter the rate from the six anaesthetic journals, 66/3634 or 1 in 55, relative risk (99%CI) 0.23 (0.08-0.68), p = 0.00022. A probability threshold of 1 in 10,000 identified 8/72 (11%) retracted trials (7 by Fujii et al.) and 82/5015 (1.6%) unretracted trials. Some p values were so extreme that the baseline data could not be correct: for instance, for 43/5015 unretracted trials the probability was less than 1 in 1015 (equivalent to one drop of water in 20,000 Olympic-sized swimming pools). A probability threshold of 1 in 100 for two or more trials by the same author identified three authors of retracted trials (Boldt, Fujii and Reuben) and 21 first or corresponding authors of 65 unretracted trials. Fraud, unintentional error, correlation, stratified allocation and poor methodology might have contributed to the excess of randomised, controlled trials with similar or dissimilar means, a pattern that was common to all the surveyed journals. It is likely that this work will lead to the identification, correction and retraction of hitherto unretracted randomised, controlled trials. PMID- 28580652 TI - Transfer of ochratoxin A from raw black tea to tea infusions prepared according to the Turkish tradition. AB - BACKGROUND: Ochratoxin A (OTA) is a natural contaminant of food including tea with multiple toxic effects, which poses a threat to human health. In terms of lifestyle, the Turkish population is a frequent visitor of tearooms, and the traditional Turkish tea preparation is one of the most popular ways of preparing tea infusion. RESULTS: The aim of this study was to investigate OTA transfer from raw black tea to the tea infusion prepared according to the Turkish tradition. A high-performance liquid chromatography method with a limit of quantification of 0.35 ng g-1 was used for OTA determination. The OTA amount in raw black teas from Turkey ranged from <=0.35 ng g-1 up to 56.7 ng g-1 . An homogenised sample of black tea naturally contaminated with 55.0 ng g-1 was used to prepare infusions. The OTA transfer from the black tea to the infusion was found to be 41.5% +/- 7%. CONCLUSION: These data are important for the realisation of a 'Total Diet study' (TDS). The TDS can be a complementary tool to estimate the population dietary exposure to OTA across the entire diet by analysing main foods prepared 'as consumed' (tea infusions) and not 'as purchased' (raw tea). (c) 2017 Society of Chemical Industry. PMID- 28580653 TI - Porokeratosis ptychotropica responding to photodynamic therapy: An alternative treatment for a refractory disease. AB - BACKGROUND: Porokeratosis ptychotropica (PP) is a rare variant of porokeratosis with a special predisposition to affect body folds, particularly the intergluteal cleft. This disease is resistant to most topical and systemic treatments, as shown in the review of the literature we provide here. Itching and discomfort are often a difficult problem to solve. PATIENTS AND METHODS: Two patients with PP that had not responded to multiple topical treatments were treated with photodynamic therapy (PDT). Changes in plaque size, thickness and symptoms were assessed after treatment. RESULTS: Pruritus disappearance was observed in both patients after treatment with PDT. Partial clearance of the plaques was observed in one case. In the other case, a moderate clearance of hyperkeratosis was observed, although the size of the lesions persisted unchanged. CONCLUSIONS: PDT seems to be a good therapeutic alternative in the treatment of PP, as it can provide symptomatic relief and clinical improvement of the lesions. However, it does not appear to be a curative treatment. Moreover, long-term response is still unknown. PMID- 28580654 TI - A prospective randomized controlled trial of two-window versus solo-window technique by lateral sinus floor elevation in atrophic posterior maxilla: Results from a 1-year observational phase. AB - BACKGROUND: Implant failures are more common when multiple missing posterior teeth need lateral sinus floor elevation owing to inadequate tissue maturation after grafting. Effects of lateral window dimensions on vital bone formation have rarely been compared. PURPOSE: To compare endo-sinus bone formation between two- and solo-window techniques to rehabilitate multiple missing posterior teeth that need substantial augmentation. METHODS AND MATERIALS: Patients with severely atrophic posterior maxilla were randomized to receive lateral sinus floor elevation via solo or two bony windows. Bone core specimens harvested from lateral aspect of the augmentation sites were histomorphometrically analyzed. Proportions of mineralized bone (MB), bone substitute materials (BS), and nonmineralized tissue (NMT) were quantified. RESULTS: Twenty-one patients underwent 23 maxillary sinus augmentations. One patient in each group dropped out during the follow-up period. Lateral window dimensions were 81.65 +/- 4.59 and 118.04 +/- 19.53 mm2 in the test and control groups, respectively. Histomorphometric analysis revealed mean MB of 42.32% +/- 13.07% and 26.00% +/- 15.23%, BS of 40.34% +/- 9.52% and 60.03% +/- 10.13%, and NMT of 18.14% +/- 14.24% and 14.75% +/- 10.38% in test and control groups, respectively, with significant differences. CONCLUSION: The two-window technique could facilitate faster maturation and consolidation of the grafted volume and is an effective alternative for rehabilitation of severely atrophic posterior maxilla with multiple missing posterior teeth. PMID- 28580657 TI - Widening the search for suspect data - is the flood of retractions about to become a tsunami? PMID- 28580655 TI - A quantitative assay for Amaranthus palmeri identification. AB - BACKGROUND: Amaranthus palmeri recently has been brought into the Midwestern USA as a contaminant in Conservation Reserve Program seeding mixes. Rapid species screening is required to mitigate the risk of continued species movement. RESULTS: Markers were developed for A. palmeri-specific nucleotide polymorphisms in the internal transcribed spacer of the ribosomal coding region. A quantitative polymerase chain reaction (qPCR) assay successfully identified A. palmeri from single-plant samples, simulated mixed-plant samples and seed mixtures. CONCLUSION: A qPCR assay for distinguishing A. palmeri from 12 other Amaranthus spp. was developed and validated. The assay can consistently detect a single A. palmeri seed when present in a pool of 100 total Amaranthus spp. seeds. (c) 2017 Society of Chemical Industry. PMID- 28580656 TI - Prepartum Psychosis and Neonaticide: Rare Case Study and Forensic-Psychiatric Synthesis of Literature. AB - Peripartum psychosis is a rare but serious psychiatric disorder characterized by the presence of a mood episode with psychotic features. Although controversy surrounds the nosological status of peripartum mental disorders, these conditions continue to be of exceptional interest to the medical and forensic mental health communities. The aim of this study was to report a rare case of prepartum psychosis which escalated to the endpoint of neonaticide and summarize literature on peripartum mental disorders and infanticide. A 30-year-old mother murdered her newborn with the spike of her serum delivery system and planned to commit suicide while in hospital after hallucinating due to an acute puerperal psychotic disorder with a prepartum onset and postpartum deterioration. Her disorder was not managed until neonaticide. Throughout this paper, the significance of a multidisciplinary approach for the optimal management of these incidents is highlighted and diagnostic as well as therapeutic issues are addressed. PMID- 28580658 TI - Improvement in perioperative care in pediatric cardiac surgery by shifting the primary focus of treatment from cardiac output to perfusion pressure: Are beta stimulants still needed? AB - OBJECTIVE: An important aspect of perioperative care in pediatric cardiac surgery is maintenance of optimal hemodynamic status using vasoactive/inotropic agents. Conventionally, this has focused on maintenance of cardiac output rather than perfusion pressure. However, this approach has been abandoned in our center in favor of one focusing primarily on perfusion pressure, which is presented here and compared to the conventional approach. DESIGN: A retrospective study. SETTING: Regional center for congenital heart disease. University Hospital of Lausanne, Switzerland. PATIENTS: All patients with Aristotle risk score >=8 that underwent surgery from 1996 to 2012 were included. Patients operated between 1996 and 2005 (Group 1: 206 patients) were treated according to the conventional approach. Patients operated between 2006 and 2012 (Group 2: 217 patients) were treated according to our new approach. INTERVENTIONS: All patients had undergone surgery for correction or palliation of congenital cardiac defects. OUTCOME MEASUREMENTS: Mortality, duration of ventilation and inotropic treatment, use of ECMO, and complications of poor peripheral perfusion (need for hemofiltration, laparotomy for enterocolitis, amputation). RESULTS: The two groups were similar in age and complexity. Mortality was lower in group 2 (7.3% in group 1 vs 1.4% in group 2, P < .005). Ventilation times (hours) and number of days on inotropic/vasoactive treatment (all agents), expressed as median and interquartile range [Q1-Q3] were shorter in group 2: 69 [24-163] hours in group 1 vs 35 [22-120] hours in group 2 (P < .01) for ventilation, and 9 [3-5] days in group 1 vs 7 [2-5] days in group 2 (P < .05) for inotropic/vasoactive agents. There were no differences in ECMO usage or complications of peripheral perfusion. CONCLUSIONS: Results in pediatric cardiac surgery may be improved by shifting the primary focus of perioperative care from cardiac output to perfusion pressure. PMID- 28580659 TI - Ex vivo MRI evaluation of prostate cancer: Localization and margin status prediction of prostate cancer in fresh radical prostatectomy specimens. AB - PURPOSE: To investigate the ability of high field ex vivo magnetic resonance imaging (MRI) to localize prostate cancer (PCa) and to predict the margin status in fresh radical prostatectomy (RP) specimens using histology as the reference standard. MATERIALS AND METHODS: This Institutional Review Board (IRB)-approved study had written informed consent. Patients with biopsy-proved PCa and a diagnostic multiparametric 3T MRI examination of the prostate prior to undergoing RP were prospectively included. A custom-made container provided reference between the 7T ex vivo MRI obtained from fresh RP specimens and histological slicing. On ex vivo MRI, PCa was localized and the presence of positive surgical margins was determined in a double-reading session. These findings were compared with histological findings obtained from completely cut, whole-mount embedded, prostate specimens. RESULTS: In 12 RP specimens, histopathology revealed 36 PCa lesions, of which 17 (47%) and 20 (56%) were correlated with the ex vivo MRI in the first and second reading session, respectively. Nine of 12 (75%) index lesions were localized in the first session, in the second 10 of 12 (83%). Seven and 8 lesions of 11 lesions with Gleason score >6 and >0.5 cc were localized in the first and second session, respectively. In the first session none of the four histologically positive surgical margins (sensitivity 0%) and 9 of 13 negative margins (specificity 69%) were detected. In second session the sensitivity and specificity were 25% and 88%, respectively. CONCLUSION: Ex vivo MRI enabled accurate localization of PCa in fresh RP specimens, and the technique provided information on the margin status with high specificity. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:439-448. PMID- 28580660 TI - Long-term outcomes after aortic coarctation repair in Maltese patients: A population-based study. AB - OBJECTIVES: To investigate survival and freedom from reintervention after aortic coarctation repair in Maltese patients and to compare cardiovascular mortality in coarctation repair survivors with that in the general population. DESIGN: All 72 aortic coarctation patients with any type of repair, born by end-1997 and logged in the local database were included. Trends in timing and type of repair were determined by comparing patients born before and after 1985. Kaplan-Meier analyses of survival and reintervention-free survival were performed on the 59 repair survivors with complete follow-up data (mean follow-up 26.13 +/- 9.62 (range 1.05-44.55 years). Cardiovascular mortality in repair survivors was compared with that in 438 age- and sex-matched general Maltese controls. RESULTS: Patients born after 1985 underwent repair at a younger age (median age 0.18 vs 13.96 years; P < .001), with less patch aortoplasties in favor of end-to-end anastomosis or transcatheter stenting. Among the 59 long-term follow-up patients, there were 7 cardiovascular deaths and 10 patients needed reintervention. Estimated mean survival was 40.33 years (95% CI 37.71, 42.95) with a survival rate of 67.5% at 40 years from repair. Estimated mean reintervention-free survival was 38.13 years (95% CI 34.52, 41.75) with freedom from reintervention rate of 77% at 30 years. Patients repaired aged <10 years required earlier reintervention (estimated mean reintervention-free survival 35.12 years (95% CI 29.54, 40.71) vs 40.80 years (95% CI 37.16, 44.37); P = .04). There was an excess of cardiovascular deaths among repaired coarctation subjects compared to the general population (11.9% vs 1.4%; P < .001) and survival in coarctation patients was significantly lower (67.90 years (95% CI 60.28, 75.52) vs 85.78 years (95% CI 83.12, 88.44); P < .001). CONCLUSIONS: Despite earlier diagnosis and repair, contemporary coarctation repair survivors remain at increased risk of cardiovascular death. An important proportion require repair site reintervention. Specialist follow-up and aggressive cardiovascular risk factor management are mandatory to improve long-term outcomes. PMID- 28580662 TI - Development and Assessment of Postcranial Sex Estimation Methods for a Guatemalan Population. AB - This study tests whether postcranial sex estimation methods generated from Hispanic, and mainly Mexican samples, can be successfully applied to other increasingly common migrant populations from Central America. We use a sample of postcranial data from a modern (1980s) Guatemalan Maya sample (n = 219). Results indicate a decrease in classification accuracies for previously established univariate methods when applied to the Guatemalan study sample, specifically for males whose accuracies ranged from 30 to 84%. This bias toward inaccuracies for Guatemalan males is associated with the smaller skeletal sizes for the Guatemalan sample as compared to the samples used in the tested sex estimation methods. In contrast, the tested multivariate discriminant function classification yielded less sex bias and improved classification accuracies ranging from 82 to 89%. Our results highlight which of the tested univariate and multivariate methods reach acceptable levels for accuracy for sex estimation of cases where the region of origin may include Guatemala. PMID- 28580661 TI - B lymphocytes repress hepatic tumorigenesis but not development in Hras12V transgenic mice. AB - Increasing reports show noninflammation underlying HCC, challenging our understanding of the roles of the immune system in hepatocarcinogenesis. By exploring a mouse model of hepatic tumor induced by hepatocyte-specific expression of the Hras12V oncogene without obvious inflammation, we found that the proportion of B cells, but not T cells, progressively and significantly decreased in 3, 5-month-old transgenic mice (Tg) compared with non-transgenic mice. Notably, the proportions of total and activated B and T cells all significantly decreased in 9-month-old Tg with multiple massive hepatic tumors. Together with the decreased B cell proportion, serum IgG1/2 also significantly decreased in 5, 9-month-old Tg. Interestingly, homozygous Tg showed significantly higher B cell proportion and IgG2 levels, accompanied by significantly lower incidences of liver nodules but not adenomas and carcinomas compared with heterozygous Tg. Treatment of Tg with PCI-32765, a potent Bruton's tyrosine kinase (BTK) inhibitor for suppressing B cell proliferation and activation, significantly decreased the B cell proportion and IgG2 levels, accompanied by a significantly higher incidence of liver nodules, but had no effects on adenoma and carcinoma. Treatment of Tg with insulin-like growth factor 1 (IGF-1) significantly increased the B cell proportion and IgG2 levels, accompanied by a significantly lower incidence of liver nodules and carcinoma, but had no effects on adenoma. Conclusively, B cells and IgG2 may play important roles in suppressing hepatic tumorigenesis, but not development. In addition, hepatocyte specific expression of the ras oncogene may play roles in suppressing B cells, while developed hepatic tumors suppress both B and T cells. PMID- 28580663 TI - Autologous blood salvage in the era of patient blood management. AB - Almost 150 years after the first autologous blood transfusion was reported, intraoperative blood salvage has become an important method of blood conservation. The primary goal of autologous transfusion is to reduce or avoid allogeneic red blood cell transfusion and the associated risks and costs. Autologous salvaged blood does not result in immunological challenge and its consequences, provides a higher quality red blood cell that has not been subjected to the adverse effects of blood storage, and can be more cost-effective than allogeneic blood when used for carefully selected surgical patients. Cardiac, orthopaedic and vascular surgery procedures with large anticipated blood loss can clearly benefit from the use of cell salvage. There are safety concerns in cases with gross bacterial contamination. There are theoretical safety concerns in obstetrical and cancer surgery; however, careful cell washing as well as leucoreduction filters makes for a safer autologous transfusion in these circumstances. Further studies are needed to determine whether oncologic outcomes are impacted by transfusing salvaged blood during cancer surgery. In this new era of patient blood management, where multimodal methods of reducing dependence on allogeneic blood are becoming commonplace, autologous blood salvage remains a valuable tool for perioperative blood conservation. Future studies will be needed to best determine how and when cell salvage should be utilized along with newer blood conservation measures. PMID- 28580664 TI - Improving heart failure health: is there a secret Swedish sauce? PMID- 28580665 TI - Versatile Self-Assembly and Biosensing Applications of DNA and Carbon Quantum Dots Coordinated Cerium Ions. AB - Self-assembly exploits noncovalent interactions to offer a facile and effective method for the construction of soft materials with multifunctionalities and diversity. In this work, fluorescence carbon quantum dots coordinated by Ce3+ ions (CQDCe) have been synthesized and exploited as building blocks to generate a series of hierarchical structures through the ionic self-assembly of CQDCe and biomolecules, namely DNA, myoglobin (Mb), and hyaluronic acid (HA). In particular, vesicles can be constructed by the simple mixing of oppositely charged CQDCe and DNA in water. The formation of unusual vesicles can be explained by the self-assembly of CQDCe with a rearranged structure and the rigid DNA biomolecular scaffolds. This facile noncovalent self-assembly method has inspired the innovative use of virgin DNA as a building block to construct vesicles rather than resorting to a sophisticated synthesis. The self-assembly of CQDCe-biopolymers was accompanied by aggregation-induced photoluminescence (PL) quenching. The biosensing platform was designed to detect polypeptides and deoxyribonuclease I through competitive binding of CQDCe and enzymatic hydrolysis of the DNA backbone, respectively. We believe that the integrative self-assembly of CQDCe and DNA will enrich the theoretical study of vesicle formation by DNA molecules and extend the application of fluorescence carbon quantum dots in the biological field. PMID- 28580667 TI - Compressed perovskite aqueous mixtures near their phase transitions show very high permittivities: New prospects for high-field MRI dielectric shimming. AB - PURPOSE: Perovskites are greatly used nowadays in many technological applications because of their high permittivity, more specifically in the form of aqueous solutions, for MRI dielectric shimming. In this study, full dielectric characterizations of highly concentrated CaTiO3 /BaTiO3 water mixtures were carried out and new permittivity maxima was reached. METHODS: Permittivity measurements were done on aqueous solutions from 0%v/v to dry powder. The permittivity dependence with pressure was investigated. Scanning electron microscopy images were performed on a few representative solutions. BaTiO3 pressed pads of different thicknesses, permittivities, and distances to the head were compared in a 7T MRI scanner. RESULTS: Perovskite aqueous mixtures undergo a pressure-dependent phase transition in terms of permittivity, with increasing water content. A new relative permittivity maximum of 475 was achieved. Microscopic images revealed structural differences between phases. A B1+ improvement in the temporal lobe was obtained with thin, high permittivity BaTiO3 head. CONCLUSIONS: This new preparation method allows improved pad geometry and placement, as a result of the high relative permittivity values achieved. This method has great significance for medical applications of MRI dielectric shimming, being easy to replicate and implement on a large scale. Magn Reson Med 79:1753-1765, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 28580668 TI - Changes in Physical Activity in the School, Afterschool, and Evening Periods During the Transition From Elementary to Middle School. AB - BACKGROUND: We examined longitudinal changes in children's physical activity during the school day, afterschool, and evening across fifth, sixth, and seventh grades. METHODS: The analytical sample included children who had valid accelerometer data in fifth grade and at least one other time-point, and provided complete sociodemographic information (N = 768, 751, and 612 for the 3 time periods studied). Accelerometer-derived total physical activity (TPA) and moderate-to-vigorous physical activity (MVPA) were expressed in minutes per hour for the school day (~7:45 am to 3:30 pm), afterschool (~2:25 to 6:00 pm), and evening (6:00 to 10:00 pm) periods. We used growth curve analyses to examine changes in TPA and MVPA. RESULTS: School day TPA and MVPA declined significantly; we observed a greater decrease from fifth to sixth grades than from sixth to seventh grades. Afterschool TPA declined significantly, but MVPA increased significantly among girls and remained stable for boys. Evening TPA decreased significantly and MVPA declined significantly in girls and remained stable among boys. CONCLUSIONS: To inform the development of effective intervention strategies, research should focus on examining factors associated with the decline in physical activity during the transition from elementary to middle school, particularly during the hours when children are in school. PMID- 28580670 TI - Erratum. PMID- 28580666 TI - Connexins and pannexins: At the junction of neuro-glial homeostasis & disease. AB - In the central nervous system (CNS), connexin (Cx)s and pannexin (Panx)s are an integral component of homeostatic neuronal excitability and synaptic plasticity. Neuronal Cx gap junctions form electrical synapses across biochemically similar GABAergic networks, allowing rapid and extensive inhibition in response to principle neuron excitation. Glial Cx gap junctions link astrocytes and oligodendrocytes in the pan-glial network that is responsible for removing excitotoxic ions and metabolites. In addition, glial gap junctions help constrain excessive excitatory activity in neurons and facilitate astrocyte Ca2+ slow wave propagation. Panxs do not form gap junctions in vivo, but Panx hemichannels participate in autocrine and paracrine gliotransmission, alongside Cx hemichannels. ATP and other gliotransmitters released by Cx and Panx hemichannels maintain physiologic glutamatergic tone by strengthening synapses and mitigating aberrant high frequency bursting. Under pathological depolarizing and inflammatory conditions, gap junctions and hemichannels become dysregulated, resulting in excessive neuronal firing and seizure. In this review, we present known contributions of Cxs and Panxs to physiologic neuronal excitation and explore how the disruption of gap junctions and hemichannels lead to abnormal glutamatergic transmission, purinergic signaling, and seizures. PMID- 28580669 TI - Implementing and Evaluating Environmental and Policy Interventions for Promoting Physical Activity in Rural Schools. AB - BACKGROUND: Schools are an important setting for improving behaviors associated with obesity, including physical activity. However, within schools there is often a tension between spending time on activities promoting academic achievement and those promoting physical activity. METHODS: A community-based intervention provided administrators and teachers with a training on evidence-based public health and then collaborated with them to identify and implement environmental (walking track) and local school policy interventions (brain breaks). The evaluation included conducting in-depth interviews and SOPLAY observations to assess the facilitators and barriers and impact of the dissemination of environmental and policy changes. RESULTS: Individual, organizational, intervention, and contextual factors influenced dissemination. Teachers reported that brain breaks increased student focus and engagement with classroom material and decreased student behavioral problems. Students decreased sedentary behavior and increased vigorous behavior. Of the 4 schools, 2 increased walking. CONCLUSIONS: Active dissemination of environmental and policy interventions by engaging school administrators and teachers in planning and implementation shows potential for increasing physical activity in rural school settings. PMID- 28580671 TI - Student Voices: Perspectives on Peer-to-Peer Sexual Health Education. AB - BACKGROUND: This process study is a companion to a randomized evaluation of a school-based, peer-led comprehensive sexual health education program, Teen Prevention Education Program (Teen PEP), in which 11th- and 12th-grade students are trained by school health educators to conduct informative workshops with ninth-grade peers in schools in North Carolina. The process study was designed to understand youth participants' perspectives on the program in order to gain insight into program effectiveness. METHODS: This is a mixed-methods study in 7 schools, with online surveys (N = 88) and 8 focus groups with peer educators (N = 116), end-of-program surveys (N = 1122), 8 focus groups with ninth-grade workshop participants (N = 89), and observations of the Teen PEP class and workshops during the semester of implementation in each school, 2012-2014. RESULTS: Both peer educators and ninth graders perceived benefits of participating in Teen PEP across a range of domains, including intentions, skills, and knowledge and that the peer education modality was important in their valuation of the experience. CONCLUSIONS: Our findings suggest that the peer-led comprehensive sexual health education approach embodied in Teen PEP can be an important educational mechanism for teaching students information and skills to promote sexual health. PMID- 28580673 TI - Evaluation of Unintended Social and Economic Consequences of an Unplanned School Closure in Rural Illinois. AB - BACKGROUND: School closure is one of the primary measures considered during severe influenza pandemics and other emergencies. However, prolonged school closures may cause unintended adverse consequences to schools, students, and their families. A better understanding of these consequences will inform prepandemic planning, and help public health and education authorities in making informed decisions when considering school closures. METHODS: We conducted a household survey and interviewed school officials following an 8-day long closure of a school district in rural Illinois. We described household responses regarding difficulties of school closure, and summarized main themes from school official interviews. RESULTS: A total of 208 (27%) household surveys were completed and returned. This school closure caused difficulties to 36 (17%) households; uncertain duration of closure, childcare arrangements, and lost pay were the most often reported difficulties. Having 1 adult in the household losing pay and household income below $25,000 were significantly associated with overall difficulty during this school closure. Concern about student health and safety was the most frequent theme in school administrator interviews. CONCLUSIONS: Whereas the majority of responding households did not report difficulties during this school closure, households with 1 adult losing pay during the closure reported incurring additional expenses for childcare. PMID- 28580672 TI - Implementation of a Computerized Tablet-Survey in an Adolescent Large-Scale, School-Based Study. AB - BACKGROUND: Computerized surveys present many advantages over paper surveys. However, school-based adolescent research questionnaires still mainly rely on paper-and-pencil surveys as access to computers in schools is often not practical. Tablet-assisted self-interviews (TASI) present a possible solution, but their use is largely untested. This paper presents a method for and our experiences with implementing a TASI in a school setting. METHODS: A TASI was administered to 3907 middle and high school students from 79 schools. The survey assessed use of tobacco products and exposure to tobacco marketing. To assess in depth tobacco use behaviors, the TASI employed extensive skip patterns to reduce the number of not-applicable questions that nontobacco users received. Pictures were added to help respondents identify the tobacco products they were being queried about. RESULTS: Students were receptive to the tablets and required no instructions in their use. None were lost, stolen, or broken. Item nonresponse, unanswered questions, was a pre-administration concern; however, 92% of participants answered 96% or more of the questions. CONCLUSIONS: This method was feasible and successful among a diverse population of students and schools. It generated a unique dataset of in-depth tobacco use behaviors that would not have been possible through a paper-and-pencil survey. PMID- 28580674 TI - Food Availability in School Stores in Seoul, South Korea After Implementation of Food- and Nutrient-Based Policies. AB - BACKGROUND: To improve school store food environments, the South Korean government implemented 2 policies restricting unhealthy food sales in school stores. A food-based policy enacted in 2007 restricts specific food sales (soft drinks); and a nutrient-based policy enacted in 2009 restricts energy-dense and nutrient-poor (EDNP) food sales. The purpose of the study was to assess how the 2 policies have changed the school store food environment. METHODS: Foods sold in school stores in Seoul, South Korea were observed before (2006, 15 stores) and after (2013, 12 stores) implementation of the school store policies. Food availability in school stores in 2006 and 2013 was compared and EDNP food availability in 2013 was examined. RESULTS: When controlling the total number of foods sold in school stores and school characteristics, the mean number of soft drinks sold in a school store in 2013 (0.3 items) was significantly lower than in 2006 (1.9 items, p = .032). Soft drinks were still available in 50% of school stores observed in 2013, with all school stores selling EDNP foods in 2013. CONCLUSIONS: South Korean policies have had a modest influence on availability of unhealthy school store foods. Alternative strategies to improve school store food environments are needed. PMID- 28580675 TI - School Nurse-Delivered Adolescent Relationship Abuse Prevention. AB - BACKGROUND: Project Connect is a national program to build partnerships among public health agencies and domestic violence services to improve the health care sector response to partner and sexual violence. Pennsylvania piloted the first school nurse-delivered adolescent relationship abuse intervention in the certified school nurses' office setting. The purpose of this study was to assess the feasibility of implementing this prevention intervention. METHODS: In 5 schools in Pennsylvania, school nurses completed a survey before and 1 year after receiving training on implementing the intervention as well as a phone interview. Students seeking care at the nurses' offices completed a brief anonymous feedback survey after their nurse visit. RESULTS: The school nurses adopted the intervention readily, finding ways to incorporate healthy relationship discussions into interactions with students. School nurses and students found the intervention to be acceptable. Students were positive in their feedback. Barriers included difficulty with school buy-in and finding time and private spaces to deliver the intervention. CONCLUSIONS: A school nurse healthy relationships intervention was feasible to implement and acceptable to the students as well as the implementing nurses. While challenges arose with the initial uptake of the program, school nurses identified strategies to achieve school and student support for this intervention. PMID- 28580676 TI - Educational Outcomes Associated With School Behavioral Health Interventions: A Review of the Literature. AB - BACKGROUND: There is an unmet need for behavioral health support and services among children and adolescents, which school behavioral health has the potential to address. Existing reviews and meta-analyses document the behavioral health benefits of school behavioral health programs and frameworks, but few summaries of the academic benefits of such programs exist. We provide exemplars of the academic benefits of school behavioral health programs and frameworks. METHODS: A literature review identified school behavioral health-related articles and reports. Articles for inclusion were restricted to those that were school-based programs and frameworks in the United States that included an empirical evaluation of intervention academic-related outcomes. RESULTS: Findings from 36 primary research, review, and meta-analysis articles from the past 17 years show the benefits of school behavioral health clinical interventions and targeted interventions on a range of academic outcomes for adolescents. CONCLUSION: Our findings are consistent with reports documenting health benefits of school behavioral health frameworks and programs and can facilitate further efforts to support school behavioral health for a range of stakeholders interested in the benefits of school behavioral health programs and frameworks on academic outcomes. PMID- 28580678 TI - Performance Enhancement of a Sulfur/Carbon Cathode by Polydopamine as an Efficient Shell for High-Performance Lithium-Sulfur Batteries. AB - Lithium-sulfur batteries (LSBs) are considered to be among the most promising next-generation high-energy batteries. It is a consensus that improving the conductivity of sulfur cathodes and impeding the dissolution of lithium polysulfides are two key accesses to high-performance LSBs. Herein we report a sulfur/carbon black (S/C) cathode modified by self-polymerized polydopamine (pDA) with the assistance of polymerization treatment. The pDA acts as a novel and effective shell on the S/C cathode to stop the shuttle effect of polysulfides. By the synergistic effect of enhanced conductivity and multiple blocking effect for polysulfides, the S/C@pDA electrode exhibits improved electrochemical performances including large specific capacity (1135 mAh g-1 at 0.2 C), high rate capability (533 mAh g-1 at 5 C) and long cyclic life (965 mAh g-1 after 200 cycles). Our smart design strategy may promote the development of high performance LSBs. PMID- 28580677 TI - LGBTQ Youth's Views on Gay-Straight Alliances: Building Community, Providing Gateways, and Representing Safety and Support. AB - BACKGROUND: Gay-Straight Alliances (GSAs) are school-based clubs that can contribute to a healthy school climate for lesbian, gay, bisexual, transgender, and questioning (LGBTQ) youth. While positive associations between health behaviors and GSAs have been documented, less is known about how youth perceive GSAs. METHODS: A total of 58 LGBTQ youth (14-19 years old) mentioned GSAs during go-along interviews in 3 states/provinces in North America. These 446 comments about GSAs were thematically coded and organized using Atlas.ti software by a multidisciplinary research team. RESULTS: A total of 3 themes describe youth perceived attributes of GSAs. First, youth identified GSAs as an opportunity to be members of a community, evidenced by their sense of emotional connection, support and belonging, opportunities for leadership, and fulfillment of needs. Second, GSAs served as a gateway to resources outside of the GSA, such as supportive adults and informal social locations. Third, GSAs represented safety. CONCLUSIONS: GSAs positively influence the physical, social, emotional, and academic well-being of LGBTQ young people and their allies. School administrators and staff are positioned to advocate for comprehensive GSAs. Study findings offer insights about the mechanisms by which GSAs benefit youth health and well-being. PMID- 28580679 TI - DichroMatch at the protein circular dichroism data bank (DM@PCDDB): A web-based tool for identifying protein nearest neighbors using circular dichroism spectroscopy. AB - Circular dichroism spectroscopy is a well-used, but simple method in structural biology for providing information on the secondary structure and folds of proteins. DichroMatch (DM@PCDDB) is an online tool that is newly available in the Protein Circular Dichroism Data Bank (PCDDB), which takes advantage of the wealth of spectral and metadata deposited therein, to enable identification of spectral nearest neighbors of a query protein based on four different methods of spectral matching. DM@PCDDB can potentially provide novel information about structural relationships between proteins and can be used in comparison studies of protein homologs and orthologs. PMID- 28580680 TI - Different drinking motives, different adverse consequences? Evidence among adolescents from 10 European countries. AB - INTRODUCTION AND AIM: This study, which builds on previous research demonstrating that drinking motives are associated with adverse consequences, investigates the associations between drinking motives and non-alcohol-attributed adverse consequences and disentangles alcohol-related and direct effects. DESIGN AND METHOD: On the basis of a sample of 22 841 alcohol-using 13- to 16-year-olds (50.6% female) from Belgium, Denmark, Estonia, Finland, Ireland, Portugal, Scotland, Slovakia, Switzerland and Wales, structural equation models were used to estimate direct and indirect effects. Additionally, differences across countries were tested in a multigroup analysis. RESULTS: The indirect effect (via alcohol use) was greater for injuries and academic problems than for more general outcomes such as life dissatisfaction and negative body image. For social, enhancement and coping motives, we found positive indirect effects (via alcohol use) on injuries and academic problems; the association was negative for conformity motives. The direct effect, that is, the effect above and beyond alcohol use, indicated more negative consequences among those who tended to drink more frequently for coping motives. More negative consequences, such as injuries and negative body image, were also found among those who drink for conformity motives. The pattern of association was largely comparable across countries. DISCUSSION AND CONCLUSION: While the actual mean level of drinking motives, alcohol use and adverse consequence varied across countries, the consistency of association patterns implies that drinking motive-inspired health promotion efforts are likely to be beneficial across Europe. This is particularly important for coping drinkers because they are especially prone to adverse consequences over and above their alcohol use. [Wicki M, Kuntsche E, Eichenberger Y, Aasvee K, Bendtsen P, Dankulincova Veselska Z, Demetrovics Z, Dzielska A, Farkas J, de Matos MG, Roberts C, Tynjala J, Valimaa R, Vieno A. Different drinking motives, different adverse consequences? Evidence among adolescents from 10 European countries. PMID- 28580682 TI - Decoding the association between herpes simplex virus and antibody-mediated encephalitis. PMID- 28580681 TI - Recently learned foreign abstract and concrete nouns are represented in distinct cortical networks similar to the native language. AB - In the native language, abstract and concrete nouns are represented in distinct areas of the cerebral cortex. Currently, it is unknown whether this is also the case for abstract and concrete nouns of a foreign language. Here, we taught adult native speakers of German 45 abstract and 45 concrete nouns of a foreign language. After learning the nouns for 5 days, participants performed a vocabulary translation task during functional magnetic resonance imaging. Translating abstract nouns in contrast to concrete nouns elicited responses in regions that are also responsive to abstract nouns in the native language: the left inferior frontal gyrus and the left middle and superior temporal gyri. Concrete nouns elicited larger responses in the angular gyri bilaterally and the left parahippocampal gyrus than abstract nouns. The cluster in the left angular gyrus showed psychophysiological interaction (PPI) with the left lingual gyrus. The left parahippocampal gyrus showed PPI with the posterior cingulate cortex. Similar regions have been previously found for concrete nouns in the native language. The results reveal similarities in the cortical representation of foreign language nouns with the representation of native language nouns that already occur after 5 days of vocabulary learning. Furthermore, we showed that verbal and enriched learning methods were equally suitable to teach foreign abstract and concrete nouns. Hum Brain Mapp 38:4398-4412, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28580683 TI - Simple method to assess stability of immobilized peptide ligands against proteases. AB - Although peptides are used as affinity chromatography ligands, they could be digested by proteases. Usually, peptide stability is evaluated in solution, which differs from the resin-bounded peptide behavior. Furthermore, the study of the degradation products requires purification steps before analysis. Here, we describe an easy method to assess immobilized peptide stability. Sample peptides were synthesized on hydroxymethylbenzamide-ChemMatrix resin. Peptidyl-resin beads were then incubated with solutions containing proteases. Peptides were detached from the solid support with ammonia vapor and analyzed by matrix-assisted laser desorption/ionization and electrospray ionization mass spectrometry, allowing the detection of the whole peptides as well as their C-terminal degradation products. The method allowed a fast evaluation of peptide ligand stability in solid phase towards proteases that may be present in the crude sample before their use as ligands in affinity chromatography. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28580684 TI - Nitrogen-Carbon Bond Formation by Reactions of a Titanium-Potassium Dinitrogen Complex with Carbon Dioxide, tert-Butyl Isocyanate, and Phenylallene. AB - Nitrogen-carbon bond-forming reactions at coordinated dinitrogen in a bifunctional titanium-potassium system are reported. A titanium atrane complex with a tris(aryloxide)methyl ligand (1) was treated with two equivalents of potassium naphthalenide under N2 atmosphere to generate a bifunctional complex (2) in which N2 binds end-on to two titanium centers and side-on to three potassium cations. Dinitrogen complex 2 reacted with carbon dioxide, tert-butyl isocyanate, and phenylallene, forming nitrogen-carbon bonds and affording diverse N-functionalized products. The reaction of 2 with CO2 followed by addition of Me3 SiCl resulted in the formation of the starting complex 1 with concomitant release of silylated carboxyl hydrazines while the reaction with two equivalents of tert butyl isocyanate proceeded by insertion into the Ti-N bonds. Treatment of 2 with phenylallene afforded vinyl-substituted hydrazido complexes. PMID- 28580686 TI - Use of skin biomarker profiles to distinguish Schnitzler syndrome from chronic spontaneous urticaria: results of a pilot study. PMID- 28580685 TI - YY1 Expression Is Sufficient for the Maintenance of Cardiac Progenitor Cell State. AB - During cardiac development, DNA binding transcription factors and epigenetic modifiers regulate gene expression in cardiac progenitor cells (CPCs). We have previously shown that Yin Yang 1 (YY1) is essential for the commitment of mesodermal precursors into CPCs. However, the role of YY1 in the maintenance of CPC phenotype and their differentiation into cardiomyocytes is unknown. In this study, we found, by genome-wide transcriptional profiling and phenotypic assays, that YY1 overexpression prevents cardiomyogenic differentiation and maintains the proliferative capacity of CPCs. We show further that the ability of YY1 to regulate CPC phenotype is associated with its ability to modulate histone modifications specifically at a developmentally critical enhancer of Nkx2-5 and other key cardiac transcription factor such as Tbx5. Specifically, YY1 overexpression helps to maintain markers of gene activation such as the acetylation of histone H3 at lysine 9 (H3K9Ac) and lysine 27 (H3K27Ac) as well as trimethylation at lysine 4 (H3K4Me3) at the Nkx2-5 cardiac enhancer. Furthermore, transcription factors associated proteins such as PoIII, p300, and Brg1 are also enriched at the Nkx2-5 enhancer with YY1 overexpression. The biological activities of YY1 in CPCs appear to be cell autonomous, based coculture assays in differentiating embryonic stem cells. Altogether, these results demonstrate that YY1 overexpression is sufficient to maintain a CPC phenotype through its ability to sustain the presence of activating epigenetic/chromatin marks at key cardiac enhancers. Stem Cells 2017;35:1913-1923. PMID- 28580690 TI - The Solvent Induced Inter-Dimensional Phase Transformations of Cobalt Zeolitic Imidazolate Frameworks. AB - Studying inter-dimensional phase transitions of zeolitic-imidazolate frameworks (ZIFs) is essential for developing strategies in controlling morphology and properties. Herein, the inter-dimensional topotactic phase transformations of 3D ZIF-67 to 2D ZIF-L are investigated in detail by employing a simple and efficient solvent-induced growth method. In addition to ZIF-67 and ZIF-L, a series of novel core-shell composites of ZIF-67@ZIF-L, with unprecedented morphologies, are also obtained and well-defined. The different behaviors of the amine hydrogen of 2-MIM in the solvents play a pivotal role for inter-dimensional phase transformations, and in combination with the concentration of 2-MIM, the 2D to 3D phase transformations are also revealed. The findings are very beneficial for morphological design of the ZIFs, along with exploration of the corresponding properties. Impressively, Co-ZIFs exhibit interesting tunable CO2 adsorption behaviors with the phase evolution, which might bring broader understanding for designing CO2 detection and adsorption devices. PMID- 28580688 TI - T-cell regulation through a basic suppressive mechanism targeting low-density lipoprotein receptor-related protein 1. AB - Cell adhesion is generally considered to depend on positive regulation through ligation of integrins and cytokine receptors. However, here we show that T-cell adhesion, and notably also T-cell receptor (TCR) -induced activation, are subject to constant suppression through shedding of low-density lipoprotein receptor related protein 1 (LRP1). The broad-spectrum metalloprotease inhibitor GM6001 abrogated shedding, so inducing prominent cell surface expression of LRP1 while enhancing TCR-induced activation and adhesion to beta1 and beta2 integrin ligands, hence arresting the cells. Integrin ligands also inhibited shedding but the effect was less potent than that of GM6001. Unlike GM6001, integrin ligands also induced cell surface expression of full-length thrombospondin-1 (TSP170) and TSP130, which associated with LRP1, and TSP110, which did not associate with LRP1. Cell surface expression of LRP1 and TSP130 were induced exclusively in adhering cells, expression of TSP110 preferentially in non-adhering cells and expression of TSP170 correlated with T-cell motility. The pro-adhesive chemokine CXCL12 also inhibited LRP1 shedding and induced surface expression of TSP170 and TSP130 while inhibiting TSP110. Exogenous TSP-1 and ligation of CD28 inhibited shedding although less effectively than GM6001, and the inhibition through CD28 was independent of TSP-1. Small interfering RNA silencing experiments confirmed involvement of LRP1 and TSP-1 in integrin-dependent adhesion and TCR-induced activation. Hence, the poor LRP1 expression in T cells depends on shedding. Integrin ligands and CXCL12 antagonize shedding through a TSP-1-dependent pathway and ligation of CD28 antagonizes shedding independent of TSP-1. The disappearance of LRP1 from the cell surface may provide basic immunosuppression at the T-cell level. PMID- 28580689 TI - High hydrostatic pressure processing affects the phenolic profile, preserves sensory attributes and ensures microbial quality of jabuticaba (Myrciaria jaboticaba) juice. AB - BACKGROUND: Jabuticaba (Myrciaria jaboticaba) is a Brazilian fruit rich in phenolic compounds and much appreciated for its sweet and slightly tangy taste. However, the high perishability of this fruit impairs its economic exploitation, creating an opportunity for the development of innovative products, such as high hydrostatic pressure (HHP) processed juices. We investigated the effect of HHP (200, 350 and 500 MPa for 5, 7.5 and 10 min) on phenolic compounds, antioxidant activity and microbiological quality of jabuticaba juice and the effect of the most effective HHP condition on its sensory acceptance. RESULTS: Pressurization increased total phenolic compound content (up to 38%) and antioxidant activity by FRAP assay (up to 46%), probably by increasing phenolic compound extractability due to tissue damage. Pressurization progressively decreased microbial counts, and colony growth was undetectable at pressures of 350 MPa or 500 MPa. With the exception of aroma, which was 10% lower in pressurized juice at 350 MPa for 7.5 min in relation to unprocessed juice, HHP did not affect sensory acceptance scores. CONCLUSION: Our results show that HHP was effective in ensuring microbiological quality, increasing bioactive potential and maintaining overall acceptance of jabuticaba juice, reinforcing the potential application of this processing technology in bioactive-rich foods. (c) 2017 Society of Chemical Industry. PMID- 28580687 TI - Theta- and delta-band EEG network dynamics during a novelty oddball task. AB - While the P3 component during target detection and novelty processing has been widely studied, less is known about its underlying network dynamics. A recent cognitive model suggests that frontal-parietal and frontal-temporal interregional connectivity are related to attention/action selection and target-related memory updating during the P3, respectively, but empirical work testing this model is lacking. Other work suggests the importance of theta- and delta-band connectivity between the medial frontal cortex and distributed cortical regions during attention, stimulus detection, and response selection processes, and similar dynamics may underlie P3-related network connectivity. The present study evaluated the functional connectivity elicited during a visual task, which combined oddball target and novelty stimuli, in a sample of 231 same-sex twins. It was hypothesized that both target and novel conditions would involve theta frontoparietal connectivity and medial frontal theta power, but that target stimuli would elicit the strongest frontotemporal connectivity. EEG time frequency analysis revealed greater theta-band frontoparietal connectivity and medial frontal power during both target and novel conditions compared to standards, which may index conflict/uncertainty resolution processes. Theta-band frontotemporal connectivity was maximal during the target condition, potentially reflecting context updating or stimulus-response activation. Delta-band frontocentral-parietal connectivity was also strongest following targets, which may be sensitive to response-related demands. These results suggest the existence of functional networks related to P3 that are differentially engaged by target oddballs and novel distractors. Compared to simple P3 amplitude, network measures may provide a more nuanced view of the neural dynamics during target detection/novelty processing in normative and pathological populations. PMID- 28580691 TI - Peptide microarray analysis of the cross-talk between O-GlcNAcylation and tyrosine phosphorylation. AB - O-GlcNAcylation of proteins regulates important cellular processes. A few reports noted that O-GlcNAcylation exhibits cross-talk with tyrosine phosphorylation. With an activity-based microarray analysis of 256 tyrosine kinase peptide substrates, we found that phosphorylation of six peptides by Jak2 inhibits their subsequent O-GlcNAcylation. However, O-GlcNAcylation has no detectable effect on their subsequent phosphorylation. A specific peptide (ZO3_357_371), derived from the ZO-3 protein, was studied in detail. Kinetic results show that the presence of a phosphate at Tyr364 of ZO3_357_371 slows the O-GlcNAcylation of nearby Ser369, while the presence of a GlcNAc at Ser369 has no significant effect on the phosphorylation of this peptide at Tyr364. These findings provide a glimpse into the new paradigm for cellular signaling control by cross-talk. PMID- 28580692 TI - Using quality improvement to decrease birth asphyxia rates after 'Helping Babies Breathe' training in Kenya. AB - AIM: The Helping Babies Breathe (HBB) programme is known to decrease neonatal mortality in low-resource settings but gaps in care still exist. This study describes the use of quality improvement to sustain gains in birth asphyxia related mortality after HBB. METHODS: Tenwek Hospital, a rural referral hospital in Kenya, identified high rates of birth asphyxia (BA). They developed a goal to decrease the suspected hypoxic-ischaemic encephalopathy (SHIE) rate by 50% within six months after HBB. Rapid cycles of change were used to test interventions including training, retention and engagement for staff/trainees and improved data collection. Run charts followed the rate over time, and chi-square analysis was used. RESULTS: Ninety-six providers received HBB from September to November 2014. Over 4000 delivery records were reviewed. Ten months of baseline data showed a median SHIE rate of 14.7/1000 live births (LB) with wide variability. Ten months post-HBB, the SHIE rate decreased by 53% to 7.1/1000 LB (p = 0.01). SHIE rates increased after initial decline; investigation determined that half the trained midwives had been transferred. Presenting data to administration resulted in staff retention. Rates have after remained above goal with narrowing control limits. CONCLUSION: Focused quality improvement can sustain and advance gains in neonatal outcomes post-HBB training. PMID- 28580693 TI - Changes in brain activity following intensive voice treatment in children with cerebral palsy. AB - Eight children (3 females; 8-16 years) with motor speech disorders secondary to cerebral palsy underwent 4 weeks of an intensive neuroplasticity-principled voice treatment protocol, LSVT LOUD(r) , followed by a structured 12-week maintenance program. Children were asked to overtly produce phonation (ah) at conversational loudness, cued-phonation at perceived twice-conversational loudness, a series of single words, and a prosodic imitation task while being scanned using fMRI, immediately pre- and post-treatment and 12 weeks following a maintenance program. Eight age- and sex-matched controls were scanned at each of the same three time points. Based on the speech and language literature, 16 bilateral regions of interest were selected a priori to detect potential neural changes following treatment. Reduced neural activity in the motor areas (decreased motor system effort) before and immediately after treatment, and increased activity in the anterior cingulate gyrus after treatment (increased contribution of decision making processes) were observed in the group with cerebral palsy compared to the control group. Using graphical models, post-treatment changes in connectivity were observed between the left supramarginal gyrus and the right supramarginal gyrus and the left precentral gyrus for the children with cerebral palsy, suggesting LSVT LOUD enhanced contributions of the feedback system in the speech production network instead of high reliance on feedforward control system and the somatosensory target map for regulating vocal effort. Network pruning indicates greater processing efficiency and the recruitment of the auditory and somatosensory feedback control systems following intensive treatment. Hum Brain Mapp 38:4413-4429, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28580694 TI - Using the cloud to enhance clinical teaching. PMID- 28580695 TI - Non-contrast-enhanced peripheral MR angiography using velocity-selective excitation. AB - PURPOSE: To develop a new non-contrast-enhanced peripheral MR angiography that provides a high contrast angiogram without using electrocardiography triggering and saturation radiofrequency pulses. METHODS: A velocity-selective excitation technique is used in conjunction with the golden-angle radial sampling scheme. The signal amplitude varies according to the velocity of the flow by the velocity selective excitation technique. Because the arterial blood velocity varies depending on the cardiac phase, the acquired data can be classified into systolic and diastolic phase based on the signal amplitude of the artery. Two images are then reconstructed from the systolic and diastolic phase data, respectively, and an image reflecting the differences between the two images is obtained to eliminate background and vein signals. The performance of the proposed method was compared with the quiescent-interval single shot (QISS) in eight healthy subjects and an elderly subject. RESULTS: The proposed method generated fewer residual venous and background signals than the QISS. Furthermore, the maximum intensity projection images, the relative contrast, and the apparent contrast-to-noise ratio results showed that the proposed method produced a better contrast than the QISS. CONCLUSIONS: The proposed non-contrast-enhanced peripheral MR angiography technique can provide a high contrast angiogram without the use of electrocardiography triggering and saturation radiofrequency pulses. Magn Reson Med 79:779-788, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28580696 TI - On low-lying excited states of extended nanographenes. AB - Low-lying excited states of planarly extended nanographenes are investigated using the long-range corrected (LC) density functional theory (DFT) and the spin flip (SF) time-dependent density functional theory (TDDFT) by exploring the long range exchange and double-excitation correlation effects on the excitation energies, band gaps, and exciton binding energies. Optimizing the geometries of the nanographenes indicates that the long-range exchange interaction significantly improves the C?C bond lengths and amplify their bond length alternations with overall shortening the bond lengths. The calculated TDDFT excitation energies show that long-range exchange interaction is crucial to provide accurate excitation energies of small nanographenes and dominate the exciton binding energies in the excited states of nanographenes. It is, however, also found that the present long-range correction may cause the overestimation of the excitation energy for the infinitely wide graphene due to the discrepancy between the calculated band gaps and vertical ionization potential (IP) minus electron affinity (EA) values. Contrasting to the long-range exchange effects, the SF-TDDFT calculations show that the double-excitation correlation effects are negligible in the low-lying excitations of nanographenes, although this effect is large in the lowest excitation of benzene molecule. It is, therefore, concluded that long-range exchange interactions should be incorporated in TDDFT calculations to quantitatively investigate the excited states of graphenes, although TDDFT using a present LC functional may provide a considerable excitation energy for the infinitely wide graphene mainly due to the discrepancy between the calculated band gaps and IP-EA values. (c) 2017 Wiley Periodicals, Inc. PMID- 28580698 TI - Spontaneous pneumomediastinum in a dermatomyositis patient with anti-melanoma differentiation-associated gene-5 antibody and interstitial lung disease despite an initial response to immunosuppressant. AB - We report a 24-year-old man with anti-melanoma differentiation-associated gene-5 (MDA5) antibody-positive dermatomyositis (DM) and interstitial lung disease (ILD) who developed spontaneous pneumomediastinum. By comparing serial thoracic high resolution computed tomography scans, we demonstrated the distinct time course showing a paradoxical occurrence of pneumomediastinum despite a radiological improvement of ILD. Our case shows that pneumomediastinum in DM can occur regardless of associated ILD and it is a serious complication that should be considered in DM patients presenting with pulmonary manifestations. Cutaneous vasculopathy may be associated with pneumomediastinum and could potentially be a useful indicator of future disease. PMID- 28580699 TI - Prognostic value of lymphovascular invasion of the primary tumor in hypopharyngeal carcinoma after total laryngopharyngectomy. AB - BACKGROUND: We aimed to determinate the prognostic value of lymphovascular invasion in the specimens resected during total laryngopharyngectomy for hypopharyngeal carcinoma. METHODS: Patients who underwent total laryngopharyngectomy at our institution between 2004 and 2014 were included in this study and retrospectively analyzed. We then discriminated for vascular invasion and lymphatic invasion of the primary tumor in all cases. RESULTS: We reviewed 135 records (120 men and 15 women; age range, 36-84 years). Tumors with lymphatic invasion tended to be associated with more metastatic lymph nodes and extracapsular spread (ECS) of metastatic lymph nodes. Tumors with vascular invasion tended to be associated with nonpyriform sinus locations. In a multivariate analysis, nonpyriform sinus locations, >3 metastatic lymph nodes, and vascular invasion remained significant prognostic factors for overall survival (OS); in recursive partitioning analysis, ECS and vascular invasion remained important categorical variables for OS. CONCLUSION: Vascular invasion is a strong prognostic biomarker for advanced hypopharyngeal carcinoma. (c) 2017 Wiley Periodicals, Inc. Head Neck 39: 1535-1543, 2017. PMID- 28580700 TI - Oriented Two-Dimensional Porous Organic Cage Crystals. AB - The formation of two-dimensional (2D) oriented porous organic cage crystals (consisting of imine-based tetrahedral molecules) on various substrates (such as silicon wafers and glass) by solution-processing is reported. Insight into the crystallinity, preferred orientation, and cage crystal growth was obtained by experimental and computational techniques. For the first time, structural defects in porous molecular materials were observed directly and the defect concentration could be correlated with crystal growth rate. These oriented crystals suggest potential for future applications, such as solution-processable molecular crystalline 2D membranes for molecular separations. PMID- 28580697 TI - Genetic influences on individual differences in longitudinal changes in global and subcortical brain volumes: Results of the ENIGMA plasticity working group. AB - Structural brain changes that occur during development and ageing are related to mental health and general cognitive functioning. Individuals differ in the extent to which their brain volumes change over time, but whether these differences can be attributed to differences in their genotypes has not been widely studied. Here we estimate heritability (h2 ) of changes in global and subcortical brain volumes in five longitudinal twin cohorts from across the world and in different stages of the lifespan (N = 861). Heritability estimates of brain changes were significant and ranged from 16% (caudate) to 42% (cerebellar gray matter) for all global and most subcortical volumes (with the exception of thalamus and pallidum). Heritability estimates of change rates were generally higher in adults than in children suggesting an increasing influence of genetic factors explaining individual differences in brain structural changes with age. In children, environmental influences in part explained individual differences in developmental changes in brain structure. Multivariate genetic modeling showed that genetic influences of change rates and baseline volume significantly overlapped for many structures. The genetic influences explaining individual differences in the change rate for cerebellum, cerebellar gray matter and lateral ventricles were independent of the genetic influences explaining differences in their baseline volumes. These results imply the existence of genetic variants that are specific for brain plasticity, rather than brain volume itself. Identifying these genes may increase our understanding of brain development and ageing and possibly have implications for diseases that are characterized by deviant developmental trajectories of brain structure. Hum Brain Mapp 38:4444 4458, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28580701 TI - Identification of DJ-1 as a contributor to multidrug resistance in human small cell lung cancer using proteomic analysis. AB - Proteomic approaches have been proven to provide an important tool in identifying drug resistance-associated proteins. The aim of this study was to investigate the protein profiling of drug resistance-related proteins in small-cell lung cancer (SCLC) by proteomic analysis. The proteomic profiling was performed by two dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with MALDI-TOF-TOF of SCLC in the multidrug-resistant cell line H69AR and its parental cell line H69. A total of 11 proteins were identified to be >2-fold up-or downregulated between the two cell lines. DJ-1, one of the differently expressed proteins identified by proteomics, was further examined by immunohistochemistry staining in 116 cases of SCLC tissues. Immunohistochemical results demonstrated that DJ-1 was expressed in 51.7% (60/116) of SCLC. DJ-1 expression was correlated significantly with survival time of SCLC patients (P < 0.05), but not with other clinical parameters such as gender, age and clinical stage (P > 0.05). Downregulation of DJ-1 using DJ-1-siRNA in H69AR cells sensitized cancer cells to chemotherapeutic drugs through increasing drug-induced cell apoptosis accompanied with G0-G1 phase arrest. These findings suggest DJ-1 may serve as a potential biomarker for chemoresistance and prognostic factor for patients with SCLC. PMID- 28580702 TI - Evidence for an attentional component of inhibition of return in visual search. AB - Inhibition of return (IOR) is typically described as an inhibitory bias against returning attention to a recently attended location as a means of promoting efficient visual search. Most studies examining IOR, however, either do not use visual search paradigms or do not effectively isolate attentional processes, making it difficult to conclusively link IOR to a bias in attention. Here, we recorded ERPs during a simple visual search task designed to isolate the attentional component of IOR to examine whether an inhibitory bias of attention is observed and, if so, how it influences visual search behavior. Across successive visual search displays, we found evidence of both a broad, hemisphere wide inhibitory bias of attention along with a focal, target location-specific facilitation. When the target appeared in the same visual hemifield in successive searches, responses were slower and the N2pc component was reduced, reflecting a bias of attention away from the previously attended side of space. When the target occurred at the same location in successive searches, responses were facilitated and the P1 component was enhanced, likely reflecting spatial priming of the target. These two effects are combined in the response times, leading to a reduction in the IOR effect for repeated target locations. Using ERPs, however, these two opposing effects can be isolated in time, demonstrating that the inhibitory biasing of attention still occurs even when response-time slowing is ameliorated by spatial priming. PMID- 28580703 TI - External Trigeminal Nerve Stimulation for the Acute Treatment of Migraine: Open Label Trial on Safety and Efficacy. AB - OBJECTIVE: The aim of the current study is to assess the safety and efficacy of external trigeminal nerve stimulation (e-TNS) via a transcutaneous supraorbital stimulator as an acute treatment for migraine attacks. MATERIALS AND METHODS: This was a prospective, open-labeled clinical trial conducted at the Columbia University Headache Center (NY, USA). Thirty patients who were experiencing an acute migraine attack with or without aura were treated with a one-hour session of e-TNS (CEFALY Technology) at the clinic. Pain intensity was scored using a visual analogue scale (VAS) before the treatment, after the one-hour treatment session, and at two hours after treatment initiation. Rescue migraine medication intake was recorded at 2 and 24 hours. RESULTS: Thirty patients were included in the intention-to-treat analysis. Mean pain intensity was significantly reduced by 57.1% after the one-hour e-TNS treatment (-3.22 +/- 2.40; p < 0.001) and by 52.8% at two hours (-2.98 +/- 2.31; p < 0.001). No patients took rescue medication within the two-hour observation phase. Within the 24-hour follow-up, 34.6% of patients used a rescue medication. No adverse events or subjective complaints were reported. CONCLUSIONS: The findings from this open-labeled study suggest that transcutaneous supraorbital neurostimulation may be a safe and effective acute treatment for migraine attacks, and merits further study with a double blind, randomized, sham-controlled trial. PMID- 28580704 TI - 3D Laser Micro- and Nanoprinting: Challenges for Chemistry. AB - 3D printing is a powerful emerging technology for the tailored fabrication of advanced functional materials. This Review summarizes the state-of-the art with regard to 3D laser micro- and nanoprinting and explores the chemical challenges limiting its full exploitation: from the development of advanced functional materials for applications in cell biology and electronics to the chemical barriers that need to be overcome to enable fast writing velocities with resolution below the diffraction limit. We further explore chemical means to enable direct laser writing of multiple materials in one resist by highly wavelength selective (lambda-orthogonal) photochemical processes. Finally, chemical processes to construct adaptive 3D written structures that are able to respond to external stimuli, such as light, heat, pH value, or specific molecules, are highlighted, and advanced concepts for degradable scaffolds are explored. PMID- 28580705 TI - The relationship among unawareness of memory impairment, depression, and dementia in older adults with memory impairment in Singapore. AB - BACKGROUND: Previous research has studied the relationships among unawareness of memory impairment, depression, and dementia in older adults with severe dementia, but it has not considered the associations and clinical implications at earlier stages of memory impairment. This study therefore sought to examine the relationship among unawareness of memory impairment, depression, and dementia in older adults with memory impairment in Singapore. METHODS: The participants were 751 older adults with memory impairment in Singapore. They were assessed for objective and subjective memory loss, depression, and dementia severity. Participants' subjective memory loss was determined based on a self-appraisal question on memory, and their objective memory loss was calculated based on their performance on three cognitive tasks. Unawareness was assessed based on the contrast between subjective and objective memory loss. RESULTS: Descriptive statistics revealed a high prevalence of unawareness (80.4%). Logistic regression analysis revealed that gender and marital status were significantly associated with unawareness. Men (odds ratio (OR) = 2.5) and those who were divorced or separated (OR = 23.0) were more likely to be unaware than women and those who were married, respectively. After chronic conditions and demographic characteristics were controlled for, multivariate logistic regression analyses revealed that older adults with depression were less likely (OR = 0.2) to be unaware than those without depression. Unawareness was also related with dementia severity; older adults with questionable (OR = 0.3) and mild dementia (OR = 0.4) were less likely to be unaware than someone without dementia. CONCLUSION: Unawareness of memory impairment was common among older adults with memory impairment. However, unawareness may be the result of denial as a strategy for coping with memory loss of which the older adult is aware. Psychological care should be integrated into the overall treatment management of dementia to mitigate the possible risk of depression while increasing individual awareness of memory loss. PMID- 28580706 TI - MR techniques for guiding high-intensity focused ultrasound (HIFU) treatments. AB - : To make full use of the ability of magnetic resonance (MR) to guide high intensity focused ultrasound (HIFU) treatment, effort has been made to improve techniques for thermometry, motion tracking, and sound beam visualization. For monitoring rapid temperature elevation with proton resonance frequency (PRF) shift, data acquisition and processing can be accelerated with parallel imaging and/or sparse sampling in conjunction with appropriate signal processing methods. Thermometry should be robust against tissue motion, motion-induced magnetic field variation, and susceptibility change. Thus, multibaseline, referenceless, or hybrid techniques have become important. In cases with adipose or bony tissues, for which PRF shift cannot be used, thermometry with relaxation times or signal intensity may be utilized. Motion tracking is crucial not only for thermometry but also for targeting the focus of an ultrasound in moving organs such as the liver, kidney, or heart. Various techniques for motion tracking, such as those based on an anatomical image atlas with optical-flow displacement detection, a navigator echo to seize the diaphragm position, and/or rapid imaging to track vessel positions, have been proposed. Techniques for avoiding the ribcage and near-field heating have also been examined. MR acoustic radiation force imaging (MR-ARFI) is an alternative to thermometry that can identify the location and shape of the focal spot and sound beam path. This technique could be useful for treating heterogeneous tissue regions or performing transcranial therapy. All of these developments, which will be discussed further in this review, expand the applicability of HIFU treatments to a variety of clinical targets while maintaining safety and precision. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:316-331. PMID- 28580708 TI - How the brain codes intimacy: The neurobiological substrates of romantic touch. AB - Humans belong to a minority of mammalian species that exhibit monogamous pair bonds, thereby enabling biparental care of offspring. The high reward value of interpersonal closeness and touch in couples is a key proximate mechanism facilitating the maintenance of enduring romantic bonds. However, surprisingly, the neurobiological underpinnings mediating the unique experience of a romantic partner's touch remain unknown. In this randomized placebo (PLC)-controlled, between-group, pharmacofunctional magnetic resonance imaging (fMRI) study involving 192 healthy volunteers (96 heterosexual couples), we intranasally administered 24 IU of the hypothalamic peptide oxytocin (OXT) to either the man or the woman. Subsequently, we scanned the subjects while they assumed that they were being touched by their romantic partners or by an unfamiliar person of the opposite sex, although in reality an identical pattern of touch was always given by the same experimenter. Our results show that intranasal OXT compared to PLC selectively enhanced the subjective pleasantness of the partner's touch. Importantly, intranasal OXT selectively increased responses to partner touch in the nucleus accumbens (NAcc) and anterior cingulate cortex. Under OXT, NAcc activations to partner touch positively correlated with the subjects' evaluation of their relationship quality. Collectively, our results suggest that OXT may contribute to the maintenance of monogamous relationships in humans by concomitantly increasing the reward value of partner touch and diminishing the hedonic quality of stranger touch. Hum Brain Mapp 38:4525-4534, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28580707 TI - A classifier integrating plasma biomarkers and radiological characteristics for distinguishing malignant from benign pulmonary nodules. AB - Lung cancer is primarily caused by cigarette smoking and the leading cancer killer in the USA and across the world. Early detection of lung cancer by low dose CT (LDCT) can reduce the mortality. However, LDCT dramatically increases the number of indeterminate pulmonary nodules (PNs), leading to overdiagnosis. Having a definitive preoperative diagnosis of malignant PNs is clinically important. Using microarray and droplet digital PCR to directly profile plasma miRNA expressions of 135 patients with PNs, we identified 11 plasma miRNAs that displayed a significant difference between patients with malignant versus benign PNs. Using multivariate logistic regression analysis of the molecular results and clinical/radiological characteristics, we developed an integrated classifier comprising two miRNA biomarkers and one radiological characteristic for distinguishing malignant from benign PNs. The classifier had 89.9% sensitivity and 90.9% specificity, being significantly higher compared with the biomarkers or clinical/radiological characteristics alone (all p < 0.05). The classifier was validated in two independent sets of patients. We have for the first time shown that the integration of plasma biomarkers and radiological characteristics could more accurately identify lung cancer among indeterminate PNs. Future use of the classifier could spare individuals with benign growths from the harmful diagnostic procedures, while allowing effective treatments to be immediately initiated for lung cancer, thereby reduces the mortality and cost. Nevertheless, further prospective validation of this classifier is warranted. PMID- 28580711 TI - Fluoxetine and Raynaud's phenomenon: friend or foe? PMID- 28580709 TI - Early ovariectomy reveals the germline encoding of natural anti-A- and Tn-cross reactive immunoglobulin M (IgM) arising from developmental O-GalNAc glycosylations. (Germline-encoded natural anti-A/Tn cross-reactive IgM). AB - While native blood group A-like glycans have not been demonstrated in prokaryotic microorganisms as a source of human "natural" anti-A isoagglutinin production, and metazoan eukaryotic N-acetylgalactosamine O-glycosylation of serine or threonine residues (O-GalNAc-Ser/Thr-R) does not occur in bacteria, the O-GalNAc glycan-bearing ovarian glycolipids, discovered in C57BL/10 mice, are complementary to the syngeneic anti-A-reactive immunoglobulin M (IgM), which is not present in animals that have undergone ovariectomy prior to the onset of puberty. These mammalian ovarian glycolipids are complementary also to the anti A/Tn cross-reactive Helix pomatia agglutinin (HPA), a molluscan defense protein, emerging from the coat proteins of fertilized eggs and reflecting the snail intrinsic, reversible O-GalNAc glycosylations. The hexameric structure of this primitive invertebrate defense protein gives rise to speculation regarding an evolutionary relationship to the mammalian nonimmune, anti-A-reactive immunoglobulin M (IgM) molecule. Hypothetically, this molecule obtains its complementarity from the first step of protein glycosylations, initiated by GalNAc via reversible O-linkages to peptides displaying Ser/Thr motifs, whereas the subsequent transferase depletion completes germ cell maturation and cell renewal, associated with loss of glycosidic bonds and release of O-glycan depleted proteins, such as complementary IgM revealing the structure of the volatilely expressed "lost" glycan carrier through germline Ser residues. Consequently, the evolutionary/developmental first glycosylations of proteins appear metabolically related or identical to that of the mucin-type, potentially "aberrant" monosaccharide GalNAcalpha1-O-Ser/Thr-R, also referred to as the Tn (T "nouvelle") antigen, and explain the anti-Tn cross-reactivity of human innate or "natural" anti-A-specific isoagglutinin and the pronounced occurrence of cross reactive anti-Tn antibody in plasma from humans with histo-blood group O. In fact, A-allelic, phenotype-specific GalNAc glycosylation of plasma proteins does not occur in human blood group O, affecting anti-Tn antibody levels, which may function as a growth regulator that contributes to a potential survival advantage of this group in the overall risk of developing cancer when compared with non-O blood groups. PMID- 28580712 TI - Kawasaki disease: State of the art. AB - Kawasaki disease is an acute febrile arteritis of childhood that can result in coronary artery aneurysms if untreated in the first 10 and ideally 7 days of illness. Kawasaki disease begins as a necrotizing arteritis with neutrophilic infiltrate, followed by subacute/chronic changes and luminal myofibroblastic proliferation that can cause coronary artery stenosis. Manifestations include the presence of >=5 days of fever, together with clinical criteria of extremity changes, rash, conjunctivitis, oral changes, and unilateral cervical lymphadenopathy. Echocardiography should be performed at the time of diagnosis, then 1-2 weeks and 4-6 weeks later, with more frequent studies in individuals with coronary artery dilation or persistent fever. Coronary artery dimensions are characterized both as z-scores and absolute measurements, and coronary architecture evolves over time in children who have aneurysms in the first weeks of illness. Systematic follow-up and therapies are tailored to the degree of coronary disease and to coronary ischemia. PMID- 28580710 TI - A nomogram for predicting the risk of neck node metastasis in pathologically node negative oral cavity carcinoma. AB - OBJECTIVE: To generate a nomogram for predicting the risk of neck node metastasis in pathologically node-negative patients using a combination of variables comprising of protein expression, ultrastructural alterations and clinicopathological parameters. MATERIALS AND METHODS: Surgically removed oral tumours (n = 103) were analysed for the expression of desmosomal and hemidesmosomal assembly proteins by immunohistochemistry and ultrastructural alterations by transmission electron microscopy (TEM). Protein expression, ultrastructural alterations and clinicopathological variables were used to construct nomogram from the training set in 75 patients. Clinical utility of the nomogram was validated in a discrete set of 28 patients. RESULTS: Univariate and multivariate analyses were performed on the training set, and obtained significant variables comprising of integrin beta4 expression (p = .027), number of hemidesmosomes (p = .027)/desmosomes (p = .046), tumour differentiation grade (p = .033) and tumour thickness (p = .024) were used for construction of the nomogram. The area under the curve was calculated for both training 0.821 (95% CI 0.725-0.918) and validation sets 0.880 (95% CI 0.743-1.000). The nomogram demonstrated a predictive accuracy of 73.3% and 78.6% with the sensitivity of 81.4% and 83.3% in the training and validation sets, respectively. CONCLUSIONS: The nomogram constructed on postsurgical tumour samples will be a value addition to histopathology for the detection of neck node metastasis in pathologically node-negative patients. PMID- 28580713 TI - Mitral valve prolapse and Marfan syndrome. AB - Marfan syndrome is a multisystemic genetic condition affecting connective tissue. It carries a reduced life expectancy, largely dependent on cardiovascular complications. More common cardiac manifestations such as aortic dissection and aortic valve incompetence have been widely documented in the literature. Mitral valve prolapse (MVP), however, has remained poorly documented. This article aims at exploring the existing literature on the pathophysiology and diagnosis of MVP in patients with Marfan syndrome, defining its current management and outlining the future developments surrounding it. PMID- 28580715 TI - Parental guided self-help family based treatment for adolescents with anorexia nervosa: A feasibility study. AB - OBJECTIVE: Family-based treatment (FBT) is an evidence-based treatment for adolescent anorexia nervosa (AN), but many families cannot access it. This study evaluated feasibility, acceptability, and preliminary treatment effects of a parental guided self-help (GSH) version of FBT for adolescent AN. METHOD: This was a case-series design. Parents of medically stable adolescents (11-18 years) with DSM-5 AN were recruited over 12 months. Parents received online training in parental GSH FBT and 12 20-30 min GSH sessions by phone or online over 6 months. Recruitment, dropout, changes in weight, and eating-related psychopathology were assessed. Analyses used mixed modeling that included all data for all participants. RESULTS: Of the 19 families that participated, most were white (94%) and from intact families (88%). Baseline median BMI (mBMI) percent was 85.01% (SD = 4.31). Participants' mBMI percent increased to 97.31% (SD +/- 7.48) at the end of treatment (EOT) (ES = 2.06; CI= 0.13-3.99). Eating-related psychopathology improved by EOT (ES = 0.58; CI=.04-1.21). Dropout rate was 21% during treatment and 33% during follow-up. DISCUSSION: Parental GSH-FBT is feasible and acceptable to families willing to undertake online treatment. Follow up data was only available for nine families (47%); thus further systematic evaluation is required before reaching conclusions about the efficacy of this approach. PMID- 28580714 TI - Marine alkaloid oroidin analogues with antiviral potential: A novel class of synthetic compounds targeting the cellular chaperone Hsp90. AB - Marine organisms and their metabolites are a diverse source of scaffolds for potential pharmacological molecular probes and, less frequently, for pharmaceutical lead compounds. In this study, 157 synthetic analogues of marine sponge-derived alkaloids clathrodin and oroidin were screened against replicon models of two RNA viruses, hepatitis C (HCV) and Chikungunya virus (CHIKV) as part of a larger screening project. Four compounds were found to selectively inhibit the HCV replicon (IC50 1.6-4.6 MUm). These belong to the 4,5,6,7 tetrahydrobenzo[1,2-d]thiazole class of compounds originally designed to target the ATP-binding site of bacterial DNA gyrase. The ATP-binding site of this bacterial protein has high structural similarity to the ATP-binding site of heat shock protein 90 (Hsp90), a host cell chaperone universally required for viral replication, which led us to examine inhibition of Hsp90 as the compounds' potential mechanism of action. Binding of the four hit compounds to Hsp90 was evaluated through microscale thermophoresis and molecular modeling, which supported our hypothesis of interaction with Hsp90 (Kd 18-79 MUm) as basis for the compounds' antiviral activity. The presented novel structural class of small molecules that target the Hsp90 ATP-binding site has excellent potential for further antiviral drug development because of the compounds' low toxicity and synthetic accessibility. PMID- 28580716 TI - Preparation and characterization of injectable PMMA-strontium-substituted bioactive glass bone cement composites. AB - In most minimally-invasive procedures used to address severe pain arising from compression fractures of the vertebral bodies, such as percutaneous vertebroplasty (PVP), a poly(methyl methacrylate) (PMMA) bone cement is used. Shortcomings of this type of cement, such as high exotherm temperature and lack of bioactivity, are well known. We prepared different formulations of a composite bone cement, whose solid constituents consisted of PMMA beads and particles of a bioactive glass (BG), where 0-20%(w/w) of the calcium component was substituted by strontium. The difference between the formulations was in the relative amounts of the solid phase constituents and in the Sr-content of BG. We determined the influence of the mixture of solid phase constituents of the cement formulation on a collection of properties, such as maximum exotherm temperature (Tmax ), setting time (tset ), and injectability (I). The selection of the PMMA beads was crucial to obtain cement composite formulations capable to be efficiently injected. Results allowed to select nine solid phase mixtures to be further tested. Then, we determined the influence of the composition of these composite bone cements on Tmax , tset , I, and cell proliferation. The results showed that the performance of various of the selected composite cements was better than that of PMMA cement reference, with lower Tmax , lower tset , and higher I. We found that incorporation of Sr-substituted BGs into these materials bestows bioactivity properties associated with the role of Sr in bone formation, leading to some composite cement formulations that may be suitable for use in PVP. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1245-1257, 2018. PMID- 28580717 TI - The development and integrity of equine pre-antral follicles cultured in vitro with follicle-stimulating hormone (FSH) supplementation. AB - This study investigated the effects of different concentrations of FSH (10, 50, 100 and 200 ng/ml) in supplemented MEM+ on the development of equine pre-antral follicles that were cultured in vitro for 2 or 6 days. The ovaries (n = 5) from mares in seasonal anoestrus were collected from a local abattoir. Ten ovarian tissue fragments of approximately 3 * 3 * 1 mm were obtained from each animal. The fragments were cultured in situ for 2 days (D2) or 6 days (D6) in MEM+ or MEM+ supplemented with FSH at four different concentrations, establishing the following 11 groups: control (D0); MEM + (D2); MEM + (D6); MEM + 10 ng/ml of FSH (D2); MEM + 10 ng/ml of FSH (D6); MEM + 50 ng/ml of FSH (D2); MEM + 50 ng/ml of FSH (D6); MEM + 100 ng/ml of FSH (D2); MEM + 100 ng/ml of FSH (D6); MEM + 200 ng/ml of FSH (D2); and MEM + 200 ng/ml of FSH (D6). Follicles were observed in only 9.65% (388 of 4,018) of the histological sections. Of the 861 follicles evaluated, 488 were in the primordial stage, and 373 were in various developmental stages; 59.7% were morphologically normal. Regarding the integrity of the pre-antral follicles, the groups with 100 ng/ml FSH of 2-days culture as well as 50, 100 and 200 ng/ml FSH of 6-days culture provided the best results. In conclusion, the in vitro culture of abattoir-derived equine ovarian fragments presented better morphological integrity when supplemented with FSH for 6 days, in comparison with the MEM culture group. However, no clear effects were observed with FSH regarding the promotion of activation from a primordial to a developing follicle. PMID- 28580718 TI - Resolution of aquagenic pruritus with intermittent UVA/NBUVB combined therapy. PMID- 28580719 TI - Platelets stored at 4 degrees C contribute to superior clot properties compared to current standard-of-care through fibrin-crosslinking. AB - Currently, platelets for transfusion are stored at room temperature (RT) for 5-7 days with gentle agitation, but this is less than optimal because of loss of function and risk of bacterial contamination. We have previously demonstrated that cold (4 degrees C) storage is an attractive alternative because it preserves platelet metabolic reserves, in vitro responses to agonists of activation, aggregation and physiological inhibitors, as well as adhesion to thrombogenic surfaces better than RT storage. Recently, the US Food and Drug Administration clarified that apheresis platelets stored at 4 degrees C for up to 72 h may be used for treating active haemorrhage. In this work, we tested the hypothesis that cold-stored platelets contribute to generating clots with superior mechanical properties compared to RT-stored platelets. Rheological studies demonstrate that the clots formed from platelets stored at 4 degrees C for 5 days are significantly stiffer (higher elastic modulus) and stronger (higher critical stress) than those formed from RT-stored platelets. Morphological analysis shows that clot fibres from cold-stored platelets were denser, thinner, straighter and with more branch points or crosslinks than those from RT-stored platelets. Our results also show that the enhanced clot strength and packed structure is due to cold-induced plasma factor XIII binding to platelet surfaces, and the consequent increase in crosslinking. PMID- 28580721 TI - Persistent hemolytic disease of the fetus and newborn (HDFN) associated with passive acquisition of anti-D in maternal breast milk. AB - BACKGROUND: Anti-D is a well-documented, significant cause of hemolytic disease of the fetus and newborn (HDFN), but its presence in breast milk is not routinely described. Theoretically, breast milk containing anti-D could have the potential to exacerbate HDFN if ingested by the affected infant. STUDY DESIGN AND METHODS: This is a case report of a 28-week premature male neonate with hydrops fetalis born to a 32-year-old woman (gravidity 3/parity 3) with anti-D and anti-G. The male neonate experienced prolonged HDFN due to passive acquisition of anti-D in the mother's breast milk. RESULTS: The mother's breast milk reacted strongly (4+) with the D-positive cells in the antibody screen test. Discontinuation of breast milk feeding and addition of total parenteral nutrition led to the cessation of clinically significant HDFN. CONCLUSION: Although anti-D is a significant cause of HDFN through placental transfer of antibody, exacerbation of the condition through breast milk antibodies is rarely described. The current case highlights the possibility of this occurring. Discontinuation of maternal breast milk feedings should be considered in infants with HDFN who do not respond to standard treatment. PMID- 28580722 TI - Response to "Quantitative analysis of hepatocellular adenoma and focal nodular hyperplasia in the hepatobiliary phase: External validation of llcer method using gadobenate dimeglumine as contrast agent". PMID- 28580720 TI - Learned control of inter-hemispheric connectivity: Effects on bimanual motor performance. AB - Bimanual movements involve the interactions between both primary motor cortices. These interactions are assumed to involve phase-locked oscillatory brain activity referred to as inter-hemispheric functional coupling. So far, inter-hemispheric functional coupling has been investigated as a function of motor performance. These studies report mostly a negative correlation between the performance in motor tasks and the strength of functional coupling. However, correlation might not reflect a causal relationship. To overcome this limitation, we opted for an alternative approach by manipulating the strength of inter-hemispheric functional coupling and assessing bimanual motor performance as a dependent variable. We hypothesize that an increase/decrease of functional coupling deteriorates/facilitates motor performance in an out-of-phase bimanual finger tapping task. Healthy individuals were trained to volitionally regulate functional coupling in an operant conditioning paradigm using real-time magnetoencephalography neurofeedback. During operant conditioning, two discriminative stimuli were associated with upregulation and downregulation of functional coupling. Effects of training were assessed by comparing motor performance prior to (pre-test) and after the training (post-test). Participants receiving contingent feedback learned to upregulate and downregulate functional coupling. Comparing motor performance, as indexed by the ratio of tapping speed for upregulation versus downregulation trials, no change was found in the control group between pre- and post-test. In contrast, the group receiving contingent feedback evidenced a significant decrease of the ratio implicating lower tapping speed with stronger functional coupling. Results point toward a causal role of inter-hemispheric functional coupling for the performance in bimanual tasks. Hum Brain Mapp 38:4353-4369, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28580723 TI - Pollen contamination in seed mixture increases the dominance of resistance to Bt maize in Spodoptera frugiperda (Lepidoptera: Noctuidae). AB - BACKGROUND: Seed mixture, also called 'RIB', has been used to provide refuge populations for delaying insect resistance. Pollen contamination in RIB could result in refuge kernels of non-Bt maize expressing variable Bt proteins. Data are lacking regarding the impact of pollen contamination on evolution of resistance for ear-feeding insects. Here, we used Spodoptera frugiperda and Cry1F maize as a model to examine if pollen contamination in RIB increases the dominance of insect resistance. RESULTS: Pollen contamination caused >66% refuge kernels in 5:95% (non-Bt:Bt) and 20:80% RIBs to express Cry1F protein. Survival at adult stage on pure non-Bt ears was similar (54.4-63.3%) among Cry1F susceptible (SS), Cry1F-resistant (RR) and Cry1F-heterozygous (RS) S. frugiperda. On Bt ears, survival was similar between SS and RS (0.0-1.7%), but it was significantly less than that of RR (59.2%). On the two RIB refuge ears, survival at adult stage for RS (42.3% in 5:95% RIB; 50.0% in 20:80% RIB) was significantly higher than for SS (8.7% in 5:95% RIB; 10.0% in 20:80% RIB). CONCLUSION: The results suggest that pollen contamination in RIB could increase the dominance of resistance for ear-feeding insects by significantly reducing susceptible refuge populations and supporting higher survival of heterozygotes relative to homozygous susceptible insects. (c) 2017 Society of Chemical Industry. PMID- 28580724 TI - Melatonin delays photoreceptor degeneration in a mouse model of autosomal recessive retinitis pigmentosa. AB - Retinitis pigmentosa (RP) comprises a group of incurable inherited retinal degenerations. Targeting common processes, instead of mutation-specific treatment, has proven to be an innovative strategy to combat debilitating retinal degeneration. Growing evidence indicates that melatonin possesses a potent activity against neurodegenerative disorders by mitigating cell damage associated with apoptosis and inflammation. Given the pleiotropic role of melatonin in central nervous system, the aim of the present study was to investigate whether melatonin would afford protection against retinal degeneration in autosomal recessive RP (arRP). Rd10, a well-characterized murine model of human arRP, received daily intraperitoneal injection of melatonin (15 mg/kg) between postnatal day (P) 13 and P30. Retinas treated with melatonin or vehicle were harvested for analysis at P30 and P45, respectively. The findings showed that melatonin could dampen the photoreceptors death and delay consequent retinal degeneration. We also observed that melatonin weakened the expression of glial fibrillary acidic protein (GFAP) in Muller cells. Additionally, melatonin could alleviate retinal inflammatory response visualized by IBA1 staining, which was further corroborated by downregulation of inflammation-related genes, such as tumor necrosis factor alpha (Tnf-alpha), chemokine (C-C motif) ligand 2 (Ccl2), and chemokine (C-X-C motif) ligand 10 (Cxcl10). These data revealed that melatonin could ameliorate retinal degeneration through potentially attenuating apoptosis, reactive gliosis, and microglial activation in rd10 mice. Moreover, these results suggest melatonin as a promising agent improving photoreceptors survival in human RP. PMID- 28580725 TI - Effects of Acute-Postacute Continuity on Community Discharge and 30-Day Rehospitalization Following Inpatient Rehabilitation. AB - OBJECTIVE: To examine the effects of facility-level acute-postacute continuity on probability of community discharge and 30-day rehospitalization following inpatient rehabilitation. DATA SOURCES: We used national Medicare enrollment, claims, and assessment data to study 541,097 patients discharged from 1,156 inpatient rehabilitation facilities (IRFs) in 2010-2011. STUDY DESIGN: We calculated facility-level continuity as the percentages of an IRF's patients admitted from each contributing acute care hospital. Patients were categorized into three groups: low continuity (<26 percent from same hospital that discharged the patient), medium continuity (26-75 percent from same hospital), or high continuity (>75 percent from same hospital). The multivariable models included an interaction term to examine the potential moderating effects of facility type (freestanding facility vs. hospital-based rehabilitation unit) on the relationships between facility-level continuity and our two outcomes: community discharge and 30-day rehospitalization. PRINCIPAL FINDINGS: Medicare beneficiaries in hospital-based rehabilitation units were more likely to be referred from a high-contributing hospital compared to those in freestanding facilities. However, the association between higher acute-postacute continuity and desirable outcomes is significantly better in freestanding rehabilitation facilities than in hospital-based units. CONCLUSIONS: Improving continuity is a key premise of health care reform. We found that both observed referral patterns and continuity-related benefits differed markedly by facility type. These findings provide a starting point for health systems establishing or strengthening acute-postacute relationships to improve patient outcomes in this new era of shared accountability and public quality reporting programs. PMID- 28580726 TI - The first case of domino-split-liver transplantation in maple syrup urine disease. AB - The enzymatic defect in MSUD results in accumulation of neurotoxic metabolites of BCAAs. LTX has shown to be a feasible strategy in patients non-responsive to diet. Because of sufficient enzyme activity in extrahepatic tissues in healthy people, the MSUD liver graft is a suitable domino organ. We present the first case of a technical challenging ex situ split of a MSUD domino organ transplanted into two pediatric recipients. The domino graft donor was a 21-year-old female (58 kg) suffering from MSUD with recurrent metabolic decompensation despite strict diet. The organ was allocated to a 14-year-old girl (55 kg) with primary sclerosing cholangitis. Due to excellent organ quality and suitable anatomy, a backward split for a girl of 3 months (5 kg) with decompensated liver cirrhosis due to biliary atresia was performed. The postoperative course was without relevant complications, and the three recipients were discharged on postoperative days 28, 29, and 45, respectively, with good organ function. BCAAs in plasma were normal in the two domino graft recipients, and the MSUD patient showed mildly elevated but stable BCAA concentrations despite an unrestricted diet. Split domino LTX enabled successful transplantation of three patients of the waiting list with only one deceased donor graft. PMID- 28580728 TI - Late graft failure in heart transplant recipients: incidence, risk factors and clinical outcomes. AB - AIM: To analyse the incidence, risk factors and clinical outcomes of late graft failure after heart transplantation. METHODS AND RESULTS: We conducted an observational, single-centre study based on 547 patients who underwent cardiac transplantation from 1991 to 2014 and who survived the in-hospital postoperative period. Late graft failure was defined as the first hospitalization due to this condition after discharge. Over a mean follow-up of 8.4 +/- 6 years, 178 (32.5%) patients were hospitalized due to late graft failure [incidence rate: 3.6 cases per 100 patient-years, 95% confidence interval (CI) 3.1-4.2]. Pre-transplant diabetes, higher pre-transplant transpulmonary pressure gradient and lower donor recipient weight ratio were independently associated with higher risk of graft failure. Cardiac allograft vasculopathy, cellular rejection grade >=1R, and antibody-mediated rejection grade >=1 were detected in 50.6%, 44.9% and 19.2% patients, respectively, admitted due to graft failure. Left ventricular ejection fraction was >=50% in 60.1% of these patients. Re-transplant free survival 1, 5, 10 and 15 years after the diagnosis of late graft failure was 72.2%, 38.4%, 18.4%, and 7.5%, respectively; the incidence rate of re-hospitalization due to decompensated heart failure was 40.9 episodes per 100 patient-years (95% CI 36.6 46.1). The need for inotropes, the presence of cardiac allograft vasculopathy, higher creatinine serum levels, lower ejection fraction and lower sodium serum levels were independent predictors of worse outcomes. CONCLUSIONS: Late graft failure is frequent after heart transplantation, as it is associated with poor outcomes. Rejection and cardiac allograft vasculopathy are the most frequent underlying causes. PMID- 28580727 TI - Integrative gene set enrichment analysis utilizing isoform-specific expression. AB - Gene set enrichment analysis (GSEA) aims at identifying essential pathways, or more generally, sets of biologically related genes that are involved in complex human diseases. In the past, many studies have shown that GSEA is a very useful bioinformatics tool that plays critical roles in the innovation of disease prevention and intervention strategies. Despite its tremendous success, it is striking that conclusions of GSEA drawn from isolated studies are often sparse, and different studies may lead to inconsistent and sometimes contradictory results. Further, in the wake of next generation sequencing technologies, it has been made possible to measure genome-wide isoform-specific expression levels, calling for innovations that can utilize the unprecedented resolution. Currently, enormous amounts of data have been created from various RNA-seq experiments. All these give rise to a pressing need for developing integrative methods that allow for explicit utilization of isoform-specific expression, to combine multiple enrichment studies, in order to enhance the power, reproducibility, and interpretability of the analysis. We develop and evaluate integrative GSEA methods, based on two-stage procedures, which, for the first time, allow statistically efficient use of isoform-specific expression from multiple RNA-seq experiments. Through simulation and real data analysis, we show that our methods can greatly improve the performance in identifying essential gene sets compared to existing methods that can only use gene-level expression. PMID- 28580729 TI - Laparoscopic harvest of the gastro-omental free flap for reconstruction after total pharyngolaryngectomy: Operative technique. AB - Circumferential defects following salvage pharyngolaryngectomy present significant challenges in reconstructive surgery. The gastro-omental free flap has been shown to reduce the incidence of major fistula and catastrophic complications. The current technique for harvest of the flap requires laparotomy, which is potentially associated with significant post-operative complications. Laparoscopic harvest of the gastro-omental free flap can negate some of the risks associated with open surgery. We describe here the operative technique for laparoscopic gastro-omental free flap harvest for use in reconstruction following total pharyngolaryngectomy. (c) 2017 Wiley Periodicals, Inc. Head Neck 39: 1696 1698, 2017. PMID- 28580730 TI - Right aortic arch with situs solitus frequently heralds a vascular ring. AB - OBJECTIVE: We hypothesized that a right aortic arch in situs solitus, with or without an associated cardiovascular malformation, is often associated with a vascular ring. METHODS: From those born in Southern Nevada between March 2012 and March 2017, we identified 50 (3.6 per 10,000 live births) with a right aortic arch and situs solitus. From the 50 patients, 6 did not meet inclusion criteria for further analysis. RESULTS: Of the 44 remaining, 33 (75%) had a vascular ring. Of the 33 with a vascular ring, 26 (79%) occurred with an isolated right aortic arch, and 7 (21%) had an associated cardiovascular malformation. Of the total 44 patients with a right aortic arch in situs solitus, 34 (79%) were diagnosed prenatally. CONCLUSIONS: In conclusion, we found a right aortic arch in situs solitus was often associated with a vascular ring. Further, to the best of our knowledge, no previous general population study has demonstrated an equal or higher right aortic arch, prenatal detection rate of 79%. PMID- 28580731 TI - Application of capability indices and control charts in the analytical method control strategy. AB - In this study, we assessed the usefulness of control charts in combination with the process capability indices, Cpm and Cpk , in the control strategy of an analytical method. The traditional X-chart and moving range chart were used to monitor the analytical method over a 2-year period. The results confirmed that the analytical method is in-control and stable. Different criteria were used to establish the specifications limits (i.e. analyst requirements) for fixed method performance (i.e. method requirements). If the specification limits and control limits are equal in breadth, the method can be considered "capable" (Cpm = 1), but it does not satisfy the minimum method capability requirements proposed by Pearn and Shu (2003). Similar results were obtained using the Cpk index. The method capability was also assessed as a function of method performance for fixed analyst requirements. The results indicate that the method does not meet the requirements of the analytical target approach. A real-example data of a SEC with light-scattering detection method was used as a model whereas previously published data were used to illustrate the applicability of the proposed approach. PMID- 28580732 TI - Polymorphic light eruption with severe abnormal phototesting sensitivity (PLESAPS). PMID- 28580733 TI - Case report of a primary effusion lymphoma successfully treated with oral valganciclovir after failing chemotherapy. AB - Primary effusion lymphoma is a rare non-Hodgkin lymphoma that presents with pleural effusions and lacking of tumour mass. It is universally associated with human herpesvirus 8 (HHV8) and is more frequent among immunosuppressed patients. There is no standard treatment, chemotherapy and anti-HIV therapy have been used with poor results, but there is still no strong evidence supporting the use of valganciclovir. We present the case of a HIV positive man that presented with pleural effusion compatible with primary effusion lymphoma and positivity for HHV8 DNA in blood. Bortezomib-containing treatment protocol was started, but the disease progressed within the chemotherapy. Therefore, treatment with oral valganciclovir was decided and the patient achieved a sustained radiological complete response. HHV8 DNA turned negative 6 months after starting the treatment with valganciclovir. PMID- 28580736 TI - Professional responsibility and decision-making in the context of a disease focused model of nursing care: The difficulties experienced by Spanish nurses. AB - When, in 1977, nurse education in Spain was transferred to universities a more patient-centred, the Anglo-American philosophy of care was introduced into a context in which nurses had traditionally prioritised their technical skills. This paper examines the characteristics of the nurse's professional role in Spain, where the model of nursing practice has historically placed them in a position akin to that of physician assistants. The study design was qualitative and used the method of analytic induction. Participants were selected by means of theoretical sampling and then underwent in-depth interviews. The resulting material was analysed using an approach based on the principles of grounded theory. Strategies were applied to ensure the credibility, transferability, dependability and confirmability of the findings. The main conclusion is that nurses in Spain continue to work within a disease-focused model of care, making it difficult for them to take responsibility for decision-making. PMID- 28580735 TI - DDAH1 mediates gastric cancer cell invasion and metastasis via Wnt/beta-catenin signaling pathway. AB - Gastric cancer (GC) represents the fourth most common malignant neoplasm and the second leading cause of cancer death. Despite therapeutic advances in recent decades, the clinical outcome remains dismal owing to the fact that most patients with GC show advanced disease at diagnosis and current chemotherapy only confers a modest survival advantage. Identification of key molecular signaling pathways involved in gastric carcinogenesis and progression would aid in early diagnosis and provide a rational design for targeted therapies in selected patients with advanced GC, to improve their outcome. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the main enzyme that can degrade asymmetric dimethylarginine, an endogenous nitric oxide synthase (NOS) inhibitor. Increased DDAH1 expression and NO production have been linked to multiple pathological conditions including cancer. However, the prognostic significance of DDAH1 in patients with GC and its function in GC progression remain undefined. In this study, we found that downregulation of DDAH1 was frequently detected in GC tissues and strongly correlated with more aggressive phenotypes and poor prognosis. Functional assays confirmed that forced expression of DDAH1 in the GC cells suppressed cell migration and invasion in vitro, as well as metastatic potential in vivo. DDAH1 overexpression inhibited the epithelial-mesenchymal transition process by increasing beta-catenin degradation through the attenuation of Wnt/GSK-3beta signaling. In contrast, knockdown of DDAH1 produced the opposite effect. These findings suggest that DDAH1 functions as a tumor suppressor in GC and may be exploited as a diagnostic and prognostic biomarker for GC. PMID- 28580734 TI - SARS-unique fold in the Rousettus bat coronavirus HKU9. AB - The coronavirus nonstructural protein 3 (nsp3) is a multifunctional protein that comprises multiple structural domains. This protein assists viral polyprotein cleavage, host immune interference, and may play other roles in genome replication or transcription. Here, we report the solution NMR structure of a protein from the "SARS-unique region" of the bat coronavirus HKU9. The protein contains a frataxin fold or double-wing motif, which is an alpha + beta fold that is associated with protein/protein interactions, DNA binding, and metal ion binding. High structural similarity to the human severe acute respiratory syndrome (SARS) coronavirus nsp3 is present. A possible functional site that is conserved among some betacoronaviruses has been identified using bioinformatics and biochemical analyses. This structure provides strong experimental support for the recent proposal advanced by us and others that the "SARS-unique" region is not unique to the human SARS virus, but is conserved among several different phylogenetic groups of coronaviruses and provides essential functions. PMID- 28580738 TI - Ibuprofen-induced distal (type 1) renal tubular acidosis and hypokalaemia: the dangers of ibuprofen-codeine combination over-the-counter preparations. PMID- 28580737 TI - Pragmatic approach to chest pain patients discharged with undetectable high sensitivity troponin T and normal electrocardiogram: the STABS + CT protocol. AB - A strategy that discharges chest pain patients with negative high-sensitivity troponin and non-ischaemic electrocardiography changes may still result in 0.44% of patients experiencing myocardial infarction within 30 days. We observed that a pragmatic approach that systematically discharged 25 patients on cardio protective medications of aspirin, metoprolol and atorvastatin followed with prompt (<10 days) coronary computed tomography angiography resulted in no major adverse cardiac event and adverse drug reaction 30 days post-presentation. The strategy resulted in three patients (12%) ultimately diagnosed with likely unstable angina, which required planned coronary intervention in two patients and medical management in one patient. No unplanned readmissions for chest pains were noted from initial presentation through to 6-month follow up. PMID- 28580739 TI - Author reply. PMID- 28580740 TI - Euglycaemic diabetic ketoacidosis in patients using sodium-glucose co-transporter 2 inhibitors. AB - Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are an increasingly prescribed class of medication for type 2 diabetes mellitus. Euglycaemic diabetic ketoacidosis (euDKA) has been reported in association with SGLT2i use. Clinicians need to understand how to recognise and treat this complication. We describe three cases of euDKA in patients treated with SGLT2i. PMID- 28580741 TI - Rapid large pulmonary embolism after prothrombin complex concentrate for warfarin reversal during colonoscopy. PMID- 28580742 TI - Palliative care and best supportive care should not be an after 'transition' missed opportunity. PMID- 28580743 TI - Great big meta-analysis of everything: follow-up complete and known, the ultimate paean. AB - Historically, selected patients or populations have been at the centre of meta analysis, with consideration of a particular patient, or population group as central to defining the question addressed. More recently, meta-analysis with studies included based on the intervention provided have been published. This paper explores the implications of extending this methodology beyond selected interventions for limited periods of time. PMID- 28580744 TI - Management of severe asthma: targeting the airways, comorbidities and risk factors. AB - Severe asthma is a complex heterogeneous disease that is refractory to standard treatment and is complicated by multiple comorbidities and risk factors. In mild to moderate asthma, the burden of disease can be minimised by inhaled corticosteroids, bronchodilators and self-management education. In severe asthma, however, management is more complex. When patients with asthma continue to experience symptoms and exacerbations despite optimal management, severe refractory asthma (SRA) should be suspected and confirmed, and other aetiologies ruled out. Once a diagnosis of SRA is established, patients should undergo a systematic and multidimensional assessment to identify inflammatory endotypes, risk factors and comorbidities, with targeted and individualised management initiated. We describe a practical approach to assessment and management of patients with SRA. PMID- 28580745 TI - Red cell transfusion thresholds in myelodysplastic syndromes: a clinician survey to inform future clinical trials. AB - Optimal red cell transfusion thresholds in myelodysplastic syndrome are not established. In this survey of 110 Australasian haematologists' practice in myelodysplastic syndrome-related anaemia, 92% of respondents set transfusion thresholds, and would typically transfuse at a haemoglobin <80 g/L aiming for a post-transfusion haemoglobin 90-100 g/L, reflecting a restrictive transfusion strategy. Higher thresholds were typically used for patients with cardiovascular disease or anaemia symptoms. These results will inform the design of clinical trials comparing transfusion thresholds. PMID- 28580746 TI - Medical certificates attesting fitness to drive. AB - Few if any sanctions have been imposed on doctors for inappropriate certification of fitness to drive. This paper reviews a recent Tribunal decision on inappropriate certification of fitness to drive. This paper reviews the facts of the case of Medical Board of Australia v Andrew and discusses the legal implications for doctors who certify patients as fit to drive. The paper offers a necessary and timely warning that the Medical Board sought harsh sanctions, more severe than were imposed by the Tribunal, but that the Tribunal also felt compelled to impose 'general deterrence' to prevent inappropriate certification. The paper emphasises the need for scrupulous attention to detail and an absolute need for circumspection when assessing patients who claim to be seizure free, or who minimise impairment from a range of other conditions, insisting on clearance to be able to drive. PMID- 28580747 TI - Difference between presumed and perceived pain in bone marrow aspiration: pilot study. PMID- 28580748 TI - Opioid addiction and misuse in adult and adolescent patients with cancer. AB - In the context of a therapeutic opioid epidemic, particularly in the USA, where increasingly stringent screening for 'at risk' individuals and close monitoring of opioid prescription and use is strongly recommended, the issue of misuse within the cancer population must be addressed. Most patients with advanced cancer will have pain requiring opioid therapy at some stage during their disease course. In the majority, this will provide good pain relief with no short- or longer-term adverse sequelae. A subset will present with substance misuse issues that will influence management and prescribing practice. The potential ethical issues of limiting effective analgesia on the basis of addiction risk or history must be acknowledged. Both a judgemental or 'relaxed' approach to such patients is problematic. Ignoring the situation will not be in the patient's best interest, but an undue focus on this aspect may damage therapeutic relationships with clinicians and adversely affect a holistic approach to care. Clinical practitioners must be aware of the risk factors for opioid misuse and in patients who are not under palliative care consider screening prior to commencing opioids. Clinicians must be able to manage and monitor those identified as having an opioid misuse problem. PMID- 28580749 TI - Mobile health: an emerging technology with implications for global internal medicine. PMID- 28580750 TI - Raising the bar on guideline utility and trustworthiness. PMID- 28580751 TI - Spontaneous pneumomediastinum: a rare entity but not to be missed. PMID- 28580752 TI - Patient consent and genuine understanding. PMID- 28580753 TI - Reporting functional status in UNOS: The weakness of the Karnofsky Performance Status Scale. PMID- 28580754 TI - Regional distribution and integrity of equine ovarian pre-antral follicles. AB - The goal of this study was to determine the distribution of pre-antral follicles in the ovarian parenchyma of mares. For Experiment 1, each ovary was cut longitudinally at the greater curvature, performing two hemiovaries. After that, six fragments from each hemiovary were obtained, resulting in 12 fragments, which were divided into the innermost region of the parenchyma, the middle region and the outermost region. All the three obtained sections were cut transversally to obtain two fragments from each one. For Experiment 2, each ovary also submitted to a longitudinal cut on the greater curvature, forming two hemiovaries. Each hemiovary was sectioned into four symmetrical fragments, resulting in eight fragments per ovary. The fragments were related as being near to or far from the ovulatory fossa. The fragments of both experiments were immediately fixed in Carnoy for 12 hr and kept in 70% ethanol for 24 hr. Follicles were classified according to the stages of development and for morphological integrity according to oocyte morphology and granulosa cells. After the histological assessment, a total of 1,130 follicles were visualized from Experiment 1, being 1,054 (93.3%) primordial follicles and 76 (4.7%) follicles in development. The innermost region had the highest percentage of pre-antral follicles compared to the other regions (p < .05). The middle and outermost regions showed higher percentages of intact primordial and developing follicles than the innermost region (p < .05). Considering Experiment 2, 938 follicles were found, being 894 (95.3%) primordial and 44 (4.7%) follicles in development. The region near the ovulatory fossa presented higher (58.7%; 551 of 938) follicular concentration compared to the region far from the ovulatory fossa (41.3%; 387 of 938; p < .05). As a conclusion, distribution of pre-antral follicles in the equine ovary has a specific pattern through the parenchyma. Also, the follicular integrity differed in the studied ovarian areas. PMID- 28580755 TI - Crabrolin, a natural antimicrobial peptide: structural properties. AB - A joint application of experimental and computational approaches has revealed the exceptionally high attitude of crabrolin, a 13-residue peptide with sequence FLPLILRKIVTAL-NH2 , to adopt alpha-helix conformation not only in membrane mimicking solvents but also in the presence of a not negligible amount of water. Our study shows that this propensity essentially resides in the intrinsic thermodynamic stability of alpha-helix conformation whose kinetic stability is drastically reduced in water solvent. Our analysis suggests that this is due to two effects enhanced by water: a more local effect consisting of the demolition of intra-peptide H-bonds, essential for the alpha-helix formation, and a bulk - electrostatic - effect favoring conformational states more polar than alpha helix. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28580756 TI - High tunnels: protection for rather than from insect pests? AB - BACKGROUND: High tunnels are a season extension tool creating a hybrid of field and greenhouse growing conditions. High tunnels have recently increased in the USA and thus research on their management is lacking. One purported advantage of these structures is protection from common field pests, but evidence to support this claim is lacking. We compared insect pest populations in high tunnels with field production over two years for three crops: tomato, broccoli and cucumber. RESULTS: Greenhouse pests (e.g. aphids, whiteflies) were more prevalent in high tunnels, compared to field plots. Hornworms (tobacco (Manduca sexta L.) and tomato (M. quinquemaculata Haworth)), a common field pest on tomato, were also more abundant in high tunnels, requiring chemical control while field populations were low. The crucifer caterpillar complex (imported cabbageworm (Pieris rapae L.), diamondback moth (Plutella xylostella L.) and cabbage looper (Trichoplusia ni Hubner)) was also more abundant in high tunnels in 2010. Cucumber beetle (striped (Acalymma vittatum F.) and spotted (Diabrotica undecimpunctata Mannerheim)) densities were higher in high tunnels in 2010 and field plots in 2011. CONCLUSION: The common assumption that high tunnels offer protection from field pests was not supported. Instead, high tunnel growing conditions may facilitate higher pest populations. (c) 2017 Society of Chemical Industry. PMID- 28580757 TI - High-Performance Ruthenium Sensitizers Containing Imidazolium Counterions for Efficient Dye Sensitization in Water. AB - A new type of water-soluble ruthenium sensitizers incorporating imidazolium counterions, denoted [DMPI]2 -Ru and [DMHI]2 -Ru, has been developed, which can be efficiently adsorbed onto TiO2 photoanodes in aqueous solution. Owing to the good thermal stability of imidazolium, [DMPI]2 -Ru adsorbed on TiO2 has a higher decomposition temperature than N719 dye [di(tetrabutylammonium) cis di(thiocyanato)bis(2,2'-bipyridine-4,4'-dicarboxylato)ruthenium(II)]. When using organic solvent-based I- /I3- electrolytes, solars cell based on [DMPI]2 -Ru sensitized TiO2 in water show high power conversion efficiencies (PCE) of up to 10.2 %, which is higher than that of N719 (9.9 %) under the common conditions for dye sensitization in organic solvent. [DMHI]2 -Ru, with poorer water solubility than [DMPI]2 -Ru, gives a smaller dye-adsorption amount on TiO2 and thus a lower PCE of 9.4 %. From the viewpoint of safety and environmental impact, the fabrication of dye-sensitized solar cells (DSSCs) by using water as solvent is undoubtedly a preferable strategy. Although the [DMPI]2 -Ru-based device fabricated by using water as the solvent for both the dye-sensitization process and the electrolyte gives a relatively low efficiency, it provides a promising approach for the practical application of DSSCs. PMID- 28580758 TI - Nuclei-specific deposits of iron and calcium in the rat thalamus after status epilepticus revealed with quantitative susceptibility mapping (QSM). AB - PURPOSE: To investigate pathological changes in the rat brain after pilocarpine induced status epilepticus using quantitative susceptibility mapping (QSM). MATERIALS AND METHODS: 3D multiecho gradient-echo (GRE) data were acquired from ex vivo brains of pilocarpine-injected and age-matched control rats at 11.7T. Maps of R2* and quantitative susceptibility were calculated from the acquired 3D GRE magnitude and phase data, respectively. QSM and R2* maps were compared with Perls' (iron) and Alizarin-red-S (calcium) stainings in the same brains to investigate the pathophysiological basis of susceptibility contrast. RESULTS: Bilaterally symmetric lesions were detected in reproducible thalamic regions of pilocarpine-treated rats, characterized by hyperintensity in R2* maps. In comparison, quantitative susceptibility maps demonstrated heterogeneous contrast within the lesions, with distinct hyperintense (paramagnetic) and hypointense (diamagnetic) areas. Comparison with histological assessment revealed localized deposits of iron- and calcium-positive granules in thalamic nuclei corresponding to paramagnetic and diamagnetic areas delineated in the susceptibility maps, respectively. Pronounced differences were observed in the lesions between background-corrected phase images and reconstructed susceptibility maps, indicating unreliable differentiation of iron and calcium deposits in phase maps. Multiple linear regression showed a significant association between susceptibility values and measured optical densities (ODs) of iron and calcium in the lesions (R2 = 0.42, P < 0.001), with a positive dependence on OD of iron and negative dependence on OD of calcium. CONCLUSION: QSM can detect and differentiate pathological iron and calcium deposits with high sensitivity and improved spatial accuracy compared to R2* or GRE phase images, rendering it a promising technique for diagnosing thalamic lesions after status epilepticus. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:554-564. PMID- 28580760 TI - Stress echocardiography: An overview for use in pediatric and congenital cardiology. AB - Currently, the role of stress echocardiography primarily resides in diagnosing acquired coronary artery disease (CAD) in adults. Besides an increasing concern for traditional CAD in young patients due to obesity and other chronic pediatric diseases, there is also a growing population of adolescents and young adults with "at risk" coronary arteries due to: reimplanted coronaries in congenital heart disease, anomalous origin of the native coronary arteries, coronary abnormalities in Kawasaki's disease, and posttransplant coronary vasculopathy. Stress echocardiography is well suited for routine screening and monitoring in these patients. Also, due to the ability of stress echocardiography to provide real time cardiac imaging, it is useful in areas beyond coronary ischemia. Utilizing Doppler derived velocities and pressure gradients, one is able to further evaluate and risk-stratify patients with valvular heart disease. In addition, stress echocardiography is useful in evaluating other areas including ventricular and coronary reserve. The benefits of stress echocardiography are it is: readily available, portable, and relatively cheap. It can be performed without sedation or radiation exposure which becomes very important in younger patients that require periodic monitoring. Stress echocardiography can also evaluate functional abnormalities instead of relative perfusion defects. Overall, stress echocardiography is currently an underutilized imaging modality that has a wide, and expanding, range of application in the practice of pediatric and congenital cardiology. PMID- 28580759 TI - A quality control circle process to improve implementation effect of prevention measures for high-risk patients. AB - The aim of the study was to analyse the influence of prevention measures on pressure injuries for high-risk patients and to establish the most appropriate methods of implementation. Nurses assessed patients using a checklist and factors influencing the prevention of a pressure injury determined by brain storming. A specific series of measures was drawn up and an estimate of risk of pressure injury determined using the Braden Scale, analysis of nursing documents, implementation of prevention measures for pressure sores and awareness of the system both before and after carrying out a quality control circle (QCC) process. The overall scores of implementation of prevention measures ranged from 74.86 +/- 14.24 to 87.06 +/- 17.04, a result that was statistically significant (P < 0.0025). The Braden Scale scores ranged from 8.53 +/- 3.21 to 13.48 +/- 3.57. The nursing document scores ranged from 7.67 +/- 3.98 to 10.12 +/- 1.63; prevention measure scores ranged from 11.48 +/- 4.18 to 13.96 +/- 3.92. Differences in all of the above results are statistically significant (P < 0.05). Implementation of a QCC can standardise and improve the prevention measures for patients who are vulnerable to pressure sores and is of practical importance to their prevention and control. PMID- 28580761 TI - Passive smoking as an independent risk factor for gestational diabetes that synergizes with prepregnancy obesity in urban Chinese women. AB - There are high-priority public health and legislative efforts around the world to reduce smoking and to reduce the spaces where smoking is allowable. These efforts are aimed at minimizing not only the adverse health effects of active smoking but also the adverse health effects of passive cigarette smoke exposure. While many cultures and societies make protection of a pregnant woman and her about-to-be born-newborn a priority, the importance of protecting them from passive smoking that is prevalent in many modern societies has not been reported. The article by Leng et al, "Passive smoking increased risk of gestational diabetes mellitus independently and synergistically with prepregnancy obesity in Tianjin, China," newly published in Diabetes Metabolism Research and Reviews, provides evidence that passive smoke inhalation during pregnancy makes gestational diabetes more likely, bringing with it negative health consequences for the mother and her baby. This study will hopefully add support to public health officials' efforts to curb cigarette use, especially in public domains. PMID- 28580763 TI - Knowledge-based reconstruction for measurement of right ventricular volumes on cardiovascular magnetic resonance images in a mixed population. AB - OBJECTIVE: Follow-up of right ventricular performance is important for patients with congenital heart disease. Cardiac magnetic resonance imaging is optimal for this purpose. However, observer-dependency of manual analysis of right ventricular volumes limit its use. Knowledge-based reconstruction is a new semiautomatic analysis tool that uses a database including knowledge of right ventricular shape in various congenital heart diseases. We evaluated whether knowledge-based reconstruction is a good alternative for conventional analysis. DESIGN: To assess the inter- and intra-observer variability and agreement of knowledge-based versus conventional analysis of magnetic resonance right ventricular volumes, analysis was done by two observers in a mixed group of 22 patients with congenital heart disease affecting right ventricular loading conditions (dextro-transposition of the great arteries and right ventricle to pulmonary artery conduit) and a group of 17 healthy children. We used Bland Altman analysis and coefficient of variation. RESULTS: Comparison between the conventional method and the knowledge-based method showed a systematically higher volume for the latter group. We found an overestimation for end-diastolic volume (bias -40 +/- 24 mL, r = .956), end-systolic volume (bias -34 +/- 24 mL, r = .943), stroke volume (bias -6 +/- 17 mL, r = .735) and an underestimation of ejection fraction (bias 7 +/- 7%, r = .671) by knowledge-based reconstruction. The intra-observer variability of knowledge-based reconstruction varied with a coefficient of variation of 9% for end-diastolic volume and 22% for stroke volume. The same trend was noted for inter-observer variability. CONCLUSION: A systematic difference (overestimation) was noted for right ventricular size as assessed with knowledge-based reconstruction compared with conventional methods for analysis. Observer variability for the new method was comparable to what has been reported for the right ventricle in children and congenital heart disease with conventional analysis. PMID- 28580762 TI - Static beam tomotherapy as an optimisation method in whole-breast radiation therapy (WBRT). AB - INTRODUCTION: TomoTherapy (Accuray, Sunnyvale, CA) has recently introduced a static form of tomotherapy: TomoDirectTM (TD). This study aimed to evaluate TD against a contemporary intensity modulated radiation therapy (IMRT) alternative through comparison of target and organ at risk (OAR) doses in breast cancer cases. A secondary objective was to evaluate planning efficiency by measuring optimisation times. METHODS: Treatment plans of 27 whole-breast radiation therapy (WBRT) patients optimised with a tangential hybrid IMRT technique were replanned using TD. Parameters included a dynamic field width of 2.5 cm, a pitch of 0.251 and a modulation factor of 2.000; 50 Gy in 25 fractions was prescribed and planning time recorded. The planning metrics used in analysis were ICRU based, with the mean PTV minimum (D99 ) used as the point of comparison. RESULTS: Both modalities met ICRU50 target heterogeneity objectives (TD D99 = 48.0 Gy vs. IMRT = 48.1 Gy, P = 0.26; TD D1 = 53.5 Gy vs. IMRT = 53.0 Gy, P = 0.02; Homogeneity index TD = 0.11 vs. IMRT = 0.10, P = 0.03), with TD plans generating higher median doses (TD D50 = 51.1 Gy vs. IMRT = 50.9 Gy, P = 0.03). No significant difference was found in prescription dose coverage (TD V50 = 85.5% vs. IMRT = 82.0%, P = 0.09). TD plans produced a statistically significant reduction in V5 ipsilateral lung doses (TD V5 = 23.2% vs. IMRT = 27.2%, P = 0.04), while other queried OARs remained comparable (TD ipsilateral lung V20 = 13.2% vs. IMRT = 14.6%, P = 0.30; TD heart V5 = 2.7% vs. IMRT = 2.8%, P = 0.47; TD heart V10 = 1.7% vs. IMRT = 1.8%, P = 0.44). TD reduced planning time considerably (TD = 9.8 m vs. IMRT = 27.6 m, P < 0.01), saving an average planning time of 17.8 min per patient. CONCLUSIONS: TD represents a suitable WBRT treatment approach both in terms of plan quality metrics and planning efficiency. PMID- 28580764 TI - Resiniferatoxin modulates the Th1 immune response and protects the host during intestinal nematode infection. AB - In the early stage of the intestinal phase of Trichinella spiralis infection, the host triggers a Th1-type immune response with the aim of eliminating the parasite. However, this response damages the host which favours the survival of the parasite. In the search for novel pharmacological strategies that inhibit the Th1 immune response and assist the host against T. spiralis infection, a recent study showed that resiniferatoxin had anti-inflammatory activity contributed to the host in T. spiralis infection. In this study, we evaluated whether RTX modulates the host immune response through the inhibition of Th1 cytokines in the intestinal phase. In addition, it was determined whether the treatment with RTX affects the infectivity of T. spiralis-L1 and the development of the T. spiralis life cycle. Our results show that RTX decreased serum levels of IL-12, INF-gamma, IL-1beta, TNF-alpha and parasite burden on muscle tissue. It was observed that T. spiralis-L1 treated with RTX decreased their infectivity affecting the development of the T. spiralis life cycle in mouse. These results demonstrate that RTX is able to inhibit the production of Th1 cytokines, contributing to the defence against T. spiralis, which places it as a potential drug modulator of the immune response. PMID- 28580766 TI - Pharmacological stress, rest perfusion and delayed enhancement cardiac magnetic resonance identifies very early cardiac involvement in systemic sclerosis patients of recent onset. AB - OBJECTIVE: To evaluate occult cardiac involvement in asymptomatic systemic sclerosis (SSc) patients by pharmacological stress, rest perfusion and delayed enhancement cardiac magnetic resonance (CMR), for a very early identification of patients at higher risk of cardiac-related mortality. METHODS: Sixteen consecutive patients with definite SSc, fulfilling the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria in less than 1 year from the onset of Raynaud's phenomenon, underwent pharmacological stress, rest perfusion and delayed enhancement CMR. At enrollment, no patient showed signs and/or symptoms suggestive for cardiac involvement. No patient showed traditional cardiovascular risk factors. Both the 12-lead electrocardiogram examination and echocardiographic evaluation did not show any alterations in our cohort. RESULTS: Stress perfusion defects of left ventricle were detected in six out of 16 (37.5%) patients and these defects did not match with the coronary flow distribution. The results showed the presence of two different patterns of stress perfusion defects: sub-endocardial and/or a midmyocardial. The presence of stress perfusion defects did not correlate with any clinical feature of enrolled patients. CONCLUSION: Myocardial stress perfusion defects may be detected early by pharmacological stress perfusion CMR, a reliable and sensitive technique for the noninvasive evaluation of SSc heart disease, in patients with SSc of recent onset. These defects seem to be independent from traditional risk factors and associated comorbidities, suggesting they are a specific hallmark of the disease. PMID- 28580767 TI - Drug-coated balloon: Long-term outcome from a real world three-center experience. AB - OBJECTIVES: In-stent restenosis (ISR) and diffuse small vessel disease still represent challenging subsets for percutaneous coronary interventions, also in the new-generation DES era. We aim at reporting on the long-term clinical outcome of drug-coated balloons (DCB) in all-comers population. METHODS: Consecutive patients treated with DCB between January 2011 and December 2014 were retrospectively studied in three centers of northern Italy. The measured end points were cardiac death, myocardial infarction (MI), target lesion revascularization (TLR), and major adverse cardiac events (MACE) defined as combination of cardiac death, MI, and TLR. RESULTS: We included 143 patients. Of the 167 lesions treated, 41 (24.5%) were de novo lesions in small coronary vessels (<2.5 mm) and 126 (75.4%) were ISR. Among ISR lesions, 78.5% were DES ISR, 32.5% were focal, 15.8% multifocal, 30.1% diffuse, 18.2% proliferative, and 3.1% were total occlusions. Procedural success was achieved in 94.6% of cases. Overall survival free from MACEs was 91.6% at 12 months, and 75.3% at 48 months, with a total of 3 cardiac deaths, 8 MI, and 27 TLR. No thrombotic event occurred in the treated segments. There were no differences in MACESs between the ISR and de novo lesions groups. At multivariate analysis, acute coronary syndromes, previous MI, previous surgical revascularization, peripheral arterial disease and diabetes were independent predictors of MACEs at long-term follow-up. CONCLUSIONS: DCB proved a valid revascularization strategy in an all-comers population of patients with ISR and de novo lesions in small vessels, with an acceptable rate of cardiac events up to 48 months follow-up. PMID- 28580768 TI - AHNS Series - Do you know your guidelines? Lip cancer. AB - BACKGROUND: Lip cancer is one of the most curable primary head and neck malignancies, as the prominent location typically lends to an early diagnosis. The incidence of lip cancer varies by sex, ethnicity, and region, but is estimated to be up to 2.5/100 000 in the United States (squamous cell carcinoma [SCC]). METHODS: This article will review the current literature and National Comprehensive Cancer Network practice guidelines in the treatment of lip cancer. RESULTS: Resection of lip cancer with negative margins remains the mainstay of therapy. Positive nodal disease should be treated with neck dissection and adjuvant radiotherapy. CONCLUSION: Lip cancer remains highly curable when diagnosed at an early stage. A multidisciplinary approach is crucial to treating patients with advanced-stage lip cancer. PMID- 28580765 TI - In vitro evaluation of a basic fibroblast growth factor-containing hydrogel toward vocal fold lamina propria scar treatment. AB - Scarring of the vocal fold lamina propria can lead to debilitating voice disorders that can significantly impair quality of life. The reduced pliability of the scar tissue-which diminishes proper vocal fold vibratory efficiency results in part from abnormal extracellular matrix (ECM) deposition by vocal fold fibroblasts (VFF) that have taken on a fibrotic phenotype. To address this issue, bioactive materials containing cytokines and/or growth factors may provide a platform to transition fibrotic VFF within the scarred tissue toward an anti fibrotic phenotype, thereby improving the quality of ECM within the scar tissue. However, for such an approach to be most effective, the acute host response resulting from biomaterial insertion/injection likely also needs to be considered. The goal of the present work was to evaluate the anti-fibrotic and anti-inflammatory capacity of an injectable hydrogel containing tethered basic fibroblast growth factor (bFGF) in the dual context of scar and biomaterial induced acute inflammation. An in vitro co-culture system was utilized containing both activated, fibrotic VFF and activated, pro-inflammatory macrophages (MPhi) within a 3D poly(ethylene glycol) diacrylate (PEGDA) hydrogel containing tethered bFGF. Following 72 h of culture, alterations in VFF and macrophage phenotype were evaluated relative to mono-culture and co-culture controls. In our co-culture system, bFGF reduced the production of fibrotic markers collagen type I, alpha smooth muscle actin, and biglycan by activated VFF and promoted wound healing/anti-inflammatory marker expression in activated MPhi. Cumulatively, these data indicate that bFGF-containing hydrogels warrant further investigation for the treatment of vocal fold lamina propria scar. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1258-1267, 2018. PMID- 28580769 TI - Factor VII and factor X deficiency in a child with a chromosome 13q duplication and deletion. PMID- 28580770 TI - Evaluating pulmonary congestion with lung ultrasound and the need to take the next steps in heart failure. PMID- 28580771 TI - In vitro oxidative degradation of a spinal posterior dynamic stabilization device. AB - This study quantified the changes of the frequency-dependant viscoelastic properties of the BDyn (S14 Implants, Pessac, France) spinal posterior dynamic stabilization (PDS) device due to in vitro oxidation. Six polycarbonate urethane (PCU) rings and six silicone cushions were degraded using a 20% hydrogen peroxide/0.1 M cobalt (II) chloride hexahydrate, at 37 degrees C, for 24 days. The viscoelastic properties of the individual components and the components assembled into the BDyn PDS device were determined using Dynamic Mechanical Analysis at frequencies from 0.01 to 30 Hz. Attenuated Total Reflectance Fourier Transform Infra-Red spectra demonstrated chemical structure changes, of the PCU, associated with oxidation while Scanning Electron Microscope images revealed surface pitting. No chemical structure or surface morphology changes were observed for the silicone cushion. The BDyn device storage and loss stiffness ranged between 84.46 N/mm to 99.36 N/mm and 8.13 N/mm to 21.99 N/mm, respectively. The storage and loss stiffness for the components and BDyn device increased logarithmically with respect to frequency. Viscoelastic properties, between normal and degraded components, were significantly different for specific frequencies only. This study demonstrates the importance of analyzing changes of viscoelastic properties of degraded biomaterials and medical devices into which they are incorporated, using a frequency sweep. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1237-1244, 2018. PMID- 28580772 TI - Exercise training increases skeletal muscle mitochondrial volume density by enlargement of existing mitochondria and not de novo biogenesis. AB - AIMS: (i) To determine whether exercise-induced increases in muscle mitochondrial volume density (MitoVD ) are related to enlargement of existing mitochondria or de novo biogenesis and (ii) to establish whether measures of mitochondrial specific enzymatic activities are valid biomarkers for exercise-induced increases in MitoVD . METHOD: Skeletal muscle samples were collected from 21 healthy males prior to and following 6 weeks of endurance training. Transmission electron microscopy was used for the estimation of mitochondrial densities and profiles. Biochemical assays, western blotting and high-resolution respirometry were applied to detect changes in specific mitochondrial functions. RESULT: MitoVD increased with 55 +/- 9% (P < 0.001), whereas the number of mitochondrial profiles per area of skeletal muscle remained unchanged following training. Citrate synthase activity (CS) increased (44 +/- 12%, P < 0.001); however, there were no functional changes in oxidative phosphorylation capacity (OXPHOS, CI+IIP ) or cytochrome c oxidase (COX) activity. Correlations were found between MitoVD and CS (P = 0.01; r = 0.58), OXPHOS, CI+CIIP (P = 0.01; R = 0.58) and COX (P = 0.02; R = 0.52) before training; after training, a correlation was found between MitoVD and CS activity only (P = 0.04; R = 0.49). Intrinsic respiratory capacities decreased (P < 0.05) with training when respiration was normalized to MitoVD. This was not the case when normalized to CS activity although the percentage change was comparable. CONCLUSIONS: MitoVD was increased by inducing mitochondrial enlargement rather than de novo biogenesis. CS activity may be appropriate to track training-induced changes in MitoVD. PMID- 28580774 TI - Clinical utility of biomarkers in heart failure. PMID- 28580773 TI - HBx-mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis. AB - Tumor metastasis is responsible for the high mortality rates in patients with hepatocellular carcinoma (HCC). Absent in melanoma 2 (AIM2) has been implicated in inflammation and carcinogenesis, although its role in HCC metastasis remains unknown. In the present study, we show that AIM2 protein expression was noticeably reduced in HCC cell lines and clinical samples. A reduction in AIM2 was closely associated with higher serum AFP levels, vascular invasion, poor tumor differentiation, an incomplete tumor capsule and unfavorable postsurgical survival odds. In vitro studies demonstrated that AIM2 expression was modulated by hepatitis B virus X protein (HBx) at transcriptional and post-translational levels. HBx overexpression markedly blocked the expression of AIM2 at mRNA and protein levels by enhancing the stability of Enhancer of zeste homolog 2 (EZH2). Furthermore, HBx interacted with AIM2, resulting in an increase of AIM2 degradation via ubiquitination induction. Functionally, knockdown of AIM2 enhanced cell migration, formation of cell pseudopodium, wound healing and tumor metastasis, whereas reintroduction of AIM2 attenuated these functions. The loss of AIM2 induced the activation of epithelial-mesenchymal transition (EMT). Fibronectin 1 (FN1) was found to be a downstream effector of AIM2, with its expression reversely modulated by AIM2. Silencing of FN1 significantly halted cell migration induced by AIM2 depletion. These data demonstrate that HBx-induced loss of AIM2 is associated with poor outcomes and facilitates HCC metastasis by triggering the EMT process. The results of the present study therefore suggest that AIM2 is a potential prognostic biomarker in hepatitis B virus-related HCC, as well as a possible therapeutic target for tumor metastasis. PMID- 28580776 TI - Do we have enough evidence for minimally-invasive cardiac surgery? A critical review of scientific and non-scientific information. AB - Reducing surgical trauma by minimizing skin incisions has transformed abdominal surgery resulting in significant improvements in outcome. In cardiac surgery, such efforts have also been made, but similar benefits could not be demonstrated. In addition, any potential benefit comes at the cost of increased cardiopulmonary bypass and clamp times, leading to questions regarding the safety of minimally invasive cardiac surgery (MICS). Nevertheless, outcomes have been equivalent to matched sternotomy cases and there is no doubt that the number of patients undergoing minimally-invasive mitral or aortic procedures is slowly increasing. To date almost half of all isolated mitral cases in Germany and roughly one fourth in the USA are performed through a minimized access. These numbers were less than half 10 years ago. So how can this development be justified, if the evidence for it seems to be questionable or even missing? We will attempt to provide some answers to this question by critically reviewing the available publications and by looking at the topic from other perspectives, including from a competitive and a patient standpoint. We will conclude that there is enough evidence to support minimally-invasive access as the primary approach to a valve in the majority of patients. We will further suggest that modern cardiac surgery may have difficulties to prevail in its full width, if these novel techniques are not embraced. Finally, we will demonstrate that minimally invasive cardiac surgery is associated with substantial improvements in patient care, however, in areas that are unlikely to be tested with randomized controlled trials. PMID- 28580777 TI - Meeting of the Strategic Advisory Group of Experts on immunization, April 2017 - conclusions and recommendations. PMID- 28580775 TI - Persistent distention of colon damages interstitial cells of Cajal through Ca2+ ERK-AP-1-miR-34c-SCF deregulation. AB - Gastrointestinal motility disorders (GMDs) are attributed to loss of interstitial cells of Cajal (ICC), whose survival and function are deeply dependent on the activation of KIT/SCF signalling. Based on the facts that gastrointestinal distention is common in GMD patients and SCF produced by smooth muscle cells (SMCs) is usually decreased before ICC loss, we considered a possible contribution of persistent gastrointestinal distention/stretch to SCF deficiency. In this study, chronic colonic distention mouse model, diabetic gastrointestinal paresis mouse model, cultured mouse colonic SMCs and colon specimens from Hirschsprung's disease patients were used. The results showed that SCF was clearly decreased in distent colon of mice and patients, and microRNA array and real-time PCR indicated a concomitant increase of miR-34c in distent colon. A negative regulation of miR-34c on SCF expression was confirmed by luciferase reporter assays together with knock-down and overexpression of miR-34c in cultured colonic SMCs. Using EMSA and ChIP assays, we further consolidated that in response to persistent stretch, the transcription factor AP-1/c-Jun was highly activated in colonic SMCs and significantly promoted miR-34c transcription by binding to miR-34c promoter. Knock-down or overexpression of AP-1/c-Jun in cultured colonic SMCs leads to down- or up-regulation of miR-34c, respectively. In addition, the activation of AP-1/c-Jun was through ERK1/2 signalling provoked by Ca2+ overload in colonic SMCs that were subject to persistent stretch. In conclusion, our data demonstrated that persistent distention/stretch on colonic SMCs could suppress SCF production probably through Ca2+ -ERK-AP-1-miR-34c deregulation, resulting in ICC loss or impairment and GMD progress. PMID- 28580778 TI - Full-State Controls of Terahertz Waves Using Tensor Coding Metasurfaces. AB - Coding metasurfaces allow us to study metamaterials from a fully digital perspective, enabling many exotic functionalities, such as anomalous reflections, broadband diffusions, and polarization conversion. Here, we propose a tensor coding metasurface at terahertz (THz) frequency that could take full-state controls of an electromagnetic wave in terms of its polarization state, phase and amplitude distributions, and wave-vector mode. Owing to the off-diagonal elements that dominant in the reflection matrix, each coding particle could reflect the normally incident wave to its cross-polarization with controllable phases, resulting in different coding digits. A 3-bit tensor coding metasurface with three coding sequences is taken as an example to show its full-state controls in reflecting a normally incident THz beam to anomalous directions with cross polarizations and making a spatially propagating wave (PW) to surface wave (SW) conversion at the THz frequency. We show that the proposed PW-SW convertor based on the tensor coding metasurface supports both x- and y-polarized normal incidences, producing cross-polarized transverse-magnetic and transverse-electric modes of THz SWs, respectively. PMID- 28580780 TI - Monolithic Mid-Infrared Integrated Photonics Using Silicon-on-Epitaxial Barium Titanate Thin Films. AB - Broadband mid-infrared (mid-IR) photonic circuits that integrate silicon waveguides and epitaxial barium titanate (BTO) thin films are demonstrated using the complementary metal-oxide-semiconductor process. The epitaxial BTO thin films are grown on lanthanum aluminate (LAO) substrates by the pulsed laser deposition technique, wherein a broad infrared transmittance between lambda = 2.5 and 7 MUm is observed. The optical waveguiding direction is defined by the high-refractive index amorphous Si (a-Si) ridge structure developed on the BTO layer. Our waveguides show a sharp fundamental mode over the broad mid-IR spectrum, whereas its optical field distribution between the a-Si and BTO layers can be modified by varying the height of the a-Si ridge. With the advantages of broad mid-IR transparency and the intrinsic electro-optic properties, our monolithic Si on a ferroelectric BTO platform will enable tunable mid-IR microphotonics that are desired for high-speed optical logic gates and chip-scale biochemical sensors. PMID- 28580781 TI - Droplet-Confined Electroless Deposition of Silver Nanoparticles on Ordered Superhydrophobic Structures for High Uniform SERS Measurements. AB - Surface-enhanced Raman scattering spectroscopy (SERS) is a nondestructive testing technique. To increase reproducibility of the SERS measurement is the key issue for improving the performance of SERS. In this article, we demonstrate an efficient method to improve the reproducibility, using confined silver nanoparticles (AgNPs) as a substrate. The AgNPs are formed uniformly on the tops of the prepared nanopillars by droplet-confined electroless deposition on the hydrophobic Si nanopillar arrays. The AgNPs present an excellent reproducibility in Raman measurement; the relative standard deviation is down to 3.40%. There exists a great linear correlation between the concentration of Rhodamine 6G (R6G) and the Raman intensity in the log-log plot; R2 is 0.998, indicating that this SERS substrate can be applied for the quantitative SERS analysis. Meanwhile, the minimum detection concentration is down to 10-11 M on the hydrophobic substrate, with R6G as a probe molecule. PMID- 28580782 TI - Correction to "Structure of Light-Harvesting Aggregates in Individual Chlorosomes". PMID- 28580783 TI - Cascade Synthesis of Benzimidazole-Linked Pyrroles via Copper Catalyzed Oxidative Cyclization and Ketonization. AB - A three-component cascade reaction of 2-aminobenzimidazole, aldehyde, and terminal alkyne has been explored for an efficient synthesis of benzimidazole linked tetrasubstituted pyrroles. The reaction sequence involves the formation of propargylamine, insertion of a terminal alkyne, and a ring opening reaction followed by an intramolecular carbonylative cyclization under aerobic conditions. It represents a novel strategy to the construction of C?N, C?C, C?O bonds and a new five-membered 2-ketopyrrole ring. In this process, the reaction conditions are crucial and an attempt to elucidate the novel reaction pathway is well supported by X-ray crystallography. PMID- 28580779 TI - Spatial Organization of Metabolic Enzyme Complexes in Cells. AB - The organization of metabolic multienzyme complexes has been hypothesized to benefit metabolic processes and provide a coordinated way for the cell to regulate metabolism. Historically, their existence has been supported by various in vitro techniques. However, it is only recently that the existence of metabolic complexes inside living cells has come to light to corroborate this long-standing hypothesis. Indeed, subcellular compartmentalization of metabolic enzymes appears to be widespread and highly regulated. On the other hand, it is still challenging to demonstrate the functional significance of these enzyme complexes in the context of the cellular milieu. In this review, we discuss the current understanding of metabolic enzyme complexes by primarily focusing on central carbon metabolism and closely associated metabolic pathways in a variety of organisms, as well as their regulation and functional contributions to cells. PMID- 28580784 TI - Doubly Reentrant Cavities Prevent Catastrophic Wetting Transitions on Intrinsically Wetting Surfaces. AB - Omniphobic surfaces, that is, which repel all known liquids, have proven of value in applications ranging from membrane distillation to underwater drag reduction. A limitation of currently employed omniphobic surfaces is that they rely on perfluorinated coatings, increasing cost and environmental impact and preventing applications in harsh environments. Thus, there is a keen interest in rendering conventional materials, such as plastics, omniphobic by micro/nanotexturing rather than via chemical makeup, with notable success having been achieved for silica surfaces with doubly reentrant micropillars. However, we found a critical limitation of microtextures comprising pillars that they undergo catastrophic wetting transitions (apparent contact angles, thetar -> 0 degrees from thetar > 90 degrees ) in the presence of localized physical damages/defects or on immersion in wetting liquids. In response, a doubly reentrant cavity microtexture is introduced, which can prevent catastrophic wetting transitions in the presence of localized structural damage/defects or on immersion in wetting liquids. Remarkably, our silica surfaces with doubly reentrant cavities could exhibit apparent contact angles, thetar ~ 135 degrees for mineral oil, where the intrinsic contact angle, thetao ~ 20 degrees . Further, when immersed in mineral oil or water, doubly reentrant microtextures in silica (thetao ~ 40 degrees for water) were not penetrated even after several days of investigation. Thus, microtextures comprising doubly reentrant cavities might enable applications of conventional materials without chemical modifications, especially in scenarios that are prone to localized damages or immersion in wetting liquids, for example, hydrodynamic drag reduction and membrane distillation. PMID- 28580786 TI - Quantitative Performance Evaluator for Proteomics (QPEP): Web-based Application for Reproducible Evaluation of Proteomics Preprocessing Methods. AB - Tandem mass spectrometry is one of the most popular techniques for quantitation of proteomes. There exists a large variety of options in each stage of data preprocessing that impact the bias and variance of the summarized protein-level values. Using a newly released data set satisfying a replicated Latin squares design, a diverse set of performance metrics has been developed and implemented in a web-based application, Quantitative Performance Evaluator for Proteomics (QPEP). QPEP has the flexibility to allow users to apply their own method to preprocess this data set and share the results, allowing direct and straightforward comparison of new methodologies. Application of these new metrics to three case studies highlights that (i) the summarization of peptides to proteins is robust to the choice of peptide summary used, (ii) the differences between iTRAQ labels are stronger than the differences between experimental runs, and (iii) the commercial software ProteinPilot performs equivalently well at between-sample normalization to more complicated methods developed by academics. Importantly, finding (ii) underscores the benefits of using the principles of randomization and blocking to avoid the experimental measurements being confounded by technical factors. Data are available via ProteomeXchange with identifier PXD003608. PMID- 28580787 TI - Printing Functional Protein Nanodots on Soft Elastomers: From Transfer Mechanism to Cell Mechanosensing. AB - Living cells sense the physical and chemical nature of their micro/nano environment with exquisite sensitivity. In this context, there is a growing need to functionalize soft materials with micro/nanoscale biochemical patterns for applications in mechanobiology. This, however, is still an engineering challenge. Here a new method is proposed, where submicronic protein-patterns are first formed on glass and are then printed on to an elastomer. The degree of transfer is shown to be governed mainly by hydrophobic interactions and to be influenced by grafting an appropriate fluorophore onto the core protein of interest. The transfer mechanism is probed by measuring the forces of adhesion/cohesion using atomic force microscopy. The transfer of functional arrays of dots with size down to about 400 nm, on elastomers with stiffness ranging from 3 kPa to 7 MPa, is demonstrated. Pilot studies on adhesion of T lymphocytes on such soft patterned substrates are reported. PMID- 28580789 TI - Associations Between Reported Dietary Sodium Intake and Osteoporosis in Korean Postmenopausal Women: The 2008-2011 Korea National Health and Nutrition Examination Survey. AB - Osteoporosis is prevalent among postmenopausal women, and increasing evidence has linked salt intake with this disease. In this article, we explored the association between dietary sodium intake and osteoporosis in Korean postmenopausal women. We analyzed data for 3635 postmenopausal women extracted from the 2008-2011 Korea National Health and Nutrition Examination Survey. We found that 1542 participants (42.4%) have osteoporosis. The adjusted prevalence rates of osteoporosis at the lumbar spine were significantly higher in participants who consumed >=4001 mg of salt than those who consumed <=2000 mg. At the femoral neck, rates were significantly higher for those who consumed >=5001 mg compared with those who consumed <=4000 mg. Participants with a higher sodium intake showed a significantly higher odds ratio of developing lumbar and femoral neck osteoporosis, compared with those with a lower intake. Our results suggest that excessive daily sodium intake is associated with a higher osteoporosis prevalence in Korean postmenopausal women. PMID- 28580788 TI - Flexible-Robust Metal-Organic Framework for Efficient Removal of Propyne from Propylene. AB - The removal of trace amounts of propyne from propylene is critical for the production of polymer-grade propylene. We herein report the first example of metal-organic frameworks of flexible-robust nature for the efficient separation of propyne/propylene mixtures. The strong binding affinity and suitable pore confinement for propyne account for its high uptake capacity and selectivity, as evidenced by neutron powder diffraction studies and density functional theory calculations. The purity of the obtained propylene is over 99.9998%, as demonstrated by experimental breakthrough curves for a 1/99 propyne/propylene mixture. PMID- 28580790 TI - One-year functional outcomes following major trauma: experience of a UK level 1 major trauma centre. AB - OBJECTIVE: To pilot a method for routine outcome data collection one year after admission to a major trauma centre, to determine current outcomes, and to identify possible methodological improvements. DESIGN: A postal questionnaire audit. SETTING: A major trauma centre in the United Kingdom. SUBJECTS: In total, 355 patients known to be alive 12 months after admission with major trauma (Injury Severity Score (ISS) of 9 or more). INTERVENTIONS: All patients received standard trauma and rehabilitation services available to them. MAIN MEASURES: The main measures used are as follows: ISS; EuroQol, five dimensions five levels (EQ 5D-5L); single questions about accommodation, mobility, and self-care; demographic and injury data collected from hospital records; and outcome data by postal questionnaire. RESULTS: In total, 429 patients were registered over six months: at one year, 64 had died and 10 had no UK address. In total, 355 questionnaires were sent out: 179 (50%) were never returned, 154 (43%) were returned with complete data, 11 forms were incomplete, 7 patients were dead, and 4 were not at the address contacted. Of the 154 with complete data, 91 had new mobility problems and 54 had new problems with personal activities. Of the 68 previously employed, 19 were unemployed, 38 were fully employed in the same job, and 13 had altered jobs. There was no association between Injury Severity Score and any of the outcome scores. CONCLUSION: A short simple questionnaire sent only once achieved a complete data set response rate of 43%. The outcome data are consistent with experience in other studies. Collection of data on specific functional outcomes might be most sensitive. PMID- 28580791 TI - A study of predictive validity, responsiveness, and minimal clinically important difference of arm accelerometer in real-world activity of patients with chronic stroke. AB - OBJECTIVE: To investigate the predictive validity, responsiveness, and minimal clinically important difference of arm accelerometer in real-world activity of patients with chronic stroke. DESIGN: Validation and psychometric study. SETTING: Three medical centers. SUBJECTS: Patients with chronic stroke came from three separated randomized controlled trials. INTERVENTIONS: Patients with stroke received upper extremity rehabilitation programs for four weeks. MAIN MEASURES: Real-world arm movements were measured by an arm accelerometer and three clinical measurement tools-the Motor Activity Log, Stroke Impact Scale, and Nottingham Extended Activities of Daily Living-administered before and after treatment. RESULTS: A total of 82 subjects were recruited in the study (mean age: 55.32 years; mean score of Fugl-Meyer Assessment: 39.91). Correlations between the arm accelerometer and three clinical measurement tools were fair to moderate (Pearson's r = 0.47, 0.42, and 0.34, respectively). The correlation between the arm accelerometer and the quality of use of Motor Activity Log subscale was moderate to good (Pearson's r = 0.57). The responsiveness of the arm accelerometer from pretreatment to posttreatment was medium (standardized response mean = 0.72). The minimal clinically important difference range for the arm accelerometer was 547-751 mean counts. CONCLUSION: The arm accelerometer demonstrated acceptable predictive validity and responsiveness in patients with chronic stroke. The affected arm activity measured by the arm accelerometer was sensitive to change. The change score of a patient with chronic stroke on the arm accelerometer should reach 574-751 mean counts to be regarded as a minimal clinically important difference. PMID- 28580792 TI - Biomechanical analysis of the Universal 2 implant in total wrist arthroplasty: a finite element study. AB - Little is known about the mechanics of in vivo loading on total wrist prostheses where many studies have looked at the mechanics of other types of arthroplasty such as for the hip and the knee which has contributed to the overall success of these types of procedures. Currently surgeons would prefer to carry out arthrodesis on the wrist rather than consider arthroplasty as clinical data have shown that the outcome of total wrist arthroplasty is poorer than compared to the hip and knee. More research is needed on the loading mechanisms of the implants in order to enhance the design of future generation implants. This study looks at the load transfer characteristics of the Universal 2 implant using a finite element model of a virtually implanted prosthesis during gripping. The results showed that the loading on the implant is higher on the dorsal and ulnar aspect than on the volar and radial aspect of the implant. The whole load is transmitted through the radius and none through the ulna. PMID- 28580785 TI - Applications of Nonenzymatic Catalysts to the Alteration of Natural Products. AB - The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogues of natural products by this approach is then described as a quintessential "late-stage functionalization" exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this Review is on the recent studies of nonenzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C-H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C-C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-selective alteration including polyketides, glycopeptides, terpenoids, macrolides, alkaloids, carbohydrates, and others. What emerges is a platform for chemical remodeling of naturally occurring scaffolds that targets virtually all known chemical functionalities and microenvironments. However, challenges for the design of very broad classes of catalysts, with even broader selectivity demands (e.g., stereoselectivity, functional group selectivity, and site-selectivity) persist. Yet, a significant spectrum of powerful, catalytic alterations of complex natural products now exists such that expansion of scope seems inevitable. Several instances of biological activity assays of remodeled natural product derivatives are also presented. These reports may foreshadow further interdisciplinary impacts for catalytic remodeling of natural products, including contributions to SAR development, mode of action studies, and eventually medicinal chemistry. PMID- 28580794 TI - Association of objectively measured physical activity and physical fitness with menopause symptoms. The Flamenco Project. AB - OBJECTIVE: The primary aim was to analyze the association of moderate-to-vigorous physical activity (MVPA) with menopause symptomatology and its overall impact. A secondary/exploratory aim was to assess the association of different components of physical fitness with menopause symptomatology. METHODS: This cross-sectional study comprised 191 perimenopausal women from Southern Spain (age range 45-60 years, mean age 52.6 +/- 4.5 years). The Blatt-Kupperman Menopausal Index was used to evaluate menopause symptomatology. Objectively measured MVPA was registered with accelerometry. Physical fitness was assessed with the Senior Fitness Test battery plus handgrip strength and sit-and-reach tests. RESULTS: After adjustment for multiple confounders, MVPA was only inversely associated with vertigo (r = -0.185, p < 0.05) and palpitations (r = -0.148, p < 0.05). Upper-body flexibility was inversely associated with the Blatt-Kupperman Menopausal Index global score (r = -0.147, p < 0.05). This test was also inversely associated with vertigo (r = -0.230, p < 0.01) and arthralgia (r = 0.168, p < 0.05). Lower-body muscle strength was associated with lower nervousness (r = -0.171, p < 0.05). Cardiorespiratory fitness was inversely associated with paresthesia (r = -0.158, p < 0.05), vertigo (r = -0.219, p < 0.01), fatigue (r = -0.159, p < 0.05) and arthralgia (r = -0.180, p < 0.05). CONCLUSION: The main findings of the present study indicate a weak association of objectively measured MVPA with menopause symptomatology. Exploratory analyses suggest that upper-body flexibility was associated with slightly lower overall menopause impact whereas neither MVPA nor any physical fitness components studied were associated with vasomotor symptoms. PMID- 28580793 TI - Rationale and protocol of MetNET-2 trial: Lanreotide Autogel plus metformin in advanced gastrointestinal or lung neuroendocrine tumors. AB - Metformin (MET) has recently emerged as a potentially active agent in cancer prevention and treatment. MET is thought to exert its antitumor effects either via modification of systemic metabolism or through cell-autonomous effects (e.g., activation of AMPK and inhibition of the mTOR pathway). Preliminary findings of the PRIME-NET study suggest that the addition of MET to treatment with everolimus (EVE) and/or somatostatin analogs (SSAs) can provide clinical benefit in diabetic neuroendocrine tumor (NET) patients. In light of this and other retrospective evidence of MET's anticancer activity in NETs, prospective studies are needed. A pilot, single-arm, open-label, prospective study (MetNET-2 trial, NCT02823691) was designed to evaluate the safety of MET in combination with lanreotide in well differentiated gastrointestinal (WD GI) and lung NETs. PMID- 28580795 TI - Effects of a Self-Directed Nutrition Intervention Among Adults With Chronic Health Conditions. AB - Chronic diseases are common among adults. A healthy diet may be beneficial for managing the consequences of such conditions. The purpose of this study was to evaluate the effects of a self-directed nutrition program on dietary behaviors among adults with chronic health conditions. As part of a larger trial examining the effects of a self-directed exercise program, participants with arthritis were randomized to a 12-week self-directed exercise or nutrition intervention. Self reported fruit and vegetable consumption, fat- and fiber-related behaviors were assessed at baseline, 12 weeks, and 9 months. Repeated measures analyses of covariance examined Group * Time changes in dietary behaviors. Effect sizes were computed. Participants ( n = 321) were, on average, 56.5 +/- 10.5 years old, had a mean body mass index of 32.9 +/- 8.3 kg/m2, and had 2.0 +/- 1.0 chronic health conditions; 88% were female, 65% White, 88% had at least some college education, and 62% married. There were significant Group * Time interactions favoring the nutrition group at 12 weeks for all dietary behaviors ( p < .05) but not at 9 months. Between-group effect sizes were small at 12 weeks and decreased at 9 months. Within-group effect sizes were larger for the nutrition group (small to medium) than the exercise group (none to small) at both time points. A self directed nutrition intervention can result in meaningful improvements in dietary behaviors among adults with chronic health conditions in the short term. PMID- 28580797 TI - Reliability and Validity of Measures for Investigating the Determinants of Health Behaviors Among Women With a History of Gestational Diabetes. AB - AIM: Assisting women with a history of gestational diabetes mellitus (GDM) to adopt healthy lifestyles is a priority for diabetes prevention. The aim of this study was to develop and evaluate measures that can be used to assess the efficacy of behavior change interventions in this group. METHOD: Measures of psychosocial influences on physical activity and diet were derived from formative research and examination of established instruments. Item reduction by principal components analysis was undertaken following telephone survey administration to 160 women with recent GDM, and the internal reliability and construct validity of the derived scales were assessed. Test-retest reliability was assessed in another sample of 97 women. RESULTS: Scales with acceptable internal reliability were developed for physical activity outcome expectancies (alpha = .82), perceived barriers (alpha = .75), encouragement (alpha = .76) and self-efficacy (alpha = .82), weight control attitudes (alpha = .90), and diabetes-related fear (alpha = .70). Construct validity in relation to physical activity participation was found for the encouragement and self-efficacy scales. The weight control attitudes scale showed construct validity in relation to fruit and vegetable intake. The test-retest reliability of most scales was moderate to good (weighted kappa = 0.55-0.69). CONCLUSION: Reliable and valid measures relevant to the psychosocial needs of women with GDM have been developed with a multiethnic population. These will assist future evidence generation, particularly in relation to the adoption of physical activity, which has been a challenging area of lifestyle intervention to date. PMID- 28580798 TI - Delaying of cataract through intervention of Hemidesmus indicus in STZ induced diabetic rats. AB - Hemidesmus indicus (L.) R. Br. was extensively used as hypoglycaemic agent and significance of this plant on secondary complications of diabetes remained unknown. The present study was to investigate the anti-cataractous activity of H. indicus against streptozotocin (STZ)-induced diabetic cataract in rodent model. Root extracts have been prepared and tested for inhibition of rat lens aldose reductase (AR) activity. In addition, its pharmacological potential has been investigated in STZ-induced diabetic cataract. Methanol extract of H. indicus inhibited AR activity in vitro decreased the blood glucose levels, inhibited the AR activity and delayed the onset and progression of cataract in a dose-dependent manner in in vivo and the antioxidant markers have been normalised. Our results demonstrate that H. indicus has decrease the osmotic stress by inhibiting the AR activity and prevented the loss of antioxidants and delayed the progression of diabetic cataract in STZ-induced diabetic rats. PMID- 28580796 TI - Artificial cell mimics as simplified models for the study of cell biology. AB - Living cells are hugely complex chemical systems composed of a milieu of distinct chemical species (including DNA, proteins, lipids, and metabolites) interconnected with one another through a vast web of interactions: this complexity renders the study of cell biology in a quantitative and systematic manner a difficult task. There has been an increasing drive towards the utilization of artificial cells as cell mimics to alleviate this, a development that has been aided by recent advances in artificial cell construction. Cell mimics are simplified cell-like structures, composed from the bottom-up with precisely defined and tunable compositions. They allow specific facets of cell biology to be studied in isolation, in a simplified environment where control of variables can be achieved without interference from a living and responsive cell. This mini-review outlines the core principles of this approach and surveys recent key investigations that use cell mimics to address a wide range of biological questions. It will also place the field in the context of emerging trends, discuss the associated limitations, and outline future directions of the field. Impact statement Recent years have seen an increasing drive to construct cell mimics and use them as simplified experimental models to replicate and understand biological phenomena in a well-defined and controlled system. By summarizing the advances in this burgeoning field, and using case studies as a basis for discussion on the limitations and future directions of this approach, it is hoped that this minireview will spur others in the experimental biology community to use artificial cells as simplified models with which to probe biological systems. PMID- 28580799 TI - Flavonoids of Alcea rosea L. and their immune stimulant, antioxidant and cytotoxic activities on hepatocellular carcinoma HepG-2 cell line. AB - Alcea rosea L. is widely cultivated in gardens of Egypt as an ornamental plant and it has a great history of folkloric medicinal uses. In the present work, phytochemical investigation of the alcoholic extract of the flowers of A. rosea L. led to the isolation of six flavonoids (1-6). Dihydrokaempferol-4'-O-beta-d glucopyranoside (1), dihydrokaempferol (2), kaempferol-3-O-[6"-(E-coumaroyl)] beta-d-glucopyranoside (3), kaempferol-3-O-beta-d-glucopyranoside (4), Apigenin (5) and kaempferol-3-O-alpha-l-rhamnopyranosyl-(1'"->6")-beta-d-glucopyranoside (6). Four of the isolated compounds were evaluated for their antioxidant, immunostimulant and cytotoxic activities against HepG-2 cell line. Compound (3) showed potent cytotoxic activity against HepG-2 cell line with high selectivity towards hepatocellular carcinoma in vitro (with IC50 = 3.8 MUg/mL). Compounds 1 and 2 exhibited significant antioxidant activity and compound 4 showed a significant immune stimulant activity. Compound 1 is isolated for the first time from genus Alcea and this is the first report for its biological investigation. PMID- 28580800 TI - Kaposi Sarcoma Associated With Iatrogenic Immunosuppression: A Rare Complication of Bullous Pemphigoid Treatment. AB - BACKGROUND: Bullous pemphigoid (BP) is an autoimmune bullous disease requiring immunosuppressive therapy. Kaposi sarcoma (KS) is an angioproliferative tumor associated with the opportunistic viral infection human herpes virus 8 (HHV-8). It is a well-known condition associated with longstanding human immunodeficiency virus infection, but it may also occur in the context of iatrogenic immunosuppression. OBJECTIVE: Although a rare complication, all dermatologists dealing with immunosuppressors must be aware and have a high index of suspicion when a patient presents with rapidly progressive violaceous papules. METHODS AND RESULTS: We describe an Italian male patient treated for bullous pemphigoid with topical and systemic corticosteroids and mycophenolate mofetil (MMF) who developed multifocal cutaneous KS after a few months of therapy. CONCLUSION: To our knowledge, KS onset associated with MMF and corticosteroids intake for BP treatment has not been reported previously. KS associated with iatrogenic immunosuppression can have an aggressive course, and it must be promptly recognised since cessation of immunosuppression therapy can lead to complete resolution. Immune restoration is the key to control this viral infection. PMID- 28580801 TI - Effectiveness and safety of wheelchair skills training program in improving the wheelchair skills capacity: a systematic review. AB - OBJECTIVE: To comprehensively assess the effectiveness and safety of wheelchair skills training program in improving wheelchair skills capacity. DATA SOURCES: PubMed, OVID, EBSCO, ScienceDirect, Web of Science, CINAHL, Cochrane Library, Google Scholar, and China Knowledge Resource Integrated Database were searched up to March 2017. METHODS: Controlled clinical trials that compared a wheelchair skills training program with a control group that received other interventions and used the wheelchair skills test scores to evaluate wheelchair skills capacity were included. Two authors independently screened articles, extracted data, and assessed the methodological quality using the Cochrane risk-of-bias tool in randomized controlled trial (RCT) and methodological index for non-randomized studies. The data results of wheelchair skills test scores were extracted. RESULTS: Data from 455 individuals in 10 RCTs and from 140 participants in seven non-randomized studies were included for meta-analysis using Stata version 12.0 (Stata Corporation, College Station, TX, USA). In the short term (immediately to one week) post-intervention, relative to a control group, manual wheelchair skills training could increase the total wheelchair skills test scores by 13.26% in RCTs (95% confidence interval (CI), 6.19%-20.34%; P < 0.001) and by 23.44% in non-randomized studies (95% CI, 13.98%-32.90%; P < 0.001). Few adverse events occurred during training; however, compared with a control group, evidence was insufficient to support the effectiveness of powered wheelchair skills training and the long-term (3-12 months) advantage of manual wheelchair skills training ( P = 0.755). CONCLUSION: The limited evidence suggests that wheelchair skills training program is beneficial in the short term, but its long-term effects remain unclear. PMID- 28580802 TI - Evaluation of a Web-Based Training in Smoking Cessation Counseling Targeting U.S. Eye-Care Professionals. AB - BACKGROUND: Smoking causes blindness-related diseases. Eye-care providers are uniquely positioned to help their patients quit smoking. AIMS: Using a pre /postevaluation design, this study evaluated a web-based training in smoking cessation counseling targeting eye-care providers. METHOD: The training was developed based on the 3A1R protocol: "Ask about smoking, Advise to quit, Assess willingness to quit, and Refer to tobacco quitlines," and made available in the form of a web-based video presentation. Providers ( n = 654) at four academic centers were invited to participate. Participants completed pretraining, posttraining, and 3-month follow-up surveys. Main outcomes were self-reported improvement in their motivation, confidence, and counseling practices at 3-month follow-up. Generalized linear mixed models for two time-points (pretraining and 3 month) were conducted for these outcomes. RESULTS: A total of 113 providers (54.0% males) participated in the study (17.7% response rate). At the 3-month evaluation, 9.8% of participants reported improvement in their motivation. With respect to the 3A1R, 8% reported improvement in their confidence for Ask, 15.5% for Advise, 28.6% for Assess, and 37.8% for Refer. Similarly, 25.5% reported improvement in their practices for Ask, 25.5% for Advise, 37.2% for Assess, and 39.4% for Refer to tobacco quitlines ( p < .001 for all except for Refer confidence p = .05). DISCUSSION: Although participation rate was low, the program effectively improved providers' smoking cessation counseling practices. CONCLUSIONS: Including training in smoking cessation counseling in ophthalmology curriculums, and integrating the 3A1R protocol into the electronic medical records systems in eye-care settings, might promote smoking cessation practices in these settings. PMID- 28580803 TI - Erratum. PMID- 28580804 TI - Burden of antimicrobial resistance in an era of decreasing susceptibility. AB - INTRODUCTION: Antimicrobial resistance has become a global problem. Many pathogens are becoming multidrug-resistant with the attendant increased risk of failure of standard therapies and the under-recognised outcomes such as increased morbidity, mortality, length of hospitalization and costs of treatment. Areas covered: We undertook a review of the literature using standard search engines including PubMed, Google Scholar, Scopus and internet sources. Key search terms included antimicrobial resistance, antibiotic resistance, bacterial resistance, clinical outcomes, economic consequences, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae and Staphylococcus aureus. Expert commentary: Antimicrobial resistance among the five-species presented demonstrates a major, and increasing, deleterious impact seen in each of the key outcomes measured. These negative changes, at a personal, health system and Societal levels, further emphasise the growing problem of increasing antimicrobial resistance at a global level and the vital need for new antimicrobials. PMID- 28580805 TI - Use of Intervention Mapping to Enhance Health Care Professional Practice: A Systematic Review. AB - BACKGROUND: Intervention Mapping is a planning protocol for developing behavior change interventions, the first three steps of which are intended to establish the foundations and rationales of such interventions. AIM: This systematic review aimed to identify programs that used Intervention Mapping to plan changes in health care professional practice. Specifically, it provides an analysis of the information provided by the programs in the first three steps of the protocol to determine their foundations and rationales of change. METHOD: A literature search was undertaken in PubMed, Scopus, SciELO, and DOAJ using "Intervention Mapping" as keyword. Key information was gathered, including theories used, determinants of practice, research methodologies, theory-based methods, and practical applications. RESULTS: Seventeen programs aimed at changing a range of health care practices were included. The social cognitive theory and the theory of planned behavior were the most frequently used frameworks in driving change within health care practices. Programs used a large variety of research methodologies to identify determinants of practice. Specific theory-based methods (e.g., modelling and active learning) and practical applications (e.g., health care professional training and facilitation) were reported to inform the development of practice change interventions and programs. DISCUSSION: In practice, Intervention Mapping delineates a three-step systematic, theory- and evidence-driven process for establishing the theoretical foundations and rationales underpinning change in health care professional practice. CONCLUSION: The use of Intervention Mapping can provide health care planners with useful guidelines for the theoretical development of practice change interventions and programs. PMID- 28580806 TI - Your Cheatin' Voice Will Tell on You: Detection of Past Infidelity from Voice. AB - Evidence suggests that many physical, behavioral, and trait qualities can be detected solely from the sound of a person's voice, irrespective of the semantic information conveyed through speech. This study examined whether raters could accurately assess the likelihood that a person has cheated on committed, romantic partners simply by hearing the speaker's voice. Independent raters heard voice samples of individuals who self-reported that they either cheated or had never cheated on their romantic partners. To control for aspects that may clue a listener to the speaker's mate value, we used voice samples that did not differ between these groups for voice attractiveness, age, voice pitch, and other acoustic measures. We found that participants indeed rated the voices of those who had a history of cheating as more likely to cheat. Male speakers were given higher ratings for cheating, while female raters were more likely to ascribe the likelihood to cheat to speakers. Additionally, we manipulated the pitch of the voice samples, and for both sexes, the lower pitched versions were consistently rated to be from those who were more likely to have cheated. Regardless of the pitch manipulation, speakers were able to assess actual history of infidelity; the one exception was that men's accuracy decreased when judging women whose voices were lowered. These findings expand upon the idea that the human voice may be of value as a cheater detection tool and very thin slices of vocal information are all that is needed to make certain assessments about others. PMID- 28580807 TI - Adverse Childhood Environment: Relationship With Sexual Risk Behaviors and Marital Status in a Large American Sample. AB - A substantial theoretical and empirical literature suggests that stressful events in childhood influence the timing and patterning of subsequent sexual and reproductive behaviors. Stressful childhood environments have been predicted to produce a life history strategy in which adults are oriented more toward short term mating behaviors and less toward behaviors consistent with longevity. This article tests the hypothesis that adverse childhood environment will predict adult outcomes in two areas: risky sexual behavior (engagement in sexual risk behavior or having taken an HIV test) and marital status (currently married vs. never married, divorced, or a member of an unmarried couple). Data come from the Behavioral Risk Factor Surveillance System. The sample contains 17,530 men and 23,978 women aged 18-54 years living in 13 U.S. states plus the District of Columbia. Adverse childhood environment is assessed through 11 retrospective measures of childhood environment, including having grown up with someone who was depressed or mentally ill, who was an alcoholic, who used or abused drugs, or who served time in prison; whether one's parents divorced in childhood; and two scales measuring childhood exposure to violence and to sexual trauma. The results indicate that adverse childhood environment is associated with increased likelihood of engaging in sexual risk behaviors or taking an HIV test, and increased likelihood of being in an unmarried couple or divorced/separated, for both men and women. The predictions are supported by the data, lending further support to the hypothesis that childhood environments influence adult reproductive strategy. PMID- 28580808 TI - Regorafenib for the treatment of unresectable hepatocellular carcinoma. AB - INTRODUCTION: Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC) and well preserved liver function. However, until recent approval of regorafenib by the Food and Drug Administration (FDA), no effective therapeutic options were available for patients resistant to sorafenib. Areas covered: The present article reviews the preclinical and clinical data of regorafenib, putting them into the context of current and future landscape of treatment options for patients with HCC. Recently, the randomized, placebo controlled, Phase III RESORCE trial, demonstrated a statistically and clinically significant increase in overall survival from 7.8 months with placebo to 10.6 months with regorafenib in patients progressing on sorafenib. Furthermore, the study showed a significant improvement in all the other efficacy endpoints. Main adverse events were hypertension, hand-foot skin reaction, fatigue and diarrhea, with no negative impact on quality of life. Expert commentary: Regorafenib is a recently approved treatment option for HCC patients who have been previously treated with sorafenib. The RESORCE trial demonstrates the beneficial effect of a sequential approach involving two multikinase inhibitors, namely sorafenib and regorafenib, whose antitumor activity extends beyond their antiangiogenic functions. PMID- 28580809 TI - Cardiovascular imaging environment: will the future be cloud-based? AB - INTRODUCTION: In cardiovascular CT and MR imaging large datasets have to be stored, post-processed, analyzed and distributed. Beside basic assessment of volume and function in cardiac magnetic resonance imaging e.g., more sophisticated quantitative analysis is requested requiring specific software. Several institutions cannot afford various types of software and provide expertise to perform sophisticated analysis. Areas covered: Various cloud services exist related to data storage and analysis specifically for cardiovascular CT and MR imaging. Instead of on-site data storage, cloud providers offer flexible storage services on a pay-per-use basis. To avoid purchase and maintenance of specialized software for cardiovascular image analysis, e.g. to assess myocardial iron overload, MR 4D flow and fractional flow reserve, evaluation can be performed with cloud based software by the consumer or complete analysis is performed by the cloud provider. However, challenges to widespread implementation of cloud services include regulatory issues regarding patient privacy and data security. Expert commentary: If patient privacy and data security is guaranteed cloud imaging is a valuable option to cope with storage of large image datasets and offer sophisticated cardiovascular image analysis for institutions of all sizes. PMID- 28580810 TI - Youth Empowerment Solutions: Evaluation of an After-School Program to Engage Middle School Students in Community Change. AB - We report on an effectiveness evaluation of the Youth Empowerment Solutions (YES) program. YES applies empowerment theory to an after-school program for middle school students. YES is an active learning curriculum designed to help youth gain confidence in themselves, think critically about their community, and work with adults to create positive community change. We employed a modified randomized control group design to test the hypothesis that the curriculum would enhance youth empowerment, increase positive developmental outcomes, and decrease problem behaviors. Our sample included 367 youth from 13 urban and suburban middle schools. Controlling for demographic characteristics and pretest outcome measures, we found that youth who received more components of the curriculum reported more psychological empowerment and prosocial outcomes and less antisocial outcomes than youth who received fewer of the intervention components. The results support both empowerment theory and program effectiveness. PMID- 28580812 TI - Platelet reactivity in stable cardiovascular patients with chronic kidney disease. AB - The study aimed to evaluate antiplatelet drug responsiveness in stable outpatients with cardiovascular disease and chronic kidney disease (CKD) and examine whether impaired antiplatelet drug responsiveness is associated with worse clinical outcomes in this population. Stable cardiovascular patients (n = 771) were enrolled at least one month after an acute ischemic atherothrombotic event. Antiplatelet drug responsiveness was assessed with specific assays (serum TxA2 for aspirin, the VASP assay for clopidogrel) and other aggregation-based assays using different agonists. All patients were followed until the first occurrence of a major adverse cardiovascular event. The 133 CKD patients were found to have higher activity of von Willebrand factor and higher fibrinogen levels. After a median follow-up of 33 months, 88 events occurred in patients without CKD and 31 events in patients with CKD (5.0 events and 8.7 events per 100 patient years, respectively, HR = 1.75 (95% CI 1.16-2.63; p = 0.008). The prevalence of poor aspirin and clopidogrel responsiveness and high platelet reactivity as assessed with different aggregation-based assays was similar in patients with estimated GFR >= 60 ml/min, 45-59 ml/min, and < 45 ml/min. No significant interaction for CKD vs. non-CKD was observed for events occurrence in patients with or without high platelet reactivity on several assays, with the exception of collagen-induced aggregation. In stable cardiovascular patients, CKD is not associated with higher platelet reactivity. Decreased antiplatelet drug responsiveness is not associated with worse clinical outcomes in CKD patients. PMID- 28580811 TI - The effects of hyperbaric oxygen therapy on neuropathic pain via mitophagy in microglia. AB - Purpose: Hyperbaric oxygen (HBO) therapy has been suggested to palliate neuropathic pain, but the mechanisms involved are not well understood. This study explored the involvement of microglial mitophagy via HBO relative to neuropathic pain therapy. Materials and methods: A total of 80 male Sprague Dawley rats were randomly divided into two groups: a normal group (n = 40) and a mitophagy inhibitor group (n = 40) in which the mitophagy inhibitor cyclosporin A (CsA) was administrated prior to chronic constriction injury (CCI). Groups (n = 10 rats per group) consisted of the following: control (C), sham operation (S), sciatic nerve with chronic constriction injury (CCI), and a CCI plus HBO treatment (CCI + HBO). Pain-related behaviors were evaluated using mechanical withdraw tendency and thermal withdraw latency analysis. Mitochondrial membrane potential was measured, and Western blot was employed to assess expression of NIX and BNIP3. Immunofluorescence changes in neuron protein (NESTIN) and mitochondria inner or outer layer proteins (TIM23, TOM20) were examined. Results: HBO significantly ameliorated pain-related behaviors, which were downregulated by mitophagy inhibitors (P < 0.05). Mitochondrial membrane potential indexes were decreased after HBO therapy, but were reversed in the mitophagy inhibitor group (P < 0.05). HBO upregulated NIX and BNIP3 expression, which did not occur in the CCI group (P < 0.05). However, expression was reduced when mitophagy inhibitors were administered. Immunofluorescence examination showed that mitophagy in microglia was induced by CCI, which was upregulated after HBO treatment. This phenomenon was not observed in the mitophagy inhibitor group. Conclusions: HBO therapy palliated CCI-induced neuropathic pain in rats by upregulating microglial mitophagy. These results could serve as guidelines to improve neuropathic pain therapy using HBO to maximize therapeutic efficiency. PMID- 28580813 TI - Induction chemotherapy vs post-operative adjuvant therapy for malignant pleural mesothelioma. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) is an aggressive neoplasia. Multidisciplinary treatments, including the association of induction and/or adjuvant therapeutic regimens with surgery, have been reported to give encouraging results. Current therapeutic options are not well standardized yet, especially regarding the best association between surgery and medical treatments. The present review aims to assess safety, efficacy and outcomes of different therapies for MPM. Areas covered: This article focuses on the multimodality treatment of mesothelioma. A systematic review was performed by using electronic databases to identify studies that considered induction and adjuvant approaches in MPM therapy in a multidisciplinary setting, including surgery. Endpoints included overall survival, disease free survival, disease recurrence, and complications. Expert commentary: This systematic review offers a comprehensive view of current multidisciplinary therapeutic strategies for MPM, suggesting that multimodality therapy offers acceptable outcomes with better results reported for trimodality approaches. Individualization of care for each patient is fundamental in choosing the most appropriate treatment. The growing complexity of treatment protocols mandates that MPM patients be referred to specialized Centers, in which every component of the interdisciplinary team can provide the necessary expertise and quality of care. PMID- 28580814 TI - Evolutions in clinical reasoning assessment: The Evolving Script Concordance Test. AB - INTRODUCTION: Script concordance testing (SCT) is a method of assessment of clinical reasoning. We developed a new type of SCT case design, the evolving SCT (E-SCT), whereby the patient's clinical story is "evolving" and with thoughtful integration of new information at each stage, decisions related to clinical decision-making become increasingly clear. OBJECTIVES: We aimed to: (1) determine whether an E-SCT could differentiate clinical reasoning ability among junior residents (JR), senior residents (SR), and pediatricians, (2) evaluate the reliability of an E-SCT, and (3) obtain qualitative feedback from participants to help inform the potential acceptability of the E-SCT. METHODS: A 12-case E-SCT, embedded within a 24-case pediatric SCT (PaedSCT), was administered to 91 pediatric residents (JR: n = 50; SR: n = 41). A total of 21 pediatricians served on the panel of experts (POE). A one-way analysis of variance (ANOVA) was conducted across the levels of experience. Participants' feedback on the E-SCT was obtained with a post-test survey and analyzed using two methods: percentage preference and thematic analysis. RESULTS: Statistical differences existed across levels of training: F = 19.31 (df = 2); p < 0.001. The POE scored higher than SR (mean difference = 10.34; p < 0.001) and JR (mean difference = 16.00; p < 0.001). SR scored higher than JR (mean difference = 5.66; p < 0.001). Reliability (Cronbach's alpha) was 0.83. Participants found the E-SCT engaging, easy to follow and true to the daily clinical decision-making process. CONCLUSIONS: The E SCT demonstrated very good reliability and was effective in distinguishing clinical reasoning ability across three levels of experience. Participants found the E-SCT engaging and representative of real-life clinical reasoning and decision-making processes. We suggest that further refinement and utilization of the evolving style case will enhance SCT as a robust, engaging, and relevant method for the assessment of clinical reasoning. PMID- 28580815 TI - GFI1B variants associated with thrombocytopenia. PMID- 28580816 TI - Can the Enterococcus faecalis identified in the root canals of primary teeth be a cause of failure of endodontic treatment? AB - OBJECTIVE: This study investigated the presence of Enterococcus faecalis in primary teeth with primary root canal infections and related to the possible failure of pulpectomy outcome after 36 months. MATERIAL AND METHODS: Root canal samples were obtained from 25 out of 244 patients using the sterile paper cone method. The identification of E. faecalis was done with culture and molecular tests using species-specific 16S rRNA gene-based polymerase chain reaction (PCR). After 36 months, the pulpectomy outcome was evaluated. RESULTS: Enterococcus faecalis was found in five (20%) samples, and dental caries were the cause of primary infection in all of them. Pulpectomy outcome was evaluated only in teeth that completed the entire clinical protocol and were followed up to 36 months (n = 8). From these, 75% (n = 6) were successful and 25% (n = 2) failed. E. faecalis was present in 50% of both successful and failed cases. CONCLUSIONS: Enterococcus faecalis was not related to the failure of endodontic treatment of primary teeth. PMID- 28580817 TI - Changes in low-molecular-weight thiol-disulphide redox couples are part of bread wheat seed germination and early seedling growth. AB - The tripeptide antioxidant glutathione (gamma-l-glutamyl-l-cysteinyl-glycine; GSH) essentially contributes to thiol-disulphide conversions, which are involved in the control of seed development, germination, and seedling establishment. However, the relative contribution of GSH metabolism in different seed structures is not fully understood. We studied the GSH/glutathione disulphide (GSSG) redox couple and associated low-molecular-weight (LMW) thiols and disulphides related to GSH metabolism in bread wheat (Triticum aestivum L.) seeds, focussing on redox changes in the embryo and endosperm during germination. In dry seeds, GSH was the predominant LMW thiol and, 15 h after the onset of imbibition, embryos of non germinated seeds contained 12 times more LMW thiols than the endosperm. In germinated seeds, the embryo contained 17 and 11 times more LMW thiols than the endosperm after 15 and 48 h, respectively. This resulted in the embryo having significantly more reducing half-cell reduction potentials of GSH/GSSG and cysteine (Cys)/cystine (CySS) redox couples (EGSSG/2GSH and ECySS/2Cys, respectively). Upon seed germination and early seedling growth, Cys and CySS concentrations significantly increased in both embryo and endosperm, progressively contributing to the cellular LMW thiol-disulphide redox environment (Ethiol-disulphide). The changes in ECySS/2Cys could be related to the mobilisation of storage proteins in the endosperm during early seedling growth. We suggest that EGSSG/2GSH and ECySS/2Cys can be used as markers of the physiological and developmental stage of embryo and endosperm. We also present a model of interaction between LMW thiols and disulphides with hydrogen peroxide (H2O2) in redox regulation of bread wheat germination and early seedling growth. PMID- 28580818 TI - Xanthomatous Posttraumatic Fibro-Osseous Lesion of the Rib: A Rare and Underrecognized Entity. Case Report and Literature Review. AB - Posttraumatic fibro-osseous lesion (PTFOL) is a rare lesion that typically affects the ribs and is probably a posttraumatic reactive process. Because PTFOL is often misdiagnosed as fibrous dysplasia, osteoid osteoma, benign fibrous histiocytoma or rib metastases, chest wall resection, leading to a significant morbidity, is the main treatment modality. We report the case of a 30-year-old male patient with no history of previous trauma presenting with chest pain. Computed tomography scan showed an eighth left rib well-defined ovoid and hypodense lesion with circumferential sclerotic margin and no cortical breakthrough. Posterolateral thoracotomy was performed and a histological diagnosis of xanthomatous posttraumatic fibro-osseous lesion of the rib was made. PTFOL is a benign lesion that should be recognized to avoid unnecessary surgical treatment and complications. We provide a summary of clinical, histopathological, and radiological aspects of PTFOL and discuss differential diagnoses. PMID- 28580819 TI - Opicapone for the management of end-of-dose motor fluctuations in patients with Parkinson's disease treated with L-DOPA. AB - INTRODUCTION: Opicapone is a third generation, highly potent and effective catechol O-methyltransferase (COMT) inhibitor that optimizes the pharmacokinetics and bioavailability of L-DOPA therapy. Areas covered: In this review, the authors describe the preclinical and clinical development of opicapone. In PD patients with motor fluctuations, once daily opicapone administration was well-tolerated and consistently reduced OFF-time and increased ON-time without increasing the frequency of troublesome dyskinesia, and these benefits were maintained over at least a year of continued open-label therapy. Expert commentary: With its convenient once-daily regimen, adjunct opicapone should be considered as an effective option for use in L-DOPA treated PD patients experiencing motor fluctuations. PMID- 28580820 TI - Twelve tips for medical students to make the best use of ward-based learning. AB - BACKGROUND: With a multitude of healthcare professionals willing to teach, a placement on a ward is an invaluable learning opportunity; yet as students, we often struggle to maximize this placements' potential. AIM: This article provides 12 tips for medical students to optimize their learning in a ward-based environment. METHODS: Current literature and personal experiences of the authors were used to develop the tips. RESULTS: The 12 tips are (1) prepare yourself, (2) identify knowledge, skills, and attributes, (3) engage in peer-to-peer learning, (4) get to know the interprofessional team, (5) talk to the patient first, (6) present findings and gain feedback, (7) tap into seniors' experience, (8) immerse yourself and be proactive, (9) check patient notes, (10) manage the clock, (11) enhance your CV, and (12) embrace the spirit of lifelong learning. CONCLUSION: These tips will enable us to effectively improve our learning and positively shape us into outstanding future doctors. PMID- 28580821 TI - Hb Southampton [beta106(G8)Leu->Pro; HBB: c.320T>C] and Codons 41/42 (-TTCT; HBB: c.124_127delTTCT) in a Chinese Girl. AB - Hb Southampton [beta106(G8)Leu->Pro; HBB: c.320T>C] is a rare, unstable hemoglobin (Hb), variant. The main clinical presentation of this variant is hemolytic anemia. We detected this mutation in a 2-year-old Chinese girl with a history of regular transfusions. To the best of our knowledge, this is the first time that this variant has been found in the Asian population. PMID- 28580823 TI - Ethanol and the Developing Brain: Inhibition of Neuronal Activity and Neuroapoptosis. AB - Ethanol induces massive neuroapoptosis in the developing brain. One of the main hypotheses that has been put forward to explain the deleterious actions of ethanol in the immature brain involves an inhibition of neuronal activity. Here, we review recent evidence for this hypothesis obtained in the somatosensory cortex and hippocampus of neonatal rodents. In both structures, ethanol strongly inhibits brain activity. At the doses inducing massive neuroapoptosis, ethanol completely suppresses the early activity patterns of spindle-bursts and gamma oscillations in the neocortex and the early sharp-waves in the hippocampus. The inhibitory effects of ethanol decrease with age and in adult animals, ethanol only mildly depresses neuronal firing and induces delta-wave activity. Suppression of cortical activity in neonatal animals likely involves inhibition of the myoclonic twitches, an important physiological trigger for the early activity bursts, and inhibition of the thalamocortical and intracortical circuits through a potentiation of GABAergic transmission and an inhibition of N-methyl-d aspartate (NMDA) receptors, that is in keeping with the neuroapoptotic effects of other agents acting on GABA and NMDA receptors. These findings provide support for the hypothesis that the ethanol-induced inhibition of cortical activity is an important pathophysiological mechanism underlying massive neuroapoptosis induced by ethanol in the developing brain. PMID- 28580822 TI - Effects of microRNA-223 on morphine analgesic tolerance by targeting NLRP3 in a rat model of neuropathic pain. AB - Objective To investigate the effects of microRNA-223 on morphine analgesic tolerance by targeting NLRP3 in a rat model of neuropathic pain. Methods Our study selected 100 clean grade healthy Sprague-Dawley adult male rats weighing 200 to 250 g. After establishment of a rat model of chronic constriction injury, these rats were divided into 10 groups (10 rats in each group): the normal control, sham operation, chronic constriction injury, normal saline, morphine, miR-223, NLRP3, miR-223 + morphine, NLRP3 + morphine, and miR-223 + NLRP3 + morphine groups. The real-time quantitative polymerase chain reaction assay, Western blotting, and enzyme-linked immunosorbent assay were used for detecting the mRNA and protein expressions of NLRP3, apoptosis-associated speck-like protein, Caspase-1, Interleukin (IL)-1beta, and IL-18 in sections of lumbar spinal cord. Immunohistochemistry was applied for detecting the positive rates of NLRP3, apoptosis-associated speck-like protein, Caspase-1, IL-1beta, and IL-18. Results The paw withdrawal threshold and percentage maximum possible effect (%MPE) were higher in chronic constriction injury group when compared with the normal control and sham operation groups. Behavioral tests showed that compared with the chronic constriction injury and normal saline groups, the morphine and miR-223 + morphine groups showed obvious analgesic effects. Expressions of miR 223 in the miR-223, miR-223 + morphine, and miR-223 + NLRP3 + morphine were significantly higher than those in the chronic constriction injury, normal saline, and morphine groups. Compared with chronic constriction injury, normal saline and morphine groups, the mRNA and protein expressions of NLRP3, apoptosis associated speck-like protein, Caspase-1, IL-1beta, and IL-18 were significantly decreased in the miR-223 and miR-223 + morphine groups, while mRNA and protein expressions of NLRP3, apoptosis-associated speck-like protein, Caspase-1, IL 1beta, and IL-18 were significantly increased in the NLRP3 and NLRP3 + morphine group. Conclusion Our study provides strong evidence that miR-223 could suppress the activities of NLRP3 inflammasomes ( NLRP3, apoptosis-associated speck-like protein, and Caspase-1) to relieve morphine analgesic tolerance in rats by down regulating NLRP3. PMID- 28580825 TI - Notable imaging features of the liver in a Chinese patient with recurrent immunoglobulin G4 hepatopathy. PMID- 28580824 TI - Addressing health workforce inequities in the Mindanao regions of the Philippines: Tracer study of graduates from a socially-accountable, community engaged medical school and graduates from a conventional medical school. AB - Developing and retaining a high-quality medical workforce in low-resource countries is a worldwide challenge. The Filipino Ateneo de Zamboanga University School of Medicine (ADZU-SOM) has adopted a strong focus on socially accountable health professional education (SAHPE) in order to address the shortage of physicians across rural and urban communities in the Western Mindanao region. A cross-sectional survey of graduates from two Philippines medical schools: ADZU SOM in the Mindanao region and a medical school with a more conventional curriculum, found ADZU-SOM graduates were more likely to have joined the medical profession due to a desire to help others (p = 0.002), came from lower socioeconomic strata (p = 0.001) and had significantly (p < 0.05) more positive attitudes to community service. ADZU graduates were also more likely to currently work in Government Rural Health Units (p < 0.001) or be generalist Medical Officers (p < 0.001) or Rural/Municipal Health Officers (p = 0.003). ADZU graduates were also less likely to work in private or specialist Government hospitals (p = 0.033 and p = 0.040, respectively) and be surgical or medical specialists (p = 0.010 and p < 0.001, respectively). The findings suggest ADZU SOM's SAHPE philosophy manifests in the practice choices of its graduates and that the ADZU-SOM can meet the rural and urban health workforce needs of the Western Mindanao region. PMID- 28580826 TI - Bone mineral density loss in clinically suspect arthralgia is associated with subclinical inflammation and progression to clinical arthritis. AB - OBJECTIVE: Peripheral bone mineral density (BMD) may be decreased in early rheumatoid arthritis (RA) but it is unknown whether BMD loss emerges before arthritis is clinically apparent. We aimed to study whether BMD loss occurs in patients with clinically suspect arthralgia (CSA), and whether it is associated with progression to clinical arthritis and magnetic resonance imaging (MRI) detected subclinical inflammation. METHOD: Patients with CSA had arthralgia for <1 year and were at risk of progressing to RA according to their rheumatologists. At baseline, a 1.5 T MRI was performed of unilateral metacarpophalangeal, wrist, and metatarsophalangeal joints, and scored on synovitis, bone marrow oedema, and tenosynovitis;. summing these features yielded the total MRI inflammation score. Digital X-ray radiogrammetry (DXR) was used to estimate BMD on two sequential conventional hand radiographs (mean interval between radiographs 4.4 months). The change in BMD was studied; BMD loss was defined as a decrease of >=2.5 mg/cm2/month. Patients were followed for arthritis development for a median of 18.4 months. RESULTS: In CSA patients (n = 108), change in BMD was negatively associated with age (beta = -0.03, p = 0.007). BMD loss in CSA patients was associated with arthritis development [adjusted for age hazard ratio (HR) = 6.1, 95% confidence interval (CI) 1.7 to 21.4] and was most frequently estimated in the months before clinical arthritis development. The total MRI inflammation scores were associated with the change in BMD (adjusted for age beta = -0.05, p = 0.047). The total MRI inflammation score and BMD loss were both independently associated with arthritis development (HR = 1.1, 95% CI 1.1 to 1.2, and HR = 4.6, 95% CI 1.2 to 17.2, respectively). CONCLUSION: In CSA patients, severe BMD loss is associated with MRI-detectable subclinical inflammation and with progression to clinical arthritis. PMID- 28580827 TI - Therapeutic management of acute pulmonary embolism. AB - INTRODUCTION: Acute pulmonary embolism (PE) is a potentially fatal manifestation of venous thromboembolism. Prompt anticoagulant treatment is crucial for PE patients, which can decrease morbidity and mortality. Risk assessment is the cornerstone of the therapeutic management of PE. It guides physicians to the most appropriate treatment and selects patients for early discharge or home treatment. Areas covered: Here, we review the current treatments of acute PE according to contemporary risk stratification strategies, highlighting each step of PE therapeutic management. Expert commentary: Currently, direct oral anticoagulants (DOACs) represent the first-line therapy of patients presenting with non-high risk PE with a better risk-benefit ratios than vitamin K antagonists (VKAs) due to lower risk of major bleeding. Only high-risk patients with PE who present in shock should be treated with systematic thrombolysis, while surgical thrombectomy or catheter direct thrombolysis (CDT) should only be considered when thrombolysis is contraindicated because of too high bleeding risk. PMID- 28580828 TI - Reproducibility of a commercially available subgingival plaque sampling strategy with oligonucleotide probes, common mistake. PMID- 28580830 TI - Thrombocytopenia and GBA gene mutation in a patient with adult type 1 Gaucher disease. AB - A 38-year-old female patient was diagnosed with anemia for 3 years. Medical examination showed slight splenomegaly (250 * 62 mm), thrombocytopenia (platelets 51 * 109/L), anemia (Hb levels 107 g/L), and beta-glucocerebrosidase activity (GBA) in leukocytes was lower than normal. Microscopic findings of bone marrow smear demonstrated that Gaucher cells in bone marrow and periodic acid-Schiff staining of them were positive. Sequencing of GBA genomic and cDNA identified one novel homozygous mutation, c.484A> G (p.Met162Val). This case suggests that we should pay attention to adult Gaucher disease as a differential diagnosis for cryptogenic thrombocytopenia and one novel homozygous mutation in GBA gene was reported for the first time. The novel mutation in homozygosity is apparently associated with mild, non-neuronopathic type 1 disease which is relatively uncommon in Asian populations. PMID- 28580829 TI - Molecular, cellular and behavioral changes associated with pathological pain signaling occur after dental pulp injury. AB - Abstract: Persistent pain can occur after routine dental treatments in which the dental pulp is injured. To better understand pain chronicity after pulp injury, we assessed whether dental pulp injury in mice causes changes to the sensory nervous system associated with pathological pain. In some experiments, we compared findings after dental pulp injury to a model of orofacial neuropathic pain, in which the mental nerve is injured. After unilateral dental pulp injury, we observed increased expression of activating transcription factor 3 (ATF3) and neuropeptide Y (NPY) mRNA and decreased tachykinin precursor 1 gene expression, in the ipsilateral trigeminal ganglion. We also observed an ipsilateral increase in the number of trigeminal neurons expressing immunoreactivity for ATF3, a decrease in substance P (SP) immunoreactive cells, and no change in the number of cells labeled with IB4. Mice with dental pulp injury transiently exhibit hindpaw mechanical allodynia, out to 12 days, while mice with mental nerve injury have persistent hindpaw allodynia. Mice with dental pulp injury increased spontaneous consumption of a sucrose solution for 17 days while mental nerve injury mice did not. Finally, after dental pulp injury, an increase in expression of the glial markers Iba1 and glial fibrillary acidic protein occurs in the transition zone between nucleus caudalis and interpolaris, ipsilateral to the injury. Collectively these studies suggest that dental pulp injury is associated with significant neuroplasticity that could contribute to persistent pain after of dental pulp injury. PMID- 28580831 TI - Markers of oxidative stress in dogs with heart failure. AB - We tested the hypothesis that indirect measures of oxidative stress (vitamin E, glutathione peroxidase, and malondialdehyde) differ in dogs in heart failure resulting from either myxomatous mitral valve disease or dilated cardiomyopathy. Dogs were classified according to the International Small Animal Cardiac Health Council (ISACHC) classification. Additionally, the effect of cardiac therapy on oxidative stress parameters and N-terminal pro-B-type natriuretic peptide (NT proBNP) in advanced stages of congestive heart failure was investigated. There were no significant differences in oxidative stress parameters between healthy dogs and the individual groups of cardiac patients. Significantly lower malondialdehyde (MDA) was observed in the ISACHC II group in comparison to ISACHC groups III and I. A significant positive correlation in treated patients was observed between NT-proBNP and MDA, NT-proBNP and vitamin E, as well as between MDA and vitamin E (and lipid-standardized vitamin E). No significant differences in any of the measured parameters were found between treated and non-treated cardiac patients. Our results suggest an association between MDA (the extent of lipid peroxidation) and NT-proBNP, vitamin E and NT-proBNP, as well as between MDA and vitamin E in treated canine patients. Plasma vitamin E concentration was maintained in all stages of cardiovascular disease in these canine patients. PMID- 28580832 TI - Syphilis gastritis: a case report. AB - Awareness of the spectrum of clinical manifestations of syphilis, especially uncommon changes, is essential for diagnosis and effective management of patients. A 48-year-old Han businessman presented to the ear, nose and throat surgeons with an eight-week history of epigastric pain, a four-week history of a widespread non-itchy rash including the scrotal skin and a one-week history of tinnitus and dizziness. On examination, he was afebrile with widespread lymphadenopathy and a maculopapular rash affecting his trunk and scrotum. His abdomen was soft but tender in the epigastrium. The Treponema pallidum particle agglutination assay result was positive, and the rapid plasma reagin was 1:2. Gastroscopy showed ulcers in the gastric antrum and pylorus. Histopathological examination of gastric mucosa lesions showed a large amount of lymphoplasmacytic infiltrate detected in the lamina propria of the gastric mucosa. The T. pallidum Liferiver real time polymerase chain reaction kit assay performed on specimens from skin lesions and gastric mucosal tissue were positive. The patient was treated with intravenous sodium penicillin followed by intramuscular benzathine penicillin. On the fourth day of the treatment, the rash, epigastric pain and lymphadenopathy subsided. Two weeks after treatment, the tinnitus alleviated and vertigo disappeared. PMID- 28580834 TI - Evaluation of the epistemic state of the speaker/author. AB - Language users are sensitive to their language's grammatical requirements, the plausibility of the situation described and the information shared by speaker and listener. We propose that they are also sensitive to whether an author is likely to be in a state of knowledge that actually supports the assertion being made. Failure to be in such a state reduces the naturalness of the assertion. Consistent with this proposal, sentences with a disjoined noun phrase are judged to be less natural than their conjunctive counterparts, presumably because the author of a disjunctive sentence must know that an event took place but not know which of the two individuals was the agent. This unlikely state of knowledge reduces the naturalness of the sentence. The results of three experiments indicate that providing evidence that the speaker could be in an unlikely epistemic state reduces the disjunction penalty; a fourth extends the demonstration of the penalty from coordinated noun phrases to coordinated verb phrases. We also present one experiment that explores the possibility that disjunction penalty is due to the unexpectedness of a disjunction. These findings demonstrate that language users evaluate linguistic input in light of the epistemic state of its author. PMID- 28580835 TI - Early retinotopic responses to violations of emotion-location associations may depend on conscious awareness. AB - Reports of modulations of early visual processing suggest that retinotopic visual cortex may actively predict upcoming stimuli. We tested this idea by showing healthy human participants images of human faces at fixation, with different emotional expressions predicting stimuli in either the upper or the lower visual field. On infrequent test trials, emotional faces were followed by combined stimulation of upper and lower visual fields, thus violating previously established associations. Results showed no effects of such violations at the level of the retinotopic C1 of the visual evoked potential over the full sample. However, when separating participants who became aware of these associations from those who did not, we observed significant group differences during extrastriate processing of emotional faces, with inverse solution results indicating stronger activity in unaware subjects throughout the ventral visual stream. Moreover, within-group comparisons showed that the same peripheral stimuli elicited differential activity patterns during the C1 interval, depending on which stimulus elements were predictable. This effect was selectively observed in manipulation-aware subjects. Our results provide preliminary evidence for the notion that early visual processing stages implement predictions of upcoming events. They also point to conscious awareness as a moderator of predictive coding. PMID- 28580833 TI - Taurine supplementation has anti-atherogenic and anti-inflammatory effects before and after incremental exercise in heart failure. AB - BACKGROUND: The purpose of this study was to examine the anti-atherogenic and anti-inflammatory effect of supplemental taurine prior to and following incremental exercise in patients with heart failure (HF). METHODS: Patients with HF and left ventricle ejection fraction less than 50%, and placed in functional class II or III according to the New York Heart Association classification, were randomly assigned to two groups: (1) taurine supplementation; or (2) placebo. The taurine group received oral taurine (500 mg) 3 times a day for 2 weeks, and performed exercise before and after the supplementation period. The placebo group followed the same protocol, but with a starch supplement (500 mg) rather than taurine. The incremental multilevel treadmill test was done using a modified Bruce protocol. RESULTS: Our results indicate that inflammatory indices [C reactive protein (CRP), platelets] decreased in the taurine group in pre exercise, post-supplementation and post-exercise, post-supplementation as compared with pre-exercise, pre-supplementation ( p < 0.05) whereas these indices increased in pre-exercise, post-supplementation and post-exercise, post supplementation as compared with pre-exercise, pre-supplementation in the placebo group ( p < 0.05). Our results also show that atherogenic indices [Castelli's Risk Index-I (CRI-I), Castelli's Risk Index-II (CRI-II) and Atherogenic Coefficient (AC)] decreased in the taurine group in pre-exercise, post supplementation and post-exercise, post-supplementation as compared with pre exercise, pre-supplementation ( p < 0.05). No such changes were noted in the placebo group ( p > 0.05). CONCLUSIONS: our results suggest that 2 weeks of oral taurine supplementation increases the taurine levels and has anti-atherogenic and anti-inflammatory effects prior to and following incremental exercise in HF patients. PMID- 28580837 TI - Representing Spatial Layout According to Intrinsic Frames of Reference. AB - Mou and McNamara have suggested that object locations are represented according to intrinsic reference frames. In three experiments, we investigated the limitations of intrinsic reference frames as a mean to represent object locations in spatial memory. Participants learned the locations of seven or eight common objects in a rectangular room and then made judgments of relative direction based on their memory of the layout. The results of all experiments showed that when all objects were positioned regularly, judgments of relative direction were faster or more accurate for novel headings that were aligned with the primary intrinsic structure than for other novel headings; however, when one irregularly positioned object was added to the layout, this advantage was eliminated. The experiments further indicated that with a single view at study, participants could represent the layout from either an egocentric orientation or a different orientation, according to experimental instructions. Together, these results suggest that environmental reference frames and intrinsic axes can influence performance for novel headings, but their role in spatial memory depends on egocentric experience, layout regularity, and instructions. PMID- 28580838 TI - A diagnostic pathologist's guide to carpal disease in racehorses. AB - As a pathologist, postmortem examination of the equine carpus can be daunting. The anatomy is complex and oftentimes, small or subtle lesions have significant impact on lameness and secondary lesions such as catastrophic musculoskeletal fractures and other injuries. In performance horses, particularly racehorses, the carpus is a common site of injury and source of lameness. Given the predisposition of racehorses to developing carpal disease, familiarity with clinically relevant anatomy and common developmental, degenerative, traumatic, and inflammatory processes are imperative for thorough postmortem examination. Our aim is (1) to provide a concise summary of clinically relevant anatomy and function that serves as a guide for postmortem evaluation of the equine carpus, and (2) to review common carpal injuries and diseases in actively training, racing, or retired racehorses, including developmental lesions (incomplete ossification, osteochondromata), infectious and inflammatory lesions (septic arthritis and tenosynovitis), and degenerative and traumatic lesions (degenerative and traumatic osteoarthritis, osteochondral fragmentation, and polyostotic catastrophic "breakdown" fractures). Representative gross and histologic images are presented along with corresponding antemortem and postmortem diagnostic images, and a review of current scientific literature pertaining to the pathogenesis of these equine carpal lesions. PMID- 28580840 TI - Gravimetric quantitative determination of packaging residues in feed from former food. AB - Valorisation of former foodstuff products (FFP) in feed is part of a long-term strategy for sustainability. An approach to valorise FFP outside the waste value chain is their use as an alternative source of feed materials, with a subsequent optimisation of the environmental impact of products. In the current practice of food production, food packaging is provided to ensure the maintenance of food quality and safety during transport and storage. One of the problems of reusing FFP is how to deal with packaging materials or remains that can become residues in the feed. The aim of this study is to propose a fast and sensitive gravimetric method, fit for routine official controls, for the determination of packaging residues in feed. The developed method can briefly be summarised as: (1) visual selection of the undesired ingredients which can be identified as remnants of packaging materials; (2) weighing of the selected materials; (3) defatting; (4) dehydration; (5) final weighing; and (6) reporting of weight and percentage. Moreover, the method has been validated through the determination of some of the parameters listed in Council Regulation 2004/882/EC (i.e., specificity, limit of quantification (LOQ), recovery, repeatability, within-laboratory reproducibility and measurement uncertainty). PMID- 28580841 TI - Safety and efficacy of Ofatumumab in chronic lymphocytic leukemia: a systematic review and meta-analysis. AB - OBJECTIVES: Increasing numbers of clinical studies have been carried out to investigate the therapeutic effect of Ofatumumab for patients with chronic lymphocytic leukemia (CLL) but no studies have yet reported a pooled estimate of the treatment effect. We performed a meta-analysis of evidence from 13 clinical trials to assess effectiveness and safety of Ofatumumab-based therapy in patients with CLL. METHODS: Relevant publications from PubMed, Web of Science, Embase, and ClinicalTrials.gov were searched. The primary efficacy outcomes were progression free survival (PFS) and overall survival (OS). The second endpoint was the adverse events. RESULTS: The pooled efficacy analysis showed that there were no significant difference in PFS [hazard ratios (HR) = 0.88, 95% confidence interval (CI) = 0.47-1.63, p = 0.677, I2 = 94.9%] and OS (HR = 0.97, 95% CI = 0.70-1.36, p = 0.878, I2 = 58.7%) between Ofatumumab-based therapy and non-Ofatumumab therapy. The pooled toxicity analysis showed that Ofatumumab-based therapy was associated with an increased risk of infusion-related reaction but decreased risk of thrombocytopenia and anemia compared with non-Ofatumumab-based therapy. Moreover, infections, and infusion-related reaction occurred more frequently in participants with single Ofatumumab studies. DISCUSSION: Our analysis showed PFS was statistically significantly improved with Ofatumumab-based treatments (including Ofatumumab alone, Ofatumumab plus chemotherapy) for CLL compared with observation or chemotherapy-based regimen groups. Ofatumumab had no statistically significant improvement on the OS of patients with CLL. The Ofatumumab-based therapy could generally decrease the risk of adverse effects except infusion related reaction and infections. PMID- 28580839 TI - Epac and Nociceptor Sensitization. AB - Abstract: Primary sensory neurons are responsible for transmitting sensory information from the peripheral to the central nervous system. Their responses to incoming stimulation become greatly enhanced and prolonged following inflammation, giving rise to exaggerated nociceptive responses and chronic pain. The inflammatory mediator, prostaglandin E2 (PGE2), released from the inflamed tissue surrounding the terminals of sensory neurons contributes to the abnormal pain responses. PGE2 acts on G protein-coupled EP receptors to activate adenylyl cyclase, which catalyzes the conversion of adenosine triphosphate to cyclic adenosine 3',5'-monophosphate (cAMP). Under normal conditions, cAMP activates primarily protein kinase A. After inflammation, cAMP also activates the exchange proteins activated by cAMP (Epacs) to produce exaggerated PGE2-mediated hyperalgesia. The role of cAMP-Epac signaling in the generation of hypersensitivity is the topic of this review. PMID- 28580843 TI - Risk assessment of combined exposure to alkenylbenzenes through consumption of plant food supplements containing parsley and dill. AB - A risk assessment was performed of parsley- and dill-based plant food supplements (PFS) containing apiol and related alkenylbenzenes. First, the levels of the alkenylbenzenes in the PFS and the resulting estimated daily intake (EDI) resulting from use of the PFS were quantified. Since most PFS appeared to contain more than one alkenylbenzene, a combined risk assessment was performed based on equal potency or using a so-called toxic equivalency (TEQ) approach based on toxic equivalency factors (TEFs) for the different alkenylbenzenes. The EDIs resulting from daily PFS consumption amount to 0.74-125 ug kg-1 bw for the individual alkenylbenzenes, 0.74-160 ug kg-1 bw for the sum of the alkenylbenzenes, and 0.47-64 ug kg-1 bw for the sum of alkenylbenzenes when expressed in safrole equivalents. The margins of exposure (MOEs) obtained were generally below 10,000, indicating a priority for risk management if the PFS were to be consumed on a daily basis. Considering short-term use of the PFS, MOEs would increase above 10,000, indicating low priority for risk management. It is concluded that alkenylbenzene intake through consumption of parsley- and dill based PFS is only of concern when these PFS are used for long periods of time. PMID- 28580836 TI - Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy; cause and effect? AB - Abstract: Cancer is the second leading cause of death worldwide and is a major global health burden. Significant improvements in survival have been achieved, due in part to advances in adjuvant antineoplastic chemotherapy. The most commonly used antineoplastics belong to the taxane, platinum, and vinca alkaloid families. While beneficial, these agents are frequently accompanied by severe side effects, including chemotherapy-induced peripheral neuropathy (CPIN). While CPIN affects both motor and sensory systems, the majority of symptoms are sensory, with pain, tingling, and numbness being the predominant complaints. CPIN not only decreases the quality of life of cancer survivors but also can lead to discontinuation of treatment, thereby adversely affecting survival. Consequently, minimizing the incidence or severity of CPIN is highly desirable, but strategies to prevent and/or treat CIPN have proven elusive. One difficulty in achieving this goal arises from the fact that the molecular and cellular mechanisms that produce CPIN are not fully known; however, one common mechanism appears to be changes in ion channel expression in primary afferent sensory neurons. The processes that underlie chemotherapy-induced changes in ion channel expression and function are poorly understood. Not all antineoplastic agents directly affect ion channel function, suggesting additional pathways may contribute to the development of CPIN Indeed, there are indications that these drugs may mediate their effects through cellular signaling pathways including second messengers and inflammatory cytokines. Here, we focus on ion channelopathies as causal mechanisms for CPIN and review the data from both pre-clinical animal models and from human studies with the aim of facilitating the development of appropriate strategies to prevent and/or treat CPIN. PMID- 28580844 TI - Relapse of childhood acute lymphoblastic leukemia and outcomes at a reference center in Latin America: organomegaly at diagnosis is a significant clinical predictor. AB - OBJECTIVE: Relapse is the major cause of treatment failure in acute lymphoblastic leukemia (ALL) of childhood; it is more frequent among high-risk patients from low-middle income than from high-income countries. The frequency, sites and outcome of relapsed ALL in children of northeast Mexico over a decade was documented. METHODS: A retrospective analysis of 246 children belonging to a low income group <16 years with de novo ALL during 2004-2015 was performed. Five-year overall survival (OS) and event-free survival was estimated by Kaplan-Meier analysis. Data on time, site, response to therapy and final outcome of relapse were analyzed. Hazard ratios (HRs) of relapse and death were estimated by the Cox regression model. Very early relapse was defined as that occurring in <18 months, early relapse between 18 and 36 months, and late relapse >36 months from diagnosis, respectively. RESULTS: Eighty-seven (35.4%) children relapsed. Five year OS was 82.6% in children without relapse vs. 42% for relapsed patients. Bone marrow (BM) was the most frequent site of relapse (51.72%). Isolated central nervous system (CNS) relapses occurred in 29.9%. Five-year OS was 11.2% for BM and 15.5% for early relapse. HR of relapse for organomegaly was 3.683, 2.247 for an initial white blood cell count >50 000 * 109/l and 1.169 for positive minimal residual disease status. CONCLUSION: A high rate of very early, CNS, and BM relapse with a considerably low 5-year OS requiring reassessment of therapy was documented. Organomegaly at diagnosis was a highly significant clinical predictor for relapse. PMID- 28580845 TI - 'Nobody teases good girls': A qualitative study on perceptions of sexual harassment among young men in a slum of Mumbai. AB - Young adulthood is a key period in which gender norms are solidified. As a result, young women are particularly vulnerable to gender-based violence. In Delhi, over 90% of women have ever experienced sexual violence in public spaces. Sexual harassment of girls and women in public spaces is commonly named 'eve teasing' in India. Experience of sexual harassment in public spaces has been found to be associated with restricted mobility, interrupted education, and early age at marriage. Little is known about men's perspectives on eve teasing and how they believe it affects women and girls. This study fills that gap through qualitative research to explore the attitudes and perceptions of adolescent boys and young men on this topic. Ten focus group discussions were conducted in two slum communities in Mumbai. Coding and thematic analysis were performed. We identified themes of acceptance of harassment, weak sanctions, traditional gender norms supportive of harassment, and ideologies of male sexual entitlement. Many of the perceived risk and protective factors for sexual harassment in public spaces are operationalised at the community level. Community mobilisation is necessary in designing interventions focused on the primary and secondary prevention of sexual harassment. PMID- 28580842 TI - Understanding Magnetic Resonance Imaging of Knee Cartilage Repair: A Focus on Clinical Relevance. AB - The aims of this review article are (a) to describe the principles of morphologic and compositional magnetic resonance imaging (MRI) techniques relevant for the imaging of knee cartilage repair surgery and their application to longitudinal studies and (b) to illustrate the clinical relevance of pre- and postsurgical MRI with correlation to intraoperative images. First, MRI sequences that can be applied for imaging of cartilage repair tissue in the knee are described, focusing on comparison of 2D and 3D fast spin echo and gradient recalled echo sequences. Imaging features of cartilage repair tissue are then discussed, including conventional (morphologic) MRI and compositional MRI techniques. More specifically, imaging techniques for specific cartilage repair surgery techniques as described above, as well as MRI-based semiquantitative scoring systems for the knee cartilage repair tissue-MR Observation of Cartilage Repair Tissue and Cartilage Repair OA Knee Score-are explained. Then, currently available surgical techniques are reviewed, including marrow stimulation, osteochondral autograft, osteochondral allograft, particulate cartilage allograft, autologous chondrocyte implantation, and others. Finally, ongoing research efforts and future direction of cartilage repair tissue imaging are discussed. PMID- 28580847 TI - The effect of facial expressions on respirators contact pressures. AB - This study investigated the effect of four typical facial expressions (calmness, happiness, sadness and surprise) on contact characteristics between an N95 filtering facepiece respirator and a headform. The respirator model comprised two layers (an inner layer and an outer layer) and a nose clip. The headform model was comprised of a skin layer, a fatty tissue layer embedded with eight muscles, and a skull layer. Four typical facial expressions were generated by the coordinated contraction of four facial muscles. After that, the distribution of the contact pressure on the headform, as well as the contact area, were calculated. Results demonstrated that the nasal clip could help make the respirator move closer to the nose bridge while causing facial discomfort. Moreover, contact areas varied with different facial expressions, and facial expressions significantly altered contact pressures at different key areas, which may result in leakage. PMID- 28580848 TI - Adsorption photobioreactor as a co-treatment system for ammonium and phosphate removal by the response surface method. AB - The co-treatment system of photosynthetic microalgae Chlorella vulgaris and adsorption was investigated as a possible combination of symbiotic mixed culture for the simultaneous removal of nutrients (ammonium and phosphate) and organic contaminants. In this study, response surface methodology for experimental design and optimization was used. For experiment operation, two factorial designs containing five chemical oxygen demand influent (CODin) concentrations (100, 200, 400, 600 and 700 mg l-1) and hydraulic retention times (0.63, 1, 1.75, 2.5 and 2.88 d) were applied. The co-treatment system performed successfully in removing both nutrients (nitrogen and phosphate) and COD, showing around 88%, 75% and 48% removal for the maximum level, respectively. The adsorption-photobioreactor (APBR) displayed superior performance of the microalgae growth rate compared to the photobioreactor. Also, the adsorption capacity (the uptake of COD) has been analysed with the first-order equation. The results showed that the experimental data of the APBR fit well with the model. PMID- 28580850 TI - [Advances in the pathogenesis of non alcoholic fatty liver disease]. AB - Non alcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, and the most common liver disease. Its more aggressive form is the non alcoholic steatohepatitis. Multiple genetic and environmental factors lead to the accumulation of triglicerides and the inflammatory cascade. High fat diet, obesity, adipocyte dysfunction with cytokine production, insulin resistance and increased lipolysis with free fatty acid flux into the liver - all are the drivers of liver cell injury. Activation of inflammasome by damage- or pathogen associated molecular patterns results in "steril inflammation" and immune response, while the hepatic stellate cells and progenitor cells lead to fibrogenesis. Small intestinal bacterial overgrowth and gut dysbiosis are also of pivotal importance in the inflammation. Among the susceptible genetic factors, mutations of patatin-like phospholipase domain containing 3 and the transmembrane 6 superfamily 2 genes play a role in the development and progression of the disease, similarly as do epigenetic regulators such as microRNAs and extracellular vesicles. Better understanding of the pathogenesis of non alcoholic fatty liver disease may identify novel therapeutic agents that improve the outcome of the disease. Orv Hetil. 2017; 158(23): 882-894. PMID- 28580849 TI - [New - epicutaneous - method for the causal treatment of allergic diseases]. AB - The only causal treatment for the allergic diseases is the allergen immunotherapy. Besides oral and injection forms, an epicutaneous form is known as well. During the immunization process the use of an adjuvant material is advisable besides the allergen. That adjuvant material can be (besides of the aluminium hydroxid and tyrosine) a bacterial toxin, too. In idealistic circumstances we can substitute the native allergen with its recombinant variant, which could keep its immunogenicity but had lost the allergenicity. In the future the recommended therapy could be the safe, painless, epicutaneous hyposensitization, with recombinant allergens, with bacterial toxin as adjuvants. Orv Hetil. 2017; 158(23): 895-899. PMID- 28580851 TI - [Female child sexual abuse]. AB - INTRODUCTION AND AIM: The prevalence of child sexual abuse is 12-13% worldwide (18% by girls, 8% by boys). The exact knowledge of sexual abuse and the spread of the adequate medical diagnosis is an essential medical, social and national requirement. In our present study we examine the medical diagnosis of female child sexual abuse. METHOD: Selective literature research in the available international and domestic databases. RESULTS: Majority of children assessed for suspected sexual abuse have normal genital and anal findings. Contrary to popular belief, the majority of child sexual abuse is a chronic multiple event, caused by a family member. The task of the medical staff is difficult and various, due to the diagnostic challenges of child sexual abuse. The difficulties of the medical diagnosis, evaluation and therapy, the complexity of the legal proceedings and prosecution, the isolation of the profession and the victim and the issue treated like a taboo subject often lead to failure. CONCLUSION: The physicians dealing with children have suboptimal knowledge of child sexual abuse, the characteristics of victims and perpetretors, the medical diagnosis and therapy of sexual abuse and the rehabilitation of victims. Orv Hetil. 2017; 158(23): 910 917. PMID- 28580853 TI - [Hungarian Philadelphia negative chronic myeloproliferative neoplasia registry. Evaluation of the Polycythemia vera patients]. AB - : Intruduction and aim: The Hungarian National Registry for Philadelphia chromosome negative myeloproliferative neoplasms has been developed. The aim of the recent study is to assess the clinical characteristics of Hungarian patients with polycythemia vera. METHOD: Data of 351 JAK2V617F and exon 12 mutation positive polycythemia vera patients were collected online from 15 haematology centres reporting epidemiologic, clinical characteristics, diagnostic tools, therapeutic interventions, thromboembolic complications, disease transformations. Vascular events prior to and after diagnosis were evaluated upon the Landolfi risk assessment scale. RESULTS: 116 thromboembolic events were reported in 106 PV patients prior to diagnosis and 152 occasions in 102 patients during follow-up. The frequency of major arterial events were significantly reduced (p<0.0001) and the minor venous events were significantly elevated (p<0.0001) after the diagnosis. Major hemorrhagic complications were found in 25 and transformation in 26 cases. CONCLUSIONS: Our registry allows to collect and evaluate the features of patients with polycythemia vera. The Landolfi risk stratification was proven to be useful. Based on evaluated data, accuracy of diagnostic criteria and compliance to risk-adapted therapeutic guidelines are needed. Orv Hetil. 2017; 158(23): 901-909. PMID- 28580855 TI - Cost-effectiveness of providing measles vaccination to all children in Guinea Bissau. AB - BACKGROUND: Measles vaccination is associated with major reductions in child mortality and morbidity. In Guinea-Bissau, to limit vaccine wastage, children are only measles-vaccinated if at least six children aged 9-11 months are present at a vaccination session. OBJECTIVE: To estimate the incremental cost-effectiveness of providing measles vaccine (MV) to all children regardless of age and number of children present. METHODS: We estimated MV coverage among children living in villages cluster-randomized to MV for all children and among children cluster randomized to the current restrictive MV policy (status quo). Prices of MV and injection equipment were obtained from the United Nations Children's Fund (UNICEF). Cost savings of hospital admissions averted were collected from a sample of health facilities. The non-specific mortality effects of MV were estimated and presented as deaths averted and life years gained (LYG) from providing MV-for-all. RESULTS: MV coverage at 36 months was 97% in MV-for-all clusters and 84% in restrictive MV policy clusters. Conservatively assuming 90% wastage of MV under the MV-for-all policy and 40% under the restrictive MV policy, cost per child vaccinated was USD 3.08 and USD 1.19, respectively. The incremental costs per LYG and death averted of the MV-for-all policy were USD 5.61 and USD 148, respectively. The MV-for-all policy became cost-saving at 88% wastage. CONCLUSIONS: Taking the low cost of MV and the beneficial non-specific effects of MV into consideration, a 10-dose MV vial should be reclassified as a '1+ dose vial'. The vial should be opened for a single child, irrespective of age, but can vaccinate up to 10 children. PMID- 28580856 TI - Short-Term Perioperative Complications and Mortality After Total Ankle Arthroplasty in the United States. AB - : This study sought to identify patient and operative demographics associated with 30-day perioperative complications in patients undergoing total ankle arthroplasty as recorded in the National Surgical Quality Improvement Project database. Complications were divided into local and systemic and further subcategorized as major and minor. A total of 404 patients underwent total ankle arthroplasty between 2007 and 2014 as captured in the National Surgical Quality Improvement Project database. The overall complication rate was 2.4% with 0.5% mortality and 0.2% infection rate. Length of hospital stay, both as an end point at >5 days and as a continuous variable, was associated with overall complications (odds ratio [OR] = 9.90, P = .002 and OR = 1.52, P = .006, respectively). Patient characteristics that predicted perioperative morbidity included presence of 3 or comorbidities (OR = 8.48, P = 0.038), American Society of Anesthesiologists class III, and history of previous cardiac surgery (OR = 12.22, P = .033). Correct patient selection is imperative in achieving improved outcomes and those that are at risk for complications should be counseled as such. LEVELS OF EVIDENCE: Level III: Database case control study. PMID- 28580857 TI - Factors Influencing Patient-Perceived Satisfaction With Community-Based Case Management Services. AB - This study aimed to identify factors that significantly affect patient-perceived satisfaction with community-based case management services and provide practical strategies for improving patient-perceived quality of care. Secondary data analyses were performed in 2010, 2013, 2015, and 2016, which included Pearson's and Spearman's correlation, Mann-Whitney U and Kruskal-Wallis tests, and stepwise multiple regression. The response variable was measured by the Korean Patient Perceived Satisfaction Scale of Community-Based Case Management Services (Korean PSCCM; a 10-level Likert-type scale), whereas explanatory variables were derived from prior studies. Significant predictors of patient-perceived satisfaction with community-based case management services included "capacity to change," "patient perceived time spent with a case manager," "support/advocacy," "working period," and "emotional connectedness." PMID- 28580854 TI - Changes in lower limb muscle function and muscle mass following exercise-based interventions in patients with chronic obstructive pulmonary disease: A review of the English-language literature. AB - Chronic obstructive pulmonary disease (COPD) patients often experience lower limb muscle dysfunction and wasting. Exercise-based training has potential to improve muscle function and mass, but literature on this topic is extensive and heterogeneous including numerous interventions and outcome measures. This review uses a detailed systematic approach to investigate the effect of this wide range of exercise-based interventions on muscle function and mass. PUBMED and PEDro databases were searched. In all, 70 studies ( n = 2504 COPD patients) that implemented an exercise-based intervention and reported muscle strength, endurance, or mass in clinically stable COPD patients were critically appraised. Aerobic and/or resistance training, high-intensity interval training, electrical or magnetic muscle stimulation, whole-body vibration, and water-based training were investigated. Muscle strength increased in 78%, muscle endurance in 92%, and muscle mass in 88% of the cases where that specific outcome was measured. Despite large heterogeneity in exercise-based interventions and outcome measures used, most exercise-based trials showed improvements in muscle strength, endurance, and mass in COPD patients. Which intervention(s) is (are) best for which subgroup of patients remains currently unknown. Furthermore, this literature review identifies gaps in the current knowledge and generates recommendations for future research to enhance our knowledge on exercise-based interventions in COPD patients. PMID- 28580858 TI - Suboptimal palliative sedation in primary care: an exploration. AB - OBJECTIVES: Palliative sedation is a therapeutic option to control refractory symptoms in terminal palliative patients. This study aims at describing the occurrence and characteristics of suboptimal palliative sedations in primary care and at exploring the way general practitioners (GPs) experience suboptimal palliative sedation in their practice. METHODS: We conducted a mixed methods study with a quantitative prospective survey in primary care and qualitative semi structured interviews with GPs. The research team defined suboptimal palliative sedation as a time interval until deep sleep >1.5 h and/ or >2 awakenings after the start of the unconsciousness. Descriptive statistics were calculated on the quantitative data. Thematic analysis was used to analyse interview transcripts. RESULTS: We registered 63 palliative sedations in 1181 home deaths, 27 forms were completed. Eleven palliative sedations were suboptimal: eight due to the long time span until deep sleep; three due the number of unintended awakenings. GPs' interview analysis revealed two major themes: the shifting perception of failure and the burden of responsibility. CONCLUSIONS: Suboptimal palliative sedation occurs frequently in primary palliative care. Efficient communication towards family members is needed to prevent them from having unrealistic expectations and to prevent putting pressure on the GP to hasten the procedure. Sharing the burden of decision-making during the procedure with other health care professionals might diminish the heavy responsibility as perceived by GPs. PMID- 28580859 TI - Isolated spinal cord compression syndrome revealing delayed extensive superficial siderosis of the central nervous system secondary to cervical root avulsion. AB - CONTEXT: Cervical root avulsion secondary to traumatic plexus injury is a rare etiology of superficial siderosis (SS) of the central nervous system (CNS). We describe the case of an isolated progressive compressive myelopathy revealing this complication and discuss the pathogenesis of such a presentation, its clinical and imaging peculiarities with a literature review. FINDINGS: We report on the case of a 48-year-old man with history of left brachial plexus injury at the age of 2 years. Since the age of 38 years, he had presented with a progressive paraplegia, bladder and erectile dysfunction, neuropathic pain and sensory level. The diagnosis was made by spinal cord and brain magnetic resonance follow-up imaging revealing hypointensity T2-weighted gradient echo linear dark rim around the entire neuraxis and cervical dural pseudomeningoceles. These MRI findings were suggestive of extensive hemosiderin deposition consolidating the diagnosis of SS of CNS. CONCLUSION/CLINICAL RELEVANCE: Our case report illustrates diagnosis difficulties in unusual or paucisymptomatic presentations of SS. A history of brachial plexus trauma with nerve root avulsion should prompt gradient-echo T2-weighted imaging to bring out such a complication. Superficial siderosis of the CNS should be included in the panel of differential diagnosis of the parethospastic syndromes and compressive myelopathy. PMID- 28580860 TI - The effects of social concern goals on the value of learning and on the intentions of medical students to change their majors. AB - BACKGROUND: In the process of developing a professional medical expertise, goals can become a psychological impetus and act as a source of retaining an individual's persistency. Therefore, the goals of medical students should be considered when designing a curriculum for health professions. PURPOSE: The purpose of this study was to examine relative effects of goal categories on the value of learning and intention to change one's major. METHOD: Data were obtained from the Korea Education Longitudinal Study, which included 1938 representative Korean college freshmen majoring in medicine, engineering, natural science and humanities. They answered a survey questionnaire about goal categories (i.e., social concern, affiliation, self-growth, leisure, wealth, and fame), the value of learning, and intention to change one's major. RESULTS: For medical students, social concern goals were positively related to the value of learning and negatively related to the intention to change one's major. Social concern goals decreased the intention to change one's major directly, and also indirectly through increased value of learning. CONCLUSION: Providing context for enhancing medical students' social concern goals is necessary in a medical training curriculum, not only for the students' professional development but also for improving society. ABBREVIATIONS: GCT: Goal contents theory GPA: Grade point average KELS: Korea education longitudinal study SDLA: Self-directed learning abilities SDT: Self-determination theory. PMID- 28580861 TI - Factors associated with upper extremity contractures after cervical spinal cord injury: A pilot study. AB - OBJECTIVE: To examine the prevalence of joint contractures in the upper limb and association with voluntary strength, innervation status, functional status, and demographics in a convenience sample of individuals with cervical spinal cord injury to inform future prospective studies. DESIGN: Cross-sectional convenience sampled pilot study. SETTING: Department of Veterans Affairs Research Laboratory. PARTICIPANTS: Thirty-eight participants with cervical level spinal cord injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Contractures were measured with goniometric passive range of motion. Every joint in the upper extremity was evaluated bilaterally. Muscle strength was measured with manual muscle testing. Innervation status was determined clinically with surface electrical stimulation. Functional independence was measured with the Spinal Cord Independence Measure III (SCIM-III). RESULTS: Every participant tested had multiple joints with contractures and, on average, participants were unable to achieve the normative values of passive movement in 52% of the joints tested. Contractures were most common in the shoulder and hand. There was a weak negative relationship between percentage of contractures and time post-injury and a moderate positive relationship between percentage of contractures and age. There was a strong negative correlation between SCIM-III score and percentage of contractures. CONCLUSIONS: Joint contractures were noted in over half of the joints tested. These joint contractures were associated with decreased functional ability as measured by the SCIM-III. This highlights the need the need for detailed evaluation of the arm and hand early after injury as well as continued monitoring of joint characteristics throughout the life course of the individual with tetraplegia. PMID- 28580862 TI - Which will Trump: human rights and professional ethics, or torture redux? AB - Recent political developments in the United States raise concerns about the potential return of aggressive interrogation strategies, particularly in the event of another large-scale terror attack on the U.S. mainland. This essay reviews various legal, ethical and policy responses to revelations of torture during the Bush administration. It asks whether they improve the prospect that, in future, human rights will trump torture, not vice versa. The essay argues that physicians could help prevent further abuses - especially given their access, social status and expertise - but that insufficient steps have been taken to empower them to do so. PMID- 28580863 TI - Validation of a quantitative Eimeria spp. PCR for fresh droppings of broiler chickens. AB - A quantitative Polymerase Chain Reaction (qPCR) for the seven chicken Eimeria spp. was modified and validated for direct use on fresh droppings. The analytical specificity of the qPCR on droppings was 100%. Its analytical sensitivity (non sporulated oocysts/g droppings) was 41 for E. acervulina, <=2900 for E. brunetti, 710 for E. praecox, 1500 for E. necatrix, 190 for E. tenella, 640 for E. maxima, and 1100 for E. mitis. Field validation of the qPCR was done using droppings with non-sporulated oocysts from 19 broiler flocks. To reduce the number of qPCR tests five grams of each pooled sample (consisting of ten fresh droppings) per time point were blended into one mixed sample. Comparison of the oocysts per gram (OPG)-counting method with the qPCR using pooled samples (n = 1180) yielded a Pearson's correlation coefficient of 0.78 (95% CI: 0.76-0.80) and a Pearson's correlation coefficient of 0.76 (95% CI: 0.70-0.81) using mixed samples (n = 236). Comparison of the average of the OPG-counts of the five pooled samples with the mixed sample per time point (n = 236) showed a Pearson's correlation coefficient (R) of 0.94 (95% CI: 0.92-0.95) for the OPG-counting method and 0.87 (95% CI: 0.84-0.90) for the qPCR. This indicates that mixed samples are practically equivalent to the mean of five pooled samples. The good correlation between the OPG-counting method and the qPCR was further confirmed by the visual agreement between the total oocyst/g shedding patterns measured with both techniques in the 19 broiler flocks using the mixed samples. PMID- 28580864 TI - Increasing Social Support for Breakfast: Project BreakFAST. AB - : High school students in the United States are known to be frequent skippers of breakfast. Social support is one key element needed to encourage adolescents to consume school breakfast. This article presents an analysis of the influence of a school policy and environment change intervention on the social support of adolescents to eat breakfast. METHOD: The intervention included school policy changes in 16 schools randomized to intervention and delayed-intervention conditions, in order to allow quick and easy access to breakfast as well as to allow breakfast consumption in classrooms and hallways; a School Breakfast Program marketing campaign to address normative and attitudinal beliefs; and increasing social support and role modeling to encourage breakfast eating. The participants in the study completed an online survey at baseline and again postintervention. RESULTS: The final analysis included only students who completed the relevant survey (n = 904) items on both the baseline and follow-up surveys. The students in the intervention group showed a higher level of social support post intervention than the control group with a significant adjusted p of .02. Most of the overall social support change was explained by a change in the "other kids at my school" and "other school staff" categories. CONCLUSIONS: The BreakFAST study shows the benefits of school staff and kids other than friends supporting a behavior change to include breakfast consumption in adolescents. PMID- 28580866 TI - Complications after hand surgery in patients with a raised International Normalized Ratio. AB - : A multicentre database was used to compare complications in 231 patients with an elevated International Normalized Ratio with 1626 control patients with a normal International Normalized Ratio. Patients with International Normalized Ratios measured within 48 hours of hand surgery were identified. Logistic regression models were used to assess the association between anticoagulation and reoperation rates, emergency department visits and hospital readmissions for the first 30 days after operation. The group with a raised International Normalized Ratio had a significantly higher Charlson Comorbidity Score. An elevated International Normalized Ratio was associated with an odds ratio for a post operative emergency department visit of 3.3 and an odds ratio of 4.7 for readmission. There was no statistically significant difference in early reoperations between the two groups. LEVEL OF EVIDENCE: III. PMID- 28580867 TI - Impact of perioperative anticoagulation on artificial urinary sphincter device survival. AB - OBJECTIVE: The aim of this study was to evaluate the impact of perioperative anticoagulation on artificial urinary sphincter (AUS) device outcomes. METHODS: Following institutional review board approval, patients undergoing AUS surgery from 1983 to 2014 were evaluated to assess device survival in patients with warfarin use compared to individuals without warfarin use. Hazard regression analysis was used to determine the association between warfarin use and device outcomes. RESULTS: From 1983 to 2014, there were 2125 AUS procedures at Mayo Clinic. Of these, information regarding anticoagulation use was available in 651, including 43 patients who were on warfarin and 608 who were not. On univariate analysis, the use of warfarin was associated with an increased rate of infection/erosion [hazard ratio (HR) 2.58, p = 0.02]. However, there was no increased risk of overall AUS failure (HR 1.66, p = 0.06), malfunction of AUS (HR 1.19, p = 0.74) or urethral atrophy (HR 1.09, p = 0.88). Kaplan-Meier assessment of device survival for individuals not on warfarin versus individuals on warfarin at 1 and 5 years was 91% versus 83% and 72% versus 57%, respectively (p = 0.058). On multivariate analysis, warfarin was not associated with an increased risk of infection/erosion (HR 1.37, p = 0.51). CONCLUSION: Perioperative management of AUS patients on warfarin requires expert care; however, long-term AUS device survival is not significantly affected by warfarin use. Recognition of these outcomes is important for improving preoperative patient counseling and surgical patient selection. PMID- 28580865 TI - The association between environmental tobacco smoke exposure and childhood respiratory disease: a review. AB - INTRODUCTION: Childhood respiratory illness is a major cause of morbidity and mortality particularly in low and middle-income countries. Environmental tobacco smoke (ETS) exposure is a recognised risk factor for both acute and chronic respiratory illness. Areas covered: The aim of this paper was to review the epidemiology of ETS exposure and impact on respiratory health in children. We conducted a search of 3 electronic databases of publications on ETS and childhood respiratory illness from 1990-2015. Key findings were that up to 70% of children are exposed to ETS globally, but under-reporting may mask the true prevalence. Maternal smoking and ETS exposure influence infant lung development and are associated with childhood upper and lower respiratory tract infection, wheezing or asthma. Further, exposure to ETS is associated with more severe respiratory disease. ETS exposure reduces lung function early in life, establishing an increased lifelong risk of poor lung health. Expert commentary: Urgent and effective strategies are needed to decrease ETS exposure in young children to improve child and long-term lung health in adults especially in low and middle income countries where ETS exposure is increasing. PMID- 28580868 TI - Cell-Cycle Therapeutics Come of Age. AB - The ability to sustain unscheduled proliferation is a hallmark of cancer. The normal process of cell division occurs via the cell cycle, a series of highly regulated steps that are orchestrated at the molecular level by specific cyclins that act in association with cyclin-dependent kinases (CDKs). Cyclin D and CDK4/6 play a key role in cell-cycle progression by phosphorylating and inactivating the retinoblastoma protein, a tumor suppressor that restrains G1- to S-phase progression. The first-generation CDK inhibitors demonstrated broad activity upon several CDKs, which likely explains their considerable toxicities and limited efficacy. Palbociclib, ribociclib, and abemaciclib represent a new class of highly specific ATP-competitive CDK4/6 inhibitors that induce reversible G1-phase cell-cycle arrest in retinoblastoma-positive tumor models. Both palbociclib and ribociclib have been approved in combination with hormone-based therapy for the treatment of naive hormone receptor-positive advanced breast cancer on the basis of an improvement in progression-free survival. In general, CDK4/6 inhibitors are cytostatic as monotherapy but demonstrate favorable tolerability, which has prompted interest in combination approaches. Combinations with phosphatidylinositol 3-kinase and mammalian target of rapamycin inhibitors in breast cancer, and inhibitors of the RAS/RAF/mitogen-activated protein kinase pathway in RAS-mutant cancers are particularly promising approaches that are currently being evaluated. Although the subject of intense preclinical study, predictive biomarkers for response and resistance to these drugs remain largely undefined. CDK4/6 inhibitors have emerged as the most promising of the cell-cycle therapeutics and intense efforts are now underway to expand the reach of this paradigm. PMID- 28580869 TI - BCR-ABL1 tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. AB - The management of chronic myeloid leukemia with BCR-ABL1 tyrosine kinase inhibitors has evolved chronic myeloid leukemia into a chronic, manageable disease. A patient-centered approach is important for the appropriate management of chronic myeloid leukemia and optimization of long-term treatment outcomes. The pharmacist plays a key role in treatment selection, monitoring drug-drug interactions, identification and management of adverse events, and educating patients on adherence. The combination of tyrosine kinase inhibitors with unique safety profiles and individual patients with unique medical histories can make managing treatment difficult. This review will provide up-to-date information regarding tyrosine kinase inhibitor-based treatment of patients with chronic myeloid leukemia. Management strategies for adverse events and considerations for drug-drug interactions will not only vary among patients but also across tyrosine kinase inhibitors. Drug-drug interactions can be mild to severe. In instances where co-administration of concomitant medications cannot be avoided, it is critical to understand how drug levels are impacted and how subsequent dose modifications ensure therapeutic drug levels are maintained. An important component of patient-centered management of chronic myeloid leukemia also includes educating patients on the significance of early and regular monitoring of therapeutic milestones, emphasizing the importance of adhering to treatment in achieving these targets, and appropriately modifying treatment if these clinical goals are not being met. Overall, staying apprised of current research, utilizing the close pharmacist-patient relationship, and having regular interactions with patients, will help achieve successful long-term treatment of chronic myeloid leukemia in the age of BCR-ABL1 tyrosine kinase inhibitors. PMID- 28580871 TI - Pharmacoeconomic evaluations in the treatment of actinic keratoses. AB - Actinic keratoses (AKs) develop as a consequence of chronic ultraviolet (UV) exposure and exist on a continuum with squamous cell carcinoma (SCC). As one of the most common conditions treated by dermatologists, AK places a significant burden on patients and the healthcare system. A range of treatments are used, including topical treatments that target the visible and subclinical lesions. The goal of such therapies is to achieve complete clearance of AKs and eliminate the risk of progression to SCC. Robust meta-analyses of trial data can provide valuable information for the optimal management of AK and cost-effectiveness evaluations of topical treatments, such as ingenol mebutate gel and diclofenac. These outcomes can facilitate prescribing physicians' decisions and shape therapeutic guidelines. Peer-reviewed meta-analysis publications and treatment guidelines favoured ingenol mebutate efficacy over diclofenac and the relative cost-effectiveness of ingenol mebutate. We discuss and critique recent evidence, from a cost-effectiveness analysis of 3% diclofenac sodium and ingenol mebutate in the treatment of AK in Italy, which has challenged this view. PMID- 28580870 TI - Application of microfluidic devices in studies of thrombosis and hemostasis. AB - Due to the importance of fluid flow during thrombotic episodes, it is quite appropriate to study clotting and bleeding processes in devices that have well defined fluid shear environments. Two common devices for applying these defined shear stresses include the cone-and-plate viscometer and parallel-plate flow chamber. While such tools have many salient features, they require large amounts of blood or other protein components. With growth in the area of microfluidics over the last two decades, it has become feasible to miniaturize such flow devices. Such miniaturization not only enables saving of precious samples but also increases the throughput of fluid shear devices, thus enabling the design of combinatorial experiments and making the technique more accessible to the larger scientific community. In addition to simple flows that are common in traditional flow apparatus, more complex geometries that mimic stenosed arteries and the human microvasculature can also be generated. The composition of the microfluidics cell substrate can also be varied for diverse basic science investigations, and clinical investigations that aim to assay either individual patient coagulopathy or response to anti-coagulation treatment. This review summarizes the current state of the art for such microfluidic devices and their applications in the field of thrombosis and hemostasis. PMID- 28580872 TI - Effects of Lactobacillus rhamnosus and Lactobacillus acidophilus on bacterial vaginal pathogens. AB - The human vagina is colonized by a variety of microbes. Lactobacilli are the most common, mainly in healthy women; however, the microbiota composition can change rapidly, leading to infection or to a state in which potential pathogenic microorganisms co-exist with other commensals. In premenopausal women, urogenital infections, such as bacterial vaginosis and aerobic vaginitis, remain an important health problem. Treatment of these infections involves different kind of antibiotics; however, the recurrence rate remains high, and it must be also underlined that antibiotics are unable to spontaneously restore normal flora characterized by an abundant community of Lactobacilli. The main limitation is the inability to offer a long-term defensive barrier, thus facilitating relapses and recurrences. We report here the antimicrobial activities of two commercially existing Lactobacillus strains, Lactobacillus rhamnosus HN001 and Lactobacillus acidophilus GLA-14 strains and their combination (Respecta(r) probiotic blend) against four different pathogens responsible for both bacterial vaginosis ( Gardenerella vaginalis and Atopobium vaginae) and aerobic vaginitis ( Staphylococcus aureus and Escherichia coli) by co-culturing assay. The probiotic combination, even if resulting in a different microbicidal activity against the different strains tested, demonstrated the efficacy of combined Lactobacillus strain treatment. PMID- 28580873 TI - Aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder with recurrent short partial transverse myelitis and favorable prognosis: Two new cases. AB - Understanding the characteristics of neuromyelitis optica spectrum disorder (NMOSD) with recurrent short partial transverse myelitis (SPTM), which is very rare, contributes to the differential diagnosis of multiple sclerosis (MS). We present two Chinese aquaporin-4 immunoglobulin G (AQP4-IgG)-seropositive NMOSD cases who had at least twice SPTM during 4 and 6 years of follow-up, respectively. Their SPTMs have been mild and responded well to corticosteroids just like in the case of MS. The findings highlight the need of searching for serum AQP4-IgG (cell-based assay strongly recommended) in patients with recurrent SPTM and suggest that those patients may have a mild acute attack phase and favorable long-term prognosis. PMID- 28580874 TI - Online detection and quantification of particles of ergot bodies in cereal flour using near-infrared hyperspectral imaging. AB - The objective of this study is to assess near-infrared (NIR) hyperspectral imaging for the detection of ergot bodies at the particle level in cereal flour. For this study, ground ergot body samples and wheat flour samples as well as mixtures of both from 100 to 500,000 mg kg-1 were analysed. Partial least squares discriminant analysis (PLS-DA) models were developed and applied to spectral images in order to detect the ergot body particles. Ergot was detected in 100% of samples spiked at more than 10,000 mg kg-1 and no false-positives were obtained with non-contaminated samples. A correlation of 0.99 was calculated between the reference values and the values predicted by the PLS-DA model. For the cereal flours containing less than 10,000 mg kg-1 of ergot, it was possible for some samples spiked as low as 100 mg kg-1 to detect enough pixels of ergot to conclude that the sample was contaminated. However, some samples were under- or overestimated, which can be explained by the lack of homogeneity in relation to the sampling issue and the thickness of the sample. This study has demonstrated the potential of NIR hyperspectral imaging combined with chemometrics as an alternative solution for discriminating ergot body particles from cereal flour. PMID- 28580877 TI - Clinical commentary on 'Aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder with recurrent short partial transverse myelitis and favorable prognosis: Two new cases', by Wang et al. PMID- 28580876 TI - Multiple Sclerosis: Associations Between Physical Disability and Depression Are Not Mediated by Self-Reported Physical Activity. AB - This study investigated the interrelatedness of physical disability, physical activity, and depression among patients with multiple sclerosis (MS). We hypothesized that self-reported physical activity would mediate the effect of disability on depressive symptoms. Twenty-seven patients with MS (mean age: 49 years; 44.5% females) completed self-rating scales covering sociodemographic variables, intake of antidepressants, physical activity, and symptoms of depression; disability was measured by the Expanded Disability Status Scale. We found a higher level of disability to be significantly associated with more symptoms of depression. While higher reported physical activity was descriptively associated with lower depression scores and unrelated to Expanded Disability Status Scale, physical activity levels did not mediate the effect of disability on depressive symptoms. PMID- 28580875 TI - Matrix-Bound Nanovesicles Recapitulate Extracellular Matrix Effects on Macrophage Phenotype. AB - The early macrophage response to biomaterials has been shown to be a critical and predictive determinant of downstream outcomes. When properly prepared, bioscaffolds composed of mammalian extracellular matrix (ECM) have been shown to promote a transition in macrophage behavior from a proinflammatory to a regulatory/anti-inflammatory phenotype, which in turn has been associated with constructive and functional tissue repair. The mechanism by which ECM bioscaffolds promote this phenotypic transition, however, is poorly understood. The present study shows that matrix-bound nanovesicles (MBV), a component of ECM bioscaffolds, are capable of recapitulating the macrophage activation effects of the ECM bioscaffold from which they are derived. MBV isolated from two different source tissues, porcine urinary bladder and small intestinal submucosa, were found to be enriched in miRNA125b-5p, 143-3p, and 145-5p. Inhibition of these miRNAs within macrophages was associated with a gene and protein expression profile more consistent with a proinflammatory rather than an anti inflammatory/regulatory phenotype. MBV and their associated miRNA cargo appear to play a significant role in mediating the effects of ECM bioscaffolds on macrophage phenotype. PMID- 28580878 TI - Optimizing adherence to advice from antimicrobial stewardship audit and feedback rounds. AB - We examined adherence to antimicrobial stewardship prospective audit and feedback rounds in a rehabilitation service compared with the remainder of the acute hospital, and explored the reasons for this. Between October 2014 and December 2015, we retrospectively assessed the rate of non-adherence to advice from antimicrobial stewardship prospective audit and feedback rounds between the rehabilitation service and the acute hospital, along with the source of the patient referral. Compared with the rehabilitation service, acute hospital medical staff were almost twice as likely to not adhere to advice provided on antimicrobial stewardship prospective audit and feedback rounds (13.8% vs. 7.6%, p < 0.0001, relative risk 1.8 [95% confidence interval 1.3, 2.5]). In the rehabilitation service, referrals were more likely to come from medical staff (61.9% vs. 16.3%, p < 0.0001). These findings may be explained by regular, direct engagement of the antimicrobial stewardship team with the rehabilitation service clinical team, a model potentially applicable to other settings. PMID- 28580880 TI - Fibromyalgia in patients with chronic CCD and CMD - A retrospective study of 555 patients. AB - OBJECTIVE: Craniomandibular dysfunction (CMD) and craniocervical dysfunction (CCD) are clearly defined musculoskeletal pain syndromes. Relationships with fibromyalgia syndrome (FMS) have not yet been investigated. The aim of the present study is to establish possible relationships between FMS and CMD/ CCD. METHODS: In a retrospective study, 555 patients with CCD and CMD were investigated with respect to the diagnostic criteria of FMS. In addition to otolaryngologic and dental examination, an instrumental functional analysis for the diagnosis of CMD/CCD was performed. RESULTS: Three hundred fifty-one (63%) of the 555 patients evaluated met the diagnostic criteria for FMS. Seventy-two percent of the patients had a widespread pain index of at least 7 and a severity scale score of at least 5. Twenty-nine percent had a widespread pain index of 3-6 and a severity scale score of at least 9. Using myocentric bite splint therapy and therapy with oral orthesis in combination with neuromuscular relaxation measures, a good to very good improvement of physical symptoms was seen in 84% of CMD-FMS patients, and an improvement of the symptoms in the jaw was achieved in 77% of cases. DISCUSSION: The substantial proportion of CMD and CCD patients who meet the criteria for FMS emphasizes the complexity of the two diseases. It must be assumed that FMS is a crucial factor for the formation of CMD and CCD. Conversely, CMD/ CCD could also be responsible for diverse clinical pictures of the FMS. FMS patients with synchronous CCD/CMD benefit from an interdisciplinary CMD/CCD treatment. PMID- 28580879 TI - Anti-homosexual legislation and HIV-related stigma in African nations: what has been the role of PEPFAR? AB - BACKGROUND: Gay men and other men who have sex with men are disproportionately burdened by HIV infection. Laws that penalize same-sex intercourse contribute to a cycle of stigma, homonegativity and discrimination. In many African nations, laws criminalizing homosexuality may be fueling the epidemic, as they dissuade key populations from seeking treatment and health care providers from offering it. OBJECTIVES: We analyzed the ways in which policies and practices of the US President's Emergency Plan for AIDS Relief (PEPFAR) program addressed pervasively harsh anti-homosexuality laws across Africa. Given the aim of the US PEPFAR program to reduce stigma surrounding HIV, we explored how PEPFAR may have used its influence to reduce the criminalization of homosexuality in the countries where it operated. METHODS: We assessed homosexuality laws in 21 African countries where PEPFAR funding sought to reduce the HIV epidemic. We examined PEPFAR Policy Framework agreements associated with those countries, and other PEPFAR documents, for evidence of attempts to reduce stigma by decriminalizing homosexuality. RESULTS: We found 16 of Africa's 21 PEPFAR-funded countries had laws characterized as harsh in relation to homosexuality. Among the top eight PEPFAR-funded countries in Africa, seven had harsh anti-homosexuality laws. Most (14) of the 16 African 'Partnership Framework' (PEPFAR) policy agreements between African governments and the US State Department call for stigma reduction; however, none call for reducing penalties on individuals who engage in homosexual behavior. CONCLUSIONS: We conclude that while PEPFAR has acknowledged the negative role of stigma in fueling the HIV epidemic, it has, so far, missed opportunities to explicitly address the role of the criminalization of homosexuality in feeding stigmatizing attitudes. Our analysis suggests mechanisms like PEPFAR Partnership Framework agreements could be ideal vehicles to call for removal of anti-homosexuality legislation. PMID- 28580881 TI - Blocking the Cycle: Cyclin-Dependent Kinase 4/6 Inhibitors in Metastatic, Hormone Receptor-Positive Breast Cancer. AB - The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 68-year-old postmenopausal woman was diagnosed with breast cancer 6 years ago when she presented with a stage II (T2N1), right-sided, invasive ductal carcinoma considered grade 2 of 3 on core biopsy, with a positive fine-needle aspiration of a palpable, ipsilateral axillary lymph node. Immunohistochemical analysis was positive for estrogen and progesterone receptor expression and negative for human epidermal growth factor receptor 2 (HER2) overexpression. She received neoadjuvant dose-dense doxorubicin, cyclophosphamide, and paclitaxel chemotherapy, followed by breast conserving surgery and axillary lymph node dissection, which revealed residual disease in three of 11 nodes. She received adjuvant radiation therapy and initiated letrozole, with excellent compliance during the interval 6-year period. While receiving adjuvant letrozole therapy, she reported 3 months of worsening back pain. Skeletal scintigraphy and cross-sectional imaging confirmed widespread osseous metastatic disease and right supraclavicular lymph node enlargement ( Fig 1 ). Core biopsy of the involved lymph node confirmed estrogen receptor (ER) positive (90%), progesterone receptor-negative, HER2-negative recurrent metastatic breast cancer. The patient reported mild pain that was adequately controlled with over-the-counter anti-inflammatory medications. She has remained active with an excellent performance status. PMID- 28580883 TI - Cyclin-Dependent Kinase 4/6 Inhibitors in the Treatment of Breast Cancer: More Breakthroughs and an Embarrassment of Riches. PMID- 28580884 TI - Specific and common processes as mediators of the long-term effects of cognitive behavioral therapy integrated with motivational interviewing for generalized anxiety disorder. AB - OBJECTIVE: A trial of psychotherapy for generalized anxiety disorder (GAD) demonstrated that motivational interviewing (MI) integrated with cognitive behavioral therapy (CBT) outperformed CBT alone on clients' worry reduction across a 12-month follow-up. In the present study, we hypothesized and tested that less client resistance and greater client-perceived therapist empathy (specific foci of MI) would account for MI's additive effect. Exploratory analyses assessed whether the common processes of homework completion and therapeutic alliance quality mediated the treatment effect. METHOD: Clients with GAD were randomized to 15 sessions of MI-CBT (n = 42) or CBT alone (n = 43). Worry was assessed throughout treatment and follow-up. Observers rated resistance at midtreatment, and clients reported on perceived therapist empathy, alliance, and homework completion throughout treatment. Mediation was tested with bootstrapping methods. RESULTS: Expectedly, MI-CBT clients evidenced less resistance and perceived greater therapist empathy, each of which related to lower 12-month worry. However, when both variables were tested simultaneously, only resistance remained a significant mediator of treatment. No indirect effects through homework completion or alliance emerged. CONCLUSIONS: Reducing client resistance may be a theory-consistent mechanism through which integrative MI-CBT promotes superior long-term improvement than traditional CBT when treating GAD. Clinical or methodological significance of this article: This study further supports the long-term clinical benefit of integrating MI into CBT when treating the highly prevalent and historically difficult-to-treat condition of GAD. In particular, it points to the theory-specific mechanism of MI (helping to reduce/resolve patients' in-treatment resistance) as accounting for the integrative treatment's additive effect on worry reduction across a follow-up period. Therapists using CBT to treat patients with GAD should be trained to incorporate MI principles (e.g., empathy, collaboration, autonomy support) in general and in response to explicit markers of resistance. PMID- 28580882 TI - MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. AB - Purpose MONARCH 2 ( ClinicalTrials.gov identifier: NCT02107703) compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, plus fulvestrant with fulvestrant alone in patients with advanced breast cancer (ABC). Patients and Methods MONARCH 2 was a global, double-blind, phase III study of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who had progressed while receiving neoadjuvant or adjuvant endocrine therapy (ET), <= 12 months from the end of adjuvant ET, or while receiving first-line ET for metastatic disease. Patients were randomly assigned 2:1 to receive abemaciclib or placebo (150 mg twice daily) on a continuous schedule and fulvestrant (500 mg, per label). The primary end point was investigator-assessed progression-free survival (PFS), and key secondary end points included overall survival, objective response rate (ORR), duration of response, clinical benefit rate, quality of life, and safety. Results Between August 2014 and December 2015, 669 patients were randomly assigned to receive abemaciclib plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223). Abemaciclib plus fulvestrant significantly extended PFS versus fulvestrant alone (median, 16.4 v 9.3 months; hazard ratio, 0.553; 95% CI, 0.449 to 0.681; P < .001). In patients with measurable disease, abemaciclib plus fulvestrant achieved an ORR of 48.1% (95% CI, 42.6% to 53.6%) compared with 21.3% (95% CI, 15.1% to 27.6%) in the control arm. The most common adverse events in the abemaciclib versus placebo arms were diarrhea (86.4% v 24.7%), neutropenia (46.0% v 4.0%), nausea (45.1% v 22.9%), and fatigue (39.9% v 26.9%). Conclusions Abemaciclib at 150 mg twice daily plus fulvestrant was effective, significantly improving PFS and ORR and demonstrating a tolerable safety profile in women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who progressed while receiving ET. PMID- 28580885 TI - beta-catenin Mutations Are Not Involved in Early-stage Hepatocarcinogenesis Induced by Protoporphyrinogen Oxidase Inhibitors in Mice. AB - We previously reported the contribution of constitutive androstane receptor (CAR) in cytotoxicity-related hepatocarcinogenesis induced by oxadiazon (OX) or acifluorfen (ACI), two pesticides categorized as protoporphyrinogen oxidase (PROTOX) inhibitors. The molecular characteristics of preneoplastic and neoplastic lesions induced by OX and ACI were immunohistochemically compared to those by phenobarbital (PB), a typical CAR activator, in wild-type (WT) and CAR knockout (CARKO) mice after diethylnitrosamine initiation. We focused on changes in beta-catenin and its transcriptional product glutamine synthetase (GS). In PB promoted foci and adenomas, nuclear accumulation of mutated beta-catenin was increased with high frequency. PB treatment also increased the multiplicity and area of GS-positive foci and adenomas in WT mice. No foci and adenomas showed nuclear accumulation of beta-catenin and expression of GS in CARKO mice, similar to both genotypes of mice treated with OX and ACI. Interestingly, hepatocellular carcinoma induced in ACI-treated WT mice showed nuclear accumulation of beta catenin and was positive for GS. Our results indicated that beta-catenin mutations were not involved in early-stage hepatocarcinogenesis induced by PROTOX inhibitors in mice, although activation of beta-catenin and CAR is important in PB-induced tumorigenesis. The significant differences in molecular profiles suggested involvements of multiple mode of actions for hepatocarcinogenesis induced by PROTOX inhibitors. PMID- 28580886 TI - Normal Developmental and Estrous Cycle-dependent Histological Features of the Female Reproductive Organs in Microminipigs. AB - The microminipig has become an increasingly attractive animal model for various experimental practices because of its manageable size; however, studies of the histological features of the female reproductive organs in microminipigs are limited. The present study investigates the sexual development of the reproductive organs and the cyclical changes during the estrous cycle in female microminipigs. The ovaries, oviducts, uteri, and vaginal tissues from 33 animals aged 0 to 26 months were utilized in this study. By evaluating the large tertiary follicles, corpora lutea, and the regressing corpora lutea, we estimated that female microminipigs reached puberty at approximately 5 months of age and sexual maturity at 8 months of age. The appearance of the follicles and corpora lutea in the ovaries, as well as the epithelium in other reproductive organs, was synchronized with each phase of the estrous cycle and was identical to that in common domestic pigs. In addition, several spontaneous findings were observed, including mesonephric duct remnants adjacent to oviducts and mineralization in ovaries. Understanding the normal histology of the reproductive organs in microminipigs is crucial for advancing pathological evaluations for future toxicological studies. PMID- 28580887 TI - Titanium Nanoparticle Size Influences Trace Concentration Levels in Skin Appendages. AB - As a result of biotribocorrosion, the surface of a titanium (Ti) biomedical device can be a potential source of systemic contamination with Ti nanoparticles (NPs). Although NPs can be chemically similar, differences in particle size may lead to different biological responses. The aim of this experimental study was to determine Ti trace levels in skin appendages and plasma and explore the influence of NP size on trace levels using a murine model. Results showed the presence of Ti traces in the nails, hair, and plasma. The concentration of the smallest NPs (5 Nm) was higher than that of 10 Nm NPs in all the studied samples. Irrespective of NP size, Ti levels were always lower in plasma than in skin appendages. Ti levels were higher in nails than in hair. Ti NPs size influenced trace concentration levels in hair/nails, suggesting that 5 Nm Ti particles are more easily eliminated through these skin appendages. Given that the nails showed the highest levels of Ti, and that these skin appendages are not exposed to agents that can leach out Ti, as occurs with hair, we propose the nails as the most suitable and reliable bioindicator for monitoring systemic contamination with Ti. PMID- 28580888 TI - Kinetic modelling of [11C]PBR28 for 18 kDa translocator protein PET data: A validation study of vascular modelling in the brain using XBD173 and tissue analysis. AB - The 18 kDa translocator protein (TSPO) is a marker of microglia activation in the central nervous system and represents the main target of radiotracers for the in vivo quantification of neuroinflammation with positron emission tomography (PET). TSPO PET is methodologically challenging given the heterogeneous distribution of TSPO in blood and brain. Our previous studies with the TSPO tracers [11C]PBR28 and [11C]PK11195 demonstrated that a model accounting for TSPO binding to the endothelium improves the quantification of PET data. Here, we performed a validation of the kinetic model with the additional endothelial compartment through a displacement study. Seven subjects with schizophrenia, all high affinity binders, underwent two [11C]PBR28 PET scans before and after oral administration of 90 mg of the TSPO ligand XBD173. The addition of the endothelial component provided a signal compartmentalization much more consistent with the underlying biology, as only in this model, the blocking study produced the expected reduction in the tracer concentration of the specific tissue compartment, whereas the non-displaceable compartment remained unchanged. In addition, we also studied TSPO expression in vessels using 3D reconstructions of histological data of frontal lobe and cerebellum, demonstrating that TSPO positive vessels account for 30% of the vascular volume in cortical and white matter. PMID- 28580889 TI - Phosphodiesterase-5 inhibitors and their analogues as adulterants of herbal and food products: analysis of the Malaysian market, 2014-16. AB - Adulteration of herbal health supplements with phosphodiesterase-5 (PDE-5) inhibitors and their analogues is becoming a worldwide problem. The aim of this study was to investigate herbal and food products sold in the Malaysian market for the presence of these adulterants. Sixty-two products that claim to enhance men's sexual health were sampled between April 2014 and April 2016. These products included unregistered products seized by the Pharmacy Enforcement Division of the Ministry of Health (n = 39), products sent to the National Pharmaceutical Regulatory Agency for pre-registration testing (n = 9) and products investigated under the post-registration market surveillance programme (n = 14). The products were tested against an in-house spectral library consisting of 61 PDE-5 inhibitors and analogues using a validated liquid chromatography-mass spectrometry ion-trap-time-of-flight (LC-MS IT-TOF) method. Thirty-two (82%) of the unregistered products and two (14%) of the registered products were found to be adulterated with at least one PDE-5 inhibitor or analogue, while none of the pre-registration products contained adulterants. A total of 16 different adulterants were detected and 36% of the adulterated products contained a mixture of two or more adulterants. This study has demonstrated that the adulteration of unregistered herbal products in the Malaysian market is an alarming issue that needs to be urgently addressed by the relevant authorities. PMID- 28580890 TI - International Federation for Emergency Medicine Consensus Statement: Sonography in hypotension and cardiac arrest (SHoC): An international consensus on the use of point of care ultrasound for undifferentiated hypotension and during cardiac arrest - CORRIGENDUM. PMID- 28580891 TI - A Stochastic Programming Model for Decision-Making Concerning Medical Supply Location and Allocation in Disaster Management. AB - We propose a stochastic programming model as a solution for optimizing the problem of locating and allocating medical supplies used in disaster management. To prepare for natural disasters, we developed a stochastic optimization approach to select the storage location of medical supplies and determine their inventory levels and to allocate each type of medical supply. Our model also captures disaster elaborations and possible effects of disasters by using a new classification for major earthquake scenarios. We present a case study for our model for the preparedness phase. As a case study, we applied our model to earthquake planning in Adana, Turkey. The experimental evaluations showed that the model is robust and effective. (Disaster Med Public Health Preparedness. 2017;11:747-755). PMID- 28580892 TI - HARMONIZING HEALTH TECHNOLOGY ASSESSMENT PRACTICES IN UNIVERSITY HOSPITALS: TO WHAT EXTENT IS THE MINI-HTA MODEL SUITABLE IN THE FRENCH CONTEXT? AB - BACKGROUND: The number of new medical devices for individual use that are launched annually exceeds the assessment capacity of the French national health technology assessment (HTA) agency. This has resulted in hospitals, and particularly university hospitals (UHs), developing hospital-based HTA initiatives to support their decisions for purchasing innovative devices. However, the methodologies used in such hospitals have no common basis. The aim of this study was to assess a mini-HTA model as a potential solution to harmonize HTA methodology in French UHs. METHODS: A systematic review was conducted on Medline, Embase, Health Technology Assessment database, and Google Scholar to identify published articles reporting the use of mini-HTA tools and decision support-like models. A survey was also carried out in eighteen French UHs to identify in-house decision support tools. Finally, topics evaluated in the Danish mini-HTA model and in French UHs were compared using Jaccard similarity coefficients. RESULTS: Our findings showed differences between topics evaluated in French UHs and those assessed in decision support models from the literature. Only five topics among the thirteen most evaluated in French UHs were similar to those assessed in the Danish mini-HTA model. The organizational and ethical/social impacts were rarely explored among the surveyed models used in French UHs when introducing new medical devices. CONCLUSIONS: Before its widespread and harmonized use in French UHs, the mini-HTA model would first require adaptations to the French context. PMID- 28580893 TI - Appropriateness of Surgical Antibiotic Prophylaxis in Pediatric Patients in Italy. AB - OBJECTIVES Appropriate use of surgical antibiotic prophylaxis (SAP) reduces intraoperative wound contamination in pediatric surgery, thus minimizing the risk of surgical site infection (SSIs). Conversely, inappropriate use of SAP exposes patients to the risk of antibiotic side effects and contributes to the emergence of antimicrobial resistance. Our aims were to describe SAP administration and to analyze factors associated with nonadherence in pediatric patients. DESIGN Descriptive study. SETTING Overall, 955 pediatric patients underwent 1,038 surgical procedures. METHODS We assessed adherence to SAP international guidelines for surgical procedures performed on children aged <18 years in 2015 in 4 randomly selected hospitals in Calabria (Italy). The clinical records of these patients were retrospectively reviewed. RESULTS Appropriate SAP administration or nonadministration pertained to 754 surgical procedures (72.6%). Surgical antibiotic prophylaxis was administered in 88.5% of 358 procedures with an SAP indication. Adherence to guidelines for appropriate drug choice were followed in 5.7% of cases, for route of administration in 76.7% of cases, for timing in 48.6% of cases, for duration in 14.5% of cases, and for dose in 91.5% of cases, and for all components in only 5 cases (1.6%). Among 680 procedures without SAP indication, 35.7% case patients received antibiotics. Inappropriate administration of antibiotics in procedures without SAP indication was associated with surgical specialty wards (P=.008), ordinary admission (P<.001), head and neck surgical procedures (P=.020), clean surgery (P=.017), and surgical duration (P=.010). CONCLUSIONS Discrepancies between SAP guidelines and actual practice behavior more frequently indicate excessive use of antibiotics than underuse. Increased awareness of SAP guidelines is required. Infect Control Hosp Epidemiol 2017;38:823-831. PMID- 28580894 TI - Hospital-Acquired Methicillin-Resistant Staphylococcus aureus Bloodstream Infections in Quebec: Impact of Guidelines. AB - OBJECTIVE We examined the impact of methicillin-resistant Staphylococcus aureus (MRSA) guidelines in Quebec adult hospitals from January 1, 2006, to March 31, 2015, by examining the incidence rate reduction (IRR) in healthcare-associated MRSA bloodstream infections (HA-MRSA), using central-line associated bloodstream infections (CLABSIs) as a comparator. METHODS In this study, we utilized a quasi experimental design with Poisson segmented regression to model HA-MRSA and CLABSI incidence for successive 4-week surveillance segments, stratified by teaching status. We used 3 distinct periods with 2 break points (April 1, 2007, and January 3, 2010) corresponding to major MRSA guideline publications and updates. RESULTS Over the study period, HA-MRSA incidence decreased significantly in adult teaching facilities but not in nonteaching facilities. Prior to MRSA guideline publication (2006-2007), HA-MRSA incidence decrease was not significant (P=.89), while CLABSI incidence decreased by 4% per 4-week period (P=.05). After the publication of guidelines (2007-2009), HA-MRSA incidence decreased significantly by 1% (P=.04), while no significant decrease in CLABSI incidence was observed (P=.75). HA-MRSA and CLABSI decreases were both significant at 1% for 2010-2015 (P<.001 and P=.01, respectively). These decreases were gradual rather than sudden; break points were not significant. Teaching facilities drove these decreases. CONCLUSION During the study period, HA-MRSA and CLABSI rates decreased significantly. In 2007-2009, the significant decrease in HA-MRSA rates with stable CLABSI rates suggests an impact from MRSA-specific guidelines. In 2010 2015, significant and equal IRRs for HA-MRSA and CLABSI may be due to the continuing impact of MRSA guidelines, to the impact of new interventions targeting device-associated infections in general by the 2010-2015 Action Plan, or to a combination of factors. Infect Control Hosp Epidemiol 2017;38:840-847. PMID- 28580895 TI - A higher Dietary Inflammatory Index score is associated with a higher risk of breast cancer among Chinese women: a case-control study. AB - Previous studies have investigated the association between dietary inflammatory potential and the development of cancer. For breast cancer the results have been equivocal. The present study aimed to investigate whether higher Dietary Inflammatory IndexTM (DII) scores were associated with increased risk of breast cancer among Chinese women. A total of 867 cases and 824 controls were recruited into the present case-control study from September 2011 to February 2016. DII scores were computed based on baseline dietary intake assessed by a validated 81 item FFQ. The OR and 95 % CI were assessed by multivariable logistic regression after adjusting for various potential confounders. DII scores in this study ranged from -5.87 (most anti-inflammatory score) to +5.71 (most proinflammatory score). A higher DII score was associated with a higher breast cancer risk (adjusted ORquartile 4 v. 1 2.28; 95 % CI 1.71, 3.03; adjusted ORcontinuous 1.40; 95 %CI 1.25, 1.39). In stratified analyses, positive associations also were observed except for underweight women or women with either oestrogen receptor+ or progesterone receptor+ status (but not both). Results from this study indicated that higher DII scores, corresponding to more proinflammatory diets, were positively associated with breast cancer risk among Chinese women. PMID- 28580896 TI - Local versus Global Perceptual Scope, Empathic Concern, and Helping Preferences in Multiple-Victim Situations. AB - Previous research on the one-among-others effect has shown that inducing empathic concern towards a victim presented alongside with a small number of other victims enhances (a) the perception of this set of victims as separate and different individuals (instead of as a group), and (b) the preference to help them individually (rather than collectively). We propose that inducing a local (vs. global) perceptual scope increases (vs. lessens) these two outcomes. In this work, participants first reported their perception of an ad that showed a victim depicted as one-among-others and, afterwards, were unexpectedly asked to indicate their preference for giving the victims either "individualized", "collective", or "equal" assistance. In Experiment 1 (N = 48), we manipulated the participants' local (vs. global) perceptual scope and allowed empathy concern to occur naturally. In Experiment 2 (N = 213), we manipulated both the perceptual scope and empathy concern. Overall, results showed that the combined presence of local scope and empathic concern increased the awareness of others (eta p 2 = .203 and .047, 95% CI = [0.05, 0.35] and [0.03, 0.13], ps < .03) and the preference for individualized assistance (zs = 2.08 and 2.74, ps < .02). Lastly, we discuss the theoretical and practical implications of perceiving a set of victims as individuals (rather than as a group) in need. PMID- 28580897 TI - The Spanish-Version of the Subjective Vitality Scale: Psychometric Properties and Evidence of Validity. AB - The Subjective Vitality Scale (SVS) assess the subjective experience of being full of energy and alive, a clinically relevant outcome measure of positive psychological well-being. The purpose of this paper was to translate the 7-item SVS into Spanish and examine its psychometric properties. In Study 1 (n = 790 adolescents) and Study 2 (n = 130 athletes) reliability and exploratory factor analysis (EFA) were carried out. In Study 1 and Study 3 (n = 197 dancers) evidence of validity of inferences based on SVS scores estimating relationships with other variables (life satisfaction, global self-esteem and emotional and physical exhaustion) was obtained. In Study 2 invariance across time was tested. Finally in Study 3, the factorial structure was cross-validated using confirmatory factor analysis (CFA). Results of EFA showed a one-factor solution. CFA also supported a unidimensional factor structure for the Spanish 6-item SVS (RMSEA = .050 (90% CI = .00, .080); NNFI = .993; CFI = .996). Reliability analysis indicated a strong internal consistency in all study samples (alpha ranged from .82 to .89). Further, results from multi-sample analysis supported the replicability of SVS factor structure across time. Finally, the SVS scores showed the expected correlations patterns (all them significant, p < .01) with the measured outcomes. In conclusion, the Spanish version of the SVS demonstrated adequate psychometric properties, indicating that the scale can be confidently used to measure the experience of possessing energy and aliveness; furthermore, differences across time can be meaningfully carried out. PMID- 28580898 TI - Increased cardiovascular mortality in people with schizophrenia: a 24-year national register study. AB - : AimsPeople who have schizophrenia die earlier from somatic diseases than do people in the general population, but information about cardiovascular deaths in people who have schizophrenia is limited. We analysed mortality in all age groups of people with schizophrenia by specific cardiovascular diseases (CVDs), focusing on five CVD diagnoses: coronary heart disease, acute myocardial infarction, cerebrovascular disease, heart failure and cardiac arrhythmias. We also compared hospital admissions for CVDs in people who had schizophrenia with hospital admissions for CVDs in the general population. METHODS: This national register study of 10 631 817 people in Sweden included 46 911 people who were admitted to the hospital for schizophrenia between 1 January 1987 and 31 December 2010. Information from national registers was used to identify people who had schizophrenia and obtain data about mortality, causes of death, medical diagnoses and hospitalisations. RESULTS: CVDs were the leading cause of death in people who had schizophrenia (5245 deaths), and CVDs caused more excess deaths than suicide. The mean age of CVD death was 10 years lower for people who had schizophrenia (70.5 years) than the general population (80.7 years). The mortality rate ratio (MRR) for CVDs in all people who had schizophrenia was 2.80 (95% confidence interval (CI) 2.73-2.88). In people aged 15-59 years who had schizophrenia, the MRR for CVDs was 6.16 (95% CI 5.79-6.54). In all people who had schizophrenia, the MRR for coronary heart disease was 2.83 (95% CI 2.73-2.94); acute myocardial infarction, 2.62 (95% CI 2.49-2.75); cerebrovascular disease, 2.4 (95% CI 2.25 2.55); heart failure, 3.25 (95% CI 2.94-3.6); and cardiac arrhythmias, 2.06 (95% CI 1.75-2.43). Hospital admissions for coronary heart disease were less frequent in people who had schizophrenia than in the general population (admission rate ratio, 0.88 (95% CI 0.83-0.94). In all age groups, survival after hospital admission for CVD was lower in people who had schizophrenia than in the general population. CONCLUSIONS: People who had schizophrenia died 10 years earlier from CVDs than did people in the general population. For all five CVD diagnoses, mortality risk was higher for those with schizophrenia than those in the general population. Survival after hospitalisation for CVDs in people who had schizophrenia was comparable with that of people in the general population who were several decades older. PMID- 28580899 TI - Human Infection with Highly Pathogenic Avian Influenza A(H7N9) Virus, China. AB - The recent increase in zoonotic avian influenza A(H7N9) disease in China is a cause of public health concern. Most of the A(H7N9) viruses previously reported have been of low pathogenicity. We report the fatal case of a patient in China who was infected with an A(H7N9) virus having a polybasic amino acid sequence at its hemagglutinin cleavage site (PEVPKRKRTAR/GL), a sequence suggestive of high pathogenicity in birds. Its neuraminidase also had R292K, an amino acid change known to be associated with neuraminidase inhibitor resistance. Both of these molecular features might have contributed to the patient's adverse clinical outcome. The patient had a history of exposure to sick and dying poultry, and his close contacts had no evidence of A(H7N9) disease, suggesting human-to-human transmission did not occur. Enhanced surveillance is needed to determine whether this highly pathogenic avian influenza A(H7N9) virus will continue to spread. PMID- 28580900 TI - Preliminary Epidemiology of Human Infections with Highly Pathogenic Avian Influenza A(H7N9) Virus, China, 2017. AB - We compared the characteristics of cases of highly pathogenic avian influenza (HPAI) and low pathogenic avian influenza (LPAI) A(H7N9) virus infections in China. HPAI A(H7N9) case-patients were more likely to have had exposure to sick and dead poultry in rural areas and were hospitalized earlier than were LPAI A(H7N9) case-patients. PMID- 28580903 TI - Orbital electronic occupation effect on metal-insulator transition in Ti x V1-x O2. AB - A series of Ti x V1-x O2 (0% ? x ? 4.48%) thin films on c-plane sapphire substrates have been fabricated by co-sputtering oxidation solutions, and the metal-insulator transition temperature (T MIT) of Ti x V1-x O2 films rises monotonically at the rate of 1.64 K/at.% Ti. The x-ray diffraction measurement results show that, after Ti4+ ion doping, the rutile structure expands along the c r axis while shrinking along the a r and b r axis simultaneously. It makes the V-O bond length shorter, which is believed to upshift the pi * orbitals. The rising of pi * orbitals in Ti-doped VO2 has been illustrated by ultraviolet infrared spectroscopy and first-principles calculation. With the Ti4+ ion doping concentration increasing, the energy levels of pi * orbitals are elevated and the electronic occupation of pi * orbitals decreases, which weakens the shielding for the strong electron-electron correlations in the d|| orbital and result in the T MIT rising. The research reveals that the T MIT of VO2 can be effected by the electronic occupancy of pi * orbitals in a rutile state, which is helpful for developing VO2-based thermal devices. PMID- 28580902 TI - Enhanced bone formation by strontium modified calcium sulfate hemihydrate in ovariectomized rat critical-size calvarial defects. AB - The development of a new generation of biomaterials with high osteogenic ability for treatment of osteoporotic fractures is being intensively investigated. The objective of this paper was to investigate new bone formation in an ovariectomized rat (OVX rat) calvarial model of critical size bone defects filled with Sr-containing alpha-calcium sulfate hemihydrate (SrCSH) cement compared to an alpha-calcium sulfate hemihydrate (alpha-CSH) cement and empty defect. X-ray diffraction analysis verified the partial substitution of Sr2+ for Ca2+ did not change the phase composition of alpha-CSH. Scanning electron microscopy showed that Sr-substituted alpha-CSH significantly increased the surface roughness. The effects of Sr substitution on the biological properties of SrCSH cement were evaluated by adhesion, proliferation, alkaline phosphatase (ALP) activity of osteoblast-like cells MC3T3-E1. The results showed that SrCSHs enhanced MC3T3-E1 cell proliferation, differentiation, and ALP activity. Furthermore, SrCSH cement was used to repair critical-sized OVX rat calvarial defects. The in vivo results revealed that SrCSH had good osteogenic capability and stimulated new blood vessel formation in a critical sized OVX calvarial defect within 12 weeks, suggesting that SrCSH cement has more potential for application in bone tissue regeneration. PMID- 28580901 TI - Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in human colorectal cancer cells by binding to Matrin 3. AB - Thousands of long noncoding RNAs (lncRNAs) have been discovered, yet the function of the vast majority remains unclear. Here, we show that a p53-regulated lncRNA which we named PINCR (p53-induced noncoding RNA), is induced ~100-fold after DNA damage and exerts a prosurvival function in human colorectal cancer cells (CRC) in vitro and tumor growth in vivo. Targeted deletion of PINCR in CRC cells significantly impaired G1 arrest and induced hypersensitivity to chemotherapeutic drugs. PINCR regulates the induction of a subset of p53 targets involved in G1 arrest and apoptosis, including BTG2, RRM2B and GPX1. Using a novel RNA pulldown approach that utilized endogenous S1-tagged PINCR, we show that PINCR associates with the enhancer region of these genes by binding to RNA-binding protein Matrin 3 that, in turn, associates with p53. Our findings uncover a critical prosurvival function of a p53/PINCR/Matrin 3 axis in response to DNA damage in CRC cells. PMID- 28580904 TI - Fabrication of core-shell nanofibers for controlled delivery of bromelain and salvianolic acid B for skin regeneration in wound therapeutics. AB - The physiological and pathological complexity of the wound healing process makes it more challenging to design an ideal tissue regeneration scaffold. Precise scaffolding with high drug loading efficiency, efficient intracellular efficacy for therapeutic delivery, minimal nonspecific cellular and blood protein binding, and maximum biocompatibility forms the basis for an ideal delivery system. This paper describes a combinational multiphasic delivery system, where biomolecules are delivered through the fabrication of coaxial electrospinning of different biocompatible polymers. The ratio and specificity of polymers for specific biofunction are optimized and the delivery system is completely characterized with reference to the mechanical property and structural integrity of bromelain (debridement enzyme) and salvianolic acid B (pro-angiogenesis and re epithelialization). The in vitro release profile illustrated the sustained release of debriding protease and bioactive component in a timely fashion. The fabricated scaffold showed angiogenic potential through in vitro migration of endothelial cells and increased new capillaries from the existing blood vessel in response to an in ovo chicken chorioallantoic membrane assay. In addition, in vivo studies confirm the efficacy of the fabricated scaffold. Our results therefore open up a new avenue for designing a bioactive combinational multiphasic delivery system to enhance wound healing. PMID- 28580905 TI - Role of temperature-dependent spin model parameters in ultra-fast magnetization dynamics. AB - In the spirit of multi-scale modelling magnetization dynamics at elevated temperature is often simulated in terms of a spin model where the model parameters are derived from first principles. While these parameters are mostly assumed temperature-independent and thermal properties arise from spin fluctuations only, other scenarios are also possible. Choosing bcc Fe as an example, we investigate the influence of different kinds of model assumptions on ultra-fast spin dynamics, where following a femtosecond laser pulse, a sample is demagnetized due to a sudden rise of the electron temperature. While different model assumptions do not affect the simulational results qualitatively, their details do depend on the nature of the modelling. PMID- 28580906 TI - Modelling the evaporation of nanoparticle suspensions from heterogeneous surfaces. AB - We present a Monte Carlo (MC) grid-based model for the drying of drops of a nanoparticle suspension upon a heterogeneous surface. The model consists of a generalised lattice-gas in which the interaction parameters in the Hamiltonian can be varied to model different properties of the materials involved. We show how to correctly choose the interactions, to minimise the effects of the underlying grid so that hemispherical droplets form. We also include the effects of surface roughness to examine the effects of contact-line pinning on the dynamics. When there is a 'lid' above the system, which prevents evaporation, equilibrium drops form on the surface, which we use to determine the contact angle and how it varies as the parameters of the model are changed. This enables us to relate the interaction parameters to the materials used in applications. The model has also been applied to drying on heterogeneous surfaces, in particular to the case where the suspension is deposited on a surface consisting of a pair of hydrophilic conducting metal surfaces that are either side of a band of hydrophobic insulating polymer. This situation occurs when using inkjet printing to manufacture electrical connections between the metallic parts of the surface. The process is not always without problems, since the liquid can dewet from the hydrophobic part of the surface, breaking the bridge before the drying process is complete. The MC model reproduces the observed dewetting, allowing the parameters to be varied so that the conditions for the best connection can be established. We show that if the hydrophobic portion of the surface is located at a step below the height of the neighbouring metal, the chance of dewetting of the liquid during the drying process is significantly reduced. PMID- 28580907 TI - Introducing the Proceedings of the CCP-EM Spring Symposium. PMID- 28580908 TI - Recent developments in the CCP-EM software suite. AB - As part of its remit to provide computational support to the cryo-EM community, the Collaborative Computational Project for Electron cryo-Microscopy (CCP-EM) has produced a software framework which enables easy access to a range of programs and utilities. The resulting software suite incorporates contributions from different collaborators by encapsulating them in Python task wrappers, which are then made accessible via a user-friendly graphical user interface as well as a command-line interface suitable for scripting. The framework includes tools for project and data management. An overview of the design of the framework is given, together with a survey of the functionality at different levels. The current CCP EM suite has particular strength in the building and refinement of atomic models into cryo-EM reconstructions, which is described in detail. PMID- 28580909 TI - The Dynamo package for tomography and subtomogram averaging: components for MATLAB, GPU computing and EC2 Amazon Web Services. AB - Dynamo is a package for the processing of tomographic data. As a tool for subtomogram averaging, it includes different alignment and classification strategies. Furthermore, its data-management module allows experiments to be organized in groups of tomograms, while offering specialized three-dimensional tomographic browsers that facilitate visualization, location of regions of interest, modelling and particle extraction in complex geometries. Here, a technical description of the package is presented, focusing on its diverse strategies for optimizing computing performance. Dynamo is built upon mbtools (middle layer toolbox), a general-purpose MATLAB library for object-oriented scientific programming specifically developed to underpin Dynamo but usable as an independent tool. Its structure intertwines a flexible MATLAB codebase with precompiled C++ functions that carry the burden of numerically intensive operations. The package can be delivered as a precompiled standalone ready for execution without a MATLAB license. Multicore parallelization on a single node is directly inherited from the high-level parallelization engine provided for MATLAB, automatically imparting a balanced workload among the threads in computationally intense tasks such as alignment and classification, but also in logistic-oriented tasks such as tomogram binning and particle extraction. Dynamo supports the use of graphical processing units (GPUs), yielding considerable speedup factors both for native Dynamo procedures (such as the numerically intensive subtomogram alignment) and procedures defined by the user through its MATLAB-based GPU library for three-dimensional operations. Cloud-based virtual computing environments supplied with a pre-installed version of Dynamo can be publicly accessed through the Amazon Elastic Compute Cloud (EC2), enabling users to rent GPU computing time on a pay-as-you-go basis, thus avoiding upfront investments in hardware and longterm software maintenance. PMID- 28580910 TI - Electron Bio-Imaging Centre (eBIC): the UK national research facility for biological electron microscopy. AB - The recent resolution revolution in cryo-EM has led to a massive increase in demand for both time on high-end cryo-electron microscopes and access to cryo electron microscopy expertise. In anticipation of this demand, eBIC was set up at Diamond Light Source in collaboration with Birkbeck College London and the University of Oxford, and funded by the Wellcome Trust, the UK Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC) to provide access to high-end equipment through peer review. eBIC is currently in its start-up phase and began by offering time on a single FEI Titan Krios microscope equipped with the latest generation of direct electron detectors from two manufacturers. Here, the current status and modes of access for potential users of eBIC are outlined. In the first year of operation, 222 d of microscope time were delivered to external research groups, with 95 visits in total, of which 53 were from unique groups. The data collected have generated multiple high- to intermediate-resolution structures (2.8-8 A), ten of which have been published. A second Krios microscope is now in operation, with two more due to come online in 2017. In the next phase of growth of eBIC, in addition to more microscope time, new data-collection strategies and sample-preparation techniques will be made available to external user groups. Finally, all raw data are archived, and a metadata catalogue and automated pipelines for data analysis are being developed. PMID- 28580911 TI - A pipeline approach to single-particle processing in RELION. AB - The formal concept of a workflow to single-particle analysis of cryo-electron microscopy (cryo-EM) images in the RELION program is described. In this approach, the structure-determination process is considered as a graph, where intermediate results in the form of images or metadata are the vertices, and different functionalities of the program are the edges. The new implementation automatically logs all user actions, facilitates file management and disk cleaning, and allows convenient browsing of the history of a project. Moreover, new functionality to iteratively execute consecutive jobs allows on-the-fly image processing, which will lead to more efficient data acquisition by providing faster feedback on data quality. The possibility of exchanging data-processing procedures among users will contribute to the development of standardized image processing procedures, and hence increase accessibility for new users in this rapidly expanding field. PMID- 28580912 TI - Trends in the Electron Microscopy Data Bank (EMDB). AB - Recent technological advances, such as the introduction of the direct electron detector, have transformed the field of cryo-EM and the landscape of molecular and cellular structural biology. This study analyses these trends from the vantage point of the Electron Microscopy Data Bank (EMDB), the public archive for three-dimensional EM reconstructions. Over 1000 entries were released in 2016, representing almost a quarter of the total number of entries (4431). Structures at better than 6 A resolution now represent one of the fastest-growing categories, while the share of annually released tomography-related structures is approaching 20%. The use of direct electron detectors is growing very rapidly: they were used for 70% of the structures released in 2016, in contrast to none before 2011. Microscopes from FEI have an overwhelming lead in terms of usage, and the use of the RELION software package continues to grow rapidly after having attained a leading position in the field. China is rapidly emerging as a major player in the field, supplementing the US, Germany and the UK as the big four. Similarly, Tsinghua University ranks only second to the MRC Laboratory for Molecular Biology in terms of involvement in publications associated with cryo-EM structures at better than 4 A resolution. Overall, the numbers point to a rapid democratization of the field, with more countries and institutes becoming involved. PMID- 28580914 TI - High-resolution cryo-EM proteasome structures in drug development. AB - With the recent advances in biological structural electron microscopy (EM), protein structures can now be obtained by cryo-EM and single-particle analysis at resolutions that used to be achievable only by crystallographic or NMR methods. We have explored their application to study protein-ligand interactions using the human 20S proteasome, a well established target for cancer therapy that is also being investigated as a target for an increasing range of other medical conditions. The map of a ligand-bound human 20S proteasome served as a proof of principle that cryo-EM is emerging as a realistic approach for more general structural studies of protein-ligand interactions, with the potential benefits of extending such studies to complexes that are unfavourable to other methods and allowing structure determination under conditions that are closer to physiological, preserving ligand specificity towards closely related binding sites. Subsequently, the cryo-EM structure of the Plasmodium falciparum 20S proteasome, with a new prototype specific inhibitor bound, revealed the molecular basis for the ligand specificity towards the parasite complex, which provides a framework to guide the development of highly needed new-generation antimalarials. Here, the cryo-EM analysis of the ligand-bound human and P. falciparum 20S proteasomes is reviewed, and a complete description of the methods used for structure determination is provided, including the strategy to overcome the bias orientation of the human 20S proteasome on electron-microscope grids and details of the icr3d software used for three-dimensional reconstruction. PMID- 28580915 TI - The potential use of single-particle electron microscopy as a tool for structure based inhibitor design. AB - Recent developments in electron microscopy (EM) have led to a step change in our ability to solve the structures of previously intractable systems, especially membrane proteins and large protein complexes. This has provided new opportunities in the field of structure-based drug design, with a number of high profile publications resolving the binding sites of small molecules and peptide inhibitors. There are a number of advantages of EM over the more traditional X ray crystallographic approach, such as resolving different conformational states and permitting the dynamics of a system to be better resolved when not constrained by a crystal lattice. There are still significant challenges to be overcome using an EM approach, not least the speed of structure determination, difficulties with low-occupancy ligands and the modest resolution that is available. However, with the anticipated developments in the field of EM, the potential of EM to become a key tool for structure-based drug design, often complementing X-ray and NMR studies, seems promising. PMID- 28580913 TI - The ribosome and its role in protein folding: looking through a magnifying glass. AB - Protein folding, a process that underpins cellular activity, begins co translationally on the ribosome. During translation, a newly synthesized polypeptide chain enters the ribosomal exit tunnel and actively interacts with the ribosome elements - the r-proteins and rRNA that line the tunnel - prior to emerging into the cellular milieu. While understanding of the structure and function of the ribosome has advanced significantly, little is known about the process of folding of the emerging nascent chain (NC). Advances in cryo-electron microscopy are enabling visualization of NCs within the exit tunnel, allowing early glimpses of the interplay between the NC and the ribosome. Once it has emerged from the exit tunnel into the cytosol, the NC (still attached to its parent ribosome) can acquire a range of conformations, which can be characterized by NMR spectroscopy. Using experimental restraints within molecular-dynamics simulations, the ensemble of NC structures can be described. In order to delineate the process of co-translational protein folding, a hybrid structural biology approach is foreseeable, potentially offering a complete atomic description of protein folding as it occurs on the ribosome. PMID- 28580916 TI - Cryo-electron microscopy of chromatin biology. AB - The basic unit of chromatin, the nucleosome core particle (NCP), controls how DNA in eukaryotic cells is compacted, replicated and read. Since its discovery, biochemists have sought to understand how this protein-DNA complex can help to control so many diverse tasks. Recent electron-microscopy (EM) studies on NCP containing assemblies have helped to describe important chromatin transactions at a molecular level. With the implementation of recent technical advances in single particle EM, our understanding of how nucleosomes are recognized and read looks to take a leap forward. In this review, the authors highlight recent advances in the architectural understanding of chromatin biology elucidated by EM. PMID- 28580918 TI - Crystal structure of Rv1220c, a SAM-dependent O-methyltransferase from Mycobacterium tuberculosis. AB - Rv1220c from Mycobacterium tuberculosis is annotated as an O-methyltransferase (MtbOMT). Currently, no structural information is available for this protein. Here, the crystal structure of MtbOMT refined to 2.0 A resolution is described. The structure reveals the presence of a methyltransferase fold and shows clear electron density for one molecule of S-adenosylmethionine (SAM), which was apparently bound by the protein during its production in Escherichia coli. Although the overall structure of MtbOMT resembles the structures of O methyltransferases from Cornybacterium glutamicum, Coxiella burnetti and Alfa alfa, differences are observed in the residues that make up the active site. Notably, substitution of Asp by His164 seems to abrogate metal binding by MtbOMT. A putative catalytic His-Asp pair located in the vicinity of SAM is absolutely conserved in MtbOMT homologues from all species of Mycobacterium, suggesting a conserved function for this protein. PMID- 28580917 TI - Crystal structures of human Fabs targeting the Bexsero meningococcal vaccine antigen NHBA. AB - Neisserial heparin-binding antigen (NHBA) is a surface-exposed lipoprotein from Neisseria meningitidis and is a component of the meningococcus B vaccine Bexsero. As part of a study to characterize the three-dimensional structure of NHBA and the molecular basis of the human immune response to Bexsero, the crystal structures of two fragment antigen-binding domains (Fabs) isolated from human monoclonal antibodies targeting NHBA were determined. Through a high-resolution analysis of the organization and the amino-acid composition of the CDRs, these structures provide broad insights into the NHBA epitopes recognized by the human immune system. As expected, these Fabs also show remarkable structural conservation, as shown by a structural comparison of 15 structures of apo Fab 10C3 which were obtained from crystals grown in different crystallization conditions and were solved while searching for a complex with a bound NHBA fragment or epitope peptide. This study also provides indirect evidence for the intrinsically disordered nature of two N-terminal regions of NHBA. PMID- 28580919 TI - Crystallization and X-ray diffraction analysis of SpaE, a basal pilus protein from the gut-adapted Lactobacillus rhamnosus GG. AB - SpaE is the predicted basal pilin subunit in the sortase-dependent SpaFED pilus from the gut-adapted and commensal Lactobacillus rhamnosus GG. Thus far, structural characterization of the cell-wall-anchoring basal pilins has remained difficult and has been limited to only a few examples from pathogenic genera and species. To gain a further structural understanding of the molecular mechanisms that are involved in the anchoring and assembly of sortase-dependent pili in less harmful bacteria, L. rhamnosus GG SpaE for crystallization was produced by recombinant expression in Escherichia coli. Although several attempts to crystallize the SpaE protein were unsuccessful, trigonal crystals that diffracted to a resolution of 3.1 A were eventually produced using PEG 3350 as a precipitant and high protein concentrations. Further optimization with a combination of additives led to the generation of SpaE crystals in an orthorhombic form that diffracted to a higher resolution of 1.5 A. To expedite structure determination by SAD phasing, selenium-substituted (orthorhombic) SpaE crystals were grown and X-ray diffraction data were collected to 1.8 A resolution. PMID- 28580920 TI - Crystal structure of the Thermoplasma acidophilum protein Ta1207. AB - The crystal structure of the Ta1207 protein from Thermoplasma acidophilum is reported. Ta1207 was identified in a screen for high-molecular-weight protein complexes in T. acidophilum. In solution, Ta1207 forms homopentamers of 188 kDa. The crystal structure of recombinant Ta1207 solved by Se-MAD at 2.4 A resolution revealed a complex with fivefold symmetry. In the crystal lattice, calcium ions induce the formation of a nanocage from two pentamers. The Ta1207 protomers comprise two domains with the same novel alpha/beta topology. A deep pocket with a binding site for a negatively charged group suggests that Ta1207 functions as an intracellular receptor for an unknown ligand. Homologues of Ta1207 occur only in Thermoplasmatales and its function might be related to the extreme lifestyle of these archaea. The thermostable Ta1207 complex might provide a useful fivefold symmetric scaffold for future nanotechnological applications. PMID- 28580921 TI - Crystal structure of the active form of native human thymidylate synthase in the absence of bound substrates. AB - Human thymidylate synthase (hTS) provides the sole de novo intracellular source of thymidine 5'-monophosphate (dTMP). hTS is required for DNA replication prior to cell division, making it an attractive target for anticancer chemotherapy and drug discovery. hTS binds 2'-deoxyuridine 5'-monophosphate (dUMP) and the folate co-substrate N5,N10-methylenetetrahydrofolate (meTHF) in a pocket near the catalytic residue Cys195. The catalytic loop, which is composed of amino-acid residues 181-197, can adopt two distinct conformations related by a 180 degrees rotation. In the active conformation Cys195 is close to the active site, while in the inactive conformation it is rotated and Cys195 is too distant from the active site for catalysis. Several hTS structures, either native or engineered, have been solved in the active conformation in complex with ligands or inhibitors and at different salt concentrations. However, apo hTS structures have been solved in an inactive conformation in high-salt and low-salt conditions (PDB entries 1ypv, 4h1i, 4gyh, 3egy and 3ehi). Here, the structure of apo hTS crystallized in the active form with sulfate ions coordinated by the arginine residue that binds dUMP is reported. PMID- 28580922 TI - Phosphate-binding protein from Polaromonas JS666: purification, characterization, crystallization and sulfur SAD phasing. AB - Phosphate-binding proteins (PBPs) are key proteins that belong to the bacterial ABC-type phosphate transporters. PBPs are periplasmic (or membrane-anchored) proteins that capture phosphate anions from the environment and release them to the transmembrane transporter. Recent work has suggested that PBPs have evolved for high affinity as well as high selectivity. In particular, a short, unique hydrogen bond between the phosphate anion and an aspartate residue has been shown to be critical for selectivity, yet is not strictly conserved in PBPs. Here, the PBP from Polaromonas JS666 is focused on. Interestingly, this PBP is predicted to harbor different phosphate-binding residues to currently known PBPs. Here, it is shown that the PBP from Polaromonas JS666 is capable of binding phosphate, with a maximal binding activity at pH 8. Its structure is expected to reveal its binding cleft configuration as well as its phosphate-binding mode. Here, the expression, purification, characterization, crystallization and X-ray diffraction data collection to 1.35 A resolution of the PBP from Polaromonas JS666 are reported. PMID- 28580923 TI - The crystal structure of human DEAH-box RNA helicase 15 reveals a domain organization of the mammalian DEAH/RHA family. AB - DEAH-box RNA helicase 15 (DHX15) plays important roles in RNA metabolism, including in splicing and in ribosome biogenesis. In addition, mammalian DHX15 also mediates the innate immune sensing of viral RNA. However, structural information on this protein is not available, although the structure of the fungal orthologue of this protein, Prp43, has been elucidated. Here, the crystal structure of the ADP-bound form of human DHX15 is reported at a resolution of 2.0 A. This is the first structure to be revealed of a member of the mammalian DEAH box RNA helicase (DEAH/RHA) family in a nearly complete form, including the catalytic core consisting of the two N-terminal RecA domains and the C-terminal regulatory domains (CTD). The ADP-bound form of DHX15 displayed a compact structure, in which the RecA domains made extensive contacts with the CTD. Notably, a potential RNA-binding site was found on the surface of a RecA domain with positive electrostatic potential. Almost all structural features were conserved between the fungal Prp43 and the human DHX15, suggesting that they share a fundamentally common mechanism of action and providing a better understanding of the specific mammalian functions of DHX15. PMID- 28580924 TI - Crystal structure of N-acetylmannosamine kinase from Fusobacterium nucleatum. AB - Sialic acids comprise a varied group of nine-carbon amino sugars that are widely distributed among mammals and higher metazoans. Some human commensals and bacterial pathogens can scavenge sialic acids from their environment and degrade them for use as a carbon and nitrogen source. The enzyme N-acetylmannosamine kinase (NanK; EC 2.7.1.60) belongs to the transcriptional repressors, uncharacterized open reading frames and sugar kinases (ROK) superfamily. NanK catalyzes the second step of the sialic acid catabolic pathway, transferring a phosphate group from adenosine 5'-triphosphate to the C6 position of N acetylmannosamine to generate N-acetylmannosamine 6-phosphate. The structure of NanK from Fusobacterium nucleatum was determined to 2.23 A resolution by X-ray crystallography. Unlike other NanK enzymes and ROK family members, F. nucleatum NanK does not have a conserved zinc-binding site. In spite of the absence of the zinc-binding site, all of the major structural features of enzymatic activity are conserved. PMID- 28580925 TI - Crystal structure of the multiple antibiotic resistance regulator MarR from Clostridium difficile. AB - Regulators of multiple antibiotic resistance (MarRs) are key players against toxins in prokaryotes. MarR homologues have been identified in many bacterial and archaeal species which pose daunting antibiotic resistance issues that threaten public health. The continuous prevalence of Clostridium difficile infection (CDI) throughout the world is associated with the abuse of antibiotics, and antibiotic treatments of CDI have limited effect. In the genome of C. difficile strain 630, the marR gene (ID 4913953) encodes a MarR protein. Here, MarR from C. difficile (MarRC.difficile) was subcloned and crystallized for the first time. MarRC.difficile was successfully expressed in Escherichia coli in a soluble form and was purified to near-homogeneity (>95%) by a two-step purification protocol. The structure of MarRC.difficile has been solved at 2.3 A resolution. The crystal belonged to the monoclinic space group P43212, with unit-cell parameters a = b = 66.569, c = 83.654 A. The structure reported reveals MarRC.difficile to be a dimer, with each subunit consisting of six alpha-helices and three antiparallel beta-hairpins. MarRC.difficile shows high structural similarity to the MarR proteins from E. coli and Staphylococcus aureus, indicating that MarRC.difficile might be a DNA-binding protein. PMID- 28580926 TI - Crystal structure of recombinant phosphoribosylpyrophosphate synthetase 2 from Thermus thermophilus HB27 complexed with ADP and sulfate ions. AB - Phosphoribosylpyrophosphate synthetase (PRPPS) from the thermophilic bacterial strain Thermus thermophilus HB27 catalyzes the synthesis of phosphoribosylpyrophosphate from ribose 5-phosphate and ATP, and belongs to the class I PRPPSs. The three-dimensional structure of the recombinant enzyme was solved at 2.2 A resolution using crystals grown in microgravity from protein solution containing ATP, magnesium and sulfate ions. An ADP molecule was located in the active site of each subunit of the hexameric enzyme molecule and sulfate ions were located in both the active and allosteric sites. It was found that the catalytic loop that restricts the active-site area and is usually missing from the electron-density map of class I PRPPSs adopts different conformations in three independent subunits in T. thermophilus PRPPS. A closed conformation of the active site was found in one of subunits where the highly ordered catalytic beta hairpin delivers the Lys and Arg residues that are essential for activity directly to the ADP molecule, which occupies the ATP-binding site. A comparison of the conformations of the catalytic loop in the three independent subunits reveals a possible mode of transition from the open to the closed state of the active site during the course of the catalyzed reaction. PMID- 28580927 TI - The ATP-binding cassette transporter A1 regulates phosphoantigen release and Vgamma9Vdelta2 T cell activation by dendritic cells. AB - Vgamma9Vdelta2 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen presenting cells. IPP is released in the extracellular microenvironment via unknown mechanisms. Here we show that the ATP-binding cassette transporter A1 (ABCA1) mediates extracellular IPP release from dendritic cells (DC) in cooperation with apolipoprotein A-I (apoA-I) and butyrophilin-3A1. IPP concentrations in the supernatants are sufficient to induce Vgamma9Vdelta2 T cell proliferation after DC mevalonate pathway inhibition with zoledronic acid (ZA). ZA treatment increases ABCA1 and apoA-I expression via IPP-dependent LXRalpha nuclear translocation and PI3K/Akt/mTOR pathway inhibition. These results close the mechanistic gap in our understanding of extracellular IPP release from DC and provide a framework to fine-tune Vgamma9Vdelta2 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation. PMID- 28580928 TI - Three-dimensional crossbar arrays of self-rectifying Si/SiO2/Si memristors. AB - Memristors are promising building blocks for the next-generation memory and neuromorphic computing systems. Most memristors use materials that are incompatible with the silicon dominant complementary metal-oxide-semiconductor technology, and require external selectors in order for large memristor arrays to function properly. Here we demonstrate a fully foundry-compatible, all-silicon based and self-rectifying memristor that negates the need for external selectors in large arrays. With a p-Si/SiO2/n-Si structure, our memristor exhibits repeatable unipolar resistance switching behaviour (105 rectifying ratio, 104 ON/OFF) and excellent retention at 300 degrees C. We further build three dimensinal crossbar arrays (up to five layers of 100 nm memristors) using fluid supported silicon membranes, and experimentally confirm the successful suppression of both intra- and inter-layer sneak path currents through the built in diodes. The current work opens up opportunities for low-cost mass production of three-dimensional memristor arrays on large silicon and flexible substrates without increasing circuit complexity. PMID- 28580929 TI - Three-dimensional Pentagon Carbon with a genesis of emergent fermions. AB - Carbon, the basic building block of our universe, enjoys a vast number of allotropic structures. Owing to its bonding characteristic, most carbon allotropes possess the motif of hexagonal rings. Here, with first-principles calculations, we discover a new metastable three-dimensional carbon allotrope entirely composed of pentagon rings. The unique structure of this Pentagon Carbon leads to extraordinary electronic properties, making it a cornucopia of emergent topological fermions. Under lattice strain, Pentagon Carbon exhibits topological phase transitions, generating a series of novel quasiparticles, from isospin-1 triplet fermions to triply degenerate fermions and further to Hopf-link Weyl-loop fermions. Its Landau level spectrum also exhibits distinct features, including a huge number of almost degenerate chiral Landau bands, implying pronounced magneto transport signals. Our work not only discovers a remarkable carbon allotrope with highly rare structural motifs, it also reveals a fascinating hierarchical particle genesis with novel topological fermions beyond the Dirac and Weyl paradigm. PMID- 28580930 TI - Cascaded spintronic logic with low-dimensional carbon. AB - Remarkable breakthroughs have established the functionality of graphene and carbon nanotube transistors as replacements to silicon in conventional computing structures, and numerous spintronic logic gates have been presented. However, an efficient cascaded logic structure that exploits electron spin has not yet been demonstrated. In this work, we introduce and analyse a cascaded spintronic computing system composed solely of low-dimensional carbon materials. We propose a spintronic switch based on the recent discovery of negative magnetoresistance in graphene nanoribbons, and demonstrate its feasibility through tight-binding calculations of the band structure. Covalently connected carbon nanotubes create magnetic fields through graphene nanoribbons, cascading logic gates through incoherent spintronic switching. The exceptional material properties of carbon materials permit Terahertz operation and two orders of magnitude decrease in power-delay product compared to cutting-edge microprocessors. We hope to inspire the fabrication of these cascaded logic circuits to stimulate a transformative generation of energy-efficient computing. PMID- 28580931 TI - The PYRIN domain-only protein POP2 inhibits inflammasome priming and activation. AB - Inflammasomes are protein platforms linking recognition of microbe, pathogen associated and damage-associated molecular patterns by cytosolic sensory proteins to caspase-1 activation. Caspase-1 promotes pyroptotic cell death and the maturation and secretion of interleukin (IL)-1beta and IL-18, which trigger inflammatory responses to clear infections and initiate wound-healing; however, excessive responses cause inflammatory disease. Inflammasome assembly requires the PYRIN domain (PYD)-containing adaptor ASC, and depends on PYD-PYD interactions. Here we show that the PYD-only protein POP2 inhibits inflammasome assembly by binding to ASC and interfering with the recruitment of ASC to upstream sensors, which prevents caspase-1 activation and cytokine release. POP2 also impairs macrophage priming by inhibiting the activation of non-canonical IkappaB kinase E and IkappaBalpha, and consequently protects from excessive inflammation and acute shock in vivo. Our findings advance our understanding of the complex regulatory mechanisms that maintain a balanced inflammatory response and highlight important differences between individual POP members. PMID- 28580933 TI - Coupled multiferroic domain switching in the canted conical spin spiral system Mn2GeO4. AB - Despite remarkable progress in developing multifunctional materials, spin-driven ferroelectrics featuring both spontaneous magnetization and electric polarization are still rare. Among such ferromagnetic ferroelectrics are conical spin spiral magnets with a simultaneous reversal of magnetization and electric polarization that is still little understood. Such materials can feature various multiferroic domains that complicates their study. Here we study the multiferroic domains in ferromagnetic ferroelectric Mn2GeO4 using neutron diffraction, and show that it features a double-Q conical magnetic structure that, apart from trivial 180o commensurate magnetic domains, can be described by ferromagnetic and ferroelectric domains only. We show unconventional magnetoelectric couplings such as the magnetic-field-driven reversal of ferroelectric polarization with no change of spin-helicity, and present a phenomenological theory that successfully explains the magnetoelectric coupling. Our measurements establish Mn2GeO4 as a conceptually simple multiferroic in which the magnetic-field-driven flop of conical spin spirals leads to the simultaneous reversal of magnetization and electric polarization. PMID- 28580932 TI - Evidence for fungal and chemodenitrification based N2O flux from nitrogen impacted coastal sediments. AB - Although increasing atmospheric nitrous oxide (N2O) has been linked to nitrogen loading, predicting emissions remains difficult, in part due to challenges in disentangling diverse N2O production pathways. As coastal ecosystems are especially impacted by elevated nitrogen, we investigated controls on N2O production mechanisms in intertidal sediments using novel isotopic approaches and microsensors in flow-through incubations. Here we show that during incubations with elevated nitrate, increased N2O fluxes are not mediated by direct bacterial activity, but instead are largely catalysed by fungal denitrification and/or abiotic reactions (e.g., chemodenitrification). Results of these incubations shed new light on nitrogen cycling complexity and possible factors underlying variability of N2O fluxes, driven in part by fungal respiration and/or iron redox cycling. As both processes exhibit N2O yields typically far greater than direct bacterial production, these results emphasize their possibly substantial, yet widely overlooked, role in N2O fluxes, especially in redox-dynamic sediments of coastal ecosystems. PMID- 28580934 TI - Organic narrowband near-infrared photodetectors based on intermolecular charge transfer absorption. AB - Blending organic electron donors and acceptors yields intermolecular charge transfer states with additional optical transitions below their optical gaps. In organic photovoltaic devices, such states play a crucial role and limit the operating voltage. Due to its extremely weak nature, direct intermolecular charge transfer absorption often remains undetected and unused for photocurrent generation. Here, we use an optical microcavity to increase the typically negligible external quantum efficiency in the spectral region of charge-transfer absorption by more than 40 times, yielding values over 20%. We demonstrate narrowband detection with spectral widths down to 36 nm and resonance wavelengths between 810 and 1,550 nm, far below the optical gap of both donor and acceptor. The broad spectral tunability via a simple variation of the cavity thickness makes this innovative, flexible and potentially visibly transparent device principle highly suitable for integrated low-cost spectroscopic near-infrared photodetection. PMID- 28580935 TI - Control of morphology and formation of highly geometrically confined magnetic skyrmions. AB - The ability to controllably manipulate magnetic skyrmions, small magnetic whirls with particle-like properties, in nanostructured elements is a prerequisite for incorporating them into spintronic devices. Here, we use state-of-the-art electron holographic imaging to directly visualize the morphology and nucleation of magnetic skyrmions in a wedge-shaped FeGe nanostripe that has a width in the range of 45-150 nm. We find that geometrically-confined skyrmions are able to adopt a wide range of sizes and ellipticities in a nanostripe that are absent in both thin films and bulk materials and can be created from a helical magnetic state with a distorted edge twist in a simple and efficient manner. We perform a theoretical analysis based on a three-dimensional general model of isotropic chiral magnets to confirm our experimental results. The flexibility and ease of formation of geometrically confined magnetic skyrmions may help to optimize the design of skyrmion-based memory devices. PMID- 28580936 TI - Quasilinear quantum magnetoresistance in pressure-induced nonsymmorphic superconductor chromium arsenide. AB - In conventional metals, modification of electron trajectories under magnetic field gives rise to a magnetoresistance that varies quadratically at low field, followed by a saturation at high field for closed orbits on the Fermi surface. Deviations from the conventional behaviour, for example, the observation of a linear magnetoresistance, or a non-saturating magnetoresistance, have been attributed to exotic electron scattering mechanisms. Recently, linear magnetoresistance has been observed in many Dirac materials, in which the electron-electron correlation is relatively weak. The strongly correlated helimagnet CrAs undergoes a quantum phase transition to a nonmagnetic superconductor under pressure. Here we observe, near the magnetic instability, a large and non-saturating quasilinear magnetoresistance from the upper critical field to 14 T at low temperatures. We show that the quasilinear magnetoresistance may arise from an intricate interplay between a nontrivial band crossing protected by nonsymmorphic crystal symmetry and strong magnetic fluctuations. PMID- 28580937 TI - Extra-embryonic tissue spreading directs early embryo morphogenesis in killifish. AB - The spreading of mesenchymal-like cell layers is critical for embryo morphogenesis and tissue repair, yet we know little of this process in vivo. Here we take advantage of unique developmental features of the non-conventional annual killifish embryo to study the principles underlying tissue spreading in a simple cellular environment, devoid of patterning signals and major morphogenetic cell movements. Using in vivo experimentation and physical modelling we reveal that the extra-embryonic epithelial enveloping cell layer, thought mainly to provide protection to the embryo, directs cell migration and the spreading of embryonic tissue during early development. This function relies on the ability of embryonic cells to couple their autonomous random motility to non-autonomous signals arising from the expansion of the extra-embryonic epithelium, mediated by cell membrane adhesion and tension. Thus, we present a mechanism of extra-embryonic control of embryo morphogenesis that couples the mechanical properties of adjacent tissues in the early killifish embryo. PMID- 28580938 TI - Harnessing speckle for a sub-femtometre resolved broadband wavemeter and laser stabilization. AB - The accurate determination and control of the wavelength of light is fundamental to many fields of science. Speckle patterns resulting from the interference of multiple reflections in disordered media are well-known to scramble the information content of light by complex but linear processes. However, these patterns are, in fact, exceptionally rich in information about the illuminating source. We use a fibre-coupled integrating sphere to generate wavelength dependent speckle patterns, in combination with algorithms based on the transmission matrix method and principal component analysis, to realize a broadband and sensitive wavemeter. We demonstrate sub-femtometre wavelength resolution at a centre wavelength of 780 nm, and a broad calibrated measurement range from 488 to 1,064 nm. This compares favourably to the performance of conventional wavemeters. Using this speckle wavemeter as part of a feedback loop, we stabilize a 780 nm diode laser to achieve a linewidth better than 1 MHz. PMID- 28580939 TI - The genetic landscape of benign thyroid nodules revealed by whole exome and transcriptome sequencing. AB - The genomic alterations for benign thyroid nodule, especially adenomatoid nodule, one of the most common types of hyperplasia lesion, are ill-studied. Here, we show whole-exome sequencing and/or transcriptome sequencing data on adenomatoid nodules with or without coincidental papillary thyroid carcinoma (PTC). Somatic mutation of BRAF (22/32) is only detected in PTC, while mutations in SPOP (4/38), ZNF148 (6/38) and EZH1 (3/38) are found enriched in adenomatoid nodule. In an expanded cohort of adenomatoid nodule (n=259) mutually exclusive SPOPP94R, EZH1Q571R and ZNF148 mutations are identified in 24.3% of them. Adenomatoid nodules show very few overlapped mutations and distinct gene expression patterns with their coincidental PTC. Phylogenetic tree analysis uncovers that PTCs evolved independently from their matched benign nodules. Our findings reveal that benign nodules possess a unique molecular signature that differs from PTC and provide genomic evidence for the conventional belief that PTC and benign nodules have independent origin. PMID- 28580941 TI - Measuring finite-range phase coherence in an optical lattice using Talbot interferometry. AB - One of the important goals of present research is to control and manipulate coherence in a broad variety of systems, such as semiconductor spintronics, biological photosynthetic systems, superconducting qubits and complex atomic networks. Over the past decades, interferometry of atoms and molecules has proven to be a powerful tool to explore coherence. Here we demonstrate a near-field interferometer based on the Talbot effect, which allows us to measure finite range phase coherence of ultracold atoms in an optical lattice. We apply this interferometer to study the build-up of phase coherence after a quantum quench of a Bose-Einstein condensate residing in a one-dimensional optical lattice. Our technique of measuring finite-range phase coherence is generic, easy to adopt and can be applied in practically all lattice experiments without further modifications. PMID- 28580940 TI - Accurate prediction of X-ray pulse properties from a free-electron laser using machine learning. AB - Free-electron lasers providing ultra-short high-brightness pulses of X-ray radiation have great potential for a wide impact on science, and are a critical element for unravelling the structural dynamics of matter. To fully harness this potential, we must accurately know the X-ray properties: intensity, spectrum and temporal profile. Owing to the inherent fluctuations in free-electron lasers, this mandates a full characterization of the properties for each and every pulse. While diagnostics of these properties exist, they are often invasive and many cannot operate at a high-repetition rate. Here, we present a technique for circumventing this limitation. Employing a machine learning strategy, we can accurately predict X-ray properties for every shot using only parameters that are easily recorded at high-repetition rate, by training a model on a small set of fully diagnosed pulses. This opens the door to fully realizing the promise of next-generation high-repetition rate X-ray lasers. PMID- 28580943 TI - New Martian valley network volume estimate consistent with ancient ocean and warm and wet climate. AB - The volume of Martian valley network (VN) cavity and the amount of water needed to create the cavity by erosion are of significant importance for understanding the early Martian climate, the style and rate of hydrologic cycling, and the possibility of an ancient ocean. However, previous attempts at estimating these two quantities were based on selected valleys or at local sites using crude estimates of VN length, width and depth. Here we employed an innovative progressive black top hat transformation method to estimate them on a global scale based on the depth of each valley pixel. The conservative estimate of the minimum global VN volume is 1.74 * 1014 m3 and minimum cumulative volume of water required is 6.86 * 1017 m3 (or ~5 km of global equivalent layer, GEL). Both are much larger than previous estimates and are consistent with an early warm and wet climate with active hydrologic cycling involving an ocean. PMID- 28580942 TI - Adenovirus prime, Env protein boost vaccine protects against neutralization resistant SIVsmE660 variants in rhesus monkeys. AB - Previous studies have shown that DNA prime, Ad5 boost vaccines protect against neutralization-sensitive but not neutralization-resistant virus variants within the SIVsmE660 swarm. Here we show that Ad prime, Env protein boost vaccines protect against neutralization-resistant SIVsmE660 variants. We perform two studies in rhesus monkeys with Ad35/Ad26 vectors expressing SIVmac239 Gag/Pol/Env with or without an AS01B-adjuvanted SIVmac32H gp140 protein boost. In a repetitive, low-dose challenge study, we observe robust protection against acquisition of infection by both Ad Alone and Ad/Env vaccines. In a single, high dose challenge study, only the Ad/Env vaccine affords significant protection against acquisition of infection. Analysis of transmitted/founder (T/F) viruses from this study demonstrates that the Ad/Env vaccine blocks both neutralization sensitive and neutralization-resistant SIVsmE660 variants in rhesus monkeys with restrictive TRIM5alpha alleles. These data demonstrate that the adjuvanted Env protein boost is critical for protecting against high-dose SIVsmE660 challenge and for blocking neutralization-resistant viruses within the SIVsmE660 swarm. PMID- 28580945 TI - Melting temperatures of MgO under high pressure by micro-texture analysis. AB - Periclase (MgO) is the second most abundant mineral after bridgmanite in the Earth's lower mantle, and its melting behaviour under pressure is important to constrain rheological properties and melting behaviours of the lower mantle materials. Significant discrepancies exist between the melting temperatures of MgO determined by laser-heated diamond anvil cell (LHDAC) and those based on dynamic compressions and theoretical predictions. Here we show the melting temperatures in earlier LHDAC experiments are underestimated due to misjudgment of melting, based on micro-texture observations of the quenched samples. The high melting temperatures of MgO suggest that the subducted cold slabs should have higher viscosities than previously thought, suggesting that the inter-connecting textural feature of MgO would not play important roles for the slab stagnation in the lower mantle. The present results also predict that the ultra-deep magmas produced in the lower mantle are peridotitic, which are stabilized near the core mantle boundary. PMID- 28580944 TI - IL-17-producing gammadelta T cells switch migratory patterns between resting and activated states. AB - Interleukin 17-producing gammadelta T (gammadeltaT17) cells have unconventional trafficking characteristics, residing in mucocutaneous tissues but also homing into inflamed tissues via circulation. Despite being fundamental to gammadeltaT17 driven early protective immunity and exacerbation of autoimmunity and cancer, migratory cues controlling gammadeltaT17 cell positioning in barrier tissues and recruitment to inflammatory sites are still unclear. Here we show that gammadeltaT17 cells constitutively express chemokine receptors CCR6 and CCR2. While CCR6 recruits resting gammadeltaT17 cells to the dermis, CCR2 drives rapid gammadeltaT17 cell recruitment to inflamed tissues during autoimmunity, cancer and infection. Downregulation of CCR6 by IRF4 and BATF upon gammadeltaT17 activation is required for optimal recruitment of gammadeltaT17 cells to inflamed tissue by preventing their sequestration into uninflamed dermis. These findings establish a lymphocyte trafficking model whereby a hierarchy of homing signals is prioritized by dynamic receptor expression to drive both tissue surveillance and rapid recruitment of gammadeltaT17 cells to inflammatory lesions. PMID- 28580946 TI - Dopamine D2 Receptor Signaling in the Nucleus Accumbens Comprises a Metabolic Cognitive Brain Interface Regulating Metabolic Components of Glucose Reinforcement. AB - Appetitive drive is influenced by coordinated interactions between brain circuits that regulate reinforcement and homeostatic signals that control metabolism. Glucose modulates striatal dopamine (DA) and regulates appetitive drive and reinforcement learning. Striatal DA D2 receptors (D2Rs) also regulate reinforcement learning and are implicated in glucose-related metabolic disorders. Nevertheless, interactions between striatal D2R and peripheral glucose have not been previously described. Here we show that manipulations involving striatal D2R signaling coincide with perseverative and impulsive-like responding for sucrose, a disaccharide consisting of fructose and glucose. Fructose conveys orosensory (ie, taste) reinforcement but does not convey metabolic (ie, nutrient-derived) reinforcement. Glucose however conveys orosensory reinforcement but unlike fructose, it is a major metabolic energy source, underlies sustained reinforcement, and activates striatal circuitry. We found that mice with deletion of dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) exclusively in D2R-expressing cells exhibited preferential D2R changes in the nucleus accumbens (NAc), a striatal region that critically regulates sucrose reinforcement. These changes coincided with perseverative and impulsive-like responding for sucrose pellets and sustained reinforcement learning of glucose-paired flavors. These mice were also characterized by significant glucose intolerance (ie, impaired glucose utilization). Systemic glucose administration significantly attenuated sucrose operant responding and D2R activation or blockade in the NAc bidirectionally modulated blood glucose levels and glucose tolerance. Collectively, these results implicate NAc D2R in regulating both peripheral glucose levels and glucose-dependent reinforcement learning behaviors and highlight the notion that glucose metabolic impairments arising from disrupted NAc D2R signaling are involved in compulsive and perseverative feeding behaviors. PMID- 28580948 TI - Free-standing supramolecular hydrogel objects by reaction-diffusion. AB - Self-assembly provides access to a variety of molecular materials, yet spatial control over structure formation remains difficult to achieve. Here we show how reaction-diffusion (RD) can be coupled to a molecular self-assembly process to generate macroscopic free-standing objects with control over shape, size, and functionality. In RD, two or more reactants diffuse from different positions to give rise to spatially defined structures on reaction. We demonstrate that RD can be used to locally control formation and self-assembly of hydrazone molecular gelators from their non-assembling precursors, leading to soft, free-standing hydrogel objects with sizes ranging from several hundred micrometres up to centimeters. Different chemical functionalities and gradients can easily be integrated in the hydrogel objects by using different reactants. Our methodology, together with the vast range of organic reactions and self-assembling building blocks, provides a general approach towards the programmed fabrication of soft microscale objects with controlled functionality and shape. PMID- 28580947 TI - Pyrin-only protein 2 limits inflammation but improves protection against bacteria. AB - Pyrin domain-only proteins (POPs) are recently evolved, primate-specific proteins demonstrated in vitro as negative regulators of inflammatory responses. However, their in vivo function is not understood. Of the four known POPs, only POP2 is reported to regulate NF-kappaB-dependent transcription and multiple inflammasomes. Here we use a transgenic mouse-expressing POP2 controlled by its endogenous human promotor to study the immunological functions of POP2. Despite having significantly reduced inflammatory cytokine responses to LPS and bacterial infection, POP2 transgenic mice are more resistant to bacterial infection than wild-type mice. In a pulmonary tularaemia model, POP2 enhances IFN-gamma production, modulates neutrophil numbers, improves macrophage functions, increases bacterial control and diminishes lung pathology. Thus, unlike other POPs thought to diminish innate protection, POP2 reduces detrimental inflammation while preserving and enhancing protective immunity. Our findings suggest that POP2 acts as a high-order regulator balancing cellular function and inflammation with broad implications for inflammation-associated diseases and therapeutic intervention. PMID- 28580949 TI - Upregulated energy metabolism in the Drosophila mushroom body is the trigger for long-term memory. AB - Efficient energy use has constrained the evolution of nervous systems. However, it is unresolved whether energy metabolism may resultantly regulate major brain functions. Our observation that Drosophila flies double their sucrose intake at an early stage of long-term memory formation initiated the investigation of how energy metabolism intervenes in this process. Cellular-resolution imaging of energy metabolism reveals a concurrent elevation of energy consumption in neurons of the mushroom body, the fly's major memory centre. Strikingly, upregulation of mushroom body energy flux is both necessary and sufficient to drive long-term memory formation. This effect is triggered by a specific pair of dopaminergic neurons afferent to the mushroom bodies, via the D5-like DAMB dopamine receptor. Hence, dopamine signalling mediates an energy switch in the mushroom body that controls long-term memory encoding. Our data thus point to an instructional role for energy flux in the execution of demanding higher brain functions. PMID- 28580950 TI - Pacific plate motion change caused the Hawaiian-Emperor Bend. AB - A conspicuous 60 degrees bend of the Hawaiian-Emperor Chain in the north-western Pacific Ocean has variously been interpreted as the result of an abrupt Pacific plate motion change in the Eocene (~47 Ma), a rapid southward drift of the Hawaiian hotspot before the formation of the bend, or a combination of these two causes. Palaeomagnetic data from the Emperor Seamounts prove ambiguous for constraining the Hawaiian hotspot drift, but mantle flow modelling suggests that the hotspot drifted 4-9 degrees south between 80 and 47 Ma. Here we demonstrate that southward hotspot drift cannot be a sole or dominant mechanism for formation of the Hawaiian-Emperor Bend (HEB). While southward hotspot drift has resulted in more northerly positions of the Emperor Seamounts as they are observed today, formation of the HEB cannot be explained without invoking a prominent change in the direction of Pacific plate motion around 47 Ma. PMID- 28580951 TI - Enantioselective decarboxylative chlorination of beta-ketocarboxylic acids. AB - Stereoselective halogenation is a highly useful organic transformation for multistep syntheses because the resulting chiral organohalides can serve as precursors for various medicinally relevant derivatives. Even though decarboxylative halogenation of aliphatic carboxylic acids is a useful and fundamental synthetic method for the preparation of a variety of organohalides, an enantioselective version of this reaction has not been reported. Here we report a highly enantioselective decarboxylative chlorination of beta ketocarboxylic acids to obtain alpha-chloroketones under mild organocatalytic conditions. The present method is also applicable for the enantioselective synthesis of tertiary alpha-chloroketones. The conversions of the resulting alpha chloroketones into alpha-aminoketones and alpha-thio-substituted ketones via SN2 reactions at the tertiary carbon centres are also demonstrated. These results constitute an efficient approach for the synthesis of chiral organohalides and are expected to enhance the availability of enantiomerically enriched chiral compounds with heteroatom-substituted chiral stereogenic centres. PMID- 28580952 TI - Threshold in North Atlantic-Arctic Ocean circulation controlled by the subsidence of the Greenland-Scotland Ridge. AB - High latitude ocean gateway changes are thought to play a key role in Cenozoic climate evolution. However, the underlying ocean dynamics are poorly understood. Here we use a fully coupled atmosphere-ocean model to investigate the effect of ocean gateway formation that is associated with the subsidence of the Greenland Scotland Ridge. We find a threshold in sill depth (~50 m) that is linked to the influence of wind mixing. Sill depth changes within the wind mixed layer establish lagoonal and estuarine conditions with limited exchange across the sill resulting in brackish or even fresher Arctic conditions. Close to the threshold the ocean regime is highly sensitive to changes in atmospheric CO2 and the associated modulation in the hydrological cycle. For larger sill depths a bi directional flow regime across the ridge develops, providing a baseline for the final step towards the establishment of a modern prototype North Atlantic-Arctic water exchange. PMID- 28580953 TI - Correspondence: Reply to 'DNA shape is insufficient to explain binding'. PMID- 28580954 TI - Single-stage plasma-based correlated energy spread compensation for ultrahigh 6D brightness electron beams. AB - Plasma photocathode wakefield acceleration combines energy gains of tens of GeV m 1 with generation of ultralow emittance electron bunches, and opens a path towards 5D-brightness orders of magnitude larger than state-of-the-art. This holds great promise for compact accelerator building blocks and advanced light sources. However, an intrinsic by-product of the enormous electric field gradients inherent to plasma accelerators is substantial correlated energy spread an obstacle for key applications such as free-electron-lasers. Here we show that by releasing an additional tailored escort electron beam at a later phase of the acceleration, when the witness bunch is relativistically stable, the plasma wave can be locally overloaded without compromising the witness bunch normalized emittance. This reverses the effective accelerating gradient, and counter-rotates the accumulated negative longitudinal phase space chirp of the witness bunch. Thereby, the energy spread is reduced by an order of magnitude, thus enabling the production of ultrahigh 6D-brightness beams. PMID- 28580956 TI - Correspondence: DNA shape is insufficient to explain binding. PMID- 28580955 TI - Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease. AB - Foxp3+ T regulatory (Treg) cells suppress immune cell activation and establish normal immune homeostasis. How Treg cells maintain their identity is not completely understood. Here we show that Ndfip1, a coactivator of Nedd4-family E3 ubiquitin ligases, is required for Treg cell stability and function. Ndfip1 deletion in Treg cells results in autoinflammatory disease. Ndfip1-deficient Treg cells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing TH2 effector cells. Proteomic analyses indicate altered metabolic signature of Ndfip1-deficient Treg cells and metabolic profiling reveals elevated glycolysis and increased mTORC1 signalling. Ndfip1 restricts Treg cell metabolism and IL-4 production via distinct mechanisms, as IL-4 deficiency does not prevent hyperproliferation or elevated mTORC1 signalling in Ndfip1-deficient Treg cells. Thus, Ndfip1 preserves Treg lineage stability and immune homeostasis by preventing the expansion of highly proliferative and metabolically active Treg cells and by preventing pathological secretion of IL-4 from Treg cells. PMID- 28580959 TI - Hafnium-an optical hydrogen sensor spanning six orders in pressure. AB - Hydrogen detection is essential for its implementation as an energy vector. So far, palladium is considered to be the most effective hydrogen sensing material. Here we show that palladium-capped hafnium thin films show a highly reproducible change in optical transmission in response to a hydrogen exposure ranging over six orders of magnitude in pressure. The optical signal is hysteresis-free within this range, which includes a transition between two structural phases. A temperature change results in a uniform shift of the optical signal. This, to our knowledge unique, feature facilitates the sensor calibration and suggests a constant hydrogenation enthalpy. In addition, it suggests an anomalously steep increase of the entropy with the hydrogen/metal ratio that cannot be explained on the basis of a classical solid solution model. The optical behaviour as a function of its hydrogen content makes hafnium well-suited for use as a hydrogen detection material. PMID- 28580960 TI - Rapid visualization of grain boundaries in monolayer MoS2 by multiphoton microscopy. AB - Grain boundaries have a major effect on the physical properties of two dimensional layered materials. Therefore, it is important to develop simple, fast and sensitive characterization methods to visualize grain boundaries. Conventional Raman and photoluminescence methods have been used for detecting grain boundaries; however, these techniques are better suited for detection of grain boundaries with a large crystal axis rotation between neighbouring grains. Here we show rapid visualization of grain boundaries in chemical vapour deposited monolayer MoS2 samples with multiphoton microscopy. In contrast to Raman and photoluminescence imaging, third-harmonic generation microscopy provides excellent sensitivity and high speed for grain boundary visualization regardless of the degree of crystal axis rotation. We find that the contrast associated with grain boundaries in the third-harmonic imaging is considerably enhanced by the solvents commonly used in the transfer process of two-dimensional materials. Our results demonstrate that multiphoton imaging can be used for fast and sensitive characterization of two-dimensional materials. PMID- 28580958 TI - Transcriptional determination and functional specificity of myeloid cells: making sense of diversity. AB - Early responses to invading pathogens and to non-microbial danger signals are mediated by different innate immune and parenchymal tissue cells, which are able to respond to a variety of pathogen- and danger-associated molecular patterns. In most if not all instances, innate immune responses to a given molecule are not uniquely confined to one responding cell type, but instead involve the engagement of different cells with intrinsically distinct properties. In this Review, we discuss the molecular basis of the differentiation of myeloid cells, which is controlled by transcription factors, transcriptional co-regulators and post transcriptional mechanisms, and examine how the functional specification of the resulting mature immune cells of the myeloid lineage affects their response to danger signals. PMID- 28580957 TI - The non-canonical NF-kappaB pathway in immunity and inflammation. AB - The nuclear factor-kappaB (NF-kappaB) family of transcription factors is activated by canonical and non-canonical signalling pathways, which differ in both signalling components and biological functions. Recent studies have revealed important roles for the non-canonical NF-kappaB pathway in regulating different aspects of immune functions. Defects in non-canonical NF-kappaB signalling are associated with severe immune deficiencies, whereas dysregulated activation of this pathway contributes to the pathogenesis of various autoimmune and inflammatory diseases. Here we review the signalling mechanisms and the biological function of the non-canonical NF-kappaB pathway. We also discuss recent progress in elucidating the molecular mechanisms regulating non-canonical NF-kappaB pathway activation, which may provide new opportunities for therapeutic strategies. PMID- 28580961 TI - Universal fragment descriptors for predicting properties of inorganic crystals. AB - Although historically materials discovery has been driven by a laborious trial and-error process, knowledge-driven materials design can now be enabled by the rational combination of Machine Learning methods and materials databases. Here, data from the AFLOW repository for ab initio calculations is combined with Quantitative Materials Structure-Property Relationship models to predict important properties: metal/insulator classification, band gap energy, bulk/shear moduli, Debye temperature and heat capacities. The prediction's accuracy compares well with the quality of the training data for virtually any stoichiometric inorganic crystalline material, reciprocating the available thermomechanical experimental data. The universality of the approach is attributed to the construction of the descriptors: Property-Labelled Materials Fragments. The representations require only minimal structural input allowing straightforward implementations of simple heuristic design rules. PMID- 28580962 TI - Probing intermediates of the induction period prior to nucleation and growth of semiconductor quantum dots. AB - Little is known about the induction period before the nucleation and growth of colloidal semiconductor quantum dots. Here, we introduce an approach that allows us to probe intermediates present in the induction period. We show that this induction period itself exhibits distinct stages with the evolution of the intermediates, first without and then with the formation of covalent bonds between metal cations and chalcogenide anions. The intermediates are optically invisible in toluene, while the covalent-bonded intermediates become visible as magic-size clusters when a primary amine is added. Such evolution of magic-size clusters provides indirect but compelling evidence for the presence of the intermediates in the induction period and supports the multi-step nucleation model. Our study reveals that magic-size clusters could be readily engineered in a single-size form, and suggests that the existence of the intermediates during the growth of conventional quantum dots results in low product yield. PMID- 28580964 TI - Corrigendum: ChEC-seq kinetics discriminates transcription factor binding sites by DNA sequence and shape in vivo. AB - This corrects the article DOI: 10.1038/ncomms15643. PMID- 28580963 TI - Ultrathin metal-organic framework array for efficient electrocatalytic water splitting. AB - Two-dimensional metal-organic frameworks represent a family of materials with attractive chemical and structural properties, which are usually prepared in the form of bulk powders. Here we show a generic approach to fabricate ultrathin nanosheet array of metal-organic frameworks on different substrates through a dissolution-crystallization mechanism. These materials exhibit intriguing properties for electrocatalysis including highly exposed active molecular metal sites owning to ultra-small thickness of nanosheets, improved electrical conductivity and a combination of hierarchical porosity. We fabricate a nickel iron-based metal-organic framework array, which demonstrates superior electrocatalytic performance towards oxygen evolution reaction with a small overpotential of 240 mV at 10 mA cm-2, and robust operation for 20,000 s with no detectable activity decay. Remarkably, the turnover frequency of the electrode is 3.8 s-1 at an overpotential of 400 mV. We further demonstrate the promise of these electrodes for other important catalytic reactions including hydrogen evolution reaction and overall water splitting. PMID- 28580967 TI - VOC emission rates over London and South East England obtained by airborne eddy covariance. AB - Volatile organic compounds (VOCs) originate from a variety of sources, and play an intrinsic role in influencing air quality. Some VOCs, including benzene, are carcinogens and so directly affect human health, while others, such as isoprene, are very reactive in the atmosphere and play an important role in the formation of secondary pollutants such as ozone and particles. Here we report spatially resolved measurements of the surface-to-atmosphere fluxes of VOCs across London and SE England made in 2013 and 2014. High-frequency 3-D wind velocities and VOC volume mixing ratios (made by proton transfer reaction - mass spectrometry) were obtained from a low-flying aircraft and used to calculate fluxes using the technique of eddy covariance. A footprint model was then used to quantify the flux contribution from the ground surface at spatial resolution of 100 m, averaged to 1 km. Measured fluxes of benzene over Greater London showed positive agreement with the UK's National Atmospheric Emissions Inventory, with the highest fluxes originating from central London. Comparison of MTBE and toluene fluxes suggest that petroleum evaporation is an important emission source of toluene in central London. Outside London, increased isoprene emissions were observed over wooded areas, at rates greater than those predicted by a UK regional application of the European Monitoring and Evaluation Programme model (EMEP4UK). This work demonstrates the applicability of the airborne eddy covariance method to the determination of anthropogenic and biogenic VOC fluxes and the possibility of validating emission inventories through measurements. PMID- 28580966 TI - Synergistic cooperation promotes multicellular performance and unicellular free rider persistence. AB - The evolution of multicellular life requires cooperation among cells, which can be undermined by intra-group selection for selfishness. Theory predicts that selection to avoid non-cooperators limits social interactions among non relatives, yet previous evolution experiments suggest that intra-group conflict is an outcome, rather than a driver, of incipient multicellular life cycles. Here we report the evolution of multicellularity via two distinct mechanisms of group formation in the unicellular budding yeast Kluyveromyces lactis. Cells remain permanently attached following mitosis, giving rise to clonal clusters (staying together); clusters then reversibly assemble into social groups (coming together). Coming together amplifies the benefits of multicellularity and allows social clusters to collectively outperform solitary clusters. However, cooperation among non-relatives also permits fast-growing unicellular lineages to 'free-ride' during selection for increased size. Cooperation and competition for the benefits of multicellularity promote the stable coexistence of unicellular and multicellular genotypes, underscoring the importance of social and ecological context during the transition to multicellularity. PMID- 28580968 TI - Collision-induced dissociation of sodiated glucose and identification of anomeric configuration. AB - Collision-induced dissociation (CID) of sodiated glucose was investigated using electronic structure calculations and resonance excitation in a low-pressure linear ion trap. The major dissociation channels in addition to desodiation are dehydration and C2H4O2 elimination reactions which the barrier heights are near to or lower than the sodiation energy of glucose. Dehydration reaction involves the transfer of the H atom from the O2 atom to the O1 atom, followed by the cleavage of the C1-O1 bond. Notably, alpha-glucose has a dehydration barrier lower than that of beta-glucose. This difference results in the larger branching ratio of dehydration reactions involving alpha-glucose, which provides a simple and fast method for identifying the anomeric configurations of glucose. The C2H4O2 elimination starts from the H atom transfer from the O1 atom to the O0 atom, followed by the cleavage of the C1-O0 bond. These results were further confirmed by experimental study using 18O-isotope-labeled compounds. Both the experimental data and theoretical calculations suggest that the dehydration reaction and cross-ring dissociation of sodiated carbohydrates mainly occur at the reducing end during low-energy CID. PMID- 28580965 TI - Functional evolution of Lepidoptera olfactory receptors revealed by deorphanization of a moth repertoire. AB - Insects detect their hosts or mates primarily through olfaction, and olfactory receptors (ORs) are at the core of odorant detection. Each species has evolved a unique repertoire of ORs whose functional properties are expected to meet its ecological needs, though little is known about the molecular basis of olfaction outside Diptera. Here we report a pioneer functional analysis of a large array of ORs in a lepidopteran, the herbivorous pest Spodoptera littoralis. We demonstrate that most ORs are narrowly tuned to ubiquitous plant volatiles at low, relevant odorant titres. Our phylogenetic analysis highlights a basic conservation of function within the receptor repertoire of Lepidoptera, across the expansive evolutionary radiation of different major clades. Our study provides a reference for further studies of olfactory mechanisms in Lepidoptera, a historically crucial insect order in olfactory research. PMID- 28580969 TI - Cavity enhanced spectroscopy for measurement of nitrogen oxides in the Anthropocene: results from the Seoul tower during MAPS 2015. AB - Cavity enhanced spectroscopy, CES, is a high sensitivity direct absorption method that has seen increasing utility in the last decade, a period also marked by increasing requirements for understanding human impacts on atmospheric composition. This paper describes the current NOAA six channel cavity ring-down spectrometer (CRDS, the most common form of CES) for measurement of nitrogen oxides and O3. It further describes the results from measurements from a tower 300 m above the urban area of Seoul in late spring of 2015. The campaign demonstrates the performance of the CRDS instrument and provides new data on both photochemistry and nighttime chemistry in a major Asian megacity. The instrument provided accurate, high time resolution data for N2O5, NO, NO2, NOy and O3, but suffered from large wall loss in the sampling of NO3, illustrating the requirement for calibration of the NO3 inlet transmission. Both the photochemistry and nighttime chemistry of nitrogen oxides and O3 were rapid in this megacity. Sustained average rates of O3 buildup of 10 ppbv h-1 during recurring morning and early afternoon sea breezes led to a 50 ppbv average daily O3 rise. Nitrate radical production rates, P(NO3), averaged 3-4 ppbv h-1 in late afternoon and early evening, much greater than contemporary data from Los Angeles, a comparable U. S. megacity. These P(NO3) were much smaller than historical data from Los Angeles, however. Nighttime data at 300 m above ground showed considerable variability in high time resolution nitrogen oxide and O3, likely resulting from sampling within gradients in the nighttime boundary layer structure. Apparent nighttime biogenic VOC oxidation rates of several ppbv h-1 were also likely influenced by vertical gradients. Finally, daytime N2O5 mixing ratios of 3-35 pptv were associated with rapid daytime P(NO3) and agreed well with a photochemical steady state calculation. PMID- 28580970 TI - Evolution of the structural, energetic, and electronic properties of the 3d, 4d, and 5d transition-metal clusters (30 TMn systems for n = 2-15): a density functional theory investigation. AB - Subnanometric transition-metal (TM) clusters have attracted great attention due to their unexpected physical and chemical properties, leastwise compared to their bulk counterparts. An in-depth understanding of the evolution of the properties as a function of the number of atoms for such systems is a basic prerequisite to leverage countless applications, from catalysis to magnetic storage, as well as to answer fundamental questions related to their intrinsic stability. Here, we reported a systematic density functional study to investigate the structural, electronic properties and stability of all TMn (30 elements) unary clusters as a function of the number of atoms (n = 2-15). We provided the complete structural patterns for all TM periodic table groups, considering the growth evolution as well as the main trends of the structural and electronic properties. The combination of the occupation of the bonding/anti-bonding d-states and the s-d hybridization is found to be the main stabilization mechanism, helping in the understanding of the structural patterns. Most TMn clusters have a magic number of atoms, for which there are peaks in s-d hybridization and null electric dipole moments. Thus, our extensive and comparative study addresses size effects along with the evolution of d-orbital occupation for the TMn gas-phase cluster properties. PMID- 28580972 TI - m-Cresol purple functionalized surface enhanced Raman scattering paper chips for highly sensitive detection of pH in the neutral pH range. AB - Herein, a pH sensitive paper SERS chip was prepared by selecting m-cresol purple, a molecule with halochromic properties in the neutral pH range as a Raman reporter. The adsorbed m-cresol purple underwent a reversible change in its electronic configuration from a non-resonant species to a resonant species, which resulted in a significant Raman signal intensity variation due to the transformation of the sensing mode from SERS to surface-enhanced resonance Raman scattering (SERRS). The chips have a sensitive pH range of 6.0 to 8.0 and exhibited good performance for the detection of natural water samples with detection precision of approximately 0.03 pH units, suggesting great potential for environmental pH monitoring applications. PMID- 28580971 TI - A micellar cisplatin prodrug simultaneously eliminates both cancer cells and cancer stem cells in lung cancer. AB - Platinum-based chemotherapy as first-line treatment for lung cancers encounters insufficient selectivity, severe side effects and drug resistance in clinics. In this study, we developed an amphiphilic prodrug of cisplatin-poly(ethylene glycol)-block-polycaprolactone and demonstrated that the prodrug formed micellar nanoparticles, NPPt(IV), with an average diameter of ~100 nm. NPPt(IV) released platinum in response to the intracellular acidic and reductive environment, and in turn induced significant anti-proliferative activity in lung cancer cells. More importantly, NPPt(IV) exhibited a prominent inhibitory effect on CD133+ lung cancer stem cells (CSCs) and suppressed tumor growth in vivo. Unlike cisplatin treatment which eventually enriches CSCs, NPPt(IV) treatment prevents the accumulation of CD133+ lung CSCs in tumors. Therefore, NPPt(IV) simutaneously targeting CSCs and non-CSCs might represent a superior strategy to improve conventional anticancer therapy directed predominantly to tumor bulk populations. PMID- 28580974 TI - Stereoselective synthesis of enamino ketones through an aza-Michael/hydrolysis cascade reaction. AB - We have developed a mild, convenient and efficient synthesis of highly functionalized (Z)-beta-enamino ketones from readily available 3,4 dihydroisoquinoline imines and ynones through an aza-Michael/hydrolysis cascade reaction. This method is also suitable for the preparation of (Z)-beta-enamino esters using alkynoates as starting materials. Complex fully substituted pyrroles can be constructed from the obtained (Z)-beta-enamino ketones. It is an attractive alternative approach for the preparation of highly functionalized enamino ketones, esters and pyrroles. PMID- 28580975 TI - Morphological imperfections of epitaxial graphene: from a hindrance to the generation of new photo-responses in the visible domain. AB - We report the discovery of remarkable photo-physical phenomena with characteristics unique to epitaxial graphene grown on 6H-SiC (000-1). Surprisingly, the electrical resistance of graphene increases under light illumination in contrast to conventional materials where it normally decreases. The resistance shows logarithmic temperature dependences which may be attributed to an Altshuler-Aronov effect. We show that the photoresistance depends on the frequency of the irradiating light, with three lasers (red, green, and violet) used to demonstrate the phenomenon. The counterintuitive rise of the positive photoresistance may be attributed to a creation of trapped charges upon irradiation. We argue that the origin of the photoresistance is related to the texture formed by the graphene flakes. Photovoltage also exists and increases with light intensity. However, its value saturates quickly with irradiation and does not change with time. The saturation of the photovoltage may be associated with the formation of a quasi-equilibrium state of the excited electrons and holes associated with a charge redistribution between the graphene and SiC substrate. The obtained physical picture is in agreement with the photoresistance measurements: X-ray photoelectron spectrometry "XPS", atomic force microscopy "AFM", Raman spectroscopy and the magnetic dependence of photoresistance decay measurements. We also observed non-decaying photoresistance and linear magnetoresistance in magnetic fields up to 1 T. We argue that this is due to topological phases spontaneously induced by persistent current formation within the graphene flake edges by magnetic fields. PMID- 28580976 TI - The role of group III, IV elements in Nb4AC3 MAX phases (A = Al, Si, Ga, Ge) and the unusual anisotropic behavior of the electronic and optical properties. AB - Niobium based Nb4AlC3, Nb4SiC3, Nb4GeC3 and Nb4GaC3 were investigated by means of density functional theory. Together with the known Nb4AlC3, the role of group III, IV elements in various properties of Nb4AC3 (A = Al, Si, Ga, Ge) was systematically investigated, and particularly the bulk moduli, shear moduli, and Young's moduli helped us to approach the ductility. All the studied compounds were found to be mechanically stable, and they also exhibit the metallic nature that results from the Nb-4d states being dominant at the Fermi level. The typical 4d-2p hybridization leads to strong Nb-C covalent bonding and a relatively weaker 4d-3p (4p) hybridization between Nb and A is identified. The latter does perturb the performance of materials. By varying A elements in Nb4AC3, the position and the width of the p states as well as hybridizations are altered, which determine the covalency and the ionicity of the chemical bonds. A high density of states at the Fermi level and the nesting effects in the Fermi surface are identified in Nb4SiC3 and linked to its unusual anisotropic behavior. Furthermore, Nb4GeC3 is predicted to be a very promising candidate solar heating barrier material. Overall, the present work gives insights into the role of A elements in the electronic structure and the physical properties of Nb4AC3 compounds. The tendencies and rules established here will help in the designing of functional ceramic materials with desirable properties. PMID- 28580977 TI - Concentration dependent phase behavior and collapse dynamics of PNIPAM microgel by dielectric relaxation. AB - The dielectric behavior of thermo-sensitive poly-(N-isopropylacrylamide) (PNIPAM) microgel with three different concentrations was investigated for the frequencies ranging from 40 Hz to 110 MHz as a function of temperature from 10 to 60 degrees C. Two remarkable and temperature-dependent relaxation processes were observed. The slow relaxation originates from the segmental motion over the whole temperature range. The fast relaxation is due to the fluctuation of counterions below the lower critical solution temperature (LCST) and the interfacial polarization above the LCST. It was concluded from the temperature-dependent dielectric parameters that the microgel concentration will not influence the LCST but affects the phase behavior of the microgel suspension: the dense system experienced a colloidal crystal-to-liquid transition and volume phase transition, while the dilute system only underwent a volume phase transition. Based on the interfacial polarization theory, the electrical parameters for the constituent phases (permittivity, conductivity, and volume fraction of the microgel (epsilonp, kappap, phi) and the conductivity of water kappaa) and the water content in the microgel (fw) were calculated using Hanai's equation. In addition, the thermodynamics parameters of the two relaxations were calculated from the Eyring equation. The electrical and thermodynamic parameters indicate that the microgel concentration influences the volume, charge density, thickness of the electric double layer, and degrees of freedom of the segments of the microgel, thereby resulting in the differences in collapse dynamics. PMID- 28580978 TI - Unprecedented formation of 3-(tetrahydrofuran-2-yl)-4H-chromen-4-one in a reaction between 3,3a-dihydro-9H-furo[3,4-b]chromen-9-one and malononitrile. AB - Chromone skeletons are widespread among natural products as well as bioactive molecules. Here, we describe an unprecedented reaction of furo[3,4-b]chromen-9 one with malononitrile to afford 3-(tetrahydrofuran-2-yl)-4H-chromen-4-ones. Experimental data suggest that a sequence of Michael/retro-Michael/nucleophilic addition is involved in this unprecedented transformation. PMID- 28580973 TI - The particle in the spider's web: transport through biological hydrogels. AB - Biological hydrogels such as mucus, extracellular matrix, biofilms, and the nuclear pore have diverse functions and compositions, but all act as selectively permeable barriers to the diffusion of particles. Each barrier has a crosslinked polymeric mesh that blocks penetration of large particles such as pathogens, nanotherapeutics, or macromolecules. These polymeric meshes also employ interactive filtering, in which affinity between solutes and the gel matrix controls permeability. Interactive filtering affects the transport of particles of all sizes including peptides, antibiotics, and nanoparticles and in many cases this filtering can be described in terms of the effects of charge and hydrophobicity. The concepts described in this review can guide strategies to exploit or overcome gel barriers, particularly for applications in diagnostics, pharmacology, biomaterials, and drug delivery. PMID- 28580979 TI - Design of TPGS-functionalized Cu3BiS3 nanocrystals with strong absorption in the second near-infrared window for radiation therapy enhancement. AB - Integrating radiation therapy with high-depth photothermal therapy in the second near-infrared (NIR) window is highly required for efficient treatment of deep seated tumor cells. Here, we constructed a multifunctional nano-theranostic with bimetallic chalcogenide nanocrystals (NCs) functionalized with amphiphilic d alpha-tocopherol polyethylene glycol 1000 succinate (TPGS-Cu3BiS3). Benefiting from the strong absorbance of both X-ray and NIR light in the second NIR window, TPGS-Cu3BiS3 CNs can not only deposit more radiation dose to trigger enhanced radiation damage in vivo, but also conduct photo-induced hyperthermia for thermal ablation in the second NIR window and effective improvement of tumor oxygenation to overcome the hypoxia-associated radio-resistance of tumors. Moreover, copper ions on the surface of TPGS-Cu3BiS3 NCs are capable of catalyzing the Fenton-like and Haber-Weiss reactions to produce highly reactive hydroxyl radicals, leading to the increase in the level of oxygen radicals and further enhance cancer cell destruction. Apart from their therapeutic application, by means of X-ray computer tomography imaging as well as multispectral optoacoustic tomography imaging, TPGS Cu3BiS3 NCs also have the potential as a nano-theranostic to offer remarkable therapeutic outcome for deep-seated tumor cells in imaging-guided synergistically enhanced radiation therapy. PMID- 28580981 TI - Seeding layer assisted selective-area growth of As-rich InAsP nanowires on InP substrates. AB - We present the first demonstration of arsenic-rich InAs1-xPx (0 <= x <= 0.33) nanowire arrays grown on InP (111)B substrates by catalyst-free selective-area metal-organic chemical vapor deposition. It is shown that by introducing a thin InAs seeding layer prior to the growth of the nanowire, an extremely high vertical yield is achieved by eliminating rotational twins between (111)A and (111)B crystal orientations. InAsP nanowire arrays show strong emission of photoluminescence (PL) at room temperature, suggesting a significant reduction of surface state density compared with InAs nanowires. The phosphorus composition deduced from the PL peak energy is verified by energy-dispersive X-ray spectroscopy. The growth temperature shows a strong impact on the aspect ratio of InAs1-xPx nanowires with different phosphorus compositions. In addition, no PL emission is observed from nanowires grown with arsenic overpressure, likely due to an exchange of phosphorus with arsenic atoms at the surface which results in an increase in the surface state density. These results provide a path for the growth of heterojunctions based on As-rich InAs1-xPx for nanoscale short wavelength infrared and mid-wavelength infrared optical devices. PMID- 28580980 TI - Polarization-resolved mechanistic investigation of fluorescence signal intensification on zinc oxide nanorod ends. AB - The superior optical properties of zinc oxide nanorods (ZnO NRs) have continued to promote their broad use in photonic, photoelectric, light detecting, and biosensing applications. One particularly important property pertinent to biodetection is fluorescence intensification on nanorod ends (FINE), a phenomenon in which a highly spatially localized and strongly intensified fluorescence signal with its extended photostability at the NR ends is seen from the emission profiles of fluorophore-coupled biomolecules on ZnO NRs. Therefore, understanding key parameters affecting the FINE phenomenon and the degree of FINE (DoF) is critical for their applications in biosensors. In this study, we describe in detail the outcomes of polarization-resolved measurements by systematically considering the polarization effects on FINE and DoF as a function of NR tilt angle and position along the NR. Specifically, we elucidate the exact roles of the different states of light polarization in FINE and quantitatively determine the explicit contributions arising from distinctive polarization states to the DoF. We confirm that the presence of the FINE phenomenon is ubiquitous from the fluorophore-coupled ZnO NR systems, regardless of the polarization setting. We subsequently show that DoF is significantly affected by the light-matter interaction geometry. We reveal the specific polarization conditions that contribute dominantly to the FINE effect. The highest DoF from a NR and the greatest NR end intensity can be achieved when both the excitation and collection polarization states are perpendicular to the NR main axis. Insights from this study provide valuable design principles for selecting the polarization state and light-matter interaction geometry to attain maximum FINE as well as DoF on ZnO NRs. The precise understanding of polarization-derived consequences on FINE and DoF manifested differently as a function of the position on individual NRs can also be important for warranting accurate interpretation and quantification of the position-dependent, fluorophore-emitted signals on single ZnO NRs. Hence, our findings from this study can be extremely beneficial in fluorescence-based sensing and detection settings utilizing polarization. PMID- 28580983 TI - Competitive C-C and C-H bond scission in the ethanol oxidation reaction on Cu(100) and the effect of an alkaline environment. AB - Direct ethanol fuel cell technology is impeded by inefficient, yet expensive anode catalysts. As such, research on effective and cheap anode catalysts towards complete ethanol oxidation reaction (EOR) is greatly needed. Herein, we report the investigations of the competitive C-C and C-H bond scissions in the EOR involving CH3CO, CH2CO, and CHCO species on Cu(100) using density functional theory and transition state theory calculations. The easiest C-C bond cleavage was found in CH2CO while the most difficult C-H bond cleavage was also found in CH2CO, both with an activation energy of 1.02 eV. The feasible C-C bond scission may take place in CH2CO with a rate constant ratio of the C-C to the C-H bond scission at 100 degrees C of 0.32. Furthermore, in an alkaline environment, the C-H bond scission activation barrier is considerably lowered but the C-C bond cleavage activation barrier is slightly increased for both CH3CO and CH2CO species. The reaction of CH3CO species on Cu(100) under alkaline conditions produces mainly acetic acid with a barrier of 0.49 eV and a rate constant of 4.93 * 105 s-1 at 100 degrees C. PMID- 28580982 TI - Layered rare-earth hydroxide nanocones with facile host composition modification and anion-exchange feature: topotactic transformation into oxide nanocones for upconversion. AB - Conical structures with hollow interiors, namely, nanocones (NCs), may exhibit better carrier transport properties than nanorods or nanotubes, which make them promising candidates for potential applications in optical/display devices, electronics and optoelectronics. Generally, conical structures belong to a metastable state between lamellar and tubular forms due to the extreme curvature causing the increase of internal strain energy. Therefore, it is very difficult to prepare NCs in high yield and purity under mild conditions. Here we firstly demonstrate a general strategy for the synthesis of layered rare-earth hydroxide (LRH) NCs intercalating dodecyl sulfate anions (C12H25SO4-, DS-) using hexamethylenetetramine (C6H12N4, HMT) hydrolysis. The rare-earth cations (RE3+) in the host layer can be conveniently modified and/or doped, resulting in a large family of monometallic (Y, Tb, Er), bi- (Y-Tb, Y-Er) and even tri-metallic (Y-Yb Er) LRH NCs with adjustable ratios. Moreover, the DS--intercalated LRH NCs can be readily modified with various inorganic or organic anions (e.g., NO3-, Cl-, and CH3COO-, etc.) through a conventional anion-exchange procedure, and the original conical morphology can be perfectly maintained. The anion-exchanged product, for example, NO3--intercalated NCs, can be more easily and topotactically transformed into oxide NCs than the original DS--intercalated form, exempt from the formation of rare-earth oxysulfates induced by the combustion of interlayer DS anions. Taking advantage of this protocol, tri-metallic (Y-Yb-Er) LRH NCs were anion exchanged into the NO3--intercalated form and subsequently calcined into Y2O3:Yb,Er oxide NCs, which showed efficient upconversion photoluminescence properties. The current strategy may become a general method for the designed synthesis of other related hydroxide and oxide NCs for a wide range of potential applications. PMID- 28580984 TI - Metastable state-induced consecutive step-like negative differential resistance behaviors in single crystalline VO2 nanobeams. AB - We demonstrate the current-dependent consecutive appearance of two different negative differential resistance (NDR) transitions in a single crystalline VO2 nanobeam epitaxially grown on a c-cut sapphire substrate. It is revealed that the first NDR occurs at an approximately constant current level as a result of the carrier injection-induced transition, independent of a thermally induced phase transition. In contrast, it is observed that the second NDR exhibits a temperature-dependent behavior and current values triggering the metal-insulator transition (MIT) are strongly mediated by Joule heating effects in a phase coexisting temperature range. Moreover, we find that the electrically and thermally triggered MIT behavior can be closely related with the alternate occurrence of current-induced multiple insulating and metallic phase coexistence in the nanobeam. These findings indicate that the current density passing through VO2 plays a critical role in both the electrical and structural phase transitions. PMID- 28580985 TI - Edge control of graphene domains grown on hexagonal boron nitride. AB - The edge structure of graphene has a significant influence on its electronic properties. However, control over the edge structure of graphene domains on insulating substrates is still challenging. Here we demonstrate edge control of graphene domains on hexagonal boron nitride (h-BN) by modifying the ratio of working-gases. Edge directions were determined with the help of both moire patterns and atomic-resolution images obtained via atomic force microscopy measurements. It is believed that the variation of graphene edges is mainly attributed to different growth rates of armchair and zigzag edges. This work demonstrates a potential approach to fabricate smooth-edge graphene ribbons on h BN. PMID- 28580986 TI - Strategies to initiate and control the nucleation behavior of bimetallic nanoparticles. AB - In this work we report strategies to nucleate bimetallic nanoparticles (NPs) made by gas phase synthesis of elements showing difficulty in homogeneous nucleation. It is shown that the nucleation assisted problem of bimetallic NP synthesis can be solved via the following pathways: (i) selecting an element which can itself nucleate and act as a nucleation center for the synthesis of bimetallic NPs; (ii) introducing H2 or CH4 as an impurity/trace gas to initiate nucleation during the synthesis of bimetallic NPs. The latter can solve the problem if none of the elements in a bimetallic NP can initiate nucleation. We illustrate the abovementioned strategies for the case of Mg based bimetallic NPs, which are interesting as hydrogen storage materials and exhibit both nucleation and oxidation issues even under ultra-high vacuum conditions. In particular, it is shown that adding H2 in small proportions favors the formation of a solid solution/alloy structure even in the case of immiscible Mg and Ti, where normally phase separation occurs during synthesis. In addition, we illustrate the possibility of improving the nucleation rate, and controlling the structure and size distribution of bimetallic NPs using H2/CH4 as a reactive/nucleating gas. This is shown to be associated with the dimer bond energies of the various formed species and the vapor pressures of the metals, which are key factors for NP nucleation. PMID- 28580987 TI - Surface-restrained growth of vertically aligned carbon nanotube arrays with excellent thermal transport performance. AB - A vertically aligned carbon nanotube (VACNT) array is a promising candidate for a high-performance thermal interface material in high-power microprocessors due to its excellent thermal transport property. However, its rough and entangled free tips always cause poor interfacial contact, which results in serious contact resistance dominating the total thermal resistance. Here, we employed a thin carbon cover to restrain the disorderly growth of the free tips of a VACNT array. As a result, all the free tips are seamlessly connected by this thin carbon cover and the top surface of the array is smoothed. This unique structure guarantees the participation of all the carbon nanotubes in the array in the heat transport. Consequently the VACNT array grown on a Cu substrate shows a record low thermal resistance of 0.8 mm2 K W-1 including the two-sided contact resistances, which is 4 times lower than the best result previously reported. Remarkably, the VACNT array can be easily peeled away from the Cu substrate and act as a thermal pad with excellent flexibility, adhesive ability and heat transport capability. As a result the CNT array with a thin carbon cover shows great potential for use as a high-performance flexible thermal interface material. PMID- 28580988 TI - Alkynyl-protected silver nanoclusters featuring an anticuboctahedral kernel. AB - Two unique silver nanoclusters protected by alkynyl and diphosphine ligands have been synthesized. Single crystal structural determination reveals that they have a centered anticuboctahedral Ag13 kernel. Such a kernel is observed for the first time in a coinage metal nanocluster. This work offers new insights into the fact that the PhC[triple bond, length as m-dash]C ligand represents a new direction in synthesizing novel metal nanoclusters. PMID- 28580989 TI - First-principles prediction on bismuthylene monolayer as a promising quantum spin Hall insulator. AB - Two-dimensional (2D) large band-gap topological insulators (TIs) with highly stable structures are imperative for achieving dissipationless transport devices. However, to date, only very few materials have been experimentally observed to host the quantum spin Hall (QSH) effect at low temperature, thus obstructing their potential application in practice. Using first-principles calculations, herein, we predicted a new 2D TI in the porous allotrope of a bismuth monolayer, i.e. bismuthylene, its geometrical stability was confirmed via phonon spectrum and molecular dynamics simulations. Analysis of the electronic structures reveal that bismuthylene is a native QSH state with a band gap as large as 0.28 eV at the Gamma point, which is larger than that (0.2 eV) of the buckled Bi (111) and suitable for room temperature applications. Note that it has a much lower energy than buckled Bi (111) and flattened Bi films; thus, bismuthylene is feasible for experimental realization. Interestingly, the topological properties can be retained under strains within the range of -6%-3% and electrical fields up to 0.8 eV A-1. A heterostructure was constructed by sandwiching bismuthylene between BN sheets, and the non-trivial topology of bismuthylene was retained with a sizable band gap. These findings provide a platform to design a large-gap QSH insulator based on the 2D bismuthylene films, which show potential applications in spintronic devices. PMID- 28580990 TI - CdS-coated TiO2 nanotube layers: downscaling tube diameter towards efficient heterostructured photoelectrochemical conversion. AB - Herein, a novel photoelectrochemical heterostructure based on TiO2 nanotube layers uniformly coated by a CdS thin layer (using ALD) is presented. Downscaling the nanotube diameter (from 95 to 35 nm) resulted in a 2-fold enhancement of the UV and Vis light photocurrents. Further photocurrent improvement resulted from the prior annealing of the TiO2 nanotube layers from 300 to 600 degrees C. PMID- 28580991 TI - Spontaneous electrification of fluoropolymer-water interfaces probed by electrowetting. AB - Fluoropolymers are widely used as coatings for their robustness, water repellence, and chemical inertness. In contact with water, they are known to assume a negative surface charge, which is commonly attributed to adsorbed hydroxyl ions. Here, we demonstrate that a small fraction of these ions permanently sticks to surfaces of Teflon AF and Cytop, two of the most common fluoropolymer materials, upon prolonged exposure to water. Electrowetting measurements carried out after aging in water are used to quantify the density of 'trapped' charge. Values up to -0.07 and -0.2 mC m-2 are found for Teflon AF and for Cytop, respectively, at elevated pH. A similar charge trapping process is also observed upon aging in various non-aqueous polar liquids and in humid air. A careful analysis highlights the complementary nature of electrowetting and streaming potential measurements in quantifying interfacial energy and charge density. We discuss the possible mechanism of charge trapping and highlight the relevance of molecular scale processes for the long term stability and performance of fluoropolymer materials for applications in electrowetting and elsewhere. PMID- 28580992 TI - Phosphine-functionalized NHC Ni(ii) and Ni(0) complexes: synthesis, characterization and catalytic properties. AB - Two families of nickel complexes bearing chelating diphenylphosphine functionalized NHC ligands [NiII(ArNHCPPh2)(allyl)]Cl 1a (Ar = Mes); 1b, (Ar = 2,6-iPr2-C6H3) and [Ni0(ArNHCPPh2)(alkene)] 2a (Ar = 2,6-iPr2-C6H3, alkene = styrene); 2b (Ar = 2,6-iPr2-C6H3, alkene = diethyl fumarate) have been prepared and fully characterized. VT-NMR experiments in solution reveal that the allyl derivatives 1a-b are stereochemically nonrigid. The solid-state structure of the Ni0 derivative 2b is also reported. These complexes display interesting catalytic properties in various cross-coupling reactions. The precatalyst [Ni0(ArNHCPPh2)(styrene)] 2a was found to be the most active system. The bulkiness of the N-substituent on the imidazole ring and the low oxidation state of the metal center in 2a accounted for its enhanced catalytic performance. This system catalyzed effectively the coupling of (hetero)aryl chlorides with a range of nucleophiles including Grignard reagents, boronic acids, secondary amines and indoles. PMID- 28580993 TI - Energy storage mechanism in aqueous fiber-shaped Li-ion capacitors based on aligned hydrogenated-Li4Ti5O12 nanowires. AB - It is reported that Li ions can contribute a lot to the capacitance of aqueous Li ion capacitors (LICs), which might be due to the intercalation/de-intercalation processes of Li+ ions that also occur at the anodes. However the energy storage mechanism in the aqueous LIC system still requires further proof. In this work, a type of aqueous fiber-shaped LIC has been designed and developed using hydrogenated Li4Ti5O12 (H-LTO) anodes, active carbon (AC) cathodes, and LiCl/PVA gel electrolytes with a double-helical structure. The obtained single LTO wire electrode exhibits a high specific capacitance in volume (34.1 F cm-3) and superior cycling stabilities (~100% over 100 000 cycles), both of which are due to the formed amorphous layers at the surface of the electrodes. Moreover, it is found via sweep voltammetry analysis that most of the energy stored in an aqueous fiber-shaped capacitor electrode is attributed to the Li ions' intercalation, whose content exceeds 85% at a low scan rate and gradually decreases with increasing scan rate; while the energy stored by the double electric layers remains almost unchanged with different scan rates. Furthermore, the well-matched wearable fiber-shaped LICs show high capacitive behaviors (18.44 MUW h cm-2) and superior static/dynamic cycling stabilities. This research would provide some insight into the charge storage mechanism in electrodes in the aqueous system, and give more suggestions to develop high-energy-density fiber-shaped energy storage devices. PMID- 28580994 TI - Detection and identification of Criegee intermediates from the ozonolysis of biogenic and anthropogenic VOCs: comparison between experimental measurements and theoretical calculations. AB - Ozonolysis of alkenes is a key reaction in the atmosphere, playing an important role in determining the oxidising capacity of the atmosphere and acting as a source of compounds that can contribute to local photochemical "smog". The reaction products of the initial step of alkene-ozonolysis are Criegee intermediates (CIs), which have for many decades eluded direct experimental detection because of their very short lifetime. We use an innovative experimental technique, stabilisation of CIs with spin traps and analysis with proton transfer reaction mass spectrometry, to measure the gas phase concentration of a series of CIs formed from the ozonolysis of a range of both biogenic and anthropogenic alkenes in flow tube experiments. Density functional theory (DFT) calculations were used to assess the stability of the CI-spin trap adducts and show that the reaction of the investigated CIs with the spin trap occurs very rapidly except for the large beta-pinene CI. Our measurement method was used successfully to measure all the expected CIs, emphasising that this new technique is applicable to a wide range of CIs with different molecular structures that were previously unidentified experimentally. In addition, for the first time it was possible to study CIs simultaneously in an even more complex reaction system consisting of more than one olefinic precursor. Comparison between our new experimental measurements, calculations of stability of the CI-spin trap adducts and results from numerical modelling, using the master chemical mechanism (MCM), shows that our new method can be used for the quantification of CIs produced in situ in laboratory experiments. PMID- 28580995 TI - Simulation of intermediate transport in nanoscale scaffolds for multistep catalytic reactions. AB - Efficient catalytic cascades that involve several sequential reactions are found frequently in nature. The efficiency of multi-step biochemical pathways is enhanced by substrate channelling, wherein the product of one reaction is directed toward and acts as substrate to the next sequential reaction. Such mechanisms can partially overcome diffusion, which is often fast compared to reaction rates, and promotes loss of intermediates. Biochemical substrate channelling is achieved by the architecture and scaffolding of enzymes, and mimicking these natural structures could lead to innovative catalyst designs. We investigate the efficiency of two channelling approaches - electrostatic interactions and surface adsorption - through continuum modelling, to identify the limits of these modes and the extent to which they can interact. The model considers transport between two active sites where an intermediate is produced at the first active site and consumed at the second. The system includes mass transport through diffusion and migration, and reaction kinetics at the active sites. The effectiveness of this model is quantified by yield of the second reaction relative to the first. Channelling via proximity between active sites and via surface adsorption are found to be inefficient, requiring high values of the rate constant at the second active site to obtain significant yields. The introduction of electrostatic interactions, however, leads to yields of over 90% at much lower values of the rate constant. PMID- 28580996 TI - A cationic aluminium complex: an efficient mononuclear main-group catalyst for the cyanosilylation of carbonyl compounds. AB - A structurally characterized cationic aluminium complex [(AT)Al(DMAP)]+[OTf]- (3) stabilized through a relatively nonbulky aminotroponate (AT) ligand is reported (DMAP = 4-(dimethylamino)pyridine). This compound was found to work as an excellent mononuclear main-group catalyst of the cyanosilylation of a variety of aldehydes and ketones. Loadings of 1 to 2 mol% of this catalyst consumed these substrates in just 5 to 30 min at room temperature. PMID- 28580997 TI - A world avoided: impacts of changes in anthropogenic emissions on the burden and effects of air pollutants in Europe and North America. AB - Emissions from anthropogenic activity are known to have deleterious impacts on human and ecosystem health and as such a significant amount of time, effort and money has been spent developing legislation to minimise their effects. Here we use a state of the art coupled chemistry-climate model HadGEM2-ES, with extended tropospheric chemistry, to assess the impacts that changes in emissions from anthropogenic activity have had on the burden and impacts of air pollutants over the last three decades. We use HadGEM2-ES to assess an alternative trajectory in air pollutant emissions to that which we have seen, with a regional focus on the contiguous United States and areas of Western Europe. This alternative trajectory can be considered to reflect a world avoided. In this world avoided, the significant levels of air pollution legislation imposed over the last three decades are simulated to not have come into effect in the contiguous United States and Western Europe. Rather a business as usual emission scenario is followed from 1970 to the present day. By combining the results of simulations of the world avoided with a base case present day atmosphere our model runs demonstrate that as a result of air pollution legislation, over 500 000 early mortalities a year have been mitigated owing to extensive reduction in sulfate aerosol and up to 8000 early mortalities a year have been mitigated as a result of improvements in ozone and nitrogen dioxide pollution. These results highlight the important role of legislation in reducing air pollution related mortality in these areas of the globe and highlight a compelling case for developing regions to follow. PMID- 28580998 TI - Ambient and laboratory observations of organic ammonium salts in PM1. AB - Ambient measurements of PM1 aerosol chemical composition at Cabauw, the Netherlands, implicate higher ammonium concentrations than explained by the formation of inorganic ammonium salts. This additional particulate ammonium is called excess ammonium (eNH4). Height profiles over the Cabauw Experimental Site for Atmospheric Research (CESAR) tower, of combined ground based and airborne aerosol mass spectrometric (AMS) measurements on a Zeppelin airship show higher concentrations of eNH4 at higher altitudes compared to the ground. Through flights across the Netherlands, the Zeppelin based measurements furthermore substantiate eNH4 as a regional phenomenon in the planetary boundary layer. The excess ammonium correlates with mass spectral signatures of (di-)carboxylic acids, making a heterogeneous acid-base reaction the likely process of NH3 uptake. We show that this excess ammonium was neutralized by the organic fraction forming particulate organic ammonium salts. We discuss the significance of such organic ammonium salts for atmospheric aerosols and suggest that NH3 emission control will have benefits for particulate matter control beyond the reduction of inorganic ammonium salts. PMID- 28580999 TI - 3D printable composite dough for stretchable, ultrasensitive and body-patchable strain sensors. AB - The recent development of strain sensor devices which can actively monitor human body motion has attracted tremendous attention, for application in various wearable electronics and human-machine interfaces. In this study, as materials for strain sensor devices, we exploit the low-cost, carbon-based, 3-dimensional (3D) printable composite dough. The dough is prepared via a chemical method based on the formation of electrostatic assemblies between 1-dimensional, amine functionalized, multi-walled carbon nanotubes and 2-dimensional graphene oxides. The resulting composite dough has an extremely high storage modulus, which allows a vertically-stackable, 3D printing process for fabricating strain sensor devices on various dense, porous and structured substrates. The device performance parameters, including gauge factor, hysteresis, linearity, and overshooting behavior are found to be adjustable by controlling the printing process parameters. The fabricated strain sensor devices demonstrate the ability to distinguish actual human body motions. A high gauge factor of over 70 as well as other excellent device performance parameters are achievable for the printed sensor devices, and even small strains, below 1%, are also detectable by the fabricated sensor devices. PMID- 28581000 TI - Shedding light on zwitterionic magnetic nanoparticles: limitations for in vivo applications. AB - Over the last few years several studies have dealt with the importance of the surface charge of nanoparticles in prolonging their blood circulation and minimizing their interaction with plasma proteins. These investigations claimed that zwitterionic nanoparticles exhibited a minimal macrophage response and long blood circulation times compared to nanoparticles with other surface charges. These differences in their in vivo behavior are mainly attributed to the interaction of nanoparticles with plasma proteins. Interestingly, most of these studies considered the total surface charge, instead of the outermost layer of the nanomaterial, as being mainly responsible for these undesirable interactions. However, the first contact with plasma proteins is most likely due to the outermost layer on the nanomaterials. Therefore, here we report a detailed study on the effect of the outermost surface charge of magnetic nanoparticles with regard to biodistribution, pharmacokinetics and bioavailability. Magnetic nanoparticles, coated with PEG chains functionalized with neutral, positive or zwitterionic groups, were intravenously injected into mice, followed in vivo by MRI and then quantified by ICP-MS in blood and the main organs. We found that neutral nanoparticles exhibited long blood circulation times, very good stealth properties and the highest bioavailability, whereas zwitterionic nanoparticles were readily recognized by the mononuclear phagocyte system and avidly taken up by the liver. Also, zwitterionic nanoparticles showed high non-specific cell internalization, whereas neutral nanoparticles showed the lowest cellular uptake, indicating that they require active transport to cross the plasma membrane, which is the desirable situation for therapeutic vehicles with low side effects. Thus, neutral nanoparticles exhibit very favorable characteristics for in vivo applications, whereas zwitterionic nanoparticles show important limitations. PMID- 28581001 TI - Structure and elasticity of composite nanoparticle/polymer nanoshells (hybridosomes(r)). AB - Our group recently introduced a new process to synthesize nanoparticle shells of about 100 nm, named "hybridosomes(r)". Here, the structure and mechanical properties of hybridosomes(r) made from iron oxide nanoparticles and poly(acrylic acid) are characterized using TEM, AFM and an osmotic compression technique. For the latter, the size distribution of the hybridosomes is monitored by nanoparticle tracking analysis (NTA) in the presence of poly(ethylene glycol)s of different molecular weights. It is found that the size of the hybridosomes(r) can be tuned from ca. 80 nm to over 110 nm by adjusting the amount of nanoparticles and that their shell consists of a single layer of nanoparticles, with a porous structure. The size of the pores is estimated from osmotic compression experiments at ca. 4000 g mol-1. The mechanical properties are measured both at the ensemble level using size measurements under osmotic pressure and at the single nanoparticle level by atomic force microscopy nanoindentation. Both osmotic and AFM experiments are analyzed in the framework of the continuum elastic theory of thin shells and yield a value of Young's modulus of the order of MPa. PMID- 28581002 TI - Predicting photon cascade emission in Pr3+ doped fluorides. AB - We present a theoretical approach, based on a density functional theoretic parametrization of a model Hamiltonian, that allows for the determination of the complete electronic 4fn and 4fn-15d valence manifolds of a lanthanide ion impurity in different host lattices in an easy, fast and reliable way. The model accounts for the electrostatic interactions, ligand field splitting due to the surroundings of the impurity and spin-orbit coupling effects, which means that the parametrization is transferable to different ligand environments. The model is applied to several Pr3+ doped fluorides, which are of great interest for designing warm white lighting devices. We show that the model correctly predicts which of them presents photon-cascade emission as experimentally observed. We also determine the absorption (emission) spectra from the dipolar transition probabilities from the lowest 4f2 (4f5d) state to the states of the 4f5d (4f2) manifold of the Pr3+ impurity, in agreement with the available experimental data. The present approach can be applied to other impurity-doped systems where the accurate determination of the valence impurity states is crucial for characterizing the relevant properties of the system. PMID- 28581003 TI - Mathematical modeling reveals differential regulation of MAPK activity by phosphatase proteins in the yeast pheromone response pathway. AB - To prevent indefinite cellular responses to external signals, cells utilize various adaptation mechanisms. The yeast mating-response pathway is a model cellular system that exhibits adaptation to persistent external signals. This pathway employs a mitogen-activated protein kinase (MAPK) cascade which is composed of two well-known negative feedback inhibitions that involve the yeast phosphatase proteins Ptp3 and Msg5. The phosphorylated form of the yeast MAPK protein Fus3 (pFus3) triggers the phosphorylation of both phosphatases, but transcriptionally upregulates only Msg5. To study the biological rationale for the existence of two distinct negative feedback inhibitions acting on pFus3, we used published experimental data to develop a mathematical model which quantifies the inhibitory roles of these phosphatase proteins on pFus3. Our analyses show that the inhibition of pFus3 due to Ptp3 is largely independent of the signal profile, and is most impactful at early time points after pheromone induction. Conversely, the feedback inhibition due to Msg5 is highly dependent on the signal profile, and is most influential after pFus3 attains its maximum cellular abundance. Similarly, Ptp3 reduces the variation in the pFus3 dynamics at early time points while the noise-reduction effects of Msg5 become stronger as time passes. PMID- 28581004 TI - DNA origami/gold nanorod hybrid nanostructures for the circumvention of drug resistance. AB - We herein demonstrate that DNA origami can work as a multifunctional platform integrating a chemotherapeutic drug (doxorubicin), gold nanorods and a tumour specific aptamer MUC-1, to realize the effective circumvention of drug resistance. Doxorubicin (DOX) was loaded efficiently onto DNA origami through base pair intercalation and surface-modified gold nanorods (AuNRs) were assembled onto the DNA origami through DNA hybridization. Due to the active targeting effect of the assembled aptamers, the multifunctional nanostructures achieved increased cellular internalization of DOX and AuNRs. Upon near-infrared (NIR) laser irradiation, the P-glycoprotein (multidrug resistance pump) expression of multidrug resistant MCF-7 (MCF-7/ADR) cells was down-regulated, achieving the synergistically chemotherapeutic (DOX) and photothermal (AuNRs) effects. PMID- 28581005 TI - Dynamics of excited-state intramolecular proton-transfer in 2-amino-3-(2' benzazolyl)quinoline cations. AB - It was found that cations formed by the protonation of 2-amino-3-(2' benzoxazolyl)-quinoline (ABO) and 2-amino-3-(2'-benzothiazolyl)-quinoline (ABT) at the nitrogen atom of the quinoline ring exhibit excited-state intramolecular proton transfer (ESIPT). The two-band fluorescence of these cations is due to the emission from two species: the initial tautomer (short-wavelength band) and the ESIPT product (long-wavelength band). The relative intensity of the long wavelength band depends on the basicity of the proton-accepting moiety and temperature. Quantum-chemical calculations demonstrated that ESIPT in cations involves overcoming a significant potential barrier, which increases with the decreasing basicity of the proton-accepting benzazole moiety. Using femtosecond absorption spectroscopy and nanosecond fluorescence spectroscopy, the effective ESIPT time in the studied cations was determined, which increased with decreasing temperature. PMID- 28581006 TI - Investigation of the reaction of ozone with isoprene, methacrolein and methyl vinyl ketone using the HELIOS chamber. AB - The rate constants for the ozonolysis of isoprene (ISO), methacrolein (MACR) and methyl vinyl ketone (MVK) have been measured using the newly built large volume atmospheric simulation chamber at CNRS-Orleans (France), HELIOS (Chambre de simulation atmospherique a irradiation naturelle d'Orleans). The OH radical yields from the ozonolysis of isoprene, MACR and MVK have also been determined, as well as the gas phase stable products and their yields. The secondary organic aerosol yield for the ozonolysis of isoprene has been tentatively measured in the presence and absence of an OH radical scavenger. The measurements were performed under different experimental conditions with and without adding cyclohexane (cHX) as an OH radical scavenger. All experiments have been conducted at 760 torr of purified dry air (RH < 1%) and ambient temperature (T = 281-295 K). The data obtained are discussed and compared with those from the literature. The use of the HELIOS facility and its associated analytical equipment enables the derivation of kinetic parameters as well as mechanistic information under near realistic atmospheric conditions. PMID- 28581007 TI - Literature-based prediction of novel drug indications considering relationships between entities. AB - There have been many attempts to identify and develop new uses for existing drugs, which is known as drug repositioning. Among these efforts, text mining is an effective means of discovering novel knowledge from a large amount of literature data. We identify a gene regulation by a drug and a phenotype based on the biomedical literature. Drugs or phenotypes can activate or inhibit gene regulation. We calculate the therapeutic possibility that a drug acts on a phenotype by means of these two types of regulation. We assume that a drug treats a phenotype if the genes regulated by the phenotype are inversely correlated with the genes regulated by the drug. Based on this hypothesis, we identify drug phenotype associations with therapeutic possibility. To validate the drug phenotype associations predicted by our method, we make an enrichment comparison with known drug-phenotype associations. We also identify candidate drugs for drug repositioning from novel associations and thus reveal that our method is a novel approach to drug repositioning. PMID- 28581008 TI - A theoretical study on the palladium-catalyzed oxidative carbocyclization alkoxycarbonylation of bisallenes to construct seven-membered carbocycles assisted by olefins. AB - The reaction mechanisms of the Pd(ii)-catalyzed oxidative carbocyclization alkoxycarbonylation of bisallenes to construct seven-membered carbocycles have been theoretically investigated with the aid of density functional theory (DFT) calculations. Our calculation results account for the experimental fact that the product should be the seven-membered carbocycle P1 instead of the spiro-type product P2. Our calculations indicate that CO coordination should occur prior to the ring closing step, which determines the regioselectivity. Through investigating the corresponding natural bond orbital (NBO) charges, we find that an electron withdrawing carbonyl group would decrease the electron density and lower the activation barrier. Therefore, the regioselectivity is dominated by the electronic effect. PMID- 28581009 TI - Decoding the anticancer activity of VO-clioquinol compound: the mechanism of action and cell death pathways in human osteosarcoma cells. AB - Vanadium compounds were studied in recent years by considering them as a representative of a new class of non-platinum metal anticancer drugs. However, a few challenges still remain in the discovery of new molecular targets of these new metallodrugs. Studies on cell signaling pathways related to vanadium compounds have scarcely been reported and so far this information is highly critical for identifying novel targets that play a key role in the antitumor actions of vanadium complexes. This research deals with the alterations in the intracellular signaling pathways promoted by an oxovanadium(iv) complex with the clioquinol (5-chloro-7-iodo-8-quinolinol), VO(CQ)2, on a human osteosarcoma cell line (MG-63). Herein are reported, for the first time, the antitumor properties of VO(CQ)2 and the relative abundance of 224 proteins (which are involved in most of the common intracellular pathways) to identify novel targets of the studied complex. Besides, full-length human recombinant AKT1 kinase was produced by using an IVTT system to evaluate the variation of relative tyrosin-phosphorylation levels caused by this compound. The results of the differential protein expression levels reveal several up-regulated proteins such as CASP3, CASP6, CASP7, CASP10, CASP11, Bcl-x, DAPK and down-regulated ones, such as PKB/AKT, DIABLO, among others. Moreover, cell signaling pathways involved in several altered pathways related to the PKC and AP2 family have been identified in both treatments (2.5 and 10 MUM) suggesting the crucial antitumoral role of VO(CQ)2. Finally, it has been demonstrated that this compound (10 MUM, 6 h) triggers a decrease of 2-fold in in situ AKT1 expression. PMID- 28581015 TI - Colloidal synthesis of silicon nanoparticles in molten salts. AB - Silicon nanoparticles are unique materials with applications in a variety of fields, from electronics to catalysis and biomedical uses. Despite technological advancements in nanofabrication, the development of a simple and inexpensive route for the synthesis of homogeneous silicon nanoparticles remains highly challenging. Herein, we describe a new, simple and inexpensive colloidal synthetic method for the preparation, under normal pressure and mild temperature conditions, of relatively homogeneous spherical silicon nanoparticles of either ca. 4 or 6 nm diameter. The key features of this method are the selection of a eutectic salt mixture as a solvent, the identification of appropriate silicon alkoxide precursors, and the unconventional use of alkali earth metals as shape controlling agents. PMID- 28581010 TI - Echinacoside ameliorates the memory impairment and cholinergic deficit induced by amyloid beta peptides via the inhibition of amyloid deposition and toxicology. AB - Echinacoside is a phenylethanoid glycoside and possesses neuroprotective activity in vitro and in vivo. This study investigates the role of the amyloid cascade and central neuronal function on the protective effects of echinacoside in amyloid beta peptide 1-42 (Abeta 1-42)-treated SH-SY5Y cells and an Abeta 1-42-infused rat. Echinacoside inhibited Abeta 1-42 oligomerization in vitro and restored the cell viability that was reduced by Abeta 1-42 in SH-SY5Y cells. Intracisternal infusion with Abeta 1-42 by an osmotic pump caused cognitive deficits, an increase in amyloid deposition and acetylcholinesterase activities, and a decrease in the brain's levels of acetylcholine and dopamine. Echinacoside reduced the cognitive deficits and amyloid deposition, and it reversed the cortical cholinergic dysfunction that was caused by Abeta 1-42 in rats. Echinacoside further reversed the memory impairment in the Morris water maze task caused by scopolamine in mice. Therefore, we suggest that echinacoside ameliorated cognitive dysfunction that was caused by Abeta 1-42 by blocking amyloid deposition via inhibiting amyloid oligomerization and reversing the cortical cholinergic neuronal function via decreasing amyloid neurotoxicity. PMID- 28581016 TI - The effect of gas-phase polycyclic aromatic hydrocarbons on the formation and properties of biogenic secondary organic aerosol particles. AB - When secondary organic aerosol (SOA) particles are formed by ozonolysis in the presence of gas-phase polycyclic aromatic hydrocarbons (PAHs), their formation and properties are significantly different from SOA particles formed without PAHs. For all SOA precursors and all PAHs, discussed in this study, the presence of the gas-phase PAHs during SOA formation significantly affects particle mass loadings, composition, growth, evaporation kinetics, and viscosity. SOA particles formed in the presence of PAHs have, as part of their compositions, trapped unreacted PAHs and products of heterogeneous reactions between PAHs and ozone. Compared to 'pure' SOA particles, these particles exhibit slower evaporation kinetics, have higher fractions of non-volatile components, like oligomers, and higher viscosities, assuring their longer atmospheric lifetimes. In turn, the increased viscosity and decreased volatility provide a shield that protects PAHs from chemical degradation and evaporation, allowing for the long-range transport of these toxic pollutants. The magnitude of the effect of PAHs on SOA formation is surprisingly large. The presence of PAHs during SOA formation increases mass loadings by factors of two to five, and particle number concentrations, in some cases, by more than a factor of 100. Increases in SOA mass, particle number concentrations, and lifetime have important implications to many atmospheric processes related to climate, weather, visibility, and human health, all of which relate to the interactions between biogenic SOA and anthropogenic PAHs. The synergistic relationship between SOA and PAHs presented here are clearly complex and call for future research to elucidate further the underlying processes and their exact atmospheric implications. PMID- 28581017 TI - Revisiting the genus Photobacterium: taxonomy, ecology and pathogenesis. AB - The genus Photobacterium, one of the eight genera included in the family Vibrionaceae, contains 27 species with valid names and it has received attention because of the bioluminescence and pathogenesis mechanisms that some of its species exhibit. However, the taxonomy and phylogeny of this genus are not completely elucidated; for example, P. logei and P. fischeri are now considered members of the genus Aliivibrio, and previously were included in the genus Vibrio. In addition, P. damselae subsp. piscicida was formed as a new combination for former Vibrio damsela and Pasteurella piscicida. Moreover, P. damselae subsp. damselae is an earlier heterotypic synonym of P. histaminum. To avoid these incovenences draft and complete genomic sequences of members of Photobacterium are increasingly becoming available and their use is now routine for many research laboratories to address diverse goals: species delineation with overall genomic indexes, phylogenetic analyses, comparative genomics, and phenotypic inference. The habitats and isolation source of the Photobacterium species include seawater, sea sediments, saline lake waters, and a variety of marine organisms with which the photobacteria establish different relationships, from symbiosis to pathogenic interactions. Several species of this genus contain bioluminescent strains in symbiosis with marine fish and cephalopods; in addition, other species enhance its growth at pressures above 1 atmosphere, by means of several high-pressure adaptation mechanisms and for this, they may be considered as piezophilic (former barophilic) bacteria. Until now, only P. jeanii, P. rosenbergii, P. sanctipauli, and the two subspecies of P. damselae have been reported as responsible agents of several pathologies on animal hosts, such as corals, sponges, fish and homeothermic animals. In this review we have revised and updated the taxonomy, ecology and pathogenicity of several members of this genus. [Int Microbiol 20(1): 1-10 (2017)]. PMID- 28581018 TI - Impact of pollution on the microbial diversity of a tropical river in an urbanized region of northeastern Brazil. AB - Rivers are important ecosystems that are integrated into biogeochemical cycles and constitute an essential resource for numerous human uses. However, the assessment of the biological diversity and composition of microbial communities found in rivers remains incomplete, partly due to methodological constraints which are only recently being resolved with the advent of next generation sequencing (NGS) techniques. Using 454-pyrosequencing of the 16S gene, the present study analyzed the microbial diversity of the planktonic and sediment populations in a tropical river in northeastern Brazil that is exposed to severe pollution. Six water and six sediment samples were analysed. The dominant bacterial phyla in both sediment and water were the Proteobacteria, followed by Bacteroidetes and Actinobacteria in the water column and by Chloroflexi and Acidobacteria in the sediment. Biological diversity appeared to be greatly decreased by environmental pollution, whereas the microbial community structure was variable across the analyzed transect. Moreover, a narrow relationship between industrial and urban sources of contamination and the bacterial genera detected at these sites has been observed. A variety of potentially pathogenic bacteria was detected, including Klebsiella, Treponema, Faecalibacterium and Enterococcus, indicating that the river might pose a substantial risk to public health. [Int Microbiol 20(1): 11-24 (2017)]. PMID- 28581019 TI - Identification by using MALDI-TOF mass spectrometry of lactic acid bacteria isolated from non-commercial yogurts in southern Anatolia, Turkey. AB - Yogurt is a dairy product obtained by bacterial fermentation of milk. Commercial yogurts are produced using standard starters while, in the production of non commercial yogurt, the microbiota is quite different since yogurts are used as starter for years. To determine the final characteristics of the fermented product it is necessary to know the biochemical properties of the starter cultures, such as acidity, aroma and flavor. This can only be achieved by identifying and characterizing the bacteria in starter cultures. In our study, 208 non-commercial yogurt samples were collected from 9 different locations in Anatolia, southern Turkey. Their pH and lactic acid bacteria profiles were analyzed. Isolated bacteria were identified by MALDI-TOF MS (matrix-assisted laser sesorption-ionization time-of-flight, mass spectrometry), which is a fast and reliable method for identification of bacterial isolates compared to classical laboratory methods. In this study, 41% of the isolates were identified by using this method, which is 99.9% and 34.0% confidence. The isolates contained two genera (Enterococcus and Lactobacillus) and four species. Afterwards, the four lactic acid bacteria were characterized physiologically and biochemically and we found that they differed from lactic acid bacteria used in commercial yogurt production. [Int Microbiol 20(1): 25-30 (2017)]. PMID- 28581020 TI - Insights into the fecal microbiota of captive Iberian lynx (Lynx pardinus). AB - The Iberian lynx (Lynx pardinus) is an endangered species restricted to several areas of Spain and Portugal. Its low genetic diversity likely provokes immune depression and high susceptibility to infectious diseases. The intestinal microbiota is closely related to host health and nutrition. In order to contribute to the knowledge of the Iberian lynx intestinal microbiota, fecal microbiota of captive specimens from two breeding centers ("La Olivilla" and "El Acebuche"), located in Southern Spain, were studied by Denaturing Gradient Gel Electrophoresis (DGGE). Results grouped microbiota in two main clusters (I and III) which included DGGE patterns of 19 out of 36 specimens, cluster I being the most frequent in "La Olivilla" (50%) and cluster III in "El Acebuche" (55.55 %) specimens. Bacteroidetes, Firmicutes and Proteobacteria phyla were identified. Segregation of clusters I and III was attributed to different microorganism presence (Pseudomonas koreensis, Pseudomonas migulae, Carnobacterium sp., Arthrobacter, Robinsoniella peorensis and Ornithinibacillus sp.) and ability to use different carbon sources. Biolog EcoPlates(r) results indicate high functional diversity of fecal microbiota, it being higher in cluster III. The great impact of intestinal microbiota on host health supports the importance of its microbial composition understanding. This study is the first report of captive Iberian lynx fecal microbiota composition. [Int Microbiol 20(1): 31-41 (2017)]. PMID- 28581021 TI - Antimicrobial peptide from Bacillus subtilis CSB138: characterization, killing kinetics, and synergistic potency. AB - We studied the prospect of synergy between the antimicrobial peptide p138c and non-peptide antibiotics for increasing the potency and bacterial killing kinetics of these agents. The production of p138c was maximized in the late exponential growth phase of Bacillus subtilis CSB138. Purification of p138c resulted in a total of 4800 arbitrary units (AU) with 19.15-fold and 3.2% recovery. Peptide p138c was thermo-tolerant up to 50 degrees C and stable at pH 5.8 to 11. The biochemical nature of p138c was determined by a bioassay, similar to tricine-SDS PAGE, indicating inhibition at 3 kDa. The amino acid sequence of p138c was Gly Leu-Glu-Glu-Thr-Val-Tyr-Ile-Tyr-Gly-Ala-Asn-Met-X-Ser. Potency and killing kinetics against vancomycin-resistant Staphylococcus aureus improved considerably when p138c was synergized with oxacillin, ampicillin, and penicillin G. The minimal inhibitory concentration (MIC) of p138c showed a 4-, 8-, and 16-fold improvement when p138c was combined with oxacillin, ampicillin, and penicillin G, respectively. The fractional inhibitory concentration index for the combination of p138c and oxacillin, ampicillin, and penicillin G was 0.3125, 0.25, and 0.09, respectively. Synergy with non-peptide antibiotics resulted in enhanced killing kinetics of p138c. Hence, the synergy between antimicrobial peptide and non peptide antibiotics may enhance the potency and bacterial killing kinetics, providing more potent and rapidly acting agents for therapeutic use. [Int Microbiol 20(1):43-53 (2017)]. PMID- 28581022 TI - A multi-method assessment of bone maintenance and loss in an Imperial Roman population: Implications for future studies of age-related bone loss in the past. AB - OBJECTIVES: One of the hallmarks of contemporary osteoporosis and bone loss is dramatically higher prevalence of loss and fragility in females post-menopause. In contrast, bioarchaeological studies of bone loss have found a greater diversity of age- and sex-related patterns of bone loss in past populations. We argue that the differing findings may relate to the fact that most studies use only a single methodology to quantify bone loss and do not account for the heterogeneity and complexity of bone maintenance across the skeleton and over the life course. METHODS: We test the hypothesis that bone mass and maintenance in trabecular bone sites versus cortical bone sites will show differing patterns of age-related bone loss, with cortical bone sites showing sex difference in bone loss that are similar to contemporary Western populations, and trabecular bone loss at earlier ages. We investigated this hypothesis in the Imperial Roman population of Velia using three methods: radiogrammetry of the second metacarpal (N = 71), bone histology of ribs (N = 70), and computerized tomography of trabecular bone architecture (N = 47). All three methods were used to explore sex and age differences in patterns of bone loss. RESULTS: The suite of methods utilized reveal differences in the timing of bone loss with age, but all methods found no statistically significant differences in age-related bone loss. DISCUSSION: We argue that a multi-method approach reduces the influence of confounding factors by building a reconstruction of bone turnover over the life cycle that a limited single-method project cannot provide. The implications of using multiple methods beyond studies of bone loss are also discussed. PMID- 28581023 TI - Effects of a daily three-meal pattern with different dietary protein contents on pig growth performance, carcass and muscle quality traits. AB - BACKGROUND: Recent research related to phase-feeding programmes for pig nutrition do not always account for the variation among individuals, and feeds are usually formulated to optimise the performance of the whole pig population. This study aimed at measuring the effects of a daily three-meal pattern with different dietary protein contents on pig growth performance, carcass and muscle quality traits. RESULTS: The results showed that compared with the 3C treatment, average daily gain (ADG) of pigs in the HCL treatment increased by 14.75% (P < 0.05) during period 1. The carcass weight (P = 0.006) and slaughter weight (P = 0.021) in the HCL group increased when compared with those in the 3C and LCH treatments. Moreover, the LCH feeding sequences contributed to reduce the drip loss in longissimus dorsi (LD) muscle (P < 0.05) when compared with the 3C treatment. The HCL or LCH feeding sequence contributed to increase the meat quality when compared with those receiving the 3C treatment. CONCLUSION: Collectively, our results indicate that feeding high protein meal in the morning and a gradual reduction of the protein content in meals over the day may improve muscle quality characteristics, maximise performance, and reduce the pig feed cost. (c) 2017 Society of Chemical Industry. PMID- 28581024 TI - Blomia tropicalis allergen 5 (Blo t 5) T-cell epitopes and their ability to suppress the allergic immune response. AB - Blomia tropicalis is the major asthma allergen in the tropics comparable to Dermatophagoides pteronyssinus. However, little is known about the B. tropicalis epitopes recognized by T cells. Our aim was to identify the T-cell epitopes in the major B. tropicalis allergen, Blo t 5, and investigate the potential of the corresponding peptides to inhibit the allergic inflammatory lung response. C57BL/6 mice were immunized with plasmid DNA encoding Blo t 5 and T-cell epitopes identified using the interferon-gamma ELISPOT assay with 15-mer overlapping peptides. C57BL/6 mice were sensitized with bone-marrow-derived dendritic cells (BMDC) pulsed with Blo t 5 allergen followed by intranasal Blo t 5 challenge. Two H-2b restricted epitopes (Bt576-90 and Bt5106-115 ) were recognized by CD4 T cells specific for Blo t 5, but no CD8 epitopes were identified. In mice sensitized with Blo t 5-pulsed BMDC and challenged with intranasal Blo t 5 Bt576 90 and Bt5106-115 , peptide-specific CD4 T cells were found to secrete the T helper type 2 cytokines interleukin-5 and interleukin-13. Intradermal administration of synthetic peptides encoding the identified T-cell epitopes suppressed allergic airway inflammation to further allergen challenges. Hence, we have identified novel CD4 T-cell epitopes specific for Blo t 5 and demonstrated that these peptides could be employed therapeutically to suppress the T-cell response in a murine model of allergic airway inflammation. PMID- 28581026 TI - Cross-sectional association between testosterone, sex hormone-binding globulin and metabolic syndrome: The Healthy Twin Study. AB - OBJECTIVES: This study evaluated an association between testosterone, sex hormone binding globulin (SHBG) and metabolic syndrome (MetS).We also evaluated the genetic and environmental influences on the association. DESIGN: Cross-sectional. SETTING: Community-based study. PARTICIPANTS: A total of 1098 Korean adult men including 139 monozygotic twin pairs. MAIN OUTCOME MEASURE: MetS was defined using the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP ATP III) and International Diabetes Federation (IDF) criteria. The associations between MetS and sex hormones were evaluated using linear mixed model and generalized estimating equation model. RESULTS: After considering covariates such as smoking, alcohol consumption and physical exercises as well as SHBG or testosterone, the risk of MetS defined by NCEP ATP III criteria decreased by 31%, 29%, and 48%, respectively, with 1-standard deviation increase in total testosterone (TT), free testosterone (cFT) and SHBG. Similar findings were revealed with IDF criteria. Metabolic component specific analysis showed that sex hormones were inversely associated with several components of MetS: TT with abdominal obesity, low high-density lipoprotein cholesterol (HDL-C) and high blood pressure; cFT with abdominal obesity and high blood pressure; SHBG with all components except high blood pressure. Cotwin control analysis found an inverse correlation between within-pair differences in testosterone and SHBG levels and within-pair differences in waist circumference only. CONCLUSION: Both testosterone and SHBG were inversely associated with MetS although the inverse associations with the sex hormones were not consistently found across individual metabolic components. Findings from cotwin analysis suggest a significant contribution of unshared unique environmental effect to the association between testosterone and SHBG and abdominal obesity. PMID- 28581025 TI - Clinical Characteristics and Treatment Patterns Among Patients Diagnosed With Cluster Headache in U.S. Healthcare Claims Data. AB - OBJECTIVE: To characterize demographics, clinical characteristics, and treatment patterns of patients with cluster headache (CH). BACKGROUND: CH is an uncommon trigeminal autonomic cephalalgia with limited evidence-based treatment options. Patients suffer from extremely painful unilateral headache attacks and autonomic symptoms with episodic and chronic cycles. DESIGN/METHODS: This retrospective analysis used insurance claims from Truven Health Analytics MarketScan(r) research databases from 2009 to 2014. Two cohorts were compared: CH patients (with >=2 CH claims) were propensity score matched with 4 non-headache controls, all with continuous enrollment for 12 months before and after the date of first CH claim or matched period among controls. RESULTS: CH patients (N = 7589) were mainly male (57.4%) and 35-64 years old (73.2%), with significantly more claims for comorbid conditions vs controls (N = 30,341), including depressive disorders (19.8% vs 10.0%), sleep disturbances (19.7% vs 9.1%), anxiety disorders (19.2% vs 8.7%), and tobacco use disorders (12.8% vs 5.3%), with 2.5 times greater odds of suicidal ideation (all P < .0001). Odds of drug dependence were 3-fold greater among CH patients (OR = 2.8 [95% CI 2.3-3.4, P < .0001]). CH patients reported significantly greater use of prescription medications compared with controls; 25% of CH patients had >12 unique prescription drug claims. Most commonly prescribed drug classes for CH patients included: opiate agonists (41%), corticosteroids (34%), 5HT-1 agonists (32%), antidepressants (31%), NSAIDs (29%), anticonvulsants (28%), calcium antagonists (27%), and benzodiazepines (22%). Only 30.4% of CH patients received recognized CH treatments without opioids during the 12-month post-index period. These patients were less likely to visit emergency departments or need hospitalizations (26.8%) as compared to CH patients with no pharmacy claims for recognized CH treatments or opioids (33.6%; P < .0001). CONCLUSIONS: The burden of CH is associated with significant co-morbidity, including substance use disorders and suicidal ideation, and treatment patterns indicating low use of recognized CH treatments. PMID- 28581027 TI - Evolutionary conservation and conversion of Foxg1 function in brain development. AB - Among the forkhead box protein family, Foxg1 is a unique transcription factor that plays pleiotropic and non-redundant roles in vertebrate brain development. The emergence of the telencephalon at the rostral end of the neural tube and its subsequent expansion that is mediated by Foxg1 was a key reason for the vertebrate brain to acquire higher order information processing, where Foxg1 is repetitively used in the sequential events of telencephalic development to control multi-steps of brain circuit formation ranging from cell cycle control to neuronal differentiation in a clade- and species-specific manner. The objective of this review is to discuss how the evolutionary changes in cis- and trans regulatory network that is mediated by a single transcription factor has contributed to determining the fundamental vertebrate brain structure and its divergent roles in instructing species-specific neuronal circuitry and functional specialization. PMID- 28581028 TI - Measuring the Value of Pharmacogenomics Evidence. AB - In recent years, there is a growing need to measure the value of pharmacogenomics testing so that policymakers are well informed to decide about adopting and reimbursing pharmacogenomics testing, prioritizing pharmacogenomics research and development, and encouraging the application of companion diagnostics. Presently, there are limited economic evaluation studies of genome-guided treatment modalities that would allow decision-makers to comparatively assess the value and clinical utility of such interventions. PMID- 28581029 TI - Carbohydrate metabolism in the subtending leaf cross-acclimates to waterlogging and elevated temperature stress and influences boll biomass in cotton (Gossypium hirsutum). AB - Short-term waterlogging and chronic elevated temperature occur concomitantly in the cotton (Gossypium hirsutum) growing season. While previous research about co occurring waterlogging and elevated temperature has focused primarily on cotton fiber, no studies have investigated carbohydrate metabolism of the subtending leaf (a major source leaf for boll development) cross-acclimation to aforementioned stressors. To address this, plants were exposed to ambient (31.6/26.5 degrees C) and elevated (34.1/29.0 degrees C) temperatures during the whole flowering and boll formation stage, and waterlogging (0, 3, 6 days) beginning on the day of anthesis. Both waterlogging and high temperature limited boll biomass (reduced by 1.19-32.14%), but effects of different durations of waterlogging coupled with elevated temperature on carbohydrate metabolism in the subtending leaf were quite different. The 6-day waterlogging combined with elevated temperature had the most negative impact on net photosynthetic rate (Pn) and carbohydrate metabolism of any treatment, leading to upregulated GhSusA and GhSusC expression and enhanced sucrose synthase (SuSy, EC 2.4.1.13) activity for sucrose degradation. A prior exposure to waterlogging for 3 days improved subtending leaf performance under elevated temperature. Pn, sucrose concentrations, Rubisco (EC 4.1.1.39) activity, and cytosolic fructose-1,6 bisphosphatase (cy-FBPase, EC 3.1.3.11) activity in the subtending leaf significantly increased, while SuSy activity decreased under 3 days waterlogging and elevated temperature combined relative to elevated temperature alone. Thus, we concluded that previous exposure to a brief (3 days) waterlogging stress improved sucrose composition and accumulation cross-acclimation to high temperature later in development not only by promoting leaf photosynthesis but also inhibiting sucrose degradation. PMID- 28581031 TI - In reference to Laboratory assessment of sudden sensorineural hearing loss: A case-control study. PMID- 28581030 TI - Postoperative anticoagulation after free flap reconstruction for head and neck cancer: A systematic review. AB - OBJECTIVE: Postoperative use of anticoagulation after free tissue transfer in head and neck ablative procedures is common practice, but a clear protocol has not been well established. The outcome measures including total flap failure, thrombosis, and hematoma formation for different anticoagulation regimens in free tissue transfer in the head and neck were reviewed. DATA SOURCES: PubMed, Ovid, and Cochrane databases were examined for patients who underwent free tissue transfer following head and neck ablative procedures. REVIEW METHODS: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were utilized to identify English-language studies reporting anticoagulation regimens following free tissue transfer in head and neck ablative procedures. Outcomes included total flap failure, thrombosis, and hematoma formation. Two independent reviewers assessed the quality of the articles by using the Methodological Index for Non Randomized Studies. RESULTS: A total of 368 articles were identified. An additional 36 articles were identified through screening of reference lists. Twenty-one of these studies met final inclusion criteria for qualitative analysis. Outcome data on total flap failure, thrombosis, and hematoma formation were extracted and analyzed for comparison against all anticoagulation regimens. Total flap failure, thrombosis, and hematoma formation rates were 4.4%, 4.5%, and 2.2%, respectively. Individual study rates ranged from 0.0% to 10.7%, 0.0% to 10.4%, and 0.6% to 7.2%, respectively. CONCLUSIONS: There is not adequate evidence to develop a standardized anticoagulation protocol for head and neck free flap procedures. Comparable flap complications were reported between all the employed anticoagulation methods studied, though significant variability in study design among articles existed. Prospective, randomized studies are warranted to determine the optimal postoperative anticoagulation regimen following free tissue transfer of the head and neck. Laryngoscope, 128:412-421, 2018. PMID- 28581032 TI - Pre-emptive rituximab for Epstein-Barr virus reactivation after haplo hematopoietic stem cell transplantation. AB - BACKGROUND: Epstein-Barr virus-related post-transplantation lymphoproliferative disease (EBV-PTLD) is a serious complication in hematopoietic stem cell transplantation (HSCT) recipients. METHODS: We conducted a retrospective study to investigate the incidence and potential risk factors for EBV reactivation and to assess the efficacy of the management of EBV reactivation with pre-emptive rituximab in children who had T-cell-replete haploidentical HSCT (TCR-haplo-SCT) with low-dose anti-thymocyte globulin (ATG). EBV-DNA level in peripheral blood (PB) was measured when suspected EBV reactivation were observed. When the EBV-DNA level in PB increased to >1,000 copies/106 peripheral blood mononuclear cells (PBMC), patients were pre-emptively treated with rituximab (375 mg/m2 /dose). RESULTS: A total of 19 (50%) of 38 patients received rituximab infusion at a median time of 56 days after HSCT (range, 17-270 days). The median viral load at initiation of therapy was 2,900 copies/106 PBMC (range, 1,000-650 000). Pre emptive therapy was started after a median of 2 days (range, 0-7 days). The median number of weekly treatment cycles was 2 (range, 1-3). None of the patients developed PTLD or other EBV-associated diseases. CONCLUSION: Pre-emptive rituximab therapy could be a useful strategy for EBV-PTLD in TCR-haplo-SCT recipients with low-dose ATG. PMID- 28581033 TI - Life and death of proteins after protease cleavage: protein degradation by the N end rule pathway. AB - : Contents Summary 929 I. INTRODUCTION: conservation and diversity of N-end rule pathways 929 II. Defensive functions of the N-end rule pathway in plants 930 III. Proteases and degradation by the N-end rule pathway 930 IV. New proteomics approaches for the identification of N-end rule substrates 932 V. Concluding remarks 932 Acknowledgements 934 References 934 SUMMARY: The N-end rule relates the stability of a protein to the identity of its N-terminal residue and some of its modifications. Since its discovery in the 1980s, the repertoire of N-terminal degradation signals has expanded, leading to a diversity of N-end rule pathways. Although some of these newly discovered N-end rule pathways remain largely unexplored in plants, recent discoveries have highlighted roles of N-end rule mediated protein degradation in plant defense against pathogens and in cell proliferation during organ growth. Despite this progress, a bottleneck remains the proteome-wide identification of N-end rule substrates due to the prerequisite for endoproteolytic cleavage and technical limitations. Here, we discuss the recent diversification of N-end rule pathways and their newly discovered functions in plant defenses, stressing the role of proteases. We expect that novel proteomics techniques (N-terminomics) will be essential for substrate identification. We review these methods, their limitations and future developments. PMID- 28581034 TI - The Clinical Features, Risk Factors, and Surgical Treatment of Cervicogenic Headache in Patients With Cervical Spine Disorders Requiring Surgery. AB - OBJECTIVE: To clarify the clinical features and risk factors of cervicogenic headache (CEH; as diagnosed according to the International Classification of Headache Disorders-Third Edition beta) in patients with cervical spine disorders requiring surgery. BACKGROUND: CEH is caused by cervical spine disorders. The pathogenic mechanism of CEH is hypothesized to involve a convergence of the upper cervical afferents from the C1, C2, and C3 spinal nerves and the trigeminal afferents in the trigeminocervical nucleus of the upper cervical cord. According to this hypothesis, functional convergence of the upper cervical and trigeminal sensory pathways allows the bidirectional (afferent and efferent) referral of pain to the occipital, frontal, temporal, and/or orbital regions. Previous prospective studies have reported an 86-88% prevalence of headache in patients with cervical myelopathy or radiculopathy requiring anterior cervical surgery; however, these studies did not diagnose headache according to the International Classification of Headache Disorders criteria. Therefore, a better understanding of the prevalence rate, clinical features, risk factors, and treatment responsiveness of CEH in patients with cervical spine disorders requiring surgery is necessary. METHODS: We performed a single hospital-based prospective cross sectional study and enrolled 70 consecutive patients with cervical spine disorders such as cervical spondylotic myelopathy, ossification of the posterior longitudinal ligament, cervical spondylotic radiculopathy, and cervical spondylotic myeloradiculopathy who had been scheduled to undergo anterior cervical fusion or dorsal cervical laminoplasty between June 2014 and December 2015. Headache was diagnosed preoperatively according to the International Classification of Headache Disorders-Third Edition beta. The Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire, Neck Disability Index, and a 0-100 mm visual analog scale (VAS) were used to evaluate clinical features, and scores were compared between baseline (ie, preoperatively) and 3, 6, and 12 months post-surgery. RESULTS: The prevalence of CEH in our population was 15/70 (21.4%, 95%CI: 11.8% to 31.0%). The main clinical features were dull and tightening/pressing headache sensations in the occipital region. Headache severity was mild (VAS, 32 +/- 11 mm) and only one patient reported use of an oral analgesic. Compared to patients without CEH, patients with CEH had higher frequencies of neck pain (86.7% vs. 50.9%; P = .017), cervical range of motion limitation (ROM) (66.7% vs. 38.2%; P = .049), and higher Neck Disability Index scores (14 vs. 3; P < .001). Among the different cervical spine disorders, the prevalence of CEH was highest in cervical spondylotic myeloradiculopathy patients (60%), being <= 20% for all other disorders. Surgical treatments including cervical laminoplasty to relieve abnormal pressure on the spinal cord via a posterior approach, were associated with initial improvements in headache VAS that slightly diminished by 12 months post-surgery (P < .001). CONCLUSIONS: We report a lower prevalence of CEH in patients with cervical spinal disorders requiring surgery than that reported previously. The main clinical features of CEH were mild, dull, and tightening/pressing headache sensations in the occipital region. Potential risk factors for CEH included neck pain, limited cervical ROM, high Neck Disability Index score, and a diagnosis of cervical spondylotic myeloradiculopathy. The further accumulation of patients in a multi-institutional study may be required in order to discuss the diagnostic criteria and pathophysiology of this condition. PMID- 28581035 TI - Effective doses and standardised risk factors from paediatric diagnostic medical radiation exposures: Information for radiation risk communication. AB - INTRODUCTION: In the paediatric medical radiation setting, there is no consistency on the radiation risk information conveyed to the consumer (patient/carer). Each communicator may convey different information about the level of risk for the same radiation procedure, leaving the consumer confused and frustrated. There is a need to standardise risks resulting from medical radiation exposures. In this study, paediatric radiographic, fluoroscopic, CT and nuclear medicine examination data have been analysed to provide (i) effective doses and radiation induced cancer risk factors from common radiological and nuclear medicine diagnostic procedures in standardised formats, (ii) awareness of the difficulties that may be encountered in communicating risks to the layperson, and (iii) an overview of the deleterious effects of ionising radiation so that the risk communicator can convey with confidence the risks resulting from medical radiation exposures. METHODS: Paediatric patient dose data from general radiographic, computed tomography, fluoroscopic and nuclear medicine databases have been analysed in age groups 0 to <5 years, 5 to <10 years, 10 to <15 years and 15 to <18 years to determine standardised risk factors. RESULTS: Mean, minimum and maximum effective doses and the corresponding mean lifetime risks for general radiographic, fluoroscopic, CT and nuclear medicine examinations for different age groups have been calculated. For all examinations, the mean lifetime cancer induction risk is provided in three formats: statistical, fraction and category. CONCLUSION: Standardised risk factors for different radiological and nuclear medicine examinations and an overview of the deleterious effects of ionising radiation and the difficulties encountered in communicating the risks should facilitate risk communication to the patient/carer. PMID- 28581037 TI - Risk Perception and Risk Talk: The Case of the Fukushima Daiichi Nuclear Radiation Risk. AB - Individuals' perceptions and their interpersonal communication about a risk event, or risk talk, can play a significant role in the formation of societal responses to the risk event. As they formulate their risk opinions and speak to others, risk information can circulate through their social networks and contribute to the construction of their risk information environment. In the present study, Japanese citizens' risk perception and risk talk were examined in the context of the Fukushima Daiichi nuclear radiation risk. We hypothesized and found that the risk information environment and risk literacy (i.e., competencies to understand and use risk information) interact to influence their risk perception and risk talk. In particular, risk literacy tends to stabilize people's risk perceptions and their risk communications. Nevertheless, there were some subtle differences between risk perception and communication, suggesting the importance of further examination of interpersonal risk communication and its role in the societal responses to risk events. PMID- 28581036 TI - Opi1p translocation to the nucleus is regulated by hydrogen peroxide in Saccharomyces cerevisiae. AB - During exposure of yeast cells to low levels of hydrogen peroxide (H2 O2 ), the expression of several genes is regulated for cells to adapt to the surrounding oxidative environment. Such adaptation involves modification of plasma membrane lipid composition, reorganization of ergosterol-rich microdomains and altered gene expression of proteins involved in lipid and vesicle traffic, to decrease permeability to exogenous H2 O2 . Opi1p is a transcriptional repressor that is inactive when present at the nuclear membrane/endoplasmic reticulum, but represseses transcription of inositol upstream activating sequence (UASINO ) containing genes, many of which are involved in the synthesis of phospholipids and fatty acids, when it is translocated to the nucleus. We investigated whether H2 O2 in concentrations inducing adaptation regulates Opi1p function. We found that, in the presence of H2 O2 , GFP-Opi1p fusion protein translocates to the nucleus and, concomitantly, the expression of UASINO -containing genes is affected. We also investigated whether cysteine residues of Opi1p were implicated in the H2 O2 -mediated translocation of this protein to the nucleus and identified cysteine residue 159 as essential for this process. Our work shows that Opi1p is redox-regulated and establishes a new mechanism of gene regulation involving Opi1p, which is important for adaptation to H2 O2 in yeast cells. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28581038 TI - Syringe-to-syringe dispersive liquid-phase microextraction solidified floating organic drop combined with high-performance liquid chromatography for the separation and quantification of ochratoxin A in food samples. AB - A new, simple, and rapid syringe-to-syringe dispersive liquid-phase microextraction with solidified floating organic drop was used for the separation and preconcentration of ochratoxin A from grain and juice samples before its quantification using high-performance liquid chromatography and fluorescence detection. Factors influencing the microextraction efficiency of ochratoxin A, such as sample solution pH, type and volume of organic extractant, salt concentration, number of injections, and volume of the sample, were studied and optimized. Under the optimum properties, the calibration graph showed linearity in the range of 65.0-700.0 ng/L (coefficient of determination = 0.9991). The limit of detection was 20.0 ng/L. The inter-day and intra-day relative standard deviations were in the range of 5.0-8.5%. This method was successfully applied for the quantification of ochratoxin A in grain and juice samples. PMID- 28581039 TI - Efficacy of cytapheresis for remission induction and dermatological manifestations of ulcerative colitis. AB - BACKGROUND: In ulcerative colitis (UC) patients, cytapheresis depletes elevated and activated leucocytes, which are known to release inflammatory cytokines including tumor necrosis factor (TNF)-alpha. Further, there are UC patients who develop erythema nodosum (EN) or pyoderma gangrenosum (PG) as extra-intestinal manifestations of UC. METHODS: Between 2008 and 2015, 181 consecutive patients with active UC received cytapheresis with either a granulocyte and monocyte apheresis (GMA) column or with a leucocyte removal filter (LCAP) as remission induction therapy. Each patient received weekly or intensive (2-3 sessions/week) cytapheresis up to 10 sessions. In 13 patients, UC was complicated by EN or PG. Lichtiger's clinical activity index (CAI) <=4 meant remission, while >=3 decrease in CAI meant response to therapy. Prednisolone sparing and the changes in the extra-intestinal manifestations were factored for assessing treatment efficacy. RESULTS: The overall remission and response rates were 52.5% and 71.8%, respectively, CAI fell from 9.4 +/- 3.3 to 4.9 +/- 3.5 (P < 0.001). The efficacy rates in subgroups on concomitant corticosteroid, anti-TNF or tacrolimus, and those without concomitant medications were not significantly different (P > 0.05). However, in 84 patients on prednisolone, the average daily prednisolone dose was reduced from 18.15 to 12.43 mg/day (P < 0.001) with 21.7% being corticosteroid free. All patients with EN or PG showed favorable response to cytapheresis, notably 2 EN patients achieving remission after just 2 cytapheresis sessions without concomitant medication. CONCLUSIONS: In this retrospective efficacy evaluation, cytapheresis was effective as remission induction therapy with steroid sparing effect and desirable safety profile. Further, patients with EN or PG responded favorably to cytapheresis. PMID- 28581040 TI - Coaxial flow-gating interface for capillary electrophoresis. AB - A coaxial flow-gating interface is described in which the separation capillary passes through the sampling capillary. Continuous flow of the sample solution flowing out of the sampling capillary is directed away from the injection end of the separation capillary by counter-current flow of the gating solution. During the injection, the flow of the gating solution is interrupted, so that a plug of solution is formed at the inlet into the separation capillary, from which the sample is hydrodynamically injected. Flow-gating interfaces are originally designed for on-line connection of capillary electrophoresis with analytical flow through methods. The basic properties of the described coaxial flow-gating interface were obtained in a simplified arrangement in which a syringe pump with sample solution has substituted analytical flow-through method. Under the optimized conditions, the properties of the tested interface were determined by separation of K+ , Ba2+ , Na+ , Mg2+ and Li+ ions in aqueous solution at equimolar concentrations of 50 MUM. The repeatability of the migration times and peak areas evaluated for K+ , Ba2+ and Li+ ions and expressed as relative standard deviation did not exceed 1.4%. The interface was used to determine lithium in mineral water and taurine in an energy drink. PMID- 28581041 TI - GENETIC VARIABILITY OF THE FACE FLY, MUSCA AUTUMNALIS DE GEER, IN RELATION TO A POPULATION BOTTLENECK. PMID- 28581043 TI - THEODOSIUS DOBZHANSKY PRIZE AWARDED. PMID- 28581042 TI - PARASEXUALITY AND MICROEVOLUTION IN EXPERIMENTAL POPULATIONS OF BACILLUS SUBTILIS. PMID- 28581044 TI - SEX RATIO CONSTANCY IN THE RED-WINGED BLACKBIRD. PMID- 28581045 TI - PREDATION PRESSURE AND GASTROPOD FORAGING: A TROPICAL-TEMPERATE COMPARISON. PMID- 28581046 TI - DISRUPTIVE SELECTION AND ASSORTATIVE MATING IN TRIBOLIUM CASTANEUM. PMID- 28581047 TI - DROSOPHILA HETERONEURA AND DROSOPHILA SILVESTRIS: HEAD SHAPES, BEHAVIOR AND EVOLUTION. PMID- 28581048 TI - "GRANDFATHER EFFECTS": THE GENETICS OF INTERPOPULATION DIFFERENCES IN OFFSPRING SIZE IN THE MOSQUITO FISH. PMID- 28581049 TI - ERRATA. PMID- 28581050 TI - PHENOLOGICAL RELATIONSHIPS OF MODEL AND MIMIC SALAMANDERS. PMID- 28581051 TI - MICROSPATIAL GENETIC HETEROGENEITY IN POCKET GOPHERS: NON-RANDOM BREEDING AND DRIFT. PMID- 28581052 TI - COURTSHIP BEHAVIOR AND CONTROL OF REPRODUCTIVE ISOLATION BETWEEN DROSOPHILA MOJAVENSIS AND DROSOPHILA ARIZONENSIS. PMID- 28581053 TI - EVOLUTION OF SEX RATIO IN STRUCTURED DEMES. PMID- 28581055 TI - CORRELATION BETWEEN SUBCELLULAR LOCATION AND PHOSPHOGLUCOSE ISOMERASE VARIABILITY. PMID- 28581054 TI - EVIDENCE FOR THE EVOLUTION OF COMPETITION BETWEEN TWO SPECIES OF ANNUAL PLANTS. PMID- 28581056 TI - POPULATIONAL HERITABILITY. PMID- 28581058 TI - Society for the Study of Evolution and American Society of Naturalists 1982 Meetings. PMID- 28581057 TI - POLLEN-OVULE RATIO, POLLEN SIZE, AND THE RATIO OF STIGMATIC AREA TO THE POLLEN BEARING AREA OF THE POLLINATOR: AN HYPOTHESIS. PMID- 28581059 TI - A CHROMOSOMAL CLINE IN THE GRASSHOPPER PODISMA PEDESTRIS. PMID- 28581060 TI - EFFECT OF INBREEDING ON THE EVOLUTION OF ALTRUISTIC BEHAVIOR BY KIN SELECTION. PMID- 28581061 TI - SELECTION PRESSURES AFFECTING MALE NUTRIENT INVESTMENT AT MATING IN HELICONIINE BUTTERFLIES. PMID- 28581062 TI - Dental evidence for wild tuber processing among Titicaca Basin foragers 7000 ybp. AB - OBJECTIVES: The objective of this work is to characterize dental wear in a skeletal sample dating to the Middle/Late Archaic period transition (8,000-6,700 cal. B.P.) from the Lake Titicaca Basin, Peru to better define subsistence behaviors of foragers prior to incipient sedentism and food production. MATERIALS AND METHODS: The dental sample consists of 251 teeth from 11 individuals recovered from the site of Soro Mik'aya Patjxa (SMP), the earliest securely dated burial assemblage in the Lake Titicaca Basin and the only burial assemblage in the region from an unequivocal forager context. Occlusal surface wear was quantified according to Smith (1984) and Scott (1979a) to characterize diversity within the site and to facilitate comparison with other foraging groups worldwide. General linear modeling was used to assess observation error and principal axis analysis was used to compare molar wear rates and angles. Teeth were also examined for caries and specialized wear. RESULTS: Occlusal surface attrition is generally heavy across the dental arcade and tends to be flat among posterior teeth. Only one carious lesion was observed. Five of the 11 individuals exhibit lingual surface attrition of the maxillary anterior teeth (LSAMAT). DISCUSSION: Tooth wear rates, molar wear plane, and caries rates are consistent with terrestrial foraging and a diverse diet. The presence of LSAMAT indicates tuber processing. The results therefore contribute critical new data toward our understanding of forager diet in the Altiplano prior to plant and animal domestication in the south-central Andes. PMID- 28581063 TI - Clinical grading of Reinke's edema. AB - OBJECTIVE: Reinke's edema (RE) is a pathologically benign structural change of the vocal folds with a wide spectrum of clinical severity. We aim to propose and validate a clinical grading system based on size of the lesion to facilitate effective universal communication of disease severity. STUDY DESIGN: Retrospective review. METHODS: Patients diagnosed with RE exclusive of other glottic pathology between December 2010 and December 2014 were included. Sixty laryngoscopy photographs were extracted from recorded archived laryngeal videostroboscopy exams, blinded and graded by four laryngologists with experience diagnosing RE. RESULTS: A high degree of agreement among all four raters was demonstrated by high interclass correlation coefficients with a 95% confidence interval. Similarly, high intra-rater reliability was seen across all raters. Forty-nine (33%) lesions were grade 1. Thirty-five lesions (29.17%) were grade 2; 18 (15%) lesions were grade 3; and nine (7.5%) lesions were grade 4. Contralateral vocal fold was not graded in cases of grade 4. CONCLUSION: This clinical grading for RE is a reliable tool for conveying severity of disease. High inter- and intra-rater reliability strongly suggest that RE similarly can be graded by different raters, and that a single rater is expected to grade RE similarly at different times. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2310-2313, 2017. PMID- 28581064 TI - Effect of transglutaminase on quality and gel properties of pork and fish mince mixtures. AB - : Transglutaminase (TGase) is widely applied in the meat industry, and mixing of meat from various sources is an efficient way to enhance the quality of meat products. In this study, sensory scores, color, gel properties, water holding capacity and microstructure of mince mixtures, treated with 0.4% TGase, were determined to investigate the effect of TGase and mixing ratios (pork/fish, 10:0, 7:3, 5:5, 3:7, 0:10) on quality and gel properties of mince mixtures composed of pork and silver carp (Hypophthalmichthys molitrix). Results indicated that the mixture improved the sensory quality and gel properties of meat products compared to control group. The addition of TGase significantly (p < .05) increased the gel strength, especially at 7:3 ratio of pork and silver carp, in which gel strength reached its maximum and was 10.26%, 64.15% greater than pork with TGase and without TGase respectively, and water holding capacity were greater, and microstructure became more compact. The results suggest the synergetic interaction between proteins of pork and silver carp. TGase increased the interaction, especially for mixing proportion of 7:3 (pork/fish). Those results could be useful for the development of mixed and new meat products in the food industry. PRACTICAL APPLICATIONS: Pork and silver carp are two main meat in diet, and mince mixtures can improve the nutrition of meat product. TGase is usually used to enhance the texture and gel properties of meat in industry. The addition of TGase in pork/fish mince mixtures can not only improve the texture, but catalyze the synergetic interaction between proteins from different meat and further enhance gel properties of mice mixtures in a certain ratio. All of that will provide reference for meat processing and development of new meat product. PMID- 28581065 TI - Physical and sensory properties of gelatin from seabass (Lates calcarifer) as affected by agar and kappa-carrageenan. AB - : Physical and sensory properties of gelatin from skin and swim bladder of seabass (SK and SW, respectively) as affected by agar or kappa-carrageenan at 10 and 20% substitution were investigated. Hardness of both SK and SW gels containing agar increased with increasing level of agar. However, the addition of kappa-carrageenan lowered hardness of mixed gels. Springiness and cohesiveness of either SK or SW gels decreased as the level of both agar or kappa-carrageenan increased. Gelling and melting temperatures generally increased when the level of hydrocolloids was increased. The highest gelling (~36C) and melting temperatures (~43C) were obtained for SK added with 20% agar and 20% kappa-carrageenan, respectively. However, the addition of both hydrocolloids at 10% affected gel microstructure differently. Furthermore, the addition of agar at 10% could increase the likeness score of sensory properties of gelatin gel. Therefore, the addition of hydrocolloids with appropriate level could improve the texture and sensory properties of gelatin from seabass. PRACTICAL APPLICATIONS: Due to the poor gelling property of fish gelatin, compared to its mammalian counterpart, improvement of this property using the selected hydrocolloids can be a promising means. In this work, it was found that agar or kappa-carrageenan can be incorporated to fish gelatin to improve gelling, textural and sensory properties of gelatin from skin of seabass (Lates calcarifer). Both agar and kappa carrageenan could increase gelling and melting temperatures of seabass gelatin. The incorporation of hydrocolloids (agar and kappa-carrageenan) could also improve the quality of fish gelatin gel, which in turn can widen the applications of fish gelatin in the food and other industries. PMID- 28581066 TI - The pregnant urologist. AB - Female urologists represent an ever-increasing percentage of the work force; more and more of our colleagues will be working through pregnancy. There is a lack of clear and concise advice for pregnant urologists about occupational risks during pregnancy. Urology exposes expectant mothers to potential risks from radiation, teratogenic and cytotoxic drugs, iodine hand scrub, infections, and long working hours. We aim to provide a review of the current evidence and guidance to aid expectant mothers in their decision making. Relevant research articles and up-to date guidance were reviewed. The millisevert (the average accumulated background radiation dose to an individual for 1 year, exclusive of radon) was used as the main unit of radiation dose. There is no published evidence to date in pregnant clinicians that shows a received radiation dose of more than the recommended dose for a pregnant lady, and no data showing an increased risk of foetal abnormalities in clinicians who continue to screen during pregnancy; however, the data are from small studies. There is strong advice suggesting avoidance of contact with crushed or broken 5alpha-reductase inhibitor tablets (finasteride and dutasteride), mitomycin and other cytotoxic drugs during pregnancy. Pregnant surgeons should avoid frequent use of iodine hand wash. Good hygiene precautions will protect from many infections along with up-to-date immunisations and use of personal protective equipment for certain cases. PMID- 28581068 TI - MALE HYBRID STERILITY IN DROSOPHILA: INTERACTIONS BETWEEN AUTOSOMES AND SEX CHROMOSOMES IN CROSSES OF D. MOJAVENSIS AND D. ARIZONENSIS. AB - By backcrossing hybrids from the cross Drosophila mojavensis female * Drosophila arizonensis male to both parental species we show that several interspecific combinations of autosomes with one or the other sex chromosome (X or Y) result in sperm abnormalities. Two of these incompatibilities will cause the same type of nonreciprocal F1 male sterility that is observed in this pair of species, but the possibility of an additional incompatibility that would have the same result, e.g., an incompatibility between the mojavensis Y and the arizonensis X chromosomes, cannot be excluded. The incompatibility between the arizonensis Y chromosome and the mojavensis fourth chromosome found to occur for all tested populations of mojavensis race B (Vigneault and Zouros, 1986) is shown also to occur for race A of this species. We further show that a dominance relationship exists between heterospecific homologous autosomes in their interactions with the sex chromosomes and that the direction of the dominance depends on whether the sex chromosome is the X or the Y. The present role of these incompatibilities in preventing gene flow between the two species may be minor, but their genetic basis and mode of action may provide useful insights about the genetic events that have played a significant role in earlier stages of speciation. PMID- 28581069 TI - HYBRIDIZATION AS A DISPERSAL MECHANISM. AB - An example from the genus Eucalyptus is used to argue that hybridization may be of evolutionary significance as a means of gene dispersal where seed dispersal is limited. A previous study of regeneration of E. risdonii and E. amygdalina indicated that the current selective regime was favoring E. risaonii. However, the dispersal of E. risdonii by seeds is shown to be limited (s, = 4.6 m). By comparison, the flow of E. risdonii genes into the range of E. amygdalina by pollen dispersal and F1 hybridization is widespread (sp = 82 m). While the actual level of hybridization is low, interspecific hybridization effectively doubles the dispersal of E. risdonii genes into the range of E. amygdalina. This pollen flow can have a significant genetic impact, since isolated hybrids or patches of abnormal phenotypes have been found 200-300 m from the species boundary. Based on lignotuber size, some of these patches appear to have been founded by F1 hybrids. The frequency of E. risdonii types in the patches appears to increase with patch size suggesting that there is selection for this phenotype in subsequent generations. E. risdonii-like individuals were recovered in the progeny from both intermediate and E. risdonii backcross phenotypes. These results suggest that E. risdonii may invade suitable habitat islands within the E. amygdalina forest, independently of seed migration, by long-distance pollen migration followed by selection for the gene combinations of the pollen parent. PMID- 28581070 TI - ELECTROPHORETIC VARIATION AND MATING SYSTEM OF THE CLONAL WEED PTERIDIUM AQUILINUM (L. KUHN) (BRACKEN). PMID- 28581071 TI - VARIATION IN PATHOGENICITY AMONG AND WITHIN POPULATIONS OF THE FUNGUS PHOMOPSIS SUBORDINARIA INFECTING PLANTAGO LANCEOLATA. AB - Pathogenicity of isolates of the fungus Phomopsis subordinaria, sampled in three scarcely or heavily infected populations of Plantago lanceolata, was investigated on three different host genotypes. The expression of the pathogen appeared to be quantitative rather than qualitative in character, which suggests polygenic inheritance of host susceptibility. Significant statistical interaction between pathogen and host pointed to some degree of physiological specialization between them. None of the individual host-pathogen combinations was found to contribute significantly to the interaction. Differences in mean pathogenicity between the pathogen populations could not explain the different intensities of disease observed in the field. As the variation in susceptibility between populations of the host at the same three locations also cannot account for the differences in intensity of disease in the field, it can be concluded that environmental factors (in particular weevils that spread the disease) are important for the development of the disease. In one of the populations, the spatial scale at which variation within the pathogen occurs was determined. It appeared that the pathogen varied in pathogenicity in the field, even among scapes within an individual host plant. The consequences of this scale of variation in the pathogen are discussed for the dynamics and evolution of the pathosystem. PMID- 28581073 TI - CORRECTIONS. PMID- 28581072 TI - ADAPTATIONS TO TEMPERATE CLIMATES AND EVOLUTION OF OVERWINTERING STRATEGIES IN THE DROSOPHILA MELANOGASTER SPECIES GROUP. AB - The Drosophila melanogaster species group is considered to have originated in the tropics and only recently invaded temperate habitats. The temperate species of this group that were studied here may be subdivided into the warm-temperate species (D. lutescens and D. rufa) and the cool-temperate species (species of the auraria complex). The warm-temperate species were more cold-hardy than were their tropical relatives (D. takahashii or D. melanogaster) at the larval and imaginal stages, and the cool-temperate species were more cold-hardy than the warm temperate species, although only at the imaginal stage. However, these species showed little or no intraspecific variation in cold-hardiness, in spite of great variation in winter temperature within the species' ranges. It is assumed that cold-hardiness is one of the main factors restricting their distributions at high latitudes and that it is the key for evolution of the warm- and cool-temperate species from their subtropical or warm-temperate ancestors. Both warm- and cool temperate species had photoperiodically controlled reproductive diapause. In the cool-temperate species, the development of cold-hardiness was affected by diapause, but diapause had little or no effect on cold-hardiness in the warm temperate species. Critical daylengths and the diapause rates varied from species to species according to variation in their overwintering plans and also varied geographically in consequence of their adaptation to local climates. Species showed different responses to temperature in preimaginal and ovarian development. These differences are considered to reflect adaptation to different environmental temperatures. PMID- 28581074 TI - ANALYSIS OF THE GENETIC STRUCTURE OF LIFE HISTORY OF DROSOPHILA MELANOGASTER USING RECOMBINANT EXTRACTED LINES. AB - A model for the evolution of senescence known as "antagonistic pleiotropy" makes the specific prediction that there should be a negative genetic correlation between early- and late-age traits associated with fitness. This model has previously been tested by classical quantitative-genetic means including sib analysis and artificial selection. We used the approach of chromosome extraction, which has both advantages and disadvantages compared to classical techniques, to test the model further. From four isogenic lines of Drosophila melanogaster, four sets of recombinant extracted lines were constructed using standard balancer chromosome techniques. The four parental lines and 53 recombinants were reared under controlled laboratory conditions and isolated as pairs for scoring daily fecundity and longevity. Even though the design is not optimal for estimating classical components of genetic variance, it afforded a uniquely direct test of the magnitude of environmental covariances, while giving a detailed genetic picture of part of the genome. There were clear differences among the recombinant series in the distribution of mean longevity and early fecundity. The genetic correlation between early fecundity (sum of egg production for the first five days posteclosion) and female longevity was significantly negative in only one of the recombinant series. When all lines were considered together, the phenotypic correlation between these traits was significantly negative (P < 0.02), while the broad-sense genetic correlation was -0.219 (P < 0.11). This result may be viewed as weakly consistent with the model of antagonistic pleiotropy, but other aspects of the data are at odds with the model. PMID- 28581067 TI - Recent advances in nanodisc technology for membrane protein studies (2012-2017). AB - Historically, the main barrier to membrane protein investigations has been the tendency of membrane proteins to aggregate (due to their hydrophobic nature), in aqueous solution as well as on surfaces. The introduction of biomembrane mimetics has since stimulated momentum in the field. One such mimetic, the nanodisc (ND) system, has proved to be an exceptional system for solubilizing membrane proteins. Herein, we critically evaluate the advantages and imperfections of employing nanodiscs in biophysical and biochemical studies. Specifically, we examine the techniques that have been modified to study membrane proteins in nanodiscs. Techniques discussed here include fluorescence microscopy, solution state/solid-state nuclear magnetic resonance, electron microscopy, small-angle X ray scattering, and several mass spectroscopy methods. Newer techniques such as SPR, charge-sensitive optical detection, and scintillation proximity assays are also reviewed. Lastly, we cover how nanodiscs are advancing nanotechnology through nanoplasmonic biosensing, lipoprotein-nanoplatelets, and sortase-mediated labeling of nanodiscs. PMID- 28581075 TI - INBREEDING DEPRESSION DOESN'T MATTER: THE GENETIC BASIS OF MATING-SYSTEM EVOLUTION. AB - Models of mating-system evolution commonly assume that inbreeding depression is independent of the genotype at loci determining the mating system. Because of the association that develops between genotypes at different loci in inbred populations, an individual that is heterozygous at a mating-type locus is more likely to be heterozygous at a fitness locus than is a randomly chosen individual. A modifier model for the evolution of self-fertilization in plants demonstrates that inbreeding depression is not an adequate descriptor of the relative fitness of inbred and outbred progeny. If inbreeding depression is primarily a result of segregation at overdominant loci, intermediate rates of self-fertilization may be favored, even if the inbreeding depression is less than 30%. Indeed, in some cases, mutants that cause some outcrossing can be introduced into completely selfing populations when the inbreeding depression is as little as 1%. If inbreeding depression is primarily a result of the expression of recessive lethals in inbred progeny, selfing can evolve in an initially random mating population, even when the inbreeding depression is over 70%. PMID- 28581076 TI - EFFECTS OF PARENTAL PHOTOPERIOD ON DEVELOPMENT TIME AND DENSITY SENSITIVITY OF PROGENY IN DROSOPHILA MELANOGASTER. PMID- 28581077 TI - INTERACTION BETWEEN GENOTYPES AT THE DIAZINON-RESISTANCE LOCUS OF THE AUSTRALIAN SHEEP BLOWFLY, LUCILIA CUPRINA. FACILITATION OF DEVELOPMENT OF SUSCEPTIBLE GENOTYPES. AB - The survival of larvae with susceptible (+ +) genotypes at the diazinon resistance locus of the Australian sheep blowfly, Lucilia cuprina is facilitated by prior conditioning of diazinon-containing media by heterozygote (R+) or resistant (RR) larvae. The effect is not observed on media without diazinon. Conditioning by + + genotypes does not affect subsequent development of susceptible larvae and the viability of R + and RR larvae is unaffected by conditioning of the media. Similar results are observed when the medium is conditioned with crushed larvae of the three genotypes. The development of + + larvae is enhanced only on media containing diazinon to which R + or RR crushed larvae are added. The results for other comparisons are equivalent for conditioned or unconditioned media. The number of crushed ++, R +, or RR larvae added to the medium containing diazinon does not affect the proportion of + + eggs that develop through larval and pupal stages to emerge as adults. The rate of development of the + + genotype is, however, positively correlated with the number of crushed R + or RR larvae added. PMID- 28581078 TI - ADAPTIVE RADIATION AND GENETIC DIFFERENTIATION IN THE HAWAIIAN SILVERSWORD ALLIANCE (COMPOSITAE: MADIINAE). AB - The Hawaiian silversword alliance consists of the three genera Dubautia, Argyroxiphium, and Wilkesia, and is a classic example of adaptive radiation in an insular setting. Genetic variation and interspecific genetic differentiation based on ten enzyme loci are described for Dubautia and Wilkesia. Genetic identities among species span the range of values expected from interpopulation comparisons within a single species (I = 0.90-1.00) to those typical of interspecific comparisons (I->=0.67). Genetic-identity values correspond to biogeographic distribution and morphological distinctiveness, supporting a correlation of increasing genetic distance associated with the time of separation among lineages. It may be inferred that the high genetic identities observed within the Hawaiian Madiinae and other island plant groups are due to limited time spans available for taxa to accumulate new genetic variation through mutation. It appears that species may remain genetically similar (I > 0.90) even after time spans on the order of magnitude of 1,000,000 years. PMID- 28581079 TI - EVOLUTIONARY GENETICS OF OVIPOSITION PREFERENCE IN SWALLOWTAIL BUTTERFLIES. AB - Models of the evolution of host shifts and speciation in phytophagous insects are often built upon the assumption that host selection is under simple genetic control, perhaps even a single locus. The genetic basis for differences in host plant preference by ovipositing insects was investigated using two closely related species of swallowtail butterfly, Papilio oregonius and P. zelicaon, which differ in the plant families on which females oviposit. Both species had been shown previously to vary within populations in host selection. A combination of analyses using reciprocal interspecific crosses and isofemale strains within populations indicated that oviposition preference in these species is determined significantly by one or more loci on the X chromosome, which female Lepidoptera inherit only paternally. Hence, preferences in hybrid females tended toward the paternal species. This is the first insect group for which partial control of oviposition preference has been localized onto a particular chromosome. In addition, one or more loci on another chromosome(s) appear to contribute to preference, as indicated by the partially intermediate preferences of some hybrid crosses. The overall differences in preference in the reciprocal interspecific hybrids were restricted to differences in the distribution of eggs laid among the local host plants of these two Papilio species; the reciprocal crosses did not differ in the small percentage of eggs laid on a novel potential host species. The variation in host selection found among the isofemale strains reinforces earlier results for these strains, indicating that there is genetic variation in host selection within these populations. Overall, the results indicate that the evolution of oviposition preference in these species involves genetic changes at two or more chromosomes with the X chromosome playing an important role in determining preference. PMID- 28581080 TI - PHENOTYPIC EVOLUTION, CONSTANT COVARIANCES, AND THE MAINTENANCE OF ADDITIVE VARIANCE. PMID- 28581081 TI - KNOWN SECONDARY CONTACT AND RAPID GENE FLOW AMONG SUBSPECIES AND DIALECTS IN THE BROWN-HEADED COWBIRD. AB - We analyze geographic variation in morphology for Sierra Nevadan populations of Brown-headed Cowbirds (Molothrus ater) in relation to two levels of geographic structure of populations: 1) subspecies and 2) vocal dialects. Two morphologically distinct subspecies occupy opposite slopes of the Sierra Nevada: M. a artemisiae on the east slope is larger than M. a. obscurus on the west slope, and its juveniles have predominantly white versus yellow rictal (bill) flanges. Populations of obscurus moved into California from the lower Colorado River around 1900 and invaded the western Sierra during the 1930's. A relatively constant type of flight whistle occurs in obscurus populations up to 700 km apart, but east-slope artemisiae are divided into many distinct dialects. The means of seven morphological measurements and of principal component 1 (i.e., body size) for 2,287 individuals show similar clinal patterns for adult males, yearling males, and females over a 60-km north-south transect along the eastern Sierra Nevada: large sizes occur at the southernmost study site at Bishop, decrease clinally to the north to Mammoth Lakes, and then increase clinally to the north from Mammoth Lakes to the northernmost site at Lee Vining. This reversal in cline slope is reiterated for variation in the frequency of white flanged juveniles. Our data do not support adaptive explanations for the clines. Rather, the most parsimonious explanation is that there has been flow of obscurus genes into artemisiae from the west slope across the crest of the Sierra Nevada into the Mammoth Lakes area. Concordantly, the Sierran crest at Mammoth Lakes is considerably lower than any other point within about 80 km to the north or 180 km to the south. Two other findings strongly support this interpretation. First, wing lengths of our longest-winged samples (at Bishop and Lee Vining) are significantly shorter than those of cowbirds collected in the same region between 1912 and 1922. Second, the wing lengths of Mammoth Lakes adult males and females during 1978-1981 are significantly larger than those of the 1982-1985 period. This putative hybridization must have been rapid, as there have been fewer than 50 years since secondary contact could have occurred. Calculation of the gene flow parameter Iota of Endler (1977) indicates that the gene-flow rate reported here is higher than for nearly all of the species he surveyed. This gene flow occurs between two subspecies with different flight whistles and across several cowbird flight-whistle dialects within artemisiae. Therefore, vocal differences among these dialects do not appear to be a strong deterrent to gene flow. PMID- 28581082 TI - DIVERGENCE AND GENETIC STRUCTURE IN ADJACENT GRASS POPULATIONS. I. QUANTITATIVE GENETICS. AB - Additive genetic variances and covariances were estimated for life history and morphological traits in two adjacent populations of the grass, Holcus lanatus L. Significant phenotypic differentiation was found between the two populations for four of the 15 morphological attributes measured. Significant differences in genetic architecture were found between the two populations for 11 of the 13 traits for which genetic variance components could be calculated. Estimates of genetic correlations also showed considerable divergence between the populations. The genetic divergence was much larger than would have been anticipated from simple measures of phenotypic differentiation. These results show that, even in plant species with relatively large population sizes, differences in genetic variance-covariance patterns can occur between adjacent populations. PMID- 28581083 TI - SEX-RATIO MANIPULATION IN RESPONSE TO HOST SIZE BY THE PARASITOID WASP SPALANGIA CAMERONI: A LABORATORY STUDY. AB - The prediction of Charnov et al.'s (1981) host-size model that there should be a negative relationship between host size and wasp sex ratio (proportion sons) was supported for Spalangia cameroni, a solitary parasitoid wasp. The relationship was shown to be a result of offspring sex manipulation by females in response to host size rather than a result of differential mortality of the sexes. A major assumption of the host-size model is that host size has a greater effect on the ultimate reproductive success of emerging female wasps than of males. This assumption was not supported. Host size had a positive effect on the size of both male and female S. cameroni. However, neither host size nor wasp size affected longevity, production of offspring by females, or ability of males to compete for mates. Host size may differentially affect the reproductive success of female and male wasps through effects on other aspects of reproductive success. Tests of the assumptions of offspring sex-ratio manipulation hypotheses are scarce but critical, not only for parasitoid wasps, but also for other organisms. PMID- 28581084 TI - SEXUAL SELECTION FOR HOMOGAMY IN THE GERRIDAE: AN EXTENSION OF RIDLEY'S COMPARATIVE APPROACH. AB - Ridley (1983) proposed that three factors are necessary and sufficient for the development of positive assortative mating (homogamy) in natural populations. These factors are 1) a correlation between male size and success in competition for mates (intrasexual selection), 2) a correlation between female size and fecundity, and 3) prolonged pairing. In the presence of these three factors, selection will favor males that select large (and thus more fecund) females as mates, thus leading to positive assortative mating. Although this simple hypothesis is generally supported by data across taxa (Ridley, 1983), the evidence for the Insecta is equivocal at best. In this paper, I test this hypothesis using three species of waterstriders (Gerridae; Hemiptera). The three factors and homogamy are measured in several samples from each species. Homogamy is predicted and observed in one species (Gerris remigis) and is not predicted and not observed in the other two (G. comatus and G. buenoi). These results support Ridley's hypothesis and suggest that the processes leading to homogamy in the insects do not, in general, differ from those dominant in other taxa. The possible influence of even low levels of homogamy on genetic variance within populations and the difficulties of assessing such levels on the basis of single samples are discussed. PMID- 28581085 TI - HETEROZYGOSITY AND GROWTH IN MARINE BIVALVES: FURTHER DATA AND POSSIBLE EXPLANATIONS. AB - In a natural population of two-year-old mussels, shell length was correlated with degree of heterozygosity. There was no correlation between an individual's glycogen level and its degree of heterozygosity, but when individuals were grouped in heterozygosity classes a near-significant correlation was observed between degree of heterozygosity and mean glycogen level corrected for the effects of sex and stage of gonad development. There was no correlation between degree of heterozygosity and index of gonad development. Such a correlation would have provided support for the hypothesis (Zouros and Foltz, 1984) that dependence of time of spawning on heterozygosity may explain the observed heterozygote deficiency. The causes of heterozygote-deficiency, a common phenomenon in populations of marine bivalves, remain obscure. The observed heterozygosity growth correlation is examined in the light of the controversy of whether allozymes act as markers in linkage association with genetic conditions that are responsible for the differences in growth among individuals or are themselves the agents of the correlation. The observations that 1) the contributions of individual loci to the correlation vary among populations, 2) the correlation is observed in samples from natural populations but not among progeny from pair matings, and 3) the correlation is nearly always accompanied with heterozygote deficiency in the population are more compatible with the first explanation and suggest that the growth-heterozygosity correlation results mostly from associative overdominance and to a lesser extent from the direct contributions of scored loci to growth. PMID- 28581086 TI - THE PROBABILITY OF PEAK SHIFTS IN A FOUNDER POPULATION. II. AN ADDITIVE POLYGENIC TRAIT. AB - Stochastic shifts between two alternative stable equilibria in an additive polygenic system are modelled. The effect of selection on the character is represented by a double-peaked function relating individual fitness to phenotypic value. The mean of a large population will equilibrate near one of the two peaks, although with weak selection there may be a substantial displacement from the closest peak, due to the attraction exerted by the other peak. It is assumed that a small population is founded as a random sample from a large population at equilibrium under selection, and that genetic drift and selection interact to determine the evolution of the mean and variance of the polygenic character during the phase of exponential population growth that follows the foundation of the population. The effects on the frequencies of peak shifts of selectively induced linkage disequilibrium, randomly induced linkage disequilibrium, and random deviations from Hardy-Weinberg equilibrium are investigated by computer simulation. The results are compared with the probabilities of shifts calculated by an approximate analytic method. It is found that the approximations are reasonably accurate when the heights of the peaks in fitness are similar, but the approximations fail when one of the peaks is much higher than the other. The probability of a peak shift is shown to be a decreasing function of the strength of selection on the character. Although substantial changes in phenotypic mean can be induced by a founder event, the probability of a peak shift that induces a significant degree of reproductive isolation is low. The significance of these findings in relation to theories of speciation is discussed. PMID- 28581087 TI - POSTPOLLINATION EFFECTS ON SEED PATERNITY: MECHANISMS IN ADDITION TO MICROGAMETOPHYTE COMPETITION OPERATE IN WILD RADISH. AB - After pollen arrives on a stigma, the paternity of seeds may be influenced by microgametophyte competition, maternal choice, genetic complementation between parents, and embryo competition. While microgametophyte competition has been well accepted, the other mechanisms are more difficult to demonstrate, and their effects are often confounded. Here, wild radish plants were pollinated with single and mixed pollen loads, and some plants were stressed such that reproduction was reduced. Effects of pollen donors, maternal families, maternal * paternal interaction, pollen donor number, and stress on fruit abortion, seed number per fruit, seed weight, and total seed weight per fruit were measured. Maternal-plant * pollen-donor interaction effects were found for all variables, indicating that genetic complementation or maternal choice occurred. Values of the components of reproduction were generally higher for multiply sired fruits than for singly sired fruits, indicating that either competition among embryos changed under multiple paternity or maternal choice for multiply sired fruits occurred. Finally, when maternal plants were stressed, the components of reproduction were more strongly affected by seed and fruit paternity. This result indicates that either competitive regimes among embryos were affected by stress or maternal plants become more selective under stress. In both cases where embryo competition might have been an explanation of the results, variation in seed weight within fruits was unaffected, suggesting that competitive regimes were unchanged. Clearly, mechanisms in addition to microgametophyte competition are important in sorting the pollen that arrives on stigmas of wild radish. These data suggest that maternal choice is likely to be important. In addition, these processes are likely to occur in the field, since the effects are stronger in stressed than in control plants. PMID- 28581088 TI - SEXUAL SELECTION: THE EVOLUTION OF CONSPICUOUS CHARACTERISTICS IN BIRDS BY MEANS OF IMPRINTING. PMID- 28581089 TI - AN EXPERIMENTAL EVALUATION OF SELECTION ON COLOR MORPHS OF THE POLYMORPHIC SPIDER ENOPLOGNATHA OVATA (ARANEAE: THERIDIIDAE). AB - The annual theridiid spider Enoplognatha ovata exhibits a genetically based color polymorphism of red and nonred phenotypes. We evaluated fitness differences between red and nonred spiders by manipulating morph frequencies in a population in which red morphs were rare (<=5%). Broods from red females were introduced to open experimental plots from which natural aggregations of spiders had been repeatedly removed. Control plots in which spiders were removed but not replaced were used to estimate spider immigration from surrounding vegetation into experimental plots. Morph frequencies observed in experimental plots one year following the manipulation were adjusted by immigration estimates and tested against frequencies predicted with the hypothesis of no selection. We found no evidence of selection against red morphs: female morph frequencies in experimental plots did not differ significantly from expected frequencies assuming no selection; female frequencies did not change significantly between subadult and adult stages; and red and nonred spiders exhibited similar fecundities. We conclude that 1) selection on E. ovata color morphs is not likely to be detected easily within a single population because of the swamping effect of dispersal and 2) local patterns of morph-frequency variation may arise more from dispersal and drift than from selection on the color phenotypes. PMID- 28581090 TI - PATTERNS OF PUFFING ACTIVITY AND CHROMOSOMAL POLYMORPHISM IN DROSOPHILA SUBOBSCURA. IV. EFFECT OF INVERSIONS ON GENE EXPRESSION. AB - We have observed that, contrary to a common assumption, the puffing patterns manifest in the salivary chromosomes of Drosophila subobscura are modified by chromosomal inversions as well as by genic content. An inversion effect is apparent in the E and A chromosomes of five strains coming from four different natural populations. An effect due to the geographical location of the populations is also detected in the J and O chromosomes. The chromosomal and geographic effects are distinguishable but not contradictory. Indeed, a statistical test using the DK2 coefficient of distance shows that, for a given chromosomal arrangement, strains of different geographic origin exhibit puffing patterns significantly different; these patterns are, however, more similar to each other than they are to those of strains carrying different chromosomal arrangements of the same chromosome. PMID- 28581091 TI - SEX-RATIO SELECTION IN A BIVOLTINE THRIPS. I. CONDITIONAL SEX-RATIO MANIPULATION AND FITNESS VARIATION. AB - Females of the bivoltine thrips Elaphrothrips tuberculatus (Hood) (Insecta: Thysanoptera) produce broods of either all males (by viviparity) or all females (by oviparity). Measurements of the sex-allocation ratio, ecological and physiological conditions affecting male and female offspring body size, and correlates of the relative fitnesses of adult males and females in relation to size indicate that female parents tend to be viviparous (produce males) if their offspring will become relatively large adults, and that males gain more in fitness from large size than do females. However, the conditions that link sex allocation with offspring fitness differ between the spring and summer generations. In spring, when breeding is synchronous, 1) oviparous and viviparous females do not differ in body size, 2) females tend to be viviparous where the fungus upon which they feed is relatively dense and where their offspring will become relatively large adults, and 3) fungus density is highly correlated with male and female offspring size. In summer, when breeding is relatively asynchronous, 1) viviparous females are much larger than oviparous females early (but not late) in the season, 2) large viviparous females begin breeding earlier than smaller ones, 3) offspring developing earlier in the season become larger adults, and 4) a higher proportion of females are viviparous earlier than later. Field experiments and field collections show that the covariation among sex allocation, conditions, and fitness is not caused by differential mortality by size or sex. Differences between the spring and summer generations in the cues used by females to adjust offspring sex ratio may be caused by seasonal variation in the factors that affect offspring size. However, in both generations, females tend to produce sons only when their offspring will become relatively large adults, whereas daughters are produced regardless of offspring size. These data suggest that females of E. tuberculatus avoid production of males (the sex with higher variance in expected fitness) when the size of their offspring is relatively uncertain. PMID- 28581092 TI - THE USE OF PARALLEL PATTERNS TO TEST NEUTRALITY: A REPLY TO VARVIO-AHO AND PAMILO. PMID- 28581093 TI - SPERM COMPETITION AND SPERM STORAGE AS DETERMINANTS OF SEXUAL DIMORPHISM IN THE DWARF SURFPERCH, MICROMETRUS MINIMUS. PMID- 28581094 TI - THE DROSOPHILIDAE ASSOCIATED WITH TROPICAL AFRICAN FIGS. PMID- 28581095 TI - GENOTYPIC DIVERSITY IN OENOTHERA LACINIATA (ONAGRACEAE), A PERMANENT TRANSLOCATION HETEROZYGOTE. PMID- 28581096 TI - THE IMPACT OF PREDATION ON LIFE HISTORY EVOLUTION IN TRINIDADIAN GUPPIES (POECILIA RETICULATA). PMID- 28581097 TI - EVOLUTION SOCIETY NEW. PMID- 28581098 TI - SEXUAL SELECTION AND THE EVOLUTION OF FEMALE CHOICE. PMID- 28581099 TI - ELECTROPHORETIC AND FUNCTIONAL ENZYMIC EVOLUTION IN FOUR SPECIES OF EASTERN PACIFIC BARRACUDAS FROM DIFFERENT THERMAL ENVIRONMENTS. PMID- 28581100 TI - POPULATION STRUCTURE, FREQUENCY-DEPENDENT SELECTION, AND THE MAINTENANCE OF SEXUAL REPRODUCTION. PMID- 28581101 TI - MORPHOMETRIC EVIDENCE FOR INCIPIENT SPECIATION IN DROSOPHILA SILVESTRIS FROM THE ISLAND OF HAWAII. PMID- 28581102 TI - AN EXPERIMENTAL TEST OF NATURAL SELECTION FOR PUPATION SITE IN SWALLOWTAIL BUTTERFLIES. PMID- 28581103 TI - ALCOHOL DEHYDROGENASE AND GLYCEROL-3-PHOSPHATE DEHYDROGENASE CLINES IN DROSOPHILA MELANOGASTER ON DIFFERENT CONTINENTS. PMID- 28581104 TI - SEARCHING FOR PARALLEL ENZYME GENE VARIATION AMONG SYMPATRIC CONGENERS. PMID- 28581105 TI - "SEX-RATIO" TRAIT, SEX COMPOSITION, AND RELATIVE ABUNDANCE IN DROSOPHILA PSEUDOOBSCURA. PMID- 28581106 TI - GENETIC STUDIES ON SEXUAL ISOLATION AND HYBRID STERILITY IN LONG-TERM CAGE POPULATIONS OF DROSOPHILA MELANOGASTER. PMID- 28581107 TI - ERRATA. PMID- 28581108 TI - GAMETIC DISEQUILIBRIUM IN THE SELF-FERTILIZING SLUG DEROCERAS LAEVE. PMID- 28581109 TI - DIFFERENTIATION OF ADJACENT STREAM POPULATIONS OF THREESPINE STICKLEBACKS. PMID- 28581110 TI - MODELS OF POLYGENIC SEX DETERMINATION AND SEX RATIO CONTROL. PMID- 28581111 TI - CHROMOSOMAL EVIDENCE FOR PARALLEL EVOLUTION OF SHELL SCULPTURE PATTERN IN GONIOBASIS. PMID- 28581112 TI - A REPLY. PMID- 28581113 TI - ADAPTIVE VERSUS INCIDENTAL EXPLANATIONS FOR THE OCCURRENCE OF PROTANDRY IN A BUTTERFLY, LEPTIDEA SINAPIS L. PMID- 28581114 TI - POLLINATOR FORAGING ON FOXGLOVE (DIGITALIS PURPUREA): A TEST OF A NEW MODEL. PMID- 28581115 TI - CONVERGENT AND DIVERGENT EFFECTS OF NATURAL SELECTION ON COLOR PATTERNS IN TWO FISH FAUNAS. PMID- 28581116 TI - Publication Charge Policy-Changes. PMID- 28581117 TI - RELATEDNESS OF NORMAL QUEENS (MACROGYNES) IN NESTS OF THE POLYGYNOUS ANT MYRMICA RUBRA LATREILLE. PMID- 28581119 TI - Long persistence of tumour necrosis factor-alpha antagonist-induced autoantibodies under subsequent treatment with ustekinumab but no adverse effects: a case study of 14 patients with psoriasis. PMID- 28581118 TI - Geographic region: Does it matter in cutaneous melanoma of the head and neck? AB - OBJECTIVES/HYPOTHESIS: The head and neck are two of the most common locations for cutaneous melanoma. We present the first population-based analysis of geographic differences in anatomic subsite, clinicopathologic and demographical traits, histopathologic subtype, treatment modality, and disease-specific survival (DSS) of cutaneous head and neck melanoma (CHNM). STUDY DESIGN: Retrospective database analysis. METHODS: The Surveillance, Epidemiology, and End Results database was queried for cases of CHNM reported between 2000 and 2013. Patients were grouped into East, Midwest, South, and West regions of the United States. Overall incidence, demographic traits, primary tumor site, clinicopathologic traits, histopathologic subtype, treatment modality, and DSS were compared among regions. RESULTS: There were 49,365 patients with CHNM identified. The West (4.60) and the South (4.42) had significantly higher incidence (per 100,000) than the East (3.84) and Midwest (3.65) (P < .05). DSS was significantly different among regions (P < .0066). The East (5 years: 89.4%, 10 years: 84.1%) had the highest DSS rate, and the South (5 years: 87.0%, 10 years: 81.8%) had the lowest DSS rate. The Midwest (5 years: 88.4%, 10 years: 84.3%) and West (5 years: 88.3%, 10 years: 83.5%) had intermediate DSS. On multivariate analysis, the South had an elevated hazard ratio (1.17, 95% confidence interval: 1.05-1.30) when compared to the West. CONCLUSIONS: Geographic region may play a significant role in CHNM. Incidence is higher in the South and the West. Incidence, histologic subtype, treatment modality, and DSS vary among regions. DSS is lower in the South than the West, even after accounting for other major prognostic factors. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2763-2769, 2017. PMID- 28581120 TI - Evaluating speech perception of the MAXUM middle ear implant versus speech perception under inserts. AB - OBJECTIVES/HYPOTHESIS: To evaluate the speech perception of the Ototronix MAXUM middle ear implant relative to the cochlear potential for speech perception of patients. STUDY DESIGN: Clinical study chart review. METHODS: We performed an evaluation of data from a prospective clinical study of 10 MAXUM patients. Primary outcome measures included comparison of word recognition (WR) scores with MAXUM (WRMAXUM ) versus word recognition under inserts (WRinserts ), and the functional gain improvement for pure-tone average (PTA) (0.5, 1, and 2 kHz) and high-frequency pure-tone average (2, 3, and 4 kHz). RESULTS: Ten ears in 10 adult patients (six female; average age 68.7 years) were included. The average speech perception gap (difference between WRinserts and WRMAXUM ) with MAXUM was -9.2% (range, -26% to 4%). A negative number indicates that WRMAXUM was higher than the WRinserts . The average PTA with MAXUM was 23.1 dB (range, 18.7-30 dB), a 38.0-dB gain over the preoperative unaided condition (range, 20-53.3 dB). The average high-frequency pure-tone average with MAXUM was 34.4 dB (range, 26-43.3 dB), a 42.8-dB gain over the preoperative unaided condition (range, 32.3-58.7 dB). CONCLUSIONS: These data demonstrate that a significant, very strong correlation was observed between WRinserts and WRMAXUM scores (r = 0.86, P = .001), and a patient's WRinserts score may be used to reasonably predict the word recognition outcomes with MAXUM. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:456-460, 2018. PMID- 28581121 TI - Omalizumab effectively protects against early and late allergic responses in asthma after 4 weeks. AB - BACKGROUND: Omalizumab is licensed for therapy in severe allergic asthma with an effect demonstrated after 8 weeks or longer treatment. As new applications for omalizumab demand precise knowledge of the onset of effects, the objective of this study was to determine the time course of the early (EAR) and late allergic reaction (LAR). MATERIALS AND METHODS: Ten patients (IgE>300 IU/mL and <700 IU/mL) with a significant response to allergen challenge were treated with omalizumab according to the approved dosing table. Bronchial allergen provocations (BAP) were repeated at weeks 1, 2, 4, and 8. RESULTS: EAR was significantly reduced after 4 weeks (DeltaFEV1 28% vs 11%; P<.001), eNO (86 vs 53 ppb; P<.05) and basophil activation after 2 weeks (CD63 expression 79% vs 32%, P<.05) and LAR already after 1 week (DeltaFEV1 26% vs 13%, P<.05). CONCLUSION: These results demonstrate the onset of protective effects earlier than previously determined, potentially improving seasonal utilization and combination with immunotherapy. PMID- 28581122 TI - The application of wireless near infrared spectroscopy on detecting peripheral circulation in patients with diabetes foot ulcer when doing Buerger's exercise. AB - BACKGROUND AND OBJECTIVES: The majority of patients with diabetes foot ulcer have peripheral arterial disease. The technique of near infrared spectroscopy (NIRS) used to monitor the dorsal foot blood circulation condition is by measuring the absorption differences between oxy-hemoglobin and deoxy-hemoglobin. STUDY DESIGNS/MATERIALS AND METHODS: Patients with diabetic foot ulcer (DFU) treated in our wound care center were divided into two sub-groups based on the Duplex ultrasound or angiography. Patients with peripheral arterial disease (PAD) and non-peripheral arterial disease were divided into group A1 and A2, respectively. We applied wireless NIRS on patients' dorsal foot to assess the peripheral circulation by continuously detect the signal penetrating the tissue while patients were asked to do Buerger's exercise. The same procedure was also repeated on 15 healthy participants as control group B. RESULTS: From January to August 2015, 30 patients with DFU (Group A) were enrolled in the study, 9 patients in Group A1 and 21 patients in Group A2. Tissue concentration of oxygenated hemoglobin (HbO2) in each group varied in a similar trend among five stages of Buerger's exercise. HbO2 concentration increases at post-exercise stages in all groups (P = 0.006 in Group A1, P = 0.223 in Group A2, P = 0.03 in Group B), however, there were significant difference in both pre- and post exercise stages (P = 0.001 and P = 0.01, respectively) between Group A and B. Moreover, significant differences (P = 0.0009) of HbO2 were also found between Group A1 and A2 in pre-exercise status, but no significant difference (P = 0.294) was found in post-exercise status. Similar results were also found in total hemoglobin (Hb) concentration analyses. CONCLUSIONS: Buerger's exercise could increase peripheral HbO2 and total Hb circulation in patients with diabetes foot ulcer. The NIRS could continuously and quantitatively monitor real-time peripheral circulation in postural changes and is novel to rehabilitation program. A larger scale study to prove the accuracy of NIRS system in detecting peripheral circulation could be worthwhile. Lasers Surg. Med. 49:652-657, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28581123 TI - Astrocyte-derived lipocalin-2 mediates hippocampal damage and cognitive deficits in experimental models of vascular dementia. AB - Lipocalin-2 (LCN2) has diverse functions in multiple pathophysiological conditions; however, its pathogenic role in vascular dementia (VaD) is unknown. Here, we investigated the role of LCN2 in VaD using rodent models of global cerebral ischemia and hypoperfusion with cognitive impairment and neuroinflammation. Mice subjected to transient bilateral common carotid artery occlusion (tBCCAo) for 50 min showed neuronal death and gliosis in the hippocampus at 7 days post-tBCCAo. LCN2 expression was observed predominantly in the hippocampal astrocytes, whereas its receptor was mainly detected in neurons, microglia, and astrocytes. Furthermore, Lcn2-deficient mice, compared with wild type animals, showed significantly weaker CA1 neuronal loss, cognitive decline, white matter damage, blood-brain barrier permeability, glial activation, and proinflammatory cytokine production in the hippocampus after tBCCAo. Lcn2 deficiency also attenuated hippocampal neuronal death and cognitive decline at 30 days after unilateral common carotid artery occlusion (UCCAo). Furthermore, intracerebroventricular (i.c.v) injection of recombinant LCN2 protein elicited CA1-neuronal death and a cognitive deficit. Our studies using cultured glia and hippocampal neurons supported the decisive role of LCN2 in hippocampal neurotoxicity and microglial activation, and the role of the HIF-1alpha-LCN2 VEGFA axis of astrocytes in vascular injury. Additionally, plasma levels of LCN2 were significantly higher in patients with VaD than in the healthy control subjects. These results indicate that hippocampal damage and cognitive impairment are mediated by LCN2 secreted from reactive astrocytes in VaD. PMID- 28581124 TI - ZBTB16 is a sensitive and specific marker in detection of metastatic and extragonadal yolk sac tumour. AB - AIMS: Accurate histological diagnosis and classification of germ cell tumours (GCTs) is key to informing successful therapeutic and surveillance strategy. The modern therapeutic approach for yolk sac tumour (YST) is highly curative. Because YST takes on a large morphological spectrum, it can be confused for other GCT subtypes as well as somatic carcinomas, particularly when YST presents in an extragonadal or a metastatic setting. Currently available immunohistochemical markers are limited by suboptimal sensitivity and specificity. We reported recently that ZBTB16 is a sensitive and specific marker for testicular YST. ZBTB16 is absent in other GCTs and in most common somatic carcinomas, including those of gastrointestinal, pancreatobillary, respiratory, genitourinary and gynaecological tracts. The purpose of this study is to investigate the diagnostic utility of ZBTB16 in the settings of metastatic and extragonadal YST. METHODS AND RESULTS: We studied 32 archived metastatic and four extragonadal primary YSTs as well as 51 somatic malignancies for their immunohistochemical expression of ZBTB16. For comparison, alpha-fetoprotein (AFP) and glypican-3 were also studied in parallel. Our results demonstrated an overall sensitivity of 91.6% for ZBTB16 in detecting metastatic and extragonadal YSTs. The non-YST elements (teratoma and embryonal carcinoma) in 15 YST-containing metastatic mixed GCTs were non reactive. With the exception of occasional myoepithelial cells of salivary gland carcinoma, all the 51 somatic malignancies were negative for ZBTB16. CONCLUSIONS: ZBTB16 is a sensitive and specific marker for YST and is diagnostically superior to AFP and glypican-3 in metastatic and extragonadal settings. PMID- 28581125 TI - Simultaneous versus sequential bilateral cochlear implants in adults: Cost analysis in a US setting. AB - OBJECTIVES/HYPOTHESIS: From a purely surgical efficiency point of view, simultaneous cochlear implantation (SimCI) is more cost-effective than sequential cochlear implantation (SeqCI) when total direct costs are considered (implant and hospital costs). However, in a setting where only SeqCI is practiced and a proportion of initially unilaterally implanted patients do not progress to a second implant, this may not be the case, especially when audiological costs are factored in. We present a cost analysis of such a scenario as would occur in our institution. STUDY DESIGN: Retrospective review and cost analysis. METHODS: Between 2005 and 2015, 370 patients fulfilled the audiological criteria for bilateral implantation. Of those, 267 (72.1%) underwent unilateral cochlear implantation only, 101 (27.3%) progressed to SeqCI, and two underwent SimCI. The total hospital, surgical, and implant costs, and initial implant stimulation series audiological costs between August 2015 and August 2016 (29 adult patients) were used in this analysis. RESULTS: The total hospital, surgical, and implant costs for this period was $2,731,360.42. Based on previous local trends, if a projected eight (27.3%) of these patients decide to progress to SeqCI, this will cost an additional $750,811.04, resulting in an overall total of $3,482,171.46 for these 29 patients. Had all 29 undergone SimCI, the total projected cost would have been $3,332,991.75, representing a total potential saving of $149,179.67 (4.3%). CONCLUSIONS: In institutions where only SeqCI is allowed in adults, overall patient management may cost marginally more than if SimCI were practiced. This will be of interest to CI programs and health insurance companies. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2615-2618, 2017. PMID- 28581126 TI - Systemic therapy for head and neck squamous cell carcinoma: Historical perspectives and recent breakthroughs. AB - OBJECTIVES: Despite dramatic developments in drugs established for other malignancies, historically there have been few novel systemic agents available for the management of head and neck squamous cell carcinoma (HNSCC). However, the last decade has observed increased interest in targeted therapies for HNSCC. In 2006, cetuximab became the first major drug for HNSCC to gain Food and Drug Administration (FDA) approval in 3 decades. Recently, both pembrolizumab and nivolumab gained FDA approval for treatment of recurrent or metastatic HNSCC, and trials for other indications in HNSCC are actively underway. As older agents including cisplatin and 5-fluorouracil continue to play a significant role in the management of advanced HNSCC, an understanding of their legacy is paramount. This historical review is not meant to exhaustively catalog every finding relating to HNSCC systemic therapy, but rather is meant to highlight important advances. DATA SOURCES: Case series and clinical trials available in the literature. REVIEW METHODS: Historically significant series and trials evaluating HNSCC systemic therapy were evaluated. RESULTS: Standard regimens employed today are largely comprised of drugs discovered over 4 decades ago, although a number of recent phase III clinical trials have shown great promise, leading to the adoption of several new chemotherapeutic agents and treatment strategies. CONCLUSIONS: These findings reinforce the importance of supporting further HNSCC drug discovery as modern treatment strategies using systemic therapy have resulted in measurable improvements in oncologic outcomes. Laryngoscope, 127:2565-2569, 2017. PMID- 28581127 TI - Correlation analysis of the HLA-DPB1*05:01 and BTNL2 genes within the histocompatibility complex region with a clinical phenotype of psoriasis vulgaris in the Chinese Han population. AB - BACKGROUND: The human major histocompatibility complex (MHC) is known to be highly polymorphic and has been identified to be associated with numerous diseases. The HLA-DPB1 and BTNL2 genes were associated with psoriasis for the first time. The present study aims to investigate the relevance of the HLA-DPB1 and BTNL2 genes with respect to clinical phenotypes of psoriasis vulgaris (PV). METHODS: To investigate whether the HLA-DPB1 and BTNL2 polymorphisms were associated with clinical phenotypes of PV in Chinese Han population, we conducted an analysis in case-controls and case-only subjects (9906 controls and 8744 cases) via MHC targeted sequencing stratified analysis. RESULTS: In cases and controls, analysis showed that the genotype of HLA-DPB1*05:01 was associated with type of guttate [p = 3.914 * 10-2 , odds ratio (OR = 0.9335)] and northern region (p = 1.182 * 10-3 , OR = 0.9108). In the case-only analysis, the genotype of HLA DPB1*05:01 was significantly correlated with geographical region (p = 1.36 * 10-3 , OR = 1.134). In cases and controls, analysis showed that the genotype of BTNL2 (rs 41355746) was associated with being male (p = 2.563 * 10-2 , OR = 0.8897), early-onset (p = 9.399 * 10-3 , OR = 0.8856), guttate (p = 2.469 * 10-2 , OR = 0.8558) and family history (p = 1.51 * 10-4 , OR = 0.772). In the case-only analysis, the genotype of BTNL2 (rs41355746) was significantly correlated with family history (p = 1.768 * 10-3 , OR = 0.757) and age of onset (p = 3.818 * 10-2 , OR = 1.195). CONCLUSIONS: The results of the present study indicate that the HLA-DPB1*05:01 gene was associated with the geographical region of PV and the BTNL2 gene was significantly associated with family history and age of onset of PV. In conclusion, the HLA-DPB1*05:01 and BTNL2 genes might be responsible for the complicacy of clinical features. PMID- 28581128 TI - Effect of dietary vitamin E and selenium supplementation on semen quality in Cairn Terriers with normospermia. AB - Among others, selenium (Se) and vitamin E (VitE) have been provided to dogs to improve semen quality. However, scientific evidence documenting an effect in dogs is lacking. The aim of this study was to investigate the effect of supplementation of these antioxidants on various ejaculate parameters in a randomized, double-blinded trial using Cairn Terrier males exhibiting normal seminal quality parameters. Three dogs each were fed a standardized diet and supplemented with 0.1 mg Se, 100 mg VitE or 0.1 mg Se + 100 mg VitE/dog for 3 months. Ejaculate analyses (volume, progressive motility, vitality, morphology, concentration) were performed before inclusion (D0) and after 1, 2 and 3 months (+1, +2, +3). At the same time, glutathione peroxidase (GSH-PX) and VitE in seminal plasma (SP) and GSH-PX in blood samples were determined. Vitamin E levels in SP were below the detection limit (1.0 mg/L) in all samples. GSH-PX in blood (164.0-2794.4 IU/L) and SP (18.4-4326.0 IU/L) was highly variable. Supplementation only significantly affected the total percentage of sperm head abnormalities (p = .011). Time significantly affected the percentage of morphologically abnormal sperm (p = .025), sperm head abnormalities (p = .007), proximal droplets (p = .001) and GSH-PX in SP (p = .015). Additionally, a significant interaction between time and group was identified for the percentage of membrane-intact sperm (p = .048), head abnormalities (p = .018), acrosomal defects (p = .043) and proximal droplets (p = .002). Although some effects could be identified for selected parameters, we failed to identify a clear trend about how a 3 months VitE and/or Se supplementation affects semen parameters in normospermic Cairn Terriers. PMID- 28581130 TI - EVOLUTION OF FOOD PREFERENCES IN FUNGUS-FEEDING DROSOPHILA: AN ECOLOGICAL STUDY. PMID- 28581129 TI - Paramecium caudatum as a source of nitric oxide: Chemiluminescent detection based on Bluestar(r) Forensic reagent connected with microdialysis. AB - Nitric oxide (NO) chemistry inside the body is the most interesting part of its behavior. NO is involved in controlling blood pressure, and in transmitting nerve signals and a variety of other signaling processes. To explain the behavior of NO, it is necessary to determine its immediate concentration or observe time dependent changes in its concentration. In Paramecium caudatum, NO is formed by calcium-dependent nNOS (NOS1)-like protein, which is distributed in the cytoplasm. NO synthesis affects the ciliary beat and consequent motility of cells and blocked NO synthesis reduces the ability of cells to move. The possibility of online coupling of microdialysis (of P. caudatum solution) with NO detection is demonstrated. Direct measurement of NO is carried out using dilute Bluestar(r) Forensic reagent (luminol-H2 O2 system; one of the NO detections is based upon the chemiluminescent reaction between NO and the luminol-H2 O2 system, which is specifically reactive to NO). The effect of a nitric oxide synthase inhibitor, NG nitro-l-arginine methyl ester was observed. NO production was inhibited and the movement of P. caudatum was restricted. These effects were time dependent and after a specific time were reversed. PMID- 28581131 TI - GENIC AND ORGANISMIC SELECTION. PMID- 28581132 TI - THE IMPACT OF FLORAL PARASITISM IN TWO NEOTROPICAL HUMMINGBIRD-POLLINATED PLANT SPECIES. PMID- 28581134 TI - SEX RATIO, BODY SIZE AND SEASONALITY IN A SOLITARY BEE, OSMIA LIGNARIA PROPINQUA CRESSON (HYMENOPTERA: MEGACHILIDAE). PMID- 28581133 TI - ENZYMATIC POLYMORPHISM IN DROSOPHILA SUBOBSCURA POPULATIONS FROM THE CANARY ISLANDS. PMID- 28581135 TI - BELTSVILLE SYMPOSIUM IN AGRICULTURAL RESEARCH VI. PMID- 28581136 TI - SELECTION FOR AMYLASE ALLOZYMES IN DROSOPHILA MELANOGASTER: SOME QUESTIONS. PMID- 28581137 TI - OUTBREEDING VIA FREQUENCY-DEPENDENT MATE SELECTION IN THE PARASITOID WASP, NASONIA (=MORMONIELLA) VITRIPENNIS WALKER. PMID- 28581139 TI - POLLINATOR FORAGING BEHAVIOR AND GENE DISPERSAL IN SENECIO (COMPOSITAE). PMID- 28581138 TI - INTERSPECIFIC HYBRIDIZATION AND THE EVOLUTIONARY ORIGIN OF A GYNOGENETIC FISH, POECILIA FORMOSA. PMID- 28581141 TI - PARENTAL INVESTMENT AND MATING SYSTEMS IN MAMMALS. PMID- 28581140 TI - GROWTH RATE IN OYSTERS: AN OVERDOMINANT PHENOTYPE AND ITS POSSIBLE EXPLANATIONS. PMID- 28581142 TI - GENETIC VARIATION AND EVOLUTIONARY RELATIONSHIPS WITHIN A GROUP OF THIRTEEN SPECIES OF PENAEID PRAWNS. PMID- 28581143 TI - SELECTIVE PREDATION OF GRAY JAYS, PERISOREUS CANADENSIS, UPON BOREAL CHORUS FROGS, PSEUDACRIS TRISERIATA. PMID- 28581144 TI - RECOMBINATION SYSTEM AND POPULATION STRUCTURE IN OENOTHERA. PMID- 28581145 TI - GEOGRAPHIC RANGE, LIFE HISTORY PATTERNS, AND BODY SIZE IN A GUILD OF CORAL DWELLING MANTIS SHRIMPS. PMID- 28581146 TI - AN EXPERIMENTAL STUDY OF KIN SELECTION. PMID- 28581147 TI - ECOLOGICAL CONSTRAINTS ON THE EVOLUTION OF BREEDING SYSTEMS IN SEED PLANTS: DIOECY AND DISPERSAL IN GYMNOSPERMS. PMID- 28581148 TI - PHYLOGENETIC AND ENVIRONMENTAL DETERMINANTS OF GEOGRAPHIC VARIATION OF THE POCKET MOUSE PEROGNATHUS GOLDMANI OSGOOD. PMID- 28581149 TI - Errata. PMID- 28581150 TI - Objectification: Seeing and treating people as things. PMID- 28581151 TI - Gas-phase fragmentation of protonated piplartine and its fungal metabolites using tandem mass spectrometry and computational chemistry. AB - Piplartine, an alkaloid produced by plants in the genus Piper, displays promising anticancer activity. Understanding the gas-phase fragmentation of piplartine by electrospray ionization tandem mass spectrometry can be a useful tool to characterize biotransformed compounds produced by in vitro and in vivo metabolism studies. As part of our efforts to understand natural product fragmentation in electrospray ionization tandem mass spectrometry, the gas-phase fragmentation of piplartine and its two metabolites 3,4-dihydropiplartine and 8,9 dihydropiplartine, produced by the endophytic fungus Penicillium crustosum VR4 biotransformation, were systematically investigated. Proposed fragmentation reactions were supported by ESI-MS/MS data and computational thermochemistry. Cleavage of the C-7 and N-amide bond, followed by the formation of an acylium ion, were characteristic fragmentation reactions of piplartine and its analogs. The production of the acylium ion was followed by three consecutive and competitive reactions that involved methyl and methoxyl radical eliminations and neutral CO elimination, followed by the formation of a four-member ring with a stabilized tertiary carbocation. The absence of a double bond between carbons C-8 and C-9 in 8,9-dihydropiplartine destabilized the acylium ion and resulted in a fragmentation pathway not observed for piplartine and 3,4-dihydropiplartine. These results contribute to the further understanding of alkaloid gas-phase fragmentation and the future identification of piplartine metabolites and analogs using tandem mass spectrometry techniques. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28581154 TI - Hypoxia-inducible factor-1 in myocardial ischaemia/reperfusion injury. PMID- 28581153 TI - Self-Reported Current Practices in Child Forensic Interviewing: Training, Tools, and Pre-Interview Preparation. AB - In child sexual abuse investigations, forensic interviewers within the Child Advocacy Center (CAC) model serve as neutral fact-finders for a team of professionals tasked with investigating and intervening in cases of alleged child sexual abuse. Although empirical evidence has led to the development of best practice techniques and protocols, there is currently no universally adopted protocol in the field. The present research gathered detailed information from a national sample of real-world child forensic interviewers about their training and current practices, with a specific focus on assessing the information interviewers typically review prior to conducting child forensic interviews. Most notably, the survey revealed a lack of uniformity in interviewing protocols adopted and pre-interview preparation practices. Although rare, some interviewers reported using an allegation-blind interviewing approach, highlighting the need for future research on this and other under-studied techniques. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28581152 TI - Neurosteroid dehydroepiandrosterone enhances activity and trafficking of astrocytic GLT-1 via sigma1 receptor-mediated PKC activation in the hippocampal dentate gyrus of rats. AB - Neurosteroid dehydroepiandrosterone (DHEA) has been reported to exert a potent neuroprotective effect against glutamate-induced excitotoxicity. However, the underlying mechanism remains to be elucidated. One of the possible mechanisms may be an involvement of astrocytic glutamate transporter subtype-1 (GLT-1) that can quickly clear spilled glutamate at the synapse to prevent excitotoxicity. To examine the effect of DHEA on GLT-1 activity, we measured synaptically induced glial depolarization (SIGD) in the dentate gyrus (DG) of adult rats by applying an optical recording technique to the hippocampal slices stained with voltage sensitive dye RH155. Bath-application of DHEA for 10 min dose-dependently increased SIGD without changing presynaptic glutamate releases, which was sensitive to the GLT-1 blocker DHK. Patch-clamp recordings in astrocytes showed that an application of 50 MUM DHEA increased glutamate-evoked inward currents (Iglu) by approximately 1.5-fold, which was dependent on the GLT-1 activity. In addition, the level of biotinylated GLT-1 protein in the surface of astrocytes was significantly elevated by DHEA. The DHEA-increased SIGD, Iglu, and GLT-1 translocation to the cell surface were blocked by the sigma1 R antagonist NE100 and mimicked by the sigma1 R agonist PRE084. DHEA elevated the phosphorylation level of PKC in a sigma1 R-dependent manner. Furthermore, the PKC inhibitor chelerythrine could prevent the DHEA-increased SIGD, Iglu, and GLT-1 translocation. Collectively, present results suggest that DHEA enhances the activity and translocation to cell surface of astrocytic GLT-1 mainly via sigma1 R-mediated PKC cascade. PMID- 28581156 TI - The usability of WeChat as a mobile and interactive medium in student-centered medical teaching. AB - Biochemistry and cellular biology courses for medical students at Tongji University include the assessment that provides students with feedback to enhance their learning, which is a type of formative assessment. However, frequent instant feedback and guidance for students is often absent or inconsistently included in the teaching process. WeChat, the most popular Chinese social media, was introduced in biochemistry and cellular biology course. A WeChat official account (OA) was set up as an instant interactive platform. Over a period of two semesters, OA sent 73 push notifications. The components included course notices, preclass thought questions, after-class study materials, answer questions and feedback, simulation exercises, teacher-student interaction, and research progress relevant to the course. WeChat OA served as an active-learning teaching tool, provided more frequent feedback and guidance to students, and facilitated better student-centered communication in the teaching process. Using the WeChat OA in medical teaching emphasized interactive, interoperable, effective, engaging, adaptable, and more participatory teaching styles. As a new platform, WeChat OA was free, Internet-reliant, and easily managed. Using this new medium as a communication tool accelerated further advancement of instant feedback and improvement in teaching activities. Notifications and interactive feedback via the mobile social medium WeChat OA anytime and anywhere facilitated a student centered teaching mode. Use of WeChat OA significantly increased the proportion of students interactively participating and resulted in a high degree of student satisfaction. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 45(5):421-425, 2017. PMID- 28581157 TI - Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4). AB - Protein arginine deiminase type IV (PAD4) is responsible for the posttranslational conversion of peptidylarginine to peptidylcitrulline. Citrullinated protein is the autoantigen in rheumatoid arthritis, and therefore, PAD4 is currently a promising therapeutic target for the disease. Recently, we reported the importance of the furan ring in the structure of PAD4 inhibitors. In this study, the furan ring was incorporated into peptides to act as the "warhead" of the inhibitors for PAD4. IC50 studies showed that the furan-containing peptide based inhibitors were able to inhibit PAD4 to a better extent than the furan containing small molecules that were previously reported. The best peptide-based inhibitor inhibited PAD4 reversibly and competitively with an IC50 value of 243.2 +/- 2.4 MUm. NMR spectroscopy and NMR-restrained molecular dynamic simulations revealed that the peptide-based inhibitor had a random structure. Molecular docking studies showed that the peptide-based inhibitor entered the binding site and interacted with the essential amino acids involved in the catalytic activity. The peptide-based inhibitor could be further developed into a therapeutic drug for rheumatoid arthritis. PMID- 28581158 TI - GENETIC VARIATION AND JUVENILE SURVIVAL IN RED DEER. AB - The survival of red deer (Cervus elaphus L.) calves to two years of age was examined in relation to electrophoretic variation in a population on the Scottish island of Rhum. Survival was analyzed using logistic analysis in which the "phenotypic" factors birth weight, birth date, subdivision of the study area, cohort, and sex, which affect the probability of a calf's survival, were taken into account. All three polymorphic loci examined, Mpi, Idh-2, and Trf (each with two detected alleles) are significantly associated with juvenile survival. At Mpi, there is selection against one allele, f (or an allele at a linked locus), and there are indications that this effect is stronger in females than males. For Idh-2, overall, the heterozygote class survives better than the two homozygotes, which survive equally well. However, again there is a difference between the sexes; female heterozygotes survive much better than homozygotes, whereas male homozygotes survive better than heterozygotes, and the difference in survival is smaller. Furthermore, there is an interaction involving Mpi, Idh-2, and survival in which Mpif carriers that are also Idh-2 homozygotes survive very badly compared with other Mpi-Idh-2 combinations, which all survive equally well. For Trf, the heterozygote class survives best, and there is also a difference in survival between the two homozygote classes. Genotype frequencies in the adult population are consistent with the results for calf survival, in that the Mpif frequency is lower in succeeding cohorts of surviving adults, whereas no significant gene frequency change is apparent for Idh-2 or Trf. PMID- 28581155 TI - Prevalence of hepatitis B antiviral drug resistance variants in North American patients with chronic hepatitis B not receiving antiviral treatment. AB - Antiviral drug resistance hepatitis B virus (HBV) variants (HBV-DR) occur spontaneously in chronic hepatitis B (CHB) patients and after exposure to nucleos(t)ide analogues (NUCs). We determined the prevalence of HBV-DR variants among participants of the Hepatitis B Research Network (HBRN) Cohort Study conducted at 21 sites in the United States (US) and Canada. Samples obtained from 1342 CHB participants aged >=18 years, and who were currently not receiving NUCs, were tested for HBV-DR variants by Sanger sequencing. In addition, next generation sequencing (NGS) was used to characterize HBV-DR variants from 66 participants with and 66 participants with no prior NUC exposure matched for HBV genotype and HBV DNA level. Half the participants were men, 75% Asian, 26% HBeAg positive. Primary HBV-DR variants were detected by Sanger sequencing in 16 (1.2%) participants: 2/142 (1.4%) with and 14/1200 (1.2%) without prior NUC exposure; only 1 of these 16 had a secondary variant. In total, 23 (1.7%) participants had secondary variants, including 1 with prior NUC experience. In the subset of 132 participants, NGS detected HBV-DR variants in a higher proportion of participants: primary variants in 18 (13.6%) (8 [12.1%] with, and 10 [15.2%] without prior NUC therapy) and secondary variants in 10 (7.6%) participants. Based on Sanger sequencing, prevalence of primary HBV-DR variants is low (1.2%) among adults with CHB in US/Canada. The similar low prevalence of HBV-DR variants in participants with and without NUC treatment suggests transmission of these variants is uncommon. PMID- 28581159 TI - EVOLUTION OF PHENOTYPIC PLASTICITY IN THE STELLARIA LONGIPES COMPLEX: COMPARISONS AMONG CYTOTYPES AND HABITATS. AB - Variation in the amount and pattern of plasticity was studied in three cytotypes (4x, 6x, and 8x) of Stellaria longipes and diploids of its suspected progenitor S. longifolia. All 13 traits considered showed plasticity. There were significant differences among cytotypes and habitats in plasticity for many traits. Overall, the diploids, S. longifolia, were most plastic, and the three cytotypes of S. longipes did not differ in amount of plasticity. Stellaria longifolia showed divergence from S. longipes in the pattern of plasticity as well. In general, cytotypes with more similar chromosome numbers had the same pattern of plasticity for more traits. Individuals from tundra populations differed in their pattern of plasticity from those of montane, boreal, and prairie origin, which were more similar to one another. Differences in plasticity among cytotypes were due primarily to divergence in amount, while differences among habitats were most often accounted for by divergent patterns of plasticity. We conclude that both polyploidy and natural selection have affected the evolution of plastic responses in this species complex. Analysis of the correlation between pairs of traits provided evidence that the pattern and amount of plasticity operate independently of one another and may be evolving separately. PMID- 28581160 TI - PARASITE LOAD, BODY SIZE, AND AGE OF WILD-CAUGHT MALE FIELD CRICKETS (ORTHOPTERA: GRYLLIDAE): EFFECTS ON SEXUAL SELECTION. AB - Comparison of male field crickets (Gryllus veletis and G. pennsylvanicus) collected either by themselves (solitary) or with one or more females (paired) showed that the paired males were significantly older and significantly less parasitized by gregarines (protozoan gut parasites) than were solitary males. Body size did not differ between the two groups. These results corroborate earlier experimental findings that females are preferentially attracted to older males and suggest that the ability of less parasitized males to produce more spermatophores under laboratory conditions may also be important in the field. Calculation of sexual-selection differentials and gradients for G. pennsylvanicus did not reveal any indirect selection on body size and confirmed the strong selection on male age. PMID- 28581161 TI - RATE TESTS FOR SELECTION ON QUANTITATIVE CHARACTERS DURING MACROEVOLUTION AND MICROEVOLUTION. PMID- 28581162 TI - EVOLUTION AND MORPHOGENETIC RULES: THE SHAPE OF THE VERTEBRATE LIMB IN ONTOGENY AND PHYLOGENY. AB - The notion of a "developmental constraint" has become a catchphrase for a collection of poorly defined notions about how ontogeny affects phylogeny. In this paper, we shall attempt to define this idea more precisely by examining the vertebrate limb from three viewpoints. First, theoretical models of morphogenesis suggest several generalizations about how limb geometry is laid down during development. Comparative studies and experimental manipulations of developing limbs independently confirm these generalizations, which amount to a set of "construction rules" for determining how the major features of limb architecture are established in ontogeny. Armed with these rules, we can inquire how limb morphology can be varied during evolution and suggest a more precise operational definition of "developmental constraints" on morphological evolution. PMID- 28581163 TI - HIERARCHICAL ORGANIZATION OF GENETIC VARIATION IN THE SAILFIN MOLLY, POECILIA LATIPINNA (PISCES: POECILIIDAE). AB - Twenty-two percent of all allozyme variation documented in the sailfin molly (Poecilia latipinna) was attributable to regional differences, while only 3% was attributable to differences among demes within regions. Of the variation documented in a given region, 6-12% was attributable to variation among demes. Cluster analyses supported these conclusions quantitatively. Spatial autocorrelation analyses offered more explicit support: demes separated by increasingly greater distances were increasingly dissimilar. Analyses using F statistics and rare alleles suggest "effective gene flow rates" (the product of effective population size and gene flow rate) of approximately 4, a level more than sufficient to prevent local independence of gene-frequency dynamics. These results, taken together, suggest that mollies do not have a population structure conducive to the operation of Wright's shifting-balance process and make the striking patterns of interdemic variation in body size and sexual behavior observed in this species all the more interesting. PMID- 28581164 TI - LIFE-HISTORY VARIATION WITHIN A POPULATION OF THE COLONIAL ASCIDIAN BOTRYLLUS SCHLOSSERI. I. THE GENETIC AND ENVIRONMENTAL CONTROL OF SEASONAL VARIATION. AB - Many empirical analyses of life-history tactics are based on the assumption that demographic variation ought to be greatest among populations or species living in different environments. However, in a single population of the sessile colonial sea squirt Botryllus schlosseri, there are two discrete life-history morphs. Semelparous colonies are characterized by a) death immediately following the production of a single clutch, b) early age at first reproduction, c) rapid growth to first reproduction, and d) high reproductive effort. In contrast, iteroparous colonies a) produce at least three clutches before dying, b) postpone sexual reproduction until they are nearly twice the age of semelparous colonies, c) grow at about half the rate of semelparous colonies, and d) invest roughly 75% less in reproductive effort than semelparous colonies. Semelparous colonies numerically dominate the population through midsummer; later in the summer, iteroparous colonies are most numerous. Field and laboratory common-garden experiments, along with breeding studies, indicate that the demographic differences between the morphs are genetically determined. Consequently, the seasonal switch from dominance by semelparous colonies to dominance by iteroparous colonies may be an evolved response to a seasonally changing environment. On theoretical grounds, temporal variation in selection is thought to play a relatively unimportant role in maintaining genetic polymorphism; nonetheless, the seasonally recurrent life-history polymorphism shown in this study indicates that temporal variation in selection can lead to the maintenance of genetic polymorphism for traits strongly affecting fitness. PMID- 28581165 TI - THE ORIGIN AND GENETIC BASIS OF OBLIGATE PARTHENOGENESIS IN DAPHNIA PULEX. AB - Sex in Daphnia is environmentally determined, and some obligately parthenogenetic clones of D. pulex have retained the ability to produce males. In the present study, males from 13 such clones were crossed to sexual females from closely related cyclical parthenogens both to determine whether the males were capable of producing viable hybrids and to determine the mode of reproduction of the hybrids. A total of 178 genetically confirmed hybrids were produced, with each of the 19 attempted crosses resulting in some viable hybrids. On average, only 34% of the hybrid eggs that initiated development survived to the reproductive stage, suggesting some incompatibility between the parents. The absence of any association between survivorship and parental or hybrid genotype indicated, however, that there is no specific genetic incompatibility associated with the marker loci used. The inability of most hybrids to produce normal resting eggs is further evidence of a general genomic incompatibility between the parents. Ten of the hybrids produced viable resting eggs, permitting tests to determine their mode of reproduction. Six of the 10 hybrids reproduced by cyclical parthenogenesis, like their maternal parent. The remaining four hybrids reproduced by obligate parthenogenesis, like their paternal parent, demonstrating that the genes suppressing meiosis can be transmitted by the male parent. These results support a model for the generation of new clones that involves the spread of genes suppressing meiosis and provide evidence that the high genotypic diversity observed in obligately parthenogenetic populations of D. pulex is a result of the multiple origin of new clones from the cyclical parthenogens. Evidence was also obtained suggesting that the obligately parthenogenetic clones carry a load of recessive deleterious genes. PMID- 28581166 TI - A COMPARISON OF GENETIC AND PHENOTYPIC CORRELATIONS. AB - Genetic variances and correlations lie at the center of quantitative evolutionary theory. They are often difficult to estimate, however, due to the large samples of related individuals that are required. I investigated the relationship of genetic- and phenotypic-correlation magnitudes and patterns in 41 pairs of matrices drawn from the literature in order to determine their degree of similarity and whether phenotypic parameters could be used in place of their genetic counterparts in situations where genetic variances and correlations cannot be precisely estimated. The analysis indicates that squared genetic correlations were on average much higher than squared phenotypic correlations and that genetic and phenotypic correlations had only broadly similar patterns. These results could be due either to biological causes or to imprecision of genetic correlation estimates due to sampling error. When only those studies based on the largest sample sizes (effective sample size of 40 or more) were included, squared genetic-correlation estimates were only slightly greater than their phenotypic counterparts and the patterns of correlation were strikingly similar. Thus, much of the dissimilarity between phenotypic- and genetic-correlation estimates seems to be due to imprecise estimates of genetic correlations. Phenotypic correlations are likely to be fair estimates of their genetic counterparts in many situations. These further results also indicate that genetic and environmental causes of phenotypic variation tend to act on growth and development in a similar manner. PMID- 28581167 TI - FOUNDER EFFECTS AND THE RATE OF MITOCHONDRIAL DNA EVOLUTION IN HAWAIIAN DROSOPHILA. AB - The nearly-neutral-mutation theory predicts that populations with small effective sizes will undergo more rapid molecular evolution than populations with very large effective sizes. In particular, Ohta (1976) predicted that populations of Hawaiian Drosophila that are known to have small population sizes and to experience repeated population bottlenecks due to founder events should show a more rapid rate of molecular evolution relative to the rate of molecular evolution of species with large population sizes such as the continental Drosophila. In this paper we test this prediction by comparing the rate of molecular evolution in two closely related lineages of Hawaiian Drosophila that have experienced very different evolutionary histories. Both lineages belong to the planitibia subgroup of Hawaiian Drosophila. The beta lineage (which includes D. silvestris, D. planitibia, D. differens, and D. hemipeza) has undergone repeated founder events, as evidenced by their geographic distribution and behavioral biology. On the other hand, evidence on geographic distribution and behavior indicates that the alpha lineage (which includes D. melanocephala, D. cyrtaloma, and D. neoperkinsi) has arisen from large ancestral populations without founder effects. The mitochondrial DNA data reveal that, within a lineage, the rate of molecular evolution is rather uniform, while all comparisons between the two lineages show that the rate of molecular evolution in the beta lineage is three times that of the alpha lineage. This analysis strongly supports the predictions made by Ohta. PMID- 28581168 TI - ESTIMATING THE FORM OF NATURAL SELECTION ON A QUANTITATIVE TRAIT. AB - The fitness function f relates fitness of individuals to the quantitative trait under natural selection. The function is useful in predicting fitness differences among individuals and in revealing whether an optimum is present within the range of phenotypes in the population. It may also be thought of as describing the ecological environment in terms of the trait. Quadratic regression will approximate the fitness function from data (e.g., Lande and Arnold, 1983), but the method does not reliably indicate features of f such as the presence of modes (stabilizing selection) or dips (disruptive selection). I employ an alternative procedure requiring no a priori model for the function. The method is useful in two ways: it provides a nonparametric estimate of f, of interest by itself, and it can be used to suggest an appropriate parametric model. I also discuss measures of selection intensity based on the fitness function. Analysis of six data sets yields a variety of forms of f and provides new insights for some familiar cases. Low amounts of variation and a low density of data points near the tails of many phenotype distributions emerge as limitations to gaining information on fitness functions. An experimental approach in which the distribution of a quantitative trait is broadened through manipulation would minimize these problems. PMID- 28581169 TI - EXTINCTION AND RECOLONIZATION: THEIR EFFECTS ON THE GENETIC DIFFERENTIATION OF LOCAL POPULATIONS. AB - In this paper, we use a model by Slatkin (1977) to investigate the genetic effects of extinction and recolonization for a species whose population structure consists of an array of local demes with some migration among them. In particular, we consider the conditions under which extinction and recolonization might enhance or diminish gene flow and increase or decrease the rate of genetic differentiation relative to the static case with no extinctions. We explicitly take into account the age-structure that is established within the array of populations by the extinction and colonization process. We also consider two different models of the colonization process, the so-called "migrant pool" and "propagule pool" models. Our theoretical studies indicate that the genetic effects of extinction and colonization depend upon the relative magnitudes of K, the number of individuals founding new colonies, and 2Nm, twice the number of migrants moving into extant populations. We find that these genetic effects are surprisingly insensitive to the extinction rate. We conclude that, in order to assess the genetic effects of the population dynamics, we must first answer an important empirical question that is essentially ecological: is colonization a behavior distinct from migration? PMID- 28581170 TI - INSEMINATION REACTION IN DROSOPHILA: FOUND IN SPECIES WHOSE MALES CONTRIBUTE MATERIAL TO OOCYTES BEFORE FERTILIZATION. PMID- 28581171 TI - UNISEXUAL/BISEXUAL BREEDING COMPLEXES IN POECILIIDAE: WHY DO MALES COPULATE WITH UNISEXUAL FEMALES? AB - Unisexual poeciliid fishes live as sexual parasites in breeding complexes with related bisexual species. Males of the host species copulate with unisexual females as well as with con-specifics, thus maintaining the unisexuals. Copulation with a unisexual offers no selective benefit for a male. A model is proposed that provides an explanation in terms of evolutionary ecology for why males copulate with unisexuals. It assumes that, before copulation, a male attempts to identify a female as conspecific or not but that the correctness of the identification depends on the length of time spent on the identification process. Some cost is involved in the passage of time, so an optimal time spent on identification must exist. Because subordinate males risk being driven away by dominant males, the optimal time is longer for males at the top of the dominance hierarchy than for males at the bottom. Such an optimal strategy gives a male the greatest possible average net benefit from a mating attempt, given his social status; this is a "best of a bad job" strategy. PMID- 28581172 TI - WHY MALE GARTER SNAKES HAVE SMALL HEADS: THE EVOLUTION AND ENDOCRINE CONTROL OF SEXUAL DIMORPHISM. PMID- 28581173 TI - HOW MAMMALS PRODUCE LARGE-BRAINED OFFSPRING. AB - Two explanations for species differences in neonatal brain size in eutherian mammals relate the size of the brain at birth to maternal metabolic rate. Martin (1981, 1983) argued that maternal basal metabolic rate puts an upper bound on the mother's ability to supply energy to the fetus, thereby limiting neonatal brain size. Hofman (1983) proposed that gestation length in mammals is constrained by maternal metabolic rate, implying an indirect constraint on neonatal brain size. Since individuals of precocial species have much larger neonatal brain sizes and are gestated longer for a given maternal body size than individuals of altricial species, Martin's and Hofman's ideas also require that mothers of precocial offspring have higher metabolic rates for their body sizes than mothers of altricial offspring. Data on 116 mammal species from 13 orders show that neither neonatal brain size nor gestation length is correlated with maternal metabolic rate when maternal body-size effects are removed. For a given maternal size, there is no difference in metabolic rates between precocial and altricial species, despite a two-fold difference between them in average neonatal brain size. However, neonatal brain size is strongly correlated with gestation length and litter size, independently of maternal size and metabolic rate. Analyses conducted within orders replicated the findings for gestation length and suggested that neonatal brain size may be at best only weakly related to metabolic rate. Differences in neonatal brain size appear to have evolved primarily with species differences in gestation length and litter size but not with differences in metabolic rate; large-brained offspring are typically produced from litters of one that have been gestated for a long time relative to maternal size. We conclude that species differences in relative neonatal brain size reflect different life-history tactics rather than constraints imposed by metabolic rate. PMID- 28581174 TI - GAMETOPHYTIC SELECTION IN RAPHANUS RAPHANISTRUM: A TEST FOR HERITABLE VARIATION IN POLLEN COMPETITIVE ABILITY. AB - Competition among many microgametophytes for a limited number of ovules can lead to both nonrandom fertilization by pollen genotypes and selection for greater sporophytic vigor. The evolutionary implications of this process depend on the extent of heritable genetic variation for pollen competitive ability. Using flower color in wild radish as a genetic marker, we demonstrate differences among pollen donors in competitive ability. Significant differences were found in four out of five pairs of donors. For three pairs of donors, competitive differences were observed in certain maternal plants but not others. To test for heritability of pollen performance, we conducted a selection experiment. We manipulated the intensity of pollen competition for two generations and then tested for differences in the performance of pollen from two selected lines. Competitive ability of pollen derived from each line was assessed relative to a standard unrelated pollen donor, using pollen mixtures on six wild maternal plants. The intensity of previous pollen competition had no overall effect on the proportion of seeds sired by each selected line. In two maternal plants, pollen from intense previous competition was actually inferior, contrary to expectation. Thus, we found no evidence for heritable variation in this trait. Other factors, such as male-female interactions, may influence the outcome of pollen competition. Prevailing theory on the genetic basis of effects of pollen competition on subsequent generations is not supported by our results. Improved protocols for future experiments are discussed. PMID- 28581175 TI - PHYSIOLOGICAL AND BEHAVIORAL ADAPTATION TO VARYING ENVIRONMENTS: A MATHEMATICAL MODEL. AB - We develop a mathematical model to explore the evolution of habitat selection and physiological adaptation in a heterogeneous environment. The model assumes the following conditions: 1) a panmictic population of infinite size; 2) prereproductive individuals mobile enough to move between patches; 3) alleles at one locus code for absence or presence of adaptation to detrimental patches; 4) alleles at a second locus code for absence or presence of behavior(s) that cause avoidance of the detrimental patches; 5) additive effects of alleles controlling physiology and behavior; 6) frequency-independent fitness. Results of the model indicate that nontrivial, polymorphic equilibria do not exist. The pattern of genotypic fitnesses and the initial allelic frequencies can influence whether the population adapts by physiological or behavioral mechanisms, or by both. Linkage between the two loci can alter the outcome of evolution, given specified genotypic fitness values and initial allelic frequencies. PMID- 28581176 TI - TWO CONSEQUENCES OF HOMOSEXUAL COURTSHIP PERFORMED BY DROSOPHILA MELANOGASTER AND DROSOPHILA AFFINIS MALES. PMID- 28581177 TI - FEMALE MATE PREFERENCE AND THE EVOLUTION OF FEMALE-LIMITED BATESIAN MIMICRY. PMID- 28581178 TI - A GENETIC AND BEHAVIORAL ANALYSIS OF MATE CHOICE AND SONG NEIGHBORHOODS IN INDIGO BUNTINGS. AB - Neighboring males of indigo buntings (Passerina cyanea) share songs in southern Michigan. We sampled polymorphic enzymes to compare the genetic variation between mates and the variation among contiguous song neighborhoods. Mate choice was independent of the genetic and morphometric similarity of female and male, and these measures were independent of each other. The incidence of extrapair copulations and fertilizations was independent of the song of cuckolding males. Breeding success of the mated pairs was independent of their genetic or morphological similarity. Males characterized by different song dialects did not differ in mean lifetime reproductive success. We found no significant genetic differences among the neighborhoods. Most birds that bred in one song neighborhood were born in another, and neighborhoods were not isolated demes. Bunting songs may provide no information to a female about genetic quality of males. The results are consistent with a neutral model of no mate choice for genes. PMID- 28581179 TI - INTRAPOPULATION DIFFERENTIATION IN ANNUAL PLANTS. III. THE CONTRASTING EFFECTS OF INTRA- AND INTERSPECIFIC COMPETITION. AB - The roles of intraspecific and interspecific competition in producing differentiation within populations of Veronica peregrina were studied in two populations under controlled, greenhouse conditions. In nature, each population spans an environmental gradient across the center and sides of a temporary, vernal pool in California. Individuals at the center are subjected to intense intraspecific competition produced by high densities (to 30 seedlings/cm2 ) generated by quasi-simultaneous germination (90% of seeds germinate in one week). Individuals at the periphery are subjected to interspecific competition with grasses, which shade out the Veronica 4-6 weeks after the onset of winter growth. I predicted that 1) when grown under immediate intraspecific competition in the greenhouse, offspring of plants from the central subpopulation (C) would perform better (i.e., grow larger and produce more seeds) than those from the periphery (P) and that 2) when grown under delayed interspecific competition provided by Agrostis tenuis and Lollium multiflorum, offspring of plants from the periphery would perform better than those from the center. Both predictions were confirmed. The center-periphery differences were pronounced and statistically significant in an undisturbed population (V-2), while in a population disturbed by yearly plowing (V-3), the differences tended to be consistent with those in V-2 but seldom significant. Distribution of variability tended to be positively skewed and/or leptokurtic in subpopulations grown under "foreign" competition (i.e., intraspecific for P plants and interspecific for C plants) but was normally distributed following exposure to "familiar" competition. Timing of competition affected many results. There were four additional significant differences between the central and peripheral subpopulations. 1) Germination rate: the faster rate in central plants can be advantageous under immediate intraspecific competition. The slower rate in peripheral plants can be advantageous under conditions of erratic and unpredictable soil moisture. 2) Response to nutrient competition: central plants were more sensitive to N-deficiency and peripheral plants were more sensitive to P-deficiency. 3) Allocation of biomass: central plants allocated a greater proportion of biomass to seeds, while peripheral plants allocated a greater proportion of biomass to leaves under all growing conditions. 4) Root elongation: at the seedling stage, central plants have longer roots, while at the adult stage, peripheral plants have longer roots (but not more root mass). Most components of this complex pattern of differentiation are interpretable in an adaptive context. Other results defy simple explanations and underline the importance of phenotypic plasticity, which was pronounced in the competition experiments. PMID- 28581180 TI - HERITABILITY OF OVIPOSITION PREFERENCE AND ITS RELATIONSHIP TO OFFSPRING PERFORMANCE WITHIN A SINGLE INSECT POPULATION. AB - Within a population of the butterfly Euphydryas editha that oviposits predominantly on two host species, heritable variation in postalighting oviposition preference was found. In a separate experiment, oviposition preference of adult females was found to be correlated with offspring performance (growth). There was a significant tendency for offspring to perform better on the host species that their female parent preferred. Analysis of the data showed that no single factor, neither maternal preference nor the host species on which the offspring were raised, accounted for any significant variation in larval performance. However, the effect of the interaction between host species and maternal preference on offspring performance was highly significant. These findings imply specialization in both oviposition preference and offspring performance by individuals within a single population. With present evidence, this preference-performance correlation is likely to be genetic. However, as in previous studies, other interpretations cannot be excluded. PMID- 28581182 TI - CORRECTIONS. PMID- 28581181 TI - EVOLUTION OF HIGHER FEEDING RATE IN DROSOPHILA DUE TO DENSITY-DEPENDENT NATURAL SELECTION. PMID- 28581183 TI - DEVELOPMENTAL CONSEQUENCES OF AN EVOLUTIONARY CHANGE IN EGG SIZE: AN EXPERIMENTAL TEST. AB - Larvae of two species of sea urchins (Strongylocentrotus droebachiensis and S. purpuratus) differ in initial form and in the rate of development. To determine whether these differences are attributable to the large interspecific difference in egg size, we experimentally reduced egg size by isolating blastomeres from embryos. The rate of development of feeding larvae derived from isolated blastomeres was quantified using a novel morphometric method. If the differences early in the life histories of these two species are due strictly to differences in egg size, then experimental reduction of the size of S. droebachiensis eggs should yield an initial larval form and rate of development similar to that of S. purpuratus. Our experimental manipulations of egg size produced three clear results: 1) smaller eggs yielded larvae that were smaller and had simpler body forms, 2) smaller eggs resulted in slower development through the early feeding larval stages, and 3) effects of egg size were restricted to early larval stages. Larvae from experimentally reduced eggs of the larger species had rates of development similar to those of the smaller species. Thus, cytoplasmic volumes of the eggs, not genetic differences expressed during development, account for differences in larval form and the rate of form change. This is the first definitive demonstration of the causal relationship between egg size (parental investment per offspring) and life-history characteristics in marine benthic invertebrates. Because larval form influences feeding capability, the epigenetic effects of egg size on larval form are likely to have important functional consequences. Adaptive evolution of egg size may be constrained by the developmental relationships between egg size and larval form: evolutionary changes in egg size alone can result in concerted changes in larval form and function; likewise evolutionary changes in larval form and function can be achieved through changes in egg size. These findings may have broader implications for other taxa in which larval morphology and, consequently, performance may be influenced by changes in egg size. PMID- 28581184 TI - A combined spectroscopic and TDDFT investigation of the solute-solvent interactions of two coumarin derivatives. AB - The UV/Vis absorption and fluorescence characteristics of 3-cyano-7 hydroxycoumarin [CHC] and 7-amino-4-methyl-3-coumarinylacetic acid [AMCA-H] were studied at room temperature in several neat solvents and binary solvent mixtures of 1,4-dioxane/acetonitrile. The effects of solvent on the spectral properties are analyzed using single and multi-parameter solvent polarity scales. Both general solute/solvent interactions and hydrogen bond interactions are operative in these systems. The solvation of CHC and AMCA-H dyes in 1,4 dioxane/acetonitrile solvent mixtures has been studied. The solutes CHC and AMCA H are preferentially solvated by acetonitrile and a synergistic effect is observed for both molecules in dioxane/acetonitrile solvent mixtures. In addition, using the solvatochromic method the ground- and the excited-state dipole moments of both the dyes were calculated. The ground- and excited-state dipole moments, absorption and emission maxima and HOMO-LUMO gap were also estimated theoretically using B3LYP/6-311+ G (d,p) level of theory in the gaseous phase, dioxane and acetonitrile solvents. Furthermore, changes in dipole moment values were also calculated using the variation of Stokes shift with the molecular-microscopic empirical solvent polarity parameter ( ETN). The observed excited-state dipole moments are larger than their ground-state counterparts, indicating a substantial redistribution of the electron densities in a more dipolar excited state for both coumarins investigated. PMID- 28581185 TI - Serial office-based steroid injections for treatment of idiopathic subglottic stenosis. AB - OBJECTIVES/HYPOTHESIS: Current treatment options for idiopathic subglottic stenosis include endoscopic interventions, resection, and tracheotomy. Recently, serial office-based steroid injections were proposed as an alternative that may stabilize or induce regression of airway stenosis without the need for repeated operations. Procedure completion rate, pain, complications, effect on stenosis, time since the last operation, and limitations have not been described. STUDY DESIGN: Retrospective case series. METHODS: Retrospective series of 19 patients undergoing serial office-based steroid injection for idiopathic subglottic stenosis. Outcome measures included completion rate, procedure-related pain scores, complications, percentage of airway stenosis, and time since the last operative intervention. RESULTS: Procedure completion rate was 98.8%. Average pain score during the procedure was 2.3 +/- 1.7 on a 10-point scale. There were no immediate complications. One patient underwent awake tracheotomy 8 days after her second injection and was later decannulated. Average stenosis decreased from 35% +/- 15% to 25% +/- 15% (n = 16; P = .086) over the first of three injections and 40% +/- 15% to 25% +/- 10% to 20% +/- 10% (n = 8; P = .002) for those patients completing two sets of three injections. Fourteen of 17 patients undergoing at least three injections have not returned to the operating room since the first injection. CONCLUSIONS: Office-based steroid injection represents a promising new treatment pathway for a disease that requires long-term management, offering a purely pharmacologic approach to a disorder that has traditionally been approached from a mechanical perspective. It is safe, well tolerated, and effective. Furthermore, it may help patients and physicians avoid repeated trips to the operating room and the associated risks. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2475-2481, 2017. PMID- 28581187 TI - Commentary 1: The Challenging Task of Addressing Power, Control, and Influence in Sibling Relationships After the First Two Decades of Life. AB - Extending the topic of power, control, and influence in the sibling relationship past the years covered in this issue is not an easy task because most adult siblings neither interact frequently nor live in geographic proximity, although there are considerable ethnic and social class variations. Thus, there are limited opportunities to observe how power is manifested, how siblings control each other and themselves to achieve their goals, nor how siblings influence each other. Comments in this commentary address the challenges presented when considering the trajectory of these dynamics in adult sibling relationships as well as the difficulties sibling dynamics present in carrying out tasks for which an egalitarian relationship is not ideal. PMID- 28581186 TI - Prevalence of chronic kidney disease in patients with chronic hepatitis B: A cross-sectional survey. AB - Renal safety is a major concern during long-term antiviral treatment for chronic hepatitis B (CHB). This study aimed to investigate the prevalence of chronic kidney disease (CKD) in patients with CHB that had been treated with antiviral therapy. This was a single-centre, cross-sectional study in a real-life cohort in which all patients received antiviral treatment. Serum creatinine-based equations from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) were used to estimate the glomerular filtration rate (GFR). CKD was defined as an eGFR <60 mL/min/1.73 m2 or a urinary albumin to creatinine ratio >= 3 mg/mmol (defined as albuminuria). Univariate and multivariate analyses were conducted to determine the risk factors of CKD. A total of 1985 patients were included in the analysis from February 2015 to December 2015. The mean age and median duration of antiviral treatment was 42.20 years and 17.05 months, respectively. The overall prevalence of CKD was 7.9% (157/1985), with 44 patients experiencing decreased renal function (eGFR less than 60 mL/min/1.73 m2) and 129 patients with albuminuria. Patients with cirrhosis had a higher prevalence of a decreased GFR (4.3% vs 1.6%, P<.001) and albuminuria (11.1% vs 5.2%, P<.001) than those without cirrhosis. In the multivariate analysis, hypertension (Odds Ratio [OR] 4.564, P<.001), diabetes mellitus (OR 2.688, P<.001) and cirrhosis (OR 1.918, P<.001) were independent factors associated with the presence of CKD. CKD was a clinically significant comorbidity in patients with CHB. Special attention should be paid to cirrhotic patients and patients with the metabolic syndrome. PMID- 28581188 TI - Cross-Cultural Differences in Sibling Power Balance and Its Concomitants Across Three Age Periods. AB - We examined cross-cultural differences in (1) sibling power balance and (2) the associations between sibling power balance and internalizing and externalizing problems in three separate cross-cultural studies (early childhood, late childhood, and adolescence). The early childhood samples consisted of 123 Turkish and 128 Dutch mothers (mean age for children was 4.9 years). In the late childhood samples, self-report data were collected from 124 Indian and 129 Dutch children (mean age 10.9 years). In the adolescent samples self-report data were collected from 165 ethnic Moroccan and 165 ethnic Dutch adolescents (mean age 15.2 years). In all studies, questionnaire data on sibling power imbalance and internalizing and externalizing problems were collected. Results showed only one significant cross-cultural difference in sibling power imbalance: The Indian sample reported more sibling power imbalance than the Dutch. Links between sibling power imbalance and problem behavior were highly similar between the different cultural samples. The only significant difference was a stronger impact of sibling power imbalance on externalizing problems for the Dutch compared to the Turkish sample. Concluding, few cross-cultural differences were found in sibling power imbalance. Across cultures and age groups, more sibling power imbalance was linked to more internalizing and externalizing problems. PMID- 28581189 TI - The Changing Nature of Power, Control, and Influence in Sibling Relationships. AB - The sibling relationship is unique in that it transforms across development from hierarchical in early childhood, to egalitarian by adulthood. The present article reviews the previous theorizing and research literature regarding how and why power, control, and therefore sibling influence, change over the course of the first couple of decades, and introduces the goals and advancements made by the new research presented in this issue. PMID- 28581190 TI - Family Perspectives on Siblings' Conflict Goals in Middle Childhood: Links to Hierarchical and Affective Features of Sibling Relationships. AB - This study examined parents' and children's descriptions of older and younger siblings' conflict goals in the late preschool and middle childhood years, and how these attributions were related to sibling relationship quality. Parents and 4- to 10-year-old children from 62 families were interviewed separately about siblings' motivations in two disputes and completed assessments of sibling relationship quality. Goal attributions varied across respondents in ways reflecting their family roles and positioning within disputes. Findings also revealed variations in the goals ascribed to older and younger siblings in line with hierarchical features of sibling relationships, such as younger siblings' conciliation/connectedness motives and older siblings' desires for autonomy/respect. Goal attributions were related to differences between families in the affective tenor of sibling relationships. Results demonstrate how power dynamics in sibling relationships play out in their everyday disputes, and underscore the importance of considering different family members' unique perspectives on children's sibling conflict experiences. PMID- 28581191 TI - Relative Power in Sibling Relationships Across Adolescence. AB - During childhood, older siblings typically hold a more powerful position in their relationship with their younger siblings, but these relationships are thought to become more egalitarian during adolescence as siblings begin to prepare for their relationships as adults and as younger siblings become more socially and cognitively competent. Little is known about relationship factors that may explain this shift in power dynamics, however. The present study therefore examined longitudinal changes in adolescents' and their siblings' perceptions of sibling relative power from age 12 to 18 (n = 145 dyads), and examined whether different levels of sibling relationship positivity and negativity, as well as sibling structural variables, indicated different over-time changes in relative power. Multilevel models indicated that adolescents reported significant declines in their siblings' relative power across adolescence, with older siblings relinquishing the most power over time. However, only siblings with less positively involved relationships reported declines in relative power, suggesting that siblings who maintain highly involved relationships may not become more egalitarian during adolescence. PMID- 28581192 TI - Sibling Influences on Risky Behaviors from Adolescence to Young Adulthood: Vertical Socialization or Bidirectional Effects? AB - This study built on research on sibling influences to assess potential bidirectional effects of older and younger siblings' risky behaviors on one another's risky behaviors; our longitudinal design allowed us to test these effects when siblings were at about the same chronological age, at different points in time. We also tested whether the strength and/or direction of effects of siblings' risky behaviors changed from middle adolescence to young adulthood. Reports of risky behaviors (i.e., deviant behaviors and excessive alcohol use) were provided by firstborn and secondborn siblings from up to 201 families on five occasions spanning 10 years. In general, accounting for known covariates, multilevel models revealed bidirectional sibling effects and some evidence that secondborns' risky behaviors were stronger and more consistent predictors of firstborns' behaviors than the reverse. Sibling influence generally declined with age and sibling effects were not moderated by gender constellation. Findings indicate that both older and younger siblings are important socializers of risk behaviors across adolescence and continue to shape each other's alcohol use into early adulthood. PMID- 28581193 TI - Siblings' Power and Influence in Polyadic Family Conflict During Early Childhood. AB - This study examined sibling behavior during polyadic family conflicts (involving three or more family members) by identifying operational conflict elements (i.e., roles, topic), power strategies, effective influence of power, and social domain argumentation. Polyadic conflict sequences (n = 210) were identified in 35/39 families with two siblings (aged 4 and 6) and their parents observed at home. The dominant conflict topic, siblings' use of power and power strategy executed in relation to social domain argumentation, revealed unique qualities of conflict in the polyadic family context; effective use of power strategies to facilitate favorable outcomes differed by sibling birth order. Our account presents a nuanced view of the intricacies of polyadic family conflict, which provides unique opportunities for children's learning and socialization by siblings and parents. PMID- 28581194 TI - Commentary 2: Sibling Power Dynamics: The Role of Family and Sociocultural Context. AB - The balance of power and control is an understudied, yet important, aspect of the sibling relationship that is theorized to shift over the course of development from early childhood to young adulthood. The investigations in this issue offer support for this overall progression, but extend prior research by providing a nuanced understanding of sibling power dynamics using different methodologies, analytic approaches, and study designs. Grounded within an ecological framework, directions for future research are offered to expand our understanding of sibling power dynamics in diverse family and sociocultural contexts. PMID- 28581195 TI - Minimal preparation CT: A literature review of a minimally invasive imaging technique for colorectal cancer in a frail, aged population. AB - Colorectal cancer (CRC) is a common malignancy with increased incidence in the elderly. When CRC is suspected, patients are typically evaluated with optical colonoscopy (OC) or CT Colonography (CTC). Unfortunately, in the frail and elderly patient, these investigations can be difficult to perform and are often not tolerated. Minimal preparation computed tomography (MPCT) is a CT technique to evaluate the colon. Although protocols vary, typically, no preparation is required apart from administration of oral contrast for faecal tagging. The patient is scanned in the supine position only and without colonic insufflation. The study is reserved for 'old-old' frail patients with clinically suspected CRC who cannot tolerate or have failed OC or CTC. In the context of an ageing population, MPCT provides a simple, minimally invasive, readily available and well-tolerated test that is able to demonstrate clinically relevant disease. We review the literature on MPCT and discuss the benefits and limitations of this investigation. PMID- 28581196 TI - Phytochemical Study of the Genus Salpichroa (Solanaceae), Chemotaxonomic Considerations, and Biological Evaluation in Prostate and Breast Cancer Cells. AB - Twelve Salpichroa taxa have been phytochemically analyzed. From the aerial parts of S. scandens, four known salpichrolides A, C, I, S, and an unreported withanolide named salpichrolide V (1), were isolated. In S. dependens, S. gayi, S. glandulosa subsp. glandulosa, S. glandulosa subps. weddellii, S. leucantha, S. micrantha, S. microloba, S. proboscidea, S. ramosissima, S. tristis var. tristis, and S. weberbauerii, no withanolides were found. The chemical content of ca. 85% of the Salpichroa taxa is in agreement with molecular studies, which suggest that Salpichroa and Jaborosa, a genus considered morphologically close to Salpichroa, are distant in the systematic of the Solanoideae subfamily. Moreover, the in vitro cytotoxic activity of a set of natural salpichrolides and derivatives was examined against two prostate carcinoma cell lines (PC3 and LNCaP) and two human breast cancer cell lines (MCF-7 and T47D). Several compounds showed moderate activity (IC50 = 64.91 - 29.97 MUm). PMID- 28581197 TI - NR4A1 is an endogenous inhibitor of vocal fold fibrosis. AB - OBJECTIVES/HYPOTHESIS: NR4A1 was recently identified as an endogenous inhibitor of transforming growth factor (TGF)-beta-induced fibrosis, and the role of this nuclear receptor has not been elucidated in tissue health or the response to injury in the vocal folds. Given the clinical implications of vocal fold fibrosis, we investigated NR4A1 expression during vocal fold wound healing in vivo and the regulatory roles of NR4A1 on vocal fold fibroblasts (VFFs) in vitro with the ultimate goal of developing targeted therapies for this challenging patient population. STUDY DESIGN: In vivo and in vitro. METHODS: In vivo, the temporal pattern of NR4A1 mRNA expression was quantified following rat vocal fold injury. In vitro, the role of NR4A1 on TGF-beta1-mediated transcription of genes underlying fibrosis as well as myofibroblast differentiation and collagen gel contraction was quantified in our human VFF line. Small interfering RNA was employed to alter NR4A1 expression to further elucidate this complex system. RESULTS: Nr4a1 mRNA increased 1 day after injury and peaked at 7 days. Knockdown of NR4A1 resulted in upregulation of COL1A1 and TGF-beta1, with TGF-beta1 stimulation (both P < .001) in VFFs. NR4A1 knockdown also resulted in increased alpha-smooth muscle actin-positive cells (P = .013) and contraction (P = .002) in response to TGF-beta1. CONCLUSIONS: NR4A1 has not been described in vocal fold health or disease. Upregulation of TGF-beta following vocal fold injury was concurrent with increased NR4A1 expression. These data provide a foundation for the development of therapeutic strategies given persistent TGF-beta signaling in vocal fold fibrosis. LEVEL OF EVIDENCE: N/A Laryngoscope, 127:E317-E323, 2017. PMID- 28581198 TI - FBXW7 inactivation in a BrafV600E -driven mouse model leads to melanoma development. PMID- 28581199 TI - Monolithic columns: A historical overview. AB - This review article is an updated and extended version of the previous review that has been published 14 years ago . Although history does not change, its interpretation may. Therefore, I took the liberty to revisit the original work and added some of my new thoughts that could be interesting for the generation of scientists who are entering the intriguing arena of monoliths and may want to know the roots of the field. The current monolithic columns that are well applicable for efficient separations, were first described less than 30 years ago, and their advent represented the initial step to their present widespread appearance. At the beginning, the monolithic columns dominated the academic studies. However, several monolithic materials have later been materialized in commercial products. In order to stay within a reasonable size of this contribution, its focus is placed on developments achieved in the previous century. The very early reports are described in more detail since it might be difficult to find the original source. PMID- 28581200 TI - Natural history of 'second' biochemical failure after salvage radiation therapy for prostate cancer: a multi-institution study. AB - OBJECTIVES: To describe the natural history of prostate cancer in men who experience a second biochemical recurrence (BCR) after salvage radiotherapy (SRT) after prostatectomy. PATIENTS AND METHODS: After undergoing SRT at one of two institutions between 1986 and 2013, 286 patients experienced a second BCR, defined as two rises in prostate-specific antigen (PSA) of >=0.2 ng/mL above nadir. Event rates for distant metastasis (DM) or freedom from DM (FFDM), castration-resistant prostate cancer (CRPC), prostate cancer-specific survival (PCSS), and overall survival (OS) were estimated using the Kaplan-Meier method. Cox regression was used for comparative analyses. RESULTS: At a median of 6.1 years after second BCR, DM, CRPC, PCSS and OS rates were 41%, 27%, 83% and 73%, respectively. On multivariable analysis, interval to second BCR <1 year (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.71-4.14; P < 0.001], Gleason score 8-10 (HR 1.65, 95% CI 1.07-2.54; P = 0.022), and concurrent ADT during SRT (HR 1.76, 95% CI 1.08-2.88; P = 0.024) were associated with FFDM, while PCSS was associated with interval to second BCR <1 year (HR 3.00, 95% CI 1.69-5.32; P < 0.001) and concurrent ADT during SRT (HR 2.15, CI 1.13-4.08; P = 0.019). These risk factors were used to stratify patients into three groups, with 6-year FFDM rates of 71%, 59% and 33%, and PCSS rates of 89%, 79%, and 65%, respectively. CONCLUSION: Following second BCR after SRT, clinical progression is enriched in a subgroup of patients with prostate cancer, while others remain without DM for long intervals. Stratifying patients into risk groups using prognostic factors may aid counselling and future trial design. PMID- 28581203 TI - Corrigendum. PMID- 28581202 TI - Switch to an everolimus-facilitated cyclosporine A sparing immunosuppression improves glycemic control in selected kidney transplant recipients. AB - BACKGROUND: Mammalian target of rapamycin inhibitors (mToRi) allow calcineurin inhibitor (CNI) sparing therapy in renal transplant recipients with possible beneficial effects on the long-term allograft function and cardiovascular risk. The influence of mToRi on glucose metabolism is still under discussion. METHODS: In a retrospective analysis, renal allograft recipients switched from a cyclosporine A (CsA) to an everolimus (EVR)-based immunosuppression in the first year after transplantation were compared with patients on continued CsA treatment. At 6-month intervals, the prevalence of impaired fasting glucose (IFG) and new onset of diabetes after transplantation (NODAT) were assessed. RESULTS: A total of 146 renal transplant recipients were included. The cumulative prevalence of IFG and NODAT 30-months post-transplantation was significantly lower in patients switched to an immunosuppression with EVR compared to patients on continued CsA treatment (10% vs 22%, P=.049). However, patients switched to EVR showed a higher incidence of acute cellular rejections in the first 12 months (23% vs 11%, P=.048). CONCLUSION: EVR-based immunosuppression was associated with a similar or even improved glycemic control and improved renal function. However, due to higher rejection rates, patients switched to EVR should be carefully selected as rejection therapy with steroids counteracts the benefit in glycemic control. PMID- 28581201 TI - Grape juice concentrate alleviates epididymis and sperm damage in cadmium intoxicated rats. AB - The possibility of long-term grape juice concentrate (GJC) consumption conferring a protective effect against cadmium (Cd)-induced damage to the epididymis, completely preserving sperm profile, was evaluated here for the first time in the scientific literature. Male Wistar rats (n = 6/per group) received an intraperitoneal Cd injection (1.2 mg/Kg) at age 80 days and GJC (2 g/Kg) by gavage from 50 days until 136 days old. Groups receiving either Cd or GJC were added. An intraperitoneal injection of saline (0.9%) and water by gavage was administered in the absence of treatment with Cd or GJC. Animals were anaesthetized and exsanguinated at 136 days; the vas deferens, left testis and epididymis were removed; and perfusion continued with fixative. The right epididymis was collected for morphological analysis. Cd had a devastating effect demonstrated by reduced sperm count in testes and epididymis, sperm production and normal sperm count, besides increased epididymis sperm transit time and completely disorganized morphology. These alterations were attributed to higher Cd levels in the testes and a lipid peroxidation (LP) process. Consumption of GJC plus Cd intoxication was effective, reducing metal accumulation and LP. Consequently, we could identify a preserved sperm profile, with improvement in testis and epididymis sperm count, normal sperm structure and sperm transit time. Moreover, GJC extends its protective effect to the epididymis, allowing complete re-establishment of its morphology, ensuring successful sperm maturation process. In conclusion, our study indicates long-term GJC as a promising therapy against reproductive chemical intoxication injury damage, preserving sperm prior to ejaculation. PMID- 28581204 TI - Nephrogenic adenoma does not express NKX3.1. PMID- 28581205 TI - Testing radical prostatectomy in men with prostate cancer and oligometastases to the bone: a randomized controlled feasibility trial. AB - This is the Protocol of the ethically-approved TRoMbone study. PMID- 28581206 TI - Upcoming Challenges in Multidisciplinary Heart Failure Management: Active Role of Future Clinical Pharmacists. AB - In their article "Role and Value of Clinical Pharmacy in Heart Failure Management" Stough and Patterson discuss the potential benefits that clinical pharmacists could bring to heart failure management. They mostly focused on chronic stable heart failure. The objective of this commentary is to provide future perspectives for clinical pharmacist involvement in multidisciplinary heart failure team in the management of patients admitted in emergency for decompensation of their heart condition. PMID- 28581208 TI - Melanocyte differentiation-beyond the master regulator. PMID- 28581207 TI - Improving postprandial hyperglycemia in patients with type 2 diabetes already on basal insulin therapy: Review of current strategies. AB - A large number of patients with type 2 diabetes (T2D) on basal insulin do not reach their HbA1c goals and require additional therapy to address postprandial hyperglycemia. Guidelines from expert bodies have outlined several approaches to accomplish postprandial glucose (PPG) control, and recent literature suggests several more. This article provides strategies for primary care physicians caring for patients with T2D who do not achieve glycemic control with basal insulin alone. Current treatment guidelines and strategies for improving PPG control are reviewed, including the efficacy, safety, and cost-effectiveness of rapid-acting insulin (RAI) analogs, premixed insulin, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and alpha-glucosidase inhibitors. Other approaches, such as combinations of newer basal insulin plus RAI and a fixed-ratio combination of basal insulin and a GLP-1 RA, are also described. PMID- 28581209 TI - Effect of continuous exenatide infusion on cardiac function and peri-operative glucose control in patients undergoing cardiac surgery: A single-blind, randomized controlled trial. AB - We performed a randomized controlled trial with the glucagon-like peptide-1 (GLP 1) receptor agonist exenatide as add-on to standard peri-operative insulin therapy in patients undergoing elective cardiac surgery. The aims of the study were to intensify peri-operative glucose control while minimizing the risk of hypoglycaemia and to evaluate the suggested cardioprotective effects of GLP-1 based treatments. A total of 38 patients with decreased left ventricular systolic function (ejection fraction <=50%) scheduled for elective coronary artery bypass grafting (CABG) were randomized to receive either exenatide or placebo in a continuous 72-hour intravenous (i.v.) infusion on top of standard peri-operative insulin therapy. While no significant difference in postoperative echocardiographic variables was found between the groups, participants receiving exenatide showed improved peri-operative glucose control as compared with the placebo group (average glycaemia 6.4 +/- 0.5 vs 7.3 +/- 0.8 mmol/L; P < .001; percentage of time in target range of 4.5-6.5 mmol/L 54.8% +/- 14.5% vs 38.6% +/- 14.4%; P = .001; percentage of time above target range 39.7% +/- 13.9% vs 52.8% +/- 15.2%; P = .009) without an increased risk of hypoglycaemia (glycaemia <3.3 mmol/L: 0.10 +/- 0.32 vs 0.21 +/- 0.42 episodes per participant; P = .586). Continuous administration of i.v. exenatide in patients undergoing elective CABG could provide a safe option for intensifying the peri-operative glucose management of such patients. PMID- 28581212 TI - Glial cell-derived neurotrophic factor promotes dental pulp stem cell migration. AB - Preserving the vitality of the teeth is critical in maintaining the function and aesthetics of teeth during dental treatment. Dental pulp stem cells (DPSCs) are mesenchymal cells that are demonstrated to possess stem cell properties, such as self-renewal, proliferation, and pluripotency. DPSCs can be obtained through non invasive procedure from the dental pulp and become potential resources for tissue regeneration. Neurotrophic factors are known to promote survival and growth of neurons. In the present study, we examined the expression of the glial cell derived neurotrophic factor (GDNF) family ligands and receptors and characterized the intracellular localization of them in DPSCs. GDNF increased the migration of the DPSCs. In addition, we found that the AKT and MAPK pathways were downstream of GDNF in regulating the DPSC wound healing and migration. Our results indicate that neurotrophic factors play a role in dental pulp regeneration and may be potential novel therapies for post pulpotomy treatment in adult teeth. PMID- 28581210 TI - Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function. AB - Glycosylphosphatidylinositol (GPI) is a glycolipid that tethers more than 150 different proteins to the cell surface. Aberrations in biosynthesis of GPI anchors cause congenital disorders of glycosylation with clinical features including intellectual disability (ID), seizures, and facial dysmorphism. Here, we present two siblings with ID, cerebellar hypoplasia, cerebellar ataxia, early onset seizures, and minor facial dysmorphology. Using exome sequencing, we identified a homozygous nonsense variant (NM_001127178.1:c.1640G>A, p.Trp547*) in the gene Phosphatidylinositol Glycan Anchor Biosynthesis, Class G (PIGG) in both the patients. Variants in several other GPI anchor synthesis genes lead to a reduced expression of GPI-anchored proteins (GPI-APs) that can be measured by flow cytometry. No significant differences in GPI-APs could be detected in patient granulocytes, consistent with recent findings. However, fibroblasts showed a reduced global level of GPI anchors and of specific GPI-linked markers. These findings suggest that fibroblasts might be more sensitive to pathogenic variants in GPI synthesis pathway and are well suited to screen for GPI-anchor deficiencies. Based on genetic and functional evidence, we confirm that pathogenic variants in PIGG cause an ID syndrome, and we find that loss of function of PIGG is associated with GPI deficiency. PMID- 28581211 TI - Sickeningly Sweet: L-rhamnose stimulates Flavobacterium columnare biofilm formation and virulence. AB - Flavobacterium columnare, the causative agent of columnaris disease, causes substantial mortality worldwide in numerous freshwater finfish species. Due to its global significance and impact on the aquaculture industry continual efforts to better understand basic mechanisms that contribute to disease are urgently needed. The current work sought to evaluate the effect of L-rhamnose on the growth characteristics of F. columnare. While we initially did not observe any key changes during the total growth of F. columnare isolates tested when treated with L-rhamnose, it soon became apparent that the difference lies in the ability of this carbohydrate to facilitate the formation of biofilms. The addition of different concentrations of L-rhamnose consistently promoted the development of biofilms among different F. columnare isolates; however, it does not appear to be sufficient as a sole carbon source for biofilm growth. Our data also suggest that iron acquisition machinery is required for biofilm development. Finally, the addition of different concentrations of L-rhamnose to F. columnare prior to a laboratory challenge increased mortality rates in channel catfish (Ictalurus punctatus) as compared to controls. These results provide further evidence that biofilm formation is an integral virulence factor in the initiation of disease in fish. PMID- 28581213 TI - Comparison of enhanced liver fibrosis test with procollagen-3 N-terminal peptide (P3NP) as a marker for liver fibrosis. PMID- 28581214 TI - A new clinical diagnostic matrix for epidermolysis bullosa. PMID- 28581215 TI - Minocycline as an alternative to doxycycline in the treatment of rosacea. PMID- 28581216 TI - Image Gallery: Complex regional pain syndrome with changes in the nail unit. PMID- 28581217 TI - Image Gallery: Kaposiform haemangioendothelioma. PMID- 28581218 TI - Biomarkers in contact dermatitis. PMID- 28581219 TI - Erratum. PMID- 28581220 TI - Psoriasis and the interleukin-10 family: evidence for a protective genetic effect, but not an easy target as a drug. PMID- 28581221 TI - Neutrophilic eccrine hidradenitis can be induced by BRAF inhibitors. PMID- 28581222 TI - Eccrine sweat gland regeneration: still a story of 'blood, toil, tears and sweat'. PMID- 28581223 TI - Image Gallery: Treatment of refractory alopecia universalis with oral tofacitinib citrate and adjunct intralesional triamcinolone injections. PMID- 28581224 TI - 'Whoever has will be given more' (Matthew 13:12): authorship of systematic reviews and clinical trials in the biological age. PMID- 28581225 TI - Image Gallery: Rhinosporidiosis. PMID- 28581226 TI - Methotrexate increases the risk of melanoma: or does it? PMID- 28581227 TI - Field treatment of actinic keratosis on the scalp. PMID- 28581228 TI - Image Gallery: Maggot on my shoulder. PMID- 28581229 TI - Daylight photodynamic therapy: where and when is it possible? PMID- 28581230 TI - Multiple sclerosis is the neurological disorder most highly associated with bullous pemphigoid. PMID- 28581231 TI - Parents managing childhood long-term conditions: longitudinal research is needed on online forums as sources of peer-to-peer information. PMID- 28581233 TI - The gathering storm: hydroxychloroquine retinopathy screening in the U.K. PMID- 28581234 TI - Oxidative stress and high-mobility group box 1 (HMGB1) protein release in vitiligo. PMID- 28581235 TI - Palliative electrochemotherapy treatment of metastatic malignant melanoma. PMID- 28581237 TI - Image Gallery: Microcystic adnexal carcinoma (syringomatous carcinoma and sclerosing sweat duct carcinoma) as an extensive sclerotic erythematous plaque with telangiectasia over the face. PMID- 28581238 TI - Insights into the regulation of proteolytic pathways in skin differentiation. PMID- 28581239 TI - Development of a multidimensional assessment tool for uraemic pruritus in dialysis patients - laying a foundation stone for itch research. PMID- 28581240 TI - Immune checkpoint inhibitor-associated alopecia areata. PMID- 28581242 TI - Treating moderate-to-severe atopic dermatitis: what do dermatologists do with limited evidence? PMID- 28581243 TI - Patients' reports as indicators of quality of care. PMID- 28581244 TI - Mesenchymal stem cells participate to inflammatory skin process of atopic dermatitis. PMID- 28581245 TI - Autophagy - how to control your intracellular diet. PMID- 28581246 TI - Corrigendum. PMID- 28581247 TI - Image Gallery: Cutaneous lesions in the external auditory canal causing hearing loss. PMID- 28581248 TI - Non-invasive tests for liver disease severity and the hepatocellular carcinoma risk in chronic hepatitis B patients with low-level viremia. AB - BACKGROUND & AIMS: We tested whether non-invasive tests for liver disease severity can stratify hepatocellular carcinoma (HCC) risk in chronic hepatitis B virus (HBV)-infected patients showing low-level viremia (LLV, HBV DNA <2000 IU/mL). METHODS: A retrospective cohort of 1006 chronic hepatitis B patients showing persistently LLV, defined by at least two consecutive assessments in the year before enrolment, was assessed for HCC development. Two non-invasive serum biomarkers, the aspartate aminotransferase to platelet ratio index (APRI) and the Fibrosis-4 (FIB-4), were tested. Cirrhosis was defined with ultrasonography. RESULTS: During a median 5.1 years of follow-up, HCC developed in 36 patients. HCC incidence rate at 5 years was significantly higher for cirrhotic patients (19/139, 13.7%), but was not null for non-cirrhotic patients (17/867, 2.0%, P<.001). APRI at a cut-off of 0.5 was more specific but less sensitive for HCC development, and FIB-4 at a cut-off of 1.45 was more sensitive but less specific. When both APRI and FIB-4 were used to group patients, the 5-year cumulative HCC incidence rate was 13.9%, 1.4% and 1.2% for both high, any high, and both low APRI and FIB-4 score among all patients (n=1006, P<.001), respectively, and was 11.4%, 1.5% and 0.4% in the same respective order among non-cirrhotic patients (n=867, P<.001). CONCLUSIONS: The combined use of two non-invasive serum biomarkers (APRI and FIB-4) could stratify HCC risk for chronic HBV-infected patients with LLV. PMID- 28581249 TI - The robotic ENT microsurgery system: A novel robotic platform for microvascular surgery. AB - OBJECTIVE: Assess the feasibility of a novel robotic platform for use in microvascular surgery. STUDY DESIGN: Prospective feasibility study. SETTING: Robotics laboratory. METHODS: The Robotic ENT (Ear, Nose, and Throat) Microsurgery System (REMS) (Galen Robotics, Inc., Sunnyvale, CA) is a robotic arm that stabilizes a surgeon's instrument, allowing precise, tremor-free movement. Six microvascular naive medical students and one microvascular expert performed microvascular anastomosis of a chicken ischiatic artery, with and without the REMS. Trials were blindly graded by seven microvascular surgeons using a microvascular tremor scale (MTS) based on instrument tip movement as a function of vessel width. Time to completion (TTC) was measured, and an exit survey assessed participants' experience. The interrater reliability of the MTS was calculated. RESULTS: For microvascular-naive participants, the mean MTS score for REMS-assisted trials was 0.72 (95% confidence interval [CI] 0.64-1.07) and 2.40 (95% CI 2.12-2.69) for freehand (P < 0.001). The mean TTC was 1,265 seconds for REMS-assisted trials and 1,320 seconds for freehand (P > 0.05). For the microvascular expert, the mean REMS-assisted MTS score was 0.71 (95% CI 0.15 1.27) and 0.86 (95% CI 0.35-1.37) for freehand (P > 0.05). TTC was 353 seconds for the REMS-assisted trial and 299 seconds for freehand. All participants thought the REMS was more accurate and improved instrument handling and stability. The intraclass correlation coefficient for MTS ratings was 0.914 (95% CI 0.823-0.968) for consistency and 0.901 (95% CI 0.795-0.963) for absolute value. CONCLUSION: The REMS is a feasible adjunct for microvascular surgery and a potential teaching tool capable of reducing tremor in novice users. Furthermore, the MTS is a feasible grading system for assessing microvascular tremor. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:2495-2500, 2017. PMID- 28581250 TI - New intermediate-stage subclassification for patients with hepatocellular carcinoma treated with transarterial chemoembolization. AB - BACKGROUND & AIM: The need for a subclassification of Barcelona Clinic Liver Cancer (BCLC) intermediate-stage (BCLC B) has arisen because of its diversity. We evaluated the prognostic capability of the BCLC B subclassification proposed by Bolondi et al. in patients treated with transarterial chemoembolization (TACE). Furthermore, we introduce a new subclassification for intermediate-stage hepatocellular carcinoma (HCC) by using a new parameter related to tumour burden (up-to-11 criteria). METHODS: Of 3268 patients treated with TACE as first-line treatment, 821 patients with intermediate-stage HCC were included in this study. RESULTS: According to the Bolondi subclassification, 208 (25.3%), 529 (64.5%), 43 (5.2%) and 41 (5%) patients were in B1, B2, B3 and B4 respectively. The B1, B2 and B3 subclasses in the Bolondi system showed significantly different survival between contiguous stages with median survival of 51.5, 26 and 14.8 months, respectively (both P<.001 for B1 vs B2 and B2 vs B3); however, survival was rather worse in B3 than B4 (14.8 vs 25 months, P=.025). According to the newly proposed subclassification, 410 (50%), 364 (44.3%) and 47 (5.7%) patients were in B1, B2 and B3 respectively. The median survival progressively decreased from B1 (44.8 months) to B2 (21.5 months) and B3 (11.3 months), with a significant difference between contiguous stages (both P<.001 for B1 vs B2 and B2 vs B3). CONCLUSIONS: Our new BCLC B substaging system, with up-to-11 criteria and Child Pugh class as main parameters, has excellent discriminatory power to subclassify TACE-treated patients into three prognostic substages. PMID- 28581251 TI - Strategies for advancing laryngeal tissue engineering. PMID- 28581252 TI - NAFLD in clinical practice: Can simple blood and anthropometric markers be used to detect change in liver fat measured by 1 H-MRS? AB - BACKGROUND & AIMS: Research in NAFLD management is commonly based on quantitative assessment of liver fat by proton-magnetic resonance spectroscopy (1 H-MRS), and translation of this into clinical practice is currently limited by availability and expense. Novel steatosis biomarkers have been proposed for the prediction of liver fatness; however, whether these are suitable for detecting changes in liver fat is unknown. We aimed to determine the accuracy of these indices, and waist circumference (WC), in quantifying longitudinal change in 1 H-MRS-quantified liver fat. METHODS: We performed a secondary analysis using data from 97 overweight/obese adults (age: 39.7+/-11.5 years, body mass index: 30.7+/-4.4 kg/m2 , liver fat: 6.0+/-4.8%, 65% male) who completed either an 8-week exercise or 12-week nutraceutical intervention, with varying degrees of change in liver fat. Baseline and post-intervention measures were liver fat (1 H-MRS), NAFLD Liver Fat Score, Liver Fat Equation (LFE), Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), the Visceral Adiposity Index (VAI) and WC. RESULTS: Only the change in HSI, FLI and WC was associated with change in liver fat; however, correlations were weak to moderate. There was no agreement between the LFE and 1 H-MRS for detecting liver fat change. Only change in WC significantly affected change in liver fat (P<.001), and WC AUROC for the presence of steatosis was 0.65 and 0.78 for men and women respectively. CONCLUSIONS: Novel indices are limited in their ability to detect longitudinal change in liver fat. Waist circumference may offer modest utility as a surrogate to infer liver fat change with lifestyle interventions. PMID- 28581253 TI - Severe hypoglycaemia among patients with type 2 diabetes requiring emergency hospital admission: The Hypoglycaemia In Portugal Observational Study-Emergency Room (HIPOS-ER). AB - AIMS: To analyse the prevalence of severe hypoglycaemia in patients with type 2 diabetes (T2DM) treated with antihyperglycaemic agents (AHA) and requiring emergency room (ER) assistance, and to analyse the prevalence according to type of AHA therapy. METHODS: The present study, the Hypoglycaemia In Portugal Observational Study-Emergency Room (HIPOS-ER), was a cross-sectional, observational, multicentre, nationwide study, with specific hypoglycaemia source data collection. RESULTS: Within the study period, a total of 425 706 admissions were recorded in the ERs of participating hospitals. The prevalence of severe hypoglycaemic episodes in patients with T2DM was 0.074%. In all, 238 patients were included, more than half of whom were on insulin-based therapy (55.0%) and a third of whom (31.5%) were on oral secretagogue-based therapy. In 61.2% of patients primary care was the main diabetes care setting. The median patient age was 77.5 years and the mean duration of diabetes was 19 years. Missing a meal or low carbohydrate meal content was the most frequent cause of hypoglycaemia (55.9%) and the most frequent triggers for seeking emergency assistance were pre syncope (19.2%) and transient loss of consciousness (17.4%). A total of 44.1% of patients were hospitalized for a median of 5.1 days. Patients in the secretagogue group were admitted to hospital more often than patients in the insulin group (70.7% vs 29.0%; P < .001). Nine patients died. CONCLUSIONS: These findings confirm that severe hypoglycaemia in patients with T2DM requiring ER assistance occurs mainly in those on insulin- and secretagogue-based therapies and is associated with a significant medical burden. Antidiabetic therapy should be individualized to minimize the risk of severe iatrogenic hypoglycaemia, and any intervention to this end should always involve primary care stakeholders. PMID- 28581254 TI - Tree spacing impacts the individual incidence of Moniliophthora roreri disease in cacao agroforests. AB - BACKGROUND: Using conventional pesticides in crop protection has raised serious environmental concerns and there is therefore a need for integrated pest management (IPM) methods. In this paper, we found that the spacing of trees can impact disease, which could result in a reduction in pesticide applications and may act as a potential IPM method. We studied Frosty Pod Rot (FPR) in 20 cacao agroforests in Costa Rica (Upala region). RESULTS: Using a generalized linear mixed model, we analyzed the impact of the neighborhood composition and distance from a studied cacao individual on its individual FPR incidence. We found that the number of cacao tree neighbors in a radius of 3.7 m and the number of fruit trees in a radius of 4.3 m had a significant negative influence on the incidence of FPR on individual cacao trees. Moreover, cacao tree neighbors had the most significant local influence compared to the neighborhood of other taller categories such as fruit or forest trees. CONCLUSION: The mechanisms involved are related to the barrier effect, due to the effectiveness of the cacao tree's architecture as an efficient barrier against FPR spore dispersal. This paper provides new insights into optimization of the spatial environment around each host as an original IPM method. (c) 2017 Society of Chemical Industry. PMID- 28581256 TI - TAZ is involved in transcriptional complexes regulating smooth muscle cell differentiation. AB - TGFbeta signaling plays an important role in the differentiation of vascular smooth muscle cells (VSMCs), yet the mechanism remains largely unknown. The study by Pagiatakis et al. identifies the transcriptional coactivator TAZ as a mediator of TGFbeta signaling in VSMC-specific transcription. TAZ is involved in the formation of stable ternary complexes of SRF/Myocardin on CArG elements that are required for the transcription of VSMC structural genes. PMID- 28581258 TI - Contribution and Responsibility of Psychiatric Researchers to Establish Sociocultural System for Psychiatric Trauma. PMID- 28581257 TI - Data Sharing Statements for Clinical Trials: A Requirement of the International Committee of Medical Journal Editors. PMID- 28581259 TI - Clinical Implication of Optical Coherence Tomography-Based Neoatherosclerosis. AB - Recent research has indicated neoatherosclerosis (NA), the de novo development of atherosclerosis within the neointimal region of the stented segment after coronary stent implantation, as a mechanism of late/very late stent thrombosis (VLST) and restenosis. This research is based on histologic and intravascular imaging studies. Optical coherence tomography (OCT) is an imaging tool that is superior with regard to resolution capacity, and can be used to visualize detailed information about distinct morphological characteristics of the restenotic tissue. Thus, OCT is a valuable imaging tool for examining NA, such as macrophage infiltration, lipid accumulation, in-stent calcification, or neointimal rupture. This article discusses the prevalence, predictors, and clinical implications of NA that can be observed by OCT. PMID- 28581261 TI - Statistical Data Editing in Scientific Articles. AB - Scientific journals are important scholarly forums for sharing research findings. Editors have important roles in safeguarding standards of scientific publication and should be familiar with correct presentation of results, among other core competencies. Editors do not have access to the raw data and should thus rely on clues in the submitted manuscripts. To identify probable errors, they should look for inconsistencies in presented results. Common statistical problems that can be picked up by a knowledgeable manuscript editor are discussed in this article. Manuscripts should contain a detailed section on statistical analyses of the data. Numbers should be reported with appropriate precisions. Standard error of the mean (SEM) should not be reported as an index of data dispersion. Mean (standard deviation [SD]) and median (interquartile range [IQR]) should be used for description of normally and non-normally distributed data, respectively. If possible, it is better to report 95% confidence interval (CI) for statistics, at least for main outcome variables. And, P values should be presented, and interpreted with caution, if there is a hypothesis. To advance knowledge and skills of their members, associations of journal editors are better to develop training courses on basic statistics and research methodology for non-experts. This would in turn improve research reporting and safeguard the body of scientific evidence. PMID- 28581260 TI - Self-Expandable Metallic Stent Placement for the Palliation of Esophageal Cancer. AB - Esophageal stents have been used to palliate patients with dysphagia caused by esophageal cancer. Early rigid plastic prostheses have been associated with a high risk of complications. However, with the development of self-expanding stents, it has developed into a widely accepted method for treating malignant esophageal strictures and esophagorespiratory fistulas (ERFs). The present review covers various aspects of self-expanding metallic stent placement for palliating esophageal cancer, including its types, placement procedures, indications, contraindications, complications, and some of innovations that will become available in the future. PMID- 28581262 TI - What Factors Impact Consumer Perception of the Effectiveness of Health Information Sites? An Investigation of the Korean National Health Information Portal. AB - Lay public's concerns around health and health information are increasing. In response, governments and government agencies are establishing websites to address such concerns and improve health literacy by providing better access to validated health information. Since 2011, the Korean government has constructed the National Health Information Portal (NHIP) website run in collaboration with the Korean Academy of Medical Sciences (KAMS). This study therefore aimed to 1) examine consumer use of NHIP, with respect to the usage patterns, evaluation on health information provided, and perceived effectiveness of the site; and 2) identify factors that may impact perceived effectiveness of the site. An online survey was conducted with 164 NHIP users, recruited through a popup window on the main screen of the portal website from October to November 2015. The significant predicting factors supported by the data include the relevance of health information on the site, the usefulness of information in making health decisions, and the effective visualization of information. These factors can inform future efforts to design more effective health information websites, possibly based on metadata systems, to further advance the lay public's information seeking and health literacy. PMID- 28581263 TI - Dose-Decreasing Effect of the First Reversed Laser Beam Collimator for C-Arm Type Angiographic Equipment. AB - This is a study on the dose-decreasing effect of the first reversed laser beam collimator (RLBC) for C-arm type angiographic equipment. A laser beam was located at the center of each plane at an oblique angle to the angiographic equipment detector. A field of view, which could be seen with the naked eye, was made by focusing the laser beam in the direction of the X-ray source. The height of the table was fixed at 75 cm and the iron balls were located within 2 mm of the top, bottom, left, and right edges of the output image. The time needed for location fixing, fluoroscopy, and measurement of dose area product (DAP) were compared by having 30 radiologists perform location fixing by looking at the fluoroscopic image while performing location fixing (no radiation) and while the RLBC was turned on. In the next test, the time needed for location fixing, fluoroscopy, and DAP were compared when varying the location of the iron balls from 2 to 10 mm from the edges of the output image. The results showed that the time needed for location fixing, the time needed for fluoroscopy, and DAP decreased, both in the first test and the second test. This study confirmed that the use of a RLBC for C arm type angiographic equipment decreases both the time needed to perform the procedure and the radiation dose received. It is expected that continuous advancement of RLBC technology will contribute greatly to decreasing the dose of radiation needed and improving convenience during angiography. PMID- 28581264 TI - Night Shift Work and Risk of Depression: Meta-analysis of Observational Studies. AB - This study aimed to assess whether night shift work is associated with the risk of depression by using a meta-analysis of observational studies. We searched PubMed and EMBASE in August, 2016 to locate eligible studies and investigated the association between night shift work and the risk of depression, reporting outcome measures with adjusted odds ratios (ORs) or relative risks (RRs) and 95% confidence intervals (CIs). In the meta-analysis of a total of 11 observational studies with 9 cross-sectional study, 1 longitudinal study, and 1 cohort study, night shift work was significantly associated with an increased risk of depression (OR/RR, 1.43; 95% CI, 1.24-1.64; I2 = 78.0%). Also, subgroup meta analyses by gender, night shift work duration, type of occupation, continent, and type of publication showed that night shift work was consistently associated with the increased risk of depression. The current meta-analysis suggests that night shift work is associated with the increased risk of depression. However, further large prospective cohort studies are needed to confirm this association. PMID- 28581265 TI - High Maternal Blood Mercury Level Is Associated with Low Verbal IQ in Children. AB - The objective of the present study was to investigate the relationship of IQ in children with maternal blood mercury concentration during late pregnancy. The present study is a component of the Mothers and Children's Environmental Health (MOCEH) study, a multi-center birth cohort project in Korea that began in 2006. The study cohort consisted of 553 children whose mothers underwent testing for blood mercury during late pregnancy. The children were given the Korean language version of the Wechsler Preschool and Primary Scale of Intelligence, revised edition (WPPSI-R) at 60 months of age. Multivariate linear regression analysis, with adjustment for covariates, was used to assess the relationship between verbal, performance, and total IQ in children and blood mercury concentration of mothers during late pregnancy. The results of multivariate linear regression analysis indicated that a doubling of blood mercury was associated with the decrease in verbal and total IQ by 2.482 (95% confidence interval [CI], 0.749 4.214) and 2.402 (95% CI, 0.526-4.279), respectively, after adjustment. This inverse association remained after further adjustment for blood lead concentration. Fish intake is an effect modifier of child IQ. In conclusion, high maternal blood mercury level is associated with low verbal IQ in children. PMID- 28581266 TI - Characteristics of Drug Resistant Tuberculosis in Sanatoria of North Korea. AB - Although several reports about drug-resistant tuberculosis (TB) in North Korea have been published, a nationwide surveillance on this disease remains to be performed. This study aims to analyze the drug resistance patterns of Mycobacterium tuberculosis among the patients in the sanatoria of North Korea, especially during the period when second-line drugs (SLDs) had not yet been officially supplied to this country. The Eugene Bell Foundation (EBF) transferred 947 sputum specimens obtained from 667 patients from 2007 to 2009 to the Clinical Research Center, Masan National Tuberculosis Hospital (MNTH), South Korea. Four hundred ninety-two patients were culture positive for TB (73.8%). Drug susceptibility test (DST) was performed for the bacilli isolated from 489 patients. Over 3 quarters of the cases (76.9%) were multidrug-resistant (MDR)-TB. Additionally, 2 patients had extremely drug-resistant (XDR)-TB. Very high resistance to first-line drugs and low resistance to fluoroquinolones (FQs) and injectable drugs (IDs) except for streptomycin (S) were detected. A small but significant regional variation in resistance pattern was observed. Big city regions had higher rate of MDR-TB, higher resistance to FQs and IDs than relatively isolated regions. In conclusion, significant number of drug-resistant TB was detected in North Korean sanatoria, and small but significant regional variations in resistance pattern were noticeable. However, the data in this study do not represent the nationwide drug resistance pattern in North Korea. Further large-scale evaluations are necessary to estimate the resistance pattern of TB in North Korea. PMID- 28581267 TI - Characterization of Oropharyngeal Carriage Isolates of Neisseria meningitidis in Healthy Korean Adolescents in 2015. AB - The meningococcus carriage rate is age-dependent, with a high prevalence in adolescents and young adults. This cross-sectional study aimed to estimate the oropharyngeal carriage rate of meningococcus among healthy Korean adolescents and its relationship with several population characteristics. The survey was conducted from April to May 2015 among 1,460 first-year high-school students in 9 high schools located in Gyeonggi province, Korea. Each student answered a short questionnaire assessing risk factors for carriage, and posterior pharyngeal wall swab samples were obtained. These samples were cultured on meningococcus selective media, with colonies resembling meningococci identified using the Vitek(r) MS system (bioMerieux, Marcy l'Etoile, France). All isolates were characterized by molecular serogrouping and multilocus sequence typing (MLST). Meningococci were identified from 3.4% (49/1,460) swabs. Current smokers had significantly higher carriage rates than non-smokers (8.2% vs. 2.9%, P = 0.002), and boys had significantly higher carriage rates than girls (4.4% vs. 1.6%, P = 0.004). Serogroup B was the most common serogroup, followed by serogroup C, then 29E and Y. Twenty-seven different sequence types (STs) were identified; the most common were ST-3091, ST-11278, and ST-44. These belonged to clonal complexes (CCs) 269, 32, and 41/44, respectively, known as the hypervirulent clones. Evaluating meningococcal carriage is important to understand the epidemiology of meningococcal disease; however, little data exist in Korea. Similar to western countries, meningococcal serogroup B has emerged in Korea, and hypervirulent clones were identified. It is necessary to monitor the genetic and serologic characteristics of circulating meningococci and to assess the potential strain coverage of meningococcal vaccines. PMID- 28581268 TI - Significance of Serology by Multi-Antigen ELISA for Tissue Helminthiases in Korea. AB - It is clinically important to differentiate tissue-invading helminthiasis. The purpose of this study was to assess the specific immunoglobulin G (IgG) antibody positive rates for clonorchiasis, paragonimiasis, cysticercosis, and sparganosis 4 helminthiases from 1996 to 2006 using multi-antigen enzyme-linked immunosorbent assay (ELISA) in Korea. Results of 6,017 samples, which were referred to our institute for serodiagnosis, were analyzed. The subjects with positive serum IgG antibodies were 1,502 (25.0%) for any of the 4 helminthiases. The overall positive numbers for clonorchiasis, paragonimiasis, cysticercosis, and sparganosis were 728 (12.1%), 166 (2.8%), 729 (12.1%), and 263 (4.4%), respectively. The positive serologic reaction to multi-antigens was determined in 309 (20.6%) of the 1,502 total seropositive subjects. Those with multi-antigen positivity were regarded as positive for the antigen of strongest reaction but cross-reaction to others with weak positive reaction. Annual seropositive rates for those 4 tissue helminthiases ranged from 12.1% to 35.7%. The highest rate was observed in age from 60 to 69 years old and prevalence of men (27.4%; 1,030/3,763) was significantly higher than of women (19.1%; 332/1,741). Hospital records of 165 ELISA positive patients were reviewed to confirm correlation with their clinical diagnosis. Paragonimiasis was highly correlated as 81.8% (9/11), cysticercosis 29.9% (20/67), clonorchiasis 29.0% (20/69), and sparganosis 11.1% (2/18). In conclusion, the multi-antigen ELISA using 4 helminth antigens is useful to differentiate suspected tissue-invading helminthiases, especially ELISA diagnosis of paragonimiasis is reliable. The seropositivity is still high among suspected patients in Korea. PMID- 28581269 TI - Subcutaneous Immunotherapy for Allergic Asthma in a Single Center of Korea: Efficacy, Safety, and Clinical Response Predictors. AB - Allergen-specific immunotherapy is the only causal treatment for allergic diseases. However, the efficacy of immunotherapy may vary around the world due to differences in climate, the nature of aero-allergens and their distribution. The aim of this study was to describe the effects of subcutaneous immunotherapy (SCIT) in Korean adults with allergic asthma (AA). As a retrospective cohort study, we reviewed medical records for 627 patients with AA in Korea who were sensitized to house dust mite (HDM) and/or pollens and who underwent SCIT with aluminum hydroxide adsorbed allergen extract from 2000 to 2012. Rates of remission, defined as no further requirement of maintenance medication, over time were determined by means of life tables and extension of survival analysis. Herein, 627 asthmatic patients achieved remission within a mean of 4.7 +/- 0.2 years. The cumulative incidence rates of remission from AA were 86.9% upon treatment with SCIT. Baseline forced expiratory volume in the first second (FEV1) >= 80% (hazard ratio [HR], 3.10; 95% confidence interval [CI], 1.79-5.39; P < 0.001), and maintenance of immunotherapy for more than 3 years (HR, 1.82; 95% CI, 1.21-2.72; P = 0.004) were significant predictors of asthma remission during SCIT. In 284 patients on SCIT with HDM alone, initial specific immunoglobulin E (IgE) levels to Dermatophagoides pteronyssinus and Dermatophagoides farinae did not show significant difference between remission and non-remission group after adjusting demographic variables. In conclusion, SCIT was effective and safe treatment modality for patients with AA. Initial FEV1 >= 80% and immunotherapy more than 3 years were found to be associated with favorable clinical responses to SCIT. PMID- 28581270 TI - Potential Association of Triglyceride Glucose Index with Cardiac Autonomic Neuropathy in Type 2 Diabetes Mellitus Patients. AB - Cardiac autonomic neuropathy (CAN) is a common and most neglected complication of diabetes, estimated to be roughly 8% in recently diagnosed patients and greater than 50% in patients with chronic disease history. The insulin resistance (IR) itself is bidirectionally associated with increased risk of type 2 diabetes mellitus (T2DM) and CAN is a predisposing factor. The primary objective of the present study was aimed to find a correlation of triglyceride glucose index (TyG index) in CAN patients along with the prevalence of CAN in T2DM patients as a secondary objective. This prevalence study was conducted on 202 patients visiting the diabetic clinic of Hamdard Institute of Medical Sciences and Research, Jamia Hamdard (HIMSR) teaching hospital in New Delhi, India who fulfilled the inclusion criteria. The Ewings autonomic function test was used for diagnosis of CAN. TyG index was calculated for patients based on fasting levels of glucose and triglyceride. The CAN was diagnosed in 62 participants out of 202 T2DM patients (overall prevalence 30.7%). The mean +/- standard deviation (SD) for TyG index was 10.3 +/- 0.2 and 9.5 +/- 0.2 in CAN positive, T2DM patients, respectively. The difference of TyG index, in CAN positive and T2DM patients, was highly significant (P < 0.001). Further correlation analysis was performed to find an association of TyG index, duration, and age with patient groups. TyG index showed a positive correlation with heart rate during deep breathing (HRD), heart rate variation during standing (HRS), blood pressure (BP) response to handgrip and BP response to standing. Our finding highlights the TyG index, low-cost IR index, might be useful as an alternative tool for the early screening of patients at a high risk of diabetic neuropathy. PMID- 28581271 TI - Helicobacter pylori Antigens Inducing Early Immune Response in Infants. AB - To identify the Helicobacter pylori antigens operating during early infection in sera from infected infants using proteomics and immunoblot analysis. Two dimensional (2D) large and small gel electrophoresis was performed using H. pylori strain 51. We performed 2D immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) antibody immunoblotting using small gels on sera collected at the Gyeongsang National University Hospital from 4-11-month-old infants confirmed with H. pylori infection by pre-embedding immunoelectron microscopy. Immunoblot spots appearing to represent early infection markers in infant sera were compared to those of the large 2D gel for H. pylori strain 51. Corresponding spots were analyzed by matrix-assisted laser desorption/ionization time of flight-mass spectrometry (MALDI-TOF-MS). The peptide fingerprints obtained were searched in the National Center for Biotechnology Information (NCBI) database. Eight infant patients were confirmed with H. pylori infection based on urease tests, histopathologic examinations, and pre-embedding immunoelectron microscopy. One infant showed a 2D IgM immunoblot pattern that seemed to represent early infection. Immunoblot spots were compared with those from whole-cell extracts of H. pylori strain 51 and 18 spots were excised, digested in gel, and analyzed by MALDI-TOF-MS. Of the 10 peptide fingerprints obtained, the H. pylori proteins flagellin A (FlaA), urease beta subunit (UreB), pyruvate ferredoxin oxidoreductase (POR), and translation elongation factor Ts (EF-Ts) were identified and appeared to be active during the early infection periods. These results might aid identification of serological markers for the serodiagnosis of early H. pylori infection in infants. PMID- 28581272 TI - The Usefulness of Platelet-derived Microparticle as Biomarker of Antiplatelet Therapy in Kawasaki Disease. AB - Little is known about platelet dynamics and the effect of antiplatelet therapy in Kawasaki disease (KD). This study sought to define platelet activation dynamics in KD patients by assaying platelet-derived microparticles (PDMPs). We measured plasma PDMPs levels in 46 patients with KD using an enzyme-linked immunosorbent assay (ELISA). Blood samples were collected before, at 2-5 days, and 9-15 days after intravenous immunoglobulin (IVIG) infusion, 2 months and 4-5 months after the onset of KD. We measured PDMP levels in 23 febrile and 10 afebrile control patients. In the acute phase of KD patients, PDMP levels increased significantly after IVIG treatment (12.04 +/- 5.58 nmol before IVIG infusion vs. 19.81 +/- 13.21 nmol at 2-5 days after IVIG infusion, P = 0.006). PDMP levels were negatively correlated with age and positively correlated with procalcitonin levels in the acute phase of KD. No significant difference was found in PDMP levels between KD patients with and without coronary artery lesion (CAL). Elevated PDMP levels after IVIG therapy significantly decreased below the pre IVIG level in subacute phase (19.81 +/- 13.21 nmol at 2-5 days after IVIG infusion vs. 8.33 +/- 2.02 nmol at 9-15 days after IVIG infusion, P < 0.001), and PDMP levels stayed below the pre-IVIG level in the convalescent phase, during which antiplatelet therapy was given. However, PDMP levels rebounded after discontinuing aspirin in 17 patients. In conclusion, enhanced platelet activation was noted before treatment of KD and peaked immediately after IVIG treatment. Recurrent rising of PDMP levels was observed after discontinuing aspirin, although there were no significant differences between the PDMP levels at 2 months after the onset of KD and those at 4-5 months after the onset of the disease. PMID- 28581273 TI - Clinical Features of Post-Vaccination Guillain-Barre Syndrome (GBS) in Korea. AB - Guillain-Barre syndrome (GBS) is the most common immune-mediated polyradiculoneuropathy and it is also the most commonly reported severe adverse event following immunization in adults. To evaluate the results of clinical and laboratory features of GBS after vaccination in Korea, we analyzed the claims based data from 2002 to 2014 using materials collected for the Advisory Committee Vaccination Injury Compensation (ACVIC) meeting including, clinical features, nerve conduction studies (NCSs), cerebrospinal fluid (CSF) profiles, treatment, and outcomes. Forty-eight compensated GBS cases (median age, 15 years; interquartile range [IQR], 13-51; male:female ratio, 1:1) of 68 suspected GBS were found following immunization and all of them with influenza immunizations with either monovalent (n = 35) or trivalent (n = 13). Among them, 30 cases fulfilled the Brighton criteria level 1-3 (62.5%). The median duration between the onset of symptoms to nadir, duration of the nadir, and total admission period were 3 (IQR, 2-7 days), 2 (IQR, 1-5 days), and 14 (IQR, 6-33 days) days, respectively. The most frequently reported symptom was quadriparesis which was present in 36 cases (75%) at nadir. CSF examination revealed albuminocytologic dissociation in 25.0% and NCS was abnormal in 61.8%. After treatment, most of them showed improvement. Clinical features were similar to typical post infectious GBS and there were both demyelinating and axonal forms suggesting heterogeneous pathogenic mechanism. In order to improve the diagnostic certainty of post-vaccination GBS, careful documentation of clinical features and timely diagnostic work-up with follow-up studies are needed. PMID- 28581274 TI - Comparison of Electroencephalography (EEG) Coherence between Major Depressive Disorder (MDD) without Comorbidity and MDD Comorbid with Internet Gaming Disorder. AB - Internet gaming disorder (IGD) has many comorbid psychiatric problems including major depressive disorder (MDD). In the present study, we compared the neurobiological differences between MDD without comorbidity (MDD-only) and MDD comorbid with IGD (MDD+IGD) by analyzing the quantitative electroencephalogram (QEEG) findings. We recruited 14 male MDD+IGD (mean age, 20.0 +/- 5.9 years) and 15 male MDD-only (mean age, 20.3 +/- 5.5 years) patients. The electroencephalography (EEG) coherences were measured using a 21-channel digital EEG system and computed to assess synchrony in the frequency ranges of alpha (7.5 12.5 Hz) and beta (12.5-35.0 Hz) between the following 12 electrode site pairs: inter-hemispheric (Fp1-Fp2, F7-F8, T3-T4, and P3-P4) and intra-hemispheric (F7 T3, F8-T4, C3-P3, C4-P4, T5-O1, T6-O2, P3-O1, and P4-O2) pairs. Differences in inter- and intra-hemispheric coherence values for the frequency bands between groups were analyzed using the independent t-test. Inter-hemispheric coherence value for the alpha band between Fp1-Fp2 electrodes was significantly lower in MDD+IGD than MDD-only patients. Intra-hemispheric coherence value for the alpha band between P3-O1 electrodes was higher in MDD+IGD than MDD-only patients. Intra hemispheric coherence values for the beta band between F8-T4, T6-O2, and P4-O2 electrodes were higher in MDD+IGD than MDD-only patients. There appears to be an association between decreased inter-hemispheric connectivity in the frontal region and vulnerability to attention problems in the MDD+IGD group. Increased intra-hemisphere connectivity in the fronto-temporo-parieto-occipital areas may result from excessive online gaming. PMID- 28581275 TI - Relationship between Mobile Phone Addiction and the Incidence of Poor and Short Sleep among Korean Adolescents: a Longitudinal Study of the Korean Children & Youth Panel Survey. AB - Three of ten teenagers in Korea are addicted to mobile phones. The aim of this study was to examine the relationship between mobile phone addiction and the incidence of poor sleep quality and short sleep duration in adolescents. We used longitudinal data from the Korean Children & Youth Panel Survey conducted by the National Youth Policy Institute in Korea (2011-2013). A total of 1,125 students at baseline were included in this study after excluding those who already had poor sleep quality or short sleep duration in the previous year. A generalized estimating equation was used to analyze the data. High mobile phone addiction (mobile phone addiction score > 20) increased the risk of poor sleep quality but not short sleep duration. We suggest that consistent monitoring and effective intervention programs are required to prevent mobile phone addiction and improve adolescents' sleep quality. PMID- 28581276 TI - Effects of Mental Health Support on the Grief of Bereaved People Caused by Sewol Ferry Accident. AB - Few studies have assessed the overall effects of multi-centered, complicated mental health support on the grief process. This study investigated the broader influence of mental health support provided practically to the bereaved family on the severity of complicated grief. Ninety-three bereaved family members of the Sewol ferry accident were recruited. Severity of complicated grief, post traumatic stress disorder (PTSD) and depressive disorder was assessed through self-reporting questionnaire, inventory of complicated grief (ICG), PTSD Check List-5 (PCL-5) and Patient Health Questionnaire-9 (PHQ-9). We also included demographic, socioeconomic, health-related variables, and Functional Social Support Questionnaire (FSSQ), which affect the ICG score. Participants were divided into 4 groups based on the experience of psychotherapy or psychiatry clinic service before the accident and mental health support after the disaster. In univariate analysis, these 4 groups showed a significant difference in the mean ICG score (P = 0.020). Participants who received mental health support only after the Sewol ferry accident (group 2) showed a lower mean ICG score than those who received neither psychotherapy or psychiatry clinic service before the disaster nor mental health support after the accident (group 4). There was no significant correlation between the ICG score and other variables except for subjective health status measured 1 month after the disaster (P = 0.005). There was no significant difference in PCL-5 (P = 0.140) and PHQ-9 scores (P = 0.603) among groups, respectively. In conclusion, mental health support significantly reduced the severity of grief only in those participants who had not received any psychotherapy or psychiatry clinic service before the accident. PMID- 28581277 TI - National Surgical Trends for Distal Radius Fractures in Korea. AB - The objective of this study was to investigate national surgical trends for distal radius fractures (DRFs) in Korea and analyze healthcare institution type specific surgical trends. We analyzed a nationwide database acquired from the Korean Health Insurance Review and Assessment Service (HIRA) from 2011 to 2015. International Classification of Diseases, 10th revision (ICD-10) codes and procedure codes were used to identify patients aged >= 20 years with newly diagnosed DRFs. A total of 459,388 DRFs occurred from 2011 to 2015. The proportion of DRF cases treated by surgery tended to increase over time, from 32.6% in 2011 to 38.3% in 2015 (P < 0.001). Open reduction with internal fixation (ORIF) using a plate steadily gained in popularity each year, increasing from 39.2% of overall surgeries in 2011 to 60.9% in 2015. The type of surgery for DRFs differed depending on the type of healthcare institution. ORIF (91%) was the most popular procedure in tertiary hospitals, whereas percutaneous pinning (58%) was most popular in clinics. In addition, general hospitals and hospitals with 30-100 beds used external fixation more frequently than tertiary hospitals and clinics did. Overall, our findings indicate that surgical treatment of DRF, particularly ORIF, continues to increase, and that the component ratio of operation codes differed according to the healthcare institution type. PMID- 28581278 TI - Reduced Mortality in Severely Injured Patients Using Hospital-based Helicopter Emergency Medical Services in Interhospital Transport. AB - Recent evidence has demonstrated the survival benefits of helicopter transport for trauma patients. The purpose of this study was to evaluate the effectiveness of hospital-based helicopter emergency medical services (H-HEMS) in comparison with ground ambulance transport in improving mortality outcomes in patients with major trauma. Study participants were divided into 2 groups according to type of transport to the trauma center; that is, either via ground emergency medical services (GEMS) or via H-HEMS. The study was conducted from October 2013 to July 2015. Mortality outcomes in the H-HEMS group were compared with those in the GEMS group by using the Trauma and Injury Severity Score (TRISS) analysis. The number of participants finally included in the study was 312. Among these patients, 63 were adult major trauma patients transported via H-HEMS, and 47.6% were involved in traffic accidents. For interhospital transport, the Z and W statistics revealed significantly higher scores in the H-HEMS group than in the GEMS group (Z statistic, 2.02 vs. 1.16; P = 0.043 vs. 0.246; W statistic, 8.87 vs. 2.85), and 6.02 more patients could be saved per 100 patients when H-HEMS was used for transportation. TRISS analysis revealed that the use of H-HEMS for transporting adult major trauma patients was associated with significantly improved survival compared to the use of GEMS. PMID- 28581279 TI - Improved Software to Browse the Serial Medical Images for Learning. AB - The thousands of serial images used for medical pedagogy cannot be included in a printed book; they also cannot be efficiently handled by ordinary image viewer software. The purpose of this study was to provide browsing software to grasp serial medical images efficiently. The primary function of the newly programmed software was to select images using 3 types of interfaces: buttons or a horizontal scroll bar, a vertical scroll bar, and a checkbox. The secondary function was to show the names of the structures that had been outlined on the images. To confirm the functions of the software, 3 different types of image data of cadavers (sectioned and outlined images, volume models of the stomach, and photos of the dissected knees) were inputted. The browsing software was downloadable for free from the homepage (anatomy.co.kr) and available off-line. The data sets provided could be replaced by any developers for their educational achievements. We anticipate that the software will contribute to medical education by allowing users to browse a variety of images. PMID- 28581280 TI - Different Age Distribution between Campylobacteriosis and Nontyphoidal Salmonellosis in Hospitalized Korean Children with Acute Inflammatory Diarrhea. AB - We investigated recent epidemiologic trends regarding campylobacteriosis vs. nontyphoidal salmonellosis (NTS), a previously known leading cause of bacterial enterocolitis in Korean children. Among 363 hospitalized children with acute inflammatory diarrhea, Campylobacter (18.7%) was the most frequently detected pathogen using multiplex polymerase chain reaction tests followed by Salmonella (15.4%). Children with campylobacteriosis were older than children with NTS (112.6 months [interquartile range (IQR) 66.0-160.1] vs. 53 months [IQR 31.0 124.0], P < 0.001) and had higher prevalences of abdominal cramping and stool hemoglobin. Campylobacteriosis may be suspected as a primary cause of acute inflammatory diarrhea in hospitalized school-aged Korean children and adolescents. PMID- 28581282 TI - Letter to the Editor: ASA Physical Status Classification in Surgical Oncology and the Importance of Improving Inter-Rater Reliability. PMID- 28581281 TI - A Case of Rheumatoid Vasculitis Involving Hepatic Artery in Early Rheumatoid Arthritis. AB - Rheumatoid vasculitis is a rare, but most serious extra-articular complications of long-standing, seropositive rheumatoid arthritis (RA). Vasculitis of hepatic artery is an extremely rare but severe manifestation of rheumatoid vasculitis. A 72-year-old woman who presented with polyarthralgia for 2 months was diagnosed with early RA. Since she had manifestations of livedo reticularis, and liver dysfunction which was atypical for RA patients, a percutaneous needle liver biopsy was performed revealing arteritis of a medium-sized hepatic artery. Extensive investigations did not reveal evidences of other systemic causes such as malignancy or systemic vasculitis. The patient was diagnosed with rheumatoid vasculitis involving hepatic arteries based on Bacon and Scott criteria for rheumatoid vasculitis. With high dose corticosteroid and cyclophosphamide induction and methotrexate and tacrolimus maintenance treatment, she was successfully recovered. Association of rheumatoid vasculitis at very early stages of the disease may represent an early aggressive form of RA. PMID- 28581283 TI - The Author's Response: ASA Physical Status Classification in Surgical Oncology and the Importance of Improving Inter-Rater Reliability. PMID- 28581284 TI - Evaluation of Corneal Endothelial Cell Loss After Uncomplicated Phacoemulsification Cataract Surgery With Intracameral Phenylephrine. AB - PURPOSE: To study the effects of intracameral phenylephrine 1.5% on corneal endothelial cell loss and morphological changes in patients who had uneventful phacoemulsification surgery. DESIGN: A double-blind randomized controlled trial. METHODS: This study comprised 295 patients who were randomized into the intracameral (ICM) mydriatic group or topical mydriatic group. Central corneal endothelial cell density (ECD), coefficient of variation (CV), and percentage of hexagonal cells were measured preoperatively and postoperatively at 1 week, 6 weeks, and 3 months with specular microscope. RESULTS: There was no significant difference in endothelial cell density and endothelial cell loss between the topical and ICM mydriatic groups. At 3 months, the mean endothelial cell density in the ICM group was 2129.76 +/- 423.53 cells/mm2 and 2100.54 +/- 393.00 cells/mm2 in the topical group (P = 0.539). The endothelial cell loss was 18.60 +/- 12.79% in the IC M group and 19.44 +/- 11.24% in the topical group (P = 0.550). No significant difference was seen in the percentage of hexagonal cells and coefficient of variation of patients between the 2 groups. CONCLUSIONS: Intracameral phenylephrine was not associated with increased risk of postoperative endothelial cell loss or morphological changes. It can be safely injected into the anterior chamber for pupil dilatation before phacoemulsification cataract surgery. PMID- 28581285 TI - Long-Term Stability of Minimally Invasive Radial Keratotomy for Mild to Moderate Keratoconus. AB - PURPOSE: This study aimed to evaluate the long-term stability of minimally invasive radial keratotomy (mini-RK) for eyes with mild to moderate keratoconus. DESIGN: Retrospective observational case series. METHODS: Eleven eyes from 6 patients with hard contact lens (HCL)-intolerant keratoconus underwent mini-RK and were followed up for more than 5 years. The mini-RK consisted of 8 radial incisions with depths of 90% of the thinnest corneal thickness, based on the Lindstrom nomogram. Best-corrected visual acuity (BCVA), keratometry, and corneal endothelial cell density (ECD) were examined preoperatively and for 5 to 10 years postoperatively. Changes in keratometric astigmatism were evaluated using power vector analysis. Severities of keratoconus preoperatively and 1 year postoperatively were graded using the Amsler-Krumeich classification. RESULTS: The postoperative observation periods were from 6 to 10 years (mean, 7.9 years). There were no changes in the BCVA, ECD, and keratometric astigmatism. The mean keratometric refraction significantly decreased from 47.5 diopters (D) preoperatively to 44.0 D at 1 month after mini-RK (P = 0.037) and was stable over 5 years, whereas keratometric astigmatism did not change from preoperatively through the postoperative period (P > 0.59). Keratoconus of grade 2 or higher improved to lower grades. CONCLUSIONS: The mini-RK treatment was safe and effective for HCL-intolerant eyes with mild to moderate keratoconus. PMID- 28581286 TI - Thermally Stable Sr2RuO4 Electrode for Oxide Heterostructures. AB - The use of thermally stable Sr2RuO4 electrodes in high-temperature synthesis of oxide heterostructures was investigated. Atomically smooth Sr2RuO4 thin films were grown on SrTiO3(001) substrates by pulsed laser deposition and used as a bottom electrode for ferroelectric BaTiO3 capacitors grown at temperatures of up to 1000 degrees C. The thermal stability of Sr2RuO4 electrodes was verified by structural and electrical measurements of the ferroelectric BaTiO3 films. The best growth temperature for the BaTiO3 films was found to be 900 degrees C, exhibiting the largest spontaneous polarization, dielectric constant, and pyroelectric response. We conclude that Sr2RuO4 films are suitable for use as thermally stable electrodes in heterostructures synthesized at temperatures up to at least 1000 degrees C and oxygen pressures from 10-6 to 10-1 Torr. This range of growth film conditions is much wider than that for other common oxide electrode materials such as SrRuO3, widening the available process window for optimizing the performance of oxide electronic devices. PMID- 28581287 TI - Electrochemical Detection of Ultratrace (Picomolar) Levels of Hg2+ Using a Silver Nanoparticle-Modified Glassy Carbon Electrode. AB - Ultratrace levels of Hg2+ have been quantified by undertaking linear sweep voltammetry with a silver nanoparticle-modified glassy carbon electrode (AgNP GCE) in aqueous solutions containing Hg2+. This is achieved by monitoring the change in the silver stripping peak with Hg2+ concentration resulting from the galvanic displacement of silver by mercury: Ag(np) + 1/2Hg2+(aq) -> Ag+(aq) + 1/2Hg(l). This facile and reproducible detection method exhibits an excellent linear dynamic range of 100.0 pM to 10.0 nM Hg2+ concentration with R2 = 0.982. The limit of detection (LoD) based on 3sigma is 28 pM Hg2+, while the lowest detectable level for quantification purposes is 100.0 pM. This method is appropriate for routine environmental monitoring and drinking water quality assessment since the guideline value set by the US Environmental Protection Agency (EPA) for inorganic mercury in drinking water is 0.002 mg L-1 (10 nM). PMID- 28581288 TI - Microporous Lanthanide Metal-Organic Framework Constructed from Lanthanide Metalloligand for Selective Separation of C2H2/CO2 and C2H2/CH4 at Room Temperature. AB - A novel pillar-layer porous lanthanide metal-organic framework [Tb3(ODA)3(BPDC)3Na2]n.Gx (UTSA-222, G = guest molecules) was constructed from an organic ligand [1,1'-biphenyl]-4,4'-dicarboxylate (BPDC2-) and a lanthanide metalloligand [Tb(ODA)]+ (H2ODA = oxydiacetic acid). The UTSA-222 contains two dimensional intersecting channels with the Brunauer-Emmett-Teller surface area and pore volume of 703 m2 g-1 and 0.344 cm3 g-1, respectively, for the activated sample. It shows moderately high adsorption selectivity for C2H2/CO2 and C2H2/CH4 separations at 1 atm and room temperature. PMID- 28581289 TI - Alkoxyurea-Based Histone Deacetylase Inhibitors Increase Cisplatin Potency in Chemoresistant Cancer Cell Lines. AB - The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of antiproliferative effects and HDAC inhibitory activity in the human ovarian cancer cell line A2780, the human squamous carcinoma cell line Cal27, and their cisplatin resistant sublines A2780CisR and Cal27CisR. The three most potent compounds 1g-i showed IC50 values in the low MUM and sub-MUM range. 1g-i revealed low nM IC50 values for HDAC6 with up to 15-fold preference over HDAC1, >3500-fold selectivity over HDAC4, and >100-fold selectivity over HDAC8. Furthermore, their ability to enhance cisplatin sensitivity was analyzed in Cal27 and Cal27CisR cells. Notably, a 48 h preincubation of 1g-i significantly enhanced the antiproliferative effects of cisplatin in Cal27 and Cal27CisR. 1g-i interacted synergistically with cisplatin. These effects were more pronounced for the cisplatin resistant subline Cal27CisR. PMID- 28581291 TI - Dipoles Inside of Dipoles: Insertion Complexes of Polar versus Nonpolar Molecules in Ion Pairs. AB - Highly polar molecular systems are in demand as a means of enabling many important practical applications based on light-matter interactions. In the present work, the insertion complexes of recently synthesized polar molecules trapped between alkali halide counterions are studied. For specific selected compositions, the M-molecule-X systems are predicted to be stable to dissociation into molecule + alkali halide. It is found that unlike their nonpolar molecule based counterparts, the polar molecule complexes can be even more stable than their common dipole-dipole MX-molecule isomers. This makes them thermodynamically stable, highly polar species, with very large dipoles of about 20 D, and they could be used, for example, to develop efficient light sensors. Furthermore, due to the neutralization of the M-X charge transfer in the excited triplet state, such complexes represent unique spin-controlled dipole-switch molecular systems with the large dipole turned off and even inverted by the spin state for the nonpolar and polar molecule complexes, respectively. This potentially could allow various spintronic and optoelectronic applications. In addition, the IR intensity spectra are predicted to sensitively indicate the formation of both the M molecule-X and MX-molecule isomers, thus facilitating their reliable detection and differentiation in experiments. PMID- 28581290 TI - Neoclerodane Diterpenoids from Reehal Fatima, Teucrium yemense. AB - Teucrium yemense (Defl), locally known as Reehal Fatima, is a medicinal plant commonly grown in Saudi Arabia and Yemen. Phytochemical investigation of the aerial parts of T. yemense yielded six new neoclerodane diterpenoids, namely fatimanol A-E (1, 2, 3, 5, and 6) and fatimanone (4), and the known teulepicephin (7). As both the Teucrium genus and the related Lamiaceae family have previously been widely reported to possess anthelmintic and antimicrobial activities, the structural and biological characterization of the seven diterpenoids was pursued. The structures of the new compounds were elucidated from their 2D NMR and MS profiles and by comparison to related compounds. The structure of fatimanol D (5) was confirmed by X-ray crystallographic analysis. The new structures contribute to the breadth of knowledge of secondary metabolites in this genus. PMID- 28581292 TI - Photoinitiated Dynamics in Amorphous Solid Water via Nanoimprint Lithography. AB - Laser pulses that act on fragile samples often alter them irreversibly, motivating single-pulse data collection. Amorphous solid water (ASW) is a good example. In addition, neither well-defined paths for molecules to travel through ASW nor sufficiently small samples to enable molecular dynamics modeling have been achieved. Combining nanoimprint lithography and photoinitiation overcomes these obstacles. An array of gold nanoparticles absorbs pulsed (10 ns) 532 nm radiation and converts it to heat, and doped ASW films grown at about 100 K are ejected from atop the irradiated nanoparticles into vacuum. The nanoparticles are spaced from one another by sufficient distance that each acts independently. Thus, a temporal profile of ejected material is the sum of about 106 "nanoexperiments," yielding high single-pulse signal-to-noise ratios. The size of a single nanoparticle and its immediate surroundings is sufficiently small to enable modeling and simulation at the atomistic (molecular) level, which has not been feasible previously. An application to a chemical system is presented in which H/D scrambling is used to infer the presence of protons in films composed of D2O and H2O (each containing a small amount of HDO contaminant) upon which a small amount of NO2 has been deposited. The pulsed laser heating of the nanoparticles promotes NO2/N2O4 hydrolysis to nitric acid, whose protons enhance H/D scrambling dramatically. PMID- 28581293 TI - Stereoselective Chiral Recognition of Amino Alcohols with 2,2'-Dihydroxybenzil. AB - 2,2'-Dihydroxybenzil is demonstrated to be a highly diastereoselective stereodynamic receptor for the chiral recognition of amino alcohols. The receptor by forming diimine compounds with amino alcohols showed good (11:1) to excellent (>50:1) diastereoselectivity in chloroform. The existence of intramolecular hydrogen bonding with amino alcohols only in an axial conformer is demonstrated by 1H NMR and CD spectroscopy, X-ray crystallography, and DFT computations. The exciton chirality method can be used with diazo-attached 2,2'-dihydroxybenzil. PMID- 28581295 TI - MQCT. I. Inelastic Scattering of Two Asymmetric-Top Rotors with Application to H2O + H2O. AB - A mixed quantum/classical theory (MQCT) for the inelastic collision of two asymmetric-top rotor molecules is developed. In this method, the quantum state-to state transitions between the rotational states of molecules (internal) are treated quantum mechanically using the time-dependent Schrodinger equation, whereas their relative translational motion (responsible for scattering) is treated classically, using the average trajectory approach. Two versions of the formula for transition matrix elements are presented: a straightforward approach that uses numerical multidimensional quadrature over all the internal degrees of freedom and a more standard analytic approach that uses the expansion of the PES over the basis set of spherical harmonics. Adaptation to the case of identical molecules scattering is presented and is applied to the rotational excitation of two water molecules, H2O + H2O, using the PES from recent literature. Calculations of collisional excitation from the ground state of the system into a number of low-lying excited rotational states are carried out in a broad range of energies. Analysis of computed opacity functions shows a rather unusual scattering regime, dominated by a strong anisotropic long-range interaction (dipole-dipole). The coupled-states (CS) approximation is tested and found to agree semiquantitatively (within a factor of 2) with the fully coupled version of the method. Differential cross sections for the elastic scattering indicate a very narrow forward scattering peak. PMID- 28581294 TI - Contrast-Matched Isotropic Bicelles: A Versatile Tool to Specifically Probe the Solution Structure of Peripheral Membrane Proteins Using SANS. AB - Obtaining structural information on integral or peripheral membrane proteins is currently arduous due to the difficulty of their solubilization, purification, and crystallization (for X-ray crystallography (XRC) application). To overcome this challenge, bicelles are known to be a versatile tool for high-resolution structure determination, especially when using solution and/or solid state nuclear magnetic resonance (NMR) and, to a lesser extent, XRC. For proteins not compatible with these high-resolution methods, small-angle X-ray and neutron scattering (SAXS and SANS, respectively) are powerful alternatives to obtain structural information directly in solution. In particular, the SANS-based approach is a unique technique to obtain low-resolution structures of proteins in interactions with partners by contrast-matching the signal coming from the latter. In the present study, isotropic bicelles are used as a membrane mimic model for SANS-based structural studies of bound peripheral membrane proteins. We emphasize that the SANS signal coming from the deuterated isotropic bicelles can be contrast-matched in 100% D2O-based buffer, allowing us to separately and specifically focus on the signal coming from the protein in interaction with membrane lipids. We applied this method to the DYS-R11-15 protein, a fragment of the central domain of human dystrophin known to interact with lipids, and we were able to recover the signal from the protein alone. This approach gives rise to new perspectives to determine the solution structure of peripheral membrane proteins interacting with lipid membranes and might be extended to integral membrane proteins. PMID- 28581296 TI - Synthesis of Donor/Acceptor-Substituted Diazo Compounds in Flow and Their Application in Enantioselective Dirhodium-Catalyzed Cyclopropanation and C-H Functionalization. AB - A tandem reaction system has been developed for the preparation of donor/acceptor substituted diazo compounds in continuous flow coupled to dirhodium-catalyzed C-H functionalization or cyclopropanation. Hydrazones were oxidized in flow by solid supported N-iodo-p-toluenesulfonamide potassium salt (PS-SO2NIK) to generate the diazo compounds, which were then purified by passing through a column of molecular sieves/sodium thiosulfate. PMID- 28581297 TI - The First Enantioselective Total Synthesis of (-)-trans-Dihydronarciclasine. AB - A feasible and enantioselective total synthesis of (-)-trans-dihydronarciclasine [(-)-1], a highly biologically active alkaloid, was devised starting from vanillin (8). The key step of this new synthesis was an asymmetric, organocatalytic Michael addition, in which an optically active nitropentanone [( )-13] was obtained from a butenone derivative (12). Excellent enantioselectivity (>99% ee) was achieved using the (8S,9S)-9-amino(9-deoxy)epiquinine (16) organocatalyst. The target molecule can be prepared in 13 steps from compound (-) 13. The total synthesis has provided a facile and first access to the ent-form of naturally occurring (+)-trans-dihydronarciclasine, a highly potent cytostatic alkaloid. PMID- 28581298 TI - Boronic Acid Mediated Coupling of Catechols and N-Hydroxylamines: A Bioorthogonal Reaction to Label Peptides. AB - An irreversible, three-component assembly with 2-formylphenylboronic acid, catechol, and N-hydroxylamines was achieved in aqueous media. The boronate ester product was formed with substituted catechols including l-DOPA. Assembly was found to be orthogonal to common biological functional groups and both copper(I) catalyzed alkyne-azide cycloaddition and aminoether/carbonyl condensations. Boronate ester formation and aminoether condensation were achieved in one pot with a hexameric peptide. PMID- 28581299 TI - Rhodium-Catalyzed Direct Bis-cyanation of Arylimidazo[1,2-alpha]pyridine via Double C-H Activation. AB - An efficient Cp*Rh(III)-catalyzed selective bis-cyanation of arylimidazo[1,2 alpha]pyridines with N-cyano-N-phenyl-p-methylbenzenesulfonamide via N-directed ortho double C-H activation has been developed. The reaction proceeds with broad functional group tolerance to furnish various cyanated imidazopyridines in high yields. The current methodology exhibits unique characteristics, including high bis-cyanation selectivity, operational convenience, and gram-scale production. PMID- 28581300 TI - Reverse ego-depletion: Acts of self-control can improve subsequent performance in Indian cultural contexts. AB - The strength model of self-control has been predominantly tested with people from Western cultures. The present research asks whether the phenomenon of ego depletion generalizes to a culture emphasizing the virtues of exerting mental self-control in everyday life. A pilot study found that whereas Americans tended to believe that exerting willpower on mental tasks is depleting, Indians tended to believe that exerting willpower is energizing. Using dual task ego-depletion paradigms, Studies 1a, 1b, and 1c found reverse ego-depletion among Indian participants, such that participants exhibited better mental self-control on a subsequent task after initially working on strenuous rather than nonstrenuous cognitive tasks. Studies 2 and 3 found that Westerners exhibited the ego depletion effect whereas Indians exhibited the reverse ego-depletion effect on the same set of tasks. Study 4 documented the causal effect of lay beliefs about whether exerting willpower is depleting versus energizing on reverse ego depletion with both Indian and Western participants. Together, these studies reveal the underlying basis of the ego-depletion phenomenon in culturally shaped lay theories about willpower. (PsycINFO Database Record PMID- 28581302 TI - Forgetting to remember our experiences: People overestimate how much they will retrospect about personal events. AB - People value experiences in part because of the memories they create. Yet, we find that people systematically overestimate how much they will retrospect about their experiences. This overestimation results from people focusing on their desire to retrospect about experiences, while failing to consider the experience's limited enduring accessibility in memory. Consistent with this view, we find that desirability is a stronger predictor of forecasted retrospection than it is of reported retrospection, resulting in greater overestimation when the desirability of retrospection is higher. Importantly, the desire to retrospect does not change over time. Instead, past experiences become less top of-mind over time and, as a result, people simply forget to remember. In line with this account, our results show that obtaining physical reminders of an experience reduces the overestimation of retrospection by increasing how much people retrospect, bringing their realized retrospection more in line with their forecasts (and aspirations). We further observe that the extent to which reported retrospection falls short of forecasted retrospection reliably predicts declining satisfaction with an experience over time. Despite this potential negative consequence of retrospection falling short of expectations, we suggest that the initial overestimation itself may in fact be adaptive. This possibility and other potential implications of this work are discussed. (PsycINFO Database Record PMID- 28581301 TI - Solidarity through shared disadvantage: Highlighting shared experiences of discrimination improves relations between stigmatized groups. AB - Intergroup relations research has largely focused on relations between members of dominant groups and members of disadvantaged groups. The small body of work examining intraminority intergroup relations, or relations between members of different disadvantaged groups, reveals that salient experiences of ingroup discrimination promote positive relations between groups that share a dimension of identity (e.g., 2 different racial minority groups) and negative relations between groups that do not share a dimension of identity (e.g., a racial minority group and a sexual minority group). In the present work, we propose that shared experiences of discrimination between groups that do not share an identity dimension can be used as a lever to facilitate positive intraminority intergroup relations. Five experiments examining relations among 4 different disadvantaged groups supported this hypothesis. Both blatant (Experiments 1 and 3) and subtle (Experiments 2, 3, and 4) connections to shared experiences of discrimination, or inducing a similarity-seeking mindset in the context of discrimination faced by one's ingroup (Experiment 5), increased support for policies benefiting the outgroup (Experiments 1, 2, and 4) and reduced intergroup bias (Experiments 3, 4, and 5). Taken together, these experiments provide converging evidence that highlighting shared experiences of discrimination can improve intergroup outcomes between stigmatized groups across dimensions of social identity. Implications of these findings for intraminority intergroup relations are discussed. (PsycINFO Database Record PMID- 28581304 TI - The relationships between religiosity and youth internalizing symptoms in African American parent-adolescent dyads. AB - OBJECTIVES: African American (AA) adolescents face a greater risk of internalizing symptoms, including symptoms of both depression and anxiety, compared with other racial groups; yet, relatively less is known about the variables that contribute to internalizing symptoms. With the aim of advancing this work, this study examined factors that may buffer against such symptoms (maternal warmth, religiosity), as well as those that may confer additional risk (maternal psychopathology). METHOD: One hundred ninety-three AA single mothers and their adolescent youth reported on religiosity, maternal warmth and depressive symptoms, and youth internalizing symptoms. Dyadic structural equation modeling was used to examine the effects of mother and adolescent religiosity, maternal warmth, maternal depressive symptoms, and adolescent age on youth internalizing symptoms as reported by both the mother and the adolescent. RESULTS: Consistent with hypotheses, maternal depressive symptoms were significantly associated with youth internalizing symptoms (as reported by the adolescent). Further, the impact of maternal religiosity on self-reported youth internalizing symptoms and its subscales was moderated by adolescent age. Specifically, maternal religiosity was associated with fewer self-reported internalizing symptoms in young adolescents, whereas the effect waned in older youth. CONCLUSIONS: Possible predictive coprocesses such as maternal influence on adolescent religious choices and identity formation are explored in the context of adolescent internalizing symptomatology. (PsycINFO Database Record PMID- 28581303 TI - Interplay between children's biobehavioral plasticity and interparental relationship in the origins of internalizing problems. AB - The present study demonstrates the interplay between interparental relationship satisfaction and child plasticity in the origins of internalizing problems in 99 community mothers, fathers, and children. Our cumulative measure of plasticity integrated genetics (5-HTTLPR polymorphism), psychophysiology (skin conductance level), and observed behavior (inhibition, sadness, joy). The interaction between plasticity and interparental relationship satisfaction reflected differential susceptibility. Compared with low-plasticity peers, high-plasticity children had more internalizing problems from 5.5 to 12 years when the interparental relationship at 4.5 years was acrimonious, but fewer problems when it was harmonious. Further, almost half of the children in this sample were "differentially affected" by the interaction such that greater plasticity was associated with fewer internalizing problems when their parents had a harmonious relationship, a key feature of differential susceptibility. (PsycINFO Database Record PMID- 28581305 TI - The roles of family, culture, and social cognitive variables in the career interests and goals of Asian American college students. AB - Although family and cultural factors have been assumed to play important roles in the career development of Asian Americans, theory-driven research on this topic remains limited. We examined culturally relevant factors that may contribute to Asian Americans' consideration of fields in which they are overrepresented (e.g., science, technology, engineering) and underrepresented (e.g., education, social science). Drawing from social cognitive career theory, a culture-specific, social cognitive model of career interests and choice was tested in Holland's (1997) Investigative (I) and Social (S) themes. A sample of 802 Asian American undergraduates completed measures of family support, self-efficacy, outcome expectations, interest, and career choice consideration in relation to both Holland themes. Two indicators of acculturation/enculturation (adherence to Asian values and generation status in the United States) were also obtained. The model accounted for a substantial amount of variance in Asian American college students' career consideration in both themes. Family support and acculturation played varying roles, depending on the Holland theme. For example, family support was linked to career choice consideration both directly (in the S theme) and indirectly, via other predictors (in both themes). Contrary to expectations, the acculturation variables did not moderate the relation of family support or interest to career consideration in either theme. We discuss the implications of these findings for efforts to understand and facilitate the career development of Asian American college students. (PsycINFO Database Record PMID- 28581307 TI - "Familiarity-based stimulus generalization of conditioned suppression": Correction to Robinson, Whitt, and Jones (2017). AB - Reports an error in "Familiarity-based stimulus generalization of conditioned suppression" by Jasper Robinson, Emma J. Whitt and Peter M. Jones (Journal of Experimental Psychology: Animal Learning and Cognition, 2017[Apr], Vol 43[2], 159 170). The article was incorrectly published under American Psychological Association copyright. The authors should have retained copyright of this article under the Creative Commons Attribution License. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2017-15338-002.) We report that stimulus novelty/familiarity is able to modulate stimulus generalization and discuss the theoretical implications of novelty/familiarity coding. Rats in Skinner boxes received clicker -> shock pairings before generalization testing to a tone. Before clicker training, different groups of rats received preexposure treatments designed to systematically modulate the clicker and the tone's novelty and familiarity. Rats whose preexposure matched novelty/familiarity (i.e., either both or neither clicker and tone were preexposed) showed enhanced suppression to the tone relative to rats whose preexposure mixed novelty/familiarity (i.e., only clicker or tone was preexposed). This was not the result of sensory preconditioning to clicker and tone. (PsycINFO Database Record PMID- 28581306 TI - Sandor Rado, American psychoanalysis, and the question of bisexuality. AB - The Hungarian-born physician and psychoanalyst Sandor Rado (1890-1972), who practiced for most of his career in the United States, played a central role in shaping American psychoanalysts' views toward homosexuality. Historians have pointed to Rado's rejection of Freud's notion of constitutional bisexuality as the key theoretical maneuver that both pathologized homosexuality and inspired an optimistic approach to its treatment. Yet scholarly analysis of the arguments that Rado made for his rejection of bisexuality is lacking. This article seeks to provide that analysis, by carefully reviewing and evaluating Rado's arguments by the standards of his own day. Because one of Rado's main arguments is that bisexuality is an outdated concept according to modern biology, I consider what contemporary biologists had to say on the topic. The work of behavioral endocrinologist Frank Beach (1911-1988) is important in this context and receives significant attention here. Rado ultimately distanced himself from Beach's behavioral endocrinology, appealing instead to evolutionary discourse to buttress his claim that homosexuality is pathological. This tactic allowed him to refashion psychoanalysis into a moralistic discipline, one with closer ties to a medical school. (PsycINFO Database Record PMID- 28581308 TI - Feeling sad makes us feel older: Effects of a sad-mood induction on subjective age. AB - A mood-induction paradigm was implemented in a sample of 144 adults covering midlife and old age (40-80 years) to investigate associations between mood and subjective age. Sad or neutral mood was induced by texts and music pieces. Subjective age was operationalized as felt age relative to chronological age. Participants receiving the sad-mood induction reported changes toward older felt ages from pre- to postinduction. Participants receiving the neutral-mood induction reported comparable levels of subjective age at pre- and postinduction. Effects were comparable across middle- and older aged participants. Results suggest that sad affective states might dampen subjective age. (PsycINFO Database Record PMID- 28581309 TI - Age differences in emotion recognition: A question of modality? AB - Previous research has suggested age deficits in unimodal emotion recognition tasks. In 2 studies with independent samples, we tested the idea that older adults' performance will be enhanced in multimodal emotion recognition tasks. In each study, participants were presented with newly developed film clips, each portraying a young or an old woman while she relived an emotional memory. As a first step, participants received the film clips in each of 3 unimodal conditions (facial, lexical, prosodic). As a second step, participants were presented with tasks that contained different combinations of these modalities. Consistent with prior research, younger adults outperformed older adults in unimodal facial and prosodic tasks (Study 1) or in all 3 unimodal tasks (Study 2). As predicted, older adults profited more from multimodal stimuli than young adults so that there were no age deficits in the multimodal tasks (Studies 1 and 2). The findings support the idea that the ecological validity of laboratory tasks influence age differences in emotion recognition. (PsycINFO Database Record PMID- 28581310 TI - Patients with Parkinson's disease display a dopamine therapy related negative bias and an enlarged range in emotional responses to facial emotional stimuli. AB - OBJECTIVE: The literature on emotional processing in Parkinson's disease (PD) patients shows mixed results. This may be because of various methodological and/or patient-related differences, such as failing to adjust for cognitive functioning, depression, and/or mood. METHOD: In the current study, we tested PD patients and healthy controls (HCs) using emotional stimuli across a variety of tasks, including visual search, short-term memory (STM), categorical perception, and emotional stimulus rating. The PD and HC groups were matched on cognitive ability, depression, and mood. We also explored possible relationships between task results and antiparkinsonian treatment effects, as measured by levodopa equivalent dosages (LED), in the PD group. RESULTS: The results show that PD patients use a larger emotional range compared with HCs when reporting their impression of emotional faces on rated emotional valence, arousal, and potency. The results also show that dopaminergic therapy was correlated with stimulus rating results such that PD patients with higher LED scores rated negative faces as less arousing, less negative, and less powerful. Finally, results also show that PD patients display a general slowing effect in the visual search tasks compared with HCs, indicating overall slowed responses. There were no group differences observed in the STM or categorical perception tasks. CONCLUSIONS: Our results indicate a relationship between emotional responses, PD, and dopaminergic therapy, in which PD per se is associated with stronger emotional responses, whereas LED levels are negatively correlated with the strength of emotional responses. (PsycINFO Database Record PMID- 28581311 TI - Facial movements facilitate part-based, not holistic, processing in children, adolescents, and adults. AB - Although most of the faces we encounter daily are moving ones, much of what we know about face processing and its development is based on studies using static faces that emphasize holistic processing as the hallmark of mature face processing. Here the authors examined the effects of facial movements on face processing developmentally in children (8-year-olds), adolescents (12-year-olds), and adults (20-year-olds). In particular, the composite face effect was used to measure the influence of facial movements on part-based versus holistic processing after participants had viewed either a moving or static face in a within-subject design. Experiment 1 examined elastic facial movement (i.e., blinking and chewing). The results showed that children, adolescents, and adults exhibited a significantly smaller composite effect after viewing a moving face than after viewing a static face. This result indicates that elastic facial movement facilitates part-based face processing from at least 8 years of age onward. Experiment 2 examined rigid facial movement (i.e., head turning) and revealed that it too facilitates part-based face processing in children, adolescents, and adults. The results taken together suggest that contrary to the prevailing view, facial movements facilitate part-based, not holistic, face processing in children, adolescents, and adults. The findings call for revision in the conventional way of thinking about what constitutes the developmental trajectory toward mature face processing and also point to the importance of using more naturalistic moving face stimuli to study face processing and its development. (PsycINFO Database Record PMID- 28581312 TI - Babies and math: A meta-analysis of infants' simple arithmetic competence. AB - Wynn's (1992) seminal research reported that infants looked longer at stimuli representing "incorrect" versus "correct" solutions of basic addition and subtraction problems and concluded that infants have innate arithmetical abilities. Since then, infancy researchers have attempted to replicate this effect, yielding mixed findings. The present meta-analysis aimed to systematically compile and synthesize all of the primary replications and extensions of Wynn (1992) that have been conducted to date. The synthesis included 12 studies consisting of 26 independent samples and 550 unique infants. The summary effect, computed using a random-effects model, was statistically significant, d = +0.34, p < .001, suggesting that the phenomenon Wynn originally reported is reliable. Five different tests of publication bias yielded mixed results, suggesting that while a moderate level of publication bias is probable, the summary effect would be positive even after accounting for this issue. Out of the 10 metamoderators tested, none were found to be significant, but most of the moderator subgroups were significantly different from a null effect. Although this meta-analysis provides support for Wynn's original findings, further research is warranted to understand the underlying mechanisms responsible for infants' visual preferences for "mathematically incorrect" test stimuli. (PsycINFO Database Record PMID- 28581313 TI - Tune yourself in: Valence and arousal preferences in music-listening choices from adolescence to old age. AB - In previous studies, older as compared with younger individuals were more strongly motivated to regulate their momentary affect toward pleasant and calm states. Whether these motivational differences are also reflected in regulatory behavior and whether this behavior is efficient in terms of affect change, however, is unclear. To address these issues, we conducted 3 studies with samples ranging in age from adolescence to old adulthood. In Study 1, we developed a novel and age-fair music browsing paradigm for music of diverse musical styles, dates of origin, and affective characteristics. The time spent listening to self selected music with varying levels of valence and arousal served as an indicator of affect-regulatory preferences in 2 different affectively relevant situations, namely after mood induction in Study 2 and before an upcoming discussion with a stranger in Study 3. As predicted, we found a higher preference for music with positive valence and low arousal in older as compared with younger individuals in both studies. Additionally, the efficacy of music listening as an affect regulatory strategy was supported because individuals' current affect significantly changed from before to after music listening (Studies 2 and 3), whereas that was not the case in an active control group listening to neutral nonmusical sounds (Study 3). These results extend previous research on affect regulation by demonstrating the utility of the music browsing paradigm as a behavioral indicator of affect-regulatory preferences in individuals from various age groups. They also provide evidence for age differences in, and affect regulatory effects of, music-choice behavior. (PsycINFO Database Record PMID- 28581314 TI - Intergenerational perceptions of mass trauma's impact on physical health and well being. AB - OBJECTIVE: This study investigated the perceived intergenerational impact of the 1932-1933 forced starvation-genocide of Ukrainians and reports the perceived impact of the mass trauma on physical health and well-being across three generations. METHOD: Interviews were conducted with survivors of the 1930s mass trauma and their adult children and grandchildren. In total, 45 interviews were conducted in Ukraine and a qualitative thematic method was used to analyze the interview texts. RESULTS: Two main themes emerged from the qualitative analysis. First, survivors noted adverse physical health outcomes stemming from their experiences with the 1930s mass trauma. Second, mainly descendants of survivors reported that the mass trauma set into motion biological, psychological and social processes, which in turn, have negatively affected physical health across generations. CONCLUSIONS: Participants viewed the mass trauma of the 1930s to have affected the physical health of not only survivors, but also their adult children and grandchildren born decades after the traumatic event. Recommendations are made for cultural awareness training for clinicians who treat patients with family histories of ancestral trauma. (PsycINFO Database Record PMID- 28581315 TI - Moral injury, posttraumatic stress disorder, and suicidal behavior among National Guard personnel. AB - OBJECTIVE: To empirically examine similarities and differences in the signs and symptoms of posttraumatic stress disorder (PTSD) and moral injury and to determine if the combination of these 2 constructs is associated with increased risk for suicidal thoughts and behaviors in a sample of U.S. National Guard personnel. METHOD: 930 National Guard personnel from the states of Utah and Idaho completed an anonymous online survey. Exploratory structural equation modeling (ESEM) was used to test a measurement model of PTSD and moral injury. A structural model was next constructed to test the interactive effects of PTSD and moral injury on history of suicide ideation and attempts. RESULTS: Results of the ESEM confirmed that PTSD and moral injury were distinct constructs characterized by unique symptoms, although depressed mood loaded onto both PTSD and moral injury. The interaction of PTSD and moral injury was associated with significantly increased risk for suicide ideation and attempts. A sensitivity analysis indicated the interaction remained a statistically significant predictor of suicide attempt even among the subgroup of participants with a history of suicide ideation. CONCLUSION: PTSD and moral injury represent separate constructs with unique signs and symptoms. The combination of PTSD and moral injury confers increased risk for suicidal thoughts and behaviors, and differentiates between military personnel who have attempted suicide and those who have only thought about suicide. (PsycINFO Database Record PMID- 28581316 TI - The relationship between childhood abuse and violent victimization in homeless and marginally housed women: The role of dissociation as a potential mediator. AB - OBJECTIVE: Previous studies have established a link between childhood abuse and dissociation. Other work has shown childhood abuse increases the likelihood of violent victimization in adulthood. Although it has been posited that dissociation may mediate childhood abuse and adult violent victimization, research investigating this hypothesis is sparse, particularly for extremely vulnerable populations such as homeless and unstably housed individuals. investigated the relationship between childhood abuse and dissociation on violent victimization in a cohort of homeless and unstably housed women. We also assessed whether dissociation mediated childhood abuse and violent victimization in this sample. METHOD: Participants were asked at an initial assessment and a 6-month follow-up to report any physical or sexual violence experienced in the previous 6 months. Questionnaires recording history of specific types of childhood abuse, dissociation, and other factors were also recorded at the initial assessment. RESULTS: Hierarchical logistic regression models revealed that childhood sexual abuse (Odds ratio [OR] = 3.10, p < .01) and severe dissociation (OR = 1.99, p < .01) were significantly associated with recent physical violence, and childhood sexual abuse (OR = 3.88, p < .01) and dissociation (OR = 1.87, p < .05) were also associated with recent sexual violence. Dissociation mediated neither childhood abuse on recent physical violence or recent sexual violence. CONCLUSION: Developing approaches that effectively identify and treat dissociation as a part of an overall framework of trauma-informed care in homeless and unstably housed women may be an effective way to decrease future physical violence in this vulnerable population. (PsycINFO Database Record PMID- 28581317 TI - "Learning how to ask": Effectiveness of a training for trauma inquiry and response in substance use disorder healthcare professionals. AB - CONTEXT: Exposure to traumatic events should be systematically assessed in health care services so that trauma-related treatment can be offered when appropriate. However, professionals often lack expertise in trauma inquiry and response, and therefore require training in this field. OBJECTIVE: We aimed to determine whether the "Learning how to ask" training for trauma inquiry and response (Read, Hammersley, & Rudegeair, 2007) is effective in increasing health care professionals' trauma inquiry behavior. METHOD: 148 professionals working in outpatient substance use disorder (SUD) services were cluster-randomized into an intervention or a waiting control group. The intervention group received a 1-day training and a refresher session 3 months later, while the control group received no training. The primary outcome was the change from baseline in the frequency of asking clients about traumatic events. Secondary outcomes were professionals' evaluation of the training, knowledge, attitudes toward and confidence in trauma inquiry and response. RESULTS: Change from baseline in the frequency of asking clients about traumatic events was significantly greater at 3-month and 6-month follow-up in the intervention group compared with the control group (b = 0.43, 95% CI [0.27, 0.59], p < .001). The training was positively evaluated by the participants. Knowledge, positive attitudes toward and confidence in trauma inquiry and response all showed significantly greater increases in the intervention group than in the control group. CONCLUSIONS: These findings suggest that health care professionals can acquire skills in trauma inquiry and response from short trainings, which may enhance systematic assessment of traumatic events. (PsycINFO Database Record PMID- 28581319 TI - Effect of the environment on participation in spinal cord injuries/disorders: The mediating impact of resilience, grief, and self-efficacy. AB - OBJECTIVE: The objective of the study was to test the hypothesis that the influence of environmental barriers on participation will be fully mediated by psychosocial factors (resilience, grief or loss, and self-efficacy) among individuals with spinal cord injuries and disorders. METHOD: This was a cross sectional mailed survey with a national sample of veterans with spinal cord injuries and disorders (n = 565), which included measures of demographics, perceived environmental barriers, participation, resilience, grief or loss, and self-efficacy. Data were analyzed using a latent variable path analysis; the model fit was assessed using chi2, normed chi2, root mean square error of approximation (RMSEA; <0.07), Comparative Fit Index (CFI; >=0.95), and Tucker Lewis Index (TLI; >=0.95). RESULTS: Participants were mostly male (93.9%), Caucasian or White (74.2%), and, on average, 62.4 years of age (SD = 10.48). Almost 62% had paraplegia, and 38.3% had a motor or sensory complete injury. The hypothesized model showed excellent fit, chi2(42) = 153.40, normed chi2 = 3.65, RMSEA = 0.07, CFI = 0.96, TLI = 0.95. To assess for full mediation, a direct path was added from environment to participation. This model showed nearly identical fit, chi2(41) = 153.39, normed chi2 = 3.74, RMSEA = 0.07, CFI = 0.96, TLI = 0.95; the path from environment to participation was not significant, unstandardized coefficient = -0.04, p = .92. Examination of indirect effects of the hypothesized model demonstrated that environment significantly influences participation through psychosocial factors, unstandardized coefficient = -4.85, p < .001. Together these results support full mediation. CONCLUSIONS: In conclusion the present study expands upon past research by suggesting that perceived environmental barriers play a role in internal factors, such as resilience and self-efficacy, which in turn influence participation. Interventions to improve environmental barriers may be warranted, but attention must also be paid to resilience, grief or loss, and self-efficacy to increase participation. (PsycINFO Database Record PMID- 28581318 TI - Effect of alcohol dose on deliberate self-harm in men and women. AB - OBJECTIVE: Nonexperimental survey and field research support the notion that alcohol use may be associated with deliberate self-harm (DSH) across the spectrum of lethality, from nonsuicidal self-injury (NSSI) through suicide. Nonexperimental studies, however, provide limited information about potential causal relationships between alcohol consumption and DSH. Two previous experiments showed that a relatively high-dose of alcohol increases the likelihood of engaging in DSH in men, with DSH defined by the self-administration of a "painful" shock (the self-aggression paradigm [SAP]; Berman & Walley, 2003; McCloskey & Berman, 2003). In this study, we examined whether (a) lower doses of alcohol also elicit DSH, (b) this effect occurs for women as well as men, and (c) individual differences in past nonsuicidal self-injury (NSSI) moderate alcohol's effects on DSH. METHOD: Nonalcohol dependent men and women (N = 210) were assigned either to .00%, .05%, .075%, or .100% blood alcohol concentration (BAC) drink conditions and completed a self-rating scale of NSSI (the Deliberate Self Harm Inventory [DSHI]; Gratz, 2001). As in previous SAP studies, DSH was operationalized by shock setting behavior during a competitive reaction time (RT) game. RESULTS: Overall, a greater proportion of participants in the .075% and .100% (but not .050%) alcohol conditions self-selected a "painful" shock to administer compared to participants in the placebo condition. NSSI predicted self administration of painful shocks, but did not moderate the alcohol effect. CONCLUSIONS: Results provide experimental evidence to support the notion that interventions for self-harm should include processes to monitor and limit alcohol intake. (PsycINFO Database Record PMID- 28581320 TI - Who self-identifies as disabled? An examination of impairment and contextual predictors. AB - PURPOSE/OBJECTIVE: According to Social Identity Theory, minority group members, like people with disabilities, manage stigma by either "passing" as majority group members or identifying with their minority group. Approximately 15% of the world's population has a disability, but only a fraction of those individuals identify themselves as people with disabilities. Disability identification has been associated with positive outcomes including psychosocial well-being, self advocacy, and political engagement. The International Classification of Functioning (ICF) recognizes that "disability" is constructed through the intersection of impairment and context (i.e., personal and environmental factors). This is the first study to examine ICF impairment factors (duration, noticeability, presence congenital impairment, pain, severity, and total number of impairments), personal factors (age, ethnicity, gender, income, and psychological distress), and environmental factors (social support and stigma) that predict disability self-identification. Research Method/Design: Participants living in the United States completed an online survey measuring the factors listed above. To avoid selection bias, disability was not mentioned in recruitment materials. Those who reported at least 1 impairment (n = 710) were retained for analysis. RESULTS: Supporting the ICF proposition that disability results from a combination of impairment and contextual factors, disability identification was predicted by severity, age, income, and stigma. Stigma partially mediated the relationship between severity and identification. CONCLUSIONS/IMPLICATIONS: Stigma and severity were the strongest predictors of disability identification. Future work should examine ways to foster positive disability identity such as cross-impairment connections through support groups, mentoring, and collective action against stigma. (PsycINFO Database Record PMID- 28581321 TI - Does functional motor incomplete (AIS D) spinal cord injury confer unanticipated challenges? AB - PURPOSE/OBJECTIVE: Examine psychological challenges associated with Spinal Cord Injury (SCI) among a cohort of Veterans. Research Method/Design: Cross-sectional descriptive study. SCI Centers participating in a multisite evaluation of longitudinal employment, quality of life, and economic outcomes among a large cohort of veterans with SCI, the Predictive Outcome Model Over Time for Employment (PrOMOTE) project. A total of 1,047 patients from participating SCI Centers provided baseline interviews. Main outcome measures included the Veterans RAND 36-Item Health Survey (VR-36) Mental Component Score (MCS); VR-36 Mental Health Scale; VR-36 Vitality Scale; VR-36 Bodily Pain Scale; Quick Inventory for Depressive Symptomatology, Self-Report (QIDS-SR); Patient Health Questionnaire Depression Scale (PHQ-9); and Diener Satisfaction with Life Scale (SWLS). RESULTS: ANOVA analysis showed that persons with AIS D SCI evidenced higher self reported depressive symptoms, higher pain, and a lower subjective quality of life. CONCLUSIONS/IMPLICATIONS: Individuals with functional motor incomplete spinal cord injury are more vulnerable to psychological distress and a low subjective quality of life than might be expected based on functional outcomes. Further study appears warranted to ascertain potential explanations for these findings. (PsycINFO Database Record PMID- 28581322 TI - Processing genuine and nongenuine smiles as social response to personal performance: An event-related brain potential (ERP) study. AB - We investigated the processing of faces with different smile expressions according to a context of personal performance. Individual judgments of smile happiness were collected to assess the processing of different types of smile when these were presented as a social response in a cognitive conflict task. Two main factors were considered: (a) Expression characteristics of the smile were manipulated: that is, happy (happy-happy), neutral (neutral-happy), or sad (sad happy) eyes were morphed in faces with smiling mouth; (b) The performance context in which the smiling face appeared as social response (after fast, average, or slow correct response). Participants rated happy-happy faces the happiest followed by neutral-happy faces, then sad-happy faces (happy-happy > neutral happy > sad-happy). Moreover, faces were rated more happy after fast responses as compared with average or slow responses (fast > average > slow). In addition to subjective ratings, we recorded the electroencephalography (EEG) and calculated event-related brain potentials (ERPs). The ERPs showed modulations of early visual potentials according to the expression characteristics of the face. The P1 was larger for sad-happy than neutral-happy faces. Moreover, the relationship between performance and face had a significant impact on the early posterior negativity (EPN), an ERP component associated with emotion processing. Faces elicited the largest EPN amplitude after average and slow responses as compared with fast responses. These results show that smile processing and interpretation are determined both by the distinctive perceptual features of the smile expression and by the performance context in which the smiling face occurs. (PsycINFO Database Record PMID- 28581323 TI - Everyday prosociality in the workplace: The reinforcing benefits of giving, getting, and glimpsing. AB - A functional analysis of prosociality considers how predispositions for prosocial behavior prompt, reinforce, and propagate kind behaviors in the real world. To examine the effects of practicing, receiving, and observing everyday prosociality as well as the mechanisms underlying these effects-we randomly assigned employees in a Spanish corporate workplace (N = 111) to be Givers, Receivers, and Controls. Givers practiced 5 acts of kindness for a personalized list of Receivers over 4 weeks. We found that Givers and Receivers mutually benefited in well-being in both the short-term (e.g., on weekly measures of competence and autonomy) and the long-term (e.g., Receivers became happier after 2 months, and Givers became less depressed and more satisfied with their lives and jobs). In addition, Givers' prosocial acts inspired others to act: Receivers paid their acts of kindness forward with 278% more prosocial behaviors than Controls. Our results reveal that practicing everyday prosociality is both emotionally reinforcing and contagious (inspiring kindness and generating hedonic rewards in others) and that receiving everyday prosociality is an unequivocally positive experience (which may further reinforce Givers' actions). Prosociality's benefits shed light on its surprising ubiquity in humanity compared with our closest evolutionary cousins. (PsycINFO Database Record PMID- 28581324 TI - Helping yourself helps others: Linking children's emotion regulation to prosocial behavior through sympathy and trust. AB - Although emotionally well-regulated children are more likely to behave prosocially, the psychological processes that connect their emotion regulation abilities and prosocial behavior are less clear. We tested if other-oriented sympathy and trust mediated the links between emotion regulation capacities (i.e., resting respiratory sinus arrhythmia [RSA], negative emotional intensity, and sadness regulation) and prosocial behavior in an ethnically diverse sample of 4- and 8-year-olds (N = 131; 49% girls). Resting RSA was calculated from children's electrocardiogram data in response to a nondescript video. Sympathy was child and caregiver reported, whereas negative emotional intensity, sadness regulation, trust, and prosocial behavior were caregiver reported. Regardless of age, higher resting RSA was linked to higher sympathy, which was associated with higher prosocial behavior. The positive link between sadness regulation and prosocial behavior was mediated by higher sympathy and trust. Children's other oriented psychological processes may play important roles in translating certain emotion regulation capacities into prosocial behavior. (PsycINFO Database Record PMID- 28581325 TI - Is affect experiencing therapeutic in major depressive disorder? Examining associations between affect experiencing and changes to the alliance and outcome in intensive short-term dynamic psychotherapy. AB - Affect experiencing (AE), defined as the facilitation of client in-session bodily arousal and visceral experiencing of affect, is a distinct theoretical process presumed to contribute to therapeutic improvement. This study examined the role of AE in the treatment of major depressive disorder by exploring its association to client distress and therapeutic alliance on a session-by-session basis. A case series design was used to conduct an intensive analysis of the treatment process of 4 clients who received time-limited intensive short-term dynamic psychotherapy, 2 of whom were considered "recovered" and 2 who showed "no change" based upon posttreatment outcomes. Consistent with our hypothesis, we found that cross-correlations between AE and client distress discriminated between "recovered" and "no change" clients. In "recovered" clients, there was evidence that higher in-session peak affect experience was associated with reduced distress 7 days later. The results did not provide consistent evidence for a reverse effect, showing that lower distress during the preceding week predicted higher AE in that session. Finally, there was evidence that AE is an in-session activity that can promote the strengthening of the therapeutic alliance. These collective findings suggest that AE is an important treatment process that contributes to alliance formation and psychotherapeutic improvement. Clinical implications include further evidence that psychodynamic therapists can utilize AE as an active change ingredient for depression. (PsycINFO Database Record PMID- 28581326 TI - Patients' crying experiences in psychotherapy: Relationship with the patient level of personality organization, clinician approach, and therapeutic alliance. AB - The present study sought to further understand patients' crying experiences in psychotherapy. We asked 64 clinicians to randomly request one patient in their practice to complete a survey concerning crying in psychotherapy as well as a measure of therapeutic alliance. All clinicians provided information regarding their practice and patient diagnostic information. Fifty-five (85.93%) patients cried at least once, and 18 (28.1%) had cried during their most recent session. Patients' frequency of crying episodes in therapy was negatively related with psychotic level of personality organization, while patients' tendency to feel more negative feelings after crying was positively related to lower levels of personality organization. Patients' feeling more in control after crying was positively related with an interpersonal therapeutic approach, while patients' perception of therapists as more supportive after crying was positively related to a psychodynamic approach. Patients' tendency to experience more negative feelings after crying was significantly related with both lower levels of personality organization and patients' perception of the therapeutic alliance as weak. In regard to their most recent crying event in treatment, therapeutic alliance was related to gaining a new understanding of experience not previously recognized by the patient. Further, patients' experiences of having never told anyone about their experience related to a crying episode, as well as their realization of new ideas and feeling of having communicated something that words could not express was positively related to the goal dimension of alliance. Patients' perception of crying as a moment of genuine vulnerability, greater feelings of self-confidence and self-disclosure as well as having had a therapist response that was compassionate and supportive, was positively related with the bond dimension of alliance. Clinical implications and future research directions regarding patient crying experiences in psychotherapy are discussed. (PsycINFO Database Record PMID- 28581327 TI - Countertransference when working with narcissistic personality disorder: An empirical investigation. AB - Narcissistic personality disorder (NPD) is one of the most challenging clinical syndromes to treat in psychotherapy, especially due to the difficulties of establishing a good enough therapist-patient relationship. Countertransference responses to NPD can be particularly intense, frustrating, and difficult to manage, as is often reported in the clinical literature though not clearly supported empirically. The aims of this study were to (a) investigate the relationship between patients' NPD and therapists' responses; (b) examine the associations between patient, clinician, therapy variables and clinicians' reactions during treatment of NPD patients; and (c) provide an empirically derived portrait of countertransference with NPD. A sample of psychiatrists and clinical psychologists (N = 67) completed the Therapist Response Questionnaire to identify patterns of countertransference, the Shedler-Westen Assessment Procedure 200, and the Global Assessment of Functioning Scale to assess the personality pathology and psychosocial functioning of a patient in their care. The results showed that NPD was positively associated with hostile/angry, criticized/devalued, helpless/inadequate, and disengaged countertransference and negatively associated with therapists' positive response, regardless of patients' personality and psychosocial functioning. NPD patients with stronger traits of cluster B personality pathology tended to elicit more negative and heterogeneous countertransference reactions than NPD patients without these features. The countertransference patterns with NPD patients were not strongly influenced by the variables of clinicians and therapy, with the exception of clinical experience. Overall, the portrait of therapists' reactions to NPD provided a clinically nuanced and empirically founded description strongly resembling theoretical-clinical accounts. The therapeutic implications of these findings were discussed. (PsycINFO Database Record PMID- 28581328 TI - Therapist adherence is associated with outcome in cognitive-behavioral therapy for bulimia nervosa. AB - Studies of therapist adherence in relation to treatment outcome have produced mixed results. The aim of the present study was to investigate change in therapist adherence to cognitive-behavioral therapy (CBT) for bulimia nervosa over time, and to investigate the relationship between adherence and client outcome in early, middle, and late phases of treatment. Thirty-six clients received the focused form of "enhanced" CBT (CBT-E) for bulimia nervosa. Trained observers rated audiotapes of 92 full-length therapy sessions from early (Session 3), middle (Session 11), and late phases (Session 20) of treatment using the Cognitive-Behavioral Therapy Treatment Protocol Adherence Scale. Change in adherence across the 3 treatment phases was examined using multilevel analysis. The relationship between early, middle, and late adherence levels and end-of treatment binging frequency was examined using multilevel Poisson regression analysis. Adherence decreased significantly over the course of treatment. Higher levels of therapist adherence in early and middle phases of treatment were associated with reduced binging frequency, whereas higher levels of adherence measured late in treatment was not. Results indicate that therapists' adherence to the CBT-E treatment protocol decreases over time and that high levels of protocol adherence in early and middle phases of treatment are more important for positive client outcomes than high levels of adherence in the end of treatment. (PsycINFO Database Record PMID- 28581329 TI - An empirical analysis of mental state talk and affect regulation in two single cases of psychodynamic child therapy. AB - Literature has shown the importance of mentalizing techniques in symptom remission and emotional understanding; however, no study to date has looked at the dynamic relations between mental state talk and affect regulation in the psychotherapy process. From a psychodynamic perspective, the emergence of the child's capacity to regulate affect through the therapist's reflection on the child's mental states is a core aspect of treatment. In an empirical investigation of 2 single cases with separation anxiety disorder, who were treated in long-term psychodynamic play therapy informed with mentalization principles, the effect of therapists' and children's use of mental state talk on children's subsequent capacity to regulate affect in play was assessed. One case was a positive outcome case, whereas the other did not show symptomatic improvement at the end of treatment. Children's and therapists' utterances in the sessions were coded using the Coding System for Mental State Talk in Narratives, and children's play was coded by Children's Play Therapy Instrument, which generated an index of children's "affect regulation." Time-series Granger Causality tests showed that even though both therapists' use of mental state talk significantly predicted children's subsequent affect regulation, the association between child's mental state talk and affect regulation was only supported for the child who showed clinically significant symptom reduction. This study provided preliminary support that mental state talk in psychodynamic psychotherapy facilitates emotion regulation in play. (PsycINFO Database Record PMID- 28581330 TI - Younger and older adults' associative memory for social information: The role of information importance. AB - The ability to associate items in memory is critical for social interactions. Older adults show deficits in remembering associative information but can sometimes remember high-value information. In two experiments, younger and older participants studied faces, names, and occupations that were of differing social value. There were no age differences in the recall of important information in Experiment 1, but age differences were present for less important information. In Experiment 2, when younger adults' encoding time was reduced, age differences were largely absent. These findings are considered in light of value-directed strategies when remembering social associative information. (PsycINFO Database Record PMID- 28581331 TI - Exploring indications for the Use of direct oral anticoagulants and the associated risks of major bleeding. AB - Thrombosis is a leading cause of morbidity and mortality in the United States. Arterial and venous thromboses are implicated in the pathogenesis of major disorders, including myocardial infarction, ischemic stroke, and venous thromboembolism. Over the past decade, direct oral anticoagulants (DOACs) (eg, direct thrombin inhibitor and factor Xa [FXa] inhibitors) have been adopted as alternatives to warfarin due to their clinical advantages and efficacy for the treatment of thrombosis. As with all anticoagulants, treatment with DOACs is associated with a risk of major bleeding, including life-threatening gastrointestinal bleeds and intracranial hemorrhages (ICHs). In turn, the burden of bleeding associated with DOAC treatment is itself associated with substantial healthcare costs that are amplified by an increased risk of thromboembolic events and mortality following major bleeding events, especially in patients with ICHs. Given the rapid adoption of the DOACs and projected usage in the large patient population affected by thromboembolic conditions, clinicians are increasingly likely to encounter patients with major bleeding events due to DOAC therapy. Unlike warfarin, effective strategies to manage these bleeds are limited. There is an unmet need for reversal agents for use in the management of patients who receive FXa inhibitors and experience life-threatening bleeding or need emergency surgery. Andexanet alfa and ciraparantag are being evaluated as potential antidotes for both direct and indirect FXa inhibitors. PMID- 28581333 TI - Relations of Early Motor Skills on Age and Socialization, Communication, and Daily Living in Young Children With Developmental Disabilities. AB - Young children with developmental disabilities experience known deficits in salient child behaviors, such as social behaviors, communication, and aspects of daily living, behaviors that generally improve with chronological age. The purpose of this study was to examine the mediating effects of motor skills on relations of age and salient child behaviors in a group of young children with developmental disabilities, thus tapping into the potential influences of motor skills in the development of salient child behaviors. One hundred thirteen young children with developmental disabilities participated in this study. Independent mediation analysis, with gender as a moderator between the mediating and outcome variable, indicated that motor skills meditated relations between age and socialization, communication, and daily living skills in young male children with developmental disabilities, but not female participants. Findings suggest motor skill content needs to be considered in combination with other child behaviors commonly focused on in early intervention. PMID- 28581334 TI - Heat Tolerances of Salmonella, Cronobacter sakazakii, and Pediococcus acidilactici Inoculated into Galactooligosaccharide. AB - Food-grade galactooligosaccharide (GOS) with low water activity (aw of ca. 0.7) is used as an ingredient in various foods. We evaluated heat tolerances of Salmonella, Cronobacter sakazakii, and Pediococcus acidilactici at temperatures (70 to 85 degrees C) used during the saturation process of GOS by comparing decimal reduction time (D-values) and thermal resistance constants (z-values). To determine the D- and z-values, GOS containing Salmonella (5.1 to 5.8 log CFU/g) or C. sakazakii (5.3 to 5.9 log CFU/g) was heat treated at 70, 77.5, or 85 degrees C for up to 40, 25, or 15 s, respectively, and GOS containing P. acidilactici (6.1 to 6.5 log CFU/g) was heat treated at 70, 77.5, or 85 degrees C for up to 150, 75, or 40 s, respectively. The D-values were calculated using a linear model for heating time versus microbial population for each bacterium. When the D-values for Salmonella, C. sakazakii, and P. acidilactici in GOS were compared, the thermal resistance of all bacteria decreased as the temperature increased. Among the three bacteria, P. acidilactici had higher D-values than did Salmonella and C. sakazakii. The z-values of Salmonella, C. sakazakii, and P. acidilactici were 30.10, 33.18, and 13.04 degrees C, respectively. Overall order of thermal resistance was P. acidilactici > Salmonella ~ C. sakazakii. These results will be useful for selecting appropriate heat treatment conditions for the decontamination of pathogenic microorganisms during GOS manufacturing. PMID- 28581335 TI - Writing interventions in older adults and former children of the World War II: impact on quality of life and depression. AB - OBJECTIVES: The aim of the current study was to analyze whether biographical writing interventions have an impact on depression and QoL compared to daily diary writing. We also wanted to investigate differential effects between structured and unstructured interventions. METHOD: In two Northern regions of Germany, 119 older adults aged 64-90 were randomly assigned to three different types of narrative writing interventions: written structured and unstructured biographical disclosure as well as daily diary writing. Depression (PHQ-9), QoL (SF-12, EUROHIS) and trauma-related symptoms (PCL-C) were obtained pre- and post interventions as well as at three-month follow-up. RESULTS: Follow-up measures were obtained from 85 participants (29% loss to follow-up; mean age = 73.88; 68.2% female). Results of repeated measurement analysis demonstrated a significant effect on depression with the daily diary writing group showing lower depressive symptoms than structured biographical writing. We did not find a significant impact on QoL. Post-hoc analyses showed that posttraumatic symptoms lead to increases in depressive symptoms. CONCLUSION: In a non-clinical sample of community-dwelling older adults, biographical writing interventions were not favorable to daily diary writing concerning the outcomes of the study. This might be related to the association of traumtic reminiscences of former children of World War II and outcome measures. PMID- 28581332 TI - PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part I: PPAR-alpha. AB - This article provides a comprehensive review about the molecular and metabolic actions of PPAR-alpha. It describes its structural features, ligand specificity, gene transcription mechanisms, functional characteristics and target genes. In addition, recent progress with the use of loss of function and gain of function mouse models in the discovery of diverse biological functions of PPAR-alpha, particularly in the vascular system and the status of the development of new single, dual, pan and partial PPAR agonists (PPAR modulators) in the clinical management of metabolic diseases are presented. This review also summarizes the clinical outcomes from a large number of clinical trials aimed at evaluating the atheroprotective actions of current clinically used PPAR-alpha agonists, fibrates and statin-fibrate combination therapy. PMID- 28581338 TI - Psychiatric Disorders and Quality of Life in the Offspring of Parents with Bipolar Disorder. AB - OBJECTIVE: To determine current and lifetime psychopathology and assess quality of life (QoL) in offspring of a parent with bipolar disorder (BD). METHODS: We investigated 43 offspring of bipolar parents (high-risk offspring [HRO]) (mean age 12.5 +/- 3.1; range 6.7-17.9 years) and 43 comparison offspring matched for sex, age, and IQ of healthy parents. Lifetime and current presence of Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) diagnoses were assessed using Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-PL). We administered parent and self-report versions of General Behavior Inventory and the Screen for Child Anxiety-Related Emotional Disorders (SCARED). QoL was evaluated using the self-report questionnaire KIDSCREN-52. RESULTS: Thirty-seven HRO (86%) and 18 controls (42%) met DSM-5 criteria for at least one lifetime psychiatric diagnosis (adjusted OR = 7.20; 95% CI 2.27-22.81). Compared to controls, HRO had higher lifetime frequency of any mood disorder (33% vs. 2%, p < 0.001), anxiety disorder (60% vs. 14%, p < 0.001), and attention-deficit/hyperactivity disorder (26% vs. 5%, p = 0.01). After adjustment for confounders, only mood (OR = 13.05; 95% CI 1.41-120.60) and anxiety (OR = 9.69; 95% CI 2.75-34.31) disorders remained significantly more frequent in the HRO group. In comparison with controls, HRO scored lower in the following domains: QoL, social support and relationship with peers (p = 0.003; Cohen's d = 0.91), parent relationships and home life (p = 0.008; d = 0.67), as well as self-perception (p = 0.04; d = 0.55). CONCLUSIONS: In agreement with other studies, we found a higher rate of lifetime anxiety and mood disorders in children and adolescents at confirmed familial risk for BD. Reduction in QoL was already evident across a number of domains. Adult psychiatrists should incorporate into their assessment procedures targeted questions on the presence of psychopathology in offspring of their adult patients with severe mental disorders and child services should bridge with adult services providing accessible services to children of affected parents. PMID- 28581337 TI - Featured Article: Electroporation-mediated gene delivery of surfactant protein B (SP-B) restores expression and improves survival in mouse model of SP-B deficiency. AB - Surfactant Protein B Deficiency is a rare but lethal monogenetic, congenital lung disease of the neonate that is unresponsive to any treatment except lung transplantation. Based on the potential that gene therapy offers to treat such intractable diseases, our objective was to test whether an electroporation-based gene delivery approach could restore surfactant protein B expression and improve survival in a compound knockout mouse model of surfactant protein B deficiency. Surfactant protein B expression can be shut off in these mice upon withdrawl of doxycycline, resulting in decreased levels of surfactant protein B within four days and death due to lung dysfunction within four to seven days. Control or one of several different human surfactant protein B-expressing plasmids was delivered to the lung by aspiration and electroporation at the time of doxycycline removal or four days later. Plasmids expressing human surfactant protein B from either the UbC or CMV promoter expressed surfactant protein B in these transgenic mice at times when endogenous surfactant protein B expression was silenced. Mean survival was increased 2- to 5-fold following treatment with the UbC or CMV promoter-driven plasmids, respectively. Histology of all surfactant protein B treated groups exhibited fewer neutrophils and less alveolar wall thickening compared to the control groups, and electron microscopy revealed that gene transfer of surfactant protein B resulted in lamellar bodies that were similar in the presence of electron-dense, concentric material to those in surfactant protein B-expressing mice. Taken together, our results show that electroporation mediated gene delivery of surfactant protein B-expressing plasmids improves survival, lung function, and lung histology in a mouse model of surfactant protein B deficiency and suggest that this may be a useful approach for the treatment of this otherwise deadly disease. Impact statement Surfactant protein B (SP-B) deficiency is a rare but lethal genetic disease of neonates that results in severe respiratory distress with no available treatments other than lung transplantation. The present study describes a novel treatment for this disease by transferring the SP-B gene to the lungs using electric fields in a mouse model. The procedure is safe and results in enough expression of exogenous SP-B to improve lung histology, lamellar body structure, and survival. If extended to humans, this approach could be used to bridge the time between diagnosis and lung transplantation and could greatly increase the likelihood of affected neonates surviving to transplantation and beyond. PMID- 28581336 TI - Challenges and progress in interpretation of non-coding genetic variants associated with human disease. AB - Genome-wide association studies have shown that the far majority of disease associated variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes contribute to disease risk. To identify truly causal non-coding variants and their affected target genes remains challenging but is a critical step to translate the genetic associations to molecular mechanisms and ultimately clinical applications. Here we review genomic/epigenomic resources and in silico tools that can be used to identify causal non-coding variants and experimental strategies to validate their functionalities. Impact statement Most signals from genome-wide association studies (GWASs) map to the non-coding genome, and functional interpretation of these associations remained challenging. We reviewed recent progress in methodologies of studying the non-coding genome and argued that no single approach allows one to effectively identify the causal regulatory variants from GWAS results. By illustrating the advantages and limitations of each method, our review potentially provided a guideline for taking a combinatorial approach to accurately predict, prioritize, and eventually experimentally validate the causal variants. PMID- 28581339 TI - A novel technique to reduce the likelihood of proximal junctional failure. PMID- 28581340 TI - Conservative Treatment of Distal Radius Fractures: A Prospective Descriptive Study. AB - BACKGROUND: Disability of the upper limb is one of the consequences of distal radius fracture (DRF). The outcome of DRF treatment is based on objective clinical variables, as strength or range of movement (ROM); sometimes these variables do not correlate with the functional level of the patient. The principal objective of our study was to assess the repercussion of conservative treatment of DRF on upper limb disability. METHODS: This is a retrospective review of prospectively collected data. We collected data of 61 nonconsecutive DRFs treated conservatively from July 2007 to August 2008. RESULTS: Average Disabilities of the Arm, Shoulder and Hand (DASH) score before fracture was 20.8 points; average DASH score after the fracture was 42.6. There was a significant increase in the upper limb disability after 1 year of follow-up in the patients treated conservatively ( P < .001; size effect, 1.06). Average radial inclination, radial tilt, and radial length were 18.18 degrees , 3.35 degrees , and 5.76 mm, respectively. Average ROM for flexion-extension was 100.6 degrees and for pronation-supination 144.0 degrees . ROM for flexion-extension of the unaffected wrist was 128.2 degrees and for pronation-supination 172.4 degrees . We did not find any significant statistical correlation between the increase in disability and the decrease in the ROM ( P > .05). We did not find any significant statistical correlation between the increase in the disability and the worsening in the radiological parameters ( P > .05). Our results confirm the hypothesis that the conservative treatment of DRF produced an increase in the upper limb disability after 1 year of follow-up. CONCLUSIONS: Our study does not show a correlation between the increase in upper limb disability and the decrease in wrist ROM. Our study did not find a correlation between radiological measures and DASH scores. PMID- 28581341 TI - Improving Cardiometabolic Monitoring of Children on Antipsychotics. AB - OBJECTIVES: This study evaluated changes in cardiometabolic monitoring for children and adolescents who were prescribed an antipsychotic medication in a state mental health system before and after a quality improvement intervention. METHODS: The intervention included education for prescribers, auditing on metabolic monitoring, and feedback to mental health center leaders regarding their monitoring. Research staff extracted yearly data on cardiometabolic monitoring from randomly selected community mental health center records before and after the intervention. Pre- and postintervention changes in monitoring were assessed with chi-squared tests. RESULTS: Evidence of past year monitoring increased: for glucose 18.9%-42.1% (chi2 = 6.75, p < 0.001), for triglycerides 13.5%-31.0% (chi2 = 4.54, p = 0.033), for cholesterol 13.5%-33.1% (chi2 = 5.48, p = 0.019), and for weight 67.6%-84.1% (chi2 = 5.21, p = 0.022). Rates of monitoring for blood pressure and waist circumference increased but not significantly. In both years studied, weight was obtained most frequently and waist circumference was obtained least frequently. CONCLUSIONS: Monitoring rates significantly improved for four out of six parameters evaluated, but overall monitoring rates remained low at the end of the study period. Prescriber education with audit and feedback may improve cardiometabolic monitoring rates, but research is needed to evaluate barriers to monitoring in children. PMID- 28581342 TI - Multiple Disease Resistance Loci Affect Soilborne Disease Resistance in Tobacco (Nicotiana tabacum). AB - Phytophthora nicotianae and Ralstonia solanacearum are two of the most important pathogens affecting tobacco worldwide. Greater insight regarding genetic systems controlling resistance to these two soilborne pathogens, as well as identification of DNA markers associated with genomic regions controlling this resistance, could aid in variety development. An evaluation of 50 historical tobacco lines revealed a high positive correlation between resistances to the two pathogens, preliminarily suggesting that some genomic regions may confer resistance to both pathogens. A quantitative trait loci (QTL) mapping experiment designed to investigate the genetic control of soilborne disease resistance of highly resistant 'K346' tobacco identified four QTL significantly associated with resistance to P. nicotianae (explaining 60.0% of the observed phenotypic variation) and three QTL to be associated with R. solanacearum resistance (explaining 50.3% of the observed variation). The two QTL with the largest effect on Phytophthora resistance were also found to be the QTL with the greatest effects on resistance to Ralstonia. This finding partially explains previously observed associations between resistances to these two pathogens among U.S. current cultivars and within breeding populations. Further study is needed to determine whether these relationships are due to the same genes (i.e., pleiotropy) or favorable coupling-phase linkages that have been established over time. PMID- 28581343 TI - Postoperative acute kidney injury following intraoperative blood product transfusions during cardiac surgery. AB - INTRODUCTION: This study explored the nature of the association between intraoperative usage of red blood cell, fresh frozen plasma, cryoprecipitate or platelet transfusions and acute kidney injury. METHODS: A total of 1175 patients who underwent cardiac surgery between 2008 and 2013 were retrospectively analyzed. We assessed the association between: (1) preoperative patient characteristics and acute kidney injury, (2) intraoperative blood product usage and acute kidney injury, (3) acute kidney injury and 30-day mortality or re hospitalization. RESULTS: In our cohort of 1175 patients, 288 patients (24.5%) developed acute kidney injury. This included 162 (13.8%), 69 (5.9%) and 57 (4.9%) developing stage 1, stage 2 or stage 3 acute kidney injury, respectively. Increased red blood cell, fresh frozen plasma or platelet transfusions increased the odds of developing acute kidney injury. Specifically, every unit of red blood cells, fresh frozen plasma or platelets transfused was associated with an increase in the covariate-adjusted odds ratio of developing ? stage 2 kidney injury of 1.18, 1.19 and 1.04, respectively. CONCLUSIONS: Intraoperative blood product transfusions were independently associated with an increased odds of developing acute kidney injury following cardiac surgery. Further randomized studies are needed to better define intraoperative transfusion criteria. PMID- 28581344 TI - Exploring the Bilingual Phonological Space: Early Bilinguals' Discrimination of Coronal Stop Contrasts. AB - It is well known that the way monolingual listeners discriminate speech sounds is strongly influenced by their native (L1) sound system. Moreover, such perceptual constraints are not limited to monolinguals: multiple studies have found evidence of language-specificity in bilingual speech perception. However, the question of whether bilinguals have simultaneous access to both of their phonologies during non-native contrast discrimination has not been systematically examined. Namely, very few studies of bilinguals have specifically examined cases where a non native contrast pair straddles the boundary between two sound systems, with one sound corresponding to a sound in the L1, and the other to a sound in the second language (L2), but with neither the L1 nor the L2 containing both. The current study aimed to do so by comparing the ability of early bilinguals to discriminate non-native phonetic contrasts consisting of sounds that exist in either their L1 or L2, but not in both. A forced-choice perception task compared two listener groups-Spanish-English bilinguals and English monolinguals-on their perception of Nepali dental-alveolar stop contrasts. Results showed that despite displaying some sensitivity to phonetic differences within each contrast pair, the bilingual group was unable to discriminate such "cross-language contrasts" significantly better than the monolingual English control group. PMID- 28581345 TI - Development and identification of a new Vero cell-based live attenuated influenza B vaccine by a modified classical reassortment method. AB - BACKGROUND: It was to generate a new Vero and cold-adapted live attenuated influenza B vaccine with enough safety and immunogenicity. METHODS: According to modified classical reassortment method, the donor strain was B/Yunnan/2/2005Vca(B), and the parental virus strain was B/Brisbane/60/2008wt. After co-infection in Vero cells, the prepared antibody serum inhibited the donor strain growth, and screening conditions inhibited the parental virus growth, which induced the growth of the new reassortant virus B/Brisbane/60/2008Vca(B) grow. Through intraperitoneal injection (i.j.) and intranasal injection (n.j.) we evaluated the safety and immunogenicity of the vaccine. RESULTS: A high-yield of the reassortant virus was produced in Vero cells at 25 degrees C, similar to the donor strains. After sequencing, it was found that B/Brisbane/60/2008Vca(B) Hemagglutinin (HA) and Neuraminidase (NA) gene fragments were from B/Brisbane/60/2008wt, while the other 6 gene fragments were from B/Yunnan/2/2005Vca(B). The n.j. immune pathway experiments showed no significant differences between the treatment and the PBS control group with respect to weight changes (P > 0.5). Furthermore, the new strain had a sufficient geometric mean titter (GMT) against B/Brisbane/60/2008wt. CONCLUSION: The new reassortant live attenuated influenza B vaccine was safe and having enough immune stimulating ability. PMID- 28581346 TI - Therapeutic Alliance and Group Cohesion in an Online Support Program for Adolescent and Young Adult Cancer Survivors: Lessons from "Recapture Life". AB - Psychological support services for adolescent and young adults (AYAs) with cancer are moving online and are increasingly peer based. It is unclear whether online service delivery impacts critical therapeutic elements such as collaborative patient-therapist rapport and group cohesion. AYA cancer survivors (N = 39) participating in a six-week online cognitive-behavioral therapy group program "Recapture Life"-rated their perception of therapeutic alliance and group cohesion. Participant-rated alliance and group cohesion were high throughout the program, and therapist-rated participant openness, trust, and motivation strengthened over time. The findings provide further support for the expansion of AYA cancer support services to the online domain. PMID- 28581347 TI - Questioning Our APHINITY for More. PMID- 28581348 TI - Safety and efficacy of the Tryton Side Branch StentTM for the treatment of coronary bifurcation lesions: an update. AB - INTRODUCTION: Percutaneous coronary interventions (PCIs) involving coronary bifurcation lesions are associated with adverse outcomes compared with non bifurcation lesions. The Tryton Side Branch Stent has been developed to improve clinical outcomes after bifurcation PCI. Areas covered: We will discuss observational data (clinical registries and intravascular imaging studies) and randomized data from the TRYTON trial (comparing Tryton [used in combination with a main branch drug-eluting stent (DES)] with side branch balloon angioplasty [in combination with a main branch DES; also referred to the provisional strategy]). Expert commentary: The published data showed that the use of Tryton was feasible (successful stent placement in ~95%) and safe (stent thrombosis rates ~0.5% at 9 12 months; no cardiac deaths in the TRYTON trial). Its use resulted in excellent acute angiographic results. However, the TRYTON trial also showed that due to neo intimal tissue growth, luminal dimension at 9 months were similar between Tryton and the provisional strategy. Furthermore, the trial showed an increased risk of peri-procedural myocardial infarction when Tryton was used in small side branches. Based on all data available, the provisional strategy should still be considered as the default strategy in the majority of bifurcation cases, although the use of Tryton may be considered in complex bifurcation anatomies with extensive disease in large side branches, especially when the device will be further improved by a drug-coating. PMID- 28581349 TI - Detection of Coxiella burnetii in Urban River Water. AB - Previous molecular-based studies have identified microorganisms of zoonotic and human nature in surface waters. Contaminated water can lead to human health issues, and the detection of pathogenic microorganisms is a valuable tool for the prevention of their spread. Water samples were taken from the River Tiber in and out of the city of Rome. Genetic analysis of the sequences obtained showed the presence of Coxiella burnetii in both the analyzed sites. Blast analysis showed that two sequences were identical to each other. Sequences from the polluted site showed high homology with different strains of C. burnetii. In this article, we report for the first time the presence of C. burnetii in environmental waters. PMID- 28581350 TI - Determining the key drivers and mitigating factors that influence the role of the Nurse and/or Midwife Consultant: a cross-sectional survey. AB - BACKGROUND: Globally, many nurses and midwives are working at an advanced practice level. The role of a Nurse and/or Midwife Consultant encompasses a diverse and complex interaction between five specified domains namely Clinical Service and Consultancy, Clinical Leadership, Research, Education, and Clinical Services Planning and Management. OBJECTIVE: The objective of this replication study was to identify the key drivers and mitigating factors that impact the role of Australian Nurse and/or Midwife Consultants. DESIGN: Cross-sectional survey. METHODS: The study was conducted in a large metropolitan health district in Sydney, Australia. Participants for this study consisted of all Nurse and/or Midwife Consultants working within a health district in New South Wales (NSW). Data were collected by an anonymous online survey. Key drivers and mitigating factors perceived to influence their role were identified using previously implemented instruments. Data were analysed using SPSS version 21. RESULTS: Responses were obtained from 122 Nurse and/or Midwife Consultants. The number of years of experience as a Nurse and/or Midwife Consultant ranged from 6 months to 25.5 years. Personal attributes which included personal motivation and own communication skills were identified as key drivers to role performance with a mean score of 7.7+/-0.6. Other key drivers included peer support, organisational culture, personal attributes, professional learning, Nurse and/or Midwife Consultant experience, and collaborative relationships. Of the 14 mitigating factors to the role, the most common factors were lack of resources to set up and develop the role (2.6 +/- 0.9), lack of secretarial support (2.6 +/- 1.1), lack of managerial support (2.45 +/- 1.1), and lack of understanding of the role by other health professionals (2.40 +/- 0.8). CONCLUSIONS: Understanding the key drivers and mitigating factors that influence the role of the Nurse and/or Midwife Consultant is important for healthcare managers. Given the changing landscape of nursing and midwifery practice, organisational strategies to provide ongoing support to address the mitigating factors are urgently needed. It is pivotal that nursing management implement strategies to empower Nurse and/or Midwife Consultants to perform and reach their potential to deliver advanced nursing care. PMID- 28581351 TI - Refractory cardiac arrest, inferior vena cava agenesis and extracorporeal cardiopulmonary resuscitation: a demanding combination. AB - Inferior vena cava abnormalities or agenesis had to be suspected in front of technical difficulties during venous catheterization. In the setting of extracorporeal life support and during chest compressions, femoral vascular access is the easiest, most efficient and, perhaps, the first approach for a successful extracorporeal cardiopulmonary resuscitation. In the case of inferior vena cava agenesis leading to cannulation failure and/or complications, the use of the right internal jugular vein for salvage venous cannulation is a potential life-saving strategy. PMID- 28581352 TI - Interferon-gamma mediates the immunosuppression of bone marrow mesenchymal stem cells on T-lymphocytes in vitro. AB - OBJECTIVES: In the present study, we first confirmed the suppressive function of MSCs in allogeneic T cell proliferation and then examined the underlying mechanisms for MSCs' immunomodulation and the role of the pro-inflammatory cytokine interferon (IFN)-gamma. METHODS: Human MSCs were cultured in the presence or absence of IFN-gamma. The expression level of prostaglandin E2 (PGE2), hepatocyte growth factor (HGF), transforming growth factor (TGF)-beta1 and indoleamine 2,3-dioxygenase (IDO) by MSCs were measured. T lymphocytes were isolated from peripheral blood of healthy donors and then induced to proliferate under the stimulation of anti-human CD3 mAb and anti-human CD28 mAb. In the presence of MSCs, T cell proliferation was examined by BrdU incorporation. In addition, PGE2, HGF, TGF-beta1, Kynurenine, recombinant human IFN-gamma and anti IFN-gamma mAb were added and cell proliferation was examined. RESULTS: Compared to the controls (MSCs alone), MSCs cocultured with IFN-gamma expressed significantly higher concentrations of PGE2, HGF and TGF-beta1. The mRNA level of IDO was remarkably increased. Human bone marrow-derived MSCs alone notably suppressed T lymphocytes proliferation in vitro. Addition of exogenous IFN-gamma did not ablate the immunosuppressive effects of MSCs. Addition of anti-IFN-gamma mAb partially restored suppression of T cell proliferation by MSCs. CONCLUSIONS: Human MSCs constitutively expressed immunosuppressive levels of PGE2, HGF and TGF beta1. The proinflammatory cytokine IFN-gamma exhibited synergistic effects with MSCs on immunosuppression, possibly by up-regulating PGE2, HGF and TGF-beta1 in MSCs and inducting MSCs expression of IDO, involved in tryptophan catabolism. PMID- 28581353 TI - Four Night Shifts Have a Degree of Performance Adaptation. AB - OBJECTIVE: In this case control study, we investigated the process of adaptation to night shift (NS) work and recovery back to a day schedule among nurses working a fast-rotation three-shift schedule. BACKGROUND: There is limited knowledge of how specific patterns of a fast-rotation shift affect nurses' performance. METHOD: The cognitive performance of off-duty nurses (OD; n = 21), those working the first night of an NS (1NS; n = 21) and the last night of two ( n = 21), three ( n = 20), and four (4NS; n = 21) successive NSs were compared. Changes in sleep propensity, cognitive function, and anxiety were compared in the daytime after working four successive NSs followed by 24 hr off (4NS-off; n = 18) and in those off duty. RESULTS: The visual attention task (VAT) of cognitive function was significantly worse in the 1NS group and significantly better on the last night in the 4NS group than in the other NS groups. The nurses in the 4NS-off group were less alert and had poorer VAT performance than the OD group during the daytime. CONCLUSION: The nurses working on NS experienced a decrease in VAT performance due to acute changes in circadian rhythm but also significant performance adaptation after four consecutive NSs. One off-duty day was insufficient to recover back to a daytime shift after four consecutive NSs. APPLICATION: In a fast-rotation three-shift schedule, performance adaptation occurred in the nurses who worked four consecutive NSs, and more than one off duty day are needed to recover back to daytime shift after those NSs. PMID- 28581354 TI - Perinatal outcomes associated with intrahepatic cholestasis of pregnancy. AB - OBJECTIVE: The objective of this study is to examine perinatal outcomes associated with cholestasis of pregnancy according to bile acid level and antenatal testing practice. STUDY DESIGN: Retrospective cohort study of women with symptoms and bile acid testing from 2005 to 2014. Women were stratified by bile acid level: no cholestasis (<10 MUmol/L), mild (10-39 MUmol/L), moderate (40 99 MUmol/L), and severe (>=100 MUmol/L). The primary outcome was composite neonatal morbidity (hypoxic ischemic encephalopathy, severe intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, or death). RESULTS: 785 women were included; 487 had cholestasis (347 mild, 108 moderate, 32 severe) and 298 did not. After controlling for gestational age (GA), severe cholestasis was associated with the composite neonatal outcome (aRR 5.6, 95% CI 1.3-23.5) and meconium-stained fluid (aRR 4.82, 95%CI 1.6-14.2). Bile acid levels were not correlated with the frequency of testing (p = .50). Women who underwent twice weekly testing were delivered earlier (p = .016) than women tested less frequently, but the difference in GA was <=4 d. Abnormal testing prompting delivery was uncommon. Among women with cholestasis, there were three stillbirths. One of these women was undergoing antenatal testing, which was normal 1 d prior to the fetal demise. CONCLUSION: Severe cholestasis is associated with neonatal morbidity which antenatal testing may not predict. PMID- 28581355 TI - Pathologizing Altitude: Does Altitude Really Increase Sleep-Disordered Breathing? PMID- 28581357 TI - Pituitary apoplexy presenting as a peripheral rim enhancing parasellar mass lesion with dural enhancement along the tentorium. AB - Pituitary apoplexy is a potentially life-threatening clinical condition caused by rapid enlargement of a pituitary adenoma because of haemorrhage or infarction. The clinical features are typically acute in onset. We report an interesting case of 25-year-old man with complaints of sudden onset of headache and ophthalmoplegia in the right eye one month previously. He had ptosis and complete ophthalmoplegia in the right eye with visual acuity 6/24 and 6/12. Imaging showed a peripheral rim-enhancing mass lesion in the right parasellar and cavernous sinus with a dural tail. He underwent craniotomy and subtotal excision of the lesion. Histopathology was reported as pituitary apoplexy. Hormonal analysis was within normal limits. At two years of follow-up he had complete resolution of ophthalmoplegia and improvement in his vision. It is very uncommon to see pituitary apoplexy evolved in right parasellar region presenting as peripheral rim-enhancing mass lesion. PMID- 28581358 TI - Effect of copper nanoparticles administered in ovo on the activity of proliferating cells and on the resistance of femoral bones in broiler chickens. AB - The objective of this study was to evaluate bone resistance after in ovo administration of copper nanoparticles (NanoCu) and to determine the number of cells positive for proliferating cell nuclear antigen (PCNA) in the femoral bones of broiler chickens (n = 12 per group). The study demonstrated that femoral bones from the NanoCu group were characterised by a higher weight and volume and by significantly greater resistance to fractures compared to the Control group. NanoCu promoted the proliferation of PCNA-positive cells in the long bones of chickens. A significantly higher number of PCNA-positive cells in the bones of birds in the NanoCu group compared with the Control group (137 and 122, respectively) indicate a stimulatory effect during embryogenesis. Considering the improvement in bone resistance to fractures and the effect of NanoCu on the number of PCNA-positive cells in femoral bones, NanoCu may be an alternative agent to minimise the ever-present problem of weak bones in broiler chickens. PMID- 28581359 TI - In Vitro Activity of Sitafloxacin and Additional Newer Generation Fluoroquinolones Against Ciprofloxacin-Resistant Neisseria gonorrhoeae Isolates. AB - Emergence of antimicrobial resistance in Neisseria gonorrhoeae is a major public health concern globally, and new antimicrobials for treatment of gonorrhea are imperative. In this study, the in vitro activity of sitafloxacin, a fluoroquinolone mainly used for respiratory tract or urogenital infections in Japan, and additional newer generation fluoroquinolones were determined against ciprofloxacin-resistant N. gonorrhoeae isolates. Minimum inhibitory concentrations (MICs) of ciprofloxacin, levofloxacin, moxifloxacin, sitafloxacin, pazufloxacin, and tosufloxacin against 47 N. gonorrhoeae isolates cultured in 2009 in Japan were determined by agar dilution method. The quinolone resistance determining region (QRDR) of gyrA and parC was sequenced. The in vitro potency of sitafloxacin was substantially higher compared with all other tested fluoroquinolones. The MICs of sitafloxacin ranged from 0.03 to 0.5 mg/L for 35 ciprofloxacin-resistant N. gonorrhoeae isolates (ciprofloxacin MICs from 2 to 32 mg/L). No identified mutations in GyrA and ParC QRDR resulted in higher sitafloxacin MIC than 0.5 mg/L. Sitafloxacin had a high activity against N. gonorrhoeae isolates, including strains with mutations in DNA gyrase and topoisomerase IV, resulting in high-level resistance to ciprofloxacin and all other newer generation fluoroquinolones examined. However, it was still to a lower extent affected by GyrA and ParC QRDR mutations resulting in sitafloxacin MICs of up to 0.5 mg/L. This indicates that sitafloxacin should not be considered for empirical first-line monotherapy of gonorrhea. However, sitafloxacin could be valuable in a dual antimicrobial therapy and for cases with ceftriaxone resistance or allergy. PMID- 28581360 TI - The role of biofilms in persistent infections and factors involved in ica independent biofilm development and gene regulation in Staphylococcus aureus. AB - Staphylococcus aureus biofilms represent a unique micro-environment that directly contribute to the bacterial fitness within hospital settings. The accumulation of this structure on implanted medical devices has frequently caused the development of persistent and chronic S. aureus-associated infections, which represent an important social and economic burden worldwide. ica-independent biofilms are composed of an assortment of bacterial products and modulated by a multifaceted and overlapping regulatory network; therefore, biofilm composition can vary among S. aureus strains. In the microniches formed by biofilms-produced by a number of bacterial species and composed by different structural components-drug refractory cell subpopulations with distinct physiological characteristics can emerge and result in therapeutic failures in patients with recalcitrant bacterial infections. In this review, we highlight the importance of biofilms in the development of persistence and chronicity in some S. aureus diseases, the main molecules associated with ica-independent biofilm development and the regulatory mechanisms that modulate ica-independent biofilm production, accumulation, and dispersion. PMID- 28581361 TI - The study of H. pylori putative candidate factors for single- and multi-component vaccine development. AB - Helicobacter pylori has grown to colonize inside the stomach of nearly half of the world's population, turning into the most prevalent infections in the universe. Medical care failures noticeably confirm the need for a vaccine to hinder or deal with H. pylori. This review is planned to discuss the most known factors as a vaccine candidate, including single (AhpC, BG, CagA, KatA, Fla, Hsp, HWC, Lpp, LPS, NAP, OMP, OMV, SOD, Tpx, Urease, VacA) and multi-component vaccines. Many promising results in the field of single and multivalent vaccine can be seen, but there is no satisfactory outcome and neither a prophylactic nor a therapeutic vaccine to treat or eradicate the infection in human has been acquired. Hence, selecting suitable antigen is an important factor as an appropriate adjuvant. Taken all together, the development of efficient anti-H. pylori vaccines relies on the fully understanding of the interactions between H. pylori and its host immune system. Therefore, more work should be done on epitope mapping, analysis of molecular structure, and determination of the antigen determinant region as well due to design a vaccine, preferably a multi-component vaccine to elicit specific CD4 T-cell responses that are required for H. pylori vaccine efficacy. PMID- 28581363 TI - Detection of canine adenovirus 1 in red foxes ( Vulpes vulpes) and raccoons ( Procyon lotor) in Germany with a TaqMan real-time PCR assay. AB - We developed a real-time (rt)PCR assay based on TaqMan probe technology for the specific detection of canine adenovirus 1 (CAdV-1). The assay is able to detect three 50% tissue culture infectious dose/mL in CAdV-1-containing cell culture supernatant. Viral genomes were not amplified of canine adenovirus 2 or of several bovine, porcine, and avian adenoviruses. In silico analysis provided no indication of amplification of other heterologous genomes. The sensitivity of the real-time assay exceeded that of a conventional gel-based CAdV-1 PCR by a factor of 100. Following the integration of the novel PCR into the Hessian wildlife monitoring program, CAdV-1 DNA was detected in none of the tested raccoons ( n = 48) but in 11 of 97 foxes. PMID- 28581364 TI - Positron emission tomography computed tomography features of monomorphic epitheliotropic intestinal T-cell lymphoma. AB - OBJECTIVE: To define the positron emission tomography/computed tomography (PET/CT) features of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), a rare malignancy in European and North American populations and the most common form of primary intestinal T-cell lymphoma in Asian populations. METHODS: 18F-fluorodeoxyglucose (FDG) PET/CT findings of a cohort of MEITL patients were retrospectively analyzed. RESULTS: Eight men and four women with MEITL investigated by PET/CT at diagnosis and relapse were retrospectively analyzed. On presentation, the primary involved sites were the small bowel (N = 8), large bowel (N = 2), stomach (N = 1) and small and large bowels (N = 1). The uninvolved small bowel did not show increased FDG-avidity to suggest enteropathy. On presentation, lymph nodes and other organs were involved in seven cases (58%). The primary lesions were hypermetabolic except in one case, where the colonic lesion was eumetabolic. At relapse, the stomach and large bowel might be involved even if the primary tumours arose from the small bowel, and multiple extra intestinal metastases occurred. Interestingly, thoracic structures and the brain were frequently involved (50% and 25% respectively). CONCLUSION: These findings showed that in contrast to classical enteropathy-associated T-cell lymphoma, where the small bowel is the exclusive primary site (owing to its origin from coeliac disease) and distant metastases even during relapse are exceptional, MEITL might on presentation and during relapse involve any part of the gut, and metastasize to multiple extra-intestinal sites. PMID- 28581366 TI - Flat-head positioning increases cerebral blood flow in anterior circulation acute ischemic stroke. A cluster randomized phase IIb trial. AB - Background Whether lying-flat improves blood flow in patients with acute ischemic stroke is unknown. Our aim was to investigate if lying-flat "changes" cerebral blood flow velocities assessed by transcranial Doppler in acute ischemic stroke patients. Methods In a multicenter cluster clinical trial, we randomly assigned patients within 12 h from onset of a neurological deficit due to cerebral ischemia of the anterior circulation to lying-flat or upright head positioning. The primary outcome was a change of 8 cm/s or more in mean cerebral blood flow velocities on transcranial Doppler to the middle cerebral artery at 1 and 24 h post-randomization, adjusted for imbalance in baseline variables. Secondary outcomes included serious adverse events and physical functioning at 90 days. Results Ninety-four of 304 patients screened were recruited. The primary outcome occurred in 11 (26%) of 43 patients in the lying-flat group and in 6 (12%) of 51 in the upright group at 1 h (adjusted odds ratio, 3.81; 95% CI, 1.07 to 13.54), and in 23 (53%) and 18 (36%) patients in these respective groups at 24 h (adjusted odds ratio, 3.04; 95% CI, 1.08 to 8.53). There were no between-group differences in serious adverse events, including pneumonia, heart failure or mortality, nor in functional outcome at 3 months (adjusted common odds ratio, 1.38; 95% CI 0.64 to 3.00). Conclusion The lying-flat head position was associated with a significant increase in cerebral blood flow velocities at one and 24 h within the ipsilateral hemisphere of anterior circulation acute ischemic stroke, without serious safety concerns. Clinical trial registration-URL: http://www.clinicaltrials.gov . Unique identifier: NCT01706094. PMID- 28581365 TI - Fine Epitope Mapping of Monoclonal Antibodies to the DNA Repair Protein, RadA. AB - Repair of DNA damage is vital to the health and survival of all organisms. In Escherichia coli, a protein known as RadA (or Sms) participates in recombinational repair, a process that uses an undamaged DNA strand in one DNA duplex to fill a gap in a homologous DNA strand in a sister DNA duplex. In a prior report, we described the production of monoclonal antibodies (MAbs) specific for RadA. Here, we investigated the epitopes recognized by two of the antibodies, MAbs 6F5 and 2A2. Premature stop codons (ochre mutations) were introduced into the radA gene at selected sites, and the truncated RadA proteins were probed by western blotting. Deletion of as few as four amino acids (457-460) from the C-terminus of RadA significantly increased the sensitivity of E. coli to ultraviolet (UV) radiation and abolished recognition of RadA by MAb 6F5. Single alanine substitutions made between positions 443-460 also adversely affected the ability of MAb 6F5 to bind to RadA, further supporting the idea that MAb 6F5 is specific for the RadA C-terminus. An ochre mutation at position 258 abolished the recognition of RadA by MAb 2A2, whereas an ochre mutation at position 279 did not, suggesting that MAb 2A2 binds to an epitope between residues 258 and 279. MAb 2A2 recognition of RadA was destroyed by endoproteinase glu-C cleavage of RadA at position 266, and by a single alanine substitution at position 265. In a competitive enzyme-linked immunosorbent assay (ELISA), a synthetic peptide comprising residues 263-273 of RadA blocked MAb 2A2 recognition of immobilized full-length RadA by more than 97%. We infer from our results that MAb 6F5 binds to the extreme C-terminus of RadA and that MAb 2A2 is specific for an epitope within positions 263-273. PMID- 28581367 TI - Carbohydrate mouth rinse improves morning high-intensity exercise performance. AB - Oral carbohydrate (CHO) rinsing has been demonstrated to provide beneficial effects on exercise performance of durations of up to one hour. The aim of the present study was to investigate the effects of CHO mouth rinsing on morning high intensity exercise performance. Following institutional ethical approval and familiarisation, 12 healthy males (mean +/- SD age: 23 +/- 3 years, height: 175.5 +/- 7.4 cm, body mass: 75.4 +/- 7.5 kg) participated in this study. Countermovement jump (CMJ) height, isometric mid-thigh pull peak force, 10 m sprint time and bench press and back squat repetitions to failure were assessed following CHO and placebo (PLA) rinsing or a control condition (CON). All testing took place at 07:30 following an 11 hour overnight fast. Performance of CMJ height (CHO: 39 +/- 7 cm; PLA: 38 +/- 7 cm; CON: 36 +/- 6 cm; P = .003, [Formula: see text] = 0.40), 10 m sprint time (CHO: 1.78 +/- 0.07 s; PLA: 1.81 +/- 0.07 s; CON: 1.85 +/- 0.05 s; P = .001, [Formula: see text] = 0.47), the number of bench press (CHO: 25 +/- 3; PLA: 24 +/- 4; CON: 22 +/- 4; P < .001, [Formula: see text] = 0.55) and squat (CHO: 31 +/- 4; PLA: 29 +/- 5; CON: 26 +/- 6; P < .001, [Formula: see text] = 0.70) repetitions and mean felt arousal (CHO: 5 +/- 1; PLA: 4 +/- 0; CON: 4 +/- 0; P = .009, [Formula: see text] = 0.25) improved following CHO rinsing. However, isometric mid-thigh pull peak force was unchanged (CHO: 2262 +/- 288 N; PLA: 2236 +/- 354 N; CON: 2212 +/- 321 N; P = .368, [Formula: see text] = 0.08). These results suggest that oral CHO rinsing solution significantly improved the morning performance of CMJ height, 10 m sprint times, bench press and squat repetitions to failure and felt arousal, although peak force during an isometric mid-thigh pull, rating of perceived exertion and heart rate were unaffected. PMID- 28581369 TI - Fostering Cross-Sector Collaboration. PMID- 28581370 TI - Midwest Nursing Research Society News. PMID- 28581362 TI - PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part II: PPAR-beta/delta and PPAR-gamma. AB - The PPARs are a subfamily of three ligand-inducible transcription factors, which belong to the superfamily of nuclear hormone receptors. In mammals, the PPAR subfamily consists of three members: PPAR-alpha, PPAR-beta/delta and PPAR-gamma. PPARs control the expression of a large number of genes involved in metabolic homeostasis, lipid, glucose and energy metabolism, adipogenesis and inflammation. PPARs regulate a large number of metabolic pathways that are implicated in the pathogenesis of metabolic diseases such as metabolic syndrome, Type 2 diabetes mellitus, nonalcoholic fatty liver disease and cardiovascular disease. The aim of this review is to provide up-to-date information about the biochemical and metabolic actions of PPAR-beta/delta and PPAR-gamma, the therapeutic potential of their agonists currently under clinical development and the cardiovascular disease outcome of clinical trials of PPAR-gamma agonists, pioglitazone and rosiglitazone. PMID- 28581371 TI - Delayed presentation of cerebral schistosomiasis presenting as a tumor-like brain lesion. AB - Schistosomiasis is the second most common parasitic infection worldwide. North America is a nonendemic area. However, there are occasional case reports among travelers and immigrants from endemic regions. We describe a case of a 55-year old Canadian woman who presented with first episode of seizure. Her magnetic resonance imaging scan revealed a mass-like lesion involving the left anterior temporal lobe. The lesion showed T1 hypo- and T2 hyperintense with perilesional brain edema. On post-gadolinium-enhanced T1-weighted sequence, the lesion showed multiple small nodular and linear enhancements, also called an "arborized" appearance. Initially, the lesion was thought to be a malignant tumor. She underwent left anterior temporal lobe resection. Histologic examination showed parasitic eggs with a characteristic lateral spine consistent with Schistosoma mansoni infection. Upon subsequent questioning, it was revealed that the patient lived in Ghana from the ages of 8-10 years and she visited Ghana again 10 years prior for two weeks. She recalled swimming in beaches and rivers. Latent disease, as in this case with presentation, many years or decades after presumed exposure is rare but has been reported. Characteristic magnetic resonance imaging findings may suggest the diagnosis and facilitate noninvasive work-up. PMID- 28581372 TI - Hospital admissions for HIV-infected prisoners in Italy. AB - Purpose The purpose of this paper is to give a description of the clinical conditions and patient demographics of inpatient admissions of human immunodeficiency virus (HIV)-infected inmates in three hospital wards that provide hospital care for inmates in Italy. Design/methodology/approach This is a retrospective review of hospital medical admissions of patients living with HIV from January 1 to December 31, 2014, in three Italian referral centers for hospitalization of inmates. Findings A total of 85 admissions for 85 different HIV-infected inmates occurred in 2014 in the three centers participating to the study. Most patients (54.1 percent) were co-infected with hepatitis C. Discharge diagnosis largely varied ranging from common HIV-related co-morbidities to completely independent diagnosis. The most commonly observed discharge diagnoses were chronic hepatitis C, liver cirrhosis, opiate dependence and thrombocytopenia. Originality/value Discharge diagnosis between HIV-infected inmates and HIV-infected patients in freedom are strikingly and significantly different. A large number of hospitalized HIV-infected inmates were affected by chronic viral hepatitis and liver cirrhosis; this is probably a direct consequence of the high prevalence of HCV and/or HBV co-infections in the inmate population in Italy. In addition, a significantly lower proportion of cancer diagnosis was observed among inmates; this is possibly justified by the fact that in our Italian settings when HIV infection is at advanced stages or if cancer treatment is started those affected are released from prison and can continue their diagnostic and treatment follow-up in freedom. PMID- 28581373 TI - Prisoners perceptions of a mental health wellness workshop. AB - Purpose The purpose of this paper is to report on the evaluation of a one-day mental health wellness workshop which was delivered to male prisoners in an urban prison in the Republic of Ireland. Design/methodology/approach A mixed methods approach was used to evaluate the workshop. This paper presents the findings of the qualitative arm of the evaluation. Qualitative data were collected using semi structured telephone interviews with ten participants who had completed the programme. Findings The participants were overwhelmingly positive about the wellness workshop and the qualitative interviews articulated the ways that the workshop impacted on their ability to manage their own and other peoples mental health. Originality/value As prisons attempt to limit the negative impact of prison life, implementing recovery orientated approaches such as the wellness workshop can have a positive impact on prisoners' mental health as well as raising their awareness and improving their attitudes towards mental distress and suicide. The concepts of self-help and peer support, espoused by the workshop offer a real opportunity to equip interested prisoners with skills to support themselves and other prisoners who are in distress. PMID- 28581374 TI - WEPHREN: a global prison health research network. PMID- 28581375 TI - Teledentistry, new oral care tool for prisoners. AB - Purpose In France, all incarcerated prisoners are required to undergo a dental examination (Ministere de la sante et de la protection sociale, 2004 and Ministere de la justice, 2004). However, only one in two prisoners benefits from this oral health check-up. Oral teleconsultation could improve the quality of oral care in prisons. The paper aims to discuss these issues. Design/methodology/approach The focus of this study was therefore to apply oral teleconsultation as an experiment. Using an oral teleconsultation system, a dentist and a nurse were separately asked to give patients a score, according to how urgently their dental issue needed to be treated. This score will henceforth be referred to as the "dental emergency scores given". Findings The separate dental emergency scores given by the dentist and the nurse were compared and the results demonstrate the following: - 36.7 per cent (11) of the two scores were equal - 53.3 per cent (16) of the two scores differed by 1 point - 10 per cent (3) of the two scores differed by 2 points. The average score of the nurse was 2.23 and that of the dentist was 2.13. The small disparity should not obscure the fact that 63 per cent of the diagnoses turned out to be incorrect. Practical implications Dental care could easily be improved with oral teleconsultation as a care plan could be developed for each patient. Social implications The condition of one's dental health is, of course, very important for general health, but it also affects social aspects. Good oral hygiene and health are very important when looking for a job after having been released from prison. Originality/value This is the first study on oral teleconsultation in prisons. Dental care is rarely studied on prisoners. Telemedicine in dentistry is just beginning all over the world. This study is the first step of an extensive project in the University Hospital of Montpellier and the Villeneuve-les-Maguelone prison. PMID- 28581376 TI - Improving collaboration between professionals supporting mentally ill offenders. AB - Purpose Interprofessional collaboration is necessary when supporting mentally ill offenders but little is understood of these interactions. The purpose of this paper is to explore prison officers' perceptions of current and desirable levels of interprofessional collaboration (relational coordination (RC)) to understand how collaboration between these systems can be improved. Design/methodology/approach Gittell's RC scale was administered to prison officers within the Norwegian prison system ( n=160) using an adaptation of the instrument in which actual and desired levels of RC are evaluated. This differentiates between prison officers' expectations of optimum levels of collaboration with other professional groups, dependent on the role function and codependence, vs actual levels of collaboration. Findings Prison officers reported different RC levels across professional groups, the lowest being with specialist mental health staff and prison doctors and highest with nurses, social workers and other prison officers. Significant differences between desired and actual RC levels suggest expertise of primary care staff is insufficient, as prison officers request much greater contact with mental health specialists when dealing with the mentally ill offender. Originality/value The paper contributes to limited literature on collaborative practice between prison and health care professionals. It questions the advisability of enforcing care pathways that promote the lowest level of effective care in the prison system and suggest ways in which mental health specialists might be better integrated into the prison system. It contributes to the continued debate on how mental health services should be integrated into the prison system, suggesting that the current import model used in Norway and other countries, may not be conducive to generating the close professional relationships required between mental health and prison staff. PMID- 28581377 TI - Fear of rape from behind prison walls. AB - Purpose The Prison Rape Elimination Act has brought significant attention to the issue of sexual victimization within correctional institutions. While the actual risk of sexual victimization remains low, the perception of rape among inmates is high. Given how one's fear can translate into behavior, understanding how institutions impact the culture surrounding prison rape highlights areas for reducing violence within prisons. The paper aims to discuss these issues. Design/methodology/approach This study includes secondary analysis of a quantitative database created from semi-structured interviews with 564 high security, general population inmates. Using fear of rape as the outcome of interest, bivariate and logistic regression analyses are used to comment on the impact of individual and facility level characteristics on this outcome. Findings In general, the results from this study suggest that the greatest risk factors for fearing rape while in prison are being male, having a mental health issue, and hearing about rape within the institution. From these specific findings a few general lessons can be learned with the hope that practitioners can translate these lessons into policy initiatives in order to combat fear of rape among our inmate population. Originality/value This paper aims to fill a gap in the research on how the facility contributes to the fear of rape within prison. The end goal is to inform policy makers so that suggestions can be made to combat this problem and prevent further misconduct within these facilities. PMID- 28581378 TI - Prison health service directors' views on research priorities and organizational issues in conducting research in prison: outcomes of a national deliberative roundtable. AB - Purpose Given that prisoners have significant health needs across most areas, the paucity of prisoner health research, and the difficulties involved in the conduct of research in this setting, there is a need to develop research priorities that align with key stakeholder groups. One such group are those responsible for health service provision in prisons - prison health service directors. The paper aims to discuss these issues. Design/methodology/approach Prison health service directors in each Australian state and territory were invited to participate in a national (deliberative) roundtable where the consensus building nominal group technique was utilized. This involved the identification of research priorities and organizational issues in conducting research with prisoners, and ranking research priorities. A thematic analysis was conducted on organizational issues. Findings In total, 13 participants attended the roundtable. Participants identified 28 research priorities and 12 organizational issues. Top ranked research priorities were mental health, cognitive and intellectual disability, post-release health maintenance, ageing prisoners, chronic health conditions and Aboriginal and Torres Strait Islander health. Themes identified from the organizational issues included prisoner access to research participation, health and research literacy of custodial staff, and institutional protectionism in response to research that may discover negative information about the custodial setting. Research limitations/implications These findings should inform future efforts to improve research infrastructures to undertake research to improve the health of people in Australian prisons, and help to align researchers' efforts with those of a key organizational stakeholder. Originality/value This is the first paper to determine the research priorities and organizational issues in conducting research in prisons of prison health service directors. PMID- 28581356 TI - Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. AB - BACKGROUND: Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer. METHODS: We randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo. RESULTS: In the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3-year rates of invasive-disease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%). CONCLUSIONS: Pertuzumab significantly improved the rates of invasive disease-free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. (Funded by F. Hoffmann-La Roche/Genentech; APHINITY ClinicalTrials.gov number, NCT01358877 .). PMID- 28581380 TI - ICTV Virus Taxonomy Profile: Corticoviridae. AB - The Corticoviridae is a family of icosahedral, internal-membrane-containing viruses with double-stranded circular DNA genomes of approximately 10 kb. Only one species, Pseudoalteromonas virus PM2, has been recognized. Pseudoalteromonas virus PM2 infects Gram-negative bacteria and was isolated from seawater in 1968. Pseudoalteromonas virus PM2 is the first bacterial virus in which the presence of lipids in the virion has been demonstrated. Viral lipids are acquired selectively during virion assembly from the host cytoplasmic membrane. The outer protein capsid is an icosahedron with a pseudo T=21 symmetry. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Corticoviridae, which is available at www.ictv.global/report/corticoviridae. PMID- 28581379 TI - Bottleneck analysis at district level to illustrate gaps within the district health system in Uganda. AB - BACKGROUND: Poor quality of care and access to effective and affordable interventions have been attributed to constraints and bottlenecks within and outside the health system. However, there is limited understanding of health system barriers to utilization and delivery of appropriate, high-impact, and cost effective interventions at the point of service delivery in districts and sub districts in low-income countries. In this study we illustrate the use of the bottleneck analysis approach, which could be used to identify bottlenecks in service delivery within the district health system. METHODS: A modified Tanahashi model with six determinants for effective coverage was used to determine bottlenecks in service provision for maternal and newborn care. The following interventions provided during antenatal care were used as tracer interventions: use of iron and folic acid, intermittent presumptive treatment for malaria, HIV counseling and testing, and syphilis testing. Data from cross-sectional household and health facility surveys in Mayuge and Namayingo districts in Uganda were used in this study. RESULTS: Effective coverage and human resource gaps were identified as the biggest bottlenecks in both districts, with coverage ranging from 0% to 66% for effective coverage and from 46% to 58% for availability of health facility staff. Our findings revealed a similar pattern in bottlenecks in both districts for particular interventions although the districts are functionally independent. CONCLUSION: The modified Tanahashi model is an analysis tool that can be used to identify bottlenecks to effective coverage within the district health system, for instance, the effective coverage for maternal and newborn care interventions. However, the analysis is highly dependent on the availability of data to populate all six determinants and could benefit from further validation analysis for the causes of bottlenecks identified. PMID- 28581381 TI - Erratum: The serology of Ebolavirus - a wider geographical range, a wider genus of viruses or a wider range of virulence? PMID- 28581382 TI - Erratum: Temporal expression profiling of novel Spodoptera litura nucleopolyhedrovirus-encoded microRNAs upon infection of Sf21 cells. PMID- 28581383 TI - Correction: Recruitment of the default mode network during a demanding act of executive control. PMID- 28581384 TI - Radiobiology and the Renewed Potential for Nanoparticles. PMID- 28581385 TI - Prostate Cancer With Isolated Bony Metastasis: Sternal Struggle. PMID- 28581386 TI - Treat All Known Disease. PMID- 28581387 TI - Prostate-Specific Membrane Antigen PET Before Aggressive Local Therapy to the Sternum. PMID- 28581388 TI - Intriguing, but Not the Right Setting. PMID- 28581389 TI - Sternum First, Perhaps Pelvis Later. PMID- 28581390 TI - Advancing Our Practice Through the Advanced Practice Radiation Therapist Model: Catching Up With Canada. PMID- 28581391 TI - Radiation Therapy in Palestine: Not Only Money, But Also Real Accessibility. PMID- 28581392 TI - Radiation Therapy in the Middle East: Local and Regional Targets. PMID- 28581393 TI - Is It Time for New Target Volumes in Radiation Oncology? PMID- 28581394 TI - Lessons From What is Not Discussed in Reports Recommending More Intensive Peer Review of Radiation Therapy Plans. PMID- 28581395 TI - Outcomes of Routine Intensity Modulated Radiation Therapy Quality Assurance in a Large Head and Neck Cancer Center. AB - PURPOSE: The primary endpoint was to ascertain whether the percentage of major changes implemented from our routine intensity modulated radiation therapy (IMRT) quality assurance (QA) process was more than 10%. The secondary endpoints were to document the percentage of minor changes, ascertain the time taken to perform the IMRT QA process, evaluate potential predictors for major changes, and ascertain the perceived value of the program by the compliance of radiation oncologists (ROs) treating head and neck cancer (HNC). METHODS AND MATERIALS: This was a retrospective analysis of a prospective database for all radically treated HNC patients. Recommended changes were predefined with criteria as either "major changes" or "minor changes." RESULTS: Of 595 patients treated radically between May 21, 2012, and May 21, 2014, 548 patients were entered, giving a compliance of 92.1%. The vast majority were treated with IMRT (470/548, 89%), 49.3% treated definitively and 50.7% treated adjuvantly; overall, 63% had stage IV disease. Eighty-one patients (14.8%) had 1 or more major changes recommended and implemented, and 21 patients (3.8%) had major changes recommended but not implemented because of a lack of consensus. Of minor recommendations, in 115 patients (21%) they were implemented and in 13 patients (2.4%) they were not implemented. No changes were recommended in the remaining 324 patients (59.1%). The only factor correlating with the likelihood of a major change was treatment with IMRT (P=.001). In the vast majority of cases (85%), the time taken for IMRT QA was less than 20 minutes. CONCLUSIONS: Our routine HNC IMRT QA program resulted in the implementation of a significant number of major changes. The high compliance with the program is indicative of the belief in its clinical value. This study can inform discussion on optimal RT QA processes in routine clinical practice. PMID- 28581396 TI - Interim 18F-FDG PET/CT During Chemoradiation Therapy in the Management of Head and Neck Cancer Patients: A Systematic Review. AB - Positron emission tomography (PET) is an imaging modality widely applied in oncology for tumor staging, volume delineation in radiation therapy planning, and therapy response assessment. F-18 fluorodeoxyglucose (FDG) PET combined with computed tomography plays a significant role in the management of locally advanced head and neck cancer patients in the pretreatment setting to predict outcome and prognosis and after chemoradiation therapy (CRT) to assess tumor response. This review aims to evaluate the use of FDG PET acquired during CRT, ad interim FDG (FDGint), to identify tumor response at an early stage, modify the treatment plan if necessary, or set up alternative strategies to enhance the therapeutic ratio. Most of the studies confirmed the value of FDGint in predicting the response to CRT, whereas a few highlighted the poor predictive value of FDGint compared with FDG acquired 2 to 4 months after the end of CRT, which was well correlated with local and regional control and survival. Such findings deserve to be further analyzed in more homogeneous series with greater patient numbers according to the tumor site and CRT schedules. The best time to assess tumor response during radiation therapy remains a matter of debate, although 2 weeks seems most favorable, still providing the opportunity to adapt the treatment strategy. PMID- 28581397 TI - Thyroid V40 Predicts Primary Hypothyroidism After Intensity Modulated Radiation Therapy for Nasopharyngeal Carcinoma. AB - PURPOSE: To investigate the various clinical and thyroid dosimetric parameters that could predict the risk of primary hypothyroidism (HT) after intensity modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC) and to determine useful thyroid dose constraints to guide radiation therapy planning. METHODS AND MATERIALS: From September 2009 to August 2012, 102 clinically euthyroid NPC patients were included in this study. All patients were treated with IMRT and randomized to induction chemotherapy followed by concurrent chemo IMRT or concurrent chemo-IMRT alone. Thyroid function was evaluated by measuring thyroid-stimulating hormone and free thyroxine at each annual follow-up visit. Various clinical and dosimetric parameters (eg, V40 [percentage of thyroid volume receiving >40 Gy]) were obtained. Univariate and multivariate logistic regression analyses were performed to identify predictors of HT. RESULTS: Median follow-up was 48.8 months. Among the 102 patients, 44 (43.1%) developed HT within 2 years after radiation therapy. The median time to HT was 36.7 months (range, 24.9-49.0 months). The 1-year and 2-year cumulative incidence rates of HT were 33% and 44.5%, respectively. Univariate analysis revealed that younger age, early T stage, minimum dose to the thyroid gland, V40, and V45 were associated with HT. On multivariate analysis, younger age (P=.017), early T stage (P=.005), and V40 (P=.009) remained statistically significant. Patients with V40 > 85% had significantly higher cumulative incidence rates of HT than patients with V40 <= 85% (P=.007). CONCLUSIONS: Thyroid V40 is predictive of primary HT after IMRT for NPC, and V40 <= 85% can be a useful dose constraint to adopt during IMRT planning without compromising tumor coverage. PMID- 28581398 TI - ASCENDE-RT: An Analysis of Health-Related Quality of Life for a Randomized Trial Comparing Low-Dose-Rate Brachytherapy Boost With Dose-Escalated External Beam Boost for High- and Intermediate-Risk Prostate Cancer. AB - PURPOSE: To report the patient-reported health-related quality of life (HR-QoL) outcomes for a multicenter randomized trial evaluating the safety and efficacy of 2 different techniques for dose escalation. METHODS AND MATERIALS: A total of 357 men with intermediate- and high-risk prostate cancer were stratified by risk group and randomized (1:1) to either a dose-escalated external beam (DE-EBRT) boost (n=177) or a low-dose-rate prostate brachytherapy (LDR-PB) boost (n=180) as part of combined modality therapy. The HR-QoL was assessed using the SF36v2 questionnaire, with additional scales for urinary, bowel, and sexual function. Date of starting androgen deprivation therapy was considered time zero, the median follow-up of 6 years. Scales were scored from 0 to 100; a decline in a mean score >=10 compared with baseline was considered a clinically significant decline. This was an intent-to-treat analysis. RESULTS: Mean domain scores at baseline were well balanced between the 2 treatment arms. A clinically significant decline in mean scores in both the arms compared with baseline was noted for role physical (DE-EBRT [-11.4] and LDR-PB [-15.3]) and sexual function scale (DE-EBRT [-15.1] and LDR-PB [-19.2]). There was a significantly larger drop in mean scores in the LDR-PB group compared with the DE-EBRT group for physical function (-15.3 vs -6.9; P=.03), urinary function (-3.6 vs -0.5; P=.04). CONCLUSION: At 6 years' follow up, there were no significant differences in mean scores in 9 of 11 scales compared with baseline in both arms. A clinically significant decline in mean scores was noted in both arms for role physical and sexual function scales. There was a statistically significant decline in physical function and urinary function scales in the LDR-PB arm compared with the DE-EBRT arm. PMID- 28581399 TI - Cognitive Function in Patients With Prostate Cancer Receiving Luteinizing Hormone Releasing Hormone Analogues: A Prospective, Observational, Multicenter Study. AB - PURPOSE: The effect of androgen deprivation therapy (ADT) on cognitive performance (CP) in prostate cancer (PCa) patients is not well understood. We evaluated changes in CP after 6 months of medical castration with luteinizing hormone-releasing hormone (LHRH) analogues. METHODS AND MATERIALS: We performed a prospective, observational, multicenter, open-label study of PCa patients scheduled to receive LHRH analogues for >=6 months. We assessed 4 domains of CP at baseline and after 6 months of ADT: (1) working memory, assessed with the Wechsler Adult Intelligence Scale III (WAIS III) Digit Span subtest; (2) visual memory, assessed with an ad hoc visual memory test; (3) visuospatial ability, assessed with the Judgment of Line Orientation test and Mental Rotation of Three Dimensional Objects test; and (4) nonverbal analytical reasoning, assessed with the WAIS III Matrix Reasoning test. Changes outside the baseline 95% confidence intervals were considered significant. RESULTS: A total of 308 patients completed the study. Of these, 245 (79.6%) experienced no statistically significant changes on any test whereas 63 (20.4%) experienced significant changes on >=1 test. Most of these patients showed a change on only 1 test, distributed evenly between improvement (58 patients, 18.8%) and worsening (56 patients, 18.2%). For individual tests, most patients (87.8%-91.8%) had no change from baseline; however, the significant changes (improvement vs deterioration) were as follows: WAIS III Digit Span subtest (6.3% vs 5.9%), visual memory (5.3% vs 5.7%), Judgment of Line Orientation test (5.3% vs 4.5%), Mental Rotation of Three Dimensional Objects test (4.1% vs 4.1%), and WAIS III Matrix Reasoning test (4.8% vs 5.8%). CONCLUSIONS: CP in patients with PCa does not appear to be adversely affected by 6 months of LHRH analogue administration. PMID- 28581400 TI - First Results of a Phase 2 Trial of Once-Weekly Hypofractionated Breast Irradiation (WHBI) for Early-Stage Breast Cancer. AB - PURPOSE: To report early outcome analysis of a prospective institutional phase 2 trial of weekly hypofractionated breast irradiation (WHBI) for patients undergoing breast-conserving surgery (BCS). METHODS AND MATERIALS: Patients who underwent BCS for American Joint Committee on Cancer stage 0, I, or II breast cancer with negative surgical margins received whole-breast radiation therapy to 30 or 28.5 Gy in 5 weekly fractions with or without an additional boost. The eligibility criteria were the same as for NSABP (National Surgical Adjuvant Breast and Bowel Project) B39/RTOG (Radiation Therapy Oncology Group) 0413, and there were no restrictions on age, breast size, tumor grade, receptor status, or the use of cytotoxic chemotherapy for otherwise eligible patients. The primary endpoint was ipsilateral breast tumor recurrence. Patients were also evaluated for acute toxicity (Common Terminology Criteria for Adverse Events version 3.0), cosmesis (Harvard Scale), development of distant metastatic disease, and overall survival. RESULTS: Between January 2011 and October 2015, 158 eligible patients underwent WHBI immediately following BCS. The median age was 60 years (range, 30 84 years), and the median follow-up period was 3 years. Ipsilateral breast tumor recurrence developed in a total of 2 patients (1.3%), 1 in conjunction with widespread metastatic disease. Distant metastatic disease developed in 4 patients (2.5%), and the 3-year disease-free survival and overall survival rates were 97.5% and 96.2%, respectively. The most common grade 1 or 2 acute toxicities were breast pain, radiation dermatitis, and fatigue. There were 2 grade 3 events (1.3%): pain requiring narcotic analgesics (1) and posttreatment infection requiring hospitalization (1). The rate of excellent or good cosmesis versus fair or poor cosmesis was 82.3% versus 17.7%. The rate of significant cosmetic change from baseline to last follow-up (dropping from excellent or good to fair or poor) was 11.6%. CONCLUSIONS: Early outcomes after WHBI are favorable and parallel those seen with daily hypofractionated whole-breast irradiation. With broader entry criteria than all previous reports of WHBI, this study will facilitate comparison to the results of NSABP B39/RTOG 0413. With continued follow-up, future reports will assess cosmetic stability and disease-specific outcomes. PMID- 28581401 TI - Prospective Study of Hippocampal-Sparing Prophylactic Cranial Irradiation in Limited-Stage Small Cell Lung Cancer. AB - PURPOSE: To prospectively evaluate cognitive function and intracranial failure patterns after hippocampal-sparing prophylactic cranial irradiation (PCI) for limited-stage small cell lung cancer (SCLC). METHODS AND MATERIALS: Adults with limited-stage SCLC, achieving a complete response to chemoradiotherapy and no brain metastases, were eligible. Patients received PCI 25 Gy/10 fractions, with a mean hippocampal dose limited to <8 Gy and >=90% of the brain receiving 90% of the prescription. A diverse battery of neuropsychological testing was performed at baseline and 6 and 12 months after PCI. Brain MRI scans were performed at baseline and 6, 12, 18, and 24 months. The primary endpoint was memory measured by the Hopkins Verbal Learning Test-Revised Delayed Recall at 6 months after PCI. The 25-Gy arm of Radiation Therapy Oncology Group protocol 0212 was used as a reference of potential efficacy. Development of intracranial metastases was recorded. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. RESULTS: Eight men and 12 women with a median age of 61 years enrolled. Two-year overall survival was 88% (95% confidence interval 68% 100%). There was no significant decline in performance between baseline and 6 or 12 months for any of the tests. The association between baseline intelligence quotient and change in performance on testing was not significant. Magnetic resonance imaging revealed asymptomatic brain metastases at a cumulative rate of 20%, with no concurrent extracranial progression. Two patients developed a metastasis in the under-dosed region. Neither involved the dentate gyrus, but 1 involved the avoidance region. Both patients concurrently developed additional metastasis in fully treated brain regions. There were 2 neurologic deaths. CONCLUSIONS: This prospective study suggests a potential benefit of hippocampal sparing in limiting the neuropsychological sequelae of brain radiation, but with a risk of failures in the spared region. These data strongly support continued enrollment on ongoing cooperative group randomized trials. Clinical Trials registration number: NCT01797159. PMID- 28581402 TI - Prophylactic Cranial Irradiation in Resected Early-Stage Small Cell Lung Cancer. PMID- 28581404 TI - Treatment-Related Toxicity in Patients With Early-Stage Non-Small Cell Lung Cancer and Coexisting Interstitial Lung Disease: A Systematic Review. AB - PURPOSE: Definitive treatment for patients with early-stage non-small cell lung cancer (ES-NSCLC) is usually well tolerated. Patients with ES-NSCLC and coexisting interstitial lung disease (ILD) are at increased risk of severe treatment-related toxicity after definitive therapy. The main objective of this systematic review is to provide a pooled estimation of treatment-related mortality and ILD-specific toxicity in this population of patients and to identify trends for further study. METHODS AND MATERIALS: The MEDLINE and Embase databases were queried from respective dates of inception to January 2016. Studies that included patients who underwent definitive treatment for ES-NSCLC not combined with other treatments were included. Patients with oligometastases who were treated with aggressive palliation were included if it did not constitute the majority of patients in a specific study. The results were summarized with weighted proportions according to the sample size of individual studies. RESULTS: Overall, 3056 records were reviewed and 50 journal articles were included in the abstraction. The weighted proportion of treatment-related mortality (and ILD-specific toxicity) in primarily medically inoperable patients was as follows: stereotactic ablative radiation therapy (SABR) 15.6% (25%), particle beam therapy 4.3% (18.2%) and radiofrequency ablation (RFA) 8.7% (25%). The data for medically operable patients who underwent surgery were extracted for reference. Treatment-related mortality and ILD-specific toxicity were 2.2% and 12%, respectively, in the surgical population. On analysis of reported SABR dose parameters, V20 <= 6.5% and mean lung dose <=4.5 Gy were found to be metrics associated with reduced mortality. CONCLUSION: A consistently high level of treatment-related mortality and ILD-specific toxicity was observed in primarily medically inoperable patients treated with SABR, particle beam therapy, and RFA. For these patients, curative treatment should be considered in the context of the high toxicity rates and overall poor prognosis. Stringent radiation dosimetric parameters may result in reduced toxicity. PMID- 28581403 TI - Plasma Levels of IL-8 and TGF-beta1 Predict Radiation-Induced Lung Toxicity in Non-Small Cell Lung Cancer: A Validation Study. AB - PURPOSE AND OBJECTIVES: We previously reported that the combination of mean lung dose (MLD) and inflammatory cytokines interleukin-8 (IL-8) and transforming growth factor-beta1 (TGF-beta1) may provide a more accurate model for radiation induced lung toxicity (RILT) prediction in 58 patients with non-small cell lung cancer (NSCLC). This study is to validate the previous findings with new patients and to explore new models with more cytokines. METHODS AND MATERIALS: One hundred forty-two patients with stage I-III NSCLC treated with definitive radiation therapy (RT) from prospective studies were included. Sixty-five new patients were used to validate previous findings, and all 142 patients were used to explore new models. Thirty inflammatory cytokines were measured in plasma samples before RT and 2 weeks and 4 weeks during RT (pre, 2w, 4w). Grade >=2 RILT was defined as grade 2, and higher radiation pneumonitis or symptomatic pulmonary fibrosis was the primary endpoint. Logistic regression was performed to evaluate the risk factors of RILT. The area under the curve (AUC) for the receiver operating characteristic curves was used for model assessment. RESULTS: Sixteen of 65 patients (24.6%) experienced RILT2. Lower pre IL-8 and higher TGF-beta1 2w/pre ratio were associated with higher risk of RILT2. The AUC increased to 0.73 by combining MLD, pre IL-8, and TGF-beta1 2w/pre ratio compared with 0.61 by MLD alone to predict RILT. In all 142 patients, 29 patients (20.4%) experienced grade >=2 RILT. Among the 30 cytokines measured, only IL-8 and TGF-beta1 were significantly associated with the risk of RILT2. MLD, pre IL-8 level, and TGF beta1 2w/pre ratio were included in the final predictive model. The AUC increased to 0.76 by combining MLD, pre IL-8, and TGF-beta1 2w/pre ratio compared with 0.62 by MLD alone. CONCLUSIONS: We validated that a combination of mean lung dose, pre IL-8 level, and TGF-beta1 2w/pre ratio provided a more accurate model to predict the risk of RILT2 compared with MLD alone. PMID- 28581405 TI - External Validity of a Risk Stratification Score Predicting Early Distant Brain Failure and Salvage Whole Brain Radiation Therapy After Stereotactic Radiosurgery for Brain Metastases. AB - BACKGROUND: A scoring system using pretreatment factors was recently published for predicting the risk of early (<=6 months) distant brain failure (DBF) and salvage whole brain radiation therapy (WBRT) after stereotactic radiosurgery (SRS) alone. Four risk factors were identified: (1) lack of prior WBRT; (2) melanoma or breast histologic features; (3) multiple brain metastases; and (4) total volume of brain metastases <1.3 cm3, with each factor assigned 1 point. The purpose of this study was to assess the validity of this scoring system and its appropriateness for clinical use in an independent external patient population. METHODS: We reviewed the records of 247 patients with 388 brain metastases treated with SRS between 2010 at 2013 at Levine Cancer Institute. The Press (Emory) risk score was calculated and applied to the validation cohort population, and subsequent risk groups were analyzed using cumulative incidence. RESULTS: The low-risk (LR) group had a significantly lower risk of early DBF than did the high-risk (HR) group (22.6% vs 44%, P=.004), but there was no difference between the HR and intermediate-risk (IR) groups (41.2% vs 44%, P=.79). Total lesion volume <1.3 cm3 (P=.004), malignant melanoma (P=.007), and multiple metastases (P<.001) were validated as predictors for early DBF. Prior WBRT and breast cancer histologic features did not retain prognostic significance. Risk stratification for risk of early salvage WBRT were similar, with a trend toward an increased risk for HR compared with LR (P=.09) but no difference between IR and HR (P=.53). CONCLUSION: The 3-level Emory risk score was shown to not be externally valid, but the model was able to stratify between 2 levels (LR and not LR [combined IR and HR]) for early (<=6 months) DBF. These results reinforce the importance of validating predictive models in independent cohorts. Further refinement of this scoring system with molecular information and in additional contemporary patient populations is warranted. PMID- 28581407 TI - Continuous Effect of Radial Resection Margin on Recurrence and Survival in Rectal Cancer Patients Who Receive Preoperative Chemoradiation and Curative Surgery: A Multicenter Retrospective Analysis. AB - PURPOSE: To elucidate the proper length and prognostic value of resection margins in rectal cancer patients who received preoperative chemoradiotherapy (CRT) followed by curative total mesorectal excision (TME). METHODS AND MATERIALS: A total of 1476 rectal cancer patients staging cT3-4N0-2M0 were analyzed. All patients received radiation dose of 50.4 Gy in 28 fractions with concurrent 5 fluorouracil or capecitabine. Total mesorectal excision was performed 4 to 8 weeks after radiation therapy. RESULTS: The recurrence-free survival (RFS) at 5 years showed a significant difference between 3 groups: patients with circumferential resection margin (CRM) <=1 mm, CRM 1.1 to 5 mm, and CRM >5 mm (46.2% vs 68.6% vs 77.5%, P<.001). Patients with CRM <=1 mm showed a significantly higher cumulative incidence of locoregional recurrence (P<.001) and distant metastasis (P<.001) at 5 years compared with the other 2 groups. Patients with CRM 1.1 to 5 mm showed a significantly higher cumulative incidence of distant metastasis (P<.001), but not locoregional recurrence (P=.192), compared with those with CRM >5 mm. Distal resection margin (<=5 vs >5 mm) did not show any significant difference in cumulative incidence of locoregional recurrence (P=.310) and distant metastasis (P=.926). CONCLUSION: Rectal cancer patients with CRM <=1 mm are a high-risk group, with the lowest RFS. Patients with CRM 1.1 to 5 mm may be at intermediate risk, with moderately increased distant recurrence. Distal resection margin was not significantly associated with RFS in rectal cancer after neoadjuvant CRT and total mesorectal excision. PMID- 28581406 TI - Long-Term Survival Analysis of Stereotactic Ablative Radiotherapy Versus Liver Resection for Small Hepatocellular Carcinoma. AB - PURPOSE: To compare the efficacy of stereotactic ablative radiation therapy (SABR) versus liver resection for small hepatocellular carcinoma (HCC) <=5 cm with Child-Pugh A cirrhosis. METHODS AND MATERIALS: This retrospective study included 117 patients with small HCCs with 1 or 2 nodules. Eighty-two patients received SABR (SABR group), and 35 patients underwent liver resection (resection group). Overall survival (OS) and progression-free survival (PFS) were analyzed. One-to-one matched pairs between the 2 groups were created using propensity score matching to reduce the potential confounding effect of treatment and selection bias. RESULTS: There was no between-group difference in OS and PFS. Before propensity score matching, the 1-, 3-, and 5-year OS was 96.3%, 81.8%, and 70.0% in the SABR group and 93.9%, 83.1%, and 64.4% in the resection group, respectively (P=.558). The 1-, 3- and 5-year PFS was 81.4%, 50.2%, and 40.7% in the SABR group and 68.0%, 58.3%, and 40.3% in the resection group, respectively (P=.932). After propensity score matching, 33 paired patients were selected from the SABR and resection groups. The 1-, 3-, and 5-year OS was 100%, 91.8%, and 74.3% in the SABR group and 96.7%, 89.3%, and 69.2% in the resection group, respectively (P=.405). The 1-, 3-, and 5-year PFS was 84.4%, 59.2%, and 43.9% in the SABR group and 69.0%, 62.4%, and 35.9% in the resection group, respectively (P=.945). There was a similarity of hepatotoxicity between the 2 groups. The SABR group showed fewer complications, such as hepatic hemorrhage, hepatic pain, and weight loss. Acute nausea was significantly more frequent in the SABR group than in the resection group. CONCLUSION: For patients with small primary HCC with 1 or 2 nodules and Child-Pugh A cirrhosis, SABR has local effects that are similar to those with liver resection. Stereotactic ablative radiation therapy has an advantage over resection in being less invasive. PMID- 28581408 TI - Integration Pattern of Human Papillomavirus Is a Strong Prognostic Factor for Disease-Free Survival After Radiation Therapy in Cervical Cancer Patients. AB - PURPOSE: The standard chemoradiation therapy currently used for locally advanced cervical cancer (LACC) patients does not reflect the biological heterogeneity of this disease, and there is an increasing need for the development of biomarkers that can help guide the individualized treatment regimens. The purpose of this study was to investigate the prognostic value of the integration pattern of human papillomavirus (HPV) in LACC patients. METHODS AND MATERIALS: The HPV integration pattern was determined by in situ hybridization and polymerase chain reaction, and the tumors were classified as the episomal pattern (group A), as the single copy integrated or multicopy tandem repetition-integrated pattern (group B), or as undetectable HPV (group C). Ninety-eight LACC patients were included in a development dataset and 106 independent patients in a validation dataset. The multivariate Cox model was used to examine the effect of the HPV integration pattern on disease-free survival (DFS). The model was validated internally by the leave-one-out cross-validation method and externally by an independent dataset. RESULTS: After adjustment for significant prognostic factors (stage, histologic grade, histologic type, and tumor size), the HPV integration pattern was significantly associated with DFS in the development (P=.032) and validation (P=.023) datasets. Survival was worst in group C and best in group A. The multivariate model with HPV integration pattern as an explanatory variable showed good discrimination ability and could separate patients with different risk profiles. CONCLUSIONS: This study identified the HPV integration pattern, as determined by in situ hybridization and polymerase chain reaction, as a strong prognostic biomarker for DFS in LACC patients treated by chemoradiation therapy. This finding may open the possibility of personalized treatment of these patients. PMID- 28581409 TI - Current Status of Targeted Radioprotection and Radiation Injury Mitigation and Treatment Agents: A Critical Review of the Literature. AB - As more cancer patients survive their disease, concerns about radiation therapy induced side effects have increased. The concept of radioprotection and radiation injury mitigation and treatment offers the possibility to enhance the therapeutic ratio of radiation therapy by limiting radiation therapy-induced normal tissue injury without compromising its antitumor effect. Advances in the understanding of the underlying mechanisms of radiation toxicity have stimulated radiation oncologists to target these pathways across different organ systems. These generalized radiation injury mechanisms include production of free radicals such as superoxides, activation of inflammatory pathways, and vascular endothelial dysfunction leading to tissue hypoxia. There is a significant body of literature evaluating the effectiveness of various treatments in preventing, mitigating, or treating radiation-induced normal tissue injury. Whereas some reviews have focused on a specific disease site or agent, this critical review focuses on a mechanistic classification of activity and assesses multiple agents across different disease sites. The classification of agents used herein further offers a useful framework to organize the multitude of treatments that have been studied. Many commonly available treatments have demonstrated benefit in prevention, mitigation, and/or treatment of radiation toxicity and warrant further investigation. These drug-based approaches to radioprotection and radiation injury mitigation and treatment represent an important method of making radiation therapy safer. PMID- 28581411 TI - Computerized System for Safety Verification of External Beam Radiation Therapy Planning. AB - PURPOSE: To report an assessment of in-house software, Verifier, developed to improve efficacy and efficiency of the radiation therapy (RT) treatment planning process and quality control review (QCR). METHODS AND MATERIALS: Radiation therapy plan parameters retrieved from our treatment planning database are used by automated tests to give 75 types of warnings, such as prescription and plan discrepancies. The software is continuously updated on the basis of new issues, ideas, and planning policies. Verifier was retrospectively assessed (2007-2015) by examining impact on treatment plan revisions, frequency of quality improvement incident reports of avoidable RT plan-related safety events, unaddressed issues, and staff efficiency. RESULTS: Plan revisions for specific issues declined dramatically in response to implementation of corresponding Verifier tests. Between 2012 and 2015 our institution's total rate of plan revisions dropped from 18.0% to 11.2%. Between 2008 and 2015 specific tests were added to Verifier while the rate of corresponding avoidable safety events was reduced from 0.34% to 0.00% over the same period. Simulations suggest Verifier saves approximately 2 to 5 minutes per QCR. CONCLUSIONS: The decrease in quantifiable metrics of plan revisions and incident reports suggests automatic RT plan-checking software enhances patient safety and clinical efficiency. Although only modest time savings may be gained using Verifier for the QCR itself, the greater impact on efficiency is through avoiding late-stage plan modifications and improving documentation via automation. We encourage other institutions to consider working toward adding similar technologies to enhance their RT quality assurance programs. PMID- 28581410 TI - Lung and Heart Dose Variability During Radiation Therapy of Non-Small Cell Lung Cancer. AB - PURPOSE: To investigate the hypothesis that positional and anatomic variations during radiation therapy induce changes in lung and heart volumes and associated radiation doses. METHODS AND MATERIALS: In this longitudinal investigation, variations in lung and heart volumes and standard dose parameters of mean lung dose, lung V20Gy, mean heart dose, and heart V40Gy were analyzed on weekly 4 dimensional CT scans of 15 lung cancer patients during conventionally fractionated radiochemotherapy. Tumor, individual lung lobes, and heart were delineated on the mid-ventilation phase of weekly 4-dimensional CT scans. Lung lobes and heart were also contoured on individual breathing phases of pre-, mid-, and end-of-treatment scans. Planning dose was transferred to consecutive scans via rigid registration. Volume and dose variations were assessed relative to the initial planning scan. RESULTS: Interfraction lung volume variability relative to week 0 was twice as large as tidal volume variability (8.0% +/- 5.3% vs 4.0% +/- 3.3%, P=.003). Interfraction lung volume variation ranged between 0.8% and 17.1% for individual patient means. Lower lung lobes had larger volume variability compared with upper lobes (13.5% +/- 8.1% vs 7.0% +/- 5.0%, P<.00001). Average mean lung dose variation was 0.5 Gy (range, 0.2-1.0 Gy for individual patient means) and average lung V20Gy variation 0.9% (range, 0.2%-1.6%). Average heart volume variation was 7.2% (range, 3.4%-12.6%). Average mean heart dose variation was 1.2 Gy (range, 0.1-3.0 Gy) and average heart V40Gy variation 1.4% (range, 0% 4.2%). CONCLUSIONS: Anatomic and positional variations during radiation therapy induce changes in radiation doses to lung and heart. Repeated lung and heart dose assessment will provide a better estimate of the actual delivered dose and will improve prediction models for normal tissue toxicity, if assessed in larger cohorts. PMID- 28581412 TI - Dosimetric Impact of Using a Virtual Couch Shift for Online Correction of Setup Errors for Brain Patients on an Integrated High-Field Magnetic Resonance Imaging Linear Accelerator. AB - PURPOSE: To quantify the dosimetric impact of using virtual couch shift (VCS) for correcting setup errors in glioblastoma multiforme (GBM) patients treated on a magnetic resonance imaging (MRI)-linac. METHODS AND MATERIALS: Six GBM patients treated with 60 Gy (30 fractions) were selected for this simulation study. For each case, 2 reference plans were generated in the MRL treatment planning system: With (WIB) and with no (NOB) MRI B field present. Subsequently, 2-mm, 4-mm, and 6 mm translational errors were simulated and corrected for using a VCS method based on shift-only, warm start segment weight (SWO), and segment weight and shape (SSO) optimization. The resulting distributions were compared with the reference plan using planning target volume (PTV) homogeneity index (HI), conformity index (CI), organs at risk (OAR) maximum dose (D0.01cc), and OAR median dose (D50). A simulated 30-fraction treatment was constructed to evaluate the cumulative effect of daily corrections. Feasibility and workflow for correcting rotations were also assessed. RESULTS: All reference plans were deemed clinically acceptable with respect to PTV and OAR objectives. The difference in HI (DeltaHI) between corrected and reference was not statistically significant between WIB and NOB (P=.89). The average DeltaHI was +0.8%, -0.1%, and -1.0% for shift-only, SWO, and SSO, respectively, with a statistically significant difference (P<.001) for shift only versus SWO and SSO. The CI remained unchanged (mean DeltaCI = -0.01) between the corrected and reference plans, with no statistically significant dependence on magnetic field presence, correction method, or shift magnitude or orientation. The brainstem D50 on average decreased with SWO and SSO; however, D0.01cc increased by a median value of 1.2%, 1.9%, and 2.0% for shift-only, SWO, and SSO, respectively. For other OARs, D0.01cc decreased using SWO or SSO. For the simulated treatment and rotational corrections, similar trends were measured. CONCLUSION: For translational errors in brain MRI-linac radiation therapy, the VCS method is an acceptable correction strategy, but caution must be used in particular for serial organs where maximum doses are most relevant. The effect of the magnetic field on relative changes between corrected versus reference plans is not clinically relevant. PMID- 28581413 TI - In Regard to Micke et al. PMID- 28581415 TI - Erratum. PMID- 28581414 TI - In Reply to Penagaricano. PMID- 28581416 TI - Africa's increasing efforts to control cancer. PMID- 28581417 TI - Less toxic treatment for multiple myeloma. PMID- 28581418 TI - Tamoxifen better than arzoxifene in breast cancer. PMID- 28581419 TI - Docetaxel induction combination for HNSCC. PMID- 28581420 TI - Defining biochemical failure in prostate cancer. PMID- 28581421 TI - Aromatase expression in lung cancer. PMID- 28581423 TI - Trabectedin too toxic in ovarian cancer? PMID- 28581422 TI - Alemtuzumab shows promise for CLL. PMID- 28581424 TI - Chemoradiotherapy in early-stage Hodgkin's disease. PMID- 28581425 TI - 'Complete oestrogen blockade' revitalised. PMID- 28581426 TI - Aspergillosis treatment in haematological malignancy. PMID- 28581427 TI - 39th Annual Conference of the International Society of Paediatric Oncology; Oct 31-Nov 3, 2007; Mumbai, India. PMID- 28581428 TI - 8th Annual Meeting of the International Society for Geriatric Oncology; Nov 8-10, 2007; Madrid, Spain. PMID- 28581430 TI - Bryan Jennett. PMID- 28581432 TI - Department of Error. PMID- 28581431 TI - Department of Error. PMID- 28581433 TI - December 10-16, 2011. PMID- 28581434 TI - Darwin on display. PMID- 28581435 TI - George E Palade. PMID- 28581436 TI - From biokinematics to a robotic active vision system. AB - Barn owls move their heads in very particular motions, compensating for the quasi immovability of their eyes. These efficient predators often perform peering side to-side head motions when scanning their surroundings and seeking prey. In this work, we use the head movements of barn owls as a model to bridge between biological active vision and machine vision. The biomotions are measured and used to actuate a specially built robot equipped with a depth camera for scanning. We hypothesize that the biomotions improve scan accuracy of static objects. Our experiments show that barn owl biomotion-based trajectories consistently improve scan accuracy when compared to intuitive scanning motions. This constitutes proof of-concept evidence that the vision of robotic systems can be enhanced by bio inspired viewpoint manipulation. Such biomimetic scanning systems can have many applications, e.g. manufacturing inspection or in autonomous robots. PMID- 28581437 TI - Silver nanowire-graphene hybrid transparent conductive electrodes for highly efficient inverted organic solar cells. AB - Silver nanowires (AgNWs) and graphene are both promising candidates as a transparent conductive electrode (TCE) to replace expensive and fragile indium tin oxide (ITO) TCE. A synergistically optimized performance is expected when the advantages of AgNWs and graphene are combined. In this paper, the AgNW-graphene hybrid electrode is constructed by depositing a graphene layer on top of the network of AgNWs. Compared with the pristine AgNWs electrode, the AgNW-graphene TCE exhibits reduced sheet resistance, lower surface roughness, excellent long term stability, and corrosion resistance in corrosive liquids. The graphene layer covering the AgNWs provides additional conduction pathways for electron transport and collection by the electrode. Benefiting from these advantages of the hybrid electrodes, we achieve a power conversion efficiency of 8.12% of inverted organic solar cells using PTB7:PC71BM as the active layer, which is compared to that of the solar cells based on standard ITO TCE but about 10% higher than that based on AgNWs TCE. PMID- 28581438 TI - Environmental monitoring through use of silica-based TLD. AB - The sensitivity of a novel silica-based fibre-form thermoluminescence dosimeter was tested off-site of a rare-earths processing plant, investigating the potential for obtaining baseline measurements of naturally occurring radioactive materials. The dosimeter, a Ge-doped collapsed photonic crystal fibre (PCFc) co doped with B, was calibrated against commercially available thermoluminescent dosimetry (TLD) (TLD-200 and TLD-100) using a bremsstrahlung (tube-based) x-ray source. Eight sampling sites within 1 to 20 km of the perimeter of the rare-earth facility were identified, the TLDs (silica- as well as TLD-200 and TLD-100) in each case being buried within the soil at fixed depth, allowing measurements to be obtained, in this case for protracted periods of exposure of between two to eight months. The values of the dose were then compared against values projected on the basis of radioactivity measurements of the associated soils, obtained via high-purity germanium gamma-ray spectrometry. Accord was found in relative terms between the TL evaluations at each site and the associated spectroscopic results. Thus said, in absolute terms, the TL evaluated doses were typically less than those derived from gamma-ray spectroscopy, by ~50% in the case of PCFc-Ge. Gamma spectrometry analysis typically provided an upper limit to the projected dose, and the Marinelli beaker contents were formed from sieving to provide a homogenous well-packed medium. However, with the radioactivity per unit mass typically greater for smaller particles, with preferential adsorption on the surface and the surface area per unit volume increasing with decrease in radius, this made for an elevated dose estimate. Prevailing concentrations of key naturally occurring radionuclides in soil, 226Ra, 232Th and 40K, were also determined, together with radiological dose evaluation. To date, the area under investigation, although including a rare-earth processing facility, gives no cause for concern from radiological impact. The current study reveals the suitability of the optical fibre based micro-dosimeter for all-weather monitoring of low-level environmental radioactivity. PMID- 28581439 TI - Tegotae-based decentralised control scheme for autonomous gait transition of snake-like robots. AB - Snakes change their locomotion patterns in response to the environment. This ability is a motivation for developing snake-like robots with highly adaptive functionality. In this study, a decentralised control scheme of snake-like robots that exhibited autonomous gait transition (i.e. the transition between concertina locomotion in narrow aisles and scaffold-based locomotion on unstructured terrains) was developed. Additionally, the control scheme was validated via simulations. A key insight revealed is that these locomotion patterns were not preprogrammed but emerged by exploiting Tegotae, a concept that describes the extent to which a perceived reaction matches a generated action. Unlike local reflexive mechanisms proposed previously, the Tegotae-based feedback mechanism enabled the robot to 'selectively' exploit environments beneficial for propulsion, and generated reasonable locomotion patterns. It is expected that the results of this study can form the basis to design robots that can work under unpredictable and unstructured environments. PMID- 28581440 TI - Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism. AB - Cleidocranial dysplasia (CCD) is an autosomal dominant human disorder characterized by abnormal bone development that is mainly due to defective intramembranous bone formation by osteoblasts. Here, we describe a mouse strain lacking the E3 ubiquitin ligase RNF146 that shows phenotypic similarities to CCD. Loss of RNF146 stabilized its substrate AXIN1, leading to impairment of WNT3a induced beta-catenin activation and reduced Fgf18 expression in osteoblasts. We show that FGF18 induces transcriptional coactivator with PDZ-binding motif (TAZ) expression, which is required for osteoblast proliferation and differentiation through transcriptional enhancer associate domain (TEAD) and runt-related transcription factor 2 (RUNX2) transcription factors, respectively. Finally, we demonstrate that adipogenesis is enhanced in Rnf146-/- mouse embryonic fibroblasts. Moreover, mice with loss of RNF146 within the osteoblast lineage had increased fat stores and were glucose intolerant with severe osteopenia because of defective osteoblastogenesis and subsequent impaired osteocalcin production. These findings indicate that RNF146 is required to coordinate beta-catenin signaling within the osteoblast lineage during embryonic and postnatal bone development. PMID- 28581441 TI - NK cell heparanase controls tumor invasion and immune surveillance. AB - NK cells are highly efficient at preventing cancer metastasis but are infrequently found in the core of primary tumors. Here, have we demonstrated that freshly isolated mouse and human NK cells express low levels of the endo-beta-D glucuronidase heparanase that increase upon NK cell activation. Heparanase deficiency did not affect development, differentiation, or tissue localization of NK cells under steady-state conditions. However, mice lacking heparanase specifically in NK cells (Hpsefl/fl NKp46-iCre mice) were highly tumor prone when challenged with the carcinogen methylcholanthrene (MCA). Hpsefl/fl NKp46-iCre mice were also more susceptible to tumor growth than were their littermate controls when challenged with the established mouse lymphoma cell line RMA-S-RAE 1beta, which overexpresses the NK cell group 2D (NKG2D) ligand RAE-1beta, or when inoculated with metastatic melanoma, prostate carcinoma, or mammary carcinoma cell lines. NK cell invasion of primary tumors and recruitment to the site of metastasis were strictly dependent on the presence of heparanase. Cytokine and immune checkpoint blockade immunotherapy for metastases was compromised when NK cells lacked heparanase. Our data suggest that heparanase plays a critical role in NK cell invasion into tumors and thereby tumor progression and metastases. This should be considered when systemically treating cancer patients with heparanase inhibitors, since the potential adverse effect on NK cell infiltration might limit the antitumor activity of the inhibitors. PMID- 28581442 TI - Photopharmacological control of bipolar cells restores visual function in blind mice. AB - Photopharmacological control of neuronal activity using synthetic photochromic ligands, or photoswitches, is a promising approach for restoring visual function in patients suffering from degenerative retinal diseases. Azobenzene photoswitches, such as AAQ and DENAQ, have been shown to restore the responses of retinal ganglion cells to light in mouse models of retinal degeneration but do not recapitulate native retinal signal processing. Here, we describe diethylamino azo-diethylamino (DAD), a third-generation photoswitch that is capable of restoring retinal ganglion cell light responses to blue or white light. In acute brain slices of murine layer 2/3 cortical neurons, we determined that the photoswitch quickly relaxes to its inactive form in the dark. DAD is not permanently charged, and the uncharged form enables the photoswitch to rapidly and effectively cross biological barriers and thereby access and photosensitize retinal neurons. Intravitreal injection of DAD restored retinal light responses and light-driven behavior to blind mice. Unlike DENAQ, DAD acts upstream of retinal ganglion cells, primarily conferring light sensitivity to bipolar cells. Moreover, DAD was capable of generating ON and OFF visual responses in the blind retina by utilizing intrinsic retinal circuitry, which may be advantageous for restoring visual function. PMID- 28581443 TI - Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages. AB - The quantity and activation state of adipose tissue macrophages (ATMs) impact the development of obesity-induced metabolic diseases. Appetite-controlling hormones play key roles in obesity; however, our understanding of their effects on ATMs is limited. Here, we have shown that human and mouse ATMs express NPFFR2, a receptor for the appetite-reducing neuropeptide FF (NPFF), and that NPFFR2 expression is upregulated by IL-4, an M2-polarizing cytokine. Plasma levels of NPFF decreased in obese patients and high-fat diet-fed mice and increased following caloric restriction. NPFF promoted M2 activation and increased the proliferation of murine and human ATMs. Both M2 activation and increased ATM proliferation were abolished in NPFFR2-deficient ATMs. Mechanistically, the effects of NPFF involved the suppression of E3 ubiquitin ligase RNF128 expression, resulting in enhanced stability of phosphorylated STAT6 and increased transcription of the M2 macrophage-associated genes IL-4 receptor alpha (Il4ra), arginase 1 (Arg1), IL-10 (Il10), and alkylglycerol monooxygenase (Agmo). NPFF induced ATM proliferation concomitantly with the increase in N-Myc downstream-regulated gene 2 (Ndrg2) expression and suppressed the transcription of Ifi200 cell-cycle inhibitor family members and MAF bZIP transcription factor B (Mafb), a negative regulator of macrophage proliferation. NPFF thus plays an important role in supporting healthy adipose tissue via the maintenance of metabolically beneficial ATMs. PMID- 28581445 TI - Glutamine supplementation suppresses herpes simplex virus reactivation. AB - Chronic viral infections are difficult to treat, and new approaches are needed, particularly those aimed at reducing reactivation by enhancing immune responses. Herpes simplex virus (HSV) establishes latency and reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus specific T cells are important to control HSV, and proliferation of activated T cells requires increased metabolism of glutamine. Here, we found that supplementation with oral glutamine reduced virus reactivation in latently HSV-1 infected mice and HSV-2-infected guinea pigs. Transcriptome analysis of trigeminal ganglia from latently HSV-1-infected, glutamine-treated WT mice showed upregulation of several IFN-gamma-inducible genes. In contrast to WT mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in latently HSV-1-infected IFN-gamma-KO mice. Mice treated with glutamine also had higher numbers of HSV-specific IFN-gamma-producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-gamma-associated immune response and reduce the rate of reactivation of latent virus infection. PMID- 28581447 TI - Time Window Is Important for Adenosine Preventing Cold-induced Injury to the Endothelium. AB - Cold cardioplegia is used to induce heart arrest during cardiac surgery. However, endothelial function may be compromised after this procedure. Accordingly, interventions such as adenosine, that mimic the effects of preconditioning, may minimize endothelial injury. Herein, we investigated whether adenosine prevents cold-induced injury to the endothelium. Cultured human cardiac microvascular endothelial cells were treated with adenosine for different durations. Phosphorylation and expression of endothelial nitric oxide synthase (eNOS), p38MAPK, ERK1/2, and p70S6K6 were measured along with nitric oxide (NO) production using diaminofluorescein-2 diacetate (DAF-2DA) probe. Cold-induced injury by hypothermia to 4 degrees C for 45 minutes to mimic conditions of cold cardioplegia during open heart surgery was induced in human cardiac microvascular endothelial cells. Under basal conditions, adenosine stimulated NO production, eNOS phosphorylation at serine 1177 from 5 minutes to 4 hours and inhibited eNOS phosphorylation at threonine 495 from 5 minutes to 6 hours, but increased phosphorylation of ERK1/2, p38MAPK, and p70S6K only after exposure for 5 minutes. Cold-induced injury inhibited NO production and the phosphorylation of the different enzymes. Importantly, adenosine prevented these effects of hypothermic injury. Our data demonstrated that adenosine prevents hypothermic injury to the endothelium by activating ERK1/2, eNOS, p70S6K, and p38MAPK signaling pathways at early time points. These findings also indicated that 5 minutes after administration of adenosine or release of adenosine is an important time window for cardioprotection during cardiac surgery. PMID- 28581444 TI - Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis. AB - Lower gastrointestinal (GI) tract graft-versus-host disease (GVHD) is the predominant cause of morbidity and mortality from GVHD after allogeneic stem cell transplantation. Recent data indicate that lower GI tract GVHD is a complicated process mediated by donor/host antigenic disparities. This process is exacerbated by significant changes to the microbiome, and innate and adaptive immune responses that are critical to the induction of disease, persistence of inflammation, and a lack of response to therapy. Here, we discuss new insights into the biology of lower GI tract GVHD and focus on intrinsic pathways and regulatory mechanisms crucial to normal intestinal function. We then describe multiple instances in which these homeostatic mechanisms are altered by donor T cells or conditioning therapy, resulting in exacerbation of GVHD. We also discuss data suggesting that some of these mechanisms produce biomarkers that could be informative as to the severity of GVHD and its response to therapy. Finally, novel therapies that might restore homeostasis in the GI tract during GVHD are highlighted. PMID- 28581446 TI - Tregs restrain dendritic cell autophagy to ameliorate autoimmunity. AB - Design of efficacious Treg-based therapies and establishment of clinical tolerance in autoimmune diseases have proven to be challenging. The clinical implementation of Treg immunotherapy has been hampered by various impediments related to the stability and isolation procedures of Tregs as well as the specific in vivo targets of Treg modalities. Herein, we have demonstrated that Foxp3+ Tregs potently suppress autoimmune responses in vivo through inhibition of the autophagic machinery in DCs in a cytotoxic T-lymphocyte-associated protein 4 dependent (CTLA4-dependent) manner. Autophagy-deficient DCs exhibited reduced immunogenic potential and failed to prime autoantigen-specific CD4+ T cells to mediate autoimmunity. Mechanistically, CTLA4 binding promoted activation of the PI3K/Akt/mTOR axis and FoxO1 nuclear exclusion in DCs, leading to decreased transcription of the autophagy component microtubule-associated protein 1 light chain 3beta (Lc3b). Human DCs treated with CTLA4-Ig, a fusion protein composed of the Fc region of IgG1 and the extracellular domain of CTLA4 (also known as abatacept, marketed as Orencia), demonstrated reduced levels of autophagosome formation, while DCs from CTLA4-Ig-treated rheumatoid arthritis patients displayed diminished LC3B transcripts. Collectively, our data identify the canonical autophagy pathway in DCs as a molecular target of Foxp3+ Treg-mediated suppression that leads to amelioration of autoimmune responses. These findings may pave the way for the development of therapeutic protocols that exploit Tregs for the treatment of autoimmunity as well as diseases in which disturbed tolerance is a common denominator. PMID- 28581449 TI - Urinary tract infections in diabetic women during menopause: new basis for a multidisciplinary approach. PMID- 28581448 TI - Trimetazidine Protects Cardiomyocytes Against Hypoxia/Reoxygenation Injury by Promoting AMP-activated Protein Kinase-dependent Autophagic Flux. AB - Trimetazidine (TMZ), a metabolic agent, may protect against myocardial ischemia/reperfusion injury. Because of the critical role of autophagy in cardioprotection, we aimed to evaluate whether autophagy was involved in TMZ induced protection during hypoxia/reoxygenation (H/R). Neonatal rat cardiomyocytes were subjected to H/R injury, and they were divided into 7 groups: control, control+TMZ, control+chloroquine (Cq)/compound C (com C), H/R, H/R+TMZ, H/R+Cq/com C, and H/R+TMZ+Cq/com C. Autophagic flux was primarily assessed by Western blot and tandem fluorescent mRFP-GFP-LC3. Assays for MTS, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and lactate dehydrogenase release were performed to assess cell injury. Our results showed that TMZ pretreatment had a cardioprotective effect against H/R injury. The H/R+TMZ group had an increased ratio of LC3-II to LC3-I and increased autophagic flux (degradation of p62 and increases in autophagosomes and autolysosomes). TMZ also reduced apoptosis and enhanced cell survival while inducing autophagy. Correspondingly, autophagy inhibition with Cq blocked this protective effect. Furthermore, TMZ-induced enhancement of autophagy could be related to increased AMP-activated protein kinase (AMPK) phosphorylation and decreased Mammalian target of rapamycin (mTOR) phosphorylation, which was abolished by an AMPK specific inhibitor (com C). Our data provide evidence that TMZ pretreatment protects against H/R injury by promoting autophagic flux through the AMPK signaling pathway. PMID- 28581450 TI - Treatment and prognosis in patients with acute severe heart failure: does etiology matter? PMID- 28581451 TI - Role of molecular genetics in diabetic foot ulcer. PMID- 28581452 TI - Primary thyroid lymphoma: a rare but challenging diagnosis. PMID- 28581453 TI - Diffuse alveolar hemorrhage as an initial presentation of ANCA-associated vasculitis in an 80-year-old man. PMID- 28581454 TI - Lung adenocarcinoma metastasis to geographic skull. PMID- 28581455 TI - Attenuation of RNA viruses by redirecting their evolution in sequence space. AB - RNA viruses pose serious threats to human health. Their success relies on their capacity to generate genetic variability and, consequently, on their adaptive potential. We describe a strategy to attenuate RNA viruses by altering their evolutionary potential. We rationally altered the genomes of Coxsackie B3 and influenza A viruses to redirect their evolutionary trajectories towards detrimental regions in sequence space. Specifically, viral genomes were engineered to harbour more serine and leucine codons with nonsense mutation targets: codons that could generate Stop mutations after a single nucleotide substitution. Indeed, these viruses generated more Stop mutations both in vitro and in vivo, accompanied by significant losses in viral fitness. In vivo, the viruses were attenuated, generated high levels of neutralizing antibodies and protected against lethal challenge. Our study demonstrates that cornering viruses in 'risky' areas of sequence space may be implemented as a broad-spectrum vaccine strategy against RNA viruses. PMID- 28581457 TI - Involved/uninvolved heavy/light chain index can predict progression in transplanted multiple myeloma patients. PMID- 28581456 TI - Epigenetic silencing of IRF1 dysregulates type III interferon responses to respiratory virus infection in epithelial to mesenchymal transition. AB - Chronic oxidative injury produced by airway disease triggers a transforming growth factor-beta (TGF-beta)-mediated epigenetic reprogramming known as the epithelial-mesenchymal transition (EMT). We observe that EMT silences protective mucosal interferon (IFN)-I and III production associated with enhanced rhinovirus (RV) and respiratory syncytial virus (RSV) replication. Mesenchymal transitioned cells are defective in inducible interferon regulatory factor 1 (IRF1) expression by occluding RelA and IRF3 access to the promoter. IRF1 is necessary for the expression of type III IFNs (IFNLs 1 and 2/3). Induced by the EMT, zinc finger E box binding homeobox 1 (ZEB1) binds and silences IRF1. Ectopic ZEB1 is sufficient for IRF1 silencing, whereas ZEB1 knockdown partially restores IRF1-IFNL upregulation. ZEB1 silences IRF1 through the catalytic activity of the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), forming repressive H3K27(me3) marks. We observe that IRF1 expression is mediated by ZEB1 de repression, and our study demonstrates how airway remodelling/fibrosis is associated with a defective mucosal antiviral response through ZEB1-initiated epigenetic silencing. PMID- 28581458 TI - When should preemptive antiviral therapy for active CMV infection be withdrawn from allogeneic stem cell transplant recipients? PMID- 28581459 TI - The evolving role of chemotherapy and hematopoietic cell transplants in Ph positive acute lymphoblastic leukemia in adults. AB - The introduction of the tyrosine kinase inhibitors (TKI) into the treatment of patients with Ph or BCR-ABL1-positive acute lymphoblastic leukemia has revolutionized the treatment of this poor prognosis acute leukemia. The combination of TKI with chemotherapy has improved response rates and allowed more patients to proceed to allogeneic hematopoietic cell transplant (alloHCT). Older patients have excellent responses to TKI and corticosteroids or in combination with minimal chemotherapy. This raises the question as to whether patients require full-intensity chemotherapy with TKI to achieve molecular remissions. The pediatricians have proposed that cure is achievable without alloHCT in children. These results have suggested that many patients may not require traditional chemotherapy in addition to TKI to achieve remission, and that patients who achieve a negative minimal residual disease state may not require alloHCT. The data in support of these questions is presented here and a suggested future clinical trial design based on these data is proposed. PMID- 28581460 TI - MRD response in a refractory paediatric T-ALL patient through anti-programmed cell death 1 (PD-1) Ab treatment associated with induction of fatal GvHD. PMID- 28581461 TI - Long-term follow-up of allogeneic stem cell transplantation in relapsed/refractory Hodgkin lymphoma. PMID- 28581462 TI - Dynamics of molecular response in AML patients with NPM1 and FLT3 mutations undergoing allogeneic stem cell transplant. PMID- 28581463 TI - The burden of chemotherapy-induced nausea and vomiting in children receiving hematopoietic stem cell transplantation conditioning: a prospective study. AB - This prospective study describes chemotherapy-induced nausea and vomiting (CINV) in children (4-18 years) receiving their first hematopoietic stem cell transplant. Emetic episodes, nausea severity (assessed using a validated, self report nausea severity assessment tool) and antiemetic administration were documented from the start of conditioning until 24 h after the last conditioning agent was administered (acute) and for a further 7 days (delayed). Relationships between CINV control and parenteral nutrition (PN) use and acute gut GvHD (aGvHD) were explored. Fifty-nine children (4.6-17.4 years) were evaluable. Complete chemotherapy-induced vomiting (CIV; acute: 24%; delayed 22%) and chemotherapy induced nausea (CIN; acute 7%; delayed 12%) control rates were low. Few children experienced complete CINV control (no vomiting/retching and no nausea) during the acute (5%) or delayed phases (12%). Children experiencing complete acute or delayed CIN control or complete delayed CIV control were more likely to have received: a lower proportion of their total energy requirement as PN at the end of the delayed phase (P<0.036) and PN for a shorter time (P<0.044). Low patient numbers did not permit evaluation of the association between gut aGvHD and CINV control. Effective and safe interventions aimed at improving CINV control in children are required. PMID- 28581464 TI - Idarubicin-intensified haploidentical HSCT with GvHD prophylaxis of ATG and basiliximab provides comparable results to sibling donors in high-risk acute leukemia. AB - We designed a novel haploidentical hematopoietic stem cell transplantation (haplo HSCT) system using idarubicin (IDA) intensified conditioning regimens and combination of antithymocyte globulin and basiliximab for GvHD prophylaxis. The outcomes of 110 high-risk acute leukemia patients undergoing haplo-HSCT were compared with 69 contemporaneous high-risk patients receiving HLA-matched sibling transplantation using uniform IDA-intensified regimens. The relapse incidence of haplo-HSCT was 23.4%, and 3-year overall survival (OS) and disease-free survival (DFS) achieved 62.9%, 59.1%, respectively. The cumulative incidences of II-IV and III-IV aGvHD were 28.6 and 14.3%, while limited and extensive cGvHD were 19.4, 13.8%. All these results were equivalent to those of concurrent identical sibling transplantation. Three-year OS and DFS for patients in advance stage reached 48.5, 47.3%. Furthermore, the relapse, 3-year OS of positive minimal residual disease (MRD) patients did not differ from negative MRD patients (18.9% vs 11.5%, 63.6% vs 69.6%), indicating our intensified haplo-HSCT technique could circumvent the dismal prognosis of MRD. These data provide reinforcing evidence that our haplo-HSCT system could dramatically improve the survival of high-risk acute leukemia with low relapse and acceptable transplantation-related mortality, and might be a promising therapeutic option for high-risk patients. PMID- 28581465 TI - Severe acute GvHD following administration of ipilimumab for early relapse of AML after haploidentical stem cell transplantation. PMID- 28581466 TI - High-dose chemotherapy and autologous stem cell transplantation for primary central nervous system lymphoma: a multi-centre retrospective analysis from the United Kingdom. AB - The prognosis of patients with primary central nervous system lymphoma (PCNSL) has improved in recent years. This has partly been achieved by remission induction protocols incorporating high-dose methotrexate (HD-MTX) and rituximab. Given the high rates of relapse, consolidation therapy is usually considered in first response. Whole brain radiotherapy may prolong PFS but appears to confer no long-term survival advantage and is associated with significant neurocognitive dysfunction. Attempts to improve efficacy and reduce neurotoxicity of consolidation therapy have included thiotepa-based high-dose chemotherapy and autologous stem cell transplant (HDC-ASCT). This multi-centre, retrospective study reports the outcome of 70 patients undergoing HDC-ASCT for PCNSL in the United Kingdom. The median age at diagnosis was 56 years and all patients received HD-MTX-containing induction regimens. All patients underwent HDC-ASCT in first response. The rate of complete response increased from 50% before HDC-ASCT to 77% following HDC-ASCT. Treatment-related mortality was 6%. At a median follow up of 12 months from HDC-ASCT, the estimated 1- and 2-year PFS rates were 71.5% and overall survival 86.4% and 83.3%, respectively. These data are comparable to published studies of HDC-ASCT for PCNSL, supporting its feasibility and efficacy. PMID- 28581467 TI - Directionality of non-permissive HLA-DPB1 T-cell epitope group mismatches does not improve clinical risk stratification in 8/8 matched unrelated donor hematopoietic cell transplantation. AB - In 8/8 HLA-matched unrelated donor (UD) hematopoietic cell transplants (HCT), HLA DPB1 mismatches between alleles from different T-cell epitope (TCE) groups (non permissive mismatches) are associated with significantly higher risks of mortality compared with those between alleles from the same TCE group (permissive mismatches); however, the relevance of mismatch directionality, that is (host vs graft (uni-directional HvG), graft vs host (uni-directional GvH) or both (bi directional) in the non-permissive setting is unknown. We show here significantly higher in vitro relative responses (RR) to bi-directional mismatches compared with uni-directional HvG or GvH mismatches in a total of 420 one-way mixed lymphocyte reactions between 10/10 matched pairs (RR 27.5 vs 7.5 vs 15.5, respectively, P<0.001). However, in 3281 8/8 matched UD HCT for leukemia or myelodysplastic syndrome, the hazards of transplant-related mortality (TRM) were similar for uni-directional HvG or GvH mismatches and bi-directional mismatches (hazard ratio (HR) 1.32, P=0.001 vs HR 1.28, P=0.005 and HR 1.34, P=0.046), compared with permissive mismatches. Similar results were observed for overall survival. No statistical differences between the uni- and the bi-directional non permissive groups were detected in pairwise comparisons for any of the outcomes tested. We conclude that consideration of directionality does not improve risk stratification by non-permissive HLA-DPB1 TCE mismatches in UD searches. PMID- 28581469 TI - Administration of high-dose chemotherapy with stem cell support in patients 40 years of age or older with advanced germ cell tumours: a retrospective study from the European Society for Blood and Marrow Transplantation database. PMID- 28581468 TI - A phase I/II minor histocompatibility antigen-loaded dendritic cell vaccination trial to safely improve the efficacy of donor lymphocyte infusions in myeloma. AB - Allogeneic stem cell transplantation (allo-SCT) with or without donor lymphocyte infusions (DLI) is the only curative option for several hematological malignancies. Unfortunately, allo-SCT is often associated with GvHD, and patients often relapse. We therefore aim to improve the graft-versus-tumor effect, without increasing the risk of GvHD, by targeting hematopoietic lineage-restricted and tumor-associated minor histocompatibility antigens using peptide-loaded dendritic cell (DC) vaccinations. In the present multicenter study, we report the feasibility, safety and efficacy of this concept. We treated nine multiple myeloma patients with persistent or relapsed disease after allo-SCT and a previous DLI, with donor monocyte-derived mHag-peptide-loaded DC vaccinations combined with a second DLI. Vaccinations were well tolerated and no occurrence of GvHD was observed. In five out of nine patients, we were able to show the induction of mHag-specific CD8+ T cells in peripheral blood. Five out of nine patients, of which four developed mHag-specific T cells, showed stable disease (SD) for 3.5-10 months. This study shows that mHag-based donor monocyte-derived DC vaccination combined with DLI is safe, feasible and capable of inducing objective mHag-specific T-cell responses. Future research should focus on further improvement of the vaccination strategy, toward translating the observed T-cell responses into robust clinical responses. PMID- 28581470 TI - Low EGF in myeloablative allotransplantation: association with severe acute GvHD in BMT CTN 0402. AB - Epidermal growth factor (EGF) is a recently described biomarker of acute GvHD (aGvHD). Whether low plasma EGF prior to hematopoietic cell transplantation (HCT) predisposes to the development of aGvHD, or whether EGF levels fall because of severe aGvHD, is unknown. To evaluate this, we tested plasma samples collected at pre-HCT baseline, day +28 and day +100 during the course of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402. We found that baseline EGF plasma concentrations were three-fold lower in HCT recipients compared to donors (24.3 vs 76.0 pg/mL, P<0.01). Ninety-one patients (43%) had a markedly low plasma EGF at pre-HCT baseline, defined as <2.7 pg/mL-an optimal cutpoint associated with development of grade III-IV aGvHD. Patients with these low EGF levels at pre HCT baseline had a 2.9-fold increased risk of grade III-IV aGvHD by day +100. Patients with low EGF at day +28 after HCT had an increased risk of death (relative risk 2.3, P=0.02) by 1 year due to transplant-related toxicities, especially aGvHD. Our results suggest that very low plasma EGF early in the HCT process may predispose patients to an increased risk of death, potentially due to epithelial damage and limited repair capacity. PMID- 28581471 TI - Complete resolution of severe ulcerative colitis after haploidentical hematopoietic stem cell transplantation followed by post-transplant high-dose cyclophosphamide. PMID- 28581472 TI - Low incidence of severe cGvHD and late NRM in a phase II trial of thymoglobulin, tacrolimus and sirolimus for GvHD prevention. AB - Chronic GvHD (cGvHD) is the leading cause of late non-relapse mortality (NRM) and morbidity after allogeneic hematopoietic stem cell transplant (AHSCT). We analyzed the late effects of a phase II trial testing the efficacy of intermediate dose rabbit anti-thymocyte globulin (Thymoglobulin Thymo) in combination with tacrolimus and sirolimus (TTS) in 47 patients (pts) for the prevention of acute and chronic GvHD after unrelated AHSCT. The median follow-up was 45.2 months. The cumulative incidence of NIH severe cGvHD at 48 months was 6.4% with no new occurrences past 6 months for the entire follow-up period. The overall cumulative incidence of cGvHD was 44.7%. Out of 20 pts who are alive and disease-free at the last follow-up, only 4 pts continue to need systemic immune suppression. We observed low late NRM with only 3 transplant-related deaths after 6 months post transplant. At 4 years of follow-up, the overall cumulative incidence of NRM and disease relapse was 27.7% and 30.0%, respectively. PFS and overall survival (OS) at 4 years were 42 and 47%. At long term follow-up, TTS was associated with low incidence of severe cGvHD and late NRM. PMID- 28581473 TI - Minimal residual disease assessment by next-generation sequencing. Better tools to gaze into the crystal ball? PMID- 28581474 TI - Extracorporeal life support survival in a pediatric hematopoietic cellular transplant recipient with presumed GvHD-related fulminant myocarditis. PMID- 28581476 TI - Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. AB - The daily renewal of the corpus epithelium is fuelled by adult stem cells residing within tubular glands, but the identity of these stem cells remains controversial. Lgr5 marks homeostatic stem cells and 'reserve' stem cells in multiple tissues. Here, we report Lgr5 expression in a subpopulation of chief cells in mouse and human corpus glands. Using a non-variegated Lgr5-2A-CreERT2 mouse model, we show by lineage tracing that Lgr5-expressing chief cells do not behave as corpus stem cells during homeostasis, but are recruited to function as stem cells to effect epithelial renewal following injury by activating Wnt signalling. Ablation of Lgr5+ cells severely impairs epithelial homeostasis in the corpus, indicating an essential role for these Lgr5+ cells in maintaining the homeostatic stem cell pool. We additionally define Lgr5+ chief cells as a major cell-of-origin of gastric cancer. These findings reveal clinically relevant insights into homeostasis, repair and cancer in the corpus. PMID- 28581478 TI - Reinstated episodic context guides sampling-based decisions for reward. AB - How does experience inform decisions? In episodic sampling, decisions are guided by a few episodic memories of past choices. This process can yield choice patterns similar to model-free reinforcement learning; however, samples can vary from trial to trial, causing decisions to vary. Here we show that context retrieved during episodic sampling can cause choice behavior to deviate sharply from the predictions of reinforcement learning. Specifically, we show that, when a given memory is sampled, choices (in the present) are influenced by the properties of other decisions made in the same context as the sampled event. This effect is mediated by fMRI measures of context retrieval on each trial, suggesting a mechanism whereby cues trigger retrieval of context, which then triggers retrieval of other decisions from that context. This result establishes a new avenue by which experience can guide choice and, as such, has broad implications for the study of decisions. PMID- 28581475 TI - The choice of in-hospital or home administration for plerixafor injection to poor mobilizers has no adverse consequence on subsequent hematopoietic stem cell harvest. PMID- 28581480 TI - Rich cell-type-specific network topology in neocortical microcircuitry. AB - Uncovering structural regularities and architectural topologies of cortical circuitry is vital for understanding neural computations. Recently, an experimentally constrained algorithm generated a dense network reconstruction of a ~0.3-mm3 volume from juvenile rat somatosensory neocortex, comprising ~31,000 cells and ~36 million synapses. Using this reconstruction, we found a small-world topology with an average of 2.5 synapses separating any two cells and multiple cell-type-specific wiring features. Amounts of excitatory and inhibitory innervations varied across cells, yet pyramidal neurons maintained relatively constant excitation/inhibition ratios. The circuit contained highly connected hub neurons belonging to a small subset of cell types and forming an interconnected cell-type-specific rich club. Certain three-neuron motifs were overrepresented, matching recent experimental results. Cell-type-specific network properties were even more striking when synaptic strength and sign were considered in generating a functional topology. Our systematic approach enables interpretation of microconnectomics 'big data' and provides several experimentally testable predictions. PMID- 28581481 TI - Charge-transfer dynamics and nonlocal dielectric permittivity tuned with metamaterial structures as solvent analogues. AB - Charge transfer (CT) is a fundamental and ubiquitous mechanism in biology, physics and chemistry. Here, we evidence that CT dynamics can be altered by multi layered hyperbolic metamaterial (HMM) substrates. Taking triphenylene:perylene diimide dyad supramolecular self-assemblies as a model system, we reveal longer lived CT states in the presence of HMM structures, with both charge separation and recombination characteristic times increased by factors of 2.4 and 1.7-that is, relative variations of 140 and 73%, respectively. To rationalize these experimental results in terms of driving force, we successfully introduce image dipole interactions in Marcus theory. The non-local effect herein demonstrated is directly linked to the number of metal-dielectric pairs, can be formalized in the dielectric permittivity, and is presented as a solid analogue to local solvent polarity effects. This model and extra PH3T:PC60BM results show the generality of this non-local phenomenon and that a wide range of kinetic tailoring opportunities can arise from substrate engineering. This work paves the way toward the design of artificial substrates to control CT dynamics of interest for applications in optoelectronics and chemistry. PMID- 28581479 TI - Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus. AB - Anorexia is a common manifestation of chronic diseases, including cancer. Here we investigate the contribution to cancer anorexia made by calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) that transmit anorexic signals. We show that CGRPPBN neurons are activated in mice implanted with Lewis lung carcinoma cells. Inactivation of CGRPPBN neurons before tumor implantation prevents anorexia and loss of lean mass, and their inhibition after symptom onset reverses anorexia. CGRPPBN neurons are also activated in Apcmin/+ mice, which develop intestinal cancer and lose weight despite the absence of reduced food intake. Inactivation of CGRPPBN neurons in Apcmin/+ mice permits hyperphagia that counteracts weight loss, revealing a role for these neurons in a 'nonanorexic' cancer model. We also demonstrate that inactivation of CGRPPBN neurons prevents lethargy, anxiety and malaise associated with cancer. These findings establish CGRPPBN neurons as key mediators of cancer-induced appetite suppression and associated behavioral changes. PMID- 28581484 TI - Autocatalytic backbone N-methylation in a family of ribosomal peptide natural products. AB - Peptide backbone N-methylation, as seen in cyclosporin A, has been considered to be exclusive to nonribosomal peptides. We have identified the first post translationally modified peptide or protein harboring internal alpha-N methylations through discovery of the genetic locus for the omphalotins, cyclic N methylated peptides produced by the fungus Omphalotus olearius. We show that iterative autocatalytic activity of an N-methyltransferase fused to its peptide substrate is the signature of a new family of ribosomally encoded metabolites. PMID- 28581483 TI - Blocking an N-terminal acetylation-dependent protein interaction inhibits an E3 ligase. AB - N-terminal acetylation is an abundant modification influencing protein functions. Because ~80% of mammalian cytosolic proteins are N-terminally acetylated, this modification is potentially an untapped target for chemical control of their functions. Structural studies have revealed that, like lysine acetylation, N terminal acetylation converts a positively charged amine into a hydrophobic handle that mediates protein interactions; hence, this modification may be a druggable target. We report the development of chemical probes targeting the N terminal acetylation-dependent interaction between an E2 conjugating enzyme (UBE2M or UBC12) and DCN1 (DCUN1D1), a subunit of a multiprotein E3 ligase for the ubiquitin-like protein NEDD8. The inhibitors are highly selective with respect to other protein acetyl-amide-binding sites, inhibit NEDD8 ligation in vitro and in cells, and suppress anchorage-independent growth of a cell line with DCN1 amplification. Overall, our data demonstrate that N-terminal acetyl dependent protein interactions are druggable targets and provide insights into targeting multiprotein E2-E3 ligases. PMID- 28581477 TI - Inter-organ signalling by HRG-7 promotes systemic haem homeostasis. AB - Growing evidence in vertebrates predicts that cellular haem levels in animals are maintained not only by a cell's internal capacity for haem synthesis in a cell autonomous manner, but also by an inter-organ haem trafficking network through cell-non-autonomous regulation. Using Caenorhabditis elegans, a genetically and optically amenable animal model for visualizing haem-dependent signalling, we show that HRG-7, a protein with homology to aspartic proteases, mediates inter organ signalling between the intestine and extra-intestinal tissues. Intestinal HRG-7 functions as a secreted signalling factor during haem starvation in extra intestinal tissues and is regulated through a DBL-1, homologous to BMP5, dependent signal from neurons. Given the evidence that vertebrate homologues exist for each of the components of the HRG-7-mediated signalling pathway, it is conceivable that the cell-non-autonomous signalling framework that we uncovered in C. elegans may have functional relevance for inter-organ regulation of iron and haem metabolism in humans. PMID- 28581482 TI - Parallel evolution of non-homologous isofunctional enzymes in methionine biosynthesis. AB - Experimental validation of enzyme function is crucial for genome interpretation, but it remains challenging because it cannot be scaled up to accommodate the constant accumulation of genome sequences. We tackled this issue for the MetA and MetX enzyme families, phylogenetically unrelated families of acyl-L-homoserine transferases involved in L-methionine biosynthesis. Members of these families are prone to incorrect annotation because MetX and MetA enzymes are assumed to always use acetyl-CoA and succinyl-CoA, respectively. We determined the enzymatic activities of 100 enzymes from diverse species, and interpreted the results by structural classification of active sites based on protein structure modeling. We predict that >60% of the 10,000 sequences from these families currently present in databases are incorrectly annotated, and suggest that acetyl-CoA was originally the sole substrate of these isofunctional enzymes, which evolved to use exclusively succinyl-CoA in the most recent bacteria. We also uncovered a divergent subgroup of MetX enzymes in fungi that participate only in L-cysteine biosynthesis as O-succinyl-L-serine transferases. PMID- 28581485 TI - Activity-based probes for functional interrogation of retaining beta glucuronidases. AB - Humans express at least two distinct beta-glucuronidase enzymes that are involved in disease: exo-acting beta-glucuronidase (GUSB), whose deficiency gives rise to mucopolysaccharidosis type VII, and endo-acting heparanase (HPSE), whose overexpression is implicated in inflammation and cancers. The medical importance of these enzymes necessitates reliable methods to assay their activities in tissues. Herein, we present a set of beta-glucuronidase-specific activity-based probes (ABPs) that allow rapid and quantitative visualization of GUSB and HPSE in biological samples, providing a powerful tool for dissecting their activities in normal and disease states. Unexpectedly, we find that the supposedly inactive HPSE proenzyme proHPSE is also labeled by our ABPs, leading to surprising insights regarding structural relationships between proHPSE, mature HPSE, and their bacterial homologs. Our results demonstrate the application of beta glucuronidase ABPs in tracking pathologically relevant enzymes and provide a case study of how ABP-driven approaches can lead to discovery of unanticipated structural and biochemical functionality. PMID- 28581486 TI - The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals. AB - The Hippo signaling pathway and the Notch signaling pathway are evolutionary conserved signaling cascades that have important roles in embryonic development of many organs. In murine liver, disruption of either pathway impairs intrahepatic bile duct development. Recent studies suggested that the Notch signaling receptor Notch2 is a direct transcriptional target of the Hippo signaling pathway effector YAP, and the Notch signaling is a major mediator of the Hippo signaling in maintaining biliary cell characteristics in adult mice. However, it remains to be determined whether the Hippo signaling pathway functions through the Notch signaling in intrahepatic bile duct development. We found that loss of the Hippo signaling pathway tumor suppressor Nf2 resulted in increased expression levels of the Notch signaling pathway receptor Notch2 in cholangiocytes but not in hepatocytes. When knocking down Notch2 on the background of Nf2 deficiency in mouse livers, the excessive bile duct development induced by Nf2 deficiency was suppressed by heterozygous and homozygous deletion of Notch2 in a dose-dependent manner. These results implicated that Notch signaling is one of the downstream effectors of the Hippo signaling pathway in regulating intrahepatic bile duct development. PMID- 28581488 TI - Osteoblast-derived Laminin-332 is a novel negative regulator of osteoclastogenesis in bone microenvironments. AB - Laminin-332 (Lm-332), a major basement membrane protein, has been shown to provide a niche for some stem cells. Here, we found that Lm-332 was expressed in osteoblasts, and is implicated in the regulation of osteoclast differentiation. Immunofluorescence analysis of laminin-beta3, a unique component of Lm-332, indicated specific expression of laminin-beta3 in osteoblast-like cells localized on bone surface. RT-PCR analysis confirmed that alpha3, beta3, and gamma2 chains of Lm-332 were all expressed in primary osteoblasts prepared from mouse calvaria. Lm-332 markedly inhibited osteoclastogenesis induced by receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL) when bone marrow-derived macrophages (BMMs) were cultured on Lm-332-coated plates. Lm-332 also blocked RANKL-induced activation of mitogen-activated protein kinases (MAPKs) (ERK, JNK, and p38) and expression of NFATc1, c-Fos, and c-Jun. Lm-332 suppressed osteoclast differentiation while retaining macrophage phenotypes, including nonspecific esterase activity and gene expression of lysozyme and EGF-like module-containing mucin-like hormone receptor-like 1 (Emr1). Furthermore, the treatment of primary osteoblasts with osteoclastogenic factors dramatically suppressed expression of Lm-332. These findings suggest that Lm-332 produced by osteoblasts in bone tissues has a pivotal role in controlling normal bone remodeling through suppressing osteoclastogenesis. PMID- 28581487 TI - EMMPRIN (CD147) is induced by C/EBPbeta and is differentially expressed in ALK+ and ALK- anaplastic large-cell lymphoma. AB - Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is characterized by expression of oncogenic ALK fusion proteins due to the translocation t(2;5)(p23;q35) or variants. Although genotypically a T-cell lymphoma, ALK+ ALCL cells frequently show loss of T-cell-specific surface antigens and expression of monocytic markers. C/EBPbeta, a transcription factor constitutively overexpressed in ALK+ ALCL cells, has been shown to play an important role in the activation and differentiation of macrophages and is furthermore capable of transdifferentiating B-cell and T-cell progenitors to macrophages in vitro. To analyze the role of C/EBPbeta for the unusual phenotype of ALK+ ALCL cells, C/EBPbeta was knocked down by RNA interference in two ALK+ ALCL cell lines, and surface antigen expression profiles of these cell lines were generated using a Human Cell Surface Marker Screening Panel (BD Biosciences). Interesting candidate antigens were further analyzed by immunohistochemistry in primary ALCL ALK+ and ALK- cases. Antigen expression profiling revealed marked changes in the expression of the activation markers CD25, CD30, CD98, CD147, and CD227 after C/EBPbeta knockdown. Immunohistochemical analysis confirmed a strong, membranous CD147 (EMMPRIN) expression in ALK+ ALCL cases. In contrast, ALK- ALCL cases showed a weaker CD147 expression. CD274 or PD-L1, an immune inhibitory receptor ligand, was downregulated after C/EBPbeta knockdown. PD-L1 also showed stronger expression in ALK+ ALCL compared with ALK- ALCL, suggesting an additional role of C/EBPbeta in ALK+ ALCL in generating an immunosuppressive environment. Finally, no expression changes of T-cell or monocytic markers were detected. In conclusion, surface antigen expression profiling demonstrates that C/EBPbeta plays a critical role in the activation state of ALK+ ALCL cells and reveals CD147 and PD-L1 as important downstream targets. The multiple roles of CD147 in migration, adhesion, and invasion, as well as T-cell activation and proliferation suggest its involvement in the pathogenesis of ALCL. PMID- 28581489 TI - alpha-Actinin-4 promotes metastasis in gastric cancer. AB - Metastasis increases the mortality rate of gastric cancer, which is the third leading cause of cancer-associated deaths worldwide. This study aims to identify the genes promoting metastasis of gastric cancer (GC). A human cell motility PCR array was used to analyze a pair of tumor and non-tumor tissue samples from a patient with stage IV GC (T3N3M1). Expression of the dysregulated genes was then evaluated in GC tissue samples (n=10) and cell lines (n=6) via qPCR. Expression of alpha-actinin-4 (ACTN4) was validated in a larger sample size (n=47) by qPCR, western blot and immunohistochemistry. Knockdown of ACTN4 with specific siRNAs was performed in GC cells, and adhesion assays, transwell invasion assays and migration assays were used to evaluate the function of these cells. Expression of potential targets of ACTN4 were then evaluated by qPCR. Thirty upregulated genes (greater than twofold) were revealed by the PCR array. We focused on ACTN4 because it was upregulated in 6 out of 10 pairs of tissue samples and 5 out of 6 GC cell lines. Further study indicated that ACTN4 was upregulated in 22/32 pairs of tissue samples at stage III &IV (P=0.0069). Knockdown of ACTN4 in GC cells showed no significant effect on cell proliferation, but significantly increased cell-matrix adhesion, as well as reduced migration and invasion of AGS, MKN7 and NCI-N87 cells. We found that NF-kappaB was downregulated in GC with the knockdown of ACTN4. In conclusion, this is the first study to indicate that ACTN4 is significantly upregulated in patients with metastatic GC. ACTN4 reduces cell adhesion and enhances migration and invasion of GC cells and may therefore be a novel therapeutic target for GC. PMID- 28581490 TI - Assessment of tumor characteristics based on glycoform analysis of membrane tethered MUC1. AB - Clinical tissue specimens are useful for pathological diagnosis, which is, in some cases, supported by visualization of biomolecule localization. In general, diagnostic specificity in molecular pathology is increased by the acquisition of a probe to distinguish the modification of isomers. Although glycosylation is one of the candidate modifications in a protein, comparative glycan analysis of disease-associated proteins derived from a single tissue section is still challenging because of the lack of analytical sensitivity. Here we demonstrate a possible method for differential glycoform analysis of an endogenous tumor associated glycoprotein MUC1 by an antibody-overlay lectin microarray. Tissue sections (5 MUm thick) of patients with cholangiocarcinoma (CCA; n=21) and pancreatic ductal adenocarcinoma (PDAC; n=50) were stained with an anti-MUC1 antibody MY.1E12 that was established as a monoclonal antibody recognizing an MUC1 glycosylation isoform with a sialyl-core 1 structure (NeuAcalpha2 3galactosyl beta1-3-N-acetylgalactosamine). MY.1E12-positive tissue areas (2.5 mm2) were selectively dissected with a laser capture microdissection procedure. The membrane MUC1 was enriched by immunoprecipitation with MY.1E12 and subjected to lectin microarray analysis. Even though the reactivities of MY.1E12 between CCA and PDAC were similar, the lectin-binding patterns varied. We found Maackia amurensis leukoagglutinin and pokeweed lectin distinguished MY.1E12-reactive MUC1 of CCA from that of PDAC. Moreover, MUC1 with M. amurensis hemagglutinin (MAH) reactivity potentially reflected the degree of malignancy. These results were confirmed with MAH-MY.1E12 double fluorescent immunostaining. These glycan changes on MUC1 were detected with high sensitivity owing to the cluster effect of immobilized lectins on a tandem repeat peptide antigen covered with highly dense glycosylation such as mucin. Our approach provides the information to investigate novel glycodynamics in biology, for example, glycoalteration, as well as diseases related to not only MUC1 but also other membrane proteins. PMID- 28581491 TI - Making individualized drugs a reality. PMID- 28581492 TI - Engineered Cpf1 variants with altered PAM specificities. AB - The RNA-guided endonuclease Cpf1 is a promising tool for genome editing in eukaryotic cells. However, the utility of the commonly used Acidaminococcus sp. BV3L6 Cpf1 (AsCpf1) and Lachnospiraceae bacterium ND2006 Cpf1 (LbCpf1) is limited by their requirement of a TTTV protospacer adjacent motif (PAM) in the DNA substrate. To address this limitation, we performed a structure-guided mutagenesis screen to increase the targeting range of Cpf1. We engineered two AsCpf1 variants carrying the mutations S542R/K607R and S542R/K548V/N552R, which recognize TYCV and TATV PAMs, respectively, with enhanced activities in vitro and in human cells. Genome-wide assessment of off-target activity using BLISS indicated that these variants retain high DNA-targeting specificity, which we further improved by introducing an additional non-PAM-interacting mutation. Introducing the identified PAM-interacting mutations at their corresponding positions in LbCpf1 similarly altered its PAM specificity. Together, these variants increase the targeting range of Cpf1 by approximately threefold in human coding sequences to one cleavage site per ~11 bp. PMID- 28581493 TI - CRISPR-STOP: gene silencing through base-editing-induced nonsense mutations. AB - CRISPR-Cas9-induced DNA damage may have deleterious effects at high-copy-number genomic regions. Here, we use CRISPR base editors to knock out genes by changing single nucleotides to create stop codons. We show that the CRISPR-STOP method is an efficient and less deleterious alternative to wild-type Cas9 for gene-knockout studies. Early stop codons can be introduced in ~17,000 human genes. CRISPR-STOP mediated targeted screening demonstrates comparable efficiency to WT Cas9, which indicates the suitability of our approach for genome-wide functional screenings. PMID- 28581495 TI - Quantitative mRNA imaging throughout the entire Drosophila brain. AB - We describe a fluorescence in situ hybridization method that permits detection of the localization and abundance of single mRNAs (smFISH) in cleared whole-mount adult Drosophila brains. The approach is rapid and multiplexable and does not require molecular amplification; it allows facile quantification of mRNA expression with subcellular resolution on a standard confocal microscope. We further demonstrate single-mRNA detection across the entire brain using a custom Bessel beam structured illumination microscope (BB-SIM). PMID- 28581494 TI - Genetically encoded fluorescent sensors reveal dynamic regulation of NADPH metabolism. AB - Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is essential for biosynthetic reactions and antioxidant functions; however, detection of NADPH metabolism in living cells remains technically challenging. We develop and characterize ratiometric, pH-resistant, genetically encoded fluorescent indicators for NADPH (iNap sensors) with various affinities and wide dynamic range. iNap sensors enabled quantification of cytosolic and mitochondrial NADPH pools that are controlled by cytosolic NAD+ kinase levels and revealed cellular NADPH dynamics under oxidative stress depending on glucose availability. We found that mammalian cells have a strong tendency to maintain physiological NADPH homeostasis, which is regulated by glucose-6-phosphate dehydrogenase and AMP kinase. Moreover, using the iNap sensors we monitor NADPH fluctuations during the activation of macrophage cells or wound response in vivo. These data demonstrate that the iNap sensors will be valuable tools for monitoring NADPH dynamics in live cells and gaining new insights into cell metabolism. PMID- 28581496 TI - Differential analysis of RNA-seq incorporating quantification uncertainty. AB - We describe sleuth (http://pachterlab.github.io/sleuth), a method for the differential analysis of gene expression data that utilizes bootstrapping in conjunction with response error linear modeling to decouple biological variance from inferential variance. sleuth is implemented in an interactive shiny app that utilizes kallisto quantifications and bootstraps for fast and accurate analysis of data from RNA-seq experiments. PMID- 28581497 TI - The extracellular matrix protein agrin promotes heart regeneration in mice. AB - The adult mammalian heart is non-regenerative owing to the post-mitotic nature of cardiomyocytes. The neonatal mouse heart can regenerate, but only during the first week of life. Here we show that changes in the composition of the extracellular matrix during this week can affect cardiomyocyte growth and differentiation in mice. We identify agrin, a component of neonatal extracellular matrix, as required for the full regenerative capacity of neonatal mouse hearts. In vitro, recombinant agrin promotes the division of cardiomyocytes that are derived from mouse and human induced pluripotent stem cells through a mechanism that involves the disassembly of the dystrophin-glycoprotein complex, and Yap- and ERK-mediated signalling. In vivo, a single administration of agrin promotes cardiac regeneration in adult mice after myocardial infarction, although the degree of cardiomyocyte proliferation observed in this model suggests that there are additional therapeutic mechanisms. Together, our results uncover a new inducer of mammalian heart regeneration and highlight fundamental roles of the extracellular matrix in cardiac repair. PMID- 28581498 TI - Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation. AB - The regenerative capacity of the adult mammalian heart is limited, because of the reduced ability of cardiomyocytes to progress through mitosis. Endogenous cardiomyocytes have regenerative capacity at birth but this capacity is lost postnatally, with subsequent organ growth occurring through cardiomyocyte hypertrophy. The Hippo pathway, a conserved kinase cascade, inhibits cardiomyocyte proliferation in the developing heart to control heart size and prevents regeneration in the adult heart. The dystrophin-glycoprotein complex (DGC), a multicomponent transmembrane complex linking the actin cytoskeleton to extracellular matrix, is essential for cardiomyocyte homeostasis. DGC deficiency in humans results in muscular dystrophy, including the lethal Duchenne muscular dystrophy. Here we show that the DGC component dystroglycan 1 (Dag1) directly binds to the Hippo pathway effector Yap to inhibit cardiomyocyte proliferation in mice. The Yap-Dag1 interaction was enhanced by Hippo-induced Yap phosphorylation, revealing a connection between Hippo pathway function and the DGC. After injury, Hippo-deficient postnatal mouse hearts maintained organ size control by repairing the defect with correct dimensions, whereas postnatal hearts deficient in both Hippo and the DGC showed cardiomyocyte overproliferation at the injury site. In the hearts of mature Mdx mice (which have a point mutation in Dmd)-a model of Duchenne muscular dystrophy-Hippo deficiency protected against overload-induced heart failure. PMID- 28581500 TI - Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2. AB - Dominant mutations in the MORC2 gene have recently been shown to cause axonal Charcot-Marie-Tooth (CMT) disease, but the cellular function of MORC2 is poorly understood. Here, through a genome-wide CRISPR-Cas9-mediated forward genetic screen, we identified MORC2 as an essential gene required for epigenetic silencing by the HUSH complex. HUSH recruits MORC2 to target sites in heterochromatin. We exploited a new method, differential viral accessibility (DIVA), to show that loss of MORC2 results in chromatin decompaction at these target loci, which is concomitant with a loss of H3K9me3 deposition and transcriptional derepression. The ATPase activity of MORC2 is critical for HUSH mediated silencing, and the most common alteration affecting the ATPase domain in CMT patients (p.Arg252Trp) hyperactivates HUSH-mediated repression in neuronal cells. These data define a critical role for MORC2 in epigenetic silencing by the HUSH complex and provide a mechanistic basis underpinning the role of MORC2 mutations in CMT disease. PMID- 28581502 TI - Genome-wide characterization of mammalian promoters with distal enhancer functions. AB - Gene expression in mammals is precisely regulated by the combination of promoters and gene-distal regulatory regions, known as enhancers. Several studies have suggested that some promoters might have enhancer functions. However, the extent of this type of promoters and whether they actually function to regulate the expression of distal genes have remained elusive. Here, by exploiting a high throughput enhancer reporter assay, we unravel a set of mammalian promoters displaying enhancer activity. These promoters have distinct genomic and epigenomic features and frequently interact with other gene promoters. Extensive CRISPR-Cas9 genomic manipulation demonstrated the involvement of these promoters in the cis regulation of expression of distal genes in their natural loci. Our results have important implications for the understanding of complex gene regulation in normal development and disease. PMID- 28581499 TI - High-quality de novo assembly of the apple genome and methylome dynamics of early fruit development. AB - Using the latest sequencing and optical mapping technologies, we have produced a high-quality de novo assembly of the apple (Malus domestica Borkh.) genome. Repeat sequences, which represented over half of the assembly, provided an unprecedented opportunity to investigate the uncharacterized regions of a tree genome; we identified a new hyper-repetitive retrotransposon sequence that was over-represented in heterochromatic regions and estimated that a major burst of different transposable elements (TEs) occurred 21 million years ago. Notably, the timing of this TE burst coincided with the uplift of the Tian Shan mountains, which is thought to be the center of the location where the apple originated, suggesting that TEs and associated processes may have contributed to the diversification of the apple ancestor and possibly to its divergence from pear. Finally, genome-wide DNA methylation data suggest that epigenetic marks may contribute to agronomically relevant aspects, such as apple fruit development. PMID- 28581501 TI - Genomic analyses in cotton identify signatures of selection and loci associated with fiber quality and yield traits. AB - Upland cotton (Gossypium hirsutum) is the most important natural fiber crop in the world. The overall genetic diversity among cultivated species of cotton and the genetic changes that occurred during their improvement are poorly understood. Here we report a comprehensive genomic assessment of modern improved upland cotton based on the genome-wide resequencing of 318 landraces and modern improved cultivars or lines. We detected more associated loci for lint yield than for fiber quality, which suggests that lint yield has stronger selection signatures than other traits. We found that two ethylene-pathway-related genes were associated with increased lint yield in improved cultivars. We evaluated the population frequency of each elite allele in historically released cultivar groups and found that 54.8% of the elite genome-wide association study (GWAS) alleles detected were transferred from three founder landraces: Deltapine 15, Stoneville 2B and Uganda Mian. Our results provide a genomic basis for improving cotton cultivars and for further evolutionary analysis of polyploid crops. PMID- 28581503 TI - Between-region genetic divergence reflects the mode and tempo of tumor evolution. AB - Given the implications of tumor dynamics for precision medicine, there is a need to systematically characterize the mode of evolution across diverse solid tumor types. In particular, methods to infer the role of natural selection within established human tumors are lacking. By simulating spatial tumor growth under different evolutionary modes and examining patterns of between-region subclonal genetic divergence from multiregion sequencing (MRS) data, we demonstrate that it is feasible to distinguish tumors driven by strong positive subclonal selection from those evolving neutrally or under weak selection, as the latter fail to dramatically alter subclonal composition. We developed a classifier based on measures of between-region subclonal genetic divergence and projected patient data into model space, finding different modes of evolution both within and between solid tumor types. Our findings have broad implications for how human tumors progress, how they accumulate intratumoral heterogeneity, and ultimately how they may be more effectively treated. PMID- 28581504 TI - Overweight and obesity in Mexican children and adolescents during the last 25 years. AB - This corrects the article DOI: 10.1038/nutd.2016.52. PMID- 28581505 TI - A decade of discovery: CRISPR functions and applications. AB - This year marks the tenth anniversary of the identification of the biological function of CRISPR-Cas as adaptive immune systems in bacteria. In just a decade, the characterization of CRISPR-Cas systems has established a novel means of adaptive immunity in bacteria and archaea and deepened our understanding of the interplay between prokaryotes and their environment, and CRISPR-based molecular machines have been repurposed to enable a genome editing revolution. Here, we look back on the historical milestones that have paved the way for the discovery of CRISPR and its function, and discuss the related technological applications that have emerged, with a focus on microbiology. Lastly, we provide a perspective on the impacts the field has had on science and beyond. PMID- 28581506 TI - Arabidopsis evolution: Roots in Africa. PMID- 28581507 TI - Isotope evidence for agricultural extensification reveals how the world's first cities were fed. AB - This study sheds light on the agricultural economy that underpinned the emergence of the first urban centres in northern Mesopotamia. Using delta13C and delta15N values of crop remains from the sites of Tell Sabi Abyad, Tell Zeidan, Hamoukar, Tell Brak and Tell Leilan (6500-2000 cal bc), we reveal that labour-intensive practices such as manuring/middening and water management formed an integral part of the agricultural strategy from the seventh millennium bc. Increased agricultural production to support growing urban populations was achieved by cultivation of larger areas of land, entailing lower manure/midden inputs per unit area-extensification. Our findings paint a nuanced picture of the role of agricultural production in new forms of political centralization. The shift towards lower-input farming most plausibly developed gradually at a household level, but the increased importance of land-based wealth constituted a key potential source of political power, providing the possibility for greater bureaucratic control and contributing to the wider societal changes that accompanied urbanization. PMID- 28581508 TI - Regulation of cargo transfer between ESCRT-0 and ESCRT-I complexes by flotillin-1 during endosomal sorting of ubiquitinated cargo. AB - Ubiquitin-dependent sorting of membrane proteins in endosomes directs them to lysosomal degradation. In the case of receptors such as the epidermal growth factor receptor (EGFR), lysosomal degradation is important for the regulation of downstream signalling. Ubiquitinated proteins are recognised in endosomes by the endosomal sorting complexes required for transport (ESCRT) complexes, which sequentially interact with the ubiquitinated cargo. Although the role of each ESCRT complex in sorting is well established, it is not clear how the cargo is passed on from one ESCRT to the next. We here show that flotillin-1 is required for EGFR degradation, and that it interacts with the subunits of ESCRT-0 and -I complexes (hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and Tsg101). Flotillin-1 is required for cargo recognition and sorting by ESCRT-0/Hrs and for its interaction with Tsg101. In addition, flotillin-1 is also required for the sorting of human immunodeficiency virus 1 Gag polyprotein, which mimics ESCRT-0 complex during viral assembly. We propose that flotillin-1 functions in cargo transfer between ESCRT-0 and -I complexes. PMID- 28581509 TI - Ultrafast lithium diffusion in bilayer graphene. AB - Solids that simultaneously conduct electrons and ions are key elements for the mass transfer and storage required in battery electrodes. Single-phase materials with a high electronic and high ionic conductivity at room temperature are hard to come by, and therefore multiphase systems with separate ion and electron channels have been put forward instead. Here we report on bilayer graphene as a single-phase mixed conductor that demonstrates Li diffusion faster than in graphite and even surpassing the diffusion of sodium chloride in liquid water. To measure Li diffusion, we have developed an on-chip electrochemical cell architecture in which the redox reaction that forces Li intercalation is localized only at a protrusion of the device so that the graphene bilayer remains unperturbed from the electrolyte during operation. We performed time-dependent Hall measurements across spatially displaced Hall probes to monitor the in-plane Li diffusion kinetics within the graphene bilayer and measured a diffusion coefficient as high as 7 * 10-5 cm2 s-1. PMID- 28581510 TI - Nanoscale manipulation of membrane curvature for probing endocytosis in live cells. AB - Clathrin-mediated endocytosis (CME) involves nanoscale bending and inward budding of the plasma membrane, by which cells regulate both the distribution of membrane proteins and the entry of extracellular species. Extensive studies have shown that CME proteins actively modulate the plasma membrane curvature. However, the reciprocal regulation of how the plasma membrane curvature affects the activities of endocytic proteins is much less explored, despite studies suggesting that membrane curvature itself can trigger biochemical reactions. This gap in our understanding is largely due to technical challenges in precisely controlling the membrane curvature in live cells. In this work, we use patterned nanostructures to generate well-defined membrane curvatures ranging from +50 nm to -500 nm radius of curvature. We find that the positively curved membranes are CME hotspots, and that key CME proteins, clathrin and dynamin, show a strong preference towards positive membrane curvatures with a radius <200 nm. Of ten CME related proteins we examined, all show preferences for positively curved membrane. In contrast, other membrane-associated proteins and non-CME endocytic protein caveolin1 show no such curvature preference. Therefore, nanostructured substrates constitute a novel tool for investigating curvature-dependent processes in live cells. PMID- 28581513 TI - KIF26B, a novel oncogene, promotes proliferation and metastasis by activating the VEGF pathway in gastric cancer. AB - Tumor metastasis is the main reason of cancer-related death for gastric cancer (GC) patients and gene expression microarray data indicate that kinesin family member 26B (KIF26B) is one of the most upregulated genes in metastatic GC samples. Specifically, KIF26B expression was upregulated in a stepwise manner from non-tumorous gastric mucosa, primary GC tissues without metastasis, via primary GC tissues with metastasis, to secondary lymph node metastatic (LNM) foci. Increased expression of KIF26B was correlated with tumor size, positive LNM or distant metastases and poor prognosis. KIF26B, negatively regulated by miR 372, promoted GC cell proliferation and metastasis in vitro and in vivo. Mechanistic investigations confirmed that the main target of KIF26B was the vascular endothelial growth factor (VEGF) signaling pathway, particularly by inhibition or overexpression of VEGFA, PXN, FAK, PIK3CA, BCL2 and CREB1. Thus, KIF26B, a novel oncogene regulated by miR-372, promotes proliferation and metastasis through the VEGF pathway in GC. PMID- 28581511 TI - RNA fate determination through cotranscriptional adenosine methylation and microprocessor binding. AB - Eukaryotic gene expression is heavily regulated at the transcriptional and post transcriptional levels. An additional layer of regulation occurs co transcriptionally through processing and decay of nascent transcripts physically associated with chromatin. This process involves RNA interference (RNAi) machinery and is well documented in yeast, but little is known about its conservation in mammals. Here we show that Dgcr8 and Drosha physically associate with chromatin in murine embryonic stem cells (mES), specifically with a subset of transcribed coding and noncoding genes. Dgcr8 recruitment to chromatin is dependent on transcription as well as methyltransferase-like 3 (Mettl3), which catalyzes RNA N6-methyladenosine (m6A). Intriguingly, we found that acute temperature stress causes radical relocalization of Dgcr8 and Mettl3 to heat shock genes, where they act to co-transcriptionally mark mRNAs for subsequent RNA degradation. Together, our findings elucidate a novel mode of co-transcriptional gene regulation, in which m6A serves as a chemical mark that instigates subsequent post-transcriptional RNA-processing events. PMID- 28581512 TI - Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. AB - Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-A crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK 8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-A structure of the hGPR40-MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands. PMID- 28581516 TI - Pancreatic cancer heterogeneity and response to Mek inhibition. AB - Our increasing knowledge of the mechanisms behind the progression of pancreatic cancer (PC) has not yet translated into effective treatments. Many promising drugs have failed in the clinic, highlighting the need for better preclinical models to assess drug efficacy and characterize mechanisms of resistance. Using different experimental models, including patient-derived xenografts (PDXs), we gauged the efficacy of therapies aimed at two hallmark lesions of PCs: activation of signaling pathways by oncogenic KRAS and inactivation of tumor-suppressor genes. Although the drug targeting inactivation of tumor suppressors by DNA methylation had little effect, the inhibition of Mek, a K-Ras effector, in combination with the standard of care (chemotherapy consisting of gemcitabine/Nab paclitaxel), reduced the growth of three out of five PC-PDXs and impaired metastasis. The two least responding PC-PDXs were composed of genetically diverse cells, which displayed sensitivities to the Mek inhibitor differing by >10-fold. Unexpectedly, our analysis of this genetic diversity unveiled different KRAS mutations. As mutation in KRAS occurs early during progression, this heterogeneity may reflect the simultaneous appearance of different malignant cellular clones or, alternatively, that cells containing two mutations of KRAS are selected during tumor evolution. In vitro and in vivo analyses indicated that the intratumoral heterogeneity, along with the selective pressure imposed by the Mek inhibitor, resulted in rapid selection of resistant cells. Together with the gemcitabine/Nab-paclitaxel backbone, Mek inhibition could be effective in treatment of PC. However, resistance because of intratumoral heterogeneity is likely to develop frequently, pointing to the necessity of identifying the factors and mechanisms of resistance to further develop this therapy. PMID- 28581514 TI - ALDH1A3 is epigenetically regulated during melanocyte transformation and is a target for melanoma treatment. AB - Despite the promising targeted and immune-based interventions in melanoma treatment, long-lasting responses are limited. Melanoma cells present an aberrant redox state that leads to the production of toxic aldehydes that must be converted into less reactive molecules. Targeting the detoxification machinery constitutes a novel therapeutic avenue for melanoma. Here, using 56 cell lines representing nine different tumor types, we demonstrate that melanoma cells exhibit a strong correlation between reactive oxygen species amounts and aldehyde dehydrogenase 1 (ALDH1) activity. We found that ALDH1A3 is upregulated by epigenetic mechanisms in melanoma cells compared with normal melanocytes. Furthermore, it is highly expressed in a large percentage of human nevi and melanomas during melanocyte transformation, which is consistent with the data from the TCGA, CCLE and protein atlas databases. Melanoma treatment with the novel irreversible isoform-specific ALDH1 inhibitor [4-dimethylamino-4-methyl pent-2-ynthioic acid-S methylester] di-methyl-ampal-thio-ester (DIMATE) or depletion of ALDH1A1 and/or ALDH1A3, promoted the accumulation of apoptogenic aldehydes leading to apoptosis and tumor growth inhibition in immunocompetent, immunosuppressed and patient-derived xenograft mouse models. Interestingly, DIMATE also targeted the slow cycling label-retaining tumor cell population containing the tumorigenic and chemoresistant cells. Our findings suggest that aldehyde detoxification is relevant metabolic mechanism in melanoma cells, which can be used as a novel approach for melanoma treatment. PMID- 28581515 TI - GATA3 targets semaphorin 3B in mammary epithelial cells to suppress breast cancer progression and metastasis. AB - Semaphorin 3B (SEMA3B) is a secreted axonal guidance molecule that is expressed during development and throughout adulthood. Recently, SEMA3B has emerged as a tumor suppressor in non-neuronal cells. Here, we show that SEMA3B is a direct target of GATA3 transcriptional activity. GATA3 is a key transcription factor that regulates genes involved in mammary luminal cell differentiation and tumor suppression. We show that GATA3 relies on SEMA3B for suppression of tumor growth. Loss of SEMA3B renders GATA3 inactive and promotes aggressive breast cancer development. Overexpression of SEMA3B in cells lacking GATA3 induces a GATA3-like phenotype and higher levels of SEMA3B are associated with better cancer patient prognosis. Moreover, SEMA3B interferes with activation of LIM kinases (LIMK1 and LIMK2) to abrogate breast cancer progression. Our data provide new insights into the role of SEMA3B in mammary gland and provides a new branch of GATA3 signaling that is pivotal for inhibition of breast cancer progression and metastasis. PMID- 28581517 TI - Functional antagonism of beta-arrestin isoforms balance IGF-1R expression and signalling with distinct cancer-related biological outcomes. AB - With very similar 3D structures, the widely expressed beta-arrestin isoforms 1 and 2 play at times identical, distinct or even opposing roles in regulating various aspects of G protein-coupled receptors (GPCR) expression and signalling. Recent evidence recognizes the beta-arrestin system as a key regulator of not only GPCRs, but also receptor tyrosine kinases, including the highly cancer relevant insulin-like growth factor type 1 receptor (IGF-1R). Binding of beta arrestin1 to IGF-1R leads to ligand-dependent degradation of the receptor and generates additional MAPK/ERK signalling, protecting cancer cells against anti IGF-1R therapy. Because the interplay between beta-arrestin isoforms governs the biological effects for most GPCRs, as yet unexplored for the IGF-1R, we sought to investigate specifically the regulatory roles of the beta-arrestin2 isoform on expression and function of the IGF-1R. Results from controlled expression of either beta-arrestin isoform demonstrate that beta-arrestin2 acts in an opposite manner to beta-arrestin1 by promoting degradation of an unstimulated IGF-1R, but protecting the receptor against agonist-induced degradation. Although both isoforms co-immunoprecipitate with IGF-1R, the ligand-occupied receptor has greater affinity for beta-arrestin1; this association lasts longer, sustains MAPK/ERK signalling and mitigates p53 activation. Conversely, beta-arrestin2 has greater affinity for the ligand-unoccupied receptor; this interaction is transient, triggers receptor ubiquitination and degradation without signalling activation, and leads to a lack of responsiveness to IGF-1, cell cycle arrest and decreased viability of cancer cells. This study reveals contrasting abilities of IGF-1R to interact with each beta-arrestin isoform, depending on the presence of the ligand and demonstrates the antagonism between the two beta-arrestin isoforms in controlling IGF-1R expression and function, which could be developed into a practical anti-IGF-1R strategy for cancer therapy. PMID- 28581518 TI - Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3. AB - Tumor suppressor and upstream master kinase Liver kinase B1 (LKB1) plays a significant role in suppressing cancer growth and metastatic progression. We show that low-LKB1 expression significantly correlates with poor survival outcome in breast cancer. In line with this observation, loss-of-LKB1 rendered breast cancer cells highly migratory and invasive, attaining cancer stem cell-like phenotype. Accordingly, LKB1-null breast cancer cells exhibited an increased ability to form mammospheres and elevated expression of pluripotency-factors (Oct4, Nanog and Sox2), properties also observed in spontaneous tumors in Lkb1-/- mice. Conversely, LKB1-overexpression in LKB1-null cells abrogated invasion, migration and mammosphere-formation. Honokiol (HNK), a bioactive molecule from Magnolia grandiflora increased LKB1 expression, inhibited individual cell-motility and abrogated the stem-like phenotype of breast cancer cells by reducing the formation of mammosphere, expression of pluripotency-factors and aldehyde dehydrogenase activity. LKB1, and its substrate, AMP-dependent protein kinase (AMPK) are important for HNK-mediated inhibition of pluripotency factors since LKB1-silencing and AMPK-inhibition abrogated, while LKB1-overexpression and AMPK activation potentiated HNK's effects. Mechanistic studies showed that HNK inhibited Stat3-phosphorylation/activation in an LKB1-dependent manner, preventing its recruitment to canonical binding-sites in the promoters of Nanog, Oct4 and Sox2. Thus, inhibition of the coactivation-function of Stat3 resulted in suppression of expression of pluripotency factors. Further, we showed that HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cancer and effective anticancer modulation of this axis with HNK treatment. PMID- 28581519 TI - Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species. AB - Activation of Ras signalling occurs in ~30% of human cancers; however, activated Ras alone is not sufficient for tumourigenesis. In a screen for tumour suppressors that cooperate with oncogenic Ras (RasV12) in Drosophila, we identified genes involved in the autophagy pathway. Bioinformatic analysis of human tumours revealed that several core autophagy genes, including GABARAP, correlate with oncogenic KRAS mutations and poor prognosis in human pancreatic cancer, supporting a potential tumour-suppressive effect of the pathway in Ras driven human cancers. In Drosophila, we demonstrate that blocking autophagy at any step of the pathway enhances RasV12-driven epithelial tissue overgrowth via the accumulation of reactive oxygen species and activation of the Jun kinase stress response pathway. Blocking autophagy in RasV12 clones also results in non cell-autonomous effects with autophagy, cell proliferation and caspase activation induced in adjacent wild-type cells. Our study has implications for understanding the interplay between perturbations in Ras signalling and autophagy in tumourigenesis, which might inform the development of novel therapeutics targeting Ras-driven cancers. PMID- 28581521 TI - Caspase-2: an orphan enzyme out of the shadows. AB - Caspase-2 has been embodied as an initiator or executioner protease in diverse apoptotic scenarios. However, accumulating evidence is challenging this view, pertaining to its true role. The enzyme's catalytic activity is currently implicated in various functions required for correct cell proliferation, such as counteracting genomic instability, as well as suppressing tumorigenesis. Here, apart from summarizing the latest observations in caspase-2-related research, we make an attempt to reconcile these findings and discuss their implications for future directions. PMID- 28581520 TI - KLF10 loss in the pancreas provokes activation of SDF-1 and induces distant metastases of pancreatic ductal adenocarcinoma in the KrasG12D p53flox/flox model. AB - Kruppel-like transcription factor 10 (KLF10), also named as TIEG1, plays essential roles in mediating transforming growth factor beta (TGFbeta) signaling and has been shown to function as a tumor suppressor in multiple cancer types. However, its roles in mediating cancer progression in vivo have yet to be fully characterized. Here, we have employed two well-characterized Pdx-1CreLSL-KrasG12D and Pdx-1CreLSL-KrasG12Dp53L/L pancreatic cancer models to ablate KLF10 expression and determine the impact of KLF10 deletion on tumor development and progression. We show that loss of KLF10 cooperates with KrasG12D leading to an invasive and widely metastatic phenotype of pancreatic ductal adenocarcinoma (PDAC). Mechanistically, loss of KLF10 in PDAC is shown to increase distant metastases and cancer stemness through activation of SDF-1/CXCR4 and AP-1 pathways. Furthermore, we demonstrate that targeting the SDF-1/CXCR4 pathway in the context of KLF10 deletion substantially suppresses PDAC progression suggesting that inhibition of this pathway represents a novel therapeutic strategy for PDAC treatment. PMID- 28581522 TI - Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance. AB - Proteasome inhibition is an effective therapy for multiple myeloma (MM) patients; however, the emergence of drug resistance is common. Novel therapeutic strategies to overcome proteasome inhibitor resistance are needed. In this study, we examined whether targeting deubiquitylating (DUB) enzymes upstream of 20S proteasome overcomes proteasome inhibitor resistance. Gene expression analysis, immunohistochemical studies of MM patient bone marrow, reverse transcription-PCR and protein analysis show that Rpn11/POH1, a DUB enzyme upstream of 20S proteasome, is more highly expressed in patient MM cells than in normal plasma cells. Importantly, Rpn11 expression directly correlates with poor patient survival. Loss-of-function studies show that Rpn11-siRNA knockdown decreases MM cell viability. Pharmacological inhibition of Rpn11 with O-phenanthroline (OPA) blocks cellular proteasome function, induces apoptosis in MM cells and overcomes resistance to proteasome inhibitor bortezomib. Mechanistically, Rpn11 inhibition in MM cells activates caspase cascade and endoplasmic stress response signaling. Human MM xenograft model studies demonstrate that OPA treatment reduces progression of tumor growth and prolongs survival in mice. Finally, blockade of Rpn11 increases the cytotoxic activity of anti-MM agents lenalidomide, pomalidomide or dexamethasone. Overall, our preclinical data provide the rationale for targeting DUB enzyme Rpn11 upstream of 20S proteasome to enhance cytotoxicity and overcome proteasome inhibitor resistance in MM. PMID- 28581523 TI - A DNA methylation map of human cancer at single base-pair resolution. AB - Although single base-pair resolution DNA methylation landscapes for embryonic and different somatic cell types provided important insights into epigenetic dynamics and cell-type specificity, such comprehensive profiling is incomplete across human cancer types. This prompted us to perform genome-wide DNA methylation profiling of 22 samples derived from normal tissues and associated neoplasms, including primary tumors and cancer cell lines. Unlike their invariant normal counterparts, cancer samples exhibited highly variable CpG methylation levels in a large proportion of the genome, involving progressive changes during tumor evolution. The whole-genome sequencing results from selected samples were replicated in a large cohort of 1112 primary tumors of various cancer types using genome-scale DNA methylation analysis. Specifically, we determined DNA hypermethylation of promoters and enhancers regulating tumor-suppressor genes, with potential cancer-driving effects. DNA hypermethylation events showed evidence of positive selection, mutual exclusivity and tissue specificity, suggesting their active participation in neoplastic transformation. Our data highlight the extensive changes in DNA methylation that occur in cancer onset, progression and dissemination. PMID- 28581524 TI - Smurf1 regulates lung cancer cell growth and migration through interaction with and ubiquitination of PIPKIgamma. AB - Type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma), a phospholipid kinase generating PIP2, is positively expressed in breast cancer tissues, which correlates intimately with the progression of patients. However, little is known about the expression level of PIPKIgamma in patients with other cancer types as well as their underlying regulation mechanisms. Here, we report that PIPKIgamma is highly expressed in lung cancer tissues and its expression level is critical for lung cancer cell proliferation, which may serve as a prognostic marker for lung cancer patients. Meanwhile, we show that E3 ubiquitin ligase Smurf1 directly interacts with PIPKIgamma and targets PIPKIgamma for ubiquitination and degradation in lung cancer cells. Also, we discover that Smurf1 directly binds to the kinase domain of PIPKIgamma via its C2 domain while Lysine 255 in PIPKIgamma acts as the major ubiquitin acceptor site for Smurf1. In addition, we demonstrate that the phosphorylation mimicking mutant of Smurf1, Smurf1 T306D, prevents PIPKIgammai2 from ubiquitination and subsequent degradation similar to the effect of forskolin-potentiated cAMP formation, suggesting that Thr306 in Smurf1 is critical for its phosphorylation by PKA. Moreover, PKA-Smurf1-PIPKIgamma signal transduction takes a significant part in lung cancer cell growth and in vivo tumorigenesis. Thus, we propose that the PKA-Smurf1-PIPKIgamma pathway has an important role in pulmonary tumorigenesis and imposes substantial clinical impact on development of novel diagnostic markers and therapeutic targets for lung cancer treatment. PMID- 28581525 TI - CK1delta/GSK3beta/FBXW7alpha axis promotes degradation of the ZNF322A oncoprotein to suppress lung cancer progression. AB - Overexpression of Cys2His2 zinc-finger 322A (ZNF322A) oncogenic transcription factor is associated with lung tumorigenesis. However, the mechanism of ZNF322A overexpression remains poorly understood. Here, we discover that protein stability of ZNF322A is regulated by coordinated phosphorylation and ubiquitination through the CK1delta/GSK3beta/FBXW7alpha axis. CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine 391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction. Overexpression of FBXW7alpha induces ZNF322A protein degradation, thereby blocks ZNF322A transcription activity and suppresses ZNF322A-induced tumor growth and metastasis in vitro and in vivo. Clinically, overexpression of ZNF322A correlates with low FBXW7alpha or defective CK1delta/GSK3beta-mediated phosphorylation in lung cancer patients. Multivariate Cox regression analysis indicates that patients with ZNF322A high/FBXW7 low expression profile can be used as an independent factor to predict the clinical outcome in lung cancer patients. Our results reveal a new mechanism of ZNF322A oncoprotein destruction regulated by the CK1delta/GSK3beta/FBXW7alpha axis. Deregulation of this signaling axis results in ZNF322A overexpression and promotes cancer progression. PMID- 28581529 TI - Editorial. AB - no summary. PMID- 28581531 TI - Genetics and pharmacogenetics of mood disorders. AB - Genetic research in Psychiatry is viewed by clinicians with both hope and curiosity sometimes mixed with disillusionment. Indeed, in the last 30 years many results have not been confirmed and clinical applications are still missing. However recent findings suggest that we are at the beginning of a new era. A set of variants within neuroplasticity and inflammation genes have been identified as a valid basis for both bipolar disorder and major depression. Similarly, a set of genes has been identified as a liability factor for response and tolerability to antidepressants and the first clinical applications are already in the market. However, some caution should be applied until definite findings are available. PMID- 28581530 TI - Mental and behavioural disorders in the ICD-11: concepts, methodologies, and current status. AB - This review provides an overview of the concepts, methods and current status of the development of the Eleventh Revision of the Mental and Behavioural Disorders chapter of the International Classification of Diseases and Related Health Problems (ICD-11) by the World Health Organization (WHO). Given the global use of the current version (ICD-10) for a wide range of applications in clinical practice and health statistics, a major aim of the development process for ICD-11 has been to increase the utility of the classification system. Expert working groups with responsibility for specific disorder groupings first suggested a set of revised diagnostic guidelines. Then surveys were performed to obtain suggestions for revisions from practicing health professionals. A completely revised structure for the classification of mental and behavioural disorders was developed and major revisions were suggested, for example, for schizophrenia and other primary psychotic disorders, substance use disorders, affective disorders and personality disorders. A new category of "gaming disorder" has been proposed and conditions related to sexual health and gender identity will be classified separately from mental disorders. An ICD-11 beta draft is freely available on the internet and public comments are invited. Field studies of the revised diagnostic guidelines are in process to obtain additional information about necessary improvements. A tabulated crosswalk from previous ICD-10 to then ICD-11 criteria will be necessary to ascertain the continuity of diagnoses for epidemiological and other statistical purposes. The final version of ICD-11 is currently scheduled for release by the World Health Assembly in 2018. PMID- 28581533 TI - Gastrointestinal complications and refeeding guidelines in patients with anorexia nervosa. AB - Anorexia nervosa (AN) is the third most common disorder, after obesity and asthma, in the population of adolescents between 13-18 years of age. Food intake reduction is associated with whole body dysfunction, affecting its physical, psychological and social spheres. As a result of starvation, dysfunction develops in virtually all systems and organs. However, most frequently patients with AN complain of digestive symptoms, such as a feeling of fullness after meals, pain in the upper abdomen, dysphagia, nausea, bloating and constipation. They can have mild functional character, but may also reflect serious complications, including diseases requiring urgent surgical intervention. In addition, gastric complaints may hinder nutritional management of AN. Care of AN patients requires cooperation of many specialists in the field of psychiatry, psychology, paediatrics, internal medicine and nutrition. However, it is often difficult to organize such a team. Therefore, we decided to approach the issues of gastrointestinal symptoms and complications in the course of AN, and the rules of nutritional therapy. PMID- 28581532 TI - Outcome, comorbidity and prognosis in anorexia nervosa. AB - Anorexia nervosa (AN) is a relatively common disorder, especially in adolescent and young adult women. The lifetime prevalence of AN in females ranges from 1.2 to 2.2%. The prevalence in males is 10-times lower. The condition is associated with a high risk of chronic course and poor prognosis in terms of treatment and the risk of death. Longer follow-up periods seemed to correspond with increased improvement rates and increased mortality. Onset of the disorder during adolescence is associated with better prognosis. It is reported that as much as 70% to over 80% of patients in this age group achieve remission. Worse outcomes are observed in patients who required hospitalization and in adults. Recent studies indicate improved prognosis for cure and lower mortality rates than previously reported. However, the recovery can take several years and AN is associated with high risk of developing other psychiatric disorders during the patients' lifetime, even after recovery from AN (mainly: affective disorders, anxiety disorders, obsessive-compulsive disorders, substance abuse disorders). Studies indicate that bulimic symptoms often occur in the course of anorexia nervosa (especially within 2-3 years from the onset of AN). The authors present a review of literature on the course, comorbidity, mortality, and prognostic factors in AN. Better knowledge of the course of anorexia can contribute to more realistic expectations of the pace of symptomatic improvement, as well as to a creation of therapeutic programs which are better adapted to the needs of the patients. PMID- 28581534 TI - Bone mineralization and densitometric evaluation of vertebral fractures in women 6-21 years after the onset of anorexia nervosa symptoms. AB - OBJECTIVES: We attempted to assess bone mineralization and the frequency of fractures occurrence in women with a history of treatment of anorexia nervosa (AN) in adolescence. METHODS: 47 women (age 20-36.8 years) were re-examined 6.33 21,2 years after the onset of AN symptoms. Bone mineral density (BMD) of total body, lumbar spine, femoral neck, total hip (DXA) and densitometric Vertebral Fracture Assessment (VFA) were performed on 46 of women and BAP, P1NP, CTX, estradiol, testosterone, cortisol, IGF-1, leptin, DHEA-S on 45 of women entered for the current study. Current BMD results were compared with available baseline results from the time of hospitalization. RESULTS: Currently BMD Z-score <-1 examined at any location occurred in 28 from 46 women (including Z-score <-2 in 5 women). In 11 from 12 women with reduced BMD at the time of hospitalization current total body BMD was within the normal range. Lumbar spine BMD was normalized or improved respectively in 5 and 6 from 15 women. Currently increased levels/activity of bone formation markers: P1NP in 27 (60%) and BAP in 28 women (62.2%) were observed. In 7 women (15.6%) increased values of bone formation markers with increased marker of bone resorption (CTX) occurred. Osteoporotic fractures and fractures in the spine in VFA were not observed during the observation period. CONCLUSIONS: Despite early treatment of adolescent-onset AN and good outcomes of the treatment, decreased BMD was currently present in 60.9% of women. During follow-up normalization or significant improvement in BMD results (total body, lumbar spine) were observed in majority of cases. PMID- 28581536 TI - Schizophrenia and anorexia nervosa - reciprocal relationships. A literature review. AB - Although schizophrenia and anorexia nervosa are seemingly very distinct psychiatric disorders, their symptoms are connected by various types of relationships. The present article reviews the literature and recapitulates the views of various authors on the links between these two disorders. Symptoms of anorexia may 1) precede the onset of psychosis; 2) evolve in its active phase or more rarely manifest in remission; and, conversely, 3) psychotic symptoms may occur transiently in the course of anorexia nervosa. When anorexia precedes the manifestation of psychosis, symptoms of anorexia can be treated as a component of the prodromal phase of schizophrenia. Another possibility of co-existence of a psychosis (e.g., schizophrenia) with anorexia is when the eating disorder syndrome manifests at the same time as the full-blown psychotic syndrome. In such cases, when the symptoms of the two disorders occur simultaneously, it is often difficult to say whether the patient is suffering from schizophrenia, in the course of which anorexia has arisen secondary to psychotic symptoms or whether he/she is suffering from anorexia during which he/she has developed psychotic symptoms, usually thematically associated with eating. Studies published so far, mainly case reports, point to the complex nature of the interrelationships between schizophrenia and anorexia nervosa. Further research is needed to conclusively explain the relationships between psychotic disorders and anorexia nervosa, which would allow physicians to use more effective methods of treatment in this group of patients. PMID- 28581527 TI - Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple negative breast cancers. AB - Basal-like/triple-negative breast cancers (TNBCs) are among the most aggressive forms of breast cancer, and disproportionally affects young premenopausal women and women of African descent. Patients with TNBC suffer a poor prognosis due in part to a lack of molecularly targeted therapies, which represents a critical barrier for effective treatment. Here, we identify EphA2 receptor tyrosine kinase as a clinically relevant target for TNBC. EphA2 expression is enriched in the basal-like molecular subtype in human breast cancers. Loss of EphA2 function in both human and genetically engineered mouse models of TNBC reduced tumor growth in culture and in vivo. Mechanistically, targeting EphA2 impaired cell cycle progression through S-phase via downregulation of c-Myc and stabilization of the cyclin-dependent kinase inhibitor p27/KIP1. A small molecule kinase inhibitor of EphA2 effectively suppressed tumor cell growth in vivo, including TNBC patient derived xenografts. Thus, our data identify EphA2 as a novel molecular target for TNBC. PMID- 28581526 TI - The role of canonical and non-canonical Hedgehog signaling in tumor progression in a mouse model of small cell lung cancer. AB - Hedgehog (Hh) signaling regulates cell fate and self-renewal in development and cancer. Canonical Hh signaling is mediated by Hh ligand binding to the receptor Patched (Ptch), which in turn activates Gli-mediated transcription through Smoothened (Smo), the molecular target of the Hh pathway inhibitors used as cancer therapeutics. Small cell lung cancer (SCLC) is a common, aggressive malignancy with universally poor prognosis. Although preclinical studies have shown that Hh inhibitors block the self-renewal capacity of SCLC cells, the lack of activating pathway mutations have cast doubt over the significance of these observations. In particular, the existence of autocrine, ligand-dependent Hh signaling in SCLC has been disputed. In a conditional Tp53;Rb1 mutant mouse model of SCLC, we now demonstrate a requirement for the Hh ligand Sonic Hedgehog (Shh) for the progression of SCLC. Conversely, we show that conditional Shh overexpression activates canonical Hh signaling in SCLC cells, and markedly accelerates tumor progression. When compared to mouse SCLC tumors expressing an activating, ligand-independent Smo mutant, tumors overexpressing Shh exhibited marked chromosomal instability and Smoothened-independent upregulation of Cyclin B1, a putative non-canonical arm of the Hh pathway. In turn, we show that overexpression of Cyclin B1 induces chromosomal instability in mouse embryonic fibroblasts lacking both Tp53 and Rb1. These results provide strong support for an autocrine, ligand-dependent model of Hh signaling in SCLC pathogenesis, and reveal a novel role for non-canonical Hh signaling through the induction of chromosomal instability. PMID- 28581538 TI - From traumatic events and dissociation to body image and depression symptoms - in search of self-destruction syndrome in adolescents who engage in nonsuicidal self injury. AB - OBJECTIVES: The aim of the study was to analyze relationships between the variables: severity of depression symptoms, feelings towards one's own body, dissociation, the number and type of traumatic life events experienced by adolescents who engage in deliberate self-injury and are psychiatrically hospitalized. METHODS: We examined 60 patients aged 13-17 (M = 15.48, SD = 1.19). More than a half (55%) were diagnosed with a mixed disturbance of emotions and conduct, 23.5% with depressive behavior disorders, 10% were diagnosed a depressive episode. The research tools: a socio-demographic survey; original Feelings Towards the Body Questionnaire created on the basis of Tomkiewicz's description; Kovacs's CDI; Scharfetter's Ego-Psychopathology questionnaire. RESULTS: The examined individuals have negative feelings toward their bodies, more than half of them experience severe depression symptoms. There are links between traumatic events, dissociation, body image and the severity of depression symptoms. The strongest links were found: between dissociation vis-a-vis the severity of depression symptoms and the feelings towards one's body; and between the severity of depression symptoms and the feelings towards one's body. CONCLUSIONS: Two thirds of the examined individuals attempted suicide. Various forms of direct self-destructive behaviors very often occur simultaneously. It also provokes reflection about the conditions under which self-inflicted injury does (or does not) prevent suicide attempts. Self-mutilation along with the interaction between clinical variables may form a self-destruction syndrome in various mental disorders and contribute to clinical pictures of these disorders, this should be taken into account in diagnosing and treatment of adolescents. PMID- 28581535 TI - Differential criteria for binge eating disorder and food addiction in the context of causes and treatment of obesity. AB - OBJECTIVES: To establish the differential criteria for Binge Eating Disorder (BED) and Food Addiction (FA). METHODS: We performed a detailed analysis of comparative diagnostic criteria for BED and Substance use disorder contained in the Diagnostic and Statistical Manual of Mental Disorders DSM-V. We applied the diagnostic criteria for both disorders to scientific publications on the issue of excessive eating in obese people, during the years 2005-2016, available on PubMed. We isolated specific similarities and differences between Binge Eating Disorder and Food Addiction. We formulated differential criteria for BED and FA. RESULTS: In BED as well as FA the following characteristics are apparent: preoccupation with food, excessive eating, loss of control over the amount of food and manner of eating, inability to change behavior, continuing behavior despite negative consequences, increased impulsiveness and emotional imbalance. Differences between BED and FA relate to the function of food, reaction to omitted food, psychological mechanisms of coping with excessive eating and body image, the issue of tolerance, withdrawal syndrome and the correlation between excessive eating and other areas of life. CONCLUSIONS: The criteria of differentiation between BED and FA concern the following: function of food, eating circumstances, reaction to the unavailability of food, awareness of the problem. Appropriate diagnosis of these disorders and their differentiation increases the chances of adequate treatment of obese patients. PMID- 28581537 TI - Clinical significance of psychotic-like experiences in children and adolescents. AB - Psychotic-like experiences (PLEs) are subtle, subclinical hallucinations and delusions which are quite common in general population. In children and youth prevalence rate is probably age-dependent with higher rate in younger population. PLEs are suggested to be a form of extended psychosis phenotype. Similar demographic, genetic and environmental risk factors observed for PLEs and schizophrenia support this hypothesis. Other mental health problems associated with PLEs include depression, suicidality, low functioning and psychiatric comorbidity. PLEs may be a risk factor for psychosis, but probably only for a minor subgroup of population. It is possible however, that PLEs are a risk factor for different psychiatric disorders. In the majority of children and adolescents PLEs disappear over time. PLEs are supposed to be a heterogenic phenomenon with different subtypes: associated with psychosis risk, associated with other psychiatric disorders and being within the normal range of experiences. Due to lack of widely acknowledged PLEs definition and because of substantial diversity of research methodology interpretation of the previous research should be made with caution. PMID- 28581539 TI - Deliberate self-injury functions and their clinical correlates among adolescent psychiatric inpatients. AB - OBJECTIVES: The aim of the study was to analyze the relationships between clinical variables (the severity of depression symptoms, feelings towards the body, dissociation, number and type of traumatic events) and deliberate self injury functions. Moreover, we investigated whether the of group self-mutilating adolescents is internally diverse in terms of how important individual functions of self-mutilation are, and whether the subgroups singled out by these functions differ between each other in terms of clinical variables. METHODS: The Inventory of Statements about Self-Injury was used. Characterizations of examined individuals and other research tools are included in our previous article (year, issue, pages). RESULTS: Associated with negative feelings towards the body are the functions of self-injuries (anti-dissociation, self-punishment) that can be described as interpersonal. High levels of depression symptoms (self-depreciation included) are mainly associated with the self-injury functions: self-punishment, anti-dissociation, establishing interpersonal boundaries. Affect regulation becomes more important as a function of self-inflicted injuries in cases of biological dysregulation and intense dissociative symptoms. CONCLUSIONS: The adolescents psychiatric inpatients are internally diverse in terms of dominant functions of self-injuries, which can be categorized into intra- and interpersonal. Intrapersonal functions dominate when an individual experiences severe depression, dissociative symptoms, and negative feelings towards the body. In cases of moderate intensity of depression, dissociative symptoms and negative feelings towards the body, both intrapersonal and interpersonal functions of self mutilation are similarly important. Further research is required to explain the lowest severity of depression symptoms, dissociative symptoms and negative feelings towards the body co-occurs with no awareness of self-injuries functions. PMID- 28581540 TI - Self-injury - placement in mental disorders classifications, risk factors and primary mechanisms. Review of the literature. AB - Self-injury is a common phenomenon among adolescents and young adults, however its prevalence in clinical population is estimated at 40-80%, especially in regard to patients during puberty. Symptoms usually appear between 12th and 14th year of age, and their average duration is approx. 2 years. According to accepted sociocultural norms self-injury can be regarded as a normal behavior. Nevertheless, the prevalence of body art phenomenon in Western culture including professional tattooing, piercing, scarification, burning tattoos and other body modification typical for tribal cultures, has forced the need to redefine the boundaries for normative behavior. Introduction of a separate nosological unit of Non-Suicidal Self Injury in the fifth edition of DSM classification proves the validity of discussion, being hold for many years, regarding classification and understanding of the underlying mechanisms of self-harm. The aim of our study was to present the current state of knowledge regarding self-harm, with an emphasis on issues devoted to their placement in newest mental disorders classifications and mechanisms responsible for their development and maintenance. Databases such as: PubMed, EBSCO (medical and psychological resources) and WEB OF SCIENCE (years 1990-2016) have been screened for the following key words: self-injury, self harm, self-mutilation, suicide, deliberate self-harm, affect regulation, NSSI, DSH, personality disorders, suicide attempt, neurobiology self-harm, DSM-5, adolescent, adults, stress coping styles, self-mutilation - children, adolescents and adults-prevalence. The analysis indicated 110 articles and 3 textbooks. We have used the following criteria: (1) for the articles presenting the latest research on risk factors for self-harm we have used the criterion of the study group number (>30 people) and meta-analyses have been included, (2) for theories explaining the mechanisms of self-harm criterion of empirical review of the assumptions and the number of the published studies that verify the theory has been applied. PMID- 28581547 TI - Initial hydration processes of magnesium chloride: size-selected anion photoelectron spectroscopy and ab initio calculations. AB - To understand the initial hydration processes of MgCl2, we measured photoelectron spectra of MgCl2(H2O)n- (n = 0-6) and conducted ab initio calculations on MgCl2(H2O)n- and their neutral counterparts up to n = 7. A dramatic drop in the vertical detachment energy (VDE) was observed upon addition of the first water molecule to bare MgCl2-. This large variation in VDE can be associated with the charge-transfer-to-solvent (CTTS) effect occurring in the MgCl2(H2O)n- clusters, as hydration induces transfer of the excess electron of MgCl2- to the water molecules. Investigation of the separation of Cl--Mg2+ ion pair shows that, in MgCl2(H2O)n- anions, breaking of the first Mg-Cl bond occurs at n = 4, while breaking of the second Mg-Cl bond takes place at n = 6. For neutral MgCl2(H2O)n clusters, breaking of the first Mg-Cl bond starts at n = 7. PMID- 28581541 TI - Validation of the Polish Version of the Washington 4-Digit Diagnostic Code for the Assessment of Fetal Alcohol Spectrum Disorders. AB - OBJECTIVES: The aim of this paper is a quantitative assessment of FASD facial phenotype in the Polish population using the Polish version of the 4-Digit Diagnostic Code. METHODS: The study covered 2 groups of children: 30 children aged 4-7 and 30 children aged 8-11 with a facial phenotype characteristic for the Fetal Alcohol Syndrome (FAS). The control group consisted of 60 children (4-11 years old) developing normally. We compared 3 facial features (small palpebral fissure lengths, smooth philtrum and thin upper lip). The repeatability, conformity and diagnostic accuracy of particular dysmorphic features of the study were assessed. RESULTS: Obtained values for palpebral fissure were "poor", "good" and "very good", for philtrum "good" and "very good" and for upper lip "good" and "very good". As for conformity, values for palpebral fissure were "moderate" and 'good", for philtrum - "good" and for upper lip also "good". In the experimental group, the FAS diagnostic criteria were met by 13 subjects, partial FAS criteria were met by 37 subjects and the criteria of static encephalopathy with no FAS phenotype were met by 2 subjects. None of the subjects in the control group met these criteria. CONCLUSIONS: The pictorial scale for the assessment of the facial dysmorphic features proved to be a useful tool in the clinical diagnostics of FAS in the Polish conditions. Due to the problems associated with the measurement of the palpebral fissure, it is necessary to verify the normal growth charts for the Polish population. PMID- 28581545 TI - Letter to Editor. In search of definition of the term "psychotic process" - thoughts and doubts. AB - no summary. PMID- 28581546 TI - A carbon nanopore model to quantify structure and kinetics of ion electrosorption with in situ small-angle X-ray scattering. AB - A new carbon model derived from in situ small-angle X-ray scattering (SAXS) enables a quantitative description of the voltage-dependent arrangement and transport of ions within the nanopores of carbon-based electric double-layer capacitors. In the first step, ex situ SAXS data for nanoporous carbon-based electrodes are used to generate a three-dimensional real-space model of the nanopore structure using the concept of Gaussian random fields. This pore model is used to derive important pore size characteristics, which are cross-validated against the corresponding values from gas sorption analysis. In the second step, simulated in situ SAXS patterns are generated after filling the model pore structure with an aqueous electrolyte and rearranging the ions via a Monte Carlo simulation for different applied electrical potentials. These simulated SAXS patterns are compared with in situ SAXS patterns recorded during voltage cycling. Experiments with different cyclic voltammetry scan rates revealed a systematic time lag between ion transport processes and the applied voltage signal. Global transport into and out of nanopores was found to be faster than the accommodation of the local equilibrium arrangement in favor of sites with a high degree of confinement. PMID- 28581542 TI - Visual impairment and traits of autism in children. AB - Visual impairment present from birth or from an early childhood may lead to psychosocial and emotional disorders. 11-40% of children in the group with visual impairment show traits of autism. The aim of this paper was to present the selected examples of how visual impairment in children is related to the occurrence of autism and to describe the available tools for diagnosing autism in children with visual impairment. So far the relation between visual impairment in children and autism has not been sufficiently confirmed. Psychiatric and psychological diagnosis of children with visual impairment has some difficulties in differentiating between "blindism" and traits typical for autism resulting from a lack of standardized diagnostic tools used to diagnosing children with visual impairment. Another difficulty in diagnosing autism in children with visual impairment is the coexistence of other disabilities in case of most children with vision impairment. Additionally, apart from difficulties in diagnosing autistic disorders in children with eye dysfunctions there is also a question of what tools should be used in therapy and rehabilitation of patients. PMID- 28581548 TI - Metal-oxide assisted surface treatment of polyimide gate insulators for high performance organic thin-film transistors. AB - We developed a facile method for treating polyimide-based organic gate insulator (OGI) surfaces with self-assembled monolayers (SAMs) by introducing metal-oxide interlayers, called the metal-oxide assisted SAM treatment (MAST). To create sites for surface modification with SAM materials on polyimide-based OGI (KPI) surfaces, the metal-oxide interlayer, here amorphous alumina (alpha-Al2O3), was deposited on the KPI gate insulator using spin-coating via a rapid sol-gel reaction, providing an excellent template for the formation of a high-quality SAM with phosphonic acid anchor groups. The SAM of octadecylphosphonic acid (ODPA) was successfully treated by spin-coating onto the alpha-Al2O3-deposited KPI film. After the surface treatment by ODPA/alpha-Al2O3, the surface energy of the KPI thin film was remarkably decreased and the molecular compatibility of the film with an organic semiconductor (OSC), 2-decyl-7-phenyl-[1]benzothieno[3,2 b][1]benzothiophene (Ph-BTBT-C10), was increased. Ph-BTBT-C10 molecules were uniformly deposited on the treated gate insulator surface and grown with high crystallinity, as confirmed by atomic force microscopy (AFM) and X-ray diffraction (XRD) analysis. The mobility of Ph-BTBT-C10 thin-film transistors (TFTs) was approximately doubled, from 0.56 +/- 0.05 cm2 V-1 s-1 to 1.26 +/- 0.06 cm2 V-1 s-1, after the surface treatment. The surface treatment of alpha-Al2O3 and ODPA significantly decreased the threshold voltage from -21.2 V to -8.3 V by reducing the trap sites in the OGI and improving the interfacial properties with the OSC. We suggest that the MAST method for OGIs can be applied to various OGI materials lacking reactive sites using SAMs. It may provide a new platform for the surface treatment of OGIs, similar to that of conventional SiO2 gate insulators. PMID- 28581550 TI - Superionic conduction in beta-eucryptite: inelastic neutron scattering and computational studies. AB - beta-Eucryptite (LiAlSiO4) is known to show super-ionic conductivity above 700 K. We performed inelastic neutron scattering measurements in beta-eucryptite over 300-900 K and calculated the phonon spectrum using classical molecular dynamics (MD) simulations. The MD simulations were used to interpret the inelastic neutron spectra at high temperatures. The calculated diffusion coefficient for Li showed superionic conduction above 1200 K in the perfect crystal. The presence of defects was found to enhance diffusion and lower the temperature for Li diffusion. The calculated trajectory of Li atoms at higher temperatures shows that preferential movement of the Li atom is along the hexagonal c-axis, which is further confirmed by the ab initio calculated activation energy profile for cooperative lithium ion displacements. The inter- and intra-channel correlated motion of Li along the hexagonal c-axis gives the minimum energy pathway for Li ion conduction in LiAlSiO4. PMID- 28581549 TI - Low oxidation state aluminum-containing cluster anions: LAlH- and LAln- (n = 2-4, L = N[Si(Me)3]2). AB - Several low oxidation state aluminum-containing cluster anions, LAlH- and LAln- (n = 2-4, L = N[Si(Me)3]2), were produced via reactions between aluminum hydride cluster anions, AlxHy-, and hexamethyldisilazane (HMDS). These clusters were characterized by mass spectrometry, anion photoelectron spectroscopy, and density functional theory (DFT) based calculations. Agreement between the experimental and theoretical vertical detachment energies (VDEs) and adiabatic detachment energies (ADEs) validated the computed geometrical structures. Reactions between aluminum hydride cluster anions and ligands promise to be a new synthetic scheme for low oxidation state, ligated aluminum clusters. PMID- 28581551 TI - Luminescence of tartrate bridged dinuclear 2,2'-bipyridine platinum(ii) complexes: emission color controlled by intra- and inter-molecular interactions in the solid state. AB - Novel dinuclear PtII complexes with a chiral (l-) and an achiral (meso-) tartrate [{PtII(bpy)}2(MU-x-tart)] (bpy: 2,2'-bipyridine; tartH22-: tartrate; x = l (1), meso (2)) and with a racemic (dl-) tartrate [{PtII(bpy)}2(MU-d tart)][{PtII(bpy)}2(MU-l-tart)] (3) were synthesized, and the influence of their stereochemistry on their molecular and crystal structures affecting their luminescence was discussed. Effects of the dinuclearity on the structures and luminescence were revealed by comparison with those of a novel racemic mononuclear complex [PtII(bpy)(d-tartH2)][PtII(bpy)(l-tartH2)] (4). The X-ray crystallography showed the crystallization of 1 in two polymorphs, namely monoclinic 3[1.6H2O] (1alpha) and triclinic 2[1.6H2O] (1beta), and those of other complexes in monoclinic hydrate crystals 2.12.5H2O, 3.4H2O, and 4.H2O. The chiral complexes in 1alpha, 1beta, and 3.4H2O showed clamshell-like structures with Pt Pt and pi-pi interactions, while the achiral complex in 2.12.5H2O displayed a twisted form without intramolecular interactions. The complexes in 1alpha were assembled in a right-handed helical arrangement through significant Pt-Pt interactions, and those in 1beta and 3.4H2O were stacked in one-dimensional columns through significant and slight pi-pi interactions, respectively. The complex in 2.12.5H2O constructed an intermolecular dimer through Pt-Pt interactions with its adjacent complex. The crystal structure of 4.H2O displayed a three-dimensional network architecture through pi-pi interactions and hydrogen bonding. These crystals exhibited luminescence depending on their molecular and crystal structures (lambdamax nm = 535 (4.H2O), 569 (3.4H2O), 621 (2.12.5H2O), 649 (1beta), and 656 (1alpha)). The formations of intermolecular dimers and clamshell-like structures through Pt-Pt interactions in 2.12.5H2O and in 3.4H2O, respectively, lead to red-shifts in emissions compared to 4.H2O, and further low energy emissions of 1alpha and 1beta were derived from the intermolecular Pt-Pt and pi-pi interactions, respectively. PMID- 28581544 TI - Polish Adaptation of the Psychache Scale by Ronald Holden and Co-workers. AB - OBJECTIVES: The conducted study was aimed at making a Polish adaptation of the Scale of Psychache by Ronald Holden and co-workers. The scale is a self assessment method which comprises 13 statements and is designed to assess subjectively experienced psychological pain. METHODS: 300 persons were examined - undergraduates and postgraduates of the University of Lodz and the Technical University of Lodz. The group of the study participants consisted of 185 women and 115 men. Moreover, there were examined 150 alcohol addicted men, 50 co addicted women and 50 major depressive episode (MDE) patients. RESULTS: The Polish version of the Scale is a reliable and valid tool. The exploratory and confirmatory factor analysis has proved the existence of one factor. The internal consistency, assessed on the basis of Cronbach's alpha, equalled 0.93. The method displays positive and statistically significant relationships to levels of depression, hopelessness, anxiety, anhedonia and negative relations to levels of optimism, life satisfaction, and positive orientation. Alcohol addicted men with presently diagnosed suicidal thoughts were characterised by a significantly higher level of psychological pain as compared to alcoholics without such thoughts. A higher level of psychache was also reported in people with depression who have a history of attempted suicide compared with those who have not attempted suicide. CONCLUSIONS: The effect of the conducted adaptation works on the Psychache Scale speaks for recommending the method for scientific research and use in therapeutic practice. PMID- 28581543 TI - The amino acid profile in blood plasma of young boys with autism. AB - OBJECTIVES: It has been suggested that some amino acids are involved in the pathogenesis of autistic disorders. The aim of the study was to evaluate the plasma amino acids profile in young males with autism. METHODS: Total of 27 autistic boys (aged 2-10 years, the study group) without any metabolic disorders and 13 healthy boys (aged 2-9 years, control group) were included in the study. In all subjects fasting blood plasma free amino acids (both exogenous and endogenous) were quantitatively measured by high performance liquid chromatography with UV-VIS detection. RESULTS: The mean plasma concentration values of citrulline, .-aminobutyric acid, isoleucine, leucine, phenylalanine, tryptophan and ornithine were significantly lower in boys with autism as compared to the control group (p < 0.03, p < 0.04, p < 0.02, p < 0.02, p < 0.05, p < 0.02, p < 0.05, respectively). The areas under the Receiver Operating Characteristic curves for these amino acids ranged from 0.637 to 0.726. None of the amino acids measured differentiate autistic children from healthy children. The sum of exogenous amino acids was lower in the study group than in the control group but this difference was not statistically significant. CONCLUSIONS: Lower levels of exogenous amino acids confirm the possible role of these amino acids in autism. Determination of exogenous amino acids in plasma, however, cannot be used as a diagnostic test but it can still support autistic patients care. PMID- 28581528 TI - DNA methylation variations are required for epithelial-to-mesenchymal transition induced by cancer-associated fibroblasts in prostate cancer cells. AB - Widespread genome hypo-methylation and promoter hyper-methylation of epithelium specific genes are hallmarks of stable epithelial-to-mesenchymal transition (EMT), which in prostate cancer (PCa) correlates with castration resistance, cancer stem cells generation, chemoresistance and worst prognosis. Exploiting our consolidated 'ex-vivo' system, we show that cancer-associated fibroblasts (CAFs) released factors have pivotal roles in inducing genome methylation changes required for EMT and stemness in EMT-prone PCa cells. By global DNA methylation analysis and RNA-Seq, we provide compelling evidence that conditioned media from CAFs explanted from two unrelated patients with advanced PCa, stimulates concurrent DNA hypo- and hyper-methylation required for EMT and stemness in PC3 and DU145, but not in LN-CaP and its derivative C4-2B, PCa cells. CpG island (CGI) hyper-methylation associates with repression of genes required for epithelial maintenance and invasion antagonism, whereas activation of EMT markers and stemness genes correlate with CGI hypo-methylation. Remarkably, methylation variations and EMT-regulated transcripts almost completely reverse qualitatively and quantitatively during MET. Unsupervised clustering analysis of the PRAD TCGA data set with the differentially expressed (DE) and methylated EMT signature, identified a gene cluster of DE genes defined by a CAF+ and AR- phenotype and worst diagnosis. This gene cluster includes the relevant factors for EMT and stemness, which display DNA methylation variations in regulatory regions inversely correlated to their expression changes, thus strongly sustaining the ex vivo data. DNMT3A-dependent methylation is essential for silencing epithelial maintenance and EMT counteracting genes, such as CDH1 and GRHL2, that is, the direct repressor of ZEB1, the key transcriptional factor for EMT and stemness. Accordingly, DNMT3A knock-down prevents EMT entry. These results shed light on the mechanisms of establishment and maintenance of coexisting DNA hypo- and hyper methylation patterns during cancer progression, the generation of EMT and cell stemness in advanced PCa, and may pave the way to new therapeutic implications. PMID- 28581552 TI - Membranes prepared by self-assembly and chelation assisted phase inversion. AB - We combine self-assembly in solution, complexation with metallic salts and phase separation induced by solvent-non-solvent exchange to prepare nanostructured membranes for separation in the nanofiltration range. This method was applied to prepare membranes from newly synthesized poly(acrylic acid)-b-polysulfone-b poly(acrylic acid) copolymers dissolved in a selective solvent mixture and immersed in aqueous Cu2+ or Ag+ solutions. PMID- 28581553 TI - Sigma-hole carbon-bonding interactions in carbon-carbon double bonds: an unnoticed contact. AB - In this manuscript, we combine high-level ab initio calculations on some small complexes and a CSD survey to analyze the existence of unprecedented noncovalent carbon bonds in X2C[double bond, length as m-dash]CH2Y systems (Y = electron-rich atom or group). The methylene group is usually seen as a weak hydrogen bond donor when interacting with an electron-rich atom. However, we demonstrate that when the electron-rich atom is located equidistant from the two H atoms and along the C[double bond, length as m-dash]C bond a sigma-hole noncovalent carbon-bonding interaction is established, instead of a bifurcated hydrogen bond, as derived from Atoms-in-Molecules (AIM) and Natural bond orbital (NBO) analyses. The physical nature of the interaction has been analyzed using the Symmetry Adapted Perturbation Theory (SAPT) method. The results indicate that electrostatics is very important followed by either the induction or dispersion terms in anionic and neutral complexes, respectively. In addition the CSD analysis reveals the existence of such interactions, giving reliability to our calculations, which are much more numerous for neutral than for anionic Y systems. PMID- 28581557 TI - A porous two-dimensional Zn(ii)-coordination polymer exhibiting SC-SC transmetalation with Cu(ii): efficient heterogeneous catalysis for the Henry reaction and detection of nitro explosives. AB - The linker 5-(benzylamino)isophthalic acid (H2L) forms a robust 2D Zn(ii) coordination polymer, {[Zn8(L)6(MU3-OH)4(H2O)6].(DMF).(H2O)2.5}n(1Zn) consisting of [Zn4(MU3-OH)2]6+ SBUs. It further shows strong pipi interactions between the layers to form an overall 3D structure with well-defined channels. Metal bound water molecules are directed towards these channels. Upon heating, these metal bound water molecules are lost along with lattice solvent molecules to afford coordinatively unsaturated metal centers that can be utilized as an efficient heterogeneous catalyst for the C-C bond forming nitroaldol or Henry reaction. The solid catalyst can be recycled at least three times without losing its catalytic activity. The easily accessible channels in 1Zn are found suitable for the SC-SC transmetalation reaction with Cu(ii) producing 1Cu. The catalytic activity of 1Cu is found to be comparable to that of 1Zn. Furthermore, the framework 1Zn gives high emission in DMSO, which can be efficiently quenched by trace amounts of nitro explosives. All the complexes have been characterized by single crystal X ray diffraction, powder X-ray diffraction, IR, thermogravimetry and elemental analysis. PMID- 28581561 TI - 2-Phenylbenzoxazole derivatives: a family of robust emitters of solid-state fluorescence. AB - The derivatives of 2-phenylbenzoxazole (PBO) are popular fluorescent organic dyes for use in solution or after dispersion in an appropriate matrix. Their spectroscopic behavior in the solid state is, unjustly, not so well known. Many of them are strongly emissive as pure solid dyes, due to a favorable crystal packing mode. The PBO fragment lends itself well to relatively simple modifications of its chemical structure, aimed at enlarging the conjugated pi electron system. Many molecules thus designed show aggregation-induced emission (AIE). Furthermore, the derivatives of 2-(2'-hydroxyphenyl)benzoxazole (HBO) are familiar excited-state intramolecular proton transfer (ESIPT) dyes. They are particularly well suited for solid-state sensing. Mechanofluorochromism is also observed in complexes and closely-related compounds. Regarding their self association properties, the general tendency of many PBO derivatives is to give elongated nano and microparticles. Very small chemical changes are enough to tune the shape and size of these particles. Nanofibers may be obtained by simple preparation methods and are of great value for wave-guiding. For all these reasons, as well as for its robustness and high photo- and thermal stability, the PBO fragment is an attractive building block to access new molecules that will be particularly well adapted for developments in the field of photoluminescent materials. PMID- 28581554 TI - [Ag59(2,5-DCBT)32]3-: a new cluster and a precursor for three well-known clusters. AB - We report the synthesis of a new silver cluster, [Ag59(2,5-DCBT)32]3- (I) (2,5 DCBT: 2,5-dichlorobenzenethiol), which acts as a precursor for the synthesis of three well-known silver clusters, [Ag44(2,4-DCBT/4-FTP)30]4- (II) (4-FTP: 4 fluorothiophenol and 2,4-DCBT: 2,4-dichlorobenzenethiol), [Ag25(2,4-DMBT)18]- (III) (2,4-DMBT: 2,4-dimethylbenzenethiol) and [Ag29(1,3-BDT)12(PPh3)4]3- (IV) (1,3-BDT: 1,3-benzenedithiol and PPh3: triphenylphosphine). This newly synthesized silver cluster, I, is characterized using UV-vis absorption studies, high resolution electrospray ionization mass spectrometry (ESI MS) and other analytical tools. The optical absorption spectrum shows distinct features which are completely different from the previously reported silver clusters. We perform the rapid transformations of I to other well-known clusters II, III and IV by reaction with different thiols. The time-dependent UV-vis and ESI MS measurements reveal that I dissociates into distinct thiolate entities in the presence of thiols and the thiolates recombine to produce different clusters. The conversion mechanism is found to be quite different from the previous reports where it occurs through the initial formation of ligand exchanged products. Here, we also show the synthesis of a different cluster core, [Ag44(2,4-DCBT)30]4- (IIa) using 2,4-DCBT, a structural isomer of 2,5-DCBT under the same synthetic conditions used for I. This observation demonstrates the effect of isomeric thiols on controlling the size of silver clusters. The conversion of one cluster to several other clusters under ambient conditions and the effect of ligand structure in silver cluster synthesis give new insights into the cluster chemistry. PMID- 28581556 TI - A co-culture microtunnel technique demonstrating a significant contribution of unmyelinated Schwann cells to the acceleration of axonal conduction in Schwann cell-regulated peripheral nerve development. AB - Schwann cells (SCs) contribute to the regulation of axonal conduction in a myelin dependent and -independent manner. However, due to the lack of investigative techniques that are able to record axonal conduction under conditions that control the proliferation of specific SC types, little is known about the extent to which myelinated SCs (mSCs) and unmyelinated SCs (umSCs) modulate axonal conduction. In this study, a microtunnel-electrode approach was applied to a neuron/SC co-culture technique. Rat dorsal root ganglion neurons and SCs were co cultured in a microtunnel-electrode device, which enabled recording of the conduction delay in multiple axons passing through microtunnels. Despite the absence of nuclei in the microtunnel when SCs were eliminated, cultured cells were densely packed and expressed S100 beta (an SC marker) at a rate of 96% in neuron/SC co-culture, indicating that SCs migrated into the microtunnel. In addition, supplementation with ascorbic acid after 6 days in vitro (DIV) successfully induced myelination from 22 DIV. Activity recording experiments indicated that the conduction delay decreased with culture length from 17 DIV in the neuron/SC co-culture but not in neuron monoculture. Interestingly, the SC modulated shortening of conduction delay was attenuated at 17 DIV and 22 DIV by supplementing the culture medium with ascorbic acid and, at the same time, suppressing SC proliferation, suggesting that immature umSCs increased axonal conduction velocity in a cell density-dependent manner before the onset of myelination. These results suggest that this method is an effective tool for investigating the contributions of mSCs or umSCs to the regulation of axonal conduction. PMID- 28581559 TI - The social cost of methane: theory and applications. AB - Methane emissions contribute to global warming, damage public health and reduce the yield of agricultural and forest ecosystems. Quantifying these damages to the planetary commons by calculating the social cost of methane (SCM) facilitates more comprehensive cost-benefit analyses of methane emissions control measures and is the first step to potentially incorporating them into the marketplace. Use of a broad measure of social welfare is also an attractive alternative or supplement to emission metrics focused on a temperature target in a given year as it incentivizes action to provide benefits over a broader range of impacts and timescales. Calculating the SCM using consistent temporal treatment of physical and economic processes and incorporating climate- and air quality-related impacts, we find large SCM values, e.g. ~$2400 per ton and ~$3600 per ton with 5% and 3% discount rates respectively. These values are ~100 and 50 times greater than corresponding social costs for carbon dioxide. Our results suggest that ~110 of 140 Mt of identified methane abatement via scaling up existing technology and policy options provide societal benefits that outweigh implementation costs. Within the energy sector, renewables compare far better against use of natural gas in electricity generation when incorporating these social costs for methane. In the agricultural sector, changes in livestock management practices, promoting healthy diets including reduced beef and dairy consumption, and reductions in food waste have been promoted as ways to mitigate emissions, and these are shown here to indeed have the potential to provide large societal benefits (~$50-150 billion per year). Examining recent trends in methane and carbon dioxide, we find that increases in methane emissions may have offset much of the societal benefits from a slowdown in the growth rate of carbon dioxide emissions. The results indicate that efforts to reduce methane emissions via policies spanning a wide range of technical, regulatory and behavioural options provide benefits at little or negative net cost. Recognition of the full SCM, which has typically been undervalued, may help catalyze actions to reduce emissions and thereby provide a broad set of societal benefits. PMID- 28581562 TI - Parallel and antiparallel cyclic d/l peptide nanotubes. AB - Nanotubes made from H-bonded cyclic d/l peptide (CP) subunits have great potential for the construction of nanomaterials of wide chemical and structural diversity but, to date, difficulties in structural characterisation have restricted development of these materials. We present the first crystal structures of continuous CP nanotubes with antiparallel and parallel stacking arrangements, assembled separately from two peptides; cyclo[(Asp-d-Leu-Lys-d Leu)2] and cyclo[(Asp-d-Ala-Lys-d-Ala)2]. PMID- 28581564 TI - Aesthetic Plastic Surgery of the Upper Face. AB - The decade of the 1990s will witness even greater public enthusiasm for aesthetic surgery of the face than previously seen. Several reasons contribute to this increase in number of procedures, among them longevity, better health, nutrition, increased competitiveness in the job market and improvements in general anaesthesia. PMID- 28581560 TI - Dewetting acrylic polymer films with water/propylene carbonate/surfactant mixtures - implications for cultural heritage conservation. AB - The removal of hydrophobic polymer films from surfaces is one of the top priorities of modern conservation science. Nanostructured fluids containing water, good solvents for polymers, either immiscible or partially miscible with water, and surfactants have been used in the last decade to achieve controlled removal. The dewetting of the polymer film is often an essential step to achieve efficient removal; however, the role of the surfactant throughout the process is yet to be fully understood. We report on the dewetting of a methacrylate/acrylate copolymer film induced by a ternary mixture of water, propylene carbonate (PC) and C9-11E6, a nonionic alcohol ethoxylate surfactant. The fluid microstructure was characterised through small angle X-ray scattering and the interactions between the film and water, water/PC and water/PC/C9-11E6, were monitored through confocal laser-scanning microscopy (CLSM) and analised both from a thermodynamic and a kinetic point of view. The presence of a surfactant is a prerequisite to induce dewetting of MUm-thick films at room temperature, but it is not a thermodynamic driver. The amphiphile lowers the interfacial energy between the phases and favors the loss of adhesion of the polymer on glass, decreasing, in turn, the activation energy barrier, which can be overcome by the thermal fluctuations of polymer film stability, initiating the dewetting process. PMID- 28581565 TI - Application of the Threedimensional CT Scan to the Reconstruction of Craniofacial Deformities. AB - New developments in computerised tomography (CT) imaging technology have paralleled advances in craniofacial surgical techniques. The ability to reconstruct congenital, neoplastic, and traumatic deformities is dependent upon good pre-operative assessment. Understanding the spatial relationship of a given deformity is limited with conventional two-dimensional CT scans. A more precise, reproducible portrayal of the craniofacial problem has been' made possible with the development of three-dimensional CT scan capabilities. PMID- 28581555 TI - Investigation of mechanisms involved in postprandial glycemia and insulinemia attenuation with dietary fibre consumption. AB - This work examines the mechanisms involved in the attenuation of postprandial glycemic and insulinemic responses associated with soluble dietary fibre (SDF) consumption. The effect of SDF, including yellow mustard mucilage, soluble flaxseed gum and fenugreek gum on in vitro amylolysis and maltose transport was studied. Furthermore, a human clinical trial was conducted to investigate the effect of SDF consumption on postprandial glycemic and insulinemic responses and gastric emptying, as estimated based on the absorption of paracetamol. Participants (n = 15) at risk for type II diabetes consumed maltose syrup- and starch-based pudding treatments supplemented with each SDF, each at a concentration to match three times the apparent viscosity (18.54 mPa s at 60 s-1) equivalent to the European Food Safety Authority (2011) glycemia control health claim for cereal beta-glucan, measured under simulated small intestinal conditions. The presence of each SDF delayed in vitro amylolysis to a similar extent, but had no effect on maltose transport. Generally, all SDF-containing treatments attenuated blood glucose and plasma insulin peak concentrations and plasma paracetamol 1 h incremental area under the curve values to a similar extent, relative to the controls, despite differences in the amounts at which each SDF was used (from 5.9 to 15.5 g). The postprandial attenuations were related to the ability of each SDF to modify digesta viscosity, perhaps through the delay of gastric emptying, as a delay of amylolysis and sugar transport under simulated upper intestinal conditions did not seem to have a substantial effect. PMID- 28581558 TI - Effects of halogens on European air-quality. AB - Halogens (Cl, Br) have a profound influence on stratospheric ozone (O3). They (Cl, Br and I) have recently also been shown to impact the troposphere, notably by reducing the mixing ratios of O3 and OH. Their potential for impacting regional air-quality is less well understood. We explore the impact of halogens on regional pollutants (focussing on O3) with the European grid of the GEOS-Chem model (0.25 degrees * 0.3125 degrees ). It has recently been updated to include a representation of halogen chemistry. We focus on the summer of 2015 during the ICOZA campaign at the Weybourne Atmospheric Observatory on the North Sea coast of the UK. Comparisons between these observations together with those from the UK air-quality network show that the model has some skill in representing the mixing ratios/concentration of pollutants during this period. Although the model has some success in simulating the Weybourne ClNO2 observations, it significantly underestimates ClNO2 observations reported at inland locations. It also underestimates mixing ratios of IO, OIO, I2 and BrO, but this may reflect the coastal nature of these observations. Model simulations, with and without halogens, highlight the processes by which halogens can impact O3. Throughout the domain O3 mixing ratios are reduced by halogens. In northern Europe this is due to a change in the background O3 advected into the region, whereas in southern Europe this is due to local chemistry driven by Mediterranean emissions. The proportion of hourly O3 above 50 nmol mol-1 in Europe is reduced from 46% to 18% by halogens. ClNO2 from N2O5 uptake onto sea-salt leads to increases in O3 mixing ratio, but these are smaller than the decreases caused by the bromine and iodine. 12% of ethane and 16% of acetone within the boundary layer is oxidised by Cl. Aerosol response to halogens is complex with small (~10%) reductions in PM2.5 in most locations. A lack of observational constraints coupled to large uncertainties in emissions and chemical processing of halogens make these conclusions tentative at best. However, the results here point to the potential for halogen chemistry to influence air quality policy in Europe and other parts of the world. PMID- 28581563 TI - A specific environment-sensitive near-infrared fluorescent turn-on probe for synergistic enhancement of anticancer activity of a chemo-drug. AB - Chemotherapy is one of the main categories of clinical cancer treatment. One of the hindrances of a popularly used chemo-drug doxorubicin (DOX) is that some types of cancer cells are or become insensitive/resistant to DOX. In this work, we report a near-infrared (NIR) fluorescent turn-on probe DBT-2EEGYLFFVFER by conjugation of an environment-sensitive fluorophore DBT with human epidermal growth factor receptor 2 (HER2) specific binding peptides. Besides the NIR fluorescence turn-on signature, DBT-2EEGYLFFVFER also has activatable capability of reactive oxygen species (ROS) generation. DBT-2EEGYLFFVFER is weakly fluorescent in aqueous solution and hardly produces ROS under white light irradiation. However, both the NIR fluorescence and ROS production ability can be switched on when DBT-2EEGYLFFVFER binds to HER2 proteins overexpressed in cancer cells. Besides specific visualization of HER2-expressed cancer cells, DBT 2EEGYLFFVFER upon exposure to light is able to effectively increase the intracellular ROS level and offer an intracellular oxidative microenvironment, which does not cause the death of cancer cells, but greatly and synergistically boosts the cytotoxicity of DOX against HER2-expressed cancer cells with a supra additive effect of "0 + 1 > 1". PMID- 28581571 TI - Endoscopic, Diagnostic and Therapeutic Procedures of the Biliary and Pancreatic Tract. AB - Endoscopic cannulation of the biliary tree and the pancreatic duct (ERCP) was first described in 1968. Six years later the technique of endoscopic sphincterotomy (ES) opened the door to endoscopic treatment procedures of pancreatic and biliary diseases. Techniques have been developed to remove bile duct stones, to break large stones and to drain bile duct or pancreatic duct strictures. PMID- 28581566 TI - Recent Advances in Breast Reconstruction. AB - The incidence of breast cancer in the United States is high and appears to be increasing. The American cancer Society has estimated that one in nine American women (11 percent) will eventually develop breast carcinoma. Recently there has been a dramatic shift away from mastectomy and toward breast-conserving therapy (Iumpectomy, axillary node dissection and whole breast irradiation). In some centres the majority of breast cancer patients are now treated with conservation therapy. Some patients, however, are not candidates for radiation, because of the size, location or histology of their tumour and are still best treated by mastectomy and reconstruction. Women who develop local recurrence following radiation therapy are likewise candidates for mastectomy with reconstruction. Additionally, there is a large group of women who had mastectomies in years past who have not had reconstruction. Thus many patients may potentially benefit from breast reconstruction. PMID- 28581567 TI - Present Status of Microsurgical Replantation. AB - The replantation of amputated parts has stimulated the imagination of writers since antiquity. It was not until the successful replantation of an arm by Malt and a hand by Chen Chung Wei in 1953 that these fables became reality. The simultaneous development of the field of microsurgery permitting the repair of one millimetre vessels made possible the replantation of structures fed by these small vessels such as fingers, ears, noses, lips, scalps and penises. PMID- 28581568 TI - Laparoscopic Cholecystectomy after the Learning Curve. AB - Management of gallbladder disease has changed dramatically since the introduction of laparoscopic cholecystectomy (LC) in 1988. Removal of the gallbladder has always been the 'gold standard'. However, the morbidity associated with the large transrectus incision has caused patients and referring physicians alike to refrain from surgical treatment whenever possible. LC offers the same excellent end results of a standard cholecystectomy, but without the pain and ileus seen with the operation. PMID- 28581573 TI - The Quadrantectomy Technique for Small Breast Carcinomas. AB - Quadrantectomy describes removal of the quadrant in which a breast neoplasm is located, by excision of skin overlying the tumour en bloc with the sub-cutaneous fatty tissue and a relatively large area of the mammary gland, including the corresponding parts of the fasciae of the major pectoralis muscle. PMID- 28581570 TI - Endoscopic Methods for Control of Non-variceal Gastrointestinal Bleeding. AB - Flexible upper gastrointestinal endoscopy has a well established place in the diagnosis of upper gastrointestinal bleeding. Increasing experience with a variety of modalities has made endoscopic therapy appropriate for many significant bleeding lesions of the upper GI tract. In many instances endoscopic therapy will eliminate the need for surgical control of the bleeding lesion. In other patients the temporary endoscopic control of bleeding may allow appropriate surgical intervention to be postponed until optimal stabilisation can be accomplished. PMID- 28581569 TI - The Future of Laparoscopic General Surgery. AB - Video controlled laparoscopy has dramatically changed general surgery. Further striking alteration is sure to occur in the immediate future. Not only are the surgeons who are concentrating on this area making great strides, but innovative equipment and technological innovation are certain to make more complex procedures feasible. Thus the future of laparoscopic surgery is very bright. PMID- 28581574 TI - Hyperparathyroidism. AB - Approximately 100,000 new cases of primary hyperparathyroidism are diagnosed in the United States each year. Thus a disorder that was once considered to be rare is now known to be relatively common. Many patients with primary hyperparathyroidism are diagnosed today with only minimal hypercalcemia (serum calcium less than 1mg/dl above the upper limit of normal) and many have few or no classic symptoms or clinical manifestations of hyperparathyroidism, such as kidney stones or osteitis fibrosa cystica. Many patients with hyperparathyroidism today have fatigue or increased lethargy, muscular weakness, bone or joint pain and depression. It is difficult preoperatively to know whether these clinical manifestations are related to the primary hyperparathyroidism or not. Our own studies suggest that in about 80 per cent of patients with hyperparathyroidism the preoperative symptoms either improve or disappear after parathyroidectomy. PMID- 28581572 TI - New Challenges in Trauma Surgery Care of the paediatric, geriatric and pregnant patient. AB - Trauma surgery originated with military surgeons who cared for otherwise healthy young males injured in combat. During the past two decades, many areas of the United States have established trauma systems, organised to sift seriously injured patients of all ages to trauma centres that have the medical personnel and equipment needed to provide immediate trauma care. The organisation of trauma care has greatly increased the experience of civilian surgeons based at designated trauma centres, and has lead to a recognition of three 'special care' areas of trauma surgery: paediatric trauma, geriatric trauma, and trauma during pregnancy. PMID- 28581575 TI - Using Lasers in Head and Neck Oncologic Surgery. AB - Few technologic advances in medicine have captured the imagination of the general public, and physicians, to the extent that the laser has. The laser clearly evokes images of space-age technology, and is frequently regarded as a panacea by patients. The reality is, of course, that the laser has no inherent special ability to cure diseases, and is simply another tool available to contemporary surgeons. We will review the current application of lasers in head and neck oncologic surgery. The basic mechanism of lasers will be discussed, with emphasis on the carbon dioxide (C02) laser. This discussion will include analysis of photodynamic therapy for cancer of the upper aerodigestive tract, which is rapidly evolving as a means of incorporating lasers in the treatment of head and neck cancer. PMID- 28581576 TI - Transjugular Intrahepatic Portosystenlic Shunts: TIPS. AB - The emergency management of patients with acute variceal bleeding has evolved dramatically over the past 20 years. Initially, bleeding was controlled by supportive medical measures in conjunction with surgical portal decompression procedures. However, the high operative mortality and the significant incidence of post-operative encephalopathy associated with emergency portal decompression led to the development of alternative therapeutic techniques. Injection sclerotherapy has been used in large numbers of patients for the past 10 years with considerable success and is now advocated by many authors as the treatment of choice for acute variceal hemorrhage. While sclerotherapy controls bleeding in approximately 70 per cent of patients, repeat sessions are necessary in 20 per cent and sclerotherapy may be unsuccessful in 10 per cent. When sclerotherapy fails, most authors recommend surgical shunting. While the side-side portacaval shunt is still the most popular operation in this setting, other types of shunts have been advocated by some authors. A small mesocaval or portacaval H-graft, or a distal splenorenal shunt may he performed in an attempt to reduce the incidence of post-operative encephalopathy and liver failure. PMID- 28581578 TI - Lung Transplantation in the 1990s. AB - Over the past 10 years there has been a rapid increase in the application of single lung, double lung and heart/lung transplantation to patients with a variety of end-stage cardiopulmonary diseases. As a result there has been a significant expansion in our knowledge of these procedures and their potential therapeutic role, limitations and complications. PMID- 28581577 TI - Regional Hyperthermic Perfusion for Cancer. AB - Regional perfusion of cancer resulted from studies that infused nitrogen mustard into arteries supplying tumours while at the same time blocking the venous return to maximise exposure of the tumour to the chemotherapeutic agent. PMID- 28581579 TI - Liver Transplantation Modern techniques in donor and recipient operations. AB - Pacific Transplant Institute, California Pacific Medical Center, San Francisco Orthotopic hepatic transplantation provides hope for patients with irreversible liver disease, and the operation is becoming more accepted by the medical community and the public in general. Still, the operation is difficult and the postoperative and long-term management can be rather complex. Unlike pancreas, kidney and heart transplantation, liver transplantation lacks a back-up system, such as Insulin, dialysis or a ventricular support device, if graft failure occurs. Therefore, the Slightest error in the management of the patient after hepatic transplantation may prove fatal. Complications during the post-operative period often originate from the time of the procurement and/or transplantation operations. Thus, good techniques are crucial for a satisfactory outcome. PMID- 28581580 TI - The Current and Future Status of Lasers in Surgery. AB - Almost from the moment of its invention, the laser was destined to play a significant role in surgery. This intense new source of coherent, radiant energy inevitably attracted the attention of imaginative physicians and surgeons, who immediately recognised its potential for precise removal of diseased tissue. PMID- 28581581 TI - The Surgical Biology of Cancer. AB - The surgical principles in the treatment of cancer were first clearly enunciated in 1906 by Halsted in the treatment of carcinoma of the breast, namely wide surgical removal of the breast together with the regional lymph nodes to which it spreads. The hope was that the regional nodes would serve as filters and prevent the spread of malignant cells into the blood stream, enabling the surgeon to excise every last cancer cell from the patient, thereby curing the cancer. PMID- 28581582 TI - The Impact of Biotechnology on Surgery in the 1990s. AB - Medical practice is generally divided into medical and surgical sub-groups based on therapeutic approaches. Physicians in medically oriented specialities, such as internal medicine and paediatrics, traditionally rely largely on drugs to influence the course of disease while general and speciality surgeons usually have some type of surgical procedure at the core of their discipline. (Obviously, these are gross generalisations; surgeons have long been at the forefront of the use of antibiotics and nutritional support.) But these distinctions are becoming increasingly blurred as cardiologists guide catheters into ever smaller vessels and gastroenterologists send fibreoptic scopes into yet other ducts and snare would-be cancers from ever more remote parts of the gut. The recent explosion in scientific knowledge will continue to fuel this trend. Greater understanding of the fundamental mechanisms of disease inevitably leads to a simpler approach to diagnosis and therapy. PMID- 28581584 TI - Advances in Anaesthetic Monitoring for the 1990s. AB - Given the anaesthesiologists 'credo 'vigilance' it should come as no surprise that monitoring is accorded high priority in anaesthetic practice. Although the critical basics of monitoring have changed little since the earliest days of the specialty, namely visual observation (i.e. skin colour, rate and depth of respiration, position and location of patient and endotracheal tube etc.) and physical contact with the patient (i.e. finger on the pulse for heart rate and estimation of blood pressure, temperature, peripheral perfusion etc.) there is no question that technological advances have greatly enhanced these basic observations. The 1980s were especially pivotal. In this decade major advances have been made in respiratory and cardiovascular monitoring. Many of these advances have been credited with facilitating a major reduction in perioperative anaesthetic morbidity and mortality. For instance, with the routine use of pulse oximetry and capnography, the chance of an unrecognized esophageal intubation of sufficient duration to result in anoxic brain damage have been almost eliminated. PMID- 28581583 TI - Functional Organ Replacement, The New Technology of Tissue Engineering. AB - Functional failure of one vital organ results in death. The surgical implantation of tissue with the capacity to replace lost organ function, from one individual into another, is termed transplantation. In Boston, in 1954, Joseph E Murray performed the first successful human organ transplant, that of a kidney from an identical twin into his brother. PMID- 28581591 TI - Endoscopic Instrumentation and Equipment for Surgery. AB - The popularity of Endoscopy for both diagnostic and therapeutic procedures is a result of advanced development of new technologies, such as industrial video and fibre optics. Surgeons have 'new sets of eyes' and therefore it becomes necessary to familiarise ourselves with articulating instruments while looking at a television monitor not at the surgical sight. With the field of endoscopy evolving so quickly, it is imperative for the surgeon to adapt his or her technology to optimise patient gain and minimise procedure risk. If new technology is ignored, the.disservice is done both to the physician and the patient. 'If you do not become part of steam roller, you become part of the road. PMID- 28581585 TI - Intrathecal lnfusional Therapies for Intractable Pain. AB - There has recently been an increased interest in the safety, efficacy and relative ease in the delivery of intraspinal analgesics for the control of intractable pain. Recent technological advances have provided clinicians with precise and accurate delivery systems for long term infusion of spinally administered drugs. Because of these advances, there has been a rapidly growing interest in long term intraspinal infusional therapy for the control of chronic pain. PMID- 28581588 TI - Uses of Ultrasound in a Surgical Practice. AB - The applications of sonography multiply year by year. The technology initially progressed from a simple A-mode signal, to contact scanners which produced B-mode images. These, in turn, were supplanted by real-time instruments capable of defining motion. The next development was the duplex Doppler machines which characterised flow from an image in a specific area. Now, colour coding of vascularity and high resolution imagery have become the standards of excellence. PMID- 28581595 TI - Fixed Combination of Fibrin Glue with a Sheet of Collagen A 'ready-to-use' local haemostyptic agent. AB - There are still situations in surgery when diffuse bleeding becomes a severe problem. This may occur especially during operations involving parenchymal tissue and, or in cases of impaired haemostasis. Several methods are available to control diffuse bleeding, and in addition to classical methods like sutures or tamponade, there are essentially two approaches: -Application of physical methods (e.g. electro-coagulation and infra-red-coagulation) -Application of local haemostyptic materials. PMID- 28581586 TI - Antibiotic Update for the Surgeon. AB - The number of antimicrobial agents that have been introduced into clinical practice continues to increase. This development, however, is not unique to the antibiotic field. All one has to do is to look at the burgeoning number of compounds for antiinflammatory or cardiovascular indications to recognise that the pharmaceutical industry continues to provide us with new compounds of increased potency and broadened therapeutic applicability. On the other hand, not all new drug introductions represent clinical breakthroughs. Some agents can be, quite frankly, classified as 'me too' drugs. Nonetheless, even a fairly simple congener could be a welcome addition to the therapeutic armamentarian if it is safer, less toxic, cheaper, and more convenient to use than previously available therapy. PMID- 28581587 TI - Treatment of Infections Associated with Implanted Medical Devices. AB - The development of an infection in the vicinity of an implanted medical device is a dramatic event in many fields of surgery, especially cardiovascular, orthopedic and neurosurgery. The diagnosis of these infections is usually difficult and their treatment is always complex and represents a challenge for both surgeons and infectious diseases specialists. As foreign materials are used with increased frequency in modern medicine, this problem will probably remain a major one in the future despite the improvement of techniques and the use of new antibiotics. For patients, infection of a prosthetic device often means the loss of its function and. is sometimes associated with a high mortality. PMID- 28581590 TI - Blood Substitutes. AB - Although the need for an alternative to red cells for transfusion has been recognised since the initial description of the circulation of the blood by William Harvey in 1628, there is still no approved product available to clinicians. Recent concern over the safety of human blood has stimulated a renewed interest in finding alternatives to transfusion of red cells. Two types of solutions, those based on perfluorocarbons and those based on haemoglobin are currently being aggressively developed. PMID- 28581593 TI - The Rapid Infusion System. AB - Haemorrhage often leads to shock with complications of acidosis, hypothermia and coagulopathy. Despite massive transfusions and supposedly adequate volume replacement, patients that are acidotic and hypothermic still develop clinically significant bleeding and clotting problems attended by a high mortality. PMID- 28581589 TI - Hepatic Resection Using Ultrasonic Fragmentation. AB - The frequency with which hepatic resection is undertaken has rapidly expanded. This is due to a better understanding of hepatic anatomy and physiology, and a better appreciation of the indications for resection. As a result of Foster's liver tumour survey of 1974, and Adson's early publications hepatic resection has become almost commonplace. However, though the mortality of the procedure has decreased to five to 10 per cent, the morbidity continues to range from 20 to 27 per cent, Ultrasonic dissection has the unique potential to decrease the morbidity and mortality of this procedure by minimizing blood loss and creating a controlled operative event. PMID- 28581594 TI - Chronic Wounds Yesterday's Challenges Healing Today. AB - Chronic, non-healing wounds have been a challenge to surgeons for years. Physicians get frustrated trying multiple modalities to heal the wounds with varying degrees of success. Patients and their families get impatient and depressed because the wounds will not heal. Hospitals in the US lose money on these patients because so many of them are in the Medicare population and require lengthy hospitalisations. Third party payors spend inordinate amounts of money on these patients since they require on-going care even though they are not healing. This scenario is a major challenge in health care today as we face caring for an aging population more prone to chronic wounds. PMID- 28581592 TI - Autotransfusion Cell-Saver and Plasma Saver. AB - Early attempts at blood salvage during surgery shared many of the complications associated with the development of cardiopulmonary (heart-lung) bypass machines; especially, coagulopathy and air embolism. By the late 1970s, the technology had developed to the point where not only were the red blood cells salvaged, but washed and processed in a manner that prevented auto-immunisation, transfusion reactions, and transmission of diseases. Blood conservation became practical. PMID- 28581598 TI - The Vascular Laboratory in the 1990s What's in and what's out. AB - The vascular laboratory as a recognised entity is, at best, only 15 years old. Many growing technologies were applied prior to this time, but it was not until the addition of Doppler ultrasound to the vascular surgeon's armamentarium that non-invasive diagnosis began to take hold. The vascular laboratory was necessary because angiography, which was felt to be the gold standard by many, was expensive, had the risk of potentially serious complications, and did not have the characteristics of a test which made it easily repeatable at frequent intervals. Most importantly, angiography was an anatomic evaluator and provided minimal information regarding function. Although pathologic anatomy and function are often related, the relationship is sufficiently weak to dictate the need for an accurate method of functional evaluation. This was the role of the early vascular laboratories. Today's vascular laboratory provides both functional and anatomic information. In some cases, the anatomic information is superior to that which can be obtained from angiography. PMID- 28581596 TI - Haemostasis by Computerised Bipolar Diathermy. AB - Modern bipolar diathermy has certain limitations, especially regarding the regulation of the short coagulation course: it is somewhat awkward to use, is prone to mechanical malfunction and time consuming. The computerised bipolar diathermy system was originally developed for solving these problems in neurosurgery. It has now gained wide acceptance by all the surgical sub specialities. Electronic feedback of the tissue impedance automatically starts and shuts off coagulation when a blood vessel is picked up by the forceps. The shut-off is related to a point in the impedance course that correlates to a temperature of 60 to 90 degrees C, i.e. after coagulation has occurred and before complete desiccation, fulguration and sticking of the forceps has taken place. PMID- 28581601 TI - Endovascular Techniques and Peripheral Vascular Surgery. AB - Endovascular is an increasingly popular term that describes the use of catheter based instruments to diagnose and treat vascular disease. Implicit in this terminology is its association with techniques that are less invasive to the patient than traditional surgical techniques. Endovascular techniques began in 1963 with the advent of the Fogarty arterial embolectomy catheter for removal of clotted blood from the peripheral arterial circulation. Shortly thereafter, radiologist Charles Dotter introduced the concept of arterial dilatation which was popularised a decade later by cardiologist Andreas Gruntzig with the use of a non-dispensible plastic balloon catheter. During the next two decades, endovascular techniques proliferated in the growing fields of interventional cardiology and interventional radiology, yet were embraced more slowly by the surgical community. PMID- 28581597 TI - Impact of Technological Advances on Vascular Surgery in the 1990s. AB - 'All change is a miracle to contemplate; but it is a miracle which is taking place every instant.' Henry David Thoreau, Walden, 1854. Progress in vascular surgery is fuelled by technology. Every advance in modern vascular surgery has been preceded by a technological development which, though apparently amazing, soon became a commonplace. Those who do not believe in change in vascular surgery or that technological advances described in this volume will have any place in the treatment of vascular disease, reflect an attitude described best by Lord Moynihan, then President of the Royal College of Surgeons of England. He said, 'surgery ... has now almost reached its limit...we can surely never hope to see the craft of surgery made much more perfect than it is today.' Changes which have occurred since that statement are a cascade of advances including antibiotics, anticoagulants, prostheses, sutures, needles, and a variety of scopes which have become as common as aseptic technique. PMID- 28581599 TI - Prosthetic Vascular Grafts The state of the art in the 1990s. AB - During the early years of vascular prosthetic development (1940-1960), the characteristics of the ideal graft were gradually defined. In order to be clinically useful, a vascular graft must be readily available in a variety of sizes and lengths and be suitable for use throughout the body. PMID- 28581600 TI - The Future of Lasers in Endovascular Surgery. AB - The potential for precise tissue ablation via a miniaturised delivery system (i.e. fibre optics) makes laser angioplasty a promising alternative for treatment of atherosclerotic occlusions which are not amenable to current forms of therapy. This is a particularly relevant consideration since the majority of developing angioplasty devices aside from balloons are difficult to miniaturise in a cost effective manner. The utility of contemporary devices is restricted to stenotic or short occlusive lesions, with a high rate of early recurrence of lesions being a significant limiting factor in most locations. In order to address and resolve the current deficiencies and define the potential of lasers as an angioplasty device, it is first appropriate to overview the current status and define unresolved issues. PMID- 28581602 TI - Will Angiosocopy Replace Operative Arteriography in the 1990s? AB - Vascular surgeons have always been concerned with the intra-operative assessment of their reconstructions. Failure of vascular reconstructions in the early post operative period is most commonly a result of a technical error at the time of surgery. Hence, any technique which aids the vascular surgeon in evaluating his reconstruction and in preventing technical errors will be beneficial to both the surgeon and their patient. Traditionally, intra-operative arteriography has been the 'gold standard' for evaluating vascular surgical procedures. PMID- 28581603 TI - Reperfusion Syndrome. AB - The interruption of blood flow causing ischemia is usually the result of an intrinsic obstruction of major arteries by clots. Emboli that originate in the heart are the main cause of such obstructions, and patients who have had myocardial infarcts or have stenosis of the mitral valve or arrhythmias such as atrial fibrillation are susceptible to the development of clots within the heart which can lead to distal thromboembolism. Another common cause of arterial obstruction is the formation of clots in an area of narrowing caused by arteriosclerosis. PMID- 28581604 TI - Steps to Technical Expertise in Carotid Endarterectomy. AB - Carotid endarterectomy is a prophylactic operation that is designed to prevent strokes related to atherosclerotic plaques in the carotid bifurcation. Once a plaque is safely removed, a major potential cause for stroke in that patient is eliminated. However, the operation itself carries two major risks: death and stroke. These risks are related to patient selection and technical expertise in the performance of the operation. This chapter will focus upon those aspects of surgical technique, when properly applied, that can minimise the risks of surgical complication and thus permit the operation to achieve its highest potential of stroke prevention. PMID- 28581606 TI - Refinements in the Techniques of Venous Surgery. AB - The surgery of venous disease falls into two distinct categories, the removal of malfunctioning unsightly superficial veins and the restoration of the function of the deep veins by repairing or replacing valves or bypassing obstructions. During the past decade surgical advances have mainly been concerned with the refinement of techniques to reduce the cost of surgery and its outward and visible manifestation - the scars, rather than the introduction of new principles or objectives. PMID- 28581608 TI - Venous Valvuloplasty. AB - The technical feasibility of surgical correction of abnormal venous valves is now established. In times past, it was generally thought that surgery inside the veins would be fraught with a virtual certainty of failure due to thrombosis of the vein. This has turned out to be not true. In 1968 the first venous valvuloplasty was done and since then hundreds more have been reported from surgeons in America and Europe with a very rare incidence of post-operative thrombosis. The operation is done today by any vascular surgeon who has taken the time to study the details of technique that are necessary to achieve a successful repair. PMID- 28581605 TI - A Technique of Carotid Endarterectomy and Carotid Shunting. AB - With the advent of carotid arterial operations, concerns of interruption of cerebral perfusion and ischemic injury loomed as the major deterrent. The physiologic basis for cerebral protection is to diminish its oxygen requirement by chemical or hypothermic means or to continue its adequate arterial perfusion. The first successful carotid reconstruction resecting an internal carotid stenosis with anastomosis of the patent external carotid to the distal internal carotid artery was performed by Carrea of Argentina in 1951. Preoperatively, ascorbic acid and phenobarbital was given but its rationale was not explained. PMID- 28581607 TI - Popliteal Vein Valve Transplantation for Deep Venous Valvular Incompetence. AB - Interest in deep venous reconstruction for severe chronic venous insufficiency (CVI) is burgeoning. Vein valve transplantation for deep venous valvular incompetence, an indirect method for correcting deep venous valvular incompetence achieves its physiologic benefits by placing a normal functioning valve harvested from the upper extremity into the deep system. By contrast, other authors in this volume have presented alternative forms of deep venous valvular reconstruction where the valve mechanism itself is directly repaired or a local segment of vein containing a functioning valve from the same anatomic area, such as the saphenous or profunda, is transposed into the deep venous circuit. Several factors influence the role of deep venous valvular surgery and its frequency. For example, the incidence of deep venous involvement in patients with advanced stage II or frank ulceration (stage III) is variable and depends upon patient selection process. PMID- 28581609 TI - New Devices and Techniques for Thrombectomy of Arteries and Grafts. AB - An arterial embolus is an obstructive segment of material which travels along the bloodstream until lodging in an artery which is too small in diameter to permit its passage. The embolus will halt flow of oxygenating blood to all tissue beyond the point of obstruction. Blood distal to the obstruction will stagnate and thrombose - or clot in place, effectively propagating the obstructive material along the artery. Arterial embolism poses a threat to both life and limb and prior to the mid-1960s was difficult for surgeons to treat because there was no simple and effective means to remove the embolus and associated distal thrombus. PMID- 28581611 TI - The Selection of Cardiac Pacing Systems. AB - Once the decision has been made to implant a permanent pacing system for the management of symptomatic bradycardias, a clinical assessment of the patient's physiological needs must be made together with a systematic determination of the pacemaker features that can best meet those needs. The primary clinical objectives should be the restoration and maintenance of optimal cardiac function, so as to enable the patient to be as active as possible. Unless the clinical goals are clearly defined and the physiological consequences of various pacemaker features understood, the implanted system may not fully benefit the patient, or may even exacerbate the patient's symptoms. Clinical assessment usually includes an ambulatory electrocardiogram to document the occurrence, frequency, and type of tachycardia, and an exercise test to assess the presence of 'chronotropic incompetence,' defined as inability to increase heart rate in response to increased metabolic need. PMID- 28581613 TI - Implantable Cardioverter Defibrillators The state of the art. AB - Implantable devices are now being routinely used for the treatment of patients with malignant ventricular tachyarrhythmias. This technology became an approved clinical therapy in the United States in 1985. The prototype implantable cardioverterdefibrillator ICD was developed in the 1970s and investigated in the 1980s. Since its approval in 1985 for general clinical application, ICDs are being increasingly used in patients with life-threatening ventricular tachyarrhythmias based upon a number of clinical trials undertaken in North America and western Europe. PMID- 28581612 TI - Current Pacemaker Therapy Surgical consideration involving leads and lead placement. AB - The implantable pacemaker, like the telephone, has evolved from a rather straightforward device, which offered virtually no choice to its early users, to a highly complex system embodying a number of choices, many of which must be made at the outset because they affect the performance of the system throughout its lifetime. The most important of these choices, is, of course, selection of the mode of pacing and its relationship to the underlying arrythmia. These considerations are discussed in considerable detail in Dr Nora Goldschlager's article on electrophysiology, and will not be repeated. The focus of this discussion will be on surgical techniques of implantation, particularly as related to the evolution of the modern lead system. PMID- 28581618 TI - Dynamic Cardiomyoplasty. AB - On January 8, 1985, Carpentier and his cardiovascular surgery group at the Broussais Hospital were the first to replace diseased human myocardium with a stimulated latissimus dorsi muscle flap. A few months later, Magovern and co workers at Allegheny General Hospital in Pittsburgh were the first to repair a large left ventricular aneurysm with a latissimus dorsi cardiomyoplasty. Over the past six years, approximately 120 patients have undergone the operation throughout the world. PMID- 28581610 TI - Angioplasty of the Completely Occluded Coronary Vessel. AB - Over the past 12 years, the development and widespread use of new interventional techniques has widened the indications for the use of percutaneous transluminal coronary angioplasty (PTCA) in the treatment of totally occluded coronary arteries. In the early reports of the National Heart Lung and Blood Institute (NHLBI) Registry investigators recommended that angioplasty should not be attempted in coronary total occlusions. However, with improvements in operator skills, advanced catheter technology, and most notably, with the development of steerable guidewire systems, angioplasty is now being used to treat totally occluded arteries in an increasing number of patients. PMID- 28581615 TI - Advances in Paedriatric Cardiac Surgery. AB - Treatment of congenital cardiac disease has been marked in the recent decade by a movement towards treatment in early infancy, the development of techniques of radical palliation for conditions previously inoperable and the emergence of transplantation as a viable alternative. PMID- 28581619 TI - Transmyocardial Revascularisation by CO2 Laser. AB - Anatomical channels connecting the left ventricular chamber to the myocardial sinusoids supplying the left ventricle with oxygenated blood in the human heart were described by Dr Wearn in 1933. He microscopically confirmed these communicating vessels or tiny clusters of arteries by gelatin filling. The second type of these channels was located at the end of the vessels almost as though woven into the fabric of the muscular fibres. These irregular shaped blood vessels were called myocardial sinusoids. Three other early investigators described connecting channels. The first was Adrian Christian Thebesius, a Dutch physician in 1708 who described connections from the atrium the coronary veins which were called Thebesian veins. The second was the American physiologist F H Pratt who, in 1898, perfused blood though the ventricle alone in a cat, keeping it alive for more than an hour. Finally, the historical work of R T Grant who in 1926 reported that a congenitally deformed heart in a child had connecting cavities with the surrounding veins and arteries. PMID- 28581616 TI - Left Ventricular Assist Device. AB - Left ventricular assist device (LVADs) have been used with increasing frequency since the late 1980s. Technology has improved these devices to make them less thrombogenic and has decreased their size to allow greater application. By definition, the LVAD only assists or supports the pumping function of the left ventricle, unlike cardiopulmonary bypass which provides total circulatory and pulmonary function. LVADs support the circulation for hours to days and occasionally for weeks when the left and/or right ventricle has failed and is therefore unable to sustain the circulation. The hope is that by temporarily supporting the circulation, ventricular function will return. In other instances, LVAD type devices (also known as prosthetic ventricles) are used to 'bridge' the time until a suitable heart donor can be located for transplantation. PMID- 28581617 TI - Intervention in the Late Stages of Congestive Heart Failure Prospects in the 1990s. AB - The human heart is a brilliant example of biological engineering. Its four engineering components, when properly integrated, is a marvel of a rugged, high performance, self regulating biological pump. The components of the heart are conduction system (rate control), coronary circulation (fuel supply), valves (directional flow) and muscle (power and force). The breakdown of any component part and failure of proper system integration leads to reduced pumping performance and appearance of clinical symptoms. Effective treatment exits for the failure of three of these components - valve repair and/or replacement; coronary artery bypass, angioplasty or pharmacologic intervention; and pacemakers and drugs for conduction problems. PMID- 28581622 TI - Antibiotic Impregnated Beads, Indications in musculoskeletal infection. AB - The management of musculoskeletal infection as a result of acute extremity injury remains a challenge to the experienced surgeon. The current treatment of acute debridement and wound irrigation remain the most important factors in the prevention of acute or chronic infection. Skeletal stabilisation and appropriate soft tissue coverage are also imperative in the standard care of these complicated traumatic wounds. Once stabilised, severe open fractures remain at risk as a result of the compromised vascularity of the bone and soft tissue. Parenteral broad-spectrum antibiotics are recommended as a prophylaxis to the open wound contamination. In such injuries the therapeutic levels of the antibiotics are frequently diminished by the impaired tissue perfusion, vasospasm, edema and vascular damage. PMID- 28581624 TI - Advances in Sports Medicine. AB - The tremendous surge of interest in sports participation and body conditioning in this country has necessitated technical advances in the field of sports medicine to diagnose and treat a variety of related injuries that are increasingly confronting orthopaedic surgeons. Perhaps the two areas of the body that deserve discussion are the advances in surgery of the knee and the shoulder. In both joints, the development of arthroscopic techniques and treatment has been perhaps the greatest advancement in the past 25 years. PMID- 28581620 TI - Technological Advances in Spine Care. AB - Spinal medicine is one of the most rapidly evolving specialities of surgery and of medicine. The more critical and life saving specialties seem to have evolved first. General surgery, of course, existed for decades before the vascular and cardiac surgeon evolved in the 1950s and 1960s. Hand surgery and total joint surgery was in its heyday by the early 1970s. Spine surgery did not become a recognised specialty by the Academy of Orthopedic Surgery until almost 1990. PMID- 28581621 TI - Technology in the Management of Spinal Cord Injuries. AB - Injury to the spinal cord is catastrophic and usually permanent. Whereas other injured tissues, such as bone, skin, blood vessels and peripheral nerves, are capable of being repaired and resuming near normal function, such is not the case with the spinal cord. Thus far, all attempts to repair the cord using every conceivable technique has ended in failure. The physician and other members of the treatment team involved with a patient with spinal cord injury, must deal with permanent, long-term consequences of the injury. PMID- 28581623 TI - Orthopaedic Trends in the 1990s An introduction. AB - Recent advances in orthopaedic technology have been among the most exciting medical developments of the past decade. More than 90 percent of the procedures and implants in use today did not exist a decade ago. The development of new prostheses and implants, the modifications of existing ones, and the development of new surgical techniques have allowed orthopaedic surgeons to treat and rehabilitate patients with diseases and deformities that were previously unmanageable. Furthermore, the newer and less invasive procedures have decreased the cost of treatment and recovery time for many patients. Prosthetic joint replacement is now capable of relieving arthritic pain in a predictable fashion, and spinal deformities of any magnitude can be treated in patients of any age with a high probability of success. The reattachment of amputated parts has become commonplace, and techniques of tissue transfer have enabled the salvage and reconstruction of cancerous or traumatised limbs that previously would have been lost to amputation. PMID- 28581625 TI - Advances in Spine Surgery. AB - Technological advances in the field of spine surgery have most often involved instrumentation. In recent years, a great deal of attention has been focused on variable hookscrew-rod systems, the prototype of which is the Cotrel-Dubousset instrumentation (CDI). This French-designed system and similar ones such as the Texas-Scottish Rite (TSRH), or the Isola, provide significantly better fixation and rigidity than has ever been possible, and they allow many patients to be spared the discomfort and inconvenience of post-operative brace or cast support. These features are particularly important for older and chronically ill patients, whose often difficult problems can also be addressed more safely and effectively with this new technology. PMID- 28581614 TI - Intra-operative Coronary Angioscopy. AB - A goal of this article is to demonstrate how easily angioscopy can be incorporated into coronary artery bypass grafting. Intra-operative angioscopy has been used in a number of applications including prebypass arterial evaluation, inspection of the interior of the vein graft, examination of graft to coronary anastomoses and outflow. And adjunctive guidance during adjunctive revascularisation procedures. Despite promising initial trials of the use of intraoperative angioscopy, this technology has not been widely adopted because of perceived demanding technique, excessive effort required, and potential complications. Moreover, the possible benefits of the additional information gained during cardiac surgery operations have thus far only been partially demonstrated. PMID- 28581627 TI - Advances in Adult Reconstructive Orthopaedics Total joint arthroplasty. AB - The greying of America has produced a strong demand for improving total joint arthroplasty. The primary application of joint replacement technology is at the hip and knee, but arthroplasty of the shoulder and elbow has also made significant advances. Increasing numbers of people are reaching retirement age and require a level of function that will enable their enjoyment of leisure activities such as golf and bicycling. The increased popularity of sports in general also has produced a population of younger adults who need arthroplasty to restore function after a disabling trauma. In addition to patients with traumatic arthritis, patients with crippling arthritis - for example, those affected by rheumatoid arthritis - need more normal function. Thus, there is a great need for total joint replacements that will perform better and last longer. PMID- 28581628 TI - Advances in Paediatric Orthopaedics. AB - As a direct result of the technological advances of the past decade, complex skeletal deformities in children are being treated with increasingly greater efficiency, and the pathologic mechanisms of heritable disorders are understood in greater depth. This chapter will briefly describe the recent innovations that have stimulated new areas of research and enhanced our ability to manage orthopaedic problems in children. PMID- 28581629 TI - Advances in Microsurgery. AB - The beginnings of microsurgery date back to the early part of the century. In 1906, the first description of small vessel anastomosis was presented to the Johns Hopkins Medical Society by Alexis Carrel, who eventually won the Nobel Prize for his work in 1912. The next major advance, reported by Jacobson and Suarez in 1960, was the anastomosis of 1mm vessels. This feat was a pivotal accomplishment and soon became clinically feasible with the manufacture of fine needles (50MU to 100MU) and sutures measuring between 15MU and 20MU, or approximately three times the size of a human red blood cell. Two years later, Malt performed a landmark operation the first replantation of an upper extremity above the elbow and soon after, Susumi Tamai of Japan successfully reattached a completely amputated thumb. The first toe-to-thumb transplant was performed in the early 1970s, and, within a few years, free microvascular muscle and bone transplantation had been described. By the early 1980s, microsurgical procedures had undergone a dramatic evolution, seeing the development of an expansive array of microvascular alternatives to address a wide variety of clinical problems. PMID- 28581626 TI - Advances in Orthopaedic Oncology. AB - Advances in MR imaging, allograft tissue use, and the design of prosthetic implants have dramatically improved survival rates and clinical results in patients with tumours. In younger patients with high-grade sarcomas, adjuvant chemotherapy has increased the chance of survival from 25 per cent to 75 per cent, and tumorous limbs now have a 90 per cent chance of being salvaged. PMID- 28581630 TI - Dispersive liquid-liquid microextraction of phenolic compounds from vegetable oils using a magnetic ionic liquid. AB - A novel method was developed for the determination of two endocrine-disrupting chemicals, bisphenol A and 4-nonylphenol, in vegetable oil by dispersive liquid liquid microextraction followed by ultra high performance liquid chromatography with tandem mass spectrometry. Using a magnetic liquid as the microextraction solvent, several key parameters were optimized, including the type and volume of the magnetic liquid, extraction time, amount of dispersant, and the type of reverse extractant. The detection limits for bisphenol A and 4-nonylphenol were 0.1 and 0.06 MUg/kg, respectively. The recoveries were 70.4-112.3%, and the relative standard deviations were less than 4.2%. The method is simple for the extraction of bisphenol A and 4-nonylphenol from vegetable oil and suitable for routine analysis. PMID- 28581633 TI - Population Pharmacokinetic Analysis of Zolmitriptan and Its Metabolite in Adults and Adolescents to Support Dose Selection in Children With Migraine. AB - Zolmitriptan is a serotonin (5-HT) 1B/1D receptor agonist effective for the treatment of migraine. This analysis aimed to develop a population pharmacokinetic (PK) model for zolmitriptan and its active metabolite in adults and adolescents and provide appropriate dosing regimens to be used in clinical trials for children 6-11 years old. The data from a single-dose clinical study of 5.0-mg zolmitriptan nasal spray (ZNS) conducted in adult and adolescent patients with migraine between migraine attacks was applied. Similar plasma concentration profiles of zolmitriptan and its metabolite, 183C91, were observed in adults and adolescents. A 1-compartment model with first-order absorption and first-order elimination reasonably described the zolmitriptan PK. With a portion of elimination of zolmitriptan being treated as the conversion from zolmitriptan to 183C91, the disposition of 183C91 was described by a 1-compartment model with first-order elimination. The estimated typical apparent volume of distribution and clearance of zolmitriptan were 136 L and 121 L/h, respectively, with 56.5% and 42.6% between-subject variability, respectively. Based on the simulation results with the final population PK model, a body weight-based dosing scheme of 5.0 and 2.5 mg ZNS in children greater than and less than 50 kg is recommended to achieve exposures similar to those of the adult and adolescent population administered 5.0 mg ZNS. The recommended doses for children to achieve exposure similar to that observed in adults given 2.5 mg ZNS are 2.5 mg (>=50 kg) and 1.0 mg (15-50 kg). These dosing regimens could be used in future clinical trials. PMID- 28581632 TI - Aqueous Synthesis of Protein-Encapsulated ZnSe Quantum Dots and Physical Significance of Semiconductor-Induced CuII Ion Sensing. AB - In view of their promising bio-applicability, we have synthesized water-soluble bovine serum albumin (BSA)-encapsulated ZnSe quantum dots (QDs) with visible emission with longer average luminescence lifetimes of approximately 125 ns at ambient conditions. BSA-ZnSe QDs are shown to be efficient selective copper ion probes in the presence of physiologically important metal ions through luminescence quenching with a high Stern-Volmer constant (3.3*105 m-1 ). The mechanism of sensing has been explained in terms of electron transfer processes and the apparent rate of electron transfer (Ket ) from ZnSe QDs to Cu2+ has been calculated to be 2.8*108 s-1 . It is demonstrated that the negative conduction band potential plays a major role in the feasibility of the electron transfer process, which is reflected in the higher efficacy of ZnSe QDs in sensing copper(II) ions over other group II-VI quantum dots, namely, CdSe, ZnS, or CdS. The results observed with cysteine-capped QDs are almost identical to those with BSA-encapsulated QDs and this presumably negates the possible reason of CuII ion induced quenching ascribed to its binding with surface groups or replacement of metal sites as proposed by several groups previously. PMID- 28581634 TI - No one size fits all-Shortening duration of therapy with direct-acting antivirals for hepatitis C genotype 1 infection. AB - The advent of shorter duration, highly effective and well-tolerated interferon free therapy now provides an opportunity for virtually all HCV-infected individuals to be cured. However, there continues to be a need to simplify and shorten treatment duration. Shortening therapy to 8 weeks with sofosbuvir and ledipasvir can be considered in treatment patients with HCV genotype 1 infection and low baseline viral load. A number of other 8-week dual and triple therapy direct-acting antiviral (DAA) regimens are in advanced clinical development. Several small studies have further demonstrated the feasibility of 6 weeks of sofosbuvir therapy in combination with an NS5A inhibitor and a protease inhibitor for HCV genotype 1. Four weeks of therapy with various combinations of the currently available DAAs appears to be suboptimal with poor response rates observed in phase 2 trials. Response-guided therapy is another promising tool that may allow for shorter therapy but require further research. Shortening therapy and retreating relapsers may be a viable cost-saving measure, but requires further cost-benefit analysis and more data on the impact of resistance on retreatment options. PMID- 28581631 TI - Public Participation: Moving Beyond the Four Walls of Therapy. AB - Family therapists have an ethical responsibility for public participation, to work toward creating a better society. Serving the public interest and developing laws to promote the profession and the public good can be achieved through policy advocacy and political participation. Political and policy work are important but overlooked aspects of family therapy, which is significant given the consequences differing policies have for clients and the profession. This paper reports on results from a random, national survey of licensed family therapists' (N = 174) advocacy actions. Findings indicate family therapists have overarching policy concerns yet lack proactive legislative and activist engagement. The exploration of therapists' actions and beliefs presented in this paper, serves as a springboard for therapists' movement into the public arena. Video abstract accessible by clicking here. PMID- 28581637 TI - Switchable-hydrophilicity solvent-based microextraction combined with gas chromatography for the determination of nitroaromatic compounds in water samples. AB - A simple, fast, sensitive, and low-cost method was developed for the quantification of nitroaromatic compounds in water samples based on CO2 -assisted liquid-phase microextraction using a switchable-hydrophilicity solvent followed by gas chromatography detection. Dipropylamine was used as extraction solvent with switchable hydrophilicity that can be miscible or immiscible upon the addition or removal of CO2 as a reagent. Experimental parameters affecting the extraction efficiency such as the volume of acceptor phase, the volume of donor phase, pH of donor phase, ionic strength, and extraction time were investigated. Under the optimal conditions, detection limits and preconcentration factors were obtained in the ranges of 0.9-1.8 MUg/L and 132-138, respectively. Also, the extraction recoveries of water samples were above 88%. Finally, the developed method was successfully applied to the determination of nitroaromatic compounds in real water samples. PMID- 28581642 TI - Improving visual observation skills through the arts to aid radiographic interpretation in veterinary practice: A pilot study. AB - Radiographic interpretation is a perceptual and cognitive skill. Recently core veterinary radiology textbooks have focused on the cognitive (i.e., the clinical aspects of radiographic interpretation) rather than the features of visual observation that improve identification of abnormalities. As a result, the skill of visual observation is underemphasized and thus often underdeveloped by trainees. The study of the arts in medical education has been used to train and improve visual observation and empathy. The use of the arts to improve visual observation skills in Veterinary Science has not been previously described. Objectives of this pilot study were to adapt the existing Visual Arts in Health Education Program for medical and dental students at the University of Melbourne, Australia to third year Doctor of Veterinary Medicine students and evaluate their perceptions regarding the program's effects on visual observation skills and confidence with respect to radiographic interpretation. This adaptation took the form of a single seminar given to third year Doctor of Veterinary Medicine students. Following the seminar, students reported an improved approach to radiographic interpretation and felt they had gained skills which would assist them throughout their career. In the year following the seminar, written reports of the students who attended the seminar were compared with reports from a matched cohort of students who did not attend the seminar. This demonstrated increased identification of abnormalities and greater description of the abnormalities identified. Findings indicated that explicit training in visual observation may be a valuable adjunct to the radiology training of Doctor of Veterinary Medicine students. PMID- 28581635 TI - Targeted unlabeled multiple reaction monitoring analysis of cell markers for the study of sample heterogeneity in isolated rat brain cortical microvessels. AB - Liquid chromatography coupled to tandem mass spectrometry-based targeted absolute protein quantification (in fmol of the analyte protein per MUg of total protein) is employed for the molecular characterization of the blood-brain barrier using isolated brain microvessels. Nevertheless, the heterogeneity of the sample regarding the levels of different cells co-isolated within the microvessels and bovine serum albumin (BSA) contamination (from buffers) are not always evaluated. We developed an unlabeled targeted liquid chromatography coupled to tandem mass spectrometry method to survey the levels of endothelial cells (ECs), astrocytes, and pericytes, as well as BSA contaminant in rat cortical microvessels. Peptide peak identities were evaluated using a spectral library and chromatographic parameters. Sprague-Dawley rat microvessels obtained on three different days were analyzed with this method complemented by an absolute quantification multiple reaction monitoring method for transporter proteins P-gp, Bcrp, and Na+ /K+ ATPase pump using stable isotope labeled peptides as internal standard. Inter-day differences in the cell markers and BSA contamination were observed. Levels of cell markers correlated positively between each other. Then, the correlation between cell marker proteins and transporter proteins was evaluated to choose the best EC marker protein for protein quantification normalization. The membrane protein Pecam-1 showed a very high correlation with the EC-specific transporter P gp (Pearson product-moment correlation coefficient (r) > 0.89) and moderate to high with Bcrp (r >= 0.77), that can be found also in pericytes and astrocytes. Therefore, Pecam-1 was selected as a marker for the normalization of the quantification of the proteins of endothelial cells. PMID- 28581646 TI - Triangulation and Parent-Adolescent Relationships: Implications for Adolescent Dating Competence and Abuse. AB - This study focuses on family predictors of conflict behavior in adolescent dating relationships, drawing on family systems and socialization perspectives. Mother adolescent, father-adolescent, and triadic relationships each was examined as predictors of adolescent dating outcomes that hold importance for developmental and prevention science (positive conflict resolution, verbal abuse, and physical abuse). We conducted a longitudinal analysis using a 6-month longitudinal design with 236 ethnically diverse high school students. Findings indicate that triangulation into parental conflicts was related to increases in positive conflict resolution and with increases in verbally abusive behavior with dating partners over time. Parent-adolescent closeness and conflict each was related to positive conflict resolution and verbal abuse, but these associations were only found for boys. PMID- 28581645 TI - Effects of a Nutritional Protein-Rich Drink on the Pharmacokinetics of Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide, and Tenofovir Compared With a Standard Meal in Healthy Japanese Male Subjects. AB - This study investigated the effects of ingested meal types on the pharmacokinetics of elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), tenofovir alafenamide (TAF), and tenofovir (TFV) following a single administration of the single-tablet regimen (STR) of EVG/COBI/FTC/TAF (150/150/200/10 mg) in Japanese HIV-negative healthy subjects (n = 12). In this open-label, randomized, 3-way crossover study, the bioequivalence of the EVG/COBI/FTC/TAF STR following ingestion of a nutritional protein-rich drink with a reference treatment of taking a standard breakfast was evaluated. Administration under fasted conditions, no food intake, resulted in decreases in the mean AUCinf and Cmax of EVG by 50% and 57%, respectively, relative to the administration with a standard breakfast, whereas the systemic exposure of EVG with a nutritional protein-rich drink was comparable to that with a standard breakfast. The mean AUCinf and Cmax of COBI, FTC, TAF, and TFV were comparable regardless of meal intake or meal types. Although the package insert of the EVG/COBI/FTC/TAF STR states that the medication is recommended to be taken with food, this study provides an additional insight into HIV-1-infected patients that a light meal like a nutritional protein-rich drink can be an alternative to a standard meal. PMID- 28581638 TI - Racial/ethnic disparities in the prevalence and awareness of Hepatitis B virus infection and immunity in the United States. AB - Hepatitis B virus (HBV) infection in the United States is the most common among Asians followed by non-Hispanic blacks. However, there have been few studies that describe HBV infection and immunity by racial group. Our study aimed to assess racial/ethnic disparities in the prevalence and awareness of HBV infection and immunity using nationally representative data. In the National Health and Nutrition Examination Survey 2011-2014, 14 722 persons had HBV serology testing. We estimated the prevalence of HBV infection, past exposure, and immunity by selected characteristics and calculated adjusted odds ratios using survey weighted generalized logistic regression. Awareness of infection and vaccination history was also investigated. The overall prevalence of chronic HBV infection, past exposure and vaccine-induced immunity was 0.34% [95%CI 0.24-0.43], 4.30% [95%CI 3.80-4.81], and 24.4% [95%CI 23.4-25.4], respectively. The prevalence of chronic infection was 2.74% [95% CI 1.72-3.76] in Asians, 0.64% [95% CI 0.35 0.92] in non-Hispanic blacks, and 0.15% [95% CI 0.06-0.24] in non-Asian, non blacks. Only 26.2% of those with chronic infection were aware of their infection. The prevalence of the past exposure was 21.5% [95%CI 19.3-23.7] in Asians, 8.92% [95%CI 7.84-9.99] in non-Hispanic blacks, 2.05% [95%CI 1.49-2.63] in non-Hispanic whites and 4.47% [95%CI 3.25-5.70] in Hispanics. Prevalence of vaccine-induced immunity by each race was 34.1% [95%CI: 32.0-36.2] in Asians, 25.5% [95%CI: 24.0 27.0] in non-Hispanic blacks, 24.0% [95%CI: 22.6-25.4] in non-Hispanic whites and 22.2% [95%CI: 21.3-23.3] in Hispanics. There are considerable racial/ethnic disparities in HBV infection, exposure and immunity. More active and sophisticated healthcare policies on HBV management may be warranted. PMID- 28581644 TI - Hepatitis B surface antigen loss and sustained viral suppression in Asian chronic hepatitis B patients: A community-based real-world study. AB - Community-based real-world outcomes on effectiveness of antiviral therapies for chronic hepatitis B virus (CHB) in Asians are limited. Whether hepatitis B surface antigen (HBsAg) loss correlates with undetectable virus and alanine aminotransferase (ALT) normalization on treatment or what predicts risk of seroreversion or detectable virus after stopping therapy is unclear. We aim to evaluate rates and predictors of HBsAg loss, seroconversion, ALT normalization and undetectable HBV DNA, including HBsAg seroreversion or re-emergence of HBV DNA among Asian CHB patients. We retrospectively evaluated 1072 CHB adults on antiviral therapy at two community gastroenterology clinics from 1997 to 2015. Rates of HBsAg loss, ALT normalization, achieving undetectable HBV DNA and developing surface antibody (anti-HBs) were stratified by HBeAg status. Following HBsAg loss, HBsAg seroreversion or re-emergence of detectable HBV DNA was analysed. With median treatment of 76.7 months, the overall rate of HBsAg loss was 4.58%, with similar HBsAg loss rates between HBeAg-positive and HBeAg negative patients (4.44% vs 4.71%, P=.85) in a predominantly Asian population (98.1%). Among HBsAg loss patients, 33.3% developed anti-HBs, 95.8% achieved undetectable virus and 66.0% normalized ALT. No significant baseline or on treatment predictors of HBsAg loss were observed. While six patients who achieved HBsAg loss had seroreversion with re-emergence of HBsAg positivity, viral load remained undetectable, demonstrating the sustainability of viral suppression. Among a large community-based real-world cohort of Asian CHB patients treated with antiviral therapy, rate of HBsAg loss was 4.58%. Despite only 33.3% of HBsAg loss patients achieving anti-HBs, nearly all patients achieved sustained undetectable virus. PMID- 28581647 TI - The Socioeconomic Pathways Leading to Romantic Relationship Outcomes: A Genetically Informed Early Life Course Investigation. AB - The present study tests a multilevel comprehensive model incorporating both life course processes and genetic influences leading to young adults' romantic relationship quality using data from 1,560 adolescents over 13 years in the nationally representative Add Health sample. Results provided evidence of a socioeconomic mediating pathway linking early family and community contexts to young adults' romantic relationship quality, and novel evidence for both direct and interactive genetic associations that relate to these mediating pathways. A cumulative genetic index showed (a) direct associations with young adults' socioeconomic attainment and (b) interactions with community adversity and mothers' marital stability on young adults' achieved socioeconomic context and relationship quality. PMID- 28581639 TI - Traceless Cleavage of Protein-Biotin Conjugates under Biologically Compatible Conditions. AB - Biotinylation of amines is widely used to conjugate biomolecules, but either the resulting label is non-removable or its removal leaves a tag on the molecule of interest, thus affecting downstream processes. We present here a set of reagents (RevAmines) that allow traceless, reversible biotinylation under biologically compatible, mild conditions. Release following avidin-based capture is achieved through the cleavage of a (2-(alkylsulfonyl)ethyl) carbamate linker under mild conditions (200 mm ammonium bicarbonate, pH 8, 16-24 h, room temperature) that regenerates the unmodified amine. The capture and release of biotinylated proteins and peptides from neutravidin, fluorescent labelling through reversible biotinylation at the cell surface and the selective enrichment of proteins from bacterial periplasm are demonstrated. The tags are easily prepared, stable and offer the potential for future application in proteomics, activity-based protein profiling, affinity chromatography and bio-molecule tagging and purification. PMID- 28581649 TI - Beyond Collective Supervision: Informal Social Control, Prosocial Investment, and Juvenile Offending in Urban Neighborhoods. AB - This article examines prosocial investment and supervision of youth as separate indicators of informal social control. Data from 599 survey respondents in 90 Indianapolis, IN, block groups indicate that, at the neighborhood level, the relationship between these two variables and delinquency during early and middle adolescence varies by severity of offense. Specifically, negative binomial models reveal an inverse relationship between supervision and both status offenses and misdemeanors, but the relationship with misdemeanors is stronger in areas with higher levels of prosocial investment. In contrast, prosocial investment has an inverse association with felony charges. Overall, these results call for future quantitative scholarship that contextualizes neighborhood-level supervision and that is attentive to neighborhood support and empowerment assets in models of urban adolescent delinquency. PMID- 28581641 TI - Clk1-regulated aerobic glycolysis is involved in glioma chemoresistance. AB - Chemoresistance remains a major challenge for the treatment of glioma. In this study, we investigated the role of Clock 1 (Clk1), which encodes an enzyme that is necessary for ubiquinone biosynthesis in glioma chemoresistance in vitro. The results showed that Clk1 was highly expressed in GL261 mouse glioma cells which were most sensitive to 1,3Bis (2-chloroethyl) 1 nitrosourea (BCNU) while was low expressed in BCNU resistant cells such as glioma cancer stem cells, T98G, U87MG and U251 glioma cells. Knockdown of Clk1 in GL261 glioma cells significantly reduced BCNU- or cisplatin-induced cell apoptosis, whereas the proliferative activity and the expression of multidrug resistance-related genes including MDR1, O6-methylguanine-DNA methyltransferase, and GSTP1 were not changed. When Clk1 was re-expressed in Clk1 knockdown GL261 glioma cells, the BCNU sensitivity was restored. The mechanistic study revealed that knockdown of Clk1 in GL261 glioma cells increased aerobic glycolysis including high glucose consumption, lactate production, and up-regulation of glycolysis-associated genes. Inhibition of glycolysis can reverse the chemoresistance elicited by Clk1 knockdown in GL261 cells. Moreover, knockdown of Clk1 induced HIF-1alpha expression in GL261 glioma cells which was found to be mediated by AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling pathway. Both metformin and rapamycin reversed the chemoresistance of Clk1 knockdown GL261 glioma cells. Over-expression of Clk1 significantly increased the sensitivity of T98G or U251 human glioblastoma cells to BCNU which was accompanied by decreased lactate secretion, decreased expression of HIF-1alpha, AMPK activation, and inhibition of mTOR pathway. Inhibition of glycolysis or activation of AMPK did not alter Clk1 expression in variant glioma cell lines suggesting that aerobic glycolysis is not an upstream event of Clk1 expression in glioma cells. Taken together, our results revealed, for the first time, that mitochondrial Clk1 regulated chemoresistance in glioma cells through AMPK/mTOR/HIF-1alpha mediated glycolysis pathway. PMID- 28581648 TI - Suicide Ideation and Attempts Among Adolescents Engaged in Risk Behaviors: A Latent Class Analysis. AB - This study addressed gaps in the literature regarding how different profiles of adolescent risk behavior relate to suicide. Data came from the 2010 Minnesota Student Survey of 9th and 12th grade students. Latent class analysis derived a set of four classes reflecting unique patterns of eight behaviors: maladaptive dieting, prescription drug misuse, illegal drug use, marijuana use, problem drinking, risky sexual behavior, perpetration of interpersonal violence, and self injury. A class demonstrating high engagement in all risk behaviors, and a class highest on self-injury and maladaptive dieting but low on several other risk behaviors, showed high risk for suicide. Practitioners should carefully monitor adolescents engaging in multiple risk behaviors for suicide, especially if self injury and maladaptive dieting are present. PMID- 28581651 TI - Configurations of Adolescents' Peer Experiences: Associations With Parent-Child Relationship Quality and Parental Problem Behavior. AB - Adolescents' peer experiences embrace behavior, relationship quality, status, and victimization, but studies that account for multiple dimensions are rare. Using latent profile modeling and measures of peer behavior, relationship quality, peer status, and victimization assessed from 1,677 adolescents, four profiles were identified: High Quality, Low Quality, Low Quality Victimized, and Deviant Peers. Multinomial logistic regressions showed that negative parent-child relationships in preadolescence reduced the likelihood of High Quality peer relations in mid adolescence but only partly differentiated between the other three profiles. Moderation by gender was partly found with girls showing greater sensitivity to parent-child relationship quality with respect to peer experiences. Results underline the multifaceted nature of peer experiences, and practical and theoretical implications are discussed. PMID- 28581653 TI - Early Childhood Maltreatment and Pubertal Development: Replication in a Population-Based Sample. AB - Early experiences are critically important for female reproductive development. Although a number of early childhood hardships predict earlier physical development in girls, research on specific populations suggests a distinct effect of childhood sexual abuse compared to other adversities. This study leverages the National Longitudinal Study of Adolescent Health (N = 6,273 girls) to test the generalizability of these findings, examining associations of early physical abuse, sexual abuse, and physical neglect with pubertal timing. Child sexual abuse predicted earlier menarche and development of secondary sexual characteristics, whereas other types of maltreatment did not. In addition to replicating results from smaller, more specialized samples, these findings reinforce the value of considering puberty within a broader "life span" continuum of birth to adolescence. PMID- 28581643 TI - Regioselective synthesis, biological evaluation, and molecular docking of dihydropyrimidin-4-ols as acetylcholinesterase inhibitors. AB - A new series of 3,6-disubstituted 2-(methylthio)-4-(trifluoromethyl)-3,4 dihydropyrimidin-4-ols displaying methyl, phenyl, aryl, and heteroaryl groups at the 6-position; and methyl, ethyl, allyl, and phenyl groups at the 3-position of the dihydropyrimidine ring, were synthesized and evaluated in vitro for acetylcholinesterase inhibitory activity. Seven compounds showed activity with IC50 values in the lower micromolar range. The compound 4-trifluoromethyl-6-(4 fluorophenyl)-3-methyl-2-methylthio-3,4-dihydropyrimidin-4-ol (6e) had the best inhibitory activity (IC50 2.2 +/- 0.9 MUm) and this inhibition was characterized as competitive. The molecular docking study showed that the acetylcholinesterase enzyme accommodates compound 6e in its catalytic site. The enantiomers of compound 6e, present similar interactions: pi-pi stacking interactions between the aromatic ring of the ligand's 4-fluorophenyl moiety and the aromatic rings of the electron-rich Trp84; and H-bonds between the hydroxyl group of Tyr121 and the hydroxyl moiety from 6e. The antioxidant effect of the dihydropyrimidin-4-ols was also investigated. PMID- 28581636 TI - Influence of endophytic root bacteria on the growth, cadmium tolerance and uptake of switchgrass (Panicum virgatum L.). AB - AIMS: This study aimed to evaluate the effect of five cadmium-tolerant endophytic plant growth-promoting bacteria (PGPB) strains on the biomass and cadmium tolerance, and accumulation of the bioenergy plant switchgrass (Panicum virgatum L.) under cadmium (Cd)-contaminated conditions. METHODS AND RESULTS: Five bacterial strains (Bj05, Le14, Ps14, So02 and Bo03) that could tolerate up to 2000 MUmol l-1 CdCl2 with a high Cd-binding capacity were isolated from plants grown in Cd-contaminated soil. These strains could promote the growth of switchgrass in the presence of 20 MUmol l-1 CdCl2 . Under Cd stress, both the root and shoot length and biomass in two switchgrass cultivars, Alamo and Cave-in Rock (CIR), increased significantly after treatment with PGPB (P ? 0.05). Of the five PGPB strains, Bj05 and Le14 most effectively alleviated the Cd-induced growth inhibition of Alamo plants. Interestingly, the five PGPB strains increased Cd tolerance and decreased the accumulation and translocation factor (TF) of Cd in switchgrass when grown in the presence of 20 MUmol l-1 CdCl2 . The Cd concentrations in roots and shoots of Alamo and CIR plants were significantly reduced (P ? 0.05) compared with noninoculated plants. By 16S rRNA sequencing, these PGPB strains were classified as Pseudomonas putida Bj05, Pseudomonas fluorescens Ps14, and Enterobacter spp. Le14, So02 and Bo03. CONCLUSION: Inoculation with PGPB protects plants from the inhibitory effects of Cd, improves plant growth and decreases Cd concentration. These observations suggest that these strains could be used to promote growth and lower the bioavailability of Cd in switchgrass. SIGNIFICANCE AND IMPACT OF THE STUDY: These strains are potential candidates for the development of low Cd-accumulating switchgrass, particularly in areas of Cd contamination and pollution, and could be used efficiently for the bioremediation of contaminated soil. PMID- 28581652 TI - Adolescent Personality as Risk and Resiliency in the Testosterone-Externalizing Association. AB - Previous investigations of testosterone and externalizing behavior have provided mixed findings. We tested the hypothesis that self-regulatory personality moderates the testosterone-externalizing behavior association in adolescence. Parents reported on their 13- to 18-year-old (N = 106, Mage = 16.01, SD = 1.29) children's personalities and psychopathology. Testosterone was measured via drool samples. As hypothesized, personality moderated the testosterone-externalizing behavior association. High testosterone predicted higher levels of externalizing behaviors, but only for adolescents low in Agreeableness and Conscientiousness. Also, personality acted as a resiliency factor: high levels of Conscientiousness, in the presence of high testosterone, predicted lower levels of rule breaking. Results highlight how endogenous factors, such as personality, may interact with testosterone, and emphasize the relevance of including personality moderators in future research. PMID- 28581654 TI - Daily Dynamics of Adolescent Mood and Identity. AB - Important linkages between daily mood and identity formation have been theorized, but have not been empirically tested as of yet. This study provided a first examination of these linkages within individuals (N = 392; 55.1% boys; Mage at T1 = 13.24, SD = 0.44) across 15 series of 5 days distributed over 5 years. Results revealed negative within-time associations of educational and relational commitment with negative mood. Negative mood was positively associated with educational in-depth exploration and educational and interpersonal reconsideration. Additionally, there were some cross-lagged effects suggesting that identity and mood mutually affect one another across days. These results contribute to the growing knowledge on how identity unfolds in everyday life by revealing important associations with daily mood. PMID- 28581658 TI - Maternal Regulation of Daughters' Emotion During Conflicts From Early to Mid Adolescence. AB - Primary caregivers play an important role in emotion socialization. Real-time mother-daughter emotion socialization was examined in 45 mother-daughter dyads with early-adolescent daughters (age M = 11.80, SD = .27) at the first observation point. Maternal supportive emotion regulation and daughters' emotions were coded during two conflict discussions, 2 years apart. With multilevel survival analysis, the likelihood of maternal supportiveness was predicted both over time, between early and mid-adolescence, and by daughters' pubertal status. Mothers were more likely to respond to daughters' negative and positive emotions with supportiveness for daughters whose pubertal maturation occurred relatively early. Results suggest that mothers adjust their socialization of daughters' emotions according to their daughters' pubertal development. PMID- 28581659 TI - "Snooping" as a Distinct Parental Monitoring Strategy: Comparisons With Overt Solicitation and Control. AB - Parents can use solicitation (asking questions) and control (disclosure rules) to obtain information about adolescents, but only if youths comply. Snooping might uncover additional information, but also strongly violates privacy expectations. Three studies of parents and adolescents examined distinctions between snooping, solicitation, and control. Differences existed in terms of factor structure and frequency (Studies 1-2), links to perceived invasion (Study 1), correlations with problematic communication, behavior, and relationships (Study 2), and parent adolescent (dis)agreement about acceptability (Study 3). Snooping is a relatively infrequent monitoring behavior, compared to solicitation and control, but appears to be a stronger indicator of problems in adolescent and family functioning. We discuss implications regarding the necessity and appropriateness of particular parental monitoring behaviors. PMID- 28581657 TI - When Parents and Adolescents Disagree About Disagreeing: Observed Parent Adolescent Communication Predicts Informant Discrepancies About Conflict. AB - Adolescence is accompanied by increased stress in the parent-adolescent relationship, which frequently results in conflict. Researchers often rely on self-reports to measure conflict, but these reports are frequently discrepant from one another. In two studies, we examined the extent to which communication observed during parent-adolescent discussions of conflict were associated with discrepancies in reports about conflict. We also examined links between informant depressive symptoms and discrepancies. Across studies, observed parent-adolescent conflict behaviors consistently predicted absolute discrepancies in reports of conflict. Informant depressive symptoms sometimes predicted directional discrepancies in reports. Results suggest that informant discrepancies about conflict may stem, in part, from a lack of open communication in the relationship. PMID- 28581656 TI - Sexual Behaviors in Mexico: The Role of Values and Gender Across Adolescence. AB - Adolescent sexuality research has expanded to include noncoital behaviors, but there is limited knowledge about individual factors such as cultural values associated with these sexual behaviors outside of industrialized nations. Thus, we examined associations between Latino values (familism, sexual guilt, and importance of female virginity) and three sexual behaviors (making out, oral sex, and vaginal sex), among adolescents ages 12-19 (53% female) in Mexico. Findings indicate that sexual guilt and importance of female virginity were consistently associated with all sexual behaviors. Some associations differed by gender and school level. For instance, sexual guilt was a better predictor of high school girls' oral and vaginal sex. This study expands our understanding of adolescent sexuality in Mexico. PMID- 28581655 TI - Retracted: Multilevel Predictors of Math Classroom Climate: A Comparison Study of Student and Teacher Perceptions. AB - The above article, published online on June 23, 2014 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Nancy Guerra, and Wiley Periodicals, Inc. The retraction has been agreed upon following the discovery that this article contained inaccurate data. It came to the author's attention that the names of some of the items reported in the Measures section of the paper could not be correct because such items did not exist in the surveys. The authors tried to identify exactly which items had been used in the data analyses but they could not establish without some doubt exactly which items had actually been used. Reference Wang, M.-T. and Eccles, J. S. (2014), Multilevel Predictors of Math Classroom Climate: A Comparison Study of Student and Teacher Perceptions. Journal of Research on Adolescence. doi: 10.1111/jora.12153. PMID- 28581661 TI - Sources and Implications of Maternal Accuracy About Young Adolescents' Vulnerability to Friendship Jealousy. AB - To assist effectively with social difficulties, parents must accurately understand the peer situations that are difficult for their child. Mothers' insight into their young adolescent's vulnerability to friendship jealousy was assessed by posing identical vignettes to 72 young adolescents and their mothers and matching their responses. Mothers and children also completed questionnaires on their relationship and the child's adjustment. Mothers as a group were poor judges of their child's jealousy, but considerable variability existed. Accuracy was greater when mother-child pairs were closer. Polynomial regression and response surface analyses indicated that maternal accuracy could dampen the friendship and aggression risks otherwise associated with being vulnerable to jealousy. PMID- 28581660 TI - Measurement of Dating Aggression During Middle School: Structure, Measurement Invariance, and Distinction From General Aggression. AB - Two studies examined the factor structure of a modified version of the Safe Dates dating aggression scale and evaluated whether dating aggression is distinct from general aggression during early adolescence. Analyses were conducted on a derivation sample of 3,894 adolescents from 37 schools (Study 1) and an independent cross-validation sample of 938 middle school youth (Study 2). Categorical confirmatory factor analyses supported a two-factor model (perpetration and victimization) over models differentiating psychological and physical forms of aggression. The model was invariant across time, sex, grade, and season. Study 2 also supported dating aggression as distinct from general aggression. Results supported measuring dating aggression perpetration and victimization as latent constructs represented by ordered categorical indicators that capture item severity and frequency. PMID- 28581670 TI - Interactive effects of predator and prey harvest on ecological resilience of rocky reefs. AB - A major goal of ecosystem-based fisheries management is to prevent fishery induced shifts in community states. This requires an understanding of ecological resilience: the ability of an ecosystem to return to the same state following a perturbation, which can strongly depend on species interactions across trophic levels. We use a structured model of a temperate rocky reef to explore how multi trophic level fisheries impact ecological resilience. Increasing fishing mortality of prey (urchins) has a minor effect on equilibrium biomass of kelp, urchins, and spiny lobster predators, but increases resilience by reducing the range of predator harvest rates at which alternative stable states are possible. Size-structured predation on urchins acts as the feedback maintaining each state. Our results demonstrate that the resilience of ecosystems strongly depends on the interactive effects of predator and prey harvest in multi-trophic level fisheries, which are common in marine ecosystems but are unaccounted for by traditional management. PMID- 28581672 TI - Preliminary investigations into developing all-D Omiganan for treating Mupirocin resistant MRSA skin infections. AB - Staphylococcus aureus is the primary pathogen responsible for the majority of human skin infections, and meticillin-resistant S. aureus (MRSA) currently presents a major clinical concern. The overuse of Mupirocin, the first-line topical antibacterial drug over 30 years, has led to the emergence of Mupirocin resistant MRSA, creating a clinical concern. The antimicrobial peptide Omiganan was touted to be a promising antibacterial drug candidate due to its rapid membrane-disrupting bactericidal mode of action, entering clinical trials in 2005 as a topical gel to prevent catheter site infections. However, drug development ceased in 2009 due to a lack of efficacy. We postulate this to be due to proteolytic degradation caused by endogenous human skin proteases. Herein, we tested our hypothesis using Omiganan and its all-D enantiomer in a human skin protease stability assay, followed by anti-MRSA activity assay against of a panel of clinical MRSA isolates, a bactericidal/static determination and a time-kill assay to gauge all-D Omiganan's potential for further topical antibacterial drug development. PMID- 28581671 TI - Digital image analysis supports a nuclear-to-cytoplasmic ratio cutoff value of 0.5 for atypical urothelial cells. AB - BACKGROUND: An elevated nuclear-to-cytoplasmic (N:C) ratio of >=0.5 is a required criterion for the diagnosis of atypical urothelial cells (AUC) in The Paris System for Reporting Urinary Cytology. METHODS: To validate the N:C ratio cutoff value and its predictive power for high-grade urothelial carcinoma (HGUC), the authors retrospectively reviewed the urinary tract cytology specimens of 15 cases of AUC with HGUC on follow-up (AUC-HGUC) and 33 cases of AUC without HGUC on follow-up (AUC-N-HGUC). The number of atypical cells in each case was recorded, and each atypical cell was photographed and digitally examined to calculate the nuclear size and N:C ratio. RESULTS: On average, the maximum N:C ratios of atypical cells were significantly different between the AUC-HGUC and AUC-N-HGUC cohorts (0.53 vs 0.43; P =.00009), whereas the maximum nuclear sizes of atypical cells (153.43 MUM2 vs 201.47 MUM2 ; P = .69) and the number of atypical cells per case (10.13 vs 7.88; P = .12) were not found to be significantly different. Receiver operating characteristic analysis demonstrated that the maximum N:C ratio alone had high discriminatory capacity (area under the curve, 79.19%; 95% confidence interval, 64.19%-94.19%). The optimal maximum N:C ratio threshold was 0.486, giving a sensitivity of 73.3% and a specificity of 84.8% for predicting HGUC on follow-up. CONCLUSIONS: The identification of AUC with an N:C ratio >0.486 has a high predictive power for HGUC on follow-up in AUC specimens. This justifies using the N:C ratio as a required criterion for the AUC category. Individual laboratories using different cytopreparation methods may require independent validation of the N:C ratio cutoff value. Cancer Cytopathol 2017;125:710-6. (c) 2017 American Cancer Society. PMID- 28581673 TI - The role of thyroid FNA cytology in pediatric malignant lesions: An overview of the literature. AB - When one is dealing with pediatric thyroid lesions, fine-needle aspiration is the first diagnostic tool for the correct characterization of these nodules. Despite the apparent infrequency of thyroid cancers in children, recent data from the National Cancer Institute prove that the incidence has been increasing, especially in adolescents. With the same data, a higher prevalence of well differentiated cancers can be estimated, with 90% diagnosed as papillary thyroid cancer. Nonetheless, some publications have demonstrated that some specific malignant variants are more frequent in children and have a more aggressive behavior that justifies the increased number of surgical procedures. For this reason, the American Thyroid Association recommends the performance of neck ultrasonography and fine-needle aspiration cytology (FNAC) for the evaluation of pediatric thyroid nodules. Accordingly, as reported in adult thyroid series, several authors have documented the high sensitivity and diagnostic accuracy of FNAC in pediatric series; they have also shared the same problematic issues encountered in adult populations, mostly in the diagnosis of indeterminate lesions. To provide precise clinical and/or surgical management, the correct cytological identification of specific malignant histotypes/entities should be mandatory because lymph nodes, distant metastases, and extrathyroidal infiltration are more frequent within specific histotypes. A perusal of the literature shows that their identification has not been extensively studied and investigated in cytological samples. This review focuses on the analysis of data from the literature on the evaluation of malignancies and specific morphological features in pediatric thyroid lesions. Cancer Cytopathol 2017;125:594-603. (c) 2017 American Cancer Society. PMID- 28581674 TI - Radial oxygen loss by the cushion plant Eriocaulon schimperi prevents methane emissions from an East-African mountain mire. AB - Groundwater-fed fens are known sources of methane (CH4 ) emissions to the atmosphere, and these are known to be mediated by the vegetation. In a fen located in the Bale Mountains, Ethiopia, we assessed the effects of a cushion plant (Eriocaulon schimperi) and a sedge (Carex monostachya) on rhizosphere biogeochemistry. Methane and CO2 concentrations and pH were measured in pore water at different depths in the profile. Redox potentials and NaCl-extractable element concentrations were analysed in soil samples from sites dominated by either E. schimperii or C. monostachya. Nutrient and element concentration were analysed in plant tissues. At Carex-dominated sites, CH4 concentrations increased from 70 MUmol.l-1 at a depth of 10 cm to 130 MUmol.l-1 at a depth of 100 cm. CH4 concentrations at Eriocaulon-dominated sites were almost zero (<1 MUmol.l-1 ) to a depth of 100 cm. Simultaneously, soil redox potentials and CO2 concentrations were higher at Eriocaulon-dominated sites, indicating a low potential for CH4 production and a high potential for CH4 oxidation. Eriocaulon schimperi displayed a root investment strategy to cope with the harsh environment, similar to the cushion plant Astelia pumila in Patagonian bogs. This strategy is characterised by high root/shoot ratios, high root porosity and density under high redox conditions. Both cushion plant species create an aerobic rhizosphere through radial oxygen loss from deep roots, which strongly reduce CH4 fluxes to the atmosphere. PMID- 28581675 TI - Concurrent chemotherapy is associated with improved survival in elderly patients with bladder cancer undergoing radiotherapy. AB - BACKGROUND: The current study was conducted to compare the overall survival (OS) of concurrent chemoradiotherapy (CCRT) versus radiotherapy (RT) alone in elderly patients (those aged >=80 years) with muscle-invasive bladder cancer (MIBC). METHODS: Patients aged >=80 years with cT2-4, N0-3, M0 transitional cell MIBC who were treated with curative RT (60-70 Gray) or CCRT were identified in the National Cancer Data Base. Univariable and multivariable frailty survival analyses, as well as 1-to-1 propensity score matching, were used to isolate the association between CCRT and OS. RESULTS: A total of 1369 patients who were treated with RT from 2004 through 2013 met eligibility criteria: 739 patients (54%) received RT alone and 630 patients (46%) received CCRT. The median age of the patients was 84 years (range, 80-90 years). The median follow-up was 21 months. The 2-year OS rate was 48%. When comparing CCRT with RT alone, the 2-year OS rate was 56% versus 42% (P<.0001), respectively. Multivariable analysis demonstrated that CCRT (hazard ratio [HR], 0.74; 95% confidence interval [95% CI], 0.65-0.84 [P<.0001]) and a higher RT dose (HR, 0.78; 95% CI, 0.67-0.90 [P<.001]) were associated with improved OS. T4 disease was associated with worse OS (HR, 1.42; 95% CI, 1.15-1.76 [P = .001]). After using 1-to-1 propensity score matching, there remained an OS benefit for the use of CCRT (HR, 0.77; 95% CI, 0.67-0.90 [P<.001]). CONCLUSIONS: CCRT is associated with improved OS compared with the use of RT alone in elderly patients with MIBC, independent of Charlson Deyo comorbidity score, suggesting that CCRT should be used in this population. Cancer 2017;123:3524-31. (c) 2017 American Cancer Society. PMID- 28581677 TI - Interplay of volume, blood pressure, organ ischemia, residual renal function, and diet: certainties and uncertainties with dialytic management. AB - Extracellular fluid volume overload and its inevitable consequence, hypertension, increases cardiovascular mortality in the long term by leading to left ventricular hypertrophy, heart failure, and ischemic heart disease in dialysis patients. Unlike antihypertensive medications, a strict volume control strategy provides optimal blood pressure control without need for antihypertensive drugs. However, utilization of this strategy has remained limited because of several factors, including the absence of a gold standard method to assess volume status, difficulties in reducing extracellular fluid volume, and safety concerns associated with reduction of extracellular volume. These include intradialytic hypotension; ischemia of heart, brain, and gut; loss of residual renal function; and vascular access thrombosis. Comprehensibly, physicians are hesitant to follow strict volume control policy because of these safety concerns. Current data, however, suggest that a high ultrafiltration rate rather than the reduction in excess volume is related to these complications. Restriction of dietary salt intake, increased frequency, and/or duration of hemodialysis sessions or addition of temporary extra sessions during the process of gradually reducing postdialysis body weight in conventional hemodialysis and discontinuation of antihypertensive medications may prevent these complications. We believe that even if an unwanted effect occurs while gradually reaching euvolemia, this is likely to be counterbalanced by favorable cardiovascular outcomes such as regression of left ventricular hypertrophy, prevention of heart failure, and, ultimately, cardiovascular mortality as a result of the eventual achievement of normal extracellular fluid volume and blood pressure over the long term. PMID- 28581676 TI - Comprehensive genomic profiling of different subtypes of nasopharyngeal carcinoma reveals similarities and differences to guide targeted therapy. AB - BACKGROUND: To date, no targeted therapy has been approved for nasopharyngeal carcinoma (NPC), and this underscores the need for an in-depth understanding of clinically relevant genomic alterations (CRGAs). METHODS: Comprehensive genomic profiling was performed for 190 NPC patients, including 20 patients with nasopharyngeal adenocarcinoma (NPAC), 62 patients with nasopharyngeal squamous cell carcinoma (NPSCC), and 108 patients with nasopharyngeal undifferentiated carcinoma (NPUC). The associations of genes and pathways with subtypes, Epstein Barr virus (EBV) infections, and the tumor mutation burden (TMB) were statistically evaluated. RESULTS: Although the overall rates of genomic alterations were similar, the 3 NPC subtypes exhibited different mutational landscapes. Notably, mutations in a proven-treatable target gene, isocitrate dehydrogenase 2 (IDH2), were significantly associated with NPUC but not with NPAC or NPSCC. The top 5 ranked CRGAs included CDKN2A (29%), IDH2 (16%), SMARCB1 (7%), PIK3CA (6%), and NF1 (5%) in NPUC; CDKN2A (27%), PIK3CA (23%), FBXW7 (11%), PTEN (11%), and EGFR (8%) in NPSCC; and CDKN2A (20%), KRAS (15%), CCND1 (10%), MAP3K1 (10%), and NOTCH1 (10%) in NPAC. The incidence of EBV infections significantly correlated with the subtypes and with TP53, CDKN2A, and CDKN2B. The TMB status correlated with the subtypes and with LRP1B, FBXW7, and PIK3CA mutations as well as DNA repair, phosphoinositide 3-kinase/mammalian target of rapamycin, and mitogen-activated protein kinase pathways. CONCLUSIONS: These results indicate that different NPC subtypes harbor different CRGAs. Both EBV infections and the TMB are associated with the NPC subtypes as well as the alterations of individual genes and pathways. The high frequency of IDH2 mutations in NPUC may facilitate potential targeted therapy and will ultimately point to new therapeutic strategies. Cancer 2017;123:3628-37. (c) 2017 American Cancer Society. PMID- 28581678 TI - TTN genotype is associated with fascicle length and marathon running performance. AB - Titin provides a molecular blueprint for muscle sarcomere assembly, and sarcomere length can vary according to titin isoform expression. If variations in sarcomere length influence muscle fascicle length, this may provide an advantage for running performance. Thus, the aim of this study was to investigate whether the titin (TTN) rs10497520 polymorphism was associated with muscle fascicle length in recreationally active men (RA; n=137) and marathon personal best time in male marathon runners (MR; n=141). Fascicle length of the vastus lateralis was assessed in vivo using B-mode ultrasonography at 50% of muscle length in RA. All participants provided either a whole blood, saliva or buccal cell sample, from which DNA was isolated and genotyped using real-time polymerase chain reaction. Vastus lateralis fascicle length was 10.4% longer in CC homozygotes, those carrying two copies of the C-allele, than CT heterozygotes (P=.003) in RA. In the absence of any TT homozygotes, reflective of the low T-allele frequency within Caucasian populations, it is unclear whether fascicle length for this group would have been smaller still. No differences in genotype frequency between the RA and MR groups were observed (P=.500), although within the MR group, the T-allele carriers demonstrated marathon personal best times 2 minutes 25 seconds faster than CC homozygotes (P=.020). These results suggest that the T-allele at rs10497520 in the TTN gene is associated with shorter skeletal muscle fascicle length and conveys an advantage for marathon running performance in habitually trained men. PMID- 28581679 TI - A simple, selective, and sensitive gas chromatography-mass spectrometry method for the analysis of five process-related impurities in atenolol bulk drug and capsule formulations. AB - An extremely sensitive and simple gas chromatography with mass spectrometry method was developed and completely validated for the analysis of five process related impurities, viz., 4-hydroxy-l-phenylglycine, 4-hydroxyphenylacetonitrile, 4-hydroxyphenylacetic acid, methyl-4-hydroxyphenylacetate, and 2-[4-{(2RS)-2 hydroxy-3-[(1-methylethyl)amino]propoxy}phenyl]acetonitrile, in atenolol. The separation of impurities was accomplished on a BPX-5 column with dimensions of 50 m * 0.25 mm i.d. and 0.25 MUm film thickness. The method validation was performed following International Conference on Harmonisation guidelines in which the method was capable to quantitate 4-hydroxy-l-phenylglycine, 4 hydroxyphenylacetonitrile, and 4-hydroxyphenylacetic acid at 0.3 ppm, and methyl 4-hydroxyphenylacetate and 2-[4-{(2RS)-2-hydroxy-3-[(1 methylethyl)amino]propoxy}phenyl]acetonitrile at 0.35 ppm with respect to 10 mg/mL of atenolol. The method was linear over the concentration range of 0.3-10 ppm for 4-hydroxy-l-phenylglycine, 4-hydroxyphenylacetonitrile, and 4 hydroxyphenylacetic acid, and 0.35-10 ppm for methyl-4-hydroxyphenylacetate and 2 [4-{(2RS)-2-hydroxy-3-[(1-methylethyl)amino]propoxy}phenyl]acetonitrile. The correlation coefficient in each case was found >=0.998. The repeatability and recovery values were acceptable, and found between 89.38% and 105.60% for all five impurities under optimized operating conditions. The method developed here is simple, selective, and sensitive with apparently better resolution than the reported methods. Hence, the method is a straightforward and good quality control tool for the quantitation of selected impurities at trace concentrations in atenolol. PMID- 28581680 TI - Photoluminescence properties of Ca2 Al2 O5 :RE3+ (RE = Eu, Dy and Tb) phosphors for solid state lighting. AB - Ca2 Al2 O5 :Eu3+ , Ca2 Al2 O5 :Dy3+ and Ca2 Al2 O5 :Tb3+ phosphors were synthesized using a combustion synthesis method. The prepared phosphors were characterized by X-ray powder diffraction for phase purity, by scanning electron microscopy for morphology, and by photoluminescence for emission and excitation measurements. The Ca2 Al2 O5 :Eu3+ phosphors could be efficiently excited at 396 nm and showed red emission at 594 nm and 616 nm due to 5 D0 -> 7 F1 and 5 D0 -> 7 F2 transitions. Dy3+ -doped phosphors showed blue emission at 482 nm and yellow emission at 573 nm. Ca2 Al2 O5 :Tb3+ phosphors showed emission at 545 nm when excited at 352 nm. Concentration quenching occurred in both Eu3+ and Dy3+ phosphors at 0.5 mol%. Photoluminescence results suggested that the aluminate based phosphor could be a potential candidate for application in environmentally friendly based lighting technologies. PMID- 28581681 TI - Anti-vascular endothelial growth factor treatment decreases bladder pain in cyclophosphamide cystitis: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network animal model study. AB - OBJECTIVE: To investigate whether treatment with anti-vascular endothelial growth factor (VEGF)-neutralizing antibodies can reduce pain and voiding dysfunction in the cyclophosphamide (CYP) cystitis model of bladder pain in mice. MATERIALS AND METHODS: Adult female mice received anti-VEGF-neutralizing antibodies (10 mg/kg i.p. B20-4.1.1 VEGF mAb) or saline (control) pre-treatment, followed by CYP (150 mg/kg i.p.) to induce acute cystitis. Pelvic nociceptive responses were assessed by applying von Frey filaments to the pelvic area. Spontaneous micturition was assessed using the void spot assay. RESULTS: Systemic anti-VEGF-neutralizing antibody treatment significantly reduced the pelvic nociceptive response to CYP cystitis compared with control (saline). In the anti-VEGF pre-treatment group, there was a significant increase in pelvic hypersensitivity, measured by the area under the curve (AUC) using von Frey filaments at 5 h post-CYP administration (P = 0.004); however, by 48 h and 96 h post-CYP administration, pelvic hypersensitivity had reduced by 54% and 47%, respectively, compared with the 5 h post-CYP administration time point, and were no longer significantly different from baseline (P = 0.22 and 0.17, respectively). There was no difference in urinary frequency and mean voided volume between the two pre-treatment groups. CONCLUSION: Systemic blockade of VEGF signalling with anti-VEGF-neutralizing antibodies was effective in reducing pelvic/bladder pain in the CYP cystitis model of bladder pain. Our data support the further investigation of the use of anti-VEGF antibodies to manage bladder pain or visceral pain. PMID- 28581682 TI - Effect of cooling rate on the microstructure and luminescence properties of Sr2 MgSi2 O7 :Eu2+ ,Dy3+ materials. AB - Sr2 MgSi2 O7 :Eu2+ ,Dy3+ long afterglow materials were prepared by a high temperature solid-state reaction method with different cooling rates. The cooling rate had a slight effect on X-ray diffraction patterns and photoluminescence performance, but significantly modified the grain boundaries and long afterglow properties of the Sr2 MgSi2 O7 :Eu2+ ,Dy3+ materials. When the cooling rate was 1 degrees C/min, grains remained intact with clear grain boundaries. As the cooling rate increased from 1 degrees C/min to 5 degrees C/min, some grain boundaries became indistinguishable. The afterglow properties were optimized, presenting best performance at the cooling rate of 3 degrees C/min. The trap state was investigated and illustrated through thermoluminescence curves. The depths of the traps of all the samples were unchanged, whereas densities changed to a large extent, leading to different afterglow properties. The retrapping process is discussed based on the afterglow curves. PMID- 28581684 TI - Editorial. PMID- 28581683 TI - The effect of early pregnancy on the formation of obstetric fistula. AB - OBJECTIVE: To assess the effect of early pregnancy on obstetric fistula. METHODS: A prospective observational study was conducted among patients with obstetric fistula caused by a long obstructed labor who presented at Selian Lutheran Hospital, Tanzania, or Kitovu Hospital, Uganda, between January 1, 2015, and January 31, 2016. Demographic and clinical variables were evaluated. RESULTS: Among 270 patients, 162 (60.0%) experienced their first pregnancy up to 2 years after menarche (early group) and 108 (40.0%) experienced their first pregnancy more than 2 years after menarche (late group). No significant differences between the early and late groups were found for median age at presentation (30.0 vs 28.0 years), median parity (both 2.0), stillbirth (n=145 [89.5%] vs n=95 [88.0%]), median duration of labor (both 2.0 days), home delivery (n=31 [19.1%] vs n=17 [15.7%]), cesarean delivery (n=79 [48.8%] vs 58 [53.7%]), median time from obstetric fistula formation to presentation (48.0 vs 24.0 months), and obstetric fistula classifications. Obstetric fistula occurred during the first pregnancy in 99 (61.1%) women in the early group and 71 (65.7%) in the late group (P=0.440). CONCLUSION: Frequency of obstetric fistula during the first pregnancy is not increased among women who experience their first pregnancy within 2 years of menarche. PMID- 28581685 TI - Voices of children and adolescents on phase 1 or phase 2 cancer trials: A new trial endpoint? AB - BACKGROUND: Pediatric participants on phase 1 or phase 2 clinical trials for incurable cancer are at risk of experiencing toxicities (adverse events [AEs]) related to trial participation. Multiple AEs are subjective; thus, the real impact of trial treatment cannot be known unless patient subjective reports are solicited. METHODS: The authors assessed the feasibility and acceptability of soliciting symptom, function, and quality of life (QOL) reports from participants aged 8 to 18 years who were enrolled on phase 1/2 clinical trials at 4 cancer centers during the first course of chemotherapy. The authors also assessed the reliability and validity of 6 self-report Patient-Reported Outcomes Measurement Information System (PROMIS) pediatric measures and 4 open-ended interview questions at 2 time points (at the time of trial enrollment [T1] and 3 to 4 weeks later [T2]). RESULTS: The enrollment rate of 75.9% (20 participants) exceeded the feasibility criterion, and missingness of measures by person, measure, and items at T1 and T2 were lower than the acceptability criteria. New QOL themes were limited to the impact of treatment on families and being away from home, family, and friends for treatment. All but one measure at T1 met the reliability criterion and all measures did so at T2. Validity support was limited however because as theorized, mobility decreased and fatigue increased as AEs increased. CONCLUSIONS: Soliciting and documenting symptom, function, and QOL reports from patients aged 8 to 18 years who are enrolled on a phase 1/2 clinical trial is feasible and acceptable to participants, particularly when embedded in trials. Reliable and valid findings can result, making patient self-reported outcomes a possible new trial endpoint. Cancer 2017;123:3799-3806. (c) 2017 American Cancer Society. PMID- 28581687 TI - Adverse life events, cardiovascular responses, and sports performance under pressure. AB - Research suggests that experiencing a moderate number of adverse life events can benefit future stress responses. This study explored the relationship between adverse life (ie, non-sport) events and cardiovascular responses to, and performance during, a pressurized sporting task. One hundred participants (64 men, 36 women; Mage =21.94 years, SDage =4.98) reported the number of adverse life events (eg, serious accident or injury) they had encountered before completing a pressurized dart-throwing task during which performance was recorded. Before the task, participants' demand and resource evaluations and cardiovascular reactivity were assessed. Adverse life events did not impact demand and resource evaluations. However, participants who reported 4-7 adverse life events displayed cardiovascular responses more reflective of a challenge state (relatively lower total peripheral resistance and/or higher cardiac output) compared to those who reported a lower (<4) or higher (>7) number of events. Furthermore, participants who reported 3-13 adverse life events outperformed those who reported a lower (<3) or higher (>13) number of events. Supplementary analyses suggested that this relationship might be due to a small number of extreme values. However, after outlier analyses, a significant linear relationship remained suggesting that a higher number of adverse life events facilitated performance. The results suggest that experiencing a moderate to high number of adverse life events might have beneficial effects on subsequent cardiovascular responses and performance under pressure. Practitioners should therefore consider prior brushes with adversity when identifying athletes who are likely to excel during stressful competition. PMID- 28581686 TI - Tongue-palatal contact changes in patients with skeletal mandibular prognathism after sagittal split ramus osteotomy: an electropalatography study. AB - The purpose of this study was to investigate the changes in tongue-palatal contact patterns using electropalatography (EPG) before and after sagittal split ramus osteotomy (SSRO) in patients with mandibular prognathism. Nine clients who underwent SSRO for mandibular setback and seven control subjects were participated in this study. Tongue-palatal contact patterns for /t/, /s/ and /k/ production were investigated using EPG before surgery and 3 months after surgery. The mean value of whole total of palate contact (WT) in the maximum contact frame was examined before and after SSRO. The correlation quantity between the change of center of gravity (COG) value and the amount of mandibular setback was also evaluated. The mean value of WT for /t/ and /s/ significantly increased after SSRO, and the EPG pattern became normal. However, a remarkable change in WT for /k/ was not observed, and the mean value was significantly larger in the SSRO group before and after surgery than in the control group. A negative correlation between COG variation and the amount of mandibular setback for /t/ and positive correlation for /s/ was observed. This study demonstrated that tongue-palatal contact patterns for /t/ and /s/ articulation improved clearly after SSRO. There was a significant correlation between COG variation and the amount of mandibular setback. However, no significant change was detected through perceptual assessment before and after SSRO. Further investigation is needed to determine whether these results will change over time. PMID- 28581688 TI - When You're Happy and I Know It: Four-Year-Olds' Emotional Perspective Taking During Online Language Comprehension. AB - Using a novel emotional perspective-taking task, this study investigated 4-year olds' (n = 97) use of a speaker's emotional prosody to make inferences about the speaker's emotional state and, correspondingly, their communicative intent. Eye gaze measures indicated preschoolers used emotional perspective inferences to guide their real-time interpretation of ambiguous statements. However, these sensitivities were less apparent in overt responses, suggesting preschoolers' ability to integrate emotional perspective cues is at an emergent state. Perspective taking during online language processing was positively correlated with receptive vocabulary and an offline measure of emotional perspective taking, but not with cognitive perspective taking, conflict or delay inhibitory control, or working memory. Together, the results underscore how children's emerging communicative competence involves different kinds of perspective inferences with distinct cognitive underpinnings. PMID- 28581689 TI - The physical deterioration of dialysis patients-Ignored, ill-reported, and ill treated. AB - The progressive physical deterioration of dialysis patients is apparent to all who are involved in their care. Exercise can help stem this decline, yet exercise uptake in chronic and end-stage kidney disease is low. The involvement of exercise professionals has been shown to significantly increase patients' physical function and improve their quality of life. However, exercise professionals are scarce in renal programs, far less than dietetic and social work services. A review of 10 years of renal exercise publications in the physical therapy and rehabilitation literature found that only 0.4% (7 out of a total of 1763) of all published articles were focused on people with kidney disease. This compared with stroke (44%, n=883), arthritis/bone (29%, n=458), cancer (9%, n=168), respiratory (8%, n=106), cardiac (5%, n=82), and diabetes (3%, n=45). These results reflect the low emphasis placed on renal rehabilitation by the physical therapy professions and the low renal content in physical therapy tertiary education programs. This is likely to have an impact on the level of involvement of physical therapists in renal programs leading to lower physical function and poorer quality of life for renal patients. PMID- 28581690 TI - Possible mechanism underlying the association between higher hemoglobin level and hypertension in older Japanese men. AB - AIM: Hemoglobin is reported to be positively associated with hypertension. However, the underlying mechanism of this association is unknown. Recently, bone marrow-derived CD34-positive cells have been reported to play an important role in endothelial repair in conjunction with platelets. As the association between hypertension and endothelial dysfunction is bidirectional, the influence of endothelial repair also might strongly influence the association between hemoglobin and hypertension. METHODS: To clarify the clinical importance of the hematological parameter on endothelial maintenance in older men, we carried out a cross-sectional study of 222 Japanese men aged 60-69 years undergoing a general health checkup. RESULTS: For participants with a lower platelet count (<=21.0/MUL), hemoglobin was significantly positively associated with hypertension, but not for participants with a higher platelet count (>21.0/MUL). The classical cardiovascular risk factor adjusted odds ratio of hypertension for 1-standard deviation increment of hemoglobin (1.0 g/dL) was 2.09 (95% CI: 1.26, 3.48) for participants with a lower platelet count, and 1.07 (95% CI: 0.68, 1.67) for participants with a higher platelet count. We also found that although there was no significant correlation between hemoglobin and circulating CD34-positive cells for participants with a lower platelet count (beta = -0.06, P = 0.603), a significant positive correlation was seen for participants with a higher platelet count (beta = 0.29, P = 0.004). CONCLUSIONS: The positive association between hemoglobin and hypertension was limited to participants with a lower platelet count as a result of insufficient endothelial repair. These results represent an efficient tool for clarifying the mechanism of endothelial maintenance that correlates with hypertension. Geriatr Gerontol Int 2017; 17: 2586-2592. PMID- 28581691 TI - Recombinant factor XIII prophylaxis is safe and effective in young children with congenital factor XIII-A deficiency: international phase 3b trial results. AB - : Essentials Prophylaxis is the standard of care for congenital factor XIII-A (FXIII-A) deficiency. Six children with FXIII-A deficiency received once-monthly prophylaxis with recombinant FXIII-A. Prophylaxis was well tolerated and no anti FXIII antibodies were detected. Prophylaxis was effective with an annualized bleeding rate of zero. SUMMARY: Background Factor XIII deficiency is a rare, severe congenital bleeding disorder. Monthly prophylaxis with recombinant FXIII A Subunit (rFXIII) has demonstrated favorable safety and efficacy in patients aged >= 6 years, and may similarly benefit younger children. Objective To evaluate the long-term safety and efficacy of rFXIII in children aged < 6 years with congenital FXIII A-subunit deficiency. Patients/methods Six children, who had previously completed a single-dose pharmacokinetic trial of rFXIII, received 35 IU kg-1 rFXIII every 28 days (+/- 2 days) for a minimum of 52 weeks, and were evaluated for bleeding and adverse events. The Berichrom FXIII activity assay was used to monitor FXIII activity. Results The children, three girls and three boys, had an average age of 3.0 years (range: 1-4 years) at enrollment. The total treatment duration was 1.8-3.5 years, giving a total of 16.6 patient-years. No antibody development, thromboembolic events or allergic reactions occurred. There were 93 mild and seven moderate adverse events. Two adverse events (lymphopenia and gastroenteritis) were reported as probably or possibly related to rFXIII in two children. Two serious adverse events, unrelated to rFXIII, were reported in a single child, each related to head injury, and neither resulting in intracranial hemorrhage. The geometric mean FXIII activity trough was 0.19 IU mL-1 . No bleeding episodes requiring treatment with an FXIII-containing hemostatic agent occurred during the trial; thus, the annualized bleeding rate was 0. Conclusions Consistent with data from older age groups, prophylaxis with rFXIII appears to be safe and effective in young children with congenital FXIII A-subunit deficiency. PMID- 28581692 TI - Examining the effects of rational emotive behavior therapy on performance outcomes in elite paralympic athletes. AB - Traditionally a psychotherapeutic intervention, rational emotive behavior therapy (REBT) is receiving increasing attention within the extant literature as an intervention to enhance the athletic performance and psychological well-being of competitive athletes. Whilst the benefits of REBT on psychological health are established, less is understood about the effects on athletic performance. This study aimed to examine the immediate and maintained effects of REBT on physiological, psychological, and performance outcomes with elite Paralympic athletes. Using a single-case research design, eight athletes recruited from the same Paralympic sport (M=40.12, SD=12.99) received five, one-to-one REBT sessions. Measures of irrational beliefs were collected weekly, whereas the remaining psychological and physiological measures were collected at a pre-, post , and at a 9-month follow-up time point. Visual and statistical analyzes of the data indicates reductions in irrational beliefs were coupled with reductions in systolic blood pressure indicative of an adaptive physiological response, improved athletic performance during competition simulations, and reductions in avoidance goals. Furthermore, social validation data indicated greater self awareness, emotional control, and enhanced focus during competition as a result of the REBT intervention. This study contributes to growing literature supporting the efficacy of REBT as an intervention that not only facilitates psychological health but also enhances athletic performance. Results are discussed with reference to theory, limitations, and future recommendations. PMID- 28581693 TI - A prospective clinical trial to assess the optical efficacy of pink neck implants and pink abutments on soft tissue esthetics. AB - OBJECTIVE: The purpose of this prospective, randomized, controlled, multicenter clinical study was to analyze the optical effects of an anodized pink colored implant shoulder/abutment system in the peri-implant mucosa of immediately placed dental implants. MATERIALS AND METHOD: Forty subjects with a restoratively hopeless tooth in the maxillary esthetic zone, were recruited and randomized to receive either a pink-neck implant, or a conventional gray implant. All patients received an immediate implant and immediate provisional and two identical CAD/CAM titanium abutments with different surface colors: pink and gray, and one zirconia all-ceramic crown. The color of the peri-implant mucosa was measured using a dental spectrophotometer and analyzed using CIELAB color system. RESULTS: The overall color difference between the peri-implant mucosa with a pink abutment and a gray abutment was DeltaE = 4.22. Patients with gray implants presented a color change of DeltaE = 3.86-4.17 with this abutment change, while patients with pink implants had a color change of DeltaE = 3.84-4.69. The peri-implant mucosa with a pink abutment was significantly more red when compared with a gray abutment (P <= .01). CONCLUSIONS: When a pink abutment was used, there is a significant color change of the peri-implant mucosa that is above the detectable color threshold. CLINICAL SIGNIFICANCE: Esthetic outcomes are important for the success of implant treatment of maxillary anterior implants. The phenomenon of the gray color of a dental implant and abutment shining through the peri-implant mucosa has been documented in the literature. The objective of this study was to assess the optical effect of an anodized pink-neck implant and a pink abutment on the color of peri-implant mucosa. This study demonstrates that using pink-neck implant and a pink abutment would contribute positively to the overall esthetic outcome for an anterior implant. PMID- 28581694 TI - Abnormal von Willebrand factor secretion, factor VIII stabilization and thrombus dynamics in type 2N von Willebrand disease mice. AB - : Essentials Type 2N von Willebrand disease involves impaired von Willebrand factor to factor VIII binding. Type 2N von Willebrand disease mutations exhibit qualitative and mild quantitative deficiencies. Type 2N von Willebrand disease mice exhibit unstable venous hemostatic thrombi. The factor VIII-binding ability of von Willebrand factor regulates arteriole thrombosis dynamics. SUMMARY: Background von Willebrand factor (VWF) and factor VIII (FVIII) circulate as a non covalent complex, with VWF serving as the carrier for FVIII. VWF indirectly influences secondary hemostasis by stabilizing FVIII and transporting it to the site of primary hemostasis. Type 2N von Willebrand disease involves impaired binding of VWF to FVIII, resulting in decreased plasma levels of FVIII. Objectives In these studies, we characterize the impact of three type 2N VWD variants (R763A, R854Q, R816W) on VWF secretion, FVIII stabilization and thrombus formation in a murine model. Methods Type 2N VWD mice were generated by hydrodynamic injections of mutant murine VWF cDNAs and the influence of these variants on VWF secretion and FVIII binding was evaluated. In vivo hemostasis and the dynamics of thrombus formation and embolization were assessed using a murine tail vein transection hemostasis model and an intravital thrombosis model in the cremaster arterioles. Results Type 2N VWD variants were associated with decreased VWF secretion using cell and animal-based models. FVIII-binding to type 2N variants was impaired in vitro and was variably stabilized in vivo by expressed or infused 2N variant VWF protein. Both transgenic type 2N VWD and FVIII knockout (KO) mice demonstrated impaired thrombus formation associated with decreased thrombus stability. Conclusions The type 2N VWD phenotype can be recapitulated in a murine model and is associated with both quantitative and qualitative VWF deficiencies and impaired thrombus formation. Patients with type 2N VWD may have normal primary hemostasis formation but decreased thrombus stability related to ineffective secondary hemostasis. PMID- 28581695 TI - A new Schiff base as a turn-off fluorescent sensor for Cu2+ and its photophysical properties. AB - A new Schiff base receptor 1 was synthesized and its photophysical properties were investigated by absorption, emission and excitation techniques. Furthermore, its chromogenic and fluorogenic sensing abilities towards various metal ions were examined. Receptor 1 selectively detects Cu2+ ion through fluorescence quenching and detection was not inhibited in the presence of other metal ions. From fluorescence titration, the limit of detection of receptor 1 as a fluorescent 'turn-off' sensor for the analysis of Cu2+ was estimated to be 0.35 MUM. PMID- 28581696 TI - Lung cancer screening rates remain very low among current and former smokers. PMID- 28581697 TI - Researchers call teen vaping "one-way bridge" to smoking. PMID- 28581698 TI - First person: Jimmie Holland, MD. PMID- 28581699 TI - Erratum. PMID- 28581700 TI - The Longitudinal Association of Being Bullied and Gender with Suicide Ideations, Self-Harm, and Suicide Attempts from Adolescence to Young Adulthood: A Cohort Study. AB - Longitudinal associations between being bullied during adolescence and suicide ideations, self-harm, and suicide attempts into young adulthood were examined. A large representative sample was examined in 1998 (N = 2,464, MA 13.7), 1999/2000, and 2012 to reassess the outcome measures. At all ages, bullied participants showed more suicide ideation, self-harm, and suicide attempts, regardless of gender. Bullied females showed a decrease in suicide ideation from adolescence to adulthood, while bullied males showed an increase in suicide attempts in the same time period. Being bullied in adolescence strongly predicts suicidal behavior and self-harm. Preventive efforts might reduce the risk of later suicidality. PMID- 28581702 TI - Universal Coating from Electrostatic Self-Assembly to Prevent Multidrug-Resistant Bacterial Colonization on Medical Devices and Solid Surfaces. AB - We provide a facile and scalable strategy for preparing gold nanoparticles (AuNPs)-based antibacterial coating on a variety of surfaces through electrostatic self-assembly. AuNPs conjugated with 4,6-diamino-2-pyrimidinethiol (DAPT, not antibacterial by itself), AuDAPT, can form stable coating on different substrates made from polyethylene (PS), polyvinyl chloride (PVC), polypropylene (PP), polyethylene (PE), polydimethylsiloxane (PDMS), and SiO2 in one step. Such a coating can efficiently eradicate pathogenic Gram-negative bacteria and even multidrug-resistant (MDR) mutants without causing any side-effect such as cytotoxicity, hemolysis, coagulation, and inflammation. We show that immobilized AuDAPT, instead of AuDAPT released from the substrate, is responsible for killing the bacteria and that the antimicrobial components do not enter into the environment to cause secondary contamination to breed drug resistance. Advantages for such coating include applicability on a broad range of surfaces, low cost, stability, high antibacterial efficiency, good biocompatibility, and low risk in antibiotics pollution; these advantages may be particularly helpful in preventing infections that involve medical devices. PMID- 28581701 TI - Mini-Nutritional Assessment Short-Form as a useful method of predicting poor 1 year outcome in elderly patients undergoing orthopedic surgery. AB - AIM: The present study aimed to determine whether the Mini-Nutritional Assessment Short-Form (MNA-SF) can predict the 1-year outcome of orthopedic fracture surgery in elderly patients. METHODS: This 1-year prospective study assessed nutrition using the MNA-SF at baseline, and postoperatively at 6 and 12 months. Repeated measures analysis of covariance was used to examine functional change over time for two MNA-SF categories. Multivariable logistic regression analysis with forward stepwise modeling was carried out to identify risk factors of functional decline, emergency department visit, hospital readmission and mortality at follow up. RESULTS: There were 312 participants, 11 of whom died (3.53%) during 1-year follow up. The mean age was 74.04 +/- 7.65 years. A total of 88.1% and 11.9% of the participants were well nourished (MNA-SF 12-14 points) or at risk of undernutrition (0-11 points), respectively. For MNA-SF as a continuous variable, lower MNA-SF scores were associated with a significantly higher risk of emergency department visit at 6-month follow up, and mortality at 12-month follow up (emergency room visit, adjusted odds ratio 0.78, 95% CI 0.63-0.96, P < 0.05; mortality, adjusted odds ratio 0.73, 95% CI 0.57-0.94, P < 0.05). No association was found between functional decline and hospital readmission, and MNA-SF scores. For MNA-SF categories, functional decline was more profound in patients at risk of undernutrition than in well-nourished patients, especially 6-12 months postoperatively. CONCLUSIONS: The MNA-SF could be an effective and non-invasive preoperative screening tool to predict functional decline, emergency department visit and mortality during the year after surgery. Geriatr Gerontol Int 2017; 17: 2361-2368. PMID- 28581704 TI - Self-Propelled Metal-Polymer Hybrid Micromachines with Bending and Rotational Motions. AB - Two self-propelled micromachines were fabricated with gold/platinum micromotors that exhibit simple translational motion in a fuel solution. In each one, two micromotors were connected with a joint of polymer tube formed by stacking cationic poly(allylamine hydrochloride) (PAH) and anionic poly(acrylic acid) (PAA) using a layer-by-layer technique. A bent structure was created by making one longitudinal side of the joint more swellable with alkaline treatment. The joint containing fewer PAA/PAH bilayers was flexible and allowed a larger range of Brownian angular fluctuation. In the fuel solution, bending and stable rotation were observed for the micromotors tethered with soft and rigid angled joints, respectively. The radius and angular velocity of the rotation depended on the angle of the joint. Such tethered micromotors can be used to realize sophisticated micro/nanomachines for microscale surgery and drug delivery. PMID- 28581703 TI - Anion-Exchange Chromatography Coupled to High-Resolution Mass Spectrometry: A Powerful Tool for Merging Targeted and Non-targeted Metabolomics. AB - In this work, simultaneous targeted metabolic profiling by isotope dilution and non-targeted fingerprinting is proposed for cancer cell studies. The novel streamlined metabolomics workflow was established using anion-exchange chromatography (IC) coupled to high-resolution mass spectrometry (MS). The separation time of strong anion-exchange (2 mm column, flow rate 380 MUL min-1, injection volume 5 MUL) could be decreased to 25 min for a target list comprising organic acids, sugars, sugar phosphates, and nucleotides. Internal standardization by fully 13C labeled Pichia pastoris extracts enabled absolute quantification of the primary metabolites in adherent cancer cell models. Limits of detection (LODs) in the low nanomolar range and excellent intermediate precisions of the isotopologue ratios (on average <5%, N = 5, over 40 h) were observed. As a result of internal standardization, linear dynamic ranges over 4 orders of magnitude (5 nM-50 MUM, R2 > 0.99) were obtained. Experiments on drug sensitive versus resistant SW480 cancer cells showed the feasibility of merging analytical tasks into one analytical run. Comparing fingerprinting with and without internal standard proved that the presence of the 13C labeled yeast extract required for absolute quantification was not detrimental to non-targeted data evaluation. Several interesting metabolites were discovered by accurate mass and comparing MS2 spectra (acquired in ddMS2 mode) with spectral libraries. Significant differences revealed distinct metabolic phenotypes of drug-sensitive and resistant SW480 cells. PMID- 28581705 TI - Characteristics of NaNO3-Promoted CdO as a Midtemperature CO2 Absorbent. AB - In this study, we explored the reaction system CdO(s) + CO2(g) ? CdCO3(s) as a model system for CO2 capture agent in the intermediate temperature range of 300 400 degrees C. While pure CdO does not react with CO2 at all up to 500 degrees C, CdO mixed with an appropriate amount of NaNO3 (optimal molar ratio NaNO3/CdO = 0.14) greatly enhances the conversion of CdO into CdCO3 up to ~80% (5.68 mmol/g). These NaNO3-promoted CdO absorbents can undergo many cycles of absorption and desorption by temperature swing between 300 and 370 degrees C under a 100% CO2 condition. Details of how NaNO3 promotes the CO2 absorption of CdO have been delineated through various techniques using thermogravimetry, coupled with X-ray diffraction and electron microscopy. On the basis of the observed data, we propose a mechanism of CO2 absorption and desorption of NaNO3-promoted CdO. The absorption proceeds through a sequence of events of CO2 adsorption on the CdO surface covered by NaNO3, dissolution of so-formed CdCO3, and precipitation of CdCO3 particles in the NaNO3 medium. The desorption occurs through the decomposition of CdCO3 in the dissolved state in the NaNO3 medium where CdO nanoparticles are formed dispersed in the NaNO3 medium. The CdO nanoparticles are aggregated into micrometer-large particles with smooth surfaces and regular shapes. PMID- 28581706 TI - "On-Water" Facile Synthesis of Novel Pyrazolo[3,4-b]pyridinones Possessing Anti influenza Virus Activity. AB - A facile and versatile "on-water" protocol for the synthesis of pyrazolo[3,4 b]pyridinones was developed by the unprecedented construction of two rings and five new bonds in one-pot. It was proved that water was an important promoter of the reaction and PEG2000 was found to improve the reaction in terms of yield. 32 Derivatives were newly synthesized and most of them were prepared in an hour. The scope and limitation indicated that electron withdrawing groups substituted on synthons, substituted benzoyl acetonitriles or aryl aldehydes, were helpful to construct the pyrazolo[3,4-b]pyridinones. The reaction media PEG2000/H2O was successfully recycled and reused at least 5 times without any obvious decrease in yield. The anti-influenza activities of the derivatives were evaluated and the screening results highlighted two derivatives, which exhibited strong inhibitory activity against H5N1 pseudovirus. These positive bioassay results implied that the library of potential anti-influenza virus agent candidates could be rapidly prepared in an eco-friendly manner, and provided a new insight into drug discovery for medicinal chemists. PMID- 28581707 TI - Unprecedented Activity of Bifunctional Electrocatalyst for High Power Density Aqueous Zinc-Air Batteries. AB - The development of nonprecious metal catalysts with desirable bifunctional activities to supersede noble metal catalysts is of vital importance for high performance aqueous zinc-air batteries. Here, an unprecedented activity of bifunctional electrocatalyst is reported by in situ growth of nitrogen-enriched carbon nanotubes with transition metal composite. The resultant catalyst delivers surprisingly high OER (potential@10 mA cm-2 of 1.58 V) and ORR (onset potential of 0.97 V, half-wave potential of 0.86 V) performance. The overall oxygen electrode activity (overvoltage between ORR and OER) of the catalyst is as low as 0.72 V. In aqueous Zn-air battery tests, primary batteries demonstrate high maximum power density and two-electrode rechargeable batteries also exhibit good cycle performance. The unprecedented electrocatalyst opens up new avenues for developing highly active nitrogen-doped carbon nanotube-supported electrocatalysts and offers prospects for the next generation of fuel cells, metal-air batteries, and photocatalysis applications. PMID- 28581709 TI - Manipulation of Thermally Activated Delayed Fluorescence of Blue Exciplex Emission: Fully Utilizing Exciton Energy for Highly Efficient Organic Light Emitting Diodes with Low Roll-Off. AB - The application of exciplex energy has become a unique way to achieve organic light-emitting diodes (OLEDs) with high efficiencies, low turn-on voltage, and low roll-off. Novel delta-carboline derivatives with high triplet energy (T1 ~ 2.92 eV) and high glass transition temperature (Tg ~ 153 degrees C) were employed to manipulate exciplex emissions in this paper. Deep blue (peak at 436 nm) and pure blue (peak at 468 nm) thermally activated delayed fluorescence (TADF) of exciplex OLEDs were demonstrated by utilizing them as emitters with the maximum current efficiency (CE) of 4.64 cd A-1, power efficiency (PE) of 2.91 lm W-1, and external quantum efficiency (EQE) of 2.36%. Highly efficient blue phosphorescent OLEDs doped with FIrpic showed a maximum CE of 55.6 cd A-1, PE of 52.9 lm W-1, and EQE of 24.6% respectively with very low turn on voltage at 2.7 V. The devices still remain high CE of 46.5 cd A-1 at 100 cd m-2, 45.4 cd A-1 at 1000 cd m-2 and 42.3 cd A-1 at 5000 cd m-2 with EQE close to 20% indicating low roll-off. Manipulating blue exciplex emissions by chemical structure gives an ideal strategy to fully utilize all exciton energies for lighting of OLEDs. PMID- 28581710 TI - Biotransformation of Silver Released from Nanoparticle Coated Titanium Implants Revealed in Regenerating Bone. AB - Antimicrobial silver nanoparticle coatings have attracted interest for reducing prosthetic joint infection. However, few studies report in vivo investigations of the biotransformation of silver nanoparticles within the regenerating tissue and its impact on bone formation. We present a longitudinal investigation of the osseointegration of silver nanoparticle-coated additive manufactured titanium implants in rat tibial defects. Correlative imaging at different time points using nanoscale secondary ion mass spectrometry, transmission electron microscopy (TEM), histomorphometry, and 3D X-ray microcomputed tomography provided quantitative insight from the nano- to macroscales. The quality and quantity of newly formed bone is comparable between the uncoated and silver coated implants. The newly formed bone demonstrates a trabecular morphology with bone being located at the implant surface, and at a distance, at two weeks. Nanoscale elemental mapping of the bone-implant interface showed that silver was present primarily in the osseous tissue and colocalized with sulfur. TEM revealed silver sulfide nanoparticles in the newly regenerated bone, presenting strong evidence that the previously in vitro observed biotransformation of silver to silver sulfide occurs in vivo. PMID- 28581711 TI - alpha-Amino Acid Rich Photophytonic Nanoparticles of Algal Origin Serendipitously Reveal Antimigratory Property against Cancer. AB - Spheroidal nanoparticles of algal ("phytonic") origin were synthesized and composed of carbonaceous architectures and surface-rich oxygenated functional groups. Nanoparticles were negatively charged and efficiently luminescent after ultraviolet-range excitation and called as "photophytonic" nanoparticles. A multitude of analytical techniques confirmed the rich profusion of hydroxyl, carboxylate, and amines at the nanoscale, while spectroscopic investigation indicated the presence of alpha-amines, a signature functionality present in amino acids. Confirmed via a series of biological assays, i.e., growth regression, antimigration, and protein-regression studies, photophytonic nanoparticles serendipitously revealed remarkable anticancer activity against various stages of breast cancer cells, barring the need for an encapsulated drug. We report that nanoparticles derived from algal biomass exhibit intrinsic antimigratory properties against cancer, likely due to the rich abundance of alpha-amino acids. PMID- 28581708 TI - Optimization of d-Peptides for Abeta Monomer Binding Specificity Enhances Their Potential to Eliminate Toxic Abeta Oligomers. AB - Amyloid-beta (Abeta) oligomers are thought to be causative for the development and progression of Alzheimer's disease (AD). Starting from the Abeta oligomer eliminating d-enantiomeric peptide D3, we developed and applied a two-step procedure based on peptide microarrays to identify D3 derivatives with increased binding affinity and specificity for monomeric Abeta(1-42) to further enhance the Abeta oligomer elimination efficacy. Out of more than 1000 D3 derivatives, we selected seven novel d-peptides, named ANK1 to ANK7, and characterized them in more detail in vitro. All ANK peptides bound to monomeric Abeta(1-42), eliminated Abeta(1-42) oligomers, inhibited Abeta(1-42) fibril formation, and reduced Abeta(1-42)-induced cytotoxicity more efficiently than D3. Additionally, ANK6 completely inhibited the prion-like propagation of preformed Abeta(1-42) seeds and showed a nonsignificant tendency for improving memory performance of tg APPSwDI mice after i.p. application for 4 weeks. This supports the hypothesis that stabilization of Abeta monomers and thereby induced elimination of Abeta oligomers is a suitable therapeutic strategy. PMID- 28581712 TI - Ionic-Liquid-Based Heterogeneous Covalent Triazine Framework Cobalt Catalyst for the Direct Synthesis of Methyl 3-Hydroxybutyrate from Propylene Oxide. AB - beta-Hydroxy esters are considered as potential building blocks for the production of fine chemicals and potential drug molecules in various industries. Developing an efficient and recyclable catalyst for the synthesis of beta-hydroxy esters is challenging. Here we report the first ionic-liquid-based heterogenized cobalt catalyst, [imidazolium-CTF][Co(CO)4], for the direct ring-opening carbonylation of propylene oxide to methyl 3-hydroxybutyrate (MHB) with 86% selectivity (>99% conversion). PMID- 28581713 TI - Regioselective Arylboration of Isoprene and Its Derivatives by Pd/Cu Cooperative Catalysis. AB - A method for the regioselective arylboration of isoprene and its derivatives is presented. These reactions allow for the synthesis of useful building blocks from simple components. Through these studies, an unusual additive effect with DMAP has been uncovered that allows for altered reactivity and the formation of quaternary carbon centers. The utility of this method is demonstrated toward the formal synthesis of mesembrine. PMID- 28581714 TI - Magnetic Properties as a Proxy for Predicting Fine-Particle-Bound Heavy Metals in a Support Vector Machine Approach. AB - The development of a reasonable statistical method of predicting the concentrations of fine-particle-bound heavy metals remains challenging. In this study, daily PM2.5 samples were collected within four different seasons from a Chinese mega-city. The annual average PM2.5 concentrations determined in industrial, city center, and suburban areas were 90, 81, and 85 MUg m-3, respectively. Environmental magnetic measurements, including magnetic susceptibility, anhysteretic remanent magnetization, isothermal remanent magnetization, hysteresis loops, and thermomagnetism, indicated that the main magnetic mineral of PM2.5 is low-coercivity pseudosingle domain (PSD) magnetite. Using a support vector machine (SVM), both the volume- and mass-related concentrations of heavy metals were predicted by the PM2.5 mass concentrations and meteorological factors, with or without magnetic properties as input variables. The inclusion of magnetic variables significantly improved the prediction results for most heavy metals. Predictions based on models that included the magnetic properties of the metals Al, Fe, Mn, Ni, and Ti were promising, with R values of >0.8 in both the training and the test stages as well as relatively low errors. Our results demonstrate that the inclusion of environmental magnetism in a SVM approach aids in the effective monitoring and assessment of airborne heavy-metal contamination in cities. PMID- 28581715 TI - HULIS Enhancement of Hydroxyl Radical Formation from Fe(II): Kinetics of Fulvic Acid-Fe(II) Complexes in the Presence of Lung Antioxidants. AB - Oxidative stress mediated by reactive oxygen species (ROS) is a hypothesized mechanism for particulate-matter related health effects. Fe(II) is a key player in ROS formation in surrogate lung fluid (SLF) containing antioxidants. Humic like substances (HULIS) in particulate matter such as biomass burning aerosol chelate Fe(II), but the effect on ROS formation in the presence of lung antioxidants is not known. We use Suwanee River Fulvic Acid (SRFA) as a surrogate for HULIS and investigate its effect on OH formation from Fe(II). For the first time, a chemical kinetics model was developed to explain behavior of Fe(II) and SRFA in SLF. Model and experimental results are used to find best-fit rate coefficients for key reactions. Modeling results indicate SRFA enhances Fe mediated reduction of O2 to O2- and destruction of H2O2 to OH to 5.1 +/- 1.5 and (4.3 +/- 1.4) * 103 M-1 s-1 respectively. Best-fit rates for Citrate-Fe(II) mediated O2 to O2- and H2O2 to OH were 3.0 +/- 0.7 and (4.2 +/- 1.7) * 103 M-1 s 1 respectively. The kinetics model agrees with both the experimental results and thermodynamic model calculations of chemical speciation for 0 and 5 MUg/mL SRFA, but both models are less successful at predicting further enhancements to OH formation at higher SRFA Concentrations. PMID- 28581716 TI - Transfer of Biomatrix/Wood Cell Interactions to Hemicellulose-Based Materials to Control Water Interaction. AB - The family of hemicelluloses stands out as a very promising natural resource that can be utilized as a biobased materials feedstock. An in-depth understanding of the hemicellulose inherent structural and property features as well as the structure-property relationships induced by the specific supramolecular hierarchical organization of lignocellulosic biopolymers will be a key enabling technology in the emerging biorefinery sector. This Review aims to give a perspective on these issues and demonstrate how the transfer of molecular wood cell interactions into hemicellulose-based materials may offer new design principles for material formulations. PMID- 28581717 TI - Determination of PAHs in Solution with a Single Reference Standard by a Combination of 1H Quantitative NMR Spectroscopy and Chromatography. AB - We have applied a combination of 1H quantitative NMR spectroscopy (1H-qNMR) and chromatography (GC or LC) to establish reliable analytical methods (qNMR/GC and qNMR/LC) for organic compounds. In this method, a reference standard is used as an internal standard for both 1H-qNMR and chromatography to estimate relative molar sensitivity (RMS) for analytes. The RMS values are calculated from the molar ratios between analytes and the reference standard obtained by 1H-qNMR; and the response ratio between them obtained by chromatography. Concentrations of analytes in the organic solution can be simultaneously determined from the RMS and amount of the reference standard added in the sample solution. This analytical method is an innovative one because only one reference standard with International System of Units (SI)-traceable property value, purity, or concentration, is necessary to determine accurate concentrations of multiple organic components in organic solutions, without the respective certified reference standards for various analytes. To verify this method, a certified reference material, NIST SRM 1647f, was used. Among the 16 polycyclic aromatic hydrocarbons (PAHs) included in NIST SRM 1647f, naphthalene and benzo[a]pyrene were selected as analytes for this method, using 1,4-bis(trimethylsilyl)benzene d4 as the reference standard. Each quantitative value obtained by qNMR/GC and qNMR/LC agreed with each certified value within its expanded uncertainty. PMID- 28581718 TI - Ruthenium Promoted On-DNA Ring-Closing Metathesis and Cross-Metathesis. AB - DNA-encoded library technology (ELT) is now widely used in pharmaceutical, biotechnological, and academic research for hit identification and target validation. New on-DNA reactions are keys to exploring greater chemical space and accessing challenging chemotypes such as configurationally constrained macrocycles. Herein, we describe the first on-DNA ring-closing metathesis (RCM) and cross-metathesis (CM) reactions promoted by fast initiating Grubbs Ru reagents. Under the optimized conditions, MgCl2 was used to protect the DNA from Ru-induced decomposition. The substrate scope for on-DNA RCM was established and the same conditions were applied to a CM reaction with good conversion. PMID- 28581719 TI - R3Au9Pn (R = Y, Gd-Tm; Pn = Sb, Bi): A Link between Cu10Sn3 and Gd14Ag51. AB - A new series of intermetallic compounds R3Au9Pn (R = Y, Gd-Tm; Pn = Sb, Bi) has been discovered during the explorations of the Au-rich parts of rare-earth containing ternary systems with p-block elements. The existence of the series is strongly restricted by both geometric and electronic factors. R3Au9Pn compounds crystallize in the hexagonal crystal system with space group P63/m (a = 8.08-8.24 A, c = 8.98-9.08 A). All compounds feature Au-Pn, formally anionic, networks built up by layers of alternating edge-sharing Au@Au6 and Sb@Au6 trigonal antiprisms of overall composition Au6/2Pn connected through additional Au atoms and separated by a triangular cationic substructure formed by R atoms. From a first look, the series appears to be isostructural with recently reported R3Au7Sn3 (a ternary ordered derivative of the Cu10Sn3-structure type), but no example of R3Au9M is known when M is a triel or tetrel element. R3Au9Pn also contains Au@Au6Au2R3 fully capped trigonal prisms, which are found to be isostructural with those found in the well-researched R14Au51 series. This structural motif, not present in R3Au7Sn3, represents a previously unrecognized link between Cu10Sn3 and Gd14Ag51 parent structure types. Magnetic property measurements carried out for Ho3Au9Sb reveal a complex magnetic structure characterized by antiferromagnetic interactions at low temperature (TN = 10 K). Two metamagnetic transitions occur at high field with a change from antiferromagnetic toward ferromagnetic ordering. Density functional theory based computations were performed to understand the materials' properties and to shed some light on the stability ranges. This allowed a better understanding of the bonding pattern, especially of the Au-containing substructure, and elucidation of the role of the third element in the stability of the structure type. PMID- 28581720 TI - Halogen Bonding: A Powerful Tool for Modulation of Peptide Conformation. AB - Halogen bonding is a weak chemical force that has so far mostly found applications in crystal engineering. Despite its potential for use in drug discovery, as a new molecular tool in the direction of molecular recognition events, it has rarely been assessed in biopolymers. Motivated by this fact, we have developed a peptide model system that permits the quantitative evaluation of weak forces in a biologically relevant proteinlike environment and have applied it for the assessment of a halogen bond formed between two amino acid side chains. The influence of a single weak force is measured by detection of the extent to which it modulates the conformation of a cooperatively folding system. We have optimized the amino acid sequence of the model peptide on analogues with a hydrogen bond-forming site as a model for the intramolecular halogen bond to be studied, demonstrating the ability of the technique to provide information about any type of weak secondary interaction. A combined solution nuclear magnetic resonance spectroscopic and computational investigation demonstrates that an interstrand halogen bond is capable of conformational stabilization of a beta hairpin foldamer comparable to an analogous hydrogen bond. This is the first report of incorporation of a conformation-stabilizing halogen bond into a peptide/protein system, and the first quantification of a chlorine-centered halogen bond in a biologically relevant system in solution. PMID- 28581721 TI - A Fusion Protein of the p53 Transaction Domain and the p53-Binding Domain of the Oncoprotein MdmX as an Efficient System for High-Throughput Screening of MdmX Inhibitors. AB - In nearly half of cancers, the anticancer activity of p53 protein is often impaired by the overexpressed oncoprotein Mdm2 and its homologue, MdmX, demanding efficient therapeutics to disrupt the aberrant p53-MdmX/Mdm2 interactions to restore the p53 activity. While many potent Mdm2-specific inhibitors have already undergone clinical investigations, searching for MdmX-specific inhibitors has become very attractive, requiring a more efficient screening strategy for evaluating potential scaffolds or leads. In this work, considering that the intrinsic fluorescence residue Trp23 in the p53 transaction domain (p53p) plays an important role in determining the p53-MdmX/Mdm2 interactions, we constructed a fusion protein to utilize this intrinsic fluorescence signal to monitor high throughput screening of a compound library. The fusion protein was composed of the p53p followed by the N-terminal domain of MdmX (N-MdmX) through a flexible amino acid linker, while the whole fusion protein contained a sole intrinsic fluorescence probe. The fusion protein was then evaluated using fluorescence spectroscopy against model compounds. Our results revealed that the variation of the fluorescence signal was highly correlated with the concentration of the ligand within 65 MUM. The fusion protein was further evaluated with respect to its feasibility for use in high-throughput screening using a model compound library, including controls. We found that the imidazo-indole scaffold was a bona fide scaffold for template-based design of MdmX inhibitors. Thus, the p53p-N-MdmX fusion protein we designed provides a convenient and efficient tool for high throughput screening of new MdmX inhibitors. The strategy described in this work should be applicable for other protein targets to accelerate drug discovery. PMID- 28581722 TI - The PipX Protein, When Not Bound to Its Targets, Has Its Signaling C-Terminal Helix in a Flexed Conformation. AB - PipX, an 89-residue protein, acts as a coactivator of the global nitrogen regulator NtcA in cyanobacteria. NtcA-PipX interactions are regulated by 2 oxoglutarate (2-OG), an inverse indicator of the ammonia abundance, and by PII, a protein that binds to PipX at low 2-OG concentrations. The structure of PipX, when bound to NtcA or PII, consists of an N-terminal, five-stranded beta-sheet (conforming a Tudor-like domain), and two long alpha-helices. These helices adopt either a flexed conformation, where they are in close contact and in an antiparallel mutual orientation, also packing against the beta-sheet, or an open conformation (observed only in the PII-PipX complex) where the last alpha-helix moves apart from the rest of the protein. The aim of this work was to study the structure and dynamics of isolated PipX in solution by NMR. The backbone chemical shifts, the hydrogen-exchange, and the NOE patterns indicated that the isolated, monomeric PipX structure was formed by an N-terminal five-stranded beta-sheet and two C-terminal alpha-helices. Furthermore, the observed NOEs between the two helices, and of alpha-helix2 with beta-strand2 suggested that PipX adopted a flexed conformation. The beta-strands 1 and 5 were highly flexible, as shown by the lack of interstrand backbone-backbone NOEs; in addition, the 15N-dynamics indicated that the C terminus of beta-strand4 and the following beta-turn (Phe42 Thr47), and the C-cap of alpha-helix1 (Arg70-Asn71) were particularly mobile. These two regions could act as hinges, allowing PipX to interact with its partners, including PlmA in the newly recognized PII-PipX-PlmA ternary complex. PMID- 28581723 TI - Photochemical Formation of Nitrite and Nitrous Acid (HONO) upon Irradiation of Nitrophenols in Aqueous Solution and in Viscous Secondary Organic Aerosol Proxy. AB - Irradiated nitrophenols can produce nitrite and nitrous acid (HONO) in bulk aqueous solutions and in viscous aqueous films, simulating the conditions of a high-solute-strength aqueous aerosol, with comparable quantum yields in solution and viscous films (10-5-10-4 in the case of 4-nitrophenol) and overall reaction yields up to 0.3 in solution. The process is particularly important for the para nitrophenols, possibly because their less sterically hindered nitro groups can be released more easily as nitrite and HONO. The nitrophenols giving the highest photoproduction rates of nitrite and HONO (most notably, 4-nitrophenol and 2 methyl-4-nitrophenol) could significantly contribute to the occurrence of nitrite in aqueous phases in contact with the atmosphere. Interestingly, dew-water evaporation has shown potential to contribute to the gas-phase HONO levels during the morning, which accounts for the possible importance of the studied process. PMID- 28581724 TI - Targeting Tumor Associated Phosphatidylserine with New Zinc Dipicolylamine-Based Drug Conjugates. AB - A series of zinc(II) dipicolylamine (ZnDPA)-based drug conjugates have been synthesized to probe the potential of phosphatidylserine (PS) as a new antigen for small molecule drug conjugate (SMDC) development. Using in vitro cytotoxicity and plasma stability studies, PS-binding assay, in vivo pharmacokinetic studies, and maximum tolerated dose profiles, we provided a roadmap and the key parameters required for the development of the ZnDPA based drug conjugate. In particular, conjugate 24 induced tumor regression in the COLO 205 xenograft model and exhibited a more potent antitumor effect with a 70% reduction of cytotoxic payload compared to that of the marketed irinotecan when dosed at the same regimen. In addition to the validation of PS as an effective pharmacodelivery target for SMDC, our work also provided the foundation that, if applicable, a variety of therapeutic agents could be conjugated in the same manner to treat other PS-associated diseases. PMID- 28581725 TI - Engineered Control of Genetic Variability Reveals Interplay among Quorum Sensing, Feedback Regulation, and Biochemical Noise. AB - Stochastic fluctuations in gene expression trigger both beneficial and harmful consequences for cell behavior. Therefore, achieving a desired mean protein expression level while minimizing noise is of interest in many applications, including robust protein production systems in industrial biotechnology. Here, we consider a synthetic gene circuit combining intracellular negative feedback and cell-to-cell communication based on quorum sensing. Accounting for both intrinsic and extrinsic noise, stochastic simulations allow us to analyze the capability of the circuit to reduce noise strength as a function of its parameters. We obtain mean expression levels and noise strengths for all species under different scenarios, showing good agreement with system-wide available experimental data of protein abundance and noise in Escherichia coli. Our in silico experiments, validated by preliminary in vivo results, reveal significant noise attenuation in gene expression through the interplay between quorum sensing and negative feedback and highlight the differential role that they play in regard to intrinsic and extrinsic noise. PMID- 28581726 TI - Ultrahigh-Resolution NMR Spectroscopy for Rapid Chemical and Biological Applications in Inhomogeneous Magnetic Fields. AB - NMR spectroscopy is a commonly used analytical technique in practical applications, and its applicability is further promoted by pure chemical shift techniques based on spectral simplification for analyses. Unfortunately, magnetic field inhomogeneity caused by adverse experimental conditions remains an obstacle restricting NMR applications. In this study, we introduce a new NMR method for high-resolution pure shift proton (1H) NMR measurements in inhomogeneous magnetic fields. We demonstrate that the method allows one to perform chemical analyses on complex solutions in deshimmed magnetic fields, to obtain metabolite information on intact biological tissues with intrinsic field inhomogeneities and to achieve in situ electrochemical detection under externally adverse field conditions. This approach is readily implemented on common commercial NMR instruments without field shimming and locking procedures, specialized hardware requirements as well as complicated sample pretreatments. It provides an effective tool for NMR applications to high-resolution chemical and biological measurements under inhomogeneous magnetic field conditions. PMID- 28581727 TI - Density Functional Theory Study of the Reaction between d0 Tungsten Alkylidyne Complexes and H2O: Addition versus Hydrolysis. AB - The reactions of early-transition-metal complexes with H2O have been investigated. An understanding of these elementary steps promotes the design of precursors for the preparation of metal oxide materials or supported heterogeneous catalysts. Density functional theory (DFT) calculations have been conducted to investigate two elementary steps of the reactions between tungsten alkylidyne complexes and H2O, i.e., the addition of H2O to the W=C bond and ligand hydrolysis. Four tungsten alkylidyne complexes, W(=CSiMe3)(CH2SiMe3)3 (A 1), W(=CSiMe3)(CH2tBu)3 (B-1), W(=CtBu)(CH2tBu)3 (C-1), and W(=CtBu)(OtBu)3 (D 1), have been compared. The DFT studies provide an energy profile of the two competing pathways. An additional H2O molecule can serve as a proton shuttle, accelerating the H2O addition reaction. The effect of atoms at the alpha and beta positions has also been examined. Because the lone-pair electrons of an O atom at the alpha position can interact with the orbital of the proton, the barrier of the ligand-hydrolysis reaction for D-1 is dramatically reduced. Both the electronic and steric effects of the silyl group at the beta position lower the barriers of both the H2O addition and ligand-hydrolysis reactions. These new mechanistic findings may lead to the further development of metal complex precursors. PMID- 28581728 TI - A Microporous Aluminosilicate with 12-, 12-, and 8-Ring Pores and Isolated 8-Ring Channels. AB - Synthesis of new zeolites with controlled pore architectures is important in the field of catalysis and separation related to chemical transformation, environmental protection, and energy-saving. Zeolites containing channels of different sizes in the same framework have been desirable. We report here the synthesis and structure of a novel aluminosilicate zeolite (designated as YNU-5), the first zeolite containing interconnected 12-, 12-, and 8-ring pores, as well as independent straight 8-ring channels. The synthesis procedure is quite simple and consists of conventional hydrothermal conditions as well as readily available starting materials. The framework structure is stable enough and Si/Al ratio is controllable between 9 and 350. Determination of the crystal structure is performed by utilizing X-ray diffraction-based techniques, revealing 9 independent tetrahedrally coordinated atoms. This robust structure is expected to be industrially valuable and several unusual combinations of composite building units are of considerable interest in an academic sense. The new zeolite YNU-5 is promising catalyst for the production of useful light olefins such as propylene and butylenes in the dimethyl ether-to-olefin reaction, when the Si/Al ratio is properly tuned by dealumination through simple acid treatments. PMID- 28581730 TI - Tellurotungstate-Based Organotin-Rare-Earth Heterometallic Hybrids with Four Organic Components. AB - A family of unprecedented tellurotungstate-based organotin-rare-earth (RE) heterometallic hybrids [H2N(CH3)2]6H12Na2 {[Sn(CH3)W2O4(IN)][(B-alpha TeW8O31)RE(H2O) (Ac)]2}2.25H2O [RE = CeIII (1), PrIII (2), NdIII (3), SmIII (4), EuIII (5), GdIII (6), TbIII (7); HIN = isonicotinic acid, HAc = acetic acid] were synthesized and characterized by elemental analyses, IR spectra, UV spectra, thermogravimetric analyses, powder X-ray diffraction, and single-crystal X-ray diffraction. The polyoxoanionic skeletons {[Sn(CH3)W2O4(IN)][(B-alpha TeW8O31)RE(H2O) (Ac)]2}220- of 1-7 are constructed from two symmetrical units {[Sn(CH3)W2O4(IN)][(B-alpha-TeW8O31)RE(H2O) (Ac)]2}10- linked by two acetate connectors, which not only represent the first inorganic-organic hybrid RE substituted tellurotungstates involving three different organic ligands, but also stand for the first samples of organotin-RE heterometallic polyoxometalate derivatives. The solid-state luminescent emission properties of 2-5 mainly display the characteristic emission bands of REIII cations, whereas during the emission procedure of 7, [B-alpha-TeW8O31]10- segments make a nonignorable contribution to the PL behavior of 7 accompanying by the occurrence of the intramolecular energy transfer from O->W LMCT energy to Tb3+ centers. Furthermore, 4@CTAB composites with peanutlike and honeycombed morphologies were prepared by a surfactant cetyltrimethylammonium bromide (CTAB). The time-resolved emission spectra of the 4@CTAB composite with CTAB/4 = 0.033/0.05 consolidate the energy transfer from CTAB to REIII centers. Variable-temperature magnetic susceptibility measurements for 2, 3, and 4 were performed. PMID- 28581729 TI - Conformational Heterogeneity and the Affinity of Substrate Molecular Recognition by Cytochrome P450cam. AB - The broad and variable substrate specificity of cytochrome P450 enzymes makes them a model system for studying the determinants of protein molecular recognition. The archetypal cytochrome P450cam (P450cam) is a relatively specific P450, a feature once attributed to the high rigidity of its active site. However, increasingly studies have provided evidence of the importance of conformational changes to P450cam activity. Here we used infrared (IR) spectroscopy to investigate the molecular recognition of P450cam. Toward this goal, and to assess the influence of a hydrogen bond (H-bond) between active site residue Y96 and substrates, two variants in which Y96 is replaced by a cyanophenyl (Y96CNF) or phenyl (Y96F) group were characterized in complexes with the substrates camphor, isoborneol, and camphane. These combinations allow for a comparison of complexes in which the moieties on both the protein and substrate can serve as a H-bond donor, acceptor, or neither. The IR spectra of heme-bound CO and the site specifically incorporated CN of Y96CNF were analyzed to characterize the number and nature of environments in each protein, both in the free and bound states. Although the IR spectra do not support the idea that protein-substrate H-bonding is central to P450cam recognition, the data altogether suggest that the differing conformational heterogeneity in the active site of the P450cam variants and changes in heterogeneity upon binding of different substrates likely contribute to their variable affinities via a conformational selection mechanism. This study further extends our understanding of the molecular recognition of archetypal P450cam and demonstrates the application of IR spectroscopy combined with selective protein modification to delineate protein-ligand interactions. PMID- 28581732 TI - Microwave-Assisted Synthesis of Perovskite SrSnO3 Nanocrystals in Ionic Liquids for Photocatalytic Applications. AB - Nanosized SrSnO3 photocatalysts have been successfully synthesized by microwave synthesis in various ionic liquids (ILs) followed by a heat treatment process to optimize the materials' crystallinity. The influence of the ILs with various cations such as 1-butyl-3-methylimidazolium ([C4mim]+), 6-bis(3-methylimidazolium 1-yl)hexane ([C6(mim)2]2+), butylpyridinium ([C4Py]+), and tetradecyltrihexylphosphonium ([P66614]+) and bis(trifluoromethanesulfonyl)amide ([Tf2N]-) as the anion on the structure, crystallization, and morphology of the products was investigated. The samples were characterized by X-ray diffraction (XRD), thermogravimetry (TG), scanning electron microscopy (SEM), surface area analysis by gas adsorption, X-ray photoelectron spectroscopy (XPS), diffuse reflectance UV-vis spectroscopy, and Raman and IR spectroscopy. According to structure characterization by XRD and Raman spectroscopy all samples crystallized phase-pure in the orthorhombic GdFeO3 perovskite structure type. SEM reveals that, on the basis of the IL, the obtained SrSnO3 nanoparticles exhibit different morphologies and sizes. Rod-shaped particles are formed in [C4mim][Tf2N], [C6(mim)2][Tf2N]2, and [P66614][Tf2N]. However, the particle dimensions and size distribution vary depending on the IL and range from quite thin and long needlelike particles with a narrow size distribution obtained in [P66614][Tf2N] to relatively larger particles with a broader size distribution obtained in [C6(mim)2][Tf2N]2. In contrast, in [C4Py][Tf2N] nanospheres with a diameter of about 50 nm form. For these particles the highest photocatalytic activity was observed. Our investigations indicate that the improved photocatalytic activity of this material results from the synergistic effect of the relatively large surface area associated with nanosize and an appropriate energy band structure. PMID- 28581731 TI - Synthesis of a Bifunctional Peptide Inhibitor-IgG1 Fc Fusion That Suppresses Experimental Autoimmune Encephalomyelitis. AB - Multiple sclerosis (MS) is a neurodegenerative disease that is estimated to affect over 2.3 million people worldwide. The exact cause for this disease is unknown but involves immune system attack and destruction of the myelin protein surrounding the neurons in the central nervous system. One promising class of compounds that selectively prevent the activation of immune cells involved in the pathway leading to myelin destruction are bifunctional peptide inhibitors (BPIs). Treatment with BPIs reduces neurodegenerative symptoms in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. In this work, as an effort to further improve the bioactivity of BPIs, BPI peptides were conjugated to the N- and C-termini of the fragment crystallizable (Fc) region of the human IgG1 antibody. Initially, the two peptides were conjugated to IgG1 Fc using recombinant DNA technology. However, expression in yeast resulted in low yields and one of the peptides being heavily proteolyzed. To circumvent this problem, the poorly expressed peptide was instead produced by solid phase peptide synthesis and conjugated enzymatically using a sortase-mediated ligation. The sortase-mediated method showed near-complete conjugation yield as observed by SDS PAGE and mass spectrometry in small-scale reactions. This method was scaled up to obtain sufficient quantities for testing the BPI-Fc fusion in mice induced with EAE. Compared to the PBS-treated control, mice treated with the BPI-Fc fusion showed significantly reduced disease symptoms, did not experience weight loss, and showed reduced de-myelination. These results demonstrate that the BPI peptides were highly active at suppressing EAE when conjugated to the large Fc scaffold in this manner. PMID- 28581733 TI - Evaluation of Novel Routes for NOx Formation in Remote Regions. AB - Photochemical cycling of nitrogen oxides (NOx) produces tropospheric ozone (O3), and NOx is traditionally considered to be directly emitted. The inability of current global models to accurately calculate NOx levels, and concurrently, difficulties in performing direct NOx measurements in low-NOx regimes (several pptv or several tens of pptv) globally introduce a large uncertainty in the modeling of O3 formation. Here, we use the near-explicit Master Chemical Mechanism (MCM v3.2) within a 0D box-model framework, to describe the chemistry of NOx and O3 in the remote marine boundary layer at Cape Verde. We explore the impact of a recently discovered NOx recycling route, namely photolysis of particulate nitrate, on the modeling of NOx abundance and O3 formation. The model is constrained to observations of long-lived species, meteorological parameters, and photolysis frequencies. Only a model with this novel NOx recycling route reproduces levels of gaseous nitrous acid, NO, and NO2 within the model and measurement uncertainty. O3 formation from NO oxidation is several times more efficient than previously considered. This study highlights the need for the inclusion of particulate nitrate photolysis in future models for O3 and for the photolysis rate of particulate nitrate to be quantified under variable atmospheric conditions. PMID- 28581734 TI - Nitrosamine Formation in Amine-Based CO2 Capture in the Absence of NO2: Molecular Modeling and Experimental Validation. AB - A computational chemistry approach was used to elucidate and verify the different nitrosamine formation mechanisms and pathways. These included nitrosamine formation under acid or basic environments in the presence of NO, O2, SO2 and CO2 without NO2. The results clearly showed that nitrosamine could be formed without NO2 via 2 different types of mechanisms, namely, addition and elimination forming N-N bond before proton transfer and proton transfer before N-N bond formation, respectively. The essence of these mechanisms identified in this work was that two reaction steps were required to complete both reaction mechanisms with different nitrosating agents. Two steps were both necessary neither of which could be neglected, if the nitrosamine formation reaction was to be completed. Computational simulation performed on the reactant, intermediate, transition state, and product for each set of reactions also validated the proposed mechanisms. Experiment also detected nitrosamine from the reaction of diethylamine and NO, SO2, O2, and CO2 in both liquid and gas phase. Thus, NO2 is not necessary for nitrosamine formation to occur in the CO2 capture system. PMID- 28581736 TI - Highly Efficient Malolactic Fermentation of Red Wine Using Encapsulated Bacteria in a Robust Biocomposite of Silica-Alginate. AB - Bacteria encapsulation to develop malolactic fermentation emerges as a biotechnological strategy that provides significant advantages over the use of free cells. Two encapsulation methods have been proposed embedding Oenococcus oeni, (i) interpenetrated polymer networks of silica and Ca-alginate and (ii) Ca alginate capsules coated with hydrolyzed 3-aminopropyltriethoxysilane (hAPTES). On the basis of our results, only the first method was suitable for bacteria encapsulation. The optimized silica-alginate capsules exhibited a negligible bacteria release and an increase of 328% and 65% in L-malic acid consumption and mechanical robustness, respectively, compared to untreated alginate capsules. Moreover, studies of capsule stability at different pH and ethanol concentrations in water solutions and in wine indicated a better behavior of silica-alginate capsules than untreated ones. The inclusion of silicates and colloidal silica in alginate capsules containing O. oeni improved markedly their capacity to deplete the levels of L-malic acid in red wines and their mechanical robustness and stability. PMID- 28581735 TI - Covalent Capture of Aligned Self-Assembling Nanofibers. AB - A great deal of effort has been invested in the design and characterization of systems which spontaneously assemble into nanofibers. These systems are interesting for their fundamental supramolecular chemistry and have also been shown to be promising materials, particularly for biomedical applications. Multidomain peptides are one such assembler, and in previous work we have demonstrated the reversibility of their assembly under mild and easily controlled conditions, along with their utility for time-controlled drug delivery, protein delivery, cell encapsulation, and cell delivery applications. Additionally, their highly compliant criteria for sequence selection allows them to be modified to incorporate protease susceptibility and biological-recognition motifs for cell adhesion and angiogenesis. However, control of their assembly has been limited to the formation of disorganized nanofibers. In this work, we expand our ability to manipulate multidomain-peptide assembly into parallel-aligned fiber bundles. Albeit this alignment is achieved by the shearing forces of syringe delivery, it is also dependent on the amino acid sequence of the multidomain peptide. The incorporation of the amino acid DOPA (3,4-dihydroxyphenylalanine) allows the self assembled nanofibers to form an anisotropic hydrogel string under modest shear stress. The hydrogel string shows remarkable birefringence, and highly aligned nanofibers are visible in scanning electronic microscopy. Furthermore, the covalent linkage induced by DOPA oxidation allows covalent capture of the aligned nanofiber bundles, enhancing their birefringence and structural integrity. PMID- 28581737 TI - Enzymatic Profile of 'Willamette' Raspberry Leaf and Fruit Affected by Prohexadione-Ca and Young Canes Removal Treatments. AB - The influence of growth regulator prohexadione-Ca (ProCa) concurrently with young canes removal on the modification of photosynthetic pigments content and antioxidant enzymes (peroxidase, POD; catalase, CAT; polyphenol oxidase, PPO; superoxide dismutase, SOD) activities in leaves and fruits of raspberry (Rubus idaeus L.) cultivar 'Willamette' was studied. ProCa increased while canes removal decreased chlorophylls and carotenoids content compared to control. POD, CAT, and PPO activities in leaves after removal of young canes were higher compared to control (2-4 times) which was visually confirmed for POD by isoelectrofocusing. Removal of young canes slithly increased, while ProCa significantly enhanced SOD activity in leaves compared to control (475.10 and 218.38 nkat mg-1 prot, respectively). Pattern of SOD activity in fruit was similar as in leaf with substantial increase compared to control (about 15 times). Combination of implemented measures increased activity of all enzymes in the leaves and fruits. Our study could provide a better knowledge of the ProCa and canes removal influences on the action of enzymes in order to regulate their activities in fruit products. PMID- 28581738 TI - Identification and Quantitation of Furocoumarins in Popularly Consumed Foods in the U.S. Using QuEChERS Extraction Coupled with UPLC-MS/MS Analysis. AB - Furocoumarins are a class of photoactive compounds found in several plant species and may be responsible for the observed association between consumption of citrus products and the risk of skin cancer. Furocoumarin contents of several foods have been reported previously, but no comprehensive database of furocoumarin content of foods is currently available. Therefore, this study aimed to determine the distribution of furocoumarins in popularly consumed foods in the U.S. Samples of three varieties of each of 29 foods known or suspected to contain furocoumarins were purchased, prepared for analysis using a solid phase extraction method, and analyzed using UPLC-MS/MS for the presence of seven major furocoumarins. Most foods measured contained more than one furocoumarin, and some contained all seven of the furocoumarins examined. Total furocoumarin concentration was greatest in fresh parsley (23215 ng/g), grapefruits (21858 ng/g), lime juice (14580 ng/g), grapefruit juice (95341 ng/g), and limes (9151 ng/g). Bergamottin was found in the greatest proportion of foods sampled (23 of 29), followed by bergapten (19 of 29) and 6'7'-dihydroxybergamottin (16 of 29). These measurements will enable more accurate estimation of dietary furocoumarin exposure and will strengthen future epidemiological work investigating the relationships between furocoumarin intake and health outcomes. PMID- 28581739 TI - Total Syntheses of Malabaricones B and C via a Cross-Metathesis Strategy. AB - The malabaricones A-D belong to the class of diarylnonanoids isolated from the Myristicaceae family of plants. Although malabaricone C displayed various interesting biological activities, its isolation remains tedious due to its close chemical similarity to malabaricones A, B, and D. Therefore, development of an efficient synthesis route has become essential to cater to the need of large amounts of malabaricone C for its pharmacological profiling. So far there is only one report of the synthesis of malabaricone C through a lengthy sequence of reactions. We have developed an efficient and short route for the syntheses of malabaricones B and C, which will also provide a convenient access to all other members of the malabaricone family. Synthesis of an important building block, omega-aryl heptyl bromide, employed in the synthesis was realized by adopting a cross-metathesis reaction as the key step. PMID- 28581740 TI - Conformational Selection as the Mechanism of Guest Binding in a Flexible Supramolecular Host. AB - This study offers a detailed mechanistic investigation of host-guest encapsulation behavior in a new enzyme-mimetic metal-ligand host and provides the first observation of a conformational selection mechanism (as opposed to induced fit) in a supramolecular system. The Ga4L4 host described features a C3-symmetric ligand motif with meta-substituted phenyl spacers, which enables the host to initially self-assemble into an S4-symmetric structure and then subsequently isomerize to a T-symmetric tetrahedron for better accommodation of a sufficiently large guest. Selective inversion recovery 1H NMR studies provide structural insights into the self-exchange behaviors of the host and the guest individually in this dynamic system. Kinetic analysis of the encapsulation-isomerization event revealed that increasing the concentration of guest inhibits the rate of host guest relaxation, a key distinguishing feature of conformational selection. A comprehensive study of this simple enzyme mimic provides insight into analogous behavior in biophysics and enzymology and aims to inform the design of efficient self-assembled microenvironment catalysts. PMID- 28581741 TI - Overexpression of HvHGGT Enhances Tocotrienol Levels and Antioxidant Activity in Barley. AB - Vitamin E is a potent lipid-soluble antioxidant and essential nutrient for human health. Tocotrienols are the major form of vitamin E in seeds of most monocots. It has been known that homogentisate geranylgeranyl transferase (HGGT) catalyzes the committed step of tocotrienol biosynthesis. In the present study, we generated transgenic barley overexpressing HvHGGT under endogenous D-Hordein promoter (proHor). Overexpression of HvHGGT increased seed size and seed weight in transgenic barley. Notably, total tocotrienol content increased by 10-15% in seeds of transgenic lines, due to the increased levels of delta-, beta-, and gamma-tocotrienol, but not alpha-tocotrienol. Total tocopherol content decreased by 14-18% in transgenic lines, compared to wild type. The antioxidant activity of seeds was determined by using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2' azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), and lipid peroxidation assays. Compared to wild type, radical scavenging activity of seed extracts was enhanced by 17-18% in transgenic lines. Meanwhile, the lipid peroxidation level was decreased by about 20% in transgenic barley seeds. Taken together, overexpression of HvHGGT enhanced the tocotrienol levels and antioxidant capacity in barley seeds. PMID- 28581742 TI - A Simple and Fast Extraction Method for the Determination of Multiclass Antibiotics in Eggs Using LC-MS/MS. AB - The purpose of this study was to develop and validate a simple, fast, and specific extraction method for the analysis of 64 antibiotics from nine classes (including sulfonamides, quinolones, tetracyclines, macrolides, lincosamide, nitrofurans, beta-lactams, nitromidazoles, and cloramphenicols) in chicken eggs. Briefly, egg samples were simply extracted with a mixture of acetonitrile-water (90:10, v/v) and 0.1 mol.L-1 Na2EDTA solution assisted with ultrasonic. The extract was centrifuged, condensed, and directly analyzed on a liquid chromatography coupled to tandem mass spectrometry. Compared with conventional cleanup methods (passing through solid phase extract cartridges), the established method demonstrated comparable efficiencies in eliminating matrix effects and higher or equivalent recoveries for most of the target compounds. Typical validation parameters including specificity, linearity, matrix effect, limits of detection (LODs) and quantification (LOQs), the decision limit, detection capability, trueness, and precision were evaluated. The recoveries of target compounds ranged from 70.8% to 116.1% at three spiking levels (5, 20, and 50 MUg.kg-1), with relative standard deviations less than 14%. LODs and LOQs were in the ranges of 0.005-2.00 MUg.kg-1 and 0.015-6.00 MUg.kg-1 for all of the antibiotics, respectively. A total of five antibiotics were successfully detected in 22 commercial eggs from local markets. This work suggests that the method is suitable for the analysis of multiclass antibiotics in eggs. PMID- 28581743 TI - Tethered 1,2-Si-Group Migrations in Radical-Mediated Ring Enlargements of Cyclic Alkoxysilanes: An EPR Spectroscopic and Computational Investigation. AB - 5- to 6-member ring enlargements of 3-oxa-2-silacyclopentylmethyl to 4-oxa-3 silacyclohexyl radicals were investigated by EPR spectroscopy and QM computations of model indano-oxasilacyclopentane and oxasilinanyl compounds. Both experimental and computational evidence favored a mechanism via a concerted 1,2-migration of the "tethered" Si-group. Thus, the "forbidden" 1,2-Si-group migration from carbon to carbon becomes allowed when the Si-group is "tethered". The EPR data from 3 oxa-2-silacyclopentylmethyl radicals disclosed ground state conformations having semioccupied p-orbitals close to antiperiplanar with respect to their beta-Si-C bonds, but indicated Si-hyperconjugation (beta-silicon effect) was insignificant in radicals. Kinetic data was obtained by the steady state EPR method for ring enlargement of indano-3-oxa-2-silacyclopentylmethyl radicals. The scope of the novel rearrangement in terms of other ring types and sizes, as well as the analogous 1,2-migration of "tethered" C-centered groups, was explored computationally. PMID- 28581744 TI - Lignans from the Roots of Taxus wallichiana and Their alpha-Glucosidase Inhibitory Activities. AB - From an EtOAc-soluble extract of the roots of Taxus wallichiana, six new (1-6) and 11 known lignans were isolated. The structures of the new compounds were elucidated based on interpretation of spectroscopic data. (+)-7'-epi-Tsugacetal (1) is a rare aryltetralin-type lignan having a cis-orientation of H-7' and H-8'. Compounds 3-6 were identified as the first naturally occurring tetrahydrofuranoid lignans having a cis-orientation of H-7 and H-8. All tested compounds were found to possess alpha-glucosidase inhibitory activity, with formosanol (9) showing the most potent effect with an IC50 value of 35.3 MUM. PMID- 28581746 TI - Reliable Estimation of Prediction Uncertainty for Physicochemical Property Models. AB - One of the major challenges in computational science is to determine the uncertainty of a virtual measurement, that is the prediction of an observable based on calculations. As highly accurate first-principles calculations are in general unfeasible for most physical systems, one usually resorts to parameteric property models of observables, which require calibration by incorporating reference data. The resulting predictions and their uncertainties are sensitive to systematic errors such as inconsistent reference data, parametric model assumptions, or inadequate computational methods. Here, we discuss the calibration of property models in the light of bootstrapping, a sampling method that can be employed for identifying systematic errors and for reliable estimation of the prediction uncertainty. We apply bootstrapping to assess a linear property model linking the 57Fe Mossbauer isomer shift to the contact electron density at the iron nucleus for a diverse set of 44 molecular iron compounds. The contact electron density is calculated with 12 density functionals across Jacob's ladder (PWLDA, BP86, BLYP, PW91, PBE, M06-L, TPSS, B3LYP, B3PW91, PBE0, M06, TPSSh). We provide systematic-error diagnostics and reliable, locally resolved uncertainties for isomer-shift predictions. Pure and hybrid density functionals yield average prediction uncertainties of 0.06-0.08 mm s-1 and 0.04 0.05 mm s-1, respectively, the latter being close to the average experimental uncertainty of 0.02 mm s-1. Furthermore, we show that both model parameters and prediction uncertainty depend significantly on the composition and number of reference data points. Accordingly, we suggest that rankings of density functionals based on performance measures (e.g., the squared coefficient of correlation, r2, or the root-mean-square error, RMSE) should not be inferred from a single data set. This study presents the first statistically rigorous calibration analysis for theoretical Mossbauer spectroscopy, which is of general applicability for physicochemical property models and not restricted to isomer shift predictions. We provide the statistically meaningful reference data set MIS39 and a new calibration of the isomer shift based on the PBE0 functional. PMID- 28581745 TI - Transient Formation and Reactivity of a High-Valent Nickel(IV) Oxido Complex. AB - A reactive high-valent dinuclear nickel(IV) oxido bridged complex is reported that can be formed at room temperature by reaction of [(L)2Ni(II)2(MU-X)3]X (X = Cl or Br) with NaOCl in methanol or acetonitrile (where L = 1,4,7-trimethyl-1,4,7 triazacyclononane). The unusual Ni(IV) oxido species is stabilized within a dinuclear tris-MU-oxido-bridged structure as [(L)2Ni(IV)2(MU-O)3]2+. Its structure and its reactivity with organic substrates are demonstrated through a combination of UV-vis absorption, resonance Raman, 1H NMR, EPR, and X-ray absorption (near-edge) spectroscopy, ESI mass spectrometry, and DFT methods. The identification of a Ni(IV)-O species opens opportunities to control the reactivity of NaOCl for selective oxidations. PMID- 28581748 TI - High-Pressure Effects on Hofmann-Type Clathrates: Promoted Release and Restricted Insertion of Guest Molecules. AB - The search for effective methods to accurately control host-guest relationship is the central theme of host-guest chemistry. In this work, high pressure successfully promotes guest release in the Hofmann-type clathrate of [Ni(NH3)2Ni(CN)4].2C6H6 (Ni-Bz) and restricts guest insertion into Ni(NH3)2Ni(CN)4 (Ni-Ni). Because of the weak host-guest interactions of Ni-Bz, external force gradually removes guest benzene from the host framework, leading to puckered layers. Further theoretical calculations reveal the positive pressure contribution to breaking the energy barrier between Ni-Bz and Ni-Ni, explaining guest release from an energy standpoint. Inversely, guest insertion is restricted in the synthesized host of Ni-Ni because of the steric hindrance effect at high pressure. This study not only reveals structural effects on host-guest behaviors but also proves the role of pressure in controlling host-guest interactions. This unique observation is also crucial for the further application of host-guest materials in sustained and intelligent drug release, molecular separation, and transportation. PMID- 28581747 TI - Catalytic Enantioselective [3 + 2] Cycloaddition of alpha-Keto Ester Enolates and Nitrile Oxides. AB - An enantioselective [3 + 2] cycloaddition reaction between nitrile oxides and transiently generated enolates of alpha-keto esters has been developed. The catalyst system was found to be compatible with in situ nitrile oxide-generation conditions. A versatile array of nitrile oxides and alpha-keto esters could participate in the cycloaddition, providing novel 5-hydroxy-2-isoxazolines in high chemical yield with high levels of diastereo- and enantioselectivity. Notably, the optimal reaction conditions circumvented concurrent reactions via O imidoylation and hetero-[3 + 2] pathways. PMID- 28581750 TI - J-Type Heteroexciton Coupling Effect on an Asymmetric Donor-Acceptor-Donor-Type Fluorophore. AB - The novel donor-acceptor-donor (D-A-D)-type fluorophore with an asymmetric structure is reported. The twisted-induced charge transfer (TICT) luminescence was observed. The degree of charge transfer and radiative rate constant in the luminescence increased simultaneously with increase in orientational polarizability of solvents. In contrast to the numerous CT fluorophore researches, this behavior has never been previously observed. This characteristic behavior reveals the existence of an effective exciton coupling between the CT states in the donor-acceptor-donor-type fluorophore for the first time. PMID- 28581749 TI - A Novel Series of Highly Potent Small Molecule Inhibitors of Rhinovirus Replication. AB - Human rhinoviruses (hRVs) are the main causative pathogen for common colds and are associated with the exacerbation of asthma. The wide variety in hRV serotypes has complicated the development of rhinovirus replication inhibitors. In the current investigation, we developed a novel series of benzothiophene derivatives and their analogues (6-8) that potently inhibit the replication of both hRV-A and hRV-B strains. Compound 6g inhibited the replication of hRV-B14, A21, and A71, with respective EC50 values of 0.083, 0.078, and 0.015 MUM. The results of a time of-addition study against hRV-B14 and hRV-A16 and resistant mutation analysis on hRV-B14 implied that 6g acts at the early stage of the viral replication process, interacting with viral capsid protein. A molecular docking study suggested that 6g has a capsid-binding mode similar to that of pleconaril. Finally, derivatives of 6 also displayed significant inhibition against poliovirus 3 (PV3) replication, implying their potential inhibitory activities against other enterovirus species. PMID- 28581751 TI - Simple Fully Nonlocal Density Functionals for Electronic Repulsion Energy. AB - From a simplified version of the mathematical structure of the strong coupling limit of the exact exchange-correlation functional, we construct an approximation for the electronic repulsion energy at physical coupling strength, which is fully nonlocal. This functional is self-interaction free and yields energy densities within the definition of the electrostatic potential of the exchange-correlation hole that are locally accurate and have the correct asymptotic behavior. The model is able to capture strong correlation effects that arise from chemical bond dissociation, without relying on error cancellation. These features, which are usually missed by standard density functional theory (DFT) functionals, are captured by the highly nonlocal structure, which goes beyond the "Jacob's ladder" framework for functional construction, by using integrals of the density as the key ingredient. Possible routes for obtaining the full exchange-correlation functional by recovering the missing kinetic component of the correlation energy are also implemented and discussed. PMID- 28581752 TI - Semilocal Exchange Energy Functional for Two-Dimensional Quantum Systems: A Step Beyond Generalized Gradient Approximations. AB - Semilocal density functionals for the exchange-correlation energy of electrons are extensively used as they produce realistic and accurate results for finite and extended systems. The choice of techniques plays a crucial role in constructing such functionals of improved accuracy and efficiency. An accurate and efficient semilocal exchange energy functional in two dimensions is constructed by making use of the corresponding hole which is derived based on the density matrix expansion. The exchange hole involved is localized under the generalized coordinate transformation and satisfies all the relevant constraints. Comprehensive testing and excellent performance of the functional is demonstrated versus exact exchange results. The accuracy of results obtained by using the newly constructed functional is quite remarkable as it substantially reduces the errors present in the local and nonempirical exchange functionals proposed so far for two-dimensional quantum systems. The underlying principles involved in the functional construction are physically appealing and hold promise for developing range separated and nonlocal exchange functionals in two dimensions. PMID- 28581753 TI - Observation of Rhenium Anion and Electron Affinity of Re. AB - It was believed that the rhenium anion Re- was not stable, just like Mn-. We report the observation of Re- in the laser ablation ion source and the further confirmation via the high-resolution photoelectron spectra of Re-. The ground state of Re- ions is 5d66s2 5D4. The electron affinity of rhenium is determined to be 487.13(51) cm-1 or 60.396(63) meV. PMID- 28581754 TI - Phase-Engineering-Induced Generation and Control of Highly Anisotropic and Robust Excitons in Few-Layer ReS2. AB - The anisotropic exciton behavior in two-dimensional materials induced by spin orbit coupling or anisotropic spatial confinement has been exploited in imaging applications. Herein, we propose a new strategy to generate high-energy and robust anisotropic excitons in few-layer ReS2 nanosheets by phase engineering. This approach overcomes the limitation imposed by the layer thickness, enabling production of visible polarized photoluminescence at room temperature. Ultrasonic chemical exfoliation is implemented to introduce the metallic T phase of ReS2 into the few-layer semiconducting Td nanosheets. In this configuration, light excitation can readily produce "hot" electrons to tunnel to the Td phase via the metal-semiconductor interface to enhance the overlap between the wave functions and screened Coulomb interactions. Owing to the strong electron-hole interaction, significant increase in the optical band gap is observed. Highly anisotropic and tightly bound excitons with visible light emission (1.5-2.25 eV) are produced and can be controlled by tailoring the T phase concentration. This novel strategy allows manipulation of polarized optical information and has great potential in optoelectronic devices. PMID- 28581755 TI - Reversible Concentration-Dependent Photoluminescence Quenching and Change of Emission Color in CsPbBr3 Nanowires and Nanoplatelets. AB - We discuss the photoluminescence (PL) of quantum-confined CsPbBr3 colloidal nanocrystals of two different shapes (nanowires and nanoplatelets) at different concentrations in solution and in solid-state films. Upon increasing the nanocrystal concentration in solution, a constant drop in photoluminescence quantum yield is observed, accompanied by a significant PL red shift. This effect is reversible, and the original PL can be restored by diluting to the original concentration. We show that this effect can be in part attributed to self absorption and partly to aggregation. In particular, for nanoplatelets, where the aggregation is mostly irreversible, while the self-absorption effect is reversible, the two contributions can be well separated. Finally, when dry solid state films are prepared, the emission band is shifted into the green spectral region, close to the bulk CsPbBr3 band gap, thus preventing blue emission from such films. PMID- 28581756 TI - Cl-Loss Dynamics of Vinyl Chloride Cations in the B2A" State: Role of the C2A' State. AB - The dissociative photoionization of vinyl chloride (C2H3Cl) in the 11.0-14.2 eV photon energy range was investigated using threshold photoelectron photoion coincidence (TPEPICO) velocity map imaging. Three electronic states, namely, A2A', B2A", and C2A', of the C2H3Cl+ cation were prepared, and their dissociation dynamics were investigated. A unique fragment ion, C2H3+, was observed within the excitation energy range. TPEPICO three-dimensional time-sliced velocity map images of C2H3+ provided the kinetic energy release distributions (KERD) and anisotropy parameters in dissociation of internal-energy-selected C2H3Cl+ cations. At 13.14 eV, the total KERD showed a bimodal distribution consisting of Boltzmann- and Gaussian-type components, indicating a competition between statistical and non-statistical dissociation mechanisms. An additional Gaussian type component was found in the KERD at 13.65 eV, a center of which was located at a lower kinetic energy. The overall dissociative photoionization mechanisms of C2H3Cl+ in the B2A" and C2A' states are proposed based on time-dependent density functional theory calculations of the Cl-loss potential energy curves. Our results highlight the inconsistency of previous conclusions on the dissociation mechanism of C2H3Cl+. PMID- 28581757 TI - Impact of Hydrogen Bonding in the Binding Site between Capsid Protein and MS2 Bacteriophage ssRNA. AB - MS2 presents a well-studied example of a single-stranded RNA virus for which the genomic RNA plays a pivotal role in the virus assembly process based on the packaging signal-mediated mechanism. Packaging signals (PSs) are multiple dispersed RNA sequence/structure motifs varying around a central recognition motif that interact in a specific way with the capsid protein in the assembly process. Although the discovery and identification of these PSs was based on bioinformatics and geometric approaches, in tandem with sophisticated experimental protocols, we approach this problem using large-scale ab initio computation centered on critical aspects of the consensus protein-RNA interactions recognition motif. DFT calculations are carried out on two nucleoprotein complexes: wild-type and mutated (PDB IDs: 1ZDH and 5MSF ). The calculated partial charge distribution of residues and the strength of hydrogen bonding (HB) between them enabled us to locate the exact binding sites with the strongest HBs, identified to be LYS43-A-4, ARG49-C-13, TYR85-C-5, and LYS61-C-5, due to the change in the sequence of the mutated RNA. PMID- 28581758 TI - Molecular Gibbs Surface Excess and CO2-Hydrate Density Determine the Strong Temperature- and Pressure-Dependent Supercritical CO2-Brine Interfacial Tension. AB - In CO2 geological storage, the interfacial tension (IFT) between supercritical CO2 and brine is critical for the storage capacitance design to prevent CO2 leakage. IFT relies not only on the interfacial molecule properties but also on the environmental conditions at different storage sites. In this paper, supercritical CO2-NaCl solution systems are modeled at 343-373 K and 6-35 MPa under the salinity of 1.89 mol/L using molecular dynamics simulations. After computing and comparing the molecular density profile across the interface, the atomic radial distribution function, the molecular orientation distribution, the molecular Gibbs surface excess (derived from the molecular density profile), and the CO2-hydrate number density under the above environmental conditions, we confirm that only the molecular Gibbs surface excess of CO2 molecules and the CO2 hydrate number density correlate strongly with the temperature- and pressure dependent IFTs. We also compute the populations of two distinct CO2-hydrate structures (T-type and H-type) and attribute the observed dependence of IFTs to the dominance of the more stable, surfactant-like T-type CO2-hydrates at the interface. On the basis of these new molecular mechanisms behind IFT variations, this study could guide the rational design of suitable injecting environmental pressure and temperature conditions. We believe that the above two molecular level metrics (Gibbs surface excess and hydrate number density) are of great fundamental importance for understanding the supercritical CO2-water interface and engineering applications in geological CO2 storage. PMID- 28581759 TI - Simple Model for the Benzene Hexafluorobenzene Interaction. AB - While the experimental intermolecular distance distribution functions of pure benzene and pure hexafluorobenzene are well described by transferable all-atom force fields, the interaction between the two molecules (in a 1:1 mixture) is not well simulated. We demonstrate that the parameters of the transferable force fields are adequate to describe the intermolecular distance distribution if the charges are replaced by a set of charges that are not located at the atoms. The simplest model that well describes the experimental distance distribution, between benzene and hexafluorobenzene, is that of a single ellipsoid for each molecule, representing the van der Waals interactions, and a set of three point charges (on the axis perpendicular to the arene plane) which give the same quadrupole moment as do the all atom charges from the transferable force fields. PMID- 28581760 TI - Enantioselective Synthesis of Functionalized 4-Aryl Hydrocoumarins and 4-Aryl Hydroquinolin-2-ones via Intramolecular Vinylogous Rauhut-Currier Reaction of para-Quinone Methides. AB - A novel strategy for the asymmetric construction of functionalized 4-aryl-3,4 dihydrocoumarins and 4-aryl-3,4-dihydroquinolin-2-ones via an intramolecular vinylogous Rauhut-Currier reaction of para-quinone methides (p-QMs) under the bifunctional catalysis of chiral amine-phosphine is described. This intramolecular mode for the catalytic enantioselective 1,6-conjugate addition of p-QMs has been explored for the first time, delivering two types of synthetically important heterocycles in high yields and enantioselectivites. PMID- 28581761 TI - Amide to Alkyne Interconversion via a Nickel/Copper-Catalyzed Deamidative Cross Coupling of Aryl and Alkenyl Amides. AB - A nickel-catalyzed deamidative cross-coupling reaction of amides with terminal alkynes as coupling partners was disclosed. This newly developed methodology allows the direct interconversion of amides to alkynes and enables a facile route for C(sp2)-C(sp) bond formation in a straightforward and mild fashion. PMID- 28581762 TI - Cu-Catalyzed Stereoselective Borylation of gem-Difluoroalkenes with B2pin2. AB - A novel and efficient method for the synthesis of (Z)-fluorinated alkenylboronic acid pinacol esters via Cu-catalyzed stereoselective borylation of gem difluoroalkenes using bis(pinacolato)diboron (B2pin2) as the boron source with the assistance of NaOtBu and Xantphos at room temperature was developed. PMID- 28581764 TI - Tumor-Targeted and Clearable Human Protein-Based MRI Nanoprobes. AB - Biocompatibility, targeting, and clearance are key challenges in the design of new MRI contrast agents. Herein, we report on a tumor-targeting, gadolinium biomineralized human transferrin (Tf) protein-based nanoparticle (Gd@Tf NP) for MRI use. As compared to the conventionally used gadolinium chelates, the resultant Gd@Tf NPs possess outstanding chemical stability and exhibited superior longitudinal relaxation. More importantly, our MR images show that Gd@Tf indeed retained the natural tumor targeting ability and the subsequent tumor retrieval biofunctions of Tf. Thus, such Tf protein-based MR NPs integrate T1 signal amplification, precise tumor targeting, and systematic clearance capabilities. They offer a new approach to design biocompatible multifunctional MRI contrast agents for a wide range of clinical imaging and treatment applications. PMID- 28581763 TI - Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged Peptidomimetics. AB - A general strategy is introduced for the efficient synthetic access of disulfide linked artificial macrocycles via a Ugi four-component reaction (U4CR) followed by oxidative cyclization. The double-mercapto input is proposed for use in the Ugi reaction, thereby yielding all six topologically possible combinations. The protocol is convergent and short and enables the production of novel disulfide peptidomimetics in a highly general fashion. PMID- 28581766 TI - Dual Activation of Nucleophiles and Electrophiles by N-Heterocyclic Carbene Organocatalysis: Chemoselective N-Imination of Indoles with Isocyanides. AB - The first chemoselective N-imination of indoles with isocyanides by using an N heterocyclic carbene (NHC) as an organocatalyst was achieved. A concurrent activation of nucleophile (indole) and electrophile (isocyanide) took place facilitated by the novel NHC organocatalysis via initial activation of isocyanide. The in situ generated indole anion and imine-azolium species performed a coupling reaction, producing several new indole-based formamidines in high yields under mild conditions, which was not feasible via previously reported strategies. PMID- 28581765 TI - Denitrogenative Imidoyl Radical Cyclization: Synthesis of 2-Substituted Benzoimidazoles from 1-Azido-2-isocyanoarenes. AB - A novel access to 2-substituted benzoimidazoles, through unprecedented denitrogenative imidoyl radical cyclization of 1-azido-2-isocyanoarenes, has been developed. This tandem radical process was initiated by adding a C- or P-centered radical to isocyanide, followed by cycloaddition of the imidoyl radical to the azido group. Then, nitrogen loss and hydrogen abstraction of the resulting aminyl radical from surroundings delivered 2-substituted benzoimidazoles. Carbon radicals generated from another annulation process could also be applied, furnishing various heterocycle linked benzoimidazole derivatives. PMID- 28581767 TI - Phosphorus Pentachloride Initiated Functionalization of Silicon Nanocrystals. AB - Phosphorus pentachloride (PCl5) has long been used to chlorinate hydrocarbons. It has also been applied in silicon surface chemistry to facilitate alkylation via a two-step halogenation/Grignard route. Here we report a study of the reaction of PCl5 with hydride-terminated silicon nanocrystals (H-SiNCs). An examination of the reaction mechanism has allowed us to establish a functionalization protocol that uses PCl5 as a surface radical initiator to introduce alkyl and alkenyl moieties to the surface of H-SiNCs. The reaction proceeds quickly in a single step, at room temperature and the functionalized silicon nanocrystals retained their morphology and crystallinity. The resulting materials exhibited size dependent photoluminescence that was approximately 3* as bright as that observed for thermally hydrosilylated SiNCs. Furthermore, the absolute PL quantum yield (AQY) was more than double. The high AQY is expected to enable SiNCs to compete with chalcogenide-based quantum dots in various applications. PMID- 28581768 TI - Spin ice Thin Film: Surface Ordering, Emergent Square ice, and Strain Effects. AB - Motivated by recent realizations of Dy_{2}Ti_{2}O_{7} and Ho_{2}Ti_{2}O_{7} spin ice thin films, and more generally by the physics of confined gauge fields, we study a model spin ice thin film with surfaces perpendicular to the [001] cubic axis. The resulting open boundaries make half of the bonds on the interfaces inequivalent. By tuning the strength of these inequivalent "orphan" bonds, dipolar interactions induce a surface ordering equivalent to a two-dimensional crystallization of magnetic surface charges. This surface ordering may also be expected on the surfaces of bulk crystals. For ultrathin films made of one cubic unit cell, once the surfaces have ordered, a square ice phase is stabilized over a finite temperature window. The square ice degeneracy is lifted at lower temperature and the system orders in analogy with the well-known F transition of the 6-vertex model. To conclude, we consider the addition of strain effects, a possible consequence of interface mismatches at the film-substrate interface. Our simulations qualitatively confirm that strain can lead to a smooth loss of Pauling entropy upon cooling, as observed in recent experiments on Dy_{2}Ti_{2}O_{7} films. PMID- 28581769 TI - Shape and Dynamics of Adhesive Cells: Mechanical Response of Open Systems. AB - Cell adhesion is an essential biological process. However, previous theoretical and experimental studies ignore a key variable, the changes of cellular volume and pressure, during the dynamic adhesion process. Here, we treat cells as open systems and propose a theoretical framework to investigate how the exchange of water and ions with the environment affects the shape and dynamics of cells adhered between two adhesive surfaces. We show that adherent cells can be either stable (convex or concave) or unstable (spontaneous rupture or collapse) depending on the adhesion energy density, the cell size, the separation of two adhesive surfaces, and the stiffness of the flexible surface. Strikingly, we find that the unstable states vanish when cellular volume and pressure are constant. We further show that the detachments of convex and concave cells are very different. The mechanical response of adherent cells is mainly determined by the competition between the loading rate and the regulation of the cellular volume and pressure. Finally, we show that as an open system the detachment of adherent cells is also significantly influenced by the loading history. Thus, our findings reveal a major difference between living cells and nonliving materials. PMID- 28581770 TI - Collimated Propagation of Fast Electron Beams Accelerated by High-Contrast Laser Pulses in Highly Resistive Shocked Carbon. AB - Collimated transport of ultrahigh intensity electron current was observed in cold and in laser-shocked vitreous carbon, in agreement with simulation predictions. The fast electron beams were created by coupling high-intensity and high-contrast laser pulses onto copper-coated cones drilled into the carbon samples. The guiding mechanism-observed only for times before the shock breakout at the inner cone tip-is due to self-generated resistive magnetic fields of ~0.5-1 kT arising from the intense currents of fast electrons in vitreous carbon, by virtue of its specific high resistivity over the range of explored background temperatures. The spatial distribution of the electron beams, injected through the samples at different stages of compression, was characterized by side-on imaging of hard x ray fluorescence. PMID- 28581771 TI - Surface States in Holographic Weyl Semimetals. AB - We study the surface states of a strongly coupled Weyl semimetal within holography. By explicit numerical computation of an inhomogeneous holographic Weyl semimetal, we observe the appearance of an electric current restricted to the surface in the presence of an electric chemical potential. The integrated current is universal in the sense that it only depends on the topology of the phases showing that the bulk-boundary correspondence holds even at strong coupling. The implications of this result are subtle and may shed some light on anomalous transport at weak coupling. PMID- 28581772 TI - Dynamical Defects in Rotating Magnetic Skyrmion Lattices. AB - The chiral magnet Cu_{2}OSeO_{3} hosts a Skyrmion lattice that may be equivalently described as a superposition of plane waves or a lattice of particlelike topological objects. A thermal gradient may break up the Skyrmion lattice and induce rotating domains, raising the question of which of these scenarios better describes the violent dynamics at the domain boundaries. Here, we show that in an inhomogeneous temperature gradient caused by illumination in a Lorentz transmission electron microscope different parts of the Skyrmion lattice can be set into motion with different angular velocities. Tracking the time dependence, we show that the constant rearrangement of domain walls is governed by dynamic 5-7 defects arranging into lines. An analysis of the associated defect density is described by Frank's equation and agrees well with classical 2D Monte Carlo simulations. Fluctuations of boundaries show a surgelike rearrangement of Skyrmion clusters driven by defect rearrangement consistent with simulations treating Skyrmions as point particles. Our findings underline the particle character of the Skyrmion. PMID- 28581773 TI - Transmodal Fabry-Perot Resonance: Theory and Realization with Elastic Metamaterials. AB - We discovered a new transmodal Fabry-Perot resonance where one elastic-wave mode is maximally transmitted to another. It occurs when the phase difference of two dissimilar modes through an anisotropic layer becomes odd multiples of pi under the reflection-free and weak mode-coupling assumptions. Unlike the well established Fabry-Perot resonance, the transmodal resonance must involve two coupled elastic waves between longitudinal and shear modes. The investigation into the origin of wiggly transmodal transmission spectra suggests that efficient broadband mode conversion can be achieved if the media satisfy the structural stability condition to some degree. The new resonance mechanism, also experimentally characterized, opens up new possibilities for manipulating elastic wave modes as an effective alternative to generating shear-mode ultrasound. PMID- 28581774 TI - High-Harmonic Generation Enhanced by Dynamical Electron Correlation. AB - We theoretically study multielectron effects in high-harmonic generation (HHG), using all-electron first-principles simulations for a one-dimensional model atom. In addition to the usual plateau and cutoff (from a cation in the present case, since the neutral is immediately ionized), we find a prominent resonance peak far above the plateau and a second plateau extended beyond the first cutoff. These features originate from the dication response enhanced by orders of magnitude due to the action of the Coulomb force from the rescattering electron, and, hence, are a clear manifestation of electron correlation. Although the present simulations are done in 1D, the physical mechanism underlying the dramatic enhancement is expected to hold also for three-dimensional real systems. This will provide new possibilities to explore dynamical electron correlation in intense laser fields using HHG, which is usually considered to be of single electron nature in most cases. PMID- 28581775 TI - Elastic Vector Solitons in Soft Architected Materials. AB - We demonstrate experimentally, numerically, and analytically that soft architected materials can support the propagation of elastic vector solitons. More specifically, we focus on structures comprising a network of squares connected by thin and highly deformable ligaments and investigate the propagation of planar nonlinear elastic waves. We find that for sufficiently large amplitudes two components-one translational and one rotational-are coupled together and copropagate without dispersion. Our results not only show that soft architected materials offer a new and rich platform to study the propagation of nonlinear waves, but also open avenues for the design of a new generation of smart systems that take advantage of nonlinearities to control and manipulate the propagation of large amplitude vibrations. PMID- 28581776 TI - Achieving Stable Radiation Pressure Acceleration of Heavy Ions via Successive Electron Replenishment from Ionization of a High-Z Material Coating. AB - A method to achieve stable radiation pressure acceleration (RPA) of heavy ions from laser-irradiated ultrathin foils is proposed, where a high-Z material coating in front is used. The coated high-Z material, acting as a moving electron repository, continuously replenishes the accelerating heavy ion foil with comoving electrons in the light-sail acceleration stage due to its successive ionization under laser fields with Gaussian temporal profile. As a result, the detrimental effects such as foil deformation and electron loss induced by the Rayleigh-Taylor-like and other instabilities in RPA are significantly offset and suppressed so that stable acceleration of heavy ions are maintained. Particle-in cell simulations show that a monoenergetic Al^{13+} beam with peak energy 3.8 GeV and particle number 10^{10} (charge >20 nC) can be obtained at intensity 10^{22} W/cm^{2}. PMID- 28581777 TI - Power Spectrum of Long Eigenlevel Sequences in Quantum Chaotic Systems. AB - We present a nonperturbative analysis of the power spectrum of energy level fluctuations in fully chaotic quantum structures. Focusing on systems with broken time-reversal symmetry, we employ a finite-N random matrix theory to derive an exact multidimensional integral representation of the power spectrum. The N >infinity limit of the exact solution furnishes the main result of this study-a universal, parameter-free prediction for the power spectrum expressed in terms of a fifth Painleve transcendent. Extensive numerics lends further support to our theory which, as discussed at length, invalidates a traditional assumption that the power spectrum is merely determined by the spectral form factor of a quantum system. PMID- 28581779 TI - Security of Continuous-Variable Quantum Key Distribution via a Gaussian de Finetti Reduction. AB - Establishing the security of continuous-variable quantum key distribution against general attacks in a realistic finite-size regime is an outstanding open problem in the field of theoretical quantum cryptography if we restrict our attention to protocols that rely on the exchange of coherent states. Indeed, techniques based on the uncertainty principle are not known to work for such protocols, and the usual tools based on de Finetti reductions only provide security for unrealistically large block lengths. We address this problem here by considering a new type of Gaussian de Finetti reduction, that exploits the invariance of some continuous-variable protocols under the action of the unitary group U(n) (instead of the symmetric group S_{n} as in usual de Finetti theorems), and by introducing generalized SU(2,2) coherent states. Crucially, combined with an energy test, this allows us to truncate the Hilbert space globally instead as at the single mode level as in previous approaches that failed to provide security in realistic conditions. Our reduction shows that it is sufficient to prove the security of these protocols against Gaussian collective attacks in order to obtain security against general attacks, thereby confirming rigorously the widely held belief that Gaussian attacks are indeed optimal against such protocols. PMID- 28581778 TI - Gamma Decay of Unbound Neutron-Hole States in ^{133}Sn. AB - Excited states in the nucleus ^{133}Sn, with one neutron outside the double magic ^{132}Sn core, were populated following one-neutron knockout from a ^{134}Sn beam on a carbon target at relativistic energies at the Radioactive Isotope Beam Factory at RIKEN. Besides the gamma rays emitted in the decay of the known neutron single-particle states in ^{133}Sn additional gamma strength in the energy range 3.5-5.5 MeV was observed for the first time. Since the neutron separation energy of ^{133}Sn is low, S_{n}=2.402(4) MeV, this observation provides direct evidence for the radiative decay of neutron-unbound states in this nucleus. The ability of electromagnetic decay to compete successfully with neutron emission at energies as high as 3 MeV above threshold is attributed to a mismatch between the wave functions of the initial and final states in the latter case. These findings suggest that in the region southeast of ^{132}Sn nuclear structure effects may play a significant role in the neutron versus gamma competition in the decay of unbound states. As a consequence, the common neglect of such effects in the evaluation of the neutron-emission probabilities in calculations of global beta-decay properties for astrophysical simulations may have to be reconsidered. PMID- 28581780 TI - Majorana Quasiparticles Protected by Z_{2} Angular Momentum Conservation. AB - We show how angular momentum conservation can stabilize a symmetry-protected quasitopological phase of matter supporting Majorana quasiparticles as edge modes in one-dimensional cold atom gases. We investigate a number-conserving four species Hubbard model in the presence of spin-orbit coupling. The latter reduces the global spin symmetry to an angular momentum parity symmetry, which provides an extremely robust protection mechanism that does not rely on any coupling to additional reservoirs. The emergence of Majorana edge modes is elucidated using field theory techniques, and corroborated by density-matrix-renormalization-group simulations. Our results pave the way toward the observation of Majorana edge modes with alkaline-earth-like fermions in optical lattices, where all basic ingredients for our recipe-spin-orbit coupling and strong interorbital interactions-have been experimentally realized over the last two years. PMID- 28581781 TI - Laser-Induced Rotation of Iodine Molecules in Helium Nanodroplets: Revivals and Breaking Free. AB - Rotation of molecules embedded in helium nanodroplets is explored by a combination of fs laser-induced alignment experiments and angulon quasiparticle theory. We demonstrate that at low fluence of the fs alignment pulse, the molecule and its solvation shell can be set into coherent collective rotation lasting long enough to form revivals. With increasing fluence, however, the revivals disappear-instead, rotational dynamics as rapid as for an isolated molecule is observed during the first few picoseconds. Classical calculations trace this phenomenon to transient decoupling of the molecule from its helium shell. Our results open novel opportunities for studying nonequilibrium solute solvent dynamics and quantum thermalization. PMID- 28581782 TI - Conformational Asymmetry and Quasicrystal Approximants in Linear Diblock Copolymers. AB - Small angle x-ray scattering experiments on three model low molar mass diblock copolymer systems containing minority polylactide and majority hydrocarbon blocks demonstrate that conformational asymmetry stabilizes the Frank-Kasper sigma phase. Differences in block flexibility compete with space filling at constant density inducing the formation of polyhedral shaped particles that assemble into this low symmetry ordered state with local tetrahedral coordination. These results confirm predictions from self-consistent field theory that establish the origins of symmetry breaking in the ordering of block polymer melts subjected to compositional and conformational asymmetry. PMID- 28581783 TI - Particle-Hole Duality in the Lowest Landau Level. AB - We derive a number of exact relations between response functions of holomorphic, chiral fractional quantum Hall states and their particle-hole (PH) conjugates. These exact relations allow one to calculate the Hall conductivity, Hall viscosity, various Berry phases, and the static structure factor of PH conjugate states from the corresponding properties of the original states. These relations establish a precise duality between chiral quantum Hall states and their PH conjugates. The key ingredient in the proof of the relations is a generalization of Girvin's construction of PH-conjugate states to inhomogeneous magnetic field and curvature. Finally, we make several nontrivial checks of the relations, including for the Jain states and their PH conjugates. PMID- 28581784 TI - Comment on "Linear Scaling of the Exciton Binding Energy versus the Band Gap of Two-Dimensional Materials". PMID- 28581785 TI - Zeno Hall Effect. AB - We show that the quantum Zeno effect gives rise to the Hall effect by tailoring the Hilbert space of a two-dimensional lattice system into a single Bloch band with a nontrivial Berry curvature. Consequently, a wave packet undergoes transverse motion in response to a potential gradient-a phenomenon we call the Zeno Hall effect to highlight its quantum Zeno origin. The Zeno Hall effect leads to retroreflection at the edge of the system due to an interplay between the band flatness and the nontrivial Berry curvature. We propose an experimental implementation of this effect with ultracold atoms in an optical lattice. PMID- 28581787 TI - Possible Precise Measurement of Delbruck Scattering Using Polarized Photon Beams. AB - The advent of high-flux-polarized gamma-ray sources makes possible the nearly isolated precise measurement of the vacuum contribution, Delbruck scattering, to the elastic scattering of these photons off nuclei. Because of the fact that the elastic scattering of the photons is a coherent summation of four processes and that up to now unpolarized sources have been used, the isolated measurement of Delbruck scattering has not been performed. We show that for the appropriate choice of scattering angles, photon polarization, and energies this scattering can be measured nearly independently of other scattering processes. This makes possible the precise measurement of the vacuum contribution to scattering and the possibility of the detection of new physics. PMID- 28581786 TI - Singlet Orbital Ordering in Bilayer Sr_{3}Cr_{2}O_{7}. AB - We perform an extensive study of Sr_{3}Cr_{2}O_{7}, the n=2 member of the Ruddlesden-Popper Sr_{n+1}Cr_{n}O_{3n+1} system. An antiferromagnetic ordering is clearly visible in the magnetization and the specific heat, which yields a huge transition entropy, Rln(6). By neutron diffraction as a function of temperature we have determined the antiferromagnetic structure that coincides with the one obtained from density functional theory calculations. It is accompanied by anomalous asymmetric distortions of the CrO_{6} octahedra. Strong coupling and Lanczos calculations on a derived Kugel-Khomskii Hamiltonian yield a simultaneous orbital and moment ordering. Our results favor an exotic ordered phase of orbital singlets not originated by frustration. PMID- 28581788 TI - Lateral p-n Junction in an Inverted InAs/GaSb Double Quantum Well. AB - We present transport measurements on a lateral p-n junction in an inverted InAs/GaSb double quantum well at zero and nonzero perpendicular magnetic fields. At a zero magnetic field, the junction exhibits diodelike behavior in accordance with the presence of a hybridization gap. With an increasing magnetic field, we explore the quantum Hall regime where spin-polarized edge states with the same chirality are either reflected or transmitted at the junction, whereas those of opposite chirality undergo a mixing process, leading to full equilibration along the width of the junction independent of spin. These results lay the foundations for using p-n junctions in InAs/GaSb double quantum wells to probe the transition between the topological quantum spin Hall and quantum Hall states. PMID- 28581789 TI - Spin-Orbit Coupling Controlled J=3/2 Electronic Ground State in 5d^{3} Oxides. AB - Entanglement of spin and orbital degrees of freedom drives the formation of novel quantum and topological physical states. Here we report resonant inelastic x-ray scattering measurements of the transition metal oxides Ca_{3}LiOsO_{6} and Ba_{2}YOsO_{6}, which reveals a dramatic spitting of the t_{2g} manifold. We invoke an intermediate coupling approach that incorporates both spin-orbit coupling and electron-electron interactions on an even footing and reveal that the ground state of 5d^{3}-based compounds, which has remained elusive in previously applied models, is a novel spin-orbit entangled J=3/2 electronic ground state. This work reveals the hidden diversity of spin-orbit controlled ground states in 5d systems and introduces a new arena in the search for spin orbit controlled phases of matter. PMID- 28581790 TI - Absolutely Maximally Entangled States of Seven Qubits Do Not Exist. AB - Pure multiparticle quantum states are called absolutely maximally entangled if all reduced states obtained by tracing out at least half of the particles are maximally mixed. We provide a method to characterize these states for a general multiparticle system. With that, we prove that a seven-qubit state whose three body marginals are all maximally mixed, or equivalently, a pure ((7,1,4))_{2} quantum error correcting code, does not exist. Furthermore, we obtain an upper limit on the possible number of maximally mixed three-body marginals and identify the state saturating the bound. This solves the seven-particle problem as the last open case concerning maximally entangled states of qubits. PMID- 28581791 TI - Dimensional Crossover in a Charge Density Wave Material Probed by Angle-Resolved Photoemission Spectroscopy. AB - High-resolution angle-resolved photoemission spectroscopy data reveal evidence of a crossover from one-dimensional (1D) to three-dimensional (3D) behavior in the prototypical charge density wave (CDW) material NbSe_{3}. In the low-temperature 3D regime, gaps in the electronic structure are observed due to two incommensurate CDWs, in agreement with x-ray diffraction and electronic-structure calculations. At higher temperatures we observe a spectral weight depletion that approaches the power-law behavior expected in one dimension. From the warping of the quasi-1D Fermi surface at low temperatures, we extract the energy scale of the dimensional crossover. This is corroborated by a detailed analysis of the density of states, which reveals a change in dimensional behavior dependent on binding energy. Our results offer an important insight into the dimensionality of excitations in quasi-1D materials. PMID- 28581792 TI - Superconductivity Provides Access to the Chiral Magnetic Effect of an Unpaired Weyl Cone. AB - The massless fermions of a Weyl semimetal come in two species of opposite chirality, in two cones of the band structure. As a consequence, the current j induced in one Weyl cone by a magnetic field B [the chiral magnetic effect (CME)] is canceled in equilibrium by an opposite current in the other cone. Here, we show that superconductivity offers a way to avoid this cancellation, by means of a flux bias that gaps out a Weyl cone jointly with its particle-hole conjugate. The remaining gapless Weyl cone and its particle-hole conjugate represent a single fermionic species, with renormalized charge e^{*} and a single chirality +/- set by the sign of the flux bias. As a consequence, the CME is no longer canceled in equilibrium but appears as a supercurrent response ?j/?B=+/ (e^{*}e/h^{2})MU along the magnetic field at chemical potential MU. PMID- 28581793 TI - Non-Abelian Majorana Modes Protected by an Emergent Second Chern Number. AB - The search for topological superconductors and non-Abelian Majorana modes ranks among the most fascinating topics in condensed matter physics. There now exist several fundamental superconducting phases which host symmetry protected or chiral Majorana modes, of which the chiral modes are protected by Chern numbers in even dimensions. Here we propose to observe novel chiral Majorana modes by realizing a Fulde-Ferrell-Larkin-Ovchinnikov state, i.e., the pair density wave (PDW) phase in a Weyl semimetal which breaks time-reversal symmetry. Without symmetry protection, the 3D gapped PDW phase is topologically trivial. However, a vortex line generated in such a phase can host chiral Majorana modes, which are shown to be protected by an emergent second Chern number of a synthetic 4D space generalized from the PDW phase. We further show that these chiral modes in the vortex rings obey 3D non-Abelian loop-braiding statistics, which can be applied to topological quantum computation. PMID- 28581794 TI - Disruption of the Accidental Dirac Semimetal State in ZrTe_{5} under Hydrostatic Pressure. AB - We study the effect of hydrostatic pressure on the magnetotransport properties of zirconium pentatelluride. The magnitude of resistivity anomaly gets enhanced with increasing pressure, but the transition temperature T^{*} is insensitive to it up to 2.5 GPa. In the case of H?b, the quasilinear magnetoresistance decreases drastically from 3300% (9 T) at ambient pressure to 230% (9 T) at 2.5 GPa. Besides, the change of the quantum oscillation phase from topological nontrivial to trivial is revealed around 2 GPa. Both demonstrate that the pressure breaks the accidental Dirac node in ZrTe_{5}. For H?c, in contrast, subtle changes can be seen in the magnetoresistance and quantum oscillations. In the presence of pressure, ZrTe_{5} evolves from a highly anisotropic to a nearly isotropic electronic system, which accompanies the disruption of the accidental Dirac semimetal state. It supports the assumption that ZrTe_{5} is a semi-3D Dirac system with linear dispersion along two directions and a quadratic one along the third. PMID- 28581796 TI - Accretion Dynamics on Wet Granular Materials. AB - Wet granular aggregates are common precursors of construction materials, food, and health care products. The physical mechanisms involved in the mixing of dry grains with a wet substrate are not well understood and difficult to control. Here, we study experimentally the accretion of dry grains on a wet granular substrate by measuring the growth dynamics of the wet aggregate. We show that this aggregate is fully saturated and its cohesion is ensured by the capillary depression at the air-liquid interface. The growth dynamics is controlled by the liquid fraction at the surface of the aggregate and exhibits two regimes. In the viscous regime, the growth dynamics is limited by the capillary-driven flow of liquid through the granular packing to the surface of the aggregate. In the capture regime, the capture probability depends on the availability of the liquid at the saturated interface, which is controlled by the hydrostatic depression in the material. We propose a model that rationalizes our observations and captures both dynamics based on the evolution of the capture probability with the hydrostatic depression. PMID- 28581795 TI - Phase Transitions in Definite Total Spin States of Two-Component Fermi Gases. AB - Second-order phase transitions have no latent heat and are characterized by a change in symmetry. In addition to the conventional symmetric and antisymmetric states under permutations of bosons and fermions, mathematical group representation theory allows for non-Abelian permutation symmetry. Such symmetry can be hidden in states with defined total spins of spinor gases, which can be formed in optical cavities. The present work shows that the symmetry reveals itself in spin-independent or coordinate-independent properties of these gases, namely as non-Abelian entropy in thermodynamic properties. In weakly interacting Fermi gases, two phases appear associated with fermionic and non-Abelian symmetry under permutations of particle states, respectively. The second-order transitions between the phases are characterized by discontinuities in specific heat. Unlike other phase transitions, the present ones are not caused by interactions and can appear even in ideal gases. Similar effects in Bose gases and strong interactions are discussed. PMID- 28581797 TI - Enhancing Near-Field Radiative Heat Transfer with Si-based Metasurfaces. AB - We demonstrate in this work that the use of metasurfaces provides a viable strategy to largely tune and enhance near-field radiative heat transfer between extended structures. In particular, using a rigorous coupled wave analysis, we predict that Si-based metasurfaces featuring two-dimensional periodic arrays of holes can exhibit a room-temperature near-field radiative heat conductance much larger than any unstructured material to date. We show that this enhancement, which takes place in a broad range of separations, relies on the possibility to largely tune the properties of the surface plasmon polaritons that dominate the radiative heat transfer in the near-field regime. PMID- 28581798 TI - Nuclear Physics Around the Unitarity Limit. AB - We argue that many features of the structure of nuclei emerge from a strictly perturbative expansion around the unitarity limit, where the two-nucleon S waves have bound states at zero energy. In this limit, the gross features of states in the nuclear chart are correlated to only one dimensionful parameter, which is related to the breaking of scale invariance to a discrete scaling symmetry and set by the triton binding energy. Observables are moved to their physical values by small perturbative corrections, much like in descriptions of the fine structure of atomic spectra. We provide evidence in favor of the conjecture that light, and possibly heavier, nuclei are bound weakly enough to be insensitive to the details of the interactions but strongly enough to be insensitive to the exact size of the two-nucleon system. PMID- 28581799 TI - Social Cooperation and Disharmony in Communities Mediated through Common Pool Resource Exploitation. AB - It was theorized that when a society exploits a shared resource, the system can undergo extreme phase transition from full cooperation in abiding by a social agreement, to full defection from it. This was shown to happen in an integrated society with complex social relationships. However, real-world agents tend to segregate into communities whose interactions contain features of the associated community structure. We found that such social segregation softens the abrupt extreme transition through the emergence of multiple intermediate phases composed of communities of cooperators and defectors. Phase transitions thus now occur through these intermediate phases which avert the instantaneous collapse of social cooperation within a society. While this is beneficial to society, it nonetheless costs society in two ways. First, the return to full cooperation from full defection at the phase transition is no longer immediate. Community linkages have rendered greater societal inertia such that the switch back is now typically stepwise rather than a single change. Second, there is a drastic increase in social disharmony within the society due to the greater tension in the relationship between segregated communities of defectors and cooperators. Intriguingly, these results on multiple phases with its associated phenomenon of social disharmony are found to characterize the level of cooperation within a society of Balinese farmers who exploit water for rice production. PMID- 28581800 TI - X-ray Phase-Contrast Imaging and Metrology through Unified Modulated Pattern Analysis. AB - We present a method for x-ray phase-contrast imaging and metrology applications based on the sample-induced modulation and subsequent computational demodulation of a random or periodic reference interference pattern. The proposed unified modulated pattern analysis (UMPA) technique is a versatile approach and allows tuning of signal sensitivity, spatial resolution, and scan time. We characterize the method and demonstrate its potential for high-sensitivity, quantitative phase imaging, and metrology to overcome the limitations of existing methods. PMID- 28581801 TI - Synchronization Dynamics in a Designed Open System. AB - We theoretically propose a unifying expression for synchronization dynamics between two-level constituents. Although synchronization phenomena require some substantial mediators, the distinct repercussions of their propagation delays remain obscure, especially in open systems. Our scheme directly incorporates the details of the constituents and mediators in an arbitrary environment. As one example, we demonstrate the synchronization dynamics of optical emitters on a dielectric microsphere. We reveal that the whispering gallery modes (WGMs) bridge the well-separated emitters and accelerate the synchronized fluorescence, known as superfluorescence. The emitters are found to overcome the significant and nonuniform retardation, and to build up their pronounced coherence by the WGMs, striking a balance between the roles of resonator and intermediary. Our work directly illustrates the dynamical aspects of many-body synchronizations and contributes to the exploration of research paradigms that consider designed open systems. PMID- 28581802 TI - Choi et al. Reply. PMID- 28581803 TI - Electrothermal Transistor Effect and Cyclic Electronic Currents in Multithermal Charge Transfer Networks. AB - A theory is developed to describe the coupled transport of energy and charge in networks of electron donor-acceptor sites which are seated in a thermally heterogeneous environment, where the transfer kinetics are dominated by Marcus type hopping rates. It is found that the coupling of heat and charge transfer in such systems gives rise to exotic transport phenomena which are absent in thermally homogeneous systems and cannot be described by standard thermoelectric relations. Specifically, the directionality and extent of thermal transistor amplification and cyclical electronic currents in a given network can be controlled by tuning the underlying temperature gradient in the system. The application of these findings toward the optimal control of multithermal currents is illustrated on a paradigmatic nanostructure. PMID- 28581804 TI - Electron and Ion Dynamics of the Solar Wind Interaction with a Weakly Outgassing Comet. AB - Using a 3D fully kinetic approach, we disentangle and explain the ion and electron dynamics of the solar wind interaction with a weakly outgassing comet. We show that, to first order, the dynamical interaction is representative of a four-fluid coupled system. We self-consistently simulate and identify the origin of the warm and suprathermal electron distributions observed by ESA's Rosetta mission to comet 67P/Churyumov-Gerasimenko and conclude that a detailed kinetic treatment of the electron dynamics is critical to fully capture the complex physics of mass-loading plasmas. PMID- 28581805 TI - Multiple-Star System Adaptive Vortex Coronagraphy Using a Liquid Crystal Light Valve. AB - We propose the development of a high-contrast imaging technique enabling the simultaneous and selective nulling of several light sources. This is done by realizing a reconfigurable multiple-vortex phase mask made of a liquid crystal thin film on which local topological features can be addressed electro-optically. The method is illustrated by reporting on a triple-star optical vortex coronagraphy laboratory demonstration, which can be easily extended to higher multiplicity. These results allow considering the direct observation and analysis of worlds with multiple suns and more complex extrasolar planetary systems. PMID- 28581806 TI - Transfer of Magnetic Order and Anisotropy through Epitaxial Integration of 3d and 4f Spin Systems. AB - Resonant x-ray scattering at the Dy M_{5} and Ni L_{3} absorption edges was used to probe the temperature and magnetic field dependence of magnetic order in epitaxial LaNiO_{3}-DyScO_{3} superlattices. For superlattices with 2 unit cell thick LaNiO_{3} layers, a commensurate spiral state develops in the Ni spin system below 100 K. Upon cooling below T_{ind}=18 K, Dy-Ni exchange interactions across the LaNiO_{3}-DyScO_{3} interfaces induce collinear magnetic order of interfacial Dy moments as well as a reorientation of the Ni spins to a direction dictated by the strong magnetocrystalline anisotropy of Dy. This transition is reversible by an external magnetic field of 3 T. Tailored exchange interactions between rare-earth and transition-metal ions thus open up new perspectives for the manipulation of spin structures in metal-oxide heterostructures and devices. PMID- 28581807 TI - Laser-Controlled Torsions: Four-Dimensional Theory and the Validity of Reduced Dimensionality Models. AB - A multitude of possible applications along with unique coherence, chirality, and symmetry properties makes the control of molecular torsion with moderately strong, nonresonant laser pulses a fascinating subject. A description of combined rotation and torsion requires at least four angular degrees of freedom, which is challenging for the majority of systems. Lower-dimensional models have been proposed but also questioned. Here, we develop a four-dimensional model for the coupled rotational-torsional motions of molecules consisting of two identical moieties. By comparing four-dimensional calculations with a two-dimensional model, we define conditions under which the lower-dimensional model is valid. In particular, we point to the crucial role of coordinate dependence of the polarizability tensor. Our results do not agree with those of previous four dimensional calculations but support the conclusions of recent experiments. PMID- 28581808 TI - Local Structure and Short-Range Order in a NiCoCr Solid Solution Alloy. AB - Multielement solid solution alloys are intrinsically disordered on the atomic scale, and many of their advanced properties originate from the local structural characteristics. The local structure of a NiCoCr solid solution alloy is measured with x-ray or neutron total scattering and extended x-ray absorption fine structure (EXAFS) techniques. The atomic pair distribution function analysis does not exhibit an observable structural distortion. However, an EXAFS analysis suggests that the Cr atoms are favorably bonded with Ni and Co in the solid solution alloys. This short-range order (SRO) may make an important contribution to the low values of the electrical and thermal conductivities of the Cr-alloyed solid solutions. In addition, an EXAFS analysis of Ni ion irradiated samples reveals that the degree of SRO in NiCoCr alloys is enhanced after irradiation. PMID- 28581809 TI - Scheme for Detection of Single-Molecule Radical Pair Reaction Using Spin in Diamond. AB - The radical pair reaction underlies the magnetic field sensitivity of chemical reactions and is suggested to play an important role in both chemistry and biology. Current experimental evidence is based on ensemble measurements; however, the ability to probe the radical pair reaction at the single-molecule level would provide valuable information concerning its role in important biological processes. Here, we propose a scheme to detect the charge recombination rate in a radical pair reaction under ambient conditions by using single nitrogen-vacancy center spin in diamond. We demonstrate theoretically that it is possible to detect the effect of the geomagnetic field on the radical pair reaction and propose the present scheme as a possible hybrid model chemical compass. PMID- 28581810 TI - Coherent Two-Dimensional Terahertz Magnetic Resonance Spectroscopy of Collective Spin Waves. AB - We report a demonstration of two-dimensional (2D) terahertz (THz) magnetic resonance spectroscopy using the magnetic fields of two time-delayed THz pulses. We apply the methodology to directly reveal the nonlinear responses of collective spin waves (magnons) in a canted antiferromagnetic crystal. The 2D THz spectra show all of the third-order nonlinear magnon signals including magnon spin echoes, and 2-quantum signals that reveal pairwise correlations between magnons at the Brillouin zone center. We also observe second-order nonlinear magnon signals showing resonance-enhanced second-harmonic and difference-frequency generation. Numerical simulations of the spin dynamics reproduce all of the spectral features in excellent agreement with the experimental 2D THz spectra. PMID- 28581811 TI - Symmetry-Enforced Line Nodes in Unconventional Superconductors. AB - We classify line nodes in superconductors with strong spin-orbit interactions and time-reversal symmetry, where the latter may include nonprimitive translations in the magnetic Brillouin zone to account for coexistence with antiferromagnetic order. We find four possible combinations of irreducible representations of the order parameter on high-symmetry planes, two of which allow for line nodes in pseudospin-triplet pairs and two that exclude conventional fully gapped pseudospin-singlet pairs. We show that the former can only be realized in the presence of band-sticking degeneracies, and we verify their topological stability using arguments based on Clifford algebra extensions. Our classification exhausts all possible symmetry protected line nodes in the presence of spin-orbit coupling and a (generalized) time-reversal symmetry. Implications for existing nonsymmorphic and antiferromagnetic superconductors are discussed. PMID- 28581812 TI - Additive Classical Capacity of Quantum Channels Assisted by Noisy Entanglement. AB - We give a capacity formula for the classical information transmission over a noisy quantum channel, with separable encoding by the sender and limited resources provided by the receiver's preshared ancilla. Instead of a pure state, we consider the signal-ancilla pair in a mixed state, purified by a "witness." Thus, the signal-witness correlation limits the resource available from the signal-ancilla correlation. Our formula characterizes the utility of different forms of resources, including noisy or limited entanglement assistance, for classical communication. With separable encoding, the sender's signals across multiple channel uses are still allowed to be entangled, yet our capacity formula is additive. In particular, for generalized covariant channels, our capacity formula has a simple closed form. Moreover, our additive capacity formula upper bounds the general coherent attack's information gain in various two-way quantum key distribution protocols. For Gaussian protocols, the additivity of the formula indicates that the collective Gaussian attack is the most powerful. PMID- 28581813 TI - Dominance of Metric Correlations in Two-Dimensional Neuronal Cultures Described through a Random Field Ising Model. AB - We introduce a novel random field Ising model, grounded on experimental observations, to assess the importance of metric correlations in cortical circuits in vitro. Metric correlations arise from both the finite axonal length and the heterogeneity in the spatial arrangement of neurons. The experiments consider the response of neuronal cultures to an external electric stimulation for a gradually weaker connectivity strength between neurons, and in cultures with different spatial configurations. The model can be analytically solved in the metric-free, mean-field scenario. The presence of metric correlations precipitates a strong deviation from the mean field. Null models of the same networks that preserve the distribution of connections recover the mean field. Our results show that metric-inherited correlations in spatial networks dominate the connectivity blueprint, mask the actual distribution of connections, and may emerge as the asset that shapes network dynamics. PMID- 28581814 TI - Hybrid Statistical and Mechanistic Mathematical Model Guides Mobile Health Intervention for Chronic Pain. AB - Nearly a quarter of visits to the emergency department are for conditions that could have been managed via outpatient treatment; improvements that allow patients to quickly recognize and receive appropriate treatment are crucial. The growing popularity of mobile technology creates new opportunities for real-time adaptive medical intervention, and the simultaneous growth of "big data" sources allows for preparation of personalized recommendations. Here we focus on the reduction of chronic suffering in the sickle cell disease (SCD) community. SCD is a chronic blood disorder in which pain is the most frequent complication. There currently is no standard algorithm or analytical method for real-time adaptive treatment recommendations for pain. Furthermore, current state-of-the-art methods have difficulty in handling continuous-time decision optimization using big data. Facing these challenges, in this study, we aim to develop new mathematical tools for incorporating mobile technology into personalized treatment plans for pain. We present a new hybrid model for the dynamics of subjective pain that consists of a dynamical systems approach using differential equations to predict future pain levels, as well as a statistical approach tying system parameters to patient data (both personal characteristics and medication response history). Pilot testing of our approach suggests that it has significant potential to well predict pain dynamics, given patients reported pain levels and medication usages. With more abundant data, our hybrid approach should allow physicians to make personalized, data-driven recommendations for treating chronic pain. PMID- 28581815 TI - Biomechanical Factors Associated With Achilles Tendinopathy and Medial Tibial Stress Syndrome in Runners. AB - BACKGROUND: There is disagreement in the literature regarding whether the excessive excursion or velocity of rearfoot eversion is related to the development of 2 common running injuries: Achilles tendinopathy (AT) and medial tibial stress syndrome (MTSS). An alternative hypothesis suggests that the duration of rearfoot eversion may be an important factor. However, the duration of eversion has received relatively little attention in the biomechanics literature. HYPOTHESIS: Runners with AT or MTSS will demonstrate a longer duration of eversion but not greater excursion or velocity of eversion compared with healthy controls. STUDY DESIGN: Controlled laboratory study. METHODS: Forty two runners participated in this study (13 with AT, 8 with MTSS, and 21 matched controls). Participants were evaluated for lower extremity alignment and flexibility, after which a 3-dimensional kinematic and kinetic running gait analysis was performed. Differences between the 2 injuries and between injured and control participants were evaluated for flexibility and alignment, rearfoot kinematics, and 3 ground-reaction force metrics. Binary logistic regression was used to evaluate which variables best predicted membership in the injured group. RESULTS: Injured participants, compared with controls, demonstrated higher standing tibia varus angles (8.67 degrees +/- 1.79 degrees vs 6.76 degrees +/- 1.75 degrees , respectively; P = .002), reduced static dorsiflexion range of motion (6.14 degrees +/- 5.04 degrees vs 11.19 degrees +/- 5.10 degrees , respectively; P = .002), more rearfoot eversion at heel-off (-6.47 degrees +/- 5.58 degrees vs 1.07 degrees +/- 2.26 degrees , respectively; P < .001), and a longer duration of eversion (86.02% +/- 15.65% stance vs 59.12% +/- 16.50% stance, respectively; P < .001). There were no differences in the excursion or velocity of eversion. The logistic regression (chi2 = 20.84, P < .001) revealed that every 1% increase in the duration of eversion during the stance phase increased the odds of being in the injured group by 1.08 (95% CI, 1.023-1.141; P = .006). CONCLUSION: Compared with healthy controls, runners currently symptomatic with AT or MTSS have a longer duration of eversion but not greater excursion or velocity of eversion. CLINICAL RELEVANCE: Static measures of the tibia varus angle and dorsiflexion range of motion, along with dynamic measures of the duration of eversion, may be useful for identifying runners at risk of sustaining AT or MTSS. PMID- 28581816 TI - Serial Changes in 3-Dimensional Supraspinatus Muscle Volume After Rotator Cuff Repair. AB - BACKGROUND: There is considerable debate on the recovery of rotator cuff muscle atrophy after rotator cuff repair. PURPOSE: To evaluate the serial changes in supraspinatus muscle volume after rotator cuff repair by using semiautomatic segmentation software and to determine the relationship with functional outcomes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Seventy-four patients (mean age, 62.8 +/- 8.8 years) who underwent arthroscopic rotator cuff repair and obtained 3 consecutive (preoperatively, immediately postoperatively, and later postoperatively [>=1 year postoperatively]) magnetic resonance imaging (MRI) scans having complete Y-views were included. We generated a 3-dimensional (3D) reconstructed model of the supraspinatus muscle by using in-house semiautomatic segmentation software (ITK-SNAP) and calculated both the 2-dimensional (2D) cross sectional area and 3D volume of the muscle in 3 different views (Y-view, 1 cm medial to the Y-view [Y+1 view], and 2 cm medial to the Y-view [Y+2 view]) at the 3 time points. The area and volume changes at each time point were evaluated according to repair integrity. Later postoperative volumes were compared with immediately postoperative volumes, and their relationship with various clinical factors and the effect of higher volume increases on range of motion, muscle power, and visual analog scale pain and American Shoulder and Elbow Surgeons scores were evaluated. RESULTS: The interrater reliabilities were excellent for all measurements. Areas and volumes increased immediately postoperatively as compared with preoperatively; however, only volumes on the Y+1 view and Y+2 view significantly increased later postoperatively as compared with immediately postoperatively ( P < .05). There were 9 patients with healing failure, and area and volume changes were significantly less later postoperatively compared with immediately postoperatively at all measurement points in these patients ( P < .05). After omitting the patients with healing failure, volume increases later postoperatively became more prominent ( P < .05) in the order of the Y+2 view, Y+1 view, and Y-view. Volume increases were higher in patients who healed successfully with larger tears ( P = .040). Higher volume increases were associated only with an increase in abduction power ( P = .029) and not with other outcomes. CONCLUSION: The supraspinatus muscle volume increased immediately postoperatively and continuously for at least 1 year after surgery. The increase was evident in patients who had larger tears and healed successfully and when measured toward the more medial portion of the supraspinatus muscle. The volume increases were associated with an increase in shoulder abduction power. PMID- 28581817 TI - Insulin Pump Use in Young Children with Type 1 Diabetes: Sociodemographic Factors and Parent-Reported Barriers. AB - BACKGROUND: Managing type 1 diabetes (T1D) in young children presents challenges to families and caregivers. Pump therapy may reduce challenges and benefit glycemic control. However, pump use is not universal; parent-reported reasons for lack of uptake are not well described. METHODS: Parents of children <7, with T1D for >=1 year, in the T1D Exchange registry completed surveys capturing demographic and clinical characteristics, as well as barriers to pump use. Data from pump users were compared to nonusers, and barriers were analyzed among parents who received pump recommendations, but decided against uptake. RESULTS: Young children (N = 515) from 41 sites were identified (mean age 5.2 +/- 1.2 years, diabetes duration 2.4 +/- 1.0 years, 46% female, and 78% Non-Hispanic White). Overall glycemic control was suboptimal (HbA1c 8.1% +/- 1.0%). The majority were pump users (64%, n = 331; nonusers 36%, n = 184). Pump users had longer T1D duration (2.5 +/- 1.1 years vs. 2.2 +/- 1.0 years, P = 0.001), were more likely to have annual household incomes >=$75,000 (62% vs. 36%, P < 0.001), have a parent with college education or higher (70% vs. 45%, P < 0.001), perform more frequent blood glucose monitoring (7.5 +/- 2.5 times/day vs. 6.5 +/- 2.3 times/day, P < 0.001), and use continuous glucose monitoring (CGM) (45% vs. 13%, P < 0.001). Only income, education, frequency of blood glucose monitoring, and CGM use remained significant in a multivariate model including age, sex, ethnicity, and duration of diabetes. Barriers to pump uptake included concerns with physical interference, therapeutic effectiveness, and to a lesser extent, financial burden. CONCLUSIONS: These findings provide an opportunity to address potentially modifiable parent-reported barriers to pump uptake through education and behavioral intervention. PMID- 28581819 TI - Co-existence of GM, conventional and organic crops in developing countries: Main debates and concerns. AB - The co-existence approach of GM crops with conventional agriculture and organic farming as a feasible agricultural farming system has recently been placed in the center of hot debates at the EU-level and become a source of anxiety in developing countries. The main promises of this approach is to ensure "food security" and "food safety" on the one hand, and to avoid the adventitious presence of GM crops in conventional and organic farming on the other, as well as to present concerns in many debates on implementing the approach in developing countries. Here, we discuss the main debates on ("what," "why," "who," "where," "which," and "how") applying this approach in developing countries and review the main considerations and tradeoffs in this regard. The paper concludes that a peaceful co-existence between GM, conventional, and organic farming is not easy but is still possible. The goal should be to implement rules that are well established proportionately, efficiently and cost-effectively, using crop-case, farming system-based and should be biodiversity-focused ending up with "codes of good agricultural practice" for co-existence. PMID- 28581818 TI - Effect of Linagliptin Versus Metformin on Glycemic Variability in Patients with Impaired Glucose Tolerance. AB - BACKGROUND: Impaired glucose tolerance (IGT) and glycemic variability may be associated with increased risk of micro- and macrovascular complications. The aim of this study was to assess the effect of linagliptin versus metformin on glycemic variability in patients with IGT. MATERIAL AND METHODS: A randomized, double-blind clinical trial with parallel groups was carried out in 16 adult patients with IGT, overweight or obesity. All patients signed an informed consent. The therapies were randomly assigned: (a) metformin 500 mg bid (n = 8) or (b) linagliptin 5 mg a.m. and placebo p.m. (n = 8), both for 90 days. At the beginning of the trial and 3 months later, fasting glucose, glycated hemoglobin A1c, oral glucose tolerance test (OGTT), and glycemic variability [area under the curve (AUC) of glucose, mean amplitude of glycemic excursion (MAGE), standard deviation (SD) of glucose, coefficient of variation (CV) of glucose, and mean blood glucose (MBG)] were measured. Mann-Whitney U, Wilcoxon, and Fisher exact tests were used for statistical analyses. RESULTS: Both groups were similar in basal characteristics. After linagliptin administration, a significant decrease in glucose levels at 120 min of OGTT (9.0 +/- 0.9 vs. 6.9 +/- 2.2 mmol/L, P = 0.012) was observed. Glycemic variability showed a similar behavior and there were no significant differences in the AUC, MAGE, SD of glucose, CV of glucose, and MBG between groups. CONCLUSION: Linagliptin administration resulted in better glycemic control according to the decrease of glucose levels by the OGTT at 120 min in patients with IGT. Meanwhile, glycemic variability was not modified in any of the study groups. PMID- 28581820 TI - Barriers and Facilitators to HIV Testing Among Zambian Female Sex Workers in Three Transit Hubs. AB - Zambia has a generalized HIV epidemic, and HIV is concentrated along transit routes. Female sex workers (FSWs) are disproportionately affected by the epidemic. HIV testing is the crucial first step for engagement in HIV care and HIV prevention activities. However, to date little work has been done with FSWs in Zambia, and little is known about barriers and facilitators to HIV testing in this population. FSW peer educators were recruited through existing sex worker organizations for participation in a trial related to HIV testing among FSWs. We conducted five focus groups with FSW peer educators (N = 40) in three transit towns in Zambia (Livingstone, Chirundu, and Kapiri Mposhi) to elicit community norms related to HIV testing. Emerging themes demonstrated barriers and facilitators to HIV testing occurring at multiple levels, including individual, social network, and structural. Stigma and discrimination, including healthcare provider stigma, were a particularly salient barrier. Improving knowledge, social support, and acknowledgment of FSWs and women's role in society emerged as facilitators to testing. Interventions to improve HIV testing among FSWs in Zambia will need to address barriers and facilitators at multiple levels to be maximally effective. PMID- 28581821 TI - Randomized Controlled Trial of Technology-Assisted Case Management in Low Income Adults with Type 2 Diabetes. AB - OBJECTIVE: To assess the efficacy of technology-assisted case management (TACM) with medication titration by nurses using guideline-based algorithms, under physician supervision in improving glycemic control in low-income rural adults with poorly controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults (aged >=18 years) from the southeastern United States with hemoglobin A1c [HbA1c] >=8% were randomized to TACM or usual care. Evidence-based guidelines were used to develop medication titration algorithms in conjunction with clinic physicians. Participants were given a telehealth device that uploaded blood glucose and blood pressure readings daily to a central server. A nurse case manager was trained on the algorithms and authorized to titrate medications every 2 weeks based on the algorithm under the supervision of an internist and an endocrinologist. Participants were assessed at baseline, 3 months, and 6 months. The primary outcome was HbA1c at 6-months postrandomization in the intent-to-treat (ITT) population. RESULTS: One hundred thirteen participants were randomized to either TACM intervention or usual care. Based on ITT population after multiple imputation, the analysis of covariance with baseline HbA1c as covariate showed that HbA1c at 6 months for TACM was significantly lower compared to the usual care group (-0. 99, P = 0.024). Moreover, longitudinal mixed effects analysis suggested that the rate of decline in HbA1c over time for TACM was significantly faster compared to the usual care group (-0.16, P = 0.038). Results based on per protocol population were similar. CONCLUSIONS: Technology-assisted case management by a nurse with medication titration under physician supervision is efficacious in improving glycemic control in low-income rural adults with poorly controlled type 2 diabetes. PMID- 28581823 TI - Importance of light in the treatment of vitiligo with JAK-inhibitors. PMID- 28581822 TI - Three new sesquiterpenes from Pterocarpus santalinus. AB - Three new sesquiterpenes of canusesnol K (1), canusesnol L (2) and 12, 15 dihydroxycurcumene (3), along with five known ones (4-8), were isolated from the heartwood extract of Pterocarpus santalinus. Their structures were established by extensive analyses of 1D and 2D NMR spectroscopy, including 1H NMR, 13C NMR, HSQC, HMBC and NOESY, and HRESI-MS. The absolute configurations of the new compounds were established with Modified Mosher's method. The cytotoxic activities of all these compounds against HepG2 (human liver cancer), MCF-7 (human breast cancer), MDA-MB-231 (human breast cancer), and Hela (human cervical carcinoma) cancer cell lines were evaluated. Compound 1 exhibited moderate cytotoxic activity toward MDA-MB-231 cell lines. PMID- 28581824 TI - Three xanthone dimers from the Thai mangrove endophytic fungus Phomopsis sp. xy21. AB - Three new xanthone dimers, named phomoxanthones C-E (1-3), were obtained from the Thai mangrove fungus Phomopsis sp. xy21, together with four known ones. The structures of these compounds were elucidated by the analysis of HRESIMS and extensive NMR spectroscopic data. The absolute configuration of 1 was established by the analysis of single-crystal X-ray diffraction with Cu Kalpha radiation. Phomoxanthones C (1) and D (2) possess a highly oxidized hexahydroxanthone skeleton. PMID- 28581825 TI - Targeted-mitochondria antioxidants therapeutic implications in inflammatory bowel disease. AB - The role of the mitochondria, particularly its implications in cellular redox and oxidative balance is important for cell survival, and is involved in a variety of human diseases including inflammatory bowel disease (IBD). In this review we address mitochondria physiology and reactive oxygen species as cognate to IBD. Several studies have reported altered mitochondria function in intestinal epithelium in IBD. However, mitochondrion significance in this disease has not been much investigated. Finally, we suggest potential for antioxidants targeted to mitochondria in IBD therapy as a treatment strategy. PMID- 28581827 TI - Therapeutic efficacy of folate receptor-targeted amphiphilic cyclodextrin nanoparticles as a novel vehicle for paclitaxel delivery in breast cancer. AB - PURPOSE: The aim of this study is to test folate-conjugated cyclodextrin nanoparticles (FCD-1 and FCD-2) as a vehicle for reducing toxicity and increasing the antitumor efficacy of paclitaxel especially for metastatic breast cancer. METHODS: For the evaluation of PCX-loaded FCD nanoparticles, animal studies were realised in terms of survival rate, tumour size, weight change, metastazis and histopathological examination. RESULTS: FCD-1 displayed significant advantages such as efficient targeting of folate receptor positive breast cancer cells and having considerably lower toxicity compared to that of Cremophor(r). When loaded with paclitaxel, FCD-1 nanoparticles, which have smaller particle size, neutral zeta potential, high encapsulation efficiency and better loading capacity for controlled release, emerged as an effective formulation in terms of cytotoxicity and high cellular uptake. In an experimental breast cancer model, anticancer activity of these nanoparticles were compatible with that of paclitaxel in Cremophor(r) however repeated administrations of FCD-1 nanoparticles were better tolerated by the animals. These nanoparticles were able to localise in tumour site. Both paclitaxel-loaded FCD-1 and FCD-2 significantly reduced tumour burden while FCD-1 significantly improved the survival. CONCLUSIONS: Folate-conjugated amphiphilic cyclodextrin nanoparticles can be considered as promising Cremophor(r)-free, low-toxicity and efficient active drug delivery systems for paclitaxel. PMID- 28581826 TI - Gold nanoparticles capped with benzalkonium chloride and poly (ethylene imine) for enhanced loading and skin permeability of 5-fluorouracil. AB - OBJECTIVE: To enhance 5-fluorouracil (5-FU) permeability through the skin by loading onto gold nanoparticles (GNPs) capped with two cationic ligands, benzalkonium chloride (BC) or poly (ethylene imine) (PEI). Whereas 5-FU has excellent efficacy against many cancers, its poor permeability through biological membranes and several adverse effects limit its clinical benefits. BC and PEI were selected to stabilize GNPs and to load 5-FU through ionic interactions. METHODS: 5-FU/BC-GNPs and 5-FU/PEI-GNPs were prepared at different 5-FU/ligand molar ratios and different pH values and were evaluated using different techniques. GNPs stability was tested as a function of salt concentration and storage time. 5-FU release from BC- and PEI-GNPs was evaluated as a function of solution pH. Ex vivo permeability studies of different 5-FU preparations were carried out using mice skin. RESULTS: 5-FU-loaded GNPs size and surface charge were dependent on the 5-FU/ligand molar ratios. 5-FU entrapment efficiency and loading capacity were dependent on the used ligand, 5-FU/ligand molar ratio and solution pH. Maximum drug entrapment efficiency of 59.0 +/- 1.7% and 46.0 +/- 1.1% were obtained for 5-FU/BC-GNPs and 5-FU/PEI-GNPs, respectively. 5-FU-loaded GNPs had good stability against salinity and after storage for 4 months at room temperature and at 4 degrees C. In vitro 5-FU release was pH- and ligand dependent where slower release was observed at higher pH and for 5-FU/BC-GNPs. 5 FU permeability through mice skin was significantly higher for drug-loaded GNPs compared with drug-ligand complex or drug aqueous solution. CONCLUSION: Based on these results, BC- and PEI-GNPs might find applications as effective topical delivery systems of 5-FU. PMID- 28581828 TI - Biomarkers used in studying air pollution exposure during pregnancy and perinatal outcomes: a review. AB - PURPOSE: This review focuses on studies among pregnant women that used biomarkers to assess air pollution exposure, or to understand the mechanisms by which it affects perinatal outcomes. METHODS: We searched PubMed and Google scholar databases to find articles. RESULTS AND CONCLUSIONS: We found 29 articles, mostly consisting of cohort studies. Interpolation models were most frequently used to assess exposure. The most consistent positive association was between polycyclic aromatic hydrocarbon (PAH) exposure during entire pregnancy and cord blood PAH DNA adducts. Exposure to particulate matter (PM) and nitrogen dioxide (NO2) showed consistent inverse associations with mitochondrial DNA (mtDNA) content, particularly in the third trimester of pregnancy. No single pollutant showed strong associations with all the biomarkers included in this review. C-reactive proteins (CRPs) and oxidative stress markers increased, whereas telomere length decreased with increasing air pollution exposure. Placental global DNA methylation and mtDNA methylation showed contrasting results with air pollution exposure, the mechanism behind which is unclear. Most studies except those on PAH DNA adducts and mtDNA content provided insufficient evidence for characterizing a critical exposure window. Further research using biomarkers is warranted to understand the relationship between air pollution and perinatal outcomes. PMID- 28581829 TI - Features of fatal injuries in older cyclists in vehicle-bicycle accidents in Japan. AB - OBJECTIVE: The purpose of this study was to identify and better understand the features of fatal injuries in cyclists aged 75 years and over involved in collisions with either hood- or van-type vehicles. METHODS: This study investigated the fatal injuries of cyclists aged 75 years old and over by analyzing accident data. We focused on the body regions to which the fatal injury occurred using vehicle-bicycle accident data from the Institute for Traffic Accident Research and Data Analysis (ITARDA) in Japan. Using data from 2009 to 2013, we examined the frequency of fatally injured body region by gender, age, and actual vehicle travel speed. We investigated any significant differences in distributions of fatal injuries by body region for cyclists aged 75 years and over using chi-square tests to compare with cyclists in other age groups. We also investigated the cause of fatal head injuries, such as impact with a road surface or vehicle. RESULTS: The results indicated that head injuries were the most common cause of fatalities among the study group. At low vehicle travel speeds for both hood- and van-type vehicles, fatalities were most likely to be the result of head impacts against the road surface. The percentage of fatalities following hip injuries was significantly higher for cyclists aged 75 years and over than for those aged 65-74 or 13-59 in impacts with hood-type vehicles. It was also higher for women than men in the over-75 age group in impacts with these vehicles. CONCLUSIONS: For cyclists aged 75 years and over, wearing a helmet may be helpful to prevent head injuries in vehicle-to-cyclist accidents. It may also be helpful to introduce some safety measures to prevent hip injuries, given the higher level of fatalities following hip injury among all cyclists aged 75 and over, particularly women. PMID- 28581830 TI - Development of a topical mupirocin spray for antibacterial and wound-healing applications. AB - OBJECTIVE: The aim of this study was to develop mupirocin topical spray using Eudragit E100 as a film-forming agent for the treatment of bacterial skin infections as well as to promote wound healing. MATERIALS AND METHODS: Twenty seven of mupirocin formulations were formulated containing Eudragit E100 and other excipients. Mupirocin spray was prepared by aerosol crimping and filling machine using HFA-134a as a propellant. The formulations were evaluated for their stability and physicochemical properties. The factorial study was applied to evaluate the effects of glycerol and PEG400 on mupirocin-loaded Eudragit E100 films. The optimized formulation was assessed of drug release, antibacterial activities and in vitro cell line studies in comparison to the ointment formulation. RESULTS AND DISCUSSION: Mupirocin sprays were formulated and optimized to obtain the formulation with excellent physicochemical and mechanical properties of the dressing film. The formulation had an excellent stability up to a year with more than 80% of mupirocin content. Mupirocin was released from the film up to 90% within 2 h. The formulation had a potent antibacterial effect against S. aureus and S. epidermidis. The formulation was safe to use as a topical formulation that had no toxicity to keratinocytes, fibroblasts and monocytes. The formulation also had an antiendotoxin effect without stimulating the production of NO and inflammatory cytokines (IL-1beta and TNF-alpha). CONCLUSIONS: Mupirocin topical spray was successful developed as a topical formulation and can be used instead of the ointment formulation. Animal experiments are warranted to further emphasize the safe use in the human skin. PMID- 28581831 TI - Development and characterization of new and scalable topical formulations containing N-acetyl-d-glucosamine-loaded solid lipid nanoparticles. AB - N-Acetyl-d-glucosamine (NAG) has been recently considered for topical treatment of hyperpigmentation disorders due to its inhibitory effect on thyrosinase enzymes in melanocytes. NAG is a precursor of hyaluronic acid, increasing its amount in skin, and consequently, preserving the skin hydration and elasticity. It may also act as an emulsion stabilizer. Solid lipid nanoparticles (SLN) are advanced delivery systems successfully used in pharmaceutical and cosmetic formulations for the improvement of active molecules penetration into the skin. Therefore, this work aimed to develop and characterize stable and scalable topical formulations containing NAG-loaded SLN. NAG was incorporated in SLN which were prepared by two high shear homogenizers and characterized regarding its morphology and particle size by transmission electron microscopy and photon correlation spectroscopy, respectively. Oil emulgel and hydrogel were used as carriers of NAG-loaded SLN. Several parameters were evaluated, including the droplet size distribution, rheology, pH and topical delivery by different techniques. It was observed that SLN size was significantly dependent on NAG incorporation and homogenization process. Most tested SLN parameters appeared to be quite suitable, that is, spherical and well-defined SLN with approximately 258 nm and -30 mV. Hereafter, both gels containing SLN presented a pseudoplastic flow. Emulgel formulation containing NAG-loaded SLN allowed a higher NAG permeation through the SC compared to the respective control (about 0.8 MUgcm-2 h 1). According to the results obtained, it can be suggested that NAG acts as an emulsion stabilizer. This stabilization was also particularly dependent on the homogenizer type which is quite important for scale-up process. This study demonstrated the potential of scalable SLN formulations to improve NAG topical delivery contributing to the improvement of skin properties on several skin disorders. PMID- 28581832 TI - Evaluation of disintegrants functionality for orodispersible mini tablets. AB - OBJECTIVE: This work evaluates the functionalities of different superdisintegrants (SD) for manufacturing orodispersible mini tablets (ODMT) by direct compression. METHODS: Twenty-three formulations varying in SD type, concentration, and lubricant were used to manufacture ODMT. The ODMT were then characterized for the following properties: friability, porosity, tensile strength, in vivo and in vitro disintegration time (DT). RESULTS: The results show that the presence, type, and concentration of SD did not influence friability, porosity, or tablet tensile strength. With regards to in vivo DT, only cross-linked poly (vinyl pyrrolidone) improved DT in all the tested formulations. Results also showed that when using microcrystalline cellulose (MCC) above 20% in the formulation, DT is longer. Cross-linked carboxymethyl cellulose accelerates DT when the MCC content is less than 20%. As for cross linked carboxymethyl starch and calcium alginate showed no improvement on DT. Results for in vitro DT were all shorter than in vivo results and there was no correlation with the in vivo evaluation. CONCLUSIONS: This study shows that there is a need to develop better in vitro testing that precisely simulates in vivo conditions and that are adapted to ODMT. This standardization of the test methods for ODMTs must be accompanied by an improvement in the comprehension of SD mechanisms. PMID- 28581834 TI - Updates on smart polymeric carrier systems for protein delivery. AB - Smart materials are those materials that are responsive to chemical (organic molecules, chemical agents or specific agents), biochemical (protein, enzymes, growth factors, substrates or ligands), physical (electric field, magnetic field, temperature, pH, ionic strength or radiation) or mechanical (pressure or mechanical stress) signals. These responsive materials interact with the stimuli by changing their properties or conformational structures in a predictable manner. Recently, smart polymers have been utilized in various biomedical applications. Particularly, they have been used as a platform to synthesize stimuli-responsive systems that could deliver therapeutics to a specific site for a specific period with minimal adverse effects. For instance, stimuli-responsive polymers-based systems have been recently reported to deliver different bioactive molecules such as carbohydrates (heparin), chemotherapeutic agents (doxorubicin), small organic molecules (anti-coagulants), nucleic acids (siRNA), and proteins (growth factors and hormones). Protein therapeutics played a fundamental role in treatment of various chronic and some autoimmune diseases. For instance insulin has been used in treatment of diabetes. However, being a protein in nature, insulin delivery is limited by its instability, short half-life, and easy denaturation when administered orally. To overcome these challenges, and as highlighted in this review article, much research efforts have been recently devoted to design and develop convenient smart controlled nanosystems for protein therapeutics delivery. PMID- 28581833 TI - Novel nano-cellulose excipient for generating non-Newtonian droplets for targeted nasal drug delivery. AB - PURPOSE: Thickening polymers have been used as excipients in nasal formulations to avoid nasal run-off (nasal drip) post-administration. However, increasing the viscosity of the formulation can have a negative impact on the quality of the aerosols generated. Therefore, the study aims to investigate the use of a novel smart nano-cellulose excipient to generate suitable droplets for nasal drug delivery that simultaneously has only marginally increased viscosity while still reducing nasal drips. METHODS: Nasal sprays containing nano-cellulose at different concentrations were investigated for the additive's potential as an excipient. The formulations were characterized for their rheological and aerosol properties. This was then compared to conventional nasal spray formulation containing the single-component hydroxyl-propyl methyl cellulose (HPMC) viscosity enhancing excipient. RESULTS: The HPMC-containing nasal formulations behave in a Newtonian manner while the nano-cellulose formulations have a yield stress and shear-thinning properties. At higher excipient concentrations and shear rates, the nano-cellulose solutions have significantly lower viscosities compared to the HPMC solution, resulting in improved droplet formation when actuated through conventional nasal spray. CONCLUSIONS: Nano-cellulose materials could potentially be used as a suitable excipient for nasal drug delivery, producing consistent aerosol droplet size, and enhanced residence time within the nasal cavity with reduced run-offs compared to conventional polymer thickeners. PMID- 28581835 TI - Development and gamma scintigraphy evaluation of gastro retentive calcium ion based oral formulation: an innovative approach for the management of gastro esophageal reflux disease (GERD). AB - Calcium chloride is an essential calcium channel agonist which plays an important role in the contraction of muscles by triggering calcium channel. First time hypothesized about its role in the treatment of GER (gastro-esophageal reflux) and vomiting disorder due to its local action. There are two objectives covered in this study as first, the development and optimization of floating formulation of calcium chloride and another objective was to evaluate optimized formulation through gamma scintigraphy in human subjects. Gastro retentive formulation of calcium chloride was prepared by direct compression method. Thirteen tablet formulations were designed with the help of sodium chloride, HPMC-K4M, and carbopol-934 along with effervescing agent sodium bicarbonate and citric acid. Formulation (F8) fitted best for Korsmeyer-Peppas equation with an R2 value of 0.993. The optimized formulation was radiolabelled with 99mTc-99 m pertechnetate for its evaluation by gamma scintigraphy. Gastric retention (6 h) was evaluated by gamma scintigraphy in healthy human subjects and efficacy of present formulation confirmed in GER positive human subjects. Gamma scintigraphy results indicated its usefulness in order to manage GERD. Stability studies of the developed formulation were carried out as per ICH guidelines for region IV and found out to be stable for 24 months. PMID- 28581836 TI - Enhanced antitumor activity in A431 cells via encapsulation of 20(R)-ginsenoside Rg3 in PLGA nanoparticles. AB - OBJECTIVE: The objective of this study is to investigate the encapsulation of 20(R)-ginsenoside Rg3 (20(R)-Rg3) using polylactic-co-glycolic acid (PLGA) and promotion for its antitumor activity. SIGNIFICANCE: Preparation and evaluation of the antitumor efficacy of 20(R)-Rg3-loaded PLGA nanoparticles were the first reported. The data will be helpful to apply 20(R)-Rg3 efficiently and broadly in new drug form development and clinical cancer treatment. METHODS: The nanoparticles were prepared using emulsion and solvent evaporation methods. The uniform particle size and good dispersion were further confirmed by scanning electron microscopy. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was applied to detect cell proliferation after 20(R)-Rg3-loaded PLGA nanoparticles treatment. Western blotting and immunofluorescent staining were used for observation of key proteins related with proliferation and apoptosis. Cell cycle and apoptosis were analyzed by flow cytometer technology. RESULTS AND DISCUSSION: The results showed that the size of 20(R)-Rg3-loaded PLGA was 97.5 nm in diameter, and zeta potential was -28 mV detected by Malvern particle size analyzer. The encapsulation efficiency was 97.5%, and drug loading was 70.2% measured by high-performance liquid chromatography. The in vitro study showed that the encapsulated 20(R)-Rg3 was consecutively released and the release ratio reached to the highest value (19.36%) at the time point of 96 h. The encapsulated 20(R)-Rg3 significantly inhibited the proliferation and induced apoptosis in A431 cancer cells compared with the unencapsulated 20(R)-Rg3, control and PLGA alone. CONCLUSION: 20(R)-Rg3-loaded PLGA nanoparticles was well prepared and characterized. The antitumor activity was increased after PLGA encapsulation. The data will be beneficial to the development of new dosage forms of 20(R)-Rg3 and extensive application. PMID- 28581837 TI - Role of Chemical Signals in the Orientation Behavior of the Sea Star Asterias forbesi. AB - The importance of chemical signals as foraging and orientation cues has been demonstrated for many marine organisms. It is still unclear whether sea stars use chemical signals during orientation and whether chemoreception occurs in the absence of macroscale flow. To determine whether the sea star Asterias forbesi can perceive chemical signals in the absence of flow and what role such signals play in orientation and foraging behavior, we tested the orientation behavior of sea stars to prey and nonprey items under conditions of nondirectional flow. Prey items were whole and broken clams (Mercenaria mercenaria) and mussels (Mytilus edulis); the nonprey item was squid flesh. Asterias forbesi showed the ability to successfully locate odor sources irrespective of the type of odor. Only in trials with the broken clam did the animals reveal an initial directional choice towards the odor source. There were significant changes in the movement rates and heading angles during orientation for all three stimuli. In addition, orientation paths were different for each of the chemical stimuli tested. From these results, we conclude that sea stars can detect and respond to chemicals in the absence of macroscale flow. Orientation paths appear to be more of a taxis, in which heading is directly guided by the stimulus field. PMID- 28581838 TI - Oxidative Stress in the Symbiotic Sea Anemone Aiptasia pulchella (Carlgren, 1943): Contribution of the Animal to Superoxide Ion Production at Elevated Temperature. AB - Production of superoxide ions within tissues of the symbiotic sea anemone Aiptasia pulchella was detected using SOD-inhibitable cytochrome c reduction and quantified by SOD-inhibitable reduction of nitro blue tetrazolium (NBT). Intact aposymbiotic and symbiotic specimens of A. pulchella produced superoxide in response to acute, sublethal thermal stress. Neither light nor inhibition of symbiont photosynthesis by (3,4-di-chlorophenyl) -1, 1-dimethylurea (DCMU) affected superoxide production. The time course of superoxide ion production strongly resembled the time course of increased dark respiration by intact anemones, suggesting that the effect of elevated temperature on host mitochondria may account for increased superoxide production. Interestingly, freshly isolated algae (FIZ) did not release superoxide ions in response to elevated temperature, and net oxygen production decreased greatly in both intact symbiotic anemones and in FIZ within 20 minutes after temperature elevation. These results show that oxidative stress in A. pulchella is primarily an animal response, and suggest that the presence of symbiotic algae, although sufficient to cause hyperoxia, is not necessary for the appearance of oxidative stress in these anemones at elevated temperature. PMID- 28581839 TI - Physiological Variation Among Clonal Genotypes in the Sea Anemone Haliplanella lineata: Growth and Biochemical Content. AB - We have explored physiological variability among clonal genotypes from a single population of the sea anemone Haliplanella lineata located at Indian Field Creek, Virginia. Information about the correlation between physiological variability and genetic differences may provide a foundation for a mechanistic understanding of the breadth of adaptation of individual genotypes (i.e., the nature of "general purpose genotypes") and of the concept of localized adaptation in clonal anemones. Anemones from three clones (A, B, C) were fed measured rations of adult Artemia, after which growth, absorption efficiency, and net growth efficiency were determined. Biochemical constituents were measured in the tissue of this group of anemones as well as in the tissue of anemones from the same clones that had fed ad libitum on Artemia nauplii. Anemones from the different clones did not differ significantly in growth, or gravimetric absorption or growth efficiencies, but significant differences were found in biochemical composition. Regardless of feeding regime and diet composition, clone B anemones consistently had lower tissue averages of triacylglycerols, fatty acids, sterol and wax esters, glycerol ethers, and carbohydrates than did clone A and clone C anemones. As a result of differences in the carbohydrate and lipid constituents, the energetic content of tissues from clone B anemones that had been fed rations was significantly lower than the energetic content of tissues of anemones from clone C. This clonal pattern in biochemical composition and energetic content may be due to differences in substrate absorption among anemones from the different clones, to differences in metabolic rate, or to a combination of both. Because anemones from this population may encyst in mucus and stop feeding when water temperatures are less than 10{deg}C, the genotypic differences in storage lipids and carbohydrate may have implications for the winter survivorship of clone B anemones in this population. PMID- 28581840 TI - Scallop Shells Exhibit Optimization of Riblet Dimensions for Drag Reduction. AB - Drag reduction by streamwise surface grooves, or riblets, has been observed by engineers and has been suggested to apply to certain biological systems. Drag reductions as high as 8% have been observed (1), leading to practical nautical and aeronautical applications (2, 3, 4). The shells of several species of scallop, including Placopecten magellanicus, display riblets arranged radially, and therefore roughly parallel to the flow during swimming (Fig. 1a). The dimensions of these riblets on particular scallops fall within the region necessary for drag reduction at experimentally measured swimming speeds. Moreover, the actual spacing of the riblets gradually migrates into the theoretically optimal spacing region as shell length increases beyond 40 mm (Figs. 2, 3). Specimens of P. magellanicus 40 to 80 mm in length demonstrate the greatest swimming ability (5); our data strongly suggest that streamwise riblets may be a contributing factor to the swimming success in scallops of this size range. PMID- 28581841 TI - Laboratory Culture of the Sepiolid Squid Euprymna scolopes: A Model System for Bacteria-Animal Symbiosis. AB - The small Hawaiian sepiolid Euprymna scolopes, with its symbiotic luminous bacterium Vibrio fischeri, was cultured through one complete life cycle in 4 months. Paralarval squid hatchlings were actively planktonic for the first 20-30 days, after which they settled and assumed the typical adult mode of nocturnal activity and diurnal quiescence. Squids were aggressive predators that preferred actively swimming prey up to 2-4 times their size; the only diet that yielded good survival and rapid growth for paralarvae was large adult mysids. Survival to settlement was 73% on this diet, whereas it was 0%-17% on controls and three other diets. Paralarvae initially lacked both detectable luminescence and V. fischeri cells in their incipient light organs; all remaining stages produced luminescence, and their light organs were colonized by apparently pure cultures of > 105 V. fischeri typical of E. scolopes symbiont strains. Survival from settlement to sexual maturity was 76%. Mating and egg laying commenced at 2 months, yet attempts to culture the next laboratory generation of hatchlings were not as successful. The results indicate that the host organism of this symbiosis can soon be cultured with consistency through its brief life cycle, thus opening new avenues of research into developmental aspects of this symbiosis. PMID- 28581842 TI - Serotonin and Dopamine Have Opposite Effects on Phototaxis in Larvae of the Bryozoan Bugula neritina. AB - Adult colonies of the bryozoan Bugula neritina release short-term anenteric larvae that initially are strongly photopositive. Over the course of several hours larvae lose their initial photopositivity and either become photonegative or alternate between positive and negative phototaxis. We report that newly released photopositive larvae rapidly become photonegative upon exposure to 10-6 10-5 M serotonin or its metabolic precursor, 5-hydroxytryptophan. This behavior was not observed in two congeners of B. neritina, nor in larvae of three other species of bryozoans and seven species from four additional phyla. Antibodies to serotonin label cells in the region of the equatorial nerve-muscle ring and in two tracts extending from the apical disc to this ring. In a separate series of experiments, larvae treated with dopamine (10-7-10-5 M) significantly prolonged their photopositive period. This effect was also obtained with the D2 dopamine receptor agonist, quinpirole (10-6-10-5 M). HPLC analysis determined that newly released photopositive larvae contained 0.120 pmol dopamine/ {mu}g protein. These findings implicate serotonin and dopamine as important neurochemical regulators of phototaxis in larvae of B. neritina. PMID- 28581843 TI - Chrysaora achlyos, a Remarkable New Species of Scyphozoan from the Eastern Pacific. AB - An enormous new species of scyphozoan jellyfish, Chrysaora achlyos, is described from the eastern Pacific. The description is based primarily on color photographs and video footage of living animals and the morphology of four specimens collected in 1989. The natural history, life cycle, and sporadic appearance of the species all are unknown. The species appeared most recently in large numbers in 1989 but has appeared at least twice previously in this century; published photographs (unlabeled or incorrectly identified) appeared in 1926 and 1965. The species is easily distinguished by its size and coloration from other known species in the genus, all of which are considerably smaller. Morphological characters are described, and limited data on nematocyst types are presented. Because of the size of the new species and the known potency of the sting of congeners, we mention briefly the possible consequences of human contact. PMID- 28581844 TI - Mucociliary Transport in Living Tissue: The Two-Layer Model Confirmed in The Mussel Mytilus edulis L. AB - The present study combined video confocal laser microscopy (1) and tissue reflectance and autofluorescence to visualize mucus position and mucociliary transport in excised living gill tissue from the blue mussel Mytilus edulis. Rafts of mucus and embedded particles were transported atop a periciliary space traversed by frontal cilia, which engaged the mucus layer and moved it during the effective stroke, disengaging and completing the cycle during the recovery stroke. These results confirm the two-layer model for mucociliary transport in the mussel gill. Given the conservative nature of ciliated epithelial structure and function (2, 3), and the structural similarity of mucociliary surfaces as diverse as terrestrial vertebrate respiratory epithelium and molluscan gill, the two-layer mechanism of mucociliary transport may be a general feature of Metazoan biology. PMID- 28581845 TI - Effects of Spatial Distribution and Reproductive Biology on in situ Fertilization Rates of a Broadcast-Spawning Invertebrate. AB - In situ fertilization was examined in the gorgonian Pseudoplexaura porosa during 1994 and 1995 spawning events in the San Blas Islands, Panama, to assess spatial and temporal variation in fertilization success and to determine whether in situ fertilization was sperm limited. Fertilization rates did not differ significantly between years (60% vs. 55%), but monthly means were significantly different, ranging from 22% to 66%. Fertilization rate varied among days, ranging from 0 to 85%; 80% of this variability was explained by daily variation in the number of colonies that spawned. A weighted average of in situ fertilization rates suggests that 67% or more of spawned eggs are fertilized in nature. Sperm limitation did not occur on the nights when most of the colonies synchronously spawned and when most of the eggs were released. Eggs collected downstream of the population often had higher fertilization rates than eggs collected either adjacent to their source colony or eggs collected in the middle of the population, which indicates that in dense populations, eggs may have multiple opportunities to be fertilized. Traits such as highly synchronous spawning, high fecundity, large egg size, large polyps, and large colonies directly and indirectly enhance P. porosa gamete production and fertilization. These life-history traits reduce the effects of gamete dilution during spawning events and thus decrease the importance of sperm limitation in the population dynamics of P. porosa. PMID- 28581846 TI - Chromosome Segregation in Fertilized Eggs From Triploid Pacific Oysters, Crassostrea gigas (Thunberg), Following Inhibition of Polar Body 1. AB - Chromosome segregation in fertilized eggs from triploid Pacific oysters, following inhibition of the first polar body (PB1), was studied with acetic orcein staining techniques. To block the release of PB1, fertilized eggs were treated with 0.5 mg/l of cytochalasin B (CB). Four types of segregation were observed, namely, "tripolar segregation" (54.5%), "united bipolar segregation" (12%), "separated bipolar segregation" (2.5%), and "incomplete united bipolar segregation" (4%). The remaining 23% could not be classified because of chromosome disorganization, but appeared to be variants of the above. It seemed clear that the predominant pattern that gave rise to tetraploids was united bipolar segregation, although certain separated bipolar segregations might also lead to the formation of tetraploids. The sequential events of meioses observed in CB-treated eggs are described. The asynchrony of meiotic events and possible mechanisms for the various types of chromosome segregation are discussed. PMID- 28581847 TI - Dose-Response Relationships for Experimental Heterochrony in a Colonial Hydroid. AB - Hydractiniid hydroids display a range of morphological variation. At one end of the spectrum, the colonies grow in a sheet-like configuration with their polyps close together and short stolons. At the other extreme, the colonies have a runner-like form in which the polyps are farther apart and connected by long stolons. These patterns exemplify the heterochronic variation found in many colonial animals and correspond to changes in the timing of the production of polyps and stolon tips relative to rates of stolon growth and colony maturation. Experimental studies of clonal replicates of a Podocoryne carnea colony demonstrated a dose-response relationship between these heterochronic traits and within-colony gastrovascular flow to peripheral stolons. A dose-response relationship was found whether flow was perturbed by manipulating the amount of food consumed by the colonies or by treating the colonies with 2, 4 dinitrophenol, an uncoupler of oxidative phosphorylation. In colonies in which flow was highly perturbed by either treatment, a similar rate of flow produced a similar morphological response. These data support the hypothesis of a causal relationship between flow rate and heterochronic variation. Nevertheless, flow was diminished by two clearly different mechanisms. Feeding manipulation altered flow relative to the size of the stolon by altering stolon thickness, without affecting the absolute quantity of flow. Uncoupling with dinitrophenol diminished the absolute quantity of flow, but did not affect the size of the stolon. A plausible assumption is that feeding manipulation affects the resistance of the stolon tissue to flow, or the fluid absorption of this tissue, or both; whereas uncoupling affects the amount of energy available to drive the flow. At the level of cellular metabolism, on the other hand, feeding manipulation and uncoupling again have similar effects, triggering metabolic activation (e.g., an increase in oxygen uptake and a shift in the mitochondrial redox state in the direction of oxidation). In the context of theories suggesting the metabolic control of development, a direct effect of feeding and uncoupling on colony development thus cannot be ruled out. Further, there may be an interaction between flow rate and metabolism, since gastrovascular flow distributes food throughout the colony, and since such substrate affects metabolic state. Both within-colony flow rate and metabolism may affect heterochronic variation in these hydroids, and methods appropriate to distinguish these two effects are discussed. PMID- 28581848 TI - Larval Shell Muscles in the Abalone Haliotis kamtschatkana. AB - I used light and electron microscopy to investigate shell-attached muscles in larvae of Haliotis kamtschatkana Jonas, 1845, because an early description of these muscles in H. tuberculata by Crofts (1937, 1955) has featured prominently in theories about gastropod evolution. Larval shell muscles in H. kamtschatkana can be grouped into two categories. The first category consists of the larval retractor muscle (LRM) and the accessory larval retractor muscle (ACC); these are striated muscles in which myofilaments begin differentiating before the head and foot rotate relative to the protoconch (this rotation is known as ontogenetic torsion). Collectively, these muscles ultimately insert on tissues within the larval head and mantle, but the ACC and mantle fibers of the LRM degenerate as metamorphic competence is achieved. The second category consists of two nonstriated pedal muscles that differentiate after cephalopodial rotation. The left pedal muscle is anchored on the back of the protoconch, to the left of the shell-attachment plaque for the LRM. It projects into the foot primarily, but also gives rise to muscle slips extending into the mantle fold. The right pedal muscle is anchored on a calcareous septum secreted along the visceral rim of the protoconch. The new data force a reconsideration of the ancestral homologues of larval shell muscles in abalone, because Crofts may have misidentified the accessory larval retractor muscle as a precursor of one of the later pedal muscles. PMID- 28581849 TI - An in vivo Comparative Study of Intersegmental Flexibility in the Ophiuroid Arm. AB - We present the first in vivo measurements of intersegmental rotation in the ophiuroid arm, comparing lateral bending performance in seven epifaunal species from Discovery Bay, Jamaica. The species studied include suspension-feeders, deposit-feeders, and scavengers, and also represent two major types of vertebral ossicle morphology. Animals were photographed with strobe illumination, and the angular deflections between arm segments were recorded. Despite considerable variation in vertebral morphology, ecology, and behavior, Discovery Bay ophiuroids show similar, overlapping distributions of maximal intersegmental rotations. Although interspecific differences in mean lateral flexibility can be statistically significant, absolute differences among species are small and of unknown functional significance. These quantitative data challenge long-standing assumptions about how the ophiuroid vertebral skeleton affects intersegmental flexibility, and how intersegmental flexibility per se affects an ophiuroid's ecological style or success. PMID- 28581850 TI - Reduction of Growth Rate as the Major Process in the Miniaturization of the Sand Dollar Sinaechinocyamus mai. AB - Sinaechinocyamus mai is an extremely small sand dollar, the maximum size being 10.9 mm. It has been suggested that Sinaechinocyamus is a miniaturized progenetic sand dollar that closely resembles the juveniles of Scaphechinus. In this study, we investigated the mechanisms responsible for the miniaturization. Our analysis of population dynamics, maturity, and annual reproductive cycles suggests that the growth rates of S. mai are about 19% the growth rates of Scaphechinus mirabilis, which reaches a maximum size of 88 mm. The developmental stages of oral and aboral surfaces were defined on the basis of the number of discontinuous interambulacral plates and the number of tube-foot porepairs, pairs, respectively. The patterns of the oral and aboral surfaces of the two species were compared, both at original size and after the Scaphechinus mirabilis pattern had been reduced to a size proportional to that of S. mai (i.e., to 19% original). On the oral surface, the patterns were different at the original sizes, but similar when the proportional sizes were compared; this indicates that the development of the oral plates is age-dependent in S. mai. On the aboral surface, the patterns were similar at the original sizes, but different in the proportional comparison, indicating that the development of the aboral plates is size-dependent in S. mai. S. mai becomes sexually mature at the age of 2 years, and Scaphechinus mirabilis matures probably at about the same age. Our data suggest that the reduction of growth rate (neoteny) is a more important mechanism of miniaturization in S. mai than is precocious cessation (progenesis). PMID- 28581851 TI - Mechanosensitive Channels: Introduction. PMID- 28581852 TI - Subcuticular Rejection: an Advanced Mode of the Allogeneic Rejection in the Compound Ascidians Botrylloides simodensis and B. fuscus. AB - Allogeneic rejection between colonies (colony specificity) was described by electron microscopy in two compound ascidians, Botrylloides simodensis and B. fuscus. When two incompatible colonies are brought into contact at their growing edges, the tunic cuticle dissolves and the tunics of the colonies partially fuse. Alloreactive, humoral factors may diffuse to the opposite colony through the partially fusing tunic, and the tunic cells (free cells distributed in the tunic) possibly recognize these factors and induce a rejection reaction. Then, blood cells--mainly morula cells--infiltrate into the tunic, while tunic cells are disintegrating near where the partial fusion of the tunic is occurring. The infiltrating blood cells aggregate, disintegrate, and discharge electron-dense materials in the tunic at the subcuticular regions where the tunics have partially fused. Since the rejection lesion is restricted to the subcuticular area, some regulatory systems may be involved in this restriction. At the end, new walls are formed in the tunic matrix to separate the rejection lesion from the contacting colonies. The new wall is a continuous layer composed of electron dense fibers and is structurally identical to the regenerating tunic cuticle. The mode of occurrence of colony specificity (Hirose et al., 1994) and the present results indicate that tunic cells are the only allorecognition sites in B. fuscus. PMID- 28581853 TI - Stages of Larval Development and Stem Cell Population Changes During Metamorphosis of a Hydrozoan Planula. AB - Scanning electron microscopy and light histology were used to reveal the changes in overall morphology and in stem cell differentiation and distribution that occur as a free-swimming, solid hydrozoan planula larva is transformed into a sessile, hollow adult polyp. Eight stages of development are described: young 10 hour planula, mature 48-hour planula, attaching planula, disc, pawn, crown, immature polyp, and primary adult polyp. The larval interstitial stem cell population (interstitial cells, nematocytes, ganglion cells) undergoes dramatic changes during metamorphosis: (1) distribution patterns change, (2) certain larval derivatives disappear, (3) new types of derivatives differentiate, and (4) migration patterns become more complex. This study is the first to examine how a stem cell system develops in an organism that goes from embryo to larva to adult. PMID- 28581854 TI - Prey Capture by the Sea Anemone Metridium senile (L.): Effects of Body Size, Flow Regime, and Upstream Neighbors. AB - The sea anemone Metridium senile is a quantitatively important passive suspension feeder in hard-bottom communities on the west coast of Sweden and occurs in aggregations with different size distributions. This study tests the hypothesis that different polyp sizes have different optimal flow regimes maximizing prey capture. Results showed that prey capture by M. senile is a function of both flow regime and polyp size, and different optimal flow regimes exist for different size classes. Large anemones had a maximum feeding efficiency at the slowest flow, medium-sized anemones at moderate flow, and small anemones at moderate- to high-flow regimes. Small anemones showed consistently higher feeding rates (per unit of biomass and area of tentacle crown) at all velocities above 10 cm s-1 and exhibited less flow-induced deformation of the tentacle crown, suggesting that small anemones are better at feeding in moderate- to high-flow habitats. Different vertical projections of large and small anemones in the boundary layer could only partly account for differences in feeding success among size classes. Feeding rate was also a function of upstream conspecifics, declining asymptotically to 30% of the maximum rate. The negative effects of neighbors on feeding in aggregations with clonal rather than polyp growth appear to be compensated for by the generally higher feeding efficiency of small polyps. PMID- 28581855 TI - Effects of Common Estuarine Pollutants on the Immune Reactions of Tunicates. AB - Tunicates are filter-feeding estuarine and marine animals that are frequently exposed to chronic environmental pollution. This study demonstrates that exposure to low-level (i.e., below the threshold of acute lethality) contamination with tributyltin, creosote, and copper can have substantial effects on natural immune reactions in tunicates. Sublethal doses of toxicants administered either in vitro or in vivo profoundly affected phagocytosis, cellular cytotoxicity, and hematopoietic cell proliferation. Effects were not always inhibitory, and responses often varied depending on the route of toxicant administration. The data suggest that pollutants can activate cascades of cellular processes and compensatory mechanisms, as well as directly inhibiting some of the responses tested. Some evidence indicates that toxicants exert their effects by altering the relative frequencies of circulatory hemocytes. PMID- 28581856 TI - Conflicting Morphological and Reproductive Species Boundaries in the Coral Genus Platygyra. AB - In mass-spawning corals, potential exists for gametes of a number of species to mix in the water column. The existence of morphologically distinct sympatric coral populations despite such an event implies the presence of isolating mechanisms to prevent hybridization and maintain species boundaries. Over 380 fertilization trials were conducted to determine the extent of reproductive isolation among the seven morphologically defined species (morphospecies) of the scleractinian coral genus Platygyra, on the Great Barrier Reef. Results from these experiments demonstrate that fertilization between-morphospecies can occur at rates equivalent to within-morphospecies fertilizations, indicating that no gametic-level barriers to fertilization exist among these morphological species. Observations of spawning times both in the field and in the laboratory have shown that all seven morphospecies spawn on the same night and that there is considerable overlap in the hour of spawning among them. These data indicate that few, if any, temporal barriers to fertilization exist among morphospecies of Platygyra on the Great Barrier Reef. In addition, larvae resulting from between morphospecies crosses are capable of settlement and subsequent growth equivalent to that of within-morphospecies larvae. Our results reveal a discontinuity between reproductive and morphological species boundaries within the scleractinian genus Platygyra and challenge species definitions within the Scleractinia. It is not yet clear what mechanisms might maintain morphological boundaries in Platygyra in the face of the clear potential for gamete mixing. The disjunct distributions of certain morphospecies along latitudinal and habitat boundaries, and the small levels of variation in reproduction may be two such mechanisms. PMID- 28581857 TI - Patterns and Consequences of Whole Colony Growth in the Compound Ascidian Polyclinum planum. AB - The size and shape of colony-forming modular animals can convey ecological advantages, but many patterns and consequences of colony-level growth are not well understood. I carried out a longitudinal study on an intertidal population of the pedunculate ascidian Polyclinum planum to determine the patterns and consequences of its colony growth. I found that each P. planum colony is a nonfragmenting genet, and that colony size is limited by water-flow forces and reproductive state. P. planum mitigates the effects of water-flow forces by having an attenuating pattern of growth and by producing a laterally flattened, zooid-bearing lobe atop its tough flexible peduncle. Growth slows as the colony nears a size limit set by the environment and as it becomes reproductively active. The laterally flattened lobe allows colonies to increase their surface-to volume ratio, to house increased numbers of zooids (thereby increasing reproductive potential), and to minimize the effects of the acceleration reaction of water. P. planum's growth pattern fits predictions for colonies living in wave or surge-impacted environments. The growth of P. planum provides insight into how indeterminate modular growth conveys ecological and reproductive advantage, even amidst a physically stressful environment. PMID- 28581858 TI - Coelenterate Cnidae Capsules: Disulfide Linkages Revealed by Silver Cytochemistry and Their Differential Responses to Thiol Reagents. AB - The sulfur cytochemistry of cnidae from the Portuguese man-of-war Physalia physalis, the scyphozoan Cassiopeia xamachana, and the black coral Cirrhipathes luetkeni was evaluated on the basis of electron microscopy, X-ray microanalysis, amino acid analysis, and response to disulfide reducing agents. The cnidae examined included large and small holotrichous isorhizas in P. physalis, another small isorhiza in C. xamachana, and both spirocysts and microbasic mastigophore nematocysts in C. leutkeni. A strong reaction with methenamine-silver reagent was characteristic of all cnidae capsules, but the pattern and extent of that argentophilia was dependent upon the type of cnida and its state of maturity. The large isorhizas of P. physalis reacted primarily in the outermost capsule layers, but in C. xamachana isorhizas, silver stained the entire capsule with the exception of the outermost region. The small isorhizas of P. physalis and the mastigophore capsules of C. leutkeni stained throughout, whereas the spirocyst capsules were outlined by silver, clearly delineating the inner and outer layers. All of these reactions were abolished with alkylation, but only after treatment with disulfide reducing agents; alkylation alone diminished silver staining only slightly, indicating that the argentophilic response was due primarily to disulfide linkages. The cystine content of these cnidae varied from 4.1 to 4.7 mole percent for a given species, but amino acid analyses did not separate components of the cnidom. Cnidae, both within and among species, exhibited differential responses to the disulfide reducing agent dithiothreitol (DTT). Isolated, unfixed, large isorhizas of P. physalis discharged and appeared to dissolve rapidly in the presence of this reagent, whereas small isorhizas from both P. physalis and C. xamachana discharged, but dissolved slowly if at all. The discharge and solution responses of the capsule coincided with the complete development of the tubule. Cnidae containing an undeveloped or partially developed tubule were resistant to DTT, displayed a weak capsular argentophilia, and contained background levels of sulfur; these results suggest that formation of disulfide linkages is one of the final steps in capsular maturation. In contrast, mature nematocyst and spirocyst capsules in C. leutkeni tentacles were resistant to DTT among other reagents, despite the presence of disulfides. This suggests that other types of covalent, intermolecular linkages could play a prominent role in the development of capsular stability in this species. PMID- 28581859 TI - Complex Signal Processing by Weakly Electric Fishes. PMID- 28581860 TI - Energy Use During the Development of a Lecithotrophic and a Planktotrophic Echinoid. AB - The energy required for development was measured in two closely related echinoids with differing modes of development. Heliocidaris tuberculata hatches from a 95 {mu}m egg (~0.1 {mu}g dry organic mass) and develops via a planktotrophic larva over 21-30 days into a juvenile (5.3-7.5 {mu}g). H. erythrogramma hatches from a ~400 {mu}m egg (11.6-19.0 {mu}g) and develops over 3.5-4 days via a lecithotrophic larva into a juvenile with a mass not detectably different from that of the egg. Oxygen consumption increased exponentially in H. tuberculata and peaked at about 200-500 pmol indiv-1 h-1, whereas the oxygen consumption of H. erythrogramma increased rapidly, reaching a plateau at about 800 pmol indiv-1 h-1 on the second day. Metabolic energy expenditure for development to metamorphosis was twofold higher for H. tuberculata (52-60 mJ indiv-1) than for H. erythrogramma (26-35 mJ indiv-1). The interspecific comparison suggests that about half the metabolic expenditure for planktotrophic development goes toward building and operating the larval feeding apparatus and that the return on this investment is 400%-600% over the larval period. When the energy equivalents of the organic masses of the juveniles are included, the energy for constructing a juvenile on a per mass basis is essentially the same for both species (cf. H. tuberculata: 37-42 mJ {mu}g-1; H. erythrogramma: 34-36 mJ {mu}g-1) and implies the absence of developmentally based energetic barriers or benefits to changes in modes of development. Substantial amounts of metabolically inactive material may be present in embryos with nonfeeding development and should be considered in physiological measurements and comparisons. PMID- 28581861 TI - Ovarian Development in the Class Holothuroidea: a Reassessment of the "Tubule Recruitment Model". AB - The "tubule recruitment model" for the development of the holothurian gonad was proposed (a) to connect the stages of oogenesis with ovarian morphology in holothurians throughout the reproductive season and (b) to emphasize the potential for the holothurian ovary as a model system for cytological and biochemical study of echinoderm oogenesis. To reassess the evidence for this model, we have examined published accounts and unpublished observations on gonad development in holothurians from both temperate and tropical habitats, in shallow water and in the deep sea. A very limited number of species were found to conform to the predictions of the tubule recruitment model. The patterns of gonad development vary substantially in holothurians, even at the individual level, and with taxonomic position, geographical location, and habitat. The tubule recruitment model can be applied to only a small subset of holothurians, specifically those in the families Stichopodidae and Holothuriidae that have gonad morphology similar to that of Parastichopus californicus. However, the tubule recruitment model is invalid for many other aspidochirotes, and does not have wider applicability within the class Holothuroidea. PMID- 28581862 TI - Uptake and Persistence of Homologous and Heterologous Zooxanthellae in the Temperate Sea Anemone Cereus pedunculatus (Pennant). AB - The uptake and persistence of symbiotic dinoflagellates (zooxanthellae) were measured in the temperate sea anemone Cereus pedunculatus (Pennant). Aposymbiotic specimens of C. pedunculatus were inoculated with zooxanthellae freshly isolated from a range of temperate and subtropical Anthozoa. Each inoculate consisted of zooxanthellae from a single host species and was either homologous (zooxanthellae from a host of the same species as the one being inoculated) or heterologous (from a host of a different species than the one being inoculated). The densities of zooxanthellae in host tissues were determined at regular intervals. C. pedunculatus took up homologous and heterologous zooxanthellae to similar degrees, except for zooxanthellae from the temperate Anthopleura ballii, which were taken up to a lesser extent. The densities of all zooxanthellae declined between 4 hours and 4 days after uptake, indicating that zooxanthellae were expelled, digested, or both during this period. The densities of all zooxanthellae increased between 2 and 8 weeks after inoculation, indicating zooxanthella growth. Over the entire 8-week period after uptake, densities of homologous zooxanthellae were always greater than those of heterologous zooxanthellae. Between 8 and 36 weeks after infection, densities of homologous zooxanthellae declined markedly and densities of some heterologous zooxanthellae increased further, resulting in homologous and heterologous zooxanthella densities being the same at 36 weeks. These densities were the same as those in naturally infected C. pedunculatus of similar size. The results suggest that zooxanthellae from a range of host species and environments can establish symbioses with C. pedunculatus and that, over long periods under laboratory conditions, heterologous zooxanthellae may populate C. pedunculatus to the same extent as homologous zooxanthellae. PMID- 28581863 TI - Effect of Salinity on Ionic Shifts in Mesohaline Scyphomedusae, Chrysaora quinquecirrha. AB - Mesohaline populations of the scyphomedusae Chrysaora quinquecirrha are found in salinities ranging from 5{permill} to 25{permill}. Osmotic and ionic adjustments within this salinity range were investigated using C. quinquecirrha ephyrae budded from polyps in the laboratory and young medusae collected from the mid salinity region of the Patuxent River, Maryland. When medusae were transferred from 20{permill} salinity to lower salinities (8{permill}, 12{permill}), concentrations of sodium and magnesium in tissue and mesogleal fluid fell rapidly and approached those of dilute seawater within 6 hours. There was some recovery of these levels relative to the 8{permill} medium, and they were significantly higher than the dilute seawater concentration after 1 week. Tissue concentrations of calcium showed no evidence of being regulated, whereas potassium was strongly regulated such that levels did not fall significantly following transfer of medusae to lower salinities. However, after 1 week, the concentration of potassium in mesogleal fluid approached that of the dilute medium. Extracellular space measured by direct blotting and weighing or using 35S was about 40%. As a result, estimates for intracellular potassium were revised to 17 mM1-1. The concentration of potassium in tissue remained stable following transfer to lower salinity, despite a substantial osmotic influx of water. This influx was measured as a >20% gain in body weight over 24 h following transfer of medusae from 16{permill} to 8{permill}. Mesogleal fluid was slightly hypo-osmolar to the medium at 15% and 20{permill} and slightly hyperosmolar to the medium at 5{permill} and 12{permill}. Sulfate concentrations in mesogleal fluid were 66% 70% those of the external medium. Medusae died or were unable to achieve positive buoyancy at 5%{permill}, which is probably very close to a lower salinity limit for C. quinquecirrha in the mesohaline Chesapeake Bay. PMID- 28581864 TI - The Route of Ion and Water Movements Across the Gill Epithelium of the Freshwater Shrimp Macrobrachium olfersii (Decapoda, Palaemonidae): Evidence From Ultrastructural Changes Induced by Acclimation to Saline Media. AB - The ultrastructure of the pillar cells in the gill lamellae of the freshwater shrimp Macrobrachium olfersii was examined to evaluate the routes of salt and water movement across the gill epithelium and into the hemolymph. Alterations were morphometrically quantified in shrimp maintained in fresh water (FW, <0.5{permill} salinity) and after acclimation to saline media (21{permill} or 28{permill} salinity). The tissue interface between the hemolymph and the external medium consists exclusively of the thin apical flange regions of the pillar cells, the upper membrane of which is highly amplified by dense microvilli and overlain by a thin cuticle. The lower flange membrane, bathed by the hemolymph, is smooth and not invaginated. Contiguous flanges are strongly bound by junctional structures including desmosomes and septate junctions. The basal surface of the pillar cell perikaryon is linked to the adjacent septal cells through many basolateral junctions. The septal cell plasmalemma is abundantly and deeply invaginated, each infolding enclosing numerous mitochondria; these characteristics are typical of salt-transporting machinery. After shrimps were acclimated to saline media for 10 days, the thickness of the pillar cell flanges was significantly reduced (from 1.3 to {approx}0.4 {mu}m), as was the height (from 0.8 to 0.3 {mu}m) and density (from 4.0 to {approx} 1.8 microvilli/{mu}m) of the apical microvilli. This reduction in the apical surface area of the pillar cells appears to lead to decreased ionic permeability, concomitant with a reduction in Na+/K+-ATPase activity, thus limiting Na+ uptake. In contrast to the brachyurans, in which the respiratory and ion-transporting mechanisms are differentially located in the anterior and posterior gills, in palaemonid shrimps the pillar cells apparently play a dual role: ions move preferentially through ion transporters in the microvilli above the pillar cell perikaryon, while respiratory gases are exchanged through the fine flange regions in contact with the hemolymph. PMID- 28581865 TI - Embryonic Coat of the Grass Shrimp Palaemonetes pugio. AB - The embryo of the grass shrimp, Palaemonetes pugio, is surrounded during development by a protective extracellular coat designated as the embryonic coat (EC). At hatching, this EC is composed of four embryonic envelopes (EE), each of which is composed of multiple layers. The outermost layer of the EC, the outer investment coat (OIC), is derived primarily, if not completely, from pleopods of the female. The first envelope (EE1) forms as a bilayered envelope, EE1a and EE1b, immediately after oviposition. The OIC becomes closely associated with EE1 and remains in close contact with EE1 until hatching occurs. An additional layer, EE1c, is added to the inner side of EE1 between 3 and 5 d after oviposition. Three more embryonic envelopes, EE2, EE3, and EE4, are formed between the embryo and EE1 by 7 d after oviposition. Formation of embryonic envelopes continues until 10 d after oviposition; by this time each envelope is morphologically distinct in composition, with "outer" and "inner" sides clearly identifiable. All but the innermost embryonic envelope (EE4) are shed by the embryo about 6 h before hatching. Permeability of the EC during the 12-d incubation period is found to decrease between 0 and 5 d after oviposition, and then increase until hatching. Fluorescently labeled lectins react positively with the OIC, indicating the presence of glucose and N-acetylglucosamine residues. Thus, the palaemonid EC is a dynamic structure throughout embryonic development. PMID- 28581866 TI - p58, a Cytoskeletal Protein, Is Associated With Muscle Cell Determinants in Ascidian Eggs. AB - The theory that p58, a cytoskeletal protein, has an important role in ascidian muscle cell development was tested by altering normal distributions of orange pigmented myoplasm in Boltenia villosa embryos and determining if muscle development is correlated with the presence of p58. Removal of the animal region of fertilized Boltenia eggs resulted in the redistribution of myoplasm into the anterior endoderm cells of the embryo. Despite alterations in the normal distribution of myoplasm, these embryos developed into larvae. However, when four celled embryos that exhibited altered distributions of pigmented myoplasm were stained with NN18, an antibody that stains p58, a maximum of two blastomeres were stained, as in control embryos. Compression of Boltenia embryos at the four celled stage caused the myoplasm to be partitioned into four blastomeres of an eight-celled embryo, instead of into two blastomeres. Compressed and cleavage arrested eight-celled embryos developed myosin and muscle actin RNA in a maximum of four blastomeres, compared to a maximum of two blastomeres in control embryos. When compressed eight-celled embryos were stained with NN18, p58 was present in a maximum of four blastomeres. These results support the idea that the cytoskeletal protein p58 is associated with muscle cell determinants in ascidian eggs. PMID- 28581867 TI - Morphology and Development of Odostomia columbiana Dall and Bartsch (Pyramidellidae): Implications for the Evolution of Gastropod Development. AB - Although pyramidellid gastropods are a phylogenetically important group of diverse and abundant ectoparasites, little is known about their life histories. Herein, we describe the adult morphology and development of the pyramidellid Odostomia columbiana, which parasitizes the scallops Chlamys hastata and C. rubida in the Northeast Pacific. Anatomically, adult O. columbiana resemble other known pyramidellids although they lack the tentacular pads typical of other Odostomia species. Embryonic development is similar to that described for other pyramidellids: cleavage is unequal, gastrulation is partially by invagination, and considerable growth occurs before hatching. However, embryonic and larval development are much slower than for other described species. The planktotrophic larvae hatch after 19 days of intracapsular development and metamorphose about 2 months later. O. columbiana veligers have a large black pigmented mantle organ to the right of the midline, a distinct metapodial tentacle, and three or four long bristles that project over the operculum from behind the foot. Observations of newly metamorphosed juveniles suggest that previous disagreements regarding the development of heterostrophy are due to variation in the degree of heterostrophy among species. Our observations also generally corroborate certain scenarios explaining the evolution of gastropod cleavage type and larval heterochrony. Unequal cleavage and larvae that hatch without well-developed eyes and tentacles may be characteristic of the common ancestor of pyramidellids and opisthobranchs; however, late development of the larval heart is probably a derived condition of opisthobranchs. PMID- 28581868 TI - Decline in Pelagic Cephalopod Metabolism With Habitat Depth Reflects Differences in Locomotory Efficiency. AB - The metabolic rates of 33 species of pelagic cephalopods from California and Hawaii were measured and correlated with minimum depth of occurrence. Mean metabolic rates ranged from 0.07 {mu}mol O2g-1 h-1 for the deep-living vampire squid, Vampyroteuthis infernalis, to 8.79 {mu}mol O2 g-1 h-1 for Gonatus onyx, a vertically migrating squid. An individual of V. infernalis, which lives within the oxygen minimum layer off California, had the lowest mass-specific metabolic rate ever measured for a cephalopod (0.02 {mu}mol O2g-1 h-1, 1050 g wet weight). For species collected in sufficient quantity and size range, metabolism was related to body size. Critical partial pressures of oxygen (Pc) were determined for Hawaiian and Californian cephalopods. Pc values for Hawaiian animals were considerably higher than for those taken off California, a trend that corresponds to the higher levels of environmental oxygen in the Hawaiian waters. Buffering capacity ({beta}) of mantle muscle, assayed in eight cephalopod species, was used to estimate the capacity for glycolytic energy production. Mean {beta} ranged from 1.43 slykes for a bathypelagic octopod, Japetella heathi, to 77.08 slykes for an epipelagic squid. Sthenoteuthis oualaniensis. Significant declines with increasing depth of occurrence were observed for both metabolism and {beta}. The decline in metabolic parameters with depth is interpreted as a decreased reliance on locomotory abilities for predator/prey interactions in the light-limited deep sea. The decline in metabolism with depth observed for pelagic cephalopods was significantly steeper than that previously observed for either pelagic fishes or crustaceans. We suggest that since strong locomotory abilities are not a priority in the deep sea, deeper-living cephalopods may rely more heavily on means of locomotion that are more efficient than jet propulsion via mantle contractions- means such as fin swimming or medusoid swimming utilizing the arms and extensive webbing present in many deep-living species. The greater efficiency of deeper living cephalopods may be responsible for the observation that the decline in metabolic rates with depth is more pronounced for pelagic cephalopods than for fishes or crustaceans. PMID- 28581869 TI - Life-History Variation in a Colonial Ascidian: Broad-Sence Heritabilities and Tradeoffs in Allocation to Asexual Growth and Male and Female Reproduction. AB - Intraspecific variation in life-history strategy provides a valuable opportunity for examining how natural selection acts on life-history variants to mold reproductive strategies. Evaluating the consequences of selection requires knowledge of the range of phenotypic variation in life histories, the extent to which variation is genetically based, and possible correlations among different traits that might constrain or promote the effect of selection on individual traits. We explored life-history variation in the colonial ascidian Botryllus schlosseri (a cyclical hermaphrodite) by growing clonal replicates of 18 genotypes in a common-garden experiment. Colonies of this species have previously been shown to vary in egg production and growth rate. We demonstrate that genotypes also vary in sperm production, which is manifested as variation in testis size. We then calculate broad-sense heritabilities for a suite of life history traits and demonstrate correlations among traits that suggest a three-way tradeoff in resource allocation to asexual growth and sexual reproduction via male and female function. This correlation structure suggests that selection cannot act independently on individual life-history traits. PMID- 28581870 TI - Plasticity in the Sclerites of a Gorgonian Coral: Tests of Water Motion, Light Level, and Damage Cues. AB - The gorgonian coral Briareum asbestinum contains skeletal elements (sclerites) that vary in length and density within and among local populations. Data from previous work suggested that the sclerite compositions of colonies may be altered in response to environmental cues such as predator damage, water motion, and light level. To test these hypotheses, colonies from shallow reefs were transplanted to racks at a single location where the three environmental factors of interest were artificially manipulated. After 9-14 weeks of growth, sclerite morphologies and densities had not changed in response to shading or to water motion reductions that mimicked deep-water conditions. However, colonies did respond significantly to two types of simulated predator damage. Following tip amputation, sclerites in the regenerated tips of damaged colonies were shorter and more dense than in the controls. In contrast, mid-branch scarring caused colonies to produce longer sclerites at lower densities. Since long sclerites deter feeding by predatory snails, the increase in sclerite length in response to scarring of mid-branch regions may function as an inducible defense. PMID- 28581871 TI - Heat-Shock Protein Expression in Mytilus californianus: Acclimatization (Seasonal and Tidal-Height Comparisons) and Acclimation Effects. AB - Heat-shock protein (hsp) expression was examined in gill of field-acclimatized and laboratory-acclimated mussels (Mytilus californianus) from the Oregon coast. Endogenous levels of heat-shock proteins in the 70-kDa class (hsp70 isoforms) and profiles of induction temperature for newly synthesized hsp 70 were measured in freshly field-collected specimens as functions of location height in the intertidal and season, and in mussels after 7 weeks of laboratory thermal acclimation. There were significant differences in endogenous levels of hsp70 as functions of season and collection height. Strong induction of new hsp70 synthesis occurred at body temperatures within the range measured in field specimens. Profiles of hsp70 thermal induction varied significantly with season, but not with height of collection. In contrast to the large differences in hsp70 expression between winter- and summer-acclimatized mussels, no differences related to temperature occurred in the differently acclimated mussels. The differences found between the effects of field acclimatization and laboratory thermal acclimation suggest that the stress response is modulated by environmental factors in addition to body temperature. Thus, caution is required in extrapolating from laboratory acclimation studies to acclimatization effects in field populations. The seasonal and tidal-height variations in the heat-shock response are discussed in the context of energy costs of protein turnover. PMID- 28581872 TI - Compound Eye Fine Structure in Paralomis multispina Benedict, an Anomuran Half Crab From 1200 m Depth (Crustacea; Decapoda; Anomura). AB - Fully grown, unsexed specimens of the anomuran half-crab Paralomis multispina Benedict were obtained from a depth of 1200 m, and the eyes of three individuals were prepared for light and electron microscopy. In their outer appearance the compound eyes of Paralomis resemble those of common shallow-water half-crabs (e.g., Petrolisthes), but facets in Paralomis were about 3 times larger in diameter (i.e., 60 {mu}m) and at least twice as long. Interommatidial angles ranged from 3{deg} to 5{deg}. The proximal width of the crystalline cone in Paralomis was 10 times that of its equivalent in the Petrolisthes eye, and the rhabdom--although only twice as long--had a radius that was 7 times greater distally and 4 times greater proximally. A clear-zone between cones and rhabdom was not developed, and cross sections of crystalline cones revealed rounded rather than square profiles. A distal retinula cell (R8) was absent, and all regular retinula cells (R1-R7) protruded microvilli of about 0.11 {mu}m diameter in many (and not only two) directions. A maximum rhabdom occupation ratio of 85% was found in the Paralomis retinula, whereas in the shallow-water half-crabs the comparable figure was 35%. Paralomis featured a wide, rhabdomless space between basement membrane and proximal rhabdom ends; the space was occupied by reflecting cells. Primary screening pigment cells and their dark granules were present; secondary screening pigment cells, however, were replaced by reflecting cells. The anatomical modifications in the Paralomis eye are consistent with habitat related adaptations seen in the eyes of other benthic and slow-moving deep-water crustaceans, but not with those of euphausiids. We conclude that the eye of Paralomis functions as an apposition eye, designed to maximize photon capture, especially from point sources (i.e., bioluminescence) rather than extended sources. We estimate that the Paralomis eye is at least 150 times more sensitive to light than the eye of shallow-water Petrolisthes. PMID- 28581873 TI - Budget impact model in moderate-to-severe psoriasis vulgaris assessing effects of calcipotriene and betamethasone dipropionate foam on per-patient standard of care costs. AB - AIMS: To develop a budget impact model (BIM) for estimating the financial impact of formulary adoption and uptake of calcipotriene and betamethasone dipropionate (C/BD) foam (0.005%/0.064%) on the costs of biologics for treating moderate-to severe psoriasis vulgaris in a hypothetical US healthcare plan with 1 million members. METHODS: This BIM incorporated epidemiologic data, market uptake assumptions, and drug utilization costs, simulating the treatment mix for patients who are candidates for biologics before (Scenario #1) and after (Scenario #2) the introduction of C/BD foam. Predicted outcomes were expressed in terms of the annual cost of treatment (COT) and the COT per member per month (PMPM). RESULTS: At year 1, C/BD foam had the lowest per-patient cost ($9,913) necessary to achieve a Psoriasis Area and Severity Index (PASI)-75 response compared with etanercept ($73,773), adalimumab ($92,871), infliximab ($34,048), ustekinumab ($83,975), secukinumab ($113,858), apremilast ($47,960), and ixekizumab ($62,707). Following addition of C/BD foam to the formulary, the annual COT for moderate-to-severe psoriasis would decrease by $36,112,572 (17.91%, from $201,621,219 to $165,508,647). The COT PMPM is expected to decrease by $3.00 (17.86%, from $16.80 to $13.80). LIMITATIONS: Drug costs were based on Medi-Span reference pricing (January 21, 2016); differences in treatment costs for drug administration, laboratory monitoring, or adverse events were not accounted for. Potentially confounding were the definition of "moderate-to severe" and the heterogeneous efficacy data. The per-patient cost for PASI-75 response at year 1 was estimated from short-term efficacy data for C/BD foam and apremilast only. CONCLUSIONS: The introduction of C/BD foam is expected to decrease the annual COT for moderate-to-severe psoriasis treatable with biologics by $36,112,572 for a hypothetical US healthcare plan with 1 million plan members, and to lower the COT PMPM by $3.00. PMID- 28581874 TI - Cost drivers for breast, lung, and colorectal cancer care in a commercially insured population over a 6-month episode: an economic analysis from a health plan perspective. AB - AIMS: In the absence of clinical data, accurate identification of cost drivers is needed for economic comparison in an alternate payment model. From a health plan perspective using claims data in a commercial population, the objective was to identify and quantify the effects of cost drivers in economic models of breast, lung, and colorectal cancer costs over a 6-month episode following initial chemotherapy. RESEARCH DESIGN AND METHODS: This study analyzed claims data from 9,748 Cigna beneficiaries with diagnosis of breast, lung, and colorectal cancer following initial chemotherapy from January 1, 2014 to December 31, 2015. We used multivariable regression models to quantify the impact of key factors on cost during the initial 6-month cancer care episode. RESULTS: Metastasis, facility provider affiliation, episode risk group (ERG) risk score, and radiation were cost drivers for all three types of cancer (breast, lung, and colorectal). In addition, younger age (p < .0001) and human epidermal growth factor receptor-2 oncogene overexpression (HER2+)-directed therapy (p < .0001) were associated with higher costs in breast cancer. Younger age (p < .0001) and female gender (p < .0001) were also associated with higher costs in colorectal cancer. Metastasis was also associated with 50% more hospital admissions and increased hospital length of stay (p < .001) in all three cancers over the 6-month episode duration. Chemotherapy and supportive drug therapies accounted for the highest proportion (48%) of total medical costs among beneficiaries observed. CONCLUSIONS: Value based reimbursement models in oncology should appropriately account for key cost drivers. Although claims-based methodologies may be further augmented with clinical data, this study recommends adjusting for the factors identified in these models to predict costs in breast, lung, and colorectal cancers. PMID- 28581875 TI - Microencapsulation by spray drying of lemon essential oil: Evaluation of mixtures of mesquite gum-nopal mucilage as new wall materials. AB - Mesquite gum (MG) and nopal mucilage (NM) mixtures were used for microencapsulation of lemon essential oil (LEO) by spray drying. Emulsions of MG, NM and MG-NM mixtures (25-75, 50-50, 75-25) were evaluated according to the droplet size (1.49-9.16 MUm), viscosity and zeta potential (-16.07 to -20.13 mV), and microcapsules were characterised in particle size (11.9-44.4 MUm), morphology, volatile oil retention (VOR) (45.9-74.4%), encapsulation efficiency (EE) (70.9-90.6%), oxidative stability and thermal analysis. The higher concentration of MG led to smaller droplet sizes and lower viscosity in the emulsions, and smaller particle sizes with the highest VOR in microcapsules. The higher concentration of NM induced to higher viscosity in the emulsions, and larger particle sizes with the highest values of EE and oxidative stability in microcapsules. This work shows evidence that MG-NM mixtures can have synergic effect in desirable characteristics such as retention and shelf life extension of LEO in microcapsules. PMID- 28581876 TI - Hypolipidemic Activity of Quercus acutissima Fruit Ethanol Extract is Mediated by Inhibition of Acetylation. AB - The acetylation of histone and nonhistone proteins is associated with adipogenesis. The objective of the present study was to investigate whether an ethanol extract of Quercus acutissima fruit (QF) exhibits antiobesity effects through inhibition of acetylation in 3T3-L1 preadipocytes and high fat diet (HFD) fed obese mice. We observed that QF acts as a histone acetyltransferase (HAT) inhibitor and that QF (400 MUg/mL) markedly inhibits the activity of p300 and CREB-binding protein. QF (200 MUg/mL) significantly attenuated lipid accumulation without apparent toxicity, which is likely attributable to a decrease in the expressions of lipogenic proteins, including fatty acid synthase, peroxisome proliferator-activated receptor gamma, sterol regulatory element-binding protein 1, and CCAAT-enhancer-binding proteins alpha that were otherwise increased by MDI (a hormonal cocktail containing methyl isobutylmethylxanthine, dexamethasone, and insulin). MDI increased the acetylation of total lysine residues in whole 3T3-L1 cell lysate, an effect that was reversed by QF treatment (200 MUg/mL). To further confirm the antiobesity activity of QF, mice were fed with HFD supplemented with QF at 50 and 200 mg/kg body weight. Mice fed with HFD exhibited increased masses of body, liver, and retroperitoneal fat, an effect that was suppressed in the presence of QF supplementation. QF-mediated decreases in body weight were attributable to a decrease in the average size of lipid droplets, as well as lipid accumulation in retroperitoneal fat and the liver, respectively. QF mediated reductions in the size of the lipid droplets in the retroperitoneal fat tissue were likely associated with decreased expression of DGAT2. Taken together, our observations suggest that QF acts as an HAT inhibitor and attenuates adipogenesis in 3T3-L1 preadipocytes, resulting in the mitigation of HFD-induced obesity. PMID- 28581877 TI - Cellular Antioxidant and Anti-Inflammatory Effects of Coffee Extracts with Different Roasting Levels. AB - During roasting, major changes occur in the composition and physiological effects of coffee beans. In this study, in vitro antioxidant effects and anti inflammatory effects of Coffea arabica green coffee extracts were investigated at different roasting levels corresponding to Light, Medium, City, and French roast. Total caffeine did not show huge difference according to roasting level, but total chlorogenic acid contents were higher in light roasted coffee extract than other roasted groups. In addition, light roasted coffee extract had the highest antioxidant activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. To determine the in vitro antioxidant property, coffee extracts were used to treat AML-12 cells. Intracellular glutathione (GSH) concentration and mRNA expression levels of genes related to GSH synthesis were negatively related to roasting levels. The anti-inflammatory effects of coffee extracts were investigated in lipopolysaccharide-treated RAW 264.7 macrophage cells. The cellular antioxidant activity of coffee extracts exhibited similar patterns as the AML-12 cells. The expression of mRNA for tumor necrosis factor-alpha and interleukin-6 was decreased in cells treated with the coffee extracts and the expression decreased with increasing roasting levels. These data suggest that coffee has physiological antioxidant and anti-inflammatory activities and these effects are negatively correlated with roasting levels in the cell models. PMID- 28581879 TI - Familiar Stranger. PMID- 28581878 TI - What happens when the doctor denies a patient's request? A qualitative interview study among general practitioners in Norway. AB - OBJECTIVE: To explore general practitioners (GPs') experiences from consultations when a patient's request is denied, and outcomes of such incidents. DESIGN AND PARTICIPANTS: We conducted a qualitative study with semi-structured individual interviews with six GPs in Norway. We asked them to tell about experiences from specific encounters where they had refused a patient's request. The texts were analysed with Systematic Text Condensation, a method for thematic cross-case analysis. MAIN OUTCOME MEASURES: Accounts of experiences from consultations when GPs refused their patients' requests. RESULTS: Subjects of dispute included clinical topics like investigation and treatment, certification regarding welfare benefits and medico-legal issues, and administrative matters. The arguments took different paths, sometimes settled by reaching common ground but more often as unresolved disagreement with anger or irritation from the patient, sometimes with open hostility and violence. The aftermath and outcomes of these disputes lead to strong emotional impact where the doctors reflected upon the incidents and sometimes regretted their handling of the consultation. Some long-standing and close patient-doctor relationships were injured or came to an end. CONCLUSIONS: The price for denying a patient's request may be high, and GPs find themselves uncomfortable in such encounters. Skills pertaining to this particular challenge could be improved though education and training, drawing attention to negotiation of potential conflicts. Also, the notion that doctors have a professional commitment to his or her own autonomy and to society should be restored, through increased emphasis on core professional ethics in medical education at all levels. PMID- 28581880 TI - Does familial Mediterranean fever affect cognitive function in children? Electrophysiological preliminary study. AB - OBJECTIVES: Familial Mediterranean fever (FMF) is a periodic autoinflammatory disease with subclinical inflammation occurring between attacks. The aim of the study was to prospectively evaluate the cognitive function of children diagnosed with FMF that were under colchicine therapy and compare them with healthy controls through electrophysiologically event-related potentials (ERPs) study. METHODS: Twelve children with FMF and 12 healthy controls were included in the study. During the electroencephalography recordings, all participants were instructed to discriminate rare stimuli (target stimuli) from frequent stimuli (standard stimuli) by pressing a botton on a mouse immediately following the target stimulus. P300, the cognitive component of ERP, was obtained in response to target stimuli and its amplitude and latency were measured. RESULTS: The amplitude of the P300 of the FMF patients was higher and the latencies of the P300 of the FMF patients were shorter than the amplitudes and latencies of control patients, respectively. The difference between the groups was statistically significant for amplitude but not for latency. CONCLUSIONS: Cognitive processing reflecting allocation of attention and visual processing speed seems not to be negatively affected in FMF patients with homozygous M694V mutations undergoing colchicine treatment. As this study is unique in its evaluation of the cognitive function of children with FMF, these findings may be helpful for counseling families and patients affected by the condition. PMID- 28581881 TI - Prevalence and Clinical Intentions of Antithrombotic Therapy on Discharge to Hospice Care. AB - BACKGROUND: There are no guidelines for antithrombotic therapy on admission to hospice care. Antithrombotic therapy may offer some benefit in these patients, but is also associated with well-described risks. OBJECTIVE: We quantified the frequency and characteristics of patients prescribed antithrombotic therapy on discharge from acute care to hospice care. DESIGN: Retrospective cohort study. Settings/Subjects: Adult (age> = 21 years) patients discharged from acute care to hospice care between January 1, 2010 and June 30, 2014. MEASURES: Our primary outcome of interest was receiving an outpatient prescription for antithrombotic therapy on discharge to hospice care. RESULTS: Among 1141 eligible patients, 77 (6.7%) patients received a prescription for antithrombotic therapy on discharge to hospice care, most frequently, aspirin (57.1%), enoxaparin (26.0%), and warfarin (20.8%). Patients actively treated for deep vein thromboembolism or pulmonary embolism, or with a history of atrial fibrillation or aortic/mitral valve replacement were significantly more likely to receive antithrombotic therapy. Patients with a history of cancer, cerebrovascular disease, or liver disease were significantly less likely to receive antithrombotic therapy (p < 0.05 for all). Among patients who received antithrombotic therapy, 22% were not receiving antithrombotic therapy before the index admission. Among patients previously receiving antithrombotic therapy, 55% continued on the same medication, of which 54.5% did not have any documented rationale for continuation. CONCLUSIONS: Prescriptions for antithrombotic therapy were infrequent and often lacked a documented rationale. Further research is needed on the safety and effectiveness of antithrombotic therapy in hospice care and what drives current medication decisions in the absence of these data. PMID- 28581882 TI - Nutriproteomic Analysis of Hwangmaemok-Induced Antiangiogenic Effect Using Antibody-Arrayed Protein Chip Assay. AB - We investigated the antiangiogenic effects of Lindera obtusiloba Blume (Hwangmaemok, HMM), which is a plant in the Lauraceae family that is commonly used to treat colds and gastritis. Moreover, given that a recent study reported the inhibitory effects of HMM extract on cancer metastasis, we hypothesized that HMM extract might possess and antiangiogenic function. Thus, this study was conducted to investigate the effects of HMM extract on endothelial cell proliferation, migration, and neovascularization in chick chorioallantoic membrane (CAM), and investigated the molecular mechanism of antiangiogenesis using a ProteoChip-based proteomics technology. To examine the effects of HMM extracts on endothelial cell proliferation and migration, we conducted basic fibroblast growth factor (bFGF)-induced human umbilical vein endothelial cell (HUVEC) proliferation and migration. To assess the molecular mechanism of the antiangiogenic effects of HMM extract, a ProteoChip-based forwarded phase antibody array was employed to identify the differential expression of cell cycle proteins in HMM-treated HUVECs. HMM extract inhibited bFGF-induced HUVEC proliferation and migration in a dose-dependent manner and CAM angiogenesis. The ProteoChip-based antibody microarray data showed upregulation of Nibrin/NBS1 and downregulation of Plk-1 and Cyclin E, which are involved in cell division and controlling the cell cycle in bFGF-induced HUVECs. These data suggest that HMM may be a potent antitumor medicinal herb. The present study demonstrates that the antiangiogenic effect of HMM may be due to suppression of endothelial cell proliferation and migration. Taken together, these results emphasize the potential to use HMM extract as a potent angiogenesis inhibitor to treat cancer. PMID- 28581884 TI - Avoidance of Negative Results in Adjuvant Endocrine Therapy Trials for Estrogen Receptor-Positive Breast Cancer. PMID- 28581885 TI - Reply to R. Goncalves et al. PMID- 28581883 TI - Discovery and characterization of a novel humanized anti-IL-15 antibody and its relevance for the treatment of refractory celiac disease and eosinophilic esophagitis. AB - Interleukin-15 (IL-15) is a critical regulator of immune responses, especially at mucosal interfaces within the gastro-intestinal tract. Here, we describe the discovery and characterization of a humanized antibody to IL-15. Data from its epitope and mode of action, cell biology and primate pharmacology, as well as translational studies in human samples and in vivo proof-of-concept experiments in mouse models demonstrate the therapeutic potential of this new antibody targeting IL-15 for refractory celiac disease and eosinophilic esophagitis. PMID- 28581886 TI - Enhanced immunization techniques to obtain highly specific monoclonal antibodies. AB - Despite fast advances in genomics and proteomics, monoclonal antibodies (mAbs) are still a valuable tool for areas such as the evolution of basic research in stem cells and cancer, for immunophenotyping cell populations, diagnosing and prognosis of diseases, and for immunotherapy. To summarize different subtractive immunization approaches successfully used for the production of highly specific antibodies, we identified scientific articles in NCBI PubMed using the following search terms: subtractive immunization, monoclonal antibody, tolerization, neonatal, high-zone tolerance, masking immunization. Patent records were also consulted. From the list of results, we included all available reports, from 1985 to present, that used any enhanced immunization technique to produce either polyclonal or monoclonal antibodies. Our examination yielded direct evidence that these enhanced immunization techniques are efficient in obtaining specific antibodies to rare epitopes, with different applications, such as to identify food contaminants or tumor cells. PMID- 28581887 TI - Impact of S-sulfocysteine on fragments and trisulfide bond linkages in monoclonal antibodies. AB - The quality of recombinant proteins such as monoclonal antibodies produced using Chinese hamster ovary cell-based mammalian systems is dependent on many factors, including cell line, process and cell culture media. Due to these factors, the generated product is heterogeneous and may have chemically-induced modifications or post-translational modifications that affect antibody stability, functionality and, in some cases, patient safety. This study demonstrates that S-sulfocysteine, a cysteine derivative, can increase the antibody specific productivity in different cell lines cultivated with different processes while minimizing trisulfide linkages in generated mAbs, mainly between heavy and light chain. The supplementation of a cell culture feed with S-sulfocysteine also proved to be useful to reduce the percentage of antibody fragments generated from the monoclonal antibody. Overall, this new component used in the upstream process allows a reduction of product heterogeneity. PMID- 28581889 TI - The role of ZKSCAN3 in the transcriptional regulation of autophagy. PMID- 28581888 TI - IL17A augments autophagy in Mycobacterium tuberculosis-infected monocytes from patients with active tuberculosis in association with the severity of the disease. AB - During mycobacterial infection, macroautophagy/autophagy, a process modulated by cytokines, is essential for mounting successful host responses. Autophagy collaborates with human immune responses against Mycobacterium tuberculosis (Mt) in association with specific IFNG secreted against the pathogen. However, IFNG alone is not sufficient to the complete bacterial eradication, and other cytokines might be required. Actually, induction of Th1 and Th17 immune responses are required for protection against Mt. Accordingly, we showed that IL17A and IFNG expression in lymphocytes from tuberculosis patients correlates with disease severity. Here we investigate the role of IFNG and IL17A during autophagy in monocytes infected with Mt H37Rv or the mutant MtDeltaRD1. Patients with active disease were classified as high responder (HR) or low responder (LR) according to their T cell responses against Mt. IL17A augmented autophagy in infected monocytes from HR patients through a mechanism that activated MAPK1/ERK2 MAPK3/ERK1 but, during infection of monocytes from LR patients, IL17A had no effect on the autophagic response. In contrast, addition of IFNG to infected monocytes, increased autophagy by activating MAPK14/p38 alpha both in HR and LR patients. Interestingly, proteins codified in the RD1 region did not interfere with IFNG and IL17A autophagy induction. Therefore, in severe tuberculosis patients' monocytes, IL17A was unable to augment autophagy because of a defect in the MAPK1/3 signaling pathway. In contrast, both IFNG and IL17A increased autophagy levels in patients with strong immunity to Mt, promoting mycobacterial killing. Our findings might contribute to recognize new targets for the development of novel therapeutic tools to fight the pathogen. PMID- 28581890 TI - Strategies parents use to give children oral medicine: a qualitative study of online discussion forums. AB - AIM: The aim of this study was to describe strategies parents use to give oral medicine to children. METHODS: We conducted an Internet-based qualitative study of posts from online forums where parents discussed how to give children oral medicine. The posts were analyzed using systematic text condensation. The investigators coded and developed groups iteratively, ending up with a consensus on final themes. RESULTS: We included 4581 posts. Parents utilized three main strategies to give oral medicine to children: (1) Open administration give medicine to the child knowingly by changing the palatability, actively involve the child in play or use persuasion; (2) Hidden administration give medicine to the child unknowingly by camouflaging it in food, while sleeping or distracted by another activity; (3) Forced administration force children to take medicine with the use of restraint. Parents expressed three perspectives towards using force: Finding it unproblematic, using force despite not liking it or refusing to use force. No single strategy was described as the obvious first choice, and the strategies were not used in any particular order. Parents who gave up getting their child to ingest the medicine reported to contact the prescriber for a different medication, or stopped the treatment completely. CONCLUSIONS: The three strategies are a robust and precise way to categorize techniques used by parents to give children oral medicine. We suggest that health professionals use the strategies to talk to parents and children about administration of oral medicines. PMID- 28581891 TI - Oral Conditions and Health-Related Quality of Life: A Systematic Review. AB - The objective of this study was to verify whether oral conditions (tooth loss, periodontal disease, dental caries) are negatively associated with health-related quality of life (HRQoL) in adults. A search was carried out on PubMed, EMBASE, Web of Science, Scopus, SciELO, and LILACS databases until the end of July 2016 with no date restrictions. Quantitative observational studies written in English were included and data extraction was performed independently by 2 reviewers. HRQoL was investigated as the outcome, and tooth loss, periodontal diseases, and dental caries were exposures. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used and the quality of the selected studies was assessed by using the Joanna Briggs Institute Meta-Analysis of Statistics assessment and review instrument (JBI-MAStARI). Twenty-one studies were included. The sample sizes ranged from 88 to 15,501 subjects; 20 studies were cross-sectional designs, while 1 was a case-control study. Case definitions of the exposures were different across the studies, mainly for tooth loss, which was defined according to 11 different criteria. Fifteen studies were of "high" and 6 of "medium" quality. Eight HRQoL instruments were identified, and the most frequent was the EuroQol ( n = 8). Ten of 16 studies reported a negative impact of tooth loss on HRQoL. Four of 7 studies reported that periodontal disease impairs HRQoL, and 1 study showed that periodontal disease is positively associated with HRQoL. All studies that assessed dental caries reported a negative association between this condition and HRQoL. Despite the different definitions and measures of tooth loss and dental caries, the majority of the available evidence reported a negative impact of these conditions on HRQoL. Mixed and inconclusive findings were observed for the association between periodontal disease and HRQoL. Longitudinal prospective studies are suggested to improve the strength of the findings. PMID- 28581892 TI - Radiation Exposure Enhances Hepatocyte Proliferation in Neonatal Mice but not in Adult Mice. AB - There is a natural tendency to expect that irradiation of an infant organ prior to development-related expansion will result in a higher risk of developing cancer than that of fully-developed adult tissue, and this has generally been observed. However, if tissues also vary in their initial responses to radiation depending on age, the interplay between tissue- and age-dependent risk would potentially be quite complex. We have previously shown opposing age-dependent induction of apoptosis for the intestinal epithelium and hematopoietic cells in mice, but such data are not yet available for the liver. Here, we have examined markers of DNA damage, initiation of DNA damage responses, cell cycle arrest, apoptosis and proliferation, as well as gene expression, in the B6C3F1 mouse liver over the hours and days after irradiation of mice at 1 or 7 weeks of age. We found that induction and resolution of radiation-induced DNA damage is not accompanied by significant changes in these cellular end points in the adult liver, while in infant hepatocytes modest induction of p53 accumulation and p21 mediated cell cycle arrest in a small fraction of damaged cells was overshadowed by a further stimulation of proliferation over the relatively high levels already found in the neonatal liver. We observed distinct expression of genes that regulate cell division between the ages, which may contribute to the differential responses. These data suggest that the growth factor signaling environment of the infant liver may mediate radiation-induced proliferation and increased liver cancer risk after irradiation during early life. PMID- 28581894 TI - Identification of Small-Molecule Noncovalent Binders Utilizing SAMDI Technology. AB - In recent years, the ability to unambiguously identify complex mixtures of analytes with high accuracy and resolving power in a label-free format continues to expand the application of mass spectrometry (MS) in the drug discovery process. This advantage combined with improved instrumentation makes MS suitable for targets with limited alternative assays for high-throughput screening (HTS). We describe a novel screening format using Self-Assembled Monolayers and matrix assisted laser Desorption Ionization (SAMDI) technology. SAMDI enables affinity capture of a target protein for use in a small-molecule-binding assay format. Subsequent ionization enables the inferred identification of noncovalent compound interactions. SAMDI technology overcomes shot-to-shot variability by uniformly saturating the surface with captured protein, thereby minimizing matrix crystallization "hot spots." Furthermore, the combination with high-resolution matrix-assisted laser desorption/ionization time of flight significantly reduces interference of small-molecule detection from salt, detergent, and matrix. By using a pooled library format, the SAMDI assay can significantly improve the throughput of MS-based screening irrespective of enzyme activity. Finally, we demonstrate binding affinity rank ordering from a pool of compounds that correlates with potency data from a biochemical assay. PMID- 28581893 TI - Roles of transient receptor potential channels in regulation of vascular and epithelial barriers. AB - Transient receptor potential (TRP) channels are a ubiquitously expressed multi family group of cation channels that are critical to signaling events in many tissues. Their roles have been documented in many physiologic and pathologic conditions. Nevertheless, direct studies of their roles in maintain barrier function in endothelial and epithelia are relatively infrequent. This seems somewhat surprising considering that calcium ion concentrations are known to regulate barrier function. This short review provides an introduction to TRP channels and reviews some of the work in which investigators directly studied the role of TRP channels in endothelial permeability to electric current, solute, or leukocytes during the inflammatory response. PMID- 28581896 TI - The Relationship of Patient-Provider Communication on Quality of Life among African-American and White Cancer Survivors. AB - Prior research has demonstrated poorer patient-provider communication ratings among African American compared to White patients. The quality of patient provider communication has been shown to impact treatment outcomes among cancer patients. A secondary data analysis design was used to determine the relationship of six patient-provider communication variables on the physical health quality of life (PHQOL) and mental health quality of life (MHQOL) of African American and White cancer patients (N = 479). We also examined whether the relationship between communication patterns and QOL differed based on race/ethnicity. Mean physical and mental health QOL scores for the sample were 69.8 and 77.6, respectively. After controlling for significant sociodemographic, clinical, and hospital variables, results showed that patients who experienced fewer interpersonal communication barriers who were more satisfied with the information given by providers had higher PHQOL and MHQOL scores. Additionally, patients who felt more comfort in asking questions or had fewer unmet information needs had higher MHQOL. A stratified analysis showed that the relationship of overall satisfaction with information on MHQOL was stronger among African American patients than White patients. Future research should focus on the development of interventions to improve patient-provider communication as a means for enhancing QOL outcomes among cancer survivors. PMID- 28581895 TI - Safety and Efficacy of Alginate Adhesion Barrier Gel in Compromised Intestinal Anastomosis. AB - BACKGROUND: For any anti-adhesive barrier developed for abdominal surgery, the use under conditions in which anastomotic healing is compromised needs to be investigated. The current study evaluates the effect of a new ultrapure alginate gel on early healing of high-risk anastomoses in the ileum and compares this with the gold standard used in clinical practice. MATERIALS AND METHODS: In 75 adult male Wistar rats, a 5 mm ileal segment was resected and continuity was restored by construction of an inverted anastomosis. Rats were divided randomly into a control group and groups receiving either alginate gel or a sodium hyaluronate carboxymethylcellulose (HA/CMC) film around the anastomosis (n = 25 each). Carprofen, given in a daily dose of 1.25 mg/kg, was used to compromise anastomotic healing. At day three, animals were killed and scored for signs of anastomotic leakage and the presence of adhesions. RESULTS: The incidence of adhesion formation was 95% in the HA/CMC film group, which was significantly higher than in the controls (64%, p = 0.010) and the alginate gel group (52%, p = 0.004). The adhesion score was nearly 40% lower in the alginate gel group compared with the HA/CMC film group. The incidence of ileal leakage in the HA/CMC film group (92%) was significantly higher than in the controls (68%, p = 0.016). Leakage rate did not differ between the alginate gel and control groups. There was no significant difference between groups in either incision bursting pressure or incision breaking strength. CONCLUSION: Ultrapure alginate gel does not interfere with repair of ileal anastomoses constructed under conditions in which chances of anastomotic dehiscence are high. The alginate gel performs better than the HA/CMC film. PMID- 28581897 TI - Mutations to Cysteine Residues in the Trypanosoma cruzi B-Cell Superantigen Tc24 Diminish Susceptibility to IgM-Mediated Hydrolysis. AB - B-cell superantigens (BC-SAgs) are immunoevasins that have evolved in response to innate catalytic IgM antibodies; germ-line encoded immunoglobulins present in the preimmune repertoire independent of prior antigen exposure. Catalysis is the result of a 2-step process that involves first the formation of a non-covalent bond between the BC-SAg and the immunoglobulin followed by covalent bond formation at the catalytic site resulting in target hydrolysis. Tc24 is a recently described Trypanosoma cruzi BC-SAg hypothesized to play a role in evading the humoral response early in the infection period. We previously demonstrated that exposure to Tc24 following immunization or infection resulted in the depletion of the catalytic IgM response, leaving a gap in the catalytic IgM repertoire. The present report compares the BC-SAg properties of wild-type Tc24 (Tc24-WT) to that of 2 recombinant Tc24 isoforms: Tc24-C2 (Cys to Ser mutations in the 2 most-proximal Cys residues) and Tc24-C4 (Cys to Ser mutations in all 4 Cys residues present). BC-SAg activity was assessed by immunizing mice with the respective isoforms and examining the ability of IgM purified from the respective groups to hydrolyze the 3 Tc24 isoforms. In addition, the ability of IgM purified from naive mice to hydrolyze the Tc24 isoforms was also assessed. Immunization with Tc24-WT, Tc24-C2, or Tc24-C4 resulted in loss of IgM-mediated hydrolysis of Tc24-WT. However, the ability of IgM purified from naive mice (previously shown to hydrolyze Tc24-WT) was less effective in hydrolyzing the 2 Tc24 isoforms. These data demonstrate that although the BC-SAg site in the mutants remained intact, their reduced susceptibility to IgM-mediated hydrolysis suggested that structural changes resulting from the Cys to Ser mutations altered accessibility to the catalytic site in the 2 isoforms. PMID- 28581898 TI - Assistive technology reasoning in rural school-based occupational therapy. AB - This study explores broad issues associated with assistive technology (AT) service provision in rural school settings. The study was designed to explore the beliefs of practitioners working in rural schools about their role in AT service provision. This article includes an extensive review of the literature and findings from a naturalistic study of AT service provision experience in rural school settings. The study portion of this article involved completion of an open ended questionnaire followed by semi-structured ethnographic interviews. The participants completing the questionnaires were 22 occupational therapy practitioners and seven individuals from a variety of professional backgrounds recognized as leaders in AT in the state of West Virginia. Data were collected over a 3-year period. Themes identified in the data emphasized concerns about the unclear role of potential AT providers resulting in the use of AT as a last resort, the lack of inclusion of AT in the core curriculum, and the limited collaboration and in-service education opportunities recognized by practitioners. This qualitative study is not generalizable. Findings can be viewed within the context of other research to help enrich the reader's understanding of AT service delivery. PMID- 28581899 TI - Should Governments Invest More in Nudging? AB - Governments are increasingly adopting behavioral science techniques for changing individual behavior in pursuit of policy objectives. The types of "nudge" interventions that governments are now adopting alter people's decisions without coercion or significant changes to economic incentives. We calculated ratios of impact to cost for nudge interventions and for traditional policy tools, such as tax incentives and other financial inducements, and we found that nudge interventions often compare favorably with traditional interventions. We conclude that nudging is a valuable approach that should be used more often in conjunction with traditional policies, but more calculations are needed to determine the relative effectiveness of nudging. PMID- 28581901 TI - Corrigendum. AB - Cavalli, E., Cole, P., Leloup, G., Poracchia-George, F., Sprenger-Charolles, L., & El Ahmadi, A. (2017). Screening for dyslexia in French-speaking university students: An evaluation of the detection accuracy of the Alouette test. Journal of Learning Disabilites. Advance online publication. (Original doi: 10.1177/0022219417704637 ) In the version of this article originally published OnlineFirst, the funding statement was incorrect. The correct funding statement is as follows: Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Labex BLRI (ANR-11-LABX-0036), managed by the French National Agency for Research (ANR), under the project title Investments of the Future A*MIDEX (ANR-11-IDEX-0001-02). Subsequent versions of the article will be corrected. PMID- 28581902 TI - Data Sharing Statements for Clinical Trials - A Requirement of the International Committee of Medical Journal Editors. PMID- 28581903 TI - A decision tree approach to screen drinking water contaminants for multiroute exposure potential in developing guideline values. AB - The consideration of inhalation and dermal routes of exposures in developing guideline values for drinking water contaminants is important. However, there is no guidance for determining the eligibility of a drinking water contaminant for its multiroute exposure potential. The objective of the present study was to develop a 4-step framework to screen chemicals for their dermal and inhalation exposure potential in the process of developing guideline values. The proposed framework emphasizes the importance of considering basic physicochemical properties prior to detailed assessment of dermal and inhalation routes of exposure to drinking water contaminants in setting guideline values. PMID- 28581904 TI - Thyroid storm: does this syndrome really exist in cats? PMID- 28581905 TI - Spot the difference? PMID- 28581906 TI - Australian and New Zealand College of Veterinary Scientists abstracts 2016. PMID- 28581907 TI - News & Views. PMID- 28581908 TI - Urinalysis in the cat: measurement of urine protein:creatinine ratio. PMID- 28581909 TI - Development of CRISPR/Cas9 mediated virus resistance in agriculturally important crops. AB - Clustered regulatory interspaced short palindromic repeats (CRISPR)/CRISPR associated nuclease 9 (Cas9) system of targeted genome editing has already revolutionized the plant science research. This is a RNA guided programmable endonuclease based system composed of 2 components, the Cas9 nuclease and an engineered guide RNA targeting any DNA sequence of the form N20-NGG for novel genome editing applications. The CRISPR/Cas9 technology of targeted genome editing has been recently applied for imparting virus resistance in plants. The robustness, wide adaptability, and easy engineering of this system has proved its potential as an antiviral tool for plants. Novel DNA free genome editing by using the preassembled Cas9/gRNA ribonucleoprotein complex for development of virus resistance in any plant species have been prospected for the future. Also, in this review we have discussed the reports of CRISPR/Cas9 mediated virus resistance strategy against geminiviruses by targeting the viral genome and transgene free strategy against RNA viruses by targeting the host plant factors. In conclusion, CRISPR/Cas9 technology will provide a more durable and broad spectrum viral resistance in agriculturally important crops which will eventually lead to public acceptance and commercialization in the near future. PMID- 28581911 TI - Evaluation of a CAT Database and Expert Appraisal of CATs Developed by Students. AB - Five steps have been recommended to provide evidence-based patient care: formulating a clinical question, searching for literature, evaluating the validity and applicability of results, implementing results into practice, and assessing if the new evidence has led to improved health care. Students can be trained in these steps by the development of knowledge summaries such as critically appraised topics (CATs). The aim of the present project was the development, use, and evaluation of a German-language CAT database and an appraisal of the quality of CATs developed by students. A total of 153 fifth-year veterinary medical students (in 21 groups) were enrolled in the project. Each group developed a CAT and most students participated in a survey. To learn more about the quality of the CATs, we asked experts to appraise the texts written by the students. The CATs were indexed with key words and assigned to specific fields corresponding to the European Colleges of Veterinary Specialisation. Currently, 57 CATs have been developed. The majority of students stated that writing CATs is a good exercise and that "it is important to teach the assessment of scientific information." In total, 13 experts completed the questionnaires, out of which 9 graded the CAT they appraised as good. In addition to English language CAT databases, German tools should also be available for students and practitioners. PMID- 28581912 TI - Use of a Garment as an Alternative to Body Painting in Equine Musculoskeletal Anatomy Teaching. AB - Living anatomy is gaining increasing popularity as an alternative to the use of preserved cadaver specimens in musculoskeletal anatomy teaching. This article describes the development of a garment painted with musculoskeletal structures as an alternative to body painting. Garments offer some advantages over traditional body painting in anatomy teaching. The technique can be used across different disciplines, enhances students' ability to identify anatomic structures in living bodies, and provides insights into the topography of one or more body systems at the same time. The fact that garments are amenable to palpation by large groups of students with no damage to the painting favors repeated use in hands-on wet labs. Garments such as the one described in this article introduce a novel approach to interdisciplinary teaching and learning, which can be combined with traditional anatomy teaching methods. The first garment produced depicts part of the equine musculoskeletal system. Steps in garment construction are highlighted and indications, advantages, and limitations of the method discussed. PMID- 28581913 TI - Evaluation of an Immersive Farm Experience to Teach and Attract Veterinary Students to Food-Animal Medicine. AB - The Bovine Educational Symposium (BES) is a unique opportunity for North Carolina State University (NCSU) veterinary students to visit dairy farms, feedlots, cow calf operations, and processing facilities, and to meet local bovine veterinarians. We hypothesized that this active learning opportunity would increase knowledge, change perceptions of animal agriculture and food-animal medicine, and provide skills that persist beyond graduation. Pre- and post-trip surveys were administered to 124 first-, second-, and third-year veterinary students attending BES over 3 years. The surveys assessed students' perceived competence with regard to 12 key areas of bovine practice, attitudes toward segments of the cattle industry, attitudes to veterinarians' role in these segments, and interest in a career in bovine practice. Content knowledge was assessed using a multiple-choice test for comparison to self-assessments. A control group of 10 fourth-year students was administered the same tests before and after a 2-week food-animal clinical rotation. A convenience sample of nine BES alumni were interviewed to assess their opinion on the educational impact of BES. BES participants exhibited significant gains in perceived competence and actual knowledge in all 12 areas, and they also had improved perceptions of animal agriculture and increased interest in food-animal careers. Benefits noted by alumni ranged from improved knowledge of basic concepts of biosecurity and population medicine to greater appreciation for professional skills, including client communication. Immersing pre-clinical veterinary students in an active learning environment can have a significant impact on their knowledge and perception of food-animal medicine, irrespective of students' ultimate career goals. PMID- 28581914 TI - Technical Skills Training for Veterinary Students: A Comparison of Simulators and Video for Teaching Standardized Cardiac Dissection. AB - The goal of the study was to evaluate alternative student-centered approaches that could replace autopsy sessions and live demonstration and to explore refinements in assessment procedures for standardized cardiac dissection. Simulators and videos were identified as feasible, economical, student-centered teaching methods for technical skills training in medical contexts, and a direct comparison was undertaken. A low-fidelity anatomically correct simulator approximately the size of a horse's heart with embedded dissection pathways was constructed and used with a series of laminated photographs of standardized cardiac dissection. A video of a standardized cardiac dissection of a normal horse's heart was recorded and presented with audio commentary. Students were allowed to nominate a preference for learning method, and students who indicated no preference were randomly allocated to keep group numbers even. Objective performance data from an objective structure assessment criterion and student perception data on confidence and competency from surveys showed both innovations were similarly effective. Evaluator reflections as well as usage logs to track patterns of student use were both recorded. A strong selection preference was identified for kinesthetic learners choosing the simulator and visual learners choosing the video. Students in the video cohort were better at articulating the reasons for dissection procedures and sequence due to the audio commentary, and student satisfaction was higher with the video. The major conclusion of this study was that both methods are effective tools for technical skills training, but consideration should be given to the preferred learning style of adult learners to maximize educational outcomes. PMID- 28581915 TI - Adaptive Comparative Judgment: A Tool to Support Students' Assessment Literacy. AB - Comparative judgment in assessment is a process whereby repeated comparison of two items (e.g., assessment answers) can allow an accurate ranking of all the submissions to be achieved. In adaptive comparative judgment (ACJ), technology is used to automate the process and present pairs of pieces of work over iterative cycles. An online ACJ system was used to present students with work prepared by a previous cohort at the same stage of their studies. Objective marks given to the work by experienced faculty were compared to the rankings given to the work by a cohort of veterinary students (n=154). Each student was required to review and judge 20 answers provided by the previous cohort to a free-text short answer question. The time that students spent on the judgment tasks was recorded, and students were asked to reflect on their experiences after engaging with the task. There was a strong positive correlation between student ranking and faculty marking. A weak positive correlation was found between the time students spent on the judgments and their performance on the part of their own examination that contained questions in the same format. Slightly less than half of the students agreed that the exercise was a good use of their time, but 78% agreed that they had learned from the process. Qualitative data highlighted different levels of benefit from the simplest aspect of learning more about the topic to an appreciation of the more generic lessons to be learned. PMID- 28581916 TI - Robust (and Ethical) Educational Research Designs. AB - Educational research can be quite confusing to individuals without formal training in educational research methods. Many educators trained in "high consensus" fields such as the health and medical sciences often expect to utilize the same esteemed experimental and quasi-experimental designs in their educational research efforts, but are surprised to learn that this is often impossible for ethical reasons. This article presents five robust research designs that generally are compatible with education studies, and discusses how each design may be used in a variety of educational research scenarios. PMID- 28581917 TI - Influence of Emission Spectrum and Irradiance on Light Curing of Resin-Based Composites. AB - PURPOSE: This study examined the influence of different emission spectra (single peak and broad-spectrum) light-curing units (LCUs) delivering the same radiant exposures at irradiance values of 1200 or 3600 mW/cm2 on the polymerization and light transmission of four resin-based composites (RBCs). METHODS AND MATERIALS: Two prototype LCUs that used the same light tip, but were either a single-peak blue or a broad-spectrum LED, were used to deliver the same radiant exposures to the top surfaces of the RBCs using either standard (1200 mW/cm2) or high irradiance (3600 mW/cm2) settings. The emission spectrum and radiant power from the LCUs were measured with a laboratory-grade integrating sphere coupled to a spectrometer, and the light beam was assessed with a beam profiler camera. Four RBCs (Filtek Supreme Ultra A2, Tetric EvoCeram A2, Tetric EvoCeram T, and TPH Spectra High Viscosity A2) were photoactivated using four different light conditions: single-peak blue/standard irradiance, single-peak blue/high irradiance, broad-spectrum/standard irradiance, and broad-spectrum/high irradiance. The degree of conversion (N=5) and microhardness at the top and bottom of 2.3-mm-diameter by 2.5-mm-thick specimens (N=5) were analyzed with analysis of variance and Tukey tests. The real-time light transmission through the RBCs was also measured. RESULTS: For all light conditions, the 2.3-mm diameter specimens received a homogeneous irradiance and spectral distribution. Although similar radiant exposures were delivered to the top surfaces of the RBCs, the amount of light energy emitted from the bottom surfaces was different among the four RBCs, and was also greater for the single-peak lights. Very little violet light (wavelengths below 420 nm) reached the bottom of the 2.5-mm-thick specimens. The degree of conversion and microhardness results varied according to the RBC (p<0.05). The RBCs that included alternative photoinitiators had greater microhardness values at the top when cured with broad-spectrum lights, while at the bottom, where little violet light was observed, the results were equal or higher when they were photoactivated with single-peak blue lights. With the exception of the microhardness at the top of TPH, equivalent or higher microhardness and degree-of-conversion values were achieved at the bottom surface when the standard (1200 mW/cm2) irradiance levels were used compared to when high irradiance levels were used. CONCLUSIONS: Considering the different behaviors of the tested RBCs, the emission spectrum and irradiance level influenced the polymerization of some RBCs. The RBCs that included alternative photoinitiators produced greater values at the top when cured with broad-spectrum lights, while at the bottom, results were equal or higher for the RBCs photoactivated with single-peak blue lights. PMID- 28581918 TI - Battery Charge Affects the Stability of Light Intensity from Light-emitting Diode Light-curing Units. AB - This study investigated the influence of battery charge levels on the stability of light-emitting diode (LED) curing-light intensity by measuring the intensity from fully charged through fully discharged batteries. The microhardness of resin composites polymerized by the light-curing units at various battery charge levels was measured. The light intensities of seven fully charged battery LED light curing units-1) LY-A180, 2) Bluephase, 3) Woodpecker, 4) Demi Plus, 5) Saab II, 6) Elipar S10, and 7) MiniLED-were measured with a radiometer (Kerr) after every 10 uses (20 seconds per use) until the battery was discharged. Ten 2-mm-thick cylindrical specimens of A3 shade nanofilled resin composite (PREMISE, Kerr) were prepared per LED light-curing unit group. Each specimen was irradiated by the fully charged light-curing unit for 20 seconds. The LED light-curing units were then used until the battery charge fell to 50%. Specimens were prepared again as described above. This was repeated again when the light-curing units' battery charge fell to 25% and when the light intensity had decreased to 400 mW/cm2. The top/bottom surface Knoop hardness ratios of the specimens were determined. The microhardness data were analyzed by one-way analysis of variance with Tukey test at a significance level of 0.05. The Pearson correlation coefficient was used to determine significant correlations between surface hardness and light intensity. We found that the light intensities of the Bluephase, Demi Plus, and Elipar S10 units were stable. The intensity of the MiniLED unit decreased slightly; however, it remained above 400 mW/cm2. In contrast, the intensities of the LY-A180, Woodpecker, and Saab II units decreased below 400 mW/cm2. There was also a significant decrease in the surface microhardnesses of the resin composite specimens treated with MiniLED, LY-A180, Woodpecker, and Saab II. In conclusion, the light intensity of several LED light-curing units decreased as the battery was discharged, with a coincident reduction in the units' ability to polymerize resin composite. Therefore, the intensity of an LED light-curing unit should be evaluated during the life of its battery charge to ensure that sufficient light intensity is being generated. PMID- 28581919 TI - Thirty-Six-Month Clinical Comparison of Bulk Fill and Nanofill Composite Restorations. AB - OBJECTIVES: The aim of this study was to evaluate the clinical performance of a nanofill and a bulk fill resin composite in class II restorations. METHODS AND MATERIALS: In accordance with a split-mouth design, 50 patients received at least one pair of restorations, restored with a nanofill resin composite (Filtek Ultimate [FU]) and with a bulk fill resin composite (Tetric EvoCeram Bulk Fill [TB]). Each restorative resin was used with its respective adhesive system according to the manufacturers' instructions. A total of 104 class II restorations were placed by two operators. The restorations were blindly evaluated by two examiners at baseline and at six, 12, 18, 24, and 36 months using modified US Public Health Service Ryge criteria. The comparison of the two restorative materials for each category was performed with the chi-square test (alpha=0.05). The baseline scores were compared with those at the recall visits using the Cochran Q-test. RESULTS: At six, 12, 18, and 24 months, the recall rate was 100%, 98%, 94%, and 82%, respectively, with a retention rate of 100%. At 36 months, 81 restorations were evaluated in 39 patients with a recall rate of 78%. For marginal adaptation, four restorations from the TB group and 10 from the FU group rated as Bravo. Two restorations from the TB and eight restorations from the FU group showed marginal discoloration. There were statistically significant differences between the two restorative resins in terms of marginal adaptation and marginal discoloration (p<0.05). No differences were observed between the restorative resins in terms of retention (p>0.05). One restored tooth from the FU group was crowned. The retention rates for the TB and the FU groups were 100%. In the FU group, two restorations showed slightly rough surfaces, and two showed a slight mismatch in color. None of the restorations showed postoperative sensitivity, secondary caries, or loss of anatomic form. CONCLUSIONS: The tested bulk fill restorative resin demonstrated better clinical performance in terms of marginal discoloration and marginal adaptation. PMID- 28581920 TI - Randomized Clinical Trial to Evaluate MTA Indirect Pulp Capping in Deep Caries Lesions After 24-Months. AB - OBJECTIVE: This clinical study aimed to assess the efficacies of mineral trioxide aggregate (MTA) and calcium hydroxide [Ca(OH)2] in the treatment of deep carious lesions by the direct complete caries removal technique. METHODS AND MATERIALS: A total of 100 permanent molar/premolar teeth were capped with either Ca(OH)2 (n=49) or MTA (n=51) and restored with composite resin in 73 patients. Periapical radiographs were acquired prior to the treatment as well as at six, 12, and 24 months posttreatment. Two calibrated examiners performed the clinical and radiographic assessment of the periapical pathology and pulpal symptoms. Intergroup comparisons of the observed values were performed using the Fisher exact test. Significance was predetermined at alpha = 0.05. RESULTS: The recall rates were 100% at six and 12 months posttreatment and 98.6% at 24 months posttreatment. Four teeth capped with Ca(OH)2 (two each at six and 12 months posttreatment) and two capped with MTA (one each at 12 and 24 months posttreatment) received endodontic emergency treatment because of symptoms of irreversible pulpitis, which were clinically and/or radiographically established. There were no significant differences in pulp vitality between the two pulp capping agents at six, 12, or 24 months posttreatment (p=0.238, p=0.606, and p=0.427, respectively). CONCLUSIONS: Both pulp-capping materials were found to be clinically acceptable at 24 months posttreatment. PMID- 28581921 TI - List of new names and new combinations previously effectively, but not validly, published. PMID- 28581922 TI - Corrigendum: Kocuria indica sp. nov., isolated from a sediment sample. PMID- 28581923 TI - Reclassification of Thiobacillus aquaesulis (Wood & Kelly, 1995) as Annwoodia aquaesulis gen. nov., comb. nov., transfer of Thiobacillus (Beijerinck, 1904) from the Hydrogenophilales to the Nitrosomonadales, proposal of Hydrogenophilalia class. nov. within the 'Proteobacteria', and four new families within the orders Nitrosomonadales and Rhodocyclales. AB - The genus Thiobacillus comprises four species with validly published names, of which Thiobacillus aquaesulis DSM 4255T (=ATCC 43788T) is the only species that can grow heterotrophically or mixotrophically - the rest being obligate autotrophs - and has a significant metabolic difference in not producing tetrathionate during the oxidation of thiosulfate during autotrophic growth. On the basis of this and differential chemotaxonomic properties and a 16S rRNA gene sequence similarity of 93.4 % to the type species Thiobacillus thioparus DSM 505T, we propose that it is moved to a novel genus, Annwoodia gen. nov., for which the type species is Annwoodia aquaesulis gen. nov., comb. nov. We confirm that the position of the genus Thiobacillus in the Betaproteobacteria falls within the Nitrosomonadales rather than the Hydrogenophilales as previously proposed. Within the Nitrosomonadales we propose the circumscription of genera to form the Thiobacilliaceae fam. nov. and the Sterolibacteriaceae fam. nov. We propose the merging of the family Methylophilaceae into the Nitrosomonadales, and that the Sulfuricellaceae be merged into the Gallionellaceae, leaving the orders Methylophilales and Sulfuricellales defunct. In the Rhodocyclales we propose the Azonexaceae fam. nov. and the Zoogloeaceae fam. nov. We also reject the Hydrogenophilales from the Betaproteobacteria on the basis of a very low 16S rRNA gene sequence similarity with the class-proper as well as physiological properties, forming the Hydrogenophilalia class. nov. in the 'Proteobacteria'. We provide emended descriptions of Thiobacillus, Hydrogenophilales, Hydrogenophilaceae, Nitrosomonadales, Gallionellaceae, Rhodocyclaceae and the Betaproteobacteria. PMID- 28581924 TI - Dyella lipolytica sp. nov., a lipolytic bacterium isolated from lower subtropical forest soil. AB - A Gram-stain-negative, aerobic, yellow-pigmented, non-spore-forming, non-motile, rod-shaped bacterium, designated strain DHOB07T, was isolated from a soil sample collected from the lower subtropical forest of the Dinghushan Biosphere Reserve, Guangdong Province, PR China (23 degrees 10' N 112 degrees 31' E). Strain DHOB07T grew at 10-37 degrees C, pH 4-7 and 0-0.5 % (w/v) NaCl, with an optimum at 28 degrees C, pH 5-5.5 and 0% (w/v) NaCl on R2A medium. Phylogenetic analyses based on 16S rRNA gene sequences showed that the strain formed a clade with Dyella jejuensis JP1T, Dyella nitratireducens DHG59T, Dyella koreensis BB4T, Dyella marensis CS5-B2Tand Dyellasoli JS12-10T, with sequence similarities of 98.9, 98.0, 97.9, 97.9 and 97.8 %, respectively. Multilocus sequence analysis based on the concatenated sequences of partial housekeeping genes gyrB, lepA and recA confirmed that strain DHOB07T belongs to thegenus Dyella but is distinct from all currently known species of the genus Dyella. The G+C content of the genomic DNA was 58.2 mol%. The DNA-DNA relatedness value between strain DHOB07T and D. jejuensis JP1T was 41.8 %. Iso-C16 : 0, iso-C15 : 0 and iso-C17 : 1omega9c were the major fatty acids, and ubiquinone-8 was the only respiratory quinone detected, all of which supported the affiliation of strain DHOB07T to the genus Dyella. On the basis of the polyphasic characterization results presented above, strain DHOB07T represents a novel species of the genus Dyella, for which the name Dyella lipolytica sp. nov. is proposed. The type strain is DHOB07T (=NBRC 111473T=KCTC 52132T). PMID- 28581925 TI - An evaluation of Thiomicrospira, Hydrogenovibrio and Thioalkalimicrobium: reclassification of four species of Thiomicrospira to each Thiomicrorhabdus gen. nov. and Hydrogenovibrio, and reclassification of all four species of Thioalkalimicrobium to Thiomicrospira. AB - Thiomicrospira(Tms) species are small sulfur-oxidizing chemolithoautotrophic members of the Gammaproteobacteria. Whilst the type species Tms. pelophila and closely related Tms. thyasirae exhibit canonical spiral morphology under sub optimal growth conditions, most species are vibrios or rods. The 16S rRNA gene diversity is vast, with identities as low as 91.6 % for Tms. pelophila versus Tms. frisia, for example. Thiomicrospira was examined with closely related genera Hydrogenovibrio and Thioalkalimicrobium and, to rationalize organisms on the basis of the 16S rRNA gene phylogeny, physiology and morphology, we reclassify Tms. kuenenii, Tms. crunogena, Tms. thermophila and Tms. halophila to Hydrogenovibrio kuenenii comb. nov., H. crunogenus corrig. comb. nov., H. thermophilus corrig. comb. nov. and H. halophilus corrig. comb. nov. We reclassify Tms. frisia, Tms. arctica, Tms. psychrophila and Tms. chilensis to Thiomicrorhabdus (Tmr) gen. nov., as Tmr. frisia comb. nov., Tmr. arctica comb. nov., Tmr. psychrophila comb. nov. and Tmr. chilensis comb. nov. - the type species of Thiomicrorhabdus is Tmr. frisia. We demonstrate that Thioalkalimicrobium species fall within the genus Thiomicrospira sensu stricto, thus reclassifying them as Tms. aerophila corrig. comb. nov., Tms. microaerophila corrig. comb. nov., Tms. cyclica corrig. comb. nov. and Tms. sibirica corrig. comb. nov. We provide emended descriptions of the genera Thiomicrospira and Hydrogenovibrio and of Tms. thyasirae. PMID- 28581926 TI - Notification that new names of prokaryotes, new combinations and new taxonomic opinions have appeared in volume 67, part 2, of the IJSEM. PMID- 28581927 TI - History and Development of Coronary Flow Reserve and Fractional Flow Reserve for Clinical Applications. AB - We discuss the historical development of clinical coronary physiology, emphasizing coronary flow reserve (CFR) and fractional flow reserve (FFR). Our analysis focuses on the clinical motivations and technologic advances that prompted and enabled the application of physiology for patient diagnosis. CFR grew from the general concepts of physiologic and coronary reserve, linking the anatomic severity of a lesion to its impact on hyperemic flow. FFR developed from existing models relating pressure measurements to the potential for flow to increase after removing a stenosis. Because pressure measurements have proved easier and more robust than flow measurements, FFR has become the dominant metric. PMID- 28581928 TI - The Concept of Functional Percutaneous Coronary Intervention: Why Physiologic Lesion Assessment Is Integral to Coronary Angiography. AB - The gold standard for assessing the severity of coronary stenoses has been coronary angiography. However, multicenter randomized clinical trials have demonstrated that treatment decisions based on angiography alone do not guarantee benefit to patients. Fractional flow reserve provides physiologic lesion assessment of coronary stenoses. The use of physiology improves clinical outcomes when used for decision making for coronary revascularization. In the era of increased scrutiny of appropriateness of cardiac catheterization and percutaneous coronary intervention, the use of physiologic assessment of the severity of coronary stenoses should be considered an integral adjunct to the anatomic evaluation provided by the coronary angiogram. PMID- 28581929 TI - Limitations and Pitfalls of Fractional Flow Reserve Measurements and Adenosine Induced Hyperemia. AB - Coronary hemodynamic measurements provide a critical tool to assess the ischemic potential of coronary stenoses. Fractional flow reserve (FFR) is a reliable method to relate translesional coronary pressures to hyperemic myocardial blood flow. Although a basic understanding in FFR can be quickly achieved, many of the nuances and potential pitfalls require special attention. The authors discuss the practical setup of coronary pressure measurement, the most common pitfalls in technique and ways to avoid them, and the limitations of available pharmacologic hyperemic methods. PMID- 28581930 TI - Landmark Fractional Flow Reserve Trials. AB - Fractional flow reserve (FFR) has become widely used for physiologic assessment of intermediate coronary lesions. The Fractional Flow Reserve to Determine Appropriateness of Angioplasty in Moderate Coronary Stenoses (DEFER) trial established the safety of deferring angioplasty for moderate lesions that are not functionally significant. DEFER and Fractional Flow Reserve versus Angiography for Multivessel Evaluation 1 trials established the feasibility of FFR-guided intervention in stable and unstable patients with moderate coronary lesions, translating to improved clinical outcome and reduced number of unnecessary stents. This article reviews the trials establishing FFR as an important tool for on-the-table functional assessment of coronary lesions. PMID- 28581932 TI - Can Resting Indices Obviate the Need for Hyperemia and Promote the Routine Use of Physiologically Guided Revascularization? AB - This article assesses the data from contemporary human studies to address some of the common assumptions regarding hyperemic and baseline physiology in the context of the baseline pressure-derived index of instant wave-free ratio and the hyperemic index of fractional flow reserve. The article aims to determine if the available evidence supports the continued investigation, development, and use of baseline indices. PMID- 28581931 TI - Evaluation of Microvascular Disease and Clinical Outcomes. AB - Although coronary microcirculatory dysfunction occurs in numerous cardiac conditions and influences prognosis, it has been largely ignored in clinical practice due to the lack of adequate methods for its assessment. Microcirculatory dysfuntion may result from a variety of causes, including structural remodelling (arterioles or capillaries), dysregulation (paradoxical arteriolar vasoconstriction), hypersensitivity to vasoactive factors or adrenergic drive, and extravascular compression of collapsable elements. Thus, the selection of a method to interrogate coronary microcirculation should be based on the suspected cause of dysfunction. This article reviews such assessment tools and their prognostic information. PMID- 28581933 TI - Fractional Flow Reserve for the Evaluation of Tandem and Bifurcation Lesions, Left Main, and Acute Coronary Syndromes. AB - Fractional flow reserve (FFR) is a well-established invasive tool to assess the physiologic significance of a coronary stenosis. Several randomized trials proved the safety of deferring revascularization based on FFR in subjects with stable coronary artery disease with single or multivessel disease. Subjects with tandem or bifurcations lesions, left main disease, and acute coronary syndromes were not included in these trials. Unique hemodynamic changes occur in each of these situations, making the measurement and interpretation of FFR challenging. This article reviews the technical aspects of assessing FFR and literature supporting FFR-guided revascularization in each of these situations. PMID- 28581934 TI - Noninvasive Fractional Flow Reserve Derived from Coronary Computed Tomography Angiography for the Diagnosis of Lesion-specific Ischemia. AB - Fractional flow reserve derived from coronary computed tomography angiography (FFRCT) has emerged as a powerful tool for the assessment of flow-limiting coronary stenoses. To date, FFRCT is the only noninvasive imaging modality for the depiction of lesion-specific ischemia and large prospective multicenter studies have established its high diagnostic value. The nature of FFRCT allows the prediction of functional outcome of coronary stenting, which will expand the role of cardiac computed tomography in the evaluation and management of coronary artery disease. PMID- 28581935 TI - Association of Wall Shear Stress with Coronary Plaque Progression and Transformation. AB - Coronary endothelial function regulation by wall shear stress (WSS), the frictional force of blood exerted against the vessel wall, can help explain the focal propensity of plaque development in an environment of systemic atherosclerosis risk factors. Sustained abnormal pathologic WSS leads to a proatherogenic endothelial cell phenotype, plaque progression and transformation, and adaptive vascular remodeling in site-specific areas. Assessing dynamic coronary plaque compositional changes in vivo remains challenging; however, recent advances in intravascular image acquisition and processing may provide swifter WSS calculations and make possible larger prospective investigations on the prognostic value of WSS in patients with coronary atherosclerosis. PMID- 28581939 TI - Coronary Physiology: Basic Concepts and Clinical Applications. PMID- 28581942 TI - Fundamentals of Optical Coherence Tomography: Image Acquisition and Interpretation. AB - Optical coherence tomography (OCT) is an intravascular imaging modality that enables high-resolution cross-sectional imaging of coronary arteries in vivo. With resolution that is a 10-fold improvement compared with intravascular ultrasonography, OCT can facilitate detailed plaque characterization. This article introduces the basic principles of OCT image acquisition and interpretation. Qualitative analysis entails the evaluation of plaque morphology, including features associated with plaque vulnerability to rupture. Quantitative analysis and recognition of OCT image artifacts are also discussed. PMID- 28581943 TI - Technical Considerations and Practical Guidance for Intracoronary Optical Coherence Tomography. AB - Optical coherence tomography (OCT) is an intravascular imaging technology analogous to intravascular ultrasound, using near-infrared light rather than ultrasound, thereby providing higher-resolution images. This review provides a practical guide to OCT imaging, with a particular emphasis on the techniques and approaches to optimize image acquisition, improve the evaluation of coronary lesions, and guide the strategies for percutaneous coronary intervention. PMID- 28581944 TI - Percutaneous Coronary Intervention Planning and Optimization with Optical Coherence Tomography. AB - Coronary angiography confirms or excludes coronary artery disease, assesses lesions severity, and helps to decide percutaneous coronary interventions (PCI). Coronary angiography has clear limitations. Intravascular imaging guides PCI. Frequency domain optical coherence tomography (OCT) gained attention for accurate planning and guidance of complex PCI. High-speed OCT image acquisition enables prompt vessel assessment in stable and unstable patients. The high-resolution images provide precise tissue characterization and a reliable quantitative assessment of the coronary pathology. Immediately after stent implantation, OCT allows accurate evaluation of stent expansion and symmetry. Real-time angio-OCT co-registration integrates OCT into the PCI workflow for accurate decision making. PMID- 28581945 TI - Assessment and Quantitation of Stent Results by Intracoronary Optical Coherence Tomography. AB - Optical coherence tomography evaluation of poststent results includes stent expansion as the absolute minimum stent area ratio by comparing the minimum stent area with the proximal and distal reference lumen areas or mean stent area defined as the total stent volume divided by the analyzed stent length; stent strut malapposition defined when the distance from the center of the blooming artifact and the surface of plaque is greater than the sum of stent thickness and polymer thickness; tissue protrusion through the stent struts; semiquantitative residual thrombus evaluation; and stent edge dissection. PMID- 28581946 TI - Diagnosis and Evaluation of Stent Thrombosis with Optical Coherence Tomography. AB - Stent thrombosis (ST) is a rare complication of percutaneous coronary interventions (PCI), especially with drug-eluting stents. ST presents as acute myocardial infarction requiring emergent repeat PCI; optimal reperfusion occurs in two-thirds of patients. As a result, ST has been associated with a high mortality rate and a high rate of recurrent thrombosis. We discuss the use of optical coherence tomography (OCT) for the diagnosis and evaluation of ST. OCT guided ST management seems a feasible, safe, and appropriate approach. Intracoronary assesses the efficacy of coronary thrombus removal procedures and detects the prevalent stent-related factor that caused ST. PMID- 28581948 TI - Neointimal Coverage After Drug-Eluting Stent Implantation: Insights from Optical Coherence Tomography. AB - Optical coherence tomography (OCT), which provides high-resolution imaging of the coronary vasculature, has provided novel insights into the pathophysiology of neointimal growth after drug-eluting stent (DES) implantation. The natural history, time course, and characteristics of strut coverage with neointima have been well defined by OCT. Pathology studies have identified strut coverage as a risk factor for stent thrombosis, and OCT studies have shown that next-generation DES have better strut coverage than first-generation DES. By reducing the incidence of stent thrombosis, improved strut coverage should lead to favorable clinical safety and the feasibility of shorter-duration dual antiplatelet therapy after DES implantation. PMID- 28581947 TI - Optical Coherence Tomography in the Diagnosis and Management of Spontaneous Coronary Artery Dissection. AB - Spontaneous coronary artery dissection (SCAD) is an infrequent condition that has been underdiagnosed and misdiagnosed. The use of intracoronary imaging with intravascular ultrasound or optical coherence tomography enables the accurate diagnosis of this challenging condition. Diagnostic and management algorithms have been proposed to improve the diagnosis and therapeutic stratification of SCAD. Optical coherence tomography has superior spatial resolution than intravascular ultrasound, and is instrumental in the diagnosis of SCAD cases where angiographic findings are ambiguous for confirming SCAD. Understanding the role and appropriate and careful use of this technology is expected to improve the diagnosis of SCAD, and also improve outcomes with percutaneous coronary intervention, when clinically indicated. PMID- 28581949 TI - Short- and Long-term Evaluation of Bioresorbable Scaffolds by Optical Coherence Tomography. AB - The analysis of bioresorbable scaffolds (BRSs) by optical coherence tomography (OCT) requires a dedicated methodology, as the polymeric scaffold has a distinct appearance and undergoes dynamic structural changes with time. The high resolution of OCT allows for the detailed assessment of scaffold implantation, rupture, discontinuity, and strut integration. OCT does not provide reliable information on the extent of scaffold degradation, as it cannot differentiate between polylactide polymer and the provisional matrix of proteoglycan formed by connective tissue. Three-dimensional OCT reconstruction can aid in the evaluation of BRS in special scenarios such as overlapping scaffold segments and bifurcations. PMID- 28581950 TI - Advances in Automated Assessment of Intracoronary Optical Coherence Tomography and Their Clinical Application. AB - Intravascular optical coherence tomography (OCT) is capable of acquiring 3 dimensional (3D) data of coronary arteries allowing for the assessment of plaques, stents, thrombus, side branches, and other relevant structures in a 3D fashion. Given that state-of-the-art OCT systems acquire images at a very high frame rate (up to 200 frames per second), typically a very large number of images per pullback (ie, 500 or more) need to be analyzed. The manual assessment of stents, plaques, and other structures is time-consuming, cumbersome, and inefficient and thus not suitable for on-line analysis during percutaneous coronary intervention procedures. PMID- 28581951 TI - Intravascular Ultrasound for the Diagnosis and Treatment of Left Main Coronary Artery Disease. AB - Limitations of angiography for assessment of coronary artery disease are well known, but are more evident and relevant in the left main coronary artery (LMCA) segment given the amount of myocardium this vessel subtends and the risks associated with the presence of atherosclerosis and subsequent intervention. Intravascular ultrasound (IVUS) characterizes the severity of luminal narrowing, plaque morphology, and plaque extension into the distal bifurcation. Once the indication for percutaneous intervention (PCI) is established, information provided by IVUS is crucial to plan treatment and optimize results. IVUS-guided PCI with drug-eluting stents improves clinical outcomes, particularly in patients with distal left main disease. PMID- 28581952 TI - Intravascular Ultrasound for the Assessment of Coronary Lesion Severity and Optimization of Percutaneous Coronary Interventions. AB - Intravascular ultrasound (IVUS) has provided valuable information on cross sectional coronary vascular structure and has played a key role in contemporary stent-based percutaneous coronary interventions (PCI). It accurately assesses coronary anatomy, assists in the selection of treatment strategy, and helps to optimize stenting outcomes. IVUS-guided PCI for drug-eluting stent implantation seems to be associated with a significantly reduced risk of death, myocardial infarction, target lesion revascularization, and stent thrombosis. PMID- 28581957 TI - Intravascular Imaging: OCT and IVUS. PMID- 28581959 TI - Pharmacoinvasive Management. AB - The goal of treatment of patients with ST-segment elevation myocardial infarction (STEMI) is timely restoration of myocardial blood flow. Primary percutaneous coronary intervention (PCI) remains the treatment of choice for STEMI patients, as shown in multiple clinical trials. However, because of logistic constraints, timely primary PCI may not be possible for many STEMI patients, most of whom are treated with fibrinolysis. Debate continues as to whether, and when, patients treated with fibrinolysis should undergo subsequent PCI. Current data support the strategy of early routine PCI after fibrinolysis rather than the conservative standard-care approach or rescue PCI for failed lysis. PMID- 28581958 TI - Lessons Learned from STEMI Clinical Trials. AB - Coronary artery disease is the leading cause of the death in the United States. From 2009 to 2010, however, the rate of heart disease causing death decreased by 2.5% in part due to evolving techniques used to treat and prevent heart disease. Management of acute ST-segment elevation myocardial infarction (STEMI) has evolved accordingly and the studies investigating treatment strategies that have led to an evidence-based approach are reviewed in this article. PMID- 28581960 TI - Optimal Anticoagulant Therapy in ST Elevation Myocardial Infarction Interventions. AB - Bivalirudin is a direct thrombin inhibitor. It is a new recommendation for the treatment of patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention. Bivalirudin combined with aspirin and P2Y12 inhibitors has proved to be an effective and safe choice for the management of thrombus in coronary artery disease. The use of bivalirudin compared with the combination of heparin plus glycoprotein IIb/IIIa inhibitors as anticoagulant therapy is associated with reduced severe bleeding and inpatient mortality, as well as diminished costs. There is only a slight increase of late stent thrombosis, which may be controlled with the use of thienopyridines. PMID- 28581961 TI - Newer Pharmaceutical Agents for STEMI Interventions. AB - ST-elevation myocardial infarction (STEMI) causes 12.6% of deaths worldwide. Treatment strategies involve early revascularization by percutaneous coronary intervention and/or fibrinolytics, with adjunctive pharmacologic therapy. While antiplatelet therapy remains the cornerstone of pharmacologic management, newer antithrombotic therapies are showing benefit in the reduction of long-term thrombotic events following acute vessel occlusion. Future directions in adjunctive STEMI management include the use of hematopoietic stem cell therapy or growth factors to induce proliferation and differentiation of cardiac myocytes. PMID- 28581962 TI - The Use of Bivalirudin in ST-Segment Elevation Myocardial Infarction: Advantages and Limitations. AB - The incidence of ST-segment elevation myocardial infarction (STEMI) is a common, albeit declining, manifestation of coronary heart disease. Significant improvements in cardiovascular outcomes and mortality in STEMI patients have occurred in recent years, reflecting evolution in the understanding of the pathophysiological mechanisms and therapeutic targets of this disease. Nonetheless, the risks of recurrent ischemia and bleeding complications in this population remain substantial. This review focuses on the adjunctive anticoagulant agents used in the management of STEMI. Major insights from the HORIZONS-AMI trial regarding the impact of bivalirudin on both hemorrhagic and ischemic outcomes in STEMI patients are discussed. PMID- 28581963 TI - Interventions for ST Elevation Myocardial Infarction in Women. AB - The management of ST-segment elevation myocardial infarction (STEMI) has significantly advanced from supportive care to reperfusion therapies with thrombolytics and percutaneous coronary revascularization techniques. These advances have improved the outcomes of patients with STEMI. Although cardiovascular disease is the leading cause of death in both men and women, the minority of patients in trials studying the impact of these therapies on outcomes are women. Multiple studies have shown that men and women do not have equivalent outcomes after STEMI. This article reviews the treatment options for STEMI and the outcomes of women after treatment with reperfusion therapies. PMID- 28581964 TI - STEMI Interventions via the Radial Route. AB - ST-elevation myocardial infarction (STEMI) management has gone through a long journey from conservative medical management, to thrombolysis, to advanced interventional treatment. Primary percutaneous coronary intervention has now been accepted as the preferred therapy for STEMI. The femoral route remains the route of choice for most cardiologists. This article highlights the relatively new radial access for STEMI interventions. We discuss the available evidence, differences in technique compared with the transfemoral approach, and advantages and limitations of transradial access. PMID- 28581965 TI - Global Acute Myocardial Infarction Perspectives: Beyond Door-to-Balloon Interventions. AB - The goal in ST-elevation myocardial infarction (STEMI) intervention is achieving a door-to-balloon time of less than 90 minutes. Challenges in North America and Europe include patient education and implementing legislative mandates for STEMI guidelines. Globally, hurdles for primary percutaneous coronary intervention include limitations of access and financial constraints to providing STEMI care to vast populations. Adherence to North American and European guidelines globally remains an unrealistic goal given the unique cultural, demographic, and fiscal dynamics in poorer countries. The authors propose a four-phased population-based strategy for global acute myocardial infarction development and a pharmacoinvasive approach to STEMI care based on socioeconomic characteristics. PMID- 28581966 TI - Compulsive Thrombus Management in STEMI Interventions. AB - Thrombus is a fundamental concept in the pathophysiology of ST-elevated myocardial infarction (STEMI). Distal embolization and no reflow are associated with less angiographic success, reduced myocardial blush, less ST resolution after primary percutaneous coronary intervention, larger enzymatic infarct size, lower left ventricular ejection fraction at discharge, and higher long-term mortality. We believe that with the use of thrombectomy devices, these shortcomings can be minimized. Based on our experience from the Single Individual Community Experience Registry (SINCERE) database, we formulated a selective thrombus burden management strategy (the Mehta classification) for thrombus management. PMID- 28581967 TI - Stenting in Acute STEMI Intervention. AB - Stenting in acute myocardial infarction (AMI) has the benefits of achieving acute optimal angiographic results and correcting residual dissection to decrease the incidence of restenosis and reocclusion. Studies have shown that percutaneous transluminal coronary angioplasty for primary treatment after AMI is superior to thrombolytic therapy regarding the restoration of normal coronary blood flow. Coronary stenting improves initial success rates, decreases the incidence of abrupt closure, and is associated with a reduced rate of restenosis. In the presence of thrombus-containing lesions, coronary stenting constitutes an effective therapeutic strategy, either after failure of initial angioplasty or electively as the primary procedure. PMID- 28581968 TI - Door-to-Balloon ST-Elevation Myocardial Infarction Interventions: Illustrated Cases. AB - ST-elevation myocardial infarction (STEMI) intervention comprises 2 components, the STEMI procedure and the STEMI process, which have unique aspects that can be modified and improved, ultimately affecting patient outcome. The 15 illustrated cases in this article highlight suggested improvements mainly in the STEMI procedure, with some references as to how the authors practically improved the STEMI process for the described procedure. The illustrated procedures have been meticulously selected from more than 1000 short door-to-balloon STEMI interventions recorded in the Single Individual Community Experience Registry (SINCERE) database, and are aimed at educating the reader about unique STEMI skills. PMID- 28581969 TI - STEMI Interventions: The European Perspective and Stent for Life Initiative. AB - The Stent for Life Initiative was launched by the European Association of Percutaneous Cardiovascular Interventions (a registered branch of the ESC) and EuroPCR. The purpose of the initiative is to support the implementation of European Society of Cardiology guidelines on management of acute myocardial infarction, help identify barriers to implementation of guidelines, and define actions to ensure that the majority of ST-segment elevation myocardial infarction (STEMI) patients in Europe have access to primary percutaneous coronary intervention. The key objectives are to define the countries with an unmet medical need in the optimal treatment of STEMI and implement an action program to increase patient access to primary percutaneous coronary intervention. PMID- 28581970 TI - Lessons Learned from the Ottawa Regional STEMI Program. AB - Percutaneous coronary intervention (PCI) has become the dominant strategy for the treatment of ST-segment elevation myocardial infarction (STEMI) when rapid access to a catheterization facility is available. In communities where primary PCI is not feasible, a pharmacoinvasive strategy has become a recommended option. At the University of Ottawa Heart Institute, a care delivery model has been developed in which primary PCI and pharmacoinvasive strategies are applied for an entire region. This article reviews the lessons learned in setting up and maintaining a regional STEMI program. PMID- 28581971 TI - Setting Up a Population-Based Program to Optimize ST-Segment Elevation Myocardial Infarction Care. AB - The development of ST-segment elevation myocardial infarction (STEMI) systems of care at the city, region, or nation levels has not only improved the speed of reperfusion but also enhanced the reach of primary angioplasty to areas far from percutaneous coronary intervention (PCI) centers. Setting up a STEMI system of care is a sophisticated process that requires a solid PCI hospital and emergency medical services infrastructure, disciplined collaboration, and a focus on outcomes measurement and continuous quality improvement. This article reviews the accumulated evidence supporting the development of STEMI systems of care and offers practical insights into this process. PMID- 28581973 TI - Percutaneous Left Ventricular Assist Devices. AB - Percutaneous left ventricular assist devices (P-LVADs) can be life saving and may permit the stabilization of a patient in cardiovascular collapse who would otherwise face imminent demise. For specific patients and clinical indications, or where a greater degree of hemodynamic support is required, numerous studies have demonstrated the feasibility and safety of the newer generation P-LVADs. The potential applications for P-LVADs have continued to expand, now including diverse uses such as support for cardiogenic shock, bridge to and following cardiac surgery, and more novel applications such as complex electrophysiologic mapping and ablation studies of unstable ventricular rhythms. PMID- 28581972 TI - The Critical Imperative: Prehospital Management of the Patient with ST-Elevation Myocardial Infarction. AB - Prehospital care is critical to achieve the goal of timely reperfusion in patients with ST-elevation myocardial infarction. Prehospital care is delivered by emergency medical services (EMS) personnel, which include emergency medical dispatchers, first responders, and ambulance response. There is considerable variation in the training and capabilities of the EMS providers in the United States depending on the location (ie, rural vs urban) and local jurisdictions. In this article, the key components of prehospital care of the patient with ST elevation myocardial infarction and the various levels of training and capabilities of EMS providers are discussed. PMID- 28581974 TI - Telemedicine: The Future of Global STEMI Care. AB - Telemedicine is an innovative tool in the setting of ST-elevation myocardial infarction (STEMI), because it addresses the greatest challenge-delivering optimal reperfusion therapies in a timely manner. Telemedicine targets delays related to geography, distance, and stated prehospital systems of care. Integration of telemedicine into prehospital STEMI management has been shown to yield cost-effective improvements in patient care. Despite socioeconomic constraints, a standard prehospital network based on telemedicine is globally feasible. This article proposes 2 models that enable the use of telemedicine in the STEMI management protocol. PMID- 28581975 TI - STEMI Interventions. PMID- 28581976 TI - Future Directions of Fetal Interventions in Congenital Heart Disease. AB - Fetal interventions for congenital heart disease have become important treatment modalities in the past 10 to 15 years. The basic hypothesis has been that a prenatal intervention may remodel cardiac morphology and function to such an extent that it may favorably alter the in utero natural history, resulting in improved prenatal and postnatal outcomes, including an increased likelihood of achieving biventricular circulation. This review discusses the current indications, techniques, and outcomes of fetal cardiac interventions and provides a glimpse into the future with regard to technical improvements and newer treatment modalities, such as maternal oxygenation and in utero pacemaker implantation. PMID- 28581977 TI - Neonatal Interventions for Left-Sided Obstructive Lesions: Alternatives to Surgery. AB - Percutaneous neonatal cardiac interventions are effective in management strategies. Aortic valve dilation has become a first line therapy with excellent outcomes and low morbidity equivalent to surgery. Percutaneous intervention for coarctation of the aorta can safely postpone surgical intervention in small unwell neonates, allowing stabilization and growth. Stent implantation can provide a stable and predictable relief of obstruction; however, care should be taken to implant stents so that they can be removed subsequently. As experience increases, the role of percutaneous techniques in the management of high-risk neonates with coarctation of the aorta will become better defined and improve the outcomes. PMID- 28581978 TI - Stenting Options for Coarctation of the Aorta. AB - The narrowing of the lumen in coarctation of the aorta can be relieved with a high degree of immediate success by transcatheter methods. All methods are associated with immediate and longer-term complications, including dissection, aneurysm formation, and recoarctation. The introduction of the use of covered stents in aortic coarctation is encouraging because the material cover provides additional protection to the acutely disrupted aortic wall and can provide long term protection of the dilated segment and the downstream area of poststenotic dilation. This review discusses the currently available options for stenting aortic coarctation. PMID- 28581979 TI - Catheter Interventions for Pulmonary Artery Stenosis: Matching the Intervention with the Pathology. AB - Pulmonary artery (PA) stenosis represents a heterogeneous defect with a wide morphology and etiology. Interventions to treat PA stenosis should be based on the location, severity, and cause of stenosis as well as the size of the patient at presentation. Specialized dilation balloons, stents, and delivery techniques have been developed to treat a variety of PA stenoses in small infants through adulthood. Early and intermediate results of angioplasty and stenting are superior to surgical results, while long-term data on angioplasty and stenting are becoming available for these proven safe and effective techniques. PMID- 28581980 TI - Complex Interventions in the Adult with Congenital Heart Disease: Percutaneous Solutions for Venous Baffles, Coronary Artery Fistulas, and Ruptured Sinus of Valsalva Aneurysms. AB - We describe 3 distinct ACHD lesions amenable to percutaneous repair: (1) venous baffle obstruction in transposition of the great arteries, (2) coronary artery fistulas, and (3) ruptured sinus of Valsalva aneurysms. For each entity, we chronicle the typical clinical scenario and indications for intervention to supplement the technical approach and potential pitfalls with treatment. PMID- 28581981 TI - Percutaneous Closure of Post-Myocardial Infarction Ventricular Septal Defect: Patient Selection and Management. AB - Percutaneous transcatheter device closure for post-myocardial infarction ventricular septal defect is a feasible alternative to open surgical patch repair. Patient selection, imaging, timing of intervention, technique, and results are discussed. PMID- 28581982 TI - Transcatheter Pulmonary Valve Replacement: Current Status and Future Potentials. AB - Although established, transcatheter pulmonary valve replacement is in its infancy compared with surgical pulmonary valve replacement. Extended clinical experience and follow-up have identified new challenges; however, careful evaluation of data through clinical trials has facilitated effective evolution of responses to these challenges. The limited patient population has resulted in less interest in new valve design, but having been the older sibling to transcatheter aortic valve replacement, transcatheter pulmonary valve replacement is likely to benefit in the future from design modifications to the more popular and commercially viable transcatheter aortic valve revolution. Improving valve longevity and applying the technology to native outflow tracts remain the short-to-medium term goals. PMID- 28581983 TI - Pulmonary Vein Stenting for Atrial Fibrillation Ablation-Induced Pulmonary Vein Stenosis. AB - Pulmonary vein stenosis (PVS) is a known complication of pulmonary vein isolation in the treatment of atrial fibrillation. Patients with PVS can present with a great variety of symptoms. Clinicians should have a low threshold to evaluate for this potentially morbid and treatable condition. PVS can be treated by stenting affected pulmonary veins via transseptal access to the left atrium and use of bare metal biliary stents. PMID- 28581984 TI - Percutaneous Mitral Valve Interventions. AB - Percutaneous interventions for mitral valve disease represent both the oldest and the newest of catheter interventions. Balloon mitral valvuloplasty was among the first effective catheter therapies for valvular heart disease. The technique and device approach was initially reported by Inoue in 1982 and, remarkably, is virtually unchanged between then and now. Conversely, novel catheter therapies to repair mitral regurgitation are now in their infancy, with only the earliest human experience. This article details the spectrum of these therapies. PMID- 28581985 TI - Transcatheter Occlusion of the Left Atrial Appendage. AB - The left atrial appendage is a primary source of thrombi in patients with nonvalvular atrial fibrillation. Transcatheter left atrial appendage occlusion/exclusion is a novel technology with the potential as an alternative approach for lifelong anticoagulation to prevent potential catastrophic embolic stroke. This article discusses important evaluation, procedural steps, and the clinical data for left atrial appendage closure. PMID- 28581986 TI - Hybrid Procedures in Congenital Heart Disease: Hypoplastic Left Heart Syndrome/Muscular Ventricular Septal Defect/Stenting of Pulmonary Arteries. AB - Hybrid therapies have increased and offer a valuable alternative to standard catheter or surgical therapies in selected patient. These hybrid therapies often combine the best of both techniques, in particular for ventricular septal defect closure and intraoperative pulmonary artery stent placement. For patients with hypoplastic left heart syndrome, the hybrid approach is an important alternative therapeutic strategy, providing similar results to conventional Norwood-type palliation. Further studies are needed and are underway to evaluate the neurodevelopmental outcome in these patients. PMID- 28581987 TI - Outcomes After Transcatheter ASD Closure. AB - Ostium secundum-type atrial septal defect closure has evolved from a surgical procedure requiring cardiopulmonary bypass to a percutaneous, catheter-based procedure usually requiring only an overnight hospital stay. The overall safety and effectiveness has compared favorably with surgical repair. Although rare, complications have been described, including erosion, device embolization, or malfunction and arrhythmias. The overall long-term clinical outcomes have been excellent: good quality of life, functional class improvement, and ventricular remodeling have been the rule after the procedure. It is mandatory to recommend indefinite follow-up of patients undergoing this procedure for potential long term complications. PMID- 28581988 TI - Influence of PFO Anatomy on Successful Transcatheter Closure. AB - Patent foramen ovale (PFO) is considered a risk factor for serious clinical syndromes, the most important of which is cryptogenic stroke in the setting of paradoxic embolism. The safety and feasibility of transcatheter PFO closure have been addressed in several studies; this procedure is performed worldwide with excellent results. Variations in the atrial septal configuration and PFO are frequent and have an impact on the technical aspects and success in transcatheter PFO closure. To minimize the rate of complications of percutaneous closure of PFO, patients must be carefully selected on the basis of morphology and location of the interatrial defect. PMID- 28581989 TI - Transcatheter Closure of Membranous Ventricular Septal Defects-Old Problems and New Solutions. AB - Isolated perimembranous ventricular septal defect (VSD) is the most common congenital heart defect (after bicuspid aortic valve). Surgery is considered the gold standard for the treatment of these VSDs. However, it is associated with morbidity and mortality. Less invasive techniques have been developed, and percutaneous closure of perimembranous VSDs is now considered a possible alternative to the standard surgical approach. The main problem associated with transcatheter closure of VSD is the occurrence of complete atrioventricular block and need for pacemaker implantation. Improvements in technology and design will help to reduce the occurrence of this problem in the near future. PMID- 28581990 TI - Stenting of Lesions in Patent Ductus Arteriosus with Duct-Dependent Pulmonary Blood Flow: Focus on Case Selection, Techniques and Outcome. AB - Stenting of patent ductus arteriosus (PDA) is an attractive alternative to the surgical aortopulmonary shunt in the palliation of cyanotic congenital heart disease. However, the diverse morphology of PDA in this setting limits its role, as stenting an overly tortuous duct may not be feasible, and in a significant number of patients, ductus-related pulmonary artery stenosis contraindicates this procedure. The major acute complications are stent migration, thrombosis, and cardiac failure. Early failure of palliation caused by in-stent stenosis is another limitation of this procedure. PMID- 28581991 TI - Congenital and Structural Heart Disease. PMID- 28581992 TI - Implementation of Regional ST-Segment Elevation Myocardial Infarction Systems of Care: Successes and Challenges. AB - Current guidelines recommend that communities create and maintain a regional system of ST-segment elevation myocardial infarction (STEMI) care that includes assessment and continuous quality improvement of emergency medical services and hospital-based activities. Availability and timely access is a challenge in many areas of the United States. This article reviews clinical trial data supporting the use of primary percutaneous coronary intervention as the optimal reperfusion strategy, and fibrinolysis as an option when this is not possible. It then describes the outcomes and benefits of implementing regional systems of STEMI care, and discusses ongoing challenges for STEMI system implementation, including inadequate data collection and feedback, and hospital and physician competition. PMID- 28581993 TI - Time to Treatment: Focus on Transfer in ST-Elevation Myocardial Infarction. AB - In the modern ST-elevation myocardial infarction (STEMI) system, the use of electrocardiogram by emergency medical services (EMS) personnel and the option to bypass emergency departments on route to a PCI-capable hospital is of particular importance. Through training and a standardized referral process, EMS personnel can now accurately diagnose and refer STEMI patients directly to the catheterization laboratory of a percutaneous coronary intervention-capable hospital. Regional STEMI models have been implemented successfully across North America, resulting in palpable reductions in door-to-balloon time, morbidity, and mortality. PMID- 28581994 TI - Reperfusion Options for ST Elevation Myocardial Infarction Patients with Expected Delays to Percutaneous Coronary Intervention. AB - Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy for ST elevation myocardial infarction (STEMI). However, only one-third of hospitals in the US have PCI availability 24/7. For non-PCI hospitals, transfer remains the optimal strategy. For expected delays of greater than 120 minutes, a pharmacoinvasive strategy is recommended. In patients with evidence of failed reperfusion or hemodynamic instability, immediate rescue PCI should be performed. All other patients should undergo routine cardiac catheterization and PCI within 24 hours after fibrinolysis. A pharmacoinvasive strategy is best implemented within an organized regional STEMI system with prospective standardized transfer protocols. PMID- 28581995 TI - False Activations for ST-Segment Elevation Myocardial Infarction. AB - First-medical-contact-to-device (FMC2D) times have improved over the past decade, as have clinical outcomes for patients presenting with ST-elevation myocardial infarction (STEMI). However, with improvements in FMC2D times, false activation of the cardiac catheterization laboratory (CCL) has become a challenging problem. The authors define false activation as any patient who does not warrant emergent coronary angiography for STEMI. In addition to clinical outcome measures for these patients, STEMI systems should collect data regarding the total number of CCL activations, the total number of emergency coronary angiograms, and the number revascularization procedures performed. PMID- 28581996 TI - In-Hospital ST Elevation Myocardial Infarction: Clinical Characteristics, Management Challenges, and Outcome. AB - Timely reperfusion therapy reduces complications and improves survival in ST elevation myocardial infarction (STEMI). An effective chain of survival has been established for STEMIs occur in the community (outpatient STEMI). Recent studies have identified a subgroup of patients who develop STEMI while hospitalized for primary conditions, often not directly related to coronary artery disease (in hospital STEMI or inpatient STEMI). This article summarizes current understanding of patient demographics, clinical characteristics, care delivery system and outcomes of in-hospital STEMI, comparing with outpatient STEMI. We also identified opportunities for quality improvement and proposed strategies and future directions to improve care for these patients. PMID- 28581998 TI - Controversies in the Management of ST Elevation Myocardial Infarction: Thrombin Inhibition. AB - Anticoagulation is essential in patients with ST elevation myocardial infarction (STEMI) to prevent further thrombosis and to maintain patency of the infarct related artery after reperfusion. The various anticoagulant medications available for use in patients with STEMI include unfractionated heparin (UFH), low molecular-weight heparin, fondaparinux, and bivalirudin, a direct thrombin inhibitor. The authors review the current anticoagulation strategies for patients with STEMI undergoing primary percutaneous coronary intervention (PCI), fibrinolysis, or no reperfusion. The authors present the latest evidence and controversies on this topic, with a focus on bivalirudin versus UFH in the setting of primary PCI for STEMI. PMID- 28581997 TI - Optimal Antiplatelet Therapy in ST-Segment Elevation Myocardial Infarction. AB - Cardiovascular disease is the leading cause of death worldwide. Case-fatality rates for myocardial infarction (MI) in the United States have decreased over the past decades, in large part due to advances in the treatment of acute MI and secondary preventive therapy after MI. Antiplatelet therapy remains the cornerstone of treatment of MI. This article reviews the current state of antiplatelet therapy in ST-segment elevation MI. PMID- 28581999 TI - Controversies in the Management of ST-Segment Elevation Myocardial Infarction: Transradial Versus Transfemoral Approach. AB - This article discusses the controversies surrounding the use of transradial versus transfemoral approaches in the management of patients with ST-segment elevation myocardial infarction, beginning with a review of the benefits of transradial percutaneous coronary intervention (PCI) in this population. The unanswered questions about the mechanism underlying the mortality benefit of transradial PCI are discussed, concluding with recommendations for safe and effective strategies for adoption of the transradial approach to optimize outcomes in these high-risk patients. PMID- 28582000 TI - Controversies in the Treatment of Women with ST-Segment Elevation Myocardial Infarction. AB - Coronary artery disease is the leading cause of death in women. Women with ST segment elevation myocardial infarctions continue to have worse outcomes compared with men despite advancements in therapies. Furthermore, these differences are particularly pronounced among young men and women with myocardial infarctions. Differences in the pathophysiology of coronary artery plaque development, disease presentation, and recognition likely contribute to these outcome disparities. Despite having worse outcomes compared with men, women clearly benefit from aggressive treatment and the latest therapies. This article reviews the treatment options for ST-segment elevation myocardial infarctions and the outcomes of women after treatment with reperfusion therapies. PMID- 28582001 TI - Management of Multivessel Disease and Cardiogenic Shock. AB - Cardiogenic shock represents a state of low cardiac output and systemic hypoperfusion resulting in insufficient end-organ perfusion and consequent multiorgan failure. The main cause of this complication in the context of acute ST-elevation myocardial infarction is left ventricular dysfunction secondary to poor myocardial perfusion. In over 50% of cardiogenic shock cases, there is evidence of significant coronary stenosis within noninfarct-related arteries. Persistent ischemia in the noninfarct territory may contribute to ongoing hypotension. Currently, ESC and ACC/AHA/SCAI guidelines advocate complete revascularization in the context of multivessel coronary artery disease in the context of cardiogenic shock, although the evidence is weak. PMID- 28582003 TI - Controversies in Out of Hospital Cardiac Arrest? AB - Cardiac arrest is a major cause of morbidity and mortality and accounts for nearly 500,000 deaths annually in the United States. In patients suffering out-of hospital cardiac arrest, survival is less than 15%, with considerable regional variation. Although most deaths occur during the initial resuscitation, an increasing proportion occur in patients hospitalized after initially successful resuscitation. In these patients, the significant subsequent morbidity and mortality is due to "post cardiac arrest syndrome." Until recently, most single interventions have yielded little improvement in rates of survival; however, there is growing recognition that optimal treatment strategies during the postresuscitation phase may improve outcomes. PMID- 28582002 TI - Controversies and Challenges in the Management of ST-Elevation Myocardial Infarction Complicated by Cardiogenic Shock. AB - The prognosis in ST-elevation myocardial infarction has improved with coronary care units, revascularization, and anticoagulant strategies; however, cardiogenic shock (CS) remains a highly fatal condition. Controversies remain about optimal pharmacologic therapies, revascularization strategies, the role of mechanical circulatory support (MCS), and evidence-based patient selection. The current informed consent paradigm for clinical trials creates challenges testing treatments in CS patients, who are too ill to consent and require immediate treatment. Several trials are underway comparing revascularization strategies and MCS options. Although the prognosis is grim, careful, new and existing treatments could change the course of this condition in the coming years. PMID- 28582004 TI - Public Reporting in ST Segment Elevation Myocardial Infarction. AB - Public reporting provides transparency and improved quality of care. However, methods in estimating risk adjusted mortality in ST-segment myocardial infarction, particularly in cardiogenic shock and cardiac arrest are contentious. There are concerns that this has resulted in risk-averse behavior in publicly reporting states, resulting in suboptimal care in these patients. PMID- 28582011 TI - Despite Dramatic Progress, Significant Controversy and Critical Challenges for Patients with ST-Segment Elevation MI. PMID- 28582005 TI - Global Challenges and Solutions: Role of Telemedicine in ST-Elevation Myocardial Infarction Interventions. AB - Major disparities exist between developed and developing countries in the management of acute myocardial infarction (AMI). These pronounced differences result in significantly increased morbidity and mortality from AMI in different regions of the world. Lack of infrastructure, insurance, facilities, and skilled personnel are the major constraints. Primary percutaneous coronary intervention has revolutionized the treatment of AMI; however, its global use is limited by the listed constraints. Telemedicine provides an efficient methodology that can hugely increase access and accuracy of AMI management. PMID- 28582012 TI - Rationale for Percutaneous Intervention of CTO. AB - Chronic total occlusion accounts for 15% of cases during diagnostic angiography with higher referral rate to surgical revascularization. With contemporary strategies and techniques, the success rate with experienced operators can exceed 90%. Currently available observational studies in carefully selected patient populations show evidence of a trend toward symptom relief; improvement in quality of life, left ventricular function, and mortality; and improved tolerance toward future ischemic events. Lack of randomized controlled trials comparing current optimal medical management with percutaneous coronary intervention for chronic total occlusion is a major barrier to widespread adaptation of this advanced complex interventional technique. PMID- 28582013 TI - Toolbox and Inventory Requirements for Chronic Total Occlusion Percutaneous Coronary Interventions. AB - More interventional cardiologists are adopting chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in their practice. This article follows the steps of the PCI procedure to describe the toolbox and inventory requirements for successful program development. Recent innovations have allowed adoption of controlled dissection and reentry techniques as a primary revascularization strategy for CTO. Other devices have special rules in CTO PCI. Equipment and techniques to enhance guide catheter support are frequently needed during CTO PCI. Tools for complication management are important components. The necessary tools are listed at the end of the article. PMID- 28582014 TI - CTO PCI Procedural Planning. AB - Chronic total occlusion percutaneous coronary intervention (CTO PCI) procedural planning involves much thought and deliberation before one actually attempts to cross the CTO lesion in the cardiac catheterization laboratory. Careful preprocedural angiographic assessment is a key to successful CTO PCI. CTO PCI represents the most complex PCI one can perform, and thus operator and staff training as well as the concept of CTO days are all essential for a successful CTO PCI program. PMID- 28582015 TI - Wire Strategy as a First Option: Properties of the Tools. AB - This article discusses interventional guidewires in general and how they are best used in chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in particular. The components that make a guidewire and the various design options are described. The specific characteristics of these options and how they relate to various aspects of PCI are discussed. Guidewire design as it applies specifically to the tasks particular to CTO PCI is discussed. PMID- 28582016 TI - Antegrade Dissection and Reentry: Tools and Techniques. AB - The hybrid approach to chronic total occlusion percutaneous coronary intervention requires facility with antegrade and retrograde strategies to achieve high success rates in a time-efficient and safe manner. Antegrade dissection and reentry is an integral component of this approach but historically has been limited by low success rates and an inability to control the site of reentry. The advent of the BridgePoint device, and multiple iterations of technique in conjunction with its use, have markedly improved success rates and procedure efficiency. PMID- 28582017 TI - Retrograde Procedural Planning, Skills Development, and How to Set Up a Base of Operations. AB - This article addresses the practical steps required when adopting retrograde access as part of the treatment of chronic total occlusions (CTOs). The article focuses on procedure rationale, equipment required, the practical steps, and considerations involved in collateral-channel crossing and setting up a "base of operations" at the proximal cap of the CTO. It also describes simple methods of wire escalation. PMID- 28582018 TI - Retrograde Dissection Reentry for Coronary Chronic Total Occlusions. AB - The retrograde technique is an important aspect to overall success in percutaneous coronary intervention of chronic total occlusions. The reverse controlled antegrade and retrograde subintimal tracking technique is the most commonly used retrograde approach for recanalization as either a primary approach or after unsuccessful antegrade dissection reentry. A stepwise approach to this technique is the key to success. PMID- 28582019 TI - The Final Steps of the Retrograde Technique: Wire Externalization, Stenting, and Wire Removal. AB - A guidewire can be externalized after retrograde lesion crossing. Wire externalization provides excellent support for ballooning and stenting and for the treatment of chronic total occlusion lesions that are long calcified, tortuous, and difficult to treat. This review discusses the final steps of the retrograde technique via wire externalization, stenting, and wire removal. PMID- 28582020 TI - The Hybrid Approach for Percutaneous Revascularization of Coronary Chronic Total Occlusions. AB - Percutaneous recanalization of coronary chronic total occlusions (CTOs) has been limited by inability to consistently achieve wire position in the distal true lumen across the CTO segment, preventing many patients from having percutaneous coronary intervention (PCI). Furthermore, low success rates, prolonged case times, and wide variability in approaches has resulted in lower adoption of CTO PCI as a routine procedure and has limited educational initiatives. The hybrid approach for CTO PCI is predicated on an algorithm that allows trained operators to react to angiograms and craft strategies in a similar manner, enabling technical success and efficiency. PMID- 28582022 TI - Informed Consent of the Chronic Total Occlusion Patient. AB - This article focuses on the general principles of informed consent, then highlights the particular risks associated with chronic total occlusion interventions. The goal is to provide a basic framework for the interventional cardiologist to use when having consent discussions with his or her patients. PMID- 28582021 TI - Transradial Approach for Chronic Total Occlusion Percutaneous Coronary Intervention. AB - Over the last two decades, the transradial approach has gained an important role in interventional cardiology. A large body of evidence exists supporting the safety and feasibility of the transradial approach in a broad spectrum of patients and settings. In addition, the transradial approach has been applied with good results for chronic total occlusion (CTO) recanalization. This article provides an overview of basic principles and techniques required to perform successful transradial CTO percutaneous coronary intervention. PMID- 28582023 TI - Complications of Chronic Total Occlusion Angioplasty. AB - Every percutaneous coronary intervention carries risk for acute and long-term complications. This is also true of chronic total occlusion (CTO) interventions, which can also have complications specific to specialized techniques, such as retrograde crossing and dissection/reentry techniques. Acute CTO intervention complications can be coronary artery-related, cardiac noncoronary, or noncardiac. In the long term, CTO interventions can be complicated by in-stent restenosis, stent thrombosis, or coronary aneurysm formation. Understanding of the pathogenesis of possible CTO intervention complications can facilitate prevention, early recognition, and prompt treatment. PMID- 28582025 TI - The Final Frontier of Percutaneous Coronary Intervention-Coronary Chronic Total Occlusions. PMID- 28582024 TI - Percutaneous Chronic Total Occlusion Revascularization: Program Development, Resource Utilization, and Economic Outcomes. AB - Against the background of current data supporting indications for chronic total occlusion (CTO) revascularization and strategies that promote incrementally higher procedural success rates, this article introduces a multidisciplinary approach to CTO program development, establishes guidelines for the performance of safe and efficient CTO percutaneous coronary intervention, and reviews considerations related to resource utilization and economic outcomes with complex percutaneous coronary revascularization. PMID- 28582026 TI - The History of Coronary Stenting. AB - The history of coronary angioplasty began with the groundbreaking work of Andreas Gruntzig, who was the first to use balloon-expandable catheters for the treatment of flow-limiting atherosclerotic coronary artery lesions. Thereafter, early investigators tested self-expanding springs as a solution to abrupt closure and restenosis seen with balloon angioplasty but these devices suffered from difficult delivery and a high complication rate. Julio Palmaz and Richard Schatz introduced the first balloon-expandable stent as a mechanical support to improve vessel patency. Their pioneering work launched a new era in the treatment of coronary artery disease. PMID- 28582027 TI - Restenosis of the Coronary Arteries: Past, Present, Future Directions. AB - Restenosis is a pathologic response to vascular injury, characterized by neointimal hyperplasia and progressive narrowing of a stented vessel segment. Although advances in stent design have led to a dramatic reduction in the incidence of restenosis, it continues to represent the most common cause of target lesion failure following percutaneous coronary intervention. Efforts to maximize restenosis prevention, through careful consideration of modifiable risk factors and an individualized approach, are critical, as restenosis, once established, can be particularly difficult to treat. Novel approaches are on the horizon that have the potential to alter the natural history of this stubborn disease. PMID- 28582028 TI - The Systems Biocompatibility of Coronary Stenting. AB - The coronary stent has propelled our understanding of the term "biocompatibility." Stents are expanded at sites of arterial blockage and mechanically reestablish blood flow. This simplicity belies the complex reactions that occur when a stent contacts living substrates. Biocompatible seek to elicit the intended response; stents should perform rather than merely exist. Because performance is assessed in the patient, stent biocompatibility is the multiscale examination of material and cell, and of material, structure, and device in the context of cell, tissue, and organism. This review tracks major biomaterial advances in coronary stent design and discusses biocompatibility clinical performance. PMID- 28582029 TI - Endovascular Drug Delivery and Drug Elution Systems: First Principles. AB - Endovascular drug delivery continues to revolutionize the treatment of atherosclerosis in coronary and peripheral vasculature. The key has been to identify biologic agents that can counter the hyperplastic tissue responses to device expansion/implantation and to develop effective local delivery strategies that can maintain efficacious drug levels across the artery wall over the course of device effects. This article reviews the evolution of endovascular drug delivery technology, explains the mechanisms they use for drug release, and provides a quantitative mechanistic framework for relating drug release mode to arterial drug distribution and effect. PMID- 28582030 TI - Antiproliferative Drugs for Restenosis Prevention. AB - Cardiovascular disease is a leading cause of death and disability worldwide. Current treatment strategies aimed at treating the symptoms and consequences of obstructive vascular disease have embraced both optimal medical therapy and catheter-based percutaneous coronary intervention with drug-eluting stents. Drug eluting stents elute antiproliferative drugs inhibiting vascular smooth muscle cell proliferation, which occurs in response to injury and thus prevents restenosis. However, all drugs currently approved for use in drug-eluting stents do not discriminate between proliferating vascular smooth muscle cells and endothelial cells, thus delaying re-endothelialization and subsequent vascular healing. PMID- 28582031 TI - Contemporary Drug-Eluting Stent Platforms: Design, Safety, and Clinical Efficacy. AB - First-generation drug-eluting stents significantly improved treatment of coronary disease, decreasing rates of revascularization. This was offset by high rates of late adverse events, driven primarily by stent thrombosis. Research and design improvements of individual DES platform components led to next-generation devices with superior clinical safety and efficacy profiles compared with bare-metal stents and first-generation drug-eluting stents. These design improvements and features are explored, and their resulting clinical safety and efficacy reviewed, focusing on platforms approved by the Food and Drug Administration currently widely used in the United States. PMID- 28582032 TI - Design Principles of Bioresorbable Polymeric Scaffolds. AB - The concept for a bioresorbable vascular scaffold combines the best features of the first 3 generations of percutaneous coronary intervention (namely), balloon angioplasty, bare metallic stents, and drug-eluting stents, into a single device. The principles of operation of a BRS follow 3 phases of functionality that reflect the different physiologic requirements over time; revascularization, restoration, and resorption. Most BRS designs make use of the continuum of hydrolytic degradation in aliphatic polyesters, such as poly(l-lactide), in which molecular weight, strength, and mass decrease progressively in 3 distinct stages, consistent with the in vivo requirements of each performance phase. PMID- 28582033 TI - Bioresorbable Scaffolds: Clinical Outcomes and Considerations. AB - Bioresorbable scaffolds (BRS) have been engineered to eliminate the theoretic stimulus to late coronary events, a caveat of conventional metallic drug-eluting stents (DESs). Outcome benefits of BRSs over current-generation DESs are expected to accrue after complete bioresorption. Before this timeframe, BRSs need to prove at least similarly safe and effective compared with DESs. Several randomized studies of the Absorb BRS have been made available. Several manufacturers are at the beginning of their line of clinical development of competing BRSs. This article reviews the contemporary clinical outcomes of the Absorb scaffold, and provides an updated state of the art on the other players in the BRS arena. PMID- 28582034 TI - Design and Comparison of Large Vessel Stents: Balloon Expandable and Self Expanding Peripheral Arterial Stents. AB - Endovascular stenting has evolved over the last 50 years since its inception into the framework of management of vascular atherosclerotic disease. Stent design has evolved as lesion complexity has increased. Nevertheless, certain first principles regarding stent design have been recapitulated time and again with every iteration of endovascular stents. This article reviews principles of endovascular stent design and compares and contrasts key aspects of balloon expandable and self-expanding stents. PMID- 28582035 TI - Design and Clinical Considerations for Endovascular Stent Grafts. AB - Endovascular treatment for aortic abnormality is an excellent alternative option for patients who are not good candidates for conventional open surgery. Although the technique of placing endovascular stent grafts has evolved since the first grafts, the basic principles remain the same. Use of endografts is limited by anatomic criteria, and advances in graft design have allowed for more widespread use for a broader patient range. The most important limitations to overcome are achieving high-quality aortic neck "healthy" landing zone, smaller-diameter delivery systems, and endografts that allow for more angled aortic necks. PMID- 28582036 TI - Pathology of Endovascular Stents. AB - Contemporary endovascular stents are the product of an iterative design and development process that leverages evolving concepts in vascular biology and engineering. This article reviews how insights into vascular pathophysiology, materials science, and design mechanics drive stent design and explain modes of stent failure. Current knowledge of pathologic processes is providing a more complete picture of the factors mediating stent failure. Further evolution of endovascular stents includes bioresorbable platforms tailored to treat plaques acutely and to then disappear after lesion pacification. Ongoing refinement of stent technology will continue to require insights from pathology to understand adverse events, refine clinical protocols, and drive innovation. PMID- 28582037 TI - Coronary Stent Failure: Fracture, Compression, Recoil, and Prolapse. AB - Current-generation coronary drug-eluting stents are associated with low rates of restenosis and target lesion revascularization. However, several mechanisms of stent failure remain clinically important. Stent fracture may occur in areas of excessive torsion or angulation. Longitudinal stent deformation is related to axial stent compression owing to extrinsic forces or secondary devices that disrupt stent architecture. Stent recoil occurs when a stent does not deploy at its optimal cross-sectional area. Tissue prolapse between stent struts may also predispose patients to adverse outcomes. Prevention, recognition, and treatment of these stent failures are necessary to optimize patient outcomes after percutaneous coronary interventions. PMID- 28582043 TI - Stent Design: Past, Present, and Future. PMID- 28582044 TI - Radial Artery Access, Hemostasis, and Radial Artery Occlusion. AB - Radial artery access is usually achieved using a micropuncture system. Hydrophilic introducers are used to improve comfort, probably by reducing spasm. A vasodilator cocktail should be administered to prevent severe spasm and anticoagulation; usually, unfractionated heparin is administered to prevent subsequent radial artery occlusion (RAO). Hemostasis at the radial artery puncture site is easily achievable by local compression. Application of local compression frequently leads to interruption of radial artery flow and subsequent occlusion. Careful attention to maintenance of radial artery patency during hemostatic compression has been shown to decrease the risk of RAO without increasing access-related bleeding complications. PMID- 28582045 TI - Strategies to Traverse the Arm and Chest Vasculature. AB - This article discusses different methods of working through arm and chest vasculature to increase the success rate of the transradial approach (TRA). Despite lower rates of bleeding and vascular complications as compared with the transfemoral approach, adoption of the TRA has been slow, particularly because of higher failure rates. Anatomic complexities of arm and chest vasculature play an important role in cases of TRA failure. Using a simple framework to classify the anatomic or functional problem and approaching these challenges in a logical sequence should facilitate management and increase the success rate for TRA. PMID- 28582047 TI - Slender Approach and Sheathless Techniques. AB - Most radial arteries cannot accommodate 7- and 8-French introducer sheaths for large-bore percutaneous coronary intervention without overstretch. In addition to being uncomfortable, radial artery overstretch is associated with spasm and higher rates of procedure-related radial artery occlusion. Methods for the transradial interventionist to overcome the limitation of radial artery-sheath size mismatch include both sheath-based and sheathless approaches. In this article we discuss a variety of techniques that can be used to minimize radial artery stretch for straightforward and complex coronary procedures. PMID- 28582046 TI - Diagnostic and Guide Catheter Selection and Manipulation for Radial Approach. AB - Transradial catheterization and percutaneous coronary interventions have multiple advantages, including reduced bleeding risk, reduced length of stay and costs, and increased patient comfort. Transradial catheterization and interventions requires the acquisition of various additional skill sets including radial arterial puncture, the ability to navigate the upper extremity vasculature, and understanding catheter selection and coronary engagement technique. Although standard femoral catheter shapes perform adequately from the left or right radial approach for coronary angiography, for percutaneous coronary intervention guide catheter support is critical. This article summarizes some practical learning points pertaining to navigating the upper extremity vasculature, and understanding catheter selection and coronary engagement technique. PMID- 28582048 TI - Transradial Primary Percutaneous Coronary Intervention. AB - Despite advances in antithrombotic and antiplatelet therapy, bleeding complications remain an important cause of morbidity and mortality in patients with acute ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Many bleeding events are related to the access site. Transradial access (TRA) PPCI is associated with significant reduction in bleeding and vascular complications and reduced cardiac mortality compared with the transfemoral approach (TFA). High-risk patients might particularly benefit from TRA. Radial skills providing procedural times and success rates comparable with those of the TFA are strongly recommended before using this technique in the STEMI PPCI setting. PMID- 28582049 TI - Transradial Peripheral Arterial Procedures. AB - Increased understanding and increased adoption of transradial catheterization across the world have led to further exploring of radial artery access for transradial endovascular interventions in peripheral artery disease (PAD). This article discusses the advantages and limitations of the transradial approach for endovascular medicine by using case examples, illustrations, and videos. The details about how to use a radial approach for PAD intervention, including and tips tricks, are discussed. PMID- 28582050 TI - Complications of Transradial Cardiac Catheterization and Management. AB - The transradial approach for coronary angiography has become an increasingly used alternative to the conventional transfemoral approach. Decreased access site complications and bleeding, reduced hospital stays and health care costs, and increased patient satisfaction contribute to the attractiveness of this approach. However, operators must be familiar with the distinct complications associated with the transradial approach. In this article, we discuss the common and less common complications of transradial catheterization, prevention strategies, and management options. PMID- 28582051 TI - The Transradial Learning Curve and Volume-Outcome Relationship. AB - This article discusses how learning curves correlate with learning in transradial catheterization. Although learning curves exist in the conversion to transradial approaches, current percutaneous coronary intervention (PCI) procedures are so safe that only surrogate end points such as contrast usage and x-ray exposure show learning effects. Using these surrogates, a learning curve of 30 to 50 patients seems typical to transition cardiologists from transfemoral to transradial PCI. This transition occurs with the immediate benefit of reduced vascular complications and bleeding and without loss of overall procedural success. These measures of safety during learning exist despite difference of procedural volumes. PMID- 28582052 TI - The Transradial Approach and Antithrombotic Therapy: Rationale and Outcomes. AB - This article reviews antithrombotic strategies for percutaneous coronary interventions according to the access site and the current evidence with the aim of limiting ischemic complications and preventing radial artery occlusion (RAO). Prevention of RAO should be part of the quality control of any radial program. The incidence of RAO postcatheterization and interventions should be determined initially using the echo-duplex and then frequently assessed using the more cost effective pulse oximetry technique. Any evidence of higher risk of RAO should prompt internal analysis and multidisciplinary mechanisms to be put in place. PMID- 28582056 TI - Radial Approach: Fundamental Techniques and Evidence. PMID- 28582058 TI - TRANSRADIAL ANGIOGRAPHY AND INTERVENTION. PMID- 28582059 TI - Calcific Aortic Stenosis: Pathology and Role of Balloon Aortic Valvuloplasty. AB - Calcific aortic stenosis (AS) is a common expression of aortic valve disease and increases in prevalence with advancing age. Recent studies have shown that calcific deposition in aortic valve leaflets is an actively regulated process with many pathophysiologic similarities to atherosclerosis. Surgical valve replacement is the definitive treatment of calcific AS, but many patients do not undergo surgery because of prohibitive comorbidities or other high-risk features. Balloon aortic valvuloplasty remains an option for temporary palliation and symptomatic relief, and continues to serve as a bridge to aortic valve replacement in certain patients with AS requiring temporary hemodynamic stabilization. PMID- 28582060 TI - Percutaneous Therapies in the Treatment of Valvular Pulmonary Stenosis. AB - Transcatheter balloon pulmonary valvuloplasty (BPV) is the standard of care in managing symptomatic patients with moderate-to-severe pulmonary valvular stenosis, or asymptomatic patients with severe pulmonary valvular stenosis or with moderate pulmonary stenosis and evidence of objective exercise intolerance or right ventricular dysfunction. This article discusses the incidence, causes, and pathophysiology of valvular pulmonary stenosis in adolescents and adults; its natural history and noninvasive evaluation; the current guideline-recommended indications for BPV; the technical aspects of performing BPV; the immediate and long-term outcomes after valvuloplasty; and the complications and safety of the procedure. Also discussed is the role of this procedure in neonatal critical pulmonary stenosis and in percutaneous pulmonary valve replacement for patients with prior pulmonic valve interventions or degenerated right ventricular pulmonary artery conduits. PMID- 28582061 TI - Transcatheter Aortic Valve Implantation: Experience with the Edwards SAPIEN Device. AB - Transcatheter aortic valve implantation (TAVI) with the Edwards SAPIEN valve has been shown to be highly beneficial to patients at high risk or with contraindications to surgical aortic valve replacement. The availability of both transfemoral and transapical approaches allows the technique to be applied in most patients. Optimal screening and technical proficiency are crucial for a successful and safe procedure. The technique poses many technical challenges in sick and fragile elderly patients. Thus, TAVI should remain confined to formally trained and proctored experienced physicians, in centers of expertise offering an optimal multidisciplinary collaboration. PMID- 28582062 TI - Percutaneous Balloon Valvuloplasty for Aortic Stenosis in Newborns and Children. AB - In all cases of congenital valvar aortic stenosis (AS), reduced effective orifice area leads to obstruction to flow, usually resulting from thickening and reduced motion of the valve leaflets. The most severe cases of valvar AS present soon after birth, with low cardiac output secondary to left ventricular dysfunction. Interventional treatment options consist of open surgical valvotomy or balloon valvuloplasty, with both therapies providing excellent but usually only temporary relief of stenosis. This article focuses on balloon aortic valvuloplasty as a therapy for congenital valvar AS in infants and children, focusing on established techniques, outcomes, and future challenges. PMID- 28582063 TI - Balloon Aortic Valvuloplasty in the Transcatheter Aortic Valve Replacement Era. AB - Initial enthusiasm for balloon aortic valvuloplasty (BAV) as an alternative to surgical aortic valve replacement waned because of the perceived failure of the procedure to alter the natural history of calcific severe aortic valve stenosis (AS) and significant initial procedural morbidity. Despite technical and procedural advances, BAV has been reserved as a palliative procedure for patients who cannot undergo valve replacement or as a bridge to surgery in hemodynamically unstable patients. This article reviews the indications, technical aspects, and outcomes of BAV for calcific AS and discusses the current role of BAV in the era of transcatheter aortic valve replacement. PMID- 28582064 TI - Looking to the Future of Percutaneous Treatment of Patients with Valvular Heart Disease. AB - The development of transcatheter valvular therapeutics has revolutionized interventional cardiology over the past decade. Nonetheless, despite these prominent advances in percutaneous valve technology, numerous obstacles regarding safety and efficacy must be overcome before the precise clinical role of these devices becomes clear. This article discusses the current status of transcatheter valve replacement and repair as it pertains to the aortic and mitral valve and deliberates on the bright future of a promising tool that will drastically affect clinical interventional practice. PMID- 28582065 TI - Transcatheter Aortic Valve Implantation: Experience with the CoreValve Device. AB - The field of transcatheter aortic valve implantation has been rapidly evolving. The Medtronic CoreValve first emerged on the landscape in 2004 with initial first human studies, and it is currently being studied in the Pivotal US trial. This article details the current experience with the self-expanding aortic valve with a focus on clinical results and ongoing challenges. PMID- 28582066 TI - Transcatheter Aortic Valve Implantation: Upcoming New Devices. AB - Transcatheter aortic valve implantation (TAVI) is an alternative to surgical aortic valve replacement in high-risk patients with symptomatic severe aortic stenosis. Several upcoming devices will optimize and facilitate the procedure: periprosthetic aortic regurgitation will be reduced by larger prosthesis sizes and repositionable next-generation transcatheter heart valves. Alternative access routes and smaller sheaths will reduce the rate of vascular complications. Cerebral protection devices might reduce the rate of strokes and silent cerebral embolism. Abandonment of balloon valvuloplasty and rapid ventricular pacing might facilitate the procedure and improve outcome. Thus, younger and healthier patients could benefit from TAVI in the near future. PMID- 28582067 TI - Percutaneous Mitral Balloon Valvuloplasty for Patients with Rheumatic Mitral Stenosis. AB - Percutaneous balloon dilatation of stenotic cardiac valves is used for the treatment of pulmonic, mitral, aortic, and tricuspid stenosis. Percutaneous mitral balloon valvuloplasty (PMV) has been used successfully as an alternative to open or closed surgical mitral commissurotomy in the treatment of symptomatic rheumatic mitral stenosis. PMV produces good immediate hemodynamic outcome, low complication rates, and clinical improvement in the majority of patients. PMV is safe and effective and provides clinical and hemodynamic improvement in rheumatic mitral stenosis. PMV is the preferred form of therapy for relief of mitral stenosis for a selected group of patients with symptomatic mitral stenosis. PMID- 28582068 TI - Percutaneous Treatment of Mitral Regurgitation: The MitraClip Experience. AB - The MitraClip device is a percutaneous catheter-delivered, implantable clip that reduces mitral regurgitation by approximating the edges of the mitral leaflets, creating an "edge-to-edge" repair. The MitraClip is the first percutaneous technology developed to provide a minimally invasive option for patients at high risk for traditional mitral valve surgery. Although percutaneous repair was less effective at reducing mitral regurgitation than conventional surgery in the EVEREST randomized trial, the procedure was associated with superior safety and similar improvements in clinical outcomes. Older, high-risk or inoperable patients with functional or degenerative mitral regurgitation seem to benefit most from this therapy. PMID- 28582069 TI - Percutaneous Treatment of Primary and Secondary Mitral Regurgitation: Overall Scope of the Problem. AB - Mitral regurgitation is a heterogeneous disorder requiring the understanding of complex mitral anatomy and pathophysiology. Advanced imaging has furthered our knowledge and ability to treat patients with this disorder. As the demand for less invasive treatment increases, a multitude of percutaneous options have emerged. This review is written for interventionalists to fully appreciate the overall scope of the problem of mitral regurgitation. Understanding and integrating mitral anatomy with pathophysiology, multimodality imaging, and current transcatheter mitral therapies are paramount for treating this disorder. PMID- 28582070 TI - Percutaneous Techniques for the Treatment of Patients with Functional Mitral Valve Regurgitation. AB - Percutaneous approaches to mitral regurgitation remain largely investigational. In the last decade, novel percutaneous strategies have opened new options in the treatment of valvular heart disease. Several studies are currently underway to determine the benefits of transcatheter mitral valve repair therapy. Transcatheter chordal procedures are being developed, including chordal cutting and chordal implantation. Transcatheter valve implantation in the mitral position might offer a desirable alternative in selected patients and has been accomplished in a compassionate fashion on rare occasions in patients who are not candidates for surgical valve repair or replacement. PMID- 28582071 TI - A New Review Periodical, Interventional Cardiology Clinics. PMID- 28582072 TI - History and Physical Examination in Diagnosis of Peripheral Artery Disease. AB - Peripheral artery disease (PAD) may be silent or present with an assortment of symptoms and signs suggesting peripheral artery ischemia. Peripheral vascular disease includes PAD and disorders of the peripheral venous system and lymphatic system. Generally, PAD is synonymous with arteries of the limbs and pelvis, but it can be expanded to include the renal arteries, carotid arteries, mesenteric arteries, and the aorta. It is imperative to recognize and treat PAD early, as appropriate management of PAD can help avoid devastating complications such as limb amputation and death. PMID- 28582073 TI - Noninvasive Testing in Peripheral Arterial Disease. AB - Most patients suspected of having peripheral arterial disease should undergo noninvasive vascular testing to confirm the diagnosis, and to determine the severity and extent of the disease. This article reviews practical aspects of commonly used noninvasive tests for lower extremity peripheral arterial disease, including the ankle-brachial index, segmental limb pressures, pulse volume recordings, duplex ultrasonography, computed tomography angiography, and magnetic resonance angiography. PMID- 28582074 TI - Endovascular Management of Brachiocephalic Disease. AB - Brachiocephalic disease can pose important clinical risks and manifestations. Most of these lesions are amenable to endovascular treatment. However, these treatments have significant risks and require modified procedural techniques. All interventions require a careful preprocedural evaluation and consultation. These endovascular interventions should be performed by experienced operators with extensive previous carotid and endovascular experience in appropriate adequately equipped venues. Most brachiocephalic disease also has surgical options for treatment. This article presents guidelines to assist experienced operators to perform these procedures with proper technique after using good clinical judgment. PMID- 28582075 TI - Management of Mesenteric Ischemia. AB - Acute mesenteric ischemia is associated with a high mortality rate and requires emergent evaluation and surgical management. However, patients with chronic mesenteric ischemia can undergo either surgical or endovascular revascularization. Review of recent medical literature suggests lower rates of mortality and complications after endovascular revascularization, but higher rates of primary patency after surgical revascularization. The decision regarding method of revascularization in patients with chronic mesenteric ischemia should be based on the patient's vascular anatomy, comorbidities, and life expectancy. PMID- 28582076 TI - Management of Renal Arterial Disease. AB - Severe atherosclerotic renal artery stenosis can manifest as treatment-resistant hypertension, ischemic nephropathy and/or cardiac disturbance syndromes of recurrent flash pulmonary edema and refractory angina. Renal artery revascularization can dramatically impact patient outcome. However, patient selection for revascularization can be challenging. Renal artery stenting is most commonly used for renal revascularization and is a safe procedure when performed in carefully selected patients. This review addresses the pathophysiology of renal artery stenosis and the data supporting revascularization in such patients. PMID- 28582077 TI - Contemporary Management of Femoral Popliteal Revascularization. AB - Symptomatic peripheral artery disease of the femoral popliteal segment can be treated by surgical and endovascular revascularization, but controversy exists about the best approach. Conventional approaches to revascularization have focused on lesion anatomy to decide on bypass versus endovascular treatment, but advances in endovascular therapy make an endovascular-first approach increasingly feasible-either as a single approach or as an adjunct to short-segment bypass (ie, hybrid procedure). In this review, we discuss the medical, endovascular, and surgical treatment of femoral popliteal revascularization with a special emphasis on advances in percutaneous therapy. PMID- 28582078 TI - Management of Atherosclerotic Aortoiliac Occlusive Disease. AB - Development of aortoiliac occlusive disease (AIOD) is associated with classic risk factors for atherosclerotic disease such as hyperlipidemia, hypertension, diabetes, or smoking. Risk factor modification, smoking cessation, and prevention of cardiovascular events remain the cornerstones of AIOD management. Symptom improvement and limb loss prevention are considered secondary goals of therapy. Continuous technological advances, new devices, as well as new revascularization techniques are constantly changing the landscape of AIOD management. Surgical interventions, which were considered a gold standard therapy for nearly 50 years, currently give way to newer and less invasive endovascular techniques. PMID- 28582079 TI - Management of Aneurysmal Disease of the Aorta. AB - Aneurysm of the aorta is largely a disease of the elderly. The incidence/prevalence of the disease has steadily increased in recent times, mainly because of the increase in awareness among patients/physicians and better imaging modalities. Early diagnosis and treatment of this disease holds the key to success and plays a part in prevention of catastrophic complications. With advancements in endovascular and surgical innovations, repair of aneurysmal disease has made significant progress, translating into better survival and long term benefits. However, with significant morbidity and mortality associated with this disease, there is still a need for further research. PMID- 28582080 TI - Acute Limb Ischemia. AB - Acute limb ischemia is a vascular event presenting with sudden decrease in limb perfusion (of <14 days' duration) that threatens limb viability. Acute thrombosis of the native artery or graft makes up the bulk of etiopathogenesis. Prompt revascularization is the cornerstone of management of acute limb ischemia in limbs that have not undergone irreversible tissue and nerve damage. Amputation is performed in patients with irreversible tissue and nerve damage. PMID- 28582081 TI - Management of Infrapopliteal Arterial Disease: Critical Limb Ischemia. AB - According to the TransAtlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease, "there is increasing evidence to support a recommendation for angioplasty in patients with critical limb ischemia and infrapopliteal artery occlusion." Management of infrapopliteal artery disease starts with diagnosis using modern preprocedural noninvasive and invasive imaging. Interventionalists need to learn the role of chronic total occlusion cap analysis and collateral zone recognition in angiosome-directed interventions for management of critical limb ischemia and be familiar with equipment and device selection and a stepwise approach for endovascular interventions. Interventionalists need to know which crossing tools to use to successfully cross complex chronic total occlusion caps. PMID- 28582082 TI - Chronic Venous Insufficiency. AB - Varicose veins are a common manifestation of chronic venous disease and affect approximately 25% of adults in the western hemisphere. The historical standard treatment has been surgery, with high ligation and stripping, combined with phlebectomies. In the past decade, alternative treatments such as endovenous ablation of the great saphenous vein (GSV) with laser, radiofrequency ablation, and ultrasonography-guided foam sclerotherapy have gained popularity. Performed as office-based procedures using tumescent local anesthesia, the new minimally invasive techniques have been shown in numerous studies to obliterate the GSV, eliminate reflux, and improve symptoms safely and effectively. PMID- 28582083 TI - Endovascular Treatment of Deep Vein Thrombosis. AB - Venous thromboembolism (VTE) is associated with substantial morbidity and mortality. Conventional treatment with anticoagulation therapy may undertreat the condition. Patients with VTE are at risk for recurrence with increasing time passage. Endovascular approaches exist for treating VTE, including deep vein thrombosis, but it is unclear which patients are appropriate candidates for endovascular versus medical approaches. Many new endovascular technologies are in development, and new oral anticoagulants are also on the market. Clinicians must be mindful of these new products and use them appropriately to better manage VTE. PMID- 28582086 TI - Peripheral Artery Disease. PMID- 28582089 TI - An Approach to Asymptomatic and Atypically or Typically Symptomatic Women with Cardiac Disease. AB - The evaluation of women who are asymptomatic or presenting for evaluation of stable cardiac disease symptoms has been the focus of much research in the past decade. The rationale for this research has been that fatality rates for coronary heart disease remain higher for women than men. Detection of high-risk populations is a core component of targeted therapeutic risk reduction and is a valuable way to identify women who may benefit from early intervention that could result in improved clinical outcomes. This article discusses the evidence on assessment of women with and without suspected cardiac symptoms. PMID- 28582090 TI - Revascularization Strategies in Women with Stable Cardiovascular Disease: What do the Trials Reveal? AB - Cardiovascular disease (CAD) is the leading cause of death worldwide in both women and men. Although the prevalence of CAD is less in women, those women affected by CAD die more often than men. Women are underrepresented in cardiovascular studies, making it difficult to determine the outcomes of different revascularization strategies. This review summarizes the current data on gender outcomes for percutaneous coronary intervention and coronary bypass grafting. PMID- 28582091 TI - Interventional Management of ACS in Women: STEMI and NSTEMI. AB - Acute coronary syndromes and ST elevation myocardial infarction are a major cause of cardiovascular morbidity and mortality in women. However, emerging data now suggest that the poorer outcomes of women undergoing percutaneous intervention may have less to do with differing vascular biology between males and females or the technical challenges of their coronary anatomy, but more with risk factors, such as age and comorbidities. Nevertheless, females have clearly been underrepresented in clinical trials, and further efforts are now required to properly define effective ways to tackle the risk-factor burden and clinical outcomes in women presenting to the catheterization laboratory. PMID- 28582092 TI - The Generations of Drug-Eluting Stents and Outcomes in Women. AB - Drug-eluting stents have become one of the mainstays of percutaneous coronary artery revascularization. Since their introduction, there have been many developments in this technology including the optimization of the stent platform, novel polymer coatings, and antiproliferative drugs. Although cardiovascular disease is the leading cause of death in women, the prevalence of obstructive coronary artery disease is lower, and women comprise a minority of patients included in clinical trials assessing the performance of drug-eluting stents. This article reviews the advances in drug-eluting stent technology and the studies reporting outcomes in women after implantation of these stents. PMID- 28582093 TI - PCI Outcomes in High-Risk Groups (Diabetes Mellitus, Smoker, Chronic Kidney Disease and the Elderly). AB - Ischemic heart disease remains the leading cause of morbidity and mortality in both genders in developed countries. Many women underestimate the effect of coronary artery disease on their health and as a result, the female population tends to be under-investigated for symptoms, with less-aggressive treatment approaches, leading to perceived worse outcomes in this group. Many assumptions about women are from studies where the female population is under-represented and in trials that do not account for gender differences. This article discusses percutaneous coronary intervention in high-risk groups and whether such a gender difference exists. PMID- 28582094 TI - Vascular Complications in Women and the Radial Approach. AB - Compared with medical therapy, percutaneous coronary intervention (PCI) is associated with higher bleeding rates and more vascular complications. Although the rate of complications is decreasing, female sex continues to be an independent risk factor. Radial access for PCI is as effective as femoral access but is associated with significantly fewer bleeding and vascular complications. Although women are at higher risk for bleeding and vascular complications than their male counterparts, the use of radial access has decreased the complications to a level in the which the difference becomes minimal. More quality improvement studies are needed to identify strategies for reducing complications in this high risk population. PMID- 28582095 TI - Is Stenting an Appropriate Therapy in Women Presenting with Acute Coronary Syndrome? A Pathologist's Perspective. AB - It has been more than 3 decades since the introduction of percutaneous transluminal coronary angioplasty for the treatment of coronary artery disease, and the introduction of bare metal stents and drug-eluting stents (DES) has significantly improved clinical outcomes by decreasing rates of acute vessel closure and restenosis. This article reviews pathologic findings from male and female patients who had received coronary stents for acute coronary syndrome and died suddenly with or without complications of stent implantation, at early (<30 days) and late (>30 days) time points after DES implantation. PMID- 28582096 TI - Does Gender have an Influence on Platelet Function and the Efficacy of Oral Antiplatelet Therapy? AB - The underlying pathophysiology of ischemic complications during acute coronary syndrome involves thrombus generation at sites of plaque rupture and endothelial erosion, in which platelet activation and aggregation play major roles. This review discusses whether there are intrinsic differences in thrombogenicity between genders. In trials of acute coronary syndromes with dual antiplatelet therapy strategies, women tend to experience more ischemic events. Controversy exists surrounding the protective role of estrogens in the premenopausal woman. In vitro studies support the attenuation of platelet function by estrogen. Sufficient data support the presence of gender differences in thrombogenicity to promote further investigation in this area. PMID- 28582097 TI - Cardiogenic Shock in Women. AB - Cardiogenic shock (CS) describes the physiologic state in which reduced cardiac output and resultant tissue hypoxia occur in the presence of adequate intravascular volume. Among patients hospitalized with myocardial infarction (MI), CS is the foremost cause of death. Women are more susceptible to CS than men in the setting of ST segment increase MI. Introduction of early revascularization strategies and mechanical ventricular support have seen a decrease in short-term mortality from CS. However, the prognosis following CS remains poor. This article examines the prevalence, causes, pathophysiology, and therapeutic options for CS among women. PMID- 28582098 TI - Percutaneous Valve Therapy: Choosing the Appropriate Patients and Outcomes. AB - Surgical aortic valve replacement (SAVR) is the current gold standard for the treatment of severe symptomatic aortic stenosis (AS), but transcatheter aortic valve implantation (TAVI) currently represents a viable alternative to conventional SAVR for patients with AS at high risk of operative mortality. On multivariate analysis it has been shown that female gender is independently associated with better recovery of the left ventricular systolic function after TAVI and that left ventricular hypertrophy reverses more frequently in female patients after SAVR. During follow-up, however, women remain significantly more symptomatic compared with men, mainly because they present with more advanced valve disease at a significantly older age. PMID- 28582099 TI - Future Perspectives on Percutaneous Coronary Interventions in Women. AB - In the United States alone, more than 1 million cardiac catheterizations are performed each year, with approximately 600,000 patients undergoing percutaneous coronary intervention (PCI). A meaningful perspective on the future of PCI in women requires not only reflection on some of the major developments in interventional cardiology but also a look back more generally at the changing patterns in the burden of coronary disease in the population and at the gains accrued in understanding and combating cardiovascular disease in women. PMID- 28582100 TI - Coronary Artery Disease in Women: Shyly Bold? PMID- 28582101 TI - Cardiogenic Shock: Background, Shock Trial/Registry, Evolving Data, Changing Survival, Best Medical Therapy. AB - Cardiogenic shock remains associated with unacceptably high mortality, but recent improvements with early revascularization, continued support with pharmacologic agents, and use of an intra-aortic balloon pump have led to improvements in the rate of mortality. Timely intervention with cardiac surgery in patients with mechanical complications, 3-vessel disease, and left main disease is beneficial. Continued research and ever-improving understanding of this once deadly condition have helped further in improving prognosis. Cutting-edge technologies, such as myocyte cell implantation and the use of a cooling system, will help in pushing the boundaries farther. PMID- 28582102 TI - Hemodynamic Support: Science and Evaluation of the Assisted Circulation with Percutaneous Assist Devices. AB - Pathophysiologic mechanisms that lead to hemodynamic abnormalities in cardiogenic shock (including hypotension, hypoperfusion, and elevated venous pressures) are reviewed within the framework of pressure-volume analysis. This approach provides the foundation for understanding how different modes of circulatory support impact key these cardiovascular parameters in various clinical settings. Four fundamentally different modes of circulatory support are reviewed, including aortic counterpulsation, left atrial-to-arterial pumping, right atrial-to arterial pumping, and left ventricular-to-aortic pumping. Each approach has a distinct hemodynamic fingerprint with regard to effects on the ventricular pressure-volume loop and key hemodynamic and metabolic parameters. PMID- 28582103 TI - Usage of Percutaneous Left Ventricular Assist Devices in Clinical Practice and High-risk Percutaneous Coronary Intervention. AB - Patients who require coronary revascularization and present with poor left ventricular function and complex coronary anatomy are at high risk for percutaneous coronary intervention (PCI) and coronary artery bypass grafting surgery. Some of these patients are poor surgical candidates because of previous cardiac surgery or significant comorbidities. The recent approval and availability of percutaneous left ventricular assist devices has created an opportunity for the highest risk patients. This article reviews currently available mechanical circulatory support systems and portable extracorporeal oxygenation, describing hemodynamic and physiologic rationales, indications, strategies, and available evidence for their use in high risk PCI. PMID- 28582104 TI - Percutaneous Assist Device for Cardiopulmonary Resuscitation. AB - Persistent cardiac arrest is often caused by coronary ischemia. Urgent revascularization during on-going resuscitation with the support of percutaneous left ventricular assist devices (PVAD) may be feasible and can have the potential to improve the prognosis. Transport during resuscitation is a challenge that may be overcome with the use of cardiopulmonary resuscitation devices. In the catheterization laboratory, rapid deployment of PVAD may reduce ischemia, contribute to electrical stabilization of the heart, and facilitate definite treatment with percutaneous coronary intervention. After revascularization, PVAD therapy may promote myocardial recovery and improve vital organ perfusion in a critical phase. PMID- 28582105 TI - Percutaneous Circulatory Assist Devices for Right Ventricular Failure. AB - Heart failure is a major cause of global morbidity and mortality affecting nearly 24 million individuals worldwide. Although the importance of right ventricular (RV) function has become more apparent over the past few decades, few therapies specifically target RV failure. Over the past 3 decades, significant advances in percutaneously delivered circulatory support devices has led to the recent development of devices specifically designed for RV failure. In this review, RV pathophysiology, device options, and clinical data exploring the utility of percutaneous RV support devices are discussed. PMID- 28582106 TI - Percutaneous Assist Devices for Left Ventricular Shock. AB - Percutaneous ventricular assist devices (PVADs) are increasingly being used for hemodynamic support in patients with cardiogenic shock as well as for patients undergoing high-risk cardiovascular procedures. The currently available PVADs for left ventricular shock are reviewed; the evidence for supporting PVAD use is discussed, and the authors' perspective on their unique clinical applications is offered. PMID- 28582107 TI - Percutaneous Assist Devices for Infarct Size Reduction. AB - Improving myocyte salvage during acute myocardial infarction (AMI) has proved elusive; the keys to success seem to be the ability to lower oxygen demand of ischemic myocardium and also activate salvage enzyme pathways to take advantage of endogenous cardioprotective mechanisms. Pharmacologic approaches have been largely unsuccessful. A percutaneous left ventricular (LV) assist device could improve myocyte salvage during AMI therapy if it were able to reduce myocardial oxygen demand, wall tension, and LV stroke work substantially. PMID- 28582108 TI - Future Directions for Percutaneous Mechanical Circulatory Support Devices. AB - Outcomes of patients in cardiogenic shock remain high, but the development of novel percutaneous mechanical circulatory support devices offers additional therapeutic options. Hand in hand with innovations in device technology, however, must also come development of integrated circulatory support networks focusing on rapid assessment of patients, multidisciplinary discussion, and timely therapeutic intervention. This article summarizes some of the recent developments in device technology; potential procedures for patient risk stratification, device selection, and response to therapy; management of vascular access to reduce insertion point complications; and some of the expanding potential roles of percutaneous mechanical circulatory support devices. PMID- 28582111 TI - Percutaneous Mechanical Support. PMID- 28582117 TI - Risk Assessment in Patient Selection for Transcatheter Aortic Valve Replacement. AB - Risk assessment models for transcatheter aortic valve replacement (TAVR) versus surgical aortic valve replacement in high-risk patients and TAVR versus palliation in inoperable patients are based on surgical data and have limited discrimination and calibration in the setting of TAVR. Several novel risk models specifically designed for TAVR have improved discrimination over existing models but require further validation. Several clinical and echocardiographic variables, such as chronic lung disease, mitral regurgitation, and stroke volume index, influence outcomes. This article reviews current and novel risk models and important predictors of TAVR outcomes and proposes a framework to integrate them into clinical decision-making for patients with severe, symptomatic aortic stenosis. PMID- 28582118 TI - Valve-in-Valve Therapy for Failed Surgical Bioprosthetic Valves: Clinical Results and Procedural Guidance. AB - With improved life expectancy and increased use of bioprosthetic heart valves, more elderly and frail patients present with degenerative surgical heart valve disease. The valve-in-valve procedure is an attractive alternative to a conventional open redo procedure. Although it is a novel extension of established transcatheter aortic valve implantation for severe aortic stenosis in a high-risk population, it is gaining momentum worldwide, particularly for aortic and mitral positions. Success depends on the operator being familiar with emerging transcatheter heart valve technology and morphology as well as that of the existing surgical heart valve, patient selection, accurate sizing, an ideal implantation position. PMID- 28582119 TI - Management of Coronary Disease in the Era of Transcatheter Aortic Valve Replacement: Comprehensive Review of the Literature. AB - Among the cohort of complex and multifaceted patients undergoing transcatheter aortic valve replacement (TAVR), the prevalence of coronary artery disease (CAD) ranges from 48% to 75%. However, optimal management of CAD in this setting has not been established. This article provides a comprehensive review of the literature to depict the actual knowledge on the subject of aortic stenosis and concomitant CAD. This article also aids heart teams in their decision-making process to appropriately manage these challenging patients with aortic stenosis and CAD. Upcoming randomized studies will clarify the influence of CAD, the best timing for percutaneous coronary intervention, and its impact on TAVR results. PMID- 28582120 TI - Imaging the Aortic Annulus with Multi-Detector Computed Tomography and 3 Dimensional Transesophageal Echocardiography. AB - Degenerative aortic stenosis is the most common cause of valvular heart disease in Western nations. Transcatheter aortic valve replacement (TAVR) is an alternative therapy for inoperable or high-risk patients with symptomatic severe aortic stenosis. Three-dimensional imaging techniques provide multiplanar imaging, allowing precise measurements of the noncircular aortic annulus and complex anatomy of the aortic root. These measurements influence patient eligibility, allow adequate prosthesis sizing, and determine the success of implantation and likelihood of complications. This review compares imaging modalities and addresses their strengths and weaknesses to assess the aortic annulus and other aortic root structures. PMID- 28582121 TI - The Role of Preoperative and Intraoperative Imaging in Guiding Transcatheter Aortic Valve Replacement. AB - Optimal intraprocedural imaging is central to transcatheter aortic valve replacement (TAVR). Familiarity with commonly used modalities is necessary. Real time, intraprocedural imaging is provided by fluoroscopy and echocardiography to ensure proper valve position and deployment, and to assess for postdeployment complications. By providing anatomic information to real-time fluoroscopy, fusion imaging has the potential to positively affect TAVR. As newer generation valves are introduced and as TAVR is potentially offered to lower risk patient populations, it will be important to ensure that improvements in intraprocedural imaging lead to better outcomes. PMID- 28582122 TI - Assessment of Paravalvular Regurgitation Following Transcatheter Aortic Valve Replacement. AB - Paravalvular regurgitation (PVR) following transcatheter aortic valve replacement is a known complication associated with poorer outcomes. This article discusses the current techniques for assessing the severity of PVR, including angiography, hemodynamics, MRI, and echocardiography. The strengths and pitfalls of each modality are reviewed. PMID- 28582123 TI - Impact and Management of Paravalvular Regurgitation After Transcatheter Aortic Valve Replacement. AB - Paravalvular regurgitation (PVR) is a frequent complication of transcatheter aortic valve replacement that has been shown to be associated with increased mortality. The objective of this article was to review the most up-to-date information about the impact and management of PVR. A multimodality, multiparametric, integrative approach including angiography, Doppler echocardiography, and/or cardiac MR is essential to accurately assess the severity of PVR and the underlying etiology. Corrective procedures such as balloon postdilation, valve-in-valve, or leak closure may be considered, depending on the severity, location, and etiology of PVR. PMID- 28582124 TI - Neurologic Events After Transcatheter Aortic Valve Replacement. AB - Early trials involving transcatheter aortic valve replacement raised concerns for an elevated risk of neurologic events compared to surgical AVR. Contemporary studies suggest declining rates with better patient selection, improved operator experience, and newer generation devices. Events are usually embolic in nature, occur in the periprocedural period, and can lead to increased morbidity and mortality. Current investigations are focused on developing embolic protection devices for intraprocedural use and optimizing antiplatelet and anticoagulant regimens. These efforts aim to further reduce the incidence of stroke, which is particularly important as the technology expands to include intermediate and possibly low surgical risk populations. PMID- 28582125 TI - Nontransfemoral Approaches to Transcatheter Aortic Valve Replacement. AB - Transcatheter aortic valve replacement (TAVR) is noninferior to surgical aortic valve replacement in patients with high operative risk and superior to medical treatment in patients deemed unsuitable for surgical intervention. However, up to 30% to 50% of patients screened for this intervention are not candidates for TAVR via the preferred transfemoral route because of severe peripheral arterial disease. Alternative access routes must be considered and include the transapical, transaortic, transsubclavian, and transcarotid approaches. The use of alternative access is predicated on appropriate patient selection as determined by a dedicated multispecialty heart valve team and can lead to excellent outcomes. PMID- 28582129 TI - Transcatheter Aortic Valve Replacement. PMID- 28582132 TI - Pathology of Saphenous Vein Grafts. AB - Saphenous vein grafts (SVGs) are the most used conduits in coronary artery bypass graft (CABG) surgery; however, they are susceptible to accelerated atherosclerosis. Clinical studies have shown 10-year patency rates of SVG can be as low as 50% to 60%. This article highlights changes that are observed following CABG surgery using SVG, including intimal thickening to the development of atherosclerotic changes, and how these changes in vein graft are different from those observed in native atherosclerosis. It also discusses the role of risk factors that contribute to acceleration of SVG atherosclerosis. PMID- 28582133 TI - Natural History of Saphenous Vein Grafts. AB - Aortocoronary saphenous vein graft is an effective treatment of coronary artery disease and a means of markedly improving long-term prognosis in certain patient subgroups. However, there is a significant failure rate with these conduits. Early failure occurs within the first 1-2 months, most likely from primary thrombosis. Intermediate failure is usually caused by the development of neointimal hyperplasia. Late failure occurs after 3-5 years and results from accelerated atherosclerosis. The impact of saphenous vein graft failure on cardiovascular outcomes is significant, and it is important to implement appropriate therapeutic strategies to prevent or minimize failure rates. PMID- 28582134 TI - Embolic Protection Devices for Saphenous Vein Graft Percutaneous Coronary Interventions. AB - Saphenous vein graft (SVG) percutaneous coronary interventions (PCIs) are associated with adverse clinical events caused by distal embolization in 10% to 20% of cases. Various embolic protection devices (EPDs) have been developed to lower the risk of distal embolization during SVG PCI: distal balloon occlusive devices, distal embolic filters, and proximal balloon occlusive devices. Despite evidence for improved outcomes and cost-effectiveness, rates of national EPD use remain low, the main cause of underutilization being operator preference. With increasing familiarity of operators with EPDs, their use should continue to increase in SVG PCI and lead to better outcomes. PMID- 28582135 TI - Pharmacotherapy During Saphenous Vein Graft Intervention. AB - Coronary revascularization using saphenous vein grafts is an important treatment modality for patients with severe coronary artery disease. Percutaneous intervention of these grafts is often the best option for patients who develop severe stenosis of the vein grafts. Use of adjunctive glycoprotein IIb/IIIa inhibitors does not confer added benefit with ischemic endpoints as compared with heparin alone, but it increases the risk of bleeding. Bivalirudin used as the primary anticoagulant lowers the risk of bleeding. No-reflow frequently complicates vein graft interventions but can be treated with vasoactive agents such as calcium channel blockers, adenosine, and nitroprusside. PMID- 28582136 TI - Drug-Eluting Stents Versus Bare Metal Stents in Saphenous Vein Graft Intervention. AB - Percutaneous coronary intervention (PCI) of saphenous vein graft (SVG) is associated with higher adverse event rates, lower procedural success, and inferior longterm patency rates compared with native vessel PCI. The ability to comply with dual antiplatelet therapy, and whether the patient will need an interruption in dual antiplatelet therapy, should be considered when deciding whether to implant a drug-eluting stent (DES) or bare metal stent (BMS) in an SVG. DES should be used for SVG PCI because they seem to reduce target vessel revascularization. This article reviews the evolution and contemporary evidence regarding use of DES versus BMS in SVG PCI. PMID- 28582137 TI - Optimal Stenting in Saphenous Vein Graft Intervention. AB - Percutaneous interventions of (usually degenerated) saphenous vein grafts (SVG) are associated with higher risk of distal embolization and worse clinical outcomes, including target vessel revascularization, myocardial infarction, and death, as compared with percutaneous coronary intervention of native coronary arteries. Embolic protection devices have demonstrated value in reducing the risk of embolization and postprocedural enzyme elevation after SVG interventions. Frequently, however, such devices are not used or cannot be used. As a result, novel stenting strategies intended to decrease the risk of periprocedural myocardial infarction seem to play a major role in enhancing the results following SVG interventions. PMID- 28582138 TI - Intervention of Saphenous Vein Graft Chronic Total Occlusion. AB - Interventions on vein graft occlusions are technically feasible procedures but carry significant risk for periprocedural complications and demonstrate questionable long-term patency. For those circumstances in which recanalization of a graft occlusion is warranted, the authors have highlighted some of the procedural considerations and available techniques that may help maximize chances for success. This should not be mistaken for a wholesale endorsement of vein graft chronic total occlusion interventions. Before undertaking a procedure of this complexity, the operator must put strong consideration into the risks, benefits, and alternatives for a given patient. PMID- 28582140 TI - Management of Complications During Saphenous Vein Graft Interventions. AB - Because of greater patient comorbidities, more diffusely diseased vessels, and the greater possibility of mechanical complications, saphenous vein graft interventions are fraught with complications. The greatest risk is a higher risk of periprocedural myocardial infarction due to distal embolization of microemboli. The risk for noreflow in a patient with concomitant native critical vessel disease can have grave consequences. Minimizing the risk of periprocedural myocardial infarction with the use of distal embolic protection, understanding the role of adjunctive pharmacotherapy, and learning how to manage less common but serious mechanical complications during saphenous vein graft interventions are important to ensure optimal patient outcomes. PMID- 28582139 TI - Degenerated Saphenous Vein Graft Intervention: Should We Target the Native Vessel instead? AB - Coronary interventions of degenerated saphenous vein grafts (SVGs) continue to present a management challenge. Although repeat coronary artery bypass grafting (CABG) remains a significant risk factor for operative mortality, percutaneous coronary intervention (PCI) is still associated with a high risk for periprocedural events. There is a lack of consensus on the optimal treatment strategy for patients with severe stenosis of SVGs. It is imperative to review the characteristics of native versus SVG disease, risk factors for complications after SVG intervention, procedural treatment strategies important to the decision on which therapeutic strategy to follow, and measures to mitigate the risks of periprocedural complications. PMID- 28582141 TI - Thrombectomy Devices in Coronary Intervention. AB - Primary percutaneous coronary intervention is the favored mode of reperfusion therapy for ST-elevation myocardial infarction (STEMI) when able to be performed in a timely fashion in appropriately selected patients. However, controversy about the role of coronary thrombectomy in the management of STEMI persists because of a paucity of favorable historical data. After the TAPAS trial thrombectomy has gained favor in recent years. The results of the TOTAL, TASTE, and SMART percutaneous coronary intervention trials will provide further insight into the use of thrombectomy in STEMI. This article examines the relevant trial evidence regarding how to best manage and apply thrombectomy in clinical practice. PMID- 28582142 TI - Utility of Thrombectomy in Primary Percutaneous Coronary Intervention. AB - Thrombectomy in the setting of primary percutaneous coronary intervention allows for improved macrovascular and microvascular perfusion, possible limitation of infarct size, and the preservation of left ventricular function and myocardial viability. The beneficial tissue level effects of thrombectomy have translated into an improvement in cardiovascular mortality. A variety of thrombectomy devices are currently available, including aspiration thrombectomy catheters and rheolytic catheters. A review of the various types of thrombectomy devices available, clinical evidence for their use, clinical pearls for use, and device troubleshooting are presented. PMID- 28582143 TI - Adjunctive Pharmacotherapy for Thrombotic Coronary Lesions. AB - Patients with unstable coronary syndromes are often found to have intracoronary thrombus on angiography. Despite advancements in catheter-based treatments for coronary disease, these lesions remain challenging, as percutaneous coronary intervention of thrombus-containing lesions may be associated with worse outcomes. This article reviews the literature on adjunctive pharmacotherapy in the treatment of thrombotic coronary lesions with special focus on ST-segment elevation myocardial infarction, lesions with high thrombus burden, and saphenous vein graft intervention. PMID- 28582144 TI - Saphenous Vein Graft Stenosis and Thrombotic Lesions in Acute Myocardial Infarction. PMID- 28582145 TI - Primary Stroke Prevention: Medical Therapy Versus Revascularization. AB - Asymptomatic carotid-artery atherosclerotic vascular disease identifies patients at heightened risk of major adverse cardiovascular events including ischemic stroke. Observational and registry analyses demonstrate that this risk extends beyond that attributable to carotid atherosclerosis itself and includes events manifesting in other vascular territories, such as myocardial infarction. However, randomized trials aimed specifically at treating carotid stenosis have shown benefit in terms of reducing ischemic stroke in appropriately selected patients. Therefore, the approach to primary prevention in patients with stable carotid disease must include a comprehensive strategy to reduce cerebrovascular specific and overall cardiovascular risk through lifestyle changes and intensive medical therapies. PMID- 28582146 TI - Complications and Solutions with Carotid Stenting. AB - Complications of carotid stenting can be classified as neurologic, cardiovascular, death, carotid, access site, device malfunctions, and general and late complications. The risk of most complications is related to readily identifiable patient and anatomic factors. Management and outcome of complications require immediate recognition and a team-based approach to patient care. PMID- 28582147 TI - Percutaneous Treatment of Vertebral Artery Stenosis. AB - Endovascular treatment of the ostial and proximal portions of the vertebral artery is a safe and effective technique for alleviating symptoms and improving cerebral blood flow to the posterior circulation. Vertebral artery angioplasty can be performed with high technical and clinical success rates, low complication rates, and durable long-term results. Although restenosis rates range from 0% to 48%, the durability of vertebral artery angioplasty is evidenced by low restenosis rates in multiple large series reported in the literature using multiple treatment options, including balloon angioplasty alone, bare metal stents, and drug-coated stents. PMID- 28582148 TI - Common Cervical and Cerebral Vascular Variants. AB - Successful open and endovascular carotid artery intervention depends on a thorough foundational knowledge of cervical and intracranial vascular anatomy. It is essential for the carotid interventionist to be familiar with the common and rare variants of the cervical and intracranial vasculature, and to understand the implications of these variants for the performance of carotid intervention with protection of the distal circulation. This article provides interventionists with a basic description of the normal and relevant variant vascular anatomy from the aortic arch to the circle of Willis, and outlines the potential difficulties that specific variants may present for endovascular therapy. PMID- 28582149 TI - Non-Invasive Carotid Imaging: A Comparative Assessment and Practical Approach. AB - Stroke originating from carotid artery disease remains a significant source of morbidity and mortality, and both medical and invasive therapies targeting the carotid artery can improve patient outcomes. Multiple noninvasive imaging methods, including duplex ultrasonography, computerized tomographic angiography, and magnetic resonance angiography, are available to assess the extracranial carotid artery and guide clinical decision making. This article discusses the advantages and limitations of these imaging modalities and provides a practical framework by which clinicians may use imaging to evaluate patients with carotid artery disease. PMID- 28582150 TI - Percutaneous Treatment of Severe Intracranial Carotid and Middle Cerebral Artery Stenosis. AB - Due to the lack of efficacy and durability data from prospective, randomized, multicenter trials, intracranial stenting remains investigational and should be used only in carefully selected patients after thorough evaluation of their clinical and anatomic factors. Stenting should not be performed in chronic total occlusions and asymptomatic lesions and generally should be avoided in very old patients, especially those with underlying dementia and severe calcification of their vessels. Symptomatic patients with angiographically documented greater than 70% stenosis and who have failed medical therapy are appropriate candidates for intracranial angioplasty and stenting and should be enrolled in clinical trials when possible. PMID- 28582151 TI - Current Reperfusion Strategies for Acute Stroke. AB - Stroke is the most common cause of permanent disability, the second most common cause of dementia, and the third most common cause of death in the Western world. The treatment of affected patients is a challenge because intravenous (IV) thrombolysis is often ineffective. IV thrombolysis on its own leads to a favorable clinical outcome in only 15% to 25% in patients with large-artery occlusion. Current reperfusion therapies enable high recanalization rates, high rate of favorable clinical outcome, and low complication rates. However, to achieve good clinical results, appropriate patient selection and the use of optimized stroke management system are obligate. PMID- 28582153 TI - Skin to Skin: Transradial Carotid Angiography and Stenting. AB - Carotid artery stenting (CAS) is a proven alternative to carotid endarterectomy in patients with significant carotid disease. The femoral artery is the conventional access site for CAS procedures. However, this approach may be problematic because of peripheral vascular disease and anatomic variations. Access site complications are the most common adverse event after CAS from the transfemoral approach (TFA) and most technical failures are related to a complex aortic arch. The transradial approach has been evaluated to address the shortcomings of TFA. In cases involving a complex arch, transradial access may be a viable alternative strategy. PMID- 28582154 TI - Skin to Skin: Transfemoral Carotid Angiography and Stenting. AB - Carotid artery stenting (CAS) has emerged as an attractive alternative to carotid endarterectomy (CEA) for the treatment of carotid artery disease. Several recent trials demonstrate excellent and improving results, even at high risk in CEA patients. Randomized North American trials suggest equivalence of CAS to CEA in high-risk and standard-risk patients. However, these improved CAS results apply only to CAS procedures performed by experienced operators at experienced centers. Furthermore, these improved results are due largely to operators' lessons learned, helping with appropriate case selection. PMID- 28582155 TI - Patient, Anatomic, and Procedural Characteristics That Increase the Risk of Carotid Interventions. AB - Subjective characteristics for increased risk of carotid artery stenting (CAS) have included thrombus-containing lesions, heavily calcified lesions, very tortuous vessels, and near occlusions. More objective high-risk features include contraindications to dual antiplatelet therapy, a history of bleeding complications, and lack of femoral artery vascular access. Variables that increase the risk of CAS complications are attributed to patient characteristics, anatomic features, or procedural factors. Operator and hospital volume affect the risk of complications occurring with CAS. As the complexity and difficulty of CAS patients increases, the need for more highly skilled operators and teams becomes even more necessary to minimize complications. PMID- 28582156 TI - Carotid Artery Stenting Versus Carotid Endarterectomy for Treatment of Asymptomatic Carotid Disease. AB - In patients with asymptomatic carotid artery stenosis the optimal strategy to reduce the risk for stroke remains controversial. Although carotid endarterectomy was traditionally considered the gold standard for revascularization, emerging data suggest that carotid artery stenting is an appropriate alternative in many asymptomatic patients. This article summarizes the evidence base and related controversies regarding carotid endarterectomy versus carotid artery stenting for the revascularization of carotid disease in asymptomatic patients. PMID- 28582157 TI - Surgery Versus Stenting in Symptomatic Patients. AB - Symptomatic carotid artery stenosis is an important cause of stroke with significant morbidity and mortality. Revascularization with carotid endarterectomy reduces the recurrence of stroke and until recently was considered the gold standard of therapy. Carotid artery stenting has emerged as an alternative method of revascularization in both high-risk and standard-risk patients. This review appraises the role of surgery versus stenting for patients with symptomatic carotid stenosis. PMID- 28582158 TI - Carotid Artery Stenting: Operator and Institutional Learning Curves. AB - Despite rapid growth in the frequency that carotid artery stenting (CAS) is performed, there remain concerns regarding the steep learning curve associated with this procedure. This article reviews the evidence base supporting operator and institutional CAS learning curves and discusses their implications for the establishment and maintenance of competencies. Attempts are made to delineate minimum volume thresholds to attain these goals and means to enhance procedural safety without compromising patient access. PMID- 28582162 TI - Preface. PMID- 28582163 TI - Stroke and Bleeding Risks in Patients with Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with a substantial risk of stroke and mortality. Strokes in patients with AF are associated with a greater disability and poorer outcomes than strokes in patients in sinus rhythm. Patients with AF are at increased risk of bleeding, especially if they use anticoagulant therapy. Recent research in the field of anticoagulation has led to development of new anticoagulants for stroke prevention in addition to antiplatelet agents and warfarin. This review discusses the role of AF as a risk factor for stroke and evaluates the role of various schemes for predicting the risk of stroke and bleeding in patients with AF. PMID- 28582164 TI - Embryology and Anatomy of the Left Atrial Appendage: Why Does Thrombus Form? AB - The left atrial appendage (LAA) is a long tubular structure that opens into the left atrium. In patients with atrial fibrillation, the LAA develops mechanical dysfunction and fibroelastotic changes on the endocardial surface. The complex anatomy of the LAA makes it a good site for relative blood stasis. In addition, systemic factors exacerbate the hypercoagulable state, eventually resulting in endothelial dysfunction, release of tissue factor, and production of inflammatory cytokines and oxidative free radicals, and eventually initiating the coagulation cascade. Thus, the LAA is susceptible to thrombus formation and is the most common source of systemic thromboembolism. PMID- 28582165 TI - Rationale for Left Atrial Appendage Exclusion. AB - Left atrial appendage (LAA) is the source of most systemic emboli in patients with atrial fibrillation. Oral anticoagulant therapy reduces stroke risk by two thirds. New oral agents have advantages over warfarin but are associated with bleeding and drug intolerance. Device therapy for atrial appendage ligation or occlusion is an alternative to drug therapy, without the cumulative incidence of bleeding or the need for anticoagulation. In the more than half century since the early reports of surgical LAA excision, the author has added considerable detail to our understanding of the rationale for LAA exclusion, which constitutes the subject of this article. PMID- 28582166 TI - Left Atrial Appendage Closure with Transcatheter-Delivered Devices. AB - Left atrial appendage (LAA) closure with transcatheter-delivered devices is an evolving story of compelling randomized data and the potential to dramatically reduce the incidence of stroke and improve the quality of life among patients with atrial fibrillation. Oral anticoagulation is the standard of care for stroke prevention in atrial fibrillation but falls short of providing an adequate solution to this common threat when considered from efficacy and safety perspectives. The robust series of Watchman device trials has demonstrated the Watchman device to provide stroke prevention efficacy similar to that of warfarin and by extension provides proof of concept of LAA closure. PMID- 28582168 TI - Managing the Left Atrial Appendage in the Era of Minimally Invasive Surgery. AB - Atrial fibrillation (AF) is the most prevalent arrhythmia encountered in clinical practice with greater than 2.2 million people in the United States being affected. Oral anticoagulant therapy has been used to reduce risk of stroke in patients with nonvalvular AF who are at a high risk of thromboembolism. Alternative treatment strategies to prevent thromboembolism have been tested in patients with AF. This article examines the history of left atrial appendage occlusion and the efficacy of the various surgical techniques and provides a brief overview of the minimally invasive surgical strategy adopted to manage the left atrial appendage. PMID- 28582167 TI - Catheter-based Epicardial Closure of the Left Atrial Appendage. AB - This article reviews novel techniques in stroke prevention based on epicardial closure of the left atrial appendage, illustrating the features of the first endo epicardial device currently available and those of devices still in development. It also provides further information about early clinical experience with the endo-epicardial device. PMID- 28582169 TI - Device- and LAA-Specific Characteristics for Successful LAA Closure: Tips and Tricks. AB - Transcatheter left atrial appendage closure for stroke prevention with nonvalvular atrial fibrillation is an emerging alternative to oral anticoagulation. Several devices and approaches have been developed to achieve optimal closure. This article describes in detail the key procedural steps and the tips and tricks required to succeed in this transcatheter technique. The 4 devices covered are the WATCHMAN, AMPLATZER Cardiac Plug, Coherex WaveCrest generation 1.3, and the LARIAT suture delivery device. PMID- 28582170 TI - Role of Transesophageal Echocardiography in Left Atrial Appendage Device Closure. AB - Left atrial appendage (LAA) occlusion or ligation by percutaneously implanted devices is increasingly an alternative management option for atrial fibrillation, particularly for patients who are intolerant or have contraindications for anticoagulation. Echocardiography plays an important part in screening, guidance of implantation, and after-device assessment. Assessment of LAA anatomy suitable for device implantation, thrombus exclusion, guidance of transseptal puncture, localization of catheter, guidance of device deployment, and after-device assessment are all important functions of echocardiography. This article reviews the role of echocardiography in device-based LAA occlusion or ligation. PMID- 28582171 TI - Pericardial Access for LARIAT Left Atrial Appendage Closure. AB - Anterior pericardial puncture requires intimate knowledge of the mediastinal anatomy and careful review of the individual anatomic characteristics of each patient. Familiarity with the procedure's anatomic foundations and with the basic principles of each procedural step are critical, but once this is achieved, the procedure is safe and, in most cases, preferable to a standard inferior puncture. An uncomplicated and properly placed pericardial puncture is the basis of a successful of LARIAT suture delivery device procedure. Operators must master the intricacies of the anterior pericardial puncture before embarking on LARIAT left atrial appendage ligation. PMID- 28582172 TI - Clinical Results with Percutaneous Left Atrial Appendage Occlusion. AB - Closure of the left atrial appendage (LAA) in patients with non-valvular atrial fibrillation is associated with reduction in embolic events. There is an initial hazard associated with closure methodologies; once successful closure is achieved, the results appear to be superior to those of anticoagulation. The evidence base is largely limited to the safety and efficacy of LAA occlusion in patients who are candidates for anticoagulation as well, and the risk/benefit ratio of competing closure technologies has not been determined. LAA occlusion plus antiplatelet therapy seems to have an acceptable therapeutic and safety profile. PMID- 28582178 TI - Approaches to Left Atrial Appendage Exclusion. PMID- 28582173 TI - Prevention and Management of Complications of Left Atrial Appendage Closure Devices. AB - Atrial fibrillation is associated with an ongoing risk of thromboembolic stroke and systemic embolism due to stasis and thrombus formation within the left atrial appendage (LAA). Transcatheter occlusion or ligation of the LAA represents a potential paradigm shift in the management of stroke prevention in at-risk patients with atrial fibrillation. This review summarizes the types and rates of procedural complications that have been observed with LAA occlusion and ligation; describes strategies that can be implemented to minimize these complications; and discusses management approaches that may limit the impact of these complications on long-term morbidity. PMID- 28582179 TI - Basics of Antithrombotic Therapy for Cardiovascular Disease: Pharmacologic Targets of Platelet Inhibitors and Anticoagulants. AB - Arterial thrombus formation is the common pathophysiologic process of cardiovascular disease manifestations, requiring interplay between platelets and coagulation factors. Current platelet inhibitors block the formation of thromboxane A2 and interfer with adenosine diphosphate stimulation mediated by the P2Y12 receptor. Novel antiplatelet agents blocking these and other pathways are under clinical development. Thrombin represents a bridge between platelets and coagulation. Indirect and direct thrombin inhibitors are pivotal in clinical settings. Other key coagulation factors include factors IX and X which are therapeutic targets of current and novel anticoagulants. This article reviews the pathophysiology of arterial thrombosis and current and novel antiplatelet and anticoagulant agents. PMID- 28582180 TI - Balance of Ischemia and Bleeding in Selecting an Antithrombotic Regimen. AB - Complications after percutaneous coronary intervention (PCI) are of 2 types: ischemic and bleeding. This article provides strategies to individualize pharmacologic regimens after PCI based on periprocedural risk assessment. A practical method to assess whether a patient is at risk for ischemic or bleeding complications is the use of risk scores. Patients at a low risk of bleeding benefit from aggressive antithrombotic therapy. Patients at a high risk of bleeding benefit from selective use of antithrombotic agents. As a large number of antithrombotic agents are currently available, individualization of the antithrombotic drug regimes should be considered in every patient. PMID- 28582181 TI - Aspirin, Platelet P2Y12 Receptor Inhibitors, and Other Oral Antiplatelets: Comparative Pharmacology and Role in Elective PCI. AB - Angina pectoris accounts for a large burden of disease worldwide. Antiplatelet agents play a crucial role in inhibiting the platelet response to vascular injury after percutaneous coronary intervention (PCI) for the management of coronary artery disease. Antiplatelet agents are also essential in the longer term, because the metallic structure of stents is inherently thrombogenic. This article examines the use of aspirin, P2Y12 inhibitors, and other oral antiplatelets in the setting of elective PCI. Dual antiplatelet therapy in elective PCI is now standard therapy. The clinical use of novel antiplatelet therapy in the setting requires further evaluation. PMID- 28582182 TI - Role of Parenteral Agents in Percutaneous Coronary Intervention for Stable Patients. AB - Numerous agents are available for anticoagulation during percutaneous coronary intervention (PCI), and various antiplatelet agents are also used. With all of the medications available, an assessment must be made regarding the ischemic risk and risk of bleeding for an individual patient during elective PCI when selecting the optimal medical strategy to support PCI. Whether new antiplatelet medications will enhance or reduce complications when paired with various newer anticoagulant agents requires further investigation. This article summarizes existing data examining the benefits and limitations of the various anticoagulant and antiplatelet medications, and summarizes guidelines for their use. PMID- 28582183 TI - Combination Antithrombotic Management for Non-ST Segment Elevation Acute Coronary Syndromes. AB - Patients with non-ST segment elevation acute coronary syndromes (NSTEACS) are at high risk for subsequent thrombotic events. Combination antithrombotic management with anticoagulant and antiplatelet medications can improve outcomes in these high-risk patients. If an early invasive strategy is planned, unfractionated heparin or bivalirudin are the anticoagulants of choice, whereas in those in whom an early conservative strategy is planned enoxaparin or fondaparinux may be preferred. All patients with NSTEACS should receive aspirin and continue it indefinitely unless they cannot tolerate it. A second antiplatelet agent should be administered both for an early invasive or early conservative strategy. PMID- 28582184 TI - Combination Antithrombotic Management of STEMI with Pharmacoinvasive Strategy, Primary PCI, or Rescue PCI. AB - The mainstay of acute ST segment elevation myocardial infarction (STEMI) emergent management consists of reperfusion therapy combined with antithrombotic treatment. Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy for STEMI. Rescue PCI consists of urgent transfer for PCI of patients with failed fibrinolysis. The pharmacoinvasive strategy consists of administration of fibrinolysis followed by immediate transfer to a PCI-capable hospital for routine early catheterization. This article provides an overview of data and recommendations on primary PCI, rescue PCI, and pharmacoinvasive strategy as well as of the antithrombotic regimens used to support STEMI reperfusion approaches. PMID- 28582185 TI - The Optimal Duration of Dual Combination Antiplatelet Therapy After Stent Implantation and Perioperative Management Issues. AB - Impending risk of stent Thrombosis (ST) after percutaneous coronary intervention (PCI) has mandated post-PCI use of dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor. As the optimal duration of DAPT remains controversial, premature discontinuation of it potentiates the risk of ST, myocardial infarction or death; while use of DAPT itself increases the risk of bleed. Similarly, perioperative DAPT management is still ill defined, where there is higher operative risk of bleed on antiplatelet therapy and higher ST risk during this thrombogenic period if off antiplatelet therapy. Additional clinical investigation is warranted in these fields. PMID- 28582187 TI - The Role of Platelet Function Testing in Risk Stratification and Clinical Decision-Making. AB - Clopidogrel (a widely used second-generation thienopyridine) therapy is associated with an unpredictable pharmacodynamic response whereby approximately 1 in 3 patients will have a high on-treatment platelet reactivity to adenosine diphosphate. High on-treatment platelet reactivity is an established risk factor for ischemic event occurrence in patients undergoing percutaneous coronary intervention. Platelet function testing may have a role in monitoring therapeutic efficacy when clopidogrel is the chosen agent and in safety when more potent drugs are used, especially in patients with high bleeding risk. At this time, it seems most reasonable to assess platelet function in high-risk clopidogrel treated patients. PMID- 28582186 TI - Triple Antiplatelet Therapy and Combinations with Oral Anticoagulants After Stent Implantation. AB - Triple oral anticoagulation or triple antiplatelet therapies may be administered for various reasons. They reduce cardiac complications following percutaneous coronary intervention and stroke or other thromboembolic phenomenon in conditions such as atrial fibrillation. There is an elevated risk of severe bleeding, so it is necessary to balance risk and benefits. Newer oral anticoagulants and antiplatelet drugs may be considered; the number of options is increasing. This article examines triple therapies and the efficacy and safety of combinations of traditional anticoagulant and antiplatelet drugs, and reviews clinical trial data on novel agents. Guidelines to inform clinical decision-making are presented. PMID- 28582188 TI - Pharmacogenomics in Interventional Pharmacology: Present Status and Future Directions. AB - Pharmacogenomics offers the possibility of tailoring a drug to a patient's unique genetic signature, improving the likelihood of clinical efficacy while minimizing risks. Clopidogrel, a platelet P2Y12 receptor inhibitor that forms the cornerstone of dual antiplatelet therapy in patients with unstable coronary artery disease and those undergoing percutaneous coronary intervention, is the first broadly used drug in cardiovascular medicine in which genotyping may help optimize outcomes. This article describes techniques to identify the genetic determinants of drug response, their application (ie, clopidogrel), and the challenges to integration of pharmacogenomics into the practice of interventional cardiology. PMID- 28582189 TI - Antithrombotic Strategies in Endovascular Interventions: Current Status and Future Directions. AB - Despite increasing numbers of endovascular interventions to treat arterial and venous disease, scant level 1 evidence is available regarding the role of antithrombotic and antiplatelet therapy in patients undergoing these procedures. The current practice in this regard is heterogeneous and has mainly been driven by data from coronary artery disease and percutaneous coronary intervention. This article discusses the role of antithrombotic and antiplatelet agents for endovascular intervention. PMID- 28582191 TI - Monitoring and Reversal of Anticoagulation and Antiplatelets. AB - Since percutaneous transluminal coronary angioplasty was first described and the breakthrough studies of the role of stents were reported, the evolution in anticoagulation and antiplatelet therapy used during percutaneous coronary intervention (PCI) has reduced periprocedural ischemic events and stent thrombosis. Although greater combinations and doses of anticoagulation with antiplatelets seem to provide the best protection against thrombogenic and embolic events, there is a significant trade-off with a higher risk of major and minor bleeding episodes. This review article expands on each of the commonly used antiplatelet and anticoagulants used at time of PCI, focusing on drug monitoring and reversal. PMID- 28582190 TI - Antithrombotic Strategies in Valvular and Structural Heart Disease Interventions: Current Status and Future Directions. AB - Antithrombotic prophylaxis is the cornerstone of adjunctive pharmacologic therapy in patients undergoing transcatheter intervention for valvular and structural heart disease. However, drugs and doses of antiplatelet and anticoagulant agents are mostly empiric for these indications and typically administered at the operator's discretion. This article describes the rationale for antithrombotic management of patients undergoing transcatheter aortic valve implantation, percutaneous mitral valve repair with the Mitraclip system, patent foramen ovale, and atrial septal defect closure, as well as common strategies for managing antiplatelet and anticoagulant therapy in patients with valvular and structural heart disease undergoing transcatheter procedures. PMID- 28582192 TI - Vasoactive and Antiarrhythmic Drugs During Percutaneous Coronary Intervention. AB - The objective in percutaneous coronary intervention (PCI) is to treat flow limiting atherothrombotic coronary plaques mechanically. Many types of antithrombotic drugs are used to prevent ischemic complications during manipulation of catheters, guidewires, balloons, and stents in coronary arteries while minimizing the risk of bleeding. However, many other types of pharmacologic agents are also used to facilitate PCI. This review focuses on the most commonly used adjunct drugs during PCI. In addition, a recommendation of which drugs should be stopped or interrupted in patients undergoing PCI is provided. PMID- 28582197 TI - Interventional Pharmacology. PMID- 28582198 TI - Left Main Percutaneous Coronary Intervention. AB - Significant unprotected left main stem (ULMS) disease is in approximately 5% to 7% of patients undergoing coronary angiography. Historically, coronary artery bypass grafting has been the gold standard treatment of these patients. With recent advances in stent technology, adjunctive pharmacotherapy, and operator experience, percutaneous coronary intervention (PCI) is increasingly regarded as a viable alternative treatment option, especially in patients with favorable coronary anatomy (low and intermediate SYNTAX (Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery) scores). This article aims to discuss the evidence supporting PCI for ULMS disease, current guidelines, and technical aspects. PMID- 28582199 TI - Saphenous Vein Graft Interventions. AB - Saphenous vein graft interventions compose a small but important subset of percutaneous coronary revascularization. Because of their unique biology, percutaneous angioplasty and stenting require tailored patient and lesion selection and modification of intervention technique to optimize outcomes. The use of embolic protection and appropriate adjunctive pharmacology can help minimize periprocedural complications, such as the no-reflow phenomenon. Recommendations for best practice in saphenous vein graft interventions continue to evolve with emerging research and therapy. PMID- 28582200 TI - Atherectomy Devices for the Treatment of Calcified Coronary Lesions. AB - The presence of moderate and severe coronary artery calcification (CAC) is associated with higher rates of angiographic complications during percutaneous coronary intervention (PCI), as well as higher major adverse cardiac events compared with noncalcified lesions. Diabetes mellitus, a risk factor for CAC, is increasing in the United States. Vessel preparation before PCI with atherectomy can facilitate successful stent delivery and expansion that may otherwise not be possible. We review here CAC prevalence, risk factors, and impact on PCI, as well as the currently available coronary atherectomy devices including rotational atherectomy, orbital atherectomy, and laser atherectomy. PMID- 28582201 TI - Percutaneous Coronary Intervention for Bifurcation Lesions. AB - This article summarizes treatment alternatives for coronary bifurcation lesions. It also reviews current definitions and classifications pertaining to bifurcation lesions and provides an overview of the impact of bifurcation lesions on clinical outcomes. PMID- 28582202 TI - Update on Coronary Chronic Total Occlusion Percutaneous Coronary Intervention. AB - Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has significantly evolved during recent years. High success rates are being achieved by experienced centers and operators, but not at less-experienced centers. Use of CTO crossing algorithms can help improve the success and efficiency of these potentially lengthy procedures. There is a paucity of clinical trial data examining clinical outcomes of CTO PCI, which is critical for further adoption and refinement of the procedure. We provide a detailed overview of the clinical evidence and current available crossing strategies, with emphasis on recent developments and techniques. PMID- 28582203 TI - Hemodynamic Support Devices for Complex Percutaneous Coronary Intervention. AB - High-risk percutaneous coronary intervention (PCI) encompasses a growing portion of total PCIs performed and typically includes patients with high-risk clinical and anatomic characteristics. Such patients may represent not only a high-risk group for complications but also a group who may derive the most benefit from complete revascularization. Several hemodynamic support devices are available. Trial data, consensus documents, and guidelines currently recommend high-risk PCI aided by hemodynamic support devices, and this article discusses the patient populations who would benefit from such an approach, the available devices and strategies, and expected outcomes. PMID- 28582204 TI - Management of Complications. AB - Percutaneous coronary intervention (PCI) has matured rapidly to tackle increasingly complex coronary disease. Operators must be aware of the incidence of the basic risks involved with coronary angiography and PCI to appropriately inform patients and obtain procedural consent. Even before a wire enters a coronary artery, specific risks, including vascular access complications, renal injury, allergic reaction, and radiation injury, are constantly present. With initiation of PCI, new risks to the coronary circulation arise. A fundamental knowledge of the presentation of these complications and expert ability to emergently manage them are of the utmost importance to the successful completion of PCI. PMID- 28582205 TI - In-stent Restenosis. AB - In-stent restenosis (ISR) is the narrowing of a stented coronary artery lesion. The mean time from percutaneous coronary intervention (PCI) to ISR was 12 months with drug-eluting stents (DES) and 6 months with bare metal stents (BMS). ISR typically presents as recurrent angina. The use of DES has significantly reduced the rate of ISR compared with BMS. Predictors of ISR include patient, lesion, and procedural characteristics. Intravascular ultrasound, optical coherence tomography, and fractional flow reserve are important tools for the anatomic and hemodynamic assessment of ISR. Treatment options for ISR include percutaneous coronary intervention with DES. PMID- 28582207 TI - Antithrombotic Therapy in Percutaneous Coronary Intervention. AB - Numerous agents are available for anticoagulation during percutaneous coronary intervention (PCI). These agents have been evaluated in a variety of clinical settings, including elective, urgent, and emergent PCI. Although unfractionated heparin remains a frequent choice, accumulating data support the use of newer agents to mitigate bleeding risk, especially in the setting of femoral access and concomitant use of glycoprotein IIb/IIa receptor inhibition. With several antithrombotic agents available, an assessment must be made regarding the ischemic and bleeding risks. This article summarizes existing data examining the benefits and limitations of the various anticoagulants and guidelines for their use. PMID- 28582208 TI - Risk Stratification for Percutaneous Coronary Intervention. AB - The Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score is a semiquantitative angiographic score developed to prospectively characterize the disease complexity of the coronary vasculature. With more than 50 validation studies, the SYNTAX score is the most-studied risk model in the setting of percutaneous coronary intervention. In this article, the evolutionary journey of the SYNTAX score is reviewed, with emphasis on its sequential modifications and adaptations, now culminating in the development and validation of the SYNTAX score II. PMID- 28582206 TI - Antiplatelet Therapy in Percutaneous Coronary Intervention. AB - Platelets play a key role in mediating stent thrombosis, which is the major cause of ischemic events immediately after percutaneous coronary intervention (PCI). Antiplatelet therapy is therefore the cornerstone of antithrombotic therapy after PCI. However, the use of antiplatelet agents increases bleeding risk, with more potent antiplatelet agents further increasing bleeding risk. In the past 5 years, potent and fast-acting P2Y12 inhibitors have augmented the antiplatelet armamentarium available to interventional cardiologists. This article reviews the preclinical and clinical data surrounding these new agents, and discusses the significant questions and controversies that still exist regarding the optimal antiplatelet strategy. PMID- 28582209 TI - Acute Myocardial Infarction/Thrombectomy. AB - This article focuses on specialized techniques and devices used in the most challenging cases of acute myocardial infarction. Areas where high-quality evidence is either clear or absent are avoided. Controversies in the use of support or thrombectomy devices, the addition of adjunct pharmacology, and the decision to treat nonculprit lesions are discussed. Recent years have seen a shift in guidelines to downgrading the use of assist devices in cardiogenic shock and aspiration thrombectomy, whereas consideration of nonculprit coronary intervention has been revived. These changes come in the wake of a series of large, practice-changing clinical trials. PMID- 28582215 TI - The New Era of Interventional Cardiology: Tackling Complex Coronary Intervention. PMID- 28582216 TI - Implications of Kidney Disease in the Cardiac Patient. AB - Traditional cardiovascular risk factors, particularly hypertension and diabetes, are common in the disease processes of both renal and cardiac pathology. Unfortunately the coexistence of renal impairment is not an innocent bystander in cardiovascular disease; it disorder not only increases the prevalence and severity of cardiovascular disease, but also negatively affects prognostic outcomes and the safety and efficacy of cardiac interventions. This article discusses the role and impact of kidney disease in the cardiac patient in 3 key common cardiovascular processes: coronary artery disease, arrhythmia, and heart failure. PMID- 28582217 TI - Contrast Media: History and Chemical Properties. AB - Contrast media are essential for cardiac catheterization, and the evolution of these agents has had a significant role in cardiology. Contrast agents are classified as ionic or nonionic based on water solubility and as monomers or dimers based on their chemical structures. Furthermore, these agents are classified on osmolality as high osmolar, low osmolar, or iso-osmolar. The last century has seen a rapid evolution of these agents from their discovery during the search for syphilis treatments to advancements in their chemical properties, making them safer for patients and improving tissue visualization. PMID- 28582218 TI - Nonrenal Complications of Contrast Media. AB - Nonrenal complications of contrast media are caused by chemotoxic or anaphylactoid reactions related to the contrast agent used. Chemotoxicity is mainly attributed to ionic concentration and osmolality. Anaphylactoid reactions are typically caused by direct activation of basophils, mast cells, and complement rather than an observable antigen-antibody interaction, and may be acute or delayed. History of an adverse reaction following prior exposure is the strongest predictor of a subsequent adverse reaction to contrast. Premedication regimens of corticosteroids or antihistamines can lower the risk of repeat adverse reactions. Treatment of anaphylactoid reactions depends on the severity of symptoms. PMID- 28582219 TI - Relative Nephrotoxicity of Different Contrast Media. AB - Contrast-induced nephropathy (CIN) is a common cause of acute kidney injury among hospitalized patients. High-osmolar contrast agents are associated with increased risk of CIN. Low-osmolar (LOCM) and iso-osmolar (IOCM) agents show no difference in the incidence of CIN, even among high-risk patients. This finding suggests that factors other than osmolality may play a role in the pathogenesis of CIN. The use of either LOCM or IOCM agents is recommended in high-risk patients. PMID- 28582220 TI - Contrast-Induced Nephropathy: Definitions, Epidemiology, and Implications. AB - Contrast-induced nephropathy, now termed contrast-induced acute kidney injury (CI AKI), has been a long-recognized complication of administering intravascular iodinated contrast. This article reviews the newest literature on subclinical CI AKI detected by novel biomarkers, and clinical CI-AKI recognized by an increase in serum creatinine and a reduction in urine output. Both components of CI-AKI are associated with adverse outcomes, including in-hospital complications, increased length of stay, need for renal replacement therapy, rehospitalization, permanent loss in renal filtration function, and death. PMID- 28582221 TI - Pathophysiology of Contrast-Induced Acute Kidney Injury. AB - Contrast-induced acute kidney injury (CI-AKI) refers to acute kidney injury (AKI) after intravenous or intra-arterial administration of contrast media (CM). The 2 key mechanisms related to AKI are acute tubular necrosis and prerenal azotemia. Although the pathophysiology of AKI is complex, modern frameworks show that AKI has 3 major pathways: hemodynamic injury, systemic inflammation, and toxic injury. In the pathophysiology of CI-AKI, 3 major distinct, but potentially interacting pathways are recognized: hemodynamic effects, increase in oxygen free radicals, and direct CM molecule tubular cell toxicity. This article reviews the pathophysiology of CI-AKI by describing and explaining these pathways. PMID- 28582222 TI - Predicting Contrast-induced Renal Complications in the Catheterization Laboratory. AB - Risk scores should undergo 3 analytical phases before they are suitable for adoption in clinical practice, namely, derivation, external validation, and assessment of effect on clinical outcomes of use of the risk score in a so-called impact study. Major risk factors for renal complications after percutaneous coronary intervention are pre-existing chronic kidney disease, diabetes mellitus, use of a high contrast dose, and hemodynamic instability. Unfortunately, only 3 of these 10 risk scores have undergone external validation. As a result, there is a great need for further research on the already designed risk scores. PMID- 28582223 TI - Biomarkers of Contrast-Induced Nephropathy: Which Ones and What Is Their Clinical Relevance? AB - Contrast-induced nephropathy, or contrast-induced acute kidney injury (AKI), is an acute impairment of renal function as manifested by an increase in serum creatinine. Different urinary and serum proteins have been intensively investigated as possible biomarkers for the early diagnosis of AKI. Promising candidate biomarkers have the ability to detect an early and graded increase in tubular epithelial cell injury and to distinguish prerenal causes of AKI from acute tubular necrosis. In this article new, emerging biomarkers of contrast induced AKI are presented and described, of which serum neutrophil gelatinase associated lipocalin appears to be the most promising. PMID- 28582224 TI - Intravenous and Oral Hydration: Approaches, Principles, and Differing Regimens. AB - Prevention of contrast-induced nephropathy is founded on minimizing the pathophysiologic consequences of contrast media (CM) interacting with a vulnerable kidney. In this article, the rationale for administering fluid (oral or intravenous) is discussed, and the clinical trials exploring different protocols are reviewed. A benefit from administration of fluids before CM exposure, which corrects volume depletion and increases urine output, can be expected. Forced diuresis without adequate volume replacement is deleterious. PMID- 28582225 TI - Pharmacologic Prophylaxis for Contrast-Induced Acute Kidney Injury. AB - In the effort to prevent contrast-induced acute kidney injury (CI-AKI), several pharmacologic agents have been tested for their single or combined nephroprotective properties. To date, however, no drug has been officially approved for this aim. This article focuses on the three agents that have been most extensively studied: statins, N-acetylcysteine, and ascorbic acid. Particular attention is paid to the impact of these drugs on the CI-AKI prevention and improved prognosis. PMID- 28582226 TI - Device-Based Therapy in the Prevention of Contrast-Induced Nephropathy. AB - Contrast-induced nephropathy (CIN) is a common condition that is associated with short- and, likely, long-term adverse outcomes. Although periprocedural intravenous hydration is the simplest and most widely used technique to prevent CIN, the limited ability of this approach to mitigate the CIN risk in high-risk populations has provided an impetus to develop new preventive strategies. A range of potentially useful device-based approaches offers new preventive techniques. Well-designed and adequately powered randomized studies of these device-based therapies are urgently needed to determine the expanding role they will play in future clinical practice. PMID- 28582228 TI - Renal Complications in Patients Undergoing Peripheral Artery Interventions. AB - Surgical or endovascular revascularization procedures for severe peripheral artery disease (PAD) are typically performed in patients with lifestyle-limiting symptoms or evidence of end-organ ischemia secondary to PAD. The role of endovascular therapy in the treatment of PAD is expanding. Contrast-induced nephropathy is the most important and most frequent renal complication of endovascular interventional procedures. Knowledge about complications and their prevention and management is essential for successful outcomes. This article focuses on renal complications during peripheral artery interventions. PMID- 28582227 TI - A Practical Approach to Preventing Renal Complications in the Catheterization Laboratory. AB - Kidney injury following cardiac catheterization is an infrequent, though persistent, complication, which in some cases may be preventable. Patients at increased risk for renal complications following catheterization can be identified through individual and procedural risk factors, and several risk prediction models are readily available. The authors advocate for the development of an easily implemented and standardized protocol, readily accessible to catheterization laboratory staff, for the identification and treatment of those patients who may be at increased risk for renal complications following cardiac catheterization. PMID- 28582229 TI - Renal Complications in Patients Undergoing Transcatheter Aortic Valve Replacement. AB - Acute kidney injury in hospitalized patients is associated with significantly increased mortality across a broad spectrum of conditions. According to the Society of Thoracic Surgeons database, patients with chronic kidney disease undergoing surgical aortic valve replacement with or without coronary artery bypass grafting had a more than 50% reduction in observed 8-year survival compared with those without chronic kidney disease. Transcatheter aortic valve replacement is an exciting new approach for the treatment of aortic stenosis in high-risk or inoperable patients with severe aortic stenosis. This article discusses the incidence, predictors, impact, and potential avoidance and management strategies of renal dysfunction associated with transcatheter aortic valve replacement. PMID- 28582234 TI - Renal Complications in the Catheterization Laboratory. PMID- 28582235 TI - Measurement and Data Transmission Validity of a Multi-Biosensor System for Real Time Remote Exercise Monitoring Among Cardiac Patients. AB - BACKGROUND: Remote telemonitoring holds great potential to augment management of patients with coronary heart disease (CHD) and atrial fibrillation (AF) by enabling regular physiological monitoring during physical activity. Remote physiological monitoring may improve home and community exercise-based cardiac rehabilitation (exCR) programs and could improve assessment of the impact and management of pharmacological interventions for heart rate control in individuals with AF. OBJECTIVE: Our aim was to evaluate the measurement validity and data transmission reliability of a remote telemonitoring system comprising a wireless multi-parameter physiological sensor, custom mobile app, and middleware platform, among individuals in sinus rhythm and AF. METHODS: Participants in sinus rhythm and with AF undertook simulated daily activities, low, moderate, and/or high intensity exercise. Remote monitoring system heart rate and respiratory rate were compared to reference measures (12-lead ECG and indirect calorimeter). Wireless data transmission loss was calculated between the sensor, mobile app, and remote Internet server. RESULTS: Median heart rate (-0.30 to 1.10 b?min-1) and respiratory rate (-1.25 to 0.39 br?min-1) measurement biases were small, yet statistically significant (all P<=.003) due to the large number of observations. Measurement reliability was generally excellent (rho=.87-.97, all P<.001; intraclass correlation coefficient [ICC]=.94-.98, all P<.001; coefficient of variation [CV]=2.24-7.94%), although respiratory rate measurement reliability was poor among AF participants (rho=.43, P<.001; ICC=.55, P<.001; CV=16.61%). Data loss was minimal (<5%) when all system components were active; however, instability of the network hosting the remote data capture server resulted in data loss at the remote Internet server during some trials. CONCLUSIONS: System validity was sufficient for remote monitoring of heart and respiratory rates across a range of exercise intensities. Remote exercise monitoring has potential to augment current exCR and heart rate control management approaches by enabling the provision of individually tailored care to individuals outside traditional clinical environments. PMID- 28582236 TI - Perceptions of Technology and Its Use for Therapeutic Application for Individuals With Hemiparesis: Findings From Adult and Pediatric Focus Groups. AB - BACKGROUND: Digital technology is becoming an increasingly popular means of delivering meaningful therapy to individuals with neurological impairments. An understanding of clients' technology use and their perspectives on incorporating technology into rehabilitation can provide researchers and designers with valuable information to inform development of technologies and technology-based rehabilitation programs. OBJECTIVE: This study was designed to establish the current use and perceptions of gaming, social media, and robotics technologies for rehabilitative purposes from the perspective of adults and children with upper limb impairments to identify barriers and enablers to their adoption and use. METHODS: We conducted three focus groups consisting of pediatric (n=7, mean age 11.0 years) and adult (n=8, mean age 60.8 years) participants with hemiparesis affecting their upper limb. We applied thematic analysis methods to the resulting data. RESULTS: We identified three key themes: (1) clients' use of technology in everyday life and rehabilitation, (2) barriers to use, and (3) enablers to therapy. Participants had limited exposure to technology for therapeutic purposes, but all acknowledged the potential benefits in providing motivation and interest for the performance of repetitive task practice. Adult participants requested efficacious, simple, and easy-to-use technology for rehabilitation with programs that could be individualized for them and expressed that they wanted these programs to provide a motivating means of repeated practice of therapeutic movements. In contrast, pediatric participants emphasized a desire for technology for rehabilitation that offered opportunities for social interaction and interactive games involving their whole body and not only their affected limb. Perceived safety and privacy were concerns for both groups. CONCLUSIONS: Our findings highlight that all participants were open to the integration of technology into rehabilitation. Adult participants were more pragmatically motivated by potential recovery gains, whereas pediatric participants were more intrinsically motivated by access to games. PMID- 28582237 TI - Interchangeability of the Wii Balance Board for Bipedal Balance Assessment. AB - BACKGROUND: Since 2010, an increasing interest in more portable and flexible hardware for balance and posture assessment led to previously published studies determining whether or not the Wii Balance Board could be used to assess balance and posture, both scientifically and clinically. However, no previous studies aimed at comparing results from different Wii Balance Boards for clinical balance evaluation exist. OBJECTIVE: The objective of this crossover study is to assess the interchangeability of the Wii Balance Board. METHODS: A total of 6 subjects participated in the study and their balance was assessed using 4 different Wii Balance Boards. Trials were recorded simultaneously with Wii Balance Boards and with a laboratory force plate. Nine relevant clinical parameters were derived from center of pressure displacement data obtained from Wii Balance Board and force plate systems. Intraclass correlation coefficients (ICC), F tests, and Friedman tests were computed to assess the agreement between trials and to compare the Wii Balance Board and force plate results. RESULTS: Excellent correlations were found between the Wii Balance Board and force plate (mean rho =.83). With the exception of 2 parameters, strong to excellent agreements were found for the 7 remaining parameters (ICC=.96). No significant differences were found between trials recorded with different Wii Balance Boards. CONCLUSIONS: Our results indicate that for most of the parameters analyzed, balance and posture assessed with one Wii Balance Board were statistically similar to results obtained from another. Furthermore, the good correlation between the Wii Balance Board and force plate results shows that Wii Balance Boards can be reliably used for scientific assessment using most of the parameters analyzed in this study. These results also suggest that the Wii Balance Board could be used in multicenter studies and therefore, would allow for the creation of larger populations for clinical studies. TRIAL REGISTRATION: Ethical Committee of the Erasme Hospital (CCB B406201215142). PMID- 28582238 TI - A Smart Insole to Promote Healthy Aging for Frail Elderly Individuals: Specifications, Design, and Preliminary Results. AB - BACKGROUND: Older individuals frequently experience reversible "frailty syndrome,", increasing incidence of disability. Although physical exercise interventions may delay functional decline, there are difficulties in implementing them and performing seamless follow-up at home. Very few technological solutions attempt to address this challenge and improve individual participation. OBJECTIVE: Our objectives are to (1) develop a technological solution designed to support active aging of frail older persons, (2) conduct a first laboratory evaluation of the device, and (3) design a multidimensional clinical trial to validate our solution. METHODS: We conducted a first phase of multidisciplinary meetings to identify real end users and health professional's unmet needs, and to produce specifications for the architecture of the solution. In a second phase, we performed laboratory tests of the first proposed prototype (a smart insole) with 3 healthy volunteers. We then designed an ongoing clinical trial to finalize the multidimensional evaluation and improvement of the solution. RESULTS: To respond to the needs expressed by the stakeholders (frailty monitoring and adherence improvement), we developed a prototype of smart shoe insole to monitor key parameters of frailty during daily life and promote walking. It is a noninvasive wireless insole, which automatically measures gait parameters and transmits information to a remote terminal via a secure Internet connection. To ensure the solution's autonomy and transparency, we developed an original energy harvesting system, which transforms mechanical energy produced by the user's walking movement into electrical energy. The first laboratory tests of this technological solution showed good reliability measures and also a good acceptability for the users. We have planned an original iterative medical research protocol to validate our solution in real life. CONCLUSIONS: Our smart insole could support preventive strategies against disability in primary care by empowering the older patients without increasing the busy health professional's workload. TRIAL REGISTRATION: Clinicaltrials.gov NCT02316600; https://clinicaltrials.gov/ct2/results?term=NCT02316600&Search=Search. Accessed: 2015-05-13 . (Archived by WebCite at http://www.webcitation.org/6YUTkObrQ). PMID- 28582239 TI - Mobile Functional Reach Test in People Who Suffer Stroke: A Pilot Study. AB - BACKGROUND: Postural instability is one of the major complications found in people who survive a stroke. Parameterizing the Functional Reach Test (FRT) could be useful in clinical practice and basic research, as this test is a clinically accepted tool (for its simplicity, reliability, economy, and portability) to measure the semistatic balance of a subject. OBJECTIVE: The aim of this study is to analyze the reliability in the FRT parameterization using inertial sensor within mobile phones (mobile sensors) for recording kinematic variables in patients who have suffered a stroke. Our hypothesis is that the sensors in mobile phones will be reliable instruments for kinematic study of the FRT. METHODS: This is a cross-sectional study of 7 subjects over 65 years of age who suffered a stroke. During the execution of FRT, the subjects carried two mobile phones: one placed in the lumbar region and the other one on the trunk. After analyzing the data obtained in the kinematic registration by the mobile sensors, a number of direct and indirect variables were obtained. The variables extracted directly from FRT through the mobile sensors were distance, maximum angular lumbosacral/thoracic displacement, time for maximum angular lumbosacral/thoracic displacement, time of return to the initial position, and total time. Using these data, we calculated speed and acceleration of each. A descriptive analysis of all kinematic outcomes recorded by the two mobile sensors (trunk and lumbar) was developed and the average range achieved in the FRT. Reliability measures were calculated by analyzing the internal consistency of the measures with 95% confidence interval of each outcome variable. We calculated the reliability of mobile sensors in the measurement of the kinematic variables during the execution of the FRT. RESULTS: The values in the FRT obtained in this study (2.49 cm, SD 13.15) are similar to those found in other studies with this population and with the same age range. Intrasubject reliability values observed in the use of mobile phones are all located above 0.831, ranging from 0.831 (time B_C trunk area) and 0.894 (displacement A_B trunk area). Likewise, the observed intersubject values range from 0.835 (time B_C trunk area) and 0.882 (displacement A_C trunk area). On the other hand, the reliability of the FRT was 0.989 (0.981-0.996) and 0.978 (0.970-0.985), intrasubject and intersubject respectively. CONCLUSIONS: We found that mobile sensors in mobile phones could be reliable tools in the parameterization of the Functional Reach Test in people who have had a stroke. PMID- 28582240 TI - Rehab on Wheels: A Pilot Study of Tablet-Based Wheelchair Training for Older Adults. AB - BACKGROUND: Alternative and innovative strategies such as mHealth and eLearning are becoming a necessity for delivery of rehabilitation services. For example, older adults who require a wheelchair receive little, if any, training for proficiency with mobility skills. This substantive service gap is due in part to restricted availability of clinicians and challenges for consumers to attend appointments. A research team of occupational therapists and computer scientists engaged clinicians, consumers, and care providers using a participatory action design approach. A tablet-based application, Enhancing Participation In the Community by improving Wheelchair Skills (EPIC Wheels), was developed to enable in-chair home training, online expert trainer monitoring, and trainee-trainer communication via secure voice messaging. OBJECTIVE: Prior to undertaking a randomized controlled trial (RCT), a pilot study was conducted to determine the acceptability and feasibility of administering an mHealth wheelchair skills training program safely and effectively with two participants of different skill levels. The findings were used to determine whether further enhancements to the program were indicated. METHODS: The program included two in-person sessions with an expert trainer and four weeks of independent home training. The EPIC Wheels application included video instruction and demonstration, self-paced training activities, and interactive training games. Participants were provided with a 10 inch Android tablet, mounting apparatus, and mobile Wi-Fi device. Frequency and duration of tablet interactions were monitored and uploaded daily to an online trainer interface. Participants completed a structured evaluation survey and provided feedback post-study. The trainer provided feedback on the training protocol and trainer interface. RESULTS: Both participants perceived the program to be comprehensive, useful, and easily navigated. The trainer indicated usage data was comprehensive and informative for monitoring participant progress and adherence. The application performed equally well with multiple devices. Some initial issues with log-in requests were resolved via tablet-specific settings. Inconsistent Internet connectivity, resulting in delayed data upload and voice messaging, was specific to individual Wi-Fi devices and resolved by standardizing configuration. Based on the pilot results, the software was updated to make content download more robust. Additional features were also incorporated such as check marks for completed content, a more consumer-friendly aesthetic, and achievement awards. The trainer web interface was updated to improve usability and provides both a numerical and visual summary of participant data. CONCLUSIONS: The EPIC Wheels pilot study provided useful feedback on the feasibility of a tablet-based home program for wheelchair skills training among older adults, justifying advancement to evaluation in an RCT. The program may be expanded for use with other rehabilitation interventions and populations, particularly for those living in rural or remote locations. Future development will consider integration of built-in tablet sensors to provide performance feedback and enable interactive training activities. TRIAL REGISTRATION: ClinicalTrials.gov NCT01644292; https://clinicaltrials.gov/ct2/show/NCT01644292 (Archived by WebCite at http://www.webcitation.org/6XyvYyTUf). PMID- 28582241 TI - Studying Upper-Limb Kinematics Using Inertial Sensors Embedded in Mobile Phones. AB - BACKGROUND: In recent years, there has been a great interest in analyzing upper limb kinematics. Inertial measurement with mobile phones is a convenient and portable analysis method for studying humerus kinematics in terms of angular mobility and linear acceleration. OBJECTIVE: The aim of this analysis was to study upper-limb kinematics via mobile phones through six physical properties that correspond to angular mobility and acceleration in the three axes of space. METHODS: This cross-sectional study recruited healthy young adult subjects. Humerus kinematics was studied in 10 young adults with the iPhone4. They performed flexion and abduction analytical tasks. Mobility angle and lineal acceleration in each of its axes (yaw, pitch, and roll) were obtained with the iPhone4. This device was placed on the right half of the body of each subject, in the middle third of the humerus, slightly posterior. Descriptive statistics were calculated. RESULTS: Descriptive graphics of analytical tasks performed were obtained. The biggest range of motion was found in pitch angle, and the biggest acceleration was found in the y-axis in both analytical tasks. Focusing on tridimensional kinematics, bigger range of motion and acceleration was found in abduction (209.69 degrees and 23.31 degrees per second respectively). Also, very strong correlation was found between angular mobility and linear acceleration in abduction (r=.845) and flexion (r=.860). CONCLUSIONS: The use of an iPhone for humerus tridimensional kinematics is feasible. This supports use of the mobile phone as a device to analyze upper-limb kinematics and to facilitate the evaluation of the patient. PMID- 28582242 TI - THERAPIST: Towards an Autonomous Socially Interactive Robot for Motor and Neurorehabilitation Therapies for Children. AB - BACKGROUND: Neurorehabilitation therapies exploiting the use-dependent plasticity of our neuromuscular system are devised to help patients who suffer from injuries or diseases of this system. These therapies take advantage of the fact that the motor activity alters the properties of our neurons and muscles, including the pattern of their connectivity, and thus their functionality. Hence, a sensor motor treatment where patients makes certain movements will help them (re)learn how to move the affected body parts. But these traditional rehabilitation processes are usually repetitive and lengthy, reducing motivation and adherence to the treatment, and thus limiting the benefits for the patients. OBJECTIVE: Our goal was to create innovative neurorehabilitation therapies based on THERAPIST, a socially assistive robot. THERAPIST is an autonomous robot that is able to find and execute plans and adapt them to new situations in real-time. The software architecture of THERAPIST monitors and determines the course of action, learns from previous experiences, and interacts with people using verbal and non-verbal channels. THERAPIST can increase the adherence of the patient to the sessions using serious games. Data are recorded and can be used to tailor patient sessions. METHODS: We hypothesized that pediatric patients would engage better in a therapeutic non-physical interaction with a robot, facilitating the design of new therapies to improve patient motivation. We propose RoboCog, a novel cognitive architecture. This architecture will enhance the effectiveness and time of-response of complex multi-degree-of-freedom robots designed to collaborate with humans, combining two core elements: a deep and hybrid representation of the current state, own, and observed; and a set of task-dependent planners, working at different levels of abstraction but connected to this central representation through a common interface. Using RoboCog, THERAPIST engages the human partner in an active interactive process. But RoboCog also endows the robot with abilities for high-level planning, monitoring, and learning. Thus, THERAPIST engages the patient through different games or activities, and adapts the session to each individual. RESULTS: RoboCog successfully integrates a deliberative planner with a set of modules working at situational or sensorimotor levels. This architecture also allows THERAPIST to deliver responses at a human rate. The synchronization of the multiple interaction modalities results from a unique scene representation or model. THERAPIST is now a socially interactive robot that, instead of reproducing the phrases or gestures that the developers decide, maintains a dialogue and autonomously generate gestures or expressions. THERAPIST is able to play simple games with human partners, which requires humans to perform certain movements, and also to capture the human motion, for later analysis by clinic specialists. CONCLUSIONS: The initial hypothesis was validated by our experimental studies showing that interaction with the robot results in highly attentive and collaborative attitudes in pediatric patients. We also verified that RoboCog allows the robot to interact with patients at human rates. However, there remain many issues to overcome. The development of novel hands-off rehabilitation therapies will require the intersection of multiple challenging directions of research that we are currently exploring. PMID- 28582243 TI - Automated Management of Exercise Intervention at the Point of Care: Application of a Web-Based Leg Training System. AB - BACKGROUND: Recent advances in information and communication technology have prompted development of Web-based health tools to promote physical activity, the key component of cardiac rehabilitation and chronic disease management. Mobile apps can facilitate behavioral changes and help in exercise monitoring, although actual training usually takes place away from the point of care in specialized gyms or outdoors. Daily participation in conventional physical activities is expensive, time consuming, and mostly relies on self-management abilities of patients who are typically aged, overweight, and unfit. Facilitation of sustained exercise training at the point of care might improve patient engagement in cardiac rehabilitation. OBJECTIVE: In this study we aimed to test the feasibility of execution and automatic monitoring of several exercise regimens on-site using a Web-enabled leg training system. METHODS: The MedExercise leg rehabilitation machine was equipped with wireless temperature sensors in order to monitor its usage by the rise of temperature in the resistance unit (Deltat degrees ). Personal electronic devices such as laptop computers were fitted with wireless gateways and relevant software was installed to monitor the usage of training machines. Cloud-based software allowed monitoring of participant training over the Internet. Seven healthy participants applied the system at various locations with training protocols typically used in cardiac rehabilitation. The heart rates were measured by fingertip pulse oximeters. RESULTS: Exercising in home chairs, in bed, and under an office desk was made feasible and resulted in an intensity dependent increase of participants' heart rates and Deltat degrees in training machine temperatures. Participants self-controlled their activities on smart devices, while a supervisor monitored them over the Internet. Individual Deltat degrees reached during 30 minutes of moderate-intensity continuous training averaged 7.8 degrees C (SD 1.6). These Deltat degrees were used as personalized daily doses of exercise with automatic email alerts sent upon achieving them. During 1-week training at home, automatic notifications were received on 4.4 days (SD 1.8). Although the high intensity interval training regimen was feasible on site, it was difficult for self- and remote management. Opportunistic leg exercise under the desk, while working with a computer, and training in bed while viewing television were less intensive than dosed exercise bouts, but allowed prolonged leg mobilization of 73.7 minutes/day (SD 29.7). CONCLUSIONS: This study demonstrated the feasibility of self-control exercise training on-site, which was accompanied by online monitoring, electronic recording, personalization of exercise doses, and automatic reporting of adherence. The results suggest that this technology and its applications are useful for the delivery of Web-based exercise rehabilitation and cardiac training programs at the point of care. PMID- 28582244 TI - Are Virtual Rehabilitation Technologies Feasible Models to Scale an Evidence Based Fall Prevention Program? A Pilot Study Using the Kinect Camera. AB - BACKGROUND: Falls in older adults are a significant public health issue. Interventions have been developed and proven effective to reduce falls in older adults, but these programs typically last several months and can be resource intensive. Virtual rehabilitation technologies may offer a solution to bring these programs to scale. Off-the-shelf and custom exergames have demonstrated to be a feasible adjunct to rehabilitation with older adults. However, it is not known if older adults will be able or willing to use a virtual rehabilitation technology to participate in an evidence-based fall prevention program. To have the greatest impact, virtual rehabilitation technologies need to be acceptable to older adults from different backgrounds and level of fall risk. If these technologies prove to be a feasible option, they offer a new distribution channel to disseminate fall prevention programs. OBJECTIVE: Stand Tall (ST) is a virtual translation of the Otago Exercise Program (OEP), an evidence-based fall prevention program. Stand Tall was developed using the Virtual Exercise Rehabilitation Assistant (VERA) software, which uses a Kinect camera and a laptop to deliver physical therapy exercise programs. Our purpose in this pilot study was to explore if ST could be a feasible platform to deliver the OEP to older adults from a variety of fall risk levels, education backgrounds, and self described level of computer expertise. METHODS: Adults age 60 and over were recruited to participate in a one-time usability study. The study included orientation to the program, navigation to exercises, and completion of a series of strength and balance exercises. Quantitative analysis described participants and the user experience. RESULTS: A diverse group of individuals participated in the study. Twenty-one potential participants (14 women, 7 men) met the inclusion criteria. The mean age was 69.2 (+/- 5.8) years, 38% had a high school education, 24% had a graduate degree, and 66% classified as "at risk for falls". Eighteen participants agreed they would like to use ST to help improve their balance, and 17 agreed or strongly agreed they would feel confident using the system in either the senior center or the home. Thirteen participants felt confident they could actually set up the system in their home. The mean System Usability Scale (SUS) score was 65.5 +/- 21.2 with a range of 32.5 to 97.5. Ten participants scored ST as an above average usability experience compared to other technologies and 5 participants scored a less than optimal experience. Exploratory analysis revealed no significant relationships between user experience, education background, self described computer experience, and fall risk. CONCLUSIONS: Results support the virtual delivery of the OEP by a Kinect camera and an avatar may be acceptable to older adults from a variety of backgrounds. Virtual technologies, like Stand Tall, could offer an efficient and effective approach to bring evidence-based fall prevention programs to scale to address the problem of falls and fall related injuries. Next steps include determining if similar or better outcomes are achieved by older adults using the virtual OEP, Stand Tall, compared to the standard of care. PMID- 28582245 TI - Designing a Mobile Health App for Patients With Dysphagia Following Head and Neck Cancer: A Qualitative Study. AB - BACKGROUND: Adherence to swallowing rehabilitation exercises is important to develop and maintain functional improvement, yet more than half of head and neck cancer (HNC) patients report having difficulty adhering to prescribed regimens. Health apps with game elements have been used in other health domains to motivate and engage patients. Understanding the factors that impact adherence may allow for more effective gamified solutions. OBJECTIVE: The aim of our study was to (1) identify self-reported factors that influence adherence to conventional home therapy without a mobile device in HNC patients and (2) identify appealing biofeedback designs that could be used in a health app. METHODS: A total of 10 (4 females) HNC patients (mean=60.1 years) with experience completing home-based rehabilitation programs were recruited. Thematic analysis of semi-structured interviews was used to answer the first objective. Convergent interviews were used to obtain reactions to biofeedback designs. RESULTS: Facilitators and barriers of adherence to home therapy were described through 6 themes: patient perceptions on outcomes and progress, clinical appointments, cancer treatment, rehabilitation program, personal factors, and connection. App visuals that provide feedback on performance during swallowing exercises should offer an immediate representation of effort relative to a goal. Simple, intuitive graphics were preferred over complex, abstract ones. Continued engagement with the app could be facilitated by tracking progress and by using visuals that build structures with each use. CONCLUSIONS: This is a detailed documentation of the initial steps in designing a health app for a specific patient group. Results revealed the importance of patient engagement in early stages of app development. PMID- 28582246 TI - Systemic Lisbon Battery: Normative Data for Memory and Attention Assessments. AB - BACKGROUND: Memory and attention are two cognitive domains pivotal for the performance of instrumental activities of daily living (IADLs). The assessment of these functions is still widely carried out with pencil-and-paper tests, which lack ecological validity. The evaluation of cognitive and memory functions while the patients are performing IADLs should contribute to the ecological validity of the evaluation process. OBJECTIVE: The objective of this study is to establish normative data from virtual reality (VR) IADLs designed to activate memory and attention functions. METHODS: A total of 243 non-clinical participants carried out a paper-and-pencil Mini-Mental State Examination (MMSE) and performed 3 VR activities: art gallery visual matching task, supermarket shopping task, and memory fruit matching game. The data (execution time and errors, and money spent in the case of the supermarket activity) was automatically generated from the app. RESULTS: Outcomes were computed using non-parametric statistics, due to non normality of distributions. Age, academic qualifications, and computer experience all had significant effects on most measures. Normative values for different levels of these measures were defined. CONCLUSIONS: Age, academic qualifications, and computer experience should be taken into account while using our VR-based platform for cognitive assessment purposes. PMID- 28582247 TI - Novel Use of a Smartphone to Measure Standing Balance. AB - BACKGROUND: Balance assessment and training is utilized by clinicians and their patients to measure and improve balance. There is, however, little consistency in terms of how clinicians, researchers, and patients measure standing balance. Utilizing the inherent sensors in every smartphone, a mobile application was developed to provide a method of objectively measuring standing balance. OBJECTIVE: We aimed to determine if a mobile phone application, which utilizes the phone's accelerometer, can quantify standing balance. METHODS: Three smartphones were positioned simultaneously above the participants' malleolus and patella and at the level of the umbilicus. Once secured, the myAnkle application was initiated to measure acceleration. Forty-eight participants completed 8 different balance exercises separately for the right and left legs. Accelerometer readings were obtained from each mobile phone and mean acceleration was calculated for each exercise at each ankle and knee and the torso. RESULTS: Mean acceleration vector magnitude was reciprocally transformed to address skewness in the data distribution. Repeated measures ANOVAs were completed using the transformed data. A significant 2-way interaction was revealed between exercise condition and the body position of the phone (P<.001). Post-hoc tests indicated higher acceleration vector magnitude for exercises of greater difficulty. ANOVAs at each body position were conducted to examine the effect of exercise. The results revealed the knee as the location most sensitive for the detection of differences in acceleration between exercises. The accelerometer ranking of exercise difficulty showed high agreement with expert clinical rater rankings (kappa statistic>0.9). CONCLUSIONS: The myAnkle application revealed significantly greater acceleration magnitude for exercises of greater difficulty. Positioning of the mobile phone at the knee proved to be the most sensitive to changes in accelerometer values due to exercise difficulty. Application validity was shown through comparison with clinical raters. As such, the myAnkle app has utility as a measurement tool for standing balance. PMID- 28582248 TI - Disease Profiling for Computerized Peer Support of Meniere's Disease. AB - BACKGROUND: Peer support is an emerging form of person-driven active health care. Chronic conditions such as Meniere's disease (a disorder of the inner ear) need continuing rehabilitation and support that is beyond the scope of routine clinical medical practice. Hence, peer-support programs can be helpful in supplementing some of the rehabilitation aspects. OBJECTIVE: The aim of this study was to design a computerized data collection system for the peer support of Meniere's disease that is capable in profiling the subject for diagnosis and in assisting with problem solving. METHODS: The expert program comprises several data entries focusing on symptoms, activity limitations, participation restrictions, quality of life, attitude and personality trait, and an evaluation of disease-specific impact. Data was collected from 740 members of the Finnish Meniere's Federation and utilized in the construction and evaluation of the program. RESULTS: The program verifies the diagnosis of a person by using an expert system, and the inference engine selects 50 cases with matched symptom severity by using a nearest neighbor algorithm. These cases are then used as a reference group to compare with the person's attitude, sense of coherence, and anxiety. The program provides feedback for the person and uses this information to guide the person through the problem-solving process. CONCLUSIONS: This computer-based peer-support program is the first example of an advanced computer oriented approach using artificial intelligence, both in the profiling of the disease and in profiling the person's complaints for hearing loss, tinnitus, and vertigo. PMID- 28582249 TI - Design and Development of a Telerehabilitation Platform for Patients With Phantom Limb Pain: A User-Centered Approach. AB - BACKGROUND: Phantom limb pain is a frequent and persistent problem following amputation. Achieving sustainable favorable effects on phantom limb pain requires therapeutic interventions such as mirror therapy that target maladaptive neuroplastic changes in the central nervous system. Unfortunately, patients' adherence to unsupervised exercises is generally poor and there is a need for effective strategies such as telerehabilitation to support long-term self management of patients with phantom limb pain. OBJECTIVE: The main aim of this study was to describe the user-centered approach that guided the design and development of a telerehabilitation platform for patients with phantom limb pain. We addressed 3 research questions: (1) Which requirements are defined by patients and therapists for the content and functions of a telerehabilitation platform and how can these requirements be prioritized to develop a first prototype of the platform? (2) How can the user interface of the telerehabilitation platform be designed so as to match the predefined critical user requirements and how can this interface be translated into a medium-fidelity prototype of the platform? (3) How do patients with phantom limb pain and their treating therapists judge the usability of the medium-fidelity prototype of the telerehabilitation platform in routine care and how can the platform be redesigned based on their feedback to achieve a high-fidelity prototype? METHODS: The telerehabilitation platform was developed using an iterative user-centered design process. In the first phase, a questionnaire followed by a semistructured interview was used to identify the user requirements of both the patients and their physical and occupational therapists, which were then prioritized using a decision matrix. The second phase involved designing the interface of the telerehabilitation platform using design sketches, wireframes, and interface mock-ups to develop a low-fidelity prototype. Heuristic evaluation resulted in a medium-fidelity prototype whose usability was tested in routine care in the final phase, leading to the development of a high fidelity prototype. RESULTS: A total of 7 categories of patient requirements were identified: monitoring, exercise programs, communication, settings, background information, log-in, and general requirements. One additional category emerged for therapists: patient management. Based on these requirements, patient and therapist interfaces for the telerehabilitation platform were developed and redesigned by the software development team in an iterative process, addressing the usability problems that were reported by the users during 4 weeks of field testing in routine care. CONCLUSIONS: Our findings underline the importance of involving the users and other stakeholders early and continuously in an iterative design process, as well as the need for clear criteria to identify critical user requirements. A decision matrix is presented that incorporates the views of various stakeholders in systematically rating and prioritizing user requirements. The findings and lessons learned might help health care providers, researchers, software designers, and other stakeholders in designing and evaluating new teletreatments, and hopefully increase the likelihood of user acceptance. PMID- 28582250 TI - A Personalized Self-Management Rehabilitation System with an Intelligent Shoe for Stroke Survivors: A Realist Evaluation. AB - BACKGROUND: In the United Kingdom, stroke is the most significant cause of adult disability. Stroke survivors are frequently left with physical and psychological changes that can profoundly affect their functional ability, independence, and social participation. Research suggests that long-term, intense, task- and context-specific rehabilitation that is goal-oriented and environmentally enriched improves function, independence, and quality of life after a stroke. It is recommended that rehabilitation should continue until maximum recovery has been achieved. However, the increasing demand on services and financial constraints means that needs cannot be met through traditional face-to-face delivery of rehabilitation. Using a participatory design methodology, we developed an information communication technology-enhanced Personalized Self Managed rehabilitation System (PSMrS) for stroke survivors with integrated insole sensor technology within an "intelligent shoe.". The intervention model was based around a rehabilitation paradigm underpinned by theories of motor relearning and neuroplastic adaptation, motivational feedback, self-efficacy, and knowledge transfer. OBJECTIVE: To understand the conditions under which this technology based rehabilitation solution would most likely have an impact on the motor behavior of the user, what would work for whom, in what context, and how. We were interested in what aspects of the system would work best to facilitate the motor behavior change associated with self-managed rehabilitation and which user characteristics and circumstances of use could promote improved functional outcomes. METHODS: We used a Realist Evaluation (RE) framework to evaluate the final prototype PSMrS with the assumption that the intervention consists of a series of configurations that include the Context of use, the underlying Mechanisms of change and the potential Outcomes or impacts (CMOs). We developed the CMOs from literature reviews and engagement with clinicians, users, and caregivers during a series of focus groups and home visits. These CMOs were then tested in five in-depth case studies with stroke survivors and their caregivers. RESULTS: While two new propositions emerged, the second importantly related to the self-management aspects of the system. The study revealed that the system should also encourage independent use and the setting of personalized goals or activities. CONCLUSIONS: Information communication technology that purports to support the self-management of stroke rehabilitation should give significant consideration to the need for motivational feedback that provides quantitative, reliable, accurate, context-specific, and culturally sensitive information about the achievement of personalized goal-based activities. PMID- 28582252 TI - Teleexercise for Persons With Spinal Cord Injury: A Mixed-Methods Feasibility Case Series. AB - BACKGROUND: Spinal cord injury (SCI) results in significant loss of function below the level of injury, often leading to restricted participation in community exercise programs. To overcome commonly experienced barriers to these programs, innovations in technology hold promise for remotely delivering safe and effective bouts of exercise in the home. OBJECTIVE: To test the feasibility of a remotely delivered home exercise program for individuals with SCI as determined by (1) implementation of the intervention in the home; (2) exploration of the potential intervention effects on aerobic fitness, physical activity behavior, and subjective well-being; and (3) acceptability of the program through participant self-report. METHODS: Four adults with SCI (mean age 43.5 [SD 5.3] years; 3 males, 1 female; postinjury 25.8 [SD 4.3] years) completed a mixed-methods sequential design with two phases: an 8-week intervention followed by a 3-week nonintervention period. The intervention was a remotely delivered aerobic exercise training program (30-45 minutes, 3 times per week). Instrumentation included an upper body ergometer, tablet, physiological monitor, and custom application that delivered video feed to a remote trainer and monitored and recorded exercise data in real time. Implementation outcomes included adherence, rescheduled sessions, minutes of moderate exercise, and successful recording of exercise data. Pre/post-outcomes included aerobic capacity (VO2 peak), the Physical Activity Scale for Individuals with Physical Disabilities (PASIPD), the Satisfaction with Life Scale (SWLS), and the Quality of Life Index modified for spinal cord injury (QLI-SCI). Acceptability was determined by participant perceptions of the program features and impact, assessed via qualitative interview at the end of the nonintervention phase. RESULTS: Participants completed all 24 intervention sessions with 100% adherence. Out of 96 scheduled training sessions for the four participants, only 8 (8%) were makeup sessions. The teleexercise system successfully recorded 85% of all exercise data. The exercise program was well tolerated by all participants. All participants described positive outcomes as a result of the intervention and stated that teleexercise circumvented commonly reported barriers to exercise participation. There were no reported adverse events and no dropouts. CONCLUSION: A teleexercise system can be a safe and feasible option to deliver home-based exercise for persons with SCI. Participants responded favorably to the intervention and valued teleexercise for its ability to overcome common barriers to exercise. Study results are promising but warrant further investigation in a larger sample. PMID- 28582251 TI - Communications Technology and Motor Neuron Disease: An Australian Survey of People With Motor Neuron Disease. AB - BACKGROUND: People with Motor Neuron Disease (MND), of which amyotrophic lateral sclerosis (ALS) is the most common form in adults, typically experience difficulties with communication and disabilities associated with movement. Assistive technology is essential to facilitate everyday activities, promote social support and enhance quality of life. OBJECTIVE: This study aimed to explore the types of mainstream and commonly available communication technology used by people with MND including software and hardware, to identify the levels of confidence and skill that people with MND reported in using technology, to determine perceived barriers to the use of technology for communication, and to investigate the willingness of people with MND to adopt alternative modes of communication. METHODS: An on-line survey was distributed to members of the New South Wales Motor Neuron Disease Association (MND NSW). Descriptive techniques were used to summarize frequencies of responses and cross tabulate data. Free text responses to survey items and verbal comments from participants who chose to undertake the survey by telephone were analyzed using thematic analysis. RESULTS: Responses from 79 MND NSW members indicated that 15-21% had difficulty with speaking, writing and/or using a keyboard. Commonly used devices were desktop computers, laptops, tablets and mobile phones. Most participants (84%) were connected to the Internet and used it for email (91%), to find out more about MND (59%), to follow the news (50%) or for on-line shopping (46%). A third of respondents used Skype or its equivalent, but few used this to interact with health professionals. CONCLUSIONS: People with MND need greater awareness of technology options to access the most appropriate solutions. The timing for people with MND to make decisions about technology is critical. Health professionals need skills and knowledge about the application of technology to be able to work with people with MND to select the best communication technology options as early as possible after diagnosis. If people with MND are willing to trial telehealth technology, there is potential for tele-consultations via Skype or its equivalent, with health professionals. People with MND can benefit from health professional involvement to match technology to their functional limitations and personal preferences. However, health professionals need a comprehensive understanding of the application of available technology to achieve this. PMID- 28582253 TI - Translating Comprehensive Conservative Care for Chronic Knee Pain Into a Digital Care Pathway: 12-Week and 6-Month Outcomes for the Hinge Health Program. AB - BACKGROUND: Chronic knee pain (CKP) affects a large number of adults, many of whom do not receive best-practice care and are at high risk for unnecessary surgery. OBJECTIVE: The aim of this study was to investigate the effect of the Hinge Health 12-week digital care program (DCP) for CKP on knee pain and function, with secondary outcomes of surgery interest and satisfaction, at 12 weeks and 6 months after starting the program. METHODS: Individuals with CKP were recruited onto the 12-week program, comprising sensor-guided physical exercises, weekly education, activity tracking, and psychosocial support such as personal coaching and cognitive behavioral therapy (CBT). We used a single-arm design with assessment of outcomes at baseline, 12 weeks, and 6 months after starting the program. We used a linear mixed effects model with Tukey contrasts to compare timepoints and report intention-to-treat statistics with last observation carried forward. RESULTS: The cohort consisted of 41 individuals (32 female, mean age 52 years, SD 9 years). Between baseline and week 12, participants reported clinically significant improvements in the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain and Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form (KOOS-PS) function scales of 16 points (95% CI 12-21, P<.001) and 10 points (95% CI 6-14, P<.001), respectively. Significant reductions of 57% (mean difference 30, 95% CI 21-38, P<.001) and 51% (mean difference 25, 95% CI 16 33, P<.001) in visual analog scale (VAS) knee pain and stiffness, respectively, were observed at 12 weeks, as well as a 67% reduction in surgery interest (mean reduction 2.3 out of 10, 95% CI 1.5-3.1, P<.001). Average satisfaction at week 12 was 9.2 out of 10. Critically, all improvements were maintained at 6 months at similar or greater magnitude. CONCLUSIONS: Participants on the Hinge Health DCP for CKP showed substantial clinical improvements that were maintained 6 months after enrolling in the program. This shows that DCPs carry strong potential to deliver evidence-based, cost-effective care to those suffering from CKP. PMID- 28582254 TI - Studies Involving People With Dementia and Touchscreen Technology: A Literature Review. AB - BACKGROUND: Devices using touchscreen interfaces such as tablets and smartphones have been highlighted as potentially suitable for people with dementia due to their intuitive and simple control method. This population experience a lack of meaningful, engaging activities, yet the potential use of the touchscreen format to address this issue has not been fully realized. OBJECTIVE: To identify and synthesize the existing body of literature involving the use of touchscreen technology and people with dementia in order to guide future research in this area. METHODS: A systematized review of studies in the English language was conducted, where a touchscreen interface was used with human participants with dementia. RESULTS: A total of 45 articles met the inclusion criteria. Four questions were addressed concerning (1) the context of use, (2) reasons behind the selection of the technology, (3) details of the hardware and software, and (4) whether independent use by people with dementia was evidenced. CONCLUSIONS: This review presents an emerging body of evidence demonstrating that people with dementia are able to independently use touchscreen technology. The intuitive control method and adaptability of modern devices has driven the selection of this technology in studies. However, its primary use to date has been as a method to deliver assessments and screening tests or to provide an assistive function or cognitive rehabilitation. Building on the finding that people with dementia are able to use touchscreen technology and which design features facilitate this, more use could be made to deliver independent activities for meaningful occupation, entertainment, and fun. PMID- 28582255 TI - Community-Based Hip Fracture Rehabilitation Interventions for Older Adults With Cognitive Impairment: A Systematic Review. AB - BACKGROUND: A hip fracture in older adulthood can result in function and mobility decline. The consequences are debilitating and place a great burden on patients, caregivers, and the health care system. Although inpatient rehabilitation programs have proven effective, the best practices for community-based rehabilitation required to maintain the gains in function and mobility post hospital discharge are currently unknown. OBJECTIVE: The aim of this systematic review is to identify and evaluate the evidence on the effectiveness of community based rehabilitation post hospital discharge interventions for older adults with cognitive impairment (CI) following a hip fracture, and to identify the physical recovery outcomes and measures used in previous studies. METHODS: The methods outlined in the Cochrane Handbook for Systematic Reviews of Intervention were followed and findings were reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search strategy included a combination of text words and subject headings relating to the concepts of CI, dementia, delirium, cognitive reserve, and hip fractures. For a study to be included in the review, it had to involve participants with CI who underwent hip fracture surgery, and consisted of an outpatient intervention that occurred in the participant's home or community. Peer-reviewed journal articles were identified by searching various databases. Two independent reviewers screened the titles and abstracts to determine which articles comprising of a rehabilitation intervention within a community setting prior to being included for a full article review. A data extraction form and an evidence and quality checklist were used during the full article data analysis and synthesis. A meta-analysis was not conducted due to heterogeneity of measures and outcomes. RESULTS: The original search resulted in over 3000 articles. Of those, three studies satisfied the necessary criteria to be included in the systematic review. All studies included inpatient and outpatient physiotherapy, with some including a cognitive component, family education, and a discharge assessment. CONCLUSIONS: The findings from this review suggest that community-based rehabilitation post hospital discharge interventions show promising results towards improving various physical function outcomes, mobility, and activities of daily living for older adults with CI following a hip fracture. This review also demonstrates and discusses the current lack of outpatient rehabilitation interventions targeted towards older adults with CI post-hip fracture. Additionally, several substantive gaps that require attention to move this field forward are highlighted. PMID- 28582256 TI - Internet-Based Exercise Therapy Using Algorithms for Conservative Treatment of Anterior Knee Pain: A Pragmatic Randomized Controlled Trial. AB - BACKGROUND: Conservative treatment remains the first-line option, and there is significant medical evidence showing that home-based exercise therapy for the treatment of common causes of knee pain is effective. SimpleTherapy created an online platform that delivers Internet-based exercise therapy for common causes of knee pain. The system is driven by an algorithm that can process the user's feedback to provide an adaptive exercise regimen. This triple-armed, pragmatic randomized pilot was designed to evaluate if this telerehabilitation platform is safe and effective. OBJECTIVE: We hypothesized that a home-based, algorithm driven exercise therapy program can be safe for use and even improve compliance over the standard of care, the paper handout. METHODS: After an independent internal review board review and approval, the website trial.simpletherapy.com was opened. Once the trial was open for enrollment, no changes to the functionality or user interaction features were performed until the trial had closed. User accrual to the website was done using website optimization and social media postings tied to existence of knee pain. Consent was obtained online through checkboxes with third-party signature confirmation. No fees were charged to any patient. Patients were recruited online from an open access website. Outcomes were self-assessed through questionnaires with no face-to-face clinician interaction. A triple-arm randomized controlled trial was used with arm 1 being a static handout of exercises, arm 2 being a video version of arm 1, and arm 3 being a video-based, algorithm-driven system that took patient feedback and changed the exercises based on the feedback. Patients used household items and were not supervised by a physical therapist or clinician. Patients were reminded at 48-hour intervals to complete an exercise session. RESULTS: A total of 860 users found the trial and initiated the registration process. These 860 were randomized, and the demographic distribution shows the randomization was successful. In all, 70 users completed the 6-week regimen (8.1%): 20 users were in arm 1, 33 users in arm 2, and 17 users in arm 3. There were no adverse events reported in any of the 3 arms. All outcomes were self-assessed. No adverse events were reported during or after the trial. CONCLUSIONS: Because only 8.1% of those who enrolled completed the trial, an intent-to-treat analysis did not reach statistical significance in this pilot trial. However, the completion rates are comparable to those of previous online-only trials. Given an early phase trial, no adverse events were reported. Ongoing data collection continues and will form the basis for further data on the efficacy of this intervention. TRIAL REGISTRATION: Clinicaltrials.gov NCT01696162; https://clinicaltrials.gov/ct2/show/NCT01696162 (Archived by WebCite at http://www.webcitation.org/6lM8jC7Gu). PMID- 28582257 TI - How Therapists Use Visualizations of Upper Limb Movement Information From Stroke Patients: A Qualitative Study With Simulated Information. AB - BACKGROUND: Stroke is a leading cause of disability worldwide, with upper limb deficits affecting an estimated 30% to 60% of survivors. The effectiveness of upper limb rehabilitation relies on numerous factors, particularly patient compliance to home programs and exercises set by therapists. However, therapists lack objective information about their patients' adherence to rehabilitation exercises as well as other uses of the affected arm and hand in everyday life outside the clinic. We developed a system that consists of wearable sensor technology to monitor a patient's arm movement and a Web-based dashboard to visualize this information for therapists. OBJECTIVE: The aim of our study was to evaluate how therapists use upper limb movement information visualized on a dashboard to support the rehabilitation process. METHODS: An interactive dashboard prototype with simulated movement information was created and evaluated through a user-centered design process with therapists (N=8) at a rehabilitation clinic. Data were collected through observations of therapists interacting with an interactive dashboard prototype, think-aloud data, and interviews. Data were analyzed qualitatively through thematic analysis. RESULTS: Therapists use visualizations of upper limb information in the following ways: (1) to obtain objective data of patients' activity levels, exercise, and neglect outside the clinic, (2) to engage patients in the rehabilitation process through education, motivation, and discussion of experiences with activities of daily living, and (3) to engage with other clinicians and researchers based on objective data. A major limitation is the lack of contextual data, which is needed by therapists to discern how movement data visualized on the dashboard relate to activities of daily living. CONCLUSIONS: Upper limb information captured through wearable devices provides novel insights for therapists and helps to engage patients and other clinicians in therapy. Consideration needs to be given to the collection and visualization of contextual information to provide meaningful insights into patient engagement in activities of daily living. These findings open the door for further work to develop a fully functioning system and to trial it with patients and clinicians during therapy. PMID- 28582259 TI - Mobile Jump Assessment (mJump): A Descriptive and Inferential Study. AB - BACKGROUND: Vertical jump tests are used in athletics and rehabilitation to measure physical performance in people of different age ranges and fitness. Jumping ability can be analyzed through different variables, and the most commonly used are fly time and jump height. They can be obtained by a variety of measuring devices, but most are limited to laboratory use only. The current generation of smartphones contains inertial sensors that are able to record kinematic variables for human motion analysis, since they are tools for easy access and portability for clinical use. OBJECTIVE: The aim of this study was to describe and analyze the kinematics characteristics using the inertial sensor incorporated in the iPhone 4S, the lower limbs strength through a manual dynamometer, and the jump variables obtained with a contact mat in the squat jump and countermovement jump tests (fly time and jump height) from a cohort of healthy people. METHODS: A cross sectional study was conducted on a population of healthy young adults. Twenty-seven participants performed three trials (n=81 jumps) of squat jump and countermovement jump tests. Acceleration variables were measured through a smartphone's inertial sensor. Additionally, jump variables from a contact mat and lower limbs dynamometry were collected. RESULTS: In the present study, the kinematic variables derived from acceleration through the inertial sensor of a smartphone iPhone 4S, dynamometry of lower limbs with a handheld dynamometer, and the height and flight time with a contact mat have been described in vertical jump tests from a cohort of young healthy subjects. The development of the execution has been described, examined and identified in a squat jump test and countermovement jump test under acceleration variables that were obtained with the smartphone. CONCLUSIONS: The built-in iPhone 4S inertial sensor is able to measure acceleration variables while performing vertical jump tests for the squat jump and countermovement jump in healthy young adults. The acceleration kinematics variables derived from the smartphone's inertial sensor are higher in the countermovement jump test than the squat jump test. PMID- 28582258 TI - Information and Communication Technologies in the Care of the Elderly: Systematic Review of Applications Aimed at Patients With Dementia and Caregivers. AB - BACKGROUND: The interest in applying information and communications technology (ICT) in older adult health care is frequently promoted by the increasing and unsustainable costs of health care services. In turn, the unprecedented growth of the elderly population around the globe has urged institutions, companies, industries, and governments to respond to older adults' medical needs. OBJECTIVE: The aim of this review is to systematically identify the opportunities that ICT offers to health services, specifically for patients with dementia and their families. METHODS: A systematic review of the literature about ICT applications that have been developed to assist patients with Alzheimer's disease (AD) and their primary caregivers was conducted. The bibliographic search included works published between January 2005 and July 2015 in the databases Springer Link, Scopus, and Google Scholar. Of the published papers, 902 were obtained in the initial search, of which 214 were potentially relevant. Included studies fulfilled the following inclusion criteria: (1) studies carried out between the years of 2005 and 2015, (2) studies were published in English or Spanish, (3) studies with titles containing the keywords, (4) studies with abstracts containing information on ICT applications and AD, and (5) studies published in indexed journals, proceedings, and book chapters. RESULTS: A total of 26 studies satisfied the inclusion criteria for the current review. Among them, 16 were aimed at the patient with AD and 10 at the primary caregivers and/or family members. The studies targeted applications that included assistive technology (44%, 7/16), telecare (37%, 6/16), and telemedicine (31%, 5/16). The information systems (56%, 9/16) and Internet (44%, 7/16) were the most commonly used enabling technologies for the studies. Finally, areas of attention more covered by the studies were care (56%, 9/16), treatment (56%, 9/16), and management (50%, 8/16). Furthermore, it was found that 20 studies (77%, 8/26) evaluated their ICT applications through carrying out tests with patients with dementia and caregivers. CONCLUSIONS: The key finding of this systematic review revealed that the use of ICT tools can be strongly recommended to be used as a lifestyle in the elderly in order to improve the quality of life for the elderly and their primary caregivers. Since patients with AD are completely dependent in most activities, it is necessary to give attention to their primary caregivers to avoid stress and depression. In addition, the use of ICT in the daily life of caregivers can help them understand the disease process and manage situations in a way that is beneficial for both parties. It is expected that future developments concerning technological projects can support this group of people. PMID- 28582260 TI - A Personalized Self-Management Rehabilitation System for Stroke Survivors: A Quantitative Gait Analysis Using a Smart Insole. AB - BACKGROUND: In the United Kingdom, stroke is the single largest cause of adult disability and results in a cost to the economy of L8.9 billion per annum. Service needs are currently not being met; therefore, initiatives that focus on patient-centered care that promote long-term self-management for chronic conditions should be at the forefront of service redesign. The use of innovative technologies and the ability to apply these effectively to promote behavior change are paramount in meeting the current challenges. OBJECTIVE: Our objective was to gain a deeper insight into the impact of innovative technologies in support of home-based, self-managed rehabilitation for stroke survivors. An intervention of daily walks can assist with improving lower limb motor function, and this can be measured by using technology. This paper focuses on assessing the usage of self-management technologies on poststroke survivors while undergoing rehabilitation at home. METHODS: A realist evaluation of a personalized self management rehabilitation system was undertaken in the homes of stroke survivors (N=5) over a period of approximately two months. Context, mechanisms, and outcomes were developed and explored using theories relating to motor recovery. Participants were encouraged to self-manage their daily walking activity; this was achieved through goal setting and motivational feedback. Gait data were collected and analyzed to produce metrics such as speed, heel strikes, and symmetry. This was achieved using a "smart insole" to facilitate measurement of walking activities in a free-living, nonrestrictive environment. RESULTS: Initial findings indicated that 4 out of 5 participants performed better during the second half of the evaluation. Performance increase was evident through improved heel strikes on participants' affected limb. Additionally, increase in performance in relation to speed was also evident for all 5 participants. A common strategy emerged across all but one participant as symmetry performance was sacrificed in favor of improved heel strikes. This paper evaluates compliance and intensity of use. CONCLUSION: Our findings suggested that 4 out of the 5 participants improved their ability to heel strike on their affected limb. All participants showed improvements in their speed of gait measured in steps per minute with an average increase of 9.8% during the rehabilitation program. Performance in relation to symmetry showed an 8.5% average decline across participants, although 1 participant improved by 4%. Context, mechanism, and outcomes indicated that dual motor learning and compensatory strategies were deployed by the participants. PMID- 28582261 TI - Validated Smartphone-Based Apps for Ear and Hearing Assessments: A Review. AB - BACKGROUND: An estimated 360 million people have a disabling hearing impairment globally, the vast majority of whom live in low- and middle-income countries (LMICs). Early identification through screening is important to negate the negative effects of untreated hearing impairment. Substantial barriers exist in screening for hearing impairment in LMICs, such as the requirement for skilled hearing health care professionals and prohibitively expensive specialist equipment to measure hearing. These challenges may be overcome through utilization of increasingly available smartphone app technologies for ear and hearing assessments that are easy to use by unskilled professionals. OBJECTIVE: Our objective was to identify and compare available apps for ear and hearing assessments and consider the incorporation of such apps into hearing screening programs. METHODS: In July 2015, the commercial app stores Google Play and Apple App Store were searched to identify apps for ear and hearing assessments. Thereafter, six databases (EMBASE, MEDLINE, Global Health, Web of Science, CINAHL, and mHealth Evidence) were searched to assess which of the apps identified in the commercial review had been validated against gold standard measures. A comparison was made between validated apps. RESULTS: App store search queries returned 30 apps that could be used for ear and hearing assessments, the majority of which are for performing audiometry. The literature search identified 11 eligible validity studies that examined 6 different apps. uHear, an app for self-administered audiometry, was validated in the highest number of peer reviewed studies against gold standard pure tone audiometry (n=5). However, the accuracy of uHear varied across these studies. CONCLUSIONS: Very few of the available apps have been validated in peer-reviewed studies. Of the apps that have been validated, further independent research is required to fully understand their accuracy at detecting ear and hearing conditions. PMID- 28582263 TI - Counting Grasping Action Using Force Myography: An Exploratory Study With Healthy Individuals. AB - BACKGROUND: Functional arm movements generally require grasping an object. The possibility of detecting and counting the action of grasping is believed to be of importance for individual with motor function deficits of the arm, as it could be an indication of the number of the functional arm movements performed by the individuals during rehabilitation. In this exploratory work, the feasibility of using armbands recording radial displacements of forearm muscles and tendons (ie, force myography, FMG) to estimate hand grasping with healthy individuals was investigated. In contrast to previous studies, this exploratory study investigates the feasibility of (1) detecting grasping when the participants move their arms, which could introduce large artifacts to the point of potentially preventing the practical use of the proposed technology, and (2) counting grasping during arm-reaching tasks. OBJECTIVE: The aim of this study was to determine the usefulness of FMG in the detection of functional arm movements. The use of FMG straps placed on the forearm is proposed for counting the number of grasping actions in the presence of arm movements. METHODS: Ten healthy volunteers participated in this study to perform a pick-and-place exercise after providing informed consent. FMG signals were simultaneously collected using 2 FMG straps worn on their wrist and at the midposition of their forearm, respectively. Raw FMG signals and 3 additional FMG features (ie, root mean square, wavelength, and window symmetry) were extracted and fed into a linear discriminant analysis classifier to predict grasping states. The transition from nongrasping to grasping states was detected during the process of counting the number of grasping actions. RESULTS: The median accuracy for detecting grasping events using FMG recorded from the wrist was 95%, and the corresponding interquartile range (IQR) was 5%. For forearm FMG classification, the median accuracy was 92%, and the corresponding IQR was 3%. The difference between the 2 median accuracies was statistically significant (P<.001) when using a paired 2-tailed sign test. The median percentage error for counting grasping events when FMG was recorded from the wrist was 1%, and the corresponding IQR was 2%. The median percentage error for FMG recorded from the forearm was 2%, and the corresponding IQR was also 2%. While the median percentage error for the wrist was lower than that of the forearm, the difference between the 2 was not statistically significant based on a paired 2-tailed sign test (P=.29). CONCLUSIONS: This study reports that grasping can reliably be counted using an unobtrusive and simple FMG strap even in the presence of arm movements. Such a result supports the foundation for future research evaluating the feasibility of monitoring hand grasping during unsupervised ADL, leading to further investigations with individuals with motor function deficits of the arm. PMID- 28582262 TI - Technologies to Support Community-Dwelling Persons With Dementia: A Position Paper on Issues Regarding Development, Usability, Effectiveness and Cost Effectiveness, Deployment, and Ethics. AB - BACKGROUND: With the expected increase in the numbers of persons with dementia, providing timely, adequate, and affordable care and support is challenging. Assistive and health technologies may be a valuable contribution in dementia care, but new challenges may emerge. OBJECTIVE: The aim of our study was to review the state of the art of technologies for persons with dementia regarding issues on development, usability, effectiveness and cost-effectiveness, deployment, and ethics in 3 fields of application of technologies: (1) support with managing everyday life, (2) support with participating in pleasurable and meaningful activities, and (3) support with dementia health and social care provision. The study also aimed to identify gaps in the evidence and challenges for future research. METHODS: Reviews of literature and expert opinions were used in our study. Literature searches were conducted on usability, effectiveness and cost-effectiveness, and ethics using PubMed, Embase, CINAHL, and PsycINFO databases with no time limit. Selection criteria in our selected technology fields were reviews in English for community-dwelling persons with dementia. Regarding deployment issues, searches were done in Health Technology Assessment databases. RESULTS: According to our results, persons with dementia want to be included in the development of technologies; there is little research on the usability of assistive technologies; various benefits are reported but are mainly based on low-quality studies; barriers to deployment of technologies in dementia care were identified, and ethical issues were raised by researchers but often not studied. Many challenges remain such as including the target group more often in development, performing more high-quality studies on usability and effectiveness and cost-effectiveness, creating and having access to high-quality datasets on existing technologies to enable adequate deployment of technologies in dementia care, and ensuring that ethical issues are considered an important topic for researchers to include in their evaluation of assistive technologies. CONCLUSIONS: Based on these findings, various actions are recommended for development, usability, effectiveness and cost-effectiveness, deployment, and ethics of assistive and health technologies across Europe. These include avoiding replication of technology development that is unhelpful or ineffective and focusing on how technologies succeed in addressing individual needs of persons with dementia. Furthermore, it is suggested to include these recommendations in national and international calls for funding and assistive technology research programs. Finally, practitioners, policy makers, care insurers, and care providers should work together with technology enterprises and researchers to prepare strategies for the implementation of assistive technologies in different care settings. This may help future generations of persons with dementia to utilize available and affordable technologies and, ultimately, to benefit from them. PMID- 28582264 TI - Machine Learning to Improve Energy Expenditure Estimation in Children With Disabilities: A Pilot Study in Duchenne Muscular Dystrophy. AB - BACKGROUND: Children with physical impairments are at a greater risk for obesity and decreased physical activity. A better understanding of physical activity pattern and energy expenditure (EE) would lead to a more targeted approach to intervention. OBJECTIVE: This study focuses on studying the use of machine learning algorithms for EE estimation in children with disabilities. A pilot study was conducted on children with Duchenne muscular dystrophy (DMD) to identify important factors for determining EE and develop a novel algorithm to accurately estimate EE from wearable sensor-collected data. METHODS: There were 7 boys with DMD, 6 healthy control boys, and 22 control adults recruited. Data were collected using smartphone accelerometer and chest-worn heart rate sensors. The gold standard EE values were obtained from the COSMED K4b2 portable cardiopulmonary metabolic unit worn by boys (aged 6-10 years) with DMD and controls. Data from this sensor setup were collected simultaneously during a series of concurrent activities. Linear regression and nonlinear machine-learning based approaches were used to analyze the relationship between accelerometer and heart rate readings and COSMED values. RESULTS: Existing calorimetry equations using linear regression and nonlinear machine-learning-based models, developed for healthy adults and young children, give low correlation to actual EE values in children with disabilities (14%-40%). The proposed model for boys with DMD uses ensemble machine learning techniques and gives a 91% correlation with actual measured EE values (root mean square error of 0.017). CONCLUSIONS: Our results confirm that the methods developed to determine EE using accelerometer and heart rate sensor values in normal adults are not appropriate for children with disabilities and should not be used. A much more accurate model is obtained using machine-learning-based nonlinear regression specifically developed for this target population. PMID- 28582265 TI - Application of fluence field modulation to proton computed tomography for proton therapy imaging. AB - This simulation study presents the application of fluence field modulated computed tomography, initially developed for x-ray CT, to proton computed tomography (pCT). By using pencil beam (PB) scanning, fluence modulated pCT (FMpCT) may achieve variable image quality in a pCT image and imaging dose reduction. Three virtual phantoms, a uniform cylinder and two patients, were studied using Monte Carlo simulations of an ideal list-mode pCT scanner. Regions of interest (ROI) were selected for high image quality and only PBs intercepting them preserved full fluence (FF). Image quality was investigated in terms of accuracy (mean) and noise (standard deviation) of the reconstructed proton relative stopping power compared to reference values. Dose calculation accuracy on FMpCT images was evaluated in terms of dose volume histograms (DVH), range difference (RD) for beam-eye-view (BEV) dose profiles and gamma evaluation. Pseudo FMpCT scans were created from broad beam experimental data acquired with a list-mode pCT prototype. FMpCT noise in ROIs was equivalent to FF images and accuracy better than -1.3%(-0.7%) by using 1% of FF for the cylinder (patients). Integral imaging dose reduction of 37% and 56% was achieved for the two patients for that level of modulation. Corresponding DVHs from proton dose calculation on FMpCT images agreed to those from reference images and 96% of BEV profiles had RD below 2 mm, compared to only 1% for uniform 1% of FF. Gamma pass rates (2%, 2 mm) were 98% for FMpCT while for uniform 1% of FF they were as low as 59%. Applying FMpCT to preliminary experimental data showed that low noise levels and accuracy could be preserved in a ROI, down to 30% modulation. We have shown, using both virtual and experimental pCT scans, that FMpCT is potentially feasible and may allow a means of imaging dose reduction for a pCT scanner operating in PB scanning mode. This may be of particular importance to proton therapy given the low integral dose found outside the target. PMID- 28582266 TI - A beam monitoring and validation system for continuous line scanning in proton therapy. AB - Line scanning represents a faster and potentially more flexible form of pencil beam scanning than conventional step-and-shoot irradiations. It seeks to minimize dead times in beam delivery whilst preserving the possibility of modulating the dose at any point in the target volume. Our second generation proton gantry features irradiations in line scanning mode, but it still lacks a dedicated monitoring and validation system that guarantees patient safety throughout the irradiation. We report on its design and implementation in this paper. In line scanning, we steer the proton beam continuously along straight lines while adapting the speed and/or current frequently to modulate the delivered dose. We intend to prevent delivery errors that could be clinically relevant through a two stage system: safety level 1 monitors the beam current and position every 10 MUs. We demonstrate that direct readings from ionization chambers in the gantry nozzle and Hall probes in the scanner magnets provide required information on current and position, respectively. Interlocks will be raised when measured signals exceed their predefined tolerance bands. Even in case of an erroneous delivery, safety level 1 restricts hot and cold spots of the physically delivered fraction dose to +/-[Formula: see text] (+/-[Formula: see text] of [Formula: see text] biologically). In safety level 2-an additional, partly redundant validation step we compare the integral line profile measured with a strip monitor in the nozzle to a forward-calculated prediction. The comparison is performed between two line applications to detect amplifying inaccuracies in speed and current modulation. This level can be regarded as an online quality assurance of the machine. Both safety levels use devices and functionalities already installed along the beamline. Hence, the presented monitoring and validation system preserves full compatibility of discrete and continuous delivery mode on a single gantry, with the possibility of switching between modes during the application of a single field. PMID- 28582267 TI - Detection of anatomical changes in lung cancer patients with 2D time-integrated, 2D time-resolved and 3D time-integrated portal dosimetry: a simulation study. AB - The aim of this work is to assess the performance of 2D time-integrated (2D-TI), 2D time-resolved (2D-TR) and 3D time-integrated (3D-TI) portal dosimetry in detecting dose discrepancies between the planned and (simulated) delivered dose caused by simulated changes in the anatomy of lung cancer patients. For six lung cancer patients, tumor shift, tumor regression and pleural effusion are simulated by modifying their CT images. Based on the modified CT images, time-integrated (TI) and time-resolved (TR) portal dose images (PDIs) are simulated and 3D-TI doses are calculated. The modified and original PDIs and 3D doses are compared by a gamma analysis with various gamma criteria. Furthermore, the difference in the D 95% (DeltaD 95%) of the GTV is calculated and used as a gold standard. The correlation between the gamma fail rate and the DeltaD 95% is investigated, as well the sensitivity and specificity of all combinations of portal dosimetry method, gamma criteria and gamma fail rate threshold. On the individual patient level, there is a correlation between the gamma fail rate and the DeltaD 95%, which cannot be found at the group level. The sensitivity and specificity analysis showed that there is not one combination of portal dosimetry method, gamma criteria and gamma fail rate threshold that can detect all simulated anatomical changes. This work shows that it will be more beneficial to relate portal dosimetry and DVH analysis on the patient level, rather than trying to quantify a relationship for a group of patients. With regards to optimizing sensitivity and specificity, different combinations of portal dosimetry method, gamma criteria and gamma fail rate should be used to optimally detect certain types of anatomical changes. PMID- 28582268 TI - The influence of anisotropic Rashba spin-orbit coupling on current-induced spin polarization in graphene. AB - We consider a disordered graphene layer with anisotropic Rashba spin-orbit coupling subjected to a longitudinal electric field. Using the linear response theory we calculate current-induced spin polarization including in-plane normal and parallel components with respect to the electric field direction. Unlike the case of isotropic Rashba spin-orbit where the normal component of spin polarization is linear in terms of Fermi energy around the Dirac point, anisotropic Rashba spin-orbit can result in non-linear dependence of this component at such energies within the Lifshitz points. Furthermore, we show that anisotropic Rashba interaction allows for tuning the direction of spin polarization from perpendicular direction to the parallel one such that for certain values of Rashba parameters the magnitudes of both components can also be quenched. The effect of carriers scattering on randomly distributed non-magnetic disorders is also taken into account by calculating vertex correction. This results in modification of spin polarization components depending on the relative strength of Rashba parameters. PMID- 28582269 TI - Automated diagnosis of prostate cancer in multi-parametric MRI based on multimodal convolutional neural networks. AB - Automated methods for prostate cancer (PCa) diagnosis in multi-parametric magnetic resonance imaging (MP-MRIs) are critical for alleviating requirements for interpretation of radiographs while helping to improve diagnostic accuracy (Artan et al 2010 IEEE Trans. Image Process. 19 2444-55, Litjens et al 2014 IEEE Trans. Med. Imaging 33 1083-92, Liu et al 2013 SPIE Medical Imaging (International Society for Optics and Photonics) p 86701G, Moradi et al 2012 J. Magn. Reson. Imaging 35 1403-13, Niaf et al 2014 IEEE Trans. Image Process. 23 979-91, Niaf et al 2012 Phys. Med. Biol. 57 3833, Peng et al 2013a SPIE Medical Imaging (International Society for Optics and Photonics) p 86701H, Peng et al 2013b Radiology 267 787-96, Wang et al 2014 BioMed. Res. Int. 2014). This paper presents an automated method based on multimodal convolutional neural networks (CNNs) for two PCa diagnostic tasks: (1) distinguishing between cancerous and noncancerous tissues and (2) distinguishing between clinically significant (CS) and indolent PCa. Specifically, our multimodal CNNs effectively fuse apparent diffusion coefficients (ADCs) and T2-weighted MP-MRI images (T2WIs). To effectively fuse ADCs and T2WIs we design a new similarity loss function to enforce consistent features being extracted from both ADCs and T2WIs. The similarity loss is combined with the conventional classification loss functions and integrated into the back-propagation procedure of CNN training. The similarity loss enables better fusion results than existing methods as the feature learning processes of both modalities are mutually guided, jointly facilitating CNN to 'see' the true visual patterns of PCa. The classification results of multimodal CNNs are further combined with the results based on handcrafted features using a support vector machine classifier. To achieve a satisfactory accuracy for clinical use, we comprehensively investigate three critical factors which could greatly affect the performance of our multimodal CNNs but have not been carefully studied previously. (1) Given limited training data, how can these be augmented in sufficient numbers and variety for fine tuning deep CNN networks for PCa diagnosis? (2) How can multimodal MP-MRI information be effectively combined in CNNs? (3) What is the impact of different CNN architectures on the accuracy of PCa diagnosis? Experimental results on extensive clinical data from 364 patients with a total of 463 PCa lesions and 450 identified noncancerous image patches demonstrate that our system can achieve a sensitivity of 89.85% and a specificity of 95.83% for distinguishing cancer from noncancerous tissues and a sensitivity of 100% and a specificity of 76.92% for distinguishing indolent PCa from CS PCa. This result is significantly superior to the state-of-the-art method relying on handcrafted features. PMID- 28582270 TI - Conversion for Unfavorable Intraoperative Events Results in Significantly Worse Outcomes During Laparoscopic Liver Resection: Lessons Learned From a Multicenter Review of 2861 Cases. AB - OBJECTIVE: To investigate the risk factors for conversion during laparoscopic liver resection and its effect on patient outcome in a large cohort of patients. Additional analysis of outcomes in patients who required conversion for unfavorable intraoperative findings and conversion for unfavorable intraoperative events will be performed to establish if the cause of conversion effects outcome. SUMMARY BACKGROUND DATA: Multiple previous studies demonstrate that laparoscopic liver surgery reduces intraoperative blood loss, hospital stay, and morbidity while maintaining comparable oncological and survival outcomes when compared with open liver resections. However, limited information is available regarding the possible sequelae of conversion to open surgery, especially with regards to cause of conversion. METHODS: A retrospective analysis of 2861 cases from prospectively maintained databases of 7 tertiary liver centers across Europe was performed. RESULTS: Neo-adjuvant chemotherapy, previous liver resection(s), resections for malignant lesions, postero-superior location, and the extent of the resection are associated with an increased risk of conversion. Patients who require conversion have longer operations with higher blood loss; a longer HDU and total hospital stay, increased frequency and severity of complications and higher 30- and 90-day mortality. Patients who had an elective conversion for an unfavorable intraoperative finding had better outcomes than patients who had an emergency conversion secondary to an unfavorable intraoperative event in terms of HDU and total hospital stay, severity of complication, and 90-day mortality. CONCLUSIONS: Our study highlights the risk factors for conversion and suggests that conversion for unfavorable intraoperative events is associated with worse outcomes. PMID- 28582271 TI - Preoperative Oral Carbohydrate Load Versus Placebo in Major Elective Abdominal Surgery (PROCY): A Randomized, Placebo-controlled, Multicenter, Phase III Trial. AB - OBJECTIVE: To explore whether preoperative oral carbohydrate (CHO) loading could achieve a reduction in the occurrence of postoperative infections. BACKGROUND: Hyperglycemia may increase the risk of infection. Preoperative CHO loading can achieve postoperative glycemic control. METHODS: This was a randomized, controlled, multicenter, open-label trial. Nondiabetic adult patients who were candidates for elective major abdominal operation were randomized (1:1) to a CHO (preoperative oral intake of 800 mL of water containing 100 g of CHO) or placebo group (intake of 800 mL of water). The blood glucose level was measured every 4 hours for 4 days. Insulin was administered when the blood glucose level was >180 mg/dL. The primary endpoint was the occurrence of postoperative infection. The secondary endpoint was the number of patients needing insulin. RESULTS: From January 2011 through December 2015, 880 patients were randomly allocated to the CHO (n = 438) or placebo (n = 442) group. From each group, 331 patients were available for the analysis. Postoperative infection occurred in 16.3% (54/331) of CHO group patients and 16.0% (53/331) of placebo group patients (relative risk 1.019, 95% confidence interval 0.720-1.442, P = 1.00). Insulin was needed in 8 (2.4%) CHO group patients and 53 (16.0%) placebo group patients (relative risk 0.15, 95% confidence interval 0.07-0.31, P < 0.001). CONCLUSIONS: Oral preoperative CHO load is effective for avoiding a blood glucose level >180 mg/dL, but without affecting the risk of postoperative infectious complication. PMID- 28582273 TI - Which Knife Was Used?: Using a Porcine Model to Assess Stab Wound Size. AB - Forensic pathologists who autopsy stab wound victims may be called upon to determine whether a specific weapon recovered as evidence caused the decedent's wounds. Some forensic training programs instruct pathologists to excise wounds and place them in formalin. There is little published information about the reliability of these assessments. To address these deficiencies, a porcine model was used to establish the limits of in situ knife wound measurements of wounds caused by 3 knives of different widths stabbed at 90 degrees to the skin surface. The results indicate that within the 95% confidence interval, most stab wounds when measured on the surface of the skin will be within 1 to 3 mm of the size of the knife blade. Four wounds from different anatomical areas of the pig were excised from the body, and after excision, their measurements differed from their in situ length. After fixation in a 10% buffered formalin solution, one wound stayed the same, one wound lengthened, one shrunk minimally, and the one from the thinner abdominal skin shrunk by 6 mm (11%). This study presents a porcine model that can be used to define parameters for testimony. PMID- 28582274 TI - Synchronous Ductal Carcinoma In Situ and Intravascular Large B-cell Lymphoma of the Breast. PMID- 28582272 TI - Ultrasound-Guided Steroid Injection of the Pisotriquetral Joint: A Multidisciplinary Effort. AB - From the perspective of a multidisciplinary team, the authors describe the first reported use of ultrasound guidance for steroid injection into the pisotriquetral joint to relieve wrist pain of a person with spinal cord injury undergoing acute inpatient rehabilitation. Musculoskeletal ultrasound guidance was used to improve the accuracy of a corticosteroid injection of the pisotriquetral joint and the basal thumb in a 70-year-old man with paraplegia experiencing multifocal degenerative wrist pain. There was no bleeding or bruising after the injections, and the patient reported complete pain resolution 1 wk after the injections, which continued for over 1 yr. A multidisciplinary team was key in diagnosis, selection of treatment, and evaluation of treatment effect. Corticosteroid injection of the pisotriquetral joint under ultrasound guidance can be used as a treatment modality for managing wrist pain stemming from that joint. Further investigation and studies evaluating the use of ultrasound versus other imaging modalities for injection of the wrist are indicated. PMID- 28582275 TI - Acute Isolated Paraplegia Revealing an Ewing Sarcoma of the Thoracic Spine. AB - Ewing sarcoma (ES) infrequently affects the spine. Diagnosis is usually made several weeks following growing symptoms. In this report, we present the case of a child with ES localized at the upper thoracic level. ES was revealed by isolated acute complete paraplegia mimicking medullary stroke. The girl was operated for decompressive laminectomy and tumor removal. Afterwards, she received adjuvant therapy. Subsequently, the child showed a slow improvement of her leg sensitivity associated with a partial motor recovery. ES can affect the mobile spine. Acute symptomatology due to intratumoral hemorrhage and sudden spinal cord compression may suggest the diagnosis. Neurological outcomes following ES are generally poor. PMID- 28582277 TI - Simulation-Based Assessment Identifies Longitudinal Changes in Cognitive Skills in an Anesthesiology Residency Training Program. AB - OBJECTIVES: We describe observed improvements in nontechnical or "higher-order" deficiencies and cognitive performance skills in an anesthesia residency cohort for a 1-year time interval. Our main objectives were to evaluate higher-order, cognitive performance and to demonstrate that simulation can effectively serve as an assessment of cognitive skills and can help detect "higher-order" deficiencies, which are not as well identified through more traditional assessment tools. We hypothesized that simulation can identify longitudinal changes in cognitive skills and that cognitive performance deficiencies can then be remediated over time. METHODS: We used 50 scenarios evaluating 35 residents during 2 subsequent years, and 18 of those 35 residents were evaluated in both years (post graduate years 3 then 4) in the same or similar scenarios. Individual basic knowledge and cognitive performance during simulation-based scenarios were assessed using a 20- to 27-item scenario-specific checklist. Items were labeled as basic knowledge/technical (lower-order cognition) or advanced cognitive/nontechnical (higher-order cognition). Identical or similar scenarios were repeated annually by a subset of 18 residents during 2 successive academic years. For every scenario and item, we calculated group error scenario rate (frequency) and individual (resident) item success. Grouped individuals' success rates are calculated as mean (SD), and item success grade and group error rates are calculated and presented as proportions. For all analyses, alpha level is 0.05. RESULTS: Overall PGY4 residents' error rates were lower and success rates higher for the cognitive items compared with technical item performance in the operating room and resuscitation domains. In all 3 clinical domains, the cognitive error rate by PGY4 residents was fairly low (0.00-0.22) and the cognitive success rate by PGY4 residents was high (0.83-1.00) and significantly better compared with previous annual assessments (P < 0.05). Overall, there was an annual decrease in error rates for 2 years, primarily driven by decreases in cognitive errors. The most commonly observed cognitive error types remained anchoring, availability bias, premature closure, and confirmation bias. CONCLUSIONS: Simulation-based assessments can highlight cognitive performance areas of relative strength, weakness, and progress in a resident or resident cohort. We believe that they can therefore be used to inform curriculum development including activities that require higher-level cognitive processing. PMID- 28582276 TI - BIOMARKERS OF NEOVASCULAR ACTIVITY IN AGE-RELATED MACULAR DEGENERATION USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To study the qualitative and quantitative features of choroidal neovascular (NV) membranes in age-related macular degeneration using optical coherence tomography angiography in patients with active and quiescent NV lesions before and after treatment with anti-vascular endothelial growth factor. METHODS: Macular optical coherence tomography angiography images were obtained using RTVue XR Avanti with AngioVue. Morphologic features and quantitative measurements of the NV lesion were analyzed using en face projection images. The NV lesion was subdivided into inner segment and outer fringe for further fractal dimension analysis. RESULTS: In a series of 31 eyes, 11 eyes with active NV lesions at baseline and after consecutive follow-up after treatment with anti-vascular endothelial growth factor therapy and 20 eyes with quiescent NV lesions were included in this study. Morphologically, all the quiescent NV lesions versus 63.6% of the active NV lesions demonstrated a prominent central vessel and active leasions demonstrated a greater rate of small vessels branching (82%) and peripheral arcades (82%) than quiescent lesions (30% and 40% respectively) and this was statistically significant. The lesion area and vessel density was not statistically significantly different after treatment or versus quiescent lesions although the latter lesions were reduced in area. Lesion pattern complexity measured by the fractal dimension was statistically significantly lower in the inner part of the lesion after treatment and statistically significantly lower in the total lesion of the quiescent NV compared with the active NV. CONCLUSION: Optical coherence tomography angiography is a new, noninvasive imaging modality that can be used to perform qualitative and quantitative analyses of NV lesions. In the future, OCT angiography may provide biomarkers of activity and guide the evaluation and treatment and monitoring of neovascularization in age-related macular degeneration. PMID- 28582278 TI - Exosomes From Adipose-derived Mesenchymal Stem Cells Protect the Myocardium Against Ischemia/Reperfusion Injury Through Wnt/beta-Catenin Signaling Pathway. AB - Mesenchymal stem cells (MSCs) and their secreted exosomes exert a cardioprotective role in jeopardized myocardium. However, the specific effects and underlying mechanisms of exosomes derived from adipose-derived MSCs (ADMSCs) on myocardial ischemia/reperfusion (I/R) injury remain largely unclear. In this study, ADMSC-derived exosomes (ADMSCs-ex) were administrated into the rats subjected to I/R injury and H9c2 cells exposed to hypoxia/reoxygenation (H/R). Consequently, administration of ADMSCs-ex significantly reduced I/R-induced myocardial infarction, accompanied with a decrease in serum levels of creatine kinase-myocardial band, lactate dehydrogenase, and cardiac troponin I (cTnI). Simultaneously, ADMSCs-ex dramatically antagonized I/R-induced myocardial apoptosis, along with the upregulation of Bcl-2 and downregulation of Bax, and inhibition of Caspase 3 activity in rat myocardium. Similarly, ADMSCs-ex significantly reduced cell apoptosis and the expression of Bax, but markedly increased cell viability and the expression of Bcl-2 and Cyclin D1 under H/R. Furthermore, ADMSCs-ex observably induced the activation of Wnt/beta-catenin signaling by attenuating I/R- and H/R-induced inhibition of Wnt3a, p-GSK-3beta (Ser9), and beta-catenin expression. Importantly, treatment with Wnt/beta-catenin inhibitor XAV939 partly neutralized ADMSC-ex-induced antiapoptotic and prosurvival effects in H9c2 cells. In conclusion, we confirmed that ADMSCs-ex protect ischemic myocardium from I/R injury through the activation of Wnt/beta catenin signaling pathway. PMID- 28582279 TI - Prevalence and influence on outcome of HER2/neu, HER3 and NRG1 expression in patients with metastatic colorectal cancer. AB - Our aim was to explore the impact of the HER2/neu, HER3 receptor as well as their ligands' neuregulin (NRG1) expression on the outcome of patients with metastatic colorectal cancer (mCRC). NRG1, HER2/neu and HER3 expression was evaluated in 208 patients with mCRC receiving 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as the first-line treatment. Biomarker expression was correlated with the outcome of patients. NRG1 (low: 192 vs. high: 16), HER2/neu (low: 201 vs. high: 7) and HER3 (low: 69 vs. high: 139) expressions were assessed in 208 patients. High versus low NRG1 expression significantly affected progression-free survival (PFS) [4.7 vs. 8.2 months, hazard ratio (HR): 2.45; 95% confidence interval (CI): 1.45-4.13; P=0.001], but not overall survival (OS) (15.5 vs. 20.7 months, HR: 1.33; 95% CI: 0.76-2.35; P=0.32). High versus low HER3 expression (PFS: 7.1 vs. 8.8 months, HR: 1.11; 95% CI: 0.82-1.50; P=0.50; OS: 19.8 vs. 21.1 months, HR: 0.95; 95% CI: 0.70-1.30; P=0.75) and high compared with low HER2/neu expression (PFS: 7.7 vs. 8.0 months, HR: 1.07; 95% CI: 0.71-1.60; P=0.75; OS: 16.6 vs. 21.1 months, HR: 1.13; 95% CI: 0.75-1.71; P=0.57) did not influence outcome. High NRG1 expression was associated with inferior PFS in the FIRE-1 trial. We did not detect a prognostic impact of HER2/neu and HER3 overexpression in mCRC. The frequency of overexpression was comparable with other studies. PMID- 28582280 TI - Lorazepam Challenge for Individuals at Varying Genetic Risk for Alzheimer Disease. AB - INTRODUCTION: This study set out to clarify the differential acute cognitive impact of lorazepam based on varying genetic risk for Alzheimer disease. METHODS: Fifty-seven cognitively unimpaired individuals aged 51 to 88, genotyped according to apolipoprotein E (APOE) and translocase of outer mitochondrial membrane (40 homolog) poly-T lengths, completed cognitive testing before, 2.5 and 5 hours after receiving a 1 mg dose of lorazepam. RESULTS: Post-lorazepam, there were significant (P<0.05) declines from baseline in memory, psychomotor processing speed, and executive function. At 2.5 hours, the magnitude of this lorazepam induced cognitive change was significantly greater in the APOE3/4 group than in the APOE3/3 group for tests of working memory and visuospatial memory/executive function. At 5 hours postchallenge, verbal memory and working memory deficits persisted in the APOE3/4 group compared with the APOE3/3 group. At 5 hours after lorazepam challenge, as compared with the very long/very long group, the short/short group performed slightly worse on a test of working memory (P<0.05), but no other differences were observed among translocase of the outer mitochondrial membrane 40 homolog poly-T variant groups. DISCUSSION: The lorazepam challenge may be unmasking presymptomatic cognitive dysfunction associated with APOE4 carriage. PMID- 28582281 TI - Relation between secondhand smoke exposure and cardiovascular risk factors in never smokers. AB - OBJECTIVE: Secondhand smoke exposure (SHSE) in nonsmokers has been associated with premature cardiovascular mortality and ischemic heart disease. We conducted a cross-sectional, population-based study evaluating the relationship between SHSE, measured by subjective and objective methods, and conventional cardiovascular risks such as blood pressure, lipid profiles, and fasting glucose. METHODS: We extracted information on 7376 healthy adults who had never smoked, for whom there were available urine cotinine levels, from the Korea National Health and Nutrition Examination Survey 2008-2011. SHSE was defined using self report questionnaires and urine cotinine levels. The main outcomes included SBP and DBP, serum lipid profiles, and fasting glucose. RESULTS: The mean age of the study population was 45.4 +/- 0.4 years and 75.2% were women. Self-reported SHSE had no significant association with study outcomes except for DBP, which had marginally positive relationships (P = 0.060). Unadjusted analysis showed higher cotinine levels were associated with lower SBP, total cholesterol, LDL cholesterol, and triglyceride. All associations lost statistical significance after multivariable adjustment. Fasting glucose had a positive relationship with urine cotinine in quartiles but not with logarithm-transformed cotinine. CONCLUSION: Although SHSE is associated with increased risk of cardiovascular mortality and morbidity, we did not find any consistent relationship among SHSE and blood pressure, lipid, or fasting glucose levels in this cross-sectional study. Using objective measurements of urine cotinine did not alter this relationship. Further long-term prospective studies are needed to evaluate the effect of SHSE as a cardiovascular risk factor. PMID- 28582282 TI - Improved treatment and control of hypertension in Swedish primary care: results from the Swedish primary care cardiovascular database. AB - OBJECTIVE: To study temporal trends in hypertension treatment and control in Swedish primary care, in relation to clinical characteristics, comorbidity, and drug treatment. MATERIALS AND METHODS: Repeated cross-sectional analysis of 43 239 hypertensive patients attending primary care in 2001-2002 and of 62 407 patients in 2007-2008. RESULTS: Mean blood pressure (BP) 2007-2008 was 143/79 mmHg in women and 142/81 mmHg in men. Cardiovascular comorbidity and diabetes were present in 13 and 15% of women, and in 18 and 20% of men. Overall BP reductions from 2001-2002 to 2007-2008 were 9.0/3.1 mmHg; greater in women than men, with advancing age, and in patients with comorbidity (all P < 0.001). Attainment of target BP (<140/90 mmHg) increased from 24 and 26% in women and men (2001-2002) to 37 and 37% (2007-2008; all P < 0.001). Most common drug classes in 2001-2002 were, in descending frequency, beta blockers, diuretics, and calcium channel blockers (both sexes), and in 2007-2008 beta blockers, diuretics, and angiotensin-converting enzyme inhibitors in women, and beta blockers, angiotensin converting enzyme inhibitors, and diuretics in men. The number of drug classes/patient increased from 1.5 (2001-2002) to 1.8 (2007-2008; P < 0.001) but remained low (1.7) in those above target BP. CONCLUSION: BP control in hypertensive patients attending Swedish primary care has improved over 5-7 years, and more so in high-risk groups. There is, however, room for improvement. In uncontrolled hypertension the combination of several drug classes remain low. PMID- 28582283 TI - Reservoir pressure analysis of aortic blood pressure: an in-vivo study at five locations in humans. AB - INTRODUCTION: The development and propagation of the aortic blood pressure wave remains poorly understood, despite its clear relevance to major organ blood flow and potential association with cardiovascular outcomes. The reservoir pressure model provides a unified description of the dual conduit and reservoir functions of the aorta. Reservoir waveform analysis resolves the aortic pressure waveform into an excess (wave related) and reservoir (compliance related) pressure. The applicability of this model to the pressure waveform as it propagates along the aorta has not been investigated in humans. METHODS: We analysed invasively acquired high-fidelity aortic pressure waveforms from 40 patients undergoing clinically indicated coronary catheterization. Aortic waveforms were measured using a solid-state pressure catheter at five anatomical sites: the ascending aorta, the transverse aortic arch, the diaphragm, the level of the renal arteries, and at the aortic bifurcation. Ensemble average pressure waveforms were obtained for these sites for each patient and analysed to obtain the reservoir pressure [Pr(t)] and the excess pressure [Px(t)] at each aortic position. RESULTS: Systolic blood pressure increased at a rate of 2.1 mmHg per site along the aorta, whereas diastolic blood pressure was effectively constant. Maximum Pr decreased only slightly along the aorta (changing by -0.7 mmHg per site), whereas the maximum of Px increased from the proximal to distal aorta (+4.1 mmHg per site; P < 0.001). The time, relative to the start of systolic upstroke, of the occurrence of the maximum excess pressure did not vary along the aorta. Of the parameters used to derive the reservoir pressure waveform the systolic and diastolic rate constants showed divergent changes with the systolic rate constant (ks) decreasing and the diastolic rate constant (kd) increasing along the aorta. CONCLUSIONS: This analysis confirms the proposition that the magnitude of the calculated reservoir pressure waveform, despite known changes in aortic structure, is effectively constant throughout the aorta. A progressive increase of excess pressure accounts for the increase in pulse pressure from the proximal to distal aorta. The reservoir pressure rate constants seem to behave as arterial functional parameters. The accompanying decrease in ks and increase in kd are consistent with a progressive decrease in aortic compliance and increase in impedance. The reservoir pressure waveform therefore provides a model that might have utility in understanding the generation of central blood pressure and in specific cases might have clinical utility. PMID- 28582285 TI - Guidelines, position studies, and blood vessel research. PMID- 28582284 TI - Favourable impact of statin use on diastolic blood pressure levels: analysis of a large database of 24-hour ambulatory blood pressure monitoring. AB - INTRODUCTION: Assumption of lipid-lowering drugs, mostly statins, is recommended at bed-time and evidence demonstrated a strong and independent correlation between night-time blood pressure (BP) and increased risk of cardiovascular events. AIM: To evaluate the effects of statins on night-time BP levels. METHODS: We analysed data derived from a large cohort of adult individuals, who consecutively underwent home, clinic and ambulatory BP monitoring at our Unit. All BP measurements were performed and BP thresholds were set according to recommendations from European guidelines. Study population was stratified according to statin use. RESULTS: We included an overall sample of 5634 adult individuals (women 48.9%, age 60.5 +/- 11.6 years, BMI 27.0 +/- 4.6 kg/m, clinic BP 144.3 +/- 18.4/90.9 +/- 12.4 mmHg, 24-h BP 130.7 +/- 13.4/79.0 +/- 9.7 mmHg), among whom 17.3% received and 82.7% did not received statins. Treated outpatients were older, had higher BMI and prevalence of risk factors and comorbidities than those who were untreated (P < 0.001 for all). Patients treated with statins showed lower DBP levels at all BP measurements, including night-time (67.3 +/- 9.4 vs. 70.9 +/- 9.7 mmHg; P < 0.001) periods, than those observed in untreated patients. Also, statin use resulted an independent factor associated with 24-h [odds ratio (95% confidence interval): 1.513(1.295-1.767); P < 0.001] and night time [odds ratio (95% confidence interval): 1.357(1.161-1.587); P < 0.001] BP control, even after adjusting for age, sex, BMI, diabetes, number of antihypertensive drugs (model 1) or presence/absence of antihypertensive treatment (model 2). CONCLUSION: Statin use was associated with significantly lower DBP levels. These effects were independently observed, even after correction for cardiovascular risk factors and comorbidities, as well as number of antihypertensive drugs. PMID- 28582286 TI - Rapidly Progressive Maxillary Atelectasis. AB - OBJECTIVE: Report of a patient with rapidly progressive maxillary atelectasis documented by sequential imaging. CLINICAL REPORT: A 51-year-old man, presented with left periorbital and retro-orbital pain associated with left nasal obstruction. An initial computed tomographic (CT) scan of the paranasal sinuses failed to reveal any significant abnormality. A subsequent CT scan, indicated for recurrence of symptoms 11 months later, showed significant maxillary atelectasis. An uncinectomy, maxillary antrostomy, and anterior ethmoidectomy resulted in a complete resolution of the symptoms. CONCLUSION: Chronic maxillary atelectasis is most commonly a consequence of chronic rhinosinusitis. All previous reports have indicated a chronic process but lacked documentation of the course of the disease. This report documents a patient of rapidly progressive chronic maxillary atelectasis with CT scans that demonstrate changes in the maxillary sinus (from normal to atelectatic) within 11 months. PMID- 28582287 TI - Does Cleft Palate Width Correlate With Veau Classification and Outcome? AB - PURPOSE: Wider cleft palates are thought to be associated with increased complications and poorer outcomes following cleft palate repair. Objective cleft palate photographic measurement and assessment of complications have not been previously performed. The purpose of this study is to quantitatively characterize a series of cleft palate dimensions and to investigate possible correlations with Veau classification and intra-, peri-, and postoperative outcomes. METHODS: The analytic sample included primary cleft palate repairs performed by the senior author over a 2-year period. Standard photographs of clefts taken at the time of repair were analyzed using Image-J software. Demographic, intraoperative, perioperative, and postoperative information were collected. Width measurements were correlated with Veau classification, intraoperative variables, perioperative variables, and adverse outcomes. Statistical tests performed included simple regression analyses and multiple regression analysis. RESULTS: Out of 70 patients, 50 had adequate photographic documentation for inclusion in the study; 44% of patients were classified as Veau I with an average cleft width of 5.4 mm, 28% Veau II with an average of 8.9 mm, 16% Veau III with an average of 11.3 mm, and 12% Veau IV with an average of 10.0 mm. No patients exhibited postoperative bleeding, dehiscence, airway problems, infection, fistula formation, or return to the operating room. The authors found that increasing cleft width significantly predicts increasing Veau classification (P < 0.01), increasing operating time (P < 0.05), increased hypernasality (P < 0.05), and speech delay (P < 0.001). Additionally, the presence of an intentional alveolar fistula (Veau III or Veau IV clefts) significantly predicts fluid emission (P < 0.001) but cleft width did not predict fluid emission. Increased cleft width did not significantly predict length of stay. CONCLUSION: Our data demonstrate that wider preoperative cleft palates correlate with Veau classification, increased operating time, and slightly worsened postoperative sequela. There were no perioperative instances of bleeding, dehiscence, respiratory complications, infection, fistula formation, and return to operating room. Hypernasality and speech delay were associated with increased cleft palate width. Length of stay did not correlate with cleft palate width. PMID- 28582288 TI - Survey of Ocular Prosthetics Rehabilitation in the United Kingdom, Part 2: Anophthalmic Patients' Satisfaction and Acceptance. AB - AIM: Ocular prostheses are integral for anophthalmic patients. Part 1 of this study reported that patients' aetiology, opinions, and attitudes significantly affected their prosthetic eyes experience. Part 2 investigates the patient satisfaction and acceptance in light of some of the aetiological demographics reported in Part 1. METHODOLOGY: One hundred sixty questionnaires were delivered to anophthalmic patients attending oculoplastic clinic. Etiological aspects presented in the questionnaire were disseminated in part 1. Patient satisfaction was assessed through 8 closed-end statements reflecting aspects concerning patient's views on prosthesis comfort and appearance; patient's expectations, self-esteem, and perception; and cooperation with ocularist. Each statement had 3 categories as agree, moderately agree, and disagree. A total of 126 questionnaires were returned (response rate was 78.8%). Data was analyzed using SPSS software. Association coefficients and correlations between variables were also analyzed. RESULTS: Total number of responses for the 8 statements was 888, averaging of 111 (expected 126) respondent per statement. Overall, 95.4% of our patients agreed with all satisfaction statements presented echoing very high satisfaction rate with their ocular prosthetics. Having an eye replacement that covers the defect is associated with high satisfaction among patients regardless of ocular prosthetic type. Patient acceptance of prosthesis in relation to employment status was high but not the same among the different categories (P > 0.05). High satisfaction with ocular prosthetics was prevalent among both genders, but there were no statistically significant differences in percentages of agreement in all statements (P > 0.05). Satisfaction and acceptance with ocular prosthetics was the same among all age groups of 12 to 85 years old (P > 0.05). CONCLUSIONS: The patient satisfaction is associated with the interplay of different variables that is related to ocular prosthesis design and its ability to disguise disfigurement (ie, prosthesis shape, resemblance to existing contra lateral eye, etc.); patients themselves (ie, gender, age, occupation, marital status, etc); and psychological well-being and social support provided. Anophthalmic patients of the north west of England are significantly happy with their ocular prosthetic rehabilitation and support they receive from their regional hospital. Ocular prosthetics enhances their psychological well-being and social interaction and factors like patients' sex, age, employment status, and type of ocular prosthesis have no effect on their acceptance and satisfaction. PMID- 28582290 TI - Atypical Growing Pattern of Superficial Temporal Artery Pseudoaneurysm. AB - Superficial temporal artery pseudoaneurysm is rare and usually caused by trauma. Pseudoaneurysms have been reported to occur most frequently from 2 to 6 weeks after trauma and they range from 1 to 3 cm in diameter. The authors present a case of a patient with an atypical delayed rapid growing pseudoaneurysm, who had undergone neurosurgery after head trauma 20 years ago.A 72-year-old woman underwent craniotomy and extradural hemorrhage removal through a left temporoparietal incision caused by head trauma after a traffic accident 20 years prior. The mass of less than 1 cm in diameter was incidentally found by magnetic resonance imaging 8 years ago. However, the patient had no symptoms and the pseudoaneurysm was not considered a significant finding. Several weeks ago, the patient recognized a palpable mass by chance. She observed it without any medical evaluation and treatment. However, the size of the mass suddenly increased without the patient undergoing trauma. It presented as a soft, pulsating round mass of about 3 cm in diameter. Under general anesthesia, the mass was removed without problems. It was a round-shaped mass of 2.2 cm * 2.4 cm in diameter. The transverse cross-section evidenced it was filled with blood clots. The biopsy revealed a dilated vascular wall with an organized thrombus and neovascularization, which are characteristic for a thrombosed pseudoaneurysm.Thus, given that a pseudoaneurysm can grow at any time, medical doctors should strongly consider surgical removal as opposed to simple observation. PMID- 28582289 TI - Chondroid Syringoma of a Cheek. AB - Chondroid syringoma is an unusual, benign skin appendageal tumor originating from the eccrine and apocrine sweat glands resembling mixed tumors of the salivary glands. It develops as a slow-enlarging, small, cutaneous nodule or mass. The lesions are usually seen in older men on head and neck. This is a clinical report of a 46-year-old lady who presented with a slowly growing nodular protruding mass in a cheek. The clinical and histologic findings of the tumor are demonstrated. The clinician and the pathologist should take into account the tumor among differential diagnosis not to overlook the lesion. Total surgical excision is needed with a long-term follow-up. PMID- 28582291 TI - Craniofacial Surgery Fellowship Selection Criteria: A National Program Director Survey. AB - BACKGROUND: Candidate characteristics for craniofacial fellowship training still remain unknown, as no data are available in the literature. This study aims to provide information on the criteria that are used to select and rank applicants for the craniofacial surgery fellowship match. METHOD: A 38-question survey was sent in April 2015 to all craniofacial surgery fellowship program directors (n = 29) involved in the US match using QuestionPro Survey Software. The survey investigated factors used for selection of applicants, including medical school, residency training, research experience, fellowship interview, and candidate characteristics. A 5-point Likert scale was used to grade 33 factors from "not at all important" (1) to "essential in making my decision" (5); or for 5 controversial factors from "very negative impact" (1) to "very positive impact in making my decision" (5). RESULTS: A total of 62% (18 out of 29) of responses were received from craniofacial surgery program directors. The most important factors were professionalism and ethics (4.7 +/- 0.5), perceived commitment to craniofacial surgery (4.6 +/- 0.8), interactions with faculty and staff (4.5 +/- 0.5), interpersonal skills (4.5 +/- 0.5), and overall interview performance (4.4 +/- 0.6). Factors that have a negative impact on the selection process include graduation from a nonplastic surgery residency program (1.9 +/- 0.7) or a non-US plastic surgery residency program (2.2 +/- 0.6), and visa requirement (2.2 +/- 0.5). CONCLUSION: This study provides data on craniofacial surgery program directors' perception on the criteria important for fellowship applicant selection. It is our hope that program directors, residency programs, and applicants find this data useful as they prepare for the craniofacial fellowship match. PMID- 28582293 TI - Alveolar Bone Grafting Changes the Inclination of Teeth and Affects Malocclusion in Patients With Unilateral Alveolar Cleft. AB - INTRODUCTION: Alveolar bone grafting not only stabilizes the alveolar arch, but also provides positive aesthetic outcomes. However, there have been no reports about the inclinations of the incisor and canine or the change in occlusion after alveolar bone grafting. Therefore, the purpose of this study is to analyze the effects of alveolar bone grafting on tooth angles and changes in occlusion in patients with a unilateral alveolar cleft, using three-dimensional computed tomography. METHODS: The authors retrospectively studied alveolar bone grafts performed in Konkuk University Medical Center between January 2008 and January 2013. A total of 40 patients with unilateral alveolar cleft were included in this study; the authors measured the changes in tooth angles and changes in anterior and molar occlusion before and after bone grafting. RESULTS: Of the 40 patients enrolled, 21 completed follow-up and had adequate computed tomography imaging studies. Ten patients who were lost during the follow-up period, and 9 with inadequate images, were excluded. The anterior occlusion increased from -2.21 to 0.19 mm (P < 0.0001) and the molar occlusion increased from 0.75 to 2.10 (P < 0.0001). The dental angle decreased from 25.23 degrees to 15.32 degrees (P = 0.001). DISCUSSION: Alveolar bone grafting provides support to the tooth root and changes the inclination of the tooth, resulting in changes in occlusion and positive aesthetic outcomes. PMID- 28582294 TI - Autologous Fat Injection for Treatment of Velopharyngeal Insufficiency. AB - BACKGROUND: Management of velopharyngeal insufficiency (VPI) has traditionally involved surgical repair to improve speech. Posterior pharyngeal augmentation using injectable synthetic materials has been advocated. However, outcomes have been equivocal. More recently, autologous fat injection (AFI) has been advocated for correction of mild to moderate VPI. However, long-term efficacy and safety of this procedure remain unsettled. METHODS: A systematic review of the literature was performed. Available studies that reported outcomes of autologous fat velopharyngeal injection for treatment of documented VPI were included. Preclinical animal studies were excluded. Study characteristics, patient demographics, treatment details including fat harvest site, volume injected, and outcome measures were evaluated. RESULTS: Fifteen studies met inclusion criteria, yielding 251 patients who underwent AFI. There was high variability in terms of indications for procedure and reporting of outcomes. Majority of studies required velopharyngeal gap closure of at least 50% in order to undergo AFI. Most common etiology of VPI was secondary to cleft palate. Some studies included patients with velocardiofacial syndromes. Improvements in speech and nasalance were reported in a majority of patients. Major complications were rare. Only 1 patient with graft hypertrophy resulting in obstructive sleep apnea was reported. CONCLUSION: Autologous fat injection offers a minimally invasive approach to the treatment of VPI. Current literature is limited to small noncomparative studies. These appear to suggest efficacy and safety in mild to moderate patients with VPI. Future prospective studies with standardized technique and objective outcomes are required to definitively establish its safety and efficacy, as well as define patient selection criteria. PMID- 28582295 TI - Cephalometric Improvement of Severe Microretrognathia With an Anterior Open Bite Using Curvilinear Mandibular Distraction Osteogenesis. AB - Curvilinear mandibular distraction osteogenesis (MDO) provides for multidimensional augmentation and rotation in mandibles with complex, abnormal morphology. This study aims to demonstrate cephalometric changes after curvilinear MDO.A prospectively maintained craniofacial database was queried for patients undergoing curvilinear MDO from 2009 to 2015. Demographic and operative data were collected. Cephalometric measurements were obtained from preoperative and postdistraction imaging, including sella-nasion-B point angle (SNB), mandibular plane angle (MPA), occlusal plane angle (OPA), and gonial angle (GA). Measurements were compared using a paired t test.Nine patients exhibiting microretrognathia and an anterior open-bite deformity had a mean age of 8.4 +/- 6.0 years and a mean follow-up of 23.2 +/- 25.3 months. Mean distance distracted was 32.6 +/- 7.2 mm, with augmentation in length and height, and rotatory closure of anterior open bites. Preoperative SNB versus postdistraction was 66.9 +/- 4.2 versus 78 +/- 9.1 degrees (P = 0.0029). MPA, OPA, and GA all decreased (61.0 +/- 10.7 vs. 45.7 +/- 11.1 degrees , P = 0.0066, 37.3 +/- 8.9 vs. 25.7 +/- 6.0 degrees , P = 0.0025, 140.3 +/- 16.1 vs. 127.3 +/- 13.2 degrees , P = 0.0019, MPA, OPA, and GA, respectively), trending toward normalization. Airway diameter increased by 7.1 +/- 2.8 mm. Anterior bite improved by 7.2 +/- 1.9 mm. Complications arose in 2 subjects including device malfunction and wound infection.Curvilinear MDO results in dramatic cephalometric improvement in patients with severe microretrognathia and anterior open-bite. The procedure is associated with a high rate of complications, and long-term stability of movement has yet to be documented. PMID- 28582296 TI - Free Vastus Intermedius Muscle Flap: A Successful Alternative for Complex Reconstruction of the Neurocranium in Preoperated Patients. AB - The reconstruction of large cranial and scalp defects is a surgical and esthetic challenge. Single autologous tissue transfer can be insufficient due to the defect size and the anatomic complexity of the recipient site. Alloplastic patient-specific preformed implants can be used to recover hard tissue defects of the neurocranium. Nevertheless, for long-term success adequate soft tissue support is required. In this brief clinical study, the authors describe calvarian reconstruction in a 33-year-old patient with wound healing disorder after an initial resection of ependymoma. The patient suffered from osteonecrosis and wound breakdown in the fronto-parietal region. An alloplastic polymethylmethacrylate implant for hard tissue support was manufactured based on 3-dimensional visualization of a computed tomography scan. After the resection of remaining pathologic bone from earlier surgical procedures, the alloplastic implant was inserted to achieve functional coverage of the brain. Due to anatomic variation of donor site vessels during anterolateral thigh flap preparation, the authors performed a vastus intermedius free flap as a new muscular flap for craniofacial reconstruction. The authors achieved excellent functional and esthetic results. The muscular vastus intermedius free flap in combination with a split skin graft proves to be a new alternative to the anterolateral thigh flap for soft tissue reconstruction of the neurocranium. PMID- 28582297 TI - Loco-Regional Control With Complete Resection and Tongue Reconstruction on the Malignant Melanoma in the Tongue. AB - Primary malignant melanoma in the tongue is very uncommon disease that is considered low in comparison to cutaneous melanoma. In this report, the authors described a case of the hemitongue reconstruction with fasciocutaneous free flap on the patient who suffered from the malignant melanoma primarily originating from the base of the tongue that was treated with surgery and radiotherapy but developed a lung metastasis. A 76-year-old man was referred to the otorhinolaryngology clinic after complaining of a painful mass present for 3 months on the right side of the tongue. A punch biopsy was revealed atypical cells with pigmentation that is consistent with malignant melanoma. After wide excision and bilateral neck dissection performed, hemipartial tongue reconstruction was done using a radial forearm free flap. The patient had an uneventful recovery and received a course of radiotherapy along with follow-up examinations for 3 years. The authors report this rare patient for providing the other surgeons with the useful information regarding the management of the malignant melanoma on the tongue with free flap reconstruction which turned out to be successful in loco-regional control. PMID- 28582298 TI - Flail Mandible and Immediate Airway Management: Traumatic Detachment of Mandibular Lingual Cortex Results in Obstructive Dyspnea and Severe Odynophagia. AB - Isolated mandibular fractures usually represent themselves as non-life threatening injuries and are not treated in emergency setting. However, some rare patterns of them may result in airway obstruction as a result of displacement of bony fragments. The authors report a patient of an open comminuted fracture of mandibular symphysis which exhibited an uncommon split pattern with retrogression of lingual cortical plate, and thereby induced glossoptosis, painful deglutition, and obstruction of the upper airway within a few hours. The patient underwent immediate intubation for establishing a definitive airway, followed by open reduction and internal fixation of fracture. Surgical airway management was not needed. Anatomic reduction of the fracture was achieved, by reestablishing the patency of upper airway and resolving the painful deglutition. Patient's occlusion and mouth opening returned to the preinjury status. Timely osteosynthesis surgery offered early relief of patient's signs and symptoms, prevented airway complications and development of traumatic mandibular osteomyelitis, as well as obviated the potential need for surgical airway management. The appropriate management of mandibular fractures placing the airway at risk requires immediate diagnosis based on knowledge of specific clinical and radiographic findings. This case emphasizes that emergency clinicians should be able to distinguish those patients who will need airway securing techniques in emergent or prophylactic context, due to an uncommon fracture pattern of facial skeleton. Moreover, emergency clinicians should be conversant with wiring techniques to achieve stabilization of the mandibular framework and to control the pain, hemorrhage, and airway patency. PMID- 28582299 TI - Face of Noma and Extreme Poverty: Development of an Economic Index Derivable From Health Data. AB - Health is wealth. Economics is creation of wealth. There is a direct relationship between health and economics. Noma, associated with extreme poverty, can be used as an economic index. PMID- 28582300 TI - Analyzing the Cost of Autogenous Cranioplasty Versus Custom-Made Patient-Specific Alloplastic Cranioplasty. AB - PURPOSE: Comparing expenses related to autogenous cranial vault reconstruction versus custom-made patient-specific alloplastic cranioplasty. METHODS: The authors retrospectively reviewed charts of a group of patients who underwent autogenous cranioplasty and poly-ether-ether ketone (PEEK) cranioplasty. The data collected from the patient files included demographic information, details of the surgery, postoperative recovery data, and also duration of surgery. The authors also added costs related to the length of surgery, utilization of intensive care unit, length of hospital stay, amount and seriousness of complications, and hardware cost. The outcomes were studied in terms of skull form maintenance and complications.Eleven of our patients had PEEK cranioplasty at Sunnybrook Hospital, Toronto, ON, in the period from July 2009 to June 2011. The authors identified 11 patients who had split skull autogenous bone graft cranioplasty. They were matched for age and skull defect size.Comparable information was collected for both patient groups. The information was examined to compare costs of custom-made patient-specific alloplastic implants and costs of autogenous cranioplasty. RESULTS: Conclusions made from this paper will hopefully serve as guidance for allocation of hospital funding and resources at the Ministry of Health level. PMID- 28582301 TI - Reducing Postoperative Bleeding After Craniosynostosis Repair Utilizing a Low Dose Transexamic Acid Infusion Protocol. AB - BACKGROUND: Craniosynostosis surgery is associated with large volume blood loss and the need for blood transfusion. Recently, the use of tranexamic acid (TXA) has been demonstrated to be helpful in reducing perioperative blood loss in many pediatric procedures. This study used a low-dose pharmacokinetic TXA dosing protocol and assessed its ability to limit perioperative blood loss for craniosynostosis repairs. METHODS: A retrospective chart review was conducted of pediatric craniosynostosis surgeries performed at our institution between September 2011 and December 2014. Outcome measures included comparisons of perioperative blood loss and transfusion rates in patients who had surgery with or without TXA. RESULTS: Twenty-five patients met inclusion criteria. Nine patients had craniosynostosis surgery without TXA (no-TXA group) and 16 patients received TXA (TXA group). The TXA group had significantly higher postoperative hemoglobin levels than the no-TXA group (P = 0.009). This finding was supported by significantly higher postoperative estimated red cell volume in the TXA group (P = 0.017). Postoperative 24-hour drain output was significantly lower in the TXA group (P = 0.042). The volume of packed red blood cells transfused perioperatively was not significantly different between groups. CONCLUSIONS: Patients who received TXA during craniosynostosis surgery at our institution had higher postoperative hemoglobin levels and lower 24-hour drain output. However, TXA was not associated with lower perioperative blood transfusion rates. PMID- 28582302 TI - Effect of Erythropoietin on Transfusion Requirements for Craniosynostosis Surgery in Children. AB - BACKGROUND: Pediatric craniosynostosis surgery is associated with significant blood loss often requiring allogenic blood transfusion (ABT). This study explores the clinical effectiveness of preoperative erythropoietin (EPO) administration in pediatric craniosynostosis surgery in reducing transfusion requirements. METHODS: A systematic review and meta-analysis of the literature was performed for studies published in English language between 1946 and 2015. Inclusion criteria included original studies in the pediatric population (0-8 years of age) involving preoperative use of EPO in craniofacial procedures with quantitative reporting of perioperative blood transfusion. Extracted data included demographics, hematocrit, hemoglobin, estimated blood loss, number of patients transfused, and amount of ABT. RESULTS: Four studies met the inclusion criteria with a total of 117 patients. Patients were divided into 2 groups: EPO versus control. No statistical differences were found in the demographics between the 2 groups. Mean preoperative hematocrit level was higher in the EPO group compared with control (43% vs 35%). The percentage of patients who required ABT and the volume of transfused blood were less in the EPO group (54% vs 98% and 84 vs 283 mL, respectively). Meta-analysis of 3 comparable studies showed a lower proportion of patients who needed blood transfusion in the EPO group. CONCLUSIONS: The present meta-analysis demonstrated that preoperative administration of EPO in pediatric craniosynostosis surgery decreased the proportion of patients requiring ABT. In addition, the volume of transfusion was reduced in patients who received EPO. Future randomized studies are needed to establish the cost-effectiveness of routine preoperative EPO administration in craniosynostosis surgery. PMID- 28582303 TI - Tranexamic Acid Reduces Blood Loss in Craniosynostosis Surgery. AB - METHODS: The authors retrospectively reviewed 79 patients with craniosynostosis who underwent either bifrontal or biparietal-occipital calvarial vault remodeling before institution of tranexamic acid (TXA) administration (non-TXA group) and 35 patients after institution of TXA administration (TXA group). The patients were analyzed in 2 groups: all open calvarial vault remodeling patients (anterior and posterior) as a whole, and anterior vaults only as a subset analysis. Primary outcomes accessed were: total intraoperative blood transfused, postoperative blood transfused, and estimated blood loss (EBL). Secondary outcomes evaluated were length of stay in the pediatric intensive care unit and hospital length of stay. RESULTS: When comparing all open calvarial vault remodeling patients, patients who received TXA required significantly less total blood transfusion during their operation (264 cc TXA group versus 428 cc non-TXA, P < 0.0001). Patients who received TXA required no blood transfusions postoperatively, compared with the non-TXA group, in which 45% of patients required postoperative blood transfusion. Weight-based EBL was also significantly lower in those patients receiving TXA (25 cc/kg in the TXA group versus 34 cc/kg in the non-TXA group [P = 0.0143]). All patients required transfusion intraoperatively. Pediatric intensive care unit length of stay was shorter in the TXA group, but there was no significant difference in total hospital length of stay. These findings also reached statistical significance when comparing only the anterior vault patients. CONCLUSION: Intraoperative TXA administration has a correlation with reduced blood transfusion requirements, as well as EBL, in patients undergoing open calvarial vault remodeling. There were no adverse events related to TXA administration. PMID- 28582305 TI - Effects of Primary Alveolar Grafting on Alveolar Bone Thickness in Patients With Cleft Lip and Palate. AB - The purpose of this study was to compare alveolar bone thickness around the teeth adjacent to the cleft using cone beam computed tomography (CBCT) in patients with cleft lip and palate (CLP) who underwent primary alveolar grafting (PAG) as compared with CLP waiting for secondary alveolar grafting (SAG) and to determine the associations with other factors such as the patient's age, sex, and type of cleft. CBCTs of 39 CLP patients were divided into either group 1 (PAG, N = 11) or group 2 (SAG, N = 28). Measurements of bone thickness around the closest tooth to the cleft were performed on the axial sections on each subject's CBCT at 3, 6, and 9 mm apical to the cementoenamel junction along the root length. Intraclass correlation coefficients and Bland-Altman plots were used to evaluate intrarater reliability. Bone measurements with 95% confidence intervals for the mean were estimated using analysis of variance models with a random patient effect to account for correlation among multiple measurements within a patient. Similar models were used to test the associations of age, sex, and type of the graft with the bone measurements. No statistically significant associations of the factors were found with mesial or distal bone measurements. Buccal bone thickness was significantly greater only at 9 mm in the primary bone graft subjects compared with secondary bone graft subjects (P = 0.009). Unilateral cleft subjects showed significantly greater buccal bone thickness at the level of 9 mm compared with bilateral cleft subjects (P = 0.046) and lingual bone thickness at the level of 6 mm (P = 0.0026) and 9 mm (P = 0.0096). In conclusion, PAG does not add benefits to the bone width on the cleft sides of the closest teeth to the cleft as compared with children with CLP who have not undergone alveolar grafts yet. PMID- 28582304 TI - Surgical Outcomes for Speech Surgery in 22q11.2 Deletion Syndrome: The Dilemma of Persistent Velopharyngeal Insufficiency After Pharyngeal Flap Operation. AB - INTRODUCTION: The majority of patients with 22q11.2 deletion syndrome suffer from velopharyngeal insufficiency (VPI). Patients with 22q11.2 deletion syndrome (22qDS) commonly present with a large central velopharyngeal gap in the setting of poor velar and pharyngeal wall motion. The posterior pharyngeal flap is considered the most effective technique to treat VPI in this complex patient group. This study aims to critically evaluate success rates of surgical management of VPI in 22qDS patients and discuss options for management of a failed posterior pharyngeal flap (PPF) with persistent VPI. METHODS: A systematic review was performed through MEDLINE and Scopus to examine the outcomes of PPF surgery to treat VPI in patients with 22qDS. Complications were defined as persistent VPI, hyponasal speech, and obstructive sleep apnea. To demonstrate an approach to management, the authors outline a recent patient with a failed PPF in this patient population at the authors' institution. RESULTS: The authors comprehensively reviewed 58 articles, 13 of which contained relevant information with extractable data. Of the 159 patients with 22qDS who underwent PPF to treat VPI, successful outcomes were reported in 135 patients (80%; range: 0%-100%). Complications were reported in 14% of patients, with need for revision operations in 3%. DISCUSSION: Surgical management of VPI in patients with 22qDS is challenging, with variable success rates reported in the literature. If unsuccessful, the surgeon faces additional challenges with the revision surgery including a scarred PPF donor site, distorted palatal recipient site, and further medialization of internal carotid arteries. Surgical revision of a failed PPF requires meticulous preoperative planning and technical execution. PMID- 28582306 TI - Delayed Presentation of Isolated Sagittal Synostosis With Raised Intracranial Pressure and Secondary Chiari Malformation With Cervical Syringomyelia. AB - Sagittal craniosynostosis (SC) is the most common type of premature suture fusion presenting in approximately 1 in every 5000 births with a 3:1 male:female ratio. The most common indication for surgery is the improvement of the cosmetic appearance of the skull, since a cranial deformation may have a significant psychosocial impact on affected patients. Relief from raised intracranial pressure is a further indication for surgery, although an increased intracranial pressure (ICP) can be demonstrated only in a minority of affected children at diagnosis. It is even more rare to have Chiari malformations (CMs) secondary to ICP in an isolated SC, as shown in a study by Strahle et al (Neurosurg Focus 2011;31:E2), demonstrating only 5 (3%) of the 183 with isolated sagittal synostosis having a CM. The authors present the rare case of a 4-year-old boy presenting late with raised intracranial pressure (40 mm Hg) and his management with 1 stage vault expansion and decompression of CM. PMID- 28582307 TI - Surgery First Orthognathic Approach Without Presurgical Orthodontic Treatment: Questions and Answers. AB - "Surgery-First" for patients with malocclusion and skeletal disharmony is a new process of employing bony corrective surgery (first) without removal of dental compensations followed by orthodontic finishing (second). This process breaks with the time-tested principles of traditional orthognathic surgery. Not unexpectedly, there is slow adoption of this new process, particularly in the West. Ten frequently asked questions regarding Surgery First are asked and answered in this report in an attempt to provide an increased level of comfort for Plastic and Maxillofacial Surgeons in instituting this process in their practice. PMID- 28582309 TI - Syndrome of the Trephined: Functional Improvement After Reconstruction of Large Cranial Vault Defects. PMID- 28582308 TI - Modified Genioglossal Advancement for Isolated Treatment of Obstructive Sleep Apnea. AB - INTRODUCTION: Genioglossal advancement is a surgical procedure for obstructive sleep apnea (OSA) that has lost favor as a primary treatment strategy. The authors describe utilization of a modified genioglossal advancement (MGA), combining a geniotubercle advancement via sliding genioplasty and a glossopexy. METHODS: A retrospective review was performed. Preoperative and postoperative apnea-hypopnea indices (AHIs) were compared to determine OSA treatment success. RESULTS: Five patients underwent MGA. Three subjects had preoperative and postoperative AHI scores which improved from 61, 28, and 19 (mean = 36) to 4.5, 2, and 6.3 (mean = 4.3), respectively. Two subjects had incomplete data for comparison. All subjects had an acceptable esthetic outcome. DISCUSSION: In properly selected subjects, MGA can alleviate OSA and provide improved esthetic outcomes. PMID- 28582310 TI - Clinical Outcome and Patients' Satisfaction Study After Otoplasty Using Hybrid Techniques in Adult Patients. AB - OBJECTIVES: There are limited data on the effect of otoplasty on health-related quality of life (HRQoL) in prominent ears. There are no data on the effect of otoplasty on Glasgow Benefit Inventory (GBI) of otoplasty using hybrid techniques in adult patients. METHODS: This study involved 28 patients who underwent otoplasty using combined procedures. We chose the GBI because it is a sensitive tool for detecting changes in health status following an intervention. Patients older than 13 years received the GBI, being retrospective well-validated questionnaires for measuring the effect of otorhinolaryngologic interventions, and particularly plastic surgery procedures, on HRQoL. An individual questionnaire was created by the standard GBI. We combined posterior auricular skin excision, Mustarde suture technique, and conchomastoid suture techniques for maximizing the cosmetic improvements. RESULTS: According to the results of this study, good outcomes with patient satisfaction were achieved with this hybrid procedure. We found a conspicuous improvement in GBI total score as well as in the general health subscale after otoplasty. This indicates the beneficial impact on the healthy self-perception of this surgical procedure with prominent ears. CONCLUSIONS: In our retrospective assessment, GBI turned out to be a very useful and valuable tool in the evaluation of otoplasty. We demonstrated a long-lasting improvement in HRQoL after otoplasty for the prominent ears. Hybrid techniques are effective and satisfying treatment methods with high success rates for patients with prominent ears. PMID- 28582311 TI - The Second-Generation Craniofacial Surgeon: Progress Through Personal Responsibility and Personal Relationships. PMID- 28582312 TI - Development of Nerve Fibre Diameter in Young Infants With Hirschsprung Disease. AB - OBJECTIVES: Finding thickened nerve fibres is one of the key elements in the diagnosis of Hirschsprung disease (HD); however, its value at different ages remains uncertain. Nerve fibre diameters <40 MUm can be observed in infants younger than 8 weeks, despite the presence of HD. The aim of this study was to identify a change in maximum nerve fibre diameter in HD patients, measured before and after 8 weeks of age. METHODS: Nerve fibre diameter was retrospectively evaluated in tissue of 20 infants treated for definite HD. Rectal suction biopsies (RSBs) obtained within the first 8 weeks of life (T1) and resected bowel obtained during primary surgery at an average of 24.7 weeks (T2), were assessed. The 2 thickest nerve fibre diameter recordings at T1 and T2 were compared in each subject, to examine changes in nerve trunk diameter with increasing age. RESULTS: In 13 cases (65%), nerve fibre diameters were >=40 MUm at T1 and T2. Six subjects (30%) had nerve trunk diameters <40 MUm at T1; however, they experienced diameter increases to >=40 MUm by T2. Thus, at T2, 19 subjects (95%) had diameter recordings >=40 MUm. Nerve fibre diameter in the remaining case (5%) stayed consistent at <40 MUm at T1 and T2, despite the presence of HD. CONCLUSIONS: After the first 8 weeks of life, nerve fibre measurements appear to be associated with HD. Measuring the 2 thickest nerve fibres can support typical HD diagnosis criteria beyond 8 weeks of age, but is not superior to histopathological confirmation of aganglionosis. PMID- 28582313 TI - Outbreaks in the neonatal ICU: a review of the literature. AB - PURPOSE OF REVIEW: Neonates in the neonatal ICU (NICU) are uniquely vulnerable to colonization and infection with pathogens such as multidrug resistant Gram negative bacteria, which in turn are associated with increased infection-related morbidities and higher case-fatality rates. We reviewed the English, French, and German language literature published between 2015 and 2017, for reports of NICU outbreaks. RECENT FINDINGS: A total of 39 outbreaks in NICUs were reported with Gram-negative bacteria (n = 21; 54%) causing most, and extended spectrum beta lactamase-producing organisms being the most frequent resistance mechanism reported (n = 5). Five viral outbreaks were reported (respiratory syncytial virus = 3). A significant proportion of outbreaks (33%) did not identify a source. Whole genome sequencing was used more (n = 6 reports). The most common described infection prevention and control interventions included staff and parent education on hand hygiene, patient isolation, additional contact precautions, including discontinuation of 'kangaroo care', and cohorting. Reporting and publication bias are likely common. SUMMARY: NICUs must be vigilant in identifying outbreaks, conduct comprehensive investigations, and implement targeted infection prevention and control strategies. Molecular epidemiology capacities are an essential element in outbreak investigation. More studies are needed to determine the added value of active colonization screening and their impact on outbreak development. PMID- 28582315 TI - Application of Clinical Intelligence to Streamline Care in Aortic Emergencies. AB - This article discusses the lessons learned by an interdisciplinary team in a large metropolitan specialty hospital during the implementation of the Code Aorta protocol for aortic emergencies and the subsequent application of technological enhancements to improve data transfer. Aortic dissections require rapid diagnosis and surgical treatment; thus, in order to optimize patient outcomes, clinicians must be accessible, data must be readily available, and proper prompts and notifications must be made to alert and ready teams. An interdisciplinary team reviewed our hospital's processes and architecture of systems to define how we provide care during aortic emergencies. Based on this insight into patient flow, we ultimately developed a Code Aorta protocol to streamline provision of care during aortic emergencies. This process focused on protocol development, human technology interfaces, and outcome-oriented metrics. The team also aimed to heighten awareness of the emergent process and to understand relevant outcomes data. After introduction of the Code Aorta protocol, a 78% reduction was achieved in time-to-treatment from the previous year's average time. In addition, the average length of stay was reduced by 2.4 days (18%). The team's efforts focused on clinical communication, aiming to link technology to maximize clinical efficiency. The initial results of our Code Aorta protocol show promise that continual refinement of patient care processes during aortic emergencies will improve outcomes for patients suffering aortic dissection. PMID- 28582316 TI - New targets for pulmonary arterial hypertension: going beyond the currently targeted three pathways. AB - PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) is a hemodynamic state defined by a resting mean pulmonary arterial pressure at or above 25 mmHg with a normal pulmonary capillary wedge pressure, ultimately leading to right heart failure and premature death. Although considerable progress has been made in the development of drug therapies for PAH targeting abnormalities found in the three main pathobiologic pathways (nitric oxide, prostacyclin, and endothelin-1), there is no drug available to specifically stop the progressive cellular accumulation into the pulmonary artery vessel wall. Indeed, this pulmonary vascular remodeling is a key pathological feature in PAH, contributing to the progressive narrowing of the lumen responsible to the functional decline and to the right ventricle hypertrophy and dysfunction. RECENT FINDINGS: Because numerous important discoveries in the PAH pathogenesis have been recently made, our improved understanding of additional pathways in this condition will presumably lead to the development of novel and more powerful therapeutic strategies in the near future. SUMMARY: In this review, we highlight some recent biological findings and discuss the opportunities that could lead to the identification of new promising targets in PAH paving the way for future therapeutic strategies. PMID- 28582314 TI - Angiopoietins and Tie2 in vascular inflammation. AB - PURPOSE OF REVIEW: As a subset of the organism-wide reaction to severe infection, the host vascular response has received increasing attention in recent years. The transformation that small blood vessels undergo to facilitate the clearance of pathogens may become harmful to the host if it occurs too broadly or if it is sustained too long. Adverse clinical manifestations of leaky and inflamed blood vessels include edema impairing the function of critical organs and circulatory shock. RECENT FINDINGS: The study suggests that this host vascular response may be both measurable and potentially targetable. Tie2 is a receptor tyrosine kinase (RTK) heavily enriched in the vascular endothelium whose tonic signaling actively maintains vascular quiescence. When Tie2 becomes inactivated, important molecular brakes are released in the endothelium, which in turn potentiate inflammation and vascular leakage. The ligands of Tie2, Angiopoietin-1 and Angiopoietin-2, regulate its activation status. Genetic and molecular studies spanning thousands of humans link Tie2 and imbalance of the Angiopoietins to major adverse clinical events arising from bacterial sepsis, other severe infections, and even acute sterile inflammation. SUMMARY: The Tie2 signaling axis may constitute a molecular switch in systemic inflammation that can be measured and manipulated to target the host vascular response therapeutically. PMID- 28582317 TI - Acute exacerbations of interstitial lung disease: lessons from idiopathic pulmonary fibrosis. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an update on acute exacerbation of interstitial lung disease (ILD), with a focus on idiopathic pulmonary fibrosis (IPF), in the light of the recently revised definition of acute exacerbation-IPF. Strengths and limitations of the current definition of acute exacerbation-IPF are also discussed. RECENT FINDINGS: Clinically, acute exacerbation-IPFs are highly relevant events with a mortality rate of approximately 50%. A 2016 working group on acute exacerbation-IPF has suggested the definition be widened to include any acute respiratory worsening with new widespread alveolar abnormality on high-resolution computed tomography of the chest not fully explained by cardiac failure or fluid overload. Management of acute exacerbation-IPF typically includes supportive care, high-dose corticosteroids and broad-spectrum antibiotics, despite the scarcity of data supporting the usefulness of these therapies. The effect of a number of novel therapeutic approaches is currently under investigation. SUMMARY: Acute exacerbation-IPF has recently been redefined. A standardized definition, similar to that of other chronic respiratory diseases, will likely facilitate the performance of highly needed studies in acute exacerbation of both IPF and other ILDs. PMID- 28582318 TI - Recent advances in childhood vasculitis. AB - PURPOSE OF REVIEW: The review aims to summarize the recent findings in vasculitis that may have an impact in our understanding or management of these diseases. RECENT FINDINGS: We are learning more about monogenic diseases that closely mimic the pediatric vasculitides. Deficiency of adenosine deaminase 2 can present with a polyarteritis nodosa (PAN)-like picture and should be included in the differential of all pediatric cases of PAN with a family history or in cases with early stroke, or in cases resistant to conventional therapy. Mutations in tumor necrosis factor alpha-induced protein 3 results in a disease that can present as Behcet disease called haploinsufficiency of A20. In fact, these patients would also fulfill the existing criteria for PAN and Behcet disease, respectively. Additional advances in Behcet disease pathogenesis come from a large genetic study of Turkish Behcet disease using data obtained from genotyping using the Immunochip. This confirmed the HLA-B-51 locus as the most significant association and identified new risk loci. Large Iranian and Japanese cohorts were used as replication cohorts. Best treatment of pediatric vasculitis remains a challenge as we continue to lack controlled studies. There are new reports in treatment on Henoch-Schonlein purpura/Immunoglobulin A vasculitis which is one of our most frequent childhood vasculitides. Small series of new treatments for central nervous system vasculitis and Takayasu disease will also be summarized. Diagnostic criteria have been reassessed in pediatric Behcet disease as well as adult and childhood forms of antineutrophil cytoplasmic antibodies-positive vasculitis. SUMMARY: The new pathways defined in monogenic diseases may help us better understand the pathogenesis and may help us design more targeted therapy. Although pediatric cases are being increasingly recognized, the relative rarity of the diseases presents an obstacle for studies. Thus, we can reach conclusive results for their management through multicenter studies only. PMID- 28582319 TI - Osteoporosis in childhood. AB - PURPOSE OF REVIEW: The aim of this review is to highlight recent findings in prevention, diagnosis, and treatment of pediatric osteoporosis. RECENT FINDINGS: Several genes are involved in bone mass acquisition, and various monogenic bone disorders characterized by reduced bone mineral density and increased bone fragility have been recently described. Moreover, many chronic diseases and/or their treatment have been associated with impaired bone mass acquisition. Pediatric osteoporosis should be adequately suspected and properly diagnosed in children at risk of fractures. Particularly, detection of vertebral fracture allows the diagnosis regardless of densitometric evaluation. Dual X-ray absorptiometry remains the most widely used densitometric technique in childhood, but interpretation of results should be made with caution because of different confounding factors. Bisphosphonates represent one of the main medical treatments of pediatric osteoporosis, and many different protocols have been proposed. Bisphosphonates administration should be characterized by a first phase, followed by a period of maintenance. Optimal route of administration, duration of therapy, and long-term safety of bisphosphonates treatment require further investigation. SUMMARY: Careful monitoring of children at risk of fractures is essential to pose early diagnosis of osteoporosis. In children with persistent risk factors and reduced probability of spontaneous recovery, medical treatment with bisphosphonates should be considered. PMID- 28582320 TI - Hepatitis E viral infection in solid organ transplant patients. AB - PURPOSE OF REVIEW: The purpose of this chapter is to review the literature published in the past 10 years with focus to the best literatures published since 2015 regarding chronic hepatitis E virus (HEV) infection in patients who received solid organ transplantation. RECENT FINDINGS: Diagnosis of this disease relies primarily on identification of HEV RNA in serum and more recently in stool as way of predicting relapse and guide therapy duration. Current management focuses primarily on primary prevention and supportive care, because additional research is needed to identify efficacious pharmacologic therapy, though use of ribavirin has shown promise in case series in treatment of some genotypes. SUMMARY: Infection with HEV is a rare but significant infection in organ transplant recipients. Though initially thought to be a primarily self-limiting infection, cases of chronic and persistent infection are increasing, being recognized both in developing and developed nations as a cause of cirrhosis, and, in some cases, of fulminant hepatic failure. Clinical manifestations of this infection, including evidence of hepatocellular liver injury, are mostly indistinguishable from alternative diagnoses. PMID- 28582321 TI - Cytomegalovirus in liver transplant recipients. AB - PURPOSE OF REVIEW: Cytomegalovirus (CMV) is the most common opportunistic infection following solid-organ transplant and remains a cause of life threatening disease and allograft rejection in liver transplant recipients. The purpose of this review is to highlight the current strategies in diagnosis and management of this disease in this vulnerable population. RECENT FINDINGS: Identification of high-risk individuals and aggressive treatment with antiviral agents, either via prophylaxis or by early initiation during active disease, has become the standard of care. Despite this, CMV continues to exert a significant effect, remaining a major cause of morbidity and mortality. SUMMARY: Given these findings, continuing efforts are underway to determine whether further therapy, vaccination, or alternative management strategies may improve outcomes in solid organ transplant recipients. Until that time, however, aggressive monitoring of post-transplant patients for signs and symptoms of CMV infection is the best strategy to prevent solid-organ loss and death. PMID- 28582323 TI - Bolstering your armamentarium with SGLT2 inhibitors. AB - Sodium-glucose cotransporter-2 inhibitors have a unique mechanism of action in the kidneys that causes glucosuria, which lowers plasma glucose. They are also associated with reduced body weight, BP, and a low incidence of hypoglycemia. The pharmacologic profiles/clinical implications of canagliflozin, dapagliflozin, and empagliflozin are discussed in this article. PMID- 28582322 TI - Atopic dermatitis phenotypes and the need for personalized medicine. AB - PURPOSE OF REVIEW: To describe recent developments in therapies which target the molecular mechanisms in atopic dermatitis. RECENT FINDINGS: Current advances in the understanding of the molecular basis of atopic dermatitis are leading to the stratification of different atopic dermatitis phenotypes. New therapies offer the option to target-specific molecules involved in the pathophysiology of atopic dermatitis. Current new therapies under investigation aim to modulate specific inflammatory pathways associated with distinctive atopic dermatitis phenotypes, which would potentially translate into the development of personalized, targeted specific treatments of atopic dermatitis. SUMMARY: Despite the unmet need for well tolerated, effective, and personalized treatment of atopic dermatitis, the current standard treatments of atopic dermatitis do not focus on the individual pathogenesis of the disease. The development of targeted, phenotype-specific therapies has the potential to open a new promising era of individualized treatment of atopic dermatitis. PMID- 28582324 TI - Sleep-related movement disorders and disturbances of motor control. AB - PURPOSE OF REVIEW: Review of the literature pertaining to clinical presentation, classification, epidemiology, pathophysiology, diagnosis, and treatment of sleep related movement disorders and disturbances of motor control. RECENT FINDINGS: Sleep-related movement disorders and disturbances of motor control are typically characterized by positive motor symptoms and are often associated with sleep disturbances and consequent daytime symptoms (e.g. fatigue, sleepiness). They often represent the first or main manifestation of underlying disorders of the central nervous system, which require specific work-up and treatment. Diverse and often combined cause factors have been identified. Although recent data provide some evidence regarding abnormal activation and/or disinhibition of motor circuits during sleep, for the majority of these disorders the pathogenetic mechanisms remain speculative. The differential diagnosis is sometimes difficult and misdiagnoses are not infrequent. The diagnosis is based on clinical and video polysomnographic findings. Treatment of sleep-related motor disturbances with few exceptions (e.g. restless legs/limbs syndrome) are based mainly on anecdotal reports or small series. SUMMARY: More state-of-the-art studies on the cause, pathophysiology, and treatment of sleep-related movement disorders and disturbances of motor control are needed. PMID- 28582326 TI - The sticky business of adhesion prevention in minimally invasive gynecologic surgery. AB - PURPOSE OF REVIEW: The negative impact of postoperative adhesions has long been recognized, but available options for prevention remain limited. Minimally invasive surgery is associated with decreased adhesion formation due to meticulous dissection with gentile tissue handling, improved hemostasis, and limiting exposure to reactive foreign material; however, there is conflicting evidence on the clinical significance of adhesion-related disease when compared to open surgery. Laparoscopic surgery does not guarantee the prevention of adhesions because longer operative times and high insufflation pressure can promote adhesion formation. Adhesion barriers have been available since the 1980s, but uptake among surgeons remains low and there is no clear evidence that they reduce clinically significant outcomes such as chronic pain or infertility. In this article, we review the ongoing magnitude of adhesion-related complications in gynecologic surgery, currently available interventions and new research toward more effective adhesion prevention. RECENT FINDINGS: Recent literature provides updated epidemiologic data and estimates of healthcare costs associated with adhesion-related complications. There have been important advances in our understanding of normal peritoneal healing and the pathophysiology of adhesions. Adhesion barriers continue to be tested for safety and effectiveness and new agents have shown promise in clinical studies. Finally, there are many experimental studies of new materials and pharmacologic and biologic prevention agents. SUMMARY: There is great interest in new adhesion prevention technologies, but new agents are unlikely to be available for clinical use for many years. High-quality effectiveness and outcomes-related research is still needed. PMID- 28582325 TI - Astroglial MicroRNA-219-5p in the Ventral Tegmental Area Regulates Nociception in Rats. AB - BACKGROUND: The authors previously reported that noncoding microRNA miR-219-5p is down-regulated in the spinal cord in a nociceptive state. The ventral tegmental area also plays critical roles in modulating nociception, although the underlying mechanism remains unknown. The authors hypothesized that miR-219-5p in the ventral tegmental area also may modulate nociception. METHODS: The authors studied the bidirectional regulatory role of ventral tegmental area miR-219-5p in a rat complete Freund's adjuvant model of inflammatory nociception by measuring paw withdrawal latencies. Using molecular biology technologies, the authors measured the effects of astroglial coiled-coil and C2 domain containing 1A/nuclear factor kappaB cascade and dopamine neuron activity on the down regulation of ventral tegmental area miR-219-5p-induced nociceptive responses. RESULTS: MiR-219-5p expression in the ventral tegmental area was reduced in rats with thermal hyperalgesia. Viral overexpression of ventral tegmental area miR-219 5p attenuated complete Freund's adjuvant-induced nociception from 7 days after complete Freund's adjuvant injection (paw withdrawal latencies: 6.09 +/- 0.83 s vs. 3.96 +/- 0.76 s; n = 6/group). Down-regulation of ventral tegmental area miR 219-5p in naive rats was sufficient to induce thermal hyperalgesia from 7 days after lentivirus injection (paw withdrawal latencies: 7.09 +/- 1.54 s vs. 11.75 +/- 2.15 s; n = 8/group), which was accompanied by increased glial fibrillary acidic protein (fold change: 2.81 +/- 0.38; n = 3/group) and reversed by intraventral tegmental area injection of the astroglial inhibitor fluorocitrate. The nociceptive responses induced by astroglial miR-219-5p down-regulation were inhibited by interfering with astroglial coiled-coil and C2 domain containing 1A/nuclear factor-kappaB signaling. Finally, pharmacologic inhibition of ventral tegmental area dopamine neurons alleviated this hyperalgesia. CONCLUSIONS: Down regulation of astroglial miR-219-5p in ventral tegmental area induced nociceptive responses are mediated by astroglial coiled-coil and C2 domain containing 1A/nuclear factor-kappaB signaling and elevated dopamine neuron activity. PMID- 28582327 TI - A comprehensive review of Asherman's syndrome: causes, symptoms and treatment options. AB - PURPOSE OF REVIEW: Intrauterine adhesions, also known as Asherman's syndrome, can have an impact on both reproductive outcomes and gynaecologic symptoms. Understanding the cause of intrauterine adhesions and the common clinical presentation will increase awareness of the condition and guide the patient to appropriate therapy. Surgical management offers favourable fertility outcomes and is often successful in restoring menstruation. RECENT FINDINGS: Surgical management with hysteroscopic lysis of adhesions is the gold standard for treatment and adopting an office-based approach offers several advantages. Prevention of reformation of adhesions remains challenging and no single method for preventing recurrence has shown superiority. Cell-based therapies using endometrial stem/progenitor cells hold promise for future use in regenerating inadequate endometrium. SUMMARY: Increased awareness of the symptoms suggestive of intrauterine adhesive disease, as well as recognition of common causes and preceding events, is crucial for early diagnosis, patient counselling and treatment. VIDEO ABSTRACT: http://links.lww.com/COOG/A36. PMID- 28582328 TI - EuroSCORE Performance in Minimally Invasive Cardiac Surgery: Discrimination Ability and External Calibration. AB - OBJECTIVE: Prediction of operative risk in adults undergoing cardiac surgery remains a challenge. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) is one of the most commonly used in clinical settings. Recently, the new EuroSCORE II was published attempting to improve the accuracy of risk prediction. We sought to assess the predictive value of EuroSCORE or EuroSCORE II in selected field of minimally invasive cardiac surgery. METHODS: Patients who underwent cardiac surgery operation with minimally invasive approach from 2007 to 2013 identified from prospective cardiac surgical database. Additional variables included in EuroSCORE II, but not in original EuroSCORE, were retrospectively collected via electronic health records reviewing. The C-statistic was calculated for the EuroSCORE (additive and logistic) and EuroSCORE II. The Hosmer-Lemeshow test was used to assess model calibration by comparing observed and expected morality in number of risk strata. RESULTS: There were 39 hospitals deaths (1.6%). A total of 2472 patients were identified from the main database. The mean +/- SD logistic EuroSCORE was 7.6 +/- 8.3, mean +/- SD additive EuroSCORE was 6.1 +/- 2.7, and mean +/- SD EuroSCORE II was 2.9 +/- 4.2. EuroSCORE logistic model performed with substantial accuracy of 0.78, EuroSCORE additive performed with accuracy of 0.78, and EuroSCORE II performed as almost perfect 0.82. Model calibration was poor in EuroSCORE II (chi = 17.57, P = 0.02), calibration for logistic EuroSCORE was also poor (chi = 140.58, P < 0.01), and additive model also (chi = 94.95, P < 0.01). The area under the curve was high in all algorithms; logistic EuroSCORE was 0.78 (95% confidence interval = 0.71-0.85), additive EuroSCORE was 0.79 (95% confidence interval = 0.71-0.86), and EuroSCORE II was 0.82 (95% confidence interval = 0.75-0.89). CONCLUSIONS: In overall settings, original EuroSCORE and EuroSCORE II perform poorly in minimally invasive operation conditions. Data suggest that EuroSCORE could not be used for estimating operative risks correctly. New risk score should be explored, developed, and implemented for selective minimally invasive cohorts. PMID- 28582329 TI - Update in the management of pediatric psoriasis. AB - PURPOSE OF REVIEW: Psoriasis is a multifactorial, chronic, inflammatory skin disease that may represent a therapeutic challenge in children. This review aims to provide a framework for the management of pediatric psoriasis, emphasizing in new insights and considerations for management. It will focus on new disease associations and innovative treatment modalities that challenge current approach of psoriasis in children. RECENT FINDINGS: There is an increasing body of literature both in adults and in children linking psoriasis with different comorbidities. This new evidence points to the need of addressing psoriasis as a systemic disease and suggests the need for screening and creating awareness of possible associations. In a similar manner, newer medications are also being investigated in children. Recent publications report on the efficacy and safety of biologics for psoriasis in pediatric patients. SUMMARY: The review provides better understanding of present and future risks of untreated and uncontrolled psoriasis in children and at the same time the benefits and risks of new treatments available. PMID- 28582330 TI - High-altitude illness in the pediatric population: a review of the literature on prevention and treatment. AB - PURPOSE OF REVIEW: Increasing numbers of children are now traveling to high altitude destinations, and pediatricians often see these children prior to and immediately following their travels. Thus, pediatricians have the opportunity to provide guidance for the prevention of altitude illness and must treat high altitude illness (HAI) in some circumstances. This review will examine guidelines for prevention and management of HAI in the pediatric population. RECENT FINDINGS: Recent research has examined children's short-term cardiorespiratory adaptation to high altitude, incidence of acute mountain sickness, hypoxic ventilator response, and maximal exercise capacity. Overall, studies indicate that children and adults are largely similar in these variables. Furthermore, studies suggest that heritability seems to be a component of response to altitude and development of altitude illness - a finding that may have implications for family vacation planning. SUMMARY: Increasing numbers of children are visiting high altitude destinations. Whereas most of these child travelers will only experience mild to moderate symptoms of HAI, a small percentage, particularly those with predisposing health conditions, may experience severe disease. Pediatricians should encourage preventive measures with an emphasis on gradual ascent and vigilance for onset of symptoms that should prompt immediate transport to medical care. PMID- 28582331 TI - Short Segment Spinal Instrumentation in Early-onset Scoliosis Patients Treated With Magnetically Controlled Growing Rods: Surgical Technique and Mid - Short term Outcomes. AB - STUDY DESIGN: A prospective, a single-institution, nonrandomized study. OBJECTIVE: The aim of this study was to evaluate the safety and effectivity of short-segment instrumentation in early-onset scoliosis (EOS) patients treated by magnetic-controlled growing rods (MCGRs). SUMMARY OF BACKGROUND DATA: Despite the common use of conventional growing rods and the recent popularity of MCGR in the treatment of progressive EOS, distal instrumented vertebra and number of the spanned levels are not standardized. METHODS: Patients with progressive EOS, characterized by the major thoracic curve and nonstructural compensatory curve, were a candidate to be treated by dual MCGR short segment spinal instrumentation spanning the major thoracic curve; such patients are followed up for a minimum period of 30 months. Radiological data were collected and analyzed in terms of Cobb angle of both primary and secondary curve, kyphosis angle, T1-T12, and T1-S1 distances, and T1-T12/T1-S1 ratio in preoperative, postoperative, and last follow up. RESULTS: Sixteen patients with different diagnoses of EOS, mean age at the operation was 7 years and 10 months (5 years and 6 months-9 years and 10 months), and mean period of follow-up was 37 (30-54) months. The Cobb angle of both major and compensatory curve are corrected by the mean value of 62 degrees (44-85), 35 degrees (22-45) preoperatively to 29 degrees (12-49), 14 degrees (9-24) postoperatively, and maintained at 28 degrees (10-47), 10 degrees (2-20) in the last follow-up, respectively. The T1-T12/T1-S1 ratio was 0.58 preoperatively, 0.6 postoperatively, and 0.62 at the last follow-up. The average yearly T1-T12 and T1 S1 length increase were calculated as 7 and 9 mm/year, respectively. CONCLUSION: Selective fusion principals are applicable to EOS, in that short segment instrumentation with MGCR in thoracic curve EOS patients is an effective technique in correction of both structural and compensatory curve, and in maintaining the correction during subsequent nonsurgical spinal distraction. LEVEL OF EVIDENCE: 4. PMID- 28582332 TI - Reply: The Effect of Neoadjuvant Chemotherapy Compared to Adjuvant Chemotherapy in Healing after Nipple-Sparing Mastectomy. PMID- 28582333 TI - Current Clinical Applications of Fat Grafting. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand the theory and principles behind successful avascular fat transfer; 2. Apply these principles into techniques that yield safe and successful fat grafting operations; 3. Identify the well-established indications and limitations of the various fat grafting operations as well as the indications that require additional clinical and translational research. SUMMARY: In this article, the authors summarize the established principles and techniques of fat grafting, discuss debated topics, and present both the well-established and the novel clinical applications of fat grafting. PMID- 28582334 TI - Introducing the International Confederation of Plastic Surgery Societies: ICOPLAST. AB - This article describes the formation of the International Confederation of Plastic Surgery Societies (ICOPLAST) as a novel, transparent, dynamic, and proactive confederation of national plastic surgery societies. ICOPLAST aspires to provide a voice for the entire international community of plastic surgeons. ICOPLAST has been designed to benefit the patient, plastic surgery as a profession, and each individual plastic surgeon. Its principal objective is to enhance international communication, education, and advocacy processes to ultimately improve patient outcomes for plastic surgery patients globally. The new ICOPLAST's focus is to add true value for patients. ICOPLAST's evolution, philosophy, governance, and bylaws are explained and all societies worldwide are encouraged and cordially invited to join. An open and warm invitation is provided. Additional information is found at www.ICOPLAST.org. PMID- 28582335 TI - A Prospective Clinical Trial Comparing Visible Light Spectroscopy to Handheld Doppler for Postoperative Free Tissue Transfer Monitoring. AB - BACKGROUND: Early detection of compromised free flap perfusion is critical. A common modality of thrombosis detection, physical examination augmented with hand held Doppler, provides only intermittent data and is insensitive to venous compromise. Visible light spectroscopy provides continuous, noninvasive evaluation of tissue perfusion. The authors hypothesized that visible light spectroscopy is a more sensitive and specific monitoring method for early detection of postoperative flap compromise than intermittent hand-held Doppler and clinical examination. METHODS: The authors prospectively conducted a controlled study evaluating the sensitivity, specificity, and accuracy of the T Stat Model 303 VLS oximeter versus that of intermittent Doppler and clinical examination. The authors prospectively collected and analyzed patient data, complications, reoperations, flap failures, and tissue oxygen saturation. RESULTS: Sixty-eight patients with 81 flaps completed the study. The majority of flaps (86.4 percent) were either transverse rectus abdominis musculocutaneous or deep inferior epigastric artery perforator flaps. The mean tissue oxygen saturation for all flaps in the study was 56.7 +/- 7.1 percent (range, 39.4 to 72.1 percent) and did not differ significantly with patient comorbidity or flap type. During the course of the study, three flaps were returned to the operating room for exploration because of a perfusion abnormality, and the resulting salvage rate was 100 percent. The sensitivity, specificity, and accuracy of visible light spectroscopy were found to be greater than both intermittent Doppler and clinical examination. CONCLUSION: Visible light spectroscopy is a reliable, continuous adjunct to free tissue transfer monitoring with advantages over intermittent hand-held Doppler and clinical examination. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 28582336 TI - Breast Cancer Molecular Subtypes and Chemotherapy Schedules Used in Neoadjuvant or Adjuvant Setting May Show Different Effects in Nipple-Sparing Mastectomy. PMID- 28582337 TI - AAOS Appropriate Use Criteria: Management of Patients with Orthopaedic Implants Undergoing Dental Procedures. PMID- 28582339 TI - Biophysics Rules the Cell Culture but Has Yet to Reach the Clinic: Why Is That? PMID- 28582338 TI - Management of Patients with Orthopaedic Implants Undergoing Dental Procedures. AB - The American Academy of Orthopaedic Surgeons, in collaboration with the American Dental Association, has developed Appropriate Use Criteria (AUC) for the Management of Patients with Orthopaedic Implants Undergoing Dental Procedures. Evidence-based information, in conjunction with the clinical expertise of physicians, was used to develop the criteria to improve patient care and obtain best outcomes while considering the subtleties and distinctions necessary in making clinical decisions. The Management of Patients with Orthopaedic Implants Undergoing Dental Procedures AUC clinical patient scenarios were derived from indications of patients with orthopaedic implants presenting for dental procedures, as well as from current evidence-based clinical practice guidelines and supporting literature to identify the appropriateness of the use of prophylactic antibiotics. The 64 patient scenarios and 1 treatment were developed by the writing panel, a group of clinicians who are specialists in this AUC topic. Next, a separate, multidisciplinary, voting panel (made up of specialists and nonspecialists) rated the appropriateness of treatment of each patient scenario using a 9-point scale to designate a treatment as Appropriate (median rating, 7 to 9), May Be Appropriate (median rating, 4 to 6), or Rarely Appropriate (median rating, 1 to 3). PMID- 28582340 TI - A Report of Ovarian Sertoli-Leydig Cell Tumors With Heterologous Intestinal-type Glands and Alpha Fetoprotein Elevation and Review of the Literature. AB - Ovarian Sertoli-Leydig cell tumors (SLCTs) are uncommon neoplasms that are occasionally associated with an elevated level of serum alpha fetoprotein (AFP), a marker of germ cell neoplasms, particularly yolk sac tumor (YST). We report 7 cases of ovarian SLCT (3 moderately differentiated, 2 poorly differentiated, 2 retiform) with heterologous intestinal-type glands, 6 of which were associated with elevated serum AFP. The intestinal-type mucinous glands were immunoreactive for SALL4 (4 cases), AFP (4 cases), glypican 3 (1 case), CDX2 (6 cases), and villin (7 cases), markers that are commonly expressed in YSTs, although the latter 2 markers would be expected to be positive in intestinal-type glands. We show that heterologous intestinal-type glands in ovarian SLCTs often have an endodermal sinus-like (YST-like) immunophenotype and stress that these should not be misinterpreted as microscopic foci of endodermal-type YST. Cases of ovarian SLCT with elevated serum AFP should be sampled extensively to look for foci of intestinal-type glands, the likely source of the AFP elevation in some of these neoplasms. PMID- 28582341 TI - Invasive Extramammary Paget Disease of the Vulva With Signet Ring Cell Morphology in a Patient With Signet Ring Cell Carcinoma of the Stomach: Report of a Case. AB - This report describes a rare case of invasive extramammary Paget disease of the vulva with signet ring cell morphology in a 58-yr-old woman with a history of signet ring cell carcinoma of the stomach. This case was initially misinterpreted as a metastatic gastric carcinoma to the vulva because an initial small, superficial biopsy specimen showed infiltration of signet ring cells in the dermis without intraepidermal Paget cells. However, a surgically resected specimen showed concordant immunophenotypes in both intraepidermal Paget cells and intradermal signet ring cell components with immunoreactivity to cytokeratin (CK) 7, CEA, and gross cystic disease fluid protein-15, and immunonegativity for CK20, MUC5AC, and MUC6. Gastric signet ring cell carcinoma showed immunoreactivity to CK7, CEA, MUC5AC, and MUC6, and immunonegativity for gross cystic disease fluid protein-15 and CK20. The diagnosis of primary invasive extramammary Paget disease of the vulva was also supported by a long interval after gastrectomy (7.5 yr), the solitary involvement of the vulva, and the absence of lymphovascular invasion. This case demonstrates that invasive extramammary Paget disease may have a signet ring cell morphology and immunohistochemical profile similar to those of gastric signet ring cell carcinoma, but the addition of gross cystic disease fluid protein-15 immunostain in the panel of markers is helpful in the differential diagnosis. PMID- 28582342 TI - Expression of GATA-3 in Testicular and Gynecologic Mesothelial Neoplastic and Non neoplastic Tissues. AB - GATA-3 expression in testicular/gynecologic mesothelial neoplasms and benign mesothelia have not been completely investigated. We graded GATA-3, calretinin, and WT1 staining in 20 adenomatoid tumors [9/20 (para)testicular and 11/20 tubal/uterine] and 38 normal mesothelia (20/38 tunica vaginalis and 18/38 fallopian tubes) as either 0 (<=5%), +1 (>5% and <25%), +2 (>=25% and <=50%), and +3 (>50%). Adenomatoid tumor GATA-3 staining: 2 urologic cases were positive (2/9, +3 and +1), no gynecologic cases were positive (0/11), and all were positive for WT1/calretinin (20/20,+2 to +3). The normal tunica vaginalis mesothelia: 3 of 20 were GATA-3 positive (+2) while 20 of 20 were WT1/calretinin (+2 to +3) positive. The gynecologic cases with walthard nests: are positive for GATA-3 (18/18,+3), WT1 (11/18, +2 to +3), and calretinin (1/18,+2). The nonmetaplastic gynecologic mesothelia were GATA-3 negative (18/18) and WT1/calretinin postive (18/18,+2 to +3). All 18 epididymi were GATA-3 positive (+3) and negative for WT1/calretinin. All 11 efferent ductules examined were negative for GATA-3, WT1/calretinin (0/11). Although GATA-3 rarely stains adenomatoid tumors, gynecologic walthard nests are consistently positive with GATA-3 staining but lose mesothelial markers reflecting a metaplastic change. Excluding the walthard nests, GATA-3 is rarely positive in normal urologic and gynecologic mesothelia. GATA-3 is uniformally positive in epididymi and negative in efferent ductules, which may be due to their embryological evolvement. Awareness of the GATA-3 staining patterns in the genitourinary and gynecologic mesothelial tissues and their respective neoplasms is important to prevent misdiagnosis and possible unnecessary interventions. PMID- 28582343 TI - Intravascular Lymphocytic Accumulation in the Uterine Cervix: A Frequent Finding. AB - Intravascular accumulation of lymphocytes in any body site can raise concerns for a lymphoproliferative disorder, mainly intravascular lymphoma, leukemia, or a form of angiocentric lymphoma. We recently found an intravascular lymphocytic accumulation of non-neoplastic nature in a uterine cervix. The aim of the study was to define the frequency and the nature of this observation in the uterine cervix. Thirty cervical excision specimens including 23 cone biopsies and 7 hysterectomies were examined for the presence of intravascular accumulation of lymphocytes. Intravascular accumulation of lymphocytes was observed in 9 of the 30 specimens (30%). These were small-sized or medium-sized lymphocytes accumulating in lymphatic channels. The lymphocytes showed no atypia or mitotic activity. Intravascular lymphocytic accumulation was more common in cases with severe cervicitis (P<0.0001). Immunohistochemically, there was a mixed population of lymphocytes that were CD20 and CD3 positive; they were negative for CD30. Similar but larger lymph-node-like structures were noted inside the paracervical tissue in cases of wide excision. Intralymphatic accumulation of small nonatypical lymphocytes sometimes forming small corpuscles is a frequent and benign finding of the uterine cervix. PMID- 28582345 TI - Microscopic Extraovarian Sex Cord Proliferations: Report of the Seventh Case With 2 Year Follow-up. PMID- 28582344 TI - Androgen Receptor Expression in Endometrial Carcinoma. AB - Endometrial carcinoma (ECA) is frequently hormonally driven and can be treated with endocrine-based therapy, yet hormone receptor status is not routinely assessed. In particular, little is known about the significance of androgen receptor (AR) in ECA. Androgen has antiproliferative effects in the healthy endometrium and could serve a similar role to progesterone in curbing the progression of estrogen-dependent neoplasia. There may also be a subset of ECA that benefits from androgen antagonistic therapy. We herein investigate AR expression across ECA subtypes and compare its expression to estrogen receptor (ER) and progesterone receptor (PR). Immunohistochemical staining for AR, ER, and PR was performed on an endometrial tissue microarray containing 50 ECA with a variety of morphologic subtypes as well as 20 benign and 9 atypical hyperplastic endometria. AR was expressed by 54% (27/50) of ECA including 60% of low grade endometrioid carcinomas, 70% high grade endometrioid carcinomas, 70% serous carcinomas, 50% carcinosarcomas, and 20% clear cell carcinomas. High AR expression was chiefly restricted to a subset of serous carcinomas (50%). AR expression occurred most often in concert with ER staining, although 5 high grade cancers (1 serous carcinoma, 4 carcinosarcomas) showed AR expression in the absence of ER. In summary, AR positivity is seen in over half of ECA in our study, including the majority of low grade endometrioid carcinomas, high grade endometrioid carcinomas, and serous carcinomas. High level expression is seen in half of serous carcinomas and a subset of serous carcinomas and carcinosarcomas show some degree of AR staining in the absence of ER, suggesting a possible role for androgen inhibition in treatment of these cases. PMID- 28582347 TI - Tissue-based Immunohistochemical Biomarker Expression in Malignant Glandular Lesions of the Uterine Cervix: A Systematic Review. AB - Literature published between 1975 and 2015 was systematically reviewed to conduct a case-comparator study of tissue based, immunohistochemical biomarker expression among malignant glandular histotypes of the uterine cervix so as to identify differences that could have diagnostic utility. Of the 902 abstracts, 154 articles had a full review, and 52 were included. Biomarker positivity in cases of adenocarcinoma in situ (AIS) were compared with atypical lobular endocervical glandular hyperplasia and invasive histotypes grouped as mucinous, endometrioid, adenosquamous, serous clear cell, minimal deviation-gastric type, and mesonephric carcinomas (7 AIS case-comparators). The invasive histotypes were compared with each other (30 adenocarcinoma case-comparators). Biomarker positivity in all 37 case-comparators was calculated as weighted averages of histotype-specific estimates. Unsupervised hierarchical clustering examined differences in expression and were visualized via heatmaps and dendrograms. Of the 56 biomarkers tested, 1 or more of 15 showed a 50% or more difference in positive expression in 6 (86%) of the AIS and 21 (70%) of the adenocarcinoma case-comparators. There was no data on the comparison of serous clear cell to mesonephric carcinoma. AIS case comparator biomarkers were HIK1083, alpha SMA, PAX8, VIL1, CEA, p53, p16, and CD10, and only alpha SMA had a difference of 100%. The adenocarcinoma case comparator biomarkers were CEA, p53, Claudin18, HIK1083, p16, Calretinin, CD10, PR, Chromogranin, MUC6, Vimentin and p63, and none had a difference of 100%. Biomarker expression in the discrimination of AIS from invasive adenocarcinoma, and the invasive histotypes from each other is understudied. One or more of 15 biomarkers could have diagnostic utility. PMID- 28582346 TI - Endometrial Carcinoma With Trophoblastic Components: Clinicopathologic Analysis of a Rare Entity. AB - Somatic endometrial carcinomas with trophoblastic components have only rarely been described. To better characterize this distinctive combination of histotypes, we report herein 4 new cases, representing the largest cohort reported thus far, and review previously reported cases. The 4 new patients ranged in age from 61 to 77 yr (mean, 68 yr). The first patient had a grade 2 endometrioid carcinoma, surgical International Federation of Gynecology and Obstetrics stage IA, that recurred 5 months later at the vaginal apex with purely choriocarcinoma elements, suggestive of unsampled trophoblastic areas in the uterus. The 3 other patients were all International Federation of Gynecology and Obstetrics stage III, and included 2 cases of dedifferentiated endometrial carcinoma with 40% and 20% choriocarcinoma components, and 1 case of grade 1 endometrioid carcinoma with a 40% choriocarcinoma component. Postoperative serum beta-human chorionic gonadotropin was elevated in all patients. All received adjuvant combination chemotherapy, but all were dead of disease with distant metastases at an average of 11.75 mo (range, 7-16 mo) after primary staging. Data from our cases were combined with those from 24 cases that had previously been reported in the literature between 1972 and 2016. Analysis of this combined data indicates that endometrial carcinoma with trophoblastic component is a rare neoplasm that occurs primarily in postmenopausal patients. The trophoblastic component is most commonly a choriocarcinoma and the somatic component is most commonly an endometrioid carcinoma or an adenocarcinoma/carcinoma reported without further specification; the somatic component may be a diverse array of histotypes or histotype admixtures. Serum and/or urine beta-human chorionic gonadotropin is elevated in almost all patients, and fluctuations of beta-human chorionic gonadotropin generally correlated with tumor relapses or recurrences. The stage distribution and patient outcomes in the current and previously reported patients suggests that trophoblastic differentiation usually, but not invariably denotes clinical aggressiveness. PMID- 28582348 TI - Phenotypic Intratumoral Heterogeneity of Endometrial Carcinomas. AB - Intratumoral heterogeneity has been shown to play an important role in diagnostic accuracy, development of treatment resistance, and prognosis of cancer patients. Recent studies have proposed quantitative measurement of phenotypic intratumoral heterogeneity, but no study is yet available in endometrial carcinomas. In our study we evaluated the phenotypic intratumoral heterogeneity of a consecutive series of 10 endometrial carcinomas using measures of dispersion and diversity. Morphometric architectural (%tumor cells, %solid tumor, %differentiated tumor, and %lumens) and nuclear [volume-weighted mean nuclear volume ((Equation is included in full-text article.))] parameters, as well as estrogen receptor, progesterone receptor, p53, vimentin, and beta-catenin immunoexpression (H-score) were digitally analyzed in 20 microscopic fields per carcinoma. Quantitative measures of intratumoral heterogeneity included coefficient of variation (CV) and relative quadratic entropy (rQE). In each endometrial carcinoma there was slight variation of architecture from field to field, resulting in globally low levels of heterogeneity measures (mean CV %tumor cells: 0.10, %solid tumor: 0.73, %differentiated tumor: 0.19, %lumens: 0.61 and mean rQE %tumor cells: 18.5, %solid tumor: 20.3, %differentiated tumor: 25.6, %lumens: 21.8). Nuclear intratumoral heterogeneity was also globally low (mean (Equation is included in full-text article.)CV: 0.23 and rQE: 27.3), but significantly higher than the heterogeneity of architectural parameters within most carcinomas. In general, there was low to moderate variability of immunoexpression markers within each carcinoma, but estrogen receptor (mean CV: 0.56 and rQE: 46.2) and progesterone receptor (mean CV: 0.60 and rQE: 39.3) displayed the highest values of heterogeneity measures. Intratumoral heterogeneity of immunoexpression was significantly higher than that observed for morphometric parameters. In conclusion, our study indicates that endometrial carcinomas present a variable but predominantly low degree of phenotypic intratumoral heterogeneity. PMID- 28582349 TI - Perioperative Factors Associated With Chronic Central Pain After the Resection of Intramedullary Spinal Cord Tumor. AB - OBJECTIVE: Some patients experience severe chronic pain after intramedullary spinal cord tumor (IMSCT) resection, but the underlying mechanisms have yet to be fully elucidated. We aimed to investigate perioperative factors associated with chronic pain after IMSCT resection. MATERIALS AND METHODS: We analyzed data from a postal survey and the medical records of patients who had undergone IMSCT resection in our institution between 2000 and 2008. Chronic pain was assessed using the Neuropathic Pain Symptom Inventory score, and its associations with factors related to tumor pathology, patient demographics, neurological findings, surgery, anesthesia, and perioperative management were determined. RESULTS: Seventy-eight consecutive patients (55 men and 23 women; age 17 to 79 y) were included in the statistical analysis of the present study. In univariate analyses, sex, body mass index, preoperative tumor-related pain, preoperative nonsteroidal anti-inflammatory drugs, intraoperative hypotension, postoperative corticosteroids, and decrease in Japanese Orthopaedic Association (JOA) scores were found to be associated with postsurgical chronic central pain. Logistic regression analysis identified 3 significant factors: a decline in JOA scores compared with preoperative values (odds ratio [OR], 3.33; 95% confidence interval [CI], 1.18-9.42; P=0.023), intraoperative hypotension (OR, 3.01; 95% CI, 1.02 8.97; P=0.047), and postoperative corticosteroids (OR, 3.21; 95% CI, 1.02-10.09; P=0.046). DISCUSSION: Decline in JOA score, intraoperative hypotension, and postoperative corticosteroids are independently associated with postsurgical chronic central pain. Intraoperative hypotension and the use of postoperative corticosteroids can be avoided or modified during perioperative management. As results from animal studies have indicated that the administration of corticosteroids may intensify chronic pain, further studies in larger cohorts are required to definitively determine the effect of corticosteroids on postsurgical central pain. PMID- 28582350 TI - Educational Opportunities for Fetal Alcohol Spectrum Disorder Prevention. PMID- 28582351 TI - Teenagers' Awareness of Peers' Substance and Drug Use in Kuwait. AB - BACKGROUND: Teenage substance use is a global challenge, and youths residing in Kuwait are not immune from it. Tobacco products are licit; however, alcohol and other mood-altering illicit substance are prohibited with severe penalties including imprisonment. Youths residing in Kuwait are being initiated into the use of mood-altering substances like tobacco at an early age, and it is postulated that, as they grow older, they may progress into using alcohol and other prohibited illicit drugs. AIMS: The aim of this study was to determine licit and illicit substance use by teenagers residing in Kuwait. The study will also explore their awareness of substance use among their peers. DESIGN: A cross sectional survey using a snowball sampling technique was used to recruit 190 teenagers aged 15-18 years residing in Kuwait. Data were collected using the 130 item questionnaire adapted from 1998 New Jersey Triennial Public High School Survey of Drug and Alcohol Use. Data collection was from September 2012 to June 2013. DATA ANALYSIS: The Statistical Package for Social Sciences Version 22 for Windows was used. Pearson's chi-square, Kruskal-Wallis, and Mann-Whitney U tests were used to test the hypotheses. RESULTS: Tobacco was the most commonly used substance by these teenagers; 8.4% were current smokers, and 50% had experimented. Age of initiation for 21% was before 14 years old. Hashish (marijuana) was the most commonly used illicit drug, with 3.7% current users and 5.3% claiming to have used it. More male than female teenagers in Grade 9 were using tobacco products (chi = 27.428, df = 5, p < .001). CONCLUSION: The use and abuse of mood/mind-altering licit and illicit substances appear to be increasing among older teenagers. Intensifying campaigns about the hazards of substance use and drug testing should start from the primary school level. PMID- 28582352 TI - Health Behaviors Survey: An Examination of Undergraduate Students' Substance Use. AB - OBJECTIVE: This study determined the prevalence of alcohol, drug, and nonmedical prescription drugs at a small private university. In addition, risk and protective factors are examined. METHOD: The Core Institute (Southern Illinois University) was contracted to administer an anonymous, Web-based 49-item survey to matriculated undergraduate students, aged 18-23 years. Data were obtained on student behaviors, perceptions, consequences of substance use, risk factors, and coping strategies. Statistical analysis included descriptive measures, cross tabs, t test, and chi-square. RESULTS: The response rate was 14%, which is consistent with other CORE Institute surveys. Almost half of the total respondents were from the college of nursing (46%), and most participants were female (82%). There was a significant association between heavy drinking and grades; the B students engaged in more binge drinking. Living on campus and being involved in Greek life confer a higher level of risk for sexual assault when alcohol was consumed. Most participants (57%) were unaware of campus resources for assistance with alcohol or drug problems. CONCLUSION: Campus administrators now have a better awareness related to the extent of drug and alcohol use among the student body. A faculty engagement workshop was developed to provide tools to assess and communicate with students. Improvements are anticipated to enhance student relationships and decrease incidents of drug- and alcohol-related sexual assault or misconduct. PMID- 28582353 TI - Effectiveness of the Sexual Health/Reproductive Health Education Given to Turkey Adolescents Who Use Alcohol or Substance. AB - OBJECTIVE: The research was conducted experimentally to evaluate the effectiveness of the sexual health/reproductive health (SH/RH) education given to Turkish adolescents who use alcohol or illicit substances. METHODS: The population was adolescents who use alcohol and substances and were inpatients at the Child and Adolescent Substance Addiction Research, Treatment and Education Center. The adolescents were grouped into the following three groups: Group 1 (control group), Group 2 (those who have received training once), and Group 3 (those who have received training twice). Data were collected between September 2011 and December 2012 using the forms Self-Introduction and Information on Sexual Health-Reproductive Health and Information on Sexual Health-Reproductive Health Education Modules. RESULTS: Upon studying the total SH/RH test scores of the groups individually, a statistically significant difference was observed in the scores of Groups 2 and 3 (p < .01). Upon studying the change in the posttest scores from the pretest ones for each group individually, the increase in the scores of Group 3 (34.57 +/- 16.33) was observed to have a statistically highly significant difference from those of Groups 1 (2.73 +/- 10.65) and 2 (20.23 +/- 12.09; p < .01). CONCLUSIONS AND PRACTICE IMPLICATIONS: Adolescents who abuse alcohol or substances should be given SH/RH education in a repetitive manner for prevention of risky sexual behavior. PMID- 28582354 TI - Withdrawal Phenomena: A Concept Analysis for the Development of a Nursing Diagnosis. AB - This study explored the concept of withdrawal phenomena from the perspective of nurses, with the aim of developing a nursing diagnosis. Concept analysis was used as the framework of the study, a systematized review was conducted to identify relevant studies, and interpretation was based on qualitative content analysis. Specifying aspects, defining characteristics, related factors, and risk factors were extracted and classified into categories. Thirteen studies were identified as a basis for the construction of two nursing diagnoses: "withdrawal phenomena" and "risk of withdrawal complications." The proposed nursing diagnoses require further discussion. The NANDA International Diagnosis Development Committee was asked to examine the proposed diagnoses. However, it was too early to determine implications for nursing practice based on the results of this study. PMID- 28582355 TI - The Effect of Positive Group Psychotherapy and Motivational Interviewing on Smoking Cessation: A Qualitative Descriptive Study. AB - OBJECTIVE: The purpose of this study was to describe the process and evaluate the effect of positive group psychotherapy and motivational interviewing as an intervention for smoking cessation. METHOD: A qualitative descriptive study was conducted at a university in South Korea. Positive group psychotherapy and motivational interviewing were attended by 36 smokers for 1 hour once a week, for 6 hours. A recorded exit interview was conducted after the intervention. The resulting transcripts were analyzed with content analysis and thematic analysis. RESULTS: Among the 36 study participants, the importance of stopping smoking was rated higher in the successful cessation (defined as those who ceased smoking for at least 3 months; hereafter, success group) group (8.6 +/- 0.4, n = 10) than in the failed cessation (defined as those who did not cease smoking for at least 3 months; hereafter, failure group) group (7.75 +/- 0.3, n = 26; p < .01). The confidence to stop smoking was rated higher by the successes (8.4 +/- 0.3) than by the failures (5.5 +/- 0.4; p < .01). More successes wanted to stop smoking for the sake of their loved ones (60%) and health (50%), whereas more failures wanted to stop smoking for saving money (45.5%). Failures had more cross-addiction than successes (three to four addictions: 31.5% vs. 20%). When participants were asked to find 10 personality merits, 78% of the successes and 47% of the failures found their 10 merits. The therapeutic process was described as "sharing the smoking cessation process with others," "detailed guidance for stress management and smoking cessation," and "compliments about efforts for smoking cessation." CONCLUSION: The importance of and confidence in smoking cessation were predictors for successful cessation for 3-6 months. Motivational interviewing increased motivations, whereas positive group psychotherapy increased positive thoughts and confidence. PMID- 28582356 TI - Pharmacology Update: Benzodiazepines. PMID- 28582357 TI - Stories From the Field. PMID- 28582358 TI - An Interview With Carmel Clancy, PhD, RGN, RMN, BSc(Hons), PGCertHE, FPH, Head of the Department for Mental Health, Social Work and Integrative Medicine, Middlesex University, London, UK. PMID- 28582360 TI - Predicting the past. PMID- 28582361 TI - Anaemic parturient and the anaesthesiologist: Are we asleep at the wheel? PMID- 28582362 TI - Publication and innovation in airway management: quality not quantity! PMID- 28582363 TI - Positive pressure ventilation through small cricothyroidotomy tubes in a model lung. PMID- 28582364 TI - Cricoid pressure impedes mask ventilation: A randomised crossover trial. PMID- 28582365 TI - Burnout compared between anaesthesiology and psychiatry residents in France: An observational study. PMID- 28582366 TI - Better safe than sorry: An observational study of #ESALondon tweets. PMID- 28582367 TI - Do effects of sodium-glucose cotransporter-2 inhibitors in patients with diabetes give insight into potential use in non-diabetic kidney disease? AB - PURPOSE OF REVIEW: Our aim was to review the rationale for the role of sodium glucose cotransporter-2 inhibitors (SGLT-2i) as renoprotective therapy in patients with and without diabetes. RECENT FINDINGS: SGLT-2i are antihyperglycemic agents, approved for treating type 2 diabetes to reduce glycosylated hemoglobin, type A1c. Primary glucoregulatory effects occur through selective inhibition of SGLT-2 at the renal proximal tubule promoting glucosuria leading to blood glucose lowering. From a hemodynamic perspective, SGLT-2 inhibition is also associated with decreased glomerular hyperfiltration, an effect that is mediated through natriuresis and tubuloglomerular feedback. With renal injury and progressive nephron loss, diabetic kidney disease, and nondiabetic chronic kidney diseases share overlapping phenotypes exhibiting single nephron hyperfiltration, along with increased proteinuria. Importantly, the impact of SGLT-2 inhibition on renal and systemic hemodynamic function, including effects on lowering blood pressure, hyperfiltration, and plasma volume, are independent of blood glucose lowering and instead are because of natriuresis. Accordingly, large clinical trials with SGLT-2i investigating the potential use of SGLT-2i in patients without diabetes are now underway. SUMMARY: Based on prominent nonglycemic effects, the clinical use of SGLT-2i as renoprotective therapy may extend to nondiabetic chronic kidney diseases subtypes, which could help to address a large, unmet clinical need. PMID- 28582368 TI - Spontaneous Resolution of Optic Neuropathy in Sphenoid Wing Meningioma. AB - The authors describe herein a case of optic neuropathy in progesterone receptor positive sphenoid wing meningioma of the greater wing which demonstrated spontaneous recovery with conservative management. PMID- 28582369 TI - Comparison of Revision Rates of Anterior- and Posterior-Approach Ptosis Surgery: A Retrospective Review of 1519 Cases. AB - PURPOSE: To compare revision rates for ptosis surgery between posterior-approach and anterior-approach ptosis repair techniques. METHODS: This is the retrospective, consecutive cohort study. All patients undergoing ptosis surgery at a high-volume oculofacial plastic surgery practice over a 4-year period. A retrospective chart review was conducted of all patients undergoing posterior approach and anterior-approach ptosis surgery for all etiologies of ptosis between 2011 and 2014. Etiology of ptosis, concurrent oculofacial surgeries, revision, and complications were analyzed. The main outcome measure is the ptosis revision rate. RESULTS: A total of 1519 patients were included in this study. The mean age was 63 +/- 15.4 years. A total of 1056 (70%) of patients were female, 1451 (95%) had involutional ptosis, and 1129 (74.3%) had concurrent upper blepharoplasty. Five hundred thirteen (33.8%) underwent posterior-approach ptosis repair, and 1006 (66.2%) underwent anterior-approach ptosis repair. The degree of ptosis was greater in the anterior-approach ptosis repair group. The overall revision rate for all patients was 8.7%. Of the posterior group, 6.8% required ptosis revision; of the anterior group, 9.5% required revision surgery. The main reason for ptosis revision surgery was undercorrection of one or both eyelids. Concurrent brow lifting was associated with a decreased, but not statistically significant, rate of revision surgery. Patients who underwent unilateral ptosis surgery had a 5.1% rate of Hering's phenomenon requiring ptosis repair in the contralateral eyelid. Multivariable logistic regression for predictive factors show that, when adjusted for gender and concurrent blepharoplasty, the revision rate in anterior-approach ptosis surgery is higher than posterior-approach ptosis surgery (odds ratio = 2.08; p = 0.002). CONCLUSIONS: The overall revision rate in patients undergoing ptosis repair via posterior-approach or anterior-approach techniques is 8.7%. There is a statistically higher rate of revision with anterior-approach ptosis repair. PMID- 28582370 TI - Isolated Neurofibroma of the Orbit: Case Report and Literature Review. AB - PURPOSE: To summarize the clinical, radiographic, and intraoperative characteristics of isolated neurofibromas of the orbit (INFO) in the literature and report a case of INFO. METHODS: Case report and a systematic review of the literature. RESULTS: A total of 45 patients were identified from 18 previous studies. There was no sex predilection and mean ages were between 32.3 and 40.0 years with a standard deviation of 9.8 to 19.5 years, median age was 32 to 38 years with a range of 1.5 to 82 years. On CT imaging, INFO reveals homogeneous precontrast radiodensity similar to that of extraocular muscles. On MR imaging, INFO appears hypointense to orbital fat and isointense to brain on precontrast T1 weighted images. On T2-weighted images, they have been described as being predominantly hyperintense with possible hypointense intralesional islands. To the best of our knowledge, our case identifies the youngest patient with the myxoid histologic variant of INFO. CONCLUSIONS: Patients with orbital neurofibromas should be evaluated for the presence of systemic neurofibromatosis, and the plexiform variant is a commonly associated subtype. The myxoid variant can be part of a lesser known condition called NAME syndrome (nevi, atrial myxoma, myxoid neurofibroma, and ephelides) which may warrant echocardiography in patients to evaluate for associated cardiac tumors. PMID- 28582371 TI - Clinical Presentation and Anatomical Location of Orbital Plasmacytomas. AB - PURPOSE: To evaluate the clinical and anatomical location of orbital plasmacytomas and assess local control following therapy. METHODS: The American Society of Ophthalmic Plastic and Reconstructive Surgery Oncology Database was queried to identify patients diagnosed with orbital plasmacytoma. These patients' records were reviewed for demographic characteristics, clinical and radiologic findings, treatments, and outcomes. RESULTS: Thirty patients from 4 institutions (24 from MD Anderson Cancer Center, 3 from SUNY Downstate Medical Center, 2 from University of California, Los Angeles, and 1 from Oregon Health and Science University) were identified. Eighteen patients (60%) were diagnosed with multiple myeloma (MM) before and 11 (37%) were diagnosed with MM immediately after orbital plasmacytoma. Based on imaging, 4 distinct anatomical patterns were identified: 1) bony plasmacytoma affecting the superotemporal orbit, epidural space, and temporal fossa (15 patients; 50%); 2) discrete orbital plasmacytoma (7 patients; 23%); 3) infiltrative plasmacytoma either originating from a sinus (4 patients; 13%); or 4) originating from the orbital floor and infiltrating facial soft tissue (4 patients; 13%). Of the 29 patients with available treatment data, 2 had radiation only, 3 had chemotherapy only, 6 had chemoradiation, and 18 had stem cell transplant following chemoradiation (n = 17) or only chemotherapy (n = 1). Following treatment, 10 patients achieved complete and 11 achieved partial responses. CONCLUSION: Orbital plasmacytomas were found exclusively in patients with MM diagnosed before or immediately after orbital plasmacytoma. Plasmacytomas can have 4 distinct anatomical patterns of origin. Following treatment, all patients had good to excellent local control of their orbital lesions. PMID- 28582372 TI - Transitional Cell Carcinoma of Lacrimal Sac. PMID- 28582373 TI - Ocular Surface Changes After Sulfur Mustard Exposure in Rabbits, Monitored by Impression Cytology. AB - PURPOSE: Ocular injuries after exposure to sulfur mustard (SM) are characterized by acute corneal erosion and inflammation of the anterior segment that may be followed by delayed corneal neovascularization and epithelial defects, associated with limbal stem cell deficiency in part of the exposed eyes. This study aimed to further clarify the mechanism of the late injury by monitoring SM-induced cytological alterations in the ocular surface, in relation to the clinical symptoms, using impression cytology (IC). METHODS: Rabbit eyes were exposed to SM vapor (n = 20) and were clinically observed up to 4 weeks. Samples for IC were collected simultaneously from the upper bulbar conjunctiva, limbus, and cornea and then fixed and stained with periodic acid-Schiff and hematoxylin. At 1 month, animals were killed and eyes dissected and processed for histology. RESULTS: Concomitant with clinical symptoms of SM ocular toxicity, IC showed significant long-term loss of conjunctival goblet cells shortly after exposure, followed by abnormal differentiation toward squamous metaplasia. Simultaneously with corneal erosion, apoptotic bodies and cellular debris were seen in the corneal epithelium, followed by regeneration at 1 week. Migration of conjunctival goblet cells toward the cornea was noted in neovascularized eyes, as early as 1 week, indicating limbal stem cell deficiency. The IC findings were supported by histological evaluation. CONCLUSIONS: Continuous monitoring of the ocular surface after SM exposure by IC enables earlier detection of pathology and therapeutic intervention, therefore, is recommended for routine follow-up of casualties. Prolonged loss of goblet cells may point toward the role of mucin in the pathogenesis. PMID- 28582374 TI - Management of Corneal Scarring Secondary to Herpes Zoster Keratitis. AB - PURPOSE: To review the management of visually significant corneal scarring secondary to herpes zoster keratitis (HZK). METHODS: Literature review. RESULTS: Management options for visually significant corneal scarring secondary to HZK include scleral contact lenses, photorefractive or phototherapeutic keratectomy, lamellar keratoplasty, penetrating keratoplasty, and keratoprosthesis. Many authors recommend tarsorrhaphy in at-risk patients at the time of corneal transplantation. Most published studies either did not mention or did not use systemic antivirals at the time of surgery. Longer quiescent periods before surgical intervention may be associated with increased rates of graft survival. Reports of HZK recurrence after live-attenuated vaccine administration suggest that risks and benefits of the vaccine should be carefully considered. Overall, the prognosis of surgical intervention for corneal scarring due to HZK relies on appropriate patient selection and measures to ensure ocular surface stability. There remains a serious risk of ocular surface instability and corneal melt in these patients. Unfortunately, there is a lack of prospective studies in this area to guide clinical management. CONCLUSIONS: Patients with visually significant corneal scarring secondary to HZK may have good outcomes with the appropriate medical and surgical considerations, particularly in the absence of active ocular surface disease and inflammation. Those with active disease may benefit from delaying surgical intervention until a satisfactory quiescent period has been achieved. Prospective studies, such as the proposed Zoster Eye Disease Study, are imperative for validating these principles and determining evidence based management guidelines. PMID- 28582375 TI - Pythium Insidiosum Keratitis: Histopathology and Rapid Novel Diagnostic Staining Technique. AB - PURPOSE: To elucidate the histopathology of Pythium insidiosum keratitis and to describe a novel, simple, and rapid staining technique for identification of oomycete Pythium insidiosum and to differentiate it from fungi. METHODS: This is a laboratory investigation study of 38 nonconsecutive cases (37 ocular samples and 1 colonic biopsy); 14 microbiologically diagnosed as Pythium insidiosum keratitis and 24 as fungal keratitis. Review of clinical, demographic details, microbiological results, and identification of cases that necessitated evisceration was performed. Reevaluation of histopathology slides was done using stains such as hematoxylin-eosin, Gomori methenamine silver (GMS), periodic acid Schiff (PAS), potassium iodide-sulfuric acid (IKI-H2SO4). Morphology, degree, and nature of inflammation and load, distribution, and staining results of Pythium insidiosum and its comparison with fungi were studied. RESULTS: Delay in zoospore formation, failure of growth, and delay in identification of Pythium were the main cause of evisceration. Corneal pythiosis showed epithelial ulceration, stromal destruction, and varying inflammation; load and distribution of Pythium were inversely proportional to inflammation. The filaments were commonly wide, with admixed narrower structures and uncommonly involved Descemet membrane. The oomycete was not discretely discerned with PAS stain and stained distinctly with GMS stain and IKI-H2SO4 stain (100% sensitive). In comparison, fungal organisms stained well with PAS and GMS stain, but not with IKI-H2SO4 stain (100% specific). CONCLUSIONS: Pythium insidiosum keratitis is perhaps not more devastating than fungal keratitis but late diagnosis, misdiagnosis, and treatment as fungal infection are major heralds. Early diagnosis may markedly improve the patient outcome. IKI-H2SO4 is a cost-effective, simple, sensitive, and specific stain for the diagnosis of oomycete Pythium. PMID- 28582376 TI - Spontaneous Canalicular Plug Erosion After Punctal Plug Placement. PMID- 28582377 TI - Is it the End for Urologic Pelvic Laparoscopic Surgery? AB - AIM: To scrutinize the rapid development of robotic versus traditional laparoscopic technique in pelvic urologic surgery. INTRODUCTION: In the last few decades, advances in research and development have led to tremendous progress in medical diagnostics and treatment of disease. Minimally invasive surgery has moved from experimental to becoming the dominant form of surgical management across the surgical specialties. Laparoscopy is nowadays used widely in abdominal surgery, from simple diagnostic laparoscopy to complex colorectal and gynecologic cancer procedures. METHODS: A literature search of electronic databases (PubMed, Medscape, Embase) using the key words: "pelvic laparoscopy, urologic oncology, robotic surgery, minimally invasive access" was performed for all relevant articles in the English language. Data were extrapolated from the abstracts alone to avoid subjective bias in drawing conclusions. RESULTS: Telemedicine and telesurgery, the diagnostic and operative process is conducted from a distance. The surgeon uses computer-assisted surgery away from the bedside via a robotic system and performs the surgical task at hand. In pelvic urological cancer surgery the use of robotic technique expands to female and reconstructive procedures as well. The leap forward is so massive, that traditional laparoscopic surgery is starting to be considered less, with a growing number of organizations being now more interested in developing a robotic service. Minimally invasive surgical techniques aim to improve surgical outcome in conjunction with delivery of high-quality patient care. Quality studies demonstrating superiority and cost effectiveness are lacking, however. CONCLUSIONS: Although tremendous accomplishments took place over a few years, there is still a lot of ground to be covered in standardizing the learning process and evaluating the outcome from the application of new technologies in the field of robotic pelvic surgery. PMID- 28582378 TI - Robotic Verse Laparoscopic Gastrectomy for Gastric Cancer: A Pooled Analysis of 11 Individual Studies. AB - OBJECTIVE: Robotic surgery is a new technique with the benefits of a 3 dimensional view, the ability to use multidegree-of-freedom forceps, the elimination of physiological tremors, and a stable camera view. The aim of this study was to evaluate the feasibility and short-term outcomes of robotic surgery for gastric cancer, compared with conventional laparoscopic surgery. METHODS: A literature search was performed for comparative studies reporting perioperative outcomes of robotic gastrectomy (RG) and laparoscopic gastrectomy (LG). The methodological quality of the selected studies was assessed. The data were analyzed using Stata (Version 13.0) software. RESULTS: Eleven studies of 3503 patients totally were included for meta-analysis. Compared with LG, RG indicated potentially favorable outcomes in terms of blood loss [weighted mean difference (WMD)=-36.50; 95% confidence interval (CI), -61.39 to -11.61], and time to oral intake (WMD=-0.28; 95% CI, -0.46 to -0.09). But RG suggested longer operative time (WMD=53.48; 95% CI, 38.84-68.12). There were no differences in terms of postoperative flatus, length of hospital stay, postoperative complications, and lymph nodes harvested (P>0.05). CONCLUSIONS: RG for the treatment of gastric cancer is a feasible and safe procedure in the hand of experienced laparoscopic surgeons. But the long-term outcomes between the 2 techniques need to be further examined. PMID- 28582379 TI - Laparoscopic Gastroepiploic Lymphovascular Pedicle Harvesting for the Treatment of Extremity Lymphedema: A Novel Technique. AB - Vascularized lymph node transfers have multiple donor sites with risk of iatrogenic lymphedema. We sought to describe in detail a surgical technique that is safe, reproducible, and efficient in harvesting gastroepiploic vascularized lymph nodes using real-time indocyanine green (ICG) fluorescent imaging. Photographs and video were acquired from a case to depict a step-by-step approach. ICG was endoscopically injected into the submucosa of the greater curvature of the stomach at the outset of the procedure. A laparoscopic harvest of the gastroepiploic vascular pedicle and lymph nodes ensued with the assistance of fluorescent imaging. Laparoscopic gastroepiploic lymph node harvesting aided by real-time ICG fluorescent mapping technique is safe, feasible, and effective at gathering vascularized lymphatic tissue for successful lymph node transfer in patients with severe lymphedema. PMID- 28582381 TI - High Expression of Retinoblastoma-Binding Protein 2 (RBP2) in Patients with Hepatocellular Carcinoma and Its Prognostic Significance. AB - BACKGROUND Recently, some studies have found that retinoblastoma-binding protein 2 (RBP2) is involved in the development and progression of many kinds of malignant tumors. This study aimed to explore the expression level of RBP2 in hepatocellular carcinoma (HCC) and its prognostic significance. MATERIAL AND METHODS Immunohistochemical analysis was used to evaluate the RBP2 expression level in 130 HCC patients and adjacent normal tissues. Tumor angiogenesis was marked by CD31 and vascular endothelial growth factor (VEGF) staining. Kaplan Meier and Cox regression analyses were performed to examine the relationship between RBP2 expression and prognosis of HCC patients. RESULTS RBP2 expression was significantly higher in HCC tissues (positive expression rate: 72.3%, 94/130). Increased RBP2 expression was dramatically associated with AFP level (P=0.016), degree of differentiation (P=0.000), and TNM stage (P=0.035). Moreover, tumors with RBP2-positive expression showed significantly higher intratumoral MVD than those with RBP2-negative expression (P=0.000). Kaplan-Meier analysis revealed RBP2-positive expression was related to decreased disease-free survival (DFS) (P=0.000) and overall survival (OS) (P=0.000). Furthermore, RBP2 was an independent poor prognostic factor of DFS and OS (P=0.029 and 0.010, respectively) as demonstrated by multivariate analysis. CONCLUSIONS Increased RBP2 expression, as an independent poor prognostic factor for DFS and OS of HCC patients, is closely related to tumor angiogenesis. RBP2 is expected to become a new potential therapeutic target for HCC. PMID- 28582383 TI - The role of scientific student societies in Paraguay. PMID- 28582382 TI - Predictive model for the development of hypertensive cardiopathy: A prospective cohort study. AB - INTRODUCTION: Predictive models of cardiovascular conditions are useful tools for risk stratification. The high morbidity and mortality resulting from hypertensive cardiopathy creates a need for the use of tools to predict the risk of cardiovascular disease. OBJECTIVE: To evaluate the capacity of a model based on risk factors to predict the development of hypertensive cardiopathy after ten years in patients with a diagnosis of essential arterial hypertension. METHODS: A prospective cohort study was carried out in hypertensive patients cared for at the specialized arterial hypertension physician?s office of the Specialty Policlinic attached to ?Carlos Manuel de Cespedes? Hospital, Bayamo Municipality, Granma Province, Cuba, from January 1, 2000 to December 31, 2009. A predictive model was constructed and validated through a process that included the random split of the whole sample in two parts: one for development (parameters estimation) and the other for validation. RESULTS: The binary regression model adjusted by the ?step-by-step backward method,? showed that in step six, 13 variables sufficed to estimate the risk of developing hypertensive cardiopathy. In the estimation sample, the area under the receiver operating characteristic curve obtained for the prediction of hypertensive heart disease was 0.985 (confidence interval: 0.980-0.990; p = <0.0005). In the validation sample the area under the receiver operating characteristic curve was 0.963 (confidence interval: 0.953-0, 0.973, p<0.0005). The calibration of the model was also adequate (p = 0.863). CONCLUSIONS: The model obtained proved is a clinical and epidemiological surveillance instrument, useful to identify subjects with greater likelihood to acquire hypertensive heart disease, and to stratify their risk in the following ten-year period. PMID- 28582384 TI - The sum of us: considerations on physician-industry relationships. AB - This essay describes critically the physician-industry relationships and how the latter influences economically in the realization of continuing medical education (CME), industry expenses in sponsoring the academic events of medical societies, travel costs and enrollment, payment for consultants and speakers. It also refers to the movements that have been created in the academic world to counteract this influence, such as No Free Lunch (Spanish version ?NoGracias?) and PharmFree. And the struggles between major scientific medical journals, with editorials and among editorialists on the concept of conflicts of interest. All this seen through the existence of an academic institution in Mexico and the exemplary life of one of its members. PMID- 28582385 TI - Corrigendum: Apoptotic effect of novel Schiff Based CdCl2(C14H21N3O2) complex is mediated via activation of the mitochondrial pathway in colon cancer cells. AB - This corrects the article DOI: 10.1038/srep09097. PMID- 28582386 TI - Cognitive functioning at the age of 10 years among children born extremely preterm: a latent profile approach. AB - BackgroundSchool-age children born extremely preterm (EP) are more likely than their term peers to have multiple neurocognitive limitations. We identify subgroups of EP children who share similar profiles on measures of intelligence quotient (IQ) and executive function (EF), and describe the nature and prevalence of cognitive impairment in EP children.MethodsOn the basis of measures of IQ and EF, subgroups of EP children with common neurocognitive function are identified using latent profile analysis (LPA). On the basis of these subgroups, we describe the nature and prevalence of impairment in EP children, and examine associations between cognitive function, gestational age, and academic achievement. Classification of neurocognitive function using IQ and EF is compared with a standard classification based on IQ Z-scores.ResultsLPA identified four neurocognitive profiles in EP children, with 34% of EP children classified as normal, 41% low-normal, 17% moderately impaired, and 8% severely impaired. Impaired children exhibited global impairment across cognitive domains, whereas children in the low-normal group tended to have impaired inhibition relative to their reasoning and working memory skills.ConclusionWithin categories of EP children defined in terms of IQ, there is substantial variation in EF; thus, both IQ and EF assessments are needed when describing school-age outcome of EP children. PMID- 28582387 TI - Spanish version of the Talent Development Environment Questionnaire for sport: Cultural adaptation and initial validation. AB - This study aimed to translate the Talent Development Environment Questionnaire into Spanish and provide an initial validation. A recommended methodology for translation and cultural adaptation of questionnaires was applied. Once this had been completed, three hundred and thirty-two young athletes completed the Talent Development Environment Questionnaire. The results revealed that the five factor solution Talent Development Environment Questionnaire was confirmed. With the exclusion of one item due to low factor loading, the Talent Development Environment Questionnaire-5 had robust statistical support for its factor structure (chi2 (df = 305) = 499.64, p<0.01, CFI = 0.90, RMSEA = 0.045, SRMR = 0.055). It also demonstrated adequate convergent and discriminant validity. While the internal reliability was lower than in previous studies, it revealed acceptable levels. Specifically the overall 27 item Talent Development Environment Questionnaire-5 had a Cronbach alpha score of .877, and the reliability scores for individual factors 1-5 were .622; .761; .658; .605; .602 respectively. As such, it is recommended that the Spanish Talent Development Environment Questionnaire-5 can be used with confidence in Spain in both applied and research settings. PMID- 28582389 TI - Evaluation of the Intel Xeon Phi 7120 and NVIDIA K80 as accelerators for two dimensional panel codes. AB - To optimize the geometry of airfoils for a specific application is an important engineering problem. In this context genetic algorithms have enjoyed some success as they are able to explore the search space without getting stuck in local optima. However, these algorithms require the computation of aerodynamic properties for a significant number of airfoil geometries. Consequently, for low speed aerodynamics, panel methods are most often used as the inner solver. In this paper we evaluate the performance of such an optimization algorithm on modern accelerators (more specifically, the Intel Xeon Phi 7120 and the NVIDIA K80). For that purpose, we have implemented an optimized version of the algorithm on the CPU and Xeon Phi (based on OpenMP, vectorization, and the Intel MKL library) and on the GPU (based on CUDA and the MAGMA library). We present timing results for all codes and discuss the similarities and differences between the three implementations. Overall, we observe a speedup of approximately 2.5 for adding an Intel Xeon Phi 7120 to a dual socket workstation and a speedup between 3.4 and 3.8 for adding a NVIDIA K80 to a dual socket workstation. PMID- 28582388 TI - Natural antibody responses to the capsid protein in sera of Dengue infected patients from Sri Lanka. AB - This study aims to characterize the antigenicity of the Capsid (C) protein and the human antibody responses to C protein from the four dengue virus (DENV) serotypes. Parker hydrophilicity prediction, Emini surface accessibility prediction and Karplus & Schulz flexibility predictions were used to bioinformatically characterize antigenicity. The human antibody response to C protein was assessed by ELISA using immune sera and an array of overlapping DENV2 C peptides. DENV2 C protein peptides P1 (located on C protein at 2-18 a.a), P11 (79-95 a.a) and P12 (86-101 a.a) were recognized by most individuals exposed to infections with only one of the 4 DENV serotypes as well as people exposed to infections with two serotypes. These conserved peptide epitopes are located on the amino (1-40 a.a) and carboxy (70-100 a.a) terminal regions of C protein, which were predicted to be antigenic using different bioinformatic tools. DENV2 C peptide P6 (39-56 a.a) was recognized by all individuals exposed to DENV2 infections, some individuals exposed to DENV4 infections and none of the individuals exposed to DENV1 or 3 infections. Thus, unlike C peptides P1, P11 and P12, which contain epitopes, recognized by DENV serotype cross-reactive antibodies, DENV2 peptide P6 contains an epitope that is preferentially recognized by antibodies in people exposed to this serotype compared to other serotypes. We discuss our results in the context of the known structure of C protein and recent work on the human B-cell response to DENV infection. PMID- 28582390 TI - Polymorphisms in dopaminergic system genes; association with criminal behavior and self-reported aggression in violent prison inmates from Pakistan. AB - Genetic factors contribute to antisocial and criminal behavior. Dopamine transporter DAT-1 (SLC6A3) and DRD2 gene for the dopamine-2 receptor are dopaminergic system genes that regulate dopamine reuptake and signaling, and may be part of the pathogenesis of psychiatric disorders including antisocial behaviors and traits. No previous studies have analyzed DAT-1 and DRD2 polymorphisms in convicted murderers, particularly from Indian subcontinent. In this study we investigated the association of 40 bp VNTR polymorphism of DAT-1 and Taq1 variant of DRD2 gene (rs1800479) with criminal behavior and self reported aggression in 729 subjects, including 370 men in Pakistani prisons convicted of first degree murder(s) and 359 control men without any history of violence or criminal tendency. The 9R allele of DAT-1 VNTR polymorphism was more prevalent in convicted murderers compared with control samples, for either one or two risk alleles (OR = 1.49 and 3.99 respectively, P = 0.003). This potential association of DAT-1 9R allele polymorphism with murderer phenotype was confirmed assuming different genetic models of inheritance. However, no genetic association was found for DRD2 Taq1 polymorphism. In addition, a combined haplotype (9R-A2) of DAT-1 and DRD2 genes was associated with this murderer phenotype. Further, 9R allele of DAT-1 was also associated with response to verbal abuse and parental marital complications, but not with other measures pertinent to self-reported aggression. These results suggest that 9R allele, which may influence levels of intra-synaptic dopamine in the brain, may contribute to criminal tendency in this sample of violent murderers of Pakistani origin. Future studies are needed to replicate this finding in other populations of murderers and see if this finding extends to other forms of violence and lesser degrees of aggression. PMID- 28582391 TI - All atom NMDA receptor transmembrane domain model development and simulations in lipid bilayers and water. AB - N-methyl-d-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family that mediate excitatory synaptic transmission in the central nervous system. The channels of NMDARs are permeable to Ca2+ but blocked by Mg2+, distinctive properties that underlie essential brain processes such as induction of synaptic plasticity. However, due to limited structural information about the NMDAR transmembrane ion channel forming domain, the mechanism of divalent cation permeation and block is understood poorly. In this paper we developed an atomistic model of the transmembrane domain (TMD) of NMDARs composed of GluN1 and GluN2A subunits (GluN1/2A receptors). The model was generated using (a) a homology model based on the structure of the NaK channel and a partially resolved structure of an AMPA receptor (AMPAR), and (b) a partially resolved X-ray structure of GluN1/2B NMDARs. Refinement and extensive Molecular Dynamics (MD) simulations of the NMDAR TMD model were performed in explicit lipid bilayer membrane and water. Targeted MD with simulated annealing was introduced to promote structure refinement. Putative positions of the Mg2+ and Ca2+ ions in the ion channel divalent cation binding site are proposed. Differences in the structural and dynamic behavior of the channel protein in the presence of Mg2+ or Ca2+ are analyzed. NMDAR protein conformational flexibility was similar with no ion bound to the divalent cation binding site and with Ca2+ bound, whereas Mg2+ binding reduced protein fluctuations. While bound at the binding site both ions retained their preferred ligand coordination numbers: 6 for Mg2+, and 7-8 for Ca2+. Four asparagine side chain oxygens, a back-bone oxygen, and a water molecule participated in binding a Mg2+ ion. The Ca2+ ion first coordination shell ligands typically included four to five side-chain oxygen atoms of the binding site asparagine residues, two water molecules and zero to two backbone oxygens of the GluN2B subunits. These results demonstrate the importance of high resolution channel structures for elucidation of mechanisms of NMDAR permeation and block. PMID- 28582392 TI - Mechanical characterization of human brain tumors from patients and comparison to potential surgical phantoms. AB - While mechanical properties of the brain have been investigated thoroughly, the mechanical properties of human brain tumors rarely have been directly quantified due to the complexities of acquiring human tissue. Quantifying the mechanical properties of brain tumors is a necessary prerequisite, though, to identify appropriate materials for surgical tool testing and to define target parameters for cell biology and tissue engineering applications. Since characterization methods vary widely for soft biological and synthetic materials, here, we have developed a characterization method compatible with abnormally shaped human brain tumors, mouse tumors, animal tissue and common hydrogels, which enables direct comparison among samples. Samples were tested using a custom-built millimeter scale indenter, and resulting force-displacement data is analyzed to quantify the steady-state modulus of each sample. We have directly quantified the quasi-static mechanical properties of human brain tumors with effective moduli ranging from 0.17-16.06 kPa for various pathologies. Of the readily available and inexpensive animal tissues tested, chicken liver (steady-state modulus 0.44 +/- 0.13 kPa) has similar mechanical properties to normal human brain tissue while chicken crassus gizzard muscle (steady-state modulus 3.00 +/- 0.65 kPa) has similar mechanical properties to human brain tumors. Other materials frequently used to mimic brain tissue in mechanical tests, like ballistic gel and chicken breast, were found to be significantly stiffer than both normal and diseased brain tissue. We have directly compared quasi-static properties of brain tissue, brain tumors, and common mechanical surrogates, though additional tests would be required to determine more complex constitutive models. PMID- 28582393 TI - High correlation between Framingham equations with BMI and with lipids to estimate cardiovascular risks score at baseline in HIV-infected adults in the Temprano trial, ANRS 12136 in Cote d'Ivoire. AB - CONTEXT: Data on cardiovascular risk (CVR) score among HIV-infected patients in sub-Saharan Africa are scarce. Our first objective was to compare the CVR score of Framingham utilizing BMI and lipids at baseline, and secondary to assess evolution of CVR score over time at Month 30 in the Temprano trial. METHODS: HIV infected adults with CD4 <800/mm3 without criteria for initiating ART were included and followed for 30 months in the Temprano trial, which assessed the benefits and risks of early antiretroviral treatment (ART) vs deferred ART. CVR score was estimated at baseline and Month-30 using Framingham equations with either BMI or lipids and classified as high (>20%), moderate (10-20%), and low risk (<10%). At baseline, we compare these two estimations utilizing the Pearson correlation test and analyze the increasing CV risk score over time by Proportional odds cumulative logit models for people attending the Month-30 (M30) visit. RESULTS: Among the 2056 patients, 78% were women, median age was 35 years, and median CD4 count was 464/mm3, 6.8% were obese, 6.3% had hypertension, 7.8% were smokers (1.8% women, 26.8% men), 19% had Total Cholesterol (TC) >5mmol/L, and 1% diabetes at baseline. At baseline the concordance between the two Framingham equations was excellent (r = 0.95; p<0.0001). Among the 1700 patients who attended M30 visit and with available data, 1.3% had a high CV risk score at baseline and 3.1% at M30 visit using Framingham equation with BMI. Adjusted odds ratio (aOR) of being at a higher CV risk score at M30 visit compared to a higher CV risk score at M0 visit was 1.35 (CI 95% 1.17-1.57). Stratified by sex, the increasing CV risk score was OR 1.73 (CI 95%: 1.30-2.29) for women and OR 1.24 (CI 95%: 1.02-1.50) for men. Early ART was not associated with an increasing CV risk score (p = 0.88). Results for the 1422 patients with Framingham equation using lipids were similar. CONCLUSION: In a large trial evaluating early ART for HIV infection in Cote d'Ivoire, Framingham equation with BMI and lipids were highly correlated and CV risk score increases over time. Early ART was not significantly associated with this increasing CV risk score. PMID- 28582394 TI - New insight into hybridization and unidirectional introgression between Ammodytes japonicus and Ammodytes heian (Trachiniformes, Ammodytidae). AB - Based on northern (NOL) and southern (SOL) mitochondrial lineages, recently, it proposed the new species Ammodytes heian and revived the species name Ammodytes japonicus to describe sand lances from the northwestern Pacific Ocean. This study used molecular methods to investigate genetic relationships between the two sand lance species in Korea and Japan. In total, 154 specimens were collected from four locations in Korea (Baengnyeongdo in the Yellow Sea, Tongyeong in the Korean Strait, and Jumunjin and Gijang in the East Sea), and 50 specimens were collected from a single location in Japan (Wakkanai in the Okhotsk Sea). Mitochondrial DNA analysis demonstrated that the individuals from Baengnyeongdo and Tongyeong all belonged to the SOL, whereas those from Gijang, Jumunjin, and Wakkanai included individuals from both the NOL and SOL (over 75% NOL). Population structure analyses were performed on the same individuals using seven microsatellite DNA markers. The population structure analysis based on 201 specimens identified two clusters (named as northern group and southern group), with the admixture proportion (q) of < 0.1 for the northern group in the Backyeongdo and Tongyeong sand lances and < 0.1 for the southern group in the Wakkanai sand lances. The high heterogeneity indicated that the former was probably A. japonicus and the latter probably A. heian. However, the admixture proportion in the Jumunjin and Gijang sand lances was 0.71-0.75 for the southern group, indicating that hybridization and unidirectional introgression from SOL to NOL occurs in southwestern margin of the East Sea. Our findings illustrate the speciation process based on different patterns of gene flow between Korean and Japanese sand lance, which is strongly influenced by both the paleo-climatic change and the contemporary local oceanic current pattern. PMID- 28582395 TI - Mechanisms of generation of membrane potential resonance in a neuron with multiple resonant ionic currents. AB - Neuronal membrane potential resonance (MPR) is associated with subthreshold and network oscillations. A number of voltage-gated ionic currents can contribute to the generation or amplification of MPR, but how the interaction of these currents with linear currents contributes to MPR is not well understood. We explored this in the pacemaker PD neurons of the crab pyloric network. The PD neuron MPR is sensitive to blockers of H- (IH) and calcium-currents (ICa). We used the impedance profile of the biological PD neuron, measured in voltage clamp, to constrain parameter values of a conductance-based model using a genetic algorithm and obtained many optimal parameter combinations. Unlike most cases of MPR, in these optimal models, the values of resonant- (fres) and phasonant- (fphi = 0) frequencies were almost identical. Taking advantage of this fact, we linked the peak phase of ionic currents to their amplitude, in order to provide a mechanistic explanation the dependence of MPR on the ICa gating variable time constants. Additionally, we found that distinct pairwise correlations between ICa parameters contributed to the maintenance of fres and resonance power (QZ). Measurements of the PD neuron MPR at more hyperpolarized voltages resulted in a reduction of fres but no change in QZ. Constraining the optimal models using these data unmasked a positive correlation between the maximal conductances of IH and ICa. Thus, although IH is not necessary for MPR in this neuron type, it contributes indirectly by constraining the parameters of ICa. PMID- 28582396 TI - Participation of androgen and its receptor in sex determination of an amphibian species. AB - INTRODUCTION: In the Japanese frog Rana (R.) rugosa the androgen receptor (AR) gene on the W chromosome (W-AR) is barely expressed. Previously we showed that incomplete female-to-male sex-reversal occurred in Z-AR transgenic female frogs. To date, however, there is no report showing that AR with androgens can determine genetically programed male sex fate in any vertebrate species. Here, we examined whether AR together with androgens functions as a sex determinant in an amphibian species. METHODS: To examine whether complete female-to-male sex-reversal occurs in R. rugosa frogs, we produced AR-transgenic (Tg) and -knockdown (KD) female R. rugosa frogs by the I-SceI meganuclease-mediated gene trap and CRISPR/Cas9 system, respectively. AR-Tg and -KD tadpoles were reared in water containing testosterone (T) at 0 to 7.1 ng/ml. Frozen sections were prepared from the gonads of metamorphosed frogs and immunostained for laminin, Vasa, Pat1a, CYP17 and AR. We also employed PCR analysis to examine Dmrt1, Pat1a and CYP17 expression in the gonads of KD and placebo-KD female frogs. RESULTS: Complete female-to-male sex reversal occurred in the AR-Tg ZW female frogs when a low dosage of T was supplied in the rearing water of tadpoles. However, no sex-reversal was observed in AR-KD ZW female frogs when the gonads were treated with dosages of T high enough to induce complete female-to-male sex-reversal even in wild type frogs. DISCUSSION: These results suggest that AR with its androgen ligand functions as a male sex-determinant in the ZW type R. rugosa frogs. PMID- 28582397 TI - Reduction of multiscale stochastic biochemical reaction networks using exact moment derivation. AB - Biochemical reaction networks (BRNs) in a cell frequently consist of reactions with disparate timescales. The stochastic simulations of such multiscale BRNs are prohibitively slow due to high computational cost for the simulations of fast reactions. One way to resolve this problem uses the fact that fast species regulated by fast reactions quickly equilibrate to their stationary distribution while slow species are unlikely to be changed. Thus, on a slow timescale, fast species can be replaced by their quasi-steady state (QSS): their stationary conditional expectation values for given slow species. As the QSS are determined solely by the state of slow species, such replacement leads to a reduced model, where fast species are eliminated. However, it is challenging to derive the QSS in the presence of nonlinear reactions. While various approximation schemes for the QSS have been developed, they often lead to considerable errors. Here, we propose two classes of multiscale BRNs which can be reduced by deriving an exact QSS rather than approximations. Specifically, if fast species constitute either a feedforward network or a complex balanced network, the reduced model based on the exact QSS can be derived. Such BRNs are frequently observed in a cell as the feedforward network is one of fundamental motifs of gene or protein regulatory networks. Furthermore, complex balanced networks also include various types of fast reversible bindings such as bindings between transcriptional factors and gene regulatory sites. The reduced models based on exact QSS, which can be calculated by the computational packages provided in this work, accurately approximate the slow scale dynamics of the original full model with much lower computational cost. PMID- 28582398 TI - Effects of low-powered RF sweep between 0.01-20 GHz on female Aedes Aegypti mosquitoes: A collective behaviour analysis. AB - There are many products claiming to be an electronic solution towards repelling mosquitoes. Several reviews were published in debunking these claims. However, there is a lack of a systematic study on effects of electromagnetic (EM) or more specifically, radio frequency (RF) waves against mosquitoes due to the conclusions made in those years. Therefore, we attempt to establish a fundamental study on female Aedes Aegypti (Linnaeus) mosquitoes by quantifying the collective behavior of the mosquitoes against a continuous stream of low-powered RF signals via a broadband horn antenna using image processing methods. By examining the average lateral and vertical positions of the mosquitoes versus frequency and time, the data shows negligible consistency in the reactions of the mosquitoes toward the different frequencies ranging from 10 to 20,000.00 MHz, with a step of 10 MHz. This was done by examining 33 hours of spatiotemporal data, which was divided into three sessions. All three sessions showed totally different convolutions in the positions in arbitrary units based on the raster scan of the image processing output. Several frequencies apparently showed up to 0.2-70% shift in both lateral and vertical components along the spectrum, without repeatability for all three sessions. This study contributes to the following: A pilot study for establishing the collective effects of RF against mosquitoes, open-source use, and finally a low-cost and easily adaptable platform for the study of EM effects against any insects. PMID- 28582399 TI - Effect of verbal task complexity in a working memory paradigm in patients with type 1 diabetes. A fMRI study. AB - Type 1 diabetes (T1D) is commonly diagnosed in childhood and adolescence, and the developing brain has to cope with its deleterious effects. Although brain adaptation to the disease may not result in evident cognitive dysfunction, the effects of T1D on neurodevelopment could alter the pattern of BOLD fMRI activation. The aim of this study was to explore the neural BOLD activation pattern in patients with T1D versus that of healthy matched controls while performing two visuospatial working memory tasks, which included a pair of assignments administered through a block design. In the first task (condition A), the subjects were shown a trial sequence of 3 or 4 white squares positioned pseudorandomly around a fixation point on a black background. After a fixed delay, a second corresponding sequence of 3 or 4 red squares was shown that either resembled (direct, 50%) or differed from (50%) the previous stimulation order. The subjects were required to press one button if the two spatial sequences were identical or a second button if they were not. In condition B, the participants had to determine whether the second sequence of red squares appeared in inverse order (inverse, 50%) or not (50%) and respond by pressing a button. If the latter sequence followed an order distinct from the inverse sequence, the subjects were instructed to press a different button. Sixteen patients with normal IQ and without diabetes complications and 16 healthy control subjects participated in the study. In the behavioral analysis, there were no significant differences between the groups in the pure visuo-spatial task, but the patients with diabetes exhibited poorer performance in the task with verbal stimuli (p < .001). However, fMRI analyses revealed that the patients with T1D showed significantly increased activation in the prefrontal inferior cortex, subcortical regions and the cerebellum (in general p < .001). These different activation patterns could be due to adaptive compensation mechanisms that are devoted to improving efficiency while solving more complex cognitive tasks. PMID- 28582400 TI - Variations in survival after cardiac arrest among academic medical center affiliated hospitals. AB - BACKGROUND: Variation exists in cardiac arrest (CA) survival among institutions. We sought to determine institutional-level characteristics of academic medical centers (AMCs) associated with CA survival. METHODS: We examined discharge data from AMCs participating with Vizient clinical database-resource manager. We identified cases using ICD-9 diagnosis code 427.5 (CA) or procedure code 99.60 (CPR). We estimated hospital-specific risk-standardized survival rates (RSSRs) using mixed effects logistic regression, adjusting for individual mortality risk. Institutional and community characteristics of AMCs with higher than average survival were compared with those with lower survival. RESULTS: We analyzed data on 3,686,296 discharges in 2012, of which 33,700 (0.91%) included a CA diagnosis. Overall survival was 42.3% (95% CI 41.8-42.9) with median institutional RSSR of 42.6% (IQR 35.7-51.0; Min-Max 19.4-101.6). We identified 28 AMCs with above average survival (median RSSR 61.8%) and 20 AMCs with below average survival (median RSSR 26.8%). Compared to AMCs with below average survival, those with high CA survival had higher CA volume (median 262 vs.119 discharges, p = 0.002), total beds (722 vs. 452, p = 0.02), and annual surgical volume (24,939 vs. 13,109, p<0.001), more likely to offer cardiac catheterization (100% vs. 72%, p = 0.007) or cardiac surgery (93% vs. 61%, p = 0.02) and cared for catchment areas with higher household income ($61,922 vs. $49,104, p = 0.004) and lower poverty rates (14.6% vs. 17.3%, p = 0.03). CONCLUSION: Using discharge data from Vizient, we showed AMCs with higher CA and surgical case volume, cardiac catheterization and cardiac surgery facilities, and catchment areas with higher socioeconomic status had higher risk-standardized CA survival. PMID- 28582401 TI - DeepNano: Deep recurrent neural networks for base calling in MinION nanopore reads. AB - The MinION device by Oxford Nanopore produces very long reads (reads over 100 kBp were reported); however it suffers from high sequencing error rate. We present an open-source DNA base caller based on deep recurrent neural networks and show that the accuracy of base calling is much dependent on the underlying software and can be improved by considering modern machine learning methods. By employing carefully crafted recurrent neural networks, our tool significantly improves base calling accuracy on data from R7.3 version of the platform compared to the default base caller supplied by the manufacturer. On R9 version, we achieve results comparable to Nanonet base caller provided by Oxford Nanopore. Availability of an open source tool with high base calling accuracy will be useful for development of new applications of the MinION device, including infectious disease detection and custom target enrichment during sequencing. PMID- 28582402 TI - A matter of months: High precision migration chronology of a Bronze Age female. AB - Establishing the age at which prehistoric individuals move away from their childhood residential location holds crucial information about the socio dynamics and mobility patterns in ancient societies. We present a novel combination of strontium isotope analyses performed on the over 3000 year old "Skrydstrup Woman" from Denmark, for whom we compiled a highly detailed month-scale model of her migration timeline. When combined with physical anthropological analyses this timeline can be related to the chronological age at which the residential location changed. We conducted a series of high-resolution strontium isotope analyses of hard and soft human tissues and combined these with anthropological investigations including CT-scanning and 3D visualizations. The Skrydstrup Woman lived during a pan-European period characterized by technical innovation and great social transformations stimulated by long-distance connections; consequently she represents an important part of both Danish and European prehistory. Our multidisciplinary study involves complementary biochemical, biomolecular and microscopy analyses of her scalp hair. Our results reveal that the Skrydstrup Woman was between 17-18 years old when she died, and that she moved from her place of origin -outside present day Denmark- to the Skrydstrup area in Denmark 47 to 42 months before she died. Hence, she was between 13 to 14 years old when she migrated to and resided in the area around Skrydstrup for the rest of her life. From an archaeological standpoint, this one-time and one-way movement of an elite female during the possible "age of marriageability" might suggest that she migrated with the aim of establishing an alliance between chiefdoms. Consequently, this detailed multidisciplinary investigation provides a novel tool to reconstruct high resolution chronology of individual mobility with the perspective of studying complex patterns of social and economic interaction in prehistory. PMID- 28582403 TI - Vitamin D and immunomodulation in early rheumatoid arthritis: A randomized double blind placebo-controlled study. AB - The aim of this study was to evaluate differences in T helper cell sub-types and osteoclast (OCs) precursors in peripheral blood between patients affected by early rheumatoid arthritis (eRA) and healthy controls. The effect of administration of cholecalcipherol on clinical and laboratory parameters was subsequently evaluated, by a parallel, randomized double blind, placebo controlled trial. Thirty nine eRA patients and 31 age-matched controls were enrolled and compared for levels of 25OH vitamin D, T helper cell sub-types, OCs precursors including both classical and non-classical and pro-inflammatory cytokines at baseline. Eligible patients were female >=18 years of age with a diagnosis of RA, as defined by the American College of Rheumatology 2010 criteria for <6 months prior to inclusion in the study. Patients with auto-immune or inflammatory diseases other than RA were excluded. Patients treated with glucocorticoids (GCs), disease modifying activity drugs and biologic agents within the past 6 months were also excluded. In the second phase of the study, eRA patients were randomly assigned to standard treatment with methotrexate (MTX) and GCs with (21) or without (18) cholecalcipherol (300,000 IU) and followed for 3 months; the randomization was done by computer generated tables to allocate treatments. Three patients didn't come back to the follow up visit for personal reasons. None of the patients experienced adverse events. The main outcome measures were T cells phenotypes, OCs precursors and inflammatory cytokines. Secondary outcome measure were clinical parameters. In eRA, 25OH vitamin D levels were significantly lower. CD4+/IFNgamma+,CD4+/IL4+, CD4+/IL17A+ and CD4+IL17A+IFNgamma+, cells were increased in eRA as well as non-classical OCs precursors, whereas T regulatory cells were not altered. TNFalpha, TGFbeta1, RANKL, IL-23 and IL-6 were increased in eRA. Non-classical OCs, IL-23 and IL-6 correlated with disease severity and activity. Standard treatment with MTX and GC ameliorated clinical symptoms and reduced IL-23, whereas it did not affect CD4+ cells sub-sets nor OCs precursors. After 3 months, the combined use of cholecalcipherol significantly ameliorated the effect of treatment on global health. In eRA, a significant imbalance in T CD4+ sub-types accompanied by increased levels of non-classical OCs precursors and pro-inflammatory cytokines was observed. A single dose of cholecalcipherol (300,000 IU) combined with standard treatment significantly ameliorates patients general health. PMID- 28582404 TI - Drug-class-specific changes in the volume and cost of antidiabetic medications in Poland between 2012 and 2015. AB - AIM: to investigate the drug-class-specific changes in the volume and cost of antidiabetic medications in Poland in 2012-2015. METHODS: This retrospective analysis was conducted based on the National Health Fund database covering an entire Polish population. The volume of antidiabetic medications is reported according to ATC/DDD methodology, costs-in current international dollars, based on purchasing power parity. RESULTS: During a 4-year observational period the number of patients, consumption of antidiabetic drugs and costs increased by 17%, 21% and 20%, respectively. Biguanides are the basic diabetes medication with a 39% market share. The insulin market is still dominated by human insulins, new antidiabetics (incretins, thiazolidinediones) are practically absent. Insulins had the largest share in diabetes medications expenditures (67% in 2015). The increase in antidiabetic medications costs over the analysed period of time was mainly caused by the increased use of insulin analogues. CONCLUSIONS: The observed tendencies correspond to the evidence-based HTA recommendations. The reimbursement status, the ratio of cost to clinical outcomes and data on the long term safety have a deciding impact on how a drug is used. PMID- 28582405 TI - Laboratory evaluation of transgenic Populus davidiana*Populus bolleana expressing Cry1Ac + SCK, Cry1Ah3, and Cry9Aa3 genes against gypsy moth and fall webworm. AB - Transgenic poplar lines 'Shanxin' (Populus davidiana*Populus bolleana) were generated via Agrobacterium-mediated transformation. The transgenic lines carried the expression cassettes of Cry1Ac + SCK, Cry1Ah3, and Cry9Aa3, respectively. The expression levels of the exogenous insect resistance genes in the transgenic lines were determined by Q-PCR and Western blot. Leaves of the transgenic lines were used for insect feeding bioassays on first instar larvae of the gypsy moth (Lymantria dispar) and fall webworm (Hyphantria cunea). At 5 d of feeding, the mean mortalities of larvae feeding on Cry1Ac + SCK and Cry1Ah3 transgenic poplars leaves were 97% and 91%, while mortality on Cry9Aa3 transgenic lines was about 49%. All gypsy moth and fall webworm larvae were killed in 7-9 days after feeding on leaves from Cry1Ac + SCK or Cry1Ah3 transgenic poplars, while all the fall webworm larvae were killed in 11 days and about 80% of gypsy moth larvae were dead in 14 days after feeding on those from Cry9Aa3 transgenic lines. It was concluded that the transgenic lines of Cry1Ac + SCK and Cry1Ah3 were highly toxic to larvae of both insect species while lines with Cry9Aa3 had lower toxicity,and H. cunea larvae are more sensitive to the insecticidal proteins compared to L. dispar. Transgenic poplar lines toxic to L. dispar and H. cunea could be used to provide Lepidoptera pest resistance to selected strains of poplar trees. PMID- 28582406 TI - Intimate partner violence adversely impacts health over 16 years and across generations: A longitudinal cohort study. AB - OBJECTIVES: To determine the impact of intimate partner violence on women's mental and physical health over a 16 year period and across three generations. PARTICIPANTS: Participants were from the Australian Longitudinal study on Women's Health, a broadly representative national sample of women comprised of three birth cohorts 1973-78, 1946-51 and 1921-26 who were randomly selected from the Australian Medicare (i.e. national health insurer) database in 1996 to participate in the longitudinal health and wellbeing survey. Since baseline, six waves of survey data have been collected. Women from each cohort who had returned all six surveys and had a baseline measure (Survey 1) for intimate partner violence were eligible for the current study. MAIN OUTCOME MEASURES: The main outcome of interest was women's physical and mental health, measured using the Medical Outcome Study Short-Form (SF-36). The experience of intimate partner violence was measured using the survey item 'Have you ever been in a violent relationship with a partner/spouse?' Sociodemographic information was also collected. RESULTS: For all cohorts, women who had lived with intimate partner violence were more likely to report poorer mental health, physical function and general health, and higher levels of bodily pain. Some generational differences existed. Younger women showed a reduction in health associated with the onset of intimate partner violence, which was not apparent for women in the older two groups. In addition, the physical health differences between women born 1921-26 who had and had not experienced intimate partner violence tapered off overtime, whereas these differences remained constant for women born 1973-78 and 1946-51. CONCLUSIONS: Despite generational differences, intimate partner violence adversely impacted on mental and physical health over the 16 year study period and across generations. PMID- 28582408 TI - Proteome-wide profiling of protein lysine acetylation in Aspergillus flavus. AB - Protein lysine acetylation is a prevalent post-translational modification that plays pivotal roles in various biological processes in both prokaryotes and eukaryotes. Aspergillus flavus, as an aflatoxin-producing fungus, has attracted tremendous attention due to its health impact on agricultural commodities. Here, we performed the first lysine-acetylome mapping in this filamentous fungus using immune-affinity-based purification integrated with high-resolution mass spectrometry. Overall, we identified 1383 lysine-acetylation sites in 652 acetylated proteins, which account for 5.18% of the total proteins in A. flavus. According to bioinformatics analysis, the acetylated proteins are involved in various cellular processes involving the ribosome, carbon metabolism, antibiotic biosynthesis, secondary metabolites, and the citrate cycle and are distributed in diverse subcellular locations. Additionally, we demonstrated for the first time the acetylation of fatty acid synthase alpha and beta encoded by aflA and aflB involved in the aflatoxin-biosynthesis pathway (cluster 54), as well as backbone enzymes from secondary metabolite clusters 20 and 21 encoded by AFLA_062860 and AFLA_064240, suggesting important roles for acetylation associated with these processes. Our findings illustrating abundant lysine acetylation in A. flavus expand our understanding of the fungal acetylome and provided insight into the regulatory roles of acetylation in secondary metabolism. PMID- 28582407 TI - Enhanced expression and phosphorylation of Sirt7 activates smad2 and ERK signaling and promotes the cardiac fibrosis differentiation upon angiotensin-II stimulation. AB - Cardiac fibroblasts (CFs) phenotypic conversion to myofibroblasts (MFs) represents a crucial event in cardiac fibrosis that leads to impaired cardiac function. However, regulation of this phenotypic transformation remains unclear. Here, we showed that sirtuin-7 (Sirt7) plays an important role in the regulation of MFs differentiation. Sirt7 expression and phosphorylation were upregulated in CFs upon angiotensin-II (Ang-II) stimulation. Sirt7 depletion by siRNA in CFs resulted in decreased cell proliferation and extracellular matrix (ECM) deposition. Further, examination of Sirt7-depleted CFs demonstrated significantly lower expression of alpha-smooth muscle actin (alpha-SMA), the classical marker of MFs differentiation, and decreased formation of focal adhesions. Moreover, overexpression of Sirt7 increased alpha-SMA expression in Ang-II treated CFs and exacerbated Ang-II-induced MFs differentiation. Moreover, Sirt7 depletion could largely reverse Ang-II induced increase of nuclear translocalization and activity of smad2 and extracellular regulated kinases (ERK) in CFs. Importantly, the increased differentiation of CFs to MFs was also abolished by smad2 siRNA or U0126. Our findings reveal a novel role of Sirt7 and its phosphorylation in the phenotypic conversion of CFs to MFs and might lead to the development of new therapeutic and prognostic tools for cardiac fibrosis. PMID- 28582409 TI - Medicine shortages in Fiji: A qualitative exploration of stakeholders' views. AB - OBJECTIVES: Medicine access is a human right; yet, concerningly, there are international instances of shortages. Quantitative data has allowed WHO to propose global solutions; however, individualised understanding of specific regions is still required to work towards national solutions. Fiji has an established issue with medication supply and the aim of this study was to use qualitative methods to gain a fuller understanding of this context. METHODS: Semi structured interviews were used to gain the perspective of key stakeholders involved in the Fijian medicine supply chain in regards to causes, impacts and possible solutions of medicine shortages. Thematic analysis was used to analyse the interview data. RESULTS: In total, 48 stakeholders participated and the information was synthesised into three main themes, causes, impacts and solutions and the sub-themes including; political, system and patient causes, adverse health effects on patients, professional dissatisfaction, monetary loss and loss of faith in the health system, workarounds, operation improvements, government intervention and education and training. CONCLUSIONS: The situation in Fiji is not dissimilar to other instances of shortages around the world and hence international solutions like that proposed by WHO are feasible; however, they must be modified to be uniquely Fijian to work in this context. PMID- 28582410 TI - A phase I study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors. AB - The PI3K/Akt/mTOR signaling pathway is aberrantly activated in various pediatric tumors. We conducted a phase I study of the Akt inhibitor perifosine in patients with recurrent/refractory pediatric CNS and solid tumors. This was a standard 3+3 open-label dose-escalation study to assess pharmacokinetics, describe toxicities, and identify the MTD for single-agent perifosine. Five dose levels were investigated, ranging from 25 to 125 mg/m2/day for 28 days per cycle. Twenty three patients (median age 10 years, range 4-18 years) with CNS tumors (DIPG [n = 3], high-grade glioma [n = 5], medulloblastoma [n = 2], ependymoma [n = 3]), neuroblastoma (n = 8), Wilms tumor (n = 1), and Ewing sarcoma (n = 1) were treated. Only one DLT occurred (grade 4 hyperuricemia at dose level 4). The most common grade 3 or 4 toxicity at least possibly related to perifosine was neutropenia (8.7%), with the remaining grade 3 or 4 toxicities (fatigue, hyperglycemia, fever, hyperuricemia, and catheter-related infection) occurring in one patient each. Pharmacokinetics was dose-saturable at doses above 50 mg/m2/day with significant inter-patient variability, consistent with findings reported in adult studies. One patient with DIPG (dose level 5) and 4 of 5 patients with high grade glioma (dose levels 2 and 3) experienced stable disease for two months. Five subjects with neuroblastoma (dose levels 1 through 4) achieved stable disease which was prolonged (>=11 months) in three. No objective responses were noted. In conclusion, the use of perifosine was safe and feasible in patients with recurrent/refractory pediatric CNS and solid tumors. An MTD was not defined by the 5 dose levels investigated. Our RP2D is 50 mg/m2/day. PMID- 28582411 TI - Ionotropic receptors signal host recognition in the salmon louse (Lepeophtheirus salmonis, Copepoda). AB - A remarkable feature of many parasites is a high degree of host specificity but the mechanisms behind are poorly understood. A major challenge for parasites is to identify and infect a suitable host. Many species show a high degree of host specificity, being able to survive only on one or a few related host species. To facilitate transmission, parasite's behavior and reproduction has been fine tuned to maximize the likelihood of infection of a suitable host. For some species chemical cues that trigger or attract the parasite in question have been identified but how metazoan parasites themselves receive these signals remains unknown. In the present study we show that ionotropic receptors (IRs) in the salmon louse are likely responsible for identification of a specific host. By using RNAi to knock down the expression level of different co-receptors, a significant change of infectivity and settlement of lice larvae was achieved on Atlantic salmon. More remarkably, knock down of the IRs changed the host specificity of the salmon louse and lice larvae settled at a significant rate on host that the wild type lice rejected within minutes. To our knowledge, this has never before been demonstrated for any metazoan parasite. Our results show that the parasites are able to identify the host quickly upon settlement, settle and initiate the parasitic life style if they are on the right host. This novel discovery opens up for utilizing the host recognition system for future parasite control. PMID- 28582413 TI - History matching through dynamic decision-making. AB - History matching is the process of modifying the uncertain attributes of a reservoir model to reproduce the real reservoir performance. It is a classical reservoir engineering problem and plays an important role in reservoir management since the resulting models are used to support decisions in other tasks such as economic analysis and production strategy. This work introduces a dynamic decision-making optimization framework for history matching problems in which new models are generated based on, and guided by, the dynamic analysis of the data of available solutions. The optimization framework follows a 'learning-from-data' approach, and includes two optimizer components that use machine learning techniques, such as unsupervised learning and statistical analysis, to uncover patterns of input attributes that lead to good output responses. These patterns are used to support the decision-making process while generating new, and better, history matched solutions. The proposed framework is applied to a benchmark model (UNISIM-I-H) based on the Namorado field in Brazil. Results show the potential the dynamic decision-making optimization framework has for improving the quality of history matching solutions using a substantial smaller number of simulations when compared with a previous work on the same benchmark. PMID- 28582412 TI - Accuracy of parasitological and immunological tests for the screening of human schistosomiasis in immigrants and refugees from African countries: An approach with Latent Class Analysis. AB - BACKGROUND: Schistosomiasis is a neglected infection affecting millions of people, mostly living in sub-Saharan Africa. Morbidity and mortality due to chronic infection are relevant, although schistosomiasis is often clinically silent. Different diagnostic tests have been implemented in order to improve screening and diagnosis, that traditionally rely on parasitological tests with low sensitivity. Aim of this study was to evaluate the accuracy of different tests for the screening of schistosomiasis in African migrants, in a non endemic setting. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective study was conducted on 373 patients screened at the Centre for Tropical Diseases (CTD) in Negrar, Verona, Italy. Biological samples were tested with: stool/urine microscopy, Circulating Cathodic Antigen (CCA) dipstick test, ELISA, Western blot, immune chromatographic test (ICT). Test accuracy and predictive values of the immunological tests were assessed primarily on the basis of the results of microscopy (primary reference standard): ICT and WB resulted the test with highest sensitivity (94% and 92%, respectively), with a high NPV (98%). CCA showed the highest specificity (93%), but low sensitivity (48%). The analysis was conducted also using a composite reference standard, CRS (patients classified as infected in case of positive microscopy and/or at least 2 concordant positive immunological tests) and Latent Class Analysis (LCA). The latter two models demonstrated excellent agreement (Cohen's kappa: 0.92) for the classification of the results. In fact, they both confirmed ICT as the test with the highest sensitivity (96%) and NPV (97%), moreover PPV was reasonably good (78% and 72% according to CRS and LCA, respectively). ELISA resulted the most specific immunological test (over 99%). The ICT appears to be a suitable screening test, even when used alone. CONCLUSIONS: The rapid test ICT was the most sensitive test, with the potential of being used as a single screening test for African migrants. PMID- 28582414 TI - Data Sharing Statements for Clinical Trials: A Requirement of the International Committee of Medical Journal Editors. AB - The International Committee of Medical Journal Editors announces requirements that a data sharing plan be prospectively registered, and a data sharing statement be included in submitted manuscripts, for clinical trials to be published in ICMJE journals. PMID- 28582415 TI - Defense related decadienal elicits membrane lipid remodeling in the diatom Phaeodactylum tricornutum. AB - Diatoms rapidly release extracellular oxylipins (oxygenated lipids) including polyunsaturated aldehydes in response to herbivory and other stresses. Oxylipins have several defense-related activities including inhibition of reproduction in herbivores and signaling to distant diatoms. Physiological changes in diatoms exposed to varying levels of oxylipins are only beginning to be understood. In this study, Phaeodactylum tricornutum cultures were treated with sublethal concentrations of the polyunsaturated aldehyde trans,trans-2,4-decadienal (DD) to assess effects on lipid composition and membrane permeability. In cells treated with DD for 3 hr, all measured saturated and unsaturated fatty acids significantly decreased (0.46-0.69 fold of levels in solvent control cells) except for 18:2 (decreased but not significantly). The decrease was greater in the polyunsaturated fatty acid pool than the saturated and monounsaturated fatty acid pool. Analysis of lipid classes revealed increased abundances of phosphatidylethanolamine and phosphatidylcholine at 3 and 6 hr. Concomitantly, these and other membrane lipids exhibited increased saturated and monounsaturated acyl chains content relative to polyunsaturated acyl chains compared to control cells. Evidence of decreased plasma membrane permeability in DD treated cells was obtained, based on reduced uptake of two of three dyes relative to control cells. Additionally, cells pre-conditioned with a sublethal DD dose for 3 hr then treated with a lethal DD dose for 2 hr exhibited greater membrane integrity than solvent pre-conditioned control cells that were similarly treated. Taken together, the data are supportive of the hypothesis that membrane remodeling induced by sublethal DD is a key element in the development of cellular resistance in diatoms to varying and potentially toxic levels of polyunsaturated aldehydes in environments impacted by herbivory or other stresses. PMID- 28582416 TI - JNSViewer-A JavaScript-based Nucleotide Sequence Viewer for DNA/RNA secondary structures. AB - Many tools are available for visualizing RNA or DNA secondary structures, but there is scarce implementation in JavaScript that provides seamless integration with the increasingly popular web computational platforms. We have developed JNSViewer, a highly interactive web service, which is bundled with several popular tools for DNA/RNA secondary structure prediction and can provide precise and interactive correspondence among nucleotides, dot-bracket data, secondary structure graphs, and genic annotations. In JNSViewer, users can perform RNA secondary structure predictions with different programs and settings, add customized genic annotations in GFF format to structure graphs, search for specific linear motifs, and extract relevant structure graphs of sub-sequences. JNSViewer also allows users to choose a transcript or specific segment of Arabidopsis thaliana genome sequences and predict the corresponding secondary structure. Popular genome browsers (i.e., JBrowse and BrowserGenome) were integrated into JNSViewer to provide powerful visualizations of chromosomal locations, genic annotations, and secondary structures. In addition, we used StructureFold with default settings to predict some RNA structures for Arabidopsis by incorporating in vivo high-throughput RNA structure profiling data and stored the results in our web server, which might be a useful resource for RNA secondary structure studies in plants. JNSViewer is available at http://bioinfolab.miamioh.edu/jnsviewer/index.html. PMID- 28582417 TI - Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A exposed men. AB - Environmental BPA exposure has been shown to impact human sperm concentration and motility, as well as rodent spermatogenesis. However, it is unclear whether BPA exposure is associated with alteration in DNA hydroxymethylation, a marker for epigenetic modification, in human sperm. A genome-wide DNA hydroxymethylation study was performed using sperm samples of men who were occupationally exposed to BPA. Compared with controls who had no occupational BPA exposure, the total levels of 5-hydroxymethylcytosine (5hmc) increased significantly (19.37% increase) in BPA-exposed men, with 72.69% of genome regions harboring 5hmc. A total of 9,610 differential 5hmc regions (DhMRs) were revealed in BPA-exposed men relative to controls, which were mainly located in intergenic and intron regions. These DhMRs were composed of 8,670 hyper-hMRs and 940 hypo-hMRs, affecting 2,008 genes and the repetitive elements. The hyper-hMRs affected genes were enriched in pathways associated with nervous system, development, cardiovascular diseases and signal transduction. Additionally, enrichment of 5hmc was observed in the promoters of eight maternally expressed imprinted genes in BPA-exposed sperm. Some of the BPA-affected genes, for example, MLH1, CHD2, SPATA12 and SPATA20 might participate in the response to DNA damage in germ cells caused by BPA. Our analysis showed that enrichment of 5hmc both in promoters and gene bodies is higher in the genes whose expression has been detected in human sperm than those whose expression is absent. Importantly, we observed that BPA exposure affected the 5hmc level in 11.4% of these genes expressed in sperm, and in 6.85% of the sperm genome. Finally, we also observed that BPA exposure tends to change the 5hmc enrichment in the genes which was previously reported to be distributed with the trimethylated Histone 3 (H3K27me3, H3K4me2 or H3K4me3) in sperm. Thus, these results suggest that BPA exposure likely interferes with gene expression via affecting DNA hydroxymethylation in a way partially dependent on trimethylation of H3 in human spermatogenesis. Our current study reveals a new mechanism by which BPA exposure reduces human sperm quality. PMID- 28582420 TI - Novel preparation of highly photocatalytically active copper chromite nanostructured material via a simple hydrothermal route. AB - Highly photocatalytically active copper chromite nanostructured material were prepared via a novel simple hydrothermal reaction between [Cu(en)2(H2O)2]Cl2 and [Cr(en)3]Cl3.3H2O at low temperature, without adding any pH regulator or external capping agent. The as-synthesized nanostructured copper chromite was analyzed by transmission electron microscopy (TEM), UV-vis diffuse reflectance spectroscopy, energy dispersive X-ray microanalysis (EDX), scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) spectroscopy. Results of the morphological investigation of the as-synthesized products illustrate that the shape and size of the copper chromite depended on the surfactant sort, reaction duration and temperature. Moreover, the photocatalytic behavior of as-obtained copper chromite was evaluated by photodegradation of acid blue 92 (anionic dye) as water pollutant. PMID- 28582419 TI - The use of Gompertz models in growth analyses, and new Gompertz-model approach: An addition to the Unified-Richards family. AB - The Gompertz model is well known and widely used in many aspects of biology. It has been frequently used to describe the growth of animals and plants, as well as the number or volume of bacteria and cancer cells. Numerous parametrisations and re-parametrisations of varying usefulness are found in the literature, whereof the Gompertz-Laird is one of the more commonly used. Here, we review, present, and discuss the many re-parametrisations and some parameterisations of the Gompertz model, which we divide into Ti (type I)- and W0 (type II)-forms. In the W0-form a starting-point parameter, meaning birth or hatching value (W0), replaces the inflection-time parameter (Ti). We also propose new "unified" versions (U-versions) of both the traditional Ti -form and a simplified W0-form. In these, the growth-rate constant represents the relative growth rate instead of merely an unspecified growth coefficient. We also present U-versions where the growth-rate parameters return absolute growth rate (instead of relative). The new U-Gompertz models are special cases of the Unified-Richards (U-Richards) model and thus belong to the Richards family of U-models. As U-models, they have a set of parameters, which are comparable across models in the family, without conversion equations. The improvements are simple, and may seem trivial, but are of great importance to those who study organismal growth, as the two new U Gompertz forms give easy and fast access to all shape parameters needed for describing most types of growth following the shape of the Gompertz model. PMID- 28582418 TI - An in vivo comparison study in goats for a novel motion-preserving cervical joint system. AB - Cervical degenerative disease is one of the most common spinal disorders worldwide, especially in older people. Anterior cervical corpectomy and fusion (ACCF) is a useful method for the surgical treatment of multi-level cervical degenerative disease. Anterior cervical disc replacement (ACDR) is considered as an alternative surgical method. However, both methods have drawbacks, particularly the neck motion decrease observed after arthrodesis, and arthroplasty should only be performed on patients presenting with cervical disc disease but without any vertebral body disease. Therefore, we designed a non fusion cervical joint system, namely an artificial cervical vertebra and intervertebral complex (ACVC), to provide a novel treatment for multi-level cervical degenerative disease. To enhance the long-term stability of ACVC, we applied a hydroxyapatite (HA) biocoating on the surface of the artificial joint. Thirty-two goats were randomly divided into four groups: a sham control group, an ACVC group, an ACVC-HA group, and an ACCF group (titanium and plate fixation group). We performed the prosthesis implantation in our previously established goat model. We compared the clinical, radiological, biomechanical, and histological outcomes among these four different groups for 24 weeks post surgery. The goats successfully tolerated the entire experimental procedure. The kinematics data for the ACVC and ACVC-HA groups were similar. The range of motion (ROM) in adjacent level increased after ACCF but was not altered after ACVC or ACVC-HA implantation. Compared with the control group, no significant difference was found in ROM and neutral zone (NZ) in flexion-extension or lateral bending for the ACVC and ACVC-HA groups, whereas the ROM and NZ in rotation were significantly greater. Compared with the ACCF group, the ROM and NZ significantly increased in all directions. Overall, stiffness was significantly decreased in the ACVC and ACVC-HA groups compared with the control group and the ACCF group. Similar results were found after a fatigue test of 5,000 repetitions of axial rotation. The histological results showed more new bone formation and better bone implant contact in the ACVC-HA group than the ACVC group. Goat is an excellent animal model for cervical spine biomechanical study. Compared with the intact state and the ACCF group, ACVC could provide immediate stability and preserve segmental movement after discectomy and corpectomy. Besides, HA biocoating provide a better bone ingrowth, which is essential for long-term stability. In conclusion, ACVC-HA brings new insight to treat cervical degenerative disease. PMID- 28582421 TI - Circulating fibroblast activation protein activity and antigen levels correlate strongly when measured in liver disease and coronary heart disease. AB - BACKGROUND AND AIM: Circulating fibroblast activation protein (cFAP) is a constitutively active enzyme expressed by activated fibroblasts that has both dipeptidyl peptidase and endopeptidase activities. We aimed to assess the correlation between cFAP activity and antigen levels and to compare variations in levels. METHODS: In plasma of 465 control individuals, 368 patients with coronary heart disease (CHD) and 102 hepatitis C virus (HCV) infected patients with severe liver disease before and after liver transplant, cFAP activity levels were measured with a newly developed cFAP activity assay. In the same samples, cFAP antigen levels were measured using a commercially available cFAP ELISA. Correlation analyses between activity and antigen levels were performed by calculating Pearson's correlation coefficient (rho). Additionally, normal ranges, determinants and differences between cohorts and between anticoagulants were investigated. RESULTS: cFAP activity and antigen levels significantly correlated in controls (rho: 0.660, p<0.001) and in CHD patients (rho: 0.709, p<0.001). cFAP activity and antigen levels in the HCV cohort were significantly lower in the samples taken after liver transplantation (p<0.001) and normalized toward levels of healthy individuals. Furthermore, cFAP activity and antigen levels were higher in men and significantly associated with body mass index. Also, cFAP activity and antigen levels were higher in EDTA plasma as compared to the levels in citrated plasma from the same healthy individuals. CONCLUSIONS: For analyzing cFAP levels, either activity levels or antigen levels can be measured to investigate differences between individuals. However, it is of importance that blood samples are collected in the same anticoagulant. PMID- 28582423 TI - Correction: The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study. AB - [This corrects the article DOI: 10.1371/journal.pone.0175207.]. PMID- 28582422 TI - Role of LRRK2 in the regulation of dopamine receptor trafficking. AB - Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson's disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle trafficking that in turn may regulate different aspects of neuronal physiology. We have analyzed the role of LRRK2 in regulating dopamine receptor D1 (DRD1) and D2 (DRD2) trafficking. DRD1 and DRD2 are the most abundant dopamine receptors in the brain. They differ in structural, pharmacological and biochemical properties, as well as in localization and internalization mechanisms. Our results indicate that disease-associated mutant G2019S LRRK2 impairs DRD1 internalization, leading to an alteration in signal transduction. Moreover, the mutant forms of LRRK2 affect receptor turnover by decreasing the rate of DRD2 trafficking from the Golgi complex to the cell membrane. Collectively, our findings are consistent with the conclusion that LRRK2 influences the motility of neuronal vesicles and the neuronal receptor trafficking. These findings have important implications for the complex role that LRRK2 plays in neuronal physiology and the possible pathological mechanisms that may lead to neuronal death in PD. PMID- 28582425 TI - Determining baselines for human-elephant conflict: A matter of time. AB - Elephant crop raiding is one of the most relevant forms of human-elephant conflict (HEC) in Africa. Northern Botswana holds the largest population of African elephants in the world, and in the eastern Okavango Panhandle, 16,000 people share and compete for resources with more than 11,000 elephants. Hence, it is not surprising this area represents a HEC 'hotspot' in the region. Crop raiding impacts lead to negative perceptions of elephants by local communities, which can strongly undermine conservation efforts. Therefore, assessing trends in conflict levels is essential to developing successful management strategies. In this context, we investigated the trend in the number of reported raiding incidents as one of the indicators of the level of HEC, and assessed its relationship to trends in human and elephant population size, as well as land-use in the study area. For each of these factors, we considered data spanning historical (since the 1970s) and contemporary (2008-2015) time frames, with the aim of comparing subsequent inferences on the drivers of crop raiding and predictions for the future. We find that the level of reported crop raiding by elephants in the eastern Panhandle appears to have decreased since 2008, which seems to be related to the reduction in agricultural land allocated to people in recent years, more than with human and elephant population size. We show that inferences regarding the drivers of HEC and predictions for the future are dependent on the time span of the data used. Although our study represents a first step in developing a HEC baseline in the eastern Panhandle, it highlights the need for additional multi-scale analyses that consider progress in conservation conflict to better understand and predict drivers of HEC in the region. PMID- 28582424 TI - Allelic variants of OsHKT1;1 underlie the divergence between indica and japonica subspecies of rice (Oryza sativa) for root sodium content. AB - Salinity is a major factor limiting crop productivity. Rice (Oryza sativa), a staple crop for the majority of the world, is highly sensitive to salinity stress. To discover novel sources of genetic variation for salt tolerance-related traits in rice, we screened 390 diverse accessions under 14 days of moderate (9 dS.m-1) salinity. In this study, shoot growth responses to moderate levels of salinity were independent of tissue Na+ content. A significant difference in root Na+ content was observed between the major subpopulations of rice, with indica accessions displaying higher root Na+ and japonica accessions exhibiting lower root Na+ content. The genetic basis of the observed variation in phenotypes was elucidated through genome-wide association (GWA). The strongest associations were identified for root Na+:K+ ratio and root Na+ content in a region spanning ~575 Kb on chromosome 4, named Root Na+ Content 4 (RNC4). Two Na+ transporters, HKT1;1 and HKT1;4 were identified as candidates for RNC4. Reduced expression of both HKT1;1 and HKT1;4 through RNA interference indicated that HKT1;1 regulates shoot and root Na+ content, and is likely the causal gene underlying RNC4. Three non synonymous mutations within HKT1;1 were present at higher frequency in the indica subpopulation. When expressed in Xenopus oocytes the indica-predominant isoform exhibited higher inward (negative) currents and a less negative voltage threshold of inward rectifying current activation compared to the japonica-predominant isoform. The introduction of a 4.5kb fragment containing the HKT1;1 promoter and CDS from an indica variety into a japonica background, resulted in a phenotype similar to the indica subpopulation, with higher root Na+ and Na+:K+. This study provides evidence that HKT1;1 regulates root Na+ content, and underlies the divergence in root Na+ content between the two major subspecies in rice. PMID- 28582427 TI - Imaging of Jurassic fossils from the Talbragar Fish Bed using fluorescence, photoluminescence, and elemental and mineralogical mapping. AB - The Talbragar Fish Bed is one of Australia's most important Jurassic deposits for freshwater fishes, land plants and aquatic and terrestrial insects. The site has yielded many well preserved fossils, which has led to the formal description of numerous new species and higher taxa. The excellent preservation of many fossils has allowed detailed anatomical studies, e.g. of the early teleost fish Cavenderichthys talbragarensis (Woodward, 1895). Here we report on the fluorescent characteristics and mineral composition of a range of Talbragar fossils. Most specimens fluoresce under ultraviolet, blue and green light. Elemental and mineralogical analyses revealed that the Talbragar fossils consist predominantly of quartz (SiO2), a mineral that is likely to account for the observed fluorescence, with trace kaolinite (Al2Si2O5(OH)4) in some of the fish fossils. Rock matrices are predominantly composed of quartz and goethite (FeO(OH)). Closer inspection of a plant leaf (Pentoxylon australicum White, 1981) establishes fluorescence as a useful tool for the visualisation of anatomical details that are difficult to see under normal light conditions. PMID- 28582426 TI - Synthesis of a novel glucose capped gold nanoparticle as a better theranostic candidate. AB - Gold nanoparticles are predominantly used in diagnostics, therapeutics and biomedical applications. The present study has been designed to synthesize differently capped gold nanoparticles (AuNps) by a simple, one-step, room temperature procedure and to evaluate the potential of these AuNps for biomedical applications. The AuNps are capped with glucose, 2-deoxy-D-glucose (2DG) and citrate using different reducing agents. This is the first report of synthesis of 2DG-AuNp by the simple room temperature method. The synthesized gold nanoparticles are characterized with UV-Visible Spectroscopy, Fourier transform infrared spectroscopy (FTIR), Transmission electron microscopy (TEM) and selected area electron diffraction (SAED), Dynamic light scattering (DLS), and Energy dispersive X-ray spectroscopy (SEM-EDS). Surface-enhanced Raman scattering (SERS) study of the synthesized AuNps shows increase in Raman signals up to 50 times using 2DG. 3-(4, 5-dimethylthiozol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay has been performed using all the three differently capped AuNps in different cell lines to assess cytotoxcity if any, of the nanoparticles. The study shows that 2DG-AuNps is a better candidate for theranostic application. PMID- 28582428 TI - Sex in the shadow of HIV: A systematic review of prevalence, risk factors, and interventions to reduce sexual risk-taking among HIV-positive adolescents and youth in sub-Saharan Africa. AB - BACKGROUND: Evidence on sexual risk-taking among HIV-positive adolescents and youth in sub-Saharan Africa is urgently needed. This systematic review synthesizes the extant research on prevalence, factors associated with, and interventions to reduce sexual risk-taking among HIV-positive adolescents and youth in sub-Saharan Africa. METHODS: Studies were located through electronic databases, grey literature, reference harvesting, and contact with researchers. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Quantitative studies that reported on HIV-positive participants (10-24 year olds), included data on at least one of eight outcomes (early sexual debut, inconsistent condom use, older partner, transactional sex, multiple sexual partners, sex while intoxicated, sexually transmitted infections, and pregnancy), and were conducted in sub-Saharan Africa were included. Two authors piloted all processes, screened studies, extracted data independently, and resolved any discrepancies. Due to variance in reported rates and factors associated with sexual risk-taking, meta-analyses were not conducted. RESULTS: 610 potentially relevant titles/abstracts resulted in the full text review of 251 records. Forty two records (n = 35 studies) reported one or multiple sexual practices for 13,536 HIV-positive adolescents/youth from 13 sub-Saharan African countries. Seventeen cross-sectional studies reported on individual, relationship, family, structural, and HIV-related factors associated with sexual risk-taking. However, the majority of the findings were inconsistent across studies, and most studies scored <50% in the quality checklist. Living with a partner, living alone, gender-based violence, food insecurity, and employment were correlated with increased sexual risk-taking, while knowledge of own HIV-positive status and accessing HIV support groups were associated with reduced sexual risk-taking. Of the four intervention studies (three RCTs), three evaluated group-based interventions, and one evaluated an individual-focused combination intervention. Three of the interventions were effective at reducing sexual risk-taking, with one reporting no difference between the intervention and control groups. CONCLUSION: Sexual risk-taking among HIV-positive adolescents and youth is high, with inconclusive evidence on potential determinants. Few known studies test secondary HIV prevention interventions for HIV-positive youth. Effective and feasible low-cost interventions to reduce risk are urgently needed for this group. PMID- 28582429 TI - Transmission dynamics and control of Rickettsia rickettsii in populations of Hydrochoerus hydrochaeris and Amblyomma sculptum. AB - BACKGROUND: Brazilian Spotted Fever (BSF), caused by the bacterium Rickettsia rickettsii, is the tick-borne disease that generates the largest number of human deaths in the world. In Brazil, the current increase of BSF human cases has been associated with the presence and expansion of capybaras Hydrochoerus hydrochaeris, which act as primary hosts for the tick Amblyomma sculptum, vector of the R. rickettsii in this area. METHODS: We proposed a semi-discrete-time stochastic model to evaluate the role of capybaras in the transmission dynamics of R. rickettsii. Through a sensitivity analysis, we identified the parameters with significant influence on the R. rickettsii establishment. Afterward, we implemented the Gillespie's algorithm to simulate the impact of potential public health interventions to prevent BSF human cases. RESULTS: The introduction of a single infected capybara with at least one infected attached tick is enough to trigger the disease in a non-endemic area. We found that to avoid the formation of new BSF-endemic areas, it is crucial to impede the emigration of capybaras from endemic areas by reducing their birth rate by more than 58%. Model results were corroborated by ex-situ data generated from field studies, and this supports our proposal to prevent BSF human cases by implementing control strategies focused on capybaras. CONCLUSION: The proposed stochastic model illustrates how strategies for the control and prevention of vector-borne infectious diseases can be focused on amplifier hosts management practices. This work provides a basis for future prevention strategies for other neglected vector-borne diseases. PMID- 28582430 TI - A multi-objective decision-making approach to the journal submission problem. AB - When researchers complete a manuscript, they need to choose a journal to which they will submit the study. This decision requires to navigate trade-offs between multiple objectives. One objective is to share the new knowledge as widely as possible. Citation counts can serve as a proxy to quantify this objective. A second objective is to minimize the time commitment put into sharing the research, which may be estimated by the total time from initial submission to final decision. A third objective is to minimize the number of rejections and resubmissions. Thus, researchers often consider the trade-offs between the objectives of (i) maximizing citations, (ii) minimizing time-to-decision, and (iii) minimizing the number of resubmissions. To complicate matters further, this is a decision with multiple, potentially conflicting, decision-maker rationalities. Co-authors might have different preferences, for example about publishing fast versus maximizing citations. These diverging preferences can lead to conflicting trade-offs between objectives. Here, we apply a multi-objective decision analytical framework to identify the Pareto-front between these objectives and determine the set of journal submission pathways that balance these objectives for three stages of a researcher's career. We find multiple strategies that researchers might pursue, depending on how they value minimizing risk and effort relative to maximizing citations. The sequences that maximize expected citations within each strategy are generally similar, regardless of time horizon. We find that the "conditional impact factor"-impact factor times acceptance rate-is a suitable heuristic method for ranking journals, to strike a balance between minimizing effort objectives and maximizing citation count. Finally, we examine potential co-author tension resulting from differing rationalities by mapping out each researcher's preferred Pareto front and identifying compromise submission strategies. The explicit representation of trade-offs, especially when multiple decision-makers (co-authors) have different preferences, facilitates negotiations and can support the decision process. PMID- 28582431 TI - Hepatitis B genotypes and surface antigen mutants present in Pakistani blood donors. AB - BACKGROUND: The prevalence of chronic Hepatitis B Virus (HBV) infection is 2-4% in the Pakistani population, defining Pakistan as an intermediate prevalence country. In this study, hepatitis B surface antigen (HBsAg) reactive blood donations were screened using a combination of serological and molecular methods to identify immune escape HBV mutant strains and to determine the HBV genotypes and subtypes present in Pakistan. METHODS: Blood donations were collected at the Armed Forces Institute of Transfusion (AFIT) located in northern Pakistan and the Hussaini Blood Bank (HBB) located in the south. From 2009 to 2013 a total of 706,575 donations were screened with 2.04% (14,409) HBsAg reactive. A total of 2055 HBsAg reactive specimens, were collected and screened using a monoclonal antibody based research assay to identify immune escape mutants followed by PCR amplification and DNA sequencing to identify the mutation present. DNA sequences obtained from 192 specimens, including mutant candidates and wild type strains, were analyzed for escape mutations, genotype, and HBsAg subtype. RESULTS: Mutations were identified in approximately 14% of HBsAg reactive donations. Mutations at HBsAg amino acid positions 143-145 are the most common (46%) with the mutation serine 143 to leucine the most frequently occurring change (28%). While regional differences were observed, the most prevalent HBV strains are subgenotypes of D with subgenotype D1/subtype ayw2 accounting for the majority of infections; 90.2% at AFIT and 52.5% at HBB. CONCLUSIONS: The high frequency of immune escape HBV mutants in HBV infected Pakistani blood donors highlights the need for more studies into the prevalence of escape mutants. Differences between vaccinated and unvaccinated populations, the correlation of escape mutant frequency with genotype, and impact of escape mutations in different genotype backgrounds on the performance of commercially available HBsAg assays represent avenues for further investigation. PMID- 28582432 TI - In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy. AB - Noonan Syndrome with Multiple Lentigines (NSML, formerly LEOPARD syndrome) is an autosomal dominant "RASopathy" disorder manifesting in congenital heart disease. Most cases of NSML are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11), encoding the SH2 domain-containing PTP-2 (SHP2) protein. We previously generated knock-in mice harboring the PTPN11 mutation Y279C, one of the most common NSML alleles; these now-termed SHP2Y279C/+ mice recapitulate the human disorder and develop hypertrophic cardiomyopathy (HCM) by 12 weeks of age. Functionally, heart and/or cardiomyocyte lysates from SHP2Y279C/+ mice exhibit increased basal and agonist induced AKT and mTOR activities. Here, we sought to determine whether we could reverse the hypertrophy in SHP2Y279C/+ mice using ARQ 092, an oral and selective allosteric AKT inhibitor currently in clinical trials for patients with PI3K/AKT driven tumors or Proteus syndrome. We obtained echocardiographs of SHP2Y279C/+ and wildtype (SHP2+/+) littermates, either in the presence or absence of ARQ 092 at 12, 14, and 16 weeks of age. While SHP2Y279C/+ mice developed significant left ventricular hypertrophy by 12 weeks, as indicated by decreased chamber dimension and increased posterior wall thickness, treatment of SHP2Y279C/+ mice with ARQ 092 normalized the hypertrophy in as early as 2 weeks following treatment, with hearts comparable in size to those in wildtype (SHP2+/+) mice. In addition, we observed an increase in fractional shortening (FS%) in SHP2Y279C/+ mice, an effect of increased compensatory hypertrophy, which was not apparent in SHP2Y279C/+ mice treated with ARQ 092, suggesting functional improvement of HCM upon treatment with the AKT inhibitor. Finally, we found that ARQ 092 specifically inhibited AKT activity, as well as its downstream effectors, PRAS and S6RP in NSML mice. Taken together, these data suggest ARQ 092 may be a promising novel therapy for treatment of hypertrophy in NSML patients. PMID- 28582434 TI - Asymptomatic aortic stenosis: An assessment of patients' and of their general practitioners' knowledge, after an indexed specialized assessment in community practice. AB - BACKGROUND: Clinical and echocardiography follow-up is recommended in patients with aortic stenosis to detect symptom onset, thus a watchful waiting approach has to be safe and effective. For both AS patients and their general practitioners, evaluation of valvular heart disease (VHD) knowledge, after the indexed specialized assessment has never been measured. AIMS: To evaluate the knowledge of clinical symptoms of aortic stenosis by both patients and their general practitioner. METHODS: Sixty-four patients, with moderate to severe and initially asymptomatic AS (median AVA (interquartile range) 1.01(0.80-1.15) cm2) previously referred to a tertiary center and medically managed for at least 6 months after the index echocardiogram, and their primary care doctors were interviewed on the phone and asked to answer specific questions related to knowledge of aortic stenosis symptoms. RESULTS: Fifty-six percent of patients quoted shortness of breath as one of the aortic stenosis symptoms, and only 16% knew the 3 aortic stenosis symptoms. Fifty percent of patients reported having received sufficient information regarding aortic stenosis; only 48% remembered receiving information regarding specific symptoms. Only 14% general practitioners quoted the 3 specific symptoms. According to the initial recommendation, only 41 patients (64%) benefitted from a 6-to-12 month clinical and echocardiography follow up. CONCLUSION: GPs are not sufficiently trained to safely manage AS patients in the community and to ensure adequate follow-up and monitoring. AS patients were not properly informed about their diagnosis and symptomatology. Hence, therapeutic education should be improved for patients with asymptomatic AS and continuous medical education on VHD should be reinforced, for GPs. PMID- 28582433 TI - Travelling to the south: Phylogeographic spatial diffusion model in Monttea aphylla (Plantaginaceae), an endemic plant of the Monte Desert. AB - Effects of Pleistocene climatic oscillations on plant phylogeographic patterns are relatively well studied in forest, savanna and grassland biomes, but such impacts remain less explored on desert regions of the world, especially in South America. Here, we performed a phylogeographical study of Monttea aphylla, an endemic species of the Monte Desert, to understand the evolutionary history of vegetation communities inhabiting the South American Arid Diagonal. We obtained sequences of three chloroplast (trnS-trnfM, trnH-psbA and trnQ-rps16) and one nuclear (ITS) intergenic spacers from 272 individuals of 34 localities throughout the range of the species. Population genetic and Bayesian coalescent analyses were performed to infer genealogical relationships among haplotypes, population genetic structure, and demographic history of the study species. Timing of demographic events was inferred using Bayesian Skyline Plot and the spatio temporal patterns of lineage diversification was reconstructed using Bayesian relaxed diffusion models. Palaeo-distribution models (PDM) were performed through three different timescales to validate phylogeographical patterns. Twenty-five and 22 haplotypes were identified in the cpDNA and nDNA data, respectively. that clustered into two main genealogical lineages following a latitudinal pattern, the northern and the southern Monte (south of 35 degrees S). The northern Monte showed two lineages of high genetic structure, and more relative stable demography than the southern Monte that retrieved three groups with little phylogenetic structure and a strong signal of demographic expansion that would have started during the Last Interglacial period (ca. 120 Ka). The PDM and diffusion models analyses agreed in the southeast direction of the range expansion. Differential effect of climatic oscillations across the Monte phytogeographic province was observed in Monttea aphylla lineages. In northern Monte, greater genetic structure and more relative stable demography resulted from a more stable climate than in the southern Monte. Pleistocene glaciations drastically decreased the species area in the southern Monte, which expanded in a southeastern direction to the new available areas during the interglacial periods. PMID- 28582435 TI - School and household tuberculosis contact investigations in Swaziland: Active TB case finding in a high HIV/TB burden setting. AB - BACKGROUND: Investigation of household contacts exposed to infectious tuberculosis (TB) is widely recommended by international guidelines to identify secondary cases of TB and limit spread. There is little data to guide the use of contact investigations outside of the household, despite strong evidence that most TB infections occur outside of the home in TB high burden settings. In older adolescents, the majority of infections are estimated to occur in school. Therefore, as part of a project to increase active case finding in Swaziland, we performed school contact investigations following the identification of a student with infectious TB. METHODS: The Butimba Project identified 7 adolescent TB index cases (age 10-20) with microbiologically confirmed disease attending 6 different schools between June 2014 and March 2015. In addition to household contact investigations, Butimba Project staff worked with the Swaziland School Health Programme (SHP) to perform school contact investigations. At 6 school TB screening events, between May and October 2015, selected students underwent voluntary TB screening and those with positive symptom screens provided sputum for TB testing. RESULTS: Among 2015 student contacts tested, 177 (9%) screened positive for TB symptoms, 132 (75%) produced a sputum sample, of which zero tested positive for TB. Household contact investigations of the same index cases yielded 40 contacts; 24 (60%) screened positive for symptoms; 19 produced a sputum sample, of which one case was confirmed positive for TB. The odds ratio of developing TB following household vs. school contact exposure was significantly lower (OR 0.0, 95% CI 0.0 to 0.18, P = 0.02) after exposure in school. CONCLUSION: School-based contact investigations require further research to establish best practices in TB high burden settings. In this case, a symptom based screening approach did not identify additional cases of tuberculosis. In comparison, household contact investigations yielded a higher percentage of contacts with positive TB screens and an additional tuberculosis case. PMID- 28582436 TI - Is hyaluronan deposition in the stroma of pancreatic ductal adenocarcinoma of prognostic significance? AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and the number of PDAC-related deaths is rising. Recently the tumour stroma and in particular one of its main components, hyaluronan (HA), have attracted considerable attention as intravenous hyaluronidase treatment together with conventional chemotherapy considerably prolonged survival in HA-rich PDA patients. We therefore wanted to investigate the prognostic significance of HA deposition in PDA using both antibodies to HA and hyaluronan binding protein (HABP). MATERIAL AND METHODS: Tissue microarrays of PDAs of 184 patients and pancreatic xenografts tumours were immunohistochemically (IHC) stained for HA using either biotinylated hyaluronic acid binding protein (HABP) or anti-HA antibody. RESULTS: The pattern of staining with HABP differed significantly from that with antibody IHC. Antibody staining was found both within cancer cells and in the extracellular matrix and staining could not be eliminated by hyaluronidase predigestion of the tissue sections. In contrast, HABP staining was generally confined to the extracellular matrix and was completely abolished by hyaluronidase pretreatment. HA positivity as determined by HABP was associated with larger primary tumours (p = 0.046). There were no correlations between overall survival, disease-free survival and HA expression. CONCLUSION: Presence of HA alone is not of prognostic importance in PDAC, and IHC with utilization of antibody detection shows no reliable staining pattern and should not be applied for HA IHC. PMID- 28582437 TI - Genomic ancestry and education level independently influence abdominal fat distributions in a Brazilian admixed population. AB - We aimed to identify the independent associations of genomic ancestry and education level with abdominal fat distributions in the 1982 Pelotas birth cohort study, Brazil. In 2,890 participants (1,409 men and 1,481 women), genomic ancestry was assessed using genotype data on 370,539 genome-wide variants to quantify ancestral proportions in each individual. Years of completed education was used to indicate socio-economic position. Visceral fat depth and subcutaneous abdominal fat thickness were measured by ultrasound at age 29-31y; these measures were adjusted for BMI to indicate abdominal fat distributions. Linear regression models were performed, separately by sex. Admixture was observed between European (median proportion 85.3), African (6.6), and Native American (6.3) ancestries, with a strong inverse correlation between the African and European ancestry scores (rho = -0.93; p<0.001). Independent of education level, African ancestry was inversely associated with both visceral and subcutaneous abdominal fat distributions in men (both P = 0.001), and inversely associated with subcutaneous abdominal fat distribution in women (p = 0.009). Independent of genomic ancestry, higher education level was associated with lower visceral fat, but higher subcutaneous fat, in both men and women (all p<0.001). Our findings, from an admixed population, indicate that both genomic ancestry and education level were independently associated with abdominal fat distribution in adults. African ancestry appeared to lower abdominal fat distributions, particularly in men. PMID- 28582439 TI - Familiarity facilitates feature-based face processing. AB - Recognition of personally familiar faces is remarkably efficient, effortless and robust. We asked if feature-based face processing facilitates detection of familiar faces by testing the effect of face inversion on a visual search task for familiar and unfamiliar faces. Because face inversion disrupts configural and holistic face processing, we hypothesized that inversion would diminish the familiarity advantage to the extent that it is mediated by such processing. Subjects detected personally familiar and stranger target faces in arrays of two, four, or six face images. Subjects showed significant facilitation of personally familiar face detection for both upright and inverted faces. The effect of familiarity on target absent trials, which involved only rejection of unfamiliar face distractors, suggests that familiarity facilitates rejection of unfamiliar distractors as well as detection of familiar targets. The preserved familiarity effect for inverted faces suggests that facilitation of face detection afforded by familiarity reflects mostly feature-based processes. PMID- 28582438 TI - In silico discovery of substituted pyrido[2,3-d]pyrimidines and pentamidine-like compounds with biological activity in myotonic dystrophy models. AB - Myotonic dystrophy type 1 (DM1) is a rare multisystemic disorder associated with an expansion of CUG repeats in mutant DMPK (dystrophia myotonica protein kinase) transcripts; the main effect of these expansions is the induction of pre-mRNA splicing defects by sequestering muscleblind-like family proteins (e.g. MBNL1). Disruption of the CUG repeats and the MBNL1 protein complex has been established as the best therapeutic approach for DM1, hence two main strategies have been proposed: targeted degradation of mutant DMPK transcripts and the development of CUG-binding molecules that prevent MBNL1 sequestration. Herein, suitable CUG binding small molecules were selected using in silico approaches such as scaffold analysis, similarity searching, and druggability analysis. We used polarization assays to confirm the CUG repeat binding in vitro for a number of candidate compounds, and went on to evaluate the biological activity of the two with the strongest affinity for CUG repeats (which we refer to as compounds 1-2 and 2-5) in DM1 mutant cells and Drosophila DM1 models with an impaired locomotion phenotype. In particular, 1-2 and 2-5 enhanced the levels of free MBNL1 in patient-derived myoblasts in vitro and greatly improved DM1 fly locomotion in climbing assays. This work provides new computational approaches for rational large-scale virtual screens of molecules that selectively recognize CUG structures. Moreover, it contributes valuable knowledge regarding two compounds with desirable biological activity in DM1 models. PMID- 28582441 TI - In vivo MR-angiography for the assessment of aortic aneurysms in an experimental mouse model on a clinical MRI scanner: Comparison with high-frequency ultrasound and histology. AB - BACKGROUND: MR-angiography currently represents one of the clinical reference standards for the assessment of aortic-dimensions. For experimental research in mice, dedicated preclinical high-field MRI scanners are used in most studies. This type of MRI scanner is not available in most institutions. The aim of this study was to evaluate the potential of MR-angiography performed on a clinical MR scanner for the assessment of aortic aneurysms in an experimental mouse model, compared to a preclinical high-resolution ultrasound imaging system and histopathology. METHODS: All in vivo MR imaging was performed with a clinical 3T MRI system (Philips Achieva) equipped with a clinical gradient system in combination with a single-loop surface-coil (47 mm). All MR sequences were based on clinically used sequences. For ultrasound, a dedicated preclinical high resolution system (30 MHz linear transducer, Vevo770, VisualSonics) was used. All imaging was performed with an ApoE knockout mouse-model for aortic aneurysms. Histopathology was performed as reference-standard at all stages of aneurysm development. RESULTS: MR-angiography on a clinical 3T system enabled the clear visualization of the aortic lumen and aneurysmal dilation at different stages of aneurysm development. A close correlation (R2 = 0.98; p < 0.001) with histological area measurements was found. Additionally, a good agreement between MR and ultrasound area measurements in systole (R2 = 0.91; p < 0.001) and diastole (R2 = 0.94; p < 0.001) were measured. Regarding interobserver reproducibility, MRI measurements yielded a smaller 95% confidence interval and a closer interreader correlation compared to ultrasound measurements (-0.37-0.46; R2 = 0.97 vs. -0.78-0.88; R2 = 0.87). CONCLUSION: This study demonstrates that MR angiography, performed on a clinical 3T MR scanner, enables the reliable detection and quantification of the aortic dilatation at different stages of aneurysm development in an experimental mouse model. PMID- 28582440 TI - Development and external validation of a clinical prognostic score for death in visceral leishmaniasis patients in a high HIV co-infection burden area in Ethiopia. AB - BACKGROUND: In Ethiopia, case fatality rates among subgroups of visceral leishmaniasis (VL) patients are high. A clinical prognostic score for death in VL patients could contribute to optimal management and reduction of these case fatality rates. We aimed to identify predictors of death from VL, and to develop and externally validate a clinical prognostic score for death in VL patients, in a high HIV co-infection burden area in Ethiopia. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a retrospective cohort study in north west Ethiopia. Predictors with an adjusted likelihood ratio >=1.5 or <=0.67 were retained to calculate the predictor score. The derivation cohort consisted of 1686 VL patients treated at an upgraded health center and the external validation cohort consisted of 404 VL patients treated in hospital. There were 99 deaths in the derivation cohort and 53 deaths in the external validation cohort. The predictors of death were: age >40 years (score +1); HIV seropositive (score +1); HIV seronegative (score -1); hemoglobin <=6.5 g/dl (score +1); bleeding (score +1); jaundice (score +1); edema (score +1); ascites (score +2) and tuberculosis (score +1). The total predictor score per patient ranged from -1 to +5. A score of -1, indicated a low risk of death (1.0%), a score of 0 an intermediate risk of death (3.8%) and a score of +1 to +5, a high risk of death (10.4-85.7%). The area under the receiver operating characteristic curve was 0.83 (95% confidence interval: 0.79-0.87) in derivation, and 0.78 (95% confidence interval: 0.72-0.83) in external validation. CONCLUSIONS/SIGNIFICANCE: The overall performance of the score was good. The score can enable the early detection of VL cases at high risk of death, which can inform operational, clinical management guidelines, and VL program management. Implementation of focused strategies could contribute to optimal management and reduction of the case fatality rates. PMID- 28582443 TI - When does activating diversity alleviate, when does it increase intergroup bias? An ingroup projection perspective. AB - The question how intergroup bias can be alleviated is of much theoretical and practical interest. Whereas diversity training and the multiculturalism ideology are two approaches prominent in practice, most theoretical models on reducing intergroup bias are based on social-identity theory and self-categorization theory. This social-identity perspective assumes that similar processes lead to intergroup bias in very different intergroup contexts if people identify with the respective social groups. A recent prominent model based on these theories is the ingroup-projection model. As this model assumes, an ingroup's norms and standards are applied to outgroups included in a common superordinate category (this is called ingroup projection). Intergroup bias results because the outgroup fulfils these norms and standards less than the ingroup. Importantly, if the diversity of the superordinate category is induced as the norm, ingroup projection and thus intergroup bias should be reduced. The present research delineates and tests how general this process is. We propose that ingroup prototypicality is not only an outcome variable, as the ingroup-projection model originally assumes, but can also be an important moderator. We hypothesize that for members considering their ingroup highly prototypical ("pars pro toto", large majorities), the superordinate group's diversity may question their ingroup's position and thus elicit threat and intergroup bias. In contrast, for members who consider their group as less prototypical (one among several, or "una inter pares" groups), activating diversity should, as originally assumed in the ingroup-projection model, reduce intergroup bias. Three experiments (total N = 345) supported these predictions in the contexts of groups defined by gender or nationality. Taken together, the ingroup-projection model can explain under which conditions activating superordinate-category diversity induces tolerance, and when it may backfire. We discuss in how far the ingroup-projection model can integrate conflicting findings on the multiculturalism ideology. PMID- 28582442 TI - The role of neuropeptide-Y in nandrolone decanoate-induced attenuation of antidepressant effect of exercise. AB - Since the increased prevalence of anabolic androgenic steroids abuse in last few decades is usually accompanied by various exercise protocols, the scope of our study was to evaluate the effects of chronic nandrolone decanoate administration in supraphysiological dose and a prolonged swimming protocol (alone and simultaneously with nandrolone decanoate) on depressive state in male rats. Simultaneously, we investigated the possible alterations in neuropeptide Y (NPY) content in blood and the hippocampus, in order to determine the role of NPY in the modulation of depressive-like behavior.Exercise induced antidepressant effects in tail suspension test (decrease of the total duration of immobility), as well as significant increase in the number of hippocampal NPY-interneurons in CA1 region. Chronic nandrolone decanoate treatment attenuated the beneficial antidepressant effects of exercise as measured by the tail suspension test parameters. Simultaneously, nandrolone decanoate treatment resulted in diminution of NPY content both in blood (decreased serum levels) and in hippocampus (the significant decrease in NPY expression in all three investigated hippocampal regions-CA1, CA2/3 and DG). Our findings indicate that alterations in serum and hippocampal NPY contents may underlie the changes in depressive state in rats. The exercise was beneficial as it exerted antidepressant effect, while chronic nandrolone decanoate treatment resulted in depressive-like behavior. Furthermore, the behavioral indicators of depression showed strong correlations with the serum levels and the hippocampal content of NPY. PMID- 28582444 TI - Selection and characterization of specific nanobody against bovine virus diarrhea virus (BVDV) E2 protein. AB - Bovine viral diarrhea-mucosal disease (BVD-MD) is caused by bovine viral diarrhea virus (BVDV), and results in abortion, stillbirth, and fetal malformation in cows. Here, we constructed the phage display vector pCANTAB 5E-VHH and then transformed it into Escherichia coli TG1-competent cells, to construct an initial anti-BVDV nanobody gene library. We obtained a BVDV-E2 antigen epitope bait protein by prokaryotic expression using the nucleotide sequence of the E2 gene of the BVDV-NADL strain published in GenBank. Phage display was used to screen the anti-BVDV nanobody gene library. We successfully constructed a high quality phage display nanobody library, with an initial library capacity of 4.32*105. After the rescue of helper phage, the titer of the phage display nanobody library was 1.3*1011. The BVDV-E2 protein was then expressed in Escherichia coli (DE3), and a 49.5 kDa band was observed with SDS-PAGE analysis that was consistent with the expected nanobody size. Thus, we were able to isolate one nanobody that exhibits high affinity and specificity against BVDV using phage display techniques. This isolated nanobody was then used in Enzyme Linked Immunosorbent Assay and qRT-PCR, and ELISA analyses of BVDV infection of MDBK cells indicated that the nanobodies exhibited good antiviral effect. PMID- 28582445 TI - Human resources and models of mental healthcare integration into primary and community care in India: Case studies of 72 programmes. AB - BACKGROUND: Given the scarcity of specialist mental healthcare in India, diverse community mental healthcare models have evolved. This study explores and compares Indian models of mental healthcare delivered by primary-level workers (PHW), and health workers' roles within these. We aim to describe current service delivery to identify feasible and acceptable models with potential for scaling up. METHODS: Seventy two programmes (governmental and non-governmental) across 12 states were visited. 246 PHWs, coordinators, leaders, specialists and other staff were interviewed to understand the programme structure, the model of mental health delivery and health workers' roles. Data were analysed using framework analysis. RESULTS: Programmes were categorised using an existing framework of collaborative and non-collaborative models of primary mental healthcare. A new model was identified: the specialist community model, whereby PHWs are trained within specialist programmes to provide community support and treatment for those with severe mental disorders. Most collaborative and specialist community models used lay health workers rather than doctors. Both these models used care managers. PHWs and care managers received support often through multiple specialist and non-specialist organisations from voluntary and government sectors. Many projects still use a simple yet ineffective model of training without supervision (training and identification/referral models). DISCUSSION AND CONCLUSION: Indian models differ significantly to those in high-income countries there are less professional PHWs used across all models. There is also intensive specialist involvement particularly in the community outreach and collaborative care models. Excessive reliance on specialists inhibits their scalability, though they may be useful in targeted interventions for severe mental disorders. We propose a revised framework of models based on our findings. The current priorities are to evaluate the comparative effectiveness, cost-effectiveness and scalability of these models in resource-limited settings both in India and in other low- and middle- income countries. PMID- 28582446 TI - Generation of an immortalized mouse embryonic palatal mesenchyme cell line. AB - Palatogenesis is a complex morphogenetic process, disruptions in which result in highly prevalent birth defects in humans. In recent decades, the use of model systems such as genetically-modified mice, mouse palatal organ cultures and primary mouse embryonic palatal mesenchyme (MEPM) cultures has provided significant insight into the molecular and cellular defects underlying cleft palate. However, drawbacks in each of these systems have prevented high throughput, large-scale studies of palatogenesis in vitro. Here, we report the generation of an immortalized MEPM cell line that maintains the morphology, migration ability, transcript expression and responsiveness to exogenous growth factors of primary MEPM cells, with increased proliferative potential over primary cultures. The immortalization method described in this study will facilitate the generation of palatal mesenchyme cells with an unlimited capacity for expansion from a single genetically-modified mouse embryo and enable mechanistic studies of palatogenesis that have not been possible using primary culture. PMID- 28582447 TI - Action of YM155 on clear cell renal cell carcinoma does not depend on survivin expression levels. AB - The dioxonapthoimidazolium YM155 is a survivin suppressant which has been investigated as an anticancer agent in clinical trials. Here, we investigated its growth inhibitory properties on a panel of immortalized and patient derived renal cell carcinoma (RCC) cell lines which were either deficient in the tumour suppressor von Hippel-Lindau (VHL) protein or possessed a functional copy. Neither the VHL status nor the survivin expression levels of these cell lines influenced their susceptibility to growth inhibition by YM155. Of the various RCC lines, the papillary subtype was more resistant to YM155, suggesting that the therapeutic efficacy of YM155 may be restricted to clear cell subtypes. YM155 was equally potent in cells (RCC786.0) in which survivin expression had been stably silenced or overexpressed, implicating a limited reliance on survivin in the mode of action of YM155. A follow-up in-vitro high throughput RNA microarray identified possible targets of YM155 apart from survivin. Selected genes (ID1, FOXO1, CYLD) that were differentially expressed in YM155-sensitive RCC cells and relevant to RCC pathology were validated with real-time PCR and western immunoblotting analyses. Thus, there is corroboratory evidence that the growth inhibitory activity of YM155 in RCC cell lines is not exclusively mediated by its suppression of survivin. In view of the growing importance of combination therapy in oncology, we showed that a combination of YM155 and sorafenib at 1/2 x IC50 concentrations was synergistic on RCC786.0 cells. However, when tested intraperitoneally on a murine xenograft model derived from a nephrectomised patient with clear cell RCC, a combination of suboptimal doses of both drugs failed to arrest tumour progression. The absence of synergy in vivo highlighted the need to further optimize the dosing schedules of YM155 and sorafenib, as well as their routes of administration. It also implied that the expression of other oncogenic proteins which YM155 may target is either low or absent in this clear cell RCC. PMID- 28582449 TI - HIV-1 adaptation to NK cell-mediated immune pressure. AB - The observation, by Alter et al., of the enrichment of NK cell "escape" variants in individuals carrying certain Killer-cell Immunoglobulin-like Receptor (KIR) genes is compelling evidence that natural killer (NK) cells exert selection pressure on HIV-1. Alter et al hypothesise that variant peptide, in complex with HLA class I molecules binds KIR receptors and either increases NK cell inhibition or decreases NK cell activation compared to wild type peptide thus leading to virus escape from the NK cell response. According to this hypothesis, in order for NK cells to select for an escape variant, an individual must carry both the KIR and an HLA ligand that binds the variant peptide. In this study we estimate the proportion of the population that is capable of selecting for escape variants and use both epidemiological modelling and a model-free approach to investigate whether this proportion explains the observed variant enrichment. We found that the fraction of individuals within whom the variant would have a selective advantage was low and was unable to explain the high degree of enrichment observed. We conclude that whilst Alter et al's data is consistent with selection pressure, the mechanism that they postulate is unlikely. The importance of this work is two-fold. Firstly, it forces a re-evaluation of some of the clearest evidence that NK cells exert a protective effect in HIV-1 infection. Secondly, it implies that there is a significant aspect of immunology that is not understood: it is possible that KIRs bind much more widely than was previously appreciated; that a gene in linkage with the KIR genes is responsible for considerable peptide dependent selection or that variant peptides are indirectly impacting KIR ligation. PMID- 28582448 TI - Acid sphingomyelinase deficiency enhances myelin repair after acute and chronic demyelination. AB - The cuprizone animal model, also known as the toxic demyelination model, is a well-reproducible model of demyelination- and remyelination in mice, and has been useful in studying important aspect of human demyelinating diseases, including multiple sclerosis. In this study, we investigated the role of acid sphingomyelinase in demyelination and myelin repair by inducing acute and chronic demyelination with 5- or 12-week cuprizone treatment, followed by a 2-week cuprizone withdrawal phase to allow myelin repair. Sphingolipids, in particular ceramide and the enzyme acid sphingomyelinase, which generates ceramide from sphingomyelin, seem to be involved in astrocyte activation and neuronal damage in multiple sclerosis. We used immunohistochemistry to study glial reaction and oligodendrocyte distribution in acid sphingomyelinase deficient mice and wild type C57BL/6J littermates at various time intervals after demyelination and remyelination. Axonal injury was quantified using amyloid precursor protein and synaptophysin, and gene expression and protein levels were measured using gene analysis and Western blotting, respectively. Our results show that mice lacking acid sphingomyelinase had a significant increase in myelin recovery and a significantly higher oligodendrocyte cell count after 2 weeks remyelination compared to wild-type littermates. Detrimental astroglial distribution was also significantly reduced in acid sphingomyelinase deficient animals. We obtained similar results in experiments using amitriptyline to inhibit acid sphingomyelinase. These findings suggest that acid sphingomyelinase plays a significant role in myelin repair, and its inhibition by amitriptyline may constitute a novel therapeutic approach for multiple sclerosis patients. PMID- 28582451 TI - Culture, social networks and HIV vulnerability among men who have sex with men in Indonesia. AB - The current study aimed to explore cultural and social network influence on HIV vulnerability among Men who have Sex with Men (MSM) population in Yogyakarta, Indonesia. A qualitative inquiry employing in-depth one-on-one interviews was carried out with 24 MSM participants in July 2015. Data were analysed using a framework analysis and guided by the Social Networks Theory (SNT) as a conceptual framework. Findings indicated that prohibitive cultural perspectives and norms against same-sex marriage made them to conceal their sexual orientation and thus secretively engaging in unprotected sex that increased their predisposition to HIV transmission. The prohibitive cultures were also instrumental in the formation of MSM sexual networks that provided supportive environment for HIV risky sexual practices among network partners. These findings provide information that can be used to improve HIV/AIDS service practices and policies. However, further studies with large numbers of MSM would be needed to improve the understanding of other HIV vulnerability determinants, the unique needs of MSM, and what and how programs could be conducted to reduce HIV vulnerability among MSM population. PMID- 28582450 TI - Spontaneous low frequency BOLD signal variations from resting-state fMRI are decreased in Alzheimer disease. AB - Previous studies have demonstrated altered brain activity in Alzheimer's disease using task based functional MRI (fMRI), network based resting-state fMRI, and glucose metabolism from 18F fluorodeoxyglucose-PET (FDG-PET). Our goal was to define a novel indicator of neuronal activity based on a first-order textural feature of the resting state functional MRI (RS-fMRI) signal. Furthermore, we examined the association between this neuronal activity metric and glucose metabolism from 18F FDG-PET. We studied 15 normal elderly controls (NEC) and 15 probable Alzheimer disease (AD) subjects from the AD Neuroimaging Initiative. An independent component analysis was applied to the RS-fMRI, followed by template matching to identify neuronal components (NC). A regional brain activity measurement was constructed based on the variation of the RS-fMRI signal of these NC. The standardized glucose uptake values of several brain regions relative to the cerebellum (SUVR) were measured from partial volume corrected FDG-PET images. Comparing the AD and NEC groups, the mean brain activity metric was significantly lower in the accumbens, while the glucose SUVR was significantly lower in the amygdala and hippocampus. The RS-fMRI brain activity metric was positively correlated with cognitive measures and amyloid beta1-42 cerebral spinal fluid levels; however, these did not remain significant following Bonferroni correction. There was a significant linear correlation between the brain activity metric and the glucose SUVR measurements. This proof of concept study demonstrates that this novel and easy to implement RS-fMRI brain activity metric can differentiate a group of healthy elderly controls from a group of people with AD. PMID- 28582452 TI - Heritability and genetic correlation between GERD symptoms severity, metabolic syndrome, and inflammation markers in families living in Mexico City. AB - OBJECTIVE: The aim of this study was to estimate the heritability (h2) and genetic correlation (rhoG) between GERD symptoms severity, metabolic syndrome components, and inflammation markers in Mexican families. METHODS: Cross sectional study which included 32 extended families resident in Mexico City. GERD symptoms severity was assessed by the ReQuest in Practice questionnaire. Heritability and genetic correlation were determined using the Sequential Oligogenic Linkage Analysis Routines software. RESULTS: 585 subjects were included, the mean age was 42 (+/-16.7) years, 57% were women. The heritability of the severity of some GERD symptoms was h2 = 0.27, 0.27, 0.37, and 0.34 (p value <1.0x10-5) for acidity complaints, lower abdominal complaints, sleep disturbances, and total ReQuest score, respectively. Heritability of metabolic syndrome components ranged from 0.40 for fasting plasma glucose to 0.61 for body mass index and diabetes mellitus. The heritability for fibrinogen and C-reactive protein was 0.64 and 0.38, respectively. Statistically significant genetic correlations were found between acidity complaints and fasting plasma glucose (rhoG = 0.40); sleep disturbances and fasting plasma glucose (rhoG = 0.36); acidity complaints and diabetes mellitus (rhoG = 0.49) and between total ReQuest score and fasting plasma glucose (rhoG = 0.43). The rest of metabolic syndrome components did not correlate with GERD symptoms. CONCLUSION: Genetic factors substantially explain the phenotypic variance of the severity of some GERD symptoms, metabolic syndrome components and inflammation markers. Observed genetic correlations suggest that these phenotypes share common genes. These findings suggest conducting further investigation, as the determination of a linkage analysis in order to identify regions of susceptibility for developing of GERD and metabolic syndrome. PMID- 28582453 TI - Preparation, characterization, and performance evaluation of UiO-66 analogues as stationary phase in HPLC for the separation of substituted benzenes and polycyclic aromatic hydrocarbons. AB - UiO-66 analogues are good candidates as stationary phase in HPLC because of their chemical/thermal stability, large surface area, and two cage structures. Here, two UiO-66 analogues, UiO-66-NH2 and UiO-67, were synthesized and used as stationary phase in HPLC to evaluate their performance in the separation of substituted benzenes (SBs) and polycyclic aromatic hydrocarbons (PAHs). The results showed that SBs could be well separated on UiO-66-NH2 column but not on UiO-67 column. Nonetheless, PAHs could be well separated on UiO-67 column. The separation mechanisms of SBs and PAHs on UiO-66 analogues may be involved in the pore size and functional group in the frameworks of UiO-66 analogues. Introduction of the-NH2 into UiO-66 significantly reduced its adsorption capacity for SB congeners, which resulted in less separation of SBs on UiO-66-NH2. As for the separation of PAHs on UiO-67 column, the pi-pi stacking effect was supposed to play a vital role. PMID- 28582455 TI - Correction: Myosin phosphatase and RhoA-activated kinase modulate neurotransmitter release by regulating SNAP-25 of SNARE complex. AB - [This corrects the article DOI: 10.1371/journal.pone.0177046.]. PMID- 28582454 TI - Insights on the mechanism of action of immunostimulants in relation to their pharmacological potency. The effects of imidazoquinolines on TLR8. AB - Imidazoquinolines are powerful immunostimulants (IMMS) that function through Toll like receptors, particularly TLR7 and TLR8. In addition to enhancing the immune response, IMMS also function as antineoplastic drugs and vaccine adjuvants. These small compounds display almost the same molecular structure, except in some cases in which atom in position 1 varies and changes the imidazole characteristics. A variable acyclic side chain is also always attached at atom in position 2, while another chain may be attached at atom in position 1. These structural differences alter immune responses, such as the production of interferon regulatory factor and nuclear factor-kappaB (IRF-NFkappaB). In this work, quantum mechanics theory and computational chemistry methods were applied to study the physicochemical properties of the crystal binding site of TLR8 complexed with the following six IMMS molecules: Hybrid-2, XG1-236, DS802, CL075, CL097 and R848 (resiquimod). The PDB IDs of the crystals were: 4R6A, 4QC0, 4QBZ, 3W3K, 3W3J, and 3W3N respectively. Thus, were calculated, the total energy, solvation energy, interaction energy (instead of free energy) of the system and interaction energy of the polar region of the IMMS. Additionally, the dipole moment, electrostatic potential, polar surface, atomic charges, hydrogen bonds, and polar and hydrophobic interactions, among others, were assessed. Together, these properties revealed important differences among the six TLR8-immunostimulant complexes, reflected as different interaction energies and therefore different electrostatic environments and binding energies. Remarkably, the interaction energy of a defined polar region composed of the highly polarized N3, N5 atoms and the N11 amino group, acted as a polar pharmacophore that correlates directly with the reported immunopharmacological potency of the six complexed molecules. Based on these results, it was concluded that accurate physicochemical analysis of the crystal binding site could reveal the binding energy (measured as interaction energy) and associated molecular mechanism of action between IMMS and TLR8. These findings may facilitate the development and design of improved small molecules with IMMS properties that are targeted to the TLR system and have enhanced pharmacological effectiveness and reduced toxicity. PMID- 28582456 TI - Detailed spatial characterization of superficial hip muscle activation during walking: A multi-electrode surface EMG investigation of the gluteal region in healthy older adults. AB - PURPOSE: A multi-electrode array was used to generate spatially resolved Surface electromyography (SEMG) data of the hip muscles in healthy older adults. The cohort was meant to serve as an age-matched, normal control population for future surgical and rehabilitative studies in patients undergoing total hip arthroplasty, in view of the large, continuously increasing number of hip joint replacements. METHODS: Bilateral hip muscle SEMG activity, including tensor fasciae latae (TFL), gluteus medius (Gmed), and gluteus maximus (Gmax), was measured during locomotion on a walkway at self-selected slow, normal, and fast walking speeds (age-matched cohort of 29 females and 25 males). Eight equally spaced, vertically oriented bipolar channels were applied on a horizontal line at mid-distance between iliac crest and greater trochanter (length 17.5 cm; named P1 to P8). Time-independent parameters (e.g., mean amplitude) were derived from the amplitude curves expressed as root mean square. RESULTS: The acquired SEMG data were not significantly influenced by gender (p = 0.202) or side (p = 0.313) and were therefore pooled. The most ventral to central electrode positions P1 to P5, representing TFL and ventral to central Gmed, showed the highest mean amplitude levels (averaged over the whole stride; 0.001 < p < 0.027 against P6 to P8; Bonferroni-adjusted paired t-test) at all walking speeds. Also, the respective curves showed two distinct amplitude peaks (representing load acceptance and hip stabilization during mid-stance), with a continuous increase of the first peak from P1 to P4 (most pronounced at fast speed) and the second peak from P1 to P3. Independently of the underlying individual muscles, both peaks displayed a continuous time shift from the most dorsal P8 to the most ventral P1 position, with the peaks for the ventral positions occurring at later time points during the normalized stride. CONCLUSIONS: The continuously changing activation patterns of the superficial muscles in the gluteal region during walking may reflect function-driven, finely tuned coordination patterns of neighboring muscles and muscle segments, rather than independent activation of anatomically defined muscles. This may be important for the definition of specific target parameters for the improvement and/or normalization of muscle function during training and post-injury rehabilitation. PMID- 28582457 TI - OGUMI-A new mobile application to conduct common-pool resource experiments in continuous time. AB - OGUMI is an Android-based open source mobile application for conducting Common Pool Resource Experiments, Choice Experiments, and Questionnaires in the field, in the laboratory, and online. A main feature of OGUMI is its capacity to capture real-time changes in human behaviour in response to a dynamically varying resource. OGUMI is simple (for example, likewise other existing software, it does not require expertise in behavioural game theory), stable, and extremely flexible with respect to the user-resource model running in the background. Here we present the motivation for the development of OGUMI and we discuss its main features with an example application. PMID- 28582458 TI - Reproducibility of up-flow column percolation tests for contaminated soils. AB - Up-flow column percolation tests are used at laboratory scale to assess the leaching behavior of hazardous substance from contaminated soils in a specific condition as a function of time. Monitoring the quality of these test results inter or within laboratory is crucial, especially if used for Environment-related legal policy or for routine testing purposes. We tested three different sandy loam type soils (Soils I, II and III) to determine the reproducibility (variability inter laboratory) of test results and to evaluate the difference in the test results within laboratory. Up-flow column percolation tests were performed following the procedure described in the ISO/TS 21268-3. This procedure consists of percolating solution (calcium chloride 1 mM) from bottom to top at a flow rate of 12 mL/h through softly compacted soil contained in a column of 5 cm diameter and 30 +/- 5 cm height. Eluate samples were collected at liquid-to-solid ratio of 0.1, 0.2, 0.5, 1, 2, 5 and 10 L/kg and analyzed for quantification of the target elements (Cu, As, Se, Cl, Ca, F, Mg, DOC and B in this research). For Soil I, 17 institutions in Japan joined this validation test. The up-flow column experiments were conducted in duplicate, after 48 h of equilibration time and at a flow rate of 12 mL/h. Column percolation test results from Soils II and III were used to evaluate the difference in test results from the experiments conducted in duplicate in a single laboratory, after 16 h of equilibration time and at a flow rate of 36 mL/h. Overall results showed good reproducibility (expressed in terms of the coefficient of variation, CV, calculated by dividing the standard deviation by the mean), as the CV was lower than 30% in more than 90% of the test results associated with Soil I. Moreover, low variability (expressed in terms of difference between the two test results divided by the mean) was observed in the test results related to Soils II and III, with a variability lower than 30% in more than 88% of the cases for Soil II and in more than 96% of the cases for Soil III. We also discussed the possible factors that affect the reproducibility and variability in the test results from the up-flow column percolation tests. The low variability inter and within laboratory obtained in this research indicates that the ISO/TS 21268-3 can be successfully upgraded to a fully validated ISO standard. PMID- 28582460 TI - Admixture mapping of pelvic organ prolapse in African Americans from the Women's Health Initiative Hormone Therapy trial. AB - Evidence suggests European American (EA) women have two- to five-fold increased odds of having pelvic organ prolapse (POP) when compared with African American (AA) women. However, the role of genetic ancestry in relation to POP risk is not clear. Here we evaluate the association between genetic ancestry and POP in AA women from the Women's Health Initiative Hormone Therapy trial. Women with grade 1 or higher classification, and grade 2 or higher classification for uterine prolapse, cystocele or rectocele at baseline or during follow-up were considered to have any POP (N = 805) and moderate/severe POP (N = 156), respectively. Women with at least two pelvic exams with no indication for POP served as controls (N = 344). We performed case-only, and case-control admixture-mapping analyses using multiple logistic regression while adjusting for age, BMI, parity and global ancestry. We evaluated the association between global ancestry and POP using multiple logistic regression. European ancestry at the individual level was not associated with POP risk. Case-only and case-control local ancestry analyses identified two ancestry-specific loci that may be associated with POP. One locus (Chromosome 15q26.2) achieved empirically-estimated statistical significance and was associated with decreased POP odds (considering grade >=2 POP) with each unit increase in European ancestry (OR: 0.35; 95% CI: 0.30, 0.57; p-value = 1.48x10 5). This region includes RGMA, a potent regulator of the BMP family of genes. The second locus (Chromosome 1q42.1-q42.3) was associated with increased POP odds with each unit increase in European ancestry (Odds ratio [OR]: 1.69; 95% confidence interval [CI]: 1.28, 2.22; p-value = 1.93x10-4). Although this region did not reach statistical significance after considering multiple comparisons, it includes potentially relevant genes including TBCE, and ACTA1. Unique non overlapping European and African ancestry-specific susceptibility loci may be associated with increased POP risk. PMID- 28582459 TI - Traumatic injury and perceived injustice: Fault attributions matter in a "no fault" compensation state. AB - BACKGROUND: Traumatic injury can lead to loss, suffering and feelings of injustice. Previous research has shown that perceived injustice is associated with poorer physical and mental wellbeing in persons with chronic pain. This study aimed to identify the relative association between injury, compensation and pain-related characteristics and perceived injustice 12-months after traumatic injury. METHODS: 433 participants were recruited from the Victorian Orthopedic Trauma Outcomes Registry and Victorian State Trauma Registry, and completed questionnaires at 12-14 months after injury as part of an observational cohort study. Using hierarchical linear regression we examined the relationships between baseline demographics (sex, age, education, comorbidities), injury (injury severity, hospital length of stay), compensation (compensation status, fault, lawyer involvement), and health outcomes (SF-12) and perceived injustice. We then examined how much additional variance in perceived injustice was related to worse pain severity, interference, self-efficacy, catastrophizing, kinesiophobia or disability. RESULTS: Only a small portion of variance in perceived injustice was related to baseline demographics (especially education level), and injury severity. Attribution of fault to another, consulting a lawyer, health-related quality of life, disability and the severity of pain-related cognitions explained the majority of variance in perceived injustice. While univariate analyses showed that compensable injury led to higher perceptions of injustice, this did not remain significant when adjusting for all other factors, including fault attribution and consulting a lawyer. CONCLUSIONS: In addition to the "justice" aspects of traumatic injury, the health impacts of injury, emotional distress related to pain (catastrophizing), and the perceived impact of pain on activity (pain self-efficacy), had stronger associations with perceptions of injustice than either injury or pain severity. To attenuate the likelihood of poor recovery from injury, clinical interventions that support restoration of health-related quality of life, and adjustment to the impacts of trauma are needed. PMID- 28582461 TI - Effects of acute physical exercise on oxidative stress and inflammatory status in young, sedentary obese subjects. AB - Circulating oxidative stress and pro-inflammatory markers change after regular physical exercise; however, how a short session of acute physical activity affects the inflammatory status and redox balance in sedentary individuals is still unclear. Aim of this study is to assess antioxidant and inflammatory parameters, both at rest and after acute exercise, in sedentary young men with or without obesity. Thirty sedentary male volunteers, aged 20-45 (mean age 32 +/- 7 years), were recruited, divided into 3 groups (normal weight: BMI < 25 kg/m2; overweight to moderate obesity: 25-35 kg/m2; severe obesity: 35-40 kg/m2), and their blood samples collected before and after a 20-min run at ~ 70% of their VO2max for the measurement of Glutathione Reductase, Glutathione Peroxidase, Superoxide Dismutase, Total Antioxidant Status (TAS) and cytokines (IL-2, IL-4, IL-6, IL-8, IL-10, IL-1alpha, IL-1beta, TNFalpha, MCP-1, VEGF, IFNgamma, EGF). Inter-group comparisons demonstrated significantly higher Glutathione Reductase activity in severely obese subjects in the post-exercise period (P = 0.036), and higher EGF levels in normal weight individuals, either before (P = 0.003) and after exercise (P = 0.05). Intra-group comparisons showed that the acute exercise stress induced a significant increase in Glutathione Reductase activity in severely obese subjects only (P = 0.007), a significant decrease in MCP-1 in the normal weight group (P = 0.02), and a decrease in EGF levels in all groups (normal weight: P = 0.025, overweight/moderate obesity: P = 0.04, severe obesity: P = 0.018). Altogether, these findings suggest that in sedentary individuals with different ranges of BMI, Glutathione Reductase and distinct cytokines are differentially involved into the adaptive metabolic changes and redox responses induced by physical exercise. Therefore, these biomarkers may have the potential to identify individuals at higher risk for developing diseases pathophysiologically linked to oxidative stress. PMID- 28582462 TI - Association between circulating fibroblast growth factor 21 and mortality in end stage renal disease. AB - Fibroblast growth factor 21 (FGF21) is an endocrine factor that regulates glucose and lipid metabolism. Circulating FGF21 predicts cardiovascular events and mortality in type 2 diabetes mellitus, including early-stage chronic kidney disease, but its impact on clinical outcomes in end-stage renal disease (ESRD) patients remains unclear. This study enrolled 90 ESRD patients receiving chronic hemodialysis who were categorized into low- and high-FGF21 groups by the median value. We investigated the association between circulating FGF21 levels and the cardiovascular event and mortality during a median follow-up period of 64 months. A Kaplan-Meier analysis showed that the mortality rate was significantly higher in the high-FGF21 group than in the low-FGF21 group (28.3% vs. 9.1%, log-rank, P = 0.034), while the rate of cardiovascular events did not significantly differ between the two groups (30.4% vs. 22.7%, log-rank, P = 0.312). In multivariable Cox models adjusted a high FGF21 level was an independent predictor of all-cause mortality (hazard ratio: 3.98; 95% confidence interval: 1.39-14.27, P = 0.009). Higher circulating FGF21 levels were associated with a high mortality rate, but not cardiovascular events in patient with ESRD, suggesting that circulating FGF21 levels serve as a predictive marker for mortality in these subjects. PMID- 28582463 TI - Drug resistance testing through remote genotyping and predicted treatment options in human immunodeficiency virus type 1 infected Tanzanian subjects failing first or second line antiretroviral therapy. AB - INTRODUCTION: Antiretroviral therapy (ART) has been successfully introduced in low-middle income countries. However an increasing rate of ART failure with resistant virus is reported. We therefore described the pattern of drug resistance mutations at antiretroviral treatment (ART) failure in a real-life Tanzanian setting using the remote genotyping procedure and thereafter predicted future treatment options using rule-based algorithm and the EuResist bioinformatics predictive engine. According to national guidelines, the default first-line regimen is tenofovir + lamivudine + efavirenz, but variations including nevirapine, stavudine or emtricitabine can be considered. If failure on first-line ART occurs, a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and boosted lopinavir or atazanavir is recommended. MATERIALS AND METHODS: Plasma was obtained from subjects with first (n = 174) or second line (n = 99) treatment failure, as defined by clinical or immunological criteria, as well as from a control group of ART naive subjects (n = 17) in Dar es Salaam, Tanzania. Amplification of the pol region was performed locally and the amplified DNA fragment was sent to Sweden for sequencing (split genotyping procedure). The therapeutic options after failure were assessed by the genotypic sensitivity score and the EuResist predictive engine. Viral load was quantified in a subset of subjects with second-line failure (n = 52). RESULTS: The HIV-1 pol region was successfully amplified from 55/174 (32%) and 28/99 (28%) subjects with first- or second-line failure, respectively, and 14/17 (82%) ART-naive individuals. HIV-1 pol sequence was obtained in 82 of these 97 cases (84.5%). Undetectable or very low (<2.6 log10 copies/10-3 L) viral load explained 19 out of 25 (76%) amplification failures in subjects at second-line ART failure. At first and second line failure, extensive accumulation of NRTI (88% and 73%, respectively) and NNRTI (93% and 73%, respectively) DRMs but a limited number of PI DRMs (11% at second line failure) was observed. First line failure subjects displayed a high degree of cross-resistance to second-generation NNRTIs etravirine (ETR; 51% intermediate and 9% resistant) and rilpivirine (RPV; 12% intermediate and 58% resistant), and to abacavir (ABC; 49% resistant) which is reserved for second line therapy in Tanzania. The predicted probability of success with the best salvage regimen at second-line failure decreased from 93.9% to 78.7% when restricting access to the NRTIs, NNRTIs and PIs currently available in Tanzania compared to when including all approved drugs. DISCUSSION: The split genotyping procedure is potential tool to analyse drug resistance in Tanzania but the sensitivity should be evaluated further. The lack of viral load monitoring likely results in a high false positive rate of treatment failures, unnecessary therapy switches and massive accumulation of NRTI and NNRTI mutations. The introduction of regular virological monitoring should be prioritized and integrated with drug resistance studies in resource limited settings. PMID- 28582464 TI - Total control of fat cells from adipogenesis to apoptosis using a xanthene analog. AB - Overcrowded adipocytes secrete excess adipokines and cytokines under stress, which results in a deregulated metabolism. This negative response to stress increases the possibility of obesity and several of its associated diseases, such as cancer and atherosclerosis. Therefore, a reduction in the number of adipocytes may be a rational strategy to relieve the undesired expansion of adipose tissue. A newly synthesized xanthene analog, MI-401, was found to have two distinct effects on the regulation of the adipocyte's life cycle. MI-401 efficiently down regulated the expression of transcription factors, PPARgamma and C/EBPalpha, and lipogenesis proteins, FAS and FABP4. This down regulation resulted in the inhibition of adipogenesis. Without newly differentiated adipocytes, the total number of adipocytes will not increase. In addition to this inhibitory effect, MI 401 was able to actively kill mature adipocytes. It specifically triggered apoptosis in adipocytes at low micro molar concentration and spared preadipocytes and fibroblasts. These dual functionalities make MI-401 an effective agent in the regulation of the birth and death of adipocytes. PMID- 28582468 TI - Correction: Plasma 1-deoxysphingolipids are early predictors of incident type 2 diabetes mellitus. AB - [This corrects the article DOI: 10.1371/journal.pone.0175776.]. PMID- 28582465 TI - Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia. AB - Glucocorticoids (GCs) and topoisomerase II inhibitors are used to treat acute lymphoblastic leukaemia (ALL) as they induce death in lymphoid cells through the glucocorticoid receptor (GR) and p53 respectively. Mechanisms underlying ALL cell death and the contribution of the bone marrow microenvironment to drug response/resistance remain unclear. The role of the microenvironment and the identification of chemoresistance determinants were studied by transcriptomic analysis in ALL cells treated with Dexamethasone (Dex), and Etoposide (Etop) grown in the presence or absence of bone marrow conditioned media (CM). The necroptotic (RIPK1) and the apoptotic (caspase-8/3) markers were downregulated by CM, whereas the inhibitory effects of chemotherapy on the autophagy marker Beclin 1 (BECN1) were reduced suggesting CM exerts cytoprotective effects. GCs upregulated the RIPK1 ubiquitinating factor BIRC3 (cIAP2), in GC-sensitive (CEM C7-14) but not in resistant (CEM-C1-15) cells. In addition, CM selectively affected GR phosphorylation in a site and cell-specific manner. GR is recruited to RIPK1, BECN1 and BIRC3 promoters in the sensitive but not in the resistant cells with phosphorylated GR forms being generally less recruited in the presence of hormone. FACS analysis and caspase-8 assays demonstrated that CM promoted a pro-survival trend. High molecular weight proteins reacting with the RIPK1 antibody were modified upon incubation with the BIRC3 inhibitor AT406 in CEM-C7 14 cells suggesting that they represent ubiquitinated forms of RIPK1. Our data suggest that there is a correlation between microenvironment-induced ALL proliferation and altered response to chemotherapy. PMID- 28582469 TI - Dynamic metabolic modeling of heterotrophic and mixotrophic microalgal growth on fermentative wastes. AB - Microalgae are promising microorganisms for the production of numerous molecules of interest, such as pigments, proteins or triglycerides that can be turned into biofuels. Heterotrophic or mixotrophic growth on fermentative wastes represents an interesting approach to achieving higher biomass concentrations, while reducing cost and improving the environmental footprint. Fermentative wastes generally consist of a blend of diverse molecules and it is thus crucial to understand microalgal metabolism in such conditions, where switching between substrates might occur. Metabolic modeling has proven to be an efficient tool for understanding metabolism and guiding the optimization of biomass or target molecule production. Here, we focused on the metabolism of Chlorella sorokiniana growing heterotrophically and mixotrophically on acetate and butyrate. The metabolism was represented by 172 metabolic reactions. The DRUM modeling framework with a mildly relaxed quasi-steady-state assumption was used to account for the switching between substrates and the presence of light. Nine experiments were used to calibrate the model and nine experiments for the validation. The model efficiently predicted the experimental data, including the transient behavior during heterotrophic, autotrophic, mixotrophic and diauxic growth. It shows that an accurate model of metabolism can now be constructed, even in dynamic conditions, with the presence of several carbon substrates. It also opens new perspectives for the heterotrophic and mixotrophic use of microalgae, especially for biofuel production from wastes. PMID- 28582467 TI - Measuring aesthetic emotions: A review of the literature and a new assessment tool. AB - Aesthetic perception and judgement are not merely cognitive processes, but also involve feelings. Therefore, the empirical study of these experiences requires conceptualization and measurement of aesthetic emotions. Despite the long standing interest in such emotions, we still lack an assessment tool to capture the broad range of emotions that occur in response to the perceived aesthetic appeal of stimuli. Elicitors of aesthetic emotions are not limited to the arts in the strict sense, but extend to design, built environments, and nature. In this article, we describe the development of a questionnaire that is applicable across many of these domains: the Aesthetic Emotions Scale (Aesthemos). Drawing on theoretical accounts of aesthetic emotions and an extensive review of extant measures of aesthetic emotions within specific domains such as music, literature, film, painting, advertisements, design, and architecture, we propose a framework for studying aesthetic emotions. The Aesthemos, which is based on this framework, contains 21 subscales with two items each, that are designed to assess the emotional signature of responses to stimuli's perceived aesthetic appeal in a highly differentiated manner. These scales cover prototypical aesthetic emotions (e.g., the feeling of beauty, being moved, fascination, and awe), epistemic emotions (e.g., interest and insight), and emotions indicative of amusement (humor and joy). In addition, the Aesthemos subscales capture both the activating (energy and vitality) and the calming (relaxation) effects of aesthetic experiences, as well as negative emotions that may contribute to aesthetic displeasure (e.g., the feeling of ugliness, boredom, and confusion). PMID- 28582466 TI - Aberrant plasma IL-7 and soluble IL-7 receptor levels indicate impaired T-cell response to IL-7 in human tuberculosis. AB - T-cell proliferation and generation of protective memory during chronic infections depend on Interleukin-7 (IL-7) availability and receptivity. Regulation of IL-7 receptor (IL-7R) expression and signalling are key for IL-7 modulated T-cell functions. Aberrant expression of soluble (s) and membrane associated (m) IL-7R molecules is associated with development of autoimmunity and immune failure in acquired immune deficiency syndrome (AIDS) patients. Here we investigated the role of IL-7/IL-7R on T-cell immunity in human tuberculosis. We performed two independent case-control studies comparing tuberculosis patients and healthy contacts. This was combined with follow-up examinations for a subgroup of tuberculosis patients under therapy and recovery. Blood plasma and T cells were characterised for IL-7/sIL-7R and mIL-7R expression, respectively. IL 7-dependent T-cell functions were determined by analysing STAT5 phosphorylation, antigen-specific cytokine release and by analysing markers of T-cell exhaustion and inflammation. Tuberculosis patients had lower soluble IL-7R (p < 0.001) and higher IL-7 (p < 0.001) plasma concentrations as compared to healthy contacts. Both markers were largely independent and aberrant expression normalised during therapy and recovery. Furthermore, tuberculosis patients had lower levels of mIL 7R in T cells caused by post-transcriptional mechanisms. Functional in vitro tests indicated diminished IL-7-induced STAT5 phosphorylation and impaired IL-7 promoted cytokine release of Mycobacterium tuberculosis-specific CD4+ T cells from tuberculosis patients. Finally, we determined T-cell exhaustion markers PD-1 and SOCS3 and detected increased SOCS3 expression during therapy. Only moderate correlation of PD-1 and SOCS3 with IL-7 expression was observed. We conclude that diminished soluble IL-7R and increased IL-7 plasma concentrations, as well as decreased membrane-associated IL-7R expression in T cells, reflect impaired T cell sensitivity to IL-7 in tuberculosis patients. These findings show similarities to pathognomonic features of impaired T-cell functions and immune failure described in AIDS patients. PMID- 28582470 TI - Estradiol upregulates voltage-gated sodium channel 1.7 in trigeminal ganglion contributing to hyperalgesia of inflamed TMJ. AB - BACKGROUND: Temporomandibular disorders (TMDs) have the highest prevalence in women of reproductive age. The role of estrogen in TMDs and especially in TMDs related pain is not fully elucidated. Voltage-gated sodium channel 1.7 (Nav1.7) plays a prominent role in pain perception and Nav1.7 in trigeminal ganglion (TG) is involved in the hyperalgesia of inflamed Temporomandibular joint (TMJ). Whether estrogen could upregulate trigeminal ganglionic Nav1.7 expression to enhance hyperalgesia of inflamed TMJ remains to be explored. METHODS: Estrous cycle and plasma levels of 17beta-estradiol in female rats were evaluated with vaginal smear and enzyme linked immunosorbent assay, respectively. Female rats were ovariectomized and treated with 17beta-estradiol at 0 MUg, 20 MUg and 80 MUg, respectively, for 10 days. TMJ inflammation was induced using complete Freund's adjuvant. Head withdrawal thresholds and food intake were measured to evaluate the TMJ nociceptive responses. The expression of Nav1.7 in TG was examined using real-time PCR and western blot. The activity of Nav1.7 promoter was examined using luciferase reporter assay. The locations of estrogen receptors (ERalpha and ERbeta), the G protein coupled estrogen receptor (GPR30), and Nav1.7 in TG were examined using immunohistofluorescence. RESULTS: Upregulation of Nav1.7 in TG and decrease in head withdrawal threshold were observed with the highest plasma 17beta-estradiol in the proestrus of female rats. Ovariectomized rats treated with 80 MUg 17beta-estradiol showed upregulation of Nav1.7 in TG and decrease in head withdrawal threshold as compared with that of the control or ovariectomized rats treated with 0 MUg or 20 MUg. Moreover, 17beta-estradiol dose dependently potentiated TMJ inflammation-induced upregulation of Nav1.7 in TG and also enhanced TMJ inflammation-induced decrease of head withdrawal threshold in ovariectomized rats. In addition, the estrogen receptor antagonist, ICI 182,780, partially blocked the 17beta-estradiol effect on Nav1.7 expression and head withdrawal threshold in ovariectomized rats. ERalpha and ERbeta, but not GPR30, were mostly co-localized with Nav1.7 in neurons in TG. In the nerve growth factor induced and ERalpha-transfected PC12 cells, 17beta-estradiol dose-dependently enhanced Nav1.7 promoter activity, whereas mutations of the estrogen response element at -1269/-1282 and -1214/-1227 in the promoter completely abolished its effect on the promoter activity. CONCLUSION: Estradiol could upregulate trigeminal ganglionic Nav1.7 expression to contribute to hyperalgesia of inflamed TMJ. PMID- 28582474 TI - Corrigendum. PMID- 28582472 TI - 18F-FDG silicon photomultiplier PET/CT: A pilot study comparing semi-quantitative measurements with standard PET/CT. AB - PURPOSE: To evaluate if the new Discovery Molecular Insights (DMI) PET/CT scanner provides equivalent results compared to the standard of care PET/CT scanners (GE Discovery 600 or GE Discovery 690) used in our clinic and to explore any possible differences in semi-quantitative measurements. METHODS: The local Institutional Review Board approved the protocol and written informed consent was obtained from each patient. Between September and November 2016, 50 patients underwent a single 18F-FDG injection and two scans: the clinical standard PET/CT followed immediately by the DMI PET/CT scan. We measured SUVmax and SUVmean of different background organs and up to four lesions per patient from data acquired using both scanners. RESULTS: DMI PET/CT identified all the 107 lesions detected by standard PET/CT scanners, as well as additional 37 areas of focal increased 18F FDG uptake. The SUVmax values for all 107 lesions ranged 1.2 to 14.6 (mean +/- SD: 2.8 +/- 2.8), higher on DMI PET/CT compared with standard of care PET/CT. The mean lesion:aortic arch SUVmax ratio and mean lesion:liver SUVmax ratio were 0.2 15.2 (mean +/- SD: 3.2 +/- 2.6) and 0.2-8.5 (mean +/- SD: 1.9 +/- 1.4) respectively, higher on DMI PET/CT than standard PET/CT. These differences were statistically significant (P value < 0.0001) and not correlated to the delay in acquisition of DMI PET data (P < 0.0001). CONCLUSIONS: Our study shows high performance of the new DMI PET/CT scanner. This may have a significant role in diagnosing and staging disease, as well as for assessing and monitoring responses to therapies. PMID- 28582471 TI - SUMO regulates p21Cip1 intracellular distribution and with p21Cip1 facilitates multiprotein complex formation in the nucleolus upon DNA damage. AB - We previously showed that p21Cip1 transits through the nucleolus on its way from the nucleus to the cytoplasm and that DNA damage inhibits this transit and induces the formation of p21Cip1-containing intranucleolar bodies (INoBs). Here, we demonstrate that these INoBs also contain SUMO-1 and UBC9, the E2 SUMO conjugating enzyme. Furthermore, whereas wild type SUMO-1 localized in INoBs, a SUMO-1 mutant, which is unable to conjugate with proteins, does not, suggesting the presence of SUMOylated proteins at INoBs. Moreover, depletion of the SUMO conjugating enzyme UBC9 or the sumo hydrolase SENP2 changed p21Cip1 intracellular distribution. In addition to SUMO-1 and p21Cip1, cell cycle regulators and DNA damage checkpoint proteins, including Cdk2, Cyclin E, PCNA, p53 and Mdm2, and PML were also detected in INoBs. Importantly, depletion of UBC9 or p21Cip1 impacted INoB biogenesis and the nucleolar accumulation of the cell cycle regulators and DNA damage checkpoint proteins following DNA damage. The impact of p21Cip1 and SUMO-1 on the accumulation of proteins in INoBs extends also to CRM1, a nuclear exportin that is also important for protein translocation from the cytoplasm to the nucleolus. Thus, SUMO and p21Cip1 regulate the transit of proteins through the nucleolus, and that disruption of nucleolar export by DNA damage induces SUMO and p21Cip1 to act as hub proteins to form a multiprotein complex in the nucleolus. PMID- 28582473 TI - Connectivity in ictal single photon emission computed tomography perfusion: a cortico-cortical evoked potential study. AB - Subtraction ictal and interictal single photon emission computed tomography can demonstrate complex ictal perfusion patterns. Regions with ictal hyperperfusion are suggested to reflect seizure onset and propagation pathways. The significance of ictal hypoperfusion is not well understood. The aim of this study was to verify whether ictal perfusion changes, both hyper- and hypoperfusion, correspond to electrically connected brain networks. A total of 36 subtraction ictal and interictal perfusion studies were analysed in 31 consecutive medically refractory focal epilepsy patients, evaluated by stereo-electroencephalography that demonstrated a single focal onset. Cortico-cortical evoked potential studies were performed after repetitive electrical stimulation of the ictal onset zone. Evoked responses at electrode contacts outside the stimulation site were used as a measure of connectivity. The evoked responses at these electrodes were compared to ictal perfusion values noted at these locations. In 67% of studies, evoked responses were significantly larger in hyperperfused compared to baseline perfused areas. The majority of hyperperfused contacts also had significantly increased evoked responses relative to pre-stimulus electroencephalogram. In contrast, baseline-perfused and hypoperfused contacts mainly demonstrated non significant evoked responses. Finally, positive significant correlations (P < 0.05) were found between perfusion scores and evoked responses in 61% of studies. When the stimulated ictal onset area was hyperperfused, 82% of studies demonstrated positive significant correlations. Following stimulation of hyperperfused areas outside seizure onset, positive significant correlations between perfusion changes and evoked responses could be seen, suggesting bidirectional connectivity. We conclude that strong connectivity was demonstrated between the ictal onset zone and hyperperfused regions, while connectivity was weaker in the direction of baseline-perfused or hypoperfused areas. In trying to understand a patient's epilepsy, one should consider the contribution of all hyperperfused regions, as these are likely not random, but represent an electrically connected epileptic network. PMID- 28582475 TI - Combined Plasma Elevation of CRP, Intestinal-Type Fatty Acid-Binding Protein (I FABP), and sCD14 Identify Older Patients at High Risk for Health Care-Associated Infections. AB - Background: We hypothesized that low-grade inflammation was driven by microbial translocation and associated with an increased risk of health care-associated infections (HAIs). Methods: We included 121 patients aged 75 years or over in this prospective cohort study. High-sensitivity C-reactive protein (hs-CRP), I FABP, and sCD14-as markers for low-grade inflammation, intestinal epithelial barrier integrity, and monocyte activation, respectively-were measured at admission. Results: HAIs occurred during hospitalization in 62 (51%) patients. Elevated hs-CRP (>=6.02 mg/L, ie, the median) was associated with a significantly higher HAI risk when I-FABP was in the highest quartile (odds ratio [OR], 4; 95% confidence interval [95% CI], 1.39-11.49; p = .010). In patients with hs-CRP elevation and highest-quartile I-FABP, sCD14 elevation (>=0.65 ug/mL, ie, the median) was associated with an 11-fold higher HAI risk (OR, 10.8; 95% CI, 2.28 51.1; p = .003). Multivariate analyses adjusted for invasive procedures and comorbidities did not change the associations linking the three markers to the HAI risk. Conclusion: Increased levels of hs-CRP, I-FABP, and sCD14 may reflect loss of intestinal epithelial barrier integrity with microbial translocation leading to monocyte activation and low-grade inflammation. In our cohort, these markers identified patients at high risk for HAIs. PMID- 28582476 TI - Capgras syndrome: neuroanatomical assessment of brain MRI findings in an adolescent patient. PMID- 28582477 TI - Gingival fibroblasts protect against experimental abdominal aortic aneurysm development and rupture through tissue inhibitor of metalloproteinase-1 production. AB - Aims: Abdominal aortic aneurysm (AAA), frequently diagnosed in old patients, is characterized by chronic inflammation, vascular cell apoptosis and metalloproteinase-mediated extracellular matrix destruction. Despite improvement in the understanding of the pathophysiology of aortic aneurysm, no pharmacological treatment is yet available to limit dilatation and/or rupture. We previously reported that human gingival fibroblasts (GFs) can reduce carotid artery dilatation in a rabbit model of elastase-induced aneurysm. Here, we sought to investigate the mechanisms of GF-mediated vascular protection in two different models of aortic aneurysm growth and rupture in mice. Methods and results: In vitro, mouse GFs proliferated and produced large amounts of anti-inflammatory cytokines and tissue inhibitor of metalloproteinase-1 (Timp-1). GFs deposited on the adventitia of abdominal aorta survived, proliferated, and organized as a layer structure. Furthermore, GFs locally produced Il-10, TGF-beta, and Timp-1. In a mouse elastase-induced AAA model, GFs prevented both macrophage and lymphocyte accumulations, matrix degradation, and aneurysm growth. In an Angiotensin II/anti-TGF-beta model of aneurysm rupture, GF cell-based treatment limited the extent of aortic dissection, prevented abdominal aortic rupture, and increased survival. Specific deletion of Timp-1 in GFs abolished the beneficial effect of cell therapy in both AAA mouse models. Conclusions: GF cell-based therapy is a promising approach to inhibit aneurysm progression and rupture through local production of Timp-1. PMID- 28582478 TI - Model-based branching point detection in single-cell data by K-branches clustering. AB - Motivation: The identification of heterogeneities in cell populations by utilizing single-cell technologies such as single-cell RNA-Seq, enables inference of cellular development and lineage trees. Several methods have been proposed for such inference from high-dimensional single-cell data. They typically assign each cell to a branch in a differentiation trajectory. However, they commonly assume specific geometries such as tree-like developmental hierarchies and lack statistically sound methods to decide on the number of branching events. Results: We present K-Branches, a solution to the above problem by locally fitting half lines to single-cell data, introducing a clustering algorithm similar to K-Means. These halflines are proxies for branches in the differentiation trajectory of cells. We propose a modified version of the GAP statistic for model selection, in order to decide on the number of lines that best describe the data locally. In this manner, we identify the location and number of subgroups of cells that are associated with branching events and full differentiation, respectively. We evaluate the performance of our method on single-cell RNA-Seq data describing the differentiation of myeloid progenitors during hematopoiesis, single-cell qPCR data of mouse blastocyst development, single-cell qPCR data of human myeloid monocytic leukemia and artificial data. Availability and implementation: An R implementation of K-Branches is freely available at https://github.com/theislab/kbranches. Contact: fabian.theis@helmholtz muenchen.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28582480 TI - PASTASpark: multiple sequence alignment meets Big Data. AB - Motivation: One basic step in many bioinformatics analyses is the multiple sequence alignment. One of the state-of-the-art tools to perform multiple sequence alignment is PASTA (Practical Alignments using SATe and TrAnsitivity). PASTA supports multithreading but it is limited to process datasets on shared memory systems. In this work we introduce PASTASpark, a tool that uses the Big Data engine Apache Spark to boost the performance of the alignment phase of PASTA, which is the most expensive task in terms of time consumption. Results: Speedups up to 10* with respect to single-threaded PASTA were observed, which allows to process an ultra-large dataset of 200 000 sequences within the 24-h limit. Availability and implementation: PASTASpark is an Open Source tool available at https://github.com/citiususc/pastaspark. Contact: josemanuel.abuin@usc.es. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28582479 TI - Restless 'rest': intrinsic sensory hyperactivity and disinhibition in post traumatic stress disorder. AB - Post-traumatic stress disorder is characterized by exaggerated threat response, and theoretical accounts to date have focused on impaired threat processing and dysregulated prefrontal-cortex-amygdala circuitry. Nevertheless, evidence is accruing for broad, threat-neutral sensory hyperactivity in post-traumatic stress disorder. As low-level, sensory processing impacts higher-order operations, such sensory anomalies can contribute to widespread dysfunctions, presenting an additional aetiological mechanism for post-traumatic stress disorder. To elucidate a sensory pathology of post-traumatic stress disorder, we examined intrinsic visual cortical activity (based on posterior alpha oscillations) and bottom-up sensory-driven causal connectivity (Granger causality in the alpha band) during a resting state (eyes open) and a passive, serial picture viewing state. Compared to patients with generalized anxiety disorder (n = 24) and healthy control subjects (n = 20), patients with post-traumatic stress disorder (n = 25) demonstrated intrinsic sensory hyperactivity (suppressed posterior alpha power, source-localized to the visual cortex-cuneus and precuneus) and bottom-up inhibition deficits (reduced posterior->frontal Granger causality). As sensory input increased from resting to passive picture viewing, patients with post traumatic stress disorder failed to demonstrate alpha adaptation, highlighting a rigid, set mode of sensory hyperactivity. Interestingly, patients with post traumatic stress disorder also showed heightened frontal processing (augmented frontal gamma power, source-localized to the superior frontal gyrus and dorsal cingulate cortex), accompanied by attenuated top-down inhibition (reduced frontal >posterior causality). Importantly, not only did suppressed alpha power and bottom-up causality correlate with heightened frontal gamma power, they also correlated with increased severity of sensory and executive dysfunctions (i.e. hypervigilance and impulse control deficits, respectively). Therefore, sensory aberrations help construct a vicious cycle in post-traumatic stress disorder that is in action even at rest, implicating dysregulated triangular sensory-prefrontal cortex-amygdala circuitry: intrinsic sensory hyperactivity and disinhibition give rise to frontal overload and disrupt executive control, fuelling and perpetuating post-traumatic stress disorder symptoms. Absent in generalized anxiety disorder, these aberrations highlight a unique sensory pathology of post-traumatic stress disorder (ruling out effects merely reflecting anxious hyperarousal), motivating new interventions targeting sensory processing and the sensory brain in these patients. PMID- 28582481 TI - FunGAP: Fungal Genome Annotation Pipeline using evidence-based gene model evaluation. AB - Motivation: Successful genome analysis depends on the quality of gene prediction. Although fungal genome sequencing and assembly have become trivial, its annotation procedure has not been standardized yet. Results: FunGAP predicts protein-coding genes in a fungal genome assembly. To attain high-quality gene models, this program runs multiple gene predictors, evaluates all predicted genes, and assembles gene models that are highly supported by homology to known sequences. To do this, we built a scoring function to estimate the congruency of each gene model based on known protein or domain homology. Availability and implementation: FunGAP is written in Python script and is available in GitHub ( https://github.com/CompSynBioLab-KoreaUniv/FunGAP ). This software is freely available only for noncommercial users. Contact: igchoi@korea.ac.kr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28582482 TI - Fusobacterium and colorectal cancer: causal factor or passenger? Results from a large colorectal cancer screening study. AB - Colorectal cancer is a leading cause of morbidity and mortality worldwide in both men and women. The gut microbiome is increasingly recognized as having an important role in human health and disease. Fusobacterium has been identified in former studies as a leading gut bacterium associated with colorectal cancer, but it is still not clear if it plays an oncogenic role. In the current study, fecal samples were collected prior to bowel preparation from participants of screening colonoscopy in the German BliTz study. Using 16S rRNA gene analysis, we examined the presence and relative abundance of Fusobacterium in fecal samples from 500 participants, including 46, 113, 110 and 231 individuals with colorectal cancer, advanced adenomas, non-advanced adenomas and without any neoplasms, respectively. We found that the abundance of Fusobacterium in feces was strongly associated with the presence of colorectal cancer (P-value < 0.0001). This was confirmed by PCR at the species level for Fusobacterium nucleatum. However, no association was seen with the presence of advanced adenomas (P-value = 0.80) or non-advanced adenomas (P-value = 0.80), nor were there any associations observed with dietary or lifestyle habits. Although a causal role cannot be ruled out, our observations, based on fecal microbiome, support the hypothesis that Fusobacterium is a passenger that multiplies in the more favorable conditions caused by the malignant tumor rather than a causal factor in colorectal cancer development. PMID- 28582483 TI - Rare GCH1 heterozygous variants contributing to Parkinson's disease. PMID- 28582484 TI - Comparison of Three Methods for Measuring Workload in Surgical Pathology and Cytopathology. AB - Objectives: Pathologist workload in the United States has traditionally been measured by relative value units (RVUs), which is often criticized for providing an inaccurate estimate of actual work. This study compares three methods for measuring workload. Methods: Surgical pathology and cytopathology workload for 1 representative month at Stanford Health Care was assessed using three different methods: RVUs, Royal College of Pathologists (RCP) point system, and University of Washington-Seattle (UW) slide count method. Results: Pearson linear regression analysis showed a strong positive correlation of RVUs with the RCP (0.93, P < .01) and UW (0.86, P < .01) systems. The correlation between the RCP and UW systems was weaker (0.70, P = .05). The RCP system rated gastrointestinal, genitourinary, and breast workload lower than the RVU system while medical liver/renal and cytology were valued higher. The UW system overvalued breast workload. Conclusions: RCP is the most advanced and well-developed system for evaluating workload. It provides more weight for higher complexity specimens, while RVUs favor specialties with higher volume of small specimens, and slide counts favor specialties with extensively sampled large specimens. PMID- 28582485 TI - COMPASS: the COMPletely Arbitrary Sequence Simulator. AB - Summary: Simulated sequence alignments are frequently used to test bioinformatics tools, but current sequence simulators are limited to defined state spaces. Here, we present the COMPletely Arbitrary Sequence Simulator (COMPASS), which is able to simulate the evolution of absolutely any discrete state space along a tree, for any form of time-reversible model. Availability and implementation: COMPASS is implemented in Python 2.7, and is freely available for all platforms with the Supplementary Information, as well as at http://labs.carleton.ca/eme/software-and data. Contact: alex_wong@carleton.ca. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28582487 TI - Reply: Capgras syndrome: neuroanatomical assessment of brain MRI findings in an adolescent patient. PMID- 28582486 TI - JDINAC: joint density-based non-parametric differential interaction network analysis and classification using high-dimensional sparse omics data. AB - Motivation: A complex disease is usually driven by a number of genes interwoven into networks, rather than a single gene product. Network comparison or differential network analysis has become an important means of revealing the underlying mechanism of pathogenesis and identifying clinical biomarkers for disease classification. Most studies, however, are limited to network correlations that mainly capture the linear relationship among genes, or rely on the assumption of a parametric probability distribution of gene measurements. They are restrictive in real application. Results: We propose a new Joint density based non-parametric Differential Interaction Network Analysis and Classification (JDINAC) method to identify differential interaction patterns of network activation between two groups. At the same time, JDINAC uses the network biomarkers to build a classification model. The novelty of JDINAC lies in its potential to capture non-linear relations between molecular interactions using high-dimensional sparse data as well as to adjust confounding factors, without the need of the assumption of a parametric probability distribution of gene measurements. Simulation studies demonstrate that JDINAC provides more accurate differential network estimation and lower classification error than that achieved by other state-of-the-art methods. We apply JDINAC to a Breast Invasive Carcinoma dataset, which includes 114 patients who have both tumor and matched normal samples. The hub genes and differential interaction patterns identified were consistent with existing experimental studies. Furthermore, JDINAC discriminated the tumor and normal sample with high accuracy by virtue of the identified biomarkers. JDINAC provides a general framework for feature selection and classification using high-dimensional sparse omics data. Availability and implementation: R scripts available at https://github.com/jijiadong/JDINAC. Contact: lxie@iscb.org. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28582488 TI - Treatment Outcomes of Mycobacterium avium Complex Lung Disease: A Systematic Review and Meta-analysis. AB - Background: The advent of macrolides has led to therapeutic advances in the treatment of Mycobacterium avium complex lung disease (MAC-LD). The aim of this study was to elucidate the treatment outcomes of macrolide-containing regimens. Methods: We performed a systematic review and meta-analysis of published studies reporting treatment outcomes of macrolide-containing regimens for MAC-LD using the Medline, Embase, and Cochrane Library databases through 31 July 2016. The rates of treatment success, default from treatment, and adverse events of macrolide-containing regimens were assessed. Treatment success was defined as either 12 months of sustained culture negativity while on therapy or achievement of culture conversion and completion of the planned treatment without relapse. Results: In total, 16 studies involving 1462 patients were included. The rate of treatment success was 60.0% (95% confidence interval [CI], 55.1%-64.8%). The proportion of patients who defaulted from the treatment was 16.0% (95% CI, 12.3% 19.7%). When a thrice-weekly dosing schedule was available, the default rate was 12.0% (95% CI, 8.9%-15.0%). Adverse events necessitating treatment discontinuation or dosage modification of macrolides were observed in 6.4% of patients (95% CI, 3.2%-9.5%), and decreased auditory acuity was the most common adverse event. Conclusions: Treatment outcomes of macrolide-containing regimens are relatively poor in terms of both the treatment success and default rates. The default rate could be reduced if a thrice-weekly dosing schedule is available. Clinicians should be aware of decreased auditory function as the most common adverse event associated with macrolide-containing regimens. PMID- 28582489 TI - Pathway engineering for the production of heterologous aromatic chemicals and their derivatives in Saccharomyces cerevisiae: bioconversion from glucose. AB - Saccharomyces cerevisiae has been extensively engineered for optimising its performance as a microbial cell factory to produce valuable aromatic compounds and their derivatives as bulk and fine chemicals. The production of heterologous aromatic molecules in yeast is achieved via engineering of the aromatic amino acid biosynthetic pathway. This pathway is connected to two pathways of the central carbon metabolism, and is highly regulated at the gene and protein level. These characteristics impose several challenges for tailoring it, and various modifications need to be applied in order to redirect the carbon flux towards the production of the desired compounds. This minireview addresses the metabolic engineering approaches targeting the central carbon metabolism, the shikimate pathway and the tyrosine and phenylalanine biosynthetic pathway of S. cerevisiae for biosynthesis of aromatic chemicals and their derivatives from glucose. PMID- 28582490 TI - Impact of minimally invasive extracorporeal circuits on octogenarians undergoing coronary artery bypass grafting. Have we been looking in the wrong direction? AB - OBJECTIVES: Minimally invasive extracorporeal circuits (MiECCs) aim at the preservation of physiologic reserves, the impact of which is expected to be most evident in patients in whom these are depleted. In this context, octogenarians present a subpopulation of specific interest. METHODS: Based on the type of the utilized ECC, we performed a retrospective comparison between all octogenarians (n = 324) who received a primary coronary artery bypass in our institution from 2003 until 2010. RESULTS: An MiECC was used in 52% of patients. Preoperative variables showed that the MiECC patients were older (83 +/- 2 vs 82 +/- 2 years; P = 0.001), had higher incidence of renal dysfunction (8% vs 3%; P = 0.04), moderately reduced left ventricular function (43 vs 33%; P = 0.07) and lower incidence of unstable angina (20% vs 28%; P = 0.06). To overcome these differences, a propensity score matching was performed and yielded 126 matched pairs of patients. The overall transfusion of packed red blood cells (2.3 +/- 2.3 vs 3.4 +/- 3.2 units per patint; P = <0.001), the rate of low cardiac output (0% vs 6%; P = 0.01) and the 30-day postoperative mortality (2.4% vs 9.5%; P = 0.02) were all in favour of the MiECC group in the matched patient population. CONCLUSIONS: The MiECC concept has shown its benefits regarding both morbidity and mortality in this high-risk patient population. We believe that this beneficial effect finds its reason in a better preservation of physiologic reserves that are essential for a positive outcome in this patient group. PMID- 28582491 TI - Role of Cell-Intrinsic and Environmental Age-Related Changes in Altered Maintenance of Murine T Cells in Lymphoid Organs. AB - Age-related changes in primary lymphoid organs are well described. Less is known about age-related changes affecting peripheral lymphoid organs, although defects in old peripheral lymph nodes (pLNs) were recently described in both steady state and during viral infection. To address whether such pLN defects were intrinsic to old T cells or extrinsic (due to aging microenvironment), we employed heterochronic parabiosis. We found no age-related intrinsic or extrinsic barriers to T cell circulation and seeding of pLN, spleen, and bone marrow. However, heterochronic parabiosis failed to improve cellularity of old pLN, suggesting an environment-based limit on pLN cellularity. Furthermore, upon parabiosis, pLN of the adult partner exhibited reduced, old-like stromal and T cell cellularity, which was restored following separation of parabionts. Decay measurement of adult and old T cell subsets following separation of heterochronic parabionts delineated both T cell-intrinsic and environmental changes in T cell maintenance. Moreover, parabiotic separation revealed differences between CD4 and CD8 T cell subset maintenance with aging, the basis of which will require further investigation. Reasons for this asymmetric and subset-specific pattern of differential maintenance are discussed in light of possible age-related changes in lymph nodes as the key sites for peripheral T cell maintenance. PMID- 28582493 TI - New yeasts-new brews: modern approaches to brewing yeast design and development. AB - The brewing industry is experiencing a period of change and experimentation largely driven by customer demand for product diversity. This has coincided with a greater appreciation of the role of yeast in determining the character of beer and the widespread availability of powerful tools for yeast research. Genome analysis in particular has helped clarify the processes leading to domestication of brewing yeast and has identified domestication signatures that may be exploited for further yeast development. The functional properties of non conventional yeast (both Saccharomyces and non-Saccharomyces) are being assessed with a view to creating beers with new flavours as well as producing flavoursome non-alcoholic beers. The discovery of the psychrotolerant S. eubayanus has stimulated research on de novo S. cerevisiae * S. eubayanus hybrids for low temperature lager brewing and has led to renewed interest in the functional importance of hybrid organisms and the mechanisms that determine hybrid genome function and stability. The greater diversity of yeast that can be applied in brewing, along with an improved understanding of yeasts' evolutionary history and biology, is expected to have a significant and direct impact on the brewing industry, with potential for improved brewing efficiency, product diversity and, above all, customer satisfaction. PMID- 28582494 TI - Engineering of Saccharomyces cerevisiae for the efficient co-utilization of glucose and xylose. AB - The rapid co-fermentation of both glucose and xylose is important for the efficient conversion of lignocellulose biomass into fuels and chemicals. Saccharomyces cerevisiae is considered to be a potential cell factory and has been used to produce various fuels and chemicals, but it cannot metabolize xylose, which has greatly limited the utilization of lignocellulose materials. Therefore, numerous studies have attempted to develop xylose fermenting strains in past decades. The simple introduction of the xylose metabolic pathway does not enable yeast to rapidly utilize xylose, and several limitations still need to be addressed, including glucose repression and slow xylose transport, cofactor imbalance in the xylose reductase/xylitol dehydrogenase pathway, functional expression of a heterologous xylose isomerase, the low efficiency of downstream pathways and low ethanol production. In this review, we will discuss strategies to overcome these limitations and the recent progress in engineering xylose fermenting S. cerevisiae strains. PMID- 28582492 TI - Genome-scale identification of microRNA-related SNPs associated with risk of head and neck squamous cell carcinoma. AB - Polymorphisms in microRNAs and their target sites can disrupt microRNA-dependent gene regulation, and have been associated with cancer susceptibility. However, genome-scale analyses of microRNA-related genetic variation in cancer are lacking. We tested the associations of ~40 000 common [minor allele frequency (MAF) >=5%], microRNA-related single nucleotide polymorphisms (miR-SNPs), with risk of head and neck squamous cell carcinoma (HNSCC) in a discovery population, and validated selected loci in an independent population among a total of 2198 cases and 2180 controls. Joint analyses across the discovery and validation populations revealed six novel miR-SNP associations with risk of HNSCC. An upstream variant of MIR548H4 (rs7834169), replicated its association with overall HNSCC risk as well as risk of oral cavity cancer. Four other variants were specifically associated with oral cavity cancer risk (rs16914640, rs1134367, rs7306991 and rs1373756). 3'UTR variant of HADH, rs221347 and rs4975616, located within known cancer risk locus 5p15.33, were specific to risk of laryngeal cancer. High confidence predicted microRNA binding sites were identified for CLEC2D, LOC37443, KDM8 and HADH overlapping rs16914640, rs7306991, rs1134367 and rs221347, respectively. Furthermore, we identified several microRNA interactions with KDM8 and HADH predicted to be disrupted by genetic variation at rs1134367 and rs221347. These results suggest microRNA-related genetic variation may contribute to the genetic susceptibility of HNSCC, and that more powerful evaluation of this class of genetic variation and their relationship with cancer risk is warranted. PMID- 28582495 TI - Burden of Chlamydia trachomatis in India: a systematic literature review. AB - Chlamydia trachomatis (hereafter CT) is Gram-negative, obligate intracellular pathogen. It causes the world's most common non-viral sexually transmitted disease. India is home to the world's greatest burden of infectious diseases, yet information on prevalence rates of CT is scarce. This article systematically reviews the literature for the prevalence rates and testing methods in India. A total of 27 studies were included. Four main patients groups (symptomatic women, infertile women, pregnant women and asymptomatic population groups) could be identified with varying rates of CT (0.1%-32% using PCR, 2.4%-75% using ELISA serology). Most of the studies originated from urban settings, 11 of them from New Delhi. In-house PCR was the most common diagnostic technique used generating the following ranges in prevalence for the four group studies: symptomatic women 10%-50%, pregnant women 0.1%-2.5% and asymptomatic populations 0.9%-24.5%. The rates among infertile women were 9%-68% based on serology results. The prevalence rates featured in this paper are in line with other locations across the Indian subcontinent. This review highlights the extreme heterogeneity in the limited studies available in India on CT and the need for standardized guidelines for diagnosis and management of CT in India. The availability of resources should be considered in the formulation of recommendations. PMID- 28582496 TI - Vaginal Candida spp. genomes from women with vulvovaginal candidiasis. AB - Candida albicans is the predominant cause of vulvovaginal candidiasis (VVC). Little is known regarding the genetic diversity of Candida spp. in the vagina or the microvariations in strains over time that may contribute to the development of VVC. This study reports the draft genome sequences of four C. albicans and one C. glabrata strains isolated from women with VVC. An SNP-based whole-genome phylogeny indicates that these isolates are closely related; however, phylogenetic distances between them suggest that there may be genetic adaptations driven by unique host environments. These sequences will facilitate further comparative analyses and ultimately improve our understanding of genetic variation in isolates of Candida spp. that are associated with VVC. PMID- 28582497 TI - Protective Role of Complement C3 Against Cytokine-Mediated beta-Cell Apoptosis. AB - Type 1 diabetes is a chronic autoimmune disease characterized by pancreatic islet inflammation and beta-cell destruction by proinflammatory cytokines and other mediators. Based on RNA sequencing and protein-protein interaction analyses of human islets exposed to proinflammatory cytokines, we identified complement C3 as a hub for some of the effects of cytokines. The proinflammatory cytokines interleukin-1beta plus interferon-gamma increase C3 expression in rodent and human pancreatic beta-cells, and C3 is detected by histology in and around the islets of diabetic patients. Surprisingly, C3 silencing exacerbates apoptosis under both basal condition and following exposure to cytokines, and it increases chemokine expression upon cytokine treatment. C3 exerts its prosurvival effects via AKT activation and c-Jun N-terminal kinase inhibition. Exogenously added C3 also protects against cytokine-induced beta-cell death and partially rescues the deleterious effects of inhibition of endogenous C3. These data suggest that locally produced C3 is an important prosurvival mechanism in pancreatic beta cells under a proinflammatory assault. PMID- 28582500 TI - Comparison of epicardial vs. endocardial reimplantation in pacemaker-dependent patients with device infection. AB - Aims: Reimplantation of cardiac implantable electronic devices (CIEDs) after extraction due to device infection is a major issue in pacemaker-dependent patients. We compared in-hospital and long-term outcomes with two techniques: epicardial reimplantation (EPI) before CIED extraction and temporary pacing (TP) with a view to delayed endocardial reimplantation. Methods and results: Two cohorts of consecutive pacemaker-dependent patients who underwent transvenous lead extraction at our tertiary centre were included in this retrospective cohort study. According to successive policies, either the EPI or the TP approach was used. In-hospital complications occurred at similar rates in the EPI (n = 59) and TP (n = 52) cohorts (37.3% vs. 32.7%, respectively; P = 0.61). Thirteen (25.0%) patients in the TP cohort eventually were reimplanted epicardially, mainly because of infection of the temporary lead. Finally, 65 patients were discharged with an epicardial device and 37 with an endocardial device. Median follow-up was 41.7 (interquartile range 34.1-51.5) months. No difference was observed in long term mortality according to the reimplantation strategy, but use of TP was associated with a reduced risk of late endocarditis and device reintervention (hazard ratio (HR) 0.25, 95% confidence interval (CI) 0.09-0.069, P = 0.01), whereas epicardial device reimplantation was associated with an increased risk (HR 3.62, 95% CI 1.07-12.21, P = 0.04). Conclusion: We observed similar in hospital outcomes in our EPI and TP cohorts. Twenty-five percent of the patients initially paced by a TP strategy finally needed an epicardial device, mainly because of infection of their TP lead. Use of TP resulted in lower rates of late endocarditis and device reintervention. PMID- 28582499 TI - Dental pulp stem cells for the study of neurogenetic disorders. AB - Dental pulp stem cells (DPSC) are a relatively new alternative stem cell source for the study of neurogenetic disorders. DPSC can be obtained non-invasively and collected from long-distances remaining viable during transportation. These highly proliferative cells express stem cell markers and retain the ability to differentiate down multiple cell lineages including chondrocytes, adipocytes, osteoblasts, and multiple neuronal cell types. The neural crest origin of DPSC makes them a useful source of primary cells for modeling neurological disorders at the molecular level. In this brief review, we will discuss recent developments in DPSC research that highlight the molecular etiology of DPSC derived neurons and how they may contribute to our understanding of neurogenetic disorders. PMID- 28582498 TI - Designing microorganisms for heterologous biosynthesis of cannabinoids. AB - During the last decade, the use of medical Cannabis has expanded globally and legislation is getting more liberal in many countries, facilitating the research on cannabinoids. The unique interaction of cannabinoids with the human endocannabinoid system makes these compounds an interesting target to be studied as therapeutic agents for the treatment of several medical conditions. However, currently there are important limitations in the study, production and use of cannabinoids as pharmaceutical drugs. Besides the main constituent tetrahydrocannabinolic acid, the structurally related compound cannabidiol is of high interest as drug candidate. From the more than 100 known cannabinoids reported, most can only be extracted in very low amounts and their pharmacological profile has not been determined. Today, cannabinoids are isolated from the strictly regulated Cannabis plant, and the supply of compounds with sufficient quality is a major problem. Biotechnological production could be an attractive alternative mode of production. Herein, we explore the potential use of synthetic biology as an alternative strategy for synthesis of cannabinoids in heterologous hosts. We summarize the current knowledge surrounding cannabinoids biosynthesis and present a comprehensive description of the key steps of the genuine and artificial pathway, systems biotechnology needs and platform optimization. PMID- 28582501 TI - What do the pictures say-snapshots of a career. AB - What follows are snapshots of my career in chicken eyes, yeast and Rhodospirillum rubrum, castor beans, Escherichia coli and finally yeast again. In contrast, only a few of the failures that realistically make up a career are included. It is a tale of the generosity and influences of those who shaped what I am and what I learned in a wonderful profession. The science described is only that which I was lucky enough to do or was performed in my laboratory by those who really deserve the credit for any success that I've enjoyed. Not mentioned for lack of space are the critical contributions of many impressive investigators in the field of nitrogen-responsive regulation for no scientific investigation occurs in isolation. PMID- 28582502 TI - A case of removal of a "dancing" Micra. PMID- 28582503 TI - HUGIn: Hi-C Unifying Genomic Interrogator. AB - Motivation: High throughput chromatin conformation capture (3C) technologies, such as Hi-C and ChIA-PET, have the potential to elucidate the functional roles of non-coding variants. However, most of published genome-wide unbiased chromatin organization studies have used cultured cell lines, limiting their generalizability. Results: We developed a web browser, HUGIn, to visualize Hi-C data generated from 21 human primary tissues and cell lines. HUGIn enables assessment of chromatin contacts both constitutive across and specific to tissue(s) and/or cell line(s) at any genomic loci, including GWAS SNPs, eQTLs and cis-regulatory elements, facilitating the understanding of both GWAS and eQTL results and functional genomics data. Availability and implementation: HUGIn is available at http://yunliweb.its.unc.edu/HUGIn. Contact: yunli@med.unc.edu or hum@ccf.org. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28582504 TI - Cytochrome P450 enzyme RosC catalyzes a multistep oxidation reaction to form the non-active compound 20-carboxyrosamicin. AB - The cytochrome P450 enzyme RosC catalyzes a two-step, hydroxylation and alcohol oxidation, oxidation reaction to form the C-20 formyl group in the biosynthesis of a 16-membered macrolide antibiotic rosamicin produced by Micromonospora rosaria IFO13697. RosC is presumed to be involved in the formation of 20 carboxyrosamicin because it has been isolated from the culture broth of M. rosaria. Here, we confirmed that RosC has catalytic activity, with E. coli expressing RosC converting rosamicin into 20-carboxyrosamicin. Therefore, it was revealed that RosC is a multifunctional P450 that catalyzes a three-step oxidation reaction that leads to the formation of the hydroxyl group, formyl group and carboxyl group at C-20 on the macrolactone ring in the rosamicin biosynthetic pathway. Moreover, the cytochrome P450 enzyme TylI, which is involved in formation of the formyl group of a 16-membered macrolide antibiotic tylosin produced by Streptomyces fradiae ATCC 19609, also converted rosamicin into 20-carboxyrosamicin. PMID- 28582505 TI - Subclinical Cardiovascular Disease and Changes in Self-Reported Mobility: Multi Ethnic Study of Atherosclerosis. AB - Background: We examined associations of three markers of subclinical cardiovascular disease (intimal-medial thickening, coronary artery calcification , and ankle-brachial index) with changes in self-reported walking over time. Methods: Data were from 6,490 Multi-Ethnic Study of Atherosclerosis participants (aged 45-84 years), free of clinical cardiovascular disease at baseline. Outcomes, assessed four times over 11 years, included self-reported walking pace (none to striding pace; score, 0-4) and total walking time (minutes/week). Linear generalized estimating equation models estimated associations of baseline intimal medial thickening (z-scored), coronary artery calcification (Agatston units), and ankle-brachial index (ratio of ankle-to-arm systolic blood pressure) with walking pace and walking time modeled continuously in separate analyses. Results: Median follow-up was 9.2 years (maximum, 11.4). Walking pace (estimate, -0.042 points [95% CI; -0.048, -0.036], p < 0.0001) and walking time (estimate, -4.71 minutes [95% CI: -8.54, -0.88], p = 0.016) decreased yearly. Greater baseline intimal medial thickening related to faster decline in walking pace in multivariable analyses: walking pace score decreased 0.004 points (95% CI: -0.008, -0.001) more per year for each 1-SD higher intimal-medial thickening z-score, equivalent to an additional 10% slower yearly walking. Greater coronary artery calcification was associated with slower walking but inconsistently related to decline in walking pace. Higher ankle-brachial index was associated with faster baseline walking pace (estimate, 0.043 points [95% CI: 0.027, 0.059] per 1-SD) but unrelated to changes in walking pace. Cardiovascular disease measures were unrelated to total walking time. Conclusions: Greater subclinical cardiovascular disease is associated with prevalent slower self-reported walking pace in middle-aged and older adults but has limited impact on changes in walking over time. PMID- 28582507 TI - Variation in the reproductive strategy of a lichenized fungus along a climatic gradient. AB - Background and aims: Onset of reproduction and reproductive allocation patterns are key components of plant reproductive strategies. Life history theory predicts that plants in adverse environments for juvenile performance start reproduction at smaller sizes and exhibit higher reproductive allocation compared to their counterparts in favourable environments. Life history theory will gain in generality if its predictions are shown to apply to a broad range of organisms and modes of reproduction. This study tested whether the asexual reproductive strategy of a lichenized fungus changed along a climatic gradient. Methods: The variation in threshold size for asexual reproduction and asexual reproductive allocation of the lichen Lobarina scrobiculata was assessed in 18 populations (9665 individuals) along a climatic gradient spanning 800 km in latitude in Southern Europe. Using generalized linear models and standardized major axis regressions, the allometric relationships and the associated variation in climatic factors according to the changes in the threshold size for reproduction and reproductive allocation patterns were assessed. Key Results: The onset of reproduction was size-dependent and the reproductive allocation increased with individual size. Both the threshold size for reproduction and the reproductive allocation varied along the rainfall gradient. A lower threshold size for reproduction and higher reproductive allocation in drier, adverse locations were found. Therefore, populations in drier locations fitted the predictions of life history theory for sexually reproducing organisms in adverse environments for juvenile performance. Conclusions: This study highlights the applicability of the life history theory to fungi and to modes of reproduction other than sexual reproduction. Based on the intraspecific variation in the asexual reproductive strategy of a fungal organism with climatic factors, these findings expand the scope of life history theory predictions and increase our understanding of life history diversity and reproductive strategies across environments. PMID- 28582506 TI - Glycan Reader is improved to recognize most sugar types and chemical modifications in the Protein Data Bank. AB - Motivation: Glycans play a central role in many essential biological processes. Glycan Reader was originally developed to simplify the reading of Protein Data Bank (PDB) files containing glycans through the automatic detection and annotation of sugars and glycosidic linkages between sugar units and to proteins, all based on atomic coordinates and connectivity information. Carbohydrates can have various chemical modifications at different positions, making their chemical space much diverse. Unfortunately, current PDB files do not provide exact annotations for most carbohydrate derivatives and more than 50% of PDB glycan chains have at least one carbohydrate derivative that could not be correctly recognized by the original Glycan Reader. Results: Glycan Reader has been improved and now identifies most sugar types and chemical modifications (including various glycolipids) in the PDB, and both PDB and PDBx/mmCIF formats are supported. CHARMM-GUI Glycan Reader is updated to generate the simulation system and input of various glycoconjugates with most sugar types and chemical modifications. It also offers a new functionality to edit the glycan structures through addition/deletion/modification of glycosylation types, sugar types, chemical modifications, glycosidic linkages, and anomeric states. The simulation system and input files can be used for CHARMM, NAMD, GROMACS, AMBER, GENESIS, LAMMPS, Desmond, OpenMM, and CHARMM/OpenMM. Glycan Fragment Database in GlycanStructure.Org is also updated to provide an intuitive glycan sequence search tool for complex glycan structures with various chemical modifications in the PDB. Availability and implementation: http://www.charmm-gui.org/input/glycan and http://www.glycanstructure.org. Contact: wonpil@lehigh.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28582509 TI - High decay of blood HIV reservoir when tenofovir/emtricitabine/elvitegravir/cobicistat is initiated during the acute primary HIV infection. PMID- 28582508 TI - Association of breast cancer risk and the mTOR pathway in women of African ancestry in 'The Root' Consortium. AB - Functional studies have elucidated the role of the mammalian target of rapamycin (mTOR) pathway in breast carcinogenesis, but to date, there is a paucity of data on its contribution to breast cancer risk in women of African ancestry. We examined 47628 SNPs in 61 mTOR pathway genes in the genome wide association study of breast cancer in the African Diaspora study (The Root consortium), which included 3686 participants (1657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 10994 SNPs that were not highly correlated (r2 < 0.8). Odds ratio (OR) and 95% confidence interval (CI) were estimated with logistic regression for each single-nucleotide polymorphism. The mTOR pathway was significantly associated with overall and estrogen receptor-negative (ER-) breast cancer risk (P = 0.003 and 0.03, respectively). PRKAG3 (Padj = 0.0018) and RPS6KA3 (Padj = 0.061) were the leading genes for the associations with overall breast cancer risk and ER- breast cancer risk, respectively. rs190843378 in PRKAG3 was statistically significant after gene-level adjustment for multiple comparisons (OR = 0.50 for each T allele, 95% CI = 0.38-0.66, Padj = 3.6E-05), with a statistical power of 0.914. These results provide new insights on the biological relevance of the mTOR pathway in breast cancer progression and underscore the need for more genetic epidemiology studies of breast cancer in the African Diaspora. PMID- 28582511 TI - A Note on the Statistical Power of Regression Analysis. PMID- 28582510 TI - A Phase 1 study evaluating AMG 337 in Asian patients with advanced solid tumors. AB - AMG 337, a selective small-molecule MET inhibitor, was evaluated in Asian patients with advanced solid tumors. Eligible patients orally self-administered AMG 337; the initial dose of 150 mg once daily (QD) was escalated to 300 mg QD (modified 3+3+3 design). Treatment continued until disease progression, intolerability, or death. The primary endpoint was adverse events (AEs) and clinical abnormalities defined as dose-limiting toxicities (DLTs). Secondary endpoints included other AEs, pharmacokinetics and tumor response. Eleven patients were enrolled. No DLTs occurred. The most common treatment-emergent AEs were headache (73%) and nausea (45%). Cmax and AUC0-24 exposures increased proportionally with dose; t1/2 was comparable between groups; plasma accumulation was minimal over 28 days. One patient (150 mg) had partial response; one patient (300 mg) had stable disease. Safety, tolerability, pharmacokinetics and efficacy of AMG 337 in Asian patients were consistent with those observed in Western patient populations. The study was terminated early. PMID- 28582512 TI - Minimally invasive mitral valve repair in osteogenesis imperfecta. AB - Osteogenesis imperfecta is a disorder of the connective tissue that affects several structures including heart valves. However, cardiac surgery is associated with high mortality and morbidity rates. In a 48-year-old man with osteogenesis imperfecta and mitral valve prolapse, we performed the first successful mitral valve repair by right anterior mini-thoracotomy. At the 1-year follow-up, he was asymptomatic and echocardiography confirmed the initial success. PMID- 28582514 TI - Conformation and dynamics of single polymer chain studied by optical microscopy techniques beyond the diffraction limit. AB - The origin of the unique properties of a polymer material is the large entropic term of a single molecule, which has a chain-like structure with a large molecular weight. From the viewpoint of understanding the fundamental polymer physics, conformation of the single polymer chain is one of the most important matters; however, it has been difficult to examine the behavior of a single chain because of the limitation of conventional experimental methods. Recent developments in optical microscopy allow the fluorescence imaging beyond the diffraction limit of light, and the author's group showed that the conformation and the dynamics of a single polymer chain can be examined by the high-resolution fluorescence imaging. This review presents the application of optical microscopy with nanometric spatial resolution to study the polymer materials at the single chain level. PMID- 28582513 TI - Evidence of Ebola Virus Replication and High Concentration in Semen of a Patient During Recovery. AB - In one patient over time, we found that concentration of Ebola virus RNA in semen during recovery is remarkably higher than blood at peak illness. Virus in semen is replication-competent with no change in viral genome over time. Presence of sense RNA suggests replication in cells present in semen. PMID- 28582516 TI - Interplay between stochastic and deterministic processes in the maintenance of alternative community states in Verrucomicrobia-dominated shallow lakes. AB - We analyzed the interplay between neutral and deterministic processes in maintaining contrasting alternative bacterioplankton communities through time in highly productive shallow lakes and evaluated the relevance of these processes when a regime shift from a clear to a turbid state occurred. We observed that local assembly is ruled primary deterministically, via local habitat filtering, with a secondary role of stochastic processes. We also found a hierarchy in the environmental sorting: while an unusual Verrucomicrobia dominance characterizes the three systems, local conditions limit within-bacterial community membership to closely phylogenetically related and ecologically similar taxa. These results indicate that bacterial abilities to establish in these lakes are strongly determined by their traits, and point toward special physiological adaptations to persist when these systems undergo a regime shift. Altogether, these results hint to a divergence in function among these alternative communities, mediated by major shifts in bacterial community trait structure, particularly regarding carbon use. PMID- 28582517 TI - Stress-responsively modulated ymdAB-clsC operon plays a role in biofilm formation and apramycin susceptibility in Escherichia coli. AB - The YmdB protein, an inhibitor of biofilm formation and an inducer of apramycin susceptibility in Escherichia coli (E. coli), is part of a putative operon. However, transcription of this operon and its subsequent effects on biological pathways has not been fully studied. Here, we characterized the operon in terms of promoter activity, transcription and function. Promoter activity assays identified two new growth- and cold-shock-responsive upstream (PymdA) and inner (PclsC) promoters, respectively. Moreover, investigation of the operon-derived transcripts identified different polycistronic transcripts harboring multiple heterogeneous 3? ends. Overexpression of YmdA or ClsC proteins inhibited biofilm formation and affected apramycin susceptibility, a process dependent on the sucA gene, suggesting that the operon genes or their encoded proteins are functionally linked. Additional investigation of the effects of polycistronic transcripts on the response of E. coli cells to apramycin revealed that transcripts containing ymdA (-213 to +27) are required for apramycin susceptibility. Thus, ymdAB-clsC is a new stress-responsive operon that plays a role in inhibiting undesired biofilm forming and antibiotic-resistant bacterial populations. PMID- 28582518 TI - Substitutions in PBP3 confer resistance to both ampicillin and extended-spectrum cephalosporins in Haemophilus parainfluenzae as revealed by site-directed mutagenesis and gene recombinants. AB - Objectives: To determine the association of amino acid substitutions in PBP3 with beta-lactam susceptibility in Haemophilus parainfluenzae. Methods: Single and multiple amino acid mutations at positions 385, 511 and 526 were introduced into PBP3 of a beta-lactam-susceptible H. parainfluenzae strain using site-directed mutagenesis. Recombinants were also generated using PCR-amplified ftsI from clinical strains encoding multiple amino acid substitutions. MICs of ampicillin, cefuroxime, cefotaxime and ceftriaxone were determined using Etest(r). Results: Transformation of a susceptible strain with ftsI from clinical strains encoding four substitutions in the transpeptidase region of PBP3 conferred resistance to ampicillin, but not to cephalosporins. Introduction of ftsI from a clinical strain encoding eight substitutions conferred resistance to ampicillin, cefotaxime and ceftriaxone. MICs for recombinants were lower than those for the donor strains. Using site-directed mutagenesis, no single substitution conferred resistance to the tested beta-lactams, although V511A increased the MIC of cefuroxime to the intermediate category for intravenous administration. Recombinants encoding N526K/H/S in combination with V511A were resistant to ampicillin. Substitution S385T increased the MICs of third-generation cephalosporins if V511A was also present. Conclusions: Substitutions in PBP3 are sufficient to confer resistance to both ampicillin and third-generation cephalosporins in H. parainfluenzae. A combination of substitutions at positions Val-511 and Asn-526 confers resistance to ampicillin. Resistance to third generation cephalosporins probably requires more than four substitutions in PBP3. PMID- 28582515 TI - Decreased Prostaglandin D2 Levels in Major Depressive Disorder Are Associated with Depression-Like Behaviors. AB - Background: Prostaglandin (PG) D2 is the most abundant prostaglandin in the mammalian brain. The physiological and pharmacological actions of PGD2 in the central nervous system seem to be associated with some of the symptoms exhibited by patients with major depressive disorder. Previous studies have found that PGD2 synthase was decreased in the cerebrospinal fluid of major depressive disorder patients. We speculated that there may be a dysregulation of PGD2 levels in major depressive disorder. Methods: Ultra-performance liquid chromatography-tandem mass spectrometry coupled with a stable isotopic-labeled internal standard was used to determine PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice. A total of 32 drug-free major depressive disorder patients and 30 healthy controls were recruited. An animal model of depression was constructed by exposing mice to 5 weeks of chronic unpredictable mild stress. To explore the role of PGD2 in major depressive disorder, selenium tetrachloride was administered to simulate the change in PGD2 levels in mice. Results: Mice exposed to chronic unpredictable mild stress exhibited depression-like behaviors, as indicated by reduced sucrose preference and increased immobility time in the forced swimming test. PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice were both decreased compared with their corresponding controls. Further inhibiting PGD2 production in mice resulted in an increased immobility time in the forced swimming test that could be reversed by imipramine. Conclusion: Decreased PGD2 levels in major depressive disorder are associated with depression-like behaviors. PMID- 28582519 TI - X chromosome inactivation in human pluripotent stem cells as a model for human development: back to the drawing board? AB - BACKGROUND: Human pluripotent stem cells (hPSC), both embryonic and induced (hESC and hiPSC), are regarded as a valuable in vitro model for early human development. In order to fulfil this promise, it is important that these cells mimic as closely as possible the in vivo molecular events, both at the genetic and epigenetic level. One of the most important epigenetic events during early human development is X chromosome inactivation (XCI), the transcriptional silencing of one of the two X chromosomes in female cells. XCI is important for proper development and aberrant XCI has been linked to several pathologies. Recently, novel data obtained using high throughput single-cell technology during human preimplantation development have suggested that the XCI mechanism is substantially different from XCI in mouse. It has also been suggested that hPSC show higher complexity in XCI than the mouse. Here we compare the available recent data to understand whether XCI during human preimplantation can be properly recapitulated using hPSC. OBJECTIVE AND RATIONALE: We will summarize what is known on the timing and mechanisms of XCI during human preimplantation development. We will compare this to the XCI patterns that are observed during hPSC derivation, culture and differentiation, and comment on the cause of the aberrant XCI patterns observed in hPSC. Finally, we will discuss the implications of the aberrant XCI patterns on the applicability of hPSC as an in vitro model for human development and as cell source for regenerative medicine. SEARCH METHODS: Combinations of the following keywords were applied as search criteria in the PubMed database: X chromosome inactivation, preimplantation development, embryonic stem cells, induced pluripotent stem cells, primordial germ cells, differentiation. OUTCOMES: Recent single-cell RNASeq data have shed new light on the XCI process during human preimplantation development. These indicate a gradual inactivation on both XX chromosomes, starting from Day 4 of development and followed by a random choice to inactivate one of them, instead of the mechanism in mice where imprinted XCI is followed by random XCI. We have put these new findings in perspective using previous data obtained in human (and mouse) embryos. In addition, there is an ongoing discussion whether or not hPSC lines show X chromosome reactivation upon derivation, mimicking the earliest embryonic cells, and the XCI states observed during culture of hPSC are highly variable. Recent studies have shown that hPSC rapidly progress to highly aberrant XCI patterns and that this process is probably driven by suboptimal culture conditions. Importantly, these aberrant XCI states seem to be inherited by the differentiated hPSC-progeny. WIDER IMPLICATIONS: The aberrant XCI states (and epigenetic instability) observed in hPSC throw a shadow on their applicability as an in vitro model for development and disease modelling. Moreover, as the aberrant XCI states observed in hPSC seem to shift to a more malignant phenotype, this may also have important consequences for the safety aspect of using hPSC in the clinic. PMID- 28582520 TI - Rapid resolution of Ortner's syndrome with giant left atrium after double-valve replacement surgery. AB - Hoarseness of voice due to recurrent laryngeal nerve palsy is an uncommon manifestation of cardiothoracic disease. Ortner's syndrome is hoarseness attributed to mechanical compression of the left recurrent laryngeal nerve in association with several cardiopulmonary disease states. We here describe a rare case of Ortner's syndrome developing in a 60-year-old woman with a giant left atrium in the context of rheumatic mitral valve stenosis. The remarkable resolution of her voice hoarseness within 1 week of valve replacement surgery has not been reported in similar cases to date. PMID- 28582522 TI - Refining success of cardiac resynchronization therapy using a simple score predicting the amount of reverse ventricular remodelling: results from the MARC study - authors reply. PMID- 28582523 TI - The interplay between adipose tissue and the cardiovascular system: is fat always bad? AB - Obesity is a risk factor for cardiovascular disease (CVD). However, clinical research has revealed a paradoxically protective role for obesity in patients with chronic diseases including CVD, suggesting that the biological 'quality' of adipose tissue (AT) may be more important than overall AT mass or body weight. Importantly, AT is recognised as a dynamic organ secreting a wide range of biologically active adipokines, microRNAs, gaseous messengers, and other metabolites that affect the cardiovascular system in both endocrine and paracrine ways. Despite being able to mediate normal cardiovascular function under physiological conditions, AT undergoes a phenotypic shift characterised by acquisition of pro-oxidant and pro-inflammatory properties in cases of CVD. Crucially, recent evidence suggests that AT depots such as perivascular AT and epicardial AT are able to modify their phenotype in response to local signals of vascular and myocardial origin, respectively. Utilisation of this unique property of certain AT depots to dynamically track cardiovascular biology may reveal novel diagnostic and prognostic tools against CVD. Better understanding of the mechanisms controlling the 'quality' of AT secretome, as well as the communication links between AT and the cardiovascular system, is required for the efficient management of CVD. PMID- 28582524 TI - Acute non-A non-B aortic dissection: incidence, treatment and outcome. AB - OBJECTIVES: Our aim was to report outcome of patients with acute non-A non-B aortic dissection involving the aortic arch but not the ascending aorta. METHODS: Dissection extension and entry location were analysed in patients with acute aortic dissection admitted between 2001 and 2016 at a tertiary centre. Non-A non B dissection was classified as descending-entry type with entry distal to the left subclavian artery and dissection extending into the aortic arch, and arch entry type with entry between the innominate and left subclavian arteries. We compared these 2 groups' clinical presentation, treatment and outcome. RESULTS: Among 396 acute aortic dissection patients, 43 (median age 60 +/- 12 years, 81% males) had non-A non-B dissection (descending-entry n = 21, arch-entry n = 22). The overwhelming majority of aortic segments were not dilated in all these patients. The 2 groups' cardiovascular risk profiles did not differ. Emergency open or endovascular aortic repair were necessary due to malperfusion or aortic rupture in 29% descending-entry and 36% arch-entry (in-hospital mortality was 1/6 and 3/8, respectively). Aortic repair within 2 weeks due to new organ malperfusion, rapid aortic growth, aortic rupture or persisting pain was performed in 43% descending-entry and 36% arch-entry patients (0% in-hospital mortality). All others (except for 1 diagnosed in 2014) required aortic repair for aneurysm at follow-up. CONCLUSIONS: Acute non-A non-B aortic dissection frequently requires emergency aortic repair due to organ malperfusion or aortic rupture. Most descending-entry and arch-entry non-A non-B dissection patients undergo aortic repair within 2 weeks after dissection onset. PMID- 28582521 TI - The Prognostic Value of Tumor Multifocality in Clinical Outcomes of Papillary Thyroid Cancer. AB - Context: Multifocality is often treated as a risk factor for papillary thyroid cancer (PTC), prompting aggressive treatments, but its prognostic value remains unestablished. Objective: To investigate the role of tumor multifocality in clinical outcomes of PTC. Methods: Multicenter study of the relationship between multifocality and clinical outcomes of PTC in 2638 patients (623 men and 2015 women) with median [interquartile range (IQR)] age of 46 (35 to 58) years and median (IQR) follow-up time of 58 (26 to 107) months at 11 medical centers in six countries. Surveillance, Epidemiology and End Results (SEER) data were used for validation. Results: Disease recurrence in multifocal and unifocal PTC was 198 of 1000 (19.8%) and 221 of 1624 (13.6%) (P < 0.001), with a hazard ratio of 1.55 [95% confidence interval (CI), 1.28 to 1.88], which became insignificant at 1.13 (95% CI, 0.93 to 1.37) on multivariate adjustment. Similar results were obtained in PTC variants: conventional PTC, follicular-variant PTC, tall-cell PTC, and papillary thyroid microcarcinoma. There was no association between multifocality and mortality in any of these PTC settings, whereas there was a strong association between classic risk factors and cancer recurrence or mortality, which remained significant after multivariate adjustment. In 1423 patients with intrathyroidal PTC, disease recurrence was 20 of 455 (4.4%) and 41 of 967 (4.2%) (P = 0.892) and mortality was 0 of 455 (0.0%) and 3 of 967 (0.3%) (P = 0.556) in multifocal and unifocal PTC, respectively. The results were reproduced in 89,680 patients with PTC in the SEER database. Conclusions: Tumor multifocality has no independent risk prognostic value in clinical outcomes of PTC; its indiscriminate use as an independent risk factor, prompting overtreatments of patients, should be avoided. PMID- 28582525 TI - Progressive mitral regurgitation in a patient with tropical endomyocardial fibrosis. PMID- 28582526 TI - Environmental Tobacco Exposure and Urinary Cotinine Levels in Smoking and Nonsmoking Adolescents. AB - Objective: We aimed to evaluate the association between environmental tobacco smoke (ETS) exposure and urinary cotinine levels in current adolescent smokers and nonsmokers. The secondary objective was to explore the association between ETS exposure and nicotine dependence in adolescent smokers. Methods: Using the results from a validation study for the 2012 Global Youth Tobacco Survey in Mexico, we quantified urinary cotinine levels in adolescent smokers and nonsmokers. We fitted a multivariate regression model to assess the association between household exposure to ETS and cotinine levels in adolescent smokers and nonsmokers. In addition, using the questionnaire's answers for morning cravings, we fitted a multivariate Poisson regression model to explore the association between household ETS exposure and nicotine dependence in adolescent smokers. Results: For each day of household ETS exposure, cotinine levels increase by 5% in adolescent smokers compared to a 2% increase in nonsmokers, adjusting for the number of cigarettes smoked per week, age and sex (exp(beta) 1.05; 95% confidence interval [CI] [1.00, 1.10]; p = .041). Morning cravings increase 11% for each day of household ETS exposure adjusting for the number of cigarettes smoked per week, age and sex (prevalence ratio [PR] 1.11; 95% CI [0.99, 1.25]; p = .064). Conclusions: There is an association between ETS exposure and cotinine levels, and ETS may contribute to nicotine dependence in adolescent smokers. If confirmed, avoiding ETS exposure could prove helpful for addiction control and quitting in adolescents. Implications: Evidence suggests that ETS increases cotinine levels in nonsmokers and adult smokers. However, no study has explored the association between ETS exposure and cotinine levels and addiction in adolescent smokers. This paper provides evidence of an association between ETS exposure and cotinine levels in adolescent smokers: each day of environmental tobacco smoke exposure at home increased cotinine levels by 5% among smokers. In addition, morning cravings in adolescent smokers increased 11% for every day of ETS exposure. ETS exposure is a significant source of nicotine for adolescent smokers and could play an important role in addiction. PMID- 28582527 TI - Transcriptional profiles of JIA patient blood with subsequent poor response to methotrexate. AB - Objective: The mechanisms that determine the efficacy or inefficacy of MTX in JIA are ill-defined. The objective of this study was to identify a gene expression transcriptional signature associated with poor response to MTX in patients with JIA. Methods: RNA sequencing was used to measure gene expression in peripheral blood mononuclear cells collected from 47 patients with JIA prior to MTX treatment and 14 age-matched controls. Differentially expressed baseline genes between responders and non-responders were evaluated. Biological differences between all JIA patients and controls were explored by constructing a signature of differentially expressed genes. Unsupervised clustering and pathway analysis was performed. Results: A signature of 99 differentially expressed genes (Bonferroni-corrected P < 0.05) capturing the biological differences between all JIA patients and controls was identified. Unsupervised clustering of samples based on this list of 99 genes produced subgroups enriched for MTX response status. Comparing this gene signature with reference signatures from sorted cell populations revealed high concordance between the expression signatures of monocytes and of MTX non-responders. CXCL8 (IL-8) was the most significantly differentially expressed gene transcript comparing all JIA patients with controls (Bonferroni-corrected P = 4.12 * 10-10). Conclusion: Variability in clinical response to MTX in JIA patients is associated with differences in gene transcripts modulated in monocytes. These gene expression profiles may provide a basis for biomarkers predictive of treatment response. PMID- 28582528 TI - Trends in obesity and diabetes across Africa from 1980 to 2014: an analysis of pooled population-based studies. AB - Background: The 2016 Dar Es Salaam Call to Action on Diabetes and Other non communicable diseases (NCDs) advocates national multi-sectoral NCD strategies and action plans based on available data and information from countries of sub Saharan Africa and beyond. We estimated trends from 1980 to 2014 in age standardized mean body mass index (BMI) and diabetes prevalence in these countries, in order to assess the co-progression and assist policy formulation. Methods: We pooled data from African and worldwide population-based studies which measured height, weight and biomarkers to assess diabetes status in adults aged >= 18 years. A Bayesian hierarchical model was used to estimate trends by sex for 200 countries and territories including 53 countries across five African regions (central, eastern, northern, southern and western), in mean BMI and diabetes prevalence (defined as either fasting plasma glucose of >= 7.0 mmol/l, history of diabetes diagnosis, or use of insulin or oral glucose control agents). Results: African data came from 245 population-based surveys (1.2 million participants) for BMI and 76 surveys (182 000 participants) for diabetes prevalence estimates. Countries with the highest number of data sources for BMI were South Africa (n = 17), Nigeria (n = 15) and Egypt (n = 13); and for diabetes estimates, Tanzania (n = 8), Tunisia (n = 7), and Cameroon, Egypt and South Africa (all n = 6). The age standardized mean BMI increased from 21.0 kg/m2 (95% credible interval: 20.3 21.7) to 23.0 kg/m2 (22.7-23.3) in men, and from 21.9 kg/m2 (21.3-22.5) to 24.9 kg/m2 (24.6-25.1) in women. The age-standardized prevalence of diabetes increased from 3.4% (1.5-6.3) to 8.5% (6.5-10.8) in men, and from 4.1% (2.0-7.5) to 8.9% (6.9-11.2) in women. Estimates in northern and southern regions were mostly higher than the global average; those in central, eastern and western regions were lower than global averages. A positive association (correlation coefficient ? 0.9) was observed between mean BMI and diabetes prevalence in both sexes in 1980 and 2014. Conclusions: These estimates, based on limited data sources, confirm the rapidly increasing burden of diabetes in Africa. This rise is being driven, at least in part, by increasing adiposity, with regional variations in observed trends. African countries' efforts to prevent and control diabetes and obesity should integrate the setting up of reliable monitoring systems, consistent with the World Health Organization's Global Monitoring System Framework. PMID- 28582529 TI - Disrupted Olfactory Integration in Schizophrenia: Functional Connectivity Study. AB - Background: Evidence for olfactory dysfunction in schizophrenia has been firmly established. However, in the typical understanding of schizophrenia, olfaction is not recognized to contribute to or interact with the illness. Despite the solid presence of olfactory dysfunction in schizophrenia, its relation to the rest of the illness remains largely unclear. Here, we aimed to examine functional connectivity of the olfactory bulb, olfactory tract, and piriform cortices and isolate the network that would account for the altered olfaction in schizophrenia. Methods: We examined the functional connectivity of these specific olfactory regions in order to isolate other brain regions associated with olfactory processing in schizophrenia. Using the resting state functional MRI data from the Center for Biomedical Research Excellence in Brain Function and Mental Illness, we compared 84 patients of schizophrenia and 90 individuals without schizophrenia. Results: The schizophrenia group showed disconnectivity between the anterior piriform cortex and the nucleus accumbens, between the posterior piriform cortex and the middle frontal gyrus, and between the olfactory tract and the visual cortices. Conclusions: The current results suggest functional disconnectivity of olfactory regions in schizophrenia, which may account for olfactory dysfunction and disrupted integration with other sensory modalities in schizophrenia. PMID- 28582530 TI - An in vivo genetic screen for genes involved in spliced leader trans-splicing indicates a crucial role for continuous de novo spliced leader RNP assembly. AB - Spliced leader (SL) trans-splicing is a critical element of gene expression in a number of eukaryotic groups. This process is arguably best understood in nematodes, where biochemical and molecular studies in Caenorhabditis elegans and Ascaris suum have identified key steps and factors involved. Despite this, the precise details of SL trans-splicing have yet to be elucidated. In part, this is because the systematic identification of the molecules involved has not previously been possible due to the lack of a specific phenotype associated with defects in this process. We present here a novel GFP-based reporter assay that can monitor SL1 trans-splicing in living C. elegans. Using this assay, we have identified mutants in sna-1 that are defective in SL trans-splicing, and demonstrate that reducing function of SNA-1, SNA-2 and SUT-1, proteins that associate with SL1 RNA and related SmY RNAs, impairs SL trans-splicing. We further demonstrate that the Sm proteins and pICln, SMN and Gemin5, which are involved in small nuclear ribonucleoprotein assembly, have an important role in SL trans-splicing. Taken together these results provide the first in vivo evidence for proteins involved in SL trans-splicing, and indicate that continuous replacement of SL ribonucleoproteins consumed during trans-splicing reactions is essential for effective trans-splicing. PMID- 28582531 TI - Biomarkers of Secondhand Smoke Exposure in Waterpipe Tobacco Venue Employees in Istanbul, Moscow, and Cairo. AB - Background: Most smoke-free legislation to reduce secondhand smoke (SHS) exposure exempts waterpipe (hookah) smoking venues. Few studies have examined SHS exposure in waterpipe venues and their employees. Methods: We surveyed 276 employees of 46 waterpipe tobacco venues in Istanbul, Moscow, and Cairo. We interviewed venue managers and employees and collected biological samples from employees to measure exhaled carbon monoxide (CO), hair nicotine, saliva cotinine, urine cotinine, urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and urine 1 hydroxypyrene glucuronide (1-OHPG). We estimated adjusted geometric mean ratios (GMR) of each SHS biomarker by employee characteristics and indoor air SHS measures. Results: There were 73 nonsmoking employees and 203 current smokers of cigarettes or waterpipe. In nonsmokers, the median (interquartile) range concentrations of SHS biomarkers were 1.1 (0.2, 40.9) ug/g creatinine urine cotinine, 5.5 (2, 15) ng/mL saliva cotinine, 0.95 (0.36, 5.02) ng/mg hair nicotine, 1.48 (0.98, 3.97) pg/mg creatinine urine NNAL, 0.54 (0.25, 0.97) pmol/mg creatinine urine 1-OHPG, and 1.67 (1.33, 2.33) ppm exhaled CO. An 8-hour increase in work hours was associated with higher urine cotinine (GMR: 1.68, 95% CI: 1.20, 2.37) and hair nicotine (GMR: 1.22, 95% CI: 1.05, 1.43). Lighting waterpipes was associated with higher saliva cotinine (GMR: 2.83, 95% CI: 1.05, 7.62). Conclusions: Nonsmoking employees of waterpipe tobacco venues were exposed to high levels of SHS, including measurable levels of carcinogenic biomarkers (tobacco-specific nitrosamines and PAHs). Implications: Smoke-free regulation should be extended to waterpipe venues to protect nonsmoking employees and patrons from the adverse health effects of SHS. PMID- 28582533 TI - Handling blood cell composition in epigenetic studies on ageing. PMID- 28582532 TI - Generating global political priority for urban health: the role of the urban health epistemic community. AB - Over the past decade there has been much discussion of the challenges posed by rapid urbanization in the developing world; yet the health of the urban poor, and especially those residing in low- and middle-income countries, continues to receive little political priority in most developing countries and at the global level. This research applies social science scholarship and a public policy analytical framework to assess the factors that have challenged efforts to make health in urban poor settings a priority. We conducted 19 semi-structured phone interviews with key urban health proponents and experts representing agencies that shape opinions and manage resources in global health. We also conducted a literature review, which included published scholarly literature and reports from organizations involved in urban health provision and advocacy. Utilizing a process-tracing method, we triangulated among these sources of data to create a historical narrative and analyse the factors that shape the global level of attention to and resources for urban health. The urban health agenda continues to be challenged by six factors, three of which concern the political context or characteristics of the issue: long-standing competition with the dominant development agenda that is rural health oriented; limited data and measurement tools that can effectively gauge the extent of the problem; and lack of evidence on how to best to address the issue. The other three factors are directly under the control of the urban health community: the community's ineffective governance; little common understanding among its members of the problem and how to address it; and an unconvincing framing of the issue to the public. The study offers suggestions as to what advocates can do to secure greater attention and resources in order to help address the health needs of the urban poor. PMID- 28582534 TI - Development, Trait Evolution, and the Evolution of Development in Trilobites. AB - Trilobites offer one of the best fossil records of any arthropod group. This is due to a number of factors, most notably the combination of (1) having inhabited areas where organisms are more likely to be buried and ultimately fossilized; and (2) having had a highly biomineralized exoskeleton more likely to survive the stresses of fossilization. This biomineralized exoskeleton was also morphologically complex, bearing traits that had ecological significance, and was present throughout postembryonic development, from larval to adult stages. Because the morphology of the exoskeleton changed gradually across molts during development, it is possible to reconstruct ontogenetic series for many species. Over the last decade, studies have documented both variation in modularity among closely related species and conserved developmental patterns among modules. In the latter case, trait evolution could still occur through modification of rates of morphological change along otherwise conserved ontogenetic trajectories. At the clade level, the pattern of expression and release of new exoskeletal segments during post-embryonic development was generally conserved across most species, but the relative timing of different segmentation events could vary, and developmental traits appear to have been relatively labile across the clade's evolutionary history. Most recently, comparative analyses indicate that the association between segmentation events and the timing of shifts in the rate of ontogenetic shape change varies across species. Despite these advances, we still know relatively little about how development constrained or contributed to trait evolution in trilobites, and almost nothing about the origin of novel traits in trilobites. A major (but removable) obstacle is the current lack of well supported trilobite phylogenies that span higher taxonomic levels. PMID- 28582535 TI - Perceived Synchrony of Frog Multimodal Signal Components Is Influenced by Content and Order. AB - Multimodal signaling is common in communication systems. Depending on the species, individual signal components may be produced synchronously as a result of physiological constraint (fixed) or each component may be produced independently (fluid) in time. For animals that rely on fixed signals, a basic prediction is that asynchrony between the components should degrade the perception of signal salience, reducing receiver response. Male tungara frogs, Physalaemus pustulosus, produce a fixed multisensory courtship signal by vocalizing with two call components (whines and chucks) and inflating a vocal sac (visual component). Using a robotic frog, we tested female responses to variation in the temporal arrangement between acoustic and visual components. When the visual component lagged a complex call (whine + chuck), females largely rejected this asynchronous multisensory signal in favor of the complex call absent the visual cue. When the chuck component was removed from one call, but the robofrog inflation lagged the complex call, females responded strongly to the asynchronous multimodal signal. When the chuck component was removed from both calls, females reversed preference and responded positively to the asynchronous multisensory signal. When the visual component preceded the call, females responded as often to the multimodal signal as to the call alone. These data show that asynchrony of a normally fixed signal does reduce receiver responsiveness. The magnitude and overall response, however, depend on specific temporal interactions between the acoustic and visual components. The sensitivity of tungara frogs to lagging visual cues, but not leading ones, and the influence of acoustic signal content on the perception of visual asynchrony is similar to those reported in human psychophysics literature. Virtually all acoustically communicating animals must conduct auditory scene analyses and identify the source of signals. Our data suggest that some basic audiovisual neural integration processes may be at work in the vertebrate brain. PMID- 28582536 TI - Is Dihydrotestosterone a Classic Hormone? PMID- 28582537 TI - June Issue of Endocrine Reviews. PMID- 28582538 TI - BreakPoint Surveyor: a pipeline for structural variant visualization. AB - Summary: BreakPoint Surveyor (BPS) is a computational pipeline for the discovery, characterization, and visualization of complex genomic rearrangements, such as viral genome integration, in paired-end sequence data. BPS facilitates interpretation of structural variants by merging structural variant breakpoint predictions, gene exon structure, read depth, and RNA-sequencing expression into a single comprehensive figure. Availability and implementation: Source code and sample data freely available for download at https://github.com/ding lab/BreakPointSurveyor, distributed under the GNU GPLv3 license, implemented in R, Python and BASH scripts, and supported on Unix/Linux/OS X operating systems. Contact: lding@wustl.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28582539 TI - More than meets the eye: IgG4-related disease presenting as isolated interstitial lung disease. PMID- 28582541 TI - Epidemiology of Rotavirus Infection in Children from a Rural and Urban Area, in Maputo, Southern Mozambique, before Vaccine Introduction. AB - This study aimed to describe the epidemiology of rotavirus infections in Mozambique before vaccine introduction. Between February 2012 and September 2013, stool specimens, demographic and clinical data were collected from 384 children <5 years old hospitalized with acute diarrhea in Mavalane General Hospital and Manhica District Hospital, southern Mozambique. The samples were tested for rotavirus A using enzyme-linked immunosorbent assay. The overall prevalence of rotavirus infection was 42.4% [95% confidence interval (95CI): 37.4-47.6%], and was similar in Manhica (44.3%; 95CI: 36.2-52.7%) and Mavalane (41.3%; 95CI: 34.9 47.9%). The highest prevalence of rotavirus infection was observed in children between 6 and 11 months old. It was also observed that 162 (43.7%) of the children were underweight (weight-for-age z-score < -2), of which 61 were infected by rotavirus. PMID- 28582540 TI - A bioassay-guided fractionation system to identify endogenous small molecules that activate plasma membrane H+-ATPase activity in Arabidopsis. AB - Plasma membrane (PM) H+-ATPase is essential for plant growth and development. Various environmental stimuli regulate its activity, a process that involves many protein cofactors. However, whether endogenous small molecules play a role in this regulation remains unknown. Here, we describe a bio-guided isolation method to identify endogenous small molecules that regulate PM H+-ATPase activity. We obtained crude extracts from Arabidopsis seedlings with or without salt treatment and then purified them into fractions based on polarity and molecular mass by repeated column chromatography. By evaluating the effect of each fraction on PM H+-ATPase activity, we found that fractions containing the endogenous, free unsaturated fatty acids oleic acid (C18:1), linoleic acid (C18:2), and linolenic acid (C18:3) extracted from salt-treated seedlings stimulate PM H+-ATPase activity. These results were further confirmed by the addition of exogenous C18:1, C18:2, or C18:3 in the activity assay. The ssi2 mutant, with reduced levels of C18:1, C18:2, and C18:3, displayed reduced PM H+-ATPase activity. Furthermore, C18:1, C18:2, and C18:3 directly bound to the C-terminus of the PM H+-ATPase AHA2. Collectively, our results demonstrate that the binding of free unsaturated fatty acids to the C-terminus of PM H+-ATPase is required for its activation under salt stress. The bio-guided isolation model described in this study could enable the identification of new endogenous small molecules that modulate essential protein functions, as well as signal transduction, in plants. PMID- 28582542 TI - Serum Bactericidal Antibody Responses of Students Immunized With a Meningococcal Serogroup B Vaccine in Response to an Outbreak on a University Campus. AB - Background: MenB-4C is a recently licensed meningococcal serogroup B vaccine. For vaccine licensure, short-term efficacy was inferred from serum bactericidal antibody (SBA) titers against 3 antigen-specific indicator strains, which are not necessarily representative of US disease-causing strains. Methods: A total of 4923 students were immunized with MenB-4C in response to an outbreak at a university. Serum samples were obtained at 1.5-2 months from 106 students who received the recommended 2 doses and 52 unvaccinated students. Follow-up serum samples were obtained at 7 months from 42 vaccinated and 24 unvaccinated participants. SBA was measured against strains from 4 university outbreaks. Results: At 1.5-2 months, the proportion of immunized students with protective titers >=1:4 against an isolate from the campus outbreak was 93% (95% confidence interval [CI], 87%-97%) vs 37% (95% CI, 24%-51%) in unvaccinated students. The proportion with protective titers against strains from 3 other university outbreaks was 73% (95% CI, 62%-82%) vs 26% (95% CI, 14%-41%) in unvaccinated; 71% (95% CI, 61%-79%) vs 19% (95% CI, 10%-33%) in unvaccinated; and 53% (95% CI, 42% 64%) vs 9% (95% CI, 3%-22%) in unvaccinated (P < .0001 for each strain). At 7 months, the proportion of immunized students with titers >=1:4 was 86% (95% CI, 71%-95%) against the isolate from the campus outbreak and 57% (95% CI, 41%-72%), 38% (95% CI, 24%-54%), and 31% (95% CI, 18%-47%), respectively, for the other 3 outbreak strains. Conclusions: MenB-4C elicited short-term protective titers against 4 strains responsible for recent university campus outbreaks. By 7 months the prevalence of protective titers was <40% for 2 of the 4 outbreak strains. A booster dose of MenB-4C may be needed to maintain protective titers. PMID- 28582544 TI - Terbinafine resistance conferred by multiple copies of the salicylate 1 monooxygenase gene in Trichophyton rubrum. AB - Resistance to antifungals is a leading concern in the treatment of human mycoses. We demonstrate that the salA gene, encoding salicylate 1-monooxygenase, is involved in resistance of the dermatophyte Trichophyton rubrum to terbinafine, one of the most effective antifungal drugs against dermatophytes. A strain with multiple copies of salA was constructed and exhibited elevated expression of salA and increased terbinafine resistance. This reflects a mechanism not yet reported in a pathogenic fungus. PMID- 28582545 TI - Stereotactic Catheter Ventriculocisternostomy for Clearance of Subarachnoid Hemorrhage in Patients with Coiled Aneurysms. AB - BACKGROUND: Cerebral vasospasm leading to delayed cerebral infarction (DCI) is a central source of poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). Current treatments of cerebral vasospasm are insufficient. Cisternal blood clearance is a promising treatment option. However, a generally applicable, safe, and effective method to access the cisterns of the brain is lacking. OBJECTIVE: To report on stereotactic catheter ventriculocisternostomy (STX-VCS) as a method to access the cisterns of the brain for clearance of subarachnoid hemorrhage in patients with aSAH and coiled aneurysms. METHODS: In 9 aSAH patients at high risk for DCI (Hunt and Hess grade >=3, modified Fisher grade >=3), access to the basal cisterns of the brain was created by STX-VCS. Fibrinolytic and/or spasmolytic lavage therapy was administered. RESULTS: STX-VCS was feasible and safe in all patients. Subarachnoid blood was rapidly cleared by irrigation with urokinase. Vasospasm occurred in 2 patients and was interrupted by irrigation with nimodipine. There was 1 fatality due to pneumogenic sepsis. Minor DCI occurred in 1 patient. Eight survived without DCI and are independent (modified Rankin score [mRS] <= 3) at 6 mo after aSAH. CONCLUSION: STX-VCS allows for rapid clearance of subarachnoid hemorrhage in patients with coiled aneurysms. PMID- 28582543 TI - Adherence to a healthy lifestyle and the risk of type 2 diabetes in Chinese adults. AB - Background: Simultaneously adhering to multiple healthy lifestyle factors has been related to up to 90% reduction in type 2 diabetes (T2DM) incidence in White populations; however, little is known about whether such protective effects persist in other non-White populations. Methods: We examined the associations of six lifestyle factors with T2DM in the China Kadoorie Biobank of 461 211 participants aged 30-79 years without diabetes, cardiovascular diseases or cancer at baseline. We defined low-risk lifestyle factors as non-smoking or having stopped for reasons other than illness; alcohol consumption of <30 g/day; upper quarter of the physical activity level; diet rich in vegetables and fruits, low in red meat and with some degree of replacement of rice with wheat; body mass index (BMI) of 18.5-23.9 kg/m2; and waist-to-hip ratio (WHR) <0.90 (men)/<0.85 (women). Results: During a median of 7.2 years of follow-up, we identified 8784 incident T2DM. In multivariable-adjusted analyses, two important risk factors for developing T2DM were higher BMI and WHR. Compared with participants without any low-risk factors, the hazard ratio [95% confidence interval (CI)] for those with at least three low-risk factors was 0.20 (0.19, 0.22). Approximately 72.6% (64.2%, 79.3%) of the incident diabetes were attributable to the combination of BMI, WHR, diet and physical activity. The population attributable risk percentage (PAR%) of diabetes appeared to be similar for men and women, and higher among urban, older and obese participants. Conclusions: Our findings indicate that adherence to a healthy lifestyle may substantially lower the burden of T2DM in the Chinese population. PMID- 28582546 TI - The contribution of homology arms to nuclease-assisted genome engineering. AB - Designer nucleases like CRISPR/Cas9 enable fluent site-directed damage or small mutations in many genomes. Strategies for their use to achieve more complex tasks like regional exchanges for gene humanization or the establishment of conditional alleles are still emerging. To optimize Cas9-assisted targeting, we measured the relationship between targeting frequency and homology length in targeting constructs using a hypoxanthine-guanine phosphoribosyl-transferase assay in mouse embryonic stem cells. Targeting frequency with supercoiled plasmids improved steeply up to 2 kb total homology and continued to increase with even longer homology arms, thereby implying that Cas9-assisted targeting efficiencies can be improved using homology arms of 1 kb or greater. To humanize the Kmt2d gene, we built a hybrid mouse/human targeting construct in a bacterial artificial chromosome by recombineering. To simplify the possible outcomes, we employed a single Cas9 cleavage strategy and best achieved the intended 42 kb regional exchange with a targeting construct including a very long homology arm to recombine ~42 kb away from the cleavage site. We recommend the use of long homology arm targeting constructs for accurate and efficient complex genome engineering, particularly when combined with the simplifying advantages of using just one Cas9 cleavage at the genome target site. PMID- 28582548 TI - Butterflies Do Not Alter Conspecific Avoidance in Response to Variation in Density. AB - SYNOPSIS: High conspecific densities are associated with increased levels of intraspecific competition and a variety of negative effects on performance. However, changes in life history strategy could compensate for some of these effects. For instance, females in crowded conditions often have fewer total offspring, but they may invest more in each one. Such investment could include the production of larger offspring, more time spent engaging in parental care, or more choosy decisions about where offspring are placed. For animals that have a relatively immobile juvenile stage, the costs of competition can be particularly high. Females may be able to avoid such costs by investing more in individual reproductive decisions, rearing young or laying eggs in locations away from other females. We tested the hypothesis that conspecific density cues during juvenile and adult life stages lead to changes in life history strategy, including both reproduction and oviposition choices. We predicted that high-density cues during the larval and adult stages of female Pieris rapae butterflies lead to lower fecundity but higher conspecific avoidance during oviposition, compared to similar low-density cues. We used a 2*2 factorial design to examine the effects of low and high conspecific density during the larval and adult stages of butterflies on avoidance behavior and fecundity. We found that past information about conspecific density did not matter; all butterflies exhibited similar levels of fecundity and a low level of conspecific avoidance during oviposition regardless of their previous experience as larvae and adults. These results suggest that P. rapae females use a fixed, rather than flexible, conspecific avoidance strategy when making oviposition decisions, and past information about conspecific density has no effect on life history and current reproductive investment. We speculate that this may be partially because past conspecific density per se is not a reliable cue for predicting current density and levels of competition, and thus it does not affect the development of life history strategies in this system. PMID- 28582547 TI - The TORC1/2 inhibitor TAK228 sensitizes atypical teratoid rhabdoid tumors to cisplatin-induced cytotoxicity. AB - Background: Atypical teratoid/rhabdoid tumors (AT/RTs) are deadly pediatric brain tumors driven by LIN28. Mammalian target of rapamycin (mTOR) is activated in many deadly, drug-resistant cancers and governs important cellular functions such as metabolism and survival. LIN28 regulates mTOR in normal cells. We therefore hypothesized that mTOR is activated downstream of LIN28 in AT/RT, and the brain penetrating mTOR complex 1 and 2 (mTORC1/2) kinase inhibitor TAK228 would reduce AT/RT tumorigenicity. Methods: Activation of mTOR in AT/RT was determined by measuring pS6 and pAKT (Ser473) by immunohistochemistry on tissue microarray of 18 primary AT/RT tumors. In vitro growth assays (BrdU and MTS), death assays (CC3, c-PARP by western blot), and survival curves of AT/RT orthotopic xenograft models were used to measure the efficacy of TAK228 alone and in combination with cisplatin. Results: Lentiviral short hairpin RNA-mediated knockdown of LIN28A led to decreased mTOR activation. Primary human AT/RT had high levels of pS6 and pAKT (Ser473) in 21% and 87% of tumors by immunohistochemistry. TAK228 slowed cell growth, induced apoptosis in vitro, and nearly doubled median survival of orthotopic xenograft models of AT/RT. TAK228 combined with cisplatin synergistically slowed cell growth and enhanced cisplatin-induced apoptosis. Suppression of AKT sensitized cells to cisplatin-induced apoptosis and forced activation of AKT protected cells. Combined treatment with TAK228 and cisplatin significantly extended survival of orthotopic xenograft models of AT/RT compared with each drug alone. Conclusions: TAK228 has efficacy in AT/RT as a single agent and synergizes with conventional chemotherapies by sensitizing tumors to cisplatin-induced apoptosis. These results suggest TAK228 may be an effective new treatment for AT/RT. PMID- 28582549 TI - Changes in bacterial community after application of three different herbicides. AB - The native soil microbiota is very important to maintain the quality of that environment, but with the intensive use of agrochemicals, changes in microbial biomass and formation of large quantities of toxic waste were observed in soil, groundwater and surface water. Thereby, the goal of this study was to evaluate if the selective pressure exerted by the presence of the herbicides atrazine, diuron and 2,4-D changes the bacterial community structure of an agricultural soil, using denaturing gradient gel electrophoresis technique. According to PERMANOVA analysis, a greater effect of the herbicide persistence time in the soil, the effect of the herbicide class and the effect of interaction between these two factors (persistence time and herbicide class) were observed. In conclusion, the results showed that the selective pressure exerted by the presence of these herbicides altered the composition of the local microbiota, being atrazine and diuron that most significantly affected the bacterial community in soil, and the herbicide 2,4-D was the one that less altered the microbial community and that bacterial community was reestablished first. PMID- 28582550 TI - Fine mapping of a quantitative trait locus for spikelet number per panicle in a new plant type rice and evaluation of a near-isogenic line for grain productivity. AB - Total spikelet number per panicle (TSN) is one of the determinants of grain productivity in rice (Oryza sativa L.). In this study, we attempted to detect quantitative trait loci (QTLs) for TSN in the introgression lines with high TSN, derived from the cross of Indica Group variety IR 64 with new plant type lines. Two QTLs were detected on the long arm of chromosome 12: qTSN12.1 in the BC4F2 population of YTH63/IR 64 and qTSN12.2 in the BC4F3 population of YTH83/IR 64. TSN of the main tiller was significantly higher in near-isogenic lines (NILs) for qTSN12.1 (IR 64-NIL1; 188.6) and for qTSN12.2 (IR 64-NIL12; 199.4) than in IR 64 (141.2), owing to a significant increase in both primary and secondary branch numbers. These results suggest the critical function of these QTLs in the promotion of rachis branching at the panicle formation stage. Fine mapping of qTSN12.2 revealed six candidate genes in a 92-kb region of the Nipponbare reference genome sequence between flanking markers RM28746 and RM28753. Detailed phenotyping of agronomic traits of IR 64-NIL12 carrying qTSN12.2 showed drastic changes in plant architecture: this line had lower panicle number, longer culm, and longer and wider leaves compared with IR 64. Percentage of fertility and 1000 grain weight tended to be greater, and grain yield per square meter was also greater in IR 64-NIL12 than in IR 64. The newly identified QTLs will be useful for genetic improvement of the yield potential of Indica Group varieties. The markers tightly linked to qTSN12.2 are available for marker-assisted breeding. PMID- 28582551 TI - Beating heart mitral valve surgery: results in 120 consecutive patients considered unsuitable for conventional mitral valve surgery. AB - OBJECTIVES: The purpose of the study was to test whether a beating heart mitral valve operation was a valuable option in a heterogeneous group of patients considered very high risk for conventional mitral valve surgery. METHODS: We conducted a retrospective, single-centre, observational cohort study of 120 patients (mean age 63.7 +/- 12.1 years, range 25.3-88.8 years; mean logistic EuroSCORE 26.1 +/- 20.6%, range 1.5-84.3%) undergoing beating heart mitral valve operations using normothermic cardiopulmonary bypass without aortic cross clamping and without cardioplegia between September 2002 and April 2014. Preoperatively, 14 (11.7%) patients were in cardiogenic shock, 16 (13%) on a ventilator, 33 (27.5%) receiving inotropic support, 12 (10%) on dialysis and 1 on extracorporeal membrane oxygenation. Sixty-five (54%) patients had had at least 1 (range 1-6) previous heart operation. The mean follow-up period was 920 +/- 973 days. RESULTS: A mitral valve procedure was performed alone in 75 (62.5%) patients and combined with additional cardiac procedures in 45 (37.5%). Fifty eight (49%) patients had emergency or urgent procedures and 62 (51%), elective procedures. The mean cardiopulmonary bypass time was 103 +/- 39 min (median 94 min, range 45-252, interquartile range 75-121.5 min). There were no conversions to conventional procedures and no intraoperative deaths. The 30-day mortality rate for patients without cardiogenic shock was 7.5% (8 deaths among 106 patients). Among 14 (11.7%) patients who underwent an operation in cardiogenic shock, 4 died during the first 30 days (30-day mortality rate = 28.6%, Fisher's exact test P = 0.338 versus patients without shock). The lowest 30-day mortality rate was in patients operated on with the beating heart because of a porcelain aorta (n = 8 patients, 30-day mortality rate = 0%). CONCLUSIONS: Patients considered unsuitable for a conventional mitral valve operation had favourable postoperative outcomes if the operation was performed on the beating heart. PMID- 28582552 TI - Lower Bone Mass and Higher Bone Resorption in Pheochromocytoma: Importance of Sympathetic Activity on Human Bone. AB - Context: Despite the apparent biological importance of sympathetic activity on bone metabolism in rodents, its role in humans remains questionable. Objective: To clarify the link between the sympathetic nervous system and the skeleton in humans. Design, Setting, and Patients: Among 620 consecutive subjects with newly diagnosed adrenal incidentaloma, 31 patients with histologically confirmed pheochromocytoma (a catecholamine-secreting neuroendocrine tumor) and 280 patients with nonfunctional adrenal incidentaloma were defined as cases and controls, respectively. Results: After adjustment for confounders, subjects with pheochromocytoma had 7.2% lower bone mass at the lumbar spine and 33.5% higher serum C-terminal telopeptide of type 1 collagen (CTX) than those without pheochromocytoma (P = 0.016 and 0.001, respectively), whereas there were no statistical differences between groups in bone mineral density (BMD) at the femur neck and total hip and in serum bone-specific alkaline phosphatase (BSALP) level. The odds ratio (OR) for lower BMD at the lumbar spine in the presence of pheochromocytoma was 3.31 (95% confidence interval, 1.23 to 8.56). However, the ORs for lower BMD at the femur neck and total hip did not differ according to the presence of pheochromocytoma. Serum CTX level decreased by 35.2% after adrenalectomy in patients with pheochromocytoma, whereas serum BSALP level did not change significantly. Conclusions: This study provides clinical evidence showing that sympathetic overstimulation in pheochromocytoma can contribute to adverse effects on human bone through the increase of bone loss (especially in trabecular bone), as well as bone resorption. PMID- 28582553 TI - 'Silent' and 'noisy' areas: acute flaccid paralysis surveillance at subnational level, Australia, 2001-2015. AB - Background: Acute flaccid paralysis (AFP) surveillance rates are used as an indicator of surveillance sensitivity to detect poliomyelitis with an expected rate of >=1 case per 100 000 population in children under 15 years of age. Methods: The Australian AFP detection rates at sub-national (statistical local area) level were analysed using chi2 goodness of fit tests and exact Poisson probabilities for the combined years 2001-2015 to detect 'silent areas', which may require improved AFP detection efforts, and areas with greater than expected rates, which may indicate unexplained clusters such as those due to enterovirus infection. Results: Eight (n=8/87, 9%) local areas had AFP surveillance detection rates that were less than expected, and eighteen local areas (n=18/87, 21%) had rates that were greater than expected. However, based on available evidence, it is unlikely that these indicated previously unidentified, enterovirus clusters. Conclusions: While Australia has regularly met the national AFP surveillance performance indicators, at the subnational level nine per cent of local areas demonstrated statistically significant lower AFP detection rates. All countries, even those with relatively small populations, should actively identify silent AFP areas to prompt surveillance improvements. PMID- 28582555 TI - Enablers of innovation in digital public health surveillance: lessons from Flutracking. AB - Opportunities for digital innovation in public health surveillance have never been greater. Social media data streams, Open Data initiatives, mHealth geotagged data, and the 'internet of things' are ripe for development. To embrace these opportunities we need to provide public health professionals with environments that support experimentation with new technology. Innovative practitioners will lead discovery, adaption, trialling and deployment of new technological solutions mostly developed outside their organisation. To enhance innovation agencies will need to learn from 'startup culture' and the practices of large organisations that ring fence innovative teams to protect them and allow them to 'break rules', 'fail fast', and innovate. PMID- 28582554 TI - Novel surveillance methods for the control of Ebola virus disease. AB - The unprecedented scale of the 2013-2016 West African Ebola virus disease (EVD) outbreak was in a large part due to failings in surveillance: contacts of confirmed cases were not systematically identified, monitored and diagnosed early, and new cases appearing in previously unaffected communities were similarly not rapidly identified, diagnosed and isolated. Over the course of this epidemic, traditional surveillance methods were strengthened and novel methods introduced. The wealth of experience gained, and the systems introduced in West Africa, should be used in future EVD outbreaks, as well as for other communicable diseases in the region and beyond. PMID- 28582557 TI - Global infectious disease surveillance: getting back to basics. PMID- 28582556 TI - Serious bacterial infections in neonates: improving reporting and case definitions. AB - Neonatal infections affect about 7 million neonates causing over 600 000 deaths every year. Estimating the burden is challenging as there are multiple reporting criteria and definitions for serious bacterial infections in neonates. Essential criteria for reporting serious neonatal bacterial infections have recently been published as the STROBE-NI checklist and, in the context of maternal vaccination, definitions have been published by the Brighton Collaboration Global Alignment of Immunization safety Assessment in pregnancy (GAIA) project. Standardisation of reporting criteria is essential to allow data comparability. This an important step in providing a clearer picture of the burden of serious bacterial infections in neonates and a welcome progress for guiding new investments in interventions. PMID- 28582559 TI - Why transition matters as much as eradication: lessons from global polio surveillance. PMID- 28582558 TI - ProMED-mail: 22 years of digital surveillance of emerging infectious diseases. AB - ProMED-mail (ProMED) was launched in 1994 as an email service to identify unusual health events related to emerging and re-emerging infectious diseases and toxins affecting humans, animals and plants. It is used daily by public health leaders, government officials at all levels, physicians, veterinarians and other healthcare workers, researchers, private companies, journalists and the general public. Reports are produced and commentary provided by a global team of subject matter experts in a variety of fields including virology, parasitology, epidemiology, entomology, veterinary and plant disease specialists. ProMED operates 24 hours a day, 7 days a week and has over 83 000 subscribers, representing every country in the world. Additionally, ProMED disseminates information via its website and through social media channels such as Twitter and Facebook as well as through RSS feeds. Over the last 22 years, it has been the first to report on numerous major and minor disease outbreaks including SARS, MERS, Ebola and the early spread of Zika. ProMED is transparent, apolitical, open to all and free of charge, making it an important and longstanding contributor to global health surveillance. PMID- 28582560 TI - The critical role of acute flaccid paralysis surveillance in the Global Polio Eradication Initiative. AB - Acute flaccid paralysis (AFP) surveillance is a key strategy used by the Global Polio Eradication Initiative (GPEI) to measure progress towards reaching the global eradication goal. Supported by a global polio laboratory network, AFP surveillance is conducted in 179 of 194 WHO member states. Active surveillance visits to priority health facilities are used to assure all children <15 years with AFP are detected, followed by stool specimen collection and testing for poliovirus in WHO-accredited polio laboratories. The quality of AFP surveillance is regularly monitored with standardized surveillance quality indicators. In highest risk countries and areas, the sensitivity of AFP surveillance is enhanced by environmental surveillance (testing of sewage samples). Genetic sequencing of detected poliovirus isolates yields programmatically important information on polio transmission pathways. AFP surveillance is one of the most valuable assets of the GPEI, with the potential to serve as a platform to build integrated disease surveillance systems. Continued support to maintain AFP surveillance systems will be essential, to reliably monitor the completion of global polio eradication, and to assure that a key resource for building surveillance capacity is transitioned post-eradication to support other health priorities. PMID- 28582561 TI - Global and national laboratory networks support high quality surveillance for measles and rubella. AB - Laboratory networks are an essential component of disease surveillance systems because they provide accurate and timely confirmation of infection. WHO coordinates global laboratory surveillance of vaccine preventable diseases, including measles and rubella. The more than 700 laboratories within the WHO Global Measles and Rubella Laboratory Network (GMRLN) supports surveillance for measles, rubella and congenial rubella syndrome in 191 counties. This paper describes the overall structure and function of the GMRLN and highlights the largest of the national laboratory networks, the China Measles and Rubella Laboratory Network. PMID- 28582562 TI - Adaptation of a malaria surveillance system for use in a visceral leishmaniasis elimination programme. AB - Background: Successful public practice relies on generation and use of high quality data. A data surveillance system (the Disease Data Management System [DDMS]) in use for malaria was adapted for use in the Indian visceral leishmaniasis elimination programme. Methods: A situational analysis identified the data flows in current use. Taxonomic trees for the vector of visceral leishmaniasis in India, Phlebotomus argentipes, were incorporated into the DDMS to allow entry of quality assurance and insecticide susceptibility data. A new quality assurance module was created to collate the concentration of DDT that was applied to walls during the indoor residual spraying (IRS) vector control programme. Results: The DDMS was implemented in Bihar State and used to collate and manage data from sentinel sites in eight districts. Quality assurance data showed that DDT was under-applied to walls during IRS; this, combined with insecticide susceptibility data showing widespread vector resistance to DDT prompted a national policy change to using compression pumps and alpha cypermethrin insecticide for IRS. Conclusions: The adapted DDMS centralises programmatic data and enhances evidence-based decision making and active policy change. Moving forward, further modules of the system will be implemented, allowing extended data capture and streamlined transmission of key information to decision makers. PMID- 28582563 TI - Participant-centred active surveillance of adverse events following immunisation: a narrative review. AB - The importance of active, participant-centred monitoring of adverse events following immunisation (AEFI) is increasingly recognised as a valuable adjunct to traditional passive AEFI surveillance. The databases OVID Medline and OVID Embase were searched to identify all published articles referring to AEFI. Only studies which sought participant response after vaccination were included. A total of 6060 articles published since the year 2000 were identified. After the application of screening inclusion and exclusion criteria, 25 articles describing 23 post-marketing AEFI systems were identified. Most countries had a single system: Ghana, Japan, China, Korea, Netherlands, Singapore, Brazil, Cambodia, Sri Lanka, Turkey and Cameroon except the USA (2), Canada (4) and Australia (6). Data were collected from participants with and without AEFI in all studies reviewed with denominator data enabling AEFI rate calculations. All studies considered either a single vaccine or specified vaccines or were time limited except one Australian system, which provides continuous automated participant-centred active surveillance of all vaccines. Post-marketing surveillance systems using solicited patient feedback are emerging as a novel AEFI monitoring tool. A number of exploratory systems utilising e-technology have been developed and their potential for scaling up and application in low and middle income countries deserves further investigation. PMID- 28582564 TI - Disengagement as Withdrawal From Public Space: Rethinking the Relation Between Place Attachment, Place Appropriation, and Identity-Building Among Older Adults. AB - Background and Objectives: Empirical research indicates that engagement with public space decreases with age. Why do some older adults withdraw from the public, and which role does the (urban) environment play in spatial (dis )engagement? Environmental gerontology's model of person-environment (PE) fit suggests an interrelation between agency and belonging and their causal effects on identity and wellbeing in later life. However, there is little research on how these dimensions are actually related. This study sets out to investigate this relationship and how PE can be better adapted for deprived neighborhoods. Research Design and Methods: The study follows a qualitative case studies approach, focusing on a deprived neighborhood in Vienna, Austria. Nonparticipant observations were conducted at this site and complemented by 13 episodic interviews with older residents. Results: The results challenge PE's model of interrelation between agency and belonging and their causal effects on identity, wellbeing, and autonomy in later life. Spatial agency in the deprived neighborhood was intense but so was spatial alienation and distancing oneself from one's neighborhood. Drawing on notions of territorial stigma, this might be a coping strategy to prevent one's self-identity from being "stained". Which strategy is being adopted by whom depends on the position and the trajectory in social and physical space. Discussion and Implications: PE can be complemented with intersubjective measures of environmental conditions (e.g., stigma) and spatial engagement. Gerontology should proceed to consider not only the poor, disadvantaged, disengaged elderly, but also the rebellious, resisting, provocative new generation of older adults. PMID- 28582565 TI - ISAMBARD: an open-source computational environment for biomolecular analysis, modelling and design. AB - Motivation: The rational design of biomolecules is becoming a reality. However, further computational tools are needed to facilitate and accelerate this, and to make it accessible to more users. Results: Here we introduce ISAMBARD, a tool for structural analysis, model building and rational design of biomolecules. ISAMBARD is open-source, modular, computationally scalable and intuitive to use. These features allow non-experts to explore biomolecular design in silico. ISAMBARD addresses a standing issue in protein design, namely, how to introduce backbone variability in a controlled manner. This is achieved through the generalization of tools for parametric modelling, describing the overall shape of proteins geometrically, and without input from experimentally determined structures. This will allow backbone conformations for entire folds and assemblies not observed in nature to be generated de novo, that is, to access the 'dark matter of protein fold space'. We anticipate that ISAMBARD will find broad applications in biomolecular design, biotechnology and synthetic biology. Availability and implementation: A current stable build can be downloaded from the python package index (https://pypi.python.org/pypi/isambard/) with development builds available on GitHub (https://github.com/woolfson-group/) along with documentation, tutorial material and all the scripts used to generate the data described in this paper. Contact: d.n.woolfson@bristol.ac.uk or chris.wood@bristol.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28582566 TI - Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women. AB - BACKGROUND: Non-classic congenital hyperplasia (NCAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by androgen excess. OBJECTIVE AND RATIONALE: We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of NCAH. A meta-analysis of epidemiological data was also performed. SEARCH METHODS: Peer-reviewed studies evaluating NCAH published up to October 2016 were reviewed. Multiple databases were searched including MEDLINE, EMBASE, Cochrane, ERIC, EBSCO, dissertation abstracts, and current contents. OUTCOMES: The worldwide prevalence of NCAH amongst women presenting with signs and symptoms of androgen excess is 4.2% (95% confidence interval: 3.2-5.4%). The clinical consequences of NCAH expand from infancy, i.e. accelerated growth, to adolescence and adulthood, i.e. premature pubarche, cutaneous symptoms and oligo-ovulation in a polycystic ovary syndrome (PCOS)-like clinical picture. The diagnosis of NCAH relies on serum 17 hydroxyprogesterone (17-OHP) concentrations. A basal 17-OHP concentration >=2 ng/ml (6 nmol/l) should be used for screening if more appropriate in-house cut off values are not available. Definitive diagnosis requires a 17-OHP concentration >=10 ng/ml (30 nmol/l), either basally or after cosyntropin stimulation. Molecular genetic analysis of the CYP21A2 gene, which is responsible for 21-hydroxylase activity, may be used for confirmation purposes and should be offered to all patients with NCAH along with genetic counseling because these patients frequently carry alleles that may result in classic CAH, the more severe form of the disease, in their progeny. Treatment must be individualized. Glucocorticoid replacement therapy may benefit pediatric patients with accelerated growth or advanced bone age or adult women seeking fertility, whereas adequate control of menstrual irregularity, hirsutism and other cutaneous symptoms is best served by the use of oral contraceptive pills and/or anti androgens. Some women may need ovulation induction or assisted reproductive technology to achieve pregnancy. Patients with NCAH have a higher risk of miscarriage and may benefit from glucocorticoid treatment during pregnancy. WIDER IMPLICATIONS: Evidence-based diagnostic and treatment strategies are essential for the proper management of women with NCAH, especially considering that these patients may need different therapeutic strategies at different stages during their follow-up and that appropriate genetic counseling may prevent the occurrence of CAH in their children. PMID- 28582567 TI - Trends in Tobacco Product Use Patterns Among U.S. Youth, 1999-2014. AB - Introduction: We examined trends in seven mutually exclusive tobacco product use patterns (T-PUPs) in nationally representative samples of U.S. youth over time and age. Methods: We used time varying effect modeling on National Youth Tobacco Surveys, 1999-2014 (N = 38662, 9-17 years, M = 15.02). Regression coefficients were estimated as a non-parametric function of time. T-PUPs were cigarette only, non-cigarette combustible only, noncombustible only, non-cigarette combustible and noncombustible dual, cigarette and noncombustible dual, cigarette and non cigarette combustible dual, and POLY (i.e. cigarettes, non-cigarette combustibles, and noncombustibles) use. Results: Among youth tobacco users, cigarette only use was the predominant T-PUP from 1999 to 2010. After 2010 and 2013, non-cigarette combustible only (AOR 1.38, CI = 1.02-1.87) and noncombustible only (AOR 1.57, CI = 1.00-2.45) use became more prevalent than cigarette only use. In 2011, dual and POLY T-PUPs were on the rise although not significantly different from cigarette only use. Cigarette only use was the predominant T-PUP among 11- to 17-year-old tobacco users. Non-cigarette combustible only (AOR 0.14, CI = 0.10-0.19), noncombustible only (AOR 0.01, CI = 0.008-0.02), non-cigarette combustible and noncombustible (AOR 0.01, CI = 0.01 0.03), cigarette and noncombustible (AOR 0.02, CI = 0.01-0.04), cigarette and non cigarette combustible (AOR 0.32, CI = 0.24-0.43), and POLY (AOR 0.02, CI = 0.01 0.04) use were less prevalent than cigarette only use at age 17. Conclusions: Non cigarette, dual, and POLY T-PUPs are rising among youth tobacco users. Screening for all tobacco use and delivering treatment during pediatrician visits should be standard clinical practice. Implications: Tracking trends in tobacco product use patterns (T-PUPs) over time and age is necessary to achieve Healthy People 2020 goal of reducing tobacco use among youth. Trends over time show a rise of non cigarette T-PUPs especially noncombustible products but cigarette only use remains the most prevalent among 11- to 17-year-old tobacco users. The recent extension of FDA's regulatory jurisdiction over all tobacco products (e.g. e cigarettes, hookah) is a step toward comprehensive tobacco control especially among youth. Public health practitioners should extend prevention and cessation efforts among youth to T-PUPs beyond exclusive cigarette smoking. PMID- 28582568 TI - Bilateral Orbital Pseudotumor in a 3-Year-Old Child: A Case Report. AB - Orbital pseudotumor is a rare, idiopathic, inflammatory process within the orbit. Early diagnosis is essential to prevent corneal, retinal and extraocular muscle damage. This article describes the presentation and clinical course of a 3-year old male with bilateral orbital pseudotumor. PMID- 28582569 TI - GPCR-SSFE 2.0-a fragment-based molecular modeling web tool for Class A G-protein coupled receptors. AB - G-protein coupled receptors (GPCRs) are key players in signal transduction and therefore a large proportion of pharmaceutical drugs target these receptors. Structural data of GPCRs are sparse yet important for elucidating the molecular basis of GPCR-related diseases and for performing structure-based drug design. To ameliorate this problem, GPCR-SSFE 2.0 (http://www.ssfa-7tmr.de/ssfe2/), an intuitive web server dedicated to providing three-dimensional Class A GPCR homology models has been developed. The updated web server includes 27 inactive template structures and incorporates various new functionalities. Uniquely, it uses a fingerprint correlation scoring strategy for identifying the optimal templates, which we demonstrate captures structural features that sequence similarity alone is unable to do. Template selection is carried out separately for each helix, allowing both single-template models and fragment-based models to be built. Additionally, GPCR-SSFE 2.0 stores a comprehensive set of pre calculated and downloadable homology models and also incorporates interactive loop modeling using the tool SL2, allowing knowledge-based input by the user to guide the selection process. For visual analysis, the NGL viewer is embedded into the result pages. Finally, blind-testing using two recently published structures shows that GPCR-SSFE 2.0 performs comparably or better than other state-of-the art GPCR modeling web servers. PMID- 28582572 TI - Surgical Treatment of Mesiotemporal Lobe Epilepsy: Which Approach is Favorable? AB - BACKGROUND: Mesiotemporal lobe epilepsy is one of the most frequent causes for pharmacoresistant epilepsy. Different surgical approaches to the mesiotemporal area are used. OBJECTIVE: To analyze epileptological and neuropsychological results as well as complications of different surgical strategies. METHODS: This retrospective study is based on a consecutive series of 458 patients all harboring pharmacoresistant mesiotemporal lobe epilepsy. Following procedures were performed: standard anterior temporal lobectomy, anterior temporal or key hole resection, extended lesionectomy, and transsylvian and subtemporal selective amygdalohippocampectomy. Postoperative outcome was evaluated according to different surgical procedures. RESULTS: Overall, 1 yr after surgery 315 of 432 patients (72.9%) were classified Engel I; in particular, 72.8% were seizure-free after anterior temporal lobectomy, 76.9% after key-hole resection, 84.4% after extended lesionectomy, 70.3% after transylvian selective amygdalohippocampectomy, and 59.1% after subtemporal selective amygdalohippocampectomy. No significant differences in seizure outcome were found between different resective procedures, neither in short-term nor long-term follow-up. There was no perioperative mortality. Permanent morbidity was encountered in 4.4%. There were no significant differences in complications between different resection types. In the majority of patients, selective attention improved following surgery. Patients after left sided operations performed significantly worse regarding verbal memory as compared to right-sided procedures. However, surgical approach had no significant effect on memory outcome. CONCLUSION: Different surgical approaches for mesiotemporal epilepsy analyzed resulted in similar epileptological, neuropsychological results, and complication rates. Therefore, the approach for the individual patient does not only depend on the specific localization of the epileptogenic area, but also on the experience of the surgeon. PMID- 28582570 TI - Phase II Proof-of-Concept Trial of the Orexin Receptor Antagonist Filorexant (MK 6096) in Patients with Major Depressive Disorder. AB - Background: We evaluated the orexin receptor antagonist filorexant (MK-6096) for treatment augmentation in patients with major depressive disorder. Methods: We conducted a 6-week, double-blind, placebo-controlled, parallel-group, Phase II, proof-of-concept study. Patients with major depressive disorder (partial responders to ongoing antidepressant therapy) were randomized 1:1 to once-daily oral filorexant 10 mg or matching placebo. Results: Due to enrollment challenges, the study was terminated early, resulting in insufficient statistical power to detect a prespecified treatment difference; of 326 patients planned, 129 (40%) were randomized and 128 took treatment. There was no statistically significant difference in the primary endpoint of change from baseline to week 6 in Montgomery Asberg Depression Rating Scale total score; the estimated treatment difference for filorexant-placebo was -0.7 (with negative values favoring filorexant) (P=.679). The most common adverse events were somnolence and suicidal ideation. Conclusions: The interpretation of the results is limited by the enrollment, which was less than originally planned, but the available data do not suggest efficacy of orexin receptor antagonism with filorexant for the treatment of depression. (Clinical Trial Registry: clinicaltrials.gov: NCT01554176). PMID- 28582571 TI - The role of Rubisco kinetics and pyrenoid morphology in shaping the CCM of haptophyte microalgae. AB - The haptophyte algae are a cosmopolitan group of primary producers that contribute significantly to the marine carbon cycle and play a major role in paleo-climate studies. Despite their global importance, little is known about carbon assimilation in haptophytes, in particular the kinetics of their Form 1D CO2-fixing enzyme, Rubisco. Here we examine Rubisco properties of three haptophytes with a range of pyrenoid morphologies (Pleurochrysis carterae, Tisochrysis lutea, and Pavlova lutheri) and the diatom Phaeodactylum tricornutum that exhibit contrasting sensitivities to the trade-offs between substrate affinity (Km) and turnover rate (kcat) for both CO2 and O2. The pyrenoid containing T. lutea and P. carterae showed lower Rubisco content and carboxylation properties (KC and kCcat) comparable with those of Form 1D containing non-green algae. In contrast, the pyrenoid-lacking P. lutheri produced Rubisco in 3-fold higher amounts, and displayed a Form 1B Rubisco kCcat-KC relationship and increased CO2/O2 specificity that, when modeled in the context of a C3 leaf, supported equivalent rates of photosynthesis to higher plant Rubisco. Correlation between the differing Rubisco properties and the occurrence and localization of pyrenoids with differing intracellular CO2:O2 microenvironments has probably influenced the divergent evolution of Form 1B and 1D Rubisco kinetics. PMID- 28582573 TI - Integrative analysis of multiple genomic variables using a hierarchical Bayesian model. AB - Motivation: Genes showing congruent differences in several genomic variables between two biological conditions are crucial to unravel causalities behind phenotypes of interest. Detecting such genes is important in biomedical research, e.g. when identifying genes responsible for cancer development. Small sample sizes common in next-generation sequencing studies are a key challenge, and there are still only very few statistical methods to analyze more than two genomic variables in an integrative, model-based way. Here, we present a novel bioinformatics approach to detect congruent differences between two biological conditions in a larger number of different measurements such as various epigenetic marks or mRNA transcript levels. Results: We propose a coefficient quantifying the degree to which genes present consistent alterations in multiple (more than two) genomic variables when comparing samples presenting a condition of interest (e.g. cancer) to a reference group. A hierarchical Bayesian model is employed to assess uncertainty on a gene level, incorporating information on functional relationships between genes. We demonstrate the approach on different data sets containing RNA-seq gene transcripton and up to four ChIP-seq histone modification measurements. Both the coefficient-based ranking and the inference based on the model lead to a plausible prioritizing of candidate genes when analyzing multiple genomic variables. Availability and implementation: BUGS code in the Supplement. Contact: m.schaefer@uni-duesseldorf.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28582574 TI - A Genetic Model to Study Increased Hexosamine Biosynthetic Flux. AB - Recently, we identified harvest moon (hmn), a fully penetrant and expressive recessive zebrafish mutant with hepatic steatosis. Larvae showed increased triacylglycerol in the absence of other obvious defects. When we attempted to raise these otherwise normal-appearing mutants to adulthood, we observed a developmental arrest and death in the early juvenile period. In this study, we report the positional cloning of the hmn locus and characterization of the defects caused by the mutation. Using bulk segregant analysis and fine mapping, we find that hmn mutants harbor a point mutation in an invariant residue within the sugar isomerase 1 domain of the gene encoding the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP) glutamine-fructose-6-phosphate transamidase (Gfpt1). The mutated protein shows increased abundance. The HBP generates beta-N acetyl-glucosamine (GlcNAc) as a spillover pathway from glucose. GlcNAc can be O linked to seryl and threonyl residues of diverse cellular proteins (O-GlcNAc modification). Although some of these O-GlcNAc modifications serve an essential structural role, many others are dynamically generated on signaling molecules, including several impacting insulin signaling. We find that gfpt1 mutants show global increase in O-GlcNAc modification, and, surprisingly, lower fasting blood glucose in males. Taken together with our previously reported work, the gfpt1 mutant we isolated demonstrates that global increase in O-GlcNAc modification causes some severe insulin resistance phenotypes (hepatic steatosis and runting) but does not cause hyperglycemia. This animal model will provide a platform for dissecting how O-GlcNAc modification alters insulin responsiveness in multiple tissues. PMID- 28582577 TI - Postnatal Weight Gain Patterns in Preterm Very-Low-Birth-Weight Infants Born in a Tertiary Care Center in South India. AB - Background: Extrauterine growth retardation is a common problem in preterm, very low-birth-weight (VLBW) babies, as well as paucity of growth charts that follow their postnatal growth. Aim: To evaluate and plot postnatal weight gain patterns of preterm VLBW babies of <34 weeks' gestation born at a tertiary care neonatal unit in South India. Methods: Weight gain patterns of all preterm (27 to < 34 weeks' gestation) and VLBW (<1500 g) neonates were used for plotting the centile curves by retrospective review of electronic medical records. The growth velocity was calculated from birth and from the time baby regained their birth weight. Results: Mean growth rate (+/-SD) of these babies was 16.2 +/- 2.4 g/kg/day and average time to regain birth weight was 14.2 days (range 12.0-17.6). Conclusion: The recommended growth velocity of 10-15 g/kg/day can be achieved using unfortified expressed breast milk, though at higher feeding volumes of 200 ml/kg/day. These centile curves can be useful for monitoring postnatal growth. PMID- 28582575 TI - The RNA workbench: best practices for RNA and high-throughput sequencing bioinformatics in Galaxy. AB - : RNA-based regulation has become a major research topic in molecular biology. The analysis of epigenetic and expression data is therefore incomplete if RNA based regulation is not taken into account. Thus, it is increasingly important but not yet standard to combine RNA-centric data and analysis tools with other types of experimental data such as RNA-seq or ChIP-seq. Here, we present the RNA workbench, a comprehensive set of analysis tools and consolidated workflows that enable the researcher to combine these two worlds. Based on the Galaxy framework the workbench guarantees simple access, easy extension, flexible adaption to personal and security needs, and sophisticated analyses that are independent of command-line knowledge. Currently, it includes more than 50 bioinformatics tools that are dedicated to different research areas of RNA biology including RNA structure analysis, RNA alignment, RNA annotation, RNA-protein interaction, ribosome profiling, RNA-seq analysis and RNA target prediction. The workbench is developed and maintained by experts in RNA bioinformatics and the Galaxy framework. Together with the growing community evolving around this workbench, we are committed to keep the workbench up-to-date for future standards and needs, providing researchers with a reliable and robust framework for RNA data analysis. AVAILABILITY: The RNA workbench is available at https://github.com/bgruening/galaxy-rna-workbench. PMID- 28582578 TI - Proteomics of the epicardial fat secretome and its role in post-operative atrial fibrillation. AB - Aims: Post-operative atrial fibrillation (POAF) is a predictor of morbidity and mortality after cardiac surgery. Latent predisposing factors may reside in the epicardial adipose tissue (EAT) due to its anatomical position and high protein production rate. In order to explore a possible mechanistic link, we characterized proteins secreted by the EAT preceding the onset of POAF. Methods and results: Epicardial adipose tissue samples were collected from 76 consecutive patients with no history of AF undergoing coronary artery bypass surgery, 50 samples for proteomic analysis and 26 for gene expression studies, further divided according to development of POAF. Ten vs. 10 matched samples representing EAT secretome were analysed by two-dimensional difference in-gel electrophoresis (2D-DIGE) and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to identify differentially expressed proteins (P < 0.05, expression change >1.2 fold). Findings were validated by Western blotting on EAT protein extracts and by gene expression studies via quantitative polymerase chain reaction (qPCR). Proteomics returned 35 differentially expressed proteins. Amongst those, gelsolin was down regulated in POAF. Western blot analysis confirmed a significant reduction in gelsolin in the AF group. Gene expression for gelsolin was significantly reduced in the AF group confirming the proteomics findings. Conclusion: For the first time we describe EAT secretome as a possible substrate for POAF. It contains various proteins differentially expressed in patients who later develop POAF. Amongst those gelsolin, involved in inflammation and ion channel regulation, was associated with maintenance of sinus rhythm. Understanding the role of EAT may offer novel insights into prevention and treatment of AF. PMID- 28582576 TI - Unique localization of the plastid-specific ribosomal proteins in the chloroplast ribosome small subunit provides mechanistic insights into the chloroplastic translation. AB - Chloroplastic translation is mediated by a bacterial-type 70S chloroplast ribosome. During the evolution, chloroplast ribosomes have acquired five plastid specific ribosomal proteins or PSRPs (cS22, cS23, bTHXc, cL37 and cL38) which have been suggested to play important regulatory roles in translation. However, their exact locations on the chloroplast ribosome remain elusive due to lack of a high-resolution structure, hindering our progress to understand their possible roles. Here we present a cryo-EM structure of the 70S chloroplast ribosome from spinach resolved to 3.4 A and focus our discussion mainly on the architecture of the 30S small subunit (SSU) which is resolved to 3.7 A. cS22 localizes at the SSU foot where it seems to compensate for the deletions in 16S rRNA. The mRNA exit site is highly remodeled due to the presence of cS23 suggesting an alternative mode of translation initiation. bTHXc is positioned at the SSU head and appears to stabilize the intersubunit bridge B1b during thermal fluctuations. The translation factor plastid pY binds to the SSU on the intersubunit side and interacts with the conserved nucleotide bases involved in decoding. Most of the intersubunit bridges are conserved compared to the bacteria, except for a new bridge involving uL2c and bS6c. PMID- 28582579 TI - Glowing Worms: Biological, Chemical, and Functional Diversity of Bioluminescent Annelids. AB - Bioluminescence, the ability to produce light by living organisms, has evolved independently in numerous lineages across the tree of life. Luminous forms are found in a wide range of taxonomic groups from bacteria to vertebrates, although the great majority of bioluminescent organisms are marine taxa. Within the phylum Annelida, bioluminescence is widespread, present in at least 98 terrestrial and marine species that represent 45 genera distributed in thirteen lineages of clitellates and polychaetes. The ecological diversity of luminous annelids is unparalleled, with species occupying a great variety of habitats including both terrestrial and marine ecosystems, from coastal waters to the deep-sea, in benthic and pelagic habitats from polar to tropical regions. This great taxonomic and ecological diversity is matched by the wide array of bioluminescent colors including yellow light, which is very rare among marine taxa-different emission wavelengths even between species of the same genus, and varying patterns, chemical reactions and kinetics. This diversity of bioluminescence colors and patterns suggests that light production in annelids might be involved in a variety of different functions, including defensive mechanisms like sacrificial lures or aposematic signals, and intraspecific communication systems. In this review, we explore the world of luminous annelids, particularly focusing on the current knowledge regarding their taxonomic and ecological diversity and discussing the putative functions and chemistries of their bioluminescent systems. PMID- 28582581 TI - Changes in blood DNA methylation and incomplete adjustment for blood cell composition. PMID- 28582580 TI - Transaortic transcatheter aortic valve implantation using SAPIEN XT or SAPIEN 3 valves in the ROUTE registry. AB - OBJECTIVES: Transaortic (TAo) access for transcatheter aortic valve implantation (TAVI) is an alternative to the conventional transfemoral or transapical routes. Data comparing the characteristics and outcomes of TAo-TAVI using the SAPIEN XT and SAPIEN 3 heart valves are scarce. The objective of the current analysis was to provide such information. METHODS: ROUTE is an international, prospective, observational registry. Patients with severe calcific aortic stenosis scheduled for TAo-TAVI with an Edwards SAPIEN XT or a SAPIEN 3 heart valve were consecutively enrolled at 22 centres across Europe between February 2013 and February 2015. Periprocedural, in-hospital and 30-day complication rates were assessed. RESULTS: Of the 301 patients included, 126 (41.9%) received a SAPIEN 3 and 175 (58.1%) a SAPIEN XT. The SAPIEN 3 was associated with shorter procedure time (101 +/- 35 vs 111 +/- 40 min; P = 0.031) and a lower quantity of contrast agent used (87 +/- 43 vs 112 +/- 50 ml; P < 0.001). Balloon dilation was performed less often before (68.0% vs 78.3%; P = 0.045) and after implantation (13.6% vs 30.1%; P = 0.001). No statistically significant differences between the valve types were documented for overall (4.1% SAPIEN 3 vs 7.6% SAPIEN XT; P = 0.21), TAVI-related (0.8% vs 4.7%; P = 0.084) and cardiovascular mortality (2.4% vs 5.9%; P = 0.158). Major vascular complications were less frequent (0.8% vs 5.3%; P = 0.049), and there was a lower rate of moderate-to-severe paravalvular regurgitation (0.8% vs 5.1%; P = 0.050) in the SAPIEN 3 group. CONCLUSIONS: Both the SAPIEN XT and SAPIEN 3 were safely implanted via the TAo route, though the SAPIEN 3 may be associated with a higher procedural success rate and improved prognosis. ClinicalTrials.gov Identifier: NCT01991431. PMID- 28582583 TI - Response to Letter to the Editor by Benmarhnia T, Leas E, Hendrickson E, Trinidad D, Strong D, Pierce J. The Potential Influence of Regulatory Environment for e cigarettes on the Effectiveness of e-cigarettes for Smoking Cessation: Different Reasons to Temper the Conclusions From Inadequate Data. PMID- 28582582 TI - Codon usage regulates protein structure and function by affecting translation elongation speed in Drosophila cells. AB - Codon usage biases are found in all eukaryotic and prokaryotic genomes and have been proposed to regulate different aspects of translation process. Codon optimality has been shown to regulate translation elongation speed in fungal systems, but its effect on translation elongation speed in animal systems is not clear. In this study, we used a Drosophila cell-free translation system to directly compare the velocity of mRNA translation elongation. Our results demonstrate that optimal synonymous codons speed up translation elongation while non-optimal codons slow down translation. In addition, codon usage regulates ribosome movement and stalling on mRNA during translation. Finally, we show that codon usage affects protein structure and function in vitro and in Drosophila cells. Together, these results suggest that the effect of codon usage on translation elongation speed is a conserved mechanism from fungi to animals that can affect protein folding in eukaryotic organisms. PMID- 28582584 TI - Systematic review: hand activity and ultrasound of the median nerve. AB - Background: Ultrasound is an established method of viewing the median nerve in the carpal tunnel syndrome (CTS). There is some evidence to suggest that immediate changes may occur in the median nerve before and after hand activity. The evidence for the validity and reliability of ultrasound for testing acute changes in the median nerve has not been systematically reviewed to date. Aims: To evaluate the evidence for visible change in ultrasound appearance of the median nerve after hand activity. Methods: A literature search was designed, and three reviewers independently selected published research for inclusion. Two reviewers independently appraised papers using the Evidence Based Library and Information Practice (EBLIP) appraisal checklist, while the third reviewer resolved discrepancies between appraisals. Results: Ten studies were appraised and the results showed an increase in median nerve cross-sectional area following activity, with a return to normal size within 1 h following activity. Both healthy individuals and those diagnosed with CTS participated, all were small convenience samples. Ultrasonographic measurements of the median nerve were reliable in the four studies reporting this, and the studies demonstrated high quality. Conclusions: Good-quality evidence as identified by the EBLIP appraisal checklist suggests that following hand activity, the median nerve changes in size in the carpal tunnel. The results may not be generalizable to all people and activities due to the use of small convenience sampling and narrow range of activities studied, in all of the studies appraised. PMID- 28582585 TI - Early Onset of HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) and Adult T-cell Leukemia/Lymphoma (ATL): Systematic Search and Review. AB - Human T-cell lymphotropic virus type 1 (HTLV-1) is endemic in some regions and its vertical transmission occurs mainly through breastfeeding. About 10% of carriers develop associated diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), adult T-cell leukemia/lymphoma (ATL) and infectious dermatitis associated with HTLV-1 (IDH). We searched for available case reports of early-onset HAM/TSP and ATL to evaluate demographic and disease aspects in infantile-juvenile patients. In the reviewed literature, 27 HAM/TSP and 31 ATL cases were found. In almost all of them, the most likely route of transmission was through breastfeeding. ATL is rarely reported, notwithstanding it may be underestimated because T-cell lymphomas are not investigated for HTLV-1 infection in this age group. IDH was frequently associated with HAM/TSP. The investigation of HTLV-1 infection in pregnant women is an important matter of public health and should be mandatory in endemic countries. PMID- 28582587 TI - Characteristics of inner reading voices. AB - This study examined the phenomenological characteristics of inner speech during silent reading (inner reading voices or IRVs), a type of inner speech that may be particularly amenable to empirical study. A survey was conducted in the general population to assess IRV frequency, location, number, identity, and controllability, and auditory qualities of IRVs. Of 570 survey respondents, 80.7% reported sometimes or always hearing an inner voice during silent reading, and the remaining 19.3% reported always understanding words being read without hearing an inner voice. Results indicated that IRVs are a routine experience for many, with 34.2% of respondents with IRVs hearing an IRV every time something was read, and 45% reporting an IRV often. Most respondents reported IRVs with specific auditory qualities such as gender, accent, pitch, loudness, and emotional tone. IRVs were reported in participants' own voices, as well as in the voices of other people. Some respondents reported being unable to control any aspect of their IRVs, while others could control one or several aspects. These results indicate that there is considerable individual variation in inner speech during silent reading. PMID- 28582588 TI - Endeavor of Iontronics: From Fundamentals to Applications of Ion-Controlled Electronics. AB - Iontronics is a newly emerging interdisciplinary concept which bridges electronics and ionics, covering electrochemistry, solid-state physics, electronic engineering, and biological sciences. The recent developments of electronic devices are highlighted, based on electric double layers formed at the interface between ionic conductors (but electronically insulators) and various electronic conductors including organics and inorganics (oxides, chalcogenide, and carbon-based materials). Particular attention is devoted to electric-double layer transistors (EDLTs), which are producing a significant impact, particularly in electrical control of phase transitions, including superconductivity, which has been difficult or impossible in conventional all-solid-state electronic devices. Besides that, the current state of the art and the future challenges of iontronics are also reviewed for many applications, including flexible electronics, healthcare-related devices, and energy harvesting. PMID- 28582586 TI - Tension sensors reveal how the kinetochore shares its load. AB - At metaphase in mitotic cells, pulling forces at the kinetochore-microtubule interface create tension by stretching the centromeric chromatin between oppositely oriented sister kinetochores. This tension is important for stabilizing the end-on kinetochore microtubule attachment required for proper bi orientation of sister chromosomes as well as for satisfaction of the Spindle Assembly Checkpoint and entry into anaphase. How force is coupled by proteins to kinetochore microtubules and resisted by centromere stretch is becoming better understood as many of the proteins involved have been identified. Recent application of genetically encoded fluorescent tension sensors within the mechanical linkage between the centromere and kinetochore microtubules are beginning to reveal - from live cell assays - protein specific contributions that are functionally important. PMID- 28582589 TI - Macrocytosis secondary to hydroxyurea therapy. AB - A 10-year-old, male neutered Shetland Sheepdog was presented to the University of Florida for evaluation of a well-granulated mast cell tumor. Hydroxyurea therapy was instituted and serial CBCs showed persistent mild anemia and macrocytosis without a corresponding increase in polychromasia. The dog's MCV increased progressively, reaching its highest value of 100.0 fL after 6 months of treatment, and a diagnosis of macrocytosis associated with hydroxyurea therapy was made. The dog's increase in MCV was prominent, and rapidly decreased after the drug was discontinued, consistent with previous observations in human and canine subjects treated with hydroxyurea. Hydroxyurea is a cytotoxic chemotherapeutic agent used in a variety of conditions in human and veterinary medicine, and megaloblastic changes associated with its use have been described in multiple species. This report shows that hydroxyurea treatment is a differential diagnosis for prominent macrocytosis in dogs in the absence of other signs of erythrocyte regeneration. PMID- 28582590 TI - Control of Circularly Polarized Electroluminescence in Induced Twist Structure of Conjugate Polymer. AB - An extremely high degree of circularly polarized photoluminescence (CPPL) and electroluminescence (CPEL) (dissymmetry factor values: |gPL | = 0.72 and |gEL | = 1.13) are generated from twisted stacking of achiral conjugated polymer induced by nonemitting chiral dopant of high helical twisting power for the first time. Using a theoretical analysis incorporating the Stokes parameter, the twisting angle and birefringence of the aligned conjugated polymer, and the degree of linear polarization in the emitted light are found to make a roughly equal contribution to the degree of CPEL as to the degree of CPPL. Moreover, it is also found that the location of the recombination zone within the emitting layer is a crucial parameter for determining the difference in the dissymmetry factor between CPEL and CPPL. This result is applied to an organic light-emitting display to improve the luminous efficiency by 60%. PMID- 28582591 TI - A tool for integrating genetic and mass spectrometry-based peptide data: Proteogenomics Viewer: PV: A genome browser-like tool, which includes MS data visualization and peptide identification parameters. AB - In this manuscript we describe Proteogenomics Viewer, a web-based tool that collects MS peptide identification, indexes to genomic sequence and structure, assigns exon usage, reports the identified protein isoforms with genomic alignments and, most importantly, allows the inspection of MS2 information for proper peptide identification. It also provides all performed indexing to facilitate global analysis of the data. The relevance of such tool is that there has been an increase in the number of proteogenomic efforts to improve the annotation of both genomics and proteomics data, culminating with the release of the two human proteome drafts. It is now clear that mass spectrometry-based peptide identification of uncharacterized sequences, such as those resulting from unpredicted exon joints or non-coding regions, is still prone to a higher than expected false discovery rate. Therefore, proper visualization of the raw data and the corresponding genome alignments are fundamental for further data validation and interpretation. Also see the video abstract here: http://youtu.be/5NzyRvuk4Ac. PMID- 28582592 TI - Indium Phosphide-Based Quantum Dots with Shell-Enhanced Absorption for Luminescent Down-Conversion. AB - It is shown that admixing small amounts of cadmium into the shell of InP/ZnSe core/shell quantum dots results in an increased absorption of blue light and a limited redshift of the band-edge emission. These effects reflect the reduced bandgap of (Zn,Cd)Se alloys and their smaller conduction-band offset with InP. Nevertheless, adjusting the InP core size enables InP/ZnSe and InP/(Zn,Cd)Se quantum dots with identical emission characteristics to be made. Processing both materials into remote phosphor disks, it is demonstrated that the shell-enhanced absorbance of InP/(Zn,Cd)Se has the double benefit of suppressing self-absorption and reducing the amount of quantum dots by weight needed to attain a given blue to-red color conversion. PMID- 28582593 TI - Secreted protein acidic and rich in cysteine functions in colitis via IL17A regulation in mucosal CD4+ T cells. AB - BACKGROUND AND AIM: Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycol that regulates cell proliferation, tissue repair, and tumorigenesis. Despite evidence linking SPARC to inflammation, the mechanisms are unclear. Accordingly, the role of SPARC in intestinal inflammation was investigated. METHODS: Colitis was induced in wild-type (WT) and SPARC knockout (KO) mice using trinitrobenzene sulfonic acid (TNBS). Colons were assessed for damage; leukocyte infiltration; Tnf, Ifng, Il17a, and Il10 mRNA expression; and histology. Cytokine profiling of colonic lamina propria mononuclear cells (LPMCs) was performed by flow cytometry. Naive CD4+ T cells were isolated from WT and SPARC KO mouse spleens, and the effect of SPARC on Th17 cell differentiation was examined. Recombination activating gene 1 knockout (RAG1 KO) mice reconstituted with T cells from either WT or SPARC KO mice were investigated. RESULTS: Trinitrobenzene sulfonic acid exposure significantly reduced bodyweight and increased mucosal inflammation, leukocyte infiltration, and Il17a mRNA expression in WT relative to SPARC KO mice. The percentage of IL17A-producing CD4+ T cells among LPMCs from KO mice was lower than that in WT mice when both groups were exposed to TNBS. Th17 cell differentiation was suppressed in cells from SPARC KO mice. In the T cell transfer colitis model, RAG1 KO mice receiving T cells from WT mice were more severely affected than those reconstituted with cells from SPARC KO mice. CONCLUSIONS: Secreted protein acidic and rich in cysteine accelerates colonic mucosal inflammation via modulation of IL17A-producing CD4+ T cells. SPARC is a potential therapeutic target for conditions involving intestinal inflammation. PMID- 28582594 TI - Histologic and cytologic bone marrow findings in dogs with suspected precursor targeted immune-mediated anemia and associated phagocytosis of erythroid precursors. AB - BACKGROUND: Precursor-targeted immune-mediated anemia (PIMA) has been suspected in dogs with nonregenerative anemia and bone marrow findings varying from erythroid hyperplasia to pure red cell aplasia. Phagocytosis of erythroid precursors/rubriphagocytosis (RP) reported in some affected dogs suggests a destructive component to the pathogenesis of PIMA. OBJECTIVES: The purpose of the study was to characterize laboratory and clinical findings in dogs with suspected PIMA and RP, with emphasis on cytologic and histologic bone marrow findings. METHODS: Dogs with PIMA and RP were identified by review of paired bone marrow aspirate and core biopsy slides collected over a 4-year period. Samples were systematically assessed and characterized along with other pertinent laboratory data and clinical findings. RESULTS: Twenty-five dogs met criteria for PIMA and had RP that was relatively stage-selective. Erythropoiesis was expanded to the stage of erythroid precursors undergoing most prominent phagocytosis, yielding patterns characterized by a hypo-, normo-, or hypercellular erythroid lineage. A 4th pattern involved severe collagen myelofibrosis, and there was a spectrum of mild to severe collagen myelofibrosis overall. Evidence of immune-mediated hemolysis was rare. Immunosuppressive therapy was associated with remission in 77% of dogs treated for at least the median response time of 2 months. CONCLUSIONS: Bone marrow patterns in dogs fulfilling criteria for PIMA were aligned with stage-selective phagocytosis of erythroid precursors and the development of collagen myelofibrosis, common in dogs with PIMA. Recognition of these patterns and detection of RP facilitates diagnosis of PIMA, and slow response to immunosuppressive therapy warrants further investigation into its pathogenesis. PMID- 28582595 TI - Why the missing heritability might not be in the DNA. AB - There are four major hypotheses (H1, H2, H3, and H4) as to the source of missing heritability. We propose that estimates obtained from GWAS underestimate heritability by not taking into account non-DNA (epigenetic) sources of heritability. Taking those factors into account (H4) should result in increased heritability estimates. PMID- 28582596 TI - A metastatic secretory gastric plasmacytoma with aberrant CD3 expression in a dog. AB - A 10-year-old crossbred dog was presented with a 6-week history of hematemesis, melena, anorexia, and lethargy. Clinical evaluation revealed a gastric mass with a regional lymphadenomegaly as well as a monoclonal gammopathy manifesting as hyperglobulinemia. Cytologic and histopathologic analyses were consistent with a round cell neoplasm; neoplastic cells showed nuclear immunoreactivity for MUM1 and diffuse cytoplasmic reactivity for CD3. Polymerase chain reactions performed on fixed and fresh tissue identified a clonal rearrangement with an IgH primer set. An extramedullary plasmacytoma (EMP) was confirmed by cellular morphology and molecular diagnostics. Following an objective response to chemotherapy, the dog was euthanized 8 months after diagnosis, and a postmortem examination confirmed the clinical findings. This is the first reported case of a monoclonal gammopathy secondary to a gastric EMP coupled with aberrant expression of CD3 in an aggressive plasmacytic tumor, and highlights the utility of molecular diagnostics for classifying atypical hemolymphoid neoplasms. PMID- 28582597 TI - Iodine Vacancy Redistribution in Organic-Inorganic Halide Perovskite Films and Resistive Switching Effects. AB - Organic-inorganic halide perovskite (OHP) materials, for example, CH3 NH3 PbI3 (MAPbI3 ), have attracted significant interest for applications such as solar cells, photodectors, light-emitting diodes, and lasers. Previous studies have shown that charged defects can migrate in perovskites under an electric field and/or light illumination, potentially preventing these devices from practical applications. Understanding and control of the defect generation and movement will not only lead to more stable devices but also new device concepts. Here, it is shown that the formation/annihilation of iodine vacancies (VI 's) in MAPbI3 films, driven by electric fields and light illumination, can induce pronounced resistive switching effects. Due to a low diffusion energy barrier (~0.17 eV), the VI 's can readily drift under an electric field, and spontaneously diffuse with a concentration gradient. It is shown that the VI diffusion process can be suppressed by controlling the affinity of the contact electrode material to I- ions, or by light illumination. An electrical-write and optical-erase memory element is further demonstrated by coupling ion migration with electric fields and light illumination. These results provide guidance toward improved stability and performance of perovskite-based optoelectronic systems, and can lead to the development of solid-state devices that couple ionics, electronics, and optics. PMID- 28582598 TI - Peripheral neuropathy as marker of severe Parkinson's disease phenotype. PMID- 28582600 TI - Effect of time and temperature on anticoagulant-dependent pseudothrombocytopenia in Gottingen minipigs. AB - BACKGROUND: A marked decrease in thrombocyte count was observed between subsequent measurements of the same EDTA blood sample in several minipigs, but little information was available explaining this finding. OBJECTIVES: The objective was to evaluate the impact of several preanalytic variables on thrombocyte counts in minipigs, in order to improve understanding of the in vitro thrombocyte decrease observed. MATERIALS AND METHODS: Hematology blood samples from male and female Gottingen minipigs were collected using EDTA or citrate as an anticoagulant. Samples were stored under different conditions (room temperature, 4 degrees C, or 37-38 degrees C) and were analyzed approximately 0.5 to one h, 3.5-4 h, 7-7.5 h, and 28-29 h after collection. RESULTS: In EDTA blood samples from male minipigs stored at room temperature, there was a progressive thrombocyte decrease over time up to -71% after 29 h, caused by in vitro aggregation. In females, no consistent change was seen up to 7.5 h, but there was a decrease up to -47% after 29 h. Thrombocyte count was most stable during storage at 4 degrees C. No consistent marked decrease in thrombocyte counts was seen for citrated blood at room temperature, although such a decrease was present in a few individual animals. CONCLUSIONS: Study results provide evidence for an anticoagulant-dependent pseudothrombocytopenia in minipigs progressing over time and depending on the storage temperature of the blood sample. It is therefore recommended to perform thrombocyte counts as soon as possible after blood collection, and in case of low counts, investigate for the presence of artifactual platelet clumping. PMID- 28582599 TI - Mechanisms of suppression: The wiring of genetic resilience. AB - Recent analysis of genome sequences has identified individuals that are healthy despite carrying severe disease-associated mutations. A possible explanation is that these individuals carry a second genomic perturbation that can compensate for the detrimental effects of the disease allele, a phenomenon referred to as suppression. In model organisms, suppression interactions are generally divided into two classes: genomic suppressors which are secondary mutations in the genome that bypass a mutant phenotype, and dosage suppression interactions in which overexpression of a suppressor gene rescues a mutant phenotype. Here, we describe the general properties of genomic and dosage suppression, with an emphasis on the budding yeast. We propose that suppression interactions between genetic variants are likely relevant for determining the penetrance of human traits. Consequently, an understanding of suppression mechanisms may guide the discovery of protective variants in healthy individuals that carry disease alleles, which could direct the rational design of new therapeutics. PMID- 28582601 TI - Hematologic RIs for healthy water buffaloes (Bubalus bubalis) in southern Mexico. AB - BACKGROUND: Baseline hematologic data are used by veterinarians and wildlife biologists to perform health assessments on target animal species. Hematologic measurements are influenced by various factors including geography. Baseline hematologic RIs have been established for domestic water buffaloes (Bubalus bubalis) from various countries in the Eastern Hemisphere, but these data are not readily available for the Western Hemisphere. OBJECTIVE: The aim of this study was to determine hematologic values for domestic water buffaloes from several commercial farms in southern Mexico. METHODS: Blood was collected from 126 healthy, postlactating females (3 to 10 years old) from the Murrah breed, and 10 hematologic variables were measured. RESULTS: Means, SDs, RIs, medians (MED), median absolute deviations (MAD), and other statistics were calculated for each hematologic variable. The MED (and MAD) for each variable are as follows: RBC count, 7.6 (1.1) * 1012 /L; hemoglobin, 116.0 (13.3) g/L; PCV, 41.5 (7.6) %; MCV, 56.8 (7.0) fL; MCH, 14.6 (1.6) pg; MCHC, 250.0 (35.6) g/L; RDW (SD), 29.7 (5.5) fL; RDW (CV), 18.2 (1.4) %; reticulocytes, 0.0 (0.0) %, and WBC count, 12.4 (1.3) * 109 /L. These values were compared to those previously reported for water buffaloes from several countries in the Eastern Hemisphere and, on most occasions, they differed significantly. CONCLUSIONS: Our data can be used by veterinarians and other personnel involved in buffalo production in Mexico during medical evaluations. PMID- 28582602 TI - Positive PCR alone should not be considered sufficient to establish Dirofilaria repens as the cause of subcutaneous nodular lesions in the absence of a clear cytologic picture. PMID- 28582603 TI - Stimuli-Responsive, Shape-Transforming Nanostructured Particles. AB - Development of particles that change shape in response to external stimuli has been a long-thought goal for producing bioinspired, smart materials. Herein, the temperature-driven transformation of the shape and morphology of polymer particles composed of polystyrene-b-poly(4-vinylpyridine) (PS-b-P4VP) block copolymers (BCPs) and temperature-responsive poly(N-isopropylacrylamide) (PNIPAM) surfactants is reported. PNIPAM acts as a temperature-responsive surfactant with two important roles. First, PNIPAM stabilizes oil-in-water droplets as a P4VP selective surfactant, creating a nearly neutral interface between the PS and P4VP domains together with cetyltrimethylammonium bromide, a PS-selective surfactant, to form anisotropic PS-b-P4VP particles (i.e., convex lenses and ellipsoids). More importantly, the temperature-directed positioning of PNIPAM depending on its solubility determines the overall particle shape. Ellipsoidal particles are produced above the critical temperature, whereas convex lens-shaped particles are obtained below the critical temperature. Interestingly, given that the temperature at which particle shape change occurs depends solely on the lower critical solution temperature (LCST) of the polymer surfactants, facile tuning of the transition temperature is realized by employing other PNIPAM derivatives with different LCSTs. Furthermore, reversible transformations between different shapes of PS-b-P4VP particles are successfully demonstrated using a solvent-adsorption annealing with chloroform, suggesting great promise of these particles for sensing, smart coating, and drug delivery applications. PMID- 28582604 TI - Layer-by-Layer Motif Architectures: Programmed Electrochemical Syntheses of Multilayer Mesoporous Metallic Films with Uniformly Sized Pores. AB - Although multilayer films have been extensively reported, most compositions have been limited to non-catalytically active materials (e.g. polymers, proteins, lipids, or nucleic acids). Herein, we report the preparation of binder-free multilayer metallic mesoporous films with sufficient accessibility for high electrocatalytic activity by using a programmed electrochemical strategy. By precisely tuning the deposition potential and duration, multilayer mesoporous architectures consisting of alternating mesoporous Pd layers and mesoporous PdPt layers with controlled layer thicknesses can be synthesized within a single electrolyte, containing polymeric micelles as soft templates. This novel architecture, combining the advantages of bimetallic alloys, multilayer architectures, and mesoporous structures, exhibits high electrocatalytic activity for both the methanol oxidation reaction (MOR) and the ethanol oxidation reaction (EOR). PMID- 28582605 TI - An Enzyme-Coated Metal-Organic Framework Shell for Synthetically Adaptive Cell Survival. AB - A bioactive synthetic porous shell was engineered to enable cells to survive in an oligotrophic environment. Eukaryotic cells (yeast) were firstly coated with a beta-galactosidase (beta-gal), before crystallization of a metal-organic framework (MOF) film on the enzyme coating; thereby producing a bioactive porous synthetic shell. The beta-gal was an essential component of the bioactive shell as it generated nutrients (that is, glucose and galactose) required for cell viability in nutrient-deficient media (lactose-based). Additionally, the porous MOF coating carried out other vital functions, such as 1) shielding the cells from cytotoxic compounds and radiation, 2) protecting the non-native enzymes (beta-gal in this instance) from degradation and internalization, and 3) allowing for the diffusion of molecules essential for the survival of the cells. Indeed, this bioactive porous shell enabled the survival of cells in simulated extreme oligotrophic environments for more than 7 days, leading to a decrease in cell viability less than 30 %, versus a 99 % decrease for naked yeast. When returned to optimal growth conditions the bioactive porous exoskeleton could be removed and the cells regained full growth immediately. The construction of bioactive coatings represents a conceptually new and promising approach for the next generation of cell-based research and application, and is an alternative to synthetic biology or genetic modification. PMID- 28582606 TI - 2,2,6,6-Tetramethylpiperydinyl-1-oxyl (TEMPO) Functionalized Benzoxazines Prepared with a One-Pot Synthesis for Reactive/Crosslinkable Initiators of Nitroxide Mediated Polymerization. AB - In this work, the incorporation of a 2,2,6,6-tetramethylpiperydinyl-1-oxyl (TEMPO) group to a benzoxazine ring is performed using a one-pot synthesis for the preparation of TEMPO-functionalized benzoxazine compounds and polymers as reactive and crosslinkable initiators for nitroxide-mediated polymerization (NMP). The TEMPO-functionalization reaction of benzoxazine, traced with 1 H NMR, is conducted with sequential radical transfer and coupling reactions. Moreover, polystyrene-grafted polybenzoxazine copolymers are prepared with the TEMPO benzoxazine initiator and NMP of styrene. The polymerization system exhibits the characteristics of controlled radical polymerization, including controlled molecular weights of products and ability for sequential polymerization. Moreover, based on the chemical reactivity and crosslinking ability of benzoxazine groups, the synthesis route developed in this work will widen the scope of the design and synthesis of functional and high-performance polymers. PMID- 28582609 TI - Coupling Reactions of Alkynyl Indoles and CO2 by Bicyclic Guanidine: Origin of Catalytic Activity? AB - Density functional theory calculations were used to investigate the three possible modes of activation for the coupling of CO2 with alkynyl indoles in the presence of a guanidine base. The first of these mechanisms, involving electrophilic activation, was originally proposed by Skrydstrup et al. (Angew. Chem. Int. Ed. 2015, 54, 6682). The second mechanism involves the nucleophilic activation of CO2 . Both of these electrophilic and nucleophilic activation processes involve the formation of a guanidine-CO2 zwitterion adduct. We have proposed a third mechanism involving the bifunctional activation of the bicyclic guanidine catalyst, allowing for the simultaneous activation of the indole and CO2 by the catalyst. We demonstrated that a second molecule of catalyst is required to facilitate the final cyclization step. Based on the calculated turnover frequencies, our newly proposed bifunctional activation mechanism is the most plausible pathway for this reaction under these experimental conditions. Furthermore, we have shown that this bifunctional mode of activation is consistent with the experimental results. Thus, this guanidine-catalyzed reaction favors a specific-base catalyzed mechanism rather than the CO2 activation mechanism. We therefore believe that this bifunctional mechanism for the activation of bicyclic guanidine is typical of most CO2 coupling reactions. PMID- 28582610 TI - Protein Corona: Impact of Lymph Versus Blood in a Complex In Vitro Environment. AB - In biological environments, the surface of nanoparticles (NPs) are modified by protein corona (PC) that determines their biological behavior. Unfortunately, in vitro tests still give different PC than in vivo tests causing in vitro-in vivo discrepancy; hence, in vitro studies are not indicative for the NPs' behavior in vivo. Here is demonstrated that PC in vitro is strongly influenced by the type of extracellular fluid (ECF), blood or lymph, by their high and low flow conditions and transitions between ECFs, and a combination of these parameters. As a result, this in vitro study approaches fluidic and dynamic variations to which NPs are exposed in vivo: different ECF that NPs encounter first in different injection routes, different transitions in-between ECFs during circulation, and simultaneous change in the exposed flow in these transitions. The most-abundant proteins in PCs are found to be not the most abundant in ECFs, but those having high affinity for binding to the surface of NPs. Moreover, some proteins are differently abundant in PCs at different flows, which indicate force-promoted binding, catch bonds. These results suggest that future in vitro studies should consider more complex incubation conditions to improve the in vitro-in vivo consistency necessary for translational research. PMID- 28582611 TI - Dynamic DNA Origami Device for Measuring Compressive Depletion Forces. AB - The ability to self-assemble nanodevices with programmed structural dynamics that can sense and respond to the local environment could enable transformative applications in fields including molecular robotics, nanomanufacturing, and nanomedicine. The responsive function of biomolecules is often driven by alterations in conformational distributions mediated by highly sensitive interactions with the local environment. Here, we mimic this approach by engineering inherent nanoscale structural dynamics (nanodynamics) into a DNA device that exhibits a distribution of conformations including two stable states separated by a transition state where the energy barrier height is on the scale of the thermal energy, kBT = 4.1 pN.nm, enabling spontaneous transitions between states. We further establish design principles to regulate the equilibrium and kinetic behavior by substituting a few DNA strand components. We use single molecule Forster resonance energy transfer measurements to show these nanodynamic properties are sensitive to sub-piconewton depletion forces in the presence of molecular crowding agents, and the device can measure depletion forces with a resolution of ~100 fN. We anticipate that this approach of engineering nanodynamic DNA devices will enable molecular-scale systems that sense and respond to their local environment with extremely high sensitivity. PMID- 28582608 TI - Prevalence and strong association of high somatic symptom severity with depression and anxiety in a Chinese inpatient population. AB - BACKGROUND: The prevalence of the high somatic symptom severity (HSSS) and its associations with sociodemographic factors, depression, and anxiety has not been surveyed in inpatient populations at general hospitals. METHODS: A sample including 1329 inpatients in a Chinese general hospital was surveyed using Chinese version of 15-item patient health questionnaire (PHQ-15), 9-item patient health questionnaire, and generalized anxiety disorder 7-item scale. RESULTS: A total of 27.8% (n = 369) of the participants had HSSS (PHQ-15 >= 10). The multivariate regression showed that HSSS was significantly associated with depression (adjusted odds ratio [aOR], 5.219), anxiety (aOR, 5.810), or depression or anxiety (aOR, 5.338) but neither with sex, age, marital status, education status, household income, nor 7 kinds of physical disease systems. DISCUSSION: The symptom profile and high prevalence of HSSS, and its association with clinically significant depression and anxiety in this inpatient population were mostly consistent to that documented by studies in other populations. PMID- 28582607 TI - Phase II study of intrabone single unit cord blood transplantation for hematological malignancies. AB - The outcomes of cord blood transplantation with non-irradiated reduced-intensity conditioning for hematological malignancies need to be improved because of graft failure and delayed engraftment. Intrabone infusion of cord blood cells has the potential to resolve the problems. In this phase II study, 21 adult patients with hematological malignancy received intrabone transplantation of serological HLA-A, B, and DR >=4/6 matched single cord blood with a median number of cryopreserved total nucleated cells of 2.7 * 107 /kg (range, 2.0-4.9 * 107 /kg) following non irradiated fludarabine-based reduced-intensity conditioning. Short-term methotrexate and tacrolimus were given as graft-versus-host disease prophylaxis, and granulocyte colony-stimulating factor was given after transplantation. No severe adverse events related to intrabone injection were observed. The cumulative incidences of neutrophils >=0.5 * 109 /L, reticulocytes >=1%, and platelets >=20 * 109 /L recoveries were 76.2%, 71.4%, and 76.2%, respectively, with median time to recoveries of 17, 28, and 32 days after transplantation, respectively. The probability of survival with neutrophil engraftment on day 60 was 71.4%, and overall survival at 1 year after transplantation was 52.4%. The incidences of grade II-IV and III-IV acute graft-versus-host disease were 44% and 19%, respectively, with no cases of chronic graft-versus-host disease. The present study showed the safety of direct intrabone infusion of cord blood. Further analysis is required to confirm the efficacy of intrabone single cord blood transplantation with non-irradiated reduced-intensity conditioning for adult patients with hematological malignancy. This study was registered with UMIN CTR, number 000000865. PMID- 28582612 TI - Investigation of Phenols Activity in Early Stage Oxidation of Edible Oils by Electron Paramagnetic Resonance and 19F NMR Spectroscopies Using Novel Lipid Vanadium Complexes As Radical Initiators. AB - A novel dynamic method for the investigation of the phenols activity in early stage oxidation of edible oils based on the formation of alpha-tocopheryl radicals initiated by oil-soluble vanadium complexes is developed. Two new vanadium complexes in oxidation states V and IV were synthesized by reacting 2,2' ((2-hydroxyoctadecyl)azanediyl)bis(ethan-1-ol) (C18DEA) with [VO(acac)2] and 1 (bis(pyridin-2-ylmethyl)amino)octadecan-2-ol (C18DPA) with VOCl2. Addition of a solution of either complex in edible oils resulted in the formation of alpha tocopheryl radical, which was monitored by electron paramagnetic resonance (EPR) spectroscopy. The intensity of the alpha-tocopheryl signal in the EPR spectra was measured versus time. It was found that the profile of the intensity of the alpha tocopheryl signal versus time depends on the type of oil, the phenolic content, and the storage time of the oil. The time interval until the occurrence of maximum peak intensity be reached (tm), the height of the maximum intensity, and the rate of the quenching of the alpha-tocopheryl radical were used for the investigation of the mechanism of the edible oils oxidation. 19F NMR of the 19F labeled phenolic compounds (through trifluoroacetate esters) and radical trap experiments showed that the vanadium complexes in edible oil activate the one electron reduction of dioxygen to superperoxide radical. Superperoxide reacts with the lipids to form alkoperoxyl and alkoxyl lipid radicals, and all these radicals react with the phenols contained in oils. PMID- 28582613 TI - Flow-Induced Shape Reconfiguration, Phase Separation, and Rupture of Bio-Inspired Vesicles. AB - The structural integrity of red blood cells and drug delivery carriers through blood vessels is dependent upon their ability to adapt their shape during their transportation. Our goal is to examine the role of the composition of bio inspired multicomponent and hairy vesicles on their shape during their transport through in a channel. Through the dissipative particle dynamics simulation technique, we apply Poiseuille flow in a cylindrical channel. We investigate the effect of flow conditions and concentration of key molecular components on the shape, phase separation, and structural integrity of the bio-inspired multicomponent and hairy vesicles. Our results show the Reynolds number and molecular composition of the vesicles impact their flow-induced deformation, phase separation on the outer monolayer due to the Marangoni effect, and rupture. The findings from this study could be used to enhance the design of drug delivery and tissue engineering systems. PMID- 28582614 TI - Local Structures and Heterogeneity of Silica-Supported M(III) Sites Evidenced by EPR, IR, NMR, and Luminescence Spectroscopies. AB - Grafting molecular precursors on partially dehydroxylated silica followed by a thermal treatment yields silica-supported M(III) sites for a broad range of metals. They display unique properties such as high activity in olefin polymerization and alkane dehydrogenation (M = Cr) or efficient luminescence properties (M = Yb and Eu) essential for bioimaging. Here, we interrogate the local structure of the M(III) surface sites obtained from two molecular precursors, amides M(N(SiMe3)2)3 vs siloxides (M(OSi(OtBu)3)3.L with L = (THF)2 or HOSi(OtBu)3 for M = Cr, Yb, Eu, and Y, by a combination of advanced spectroscopic techniques (EPR, IR, XAS, UV-vis, NMR, luminescence spectroscopies). For paramagnetic Cr(III), EPR (HYSCORE) spectroscopy shows hyperfine coupling to nitrogen only when the amide precursor is used, consistent with the presence of nitrogen neighbors. This changes their specific reactivity compared to Cr(III) sites in oxygen environments obtained from siloxide precursors: no coordination of CO and oligomer formation during the polymerization of ethylene due to the presence of a N-donor ligand. The presence of the N-ligand also affects the photophysical properties of Yb and Eu by decreasing their lifetime, probably due to nonradiative deactivation of excited states by N-H bonds. Both types of precursors lead to a distribution of surface sites according to reactivity for Cr, luminescence spectroscopy for Yb and Eu, and dynamic nuclear polarization surface-enhanced 89Y NMR spectroscopy (DNP SENS). In particular, DNP SENS provides molecular-level information about the structure of surface sites by evidencing the presence of tri-, tetra-, and pentacoordinated Y-surface sites. This study provides unprecedented evidence and tools to assess the local structure of metal surface sites in relation to their chemical and physical properties. PMID- 28582615 TI - Iron-Induced Activation of Ordered Mesoporous Nickel Cobalt Oxide Electrocatalyst for the Oxygen Evolution Reaction. AB - Herein, ordered mesoporous nickel cobalt oxides prepared by the nanocasting route are reported as highly active oxygen evolution reaction (OER) catalysts. By using the ordered mesoporous structure as a model system and afterward elevating the optimal catalysts composition, it is shown that, with a simple electrochemical activation step, the performance of nickel cobalt oxide can be significantly enhanced. The electrochemical impedance spectroscopy results indicated that charge transfer resistance increases for Co3O4 spinel after an activation process, while this value drops for NiO and especially for CoNi mixed oxide significantly, which confirms the improvement of oxygen evolution kinetics. The catalyst with the optimal composition (Co/Ni 4/1) reaches a current density of 10 mA/cm2 with an overpotential of a mere 336 mV and a Tafel slope of 36 mV/dec, outperforming benchmarked and other reported Ni/Co-based OER electrocatalysts. The catalyst also demonstrates outstanding durability for 14 h and maintained the ordered mesoporous structure. The cyclic voltammograms along with the electrochemical measurements in Fe-free KOH electrolyte suggest that the activity boost is attributed to the generation of surface Ni(OH)2 species that incorporate Fe impurities from the electrolyte. The incorporation of Fe into the structure is also confirmed by inductively coupled plasma optical emission spectrometry. PMID- 28582616 TI - Molecular Engineering of Robustness and Resilience in Enzymatic Reaction Networks. AB - Living systems rely on complex networks of chemical reactions to control the concentrations of molecules in space and time. Despite the enormous complexity in biological networks, it is possible to identify network motifs that lead to functional outputs such as bistability or oscillations. One of the greatest challenges in chemistry is the creation of such functionality from chemical reactions. A key limitation is our lack of understanding of how molecular structure impacts on the dynamics of chemical reaction networks, preventing the design of networks that are robust (i.e., function in a large parameter space) and resilient (i.e., reach their out-of-equilibrium function rapidly). Here we demonstrate that reaction rates of individual reactions in the network can control the dynamics by which the system reaches limit cycle oscillations, thereby gaining information on the key parameters that govern the dynamics of these networks. We envision that these principles will be incorporated into the design of network motifs, enabling chemists to develop "molecular software" to create functional behavior in chemical systems. PMID- 28582617 TI - Molecular Switch for Sub-Diffraction Laser Lithography by Photoenol Intermediate State Cis-Trans Isomerization. AB - Recent developments in stimulated-emission depletion (STED) microscopy have led to a step change in the achievable resolution and allowed breaking the diffraction limit by large factors. The core principle is based on a reversible molecular switch, allowing for light-triggered activation and deactivation in combination with a laser focus that incorporates a point or line of zero intensity. In the past years, the concept has been transferred from microscopy to maskless laser lithography, namely direct laser writing (DLW), in order to overcome the diffraction limit for optical lithography. Herein, we propose and experimentally introduce a system that realizes such a molecular switch for lithography. Specifically, the population of intermediate-state photoenol isomers of alpha-methyl benzaldehydes generated by two-photon absorption at 700 nm fundamental wavelength can be reversibly depleted by simultaneous irradiation at 440 nm, suppressing the subsequent Diels-Alder cycloaddition reaction which constitutes the chemical core of the writing process. We demonstrate the potential of the proposed mechanism for STED-inspired DLW by covalently functionalizing the surface of glass substrates via the photoenol-driven STED inspired process exploiting reversible photoenol activation with a polymerization initiator. Subsequently, macromolecules are grown from the functionalized areas and the spatially coded glass slides are characterized by atomic-force microscopy. Our approach allows lines with a full-width-at-half-maximum of down to 60 nm and line gratings with a lateral resolution of 100 nm to be written, both surpassing the diffraction limit. PMID- 28582618 TI - Estimating Infection Risks and the Global Burden of Diarrheal Disease Attributable to Intermittent Water Supply Using QMRA. AB - Intermittent water supply (IWS) is prevalent throughout low and middle-income countries. IWS is associated with increased microbial contamination and potentially elevated risk of waterborne illness. We used existing data sets to estimate the population exposed to IWS, assess the probability of infection using quantitative microbial risk assessment, and calculate the subsequent burden of diarrheal disease attributable to consuming fecally contaminated tap water from an IWS. We used reference pathogens Campylobacter, Cryptosporidium, and rotavirus as conservative risk proxies for infections via bacteria, protozoa, and viruses, respectively. Results indicate that the median daily risk of infection is an estimated 1 in 23 500 for Campylobacter, 1 in 5 050 000 for Cryptosporidium, and 1 in 118 000 for rotavirus. Based on these risks, IWS may account for 17.2 million infections causing 4.52 million cases of diarrhea, 109 000 diarrheal DALYs, and 1560 deaths each year. The burden of diarrheal disease associated with IWS likely exceeds the WHO health-based normative guideline for drinking water of 10-6 DALYs per person per year. Our results underscore the importance water safety management in water supplies and the potential benefits of point-of-use treatment to mitigate risks. PMID- 28582619 TI - Phytohormone Behavior in the Model Environment of Plant and Human Lipid Membranes. AB - Interactions between three auxins (indole-3-acetic acid (IAA), 2-naphthoxyacetic acid (BNOA), and 2,4-dichlorophenoxyacetic acid (2,4-D)) and model two dimensional lipid systems mimicking plant and human cell membranes were investigated in monolayers formed at the air/water solution interface. The analysis was based on the recorded pi-A isotherm characteristics complemented with Brewster angle microscopy. The influence of auxins on model membranes was discussed on the basis of condensation changes, modification of mutual lipid lipid interactions in the mixed films, and morphological alteration of the surface domains on the microscopic scale. It was demonstrated that the lipid composition and mutual proportion of the artificial membranes together with sterol to main the phospholipid ratio play a crucial role in the context of auxin behavior in the membrane-mimicking environment. Apart from specific molecular interactions between studied phytohormones represented by auxins and lipids, the condensation of the investigated monolayers was found to be a regulative factor of model systems' susceptibility toward auxin action. Two effects were recognized: fluidizing of monolayers being in the liquid state (model membranes) and initialization of the three-dimensional structure formation in ordered sterol films at high surface pressure. The influence of auxin molecules on lipid interactions in the monolayer and diminishing of the film condensation was the largest for BNOA, due to the presence of the most bulky nonpolar, aromatic fragment in the molecule. It was also demonstrated that auxins interact with model plant membranes more selectively, stronger, and at markedly lower concentration than with the human membrane models. PMID- 28582621 TI - Self-Rotation-Induced Propulsion of a Leidenfrost Drop on a Ratchet. AB - A Leidenfrost drop is capable of self-propelling on a ratchet, which consists of asymmetric teeth. In this work, the corresponding movements were first experimentally investigated. Because the detected motion could not be interpreted using existing propulsive mechanisms, a new propulsive mechanism was then developed, followed by force analysis using a scaling law. PMID- 28582620 TI - Observation of Enhanced Chiral Asymmetries in the Inner-Shell Photoionization of Uniaxially Oriented Methyloxirane Enantiomers. AB - Most large molecules are chiral in their structure: they exist as two enantiomers, which are mirror images of each other. Whereas the rovibronic sublevels of two enantiomers are almost identical (neglecting a minuscular effect of the weak interaction), it turns out that the photoelectric effect is sensitive to the absolute configuration of the ionized enantiomer. Indeed, photoionization of randomly oriented enantiomers by left or right circularly polarized light results in a slightly different electron flux parallel or antiparallel with respect to the photon propagation direction-an effect termed photoelectron circular dichroism (PECD). Our comprehensive study demonstrates that the origin of PECD can be found in the molecular frame electron emission pattern connecting PECD to other fundamental photophysical effects such as the circular dichroism in angular distributions (CDAD). Accordingly, distinct spatial orientations of a chiral molecule enhance the PECD by a factor of about 10. PMID- 28582622 TI - Self-Organized Freestanding One-Dimensional Au Nanoparticle Arrays. AB - One-dimensional Au nanoparticle arrays encapsulated within freestanding SiO2 nanowires are fabricated by thermal oxidation of Au-coated Si nanowires with controlled diameter and surface modulation. The nanoparticle diameter is determined by the Si nanowire diameter and Au film thickness, while the interparticle spacing is independently controlled by the Si nanowire modulation. The optical absorption of randomly oriented Au nanoparticle arrays exhibits a strong plasmonic response at 550 nm. Scanning transmission electron microscopy (STEM)-electron energy loss spectrum (EELS) of nanoparticle arrays confirmed the same plasmonic response and demonstrated uniform optical properties of the Au nanoparticles. The plasmonic response in the STEM-EELS maps is primarily confined around the vicinity of the nanoparticles. On the other hand, examination of the same nanowires by energy-filtered transmission electron microscopy also revealed significant enhancement in the plasmonic excitation in the regions in between the nanoparticles. This versatile route to synthesize one-dimensional Au nanoparticle arrays with independently tailorable nanoparticle diameter and interparticle spacing opens up opportunities to exploit enhanced design flexibility and cost effectiveness for future plasmonic devices. PMID- 28582623 TI - Excitonic Circular Dichroism of Chiral Quantum Rods. AB - As an emerging type of optically active materials, chiral molecules-stabilized semiconductor quantum dots (QDs) have achieved extensive attention. Unfortunately, understanding of the optical characteristics of chiral QDs observed by circular dichroism (CD) spectroscopy remains a great challenge due to their rather weak signals. Herein, we successfully achieve much enhanced CD responses from l- or d-cysteine-stabilized wurtzite CdSe quantum rods (QRs) thanks to their unique optical anisotropy. Furthermore, the optical activity of CdSe QRs is explored to be improved and subsequently become stable with the geometrical aspect ratio (AR) increasing, and such change matches well with alternation of the polarization factor of CdSe QRs. A non-degenerate coupled oscillator (NDCO) model is established to elucidate the optical activity of chiral QRs, and the positive and negative natures of the CD peaks appearing at the first exciton band are clearly assigned to different transition polarization along 4pz,Se -> 5sCd and 4p(x,y),Se -> 5sCd, respectively. This work opens the door toward comprehension and design of optically active semiconductor nanomaterials. PMID- 28582624 TI - Edge Epitaxy of Two-Dimensional MoSe2 and MoS2 Nanosheets on One-Dimensional Nanowires. AB - Rational design and synthesis of heterostructures based on transition metal dichalcogenides (TMDs) have attracted increasing interests because of their promising applications in electronics, catalysis, etc. However, the construction of epitaxial heterostructures with an interface at the edges of TMD nanosheets (NSs) still remains a great challenge. Here, we report a strategy for controlled synthesis of a new type of heterostructure in which TMD NSs, including MoS2 and MoSe2, vertically grow along the longitudinal direction of one-dimensional (1D) Cu2-xS nanowires (NWs) in an epitaxial manner. The obtained Cu2-xS-TMD heterostructures with tunable loading amount and lateral size of TMD NSs are achieved by the consecutive growth of TMD NSs on Cu2-xS NWs through gradual injection of chalcogen precursors. After cation exchange of Cu in Cu2-xS-TMD heterostructures with Cd, the obtained CdS-MoS2 heterostructures retained their original architectures. Compared to the pure CdS NWs, the CdS-MoS2 heterostructures with 7.7 wt % loading of MoS2 NSs exhibit the best performance in the photocatalytic hydrogen evolution reaction with a H2 production rate up to 4647 MUmol.h-1.g-1, about 58 times that catalyzed with pure CdS NWs. Our synthetic strategy opens up a new way for the controlled synthesis of TMD-based heterostructures, which could have various promising applications. PMID- 28582625 TI - Quantitative Characterization of the Binding and Unbinding of Millimolar Drug Fragments with Molecular Dynamics Simulations. AB - A quantitative characterization of the binding properties of drug fragments to a target protein is an important component of a fragment-based drug discovery program. Fragments typically have a weak binding affinity, however, making it challenging to experimentally characterize key binding properties, including binding sites, poses, and affinities. Direct simulation of the binding equilibrium by molecular dynamics (MD) simulations can provide a computational route to characterize fragment binding, but this approach is so computationally intensive that it has thus far remained relatively unexplored. Here, we perform MD simulations of sufficient length to observe several different fragments spontaneously and repeatedly bind to and unbind from the protein FKBP, allowing the binding affinities, on- and off-rates, and relative occupancies of alternative binding sites and alternative poses within each binding site to be estimated, thereby illustrating the potential of long time scale MD as a quantitative tool for fragment-based drug discovery. The data from the long time scale fragment binding simulations reported here also provide a useful benchmark for testing alternative computational methods aimed at characterizing fragment binding properties. As an example, we calculated binding affinities for the same fragments using a standard free energy perturbation approach and found that the values agreed with those obtained from the fragment binding simulations within statistical error. PMID- 28582626 TI - Molecular Recognition in Asymmetric Counteranion Catalysis: Understanding Chiral Phosphate-Mediated Desymmetrization. AB - We describe the first theoretical study of a landmark example of chiral anion phase-transfer catalysis: the enantioselective ring-opening of meso-aziridinium and episulfonium cations promoted by asymmetric counteranion-directed catalysis (ACDC). The mechanism of ion-pairing, ring-opening, and catalyst deactivation have been studied in the condensed phase with both classical and quantum methods using explicitly and implicitly solvated models. We find that the stability of chiral ion-pairs, a prerequisite for asymmetric catalysis, is dominated by electrostatic interactions at long range and by CH...O interactions at short range. The decisive role of solvent upon ion-pair formation and of nonbonding interactions upon enantioselectivity are quantified by complementary computational approaches. The major enantiomer is favored by a smaller distortion of the substrate, demonstrated by a distortion/interaction analysis. Our computational results rationalize the stereoselectivity for several experimental results and demonstrate a combined classical/quantum approach to perform realistic modeling of chiral counterion catalysis in solution. PMID- 28582627 TI - Gyrification-Inspired Highly Convoluted Graphene Oxide Patterns for Ultralarge Deforming Actuators. AB - Gyrification in the human brain is driven by the compressive stress induced by the tangential expansion of the cortical layer, while similar topographies can also be induced by the tangential shrinkage of the spherical substrate. Herein we introduce a simple three-dimensional (3D) shrinking method to generate the cortex like patterns using two-dimensional (2D) graphene oxide (GO) as the building blocks. By rotation-dip-coating a GO film on an air-charged latex balloon and then releasing the air slowly, a highly folded hydrophobic GO surface can be induced. Wrinkling-to-folding transition was observed and the folding state can be easily regulated by varying the prestrain of the substrate and the thickness of the GO film. Driven by the residue stresses stored in the system, sheet-to tube actuating occurs rapidly once the bilayer system is cut into slices. In response to some organic solvents, however, the square bilayer actuator exhibits excellent reversible, bidirectional, large-deformational curling properties on wetting and drying. An ultralarge curvature of 2.75 mm-1 was observed within 18 s from the original negative bending to the final positive bending in response to tetrahydrofuran (THF). In addition to a mechanical hand, a swimming worm, a smart package, a bionic mimosa, and two bionic flowers, a crude oil collector has been designed and demonstrated, aided by the superhydrophobic and superoleophilic modified GO surface and the solvent-responsive bilayer system. PMID- 28582628 TI - Energetic demand and physical conditioning of table tennis players. A study review. AB - Table tennis is a racket sport characterised by an intermittent movement profile, including short rallies interspersed with short breaks. In contrast to other racket sports, information is lacking regarding the: (i) physiological responses during table tennis matches and training; and (ii) practical recommendations for enhancing aerobic and anaerobic performance in table tennis by improving cardio metabolic and neuro-muscular fitness, anthropometry and nutritional strategies. Therefore, this review article attempts to narratively provide an overview of the physiology of table tennis by describing the metabolic mechanisms underlying match play and outlining a framework for practical recommendations for improving cardio-metabolic and neuro-muscular fitness, anthropometry as well as nutritional strategies. A second aim was to stimulate future research on table tennis and to point out study limitations in this context. In general, the most important finding is that the rally duration is short at around 3.5s, with a longer rest time of around 8-20s, resulting in an effort-rest ratio ranging from 0.15 to 0.22 in official matches and energetic demands during match relatively low. Future studies should focus on the relationship between energetic demand and table tennis performance with a view to predicting performance in table tennis using physiological parameters. PMID- 28582630 TI - Attitudes and Expectations in the Intergenerational Transmission of Breastfeeding: A Phenomenological Study. AB - BACKGROUND: The socially constructed meanings of breastfeeding that have been passed from generation to generation by grandmothers produce continuities and discontinuities in the practices of breastfeeding. Research aim: The aim of this study is to explore the objectives and positioning of women today with respect to their role as future grandmothers, based on their experiences with breastfeeding. That is, what role do future grandmothers wish to have in the lives of their breastfeeding daughters and grandchildren? METHODS: A qualitative study with interpretative phenomenological analysis was conducted based on the philosophy of Martin Heidegger, using a sample of unstructured interviews from 20 women in Madrid. The data were analyzed using the steps of interpretative phenomenological analysis. RESULTS: Among the women who desired to have a supportive role for their future breastfeeding daughters and daughters-in-law, three emergent themes were identified that aimed at being supportive but remaining flexible and respecting their autonomy: "I'll give you what I didn't have," "the well-being of my daughter/daughter-in-law," and "seeking professional help." Two additional themes were identified that show the desire of these women to be present during this stage of family development and the lifecycle: "my role in the family" and "continuing to share." CONCLUSION: Future grandmothers desire to be involved in their daughters and daughters-in-law breastfeeding experience through flexibility and support and with the use of specialized and personalized professional help. In addition, future grandmothers desire to be valued and included in the vital process of breastfeeding. PMID- 28582629 TI - Molecular diagnostics for Chagas disease: up to date and novel methodologies. AB - INTRODUCTION: Chagas disease is caused by the parasite Trypanosoma cruzi. It affects 7 million people, mainly in Latin America. Diagnosis is usually made serologically, but at some clinical scenarios serology cannot be used. Then, molecular detection is required for early detection of congenital transmission, treatment response follow up, and diagnosis of immune-suppression reactivation. However, present tests are technically demanding and require well-equipped laboratories which make them unfeasible in low-resources endemic regions. Areas covered: Available molecular tools for detection of T. cruzi DNA, paying particular attention to quantitative PCR protocols, and to the latest developments of user-friendly molecular diagnostic methodologies. Expert commentary: In the absence of appropriate biomarkers, molecular diagnosis is the only option for the assessment of treatment response. Besides, it is very useful for the early detection of acute infections, like congenital cases. Since current Chagas disease molecular tests are restricted to referential labs, research efforts must focus in the implementation of easy-to-use diagnostic tools in order to overcome the access to diagnosis gap. PMID- 28582631 TI - Chronic kidney disease as a risk factor for vestibular dysfunction. AB - OBJECTIVES: The aim of this study was to determine whether chronic kidney disease (CKD) is associated with vestibular dysfunction in a general population. METHODS: Of the total participants, 7,799 of participants were included in this study. The data collected from the participants during the health examination included an estimated glomerular filtration rate (eGFR) and balancing test results. Mild CKD was defined as an eGFR of 60-90 mL/min/1.73 m2 or an eGFR >= 90 mL/min/1.73 m2 with dipstick proteinuria (>= 1+). Moderate CKD was defined as an eGFR of 45-59 mL/min/1.73 m2. Severe CKD was defined as an eGFR of 30-44 mL/min/1.73 m2. Very severe CKD was defined as an eGFR < 30 mL/min/1.73 m2. RESULTS: The number of participants with vestibular dysfunction was 268. Univariate and multivariate linear regression analyses showed that eGFR levels were inversely associated with the presence of vestibular dysfunction. Multivariate analysis revealed that those with moderate, severe, and very severe CKD had a 1.830-, 4.496-, and 6.055-fold increased risk of vestibular dysfunction, respectively, compared to the participants without CKD. CONCLUSION: CKD was found to be associated with vestibular dysfunction in the general population. Therefore, the participants with CKD may be closely monitored for vestibular dysfunction. PMID- 28582632 TI - Prostate Cancer: A Correlative Study of Multiparametric MR Imaging and Digital Histopathology. AB - Purpose To correlate multiparametric magnetic resonance (MR) imaging and quantitative digital histopathologic analysis (DHA) of the prostate. Materials and Methods This retrospective study was approved by the local institutional review board and was HIPAA compliant. Forty patients (median age, 60 years; age range, 44-71 years) who underwent prostate MR imaging consisting of T2-weighted and diffusion-weighted (DW) MR imaging along with subsequent robot-assisted radical prostatectomy gave informed consent to be included. Whole-mount tissue specimens were obtained with a patient-specific mold, and DHA was performed to assess the lumen, epithelium, stroma, and epithelial nucleus. These DHA images were registered with MR images and were correlated on a per-voxel basis. The relationship between MR imaging and DHA was assessed by using a linear mixed effects model and the Pearson correlation coefficient. Results T2-weighted MR imaging, apparent diffusion coefficient (ADC) of DW imaging, and high-b-value DW imaging were significantly related to specific DHA parameters (P < .01). For instance, lumen density (ie, the percentage area of tissue components) was associated with T2-weighted MR imaging (slope = 0.36 +/- 0.05 [standard error], gamma = 0.35), ADC (slope = 0.47 +/- 0.05, gamma = 0.50), and high-b-value DW imaging (slope = -0.44 +/- 0.05, gamma = -0.44). Differences between regions harboring benign tissue and those harboring malignant tissue were observed at MR imaging and DHA (P < .01). Gleason score was significantly associated with MR imaging and DHA parameters (P < .05). For example, it was positively related to high-b-value DW imaging (slope = 0.21 +/- 0.16, gamma = 0.18) and negatively related to lumen density (slope = -0.19 +/- 0.18, gamma = -0.35). Conclusion Overall, significant associations were observed between MR imaging and DHA, regardless of prostate anatomy. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28582633 TI - Performance Benchmarks for Screening Breast MR Imaging in Community Practice. AB - Purpose To compare screening magnetic resonance (MR) imaging performance in the Breast Cancer Surveillance Consortium (BCSC) with Breast Imaging Reporting and Data System (BI-RADS) benchmarks. Materials and Methods This study was approved by the institutional review board and compliant with HIPAA and included BCSC screening MR examinations collected between 2005 and 2013 from 5343 women (8387 MR examinations) linked to regional Surveillance, Epidemiology, and End Results program registries, state tumor registries, and pathologic information databases that identified breast cancer cases and tumor characteristics. Clinical, demographic, and imaging characteristics were assessed. Performance measures were calculated according to BI-RADS fifth edition and included cancer detection rate (CDR), positive predictive value of biopsy recommendation (PPV2), sensitivity, and specificity. Results The median patient age was 52 years; 52% of MR examinations were performed in women with a first-degree family history of breast cancer, 46% in women with a personal history of breast cancer, and 15% in women with both risk factors. Screening MR imaging depicted 146 cancers, and 35 interval cancers were identified (181 total-54 in situ, 125 invasive, and two status unknown). The CDR was 17 per 1000 screening examinations (95% confidence interval [CI]: 15, 20 per 1000 screening examinations; BI-RADS benchmark, 20-30 per 1000 screening examinations). PPV2 was 19% (95% CI: 16%, 22%; benchmark, 15%). Sensitivity was 81% (95% CI: 75%, 86%; benchmark, >80%), and specificity was 83% (95% CI: 82%, 84%; benchmark, 85%-90%). The median tumor size of invasive cancers was 10 mm; 88% were node negative. Conclusion The interpretative performance of screening MR imaging in the BCSC meets most BI-RADS benchmarks and approaches benchmark levels for remaining measures. Clinical practice performance data can inform ongoing benchmark development and help identify areas for quality improvement. (c) RSNA, 2017. PMID- 28582634 TI - Spectral Doppler Waveforms for Diagnosis of Appendicitis: Potential Utility of Point Peak Systolic Velocity and Resistive Index Values. AB - Purpose To test the hypothesis that appendiceal spectral Doppler waveforms can distinguish patients with and patients without appendicitis. Materials and Methods In this retrospective study, Doppler waveforms were obtained from intramural appendiceal arteries identified with color Doppler imaging in 60% (93 of 155) of consecutive patients whose appendices were visualized at graded compression ultrasonography (US) performed for suspected appendicitis (53 male and 40 female; age, 1-56 years; mean, 14.5 years) over the 5-month period from November 2015 through March 2016. Point, non-angle-corrected peak systolic velocity (PSV) and resistive index (RI) values were compared between patients with and patients without appendicitis by utilizing histopathologically proven appendicitis and 6-week clinical follow-up as diagnostic reference standards. Data were assessed by using the Student t test, exact binomial distribution, two sample test of proportions, and receiver operating characteristic analysis. Results Among the 93 patients, 36 (38.7%) had proven appendicitis (mean PSV, 19.7 cm/sec; mean RI, 0.69) and 57 patients (61.2%) did not (mean PSV, 7.1 cm/sec, P < .0001; mean RI, 0.50, P < .0001). The area under the receiver operating characteristic curve for the diagnosis of appendicitis was 0.97 (95% confidence interval [CI]: 0.95, 1.00) for PSV and 0.86 (95% CI: 0.78, 0.95; P = .011) for RI. Chosen discriminatory criteria of PSV greater than 10 cm/sec and RI greater than 0.65 yielded specificity for appendicitis of 94.7% and 96.5% with sensitivity of 88.9% and 63.9% (P = .013) and negative predictive value of 93.1% and 80.9% (P = .045), respectively. Original clinical graded compression US interpretations based on established US findings demonstrated specificity of 96.2% and sensitivity of 100.0%. Considering the subset of 20 patients whose maximum outer diameter measured 6-8 mm, the discriminatory criteria of PSV greater than 10 cm/sec and RI greater than 0.65 yielded specificity for appendicitis of 88.9% each, with sensitivity of 100.0% and 63.6% and negative predictive value of 100.0% and 66.6%, respectively. Conclusion In patients with visualized appendices at US, those with appendicitis exhibit significantly higher point PSV and point RI values than do patients without appendicitis and are distinguishable with high specificity by using a PSV greater than 10 cm/sec and an RI greater than 0.65 as diagnostic criteria. (c) RSNA, 2017. PMID- 28582635 TI - Prenylated flavonoids from Commiphora opobalsamum stem bark. AB - A phytochemical study on the stem bark of Commiphora opobalsamum looking for cytotoxic compounds afforded eleven flavonoids, including six previously undescribed prenylated congeners, comophorin A-E, and comophoroside A. The structures of the isolated compounds were elucidated on the basis of spectroscopic evidences and correlated with known compounds. Isolated compounds were biologically evaluated using in vitro cytotoxicity MTT-based assay against two cancer cell lines; namely human hepato-cellular carcinoma (HepG-2) and human breast adenocarcinoma (MCF-7). Comophoroside A revealed to retain the strongest cytotoxic activity against MCF-7 and HepG-2 cell lines with IC50 values of 8 and 12 MUg/mL, respectively. PMID- 28582636 TI - Living with the burden of relapse in multiple myeloma from the patient and physician perspective. AB - Multiple myeloma (MM) is a progressive plasma cell malignancy, with a range of clinical features including bone lesions, renal insufficiency, anaemia, and hypercalcaemia. Novel agents have significantly improved patient survival, however most patients will suffer multiple relapses. Although clinical challenges and economic costs of relapse are recognised, the psychological impact of relapse is not fully appreciated. Additionally, there is little information on how physicians perceive the impact of relapse on their patients' emotional state and how this might affect patient management. Through face-to-face interviews with 50 relapsed and/or refractory MM patients and 30 haematologists across ten countries, we have used real-world evidence to explore and characterise the burden of living with MM, particularly the impact of relapsed disease. This exploratory study illustrates the impact of the disease on friends and family, and the physical and emotional burden experienced by the patient resulting from both MM and its treatment. Haematologists feel poorly equipped to deal with the emotional aspects of patient relapse, lacking the time and resources to adequately deal with these issues. Focused educational and support tools/resources targeted at both physicians and patients are required to facilitate physician-patient communication to help reduce the emotional burden of living with MM. PMID- 28582637 TI - Different time course of plasma lactate, troponin I and Nt-proBNP concentrations in patients with acute pulmonary embolism. PMID- 28582638 TI - Association of CD147 genetic polymorphisms with carotid atherosclerotic plaques in a Han Chinese population with cerebral infarction. AB - INTRODUCTION: Given the important role of CD147 in the development of atherosclerosis, we speculated that CD147 genetic polymorphisms might influence the formation of carotid atherosclerotic plaques. The study was to investigate the association between CD147 gene polymorphisms and susceptibility to carotid atherosclerotic plaques in individuals with cerebral infarction (CI). METHODS: Eight SNPs in the regulatory and coding regions of the CD147 gene were examined using polymerase chain reaction-ligase detection reaction (PCR-LDR) in DNA samples from 732 Chinese patients with CI, divided into a carotid plaque group (n=475) and a non-carotid plaque group (n=257). RESULTS: Significant differences were found in the genotypes and allele frequencies of the rs4919862 SNP between the carotid plaque and non-carotid plaque groups of CI patients (P<0.05), while the frequencies of the C allele and the CC genotype in the non-carotid plaque group were significantly lower than those in the carotid plaque group, and the frequencies of the T allele in the non-carotid plaque group were significantly higher than those in the carotid plaque group (P<0.05). In addition, there was strong linkage disequilibrium among the rs4919862, rs8637 and rs8259 sites. In a haplotype analysis, the occurrence rate of the haplotype GATGCAGC was 2.095 times higher in the carotid plaque group than in the non-carotid plaque group (P<0.05). CONCLUSION: These results showed that the rs4919862 SNP of CD147 was closely associated with carotid atherosclerotic plaques formation. Thus, polymorphisms of the CD147 gene may be related to the tendency for carotid atherosclerotic plaques. PMID- 28582639 TI - Heparin-calibrated chromogenic anti-Xa assays are not suitable to assess the presence of significant direct factor Xa inhibitors levels. PMID- 28582641 TI - ABO blood groups: A risk factor for left atrial and left atrial appendage thrombogenic milieu in patients with non-valvular atrial fibrillation. AB - BACKGROUND: Previous studies have identified ABO blood groups as predictors of thromboembolic diseases. In patients with atrial fibrillation (AF), however, potential association between ABO blood groups and the risk of left atrial (LA) and/or left atrial appendage (LAA) thrombogenic milieu (TM) has not been established. METHODS: This is a retrospective case-control study that included 125 consecutive patients with non-valvular atrial fibrillation (NVAF) plus TM, as evidenced by transesophageal echocardiography (TEE) during a period from1 January 2010 to 31 December 2016. The controls were selected randomly from 1072 NVAF without TM at a 1:2 ratio. Potential association between ABO blood groups and TM was analyzed using multivariate logistic regression analysis. RESULTS: The risk of TM was higher in patients with blood group A (33.6% vs. 20.2% in non-A blood groups, P=0.005). After adjusting for age, sex, oral anticoagulant use, AF type and duration, and relevant functional measures (e.g., NT-pro BNP level, left atrium diameter, and left ventricular ejection fraction), blood group A remained associated with an increased risk of TM (OR=2.99, 95% CI 1.4-6.388, P=0.005). CONCLUSION: Blood group A is an independent risk factor for TM in NVAF patients. PMID- 28582640 TI - The causes of thrombocytopenia after transcatheter aortic valve implantation. AB - INTRODUCTION: Even though thrombocytopenia following transcatheter aortic valve implantation (TAVI) has been described, further investigation of this phenomenon is needed. AIMS: To determine which factors may explain the fall in platelet count that occurs after implantation of a TAVI device, including markers of platelet and blood coagulation activation. MATERIAL AND METHODS: 32 patients without previous indications for dual antiplatelet therapy (mean age 78.5+/-7.9 years, 62% females) with severe aortic valve stenosis (mean gradient 54.6+/ 16.9mmHg) who qualified for TAVI procedure (Edwards Sapien XT) were prospectively analyzed. Platelet counts were analyzed before the surgery, on the day of the procedure and for the three following postoperative days (POD 1 to 3). To assess platelet activation P-selectin (PS, serum) and platelet factor 4 (PF-4, CTAD plasma) were measured, whereas for the evaluation of coagulation activation prothrombin fragments 1+2 (F1+2, plasma) were assessed before the procedure, on POD-1 and POD-3 (ELISA). RESULTS: During the postoperative period a significant platelet count drop, the most evident on POD-2, was observed followed by a platelet count raise. The platelet count drop correlated directly with the amount of iodinated contrast agent (r=0.42, p=0.016) and inversely with baseline mean platelet volume (r=-0.37, p=0.046). Neither clinical nor perioperative parameters, except contrast medium, influenced platelet count decrease. No significant differences regarding the concentration of the evaluated markers in patients with and without thrombocytopenia were found. PF-4 and F1+2 significantly changed during the study (p<0.05). Greater acute PF-4 decrease correlated with greater acute platelet count drop (r=0.48, p=0.043), and during the study slower PF-4 increase correlated with higher platelet count increase on POD-3 (r=-0.505, p=0.032). Lower baseline PS correlated with lower baseline platelet count and higher platelet count increase on POD-3 (r=0.45, p=0.04 and = 0.55, p=0.02, respectively). No significant correlations between F1+2 concentrations and platelet count changes have been found. CONCLUSIONS: Platelet reduction shortly after TAVI procedure is related to the amount of contrast agent applied during the procedure. Platelet activation and blood coagulation along with impaired baseline platelet renewal might be the mechanisms of thrombocytopenia following TAVI procedure. PMID- 28582642 TI - Movement of the sacroiliac joint during the Active Straight Leg Raise test in patients with long-lasting severe sacroiliac joint pain. AB - BACKGROUND: The Active Straight Leg Raise is a functional test used in the assessment of pelvic girdle pain, and has shown to have good validity, reliability and responsiveness. The Active Straight Leg Raise is considered to examine the patients' ability to transfer load through the pelvis. It has been hypothesized that patients with pelvic girdle pain lack the ability to stabilize the pelvic girdle, probably due to instability or increased movement of the sacroiliac joint. This study examines the movement of the sacroiliac joints during the Active Straight Leg Raise in patients with pelvic girdle pain. METHODS: Tantalum markers were inserted in the dorsal sacrum and ilium of 12 patients with long-lasting pelvic girdle pain scheduled for sacroiliac joint fusion surgery. Two to three weeks later movement of the sacroiliac joints during the Active Straight Leg Raise was measured with radiostereometric analysis. FINDINGS: Small movements were detected. There was larger movement of the sacroiliac joint of the rested leg's sacroiliac joint compared to the lifted leg's side. A mean backward rotation of 0.8 degrees and inward tilt of 0.3 degrees were seen in the rested leg's sacroiliac joint. INTERPRETATION: The movements of the sacroiliac joints during the Active Straight Leg Raise are small. There was a small backward rotation of the innominate bone relative to sacrum on the rested leg's side. Our findings contradict an earlier understanding that a forward rotation of the lifted leg's innominate occur while performing the Active Straight Leg Raise. PMID- 28582643 TI - Identification of double four-ring units in germanosilicate ITQ-13 zeolite by solid-state NMR spectroscopy. AB - Well-crystallized Ge-free and Ge-ITQ-13 were successfully obtained by solid state synthesis method. The Ge/Si ratio and the water content that are the two important factors in the synthesis of germanosilicate zeolites were explored for the formation of ITQ-13. The effect of the mineralizing agents (NH4F and NH4Cl) on the ITQ-13 synthesis was investigated as well. The obtained pure silica ITQ-13 and Ge-ITQ-13 were characterized by one- and two-dimensional solid- state NMR techniques. One-dimensional (1D) 19F MAS, 1H->29Si CP/MAS and 19F->29Si CP/MAS NMR spectroscopy evidenced the formation of pure Si-D4R (double four ring) and Ge D4R units, with the latter being generated by substitution of Si atom from the former units. The detailed configurations of the Ge-D4R units in ITQ-13 was revealed by two-dimensional (2D) 29Si{19F} HETCOR NMR spectroscopy. With the help of theoretical calculations on the 19F and 29Si NMR chemical shifts, six types of D4R units were determined. The formation of the specific D4R unit confirms the structural directing roles of Ge atom and F ions in the formation of the D4R units in zeolite framework. The identification of the SiOSi bonds in the D4R units that connects the layers of ITQ-13 framework provided rationale for the high stability of the ITQ-13 in the degermanation treatment. PMID- 28582644 TI - No prolongation of skin allograft survival by immunoproteasome inhibition in mice. AB - The immunoproteasome, a distinct class of proteasomes, which is inducible under inflammatory conditions and constitutively expressed in monocytes and lymphocytes, is known to shape the antigenic repertoire presented on major histocompatibility complex (MHC) class I molecules. Moreover, inhibition of the immunoproteasome subunit LMP7 ameliorates clinical symptoms of autoimmune diseases in vivo and was shown to suppress the development of T helper cell (Th) 1 and Th17 cells and to promote regulatory T-cell (Treg) generation independently of its function in antigen processing. Since Th1 and Th17 cells are detrimental and Treg cells are critical for transplant acceptance, we investigated the influence of the LMP7-selective inhibitor ONX 0914 in a mixed lymphocyte reaction (MLR) in vitro as well as on allograft rejection in a MHC-disparate (C57BL/6 to BALB/c) and a multiple minor histocompatibility antigen (miHA)-disparate (B10.Br to C3H) model of skin transplantation in vivo. Although we observed reduced allo specific IL-17 production of T cells in vitro, we found that selective inhibition of LMP7 had neither an influence on allograft survival in an MHC-mismatch model nor in a multiple minor mismatch skin transplantation model. We conclude that inhibition of the immunoproteasome is not effective in prolonging skin allograft survival in skin allotransplantation. PMID- 28582645 TI - Staphylococcus aureus VraX specifically inhibits the classical pathway of complement by binding to C1q. AB - VraX is a protein secreted by Staphylococcus aureus, an important human pathogen. A dramatic over expression of VraX is observed when S. aureus is exposed to several antimicrobial agents; however, its function remains unclear. Here, we aimed to reveal the function of this protein and the mechanism by which it affects the immune system to enhance the pathogenesis of the bacterium. Our results showed that VraX specifically inhibited the classical pathway of the complement system. In particular, VraX could bind to the C1q protein and block the formation of the C1 complex. Deletion of VraX decreased the pathogenesis of S. aureus. Our findings indicate that over expression of VraX might be a protective response for S. aureus survival. PMID- 28582646 TI - Increased risk of chronic obstructive pulmonary disease in patients with bipolar disorder: A population-based study. AB - BACKGROUND: We conducted this nationwide study to examine the prevalence and incidence of chronic obstructive pulmonary disease (COPD) among patients with bipolar disorder in Taiwan. METHODS: We used a random sample of 766,427 subjects who were aged >=18 years in 2005. Patients with at least one primary diagnosis of bipolar disorder were identified. Study participants with one primary or secondary diagnosis of COPD for either ambulatory or inpatient care were also identified. We compared the prevalence of COPD in patients with bipolar disorder and the general population in 2005. In addition, we further investigated this cohort from 2006 to 2010 to detect incident cases of COPD in patients with bipolar disorder compared with the general population. The factors associated with COPD among patients with bipolar disorder were also analyzed. RESULTS: The prevalence of COPD in patients with bipolar disorder was higher than in the general population in 2005 (5.68% vs. 2.88%, odds ratio 2.03; 95% confidence interval, 1.53-2.67). The average annual incidence of COPD in patients with bipolar disorder was also higher than in the general population (2.03% vs. 1.03%, risk ratio 1.94; 95% confidence interval, 1.65-2.29) from 2006 to 2010. LIMITATIONS: Some risk factors for COPD such as substance use, obesity, or lifestyle pattern were not available in this study. CONCLUSIONS: Patients with bipolar disorder had a higher prevalence and incidence of COPD compared with the general population. Higher prevalence of COPD among bipolar patients was associated with increased age, males, hypertension, and second-generation antidepressant use. PMID- 28582647 TI - Inflammatory serum cytokines and chemokines increase associated with the disease extent in pediatric Langerhans cell histiocytosis. AB - OBJECTIVE: Langerhans cell histiocytosis (LCH) is characterized by immature dendritic cell proliferation, infiltration of LCH lesions by various inflammatory cells, and a lesional cytokine storm. It is classified into three groups on the basis of disease extent, namely, multisystem with risk-organ involvement (MS+), multisystem without risk-organ involvement (MS-), and single-system (SS) disease. We comprehensively analyzed whether serum levels of cytokines/chemokines reflect the disease extent. METHODS: Serum samples from 52 children with LCH (eight, 25, and 19 with MS+, MS-, and SS, respectively) and 34 control children were analyzed quantitatively for 48 humoral factors. DNA samples extracted from biopsied LCH lesions from 12 patients were tested for BRAF V600E status. RESULTS: The LCH patients had significantly higher serum levels of IL-1Ra, IL-3, IL-6, IL-8, IL-9, IL-10, IL12, IL-13, IL-15, IL-17, IL-18, TNF-alpha, G-CSF, M-CSF, MIF, HGF, VEGF, CCL2, CCL3, CCL7, CXCL1, and CXCL9 than the controls by univariate analysis. Of these IL-9, IL-15 and MIF were significant by multivariate analysis; but not differed between MS and SS diseases. MS disease associated with significantly higher IL-2R, IL-3, IL-8, IL-18, M-CSF, HGF, CCL2, CXCL1, and CXCL9 levels than SS disease by univariate analysis. Of these, CCL2 and M-CSF were significant by multivariate analysis. IL-18 levels were significantly higher in MS+ disease than MS- disease. The LCH patients with BRAF V600E mutation had higher serum levels of CCL7. CONCLUSION: Numerous inflammatory cytokines and chemokines play a role in LCH. Of those, more specific ones reflect the disease extent (MS vs. SS and MS+ vs. MS-) or the BRAF V600E mutation status. It is thought that the most responsible cytokines and chemokines involved in the poor outcome may become future candidate therapeutic targets in LCH. PMID- 28582648 TI - Prognostic factors of early death in children with hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis is a rapidly progressing and fatal disease. Early identification of early death for HLH patients based on the laboratory findings at the time of diagnosis could improve the overall survival. A retrospective study was performed on 95 Chinese pediatric patients with HLH. Patients' data including clinical features and laboratory findings at diagnosis were collected. In a multivariate Cox proportional hazard regression model analysis, albumin<=27.75g/L (hazard ratio (HR)=11.82, 95% confidence interval (CI) 2.58-54.23; P=0.001), LDH>=3707.5 U/L (HR=4.15, 95%CI 1.43-12.01; P=0.009), and IL-10>=456pg/ml (HR=12.39, 95%CI 1.59-96.79; P=0.016) at diagnosis were independent prognostic factors of early death. The risk of early death was 33 fold increase in patients with three risk factors (HR=33.33; 95%CI 8.40-125.00; P<0.001), and 12-fold increase in patients with two risk factors (HR=12.80; 95%CI 2.34-69.80; P=0.002) when compared to it in patients with zero to one risk factor. Our results reveal that HLH patients with the risk of early death can be identified by laboratory findings at diagnosis, which may help guide the treatment decision making for this disease. PMID- 28582650 TI - Magical thinking and decision-making strategies among late adolescent regular gamblers: A mediation model. AB - In the present study, the relation between the tendency to seek supernatural connections between external events and one's own thoughts, words, and actions and gambling among late adolescents has been studied. Psychologists have called this tendency magical thinking. The principal aim of the present study was to test the fit of an explanatory model of risk that starts from magical thinking and passes through maladaptive decision-making strategies, culminating with pathological gambling. Two hundred twenty-two Italian late adolescents, regularly attending bingo halls, aged between 19 and 21 years, completed measures on magical thinking, decision-making strategies, and gambling. Results highlight that young adults adopting dysfunctional modes of thought (i.e. magical thinking) tend to engage with maladaptive styles of decision-making that predispose them to gamble. PMID- 28582649 TI - Synthesis, molecular docking and anti-diabetic evaluation of 2,4 thiazolidinedione based amide derivatives. AB - A series of thiazolidinedione based amide derivatives were designed, synthesized and docked against the PPARgamma receptor target. 11 compounds from the series with good glide scores were selected for in vivo antidiabetic study based on streptozotocin induced diabetic rat model. It was observed that 4 compounds (6c, 6e, 6m &6n) showed significantly good antidiabetic activity in comparison to rosiglitazone and pioglitazone as reference drugs. Compound 6c appeared as the most potent derivative in lowering blood glucose level and showed excellent interaction with SER 342, ILE 281, pi-pi interaction with ARG 288 and halogen bond interaction with LYS 367. Further, PPARgamma transactivation and gene expression studies of compound 6c were carried out to investigate the possible mechanism of action through PPARgamma modulation. Compound 6c exhibited 53.65% transactivation and elevated PPARgamma gene expression by 2.1 folds. The biochemical parameters (AST, ALT and ALP levels) were found within the range with no noteworthy damage to liver. PMID- 28582651 TI - Do family environment factors play a role in adolescents' involvement in organized activities? AB - The study assessed the association of family environment factors with adolescents' participation in organized leisure-time activities (OLTA). We used data on 10,472 Czech adolescents aged 11-15 years (49.2% boys) from the 2013/2014 Health Behaviour in School-aged Children study. The associations of family support, the presence of parental screen-time rules and joint family activities with participation in at least one OLTA were assessed using logistic regression. High family support and the presence of parental screen-time rules were associated with higher odds of OLTA participation. Moreover, adolescents playing sports, indoor games and going for walks with their families at least weekly were more likely to participate in OLTA. Conversely, those spending time in joint family TV/video watching on most days were less likely to do so. A supportive family environment and direct parental involvement in their adolescent children's leisure are associated with OLTA participation in early to middle adolescence. PMID- 28582652 TI - Revisiting the immigrant paradox: Suicidal ideations and suicide attempts among immigrant and non-immigrant adolescents. AB - The current study examined the immigrant paradox in suicidal ideations and attempts, whether rates and correlates varied across immigrant/non-immigrant youth in a nationally representative sample of 7,287 Swiss adolescents (10.2% 1st generation immigrants, 10.3% 2nd generation, and 16.1% mixed parentage; Mage = 17.45, SD = 1.85, 46.6% females). Known risk and protective factors for suicidal ideations and attempts (depressive symptoms, family and peer connectedness, and demographics) were used as correlates, and their effects were compared across groups. About 27% of youth thought about suicide in past 12 months, while 5.5% reported attempting suicide once in their lifetime. After controlling for known predictors and nationality, being an immigrant adolescent (1st, 2nd generation, or mixed parentage) lowered the risk for suicidal ideations as compared to native Swiss youth; immigrant status was unrelated to attempts. Findings provide mixed support for the immigrant paradox; both immigrant and native youth would benefit from effective intervention strategies. PMID- 28582653 TI - Gender matters: Experiences and consequences of digital dating abuse victimization in adolescent dating relationships. AB - Digital dating abuse (DDA) behaviors include the use of digital media to monitor, control, threaten, harass, pressure, or coerce a dating partner. In this study, 703 high school students reported on the frequency of DDA victimization, whether they were upset by these incidents, and how they responded. Results suggest that although both girls and boys experienced DDA at similar rates of frequency (with the exception of sexual coercion), girls reported that they were more upset by these behaviors. Girls also expressed more negative emotional responses to DDA victimization than boys. Although DDA is potentially harmful for all youth, gender matters. These findings suggest that the experience and consequences of DDA may be particularly detrimental for girls. PMID- 28582654 TI - Can present biasedness explain early onset of diabetes and subsequent disease progression? Exploring causal inference by linking survey and register data. AB - Diabetes is a major cause of morbidity, disability, mortality and health care resource use. The increasing prevalence of diabetes may therefore have dramatic future consequences for western societies. Diabetes entails a significant self management component and it has previously been estimated that people with diabetes provide about 95% of their own care. Despite increased focus, self management skills including basic knowledge acquisition, problem solving and setting realistic goals are often not mastered. The main contribution of this paper is to provide evidence that the heterogeneity in self-management and health outcomes amongst diabetes patients is partly attributable to individual differences in time-inconsistent preferences in terms of present biased behaviour. Using a unique data set consisting of survey data from 2014 merged with registry data on a sample of 79 chronically ill patients, we present empirical evidence that present biased individuals are more prone to onset of diabetes at an early age, and have a poorer prognosis after diagnosis. Furthermore, we conclude that present biasedness has a casual effect on the onset and management of diabetes. PMID- 28582655 TI - Coopetition in health care: A multi-level analysis of its individual and organizational determinants. AB - Cooperative inter-organizational relations are salient to healthcare delivery. However, they do not match with the pro-competitive healthcare reforms implemented in several countries. Healthcare organizations thus need to balance competition and cooperation in a situation of 'coopetition'. In this paper we study the individual and organizational determinants of coopetition versus those of cooperation in the price-competitive specialized care sector of the Netherlands. We use shared medical specialists as a proxy of collaboration between healthcare organizations. Based on a sample of 15,431 medical specialists and 371 specialized care organizations from March 2016, one logistic multi-level model is used to predict medical specialists' likelihood to be shared and another to predict their likelihood to be shared to a competitor. We find that different organizations share different specialists to competitors and non-competitors. Cooperation and coopetition are hence distinct organizational strategies in health care. Cooperation manifests through spin-off formation. Coopetition occurs most among organizations in the price-competitive market segment but in alternative geographical markets. Hence, coopetition in health care does not appear to be particularly anti-competitive. However, healthcare organizations seem reluctant to share their most specialized human resources, limiting the knowledge-sharing effects of this type of relation. Therefore, it remains unclear whether coopetition in health care is beneficial to patients. PMID- 28582656 TI - Non-linear relationship between maternal work hours and child body weight: Evidence from the Western Australian Pregnancy Cohort (Raine) Study. AB - Using longitudinal data from the Western Australia Pregnancy Cohort (Raine) Study and both random-effects and fixed-effects models, this study examined the connection between maternal work hours and child overweight or obesity. Following children in two-parent families from early childhood to early adolescence, multivariate analyses revealed a non-linear and developmentally dynamic relationship. Among preschool children (ages 2 to 5), we found lower likelihood of child overweight and obesity when mothers worked 24 h or less per week, compared to when mothers worked 35 or more hours. This effect was stronger in low to-medium income families. For older children (ages 8 to 14), compared to working 35-40 h a week, working shorter hours (1-24, 25-34) or longer hours (41 or more) was both associated with increases in child overweight and obesity. These non linear effects were more pronounced in low-to-medium income families, particularly when fathers also worked long hours. PMID- 28582657 TI - Extended kin and children's behavioral functioning: Family structure and parental immigrant status. AB - Using the Los Angeles Family and Neighborhood Survey (L.A. FANS), this paper examines the association between the presence of co-resident extended kin and children's internalizing and externalizing behaviors. The paper demonstrates the differential role of extended kin by family structure, as well as across parental immigrant status - specifically, nativity and documentation status. Children in the sample were found to be disadvantaged in extended family households, especially with regard to internalizing behaviors. This disadvantageous association was found mostly among married-parent extended family households, whereas there was no association between the presence of extended kin and behavior problems in children from single-parent families. This pattern emerged more clearly among children of documented immigrants, compared to those with native-born parents and those whose parents were unauthorized immigrants. These findings suggest a need to modify previous theories on extended family living arrangements; they also provide policy implications for immigrant families. PMID- 28582658 TI - A method to improve the quality of 2.5 dimensional micro-and nano-structures produced by focused ion beam machining. AB - The present work deals with a new technique to produce complex micro- and nano scale patterns with high accuracy by FIB micro machining. The proposed method is related to the production of stream file, which is optimized through a software interface. A unique sampling approach is used to optimize the conversion from a 3D meshed CAD object to the focused ion beam (FIB) digital to analogue converter (DAC). The method uses a novel scan strategy, sensitive to the pattern local geometry and size, to define the optimal ion beam path, dwell time and the scanning pitch. This not only allows to minimize the redeposition but also to obtain accurate and scalable milling routines. In order to show the applicability of the method, a hemisphere and a pyramid shape are milled and compared to the shapes obtained using the conventional techniques. Results show that the method is very effective in producing complex shapes while overcoming the detrimental effect of conventional raster/serpentine FIB strategies, such as redeposition. Lastly, a fish-net structure with a pitch of ~200nm as well as a series of truncated cones with sub-micrometrical details are realized to show the potential impact of this new method. Results show that a spatial resolution of less than 100nm is achievable with the help of this method. PMID- 28582659 TI - Increased use of heroin as an initiating opioid of abuse. AB - INTRODUCTION: Given the relatively recent growth in access to heroin and a more permissive atmosphere surrounding its use, we hypothesized that an increasing number of persons with limited experience and tolerance to opioids would experiment with heroin as their first opioid rather than more common prescription opioid analgesics. METHODS: Individuals entering substance abuse treatment for an opioid use disorder in the period 2010-2016 (N=5885) were asked about the specific opioid they first regularly used to get high. To limit long-term recall and survival bias, analyses was restricted to opioid initiation that occurred in the past ten years (2005-2015). RESULTS: In 2005, only 8.7% of opioid initiators started with heroin, but this sharply increased to 33.3% (p<0.001) in 2015, with no evidence of stabilization. The use of commonly prescribed opioids, oxycodone and hydrocodone, dropped from 42.4% and 42.3% of opioid initiators, respectively, to 24.1% and 27.8% in 2015, such that heroin as an initiating opioid was now more frequently endorsed than prescription opioid analgesics. CONCLUSIONS: Our data document that, as the most commonly prescribed opioids - hydrocodone and oxycodone - became less accessible due to supply-side interventions, the use of heroin as an initiating opioid has grown at an alarming rate. Given that opioid novices have limited tolerance to opioids, a slight imprecision in dosing inherent in heroin use is likely to be an important factor contributing to the growth in heroin-related over dose fatalities in recent years. PMID- 28582661 TI - Preparative separation of TL1-1 from Daldinia eschscholzii extract by macroporous resin and evaluation of its antimicrobial activities. AB - 2,3-Dihydro-5-hydroxy-2-methylchromen-4-one (TL1-1) has already been reported to exhibit significant activities such as cytotoxicity, antifungal activity and growth inhibitory activity. In order to simply and efficiently separate TL1-1 from crude extracts of Daldinia eschscholzii on a large-preparative scale, XAD-16 resin was selected from ten types of resin based on its superior adsorption and desorption performance. Adsorption equilibrium data for this resin fitted well with pseudo-first order kinetics and the Freundlich model, which were elucidated from kinetic experiments and adsorption isotherms. Under optimized conditions, the purity of TL1-1 increased from 19.21% (w/w) in the crude extract, to 84.64% (w/w) in the final product, with a recovery yield of 75.06% (w/w) by a one-step treatment. Moreover, in a large-scale separation, the purity and recovery of TL1 1 was 80.33% and 72.02% (w/w), respectively. These results demonstrated that a simple adsorption-desorption strategy, using XAD-16 resin, was efficient, which also highlighted its potential for the future large-scale purification and preparation of TL1-1. In addition, studies showed that the purified TL1-1 exhibited moderate antibacterial activity against Ralstonia solanacearum. PMID- 28582660 TI - The phytochemical 3,3'-diindolylmethane decreases expression of AR-controlled DNA damage repair genes through repressive chromatin modifications and is associated with DNA damage in prostate cancer cells. AB - Androgen receptor (AR) is a transcription factor involved in normal prostate physiology and prostate cancer (PCa) development. 3,3'-Diindolylmethane (DIM) is a promising phytochemical agent against PCa that affects AR activity and epigenetic regulators in PCa cells. However, whether DIM suppresses PCa via epigenetic regulation of AR target genes is unknown. We assessed epigenetic regulation of AR target genes in LNCaP PCa cells and showed that DIM treatment led to epigenetic suppression of AR target genes involved in DNA repair (PARP1, MRE11, DNA-PK). Decreased expression of these genes was accompanied by an increase in repressive chromatin marks, loss of AR occupancy and EZH2 recruitment to their regulatory regions. Decreased DNA repair gene expression was associated with an increase in DNA damage (gammaH2Ax) and up-regulation of genomic repeat elements LINE1 and alpha-satellite. Our results suggest that DIM suppresses AR dependent gene transcription through epigenetic modulation, leading to DNA damage and genome instability in PCa cells. PMID- 28582662 TI - Development and validation of HPLC-MS/MS procedure for determination of 3,4,4',5 tetra-methoxystilbene (DMU-212) and its metabolites in ovarian cancer cells and culture medium. AB - The synthetic resveratrol analogue DMU-212 (3,4,4',5-tetramethoxystilbene) has been shown to possess stronger anticancer activity than resveratrol in a variety of tumour cells. To date, there has been no appropriate procedure that would ensure a reliable data about levels of metabolic products of DMU-212 in cancer cell lines. The purpose of this study was to develop a new procedure for determination of DMU-212 and its three metabolites (DMU-214, DMU-281, DMU-291) in cell lines. Analyses were performed using an HPLC system coupled with a triple quadrupole mass spectrometer operating in multiple reaction monitoring mode. Separation was conducted using a C18 column at a flow rate 800MUL/min with a mobile phase consisting of 5mM ammonium acetate with 0.1% formic acid (solvent A) and acetonitrile (solvent B). The new methodology is fast, simple and has excellent specificity. Moreover, it showed good linearity in two matrices - cell lysates and culture media. Accuracy values for analytes evaluated at different concentration levels ranged from 0.43 to 18% (%bias). The intra-day and inter-day precision, expressed as CV, was in a range 0.49-5.5% and 0.83-13%, respectively. The validated procedure was successfully applied to quantify the resveratrol analogues in the human ovarian cancer cell line SKOV3. PMID- 28582663 TI - Molecular and epidemiological characterization of staphylococcal foodborne outbreak of Staphylococcus aureus harboring seg, sei, sem, sen, seo, and selu genes without production of classical enterotoxins. AB - Staphylococcal food poisoning is the result of consumption of food contaminated with staphylococcal enterotoxins (SEs) produced by Staphylococcus aureus. To date, 23 SEs and SE-like enterotoxins (SEls) have been described in the literature. They are divided into classical SEs (SEA-SEE) and new SE/SEls (SEG SElX). Some have proved to be foodborne-inducible, but others remain unidentified. In May 2016, at an elderly group home in Osaka city, Japan, an outbreak from foodborne pathogens occurred among lunch party participants. Within 2h 30min to 4h 40min, 15 of 53 participants presented gastrointestinal symptoms of vomiting, diarrhea, and nausea. A subsequent laboratory investigation detected S. aureus from most stool samples from patients, several left-over food items, a kitchen swab, and hand swabs from two food handlers. Classical SEs was not detected from S. aureus isolates or left-over food items. From examination for the presence of SE/SEl genes of 20 kinds by PCR, seg, sei, sem, sen, seo, and selu genes were detected in almost all isolates. These isolates exhibited identical or closely related types by coagulase type (type VII), Sma I digested pulsed-field gel electrophoresis analysis and multi-locus sequence typing (MLST CC45 lineage). These results suggest that the foodborne outbreak was caused by S. aureus harboring seg, sei, sem, sen, seo, and selu genes without production of classical SEs. Additionally, some S. aureus isolates from human nasal swabs and healthy human feces harboring seg, sei, sem, sen, seo, and selu genes without production of classical SEs were classified into CC45 lineage using MLST. These findings suggest new SE/SEls as a potential cause of foodborne outbreaks. PMID- 28582664 TI - Interactions between water activity and temperature on the Aspergillus flavus transcriptome and aflatoxin B1 production. AB - Effects of Aspergillus flavus colonization of maize kernels under different water activities (aw; 0.99 and 0.91) and temperatures (30, 37 degrees C) on (a) aflatoxin B1 (AFB1) production and (b) the transcriptome using RNAseq were examined. There was no significant difference (p=0.05) in AFB1 production at 30 and 37 degrees C and 0.99 aw. However, there was a significant (p=0.05) increase in AFB1 at 0.91 aw at 37 degrees C when compared with 30 degrees C/0.99 aw. Environmental stress effects using gene ontology enrichment analysis of the RNA seq results for increasing temperature at 0.99 and 0.91 aw showed differential expression of 2224 and 481 genes, respectively. With decreasing water availability, 4307 were affected at 30 degrees C and 702 genes at 37 degrees C. Increasing temperature from 30 to 37 degrees C at both aw levels resulted in 12 biological processes being upregulated and 9 significantly downregulated. Decreasing aw at both temperatures resulted in 22 biological processes significantly upregulated and 25 downregulated. The interacting environmental factors influenced functioning of the secondary metabolite gene clusters for aflatoxins and cyclopiazonic acid (CPA). An elevated number of genes were co regulated by both aw and temperature. An interaction effect for 4 of the 25 AFB1 genes, including regulatory and transcription activators occurred. For CPA, all 5 biosynthetic genes were affected by aw stress, regardless of temperature. The molecular regulation of A. flavus in maize is discussed. PMID- 28582665 TI - The influence of CHRNA4, COMT, and maternal sensitivity on orienting and executive attention in 6-month-old infants. AB - Despite claims concerning biological mechanisms sub-serving infant attention, little experimental work examines its underpinnings. This study examines how candidate polymorphisms from the cholinergic (CHRNA4 rs1044396) and dopaminergic (COMT rs4680) systems, respectively indicative of parietal and prefrontal/anterior cingulate involvement, are related to 6-month-olds' (n=217) performance during a visual expectation eye-tracking paradigm. As previous studies suggest that both cholinergic and dopaminergic genes may influence susceptibility to the influence of other genetic and environmental factors, we further examined whether these candidate genes interact with one another and/or with early caregiving experience in predicting infants' visual attention. We detected an interaction between CHRNA4 genotype and observed maternal sensitivity upon infants' orienting to random stimuli and a CHRNA4-COMT interaction effect upon infants' orienting to patterned stimuli. Consistent with adult research, we observed a direct effect of COMT genotype on anticipatory looking to patterned stimuli. Findings suggest that CHRNA4 genotype may influence susceptibility to other attention-related factors in infancy. These interactions may account for the inability to establish a link between CHRNA4 and orienting in infant research to date, despite developmental theorizing suggesting otherwise. Moreover, findings suggest that by 6months, dopamine, and relatedly, the prefrontal cortex/anterior cingulate, may be important to infant attention. PMID- 28582666 TI - Quantum dot-linked immunosorbent assay (QLISA) using orientation-directed antibodies. AB - An approach similar to the enzyme-linked immunosorbent assay (ELISA), with the advantage of saving time and effort but exhibiting high performance, was developed using orientation-directed half-part antibodies immobilized on CdSe/ZnS quantum dots. ELISA is a widely accepted assay used to detect the presence of a target substance. However, it takes time to quantify the target with specificity and sensitivity owing to signal amplification. In this study, CdSe/ZnS quantum dots are introduced as bright and photobleaching-tolerant fluorescent materials. Since hydrophilic surface coating of quantum dots rendered biocompatibility and functional groups for chemical reactions, the quantum dots were modified with half-sized antibodies after partial reduction. The half-sized antibody could be bound to a quantum dot through a unique thiol site to properly display the recognition domain for the core process of ELISA, which is an antigen-antibody interaction. The reducing conditions were investigated to generate efficient conjugates of quantum dots and half-sized antibodies. This was applied to IL-6 detection, as the quantification of IL-6 is significant owing to its close relationships with various biomedical phenomena that cause different diseases. An ELISA-like assay with CdSe/ZnS quantum dot institution (QLISA; Quantum dot-linked immunosorbent assay) was developed to detect 0.05ng/mL IL-6, which makes it sufficiently sensitive as an immunosorbent assay. PMID- 28582667 TI - How preferences for volume-based promotions differ between at-risk and non problem female drinkers. PMID- 28582668 TI - The utility of drug checking services as monitoring tools and more: A response to Pirona et al. PMID- 28582671 TI - Pinning synchronization of memristor-based neural networks with time-varying delays. AB - In this paper, the synchronization of memristor-based neural networks with time varying delays via pinning control is investigated. A novel pinning method is introduced to synchronize two memristor-based neural networks which denote drive system and response system, respectively. The dynamics are studied by theories of differential inclusions and nonsmooth analysis. In addition, some sufficient conditions are derived to guarantee asymptotic synchronization and exponential synchronization of memristor-based neural networks via the presented pinning control. Furthermore, some improvements about the proposed control method are also discussed in this paper. Finally, the effectiveness of the obtained results is demonstrated by numerical simulations. PMID- 28582669 TI - QSAR-driven design, synthesis and discovery of potent chalcone derivatives with antitubercular activity. AB - New anti-tuberculosis (anti-TB) drugs are urgently needed to battle drug resistant Mycobacterium tuberculosis strains and to shorten the current 6-12 month treatment regimen. In this work, we have continued the efforts to develop chalcone-based anti-TB compounds by using an in silico design and QSAR-driven approach. Initially, we developed SAR rules and binary QSAR models using literature data for targeted design of new heteroaryl chalcone compounds with anti-TB activity. Using these models, we prioritized 33 compounds for synthesis and biological evaluation. As a result, 10 heteroaryl chalcone compounds (4, 8, 9, 11, 13, 17-20, and 23) were found to exhibit nanomolar activity against replicating mycobacteria, low micromolar activity against nonreplicating bacteria, and nanomolar and micromolar against rifampin (RMP) and isoniazid (INH) monoresistant strains (rRMP and rINH) (<1 MUM and <10 MUM, respectively). The series also show low activity against commensal bacteria and generally show good selectivity toward M. tuberculosis, with very low cytotoxicity against Vero cells (SI = 11-545). Our results suggest that our designed heteroaryl chalcone compounds, due to their high potency and selectivity, are promising anti-TB agents. PMID- 28582672 TI - Work zone sign design for increased driver compliance and worker safety. AB - Many studies have investigated the effect of dynamic message signs (DMS) on drivers' speed reduction and compliance in work zones, yet only a few studies have examined the design of sign content of DMS. The purpose of this study was to develop design standards for DMS to improve driver compliance and worker safety. This study investigated the impact of sign content, frame refresh rate, and sign placement on driver speed reduction, compliance, and eye movements. A total of 44 participants were recruited for this study. Each participant completed 12 simulated driving tasks in a high-fidelity driving simulator. A small-scale field study was also conducted to test the effect of DMS on vehicle speed in a highway work zone. Results showed sign content and placement had no impact on speed reduction and compliance. However, sign frame refresh rate was found to have a significant effect on drivers' initial speed and speed reduction. Participants had longer fixation duration on DMS when worker presence was mentioned in the sign content. Results of the field study suggested that the DMS is most effective at night. PMID- 28582670 TI - Substituted arylsulphonamides as inhibitors of perforin-mediated lysis. AB - The structure-activity relationships for a series of arylsulphonamide-based inhibitors of the pore-forming protein perforin have been explored. Perforin is a key component of the human immune response, however inappropriate activity has also been implicated in certain auto-immune and therapy-induced conditions such as allograft rejection and graft versus host disease. Since perforin is expressed exclusively by cells of the immune system, inhibition of this protein would be a highly selective strategy for the immunosuppressive treatment of these disorders. Compounds from this series were demonstrated to be potent inhibitors of the lytic action of both isolated recombinant perforin and perforin secreted by natural killer cells in vitro. Several potent and soluble examples were assessed for in vivo pharmacokinetic properties and found to be suitable for progression to an in vivo model of transplant rejection. PMID- 28582673 TI - Characterization and quantification of antibiotic resistance genes in manure of piglets and adult pigs fed on different diets. AB - Studies have shown that pig manure is a reservoir of antibiotic resistance genes (ARGs). However, little is known about the characteristics of ARGs in the manure of piglets and adult pigs fed on different diets. In the present study, the ARG characteristics of the manure of piglets and adult pigs fed on different diets (feed, grain) were analyzed using high-throughput fluorescence quantitative PCR. Correlations between heavy metals, antibiotics, and ARGs in pig manure were analyzed. The results showed that the heavy metal and antibiotic contents in the manure of pigs receiving feed significantly exceeded those in the manure of pigs receiving grain. The heavy metal and antibiotic contents were higher in manure of piglets than in that of adult pigs. Feed significantly increased the ARG diversity in the pig manure. The ARG diversity was higher in manure of piglets than in that of adult pigs. In the manure of pigs receiving feed, 25 (from piglets), 12 (from adult pigs) ARGs were enriched significantly compared with pig fed with grain. In particular, sat4 (in piglets) and vatE-01 (in adult pigs) showed the highest enrichment, being increased by 59 and 19-fold, respectively. The ARG diversity correlated positively with the concentrations of antibiotics and heavy metals in the manure. PMID- 28582674 TI - Spatial distributions and enantiomeric signatures of DDT and its metabolites in tree bark from agricultural regions across China. AB - Tree bark is considered as an effective passive sampler for estimating the atmospheric status of pollutants. In this study, we conducted a national scale tree bark sampling campaign across China. Concentration profiles revealed that Eastern China, especially the Jing-Jin-Ji region (including Hebei Province, Beijing and Tianjin) was a hot spot of bark DDT pollution. The enantioselective accumulation of o,p'-DDT was observed in most of the samples and 68% of them showed a preferential depletion of (+)-o,p'-DDT. These results suggest that DDTs in rural bark are likely from combined sources including historical technical DDTs and fresh dicofol usage. The tree bulk DDT levels were found to correlate with soil DDT concentrations, socioeconomy and PM2.5 of the sampling sites. It thus becomes evident that the reemission from soils and subsequent atmospheric deposition were the major pathways leading to the accumulation of DDTs in bark. Based on a previously established bark-air partitioning model, the concentrations of DDTs in the air were estimated from measured concentrations in tree bark, and the results were comparable to those obtained by the use of passive sampling with polyurethane foam (PUF) disks. Our results demonstrate the feasibility of delineating the spatial variations in atmospheric concentration and tracing sources of DDTs by integrating the use of tree bark with enantiomeric analysis. PMID- 28582675 TI - Impacts of climate and management on water balance and nitrogen leaching from montane grassland soils of S-Germany. AB - In this study water balance components as well as nitrogen and dissolved organic carbon leaching were quantified by means of large weighable grassland lysimeters at three sites (860, 770 and 600 m a.s.l.) for both intensive and extensive management. Our results show that at E600, the site with highest air temperature (8.6 degrees C) and lowest precipitation (981.9 mm), evapotranspiration losses were 100.7 mm higher as at the site (E860) with lowest mean annual air temperature (6.5 degrees C) and highest precipitation (1359.3 mm). Seepage water formation was substantially lower at E600 (-440.9 mm) as compared to E860. Compared to climate, impacts of management on water balance components were negligible. However, intensive management significantly increased total nitrogen leaching rates across sites as compared to extensive management from 2.6 kg N ha 1 year-1 (range: 0.5-6.0 kg N ha-1 year-1) to 4.8 kg N ha-1 year-1 (range: 0.9 12.9 kg N ha-1 year-1). N leaching losses were dominated by nitrate (64.7%) and less by ammonium (14.6%) and DON (20.7%). The low rates of N leaching (0.8-6.9% of total applied N) suggest a highly efficient nitrogen uptake by plants as measured by plant total N content at harvest. Moreover, plant uptake was often exceeding slurry application rates, suggesting further supply of N due to soil organic matter decomposition. The low risk of nitrate losses via leaching and surface runoff of cut grassland on non-sandy soils with vigorous grass growth may call for a careful site and region specific re-evaluation of fixed limits of N fertilization rates as defined by e.g. the German Fertilizer Ordinance following requirements set by the European Water Framework and Nitrates Directive. PMID- 28582676 TI - Cerium oxide nanoparticles alter the salt stress tolerance of Brassica napus L. by modifying the formation of root apoplastic barriers. AB - Rapidly growing global population adds significant strains on the fresh water resources. Consequently, saline water is increasingly tapped for crop irrigation. Meanwhile, rapid advancement of nanotechnology is introducing more and more engineered nanoparticles into the environment and in agricultural soils. While some negative effects of ENPs on plant health at very high concentrations have been reported, more beneficial effects of ENPs at relatively low concentrations are increasingly noticed, opening doors for potential applications of nanotechnology in agriculture. In particular, we found that cerium oxide nanoparticles (CeO2NPs) improved plant photosynthesis in salt stressed plants. Due to the close connections between salt stress tolerance and the root anatomical structures, we postulated that CeO2NPs could modify plant root anatomy and improve plant salt stress tolerance. This study aimed at testing the hypothesis with Brassica napus in the presence of CeO2NPs (0, 500 mg kg-1 dry sand) and/or NaCl (0, 50 mM) in a growth chamber. Free hand sections of fresh roots were taken every seven days for three weeks and the suberin lamellae development was examined under a fluorescence microscope. The results confirmed the hypothesis that CeO2NPs modified the formation of the apoplastic barriers in Brassica roots. In salt stressed plants, CeO2NPs shortened the root apoplastic barriers which allowed more Na+ transport to shoots and less accumulation of Na+ in plant roots. The altered Na+ fluxes and transport led to better physiological performance of Brassica and may lead to new applications of nanotechnology in agriculture. PMID- 28582677 TI - Fast and safe gas detection from underground coal fire by drone fly over. AB - Underground coal fires start naturally or as a result of human activities. Besides burning away the important non-renewable energy resource and causing financial losses, burning coal seams emit carbon dioxide, carbon monoxide, sulfur oxide and methane, and is a leading cause of smog, acid rain, global warming, and air toxins. In the U.S. alone, the combined cost of coal-fire remediation projects that have been completed, budgeted, or projected by the U.S. Department of the Interior's Office of Surface Mining Remediation and Enforcement (OSM), exceeds $1 billion. It is estimated that these fires generate as much as 3% of the world's annual carbon dioxide emissions and consume as much as 5% of its minable coal. Considering the magnitude of environmental impact and economic loss caused by burning underground coal seams, we have developed a new, safe, reliable surface measurement of coal fire gases to assess the nature of underground coal fires. We use a drone mounted with gas sensors. Drone collected gas concentration data provides a safe alternative for evaluating the rank of a burning coal seam. In this study, a new method of determining coal rank by gas ratios is developed. Coal rank is valuable for defining parameters of a coal seam such as burn temperature, burn rate, and volume of burning seam. PMID- 28582678 TI - Using expansive grasses for monitoring heavy metal pollution in the vicinity of roads. AB - We propose a method for monitoring heavy metal deposition in the vicinity of roads using the leaf surfaces of two expansive grass species which are greatly abundant. A principle of the proposed procedure is to minimize the number of operations in collecting and preparing samples for analysis. The monitored elements are extracted from the leaf surfaces using dilute nitric acid directly in the sample-collection bottle. The ensuing steps, then, are only to filter the extraction solution and the elemental analysis itself. The verification results indicate that the selected grasses Calamagrostis epigejos and Arrhenatherum elatius are well suited to the proposed procedure. Selected heavy metals (Zn, Cu, Pb, Ni, Cr, and Cd) in concentrations appropriate for direct determination using methods of elemental analysis can be extracted from the surface of leaves of these species collected in the vicinity of roads with medium traffic loads. Comparing the two species showed that each had a different relationship between the amounts of deposited heavy metals and distance from the road. This disparity can be explained by specific morphological properties of the two species' leaf surfaces. Due to the abundant occurrence of the two species and the method's general simplicity and ready availability, we regard the proposed approach to constitute a broadly usable and repeatable one for producing reproducible results. PMID- 28582679 TI - Small peptide signaling pathways modulating macronutrient utilization in plants. AB - Root system architecture (RSA) and physiological functions define macronutrient uptake efficiency. Small signaling peptides (SSPs), that act in manners similar to hormones, and their cognate receptors transmit signals both locally and systemically. Several SSPs controlling morphological and physiological traits of roots have been identified to be associated with macronutrient uptake. Recent development in plant genome research has provided an avenue toward systems-based identification and prediction of additional SSPs. This review highlights recent studies on SSP pathways important for optimization of macronutrient uptake and provides new insights into the diversity of SSPs regulated in response to changes in macronutrient availabilities. PMID- 28582680 TI - Evolutionary Relationship of the Scale-Bearing Kraken (incertae sedis, Monadofilosa, Cercozoa, Rhizaria): Combining Ultrastructure Data and a Two-Gene Phylogeny. AB - The genus Kraken represents a distinct lineage of filose amoebae within the Cercozoa. Currently a single species, Kraken carinae, has been described. SSU rDNA phylogeny showed an affiliation to the Cercomonadida, branching with weak support at its base, close to Paracercomonas, Metabolomonas, and Brevimastigomonas. Light microscopical analyses showed several unique features of the genus Kraken, but ultrastructure data were lacking. In this study, K. carinae has been studied by electron microscopy, these data conjoined with a two-gene phylogeny were used to give more insight into the evolutionary relationship of the genus Kraken within Cercozoa. The data confirmed the absence of flagella, but also showed novel characteristics, such as the presence of extrusomes, osmiophilic bodies, and mitochondria with flat cristae. Surprising was the presence of single-tier scales which are carried by cell outgrowths, much of what is expected of the last common ancestor of the class Imbricatea. The phylogenetic analyses however confirmed previous results, indicating Kraken as a sister group to Paracercomonas in Sarcomonadea with an increased but still low support of 0.98 PP/63 BP. Based on the unique features of Kraken we establish the Krakenidae fam. nov. that we, due to contradictory results in morphology and phylogeny, assign incertae sedis, Monadofilosa. PMID- 28582681 TI - Translational control and the cancer cell response to stress. AB - The evidence for the importance of aberrant translation in cancer cells is overwhelming. Reflecting the wealth of data, there are excellent reviews delineating how ribosomes and initiation factors are linked to cancer [1-3], and the therapeutic strategies being devised to target them [4]. Changes in translational efficiency can engender a malignant phenotype without the need for chromatin reorganization, transcription, splicing and mRNA export [5,6]. Thus, cancer-related modulations of the translational machinery are ideally suited to allow cancer cells to respond to the various stresses encountered along the path of tumorigenesis and organism-wide dissemination [7*,8,9,10*]. Emerging findings supporting this notion are the focus of this review. PMID- 28582682 TI - Rotator cuff-related pain: Patients' understanding and experiences. AB - BACKGROUND: Persistent musculoskeletal pain is a multi-factorial entity, influenced by biological, genetic and psychosocial factors. Psychosocial factors, such as individuals' beliefs and experiences, need to be considered in the management of such pain. While extensive research has explored beliefs of individuals with spinal pain, less is known about individuals' beliefs regarding shoulder pain. OBJECTIVES: To explore beliefs about the cause of pain in individuals with persistent rotator cuff-related pain, as well as the experiences of the effect of pain on their daily lives. DESIGN: A mixed methods design, using semi-structured interviews and validated outcome questionnaires. METHOD: Five men and five women, aged 47-68 years, with shoulder pain for at least three months were recruited. Individual semi-structured interviews were audio-recorded, transcribed verbatim and analysed using the general inductive approach. RESULTS/FINDINGS: Four key themes emerged. The cause of pain, 'Understanding the pain', was described in terms of anatomical factors within the context of the participants' lives. The pain impacted all areas of life, creating another theme, 'It affects everything'. Participants responded to their pain by adopting certain, 'Pain-associated behaviours' and sought information for diagnosis, general management and exercise prescription, 'Emotional responses and the future'. CONCLUSIONS: The participants with rotator cuff-related pain believed the cause of their pain to be local to the shoulder region. However, they also described various stressors in their work-, sports- and family-related lives. Rehabilitation may need to include educating the individual, expanding their understanding regarding pain mechanisms and appropriate interventions, based on individual goal-setting. PMID- 28582683 TI - Action recognition is sensitive to the identity of the actor. AB - Recognizing who is carrying out an action is essential for successful human interaction. The cognitive mechanisms underlying this ability are little understood and have been subject of discussions in embodied approaches to action recognition. Here we examine one solution, that visual action recognition processes are at least partly sensitive to the actor's identity. We investigated the dependency between identity information and action related processes by testing the sensitivity of neural action recognition processes to clothing and facial identity information with a behavioral adaptation paradigm. Our results show that action adaptation effects are in fact modulated by both clothing information and the actor's facial identity. The finding demonstrates that neural processes underlying action recognition are sensitive to identity information (including facial identity) and thereby not exclusively tuned to actions. We suggest that such response properties are useful to help humans in knowing who carried out an action. PMID- 28582685 TI - Meaningful questions: The acquisition of auxiliary inversion in a connectionist model of sentence production. AB - Nativist theories have argued that language involves syntactic principles which are unlearnable from the input children receive. A paradigm case of these innate principles is the structure dependence of auxiliary inversion in complex polar questions (Chomsky, 1968, 1975, 1980). Computational approaches have focused on the properties of the input in explaining how children acquire these questions. In contrast, we argue that messages are structured in a way that supports structure dependence in syntax. We demonstrate this approach within a connectionist model of sentence production (Chang, 2009) which learned to generate a range of complex polar questions from a structured message without positive exemplars in the input. The model also generated different types of error in development that were similar in magnitude to those in children (e.g., auxiliary doubling, Ambridge, Rowland, & Pine, 2008; Crain & Nakayama, 1987). Through model comparisons we trace how meaning constraints and linguistic experience interact during the acquisition of auxiliary inversion. Our results suggest that auxiliary inversion rules in English can be acquired without innate syntactic principles, as long as it is assumed that speakers who ask complex questions express messages that are structured into multiple propositions. PMID- 28582684 TI - Compounding as Abstract Operation in Semantic Space: Investigating relational effects through a large-scale, data-driven computational model. AB - In many languages, compounding is a fundamental process for the generation of novel words. When this process is productive (as, e.g., in English), native speakers can juxtapose two words to create novel compounds that can be readily understood by other speakers. The present paper proposes a large-scale, data driven computational system for compound semantic processing based on distributional semantics, the CAOSS model (Compounding as Abstract Operation in Semantic Space). In CAOSS, word meanings are represented as vectors encoding their lexical co-occurrences in a reference corpus. Given two constituent words, their composed representation (the compound) is computed by using matrices representing the abstract properties of constituent roles (modifier vs. head). The matrices are also induced through examples of language usage. The model is then validated against behavioral results concerning the processing of novel compounds, and in particular relational effects on response latencies. The effects of relational priming and relational dominance are considered. CAOSS predictions are shown to pattern with previous results, in terms of both the impact of relational information and the dissociations related to the different constituent roles. The simulations indicate that relational information is implicitly reflected in language usage, suggesting that human speakers can learn these aspects from language experience and automatically apply them to the processing of new word combinations. The present model is flexible enough to emulate this procedure, suggesting that relational effects might emerge as a by product of nuanced operations across distributional patterns. PMID- 28582686 TI - Incidental orthographic learning during a color detection task. AB - Orthographic learning refers to the acquisition of knowledge about specific spelling patterns forming words and about general biases and constraints on letter sequences. It is thought to occur by strengthening simultaneously activated visual and phonological representations during reading. Here we demonstrate that a visual perceptual learning procedure that leaves no time for articulation can result in orthographic learning evidenced in improved reading and spelling performance. We employed task-irrelevant perceptual learning (TIPL), in which the stimuli to be learned are paired with an easy task target. Assorted line drawings and difficult-to-spell words were presented in red color among sequences of other black-colored words and images presented in rapid succession, constituting a fast-TIPL procedure with color detection being the explicit task. In five experiments, Greek children in Grades 4-5 showed increased recognition of words and images that had appeared in red, both during and after the training procedure, regardless of within-training testing, and also when targets appeared in blue instead of red. Significant transfer to reading and spelling emerged only after increased training intensity. In a sixth experiment, children in Grades 2-3 showed generalization to words not presented during training that carried the same derivational affixes as in the training set. We suggest that reinforcement signals related to detection of the target stimuli contribute to the strengthening of orthography-phonology connections beyond earlier levels of visually-based orthographic representation learning. These results highlight the potential of perceptual learning procedures for the reinforcement of higher-level orthographic representations. PMID- 28582687 TI - Evaluating relationships among clinical working memory assessment and inattentive and hyperactive/impulsive behaviors in a community sample of children. AB - OBJECTIVE: This study examined relationships between inattentive and hyperactive/impulsive behaviors and working memory (WM) functioning, and the utility of WM in categorical diagnosis of ADHD versus considering ADHD symptoms on a continuum. METHOD: The study included 50 male children (6-12 years). Inattentive and hyperactive/impulsive behaviors were measured by the Conners-3P parent report, and WM was assessed by the WISC-IV WM subtests and Working Memory Index (WMI). RESULTS: WISC-IV Arithmetic and Digit Span Backward were most consistently related to inattentive behaviors, and no WM measure was consistently related to ADHD hyperactive/impulsive behaviors. Arithmetic and Digit Span Backward also accounted for significant variance in inattentive behaviors and ADHD inattention symptoms, respectively. Neither the WMI nor the Arithmetic subtest correctly classified individuals diagnosed with ADHD. CONCLUSION: Measurement of inattentive behaviors on a continuum best characterized relationships between symptoms of ADHD and WM functioning; WM functioning did not have utility in categorical understanding of ADHD. PMID- 28582688 TI - A simplified pressure adjustment clinical pathway for programmable valves in NPH patients. AB - OBJECTIVE: The goal of this study is to provide a clinical pathway for shunt valve adjustment in the treatment of normal pressure hydrocephalus (NPH) patients. PATIENT AND METHODS: The authors conducted a single-center retrospective study of 102 patients (mean age 74 years, 66 men, 36 women) diagnosed with NPH. In all cases, a Medtronic Strata Adjustable Pressure valve set initially at 1.5 was implanted. Outcome was based on the clinical status of the patient at the last contact point with the senior author. Patients were adjusted with reductions or increases of 0.5 per follow-up visit to achieve the best clinical outcome and avoid complications. Complications were categorized as infection, shunt malfunction, subdural hygroma/hematoma, or any adverse event able to be attributed to a change in shunt setting or surgical procedure. RESULTS: Of the 102 patients, 60% had the triad of clinical symptoms, 5% had gait dysfunction only, 2% had dementia only, 4% had urine incontinence and gait dysfunction, 1% had urine incontinence and dementia, and 28% had gait dysfunction and dementia. Over a mean clinical follow-up of 19 months, 71 patients had improvement or resolution of NPH symptoms at the last point of contact with the senior author. Of the 71 patients, 24% improved in all 3 symptoms, 8% improved in urine incontinence only, 17% improved in gait dysfunction only, 15% improved in dementia only, 15% improved in urine incontinence and gait dysfunction only, 4% improved in urine incontinence and dementia only, and 15% improved in gait dysfunction and dementia only. Valve pressure adjustment was required at least once in 85 patients (mean number of 1.68 adjustments, 7 maximum); 10% had 0.5 as the final setting, 47% had 1.0 as the final setting, 36% had 1.5 as the final setting, 7% had 2.0 as the final setting, and 0% had 2.5 as the final setting. There were 41 (40%) complications overall: 28 subdural hygromas/hematomas, of which 5 required surgical evacuation; 9 distal obstructions requiring surgical revision; 4 seizures; 2 infections; 1 exposed shunt tubing; 1 intraparenchymal hematoma of unknown etiology. CONCLUSION: Standardization of post-operative care for patients with NPH is possible. The present manuscript offers a safe and effective pathway for treatment of NPH patients with the Strata Adjustable Pressure Valve. PMID- 28582689 TI - The impact of white matter lesions on the cognitive outcome of subthalamic nucleus deep brain stimulation in Parkinson's disease. AB - OBJECTIVES: White Matter lesions (WML) are a risk factor for cognitive impairment in Parkinson's disease. There is no clear evidence of reduced general cognitive function after DBS. However, a subgroup of patients develops dementia rapidly after DBS despite careful patient selection processes. The aim of this study was to evaluate the load of WML as a possible risk factor for cognitive decline following STN DBS. PATIENTS AND METHODS: 40 PD-patients receiving bilateral STN DBS were followed at least three years after surgery to detect dementia. All patients underwent comprehensive neuropsychological assessment and MRI before surgery. The extent of WML was assessed using an automated approach. WML volume was correlated to the onset of dementia and the decline of a cognitive composite score retrospectively. RESULTS: Patients with a rapid onset of dementia within one, respective three following DBS showed significant higher WML volumes compared to cognitive normal and MCI patients (55.8cm3+/-18.836 vs. 9.3cm3+/ 12.2; p=0.002). The same significant association was found in a multivariable model, including the covariables age, gender and PD disease duration (p=0.01). WML volume was associated to the rate of decline in cognitive composite score within three years after DBS surgery (p=0.006; R2=0.40) after correction for age. CONCLUSIONS: Damaged white matter may lead to a reduced compensation of disconnections in cognitive circuits caused by the implantation of the DBS electrodes or by chronic stimulation. The role of WML as a prognostic factor for the cognitive outcome after DBS may be underestimated. The WML burden should be taken seriously in preoperative risk stratification. PMID- 28582690 TI - Use of alcohol and drugs in the view of people living with HIV/AIDS: a qualitative study. AB - OBJECTIVE: To investigate the meaning of the experiences of patients infected by HIV using antiretroviral therapy, regarding the use of alcohol and drugs. STUDY DESIGN: A qualitative phenomenological study. METHOD: A total of 25 patients receiving antiretroviral treatment participated in the investigation, of which 14 were male and 11 were females, who expressed their feelings and perceptions through participation in focus groups and the interpretation of costumes. The empirical material was transcribed in full and later organized and analyzed using the phenomenological method. RESULTS: Based on this amusing experience we realized that participants were unaware of the effects of the use of alcohol and drugs in the AIDS progression. Since they have kept with their smoking and alcoholism habits to be accepted in a social group and consequently prevent prejudice. We believe that our health education strategy was adequate to improve antiretroviral therapy, since it helped in subject comprehension and patients self-care body expression. CONCLUSION: This phenomenological study made it possible to understand the experience of patients living with HIV regarding the use of alcohol and drugs, and contributes to the planning and implementation of intervention programs based on a participative model of care, with a view to prioritizing the holistic aspects involved in the treatment of people living with HIV/AIDS. PMID- 28582691 TI - Biological functions and role of mitogen-activated protein kinase activated protein kinase 2 (MK2) in inflammatory diseases. AB - The p38/MK2 pathway regulates a wide range of biological functions, and thus has most been explored as a therapeutic target for inhibition of severe and chronic inflammatory diseases. Till date, several p38 inhibitors with potent anti inflammatory effects in pre-clinical models have been discovered, but most of them have failed in clinics due to serious systemic toxicity issues. MK2 is a serine-threonine kinase downstream to p38 and is activated directly through phosphorylation of p38 under stress and inflammatory stimulus. MK2 has been shown to be a direct and essential component in regulating the biosynthesis of pro inflammatory cytokines. Disruption of MK2 signaling leads to a significant reduction in the level of several pro-inflammatory cytokine production. For these reasons, MK2 has been identified as an alternate molecular target in order to block the pathway with an assumption that this approach would show similar efficacy as that of p38 inhibitors with lesser toxicity concerns. This review briefly summarizes the molecular structure of MK2 and major biological functions in context with its pharmacological modulation to address various inflammatory diseases. It also discusses the points of advantages over p38 inhibition along with recent update in the development of small molecule MK2 inhibitors. PMID- 28582692 TI - Exploring the interaction of silver nanoparticles with lysozyme: Binding behaviors and kinetics. AB - The role of nanoparticle interaction with biomolecules to form a biocorona is the key to nanoparticle behavior and its consequences in the physiological environment. Since the adsorbed biocorona decides the fate of a nanomaterials in vivo, and thus a comprehensive understanding of the dynamic interactions of the proteins with the nanoparticle is imperative. Herein we investigate the interaction of a model protein, lysozyme with silver nanoparticles (AgNPs) using fluorescence, synchronous fluorescence, UV-vis absorption spectrum and circular dichroism (CD) techniques under the physiological conditions. The results indicated that the binding of AgNPs to lysozyme may be a static quenching mechanism. With the analysis of the fluorescence spectral data, the binding constants and the thermodynamic parameters were determined, which suggests that the binding of AgNPs to lysozyme is a spontaneous process. Moreover, it was demonstrated that the main acting forces between AgNPs and lysozyme may be hydrophobic interactions. At the same time, the conformational change of lysozyme induced by AgNPs was investigated with synchronous fluorescence spectroscopy and CD techniques. The results of kinetic studies reveal that the adsorption of lysozyme on AgNPs surface tends to follow pseudo-second-order kinetic characteristic with obvious hysteresis effect. PMID- 28582693 TI - Analysis of the pen pressure and grip force signal during basic drawing tasks: The timing and speed changes impact drawing characteristics. AB - Writing is a complex fine and trained motor skill, involving complex biomechanical and cognitive processes. In this paper, we propose the study of writing kinetics using three angles: the pen-tip normal force, the total grip force signal and eventually writing quality assessment. In order to collect writing kinetics data, we designed a sensor collecting these characteristics simultaneously. Ten healthy right-handed adults were recruited and were asked to perform four tasks: first, they were instructed to draw circles at a speed they considered comfortable; they then were instructed to draw circles at a speed they regarded as fast; afterwards, they repeated the comfortable task compelled to follow the rhythm of a metronome; and eventually they performed the fast task under the same timing constraints. Statistical differences between the tasks were computed, and while pen-tip normal force and total grip force signal were not impacted by the changes introduced in each task, writing quality features were affected by both the speed changes and timing constraint changes. This verifies the already-studied speed-accuracy trade-off and suggest the existence of a timing constraints-accuracy trade-off. PMID- 28582694 TI - SlCOR413IM1: A novel cold-regulation gene from tomato, enhances drought stress tolerance in tobacco. AB - Drought stress adversely affects plant growth, development, and productivity. Genes functioning in plant response to drought stress are essential for drought tolerance. In this study, SlCOR413IM1, a cold-regulated gene isolated from Solanum lycopersium, was transferred to Nicotiana tabacum to investigate its function under drought stress. The subcellular localisation of SlCOR413IM1-GFP fusion protein in Arabidopsis protoplasts suggested that SlCOR413IM1 is a chloroplast protein. Expression analyses revealed that SlCOR413IM1 responded to drought and cold stresses. Under drought stress, transgenic plants maintained the high maximum photochemical efficiency, net photosynthetic rate (Pn) and D1 protein content of photosystem II (PSII). Compared with wild-type (WT) plants, transgenic plants showed higher superoxide dismutase (SOD) and ascorbate peroxidase (APX) activities and proline and soluble sugar content, which reduced reactive oxygen species (ROS) generation. However, the high SOD and APX activities in transgenic plants were independent of their transcription levels. Moreover, the transgenic plants exhibited better seed germination, water status and survival, as well as lower malondialdehyde (MDA) content and relative electrical conductivity (REC) than WT plants under drought stress. Taken together, these data demonstrated that overexpression of SlCOR413IM1 enhanced drought stress tolerance in transgenic tobacco. PMID- 28582695 TI - Identification of potent inhibitors of DNA methyltransferase 1 (DNMT1) through a pharmacophore-based virtual screening approach. AB - DNA methylation is an epigenetic change that results in the addition of a methyl group at the carbon-5 position of cytosine residues. DNA methyltransferase (DNMT) inhibitors can suppress tumour growth and have significant therapeutic value. However, the established inhibitors are limited in their application due to their substantial cytotoxicity. Additionally, the standard drugs for DNMT inhibition are non-selective cytosine analogues with considerable cytotoxic side-effects. In the present study, we have designed a workflow by integrating various ligand based and structure-based approaches to discover new agents active against DNMT1. We have derived a pharmacophore model with the help of available DNMT1 inhibitors. Utilising this model, we performed the virtual screening of Maybridge chemical library and the identified hits were then subsequently filtered based on the Naive Bayesian classification model. The molecules that have returned from this classification model were subjected to ensemble based docking. We have selected 10 molecules for the biological assay by inspecting the interactions portrayed by these molecules. Three out of the ten tested compounds have shown DNMT1 inhibitory activity. These compounds were also found to demonstrate potential inhibition of cellular proliferation in human breast cancer MDA-MB-231 cells. In the present study, we have utilized a multi-step virtual screening protocol to identify inhibitors of DNMT1, which offers a starting point to develop more potent DNMT1 inhibitors as anti-cancer agents. PMID- 28582696 TI - Structural basis for the potent inhibition of the HIV integrase-LEDGF/p75 protein protein interaction. AB - Integrase (IN) constitutes one of the key enzymes involved in the lifecycle of the Human Immunodeficiency Virus (HIV), the etiological agent of AIDS. The biological role of IN strongly depends on the recognition and binding of cellular cofactors belonging to the infected host cell. Thus, the inhibition of the protein-protein interaction (PPI) between IN and cellular cofactors has been envisioned as a promising therapeutic target. In the present work we explore a structure-activity relationship for a set of 14 compounds reported as inhibitors of the PPI between IN and the lens epithelium-derived growth factor (LEDGF/p75). Our results demonstrate that the possibility to adopt the bioactive conformation capable of interacting with the hotspots IN-LEDGF/p75 hotspots residues constitutes a critical feature to obtain a potent inhibition. A ligand efficiency (|Lig-Eff|) quantitative descriptor combining both interaction energetics and conformational requirements was developed and correlated with the reported biological activity. Our results contribute to the rational development of IN LEDGF/p75 interaction inhibitors providing a solid quantitative structure activity relationship aimed for the screening of new IN-LEDGF/p75 interaction inhibitors. PMID- 28582697 TI - Increases in self-reported fentanyl use among a population entering drug treatment: The need for systematic surveillance of illicitly manufactured opioids. AB - BACKGROUND/PURPOSE: Recent reports indicate a sharp increase in fentanyl-related overdose deaths across the United States, much of which is likely related to the introduction of cheap, illicitly manufactured fentanyl derivatives. In this study, we sought to estimate the magnitude of illicit fentanyl use from 2012 to 2016 using a national opioid abuse surveillance system. METHODS: The study program surveyed 10,900 individuals entering substance abuse treatment for opioid use disorder, with participants asked to endorse past month 'use to get high' of fentanyl drugs, stratified by identifiable (i.e., branded) fentanyl formulations or a 'type unknown' drug alleged to contain fentanyl. MAIN FINDINGS: Total past month fentanyl-use rose modestly from 2012 to 2016. While use of known fentanyl products remained relatively stable (mean=10.9%; P=0.25), endorsements of 'unknown' fentanyl products nearly doubled from 9% in 2013 to 15.1% by 2016 (P<0.001). Data show no discernable indication that this increase is diminishing or stabilizing. CONCLUSIONS: This first attempt to assess the prevalence of illicit fentanyl use shows that recent increases in fentanyl use seem to be due almost entirely to 'unknown' fentanyl presumed to be illicitly manufactured. Given that it is difficult to assess the extent to which fentanyl may have been substituted for another drug (i.e., oxycodone, alprazolam, etc.) or was used as a heroin admixture, our data likely represent an underestimation of the full magnitude of illicit fentanyl abuse. As such, this growing public health problem requires immediate attention and more systematic efforts to identify and track its abuse. PMID- 28582698 TI - Co-occurrence of tobacco product use, substance use, and mental health problems among adults: Findings from Wave 1 (2013-2014) of the Population Assessment of Tobacco and Health (PATH) Study. AB - BACKGROUND: Although non-cigarette tobacco product use is increasing among U.S. adults, their associations with substance use and mental health problems are unclear. This study examined co-occurrence of tobacco use, substance use, and mental health problems, and its moderation by gender, among 32,202U.S. adults from Wave 1 (2013-2014) of the nationally representative longitudinal Population Assessment of Tobacco and Health (PATH) Study. METHODS: Participants self reported current cigarette, e-cigarette, traditional cigar, cigarillo, filtered cigar, hookah, smokeless tobacco and other tobacco product use; past year alcohol, marijuana, and other drug use; and past year substance use, internalizing and externalizing problems. RESULTS: Compared to non-current tobacco users, current users were more likely to report alcohol or drug use (adjusted odds ratio (AOR)=2.6; 95% confidence interval (CI): 2.3, 2.9), with the strongest associations observed for cigarillo and hookah users. Across all tobacco product groups, users were more likely to report internalizing (AOR=1.9; 95% CI: 1.7, 2.1), externalizing (AOR=1.6; 95% CI: 1.5, 1.8), and substance use (AOR=3.4; 95% CI: 2.9, 4.1) problems than non-users. Gender moderated many of these associations and, of these, all non-cigarette tobacco product associations were stronger among females. CONCLUSIONS: This nationally representative study of U.S. adults is the first to comprehensively document tobacco use, substance use, and mental health comorbidities across the range of currently available tobacco products, while also demonstrating that female tobacco users are at increased risk for substance use and mental health problems. These findings may point to gender differences in vulnerability and suggest that interventions incorporate gender-specific approaches. PMID- 28582700 TI - Effects of road salt on larval amphibian susceptibility to parasitism through behavior and immunocompetence. AB - Large quantities of road salts are used for de-icing in temperate climates but often leach into aquatic ecosystems where they can cause harm to inhabitants, including reduced growth and survival. However, the implications of road salt exposure for aquatic animal susceptibility to pathogens and parasites have not yet been examined even though infectious diseases can significantly contribute to wildlife population declines. Through a field survey, we found a range of NaCl concentrations (50-560mg/L) in ponds known to contain larval amphibians, with lower levels found in sites close to gravel- rather than hard-surfaced roads. We then investigated how chronic exposure to environmentally-realistic levels of road salt (up to 1140mg/L) affected susceptibility to infection by trematode parasites (helminths) in larval stages of two amphibian species (Lithobates sylvaticus - wood frogs, and L. pipiens - northern leopard frogs) by considering effects on host anti-parasite behavior and white blood cell profiles. Wood frogs exposed to road salt had higher parasite loads, and also exhibited reduced anti parasite behavior in these conditions. In contrast, infection intensity in northern leopard frogs had a non-monotonic response to road salts even though lymphocytes were only elevated at the highest concentration. Our results indicate the potential for chronic road salt exposure to affect larval amphibian susceptibility to pathogenic parasites through alterations of behavior and immunocompetence, with further studies needed at higher concentrations, as well as that of road salts on free-living parasite infectious stages. PMID- 28582699 TI - Association of prenatal cocaine exposure, childhood maltreatment, and responses to stress in adolescence. AB - BACKGROUND: Prenatal cocaine exposure (PCE) may alter responses to stress. Children with PCE tend to grow up in suboptimal caregiving environments, conducive to child maltreatment (CM). Guided by the diathesis-stress model, the present study examined differences in self-reported responses to stress and coping in adolescents with and without PCE and explored whether childhood maltreatment (CM) moderated the effects of PCE. METHODS: Adolescents (N=363; 184 PCE, 179 non-cocaine exposed (NCE)), primarily African-American and of low socioeconomic status, were prospectively enrolled in a longitudinal study at birth. The Responses to Stress Questionnaire was used to assess volitional coping (primary control, secondary control, disengagement) and involuntary responses (involuntary engagement, involuntary disengagement) to stress at the 15- and 17 year follow-up visits. CM was assessed retrospectively at age 17 using the Juvenile Victimization Questionnaire. RESULTS: Findings from longitudinal mixed model analyses indicated that PCE was associated with poorer coping strategies only among adolescents with a history of CM. Adolescents with PCE who experienced CM reported less dominant use of primary (e.g., problem solving, emotional regulation) and secondary control (e.g., cognitive restructuring) and more dominant use of disengagement (e.g., denial, avoidance) and involuntary disengagement (e.g., inaction) than adolescents with PCE who did not experience CM or NCE adolescents regardless of CM. CM was associated with more dominant use of involuntary engagement (e.g., intrusive thoughts). CONCLUSIONS: PCE may increase sensitivity to CM, predisposing increased vulnerability to environmental risk. Continued studies into adulthood will elucidate how coping and involuntary stress responses affect social, vocational, and behavioral adjustment. PMID- 28582701 TI - Oxidative stress in the algae Chlamydomonas reinhardtii exposed to biocides. AB - The toxicity of biocides can be associated with the formation of reactive oxygen species (ROS) and subsequent oxidative damage, interfering with the normal function of photosynthetic organisms. This study investigated the formation and effects of ROS in the unicellular green algae Chlamydomonas reinhardtii exposed to three environmentally relevant biocides, aclonifen, dichlofluanid and triclosan. After a first screening to identify which biocides induced ROS, a 24h multi-endpoint analysis was used to verify the possible consequences. A battery of high-throughput methods was applied in algae for measuring ROS formation, reduced glutathione (GSH), lipid peroxidation (LPO), photosystem (PS) II performance and pigments (chlorophylls a, b and carotenoids). Results show that only aclonifen induced ROS after the first 6h exposure, with the other two biocides not showing any ROS formation. Aclonifen, a Protox and carotenoid inhibitor, induced a concentration-dependent ROS formation, LPO and interfered with algae pigments content, while no alterations were detected in GSH content. A significant effect was also seen in the photosynthetic process, especially a reduction in the maximum and effective quantum yields, accompanied by alterations in energy dissipation in PSII reaction centers and the impairment of the electron transport rate. This study demonstrated the successful use of a battery of high throughput methods for quickly screening biocides capacity to induce the formation of ROS and the subsequent effects in C. reinhardtii, thus revealing their mode of action (MoA) at concentrations before an impact on growth can become effective. PMID- 28582702 TI - ShapeCut: Bayesian surface estimation using shape-driven graph. AB - A variety of medical image segmentation problems present significant technical challenges, including heterogeneous pixel intensities, noisy/ill-defined boundaries and irregular shapes with high variability. The strategy of estimating optimal segmentations within a statistical framework that combines image data with priors on anatomical structures promises to address some of these technical challenges. However, methods that rely on local optimization techniques and/or local shape penalties (e.g., smoothness) have been proven to be inadequate for many difficult segmentation problems. These challenging segmentation problems can benefit from the inclusion of global shape priors within a maximum-a-posteriori estimation framework, which biases solutions toward an object class of interest. In this paper, we propose a maximum-a-posteriori formulation that relies on a generative image model by incorporating both local and global shape priors. The proposed method relies on graph cuts as well as a new shape parameters estimation that provides a global updates-based optimization strategy. We demonstrate our approach on synthetic datasets as well as on the left atrial wall segmentation from late-gadolinium enhancement MRI, which has been shown to be effective for identifying myocardial fibrosis in the diagnosis of atrial fibrillation. Experimental results prove the effectiveness of the proposed approach in terms of the average surface distance between extracted surfaces and the corresponding ground-truth, as well as the clinical efficacy of the method in the identification of fibrosis and scars in the atrial wall. PMID- 28582703 TI - The Cell Cycle Inhibitors p21Cip1 and p27Kip1 Control Proliferation but Enhance DNA Damage Resistance of Glioma Stem Cells. AB - High-grade gliomas are the most prevalent and lethal primary brain tumors. They display a hierarchical arrangement with a population of self-renewing and highly tumorigenic cells called cancer stem cells. These cells are thought to be responsible for tumor recurrence, which make them main candidates for targeted therapies. Unbridled cell cycle progression may explain the selective sensitivity of some cancer cells to treatments. The members of the Cip/Kip family p21Cip1 and p27Kip1 were initially considered as tumor suppressors based on their ability to block proliferation. However, they are currently looked at as proteins with dual roles in cancer: one as tumor suppressor and the other as oncogene. Therefore, the aim of this study was to determine the functions of these cell cycle inhibitors in five patient-derived glioma stem cell-enriched cell lines. We found that these proteins are functional in glioma stem cells. They negatively regulate cell cycle progression both in unstressed conditions and in response to genotoxic stress. In addition, p27Kip1 is upregulated in nutrient-restricted and differentiating cells, suggesting that this Cip/Kip is a mediator of antimitogenic signals in glioma cells. Importantly, the lack of these proteins impairs cell cycle halt in response to genotoxic agents, rendering cells more vulnerable to DNA damage. For these reasons, these proteins may operate both as tumor suppressors, limiting cell proliferation, and as oncogenes, conferring cell resistance to DNA damage. Thus, deepening our knowledge on the biological functions of these Cip/Kips may shed light on how some cancer cells develop drug resistance. PMID- 28582705 TI - Highly sensitive photoelectrochemical biosensor for kinase activity detection and inhibition based on the surface defect recognition and multiple signal amplification of metal-organic frameworks. AB - A turn-on photoelectrochemical (PEC) biosensor based on the surface defect recognition and multiple signal amplification of metal-organic frameworks (MOFs) was proposed for highly sensitive protein kinase activity analysis and inhibitor evaluation. In this strategy, based on the phosphorylation reaction in the presence of protein kinase A (PKA), the Zr-based metal-organic frameworks (UiO 66) accommodated with [Ru(bpy)3]2+ photoactive dyes in the pores were linked to the phosphorylated kemptide modified TiO2/ITO electrode through the chelation between the Zr4+ defects on the surface of UiO-66 and the phosphate groups in kemptide. Under visible light irradiation, the excited electrons from [Ru(bpy)3]2+ adsorbed in the pores of UiO-66 injected into the TiO2 conduction band to generate photocurrent, which could be utilized for protein kinase activities detection. The large surface area and high porosities of UiO-66 facilitated a large number of [Ru(bpy)3]2+ that increased the photocurrent significantly, and afforded a highly sensitive PEC analysis of kinase activity. The detection limit of the as-proposed PEC biosensor was 0.0049UmL-1 (S/N!=!3). The biosensor was also applied for quantitative kinase inhibitor evaluation and PKA activities detection in MCF-7 cell lysates. The developed visible-light PEC biosensor provides a simple detection procedure and a cost-effective manner for PKA activity assays, and shows great potential in clinical diagnosis and drug discoveries. PMID- 28582704 TI - A Novel Antagonist of the Immune Checkpoint Protein Adenosine A2a Receptor Restores Tumor-Infiltrating Lymphocyte Activity in the Context of the Tumor Microenvironment. AB - BACKGROUND: Therapeutic strategies targeting immune checkpoint proteins have led to significant responses in patients with various tumor types. The success of these studies has led to the development of various antibodies/inhibitors for the different checkpoint proteins involved in immune evasion of the tumor. Adenosine present in high concentrations in the tumor microenvironment activates the immune checkpoint adenosine A2a receptor (A2aR), leading to the suppression of antitumor responses. Inhibition of this checkpoint has the potential to enhance antitumor T cell responsiveness. METHODS: We developed a novel A2aR antagonist (PBF-509) and tested its antitumor response in vitro, in a mouse model, and in non-small cell lung cancer patient samples. RESULTS: Our studies showed that PBF-509 is highly specific to the A2aR as well as inhibitory of A2aR function in an in vitro model. In a mouse model, we found that lung metastasis was decreased after treatment with PBF-509 compared with its control. Furthermore, freshly resected tumor infiltrating lymphocytes from lung cancer patients showed increased A2aR expression in CD4+ cells and variable expression in CD8+ cells. Ex vivo studies showed an increased responsiveness of human tumor-infiltrating lymphocytes when PBF-509 was combined with anti-PD-1 or anti-PD-L1. CONCLUSIONS: Our studies demonstrate that inhibition of the A2aR using the novel inhibitor PBF-509 could lead to novel immunotherapeutic strategies in non-small cell lung cancer. PMID- 28582706 TI - Zinc-doping enhanced cadmium sulfide electrochemiluminescence behavior based on Au-Cu alloy nanocrystals quenching for insulin detection. AB - Novel and sensitive sandwich-type electrochemiluminescence (ECL) immunosensor was fabricated for insulin detection. Au-ZnCd14S combined nitrogen doping mesoporous carbons (Au-ZnCd14S/NH2-NMCs) acted as sensing platform and Au-Cu alloy nanocrystals were employed as labels to quench the ECL of Au-ZnCd14S/NH2-NMCs. Zinc-doping promoted the ECL behavior of CdS nanocrystals, with the best ECL emission obtained when the molar ratio of Zn/Cd was 1:14. Simultaneously, the modification of gold nanoparticles (Au NPs) and combination with NH2-NMC further enhanced the ECL emission of ZnCd14S due to its excellent conductivity and large specific surface area, which is desirable for the immunosensor construction. Au Cu alloy nanocrystals were employed in the ECL system of ZnCd14S/K2S2O8 triggering ECL quenching effects. The ECL spectra of ZnCd14S, acting as the energy donor, exhibited well overlaps with the absorption band of Au-Cu alloy nanocrystals which acted as the energy acceptor, leading to an effective ECL resonance energy transfer (ECL-RET). On the basis of the ECL quenching effects, a sensitive ECL immunosensor for insulin detection was successfully constructed with a linear response range of insulin concentration from 0.1pg/mL to 30ng/mL and the limit of detection was calculated to be 0.03pg/mL (S/N = 3). PMID- 28582708 TI - New immobilisation method for oligonucleotides on electrodes enables highly sensitive, electrochemical label-free gene sensing. AB - We present a versatile and facile procedure for the immobilisation of bioprobe molecules to an electrochemical sensing element. We eliminate lengthy preparation procedures for direct functionalisation of electrode surfaces by pre-attaching probe molecules to carboxylic acid bearing termonomers of pyrrole phenylenes or thiophene phenylenes. We demonstrate that these conjugates can be electrodeposited at low potentials to form nano-scale porous, electroactive conducting polymer films, exposing the bioprobe and retaining activity and specificity for binding, exemplified here with DNA sensors. The electrochemical reaction impedance for Fe(CN)63-/4- on oligonucleotide-modified electrodes showed remarkable (down to aM) detection sensitivity for target DNA sequences present in solution. Cross-sensitivity to non-complementary target sequences is small and multi-target arrays are easily made. There is no need for labelling of either probe or target oligonucleotide. PMID- 28582707 TI - An ultrasensitive label-free electrochemiluminescent immunosensor for measuring Cry1Ab level and genetically modified crops content. AB - The development of genetically modified (GM) insect-resistant crops has aroused great public concern about the risks on the eco-environment resulting from a release of toxic Cry proteins (such as Cry1Ab) to the soil. Therefore, it is of crucial importance to measure the Cry proteins level and the GM crops content. Here, we have tested for the first time a method that uses novel carbon nanospheres (CNPs) label-free electrochemiluminescent (ECL) immunosensor for the ultrasensitive quantification of Cry1Ab and GM crops. In this work, novel CNPs were prepared from printer toner with a very facile approach, and linked with anti-Cry1Ab antibodies to modify a golden working electrode. The immunoreaction between Cry1Ab and its antibody formed an immunocomplex on the bioreceptor region of the sensor, which inhibited electron transfer between the electrode surface and the ECL substance, leading to a decrease of ECL response. Under the optimal conditions, the fabricated label-free ECL immunosensor determined Cry1Ab down to 3.0pgmL-1 within a linear range of 0.010-1.0ngmL-1, showing significant improvement of sensitivity than that of most previous reports. Meanwhile, the proposed method was successfully applied for GM rice BT63 and GM maize MON810 detections down to 0.010% and 0.020%, respectively. Due to its outstanding advantages such as high sensitivity, ideal selectivity, simple fabrication, rapid detection, and low cost, the developed method can be considered as a powerful and pioneering tool for GM crops detection. Its use can also be extended to other toxin protein sensing in foods. PMID- 28582709 TI - Electrodepositable alginate membranes for enzymatic sensors: An amperometric glucose biosensor for whole blood analysis. AB - Simple and disposable point of care systems are usually the best solution for chronic patients to get a rapid diagnosis in home care context. However, their main drawback relies on the poor reliability derived from the low stability of the bio-recognition elements and low quality of the transducers. In the current work, we study the use of electrodeposited calcium alginate hydrogels as a biocompatible matrix in the development of enzymatic amperometric biosensors for whole blood analysis, to enhance the enzymes stability and to protect the transducer from biofouling. The alginate electrodeposition involves the controlled Ca2+ release, so the gel thickness can be modulated. In the biosensor, horseradish peroxidase (HRP) and glucose oxidase (GOD) were electrodeposited within the hydrogel and the activity of the bi-enzymatic system was analyzed chronoamperometrically using 3,3',5,5'-Tetramethylbenzidine (TMB) as the mediator. Besides enzyme entrapment, the obtained gels protected the transducer from biofouling, enabling the reuse of the transducer after hydrogel removal and re-electrodeposition. The biosensors showed good analytical characteristics to glucose determination in whole blood samples, discriminating among healthy and hyperglycemic samples, with good sensitivity (- 0.27uAcm-2mM-1), low limit of detection (126uM) and long lineal range (2-12mM). PMID- 28582710 TI - Limitations in the use of 18F-FDG PET in the pre-operative staging of gastric cancer: A case series. AB - INTRODUCTION: Positron emission tomography (PET) is a mainstay in the preoperative evaluation of various cancers. In gastric cancer however, its role in the initial staging remains contentious. Presented is a case series of three gastric patients wherein the use of fluorodeoxyglucose (18F-FDG) PET/CT (computer tomography) as part of the initial staging was inconsequential to treatment, demonstrating its limited role in the staging of primary gastric cancer. METHODS: We analyzed retrospective data from 12/1/2010 to 10/31/2016 of patient with gastric cancer whose initial staging included a PET/CT. Only patients 18 years and older with gastric and gastro-oesophageal junction cancers were included. The data was derived from a single institution. Management of patients involved both an academic institution and a community practice. RESULTS: Of the three cases reported, an FDG-avid mass with minimal FDG uptake was reported in a single case and no FDG-avid lesion was reported in the other two. Neither of the patients underwent an endoscopic ultrasound for lack of availability. CONCLUSION: While various imaging studies such as endoscopic ultrasound have an established role in the initial staging, the role of FDG-PET is yet to be established and its routine use remains contentious. Based on our clinical experience and review of the literature, we believe FDG-PET/CT imaging is of limited clinical and cost effective value in the initial staging workup of gastric cancer. PMID- 28582711 TI - Biomedical applications of green synthesized Nobel metal nanoparticles. AB - Synthesis of Nobel metal nanoparticles, play a key role in the field of medicine. Plants contain a substantial number of organic constituents, like phenolic compounds and various types of glycosides that help in synthesis of metal nanoparticles. Synthesis of metal nanoparticles by green method is one of the best and environment friendly methods. The major significance of the green synthesis is lack of toxic by-products produced during metal nanoparticle synthesis. The nanoparticles, synthesized by green method show various significant biological activities. Most of the research articles report the synthesized nanoparticles to be active against gram positive and gram negative bacteria. Some of these bacteria include Escherichia coli, Bacillus subtilis, Klebsiella pneumonia and Pseudomonas fluorescens. The synthesized nanoparticles also show significant antifungal activity against Trichophyton simii, Trichophyton mentagrophytes and Trichophyton rubrum as well as different types of cancer cells such as breast cancer cell line. They also exhibit significant antioxidant activity. The activities of these Nobel metal nano-particles mainly depend on the size and shape. The particles of small size with large surface area show good activity in the field of medicine. The synthesized nanoparticles are also active against leishmanial diseases. This research article explores in detail the green synthesis of the nanoparticles and their uses thereof. PMID- 28582712 TI - Trifunctional fluorescent unnatural nucleoside: Label free detection of T-T/C-C base mismatches, abasic site and bulge DNA. AB - The detection and targeting of both the mismatched and abasic DNA is highly important which would ultimately help in designing new diagnostics and chemotherapeutics. Furthermore, sensing and targeting the bulge sequence with a fluorescent probe would be useful to study the role of bulges in nucleic acid function or could have significant therapeutic potential. Thus, detection of specific bulges by small fluorescent molecules is an attractive research area since the past several years. Many attempts have been made to prepare such compounds. We report herein a label free strategy for the detection of pyrimidine base mismatches (T/T and C/C), sensing of abasic site, and pyrimidine base bulge DNA using an unnatural tetrazolylpyrene nucleoside (TPyBDo) as a bare fluorescent probe. The H-bonding/hydrophobic force mediated interactions allow the sensing of all three deformed DNA via an enhancement of fluorescence signal using our simple "Just-Mix and Read" strategy. The binding of the probe to all the three deformed DNA duplexes is accompanied by an increase in the thermal melting stability of the deformed DNAs. That the probe binds efficiently to the minor groove near the deformed site was evident from spectroscopic studies. All the spectral evidences open up a multitude of possibilities for using our probe, tetrazolylpyrene nucleoside, as an efficient fluorescent light-up bio-probe for label free DNA detection. PMID- 28582713 TI - Cesium-induced inhibition of bacterial growth of Pseudomonas aeruginosa PAO1 and their possible potential applications for bioremediation of wastewater. AB - Radioactive isotopes and fission products have attracted considerable attention because of their long lasting serious damage to the health of humans and other organisms. This study examined the toxicity and accumulation behavior of cesium towards P. aeruginosa PAO1 and its capacity to remove cesium from waste water. Interestingly, the programmed bacterial growth inhibition occurred according to the cesium environment. The influence of cesium was analyzed using several optical methods for quantitative evaluation. Cesium plays vital role in the growth of microorganisms and functions as an anti-microbial agent. The toxicity of Cs to P. aeruginosa PAO1 increases as the concentration of cesium is increased in concentration-dependent manner. P. aeruginosa PAO1 shows excellent Cs removal efficiency of 76.1% from the contaminated water. The toxicity of cesium on the cell wall and in the cytoplasm were studied by transmission electron microscopy and electron dispersive X-ray analysis. Finally, the removal of cesium from wastewater using P. aeruginosa PAO1 as a potential biosorbent and the blocking of competitive interactions of other monovalent cation, such as potassium, were assessed. Overall, P. aeruginosa PAO1 can be used as a high efficient biomaterial in the field of radioactive waste disposal and management. PMID- 28582714 TI - Impact of suspended coal dusts on methane deflagration properties in a large scale straight duct. AB - Knowledge about flame deflagrations in mixtures of methane and diluted coal dust assists in the prediction of fires and explosions, and in the design of adequate protective systems. This vital lack of information on the role of hybrid mixtures (methane/coal dust) is covered in this work by employing a novel Large-Scale Straight Duct (LSSD) designed specifically for this purpose. The hybrid fuel was injected along the first 8m of the 30m long LSSD. The results revealed that a 30gm-3 coal dust concentration boosted the flame travel distance, from 6.5m to 28.5m, and increased the over pressure rise profile to 0.135bar. The over pressure rise (OPR), pressure wave velocity, flame intensity and the flame velocity were significantly boosted along the LSSD in the presence of 10gm-3 or 30gm-3 coal dust concentrations in the methane flame deflagrations. Finally, the high speed camera showed that the presence of the coal dust enhanced the turbulence in the front flame. Consequently, the pressure wave and flame velocities were both increased when a 10gm-3 coal dust concentration coexisted with a 9.5% methane concentration in the deflagration. PMID- 28582715 TI - In vivo stem cell tracking with imageable nanoparticles that bind bioorthogonal chemical receptors on the stem cell surface. AB - It is urgently necessary to develop reliable non-invasive stem cell imaging technology for tracking the in vivo fate of transplanted stem cells in living subjects. Herein, we developed a simple and well controlled stem cell imaging method through a combination of metabolic glycoengineering and bioorthogonal copper-free click chemistry. Firstly, the exogenous chemical receptors containing azide (-N3) groups were generated on the surfaces of stem cells through metabolic glycoengineering using metabolic precursor, tetra-acetylated N-azidoacetyl-d mannosamine(Ac4ManNAz). Next, bicyclo[6.1.0]nonyne-modified glycol chitosan nanoparticles (BCN-CNPs) were prepared as imageable nanoparticles to deliver different imaging agents. Cy5.5, iron oxide nanoparticles and gold nanoparticles were conjugated or encapsulated to BCN-CNPs for optical, MR and CT imaging, respectively. These imageable nanoparticles bound chemical receptors on the Ac4ManNAz-treated stem cell surface specifically via bioorthogonal copper-free click chemistry. Then they were rapidly taken up by the cell membrane turn-over mechanism resulting in higher endocytic capacity compared non-specific uptake of nanoparticles. During in vivo animal test, BCN-CNP-Cy5.5-labeled stem cells could be continuously tracked by non-invasive optical imaging over 15 days. Furthermore, BCN-CNP-IRON- and BCN-CNP-GOLD-labeled stem cells could be efficiently visualized using in vivo MR and CT imaging demonstrating utility of our stem cell labeling method using chemical receptors. These results conclude that our method based on metabolic glycoengineering and bioorthogonal copper-free click chemistry can stably label stem cells with diverse imageable nanoparticles representing great potential as new stem cell imaging technology. PMID- 28582716 TI - Combination of active targeting, enzyme-triggered release and fluorescent dye into gold nanoclusters for endomicroscopy-guided photothermal/photodynamic therapy to pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating malignancies in patients, and there is an urgent need for an effective treatment method. Herein, we report a novel gold nanocluster-based platform for confocal laser endomicroscopy-guided photothermal therapy (PTT)/photodynamic therapy (PDT) for PDAC, which consists of four components: the PTT-carrier gold nanocluster, an active targeting ligand U11 peptide, a Cathepsin E (CTSE)-sensitive PDT therapy prodrug, and a CTSE-sensitive imaging agent (cyanine dye Cy5.5). Due to the strong coupling among cross-linked gold nanoparticles (AuNPs), the surface plasmon resonance peak of nanoclusters shifts to the near-infrared (NIR) region, thus making the nanoclusters useful in the effective PTT therapy. In the system, the labeling of nanoclusters with U11 peptide can distinctly increase their affinity and accelerate their uptake by pancreatic cancer cells. Cell apoptosis staining demonstrates that, upon incorporation of the uPAR-targeted unit, the antitumor efficacy of CTSE-sensitive nanocluster AuS-U11 is significantly enhanced with respect to that of the non-targeted nanocluster AuS-PEG and the insensitive nanocluster AuC-PEG. In vivo and ex vivo optical imaging confirms the high accumulation of AuS-U11 in the in situ pancreatic tumor model. Therapeutic studies further show that the combination of active targeting for tumor tissue, enzyme-triggered drug release of 5-ALA and fluorescent dye Cy5.5 in nanoclusters AuS-U11 could achieve optimal therapeutic efficacy with endomicroscopy-guided photothermal/photodynamic therapy with minimal side effects. As a consequence, the delicate gold nanocluster concept provides a promising strategy to enhance the therapy efficiency in the most challenging PDAC treatment. PMID- 28582717 TI - Modulating the phenotype of host macrophages to enhance osteogenesis in MSC-laden hydrogels: Design of a glucomannan coating material. AB - The biomaterials-host interaction is a dynamic process in which macrophages play a vital role of regulation. Depending on the biochemical signals they sense, these highly plastic cells can mediate the immune response against the implanted scaffolds and/or exert regenerative potency to varying extent. Designing appropriate 'exterior signals' for scaffolds may exploit the power of endogenous macrophages to aid the regeneration of engineered tissues. To realise this goal, this study devised an injectable, instantaneously-solidifying coating material (acBSP) based on a unique, macrophage-affinitive glucomannan polysaccharide. Coating of three-dimensional hydrogel constructs with acBSP was rapid, neat and complete, requiring neither chemical reactions nor harsh conditions. Comprehensive in vitro analyses indicated that acBSP efficiently facilitated the adhesion and activation of macrophages and notably induced the macrophages to express pro-osteogenic/-angiogenic genes. Further in vivo assessment of acBSP coated, mesenchymal stem cells-laden hydrogels in a murine dorsal subcutaneous pocket model demonstrated efficient macrophage activation, desirable scaffold tissue integration and improved osteogenic differentiation in the delivered cells. In summary, by activating macrophages into a pro-osteogenic phenotype, the acBSP coating has demonstrated its competency as an innovative, open and efficacious platform to harness the power of host immunity for enhancing the regenerative performance of engineered tissue constructs. PMID- 28582718 TI - Stigma and discrimination experienced by people with schizophrenia living in the community in Guangzhou, China. AB - The aims of this study were to investigate experienced stigma and discrimination and their associated factors in people with schizophrenia who live in the community in Guangzhou, China. A total of 384 people with schizophrenia were randomly recruited from four districts of Guangzhou and completed the scales and questionnaires: Internalized Stigma of Mental Illness scale (ISMI), Self-Esteem Scale (SES), Discrimination and Stigma Scale (DISC-12), Brief Psychiatric Rating Scale (BPRS), PANSS negative scale (PANSS-N), Global Assessment of Functioning (GAF) and Schizophrenia Quality of Life Scale (SQLS). Insight and medication compliance were evaluated by psychiatrists. Data were analyzed by using descriptive statistics, Pearson correlation and multivariable linear regression. We found a significant positive correlation between BPRS score and PANSS-N score, GAF score was significantly negative correlated with SQLS score, Insight score was significantly negative correlated with medication compliance score, ISMI score was significantly positive correlated with SES score and experienced discrimination score. Multivariable linear regression found SQLS, SES and experienced discrimination were the main independent variables of ISMI and experienced discrimination was the most important factor of ISMI. Our findings suggest that people with schizophrenia often experienced stigma and discrimination in this Chinese population, and more anti-stigma interventions should be provided. PMID- 28582719 TI - Is adolescent alcohol use associated with self-reported hypomanic symptoms in adulthood? - Findings from a prospective birth cohort. AB - High rates of alcohol use disorder (AUD) are reported in people with major depression (MD) and bipolar disorder (BD). Substance abuse problems in adolescence may also indicate risk for future onset of mood disorders, especially BD. Data collected from the Avon Longitudinal Study of Parents and Children (ALSPAC), a large UK birth cohort, allowed information to be collected over several different time points and to test whether problematic alcohol use at age 16 was predictive of vulnerability to hypomanic symptoms at age 23. Controlling for a participant's gender, SES, marital status of the mother, a likely history of maternal depression, and adolescents' level of depressive symptoms at age 16, a hierarchical linear regression revealed that self-reported alcohol use in adolescence predicted the future onset of hypomanic/manic symptoms. Limitations include attrition and relying solely on self-ratings. Despite these limitations, the results suggest problematic alcohol use in adolescence predicts a vulnerability to hypomanic or manic symptoms. PMID- 28582720 TI - A little trouble getting started: Initial slowness in Parkinson's disease step negotiation. AB - Bradykinesia is a prominent problem for persons with Parkinson's disease (PD) and has been studied extensively with upper extremity tasks; however there is a lack of research examining bradykinesia in targeted lower extremity tasks related to mobility. Navigating steps and curbs are challenging tasks for older adults and neurologically impaired and thus utilizing these behaviors provides ecological validity to the study of bradykinesia. Herein we assess differences in step negotiation performance between individuals with PD and aged matched older adults. Three-dimensional kinematics and ground reaction forces were collected while 12 participants with PD and 12 older adults performed a single step up onto a platform. Persons with PD spent a significantly greater amount of time in the heel lift phase (P=0.0003, d=1.80). Peak vertical foot velocity of the lead foot was also significantly less in PD (P=0.02, d=1.05). Lastly, persons with PD displayed reduced sagittal hip and knee range of motion during the trail step (P=0.01, d=1.20 and P=0.02, d=1.05, respectively). Parkinson's participants exhibited slight decrement in step negotiation execution. Increased step time and decreased foot velocity and range of motion were attributes associated with Parkinson's step negotiation performance. Contrary to our hypothesis, in many comparisons, persons with PD during their best medicated state performed comparable to older adults, indicative of successful pharmacotherapy. Rehabilitation efforts can seek to improve performance in motor control tasks such as step negotiation, by restoring the relationship between perceived and actual motor output and enhancing muscle coordination and output as well as ranges of motion. PMID- 28582721 TI - Sequential enhanced cleaning eliminates multidrug-resistant organisms in general intensive care unit of a traditional Chinese medicine hospital. AB - PURPOSE: Effective cleaning of surfaces within hospital wards is necessary to reduce pathogen transmission. We investigated the roles of sequential enhanced cleaning by culturing pathogens from high-touch surfaces in a general intensive care unit. METHODS: A before-after controlled study was conducted during a 17 month period in the 25-bed general intensive care unit. The study comprised a baseline period (period 1) and 4 sequential tiered interventions: each patient zone was wiped with a single clean microfiber cloth daily (period 2), fluorescent markers and adenosine triphosphate assay were used to monitor and provide feedback on the effectiveness of cleaning (period 3), wiping a single patient zone with 3 clean microfiber cloths daily (period 4), and withdrawal of the feedback (period 5). RESULTS: Compared with period 1, the cultures of multidrug resistant organisms from high-touch surfaces were reduced by 41.0% (prevalence ratio [OR] = 0.59, P < .001), 70.8% (OR = 0.29, P < .001), 82.6% (OR = 0.17, P < .001), and 70.8% (OR = 0.29, P < .0001) in the subsequent sequential interventions, respectively. CONCLUSION: Adoption of fluorescent markers and adenosine triphosphate bioluminescence reduced environmental contamination. Use of 3 cleaning cloths for 1 patient zone was more effective compared with a single cloth. PMID- 28582722 TI - Adsorption of mercury ions from wastewater by a hyperbranched and multi functionalized dendrimer modified mixed-oxides nanoparticles. AB - In this paper, a novel heterogeneous nanodendrimer with generation of G2.0 was prepared by individual grafting of diethylenetriamine, triazine and l-cysteine methyl ester on the modified aluminum-silicate mixed oxides as a potent adsorbent of Hg(II) ions from aqueous media. The prepared nanodendrimer was characterized by nuclear magnetic resonance spectrum (1H NMR and 13C NMR), Fourier transform infrared spectroscopy (FT-IR), Diffuse reflectance UV-Vis spectroscopy (DR UV Vis), zeta potential (zeta), inductively coupled plasma atomic emission spectroscopy (ICP-AES), transmission electron microscopy (TEM), scanning electron microscopy (SEM), nitrogen adsorption experiments at -196 degrees C and elemental analysis. Equilibrium and kinetic models for Hg(II) ions removal were used by investigating the effect of the contact time, adsorbent dosage, initial Hg(II) ions concentrations, effect of solution's temperature, interfering ions, and initial pH. The contact time to approach equilibrium for higher removal was 6min (3232mgg-1). The removal of Hg(II) ions has been assessed in terms of pseudo first- and -second-order kinetics, and the Freundlich, Langmuir and Sips isotherms models have also been applied to the equilibrium removal data. The removal kinetics followed the mechanism of the pseudo-second order equation, where the chemical sorption is the rate-limiting step of removal process and not involving mass transfer in solution, which was further proved by several techniques such as zeta potential, FT-IR and DS UV-vis. The thermodynamic parameters (DeltaG, DeltaH and DeltaS) implied that the removal of mercury ions was feasible, spontaneous and chemically exothermic in nature between 15 and 80 degrees C. The nanodendrimer indicated high reusability due to its high removal ability after 15 adsorption-desorption runs. The adsorption mechanisms of Hg(II) ions onto the nanodendrimer was further studied by diverse techniques such as FTIR, EDS, zeta potential, DR UV-Vis spectroscopy and SEM. The possible mechanism of the Hg(II) ions adsorption onto the nanodendrimer could be carried out through the various paths such as electrostatic interaction, complexation, toxic metal chelation and ionic exchange, which eventually resulted in the hydrolysis and precipitation of the adsorbed Hg(II). The l-cysteine methyl ester nanodendrimer could also remove the mercury ions from the Persian Gulf water even after five times of recycling. PMID- 28582723 TI - Neutrophil-to-lymphocyte ratio is associated with diabetic peripheral neuropathy in type 2 diabetes patients. AB - OBJECTIVE: Diabetic peripheral neuropathy (DPN) had been demonstrated as a chronic inflammation state and one of the most common complications of type 2 diabetes mellitus (T2DM). Neutrophil-to-lymphocyte ratio (NLR) is a novel marker to reflect many kinds of chronic inflammation disease including diabetes. We aim to evaluate the association between NLR and DPN and to determine whether NLR could be a new indicator of DPN in type 2 diabetes patients. METHODS: We retrospect the consecutive medical files of T2DM patients. Nerve conduction velocity (NCV), vibration perception threshold (VPT) and the data for complete blood count were recorded. Patients were divided into tertiles based on admission NLR values. Clinical parameters were firstly compared among groups. Then, logistic regression and ROC analysis were performed. RESULTS: Percentages of DPN were 42.60%, 54.97% and 65.50%, in the low, middle and high tertile, respectively (n=72, 94 and 112, p<0.05). VPT values were 13.75+/-7.97, 15.01+/-9.60 and 16.78+/-10.92, respectively, (p<0.05). NCV in different nerves decreased with the increase of NLR (p<0.05). After adjusting potential related factors, NLR was still related to status of DPN in the logistic regression (r=1.743, p=0.001). Area under ROC was 0.619 (p<0.001). CONCLUSION: The present study showed that T2DM patients with higher NLR levels might be more likely to develop peripheral neuropathy complication. NLR levels grow with the increase of NCV and VPT results. As a predictor of DPN, NLR could be used in clinical practice to help doctors understand the level of DPN progression. PMID- 28582724 TI - A rhodol-based fluorescent chemosensor for hydrazine and its application in live cell bioimaging. AB - A rhodol cinnamate fluorescent chemosensor (RC) has been developed for selective detection of hydrazine (N2H4). In aqueous medium, the rhodol-based probe exhibited high selectivity for hydrazine among other molecules. The addition of hydrazine triggered a fluorescence emission with 48-fold enhancement based on hydrazinolysis and a subsequent ring-opening process. The chemical probe also displayed a selective colorimetric response toward N2H4 from colorless solution to pink, readily observed by the naked eye. The detection limit of RC for hydrazine was calculated to be 300nM (9.6ppb). RC is membrane permeable and was successfully demonstrated to detect hydrazine in live HepG2 cells by confocal fluorescence microscopy. PMID- 28582725 TI - Investigations of vibrational spectra and bioactivity of novel anticancer drug N (6-ferrocenyl-2-naphthoyl)-gamma-amino butyric acid ethyl ester. AB - The bioactivity of compounds is mainly dependent on molecular structure and the present work aims to explore the bonding features responsible for biological activity of novel anticancer drug N-(6-ferrocenyl-2-naphthoyl)-gamma-amino butyric acid ethyl ester (FNGABEE). In the present study, we investigate the molecular structural properties of newly synthesized title compound through experimental and quantum chemical studies. The detailed vibrational analysis has been performed using FT IR and FT Raman spectrum, aided by DFT computed geometry, vibrational spectrum, Eigen vector distribution and PED, at B3LYP/6-311++G(d,p) level. The resonance structure of naphthalene, different from that of benzene, revealed by molecular structure has been investigated using CC and CC stretching modes. The proton transfer in amide has been analyzed to obtain spectral distinction between different carbonyl and CN groups which point to the reactive sites responsible for binding with DNA and bovine serum albumin (BSA). The spectral distinction between eclipsed and staggered form of ferrocene has been analyzed. The molecular docking of FNGABEE with BSA and DNA has been performed to find the strength of binding and the moieties responsible for the interactions. The experimental binding studies of FNGABEE with BSA and DNA has been performed using UV absorption spectroscopy and fluorometric assay, to find the nature and strength of binding. PMID- 28582726 TI - The vibrational properties of the bee-killer imidacloprid insecticide: A molecular description. AB - The chemical imidacloprid belongs to the neonicotinoids insecticide class, widely used for insect pest control mainly for crop protection. However, imidacloprid is a non-selective agrochemical to the insects and it is able to kill the most important pollinators, the bees. The high toxicity of imidacloprid requires controlled release and continuous monitoring. For this purpose, high performance liquid chromatography (HPLC) is usually employed; infrared and Raman spectroscopy, however, are simple and viable techniques that can be adapted to portable devices for field application. In this communication, state-of-the-art quantum level simulations were used to predict the infrared and Raman spectra of the most stable conformer of imidacloprid. Four molecular geometries were investigated in vacuum and solvated within the Density Functional Theory (DFT) approach employing the hybrid meta functional M06-2X and the hybrid functional B3LYP. The M062X/PCM model proved to be the best to predict structural features, while the values of harmonic vibrational frequencies were predicted more accurately using the B3LYP functional. PMID- 28582727 TI - Validation of the Chinese version of public attitudes toward epilepsy scale in Mainland China. AB - PURPOSE: Epilepsy is a significant yet seriously underappreciated public health issue in Mainland China. The stigma and discrimination toward people with epilepsy (PWE) and their families are especially severe in China based on cultural misconceptions which cause tremendous psychological, economic and social burdens. It is imperative to formulate a targeted public intervention to eliminate knowledge gaps and correct these misconceptions of epilepsy. However, to date, the essential tools that may drive such an intervention by measuring the public perspective on PWEs is lacking in China. The goal of this study is to test the reliability and validity of a Simplified Chinese version of the "Public Attitude Toward Epilepsy" scale (PATE) in Mainland China which can be used to understand the content and identify the possible sources of stigma to better inform the design and focus of future stigma reduction interventions. METHODS: The standard procedure of cross-cultural adaptation was used in the translation process. Subjects from different economic and social backgrounds were enrolled by convenience sampling in central China. Exploratory factor analysis and confirmatory factor analysis were used to check the underlying factor structure of the items. Furthermore, Cronbach's alpha was utilized to assess internal consistency. RESULTS: 199 respondents were included in the final analysis. Content validity of this Chinese PATE was assessed to be adequate for assessing public attitudes toward epilepsy among the mainland Chinese. Two factors were extracted from the data by exploratory factor analysis; confirmatory factor analysis further confirmed good consistency of theoretical constructs between the original Public Attitudes Toward Epilepsy scale and our Chinese PATE. Our Chinese PATE presented excellent internal consistency (alpha=0.853-0.909). CONCLUSION: This version of the Chinese PATE showed acceptable psychometric properties, indicating that it can be implemented in surveying public attitudes toward epilepsy in Mainland China. PMID- 28582728 TI - Mitochondrial aldehyde dehydrogenase-2 deficiency compromises therapeutic effect of ALDH bright cell on peripheral ischemia. AB - The autologous ALDH bright (ALDHbr) cell therapy for ischemic injury is clinically safe and effective, while the underlying mechanism remains elusive. Here, we demonstrated that the glycolysis dominant metabolism of ALDHbr cells is permissive to restore blood flow in an ischemic hind limb model compared with bone marrow mononuclear cells (BMNCs). PCR array analysis showed overtly elevated Aldh2 expression of ALDHbr cells following hypoxic challenge. Notably, ALDHbr cells therapy induced blood flow recovery in this model was reduced in case of ALDH2 deficiency. Moreover, significantly reduced glycolysis flux and increased reactive oxygen species (ROS) levels were detected in ALDHbr cell from Aldh2-/- mice. Compromised effect on blood flow recovery was also noticed post transplanting the human ALDHbr cell from ALDH2 deficient patients (GA or AA genotypes) in this ischemic hindlimb mice model. Taken together, our findings illustrate the indispensable role of ALDH2 in maintaining glycolysis dominant metabolism of ALDHbr cell and advocate that patient's Aldh2 genotype is a prerequisite for the efficacy of ALDHbr cell therapy for peripheral ischemia. PMID- 28582729 TI - The role of Nrf1 and Nrf2 in the regulation of glutathione and redox dynamics in the developing zebrafish embryo. AB - Redox signaling is important for embryogenesis, guiding pathways that govern processes crucial for embryo patterning, including cell polarization, proliferation, and apoptosis. Exposure to pro-oxidants during this period can be deleterious, resulting in altered physiology, teratogenesis, later-life diseases, or lethality. We previously reported that the glutathione antioxidant defense system becomes increasingly robust, including a doubling of total glutathione and dynamic shifts in the glutathione redox potential at specific stages during embryonic development in the zebrafish, Danio rerio. However, the mechanisms underlying these changes are unclear, as is the effectiveness of the glutathione system in ameliorating oxidative insults to the embryo at different stages. Here, we examine how the glutathione system responds to the model pro-oxidants tert butylhydroperoxide and tert-butylhydroquinone at different developmental stages, and the role of Nuclear factor erythroid 2-related factor (Nrf) proteins in regulating developmental glutathione redox status. Embryos became increasingly sensitive to pro-oxidants after 72h post-fertilization (hpf), after which the duration of the recovery period for the glutathione redox potential was increased. To determine whether the doubling of glutathione or the dynamic changes in glutathione redox potential are mediated by zebrafish paralogs of Nrf transcription factors, morpholino oligonucleotides were used to knock down translation of Nrf1 and Nrf2 (nrf1a, nrf1b, nrf2a, nrf2b). Knockdown of Nrf1a or Nrf1b perturbed glutathione redox state until 72 hpf. Knockdown of Nrf2 paralogs also perturbed glutathione redox state but did not significantly affect the response of glutathione to pro-oxidants. Nrf1b morphants had decreased gene expression of glutathione synthesis enzymes, while hsp70 increased in Nrf2b morphants. This work demonstrates that despite having a more robust glutathione system, embryos become more sensitive to oxidative stress later in development, and that neither Nrf1 nor Nrf2 alone appear to be essential for the response and recovery of glutathione to oxidative insults. PMID- 28582731 TI - FRET-based glucose imaging identifies glucose signalling in response to biotic and abiotic stresses in rice roots. AB - Glucose is the primary energy provider and the most important sugar-signalling molecule, regulating metabolites and modulating gene expression from unicellular yeast to multicellular plants and animals. Therefore, monitoring intracellular glucose levels temporally and spatially in living cells is an essential step for decoding the glucose signalling in response to biotic and abiotic stresses. In this study, the genetically encoded FRET (Forster resonance energy transfer) nanosensors, FLIPglu-2MU?13 and FLIPglu-600MUDelta13, were used to measure cytosolic glucose dynamics in rice plants. First, we found that the FRET signal decreased in response to external glucose in a concentration-dependent manner. The glucose concentration at which the cytosolic level corresponded to the K0.5 value for FLIPglu-2MUDelta13 was approximately 10.05MUM, and that for FLIPglu 600MUDelta13 was 0.9mM, respectively. The substrate selectivity of nanosensors for glucose and its analogues is D-Glucose>2-deoxyglucose>3-O-methylglucose>L Glucose. We further showed that the biotic elicitors (flg22 and chitin) and the abiotic elicitors (osmotic stress, salinity and extreme temperature) induce the intracellular glucose increases in the detached root segments of transgenic rice containing FLIPglu-2MUDelta13 in a stimulus-specific manner, but not in FLIPglu 600MUDelta13 transgenic lines. These results demonstrated that FRET nanosensors can be used to detect increases in intracellular glucose within the physiological range of 0.2-20MUM in response to various stimuli in transgenic rice root cells, which indicated that intracellular glucose may act as a potential secondary messenger to connect extracellular stimuli with cellular physiological responses in plants. PMID- 28582730 TI - RITA plus 3-MA overcomes chemoresistance of head and neck cancer cells via dual inhibition of autophagy and antioxidant systems. AB - : Reactivation of p53 and induction of tumor cell apoptosis (RITA) is a small molecule that blocks p53-MDM2 interaction, thereby reactivating p53 in tumors. RITA can induce exclusive apoptosis in cancer cells independently of the p53 pathway; however, the resistance of cancer cells remains a major drawback. Here, we found a novel resistance mechanism of RITA treatment and an effective combined treatment to overcome RITA resistance in head and neck cancer (HNC) cells. The effects of RITA and 3-methyladenine (3-MA) were tested in different HNC cell lines, including cisplatin-resistant and acquired RITA-resistant HNC cells. The effects of each drug alone and in combination were assessed by measuring cell viability, apoptosis, cell cycle, glutathione, reactive oxygen species, protein expression, genetic inhibition of p62 and Nrf2, and a mouse xenograft model of cisplatin-resistant HNC. RITA induced apoptosis of HNC cells at different levels without significantly inhibiting normal cell viability. Following RITA treatment, RITA-resistant HNC cells exhibited a sustained expression of other autophagy related proteins, overexpressed p62, and displayed activation of the Keap1-Nrf2 antioxidant pathway. The autophagy inhibitor 3-MA sensitized resistant HNC cells to RITA treatment via the dual inhibition of molecules related to the autophagy and antioxidant systems. Silencing of the p62 gene augmented the combined effects. The effective antitumor activity of RITA plus 3-MA was also confirmed in vivo in mouse xenograft models transplanted with resistant HNC cells, showing increased oxidative stress and DNA damage. The results indicate that RITA plus 3 MA can help overcome RITA resistance in HNC cells. CONDENSED ABSTRACT: This study revealed a novel RITA resistant mechanism associated with the sustained induction of autophagy, p62 overexpression, and Keap1-Nrf2 antioxidant system activation. The combined treatment of RITA with the autophagy inhibitor 3-methyladenine overcomes RITA resistance via dual inhibition of autophagy and antioxidant systems in vitro and in vivo. PMID- 28582733 TI - Predicting the fate of micropollutants during wastewater treatment: Calibration and sensitivity analysis. AB - The presence of micropollutants in the environment and their toxic impacts on the aquatic environment have raised concern about their inefficient removal in wastewater treatment plants. In this study, the fate of micropollutants of four different classes was simulated in a conventional activated sludge plant using a bioreactor micropollutant fate model coupled to a settler model. The latter was based on the Burger-Diehl model extended for the first time to include micropollutant fate processes. Calibration of model parameters was completed by matching modelling results with full-scale measurements (i.e. including aqueous and particulate phase concentrations of micropollutants) obtained from a 4-day sampling campaign. Modelling results showed that further biodegradation takes place in the sludge blanket of the settler for the highly biodegradable caffeine, underlining the need for a reactive settler model. The adopted Monte Carlo based calibration approach also provided an overview of the model's global sensitivity to the parameters. This analysis showed that for each micropollutant and according to the dominant fate process, a different set of one or more parameters had a significant impact on the model fit, justifying the selection of parameter subsets for model calibration. A dynamic local sensitivity analysis was also performed with the calibrated parameters. This analysis supported the conclusions from the global sensitivity and provided guidance for future sampling campaigns. This study expands the understanding of micropollutant fate models when applied to different micropollutants, in terms of global and local sensitivity to model parameters, as well as the identifiability of the parameters. PMID- 28582732 TI - The dynamics and endocytosis of Flot1 protein in response to flg22 in Arabidopsis. AB - Membrane microdomains play vital roles in the process of bacterial infection. The membrane microdomain-associated protein Flot1 acts in an endocytic pathway and is required for seedling development, however, whether Flot1 is a part of host defense mechanisms remains unknown. During an analysis of callose deposition, we found that Flot1 amiRNAi mutants exhibited defects in response to flg22. Using variable-angle total internal reflection fluorescence microscopy (VA-TIRFM), structured illumination microscopy (SIM) and fluorescence cross spectroscopy (FCS), we determined that the dynamic behavior of GFP-Flot1 in Arabidopsis thaliana cotyledon epidermal cells changed significantly in plants treated with the elicitor flg22. Moreover, we found that Flot1 was constitutively recycled via an endocytic pathway and that flg22 could promote endocytosis. Importantly, targeting of Flot1 to the late endosome/vacuole for degradation increased in response to flg22 treatment; immunoblot analysis showed that when triggered by flg22, GFP-Flot1 was gradually degraded in a time-dependent manner. Taken together, these findings support the hypothesis that the changing of dynamics and oligomeric states can promote the endocytosis and degradation of Flot1 under flg22 treatment in plant cells. PMID- 28582734 TI - Characterization of titanium dioxide nanoparticle removal in simulated drinking water treatment processes. AB - This study characterized the fate of nano-TiO2 in both powder (TiO2(P)) and suspension (TiO2(S)) forms in simulated drinking water treatments. Nano-TiO2 solutions of 0.1, 1.0, and 10mg/L were prepared with deionized water and raw waters from the Changxing and Fengshan Water Treatment Plants in Taiwan to assess the effects of water matrices on nano-TiO2 behavior during water treatment. After the laboratory simulated water treatment, including pre-chlorination, coagulation, sedimentation, filtration and post-chlorination, the residual Ti concentration ranged from 2.7 to 47.4% in different treatment units and overall removal efficiency was between 52.6% and 97.3% in all cases except for nano-TiO2 at concentration of 0.1mg/L. Overall removal efficiency for the TiO2 at 10mg/L concentration ranged from 9.3 to 53.5%. Sedimentation (after coagulation) and filtration were the most important processes for removing nano-TiO2 due in part to particle agglomeration, which was confirmed by size distribution and zeta potential measurements. The size of nano-TiO2 increased from 21-36nm to 4490nm in the supernatant after sedimentation, and subsequent filtration treatment further removed all agglomerates at size >1MUm. Zeta potential revealed interactions between nano-TiO2 particles and anionic functional groups or negatively-charged natural organic matters, leading to a decrease in surface charge. After sedimentation and filtration, the zeta potential of supernatants and filtrates were close to zero, meaning the absence of nanoparticles. The highest Ti removal after sedimentation occurred in Fengshan raw water due to higher ionic strength and coagulant dosage applied. On the other hand, the surfactant additives in TiO2(S) promoted dispersion of nano-TiO2 particles, which in turn led to lower particle removal. SEM images of nanoparticles after chlorination or coagulation revealed the coverage of nano-TiO2 particles by viscous substances and formation of colloidal structures. PMID- 28582735 TI - Carbon dioxide, methane and nitrous oxide fluxes from a fire chronosequence in subarctic boreal forests of Canada. AB - Forest fires are one of the most important natural disturbances in boreal forests, and their occurrence and severity are expected to increase as a result of climate warming. A combination of factors induced by fire leads to a thawing of the near-surface permafrost layer in subarctic boreal forest. Earlier studies reported that an increase in the active layer thickness results in higher carbon dioxide (CO2) and methane (CH4) emissions. We studied changes in CO2, CH4 and nitrous oxide (N2O) fluxes in this study, and the significance of several environmental factors that influence the greenhouse gas (GHG) fluxes at three forest sites that last had fires in 2012, 1990 and 1969, and we compared these to a control area that had no fire for at least 100years. The soils in our study acted as sources of CO2 and N2O and sinks for CH4. The elapsed time since the last forest fire was the only factor that significantly influenced all studied GHG fluxes. Soil temperature affected the uptake of CH4, and the N2O fluxes were significantly influenced by nitrogen and carbon content of the soil, and by the active layer depth. Results of our study confirm that the impacts of a forest fire on GHGs last for a rather long period of time in boreal forests, and are influenced by the fire induced changes in the ecosystem. PMID- 28582736 TI - Source apportionment of PM10 and PM2.5 in major urban Greek agglomerations using a hybrid source-receptor modeling process. AB - A hybrid source-receptor modeling process was assembled, to apportion and infer source locations of PM10 and PM2.5 in three heavily-impacted urban areas of Greece, during the warm period of 2011, and the cold period of 2012. The assembled process involved application of an advanced computational procedure, the so-called Robotic Chemical Mass Balance (RCMB) model. Source locations were inferred using two well-established probability functions: (a) the Conditional Probability Function (CPF), to correlate the output of RCMB with local wind directional data, and (b) the Potential Source Contribution Function (PSCF), to correlate the output of RCMB with 72h air-mass back-trajectories, arriving at the receptor sites, during sampling. Regarding CPF, a higher-level conditional probability function was defined as well, from the common locus of CPF sectors derived for neighboring receptor sites. With respect to PSCF, a non-parametric bootstrapping method was applied to discriminate the statistically significant values. RCMB modeling showed that resuspended dust is actually one of the main barriers for attaining the European Union (EU) limit values in Mediterranean urban agglomerations, where the drier climate favors build-up. The shift in the energy mix of Greece (caused by the economic recession) was also evidenced, since biomass burning was found to contribute more significantly to the sampling sites belonging to the coldest climatic zone, particularly during the cold period. The CPF analysis showed that short-range transport of anthropogenic emissions from urban traffic to urban background sites was very likely to have occurred, within all the examined urban agglomerations. The PSCF analysis confirmed that long range transport of primary and/or secondary aerosols may indeed be possible, even from distances over 1000km away from study areas. PMID- 28582737 TI - Oxidative stress response in the seagrass Posidonia oceanica and the seaweed Dasycladus vermicularis associated to the invasive tropical green seaweed Halimeda incrassata. AB - The Mediterranean Sea is one of the most affected areas by the presence of invasive species. Halimeda incrassata (J Ellis) JV Lamoroux is newly arrived tropical seaweed in waters of the Mallorca Island (Balearic Islands, Western Mediterranean). The aim was to evaluate the effect of a potential competition between the invasive Halimeda incrassata, the native Posidonia oceanica and Dasycladus vermicularis, by means of antioxidant-related biomarkers in waters of Mallorca. The activities of the antioxidant enzymes-catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRd)-, the levels of reduced glutathione (GSH) and malondialdehyde as indicator of lipid peroxidation were evaluated. The concentration of 3,6,7-trihydroxycoumarin (THC) was measured in D. vermicularis. P. oceanica biomarkers were not altered while D. vermicularis coexisting with the invader showed higher GSH levels (46%) and antioxidant enzyme activities (catalase 74%, SOD 65%, GPx 86% and GRd 98%), although without lipid damage. H. incrassata showed higher malondialdehyde and GSH levels (30% and 31%, respectively), and catalase, superoxide dismutase and glutathione reductase activities (51%, 35% and 84%, respectively) in presence of P. oceanica respect to being alone; and higher superoxide dismutase and glutathione reductase in the presence of D. vermicularis (22% and 42%, respectively). THC concentration in D. vermicularis was significantly higher (53%) in samples competing with H. incrassata. Altogether, native P. oceanica meadows seem unaffected by the alien H. incrassata-which suffered oxidative stress competing with the other species-; whereas increased antioxidant capacities were evidenced in D. vermicularis, possibly as an adaptation mechanism to the new stressful situation that reflect differences in the physiological activities of the three species. In conclusion, the presence of the invasive H. incrassata may be a competitor to be considered for D. vermicularis, while it does not seem to be a major problem for P. oceanica. PMID- 28582738 TI - Effects of ship-induced waves on aquatic ecosystems. AB - Most larger water bodies worldwide are used for navigation, and the intensity of commercial and recreational navigation is expected to further increase. Navigation profoundly affects aquatic ecosystems. To facilitate navigation, rivers are trained and developed, and the direct effects of navigation include chemical and biological impacts (e.g., inputs of toxic substances and dispersal of non-native species, respectively). Furthermore, propagating ships create hydrodynamic alterations, often simply summarized as waves. Although ship-induced waves are recognized as influential stressors, knowledge on their effects is poorly synthesized. We present here a review on the effects of ship-induced waves on the structure, function and services of aquatic ecosystems based on more than 200 peer reviewed publications and technical reports. Ship-induced waves act at multiple organizational levels and different spatial and temporal scales. All the abiotic and biotic components of aquatic ecosystems are affected, from the sediment and nutrient budget to the planktonic, benthic and fish communities. We highlight how the effects of ship-induced waves cascade through ecosystems and how different effects interact and feed back into the ecosystem finally leading to altered ecosystem services and human health effects. Based on this synthesis of wave effects, we discuss strategies for mitigation. This may help to develop scientifically based and target-oriented management plans for navigational waters that optimize abiotic and biotic integrity and their ecosystem services and uses. PMID- 28582739 TI - Floor dust bacteria and fungi and their coexistence with PAHs in Jordanian indoor environments. AB - Floor dust samples were collected from Jordanian indoor environments (eight dwellings and an educational building) in Amman. Quantitative PCR (qPCR) analyses of selected fungal and bacterial groups were performed. The bacterial and fungal concentrations were also correlated with PAHs concentrations, which were previously measured in the same samples by using GC-MS. The bacterial and fungal concentrations varied significantly among and within the tested indoor environments. Based on the collected samples in the entrance area of the dwellings, the largest variation was found in Gram-negative bacteria and total fungi concentration. The lowest bacterial and fungal concentrations were found in the dwelling that was least occupied and the most recently built. At the educational building, the Gram-positive bacteria concentrations were lower than those observed in the dwellings. Unlike for bacteria, we observed significant negative correlation with some polycyclic aromatic hydrocarbons (PAHs). This calls for further studies investigating biodegradation of PAHs in house dust and presence of potentially health hazardous PAH metabolites. Since biocontamination in floor dust has been given relatively little to no attention in the MENA region we recommend that more extensive measurements be conducted in the future with chemical and biological analysis of floor dust contaminants and their exposure indoors. PMID- 28582740 TI - Runoff changes have a land cover specific effect on the seasonal fluxes of terminal electron acceptors in the boreal catchments. AB - Climate change influences the volume and seasonal distribution of runoff in the northern regions. Here, we study how the seasonal variation in the runoff affects the concentrations and export of terminal electron acceptors (i.e. TEAs: NO3, Mn, Fe and SO4) in different boreal land-cover classes. Also, we make a prediction how the anticipated climate change induced increase in runoff will alter the export of TEAs in boreal catchments. Our results show that there is a strong positive relationship between runoff and the concentration of NO3-N, Mn and Fe in agricultural catchments. In peaty catchments, the relationship is poorer and the concentrations of TEAs tend to decrease with increasing runoff. In forested catchments, the correlation between runoff and TEA concentrations was weak. In most catchments, the concentrations of SO4 decrease with an increase in runoff regardless of the land cover or season. The wet years export much higher amounts of TEAs than the dry years. In southern agricultural catchments, the wet years increased the TEA export for both spring (January-May) and autumn (September December) periods, while in the peaty and forested catchments in eastern and northern Finland the export only increased in the autumn. Our predictions for the year 2099 indicate that the export of TEAs will increase especially from agricultural but also from forested catchments. Additionally, the predictions show an increase in the export of Fe and SO4 for all the catchments for the autumn. Thus, the climate induced change in the runoff regime is likely to alter the exported amount of TEAs and the timing of the export downstream. The changes in the amounts and timing in the export of TEAs have a potential to modify the mineralization pathways in the receiving water bodies, with feedbacks in the cycling of C, nutrients and metals in aquatic ecosystems. PMID- 28582741 TI - Testing of two different strains of green microalgae for Cu and Ni removal from aqueous media. AB - The concentration of metal ions in aqueous media is a major environmental problem due to their persistence and non-biodegradability that poses hazards to the ecosystem and human health. In this study, the effect of Cu and Ni on the growth of two green microalgal strains, Chlorella vulgaris and Desmodesmus sp., was evaluated along with the removal capacity from single metal solutions (12days exposure; metal concentration range: 1.9-11.9mgL-1). Microalgal growth showed to decrease at increasing metal concentrations, but promising metal removal efficiencies were recorded: up to 43% and 39% for Cu by Desmodesmus sp. and C. vulgaris, respectively, with a sorption capacity of 33.4mggDW-1 for Desmodesmus sp. As for Ni, at the concentration of 5.7mgL-1, the removal efficiency reached 32% for C. vulgaris and 39% for Desmodesmus sp. In addition, Desmodesmus sp. growth and metal removal were evaluated employing bimetallic solutions. In these tests, the removal efficiency for Cu was higher than that of Ni for all the mix solutions tested with a maximum of 95%, while Ni-removal reached 90% only for the lowest concentrations tested. Results revealed that the biosorption of both metals reached maximum removal levels within the fourth day of incubation (with metal uptakes of 67mgCugDW-1 and 37mgNigDW-1). Intracellular bioaccumulation of metals in Desmodesmus sp. was evaluated by confocal laser scanning microscopy after DAPI staining of cells exposed or not to Cu during their growth. Imaging suggested that Cu is sequestered in polyphosphate bodies within the cells, as observable also in phosphorus deprived cultures. Our results indicate the potential of employing green microalgae for bioremediation of metal-polluted waters, due to their ability to grow in the presence of high metal concentrations and to remove them efficiently. PMID- 28582742 TI - Bioaccessibility of PAHs in contaminated soils: Comparison of five in vitro methods with Tenax as a sorption sink. AB - For hydrophobic organic contaminants, physiologically based in vitro methods may need to include a sorption sink to simulate in vivo intestinal uptake. We compared PAH bioaccessibility in contaminated soils using five in vitro methods including physiologically based extraction test (PBET), in vitro digestion assay (IVD), method from Deutsches Institut fur Normung (DIN), unified bioaccessibility method (UBM), and fed organic estimation human simulation test (FOREhST) in the absence and presence of Tenax as a sorption sink. The PAH bioaccessibility without Tenax were pretty low with values ranging from below detection limit to 13.4%, indicating the limited capacity of these in vitro models to accommodate PAHs. With addition of Tenax, bioaccessibility increased to 0.59-75.5% for all PAH congeners. Even with the dominant effect of sorption sink, bioaccessibility values significantly varied among all the five methods with DIN result being the highest at 7.0-34.8%. Based on multiple linear regression, Tenax, incubation time, and bile contents are identified to be the most important factors in controlling bioaccessibility. The understanding of these key factors for bioaccessibility is highly necessary to standardize in vitro methods, which helps to refine the assessment of health risk through exposure to ingested contaminants. PMID- 28582743 TI - UV filters and benzotriazoles in urban aquatic ecosystems: The footprint of daily use products. AB - The increased use of beauty and other daily use products, in particular those containing UV filters (UV-Fs) and benzotriazoles, results in their introduction in significant amounts into the aquatic environment. In this study, we aim to assess the occurrence and impact of UV-Fs and benzotriazoles in aquatic ecosystems in the metropolitan area of Barcelona, Spain. River water samples from the Llobregat and Besos Rivers were analysed together with sediment, suspended particulate matter, and wastewater samples from 6 wastewater treatment plants (WWTPs) along their basins. The analysis of 6 UV-Fs and 2 benzotriazoles in water samples was performed using an automatized on-line solid phase extraction coupled to liquid chromatography tandem mass spectrometry (SPE-HPLC-MS/MS) method. The analysis of the target compounds in the suspended solids and in the sediments was performed by HPLC-MS/MS. The analysis of the water samples showed the ubiquitous presence of UV-Fs. Benzotriazole (BZT; partition coefficient octanol-water Log Kow=1.23) and methylbenzotriazole (MeBZT; Log Kow=1.89) had the highest levels in both river water and wastewater. Removal rates in the selected WWTPs were highly variable (4-100%). Concentrations of lipophilic UV-Fs (Log Kow 4.95-7.53) in suspended particulate matter from wastewaters were high (up to 1,031,868.2ngg 1dry weight (dw)), whereas in sediment the concentrations were always below 300ng g-1 dw. The risk assessment expressed in terms of hazard quotients (HQs) revealed that most UV-Fs were not likely to produce adverse ecotoxicological effects against the living organisms assayed in river waters and influent wastewaters at the concentrations observed. However, HQs above 1 were obtained for BZT and MeBZT in effluent wastewaters discharged to the river. PMID- 28582744 TI - Active layer monitoring at CALM-S site near J.G.Mendel Station, James Ross Island, eastern Antarctic Peninsula. AB - The Circumpolar Active Layer Monitoring - South (CALM-S) site was established in February 2014 on James Ross Island as the first CALM-S site in the eastern Antarctic Peninsula region. The site, located near Johann Gregor Mendel Station, is labelled CALM-S JGM. The grid area is gently sloped (<3 degrees ) and has an elevation of between 8 and 11ma.s.l. The lithology of the site consists of the muddy sediments of Holocene marine terrace and clayey-sandy Cretaceous sedimentary rocks, which significantly affect the texture, moisture content, and physical parameters of the ground within the grid. Our objective was to study seasonal and interannual variability of the active layer depth and thermal regime at the CALM-S site, and at two ground temperature measurement profiles, AWS-JGM and AWS-CALM, located in the grid. The mean air temperature in the period March 2013 to February 2016 reached -7.2 degrees C. The mean ground temperature decreased with depth from -5.3 degrees C to -5.4 degrees C at 5cm, to -5.5 degrees C to -5.9 degrees C at 200cm. Active layer thickness was significantly higher at AWS-CALM and ranged between 86cm (2014/15) and 87cm (2015/16), while at AWS-JGM it reached only 51cm (2013/14) to 65cm (2015/16). The mean probed active layer depth increased from 66.4cm in 2013/14 to 78.0cm in 2014/15. Large differences were observed when comparing the minimum (51cm to 59cm) and maximum (100cm to 113cm) probed depths. The distribution of the active layer depth and differences in the thermal regime of the uppermost layer of permafrost at CALM-S JGM clearly show the effect of different lithological properties on the two lithologically distinct parts of the grid. PMID- 28582745 TI - Changing perceptions of protected area benefits and problems around Kibale National Park, Uganda. AB - Local residents' changing perceptions of benefits and problems from living next to a protected area in western Uganda are assessed by comparing household survey data from 2006, 2009, and 2012. Findings are contextualized and supported by long term data sources for tourism, protected area-based employment, tourism revenue sharing, resource access agreements, and problem animal abundance. We found decreasing perceived benefit and increasing perceived problems associated with the protected area over time, with both trends dominated by increased human wildlife conflict due to recovering elephant numbers. Proportions of households claiming benefit from specific conservation strategies were increasing, but not enough to offset crop raiding. Ecosystem services mitigated perceptions of problems. As human and animal populations rise, wildlife authorities in Sub Saharan Africa will be challenged to balance perceptions and adapt policies to ensure the continued existence of protected areas. Understanding the dynamic nature of local people's perceptions provides a tool to adapt protected area management plans, prioritize conservation resources, and engage local communities to support protected areas. PMID- 28582746 TI - Development of lightweight aggregates from stone cutting sludge, plastic wastes and sepiolite rejections for agricultural and environmental purposes. AB - Three different wastes have been assessed for lightweight aggregate (LWA) manufacturing: granite and marble sludge (COR), sepiolite rejections (SEP) and polyethylene-hexene thermoplastics (P). A preliminary study of the physical and chemical properties of the raw materials was carried out to design proper batches. It was mixed 10% SEP with 90% COR to confer plasticity, and in turn, 0, 2.5, 5 and 10% (w/w) of P was added to check its suitability as a bloating agent. The mixtures were milled, kneaded with water, extruded, shaped into pellets, oven dried and finally fired at 1100, 1125 and 1150 degrees C for 4, 8 and 16 min. The main technological properties of the aggregates related to bloating, density, porosity, loss on ignition, water absorption and compressive strength were measured. Scanning Electron Microscopy was used to study the microstructure of some LWAs. 23 out of 29 types of aggregate were lightweight, although neither bloating effect was observed, nor the typical cellular structure comprised of shell and core with relatively large pores was obtained, but a structure consisting of micropores and microchannels. The increase of temperature and time of firing involved a greater sintering, which in turn was translated into higher shrinkage, density and compressive strength values, but less porosity and water absorption. The addition of P did not involve any improvement, indeed it caused a significant decrease in compressive strength. The LWA sintered without P at the minimum time (4 min) and temperature of firing (1100 degrees C) was selected to assess its water suction capability. The results pointed out that this LWA could be suitable in hydroponics and/or water filtration systems, even better than the commercial LWA Arlita G3. A new and most environment-friendly perspective in LWA industry arises from here, promoting LWA production at relative low temperatures (prior to significant sintering occurs) and using non-plastic silty wastes instead of clays as major components. PMID- 28582747 TI - Application of drum compost and vermicompost to improve soil health, growth, and yield parameters for tomato and cabbage plants. AB - Utilization of different types of solid wastes through composting is important for environmental sustainability and restoring soil quality. Although drum composting is an efficient technology, the possibility of heavy metal contamination restricts its large-scale use. In this research, a field experiment was conducted to evaluate the impact of water hyacinth drum compost (DC) and traditional vermicompost (VC) on soil quality and crop growth in an agro ecosystem cultivated intensively with tomato and cabbage as test crops. A substantial improvement in soil health was observed with respect to nutrient availability, physical stability, and microbial diversity due to the application of drum compost and traditional vermicompost. Moreover, soil organic carbon was enriched through increased humic and fulvic acid carbon. Interestingly, heavy metal contamination was less significant in vermicompost-treated soils than in those receiving the other treatments. The use of VC and DC in combination with recommended chemical fertilization effectively stimulated crop growth, yield, product quality, and storage longevity for both tomato and cabbage. PMID- 28582748 TI - Mediational influence of spent mushroom compost on phytoremediation of black-oil hydrocarbon polluted soil and response of Megathyrsus maximus Jacq. AB - Ability of a plant to develop different adaptive strategies can also determine its capability for effective soil remediation. In this study, influence of spent mushroom compost (SMC) was tested on the phytoremediation of black oil hydrocarbon polluted soil and the response of Megathyrsus maximus (guinea grass). Studies were carried out in microcosm conditions by mixing different concentration of SMC viz., 10, 20, 30 and 40% in a 5 kg of contaminated soil along with control. Seeds of M. maximus was sown in tray for two weeks and allowed to grow for height of 10 cm and transplanted in to the different experimental pots. Soil nutrient, heavy metal and PAH contents were analyzed before and after the experiment. Ecophysiological and anatomical responses due to the contaminants in the soil by M. Maximus were analyzed after 120 days. Phytomass efficiency, potential photosynthesis (Amax) and contents of chlorophylls (a and b) as well as the total chlorophyll along with anatomical evaluations were recorded. Plant alone (control) reduced the soil heavy metal and PAH contents but further improvements were observed in SMC treatments, similar results were also observed as regards to the plant's phytoremediation efficiency (PE), phytomass and potential photosynthetic rates (m mol O2 M-2S-1). The plant's root and shoot anatomical responses were enhanced in treatments compared to control, study infers that the treatment enhances the biostimulation and development of adaptive characteristics for M. maximus survival in contaminated soils and promotes its co-degradation of hydrocarbon. SMC supports remediation and as well enhances the anatomical evaluations, we therefore recommend the use of SMC on response of Megathyrsus maximus Jacq for remediation of petrochemical based phytoremediation. PMID- 28582749 TI - Modeling washoff of total suspended solids in the tropics. AB - Washoff behavior in the tropics is expected to behave differently from temperate areas due to differences in rainfall characteristics. In this study, rainfall, runoff and total suspended solids (TSS) were monitored from 9 catchments distinguished by different types of land use, in Singapore. The catchments ranged in size from 5.7ha to 85.2ha. Over 120 rain events were studied and more than 1000 storm samples were collected and analyzed. Monte Carlo analysis was applied to obtain the best fit values of the washoff model parameters consisting the washoff coefficient c3, washoff exponent c4 and initial mass on surface Bini. The exponent c4 was found to be approximately unity for all the events monitored, in agreement with other studies. The values of c3 and Bini were found to vary between events. Among all the rainfall and runoff characteristics studied, rainfall depth of the current event (d) was found to be the single parameter that significantly influenced the values of c3 and Bini. Contrary to expectations, Bini did not correlate well with antecedent dry period or with rainfall depth of the prior storm event. The results show that the common modeling practice where Bini is assumed to vary with antecedent dry period and previous rainfall depth should be reassessed when applied to catchments in the tropics. ANCOVA analysis showed that land use was not significant, but rather the variation of c3 and Bini with d was found to correlate well with the catchment area. PMID- 28582750 TI - Flocculation of thermomechanical pulping spent liquor with polydiallyldimethylammonium chloride. AB - Currently, the dissolved lignocelluloses in the spent liquor (SL) of a thermomechanical pulping process are treated in wastewater treatment systems and thus they are wasted. In this work, polydiallyldimethylammonium chloride (PDADMAC), with different molecular weights, was used for flocculating lignocelluloses of SL and thus isolating them from SL. Results showed that the maximum removals were 38% via treating SL with 100 mg/L of PDADMAC (with 1045 kg/mol molecular weight) at 25 degrees C for 30 min. The focused beam reflectance measurement of the flocculation process revealed that the chord length of the flocs with the maximum square weighted counts was increased from 70 to 100 MUm and also their maximum square weighted counts was increased from 5 to 25 MUm2/s. The flocs contained 60.71-74.41 wt% PDADMAC, the balance of lignocelluloses and the heating value of 24-25 MJ/kg. The high molecular PDADMAC generated flocs with more organics and a higher heating value. PMID- 28582751 TI - Removal of bovine serum albumin from wastewater using fouling resistant ultrafiltration membranes based on the blends of cellulose acetate, and PVP-TiO2 nanoparticles. AB - Fouling resistant ultrafiltration membranes based on the blends of polyvinylpyrrolidone (PVP), TiO2 nanoparticles and cellulose acetate, CA-PVP-TiO2 (CATP), for removal of bovine serum albumin (BSA) were prepared by using phase inversion process. The influences of PVP and TiO2 on the preparation of phase inverted cellulose acetate (CA) ultrafiltration membrane were explored in terms of morphology study, equilibrium water content (EWC), hydraulic resistance, permeability performance, hydrophilicity, and thermal stability. After the introduction of PVP and TiO2 to the ternary (polymer-solvent-non-solvent) system, the formations of finger-like structures and macro-voids were reduced significantly. An improvement in porosity, average pore size, and hydrophilic nature of the CA membranes were detected after the introduction of PVP and TiO2 into the polymer matrix. The interaction between TiO2 and CA was confirmed and the degradation temperature of the CA membrane was significantly improved. BSA protein removal efficiency, anti-fouling performance, and recycling potential of the UF membranes were investigated. The CATP membrane (10.5 wt % CA: 4 wt % PVP: 2 wt % TiO2) has displayed high BSA removal efficiency and flux recovery ratios (NFR) with enhanced anti-fouling performances for the three fouling/rinsing cycles. PMID- 28582752 TI - Pore geometry effect on the synthesis of silica supported perovskite oxides. AB - The formation of perovskite oxide nanoparticles supported on ordered mesoporous silica with different pore geometry is here presented. Systematic study was performed varying both pore shape (gyroidal, cylindrical, spherical) and size (7.5, 12, 17nm) of the hosts. LaFeO3, PrFeO3 and LaCoO3 were chosen as target guest structures. The distribution of the oxide nanoparticles on silica was comprehensively assessed using a multi-technique approach. It could be shown that the pore geometry plays a determining role in the conversion of the infiltrated metal nitrates to metal oxide. In particular, slow degradation kinetic was observed in highly curved pores, which fostered nucleation and crystallization of the guest species. In spherical pore systems the enhancement of pore size caused a remarkable delay of the decomposition of the metal salts, but at the same time improved the homogeneous distribution of the oxide particles in the matrix. PMID- 28582753 TI - Changes within the stabilizing layer of ZnO nanoparticles upon washing. AB - ZnO nanoparticles (NPs) are highly relevant for various industrial applications, however, after synthesis of the NPs residual chemicals need to be removed from the colloidal raw product by washing, as they may influence the performance of the final device. In the present study we focus on the effect of washing by antisolvent flocculation with subsequent redispersion of the NPs on the stabilizing acetate shell. Purification of the ZnO nanoparticles is reported to be optimal with respect to zeta potential that has a maximum after one washing cycle. In this work, we will shed light on this observation using small angle X ray and neutron scattering (SAXS, SANS) by demonstrating that after the first washing cycle the content of acetate in the ligand shell around the ZnO NPs increases. In detail, it was observed that the diffuse acetate shell shrinks to the size of a monolayer upon washing but the acetate content of this monolayer is higher than within the diffuse shell of the particles of the native dispersion. A second washing cycle reduces the acetate concentration within the stabilizing shell and the stability of the dispersion drops accordingly. After another (third) washing cycle strong agglomeration was observed for all investigated samples. PMID- 28582754 TI - l-Glutamic acid assisted eco-friendly one-pot synthesis of sheet-assembled platinum-palladium alloy networks for methanol oxidation and oxygen reduction reactions. AB - In this work, bimetallic platinum-palladium sheet-assembled alloy networks (PtPd SAANs) were facilely synthesized by an eco-friendly one-pot aqueous approach under the guidance of l-glutamic acid at room temperature, without any additive, seed, toxic or organic solvent involved. l-Glutamic acid was served as the green shape-director and weak-stabilizing agent. A series of characterization techniques were employed to examine the morphology, structure and formation mechanism of the product. The architectures exhibited improved electrocatalytic activity and durable ability toward methanol oxidation reaction (MOR) and oxygen reduction reaction (ORR) in contrast with commercial Pt black and Pd black catalysts. This is ascribed to the unique structures of the obtained PtPd SAANs and the synergistic effects of the bimetals. These results demonstrate the potential application of the prepared catalyst in fuel cells. PMID- 28582755 TI - Ultra-sensitive and selective NH3 room temperature gas sensing induced by manganese-doped titanium dioxide nanoparticles. AB - The study of the fabrication of ultra-high sensitive and selective room temperature ammonia (NH3) and nitrogen dioxide (NO2) gas sensors remains an important scientific challenge in the gas sensing field. This is motivated by their harmful impact on the human health and environment. Therefore, herein, we report for the first time on the gas sensing properties of TiO2 nanoparticles doped with various concentrations of manganese (Mn) (1.0, 1.5, 2.0, 2.5 and 3.0mol.% presented as S1, S2, S3, S4 and S5, respectively), synthesized using hydrothermal method. Structural analyses showed that both undoped and Mn-doped TiO2 crystallized in tetragonal phases. Optical studies revealed that the Mn doped TiO2 nanoparticles have enhanced UV->Vis emission with a broad shoulder at 540nm, signifying induced defects by substituting Ti4+ ions with Mn2+. The X-ray photoelectron spectroscopy and the electron paramagnetic resonance studies revealed the presence of Ti3+ and singly ionized oxygen vacancies in both pure and Mn doped TiO2 nanoparticles. Additionally, a hyperfine split due to Mn2+ ferromagnetic ordering was observed, confirming incorporation of Mn ions into the lattice sites. The sensitivity, selectivity, operating temperature, and response recovery times were thoroughly evaluated according to the alteration in the materials electrical resistance in the presence of the target gases. Gas sensing studies showed that Mn2+ doped on the TiO2 surface improved the NH3 sensing performance in terms of response, sensitivity and selectivity. The S1 sensing material revealed higher sensitivity of 127.39 at 20 ppm NH3 gas. The sensing mechanism towards NH3 gas is also proposed. PMID- 28582756 TI - Therapeutic applications of synthetic nucleic acid aptamers. AB - It is possible to generate oligonucleotide aptamers for a wide variety of target molecules using a process known as Systematic Evolution of Ligands by Exponential Enrichment. Researchers have successfully generated aptamers which recognize specific metal ions, small chemical compounds, peptides, proteins, saccharides, and even whole cells. Aptamers show much promise as future therapeutics and as drug targeting agents. A particularly active area of aptamer research in the past two years was development of aptamer based cancer therapeutics and development of aptamer based cancer drug delivery systems. Aptamers were also used to address inflammatory diseases, infectious diseases, cardiovascular diseases, and eye diseases. PMID- 28582758 TI - Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy. AB - An autoimmune disease is defined as a clinical syndrome resulted from an instigation of both T cell and B cell or individually, in the absence of any present infection or any sort of distinguishable cause. Clonal deletion of auto reactive cells remains the central canon of immunology for decades, keeping the role of T cell and B cell aside, which are actually the guards to recognize the entry of foreign body. According to NIH, 23.5 million Americans are all together affected by these diseases. They are rare, but with the exception of RA. Rheumatoid arthritis is chronic and systemic autoimmune response to the multiple joints with unknown ethology, progressive disability, systemic complications, early death and high socioeconomic costs. Its ancient disease with an old history found in North American tribes since 1500 BCE, but its etiology is yet to be explored. Current conventional and biological therapies used for RA are not fulfilling the need of the patients but give only partial responses. There is a lack of consistent and liable biomarkers of prognosis therapeutic response, and toxicity. Rheumatoid arthritis is characterized by hyperplasic synovium, production of cytokines, chemokines, autoantibodies like rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA), osteoclastogensis, angiogenesis and systemic consequences like cardiovascular, pulmonary, psychological, and skeletal disorders. Cytokines, a diverse group of polypeptides, play critical role in the pathogenesis of RA. Their involvement in autoimmune diseases is a rapidly growing area of biological and clinical research. Among the proinflammatory cytokines, IL-1alpha/beta and TNF-alpha trigger the intracellular molecular signalling pathway responsible for the pathogenesis of RA that leads to the activation of mesenchymal cell, recruitment of innate and adaptive immune system cells, activation of synoviocytes which in term activates various mediators including tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL 1), interleukin-6 (IL-6) and interleukin-8 (IL-8), resulting in inflamed synovium, increase angiogenesis and decrease lymphangiogensis. Their current pharmacotherapy should focus on their three phases of progression i.e. prearthritis phase, transition phase and clinical phase. In this way we will be able to find a way to keep the balance between the pro and anti-inflammatory cytokines that is believe to be the dogma of pathogenesis of RA. For this we need to explore new agents, whether from synthetic or natural source to find the answers for unresolved etiology of autoimmune diseases and to provide a quality of life to the patients suffering from these diseases specifically RA. PMID- 28582757 TI - Comparative analysis of muscle phosphoproteome induced by salt curing. AB - Phosphorylated proteins in ovine muscle induced by salt curing were well investigated. Ten topside muscles of crossbred sheep were ground, mixed and divided into two groups, which were cured for 16h with 0% and 3% NaCl, respectively. Muscle proteins of two cured groups were analyzed by two dimensional electrophoresis coupled with Pro-Q Diamond and SYPRO Ruby staining. The differential phosphorylated proteins were determined using LC-MS/MS and the UniProt database. Ten different phosphoproteins (>1.5 fold) induced by salting were identified, including triosephosphate isomerase, glycogen phosphorylase, creatine kinase M-type, myoglobin, troponin T fast skeletal muscle type, actin, myosin light chain 1/3, tropomyosin beta chain, etc. Most of the different phosphoproteins were involved in glycometabolism, protein function and protein degradation. It is conclusively that salting may influence meat quality through protein phosphorylation, which regulates glycolysis metabolism, protein function and degradation. PMID- 28582759 TI - alpha-Mangostin inhibits DMBA/TPA-induced skin cancer through inhibiting inflammation and promoting autophagy and apoptosis by regulating PI3K/Akt/mTOR signaling pathway in mice. AB - Skin cancer is the most common form of cancer responsible for considerable morbidity and mortality, the treatment progress of which remains slow though. Therefore, studies identifying anti-skin cancer agents that are innocuous are urgently needed. alpha-Mangostin, a natural product isolated from the pericarp of mangosteen fruit, has potent anti-cancer activity. However, its role in skin cancer remains unclear. The aim of this study was to evaluate the treatment effect of alpha-mangostin on skin tumorigenesis induced by 9,10 dimethylbenz[a]anthracene (DMBA)/TPA in mice and the potential mechanism. Treatment with alpha-mangostin significantly suppressed tumor formation and growth, and markedly reduced the incidence rate. alpha-Mangostin not only inhibited the expressions of pro-inflammatory factors, but also promoted the production of anti-inflammatory factors in tumor and blood. It induced autophagy of skin tumor and regulated the expressions of autophagy-related proteins. The protein expressions of LC3, LC3-II and Beclin1 increased whereas those of LC3-I and p62 decreased after treatment with alpha-mangostin. Moreover, alpha-mangostin promoted the apoptosis of skin tumor dose-dependently by up-regulating of Bax, cleaved caspase-3, cleaved PARP and Bad, and down-regulating of Bcl-2 and Bcl-xl. Furthermore, showed alpha-mangostin inhibited the PI3K/AKT/mTOR (mammalian target of rapamycin) signaling pathway, as evidenced by decreased expressions of phospho PI3K (p-PI3K), p-Akt and p-mTOR, but did not affect the expressions of t-PI3K, t Akt or t-mTOR. Collectively, alpha-mangostin suppressed murine skin tumorigenesis induced by DMBA/TPA through inhibiting inflammation and promoting autophagy and apoptosis by regulating the PI3K/Akt/mTOR signaling pathway, as a potential candidate for future clinical therapy. PMID- 28582760 TI - Current status and future therapeutic perspectives of glioblastoma multiforme (GBM) therapy: A review. AB - Glioblastoma multiforme (GBM) is the deadliest form of heterogeneous brain cancer. It affects an enormous number of patients every year and the survival is approximately 8 to 15 months. GBM has driven by complex signaling pathways and considered as a most challenging to treat. Standard treatment of GBM includes surgery, radiation therapy, chemotherapy and also the combined treatment. This review article described inter and intra- tumor heterogeneity of GMB. In addition, recent chemotherapeutic agents, with their mechanism of action have been defined. FDA-approved drugs also been focused over here and most importantly highlighting some natural and synthetic and novel anti- glioma agents, that are the main focus of researchers nowadays. PMID- 28582761 TI - Facile synthesis of magnetic sludge-based carbons by using Electro-Fenton activation and its performance in dye degradation. AB - Highly stable iron based magnetic carbon were prepared by sequential Electro Fenton (EF) activation and pyrolysis of sewage sludge. The applied voltage exerts great influence on EF treated sludge flocs and thus poses significant effect on physiochemical properties of the as-prepared carbons. High insertion rate of iron into sludge from EF activation resulted in carbons with highly dispersed iron oxides, which had average size of iron nanoparticles being 4.77nm. The carbon also presented well developed porosity which had Brunauer-Emmett-Teller (BET) surface area attaining 341m2/g. Carbons prepared by traditional Iron Impregnation (IM) were used as comparison to gain further insight into their catalytic role as Fenton-like catalyst. Results showed that EF-activated sludge carbon could yield 96.1% of Methyl Orange (MO) removal in 60min together with only 1.4% of iron leaching. After three cycles, the MO removal can still reach 80% with EF activated carbons. PMID- 28582762 TI - Enhancing thermophilic co-digestion of nitrogen-rich substrates by air side stream stripping. AB - High ammonia concentrations can inhibit thermophilic anaerobic digestion, thus limiting the advantageous treatment of wastes rich both in carbon and nitrogen. In the present paper, an air side-stream stripping column was coupled to two thermophilic digesters to control ammonia content. The effects of exposing an increasing biomass fraction to the harsh conditions inside the column (pH above 9, O2 at saturation and high T) on digester performance were tested by treating and recirculating 21% of reactor volume 3 or 5 times per week. Neither biomass/liquid separation before stripping nor addition of chemicals to control pH were required. Ammonium nitrogen concentration was lowered from 2.4 to 1.1+/ 0.1gN-TANL-1 and from 4.5 to 2.0+/-0.1gN-TANL-1 without compromising process stability. The air side-stream stripping process was successfully implemented to maintain ammonia concentration below 0.6+/-0.1gN-NH3L-1 while boosting methane production by doubling organic (and therefore nitrogen) loading rate. PMID- 28582763 TI - Membrane fouling in a submerged membrane bioreactor: New method and its applications in interfacial interaction quantification. AB - Quantification of interfacial interactions between two rough surfaces represents one of the most pressing requirements for membrane fouling prediction and control in membrane bioreactors (MBRs). This study firstly constructed regularly rough membrane and particle surfaces by using rigorous mathematical equations. Thereafter, a new method involving surface element integration (SEI) method, differential geometry and composite Simpson's rule was proposed to quantify the interfacial interactions between the two constructed rough surfaces. This new method were then applied to investigate interfacial interactions in a MBR with the data of surface properties of membrane and foulants experimentally measured. The feasibility of the new method was verified. It was found that asperity amplitude and period of the membrane surface exerted profound effects on the total interaction. The new method had broad potential application fields especially including guiding membrane surface design for membrane fouling mitigation. PMID- 28582764 TI - Lignocellulose degradation patterns, structural changes, and enzyme secretion by Inonotus obliquus on straw biomass under submerged fermentation. AB - This study examined the white rot fungus I. obliquus on the degradation of three types of straw biomass and the production of extracellular lignocellulolytic enzymes under submerged fermentation. The fungus process resulted in a highest lignin loss of 72%, 39%, and 47% in wheat straw, rice straw, and corn stover within 12days, respectively. In merely two days, the fungus selectively degraded wheat straw lignin by 37%, with only limited cellulose degradation (13%). Fourier transform infrared spectroscopy revealed that the fungus most effectively degraded the wheat straw lignin and rice straw crystalline cellulose. Scanning electronic microscopy showed the most pronounced structural changes in wheat straw. High activities of manganese peroxidase (159.0U/mL) and lignin peroxidase (123.4U/mL) were observed in wheat straw culture on Day 2 and 4, respectively. Rice straw was the best substrate to induce the production of cellulase and xylanase. PMID- 28582765 TI - New applications of genetically modified Pseudomonas aeruginosa for toxicity detection in water. AB - A novel mediator-free method based on genetically modified bacteria was developed for detecting water toxicity, where genetically modified Pseudomonas aeruginosa (GM P. aeruginosa) was selected as the biosensor strain and pyocyanin (PYO) produced by this strain was used as the indicator. The toxicity response of GM P. aeruginosa to 3, 5-dichlorophenol (3, 5-DCP) was measured electrochemically and spectroscopically, and the half maximal inhibitory concentration (IC50) of 3, 5 DCP was determined to be 15.1 mg/L. Strikingly, the toxicity of sample solution with 3, 5-DCP could also be estimated visually by naked eyes at a concentration as low as 10 mg/L. The present study provided a convenient, sensitive and cost effective method for water toxicity detection, and extended biosensing application of the genetically modified bacterium. PMID- 28582766 TI - Enrichment and geochemical mobility of heavy metals in bottom sediment of the Hoedong reservoir, Korea and their source apportionment. AB - Physicochemical characteristics of bottom sediment in the Hoedong reservoir were studied to evaluate the effectiveness of the reservoir as traps for trace metals. Roadside soil, stream sediment and background soil were also studied for comparison. Sequential extractions were carried out, and lead isotopic compositions of each extraction were determined to apportion Pb sources. Besides, particle size distribution of roadside soil, and metal concentrations and Pb isotopes of each size group were determined to characterize metal contamination. In result, Zn and Cu were enriched in sediment through roadside soil. The data on metal partitioning implied that Zn posed potential hazards for water quality. Meanwhile, the noticeable reduction of the 206Pb/207Pb isotopic ratio in the acid soluble fraction in the size group 200 MUm - 2 mm of national roadside soil indicated that this size group was highly contaminated by automotive emission with precipitation of acid-soluble secondary minerals during evaporation. Based on the Pb isotopic ratios, the dry deposition of Asian dust (AD) and non-Asian dust (NAD) affected roadside soil, while the effects of AD and NAD on bottom sediment appeared to be low given the low metal concentrations in sediment. Metal concentrations and Pb isotopic compositions indicated that sediments were a mixture of background and roadside soil. Source apportionment calculations showed that the average proportion of traffic Pb in bottom and stream sediments was respectively 34 and 31% in non-residual fractions, and 26 and 28% in residual fraction. The residual fraction of sediments appeared to be as contaminated as the non-residual fractions. PMID- 28582767 TI - Effects of soil water saturation on sampling equilibrium and kinetics of selected polycyclic aromatic hydrocarbons. AB - Passive sampling can be applied for measuring the freely dissolved concentration of hydrophobic organic chemicals (HOCs) in soil pore water. When using passive samplers under field conditions, however, there are factors that might affect passive sampling equilibrium and kinetics, such as soil water saturation. To determine the effects of soil water saturation on passive sampling, the equilibrium and kinetics of passive sampling were evaluated by observing changes in the distribution coefficient between sampler and soil (Ksampler/soil) and the uptake rate constant (ku) at various soil water saturations. Polydimethylsiloxane (PDMS) passive samplers were deployed into artificial soils spiked with seven selected polycyclic aromatic hydrocarbons (PAHs). In dry soil (0% water saturation), both Ksampler/soil and ku values were much lower than those in wet soils likely due to the contribution of adsorption of PAHs onto soil mineral surfaces and the conformational changes in soil organic matter. For high molecular weight PAHs (chrysene, benzo[a]pyrene, and dibenzo[a,h]anthracene), both Ksampler/soil and ku values increased with increasing soil water saturation, whereas they decreased with increasing soil water saturation for low molecular weight PAHs (phenanthrene, anthracene, fluoranthene, and pyrene). Changes in the sorption capacity of soil organic matter with soil water content would be the main cause of the changes in passive sampling equilibrium. Henry's law constant could explain the different behaviors in uptake kinetics of the selected PAHs. The results of this study would be helpful when passive samplers are deployed under various soil water saturations. PMID- 28582768 TI - Investigation on the influence of time-of-day on benzene metabolic pharmacokinetics by direct breath analysis in mice. AB - Benzene, well known as a ubiquitous environmental pollutant, can lead to increasing risk of cancer, bone marrow failure as well as other serious diseases. Benzene has been classified as carcinogenic to humans with no recommended safe level of exposure. In this study, the influence of time-of-day on benzene metabolism has been tentatively explored in a mouse model based on direct real time breath analysis by using membrane inlet single photon ionization time of flight mass spectrometry (MI-SPI-TOFMS). The exhaled breath of eight mice was monitored at a time resolution of less than 20 s after intraperitoneal (I.P.) injection of benzene in the morning, afternoon and evening on different days, and two rounds of experiments were carried out in total. The pharmacokinetic parameters such as total exposure AUC0-infinity (h ng/mL), peak level Cmax (ng/mL), time of peak level tmax (h), and terminal half-life t1/2z (h) were calculated and discussed. The values of individual parameter varied greatly among the eight mice, e.g., AUC0-infinity in the morning of the first round of experiment ranged from 10.66 to 162.17 h ng/mL and the mean +/- SD was 103.72 +/- 99.72 h ng/mL (n = 8). Significant difference has also been observed between two rounds of experiments, implying the damage in the liver caused by the benzene exposure. However, there is no significant difference among the results from the morning, afternoon and evening for each round of the experiment. In our follow-up study, the influence of time-of-day will be further investigated, in which the metabolites of benzene as well as endogenous metabolites will be considered. PMID- 28582769 TI - Inhibition of phosphorus sorption on calcite by dairy manure-sourced DOC. AB - In confined animal feeding operations, such as dairies, manure is amended to soils at high rates leading to increases in P and organic matter in the soils. Phosphorus reacts with soil-Ca to form Ca-P minerals, which controls P availability for leaching and transport through the watershed. In this research, the effects of manure sourced dissolved organic matter (DOM) on P sorption on calcite were measured at different reaction times and concentrations. Reactions were monitored in 1% and 10% manure-to-water extract solutions spiked with P. When manure-DOM was present, a significant reduction in P sorption occurred (2 90% absolute decrease) compared to samples without manure-DOM. The greatest decrease occurred in the samples reacted in the 10% manure solution. XANES spectroscopic analysis showed that at 1% manure solution, a Ca-P phase similar to hydroxyapatite formed. In the calcite samples reacted in the 10% manure solution, K-edge XANES spectroscopy revealed that P occurred as a Ca-Mg-P phase instead of the less soluble hydroxyapatite-like phase. Results from this study suggest that in manure-amended calcareous soils, increased DOM from manure will decrease P sorption capacity and increase the overall P concentration in solution, which will increase the mobility of P and subsequently pose greater risks for impairment of surface water quality. PMID- 28582770 TI - The protective effect of Epimedii Folium and Curculiginis Rhizoma on Alzheimer's disease by the inhibitions of NF-kappaB/MAPK pathway and NLRP3 inflammasome. AB - The purpose of the current study was to explore the effects of the water extracts of Epimedii Folium and Curculiginis Rhizoma (EX) on Abeta-induced Alzheimer's disease. Abeta1-42 was stereotaxically injected bilaterally into the dorsal hippocampus, and then the rats were orally received EX at the doses of 2 g/kg and 6 g/kg for 30 days. Behavior was monitored through Morris water maze test. The neuroprotective effect of EX were examined with methods of histochemistry and biochemistry. EX reduced the contents of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and interleukin 6 (IL-6) in hippocampus and cortex. EX also reduced the levels of malondialdehyde (MDA) and increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GSH-Px) in the serum. Immunohistochemical analysis demonstrated that EX inhibited the expressions of NLRP3. In addition, we further confirmed that EX suppressed the expression of the NLRP3 inflammasome. EX inhibited the phosphorylations MAPKs, nuclear factor kappaB (NF-kappaB), myeloid differentiation factor 88(MyD88), cathepsin B. In conclusion, these results suggest that EX may be a potential agent for treating Alzheimer's disease. PMID- 28582771 TI - Error-prone DNA polymerase and oxidative stress increase the incidences of A to G mutations in tumors. AB - Mutational processes for A->G mutations in tumors are not well understood. To uncover the mutational mechanisms, we analyzed molecular profiles of more than 9,000 tumor samples from The Cancer Genome Atlas (TCGA). The present study found that error-prone DNA polymerases were involved in stomach tumors with high fraction of A->G mutations. High levels of apoptosis in kidney cancers and high levels of energy metabolism in thyroid cancers increased A->G mutation rate, which was associated with high oxidative stress. We also found that the frequencies of RAS gene mutations were increased in thyroid cancers with high level of energy metabolism because of high-frequency A->G mutations. PMID- 28582772 TI - Correction: Patterns of brain atrophy associated with episodic memory and semantic fluency decline in aging. PMID- 28582783 TI - Contribution of Simultaneous Breast Reconstruction by Deep Inferior Epigastric Artery Perforator Flap to the Efficacy of Vascularized Lymph Node Transfer in Patients with Breast Cancer-Related Lymphedema. PMID- 28582784 TI - Tibial Onlay Posterior Cruciate Ligament Reconstruction: Surgical Technique and Results. AB - The posterior cruciate ligament (PCL) is a fundamental structure in knee kinematics. PCL tears may lead to adverse consequences, such as impaired functional performance and an increased risk of osteoarthritis. Although surgical treatment is a well-established option for the patients of PCL rupture, many surgeons opt for conservative treatment because of the lack of consensus in the orthopedic literature concerning the best surgical method with less risk of iatrogenic lesions to the neurovascular structures in the popliteal region. Here, we describe an onlay technique for PCL reconstruction, which has some advantages over the traditional transtibial and over inlay techniques. The technique described in this study avoids the "killer angle"-frequently considered the cause of laxity of the reconstructed ligament-while simultaneously permitting safe retraction of the neurovascular structures without the need for a change in the patient's position. This technique has been used at our institution for approximately 10 years with very satisfactory results. The aim of this study is to describe the technique and perform a retrospective evaluation of the results of a case series. PMID- 28582785 TI - Sagittal Plane Corrections around the Knee. PMID- 28582774 TI - A giant planet undergoing extreme-ultraviolet irradiation by its hot massive-star host. AB - The amount of ultraviolet irradiation and ablation experienced by a planet depends strongly on the temperature of its host star. Of the thousands of extrasolar planets now known, only six have been found that transit hot, A-type stars (with temperatures of 7,300-10,000 kelvin), and no planets are known to transit the even hotter B-type stars. For example, WASP-33 is an A-type star with a temperature of about 7,430 kelvin, which hosts the hottest known transiting planet, WASP-33b (ref. 1); the planet is itself as hot as a red dwarf star of type M (ref. 2). WASP-33b displays a large heat differential between its dayside and nightside, and is highly inflated-traits that have been linked to high insolation. However, even at the temperature of its dayside, its atmosphere probably resembles the molecule-dominated atmospheres of other planets and, given the level of ultraviolet irradiation it experiences, its atmosphere is unlikely to be substantially ablated over the lifetime of its star. Here we report observations of the bright star HD 195689 (also known as KELT-9), which reveal a close-in (orbital period of about 1.48 days) transiting giant planet, KELT-9b. At approximately 10,170 kelvin, the host star is at the dividing line between stars of type A and B, and we measure the dayside temperature of KELT-9b to be about 4,600 kelvin. This is as hot as stars of stellar type K4 (ref. 5). The molecules in K stars are entirely dissociated, and so the primary sources of opacity in the dayside atmosphere of KELT-9b are probably atomic metals. Furthermore, KELT-9b receives 700 times more extreme-ultraviolet radiation (that is, with wavelengths shorter than 91.2 nanometres) than WASP-33b, leading to a predicted range of mass loss rates that could leave the planet largely stripped of its envelope during the main-sequence lifetime of the host star. PMID- 28582786 TI - Management of Persistent Air Leaks with Intrabronchial Valves. AB - Persistent air leaks (PALs) are regarded as a frequent complication after thoracic surgery resulting in prolonged hospitalization and increased morbidity. Several more or less invasive therapeutic approaches are available for treatment of PAL with varying degrees of success. The endoscopic placement of one-way intrabronchial valves in the segment(s) in which the air leak has been located offers a highly effective and well-tolerated minimal invasive option for patients with PAL. PMID- 28582787 TI - The Prognostic Role of SYNTAX Score in Moderate Ischemic Mitral Regurgitation Puzzle. PMID- 28582788 TI - Midterm Results of a Minimally Invasive Approach in David Procedure. AB - BACKGROUND: The David procedure is a well-known technique in selected patients with aortic root pathology. A minimally invasive approach in heart surgery increases open interest. METHODS: From 1991 to 2015, the David technique was performed in 296 patients in our unit. In 90 cases, operations were performed through partial upper sternotomy. The patient mean age was 57 +/- 14 years in the minimally invasive group (n = 90) and 58 +/- 14 years in the complete sternotomy group (n = 206; p = 0.2). The neosinus modification was performed in 80 patients (89%) in the minimally invasive group and in 79 patients (38%) in the complete sternotomy group (p < 0.01). Mean follow-up was 3 +/- 2 years in the minimally invasive group and 8 +/- 4 years in the complete sternotomy group. RESULTS: Thirty-day mortality was zero in the minimally invasive group and was 3% (n = 6) in the complete sternotomy group (p = 0.1). The need for packed red blood cells was significantly lower in the minimally invasive group (1.6 +/- 3 U) than in the complete sternotomy group (3.7 +/- 6 U; p < 0.01). Thirty late deaths (2% per patient-year) were observed in the complete sternotomy group versus zero in the minimally invasive group (p < 0.01). One patient (0.5% per patient-year) in the minimally invasive group and 12 patients (0.8% per patient-year) in the complete sternotomy group required reoperation in the follow-up period (p = 0.05). CONCLUSIONS: Minimally invasive David technique for patients with ascending aortic aneurysm and aortic valve insufficiency offers a good solution with low perioperative blood transfusion rate. Our midterm results show low valve-related complications and reoperation rate. However, long-term follow-up of the minimally invasive group is necessary. PMID- 28582789 TI - Reply by the Authors of the Original Article: SYNTAX Score and Left Ventricular Reverse Remodeling after Bypass. PMID- 28582790 TI - Surgical Repair of Pleuroperitoneal Communication with Continuous Ambulatory Peritoneal Dialysis. PMID- 28582791 TI - Association of Resident Duty Hour Reform and Neonatal Outcomes of Very Preterm Infants. PMID- 28582792 TI - Ultrasonographic Change in Uterocervical Angle is not a Risk Factor for Preterm Birth in Women with a Short Cervix. PMID- 28582793 TI - Anemia in Glucose Transporter Type 1 Deficiency Syndrome: Often Expected, Rarely Encountered, and with a Fascinating Explanation. PMID- 28582794 TI - Epileptiform Activity in Electroencephalogram of Normal Children. PMID- 28582795 TI - Another Case of Glucose Transporter 1 Deficiency Syndrome with Periventricular Calcification, Cataracts, Hemolysis, and Pseudohyperkalemia. PMID- 28582796 TI - Relative molar response of lipophilic marine algal toxins in liquid chromatography/electrospray ionization mass spectrometry. AB - RATIONALE: Accurate quantitative analysis of lipophilic toxins by liquid chromatography/mass spectrometry (LC/MS) requires calibration solution reference materials (RMs) for individual toxin analogs. Untargeted analysis is aimed at identifying a vast number of compounds and thus validation of fully quantitative untargeted methods is not feasible. However, a semi-quantitative approach allowing for profiling is still required and will be strengthened by knowledge of the relative molar response (RMR) of analogs in LC/MS with electrospray ionization (ESI). METHODS: RMR factors were evaluated for toxins from the okadaic acid (OA/DTXs), yessotoxin (YTX), pectenotoxin (PTX), azaspiracid (AZA) and cyclic imine (CI) toxin groups, in both solvent standards and environmental sample extracts. Since compound ionization and fragmentation influences the MS response of toxins, RMRs were assessed under different chromatographic conditions (gradient, isocratic) and MS acquisition modes (SIM, SRM, All-ion, target MS/MS) on low- and high-resolution mass spectrometers. RESULTS: In general, RMRs were not significantly impacted by chromatographic conditions (isocratic vs gradient), with the exception of DTX1. MS acquisition modes had a more significant impact, with PnTX-G and SPX differing notably. For a given toxin group, response factors were generally in the range of 0.5 to 2. The cyclic imines were an exception. CONCLUSIONS: Differences in RMRs between toxins of a same chemical base structure were not significant enough to indicate major issues for non-targeted semi quantitative analysis, where there is limited or no availability of standards for many compounds, and where high degrees of accuracy are not required. Differences in RMRs should be considered when developing methods that use a standard of a single analogue to quantitate other toxins from the same group. PMID- 28582797 TI - The detrimental impact of persistent vs an isolated occurrence of de novo donor specific antibodies on intermediate-term renal transplant outcomes. AB - BACKGROUND: De novo donor-specific antibodies (dnDSA) after renal transplant are associated with acute rejection (AR) and graft loss, yet most recipients with dnDSA have stable function and no AR. We assessed whether the persistence of dnDSA increased the risk of a detrimental outcome. METHODS: A single-center review of renal transplant recipients monitored for dnDSA at multiple time points post-transplant. An Isolated dnDSA was defined as one positive dnDSA and no additional positive tests, whereas >=2 positive dnDSA was defined as persistent dnDSA. RESULTS: Of 708 recipients, 22% developed dnDSA, of whom 64% had persistent dnDSA. At median follow-up of 35 (range 12-74) months, there were fewer episodes of AR in the isolated dnDSA vs the persistent dnDSA group (2% vs 22%; P<.001,) and fewer graft losses with isolated dnDSA vs persistent dnDSA (0% vs 10%; P=.03). Within the persistent dnDSA group, recipients with dnDSA >=60% of time points, had more AR (32% vs 16%, P=.10) and more graft losses (21% vs 2%; P=.003) than those with dnDSA<60%. CONCLUSIONS: Persistence of dnDSA resulted in more AR and graft failure than a single positive value. Recipients with longer duration of dnDSA persistence had an additional increased risk of AR and graft failure. PMID- 28582798 TI - Editorial Comment to Surgical procedures for benign prostatic hyperplasia: A nationwide survey in Japan, 2014 update. PMID- 28582801 TI - Emergency airway management in Australian and New Zealand emergency departments: A multicentre descriptive study of 3710 emergency intubations. AB - OBJECTIVE: The aim of this study was to describe the practice of endotracheal intubation across a range of Australasian EDs. METHODS: We established a multicentre airway registry (The Australian and New Zealand Emergency Department Airway Registry [ANZEDAR]) prospectively capturing intubations from 43 Australian and New Zealand EDs over 24 months using the ANZEDAR form. Information recorded included patient demographics, intubation indications, predicted difficulty, rapid sequence induction and endotracheal intubation preparation technique, induction drugs, airway adjuncts and complications. Factors associated with first attempt success were explored. RESULTS: Of the 3710 intubations captured, 3533 were in adults (95.2%), 2835 (76.4%) for medical and 810 (21.8%) for trauma indications. Overall, 3127 (84.3%) patients were successfully intubated at the first attempt; the majority by ED doctors (2654 [72.1%]). A total of 10 surgical airways were performed, all of which were successful cricothyroidotomies. Propofol, thiopentone or ketamine were used with similar frequency for induction, and suxamethonium was the most often used muscle relaxant. Adverse events were reported in 964 (26%), the majority involving desaturation or hypotension. CONCLUSION: Australasian ED doctors, predominantly specialist emergency physicians or trainees, perform the majority of ED intubations using rapid sequence induction as their preferred technique mainly for medical indications. First attempt success rate was not different between different types of EDs, and is comparable published international data. Complications are not infrequent, and are comparable to other published series. Monitoring and reporting of ED intubation practice will enable continued improvements in the safety of this high risk procedure. PMID- 28582802 TI - Altered serum levels of TNF-alpha, IL-6, and IL-18 in depressive disorder patients. AB - OBJECTIVE: Depressive disorder is associated with abnormal changes in cytokines levels. This study aimed to assess serum concentrations of tumor necrosis factor (TNF) alpha, interleukin (IL) 6, and IL-18 in depressive patients. The correlations between these three cytokine concentrations and the patients' clinical characteristics were also assessed. METHODS: Serum TNF-alpha, IL-6, and IL-18 concentrations were assessed using enzyme-linked immunosorbent assay from 64 depressive patients and 80 healthy control subjects. Depressive symptoms of patients were assessed using Hamilton Depression Scale-17. RESULTS: Depressive patients had increased serum TNF-alpha and IL-6 concentrations but decreased IL 18 concentrations than controls. TNF-alpha and IL-6 concentrations were significantly positively associated with Hamilton Depression Scale-17 scores in depressive patients. CONCLUSION: These findings provided additional evidence that altered TNF-alpha, IL-6, and IL-18 activities may contribute to the pathophysiology of depressive disorder. PMID- 28582804 TI - Food components and ocular pathophysiology: a critical appraisal of the role of oxidative mechanisms. AB - BACKGROUND AND OBJECTIVES: Three of the major ocular diseases, namely cataracts, age-related macular degeneration and glaucoma are associated with oxidative damage. Disease risk and progression may be reduced through consumption of dietary components. To critically examine the literature on dietary and supplemental intakes of fruit and vegetables, meat, antioxidants (vitamins C, E and A), calcium, folate, iron, and their association with ocular disease. METHODS AND STUDY DESIGN: Google Scholar and key references from texts and publications were searched using search terms (eye disease, antioxidants), (vision, nutrition), no date restriction, only articles in English were included. RESULTS: We found probable evidence that dietary intake of fruits and vegetables, and vitamin C lowered incidence of cataracts and age-related macular degeneration. In high supplemental doses, vitamin C increases macular degeneration risk. Vitamin A from food was protective for cataracts and glaucoma, but not in supplemental form. Vitamin A was associated with lower incidence of macular degeneration. We also found probable evidence that higher intakes of meat increased the risk of cataracts and macular degeneration. Dietary calcium and iron appeared protective against glaucoma, but not in supplemental form. CONCLUSIONS: While a nutrient rich diet high in fruit and vegetables, and associated antioxidants appeared to be protective, we would caution intake of supplementary antioxidants for those with ocular disease. PMID- 28582800 TI - Regulation of CD4 T cells and their effects on immunopathological inflammation following viral infection. AB - CD4 T cells help immune responses, but knowledge of how memory CD4 T cells are regulated and how they regulate adaptive immune responses and induce immunopathology is limited. Using adoptive transfer of virus-specific CD4 T cells, we show that naive CD4 T cells undergo substantial expansion following infection, but can induce lethal T helper type 1-driven inflammation. In contrast, memory CD4 T cells exhibit a biased proliferation of T follicular helper cell subsets and were able to improve adaptive immune responses in the context of minimal tissue damage. Our analyses revealed that type I interferon regulates the expansion of primary CD4 T cells, but does not seem to play a critical role in regulating the expansion of secondary CD4 T cells. Strikingly, blockade of type I interferon abrogated lethal inflammation by primary CD4 T cells following viral infection, despite that this treatment increased the numbers of primary CD4 T-cell responses. Altogether, these data demonstrate important aspects of how primary and secondary CD4 T cells are regulated in vivo, and how they contribute to immune protection and immunopathology. These findings are important for rational vaccine design and for improving adoptive T-cell therapies against persistent antigens. PMID- 28582805 TI - Enteral nutritional support in non-ICU hospitalized patients: current practice in Mexico. AB - BACKGROUND AND OBJECTIVES: Patients receiving >=80% of their energy requirements by enteral nutrition (EN) have better clinical outcomes; unfortunately, there are discrepancies between the amount prescribed and amount received. The aim of this study was to explore the nutritional clinical practice, determine the adequacy and identify reasons for underfeeding. METHODS AND STUDY DESIGN: A retrospective study was conducted in hospitalized, non-intensive care unit, adult patients receiving EN for >=72 h. The following data were recorded: the prescribed target of energy and protein per day, daily energy intake, and the percentage of adequacy of the energy and protein requirement up to hospital day seven. Complications during administration or reasons for interruption and the proportion of patients who received >=80% of the energy goals on days four and seven were also recorded. RESULTS: In total, 52 patients were included (61.5% women), with a median age of 57.5 years; 20.4% and 6.1% of the patients received >=80% of their energy and protein goals, respectively, on day four, which improved to 28% (p<0.005) and 19% (p<0.001), respectively, on day seven. During the first seven days, a statistically significant (p<0.001) difference was observed between the amount of prescribed and administered energy over 24 h. The patients who received <80% of their total energy requirement remained hospitalized for 29 days (IQR 16.5-45.5), while those who received >=80% were hospitalized for 18 days (IQR 13.3-28.8) (p<0.05). CONCLUSIONS: Significant energy and protein deficits were documented. Furthermore, it is necessary to use strategies such as the implementation of an algorithm to optimize EN. PMID- 28582803 TI - A random walk-based segmentation framework for 3D ultrasound images of the prostate. AB - PURPOSE: Accurate segmentation of the prostate on ultrasound images has many applications in prostate cancer diagnosis and therapy. Transrectal ultrasound (TRUS) has been routinely used to guide prostate biopsy. This manuscript proposes a semiautomatic segmentation method for the prostate on three-dimensional (3D) TRUS images. METHODS: The proposed segmentation method uses a context classification-based random walk algorithm. Because context information reflects patient-specific characteristics and prostate changes in the adjacent slices, and classification information reflects population-based prior knowledge, we combine the context and classification information at the same time in order to define the applicable population and patient-specific knowledge so as to more accurately determine the seed points for the random walk algorithm. The method is initialized with the user drawing the prostate and non-prostate circles on the mid-gland slice and then automatically segments the prostate on other slices. To achieve reliable classification, we use a new adaptive k-means algorithm to cluster the training data and train multiple decision-tree classifiers. According to the patient-specific characteristics, the most suitable classifier is selected and combined with the context information in order to locate the seed points. By providing accuracy locations of the seed points, the random walk algorithm improves segmentation performance. RESULTS: We evaluate the proposed segmentation approach on a set of 3D TRUS volumes of prostate patients. The experimental results show that our method achieved a Dice similarity coefficient of 91.0% +/- 1.6% as compared to manual segmentation by clinically experienced radiologist. CONCLUSIONS: The random walk-based segmentation framework, which combines patient specific characteristics and population information, is effective for segmenting the prostate on ultrasound images. The segmentation method can have various applications in ultrasound-guided prostate procedures. PMID- 28582806 TI - Prevalence and risk factors for complications in adult patients with short bowel syndrome receiving long-term home parenteral nutrition. AB - BACKGROUND AND OBJECTIVES: Short bowel syndrome (SBS) is a complicated and challenging disease where home parenteral nutrition (HPN) is widely used. The complications of long-term HPN-dependent in adult patients with SBS are poorly documented. This study was mainly aimed to assess the prevalence and risk factors of HPNassociated complications in adult patients with SBS, especially the catheter-related sepsis and HPN-associated liver/biliary disorders. METHODS AND STUDY DESIGN: 47 non-malignant adult patients with SBS who received HPN for more than 2 years in our clinical nutrition center were included. Patients were divided into two groups according to whether HPN-associated complications were present or not. Student's t-test and chi2 test were applied to compare the differences between the two groups. RESULTS: The mean frequency of catheter related sepsis was 0.31+/-0.05 per catheter year of HPN. An higher incidence of catheter-related infections (p<0.001) and shorter delay between HPN onset and first infection (p<0.001) were identified as risk factors for catheter-related sepsis. A total of 25 patients (53.2%) developed HPN-associated liver/biliary diseases. The identified risk factors for HPNassociated liver/biliary disorders were higher rate of catheter-related infections (p=0.009), shorter delay between HPN onset and first infection (p=0.017), higher energy content of HPN (p=0.014), higher glucose rate of HPN (p=0.009), and lower lipid rate of HPN (p=0.022). CONCLUSION: Our study revealed that adult patients with SBS receiving long-term HPN treatment developed a low prevalence of catheter-related sepsis but a rather high prevalence of HPN-associated liver/biliary disorders. We also identified several risk factors for HPN-associated complications which should be taken notice of in clinical practice. PMID- 28582807 TI - Dietary fiber intake is associated with chronic kidney disease (CKD) progression and cardiovascular risk, but not protein nutritional status, in adults with CKD. AB - BACKGROUND AND OBJECTIVES: Evidence suggests that dietary fiber benefits patients with chronic kidney disease (CKD); however, this conclusion requires further validation. In this study, we examined the effects of dietary fiber on kidney function, inflammation, indoxyl sulfate, nutritional status, and cardiovascular risk in patients with advanced CKD. METHODS AND STUDY DESIGN: We performed linear regressions to assess the association between dietary fiber intake and CKD parameters. The aforementioned parameters were compared over an 18-month follow- up period. Kaplan-Meier analysis was used to investigate the association between fiber intake and Cardiac vascular disease (CVD). RESULTS: In total, 157 patients were included in this study. Dietary fiber and inflammatory indices were associated (interleukin [IL]-6: beta=-0.024, p=0.035). The differential estimated glomerular filtration rate (DeltaeGFR) as well as levels of C-reactive protein, IL-6, indoxyl sulfate, and serum cholesterol in the higher fiber intake (>=25 g/day) group were lower than those in the lower fiber intake (<25 g/day) group (p<0.05). Differences in IL-6 and indoxyl sulfate levels were more significant in patients in the higher protein intake group (p<0.05). Dietary fiber intake may be a protective factor associated with CVD (hazard ratio=0.537 and 0.305- 0.947). The protein nutritional status was not different between the two groups (p>0.05). CONCLUSIONS: Our results suggest that increasing fiber intake can retard the decrease in the eGFR; can reduce the levels of proinflammatory factors, indoxyl sulfate, and serum cholesterol; and is negatively associated with cardiovascular risk, but does not disrupt the nutritional status of patients with CKD. PMID- 28582808 TI - The effect of an Annona muricata leaf extract on nutritional status and cytotoxicity in colorectal cancer: a randomized controlled trial. AB - BACKGROUND AND OBJECTIVES: Annona muricata leaf infusion has traditionally been consumed to maintain health, but is now considered for use in treating cancer patients. The objective of this study was to elucidate the effects of A. muricata leaf extract in humans and human cell lines. METHODS AND STUDY DESIGN: Thirty outpatients with colorectal cancer who had undergone primary tumor resection were enrolled in a randomized double-blind placebo- controlled pre-post-trial. They were divided into two groups: those who ingested A. muricata leaf extract (n=14) and those who ingested a placebo (n=14) daily for 8 weeks. Twenty-eight subjects completed the trial; they were equally distributed between the two groups. Serum from patients of both groups was compared for cytotoxicity against colorectal cancer cell lines. The nutritional status of patients was monitored throughout the study. RESULTS: Ex vivo and clinical studies showed higher cytotoxicity in the supplemented group compared with the placebo group. Further research is required to investigate the long-term effect of A.muricata leaf extract, particularly on parameters directly related to cytotoxic activity toward colorectal cancer cells and nutrition status. PMID- 28582809 TI - Dietary galacto-oligosaccharides improve skin health: a randomized double blind clinical trial. AB - BACKGROUND AND OBJECTIVES: To study the effects of galacto-oligosaccharides (GOS) on the skin, we investigated skin-related parameters in healthy adults who received GOS for 12 weeks. METHODS AND STUDY DESIGN: This double-blind, randomized, placebo-controlled study included subjects divided into two groups (control and GOS) by stratified block randomization. The GOS group received 1.0 g of GOS twice a day, whereas the control group received only vehicle. RESULTS: The results showed that the increase in corneometer values from baseline to week 12 was significantly greater in the GOS group than in the control group (6.91 vs 2.88 arbitrary units, p<0.05). The transepidermal water loss (TEWL) in the GOS group was reduced significantly after 12 weeks of GOS treatment (20.1 g/h/m2 at baseline vs 17.5 g/h/m2 at week 12, p<0.05). The differences in total and percentage of wrinkle areas between the two groups were statistically significant after 12 weeks of GOS treatment (p<0.05). CONCLUSION: Our findings support that oral treatment with GOS is beneficial to the skin and present the possibility of new nutritional strategies for skin care. PMID- 28582810 TI - Lactobacillus intake for 60 days favors antioxidant status of human breast milk: an RCT. AB - BACKGROUND AND OBJECTIVES: This study aimed to evaluate the effects of lactobacillus supplementation on trends of breast milk antioxidant parameters. METHODS AND STUDY DESIGN: In an interventional study, 50 lactating women were randomly allocated to receive a daily supplement of lactobacillus (n=25) or a placebo (n=25) for 60 days. Daily dietary intake, anthropometric measures and breast milk antioxidant parameters were determined at the onset, and days 30 and 60 of the study. Repeated-measures ANOVA were performed to assess the change over time in the anthropometric and biochemical parameters between the two groups. The main effect of treatment was compared by using Bonferroni's procedure for CI adjustment. The significance level was set at p<0.05. RESULTS: There was a significant increase in breast milk total antioxidant capacity (TAC) between onset of study and day 30 (p=0.01) and day 60 (p=0.001) after lactobacillus supplementation; however, breast milk TAC level did not change significantly between days 30 and 60 (p=0.7). In the placebo group, breast milk TAC levels decreased significantly after 60 days (p=0.001). Breast milk malondialdehyde (MDA) levels decreased progressively during the study in the lactobacillus group (p=0.001); however, there was a significant increase in MDA with time in breast milk samples in the placebo group (p=0.015). CONCLUSIONS: Based on the findings, lactobacillus supplementation for 60 days could significantly increase breast milk TAC and decrease breast milk MDA levels, compared with baseline; however, further studies are needed to confirm these results. PMID- 28582811 TI - Snack bar compositions and their acute glycaemic and satiety effects. AB - BACKGROUND AND OBJECTIVES: Maintaining blood glucose within homeostatic limits and eating foods that sup-press hunger and promote satiety have beneficial impacts for health. This study investigated the glycaemic re-sponse and satiety effects of a serving size of a healthier snack bar, branded Nothing Else, that met the required nutrient profiling score criteria for a health claim, in comparison to two top-selling commercial snack bars. METHODS AND STUDY DESIGN: In an experimental study, 24 participants aged >=50 years were recruited. On three different days blood glucose concentration was measured twice at baseline and 15, 30, 45, 60, 90 and 120 minutes after consumption of a serving size of each bar. Satiety effects were self-reported hunger, fullness, desire to eat, and amount could eat ratings on visual analogue scales. RESULTS: The incremental area under the blood glucose response curve (iAUC) over two hours for the Nothing Else bar was 30% lower than commercial Bar 2 (p<0.001). At 45 minutes after eating, the Nothing Else bar induced the highest fullness rating and lowest hunger rating among the three snack bars. At two hours, fullness induced by the Nothing Else bar was twice that of Bar 2 (p=0.019), but not different to Bar 1 (p=0.212). CONCLUSIONS: The Nothing Else snack bar developed using the nutrient profiling scheme as a guideline, with its high protein and dietary fibre contents, had a lower glycaemic impact and induced a higher subjective satiety than the two commercial snack bars of equal weight. PMID- 28582812 TI - Symptomatic efficacy of buckwheat products in Non-Celiac Gluten Sensitivity (NCGS). AB - BACKGROUND AND OBJECTIVES: Buckwheat (Fagopyrum esculentum) is a gluten-free grain with acclaimed benefi-cial effects on human health. Our aim was to assess the effect of buckwheat products on intestinal/extra-intestinal symptoms and biochemical parameters in patients with Non-Celiac Gluten Sensitivity (NCGS). METHODS AND STUDY DESIGN: A randomized, crossover trial with two intervention phases was conducted on 19 NCGS patients over a 12 week-period. The participants were assigned to consume products made from buckwheat or to maintain their normal gluten-free diet for 6 weeks in a random order. Symptoms due to NCGS were evaluated using two questionnaires. RESULTS: During the intervention period with buckwheat products, patients experienced a signifi-cant decrease in the severity of abdominal pain and bloating (p=0.03). In contrast, the control group showed a significant worsening trend for the majority of NCGS symptoms such as nausea, headache, joint/muscle pain, and attention disorders. The replacement diet with buckwheat products also resulted in a significant increase of serum magnesium (+4.7%) and a significant reduction in the circulating levels of some pro inflammatory cytokines such as interferon gamma (-33.3%) and monocyte chemotactic protein-1 (-46.5%). CONCLUSION: The study supports the positive effects of buckwheat for NCGS patients, showing that this alternative cereal can contribute to the re-duction of both negative gastro-intestinal and related symptoms, and nutritional deficiencies, and lead to an im-provement in inflammatory profile. PMID- 28582813 TI - Body mass index above 24 is beneficial for the 6-month survival rate in hepatocellular carcinoma patients with extrahepatic metastases. AB - BACKGROUND AND OBJECTIVES: To investigate the effect of overweight status on the 6-month survival rate in patients with extrahepatic hepatocellular carcinoma (HCC). METHODS AND STUDY DESIGN: We retrospectively analyzed the records of 51 patients with hepatocellular carcinoma and extrahepatic metastases between 2007 and 2010 before treatment. The associations among overweight status (body mass index [BMI] >24 kg/m2), demographic variables, and survival outcome were analyzed by univariate and multivariate analysis. RESULTS: BMI>24 kg/m2 was significantly associated with the 6-month survival rate (p=0.042). Gender (p=0.149), Child Pugh classification (p=0.149), Okuda staging (p=0.093), and albumin concentration >3.5 mg/dL (p=0.082) showed marginal survival benefits in univariate analysis. Multivariate analysis confirmed that BMI >24 kg/m2 was an independent prognostic factor for the 6-month survival rate (p=0.03). CONCLUSIONS: BMI >24 kg/m2 was associated with an improved 6-month survival rate in patients with extrahepatic metastatic hepatocellular carcinoma. PMID- 28582814 TI - Dietary choline and folate relationships with serum hepatic inflammatory injury markers in Taiwanese adults. AB - BACKGROUND AND OBJECTIVES: The relationships of dietary choline and folate intake with hepatic function have yet to be established in the Taiwanese population. We investigated the associations of choline and folate intake with hepatic inflammatory injury in Taiwanese adults. METHODS AND STUDY DESIGN: Blood samples and data on dietary choline components and folate intake from 548 Taiwanese adults without pathological liver disease were collected. Dietary intake was derived using a semiquantitative food-frequency questionnaire. Serum liver injury markers of alanine transaminase, aspartate transaminase, and hepatitis viral infection were measured. RESULTS: Elevated serum hepatic injury markers (>40 U/L) were associated with low folate and free choline intake (p<0.05). Folate intake was the most significant dietary determinant of serum aspartate transaminase concentration (beta=-0.05, p=0.04), followed by free choline intake (beta=-0.249, p=0.055). Folate intake exceeding the median level (268 MUg/d) was correlated with a reduced rate of hepatitis viral infection (p=0.032) and with normalized serum aspartate transaminase (odds ratio [OR]=0.998, 95% confidence interval [CI]=0.996-1, p=0.042) and alanine transaminase (OR=0.998, 95% CI=0.007-1, p=0.019). Total choline intake exceeding the median level (233 mg/d) was associated with normalized serum aspartate transaminase (OR=0.518, 95% CI=0.360 0.745, p=0.018). CONCLUSIONS: The newly established relationships of dietary intake of total choline and folate with normalized hepatic inflammatory markers can guide the development of dietary choline and folate intake recommendations for Taiwanese adults. PMID- 28582816 TI - Dietary behaviours, weight loss attempts and change in waist circumference: 15 year longitudinal study in Australian adults. AB - BACKGROUND AND OBJECTIVES: Dietary behaviours are suitable as clearly identifiable targets of dietary counselling to prevent weight gain. We therefore investigated associations between dietary behaviours, weight loss attempts and waist circumference change. METHODS AND STUDY DESIGN: Participants were a community-based sample population residing in Nambour, Australia, including 1,317 adults, aged 25-75 years at baseline. Waist circumference was measured in 1992 and 2007, and dietary behaviours data were derived concurrently from repeated self-completed short dietary questions. Multivariable models, stratified by sex, were adjusted for potential confounders. RESULTS: In men, consumption of visible fat on meat and in women, weight loss attempts in the last 10 years were the most important predictors of waist circumference gain independent of socio-demographic and lifestyle characteristics and energy intake. Men who consumed most visible fat on meat had a 2.6 times larger yearly increase in waist circumference than men who tended to cut the fat off meat: 0.47 (95% CI 0.23, 0.72) vs 0.18 (95% CI 0.01, 0.34) cm/year, p=0.01. Women who reported that they were always trying to lose weight had a 2.7 times larger yearly increase in waist circumference than women who never tried to lose weight: 0.78 (0.54, 1.02) vs 0.29 (0.06, 0.52) cm/year, p=0.0001. Other dietary behaviours were not associated with change in waist circumference. CONCLUSIONS: Consumption of visible fat on meat by men and more frequent attempts to lose weight by women were main dietary behaviours associated with gain in abdominal adiposity in Australian adults. PMID- 28582815 TI - Determination of new anthropometric cut-off values for obesity screening in Indonesian adults. AB - BACKGROUND AND OBJECTIVES: Body mass index (BMI), waist circumference (WC), waist to-hip ratio (WHR), and waist-to-stature ratio (WSR) have increasingly been used as screening tools for obesity. However, optimal cut-off values may be different between populations. The current study determined the optimum cut-off values for BMI, WC, WHR, and WSR for obesity screening in Indonesian adults using receiver operating characteristic (ROC) analysis. METHODS AND STUDY DESIGN: Stature, body weight, waist and hip circumferences were measured on 600 Indonesians aged 18-65 years (males, n=292; females, n=308) and BMI, WHR, and WSR calculated. Percentage of body fat (%BF) was determined using the deuterium isotope (D2O) dilution technique. Some existing cut-off points for obesity determination were evaluated for sensitivity and specificity. RESULTS: The existing cutoff values showed low sensitivity in our sample (between 18.4 and 71.1%) and new proposed cut-offs increased the sensitivity to reach 66.7 to 88.5%. The new cut-offs for BMI, WC, WHR, and WSR for determination of obesity were 21.9 (kg/m2), 76.8 (cm), 0.86, and 0.48, respectively, for males and 23.6 (kg/m2), 71.7 (cm), 0.77, and 0.47, respectively, for females. CONCLUSIONS: WC and WSR are the most predictive both for males and females, and therefore are considered as better screening tools for obesity in this population. PMID- 28582817 TI - Nutritional status and dietary diversity of Kamea in Gulf Province, Papua New Guineas. AB - BACKGROUND AND OBJECTIVES: To assess the nutritional status of infants, children and non-pregnant women and underlying factors, dietary diversity and community food security, in the Kamea community in Gulf Province, Papua New Guinea. METHODS AND STUDY DESIGN: Prospective cross sectional study. Study population 69 infants (0-59 months), 151 children (6-12 years) and 79 non-pregnant women from 10 villages in Kotidanga Local Level Government, Kerema District, Gulf Province, Papua New Guinea. RESULTS: Among infants prevalence of moderate stunting, wasting and underweight were 38.9%, 8.3% and 44.4%, respectively; after adjusting Hb concentration for altitude, the anaemia prevalence was 53.8%. Among children prevalence of severe stunting was 21.2%; moderate stunting, wasting and underweight were 57.6%, 12.2% and 48.5%, respectively; anaemia was 30.3%; median urinary iodine concentration was 32.0 MUg/L and iodine deficiency was prevalent among 88.1%. Among women, mean height, weight and BMI were 1.46+/-0.04 m, 43.9+/ 5.91 kg and 20.4+/-2.32 kg/m2, respectively; low BMI (<18.5 kg/m2) and anaemia were prevalent among 22.8% and 35.4%, respectively; median urinary iodine concentration was 36.0 MUg/L and iodine deficiency was prevalent among 80.3%. Exclusive breastfeeding was universal for young infants; complementary foods were limited in variety and frequency. Dietary diversity was limited, implementation of the universal salt iodisation strategy restricted and community food security was inadequate. CONCLUSIONS: The high prevalence of malnutrition and anaemia among the three age groups, including moderate status of iodine deficiency among women and children, are significant public health concerns. Improvements in dietary diversity, adequate use of iodised salt and community food security are needed. PMID- 28582818 TI - Goitre and urinary iodine in coastal and inland areas with low and high iodized salt coverage in Zhejiang province, China. AB - BACKGROUND AND OBJECTIVES: WHO recommended that iodized salt are more than 90% of households in USI programs, which may not be suitable for all regions, especially in coastal areas. This study intended to find out levels of iodine nutrition and give advice from the USI programs for areas with different iodized salt coverage. METHODS AND STUDY DESIGN: Coastal and inland areas were selected according to geographical regions in Zhejiang Province, China. The water iodine concentration (spectrophotometer analysis), salt iodine concentration (the colorimetric titration method), salt intake, urinary iodine concentration (spectrophotometer analysis), and thyroid volume examination (ultrasonography), as well as questionnaire, were measured in the two areas. RESULTS: Mean Urinary Iodine concentration (MUIs) of children in coastal areas was 149 MUg/L, which was significantly lower than that in inland areas (191 MUg/L). MUIs of pregnant women in coastal and inland areas were111 and 138 MUg/L, respectively. Pregnant women who consumed iodine-containing supplements had higher MUIs (207 MUg/L) than those did not (134 MUg/L) in inland areas. Prevalence of goitre in children reached 7.0% and 6.6% in coastal and inland areas, respectively. The lowest prevalence of goitre was reached when the urinary iodine concentration was approximately 120 160 MUg/L in coastal areas. CONCLUSION: Iodine levels of coastal and inland areas were in the adequate range. Advice from the USI program should be specialized for different areas to appropriately reduce the salt iodine concentrations in inland areas and to determine an appropriate proportion of households using iodized salt in coastal areas. Moreover, iodine supplement intake during pregnancy should officially be recommended. PMID- 28582820 TI - Body mass index is associated with fat mass in normal, overweight/obese, and stunted preschool children in central Thailand. AB - BACKGROUND AND OBJECTIVES: Body mass index (BMI) is widely used as a surrogate measure of adiposity. The relationship between BMI and body fatness varies by race, sex, and age and more variations have been found among children. This study investigated the relationship between BMI and fat mass among 3-5 year old children having different nutritional status. METHODS AND STUDY DESIGN: A cross sectional study was conducted in 15 daycare centers in central Thailand. 137 healthy preschool children were recruited according to their nutritional status: thin [BMI for age Z scores, (BAZ) <-2 SD], normal BMI (-2 SD<= BAZ <=+2 SD), overweight/obese (BAZ >+2 SD), and stunted [height for age Z scores < -2 SD]. Fat free mass was determined by deuterium dilution technique. Fat mass (FM) in kilograms (TFM) and in percentage (FM%), and fat mass index (FMI, FM/height2) were calculated. RESULTS: FM and FMI were the highest in the overweight/obese groups. In the thin group, girls had higher FMI compared to boys (3.2 vs 2.8 kg/m2, p<0.05). The relationship between BMI with FMI and FM differed by nutritional status. BMI was more strongly associated with FMI, TFM, and FM% in the overweight/ obese (r=0.97, 0.95, 0.80, p<0.05) and the normal (r=0.88, 0.84, 0.68, p<0.05) groups but not in the stunted group, and inconsistent in the thin group. CONCLUSIONS: The inconsistency in the relationship between BMI and body fatness suggests that BMI is appropriate for reflecting adiposity in normal and overweight/obese children, but not undernourished preschool children. PMID- 28582819 TI - The influence of mandatory iodine fortification on the iodine status of Australian school children residing in an iodine sufficient region. AB - BACKGROUND AND OBJECTIVES: To counter emerging iodine deficiency mandatory iodine fortification of bread was introduced throughout Australia in 2009. This study investigated the impact of iodine fortification on the iodine status of school aged children living in the iodine replete state of Queensland, and investigated which foods had greatest influence on overall iodine status. METHODS AND STUDY DESIGN: A convenience sample of 30 children aged 8.0-10.9 years living in south east Queensland, Australia, provided spot morning and afternoon urine samples on two consecutive days. Iodine status was categorised by the World Health Organization criterion. Semiquantitative food questionnaires (FFQ) completed by carers were used to investigate which foods were having the greatest influence on UIC. Analysis of variance was used to reduce the within person variation observed in urinary iodine concentrations (UIC) and the data were log transformed before statistical analysis. RESULTS: Adjusted median UIC was 144 ug/L (IQR 120-210 ug/L) indicating iodine sufficient status. No samples were above the cut off for excessive UIC. Bread was the only statistically significant contributor to UIC (standardized beta=0.37, p=0.04) with 14% of variation in UIC explained by bread consumption. UIC increased by 8.7% for each additional serve of bread. CONCLUSIONS: Iodine fortification of bread has increased the iodine status of school aged children in this Queensland cohort. Despite the small sample size in this study, improvements in methodology allowed its findings to be comparable to other, larger surveys. PMID- 28582821 TI - Normal-weight central obesity is associated with metabolic disorders in Chinese postmenopausal women. AB - BACKGROUND AND OBJECTIVES: This cross-sectional study examined whether normal weight central obesity, defined as a high waist-to-height ratio (WHtR), is associated with metabolic disorders in Chinese postmenopausal women. METHODS AND STUDY DESIGN: We recruited 634 community-dwelling postmenopausal women with a normal body mass index (BMI) who participated in an annual health checkup. Normal weight obesity (NWO) was defined as a normal BMI and WHtR in the highest tertile of the study population. The updated National Cholesterol Education Program/Adult Treatment Panel III criteria were used to assess metabolic abnormalities, and binary logistic regression models were employed to estimate the associations between NWO and metabolic disorders. RESULTS: The prevalence of each metabolic disorder showed a graded increase (p<0.05) across the WHtR tertiles in the study population. NWO was significantly associated with some non-adipose components of metabolic syndrome (MetS) (p<0.05) after adjusting for age, smoking status, drinking status, inflammatory markers, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), body fat percentage (BF%), and the remaining non adipose MetS components. Participants in the highest WHtR tertile had a higher odds ratio [2.00 (1.19- 3.33), p<0.01] for the presence of at least two non adipose MetS components than those in the lowest tertile after adjusting for age, lifestyle factors, inflammatory markers, TC, LDL-c, and BF%. CONCLUSIONS: NWO is significantly associated with metabolic disorders, suggesting that a clinical assessment of abdominal obesity indices should be conducted in postmenopausal women, even in those with a normal BMI. PMID- 28582822 TI - High consumption of salt-fermented vegetables and hypertension risk in adults: a 12-year follow-up study. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the causal relationship between high consumption of salt-fermented vegetables and hypertension risk in adults. METHODS AND STUDY DESIGN: Data came from the Korean Genome and Epidemiology Study, an ongoing community-based cohort study that began in 2001. In the final analysis, a total of 5,932 participants (men=2,822, women=3,110) was included. Daily energy, nutrient, and major salt-fermented vegetables for Korean (kimchi) intakes were assessed using a semi-quantitative food frequency questionnaire. Relative risks and 95% CIs associated with kimchi intake by gender and body mass index (BMI) were estimated using the multivariate Cox proportional hazards regression model. RESULTS: Out of the 5,932 participants, 1,798 (905 men, 893 women) developed hypertension during the 12 year follow-up period. A significant difference in baseline BMI was shown between the non-hypertension and hypertension groups. There was no significant difference with regard to the risk of developing hypertension across quintiles for total kimchi intake and quartile or quartiles for specific kimchi intake in multivariate models by gender and baseline BMI. The trend for increased risk of hypertension according to increasing quartile of watery kimchi intake was significant for obese men in the multivariate model (p<0.05). CONCLUSION: High consumption of salt-fermented vegetables was not shown to be associated with increased risk of hypertension. The trend for increased risk of hypertension according to increasing quartile of watery kimchi intake was significant only in obese men. PMID- 28582823 TI - Bimodal distribution of fasting plasma glucose in the Uyghur and Han populations of Xinjiang, China. AB - BACKGROUND AND OBJECTIVES: Bimodality in fasting plasma glucose (FPG) distribution has been detected in several populations. However, information regarding this phenomenon among Chinese ethnic groups is minimal. This study aimed to describe and update the distribution of FPG in the Uyghur and Han populations of Xinjiang, China, as well as to estimate the cut points of FPG on the basis of bimodal distribution. METHODS AND STUDY DESIGN: A cross-sectional study was performed among the Uyghur and Han populations of Xinjiang, China in 2013. Questionnaire survey and FPG tests were conducted among 5,923 participants aged 20-80 years. We fitted the unimodal and bimodal distributions into the FPG data by ethnicity, age, gender, and location to test whether the FPG values were consistent with a bimodal distribution. RESULTS: The FPG distribution could be described as bimodal, except for the age group of 50 years old and below among the Uyghur and Han populations and the age group of 70-80 years old among the Uyghur population (p<0.01). However, most of the cut points estimated using this method did not fall between the corresponding means of the first and second modes. CONCLUSIONS: Although a bimodal distribution of FPG was observed in the Uyghur and Han populations of Xinjiang, China, the cut points estimated using this method were not biologically meaningful, and thus, a bimodal distribution of FPG was not useful for defining cut points to diagnose diabetes in Xinjiang. PMID- 28582824 TI - Metabolic syndrome in Korean adolescents and young adult offspring and their parents. AB - BACKGROUND AND OBJECTIVES: Studies have investigated the associations between parental metabolic syndrome (MetS) and offspring MetS. This study aimed to uncover parental-offspring associations for MetS and its components according to offspring sex and age. METHODS AND STUDY DESIGN: A cross-sectional study in 1,403 fathers, 1,451 mothers, and 1,532 offspring (340 male and 404 female offspring aged 10-18 years; 283 male and 505 female offspring aged 19-25 years) using the Korea National Health and Nutrition Examination Survey data between 2010 and 2013. RESULTS: All categorized MetS components in fathers and mothers were significantly associated with the same components in male offspring, while high waist circumference, high triglycerides, and low high-density lipoprotein in fathers and mothers were associated with the same components in female offspring. The number of categorized MetS components which were significantly associated between parent-offspring pairs was greater in offspring aged 19-25 years than in those aged 10-18 years. All categorized MetS components were significantly associated between father-male offspring aged 19-25 years pairs, but not in other parent-offspring pairs. The MetS per se in fathers and mothers was significantly associated with that in male offspring aged 10-18 years. CONCLUSIONS: There were differential associations according to offspring sex and age group and parent's sex with respect to parental-offspring associations for MetS and its individual components. The associations for MetS and its components were stronger in young adult versus adolescent offspring, in male offspring versus female offspring. PMID- 28582825 TI - Awareness of coeliac disease among chefs and cooks depends on the level and place of training. AB - BACKGROUND AND OBJECTIVES: Coeliac disease is triggered by gluten. The only treatment is lifelong avoidance of dietary gluten. Dining out and travelling are particular challenges with a huge impact on quality of life. We examined the knowledge about coeliac disease and gluten-free food preparation among chefs and cooks, and culinary students in Dunedin, New Zealand. METHODS AND STUDY DESIGN: Outlets serving gluten-free food were identified. The head chefs or cooks were invited to complete a questionnaire regarding demographics, education, qualification, experience and knowledge of coeliac disease and gluten-free food preparation. Ninety restaurant chefs and cooks, and 35 first-year culinary students participated. RESULTS: Half of participating chefs and cooks had received no formal training, but all were aware of the term gluten-free diet. Twelve (13%) were unaware of coeliac disease, all of whom were non-European and worked at an ethnic restaurant which did not have gluten-free policies in place. There was no significant difference in awareness of coeliac disease between chefs and students (p=0.36). However, students were significantly more aware of necessary gluten-free food preparation (p=0.007) and scored better in the gluten free quiz (p=0.01) than chefs and cooks. CONCLUSIONS: Awareness of coeliac disease did not necessarily mean that policies were in place to prepare contamination-free gluten-free meals. Chefs and cooks from countries with a low incidence of coeliac disease lacked knowledge about gluten-free food preparation and had difficulties recognising gluten containing foods. Patients with coeliac disease wanting to dine out should be advised to choose a restaurant with care. PMID- 28582826 TI - Associations of self-efficacy, social support, and knowledge with fruit and vegetable consumption in Japanese workers. AB - BACKGROUND AND OBJECTIVES: Previous studies have suggested that self-efficacy, social support, and knowledge are primary psychosocial predictors of dietary behavior in adults. The present study aimed to investigate the associations of self-efficacy, social support, and knowledge with fruit and vegetable consumption in Japanese workers. METHODS AND STUDY DESIGN: From September to November 2014, a self-administered questionnaire was completed by Japanese workers at 8 workplaces in Niigata, Japan. Self-efficacy and social support for fruit and vegetable consumption were measured using a 3-item Likert scale across particular situations. Knowledge was measured using a single item about the recommended guidelines for fruit and vegetable consumption in Japan. Fruit and vegetable consumption was assessed using a validated, brief-type self-administered diet history questionnaire. RESULTS: Of the 457 respondents, 395 participants' data were analyzed. Scores in self-efficacy and social support showed a significant and positive association with fruit (p<0.001, p=0.002) and vegetable consumption (p=0.001, p=0.015). Knowledge was significantly and positively associated with vegetable consumption (p=0.015) but did not statistically differ in fruit consumption (p=0.645). CONCLUSIONS: The findings of this study suggest that selfefficacy and social support are positively associated with fruit and vegetable consumption in Japanese workers. PMID- 28582827 TI - Differences in health-related behaviors between middle school, high school, and college students in Jiangsu province, China. AB - BACKGROUND AND OBJECTIVES: Increasing rates of obesity among Chinese adolescents has become a major public health concern in recent years. Studies have shown that factors such as food choices, physical activity, and screen time play important roles in fostering obesity. We examined a number of biological and social determinants that influence these factors. To determine whether dietary behavior, physical activity, and screen time varied among students in different stages of their education. METHODS AND STUDY DESIGN: Students in 13 cities across Jiangsu Province completed an anonymous survey assessing demographics and various health related behaviors in a controlled setting. The survey population ranged from middle school students to undergraduates. 55,361 surveys were returned, and 46,611 (84.2%) were usable for the analysis. Multiple linear regression models were used to investigate the relationship between four behavioral factors (dietary behavior, screen time, physical activity, and moderate exercise) and seven predictors (gender, age, BMI, mother's education, nearsightedness, allowance, and geographic region). RESULTS: Baseline characteristics of the survey population analyzed by education level (middle school, high school, college and beyond) showed moderate differences in demographics among the three groups. Physical activity, moderate exercise, and dietary behavior decreased with educational level, while screen time increased. All predictors in the four considered regression models were statistically significant. CONCLUSIONS: This unique, large-scale survey of Chinese students in a region of contrasting economic development revealed numerous relationships between health-related diet and physical-activity, region, and education level. These findings can inform the development of measures to counteract the rise of obesity in China. PMID- 28582828 TI - Rising food accessibility contributed to the increasing dietary diversity in rural and urban China. AB - China has undergone a dramatic transition in food consumption in the past few decades. Diet composition has changed significantly because of an increase in food accessibility and lifestyle changes. To investigate dietary changes in China from the perspective of dietary diversity, we assessed the trend of dietary diversity in China by using the following 4 indicators: count index, dietary diversity score, entropy, and Simpson index. Data of 24,542 adults (age >=18 y) were obtained from the China Health and Nutrition Survey (CHNS) conducted in 2004, 2006, 2009, and 2011. Furthermore, the association between dietary diversity and the number of food facilities was investigated using multivariable regression and local polynomial regression. Results indicate that dietary diversity increased over time and was unequally distributed among regions and families. Urban residents had a significantly more diverse diet compared with their rural counterparts (p<0.01). Moreover, dietary diversity was positively associated with food accessibility (p<0.01), and it was affected by socioeconomic factors such as the family income, household size, gender, age, education, and region. Taken together, these data suggest that the increase in dietary diversity in China in the past decade can be partially attributed to the increase in food accessibility. PMID- 28582829 TI - What Could be the Mechanism of the Delayed Normalization of the Electrocardiogram in Patients with Aneurysmal Subarachnoid Hemorrhage-Triggered Takotsubo Syndrome? PMID- 28582830 TI - In Reply to "What Could be the Mechanism of the Delayed Normalization of the Electrocardiogram in Patients with Aneurysmal Subarachnoid Hemorrhage-Triggered Takotsubo Syndrome?" PMID- 28582831 TI - Moyamoya Disease: Impact of Evolving Different Management Approaches to Improve Overall Neurologic Outcome. PMID- 28582832 TI - In Reply to "Moyamoya Disease: Impact of Evolving Different Management Approaches to Improve Overall Neurologic Outcome". PMID- 28582833 TI - A Letter to the Editor regarding "The Impact of Hospital Teaching Status on Timing of Intervention, Inpatient Morbidity, and Mortality After Surgery for Vertebral Column Fractures with Spinal Cord Injury". PMID- 28582834 TI - In Reply to A Letter to the Editor regarding "The Impact of Hospital Teaching Status on Timing of Intervention, Inpatient Morbidity, and Mortality After Surgery for Vertebral Column Fractures with Spinal Cord Injury." PMID- 28582835 TI - Oblique Lumbar Interbody Fusion: Utility and Perioperative Complications. PMID- 28582836 TI - In Reply to "Oblique Lumbar Interbody Fusion: Utility and Perioperative Complications". PMID- 28582837 TI - Impact Factor. PMID- 28582838 TI - The effect of gigantomasty on vertebral degeneration: A computed tomography study. AB - The main reason for waist and back pain in patients with gigantomasty is increased thoracic kyphosis and lumber lordosis. These symptoms and abnormal spinal angulations regress after reduction mammoplasty operations. However, the effect of chronic mechanical stress caused by gigantomasty on the spinal degenerative process is not clear yet. In this study with computed tomography it is shown that degenerative spondylosis is more widespread and severe in patients with large breasts. PMID- 28582839 TI - Beneficial effect of faradic stimulation treatment on the rehabilitation of hysterical paraplegia. AB - Hysterical paralysis, a type of conversion disorder, presents with the loss of motor or sensory function. Although this disorder is nonorganic, it resembles the symptoms of a structural disease of the nervous system. It is generally associated with a traumatic or social event. The patients often require excessive testing and comprehensive assessment in exposing this psychogenic ailment. We reported the most dramatic type of conversion disorder, hysterical paralysis, in which full recovery was obtained with early recognition and rehabilitation approach including faradic stimulation. PMID- 28582840 TI - Bim may be a poor prognostic biomarker in breast cancer patients especially in those with luminal A tumors. AB - BACKGROUND: Bcl-2 interacting mediator of cell death (Bim) appears to have contradictory roles in cancer. It is uncertain whether Bim show prognostic significance in patients with breast cancer. OBJECTIVE: To investigate the correlation between Bim expression and clinicopathological characteristics of breast cancer and to evaluate Bim's effect on overall survival (OS). METHODS: We used immunohistochemistry (IHC) technique to detect the expression of Bim via tissue microarray in 275 breast cancer samples, Kaplan-Meier analysis to perform survival analysis, and Cox proportional hazards regression model to explore the risk factors of breast cancer. RESULTS: The results revealed that Bim expression was significantly correlated with age, estrogen receptor (ER) and/or progesterone receptor (PR), human epidermal growth factor receptor (HER2) and Ki67 expression (P< 0.05). Bim expression was significantly different in the four molecular subtypes (P= 0.000). Survival analysis showed that Bim positive expression contributed to a shorter OS (P= 0.034), especially in patients with luminal A tumors (P= 0.039). Univariate and multivariate regression analysis showed that Bim was an independent prognostic factor for breast cancer (P< 0.05). CONCLUSION: Bim may serve as an effective predictive factor for lower OS in breast cancer patients, especially in those with luminal A tumors. PMID- 28582841 TI - Higher expression of SALL4 predicts poor cancer prognosis: A meta-analysis. AB - BACKGROUND: Sal-like protein 4 (SALL4) is recognized as a potential biomarker for assessing cancer prognosis. Many experiments have been done to explore the aberrant expression of SALL4 in cancer patients. OBJECTIVE: To explore the association between SALL4 expression and cancer prognosis. METHODS: A systematically comprehensive search was performed through PubMed, Web of Science, and CNKI. The prognostic value of SALL4 expression in cancer patients was evaluated by pooled hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The overexpression of SALL4 was identified to be significantly associated with a poor prognosis in cancer patients (pooled HR: 2.02, 95% CI: 1.67-2.46). This association was also detected in digestive system neoplasms subgroup (pooled HR: 1.91, 95% CI: 1.52-2.39) and reproductive system neoplasms subgroup (pooled HR: 1.95, 95% CI: 1.17-3.26). In the geography subgroup analysis, a statistical association was confirmed in the Chinese subgroup (pooled HR: 1.982, 95% CI: 1.526-2.576). In the respect of disease progression, there was a certain degree of relationship between higher expression of SALL4 and recurrence-free survival (RFS) (pooled HR: 1.617, 95% CI: 1.190-2.196). CONCLUSION: SALL4 is a promising prognostic biomarker for cancer, and is appropriate for the assessment of cancer prognosis in the Chinese people. PMID- 28582842 TI - Chitotriosidase, a marker of innate immunity, is elevated in patients with primary breast cancer. AB - BACKGROUND: Cancer progression has been associated with altered immune cell function and activation. Neopterin, which is secreted by interferon-gamma stimulated macrophages, exhibits an association with multiple cancer types and metastatic disease. Chitotriosidase, which is secreted by chronically activated macrophages and granulocyte-macrophage colony-stimulating factor stimulated neutrophils has not been studied in the setting of cancer. OBJECTIVE: The goal of this discovery study was to screen chitotriosidase for diagnostic capacity in detecting cancer and compare its operating characteristics with those of neopterin. METHODS: Serum from subjects with breast (n= 66) or prostate (n= 70) cancer, and from 204 subjects free of malignant disease were studied. Chitotriosidase was measured by enzyme activity assay, while neopterin was measured by a competitive enzyme immunoassay. Statistical analyses included group comparisons by Mann Whitney U test, diagnostic capacity by receiver operating characteristics (ROC) curve analysis and biomarker associations with physiologic and clinical measures by Spearman correlation. RESULTS: Chitotriosidase activity was significantly higher in both cancer types compared with gender matched controls, though only in breast cancer was the diagnostic capacity significant (area under the ROC curve of 0.97 +/- 0.01). In contrast, neopterin was significantly elevated in prostate cancer and exhibited discriminatory capacity (area under the ROC curve of 0.76 +/- 0.05). Age, BMI, % body fat and metastasis were variables that correlated with neopterin, but not chitotriosidase levels. CONCLUSIONS: The operating characteristics of serum chitotriosidase were different from neopterin and further analysis of chitotriosidase as a biomarker for breast cancer is warranted. PMID- 28582844 TI - Postoperative recurrence analysis of breast cancer patients based on clinical serum markers using discriminant methods. AB - BACKGROUND: Breast cancer is a common gynecological malignant tumor and currently its clinical diagnosis mainly depends on methods of iconography and measurement of serum level. OBJECTIVE: To analyze correlation between serum index levels and prognosis of patients with breast cancer in one week and six months after operation, and to establish support vector machine (SVM) model to evaluate its effectiveness. METHODS: One hundred sixty eight patients diagnosed with breast cancer at Affiliated Cancer Hospital of Zhengzhou University were collected, 46 of which did palindromia while other 122 didn't six months after operation. Serum CA153, CA125 and CEA levels of different periods in two groups were analyzed from their differences. Through receiver operating characteristic (ROC) curve analysis, their diagnostic threshold values were calculated, at the same time, SVM model was built. RESULTS: There was a significant difference between serum index levels of recurrence group and non-recurrence group in one week and six months after operation (P< 0.05); SVM model was established with an accuracy of 96.67% (29/30), a sensitivity of 90% (9/10) and a specificity of 100% (20/20). CONCLUSIONS: Serum CAl53, CEA and CA125 levels after operation have certain instructional significance for prognosis of breast cancer patients, and the established SVM model has high clinical application value. PMID- 28582843 TI - Acute lymphoblastic leukemia and genetic variations in BHMT gene: Case-control study and computational characterization. AB - BACKGROUND: Remethylation of homocysteine is catalyzed by B12 dependent methionine synthase (MTR) in all types of cells and by B12 non-dependent betaine homocysteine methyltransferase (BHMT) in liver and kidney cells. Of many etiologies of cancer, an unexplored area is the variations of genes implicated in methylation reaction. OBJECTIVE: The study evaluated the association of BHMT (rs3733890) with acute lymphoblastic leukemia (ALL), followed by in-silico characterization of variations in BHMT gene. METHODS: BHMT [rs3733890; c.742G > A, which substitutes an arginine by a glutamine at codon 239 (R239Q)] was screened by Tetra-primer Amplification Refractory Mutation System PCR (T-ARMS PCR) and confirmed using DNA sequencing. In-silico analysis was conducted using bioinformatics tools. RESULTS: BHMT (rs3733890) showed an insignificant association with both childhood and adult ALL. Bioinformatics analysis showed that 18 nsSNPs are deleterious, 3 SNPs in 3'-UTR (rs59109725, rs116634518 and rs138578732) alter the miRNA-binding site, and 11 CNVs are present in the BHMT gene. As consequence of BHMT (rs3733890) polymorphism the free energy changes from -101210.1 kJ/mol to -200021.8 kJ/mol. CONCLUSIONS: BHMT (rs3733890) polymorphism showed no association with ALL. Hence this investigation needs further evaluation in larger sample size and effect of other SNPs, CNVs and miRNA's is required to elucidate the role of BHMT gene in ALL development. PMID- 28582845 TI - Elevated lactate dehydrogenase (LDH) can be a marker of immune suppression in cancer: Interplay between hematologic and solid neoplastic clones and their microenvironments. AB - Metabolism of neoplastic cells is shifted toward high glucose uptake and enhanced lactate production. Lactate dehydrogenase (LDH), which is comprised of two major subunits, LDH-A and LDH-B, reversibly catalyzes the conversion of pyruvate to lactate or lactate to pyruvate. LDH-A has a higher affinity for pyruvate and is a key enzyme in the glycolytic pathway. Elevated LDH is a negative prognostic biomarker not only because it is a key enzyme involved in cancer metabolism, but also because it allows neoplastic cells to suppress and evade the immune system by altering the tumor microenvironment. LDH-A alters the tumor microenvironment via increased production of lactate. This leads to enhancement of immune suppressive cells, such as myeloid-derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), and dendritic cells (DCs); and inhibition of cytolytic cells, such as natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs). By promoting immune-suppression in the tumor microenvironment, LDH-A is able to promote resistance to chemo/radio/targeted therapy. Here we discuss the evidence that LDH is both a metabolic and an immune surveillance prognostic biomarker and its elevation is harbinger of negative outcome in both solid and hematologic neoplasms. PMID- 28582847 TI - MiR-133b inhibits proliferation and invasion of gastric cancer cells by up regulating FBN1 expression. AB - We aimed to investigate the influence of miR-133b/fibrillin 1 (FBN1) on proliferation and invasion of human gastric cancer (GC) cells. Carcinomatous and adjacent tissues of 43 GC patients, normal gastric mucosa cell line GES-1 and GC cell lines including AGS, HGC-27, KATO III, NCI-N87, SGC-7901, MKN-45 and MGC-803 were collected. Then, the expressions of miR-133b and FBN1 were detected by qRT PCR. The dual luciferase reporter gene assay was conducted to determine the targeting relationship between miR-133b and FBN1.The protein expression levels of FBN1, beta-catenin, Cyclin D1, C-myc and MMP-7 were detected by Western Blot. Furthermore, the cell viability, proliferation, migration and invasion ability were measured by CCK-8, colony formation assay, wound healing assay and Transwell assay, respectively. MiR-133b was down-regulated in GC tissues and cells compared with adjacent tissues and normal cells. Conversely, FBN1 was up-regulated in GC tissues and cells in contrast with adjacent tissues and normal cells. MGC-803 and MKN-45 cell lines were chosen to conduct the following assays. The luciferase reporter assay proved that miR-133b directly targeted FBN1. The overexpression of miR-133b and silence of FBN1 could inhibit the cell proliferative, migratory and invasive abilities of GC cells, while the influence of down-regulated miR-133b expression and up-regulated FBN1 expression were quite the contrary. Compared with NC group, in the miR-133b mimics group, the expression of beta-catenin, N cadherin and Wnt1 of Wnt/beta-catenin signal pathway increased, while the expressions of E-cadherin decreased. MiR-133b inhibits the proliferative, migratory and invasive abilities of GC cells by increasing FBN1 expression. PMID- 28582846 TI - Decreased SIRT4 protein levels in endometrioid adenocarcinoma tissues are associated with advanced AJCC stage. AB - BACKGROUND: Members of the SIRT family are a highly conserved family of NAD+ dependent enzymes, many of which (SIRT1-7) play an important role in tumor formation. Recently, several studies have suggested that SIRT4 not only regulates glutamine metabolism, but also serves as a tumor suppressor. There are no studies have assessed its clinical significance in endometrioid adenocarcinoma. METHODS: We investigated SIRT4 protein levels in endometrioid adenocarcinoma and its possible association with selected clinico-pathological parameters by immunohistochemical staining of a tissue microarray that included 65 endometrioid adenocarcinoma patients. RESULTS: SIRT4 protein levels in endometrioid adenocarcinoma were markedly lower than its non-neoplastic tissue counterpart (P< 0.001). Moreover, lower SIRT4 expression levels were observed in advanced AJCC stages of development (P= 0.002). CONCLUSIONS: Our results indicated that SIRT4 may be involved in the development of endometrioid adenocarcinoma and is a promising target for both the diagnosis and potential therapy of endometrioid adenocarcinoma. PMID- 28582848 TI - Curative effect of transcatheter arterial chemoembolization combined with radiofrequency ablation in treating hepatic cell carcinoma and its effect on serum markers. AB - BACKGROUND: Hepatic cell carcinoma (HCC) is more common in clinical practice, and has high malignant degree. OBJECTIVE: This study aims to analyze the curative effect of transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) in treating hepatic cell carcinoma (HCC) and its effect on serum markers. METHODS: A total of 106 cases of patients with hepatic cell carcinoma treated in our hospital were randomly divided into two groups: observation group and control group. Patients in the observation group (53 cases) received transcatheter arterial chemoembolization combined with radiofrequency ablation therapy, while subjects in the control group (53 cases) received transcatheter arterial chemoembolization therapy. Differences in the overall effect, indicators of inflammation and oxidative stress, tumor activity-related indicators and tumor recurrence-related indicators between these two groups were compared. RESULTS: At one and two weeks after treatment, the number of cases of CR and PR in the observation group was higher than that in the control group, the number of cases of SD was not different from that in the control group, and the number of cases of PD was lower than that in the control group. At two weeks after treatment, differences in serum MDA, SOD, GSH, CRP, TNF-alpha and ESR between the two groups were significant. However, serum EC, VEGF, MMP, AFP, CA199 and GGT content was significantly lower in the observation group than that in the control group. CONCLUTIONS: Transcatheter arterial chemoembolization combined with radiofrequency ablation therapy can effectively control the growth of liver cancer lesions, reduce the levels of tumor-related serum markers, and inhibit the activity of tumor cells. PMID- 28582849 TI - MicroRNA-451 as a prognostic marker for diagnosis and lymph node metastasis of papillary thyroid carcinoma. AB - BACKGROUND AND OBJECTIVE: To investigate the diagnostic potentials of microRNA 451(miR-451) in papillary thyroid carcinoma (PTC) diagnosis and lymph node (LN) metastasis, formalin-fixed, paraffin-embedded (FFPE) tissue specimens corresponding to PTC tumors (n= 60) and their normal counterparts (Normal tissues Adjacent to Tumor, NAT, n= 60), along with sera from PTC patients with malignant tumors (n= 70) and benign lesions (n= 70) were analyzed for the expression of miR 451 by real-time PCR. METHODS: The usefulness of miR-451 expression as a prognostic marker for diagnosis of PTC malignancies was evaluated by Receiver Operating Curve (ROC). We reported that when compared to those in NAT, the levels of miR-451 in FFPE tissues from various stages of PTC patients (n= 60) were significantly lower (Mean +/- SEM; 12.62 +/- 1.73 vs 38.8 +/- 3.51, p< 0.0001). Receiver operating curve (ROC) analysis revealed that the area under curve (AUC) was 0.808; suggesting miR-451 expression was a reliable tissue biomarker for PTC malignancies. Further in depth analyses of these specimens revealed that miR-451 levels were significantly lower in PTC patients with lymph node (LN) metastasis than those without LN metastasis (3.96 +/- 1.67 vs. 14.15 +/- 1.95, p= 0.006) with calculated AUC of 0.792, supporting the notion that miR-451 expression was also a good indicator for PTC lymph node involvements. Analyses sera from the cohorts of PTC patients indicated that miR-451 levels in patients with malignant lesions (n= 70) were significantly lower (10.72 +/- 1.52 vs. 19.28 +/- 2.73, p= 0.010) than those with benign ones (n= 70). Parallel analyses of serum miR-451 levels in patients with LN metastasis also showed that they were significantly lower when compared to those without LN metastasis (6.79 +/- 2.29 vs. 12.08 +/- 1.86, p= 0.017). RESULTS: ROC analyses revealed that AUC was 0.626 for malignancies and was 0.690 for lymph node involvement, respectively, suggesting that miR-451was a modest blood based biomarker for PTC malignancies and lymph node metastasis. CONCLUSIONS: We concluded that miR-451 expression is a reliable FFPE tissue biomarker for PTC malignancies and it may have potentials to become a noninvasive, blood-based biomarker for PTC diagnosis and evaluation of LN status. PMID- 28582850 TI - FOXF2 deficiency promotes hepatocellular carcinoma metastasis by inducing mesenchymal-epithelial transition. AB - OBJECTIVE: The transcription factor FOXF2 is reported to be down-regulated in HCC. Its deficiency is correlated with shorter disease-free survival and overall survival of HCC patients; however, the mechanism remains to be elucidated. MATERIALS AND METHODS: In this study, we performed qRT-PCR and western blotting to confirm the down-regulated FOXF2 in HCC tissue and cell lines. Then the HCC cell line Huh7 transduced with FOXF2 shRNA was adopted in a series of in vitro and in vivo assays to evaluate the cell phenotype change, migration, invasion, proliferation, colonization of circulating cell and the formation of metastatic nodules. RESULTS: We found that FOXF2 was down-regulated in HCC tissues and cell lines. FOXF2 deficiency in Huh7 cells increased E-cadherin and decreased Vimentin. The down-regulation of FOXF2 impeded HCC cell migration and invasion capacity, but promoted the proliferation of HCC cells and the growth of subcutaneous tumors in nude mice, which indicated a mesenchymal-to-epithelial phenotypic change in Huh7 cells. FOXF2 deficiency enhanced the colonization of circulating HCC cell, thus promoted the formation of metastatic nodules. CONCLUSIONS: FOXF2 deficiency induced mesenchymal-epithelial transition (MET) in Huh7 cell which might facilitate the colonization of circulating tumor cells and the formation of metastasis. PMID- 28582851 TI - Fenofibrate protects against acute myocardial I/R injury in rat by suppressing mitochondrial apoptosis as decreasing cleaved caspase-9 activation. AB - BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor-alpha (PPAR alpha) activation has been reported to reduce myocardial ischemia-reperfusion (I/R) injury by inhibiting cell apoptosis. However, the antiapoptotic mechanism of PPAR-alpha is still unknown. Fenofibrate is a PPAR-alpha agonist In the present study, we investigate the effects and relevant mechanism of fenofibrate on experimental myocardial ischemia-reperfusion (I/R) injury in rats. METHODS: Adult male Wistar rats were pretreated with fenofibrate (80 mg/kg) daily for a period of 7 days. After the treatment period, myocardial I/R injury model was made by left anterior descending coronary artery ligation for 45 min and reperfusion for 120 min. Myocardial infarct size, malondialdehyde (MDA) cleaved caspase-9 protein expression, PPARalpha and uncoupling protein 2 (UCP2) mRNA levels in myocardial tissue were detected Cell apoptosis was detected by Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Serum lactate dehydrogenase and creatine kinase activities were measured in rats pretreated with fenofibrate The ultrastructure of myocardial tissues was observed. RESULTS: Significant increases in myocardial cell apoptosis, malondialdehyde (MDA) level and cleaved-caspase-9 protein expression level in myocardial tissue were observed, along with reductions of PPARalpha and uncoupling protein 2 (UCP2) mRNA levels in myocardial tissue of the experimental myocardial ischemia-reperfusion (I/R) injury in rats. Impaired mitochondria were also observed under electron microscopic. However, pretreatment of ischemia/reperfusion rats with fenofibrate brought the biochemical parameters and related genes expression levels to near normalcy, indicating the protective effect of fenofibrate against myocardial ischemia/reperfusion injury in rats. CONCLUSIONS: The PPAR-alpha activator fenofibrate conferred cytoprotective effect against myocardial ischemia-reperfusion (I/R) injury in rats. Associated mechanisms involved decreased cleaved-caspase-9 expression and decreased cell apoptosis. PMID- 28582852 TI - Human Anti-Lipopolysaccharid (LPS) antibodies against Legionella with high species specificity. AB - Legionella are Gram-negative bacteria that are ubiquitously present in natural and man-made water reservoirs. When humans inhale aerosolized water contaminated with Legionella, alveolar macrophages can be infected, which may lead to a life threatening pneumonia called Legionnaires' disease. Due to the universal distribution of Legionella in water and their potential threat to human health, the Legionella concentration in water for human use must be strictly monitored, which is difficult since the standard detection still relies on lengthy cultivation and analysis of bacterial morphology. In this study, an antibody against L. pneumophila has been generated from the naive human HAL antibody libraries by phage-display for the first time. The panning was performed on whole bacterial cells in order to select antibodies that bind specifically to the cell surface of untreated Legionella. The bacterial cell wall component lipopolysaccharide (LPS) was identified as the target structure. Specific binding to the important pathogenic L. pneumophila strains Corby, Philadelphia-1 and Knoxville was observed, while no binding was detected to seven members of the families Enterobacteriaceae, Pseudomonadaceae or Clostridiaceae. Production of this antibody in the recombinant scFv-Fc format using either a murine or a human Fc part allowed the set-up of a sandwich-ELISA for detection of Legionella cells. The scFv-Fc construct proved to be very stable, even when stored for several weeks at elevated temperatures. A sensitivity limit of 4,000 cells was achieved. The scFv-Fc antibody pair was integrated on a biosensor, demonstrating the specific and fast detection of L. pneumophila on a portable device. With this system, 10,000 Legionella cells were detected within 35 min. Combined with a water filtration/concentration system, this antibody may be developed into a promising reagent for rapid on-site Legionella monitoring. PMID- 28582853 TI - Investigating the exon 6 sequence changes of interleukin 7 receptor A (IL7RA) gene in patients with relapsing-remitting multiple sclerosis. AB - BACKGROUND: Interleukin 7 receptor alpha (IL7RA) gene that encodes a subunit of IL7 receptor has been reported to be associated with different immunologic disease. OBJECTIVE: Multiple Sclerosis (MS) patients have shown an aberrant blood level of soluble form of IL7R protein. The genomic changes in the sequence of this gene have been suggested to be correlated with its altered splicing specially, variants in the exon 6 of the gene have been reported to influence the maintenance or skipping of this exon and control the soluble or insoluble form of the final product. In order to evaluate this changes in the IL7RA gene and to determine a possible correlation between these changes and the MS susceptibility the whole sequence of the exon 6 and 7 and their flanking sequences were analyzed. METHODS: In this regard, we investigate the sequence changes of the exon 6 and 7 of the IL7RA gene in 75 relapsing-remitting MS patients and compare the results with 75 healthy control using sequence analyzing. RESULTS: The results of the sequence analysis were used in two aspects. The allelic and genotypic estimated frequencies of a reported risk variant rs6897932 in patients and controls in our population confirmed its association with the disease (P= 0.009, OR = 6.273, for TT genotype). Also, we report a possible hazardous cutoff for changes in a potential exon splicing silencer element (ESS (nt. 20-24)) and its correlation with rs6897932 to confer the risk of developing MS. CONCLUSION: In conclusion our results confirm the association between IL7RA exon 6 sequence changes and increased susceptibility for multiple sclerosis. PMID- 28582854 TI - Activation of Macrophages and Microglia by Interferon-gamma and Lipopolysaccharide Increases Methylglyoxal Production: A New Mechanism in the Development of Vascular Complications and Cognitive Decline in Type 2 Diabetes Mellitus? AB - Methylglyoxal (MGO), a dicarbonyl compound derived from glucose, is elevated in diabetes mellitus and contributes to vascular complications by crosslinking collagen and increasing arterial stiffness. It is known that MGO contributes to inflammation as it forms advanced glycation end products (AGEs), which activate macrophages via the receptor RAGE. The aim of study was to investigate whether inflammatory activation can increase MGO levels, thereby completing a vicious cycle. In order to validate this, macrophage (RAW264.7, J774A.1) and microglial (N11) cells were stimulated with IFN-gamma and LPS (5 + 5 and 10 + 10 IFN-gamma U/ml or MUg/ml LPS), and extracellular MGO concentration was determined after derivatization with 5,6-Diamino-2,4-dihydroxypyrimidine sulfate by HPLC. MGO levels in activated macrophage cells (RAW264.7) peaked at 48 h, increasing 2.86 fold (3.14+/-0.4 MUM) at 5 U/ml IFN-gamma+5 MUg/ml LPS, and 4.74-fold (5.46+/ 0.30 MUM) at 10 U/ml IFN-gamma+10 MUg/ml LPS compared to the non-activated controls (1.15+/-0.02 MUM). The other two cell lines, J774A.1 macrophages and N11 microglia, showed a similar response. We suggest that inflammation increases MGO production, possibly exacerbating arterial stiffness, cardiovascular complications, and diabetes-related cognitive decline. PMID- 28582855 TI - Diabetes and Alzheimer's Disease: Can Tea Phytochemicals Play a Role in Prevention? AB - Dementia and diabetes mellitus are prevalent disorders in the elderly population. While recognized as two distinct diseases, diabetes has more recently recognized as a significant contributor to risk for developing dementia, and some studies make reference to type 3 diabetes, a condition resulting from insulin resistance in the brain. Alzheimer's disease, the most common form of dementia, and diabetes, interestingly, share underlying pathological processes, commonality in risk factors, and, importantly, pathways for intervention. Tea has been suggested to possess potent antioxidant properties. It is rich in phytochemicals including, flavonoids, tannins, caffeine, polyphenols, boheic acid, theophylline, theobromine, anthocyanins, gallic acid, and finally epigallocatechin-3-gallate, which is considered to be the most potent active ingredient. Flavonoid phytochemicals, known as catechins, within tea offer potential benefits for reducing the risk of diabetes and Alzheimer's disease by targeting common risk factors, including obesity, hyperlipidemia, hypertension, cardiovascular disease, and stroke. Studies also show that catechins may prevent the formation of amyloid beta plaques and enhance cognitive functions, and thus may be useful in treating patients who have Alzheimer's disease or dementia. Furthermore, other phytochemicals found within tea offer important antioxidant properties along with innate properties capable of modulating intracellular neuronal signal transduction pathways and mitochondrial function. PMID- 28582856 TI - Lipidomic Profiles in Diabetes and Dementia. AB - Lipids are a diverse class of hydrophobic and amphiphilic molecules which make up the bulk of most biological systems and are essential for human life. The role of lipids in health and disease has been recognized for many decades, as evidenced by the early identification of cholesterol as an important risk factor of heart disease and the development and introduction of statins as a one of the most successful therapeutic interventions to date. While several studies have demonstrated an increased risk of dementia, including Alzheimer's disease (AD), in those with diabetes mellitus, the nature of this risk is not well understood. Recent developments in the field of lipidomics, driven primarily by technological advances in high pressure liquid chromatography and particularly mass spectrometry, have enabled the detailed characterization of the many hundreds of individual lipid species in mammalian systems and their association with disease states. Diabetes mellitus and AD have received particular attention due to their prominence in Western societies as a result of the ongoing obesity epidemic and the aging populations. In this review, we examine how these lipidomic studies are informing on the relationship between lipid metabolism with diabetes and AD and how this may inform on the common pathological pathways that link diabetes risk with dementia. PMID- 28582858 TI - Alterations in the Peripheral Immune System in Dementia. AB - Alterations in the immune response that result in inflammation might play a role in the pathology of dementias. In order to analyze changes of the peripheral immune system associated with different types of dementias, we determined several innate and adaptive cell populations in whole blood using flow cytometry. We included patients with Alzheimer's disease (AD; n = 60), vascular dementia (VaD; n = 20), and frontotemporal dementia (FTD; n = 12) at the time point of diagnosis and 24 age-matched neuropsychiatric healthy persons. Monocytes and NK cells were diminished in VaD, but not in AD and FTD. B cell and T cell numbers were decreased in all investigated forms of dementia. Changes in the contribution of naive/memory T cells were only present in AD. Correlation and regression analyses revealed associations between altered immune cell populations and Q Albumin as marker for the integrity of the blood-cerebrospinal fluid-barrier, Mini-Mental State Examination values, and age. The peripheral immune system is altered in AD, VaD, and FTD. However, each disorder presents unique changes in the investigated cell types indicating different mechanisms underlying the pathology. PMID- 28582857 TI - Identification of Successful Cognitive Aging in the Alzheimer's Disease Neuroimaging Initiative Study. AB - The present prospective observational study aimed to identify the existence of successful cognitive agers among a group of well-defined cognitively healthy older adults (n = 354, mean age = 75 years), and to examine baseline individual level predictors and associated health outcomes over time. Episodic memory (EM) and executive function (EF) composite scores and multiple health outcomes were obtained annually over 5 years. Potential individual-level predictors that were related to Alzheimer's disease pathology or genetic risk, neurodegeneration, and vascular risks were collected at baseline. Three latent classes with matched age and education were identified using growth mixture modeling: a group of participants who exhibited high, stable EM and EF (40.7% of the sample, "successful agers"); a group who had initial high cognitive performance that declined over time (21.2%, "declining agers"); and a group who had normal (EM) or poor (EF) but stable cognitive performance over time (38.1%, "low stable agers"). The group classification predicted significant differences in the incidence of global cognitive impairment, the development of at least one depressive symptom, and everyday functional impairment. Sex, apolipoprotein E allele 4, amyloid-beta1 42, and t-tau significantly contributed to the difference in cognitive trajectories between the successful agers and the other two groups. Characterizing successful cognitive agers who are relatively resistant to both tau and amyloid pathology provides potential pathways for promoting successful cognitive aging and preventing cognitive decline. PMID- 28582861 TI - Post-Translational Oxidative Modifications of Mitochondrial Complex I (NADH: Ubiquinone Oxidoreductase): Implications for Pathogenesis and Therapeutics in Human Diseases. AB - Mitochondrial complex I (NADH: ubiquinone oxidoreductase; CI) is central to the electron transport chain (ETC), oxidative phosphorylation, and ATP production in eukaryotes. CI is a multi-subunit complex with a complicated yet organized structure that optimally connects electron transfer with proton translocation and forms higher-order supercomplexes with other ETC complexes. Efforts to understand the molecular genetics, expression profile of subunits, and structure-function relationship of CI have increased over the years due to the direct role of the complex in human diseases. Although mutations in the nuclear and mitochondrial genes of CI and altered expression of subunits could potentially lower CI activity leading to mitochondrial dysfunction in many diseases, oxidative post translational modifications (PTMs) have emerged as an important mechanism contributing to altered CI activity. These mainly include reversible and irreversible cysteine modifications, tyrosine nitration, carbonylation, and tryptophan oxidation that are generated following exposure to reactive oxygen species/reactive nitrogen species. Interestingly, oxidative PTMs could contribute either to CI damage, mitochondrial dysfunction, and ensuing cell death or a response mechanism with potential cytoprotective effects. This has also emerged as a promising field for structural biologists since analysis of PTMs could assist in understanding the structure-function relationship of the complex and correlate electron transfer mechanism with energy production. However, analysis of PTMs of CI and their contribution to CI function are incomplete in many physiological and pathological conditions. This review aims to highlight the role of oxidative PTMs in modulating CI activity with implications toward pathobiology of CNS diseases and novel therapeutics. PMID- 28582860 TI - No Genetic Overlap Between Circulating Iron Levels and Alzheimer's Disease. AB - Iron deposition in the brain is a prominent feature of Alzheimer's disease (AD). Recently, peripheral iron measures have also been shown to be associated with AD status. However, it is not known whether these associations are causal: do elevated or depleted iron levels throughout life have an effect on AD risk? We evaluate the effects of peripheral iron on AD risk using a genetic profile score approach by testing whether variants affecting iron, transferrin, or ferritin levels selected from GWAS meta-analysis of approximately 24,000 individuals are also associated with AD risk in an independent case-control cohort (n~10,000). Conversely, we test whether AD risk variants from a GWAS meta-analysis of approximately 54,000 account for any variance in iron measures (n~9,000). We do not identify a genetic relationship, suggesting that peripheral iron is not causal in the initiation of AD pathology. PMID- 28582859 TI - Blood Pressure and Hispanic/Latino Cognitive Function: Hispanic Community Health Study/Study of Latinos Results. AB - BACKGROUND: Hispanics/Latinos are at increased risk for cardiovascular disease and cognitive decline and dementias. High blood pressure (BP) has been implicated in both stroke and dementias. Associations between BP and cognition among diverse Latinos are still unpublished. OBJECTIVE: We examined associations between cognition and four BP based measures among diverse Hispanics/Latinos. We hypothesized that higher BP, particularly systolic pressure, and increased arterial stiffness (i.e., pulse pressure), would be associated with lower cognitive function. METHODS: We used baseline (2008-2011) Hispanic Community Health Study/Study of Latinos (HCHS/SOL; n = 9,019; ages 45-74 years) data to examine cognition in relation to BP measures. RESULTS: In age, sex, and education adjusted models, systolic, pulse, and mean arterial pressure were consistently negatively associated with executive function, psychomotor speed and sustained attention, verbal episodic learning and memory, speech fluency, and mental status measures. These associations were attenuated but remained statistically significant in fully adjusted models. CONCLUSION: Among middle-aged and older diverse Hispanics/Latinos, we found modest but consistent associations between indicators of arterial stiffness, and compromised blood flow and lower cognitive function. Clinical management and public health interventions to raise awareness and enhance BP management beginning in midlife could reduce disparities and improve population health by reducing cognitive decline burdens. PMID- 28582862 TI - Midlife Metabolic Profile and the Risk of Late-Life Cognitive Decline. AB - Among metabolic syndrome components, the effects of higher plasma glucose levels on cognitive decline (CD) have been considered in few studies. We evaluated the associations among midlife glycemia, total cholesterol, high-density lipoprotein cholesterol, triglycerides, midlife insulin resistance [homeostasis model assessment for insulin resistance (HOMA-index)], and CD in the older subjects of the population-based MICOL Study (Castellana Grotte, Italy) at baseline (M1) and at follow-ups seven (M2) and twenty years later (M3). At M1, a dementia risk score and a composite cardiovascular risk score for dementia were calculated. For 797 subjects out of 833, we obtained a Mini-Mental State Examination (MMSE) score at M3, subdividing these subjects in three cognitive functioning subgroups: normal cognition, mild CD, and moderate-severe CD. Mean fasting glycemia at baseline was significantly higher in moderate-severe CD subgroup (114.6+/-71.4 mg/dl) than in the normal cognition subgroup (101.2+/-20.6). Adjusting for gender, age, and other metabolic components, higher fasting glycemia values both at M1 [odds ratio (OR) = 1.31; 95% confidence interval (CI): 1.08-1.59] and M2 (OR = 1.26; 95% CI: 1.01-1.57) were associated with an increased risk of moderate severe CD. Mean HOMA index value was significantly higher in the moderate-severe CD subgroup (5.7+/-9.4) compared to the normal cognition subgroup (2.9+/-1.4) at M1. The dementia risk probability (MMSE < 24) increased moving through higher categories of the dementia risk score and decreased as long as the cardiovascular score increased. The present findings highlighted the indication to control blood glucose levels, regardless of a diagnosis of diabetes mellitus, as early as midlife for prevention of late-life dementia. PMID- 28582863 TI - Framingham Risk Score and the Risk of Progression from Mild Cognitive Impairment to Dementia. AB - BACKGROUND: Mild cognitive impairment (MCI) often represents the clinical manifestation of cognitive deterioration preceding Alzheimer's disease (AD). Currently, there are no reliable approaches for an objective evaluation of the risk of developing AD in MCI patients. OBJECTIVE: The aim of this study was to verify whether the Framingham cardiovascular risk profile (FCRP) could be useful to identify patients at the highest risk of conversion from MCI to AD. METHODS: Patients with amnestic MCI (aMCI) were carefully investigated to assess their vascular risk profile. They were also submitted to a comprehensive neuropsychological evaluation. The FCRP was calculated for each patient and the apolipoprotein E (ApoE) genotype was determined from peripheral blood cells. The main outcome was defined as a conversion to AD within 24 months after inclusion. RESULTS: 385 consecutive aMCI subjects were included. Age, FCRP, and vascular age showed a fairly predictive value on conversion to AD. Selecting the subpopulation of ApoE E4 carriers, we observed that FCRP had an increased performance in predicting the conversion. The rate of conversion increased from 12.5% in the FCRP low-risk group to 43.2% in the high-risk group (p < 0.0001). ApoE E4 carriers had a 3.7-times increased probability of conversion with respect to the other subjects (p < 0.0001). CONCLUSIONS: FCRP assessment could be considered a reliable approach to predict conversion to AD in aMCI subjects. The presence of ApoE E4 increases significantly the risk of conversion. These data confirm the narrow relationship between genetic and vascular risk factors in influencing the evolution of cognitive impairment. PMID- 28582865 TI - Motoric Cognitive Risk Syndrome: Association with Incident Dementia and Disability. AB - BACKGROUND: It is important to examine the etiology of motoric cognitive risk syndrome (MCR) and its association with dementia and disability to obtain biological insights and to develop preventive strategies. OBJECTIVE: This study aimed to examine the association of MCR with incidence of dementia and disability in a Japanese community-dwelling sample of older adults. METHODS: Participants were 4,235 older adults (50% women, mean age: 72.0 years). MCR was diagnosed at baseline using established criteria in non-demented seniors with self-reported cognitive complaints and slow gait. Incident cases of dementia were identified from insurance data monthly. Disability was regarded as certification by long term care insurance. RESULTS: At baseline, 265 participants (6.3%) met criteria for MCR. During follow-up (mean duration: 29 months), there were 138 incident cases of dementia (3.3%) and 207 incident cases of disability (4.9%). Cox proportional hazards models, adjusted for demographical data, lifestyle, and medical conditions, showed that presence of MCR at baseline was a major risk factor for developing dementia (HR 2.49, 95% CI 1.52-4.10, p < 0.001). MCR also predicted risk for disability (HR 1.69, 95% CI 1.08-2.02, p < 0.001). CONCLUSIONS: MCR is helpful in the short-term prediction of risk for dementia and disability in the elderly Japanese population. Identification of seniors with MCR is recommended for early detection and instituting preventive measures for reducing the risk of dementia and disability. PMID- 28582864 TI - Transactive DNA Binding Protein 43 Rather Than Other Misfolded Proteins in the Brain is Associated with Islet Amyloid Polypeptide in Pancreas in Aged Subjects with Diabetes Mellitus. AB - A link between diabetes mellitus (DM) related islet amyloid polypeptide (IAPP) and Alzheimer's disease (AD) related amyloid-beta (Abeta) has been suggested in epidemiological and clinical studies. In 2017, proof for existing interaction between type 2 DM and AD on a molecular level was provided based on research carried out in experimental animal models. We assessed aging-related neurodegenerative lesions, i.e., misfolded proteins, associated with dementia such as hyperphosphorylated tau (HPtau), Abeta, alpha-synuclein (alphaS), and phosphorylated transactive DNA binding protein 43 (pTDP43) seen in the brain and IAPP seen in the pancreas in subjects with and without DM applying immunohistochemical techniques. HPtau in the brain and IAPP in the pancreas were observed in most subjects. The prevalence and the extent of all misfolded proteins increased with age but this increase was not influenced by DM. Interestingly the extent of misfolded proteins in the brain was higher in non diabetics when compared with diabetics in demented. A significant correlation was observed between HPtau, Abeta, alphaS, and pTDP43, whereas IAPP showed no association with HPtau, Abeta, and alphaS. In subjects with DM, the extent of pTDP43 in brain correlated with the extent of IAPP in pancreas. Thus, there is no evidence of a link between AD-related pathology and DM in humans, whereas an association was found between pTDP43 and IAPP in DM. TDP43 is ubiquitously expressed in all organs but whether TDP43 is phosphorylated in other organs in DM or whether the phosphorylation of TDP43 is influenced by glucose metabolism is yet unknown. PMID- 28582866 TI - Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer's Disease. AB - BACKGROUND: Alzheimer's disease (AD) presents with an earlier onset age and increased symptom severity in African Americans and Hispanics. OBJECTIVE: Although the prevalence of plaques and tangles may not exhibit ethnicity-related differences, levels of neurodegenerative proteins have not been described. METHODS: Here, levels of five proteins (i.e., S100B, sRAGE, GDNF, Abeta40, and Abeta42) and the Abeta42/Abeta40 ratio were measured in postmortem samples of the middle temporal gyrus (BA21) from age-matched African Americans and Caucasians with AD (n = 6/gender/ethnicity). RESULTS: S100B levels were increased 17% in African Americans (p < 0.003) while sRAGE was mildly decreased (p < 0.09). Abeta42 levels were increased 121% in African Americans (p < 0.02), leading to a 493% increase in the Abeta42/Abeta40 ratio (p < 0.002). Analysis of GDNF levels did not indicate any significant effects. There were no significant effects of gender and no significant ethnicity with gender interactions on any analyte. Effect size calculations indicated "medium" to "very large" effects. CONCLUSION: S100B is typically elevated in AD cases; however, the increased levels in African Americans here may be indicative of increased severity in specific populations. Increased Abeta42/Abeta40 ratios in the current study are compatible with increased disease severity and might indicate increased AD pathogenesis in African Americans. Overall, these results are compatible with a hypothesis of increased neuroinflammation in African Americans with AD. PMID- 28582867 TI - Understanding the Link between Dementia and Diabetes. PMID- 28582868 TI - Dynamic Prediction of Motor Diagnosis in Huntington's Disease Using a Joint Modeling Approach. AB - BACKGROUND: Prediction of motor diagnosis in Huntington's disease (HD) can be improved by incorporating other phenotypic and biological clinical measures in addition to cytosine-adenine-guanine (CAG) repeat length and age. OBJECTIVE: The objective was to compare various clinical and biomarker trajectories for tracking HD progression and predicting motor conversion. METHODS: Participants were from the PREDICT-HD study. We constructed a mixed-effect model to describe the change of measures while jointly modeling the process with time to HD diagnosis. The model was then used for subject-specific prediction. We employed the time dependent receiver operating characteristic (ROC) method to assess the discriminating capability of the measures to identify high and low risk patients. The strongest predictor was used to illustrate the dynamic prediction of the disease risk and future trajectories of biomarkers for three hypothetical patients. RESULTS: 1078 individuals were included in this analysis. Five longitudinal clinical and imaging measures were compared. The putamen volume had the best discrimination performance with area under the curve (AUC) ranging from 0.74 to 0.82 over time. The total motor score showed a comparable discriminative ability with AUC ranging from 0.69 to 0.78 over time. The model showed that decreasing putamen volume was a significant predictor of motor conversion. A web based calculator was developed for implementing the methods. CONCLUSIONS: By jointly modeling longitudinal data with time-to-event outcomes, it is possible to construct an individualized dynamic event prediction model that renews over time with accumulating evidence. If validated, this could be a valuable tool to guide the clinician in predicting age of onset and potentially rate of progression. PMID- 28582869 TI - Postnatal Development of Spasticity Following Transgene Insertion in the Mouse betaIV Spectrin Gene (SPTBN4). AB - BACKGROUND: The L25 mouse line was generated by random genomic insertion of a lens-specific transgene. Inbreeding of L25 hemizygotes revealed an unanticipated spastic phenotype in the hind limbs. OBJECTIVE: The goals were to characterize the motor phenotype in the L25 mice and to map the transgene insert site within the mouse genome. METHODS: Six pairs of L25+/- mice were repeatedly mated. Beginning at weaning, all progeny were inspected for body weight and motor signs twice weekly until they displayed predefined ethical criteria for termination. The transgene insert site was determined by whole genome sequencing. Western blotting was used to compare the expression levels of beta-IV spectrin protein in the brain. RESULTS: Matings of hemizygous L25+/- * L25+/- mice yielded 20% (29/148) affected weanlings, identified by an abnormal retraction of the hind limbs when lifted by the tail, and a fine tremor. Affected mice were less mobile and grew more slowly than wild-type littermates. All affected mice required termination due to >15% loss of body weight (50% survival age 92 days). At the endpoint, mice showed varying degrees of spastic paresis or spastic paralysis localised to the hind limbs. Motor endplates remained fully innervated. Genome sequencing confirmed that the transgene was inserted in the locus of betaIV spectrin of L25 mice. Western blotting indicated that this random insertion had greatly reduced the expression of betaIV spectrin protein in the affected L25 mice. CONCLUSIONS: The results confirm the importance of betaIV spectrin for maintaining central motor pathway control of the hind limbs, and provide a developmental time course for the phenotype. PMID- 28582870 TI - Cutaneous Alpha-Synuclein From Paraffin Embedded Autopsy Specimens in Parkinson's Disease. AB - BACKGROUND: Parkinson disease (PD) is neurodegenerative disorder characterized by tremor, rigidity and bradykinesia and pathologically by the deposition of alpha synuclein within different tissues. We, and others, have reported the detection of cutaneous alpha-synuclein in individuals with PD. OBJECTIVE: The goal of the present study was to detect alpha-synuclein deposition by immunohistochemical staining of skin samples in pathologically confirmed cases of PD. METHODS: Post mortem skin biopsy samples from 11 individuals with PD, and 5 non-synucleinopathy control subjects were paraffin embedded and stained for total alpha-synuclein and protein gene product 9.5. RESULTS: Alpha-synuclein deposition was greater in both scalp and abdominal skin biopsy PD samples compared to control samples in pilomotor nerves (P < 0.05), sudomotor nerves (P < 0.05) and vasomotor nerves (P < 0.05). Deposition of alpha-synuclein in scalp and abdominal tissue did not correlate with age, duration of PD, or severity of PD. CONCLUSIONS: There is greater deposition of alpha-synuclein within pilomotor, sudomotor and vasomotor nerve fibers of paraffin embedded samples from autopsy confirmed cases of PD compared to control samples. However, assessment of alpha-synuclein deposition in post-mortem paraffin embedded tissue has many limitations and the utility of this technique in clinical and research studies is uncertain. PMID- 28582874 TI - The first ever Cochrane event in Russia and Russian speaking countries - Cochrane Russia Launch - Evidence-based medicine: Achievements and barriers (QiQUM 2015) International Conference, Kazan, December 7-8, 2015. AB - Kazan hosted Russia's second International Conference QiQUM 2015 on Cochrane evidence for health policy, which was entirely independent of the pharmaceutical or other health industry, bringing together 259 participants from 11 countries and 13 regions of the Russian Federation. The Conference was greeted and endorsed by world leaders in Evidence-based medicine, health and pharmaceutical information, policy and regulation, and the World Health Organization. Participants discussed the professional and social problems arising from biased health information, unethical pharmaceutical promotion, misleading reporting of clinical trials with consequent flaws in health care delivery and the role of Cochrane evidence for informed decisions and better health. The first in history Cochrane workshop, facilitated jointly by experts from Cochrane and the WHO, with 40 participants from Kazakhstan, Kyrgyzstan, Tajikistan and Russia introduced the concept of Cochrane systematic review and the Use of Cochrane evidence in WHO policy setting. Websites document conference materials and provide interface for future collaboration: http://kpfu.ru/biology-medicine/struktura instituta/kafedry/kfikf/konferenciya/mezhdunarodnaya-konferenciya 39dokazatelnaya.html and http://russia.cochrane.org/news/international conference. PMID- 28582871 TI - Global, Yet Incomplete Overview of Cohort Studies in Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is characterized by heterogeneity and multifactorial longitudinal changes. To identify PD subtypes and factors influencing the disease course, multiple cohort studies have been designed globally. Knowledge about existing cohorts is pivotal to foster collaboration, which may help to advance the understanding of PD. OBJECTIVE: To raise the awareness about PD cohorts and potential global collaboration opportunities. METHODS: Observational cohort studies in clinical PD were identified by a European working group (JPND BioLoC-PD) and through literature search. Using a structured survey investigators of 44 cohorts provided basic information on cohorts and assessments performed. RESULTS: For the 44 cohorts (32% on early/de novo PD), 14.666 participants (cohorts' median: 138; range: 23-3.090), a median 1.5-year follow-up interval (0.5-4 years) and a median (planned) observational period of 5 years (1-20 years) were indicated. All studies have assessed motor functions often using rating scales (UPDRS-III; 93% of studies) and less frequently quantitative gait/balance (25%) or fine motor assessments (27%). Cognitive (100%), neuropsychiatric (91%), daily living (78%), sleep (70%), sensory (63%), and gastrointestinal/autonomic (55%) assessments were common and often comparable. Neuroimaging data (82%) and biomaterial (69%) have been collected in many studies. Surprisingly, possible disease modifiers, such as sport/physical activity (11%), have rarely been assessed. CONCLUSIONS: Existing data of PD cohorts provide vast collaboration opportunities. We propose to establish a comprehensive, up-to-date, open-access internet platform with easy-to use search tools of PD cohort descriptions and potentially available data. Bringing researchers together to enable collaborative joint, meta- and replication analyses is timely and necessary to advance PD research ultimately required for an understanding of PD that can be translated into more effective therapies. PMID- 28582875 TI - Defensive medicine: No wonder policymakers are confused. AB - Discussions regarding defensive medical practice often result in proposals for public policy actions. Such proposals generally are premised on assumptions about defensive medicine, namely, that it (a) is driven by physicians' legal anxieties, (b) constitutes bad medical practice, (c) drives up health care costs, (d) varies depending on a jurisdiction's particular tort law climate, (e) depends on medical specialty and a physician's own prior experience as a malpractice defendant, and (f) is a rational response to actual legal risks confronting physicians. This article examines a sample of recent literature focusing on defensive medicine and finds that the messages conveyed vary widely, helping to explain the confusion experienced by many policymakers trying to improve the quality and affordability of health care. PMID- 28582876 TI - FDA safety actions for antidiabetic drugs marketed in the US, 1980-2015. AB - OBJECTIVES: Concerns about safety and complexity of diabetes treatments have increased overtime. We assessed secular trends in the FDA approvals, market discontinuations, and safety actions of all antidiabetic drugs marketed in the US in the period 1980-2015. METHODS: Regulatory and safety related information about FDA-approved pharmaceuticals for diabetes treatment was collected from the FDA databases, the Orange Book, and Drugs@FDA. Descriptive statistics were performed to describe trends in approvals, discontinuations, and safety actions. RESULTS: The number of insulins and analogue approvals declined after the 1980s; whereas, the approvals of non-insulin antidiabetic drugs increased after 1995. The number of antidiabetic drugs with FDA safety actions significantly increased overtime. Overall, 59.0% of insulins and analogues and 5.7% of non-insulin antidiabetic drugs were discontinued from the market. The FDA released at least one safety action for 7.7% of insulins and analogues and 88.7% of non-insulin antidiabetic drugs. CONCLUSION: Newly approved antidiabetic drugs have raised safety concerns and led to FDA safety regulatory actions including boxed warnings, risk evaluation and mitigation strategies, medication guides, and safety communications to health care providers. There is a need for systematic post marketing studies assessing the long-term safety of antidiabetic drugs to improve patient safety and health outcomes. PMID- 28582877 TI - Common analgesic agents and their role in analgesic nephropathy: A commentary of the evidence. AB - An association between non-opioid analgesic agents and chronic kidney disease has long been suspected. The presumed development of chronic renal impairment following protracted excessive use of non-opioid analgesia is known as analgesic nephropathy. Many accept analgesic nephropathy as a real entity despite a paucity of robust scientific evidence. The weight of available observational literature suggests that long-term ingestion of paracetamol and combination mixtures of aspirin and paracetamol probably contribute to chronic renal impairment, however there is no convincing data to implicate non-steroidal anti-inflammatory drugs or aspirin monotherapy. While controversy persists most physicians consider all non narcotic analgesics nephrotoxic and discourage heavy use where possible. PMID- 28582878 TI - In-hospital use of non-steroidal anti-inflammatory drugs in patients with heart failure in academic centers in the United States. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs are considered potentially harmful for patients with heart failure. OBJECTIVE: To determine the prevalence of in-hospital NSAID use, their type, associated diagnosis and impact in clinical outcomes among patients with a diagnosis of heart failure. METHODS: The University Health System Consortium Database was used to identify all first hospitalizations with an International Classification of Diseases-9 discharge diagnosis code of systolic heart failure as the primary diagnosis between January 1, 2011, and December 31st 2014. RESULTS: Among 65,902 patients admitted for a primary diagnosis of SHF, 2675 (4.1%) were exposed to NSAID. The most frequent NSAID used was ibuprofen (51.63%), followed by ketorolac (29.38%) naproxen (8.07%) celecoxib (5.61%), and others. On multivariable analyses, the length of stay of patients exposed to NSAID was longer compared to non-exposed (OR: 4.67, p < 0.001, 95% CI 4.10-5.25), but differences in mortality were not statistically different (OR: 0.90, p = 0.476, 95% CI 0.69-1.19). CONCLUSION: The use of NSAID in patients admitted with a primary diagnosis of systolic heart failure was low but was associated with longer length of stay. Further studies are needed to understand the impact of NSAID use in this patient population. PMID- 28582879 TI - Measuring patient safety culture in pediatric long-term care. AB - PURPOSE: The purpose of this study was to test the reliability, feasibility and utility of a modified patient safety survey for use in pediatric long term care (pLTC) settings and describe patient safety culture in a sample of providers from pLTC facilities. METHODS: A survey was adapted from the Agency for Healthcare Research and Quality Nursing Home Survey on Patient Safety Culture (PSC-pLTC) and administered to a convenience sample of providers who work in pLTC during an educational workshop in November 2015. RESULTS: Forty-nine respondents from 32 facilities across all 4 U.S. census regions completed the survey. The adapted survey demonstrated excellent face validity, usability, feasibility and internal consistency reliability (Cronbach alpha = 0.94). Highest ratings were given to overall perceptions of safety, feedback and incident communication, supervisors' expectations and actions and management support. Lower ratings were given to dimensions of teamwork, communication, handoffs and transitions, with the lowest ratings given to staffing and organizational learning. Ratings were associated with population and geographic region served. CONCLUSION: This survey to measure patient safety culture adapted for pLTC demonstrated components of reliability and validity, was useable and group discussants were eager for such a measure. PMID- 28582880 TI - The effect of botulinum toxin A (Botox) injections used to treat limb spasticity on speech patterns in children with dysarthria and cerebral palsy: A report of two cases. AB - Botulinum toxin A (Btx-A) injections are used to treat limb spasticity in children with cerebral palsy (CP) resulting in improved gross and fine motor control. This treatment has also been reported to have additional functional effects, but the effect of treatment on speech has not been reported. This report presents results of longitudinal speech evaluation of two children with CP given injections of Btx-A for treatment of limb spasticity. Speech evaluations were accomplished at baseline (date of injections) and 4- and 10-weeks post injections. Improvements in production of consonants, loudness control, and syllables produced per breath were found. Parental survey also suggested improvements in subjects' speech production and willingness to speak outside the testing situation. Future larger studies are warranted to assess the nature of the changes observed related to Btx-A. PMID- 28582881 TI - Participation and community-based walking activity after neuroprosthesis use in children with hemiplegic cerebral palsy: A pilot study1. AB - PURPOSE: To explore the effects of neuroprosthesis use on participation, level of community-based walking activity, safety and satisfaction in children with hemiplegic CP. METHODS: Eleven children (mean 9 years 11 months) with hemiplegic CP Gross Motor Function Classification System (GMFCS) Level I and II participated in a 16-week intervention using the Ness L300 neuroprosthesis. Outcome measures included satisfaction and performance with self-selected participation goals (Canadian Occupational Performance Measure (COPM)), level of community-based walking activity (Step Watch Activity Monitor (SAM)), trip and fall frequency (caregiver report) and a satisfaction questionnaire. RESULTS: Significant (p< 0.001) improvements in performance and satisfaction with self-selected participation goals (COPM) were demonstrated. No significant changes were noted in SAM values. A significant (p= 0.01) decrease in trips was demonstrated from baseline to post. Satisfaction with the device was high. CONCLUSION: Results indicate that daily neuroprosthesis use may improve performance and satisfaction with participation goals and reduce trips. No changes in community-based walking activity were noted. Further study is needed to examine response based on GMFCS levels, across geographical regions and between FES neuroprosthesis and a control group. PMID- 28582882 TI - Pediatric feeding and swallowing rehabilitation: An overview. AB - Children with neurological disabilities frequently have problems with feeding and swallowing. Such problems have a significant impact on the health and well-being of these children and their families. The primary aims in the rehabilitation of pediatric feeding and swallowing disorders are focused on supporting growth, nutrition and hydration, the development of feeding activities, and ensuring safe swallowing with the aim of preventing choking and aspiration pneumonia. Pediatric feeding and swallowing disorders can be divided into four groups: transient, developmental, chronic or progressive.This article provides an overview of the available literature about the rehabilitation of feeding and swallowing disorders in infants and children. Principles of motor control, motor learning and neuroplasticity are discussed for the four groups of children with feeding and swallowing disorders. PMID- 28582883 TI - Evidence to support treatment options for children with swallowing and feeding disorders: A systematic review. AB - PURPOSE: A rise in pediatric patients with swallowing and feeding problems has resulted in increased interest in multidisciplinary treatments to address these issues. This evidence based systematic review (EBSR) examined the published evidence for the use of common strategies used by clinicians across disciplines to treat pediatric swallowing and feeding problems. METHODS: A systematic search of 10 electronic databases was completed to identify relevant, peer reviewed literature published in English prior to December 2015 reporting original data that addressed at least one of the five identified clinical questions. RESULTS: Sixty-one studies of varying methodological quality were included. The majority of the included studies (60/61) focused on the use of behavioral therapies to remediate swallowing and feeding disorders in children and reported mixed findings across all of the targeted outcomes. CONCLUSION: There is insufficient quantity of evidence to determine the effects of oral motor, sensory, and pharmaceutical therapies on functional feeding outcomes in pediatric populations. A larger body of phase 1 evidence is available that establishes the efficacy of behavioral strategies to treat some swallowing and feeding difficulties in small cohort and single subject studies. This analysis identified limited high quality (phase 4) research articles that establish the efficacy and benefit of joint nutrition and behavior intervention programs and systematic desensitization and operant conditioning behavioral therapy approaches to improve functional feeding and swallowing outcomes in children. PMID- 28582884 TI - Impact of functional status and medical comorbidities on tracheostomy decannulation in pediatric patients. AB - PURPOSE: To determine if medical or functional factors influence the ability of a pediatric patient with a tracheostomy to tolerate decannulation. Retrospective evaluation of patients at a tertiary Children's Hospital undergoing evaluation with capped tracheostomy polysomnogram (cPSG) for possible tracheostomy decannulation. Charts were reviewed for demographic information, functional status, cPSG characteristics, and success or failure of decannulation. Statistical analysis was performed to determine which patient factors were predictive of successful decannulation. A total of 139 sleep studies were analyzed in 104 unique children followed for at least 1 year after a cPSG was performed to determine readiness for decannulation. At 1 year after most recent PSG, 79.8% of children were decannulated. There was no significant association between any single comorbid condition and the ability to decannulate. There was no association between individual or total functional status score and successful decannulation. Patients with at least 3 comorbid conditions investigated and a total functional score less than 7 were less likely to be decannulated successfully than other patients (71% vs. 93%, p= 0.04). Functional status and comorbid conditions do not independently predict successful decannulation. Regular multi-disciplinary team reevaluation is indicated in patients with lower functional status, as removal of tracheostomy tube may be successfully accomplished. PMID- 28582885 TI - Home-based Nintendo Wii training to improve upper-limb function in children ages 7 to 12 with spastic hemiplegic cerebral palsy. AB - This pilot study compared a Nintendo Wii intervention to single-joint resistance training for the upper limb in children ages 7 to 12 with spastic hemiplegic cerebral palsy (CP). Children were randomized to Wii training (n= 3), or resistance training (n= 3) and trained at home for 6 weeks. Pre, post and 4-week follow-up measures were collected. Outcome measures were the Melbourne Assessment (MA2), and ABILHAND-Kids, and grip strength. Compliance, motivation and feasibility of each intervention was explored using daily logbook responses and questionnaires. Descriptive statistics were used. Three children improved in the MA2, two of which were in the Wii training group. Improvements in the ABILHAND Kids were minimal for all participants. Grip strength improvements were observed in 3 participants, two of which were in the resistance training group. The Wii training group reported higher compliance and more consistently positive responses to motivation and feasibility questions. Therefore, Wii training may be an effective home-based rehabilitation strategy, and is worth exploring in a larger trial. Implications of Wii training in the context of motivation theory are discussed. PMID- 28582886 TI - Design of a wearable cable-driven upper limb exoskeleton based on epicyclic gear trains structure. AB - BACKGROUND: Many countries, including Japan, Italy, and China are experiencing demographic shifts as their populations age. Some basic activities of daily living (ADLs) are difficult for elderly people to complete independently due to declines in motor function. OBJECTIVE: In this paper, a 6-DOF wearable cable driven upper limb exoskeleton (CABexo) based on epicyclic gear trains structure is proposed. METHODS: The main structure of the exoskeleton system is composed of three epicyclic gear train sections. This new exoskeleton has a parallel mechanical structure to the traditional serial structure, but is stiffer and has a stronger carrying capacity. The traditional gear transmission structure is replaced with a cable transmission system, which is quieter, and has higher accuracy and smoother transmission. RESULTS AND CONCLUSIONS: The static workspace of the exoskeleton is large enough to meet the demand of assisting aged and disabled individuals in completing most of their activities of daily living (ADLs). PMID- 28582888 TI - Effect of different expansion strategies on coronary stent deployment in a tapered artery. AB - BACKGROUND: Vascular stenting has been widely used to treat vessel stenosis. However, long-term successes of the procedure are often compromised by late stent thrombosis (ST) and in-stent restenosis (ISR), especially in tapered arteries. OBJECTIVE: The aim of this study was to choose a reasonable expansion strategy for tapered arteries. METHODS: A balloon-expandable coronary stent deployment in a tapered vessel was numerically studied fol-lowing three strategies: (i) selecting the proximal diameter of the tapered vessel as the reference diameter to expand the stent, (ii) selecting the middle diameter of the tapered vessel as the reference diameter to expand the stent, and (iii) selecting the distal diameter of the tapered vessel as the reference diameter to expand the stent. RESULTS: Computational results showed that the first expansion strategy resulted in the maximum vessel stress and the best stent apposition, while the third strategy resulted in the minimal vessel stress and the worst stent appo-sition. Meanwhile, the second expansion strategy achieved a trade-off between the first and third strategies, leading to acceptable vessel stress and stent apposition. CONCLUSIONS: The second expansion strategy is the most reasonable choice for tapered vessels, and it should be considered when implanting a stent. PMID- 28582887 TI - Effects of pulsed electromagnetic fields on histomorphometry and osteocalcin in disuse osteoporosis rats. AB - OBJECTIVE: Bone histomorphometry and the concentration of the serum osteocalcin expression were observed in disuse osteoporosis (DOP) rats in order to explore the mechanism of pulsed electromagnetic fields in treating DOP. METHODS: Female SD rats, weighing 250 ~ 280 g, were randomly divided into 4 groups: a control group and three experimental groups. The right hindlimbs of all the rats were immobilized by tibia-tail fixation, except for those in the INT group. The ALN group rats were given an alendronate sodium (1 mg kg-1 d-1) treatment, and the rats in the PEMF group received PEMF irradiation. Bone histomorphometry and the concentration of serum osteocalcin expression were detected in 2, 4, 8, and 12 weeks. RESULTS: Four weeks after modeling, as compared with the DOP group, the %Tb-Ar and Tb-N in the ALN group were increased, and the difference was significant (P< 0.05 or P< 0.01). At 8 weeks, as compared with the DOP group, the %Tb-Ar and Tb-N in the ALN group and the PEMF group both increased, and there was a significant difference (P< 0.05 or P< 0.01). At 12 weeks, as compared with the DOP group, the BGP serum concentration of the ALN group was reduced, and there was a statistical difference (P< 0.05). CONCLUSION: Pulse electromagnetic field with drug can prevent disuse osteoporosis by changing the bone microstructure. In the long run, PEMF improves the mechanical performance of biological structures better than alendronate sodium does. PEMF may influence the process of bone remodeling by promoting the level of osteocalcin. PMID- 28582889 TI - Mastication noise reduction method for fully implantable hearing aid using piezo electric sensor. AB - BACKGROUND: Fully implantable hearing devices (FIHDs) can be affected by generated biomechanical noise such as mastication noise. OBJECTIVE: To reduce the mastication noise using a piezo-electric sensor, the mastication noise is measured with the piezo-electric sensor, and noise reduction is practiced by the energy difference. METHODS: For the experiment on mastication noise, a skull model was designed using artificial skull model and a piezo-electric sensor that can measure the vibration signals better than other sensors. A 1 kHz pure-tone sound through a standard speaker was applied to the model while the lower jawbone of the model was moved in a masticatory fashion. RESULTS: The correlation coefficients and signal-to-noise ratio (SNR) before and after application of the proposed method were compared. It was found that the signal-to-noise ratio and correlation coefficients increased by 4.48 dB and 0.45, respectively. CONCLUSION: The mastication noise is measured by piezo-electric sensor as the mastication noise that occurred during vibration. In addition, the noise was reduced by using the proposed method in conjunction with MATLAB. In order to confirm the performance of the proposed method, the correlation coefficients and signal-to noise ratio before and after signal processing were calculated. In the future, an implantable microphone for real-time processing will be developed. PMID- 28582890 TI - Mechanical and physiological effect of partial pressure suit: Experiment and numerical study. AB - BACKGROUND: During high-altitude flight, the protection of the pilot is vital. A partial pressure suit may affect human physiology, especially circulatory physiology. OBJECTIVE: The purpose of this study was to investigate how a partial pressure suit works. METHOD: Ten subjects took part in the flight simulation experiments. Counter pressure at the chest, abdomen, thigh and shank were detected, together with physiological parameters such as heart rate (HR), mean arterial pressure (MAP), stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR). A numerical model was also established to simulate hemo-physiological effects of the partial pressure suit. RESULTS: The experiment's results show the non-uniform counter pressure distribution in different parts of the body. There is a linear, proportional relation between TPR and the pressurizing level. HR and MAP increase along with that of the pressure level. SV and CO decrease with the increase of the pressure level. The numerical model simulated the physiological effect of a partial pressure suit. The results were verified by experiment data. The simulation estimated the change of blood flow with the pressure level. CONCLUSIONS: The numerical model provides a potential way to improve the protection of pilots. PMID- 28582891 TI - Study on the control of variable resistance for isokinetic muscle training system. AB - BACKGROUND: Isokinetic muscle strength training is presently the most advanced method of muscle strength training. However, the existing control schemes of the training equipment are usually limited to the structure of the brake. OBJECTIVE: In order to solve this problem, this paper presents a solution to an isokinetic system based on the force control of a DC servomotor. METHODS: A new fuzzy impedance nonlinear controller is designed by analyzing the relevant requirements of isokinetic motion. A series of force tracking comparison experiments between a fuzzy PI controller and a classical PI controller are studied. In addition, some strength training experiments employing different driving forces and target speeds are also conducted. RESULTS: The results demonstrate the effectiveness of this fuzzy impedance force tracking control strategy. CONCLUSION: Using the aforementioned methods, a comprehensive motion algorithm was designed. PMID- 28582892 TI - Comparative analysis of the stress distribution in five anatomical types of maxillary central incisor. AB - BACKGROUND: The maxillary central incisor is one of the most important anatomical indicators in esthetics, and stress distribution may vary among its five anatomical views (labial, palatal, mesial, distal, and incisal). OBJECTIVE: To compare stress distribution among the five anatomical views of the maxillary central incisor under loading force at five angles and to observe and analyze the stress distribution in the dentin and periodontal ligament. METHODS: We established three-dimensional finite element models of the five different views, which simulated the bite force with a static load force at 0?, 30?, 45?, 60?, and 90?. The stress and displacement values for the cementoenamel junction (CEJ) apical labial, palatal, mesial, and distal and the equivalent stress values on the periodontal ligament of the maxillary central incisor were calculated. RESULTS: As the angle increased, the equivalent stress on the periodontal ligament, overall tooth displacement, equivalent stress, and displacement over the four views increased. The peaks of equivalent stress over the four views appeared within 0.8-17 mm below the CEJ, although all equivalent stress values decreased while approaching the peak. Within 1-19 mm below the CEJ, the equivalent stress over the M1 and P1 views of the maxillary central incisor decreased substantially. CONCLUSION: The peaks of the equivalent stress over the M1 and P1 views of the maxillary central incisor and their stress distribution were lower than those of the other three types. Our findings provided theoretical data on the biomechanics of this esthetically important tooth, which may be useful during implantation of missing maxillary central incisors. PMID- 28582893 TI - Numerical analysis of urine flow through the side holes of a double J stent in a ureteral stenosis. AB - Ureteral stenosis presents with a narrowing in the ureter, due to an intrinsic or extrinsic ureteral disease, such as ureter cancer or retroperitoneal fibrosis. The placement of a double J stent in the upper urinary system is one of the most common treatments of ureteral stenosis, along with the insertion of a percutaneous nephrostomy tube into the renal pelvis. The effect that the side holes in a double J stent have on urine flow has been evaluated in a few studies using straight ureter models. In this study, urine flow through a double J stent's side holes was analyzed in curved ureter models, which were based on human anatomy. In ureteral stenosis, especially in severe ureteral stenosis, a stent with side holes had a positive effect on the luminal and total flow rates, compared with the rates for a stent without side holes. The more side holes a stent has, the greater the luminal and total flow rates. However, the angular positions of the side holes did not affect flow rate. In conclusion, the side holes in a double J stent had a positive effect on ureteral stenosis, and the effect became greater as the ureteral stenosis became more severe. PMID- 28582894 TI - A study on trunk muscle activation patterns according to tilt angle during whole body tilts. AB - BACKGROUND: Lower back pain has a lifetime prevalence of 80% for people in a modern society, and in recent years, spinal stabilization movement has been highlighted as a method to treat lower back pain and an unbalanced position. OBJECTIVE: The objectives of this study were to assess the trunk muscle activities in accordance with the tilt angles (10?, 20?, 30?, 40?) during trunk tilt exercises with a 3D dynamic exercise device. METHODS: Active tilt mode (a self-generated active movement in the angle and direction steered by the user) was used in this study. The rotation capability enabled the investigation of the anterior (A), anterior right (AR), right (R), posterior right (PR), posterior (P), posterior left (PL), left (L), and anterior left (AL) tilt directions. EMG signals of the trunk (3 global muscles: rectus abdominis, RA, external obliques, EO, latissimus dorsi, LD, and 1 local muscle: multifidus, MF) muscles were obtained. RESULTS: The MF muscle activity was higher while the anterior tilt was maintained, and the abdominal muscle activity was higher while the posterior tilt was maintained. Also, as the tilt angle increased, the activity of the muscles opposite the tilt direction increased. CONCLUSIONS: The results indicate that to maintain equilibrium through posture stabilization during whole body tilting, the human body maintains a proper interaction among the body segments as well as between the body and the execution environment. Moreover, stability is maintained through the co-contraction of antagonistic and agonistic muscles. In future studies, it will be important to conduct research on improving imbalance in the trunk muscles. PMID- 28582895 TI - Implementation of integrated circuit and design of SAR ADC for fully implantable hearing aids. AB - BACKGOUND: The hearing impaired population has been increasing; many people suffer from hearing problems. To deal with this difficulty, various types of hearing aids are being rapidly developed. In particular, fully implantable hearing aids are being actively studied to improve the performance of existing hearing aids and to reduce the stigma of hearing loss patients. It has to be of small size and low-power consumption for easy implantation and long-term use. OBJECTIVE: The objective of the study was to implement a small size and low-power consumption successive approximation register analog-to-digital converter (SAR ADC) for fully implantable hearing aids. METHODS: The ADC was selected as the SAR ADC because its analog circuit components are less required by the feedback circuit of the SAR ADC than the sigma-delta ADC which is conventionally used in hearing aids, and it has advantages in the area and power consumption. So, the circuit of SAR ADC is designed considering the speech region of humans because the objective is to deliver the speech signals of humans to hearing loss patients. If the switch of sample and hold works in the on/off positions, the charge injection and clock feedthrough are produced by a parasitic capacitor. These problems affect the linearity of the hold voltage, and as a result, an error of the bit conversion is generated. In order to solve the problem, a CMOS switch that consists of NMOS and PMOS was used, and it reduces the charge injection because the charge carriers in the NMOS and PMOS have inversed polarity. So, 16 bit conversion is performed before the occurrence of the Least Significant Bit (LSB) error. In order to minimize the offset voltage and power consumption of the designed comparator, we designed a preamplifier with current mirror. Therefore, the power consumption was reduced by the power control switch used in the comparator. RESULTS: The layout of the designed SAR ADC was performed by Virtuoso Layout Editor (Cadence, USA). In the layout result, the size of the designed SAR ADC occupied 124.9 MUm * 152.1 MUm. The circuit verification was performed by layout versus schematic (LVS) and design rule check (DRC) which are provided by Calibre (Mentor Graphics, USA), and it was confirmed that there was no error. The designed SAR ADC was implemented in SMIC 180 nm CMOS technology. The operation of the manufactured SAR ADC was confirmed by using an oscilloscope. The SAR ADC output was measured using a distortion meter (HM 8027), when applying pure tone sounds of 94 dB SPL at 500, 800, and 1600 Hz regions. As a result, the THD performance of the proposed chip was satisfied with the ANSI. s3. 22. 2003 standard. CONCLUSIONS: We proposed a low-power 16-bit 32 kHz SAR ADC for fully implantable hearing aids. The manufactured SAR ADC based on this design was confirmed to have advantages in power consumption and size through the comparison with the conventional ADC. Therefore, the manufactured SAR ADC is expected to be used in the implantable medical device field and speech signal processing field, which require small size and low power consumption. PMID- 28582896 TI - Adaptive locomotor network activation during randomized walking speeds using functional near-infrared spectroscopy. AB - BACKGROUND: An improved understanding of the mechanisms underlying locomotor networks has the potential to benefit the neurorehabilitation of patients with neurological locomotor deficits. However, the specific locomotor networks that mediate adaptive locomotor performance and changes in gait speed remain unknown. OBJECTIVE: The aim of the present study was to examine patterns of cortical activation associated with the walking speeds of 1.5, 2.0, 2.5, and 3.0 km/h on a treadmill. METHODS: Functional near-infrared spectroscopy (fNIRS) was performed on a 30-year-old right-handed healthy female subject, and cerebral hemodynamic changes were observed in cortical locomotor network areas including the primary sensorimotor cortex (SMC), premotor cortex (PMC), supplementary motor area (SMA), prefrontal cortex (PFC), and sensory association cortex (SAC). The software package NIRS-statistical parametric mapping (NIRS-SPM) was utilized to analyze fNIRS data in the MATLAB environment. SPM t-statistic maps were computed at an uncorrected threshold of p< 0.00001. RESULTS: At faster walking speeds, oxygenated hemoglobin (OxyHb) was concentrated in the PFC and indicated globalized locomotor network activation of the SMC, PMC, SMA, and PMC; additionally, the site with the highest cortical activation ratio shifted from the SMC to the SMA. CONCLUSIONS: Global locomotor network recruitment, in particular PFC activation indicated by OxyHb in our study, may indicate a response to increased cognitive-locomotor demand due to simultaneous postural maintenance and leg movement coordination. PMID- 28582897 TI - Reflex-mediated dynamic neuromuscular stabilization in stroke patients: EMG processing and ultrasound imaging. AB - BACKGROUND: Postural core instability is associated with poor dynamic balance and a high risk of serious falls. Both neurodevelopmental treatment (NDT) and dynamic neuromuscular stabilization (DNS) core stabilization exercises have been used to improve core stability, but the outcomes of these treatments remain unclear. OBJECTIVE: This study was undertaken to examine the therapeutic effects of NDT and DNS core stabilization exercises on muscular activity, core stability, and core muscle thickness. METHODS: Ten participants (5 healthy adults; 5 hemiparetic stroke patients) were recruited. Surface electromyography (EMG) was used to determine core muscle activity of the transversus abdominis/internal oblique (TrA/IO), external oblique (EO), and rectus abdominis (RA) muscles. Ultrasound imaging was used to measure transversus abdominals/internal oblique (TrA/IO) thickness, and a pressure biofeedback unit (PBU) was used to measure core stability during the DNS and NDT core exercise conditions. Data are reported as median and range and were compared using nonparametric Mann - Whitney U test and Wilcoxon signed rank test at p< 0.05. RESULTS: Both healthy and hemiparetic stroke groups showed greater median EMG amplitude in the TrA/IO muscles, core stability, and muscle thickness values during the DNS exercise condition than during the NDT core exercise condition, respectively (p< 0.05). However, the relative changes in the EMG amplitude, core stability, and muscle thickness values were greater during the DNS exercise condition than during the NDT core exercise condition in the hemiparetic stroke patient group (p< 0.05). CONCLUSIONS: Our novel results provide the first clinical evidence that DNS is more effective than NDT in both healthy and hemiparetic stroke subjects to provide superior deep core muscle activation, core stabilization, and muscle thickness. Moreover, such advantageous therapeutic benefits of the DNS core stabilization exercise over the NDT exercise were more apparent in the hemiparetis stroke patients than normal controls. PMID- 28582898 TI - Dosimetric comparisons of IMRT planning using MCO and DMPO techniques. AB - The goal of this study was to evaluate the use of multi-criteria optimization (MCO) in the planning and optimization of intensity-modulated radiotherapy (IMRT). Twenty (20) IMRT patients (ten (10) with prostate cancer and ten (10) with lung cancer) were randomly selected. The treatment plans for these patients were designed using direct machine parameter optimization (DMPO). Based on these plans, new plans were designed using multi-criteria optimization (MCO), keeping the optimization objectives and constraints unchanged. Comparisons were made between the new plans, which were based on MCO and DMPO, including the dose distribution, dose volume histogram (DVH), the optimization time and the number of monitor units (MUs). The plan designed using both optimization approaches satisfied all clinical requirements. For similar or better target coverage, the rectum, bladder and small bowel were better protected using MCO than when using DMPO. Additionally, MCO reduced the time for optimization by 58% on average, whereas the MUs increased the time for optimization by 32% on average for prostate cancer. For lung cancer cases, the entire lung, heart and spinal cord were better protected using MCO compared to DMPO. Similarly, MCO reduced the time for optimization by 59% on average, whereas the MUs increased the time for optimization by 11% on average. Compared to DMPO, MCO reduces the dose of the organs at risk (OAR) and shortens the time required for optimization. PMID- 28582899 TI - Effect of whole body vibration on lactate level recovery and heart rate recovery in rest after intense exercise. AB - OBJECTIVE: In this paper, we investigated the recovery of the lactate level, muscular fatigue, and heart rate recovery (HRR) with respect to whole body vibration (WBV) during the rest stage after a gait exercise. METHODS: A total of 24 healthy subjects with no medical history of exercise injury participated. The participants were divided into a training group with vibration during rest and a control group with the same conditions but without vibration. The subjects performed a gait exercise with a slope of 15% and velocity of 4 km/h to consume 450 kcal in 30 min. Then, they rested on a vibrating chair or on a chair without vibrations for 30 min. The vibration protocol consists of a frequency of 10 Hz and amplitude of 5 mm. To estimate the recovery effect, we measured the lactate levels in blood, spectral edge frequency (SEF) of MVIC, and HRR before, immediately after exercise, and after rest. RESULTS: The results showed that the lactate level in the training group decreased more (93.8%) than in the control group (32.8%). Also, HRR showed a similar trend with a recovery of 88.39% in the training group but 64.72% in the control group. We considered that whole-body vibrations during rest would help remove lactic acid by improving the level of lactic acid oxidation with stimulated blood vessels in the muscles and by helping to maintain blood flow. Also, WBV would lead to compensation to actively decrease the fast excess post-exercise oxygen consumption from blood circulation. CONCLUSIONS: We suggest that whole-body vibrations during rest can provide fast, efficient fatigue recovery as a cool down exercise for women, the elderly, and patients without other activity after intense exercise. PMID- 28582900 TI - Computer-aided detection for the automated evaluation of pulmonary embolism. AB - BACKGROUND: There are few quantitative studies that directly evaluate methods of determining pulmonary embolism (PE). New computer-aided detection (CAD) methods for measuring PE may help in defining the relationship of PE to right heart failure (RHF). OBJECTIVES: We used CAD to investigate the severity of PE and explored whether the severity of PE was associated with RHF. METHODS: A fully automatic calculation conducted by CAD was made of the embolism area/lumen area, which was used to evaluate the severity of the PE. The vascular obstruction index (VOI) was also used to evaluate PE, using the Mastora and Qanadli scores. Paired t tests were used to compare the severity of PE evaluated by Mastora or Qanadli score, to the severity determined by CAD. Correlation between the severity of the PE and RHF was also evaluated by Spearman's rank correlation analysis. RESULTS: There was no significant difference between the PE evaluated by Mastora compared with the measurement by CAD (P= 0.720), and also no difference between evaluation by Qanadli and automatic measurement by CAD (P= 0.617). The severity of PE evaluated by Mastora, Qanadli, and CAD had significant positive correlation with RHF (R= 0.75 P= 0.01, R= 0.69 P= 0.02, R= 0.80 P= 0.00). CONCLUSION: We found strong correlation between RHF and the severity of PE evaluated by CAD, and the method was found to be simple and reliable. PMID- 28582902 TI - Research on highly sensitive optomagnetic sensor for rapid detection of inflammation. AB - BACKGROUND: C-reactive protein (CRP) is used to evaluate the evolution of infections and sepsis in critically ill patients. For POCT testing, biosensor based detection techniques offer quick and convenient application. OBJECTIVE: A prototype three dimensional chip was fabricated based on a new optomagnetic method to achieve the rapid detection of CRP. METHODS: This work investigates a new technology for the quick quantitative detection of the C-reactive protein (CRP) by total internal reflection magnetic imaging (TIRMI) on a three dimensional optomagnetic sensor. Transparent glass and hydrophilic plastic film with channels were used to construct the three dimensional sensor. The magnetic nanoparticles and immunological reagent were immobilized on the reaction area of the sensor. Samples were detected using total internal reflection magnetic spot imaging (TIRMI) based on a sandwich magnetic immunoassay by one-step assay. RESULTS: The developed 3D biosensor-TIRMI method showed a wide dynamic linear range (0.2-200 ng/ml) and quick detection (5 min) with low-sample volume (10 MUL). CONCLUSIONS: We have presented a three dimensional optical protein chip that fulfills the demanding for point-of-care diagnostics in terms of ease-of-use (one step assay), miniaturization, assay time. This approach shows great promise for application in clinical investigations of biological samples. PMID- 28582901 TI - Objective research on tongue manifestation of patients with eczema. AB - BACKGROUND: Tongue observation often depends on subjective judgment, it is necessary to establish an objective and quantifiable standard for tongue observation. OBJECTIVE: To discuss the features of tongue manifestation of patients who suffered from eczema with different types and to reveal the clinical significance of the tongue images. METHODS: Two hundred patients with eczema were recruited and divided into three groups according to the diagnostic criteria. Acute group had 47 patients, subacute group had 82 patients, and chronic group had 71 patients. The computerized tongue image digital analysis device was used to detect tongue parameters. The L*a*b* color model was applied to classify tongue parameters quantitatively. RESULTS: For parameters such as tongue color, tongue shape, color of tongue coating, and thickness or thinness of tongue coating, there was a significant difference among acute group, subacute group and chronic group (P< 0.05). For Lab values of both tongue and tongue coating, there was statistical significance among the above types of eczema (P< 0.05). CONCLUSIONS: Tongue images can reflect some features of eczema, and different types of eczema may be related to the changes of tongue images. The computerized tongue image digital analysis device can reflect the tongue characteristics of patients with eczema objectively. PMID- 28582903 TI - Magnetic stimulation at acupoints relieves mental fatigue: An Event Related Potential (P300) study. AB - BACKGROUND: Mental fatigue caused by continuous cognitive tasks represents one of the most worrying modern health problems. Event Related Potential (ERP) P300 is thought to be associated with cognitive function. OBJECTIVE: This study aimed at characterizing the neural activity correlated with the attentional processes and exploring a novelty method which combine the magnetic stimulation and acupoint to relieve mental fatigue caused by continuous cognitive tasks. METHODS: P300 (P3a and P3b) were extracted at three points: when subjects felt relaxed, at the point of mental fatigue, and after the subjects were stimulated at acupoints. The amplitudes and latencies of P3a and P3b were analyzed statistically. RESULTS: Among the four features (P3a amplitude, P3a latency, P3b amplitude, and P3b latency), only P3b amplitude was found to have a significant difference between the resting state and the mental fatigue state. And P3b amplitude significantly increased after magnetic stimulation at the acupoints. CONCLUSIONS: Subjects experiencing mental fatigue demonstrated a significant decrease in P3b amplitude in the parietal region, suggesting attenuation of resource allocation for selective attention. P3b amplitude significantly increased after magnetic stimulation at acupoints indicating that this strategy can be used to improve selective attention and relieve mental fatigue. PMID- 28582904 TI - A method and system to simulate human electrophysiological activity. AB - Accurate electrophysiological diagnosis relies on high precision and well calibrated instruments. A method to simulate the human electrophysiological activity is proposed and a simulation system is developed, as a calibration tool for electrophysiological inspectors. The system performance is tested by calibrating the amplitude and the latency of a commercial visual electrophysiological instrument. Several typical simulating signals are tested. The minimum amplitude of the simulating signal can be lower than 1 MUV. Measurement errors and uncertainties are calculated. The traceability of the measurement results to metrological standards is also demonstrated. It is proved by experimental results that the system can generate simulating signals with different waveforms and variable parameters and it can be used to simulate the human visual electrophysiological activities. With simple modifications to the simulation system, it can also be used to calibrate other electrophysiological inspectors. PMID- 28582905 TI - A comparative study on the mechanical behavior of intervertebral disc using hyperelastic finite element model. AB - BACKGROUND: Lumbar disc herniation may result in excruciating pain due to it being one of the most common diseases related to changes of intervertebral disc (IVD). In order to find a better clinical treatment and prevention scheme for relieving the pain caused by spine degeneration, the mechanical behavior analysis of IVD must be studied. OBJECTIVE: A finite element method (FEM) is used in this study to analyze the mechanical behaviors of healthy and herniated IVD. METHOD: In order to compare the responses of IVD under different loading conditions for the annulus fibrosus of IVD, the hyperelastic and elastic constitutive FE models were used in the FEM. RESULTS: The comparison shows that hyperelastic FE models have a much better capability to describe the mechanical behaviors of the IVD than elastic FE models. It can be found from FE simulation that there was a higher stress concentration at the annulus fibrosus of the herniated disc than the healthy disc. CONCLUSIONS: Higher stress concentration resulted in more damage and ease of bringing out lumbar disc herniation. Numerical examples of FE simulation indicate that the FEM with hyperelastic constitutive model has very good capability for analyzing the mechanical behaviors of IVD. PMID- 28582906 TI - Paroxysmal atrial fibrillation recognition based on multi-scale Renyi entropy of ECG. AB - BACKGROUND: Atrial fibrillation (AF) is a common type of arrhythmia disease, which has a high morbidity and can lead to some serious complications. The ability to detect and in turn prevent AF is extremely significant to the patient and clinician. OBJECTIVE: Using ECG to detect AF and develop a robust and effective algorithm is the primary objective of this study. METHODS: Some studies show that after AF occurs, the regulatory mechanism of vagus nerve and sympathetic nerve will change. Each R-R interval will be absolutely unequal. After studying the physiological mechanism of AF, we will calculate the Renyi entropy of the wavelet coefficients of heart rate variability (HRV) in order to measure the complexity of PAF signals, as well as extract the multi-scale features of paroxysmal atrial fibrillation (PAF). RESULTS: The data used in this study is obtained from MIT-BIH PAF Prediction Challenge Database and the correct rate in classifying PAF patients from normal persons is 92.48%. CONCLUSIONS: The results of this experiment proved that AF could be detected by using this method and, in turn, provide opinions for clinical diagnosis. PMID- 28582907 TI - Mining association rules between stroke risk factors based on the Apriori algorithm. AB - BACKGROUND: Stroke is a frequently-occurring disease and is a severe threat to human health. OBJECTIVE: We aimed to explore the associations between stroke risk factors. METHODS: Subjects who were aged 40 or above were requested to do surveys with a unified questionnaire as well as laboratory examinations. The Apriori algorithm was applied to find out the meaningful association rules. Selected association rules were divided into 8 groups by the number of former items. The rules with higher confidence degree in every group were viewed as the meaningful rules. RESULTS: The training set used in association analysis consists of a total of 985,325 samples, with 15,835 stroke patients (1.65%) and 941,490 without stroke (98.35%). Based on the threshold we set for the Apriori algorithm, eight meaningful association rules were obtained between stroke and its high risk factors. While between high risk factors, there are 25 meaningful association rules. CONCLUSIONS: Based on the Apriori algorithm, meaningful association rules between the high risk factors of stroke were found, proving a feasible way to reduce the risk of stroke with early intervention. PMID- 28582908 TI - The collagen microstructural changes of rat menisci and tibiofemoral cartilages under the influence of mechanical loading: An in vitro wear test of whole joints. AB - BACKGROUND: Knee osteoarthritis (OA) is suggested to be induced by multi-factors, and mechanical environment is regarded as a risky factor. OBJECTIVE: To investigate the effect of isolated mechanical factor on cartilage. METHODS: An active wear test system was designed to perform parameters-controlled in vitro wear tests on rat knee joints with specific load magnitude, flexion-extension angle, and movement frequency. Six hind limbs of 9-month-old male Sprague-Dawley rats, with an additional spring on the medial side, were worn by using the custom designed apparatus. Researchers observed both the menisci and tibial cartilages of these hind limbs using multiphoton laser scanning microscopy to analyze the change of the collagen microstructure caused by wear. RESULTS: Collagen microstructure of both the medial and lateral meniscus became disordered under cyclic load. Some tissues on the surface of the medial tibial cartilage were removed and the middle layer of the medial compartment displayed cracks. On the contrary, the lateral tibial cartilage was intact. CONCLUSIONS: The results implied that cyclic load caused menisci microstructure disarrangement prior to tibial cartilage damage and the collagen structure of mid-layer tibial cartilage failed before that of the superficial layer under the kinematics adopted in the study. PMID- 28582909 TI - Measuring the 3D motion space of the human ankle. AB - BACKGROUND: The 3D motion space of the human ankle is an important area of study in medicine. The 3D motion space can provide significant information for establishing more reasonable rehabilitation procedures and standards of ankle injury care. OBJECTIVE: This study aims to measure the 3D motion space of the human ankle and to use mathematical methods to quantify it. METHODS: A motion capturing system was used to simultaneously capture the 3D coordinates of points marked on the foot, and convert these coordinate values into rotation angles through trigonometric functions and vectors. The mathematical expression of the ankle's motion space was obtained by screening, arranging, and fitting the converted data. RESULTS: The mathematical expression of the 3D motion space of the participants was obtained. We statistically analyzed the data and learned that, in terms of 3D motion space, the right foot is more flexible than the left foot and the female foot is more flexible than the male foot. CONCLUSIONS: The adduction and abduction rotation ranges are affected by the plantar flexion or dorsal flexure rotation angles. This relationship can be expressed mathematically, which is significant in the study of the ankle joint. PMID- 28582910 TI - ChainMail based neural dynamics modeling of soft tissue deformation for surgical simulation. AB - BACKGROUND: Realistic and real-time modeling and simulation of soft tissue deformation is a fundamental research issue in the field of surgical simulation. OBJECTIVE: In this paper, a novel cellular neural network approach is presented for modeling and simulation of soft tissue deformation by combining neural dynamics of cellular neural network with ChainMail mechanism. METHOD: The proposed method formulates the problem of elastic deformation into cellular neural network activities to avoid the complex computation of elasticity. The local position adjustments of ChainMail are incorporated into the cellular neural network as the local connectivity of cells, through which the dynamic behaviors of soft tissue deformation are transformed into the neural dynamics of cellular neural network. RESULTS: Experiments demonstrate that the proposed neural network approach is capable of modeling the soft tissues' nonlinear deformation and typical mechanical behaviors. CONCLUSIONS: The proposed method not only improves ChainMail's linear deformation with the nonlinear characteristics of neural dynamics but also enables the cellular neural network to follow the principle of continuum mechanics to simulate soft tissue deformation. PMID- 28582911 TI - The curvature calculation mechanism based on simple cell model. AB - A conclusion has not yet been reached on how exactly the human visual system detects curvature. This paper demonstrates how orientation-selective simple cells can be used to construct curvature-detecting neural units. Through fixed arrangements, multiple plurality cells were constructed to simulate curvature cells with a proportional output to their curvature. In addition, this paper offers a solution to the problem of narrow detection range under fixed resolution by selecting an output value under multiple resolution. Curvature cells can be treated as concrete models of an end-stopped mechanism, and they can be used to further understand "curvature-selective" characteristics and to explain basic psychophysical findings and perceptual phenomena in current studies. PMID- 28582912 TI - Time course of EEG activities in continuous tracking task: A pilot study. AB - BACKGROUND: Motor learning is important in daily activities and rehabilitation, but its neural mechanism has been only investigated using some simple tasks with limited motor involvement. OBJECTIVE: This study aimed to gain better understanding of the neural dynamics during motor learning by investigating the time course of electroencephalogram (EEG) activities in the continuous tracking task with more motor components. METHODS: One participant performed 16 trials of the continuous tracking task on Day1 and Day2 respectively. The 16-channel EEG signals were recorded and analyzed in both the resting and active states. RESULTS: The tracking performance improved from Day1 to Day2. Regarding the EEG, it was found that the relative amplitude in the individual alpha band (IAB) decreased locally over primary motor cortex from the resting state to the active state on both days, and this reduction was more focused on the left primary motor cortex on Day2 compared to Day1. Moreover, in the active state the alpha coherence between central and frontal areas also significantly increased from Day1 to Day2. CONCLUSION: Time course of alpha activities may explain the tracking performance enhancement from Day1 to Day2. Future work will include more participants to extend the validity of current results. PMID- 28582913 TI - The improved differential demon algorithm. AB - BACKGROUND: Differential demon is a fast and efficient registration algorithm. It drives the floating image to deform using the force based on the gradient between the reference and floating image. But it will cause abnormal deformation when the driving force approaches zero,which limits its practical applications. OBJECTIVE: This paper proposed an improved differential demon algorithm, which aimed to enhance the registration performance of the existing demon algorithm. METHODS: Firstly, we review the original differential demon algorithm. Then, we propose an improved differential demon algorithm and the process of mathematical deduction. Finally, we use experiment to prove that the improved differential demon algorithm is effective and it can improve the accuracy of registration. RESULTS: We tested our method on data sets provided by Xuanwu Hospital Capital Medical University. The registration performance proved to be better than the original demon algorithm in terms of mutual information, normalized correlation coefficient, mean square error and iteration number. CONCLUSIONS: Experiment results demonstrate the superiority of method proposed in this paper to the original demon algorithm. PMID- 28582914 TI - The incidence and distribution characteristics of MLL rearrangements in Chinese acute myeloid leukemia patients by multiplex nested RT-PCR. AB - Occurrence of MLL (Mixed Lineage Leukemia) gene rearrangements indicates poor prognosis in acute myeloid leukemia (AML) patients. This is the first study to report the positive rate and distribution characteristics of MLL rearrangements in AML patients in north China. We used multiplex nested real time PCR (RT-PCR) to screen for incidence of 11 MLL rearrangements in 433 AML patients. Eleven MLL rearrangements included (MLL-PTD, MLL-AF9, MLL-ELL, MLL-AF10, MLL-AF17, MLL-AF6, MLL-ENL, MLL-AF1Q, MLL-CBP, MLL-AF1P, MLL-AFX1). There were 68 AML patients with MLL rearrangements, and the positive rate was 15.7%. MLL-PTD (4.84%) was detected in 21 patients, MLL-AF9 in 15, (3.46%), MLL-ELL in 10 (2.31%), MLL-AF10 in 8 (1.85%), MLL-AF1Q in 2 (0.46%), 3 cases each of MLL-AF17, MLL-AF6, MLL-ENL (0.69% each), a and single case each of MLL-CBP, MLL-AF1P, and MLL-AFX1 (0.23% each). The highest rate of MLL rearrangements was found in 24 patients with M5 subtype AML, occurring in 24 cases (35.3%). MLL rearrangements occurred in 21 patients with M2 subtype AML (30.9%), and in 10 patients with M4 subtype AML (14.7%). Screening fusion genes by multiplex nested RT-PCR is a convenient, fast, economical, and accurate method for diagnosis and predicting prognosis of AML. PMID- 28582915 TI - Biomechanical design of escalading lower limb exoskeleton with novel linkage joints. AB - In this paper, an obstacle-surmounting-enabled lower limb exoskeleton with novel linkage joints that perfectly mimicked human motions was proposed. Currently, most lower exoskeletons that use linear actuators have a direct connection between the wearer and the controlled part. Compared to the existing joints, the novel linkage joint not only fitted better into compact chasis, but also provided greater torque when the joint was at a large bend angle. As a result, it extended the angle range of joint peak torque output. With any given power, torque was prioritized over rotational speed, because instead of rotational speed, sufficiency of torque is the premise for most joint actions. With insufficient torque, the exoskeleton will be a burden instead of enhancement to its wearer. With optimized distribution of torque among the joints, the novel linkage method may contribute to easier exoskeleton movements. PMID- 28582916 TI - The force control and path planning of electromagnetic induction-based massage robot. AB - BACKGROUND: Massage robot is considered as an effective physiological treatment to relieve fatigue, improve blood circulation, relax muscle tone, etc. The simple massage equipment quickly spread into market due to low cost, but they are not widely accepted due to restricted massage function. Complicated structure and high cost caused difficulties for developing multi-function massage equipment. OBJECTIVE: This paper presents a novel massage robot which can achieve tapping, rolling, kneading and other massage operations, and proposes an improved reciprocating path planning algorithm to improve massage effect. METHODS: The number of coil turns, the coil current and the distance between massage head and yoke were chosen to investigate the influence on massage force by finite element method. The control system model of the wheeled massage robot was established, including control subsystem of the motor, path algorithm control subsystem, parameter module of the massage robot and virtual reality interface module. The improved reciprocating path planning algorithm was proposed to improve regional coverage rate and massage effect. RESULTS: The influence caused by coil current, the number of coil turns and the distance between massage head and yoke were simulated in Maxwell. It indicated that coil current has more important influence compared to the other two factors. The path planning simulation of the massage robot was completed in Matlab, and the results show that the improved reciprocating path planning algorithm achieved higher coverage rate than the traditional algorithm. CONCLUSIONS: With the analysis of simulation results, it can be concluded that the number of coil turns and the distance between the moving iron core and the yoke could be determined prior to coil current, and the force can be controllable by optimizing structure parameters of massage head and adjusting coil current. Meanwhile, it demonstrates that the proposed algorithm could effectively improve path coverage rate during massage operations, therefore the massage effect can be improved. PMID- 28582917 TI - Potential for false positive results from multi-voxel pattern analysis on functional imaging data. AB - BACKGROUND: Multi-voxel pattern analysis (MVPA) provides a powerful tool to investigate neural mechanisms for various cognitive processes under functional brain imaging. However, the high sensitivity of the MVPA method could bring about false positive results, which has been overlooked by previous research. OBJECTIVE: We investigated the potential for obtaining false positives from the MVPA method. METHODS: We conducted MVPA on a public functional MRI dataset on the neural encoding of various object categories. Different scenarios for pattern classification were involved by varying the number of voxels for each region of interest (ROI) and the number of object categories. RESULTS: The classification accuracy became higher with more voxels involved, and false positive results emerged for the primary auditory cortex and even a white matter ROI, where object related neural processing was not supposed to occur. CONCLUSIONS: Our results imply that the classification accuracy obtained from MVPA may be inflated due to the high sensitivity of the method. Therefore, we suggest involving control ROIs in future MVPA studies and comparing the classification accuracy for a target ROI with that for a control ROI, instead of comparing the obtained accuracy with the chance-level accuracy. PMID- 28582918 TI - Differential barometric-based positioning technique for indoor elevation measurement in IoT medical applications. AB - BACKGROUND: Medical applications have begun to benefit from Internet of Things (IoT) technology through the introduction of wearable devices. Several medical applications require accurate patient location as various changes affect pressure parameters inside the body. OBJECTIVE: This study aims to develop a system to measure indoor altitude for IoT medical applications. METHODS: We propose a differential barometric-based positioning system to estimate the altitude between a reference sensor and a localizing sensor connected to the human body. The differential barometric altimetry model is introduced to estimate indoor elevations and eliminate environmental artifacts. In addition, a Gaussian filter processing is adopted to remove noise from the elevation measurements. The proposed system is then investigated through extensive experiments, using various evaluation criteria. RESULTS: The results indicate that the proposed system yielded good accuracy with reduced implementation complexity and fewer costs. CONCLUSIONS: The proposed system is resilient compared to other indoor localization approaches, even when numerous environmental artifacts in indoor environments are present. PMID- 28582919 TI - Design of an ultrasonic physiotherapy system with pulse wave feedback control. AB - BACKGROUND: Due to different physical and biological mechanisms behind ultrasound hyperthermia and phonophoresis, the requirement for ultrasound power, frequency and control modes varies. OBJECTIVE: This paper introduces an adaptive ultrasonic physiotherapy system based on real-time surveillance over physiological characteristics of the patients, which in turn assists the individual treatment and dose limitation in auxiliary rehabilitation. METHODS: The method essentially takes advantage of distinctive characteristics of two different phases (systole and diastole) of the human cardiac cycle as a medium for modulation. The abundance of blood flow during systole enables energy exchange for hyperthermia while blood flow insufficiency caused by diastole assists in drug penetration. Said method could improve the adjuvant therapy as it provides partial drug penetration and therapeutic dosage control. RESULTS: By adjusting time window and intensity of multi-frequency ultrasound, it is possible to reduce the irradiation dosage to around 22% of that during continuous irradiation at 1 MHz. The method shows high potential in clinical practice. CONCLUSION: Frequency-tuning ultrasound therapy would be more efficient regarding drug penetration and improve the therapeutic efficacy of hyperthermia. PMID- 28582920 TI - Optimization of a passively suspended injection impeller for Left ventricular assist device. AB - BACKGROUND: A rotary blood pump with a passively levitated impeller and a large bearing gap between housing and impeller in the range of 0.6 mm has been developed for Left ventricular assist device (LVAD). OBJECTIVE: The purpose of the present study is to determine the optimal injection angle of the impeller to improve its radial stability by increasing the radial suspension force. MTEHODS: Since the radial and axial suspension forces generated by an injection channel were equal, the axial suspension force obtained from numerical simulation was chosen as the evaluation parameter. First, the impellers with different injection angles were calculated with numerical simulation to obtain the maximum axial suspension force. Second, the radial motion of the impeller was experimentally measured for the evaluation of the radial stability. RESULTS: The numerical analysis revealed that the axial suspension force acting on the impeller reached the maximum value at the injection angle of 60 degrees. In the measurement test, the impeller with injection angle of 60 degrees achieved the most stable radial movement. Therefore, the effectiveness of the numerical analysis was validated. CONCLUSIONS: The injection angle of impeller could be optimized to improve its radial stability, and the optimal injection angle was 60 degrees. PMID- 28582921 TI - Grouped fuzzy SVM with EM-based partition of sample space for clustered microcalcification detection. AB - BACKGROUND: Detection of clustered microcalcification (MC) from mammograms plays essential roles in computer-aided diagnosis for early stage breast cancer. OBJECTIVE: To tackle problems associated with the diversity of data structures of MC lesions and the variability of normal breast tissues, multi-pattern sample space learning is required. METHODS: In this paper, a novel grouped fuzzy Support Vector Machine (SVM) algorithm with sample space partition based on Expectation Maximization (EM) (called G-FSVM) is proposed for clustered MC detection. The diversified pattern of training data is partitioned into several groups based on EM algorithm. Then a series of fuzzy SVM are integrated for classification with each group of samples from the MC lesions and normal breast tissues. RESULTS: From DDSM database, a total of 1,064 suspicious regions are selected from 239 mammography, and the measurement of Accuracy, True Positive Rate (TPR), False Positive Rate (FPR) and EVL = TPR* 1-FPR are 0.82, 0.78, 0.14 and 0.72, respectively. CONCLUSION: The proposed method incorporates the merits of fuzzy SVM and multi-pattern sample space learning, decomposing the MC detection problem into serial simple two-class classification. Experimental results from synthetic data and DDSM database demonstrate that our integrated classification framework reduces the false positive rate significantly while maintaining the true positive rate. PMID- 28582922 TI - Cellular neural network modelling of soft tissue dynamics for surgical simulation. AB - BACKGROUND: Currently, the mechanical dynamics of soft tissue deformation is achieved by numerical time integrations such as the explicit or implicit integration; however, the explicit integration is stable only under a small time step, whereas the implicit integration is computationally expensive in spite of the accommodation of a large time step. OBJECTIVE: This paper presents a cellular neural network method for stable simulation of soft tissue deformation dynamics. METHOD: The non-rigid motion equation is formulated as a cellular neural network with local connectivity of cells, and thus the dynamics of soft tissue deformation is transformed into the neural dynamics of the cellular neural network. RESULTS: Results show that the proposed method can achieve good accuracy at a small time step. It still remains stable at a large time step, while maintaining the computational efficiency of the explicit integration. CONCLUSION: The proposed method can achieve stable soft tissue deformation with efficiency of explicit integration for surgical simulation. PMID- 28582923 TI - A novel lung cancer detection algorithm for CADs based on SSP and Level Set. AB - The fuzzy degree of lung nodule boundary is the most important cue to judge the lung cancer in CT images. Based on this feature, the paper proposes a novel lung cancer detection method for CT images based on the super-pixels and the level set segmentation methods. In the proposed methods, the super-pixels method is used to segment the lung region and the suspected lung cancer lesion region in the CT image. The super-pixels method and a level set method are used to segment the suspected lung cancer lesion region simultaneously. Finally, the cancer is determined by the difference between results of the two segmentation methods. Experimental results show that the proposed algorithm has a high accuracy for lung cancer detection in CT images. For gross glass nodule, pleural nodule, the vascular nodules and solitary nodules, the sensitivity of the detection algorithm are respectively 91.3%, 96.3%, 80.9% and 82.3%. PMID- 28582924 TI - GPU-based interactive near-regular texture synthesis for digital human models. AB - Near-regular texture is a common feature for both nature scene and 3D human models. However, traditional texture synthesis has only been able to produce a single result. This study proposes a parallel, and interactive, method for the texture synthesis of irregular appearance in 3D human models. The new method includes two major procedures: (1) iterative edge extraction and processing, and (2) parallel texture synthesis, which generates a texture with higher quality. In this paper, the effectiveness of near-regular texture synthesis algorithm is demonstrated experimentally. PMID- 28582925 TI - Medical image watermarking using bit threshold map based on just noticeable distortion in discrete cosine transform. AB - BACKGROUND: Medical images stored in a hospital system are generally confidential and integrated and require strict security. However, medical information stored on digital medical imaging systems, as well as picture archiving and communication systems (PACS), are vulnerable to attack when the data are transferred over wireless or wired communication networks. OBJECTIVE: To solve this problem, a watermarking algorithm for medical images is proposed using a bit threshold map based on just noticeable distortion (JND) in the discrete cosine transform (DCT) method. METHODS: The low-frequency component comprises a considerable amount of the signal energy for most images. As a result, it has a crucial effect on the image quality. Therefore, in this paper, the proposed algorithm embeds watermarks based on the low-frequency components of the image, such as the DC coefficient of the DCT. RESULTS: When watermarks are embedded in a low frequency area, the subjective image quality is often degraded. To compensate for the degradation of the imperceptibility of the watermarking system, which results from embedding watermarks in the low-frequency component, this research considers the human visual system. In addition, the embedding strength of the JND value is used to improve the watermarking imperceptibility. CONCLUSIONS: We applied the proposed watermarking algorithm to a variety of medical images using a computer simulation. The algorithm's performance was verified using a variety of attacks for eliminating watermarks. The simulation results show that the proposed algorithm robustly provides protection against a variety of possible attacks. PMID- 28582926 TI - An automatic glioma grading method based on multi-feature extraction and fusion. AB - BACKGROUND: An accurate assessment of tumor malignancy grade in the preoperative situation is important for clinical management. However, the manual grading of gliomas from MRIs is both a tiresome and time consuming task for radiologists. Thus, it is a priority to design an automatic and effective computer-aided diagnosis (CAD) tool to assist radiologists in grading gliomas. OBJECTIVE: To design an automatic computer-aided diagnosis for grading gliomas using multi sequence magnetic resonance imaging. METHODS: The proposed method consists of two steps: (1) the features of high and low grade gliomas are extracted from multi sequence magnetic resonance images, and (2) then, a KNN classifier is trained to grade the gliomas. In the feature extraction step, the intensity, volume, and local binary patterns (LBP) of the gliomas are extracted, and PCA is used to reduce the data dimension. RESULTS: The proposed "Intensity-Volume-LBP-PCA-KNN" method is validated on the MICCAI 2015 BraTS challenge dataset, and an average grade accuracy of 87.59% is obtained. CONCLUSIONS: The proposed method is an effective method for automatically grading gliomas and can be applied to real situations. PMID- 28582927 TI - Analysis of SAR distribution in human head of antenna used in wireless power transform based on magnetic resonance. AB - In this paper, a novel wireless power transfer antenna system was designed for human head implantable devices. The antenna system used the structure of three plates and four coils and operated at low frequencies to transfer power via near field. In order to verify the electromagnetic radiation safety on the human head, the electromagnetic intensity and specific absorption rate (SAR) were studied by finite-difference-time-domain (FDTD) method. A three-layer model of human head including skin, bone and brain tissues was constructed. The transmitting and receiving antenna were set outside and inside the model. The local and average SAR were simulated at the resonance frequency of 18.67 MHz in two situations, in one scenario both transmitting and receiving coil worked, while in the other scenario only the transmitting coil worked. The results showed that the maximum of 10 g SAR average value of human thoracic were 0.142 W/kg and 0.148 W/kg, respectively, both were lower than the international safety standards for human body of the ICNIRP and FCC, which verified the safety of the human body in wireless power transmission based on magnetic coupling resonance. PMID- 28582928 TI - Epileptic seizure detection based on the kernel extreme learning machine. AB - This paper presents a pattern recognition model using multiple features and the kernel extreme learning machine (ELM), improving the accuracy of automatic epilepsy diagnosis. After simple preprocessing, temporal- and wavelet-based features are extracted from epileptic EEG signals. A combined kernel-function based ELM approach is then proposed for feature classification. To further reduce the computation, Cholesky decomposition is introduced during the process of calculating the output weights. The experimental results show that the proposed method can achieve satisfactory accuracy with less computation time. PMID- 28582929 TI - Relationships between lung cancer incidences and air pollutants. AB - BACKGROUND: Statistics on lung cancer incidences and air pollutants show a strong correlation between air pollutant concentrations and pulmonary diseases. And environmental effects on lung cancer incidences remain highly unknown and uncertain in China. OBJECTIVE: This study aims to measure the relationships between different air pollutants and lung cancer incidences in Tianjin. METHODS: One thusand five hundred patients across 27 districts in Tianjin were studied for lung cancer incidences. The patients had come into contact with various air pollutants such as PM2.5, PM10, SO2, NO2, CO, and O3. These pollutants were measured daily and were published via a Geographic Information System across the 27 districts of Tianjin. The air pollutant compositions of environments the patients lived in were determined using the nearest air monitoring station to the patient. And we used rough set theory to measure the relationships between different air pollutants and lung cancer incidences. RESULTS: Different air pollutants and combinations of pollutants impacted lung cancer incidences differently across different districts, sexes, and lung cancer types in Tianjin. CONCLUSIONS: Based on data analysis and interpretation, rough set theory provided data relationships that were objective and interpretable. The method is simple, general, and efficient, and lays the foundation for further applications in other cities. PMID- 28582930 TI - Optimal three-dimensional reconstruction for lung cancer tissues. AB - The existing three-dimensional (3D) x-ray reconstruction methods for lung cancer tissue reconstruct the investigated objects based on a series of two-dimensional (2D) image sections and a chosen 3D reconstruction algorithm. However, because these procedures apply the same segmentation method for all 2D image sections, they may not achieve the optimal segmentation for each section. As a result, the reconstructed 3D images have limited spatial resolution. Furthermore, the existing 3D reconstruction method is time-consuming and results in a limited time resolution. This research presents an innovation of 3D reconstruction by reformulating two main components of the method. First, a validity index for fuzzy clustering is used to obtain the optimal segmentations of any 2D x-ray image. The process is realized by automatically determining the optimal number of clusters for the image. Second, unlike the existing 3D reconstruction methods, a fast-FCM algorithm is used to speed up the 2D image segmenting process, thereby raising the time resolution of the 3D reconstruction process. With the aid of commonly used VTK software, the proposed method has been used to visualize four classes of typical lung cancer tissues: adenocarcinoma, large cell carcinoma, small cell carcinoma, and squamous cell carcinoma. Experimental results validate the effectiveness and efficiency of the proposed algorithm. Thus, the method contributes a useful tool for x-ray-based 3D image reconstruction. PMID- 28582931 TI - A surface acoustic wave ICP sensor with good temperature stability. AB - BACKGROUND: Intracranial pressure (ICP) monitoring is very important for assessing and monitoring hydrocephalus, head trauma and hypertension patients, which could lead to elevated ICP or even devastating neurological damage. The mortality rate due to these diseases could be reduced through ICP monitoring, because precautions can be taken against the brain damage. OBJECTIVE: This paper presents a surface acoustic wave (SAW) pressure sensor to realize ICP monitoring, which is capable of wireless and passive transmission with antenna attached. METHODS: In order to improve the temperature stability of the sensor, two methods were adopted. First, the ST cut quartz was chosen as the sensor substrate due to its good temperature stability. Then, a differential temperature compensation method was proposed to reduce the effects of temperature. Two resonators were designed based on coupling of mode (COM) theory and the prototype was fabricated and verified using a system established for testing pressure and temperature. RESULTS: The experiment result shows that the sensor has a linearity of 2.63% and hysteresis of 1.77%. CONCLUSIONS: The temperature stability of the sensor has been greatly improved by using the differential compensation method, which validates the effectiveness of the proposed method. PMID- 28582932 TI - A study of the application of Brain Atlas with and without +Gz acceleration conditions. AB - The purposes of this study were to utilize Brain Atlas to investigate the fluctuations in the characteristics of human EEG, with and without +Gz acceleration produced by human centrifuge, and also to examine the G load endurance of human body. The Brain Atlas of the EEG signal with and without +Gz acceleration in a static state were compared in order to reveal the correlation and differences. When compared with those in a static state, it was found that for the EEG readings of the subjects undergoing +Gz acceleration conditions, the energy and gray scale values of the low-frequency component-delta rhythm showed significant increases, while the energy and gray scale values of the high frequency component-beta rhythm showed significant decreases. Among these, the beta2 rhythm was determined to be significantly inhibited. These fluctuations suggested that the ischemia conditions of brain had been improved. Also, the recoveries in the energy and gray-scale values were determined to be faster, which suggested that the G load endurance of human body had been enhanced. The Brain Atlas was found to show observable changes in color. The experimental results indicated that the Brain Atlas was able to provide assistance during the exploration of the fluctuations in the characteristics of EEG, and provided a criterion to assist in the observations of the function state fluctuations of human brain with +Gz acceleration. It also assisted in the evaluations of the G load endurance of human body. PMID- 28582933 TI - The diagnostic value of susceptibility-weighted imaging for ischemic penumbra in patients with acute ischemic stroke. AB - BACKGROUND: The ischemia penumbra area is not easy to be detected accurately using noninvasive imaging methods. OBJECTIVE: We aim to assess the diagnostic value of susceptibility-weighted imaging (SWI) for ischemic penumbra in patients with acute ischemic stroke. METHODS: A retrospective analysis was carried out in 47 patients with ischemic stroke involving the middle cerebral artery. Mean transit time (MTT), time to peak, relative cerebral blood flow, and relative cerebral blood volume maps were created after image processing. RESULTS: No significant difference was found in the mismatch between the SWI and diffusion weighted imaging (SWI-DWI) or in the MTT-DWI mismatch scores (P= 0.056, Kappa = 0.864). CONCLUSIONS: SWI provides information comparable to PWI and, thus, could serve as a reliable magnetic resonance technique for assessing ischemic penumbrae. PMID- 28582934 TI - A new idea for visualization of lesions distribution in mammogram based on CPD registration method. AB - BACKGROUND: Mammography is currently the most effective technique for breast cancer. Lesions distribution can provide support for clinical diagnosis and epidemiological studies. OBJECTIVE: We presented a new idea to help radiologists study breast lesions distribution conveniently. We also developed an automatic tool based on this idea which could show visualization of lesions distribution in a standard mammogram. METHODS: Firstly, establishing a lesion database to study; then, extracting breast contours and match different women's mammograms to a standard mammogram; finally, showing the lesion distribution in the standard mammogram, and providing the distribution statistics. The crucial process of developing this tool was matching different women's mammograms correctly. We used a hybrid breast contour extraction method combined with coherent point drift method to match different women's mammograms. RESULTS: We tested our automatic tool by four mass datasets of 641 images. The distribution results shown by the tool were consistent with the results counted according to their reports and mammograms by manual. We also discussed the registration error that was less than 3.3 mm in average distance. CONCLUSIONS: The new idea is effective and the automatic tool can provide lesions distribution results which are consistent with radiologists simply and conveniently. PMID- 28582936 TI - The comparison of stepping responses following perturbations applied to pelvis during overground and treadmill walking. AB - BACKGROUND: Treadmills are used frequently in rehabilitation enabling neurologically impaired subjects to train walking while being assisted by therapists. Numerous studies compared walking on treadmill and overground for unperturbed but not also perturbed conditions. OBJECTIVE: The objective of this study was to compare stepping responses (step length, step width and step time) during overground and treadmill walking in a group of healthy subjects where balance assessment robots applied perturbing pushes to the subject's pelvis in sagittal and frontal planes. METHODS: During walking in both balance assessment robots (overground and treadmill-based) with applied perturbations the stepping responses of a group of seven healthy subjects were assessed with a motion tracking camera. RESULTS: The results show high degree of similarity of stepping responses between overground and treadmill walking for all perturbation directions. Both devices reproduced similar experimental conditions with relatively small standard deviations in the unperturbed walking as well as in perturbed walking. CONCLUSIONS: Based on these results we may conclude that stepping responses following perturbations can be studied on an instrumented treadmill where ground reaction forces can be readily assessed which is not the case during perturbed overground walking. PMID- 28582937 TI - The impact of breathing pattern and rate on inspiratory muscles activity. AB - Different rehabilitation programs are used to relieve dyspnea for hyper-inflated lung patients. In this study, a new approach, based on integrated changes in respiratory rate and pattern, for inspiratory muscles rehabilitation and training was examined utilizing noninvasive measurements of the two inspiratory muscles (rib cage inspiratory and neck inspiratory muscles) activity during controlled breathing in healthy subjects. Muscles activity was measured using electromyography, while subjects, breathed at different combinations of respiratory rate (6, 10, 16 breath per minutes) and inspiratory duty cycles (TI/Ttot). The results clearly show that both muscles were most active at the lowest evaluated respiratory rate, and that alteration of the duty cycle at the lowest rate significantly (p< 0.05) changes their electrical activity. Breathing at low respiratory rate RR is recommended for hyper-inflated lung patients in order to improve their gas exchange, therefore, it is recommended for these patients to find their most effective combination of RR and TI/Ttot and to use control breathing to practice their breath at optimum combination. PMID- 28582938 TI - Effective mammogram classification based on center symmetric-LBP features in wavelet domain using random forests. AB - Mammogram classification is a crucial and challenging problem, because it helps in early diagnosis of breast cancer and supports radiologists in their decision to analyze similar mammograms out of a database by recognizing the classes of current mammograms. This paper proposes an effective method for classifying mammograms using random forests with wavelet based center-symmetric local binary pattern (WCS-LBP). To classify mammograms, multi-resolution CS-LBP texture characteristics from non-overlapping regions of the mammograms are captured. Further, we examine most relevant features using support vector machine-recursive feature elimination (SVM-RFE). Finally, we feed the selected features to decision trees and construct random forests which are an ensemble of random decision trees. Using wavelet based local CS-LBP features with random forest, we classify the test images into different categories having the maximum posterior probability. The proposed method shows the improved performance as compared with other variant features and state-of-art methods. The obtained performance measures are 97.3% accuracy, 97.3% precision, 97.2% recall, 97.2% F-measure and 94.1% Matthews correlation coefficient (MCC). PMID- 28582939 TI - Elaboration of the contextual factors of the ICF for Occupational Health Care. AB - BACKGROUND: Many work-related items are not included in the current classification of environmental factors from the International Classification of Functioning, Disability and Health (ICF). Furthermore, personal factors are not classified and the ICF only provides a very limited list of examples. These facts make the ICF less useful for occupational health care and for research in the field of occupation and health. OBJECTIVE: The objective of this discussion paper is to introduce an elaboration of contextual factors, focussing on factors that influence work participation. METHODS: During the last 12 years, we developed two concept lists from the bottom up. These lists are based on our experiences in teaching and research, suggestions from students and other researchers, and factors found in the literature. In the fall of 2015 a scoping literature review was done to check for missing factors in these two concept lists. RESULTS: An elaboration of contextual factors, consisting of a list of work-related environmental factors and a list of personal factors. CONCLUSIONS: Important contextual factors that influence work participation are identified. Researchers, teachers, students, occupational and insurance physicians, allied health care professionals, employers, employees, and policy makers are invited to use the elaboration and to make suggestions for improvement. The elaboration and the suggestions received can be used in the ICF revision process. The development of an ICF ontology must be given priority, to give room to this elaboration, which will increase the applicability of the ICF and enable mapping with other terminologies and classifications. PMID- 28582940 TI - Experiences of occupational physicians with the implementation of indicated prevention for long term sickness absence. AB - BACKGROUND: Functioning including work participation, is an emerging challenge in occupational health. The prevention of long term sickness absence (LTSA) through a strategy involving screening and structured early consultation (preventive strategy) was proven effective and can address participation issues. Implementation of this strategy has proven difficult. OBJECTIVE: The aim of this study is to investigate the experiences of occupational physicians (OPs) delivering a structured early consultation to office workers, in order to enhance implementation of the strategy. METHODS: In this case study, a mixed method design was used. Interviews and surveys were conducted to obtain an in-depth picture of OPs experiences. RESULTS: Factors hindering implementation in relation to the OPs were difficulties in communicating the risk of future sick leave, prioritization of other tasks, maintaining a reactive approach due to work pressure, preference for prevention on the level of the work environment, privacy issues related to labeling workers to have mental or psychosocial issues, and the biomedical model being the mental model in use. CONCLUSIONS: Implementation of the preventive strategy seems to require a more profound focus on the biopsychosocial approach. Training of relevant skills is important to achieve a focus on prevention and fostering health over the lifespan. PMID- 28582941 TI - Fostering functioning of workers: A new challenge for prevention in occupational health. AB - Given large changes in working conditions and society, occupational health care has to prioritize its efforts towards fostering health and functioning of workers and as such promote work participation. This requires that more emphasis is given on the application of biopsychological models in the care of workers. Although a biopsychological approach is often mentioned as essential part of occupational health care, it's application is often hampered in practice, by practical barriers and lack of practical knowledge. This is illustrated by a study that uncovered facilitating and hindering factors in the implementation process of a preventive strategy, proven effective in reducing the risk of long term sickness absence. To facilitate the use of biopsychological models in occupational health care, it is shown that setting up a training curriculum is possible, based on the International Classification of Functioning, Disability and Health (ICF) grafted on available training in evidence based practice skills is possible. Furthermore, there is a need for elaboration of the personal factors relevant for workers and the relevant work-related environmental factors to support practical application of ICF in occupational health care. A paradigm shift in occupational health care can facilitate widespread implementation of the biopsychosocial approach in occupational health and may stimulate occupational health professionals to further integrate this approach in their daily practice. PMID- 28582942 TI - Applying a biopsychosocial perspective in occupational health: Easier said than done! PMID- 28582943 TI - "I've never been able to stay in a job": A qualitative study of Veterans' experiences of maintaining employment. AB - BACKGROUND: Ensuring Veteran employment needs are met is a top priority for the Department of Veteran Affairs and the United States government. However, Veterans, especially those with mental health disorders, continue to encounter difficulties when employed. While many employment related programs offer numerous services aimed at helping Veterans gain employment, their ability to maintain long-term employment remains unknown. OBJECTIVE: The objective of this study was to understand factors that affect the ability of Veterans with mental health disorders to maintain long-term employment. METHODS: An exploratory, qualitative study design consisting of semi-structured interviews with 10 Veterans was performed. Inductive thematic analysis was performed to identify salient themes. RESULTS: We found that participants' symptoms manifested themselves within the workplace affecting their ability to maintain employment, participants felt as if they had been demoted from what they did in the military, and they felt unable to relate to civilian co-workers. Strategies that helped some transition into the civilian workforce were also identified. CONCLUSIONS: A better understanding of the difficulties some Veterans face when trying to maintain employment is needed. Our findings suggest that increasing awareness of existing programs and ensuring that services provide resources and skills that help Veterans maintain long-term employment is critical. PMID- 28582945 TI - Stress monitoring through non-invasive instrumental analysis of skin conductivity. AB - BACKGROUND: This paper envelops the notion of yogic breathing and its applications as one of the techniques for stress management through regulation of skin conductivity among Indian engineering students. Stress perturbs the normal physiological or psychological functioning of an individual. Thus, it is extremely vital to manage stress. OBJECTIVE: To explore the consequence of yogic breathing on skin conductivity using galvanic skin response sensor meter (GSRSM) on engineering students, of different universities. METHODS: The study uses stratified random sampling technique for the experimental study undertaken to measure skin conductivity. 471 Engineering students, in the age group of 18-22 years who gave informed written consent were screened, of which 71 (15%) dropped out and 400 students (84.9%) completed the study. The GSRSM was used to record skin conductivity (pre and post) among experimental (n = 200) and Control group (n = 200) each comprising of 52 females (26%) and 148 males (74%). The Experimental group underwent yogic breathing whereas the Control group did not do so. RESULTS: The experimental group reported reduction in mean value in skin conductivity after deep breathing for the time period (t = 300 sec) as compared to the control group, and this was significant (p < 0.01 and p < 0.05). CONCLUSION: It is recommended that, this uncomplicated and yet extremely effectual ancient technique of yogic breathing could be included in core curriculum to reduce and manage stress among engineering students. The paper thus highlights the use of yogic technique as an effective mode for Stress Management amongst Indian Engineering students. PMID- 28582944 TI - Good job, bad job: The employment experiences of women in recovery from substance abuse. AB - BACKGROUND: Women in metropolitan areas have lower employment participation and employment rates than men. Although women face multiple challenges in the labor market, those who have a history of substance use and are abstinent may have a greater disadvantage in obtaining viable employment opportunities due to factors associated with substance use. No research to date has examined employment experiences among women in recovery from substance use. OBJECTIVE: This study examined employment characteristics and experiences of women who had a history of substance use and lived in sober-living environments in urban areas. METHOD: Data were collected through telephone interviews to sober living homes that were located in 20 urban areas. RESULTS: Themes identified through thematic analysis included employment challenges, the importance of work to substance abuse recovery, job satisfaction, employment aspirations, and employment support in the sober living home. CONCLUSION: Employment is important to women in substance abuse recovery, not only as a means for financial support, but also as a life priority. The results highlight how employer scheduling practices, low-level positions, and lack of employment supports impact recovery. Findings provide insight into the need for employment support services, including employer education and flexible policies for women in recovery. PMID- 28582946 TI - Suicide among emergency and protective service workers: A retrospective mortality study in Australia, 2001 to 2012. AB - BACKGROUND: Emergency and protective services personnel (e.g., police, ambulance, fire-fighters, defence, prison and security officers) report elevated levels of job stress and health problems. While population-level research is lacking, there has been some research suggesting suicide rates may be elevated in emergency and protective services. OBJECTIVES: This paper compares suicide rates between emergency and protective services occupational groups over a 12-year period (2001 2012) in Australia. METHOD: Labour force data was obtained from the 2006 Australian Census. Suicide data was obtained from the National Coroners Information System (NCIS). Negative binomial regression was used to estimate the association between suicide and employment as an emergency or protective service worker (including prison and security officers) over the period 2001-2012, as compared to all other occupations. Information on suicide method was extracted from the NCIS. RESULTS: The age-adjusted suicide rate across all emergency and protective service workers was 22.4 (95% CI 19.5 to 25.2) per 100,000 in males and 7.8 in females (95% CI 4.6 to 11.00), compared to 15.5 per 100,000 (95% CI 15.2 to 15.9) for males and 3.4 (95% CI 3.2 to 3.6) for females in other occupations. The highest risk by subgroup was observed among those employed in the defence force, prison officers, and ambulance personnel. The major method of death for all occupational groups was hanging. CONCLUSIONS: Our results clearly highlight the need for suicide prevention among emergency and protective service occupations. PMID- 28582947 TI - Age-related associations between work over-commitment and zest for work among Swedish employees from a cross-sectional and longitudinal perspective. AB - BACKGROUND: In aging societies, zest for work may be pivotal when deciding to stay occupationally active longer. Psychosocial work stress is a prevalent public health problem and may have an impact on zest for work. Work over-commitment (WOC) is a personal coping strategy for work stress with excessive striving and a health risk. However, the long-term effect of WOC on zest for work is poorly understood. OBJECTIVE: To investigate the age-related associations of work over commitment with zest for work. METHODS: During 1996-1998 and 2000-2003, predominantly industrial workers (n = 2940) participated in the WOLF-Norrland study and responded to a questionnaire referring to socio-demographics, WOC, zest for work, effort-reward imbalance proxies, and mental health. Age-adjusted multiple logistic regressions were performed with original and imputed datasets. RESULTS: Cross-sectionally, work overcommitted middle-aged employees had an increased prevalence of poor zest for work compared to their contemporaries without WOC (OR: 3.74 [95%-CI 2.19; 6.40]). However, in a longitudinal analysis associations between onset of 'poor zest for work' and the WOC subscales 'need for approval' (OR: 3.29 [95%-CI 1.04; 10.37]) and 'inability to withdraw from work' (OR: 5.14 [95%-CI 1.32; 20.03]) were observed. CONCLUSION: The longitudinal findings among older employees could be relevant regarding the expected need to remain occupationally active longer. PMID- 28582948 TI - The big sell: Managing stigma and workplace discrimination following moderate to severe brain injury. AB - BACKGROUND: Misperceptions regarding persons with brain injuries (PWBI) can lead to stigmatization, workplace discrimination and, in turn, influence PWBIs full vocational integration. OBJECTIVE: In this study we explored how stigma may influence return-to-work processes, experiences of stigma and discrimination at the workplace for persons with (moderate to severe) brain injuries, and strategies that can be employed to manage disclosure. METHODS: Exploratory qualitative study; used in-depth interviews and an inductive thematic analytical approach in data analysis. Ten PWBI and five employment service providers participated. PWBI discussed their work experiences, relationships with supervisors and co-workers and experiences of stigma and/or discrimination at work. Employment service providers discussed their perceptions regarding PWBI's rights and abilities to work, reported incidents of workplace discrimination, and how issues related to stigma, discrimination and disclosure are managed. RESULTS: Three themes were identified: i) public, employer and provider knowledge about brain injury and beliefs about PWBI; ii) incidents of workplace discrimination; iii) disclosure. Misperceptions regarding PWBI persist amongst the public and employers. Incidents of workplace discrimination included social exclusion at the workplace, hiring discrimination, denial of promotion/demotion, harassment, and failure to provide reasonable accommodations. Disclosure decisions required careful consideration of PWBI needs, the type of information that should be shared, and the context in which that information is shared. CONCLUSIONS: Public understanding about PWBI remains limited. PWBI require further assistance to manage disclosure and incidents of workplace discrimination. PMID- 28582949 TI - Exploring service delivery in occupational therapy: The use of convergent interviewing. AB - BACKGROUND: Occupational therapy clinicians working in South Africa's public healthcare had views on what patients thought about their vocational rehabilitation services that were based on anecdotal evidence. However evidence based practice requires more than that. Reliable information is important in patient-centred practice and in the assessment of service quality. OBJECTIVE: Clinical occupational therapists used the convergent interviewing technique to explore patients' views of the vocational rehabilitation services on offer in public hospitals. METHOD: An Action Learning Action Research (ALAR) approach was used to explore the vocational rehabilitation services occupational therapy clinicians provided over a two week period in three settings. RESULTS: The majority (96%) of patients interviewed were not aware that occupational therapists offered vocational rehabilitation services. The convergent interview technique allowed continued unrestricted discussion of their vocational rehabilitation concerns and provided evidence that patients had significant concerns about work. Critical reflection on the interview experience and technique indicated that therapists were in favour of using convergent interviewing to obtain their patients views about the services offered. Therapists found the convergent interview technique easy to apply in clinical practice. CONCLUSION: Establishing patients' views of a clinical service have multiple values. However it is meaningless unless clinicians use the knowledge to improve service delivery to the patients who provided the views. Convergent interviewing was a valuable technique for occupational therapy clinicians to incorporate patients' views of their services into service development. PMID- 28582950 TI - The prevalence of work-related musculoskeletal disorders among sonographers. AB - BACKGROUND: Work-related musculoskeletal disorders (WRMSDs) have a significant effect on the psychological and physical function of the sonographer. OBJECTIVE: This study is concerned about finding the prevalence of WRMSDs among sonographers in the Kingdom of Saudi Arabia and assessing how to improve future practices and develop guidelines for safe, pain-free ultrasound departments. METHODS: A survey was distributed to sonographers working in major hospitals in Riyadh, Saudi Arabia (n = 100, 83% response rate). The questionnaire focused on workload and ergonomics, pain existence and history, and the level of the sonographers' awareness of prevention measures and best practices. Ethical approval was obtained from a local Institutional Review Board. RESULTS: Eighty-four percent of respondents suffer from pain they associated with their ultrasound practice. The shoulder, back, neck and right hand were the main symptomatic body areas. Low levels of awareness about best practices and safety measures were revealed. There was a strong correlation between the degree of pain suffered and the years of practice, the number of patients scanned per day, and movements during the exam. CONCLUSION: Implementing standards and guidelines for best ultrasound practices is needed to develop better and safer ultrasound departments in Saudi hospitals for every practitioner. PMID- 28582951 TI - The effects of physical and psychosocial factors and ergonomic conditions on the prevalence of musculoskeletal disorders among dentists in Malaysia. AB - BACKGROUND: Musculoskeletal disorders (MSDs) have been recognized as one of the main occupational health problems for dentists. Many studies have suggested that dentists experience work-related pain or discomfort in the neck, shoulder, and back, as well as in other parts of the body. OBJECTIVE: This study aimed to examine the relationship between specific physical and psychosocial factors and/or ergonomic conditions on MSD symptoms among dentists in Malaysia. METHODS: A group of 85 dentists was asked to complete a questionnaire to determine whether their complaints were related to physical and psychosocial factors and/or ergonomic conditions in their practices. RESULTS: Among the nine reviewed body areas, the shoulders were most often affected by symptoms of MSDs (92.7%). Moreover, MSDs of the neck and upper back were most likely to prevent these practitioners from engaging in normal activities (32.9%). In general, no significant differences were found in the prevalence of MSD symptoms in relation to gender, age, body mass index, years in practice, number of patients, and frequency of breaks. CONCLUSIONS: Our results were consistent with those reported in other studies that focused on MSD problems among dentists in other countries. To reduce the prevalence of MSDs, more attention should be paid to instituting ergonomically sensible approaches in the dental practice setting. PMID- 28582952 TI - Improving work conditions through strike: Examination of nurses' attitudes through perceptions of two physician strikes in Israel. AB - BACKGROUND: Strikes are means to influence policies related to working conditions, yet raise ethical dilemmas for healthcare workers. Nurse strikes have become more prominent around the world. OBJECTIVE: To assess the change in Israeli nurses' attitudes towards strikes in light of two physician strikes that have preceded a nursing strike. METHODS: An anonymous survey was administered once in 2000 (N = 106) and again in 2011 (n = 175) following 110 days of a physician strike, to assess nurses' attitudes towards the strike and resulting ethical issues. RESULTS: A statistically significant change (p < 0.05) between administrations revealed that in 2011 more nurses identified striking as a legitimate mechanism, would strike under the same circumstances, and felt that collaboration with physicians persisted despite the strike. Additionally, an increasing number of nurses said that the suffering of patients due to the strike is somewhat or entirely justified, although they were faced with a difficult dilemma of loyalty to physician colleagues vs. PATIENTS: Nurses reported finding ways to mitigate the suffering of patients resulting from the strike. CONCLUSIONS: While patient-centered care remains nurses' first and foremost priority, findings indicate an increasing support of collective bargaining and strike to promote working conditions related to professional and public health agendas. PMID- 28582955 TI - Craniofacial Endoscopic Surgery: Trend of the Past Moving Into Reality of the Future. PMID- 28582954 TI - Virtual scatter modulation for X-ray CT scatter correction using primary modulator. AB - A new scatter estimation algorithm with a concept of virtual scatter modulation for X-ray scatter correction using primary modulator is proposed to reduce the aliasing errors in the estimated scatter. Virtual scatter modulation can be realized through dividing the measured primary-modulated image by the measured modulation function. After the division, the aggravation of the aliasing of primary due to the non-uniformity of the modulation function is largely transferred to that of scatter. Since scatter in general has less high frequencies than primary does, the aggravation of its aliasing is expected to be weaker, and therefore the overall aliasing can be reduced. A CatPhan(c)600 phantom and an anthropomorphic thorax phantom are scanned on a tabletop X-ray cone-beam computed tomography system to validate our proposed algorithm. On the Catphan phantom, the oscillations that are clearly observed in the central region of the Catphan scatter profile estimated using the original primary-modulation algorithm, are mostly eliminated with the proposed scatter modulation algorithm, leading to less residual artifacts and better CT number uniformity in the reconstructed image. Compared with 38.9 HU of CT nonuniformity in a selected uniform region when the primary-modulation algorithm is used, the new algorithm significantly reduces it to 4.5 HU, reaching the same level of uniformity as the ground truth reference. On the thorax phantom, overall better CT number uniformity is also achieved. PMID- 28582957 TI - A Case of Organizing Hematoma in a Maxillary Sinus After Reconstruction of a Blow Out Fracture. AB - A 36-year-old man presented because of nasal obstruction, rhinorrhea, and postnasal drip. The patient had undergone reconstruction of a blow-out fracture of the orbital floor 12 years before and had sinusitis that likely had resulted from implant migration into the maxillary sinus. The inflammation was successfully resolved, and the implant was removed through a minimally invasive endoscopic sinus surgery technique. On pathologic examination, an organizing hematoma was identified as the cause of the lesion. Pre- and postoperational paranasal sinus computed tomography images were taken to compare the anatomy of the sinus before and following surgery. PMID- 28582956 TI - Endoscopic Endonasal Transsphenoidal Approach From the Surgeon Point of View. AB - OBJECTIVE: In February 2009, the authors' center formed a team of neurosurgeons, otolaryngologists, endocrinologists, and radiologists to perform pituitary surgery using the endoscopic endonasal transsphenoidal approach (EETSA). This paper reviews the authors' experience with the technique, pathological outcomes, hormone profiles, and postoperative complications. METHODS: Between February 2009 and December 2015, 535 patients underwent the EETSA with 2-nostrils/4-hands surgery. All of the patients had preoperative neurophthalmological and endocrinological assessments and neuroimaging. Patients were followed for at least 6 months with otolaryngological evaluations. RESULTS: The most common pathology treated was pituitary adenomas, with 390 (72.9%) patients. Of these, 287 (73.6%) were nonfunctioning adenomas. As the surgical method, the conventional 2-nostrils/4-hands technique was performed in 77 patients (14.4%), a right conventional nasoseptal flap and left modified nasoseptal rescue flap technique was used in 135 patients (25.2%), and bilateral modified nasoseptal rescue flaps were used in 323 patients (60.4%). Postoperative complications occurred in 46 patients (8.6%). The most common complications were vascular injury or hematoma (10 patients, 1.9%), and the most common postoperative sinonasal complaints were hyposmia or anosmia. Olfactory function was significantly decreased according to the Connecticut Chemosensory Clinical Research Center test (P <0.001) and Cross-Cultural Smell Identification Test scores (P <0.001) evaluated 6 months postoperatively. CONCLUSIONS: Skull-base tumor surgery via an EETSA with a team approach was performed for various extended tumors. It is important to consider postoperative sinonasal dysfunction, such as hyposmia or anosmia, and to have this followed by an otolaryngologist. PMID- 28582958 TI - Using Osseointegrated Implants Concomitant With Onlay Bone Grafting for Auricular Reconstruction. AB - Conventional dental implants have been reported for nasal and orbital regions but due to limited thickness of calvarium they are not used in mastoid region. Onlay bone grafting in skull concomitant with implants is a predictable method and experimental animal studies confirm it. Parietal bone and lateral mandibular ramus are suggested source of bone grafts and dental implants with 7 mm length can be used safely. Increased fixture length may lead to increase survival in long term. PMID- 28582959 TI - Supernumerary Nostril: Two Years Follow-Up. AB - Supernumerary nostril is a very rare congenital anomaly of the nose. Since the first patient reported by Lindsay in 1906, few number of patients were reported in the literature. Various types had been described with different surgical modalities for correction. It can be isolated or associated with other malformations such as facial cleft, esophageal atresia, and imperforate anus. Most of the patients are unilateral, but it may be bilateral. It may have a communication with a normal nasal cavity or not.In this study, the authors present a case of a 1-year-old male with a positive perinatal history of teratogen exposure had isolated supernumerary left nostril with communication to the nasal cavity.The authors will discuss different theories related to supernumerary nostril development, differences between published reports, the proposed surgical techniques, and the outcome of their treatment approach. PMID- 28582960 TI - Activated Carbon Fibers with Hierarchical Nanostructure Derived from Waste Cotton Gloves as High-Performance Electrodes for Supercapacitors. AB - One of the most challenging issues that restrict the biomass/waste-based nanocarbons in supercapacitor application is the poor structural inheritability during the activating process. Herein, we prepare a class of activated carbon fibers by carefully selecting waste cotton glove (CG) as the precursor, which mainly consists of cellulose fibers that can be transformed to carbon along with good inheritability of their fiber morphology upon activation. As prepared, the CG-based activated carbon fiber (CGACF) demonstrates a surface area of 1435 m2 g 1 contributed by micropores of 1.3 nm and small mesopores of 2.7 nm, while the fiber morphology can be well inherited from the CG with 3D interconnected frameworks created on the fiber surface. This hierarchically porous structure and well-retained fiber-like skeleton can simultaneously minimize the diffusion/transfer resistance of the electrolyte and electron, respectively, and maximize the surface area utilization for charge accumulation. Consequently, CGACF presents a higher specific capacitance of 218 F g-1 and an excellent high rate performance as compared to commercial activated carbon. PMID- 28582961 TI - Synthesis of Reabsorption-Suppressed Type-II/Type-I ZnSe/CdS/ZnS Core/Shell Quantum Dots and Their Application for Immunosorbent Assay. AB - We report a phosphine-free one-pot method to synthesize ZnSe/CdS/ZnS core-shell quantum dots (QDs) with composite type-II/type-I structures and consequent reabsorption suppression properties. The as-synthesized QDs possess high efficient red emission (with quantum yield of 82%) and high optical stability. Compared to type-I QDs, the ZnSe/CdS/ZnS QDs show larger Stokes shift and lower reabsorption which can reduce the emission loss and improve the level of fluorescence output. The ZnSe/CdS/ZnS QDs are used as fluorescent labels to exploit their application in fluorescence-linked immunosorbent assay (FLISA) for the first time in the detection of C-reactive protein (CRP) with a limit of detection (LOD) of 0.85 ng/mL, which is more sensitive than that of CdSe/ZnS type I QDs based FLISA (1.00 ng/mL). The results indicate that the ZnSe/CdS/ZnS type II/type-I QDs may be good candidates for applications in biomedical information detection. PMID- 28582962 TI - Nanostructured Silica/Gold-Cellulose-Bonded Amino-POSS Hybrid Composite via Sol Gel Process and Its Properties. AB - It is demonstrated in this paper that silica nanoparticles coated with core/shell gold provide efficient thermal, optical, and morphological properties with respect to the cellulose-polyhedral oligomeric silsesquioxanes (POSS) hybrid system. The one-step synthesis of a silica/gold nanocomposite is achieved with a simultaneous hydrolysis and reduction of gold chloride in the presence of formic acid, and the trimethoxysilane group acts as a silica precursor. The focus here comprises the synthesis of cellulose-POSS and silica/gold hybrid nanocomposites using the following two methods: (1) an in situ sol-gel process and (2) a polyvinyl alcohol/tetrakis (hydroxymethyl)phosphonium chloride process. Accordingly, the silica/gold core/shell nanoparticles are synthesized. The growth and attachment of the gold nanoparticles onto the functionalized surface of the silica at the nanometer scale is achieved via both the sol-gel and the tetrakis (hydroxymethyl) phosphonium chloride processes. The cellulose-POSS-silica/gold nanocomposites are characterized according to Fourier transformed infrared spectroscopy, Raman, X-ray diffraction, UV, photoluminescence, SEM, energy dispersive X-ray spectroscopy, TEM, thermogravimetric, and Brunauer-Emmett-Teller analyses. PMID- 28582963 TI - Percolation Magnetism in Ferroelectric Nanoparticles. AB - Nanoparticles of potassium tantalate (KTaO3) and potassium niobate (KNbO3) were synthesized by oxidation of metallic tantalum in molten potassium nitrate with the addition of potassium hydroxide. Magnetization curves obtained on these ferroelectric nanoparticles exhibit a weak ferromagnetism, while these compounds are nonmagnetic in a bulk. The experimental data are used as a start point for theoretical calculations. We consider a microscopic mechanism that leads to the emerging of a ferromagnetic ordering in ferroelectric nanoparticles. Our approach is based on the percolation of magnetic polarons assuming the dominant role of the oxygen vacancies. It describes the formation of surface magnetic polarons, in which an exchange interaction between electrons trapped in oxygen vacancies is mediated by magnetic impurity Fe3+ ions. The dependences of percolation radius on concentration of the oxygen vacancies and magnetic defects are determined in the framework of percolation theory. PMID- 28582964 TI - Graphene and Polymer Composites for Supercapacitor Applications: a Review. AB - Supercapacitors, as one of the energy storage devices, exhibit ultrahigh capacitance, high power density, and long cycle. High specific surface area, mechanical and chemical stability, and low cost are often required for supercapacitor materials. Graphene, as a new emerging carbon material, has attracted a lot of attention in energy storage field due to its intrinsic properties. Polymers are often incorporated into graphene for a number of enhanced or new properties as supercapacitors. In this paper, different polymers which are used to form composite materials for supercapacitor applications are reviewed. The functions, strategies, and the enhanced properties of graphene and polymer composites are discussed. Finally, the recent development of graphene and polymers for flexible supercapacitors are also discussed. PMID- 28582966 TI - Polarization-Dependent Quasi-Far-Field Superfocusing Strategy of Nanoring-Based Plasmonic Lenses. AB - The two-dimensional superfocusing of nanoring-based plasmonic lenses (NRPLs) beyond the diffraction limit in the far-field region remains a great challenge at optical wavelengths. In this paper, in addition to the modulation of structural parameters, we investigated the polarization-dependent focusing performance of a NRPL employing the finite-difference time-domain (FDTD) method. By utilizing the state of polarization (SOP) of incident light, we successfully realize the elliptical-, donut-, and circular-shape foci. The minimum full widths at half maximum (FWHMs) of these foci are ~0.32, ~0.34, and ~0.42 lambda 0 in the total electric field, respectively, and the depth of focus (DOF) lies in 1.41~1.77 lambda 0. These sub-diffraction-limit foci are well controlled in the quasi-far field region. The underlying physical mechanism on the focal shift and an effective way to control the focusing position are proposed. Furthermore, in the case of a high numerical aperture, the longitudinal component, which occupies over 80% of the electric-field energy, decides the focusing patterns of the foci. The achieved sub-diffraction-limit focusing can be widely used for many engineering applications, including the super-resolution imaging, particle acceleration, quantum optical information processing, and optical data storage. PMID- 28582965 TI - Compliance-Free ZrO2/ZrO2 - x /ZrO2 Resistive Memory with Controllable Interfacial Multistate Switching Behaviour. AB - A controllable transformation from interfacial to filamentary switching mode is presented on a ZrO2/ZrO2 - x /ZrO2 tri-layer resistive memory. The two switching modes are investigated with possible switching and transformation mechanisms proposed. Resistivity modulation of the ZrO2 - x layer is proposed to be responsible for the switching in the interfacial switching mode through injecting/retracting of oxygen ions. The switching is compliance-free due to the intrinsic series resistor by the filaments formed in the ZrO2 layers. By tuning the RESET voltages, controllable and stable multistate memory can be achieved which clearly points towards the capability of developing the next-generation multistate high-performance memory. PMID- 28582967 TI - Unraveling the Morphological Evolution and Etching Kinetics of Porous Silicon Nanowires During Metal-Assisted Chemical Etching. AB - Many potential applications of porous silicon nanowires (SiNWs) fabricated with metal-assisted chemical etching are highly dependent on the precise control of morphology for device optimization. However, the effects of key etching parameters, such as the amount of deposited metal catalyst, HF-oxidant molar ratio (chi), and solvent concentration, on the morphology and etching kinetics of the SiNWs still have not been fully explored. Here, the changes in the nanostructure and etch rate of degenerately doped p-type silicon in a HF-H2O2-H2O etching system with electrolessly deposited silver catalyst are systematically investigated. The surface morphology is found to evolve from a microporous and cratered structure to a uniform array of SiNWs at sufficiently high chi values. The etch rates at the nanostructure base and tip are correlated with the primary etching induced by Ag and the secondary etching induced by metal ions and diffused holes, respectively. The H2O concentration also affects the chi window where SiNWs form and the etch rates, mainly by modulating the reactant dilution and diffusion rate. By controlling the secondary etching and reactant diffusion via chi and H2O concentration, respectively, the fabrication of highly doped SiNWs with independent control of porosity from length is successfully demonstrated, which can be potentially utilized to improve the performance of SiNW-based devices. PMID- 28582968 TI - Influence of Conditions of Pd/SnO2 Nanomaterial Formation on Properties of Hydrogen Sensors. AB - Metal oxide sensors were created using nanosized tin dioxide obtained by a sol gel method. Gas-sensitive layers of the sensors were impregnated with PdCl2 solutions of different concentrations to increase sensitivities of the proposed sensors. Influence of different temperature conditions of the sensor formation on the sensor properties was studied. It was found that decreasing duration of high temperature sensor treatment prevents enlargement of particles of the gas sensitive materials. It was shown that the sensors based on materials with smaller particle sizes showed higher sensor responses to 40 ppm H2. Obtained results were explained in terms of substantial influence of length of the common boundaries between the material particles of tin dioxide and palladium on the gas sensitive properties of the sensors. The obtained sensors had possessed a fast response and recovery time and demonstrated stable characteristics during their long-term operation. PMID- 28582969 TI - Batch Fabrication of Broadband Metallic Planar Microlenses and Their Arrays Combining Nanosphere Self-Assembly with Conventional Photolithography. AB - A novel low-cost, batch-fabrication method combining the spin-coating nanosphere lithography (NSL) with the conventional photolithographic technique is demonstrated to efficiently produce the metallic planar microlenses and their arrays. The developed microlenses are composed of subwavelength nanoholes and can focus light effectively in the entire visible spectrum, with the foci sizes close to the Rayleigh diffraction limit. By changing the spacing and diameter of nanoholes, the focusing efficiency can be tuned. Although the random defects commonly exist during the self-assembly of nanospheres, the main focusing performance, e.g., focal length, depth of focus (DOF), and full-width at half maximum (FWHM), keeps almost invariable. This research provides a cheap way to realize the integrated nanophotonic devices on the wafer level. PMID- 28582970 TI - A novel constructed SPT15 mutagenesis library of Saccharomyces cerevisiae by using gTME technique for enhanced ethanol production. AB - During the last few years, the global transcription machinery engineering (gTME) technique has gained more attention as an effective approach for the construction of novel mutants. Genetic strategies (molecular biology methods) were utilized to get mutational for both genes (SPT15 and TAF23) basically existed in the Saccharomyces cerevisiae genome via screening the gTME approach in order to obtain a new mutant S. cerevisiae diploid strain. The vector pYX212 was utilized to transform these genes into the control diploid strain S. cerevisiae through the process of mating between haploids control strains S. cerevisiae (MAT-a [CICC 1374]) and (MAT-alpha [CICC 31144]), by using the oligonucleotide primers SPT15 EcoRI-FW/SPT15-SalI-RV and TAF23-SalI-FW/TAF23-NheI-RV, respectively. The resultant mutants were examined for a series of stability tests. This study showed how strong the effect of using strategic gTME with the importance of the modification we conducted in Error Prone PCR protocol by increasing MnCl2 concentration instead of MgCl2. More than ninety mutants we obtained in this study were distinguished by a high level production of bio-ethanol as compared to the diploid control strain. PMID- 28582971 TI - Degradation of aflatoxin B1 from naturally contaminated maize using the edible fungus Pleurotus ostreatus. AB - Aflatoxins are highly carcinogenic secondary metabolites that can contaminate approximately 25% of crops and that cause or exacerbate multiple adverse health conditions, especially in Sub-Saharan Africa and South and Southeast Asia. Regulation and decontamination of aflatoxins in high exposure areas is lacking. Biological detoxification methods are promising because they are assumed to be cheaper and more environmentally friendly compared to chemical alternatives. White-rot fungi produce non-specific enzymes that are known to degrade aflatoxin in in situ and ex situ experiments. The aims of this study were to (1) decontaminate aflatoxin B1 (AFB1) in naturally contaminated maize with the edible, white-rot fungus Pleurotus ostreatus (oyster mushroom) using a solid state fermentation system that followed standard cultivation techniques, and to (2) and to assess the risk of mutagenicity in the resulting breakdown products and mushrooms. Vegetative growth and yield characteristics of P. ostreatus were not inhibited by the presence of AFB1. AFB1 was degraded by up to 94% by the Blue strain. No aflatoxin could be detected in P. ostreatus mushrooms produced from AFB1-contaminated maize. Moreover, the mutagenicity of breakdown products from the maize substrate, and reversion of breakdown products to the parent compound, were minimal. These results suggest that P. ostreatus significantly degrades AFB1 in naturally contaminated maize under standard cultivation techniques to levels that are acceptable for some livestock fodder, and that using P. ostreatus to bioconvert crops into mushrooms can reduce AFB1-related losses. PMID- 28582972 TI - The impact of DO and salinity on microbial community in poly(butylene succinate) denitrification reactors for recirculating aquaculture system wastewater treatment. AB - The interactions between environmental factors and bacterial community shift in solid-phase denitrification are crucial for optimum operation of a reactor and to achieve maximum treatment efficiency. In this study, Illumina high-throughput sequencing was applied to reveal the effects of different operational conditions on bacterial community distribution of three continuous operated poly(butylene succinate) biological denitrification reactors used for recirculating aquaculture system (RAS) wastewater treatment. The results indicated that salinity decreased OTU numbers and diversity while dissolved oxygen (DO) had no obvious influence on OTU numbers. Significant microbial community composition differences were observed among and between three denitrification reactors under varied operation conditions. This result was also demonstrated by cluster analysis (CA) and detrended correspondence analysis (DCA). Hierarchical clustering and redundancy analysis (RDA) was performed to test the relationship between environmental factors and bacterial community compositions and result indicated that salinity, DO and hydraulic retention time (HRT) were the three key factors in microbial community formation. Besides, Simplicispira was detected under all operational conditions, which worth drawing more attention for nitrate removal. Moreover, the abundance of nosZ gene and 16S rRNA were analyzed by real-time PCR, which suggested that salinity decreased the proportion of denitrifiers among whole bacterial community while DO had little influence on marine reactors. This study provides an overview of microbial community shift dynamics in solid-phase denitrification reactors when operation parameters changed and proved the feasibility to apply interval aeration for denitrification process based on microbial level, which may shed light on improving the performance of RAS treatment units. PMID- 28582975 TI - Crystalline Supramolecular Gyroscope with a Water Molecule as an Ultrasmall Polar Rotator Modulated by Charge-Assisted Hydrogen Bonds. AB - A new strategy for the construction of crystalline molecular rotors is presented. The combination of a conformation-modifiable macrocyclic host and two cooperative guests affords one supramolecular gyroscope-like compound, (t-BuNH3)(18-crown 6)[ZnCl3(H2O)], in which the coordinated water molecule functions as an ultrasmall polar rotator, revealed by its significant dielectric relaxation and the molecular dynamics simulations. In addition, such a compound can reversibly undergo a polar-to-polar phase transition triggered by the changed conformation of the 18-crown-6 host, leading to a switchable on/off rotation of water molecule, well controlled by strength and direction of charge-assisted hydrogen bonds. PMID- 28582976 TI - Our Stainfree Future? A Virtual Issue on Poly- and Perfluoroalkyl Substances. PMID- 28582974 TI - Breathable Vapor Toxicant Barriers Based on Multilayer Graphene Oxide. AB - There is tremendous interest in graphene-based membranes as protective molecular barriers or molecular sieves for separation technologies. Graphene oxide (GO) films in the dry state are known to be effective barriers for molecular transport and to expand in the presence of moisture to create enlarged intersheet gallery spaces that allow rapid water permeation. Here we explore an application for GO membranes as water-breathable barrier layers for personal protective equipment, which are designed to allow outward perspiration while protecting the wearer from chemical toxicants or biochemical agents in the local environment. A device was developed to measure permeation rates of small-molecular toxicants in the presence of counter-current water flow simulating active perspiration. The technique was applied to trichloroethylene (TCE) and benzene, which are important environmental toxicants, and ethanol as a limiting case to model very small, highly water-soluble organic molecules. Submicron GO membranes are shown to be effective TCE barriers, both in the presence and absence of simulated perspiration flux, and to outperform current barrier technologies. A molecular transport model is developed, which suggests the limited toxicant back-permeation observed occurs not by diffusion against the convective perspiration flow in hydrophobic channels, but rather through oxidized domains where hydrogen-bonding produces a near-stagnant water phase. Benzene and ethanol permeation fluxes are higher than those for TCE, likely reflecting the effects of higher water solubility and smaller minimum molecular dimension. Overall, GO films have high water breathability relative to competing technologies and are known to exclude most classes of target toxicants, including particles, bacteria, viruses, and macromolecules. The present results show good barrier performance for some very small-molecule species, but not others, with permeation being favored by high water solubility and small minimum molecular dimension. PMID- 28582973 TI - A novel anti-CD22 scFv-apoptin fusion protein induces apoptosis in malignant B cells. AB - CD22 marker is a highly internalizing antigen which is located on the surface of B-cells and is being used as a promising target for treatment of B cell malignancies. Monoclonal antibodies targeting CD22 have been introduced and some are currently under investigation in clinical trials. Building on the success of antibody drug conjugates, we developed a fusion protein consisting of a novel anti-CD22 scFv and apoptin and tested binding and therapeutic effects in lymphoma cells. The recombinant protein was expressed in E. coli and successfully purified and refolded. In vitro binding analysis by immunofluorescence and flow cytometry demonstrated that the recombinant protein specifically binds to CD22 positive Raji cells but not to CD22 negative Jurkat cells. The cytotoxic properties of scFv-apoptin were assessed by an MTT assay and Annexin V/PI flow cytometry analysis and showed that the recombinant protein induced apoptosis preferentially in Raji cells with no detectable effects in Jurkat cells. Our findings indicated that the recombinant anti-CD22 scFv-apoptin fusion protein could successfully cross the cell membrane and induce apoptosis with high specificity, make it as a promising molecule for immunotherapy of B-cell malignancies. PMID- 28582977 TI - Sorption of Poly- and Perfluoroalkyl Substances (PFASs) Relevant to Aqueous Film Forming Foam (AFFF)-Impacted Groundwater by Biochars and Activated Carbon. AB - Despite growing concerns about human exposure to perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS), other poly- and perfluoroalkyl substances (PFASs) derived from aqueous film-forming foams (AFFFs) have garnered little attention. While these other PFASs may also be present in AFFF-impacted drinking water, their removal by conventional drinking-water treatment is poorly understood. This study compared the removal of 30 PFASs, including 13 recently discovered PFASs, from an AFFF-impacted drinking water using carbonaceous sorbents (i.e., granular activated carbon, GAC). The approach combined laboratory batch experiments and modeling: batch sorption data were used to determine partition coefficients (Kd) and calibrate a transport model based on intraparticle diffusion-limited sorption kinetics, which was used to make forward predictions of PFAS breakthrough during GAC adsorption. While strong retention was predicted for PFOS and PFOA, nearly all of the recently discovered polyfluorinated chemicals and PFOS-like PFASs detected in the AFFF-impacted drinking water were predicted to break through GAC systems before both PFOS and PFOA. These model breakthrough results were used to evaluate a simplified approach to predicting PFAS removal by GAC using compound-specific retention times on a C18 column (RTC18). Overall, this study reveals that GAC systems for the treatment of AFFF-impacted sources of water for PFOA and PFOS likely achieve poor removal, when operated only for the treatment of PFOS and PFOA, of many unmonitored PFASs of unknown toxicity. PMID- 28582978 TI - Detection and prevalence of antimicrobial resistance genes in Campylobacter spp. isolated from chickens and humans. AB - Campylobacter spp. are common pathogenic bacteria in both veterinary and human medicine. Infections caused by Campylobacter spp. are usually treated using antibiotics. However, the injudicious use of antibiotics has been proven to spearhead the emergence of antibiotic resistance. The purpose of this study was to detect the prevalence of antibiotic resistance genes in Campylobacter spp. isolated from chickens and human clinical cases in South Africa. One hundred and sixty one isolates of Campylobacter jejuni and Campylobacter coli were collected from chickens and human clinical cases and then screened for the presence of antimicrobial resistance genes. We observed a wide distribution of the tetO gene, which confers resistance to tetracycline. The gyrA genes that are responsible quinolone resistance were also detected. Finally, our study also detected the presence of the blaOXA-61, which is associated with ampicillin resistance. There was a higher (p < 0.05) prevalence of the studied antimicrobial resistance genes in chicken faeces compared with human clinical isolates. The tetO gene was the most prevalent gene detected, which was isolated at 64% and 68% from human and chicken isolates, respectively. The presence of gyrA genes was significantly (p < 0.05) associated with quinolone resistance. In conclusion, this study demonstrated the presence of gyrA (235 bp), gyrA (270 bp), blaOXA-61 and tetO antimicrobial resistance genes in C. jejuni and C. coli isolated from chickens and human clinical cases. This indicates that Campylobacter spp. have the potential of resistance to a number of antibiotic classes. PMID- 28582979 TI - The sero-prevalence and sero-incidence of African horse sickness and equine encephalosis in selected horse and donkey populations in Zimbabwe. AB - Sentinel herds and samples submitted by private equine practitioners were used to determine the sero-prevalence and sero-incidence of African horse sickness virus (AHSV) and equine encephalosis virus (EEV) in horse and donkey populations in the Highveld region of Zimbabwe. The sero-prevalence and sero-incidence of antibodies against these viruses were determined using the competitive enzyme-linked immunosorbent assay (ELISA) for the detection of serum antibodies. In donkeys, the median sero-prevalence of AHSV antibodies, across the three rainy seasons under study, was 75% (inter quartile range [IQR] 67-83), with a seasonal median sero-incidence of 45% (IQR 40-63). In horses, the median sero-prevalence of EEV antibodies was 63% (IQR 21-73), with a median seasonal sero-incidence of 10.5% (IQR 10-14), while in donkeys the median sero-prevalence of EEV antibodies was 80% (IQR 67-90), with a median seasonal sero-incidence of 50% (IQR 40-60). This study highlighted the significant levels of exposure of donkeys to AHSV and horses and donkeys to EEV in Zimbabwe despite equine encephalosis remaining unreported by Zimbabwean veterinarians to date. Most seroconversions in sentinel herd animals to AHSV and EEV occurred towards the end of the rainy season in March, April and May corresponding to the time of the year when the Culicoides vectors are in high abundance. In order to determine the clinical significance of these infections, blood and spleen samples, submitted by private equine veterinary practitioners over a 5-year period, from horses showing characteristic clinical signs of African horse sickness were tested for the presence of viral antigen using the antigen capture ELISA. The median sero-prevalence of AHSV antigen in horses recorded from these samples was 38% (IQR 33-88). The predominant AHSV antigen from these samples was serotype 7 (33%) followed by serotype 2 (26%) and serotypes 4 and 8 (16% each). African horse sickness virus serotypes 3 and 9, identified in this study, had not been previously reported in Zimbabwe. PMID- 28582980 TI - Prevalence of adolescent obesity at a high school in the City of Tshwane. AB - BACKGROUND: Obesity has been reported to be on the rise in the world and South Africa is no exception. In recent years obesity has been reported to contribute to the increasing number of people with hypertension and diabetes mellitus. Africa has the fastest growing number of overweight and obese adolescents, with indications that in 2010, it had more than doubled since 1990. Some people might perceive being overweight as being round and healthy which might contribute to the increased rate of obesity in South Africa. Physical and psychological changes that occur during adolescence can also be observed earlier during the preteen years (ages 9-12 years). During this time, peer groups and external appearance are of importance. Physical changes, such as obesity, might be perceived negatively by adolescents, affecting their self-esteem. OBJECTIVES: The purpose of the study was to determine the prevalence of adolescent obesity at a high school in the City of Tshwane. METHOD: A cross-sectional survey was conducted. Stratified random sampling was used and data were collected from 30% of the total population as recommended by the statistician. Data analysis was performed using descriptive analysis. Validity and reliability were ensured through calibrating the weight-monitoring scale and the measuring tape, which are collection tools. RESULTS: The results identified the prevalence of adolescent obesity at 8.57%. There is evidence of abdominal obesity and waist-hip ratio >= 1. The results show that there is a steady increase in obesity levels among adolescents. The poor response of parents was observed and could demonstrate the need to form stronger partnerships for weight reduction interventions. CONCLUSION: Evidence-based prevalence allowed for conceptualisation of the scope of the obesity epidemic and how children and young people are also affected. To enable proper planning for adolescent obesity interventions, the depth of consequences of obesity for the adolescent cohort should be well defined and clarified. PMID- 28582981 TI - Professional nurses' perceptions and experiences with the implementation of an integrated chronic care model at primary healthcare clinics in South Africa. AB - BACKGROUND: An integrated chronic disease management model has been implemented across primary healthcare clinics in order to transform the delivery of services for patients with chronic diseases. The sustainability and rapid scale-up of the model is dependent on positive staff perceptions and experiences. OBJECTIVES: The aim of the study was to determine the perceptions and experiences of professional nurses with the integrated chronic care model that has been implemented. METHOD: A cross-sectional descriptive survey utilising a self-administered questionnaire was conducted amongst all professional nurses who were involved in delivering primary healthcare services at the 42 implementing facilities in September 2014. Each facility has between four and eight professional nurses providing a service daily at the facilitiesResults: A total of 264 professional nurses participated in the survey. Prior to the implementation, 34% (91) of the staff perceived the model to be an added programme, whilst 36% (96) of the staff experienced an increased workload. Staff noted an improved process of care, better level of interaction with patients, improved level of knowledge and better teamwork coupled with an improved level of satisfaction with the work environment at the clinic after implementation of the integrated chronic disease model. CONCLUSION: Professional nurses have a positive experience with the implementation of the integrated chronic disease management model. PMID- 28582982 TI - The role of emotional intelligence and organisational support on work stress of nurses in Ibadan, Nigeria. AB - BACKGROUND: Universally, nurses have been reported to be a group at high risk of workplace stress. However, nurses' responses to stressful situations at work could be the outcomes of individual differences and organisational factors. OBJECTIVES: We examined the independent and joint contributions of four dimensions of emotional intelligence and perceived organisational support in work stress of nurses in a teaching hospital in Nigeria. METHODS: The study was a cross-sectional survey research design, which selected 228 (41 male and 187 female nurses) nurses through the use of convenience sampling. Questionnaires comprising demographics with work stress, organisational support and emotional intelligence scales were administered to the sampled 228 nurses in the study. Data were analysed with the use of correlational matrix and hierarchical multiple regression. RESULTS: Self-emotion appraisal, others' emotion appraisal, use of emotion, regulation of emotion and perceived organisational support were found to have joint contributions to explaining work stress among nurses. Others' emotion appraisal, use of emotion and perceived organisational support were found to have independent relationships with work stress. CONCLUSION: Our findings stress that judgement of others' emotions, accurate use of emotion by nurses and support from management of the hospital are most important in explaining their reactions towards work-related stress. PMID- 28582983 TI - Occurrence of Coxiella burnetii, Ehrlichia canis, Rickettsia species and Anaplasma phagocytophilum-like bacterium in ticks collected from dogs and cats in South Africa. AB - Ticks are major vectors of arthropod-borne infections and transmit a wide variety of zoonotic pathogens. This study was conducted mainly to determine the occurrence of canine tick-borne bacterial and rickettsial pathogens especially those with zoonotic potential. We examined 276 Rhipicephalus sanguineus, 38 Haemaphysalis elliptica and 4 Amblyomma hebraeum ticks from 90 dogs and 4 cats from the Free State, KwaZulu-Natal, North West and Mpumalanga provinces. DNA of Coxiella burnetii (41%), Ehrlichia or Anaplasma (18%), Rickettsia spp. (37%), Anaplasma phagocytophilum-like bacterium (18%) and Ehrlichia canis (19%) was detected by polymerase chain reaction (PCR) from a total of 147 pooled DNA samples. All samples were negative for the presence of Borrelia burgdorferi DNA. Ehrlichia canis was detected in samples from all the provinces except the North West; A. phagocytophilum was absent in KwaZulu-Natal samples, whereas Rickettsia species and C. burnetii were detected in all sampled provinces. The PCRpositive samples were confirmed by direct sequencing of the product. Data from this study calls for a joint effort by both veterinary and medical sectors to conduct epidemiological studies of the zoonotic pathogens in both animals and humans. PMID- 28582984 TI - Ileal hypertrophy and associated true diverticulum as a cause of colic in a horse. AB - A 4-year-old Thoroughbred gelding underwent an explorative celiotomy for a suspected small intestinal obstruction. During surgery, an impacted diverticulum of the ileum was suspected, necessitating a jejunocaecostomy. The owner opted for euthanasia. On post-mortem examination and histopathology, a true diverticulum on the mesenteric side of the ileum, with ileal hypertrophy, was diagnosed. PMID- 28582985 TI - Septic pericarditis and pneumopericardium in a dog with an oesophageal foreign body. AB - A 5-year-old, intact, male Yorkshire Terrier presented with a 6-day history of lethargy and anorexia. Clinical examination revealed dental plaque accumulation, abdominal effort during respiration and muffled heart sounds. Thoracic radiographs revealed an enlarged globoid cardiac silhouette and mild pneumopericardium, transthoracic ultrasonography revealed a pericardial effusion after which pericardiocentesis, cytology and culture diagnosed septic pericarditis. Three multidrug-resistant bacteria were isolated, two of which have been implicated in gas-producing infections before. Medical management failed to resolve the pericarditis and euthanasia was opted for. A chronic osseocartilaginous oesophageal foreign body cranial to the heart base was found on necropsy. Septic pericarditis and pneumopericardium are rare conditions in dogs. This is the first case to describe a multidrug-resistant polybacterial aetiology causing mild pneumopericardium and only the second case to describe septic pericarditis associated with an oesophageal foreign body. PMID- 28582986 TI - Reaching national consensus on the core clinical skill outcomes for family medicine postgraduate training programmes in South Africa. AB - BACKGROUND: Family physicians play a significant role in the district health system and need to be equipped with a broad range of clinical skills in order to meet the needs and expectations of the communities they serve. A previous study in 2007 reached national consensus on the clinical skills that should be taught in postgraduate family medicine training prior to the introduction of the new speciality. Since then, family physicians have been trained, employed and have gained experience of working in the district health services. The national Education and Training Committee of the South African Academy of Family Physicians, therefore, requested a review of the national consensus on clinical skills for family medicine training. METHODS: A Delphi technique was used to reach national consensus in a panel of 17 experts: family physicians responsible for training, experienced family physicians in practice and managers responsible for employing family physicians. RESULTS: Consensus was reached on 242 skills from which the panel decided on 211 core skills, 28 elective skills and 3 skills to be deleted from the previous list. The panel was unable to reach consensus on 11 skills. CONCLUSION: The findings will guide training programmes on the skills to be addressed and ensure consistency across training programmes nationally. The consensus will also guide formative assessment as documented in the national portfolio of learning and summative assessment in the national exit examination. The consensus will be of interest to other countries in the region where training programmes in family medicine are developing. PMID- 28582987 TI - A review of patients presenting to accident and emergency department with deliberate self-harm, KwaZulu-Natal, South Africa. AB - BACKGROUND: The World Health Organization has described deliberate self-harm (DSH) as a major global health challenge. Little is known about the profile of patients admitted following DSH at district and regional combo hospitals in KwaZulu-Natal, South Africa. AIM: The aim of this study was to assess the profiles of patients and reasons for admission following DSH. SETTING: The study was conducted on data from a busy Accident and Emergency (A&E) department in a combination district and regional hospital situated in Empangeni in northern KwaZulu-Natal. METHOD: This was a retrospective descriptive study. Data were collected from charts of all patients admitted to the A&E department from April 2012 to March 2013 following DSH. Variables assessed included age, gender, race, occupation, religion, education level, coexisting medical and mental health conditions, and reasons for DSH. Data were entered into SPSS and analysed descriptively. RESULTS: A total of 262 charts were identified and 215 (82%) were selected for inclusion. Most patients admitted following DSH were young, single African women with at least secondary-level education. Most (169/215;78%) admissions were for parasuicide, with relational issues contributing in more than 50% of cases and circumstance challenges contributing in just under 30%. CONCLUSION: Although an underestimation, DSH is not an uncommon reason for patients to present in the A&E at this district and regional combo hospital. Findings from this study are consistent with those of other studies on DSH and highlight the need for a validated screening tool for the identification of patients at risk of DSH. There is a need to explore community-based intervention, which could address reasons for DSH and prevent future admissions. PMID- 28582988 TI - Trust of community health workers influences the acceptance of community-based maternal and child health services. AB - BACKGROUND: Community health workers (CHWs) are a component of the health system in many countries, providing effective community-based services to mothers and infants. However, implementation of CHW programmes at scale has been challenging in many settings. AIM: To explore the acceptability of CHWs conducting household visits to mothers and infants during pregnancy and after delivery, from the perspective of community members, professional nurses and CHWs themselves. SETTING: Primary health care clinics in five rural districts in KwaZulu-Natal, South Africa. METHODS: A qualitative exploratory study was conducted where participants were purposively selected to participate in 19 focus group discussions based on their experience with CHWs or child rearing. RESULTS: Poor confidentiality and trust emerged as key barriers to CHW acceptability in delivering maternal and child health services in the home. Most community members felt that CHWs could not be trusted because of their lack of professionalism and inability to maintain confidentiality. Familiarity and the complex relationships between household members and CHWs caused difficulties in developing and maintaining a relationship of trust, particularly in high HIV prevalence settings. Professional staff at the clinic were crucial in supporting the CHW's role; if they appeared to question the CHW's competency or trustworthiness, this seriously undermined CHW credibility in the eyes of the community. CONCLUSION: Understanding the complex contextual challenges faced by CHWs and community members can strengthen community-based interventions. CHWs require training, support and supervision to develop competencies navigating complex relationships within the community and the health system to provide effective care in communities. PMID- 28582989 TI - A situation analysis of psychiatrists in South Africa's rural primary healthcare settings. AB - BACKGROUND: South Africa (SA) has been facing serious challenges in providing human resources for the delivery of essential mental health (MH) services. The majority of its prescribing MH specialists, psychiatrists, practise in private, urban and peri-urban areas. The findings of a situation analysis audit of psychiatrist human resources in the public rural primary healthcare (PRPHC) sector are presented in this paper. METHOD: This audit was based on both primary and secondary data. The primary data were obtained from key informant interviews with the clinical heads of 160 PRPHC facilities, while the secondary data comprised a literature review. RESULTS: The results indicate that psychiatrists are severely underrepresented, employed at a rate of 0.03 per 100 000 population in SA's PRPHC settings. CONCLUSIONS: Because of a lack of MH nurses and medical officers dedicated to MH in PRPHC facilities, recommendations are made that the current task shifting strategy be revisited to include more cadres of MH professionals with specialised psychopharmacological training, as non-medical prescribers at PRPHC level. It is advised that visiting psychiatrists and family physicians be involved in the construction of training and supervision programmes for non-medical prescribers at the primary healthcare level. PMID- 28582990 TI - To what extent does access to improved sanitation explain the observed differences in infant mortality in Africa? AB - BACKGROUND: To my knowledge, there was no systematic study so far that analysed the extent of the impact of improved sanitation on infant mortality in the African context with long years of full-fledged longitudinal data. AIM: The aim of this study was to empirically examine the extent to which improved sanitation explains the observed differences in infant mortality under 5 years of age across African countries. SETTING: The study covered a panel of 33 countries from north, south, east, west and central Africa for the years 1994-2013. METHODS: The study first conducted Durbin-Wu-Hausman specification test and then used fixed effect model. In addition, Praison-Winsten regression with corrected heteroscedasticity was employed to verify the consistency of the results that were revealed in using fixed effect estimation method. RESULTS: The study revealed that a 1% increase in access to improved sanitation would reduce infant mortality by a rate of about two infant deaths per 1000 live births. Also, the study confirmed that a significant decline in infant mortality rate was highly linked to improvements in education, health and sustainable economic growth. CONCLUSION: The findings have wide implications especially for African countries for which decreasing infant mortality is one of the most crucial priorities in the continent to reverse the current deep-rooted challenges related to human capital formation. PMID- 28582991 TI - Insights into health care seeking behaviour for children in communities in KwaZulu-Natal, South Africa. AB - BACKGROUND: South African infant and child mortality remains high, with many deaths occurring outside the formal health services. Delayed health care seeking represents a large proportion of these deaths. AIM: To generate knowledge about the role of, and influences on, caregivers with regard to decision-making about when and where to seek care for sick children. SETTING: Two communities in KwaZulu-Natal. METHODS: A qualitative, exploratory design employing participatory research techniques was used to undertake focus group discussions with community members. RESULTS: Health care seeking for a sick child was described as a complex process influenced by multiple carers using multiple providers. Decision-making about seeking health care for a sick child was not an individual effort, but was shared with others in the household and guided by how the symptoms were perceived, either a Western illness or African illness. A sick child could either be treated at home or be taken to a variety of places including clinics, private doctors, traditional healers, faith healers and hospitals. Traditional healers were associated with the treatment of illnesses perceived to be traditional. Few participants said that they would take their child back to the original health provider if the child remained ill, but would move from one provider to another until the child's health improved. CONCLUSION: The formal health system needs to ensure that sick children are identified and managed appropriately to reduce child deaths. Knowledge and understanding of health care seeking behaviour for sick children by carers is an important aspect. Interventions need to be designed with these contextual issues in mind. PMID- 28582992 TI - The perceived role of ward-based primary healthcare outreach teams in rural KwaZulu-Natal, South Africa. AB - BACKGROUND: The aim of ward-based outreach teams (WBOTs) is to improve access to primary healthcare (PHC) services including health promotion and disease prevention in South Africa. Limited information is available in South Africa on user perceptions of services provided by WBOTs in rural households. AIM: The study aimed to explore community awareness and perception of WBOTs, as well people's motivation to engage and use WBOT services. SETTING: The study was conducted between July and September 2015 in iLembe district, KwaZulu-Natal. METHODS: This was exploratory-descriptive qualitative research. Purposive sampling technique was used in this study. A total of 16 key informant interviews and 4 focus group discussions were conducted. The voice recordings were transcribed in isiZulu and translated into English. RESULTS: Four themes emerged from the data analysis, namely bringing services closer, organising services, expanding services and forming bridges. Respondents demonstrated insightful knowledge and understanding of services provided by WBOTs. They expressed an appreciation of the way WBOT services brought healthcare closer to people and serve to bridge the gap between the community and local healthcare facilities. Respondents identified unclear WBOT work schedules and the failure to carry medication other than vitamin A as the main challenges. However, WBOTs did deliver medication for controlled chronic patients in their households. CONCLUSION: The study suggests that WBOTs provide a commendable service, but need to expand their service package to further increase access to PHC services and cater for community health needs. PMID- 28582993 TI - Mapping evidence of interventions and strategies to bridge the gap in the implementation of the prevention of mother-to-child transmission of HIV programme policy in sub-Saharan countries: A scoping review. AB - BACKGROUND: Prevention of mother-to-child transmission (PMTCT) of HIV is a life saving public health intervention. Sub-Saharan African (SSA) countries have made significant progress in the programme, but little is known about the strategies used by them to eliminate mother-to-child transmission of HIV. AIM: To map evidence of strategies and interventions employed by SSA in bridging the implementation gap in the rapidly changing PMTCT of HIV programme policy. METHODS: Electronic search of the databases MEDLINE, PubMed and SABINET for articles published in English between 2001 and August 2016. Key words included 'Sub-Saharan African countries', 'implementation strategies', 'interventions to bridge implementation gap', 'prevention of mother-to-child transmission of HIV' and 'closing implementation gap'. RESULTS: Of a total of 743 articles, 25 articles that met the inclusion criteria were included in the study. Manual content analysis resulted in the identification of three categories of strategies: (1) health system (referral systems, integration of services, supportive leadership, systematic quality-improvement approaches that vigorously monitors programme performance); (2) health service delivery (task shifting, networking, shared platform for learning, local capacity building, supportive supervision); as well as (3) community-level strategies (community health workers, technology use - mHealth, family-centred approaches, male involvement, culturally appropriate interventions). CONCLUSION: There are strategies that exist in SSA countries. Future research should examine multifaceted scientific models to prioritise the highest impact and be evaluated for effectiveness and efficiency. PMID- 28582994 TI - Which primary care model? A qualitative analysis of ward-based outreach teams in South Africa. AB - : Globally, models of extending universal health coverage through primary care are influenced by country-specific systems of health care and disease management. In 2015 a rapid assessment of the ward-based outreach component of primary care reengineering was commissioned to understand implementation and rollout challenges. AIM: This article aims to describe middle- and lower-level managers' understanding of ward-based outreach teams (WBOTs) and the problems of authority, jurisdiction and practical functioning that arise from the way the model is constructed and has been operationalised. SETTING: Data are drawn from a rapid assessment of National Health Insurance (NHI) pilot sites in seven provinces. METHODS: The study used a modified version of CASCADE. Peer-review teams of public health researchers and district/sub-district managers collected data in two sites per province between March and July 2015. RESULTS: Respondents unequivocally support the strategy to extend primary health care services to people in their homes and communities both because it is responsive to the family context of individual health and because it reaches marginal people. They, however, identify critical issues that arise from basing WBOTs in facilities, including unspecific team leadership, inadequate supervision, poorly constituted teams, limited community reach and serious infrastructural and material under provision. CONCLUSION: Many of the shortcomings of a facility-based extension model can be addressed by an independently resourced, geographic, community-based model of fully constituted teams that are clinically and organisationally supported in an integrated district health system. However, a community-oriented primary care approach will still have to grapple with overarching framework problems. PMID- 28582995 TI - Palliative care needs of patients living with end-stage kidney disease not treated with renal replacement therapy: An exploratory qualitative study from Blantyre, Malawi. AB - BACKGROUND: The burden of end-stage kidney disease (ESKD) in sub-Saharan Africa is increasing rapidly but the palliative care needs of patients living with ESKD are not well described. Resource limitations at both health system and patient level act as major barriers to patients receiving renal replacement therapy (RRT) in the form of dialysis. We undertook an exploratory qualitative study to describe the palliative care needs of patients with ESKD who were not receiving RRT, at a government teaching hospital in Blantyre, Malawi. METHODS: A qualitative, explorative and descriptive design was used. Study participants were adults aged > 18 years with an estimated glomerular filtration rate < 15 ml/min on two separate occasions, three months apart, who either chose not to have or were not deemed suitable for RRT. Data were collected by means of semi-structured interviews. RESULTS: In October and November 2013, interviews were conducted with 10 adults (7 women with median age of 60.5 years). All were hypertensive and four were on treatment for HIV. Four themes emerged from the data: changes in functional status because of physical symptoms, financial challenges impacting hospital care, loss of role within the family and the importance of spiritual and cultural beliefs. CONCLUSION: This study reports on four thematic areas which warrant further quantitative and qualitative studies both in Malawi and other low resource settings, where a growing number of patients with ESKD unable to access RRT will require palliative care in the coming years. PMID- 28582998 TI - Comparison of Levetiracetam Dosing Regimens in End-Stage Renal Disease Patients Undergoing Intermittent Hemodialysis. AB - BACKGROUND: Levetiracetam (LEV) is primarily renally eliminated. In end-stage renal disease (ESRD) patients on hemodialysis (HD), pharmacokinetic studies recommend daily dosing with 50% supplemental doses after 4-hour HD sessions. However, poor medication adherence after HD could result in fluctuating plasma drug levels. OBJECTIVE: To compare two LEV dosing regimens, daily versus twice daily (BID), in ESRD patients undergoing HD. METHODS: Consecutive ESRD patients (April 2013 to May 2014) receiving maintenance inpatient HD and prescribed LEV prior to admission to our academic tertiary hospital were prospectively analyzed. Demographics, initial lab values, adverse reactions, seizures, and LEV regimens were recorded. LEV levels were obtained pre-HD and post-HD along with levels after receiving post-HD doses. Recovery of plasma levels after HD was assessed by comparison of levels predialysis versus postdialysis and post-HD doses. RESULTS: We identified 22 patients who met inclusion criteria; 14 BID and 8 daily dosing. Mean predialysis, postdialysis, and post-HD dose plasma levels were higher in patients receiving LEV BID compared with daily (43.1 +/- 6.3, 19.4 +/- 5.2, 34.9 +/- 4.3 vs 21.1 +/- 3.9, 6.9 +/- 1.5, 11.9 +/- 1.7 ug/mL; P < 0.05). BID post-HD levels were 41.9 +/- 4.6% of predialysis levels versus 36.9 +/- 7.3% with daily dosing ( P = 0.275). Post-HD dose levels were 81.4+/-4.3% of predialysis on LEV BID versus 65.7 +/- 8.8% on LEV daily ( P = 0.045). No seizures were reported during hospital admission in either group. CONCLUSIONS: Compared to LEV daily, BID dosing achieved significantly higher levels and a better recovery to predialysis levels. Although limited by small numbers, a similar relationship between postdialysis levels was not detected. PMID- 28582996 TI - Barriers and opportunities to implementation of sustainable e-Health programmes in Uganda: A literature review. AB - BACKGROUND: Most developing countries, including Uganda, have embraced the use of e-Health and m-Health applications as a means to improve primary healthcare delivery and public health for their populace. In Uganda, the growth in the information and communications technology industry has benefited the rural communities and also created opportunities for new innovations, and their application into healthcare has reported positive results, especially in the areas of disease control and prevention through disease surveillance. However, most are mere proof-of-concepts, only demonstrated in use within a small context and lack sustainability. This study reviews the literature to understand e Health's current implementation status within Uganda and documents the barriers and opportunities to sustainable e-Health intervention programmes in Uganda. METHODS: A structured literature review of e-Health in Uganda was undertaken between May and December 2015 and was complemented with hand searching and a document review of grey literature in the form of policy documents and reports obtained online or from the Ministry of Health's Resource Centre. RESULTS: The searches identified a total of 293 resources of which 48 articles met the inclusion criteria of being in English and describing e-Health implementation in Uganda. These were included in the study and were examined in detail. CONCLUSION: Uganda has trialled several e-Health and m-Health solutions to address healthcare challenges. Most were donor funded, operated in silos and lacked sustainability. Various barriers have been identified. Evidence has shown that e-Health implementations in Uganda have lacked prior planning stages that the literature notes as essential, for example strategy and need readiness assessment. Future research should address these shortcomings prior to introduction of e-Health innovations. PMID- 28582997 TI - Breastfeeding and swallowing in a neonate with mild hypoxic-ischaemic encephalopathy. AB - BACKGROUND: Specific breastfeeding and swallowing characteristics in neonates with hypoxic-ischaemic encephalopathy (HIE) have not yet been well described in the literature. Considering the relatively high incidence of HIE in resource-poor settings, speech-language therapists should be cognisant of the feeding difficulties in this population during breastfeeding. OBJECTIVE: To systematically describe the breastfeeding and swallowing of a single case of a neonate diagnosed with mild HIE from admission to discharge. METHOD: A case study of a 2-day old neonate with mild HIE in a neonatal intensive care unit at an urban teaching hospital, is presented. Data were prospectively collected during four sessions in a 12-day period until the participant's discharge. Feeding and swallowing were assessed clinically, as well as instrumentally using a video fluoroscopic swallow study. RESULTS: After parenteral feeding, nasogastric tube feeding commenced. Breastfeeding was introduced on Day 6, as it was considered a safe option, and revealed problematic rooting, shallow latching, short sucking bursts, infrequent swallowing, and a drowsy state of arousal, with coughing and choking. No penetration or aspiration was identified instrumentally. After 13 days, the neonate was breastfeeding safely. CONCLUSION: Although the pharyngeal stage of swallowing was intact, symptoms of oral stage dysphagia were revealed using a combination of clinical and instrumental measures. Breastfeeding difficulties were identified, exacerbated by poor state regulation, which lead to prolonged hospitalisation. The case study highlights the unexpected long duration of feeding difficulties in an infant with mild HIE and indicates further research. PMID- 28582999 TI - Addressing College Drinking as a Statewide Public Health Problem: Key Findings From the Maryland Collaborative. AB - Excessive drinking among college students is a serious and pervasive public health problem. Although much research attention has focused on developing and evaluating evidence-based practices to address college drinking, adoption has been slow. The Maryland Collaborative to Reduce College Drinking and Related Problems was established in 2012 to bring together a network of institutions of higher education in Maryland to collectively address college drinking by using both individual-level and environmental-level evidence-based approaches. In this article, the authors describe the findings of this multilevel, multicomponent statewide initiative. To date, the Maryland Collaborative has succeeded in providing a forum for colleges to share knowledge and experiences, strengthen existing strategies, and engage in a variety of new activities. Administration of an annual student survey has been useful for guiding interventions as well as evaluating progress toward the Maryland Collaborative's goal to measurably reduce high-risk drinking and its radiating consequences on student health, safety, and academic performance and on the communities surrounding college campuses. The experiences of the Maryland Collaborative exemplify real-world implementation of evidence-based approaches to reduce this serious public health problem. PMID- 28583000 TI - Suicide in primary headaches in 48 countries: A physician-survey based study. AB - Aim To investigate the relationship between primary headache types and accomplished or attempted suicide in countries from all world regions. Methods Data were obtained using a questionnaire about suicide due to headache in a face to-face interview with 203 physicians with expertise in headaches. They came from 48 countries, and from all continents. Results Primary headaches cause one suicide per 1,000,000 population each year (1% of the suicide rate due to all causes). Cluster headache and migraines account for 70-80% of them. Suicide attempts are 10 times more frequent than accomplished suicides. Cluster headache poses more risk than migraine. This risk is not often acknowledged, and is increased if there is previous psychiatric history. More than half of the physicians interviewed think it could be reduced with a more aggressive treatment of headaches. Conclusions Cluster headache and migraine are not always benign, and are the cause of the majority of suicides due to headache. PMID- 28583001 TI - Redox-triggered mitoxantrone prodrug micelles for overcoming multidrug-resistant breast cancer. AB - Multidrug resistance (MDR) severely hinders the efficient chemotherapeutic treatments of cancer. d-alpha-Tocopherol polyethylene 1000 succinate (TPGS) based drug delivery system holds the potential of re-sensitizing resistant cancer cells. In this study, a TPGS prodrug containing both TPGS and mitoxantrone (MTO) via a disulphide bond was synthesised and assembled into micelle (TSMm) with a monodispersed diameter of 46.50 +/- 1.12 nm. The disulphide bonds within the micelles could be cleaved in response to a high concentration of intracellular glutathione (GSH) after entering the tumour cells, leading a rapid release of MTO. In vitro cytotoxicity study showed TSMm significantly inhibited the growth of resistant breast tumour cells MDA-MB-231/MDR comparing to either free MTO or disulphide-free prodrug micelle (TCMm). In addition, TSMm could sustain favourable intracellular retention and cause the depletion of ATP activity, leading to the preferential transportation of MTO into the nucleus and the reversal of MDR. In vivo imaging also verified that TSMm was specifically targeted to the tumour regions at 24 h post injection. Finally, TSMm has significantly stronger antitumor activity in xenograft nude mice with negligible side effects. Hence, TSMm can serve as promising prodrug candidates to strengthen the reversal of MDR in tumours with less side effects. PMID- 28583002 TI - Telomere Length Is Associated With Cardiometabolic Factors in US Adults. AB - Telomere length (TL) has been associated with age-related health outcomes. We investigated the relationship of TL with cardiometabolic risk profile in adult Americans. We used the National Health and Nutrition Examination Surveys for 1999 to 2002, accounting for complex sampling and survey design. Of the 8892 eligible participants, 47.8% (n = 4123) were men. Mean serum high-density lipoprotein cholesterol concentrations significantly increased across increasing TL quarters ( P = .013), and mean fat mass, fat-free mass, hemoglobin A1c (HbA1c), and C reactive protein significantly decreased across increasing TL quarters (all P < .001) in men. Only HbA1c levels significantly decreased across increasing TL quarters ( P = .041) in women. Males in the upper quarter of TL had lower (38%) odds of prevalent metabolic syndrome compared with those in the lower quarter ( P < .001). These results support the hypotheses that cardiometabolic factors are related to TL, especially in men. PMID- 28583003 TI - Transcranial Doppler to Detect Right to Left Communication: Evaluation Versus Transesophageal Echocardiography in Real Life. AB - We compared transcranial Doppler (TCD) with transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE) for the detection of right to left communication (RLC) in the heart. All patients explored from 2013 to 2016 in a vascular medicine unit to detect RLC by TCD were included. Right to left communication was detected by TCD monitoring for microembolic signals after intravenous injection of agitated 5% glucose and air. One hundred one patients were explored for RLC by TCD, 64 by TEE (not possible in 10, bubble injection in 51), and 93 by TTE because of unexplained stroke or arterial thrombosis (51 males, 50 females, age 51.0 +/- 15.8 years) (bubble injection in 35). Fifty-three patients were positive after TCD (TEE: 4 negative, TTE: 7 negative). Of the negative patients after TCD, none was positive for TEE and 1 was positive for TTE with no evidence of patent foramen ovale. Transcranial Doppler was sensitive to detect RLC, even in patients with negative TTE or TTE. A negative TEE did not exclude RLC demonstrated by TCD. Transcranial Doppler might be proposed as first line to detect RLC. PMID- 28583004 TI - Optimizing health system response to patient's needs: an argument for the importance of functioning information. AB - BACKGROUND: Current health systems are increasingly challenged to meet the needs of a growing number of patients living with chronic and often multiple health conditions. The primary outcome of care, it is argued, is not merely curing disease but also optimizing functioning over a person's life span. According to the World Health Organization, functioning can serve as foundation for a comprehensive picture of health and augment the biomedical perspective with a broader and more comprehensive picture of health as it plays out in people's lives. The crucial importance of information about patient's functioning for a well-performing health system, however, has yet to be sufficiently appreciated. METHODS: This paper argues that functioning information is fundamental in all components of health systems and enhances the capacity of health systems to optimize patients' health and health-related needs. RESULTS AND CONCLUSION: Beyond making sense of biomedical disease patterns, health systems can profit from using functioning information to improve interprofessional collaboration and achieve cross-cutting disease treatment outcomes. Implications for rehabilitation Functioning is a key health outcome for rehabilitation within health systems. Information on restoring, maintaining, and optimizing human functioning can strengthen health system response to patients' health and rehabilitative needs. Functioning information guides health systems to achieve cross-cutting health outcomes that respond to the needs of the growing number of individuals living with chronic and multiple health conditions. Accounting for individuals functioning helps to overcome fragmentation of care and to improve interprofessional collaboration across settings. PMID- 28583005 TI - Development and Validation of the Faceted Inventory of the Five-Factor Model (FI FFM). AB - The Faceted Inventory of the Five-Factor Model (FI-FFM) is a comprehensive hierarchical measure of personality. The FI-FFM was created across five phases of scale development. It includes five facets apiece for neuroticism, extraversion, and conscientiousness; four facets within agreeableness; and three facets for openness. We present reliability and validity data obtained from three samples. The FI-FFM scales are internally consistent and highly stable over 2 weeks (retest rs ranged from .64 to .82, median r = .77). They show strong convergent and discriminant validity vis-a-vis the NEO, the Big Five Inventory, and the Personality Inventory for DSM-5. Moreover, self-ratings on the scales show moderate to strong agreement with corresponding ratings made by informants ( rs ranged from .26 to .66, median r = .42). Finally, in joint analyses with the NEO Personality Inventory-3, the FI-FFM neuroticism facet scales display significant incremental validity in predicting indicators of internalizing psychopathology. PMID- 28583006 TI - Perceived effects of home renovation on independence of physically disabled Koreans living at home. AB - PURPOSE: This study aims to identify the potential effects of home renovation on independence promotion of physically disabled Koreans living at home. METHOD: The method of the study is a survey with a questionnaire; subjects are physically disabled people living at home in rural and urban areas in Korea. The Functional Independence Measure was used to measure changes in subjects' levels of independence. RESULTS: It was expected that if homes were renovated according to individual needs, disabled people's independence level would be increased by one or more level compared to their current daily independence level in their existing homes. In particular, independence levels concerning bathing and locomotion, which are low in existing conditions, were expected to increase significantly with renovation. Such effects on independence level were conspicuous for disabled people in rural area. CONCLUSION: The results prove the positive effects of home renovations of disabled people's independence, thus providing meaningful academic evidence on home renovations for disabled people. Implication for rehabilitation Korea had a culture where support measures to aid the life independence of disabled persons relied heavily on human services, leading to a lack of diversity in support measures. By closing the gap between the resident's disability and the inadequacy in their prevailing environment, house remodeling can be a crucial intervention for improving the independence of disabled persons in their daily lives. Depending on the nature of their disabilities and their residential arrangements, disabled persons have diverse needs regarding home remodeling. Implementing home remodeling in such a manner that suits the resident's needs is crucial to boosting their independence. Because of this, remodeling personnel must interact with residents prior to the renovation while also strengthening their expertise. PMID- 28583007 TI - Biosynthesized gold and silver nanoparticles by aqueous fruit extract of Chaenomeles sinensis and screening of their biomedical activities. AB - The design of mild and non-toxic synthesis of metallic nanoparticles is a topical subject in the nanotechnology field. The objective of this present study is to screen the bioactivity of biosynthesized nanoparticles by aqueous fruit extract of Chaenomeles sinensis. The reducing and stabilizing ability of C. sinensis to fabricate gold (Cs-AuNps) and silver (Cs-AgNps) nanoparticles was confirmed by UV visible (UV-Vis) spectroscopy at 562 nm and 477 nm, respectively. The field emission transmission electron microscopy (FE-TEM) and X-ray diffraction analysis (XRD) verify the nano-scale morphology and crystallinity of Cs-AuNps (20-40 nm) and Cs-AgNps (5-20 nm). Furthermore, we evaluated the 2,2-diphenyl-1 picrylhydrazyl (DPPH) radical-scavenging capacity, antimicrobial activity against Staphylococcus aureus and Escherichia coli and cytotoxicity against breast cancer cells. The results showed that Cs-AuNps (IC50: 725.93 MUg/mL) displayed superior inhibitory activities on DPPH than Cs-AuNps. The biosynthesized Cs-AuNps successfully inhibited the growth of pathogenic bacteria S. aureus (ATCC 6538) and E. coli (BL21). The cytotoxic effect of Cs-AuNps and Cs-AgNps was evaluated in murine macrophage (RAW264.7) and human breast cancer cell lines (MCF7) by MTT assay. Thus, the present study explores the biomedical applications of gold and silver nanoparticles synthesized by C. sinensis. PMID- 28583008 TI - Effect of exposure time, particle size and uptake pathways in immune cell lysosomal cytotoxicity of mussels exposed to silver nanoparticles. AB - Cytotoxicity evaluation of hemocytes (lysosomal membrane stability [LMS] assay) from Mytilus galloprovincialis Lamarck, exposed to a sublethal dose (100 MUg/L) of two size of silver nanoparticles (AgNPs: <50 nm and <100 nm) - prior to and after inhibition of potential uptake pathways (i.e., clathrin- and caveolae mediated endocytosis) within different times of exposure (3, 6, 12 h) - showed that there was a significant cytotoxic effect on immune cells of mussels exposed for different times to either AgNP size (p < 0.01); the greater effect was with the smaller size. However, hemocytes seemed more sensitive to the larger AgNP after clathrin-mediated endocytosis was blocked (p < 0.01); this was not so with inhibition of caveolae-mediated endocytosis. Dimethyl-sulfoxide (DMSO) did not impart a carrier-mediated effect despite an enhanced cytotoxicity when DMSO was present with AgNP. From these results, it is concluded that the immunotoxicity of AgNP in mussels was size-dependent as well as length of exposure-dependent. It was also clear that nanoparticles (NP) internalization mechanisms were a major factor underlying any toxicity. PMID- 28583009 TI - Inhibition of alpha-Synuclein contributes to the ameliorative effects of dietary flavonoids luteolin on arsenite-induced apoptotic cell death in the dopaminergic PC12 cells. AB - Arsenite is a toxic metalloid that may increase the risk of Parkinson's disease by inducing dopaminergic neuronal apoptosis. Luteolin, a common dietary flavonoid, possesses variety of biological functions, but potential effects of luteolin on arsenite toxicity remain elusive. In this study, we demonstrated that luteolin prevented arsenite-induced apoptosis in the dopaminergic PC12 cells. Administration of luteolin to cells attenuated arsenite-induced ROS production, enhanced caspase-3 activity and gamma-H2AX expression. Our results further showed the expression of alpha-Synuclein (alpha-Syn) was significantly increased in arsenite-treated cells, but co-treatment with luteolin reversed the expression of alpha-Syn back toward normal level. Inhibition of alpha-Syn by siRNA remarkably enhanced the beneficial effect of luteolin against arsenite-induced apoptotic cell death. Taken together, these results demonstrate that the ameliorative effects of luteolin against arsenite in the dopaminergic cell may be modulated by alpha-Syn, and indicating that luteolin may be developed as a chemopreventive supplementary agent to ameliorate dopaminergic cell apoptosis resulting from arsenite exposure. PMID- 28583010 TI - Occurrence and incidence of 18 per- and polyfluoroalkyl compounds in edible oils commonly consumed in Guiyang, China. AB - A systematic examination was conducted for the first time of a wide carbon-chain range of per- and polyfluoroalkyl compounds (PFASs) in 83 samples of edible vegetable and animal oils from Guiyang, China. The occurrence and levels of 18 PFASs in seven types of edible oil were analysed. Analytes were determined based on a simplified, sensitive and reliable solvent extraction and liquid chromatography-tandem mass spectrometry method. Ten target PFASs were found and the most frequently detected compounds with maximum concentration were PFOS (88%, 1.93 ng g-1), PFNA (55.4%; 6.76 ng g-1), PFHxS (39.8%; 0.36 ng g-1), and PFOA (16.9%; 0.15 ng g-1), respectively. The total PFASs concentrations ranged from 0.02 to 6.76 ng g-1, with a mean of 0.94 ng g-1. Significant differences of occurrence between vegetable oils and animal oils were demonstrated based on comparative analysis of the existing data. The investigation results showed that the effect of production reductions of PFOS and PFOA by regulatory was also reflected in edible oils. The dietary intakes of PFOS and PFOA for adults were estimated, which were lower than the available tolerable daily intake (TDI). Because of the global lack of food regulatory thresholds for most per- or polyfluoroalkyl compounds, it was difficult to draw any conclusion at this stage as to how human health is affected through exposure to these compounds. The baseline information of this study will assist in guiding the direction for future investigations and monitoring studies on occurrence, fate and human health effect research of PFASs. PMID- 28583011 TI - Cognitive Training and Noninvasive Brain Stimulation for Cognition in Parkinson's Disease: A Meta-analysis. AB - BACKGROUND: Many people with Parkinson's disease (PD) experience cognitive decline. It is not known whether cognitive training or noninvasive brain stimulation are effective at alleviating cognitive deficits in PD. OBJECTIVE: To examine cognitive training and non-invasive brain stimulation interventions for cognition in PD. METHODS: An extensive search was conducted of published and unpublished studies in online databases. Studies were selected if they were controlled trials examining standard (not individualized) or tailored (individualized) cognitive training, repetitive transcranial magnetic stimulation (rTMS), or transcranial direct current stimulation (tDCS) in PD, with outcomes measured by standardized neuropsychological tests. RESULTS: Fourteen controlled trials met inclusion criteria. For executive function, the pooled effect size (Hedges' g) for cognitive training (standard and tailored combined) was small ( g = 0.42) but statistically significant (95% CI 0.15-0.68). The pooled effect for standard cognitive training (alone) was medium ( g = 0.51) and significant (95% CI 0.16-0.85). For attention/working memory, small pooled effect sizes were found when combining standard and tailored cognitive training ( g = 0.23; 95% CI 0.02 0.44) and for standard cognitive training alone ( g = 0.29; 95% CI 0.04-0.53), both significant. For memory, small but significant pooled effect sizes were also found when combining standard and tailored cognitive training and for standard cognitive training alone. CONCLUSIONS: The results suggest that standard and tailored cognitive training may improve executive function, attention/working memory, and memory in PD. Future studies must adopt randomized controlled trial designs to explore the therapeutic potential of these interventions. PMID- 28583012 TI - Exhaled breath analysis in obstructive sleep apnea. AB - INTRODUCTION: Breath analysis is a novel application that can be used for non invasive metabolic phenotyping and identification of disease specific breath patterns. Obstructive sleep apnea (OSA) is highly prevalent and has diverse metabolic and cardiovascular consequences, many of them incompletely understood. Areas covered: This review systematically summarizes the current evidence from breath metabolomics using immunoassays of breath condensate, off-line mass spectrometry as well as real-time analysis by electronic sensors and by untargeted mass spectrometry, and discusses the challenges and perspectives of breath analysis in OSA. Expert commentary: Analysis of exhaled breath is an innovative approach that is likely to provide profound insights into the metabolomics of OSA and its consequences and might facilitate diagnosis and therapy monitoring. PMID- 28583013 TI - Probabilistic migration modelling focused on functional barrier efficiency and low migration concepts in support of risk assessment. AB - Migration modelling provides reliable migration estimates from food-contact materials (FCM) to food or food simulants based on mass-transfer parameters like diffusion and partition coefficients related to individual materials. In most cases, mass-transfer parameters are not readily available from the literature and for this reason are estimated with a given uncertainty. Historically, uncertainty was accounted for by introducing upper limit concepts first, turning out to be of limited applicability due to highly overestimated migration results. Probabilistic migration modelling gives the possibility to consider uncertainty of the mass-transfer parameters as well as other model inputs. With respect to a functional barrier, the most important parameters among others are the diffusion properties of the functional barrier and its thickness. A software tool that accepts distribution as inputs and is capable of applying Monte Carlo methods, i.e., random sampling from the input distributions of the relevant parameters (i.e., diffusion coefficient and layer thickness), predicts migration results with related uncertainty and confidence intervals. The capabilities of probabilistic migration modelling are presented in the view of three case studies (1) sensitivity analysis, (2) functional barrier efficiency and (3) validation by experimental testing. Based on the predicted migration by probabilistic migration modelling and related exposure estimates, safety evaluation of new materials in the context of existing or new packaging concepts is possible. Identifying associated migration risk and potential safety concerns in the early stage of packaging development is possible. Furthermore, dedicated material selection exhibiting required functional barrier efficiency under application conditions becomes feasible. Validation of the migration risk assessment by probabilistic migration modelling through a minimum of dedicated experimental testing is strongly recommended. PMID- 28583014 TI - Evaluation of the Effects of Quetiapine on QTc Prolongation in Critically Ill Patients. AB - Quetiapine, an atypical antipsychotic used in the intensive care unit (ICU) to manage delirium, has a possible adverse effect of corrected QT (QTc) interval prolongation. The objective of this analysis was to describe the impact of quetiapine on QTc interval prolongation in critically ill patients. This was a single-center, prospective cohort analysis of ICU patients who received quetiapine between October 2015 and February 2016. The major end point was the incidence of QTc prolongation greater than 60 milliseconds above baseline during therapy. Minor end points included median change in QTc interval and incidence of Torsades de Pointes (TdP). Univariate and multivariable analyses were performed to determine variables associated with higher risk of QTc prolongation. During the study period, 103 patients were enrolled in the analysis. QTc interval prolongation greater than 60 milliseconds occurred in 14 (13.6%) patients. The median change in QTc interval was 20 milliseconds. There were no cases of TdP. On multivariable analysis, the only variable associated with higher incidence of QTc prolongation was administration of a concomitant medication known to prolong the QTc interval ( P = .046). QTc prolongation was relatively uncommon among critically ill patients utilizing quetiapine. Patients receiving concomitant medications known to prolong the QTc interval may be at an increased risk. PMID- 28583015 TI - Chlamydia trachomatis infection positivity rates determined by nucleic acid amplification test in patients of hospitals in the northeastern region of Ukraine. AB - There are no accurate data regarding the prevalence of Chlamydia trachomatis infection in Ukraine. This study aims to estimate the prevalence in the northeastern region of the country through reviewing nucleic acid amplification test results in patients of medical institutions in the Kharkov region during 2014-2016. Samples from 6920 patients (5028 women and 1892 men) aged 12-76 years were tested. The overall positivity rate was 4.5% (95% CI 4.0-5.0): 3.9% (95% CI 3.4-4.5) in women and 6.1% (95% CI 5.1-7.3) in men. The highest prevalence was found in the 16-20 (8.5%, CI 6.3-11.4) and 21-25 (8.0%, CI 6.7-9.4) year age groups. The prevalence in men was higher than in women in all investigated groups. The results show the need for more attention to the prevention, diagnosis, and treatment of chlamydial infection in these age groups of women and men in this region. PMID- 28583016 TI - A comparison of enriched culture and Xpert polymerase chain reaction assay of Group B streptococcus carrier status at 35-37-week gestation to labor onset: a prospective controlled study. AB - OBJECTIVES: (1) To compare the accuracy of vagino-rectal enriched culture (EC) and a rapid polymerase chain reaction (PCR) test for the detection of Group B streptococcus (GBS) carrier status at 35-37-week gestation and at onset of labor. (2) To assess the conversion rate of GBS carrier status between 35-37 weeks to the onset of labor according to the EC/PCR tests. A prospective study was performed at a women's health clinic, referred to give birth at one medical center. STUDY POPULATION: Low risk pregnant women at 35-37-week gestation who did not know their GBS carrier status. METHODS: Participants were evaluated for GBS status both at 35-37 weeks and at labor onset. Correlation between tests was calculated by Spearman correlation. RESULTS: One hundred and ten specimens were analyzed. Correlations: EC-PCR: 35-37 weeks - very high (r = 0.8), at labor - high (r = 0.5). EC-EC: 35-37 weeks and at labor - high (r = 0.39); PCR-PCR: 35-37 weeks and at labor- high (r = 0.7). CONCLUSIONS: Both the EC and Xpert PCR tests are accurate for detecting GBS carrier, both at 35-37 weeks and at labor onset. We did not detect a significant conversion of the GBS status from negative at 35 37 weeks to positive at onset of labor. PMID- 28583017 TI - Three-dimensional prostate tumor model based on a hyaluronic acid-alginate hydrogel for evaluation of anti-cancer drug efficacy. AB - In vitro cell-based assays are widely applied to evaluate anti-cancer drug efficacy. However, the conventional approaches are mostly based on two dimensional (2D) culture systems, making it difficult to recapitulate the in vivo tumor scenario because of spatial limitations. Here, we develop an in vitro three dimensional (3D) prostate tumor model based on a hyaluronic acid (HA)-alginate hybrid hydrogel to bridge the gap between in vitro and in vivo anticancer drug evaluations. In situ encapsulation of PCa cells was achieved by mixing HA and alginate aqueous solutions in the presence of cells and then crosslinking with calcium ions. Unlike in 2D culture, cells were found to aggregate into spheroids in a 3D matrix. The expression of epithelial to mesenchyme transition (EMT) biomarkers was found to be largely enhanced, indicating an increased invasion and metastasis potential in the hydrogel matrix. A significant up-regulation of proangiogenic growth factors (IL-8, VEGF) and matrix metalloproteinases (MMPs) was observed in 3D-cultured PCa cells. The results of anti-cancer drug evaluation suggested a higher drug tolerance within the 3D tumor model compared to conventional 2D-cultured cells. Finally, we found that the drug effect within the in vitro 3D cancer model based on HA-alginate matrix exhibited better predictability for in vivo drug efficacy. PMID- 28583018 TI - A review of CD19-targeted immunotherapies for relapsed or refractory acute lymphoblastic leukemia. AB - Aim Novel immunotherapies have generated high response rates and unique adverse effects among patients with relapsed or refractory acute lymphoblastic leukemia. Therapies engaging endogenous T-cells against acute lymphoblastic leukemia are emerging for children and adults with various poor prognostic factors, thus accurate knowledge of immunotherapies is necessary for their effective implementation in the future. In this review, we evaluate clinical trial data regarding chimeric antigen receptor T-cells and blinatumomab, for the treatment of relapsed or refractory acute lymphoblastic leukemia. Summary In the relapsed or refractory setting, response rates rapidly diminish after subsequent lines of chemotherapy and cumulative toxicities may cause significant patient harm. Immunotherapies provide an approach to improve response rates and minimize traditional toxicities via novel mechanisms of action. Two therapies targeting CD19 antigens expressed on B-cell acute lymphoblastic leukemia lineages, chimeric antigen receptor T-cells, and blinatumomab have induced complete remissions among high-risk patient populations, especially those refractory to multiple therapies. Adverse effects such as cytokine release syndrome and neurologic sequelae remain serious precautions of each therapy. Conclusion Knowledge of immunotherapy mechanisms and clinical outcomes associated with immunotherapies is critical for the optimization of treating patients with relapsed or refractory acute lymphoblastic leukemia. Future use of chimeric antigen receptor T-cells and blinatumomab demands proper assessment of a patient's disease and treatment history in addition to unique monitoring and supportive care interventions. PMID- 28583019 TI - Promoting the legitimacy and agency of new graduate nurses' participation in nursing research. AB - AIM: This paper explores the legitimacy and agency of new graduate mental health nurses to participate in research activities as a regular part of their professional nursing role. BACKGROUND: There is a wealth of literature describing personal and organisational factors that act as barriers to nurses' engagement in research and overcoming these barriers remains a challenge for health organisations. Some new graduate nurses are well positioned to contribute to research and yet the literature has given little attention to this specific cohort. RESULTS: This paper will show how facilitating new graduates' participation in research benefits the new graduate and the health service. CONCLUSION: New graduates learn research skills from experienced researchers and this ensures a sustainable future workforce of researchers. Employers who support staff to pursue professional challenges such as research are more likely to generate organisational commitment and loyalty amongst staff. PMID- 28583020 TI - Resilient health care, volume 3: reconciling Work-as-Imagined and Work-as-Done. PMID- 28583021 TI - Relationships matter: contraceptive choices among HIV-positive women in Tanzania. AB - Efforts to eliminate mother-to-child transmission of HIV in Tanzania are guided by a four-prong strategy advocated by the World Health Organization (WHO). Prong 2, prevention of unintended pregnancies among women living with HIV, has, however, received the least attention and contraceptive use to prevent unintended pregnancies remains low. This study explored the perceived barriers to the use of modern methods of contraception, and factors influencing contraceptive choice among HIV-positive women in urban Dar-es-Salaam, Tanzania. A qualitative multi site study was conducted, utilising in-depth interviews and focus group discussions with 37 sexually active HIV-positive women aged between 20 and 44 years, attending three health facilities within Dar-es-Salaam. The theoretical framework was a patient centred model. Four barriers were identified: the influence of the women's spousal relationships; personal beliefs and the relationship of these in understanding her disease; the influence of the social demands on the woman and her relationships; and the importance of a woman's relationship with her healthcare provider/healthcare system. Being the bearers of bad news (HIV-positive status) the pregnant women experienced conflicts, violence, abandonment and rejection. The loss in negotiating power for the women was in relation to their intimate partners, but also in the patient-healthcare provider relationship. The role of the male partner as a barrier to contraceptive use cannot be understated. Therefore, the results suggest that healthcare providers should ensure patient-focused education and provide support that encompasses the importance of their relationships. Additional research is required to elucidate the functional association between contraceptive choices and personal and social relationships. PMID- 28583022 TI - Implementation of the new VIRTUO blood culture system: evaluation and comparison to the 3D system using simulated blood cultures. AB - PURPOSE: To evaluate the performances of the newly approved BacT/ALERT VIRTUO blood culture system for the recovery of bloodstream pathogens and compare it to the BacT/ALERT 3D system. METHODS: Simulated blood cultures of eight clinically relevant microorganisms were used: Bacteroides fragilis (ATCC 25285), Escherichia coli (ATCC 25922), Haemophilus influenzae (ATCC 49247), Pseudomonas aeruginosa (ATCC 27853), Enterococcus faecalis (ATCC 29212), Staphylococcus aureus (ATCC 29213), Streptococcus pneumoniae (ATCC 49619) and Candida krusei (ATCC 6258). Criteria for comparison were culture positivity and time to detection (TTD). The effects of delayed entry on recovery and TTD were also evaluated. RESULTS: The VIRTUO exhibited around 3 h faster detection time compared to the 3D system. (p < 0.01) for aerobic and facultative microorganisms. The difference in TTD was greatest for the B. fragilis, with a median difference of 46.67 h. The anaerobic bottle of the VIRTUO (FN Plus) did not support the growth of obligate aerobes, whereas the 3D did so. Delayed entry (studied with an E. Coli isolate) had no effect on the recovery rate but proportionally reduced TTD. CONCLUSIONS: The VIRTUO performed better than the 3D in terms of TTD and hands-on-time. FN Plus vial appears to be more efficient than the SN bottle in the recovery of anaerobes. PMID- 28583023 TI - Safety of Outpatient Total Ankle Arthroplasty vs Traditional Inpatient Admission or Overnight Observation. AB - BACKGROUND: Total joint surgeons have successfully performed hip, knee, and shoulder arthroplasty procedures in the outpatient setting without compromising safety, satisfaction, or results. The purpose of this study was to evaluate outpatient total ankle arthroplasty (TAA) as compared with overnight or extended inpatient stay, with regard to 90-day medical and operative complications, reoperations, readmissions or emergency room visits, and pain control. METHODS: The medical records of patients who underwent TAA with 1 fellowship-trained orthopedic foot and ankle surgeon were reviewed. Outcome measures included operative complications, adverse medical events, readmission or emergency room visit for any reason, or reoperation within 90 days following surgery; surgeon's office contact before first postoperative visit regarding pain or other issues; visual analog scale pain score at the first postoperative visit; and need for narcotic refill. Outcomes were assessed by admission status: outpatient, overnight observation, or inpatient admission. Standard statistical analysis was used, and P < .05 was considered significant. RESULTS: Eighty-one patients underwent TAA who met inclusion criteria, and 8 had a complication (10%). A significant difference in complication rate was seen among groups ( P = .01) but not rate of readmission or reoperation. Of 16 patients, 5 (31%) who were admitted for 2 or more nights following surgery had a complication, as opposed to 3 of 65 (5%) who were outpatient or admitted overnight ( P = .01). There were no differences in frequency of postoperative phone calls, narcotic refills, or visual analog scale pain scores at the first postoperative visit. There were no adverse medical events. CONCLUSION: With proper instruction, TAA was performed safely in the outpatient setting. As health care policy continues to evolve in the United States, safe and efficient practices will remain a priority. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 28583024 TI - Reach Out Churches: A Community-Based Participatory Research Pilot Trial to Assess the Feasibility of a Mobile Health Technology Intervention to Reduce Blood Pressure Among African Americans. AB - Innovative strategies are needed to reduce the hypertension epidemic among African Americans. Reach Out was a faith-collaborative, mobile health, randomized, pilot intervention trial of four mobile health components to reduce high blood pressure (BP) compared to usual care. It was designed and tested within a community-based participatory research framework among African Americans recruited and randomized from churches in Flint, Michigan. The purpose of this pilot study was to assess the feasibility of the Reach Out processes. Feasibility was assessed by willingness to consent (acceptance of randomization), proportion of weeks participants texted their BP readings (intervention use), number lost to follow-up (retention), and responses to postintervention surveys and focus groups (acceptance of intervention). Of the 425 church members who underwent BP screening, 94 enrolled in the study and 73 (78%) completed the 6-month outcome assessment. Median age was 58 years, and 79% were women. Participants responded with their BPs on an average of 13.7 (SD = 10.7) weeks out of 26 weeks that the BP prompts were sent. All participants reported satisfaction with the intervention. Reach Out, a faith-collaborative, mobile health intervention was feasible. Further study of the efficacy of the intervention and additional mobile health strategies should be considered. PMID- 28583025 TI - Freshman Flu Vaccination Behavior and Intention During a Nonpandemic Season. AB - OBJECTIVE: To examine predictors of flu vaccination and vaccination intention among college freshmen during a nonpandemic influenza season using the health belief model (HBM). PARTICIPANTS: A total of 184 college freshmen at a single institution participated in a mixed-mode (paper or online) survey in October November 2015. METHOD: Flu vaccination and intention to vaccinate were predicted using binomial logistic regression on HBM constructs (perceived susceptibility, severity, benefits, barriers, cues to action, and availability), prior flu vaccination history, family and peer reference behaviors, and demographics. RESULTS: Overall, 31.5% of participants received the seasonal flu vaccine by mid November, and 25% intended to receive it. In full models, history of past flu vaccination (adjusted odds ratio [aOR] = 7.90; 95% confidence interval [CI] = 2.55-24.49) was significant for vaccination while availability (aOR = 2.00; 95% CI = 1.32-3.01) and family intention (aOR = 250.59; 95% CI = 3.77 to >999) were positively associated with intent to vaccinate. Significant confounding by past behavior and family intentions existed for both outcomes. CONCLUSIONS: Past flu vaccination behavior and family member intentions to vaccinate were better predictors of annual flu vaccination behavior and intention than HBM constructs among college freshmen. College campuses may enhance flu vaccine coverage by highlighting benefits and availability to students and families. PMID- 28583026 TI - A prolonged antibiotic protocol to treat persistent Chlamydophila pneumoniae infection improves the extracranial venous circulation in multiple sclerosis. AB - Objective Chronic cerebrospinal venous insufficiency (CCSVI) is a condition associated with multiple sclerosis (MS). One mechanism that has been proposed is that the venous obstructions found in MS are due to a chronic persistent venulitis caused by the intra-cellular bacterial parasite, Chlamydophila pneumoniae (Cpn). The objective of the current study is to determine the effect of a combined antibiotic protocol (CAP) on the venous flow in MS patients as measured by a quantitative duplex ultrasound examination (QDUS). Method A non randomised before-after cohort study was conducted to investigate differences in blood flow volumes pre and 6-months post antibiotic treatment for Cpn infection. Flow volume data were measured by QDUS across affected and unaffected sides from multiple veins segments, including internal jugular vein (IJV) segments J2 and J3, and vertebral vein (VV), as well as global arterial blood flow (GABF). Results 91 patients were included in the study. 64 (70%) were found to have positive Cpn serology. There was a statistically significant post-treatment difference seen for the affected side of Cpn infected patients (mean difference = 56 mL/min, p = 0.02). There was a non-significant increase seen for the affected side of uninfected patients (mean difference = 23 mL/min, p = 0.2). The difference in these effects (34 mL/min) was not statistically significant ( p = 0.3). The mean flow rate decreased in the unaffected side for both infected (-27 mL/min, p = 0.5) and uninfected patients (-69 mL/min, p = 0.01). There was a statistically significant post-treatment increase in GABF for the infected patients (mean difference = 90 mL/min, p = 0.02) and a difference of 76 mL/min for non-infected patients ( p = 0.01). Conclusion A CAP appears to improve the extra-cranial circulation in patients diagnosed with MS. This effect is statistically significant in patients with positive Cpn serology, although patients with negative Cpn serology also show some benefit, betraying a lack of specificity of this effect. PMID- 28583027 TI - Brentuximab vedotin consolidation post-autologous stem cell transplant in Hodgkin lymphoma patients at risk of residual disease: number needed to treat. AB - The number needed to treat (NNT) with brentuximab vedotin consolidation therapy post-autologous stem cell transplant (ASCT) versus placebo in the phase 3 AETHERA trial to avoid one additional event of disease progression/death was evaluated. AETHERA included 329 Hodgkin lymphoma patients at increased risk of progression post-ASCT who received brentuximab vedotin 1.8 mg/kg (n = 165) or placebo (n = 164) on day 1 of each 21-d cycle (up to 16 cycles). Over 60 months, the NNT with brentuximab vedotin ranged from 4.08 to 7.79 for the intent-to-treat population, 3.18-6.07 for patients with >=2 risk factors, and 2.98-5.65 for patients with >=3 risk factors. At various time points, and dependent on the risk group, 3-8 patients would need to be treated with brentuximab vedotin consolidation therapy to prevent a disease progression/death, compared with placebo. Patients with increased risk of relapse may benefit most from brentuximab vedotin. PMID- 28583028 TI - A Novel Method for Isolation of Pluripotent Stem Cells from Human Umbilical Cord Blood. AB - Very small embryonic-like cells (VSELs) are a population of very rare pluripotent stem cells isolated in adult murine bone marrow and many other tissues and organs, including umbilical cord blood (UCB). VSEL existence is still not universally accepted by the scientific community, so for this purpose, we sought to investigate whether presumptive VSELs (pVSELs) could be isolated from human UCB with an improved protocol based on the isolation of enriched progenitor cells by depletion of nonprogenitor cells with magnetic separation. Progenitor cells, likely including VSELs, cultured with retinoic acid were able to form dense colonies and cystic embryoid bodies and to differentiate toward the ecto-meso endoderm lineages as shown by the positivity to specific markers. VSEL differentiative potential toward mesodermal lineage was further demonstrated in vitro upon exposure to an established inductive protocol, which induced the acquisition of renal progenitor cell phenotype. VSEL-derived renal progenitors showed regenerative potential in a cisplatin model of acute kidney injury by restoring renal function and tubular structure through induction of proliferation of endogenous renal cells. The data presented here foster the great debate that surrounds VSELs and, more in general, the existence of cells endowed with pluripotent features in adult tissues. In fact, the possibility to find and isolate subpopulations of cells that fully fit all the criteria utilized to define pluripotency remains, nowadays, almost unproven. Thus, efforts to better characterize the phenotype of these intriguing cells are crucial to understand their possible applications for regenerative and precision medicine purposes. PMID- 28583030 TI - Sexual Murderers: Sex Offender, Murderer, or Both? AB - Sexual murderers perpetrate homicide and rape/sexual abuse, but it is unclear whether they should primarily be considered homicide offenders, sexual offenders, or both. Most studies have merged together different types of non-homicidal sex offenders (NHSOs), neglecting to consider the potential differences between the nonviolent and violent sex offenders. Here, we suggest it is important to isolate those violent sex offenders who inflict severe physical injuries that could potentially lead to a lethal outcome. Therefore, the aim of the current study is to compare different measures of the criminal career on three groups of sex offenders: NHSOs, violent NHSOs, and sexual homicide offenders (SHOs) using data from 616 incarcerated male sex offenders in a Federal penitentiary in Canada. Interestingly, the group of sex offenders with the worst criminal career profile was not the SHOs, but the violent NHSOs. Violent NHSOs had the greatest number of prior convictions and the most varied and versatile criminal career. Therefore, we suggest that based on their criminal career, SHOs should be considered more as murderers than sex offenders. However, to fully answer this question, future studies should include a group of non-sexual homicide offenders. PMID- 28583029 TI - P-gp expression levels in the erythrocytes of brown trout: a new tool for aquatic sentinel biomarker development. AB - CONTEXT: P-glycoprotein (P-gp) is a ubiquitous membrane detoxification pump involved in cellular defence against xenobiotics. Blood is a hub for the trade and transport of physiological molecules and xenobiotics. Our recent studies have highlighted the expression of a 140-kDa P-gp in brown trout erythrocytes in primary cell culture and its dose-dependent response to Benzo[a]pyrene pollutant. OBJECTIVE: The purpose of this study was focused on using P-gp expression in brown trout erythrocytes as a biomarker for detecting the degree of river pollution. METHODS: abcb1 gene and P-gp expression level were analysed by reverse transcriptase-PCR and Western blot, in the erythrocytes of brown trouts. The latter were collected in upstream and downstream of four rivers in which 17 polycyclic aromatic hydrocarbons and 348 varieties of pesticides micro-residues were analysed by liquid chromatography and mass spectrometry. RESULTS: The abcb1 gene and the 140-kDa P-gp were not expressed in trout erythrocytes from uncontaminated river. In contrast, they are clearly expressed in contaminated rivers, in correlation with the river pollution degree and the nature of the pollutants. CONCLUSIONS: This biological tool may offer considerable advantages since it provides an effective response to the increasing need for an early biomarker. PMID- 28583031 TI - Association between bortezomib dose intensity and overall survival in mantle cell lymphoma patients on frontline VR-CAP in the phase 3 LYM-3002 study. AB - The pivotal LYM-3002 study compared frontline rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) with bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone (VR-CAP) in newly diagnosed mantle cell lymphoma (MCL) patients for whom stem cell transplantation was not an option. This post hoc subanalysis of the VR-CAP data from LYM-3002 evaluated the effect of bortezomib dose intensity on OS in patients who completed >=6 cycles of treatment. From the end of cycle 6, patients receiving >=4.6 mg/m2/cycle of bortezomib had significantly longer OS (but not PFS) compared with those receiving <4.6 mg/m2/cycle by univariate analysis (HR 0.43 [95% CI: 0.23-0.80]; p = .0059). This association remained significant in multivariate analysis adjusting for baseline patient and disease characteristics (HR 0.40 [95% CI: 0.20 0.79]; p = .008]. Higher bortezomib dose intensity was the strongest predictor of OS in newly diagnosed MCL patients receiving VR-CAP. Clinicaltrials.gov identifier: NCT00722137. PMID- 28583032 TI - Patient and practitioner perspectives on reducing sedentary behavior at an exercise-based cardiac rehabilitation program. AB - PURPOSE: To understand the awareness of sedentary behavior, as well as the perceived facilitators and barriers to reducing sedentary behaviors from the perspectives of patients undertaking an exercise-based cardiac rehabilitation program, and from staff involved in supporting patient self-management. MATERIALS AND METHODS: A qualitative study was conducted at a large cardiac rehabilitation program in a metropolitan city in Canada. Guided by an ecological framework, semi structured interviews were conducted individually with 15 patients, and in two focus groups with six staff. Transcribed interviews were analyzed by thematic analysis. RESULTS: Patients placed little importance on reducing sedentary behavior as they were unconvinced of the health benefits, did not perceive themselves to be sedentary, or associated such behaviors with enjoyment and relaxation. While staff were aware of the risks, they saw them as less critical than other health behaviors. Intrapersonal factors (physical and psychosocial health) and environment factors (the information environment, socio-cultural factors) within leisure time, the home, and work, influenced sedentary behavior. CONCLUSIONS: While these findings require further testing, future interventions may be effective if aimed at increasing awareness of the health benefits of reducing sedentary behavior, utilizing existing behavior change strategies, and using a participatory approach to tailor strategies to patients. Implications for rehabilitation Cardiac rehabilitation programs effectively use exercise promotion to improve the health of people with established cardiovascular disease. As sedentary lifestyles become more prevalent, recommendations to reduce the health risks of prolonged sedentary behavior that are specific to the characteristics and prognostic profiles of cardiac rehabilitation patients are needed. Cardiac rehabilitation programs must consider extending existing behavior change strategies utilized for exercise promotion towards addressing sedentary behaviors in order to be effective at reducing the sedentary time of patients. A participatory approach involving both patients and health professionals can support patients in reducing their sedentary behavior by providing a supportive environment for behavior change, increasing awareness and understanding of risks, discussing the feasibility of potential strategies, and setting achievable and actionable goals. PMID- 28583033 TI - Burkitt lymphoma and diffuse large B-cell lymphoma: a unique case of a composite lymphoma of different clonal origin. PMID- 28583034 TI - Aging-Related Microstructural Alterations Along the Length of the Cingulum Bundle. AB - The aim of this study was to investigate the aging-related structural changes of the cingulum, one of the major components of the limbic network, which has a critical role in emotion, attention, and memory. Thirty-five healthy young adults (22.3 +/- 2.7 years) and 33 healthy older adults (69.5 +/- 3.5 years) were recruited. Diffusion weighted imaging data were acquired with a b-value = 2000 sec/mm2 and 61 diffusion directions and 4 non-weighted images. The fiber directions in each voxel were based on the constrained spherical deconvolution model. The cingulum was segmented into three branches using deterministic tractography (subgenual, retrosplenial, and parahippocampal), using a region-of interest-based approach. Atlas-based tractography was the method used to obtain the output tracts of each branch of the cingulum. Along-tract analysis was performed on each branch. We found a statistically significant change with aging in the left subgenual branch of the cingulum with a decrease in fractional anisotropy and axial diffusivity, as well as an increase in radial diffusivity. No statistically significant differences were found between young and older groups in the other two branches. This study adds to knowledge about how the cingulum changes structurally along its entire length during aging in a more detailed way, thanks to an advanced methodological approach. PMID- 28583036 TI - Interaction of a flavone loaded on surface-modified dextran-spooled superparamagnetic nanoparticles with beta-cyclodextrin and DNA. AB - Flavones are biologically active compounds obtained mainly from plant sources. Pharmaceutically important compounds can be delivered to the physiological target by loading them in carriers like cyclodextrins and magnetic nanoparticles. Herein, the binding of 6-methoxyflavone to beta-cyclodextrin and DNA is studied using UV-visible absorption and fluorescence spectroscopy. The loading of 6 methoxyflavone onto a magnetic nanoparticles is employed. beta-cyclodextrin encapsulates the 6-methoxyflavone to form an inclusion complex. beta-cyclodextrin also used to draw forth 6-methoxyflavone loaded onto a magnetic nanoparticles. The morphology, magnetic property and the crystallite size of the nanoparticles are studied using scanning electron microscopy, vibrating sample magnetometry and X-ray diffraction techniques, respectively. The binding of the drug-loaded magnetic nanoparticles to DNA shows that the compound is accessible to DNA and available mostly on the surface of the nanoparticles despite a modified dextan polymer supposedly encapsulates the flavone. PMID- 28583035 TI - Intraorganizational Communication and Job Satisfaction Among Flemish Hospital Nurses: An Exploratory Multicenter Study. AB - Intraorganizational communication affects job satisfaction and turnover. The goal of this study was to explore relationships between communication and job satisfaction, intention to leave, and burnout among Flemish hospital nurses. A multicenter questionnaire study was conducted in three hospitals using the Communication Satisfaction Questionnaire, the Turnover Intention subscale of the Questionnaire on the Experience and Evaluation of Work, and the Maslach Burnout Inventory. A visual analog scale measured job satisfaction. The mean job satisfaction score was 7.49/10 (+/-1.43). Almost 7% of nurse participants (93/1,355) reported a high intent to leave, and 2.9% of the respondents (41/1,454) had a score indicative of burnout. All dimensions of communication were associated with job satisfaction. A low score on any dimension of communication satisfaction, except "Relationship With Employees," was associated with higher intent to leave and burnout. Study findings support the need for management interventions to enhance efficient communication and ensure high quality care and patient safety. PMID- 28583037 TI - Addressing a multidisciplinary challenge from animal nutrition to analytical science. PMID- 28583038 TI - Carfilzomib as salvage therapy in Waldenstrom macroglobulinemia: a case series. PMID- 28583041 TI - IMSCOGS 2017 Abstracts. PMID- 28583039 TI - Experimental Models of Autoimmune Demyelinating Diseases in Nonhuman Primates. AB - Human idiopathic inflammatory demyelinating diseases (IIDD) are a heterogeneous group of autoimmune inflammatory and demyelinating disorders of the central nervous system (CNS). These include multiple sclerosis (MS), the most common chronic IIDD, but also rarer disorders such as acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO). Great efforts have been made to understand the pathophysiology of MS, leading to the development of a few effective treatments. Nonetheless, IIDD still require a better understanding of the causes and underlying mechanisms to implement more effective therapies and diagnostic methods. Experimental autoimmune encephalomyelitis (EAE) is a commonly used animal model to study the pathophysiology of IIDD. EAE is principally induced through immunization with myelin antigens combined with immune-activating adjuvants. Nonhuman primates (NHP), the phylogenetically closest relatives of humans, challenged by similar microorganisms as other primates may recapitulate comparable immune responses to that of humans. In this review, the authors describe EAE models in 3 NHP species: rhesus macaques ( Macaca mulatta), cynomolgus macaques ( Macaca fascicularis), and common marmosets ( Callithrix jacchus), evaluating their respective contribution to the understanding of human IIDD. EAE in NHP is a heterogeneous disease, including acute monophasic and chronic polyphasic forms. This diversity makes it a versatile model to use in translational research. This clinical variability also creates an opportunity to explore multiple facets of immune-mediated mechanisms of neuro-inflammation and demyelination as well as intrinsic protective mechanisms. Here, the authors review current insights into the pathogenesis and immunopathological mechanisms implicated in the development of EAE in NHP. PMID- 28583040 TI - Basal Autophagy Is Altered in Lagotto Romagnolo Dogs with an ATG4D Mutation. AB - A missense variant in the autophagy-related ATG4D-gene has been associated with a progressive degenerative neurological disease in Lagotto Romagnolo (LR) dogs. In addition to neural lesions, affected dogs show an extraneural histopathological phenotype characterized by severe cytoplasmic vacuolization, a finding not previously linked with disturbed autophagy in animals. Here we aimed at testing the hypothesis that autophagy is altered in the affected dogs, at reporting the histopathology of extraneural tissues and at excluding lysosomal storage diseases. Basal and starvation-induced autophagy were monitored by Western blotting and immunofluorescence of microtubule associated protein 1A/B light chain3 (LC3) in fibroblasts from 2 affected dogs. The extraneural findings of 9 euthanized LRs and skin biopsies from 4 living affected LRs were examined by light microscopy, electron microscopy, and immunohistochemistry (IHC), using antibodies against autophagosomal membranes (LC3), autophagic cargo (p62), and lysosomal membranes (LAMP2). Biochemical screening of urine and fibroblasts of 2 affected dogs was performed. Under basal conditions, the affected fibroblasts contained significantly more LC3-II and LC3-positive vesicles than did the controls. Morphologically, several cells, including serous secretory epithelium, endothelial cells, pericytes, plasma cells, and macrophages, contained cytoplasmic vacuoles with an ultrastructure resembling enlarged amphisomes, endosomes, or multivesicular bodies. IHC showed strong membranous LAMP2 positivity only in sweat glands. The results show that basal but not induced autophagy is altered in affected fibroblasts. The ultrastructure of affected cells is compatible with altered autophagic and endo-lysosomal vesicular traffic. The findings in this spontaneous disease provide insight into possible tissue specific roles of basal autophagy. PMID- 28583042 TI - Cervical cord decompression following embolisation of a giant cervical vertebro vertebral arteriovenous fistula. AB - Arteriovenous fistulation between the vertebral arteries to extradural (epidural) veins, termed vertebro-vertebral arteriovenous fistulae, are uncommon diagnoses without established diagnostic algorithms or treatment options. Minimal evidence exists describing the management of this pathology. Endovascular treatment was performed under general anaesthesia by coil occlusion of the vertebral artery from the point of the fistula to the mid-vertebral artery. Repeat magnetic resonance angiographic imaging one week following the procedure confirmed an 80% reduction in the size of the epidural vein and decompression of the cervical spinal cord. At four-week follow-up there was significant qualitative improvement in the myelopathic symptoms including walking distance and pain. Normal physiological filling of the collapsed extradural vein was observed on follow-up digital subtraction angiography at five months. Catheter angiography by an experienced interventional neuro-radiologist is critical in defining the anatomy and providing minimally invasive treatment. PMID- 28583043 TI - Intracranial stenting for nilotinib treatment-associated cerebrovascular stenosis in chronic myeloid leukemia. AB - One of the second-generation tyrosine kinase inhibitors (TKIs), nilotinib, is increasingly used for imatinib-resistant or intolerant chronic myeloid leukemia (CML). Nilotinib is considered well tolerated with few side effects including hyperglycemia, hyperbilirubinemia and elevated levels of pancreatic enzymes. However, there is growing evidence that nilotinib accelerates atherosclerosis and causes peripheral arterial occlusive disease such as stroke, transient ischemic attack (TIA) and cardiovascular diseases. Herein, we report a case of a 74-year old male CML patient with intracranial stenosis of the internal carotid artery developed during treatment with nilotinib successfully cured by the intracranial stent, Wingspan. PMID- 28583044 TI - Acquired intracranial arterial aneurysm and stroke after vessel dissection in a child with coarctation of the aorta. AB - Vascular events in patients with coarctation of the aorta have been extensively reported and account for the majority of morbidity and mortality in untreated patients. The exact mechanism for this association is not completely understood and may include acquired anomalies or congenital abnormalities of intracranial vessel. Here we report a case of intracranial internal carotid artery dissection with subsequent formation of acquired large carotid aneurysm in a child with severe systemic hypertension and coarctation of the aorta. Endovascular aneurysm exclusion was pursued and it was able to control this potentially lethal complication. This case supports the notion of acquired nature of intracranial vessel abnormalities and underscores the clinical role of interventional neuroradiology in a subset of patients with congenital heart disease. PMID- 28583045 TI - Recommendations for Clinical Pathology Data Generation, Interpretation, and Reporting in Target Animal Safety Studies for Veterinary Drug Development. AB - Clinical pathology testing is routinely performed in target animal safety studies in order to identify potential toxicity associated with administration of an investigational veterinary pharmaceutical product. Regulatory and other testing guidelines that address such studies provide recommendations for clinical pathology testing but occasionally contain outdated analytes and do not take into account interspecies physiologic differences that affect the practical selection of appropriate clinical pathology tests. Additionally, strong emphasis is often placed on statistical analysis and use of reference intervals for interpretation of test article-related clinical pathology changes, with limited attention given to the critical scientific review of clinically, toxicologically, or biologically relevant changes. The purpose of this communication from the Regulatory Affairs Committee of the American Society for Veterinary Clinical Pathology is to provide current recommendations for clinical pathology testing and data interpretation in target animal safety studies and thereby enhance the value of clinical pathology testing in these studies. PMID- 28583046 TI - Influence of roasting on the chemopreventive potential of in vitro fermented almonds in LT97 colon adenoma cells. AB - The consumption of almonds may contribute to the prevention of colon cancer due to their unique composition of health promoting compounds. Since almonds are often consumed roasted, the impact of different roasting (R) conditions (R1 = 139.2 degrees C/25 min, R2 = 161.5 degrees C/20 min and R3 = 170.8 degrees C/15 min) on chemopreventive effects of in vitro-fermented almonds was analysed in LT97 colon adenoma cells. Fermentation supernatants (FS) of raw and roasted almonds had no genotoxic effects. FS obtained from raw or mildly roasted almonds (R1) significantly increased mRNA levels of CAT (4.6-fold), SOD2 (5.6-fold) and GSTP1 (3.9-fold) but not of GPx1. FS of almonds significantly reduced the growth of LT97 cells in a time- and dose-dependent manner. Treatment with 5% almonds FS increased the number of early apoptotic cells (17.4%, on average) and caspase-3 activity (4.9-fold, on average). The results indicate a chemopreventive potential of in vitro-fermented almonds which is largely independent of the roasting process. PMID- 28583047 TI - Surgery in overweight patients with insulinoma: effects on weight loss. AB - OBJECTIVE: Weight loss induced by the complete resection of insulinoma is controversial in overweight patients. The study sought to explore postoperative weight loss and metabolic changes in overweight insulinoma patients. METHODS: A retrospective study was conducted to review the follow-up data of insulinoma patients with a BMI >=25kg/m2 who underwent complete lesion resection between May 2010 and May 2015. Body mass index (BMI), weight loss (WL) and percentage weight loss (%WL) were main outcomes. RESULTS: Fifty-one patients were included with a median follow-up of 28 months. The BMI at 3 months, 1 year, 2 years and 3 years postoperatively were significantly lower than the preoperative BMI values (p < .01). The WL% was 12.9% at 3 months postoperatively without significant changes throughout the 3-year follow-up. WL and the %WL were significantly higher in the high BMI group (BMI>= 27.5 kg/m2). Multivariate analysis indicated that higher initial BMI was associated with increased weight loss (p = .001). 63.8% of patients with hypertension recovered and improved sleep quality was evident in all patients with obstructive sleep apnea syndrome within 1 year postoperatively. CONCLUSIONS: Weight significantly decreased postoperatively in overweight insulinoma patients, which was more evident in patients with higher BMI and metabolic comorbidities were largely improved. PMID- 28583048 TI - Confusing preclinical (predictive) drug screens with animal 'models' of psychiatric disorders, or 'disorder-like' behaviour, is undermining confidence in behavioural neuroscience. AB - Preclinical (predictive) screens for psychotropic drugs are often used, incorrectly, as animal 'models' of psychiatric disorders, or to study 'disorder like' behaviours. This misunderstanding is contributing to poor translation and is undermining confidence in behavioural neuroscience. In this editorial, I discuss some of the reasons why the interpretation of results from many of these procedures is dubious because the criteria for validity of the test, as a model of the disorder, have been ignored. Arising from this, I propose that the description of any abnormal behaviour of rodents as a 'model' of a psychiatric disorder, or even 'disorder-like', without evidence-based justification, should be regarded as unacceptable in this journal. PMID- 28583050 TI - MU-Opioid and 5-HT1A receptors in the dorsomedial hypothalamus interact for the regulation of panic-related defensive responses. AB - The dorsomedial hypothalamus (DMH) and the dorsal periaqueductal gray (DPAG) have been implicated in the genesis and regulation of panic-related defensive behaviors, such as escape. Previous results point to an interaction between serotonergic and opioidergic systems within the DPAG to inhibit escape, involving u-opioid and 5-HT1A receptors (5-HT1AR). In the present study we explore this interaction in the DMH, using escape elicited by electrical stimulation of this area as a panic attack index. The obtained results show that intra-DMH administration of the non-selective opioid receptor antagonist naloxone (0.5 nmol) prevented the panicolytic-like effect of a local injection of serotonin (20 nmol). Pretreatment with the selective MU-opioid receptor (MOR) antagonist CTOP (1 nmol) blocked the panicolytic-like effect of the 5-HT1AR agonist 8-OHDPAT (8 nmol). Intra-DMH injection of the selective MOR agonist DAMGO (0.3 nmol) also inhibited escape behavior, and a previous injection of the 5-HT1AR antagonist WAY 100635 (0.37 nmol) counteracted this panicolytic-like effect. These results offer the first evidence that serotonergic and opioidergic systems work together within the DMH to inhibit panic-like behavior through an interaction between u-opioid and 5-HT1A receptors, as previously described in the DPAG. PMID- 28583051 TI - Monoclonal B-cell lymphocytosis in blood donors in Turkey. AB - OBJECTIVES: Monoclonal B-cell lymphocytosis (MBL) is a precursor state of chronic lymphocytic leukemia (CLL) with peripheral lymphocytosis below 5 * 109/l. The diagnostic criteria exclude the presence of lymphadenopathy, organomegaly, infections, autoimmune diseases or any sign of a lymphoproliferative disorder. This prospective study was designed in order to evaluate the frequency of MBL in blood donors in Turkey. METHODS: The diagnosis of MBL was identified by flow cytometry method based on the International Familial CLL Consortium Report. A total of 999 volunteers [median age 34 (18-78) years; male/female: 705/294] were included in the study. RESULTS: Monoclonal B-cell lymphocytosis was demonstrated in 18 cases (1.8%). A total of 16 cases (1.6%) was evaluated as CLL-like MBL, while 2 (0.2%) had a non-CLL-like phenotype. The subjects were divided into three groups according to age, as <40 years, 40-60 years and >60 years. The prevalence of MBL was 1.1% below 40 years, 0.6% between 40 and 60 years and 0.1% in cases over 60 years, without statistical significance (p > 0.05). DISCUSSION: The sensitivity of the flow cytometry method is essential and may be responsible for the variations in the prevalence of MBL in different populations which can also be attributed to study design, higher detection rates in the elderly and families with genetic predisposition to CLL. CONCLUSION: Large population-based studies and standardized laboratory methods are needed to determine the potential risk factors of progression to CLL, including molecular markers and genetic profile. PMID- 28583052 TI - Two Postmodernisms in Rheumatology. AB - While randomization is an essential tool of data collection and interpretation, it can be misused. One such misuse is using a subgroup of a data set for validation purposes after randomizing the whole data set into two groups after which we attempt to validate the outcome data from one group with the outcome in the other. This surely validates only the randomization process. Two examples are given from disease criteria reports from Behcet's syndrome and gout. P-values are misunderstood and misused, and this is usually in the direction of investigators trying to show significant differences in their studies. Another, less criticized, misuse of the p-value is when the investigators try to use an insignificant and close to unity p-value as evidence for no difference. This author calls this a postmodern p-value. PMID- 28583049 TI - N-arachidonoyl-serotonin, a dual FAAH and TRPV1 blocker, inhibits the retrieval of contextual fear memory: Role of the cannabinoid CB1 receptor in the dorsal hippocampus. AB - Anandamide, an endocannabinoid, inhibits aversive responses by activating the CB1 cannabinoid receptor. At high concentrations, however, anandamide may exert pro aversive activities mediated by the transient receptor potential vanilloid type-1 channel (TRPV1). Accordingly, N-arachidonoyl-serotonin (AA-5-HT), a dual blocker of the anandamide-hydrolysing enzyme fatty acid amide hydrolase (FAAH) and the TRPV1 channel, induces anxiolytic-like effects. Here we tested the hypothesis that AA-5-HT inhibits the expression of contextual fear conditioning by facilitating CB1 receptor signalling in the dorsal hippocampus of mice. Intraperitoneal injection of AA-5-HT (0.1, 0.3, 1 mg/kg) inhibited the retrieval of contextual fear memory (freezing response). The effect of AA-5-HT (0.3 mg/kg) was prevented by systemic injection of the CB1 receptor antagonist, AM251 (1.0 mg/kg), and mimicked by simultaneous FAAH inhibition (URB597, 0.3 mg/kg) and TRPV1 blockage (SB366791, 1 mg/kg). Injection of AA-5-HT (0.125, 0.25, 0.5 nmol) into the dorsal hippocampus also reduced freezing. Finally, the effect of systemic AA-5-HT (0.3 mg/kg) was prevented by intra-hippocampal injection of AM251 (1 nmol). In conclusion, dual FAAH and TRPV1 blockage inhibits contextual fear memory by facilitating anandamide-induced CB1 receptor activation in the dorsal hippocampus. This approach may lead to new pharmacological treatments for traumatic memories and related psychiatric disorders. PMID- 28583053 TI - The Use of MDHAQ/RAPID3 in Different Rheumatic Diseases A Review of the Literature. AB - Composite indices are frequently used for most rheumatic diseases because of the absence of a single "gold standard" measure applicable to all individual patients with a specific diagnosis. Some of the most commonly used composite indices in rheumatology are too complex and time-consuming for usual clinical care. Nowadays, there is an increasing focus on patient-centered care, and the use of patient-reported outcome measures (PROMs) might offer a patient-friendly, time and cost efficient strategy to monitor chronic diseases. Although initially developed for rheumatoid arthritis (RA), a multidimensional health assessment questionnaire (MDHAQ), which only includes PROMs, has been found informative in many rheumatic diseases. Assessment of a patient with any rheumatic disease requires information beyond what is found on a patient questionnaire, including a careful history and physical examination, as well as relevant laboratory tests and imaging studies, to formulate an optimal treatment plan for each individual patient. Nonetheless, documentation of patient clinical status and change in status may be best accomplished through patient questionnaires. This review summarizes all the evidence relevant to the use of MDHAQ in other rheumatic diseases apart from RA. PMID- 28583054 TI - Finger and Wrist Pain in Children Using Game Consoles and Laptops Younger Children and Longer Time Are Associated with Increased Pain. AB - Game consoles, handheld units, and laptops are commonly used by children. Students at schools in St. Louis, Missouri, were asked to complete questionnaires asking about type, duration, and pain levels in their wrists and fingers related to the devices they used. Roughly, 75% of students were found to be using one of the devices. Younger age, female gender, and longer playing duration were associated with increase wrist and finger pain. Use of gaming and laptops, especially in younger children and with longer duration of use, is associated with increased pain in fingers and wrists. PMID- 28583055 TI - Fracture of the Distal Ulna Metaphysis in the Setting of Distal Radius Fractures. AB - BACKGROUND: Fracture of the metaphyseal region of the distal ulna is an uncommon injury that has been reported to occur concomitantly with distal radius fracture. We aimed to report the incidence and types of distal ulnar head and neck fractures associated with distal radius fractures and compare outcomes in operatively versus non-operatively treated patients. METHODS: Over a 5-year period a distal radius fracture registry was maintained at our institution. Eleven of 512 consecutive patients had metaphyseal distal ulna fractures in association with distal radius fractures and at least 1-year follow-up. Baseline radiographs and functional data were obtained, and patients were followed at 1 week, 2-week, 3-week, 6-week, 3-month, 6-month, 1-year, and 2-year intervals. Patients were split into two treatment groups: Group 1 consisted of five non operatively treated patients, and Group 2 consisted of six operatively treated patients. RESULTS: Four separate fracture patterns were observed: simple transverse or oblique fracture of the ulnar neck just proximal to the ulnar head, fracture of the neck region with concomitant fracture of the tip of the ulnar styloid, simple fracture of the ulnar head, and comminuted fracture of the ulnar head. There were no statistical differences between the two groups with regard to flexion, extension, supination, pronation, and functional outcomes. CONCLUSIONS: Ulnar fracture patterns observed did not easily fall into previously described categories, and we have proposed a new classification system. Simple fractures of the ulnar neck or head often do not require operative fixation. PMID- 28583056 TI - The Impact of Body Mass Index on Outcomes Following Open Sub-Pectoralis Major Biceps Tenodesis. AB - PURPOSE: Traditionally, biceps tenotomy has been recommended for obese, older, and less active patient populations, while tenodesis is preferred in younger, thinner, and more active individuals. In an effort to better understand the impact obesity has on the surgical management of long head of the biceps tendinopathy, the current study analyzed the effect body mass index had on surgical outcomes following open subpectoralis major biceps tenodesis. METHODS: Patients who underwent biceps tenodesis between June 2006 and December 2013 were identified from our institution's surgical database. They were then contacted to assess their functional outcomes using validated outcome measures. Comparisons were made between the outcomes seen in obese patients (BMI >= 30) and non-obese patients (BMI < 30) with subgroup analyses looking at gender, age, and length of follow-up. RESULTS: One hundred and twenty-two patients completed a follow-up assessment with a mean follow-up of 29.3 months. The non-obese cohort was composed of 84 patients with a mean BMI of 25.8. The obese cohort was composed of 38 patients with a mean BMI of 33.4. No significant difference was noted to be present with respect to postoperative outcome measures. Regression analysis with BMI as an independent variable demonstrated poor correlation with outcome measures. CONCLUSIONS: The results of the current study support open subpectoralis biceps tenodesis as an acceptable option for the treatment of LHB pathology irrespective of the treated patient's body mass index. Both obese and non-obese patients demonstrated low postoperative DASH scores and high Oxford Shoulder scores. PMID- 28583057 TI - Auricular Acupressure in the Prevention of Postoperative Nausea and Emesis A Randomized Controlled Trial. AB - INTRODUCTION: Successful antiemesis contributes significantly to quality, safety, and patient satisfaction. Patients undergoing general anesthesia often experience postoperative nausea and vomiting (PONV). Acupressure offers a side effect-free alternative to common first-line antiemetics. Because the patient may perceive needle acupuncture as uncomfortable, acupressure is a desirable alternative for the prevention of PONV. METHODS: This study was a randomized, prospective, double blinded clinical trial investigating the effect of acupressure in patients with a history of PONV and motion sickness. The three auricular acupressure points chosen were shen men, point zero, and the subcortex point. Rescue treatment for PONV with 4 mg intravenous ondansetron was used if the patient reported persistent nausea. A blinded observer recorded antiemetic rescue data, and postoperative analgesic use was recorded over 24 hours. Nausea, vomiting, and retching were assessed in the post-anesthesia care unit (PACU). RESULTS: Using univariate analysis, we ruled out the null hypothesis of equal means as a function of intervention group (p = 0.001). Pair-wise comparisons revealed a difference between placebo and test groups (p = 0.000) and also sham and test groups (p = 0.033) where age (p = 0.048) and gender (p = 0.003) were significant covariates. DISCUSSION: Our data reveal that auricular acupressure significantly decreases nausea during the PACU stay and within the 24 hours postoperatively. It is not clear whether the intervention decreases nausea as a primary effect or as a secondary result by decreasing narcotic requirements. Also, perception of nausea may be in part subjective. This is evidenced by our results in which subjects who received sham points fared better than the placebo subjects. PMID- 28583058 TI - Bone Grafts, Substitutes, and Augments in Benign Orthopaedic Conditions Current Concepts. AB - Musculoskeletal tumors are relatively rare diagnoses made by orthopaedic surgeons. While approximately 2,500 primary bone sarcomas are diagnosed annually in the USA, the number of benign orthopaedic tumors encountered annually is far more difficult to quantify. Some studies have documented between 3% and 10% of the general population having benign bony lesions. Many of these conditions can be simply observed, while others will require surgical intervention. Surgical treatments for benign conditions range from a one-step curettage to extensive resection and reconstruction. With treatment of larger lesions, significant bony defects may need to be addressed surgically. Treatment options have evolved over time with the use of various bone graft and bone void fillers, including methyl methacrylate cement, autograft, allograft bone chips, struts and osteoarticular segments, synthetic bone graft substitutes, and metal augments. This review provides an overview of the present status of bone graft, substitutes, and augment options for the orthopaedic surgeon treating benign musculoskeletal conditions. PMID- 28583059 TI - Mid-Term Results of the SL-PLUS Femoral Prosthesis The Influence of Femoral Bone Type. AB - BACKGROUND: Cementless fixation of the femoral stem has been shown to be durable and predictable in total hip arthroplasty (THA), primarily as a result ofrecent improvements in prosthesis geometry and porous surface. Although patients with osteoporotic bone have been considered poor candidates for the use of a cementless femoral component, some recent studies have indicated satisfactory results. However, the indications and selection criteria of cementless stems based on the morphology of the femoral canal have not been established. PURPOSE: We aimed to assess and compare the mid-term results of cementless THA with an SL PLUS(r) femoral component in patients classified as Dorr types A, B, and C. METHODS: We evaluated the clinical and radiographic results of primary THA with the cementless SL-PLUS(r) stem for 34 hips (25 patients). The preoperative femoral bones were classified as Dorr types A, B, and C in 12, 15, and 7 hips, respectively. Implant survival rates were calculated, hip function was evaluated using the Japanese Orthopaedic Association hip score, and radiographic signs were determined from anteroposterior radiographs. RESULTS: The mean follow-up period was 9.4 years (range: 7 to 13 years), and the mean Japanese Orthopaedic Association hip score improved from 43.8 points preoperatively to 85.3 points at the latest follow-up. The overall implant survival rate was 100% at 10 years; radiographic loosening or revision for any reason was used as the endpoint. Third and fourth degrees of stress shielding were observed in 29.4% of cases and were found to be significantly associated with a low cortical index, a Dorr type C femur, and a larger stem size. CONCLUSIONS: The use of the SL-PLUS(r) stem provided satisfactory mid-term clinical and radiographic results in patients with any type of femoral canal morphology. PMID- 28583060 TI - Impact of Social Support and Pain Coping Abilityon Length of Stay and Discharge Disposition following Hip and Knee Arthroplasty A Prospective Study. AB - INTRODUCTION: While there are many factors known to predict the outcomes of hip and knee arthroplasty procedures, there is a growing interest in predictors that take into consideration the social and psychological preparedness of patients prior to surgery. This study's aim was to determine whether patients' preoperative social support and pain catastrophizing characteristics are independently associated with the outcomes of postoperative length of stay or discharge disposition following primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: Data on a prospective sample of 189 THA and TKA adult patients using the pain catastrophizing scale and the medical outcomes study social support expectation score were analyzed. Demographic characteristics, such as age, gender, and race (Caucasian versus non-Caucasian), which served as covariates, were also collected. Bivariate associations between our outcome variables and covariates using Pearson's and Spearman's rank correlation coefficients and Mann Whitney U test for continuous variables (age, MOS-SSS) and Chi-squared tests for categorical variables (gender, race, ethnicity, procedure, catastrophizing) were employed. Statistical significance was set at p <= 0.05. Data are presented as median with range values, frequencies with percentages, or adjusted odds ratios (OR) and betas (beta) with 95% confidence intervals (CI). RESULTS: There were 73 (38.6%) patients categorized as catastrophizers. Median score for social support was 90.8 (range: 3.9 to 100). No statistically significant associations between pain catastrophizing or social support were observed for length of stay (beta: 0.03, 95% CI: - 0.24-0.31, p = 0.81; beta: - 0.002, 95% CI: - 0.010-- 0.006, p = 0.58) and discharge disposition (OR: 1.15, 95% CI: 0.51-2.55, p = 0.74; OR: 0.99, 95% CI: 0.97-1.01, p = 0.37). Significant associations with discharge to a rehabilitation facility included non Caucasian (OR: 5.4, 95% CI: 2.4-11.8, p < 0.001) and longer length of stay (OR: 1.6, 95% CI: 1.01-2.4, p = 0.04). Female gender and non-Caucasian were associated with longer length of stay (beta: 0.3, 95% CI: 0.03-0.6, p = 0.03; and beta: 0.4, 95% CI: 0.1-0.6, p=0.008, respectively). CONCLUSION: We did not find a significant association between pain catastrophizing behavior and level of social support with length of stay or discharge disposition. PMID- 28583061 TI - Infection after Total Knee Arthroplasty by M. Catarrhalis Associated with Rheumatoid Arthritis and DMARDs Therapy. AB - Moraxella catarrhalis is not commonly associated with prosthetic joint infection (PJI). We present the first case of a patient with rheumatoid arthritis on certolizumab, an antitumor necrosis factor therapy, who developed PJI following a total knee replacement. PMID- 28583062 TI - Multiple Ligament Reconstruction for Absent Cruciate and a Congenital Short Femur Case Report and Review of the Literature. AB - Congenital short femur syndrome is a rare condition affecting about 0.017 of every 1,000 births. Patients frequently have ligamentous abnormalities, most frequently aplastic or hypoplastic cruciate ligaments. Advances in limb lengthening procedures have increased movement expectations for these patients, thus necessitating surgical treatment for their ligamentous abnormalities. An individual case is presented, including history, physical exam, and imaging demonstrating both the short femur and absent cruciate ligaments. A surgical reconstruction technique of the anterior cruciate ligament, posterior cruciate ligament, and posterolateral corner is described. At 1-year follow-up, the patient had 0 degrees to 135 degrees of ROM. He reported no pain but mild swelling experienced during squatting. His knee continues to be stable in all planes with a grade 1A Lachman exam and a grade 1 posterior drawer with no posterolateral corner laxity. PMID- 28583063 TI - Characterization of the Development of Acute-on-Chronic Exertional Compartment Syndrome A Case Report of Symmetric Compartment Syndromes and Review of the Literature. AB - Acute-on-chronic exertional compartment syndrome is a rare and severe progression of the likely common and more benign chronic exertional compartment syndrome. This is a report of one 17-year-old male on a pediatric inpatient service with bilateral anterior leg pain of unknown origin. Because of the nonspecific nature of pain, a high level of suspicion is required for timely diagnosis to avoid compartment ischemia and irreversible soft tissue and nerve damage. While high energy orthopaedic trauma, orthopaedic surgery, or closed reduction and casting are common preceding events for compartment syndrome, this patient presented with acute-on-chronic exertional compartment syndrome. A dearth of literature of this condition hampered its morbiditysparing diagnosis. While there is a spectrum of clinical findings for the acute decompensation of chronic exertional compartment syndrome, like any compartment syndrome, pain disproportionate to physical exam is the most sensitive sign. Understanding the exertional compartment syndrome spectrum is tantamount to avoid the devastating complications of a missed diagnosis of acute compartment syndrome. PMID- 28583065 TI - Application of nonsense-mediated primer exclusion (NOPE) for preparation of unique molecular barcoded libraries. AB - BACKGROUND: Recently we proposed efficient method to exclude undesirable primers at any stage of amplification reaction, here termed NOPE (NOnsense-mediated Primer Exclusion). According to this method, added oligonucleotide overlapping with the 3'-end of unwanted amplification primer (NOPE oligo) simultaneously provides a template for its elongation. This elongation disrupts specificity of unwanted primer, preventing its further participation in PCR. The suggested approach allows to rationally manage the course of PCR reactions in order to facilitate analysis of complex DNA mixtures as well as to perform multistage PCR bypassing intermediate purification steps. RESULTS: Here we apply NOPE method to DNA library preparation for the high-throughput sequencing (HTS) with the PCR based introduction of unique molecular identifiers (UMI). We show that NOPE oligo efficiently neutralizes UMI-containing oligonucleotides after introduction of UMI into sample DNA molecules, thus allowing to proceed with further amplification steps without purification and associated loss of starting material. At the same time, NOPE oligo does not affect the efficiency of target PCR amplification. CONCLUSION: We describe a simple, robust and cheap modification of UMI-labeled HTS libraries preparation procedure, that allows to bypass purification step and thus to preserve starting material which may be limited, e.g. circulating tumor DNA, circulating fetal DNA, or small amounts of isolated cells of interest. Furthermore, demonstrated simplicity and robustness of NOPE method should make it popular in various PCR protocols. PMID- 28583064 TI - Genomic and transcriptomic analyses reveal distinct biological functions for cold shock proteins (VpaCspA and VpaCspD) in Vibrio parahaemolyticus CHN25 during low temperature survival. AB - BACKGROUND: Vibrio parahaemolyticus causes serious seafood-borne gastroenteritis and death in humans. Raw seafood is often subjected to post-harvest processing and low-temperature storage. To date, very little information is available regarding the biological functions of cold shock proteins (CSPs) in the low temperature survival of the bacterium. In this study, we determined the complete genome sequence of V. parahaemolyticus CHN25 (serotype: O5:KUT). The two main CSP encoding genes (VpacspA and VpacspD) were deleted from the bacterial genome, and comparative transcriptomic analysis between the mutant and wild-type strains was performed to dissect the possible molecular mechanisms that underlie low temperature adaptation by V. parahaemolyticus. RESULTS: The 5,443,401-bp V. parahaemolyticus CHN25 genome (45.2% G + C) consisted of two circular chromosomes and three plasmids with 4,724 predicted protein-encoding genes. One dual-gene and two single-gene deletion mutants were generated for VpacspA and VpacspD by homologous recombination. The growth of the DeltaVpacspA mutant was strongly inhibited at 10 degrees C, whereas the VpacspD gene deletion strongly stimulated bacterial growth at this low temperature compared with the wild-type strain. The complementary phenotypes were observed in the reverse mutants (DeltaVpacspA-com, and DeltaVpacspD-com). The transcriptome data revealed that 12.4% of the expressed genes in V. parahaemolyticus CHN25 were significantly altered in the DeltaVpacspA mutant when it was grown at 10 degrees C. These included genes that were involved in amino acid degradation, secretion systems, sulphur metabolism and glycerophospholipid metabolism along with ATP-binding cassette transporters. However, a low temperature elicited significant expression changes for 10.0% of the genes in the DeltaVpacspD mutant, including those involved in the phosphotransferase system and in the metabolism of nitrogen and amino acids. The major metabolic pathways that were altered by the dual-gene deletion mutant (DeltaVpacspAD) radically differed from those that were altered by single-gene mutants. Comparison of the transcriptome profiles further revealed numerous differentially expressed genes that were shared among the three mutants and regulators that were specifically, coordinately or antagonistically modulated by VpaCspA and VpaCspD. Our data also revealed several possible molecular coping strategies for low-temperature adaptation by the bacterium. CONCLUSIONS: This study is the first to describe the complete genome sequence of V. parahaemolyticus (serotype: O5:KUT). The gene deletions, complementary insertions, and comparative transcriptomics demonstrate that VpaCspA is a primary CSP in the bacterium, while VpaCspD functions as a growth inhibitor at 10 degrees C. These results have improved our understanding of the genetic basis for low-temperature survival by the most common seafood-borne pathogen worldwide. PMID- 28583066 TI - Identification of genetic loci associated with crude protein and mineral concentrations in alfalfa (Medicago sativa) using association mapping. AB - BACKGROUND: Alfalfa (Medicago sativa) is one of the most important legume forage species in China and many other countries of the world. It provides a quality source of proteins and minerals to animals. Genetic underpinnings for these important traits, however, are elusive. An alfalfa (M. sativa) association mapping study for six traits, namely crude protein (CP), rumen undegraded protein (RUP), and four mineral elements (Ca, K, Mg and P), was conducted in three consecutive years using a large collection encompassing 336 genotypes genotyped with 85 simple sequence repeat (SSR) markers. RESULTS: All the traits were significantly influenced by genotype, environment, and genotype * environment interaction. Eight-five significant associations (P < 0.005) were identified. Among these, five associations with Ca were repeatedly observed and six co localized associations were identified. CONCLUSIONS: The identified marker alleles significantly associated with the traits provided important information for understanding genetic controls of alfalfa quality. The markers could be used in assisting selection for the individual traits in breeding populations for developing new alfalfa cultivars. PMID- 28583068 TI - lncRNA-screen: an interactive platform for computationally screening long non coding RNAs in large genomics datasets. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) have emerged as a class of factors that are important for regulating development and cancer. Computational prediction of lncRNAs from ultra-deep RNA sequencing has been successful in identifying candidate lncRNAs. However, the complexity of handling and integrating different types of genomics data poses significant challenges to experimental laboratories that lack extensive genomics expertise. RESULT: To address this issue, we have developed lncRNA-screen, a comprehensive pipeline for computationally screening putative lncRNA transcripts over large multimodal datasets. The main objective of this work is to facilitate the computational discovery of lncRNA candidates to be further examined by functional experiments. lncRNA-screen provides a fully automated easy-to-run pipeline which performs data download, RNA-seq alignment, assembly, quality assessment, transcript filtration, novel lncRNA identification, coding potential estimation, expression level quantification, histone mark enrichment profile integration, differential expression analysis, annotation with other type of segmented data (CNVs, SNPs, Hi C, etc.) and visualization. Importantly, lncRNA-screen generates an interactive report summarizing all interesting lncRNA features including genome browser snapshots and lncRNA-mRNA interactions based on Hi-C data. CONCLUSION: lncRNA screen provides a comprehensive solution for lncRNA discovery and an intuitive interactive report for identifying promising lncRNA candidates. lncRNA-screen is available as open-source software on GitHub. PMID- 28583067 TI - PFASUM: a substitution matrix from Pfam structural alignments. AB - BACKGROUND: Detecting homologous protein sequences and computing multiple sequence alignments (MSA) are fundamental tasks in molecular bioinformatics. These tasks usually require a substitution matrix for modeling evolutionary substitution events derived from a set of aligned sequences. Over the last years, the known sequence space increased drastically and several publications demonstrated that this can lead to significantly better performing matrices. Interestingly, matrices based on dated sequence datasets are still the de facto standard for both tasks even though their data basis may limit their capabilities. We address these aspects by presenting a new substitution matrix series called PFASUM. These matrices are derived from Pfam seed MSAs using a novel algorithm and thus build upon expert ground truth data covering a large and diverse sequence space. RESULTS: We show results for two use cases: First, we tested the homology search performance of PFASUM matrices on up-to-date ASTRAL databases with varying sequence similarity. Our study shows that the usage of PFASUM matrices can lead to significantly better homology search results when compared to conventional matrices. PFASUM matrices with comparable relative entropies to the commonly used substitution matrices BLOSUM50, BLOSUM62, PAM250, VTML160 and VTML200 outperformed their corresponding counterparts in 93% of all test cases. A general assessment also comparing matrices with different relative entropies showed that PFASUM matrices delivered the best homology search performance in the test set. Second, our results demonstrate that the usage of PFASUM matrices for MSA construction improves their quality when compared to conventional matrices. On up-to-date MSA benchmarks, at least 60% of all MSAs were reconstructed in an equal or higher quality when using MUSCLE with PFASUM31, PFASUM43 and PFASUM60 matrices instead of conventional matrices. This rate even increases to at least 76% for MSAs containing similar sequences. CONCLUSIONS: We present the novel PFASUM substitution matrices derived from manually curated MSA ground truth data covering the currently known sequence space. Our results imply that PFASUM matrices improve homology search performance as well as MSA quality in many cases when compared to conventional substitution matrices. Hence, we encourage the usage of PFASUM matrices and especially PFASUM60 for these specific tasks. PMID- 28583071 TI - Volume-time curve of cardiac magnetic resonance assessed left ventricular dysfunction in coronary artery disease patients with type 2 diabetes mellitus. AB - BACKGROUND: Type 2 diabetes mellitus (DM2) may induce epicardial coronary artery diseases and left ventricular myocardial damaging as well. Left ventricular dysfunction was found in DM2. In this research, we compared the left ventricular dysfunction of coronary artery disease (CAD) patients with and without type 2 diabetes mellitus as well as normal controls using the volume-time curve of cardiac magnetic resonance (CMR). METHODS: Sixty-one CAD patients (28 with DM2 and 33 without DM2) and 18 normal individuals were enrolled in this study. Left ventricular function parameters, including the end-diastolic and end-systolic volumes (EDV, ESV), stroke volume (SV) and ejection fraction (EF), and morphologic dimension parameters (end diastolic and systolic diameter (EDD and ESD), were measured and compared. Volume-time curve parameters, including the peak ejection rate (PER), peak ejection time (PET), peak filling rate (PFR), peak filling time from ES (PFT), peak ejection rate normalized to EDV (PER/EDV), and peak filling rate normalized to EDV (PFR/EDV), were derived automatically and compared. RESULTS: LVEF in the diabetic CAD group was markedly reduced when compared to the normal and CAD without DM2 groups (all p < 0.05). LVEDD of the diabetic CAD group was significantly enlarged compared to the normal and non diabetic CAD groups (all p < 0.05). More importantly, the lowest parameters of the left ventricle volume time curve (i.e., PER, PFR, PER/EDV and PFR/EDV) were obtained in diabetic CAD patients (all p < 0.05). In diabetic CAD patients, logistic regression analysis indicated that PET, PFT and PFR/EDV were independent predictors of left ventricular dysfunction (odds ratio [OR]: 1.1208, 1.0161, and 0.0139, respectively). The sensitivity and specificity of PET were 81.2 and 90%, respectively, when the threshold value was greater than 164.4 msec; for PFT, the sensitivity and specificity were 87.5 and 95.0%, respectively (criterion >166.0 msec). Higher sensitivity (87.5%) and specificity (100.0%) were obtained for PFR/EDV (criterion <=3.7EDV/s). CONCLUSIONS: Parameters that are derived from the volume-time curve on CMR, including PET, PFT and PFR/EDV, allow clinicians to predict left ventricular dysfunction in diabetic CAD subjects with a high degree of sensitivity and specificity. PMID- 28583069 TI - Trajectories of the relationships of physical activity with body composition changes in older men: the MrOS study. AB - BACKGROUND: Excess adiposity gains and significant lean mass loss may be risk factors for chronic disease in old age. Long-term patterns of change in physical activity (PA) and their influence on body composition decline during aging has not been characterized. We evaluated the interrelationships of PA and body composition at the outset and over longitudinal follow-up to changes in older men. METHODS: Self-reported PA by the Physical Activity Scale for the Elderly (PASE), clinic body weight, and whole-body lean mass (LM) and fat mass, by dual energy x-ray absorptiometry (DXA), were assessed in 5964 community-dwelling men aged >=65 years at baseline (2000-2002) and at two subsequent clinic visits up until March 2009 (an average 4.6 and 6.9 years later). Group-based trajectory modeling (GBTM) identified patterns of change in PA and body composition variables. Relationships of PA and body composition changes were then assessed. RESULTS: GBTM identified three discrete trajectory patterns, all with declining PA, associated primarily with initial PA levelshigh-activity (7.2% of men), moderate-activity (50.0%), and low-activity (42.8%). In separate models, GBTM identified eight discrete total weight change groups, five fat mass change groups, and six LM change groups. Joint trajectory modeling by PA and body composition group illustrated significant declines in total weight and LM, whereas fat mass levels were relatively unchanged among high-activity and low activity-declining groups, and significantly increased in the moderate-activity declining group. CONCLUSION: Although patterns of change in PA and body composition were identified, groups were primarily differentiated by initial PA or body composition rather than by distinct trajectories of change in these variables. PMID- 28583070 TI - High risk of malnutrition is associated with low muscle mass in older hospitalized patients - a prospective cohort study. AB - BACKGROUND: Malnutrition, low muscle strength and muscle mass are highly prevalent in older hospitalized patients and associated with adverse outcomes. Malnutrition may be a risk factor for developing low muscle mass. We aimed to investigate the association between the risk of malnutrition and 1) muscle strength and muscle mass at admission and 2) the change of muscle strength and muscle mass during hospitalization in older patients. METHODS: The EMPOWER study included 378 patients aged seventy years or older who were acutely or electively admitted to four different wards of an academic teaching hospital in Amsterdam. Patients were grouped into low risk of malnutrition and high risk of malnutrition based on the Short Nutritional Assessment Questionnaire (SNAQ) score and were assessed for hand grip strength and muscle mass using hand held dynamometry respectively bioelectrical impedance analysis (BIA) within 48 h after admission and at day seven, or earlier at the day of discharge. Muscle mass was expressed as skeletal muscle mass, appendicular lean mass, fat free mass and the skeletal muscle index. RESULTS: The mean age of the patients was 79.7 years (SD 6.39), 48.9% were female. At admission, being at high risk of malnutrition was significantly associated with lower muscle mass (Odds Ratio, 95% CI, 0.90, 0.85 0.96), but not with muscle strength. Muscle strength and muscle mass did not change significantly during hospitalization in both groups. CONCLUSION: In older hospitalized patients, a high risk of malnutrition is associated with lower muscle mass at admission, but not with muscle strength nor with change of either muscle strength or muscle mass during hospitalization. PMID- 28583073 TI - Does the presence of cardiovascular disease risk factors or established disease influence the dietary intake of affected adults and their children residing in the same household? A secondary analysis of the Australian Health Survey (2011 2013). AB - BACKGROUND: Diet is an important contributor to risk of cardiovascular disease (CVD) and integral in management and delaying progression. Little is known however about whether increased CVD risk or established CVD has any influence on dietary intakes of Australian adults or children residing in the same household. This study aimed to determine whether the presence of CVD or CVD risk factors influences dietary intake of Australian adults and if the presence of an adult with increased CVD risk influences the dietary intake of a child living in the same household. METHODS: Data were sourced from the 2011-2013 Australian Health Survey for: (1) adults >=18 years with risk factors or established CVD and (2) children 2-17 years residing in the same household as adults with CVD risk factors or established CVD. Selected nutrient intakes (total fat, saturated fat plus trans fat, alpha-linolenic acid, total long chain omega 3 fatty acids, fibre and sodium) collected by repeated 24 h recalls were compared to national dietary recommendations and to the intakes of all other adults and children surveyed. Standard errors of the estimates were calculated using the replicate weights method, and an alpha value of <0.05 considered statistically significant. RESULTS: Six thousand two hundred sixty five of 9435 adults surveyed were identified as having CVD risk factors or established disease and of these 1609 had a child in the same household that also contributed data in this survey. No differences were observed in adjusted mean dietary intakes between those without risk factors or established CVD and those with, except for total energy and sodium which were significantly lower in the adults with CVD risk factors and/or established disease. However sodium intakes across both groups were higher than recommended targets. There were no differences for selected nutrients between children residing with affected adults and other children surveyed. CONCLUSIONS: While intakes of Australian adults with CVD risk factors or established disease were favourable for sodium, compared to unaffected adults, there is still scope for improvement as many Australian adults, despite CVD risk, are unable to achieve targets for selected nutrients. Effective dietary behaviour change strategies and resources are urgently needed. PMID- 28583072 TI - Identification of candidate transmission-blocking antigen genes in Theileria annulata and related vector-borne apicomplexan parasites. AB - BACKGROUND: Vector-borne apicomplexan parasites are a major cause of mortality and morbidity to humans and livestock globally. The most important disease syndromes caused by these parasites are malaria, babesiosis and theileriosis. Strategies for control often target parasite stages in the mammalian host that cause disease, but this can result in reservoir infections that promote pathogen transmission and generate economic loss. Optimal control strategies should protect against clinical disease, block transmission and be applicable across related genera of parasites. We have used bioinformatics and transcriptomics to screen for transmission-blocking candidate antigens in the tick-borne apicomplexan parasite, Theileria annulata. RESULTS: A number of candidate antigen genes were identified which encoded amino acid domains that are conserved across vector-borne Apicomplexa (Babesia, Plasmodium and Theileria), including the Pfs48/45 6-cys domain and a novel cysteine-rich domain. Expression profiling confirmed that selected candidate genes are expressed by life cycle stages within infected ticks. Additionally, putative B cell epitopes were identified in the T. annulata gene sequences encoding the 6-cys and cysteine rich domains, in a gene encoding a putative papain-family cysteine peptidase, with similarity to the Plasmodium SERA family, and the gene encoding the T. annulata major merozoite/piroplasm surface antigen, Tams1. CONCLUSIONS: Candidate genes were identified that encode proteins with similarity to known transmission blocking candidates in related parasites, while one is a novel candidate conserved across vector-borne apicomplexans and has a potential role in the sexual phase of the life cycle. The results indicate that a 'One Health' approach could be utilised to develop a transmission-blocking strategy effective against vector-borne apicomplexan parasites of animals and humans. PMID- 28583074 TI - A comprehensive assessment of RNA-seq protocols for degraded and low-quantity samples. AB - BACKGROUND: RNA-sequencing (RNA-seq) has emerged as one of the most sensitive tool for gene expression analysis. Among the library preparation methods available, the standard poly(A) + enrichment provides a comprehensive, detailed, and accurate view of polyadenylated RNAs. However, on samples of suboptimal quality ribosomal RNA depletion and exon capture methods have recently been reported as better alternatives. METHODS: We compared for the first time three commercial Illumina library preparation kits (TruSeq Stranded mRNA, TruSeq Ribo Zero rRNA Removal, and TruSeq RNA Access) as representatives of these three different approaches using well-established human reference RNA samples from the MAQC/SEQC consortium on a wide range of input amounts (from 100 ng down to 1 ng) and degradation levels (intact, degraded, and highly degraded). RESULTS: We assessed the accuracy of the generated expression values by comparison to gold standard TaqMan qPCR measurements and gained unprecedented insight into the limits of applicability in terms of input quantity and sample quality of each protocol. We found that each protocol generates highly reproducible results (R 2 > 0.92) on intact RNA samples down to input amounts of 10 ng. For degraded RNA samples, Ribo-Zero showed clear performance advantages over the other two protocols as it generated more accurate and better reproducible gene expression results even at very low input amounts such as 1 ng and 2 ng. For highly degraded RNA samples, RNA Access performed best generating reliable data down to 5 ng input. CONCLUSIONS: We found that the ribosomal RNA depletion protocol from Illumina works very well at amounts far below recommendation and over a good range of intact and degraded material. We also infer that the exome-capture protocol (RNA Access, Illumina) performs better than other methods on highly degraded and low amount samples. PMID- 28583076 TI - Diagnostic accuracy of nucleic acid amplification tests (NAATs) in urine for genitourinary tuberculosis: a systematic review and meta-analysis. AB - BACKGROUND: Genitourinary tuberculosis is the third most common form of extrapulmonary tuberculosis. Diagnosis is difficult because of unspecific clinical manifestations and low accuracy of conventional tests. Unfortunately, the delayed diagnosis impacts the urinary tract severely. Nucleic acid amplification tests yield fast results, and among these, new technologies can also detect drug resistance. There is lack of consensus regarding the use of these tests in genitourinary tuberculosis; we therefore aimed to assess the accuracy of nucleic acid amplification tests in the diagnosis of genitourinary tuberculosis and to evaluate the heterogeneity between studies. METHODS: We did a systematic review and meta-analysis of research articles comparing the accuracy of a reference standard and a nucleic acid amplification test for diagnosis of urinary tract tuberculosis. We searched Medline, EMBASE, Web of Science, LILACS, Cochrane Library, and Scopus for articles published between Jan 1, 1990, and Apr 14, 2016. Two investigators identified eligible articles and extracted data for individual study sites. We analyzed data in groups with the same index test. Then, we generated pooled summary estimates (95% CIs) for sensitivity and specificity by use of random-effects meta-analysis when studies were not heterogeneous. RESULTS: We identified eleven relevant studies from ten articles, giving information on PCR, LCR and Xpert MTB/RIF tests. All PCR studies were "in house" tests, with different gene targets and had several quality concerns therefore we did not proceed with a pooled analysis. Only one study used LCR. Xpert studies were of good quality and not heterogeneous, pooled sensitivity was 0.87 (0.66-0.96) and specificity was 0.91 (0.84-0.95). CONCLUSION: PCR studies were highly heterogeneous. Among Xpert MTB/RIF studies, specificity was favorable with an acceptable confidence interval, however new studies can update meta analysis and get more precise estimates. Further high-quality studies are urgently needed to improve diagnosis of genitourinary tuberculosis. PROTOCOL REGISTRATION: PROSPERO CRD42016039020. PMID- 28583075 TI - Gene expression and adaptive noncoding changes during human evolution. AB - BACKGROUND: Despite evidence for adaptive changes in both gene expression and non protein-coding, putatively regulatory regions of the genome during human evolution, the relationship between gene expression and adaptive changes in cis regulatory regions remains unclear. RESULTS: Here we present new measurements of gene expression in five tissues of humans and chimpanzees, and use them to assess this relationship. We then compare our results with previous studies of adaptive noncoding changes, analyzing correlations at the level of gene ontology groups, in order to gain statistical power to detect correlations. CONCLUSIONS: Consistent with previous studies, we find little correlation between gene expression and adaptive noncoding changes at the level of individual genes; however, we do find significant correlations at the level of biological function ontology groups. The types of function include processes regulated by specific transcription factors, responses to genetic or chemical perturbations, and differentiation of cell types within the immune system. Among functional categories co-enriched with both differential expression and noncoding adaptation, prominent themes include cancer, particularly epithelial cancers, and neural development and function. PMID- 28583078 TI - The conquering of North America: dated phylogenetic and biogeographic inference of migratory behavior in bee hummingbirds. AB - BACKGROUND: Geographical and temporal patterns of diversification in bee hummingbirds (Mellisugini) were assessed with respect to the evolution of migration, critical for colonization of North America. We generated a dated multilocus phylogeny of the Mellisugini based on a dense sampling using Bayesian inference, maximum-likelihood and maximum parsimony methods, and reconstructed the ancestral states of distributional areas in a Bayesian framework and migratory behavior using maximum parsimony, maximum-likelihood and re-rooting methods. RESULTS: All phylogenetic analyses confirmed monophyly of the Mellisugini and the inclusion of Atthis, Calothorax, Doricha, Eulidia, Mellisuga, Microstilbon, Myrmia, Tilmatura, and Thaumastura. Mellisugini consists of two clades: (1) South American species (including Tilmatura dupontii), and (2) species distributed in North and Central America and the Caribbean islands. The second clade consists of four subclades: Mexican (Calothorax, Doricha) and Caribbean (Archilochus, Calliphlox, Mellisuga) sheartails, Calypte, and Selasphorus (incl. Atthis). Coalescent-based dating places the origin of the Mellisugini in the mid-to-late Miocene, with crown ages of most subclades in the early Pliocene, and subsequent species splits in the Pleistocene. Bee hummingbirds reached western North America by the end of the Miocene and the ancestral mellisuginid (bee hummingbirds) was reconstructed as sedentary, with four independent gains of migratory behavior during the evolution of the Mellisugini. CONCLUSIONS: Early colonization of North America and subsequent evolution of migration best explained biogeographic and diversification patterns within the Mellisugini. The repeated evolution of long-distance migration by different lineages was critical for the colonization of North America, contributing to the radiation of bee hummingbirds. Comparative phylogeography is needed to test whether the repeated evolution of migration resulted from northward expansion of southern sedentary populations. PMID- 28583079 TI - Lateral cortical Cdca7 expression levels are regulated by Pax6 and influence the production of intermediate progenitors. AB - BACKGROUND: We studied whether regulation of Cdca7 (Cell division cycle associated 7) expression by transcription factor Pax6 contributes to Pax6's cellular actions during corticogenesis. The function of Cdca7 in mediating Pax6's effects during corticogenesis has not been explored. Pax6 is expressed by radial glial progenitors in the ventricular zone of the embryonic cortical neuroepithelium, where it is required for the development of a normal complement of Tbr2-expressing intermediate progenitor cells in the subventricular zone. Pax6's expression levels are graded across the ventricular zone, with highest levels laterally where Tbr2-expressing progenitors are generated in greatest numbers at early stages of corticogenesis. METHODS: We used in situ hybridization and immunohistochemistry to analyse patterns of Cdca7 and Pax6 expression in cortical tissue from wild-type and Pax6 -/- embryos. In each genotype we compared the graded expression of the two genes quantitatively at several ages. To test whether defects in Cdca7 expression in lateral cortical cells might contribute to the cellular defects in this region caused by Pax6 loss, we electroporated a Cdca7 expression vector into wild-type lateral cortex and examined the effect on the production of Tbr2-expressing cells. RESULTS: We found that Cdca7 is co expressed with Pax6 in cortical progenitors, at levels opposite to those of Pax6. Lowest levels of Cdca7 are found in the radial glial progenitors of lateral cortex, where Pax6 levels are highest. Higher levels of Cdca7 are found in ventral telencephalon, where Pax6 levels are low. Loss of Pax6 causes Cdca7 expression to increase in the lateral cortex. Elevating Cdca7 in normal lateral cortical progenitors to levels close to those normally found in ventral telencephalon reduces their production of Tbr2-expressing cells early in lateral cortical formation. CONCLUSION: Our results suggest that Pax6 normally represses Cdca7 expression in the lateral cortex and that repression of Cdca7 in cells of this region is required for their production of a normal complement of Tbr2 expressing intermediate progenitors. PMID- 28583077 TI - Identification of conserved genes triggering puberty in European sea bass males (Dicentrarchus labrax) by microarray expression profiling. AB - BACKGROUND: Spermatogenesis is a complex process characterized by the activation and/or repression of a number of genes in a spatio-temporal manner. Pubertal development in males starts with the onset of the first spermatogenesis and implies the division of primary spermatogonia and their subsequent entry into meiosis. This study is aimed at the characterization of genes involved in the onset of puberty in European sea bass, and constitutes the first transcriptomic approach focused on meiosis in this species. RESULTS: European sea bass testes collected at the onset of puberty (first successful reproduction) were grouped in stage I (resting stage), and stage II (proliferative stage). Transition from stage I to stage II was marked by an increase of 11ketotestosterone (11KT), the main fish androgen, whereas the transcriptomic study resulted in 315 genes differentially expressed between the two stages. The onset of puberty induced 1) an up-regulation of genes involved in cell proliferation, cell cycle and meiosis progression, 2) changes in genes related with reproduction and growth, and 3) a down-regulation of genes included in the retinoic acid (RA) signalling pathway. The analysis of GO-terms and biological pathways showed that cell cycle, cell division, cellular metabolic processes, and reproduction were affected, consistent with the early events that occur during the onset of puberty. Furthermore, changes in the expression of three RA nuclear receptors point at the importance of the RA-signalling pathway during this period, in agreement with its role in meiosis. CONCLUSION: The results contribute to boost our knowledge of the early molecular and endocrine events that trigger pubertal development and the onset of spermatogenesis in fish. These include an increase in 11KT plasma levels and changes in the expression of several genes involved in cell proliferation, cell cycle progression, meiosis or RA-signalling pathway. Moreover, the results can be applied to study meiosis in this economically important fish species for Mediterranean countries, and may help to develop tools for its sustainable aquaculture. PMID- 28583080 TI - The effect of body size evolution and ecology on encephalization in cave bears and extant relatives. AB - BACKGROUND: The evolution of larger brain volumes relative to body size in Mammalia is the subject of an extensive amount of research. Early on palaeontologists were interested in the brain of cave bears, Ursus spelaeus, and described its morphology and size. However, until now, it was not possible to compare the absolute or relative brain size in a phylogenetic context due to the lack of an established phylogeny, comparative material, and phylogenetic comparative methods. In recent years, many tools for comparing traits within phylogenies were developed and the phylogenetic position of cave bears was resolved based on nuclear as well as mtDNA. RESULTS: Cave bears exhibit significantly lower encephalization compared to their contemporary relatives and intraspecific brain mass variation remained rather small. Encephalization was correlated with the combined dormancy-diet score. Body size evolution was a main driver in the degree of encephalization in cave bears as it increased in a much higher pace than brain size. In Ursus spelaeus, brain and body size increase over time albeit differently paced. This rate pattern is different in the highest encephalized bear species within the dataset, Ursus malayanus. The brain size in this species increased while body size heavily decreased compared to its ancestral stage. CONCLUSIONS: Early on in the evolution of cave bears encephalization decreased making it one of the least encephalized bear species compared to extant and extinct members of Ursidae. The results give reason to suspect that as herbivorous animals, cave bears might have exhibited a physiological buffer strategy to survive the strong seasonality of their environment. Thus, brain size was probably affected by the negative trade-off with adipose tissue as well as diet. The decrease of relative brain size in the herbivorous Ursus spelaeus is the result of a considerable increase in body size possibly in combination with environmental conditions forcing them to rest during winters. PMID- 28583081 TI - Addition of plant-growth-promoting Bacillus subtilis PTS-394 on tomato rhizosphere has no durable impact on composition of root microbiome. AB - BACKGROUND: Representatives of the genus Bacillus are increasingly used in agriculture to promote plant growth and to protect against plant pathogens. Unfortunately, hitherto the impact of Bacillus inoculants on the indigenous plant microbiota has been investigated exclusively for the species Bacillus amyloliquefaciens and was limited to prokaryotes, whilst eukaryotic member of this community, e.g. fungi, were not considered. RESULTS: The root-colonizing Bacillus subtilis PTS-394 supported growth of tomato plants and suppressed soil borne diseases. Roche 454 pyrosequencing revealed that PTS-394 has only a transient impact on the microbiota community of the tomato rhizosphere. The impact on eukaryota could last up to 14 days, while that on bacterial communities lasted for 3 days only. CONCLUSIONS: Ecological adaptation and microbial community-preserving capacity are important criteria when assessing suitability of bio-inoculants for commercial development. As shown here, B. subtilis PTS-394 is acting as an environmentally compatible plant protective agent without permanent effects on rhizosphere microbial community. PMID- 28583082 TI - Integrated QTL detection for key breeding traits in multiple peach progenies. AB - BACKGROUND: Peach (Prunus persica (L.) Batsch) is a major temperate fruit crop with an intense breeding activity. Breeding is facilitated by knowledge of the inheritance of the key traits that are often of a quantitative nature. QTLs have traditionally been studied using the phenotype of a single progeny (usually a full-sib progeny) and the correlation with a set of markers covering its genome. This approach has allowed the identification of various genes and QTLs but is limited by the small numbers of individuals used and by the narrow transect of the variability analyzed. In this article we propose the use of a multi-progeny mapping strategy that used pedigree information and Bayesian approaches that supports a more precise and complete survey of the available genetic variability. RESULTS: Seven key agronomic characters (data from 1 to 3 years) were analyzed in 18 progenies from crosses between occidental commercial genotypes and various exotic lines including accessions of other Prunus species. A total of 1467 plants from these progenies were genotyped with a 9 k SNP array. Forty-seven QTLs were identified, 22 coinciding with major genes and QTLs that have been consistently found in the same populations when studied individually and 25 were new. A substantial part of the QTLs observed (47%) would not have been detected in crosses between only commercial materials, showing the high value of exotic lines as a source of novel alleles for the commercial gene pool. Our strategy also provided estimations on the narrow sense heritability of each character, and the estimation of the QTL genotypes of each parent for the different QTLs and their breeding value. CONCLUSIONS: The integrated strategy used provides a broader and more accurate picture of the variability available for peach breeding with the identification of many new QTLs, information on the sources of the alleles of interest and the breeding values of the potential donors of such valuable alleles. These results are first-hand information for breeders and a step forward towards the implementation of DNA-informed strategies to facilitate selection of new cultivars with improved productivity and quality. PMID- 28583083 TI - The skeletal proteome of the sea star Patiria miniata and evolution of biomineralization in echinoderms. AB - BACKGROUND: Proteomic studies of skeletal proteins have revealed large, complex mixtures of proteins occluded within the mineral. Many skeletal proteomes contain rapidly evolving proteins with repetitive domains, further complicating our understanding. In echinoderms, proteomic analysis of the skeletal proteomes of mineralized tissues of the sea urchin Strongylocentrotus purpuratus prominently featured spicule matrix proteins with repetitive sequences linked to a C-type lectin domain. A comparative study of the brittle star Ophiocoma wendtii skeletal proteome revealed an order of magnitude fewer proteins containing C-type lectin domains. A number of other proteins conserved in the skeletons of the two groups were identified. Here we report the complete skeletal proteome of the sea star Patiria miniata and compare it to that of the other echinoderm groups. RESULTS: We have identified eighty-five proteins in the P. miniata skeletal proteome. Forty-two percent of the proteins were determined to be homologous to proteins found in the S. purpuratus skeletal proteomes. An additional 34 % were from similar functional classes as proteins in the urchin proteomes. Thirteen percent of the P. miniata proteins had homologues in the O. wendtii skeletal proteome with an additional 29% showing similarity to brittle star skeletal proteins. The P. miniata skeletal proteome did not contain any proteins with C-lectin domains or with acidic repetitive regions similar to the sea urchin or brittle star spicule matrix proteins. MSP130 proteins were also not found. We did identify a number of proteins homologous between the three groups. Some of the highly conserved proteins found in echinoderm skeletons have also been identified in vertebrate skeletons. CONCLUSIONS: The presence of proteins conserved in the skeleton in three different echinoderm groups indicates these proteins are important in skeleton formation. That a number of these proteins are involved in skeleton formation in vertebrates suggests a common origin for some of the fundamental processes co-opted for skeleton formation in deuterostomes. The proteins we identify suggest transport of proteins and calcium via endosomes was co-opted to this function in a convergent fashion. Our data also indicate that modifications to the process of skeleton formation can occur through independent co-option of proteins following species divergence as well as through domain shuffling. PMID- 28583084 TI - Expression and functional analysis of the transcription factor-encoding Gene CsERF004 in cucumber during Pseudoperonospora cubensis and Corynespora cassiicola infection. AB - BACKGROUND: Cucumber downy mildew, caused by P. cubensis, is an important leaf disease that can severely affect cucumber production. In recent years, cucumber target spot, caused by C. cassiicola, has been reported in both Asia and Europe and is now considered as a major disease disrupting cucumber production. Single disease-resistant cucumber varieties have been unable to satisfy production needs. To explore the molecular mechanisms of cucumber resistance to these two diseases, cucumber cultivars D9320 (resistant to downy mildew and target spot) and D0401 (susceptible to downy mildew and target spot) were used as experimental materials in this study. We used transcriptome sequencing technology to identify genes related to disease resistance and verified using transgenic technology. RESULTS: We screened out the cucumber resistance-related gene CsERF004 using transcriptome sequencing technology. Induction by pathogens, salicylic acid (SA), and ethylene (ET) resulted in the up-regulation of CsERF004. Three treatments, namely, inoculation with C. cassiicola alone, inoculation with P. cubensis alone, and simultaneous inoculation with both pathogens, all resulted in the significant and sustained up-regulation of CsERF004 in the resistant cultivar D9320, during the early stage of infection. In the susceptible cultivar D0401, CsERF004 expression was also significantly up-regulated at the later stage of infection but to a lesser extent and for a shorter duration than in the resistant cultivar D9320. The CsERF004 gene encodes a protein localizes to the nucleus. The over expression of CsERF004 in the susceptible cultivar D0401 resulted in the significant up-regulation of the CsPR1 and CsPR4 genes and increased the levels of SA and ET, which enhanced the resistance of cucumber to downy mildew and target spot. CONCLUSIONS: Analyses of the CsERF004 expression pattern in disease resistant and susceptible cucumber cultivars and transgenic validation indicate that CsERF004 confers resistance to P. cubensis and C. cassiicola. The findings of this study can help to better understanding of mechanisms of response to pathogens and in establishment the genetic basis for the development of cucumber broad-spectrum resistant cultivars. PMID- 28583085 TI - Intricacies in arrangement of SNP haplotypes suggest "Great Admixture" that created modern humans. AB - BACKGROUND: Inferring history from genomic sequences is challenging and problematic because chromosomes are mosaics of thousands of small Identicalby descent (IBD) fragments, each of them having their own unique story. However, the main events in recent evolution might be deciphered from comparative analysis of numerous loci. A paradox of why humans, whose effective population size is only 104, have nearly three million frequent SNPs is formulated and examined. RESULTS: We studied 5398 loci evenly covering all human autosomes. Common haplotypes built from frequent SNPs that are present in people from various populations have been examined. We demonstrated highly non-random arrangement of alleles in common haplotypes. Abundance of mutually exclusive pairs of common haplotypes that have different alleles at every polymorphic position (so-called Yin/Yang haplotypes) was found in 56% of loci. A novel widely spread category of common haplotypes named Mosaic has been described. Mosaic consists of numerous pieces of Yin/Yang haplotypes and represents an ancestral stage of one of them. Scenarios of possible appearance of large number of frequent human SNPs and their habitual arrangement in Yin/Yang common haplotypes have been evaluated with an advanced genomic simulation algorithm. CONCLUSIONS: Computer modeling demonstrated that the observed arrangement of 2.9 million frequent SNPs could not originate from a sole stand-alone population. A "Great Admixture" event has been proposed that can explain peculiarities with frequent SNP distributions. This Great Admixture presumably occurred 100-300 thousand years ago between two ancestral populations that had been separated from each other about a million years ago. Our programs and algorithms can be applied to other species to perform evolutionary and comparative genomics. PMID- 28583086 TI - Independent prognostic role of human papillomavirus genotype in cervical cancer. AB - BACKGROUND: Although the correlation of HPV genotype with cervical precursor lesions and invasive cancer has been confirmed, the role of HPV genotype in cervical cancer prognosis is less conclusive. This study aims to systematically investigate the independent prognostic role of HPV genotype in cervical cancer. METHODS: A total of 306 eligible patients provided cervical cell specimens for HPV genotyping before therapy and had a median follow-up time of 54 months after diagnosis. Survival times were measured from the date of diagnosis to the date of cervical cancer-related death (overall survival, OS) and from the date of diagnosis to the date of recurrence or metastasis (disease free survival, DFS). Log-rank tests and Cox proportional hazard models were performed to evaluate the association between HPV genotype and survival times. RESULTS: A total of 12 types of high-risk HPV were detected and the leading ten types belong to two species: alpha-9 and alpha-7. HPV16 and 18 were the two most common types, with the prevalence of 60.8% and 8.8%, respectively. In the univariate analysis, HPV16 positive cases were associated with better OS (P = 0.037) and HPV16-related species alpha-9 predicted better OS and DFS (both P < 0.01). After adjusting for age, FIGO stage, and therapy, HPV16 showed a hazard ratio (HR) of 0.36 (95% CI: 0.18, 0.74; P = 0.005) for OS, and alpha-9 resulted in a HR of 0.17 (95% CI: 0.08, 0.37; P < 0.001) for OS and 0.32 (95% CI: 0.17, 0.59; P < 0.001) for DFS. CONCLUSIONS: HPV genotype poses differential prognoses for cervical cancer patients. The presence of HPV16 and its related species alpha-9 indicates an improved survival. PMID- 28583087 TI - Incomplete ileus and hemafecia as the presenting features of multi-organ involved primary systemic AL amyloidosis: a rare case report. AB - BACKGROUND: AL Amyloidosis is known to be a systemic disease affecting multiple organs and tissue while it's rare that patients present with gastrointestinal symptoms at first and later develop multiple-organ dysfuction. Clinical signs are not specific and the diagnosis is rarely given before performing immunofixation and endoscopy with multiple biopsies. We would like to emphasize the value of precise diagnostic process of AL amyloidosis. CASE PRESENTATION: In this case report, we describe a 56-year-old man who presented with recurrent periumbilical pain for 4 months and gradually worsened over a month. After a series of tests, he was finally diagnosed with primary systemic AL amyloidosis. He was treated with a chemotherapy regimen (Melphalan, dexamethasone and thalidomide) achieving a good clinical response. CONCLUSION: On account of the high misdiagnosis rate, establishing the most precise diagnosis in first time with typing amyloidogenic protein becomes increasingly vital. Although the presenting feature is usually nonspecific, AL amyloidosis ought to be considered when multiple organs are involved in a short period. PMID- 28583089 TI - Genome-enabled predictions for fruit weight and quality from repeated records in European peach progenies. AB - BACKGROUND: Highly polygenic traits such as fruit weight, sugar content and acidity strongly influence the agroeconomic value of peach varieties. Genomic Selection (GS) can accelerate peach yield and quality gain if predictions show higher levels of accuracy compared to phenotypic selection. The available IPSC 9K SNP array V1 allows standardized and highly reliable genotyping, preparing the ground for GS in peach. RESULTS: A repeatability model (multiple records per individual plant) for genome-enabled predictions in eleven European peach populations is presented. The analysis included 1147 individuals derived from both commercial and non-commercial peach or peach-related accessions. Considered traits were average fruit weight (FW), sugar content (SC) and titratable acidity (TA). Plants were genotyped with the 9K IPSC array, grown in three countries (France, Italy, Spain) and phenotyped for 3-5 years. An analysis of imputation accuracy of missing genotypic data was conducted using the software Beagle, showing that two of the eleven populations were highly sensitive to increasing levels of missing data. The regression model produced, for each trait and each population, estimates of heritability (FW:0.35, SC:0.48, TA:0.53, on average) and repeatability (FW:0.56, SC:0.63, TA:0.62, on average). Predictive ability was estimated in a five-fold cross validation scheme within population as the correlation of true and predicted phenotypes. Results differed by populations and traits, but predictive abilities were in general high (FW:0.60, SC:0.72, TA:0.65, on average). CONCLUSIONS: This study assessed the feasibility of Genomic Selection in peach for highly polygenic traits linked to yield and fruit quality. The accuracy of imputing missing genotypes was as high as 96%, and the genomic predictive ability was on average 0.65, but could be as high as 0.84 for fruit weight or 0.83 for titratable acidity. The estimated repeatability may prove very useful in the management of the typical long cycles involved in peach productions. All together, these results are very promising for the application of genomic selection to peach breeding programmes. PMID- 28583090 TI - Prediction of bioluminescent proteins by using sequence-derived features and lineage-specific scheme. AB - BACKGROUND: Bioluminescent proteins (BLPs) widely exist in many living organisms. As BLPs are featured by the capability of emitting lights, they can be served as biomarkers and easily detected in biomedical research, such as gene expression analysis and signal transduction pathways. Therefore, accurate identification of BLPs is important for disease diagnosis and biomedical engineering. In this paper, we propose a novel accurate sequence-based method named PredBLP (Prediction of BioLuminescent Proteins) to predict BLPs. RESULTS: We collect a series of sequence-derived features, which have been proved to be involved in the structure and function of BLPs. These features include amino acid composition, dipeptide composition, sequence motifs and physicochemical properties. We further prove that the combination of four types of features outperforms any other combinations or individual features. To remove potential irrelevant or redundant features, we also introduce Fisher Markov Selector together with Sequential Backward Selection strategy to select the optimal feature subsets. Additionally, we design a lineage-specific scheme, which is proved to be more effective than traditional universal approaches. CONCLUSION: Experiment on benchmark datasets proves the robustness of PredBLP. We demonstrate that lineage-specific models significantly outperform universal ones. We also test the generalization capability of PredBLP based on independent testing datasets as well as newly deposited BLPs in UniProt. PredBLP is proved to be able to exceed many state-of art methods. A web server named PredBLP, which implements the proposed method, is free available for academic use. PMID- 28583088 TI - Uncovering the transcriptomic and epigenomic landscape of nicotinic receptor genes in non-neuronal tissues. AB - BACKGROUND: Nicotinic acetylcholine receptors (nAChRs) play an important role in cellular physiology and human nicotine dependence, and are closely associated with many human diseases including cancer. For example, previous studies suggest that nAChRs can re-wire gene regulatory networks in lung cancer cell lines. However, the tissue specificity of nAChRs genes and their regulation remain unexplored. RESULT: In this study, we integrated data from multiple large genomic consortiums, including ENCODE, Roadmap Epigenomics, GTEx, and FANTOM, to define the transcriptomic and epigenomic landscape of all nicotinic receptor genes across many different human tissues and cell types. We found that many important nAChRs, including CHRNA3, CHRNA4, CHRNA5, and CHRNB4, exhibited strong non neuronal tissue-specific expression patterns. CHRNA3, CHRNA5, and CHRNB4 were highly expressed in human colon and small intestine, and CHRNA4 was highly expressed in human liver. By comparing the epigenetic marks of CHRNA4 in human liver and hippocampus, we identified a novel liver-specific transcription start site (TSS) of CHRNA4. We further demonstrated that CHRNA4 was specifically transcribed in hepatocytes but not transcribed in hepatic sinusoids and stellate cells, and that transcription factors HNF4A and RXRA were likely upstream regulators of CHRNA4. Our findings suggest that CHRNA4 has distinct transcriptional regulatory mechanisms in human liver and brain, and that this tissue-specific expression pattern is evolutionarily conserved in mouse. Finally, we found that liver-specific CHRNA4 transcription was highly correlated with genes involved in the nicotine metabolism, including CYP2A6, UGT2B7, and FMO3. These genes were significantly down-regulated in liver cancer patients, whereas CHRNA4 is also significantly down-regulated in cancer-matched normal livers. CONCLUSIONS: Our results suggest important non-neuronally expressed nicotinic acetylcholine receptors in the human body. These non-neuronal expression patterns are highly tissue-specific, and are epigenetically conserved during evolution in the context of non-conserved DNA sequence. PMID- 28583091 TI - Reconciliation feasibility in the presence of gene duplication, loss, and coalescence with multiple individuals per species. AB - BACKGROUND: In phylogenetics, we often seek to reconcile gene trees with species trees within the framework of an evolutionary model. While the most popular models for eukaryotic species allow for only gene duplication and gene loss or only multispecies coalescence, recent work has combined these phenomena through a reconciliation structure, the labeled coalescent tree (LCT), that simultaneously describes the duplication-loss and coalescent history of a gene family. However, the LCT makes the simplifying assumption that only one individual is sampled per species whereas, with advances in gene sequencing, we now have access to multiple samples per species. RESULTS: We demonstrate that with these additional samples, there exist gene tree topologies that are impossible to reconcile with any species tree. In particular, the multiple samples enforce new constraints on the placement of duplications within a valid reconciliation. To model these constraints, we extend the LCT to a new structure, the partially labeled coalescent tree (PLCT) and demonstrate how to use the PLCT to evaluate the feasibility of a gene tree topology. We apply our algorithm to two clades of apes and flies to characterize possible sources of infeasibility. CONCLUSION: Going forward, we believe that this model represents a first step towards understanding reconciliations in duplication-loss-coalescence models with multiple samples per species. PMID- 28583092 TI - Postpartum hemorrhage prevention in Nepal: a program assessment. AB - BACKGROUND: In 2009, the Nepal Ministry of Health and Population launched a national program for prevention of postpartum hemorrhage (PPH) during home births that features advance distribution of misoprostol to pregnant women. In the years since, the government has scaled-up the program throughout much of the country. This paper presents findings from the first large-scale assessment of the effectiveness of the advance distribution program. METHODS: Data collection was carried out in nine districts and all three ecological zones. To assess knowledge, receipt and use of misoprostol, household interviews were conducted with 2070 women who had given birth within the past 12 months. To assess supply and provision of misoprostol, interviews were conducted with 270 Female Community Health Volunteers (FCHVs) and staff at 99 health facilities. RESULTS: Among recently delivered women, only 15% received information about misoprostol and 13% received misoprostol tablets in advance of delivery. Yet 87% who received advance misoprostol and delivered at home used it for PPH prevention. Among FCHVs, 96% were providing advance misoprostol for PPH prevention; however 81% had experienced at least one misoprostol stock out within the past year. About one half of FCHVs were providing incomplete information about the use of misoprostol; in addition, many did not discuss side effects, how to recognize PPH or where to go if PPH occurs. Among health facilities, just one-half had sufficient misoprostol stock, while 95% had sufficient oxytocin stock, at the time of this assessment. CONCLUSIONS: In Nepal, women who receive advance misoprostol are both willing and able to use the medication for PPH prevention during home births. However the supply and personnel challenges identified raise questions about scalability and impact of the program over the long-term. Further assessment is needed. PMID- 28583093 TI - Physical working conditions as covered in European monitoring questionnaires. AB - BACKGROUND: The prevalence of workers with demanding physical working conditions in the European work force remains high, and occupational physical exposures are considered important risk factors for musculoskeletal disorders (MSD), a major burden for both workers and society. Exposures to physical workloads are therefore part of the European nationwide surveys to monitor working conditions and health. An interesting question is to what extent the same domains, dimensions and items referring to the physical workloads are covered in the surveys. The purpose of this paper is to determine 1) which domains and dimensions of the physical workloads are monitored in surveys at the national level and the EU level and 2) the degree of European consensus among these surveys regarding coverage of individual domains and dimensions. METHOD: Items on physical workloads used in one European wide/Spanish and five other European nationwide work environment surveys were classified into the domains and dimensions they cover, using a taxonomy agreed upon among all participating partners. RESULTS: The taxonomy reveals that there is a modest overlap between the domains covered in the surveys, but when considering dimensions, the results indicate a lower agreement. The phrasing of items and answering categories differs between the surveys. Among the domains, the three domains covered by all surveys are "lifting, holding & carrying of loads/pushing & pulling of loads", "awkward body postures" and "vibrations". The three domains covered less well, that is only by three surveys or less, are "physical work effort", "working sitting", and "mixed exposure". CONCLUSIONS: This is the first thorough overview to evaluate the coverage of domains and dimensions of self-reported physical workloads in a selection of European nationwide surveys. We hope the overview will provide input to the revisions and updates of the individual countries' surveys in order to enhance coverage of relevant domains and dimensions in all surveys and to increase the informational value of the surveys. PMID- 28583094 TI - Most children with cancer are not enrolled on a clinical trial in Canada: a population-based study. AB - BACKGROUND: Primary objective was to describe the proportion of children newly diagnosed with cancer enrolled on a therapeutic clinical trial. Secondary objectives were to describe reasons for non-enrollment and factors associated with enrollment on trials. METHODS: In this retrospective cohort study, we included children newly diagnosed with cancer between 0 and 14 years of age and diagnosed from 2001 to 2012. We used data from the Cancer in Young People in Canada (CYP-C) national pediatric cancer population-based database. CYP-C captures all cases of pediatric cancer (0-14 years) diagnosed and treated at one of the 17 tertiary pediatric oncology centers in Canada. Non-enrollment was evaluated using univariate and multiple logistic regression analysis. RESULTS: There were 9204 children with cancer included, of whom 2533 (27.5%) were enrolled on a clinical trial. The most common reasons cited for non-enrollment were lack of an available trial (52.2%) and physician choice (11.2%). In multiple regression, Asian and Arab/west Asian race were associated with lower enrollment (P = 0.006 and P = 0.032 respectively). All cancer diagnoses were more likely to be enrolled compared to astrocytoma and children with acute lymphoblastic leukemia had an almost 18-fold increased odds of enrollment compared to astrocytoma (P < 0.0001). Greater distance from the tertiary care center was independently associated with non-enrollment (P < 0.0001). CONCLUSIONS: In Canada, 27.5% of children with cancer are enrolled onto therapeutic clinical trials and lack of an available trial is the most common reason contributing to non-enrollment. Future research should better understand reasons for lack of trial availability and physician preferences to not offer trials. PMID- 28583095 TI - The prognostic significance of KRAS and BRAF mutation status in Korean colorectal cancer patients. AB - BACKGROUND: BRAF and KRAS mutations are well-established biomarkers in anti-EGFR therapy. However, the prognostic significance of these mutations is still being examined. We determined the prognostic value of BRAF and KRAS mutations in Korean colorectal cancer (CRC) patients. METHODS: From July 2010 to September 2013, 1096 patients who underwent surgery for CRC at Seoul St. Mary's Hospital were included in the analysis. Resected specimens were examined for BRAF, KRAS, and microsatellite instability (MSI) status. All data were reviewed retrospectively. RESULTS: Among 1096 patients, 401 (36.7%) had KRAS mutations and 44 (4.0%) had BRAF mutations. Of 83 patients, 77 (92.8%) had microsatellite stable (MSS) or MSI low (MSI-L) status while 6 (7.2%) patients had MSI high (MSI-H) status. Patients with BRAF mutation demonstrated a worse disease-free survival (DFS, HR 1.990, CI 1.080-3.660, P = 0.02) and overall survival (OS, HR 3.470, CI 1.900-6.330, P < 0.0001). Regarding KRAS status, no significant difference was noted in DFS (P = 0.0548) or OS (P = 0.107). Comparing the MSS/MSI-L and MSI-H groups there were no significant differences in either DFS (P = 0.294) or OS (P = 0.557). CONCLUSIONS: BRAF mutation, rather than KRAS, was a significant prognostic factor in Korean CRC patients at both early and advanced stages. The subgroup analysis for MSI did not show significant differences in clinical outcome. BRAF should be included in future larger prospective biomarker studies on CRC. PMID- 28583096 TI - The impact of hip fracture on mortality in Estonia: a retrospective population based cohort study. AB - BACKGROUND: Estimates of hip fracture mortality in Eastern Europe are scarce. We aimed to estimate the magnitude and duration of excess mortality after hip fracture in Estonia. METHODS: Retrospective, population-based 10-year study of persons aged >=50 in two cohorts: with hip fracture and an age- and sex-matched (in a 1:4 ratio) random sample from the national health insurance fund database for comparison. Cumulative risks, excess risks and relative risks of death were estimated using Poisson regression with 95% bootstrap confidence intervals (CI). Risks were adjusted for age and Charlson comorbidity index. RESULTS: We identified 8298 (2383 men, 5915 women) incident hip fracture patients from 2005 to 2013 and 33,191 (9531 men, 23,660 women) individuals for the reference group. 5552 (1564 men, 3988 women) cases and 14,037 (3514 men, 10,523 women) reference individuals died during the 10-year follow-up period. Among hip fracture patients we observed a pronounced and durable excess risk of death that was highest within 3-6 months after fracture and persisted for the full 10-year follow-up period. After adjustment for age and Charlson index, hip fracture was associated with a 21.1% (95% CI 20.0-22.5%) 10-year cumulative excess risk of death (RR 1.37, 95% CI 1.35-1.40). We found a high immediate excess risk of death in older age groups (>=80 years) and gradually accumulating excess risk in younger age groups (50-79 years). The excess risk was more pronounced among men than women. CONCLUSIONS: By the end of the 10-year follow-up, 1 in 4 deaths in the hip fracture group was attributable to the hip fracture. The results indicate a high attributable impact of hip fracture as an independent risk factor for death. PMID- 28583097 TI - NRAMP1 and VDR gene polymorphisms in susceptibility to pulmonary tuberculosis among Andhra Pradesh population in India: a case-control study. AB - BACKGROUND: The aim of the present study was to evaluate the association of NRAMP1 -3'UTR, 274-CT,VDR- Fok1 VDR-Taq1 Polymorphisms with the risk of pulmonary tuberculosis. METHOD: A case -control study was conducted on Andhra Pradesh Population of India. Analysis of gene polymorphisms of NRAMP1 gene (3'UTR, 274CT) and VDR gene (Fok1 and Taq1) was done by using Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) in Tuberculosis (TB) patients and healthy controls. The obtained results were observed using 2% Agarose Gel electrophoresis and analysed statistically using Chi-square test and Odds Ratio. RESULTS: Statistical significance was observed between the patients and the controls in the NRAMP1-3'UTR (P = 0.005; OR = 2.997; 95% CI = 1.019-8.813) and VDR-Taq1 (P < 0.001; OR = 0.140;95% C.I = 0.050-0.386) polymorphisms in Andhra Pradesh population. No statistical significance was observed between patients and controls of the same population in NRAMP1-274CT and VDR-Fok1 polymorphisms (p > 0.05). CONCLUSION: 3'UTR-NRAMP1 gene and VDR-Taq1 gene Polymorphisms are statistically associated with the susceptibility of TB in Andhra Pradesh Population in India. PMID- 28583098 TI - Contours of a causal feedback mechanism between adaptive personality and psychosocial function in patients with personality disorders: a secondary analysis from a randomized clinical trial. AB - BACKGROUND: Patients with personality disorders commonly exhibit impairment in psychosocial function that persists over time even with diagnostic remission. Further causal knowledge may help to identify and assess factors with a potential to alleviate this impairment. Psychosocial function is associated with personality functioning which describes personality disorder severity in DSM-5 (section III) and which can reportedly be improved by therapy. METHODS: The reciprocal association between personality functioning and psychosocial function was assessed, in 113 patients with different personality disorders, in a secondary longitudinal analysis of data from a randomized clinical trial, over six years. Personality functioning was represented by three domains of the Severity Indices of Personality Problems: Relational Capacity, Identity Integration, and Self-control. Psychosocial function was measured by Global Assessment of Functioning. The marginal structural model was used for estimation of causal effects of the three personality functioning domains on psychosocial function, and vice versa. The attractiveness of this model lies in the ability to assess an effect of a time - varying exposure on an outcome, while adjusting for time - varying confounding. RESULTS: Strong causal effects were found. A hypothetical intervention to increase Relational Capacity by one standard deviation, both at one and two time-points prior to assessment of psychosocial function, would increase psychosocial function by 3.5 standard deviations (95% CI: 2.0, 4.96). Significant effects of Identity Integration and Self-control on psychosocial function, and from psychosocial function on all three domains of personality functioning, although weaker, were also found. CONCLUSION: This study indicates that persistent impairment in psychosocial function can be addressed through a causal pathway of personality functioning, with interventions of at least 18 months duration. PMID- 28583099 TI - Magnetic resonance imaging of bacterial and tuberculous spondylodiscitis with associated complications and non-infectious spinal pathology mimicking infections: a pictorial review. AB - Magnetic resonance (MR) imaging plays an important role in the evaluation of bacterial and tuberculous spondylodiscitis and associated complications. Owing to its high sensitivity and specificity, it is a powerful diagnostic tool in the early diagnosis of ongoing infections, and thus provides help in prompt initiation of appropriate, therapy which may be medical or surgical, by defining the extent of involvement and detection of complications such as epidural and paraspinal abscesses. More specifically, MR imaging helps in differentiating bacterial from tuberculous infections and enables follow up of progression or resolution after appropriate treatment. However, other non-infectious pathology can demonstrate similar MR imaging appearances and one should be aware of these potential mimickers when interpreting MR images. Radiologists and other clinicians need to be aware of these potential mimics, which include such pathologies as Modic type I degenerative changes, trauma, metastatic disease and amyloidosis. In this pictorial review, we will describe and illustrate imaging findings of bacterial and tuberculous spondylodiscitis, their complications and non-infectious pathologies that mimic these spinal infections. PMID- 28583101 TI - Healthcare interventions for the prevention and control of gestational diabetes mellitus in China: a scoping review. AB - BACKGROUND: Gestational Diabetes Mellitus (GDM) is a type of diabetes which occurs during pregnancy. Women with GDM are at greater risk of complications during pregnancy and delivery, while babies born from mothers with GDM are at greater risk of post-natal complications. Using the most updated diagnosis criteria, the GDM prevalence is estimated at 9.3-25.5% worldwide and 9.3-18.9% in China. Our objective was to identify healthcare interventions aimed at GDM prevention and control in China. METHODS: A best-evidence synthesis was performed based on a systematic search of literature published between 1997 and October 2015 in PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Wan-fang databases using keywords "Gestational Diabetes Mellitus", "GDM", "Intervention" "Medical Intervention" "Early Medical Intervention", "Dietary Intervention", "Exercise Intervention", "Lifestyle Intervention", "Therapy", "Treatment" and "China". Inclusion criteria were studies conducted in China, reporting GDM healthcare interventions, and published in either Chinese or English. Two reviewers independently assessed eligibility and quality of the studies and extracted the data. Treatment efficacy was examined with weighted pooled odds ratio (OR) meta-analyses. RESULTS: The search resulted in 5961 articles (published in 276 different Chinese language journals and 6 English language journals), of which 802 were included in this synthesis. While 39.4% (n = 316) failed to report the GDM diagnostic criteria used, the remaining studies classified GDM with various international (n = 5) or Chinese (n = 7) diagnostic standards. Treatment interventions were categorized into 6 types: dietary (18.6%), exercise (1.6%), medication (20.7%), health education (9.0%), psychological (2.6%) and combination (47.4%). No interventions aimed at GDM prevention were identified. Meta-analyses demonstrated a statistically significant overall benefit of GDM treatment strategies in reducing the odds of maternal and infant adverse outcomes (ORs range 0.20-0.34, 95% CI 0.17-0.49, P < 0.05 for all). Dietary, western medication, and combined interventions were the most effective inteventions. CONCLUSIONS: An increasing number of healthcare interventions were found in China aimed at controlling GDM while no interventions were intended for GDM prevention. Well-designed clinical trials are needed to determine the comparative and cost effectiveness of GDM prevention and treatment strategies. PMID- 28583100 TI - Insomnia, psychiatric disorders and suicidal ideation in a National Representative Sample of active Canadian Forces members. AB - BACKGROUND: Past research on the association between insomnia and suicidal ideation (SI) has produced mixed findings. The current study explored the relationship between insomnia, SI, and past-year mental health status among a large Canadian Forces (CF) sample. METHOD: Data was obtained from the 2013 Canadian Forces Mental Health Survey (CFMHS), and included a large representative sample of Canadian Regular Forces personnel (N = 6700). A series of univariate logistic regressions were conducted to test individual associations between past year mental health status, insomnia, and potential confounds and SI. Mental health status included three groups: 0, 1, or two or more probable diagnoses of posttraumatic stress disorder (PTSD), major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder (PD) and alcohol abuse/dependence. Stepwise multivariate logistic regression was used to assess the relationship between insomnia and SI with mental health status as a moderator. RESULTS: 40.8% of respondents reported experiencing insomnia. Both insomnia and number of mental health conditions incrementally increased the risk of SI. However, past-year mental health status was a significant moderator of this relationship, such that for CF personnel with either no (AOR = 1.61, 1.37 1.89) or only one past-year mental health condition (AOR = 1.39, 1.12-1.73), an incremental increase in insomnia was associated with an increased likelihood of SI. However, in personnel with two or more past-year mental health disorders, insomnia was no longer significantly associated with SI (AOR = 1.04, 0.81-1.33). CONCLUSIONS: Insomnia significantly increased the odds of SI, but only among individuals with no or one mental health condition. Findings highlight the importance of assessing insomnia among CF members in order to further suicide prevention efforts. PMID- 28583104 TI - Development and validation of a claims-based measure as an indicator for disease status in patients with multiple sclerosis treated with disease-modifying drugs. AB - BACKGROUND: Administrative healthcare claims data provide a mechanism for assessing and monitoring multiple sclerosis (MS) disease status across large, clinically representative "real-world" populations. The estimation of MS disease status using administrative claims can be a challenge, however, due to a lack of detailed clinical information. Retrospective claims analyses in MS have traditionally used rates of MS relapses to approximate disease status. Healthcare costs may be alternate, broader claims-based indicators of disease activity because costs reflect multiple facets of care of patients with MS, and there is a strong correlation between quality of life of patients with MS and costs of the disease. This study developed, tested, and validated a healthcare cost-based measure to serve as an indicator of overall disease status in patients with MS treated with disease-modifying drugs (DMDs) utilizing administrative claims. METHODS: Using IMS Health Real World Data Adjudicated Claims - US data (January 2006-June 2013), a negative binomial regression predicted annual all-cause medical costs. Coefficients reaching statistical significance (p < 0.05) and increasing costs by >=5% were selected for inclusion into an MS-specific severity score (scale of 0 to 100). Components of the score included rehabilitation services, altered mental state, pain, disability, stiffness, balance disorder, urinary incontinence, numbness, malaise/fatigue, and infections. Coefficient weights represented each predictor's contribution. The predictive model was derived using 50% of a random sample and tested/validated using the remaining 50%. RESULTS: Average overall predicted annual total medical cost was $11,134 (development sample, n = 11,384, vs. $10,528 actual) and $11,303 (validation sample, n = 11,385, vs. $10,620 actual). The model had consistent bias (approximately +$600 or +6% of actual costs) for both samples. In the validation sample, mean MS disease status scores were 0.24, 8.95, and 21.77 for low, medium, and high tertiles, respectively. Mean costs were most accurately predicted among less severe patients ($5243 predicted vs. $5233 actual cost for lowest tertile). CONCLUSION: The algorithm developed in this study provides an initial step to helping understand and potentially predict cost changes for a commercially insured MS population. PMID- 28583102 TI - Analysis of epidemiological trends in human papillomavirus infection among gynaecological outpatients in Hangzhou, China, 2011-2015. AB - : BACKGROUND: HPV infection is the major pathogenic factor underlying cervical cancer and precancerous lesions. The cervical HPV infection rates in gynaecological outpatients from Hangzhou, China, were studied in the period from January 2011 to December 2015. METHODS: Exfoliated cervical cells were harvested from gynaecological outpatients in Hangzhou from January 2011 to December 2015. Twenty-one HPV subtypes were detected using flow-through hybridization. The HPV infection rates in various disease groups were compared using the Chi-square test. The infection rates of different HPV subtypes in different calendar years and in different age groups were analysed using the linear-by-linear association test and gamma value. RESULTS: A total of 43,804 patients were recruited, of whom 9752 (22.3%) were infected with HPV. The top five among the 21 HPV subtypes detected in terms of infection rates were HPV-16, 52, -58, -53 and -18. No significant differences (linear-by-linear association test) were found in the HPV infection rates when compared over the studied years (P > 0.05). However, the 15-24-year-old age group showed the highest HPV infection rate, and significant differences (linear-by-linear association test) were detected among the different age groups (P < 0.05). The HPV infection rates exhibited an upward trend in the 15-24-year-old and >24-34-year-old groups over the past five years. There were significant differences in the HPV infection rates among the disease groups (P < 0.05). CONCLUSIONS: HPV-16, -52 and -58 were the major HPV infection subtypes in Hangzhou, China. The 15-24-year-old age group had a relatively high HPV infection rate with an upward trend over the past five years and thus represented a population susceptible to HPV infection. PMID- 28583103 TI - In-patient costs of agitation and containment in a mental health catchment area. AB - BACKGROUND: There is a scarce number of studies on the cost of agitation and containment interventions and their results are still inconclusive. We aimed to calculate the economic consequences of agitation events in an in-patient psychiatric facility providing care for an urban catchment area. METHODS: A mixed approach combining secondary analysis of clinical databases, surveys and expert knowledge was used to model the 2013 direct costs of agitation and containment events for adult inpatients with mental disorders in an area of 640,572 adult inhabitants in South Barcelona (Spain). To calculate costs, a seven-step methodology with novel definition of agitation was used along with a staff survey, a database of containment events, and data on aggressive incidents. A micro-costing analysis of specific containment interventions was used to estimate both prevalence and direct costs from the healthcare provider perspective, by means of a mixed approach with a probabilistic model evaluated on real data. Due to the complex interaction of the multivariate covariances, a sensitivity analysis was conducted to have empirical bounds of variability. RESULTS: During 2013, 918 patients were admitted to the Acute Inpatient Unit. Of these, 52.8% were men, with a mean age of 44.6 years (SD = 15.5), 74.4% were compulsory admissions, 40.1% were diagnosed with schizophrenia or non-affective psychosis, with a mean length of stay of 24.6 days (SD = 16.9). The annual estimate of total agitation events was 508. The cost of containment interventions ranges from 282? at the lowest level of agitation to 822? when verbal containment plus seclusion and restraint have to be used. The annual total cost of agitation was 280,535?, representing 6.87% of the total costs of acute hospitalisation in the local area. CONCLUSIONS: Agitation events are frequent and costly. Strategies to reduce their number and severity should be implemented to reduce costs to the Health System and alleviate patient suffering. PMID- 28583106 TI - Prescription drug use during pregnancy in Southern Tigray region, North Ethiopia. AB - BACKGROUND: Judicious utilization of drugs rescues the fetus from the harmful effects while treating the health problems of the pregnant women. This study aimed at evaluating drug utilization pattern and its associated factors among pregnant women in Southern Tigray, Ethiopia. METHOD: Institution based cross sectional study was conducted among 647 pregnant women who had been attending obstetrics-gynecology and antenatal care units in different health facilities of Southern Tigray region. The study participants were selected using multistage sampling technique. Data collection was done using pre-tested semi-structured questionnaires and by reviewing antenatal follow-up cards. Descriptive and inferential statistics were analyzed, to assess drug utilization pattern and its associated factors among pregnant women, using SPSS version 20 software. RESULTS: Of 647 pregnant women, 87.5% were prescribed with at least one medication. As per the United States Food and Drug Administration (US-FDA) risk classification system, 87.7, 7.9, 3.9, and 0.5% of the prescribed drug were from category A, B, C and D, respectively. Prescription drug use was more likely among gynecology ward visitors [AOR = 8.97, 95% Cl (2.69-29.88)] and among those who visited health facilities for the first time during their first [AOR =2.65, 95% Cl (1.44 4.84)] and second [AOR = 2.50, 95% Cl (1.36-4.61)] trimesters. CONCLUSION: Majority of the study population used safe and appropriate medications according to US-FDA risk classification system, with the exception of low proportion (0.5%) of medication with potential risk for the fetus. The average number of drug prescribed per pregnant women was in the recommended range of WHO drug use indicators guideline. PMID- 28583105 TI - Characteristics and potentials of stem cells derived from human degenerated nucleus pulposus: potential for regeneration of the intervertebral disc. AB - BACKGROUND: Eliminating the symptoms during treatment of intervertebral disc degeneration (IVDD) is only a temporary solution that does not cure the underlying cause. A biological method to treat this disorder may be possible by the newly discovered nucleus pulposus derived stem cells (NPDCs). However, the uncertain characteristics and potential of NPDCs calls for a comprehensive study. METHODS: In the present study, nucleus pulposus samples were obtained from 5 patients with IVDD undergoing discectomy procedure and NPDCs were harvested using fluorescence activated cell sorting (FACS) by the co-expression of GD2+ and Tie2+. After in vitro expansion, the properties of NPDCs were compared with those of bone marrow mesenchyme stem cells (BMSCs) from the same subjects. RESULTS: NPDCs performed similar properties in cell colony-forming ability, cell proliferation rate, cell cycle and stem cell gene expression similar to those of BMSCs. In addition, NPDCs could be differentiated into osteoblasts, adipocytes, and chondrocytes, and are found to be superior in chondrogenesis but inferior in adipocyte differentiation. CONCLUSIONS: NPDCs derived from the degenerated intervertebral disc still keep the regeneration ability similar to BMSCs. Besides, the superior capacity in chondrogenesis may provide a promising cell candidate for cell-based regenerative medicine and tissue engineering in IVDD. PMID- 28583107 TI - The impact of peritoneal dialysis-related peritonitis on mortality in peritoneal dialysis patients. AB - BACKGROUND: Results concerning the association between peritoneal dialysis related peritonitis and mortality in peritoneal dialysis patients are inconclusive, with one potential reason being that the time-dependent effect of peritonitis has rarely been considered in previous studies. This study aimed to evaluate whether peritonitis has a negative impact on mortality in a large cohort of peritoneal dialysis patients. We also assessed the changing impact of peritonitis on patient mortality with respect to duration of follow-up. METHODS: This retrospective cohort study included incident patients who started peritoneal dialysis from 1 January 2006 to 31 December 2011. Episodes of peritonitis were recorded at the time of onset, and peritonitis was parameterized as a time dependent variable for analysis. We used the Cox regression model to assess whether peritonitis has a negative impact on mortality. RESULTS: A total of 1321 patients were included. The mean age was 48.1 +/- 15.3 years, 41.3% were female, and 23.5% with diabetes mellitus. The median (interquartile) follow-up time was 34 (21-48) months. After adjusting for confounders, peritonitis was independently associated with 95% increased risk of all-cause mortality (hazard ratio, 1.95; 95% confidence interval: 1.46-2.60), 90% increased risk of cardiovascular mortality (hazard ratio, 1.90; 95% confidence interval: 1.28-2.81) and near 4 fold increased risk of infection-related mortality (hazard ratio, 4.94; 95% confidence interval: 2.47-9.86). Further analyses showed that peritonitis was not significantly associated with mortality within 2 years of peritoneal dialysis initiation, but strongly influenced mortality in patients dialysed longer than 2 years. CONCLUSIONS: Peritonitis was independently associated with higher risk of all-cause, cardiovascular and infection-related mortality in peritoneal dialysis patients, and its impact on mortality was more significant in patients with longer peritoneal dialysis duration. PMID- 28583108 TI - A novel SYNE1 gene mutation in a Chinese family of Emery-Dreifuss muscular dystrophy-like. AB - BACKGROUND: In the present study, a novel mutation in exon 46 at codon 2304 (G2304R) of the SYNE1 gene is described in a Chinese family (proband, mother, and sister) with Emery-Dreifuss muscular dystrophy-like, which clinically manifests as muscle weakness, muscle atrophy, joint contracture, and without significant cardiac abnormalities. METHODS: Clinical examination and neuroimaging of the captured target region and high-throughput sequencing were performed in a family of four generations. Muscle changes were evaluated using magnetic resonance imaging and muscle biopsies. RESULTS: Target region capture sequencing yielded a novel missense mutation in codon 2304 (G2304R), which is a heterozygous A to G point mutation at position 6910 (c.6910A > G) in exon 46 of SYNE1 leading to a glycine-to-arginine substitution (p.Gly2304Arg). The results were also identified by Sanger sequencing in three family members but not in the other three unaffected family members and 100 control subjects. CONCLUSIONS: This mutation is probably pathogenic and is the first of its kind reported in a familial Emery Dreifuss muscular dystrophy-like. PMID- 28583110 TI - Jack stone in the bladder: case report of a rare entity. AB - BACKGROUND: Jackstone is a bladder stone that has a similar appearance to toy jacks. However review of the English language medical literature revealed only a few previous reports of jackstone calculus. CASE PRESENTATION: We report a case in which a large jackstone calculus was incidentally detected during the evaluation of 67 year old male presenting with lower urinary tract symptoms. X Ray kidney, ureter, bladder showed a large irregular shaped radio-opaque shadow in the pelvic region. He underwent cystolitholapaxy and transurethral resection of the prostate. CONCLUSION: It is important to recognize the characteristic shape of the urinary bladder calculi in the diagnosis of the jack stones and to treat the primary cause of calculi formation. PMID- 28583111 TI - Promoting early presentation of breast cancer in older women: sustained effect of an intervention to promote breast cancer awareness in routine clinical practice. AB - BACKGROUND: Older women have poorer survival from breast cancer, which may be at least partly due to poor breast cancer awareness leading to delayed presentation and more advanced stage at diagnosis. In a randomised trial, an intervention to promote early presentation of breast cancer in older women increased breast cancer awareness at 1 year compared with usual care (24 versus 4%). We examined its effectiveness in routine clinical practice. METHODS: We piloted the intervention delivered by practising health professionals to women aged about 70 in four breast screening services. We measured the effect on breast cancer awareness at 1 year compared with comparison services, where women did not receive the intervention. RESULTS: At 1 year, 25% of women in pilot services were breast cancer aware compared with 4% in comparison services (p = 0.001). The components of breast cancer awareness were knowledge of breast cancer non-lump symptoms (pilot: 63% vs comparison: 82% at 1 year; OR = 2.56, 95% CI 1.92-3.42), knowledge of age related risk (pilot: 8% vs comparison: 36% at 1 year; OR = 5.56, 95% CI 4.0-7.74) and reported breast checking (pilot: 70% vs comparison: 78% at 1 year; OR = 1.49, 95% CI 1.13-1.96). CONCLUSION: The intervention may be as effective in routine clinical practice as in a randomised controlled trial. This intervention has the potential to reduce patient delay in the diagnosis of breast cancer in older women. TRIAL REGISTRATION: The PEP trial was registered with the International Standard Registered Clinical/soCial sTudy Number (ISRCTN) as a clinical trial ( ISRCTN31994827 ) on 3rd October 2007. PMID- 28583109 TI - Prevalence and distribution of Gardnerella vaginalis subgroups in women with and without bacterial vaginosis. AB - BACKGROUND: Bacterial vaginosis (BV) is one of the leading causes of vaginal complaints among women of childbearing age. The role of Gardnerella vaginalis remains controversial due to its presence in healthy and BV-type vaginal microflora. The phenotypic and genotypic heterogeneity of G. vaginalis suggested the existence of strain variants linked with different health conditions. We sought to analyze prevalence and distribution of G. vaginalis subgroups (clades) in BV-positive (n = 29), partial BV (n = 27), and BV-negative (n = 53) vaginal samples from Lithuanian women. METHODS: Vaginal samples were characterized by Amsel criteria and the Nugent method. Bacterial signatures characteristic of BV and concomitant infections were identified by culture and PCR. Using singleplex PCR assays, G. vaginalis subgroups were identified in 109 noncultured vaginal specimens by targeting clade-specific genes. Isolated G. vaginalis clinical strains were subtyped and the presence of the sialidase coding gene was detected by PCR. Data analysis was performed using GraphPad Prism statistical software. RESULTS: G. vaginalis was found in 87% of women without BV. Clade 4 was most frequently detected (79.4%), followed by clade 1 (63.7%), clade 2 (42.2%), and clade 3 (15.7%). Multi-clade G. vaginalis communities showed a positive association with Nugent score (NS) >= 4 (OR 3.64; 95% CI 1.48-8.91; p = 0.005). Clade 1 and clade 2 were statistically significantly more common in samples with NS 7-10 (OR 4.69; 95% CI 1.38-15.88; p = 0.01 and OR 6.26; 95% CI 2.20-17.81; p <= 0.001, respectively). Clade 3 and clade 4 showed no association with high NS (OR 0.88; 95% CI 0.26-3.04; p = 1.00 and OR 1.31; 95% CI 0.39-4.41; p = 0.767, respectively). The gene coding for sialidase was detected in all isolates of clade 1 and clade 2, but not in clade 4 isolates. CONCLUSIONS: We showed an association between the microbial state of vaginal microflora and specific subgroups of G. vaginalis, the distribution of which may determine the clinical manifestation of BV. The frequent detection of clade 4 in the BV-negative samples might be due its lack of the gene coding for sialidase. PMID- 28583112 TI - Clinical and genetic factors associated with kidney tubular dysfunction in a real life single centre cohort of HIV-positive patients. AB - BACKGROUND: Tenofovir (TDF) is one of the most widely used antiretroviral drug. Despite the high degree of tolerability a small percentage of patients experienced alteration in tubular function during TDF use. Intracellular TDF disposition is regulated by ATP-binding cassette (ABC) drug efflux transporters and, a reduced transport activity may be implicated in accumulation of TDF into the cells. The aim of our study was to assess the major determinants of TDF associated tubular dysfunction (KTD) in a real-life setting including the usefulness of single-nucleotide polymorphisms (SNPs) mapping into ABCC2, ABCC4 and ABCC10 genes. METHODS: We retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from April 2013 to June 2016. All patients treated with TDF who underwent a genotypization for the functional variants mapping in ABCC2 rs717620 (-24 C > T), ABCC4 rs1751034 (3463 A > G) and ABCC10 rs2125739 (T > C) were evaluated. KTD was defined as the presence of urine phosphate wasting and/or proteinuria at 24 h urine analysis. RESULTS: One hundred fifty-eight patients were genotyped, of which 42 (26.6%) experienced signs of KTD. No statistical significant differences were observed among patients with or without KTD regarding age, gender, ethnicity and comorbidities (hypertension and diabetes). The percentage of patients with KTD was higher among those with "GG" genotype at rs1751034 of ABCC4 compared to patients without KTD [6 (14.3%) vs 4 (3.5%), p = 0.01]. No statistical significant differences were observed regarding the distribution of ABCC2 and ABCC10 SNPs. Carriers of "G" allele in homozygous status at rs1751034 of ABCC4 showed a significant association with KTD (Odds Ratio 4.67, 95% CI 1.25-17.46, p = 0.02) in bivariate analysis, but this association was lost in multivariable analysis. A significant association between bone diseases and KTD was observed (Odds Ratio 3.178, 95%CI 1.529-6.603, p = 0.002). CONCLUSIONS: According to our results ABCC4 rs1751034 could be a genetic determinant of KTD; however validation studies are needed for therapy personalization. Noteworthy, a strong association between bone disease and KTD was also observed. PMID- 28583113 TI - Patterns, control and complications of diabetes from a hospital based registry established in a low income country. AB - BACKGROUND: Diabetes registry enables practitioners to measure the characteristics and patterns of diabetes across their patient population. They also provide insight into practice patterns which can be very effective in improving care and preventing complications. The aim of this study was to assess the patterns, control levels and complications at the baseline of the patients attending clinic at the large tertiary care hospital in Karachi, Pakistan with the help of the registry. This can be used as a reference to monitor the control and also for a comparison between peer groups. METHODS: This was a cross sectional study with the data obtained from diabetes registry collected with the help of pre-designed questionnaire. HbA1c was used as a central diabetes measure and other related factors and complications were assessed with it. RESULTS: Only 16.6% of the participants had optimal HbA1c <= 7.0%. 52.9% of the patients were classified as having poor control defined by HbA1c of >8%. Three fourth of the study population were obese according to Asian specific BMI cutoffs and majority had type 2 diabetes with duration of diabetes ranging from less than one to about 35 years, mean(SD) duration being 7.6 years (7.1). Overall only 4% of the patients were on combine target of HbA1c, LDL and BP. Results of multivariable logistic regression showed that the odds of having optimal glycemic control increased by 3% with every one year increase in age. In addition, having longer duration of diabetes was associated with 56% lower odds of having good glycemic control. Moreover, having higher triglyceride levels was associated with 1% lower odds of having good glycemic control. CONCLUSION: This highlights the large burden of sub optimally controlled people with diabetes in Pakistani population, a low income country with huge diabetes prevalence and ineffective primary health care system creating enormous health and economic burden. PMID- 28583114 TI - The peripheral monocyte count is associated with the density of tumor-associated macrophages in the tumor microenvironment of colorectal cancer: a retrospective study. AB - BACKGROUND: Inflammation is widely recognized to play an important role in cancer progression, and the peripheral monocyte count has been reported to correlate with the prognosis in patients with colorectal cancer. This is based on the hypothesis that the peripheral monocyte level and the density of tumor-associated macrophages (TAMs) in the cancer microenvironment correlate with each other. However, the influence of TAMs on the prognosis and the correlation between the peripheral monocyte count and the density of TAMs have not yet been elucidated. METHODS: A total of 168 patients with stage II/III colorectal cancer were enrolled in this study. Preoperative blood samples were obtained at the time of the diagnosis before surgery. The expression of TAMs in the cancer microenvironment was assessed by immunohistochemistry. RESULTS: The progression free and overall survival rate were significantly worse in the high-TAMs group than in the low-TAMs group (p = 0.0012 and p = 0.0207, respectively). The peripheral monocyte count was significantly associated with the number of TAMs (correlation coefficients: 0.202, p = 0.047). CONCLUSIONS: The peripheral monocyte count was associated with the density of the TAMs, which created a microenvironment favorable for cancer development and were correlated with a poor prognosis. Therefore, the peripheral monocyte count is a useful prognostic marker reflecting the status of the tumor microenvironment. PMID- 28583115 TI - Tuberculosis arthritis of the sternoclavicular joint after uncomplicated falciparum malaria: a case report. AB - BACKGROUND: Malaria and tuberculosis are co-endemic in many developing countries. However their associations are rarely reported. Yet, it has been suggested that a pathological process may link the two diseases. CASE PRESENTATION: A 20-year-old female patient was admitted in the internal medicine service of Aristide Le Dantec Hospital for uncomplicated malaria. She was previously treated for autoimmune hemolytic anaemia using prednisone at 5 mg per day. Clinical examination showed swelling in front of the sternoclavicular joint. She presented with fever and headache. Thick smear from blood revealed trophozoites of P. falciparum at parasite density of 52,300 parasites/MUl. The Ziehl-Neelsen stained smear showed the presence of acid-fast bacilli from the fluid puncture of the swelling. Mycobacterium tuberculosis was further isolated in culture. The diagnosis of falciparum malaria co-infection with sternoclavicular tuberculosis was posed. The patient was treated successfully using antimalarial drugs subsequently followed by multidrug antitubercular therapy. CONCLUSION: Interactions between malaria and tuberculosis need to be largely and prospectively investigated and appropriate treatment should be undertaken. PMID- 28583116 TI - Association between total-Tau and brain atrophy one year after first-ever stroke. AB - BACKGROUND: Although the most serious consequence of neuronal ischemia is acute neuronal death, mounting evidence suggests similarities between stroke and neurodegenerative disease. Brain atrophy visualized on structural MRI and pathological cerebrospinal fluid (CSF) concentrations of microtubule-associated protein tau (T-tau) and phosphorylated microtubule-associated protein tau indicate neurofibrillary degeneration. We aimed to explore the association between CSF T-tau and brain atrophy 1 year post-stroke. METHODS: We included 210 patients with first-ever ischemic stroke or transitory ischemic attack without pre-existing cognitive impairment. After 12 months, subjects underwent MRI, and CSF biomarkers were assessed. Using SIENAX (part of FSL), ventricular CSF volume and total brain volume were estimated and normalized for subject head size. The association between T-tau as explanatory variable and ventricular and total brain volume as outcome variables were studied using linear regression. RESULTS: One hundred eighty-two patients completed the follow-up. Forty-four had a lumbar puncture. Of these, 31 had their MRI with identical scan parameters. Mean age was 70.2 years (SD 11.7). Ventricular volume on MRI was significantly associated with age, but not with gender. In the multiple regression model, there was a significant association between T-tau and both ventricular (beta 0.44, 95% CI 376.3, 394.9, p = 0.021) and global brain volume (beta -0.50, 95% CI -565.9, 78.3, p = 0.011). There was no significant association between CSF T-tau 1 year post-stroke and baseline volumes. CONCLUSION: T-tau measured 1 year post-stroke is associated with measures of brain atrophy. The findings indicate that acute stroke may enhance or trigger tau-linked neurodegeneration with loss of neurons. TRIAL REGISTRATION: Clinicaltrials.gov NCT00506818 , July 23, 2007. Inclusion from February 2007, randomization and intervention from May 2007 and trial registration in July 2007. PMID- 28583118 TI - Single-cell study links metabolism with nutrient signaling and reveals sources of variability. AB - BACKGROUND: The yeast AMPK/SNF1 pathway is best known for its role in glucose de/repression. When glucose becomes limited, the Snf1 kinase is activated and phosphorylates the transcriptional repressor Mig1, which is then exported from the nucleus. The exact mechanism how the Snf1-Mig1 pathway is regulated is not entirely elucidated. RESULTS: Glucose uptake through the low affinity transporter Hxt1 results in nuclear accumulation of Mig1 in response to all glucose concentrations upshift, however with increasing glucose concentration the nuclear localization of Mig1 is more intense. Strains expressing Hxt7 display a constant response to all glucose concentration upshifts. We show that differences in amount of hexose transporter molecules in the cell could cause cell-to-cell variability in the Mig1-Snf1 system. We further apply mathematical modelling to our data, both general deterministic and a nonlinear mixed effect model. Our model suggests a presently unrecognized regulatory step of the Snf1-Mig1 pathway at the level of Mig1 dephosphorylation. Model predictions point to parameters involved in the transport of Mig1 in and out of the nucleus as a majorsource of cell to cell variability. CONCLUSIONS: With this modelling approach we have been able to suggest steps that contribute to the cell-to-cell variability. Our data indicate a close link between the glucose uptake rate, which determines the glycolytic rate, and the activity of the Snf1/Mig1 system. This study hence establishes a close relation between metabolism and signalling. PMID- 28583117 TI - Population awareness of cardiovascular disease and its risk factors in Buea, Cameroon. AB - BACKGROUND: Adequate awareness of cardiovascular diseases (CVD) and their risk factors may help reduce the population's exposure to modifiable risk factors and thereby contribute to prevention and control strategies. There is limited data on knowledge among the general population in sub-Saharan Africa regarding CVD and risk factors. We aimed to assess the population awareness (and associated factors) of CVD types and risk factors in Buea, Cameroon. METHODS: This was a community-based cross-sectional study conducted in 2016 among randomly selected adults (>18 years). Data on socio-demographic characteristics, knowledge about CVD types, their risk factors and warning signs for CVD events (stroke and heart attack) were acquired using a self-administered questionnaire. Logistic regression analysis was used to investigate factors associated with moderate-to good knowledge. RESULTS: Of the 1162 participants (61.7% women, mean age 32 years), 52.5% had overall poor knowledge (mean score 12.1 on total of 25) on CVD with only about a quarter correctly identifying types of CVD. Overall, 36, 63 and 45% were unaware of CVD risk factors, warning signs of heart attack and stroke respectively. In multivariable analysis; high level of education (aOR = 2.26 (1.69-3.02), p < 0.0001), high monthly income (aOR = 1.64 (1.07-2.51), p = 0.023), having a family history of CVD (aOR = 1.59 (1.21-2.09), p = 0.001) and being a former smoker (aOR = 1.11 (1.02-1.95), p = 0.043) were associated with moderate-to-good knowledge. CONCLUSIONS: There exists a significant gap in population awareness about CVDs in Cameroon and this is similar to previous reports. Cost-effective community health education interventions taking into account socioeconomic status may be beneficial in this setting. PMID- 28583119 TI - Surveillance for sulfadoxine-pyrimethamine resistant malaria parasites in the Lake and Southern Zones, Tanzania, using pooling and next-generation sequencing. AB - BACKGROUND: Malaria in pregnancy (MiP) remains a major public health challenge in areas of high malaria transmission. Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended to prevent the adverse consequences of MiP. The effectiveness of SP for IPTp may be reduced in areas where the dhps581 mutation (a key marker of high level SP resistance) is found; this mutation was previously reported to be common in the Tanga Region of northern Tanzania, but there are limited data from other areas. The frequency of molecular markers of SP resistance was investigated in malaria parasites from febrile patients at health centres (HC) in seven regions comprising the Lake and Southern Zones of mainland Tanzania as part of the ongoing efforts to generate national-wide data of SP resistance. METHODS: A cross-sectional survey was conducted in the outpatient departments of 14 HCs in seven regions from April to June, 2015. 1750 dried blood spot (DBS) samples were collected (117 to 160 per facility) from consenting patients with positive rapid diagnostic tests for malaria, and no recent (within past 2 months) exposure to SP or related drugs. DNA was extracted from the DBS, pooled by HC, and underwent pooled targeted amplicon deep sequencing to yield estimates of mutated parasite allele frequency at each locus of interest. RESULTS: The dhps540 mutation was common across all 14 sites, ranging from 55 to 98.4% of sequences obtained. Frequency of the dhps581 mutation ranged from 0 to 2.4%, except at Kayanga HC (Kagera Region, Lake Zone) where 24.9% of sequences obtained were mutated. The dhfr164 mutation was detected only at Kanyanga HC (0.06%). CONCLUSION: By pooling DNA extracts, the allele frequency of mutations in 14 sites could be directly determined on a single deep sequencing run. The dhps540 mutant was very common at all locations. Surprisingly, the dhps581 was common at one health center, but rare in all the others, suggesting that there is geographic micro-heterogeneity in mutant distribution and that accurate surveillance requires inclusion of multiple sites. A better understanding of the effect of the dhps581 mutant on the efficacy of IPTp-SP is needed. PMID- 28583120 TI - "Until people start dying in droves, no actions will be taken": perception and experience of HIV-preventive measures among people who inject drugs in northwestern Russia. AB - BACKGROUND: The HIV epidemic among people who inject drugs (PWID) in Russia continues to spread. This exploratory study examines how HIV-prevention measures are perceived and experienced by PWID in the northwestern region of Russia. METHODS: Purposive sampling was used to obtain a variety of cases that could reflect possible differences in perception and experience of HIV-prevention efforts. We conducted 22 semi-structured interviews with PWID residing in the Arkhangelsk and St. Petersburg regions. RESULTS: The main sources of prevention information on HIV for PWID were media campaigns directed to the general population. These campaigns were effective with regard to communicating general knowledge on HIV but were ineffective in terms of risk behavior change. The subjects generally had trust in medical professionals and their advice but did not follow prevention recommendations. Most informants had no or very little prior contact with harm reduction services. On the level of attitudes towards HIV prevention efforts, we discovered three types of fatalism among PWID: "personal fatalism" - uselessness of HIV prevention efforts, if one uses drugs; "prevention related fatalism" - prevention programs are low effective, because people do not pay attention to them before they get infected; "state-related fatalism" - the lack of belief that the state is concerned with HIV prevention issues. Despite this fatalism the participants opined that NGOs would do a better job than the state as they are "really working" with risk groups. CONCLUSIONS: As HIV prevention campaigns targeted at the general population and prevention advice received from medical professionals are not sufficiently effective for PWID in terms of risk behavior change, prevention programs, such as community-based and peer-based interventions specifically tailored to the needs of PWID are needed, which can be achieved by a large expansion of harm reduction services in the region. Personal communication should be a crucial element in such interventions in addition to harm reduction materials provision. Training programs, peer outreach, and culture-change interventions which try to alter widespread fatalistic norms or attitudes towards their health are especially needed, since this study indicates that fatalism is a major barrier for behavior change. PMID- 28583121 TI - Harm reduction in hospitals. PMID- 28583122 TI - Decision-making experiences of family members of older adults with moderate dementia towards community and residential care home services: a grounded theory study protocol. AB - BACKGROUND: Caring and supporting older people with dementia have become a major public health priority. Recent reports have also revealed a diminishing number of family carers to provide dementia care in the future. Carers who are engaged in the caring role are known to bear significant psychological, practical and economic challenges as the disease advances over time. Seemingly, evidence indicates that the burden of care can be relieved by formal services. This study aims to explore decision-making experiences of family members of older adults with moderate dementia towards the use of community support (CS) and residential care home (RCH) services. METHOD: A large multi-site constructivist grounded theory in a range of non-government organizations and a private aged home will frame this Hong Kong study. Purposive sampling will begin the recruitment of family members, followed by theoretical sampling. It is estimated that more than 100 family members using CS and RCH services will participate in an interview. The process of successive constant comparative analysis will be undertaken. DISCUSSION: The final product, a theory, will generate an integrated and comprehensive conceptual understanding which will explain the processes associated with decision-making of family members for dementia sufferers. Deeper understanding of issues including, but not exclusive to, service needs, expectations and hopes among family carers for improving service support to serve dementia sufferers in CS and RCH services will also be revealed. Importantly, this study seeks to illustrate the practical and strategic aspects of the theory and how it may be useful to transfer its applicability to various service settings to better support those who deliver formal and informal care to the dementia population. PMID- 28583123 TI - Arsenic affects inflammatory cytokine expression in Gallus gallus brain tissues. AB - BACKGROUND: The heavy metal arsenic is widely distributed in nature and posses a serious threat to organism's health. However, little is known about the arsenic induced inflammatory response in the brain tissues of birds and the relationship and mechanism of the inflammatory response. The purpose of this study was to explore the effects of dietary arsenic on the expression of inflammatory cytokines in the brains of Gallus gallus. RESULTS: Seventy-two 1-day-old male Hy line chickens were divided into a control group, a low arsenic trioxide (As2O3) treated (7.5 mg/kg) group, a middle As2O3-treated (15 mg/kg) group, and a high As2O3-treated (30 mg/kg) group. Arsenic exposure caused obvious ultrastructural changes. The mRNA levels of the transcription factor nuclear factor-kappaB (NF kappaB) and of pro-inflammatory cytokines, including inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and prostaglandin E synthase (PTGEs), in chicken brain tissues (cerebrum, cerebellum, thalamus, brainstem and myelencephalon) on days 30, 60 and 90, respectively, were measured by real-time PCR. The protein expression of iNOS was detected by western blot. The results showed that after being treated with As2O3, the levels of inflammatory-related factor NF-kappaB and pro-inflammatory cytokines in chicken brain tissues increased (P < 0.05). CONCLUSIONS: Arsenic exposure in the chickens triggered host defence and induced an inflammatory response by regulating the expression of inflammatory-related genes in the cerebrum, cerebellum, thalamus, brainstem and myelencephalon. These data form a foundation for further research on arsenic induced neurotoxicity in Gallus gallus. PMID- 28583124 TI - Newborn sex-specific transcriptome signatures and gestational exposure to fine particles: findings from the ENVIRONAGE birth cohort. AB - BACKGROUND: Air pollution exposure during pregnancy has been associated with adverse birth outcomes and health problems later in life. We investigated sex specific transcriptomic responses to gestational long- and short-term exposure to particulate matter with a diameter < 2.5 MUm (PM2.5) in order to elucidate potential underlying mechanisms of action. METHODS: Whole genome gene expression was investigated in cord blood of 142 mother-newborn pairs that were enrolled in the ENVIRONAGE birth cohort. Daily PM2.5 exposure levels were calculated for each mother's home address using a spatial-temporal interpolation model in combination with a dispersion model to estimate both long- (annual average before delivery) and short- (last month of pregnancy) term exposure. We explored the association between gene expression levels and PM2.5 exposure, and identified modulated pathways by overrepresentation analysis and gene set enrichment analysis. RESULTS: Some processes were altered in both sexes for long- (e.g. DNA damage) or short-term exposure (e.g. olfactory signaling). For long-term exposure in boys neurodevelopment and RhoA pathways were modulated, while in girls defensin expression was down-regulated. For short-term exposure we identified pathways related to synaptic transmission and mitochondrial function (boys) and immune response (girls). CONCLUSIONS: This is the first whole genome gene expression study in cord blood to identify sex-specific pathways altered by PM2.5. The identified transcriptome pathways could provide new molecular insights as to the interaction pattern of early life PM2.5 exposure with the biological development of the fetus. PMID- 28583125 TI - Considerations and guidance in designing equity-relevant clinical trials. AB - Health research has documented disparities in health and health outcomes within and between populations. When these disparities are unfair and avoidable they may be referred to as health inequities. Few trials attend to factors related to health inequities, and there is limited understanding about how to build consideration of health inequities into trials. Due consideration of health inequities is important to inform the design, conduct and reporting of trials so that research can build evidence to more effectively address health inequities and importantly, ensure that inequities are not aggravated. In this paper, we discuss approaches to integrating health equity-considerations in randomized trials by using the PROGRESS Plus framework (Place of residence, Race/ethnicity/culture/language, Occupation, Gender, Religion, Education, Socio economic status, Social capital and "Plus" that includes other context specific factors) and cover: (i) formulation of research questions, (ii) two specific scenarios relevant to trials about health equity and (iii) describe how the PROGRESS Plus characteristics may influence trial design, conduct and analyses. This guidance is intended to support trialists designing equity-relevant trials and lead to better design, conduct, analyses and reporting, by addressing two main issues: how to avoid aggravating inequity among research participants and how to produce information that is useful to decision-makers who are concerned with health inequities. PMID- 28583126 TI - Blood pressure in young adulthood and residential greenness in the early-life environment of twins. AB - BACKGROUND: Previous research shows that, besides risk factors in adult life, the early-life environment can influence blood pressure and hypertension in adults. However, the effects of residential traffic exposure and residential greenness in the early-life on blood pressure in young adulthood are currently unknown. METHODS: Ambulatory (24-h) blood pressures of 278 twins (132 pairs) of the East Flanders Prospective Twins Study were obtained at the age of 18 to 25 years. Prenatal and adulthood residential addresses were geocoded and used to assign prenatal and postnatal traffic and greenness indicators. Mixed modelling was performed to investigate blood pressure in association with greenness while adjusting for potential confounding factors. RESULTS: Night-time systolic blood pressure was inversely associated with greenness at the residential address in twins living at the same address their entire life (non-movers, n = 97, 34.9%). An interquartile increase in residential greenness exposure (1000 m radius) was associated with a 3.59 mmHg (95% CI: -6.0 to -1.23; p = 0.005) lower adult night systolic blood pressure. Among twins who were living at a different address than their birth address at time of the measurement (n = 181, 65.1%), night-time blood pressure was inversely associated with residential surrounding greenness at adult age as well as with residential greenness in early-life. However after additional adjustment for residential greenness exposure in adulthood, only residential greenness exposure in early-life was significantly associated with night systolic blood pressure. While no significant effect of adult residential greenness with adult blood pressure was observed, while accounting for the early-life greenness exposure. CONCLUSIONS: Lower residential greenness in the early-life environment was independently associated with a higher adult blood pressure. This indicates that residential greenness has persistent effects on blood pressure. PMID- 28583127 TI - CMOST: an open-source framework for the microsimulation of colorectal cancer screening strategies. AB - BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related mortality. CRC incidence and mortality can be reduced by several screening strategies, including colonoscopy, but randomized CRC prevention trials face significant obstacles such as the need for large study populations with long follow-up. Therefore, CRC screening strategies will likely be designed and optimized based on computer simulations. Several computational microsimulation tools have been reported for estimating efficiency and cost-effectiveness of CRC prevention. However, none of these tools is publicly available. There is a need for an open source framework to answer practical questions including testing of new screening interventions and adapting findings to local conditions. METHODS: We developed and implemented a new microsimulation model, Colon Modeling Open Source Tool (CMOST), for modeling the natural history of CRC, simulating the effects of CRC screening interventions, and calculating the resulting costs. CMOST facilitates automated parameter calibration against epidemiological adenoma prevalence and CRC incidence data. RESULTS: Predictions of CMOST were highly similar compared to a large endoscopic CRC prevention study as well as predictions of existing microsimulation models. We applied CMOST to calculate the optimal timing of a screening colonoscopy. CRC incidence and mortality are reduced most efficiently by a colonoscopy between the ages of 56 and 59; while discounted life years gained (LYG) is maximal at 49-50 years. With a dwell time of 13 years, the most cost-effective screening is at 59 years, at $17,211 discounted USD per LYG. While cost-efficiency varied according to dwell time it did not influence the optimal time point of screening interventions within the tested range. CONCLUSIONS: Predictions of CMOST are highly similar compared to a randomized CRC prevention trial as well as those of other microsimulation tools. This open source tool will enable health-economics analyses in for various countries, health-care scenarios and CRC prevention strategies. CMOST is freely available under the GNU General Public License at https://gitlab.com/misselwb/CMOST. PMID- 28583128 TI - Terpene constituents of the aerial parts, phenolic content, antibacterial potential, free radical scavenging and antioxidant activity of Callistemon citrinus (Curtis) Skeels (Myrtaceae) from Eastern Cape Province of South Africa. AB - BACKGROUND: Volatile oil from aromatic plants has been used by ancient Egyptians in embalming for the inhibition of bacterial growth and prevention of decay, Callistemon citrinus is used in traditional therapies for the treatment of bronchitis, cough, inflammation and as an antimicrobial herbs. This study examines the essential constituents of the volatile oils obtained from the aerial parts of the plant as well as its antioxidant activity, free radical scavenging, phenolic content and the antibacterial potential of the oils. METHODS: A portion of 500 g, 250 g and 150 g of the leaves, flowers and stems of this plant respectively were subjected to hydro-distillation process for three hours. The oils collected from the various plant parts were immediately subjected to GC-MS analysis. The overall phenolic content of the leaves oil, radical scavenging, antibacterial action and antioxidant activities of the essential oils of both the leaves and flowers of Callistemon citrinus were determined using standard methods, with free radical DPPH and ABTS as a reference antioxidant. RESULTS: Analyses of the three oils revealed a total of twenty-six components for the leaves oil representing 96.84% of the total oil composition, forty-one components for the flowers oil accounting for 98.92% of the whole composition and ten components for the stem oil amounting to 99.98% of the entire oil constituents. The dominant compounds in the leaves oil were eucalyptol (48.98%) and alpha terpineol (8.01%), while alpha-eudesmol (12.93%), caryophyllene (11.89%), (-) bornyl-acetate (10.02%) and eucalyptol (8.11%) were the main constituents of the flowers oil. In the same vein, the leading constituents in the stems oil were eucalyptol (56.00%) and alpha-pinene (31.03%). The antioxidant capacities of both the leaves and flowers oils of the plant were evaluated and their IC50 were (1.49 and 1.13) for DPPH and (0.14 and 0.03) for ABTS assay respectively. The antibacterial activities of the oils from the (leaves and flowers) were also examined and were found to have wide range of activities against the bacterial strains used in this study. CONCLUSION: Observations drawn from this experiment shows clearly that the leaves and flowers of Callistemon citrinus possess phenolic compounds and cyclic ether of several pharmacological behaviors. PMID- 28583129 TI - Co-expressed Pathways DataBase for Tomato: a database to predict pathways relevant to a query gene. AB - BACKGROUND: Gene co-expression, the similarity of gene expression profiles under various experimental conditions, has been used as an indicator of functional relationships between genes, and many co-expression databases have been developed for predicting gene functions. These databases usually provide users with a co expression network and a list of strongly co-expressed genes for a query gene. Several of these databases also provide functional information on a set of strongly co-expressed genes (i.e., provide biological processes and pathways that are enriched in these strongly co-expressed genes), which is generally analyzed via over-representation analysis (ORA). A limitation of this approach may be that users can predict gene functions only based on the strongly co-expressed genes. RESULTS: In this study, we developed a new co-expression database that enables users to predict the function of tomato genes from the results of functional enrichment analyses of co-expressed genes while considering the genes that are not strongly co-expressed. To achieve this, we used the ORA approach with several thresholds to select co-expressed genes, and performed gene set enrichment analysis (GSEA) applied to a ranked list of genes ordered by the co-expression degree. We found that internal correlation in pathways affected the significance levels of the enrichment analyses. Therefore, we introduced a new measure for evaluating the relationship between the gene and pathway, termed the percentile (p)-score, which enables users to predict functionally relevant pathways without being affected by the internal correlation in pathways. In addition, we evaluated our approaches using receiver operating characteristic curves, which concluded that the p-score could improve the performance of the ORA. CONCLUSIONS: We developed a new database, named Co-expressed Pathways DataBase for Tomato, which is available at http://cox-path-db.kazusa.or.jp/tomato . The database allows users to predict pathways that are relevant to a query gene, which would help to infer gene functions. PMID- 28583130 TI - High prevalence of Enterocytozoon bieneusi zoonotic genotype D in captive golden snub-nosed monkey (Rhinopithecus roxellanae) in zoos in China. AB - BACKGROUND: Enterocytozoon bieneusi is the dominant specie of microsporidia which can infect both anthroponotic and zoonotic species. The golden snub-nosed monkey is an endangered primate which can also infect by E. bieneusi. To date, few genetic data on E. bieneusi from golden snub-nosed monkeys has been published. Therefore, to clarify the prevalence and genotypes of E. bieneusi in captive golden snub-nosed monkeys is necessary to assess the potential for zoonotic transmission. RESULT: We examined 160 golden snub-nosed monkeys from six zoos in four cities in China, using PCR and comparative sequence analysis of the ribosomal internal transcribed spacer (ITS). The overall prevalence of E. bieneusi was 46.2% (74/160); while the prevalence was 26.7%, 69.1%, 69.4% and 33.3% in Shanghai Zoo, Shanghai Wild Animal Park, Tongling Zoo, and Taiyuan Zoo respectively (P = 0.006). A total of seven E. bieneusi genotypes were found that included four known (D, J, CHG1, and CHG14) and three new (CM19-CM 21) genotypes. The most common genotype was D (54/74, 73.0%), followed by J (14/74, 18.9%); other genotypes were restricted to one or two samples. Phylogenetic analysis revealed that genotype D belonged to the previously-characterized Group 1, with zoonotic potential; whereas genotypes J, CHG1, CHG14 and CM19-CM 21 clustered in the previously-characterized Group 2, the so-called cattle host specificity group. CONCLUSIONS: The findings of high prevalence of zoonotic E. bieneusi genotypes D and J in golden snub-nosed monkeys suggest that golden snub-nosed monkeys may be the reservoir hosts for human microsporidiosis, and vice versa. PMID- 28583133 TI - Comparative physical genome mapping of malaria vectors Anopheles sinensis and Anopheles gambiae. AB - BACKGROUND: Anopheles sinensis is a dominant natural vector of Plasmodium vivax in China, Taiwan, Japan, and Korea. Recent genome sequencing of An. sinensis provides important insights into the genomic basis of vectorial capacity. However, the lack of a physical genome map with chromosome assignment and orientation of sequencing scaffolds hinders comparative analyses with other genomes to infer evolutionary changes relevant to the vector capacity. RESULTS: Here, a physical genome map for An. sinensis was constructed by assigning 52 scaffolds onto the chromosomes using fluorescence in situ hybridization (FISH). This chromosome-based genome assembly composes approximately 36% of the total An. sinensis genome. Comparisons of 3955 orthologous genes between An. sinensis and Anopheles gambiae identified 361 conserved synteny blocks and 267 inversions fixed between these two lineages. The rate of gene order reshuffling on the X chromosome is approximately 3.2 times higher than that on the autosomes. CONCLUSIONS: The physical map will facilitate detailed genomic analysis of An. sinensis and contribute to understanding of the patterns and mechanisms of large scale genome rearrangements in anopheline mosquitoes. PMID- 28583131 TI - Association between store food environment and customer purchases in small grocery stores, gas-marts, pharmacies and dollar stores. AB - BACKGROUND: Purchases at small/non-traditional food stores tend to have poor nutritional quality, and have been associated with poor health outcomes, including increased obesity risk The purpose of this study was to examine whether customers who shop at small/non-traditional food stores with more health promoting features make healthier purchases. METHODS: In a cross-sectional design, data collectors assessed store features in a sample of 99 small and non traditional food stores not participating in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in Minneapolis/St. Paul, MN in 2014. Customer intercept interviews (n = 594) collected purchase data from a bag check and demographics from a survey. Store measures included fruit/vegetable and whole grain availability, an overall Healthy Food Supply Score (HFSS), healthy food advertisements and in-store placement, and shelf space of key items. Customer nutritional measures were analyzed using Nutrient Databases System for Research (NDSR), and included the purchase of >=1 serving of fruits/vegetables; >=1 serving of whole grains; and overall Healthy Eating Index-2010 (HEI-2010) score for foods/beverages purchased. Associations between store and customer measures were estimated in multilevel linear and logistic regression models, controlling for customer characteristics and store type. RESULTS: Few customers purchased fruits and vegetables (8%) or whole grains (8%). In fully adjusted models, purchase HEI-2010 scores were associated with fruit/vegetable shelf space (p = 0.002) and the ratio of shelf space devoted to healthy vs. less healthy items (p = 0.0002). Offering >=14 varieties of fruit/vegetables was associated with produce purchases (OR 3.9, 95% CI 1.2-12.3), as was having produce visible from the store entrance (OR 2.3 95% CI 1.0 to 5.8), but whole grain availability measures were not associated with whole grain purchases. CONCLUSIONS: Strategies addressing both customer demand and the availability of healthy food may be necessary to improve customer purchases. TRIAL REGISTRATION: ClinialTrials.gov: NCT02774330 . Registered May 4, 2016 (retrospectively registered). PMID- 28583134 TI - Sphingosine kinase 1 expression enhances colon tumor growth. AB - BACKGROUND: Accumulating evidence suggests that sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate pathway plays a pivotal role in colon carcinogenesis. METHODS: To further support the evidence, we investigated the effects of SphK1 using three separate animal models: SphK1 knockout mice, SphK1 overexpressing transgenic mice, and SphK1 overexpression in human colon cancer xenografts. Using azoxymethane (AOM, colon carcinogen), we analyzed colon tumor development in SphK1 KO and SphK1 overexpression in intestinal epithelial cells regulated by a tet-on system. Then, we analyzed subcutaneous tumor growth using xenografts of HT-29 human colon cancer cell. Finally, immunohistochemical analyses for SphK1 and COX-2 were performed on human colon cancer tissue microarray. RESULTS: SphK1 KO mice, compared to wild-type mice, demonstrated a significant inhibition in colon cancer development induced by AOM (58.6% vs. 96.4%, respectively, P < 0.005). Tumor multiplicity (1.00 vs. 1.64 per colon, respectively, P < 0.05) and tumor volume (14.82 mm3 vs. 29.10 mm3, P < 0.05) were both significantly reduced in SphK1 KO mice compared to wild-type mice. Next, SphK1 overexpression in HT-29 enhanced tumor growth as compared to GFP control in nude mice (229.5 mm3 vs. 90.9 mm3, respectively, P < 0.05). Furthermore, overexpression of SphK1 in intestinal epithelial cells significantly enhances AOM induced colon tumor formation (P < 0.05). Lastly, SphK1 and COX-2 intensity tended to reduce overall survival of late stage colon cancer patients. CONCLUSIONS: SphK1 expression regulates the early stage of colon carcinogenesis and tumor growth, thus inhibition of SphK1 may be an effective strategy for colon cancer chemoprevention. PMID- 28583132 TI - A bacosides containing Bacopa monnieri extract alleviates allodynia and hyperalgesia in the chronic constriction injury model of neuropathic pain in rats. AB - BACKGROUND: The current therapy of neuropathic pain is inadequate and is limited by the extent of pain relief and the occurrence of dose dependant side effects. Insufficient control of pain with conventional medications prompts the use of complementary and alternative medicine therapies by patients with neuropathic pain. This study therefore investigated a standardized methanolic extract of Bacopa monnieri, a widely reputed nootropic plant, for prospective antinociceptive effect in the chronic constriction injury (CCI) model of neuropathic pain. METHODS: Placement of four loose ligatures around the sciatic nerve produced partial denervation of the hindpaw in rats. Bacopa monnieri (40 and 80 mg/kg, p.o) and the positive control, gabapentin (75 mg/kg, i.p), were administered daily after CCI or sham surgery and the behavioral paradigms of static- and dynamic-allodynia (paw withdrawal threshold to von Frey filament stimulation [PWT] and paw withdrawal latency to light-brushing [PWL]), cold allodynia (paw withdrawal duration [PWD] to acetone), heat- (PWL to heat stimulus) and punctate-hyperalgesia (PWD to pin-prick) were assessed on days 3, 7, 14 and 21. RESULTS: CCI consistently generated static- (days 3-21), dynamic- (days 14-21) and cold-allodynia (days 3-21) plus heat- and mechano-hyperalgesia (days 3-21). The tested doses of Bacopa monnieri significantly attenuated the CCI induced allodynia and hyperalgesia, exemplified by increased PWT (days 7-21), PWL to light brushing (days 14-21) and heat (days 7-21) as well as decreased PWD to pin prick and cold stimuli (days 3-21). The extract also counterbalanced the CCI induced aberrations in the nociceptive behaviors by increasing the pain threshold to that of pre-surgery baseline. Gabapentin also afforded analogous beneficial behavioral profile but of higher magnitude. CONCLUSIONS: Our findings suggest that Bacopa monnieri can be used as adjuvant therapy for neuropathic pain conditions afflicted with allodynia and hyperalgesia. PMID- 28583135 TI - Outcomes and prognostic factors of non-HIV patients with pneumocystis jirovecii pneumonia and pulmonary CMV co-infection: A Retrospective Cohort Study. AB - BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) and pulmonary cytomegalovirus (CMV) infection are common opportunistic infections among immunocompromised patients. However, few studies have evaluated their co-infection, especially among non-HIV patients. Therefore, we aimed to evaluate the outcomes and prognostic factors among non-HIV patients with PJP according to their CMV infection status. METHODS: This retrospective study evaluated non-HIV patients who were diagnosed with PJP between January 2009 and January2016.The patients were classified and compared according to their pulmonary CMV infection status (positive infection: bronchoalveolar lavage fluid [BALF] CMV DNA loads of >500copies/mL). RESULTS: Among 70 non-HIV patients with PJP, we identified 38 patients (54.3%) with pulmonary CMV infection. There was no significant difference in the mortality rates for the two groups (p = 0.15). Pulmonary CMV infection was significantly more common among patients who were receiving glucocorticoids and immunosuppressants, compared to corticosteroids only (p = 0.02). Pulmonary CMV infection was also significantly associated with severe dyspnea, a lower PaO2/FiO2, and the presence of centrilobular nodules (p = 0.008). Higher CMV DNA loads in the BALF were positively associated with mortality (p = 0.012). CONCLUSIONS: Combined therapy using corticosteroids and other immunosuppressants may be a risk factor for pulmonary CMV co-infection among patients with PJP. In addition, CMV pneumonia should be considered when centrilobular nodules and/or severe hypoxemia are observed in non-HIV patients with PJP. Furthermore, antiviral treatment should be promptly initiated for patients with a high CMV DNA load in BALF, based on their poor prognosis. PMID- 28583137 TI - Protective effects of synbiotic diets of Bacillus coagulans, Lactobacillus plantarum and inulin against acute cadmium toxicity in rats. AB - BACKGROUND: Cadmium is a heavy metal that causes oxidative stress and has toxic effects in humans. The aim of this study was to investigate the influence of two probiotics along with a prebiotic in preventing the toxic effects of cadmium in rats. METHODS: Twenty-four male Wistar rats were randomly divided into four groups namely control, cadmium only, cadmium along with Lactobacillus plantarum (1 * 109 CFU/day) and inulin (5% of feedstuff) and cadmium along with Bacillus coagulans (1 * 109 spore/day) and inulin (5% of feedstuff). Cadmium treated groups received 200 MUg/rat/day CdCl2 administered by gavage. During the 42-day experimental period, they were weighed weekly. For evaluation of changes in oxidative stress, the levels of some biochemicals and enzymes of serum including SOD, GPX, MDA, AST, ALT, total bilirubin, BUN and creatinine, and also SOD level of livers were measured at day 21 and 42 of treatment. The cadmium content of kidney and liver was determined by using atomic absorption mass spectrophotometry. Data were analyzed using analysis of variance (ANOVA) followed by Duncan's post hoc test. RESULTS: Treatment of cadmium induced rats with synbiotic diets significantly improved the liver enzymes and biochemical parameters that decreased AST, ALT, total bilirubin, BUN and metal accumulation in the liver and kidney and increased body weight, serum and liver SOD values in comparison with the cadmium-treated group. No significant differences were observed with MDA and GPX values between all groups (p > 0.05). CONCLUSIONS: This study showed that synbiotic diets containing probiotics (L. plantarum and B. coagulans) in combination with the prebiotic (inulin) can reduce the level of cadmium in the liver and kidney, preventing their damage and recover antioxidant enzymes in acute cadmium poisoning in rat. PMID- 28583136 TI - Social-structural factors influencing periods of injection cessation among marginalized youth who inject drugs in Vancouver, Canada: an ethno epidemiological study. AB - BACKGROUND: Injection drug use is associated with HIV and hepatitis C transmission, overdose, and other preventable harms. These harms are heightened for structurally vulnerable injection drug-using populations, as their social conditions pose barriers to safer injecting. Previous research on injection cessation has largely focused on adult drug-using populations. Little qualitative work has examined the social, structural, and environmental factors that shape periods of injection cessation among youth and young adults. Such research is essential to understanding how we can best reduce harms among this vulnerable population as they move in and out of periods of injection cessation. METHODS: We conducted 22 semi-structured, qualitative interviews with street-involved young people who use drugs (SY), focused on characterizing their transitions into periods of injection cessation and perceived barriers to injection cessation. Adopting an ethno-epidemiological approach, participants who had experienced at least 6 months of injection cessation were purposively recruited from an ongoing prospective cohort study of SY in Vancouver, Canada to participate in qualitative interviews. Qualitative interview findings were triangulated with the findings of a longitudinal program of ethnographic research with SY in this setting. This ethno-epidemiological approach allowed for a more robust exploration of contextual factors surrounding drug use patterns than would be possible through traditional epidemiological methods alone. RESULTS: Findings indicate that periods of injection cessation were influenced by access to harm reduction informed youth-focused services, transitions in route of administration (e.g., from injecting methamphetamine to the smoking of methamphetamine), and the provision of housing and social supports (e.g., from friends, family, and care providers). Conversely, participants indicated that inadequate social supports and, for some, abstinence-focused treatment methods (e.g., 12-step programs), impeded efforts to cease injecting. CONCLUSIONS: To reduce harms, it is imperative to reorient attention toward the social, structural, and spatial contexts that surround injection drug use and shape periods of injection cessation for SY. There is an urgent need for more comprehensive youth-focused services for those engaged in injection drug use, and further study of innovative means of engaging youth. PMID- 28583139 TI - Cell cycle arrest and apoptosis induction by methanolic leaves extracts of four Annonaceae plants. AB - BACKGROUND: Uvaria longipes (Craib) L.L.Zhou, Y.C.F.Su & R.M.K.Saunders, Artabotrys burmanicus A.DC, Marsypopetalum modestum (Pierre) B.Xue & R.M.K.Saunders and Dasymaschalon sp. have been used for traditional medicine to treat cancer-like symptoms in some ethnic groups of Thailand and Laos. METHODS: We evaluated the anti-cancer activity of these Annonaceae plants against several human cancer cell lines. The apoptosis induction was detected by Annexin/propidium iodide (PI) staining. Phytochemical screening was tested by standard protocols and bioactive compounds were determined by HPLC. RESULTS: The crude extracts from leaves of U. longipes, Dasymaschalon sp., A. burmanicus, and M. modestum showed particular effects that were found to vary depending on the cancer cell line, suggesting that the effect was in a cell-type specific manner. Interestingly, the induction of apoptotic cell death was prominent by the leaves derived crude extract of M. modestum. This crude was, therefore, subjected to cell cycle analysis by PI staining. Results showed that this crude extract arrested cell cycle and increased the percentage of cells in the SubG1 phase in some cancer cell lines. The phytochemical screening tests indicated that all crude extracts contained tannins and flavonoids. HPLC of flavonoids using standards identified rutin as an active compound in U. longipes and Dasymaschalon sp., whereas quercetin was found in U. longipes and M. modestum. CONCLUSIONS: These crude extracts provide a new source for rutin and quercetin, which might be capable of inducing cancer cell apoptotic death in a cell-type specific manner. This suggests, by analyzing the major bioactive compounds, the potential use of these crudes for chemotherapy in the future. PMID- 28583140 TI - Live birth after fresh versus frozen single blastocyst transfer (Frefro blastocyst): study protocol for a randomized controlled trial. AB - BACKGROUND: Multiple pregnancies are one of the major safety concerns of in vitro fertilization (IVF) due to the increased risk of maternal and neonatal complications. Single embryo transfer is the most effective way to reduce the risk of multiple pregnancies. Selection of the embryo and optimization of the implantation environment are crucial to retain the success rate when the number of transferred embryos is diminished. Fresh embryo transfer with supra physiological levels of hormones has been suggested to have an adverse effect on implantation. Elective frozen embryo transfer has been suggested to result in a higher rate of live birth than fresh embryo transfer. However, there is still a lack of evidence from randomized clinical trials comparing the efficacy and safety between frozen and fresh single blastocyst transfers. METHODS/DESIGN: We are conducting a randomized controlled trial in women aged 20-35 undergoing their first cycle of IVF with or without intracytoplasmic sperm injection. After ovarian stimulation with a gonadotropin-releasing hormone antagonist protocol, women who obtain four or more embryos on day 3 of the embryo culture are randomized into two parallel groups: a single fresh blastocyst transfer group and a single frozen blastocyst transfer group (all blastocysts vitrified and a deferred frozen blastocyst transfer). The primary outcome is singleton live birth. DISCUSSION: The results of this study will provide evidence for the efficacy and safety of the strategy of elective frozen single blastocyst transfer in women with a good prognosis. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IOR-14005405 . Registered on 30 Oct 2014. PMID- 28583138 TI - Molecular characterization of breast cancer cell lines through multiple omic approaches. AB - BACKGROUND: Breast cancer cell lines are frequently used as model systems to study the cellular properties and biology of breast cancer. Our objective was to characterize a large, commonly employed panel of breast cancer cell lines obtained from the American Type Culture Collection (ATCC 30-4500 K) to enable researchers to make more informed decisions in selecting cell lines for specific studies. Information about these cell lines was obtained from a wide variety of sources. In addition, new information about cellular pathways that are activated within each cell line was generated. METHODS: We determined key protein expression data using immunoblot analyses. In addition, two analyses on serum starved cells were carried out to identify cellular proteins and pathways that are activated in these cells. These analyses were performed using a commercial PathScan array and a novel and more extensive phosphopeptide-based kinome analysis that queries 1290 phosphorylation events in major signaling pathways. Data about this panel of breast cancer cell lines was also accessed from several online sources, compiled and summarized for the following areas: molecular classification, mRNA expression, mutational status of key proteins and other possible cancer-associated mutations, and the tumorigenic and metastatic capacity in mouse xenograft models of breast cancer. RESULTS: The cell lines that were characterized included 10 estrogen receptor (ER)-positive, 12 human epidermal growth factor receptor 2 (HER2)-amplified and 18 triple negative breast cancer cell lines, in addition to 4 non-tumorigenic breast cell lines. Within each subtype, there was significant genetic heterogeneity that could impact both the selection of model cell lines and the interpretation of the results obtained. To capture the net activation of key signaling pathways as a result of these mutational combinations, profiled pathway activation status was examined. This provided further clarity for which cell lines were particularly deregulated in common or unique ways. CONCLUSIONS: These two new kinase or "Kin-OMIC" analyses add another dimension of important data about these frequently used breast cancer cell lines. This will assist researchers in selecting the most appropriate cell lines to use for breast cancer studies and provide context for the interpretation of the emerging results. PMID- 28583141 TI - Characterization and effectiveness of pay-for-performance in ophthalmology: a systematic review. AB - BACKGROUND: To identify, characterize and compare existing pay-for-performance approaches and their impact on the quality of care and efficiency in ophthalmology. METHODS: A systematic evidence-based review was conducted. English, French and German written literature published between 2000 and 2015 were searched in the following databases: Medline (via PubMed), NCBI web site, Scopus, Web of Knowledge, Econlit and the Cochrane Library. Empirical as well as descriptive articles were included. Controlled clinical trials, meta-analyses, randomized controlled studies as well as observational studies were included as empirical articles. Systematic characterization of identified pay-for-performance approaches (P4P approaches) was conducted according to the "Model for Implementing and Monitoring Incentives for Quality" (MIMIQ). Methodological quality of empirical articles was assessed according to the Critical Appraisal Skills Programme (CASP) checklists. RESULTS: Overall, 13 relevant articles were included. Eleven articles were descriptive and two articles included empirical analyses. Based on these articles, four different pay-for-performance approaches implemented in the United States were identified. With regard to quality and incentive elements, systematic comparison showed numerous differences between P4P approaches. Empirical studies showed isolated cost or quality effects, while a simultaneous examination of these effects was missing. CONCLUSION: Research results show that experiences with pay-for-performance approaches in ophthalmology are limited. Identified approaches differ with regard to quality and incentive elements restricting comparability. Two empirical studies are insufficient to draw strong conclusions about the effectiveness and efficiency of these approaches. PMID- 28583142 TI - Radical antegrade modular pancreatosplenectomy versus standard procedure in the treatment of left-sided pancreatic cancer: A systemic review and meta-analysis. AB - BACKGROUND: Radical antegrade modular pancreatosplenectomy (RAMPS), first reported by Strasberg in 2003, has attracted increasing attention in the treatment of left-sided pancreatic cancer. The limited number of cases eligible for RAMPS makes it difficult to perform any prospective randomized trial of RAMPS versus the standard procedure. Therefore, we performed this systemic review and meta-analysis of the current data to clarify the role of the RAMPS procedure. METHODS: A literature search was performed in electronic databases, including PubMed, Medline, Embase, CNKI and the Cochrane Library. Studies comparing RAMPS with the standard procedure were included in this meta-analysis. R0 resection rate, recurrence rate at the end of the follow-up, overall survival (OS) and disease-free survival (DFS) were measured as primary outcomes. Revman 5.3 was used to perform the analysis. RESULTS: Six retrospective cohort studies with a total number of 378 patients were included in our analysis. Meta-analysis revealed that RAMPS was correlated with higher R0 resection rates [Odds Ratio (OR) 95% confidence interval (CI), 2.19 (1.16 ~ 4.13); P = 0.02] and successful harvest of more lymph nodes [weighted mean difference (WMD) 95% CI, 7.06 (4.52 ~ 9.60); P < 0.01] compared with the standard procedure. However, no statistically significant difference was found between the procedures with respect to recurrence rates [OR 95% CI, 0.66 (0.40 ~ 1.09); P = 0.10], OS [Hazard ratio (HR) 95% CI, 0.65 (0.42 ~ 1.00); P = 0.05] or DFS [HR 95% CI, 1.02 (0.62 ~ 1.68); P = 0.93]. CONCLUSIONS: RAMPS is safe and oncologically superior to the standard procedure for the treatment of left-sided pancreatic cancer. However, high-grade evidence will be necessary to confirm the potential survival benefits of RAMPS. PMID- 28583144 TI - Extramedullary versus intramedullary femoral alignment technique in total knee arthroplasty: a meta-analysis of randomized controlled trials. AB - BACKGROUND: There is no consensus whether the use of the extramedullary femoral cutting guide takes advantage over the intramedullary one in total knee arthroplasty. The aim of this study was to compare the extramedullary femoral alignment guide system with the conventional intramedullary alignment guide system for lower limb alignment, blood loss, and operative time during total knee arthroplasty. METHODS: The Medline, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang Chinese Periodical, Google, and reference lists of all the included studies were searched for randomized controlled trials. The following parameters were compared between the extramedullary technique and the intramedullary technique: (1) lower limb coronal alignment, (2) coronal alignment of femoral component, (3) sagittal alignment of femoral component, (4) blood loss, (5) and operation time. RESULTS: Four randomized controlled trials consisting of 358 knees were included in our study. There was no significant difference between the extramedullary and intramedullary groups for the lower limb coronal alignment (RR = 1.20, 95%CI 0.28~5.21, n.s.), coronal alignment of femoral component (RR = 0.65, 95%CI 0.19~2.22, n.s.), and sagittal alignment of femoral component (RR = 0.73, 95%CI 0.38~1.41, n.s.). A reduced blood loss was associated with the use of the extramedullary guide (MD = 120.34, 95%CI -210.08~-30.59, P = 0.009). No significant difference in operation time was noted between the two groups (MD = 1.41, 95%CI -1.82~4.64, n.s.). CONCLUSIONS: Neither extramedullary nor intramedullary femoral alignment is more accurate than the other in facilitating the femoral cut in total knee arthroplasty. Use of the extramedullary guide results in less blood loss and exhibits a similar operation time as compared with the intramedullary guide. PMID- 28583143 TI - Fatigue mitigation with SleepTrackTXT2 in air medical emergency care systems: study protocol for a randomized controlled trial. AB - BACKGROUND: Most air medical Emergency Medical Services (EMS) clinicians work extended duration shifts, and more than 50% report inadequate sleep, poor sleep quality, and/or poor recovery between shifts. The SleepTrackTXT pilot trial (ClinicalTrials.gov, NCT02063737) showed that use of mobile phone text messages could impact EMS clinician self-reported fatigue and sleepiness during long duration shifts. The purpose of the SleepTrackTXT2 trial is to leverage lessons learned from the first SleepTrackTXT study and test an enhanced intervention targeting air medical EMS clinicians. METHODS/DESIGN: We will conduct a multi site randomized trial with a sample of adult EMS clinicians recruited from four air medical EMS systems located in the midwest, northeastern, and southern USA. Participants will be allocated to one of two possible arms for a 4-month (120 day) study period. The intervention arm will involve text-message assessments of sleepiness, fatigue, and difficulty concentrating at the beginning, every 4 hours during, and at the end of scheduled shifts. Participants reporting high levels of sleepiness, fatigue, or difficulty with concentration will receive one of nine randomly selected intervention messages to promote behavior change during shift work to improve alertness. Intervention participants will receive a text-message report on Friday of each week that shows their sleep debt over the previous 7 days followed by a text message to promote paying back sleep debt recovery when feasible. Participants in the control group receive text messages that only include assessments. Both arms will receive text-message assessments of perceived recovery since last shift, sleepiness, fatigue, or difficulty with concentration at noon (1200 hours) on days between scheduled shifts (off-duty days). We have two aims for this study: (1) to determine the short-term impact of the enhanced SleepTrackTXT2 intervention on air medical clinician fatigue reported in real time during and at the end of shift work, and (2) to determine the long-term impact of the SleepTrackTXT2 intervention on sleep quality and sleep health indicators including hours of sleep and recovery between shift work. DISCUSSION: The SleepTrackTXT2 trial may provide evidence of real-world effectiveness that would support widespread expansion of fatigue mitigation interventions in emergency care clinician shift workers. The trial may specifically support use of real-time assessments and interventions delivered via mobile technology such as text messaging. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02783027 . Registered on 23 May 2016. PMID- 28583145 TI - Influences of De Qi induced by acupuncture on immediate and accumulated analgesic effects in patients with knee osteoarthritis: study protocol for a randomized controlled trial. AB - BACKGROUND: De Qi is a special sensational response upon acupuncture needling. According to traditional acupuncture theory, the treatment is "effective only after Qi arrival"; that is, De Qi is an important indicator of therapeutic efficacy and good prognosis. However, it is still disputable whether De Qi improves the efficacy of acupuncture therapy. This prospective, randomized controlled trial aims to explore the influence of De Qi induced by acupuncture on immediate and accumulated analgesic effects in patients with knee osteoarthritis (KOA). METHODS/DESIGN: Eighty-eight patients with KOA will be recruited and randomly assigned to the De Qi group (enhanced stimulation to evoke De Qi) and the control group (weak stimulation to avoid De Qi) in the Department of Acupuncture and Physical Therapy, Beijing Luhe Hospital Affiliated to Capital Medical University. Each patient will receive three 30-minute sessions per week for 4 consecutive weeks and undergo a 1 month follow-up. The severity of knee pain, as measured on a 100-mm visual analog scale (where 0 indicates no pain and 100 indicates intolerable pain) will be used as the primary outcome, and the Knee injury and Osteoarthritis Outcome Score will be used as the secondary outcome. Both indexes will be measured before and after the 1st (for evaluating the immediate analgesic effects), 3rd, 6th, 9th, and 12th (for evaluating the accumulated analgesic effects) treatments and at the end of the follow-up. The intensity of the De Qi sensation will be assessed by the Chinese-Modified Massachusetts General Hospital Acupuncture Sensation Scale at the end of each treatment. Side effects during the treatments will be recorded and analyzed as well. The comparisons between the De Qi group and the control group will be done by using both an intention-to-treat analysis and a per-protocol analysis. DISCUSSION: This prospective randomized controlled study will be helpful in enhancing our understanding of the analgesic effect of De Qi on patients with KOA and may provide a clinical basis for further investigation of the relationship between De Qi and the therapeutic efficacy of acupuncture, thereby offering some evidence for the role of De Qi in an efficacious acupuncture therapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IIR-16008972 . Registered on 4 August 2016 Additional file 2. PMID- 28583147 TI - Resting energy expenditure and optimal nutrition in critical care: how to guide our calorie prescriptions. PMID- 28583146 TI - The effect of volumetric breast density on the risk of screen-detected and interval breast cancers: a cohort study. AB - BACKGROUND: In the light of the breast density legislation in the USA, it is important to know a woman's breast cancer risk, but particularly her risk of a tumor that is not detected through mammographic screening (interval cancer). Therefore, we examined the associations of automatically measured volumetric breast density with screen-detected and interval cancer risk, separately. METHODS: Volumetric breast measures were assessed automatically using Volpara version 1.5.0 (Matakina, New Zealand) for the first available digital mammography (DM) examination of 52,814 women (age 50 - 75 years) participating in the Dutch biennial breast cancer screening program between 2003 and 2011. Breast cancer information was obtained from the screening registration system and through linkage with the Netherlands Cancer Registry. We excluded all screen-detected breast cancers diagnosed as a result of the first digital screening examination. During a median follow-up period of 4.2 (IQR 2.0-6.2) years, 523 women were diagnosed with breast cancer of which 299 were screen-detected and 224 were interval breast cancers. The associations between volumetric breast measures and breast cancer risk were determined using Cox proportional hazards analyses. RESULTS: Percentage dense volume was found to be positively associated with both interval and screen-detected breast cancers (hazard ratio (HR) 8.37 (95% CI 4.34 16.17) and HR 1.39 (95% CI 0.82-2.36), respectively, for Volpara density grade category (VDG) 4 compared to VDG1 (p for heterogeneity < 0.001)). Dense volume (DV) was also found to be positively associated with both interval and screen detected breast cancers (HR 4.92 (95% CI 2.98-8.12) and HR 2.30 (95% CI 1.39 3.80), respectively, for VDG-like category (C)4 compared to C1 (p for heterogeneity = 0.041)). The association between percentage dense volume categories and interval breast cancer risk (HR 8.37) was not significantly stronger than the association between absolute dense volume categories and interval breast cancer risk (HR 4.92). CONCLUSIONS: Our results suggest that both absolute dense volume and percentage dense volume are strong markers of breast cancer risk, but that they are even stronger markers for predicting the occurrence of tumors that are not detected during mammography breast cancer screening. PMID- 28583148 TI - Daily cost of delay to adequate antibiotic treatment among patients surviving a hospitalization with community-onset Acinetobacter baumannii pneumonia or sepsis. PMID- 28583149 TI - Effect sizes in ongoing randomized controlled critical care trials. AB - BACKGROUND: An important limitation of many critical care trial designs is that they hypothesize large, and potentially implausible, reductions in mortality. Interpretation of trial results could be improved by systematic assessment of the plausibility of trial hypotheses; however, such assessment has not been attempted in the field of critical care medicine. The purpose of this study was to determine clinicians' views about prior probabilities and plausible effect sizes for ongoing critical care trials where the primary endpoint is landmark mortality. METHODS: We conducted a systematic review of clinical trial registries in September 2015 to identify ongoing critical care medicine trials where landmark mortality was the primary outcome, followed by a clinician survey to obtain opinions about ten large trials. Clinicians were asked to estimate the probability that each trial would demonstrate a mortality effect equal to or larger than that used in its sample size calculations. RESULTS: Estimates provided by individual clinicians varied from 0% to 100% for most trials, with a median estimate of 15% (IQR 10-20%). The median largest absolute mortality reduction considered plausible was 4.5% (IQR 3.5-5%), compared with a median absolute mortality reduction used in sample size calculations of 5% (IQR 3.6-10%) (P = 0.27). CONCLUSIONS: For some of the largest ongoing critical care trials, many clinicians regard prior probabilities as low and consider that plausible effects on absolute mortality are less than 5%. Further work is needed to determine whether pooled estimates obtained by surveying clinicians are replicable and accurate or whether other methods of estimating prior probability are preferred. PMID- 28583151 TI - Identification and validation of a Schistosoma japonicum U6 promoter. AB - BACKGROUND: RNA polymerase III promoters have been widely used to express short hairpin-RNA (shRNA), microRNA (miRNA), and small guide RNA (sgRNA) in gene functional analysis in a variety of organisms including Schistosoma mansoni. However, no endogenous RNA polymerase III promoters have been identified in Schistosoma japonicum. The lack of appropriate promoters in S. japonicum has hindered its gene functional analysis. Identification of functional promoters in S. japonicum is therefore in urgent need. RESULTS: Via sequence alignment, a 347 bp sequence upstream from the coding region of S. japonicum U6 small nuclear RNA (snRNA) was identified, cloned, and named as S. japonicum U6 (sjU6) promoter. A sgRNA sequence named as sgRNA970 was designed, and its Cas9 nuclease guiding activity was confirmed by in vitro cleavage assay. The sjU6 promoter was ligated with sgRNA970 coding sequence by overlap PCR to generate a sjU6-sgRNA970 expression cassette. The expression cassette was inserted into a lentiviral plasmid to construct the pHBLV-sgRNA970 plasmid. First, we tested the sjU6 promoter activity in HEK293 cells by transfecting HEK293 cells with the pHBLV sgRNA970 plasmid. RT-PCR amplification of the total RNA from the transfected HEK293 cells confirmed the presence of sgRNA970 transcript and indicated sjU6 promoter was functional to initiate transcription in HEK293 cells. Then we transduced the lentivirus expressing Cas9-ZsGreen fusion protein into 14 dpi schistosomula to test whether lentivirus was capable to induce exogenous gene expression in S. japonicum. Fluorescence microscopy and western blot results confirmed the expression of Cas9-ZsGreen fusion protein in S. japonicum. Therefore, this lentiviral system was adapted to test promoter activity in S. japonicum. Finally, we transduced 14 dpi S. japonicum with lentivirus produced from the pHBLV-sgRNA970 plasmid. RT-PCR amplification of the total RNA from transduced schistosomula confirmed the presence of sgRNA970 transcript and therefore indicated sjU6 promoter was functional to initiate transcription in S. japonicum. CONCLUSION: To our knowledge, sjU6 promoter would be the first identified and validated endogenous RNA polymerase III promoter in S. japonicum, which could be used for future CRISPR/Cas9 studies in S. japonicum. PMID- 28583150 TI - Prevalence of pregnancy-relevant infections in a rural setting of Ghana. AB - BACKGROUND: Although infectious diseases still account for a high burden of morbidity and mortality in sub-Saharan Africa, simultaneous investigations on multiple infections affecting maternal and child health are missing. METHODS: We conducted a cross-sectional, single-centre pilot study in a rural area of Ghana to assess the infectiological profile during pregnancy. Screening of 180 expectant mothers was done by vaginal swabs and serology to detect the most common pregnancy-relevant infections. They were also interviewed for potential risk factors, outcome of previous pregnancies, and socio-economic aspects. RESULTS: We found a high prevalence of infections caused by hepatitis B virus (16.7% HBs antigen positive). In contrast, infections caused by hepatitis C virus (1.1% anti-HCV) and HIV (0.6%) were rare. Maternal malaria was frequent (10.6%), despite increasing acceptance of intermittent preventive treatment during pregnancy (IPTp). Group B streptococci were present in 10.6% of all pregnant women. Absence of antibodies against varicella zoster virus in 43.2%, Toxoplasma gondii in 26.8%, parvovirus B19 in 20.0%, and rubella virus in 15.7% makes a significant proportion of pregnant women susceptible for acquiring primary infections. Whereas all study participants had specific IgG antibodies against human cytomegalovirus, infections with Listeria, Brucella, or Neisseria gonorrhoeae as well as active syphilis were absent. CONCLUSIONS: Our pilot study in a rural community in Ghana indicates an urgent need for action in dealing at least with high-prevalent pregnancy-relevant infections, such as hepatitis B, malaria and those caused by group B streptococci. In addition, the resulting prevalence rates of various other infections may offer guidance for health officials to prioritize possible future intervention schemes. PMID- 28583152 TI - Utilization of ultrasonography to detect developmental dysplasia of the hip: when reality turns selective screening into universal use. AB - BACKGROUND: Developmental dysplasia of the hip (DDH) occurs in 3-5 of 1000 live births and is associated with known risk factors. In most countries, formal practice for early detection of DDH entails the combination of risk factor identification and physical examination of the hip, while the golden standard diagnostic instrument is hip ultrasonography (US). This practice is commonly referred to as selective screening. Infants with positive US findings are treated with a Pavlik harness, a dynamic abduction splint. The objective of our study was to evaluate hip US utilization patterns in Maccabi Healthcare Services (MHS), a large health plan. METHODS: Study population: All MHS members, born between June 2011 and October 2014, who underwent at least one US before the age of 15 months. STUDY VARIABLES: Practice specialty and number of enrolled infants. Positive US result was defined as referral to an abduction splint. Cost was based on Ministry of Health price list. Chi square and correlation coefficients were employed in the statistical analysis. RESULTS: Of the 115,918 infants born during the study period, 67,491 underwent at least one hip US. Of these, 60.6% were female, mean age at performance: 2.2 months. Of those who underwent US, 625 (0.93%) were treated with a Pavlik harness: 0.24% of the male infants and 1.60% of the female infants (p < 0.001). Analysis of physician practice characteristics revealed that referral to US was significantly higher among pediatricians as compared with general practitioners (60% and 35%, respectively). Practice volume had no influence on referral rate. Direct medical costs of the 107 hip US examinations performed that led to detection of one positive case (treated by Pavlik): US$10,000. CONCLUSIONS: Current pattern of hip US utilization for early detection of DDH resembles universal screening more closely than selective screening. This can inform policy decisions as to whether a stricter selective screening or a formal move to universal screening is appropriate in Israel. PMID- 28583153 TI - In vitro antibacterial activity of poly (amidoamine)-G7 dendrimer. AB - BACKGROUND: Nano-scale dendrimers are synthetic macromolecules that frequently used in medical and health field. Traditional anibiotics are induce bacterial resistence so there is an urgent need for novel antibacterial drug invention. In the present study seventh generation poly (amidoamine) (PAMAM-G7) dendrimer was synthesized and its antibacterial activities were evaluated against representative Gram- negative and Gram-positive bacteria. METHODS: PAMAM-G7 was synthesized with divergent growth method. The structural and surface of PAMAM-G7 were investigated by transmission electron microscopy, scanning electron microscope and fourier transform infrared. Pseudomonas. aeruginosa (n = 15), E. coli (n = 15), Acinetobacter baumanni (n = 15), Shigella dysenteriae (n = 15), Klebsiella pneumoniae (n = 10), Proteus mirabilis (n = 15), Staphylococcus aureus (n = 15) and Bacillus subtilis (n = 10) have been used for antibacterial activity assay. Additionally, representative standard strains for each bacterium were included. Minimum Inhibitory Concentration (MIC) was determined using microdilution method. Subsequently, Minimum Bactericidal Concentration (MBC) was determined by sub-culturing each of the no growth wells onto Mueller Hinton agar medium. The cytotoxicity of PAMAM-G7 dendrimer were evaluated in HCT116 and NIH 3 T3 cells by MTT assay. RESULTS: The average size of each particle was approximately 20 nm. PAMAM-G7 was potentially to inhibit both Gram positive and gram negative growth. The MIC50 and MIC90 values were determined to be 2-4 MUg/ml and 4-8 MUg/ml, respectively. The MBC50 and MBC90 values were found to be 64-256 MUg/ml and 128-256 MUg/ml, respectively. The cytotoxity effect of dendrimer on HCT116 and NIH 3 T3 cells is dependent upon exposure time to and concentration of dendrimers. The most reduction (44.63 and 43%) in cell viability for HCT116 and NIH 3 T3 cells was observed at the highest concentration, 0.85 MUM after 72 h treatmentm, respectively. CONCLUSIONS: This study we conclude that PAMAM-G7 dendrimer could be a potential candidate as a novel antibacterial agent. PMID- 28583154 TI - A cohort analysis of neonatal hospital mortality rate and predictors of neonatal mortality in a sub-urban hospital of Cameroon. AB - BACKGROUND: In Cameroon, sustainable effort needs to be done to reduce the current neonatal mortality rate from 21 deaths per 1000 live births to the global target of fewer than ten deaths per 1000 live births by 2035. We aimed to determine the neonatal hospital mortality rate and predictors of neonatal hospital mortality (NHM) in a major referral sub-urban hospital of Cameroon in a bit to formulate interventions to curb this burden. METHODS: This was a prospective cohort study consecutively enrolling all neonates admitted into the neonatology unit of the Bamenda Regional Hospital (BRH) from November 2015 to February 2016. Through interviewed questionnaires to parents and physical examination of neonates, we studied socio-demographic characteristics, antenatal history, intrapartum history and clinical findings of neonates. Neonates further underwent relevant laboratory investigations for diagnosis. All neonates were followed up till 28 days after the post-menstrual term for the neonatal outcomes. Multiple logistic regression was used to determine predictors of NHM. RESULTS: We enrolled 332 out of 337 neonates admitted to the neonatology unit of BRH during the study period. Fifty-three percent (53%) were males. Their mean gestational age and birth weight were 36.9 +/- 3.9 weeks and 2677.2 +/- 923 g, respectively. The main causes of neonatal admissions were complications of preterm birth (32.2%), neonatal infections (31.3%), and birth asphyxia (14.5%). The neonatal hospital mortality rate was 15.7%. NHM was related to complications of preterm birth (69%), birth asphyxia (23%) and neonatal infections (6%). A five-minute Apgar score less than seven was the only predictor of NHM (aOR: 16.41; CI 95%: 6.35-42.47; p < 0.01). CONCLUSION: Neonatal mortality still remains a significant health problem in sub-urban Cameroon, mainly as a result of three pathologies; complications of preterm birth, birth asphyxia, and infections. There is an urgent need to revamp the current health policies through the improvement of antenatal care, skilled birth attendants, neonatal resuscitation, timely detection and treatment of complications of preterm births, birth asphyxia, and infections. PMID- 28583155 TI - Molecular diagnosis of Pseudoterranova decipiens s.s in human, France. AB - BACKGROUND: Anisakis and Pseudoterranova are the main genera involved in human infections caused by nematodes of the Anisakidae family. Species identification is complicated due to the lack of differential morphological characteristics at the larval stage, thus requiring molecular differentiation. Pseudoterranova larvae ingested through raw fish are spontaneously eliminated in most cases, but mechanical removal by means of endoscopy might be required. To date, only very few cases of Pseudoterranova infection have been reported in France. CASE PRESENTATION: A 19-year-old woman from Northeastern France detected, while brushing her teeth, a larva exiting through her mouth. The patient who presented with headache, diarrhea, and abdominal cramps reported having eaten baked cod. The worm was a fourth-stage larva with a size of 22 * 0.9 mm, and molecular biology identified it as Pseudoterranova decipiens sensu stricto (s. s.). In a second P. decipiens infection case, occurring a few months later, a worm exited through the patient's nose after she had eaten raw sea bream. CONCLUSION: These two cases demonstrate that Pseudoterranova infection is not uncommon among French patients. Therefore, molecular techniques should be more widely applied for a better characterization of anisakidosis epidemiology in France. PMID- 28583156 TI - Patient-reported negative experiences related to caries and its treatment among Swedish adult patients. AB - BACKGROUND: It has been suggested that dental caries should be regarded as a chronic disease as many individuals repeatedly develop new caries lesions. How this is perceived by caries active patients is unclear. The aim of this study was to measure patient-reported attitudes and negative experiences related to caries and dental treatment. METHODS: A questionnaire was mailed to 134 caries active (CA) and 40 caries inactive (CI) adult patients treated at a Swedish public dental service clinic. The questionnaire included items regarding patient reported oral health; attitudes towards caries and efforts to prevent them; and negative experiences related to caries and dental treatment. Questionnaire data were supplemented with data on caries and caries prophylaxis from patients' dental records. Exploratory factor analysis was conducted on items related to patients' perceptions of problems to see whether scales could be created. Experiences, perceptions and dental records of CA and CI patients were compared. RESULTS: The overall response rate was 69%. Dental records confirmed that CA patients had significantly more decayed teeth per year and a longer period of caries-active time than CI patients. Factor analysis resulted in 3 distinct scales measuring problems related to caries; 1) caries-related information; 2) negative experiences; and 3) negative treatment/staff attitudes. A fourth scale measuring perceived problems related to caries was also created. The CA group reported significantly more problems related to caries and dental treatment, received significantly more caries-related information, and reported significantly more negative treatment experiences compared to CI patients. CONCLUSIONS: Caries prophylaxis methods need to be improved in order to better meet the needs of caries active patients and to create a more positive experience with dental care. PMID- 28583158 TI - Gastrointestinal parasites of canids, a latent risk to human health in Tunisia. AB - BACKGROUND: Although data on the parasite environmental contamination are crucial to implement strategies for control and treatment, information about zoonotic helminths is very limited in Tunisia. Contamination of areas with canid faeces harboring infective parasite elements represents a relevant health-risk impact for humans. The aim of this study was to assess the environmental contamination with eggs and oocysts of gastrointestinal parasites of dogs and wild canids in Tunisia with special attention to those that can be transmitted to humans. RESULTS: One thousand two hundred and seventy faecal samples from stray dogs and 104 from wild canids (red foxes and golden jackals) were collected from different geographical regions throughout Tunisia. The helminth eggs and protozoan oocysts were concentrated by sucrose flotation and identified by microscopic examination. The most frequently observed parasites in dog samples were Toxocara spp. (27.2%), E. granulosus (25.8%), and Coccidia (13.1%). For wild canid faeces, the most commonly encountered parasites were Toxocara spp. (16.3%) followed by Capillaria spp. (9.6%). The parasite contamination of dog faeces varied significantly from one region to another in function of the climate. CONCLUSION: To our knowledge, the study highlights for the first time in Tunisia a serious environmental contamination by numerous parasitic stages infective to humans. Efforts should be made to increase the awareness of the contamination risk of such parasites in the environment and implement a targeted educational program. PMID- 28583157 TI - Role of nutrition support in adult cardiac surgery: a consensus statement from an International Multidisciplinary Expert Group on Nutrition in Cardiac Surgery. AB - Nutrition support is a necessary therapy for critically ill cardiac surgery patients. However, conclusive evidence for this population, consisting of well conducted clinical trials is lacking. To clarify optimal strategies to improve outcomes, an international multidisciplinary group of 25 experts from different clinical specialties from Germany, Canada, Greece, USA and Russia discussed potential approaches to identify patients who may benefit from nutrition support, when best to initiate nutrition support, and the potential use of pharmaco nutrition to modulate the inflammatory response to cardiopulmonary bypass. Despite conspicuous knowledge and evidence gaps, a rational nutritional support therapy is presented to benefit patients undergoing cardiac surgery. PMID- 28583159 TI - Exploring the strategies that midwives in British Columbia use to promote normal birth. AB - BACKGROUND: Rates of normal birth have been declining steadily over the past 20 years, despite the evidence of the benefits to mother and baby. This is most obvious in steadily increasing caesarean section rates across countries and studies of the factors involved suggest it may be more to do with the organization of maternity care and the preferences of healthcare providers than changes in maternal or demographic conditions. The proportion of women in British Columbia (BC) receiving care from a midwife continues to grow and there is a particular focus on promoting and supporting normal pregnancy and birth in the midwifery philosophy of care. In BC, women receiving care from a midwife are less likely to have a caesarean section and other birth interventions. METHODS: An interpretive approach, based on interpretive phenomenology was used to explore the experiences of midwives in BC of normal birth and the strategies that they use to keep birth normal. Fourteen experienced midwives were purposively selected from across the range of practice, geographical, and rural/urban contexts to participate in depth interviews. Data were analyzed using Thematic Network Analysis. RESULTS: Seven key themes were identified in the data: working with women from the early pregnancy, informing choice, the birth environment, careful watching and waiting, managing early labour, helping the woman to cope with labour, and tools in the tool kit. CONCLUSIONS: Midwives in BC work closely with women from early pregnancy to prepare them for a normal birth, and as "instruments of care" they adopt a range of approaches to support women to achieve this. The emphasis on continuity of care in the BC model of midwifery care plays a vital role in this. PMID- 28583160 TI - Differential expression of Cathepsin E in transthyretin amyloidosis: from neuropathology to the immune system. AB - BACKGROUND: Increasing evidence supports a key role for inflammation in the neurodegenerative process of familial amyloidotic polyneuropathy (FAP). While there seems to be an overactivation of the neuronal interleukin-1 signaling pathway, the immune response is apparently compromised in FAP. Accordingly, little immune cell infiltration is observed around pre-fibrillar or fibrillar amyloid deposits, with the underlying mechanism for this phenomenon remaining poorly understood. Cathepsin E (CtsE) is an important intermediate for antigen presentation and chemotaxis, but its role in the pathogenesis of FAP disease remains unknown. METHODS: In this study, we used both mouse primary macrophages and in vivo studies based on transgenic models of FAP and human samples to characterize CtsE expression in different physiological systems. RESULTS: We show that CtsE is critically decreased in bone marrow-derived macrophages from a FAP mouse model, possibly contributing for cell function impairment. Compromised levels of CtsE were also found in injured nerves of transgenic mice and, most importantly, in naive peripheral nerves, sensory ganglia, murine stomach, and sural nerve biopsies derived from FAP patients. Expression of CtsE in tissues was associated with transthyretin (TTR) deposition and differentially regulated accordingly with the physiological system under study. Preventing deposition with a TTR small interfering RNA rescued CtsE in the peripheral nervous system (PNS). In contrast, the expression of CtsE increased in splenic cells (mainly monocytes) or peritoneal macrophages, indicating a differential macrophage phenotype. CONCLUSION: Altogether, our data highlights the potential of CtsE as a novel FAP biomarker and a possible modulator for innate immune cell chemotaxis to the disease most affected tissues-the peripheral nerve and the gastrointestinal tract. PMID- 28583161 TI - A case-control study on egg consumption and risk of stroke among Iranian population. AB - BACKGROUND: Most available data that linked intake of egg to risk of stroke came from western countries, with conflicting findings. We aimed to examine the association between egg consumption and risk of stroke among Iranian adults. METHODS: In a hospital-based case-control study, 195 stroke patients, hospitalized in Alzahra University Hospital, were selected as cases and 195 control subjects, from patients hospitalized in other wards with no history of cerebrovascular diseases or neurologic disorders, were recruited. A validated 168 item food frequency questionnaire (FFQ) was used to assess participants' usual dietary intake, including egg consumption, over the previous year. Other required information was gathered by the use of questionnaires. RESULTS: Consumption of eggs was associated with lower odds of stroke, such that after adjustment for potential confounders, those in the highest category of egg intake (>2 eggs/week) were 77% lower odds to have stroke, compared with those with the lowest category of egg intake (<1 egg/week) (OR 0.23; 95% CI 0.11-0.45). Further controlling for body mass index strengthened the association (OR 0.20; 95% CI 0.09-0.41). CONCLUSIONS: We found evidence indicating that high intake of eggs (>2 eggs/week) during the past 1 year was associated with a lower risk of stroke. Further prospective studies are required to confirm these findings. PMID- 28583162 TI - Steroids in chronic subdural hematomas (SUCRE trial): study protocol for a randomized controlled trial. AB - BACKGROUND: Chronic subdural hematoma (CSDH) is a common neurological pathology, especially in older patients. The actual "gold standard" of treatment is surgical evacuation, with various techniques used across neurosurgical teams. Over the years, there has been growing evidence that inflammatory processes play a major role in the pathogenesis of CSDH. In that context, the use of corticosteroids has been proposed alone or as an adjuvant treatment to surgery. However, this practice remains very empirical and there is a need for high-quality-of-evidence studies to clarify the role of corticosteroids in the management of CSDH. METHODS/DESIGN: We propose a double-blind, randomized controlled trial comparing methylprednisolone versus placebo in the treatment of CSDH without clinical and/or radiological signs of severity. The treatment will be administered daily for a duration of 3 weeks, at a dose of 1 mg/kg. The primary endpoint will be the delay of occurrence of surgical treatment at 1 month following the introduction of the treatment. Secondary endpoints will include the rate of recourse to surgery, survival rate, quality of life and functional assessments, occurrence of systemic secondary effects and radiological assessment of the response to treatment. This multimodal assessment will be done at 1, 3 and 6 months. Two hundred and two patients (101 per arm) are expected to be included considering our primary hypotheses. DISCUSSION: This trial started in June 2016; its results may open interesting alternatives to surgery in the management of patients harboring a CSDH, and may provide insights into the natural history of this common pathology. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02650609 . Registered on 4 January 2016. Graphical output of the OBF boundaries. PMID- 28583163 TI - Erratum to: Physical human-robot interaction of an active pelvis orthosis: toward ergonomic assessment of wearable robots. PMID- 28583165 TI - Validity and reliability of the Sri Lankan version of the kidney disease quality of life questionnaire (KDQOL-SFTM). AB - BACKGROUND: The disabling symptoms, various food and fluid restrictions, restrictions to social life and stigma and taboos attached to Chronic Kidney Disease (CKD), have shown to pose a significant bearing on a patient's Quality of Life (QOL). In the present study the Kidney Disease QOL-Short Form (KDQOL-SFTM) was culturally adapted, modified and translated into Sinhala and validity and reliability were assessed. METHOD: The process to culturally adapt the Kidney Disease Specific Component (KDSC) of KDQOL-SFTM was carried out by the modified Delphi process with a group of experts. The construct validity of the KDSC was assessed using Exploratory Factor Analysis (EFA). Appraising construct validity of SF-36 component of KDQOL-SFTM was done by assessing the convergent and discriminant validity using the Multitrait-Multimethod Matrix technique (MTMM). Randomly selected 250 CKD patients attending the five renal clinics in Polonnauwa were used to assess the construct validity. To assess the test-retest reliability of the instrument, within a period of one week, 30 randomly selected study participants were visited at their households. RESULTS: Two hundred and fifty adults with documented evidence of CKD participated. The EFA carried out using principal component factoring method and rotated by Varimax orthogonal method resulted in 14 factors with Eigen values ranging from 1.062-8.746. This 14 factor model explained 84.1% of total variance of the initial system. The communalities extracted for domains were all close to one. All the items were loaded to one or more domains with factor coefficients of more than 0.4, not requiring any of the items to be dropped. Few items which showed similarly high factor coefficients in more than one factor were assigned to a factor ensuring the pattern in the theoretical framework of the questionnaire based on expert opinion and vigorous analysis of literature. Convergent and divergent validity assessed using MTMM, revealed satisfactory construct validity. Cronbach's alpha of all domains of KDQOL-SFTM except for cognitive function and Social function, exceeded Nunnally's criteria of 0.7. The Intra class Correlation Coefficients (ICC) were more than 0.8 for all the domains, which indicated good test re-test reliability. CONCLUSIONS: KDQOL-SFTM is a valid and reliable instrument which can be used to assess QOL of CKD patients in Sri Lanka. PMID- 28583164 TI - Health professionals' views on the barriers and enablers to evidence-based practice for acute stroke care: a systematic review. AB - BACKGROUND: Adoption of contemporary evidence-based guidelines for acute stroke management is often delayed due to a range of key enablers and barriers. Recent reviews on such barriers focus mainly on specific acute stroke therapies or generalised stroke care guidelines. This review examined the overall barriers and enablers, as perceived by health professionals which affect how evidence-based practice guidelines (stroke unit care, thrombolysis administration, aspirin usage and decompressive surgery) for acute stroke care are adopted in hospital settings. METHODOLOGY: A systematic search of databases was conducted using MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, PsycINFO, Cochrane Library and AMED (Allied and Complementary Medicine Database from 1990 to 2016. The population of interest included health professionals working clinically or in roles responsible for acute stroke care. There were no restrictions to the study designs. A quality appraisal tool for qualitative studies by the Joanna Briggs Institute and another for quantitative studies by the Centre for Evidence-Based Management were used in the present study. A recent checklist to classify barriers and enablers to health professionals' adherence to evidence-based practice was also used. RESULTS: Ten studies met the inclusion criteria out of a total of 9832 search results. The main barriers or enablers identified included poor organisational or institutional level support, health professionals' limited skills or competence to use a particular therapy, low level of awareness, familiarity or confidence in the effectiveness of a particular evidence-based therapy, limited medical facilities to support evidence uptake, inadequate peer support among health professionals', complex nature of some stroke care therapies or guidelines and patient level barriers. CONCLUSIONS: Despite considerable evidence supporting various specific therapies for stroke care, uptake of these therapies is compromised by barriers across organisational, patients, guideline interventions and health professionals' domains. As a result, we recommend that future interventions and health policy directions should be informed by these findings in order to optimise uptake of best practice acute stroke care. Further studies from low- to middle-income countries are needed to understand the barriers and enablers in such settings. TRIAL REGISTRATION: The review protocol was registered in the international prospective register of systematic reviews, PROSPERO 2015 (Registration Number: CRD42015023481 ). PMID- 28583166 TI - Tardive akathisia related to the anti-hypertensive agent Sevikar-a case report. AB - BACKGROUND: Tardive akathisia (TA) is a subtype of tardive syndrome, and its etiology is still uncertain. Sevikar is an anti-hypertensive agent containing both amlodipine and olmesartan, and has never been reported to have an adverse reaction in patients with tardive syndrome. CASE PRESENTATION: A 57-year-old woman who took Sevikar for hypertension for 10 years developed TA one and a half years before receiving any psychiatric treatment. After switching from Sevikar to bisoprolol, she reported obvious improvement in her akathisia. CONCLUSIONS: It is noteworthy that her TA developed before receiving any antidepressant medication, and that her TA improved after discontinuation of Sevikar. In light of these pharmacodynamic properties, it is therefore concluded that use of amlodipine and olmesartan might have caused TA in this patient. We reported this rare case to remind clinicians to be aware of possible akathisia when using amlodipine and olmesartan in combination as anti-hypertensive agents. PMID- 28583167 TI - Engineering biomimetic periosteum with beta-TCP scaffolds to promote bone formation in calvarial defects of rats. AB - BACKGROUND: There is a critical need for the management of large bone defects. The purpose of this study was to engineer a biomimetic periosteum and to combine this with a macroporous beta-tricalcium phosphate (beta-TCP) scaffold for bone tissue regeneration. METHODS: Rat bone marrow-derived mesenchymal stem cells (rBMSCs) were harvested and cultured in different culture media to form undifferentiated rBMSC sheets (undifferentiated medium (UM)) and osteogenic cell sheets (osteogenic medium (OM)). Simultaneously, rBMSCs were differentiated to induced endothelial-like cells (iECs), and the iECs were further cultured on a UM to form a vascularized cell sheet. At the same time, flow cytometry was used to detect the conversion rates of rBMSCs to iECs. The pre-vascularized cell sheet (iECs/UM) and the osteogenic cell sheet (OM) were stacked together to form a biomimetic periosteum with two distinct layers, which mimicked the fibrous layer and cambium layer of native periosteum. The biomimetic periostea were wrapped onto porous beta-TCP scaffolds (BP/beta-TCP) and implanted in the calvarial bone defects of rats. As controls, autologous periostea with beta-TCP (AP/beta-TCP) and beta-TCP alone were implanted in the calvarial defects of rats, with a no implantation group as another control. At 2, 4, and 8 weeks post-surgery, implants were retrieved and X-ray, microcomputed tomography (micro-CT), histology, and immunohistochemistry staining analyses were performed. RESULTS: Flow cytometry results showed that rBMSCs were partially differentiated into iECs with a 35.1% conversion rate in terms of CD31. There were still 20.97% rBMSCs expressing CD90. Scanning electron microscopy (SEM) results indicated that cells from the wrapped cell sheet on the beta-TCP scaffold apparently migrated into the pores of the beta-TCP scaffold. The histology and immunohistochemistry staining results from in vivo implantation indicated that the BP/beta-TCP and AP/beta-TCP groups promoted the formation of blood vessels and new bone tissues in the bone defects more than the other two control groups. In addition, micro-CT showed that more new bone tissue formed in the BP/beta-TCP and AP/beta-TCP groups than the other groups. CONCLUSIONS: Inducing rBMSCs to iECs could be a good strategy to obtain an endothelial cell source for prevascularization. Our findings indicate that the biomimetic periosteum with porous beta-TCP scaffold has a similar ability to promote osteogenesis and angiogenesis in vivo compared to the autologous periosteum. This function could result from the double layers of biomimetic periosteum. The prevascularized cell sheet served a mimetic fibrous layer and the osteogenic cell sheet served a cambium layer of native periosteum. The biomimetic periosteum with a porous ceramic scaffold provides a new promising method for bone healing. PMID- 28583168 TI - Mesenchymal stem cells for treating autoimmune dacryoadenitis. AB - Autoimmune dacryoadenitis, such as Sjogren syndrome, comprises multifactorial and complex diseases. Inflammation of the lacrimal gland plays a key role in the pathogenesis of diseases. Unfortunately, current treatment strategies, including artificial tears, anti-inflammatory drugs, punctual occlusion, and immunosuppressive drugs, are only palliative, and long-term administration of these strategies is associated with adverse effects that limit their utility. Hence, an effective and safe treatment for autoimmune dacryoadenitis is urgently needed. Mesenchymal stem cells (MSCs) have emerged as a promising tool for treating autoimmune dacryoadenitis, owing to their immunosuppressive properties, tissue repair functions, and powerful differentiation capabilities. A large number of studies have focused on the effect of MSCs on autoimmune diseases, such as autoimmune uveitis, inflammatory bowel disease, and collagen-induced arthritis, but few studies have, to date, unequivocally established the efficacy of MSCs for treating autoimmune dacryoadenitis. In this review, we discuss recent advances in MSC treatment for autoimmune dacryoadenitis. PMID- 28583169 TI - Letter to the Editor on "Mesenchymal stem cells enhance the oncolytic effect of Newcastle disease virus in glioma cells and glioma stem cells via the secretion of TRAIL". PMID- 28583170 TI - Community dialogues for child health: results from a qualitative process evaluation in three countries. AB - BACKGROUND: Across the developing world, countries are increasingly adopting the integrated community case management of childhood illnesses (iCCM) strategy in efforts to reduce child mortality. This intervention's effectiveness is dependent on community adoption and changes in care-seeking practices. We assessed the implementation process of a theory-driven community dialogue (CD) intervention specifically designed to strengthen the support and uptake of the newly introduced iCCM services and related behaviours in three African countries. METHODS: A qualitative process evaluation methodology was chosen and used secondary project data and primary data collected in two districts of each of the three countries, in purposefully sampled communities. The final data set included 67 focus group discussions and 57 key informant interviews, totalling 642 respondents, including caregivers, CD facilitators community leaders, and trainers. Thematic analysis of the data followed the 'Framework Approach' utilising both a deduction and induction process. RESULTS: Results show that CDs contribute to triggering community uptake of and support for iCCM services through filling health information gaps and building cooperation within communities. We found it to be an effective approach for addressing social norms around child care practices. This approach was embraced by communities for its flexibility and value in planning individual and collective change. CONCLUSIONS: Regular CDs can contribute to the formation of new habits, particularly in relation to seeking timely care in case of child sickness. This study also confirms the value of process evaluation to unwrap the mechanisms of community mobilisation approaches in context and provides key insights for improving the CD approach. PMID- 28583171 TI - Comparison of neurons derived from mouse P19, rat PC12 and human SH-SY5Y cells in the assessment of chemical- and toxin-induced neurotoxicity. AB - BACKGROUND: Exposure to chemicals might be toxic to the developing brain. There is a need for simple and robust in vitro cellular models for evaluation of chemical-induced neurotoxicity as a complement to traditional studies on animals. In this study, neuronally differentiated mouse embryonal carcinoma P19 cells (P19 neurons) were compared with human neuroblastoma SH-SY5Y cells and rat adrenal pheochromocytoma PC12 cells for their ability to detect toxicity of methylmercury (MeHg), okadaic acid and acrylamide. METHODS: Retinoic acid-treated P19 and SH SY5Y cells and nerve growth factor-stimulated PC12 cells, allowed to differentiate for 6 days, were exposed to MeHg, okadaic acid and acrylamide for 48 h. Cell survival and neurite outgrowth were assessed with the calcein-AM assay and fluorescence detection of antibodies against the cytoskeletal neuron-specific protein betaIII-tubulin, respectively. The effects of glutathione (GSH) and the potent inhibitor of GSH synthesis buthionine sulfoximine (BSO) on the MeHg induced-toxicity were assessed using the PrestoBlueTM cell viability assay and the TMRE mitochondrial membrane potential assay. RESULTS: Differentiated P19 cells developed the most extensive neuronal network among the three cell models and were the most sensitive neuronal model to detect neurotoxic effects of the test compounds. MeHg produced a concentration-dependent toxicity in differentiated P19 cells and SH-SY5Y cells, with statistically significant effects at concentrations from 0.1 MUM in the P19 neurons and 1 MUM in the SH SY5Y cells. MeHg induced a decrease in the cellular metabolic activity and mitochondrial membrane potential (DeltaPsim) in the differentiated P19 cells and SH-SY5Y cells, that were attenuated by GSH. Okadaic acid and acrylamide also showed statistically significant toxicity in the P19 neurons, but not in the SH SY5Y cells or the P12 cells. CONCLUSIONS: P19 neurons are more sensitive to detect cytotoxicity of MeHg, okadaic acid and acrylamide than retinoic acid differentiated SH-SY5Y cells and nerve growth factor-treated PC12 cells. P19 neurons are at least as sensitive as differentiated SH-SY5Y cells to detect the loss of mitochondrial membrane potential produced by MeHg and the protective effects of extracellular GSH on MeHg toxicity. P19 neurons may be a useful model to study neurotoxic effects of chemicals. PMID- 28583172 TI - Fluorescent tagged episomals for stoichiometric induced pluripotent stem cell reprogramming. AB - BACKGROUND: Non-integrating episomal vectors have become an important tool for induced pluripotent stem cell reprogramming. The episomal vectors carrying the "Yamanaka reprogramming factors" (Oct4, Klf, Sox2, and L-Myc + Lin28) are critical tools for non-integrating reprogramming of cells to a pluripotent state. However, the reprogramming process remains highly stochastic, and is hampered by an inability to easily identify clones that carry the episomal vectors. METHODS: We modified the original set of vectors to express spectrally separable fluorescent proteins to allow for enrichment of transfected cells. The vectors were then tested against the standard original vectors for reprogramming efficiency and for the ability to enrich for stoichiometric ratios of factors. RESULTS: The reengineered vectors allow for cell sorting based on reprogramming factor expression. We show that these vectors can assist in tracking episomal expression in individual cells and can select the reprogramming factor dosage. CONCLUSIONS: Together, these modified vectors are a useful tool for understanding the reprogramming process and improving induced pluripotent stem cell isolation efficiency. PMID- 28583173 TI - HIV and syphilis in the context of community vulnerability among indigenous people in the Brazilian Amazon. AB - BACKGROUND: Contextual factors shape the risk of acquiring human immunodeficiency virus (HIV) and syphilis. We estimated the prevalence of both infections among indigenous people in nine indigenous health districts of the Brazilian Amazon and examined the context of community vulnerability to acquiring these infections. METHODS: We trained 509 health care workers to screen sexually active populations in the community for syphilis and HIV using rapid testing (RT). We then assessed the prevalence of HIV and syphilis using RT. A multivariable analysis was used to identify factors associated with syphilis infection (sociodemographic, condom use, intrusion, population mobility, and violence). RESULTS: Of the 45,967 indigenous people tested, the mean age was 22.5 years (standard deviation: 9.2), and 56.5% were female. Overall, for HIV, the prevalence was 0.13% (57/43,221), and for syphilis, the prevalence was 1.82% (745/40,934). The prevalence in men, women, and pregnant women for HIV was 0.16%, 0.11%, and 0.07%, respectively, and for syphilis, it was 2.23%, 1.51%, and 1.52%, respectively. The district Vale do Javari had the highest prevalence of both infections (HIV: 3.38%, syphilis: 1.39%). This district also had the highest population mobility and intrusion and the lowest availability of prenatal services. Syphilis infection was independently associated with age (odds ratio [OR] 1.04, 95% confidence interval [CI]: 1.03-1.05), male sex (OR 1.32, 95% CI: 1.14-1.52), and mobility (moderate: OR: 7.46, 95% CI: 2.69-20.67; high: OR 7.09, 95% CI: 3.79-13.26). CONCLUSIONS: The large-scale integration of RT in remote areas increased case detection among pregnant women, especially for syphilis, in districts with higher vulnerability. Mobility is an important risk factor, especially in districts with higher vulnerability. Contextually appropriate approaches that address this factor could contribute to the long-term success of HIV and syphilis control programs. PMID- 28583175 TI - Are advance directives helpful for good end of life decision making: a cross sectional survey of health professionals. AB - BACKGROUND: This paper joins the debate over changes in the role of health professionals when applying advance directives to manage the decision-making process at the end of life care. Issues in relation to advance directives occur in clinical units in Lithuania; however, it remains one of the few countries in the European Union (EU) where the discussion on advance directives is not included in the health-care policy-making agenda. To encourage the discussion of advance directives, a study was designed to examine health professionals' understanding and preferences related to advance directives. In addition, the study sought to explore the views of health care professionals of the application of Advance Directives (AD) in clinical practice in Lithuania. METHODS: A cross sectional survey was conducted by interviewing 478 health professionals based at major health care centers in Kaunas district, Lithuania. The design of the study included the use of a questionnaire developed for this study and validated by a pilot study. The collected data were analyzed using standard descriptive statistical methods. RESULTS: The analysis of knowledge about AD revealed some statistically significant differences when comparing the respondents' profession and gender. The analysis also indicated key emerging themes among respondents including tranquility of mind, the longest possible life expectancy and freedom of choice. Further, the study findings revealed that more than half of the study participants preferred to express their will while alive by using advance directives. CONCLUSIONS: The study findings revealed a low level of knowledge on advance directives among health professionals. Most health professionals agreed that AD's improved end-of-life decision making while the majority of physicians appreciated AD as the best tool for sharing responsibilities in clinical practice in Lithuania. More physicians than nurses preferred the presence of advance directives to support their decision making in end-of-life situations. PMID- 28583174 TI - Follistatin is a metastasis suppressor in a mouse model of HER2-positive breast cancer. AB - BACKGROUND: Follistatin (FST) is an intrinsic inhibitor of activin, a member of the transforming growth factor-beta superfamily of ligands. The prognostic value of FST and its family members, the follistatin-like (FSTL) proteins, have been studied in various cancers. However, these studies, as well as limited functional analyses of the FSTL proteins, have yielded conflicting results on the role of these proteins in disease progression. Furthermore, very few have been focused on FST itself. We assessed whether FST may be a suppressor of tumorigenesis and/or metastatic progression in breast cancer. METHODS: Using publicly available gene expression data, we examined the expression patterns of FST and INHBA, a subunit of activin, in normal and cancerous breast tissue and the prognostic value of FST in breast cancer metastases, recurrence-free survival, and overall survival. The functional effects of activin and FST on in vitro proliferation, migration, and invasion of breast cancer cells were also examined. FST overexpression in an autochthonous mouse model of breast cancer was then used to assess the in vivo impact of FST on metastatic progression. RESULTS: Examination of multiple breast cancer datasets revealed that FST expression is reduced in breast cancers compared with normal tissue and that low FST expression predicts increased metastasis and reduced overall survival. FST expression was also reduced in a mouse model of HER2/Neu-induced metastatic breast cancer. We found that FST blocks activin-induced breast epithelial cell migration in vitro, suggesting that its loss may promote breast cancer aggressiveness. To directly determine if FST restoration could inhibit metastatic progression, we transgenically expressed FST in the HER2/Neu model. Although FST had no impact on tumor initiation or growth, it completely blocked the formation of lung metastases. CONCLUSIONS: These data indicate that FST is a bona fide metastasis suppressor in this mouse model and support future efforts to develop an FST mimetic to suppress metastatic progression. PMID- 28583177 TI - Dead simple OWL design patterns. AB - BACKGROUND: Bio-ontologies typically require multiple axes of classification to support the needs of their users. Development of such ontologies can only be made scalable and sustainable by the use of inference to automate classification via consistent patterns of axiomatization. Many bio-ontologies originating in OBO or OWL follow this approach. These patterns need to be documented in a form that requires minimal expertise to understand and edit and that can be validated and applied using any of the various programmatic approaches to working with OWL ontologies. RESULTS: Here we describe a system, Dead Simple OWL Design Patterns (DOS-DPs), which fulfills these requirements, illustrating the system with examples from the Gene Ontology. CONCLUSIONS: The rapid adoption of DOS-DPs by multiple ontology development projects illustrates both the ease-of use and the pressing need for the simple design pattern system we have developed. PMID- 28583176 TI - Nurse-led navigation to provide early palliative care in rural areas: a pilot study. AB - BACKGROUND: Few services are available to support rural older adults living at home with advancing chronic illness. The objective of this project was to pilot a nurse-led navigation service to provide early palliative support for rural older adults and their families living at home with advancing chronic illness. METHODS: Twenty-five older adults and 11 family members living with advancing chronic illness received bi-weekly home visits by a nurse navigator over a 2-year period. Navigation services included symptom management, education, advance care planning, advocacy, mobilization of resources, and psychosocial support. The nurse navigator collected longitudinal data on older adult and family needs, and older adult quality of life and healthcare utilization. RESULTS: Satisfaction with the service was high. There was no attrition over the 2-year period except through death, and few cancelled visits, indicating a high degree of acceptability of the intervention. The navigator addressed complex, multi-faceted needs through connecting health, social, and informal community resources. Participants who indicated a preferred place of death were able to die in that preferred place (n = 7). Emergency room use by participants was minimal and largely unpreventable by the nurse navigator. Longitudinal health-related quality of life scores for many participants were poor, lending further support to the need for more focused attention to this upstream palliative population. CONCLUSIONS: Using a nurse navigator to facilitate early palliative care for rural older adults living with advanced chronic illness is a promising innovation for meeting the needs of this population. Further research is required to evaluate outcomes on a larger scale. PMID- 28583178 TI - Therapeutic angiogenesis of adipose-derived stem cells for ischemic diseases. AB - Ischemic diseases, the leading cause of disability and death, are caused by the stenosis or obstruction of arterioles/capillaries that is not compensated for by vessel dilatation or collateral circulation. Angiogenesis is a complex process leading to new blood vessel formation and is triggered by ischemic conditions. Adequate angiogenesis, as a compensatory mechanism in response to ischemia, may increase oxygen and nutrient supplies to tissues and protect their function. Therapeutic angiogenesis has been the most promising therapy for treating ischemic diseases. In recent years, stem cell transplantation has been recognized as a new technique with therapeutic angiogenic effects on ischemic diseases. Adipose-derived stem cells, characterized by their ease of acquisition, high yields, proliferative growth, and low immunogenicity, are an ideal cell source. In this review, the characterization of adipose-derived stem cells and the role of angiogenesis in ischemic attack are summarized. The angiogenic effects of adipose-derived stem cells are discussed from the perspectives of in-vitro, in vivo, and clinical trial studies for the treatment of ischemic diseases, including ischemic cardiac, cerebral, and peripheral vascular diseases and wound healing. The microvesicles/exosomes released from adipose-derived stem cells are also presented as a novel therapeutic prospect for treating ischemic diseases. PMID- 28583180 TI - Improving Hospital at Home for frail older people: insights from a quality improvement project to achieve change across regional health and social care sectors. AB - BACKGROUND: Against a background of rising numbers of frail older people, there is a need to improve quality and safety of services whilst containing costs. Improving patient outcomes requires change across hospital and community systems. Our objective was to change practice in order to deliver a Hospital at Home programme (admission avoidance and early supported discharge) for frail older people across a regional commissioning area. The programme, undertaken within the Northern, Eastern & Western Devon Clinical Commissioning Group (CCG) sub localities of Exeter (population 120,000) and Woodbury, Exmouth and Budleigh Salterton (towns with populations of around 10,000), involved reconfiguration of existing services rather than being a stand-alone intervention. METHODS: Quality Improvement methodology, with hospital and community staff using Plan-Do-Study Act (PDSA) cycles to implement and test service changes. OUTCOME MEASURES: 1) Discharge destination; 2) Length of stay; 3) Acute Community Team referrals. RESULTS: Against a backdrop of intense financial pressures, significant community bed closures, and difficult relations between hospital and community services, outcomes remained stable (discharge destination, length of hospital stay, and number of referrals to the community team). CONCLUSION: PDSA cycles enabled stakeholders across acute and community services to be involved, promoted a process of collaborative inquiry and ownership of findings, and improved motivation to act on results and produce change. Practitioners and managers seeking to improve the delivery of complex, cross-cutting services in other areas can learn from the experience of applying Quality Improvement methods reported here. PMID- 28583179 TI - Comparison between the effects of potassium phosphite and chitosan on changes in the concentration of Cucurbitacin E and on antibacterial property of Cucumis sativus. AB - BACKGROUND: Cucurbitacins are mostly found in the members of the family Cucurbitaceae and are responsible for the bitter taste of cucumber. Pharmacological activities such as anti-bacterial and anti-tumor effects have been attributed to these structurally divers triterpens. The aim of this study was to investigate the effect of potassium phosphite (KPhi) and chitosan on Cucurbitacin E (CuE) concentration in different tissues of Cucumis sativus. The antibacterial effect of plant ethanolic extracts was also examined against E.coli PTCC 1399 and Pseudomonas aeruginosa PTCC 1430 bacterial strains. METHODS: After emergence of secondary leaves, cucumber plants were divided into 4 groups (each group consisted of 6 pots and each pot contained one plant) and different treatments performed as follows: group1. Leaves were sprayed with distilled water (Control), group 2. The leaves were solely treated with potassium phosphite (KPhi), group 3. Leaves were solely sprayed with chitosan (Chitosan), group 4. Leaves were treated with KPhi and chitosan (KPhi + chitosan). The KPhi (2 g L-1) and chitosan (0.2 g L-1) were applied twice every 12 h for one day. Fruits, roots and leaves were harvested 24 h later. The ethanolic extract of plant organs was used for determination of CuE concentration using HPLC approach. The antimicrobial activity was evaluated by the agar well diffusion method. The experiments were arranged in a completely randomized design (CRD) and performed in six biological replications for each treatment. Analysis of variance was performed by one-way ANOVA and Dunnette multiple comparison using SPSS. RESULTS: The highest level of CuE was recorded in fruit (2.2 g L-1) of plants under concomitant applications of KPhi and chitosan. Result of antibacterial activity evaluation showed that under concomitant treatments of KPhi and chitosan, fruit extract exhibited the highest potential for activity against E. coli PTCC 1399 (with mean zone of inhibition equal to 36 mm) and Pseudomonas aeruginosa PTCC 1430 (with mean zone of inhibition equal to 33 mm). CONCLUSIONS: KPhi and chitosan can induce production of CuE compound and increase antibacterial potential of cucumber plant extract. The application of KPhi and chitosan may be considered as promising prospect in the biotechnological production of CuE. PMID- 28583181 TI - Bringing the age-related macular degeneration high-risk allele age-related maculopathy susceptibility 2 into focus with stem cell technology. AB - Age-related macular degeneration (AMD) is a major cause of blindness in older adults in developed countries. It is a multifactorial disease triggered by both environmental and genetic factors. High-temperature requirement A serine peptidase 1 (HTRA1) and age-related maculopathy susceptibility 2 (ARMS2) are two genes that are strongly associated with AMD. Because ARMS2 is an evolutionarily recent primate-specific gene and because the ARMS2/HTRA1 genes are positioned at a locus on chromosome 10q26 in a region with strong linkage disequilibrium, it is difficult to distinguish the functions of the individual genes. Therefore, it is necessary to bring these genes into focus. Patient-specific induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) provides direct access to a patient's genetics and allows for the possibility of identifying the initiating events of RPE-associated degenerative diseases. In this paper, a review of recent epidemiological studies of AMD is offered. An argument for a definite correlation between the ARMS2 gene and AMD is presented. A summary of the use of ARMS2 genotyping for medical treatment is provided. Several ARMS2 related genetic models based on such stem cells as iPSCs are introduced. The possibility of applying gene-editing techniques and stem-cell techniques to better explore the mechanisms of the ARMS2 high-risk allele, which will lead to important guidance for treatment, is also discussed. PMID- 28583183 TI - Design and implementation of a decision aid for juvenile idiopathic arthritis medication choices. AB - BACKGROUND: Randomized trials have demonstrated the efficacy of patient decision aids to facilitate shared decision making in clinical situations with multiple medically reasonable options for treatment. However, little is known about how best to implement these tools into routine clinical practice. In addition, reliable implementation of decision aids has been elusive and spread within pediatrics has been slow. We sought to develop and reliably implement a decision aid for treatment of children with juvenile idiopathic arthritis. METHODS: To design our decision aid, we partnered with patient, parent, and clinician stakeholders from the Pediatric Rheumatology Care and Outcomes Improvement Network. Six sites volunteered to use quality improvement methods to implement the decision aid. Four of these sites collected parent surveys following visits to assess outcomes. Parents reported on clinician use of the decision aid and the amount of shared decision making and uncertainty they experienced. We used chi square tests to compare eligible visits with and without use of the decision aid on the experience of shared decision making and uncertainty. RESULTS: After 18 rounds of testing and revision, stakeholders approved the decision aid design for regular use. Qualitative feedback from end-users was positive. During the implementation project, the decision aid was used in 35% of visits where starting or switching medication was discussed. Clinicians used the decision aid as intended in 68% of these visits. The vast majority of parents reported high levels of shared decision making following visits with (64/76 = 84%) and without (80/95 = 84%) use of the decision aid (p = 1). Similarly, the vast majority of parents reported no uncertainty following visits with (74/76 = 97%) and without (91/95 = 96%) use of the decision aid (p = 0.58). CONCLUSIONS: Although user acceptability of the decision aid was high, reliable implementation in routine clinical care proved challenging. Our parsimonious approach to outcome assessment failed to detect a difference between visits with and without use of our aid. Innovative approaches are needed to facilitate use of decision aids and the assessment of outcomes. PMID- 28583182 TI - Tissue-specific bioactivity of soluble tendon-derived and cartilage-derived extracellular matrices on adult mesenchymal stem cells. AB - BACKGROUND: Biological scaffolds composed of tissue-derived extracellular matrix (ECM) can promote homologous (i.e., tissue-specific) cell differentiation through preservation of biophysical and biochemical motifs found in native tissues. Solubilized ECMs derived from decellularized tendon and cartilage have recently been promoted as tissue-specific biomaterials, but whether tissue-specific bioactivity is preserved following solubilization is unknown. This study explored the tissue-specific bioactivity of soluble decellularized tendon and cartilage ECMs on human bone marrow-derived mesenchymal stem cells (MSCs) presented across different culture microenvironments, including two-dimensional (2D) tissue culture plastic, aligned electrospun nanofibers, cell pellets, and cell-seeded photocrosslinkable hydrogels. METHODS: Tendon and cartilage ECMs were decellularized using established methods and solubilized either via pepsin digestion or urea extraction. The effect of soluble ECMs on cell proliferation and differentiation was initially explored by supplementing basal medium of human MSCs cultured on 2D tissue culture plastic. In subsequent experiments, MSCs were cultured on aligned electrospun nanofibers, ascell pellets, or encapsulated within photocrosslinkable methacrylated gelatin (GelMA) hydrogels. Urea-extracted tendon and cartilage ECMs were added as supplements. RESULTS: Pepsin-digested ECMs did not promote homologous differentiation in human MSCs, whether provided as a medium supplement or three-dimensional (3D) hydrogels. In contrast, urea extracted ECMs tended to promote tissue-specific differentiation of MSCs cultured in 2D and 3D microenvironments. The application of the small molecule TGF-beta signaling inhibitor SB-431542 largely negated the tissue-specific gene expression patterns mediated by tendon and cartilage ECMs. This suggests that the action of endogenous TGF-beta was required, but was not sufficient, to impart tissue specific bioactivity of urea-extracted ECMs. When urea-extracted cartilage ECM was incorporated within a photocurable GelMA hydrogel it independently enhanced chondrogenesis in encapsulated MSCs, and showed additive prochondrogenesis upon TGF-beta supplementation in the medium. CONCLUSIONS: Urea-extracted ECM fractions of decellularized tendon and cartilage are soluble supplements capable of enhancing tissue-specific differentiation of adult stem cells. PMID- 28583185 TI - Temporal changes and determinants of childhood nutritional status in Kenya and Zambia. AB - BACKGROUND: The prevalence of undernutrition is decreasing in many parts of the developing world, but challenges remain in many countries. The objective of this study was to determine factors influencing childhood nutrition status in Kenya and Zambia. The objective of this study is to determine factors associated with temporal changes in childhood nutritional status in two countries in sub-Saharan Africa. METHODS: Data from national demographic and health surveys from the World Bank for Kenya (1998-2009) and Zambia (1996-2014) were used to select the youngest child of each household with complete data for all variables studied. Multiple linear regression analyses were used for data from 2902 and 11,335 children from Kenya and Zambia, respectively, in each year to determine the relationship between social and economic factors and measures of nutritional status, including wasting, stunting, and overweight. RESULTS: There was a decreased prevalence of stunting (35% in Kenya and 40% in Zambia), while the prevalence of wasting was unchanged (6-8% in both countries). From 1998 to 2009, there was a protective effect against stunting for wealthier families and households with electricity, for both countries. Finally, better educated mothers were less likely to have stunted children and girls were less likely to be stunted than boys. CONCLUSIONS: Based on the data analyzed, there was a higher risk of stunting in both Kenya and Zambia, for those with lower literacy, less education, no electricity, living in rural areas, no formal toilet, no car ownership, and those with an overall lower wealth index. Improving the education of mothers was also a significant determinant in improving the nutritional status of children in Kenya and Zambia. More broad-based efforts to reduce the prevalence of undernutrition need to focus on reducing the prevalence of undernutrition without promoting excess weight gain. Future economic advances need to consider integrated approaches to improving economic standings of households without increasing the risk for overnutrition. PMID- 28583186 TI - Assessment of dog owner adherence to veterinarians' flea and tick prevention recommendations in the United States using a cross-sectional survey. AB - BACKGROUND: Adherence to a prescribed therapeutic regimen is a critical factor for achieving medication effectiveness and therefore treatment success. In the case of companion animal ectoparasite control, suboptimal owner adherence to medication recommendations is thought to be a common cause of treatment failure, and previous reports have found pet owners applying an average of 4.0-4.6 monthly flea and tick treatments per year to their dogs. This study investigated: US veterinary hospital self-reported flea and tick prevention recommendations; dog owner recollection of these recommendations; dog owner opinion on flea/tick recommendations and estimated owner flea and tick medication adherence based on veterinary hospital purchase records. RESULTS: Veterinarians at 24 veterinary hospitals in 4 United States regions provided their flea and tick prevention recommendations. Five hundred fifty-nine dog owners, clients of the 24 hospitals, completed a survey evaluating their recollection of the hospitals' recommendations and their opinions regarding required treatment frequency. Almost all veterinary hospitals in this study recommended 12 months of flea and tick prevention but only 62% of participating dog owners recalled this recommendation. The average owner response was that their dogs require 10.5 months of flea and tick prevention annually. Owner opinions were significantly different among U.S. regions with pet owners in the northeast U.S. believing that they needed significantly less canine flea and tick protection than pet owners in other parts of the United States. The estimated actual flea and tick prevention coverage was 6.1 months based on owner medication purchases over a 12-month period. CONCLUSIONS: In the United States, dog owner opinions and actions show that their flea and tick treatment adherence falls short of veterinarians' recommendations. PMID- 28583187 TI - Antimicrobial susceptibility pattern of Shigella spp. isolated from children under 5 years of age attending tertiary care hospitals, Nepal along with first finding of ESBL-production. AB - BACKGROUND: Shigella is an important cause of bacterial gastroenteritis in resource-poor countries. The treatment of shigellosis mostly requires antibiotics. However, the increase of multidrug resistance along with emergence of extended-spectrum beta-lactamase and ciprofloxacin resistance among Shigella spp. has challenged the situation. This study was conducted to determine the distribution of species and antibiotic susceptibility pattern of Shigella species isolated from stool specimen among children less than 5 years of age in Nepal. RESULTS: Out of total 717 stool samples collected, 15 cases of Shigella spp. was isolated which includes 12 S. flexneri and 3 S. sonnei. Multidrug resistance was found among 13(86%) of the isolates. One of the isolates of S. flexneri was found to be ESBL-producer with MIC >256 mg/L for cefixime. CONCLUSION: The high occurrence of multidrug resistance among Shigella spp. along with a case of ESBL production for the first time in Nepal alarms the concerns about dissemination of the resistant isolates. So, systemic monitoring of the antimicrobial susceptibility pattern of Shigella spp. is becoming crucial to guide therapy. PMID- 28583184 TI - Effect of single intralesional treatment of surgically induced equine superficial digital flexor tendon core lesions with adipose-derived mesenchymal stromal cells: a controlled experimental trial. AB - BACKGROUND: Adipose tissue is a promising source of mesenchymal stromal cells (MSCs) for the treatment of tendon disease. The goal of this study was to assess the effect of a single intralesional implantation of adipose tissue-derived mesenchymal stromal cells (AT-MSCs) on artificial lesions in equine superficial digital flexor tendons (SDFTs). METHODS: During this randomized, controlled, blinded experimental study, either autologous cultured AT-MSCs suspended in autologous inactivated serum (AT-MSC-serum) or autologous inactivated serum (serum) were injected intralesionally 2 weeks after surgical creation of centrally located SDFT lesions in both forelimbs of nine horses. Healing was assessed clinically and with ultrasound (standard B-mode and ultrasound tissue characterization) at regular intervals over 24 weeks. After euthanasia of the horses the SDFTs were examined histologically, biochemically and by means of biomechanical testing. RESULTS: AT-MSC implantation did not substantially influence clinical and ultrasonographic parameters. Histology, biochemical and biomechanical characteristics of the repair tissue did not differ significantly between treatment modalities after 24 weeks. Compared with macroscopically normal tendon tissue, the content of the mature collagen crosslink hydroxylysylpyridinoline did not differ after AT-MSC-serum treatment (p = 0.074) while it was significantly lower (p = 0.027) in lesions treated with serum alone. Stress at failure (p = 0.048) and the modulus of elasticity (p = 0.001) were significantly lower after AT-MSC-serum treatment than in normal tendon tissue. CONCLUSIONS: The effect of a single intralesional injection of cultured AT-MSCs suspended in autologous inactivated serum was not superior to treatment of surgically created SDFT lesions with autologous inactivated serum alone in a surgical model of tendinopathy over an observation period of 22 weeks. AT-MSC treatment might have a positive influence on collagen crosslinking of remodelling scar tissue. Controlled long-term studies including naturally occurring tendinopathies are necessary to verify the effects of AT-MSCs on tendon disease. PMID- 28583188 TI - HNF4A expression as a potential diagnostic tool to discriminate primary gastric cancer from breast cancer metastasis in a Brazilian cohort. AB - BACKGROUND: Among the many challenges in cancer diagnosis is the early distinction between metastatic cancer and a secondary tumor. This difficulty stems from the lack of markers that offer high sensitivity and specificity and can be easily applied in routine laboratory work. An example of this challenge is distinguishing gastric metastases originating from breast cancer from a gastric primary tumor. Hepatocyte nuclear factor 4 alpha (HNF4A) has been suggested as a potential marker in these cases. The aim of this study was to analyze the expression of HNF4A, estrogen receptor (ER), progesterone receptor (PR) and gross cystic disease fluid protein 15 (GCDFP-15) in a Brazilian cohort. METHODS: We performed immunohistochemistry analysis of HNF4A, ER, PR and GCDFP-15 in 126 patients divided into three cohorts: primary breast cancer, primary gastric cancer and both types of tumors. RESULTS: Our data confirmed the sensitivity and specificity of the HNF4A marker compared to other currently used clinical markers. CONCLUSION: HNF4A alone could be a gold standard marker for distinguishing primary gastric cancer from breast metastasis, thus validating its potential clinical use, especially in populations with high genetic diversity. PMID- 28583189 TI - Use of bacteriophages in the treatment of colistin-only-sensitive Pseudomonas aeruginosa septicaemia in a patient with acute kidney injury-a case report. PMID- 28583190 TI - ERbeta1 inhibits metastasis of androgen receptor-positive triple-negative breast cancer by suppressing ZEB1. AB - BACKGROUND: Increasing evidence has indicated an important role for estrogen receptor beta 1 (ERbeta1) in breast cancer. However, the role of ERbeta1 in the metastasis of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) and the underlying mechanisms are still unknown. METHODS: Stable ERbeta1 expressing TNBC cell lines were generated for this study. We detected the abilities of cell migration and invasion by wound-healing and transwell assays and the expression of E-cadherin and N-cadherin by quantitative RT-PCR (qRT-PCR) and western blotting assays in TNBC cell lines. Chromatin immunoprecipitation (ChIP) analysis was performed to assess the effect of AR on ERbeta1 promoter. Tumor metastasis was evaluated in vivo using a lung metastasis mouse model. Lastly, immunohistochemical expression of ERbeta1 in TNBC tissues was analyzed and correlated with clinicopathological features. RESULTS: ERbeta1 suppressed the invasion and migration abilities of AR-positive TNBC cells and induced the downregulation of ZEB1. ZEB1 overexpression abrogated the increase in E-cadherin expression and the decrease in N-cadherin expression modulated by ERbeta1. A lung metastasis mouse model showed that the incidence of metastasis was lower in ERbeta1-expressing TNBC cells. Further, AR activation increased the anti metastatic effect of ERbeta1 in AR-positive TNBC cells, which accelerated ERbeta1 transcription by functioning as a transcription factor that bound to the promoter of ERbeta1. No significant change was observed in AR expression induced by ERbeta1. Immunohistochemistry (IHC) analysis of TNBC clinical samples showed that ERbeta1 and AR were positive in 31.7% and 23.2% of samples, respectively. ERbeta1 expression was negatively correlated with ZEB1 expression and lymph node metastasis, and positively correlated with the expression of AR and E-cadherin. CONCLUSION: Our findings suggested a potential role of ERbeta1 in metastasis of AR-positive TNBC and provided novel insights into the mechanism of action of ERbeta1 and the possible relationship between ERbeta1 and AR. PMID- 28583192 TI - Isolated talonavicular arthrodesis and talonavicular-cuneiform arthrodesis for the Muller-Weiss disease. AB - BACKGROUND: The study aimed to introduce the isolated talonavicular and talonavicular-cuneiform arthrodesis for the stage III and IV Muller-Weiss disease and analyze their clinical outcomes. METHODS: Thirty patients of stage III and IV Muller-Weiss disease were divided into the talonavicular (TN) arthrodesis group and the talonavicular-cuneiform (TNC) arthrodesis group according to the perinavicular osteoarthritis by MRI scans. For the isolated talonavicular arthrodesis group, 16 patients underwent talonavicular arthrodesis with two 4.0 mm hollow headless compression screws. For the TNC arthrodesis group, 14 patients were received the TNC arthrodesis with reverse "V" shape osteotomy and autoallergic iliac bone graft. All patients were followed up at 3, 6, 9, and 12 months, and per 6 months after 1 year, by the AOFAS ankle-midfoot scores, and evaluated by radiographic measurements. RESULTS: All of them were followed up in two groups and all patients were satisfied with their clinical results. At the TN arthrodesis group, the patients' mean was 39.8 months (range, 11-66 months) follow-up. The mean AOFAS ankle and hindfoot scores had improved from 38.3 +/- 5.1 preoperatively to 88.9 +/- 1.9 at the last postoperative assessment. At the TNC arthrodesis group, the mean follow-up was 51.7 months (range, 12-90 months). The mean AOFAS ankle and hindfoot scores were 40.1 +/- 7.9 preoperatively to 90.1 +/- 2.0 at the last postoperative. All of the cases were solid fusion on the radiograph. CONCLUSIONS: According to MRI evaluation, either TN or TNC arthrodesis for stage III or IV Muller-Weiss disease have the good clinical outcomes with solid fusion rate and obvious improvement of the quality of life of patients. PMID- 28583193 TI - A modified multiple branched graft for thoracoabdominal aortic aneurysm repair. AB - BACKGROUND: To reduce some problems of traditional graft, we devise a modified multiple branched graft for repair of Crawford extent II and III thoracoabdominal aortic aneurysm (TAAA). CASE PRESENTATION: We described a modified multiple branched graft for Crawford extent II and III thoracoabdominal aortic aneurysm (TAAA) repair in 8 patients, Which comprised a main graft and three branches, and the third branch was bifurcated into two limbs. CONCLUSIONS: Our initial experience demonstrated that this modified multiple branched graft may make the thoracoabdominal aortic aneurysm(TAAA) repair easier and safer. PMID- 28583191 TI - HIV drug resistance against strand transfer integrase inhibitors. AB - Integrase strand transfer inhibitors (INSTIs) are the newest class of antiretroviral drugs to be approved for treatment and act by inhibiting the essential HIV protein integrase from inserting the viral DNA genome into the host cell's chromatin. Three drugs of this class are currently approved for use in HIV positive individuals: raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG), while cabotegravir (CAB) and bictegravir (BIC) are currently in clinical trials. RAL and EVG have been successful in clinical settings but have relatively low genetic barriers to resistance. Furthermore, they share a high degree of cross-resistance, which necessitated the development of so-called second generation drugs of this class (DTG, CAB, and BIC) that could retain activity against these resistant variants. In vitro selection experiments have been instrumental to the clinical development of INSTIs, however they cannot completely recapitulate the situation in an HIV-positive individual. This review summarizes and compares all the currently available information as it pertains to both in vitro and in vivo selections with all five INSTIs, and the measured fold changes in resistance of resistant variants in in vitro assays. While the selection of resistance substitutions in response to RAL and EVG bears high similarity in patients as compared to laboratory studies, there is less concurrence regarding the "second-generation" drugs of this class. This highlights the unpredictability of HIV resistance to these inhibitors, which is of concern as CAB and BIC proceed in their clinical development. PMID- 28583194 TI - Differences in reported linguistic thermal sensation between Bangla and Japanese speakers. AB - BACKGROUND: Thermal sensation is a fundamental variable used to determine thermal comfort and is most frequently evaluated through the use of subjective reports in the field of environmental physiology. However, there has been little study of the relationship between the semantics of the words used to describe thermal sensation and the climatic background. The present study investigates the linguistic differences in thermal reports from native speakers of Bangla and Japanese. METHODS: A total of 1141 university students (932 in Bangladesh and 209 in Japan) responded to a questionnaire survey consisting of 20 questions. Group differences between Bangladeshi and Japanese respondents were then tested with a chi-square test in a crosstab analysis using SPSS (version 21). RESULTS: For the Bangla-speaking respondents, the closest feeling of thermal comfort was "neutral" (66.6%) followed by "slightly cool" (10.2%), "slightly cold" (6.0%), "slightly hot" (4.1%), and "cold" (3.8%). For the Japanese respondents, the closest feeling of thermal comfort was "cool" (38.3%) followed by "slightly cool" (20.4%), "neutral" (14.6%), "slightly warm" (13.1%), and "warm" (10.7%). Of the Bangladeshi respondents, 37.7% reported that they were sensitive to cold weather and 18.1% reported that they were sensitive to hot weather. Of the Japanese respondents, 20.6% reported that they were sensitive to cold weather and 29.2% reported that they were sensitive to hot weather. Of the Bangladeshi respondents, 51.4% chose "higher than 29 degrees C" as hot weather and 38.7% of the Japanese respondents chose "higher than 32 degrees C" as hot weather. In the case of cold weather, 43.1% of the Bangladeshi respondents selected "lower than 15 degrees C" as cold weather and 53.4% of the Japanese respondents selected "lower than 10 degrees C" as cold weather. CONCLUSIONS: Most of the Bangla-speaking respondents chose "neutral" as the most comfortable temperature, and most of the Japanese respondents chose "cool." Most of the Bangladeshi respondents reported that they were sensitive to "cold temperatures," but most of the Japanese respondents reported that they were sensitive to "hot temperatures." PMID- 28583195 TI - Effects of phosphodiesterase 3A modulation on murine cerebral microhemorrhages. AB - BACKGROUND: Cerebral microbleeds (CMB) are MRI-demonstrable cerebral microhemorrhages (CMH) which commonly coexist with ischemic stroke. This creates a challenging therapeutic milieu, and a strategy that simultaneously protects the vessel wall and provides anti-thrombotic activity is an attractive potential approach. Phosphodiesterase 3A (PDE3A) inhibition is known to provide cerebral vessel wall protection combined with anti-thrombotic effects. As an initial step in the development of a therapy that simultaneously treats CMB and ischemic stroke, we hypothesized that inhibition of the PDE3A pathway is protective against CMH development. METHODS: The effect of PDE3A pathway inhibition was studied in the inflammation-induced and cerebral amyloid angiopathy (CAA) associated mouse models of CMH. The PDE3A pathway was modulated using two approaches: genetic deletion of PDE3A and pharmacological inhibition of PDE3A by cilostazol. The effects of PDE3A pathway modulation on H&E- and Prussian blue (PB)-positive CMH development, BBB function (IgG, claudin-5, and fibrinogen), and neuroinflammation (ICAM-1, Iba-1, and GFAP) were investigated. RESULTS: Robust development of CMH in the inflammation-induced and CAA-associated spontaneous mouse models was observed. Inflammation-induced CMH were associated with markers of BBB dysfunction and inflammation, and CAA-associated spontaneous CMH were associated primarily with markers of neuroinflammation. Genetic deletion of the PDE3A gene did not alter BBB function, microglial activation, or CMH development, but significantly reduced endothelial and astrocyte activation in the inflammation-induced CMH mouse model. In the CAA-associated CMH mouse model, PDE3A modulation via pharmacological inhibition by cilostazol did not alter BBB function, neuroinflammation, or CMH development. CONCLUSIONS: Modulation of the PDE3A pathway, either by genetic deletion or pharmacological inhibition, does not alter CMH development in an inflammation-induced or in a CAA-associated mouse model of CMH. The role of microglial activation and BBB injury in CMH development warrants further investigation. PMID- 28583196 TI - Effects of unilateral real-time biofeedback on propulsive forces during gait. AB - BACKGROUND: In individuals with post-stroke hemiparesis, reduced push-off force generation in the paretic leg negatively impacts walking function. Gait training interventions that increase paretic push-off can improve walking function in individuals with neurologic impairment. During normal locomotion, push-off forces are modulated with variations in gait speed and slope. However, it is unknown whether able-bodied individuals can selectively modulate push-off forces from one leg in response to biofeedback. Here, in a group of young, neurologically unimpaired individuals, we determined the effects of a real-time visual and auditory biofeedback gait training paradigm aimed at unilaterally increasing anteriorly-directed ground reaction force (AGRF) in the targeted leg. METHODS: Ground reaction force data during were collected from 7 able-bodied individuals as they walked at a self-selected pace on a dual-belt treadmill instrumented with force platforms. During 11-min of gait training, study participants were provided real-time AGRF biofeedback encouraging a 20-30% increase in peak AGRF generated by their right (targeted) leg compared to their baseline (pre-training) AGRF. AGRF data were collected before, during, and after the biofeedback training period, as well as during two retention tests performed without biofeedback and after standing breaks. RESULTS: Compared to AGRFs generated during the pre training gait trials, participants demonstrated a significantly greater AGRF in the targeted leg during and immediately after training, indicating that biofeedback training was successful at inducing increased AGRF production in the targeted leg. Additionally, participants continued to demonstrate greater AGRF production in the targeted leg after two standing breaks, showing short-term recall of the gait pattern learned during the biofeedback training. No significant effects of training were observed on the AGRF in the non-targeted limb, showing the specificity of the effects of biofeedback toward the targeted limb. CONCLUSIONS: These results demonstrate the short-term effects of using unilateral AGRF biofeedback to target propulsion in a specific leg, which may have utility as a training tool for individuals with gait deficits such as post stroke hemiparesis. Future studies are needed to investigate the effects of real time AGRF biofeedback as a gait training tool in neurologically-impaired individuals. PMID- 28583197 TI - No evidence of Borrelia mayonii in an endemic area for Lyme borreliosis in France. AB - BACKGROUND: Borrelia mayonii is currently the latest species belonging to the Borrelia burgdorferi (sensu lato) complex to be discovered. Interestingly it is involved in human pathology causing a high fever. We looked for its presence in post- tick bite febrile patients as well as in Ixodes ricinus ticks in an endemic area of France. RESULTS: After ensuring that our molecular technics correctly detected B. mayonii, 575 patients and 3,122 Ixodes ricinus nymphs were tested. Neither B. mayonii nor another species of the B. burgdorferi (s.l.) complex previously not reported in Europe has been identified. CONCLUSIONS: For now, B. mayonii seems to be an epiphenomenon. However, its discovery broadens the etiology of post-Ixodes bite febrile syndromes. PMID- 28583198 TI - A brief review: adipose-derived stem cells and their therapeutic potential in cardiovascular diseases. AB - Adipose-derived stem cells (ADSCs) are easily obtained and expanded, and have emerged as a novel source of adult stem cells for the treatment of cardiovascular diseases. These cells have been shown to have the capability of differentiating into cardiomyocytes, vascular smooth muscle cells, and endothelial cells. Furthermore, ADSCs secrete a series of paracrine factors to promote neovascularization, reduce apoptosis, and inhibit fibrosis, which contributes to cardiac regeneration. As a novel therapy in the regenerative field, ADSCs still face various limitations, such as low survival and engraftment. Thus, engineering and pharmacological studies have been conducted to solve these problems. Investigations have moved into phase I and II clinical trials examining the safety and efficacy of ADSCs in the setting of myocardial infarction. In this review, we discuss the differentiation and paracrine functions of ADSCs, the strategies promoting their therapeutic efficacy, and their clinical usage. PMID- 28583199 TI - Role of mesenchymal stem cells, their derived factors, and extracellular vesicles in liver failure. AB - Liver failure is a severe clinical syndrome with a poor prognosis. Mesenchymal stem cell (MSC) transplantation has emerged as a new intervention in treating liver failure. It is conventionally recognized that MSCs exert their therapeutic effect mainly through transdifferentiation. Recently, published articles have shown that MSCs work in liver failure by secreting trophic and immunomodulatory factors as well as extracellular vesicles (EVs) before transdifferentiation. In particular,MSC-derived EVs have shown similar curative effects as MSCs. Here we review the role of MSCs as well as their derived factors and EVs in liver failure and discuss the use of MSC-derived EVs instead of intact MSCs in treating liver failure. PMID- 28583201 TI - Molecular signatures of neutrophil extracellular traps in human visceral leishmaniasis. AB - BACKGROUND: Infections with parasites of the Leishmania donovani complex result in clinical outcomes that range from asymptomatic infection to severe and fatal visceral leishmaniasis (VL). Neutrophils are major players of the immune response against Leishmania, but their contribution to distinct states of infection is unknown. Gene expression data suggest the activation of the NETosis pathway during human visceral leishmaniasis. Thus, we conducted an exploratory study to evaluate NET-related molecules in retrospective sera from VL patients, asymptomatic individuals and uninfected endemic controls. RESULTS: We demonstrate that VL patients and asymptomatic individuals exhibit differential regulation of molecules associated with neutrophil extracellular traps (NET). These differences were observed at the transcriptional level of genes encoding NET-associated proteins; in quantifications of cell free DNA and metalloproteinase 9; and in enzymatic activity of DNAse and elastase. Moreover, multivariate analysis resulted in class-specific signatures, and ROC curves demonstrate the ability of these molecules in discriminating asymptomatic infection from uninfected controls. CONCLUSION: Molecules that are associated with NETs are differentially regulated between distinct states of infection with L. infantum, suggesting that NETs might have distinct roles depending on the clinical status of infection. Although unlikely to be exclusive for VL, these signatures can be useful to better characterize asymptomatic infections in endemic regions of this disease. PMID- 28583200 TI - High quality clinical grade human embryonic stem cell lines derived from fresh discarded embryos. AB - BACKGROUND: Human embryonic stem cells (hESCs) hold tremendous promise for cell replacement therapies for a range of degenerative diseases. In order to provide cost-effective treatments affordable by public health systems, HLA-matched allogeneic tissue banks of the highest quality clinical-grade hESCs will be required. However only a small number of existing hESC lines are suitable for clinical use; they are limited by moral and ethical concerns and none of them apply Good Manufacturing Practice (GMP) standards to the earliest and critical stages of gamete and embryo procurement. We thus aimed to derive new clinical grade hESC lines of highest quality from fresh surplus GMP grade human embryos. METHODS: A comprehensive screen was performed for suitable combinations of culture media with supporting feeder cells or feeder-free matrix, at different stages, to support expansion of the inner cell mass and to establish new hESC lines. RESULTS: We developed a novel two-step and sequential media system of clinical-grade hESC derivation and successfully generated seven new hESC lines of widely varying HLA type, carefully screened for genetic health, from human embryos donated under the highest ethical and moral standards under an integrated GMP system which extends from hESC banking all the way back to gamete and embryo procurement. CONCLUSIONS: The present study, for the first time, reports the successful derivation of highest-quality clinical-grade hESC lines from fresh poor-quality surplus human embryos generated in a GMP-grade IVF laboratory. The availability of hESC lines of this status represents an important step towards more widespread application of regenerative medicine therapies. PMID- 28583202 TI - Systematic review with meta-analysis: the efficacy and safety of stem cell therapy for Crohn's disease. AB - BACKGROUND AND AIMS: Stem cell therapy (SCT) for the treatment of Crohn's disease (CD) is still in its infancy, and whether SCT is associated with improved outcomes is unclear. We performed a meta-analysis to evaluate the efficacy and safety of patients receiving SCT. METHODS: Electronic databases were searched for studies that reported the use of stem cells for the treatment of patients with CD. Raw data from included studies were pooled for effect estimates. Subgroup analyses were performed for exploration of heterogeneity regarding all outcomes. RESULTS: We analyzed 21 studies comprising 514 patients with active CD. A random effects meta-analysis of studies of SCT as systemic infusion showed 56% (95% confidence interval (CI) 33-76, n = 150) of patients achieved clinical response. Similarly, random-effects pooled rates of clinical or endoscopic remission were 46% (95% CI 25-69, n = 116) and 15% (95% CI 0-50, n = 48), respectively. A random effects meta-analysis of all perianal CD studies showed that 57% (95% CI 44-69%, n = 251) of patients had healed fistula with SCT, with an odds ratio of 3.83 (95% CI 1.06-13.86, n = 121, P = 0.04) versus control. The pooled rate of clinical recurrence was high at 16% (95% CI 4-34, n = 101) with follow-up >12 months. The pooled rates of severe adverse events (SAEs) and SAEs related to SCT were 12% (95% CI 6-23, n = 378) and 8% (95% CI 3-18, n = 378), respectively. The Egger test suggests no publication bias existed for fistula healing (P = 0.36), but did for clinical response (P = 0.003). CONCLUSIONS: SCT seems potentially effective and may serve as an alternative treatment for refractory active CD. Toxicity will remain the most significant barrier to systemic SCT in patients with CD. PMID- 28583203 TI - Factors associated with mothers' knowledge on infant and young child feeding recommendation in slum areas of Bahir Dar City, Ethiopia: cross sectional study. AB - BACKGROUND: Malnutrition is a public health concern in Ethiopia. This might be correlated with inappropriate infant and young child feeding practice. This in turn is affected by Mothers' knowledge on feeding practice. However, information on mothers' knowledge on infant and young child feeding recommendation was scarce in Ethiopia. Therefore, this study was designed to assess mothers' knowledge on infant and young child feeding recommendation and associated factors in slum areas of Bahir Dar City, Ethiopia. METHODS: A community based cross-sectional study was conducted from May 1-26/2015. Systematic sampling technique was used to select respondents. Data were collected by pretested, structured, interviewer administered questionnaire. Data were entered and analyzed by SPSS version 20 software. Knowledge score was computed. Binary and multivariable logistic regression analysis were used to identify factors associated with maternal knowledge. RESULTS: Only 28.7% of mothers had sufficient knowledge on infant and young child feeding recommendation. Factors associated with mothers, knowledge were above primary education [AOR 2.5, 95% CI (1.5, 3.9)], possession of radio [AOR 1.7, 95% CI (1.1, 2.7)], attending antenatal care [AOR 2.4, 95% CI (1.5, 4.0)], and having employed husband [AOR 2.3, 95% CI (1.2, 4.4)]. CONCLUSION: Mothers' knowledge on infant and young child feeding recommendation was very low. Hence, education on infant and young child feeding recommendation should be strengthened during antenatal care visit and using mass media especially for mothers with lower educational status to fill up of this gap. PMID- 28583204 TI - Building a semantic web-based metadata repository for facilitating detailed clinical modeling in cancer genome studies. AB - BACKGROUND: Detailed Clinical Models (DCMs) have been regarded as the basis for retaining computable meaning when data are exchanged between heterogeneous computer systems. To better support clinical cancer data capturing and reporting, there is an emerging need to develop informatics solutions for standards-based clinical models in cancer study domains. The objective of the study is to develop and evaluate a cancer genome study metadata management system that serves as a key infrastructure in supporting clinical information modeling in cancer genome study domains. METHODS: We leveraged a Semantic Web-based metadata repository enhanced with both ISO11179 metadata standard and Clinical Information Modeling Initiative (CIMI) Reference Model. We used the common data elements (CDEs) defined in The Cancer Genome Atlas (TCGA) data dictionary, and extracted the metadata of the CDEs using the NCI Cancer Data Standards Repository (caDSR) CDE dataset rendered in the Resource Description Framework (RDF). The ITEM/ITEM_GROUP pattern defined in the latest CIMI Reference Model is used to represent reusable model elements (mini-Archetypes). RESULTS: We produced a metadata repository with 38 clinical cancer genome study domains, comprising a rich collection of mini Archetype pattern instances. We performed a case study of the domain "clinical pharmaceutical" in the TCGA data dictionary and demonstrated enriched data elements in the metadata repository are very useful in support of building detailed clinical models. CONCLUSION: Our informatics approach leveraging Semantic Web technologies provides an effective way to build a CIMI-compliant metadata repository that would facilitate the detailed clinical modeling to support use cases beyond TCGA in clinical cancer study domains. PMID- 28583205 TI - Human liver mesenchymal stem/progenitor cells inhibit hepatic stellate cell activation: in vitro and in vivo evaluation. AB - BACKGROUND: Progressive liver fibrosis leads to cirrhosis and end-stage liver disease. This disease is a consequence of strong interactions between matrix producing hepatic stellate cells (HSCs) and resident and infiltrating immune cell populations. Accumulated experimental evidence supports the involvement of adult derived human liver mesenchymal stem/progenitor cells (ADHLSCs) in liver regeneration. The aim of the present study was to evaluate the influence of ADHLSCs on HSCs, both in vitro and in vivo. METHODS: Activated human HSCs were co cultured with ADHLSCs or ADHLSC-conditioned culture medium. The characteristics of the activated human HSCs were assessed by microscopy and biochemical assays, whereas proliferation was analyzed using flow cytometry and immunocytochemistry. The secretion profile of activated HSCs was evaluated by ELISA and Luminex. ADHLSCs were transplanted into a juvenile rat model of fibrosis established after co-administration of phenobarbital and CCl4. RESULTS: When co-cultured with ADHLSCs or conditioned medium, the proliferation of HSCs was inhibited, beginning at 24 h and for up to 7 days. The HSCs were blocked in G0/G1 phase, and showed decreased Ki-67 positivity. Pro-collagen I production was reduced, while secretion of HGF, IL-6, MMP1, and MMP2 was enhanced. Neutralization of HGF partially blocked the inhibitory effect of ADHLSCs on the proliferation and secretion profile of HSCs. Repeated intrahepatic transplantation of cryopreserved/thawed ADHLSCs without immunosuppression inhibited the expression of markers of liver fibrosis in 6 out of 11 rats, as compared to their expression in the vehicle-transplanted group. CONCLUSIONS: These data provide evidence for a direct inhibitory effect of ADHLSCs on activated HSCs, which supports their development for the treatment of liver fibrosis. PMID- 28583206 TI - Iron availability affects West Nile virus infection in its mosquito vector. AB - BACKGROUND: Mosquitoes are responsible for transmission of viruses, including dengue, West Nile and chikungunya viruses. Female mosquitoes are infected when they blood-feed on vertebrates, a required step for oogenesis. During this process, mosquitoes encounter high iron loads. Since iron is an essential nutrient for most organisms, including pathogens, one of the defense mechanisms for the host includes sequestration of iron away from the invading pathogen. Here, we determine whether iron availability affects viral replication in mosquitoes. METHODS: To elucidate effect of iron availability on mosquito cells during infection, Culex cells were treated with either ferric ammonium citrate (FAC) or the iron chelator, deferoxamine (DFX). Real time RT-PCR was performed using ferritin (heavy chain) and NRAMP as a measure of iron homeostasis in cells. To determine iron requirement for viral replication, Culex cells were knocked down for NRAMP using dsRNA. Finally, the results were validated in Culex mosquito infection model, by treating infected mosquitoes with DFX to reduce iron levels. RESULTS: Our results show that infection of Culex cells led to induction in levels of ferritin (heavy chain) and NRAMP mRNAs in time-dependent manner. Results also showed that treatment of cells with FAC, reduced expression of NRAMP (iron transporter) and increase levels of ferritin (heavy chain). Interestingly, increasing iron levels increased viral titers; while reducing intracellular iron levels, either by NRAMP knock-down or using DFX, reduced viral titers. The results from Culex mosquito infection showed that mosquitoes treated with DFX had reduced viral titers compared with untreated controls in midgut as well as carcass 8 days pi. Saliva from mosquitoes treated with DFX also showed reduced viral titers compared with untreated controls, indicating low viral transmission capacity. CONCLUSIONS: Our results indicate that iron is required for viral replication in mosquito cells. Mosquitoes respond to viral infection, by inducing expression of heavy chain ferritin, which sequesters available iron, reducing its availability to virus infected cells. The data indicates that heavy chain ferritin may be part of an immune mechanism of mosquitoes in response to viral infections. PMID- 28583207 TI - Knockdown resistance (kdr) of the voltage-gated sodium channel gene of Aedes aegypti population in Denpasar, Bali, Indonesia. AB - BACKGROUND: Aedes aegypti is the main vector of several arthropod-borne viral infections in the tropics profoundly affecting humans, such as dengue fever (DF), West Nile (WN), chikungunya and more recently Zika. Eradication of Aedes still largely depends on insecticides, which is the most cost-effective strategy, and often inefficient due to resistance development in exposed Aedes populations. We here conducted a study of Ae. aegypti resistance towards several insecticides regularly used in the city of Denpasar, Bali, Indonesia. METHODS: Aedes aegypti egg samples were collected with ovitraps and thereafter hatched in the insectary of the Gadjah Mada University. The F0 generation was used for all bioassay related experiments and knockdown resistance (kdr) assays. RESULTS: Results clearly showed resistance development of Ae. aegypti against tested insecticides. Mortalities of Ae. aegypti were less than 90% with highest resistance observed against 0.75% permethrin. Mosquitoes from the southern parts of Denpasar presented high level of resistance pattern in comparison to those from the western and northern parts of Denpasar. Kdr analysis of voltage-gated sodium channel (Vgsc) gene showed significant association to S989P and V1016G mutations linked to resistance phenotypes against 0.75% permethrin. Conversely, Ae. aegypti F1534C gene mutation did not result in any significant correlation to resistance development. CONCLUSIONS: Periodically surveillance of insecticide resistances in Ae. aegypti mosquitoes will help local public health authorities to set better goals and allow proper evaluation of on-going mosquito control strategies. Initial detection of insecticide resistance will contribute to conduct proper actions in delaying mosquito resistance development such as insecticide rotation or combination of compounds in order to prolong chemical efficacy in combating Ae. aegypti vectors in Indonesia. PMID- 28583210 TI - Long-read sequencing improves assembly of Trichinella genomes 10-fold, revealing substantial synteny between lineages diverged over 7 million years. AB - Genome assemblies can form the basis of comparative analyses fostering insight into the evolutionary genetics of a parasite's pathogenicity, host-pathogen interactions, environmental constraints and invasion biology; however, the length and complexity of many parasite genomes has hampered the development of well resolved assemblies. In order to improve Trichinella genome assemblies, the genome of the sylvatic encapsulated species Trichinella murrelli was sequenced using third-generation, long-read technology and, using syntenic comparisons, scaffolded to a reference genome assembly of Trichinella spiralis, markedly improving both. A high-quality draft assembly for T. murrelli was achieved that totalled 63.2 Mbp, half of which was condensed into 26 contigs each longer than 571 000 bp. When compared with previous assemblies for parasites in the genus, ours required 10-fold fewer contigs, which were five times longer, on average. Better assembly across repetitive regions also enabled resolution of 8 Mbp of previously indeterminate sequence. Furthermore, syntenic comparisons identified widespread scaffold misassemblies in the T. spiralis reference genome. The two new assemblies, organized for the first time into three chromosomal scaffolds, will be valuable resources for future studies linking phenotypic traits within each species to their underlying genetic bases. PMID- 28583209 TI - Fine mapping by composite genome-wide association analysis. AB - Genome-wide association (GWA) studies play a key role in current genetics research, unravelling genomic regions linked to phenotypic traits of interest in multiple species. Nevertheless, the extent of linkage disequilibrium (LD) may provide confounding results when significant genetic markers span along several contiguous cM. In this study, we have adapted the composite interval mapping approach to the GWA framework (composite GWA), in order to evaluate the impact of including competing (possibly linked) genetic markers when testing for the additive allelic effect inherent to a given genetic marker. We tested model performance on simulated data sets under different scenarios (i.e., qualitative trait loci effects, LD between genetic markers and width of the genomic region involved in the analysis). Our results showed that the genomic region had a small impact on the number of competing single nucleotide polymorphisms (SNPs) as well as on the precision of the composite GWA analysis. A similar conclusion was derived from the preferable range of LD between the tested SNP and competing SNPs, although moderate-to-high LD seemed to attenuate the loss of statistical power. The composite GWA improved specificity and reduced the number of significant genetic markers. The composite GWA model contributes a novel point of view for GWA analyses where testing circumscribed to the genomic region flanking each SNP (delimited by the nearest competing SNPs) and conditioning on linked markers increases the precision to locate causal mutations, but possibly at the expense of power. PMID- 28583208 TI - miR199a-3p regulates P53 by targeting CABLES1 in mouse cardiac c-kit+ cells to promote proliferation and inhibit apoptosis through a negative feedback loop. AB - BACKGROUND: MicroRNAs (miRNAs) have emerged as crucial factors that regulate proliferation and apoptosis of cardiac c-kit+ cells. Although much is known about their role in maintaining cardiac c-kit+ cell pluripotency, the mechanisms by which they affect cell fate decisions that are an essential part of the repair of heart failure remain poorly understood. METHODS: Cardiac c-kit+ cells were obtained from Balb/c mice and cultured in vitro. Lentiviral vectors of miR199a 3p, its corresponding anti-miRNA, or short hairpin RNA against Cables1 were transfected into cells. The proliferation of cardiac c-kit+ cells was evaluated using EdU and flow cytometry. Furthermore, we examined cell apoptosis by flow cytometry under treatment with 200nM angiotensin II for 48 h. The levels of miR199a-3p and Cables1 mRNA were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was performed to examine the expression of Cables1 and P53 proteins. RESULTS: We demonstrated a significantly decreased expression of miR199a-3p in heart failure samples compared with healthy donors. Meanwhile, we identified miR199a-3p as a proliferation- and apoptosis-associated regulator impacted through Cdk5 and Abl enzyme substrate 1 (CABLES1) targeting, and also attributed their repression to P53 protein expression. We further demonstrated that P53 induced miR199a-3p expression and, in turn, miR199-3p decreased P53 activity. CONCLUSION: Collectively, our findings uncover one new mechanism by which P53 induced miR199a-3p expression and, in turn, miR199-3p decreased P53 activity. Therefore, miR199a-3p and P53 are coupled through CABLES1 and comprise a novel negative feedback loop that likely contributes to cardiac c kit+ cell proliferation and apoptosis. PMID- 28583211 TI - Parenting a child at home with hypoplastic left heart syndrome: experiences of commitment, of stress, and of love. AB - OBJECTIVE: To evaluate the experiences of parenting a child with hypoplastic left heart syndrome after the child has been discharged home from hospital. DESIGN: A study of the parents' experiences using face-to-face interviews and psychometric measures with parents whose child had survived stage surgery. SETTING: Parents were interviewed within the home environment or within the hospital if that was their choice. SUBJECTS: A total of 29 parents (16 mothers and 13 fathers) of surviving children. Intervention A semi-structured face-to-face interview plus psychometric tests (parent demographics, Maslach Burnout Inventory, Impact on Family Scale, and the Psychological Check List - Civilian). Measurements and main results The parents' experience in supporting a child with hypoplastic left heart syndrome is one of stress, of commitment, and of love. Although parents experienced joy in their child, they were also subjected to anxiety with four parents test positive to post-traumatic stress disorder and hypervigilance while monitoring their child's condition. Parents lived with many difficulties, and demands. PMID- 28583212 TI - Lineage-specific expansion and loss of tyrosinase genes across platyhelminths and their induction profiles in the carcinogenic oriental liver fluke, Clonorchis sinensis. AB - Tyrosinase provides an essential activity during egg production in diverse platyhelminths by mediating sclerotization of eggshells. In this study, we investigated the genomic and evolutionary features of tyrosinases in parasitic platyhelminths whose genomic information is available. A pair of paralogous tyrosinases was detected in most trematodes, whereas they were lost in cyclophyllidean cestodes. A pseudophyllidean cestode displaying egg biology similar to that of trematodes possessed an orthologous gene. Interestingly, one of the paralogous tyrosinases appeared to have been multiplied into three copies in Clonorchis sinensis and Opisthorchis viverrini. In addition, a fifth tyrosinase gene that was minimally transcribed through all developmental stages was further detected in these opisthorchiid genomes. Phylogenetic analyses demonstrated that the tyrosinase gene has undergone duplication at least three times in platyhelminths. The additional opisthorchiid gene arose from the first duplication. A paralogous copy generated from these gene duplications, except for the last one, seemed to be lost in the major neodermatans lineages. In C. sinensis, tyrosinase gene expressions were initiated following sexual maturation and the levels were significantly enhanced by the presence of O2 and bile. Taken together, our data suggest that tyrosinase has evolved lineage-specifically across platyhelminths related to its copy number and induction mechanism. PMID- 28583213 TI - Childhood abuse and neglect and insecure attachment states of mind in adulthood: Prospective, longitudinal evidence from a high-risk sample-CORRIGENDUM. PMID- 28583214 TI - Trichomonas tenax and periodontal diseases: a concise review. AB - Periodontal diseases (gingivitis and periodontitis), result from a disruption of the host-oral microbiome homoeostasis. Whereas the pathological role of some specific bacterial strains during periodontal diseases is well documented, the impact of parasites in periodontium pathophysiology is still under debate. This review aims to collect data about the prevalence and the potential role of Trichomonas tenax during periodontal diseases. Data from 47 studies revealed that T. tenax prevalence in diseased periodontium ranged from 0 to 94.1%. The prevalence of oral protozoan infections was found to be largely greater in patients with periodontal diseases than with healthy periodontium. The parasite detection was mainly performed by direct microscopy. Trichomonas tenax presence was clearly correlated with periodontal disease. The high heterogeneity of its periodontal prevalence may be correlated with the diversity of the population screened (age, sex, systemic diseases), and the methods used for diagnosis. This protozoan seems to have the capacity to be involved in the inflammatory process of gum disease. Animal experimentation, using relevant physiopathological models of periodontitis, needs to be performed to investigate the ability of T. tenax to cause and/or worsen the disease. Further investigations using standardized experimental designs of epidemiologic studies are also needed. PMID- 28583215 TI - Waist circumference as a predictor of mortality in peritoneal dialysis patients: a follow-up study of 48 months. AB - Body-fat gain is a common finding among peritoneal dialysis (PD) patients, and the accumulation of adipose tissue occurs predominantly in the abdominal area. Waist circumference (WC) is a reliable marker of abdominal obesity and its association with worse outcomes has been demonstrated in non-dialysis and haemodialysis patients. We aimed at investigating whether WC measurements as well as the changes over time in WC were able to predict mortality in PD patients. This prospective study included 109 patients undergoing PD (57 % male, age 52 (sd 16) years, 32 % diabetics, 48 % BMI>=25 kg/m2). WC was measured at the umbilicus level (empty abdominal cavity), and values >88 cm for women and >102 cm for men were considered high. Nutritional status and laboratory parameters were also evaluated. WC was measured at baseline and after 6 months, and mortality was registered during a period of 48 months. High WC was observed in 55 % of women and in 23 % of men at baseline. After 6 months, 61 % of the patients showed an increased WC. At the end of the study, twenty-seven deaths were registered. A significant increase in WC was observed only in the non-survivor group. In the Cox regression analysis adjusting for sex, age, duration on dialysis, diabetes, BMI, serum albumin and C-reactive protein, high WC at baseline as well as the 6 month increase in WC were independently associated with mortality. This study demonstrated that a high WC and the increase over time in WC were both predictors of mortality in PD patients. PMID- 28583217 TI - Denis Burkitt and the origins of the dietary fibre hypothesis. AB - For more than 200 years the fibre in plant foods has been known by animal nutritionists to have significant effects on digestion. Its role in human nutrition began to be investigated towards the end of the 19th century. However, between 1966 and 1972, Denis Burkitt, a surgeon who had recently returned from Africa, brought together ideas from a range of disciplines together with observations from his own experience to propose a radical view of the role of fibre in human health. Burkitt came late to the fibre story but built on the work of three physicians (Peter Cleave, G. D. Campbell and Hugh Trowell), a surgeon (Neil Painter) and a biochemist (Alec Walker) to propose that diets low in fibre increase the risk of CHD, obesity, diabetes, dental caries, various vascular disorders and large bowel conditions such as cancer, appendicitis and diverticulosis. Simply grouping these diseases together as having a common cause was groundbreaking. Proposing fibre as the key stimulated much research but also controversy. Credit for the dietary fibre hypothesis is given largely to Burkitt who became known as the 'Fibre Man'. This paper sets out the story of the development of the fibre hypothesis, and the contribution to it of these individuals. PMID- 28583218 TI - Demodex canis regulates cholinergic system mediated immunosuppressive pathways in canine demodicosis. AB - Demodex canis infestation in dogs remains one of the main challenges in veterinary dermatology. The exact pathogenesis of canine demodicosis is unknown but an aberration in immune status is considered very significant. No studies have underpinned the nexus between induction of demodicosis and neural immunosuppressive pathways so far. We have evaluated the involvement of cholinergic pathways in association with cytokines regulation as an insight into the immuno-pathogenesis of canine demodicosis in the present study. Remarkable elevations in circulatory immunosuppressive cytokine interleukin-10 and cholinesterase activity were observed in dogs with demodicosis. Simultaneously, remarkable reduction in circulatory pro-inflammatory cytokine tumour necrosis factor-alpha level was observed in dogs with demodicosis. Findings of the present study evidently suggest that Demodex mites might be affecting the cholinergic pathways to induce immunosuppression in their host and then proliferate incessantly in skin microenvironment to cause demodicosis. PMID- 28583219 TI - Amblyomma birmitum a new species of hard tick in Burmese amber. AB - Amblyomma birmitum sp. nov. is formally described as a new record from 99 Ma old Burmese amber from Myanmar. This confirms the presence of the extant hard tick genus Amblyomma C.L. Koch, 1844 (Ixodida: Ixodidae) in the Late Cretaceous. This discovery is placed in its wider context and some reports of fossil hard ticks, such as a Hyalomma C.L. Koch, 1844 in Eocene Baltic amber, are misidentifications. The genus Amblyomma belongs to the clade Metastriata, a group which probably also accommodates two extinct genera, Cornupalpatum Poinar and Brown, 2003 and Compluriscutata Poinar and Buckley, 2008, also found in Burmese amber. All three fossils are thus only a little younger than published molecular divergence time estimates (ca. 124 +/- 17 Ma) for the Metastriata lineage. Amblyomma has a largely Gondwanan distribution today. However, in some biogeographical scenarios, e.g. the Samafrica model, its predicted radiation time postdates the dissolution of the original Gondwana supercontinent raising questions about how its current distribution pattern was achieved. PMID- 28583216 TI - The role of rare innate immune cells in Type 2 immune activation against parasitic helminths. AB - The complexity of helminth macroparasites is reflected in the intricate network of host cell types that participate in the Type 2 immune response needed to battle these organisms. In this context, adaptive T helper 2 cells and the Type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have been the focus of research for years, but recent work has demonstrated that the innate immune system plays an essential role. Some innate immune cells that promote Type 2 immunity are relatively abundant, such as macrophages and eosinophils. However, we now appreciate that more rare cell types including group 2 innate lymphoid cells, basophils, mast cells and dendritic cells make significant contributions to these responses. These cells are found at low frequency but they are specialized to their roles - located at sites such as the skin, lung and gut, where the host combats helminth parasites. These cells respond rapidly and robustly to worm antigens and worm-induced damage to produce essential cytokines, chemokines, eicosanoids and histamine to activate damaged epithelium and to recruit other effectors. Thus, a greater understanding of how these cells operate is essential to understand how the host protects itself during helminth infection. PMID- 28583220 TI - Expression and localization of tubulin cofactors TBCD and TBCE in human gametes. AB - The tubulin cofactors TBCD and TBCE play an essential role in regulation of the microtubule dynamics in a wide variety of somatic cells, but little information is known about the expression of these cofactors in human sperm and oocytes. In this study, we focused on the investigation of the presence of, and the differential distribution of, the tubulin cofactors TBCD and TBCE in human sperm and during human oocyte maturation. We performed expression assays for TBCD and TBCE by reverse transcription-polymerase chain reaction (RT-PCR), western blot and immunofluorescence and verified the presence of both cofactors in human gametes. TBCD and TBCE were located mainly in the middle region and in the tail of the sperm while in the oocyte the localization was cytosolic. The mRNA of both tubulin cofactors were present in the human oocytes but not in sperm cells. This finding gives a first insight into where TBCD and TBCE could carry out their function in the continuous changes that the cytoskeleton experiences during gametogenesis and also prior to fertilization. PMID- 28583221 TI - Impact of dysfunctional maternal personality traits on risk of offspring depression, anxiety and self-harm at age 18 years: a population-based longitudinal study. AB - BACKGROUND: The impact of underlying parental psychological vulnerability on the future mental health of offspring is not fully understood. Using a prospective cohort design, we investigated the association between dysfunctional parental personality traits and risks of offspring self-harm, depression and anxiety. METHODS: The association between dysfunctional parental personality traits (monotony avoidance, impulsivity, anger, suspicion, and detachment), measured in both mothers and fathers when offspring were age 9 years, and risk of offspring depression, anxiety and self-harm at age 18 years, was investigated in a population-based cohort (ALSPAC) from over 8000 parents and children. RESULTS: Higher levels of dysfunctional maternal, but not paternal, personality traits were associated with an increased risk of self-harm, depression, and anxiety in offspring. Maternal associations were best explained by the accumulation of dysfunctional traits. Associations were strongest for offspring depression: Offspring of mothers with three or more dysfunctional personality traits were 2.27 (1.45-3.54, p < 0.001) times as likely to be depressed, compared with offspring of mothers with no dysfunctional personality traits, independently of maternal depression and other variables. CONCLUSIONS: The accumulation of dysfunctional maternal personality traits is associated with the risk of self harm, depression, anxiety in offspring independently of maternal depression and other confounding variables. The absence of associations for equivalent paternal traits makes a genetic explanation for the findings unlikely. Further research is required to elucidate the underlying mechanism. Mothers with high levels of dysfunctional personality traits may benefit from additional support to reduce the risk of adverse psychological outcomes occurring in their offspring. PMID- 28583222 TI - Maternal perception of child overweight status and its association with weight related parenting practices, their children's health behaviours and weight change in China. AB - OBJECTIVE: Childhood obesity has increased rapidly in China, but understanding is limited on how parents perceive their child's weight status and how this perception affects weight-related parenting practices. We examined maternal perception of her child's weight status and its association with demographics, subsequent weight-related parenting practices, the child's health behaviours and weight change. Design/Setting/Subjects Maternal perception of child's weight status and health behaviours from the China Health and Nutrition Surveys were assessed at baseline and in follow-up surveys for 816 children aged 6-18 years during 2004-2011. Associations were tested using mixed models. RESULTS: Overall, maternal and child perceptions of the child's weight status were fairly consistent (kappa w=0.56), 63.8 % of mothers had correct perception. While 9.6 % of mothers perceived their child as overweight, 10.9 % of children did so, and 13.6 % of children were indeed overweight. Compared with mothers who viewed their children as normal weight, mothers who thought their children were overweight were more likely to encourage their children to increase their physical activity (OR; 95 % CI: 1.8; 1.0, 3.3) and to diet (4.3; 2.3, 7.8). Children perceived as overweight by their mothers were more likely to have insufficient physical activity (2.8; 1.6, 4.7) and gain more weight during follow-up (BMI Z-score, beta (se): 1.0 (0.1); P<0.01) than children perceived by their mothers as normal weight. CONCLUSIONS: In China, mothers who perceive their child as overweight are more likely to encourage their child to exercise and modify their diet for weight management, but this encouragement does not seem to improve the child's health behaviours and weight status. PMID- 28583223 TI - ASSESSMENT OF UNIVERSAL NEWBORN HEARING SCREENING AND INTERVENTION IN SHANGHAI, CHINA. AB - OBJECTIVES: The aim of this study was to evaluate the universal newborn hearing screening (UNHS) and intervention program in Shanghai, China. METHODS: This study included the quantitative analyses of the UNHS-Shanghai database in 2002-12 and qualitative assessment of the program. The Otoacoustic Emissions and the Automated Auditory Brainstem Evoked Responses tests were conducted in screening. The costs and benefits were calculated based on the number of participants in each stage. The short-term and long-term periods were defined as from birth to 15 years of age or to death (82-year-olds), respectively. Sensitivity analyses were conducted. RESULTS: A total 1,574,380 newborns were included, representing 93.6 percent of all eligible babies in Shanghai during the study period. The prevalence of newborn hearing loss was 1.660/00. The short-term/long-term program costs were Y488.5 million (US$75.52 million)/Y1.08 billion (US$167.12 million), and the short-term/long-term program benefit was Y980.1 million (US$151.53 million)/Y8.13 billion (US$1.26 billion). The program benefit was greater than its cost if the proportion of hearing-loss children enrolled in regular schools was no less than 41.4 percent of all hearing impaired children, as well as if the wage growth rate ranged from 3 percent to 8 percent. Qualitative results also suggested that stakeholders strongly supported this program. CONCLUSIONS: The universal newborn hearing screening and intervention program in Shanghai is justified in terms of the resource input in the long run, although there is still room for further improvement with respect to educational rehabilitation and a better infrastructure system. PMID- 28583225 TI - The two-hit hypothesis and paraganglioma of the head and neck. PMID- 28583224 TI - Anti-parasitic effect of the diuretic and Na+-ATPAse inhibitor furosemide in cutaneous leishmaniasis. AB - Leishmania amazonensis promastigotes are known to express furosemide (Lasix(r)) sensitive P-type membrane Na+-ATPase. In the present study, furosemide activity was studied in intracellular amastigotes and infected BALB/c mice to investigate its efficacy in cutaneous leishmaniasis (CL). Intracellular parasites, but not macrophages, were found to be sensitive to killing by furosemide (IC50 = 87 u m vs CC50 ? 1000 u m, respectively). Although furosemide did not induce nitric oxide production or intracellular pH changes in infected macrophages, it led to a significant reactive oxygen species (ROS) burst. Freshly isolated tissue parasites expressed a high degree of Na+-ATPase activity that decreased with culture, indicative of a higher enzyme expression in amastigotes than in promastigotes. Both intraperitoneal and oral treatment of L. amazonensis-infected mice with furosemide dosages equivalent to that prescribed as a diuretic significantly reduced the parasite's growth compared with the situation in untreated mice. Combination with oral furosemide increased the efficacy and safety of intraperitoneal treatment with sodium stibogluconate (SSG). To summarize, furosemide control of intracellular leishmanial growth by means of parasite Na+-ATPase inhibition, and macrophage ROS activation may help explain its sole and SSG-combined therapeutic effect against murine CL. PMID- 28583227 TI - Differential diagnosis and proper treatment of acute rhinosinusitis: Guidance based on historical data analysis. AB - BACKGROUND: The time course of rhinovirus positive and negative rhinosinusitis has not been quantified yet, which aggravates proper selection and justification of the optimum treatment for this illness. Such quantitative information would facilitate an early and proper identification of the disease and its differentiation from acute bacterial rhinosinusitis, and could diminish harmful overuse of antibiotics, arguably driven by patients' want for attention and the treating physicians' inability to offer an adequate verbal comfort in its stead. OBJECTIVE: Extraction of the quantitative information needed to identify rhinovirus positive or negative rhinosinusitis and to allow selection of the most appropriate treatment from the published time dependence of individual clinical symptoms of the disease. METHODS: Scrutiny (and modeling) of temporal evolution of all noteworthy symptoms of rhinosinusitis with a simple mathematical expression that relies on two adjustable parameters per symptom (and potentially a general time offset as an extra adjustable parameter). RESULTS: Adverse effects of rhinosinusitis can be grouped according to the sequence of their exponential appearance and ~2.6 times slower exponential disappearance, rhinovirus negative rhinosinusitis generally improving ~25% faster and being ~40% less severe. The major early local symptoms (throat soreness and scratchiness, headache) vanish with a half-life of ~1.8 days, whereas further local symptoms take ~1.6 times longer to disappear. At least 50-60% improvement of two prominent early symptoms, sore throat and sneezing (but not of nasal discharge, cough, and hoarseness) by day 5 of the disease implies a nonbacterial origin of rhinitis and should exclude use of antibiotics. CONCLUSION: Temporal evolution of all rhinosinusitis symptoms is qualitatively similar, which makes the early symptom decay a good proxy for, and predictor of, the disease perspective. Knowing a symptom intensity at just three to four time points suffices for reconstructing its entire time course and total intensity or gravity. This permits an easy and early identification of rhinosinusitis, and its plausible differentiation from acute bacterial rhinosinusitis, disease treatment optimization, and corresponding clinical trials simplification and/or shortening. PMID- 28583226 TI - Magnetic resonance imaging findings in Meniere's disease. AB - OBJECTIVES: To identify and evaluate cranial magnetic resonance imaging findings associated with Meniere's disease. METHODS: Seventy-eight patients with a documented diagnosis of Meniere's disease and 35 controls underwent 1.5 T or 3 T magnetic resonance imaging of the brain. Patients also underwent otological, vestibular and audiometric examinations. RESULTS: Lack of visualisation of the left and right vestibular aqueducts was identified as statistically significant amongst Meniere's disease patients (left, p = 0.0001, odds ratio = 0.02; right, p = 0.0004, odds ratio = 0.03). Both vestibular aqueducts were of abnormal size in the Meniere's disease group, albeit with left-sided significance (left, p = 0.008, odds ratio = 10.91; right, p = 0.49, odds ratio = 2.47). CONCLUSION: Lack of vestibular aqueduct visualisation on magnetic resonance imaging was statistically significant in Meniere's disease patients compared to the general population. The study findings suggest that magnetic resonance imaging can be useful to rule out retrocochlear pathology and provide radiological data to support the clinical diagnosis of Meniere's disease. PMID- 28583228 TI - Diagnosing environmental allergies: Comparison of skin-prick, intradermal, and serum specific immunoglobulin E testing. AB - BACKGROUND: Allergists commonly perform intradermal skin testing (IDST) after negative skin-prick testing (SPT) to comprehensively diagnose environmental allergic sensitization. However, with the availability of modern methods to detect serum-specific immunoglobulin E (ssIgE), it is unclear if ssIgE testing could substitute for IDST. OBJECTIVE: To determine the efficacy of ssIgE testing and IDST when added to SPT in diagnosing environmental allergic sensitizations. METHODS: SPT, IDST, and ssIgE testing to nine common environmental allergens were analyzed in 75 patients with oculonasal symptoms who presented to our allergy clinics in the Bronx, New York, between January 2014 and May 2015. RESULTS: A total of 651 SPT and 499 ssIgE tests were independently performed and revealed 162 (25%) and 127 (25%) sensitizations, respectively. When SPT results were negative, IDST results revealed 108 of 452 additional sensitizations (24%). In contrast, when SPT results were negative, ssIgE test results only revealed 9% additional sensitizations. When both SPT and IDST results were negative, ssIgE testing only detected 3% of additional sensitizations, and ssIgE levels were typically low in these cases (median, 1.25 kU/L; range, 0.357-4.47 kU/L). When both SPT and ssIgE test results were negative, IDST results detected 15% additional sensitizations. CONCLUSION: IDST detected more additional environmental sensitizations compared with ssIgE testing. IDST, therefore, may be useful when the SPT and/or ssIgE testing results were negative, but the exposure history indicated relevant allergic sensitization. Serology added only a little more information if both SPT and IDST results were negative but may be useful in combination with SPT if IDST cannot be performed. PMID- 28583230 TI - Differential expression of microRNAs and their possible roles in patients with chronic idiopathic urticaria and active hives. AB - BACKGROUND: Chronic idiopathic urticaria (CIU) is a complicated skin disease with unknown pathophysiology. MicroRNAs (miRNA) have been shown to be active in cellular regulation. The goal of this pilot study was to examine whether miRNAs may be involved in the regulation of CIU or as biomarkers for CIU. METHODS: Four groups of three patients each were selected: patients with either active hives or no hives and with positive or negative chronic urticaria (CU) index results. MiRNAs were isolated from patient plasma and analyzed by using miRNA microarray technology to determine the amount of each of the 2567 known human miRNAs. RESULTS: A total of 16 miRNAs were found to be differentially expressed in patients with active hives. Among them, five (2355-3p, 4264, 2355-5p, 29c-5p, and 361-3p) were significantly increased in samples with positive CU index results, which could be useful biomarkers for patients with chronic autoimmune urticaria. The miRNA data bases were used to find the targets of these selected miRNA sequences. These potential targets were then compared against a list of 154 urticaria-related genes. Twenty-five genes were found to match. These included eight that were significantly downregulated and eight that were significantly upregulated; however, seven of the eight downregulated genes (FBXL20, OPHN1, YPEL2, STARD9, EZH1, KLHL24, ING4) and five of the eight upregulated genes (BYSL, PNO1, ADAMTS9, STEAP4, SRGN) have no reported roles in signaling. For the 13 genes with reported roles in signaling, the following pathways were found: transforming growth factor beta signaling pathway (NRC31, KITLG, THBS1, CCL2), glucocorticoid receptor signaling pathway (NR3C1, SELE, CCL2), p53 signaling pathway (CCNG2, THBS1, CCL2), p21-activated kinase pathway (PAK1IP1, KITLG, CCL2), phosphoinositide-3 kinase protein kinase B signaling pathway (KITLG, CHRM, THBS1), and neuroactive ligand-receptor interaction (NRC31, HRH1, CHRM), which could play important roles in CIU. CONCLUSION: A better understanding of those genes with undefined function and simultaneous quantitation of both miRNAs and messenger RNAs are needed to fully understand CIU disease. PMID- 28583229 TI - Landmarks for rapid localization of the sphenopalatine foramen: A radiographic morphometric analysis. AB - BACKGROUND: Transnasal endoscopic sphenopalatine artery ligation is becoming the procedure of choice for surgical management of intractable posterior epistaxis. Landmarks for localization of the sphenopalatine foramen can assist in rapid surgical exposure of the sphenopalatine artery. OBJECTIVE: This study examined distances from easily identified endoscopic surgical landmarks to the sphenopalatine foramen. METHODS: By using computed tomography of the sinus to study radiologic anatomy in 50 adults, distances were measured between five simple endoscopic landmarks and the sphenopalatine foramen. The two-tailed t-test was used for statistical analysis. RESULTS: Right- and left-sided measurements were similar. The mean (standard deviation [SD]) anteroposterior distances to the sphenopalatine foramen were the following: from the maxillary line (36.7 +/- 5.5 mm), anterior head of the middle turbinate (33.8 +/- 6.7 mm), basal lamella (11.8 +/- 1.9 mm), and choanal arch (-9.2 +/- 1.4 mm). The mean (SD) distance in the vertical dimension from the nasal floor was 26.6 +/- 2.6 mm. Female patients had statistically shorter distances to the sphenopalatine foramen from the maxillary line, anterior head of the middle turbinate, choanal arch, and nasal floor. CONCLUSION: Reliable endoscopic landmarks exist in relation to consistent anatomic structures and can be used to help quickly estimate the location of the sphenopalatine foramen at the onset of the procedure. PMID- 28583231 TI - Utility of intraoperative flexible endoscopy in frontal sinus surgery. AB - BACKGROUND: Surgical management of the frontal sinus can be challenging. Extensive frontal sinus pneumatization may form a far lateral or supraorbital recess that can be difficult to reach by conventional endoscopic surgical techniques, requiring extended approaches such as the Draf III (or endoscopic modified Lothrop) procedure. Rigid endoscopes may not allow visualization of these lateral limits to ensure full evacuation of the disease process. METHODS: Here we describe the utility of intraoperative flexible endoscopy in two patients with far lateral frontal sinus disease. RESULTS: In both cases, flexible endoscopy allowed confirmation of complete evacuation of pathologic material, thereby obviating more extensive surgical dissection. CONCLUSION: In cases where visualization of the far lateral frontal sinus is inadequate with rigid endoscopes, flexible endoscopy can be used to determine the need for more extensive dissection. PMID- 28583233 TI - Myxofibrosarcoma of the maxillary sinus. AB - BACKGROUND: Myxofibrosarcoma (MFS) is a common sarcoma in the extremities of older individuals but is extremely uncommon in the head and neck region. Diagnosis may be challenging but is critical to the management of the patient. We discuss the radiographic and histopathologic characteristics of this destructive tumor. The distinguishing features of MFS and its differential diagnosis are reviewed to familiarize the managing otolaryngologist with this rare entity. METHODS: A 61-year-old woman presents with a 6-week history of severe left facial pain and left eye pain. Imaging demonstrates significant right and left-sided maxillary sinus opacification with destruction of the left maxillary sinus as well as the left medial and inferior orbital walls. RESULTS: Histopathologic examination revealed spindle and stellate tumor cells of variable cellularity in myxoid stroma with cellular pleomorphism consistent with MFS of intermediate-to high grade. The patient underwent resection of the left-sided lesion with orbital exenteration and repair of the defect with microvascular free flap followed by postoperative radiotherapy. CONCLUSION: MFS must be differentiated from other lesions with myxoid qualities. Histopathologic examination is required for definitive diagnosis. Management includes complete tumor excision with adequate tumor margins. Adjuvant postoperative radiotherapy should be considered for larger tumors with positive resection margins or lesions of intermediate-to-high grade. PMID- 28583234 TI - Bilateral silent sinus syndrome: A rare case and review of literature. AB - OBJECTIVE: In this report, we presented a rare case of bilateral silent sinus syndrome (SSS) in an otherwise healthy 57-year-old man treated with functional endoscopic sinus surgery (FESS). A systematic review of the literature regarding bilateral SSS was performed. CASE REPORT: A 57-year-old man with well-controlled allergic rhinitis in the absence of previous surgery or trauma presented with bilateral SSS, which was successfully managed with bilateral FESS. METHODS: A medical literature data base search of the terms "silent sinus syndrome" "maxillary atelectasis," "imploding antrum syndrome," and "bilateral silent sinus syndrome" was performed. The results were then narrowed to include only relevant articles. RESULTS: Relevant articles included three case reports and two articles that describe or mention bilateral SSS. Of the three case reports found, two patients presented with bilateral SSS, whereas the third patient presented metachronously, with the contralateral SSS manifesting 4 months after presentation of the initial ipsilateral SSS. CONCLUSION: The present literature regarding bilateral SSS is likely incomplete, and further investigation is required to provide greater insight into the prevalence of this disease. In this report, bilateral FESS was successful in resolving symptoms and preventing disease progression. PMID- 28583232 TI - Effect of topical beclomethasone on inflammatory markers in adults with eosinophilic esophagitis: A pilot study. AB - BACKGROUND: Topical corticosteroids have proven efficacy in the treatment of eosinophilic esophagitis (EoE) and are considered the cornerstone of therapy. OBJECTIVE: To evaluate the effect of topical beclomethasone dipropionate (BDP) therapy on clinical outcomes, esophageal eosinophilia, and other markers of inflammation in patients with EoE. METHODS: Nine subjects with a biopsy-proven diagnosis of EoE were enrolled. In a cross-over design, the subjects were randomly assigned to a sequence of BDP and placebo. Treatment periods were 8 weeks, with a 4-week washout period. The subjects had endoscopic biopsies and blood tests at baseline and after each treatment period. They were instructed to maintain a diary of symptoms. Immuno-histochemical studies were performed for interleukins IL-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and transforming growth factor (TGF) beta. Reverse transcription polymerase chain reaction was performed for IL-3, IL-4, IL-5, IL-10, IL-13, IL 17F, IL-25, IL-33, chemokine ligands (CCL)2, CCL5, CCL11, GM-CSF, and TGF-beta levels. The mast cell tryptase (MCT) level was measured in esophageal tissues. RESULTS: BDP led to a significantly larger decrease in esophageal eosinophilia compared with placebo, but there was no significant change in peripheral eosinophilia and high-sensitivity C-reactive protein between the two groups. The study was not powered enough for us to report a significant improvement in clinical symptoms. There was a significant decrease in tissue IL-13 and MCT levels from baseline to the end of treatment between the treatment and placebo groups. Mean fold decreases in cytokine expression between the baseline and treatment groups were observed for IL-17F, IL-25, CCL2, and CCL5. CONCLUSION: Treatment with topical BDP was associated with significant decrease in esophageal eosinophilia, MCT and IL-13. BDP is a potential alternative to fluticasone propionate and budesonide for treatment of EoE. Larger studies are needed to validate these findings. PMID- 28583235 TI - Type 1 Kounis syndrome in a patient with idiopathic anaphylaxis. AB - Anaphylactic insults that cause cardiovascular signs and symptoms have been defined as Kounis syndrome, which has been associated with specific triggered anaphylactic reactions. Kounis syndrome has not been described in patients with no evidence of coronary artery disease (type I Kounis) in a scenario of idiopathic anaphylaxis. We reported a case of a 65-year-old white woman with no evidence of coronary artery disease who experienced two myocardial infarctions on separate occasions attributable to idiopathic anaphylaxis. PMID- 28583236 TI - Complete response of skull base inverted papilloma to chemotherapy: Case report. AB - BACKGROUND: Inverted papilloma (IP) is the most common benign sinonasal neoplasm. Endoscopic techniques, improved understanding of pathophysiology, and novel surgical approaches have allowed rhinologists to treat IPs more effectively, with surgery being the mainstay of therapy. Frontal sinus IP poses a challenge for surgical therapy due to complex anatomy and potentially difficult surgical access. OBJECTIVES: We reported a unique case of a massive frontal sinus IP that presented with intracranial and orbital extension, with near resolution after chemotherapy. METHODS: A retrospective case review of a patient with a frontal sinus IP treated at a tertiary academic medical center. RESULTS: A 75-year-old male patient presented with nasal obstruction, purulent nasal discharge, and a growing left supraorbital mass. Endoscopy demonstrated a mass that filled both frontal and ethmoid sinuses, with orbital invasion. There also was substantial erosion of the posterior table, which measured 1.73 * 1.40 cm. A biopsy specimen demonstrated IP with carcinoma in situ. The patient was deemed unresectable on initial evaluation and, subsequently, underwent chemotherapy (carboplatin and paclitaxel). The tumor had a dramatic response to chemotherapy, and the patient elected for definitive surgery to remove any residual disease. During surgery, only a small focus of IP was found along the superior wall of the frontal sinus. No tumor was found elsewhere, including at the site of skull base erosion. The final pathology was IP without carcinoma in situ or dysplasia. CONCLUSION: This was the first reported case of chemotherapeutic "debulking" of IP, which facilitated surgical resection, despite substantial intracranial and orbital involvement. Although nearly all IPs can be treated surgically, rare cases, such as unresectable tumors, may benefit from systemic chemotherapy. PMID- 28583237 TI - Intrapulpal Temperature Rise During Light Activation of Restorative Composites in a Primary Molar. AB - PURPOSE: To investigate intrapulpal temperature rise in a primary molar during light activation of a composite restoration to determine if clinically significant pulpal temperatures (greater than 5.5 degrees Celsius) were reached. METHODS: Restorative composites (EsthetX HD, Filtek Supreme Ultra, Filtek Bulk Fill) were placed into a primary molar with occlusal preparation (1.5 mm depth; remaining pulpal floor thickness one mm). The pulp was extirpated through a root access to place a thermocouple against the pulpal roof. Temperature changes were recorded during composite restoration light polymerization with three curing lights (one quartz-tungsten-halogen, two LEDs). Sample size was 10. Samples received additional irradiation to assure complete polymerization, followed by a third irradiation for calculating the exothermic heat contribution (subtracting third irradiation temperatures from first irradiation temperatures). Cured restorations were removed after each test, and the tooth was reused. Results were analyzed with Kruskal-Wallis (alpha =0.05). RESULTS: Type of curing light and composite material affected the intrapulpal temperature rise, which was up to five degrees Celsius for one combination of LED-composite. CONCLUSIONS: Clinicians should be aware of the potential for clinically significant intrapulpal temperature rises when light-activating composite restorations in a primary molar with a moderately deep cavity. PMID- 28583238 TI - Regenerative Endodontic Treatment of Necrotic Primary Molars with Missing Premolars: A Case Series. AB - The endodontic treatment of necrotic primary teeth with missing successors presents a unique clinical challenge. The purpose of this report was to describe the clinical and radiological outcomes of regenerative endodontic treatment (revascularization) of necrotic primary molars. Four infected necrotic primary second molars with missing premolars were treated with a two-visit revascularization protocol. The crowns were restored with amalgam or acid-etch composite resin. The teeth were followed-up clinically and radiographically for 18 months. At six months, all teeth demonstrated radiographic evidence of complete periradicular healing and positive response to cold test, and remained symptomless thereafter. PMID- 28583239 TI - Back to the Future. PMID- 28583240 TI - Letter to the Editor. PMID- 28583241 TI - Abstract of the Scientific Literature. PMID- 28583242 TI - Postoperative Pain After Root Canal Preparation with Hand and Rotary Files in Primary Molar Teeth. AB - PURPOSE: The purpose of this study was to evaluate the intensity and duration of postoperative pain after root canal preparation of primary maxillary molar teeth using two preparation techniques. METHODS: A total of 110 patients requiring pulpectomy for asymptomatic primary molar teeth with non-vital pulps were included in the study. The patients were randomly assigned to two groups of 55 patients each, according to the canal preparation method used. In Group one, teeth were prepared up to size 35 with hand files. In Group two, teeth were prepared up to size 35 with Revo-S rotary instruments. Following canal preparation, teeth were obturated with zinc-oxide eugenol paste and then permanently restored. The presence of postoperative pain was assessed after six, 12, 24, 48, and 72 hours and after one week, using a four-point pain-intensity scale. RESULTS: Except for those assessed after 72 hours and one week, patients who had their teeth prepared with hand files reported more intense postoperative pain than those who had their teeth prepared with Revo-S rotary files (P<0.05). In both groups, postoperative pain decreased over time. CONCLUSIONS: Hand files caused more postoperative pain after pulpectomy in primary maxillary molar teeth compared to the rotary system. PMID- 28583243 TI - Significant Factors Related to Failed Pediatric Dental General Anesthesia Appointments at a Hospital-based Residency Program. AB - PURPOSE: The purposes of this study were to: (1) evaluate the relationship between appointment failure and the factors of age, gender, race, insurance type, day of week, scheduled time of surgery, distance traveled, and weather; (2) investigate reasons for failure; and (3) explore the relationships between the factors and reasons for failure. METHODS: Electronic medical records were accessed to obtain data for patients scheduled for dental care under general anesthesia from May 2012 to May 2015. Factors were analyzed for relation to appointment failure. RESULTS: Data from 3,513 appointments for 2,874 children were analyzed. Bivariate associations showed statistically significant (P<0.05) relationships between failed appointment and race, insurance type, scheduled time of surgery, distance traveled, snowfall, and temperature. Multinomial regression analysis showed the following associations between factors and the reason for failure (P<0.05): (1) decreased temperature and increased snowfall were associated with weather as reason for failure; (2) the African American population showed an association with family barriers; (3) Hispanic families were less likely to give advanced notice; and (4) the "additional races" category showed an association with fasting violation. CONCLUSION: Patients who have treatment under general anesthesia face specific barriers to care. PMID- 28583244 TI - Association Between Childhood Traumatic Stress and Behavior in the Pediatric Dental Clinic. AB - PURPOSE: The purpose of this study was to examine the relationship between a history of potentially traumatic events (PTE) and a child's behavior during dental treatment. METHODS: Parents of healthy children, age four years and older and attending their initial dental appointment at a university pediatric dental clinic, were asked to complete the Traumatic Events Screening Inventory-Parent Report Revised and a demographic survey. Following the dental appointment, a pediatric dental resident reported the child's behavior using the Frankl scale. RESULTS: A total of 170 parent-child pairs participated; 53 percent of parents indicated their child had experienced at least one PTE; 44 percent reported their child had a prior negative experience at the dentist. Adjusted multivariable logistic regression analysis showed no significant association between PTE history and poor dental behavior (P=0.994), but a significant association was observed between a previous negative dental experience and poor dental behavior (P=0.000) as well as between age (younger than five years old) and poor behavior (P=0.006). CONCLUSIONS: Children with a history of potentially traumatic events did not exhibit uncooperative behavior more often than those who did not. A previous negative dental experience and the child's young age were significantly associated with uncooperative behavior. PMID- 28583245 TI - "They Told Me to Take Him Somewhere Else": Caregivers' Experiences Seeking Emergency Dental Care for Their Children. AB - PURPOSE: The purpose of this mixed-methods study was to examine pediatric emergency dental trends in two safety net clinics and care-seeking experiences of young children's caregivers. METHODS: Administrative data were used to describe and compare emergency first visits of children ages zero to six years in a community-based (CC) and a University-based (UC) safety net clinic from 2010 to 2014. In-person interviews were conducted with 11 caregivers of children ages zero to six presenting for nontrauma-related emergency visits at the UC from January to August 2016. Interviews were transcribed verbatim, coded, and analyzed inductively using Atlas. ti.7.5.9. RESULTS: The UC experienced significantly more emergency first visits (33 percent) than the CC (five percent, P<0.001), and the majority of these UC visits were referrals. Caregivers were dissatisfied with the experienced barriers of access to care and lack of child-centeredness, specifically the referral out of the dental home for emergency dental care. CONCLUSIONS: A considerable proportion of children's first visits at dental safety net clinics was emergency related. Children's caregivers voiced issues related to access to care and lack of child-centered care. Discordance was apparent between how professional organizations define the dental home and how caregivers experience it in the context of emergency care. PMID- 28583246 TI - Ectopic Eruption of the Permanent Maxillary First Molar: Predictive Factors for Irreversible Outcome. AB - PURPOSE: The purpose of this study was to determine the rate of self-correction and predictive factors for irreversible outcome of mesial ectopic eruption of permanent maxillary first molars (EE), in a sample population where no interceptive treatment was initiated. METHODS: Charts of patients diagnosed with EE were reviewed, and radiographs were analyzed for predictive factors reported in the literature. RESULTS: Sixty-five EE were included in the study; 46 (71 percent) self-corrected, of which one-third occurred after age nine years. Space loss, with an average of approximately three mm, occurred in 18 EE (28 percent). Increased magnitude of impaction, degree of resorption of the primary second molar, severe lock, and bilateral occurrence were positively correlated with irreversible EE. Multiple regression analysis was positive for increased magnitude of impaction when adjusted for gender and bilateral occurrence. CONCLUSION: Spontaneous self-correction occurred in 71 percent of permanent maxillary first molars with ectopic eruption; one third of self-corrections occurred after nine years of age. Delaying treatment of ectopic eruption of permanent maxillary first molars may be a viable option when the outcome is uncertain. Increased magnitude of impaction was the most reliable predictor associated with irreversible outcome. PMID- 28583248 TI - Pediatric Phantom Dosimetry of Kodak 9000 Cone-beam Computed Tomography. AB - PURPOSE: The purpose of the study was to evaluate the radiation dose of the Kodak 9000 cone-beam computed tomography (CBCT) device for different anatomical areas using a pediatric phantom. METHODS: Absorbed doses resulting from maxillary and mandibular region three by five cm CBCT volumes of an anthropomorphic 10-year-old child phantom were acquired using optical stimulated dosimetry. Equivalent doses were calculated for radiosensitive tissues in the head and neck area, and effective dose for maxillary and mandibular examinations were calculated following the 2007 recommendations of the International Commission on Radiological Protection (ICRP). RESULTS: Of the mandibular scans, the salivary glands had the highest equivalent dose (1,598 microsieverts [MUSv]), followed by oral mucosa (1,263 MUSv), extrathoracic airway (pharynx, larynx, and trachea; 859 MUSv), and thyroid gland (578 MUSv). For the maxilla, the salivary glands had the highest equivalent dose (1,847 MUSv), followed closely by oral mucosa (1,673 MUSv), followed by the extrathoracic airway (pharynx, larynx, and trachea; 1,011 MUSv) and lens of the eye (202 MUSv). CONCLUSION: Compared to previous research of the Kodak 9000, completed with the adult phantom, a child receives one to three times more radiation for mandibular scans and two to 10 times more radiation for maxillary scans. PMID- 28583249 TI - Efficacy of Four Remineralizing Agents on Primary Teeth: In Vitro Evaluation Using Microhardness Testing and Quantitative Light-induced Fluorescence. AB - PURPOSE: This study's purpose was to evaluate the remineralization of primary enamel using GC Tooth Mousse, Clinpro Tooth Creme, SHY-NM, and Pronamel by employing microhardness testing and quantitative light-induced fluorescence (QLF) values. METHODS: An in vitro study was performed with 100 intact primary anterior teeth. After specimen preparation, they were subjected to baseline microhardness and QLF testing. The specimens were immersed in demineralizing solution, subjected again to microhardness and QLF testing, and divided randomly into five groups of 20 teeth: group one-control group (artificial saliva); group two-GC Tooth Mousse; group three-ClinPro tooth creme; group four-SHY-NM; and group five Pronamel. The pastes were respectively applied for the specific group specimens for 15 consecutive days. The samples were subjected to microhardness and QLF testing. RESULTS: The results were analyzed using analysis of variance testing. A post-hoc comparison was done using a paired t test. There were mean increases in microhardness and QLF values with all remineralizing agents. Group two showed a statistically significant increase (P<0.05) in microhardness and QLF values. Group four showed a significant increase only in microhardness values. (P<0.05). CONCLUSION: GC Tooth Mousse and SHY-NM are promising materials for remineralizing incipient lesions in primary teeth. PMID- 28583250 TI - Oral Juvenile Xanthogranuloma: Report of Two Cases. AB - Juvenile xanthogranuloma is a rare non-Langerhans cell histiocytosis that usually occurs in the skin of children. Extracutaneous involvement is rare, and few cases affecting the oral cavity have been reported. The purpose of the present study was to report two cases of oral juvenile xanthogranuloma affecting the lower lip of a 14-year-old girl and the soft palate of a second 14-month-old girl, both present as yellowish papules. The lesions were surgically excised, and histological and immunohistochemical analysis showed a proliferation of non Langerhans cells histiocytes and foamy cells, fulfilling the morphologic features of juvenile xanthogranuloma. The patients have been followed up, respectively, for 36 and 49 months with no signs of recurrence. Based on these results, juvenile xanthogranuloma should be included in the differential diagnosis of oral yellowish soft-tissue swellings in children and adolescents and should be managed through conservative surgical excision. PMID- 28583247 TI - Pediatric Caries Risk Assessment as a Predictor of Caries Outcomes. AB - PURPOSE: To determine cumulative dental treatment experience in a retrospective clinical cohort, according to baseline caries risk assessment (CRA) information. METHODS: Evaluated were electronic records from a university pediatric dental clinic (2009 to 2014) of new, six- to 72- month-old patients who were not treated under sedation or general anesthesia (N equals 750). The mean number of teeth restored or extracted (two-year total and omitting the first 190 days post-baseline to discount initial treatment needs) was compared by baseline CRA category and CRA items (caries risk indicators, protective items, and clinical disease indicators). RESULTS: The CRA category was associated with mean treated teeth over two years (low equals 0.53, moderate equals 1.02, high/extreme equals 4.47) and post 190 days (low equals 0.51, moderate equals 0.89, high/extreme equals 2.11). Any treatment probability was greatest for high/extreme-risk children but not statistically significantly different between low- and moderate-risk. Age-standardized means were greater for all individual baseline clinical indicators and most risk indicators, but lower for most protective items (not statistically significantly for all items). Clinical indicators were the strongest outcome correlates. CONCLUSIONS: In this population, baseline risk information was associated with clinical outcomes. CRA can help identify patients needing more intensive caries prevention. PMID- 28583251 TI - Are changes in Australian national primary healthcare policy likely to promote or impede equity of access? A narrative review. AB - Significant changes have occurred in Australia's national primary healthcare (PHC) policy over the last decade, but little assessment has been made of implications for equity. This research aimed to identify key recent changes in national PHC policy and assess implications for equity of access to PHC. Academic literature was reviewed to identify issues affecting equity of access in national PHC policy, and grey literature was also reviewed to identify significant policy changes during 2005-16 with implications for equitable access. Equity implications of four areas of policy change, set against the existing Medicare system, were assessed. It was found that Medicare supports equitable access to general practice, but there is a risk of reduced equity under current policy settings. Four changes in PHC policy were selected as having particular implications for equity of access and these were assessed as follows: increased involvement of private health insurance presents risks for equity; equity implications of new models of coordinated care are unclear; and regional primary health organisations and current policy on Aboriginal and Torres Strait Islander health have potential equity benefits, but these will depend on further implementation. PMID- 28583254 TI - Foreword. PMID- 28583252 TI - Mice deficient of Myc super-enhancer region reveal differential control mechanism between normal and pathological growth. AB - The gene desert upstream of the MYC oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire MYC upstream super-enhancer region in mice results in 50% to 80% decrease in Myc expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. These results reveal that only cells whose MYC activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy. PMID- 28583253 TI - Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration. AB - Neuromuscular junction degeneration is a prominent aspect of sarcopenia, the age associated loss of skeletal muscle integrity. Previously, we showed that muscle stem cells activate and contribute to mouse neuromuscular junction regeneration in response to denervation (Liu et al., 2015). Here, we examined gene expression profiles and neuromuscular junction integrity in aged mouse muscles, and unexpectedly found limited denervation despite a high level of degenerated neuromuscular junctions. Instead, degenerated neuromuscular junctions were associated with reduced contribution from muscle stem cells. Indeed, muscle stem cell depletion was sufficient to induce neuromuscular junction degeneration at a younger age. Conversely, prevention of muscle stem cell and derived myonuclei loss was associated with attenuation of age-related neuromuscular junction degeneration, muscle atrophy, and the promotion of aged muscle force generation. Our observations demonstrate that deficiencies in muscle stem cell fate and post synaptic myogenesis provide a cellular basis for age-related neuromuscular junction degeneration and associated skeletal muscle decline. PMID- 28583256 TI - Current management of perianal Crohn's disease. PMID- 28583257 TI - In Vitro and In Vivo Comparison of Two Nebulizers Used for Inhaled Pentamidine Delivery. PMID- 28583259 TI - Advanced clinical testing of the adaptive immune system. PMID- 28583258 TI - Hymenoptera venoms used to produce allergen extracts. AB - OBJECTIVE: To review the methods and materials used for collection, purification, commercial production, and clinical application of Hymenoptera venoms. DATA SOURCES: Most of the sources for this review are the experience and expertise of the authors. Published reports and review articles on Hymenoptera venom collection and production were identified through database searches (PubMed). STUDY SELECTIONS: Studies describing the methods for Hymenoptera venom collection and production were selected for review. RESULTS: Meticulous methods for identification and collection of the insects are required. Collection and purification of the venoms from the insects are based on validated methods and result in a commercial extract that is standardized for the major allergenic proteins required for accurate diagnosis and safe and effective treatment of patients allergic to insect sting. The steps required for mixing, purifying, testing, and standardizing the products are described. CONCLUSION: Hymenoptera venom extracts were developed using many new methods for the collection, purification, and commercial production of the unique materials required for this product. Clinical applications for diagnosis and treatment are affected by the integrity and stability of the allergens after processing and purification. PMID- 28583261 TI - Cellular and noncellular bloodborne biomarkers in asthma. AB - OBJECTIVE: To provide an overview of studied cellular and noncellular blood derived asthma biomarkers. DATA SOURCES: PubMed literature review. STUDY SELECTIONS: Articles discussing cellular and noncellular bloodborne asthma biomarkers. RESULTS: Discussed asthma biomarkers include peripheral blood cell counts of T cells, fibrocytes, or granulocytes, as well as levels of cytokines, periostin, IgE, and lipid mediators with or without stimulation. Moreover, this article summarizes the association of various blood biomarkers with the type of airway inflammation, presence of atopy, and dominance of specific T-cell subsets and associated pathways in asthma. Furthermore, biomarkers are here listed according to their proposed clinical use, such as diagnosis, disease phenotyping, classification of severity, assessment of disease control, and monitoring of and predicting treatment response. CONCLUSION: Further research on asthma biomarkers may improve asthma endotyping and ultimately lead to personalized treatment. PMID- 28583262 TI - Different prevalence and clinical characteristics of asthma-chronic obstructive pulmonary disease overlap syndrome according to accepted criteria. AB - BACKGROUND: A unified definition of asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) is not available, which makes it difficult to evaluate the prevalence and clinical features of patients with ACOS. OBJECTIVE: To investigate the prevalence and clinical characteristics of ACOS according to the updated widely accepted diagnostic criteria. METHODS: Participants were enrolled from a prospective cohort study conducted between April 2013 and November 2016 in South Korea. We adopted 4 criteria of ACOS: modified Spanish, American Thoracic Society (ATS) Roundtable criteria, the Latin American Project for the Investigation of Obstructive Lung Disease (PLATINO), and the Global Initiative for Asthma/Global Initiative for Chronic Obstructive Lung Disease (GINA/GOLD) criteria. The prevalence, clinical characteristics, and exacerbations of ACOS were investigated. RESULTS: Among 301 patients with chronic obstructive pulmonary disease, 31.3%, 11.9%, 48.3%, and 46.15% were diagnosed with ACOS according to the modified Spanish, ATS Roundtable criteria, PLATINO, and GINA/GOLD criteria, respectively. Compared with other criteria, patients with ACOS diagnosed according to the modified Spanish criteria had better exercise capacity and lung function at baseline but higher risk of moderate to severe (adjusted hazard ratio, 1.97; 95% confidence interval, 1.14-3.41; P = .01) and total (adjusted odds ratio, 2.10; 95% confidence interval, 1.33-3.31; P < .01) exacerbations during at least a 1-year follow-up period than patients without ACOS. CONCLUSION: The prevalence of ACOS varied according to the diagnostic criteria. Among the different criteria, the modified Spanish criteria could identify patients with more asthmatic features and higher risk of exacerbation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02527486. PMID- 28583260 TI - The case for impulse oscillometry in the management of asthma in children and adults. AB - OBJECTIVE: To provide a clinical rationale for including impulse oscillometry (IOS) as a part of standard office-based asthma assessment. DATA SOURCES: PubMed and Google search, limited to English language and human disease, with the keywords IOS and asthma. STUDY SELECTIONS: Articles included in this review were based on the expert opinion and previous publications by the authors. RESULTS: In children, IOS was more useful than spirometry in identifying asthma and uncontrolled asthma and predicting loss of control and exacerbations. IOS predicts young children at risk for loss of lung function with age and the potential for early intervention to prevent further sequelae. In adults, peripheral airway impairment detected by IOS or spirometry (ie, forced expiratory flow between 25% and 75%) commonly occurs across severity, and each measure may be complementary in predicting loss of control even with normal forced expiratory volume in 1 second. Extrafine inhaled corticosteroids with or without long-acting beta-agonists proved superior to standard particle aerosols in improving IOS detected peripheral airway obstruction. Our data also suggest that currently available commercial reference values for lung resistance at 5 Hz and lung reactance at 5 Hz are applicable across diverse populations, but further studies are needed. CONCLUSION: The findings of this review suggest that IOS can add value to traditional clinical and spirometric assessment and thus improve management of asthma in children and adults, as well as have the potential to detect early dysfunction of the peripheral airways, which may result in better outcomes. PMID- 28583263 TI - Increased serum soluble vascular endothelial cadherin levels in patients with chronic spontaneous urticaria. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) is a common skin disease characterized by recurrent itchy wheals with or without angioedema that lasts longer than 6 weeks. Vascular endothelial (VE)-cadherin is an endothelial cell specific adhesion molecule that plays critical roles in angiogenesis and endothelial permeability. OBJECTIVE: To investigate serum levels of soluble VE (sVE)-cadherin in patients with CSU. METHODS: Serum levels of sVE-cadherin in patients with CSU, patients with atopic dermatitis, and healthy controls were determined by enzyme-linked immunosorbent assay. In addition, changes in sVE cadherin serum levels were compared in patients with CSU before and after H1 antihistamine treatment. Furthermore, the effects of histamine on sVE-cadherin release by HMEC-1 cells were determined by enzyme-linked immunosorbent assay. The inhibition effects of H1 antihistamine and H2 antihistamine on sVE-cadherin release, VE-cadherin phosphorylation, and VE-cadherin disruption were evaluated in histamine-treated HMEC-1 cells by western blot and immunofluorescence. RESULTS: Serum levels of sVE-cadherin in patients with CSU were significantly higher than those in patients with atopic dermatitis and healthy controls. Serum sVE-cadherin levels in patients with CSU were correlated with the severity of CSU according to Urticaria Activity Scores. Furthermore, serum sVE-cadherin levels in patients with CSU at pretreatment decreased after H1 antihistamine treatment. In addition, histamine markedly induced sVE-cadherin release in HMEC-1 cells. Moreover, H1 antihistamine, but not H2 antihistamine, significantly inhibited sVE cadherin release in histamine-treated HMEC-1 cells. Western blot data showed that histamine induced phosphorylation of VE-cadherin in HMEC-1 cells, which was blocked by H1 antihistamine. CONCLUSION: The present data showed serum levels of sVE-cadherin are increased in patients with CSU. Histamine-induced sVE-cadherin release from endothelial cells could play a role in the pathogenesis of CSU. PMID- 28583265 TI - Use of the basophil activation test in monitoring clinical tolerance after desensitization to brentuximab vedotin. PMID- 28583264 TI - Atopic dermatitis and food sensitization in South African toddlers: Role of fiber and gut microbiota. PMID- 28583266 TI - A case of green tea (Camellia sinensis) imbibement causing possible anaphylaxis. PMID- 28583267 TI - Insights into the global effect of nickel dermatitis on polysensitization. PMID- 28583268 TI - Voice disorders in residual paracoccidioidomycosis in upper airways and digestive tract. AB - BACKGROUND: Paracoccidioidomycosis (PCM) is a systemic mycosis of acute and chronic evolution, caused by species belonging to the genus Paracoccidioides. It is considered the most prevalent systemic endemic mycosis in Latin America, with cases in the tropical and subtropical regions. Residual PCM refers to the fibrotic scar sequelae resulting from the disease treatment which, when associated with collagen accumulation, leads to functional and anatomic alterations in the organs. AIMS: The aim of this study was to evaluate the vocal function of patients with residual PCM in upper airways and digestive tract. METHODS: We performed a cross-sectional study in 2010 in a cohort of 21 patients with residual PCM in upper airways and digestive tract. RESULTS: The average age was 49.48+/-9.1 years, and only two (9.5%) patients were female. The study was performed in the 1-113 month-period (median 27) after the end of drug treatment. Five (23.8%) patients had alterations in the larynx as a sequela of the disease. However, all patients had vocal changes in vocal auditory perceptual analysis by GRBASI scale. The computerized acoustic analysis using the software Vox Metria, showed that 11 patients (52.4%) presented alterations in jitter, 15 (71.4%) in shimmer, 8 (38.1%) in F0, 4 (19%) in glottal to noise excitation (GNE), 7 (33.3%) in the presence of noise and 12 (57.1%) in the presence of vibratory irregularity. CONCLUSIONS: The great frequency of alterations in residual PCM suggests that the patients in such phase could benefit from a multidisciplinary treatment, offering them integral monitoring of the disease, including speech rehabilitation after the PCM is healed. PMID- 28583269 TI - The METOP Study: Further Evidence for the Use of Subcutaneous Methotrexate in Psoriasis. PMID- 28583271 TI - Unruptured intracranial aneurysms: An updated review of current concepts for risk factors, detection and management. AB - The management of patients with unruptured intracranial aneurysms (UIAs) is a complex clinical challenge and constitutes an immense field of research. While a preponderant proportion of these aneurysms never rupture, the consequences of such an event are severe and represent an important healthcare problem. To date, however, the natural history of UIAs is not completely understood and there is no accurate means to discriminate the UIAs that will rupture from those that will not. Yet, a good understanding of the recent evidence and future perspectives is needed when advising a patient with IA to tailor any information to the given patient's level of risk and psychoaffective status. Thus, this review addresses the current concepts of epidemiology, risk factors, detection and management of UIAs. PMID- 28583272 TI - Letter from the Editors. PMID- 28583270 TI - Central pontine myelinolysis in a type 1 diabetes patient with chronic hepatitis. PMID- 28583273 TI - Guest Editorial on PET of Benign Musculoskeletal Conditions. PMID- 28583274 TI - Benign Bone Conditions That May Be FDG-avid and Mimic Malignancy. AB - Positron emission tomography with the radiotracer 18F-fluoro-2-deoxy-d-glucose (FDG) plays an important role in the evaluation of bone pathology. However, FDG is not a cancer-specific agent, and knowledge of the differential diagnosis of benign FDG-avid bone alterations that may resemble malignancy is important for correct patient management, including the avoidance of unnecessary additional invasive tests such as bone biopsy. This review summarizes and illustrates the spectrum of benign bone conditions that may be FDG-avid and mimic malignancy, including osteomyelitis, bone lesions due to benign systemic diseases (Brown tumor, Erdheim-Chester disease, Gaucher disease, gout and other types of arthritis, Langerhans cell histiocytosis, and sarcoidosis), benign primary bone lesions (bone cysts, chondroblastoma, chondromyxoid fibroma, desmoplastic fibroma, enchondroma, giant cell tumor and granuloma, hemangioma, nonossifying fibroma, and osteoid osteoma and osteoblastoma), and a group of miscellaneous benign bone conditions (post bone marrow biopsy or harvest status, bone marrow hyperplasia, fibrous dysplasia, fractures, osteonecrosis, Paget disease of bone, particle disease, and Schmorl nodes). Several ancillary clinical and imaging findings may be helpful in discriminating benign from malignant FDG-avid bone lesions. However, this distinction is sometimes difficult or even impossible, and tissue acquisition will be required to establish the final diagnosis. PMID- 28583275 TI - Benign Cutaneous and Subcutaneous Lesions on FDG-PET/CT. AB - 18F-FDG, the most commonly used PET radiopharmaceutical in clinical practice, can also accumulate in inflammatory and infectious conditions. This may account for false-positive PET findings when staging or restaging a patient with malignancy. As clinical use of FDG-PET-CT is increasing, nuclear medicine physicians are encountering a myriad of cutaneous and subcutaneous lesions, many of which are incidental and benign. The most common cause for the FDG avidity of these lesions is inflammation. Although a specific diagnosis may not always be possible, background clinical history and morphologic features of the lesion on CT may help narrow the differential diagnosis. This article aims to familiarize nuclear medicine physicians and radiologists with various benign cutaneous and subcutaneous conditions encountered in routine clinical practice. PMID- 28583276 TI - FDG-PET/CT in Skeletal Muscle: Pitfalls and Pathologies. AB - FDG-PET/CT is an integral part of modern-day practice of medicine. By detecting increased cellular metabolism, FDG-PET/CT can help us detect infection, inflammatory disorders, or tumors, and also help us in prognostication of patients. However, one of the most important challenges is to correctly differentiate the abnormal uptake that is potentially pathologic from the physiological uptake. So while interpreting a PET/CT, one must be aware of normal biodistribution and different physiological variants of FDG uptake. Skeletal muscles constitute a large part of our body mass and one of the major users of glucose. Naturally, they are often the site of increased FDG uptake in a PET study. We as a nuclear medicine physician must be aware of all the pitfalls of increased skeletal muscle uptake to differentiate between physiological and pathologic causes. In this review, we have discussed the different causes and patterns of physiological FDG uptake in skeletal muscles. This knowledge of normal physiological variants of FDG uptake in the skeletal muscles is essential for differentiating pathologic uptake from the physiological ones. Also, we reviewed the role of FDG-PET/CT in various benign and malignant diseases involving skeletal muscle. PMID- 28583277 TI - Dual-time point 18F-FDG-PET and PET/CT for Differentiating Benign From Malignant Musculoskeletal Lesions: Opportunities and Limitations. AB - In this review, we summarize the false-positive and false-negative results of standard 18F-FDG-PET/CT in characterizing musculoskeletal lesions and discussed the added value and limitations of dual-time point imaging (DTPI) and delayed imaging in differentiating malignant from benign musculoskeletal lesions, based on review of the peer-reviewed literature. The quantitative and semiquantitative parameters adopted for DTPI are standardized uptake value (mainly maximum standardized uptake value [SUVmax]) and retention index (RI), calculated as RI (%) = 100% * (SUV [maxD-Delayed] - SUV [maxE-Early])/SUV [maxE-Early], although the criteria and cutoff for diagnosing malignancy in studies have varied considerably. Also, there has been considerable heterogeneity in protocol (time point of delayed imaging), interpretation, and results in dual-time point (DTP) 18F-FDG-PET for differentiating malignant from benign musculoskeletal lesions in various research studies. The specificity of DTPI is a function of many factors such as the nature of the musculoskeletal lesion or malignancy in question, the prevalence of false-positive etiologies in the patient population, and the cutoff values (either SUVmax or RI) employed to define a malignancy. Despite the apparent conflicting reports on the performance, there have been certain common points of agreement regarding DTPI: (1) DTP PET increases the sensitivity of 18F FDG-PET/CT due to continued clearance of background activity and increasing 18F FDG accumulation in malignant lesions, when the same diagnostic criteria (as in the initial standard single-time point imaging) are used. Increased sensitivity for lesion detection can be viewed as a strong point of DTP and delayed-time point imaging. (2) The causes for false positives (such as active infectious or inflammatory lesions and locally aggressive benign tumors) and false negatives (eg, low-grade sarcomas) are the major hurdles accounting for reduced diagnostic value of the technique, with overlap of 18F-FDG uptake patterns between benign and malignant musculoskeletal lesions on DTPI. (3) DTPI, however, could still be potentially useful in increasing the confidence of interpretation such as differentiating malignancy from sites of inactive or chronic inflammation, post treatment viable residue vs necrosis, and certain other benign lesions. (4) Consideration of diagnostic CT component of PET/CT and the patient's clinical picture can lead to increase in specificity of interpretation in a given case scenario. Further systematic research, adoption of uniform protocol, and interpretation criterion could evolve the specific indications and interpretation criteria of DTPI for improved diagnostic accuracy in musculoskeletal lesions and its clinical applications. PMID- 28583278 TI - Spectrum of Benign Bone Conditions on NaF-PET. AB - Fluoride imaging with 18F (NaF-PET), although not a new technique, is becoming increasingly utilized for evaluation of skeletal metastatic disease using PET/CT. As its use becomes more widespread, a variety of nonmalignant bone disorders will be encountered by the interpreting physician. It is important, therefore, to recognize these nonmalignant conditions to avoid errors in interpretation. Beyond this, there is increasing evidence in the literature that NaF-PET/CT imaging may provide valuable information for the primary diagnosis of these nonmalignant conditions, and furthermore may provide insight into the underlying biology leading to management decisions. In this article, we review a spectrum of benign bone conditions that can be visualized on NaF-PET. PMID- 28583279 TI - PET in Benign Bone Marrow Disorders. AB - This review aims to describe the current status of benign bone marrow (BM) imaging using PET. BM imaging is important as the BM is not only involved in poiesis of different vital cell lines and can be affected by primary BM disorders, but it is also frequently affected by several extramedullary diseases. Indications for the use of PET in benign BM disorders are the detection of extramedullary hematopoiesis, evaluation of patients with a discrepancy between BM histology and clinical status, visualizing BM infarctions, location of the optimal site for BM biopsy, diagnosing and staging of other hematological BM disorders, evaluation of radiotherapy effect on BM, and evaluation of BM transplantation. The 3'-18F-fluoro-3'-deoxy-L-thymidine (FLT) and 2-18F-2-deoxy-D glucose (FDG) are the current main PET tracers to image BM physiology and pathology. FLT is a DNA synthesis-related tracer that can be used effectively in primary BM disorders in both diagnosis and monitoring treatment response, for example, in aplastic anemia. In secondary benign BM disorders, FDG-PET reveals that the prevalence of BM involvement in several benign diseases is more common than thought before. Novel PET tracers, such as the proliferation marker 4DST and hypoxia markers FAZA, MISO, and ATSM, are promising to visualize (benign) BM pathology more specifically. PET/MRI using innovative MRI sequences is promising to improve BM imaging in the near future. Additional trials are recommended to evaluate possible clinical applications of these newer tracers and new applications of PET/MRI in daily practice. This should be followed by updated guidelines on the use of PET in benign BM diseases. PMID- 28583280 TI - Clinical Value of FDG-PET/CT for the Evaluation of Rheumatic Diseases: Rheumatoid Arthritis, Polymyalgia Rheumatica, and Relapsing Polychondritis. AB - FDG is a tracer for visualizing glucose metabolism. PET/CT using FDG is widely used for the diagnosis of cancer, because glycolysis is elevated in cancer cells. Similarly, active inflammatory tissue also exhibits elevated glucose metabolism because of glycolysis in activated macrophages and proliferating fibroblasts. Elevated FDG uptake by active inflammatory tissues, such as those affected by arthritis, vasculitis, lymphadenitis, and chondritis, has enabled the diagnosis of inflammatory diseases using FDG-PET/CT. Rheumatoid arthritis (RA) is a systemic, chronic inflammation of the joints resulting in synovitis. Several clinical studies of RA have demonstrated that FDG uptake in affected joints reflects the disease activity of RA, with strong correlations between FDG uptake and various clinical parameters having been noted. Furthermore, the use of FDG PET for the sensitive detection and early monitoring of the response to RA therapy has been reported. RA is sometimes associated with subclinical vasculitis, which is related to systemic inflammation. FDG-PET/CT can be used to evaluate subclinical vasculitis in the aorta or carotid artery. Polymyalgia rheumatica (PMR) is an autoimmune musculoskeletal disease of unknown etiology characterized by pain and stiffness in the shoulder, neck, and pelvic girdle, but not in the small finger joints in the hands, together with fever, fatigue, and weight loss. There is no specific test for PMR, and its diagnosis is based on clinical diagnostic criteria and the exclusion of other diseases with similar symptoms. However, FDG-PET/CT reveals a characteristic FDG uptake by the bursitis in ischial tuberosity, greater trochanter, lumbar or cervical spinous process, and scapulohumeral joint. A combination of FDG-PET/CT findings showed a high diagnostic value for PMR in a differential diagnosis from RA. FDG-PET/CT is also very useful for evaluating large vessel vasculitis, which is often associated with PMR. Relapsing polychondritis is a rare multisystem disease of unknown etiology involving cartilaginous and proteoglycan-rich structures. Its rarity and diversity of symptoms often result in a delayed diagnosis. FDG-PET/CT reveals unique FDG uptake findings for chondritis in the auricular, nasal, trachea, bronchial tree, and costal cartilage and in the cartilage of joints. Thus, the spread of knowledge regarding these very specific FDG-PET/CT findings could promote the early diagnosis and improved disease control of relapsing polychondritis. PMID- 28583281 TI - A fundamental experimental approach for optimal design of speed bumps. AB - Speed bumps and humps are utilized as means of calming traffic and controlling vehicular speed. Needless to say, bumps and humps of large dimensions in length and width force drivers to significantly reduce their driving speeds so as to avoid significant vehicle vertical acceleration. It is thus that this experimental study was conducted with the aim of determining a speed bump design that performs optimally when leading drivers to reduce the speed of their vehicles to safe levels. The first step of the investigation starts off by considering the following question: "What is the optimal design of a speed bump that will - at the same time - reduce the velocity of an incoming vehicle significantly and to a speed that resulting vertical acceleration does not jeopardize road safety? The experiment has been designed to study the dependent variables and collect data in order to propose an optimal design for a speed bump. To achieve this, a scaled model of 1:6 to real life was created to simulate the interaction between a car wheel and a speed bump. During the course of the experiment, a wheel was accelerated down an inclined plane onto a horizontal plane of motion where it was allowed to collide with a speed bump. The speed of the wheel and the vertical acceleration at the speed bump were captured by means of a Vernier Motion Detector. PMID- 28583282 TI - Putting a stop to exsanguination. PMID- 28583283 TI - Subcutaneous rituximab-a meaningful advance in care. PMID- 28583284 TI - Unrelated donor haemopoietic stem-cell transplantation: ATG or not? PMID- 28583285 TI - Evaluation of direct oral anticoagulants in superficial-vein thrombosis. PMID- 28583287 TI - Correction to Lancet Haematol 2017; 4: e258-71. PMID- 28583286 TI - Evaluation of direct oral anticoagulants in superficial-vein thrombosis - Authors' reply. PMID- 28583288 TI - Correction to Lancet Haematol 2017; 4: e165-75. PMID- 28583289 TI - Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial. AB - BACKGROUND: Previously, we demonstrated that the addition of anti-human-T lymphocyte immunoglobulin (ATLG) to standard ciclosporin and methotrexate prophylaxis reduced graft-versus-host disease (GvHD) in adult patients treated with allogeneic haemopoietic cell transplantation from matched unrelated donors without negatively affecting relapse and survival. Since reports on long-term results from randomised trials testing anti-thymocyte globulin are scarce, we performed an extended follow-up of the trial. METHODS: Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation to receive ciclosporin and methotrexate with or without ATLG. 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATLG n=103, non-ATLG n=98). We assessced chronic GvHD, non-relapse mortality, relapse, relapse mortality, disease-free survival, overall survival, severe GvHD free (acute GvHD III-IV, and extensive chronic GvHD) and relapse-free survival, and time under immunosuppressive therapy after long-term follow-up. The trial is registered with the German Clinical Trials Register (DRKS00000002), ClinicalTrials.gov (NCT00655343), and EudraCT (2004-000232-91). FINDINGS: Median follow-up was 8.6 years (IQR 8.0-9.3). Only patients at risk for chronic GvHD (ie, patients who were alive and without a second transplant at 100 days) were included in the analyses of chronic GvHD (90 patients in the ATLG group, 80 patients in the non-ATLG group). At 8 years, the incidence of extensive chronic GvHD was 14% (95% CI 8-29) in the ATLG group versus 52% (42-64) in the non-ATLG group (adjusted hazard ratio [HR] 0.18, 95% CI 0.09-0.34; p<0.0001). Non-relapse mortality was 21% (95% CI 14-30) versus 34% (26-45; adjusted HR 0.66, 95% CI 0.38 1.16; p=0.15), incidence of relapse was 35% (95% CI 27-46) versus 30% (22-41; adjusted HR 1.17, 95% CI 0.71-1.93; p=0.54), relapse mortality was 31% (95% CI 23 41) versus 29% (21-40; adjusted HR 1.03, 95% CI 0.61-1.76; p=0.90), disease-free survival was 44% (95% CI 35-54) versus 36% (27-46) (adjusted HR 0.91, 95% CI 0.63 1.31; p=0.60), overall survival was 49% (95% CI 39-59) versus 37% (27-47; adjusted HR 0.82, 95% CI 0.56-1.20; p=0.31), and severe GvHD-free and relapse free survival was 34% (25-43) versus 13% (7-21) (adjusted HR 0.55, 95% CI 0.39 0.76; p=0.0003). The probability of being alive and free of immunosuppressive therapy was 47% (95% 37-57) in the ATLG group and 11% (5-18) in the non-ATLG group at 8 years. INTERPRETATION: ATLG in addition to standard ciclosporin and methotrexate as GvHD prophylaxis improves severe GvHD-free and relapse-free survival in the long term. The use of ATLG in unrelated donor transplantation after myeloablative conditioning substantially increases the probability of surviving free of immunosuppressive therapy, and thus reduces the risk associated with long-term immunosuppression. FUNDING: Neovii Biotech. PMID- 28583290 TI - NMR investigations unveil phase composition-property correlations in Sr0.55Na0.45SiO2.775 fast ion conductor. AB - This paper reports results of 23Na and 29Si solid-state NMR investigations carried out on sodium strontium silicate ion conductor, Sr0.55Na0.45SiO2.775 and presents the first experimental evidence to show that different synthesis conditions induce multiple devitrified phases. Along with 1-dimensional NMR, 23Na MQMAS spectra have been used to identify the phases corresponding to polymorphs of Na2Si2O5, in addition to the crystalline SrSiO3 and the glass/amorphous Na2Si2O5 phases. The surprising observation of about an order of magnitude higher ionic conductivity achieved in devitrified samples is attributed to the growth of the crystalline delta-Na2Si2O5 phase within the amorphous Na2Si2O5 phase domains, identified using NMR. Together with XRD and conductivity measurement data, the study leads to the identification of the chemical phase composition and an understanding of the composition-property-structure correlation in this material. Present findings, while do not show any evidence of Na doping in the SrSiO3 phase confirming earlier reports, explain the large discrepancy in the conductivity reported in the literature. PMID- 28583291 TI - Evaluation of a commercial Model Based Iterative reconstruction algorithm in computed tomography. AB - INTRODUCTION: Iterative reconstruction algorithms have been introduced in clinical practice to obtain dose reduction without compromising the diagnostic performance. PURPOSE: To investigate the commercial Model Based IMR algorithm by means of patient dose and image quality, with standard Fourier and alternative metrics. MATERIALS AND METHODS: A Catphan phantom, a commercial density phantom and a cylindrical water filled phantom were scanned both varying CTDIvol and reconstruction thickness. Images were then reconstructed with Filtered Back Projection and both statistical (iDose) and Model Based (IMR) Iterative reconstruction algorithms. Spatial resolution was evaluated with Modulation Transfer Function and Target Transfer Function. Noise reduction was investigated with Standard Deviation. Furthermore, its behaviour was analysed with 3D and 2D Noise Power Spectrum. Blur and Low Contrast Detectability were investigated. Patient dose indexes were collected and analysed. RESULTS: All results, related to image quality, have been compared to FBP standard reconstructions. Model Based IMR significantly improves Modulation Transfer Function with an increase between 12% and 64%. Target Transfer Function curves confirm this trend for high density objects, while Blur presents a sharpness reduction for low density details. Model Based IMR underlines a noise reduction between 44% and 66% and a variation in noise power spectrum behaviour. Low Contrast Detectability curves underline an averaged improvement of 35-45%; these results are compatible with an achievable reduction of 50% of CTDIvol. A dose reduction between 25% and 35% is confirmed by median values of CTDIvol. CONCLUSION: IMR produces an improvement in image quality and dose reduction. PMID- 28583292 TI - Design of experiments in medical physics: Application to the AAA beam model validation. AB - PURPOSE: The purpose of this study is to evaluate the usefulness of the design of experiments in the analysis of multiparametric problems related to the quality assurance in radiotherapy. The main motivation is to use this statistical method to optimize the quality assurance processes in the validation of beam models. METHOD: Considering the Varian Eclipse system, eight parameters with several levels were selected: energy, MLC, depth, X, Y1 and Y2 jaw dimensions, wedge and wedge jaw. A Taguchi table was used to define 72 validation tests. Measurements were conducted in water using a CC04 on a TrueBeam STx, a TrueBeam Tx, a Trilogy and a 2300IX accelerator matched by the vendor. Dose was computed using the AAA algorithm. The same raw data was used for all accelerators during the beam modelling. RESULTS: The mean difference between computed and measured doses was 0.1+/-0.5% for all beams and all accelerators with a maximum difference of 2.4% (under the 3% tolerance level). For all beams, the measured doses were within 0.6% for all accelerators. The energy was found to be an influencing parameter but the deviations observed were smaller than 1% and not considered clinically significant. CONCLUSION: Designs of experiment can help define the optimal measurement set to validate a beam model. The proposed method can be used to identify the prognostic factors of dose accuracy. The beam models were validated for the 4 accelerators which were found dosimetrically equivalent even though the accelerator characteristics differ. PMID- 28583294 TI - Hataedock treatment has preventive therapeutic effects for atopic dermatitis through skin barrier protection in Dermatophagoides farinae-induced NC/Nga mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hataedock treatment is traditionally used for the purpose of preventing the future skin disease by feeding herbal extracts to the newborn in traditional Chinese and Korean medicine. AIM OF THE STUDY: This study investigated the preventive therapeutic effects of Hataedock (HTD) treatment for atopic dermatitis (AD) through skin barrier protection in Dermatophagoides farinae-induced NC/Nga mice. MATERIALS AND METHODS: To the HTD treatment group, the extract of Coptis japonica Makino and Glycyrrhiza uralensis Fischer, which analyzed with High Performance Liquid Chromatography (HPLC)-fingerprint for quality consistency, was administered orally to the 3-week-old mice before inducing AD. After that, Dermatophagoides farinae was applied except the control group to induce AD-like skin lesions. We confirmed the effects of HTD on morphological changes, protection of skin barrier, regulation of Th2 differentiation, inflammation regulation and induction of apoptosis through histochemistry, immunohistochemistry, and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. RESULTS: HTD effectively reduced edema, angiogenesis and skin lesion. HTD also increased the levels of liver X receptor (LXR) and filaggrin but decreased the level of protein kinase C (PKC) (p<0.01). The levels of interleukin-4 (IL-4), IL-13, signal transducer and activator of transcription-6 (STAT-6) and Cluster of differentiation 40 (CD40) were significantly reduced in the HTD treated group (p<0.01). HTD also suppressed the mast cell degranulation and the level of the high-affinity IgE receptor (FcERI), substance P, Matrix metalloproteinases-9 (MMP-9) and 5-hydroxytryptamine (5-HT) (p<0.01). The levels of inflammatory factors such as nuclear factor-kappaB (NF kappaB) p65, phosphorylated IkappaB (p-IkappaB) and inducible nitric oxide synthase (iNOS) were also decreased (p<0.01). Apoptosis of inflammatory cells was also found to increase (p<0.01). CONCLUSION: Our results indicate that HTD effectively regulate the Th2 differentiation, mast cell activation and various inflammatory responses on AD-induced mice through protection of skin barrier. Therefore, HTD may have potential applications for alternative and preventive treatment in the management of AD. PMID- 28583295 TI - Chlorin e6 conjugated silica nanoparticles for targeted and effective photodynamic therapy. AB - Photodynamic therapy (PDT) using photosensitizer drug has become an important therapeutic modality. However, the stability and targeted delivery of photosensitizer remain a critical challenge for efficient PDT treatment. In the present study, we developed chlorin e6 (Ce6)-conjugated and folic acid (FA) decorated silica nanoparticles (silica-Ce6-FA) for targeted delivery of photosensitizer to the cancer cells. The synthesized NPs exhibited excellent stability and biocompatibility with MDA-MB-231 cells. The formulated particles were efficiently taken up by folate receptor-positive MDA-MB-231 cells, which were confirmed by comparative analysis with folate receptor-negative HepG2 cells. The folate receptor-targeted silica-Ce6-FA was highly accumulated inside the MDA MB-231 cells than free Ce6. The obtained NPs produced singlet oxygen efficiently under 670-nm laser exposure. The cell-killing effect of silica-Ce6-FA was higher when compared with free Ce6 under PDT treatment. The PDT-induced mitochondrial damage and apoptotic cell death were detected in silica-Ce6-FA-treated cells. PMID- 28583296 TI - Giant paraesophageal hiatal hernia: A complex clinical entity. PMID- 28583293 TI - Cell-cell communication in diabetic retinopathy. AB - In diabetic retinopathy, high glucose (HG)-mediated breakdown in cell-cell communication promotes disruption of retinal homeostasis. Several studies indicate that HG condition alters expression of connexin genes and subsequent gap junction intercellular communication (GJIC) in retinal vascular cells and non vascular cells. A serious consequence of disrupted cell-cell communication is apoptosis and breakdown of the blood-retinal barrier (BRB). More recently, studies suggest adverse effects from HG on retinal Muller cells. This article focuses on HG-mediated changes in connexin expression and GJIC and their subsequent effects on the breakdown of retinal homeostasis, cell death, compromised vascular permeability, and interactions between endothelial cells, pericytes and retinal Muller cells in the pathogenesis of diabetic retinopathy. Additionally, options for rectifying disrupted homeostasis under HG condition associated with diabetic retinopathy are reviewed. PMID- 28583298 TI - Discussion. PMID- 28583297 TI - The Cox-Maze IV procedure for atrial fibrillation is equally efficacious in patients with rheumatic and degenerative mitral valve disease. AB - OBJECTIVE: To determine whether the etiology of mitral valve disease (MVD), due to either rheumatic or degenerative pathology, influences long-term outcomes after the Cox-Maze IV procedure (CMPIV). METHODS: Between February 2001 and July 2015, 245 patients received a CMIV and concomitant mitral valve procedure. Patients were separated into 2 cohorts based on their etiology of MVD, degenerative (n = 153) and rheumatic (n = 92). Patients were followed prospectively (mean follow-up: 41 +/- 37 months) for recurrent atrial tachyarrhythmias (ATAs). Perioperative variables and long-term freedom from ATAs on and off antiarrhythmic drugs (AADs) were analyzed retrospectively. RESULTS: The 2 groups differed in that patients with rheumatic MVD were younger, more likely female, had a larger preoperative left atrial diameter, a longer duration of atrial fibrillation (AF), a greater percentage of longstanding persistent AF, and worse New York Heart Association functional class (P <= .001). Although there was no difference in operative mortality or overall major complications between the groups, the median length of stay in the intensive care unit was longer in the rheumatic cohort. Freedom from recurrent ATAs through 5 years was similar between the 2 cohorts. Predictors of recurrence included failure to use a box lesion (P = .012), the duration of preoperative AF (P = .001), and early occurrence of ATAs (P = .015). CONCLUSIONS: The long-term efficacy of the CMPIV in restoring sinus rhythm was similar in patients with either rheumatic or degenerative mitral valve disease. Despite representing a sicker patient population with a longer duration of preoperative AF, patients with rheumatic MVD equally benefit from the CMPIV. PMID- 28583299 TI - Arresting pulmonary atresia intact ventricular septum...only if you have to. PMID- 28583300 TI - Testing evidence routine practice: Using an implementation framework to embed a clinically proven asthma service in Australian community pharmacy. AB - INTRODUCTION: Community pharmacists are well placed and evidence clearly demonstrates that they can be suitably trained to deliver professional services that improve the management of asthma patients in clinical, economic and humanistic terms. However the gap between this evidence and practice reality remains wide. In this study we measure the implementation process as well as the service benefits of an asthma service model. METHODS: Using an effectiveness implementation hybrid design, a defined implementation process (progression from Exploration through Preparation and Testing to Operation stages) supporting an asthma service (promoting asthma control and inhaler technique) was tested in 17 community pharmacies across metropolitan Sydney. RESULTS: Seven pharmacies reached the Operation stage of implementation. Eight pharmacies reached the Testing stage of implementation and two pharmacies did not progress beyond the Preparation stage of implementation. A total of 128 patients were enrolled in the asthma service with 110 patients remaining enrolled at the close of the study. Asthma control showed a positive trend throughout the service with the overall proportion of patients with 'poor' asthma control at baseline decreasing from 72% to 57% at study close. There was a statistically significant increase in the proportion of patients with correct inhaler technique from 12% at Baseline (Visit 1) to 33% at Visit 2 and 57% at study close. CONCLUSION: Implementation of the asthma service varied across pharmacies. Different strategies specific to practice sites at different stages of the implementation model may result in greater uptake of professional services. The asthma service led to improved patient outcomes overall with a positive trend in asthma control and significant change in inhaler technique. PMID- 28583302 TI - Implementation of a mental health medication management intervention in Australian community pharmacies: Facilitators and challenges. AB - BACKGROUND: Community pharmacists are in an ideal position to promote and provide mental health medication management services. However, formalised or structured pharmacy services to support consumers with mental health conditions are scarce. Australian mental health consumers indicated a need for targeted community pharmacy mental health services which presented an opportunity to develop an intervention that were integrated with remunerated professional services. OBJECTIVES: The study aimed to pilot a mental health medication management intervention in Australian community pharmacies. Pharmacists worked in partnership with consumers, carers and mental health workers over three to six months to set and support achievement of individual goals related to medicines use, physical health and mental wellbeing. This paper provides a comparison of community pharmacies that successfully delivered the intervention with those that did not and identifies facilitators and challenges to service implementation. METHODS: One hundred pharmacies opted to pilot the delivery of the intervention in three Australian states (Queensland, Western Australia and northern New South Wales). Of those, 55 successfully delivered the intervention (completers) whilst 45 were unsuccessful (non-completers). A mixed methods approach, including quantitative pharmacy surveys and qualitative semi-structured interviews, was used to gather data from participating pharmacies. Following intervention development, 142 pharmacists and 21 pharmacy support staff attended training workshops, received resource kits and ongoing support from consumer and pharmacist mentors throughout intervention implementation. Baseline quantitative data was collected from each pharmacy on staff profile, volume of medicines dispensed, the range of professional services delivered and relationships with health professionals. At the completion of the study participants were invited to complete an online exit survey and take part in a semi-structured interview that explored their experiences of intervention implementation and delivery. Twenty nine staff members from completer pharmacies returned exit surveys and interviews were conducted with 30 staff from completer and non-completer pharmacies. RESULTS: Descriptive analyses of quantitative data and thematic analyses of qualitative data were used to compare completers and non-completers. Baseline similarities included numbers of general and mental health prescriptions dispensed and established professional services. However, there was greater prevalence of diabetes management, opioid substitution services, and relationships with mental health services in completer pharmacies. Key facilitators for completers included pharmacy owner/manager support, staff buy-in and involvement, intervention flexibility, recruitment immediately following training, integration of intervention with existing services, changes to workflow, and regular consumer contact. Key barriers for both groups included lack of pharmacy owner/manager support or staff buy-in, time constraints, privacy limitations and pilot project associated paperwork. CONCLUSIONS: Insights into factors that underpinned successful intervention implementation and delivery should inform effective strategies for similar future studies and allocation of pharmacy mental health service delivery resources. PMID- 28583301 TI - The TOronto ThromboProphylaxis Patient Safety Initiative (TOPPS): A cluster randomised trial. AB - BACKGROUND: Although venous thromboembolism (VTE) is one of the most common and most preventable complications of hospital stay, review of the literature demonstrates large evidence-care gaps for VTE prevention. OBJECTIVES: This study aimed to determine if a multi-component quality improvement (QI) strategy, including the support of hospital leadership, use of order sets, audit and feedback, and active pharmacy involvement, could increase the use of appropriate thromboprophylaxis in patients hospitalized for hip fracture surgery (HFS), major general surgery (MGS) and acute medical illness (MED). METHODS: TOPPS was a cluster randomized trial involving eight hospitals. After a baseline data collection phase, one of the three patient groups at each site was randomized to the targeted QI intervention while the other two groups served as controls. In the next phase, an additional patient group at each site was randomized to the intervention while the third group remained controls. Standardized chart audits were conducted to assess the rates of appropriate thromboprophylaxis use. RESULTS: At baseline, the rates of appropriate thromboprophylaxis were 79% in HFS, 43% in MGS and 31% in MED. By the end of phase 3, 89% of HFS, 65% of MGS and 70% of MED patients were receiving appropriate prophylaxis. Improvement was greater in the intervention groups compared to controls (85% vs. 76% in HFS; 67% vs. 54% in MGS; 64% vs. 62% in MED) and this difference reached significance in the MGS group (p = 0.048). CONCLUSIONS: Use of a multi-component intervention can be effective in improving the appropriate use of thromboprophylaxis. PMID- 28583303 TI - Keap1 knockdown in melanocytes induces cell proliferation and survival via HO-1 associated beta-catenin signaling. AB - BACKGROUND: Nrf2-Keap1 signaling pathway protects cells against photo-oxidative stress. Yet in recent works, its role in melanogenesis together with cell protection functions against oxidative stress has been gaining interest. However, its effect on melanogenesis still has contradictory results from different studies. OBJECTIVE: The aims of our study were to investigate the effect of Keap1 silencing in melanocyte on melanogenesis and its associated mechanism. METHODS: Primary human epidermal melanocytes and melan-a cell line were used for this experiment. RNA sequencing was done to identify genes involved in melanocyte biology using Keap1 knockdown through siRNA techniques. And melanogenesis and the expression of melanogenesis-associated molecules were evaluated in Keap1 silenced melanocyte to examine the effects of Keap1 on melanogenesis, melanocyte growth, and related pathways. RESULTS: RNA-sequencing data revealed that Keap1 knockdown in primary human epidermal melanocytes (PHEMs) induced cell survival-related gene expression. Additionally, siRNA-mediated inhibition of Keap1 led to upregulation of MITF and melanogenesis-associated molecules along with Nrf2 activation in PHEMs. HO-1, a major gene that is upregulated in RNA-sequencing using Keap1 silenced PHEMs, protected melanocytes against H2O2-induced cell death and upregulated MITF and beta-catenin expression. Further, increased expression of melanogenesis-associated molecules after Keap1 silencing was validated to occur through HO-1-associated beta-catenin activation in a Keap1 and HO-1 double knockdown experiment. CONCLUSION: This work suggests that Keap1 silencing in melanocytes induced melanogenesis and the expression of melanogenesis-associated molecules through HO-1-associated beta-catenin activation. Keap1 downregulation in melanocytes is important for cell proliferation and survival. PMID- 28583305 TI - Immunogenicity and safety of a new hexavalent vaccine (DTaP5-IPV-HB-Hib) administered in a mixed primary series schedule with a pentavalent vaccine (DTaP5 IPV-Hib). AB - DTaP5-IPV-HB-Hib vaccine is a fully-liquid, combination hexavalent vaccine. This phase III, open-label, multicentre study conducted in Spain, evaluated the immune response to all DTaP5-IPV-HB-Hib antigens when the vaccine was used in a mixed hexa/penta/hexa primary series. Infants (who had received one dose of hepatitis B vaccine at birth) received a mixed schedule including DTaP5-IPV-HB-Hib (PRP-OMP conjugate) at 2 and 6months of age, DTaP5-IPV-Hib at 4months, meningococcal serogroup C conjugate (MCC) vaccine at 2 and 4months, and routine rotavirus and pneumococcal vaccination. One month post-dose 3 of the mixed schedule, response rates were considered acceptable if the lower bound of the two-sided 95% confidence interval around the post-vaccination response rate was >90% for hepatitis B and >80% for Haemophilus influenzae type b (Hib). Secondary immunogenicity objectives included description of the antibody response to all hexavalent antigens one month after completion of the mixed schedule, and to MCC antigen one month after the second MCC dose. The safety profile after each dose of study vaccine was described. Of 385 healthy infants enrolled, 384 completed the study. The primary objective was achieved for both hepatitis B and Hib; the lower bound of the 2-sided 95% CI of the response rates (97.2% and 99.0%, respectively) were greater than the pre-specified acceptability thresholds. One month post-dose 3 of the mixed schedule, all participants were seroprotected against diphtheria, tetanus and polio. The mixed schedule induced a robust immune response to all hexavalent antigens. The co-administration of the hexavalent vaccine in a mixed schedule with MCC vaccine did not reduce the immune response to vaccine antigens. Vaccines were well tolerated. In conclusion, the acceptability of response rates against Hib and hepatitis B were demonstrated one month post-dose 3 of the mixed schedule; robust immune responses against all other hexavalent antigens were observed. clinicaltrial.gov: NCT01839188; EudraCT: 2012-004221-25. PMID- 28583306 TI - Developing and utilizing controlled human models of infection. AB - The controlled human infection model (CHIM) to assess the efficacy of vaccines against Shigella and enterotoxigenic Escherichia coli (ETEC) has several unique features that could significantly enhance the ability to test candidate vaccines. Despite increasing interest in these models, questions remain as to how to best incorporate them into vaccine development and how to maximize results. We designed a workshop focused on CHIM as part of the Vaccines Against Shigella and ETEC (VASE) Conference. The workshop, using the World Cafe method, focused on; clinical outcomes, nonclinical outcomes and model standardization. Researchers with a variety of expertise and experience rotated through each focus area and discussed relevant sub-topics. The results of these discussions were presented and questions posed to guide future workshops. Clinical endpoint discussions focused on the need for harmonized definitions; optimized attack rates; difficulties of sample collection and a need for non-stool based endpoints. Nonclinical discussions centered on evolving omics-based opportunities, host predictors of susceptibility and novel characterizations of the immune response. Model standardization focused on the value of shared procedures across institutions for clinical and non-clinical endpoints as well as for strain preparation and administration and subject selection. Participants agreed CHIMs for Shigella and ETEC vaccine development could accelerate vaccine development of a promising candidate; however, it was also appreciated that variability in the model and our limited understand of the host-pathogen interaction may yield results that could negatively impact a suitable candidate. Future workshops on CHIM are needed to ensure the optimal application of these models moving forward. PMID- 28583304 TI - Transgenerational inheritance of neurobehavioral and physiological deficits from developmental exposure to benzo[a]pyrene in zebrafish. AB - Benzo[a]pyrene (B[a]P) is a well-known genotoxic polycylic aromatic compound whose toxicity is dependent on signaling via the aryl hydrocarbon receptor (AHR). It is unclear to what extent detrimental effects of B[a]P exposures might impact future generations and whether transgenerational effects might be AHR-dependent. This study examined the effects of developmental B[a]P exposure on 3 generations of zebrafish. Zebrafish embryos were exposed from 6 to 120h post fertilization (hpf) to 5 and 10MUM B[a]P and raised in chemical-free water until adulthood (F0). Two generations were raised from F0 fish to evaluate transgenerational inheritance. Morphological, physiological and neurobehavioral parameters were measured at two life stages. Juveniles of the F0 and F2 exhibited hyper locomotor activity, decreased heartbeat and mitochondrial function. B[a]P exposure during development resulted in decreased global DNA methylation levels and generally reduced expression of DNA methyltransferases in wild type zebrafish, with the latter effect largely reversed in an AHR2-null background. Adults from the F0 B[a]P exposed lineage displayed social anxiety-like behavior. Adults in the F2 transgeneration manifested gender-specific increased body mass index (BMI), increased oxygen consumption and hyper-avoidance behavior. Exposure to benzo[a]pyrene during development resulted in transgenerational inheritance of neurobehavioral and physiological deficiencies. Indirect evidence suggested the potential for an AHR2-dependent epigenetic route. PMID- 28583307 TI - The effect of timing of influenza vaccination and sample collection on antibody titers and responses in the aged. AB - Antibody responses, B cell subset distribution in blood and the blood transcriptome were analyzed in younger and aged human subjects before and after vaccination with the inactivated influenza vaccine. In the aged, but not the younger, individuals we saw a clear difference in antibody titers including those at baseline depending on the time of vaccination and sample collection. Differences in baseline titers in aged individuals treated in the morning or afternoon in turn affected responsiveness to the vaccine. In both younger and aged individuals, the time of sample collection also affected relative numbers of some of the B cell subsets in blood. A global gene expression analysis with whole blood samples from the aged showed small but statistically significant differences depending on the time of sample collection. Our data do not indicate that timing of vaccination affects immune responsiveness of the aged, but rather shows that in clinical influenza vaccine trials timing of collection of samples can have a major and potentially misleading influence on study outcome. In future vaccine trials, timing of vaccination and sample collection should be recorded carefully to allow for its use as a study covariant. PMID- 28583309 TI - Reply to Rodolfo Montironi, Silvia Gasparrini, Antonio Lopez-Beltran, et al's Letter to the Editor re: Umberto Leone Roberti Maggiore, Simone Ferrero, Massimo Candiani, et al. Bladder Endometriosis: A Systematic Review of Pathogenesis, Diagnosis, Treatment, Impact on Fertility, and Risk of Malignant Transformation. Eur Urol 2017;71:790-807. Benign Mullerian Lesions in the Urinary Bladder: Endometriosis, Endocervicosis, Endosalpingiosis, and Mullerianosis. PMID- 28583308 TI - An epitope-specific DerG-PG70 LEAPS vaccine modulates T cell responses and suppresses arthritis progression in two related murine models of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune joint disease maintained by aberrant immune responses involving CD4+ T helper (Th)1 and Th17 cells. In this study, we tested the therapeutic efficacy of Ligand Epitope Antigen Presentation System (LEAPSTM) vaccines in two Th1 cell-driven mouse models of RA, cartilage proteoglycan (PG)-induced arthritis (PGIA) and PG G1-domain-induced arthritis (GIA). The immunodominant PG peptide PG70 was attached to a DerG or J immune cell binding peptide, and the DerG-PG70 and J-PG70 LEAPS vaccines were administered to the mice after the onset of PGIA or GIA symptoms. As indicated by significant decreases in visual and histopathological scores of arthritis, the DerG-PG70 vaccine inhibited disease progression in both PGIA and GIA, while the J-PG70 vaccine was ineffective. Splenic CD4+ cells from DerG-PG70-treated mice were diminished in Th1 and Th17 populations but enriched in Th2 and regulatory T (Treg) cells. In vitro spleen cell-secreted and serum cytokines from DerG-PG70 treated mice demonstrated a shift from a pro-inflammatory to an anti inflammatory/regulatory profile. DerG-PG70 peptide tetramers preferentially bound to CD4+ T-cells of GIA spleen cells. We conclude that the DerG-PG70 vaccine (now designated CEL-4000) exerts its therapeutic effect by interacting with CD4+ cells, which results in an antigen-specific down-modulation of pathogenic T-cell responses in both the PGIA and GIA models of RA. Future studies will need to determine the potential of LEAPS vaccination to provide disease suppression in patients with RA. PMID- 28583310 TI - Robotic-assisted Radical Prostatectomy for High-risk Cancer: Time for "Sexta fecta". PMID- 28583313 TI - Re: Clonal Evolution of Chemotherapy-resistant Urothelial Carcinoma. PMID- 28583314 TI - Characterization of high-intensity plaques on noncontrast T1-weighted magnetic resonance imaging by coronary angioscopy. AB - BACKGROUND: A recent study showed that coronary high-intensity plaques (HIPs) visualized by noncontrast T1-weighted imaging (T1WI) in cardiac magnetic resonance were associated with coronary events. We used coronary angioscopy to analyze HIP plaque morphology. METHODS AND RESULTS: A total 17 lesions from 17 patients with stable or unstable angina pectoris were evaluated at the culprit lesion by noncontrast T1WI using 1.5-T magnetic resonance; of them, nine (53%) were HIPs and eight (47%) were non-HIPs, and all were analyzed by coronary angioscopy. We assessed the existence of thrombus and plaque yellow color grade (YG). YG was assessed visually according to a four-grade scale: 0, white; 1, light yellow; 2, yellow; 3, intense yellow. The frequency of thrombus was significantly higher in HIPs than in non-HIPs (89% vs. 25%, respectively; p=0.007). YG was significantly more frequent in HIPs than in non-HIPs (2.2+/-0.4 vs. 0.7+/-0.7, respectively; p=0.01). CONCLUSIONS: These data indicated that HIPs on noncontrast T1WI were associated with the presence of high-grade yellow plaque with thrombus. PMID- 28583311 TI - Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets. AB - BACKGROUND: Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies. OBJECTIVE: To identify genetic alterations with potential clinical implications in NMIBC. DESIGN, SETTING, AND PARTICIPANTS: Pretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory Improvement Amendments-certified clinical laboratory. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Comutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Guerin (BCG) were estimated using Kaplan-Meier and Cox regression analyses. RESULTS AND LIMITATIONS: TERT promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. ERBB2 or FGFR3 alterations were present in 57% of high-grade NMIBC tumors in a mutually exclusive pattern. DNA damage repair (DDR) gene alterations were seen in 30% (25/82) of high-grade NMIBC tumors, a rate similar to MIBC, and were associated with a higher mutational burden compared with tumors with intact DDR genes (p<0.001). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio=3.14, 95% confidence interval: 1.51-6.51, p=0.002). CONCLUSIONS: Next-generation sequencing of treatment-naive index NMIBC tumors demonstrated that the majority of NMIBC tumors had at least one potentially actionable alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy. DDR gene alterations were frequent in high grade NMIBC and were associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. ARID1A mutations were associated with an increased risk of recurrence after BCG therapy. Whether ARID1A mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation. PATIENT SUMMARY: Analysis of frequently mutated genes in superficial bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests. PMID- 28583312 TI - Prognostic Impact of a 12-gene Progression Score in Non-muscle-invasive Bladder Cancer: A Prospective Multicentre Validation Study. AB - BACKGROUND: Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle invasive bladder cancer (MIBC) is life-threatening and cannot be accurately predicted using clinical and pathological risk factors. Biomarkers for stratifying patients to treatment and surveillance are greatly needed. OBJECTIVE: To validate a previously developed 12-gene progression score to predict progression to MIBC in a large, multicentre, prospective study. DESIGN, SETTING, AND PARTICIPANTS: We enrolled 1224 patients in ten European centres between 2008 and 2012. A total of 750 patients (851 tumours) fulfilled the inclusion and sample quality criteria for testing. Patients were followed for an average of 28 mo (range 0-76). A 12-gene real-time qualitative polymerase chain reaction assay was performed for all tumours and progression scores were calculated using a predefined formula and cut-off values. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured progression to MIBC using Cox regression analysis and log rank tests for comparing survival distributions. RESULTS AND LIMITATIONS: The progression score was significantly (p<0.001) associated with age, stage, grade, carcinoma in situ, bacillus Calmette-Guerin treatment, European Organisation for Research and Treatment of Cancer risk score, and disease progression. Univariate Cox regression analysis showed that patients molecularly classified as high risk experienced more frequent disease progression (hazard ratio 5.08, 95% confidence interval 2.2-11.6; p<0.001). Multivariable Cox regression models showed that the progression score added independent prognostic information beyond clinical and histopathological risk factors (p<0.001), with an increase in concordance statistic from 0.82 to 0.86. The progression score showed high correlation (R2=0.85) between paired fresh-frozen and formalin-fixed paraffin-embedded tumour specimens, supporting translation potential in the standard clinical setting. A limitation was the relatively low progression rate (5%, 37/750 patients). CONCLUSIONS: The 12-gene progression score had independent prognostic power beyond clinical and histopathological risk factors, and may help in stratifying NMIBC patients to optimise treatment and follow-up regimens. PATIENT SUMMARY: Clinical use of a 12-gene molecular test for disease aggressiveness may help in stratifying patients with non-muscle-invasive bladder cancer to optimal treatment regimens. PMID- 28583315 TI - A case of eel collagen allergy. PMID- 28583316 TI - Formulation development and evaluation of antimicrobial polyherbal gel. AB - OBJECTIVE: In the recent years, there has been a gradual revival of interest in the use of medicinal plants in developing countries because herbal medicines have been reported safe with minimal adverse side effect especially when compared with synthetic drugs. METHOD: In the present study we prepared gel formulations (formulations A and B) which comprised of ethanolic extract of Azadirachta indica, Curcuma longa, Allium sativum, Ocimum sactum, Cinnamomum zeylanicum nees and Tamarindus indica in a concentration of 0.1 and 0.5%, respectively in a base. The base was prepared by using carbapol 940, propylene glycol-400, ethanol, methyl paraben, propylparaben, EDTA, triethanolamine and required amount of water in a quantity sufficient to prepare 50g. The prepared formulations were screened for their antimicrobial activity by agar well diffusion technique against S. aureus, B. subtilis, A. niger and E. coli which are representative types of Gram positive and Gram negative organisms. The formulations were also evaluated for appearance and homogeneity, pH, viscosity and rheological studies, spreadability, drug content uniformity, skin irritation test (Patch test) and washability. RESULT: The results of the studies revealed that both formulation under study viz A and B showed better zone of inhibition as compared with the base. However, formulation B exhibited maximum activity against the selected strains which may be attributed to its greater amount of herbal extracts as compared to formulation A. CONCLUSION: Based on our research, it could be concluded that these formulations possess antimicrobial activity and can be used safely on human skin. PMID- 28583317 TI - [The French medecine pricing committee]. AB - The French medicine pricing committee (CEPS) has to reconcile several major constraints, including optimal patient access to medicines and a good control of expenditures on reimbursable medicines. From 2013 to 2015, drug price decreases and discounts obtained by CEPS contributed more than ? 5 billion to the balance of the health insurance accounts. As for price setting, there is a significant drop in the prices of medicines in France once they are registered for reimbursement. France is affected by a limited, but costly, flow of innovative medicines, whose prices are higher than those of previous generations, a reflection of an international gradient to which France is obviously subject, despite prices that remain at the low end of the range in Western Europe. The provision of innovative medicines for all patients who need them has been ensured in France over the last fifteen years at a controlled cost. But with the arrival of new expensive products, a resolute policy of control of expenditures must take over from the fall in prices, and original financing channels will have to be explored. PMID- 28583318 TI - [Pharmacist's interview with type 2 diabetes: Development of a follow-up form]. AB - OBJECTIVES: Type 2 diabetes is a major public health concern because of its prevalence, the severity of complications and the financial implications. Compliance and patient's autonomy in medications intake play key roles in the success of treatment. Pharmacists' interviews ensure an optimized and individual follow-up. Type 2 diabetes is not one of the targeted diseases to perform pharmacists' interviews on under Health Insurance. We thus judged useful to contribute to their development. METHODS: We applied a cross-disciplinary methodological process in order to define the specifications of the follow-up form useful to conduct the pharmacist's interview 1 by focusing on the identification of a non-compliance and its origins. A feasibility study was carried out in order to check its workability to the pharmacy practice. RESULTS: The follow-up form, associated with a pharmacist practical guide, includes 3 parts: (1) General informations, (2) Survey establishing patient's knowledge, (3) Summary including a level of knowledge assessment grid. Outcomes provide a long but appropriate-felt duration, few difficulties to conduct the interview and a proven usefulness in 90% of all cases that make the follow-up form suitable to the pharmacy practice. CONCLUSIONS: This tool could serve as a model for the pharmacist to conduct his future interviews for the type 2 diabetes patients, thus improving patient care, together with other health professionals. PMID- 28583319 TI - "Spot diagnosis" or "spot the diagnosis"? PMID- 28583320 TI - KAI1 overexpression promotes apoptosis and inhibits proliferation, cell cycle, migration, and invasion in nasopharyngeal carcinoma cells. AB - OBJECTIVES: The purpose of this study is to characterize the effect of KAI1 overexpression on the biological behavior of nasopharyngeal carcinoma (NPC) cells. BACKGROUND: Nasopharyngeal carcinoma is a highly malignant tumor with a high rate of incidence in China. Currently, there are no ideal therapeutic options for patients with NPC, but a targeted therapy would have great potential for treating it. Therefore, there is an urgent need for novel therapeutic targets to provide new options for treating NPC. The KAI1 gene was originally identified as a metastasis suppressor gene for advanced human cancer. In NPC cell lines and tissues, the expression of KAI1 decreased as the metastatic potential of cells increased, but its potential as a therapeutic target has not been elucidated. METHODS: Non-transformed nasopharyngeal epithelium cell NP69 and NPC cell line C666-1 were cultured and KAI1 expression in these cells was detected by qRT-PCR and Western blot. After the transfection of KAI1-pCDNA3.1 to NP69 and C666-1, the KAI1 expression in these cells was detected by qRT-PCR and Western blot, the proliferation was performed by MTS, the cell cycle and apoptosis were performed by flow cytometry, the migration and invasion were examined by transwell. RESULTS: Our results showed that KAI1 was significantly upregulated in C666-1 cells compared to that in NP69 cells. In addition, KAI1 overexpression significantly inhibited the proliferation, cell cycle, migration, and invasion, and promoted apoptosis of C666-1 cells, but had no significant effect on NP69 cells. CONCLUSION: Our findings suggest that KAI1 overexpression promotes apoptosis and inhibits proliferation, cell cycle, migration, and invasion in NPC cells. We hypothesize that KAI1 overexpression could be a potential therapeutic target for NPC. PMID- 28583321 TI - Text Message Reminders Reduce Outpatient Radiology No-Shows But Do Not Improve Arrival Punctuality. AB - PURPOSE: To assess whether text-based appointment reminders are a cost-effective strategy to decrease patient no-shows and improve arrival punctuality in the setting of outpatient radiology imaging. METHODS AND MATERIALS: From July 2016 through October 2016, all patients scheduled for MRI imaging at two outpatient locations were randomly assigned to a texting or nontexting arm based on the day. On texting days, patients scheduled for MRI received both the traditional phone call reminder as well as a text-based reminder of their MRI examination. On nontexting days, patients scheduled for MRI received only the traditional phone call reminder. All patients were evaluated based on whether they attended the MRI appointment and, if attended, whether they arrived 30 minutes before the MRI appointment as requested in the text message. Potential associations between the text reminder and examination attendance and punctuality were assessed by chi2 test with associations considered significant at P <= .05. RESULTS: A total of 6,989 patients were eligible for analysis, 3,086 in the texting group and 3,903 in the nontexting group. In the texting group, 67.5% (2,083/3,086) of patients were successfully texted with an appointment reminder, with the other 32.5% not having text accessibility. The percent of no-shows was significantly decreased for the texting group compared with the nontexting group (3.8% versus 5.1%, P = .02, odds ratio 0.75, 95% confidence interval 0.59 to 0.94). There was no significant difference between the percent of patients arriving the requested 30 minutes before the MRI appointment between the texting and nontexting groups (60.0% versus 58.5%, P = .25). CONCLUSION: Text message appointment reminders are an effective strategy for decreasing radiology no-shows, even in the presence of traditional phone reminders, but do not improve patient arrival punctuality. PMID- 28583322 TI - Ocular findings in patients with cholestatic disorders of infancy: A single centre experience. AB - BACKGROUND AND STUDY AIMS: Neonatal cholestasis can be associated with ocular findings that might aid in its diagnosis, e.g., Alagille syndrome (AGS) and Niemann Pick disease (NPD). We aimed to investigate the frequency of ocular manifestations in infants with cholestasis. PATIENTS AND METHODS: This cross sectional study included cholestatic infants presenting to the Paediatric Hepatology Unit, Cairo University Paediatric Hospital, Cairo, Egypt. All infants underwent examination of lid, ocular motility, anterior and posterior segments and measurement of intraocular pressure, cycloplegic refraction, ocular ultrasonography and vision. RESULTS: The study included 112 infants with various cholestasis; 73 (65.2%) were males. The median age was 2months. Diagnosis was reached in 39 cases: 14 had AGS, 14 had biliary atresia (BA), 4 had NPD, 4 had post-haemolytic cholestasis, 2 had cytomegalovirus neonatal hepatitis, and one case had hepatorenal tyrosinaemia. Thirteen cases were probably having progressive familiar intrahepatic cholestasis (PFIC) type 1 or 2 considering their persistent cholestasis in the presence of normal gamma-glutamyl transpeptidase; 28 were left with a diagnosis of "idiopathic neonatal hepatitis" (INH), and 32 (28.6%) had no definite diagnosis. Ophthalmologic abnormalities were found in 39 cases (34.8%). The commonest finding was unilateral/bilateral optic nerve drusen in 12 (10.7%), followed by posterior embryotoxon in 11 (9.8%). Ocular findings were observed in 64.3% patients with AGS, 50% patients with NPD, 30.8% cases with suspected PFIC type 1or 2, 28.6% infants with INH, and 14.3% patients with BA. CONCLUSION: Ophthalmologic findings are not uncommon among cholestatic infants. Ophthalmologic examination should be routinely performed, including assessment of anterior segment, fundus examination, and ocular ultrasound. PMID- 28583323 TI - Evaluation of the efficacy and toxicity profile associated with intraperitoneal chemotherapy use in older women. AB - OBJECTIVE: Intraperitoneal (IP) chemotherapy (CT) for treatment of epithelial ovarian cancer (EOC) has been shown to provide a substantial OS advantage. This study aims to compare the toxicity and benefits of IP CT in patients >=70 with those <70. METHODS: We performed a single institution retrospective review of patients diagnosed with Stage IIA-IIIC EOC from 2000 to 2013 who received IP CT. Clinicopathologic characteristics were extracted, and survival was calculated. RESULTS: 133 patients were included with 100 pts. <70years old and 33 pts. >=70years old. Clinical trial enrollment was similar despite age. In trial enrolled patients, older patients received statistically fewer cycles of therapy (6.4 vs 5.8, p=0.002) but had similar dose delays (0.9 vs 0.7, p=0.72), and modifications (0.9 vs 0.36, p=0.11). Median PFS (27 vs 31months) and OS (71 and 62months) were not statistically different. Grade 3/4 neutropenia was significantly worse in the older patients (82% vs 100%, p=0.04). Neuropathy grade >=2 and other non-hematologic toxicities were not different between age groups. CONCLUSIONS: Despite completing fewer cycles of IP CT, older EOC patients had comparable survival to younger patients. The population of older patients receiving IP CT in this study were on clinical trial and likely to be heartier than the general older population. IP CT appears well tolerated and effective among select older patients and is likely under-utilized outside of clinical trials. PMID- 28583324 TI - Association of general and central obesity with hypertension. AB - BACKGROUND & AIM: Hypertension as a risk factor for cardiovascular disease has growing prevalence. An increase in body weight is typically followed by an increase in blood pressure. This study aimed to investigate the association of general and central obesity with hypertension in Indonesian women using WHO and Indonesian classification systems. METHODS: Cross-sectional study of Indonesian women aged 18 years or and more (313,714 participants), using national level Indonesia National Basic Health Research (2013). RESULTS: The prevalence of hypertension in Indonesian women in this study was 32.8%. Based on logistic regression analysis, hypertension was significantly associated with residential area, educational attainment, self-reported smoking status, cardiovascular disease, chronic kidney disease, diabetes mellitus, body mass index and waist circumference. Furthermore, the odds of having hypertension for general and central obesity according to WHO classification were adjusted odds ration (aOR) 2.61, 95% CI 2.52-2.70 and aOR 1.50, 95% CI 1.46-1.53. By Indonesian classification were aOR 2.21, 95% CI 2.16-2.26 and aOR 1.48, 95% CI 1.45-1.51. CONCLUSION: By using International WHO and standard Indonesia classification systems, general and central obesity were associated with hypertension in Indonesia women. Thus, not only general obesity but also central obesity should be used to assess obesity in Indonesian women. PMID- 28583325 TI - Neuroprotective Effect of Low-Intensity Pulsed Ultrasound Against MPP+-Induced Neurotoxicity in PC12 Cells: Involvement of K2P Channels and Stretch-Activated Ion Channels. AB - Parkinson's disease is the second most common neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. 1-Methyl-4-phenylpyridinium (MPP+) is a dopaminergic neuronal toxin that is widely used in constructing Parkinson's disease models in vitro. Low intensity pulsed ultrasound (LIPUS) is a non-invasive therapeutic approach that has neuromodulation and neuroprotective effects in the central neural system; however, whether LIPUS can provide protection for dopaminergic neurons against MPP+-induced neurocytotoxicity remains unknown. In this study, we found that pre treatment with LIPUS (1 MHz, 50 mW/cm2, 20% duty cycle and 100-Hz pulse repetition frequency, 10 min) inhibited MPP+-induced neurotoxicity and mitochondrial dysfunction in PC12 cells. LIPUS decreased MPP+-induced oxidative stress by modulating antioxidant proteins, including thioredoxin-1 and heme oxygenase-1, and prevented neurocytotoxicity via the phosphoinositide 3-kinase (PI3K)-Akt and ERK1/2 pathways. Furthermore, these beneficial effects were attributed to the activation of K2P channels and stretch-activated ion channels by LIPUS. These data indicate that LIPUS protects neuronal cells from MPP+ induced cell death through the K2P channel- and stretch-activated ion channel mediated downstream pathways. The data also suggest that LIPUS could be a promising therapeutic method in halting or retarding the degeneration of dopaminergic neurons in Parkinson's disease in a non-invasive manner. PMID- 28583326 TI - Cystathionine beta-synthase deficiency: Of mice and men. AB - Cystathionine beta-synthase (CBS) deficiency (Online Mendelian Inheritance in Man [OMIM] 236,200) is an autosomal recessive disorder that is caused by mutations in the CBS gene. It is the most common inborn error of sulfur metabolism and is the cause of classical homocystinuria, a condition characterized by very high levels of plasma total homocysteine and methionine. Although recognized as an inborn error of metabolism over 60years ago, these is still much we do not understand related to how this specific metabolic defect gives rise to its distinct phenotypes. To try and answer these questions, several groups have developed mouse models on CBS deficiency. In this article, we will review various mouse models of CBS deficiency and discuss how these mouse models compare to human CBS deficient patients. PMID- 28583327 TI - 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients. AB - 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare inborn error of ketone body synthesis and leucine degradation, caused by mutations in the HMGCL gene. In order to obtain a comprehensive view on this disease, we have collected clinical and biochemical data as well as information on HMGCL mutations of 37 patients (35 families) from metabolic centers in Belgium, Germany, The Netherlands, Switzerland, and Turkey. All patients were symptomatic at some stage with 94% presenting with an acute metabolic decompensation. In 50% of the patients, the disorder manifested neonatally, mostly within the first days of life. Only 8% of patients presented after one year of age. Six patients died prior to data collection. Long-term neurological complications were common. Half of the patients had a normal cognitive development while the remainder showed psychomotor deficits. We identified seven novel HMGCL mutations. In agreement with previous reports, no clear genotype-phenotype correlation could be found. This is the largest cohort of HMGCLD patients reported so far, demonstrating that HMGCLD is a potentially life-threatening disease with variable clinical outcome. Our findings suggest that the clinical course of HMGCLD cannot be predicted accurately from HMGCL genotype. The overall outcome in HMGCLD appears limited, thus rendering early diagnosis and strict avoidance of metabolic crises important. PMID- 28583328 TI - 3D printed tablets loaded with polymeric nanocapsules: An innovative approach to produce customized drug delivery systems. AB - The generation of multi-functional drug delivery systems, namely solid dosage forms loaded with nano-sized carriers, remains little explored and is still a challenge for formulators. For the first time, the coupling of two important technologies, 3D printing and nanotechnology, to produce innovative solid dosage forms containing drug-loaded nanocapsules was evaluated here. Drug delivery devices were prepared by fused deposition modelling (FDM) from poly(epsilon caprolactone) (PCL) and Eudragit(r) RL100 (ERL) filaments with or without a channelling agent (mannitol). They were soaked in deflazacort-loaded nanocapsules (particle size: 138nm) to produce 3D printed tablets (printlets) loaded with them, as observed by SEM. Drug loading was improved by the presence of the channelling agent and a linear correlation was obtained between the soaking time and the drug loading (r2=0.9739). Moreover, drug release profiles were dependent on the polymeric material of tablets and the presence of the channelling agent. In particular, tablets prepared with a partially hollow core (50% infill) had a higher drug loading (0.27% w/w) and faster drug release rate. This study represents an original approach to convert nanocapsules suspensions into solid dosage forms as well as an efficient 3D printing method to produce novel drug delivery systems, as personalised nanomedicines. PMID- 28583329 TI - RTD modeling of a continuous dry granulation process for process control and materials diversion. AB - Disturbance propagation during continuous manufacturing processes can be predicted by evaluating the residence time distribution (RTD) of the specific unit operations. In this work, a dry granulation process was modelled and four scenarios of feeding events were simulated. We performed characterization of the feeders and developed RTD models for the blender and the roller compactor based on impulse-response measurements via color tracers. Out-of-specification material was defined based on the active pharmaceutical ingredient (API) concentration. We calculated the amount of waste material at various diversion points, considering four feeder-related process-upset scenarios and formulated considerations for the development of a control concept. The developed RTD models allow material tracking of materials that may be used for following the spread contaminants within the process and for batch definition. The results show that RTD modeling is a valuable tool for process development and design, as well as for process monitoring and material tracking. PMID- 28583330 TI - Liposomal andrographolide dry powder inhalers for treatment of bacterial pneumonia via anti-inflammatory pathway. AB - Andrographolide (AG) is a chemical entity from traditional Chinese herbs and its oral pills have been applied to the treatment of respiratory inflammation. Here we report pulmonary delivery of liposomal AG dry powder inhalers (LADPIs) for treatment of Staphylococcus aureus-induced pneumonia. AG liposomes were prepared with the injection method and then freeze-dried for preparation of LADPIs. AG liposomes were small and stable with a mean size of 77.91nm and a zeta potential of -56.13mV. Liposomes were well recovered after re-hydration of LADPIs that were suitable for pulmonary delivery with a mass mean aerodynamic diameter (MMAD) of 4.87MUm and a fine particle fraction (FPF) of 23.03%. However, the MMAD and FPF of AG powders were 10.14MUm and 8.37%, respectively. The in vitro anti-S. aureus effects of AG powders and LADPIs were investigated, but were not found. They were intratracheally sprayed into the rat lungs for treatment of S. aureus pneumonia. Surprisingly, LADPIs showed a stronger anti-S. aureus pneumonic effect in vivo, than AG at a ten-fold dose or than an antibiotic, penicillin. LADPIs significantly decreased many pro-inflammatory cytokines including TNF-alpha, IL 1. Furthermore, the phosphorylation of IkappaB-alpha in the nuclear factor-kappaB (NF-kappaB) pathway was also remarkably inhibited. AG regulated the immune reaction to maintain the antibacterial effect while downregulating inflammatory response so that AG showed a strong effect on bacterial pneumonia. LADPIs are a promising pulmonary delivery medicine for the treatment of bacterial pneumonia. PMID- 28583332 TI - Determination of the release mechanism of Theophylline from pellets coated with Surelease(r)-A water dispersion of ethyl cellulose. AB - The aim of this study was to investigate the water transport over free standing films based on the aqueous ethyl cellulose (EC) coating Surelease(r) and the drug (Theophylline) release mechanism from coated pellets. It was found that the main drug release rate from pellets was controlled by a diffusion mechanism. However, the drug release rate was altered by addition of sodium chloride to the external release medium. A decrease in the drug release rate when sodium chloride is added to the release medium has traditionally been used to indicate an osmotic drug release mechanism. However, our findings that the release rate decreased by sodium chloride addition could be explained by sodium chloride diffusing through the coating layer into the inner parts of the pellets, decreasing the solubility of Theophylline. This gave a reduced drug concentration gradient over the coating layer and thus a slower release rate. Furthermore, this study shows, as expected, that the transport of water through Surelease(r) films into the pellets was faster than the transport out of Theophylline (approx. seven times), which was the reason why the pellets were swelling during the release. It was also shown that the drug release rate, determined for both whole dose release and for single pellets, decreased with increasing thickness (from 16 to 51MUm) of the coating layer controlling the drug release rate. PMID- 28583331 TI - A novel immunoliposome mediated by CD123 antibody targeting to acute myeloid leukemia cells. AB - The application of the tumor targeting antibody-mediated immunoliposomes (ILP) provides us a potential effective strategy for treating malignancies, such as acute myeloid leukemia (AML). CD123, which is specifically overexpressed on AML cells, plays an important role in cell cycling and enhances the cell resistance to the apoptotic stimuli. Given such a unique role of CD123 in AML cells, we aim to develop a novel drug targeting delivery system using CD123 monoclonal antibody (mAb) in this study. On the basis of the daunorubicin (DNR) loaded PEGylated liposomes (DNR-LP), a post-insertion method was applied to covalently attach the anti-CD123 mAb onto the surface of the liposomes to obtain the anti-CD123 mAb modified immunoliposomes (CD123-ILP). Immunoliposomes with different anti-CD123 mAb density (mAb/liposomal S100PC, molar ratio, 0.06%, L-CD123-ILP and 0.14%, H CD123-ILP) were prepared, respectively. The expressions of CD123 in KG-1a, Kasumi 1, HL-60, NB4 and THP-1 cells were determined by flow cytometry. The cell binding and uptake assays revealed that CD123-ILP was internalized into the CD123+ AML cells, while the MTT assay indicated that CD123-ILP had stronger inhibitory effect on the growth of THP-1 and KG-1a cells, in which CD123 were highly expressed. Furthermore, in vitro drug release studies of DNR-LP and CD123-ILP showed a sustained release profile for both systems, which were further confirmed by in vivo pharmacokinetics study of liposomal DNR in rats. In this study, we reported the development of CD123-ILP for the first time by our best knowledge, which offered a promising drug targeting delivery system against CD123+ AML cells. PMID- 28583333 TI - Dry powder formulation of kanamycin with enhanced aerosolization efficiency for drug-resistant tuberculosis. AB - BACKGROUND: Kanamycin, an injectable agent, is currently used to treat drug resistant tuberculosis (TB). Parenteral kanamycin causes high systemic toxicity which could be avoided by direct delivery to the lungs. This study focused on producing a highly aerosolizable dry-powder of hygroscopic kanamycin by spray drying with l-leucine. METHODS: Kanamycin powders were prepared with different concentrations (0, 5, 10, 15 and 20% w/w) of l-leucine using the Buchi B-290 Mini Spray-Dryer. In vitro aerosolization efficiency, particle size, morphology, crystallinity, surface composition, drug-excipient interaction and moisture content of the powders were characterized by a Next Generation Impactor (NGI), laser diffraction, scanning electron microscopy, X-ray diffractometry, XPS, ATR FTIR and thermogravimetric analysis. The physicochemical and aerosolization stability of the powders were investigated after one-month storage at 25+/-2 degrees C/15% RH and 25+/-2 degrees C/75% RH. The cytotoxicity on Calu-3 and A549 cells of the kanamycin powders was evaluated by MTT assay. RESULTS: The spray dried powder particles were in the inhalable size range (<6.1MUm). The powders with l-leucine were wrinkled in shape, amorphous in nature and had low moisture content (<5.0%). Kanamycin with 5% (w/w) of l-leucine showed the best aerosolization efficiency of 73.0+/-2.5%. The powders remained stable during storage at 25+/-2 degrees C/15% RH and tolerated by respiratory cell lines. CONCLUSION: l-leucine improved the aerosolization of kanamycin by surface modification, which may be helpful for the effective treatment of drug-resistant tuberculosis. PMID- 28583334 TI - Multivariate statistical process control of a continuous pharmaceutical twin screw granulation and fluid bed drying process. AB - A multivariate statistical process control (MSPC) strategy was developed for the monitoring of the ConsiGmaTM-25 continuous tablet manufacturing line. Thirty-five logged variables encompassing three major units, being a twin screw high shear granulator, a fluid bed dryer and a product control unit, were used to monitor the process. The MSPC strategy was based on principal component analysis of data acquired under normal operating conditions using a series of four process runs. Runs with imposed disturbances in the dryer air flow and temperature, in the granulator barrel temperature, speed and liquid mass flow and in the powder dosing unit mass flow were utilized to evaluate the model's monitoring performance. The impact of the imposed deviations to the process continuity was also evaluated using Hotelling's T2 and Q residuals statistics control charts. The influence of the individual process variables was assessed by analyzing contribution plots at specific time points. Results show that the imposed disturbances were all detected in both control charts. Overall, the MSPC strategy was successfully developed and applied. Additionally, deviations not associated with the imposed changes were detected, mainly in the granulator barrel temperature control. PMID- 28583335 TI - Improved respirable fraction of budesonide powder for dry powder inhaler formulations produced by advanced supercritical CO2 processing and use of a novel additive. AB - A budesonide (BDS) suspension was obtained via advanced supercritical carbon dioxide (scCO2) processing. Thereafter, the suspension was freeze-dried (FD) to produce BDS particles for dry powder inhaler formulations (scCO2/FD processing). The scCO2/FD processed BDS powder showed low crystallinity by powder X-ray diffraction and a rough surface by scanning electron microscopy. The respirable fraction of BDS was assessed using a twin impinger and revealed that the amount of the scCO2/FD processed sample that reached stage 2 was 4-fold higher than that of the supplied powder. To extend the utility of scCO2 processing, BDS particles for dry powder inhalers were fabricated by combining the scCO2 system with various additives. When BDS was processed via scCO2/FD in the presence of the novel additive, namely, monoglyceride stearate (MGS), the residual BDS/MGS particles remaining in the capsule and devices decreased, followed by an increase in the respirable fraction of BDS 6-fold higher than with the supplied powder. The scCO2/FD processed BDS/MGS particles had a smooth surface, in contrast to the scCO2/FD processed BDS particles. A combination of BDS and an appropriate additive in scCO2 treatment may induce changes in particle surface morphology, leading to an improvement in the inhalation properties of BDS. PMID- 28583336 TI - Assessing Competence in Surgical Training and Becoming a Better Educator. PMID- 28583337 TI - Pelvic Floor Physical Therapy for Erectile Dysfunction-Fact or Fallacy? PMID- 28583338 TI - Distal Corporal Anchoring Stitch: A Technique to Address Distal Corporal Crossovers and Impending Lateral Extrusions of a Penile Prosthesis. AB - BACKGROUND: Unidentified distal crossovers, delayed distal crossovers, and impending lateral extrusion are complications of penile prosthesis implant insertion but are not as common as prosthesis infection or mechanical failure. AIM: To evaluate results of a surgical technique, the distal corporal anchoring stitch, that addresses fixation of the penile prosthesis in patients with these complications. METHODS: A lateral sub-coronal incision is used on the side where the crossover or laterally extruding cylinder should be positioned. Dissection is carried through the Buck fascia, followed by a transverse incision of the tunica albuginea, where the distal aspect of the affected cylinder is delivered. A 4-0 PDS suture is threaded through the distal cylinder ring of the implant. A new, properly positioned intracorporal channel is created and the suture is passed through the distal end of the channel. Once the suture is through the glans and the cylinder is in the correct position, a small cruciate incision is made on the glans at the location of the anchor stitch. The suture is tied with the knot buried in the glans tissue. OUTCOMES: Fifty-three patients underwent treatment of their distal penile implant crossover with a distal corporoplasty using this method and their anatomic and functional outcomes and overall satisfaction were evaluated. RESULTS: This technique ensured that the cylinder remained in the newly created, appropriately positioned channel. No patients developed infections, wound-healing defect, glandular hypoesthesia, anesthesia, or altered sensation or pain in the glans related to the suture and only two reported recurrence of a lateral herniation that did not require further treatment. CLINICAL IMPLICATIONS: Distal fixation of the penile prosthesis is a useful surgical adjunct to treating patients with prosthetic lateral extrusions or crossovers that can be applied in almost all cases. STRENGTHS AND LIMITATIONS: Considering these rare complications, our experience is based on a relatively large number of patients and showed a low incidence of complications and a high satisfaction rate. The main limitation of this study is the retrospective nature of the data and the series included patients from two high-volume surgeons that might not be generalizable to all practices. CONCLUSION: The distal corporal anchoring stitch is safe and effective in securing distal fixation of the extruding inflatable penile prosthesis. Antonini G, Busetto GM, Del Giudice F, et al. Distal Corporal Anchoring Stitch: A Technique to Address Distal Corporal Crossovers and Impending Lateral Extrusions of a Penile Prosthesis. J Sex Med 2017;14:767-773. PMID- 28583339 TI - Off-Label Use of Phosphodiesterase Type 5 Inhibitor Erectile Dysfunction Medication to Enhance Sex Among Gay and Bisexual Men in Australia: Results From the FLUX Study. AB - BACKGROUND: Gay and bisexual men (GBM) use oral erectile dysfunction medications (EDMs) often with little evidence of medical indication necessitating their use. AIM: To investigate the prevalence, contexts, and motivations for oral EDM use and its relation to sexual risk behavior. METHODS: A total of 2,250 Australian GBM completed an online survey of licit and illicit drug use and their associated behaviors. Multivariate logistic regression analysis identified factors associated with use of EDMs in the previous 6 months and, for those who had used EDMs, factors associated with use on a weekly basis. OUTCOMES: Any EDM use and at least weekly use in the previous 6 months. RESULTS: The median age of the sample was 33.0 years (range = 16-81). Two thirds (67.7%) reported no lifetime history of EDM use. Approximately 1 in 10 participants (11.1%) had last used an EDM more than 6 months previously. In the previous 6 months, 11.5% reported using EDMs less than monthly, 5.3% reported using EDMs approximately monthly, and 4.5% reported using EDMs at least weekly. Of men who had used EDMs in the previous 6 months, common reasons cited for its use were to maintain an erection for longer (73.3%), to make it easier to "get hard" (67.3%), and difficulty in attaining or maintain an erection (53.5%). Use of EDMs in the previous 6 months was associated with illicit drug use and higher rates of sexual risk behavior. Weekly users were more likely to have severe anxiety than less frequent users. CLINICAL TRANSLATION: The use of EDMs in the context of intensive sex partying, with the associated potential for increased risk of HIV transmission and illicit drug use, indicates a need to consider the use of EDMs among GBM in HIV prevention and minimizing harm. STRENGTHS AND LIMITATIONS: This large-scale study of drug use among GBMs includes comprehensive detailed data on their history of use and rationales for use. Our online methodology potentially decreases social desirability bias in reporting illegal or stigmatized behaviors. This volunteer online convenience sample might not be representative of all GBMs in Australia. CONCLUSION: GBMs who used an oral EDM in the previous 6 months often used it for recreational purposes, but many of those who used it on a weekly basis also might have used it for therapeutic reasons. GBMs often use EDMs to enhance their sexual experiences often in the context of intensive sex partying (which can include risky sexual behavior). Hammoud MA, Jin F, Lea T, et al. Off-Label Use of Phosphodiesterase Type 5 Inhibitor Erectile Dysfunction Medication to Enhance Sex Among Gay and Bisexual Men in Australia: Results From the FLUX Study. J Sex Med 2017;14:774-784. PMID- 28583340 TI - Perceived Sexual Difficulties and Sexual Counseling in Men and Women Across Heart Diagnoses: A Nationwide Cross-Sectional Study. AB - BACKGROUND: Ischemic heart disease and heart failure often lead to sexual difficulties in men, but little is known about the sexual difficulties in women and patients with other heart diagnoses or the level of information patients receive about the risk of sexual difficulties. AIM: To investigate perceived sexual difficulties and associated factors in a mixed population of men and women newly diagnosed with heart disease and provide insight into sexual counseling and information given by health care professionals. METHODS: This article reports on a cross-sectional, questionnaire study sent to a randomly selected sample of men and women newly diagnosed with heart failure, ischemic heart disease, atrial fibrillation, or heart valve surgery. Eligible patients were identified by diagnosis using the Danish National Patient Register, which contains all diagnoses. OUTCOMES: Sexual difficulties were self-reported using single-item questions, and factors associated with sexual difficulties were collected from the survey and national registers. RESULTS: The study population consisted of 1,549 men and 807 women (35-98 years old) with heart failure (n = 243), ischemic heart disease (n = 1,036), heart valve surgery (n = 375), and atrial fibrillation (n = 702). Sexual difficulties were reported by 55% of men and 29% of women. In a multiple regression analysis, difficulties in men were associated with being older (>=75 years old; odds ratio [OR] = 1.97, 95% CI = 1.13-3.43), having heart failure (OR = 2.07, 95% CI = 1.16-3.71), diabetes (OR = 1.80, 95% CI = 1.15 2.82), hypertension (OR = 1.43, 95% CI = 1.06-1.93), receiving beta-blockers (OR = 1.37, 95% CI = 1.02-1.86), or having anxiety (OR = 2.25, 95% CI = 1.34-3.80) or depression (OR = 2.74, 95% CI = 1.38-5.43). In women, difficulties were significantly associated with anxiety (OR = 3.00, 95% CI = 1.51-5.95). A total of 48.6% of men and 58.8% of women did not feel informed about sexuality, and 18.1% of men and 10.3% of women were offered sexual counseling. CLINICAL IMPLICATIONS: Heart disease increases the risk of sexual difficulties and there is a need for improved information and counseling about sex and relationships for patients. STRENGTHS AND LIMITATIONS: This large nationwide survey of men and women combined a survey with administrative data from national registries. However, this study used non-validated single-item questions to assess sexual difficulties without addressing sexual distress. CONCLUSION: More than half the men and one fourth the women across common heart diagnoses had sexual difficulties. No difference was found among diagnoses, except heart failure in men. Despite guidelines recommending sexual counseling, sexual difficulties were not met by sufficient information and counseling. Rundblad L, Zwisler AD, Johansen PP, et al. Perceived Sexual Difficulties and Sexual Counseling in Men and Women Across Heart Diagnoses: A Nationwide Cross-Sectional Study. J Sex Med 2017;14:785-796. PMID- 28583341 TI - Exploring the Optimal Erectile Function Domain Score Cutoff That Defines Sexual Satisfaction After Radical Prostatectomy. AB - INTRODUCTION: The International Index of Erectile Function (IIEF) is the gold standard validated instrument for defining erectile function (EF) and its response to treatment. The EF domain (EFD) contains six questions and is a sensitive and specific measurement of treatment-related changes in EF. The EFD score has been widely used as a primary assessment end point for clinical trials of EF recovery after radical prostatectomy (RP). Various EFD scores have been used to define functional erections. Recently, an EFD score of at least 22 has been used as a threshold in major post-RP penile rehabilitation studies. AIM: To define the EFD score that optimally defines "functional" erections after RP. METHODS: We assessed men 24 months after RP using the IIEF and specifically analyzed the scores of the EFD and intercourse satisfaction domain (ISD). MAIN OUTCOME MEASURES: We used two questions on satisfaction (score = 0-5) and enjoyment (score = 0-5) from the ISD to classify IS (score = 0-10). We tested the following intercourse satisfaction classifications: ISD score equal to 10, ISD score of at least 8, and a score of at least 4 for the ISD questions on satisfaction and enjoyment. We used the classification that produced the largest area under the curve (AUC) using a receiver operating characteristic (ROC) curve. Then, we used a three-step process to determine the optimal EFD score cutoff using sensitivity and specificity analysis. RESULTS: One hundred seventy-eight men had an average age at RP of 58 +/- 7 years and a 24-month EFD score of 20 +/- 9. Sixty-four percent had complete nerve-sparing surgery, 35% had partial nerve sparing surgery, and 1% had the nerves fully resected. Thirty-three percent had laparoscopic RP and 67% had open RP. The ROC curves produced AUCs of 0.80 (ISD score = 10), 0.85 (ISD score >= 8), and 0.86 (ISD scores for satisfaction and enjoyment >= 4; P < .001 for all comparisons). Using the IS criterion of ISD scores for satisfaction and enjoyment of at least 4 (largest AUC), the sensitivity and specificity values were 0.89 and 0.66 for an ESD score equal to 22, 0.78 and 0.71 for a score equal to 23, 0.78 and 0.80 for a score equal to 24, 0.77 and 0.82 for a score equal to 25, and 0.73 and 0.85 for a score equal to 26. The scores of 24 and 25 met the criteria outlined in the first two steps of analysis. The score of 24 was selected as the cutoff using face valid judgment and the previous literature. CONCLUSION: These data support an EFD score of 24 as a valid cutoff defining "functional" erection in men with erectile dysfunction after RP. These data are important for clinicians in counseling patients and to researchers to define inclusion criteria and treatment end points for trials of erectile dysfunction after RP. Terrier JE, Muhall JP, Nelson CJ. Exploring the Optimal Erectile Function Domain Score Cutoff That Defines Sexual Satisfaction After Radical Prostatectomy. J Sex Med 2017;14:804-809. PMID- 28583343 TI - Relational Intimacy Mediates Sexual Outcomes Associated With Impaired Sexual Function: Examination in a Clinical Sample. AB - BACKGROUND: Relational intimacy is hypothesized to underlie the association between female sexual functioning and various sexual outcomes, and married women and women with sexual dysfunction have been generally absent from prior studies investigating these associations, thus restricting generalizability. AIM: To investigate whether relational intimacy mediates sexual outcomes (sexual satisfaction, coital frequency, and sexual distress) in a sample of married women with and without impaired sexual functioning presenting in clinical settings. METHODS: Using a cross-sectional design, 64 heterosexual married women with (n = 44) and without (n = 20) impaired sexual functioning completed a battery of validated measurements assessing relational intimacy, sexual dysfunction, sexual frequency, satisfaction, and distress. Intimacy measurements were combined using latent factor scores before analysis. Bias-corrected mediation models of the indirect effect were used to test mediation effects. Moderated mediation models examined whether indirect effects were influenced by age and marital duration. OUTCOMES: Patients completed the Female Sexual Function Index, the Couple's Satisfaction Index, the Sexual Satisfaction Scale for Women, the Inclusion of the Other in the Self Scale, and the Miller Social Intimacy Test. RESULTS: Mediation models showed that impaired sexual functioning is associated with all sexual outcomes directly and indirectly through relational intimacy. Results were predominantly independent of age and marital duration. CLINICAL IMPLICATIONS: Findings have important treatment implications for modifying interventions to focus on enhancing relational intimacy to improve the sexual functioning of women with impaired sexual functioning. STRENGTHS AND LIMITATIONS: The importance of the role relational intimacy plays in broad sexual outcomes of women with impaired sexual functioning is supported in clinically referred and married women. Latent factor scores to improve estimation of study constructs and the use of contemporary mediation analysis also are strengths. The cross-sectional design precludes any causal conclusions and it is unknown whether the results generalize to male partners, partners within other relationship structures, and non heterosexual couples. CONCLUSION: Greater relational intimacy mitigates the adverse impact of impaired sexual functioning on sexual behavior and satisfaction in women. Witherow MP, Chandraiah S, Seals SR, et al. Relational Intimacy Mediates Sexual Outcomes Associated With Impaired Sexual Function: Examination in a Clinical Sample. J Sex Med 2017;14:843-851. PMID- 28583342 TI - Flibanserin in Postmenopausal Women With Hypoactive Sexual Desire Disorder: Results of the PLUMERIA Study. AB - BACKGROUND: Hypoactive sexual desire disorder (HSDD) is a common sexual disorder in younger and older women. Flibanserin is approved for the treatment of acquired generalized HSDD in premenopausal women only. The efficacy of flibanserin for postmenopausal women with HSDD was demonstrated in the first of two North American randomized, double-blinded, placebo-controlled trials (SNOWDROP). AIM: To evaluate the safety and efficacy of flibanserin in postmenopausal women with HSDD in a second randomized, double-blinded, placebo-controlled trial (PLUMERIA). METHODS: Naturally postmenopausal women were randomly assigned to receive flibanserin (100 mg/d) or placebo. Efficacy outcomes were assessed using the last observation-carried-forward imputation method. OUTCOMES: Safety assessment included incidence of adverse events. Primary efficacy outcomes were the number of satisfying sexual events and the Female Sexual Function Index desire domain (FSFI-d) score. RESULTS: The study population (flibanserin, n = 376; placebo, n = 369) included primarily white women (84.7%), with a mean age of 56.1 years and a mean HSDD duration of 5.0 years. When the study was discontinued early by the sponsor, 45.3% of randomly assigned patients had completed week 16 (which served as the primary analysis time point). The most common adverse events in flibanserin-treated patients were insomnia (7.7%), somnolence (6.9%), and dizziness (6.4%). Improvement from baseline to week 16 (last-observation-carried forward) in FSFI-d score was significantly greater for flibanserin compared with placebo (P = .011); however, the between-group comparison for satisfying sexual events did not reach statistical significance. CLINICAL IMPLICATIONS: Considered with the findings of the previous randomized controlled trial (SNOWDROP), the results of this study support the safety and efficacy of flibanserin in postmenopausal women. STRENGTHS AND LIMITATIONS: This was a well-designed randomized, placebo-controlled trial. A key limitation was early discontinuation by the study sponsor, which decreased the sample size. In addition, the validity of satisfying sexual events as a primary outcome measurement in HSDD studies has been called into question (but was required by the US Food and Drug Administration as a primary end point in studies of female sexual dysfunction at the time this study was conducted). CONCLUSION: Flibanserin was generally well tolerated in this population of naturally postmenopausal women. Despite the greatly decreased power to detect improvement compared with placebo on the efficacy measurements used, results suggest that flibanserin could be efficacious in postmenopausal women with HSDD. Portman DJ, Brown L, Yuan J, et al. Flibanserin in Postmenopausal Women With Hypoactive Sexual Desire Disorder: Results of the PLUMERIA Study. J Sex Med 2017;14:834-842. PMID- 28583344 TI - Re: Botox for Erectile Dysfunction.